PMID- 17687732 TI - Effects of contrast baths on skin blood flow on the dorsal and plantar foot in people with type 2 diabetes and age-matched controls. AB - Contrast baths have been used for therapy for over 2,000 years. The basic concept is to alternate warm and cool water baths during a treatment session. It is believed that this will increase circulation better than just placing the limb in a warm water bath. However, there is little supportive evidence for this assertion. Further, for subjects with diabetes, with underlying impairments in their circulation, this may not work at all. Fourteen people with type 2 diabetes were compared to 14 age-matched controls. Skin blood flow of the foot (BF) was measured during 16 minutes of contrast baths at two different intervals: 3 minutes warm and 1 minute cold and 6 minutes warm and 2 minutes cold. In control subjects, warm and cold contrast baths with the ratio 3 minutes warm to 1 minute cold elicited significantly (p < 0.01) greater BF than placing the limb continuously in warm water or using a 6:2 ratio of warm to cold bath time. In control subjects, there was also a greater plantar than dorsal BF. For subjects with diabetes, there was no statistical difference between BF with contrast baths versus warm whirlpool; but in both cases BF was significantly less than that seen in control subjects under similar circumstances. There was also very little difference between BF on the plantar and dorsal aspects of the foot in the subjects with diabetes. Patients with diabetes do not show a vascular response to contrast bath therapy. The BF response to contrast temperatures may be a good diagnostic test for diabetic vascular impairment. PMID- 17687733 TI - Experiences of moving with persistent pain--a qualitative study from a patient perspective. AB - OBJECTIVE: The aim of the present study was to use a phenomenological approach to explore how patients with persistent musculoskeletal pain experienced moving with their pain. DESIGN: In-depth interviews were performed by a physical therapy researcher with many years' experience with the rehabilitation of patients with persistent musculoskeletal pain. SETTING: The patients took part in individual rehabilitation at two different physical therapy departments. All but one patient opted to be interviewed in a room at the physical therapy department. METHOD: The sample was purposive and consisted of 10 Swedish outpatients with heterogeneous nonmalignant persistent musculoskeletal pain. SUBJECTS: The interviews were analyzed according to a qualitative method known as the Empirical Phenomenological Psychological (EPP) method. The results were coded, analyzed, and described in typologies. RESULTS: The experience of moving with pain implied much more than pure physical movement. Pain was a threatening challenge to the informants' existence and identity. Three typologies were identified: failed adaptation, identity restoration, and finding the way out. CONCLUSIONS: In conclusion, to move with persistent pain was described by the informants as having deep existential impact on the individual's life. It was also evident that all of the informants experienced a dramatic change in their identity. These experiences would most likely affect the patients' chances of recovery. To help him/her through the rehabilitation process, we need to extend our knowledge about what it means to the patient in an existential context to be unable to move as before. PMID- 17687734 TI - A preliminary study into the effect of low-intensity pulsed ultrasound on chronic maxillary and frontal sinusitis. AB - Sinusitis is a very common acute or chronic illness that affects a significant percentage of individuals. Recently, therapeutic ultrasound was reported as a treatment for chronic sinusitis. The purpose of this study was twofold: 1) to evaluate the effectiveness of low-intensity pulsed ultrasound (US) in chronic sinusitis using a pretest-posttest research design and 2) to determine the level of association between the independent variables of initial presence of symptoms, age, gender, and duration of disease and the dependent variable of improvement of symptoms. Patients with chronic sinusitis were treated with low-intensity pulsed US, 3 days per week for 15 sessions. Fifty-seven patients (18 females and 39 males; mean age, 35 years) were included in the study. The results of the McNemar test showed a significant change in proportions of post nasal drip and nasal obstruction, two common leading symptoms of patients with chronic sinusitis (p < 0.001). Most of the major and minor symptoms showed significant changes after US therapy (p < 0.05). The total improvement of symptoms was 81.3%. The greatest improvement in symptoms was observed in nasal discharge (100%), followed by facial pain (95.4%) and postnasal drip (82.7%), three major factors in sinusitis. There was a significant, low association between the initial presence of symptoms and the improvement of symptoms after US therapy (chi(2) = 30.352; df = 12; p = 0.002; phi value = 0.356). A significant, low association was also noted between the age and the improvement of symptoms after intervention (chi(2) = 17.548; df = 6; p = 0.007; phi value = 0.270). It may be concluded that low-intensity pulsed US has a significant effect on chronic sinusitis and improves patient symptoms in our study group. PMID- 17687735 TI - Motor and functional outcomes of a patient post-stroke following combined activity and impairment level training. AB - The purpose of this single-subject report was to determine the effect of a targeted training regimen aimed at improving motor and functional outcomes for a patient with chronic deficits after stroke. A 51-year-old woman with hemiparesis, 6 months post-stroke, participated in this prospective study. During the baseline, intervention, and immediate retention phases, performance was established by using repeated measures of four dependent variables: Fugl-Meyer assessment, Berg Balance Scale, 10-meter walk, and 6-minute walk. Two standard deviation band analyses were conducted on the four dependent variables with repeated measures. The Frenchay Activities Index and step length/single-limb support time measured at baseline and immediate retention were compared. During intervention, the participant was involved in a combined treatment protocol including body weight supported (BWS) treadmill training and strengthening exercises. Results indicated significant improvements in motor activity, balance, gait speed, and endurance. Progression was found in self-perceived participation. Although an improvement in step length symmetry occurred following training, a decrease in single-limb support time symmetry was found. BWS treadmill training, combined with strength training, significantly improved motor and functional performance in this participant with chronic deficits after stroke. PMID- 17687736 TI - Differential diagnosis of atypical focal peripheral neuropathy: case report. AB - Carpal tunnel syndrome (CTS) is the most frequent form of focal peripheral neuropathy but is commonly misdiagnosed. The aim of this case report was to describe the differential diagnosis of CTS and atypical focal peripheral neuropathy in a 34-year-old female. Although the patient's medical diagnosis was CTS, she did not report night pain, did not exhibit hand atrophy, had no sensory loss, did not meet the five criteria of the clinical prediction rule for CTS, and demonstrated symptoms associated with radial and median nerve pain. The patient's concordant symptoms were associated with wrist passive accessory stiffness and functional activities that required repetitive end range movements. Interventions included treatment of two priority impairments: 1) pain and 2) wrist accessory stiffness. After five treatments, the patient no longer reported pain with activities and was able to return to work with no restrictions. Although the patient in this case report exhibited isolated features consistent with CTS, compelling cumulative evidence suggested a distinct diagnosis. Limited evidence exists to support the use of mobilization, strengthening, and pain reduction based modalities for the treatment of focal peripheral neuropathy; subsequently, treatments must be individually effective when targeted toward the patient's priority impairments. The diagnosis of CTS is challenging because there are a variety of possible clinical presentations. Using evidence-based indices, such as the clinical prediction rule for CTS and other comparative history and physical measures, should improve the likelihood of accurate diagnosis and treatment. PMID- 17687737 TI - Moyamoya-like vascular pattern of the hepatic portal in primary sclerosing cholangitis associated with portal vein occlusion. PMID- 17687746 TI - [Protocols of the Swiss Society for Ultrasonography in Medicine in Davos Sep 9 2007]. PMID- 17687744 TI - [New developmental materials for new techniques and methods for quality control of instruments]. PMID- 17687753 TI - [Low level auditory skills compared to writing skills in school children attending third and fourth grade: evidence for the rapid auditory processing deficit theory?]. AB - BACKGROUND: The rapid auditory processing defi-cit theory holds that impaired reading/writing skills are not caused exclusively by a cognitive deficit specific to representation and processing of speech sounds but arise due to sensory, mainly auditory, deficits. To further explore this theory we compared different measures of auditory low level skills to writing skills in school children. METHODS: DESIGN: prospective study. SAMPLE: School children attending third and fourth grade. DEPENDENT VARIABLES: just noticeable differences for intensity and frequency (JNDI, JNDF), gap detection (GD) monaural and binaural temporal order judgement (TOJb and TOJm); grade in writing, language and mathematics. STATISTICS: correlation analysis. RESULTS: No relevant correlation was found between any auditory low level processing variable and writing skills. DISCUSSION: These data do not support the rapid auditory processing deficit theory. PMID- 17687754 TI - [Salmonella enteritidis infection presenting with septic shock, renal failure and cutaneous manifestations]. AB - Infections by Salmonella enteritidis commonly present with diarrhoea, vomiting and fever and complications such as septicaemia, pleural effusion and acute renal failure are usually rare. There are only few reports of cutaneous manifestations and especially septic shock in patients with Salmonella enteritidis infection. We report on a previously healthy seven-year-old boy suffering from Salmonella enteritidis septicaemia presenting with septic shock, pleural effusion, renal failure and an unusual maculopapular skin eruption on both wrists and ankles. The boy had no underlying immunodeficiency. PMID- 17687755 TI - [Acute encephalopathy in salmonella infection]. AB - While infections with salmonella typhi may frequently result in encephalopathy, this complication is rare in infections with salmonella enteritidis and has been rarely reported. We report about a 21 months old girl which developed encephalopathy with convulsion, ataxia and cortical blindness following salmonella infection. Moreover, we show a summary of ten previous case reports. PMID- 17687756 TI - [Tracheal aplasia--an especially rare and dramatic anomaly]. AB - Tracheal agenesis (TA), aplasia or total atresia of the trachea are congenital anomalies which are still incompatible with life. Despite the many attempts of different interventions, there are yet no promising, long-term methods of treatment. Only with sufficient proportion of the proximal or distal trachea available, it is possible to place a tracheostomy, which also opens up new vistas of life for the affected child. In most cases the seldom deformation, trachealagenesis, does not get recognised before the child is born. It may therefore be the immediate diagnosis postnatal that is decisive over the final prognosis of the child. The prepartal suspicion of a duodenal stenosis, an aphonic newborn as well as the frustrane attempts of intubation are possible guidelines of TA. In independence of peripartal and anamnestical factors, individual disciplinary decisions are necessary for further treatments. After the cancellation of intensive care the premature infant of the case report died as consequence of postnatal diagnosed tracheal aplasia. Under circumstances, medical treatments such as the ex utero intrapartum procedure (Exit), the temporary method of extracorporal membrane oxygenation (ECMO) or the use of cartilage tissue for the plastic trachea reconstruction can provide advanced medical opportunities. PMID- 17687757 TI - [Kelley-Seegmiller syndrome]. AB - BACKGROUND: Hypoxanthinguanin-phosphoribosyltransferase (HPRT) deficiency, an x linked inherited disease can cause two presentations: A complete deficiency (Lesch-Nyhan syndrome) accompanies with grave renal and neurological symptoms. A second form is the partial enzyme deficiency (Kelley-Seegmiller syndrome). PATIENT: We present a thirteen year old boy with relapsing hyperuricemia and hypercreatininemia. In the framework of postoperative renal insufficiency the diagnose of a Kelley-Seegmiller syndrome was elaborated. RESULT: About 25% of patients with Kelley-Seegmiller syndrome present mild neurological symptoms but never with self-destructive behavior. Pathophysiological an increased de novo purinsynthesis is present. Therefore, it comes to an overproduction of urine acid. Urolithiasis is one clinical manifestation. CONCLUSION: Relapsing urolithiasis and renal insufficiency has to be worked up. In the differential diagnosis a disorder of purine metabolism has to be discussed. PMID- 17687758 TI - Altitude, heart rate variability and aerobic capacities. AB - We analyzed the relationship between aerobic capacities and changes in heart rate variability (HRV) in Nordic-skiers during living high-training low (Hi-Lo). Eleven skiers trained for 18 days at 1200 m, sleeping at 1200 m (LL, n = 5) or in hypoxic rooms (HL, n = 6, 3 x 6 days at altitudes of 2500 - 3000 - 3500 m, 11 h . day (-1)). Measurements were performed before, during and two weeks after Hi-Lo. VO(2max), peak power output were not improved in HL nor in LL, whereas VO(2) and power at the respiratory compensation point (VO(2RCP) and PRCP) increased by 7.5 % and 5.0 % only in HL. Significant changes in HRV occurred only in LL, in the standing position, including a 30 % (p < 0.05) increase in resting heart rate (HR), a 50 % (p < 0.05) decrease in total spectral power (TP) and a 77 % (p < 0.05) decrease in high frequency activity (HF). When all the subjects were pooled, the changes in HRV in the supine position were correlated to the changes in aerobic capacities, i.e., HF, LF and TP were correlated to VO(2RCP) and HR, HF and TP were correlated to PRCP. This study confirms the relationship between HRV and changes in aerobic capacity, therefore highlighting the potential value of HRV for monitoring altitude training adaptations. PMID- 17687759 TI - AMPD1 genotypes and exercise capacity in McArdle patients. AB - The purpose of this study was to assess if there exists an association between C34T muscle adenosine monophosphate deaminase ( AMPD1) genotypes (i.e., normal homyzygotes [CC] vs. heterozygotes [ CT]) and directly measured indices of exercise capacity (peak oxygen uptake [VO(2peak)], ventilatory threshold [VT], gross mechanical efficiency [GE], etc.) in 44 Caucasian McArdle patients (23 males, 21 females). All patients performed a graded cycle ergometer test until exhaustion (for VO(2peak) and VT determination) and a 12-min constant-load test at the power output eliciting the VT (for GE determination). We found no significant difference in indices of exercise capacity between CC (n = 18) and CT genotypes (n = 5) in the group of male patients (p > 0.05). In contrast, the VO(2) at the VT was significantly lower (p < 0.05) in CT (n = 4; 7.9 +/- 0.4 ml/kg/min) than in CC female patients (n = 17; 11.0 +/- 0.9 ml/kg/min). In summary, heterozigosity for the C34T allele of the AMPD gene is associated with reduced submaximal aerobic capacity in female patients with McArdle disease and might partly account, in this gender, for the variability that exists in the phenotypic manifestation of the disease. PMID- 17687760 TI - Spectroscopic properties of the nonplanar amide group: a computational study. AB - Experimental studies suggest that amide bond may significantly deviate from planar arrangement even in linear peptides and proteins. In order to find out the extent to which such deviation may influence principal amide spectroscopic properties, we conducted a computational study of nonplanar N-methylacetamide (NMA) conformers. Vibrational absorption, Raman, and electronic spectra including optical activity were simulated with ab initio and density functional theory (DFT) methods. According to the results, small nonplanarity deviations may be detectable by nonpolarized spectroscopic techniques, albeit as subtle spectral changes. The optical activity methods, such as the vibrational circular dichroism (VCD), Raman optical activity (ROA), and electronic circular dichroism (CD, ECD), provide enhanced information about the amide nonplanarity, because planar amide is not optically active (chiral). For VCD, however, the inherently chiral contribution in most peptides and proteins most probably provides very weak signal in comparison with other contributions, such as the dipolar coupling. For the electronic CD, the nonplanarity contribution is relatively big and causes a strong CD couplet in the n-pi* absorption region accompanied by a red frequency shift. The pi-pi* CD region is relatively unaffected. The ROA spectroscopy appears most promising for the nonplanarity detection and the inherent chiral signal may dominate entire spectral parts. The amide I and III vibrational ROA bands are most challenging experimentally because of their relatively weak coupling to other peptide vibrations. PMID- 17687761 TI - Stereoselective behavior of a novel biodegradable racemic ketoprofen injectable implant in rats. AB - The stereoselectivity of release of ketoprofen (KET) enantiomers from a biodegradable injectable implant containing racemic KET (rac-KET) was investigated in vivo. A pre-column chiral derivatization RP-HPLC method was employed to assay diastereoisomeric derivatives of R- and S-KET. The rac-KET injectable implant, once injected subcutaneously in rats, produced long-lasting plasma levels of S-KET, which were always greater than those of R-KET. The difference in enantiomer concentration was to be related to stereoselective release, due to stereoselective interaction between D,L-PLG in the implant and KET enantiomers, as well as the chiral inversion of KET in vivo. The rac-KET injectable implant provided the sustained release of S-KET with effective plasma levels maintained for about 8 wk after a single injection. PMID- 17687762 TI - Circular dichroism of diglycosyl dichalcogenides in solution and solid state. AB - Solution and solid-state CD spectra of nine peracetylated and deacetalyted diglycosyl disulfides were measured to study the relationship between the low energy CD transitions (n1-->sigma*(S--S) and n2-->sigma*(S--S)) and helicity of the inherently chiral disulfide chromophore as perturbed by chiral carbohydrate moieties. The solid-state CD spectra were directly correlated with the reported X ray structures of Ac4GlcSSGlcAc4 and Ac4GlcSSGalAc4, and the CD data revealed that all the disulfides have M helicity with C1--S--S--C1' dihedral angles -90 degrees < phi < 0 degrees both in solution and in the solid state. A TDDFT CD study was carried out on dimethyl diselenide which confirmed that the same quadrant rule is relevant between the signs of the low-energy CD transitions and the diselenide torsional angle as formulated previously for the disulfide chromophore. The CD spectra of Ac4GlcSeSeGlcAc4 measured in solution and in the solid state were correlated with its X-ray structure and reproduced well by TDDFT CD calculations performed on its tetra-O-acetyl derivative. PMID- 17687763 TI - Linear free energy relationships in C-N bond dissociations in molecular ions of 4 substituted N-(2-furylmethyl)anilines in the gas phase. AB - The substituent effect on the reactivity of the C-N bond of molecular ions of 4 substituted N-(2-furylmethyl)anilines toward two dissociation pathways was studied. With this aim, six of these compounds were analyzed by mass spectrometry using electron ionization with energies between 7.8 and 69.9 eV. Also, the UB3LYP/6-31G (d,p) and UHF/6-31G (d, p) levels of theory were used to calculate the critical energies (reaction enthalpies at 0 K) of the processes that lead to the complementary ions [C(5)H(5)O](+) and [M - C(5)H(5)O](+), assuming structures that result from the heterolytic and homolytic C-N bond cleavages of the molecular ions, respectively. A kinetic approach proposed in the 1960s was applied to the mass spectral data to obtain the relative rate coefficients for both dissociation channels from ratios of the peak intensities of these ions. Linear relationships were obtained between the logarithms of the relative rate coefficients and the calculated critical energies and other thermochemical properties, whose slopes showed to be conditioned by the energy provided to the compounds within the ion source. Moreover, it was found that the dissociation that leads to [C(5)H(5)O](+) is a process strongly dependent upon the electron withdrawing or donating properties of the substituent, favored by those factors that destabilize the molecular ion. On the contrary, the dissociation that leads to [M - C(5)H(5)O](+) is indifferent to the polar electronic effects of the substituent. The abundance of both products was governed by the rule of Stevenson Audier, according to which the major ion is the one of less negative electronic affinity. PMID- 17687764 TI - Unusual silicon coordination polyhedra: non-VSEPR structures of zwitterionic lambda5-Si silicon(IV) complexes with an SiS2N2C or SiS2O2C skeleton. PMID- 17687765 TI - Vertigo. Stop the spin. PMID- 17687766 TI - Study questions cardiovascular benefits of tea with milk. PMID- 17687767 TI - Staying mentally sharp. Maintaining your brain. PMID- 17687768 TI - I was recently diagnosed with laryngospasm. When it occurs, I suddenly can't breathe or talk for about half a minute. It's very scary. My doctor tells me I won't die from it and that I should try to relax when it happens. Can anything be done to prevent it? PMID- 17687769 TI - [Hepatitis C virus RNA qualitative detection in seminal fluid and in intermediate or final part of spermatozoids]. PMID- 17687770 TI - [HIV genoma detection in various parts of sperm]. PMID- 17687771 TI - A view from Armenia: Karlen G. Adamyan, MD. Interview by Judy Ozkan. PMID- 17687772 TI - First Heart Health Charter for Europe. PMID- 17687773 TI - Bodies in motion. PMID- 17687774 TI - Current awareness in prenatal diagnosis. PMID- 17687776 TI - [Use of percutaneous diaphragmatic electrostimulation on transition of the severely burnt to spontaneous breathing]. AB - The paper deals with the study of the efficiency of using assisted ventilation (AV) and percutaneous diaphragmatic electrostimulation (PDE) when severely burnt patients are transited after sustained artificial ventilation to spontaneous breathing. A procedure for combined use of AV in the SIMV mode and PDE was perfected during the study that indicated that the incidence of pneumonias statistically significantly decreased and sputum discharge improved. PMID- 17687775 TI - [Assessment of current methods quantitating extravascular lung water and pulmonary aeration in inhomogeneous lung injury: an experimental study]. AB - BACKGROUND: Single transpulmonary thermodilution (STTD) is a widely recognized technique for the quantification of extravascular lung water (EVLW). However, the accuracy of STTD can be substantially reduced in acute lung lesion (ALL) characterized by inhomogeneous distribution of edematous zones and major ventilation-perfusion mismatch. Quantitative computed tomography (CT) may be a helpful clinical adjunct allowing an assessment of pulmonary gas and tissue content. The purpose of the study was to compare the tissue volume index, as estimated by spiral CT (TVICT), with EVLW indices determined with STTD (EVLWISTTD), thermal-dye dilution (EVLWITDD), and postmortem gravimetry (EVLWIG) before and after oleic acid-induced ALL in sheep. MATERIALS: Eleven yearling sheep were randomly assigned to either an oleic acid (OA) group receiving an infusion of OA in a dose of 0.08 ml/kg i.v. or to a control group. The day before and immediately after the experiment, sheep underwent CT examinations. Pulmonary and systemic hemodynamics, oxygenation, EVLWISTTD and EVLWITDD were recorded. Linear regression analysis was used to assess the relationships between EVLWISTTD, EVLWITDD, EVLWIG, and TVICT (syngo PulmpCT, Siemens, Germany). RESULTS: OA caused 5- and 7-fold increments in poorly and nonaerated lung volumes, respectively, and increased total lung volume and TVICT, EVLWISTTD, EVLWITDD, and TVICT demonstrated a close agreement with EVLWIG (r = 0.86, 0.90, and 0.97, respectively; p < 0.001). TVICT overestimated reference EVLWIG values to the greatest extent. CONCLUSION: In a sheep model of OA-induced ALL, pulmonary tissue volume as estimated by quantitative CT closely correlates with EVLWI measured by dilutional methods and postmortem gravimetry. PMID- 17687777 TI - [Use of capnography during endoscopic cholecystectomy under different artificial ventilation modes]. AB - A portable multigas monitoring system was used in 20 patients during labaroscopic cholecystectomy. The system was found to provide useful on-line information on ventilatory changes, which permitted the prevention of cardiopulmonary abnormalities during this type of surgery. Expiratory CO2 and CO2 production closely correlated with PaCO2. PMID- 17687778 TI - [Jet transcatheter artificial ventilation in the surgical treatment of tracheal cicatricial stenosis]. AB - The authors present the results of a study of the baseline condition, the parameters of external respiratory function, gas exchange, and hemodynamics in 42 patients with tracheal cicatricial stenosis (TCS). The impact of transcatheter normofrequency artificial ventilation (AL) on the respiratory and circulatory parameters was studied during surgical TCS removal. The baseline impairments were identified in the external respiratory system and in the hemodynamic provision of breathing processes, which corresponded to first-second grade respiratory failure disorders, despite preoperative tracheal bougienage elimination. Normofrequency and high-frequency AL is the method of choice in treating patients with concomitant respiratory diseases. PMID- 17687779 TI - [Comparative estimation of currently available approaches to early identification of severe acute pancreatitis]. AB - It is difficult to precisely predict the severity of each specific patient with acute pancreatitis (AP), by using conventional statistical methods or single clinical and laboratory criteria. By using the patient database, the authors developed an artificial neuronal network (ANN) to predict the severity of AP and compared it with the Ranson, Imrie/Glasgow, APACHE II, and Physiological Condition Severity scoring systems, ultrasound/radiological criteria, and linear regression analysis. ANN was found to be significantly better than all the scoring systems, but not better than a linear regression model (the area under the receiver operating characteristic curves were equal to 0.83). With 81% sensitivity, ANN showed a 70% specificity, and positive/negative predictive values of 73 and 79%, respectively. ANN is an effective tool in developing prediction models for poor outcomes in patients with AP that is precisely similar with linear regression models. PMID- 17687780 TI - [Nutritional support in critical conditions as intensive care technology]. AB - The patients of intensive care units represent a group in which nutritional support methods, such as enteral and parenteral feeding, are most frequently used to correct protein and energy metabolisms. The purpose of this paper is to analyze the most significant clinical problems ensuing in nutritional support in an intensive care unit, such as the high incidence of hospital exhaustion, difficulties in metabolic monitoring and in the determination of patients' needs for nutrients, in the choice for media for intravenous and enteral feeding, in the prevention of possible complications of nutritional support; organizational aspects. PMID- 17687785 TI - Many errors in story on Tokanui history. PMID- 17687787 TI - Shoulder replacement: better than it sounds. Shoulder surgery is less risky than hip or knee replacement. PMID- 17687786 TI - Creating environments for health--20 years on. PMID- 17687788 TI - Coronary artery disease: medical therapy is sometimes best. Invasive treatment is not always necessary; angioplasty may not offer any added advantage. PMID- 17687789 TI - Three early-warning Alzheimer's tests. Timelier detection can lead to longer and improved quality of life. PMID- 17687790 TI - Does your doctor really know best? Surgeon bias often influences the decision to have breast reconstruction after mastectomy. PMID- 17687791 TI - Exercise, even if you're older, is key to managing arthritis symptoms. Australian study shows that women over 70 can reduce the incidence of pain by being active. PMID- 17687792 TI - Asthma triggers & treatments. Now, excess weight and obesity are also implicated in contributing to asthma attacks. PMID- 17687793 TI - I've had atrial fibrillation without associated heart disease for 40 years. I'm unable to take Coumadin, so for many years I've taken one 325 mg aspirin daily for its anticoagulation effect. How do you compare aspirin's benefits with Coumadin's? PMID- 17687794 TI - Lifestyle therapy for prostate cancer: does it work? PMID- 17687795 TI - Preventing diabetes, Part II: an action plan. PMID- 17687796 TI - Aspirin for hypertension? PMID- 17687797 TI - On call. Your article on new immunizations for adults was very helpful. I already got my booster for tetanus, diphtheria, and whooping cough, but even though I'm 61, my doctor didn't want to give me the shingles because I've already had shingles. Should I get the vaccine? PMID- 17687798 TI - Medicare program; inpatient rehabilitation facility prospective payment system for federal fiscal year 2008. Final rule. AB - This final rule will update the prospective payment rates for inpatient rehabilitation facilities (IRFs) for Federal fiscal year (FY) 2008 (for discharges occurring on or after October 1, 2007 and on or before September 30, 2008) as required under section 1886(j)(3)(C) of the Social Security Act (the Act). Section 1886(j)(5) of the Act requires the Secretary to publish in the Federal Register on or before the August 1 that precedes the start of each fiscal year, the classification and weighting factors for the IRF prospective payment system's (PPS) case-mix groups and a description of the methodology and data used in computing the prospective payment rates for that fiscal year. We are revising existing policies regarding the PPS within the authority granted under section 1886(j) of the Act. PMID- 17687799 TI - [Reaction to "Guidelines in Dutch mental health institutions for dealing with persons attempting suicide" and "Moderate policy concerning suicide prevention"]. PMID- 17687800 TI - Medical devices: immunology and microbiology devices: classification of in vitro human immunodeficiency virus drug resistance genotype assay. Final rule. AB - The Food and Drug Administration (FDA) is classifying an in vitro human immunodeficiency virus (HIV) drug resistance genotype assay into class II (special controls). The special control that will apply to this device is the guidance document entitled "Class II Special Controls Guidance Document: In Vitro HIV Drug Resistance Genotype Assay." FDA is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of this device. Elsewhere in this issue of the Federal Register, FDA is announcing the availability of the guidance document that will serve as the special control for this device. PMID- 17687801 TI - The dynamic cell. PMID- 17687802 TI - Common hepatitis B drug linked to HIV antiviral resistance. PMID- 17687803 TI - A proposal for addressing the effects of hindsight and positive outcome biases in medical malpractice cases. PMID- 17687804 TI - Quiz page. Acute rheumatic fever with concomitant poststreptococcal glomerulonephritis. PMID- 17687805 TI - Quiz page. Minimal change glomerulonephritis associated with secondary syphilis. PMID- 17687806 TI - Quiz page. Fibromuscular dysplasia of the right renal artery. PMID- 17687807 TI - Quiz page. Collapsing FSGS. PMID- 17687808 TI - Quiz page. Horseshoe kidney with a double calyces on the left side and a stone on the right side. PMID- 17687809 TI - Quiz page. Renal AA amyloidosis with vascular predominance, secondary to rheumatoid arthritis. PMID- 17687810 TI - Surgery in developing countries: why and how to meet surgical needs worldwide. PMID- 17687811 TI - Non invasive imaging of coronary arteries with 64-slice CT and 1.5T MRI: challenging invasive techniques. AB - Non-invasive coronary artery imaging challenges any diagnostic modality, because of the complex and tortuous anatomy and cardiac contraction and respiration. Therefore, non-invasive coronary imaging requires high spatial and temporal resolution. Our purpose is to discuss the feasible applications in coronary imaging of Magnetic Resonance Imaging and Multi-slice Computed Tomography (MSCT). Focus will be devoted to potential indications and clinical impact of MSCT because of the fast development and the important results recently reported, in particular with the recent introduction of 64-slice equipments. MSCT of the coronary arteries is a promising imaging modality for the assessment of coronary lumen and wall. PMID- 17687812 TI - Comparing treatment effects in a clinical sample of patients with probable Alzheimer's disease treated with two different cholinesterase inhibitors. AB - BACKGROUND: The aim of this study was to compare the effect of treatment with different cholinesterase inhibitors (ChEIs) on mental status and every day function in a natural outpatient clinic setting, so that this evaluation could more realistically reveal the effects which are likely to be observed in patients attending ordinary dementia clinics rather than in the context of a randomised controlled drug trial. METHODS: Long term outcome of treatment with the ChEIs donepezil and rivastigmine was retrospectively evaluated in 147 patients with a clinical diagnosis of probable Alzheimer's disease of mild to moderate level of severity who had been monitored for a period of nine months. Measures included Mini Mental State Examination, Activity of Daily Living and Instrumental Activity of Daily Living scales. RESULTS: Response rate was similar to that of other published clinical trials on ChEIs. Patients who responded well to treatment with ChEIs better maintained their improved performance. CONCLUSIONS: Treatment with both ChEIs resulted in improved performance in those patients responding to therapy. Greater response was observed in previously untreated patients who had a shorter disease history but overall the findings in this unselected clinical sample confirmed that patients gain some benefit from intervention with ChEI treatment. PMID- 17687813 TI - Psychopathological predictors of compliance and outcome in weight-loss obesity treatment. AB - BACKGROUND: To detect pre-treatment psychopathological predictors of compliance and outcome in a behavioural weight-loss program for obesity. METHODS: 68 consecutive obese outpatients were evaluated on a wide range of psychopathological variables before entering a behavioural weight reduction program. Baseline assessment included detection of psychiatric (Axis I) and personality (Axis II) disorders, anxiety and depression levels, temperament and character patterns, alexithymia, and eating attitudes. These variables were then tested as predictors of compliance and weight loss after eight months of active treatment. RESULTS: Baseline presence of Axis I diagnoses was found to enhance the likelihood of good compliance to treatment but to lower probability of good outcome. Different psychopathological (and specifically personality) predictors of outcome were found among patients with and without psychiatric disorders. CONCLUSIONS: These data suggest the need to perform a full psychiatric evaluation, including personality assessment, to implement obesity treatment strategies. PMID- 17687814 TI - A study of piglets born by spontaneous parturition under uncontrolled conditions: could this be a naturalistic model for the study of intrapartum asphyxia? AB - In order to evaluate how spontaneously born piglets could be a suitable model for the study of intrapartum hypoxia, 230 newborn piglets were studied. Out them, 8.3% (n = 19) died intrapartum, 21.7% (n = 50) were born with moderate-to-severe intrapartum hypoxia, and 70% (n = 161) were born with mild or no evidence of intrapartum distress. Piglets born without any evidence of intrapartum asphyxia weighed approximately 240 g lower than those born with intrapartum hypoxia and intrapartum-dead piglets (P<0.0001). The viability score was approximately 3 units lower and the latency to contact the udder was two times longer in the piglets surviving intrapartum hypoxia than in controls (P <0.0001). In comparison with the control group, metabolic acidosis was most severe among intrapartum-dead piglets followed by piglets surviving intrapartum asphyxia (P =0.002). According to a multiple linear regression analysis, pCO2 and lactate blood levels, and birth weight were identified as explanatory variables of viability score (r: 0.78; P <0.001). Viability score, K+ and lactate blood levels, and birth weight were identified as explanatory variables of latency to contact the udder (r: 0.80; P <0.001). In conclusion, the spontaneously-born asphyxiated piglet could be considered as a naturalistic model for the study of intrapartum asphyxia. Histopathologic and more rigorous functional and behavioral evaluations are still required to further characterize the model. (www.actabiomedica.it) PMID- 17687815 TI - Reduction of the risk of cervical intraepithelial neoplasia in HIV-infected women treated with highly active antiretroviral therapy. AB - BACKGROUND AND AIM OF THE WORK: The purpose of our study was to determine whether highly active antiretroviral therapy (HAART) reduces the onset of cervical intraepithelial neoplasia (CIN) in HIV-positive women. METHODS: The study was designed to assess CIN incidence in a cohort of 101 HIV-positive women and to evaluate its relationship with ongoing antiretroviral therapy. The patients were screened through a combined Pap smear and colposcopic examination on a yearly basis. If any abnormalities were reported, the patients underwent targeted biopsy with histological confirmation of the diagnosis. RESULTS: During the follow-up period, 38 patients (37.6%) developed histologically verified CIN, including low grade CIN in seven patients (6.9%) and high-grade CIN in 31 patients (30.4%). Over the study period, 43 patients (42.6%) were treated with HAART for at least 6 months, the average duration of treatment being 37 months. Analysis of HAART efficacy in preventing CIN onset, determined by the Cox regression model with a time-dependent covariate adjusted for the CD4 level at the first visit, showed that HAART significantly reduced the risk of developing CIN (hazard ratio, 0.3; p = 0.004). CONCLUSION: HIV-positive patients present a high incidence of CIN and of high-grade CIN in particular. HAART exhibits a protective action against the onset of cervical lesions. PMID- 17687816 TI - Lung metastasectomy in patients with renal cell cancer (RCC). A 17-year experience in Parma Hospital. AB - AIM: We aim to report the results of the curative, non-palliative, treatment of resection of lung metastases that are secondary to renal cell carcinoma (RCC). METHODS: Between 1988 and 2004, a radical metastasectomy with curative purposes was performed in 20 (11 males and 9 females) patients with renal clear cell carcinoma (RCC) who had already undergone nephrectomy and subsequently metastasectomy of lung metastases. The mean age was 66,9 years (range 48-81 years). RESULTS: the intraoperative mortality of patients undergoing surgical resection of lung metastases from RCC was 0%; 17 out of 20 patients returned at follow up; 9 patients died; the mean survival-time after nephrectomy was 64+/-42 months (range 7-132 months) and the mean survival-time after metastasectomy was 31+/-29 months (range 4-99 months); 4 out of 9 pts had pulmonary recurrence after surgery. 8 patients are still alive; the mean follow up after nephrectomy was 134+/-115 months (range 30-372 months) and 72+/-44 months (range 25-150 months) after metastasectomy. 1 out of 8 pts had a pulmonary recurrence that was treated by surgery. CONCLUSIONS: the radical resection of lung metastases is a safe and effective treatment in selected RCC patients. PMID- 17687817 TI - Retroperitoneal hematoma due to spontaneous lumbar artery rupture during fondaparinux treatment. Case report and review of the literature. AB - We present the case of a 78 year-old man who developed a spontaneous rupture of the lumbar artery leading to a retroperitoneal hematoma while receiving fondaparinux therapy after a total hip replacement. A selective angiographic embolization stopped the bleeding. Fondaparinux was discontinuated and the patient presented a complete resolution of his medical status. Spontaneous hematomas has been well described during low molecular weight heparin (LMWH) treatment, expecially in elderly patients, but there are no previous reports of hematomas induced by fondaparinux. We reviewed the literature to identify the possible risk-factors of bleeding. Our review shows that even if many works suggest that fondaparinux is a safe and effective alternative to LMWH in the prevention of venous thromboembolism following major orthopaedic surgery, it should carefully be used in elderly people and patients with renal disfunction. PMID- 17687818 TI - HCV-related cryoglobulinemic glomerulonephritis: implications of antiviral and immunosuppressive therapies. AB - The most frequent renal involvement in patients with chronic hepatitis C virus (HCV) infection is cryoglobulinemic glomerulonephritis, with type I membranoproliferative glomerulonephritis (MPGN) being the predominant histological pattern. The pathogenesis of HCV-related cryoglobulinemic MPGN is unknown, but the glomerular damage may be due to the deposition of immune complexes of HCV, IgG, and IgM rheumatoid factors. Clinically, cryoglobulinemic MPGN may range from isolated proteinuria to overt nephritic or nephrotic syndrome, with variable progression to chronic renal insufficiency. The management of cryoglobulinemic MPGN is difficult; the eradication of HCV by means of antiviral therapy (peginterferon plus ribavirin) leads to clinical remission in a proportion of patients, but severe renal disease may be resistant to antiviral therapy. In such cases, corticosteroids and immunosuppressive agents have been used to decrease cryoglobulin production and improve the vasculitic manifestations, but long-lasting remission of the renal disease is uncommon. Here we describe four patients with HCV-related cryoglobulinemic MPGN and the strategies used for their management. The principal message provided by these illustrative cases is that antiviral therapy alone can be the first-line treatment for patients with mild-to-moderate kidney involvement, whereas a short term course of corticosteroids and cytotoxic agents followed by antiviral therapy may be a reasonable therapeutic strategy for patients with severe/active renal disease. PMID- 17687819 TI - 2006: the value of pelvic and femoral osteotomies in hip surgery. AB - Hip problems are frequent and can represent a therapeutic challenge for the orthopaedic surgeon. In the wide spectrum of hip pathologies, coxarthrosis still remains the most common cause of hip disability. The treatment of hip disorders in adult patients has rapidly evolved during the past decades because of the enhanced understanding of osteoarthritis (OA) aetiology combined with improved imaging, better patient selection and refinements in surgical procedures. Despite great strides that have been made in the field of total hip arthroplasty (THA), femoral and pelvic osteotomy still play a successful role in the prevention and treatment of OA. Primary OA is rare, or may not exist at all, and the majority of cases that are considered as primary are secondary to a pre-existing anatomical deformity. If an identifiable anatomic and biomechanical hip abnormality is diagnosed, its surgical correction may prevent or lessen OA and postpone THA for many years or even indefinitely in certain cases. The success of such surgery depends on the correct indication, time of surgery, completeness with which osteotomies normalize the environment of the hip, and the grade of OA present when procedure is performed. PMID- 17687820 TI - Why English is fundamental in an increasingly interconnected world. AB - In the last few years, the advances in technological progress have been amazing. Given the importance of English as the main means of communication in our increasingly interconnected world, it is a pity that schools, and to a lesser degree universities, do not put more emphasis on the acquisition of listening and speaking skills since, when it comes to speaking English, Italian students do not fare brilliantly compared to those in the rest of Europe. Of the 4 medical schools viewed in Italy, Parma gives the least importance to learning Medical English. When comparing universities in Europe, the French come out on top, putting a lot of emphasis on learning Medical English. PMID- 17687821 TI - Quality improvement programme for diabetes care in family practice settings in Dubai. AB - A continuous quality improvement programme for the care of registered diabetes patients was introduced in 16 government-affiliated primary health care centres in Dubai. Quality improvement teams were formed, clinical guidelines and information systems were developed, diabetes nurse practitioners were introduced and a team approach was mobilized. Audits before and after the introduction of the scheme showed significant improvements in rates of recording key clinical indicators and in their outcomes. For example, the proportion of patients with glycosylated haemoglobin levels < 7% increased from 20.6% to 31.7% and with LDL cholesterol < 100 mg/dL increased from 20.8% to 33.6%. Mean systolic blood pressure of registered patients fell from 135.3 mmHg to 133.2 mmHg. PMID- 17687822 TI - [Knowledge of patients with type 2 diabetes about their condition in Sousse, Tunisia]. AB - We assessed the knowledge of 404 type 2 diabetic patients about their condition in order to evaluate the quality of diabetes education in primary health care units in Sousse in 2003. We found that knowledge was satisfactory in only 59% of the patients. Their knowledge about the definition of diabetes and its pathophysiology were the 2 main areas where knowledge was lacking: the proportion of correct answers were 62.6% and 50.3% respectively. More attention should be paid to educating diabetic patients within the chronic disease care national programme. PMID- 17687823 TI - Relation between hypercholesterolaemia and vascular endothelial microinflammation. AB - We investigated the correlation between hypercholesterolaemia and oxidative stress and P-selectin and interleukin-6 (IL-6) as markers for endothelial status. We studied 40 Egyptian adults with asymptomatic hypercholesterolaemia and 20 age- and sex-matched controls. Lipid peroxidation was significantly higher (P < 0.001) in the study group and positively correlated with cholesterol (P < 0.001) and low density lipoprotein (LDL) (P < 0.002). Glutathione peroxidase activity was also significantly higher (P < 0.001) with positive correlation with cholesterol (P < 0.001) and LDL (P < 0.001). Markers for endothelial cell function were significantly higher in the study group (P < 0.001) with a positive correlation with cholesterol (P < 0.001) and LDL (P < 0.001). Hypercholesterolaemia causes endothelial microinflammation, and P-selectin and IL-6 may also be risk factors for cardiovascular disease. PMID- 17687824 TI - Diagnostic value of homocysteine, C-reactive protein and bilirubin for coronary artery disease. AB - We evaluated 3 new markers for coronary artery disease (CAD) [bilirubin, total homocysteine (t-Hcy) and high-sensitivity C-reactive protein (hs-CRP)] in 319 patients with chest pains divided into 2 groups based on coronary angiography: CAD group (n = 262) and non-CAD group (n = 57). A control group consisted of 50 healthy subjects. t-Hcy had the highest diagnostic value for diagnosis of angiographically documented patients; bilirubin had the lowest. The sensitivities and specificities (based on ROC curves) of bilirubin, hs-CRP and t-Hcy were 70.9%, 50% and 76.8% respectively, and 40.4%, 80.7% and 70.2% respectively. We conclude that serum bilirubin levels cannot identify people at risk of CAD and t Hcy and hs-CRP may be stronger markers. PMID- 17687825 TI - [Distribution of cardiovascular risk factors in coronary patients in Sahel, Tunisia]. AB - We evaluated cardiovascular risk factors and their association in patients in Sahel, hospitalized for coronary disease over the period 1994-1998. The clinical features of 3455 patients (72.4% men, 1741 with myocardial infarction, 1714 with unstable angina) were analysed on hospital admission. The prevalence of smoking, dyslipidaemia, hypertension, diabetes and obesity was 77.4%, 39.4%, 28.5%, 42.5% and 25.1% respectively in men and 2.9%, 43.7%, 59.2%, 56.6% and 31.9% respectively in women. With this risk factor profile a national strategy of primary prevention and heart health promotion is needed in Tunisia. PMID- 17687826 TI - Does the number of previous caesarean deliveries affect maternal outcome and complication rates? AB - We evaluated maternal complications in relation to number of previous caesarean sections in Princess Badea Teaching Hospital, Irbid, Jordan. Analysis of the medical records of 1739 patients delivered by caesarean section was conducted. It revealed a 14-fold increase in the risk of caesarean hysterectomy in patients with placenta praevia and previous caesarean section compared to patients with placenta praevia and no previous caesarean section. The risk of caesarean hysterectomy increased with increasing number of previous caesarean sections. Those with 3 or more previous caesarean sections were at significantly higher risk of blood transfusion. Post-operative pyrexia was commoner in women with 3 or more previous caesarean sections compared to those undergoing their first one. PMID- 17687827 TI - Preterm delivery risk factors: a prevention strategy in Shiraz, Islamic Republic of Iran. AB - From 3 February-5 March, 2000, 1117 pregnant women attending 36 health centres in Shiraz were categorized as high risk (n = 519) and low risk (n = 598) based on the presence of preterm delivery risk factors. High-risk women received training on strategies to reduce the risk of premature delivery. The frequencies of preterm delivery in the low- and the high-risk groups were 3.0% and 14.6% respectively (P < 0.001). The significant factors for preterm delivery were cervical dilation > 1 cm, premature uterine contractions, multifetal gestation and smoking. Premature delivery was significantly lower in the high-risk group compared with a similar group in a previous study who had not received training. PMID- 17687828 TI - Epidemiology of neural tube defects in northern Iran, 1998-2003. AB - We determined the rates of neural tube defects at a referral hospital in Gorgan, north Islamic Republic of Iran, and the relations of these abnormalities to sex, maternal ethnicity, maternal age and season. During 1998-2003, there were 109 cases among 37 951 births, a prevalence of 28.7 per 10000 (24.8 and 32.8 per 10 000 among males and females respectively). The rates in Turkmen, native Fars and Sistani ethnic groups were 40.5, 25.2 and 30.8 per 10 000 respectively. The rates of spina bifida and anencephaly were 16.3 and 11.3 per 10 000 respectively. The rate of affected newborns was highest in mothers aged over 35 years (50.7 per 10 000). The peak prevalence was in December. PMID- 17687829 TI - Parental consanguinity among parents of neonates with congenital hypothyroidism in Isfahan. AB - We determined the prevalence of congenital hypothyroidism and the rate of consanguin-ity among parents of hypothyroid neonates among 93 381 neonates born in 17 hospitals in Isfahan from May 2002 to April 2005. Serum thyroxine (T4) and thyroid stimulating hormone (TSH) levels were measured on the 3rd-7th day of birth and neonates with abnormal levels were recalled and the levels reassessed. Those with TSH > or = 10 mlU/L and T4 < 6.5 microg/dL on the second assay were considered hypothyroid. In all, 1038 neonates were recalled and 274 were diagnosed as hypothyroid. There was a significant association between parental consanguinity and congenital hypothyroidism (P = 0.006); congenital hypothyroidism was commoner in neonates with 1st cousin parental consanguinity than 2nd cousin parental consanguinity (P = 0.008). PMID- 17687830 TI - Prevalence of refractive error and low vision among schoolchildren in Cairo. AB - A preliminary survey was conducted to detect the prevalence of refractive error (RE) and low vision among 5839 schoolchildren aged 7-14 years in Cairo, Egypt. Screening was done using Landolt broken ring chart and pinhole test. The prevalence of RE (visual acuity < or = 6/12) among the schoolchildren was 22.1% and low vision (visual acuity < or = 6/18) was 12.5%. The prevalence of low vision was greatest among the preparatory schoolchildren aged 12+ years. RE was higher among the female students than males (21.4% and 13.6% respectively). Development of a national survey for detection of visual problems for both preschool and school-aged children is recommended. PMID- 17687831 TI - Prevalence and causes of childhood blindness in camps for displaced persons in Khartoum: results of a household survey. AB - The prevalence and causes of visual impairment and blindness were determined in 29 048 children < 16 years in all households of 5 camps for internally displaced people in Khartoum State, Sudan. After house-to-house visits by trained health care workers, 916 children received further assessment, 2.7% of whom were found to be blind, 1.6% to be severely visually impaired and 5.5% to be visually impaired, according to World Health Organization criteria. The prevalence of blindness in children in the camps was estimated as 1.4 per 1000 children. The leading causes of blindness were found to be corneal opacities (40.0%), mainly due to vitamin A deficiency, followed by amblyopia (32.5%). PMID- 17687832 TI - Prevalence and risk factors for hearing disorders in secondary school students in Ismailia, Egypt. AB - This study estimated the prevalence of hearing disorders and associated risk factors in a 10% sample of all secondary-school students in Ismailia city, Egypt. All participants were given a questionnaire and Weber and Rinne tests for hearing disabilities. Among 2633 students, the prevalence of hearing loss was 22.2%, mostly sensorineural hearing loss. More students at technical schools had mixed sensorineural and conductive hearing loss (46.2%) than students at general (28.6%) or commercial (25.3%) schools. Multivariate logistic regression analysis identified the number of attacks of otitis media, history of ear disease treatment, history of admission to fever hospital and history of ear surgery as independent risk factors for sensorineural hearing loss. PMID- 17687833 TI - Evaluation of the Ministry of Health school oral health programme in the West Bank region of Palestine. AB - This paper reports an evaluation of the activities and outcomes of the school oral health programme conducted by the Ministry of Health in public schools in the West Bank region of Palestine from 1997-98 to 2003-04. Retrospective analysis of official records focused on oral health indices and student referrals. A slight improvement in DMFT scores in students in some governorates in the last 2 years showed some progress in caries control. However, maintenance efforts are required to ensure that caries level does not rise in disease-stable areas, and an increase in strategic effort is required to address the high caries level in high-risk areas. In-depth interviews with stakeholders identified the strengths and weaknesses of the screening programme and recommendations for improvements. PMID- 17687834 TI - Traumatic and non-traumatic coma in children in the referral hospital, Al-Hasa, Saudi Arabia. AB - Fahad Hospital, which is the only referral centre for Al-Hasa region, Saudi Arabia. PMID- 17687835 TI - Effectiveness of cognitive behaviour therapy in schoolchildren with depressive symptoms in Alexandria, Egypt. AB - We evaluated the effectiveness of cognitive behaviour therapy for 12-14-year-old school-children from a low socioeconomic area in Alexandria, Egypt during the academic year 2003-04. Our sample comprised 198 boys and 136 girls. Students were assessed using the Child Depression Inventory and the Coopersmith Self-Esteem Inventory. The frequency of depression was 9.6%; 7.1% in boys and 13.2% in girls. The 32 children with depression were offered cognitive behaviour therapy. Only 17 accepted the offer and received 9 sessions of therapy. They were assessed 3 months after the intervention using the same tools and the results indicate the short-term effectiveness of the therapy. PMID- 17687836 TI - Neuroleptic-induced tardive dyskinesia among Arab psychotic patients. AB - We carried out a retrospective descriptive study to determine prevalence and risk factors for tardive dyskinesia (TD) among psychotic patients treated with conventional neuroleptics in 4 centres in Saudi Arabia. Records of patients who had been taking > or = 1 conventional neuroleptic for > or = 6 months from January 1997 to December 2000 were examined; 151 patients were included in the final analysis. Only 51 had TD; another 59 (6.8%) patients had drug-induced Parkinson disease. Duration of treatment (P < 0.001), higher doses of neuroleptics (P < 0.01) and age over 40 years (P < 0.01) were associated with TD. A statistically significant difference in prevalence was found between Arabs (23.5%) and Afro-Arabs (45.5%) (P < 0.01). Overall prevalence of TD among psychotic patients was 5.9%. PMID- 17687837 TI - Sleep-wake cycle disturbances in protein-energy malnutrition: effect of nutritional rehabilitation. AB - A standard sleep questionnaire was given to the parents of 26 infants with protein-energy malnutrition who underwent polysomnographic evaluation. These investigations were repeated approximately 2 months after enrolment in a nutritional rehabilitation programme based on World Health Organization guidelines. Anthropometric values and serum serotonin levels were also measured. After nutritional rehabilitation there was a significantly higher percentage of non-rapid eye movement (REM) sleep; 2nd REM time, and latency times for sleep and REM sleep increased. Percentages of REM sleep and serum serotonin levels decreased significantly. Protein-energy malnutrition seems to affect the sleep wake cycle; disturbed serotonin levels may be among the factors responsible. PMID- 17687838 TI - In vivo (rat assay) assessment of nutritional improvement of peas (Pisum sativum L.). AB - This study was conducted to determine the nutritional value of peas (Pisum sativum L.) in raw and cooked form and when supplemented with chicken, mutton or beef. Peas had 3.0% lysine, which decreased to 0.6% on cooking. Protein efficiency ratio (PER) of the raw pea diet improved significantly on cooking (P < 0.05). True digestibility (TD) and net protein utilization (NPU) also showed significant improvement (P < 0.05). Supplementation of cooked peas with 15% poultry meat, mutton or beef improved PER significantly (P < 0.05). Higher PER, TD and NPU values were observed in diets supplemented with 15%-20% mutton or beef. PMID- 17687839 TI - Epidemiology and cost of haemodialysis in Jordan. AB - To assess the epidemiology and burden of haemodialysis in Jordan, all patients on haemodialysis (1711 patients) were surveyed during September/October 2003. Mean age was 48.9 years, 56% were male, 86.8% were unemployed and 92% were poor. Mean distance to the haemodialysis service was 13.6 km. Annual hepatitis B and C seroconversion for patients negative before dialysis was 0.34% and 2.6% respectively. Prevalence of haemodialysis was 312 per million population; the incidence in 2002 was 111 per million population. Fatality rate at 1 year was 20%. Diabetes mellitus was the leading cause of haemodialysis, 29.2% of cases. Total estimated cost of haemodialysis in 2003 was US$ 29.7 million. PMID- 17687840 TI - Efficacy of DOTS strategy in treatment of respiratory tuberculosis in Gorgan, Islamic Republic of Iran. AB - We carried out a follow-up cohort study of 260 smear-positive patients [178 on directly observed treatment, short-course (DOTS); 82 on non-DOTS] over a 2-year period to evaluate the efficacy of the DOTS strategy in treatment of tuberculosis (TB). All the patients had had cough for > 3 weeks; 91.9% had fever, 60.8% of them with sputum; and 27.7% had a positive family history. The rate of treatment failure with DOTS was 9.0% at the end of the 2nd month and 1.7% at the beginning of the 5th month. In the control group these rates were 18.3% and 7.3% respectively. The DOTS strategy significantly increased the success rate of TB treatment (P < 0.05). PMID- 17687841 TI - Tuberculosis of the breast: report of 4 clinical cases and literature review. AB - Nearly 18% of tuberculosis (TB) cases have only extrapulmonary manifestations. Breast tuberculosis is a rare type of extrapulmonary TB. This paper reports 4 cases of breast TB confirmed either pathologically or mycobacteriologically or both. These reports showed that TB should always be considered first in the differential diagnosis of granulomatous mastitis in TB-endemic areas. Therapy included at least 6 months of anti-TB medication and surgery when indicated. PMID- 17687842 TI - Epidemiology and risk factors of brucellosis in Alexandria governorate. AB - This study aimed to describe the trend and to identify possible risk factors for brucellosis in Alexandria in northern Egypt. We enrolled 72 confirmed cases of brucellosis and 144 age-matched controls in this study. Participants were interviewed at home using a structured questionnaire. Working with animals, breeding goats and eating ice cream bought from street vendors were significantly associated (P < 0.05) with brucellosis by univariate and multivariate analysis. Contact with infected animals and their products was the most important method of transmission. PMID- 17687843 TI - Vectors and reservoirs of cutaneous leishmaniasis in Marvdasht district, southern Islamic Republic of Iran. AB - An epidemiological study was made of vectors and reservoirs of cutaneous leishmaniasis in rural regions of Marvdasht, Fars province, southern Islamic Republic of Iran during 2003-04. Using live traps, 126 rodents were collected: 75.4% were Meriones libycus, 14.3% Cricetulus migratorius and 10.3% Microtus arvalis. Eight out of 95 Meriones libycus (8.4%) were found to be infected with Leishmania major, identified by nested-PCR; none of the other rodents were positive. Female sandflies were collected from indoor locations: 75% were Phlebotomus papatasi and only 2.7% were found naturally infected with L. major. This is the first report of P. papatasi as a proven vector of zoonotic cutaneous leishmaniasis in this area. PMID- 17687844 TI - [Medical waste management in healthcare centres in the occupied Palestinian territory]. AB - Medical waste management in primary and secondary healthcare centres in the occupied Palestinian territory was assessed. The overall monthly quantity of solid healthcare waste was estimated to be 512.6 tons. Only 10.8% of the centres completely segregated the different kinds of healthcare waste and only 15.7% treated their medical waste. In the centres that treated waste, open burning was the main method of treatment. The results indicate that Palestinians are exposed to health and environmental risks because of improper disposal of medical waste and steps are needed to improve the situation through the establishment and enforcement of laws, provision of the necessary infrastructure for proper waste management and training of healthcare workers and cleaners. PMID- 17687845 TI - Khat (Catha edulis): health aspects of khat chewing. AB - Catha edulis Forsk leaves (khat) are chewed daily by a high proportion of the adult population in Yemen for the mild stimulant effect. Cathinone is believed to be the main active ingredient in fresh khat leaves and is structurally related and pharmacologically similar to amphetamine. The habit of khat chewing is widespread with a deep-rooted sociocultural tradition in Yemen and as such poses a public health problem. The objective of this literature review was to examine studies on khat, particularly human studies, with special reference to its effect on the central nervous system, cardiovascular, digestive and genitourinary systems, oral-dental tissues, diabetes mellitus and cancer. PMID- 17687846 TI - Tobacco control in Bahrain: an overview. AB - Tobacco control interventions in Bahrain started in the late 1970s and tobacco legislation was introduced in 1994. The tobacco control approach incorporated the international recommended strategies according to the Gulf Cooperation Council and World Health Organization. Recently the tobacco control plan and tobacco legislation were reviewed. A new national comprehensive plan is put forward for implementation by the Ministry of Health. This report examines the Bahrain tobacco control approach, focusing on tobacco legislation, youth smoking, waterpipe smoking, tobacco surveillance and the smoking cessation plan. A number of recommendations for further improvement are discussed. PMID- 17687847 TI - Health research priority setting in developing countries of the eastern Mediterranean region: partnering with the Cochrane Collaboration. AB - Healthcare research in the Eastern Mediterranean Region (EMR) is fragmented and often weak. A coordinated approach is required to strengthen and focus efforts. Given the low resource base, priority-setting is an essential component. Healthcare policy and programmes in the EMR should be underpinned by reliable evidence of "what works for whom and why", with special attention to the health needs of the disadvantaged. Collaboration with international health research organizations, such as The Cochrane Collaboration, is essential and would provide an opportunity to examine evidence, prioritize knowledge areas, and identify research gaps. PMID- 17687848 TI - Pseudomonas stutzeri: a rare cause of neonatal septicaemia. PMID- 17687849 TI - Spontaneous splenic rupture in a pregnant Sudanese woman with Falciparum malaria: a case report. PMID- 17687850 TI - [General surgery--present and future]. PMID- 17687851 TI - [Florian Mandache (1912-1989)]. PMID- 17687852 TI - Intrahepatic bile duct rupture of hydatid cyst: a severe complication for the patient. AB - In most cases of echinococcal disease the liver is the mainly affected organ. The clinical manifestations are defined by the size and the localization of the hydatid cyst. The appearance of complications, such as purulence and rupture of the cyst, aggravate the patients' clinical condition. Intrabiliary rupture, although rare, carries severe health risks; timely diagnosis and appropriate management of this entity are vital for the patient's survival. PMID- 17687853 TI - [Hemodynamic changes induced by positive pressure capnothorax during thoracoscopic thymectomy]. AB - Low-flow insufflation of CO2 into the thorax helps the surgeon by increasing the surgical field during thoracoscopy, but older studies performed on animals (pigs and dogs) showed that positive pressure capnothorax had negative hemodynamic impact on animals and strongly recommended against using it on humans. We included in our study 24 ASA I-II myasthenic patients (20 females and 4 males) age 29 yo (+/- 10.2) weight 62.8 kg (+/- 10.6) whose thymuses were surgically removed by thoracoscopy. Using thoracic electrical bioimpedance (TEB) we assessed noninvasively cardiac index (CI) stroke index (SI) systemic stroke vascular resistance index (SSVRI) and end diastolic index (EDI). Well known for its hemodynamic stability we chose sevoflurane for induction and maintenance of anesthesia (VIMA). According to Copenhagen scale, adding minimal iv dose of fentanyl (3 mcg/kg) to sevoflurane induction, allowed us to endobronchial intubate in good and excellent conditions. During anesthesia almost all measured parameters (CI, SI, MAP, EDI) recorded statistically significant decrease but with minimal clinical significance. Thus, the maximal drop was measured during application of 10 mm Hg capnothorax: CI and SI dropped by 1.16 1/min/m2 (19%) (p = 0.02) and respectively 16.58 ml/m2 (21%) (p = 0.001). Thereby we are applying low-flow positive pressure insufflation of CO2 into the thorax, to almost all thoracoscopies performed in our clinic. PMID- 17687854 TI - [Immunologic and bacteriologic study of severe acute appendicitis. Diagnostics and therapeutic considerations]. AB - Acute appendicitis remains an up to date issue, being the most frequent cause of surgical acute abdomen round the globe. The complications that occurs creates important therapeutically difficulties. The study, based on 114 cases, had analyzed not only the pathogen flora (type, association, frequency of certain germs, the relation between them and different pathological lesion), but also the immune response of the organism to septic aggression. The microbiological tests from the lumen and bont of the appendix and also from peritoneal cavity showed monobacterial infection (11%) and pluribacterial infection (89%). Association between aerobes and anaerobes germs was identified in 85%. The most frequent germs identified were E. coli (87%) and Bacteroides (55%). We didn't identify germs with particular pathogenesis and the immune response had no malfunction. We can conclude that time factor is the main element in constituting of complications during acute appendicitis. A late diagnosis and also a late surgical intervention are the bases for the gravity of the pathogenic process. PMID- 17687855 TI - [When and what will we do with the descendants of colorectal cancer patients? Case study and research project presentation]. AB - The polygenic etiology of familial colorectal cancer and other digestive tract cancers has been acknowledged and therefore a study subject by means of various techniques such comparative genomic hybridization, serial genetic analysis (APC, CGH) or DNA arrays. Our paper is the first presentation of a CNCSIS research project named: "Analiza unor factori moleculari implicati in stabilirea riscului statistic de imbolnavire la descendentii probanzilor cu cancer rectocolonic" and also presents the case of a 12 members family in which 3 had already been diagnosed with colonic or rectal cancer. The APC gene methylation profile was studied in order to establish both the gene implication in cancer development within the family and the risk of colorectal cancer for the healthy family members. The paper shows the present means of interaction between the surgeon and the familial colorectal cancer cases and the research project advocates for the necessity of a genetic counseling network to which such cases should be referred. PMID- 17687856 TI - [The sentinel lymph node technique in colorectal cancer using in vivo dye- utility and limits]. AB - The aim of this work is to analyze the importance of sentinel lymph node technique in the treatment of colorectal cancer. There are presented data from literature concerning sentinel lymph node, especially papers about the place of sentinel lymph node method in the treatment of colorectal cancer. This work also shows the experience of Surgical Clinical Department of Coltea Hospital in the use of sentinel lymph node method in colorectal cancer (8 patients with colon cancer and 9 with rectal cancer). There are presented the criteria for inclusion in the study group (26 patients initially proposed for the study) and the exclusion criteria, the diagnostic method using an in vivo dye and the pathology study. The study of the literature and our experience leads to the conclusion that the identification of the sentinel lymph node in colorectal cancer doesn't modify the dissection of the lymphatic area. This procedure may change the adjuvant treatment for colorectal cancer. The discussion is still open concerning the importance of lymphatic micro metastases found by RT-PCR and immunohistochemistry methods. More studies are necessary to clarify these problems. PMID- 17687857 TI - [Differentiated thyroid carcinoma. Diagnosis and therapeutic aspects]. AB - The significant increase in incidence of thyroid cancer in the last decade, augmented the interest in reevaluation of treatment and diagnosis methods. Those aspects let us into making this retrospective study regarding the differentiated thyroid carcinoma. The clinical material consist in 70 C.T. patients, of which 54 (77.14%) C.T.D. patients, ages between 17-80 year old, sex ratio W/M 3.5/1.9. Preoperatively malignancy diagnosis was made by FNAC in 38.88%, intraoperatively by extemporaneous pathological exam 42.59%, postoperatively by paraffin exam 18.51%. Papillary CTD 30 (55.55%), follicular 20 (41.25%), Hurthle cells carcinoma 4 (7.2%). From the therapeutical point of view, the elective procedure of thyroidectomy was dictated by the histological type, staging and specific prognostic factors. There was 41 (75.9%) patients with total thyroidectomy (T.T), with a specific morbidity of 7 (12.96%) and 5-years survival rate of 88.88%. Preoperatively diagnosis of C.T was suspected through clinic, ultrasonography and scintigraphy arguments and confirmed by FNAC. The non conclusive cases were diagnosed intraoperatively by extemporaneous exam or postoperatively by paraffin exam. In most cases total thyroidectomy remains the essential surgical procedure. Also clinical, imaging and biological postoperative monitoring as well as suppress and substitution hormonotherapy are mandatory. PMID- 17687858 TI - [Reoperations of the thyroid gland]. AB - Reoperative thyroid surgery may be necessary in recurrent simple goiters, thyrotoxicosis and especially cancers of the thyroid gland. The present series reviewed 33 cases representing 7.3 % from our experience consisting of 440 thyroid operations. Five patients had undergone two prior operation. Details of original procedures were available only for 26 patients, the first operations being carried "extra muros" in 20 cases. There were 25 women and 8 men with mean patient age 44.5 (range 22-75) years, which had undergone one prior operations. The interval between the primary operation and the second one varies between 5 days and 44 years. Eleven cases had benign lesions: eight with uni or bilateral nodular goiters and three thyrotoxicosis (two with Basedow-Graves'disease and one with toxic adenoma) for which nodulectomy, subtotal lobectomies or thyroidectomies were performed. In twenty one cases the surgical indication was done for persistent or recurrent thyroid carcinomas (16 papillary, two follicular and one case each of medullary, anaplastic and malignant lymphoma). Among these 6 patients underwent completion total thyroidectomies associated in 9 another patients with radical or modified neck dissection and in the 6 remaining cases conservative procedures (lobectomies, tumoral excision) of the gland or nodes were done. Complications, includes two recurrent laryngeal nerve palsy, two spontaneously healed esophageal fistulas and one case each of permanent hypothyroidism and hypoparathyroidism. Reoperative thyroid surgery constitute a valuable surgical procedure for persistence or recurrence of benign and especially malignant thyroid lesions but is associated with significant increased risk of functional and anatomic complications rate than those of the initial surgery. PMID- 17687859 TI - [Abdominal tuberculosis--a surgical reality]. AB - Abdominal tuberculosis is a rare disease, with non-specific findings. Peritoneal tuberculosis is a frequent cause of low gradient ascites. The records of 22 patients (Il males, 11 females, mean age 41,17 years, and range 17-74 years) diagnosed with abdominal tuberculosis (TBC) in First Surgical Clinic, "St. Spiridon" University Hospital Iasi between 1995 and 2006 were analyzed retrospectively and the literature was reviewed. From these 22 patients diagnosed with abdominal tuberculosis, there were: peritoneal TBC in 16 cases, intestinal TBC in 5 cases, mesenteric lymph nodes TBC in 1 case. The patients with intestinal TBC, were presented with complications, 2 perforations with peritonitis, 1 intestinal obstruction, and 2 as ileo-cecal "tumors" solved by right colectomy, 4 enterectomy (3 entero-enterostomies and 1 ileo-colic anastomosis). The patients with peritoneal TBC were diagnosed by laparoscopy and peritoneal biopsy in 13 cases, and by laparotomy in 3 cases. In peritoneal tuberculosis ascites was present in 15 cases. Other common findings were weight loss (12 cases), weakness (5 cases), abdominal pain (15 cases), anorexia (5 cases) and night sweat (2 cases). Only two patients had chest radiography suggestive of a new TBC lesion. In those patients with peritoneal tuberculosis, subjected to operation, the findings were multiple diffuse involvements of the visceral and parietal peritoneum, white "miliary nodules" or plaques, enlarged lymph nodes, ascites, "violin string" fibrinous strands, and omental thickening. Biopsy specimens showed granulomas, while ascitic fluid showed numerous lymphocytes. Post operatory evolution and management were applied by the TBC Medical System and the patients were treated 6 months by tuberculostatics, with favorable evolution. Abdominal tuberculosis should be considered for diagnosis, in patients with non-specific symptoms of abdominal pain, fever, loss of appetite, abdominal distension and even symptoms of acute abdomen. Laparoscopy is the best approach for peritoneal tuberculosis, and emergency surgery is necessary for acute complication like obstruction and peritonitis. Specific antituberculosis drugs are indicated in postoperative period. PMID- 17687860 TI - [Splenic abscess--etiologic, clinical and diagnostic features]. AB - The aim of the study is to elucidate premorbid grounds, diagnostic and clinical peculiarities, as well as medical and surgical management of non-parasitic spleen abscess. We study 6 cases, with median age 56.7 years, men/women ratio--2:1. Onset-diagnosis period was of median 20 days. In 5 cases (83.3%) spleen abscess developed in immune compromised patients (diabetes mellitus, liver cirrhosis, pancreatitis) and in one case (16.7%) subsequent to blunt abdominal trauma. Clinically, patients presented fever, weight loss and pain in the left upper quadrant of the abdomen. The imaging data (USG, CT, and Rx-thoracic) performed prior to surgery confirmed the diagnosis. USG revealed splenic injury in 80%, CT had a 100% sensibility and thoracic Rx revealed left-side pleuro-pulmonary reaction in 83% of cases. Bacteriological test was positive in 50% of cases. One death was recorded in first 24 hours after surgery. The rest of the cases had a favorable evolution, although, in 2 cases a left subphrenic abscess was noticed, one requiring drainage; in one case--colonic fistula, which closed spontaneously. Although, it's a rare pathology, an early diagnosis is as important, as impossible, and it's delay exhausts the organism and increases the postoperative morbidity rate, splenectomy remaining the safest method of treatment. PMID- 17687861 TI - [Role of Doppler ultrasonography in the diagnosis and treatment of varicocele]. AB - Varicocele is a frequent condition in male population. Our objectives were to asses the role of Doppler ultrasonography in varicocele diagnosis, evaluation of surgical outcome and identify predictive factors for infertility. We studied 45 patients (21-46 years old), Doppler ultrasonography being used to determine the stage and reflux grade. In all patients presence of anti-spermatic antibodies was assessed. 27 patients were surgical treated. Postoperatively, presence or absence of reflux was assessed by Doppler ultrasonography. Spermogram was repeated in infertile patients. Our patients presented stage I (12 cases), stage II (18 cases) or stage III varicocele (15 cases). 16 patients (35%) were infertile (12 with grade III and 4 with grade II reflux), in 10 of these patients high levels of anti-spermatic antibodies being detected. Postoperatively, venous reflux was absent in all 27 patients. Among infertile patients, 80% of those younger than 25 years, 42% of those with ages between 25-30 years and none of those over 30 presented postoperative improvements of spermogram. Doppler ultrasonography is a non-invasive investigation for diagnosis, evaluation of venous reflux and detection of intratesticular varicocele. Opportunity of surgical treatment and evaluation of operative outcome can be determined using Doppler ultrasonography. PMID- 17687862 TI - [The radial forearm free flap in oro-maxillo-facial reconstruction. Experience of a multidisciplinary team approach--maxillofacial and plastic surgery]. AB - The treatment of extended oro-maxillofacial lesions is a difficult task. Free flaps are the optimal reconstruction method in well defined situations. Though not improving survival, they have lead to a lower morbidity and to the improvement of the patient's life quality. A great step forward was represented by the radial forearm flap. This paper reflects the experience of a team approach (oro-maxillofacial and plastic surgery). The radial forearm free flap was considered as the optimal solution for 22 patients with defects concerning the tongue and/or mouth floor (8), the lower lip (7), or other facial regions (5). The defects were due to the resection of malignant tumors spinocellular (18) or basocellular carcinoma (2), benign tumors (1) or posttraumatic (1). Flap's characteristics allow wide area coverage and high plasticity. Thus, in case of malignant tumors, surgeons may perform resections within the oncological limits, while post-resectional defects can be covered with very good functional and aesthetic results. The morbidity of the donor region is within acceptable limits. Team approach in head and neck reconstruction (oromaxillofacial surgeon-plastic surgeon) leads to superior quality results, allowing each specialist to focus on the aspects he/she is most familiar. PMID- 17687863 TI - [D3 lymphatic dissection in surgery for gastric cancer]. PMID- 17687864 TI - [Letter of a Parisian surgeon: Parisian surgery in 1938 by Jean Braine, surgeon of Paris Hospital, director of the Amphitheatre Anatomy, member of the Academy of Surgery]. PMID- 17687865 TI - [Liver resection after downstaging with systemic chemotherapy in a case of a multicentric hepatocellular carcinoma with virus B cirrhosis]. AB - Hepatocellular carcinoma is often diagnosed in an advanced stage when curative therapeutical options are limited, especially with coexisted cirrhosis. Downstaging-resection plays a role in improving prognosis of unresectable hepatocarcinoma. We report the case of a 27 years old woman with multicentric hepatocellular carcinoma and virus B cirrhosis, portal vein thrombosis with systemic chemotherapy followed be hepatic resection--left hepatectomy and lymph node dissection for the remaining tumor. Postoperative outcome was uneventful, the patient being alive at 22 month after diagnosis, without recurrence. Combined modalities with systemic chemotherapy and surgical resection can achieve complete clinical remission and long-term control of disease in patients with unresectable hepatocarcinoma. PMID- 17687866 TI - [Intestinal fistula--a complication in the surgical treatment of the substitution mesh infection]. AB - The infection of the substitute mesh, used in the treatment of the large abdominal eventrations is a very severe complication for the patient and also for the surgeon. The surgical treatment of this complication represents the ablation of the mesh with concomitant evacuation of the purulent collection and the annihilation of the infectious source. In the next stage, it will be applied a reconstruction method of the abdominal wall. The ablation of the mesh, especially if the infection was continuous for a long period, is very difficult and can have as consequences severe complications, one of them being the small intestine fistula. This paper presents the case of one patient with an infection of the substitution mesh that had a continuous evolution over a long period, approximately 3 years, and its ablation being complicated with a small intestine fistula. PMID- 17687867 TI - [Acute urinary retention in primary vaginal carcinoma: therapeutic approach]. AB - Carcinoma of the vagina is a very rare disease. Primary vaginal carcinoma tends to spread by local invasion of the adjacent pelvic organs (without any kind of metastases) and secondarily through lymphatic channels. The aim of this report is to add observations concerning the surgical treatment of this rare occurrence of carcinoma. The 33-year old patient's history began with an acute urinary retention which imposed bladder catheterization. Local examination revealed a hard 3/3 cm large mass on the middle third of the anterior vaginal wall, invasive in the urinary bladder. Cystoscopic examination confirmed the tumor invasion in the trigone. Biopsy specimens of the tumor and histological examination showed carcinoma. Anterior pelvic exenteration with pelvic lymph nodes dissection and total colpectomy was performed and the patient received a continent urinary diversion to the skin (modified Indiana pouch), ovary transposition, vaginal reconstruction with gracilis myocutaneous flaps. Postoperative evolution was uneventful. Organ reconstruction surgery including continent urinary diversion, vaginal reconstruction will significantly improve the quality of life and don't change the body image of the patients after pelvic major surgical procedures such pelvic exenteration. PMID- 17687868 TI - [The surgical angioplasty of the left main coronary ostial stenosis--a low risk operation]. AB - To evaluate a different technique for the treatment of the left main coronary artery ostial stenosis, the coronary ostial surgical angioplasty. Three patients underwent this operation. After placing the patient on cardiopulmonary bypass and aortic cross clamping, the main pulmonary trunk was retracted laterally. The left main coronary artery was approached anteriorly through a curved aortotomy. Reconstruction was performed using fresh or treated with glutaraldehyde pericardial patch. There were no in-hospital deaths. In one case, the aortic suture had to be reconstructed with a GoreTex patch. We didn't note other complications. The patch plasty of the left main coronary trunk is a safe procedure, with no important complications, despite its technical difficulty. PMID- 17687869 TI - Clinical, radiological and histological correlation in the diagnostic work-up of cemento-ossifying fibroma of the maxilla: case report. AB - Cemento-ossifying fibroma is a relatively rare tumor classified between fibro osseous lesions. This lesion appears within the bone although in some occasions it involves the gingivae soft tissues. It is a slow growing and well-defined tumorous lesion, because of this, it is considered as a benign lesion. We report a case of a young female presenting a mass in the right cheek. The evolution of the process was 4 years. She was treated with surgical resection via a Weber Fergusson approach. The histology was that of a benign fibro-osseous proliferation composed of bony spicules and spherules admixed with a fibrous stroma. Clinical and radiological information was essential for the final diagnosis. The histologic findings alone may be similar to other pathologies such as osteoblastoma, low-grade osteosarcoma and particularly to fibrous dysplasia. An accurate diagnosis requires careful clinical, radiological and histological correlation in order to make an optimal treatment and an excellent outcome. PMID- 17687870 TI - [Giant parotid pleomorphic adenoma--presentation of a case and review of the literature]. AB - This is a case presentation of a 51-year-old patient, with a giant parotid tumor on the right side (18 x 11 cm on the longer, cranio-caudal axis, 950 g), with an extremely slow evolution, since 1978. There are no clinical signs of malignancy within the tumor. A total parotidectomy with conservation of the facial nerve and a cervico-facial plasty were performed. The pathological result indicated a pleomorphic adenoma with central malignant foci. Such cases are rare in the literature, approximately 12 similar cases. PMID- 17687871 TI - ["News in hepato-bilio-pancreatic surgery and hepatic transplant". Romanian National Surgery Conference, Bucuresti, April 18-21, 2007]. PMID- 17687872 TI - The synovial joints of the human foot. AB - The human foot is considered an organ with an assortment of tissues with different morphological characteristics and well defined limits, but effectively has a simple functionality when static that becomes extremely complex when in movement. Its complex structure, comprised of an elastic and resistant skin covering a bone framework, joints, muscles, tendons, veins and nerves, can be compared to an efficient mechanical assembly. After a long and extraordinary evolutive journey, the human foot has undergone numerous changes to perfect its function; it has lost most of its grabbing function whilst gaining new characteristics that have ultimately allowed the modern man to stand upright. The complex articular structure of the human foot consists of thirty four synovial joints, of which eighteen have curved surfaces and sixteen plane surfaces. Following the criteria set by the systematic, radiological and clinical anatomy, the Authors contribute further to the current knowledge on the ankle, tarsal (anatomic subtalar, transverse tarsal, cuneonavicular, intercuneiform and cuneocuboid), tarsometatarsal, intermetatarsal, metatarsophalangeal and interphalangeal joints and dorsal, plantar and interosseous ligaments of the human foot. The articular lines of the transverse tarsal (Chopart) and tarsometatarsal (Lisfranc) joints are particularly interesting and not only from a surgical point of view; through a straightforward identification of few reference points, it is possible to find the medial and lateral extremities of the Chopart's and Lisfranc's lines, the former pinpoints the boundary between the hindfoot and midfoot and the latter between the midfoot and forefoot. PMID- 17687873 TI - Validation study of a cell culture model of colorectal cancer. AB - Colorectal cancer is a significant cause of morbidity and mortality in Western populations. Due to the fact that epithelial cells of colon have an important role in the pathophysiology of cancer, we set up a mechanical method combined with an enzymatic digestion of surgical resections derived from our Clinical Centre to obtain tumoral colon epithelium cell cultures. The cells proliferated under the chosen culture conditions and were maintained for several weeks, including subcultivation steps. We characterised the cell morphology by light and phase contrast microscopes and by immunoistochemistry analysis. Moreover, we also demonstrated the preservation of the secretory function of the cultured cells over the time. This validated model of primary epithelial cells from colon cancer will be used to understand the biological and pathological features of human tumoral colonic cells. This will be done by studying the expression of specific proteins in the tumor and analysing mutations of specific genes in each patient to relate each genetic signature to a precise pharmacological response. PMID- 17687874 TI - Hepatic "stem" cells: state of the art. AB - As previously showed for the classical self renewing tissues (i.e., bone marrow, gut and skin), rapidly changing concepts about tissue stem cell biology identify the liver as a maturational lineage system capable to generate mature cells (hepatocytes and cholangiocytes) from a resident stem cells compartment localized near the so called Canals of Hering. At present liver transplantation is the only available therapy for end stage liver diseases and there is an ever increasing shortage of donor livers. Thus in the last decades, HPC has becoming the object of many researchers since HPC might offer a new therapeutic approach for controlling the evolution of chronic liver diseases. The aim of the present review is to update readers with the evolving concepts about hepatic stem cells biology, their characterization and isolation methods and finally their therapeutic potential. PMID- 17687875 TI - Modified Kluver-Barrera staining for the study and diagnosis of fetal encephalopathies. AB - In fetal post-mortem examinations of the Central Nervous System, any lesions must be carefully detected and identified in order to determine their etiology. Common abnormalities found in a fetal brain can be ascribed to incomplete or defective neuronal migration, often correlated with genetic syndromes or exogenous etiological factors. Neuronal migration begins between the 7th and 8th week of gestation, whereby neuroblasts migrate along radial extensions of glial cells located in paraventricular buds. In fetuses less than 20 weeks gestational age, since myelization has not begun yet in the telencephalon, histochemical techniques such as luxol fast blue (for myelin) or Kluever-Barrera staining (for myelin and neuroblasts) cannot be employed. In order to identify the (normal or pathologic) topography of these guiding fibers and their relation with migrating neuroblasts, we are proposing here to replace luxol fast blue with PAS, thus taking advantage of PAS-positivity of glycogen contained in the guiding glial fibers. From 1984 to 2004, we performed 922 fetal-perinatal post-mortem examinations (46% before the 20th week of gestation). A double PAS-cresyl violet staining was developed on theses cases, using Kluver-Barrera staining as a basis: cresyl violet was employed to highlight neurons, and luxol fast blue for myelin was replaced with a PAS staining for glycogen. RESULTS: PAS stains glycogen contained in glial fascicles which guide neuronal migration, highlighting migration trajectories with a Magenta red; conversely, neuroblasts are selectively blue stained by cresyl violet. Histochemical stainings normally employed to study the nervous system in adult individuals, cannot be used to investigate fetal encefalon, because there is no myelin before week 20 of gestation. The double PAS-cresyl violet staining has proved to be a valuable tool in fetal encefalon diagnosis and in the study of neuronal migration and its likely defects. PMID- 17687876 TI - Apocrine secretory processes in the goblet cells of rat colon following stimulation with carbamylcholine. AB - Goblet cells have been shown to secrete via apocrine process, but there are no detailed morphological features that show the types of apocrine release processes. The goblet cells of the colon of the male albino rats were stimulated with carbamylcholine (CCh) and examined by transmission and scanning electron microscopy for the purpose of studying the morphology of apocrine secretory processes. In the unstimulated control rats goblet cells secreted via exocytosis and apocrine mechanisms; but apocrine secretion was more commonly observed than exocytosis. The lumina contained intact vesicles and cytoplasmic fragments and cells with apical protrusions were also observed. Stimulation with CCh in HEPES buffered Ringer's solution resulted into enhanced secretion and apocrine features became prominent. Apocrine secretion occurred via formation of apical protrusions and non-protrusion forming processes. The protrusions were covered with the plasma membrane and contained the secretory vesicles. Two types of apical protrusions were identified; oval-round and elongated protrusions. The elongated protrusions were released from the cell via decapitation and the oval-round protrusions were released via pinching-off process. Observations also indicated that some goblet cells of the surface epithelium and intestinal glands did not show apical protrusion but appeared to secrete via apocrine. This was non protrusion forming apocrine secretion in which the exocytotic and the associated vesicles together with the intervening cytoplasm were released into the lumen causing appearance of wide concavities on the apical surface. The present results have demonstrated that apocrine secretion in the goblet cells involves multiple release processes and that these cells are capable of secreting with or without the formation of the apical protrusion. PMID- 17687877 TI - [What we drink when we drink? The role of the acetaldehyde in the alcohol consumption]. AB - Although ethyl alcohol (ethanol) is the most widely consumed drug in the Western society, ethanol mechanisms of action in the Central Nervous System (CNS) remain unknown. In consequence, the development of pharmacological strategies to treat excessive alcohol consumption and alcoholism has proven to be difficult. A major difficulty in those attempts arises from the molecular properties of ethanol, which do not allow a sterocomplementary binding to any known receptor. Therefore, over the last years, it has been proposed that a large number of effects observed alter ethanol administration/consumption might be actually mediated by its first metabolite, namely acetaldehyde, produced inside the CNS via catalase activity. Nowadays, a large number of evidences support this proposal, leading the possibility of new pharmacological strategies (i.e. pharmacological inactivation of acetaldehyde) in the management of alcohol excessive consumption. PMID- 17687878 TI - [Strengthening family interventions for the prevention of substance abuse in children of addicted parents]. AB - The scientific literature consistently reports that while children of substance abusers may be at biological, psychological, or environmental risk, the effects of these risks can be abbreviated through the use of effective interventions and treatments. Research has consistently demonstrated reductions in family and child dysfunction when effective family intervention programs are consistently utilized. While a number of effective family-based approaches have been developed and evaluated, only a few have been designed specifically for children of substance abusing parents. Just two have been tested in randomized control trials -The Streghtening Families Program and Focus on the Family. The Streghtening Families Program has demonstrated statistically significant reductions in family and child dysfunctions across several ethnocultural groups when consistently utilized. Clinical and advanced graduate programs should stress training in these evidence-based practices as well as how to adapt these models to be more culturally sensitive and age or gender appropriate in order to serve a growing and needy population of families. PMID- 17687879 TI - [Implementation perspectives on family prevention programs]. PMID- 17687880 TI - [Cocaine abuse, a problem of supply or social demand? A transcultural and correlational study which compares macrosocial, economic and cultural variables]. AB - Cocaine consumption in Spain continues to rise and is reaching an alarming level. This is a descriptive and correlational study in which a transcultural analysis is made with a sample of 62 different countries. The aim of this study is to compare the influence of macrosocial, cultural and economic variables on the behaviour of cocaine abuse. Thus, the importance of the cocaine traffic and supply is shown in relation to the abuse of the same, but recognition and emphasis is given to the presence of other explanatory factors characteristic of societies in which cocaine is abused and demanded. These factors are: predominance of cultural values of self-expression, high index of subjective wellbeing and a high GNP per capita. Finally, the relevance of social factors, environment and socio-economic context, as determinants of cocaine abuse from a trans-cultural perspective, are discussed. The implementation of different actions is proposed: the promotion of values oriented towards self-regulation and self-control, the control of the cocaine supply (direct and indirect), combating early cultural destruction by means of publicity and promoting cultural creation and the diversification of leisure. PMID- 17687881 TI - [Gender analysis of Spanish scientific publications in the area of substance abuse in biomedicine 1999-2004]. AB - BACKGROUND AND OBJECTIVE: Concern for encouraging gender equality makes it one of the high priority spheres of action for governments and organisations responsible for instigating scientific policies, with particular importance being placed on including the gender variable in evaluative analyses of scientific and technological activity. A comparative study was made, broken down by gender, of the scientific output of Spanish researchers with a high production in the field of substance abuse. MATERIAL AND METHOD: We identified the gender of 338 authors who had published more than four different articles during the period from 1999 2004 and which were indexed in the IME/Indice Medico Espanol and the SCI/Science Citation Index databases, making a comparative analysis of their output and collaboration patterns, based on the gender variable. RESULTS: In the area of substance abuse, of those with the highest output (> 9 papers), 70% were men compared with 30% women. Among the average producers (5-9 papers), 57% of the authors identified were men and 43% women. Statistically significant differences were observed between men and women with the highest output with regard to the number of published works and those with whom they had collaborated. CONCLUSIONS: There is no gender equality in the area of substance abuse, particularly when considering the top researchers. It is essential to make in-depth studies that evaluate scientific output, broken down by gender, in order to adopt the necessary corrective measures to eliminate the disparity between men and women. PMID- 17687882 TI - [Community reinforcement approach plus vouchers for cocaine dependence treatment]. AB - Cocaine use is an increasingly serious problem in Spain. The absence of effective drugs for the treatment of cocaine addiction and of empirically validated therapy programmes makes it necessary to resort to programmes that have shown their effectiveness in other countries. The aim of the present study was to explore the effectiveness of one of the programmes that has obtained the best results in the United States: the Community Reinforcement Approach (CRA) Plus Vouchers for the treatment of cocaine addiction. We assessed treatment retention and dropout rates and cocaine use during the first three months of intervention. The sample was made up of 37 patients addicted to cocaine who were assigned at random to one of two conditions: experimental (CRA Plus Vouchers) or control (Standard Treatment), both in the outpatient context. The results showed that 85.7% of the experimental group patients completed 12 weeks of treatment, compared to 69.6% of the control group. In the experimental group, 57.1% of the patients maintained continuous abstinence, compared to 39.1% of the control group. These results coincide with those of previous studies, all from outside Spain. Nevertheless, longer-term studies with larger samples are necessary in order to confirm the effectiveness of this program. PMID- 17687883 TI - [A comparative analysis of SF-12 with the SF-36 among patients in methadone treatment]. AB - BACKGROUND: The concordance of the physical and mental component summary scores of the Short Form (SF)-36 has been established using the SF-12 in general and selected patient populations but has yet to be assessed in patients with drug addiction. OBJECTIVE: To investigate whether a shorter health status instrument, the short form (SF)-12, is comparable with its longer version, the SF-36, for measuring health-related quality of life of patients with addictive disorders in treatment with methadone. METHOD: A cross-sectional study was carried out on a stratified random sample (n= 726) of users included in the Methadone Maintenance Programmes in the Basque Country in Spain. The SF-36 Health Survey was used and the physical component summary (PCS) and mental component summary (MCS) of the SF 36 and SF-12 were calculated. Intraclass correlation coefficients (ICCs) and linear regression were used to assess the ability of the SF-12 physical component summary (PCS-12) scores to predict PCS-36 scores and the SF-12 mental component summary (MCS-12) scores to predict MCS-36 scores. RESULTS: The concordance between the SF-12 and the SF-36 on both physical (ICC = 0.97) and mental (ICC = 0.98) component summary scores (PCS and MCS respectively) is high and the relationship is linear and positive. Most of the variance in the SF-36 PCS (R2 = 0.88) and MCS (R2 = 0.91) can be explained by their SF-12 counterparts. CONCLUSIONS: The SF-12 reproduced SF-36 summary scores without substantial loss of information when used on patients undergoing methadone treatment. The SF-12 appears to be an efficient alternative to the SF-36 for the assessment of health related quality of life of patients with addictive disorders and their treatment. PMID- 17687884 TI - [Clinical intervention of nicotine dependence from a systemic-relational focus. Results of a descriptive study of series of cases]. AB - We present in this work a descriptive study of series of cases in treatment for nicotine addiction with a multicomponent program focusing on a systemic relational therapy. While a good number of smokers are able to stop smoking, with the help of different programs with different levels of complexity depending on their level of addiction, there is a group of smokers who associate their difficulty to stop smoking with aspects related to their life cycle situation, problems with their family of origin or with their social network. We revised the most relevant clinical aspects of the model and presented the results of a descriptive study of a series of 128 patients, of wich 60.50% expressed family and/or personal problems that made the possibilities of success in the program more difficult. After an intervention that lasted a year during wich there were 25 therapy sessions together with combined substitute therapy with nicotine (STN) during the first 3 months of treatment, 77.30% maintained abstinence. Nowadays we know much more about nicotine addictions, giving different answers to different needs, just like the different levels of complexity of each addict. We consider that the contributions of the systemic-relational model in its different ways of understanding the intervention, can better the results of the treatment. We are justified in increasing the level of complexity of the interventions when there exist complications in the clinical handling of nicotine addiction because of other models of treatment of lesser intensity. PMID- 17687885 TI - [Resilience and drug consumption: a review]. AB - In the last few years, resilience, or the successful adaptation achieved by an individual despite very adverse or traumatic situations during their childhood, has become a concept of great importance both in the field of mental health and in drug abuse. Understanding how these individuals attain a level of normal functioning without developing personal or psychopathological problems in their adolescence or adulthood is of great relevance in not only the prevention but also the treatment of several disorders. In this paper we revised the studies that have analysed the relationship between resilience and drug consumption (tobacco, alcohol, and illegal drugs). The studies, both longitudinal and transversal, indicate that a number of individuals can be resilient (can make a normal adaptation) in adolescence or in adult life, in spite of having suffered serious traumas or adversities in their childhood. Several studies have shown clearly that resilience is a protective factor in determining whether or not an individual uses or abuses different drugs. We conclude that this concept is of great relevance to the field of drug use and abuse and, specifically, for the development of preventive programmes based on resilience. PMID- 17687886 TI - Few bicyclic acetals at reducing end of low-molecular-weight heparins: might they restrict specification of pharmacopoeia? AB - The alkaline hydrolysis of heparin benzyl ester originates enoxaparin. The depolymerization by beta-elimination is the primary effect of reaction; but side reactions can happen and the bicyclic acetal at the reducing end of glucosamine N,6-disulphate, called 1,6-anhydro ring, is a product of a side reaction. The amount of this predictable moiety of enoxaparin can be controlled to a lowest extent (6%) and to extent higher than 40% by modulating the alkalinity and duration of the reaction of hydrolysis. With the exclusion of the beta elimination effects and of these non significative side reactions, the chemical structure of the parent heparin is entirely maintained in enoxaparin as it results by the same profiles of constituent disaccharides. The content of 1,6 anhydro rings is assessed by a not yet validated NMR method. The chains of enoxaparin bearing, at their reducing end, 1,6-anhydro rings could be regarded as Related Substances of enoxaparin. If present, even in an amount less than, or equal to, 30% of chains, these "related substances" affect neither activities nor safety of enoxaparin. PMID- 17687887 TI - The control of impurities in chlortalidone using a reversed-phase stationary phase. AB - A reversed-phased liquid chromatographic method for the control of impurities of nine impurities in Chlortalidone drug substance is presented. The method is sufficiently sensitive to quantify down to the level of 0.0015 per cent equivalent to a concentration of 15 microg/ml. PMID- 17687888 TI - Factor VIII test in reference preparations: compensation for different dilutions. AB - An approach is described that aims to prevent the problems associated with factor VIII (FVIII) assays. This approach takes a number of factors into consideration: 2 different assay types are currently being performed (clotting and chromogenic), different standards coexist (for plasma and for concentrates) and not only are reference standards being diluted for test purposes, but likewise plasmas are diluted by adding reference standards which are significantly less concentrated than commercial concentrates. Moreover, artificially FVIII-depleted plasmas are diluted as compared to normal or haemophilic plasma with respect to non-FVIII proteins as well. Taken together, these observations have led us to re-examine FVIII assays and to establish an algorithm for FVIII measurements with plasma as the natural reference. PMID- 17687889 TI - The control of impurities in amitriptyline hydrochloride using a reversed-phase hybrid stationary phase. AB - An isocratic reversed-phase liquid chromatographic method is described using a hybrid column for the control of synthetic impurities potentially found in amitriptyline hydrochloride. The method has been validated and is capable of controlling impurities to 0.1 per cent. PMID- 17687890 TI - A precise colour determination method for tablets--an application of instrumental colour measurement in the pharmaceutical development. AB - ICH guideline Q6A requires a quantitative procedure to investigate changes in colour. For such purpose, it is necessary to conduct the instrumental colour measurement according to USP 28 <1061>. An adequate, precise, reproducible, and reliable equipment is introduced and the equipment qualification data presented. The colour of tablets coated with inorganic pigments like red and yellow ferric oxide, and white titanium dioxide shows the within-batch and batch-to-batch variabilities the extent of which is tested by CIELAB. Visual colour matching data reveal a considerable variability during the stability program while the mean CIELAB values do not vary. The visual matching should rather be replaced by the instrumental colour matching because the latter is free from the variabilities caused by human perception. The instrumental colour matching method is presented and proven to be reproducible, reliable and precise. PMID- 17687891 TI - Development of an in vivo test procedure for the ease of breaking of scored tablets. AB - An in vivo test for ease of breaking of scored tablets was developed. Scored tablets covering a wide range of dimensions, type of break-mark and ease of breaking were used as training set. Test panels of healthy volunteers (25-61 years old), and panels of elderly (mean age > or =75 years old) were used. Five different test procedures were investigated. Subjective assessment of ease of breaking appeared more cumbersome than objective scaling in "breakable" and "not breakable". Elderly were far less able to break the tablets than healthy volunteers. So, healthy volunteer panels are not a good substitute for the "worst case" patients situation. A test procedure is proposed specifying that not less than 80% of a panel of elderly (mean age > or =75 years old and none younger than 65 years old) must be able to break the scored tablet, with a confidence of not less than 90%. PMID- 17687892 TI - Chromogenic assay of human coagulation factor VIII: statistical comparison of 2 working dilution procedures. AB - The effect of 2 different practices for preparation of working dilutions in the chromogenic substrate method for potency assay of factor VIII was evaluated. In this study the potency of several concentrate materials was shown to be statistically equivalent, whether performing the assay with independent or serial working dilutions. PMID- 17687893 TI - Impurity profile of amino acids? AB - Amino acids are produced by various manufacturing processes, i.e. chemical and enzymatic synthesis, extraction from protein hydrolysates, and fermentation. Each process produces a different impurity profile. Since the European Pharmacopoeia wants to replace the non-selective and non-sensitive "ninhydrin-positive substance" TLC test with chromatographic or electrophoretic methods limiting the impurities to 0.1 per cent, the information about the production processes and the related impurity profile is urgently needed from the manufacturers. PMID- 17687894 TI - Batch variability of bacitracin: HPLC versus MEKC. AB - 10 lots of bacitracin collected from the European market were studied applying the European Pharmacopoeia HPLC method, and the results were compared to the findings of an orthogonal micellar electrokinetic chromatographic method. The latter method exhibited a far higher selectivity, resulting in a baseline separation of all bacitracin components, which could not be achieved with HPLC. Considering the contents of bacitracin A, B1, and B3, the lots could be organised into 2 groups. Due to high amounts of bacitracin B1 and B3, one lot did not fit into either group. All lots met the requirements of the European Pharmacopoeia. PMID- 17687895 TI - Quality criteria of homoeopathic mother tinctures: considerations regarding suitable tests for homoeopathic monographs. AB - Quantitative determination of markers may improve quality control of herbal homoeopathic mother tinctures. Since the activity of homoeopathic medicinal products does not depend on the specific content of such markers, appropriate substances can be selected according to analytical aspects only. We tested carbohydrates, amino acids, total polyphenols and flavonols in different mother tinctures. The results obtained with the latter two groups of substances imply that corresponding tests might be useful for inclusion into pharmacopoeial monographs. PMID- 17687896 TI - Subepithelial connective-tissue graft: the tunnel technique. PMID- 17687897 TI - Synergistic use of ultrasound and sonic motion for removal of dental plaque bacteria. AB - Proving that an idea has merit for further investigation is one of the earliest steps in product development. This proof of concept can be effectively studied in a dynamic, multidisciplinary environment where ideas can be quickly tested in a manner related to final product use. In this article, the authors demonstrate the fecundity of a multidisciplinary environment by reviewing their early work that shows that ultrasound could be added to a power toothbrush to enhance the removal of dental plaque bacteria. They hypothesized that sonic brush head motion would generate bubbles in a dentifrice so that ultrasound beamed into that slurry would cause those bubbles to expand and contract in a manner that would dislodge the plaque bacteria adherent to the tooth surfaces. In this work, Streptococcus mutans bacteria adherent to various surfaces was used as a model of dental plaque on human teeth. Prototype power toothbrushes were created using commercially available and custom components so that the ultrasound and sonic processes could be individually modified and applied. Research demonstrated that the combination of sonic and ultrasound processes could synergistically remove S mutans biofilm. This finding established the proof of concept that eventually led to the development of a power toothbrush that uses both ultrasound and sonic activity. PMID- 17687898 TI - Can material properties predict survival of all-ceramic posterior crowns? AB - Increasingly strong all-ceramic materials have been introduced often with great fanfare and promise for long-term clinical performance. However, especially on posterior teeth, performance has been less than anticipated. This article reviews failure rates and modes of all-ceramic crowns and addresses the question of whether material properties can accurately predict clinical survival. Guidelines for selecting new and existing ceramics are provided. PMID- 17687899 TI - Resin-modified glass-ionomer restoration of primary molars with proximating Class II caries lesions. AB - Tooth-colored resin-modified glass-ionomer cement has been shown to be a durable and reliable bonded restorative material for primary molars with Class II caries lesions. This technique description identifies a series of steps that can be used to make Class II restorations of primary molars with proximating caries lesions easier, quicker, and more precise. In addition, a nano-filled resin-modified glass-ionomer is introduced. PMID- 17687900 TI - Revisiting the intensity output of curing lights in private dental offices. AB - In a survey published in 1994, it was reported that nearly 30% of dental office curing lights had an intensity output (power density) of < 200 mW/cm2. This study was designed to examine the types of curing lights and the adequacy of the intensity output in the same localities after 10 years. A total of 161 curing lights in 65 dental offices located in 2 metropolitan areas in Texas were examined for the following variables: types of light, power density, resin build up on the tips, and size of the tips. Two new radiometers were used to measure the outputs. The average intensity output for each light was placed in 5 categories ranging from < 150 mW/cm2 to > 500 mW/cm2. Of 161 lights examined, 127 (78.9%) were halogen, 22 (13.6%) were lightemitting diodes (LEDs), and 12 (7.4%) were plasma arc curing (PAC) lights. The intensity outputs (mW/cm2) of all examined lights were placed into 5 groups: (1) < 149 = 1.8% of lights; (2) 150 to 249 = 8.6%; (3) 250 to 349 = 6.2%; (4) 350 to 499 = 18.6%; and (5) >500 = 64.0%. Build-up on the tip was: none (23%), light (49.7%), moderate (12.4%), and heavy (13.7%). A comparison of the results of this study with the 1994 survey report shows an overall improvement in the intensity output in dental offices. LED and PAC lights constituted 21.2% of curing lights in this survey. PMID- 17687901 TI - Criteria for the ideal treatment option for failed endodontics: surgical or nonsurgical? AB - In case of failure of initial root canal therapy, modern endodontics provides clinicians with different treatment options to save the natural tooth from extraction. This article reviews the reasons for conventional treatment failure and discusses guidelines and diagnostic criteria for conventional and surgical re treatment. The decision-making process for choosing among conventional re treatment, surgical microendodontics, or extraction of the tooth with subsequent placement of an endosseous implant is described, and indications are illustrated by case examples. PMID- 17687902 TI - Endodontic microsurgery. AB - The field of endodontics has seen vast improvements in technology and techniques over the past several years. Perhaps the one area of endodontics that has improved the most is the way in which surgery is performed. With the use of state of-the-art instruments, new and improved materials, and a surgical operating microscope, the gap has narrowed between biological concepts and the ability to achieve consistently successful clinical results. The practice of these techniques is now referred to as endodontic microsurgery. PMID- 17687903 TI - Battling the overhead demon. PMID- 17687904 TI - [Ocular changes and general condition in lupus erythematosus (SLE)--own observation]. AB - The aim of the study was to assess ocular manifestations in patients with systemic lupus erythematosus (SLE). The following, were included in the evaluation: clinical condition, duration of the disease and treatment used. The study was performed in 100 patients with SLE. Evaluation of the clinical condition and opththalmoscopic findings in patients with SLE demonstrated abnormal Schirmer tests in 41% patients, scleritis 2%, retinopathy 7% and neuritis 1%. Inflammatory changes in the anterior segment of the eyeball, neuritis and retinopathy occurred solely in the phase of exacerbation. Adverse events observed after treatment with chloroquine or prednisone (chloroquine maculopathy,cataract, glaucoma) are related to dosage and duration of the treatment. PMID- 17687905 TI - [Inflammation of retinal vessels--own observations]. AB - PURPOSE: Inflammation of retinal vessels occures in variety of ophthalmic and systemic conditions. In this paper we attempt to reconstruct the events that lead to retinal vessels inflammation. MATERIAL AND METHODS: We have studied 30 patients (14 F, 16 M)(age 27-54 years) with retinal vessels inflammation. 25 have additionally uveitis during 2 weeks to 21 years. In 7 cases etiology was established (sarcoidosis, tuberculosis, toxoplasmosis, systemic lupus erythematosus, hepatitis C). All patients were evaluated with ophthalmoscopic fundus examination. In some cases fluoresceine angiography and magnetic resonance imaging (MRI) was obtained. We are looking for the systemic, parasites and demyelination disorders. RESULTS AND CONCLUSIONS: Exact etiology was recognized in 5 patients (Ealse disease, sarcoidosis, SM). In 10 patients retinal vascullitis was connected with changes in central nervous system. PMID- 17687906 TI - [Evaluation of the results of treatment orbital rhabdomyosarcoma in children]. AB - PURPOSE: To estimate the state of the vision organ in the children treated for orbital rhabdomyosarcoma. Rhabdomyosarcoma (RMS) is the most common primary malignant orbital tumor in children. RMS usually manifest clinically as rapidly progressive exophthalmus and displacement of the globe. The diagnosis is based on biopsy, CT and MR images. The treatment includes radiation, chemotherapy, and surgery. MATERIAL AND METHODS: The retrospective review of data of 14 children between 0 and 11 years old with rhabdomyosarcmoa of orbit. After a biopsy, with precedent CT or MRI, all patients were treated with chemotherapy including or not including radiotherapy. RESULTS: 3 children died, orbital exentaration was necessary because of tumor recurrence in 3 cases, 8 children remained healthy (without recurrent disease). CONCLUSIONS: Fast diagnosis using CT, MRI and the result of biopsy, have a positive influence on the effect of neoplastic treatment and prognosis. PMID- 17687907 TI - [The role of apoptosis in induction ocular changes in patients with cystic fibrosis]. AB - PURPOSE: To evaluate the concentration of sFas in tear film of cystic fibrosis patients. MATERIAL AND METHODS: Tear samples were collected from 20 patients with cystic fibrosis and 20 patients from control group. The sFas levels were determined by immunoenzymatic assay ELISA. RESULTS: We found statistically increased levels of sFas in tear film of patients with cystic fibrosis compared with control group. CONCLUSIONS: Apoptosis may play role in the pathogenesis of ocular changes in cystic fibrosis patients. The above results are important for the choice of the treatment of dry eye syndrome in patients with cystic fibrosis. PMID- 17687908 TI - [Strabismus surgery in pseudophakic patients]. AB - PURPOSE: To analyze the results of strabismus surgery after previous cataract extraction with primary or secondary IOL implantation and to determine predicting factors of squint. MATERIAL AND METHODS: Eight patients with squint deviation after cataract surgery with primary or secondary IOL implantation were enrolled into this study. Each patient had complete ophthalmologic and orthoptic examination. Patients were divided into two groups. Group I consisted of 5 patients with secondary IOL implantation after traumatic cataract surgery, and group II consisted of 3 patients without ocular trauma, with primary IOL implantation. Five patients from both of groups had diplopia after IOL implantation. RESULTS: Strabismus surgery was performed in all cases. Surgery was combined with preoperative botuline toxin injections and Fresnel prism correction. Two patients were treated with adjustable suture technique. Treatment was successful in all cases. Five patients had no diplopia in primary position, two of them had occasional diplopia in secondary positions, while 3 patients with pour visual acuity achieved only esthetic effect. CONCLUSIONS: 1. Strabismus surgery in patients with pseudophakia is a complicated procedure which can optimize visual alignment, improve binocular vision and reduce diplopia. 2. Patients with diplopia or squint after IOL implantation ought to be informed about the possibility of strabismus surgery, both for diplopia and esthetic effect. PMID- 17687909 TI - [Work with visual display units and its effect on the eye]. AB - PURPOSE: To examine the condition of visual functions of computer operators and the influence of work at VDU on visual functions and on self-satisfaction of computer users. The results of such studies can be used to determine the range and methods of carrying out qualification and prophylactic examinations. MATERIAL AND METHODS: The investigation involved 5 groups consisted of 241 people at the age 21 to 60 years (37 years on the average). A short-term visual work (1-hour work with computer) was the subject of the study of the first group. The influence of 6-hour work at VDU on the eye was studied in case of the second group. The subjects of the third group performed a routine office work without computer. The relation between the type of visual discomfort and working conditions (eg. natural and artificial lighting) was examined with the fourth group, while the examination of the fifth group aimed at revealing whether the correction of ergonomic conditions of workplaces had an effect on the reduction of complaints and on visual functions (the research was performed one year before the modernisation of workplaces and one year after). The study of visual complaints carried out with the use of questionnaires included the evaluation of visual functions (like: visual acuity, refraction, convergence, accommodation, critical flicker frequency, contrast sensitivity, binocular vision), and visual system and the assessment of ergonomic conditions of workplaces provided with VDUs. RESULTS: The work at VDUs caused a statistically considerable deterioration of convergence, accommodation, near and distant phoria, contrast sensitivity and critical flicker frequency. CONCLUSIONS: The reduced efficiency of examined functions may lead to visual discomfort of VDU operators. The improvement of ergonomic conditions of workplaces and individual adjustment of work-time has a favourable effect on the reduction of reported eye discomforts. PMID- 17687910 TI - Relation between grade of diabetic retinopathy and perilimbal capillary density: digital fluorescein angiographic study. AB - PURPOSE: To evaluate the relation between the capillary drop out in perilimbal area and the stage of diabetic retinopathy using the new approach of digital fluorescein angiography and digital image analysis technology. MATERIAL AND METHODS: Anterior and posterior segment fluorescein angiography were performed in 100 diabetic participants (43 males and 57 females, mean age +/- SD was 60 +/- 10.9 years) and 81 healthy persons as control group (41 males and 40 females, mean age +/- SD was 60.8 +/- 16.7 years). The loss in perilimbal capillary was estimated objectively by measuring the perilimbal intercapillary area (PIA). RESULTS: A significant loss in the perilimbal capillary density was observed in all stages of diabetic retinopathy (P < 0.05). 31.7 +/- 18% increase in perilimbal intercapillary area in average due to diabetes comparing to the control group, was observed. CONCLUSIONS: The perilimbal capillary area drops and ischemic changes associated with diabetic retinopathies showed strong correspondence. PMID- 17687911 TI - [Pathogenesis of Purtscher's retinopathy and Purtscher-like retinopathy]. AB - PURPOSE: The pathogenesis of Purtscher's retinopathy (PR) or Purtscher-like retinopathy (PIR) is illustrated on two case reports. MATERIAL AND METHODS: Five patients with PR or PIR were examined ophthalmologically. Fluorescein angiography, fundus photography, visual field testing, and electroretinography were also performed. RESULTS: In three cases, the PIR was observed after acute pancreatitis, in one case it arosed from cryoglobulinemy, because of hepatitis C, and in one case it was due to a classic PR after the thorax trauma. In the case of a slow resolution of retinal edema, atrophy of the retinal pigment epithelium and optic nerve, occurred. The therapy has been based on the internal medicine treatment of the causal disease and the administration of corticosteroids, to reduce retinal edema. CONCLUSIONS: PR and PIR are interdisciplinary diseases caused by microembolization of retinal vessels. If changes are intensive and long lasting, visual prognosis is poor. PMID- 17687912 TI - [The evaluation of the efficacy of treatment in glaucoma associated with Sturge Weber syndrome]. AB - PURPOSE: To estimate the efficiency of glaucoma treatment in Sturge-Weber syndrome. MATERIAL AND METHODS: 4 patients with Sturge-Weber syndrome and the consecutive glaucoma seen at the Department of Ophthalmology in Bialystok between the years 1999-20005, were reviewed. Glaucoma associated with Sturge-Weber syndrome was diagnosed at the age of 6 months in 1 patient, of 10-11 years in 2 patients and of 14 years in 1 patients. All patients underwent surgery. 2 eyes underwent trabeculectomy and 2 eyes had nonpenetrating deep sclerectomy with SKGel implant. RESULTS: Before the surgery the intraocular pressure was 35.2 mmHg (range from 25 to 48 mmHg). All patients required anti-glaucoma medications after surgery to keep intraocular pressure less than 22 mmHg. After surgery the mean intraocular pressure was 26.25 mmHg (range from 22 to 32 mmHg). 2 patients required 2 medications: Betoptic, and/or Trusopt, and/or Xalatan and 2 patients required 1 medication. After antiglaucoma medications mean IOP was 15.2 mmHg (range from 12 to 18 mmHg). CONCLUSION: The results of therapy for glaucoma associated with the Sturge-Weber syndrome are often disappointing. PMID- 17687913 TI - [Central aleolar choroidal dystrophy in sibilings coexisting with alopecia]. AB - Central areolar choroidal dystrophy is localized in macular region and is characterized by atrophy of pigment epithelium, photoreceptors and choriocapillaris. This paper presents the history of two sibilings at the age of 23 and 30, with central aleolar choroidal dystrophy coexisting with alopecia. The results of erg, eog and fluorescein angiography are presented. CONCLUSION: The results of therapy for glaucoma associated with the Sturge-Weber syndrome are often disappointing. PMID- 17687914 TI - [Helicoidal peripapillary chorioretinal degeneration (HCPD)]. AB - Helicoidal peripapillary chorioretinal degeneration (HCPD) is characterized by bilateral wing- shaped atrophic areas in retina, radiating from the optic disc. Two cases (women: 23 and 58 years old) of this rare degeneration are presented. No changes of eye fundus and erg, eog, visual field evaluations had been noticed during 2 years follow-up. PMID- 17687915 TI - [Photodynamic therapy for treatment choroidal neovascularization in angioid streaks--case report]. AB - The aim of this paper is to present the effects of photodynamic therapy for treatment of bilateral macular choroidal neovascularization in angioid streaks during 16 months period. 50 years old man has one PDT in the right eye and three in the left eye. In the left eye conversion from choroidal neovascular membrane (CNV) to a fibrous disciform lesion following photodynamic therapy, was observed. In the right eye vision decreased from 1.0 to 0.2, but the leakage was minimal and stabilization of CNV size after the progression was noted. PMID- 17687916 TI - [Neuro-hormonal regulation of aqueous humor dynamics as the basis of glaucoma pharmacotherapy. Part I. Aqueous humor secretion]. AB - The aim of this article is to present current opinion on aqueous humor dynamics regulation and antiglaucoma drugs mechanisms of action. Glaucoma pharmacotherapy is based mainly on neuro-hormonal processes controlling aqueous humor dynamics. Systemic hormones as well as local hormones and autonomic nervous system mediators are involved in the processes of aqueous humor formation and drainage. Antiglaucoma medications act mainly through activation or inhibition of these systems' receptors, helping to decrease aqueous humor production or improve aqueous humor outflow. In this article (part 1) we describe three groups of antiglaucoma medications (beta-antagonists, adrenergic agonists, carbonic anhydrase inhibitors), inhibiting the aqueous humor production and mechanisms of their hypotensive effect in the eye. PMID- 17687917 TI - [Neuro-hormonal regulation of aqueous humor dynamics as the basis of glaucoma pharmacotherapy. Part II - Aqueous humor outflow]. AB - The aim of this article is to present current opinion on aqueous humor dynamics regulation and antiglaucoma drugs mechanisms of action. Pharmacotherapy of glaucoma is based mainly on neuro-hormonal processes controlling aqueous humor dynamics. Systemic hormones as well as local hormones and autonomic nervous system mediators are involved in the processes of aqueous humor formation and drainage. Antiglaucoma medications act mainly through activation or inhibition of these systems' receptors, helping to decrease aqueous humor production or improve aqueous humor outflow. In this article (part 2) we describe two groups of antiglaucoma medications (parasympathicomimetics, prostaglandin analogues), inhibiting the aquoeus humor outflow and mechanisms of their hypotensive effect in the eye. PMID- 17687918 TI - [General and ocular symptoms in systemic lupus erythematosus (SLE)]. AB - Systemic lupus erythematosus (SLE) is a chronic, immunologically mediated inflammatory connective tissue disorder with manifestations including various body organs (joints, pleura, pericardium, kidneys, brain, skin), caused by accumulation of immune complexes. According to epidemiological data SLE affects 0.12% of the population worldwide, while in Poland the number of reported cases is c. 60 000 - 80 000. SLE may also involve the eye. Anterior segment findings include keratoconjunctivitis sicca, keratitis and scleritis. Retinal manifestations of SLE are cotton wool spots, hemorrhage and vasculitis. The ARA (American Rheumatism Association), criteria are used in establishing the diagnosis of SLE. Although the ocular symptoms are not included in the ARA criteria, they may be initial findings and precede other manifestations of SLE. PMID- 17687919 TI - [Retinal vasculitis--causes, diagnosis, treatment]. AB - Particular types of retinal vasculitis are described and discussed: primary (idiopathic) and secondary to bacterial, viral, fungal, parasite infections and retinal vasculitis coexisting with systemic disease. Symptoms depend on the size and location of the vessels involved. Retinal vasculitis is often accompanied by uveitis. PMID- 17687920 TI - [Cytomegalovirus infection--selected aspects of clinical pathology]. AB - In this review short biological characteristics of human cytomegalovirus (CMV), the sources and its modes of transmission to human organisms, are presented. The authors described clinical pathology mainly of ocular organ and central nervous system in children with congenital cytomegalovirus infection and in acquired form of cytomegaly in adults with immunosupression (especially with HIV infection and AIDS). In review there are included contemporary diagnostic laboratory methods used in detection of CMV infection and in evaluation of clinical pathology. PMID- 17687921 TI - [Effect of anti-inflammatory therapy on the treatment of dry eye syndrome]. AB - Dry eye syndrome is a common chronic disease; agents and strategies for its effective management are still lacking. The syndrome tends to be accompanied by ocular surface inflammation; therefore, the use of anti-inflammatory agents might prove beneficial. The authors present up-to-date guidelines, strategies, and efficacy of dry eye syndrome management, including anti-inflammatory treatment. As no diagnostic tests are now available to assess ocular surface inflammation severity, the right timing to launch an anti-inflammatory agent is difficult to determine. Patients with mild intermittent bouts of symptoms which can be alleviated with ophthalmic lubricants do not typically require anti-inflammatory therapy. The latter should be considered in those who do not respond to lubricating drops, obtain poor results on clinical tests, and show symptoms of ocular surface irritation (eg. conjunctivae redness). Anti-inflammatory treatment of dry eye syndrome may include short-term corticosteroids, cyclosporine A emulsion, oral tetracycline therapy, oral omega-3 fatty acid supplements, and autologous serum eye drops. Anti-inflammatory treatment should be safe and effective; potential benefits should be evaluated for each individual patient. The authors have reviewed the advantages of anti-inflammatory treatment in dry eye syndrome, presented in literature. PMID- 17687922 TI - [Retinal dysfunction in patients treated with vigabatrin]. AB - PURPOSE: To present the current knowledge of vigabatrin influence on the retinal function and to introduce a case report of toxic retinopathy diagnosed in our laboratory, in patient treated with vigabatrin. MATERIAL AND METHODS: A review study based on other authors', concerning the role of diagnostic tests like: perimetry, flash electroretinography (ERG), multifocal electroretinography (mfERG), electrooculography (EOG) in patients treated with vigabatrin and presentation of toxic retinopathy in drug-resistant epileptic patient treated with vigabatrin. RESULTS: In vigabatrin treated patients a functional or structural retinal changes may occur, what can be measured by electrophysiological and visual field testing. Irreversible abnormalities of visual field and ERG tests results prove the toxic character of retinopathy in presented vigabatrin treated patient. CONCLUSIONS: ERG tests and visual field assessment should be performed in patients treated with vigabatrin. Initial abnormalities occurrence should be a signal for considering the change of therapy. PMID- 17687923 TI - [The applications of three-dimensional ultrasound scans in ophthalmology]. AB - Development of ophthalmology in recent years is connected with perfecting diagnostic methods and equipment. Ultrasound examination, because of its good availability, repetitiveness and non-invasiveness has become a commonly used method in ophthalmic diagnosis. Three-dimensional ultrasound (3DUS), also called three-dimensional ultrasound tomography, is an advanced method based on digital analysis of series of two-dimensional images. This technique is especially useful in ocular oncology, vitreoretinal pathologies and ocular trauma. Authors present selected cases visualised using 3DUS technique and discuss its advantages in comparison with traditional two-dimensional scans. PMID- 17687924 TI - [VEGF in age-related macular degeneration. Part I. Physiologic and pathologic role of VEGF]. AB - VEGF, an endothelial specific growth factor, stimulates vascular permeability and angiogenesis. VEGF is involved in many physiological and pathological processes including embryogenesis, wound healing, tumor growth, choroidal neovascularization and many others. Authors discuss VEGF structure, known isoforms and their mechanisms of function, focusing on VEGF influence on eye tissues. PMID- 17687925 TI - [VEGF in age-related macular degeneration. Part II. VEGF inhibitors use in age related macular degeneration treatment]. AB - Wet AMD remains a therapeutic challenge. VEGF inhibitors are new promising group of medical agents undergoing advanced clinical trials. Oncology is the main specialty using anti-VEGF therapy. Two agents were designed from the beginning as ophthalmologic medicines. These are pegaptanib and ranibizumab. In the paper there is mechanism, efficacy and safety data presented, especially coming from multi-center randomized clinical trials. Monoclonal VEGF-antibodies (ranibizumab and bevacizumab) seem to be most effective in wet AMD treatment. Because of important physiological VEGF role long-term observation is needed to confirm safety of VEGF inhibition. PMID- 17687926 TI - [The history of cocaine in medicine and its importance to the discovery of the different forms of anaesthesia]. AB - The first description of the use of cocaine by humans can be found in the memoirs of the Florentine traveller Amerigo Vespucci (1451-1512). For the next 300 years mostly the advantages of cocaine use, also as a medication, were emphasized. In 1860 Albert Niemann (1834-1861) isolated an active ingredient of coca leaves, which he named cocaine. After his death, his work was carried on by his disciple Wilhelm Lossen (1838-1906), who finally, in 1865, determined its proper chemical formula. Although the first observations concerning the effect of cocaine on mucous membranes were made by Niemann and Lossen, the first experimental studies involving the application of cocaine to animals were performed by the Peruvian surgeon Moreno y Maiz. In 1880 Basil von Anrep (1852-1925) published the results of his studies concerning the application of cocaine to humans. In the conclusion of his work he recommended cocaine as a surgical anaesthesia. But it was finally Carl Koller (1857-1944) who, in 1884, empirically demonstrated the benefits of cocaine use in medicine, most of all in ophthalmology. Subsequently, within a couple of months, the medical world learnt about and got interested in the use of cocaine for local anaesthesia. William Stewart Halsted (1852-1922) and his collaborator Richard John Hall (1856-1897) began their own research on cocaine injections. Eventually they developed the nerve and regional blocking techniques. Nowadays, due to the potential harmful effects of cocaine and the risk of addiction, the indications for the use of cocaine as an anaesthetic are strictly limited. PMID- 17687927 TI - Evaluation of certain food additives and contaminants. AB - This report represents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of various food additives with a view to recommending acceptable daily intakes (ADIs) and to preparing specifications for identity and purity. The Committee also evaluated the risk posed by a number of food contaminants, with the aim of advising on risk management options for the purpose of public health protection. The first part of the report contains a general discussion of the principles governing the toxicological evaluation and assessments of intake of food additives (in particular, flavouring agents) and contaminants. A summary follows of the Committee's evaluations of technical, toxicological and intake data for certain food additives (annatto extracts, natamycin, propyl paraben, synthetic lycopene and lycopene from Blakeslea trispora and food contaminants (aluminium, 3-chloro-1,2-propanediol, 1,3-dichloro 2-propanol and methylmercury). Specifications for the following food additives were revised: carob bean gum, guar gum, titanium dioxide and zeaxanthin. Annexed to the report are tables summarizing the Committee's recommendations for intakes and toxicological evaluations of the food additives and contaminants considered. PMID- 17687928 TI - Molecular phylogenetics of representative Paramecium species. AB - The genus Paramecium has been known to science for 250 years and contains some of the most widely studied species of ciliates. At present, the basic research object for phylogenetic studies is the genome of various paramecia. One of the most widely used markers are genes coding for various rRNA's. Comparative analyses of sequences coding rRNA were applied for resolving the systematic position of some paramecia species and also for the establishment of an accurate taxonomy of Paramecium. Paramecia were also model organisms for their systematic group in more general studies in a comparative analysis among ciliates, fungi, plants and multicellular animals, illustrating the evolutionary relationships between Archaebacteria and Eucaryota. A new, revolutionary genealogy proposed the shifting of presumptively advanced groups towards more primitive ones, and traditionally primitive forms were located closer to highly specialized taxa, but rRNA analysis did not unambiguously resolve associations within the studied groups. Because of the aforementioned concerns, the number of molecular markers used for alternative studies is growing, such as genes coding proteins from the Hsp family or histone proteins. Other promising candidate markers may be hemoglobin genes or genes coding a-tubulins. In case of comparative analyses ofnucleotide sequences, the outcome of the research usually depends upon a subjective choice of DNA. One of the directions of research in molecular phylogenetics include indirect methods that allow for an estimation of entire genomes, for example RAPD-PCR-fingerprinting. PMID- 17687929 TI - Some difficulties in research into cell motile activity under isotropic conditions. AB - Movement of Dictyostelium discoideum amoebae under isotropic and anisotropic conditions was recorded and analysed with computer-aided methods and the results are presented in various manners as described in the subject literature. Cell movement under isotropic conditions showed great diversity. Some cells moved almost in a straight path whereas others in close proximity turned around with little net translocation. When cell movement under isotropic conditions was observed, no direct correlation was found between the total length of cell trajectories and the length of final displacements of the cells. It was necessary to present the results in the form of histograms, circular diagrams of cell trajectories or in scatter correlation diagrams showing the motile behaviour of many individual cells. These methods of presentation are more informative than methods which present only average values, the "representative" behaviour of single cells, or start and end points of cell tracks. The latter methods can only illustrate but do not document the results of experiments. The use of statistical methods appears necessary in cases when it is difficult to monitor the same cells before and during experimental treatment. However, when cell movement under anisotropic conditions becomes oriented and ordered as during tactic cell movements, then the diversity in cell behaviour decreases and methods based on estimation of starting and end points of cell positions appear more credible. PMID- 17687930 TI - Cytogenetic characterization of the Trinidad endemic, Arachnocoris trinitatus Bergroth: the first data for the tribe Arachnocorini (Heteroptera: Cimicomorpha: Nabidae). AB - As an extension of the ongoing cytogenetic studies of the bug family Nabidae (Heteroptera: Cimicomorpha), the first evidence for the tribe Arachnocorini (the subfamily Nabinae), with reference to the Trinidad endemic, Arachnocoris trinitatus Bergroth, is provided. This is an attempt to gain a better insight into the evolution, systematics and within-family relationships of the family Nabidae. The studies were conducted using a number of cytogenetic techniques. The male karyotype (chromosome number and size; sex chromosome system; NOR location; C-heterochromatin amount, distribution and characterization in terms of the presence of AT-rich and GC-rich DNA), and male meiosis with particular emphasis on the behavior of the sex chromosomes in metaphase II are described. Also investigated are the male and female internal reproductive organs with special reference to the number of follicles in a testis and the number of ovarioles in an ovary. A. trinitatus was found to display a number of characters differentiating it from all hitherto studied nabid species placed in the tribe Nabini of the subfamily Nabinae, and in the tribe Prostemmatini of the subfamily Prostemmatinae. Among these characters are chromosome number 2n = 12 (10 + XY), the lowest within the family, nucleolus organizer regions (NORs) situated on the autosomes rather than on the sex chromosomes as is the case in other nabid species, and testes composed of 3 follicles but not of 7 as in other nabids. All the data obtained suggest many transformations during the evolution ofA. trinitatus. PMID- 17687931 TI - Meiotic karyotypes in males of nineteen species of Psylloidea (Hemiptera) in the families Psyllidae and Triozidae. AB - Meiotic karyotypes in males of 16 species (assigned to 9 genera and 7 subfamilies) ofthe family Psyllidae and 3 species (assigned to 3 genera of the subfamily Triozinae) of the family Triozidae are described for the first time. The first data on the genus Ligustrinia are presented. All the species were shown to exhibit the modal karyotype for psyllids, 2n = 24 + X, except Bactericera nigricornis and Arytainilla spartiophila, in which 2n = 24 + XY and 2n = 22 + X were found, respectively. The karyotype of Ctenarytaina eucalypti (Psyllidae, Spondyliaspidinae) was reinvestigated, and the karyotype 2n = 10 + X, characteristic of Spondyliaspidinae, was revealed. The karyotypes ofStrophingia fallax, S. arborea, and Craspedolepta topicalis were studied using the C-banding technique. PMID- 17687932 TI - Description of the Anser anser goose karyotype. AB - The karyotype of the Italian goose originating from Anser anser was characterised on the basis of R and C bands. Chromosomal preparations obtained from an in vitro culture of blood lymphocytes were stained with the RBG and CBG techniques. The RBG technique enabled the analysis of the structure of nine pairs of chromosomes whereas the CBG technique - fourteen pairs ofchromosomes from the total ofeighty goose chromosomes. The morphology and the R and C banding patterns were described. The size and arrangement of the blocks of constitutive chromatin were determined. Ideograms of R and C banded patterns were drawn. The morphological structure of the analysed chromosomes was evaluated. PMID- 17687933 TI - Effect of bromocriptine on the larval skin of the green toad, Bufo viridis viridis leurenti. AB - In the premetamorphic larval green toad, B. viridis viridis, as in other anurans, the skin is made up of a fibrous dermis and an epidermis of stratified epithelium. The effects of bromocriptine, an antiprolactin drug, on the premetamorphic skin of B. viridis viridis was examined. Bromocriptine, dissolved in rearing water at four different concentrations, induced a number of changes in the skin of treated tadpoles. In rough sequence of appearance, these changes include: retraction ofthe melanocyte dendrites, synchronous burst ofthe apical vesicles of the superficial epithelial cells, gradual disappearance of the melanosomes from the epithelial cells and widening of the intercellular spaces. In addition, macrophages appeared in the superficial dermis amongst the retracted melanocytes. White crystals were observed on the skin surface and similar crystals were ingested by the macrophages. Prolonged treatment with bromocriptine resulted in hypertrophy and extraction of some epidermal cells. Deep melanocytes of the mesenteries were not affected by bromocriptine-treatment indicating that the drug did not penetrate deep into the tadpole tissue. Whether the macrophages observed in the dermis were recruited from deeper tissues or were converted melanocytes is another issue in need of study. PMID- 17687934 TI - Effect of hibernation on sodium and chloride ion transport in isolated frog skin. AB - The aim of the study was to evaluate the effect of hibernation on electrophysiological parameters of isolated frog skin under control incubation (Ringer solution) and after inhibition of Na+ and CI- transepithelial transport by application of amiloride and bumetanide. The transepithelial electrical potential difference (PD in mV) was measured before and after mechanical stimulation of isolated frog skin. The tissues were mounted in a modified Ussing chamber. The results revealed a reduced PD of frog skin during hibernation. In February, as compared with November, PD of frog skin incubated in Ringer solution decreased by about 50%. Hibernation also affected hyperpolarization (dPD) of frog skin after mechanical stimulation. In November and December, dPD was about 50% and 30% lower, respectively, compared with the subsequent two months of the experiment. The incubation of frog skin with amiloride, a sodium ion channel blocker, resulted in reduced values of all measured electrophysiological parameters irrespective of the phase of hibernation. After application of chloride ion transport inhibitor (bumetanide), the PD in November and December decreased compared with the control incubation by about 80% and 75%, while in January and February by about 40% and 25%, respectively. In January and February dPD increased by four times and three times as compared with November and December. Hibernation reduces net ion flow in isolated frog skin. During the initial period of hibernation the sensitivity of the skin to mechanical stimulation also decreases. Towards the end of hibernation, on the other hand, excitation of mechanosensitive ion channels takes place. PMID- 17687935 TI - First American stand of Paramecium novaurelia and intra-specific differentiation of the species. AB - A stand of Paramecium novaurelia was found in Boston Massachusetts, USA, the first on this continent. Molecular studies (RAPD and sequencing ofrRNA [3'SSUrRNA ITS1, 5' LSU rRNA] and COI mtDNA fragments) of P. novaurelia strains show intra specific polymorphism within the species as strain clusters characterized by variable relationships. PMID- 17687936 TI - Laying characteristics of one- and two-year old pheasants (Phasianus colchicus, L.). AB - The aim ofthe study was to assess laying traits, the weight of eggs and characters ofthe laying rhythm of pheasants in the first and second years of reproduction. Pheasants (10 cockerels and 50 hens) were kept in aviaries. Daily, individual control of laying was performed beginning with the day of the first laying and ending with the last egg. The following parameters were evaluated: age at first laying, length of the laying period, number of laid eggs and the average weight of the egg in the 8th week of laying. The laying rhythm was also assessed and comprised: the number of egg clutches, the number of eggs in a clutch, the number of eggs in the longest clutch, the number of intervals, the length of intervals and the longest interval between clutches. During the first period of reproduction, in comparison with the second, pheasants laid slightly more eggs of similar average weight. The first laying period was longer than the second and was characterised by a greater number of egg clutches and greater number of intervals between clutches. The greatest number of eggs was laid in 10-egg and longer clutches, although the l-egg clutches were the most numerous. A positive correlation was found between the number of eggs and the number of clutches, the greatest number of eggs in a clutch and the number of intervals between clutches. The similar values of the reproductive characters of one- and two-year old pheasants point to the possibility of longer utilization of these birds than only for one laying period. On the other hand, the considerable variability between the experimental hens with regard to the number and the length of egg clutches, as well as the intervals between them, indicate the possibility to carry out selection taking into account traits characterising the laying rhythm. PMID- 17687937 TI - Cases of coat colour anomalies in the common shrew, Sorex araneus L. AB - Coat colour anomalies in the common shrew, Sorex araneus L., in the geographical range of this species, including Poland, are extremely rare. This study describes atypically coloured common shrews. Light colouration of the coat is a result of lack ofpigment in the entire hair or hair fragments. It appears that atypically coloured shrews occur more often in isolated populations whose gene transfer with neighboring populations is limited. PMID- 17687938 TI - New observations on green hydra symbiosis. AB - New observations on green hydra symbiosis are described. Herbicide norflurazon was chosen as a "trigger" for analysis of these observations. Green hydra (Hydra viridissima Pallas, 1766) is a typical example of endosymbiosis. In its gastrodermal myoeptihelial cells it contains individuals of Chlorella vulgaris Beij. (KESSLER & HUSS 1992). Ultrastructural changes were observed by means of TEM. The newly described morphological features of green hydra symbiosis included a widening of the perialgal space, missing symbiosomes and joining of the existing perialgal spaces. Also, on the basis of the newly described mechanisms, the recovery of green hydra after a period of intoxication was explained. The final result of the disturbed symbiosis between hydra and algae was the reassembly of the endosymbiosis in surviving individuals. PMID- 17687939 TI - [Beware of ticks--part 2. How to protect oneself against Lyme disease?]. PMID- 17687940 TI - [Impact of some constitutional characteristics on the development of basal cell carcinoma]. AB - BACKGROUND/AIM: Basal cell carcinoma (BCC) is the most common form of skin cancer in the white population. Increasing incidence of BCC imposes the requirement to indentify the risk factors due to eventual preventive action. The aim of this study was to assess the role of some constitutional characteristics in development of BCC among the Montenegrian population. METHODS: A case-control study was conducted at the Dermatology Department of Clinical Center of Montenegro in Podgorica from 2002-2003. The study group included 100 histopatologically confirmed BCC cases, while the control group consisted of 100 patients from the same department, who did not present skin cancer and who were individually matched to the cases by sex and age (+/-5 years). All participants were interviewed using an epidemiological questionnaire. For statistical analysis t test and McNemar chi2 test for matched pairs and multivariate logistic regression analyses were used. RESULTS: The risk for development of BCC was increased among the persons with lighter hair color (t = 4.63; df = 99; p < 0.001), fair skin (t = 2.37; df = 99; p = 0.020), lighter eyes color (t = 2.86; df = 99; p = 0.005), with nevuses (OR = 13.13; p = 0.025; 95% IP = 1.39-12.03), and among those whose skin tone after sun exposure remained light (OR = 3.14; p = 0.001; 95%IP = 1.59-6.18). CONCLUSION: Our study confirmed the significance of constitutional characteristics such as lighter hair color, fair skin, lighter eyes color, and the presence of nevuses in the development of BCC. PMID- 17687941 TI - Urological complications after radical hysterectomy: incidence rates and predisposing factors. AB - BACKGROUND/AIM: [corrected] Radical hysterectomy is a surgical approach for stage Ib and IIa of cervical cancer. The incidence of intraoperative injuries of the bladder during radical hysterectomy ranges from 0.4-3.7%. The ureter can be crushed, caught in sutures, transsected, obstructed by angulation, or ischemic by the stippling or periureteric fascia. Vesicovaginal and ureterovaginal fistuls are reported to develop in 0.9-2% of patients after radical abdominal hysterectomy. Fistulas usually become manifested or visible at speculum examination within 14 days following the surgery. The aim of this study was to establish the incidence and predisposing factor of urological complications after radical hysterectomy. METHODS: The study included a total of 536 patients with invasive stage Ib to IIb cancer of the cervix uteri who had underwent radical hysterectomy. The special elements considered were: the patient's age; the International Federation of Ginecology and Obstetrics (FIGO) stage after pathohistology; duration of operation; the result of preoperative laboratory tests for diabetes, anemia, hypoproteinemia, or disorders of liver or kidney function; ASA status; postoperative surgical infection. RESULTS: The average age of the patients with complications was 48.68 years. All patients with intraoperative ureteric and bladder injuries had statisticaly significant higher stage of disease and operation lasted more than in others without injury. We noticed 1.3% ureteral injuries and 1.49% bladder injuries, more than 50% of the patients with a previously mentoned injuries were operated on more than 3 hours. We found 2.61% vesicovaginal and 2.43% ureterovaginal fistuls. A total of 50% of the patients with bladder injury and vesicovaginal fistuls and 70% of the patients with ureterovaginal fistuls had diabetes mellitus. Postoperative infection of surgical site is a very important factor for the development of fistule. Half of the patients with vesicovaginal fistuls had abscess of vaginal cuff. CONCLUSION: The stage of the disease seem to be the most significant factor in the development of intraoperative ureter and bladder injuries. The stage of the disease, intraoperative bladder injury, diabetes mellitus and postoperative infection of surgical site are the most significant factors in the development of postoperative fistuls. PMID- 17687942 TI - [Mycophenolate mofetil combined with steroids: new experiences in the treatment of idiopathic retroperitoneal fibrosis]. AB - BACKGROUND/AIM: [corrected] Idiopathic retroperitoneal fibrosis (IRF) is an uncommon disease characterized by a retroperitoneal fibrotic tissue that often involve the ureters, leading to the obstructive nephropathy and variable impairment of renal function. Findings strongly suggest an autoimmune etiology. Surgery, medical treatment with immunosuppressive drugs, or a combination of both are proposed. The optimal treatment has not been established yet. The aim of this study was to present our experience with combined immunosuppressive therapy of IRF, steroids (S) and mycophenolate mofetil (MMF). METHODS: We prospectively followed four patients with IRF from January 2004 to December 2006. Three patients had an active disease with bilateral hydronephrosis. In the two of them acute renal failure was presented, and ureteral catheters were inserted in one in order to manage ureteral obstruction. One patient has came to our unit with a relapse of IRF and incipient chronic renal failure after the prior therapy with ureterolysis and immunosuppressive drugs (azathioprine and tamoxifen). All patients received steroids and MMF. Two patients were treated with intravenous methylprednisolone pulses (250 mg each), for three consecutive days, followed by oral prednisone 0.5 mg/kg/day. The other two patients received oral prednisone at the same dose. Prednisone was gradually tappered to a maintenance dose of 10 mg/kg/day. Simultaneously, all patients received MMF, initially 1 g/day with the increase to 2 g/day. RESULTS: After four weeks of the therapy all symptoms disappeared, as well as a hydronephrosis with a decrease of erythrocyte sedimentation rate and Creactive protein (CRP) to normal level in all patients. Three patents remain in remission untill the end of the follow up. One patient had a relapse because of stopping taking the therapy after six months. He was treated by oral prednisone 0.5 mg/kg/day, which was gradually decreased. After twelve weeks hydronephrosis disappeared and CRP returns to the normal level. CONCLUSION: The combination of steroids and mycophenolate mofetil led to the remission of IRF with a strong and quick immunosuppressive effect. It also provided avoiding the long-term use of high steroid dose and surgical procedures. PMID- 17687943 TI - Susceptibility to oxidative stress, insulin resistance, and insulin secretory response in the development of diabetes from obesity. AB - BACKGROUND/AIM: [corrected] Oxidative stress plays a critical role in the pathogenesis of various diseases. Recent reports indicate that obesity may induce systemic oxidative stress. The aim of the study was to potentiate oxidative stress as a factor which may aggravate peripheral insulin sensitivity and insulinsecretory response in obesity in this way to potentiate development of diabetes. The aim of the study was also to establish whether insulin-secretory response after glucagonstimulated insulin secretion is susceptible to prooxidant/antioxidant homeostasis status, as well as to determine the extent of these changes. METHODS: A mathematical model of glucose/insulin interactions and C-peptide was used to indicate the degree of insulin resistance and to assess their possible relationship with altered antioxidant/prooxidant homeostasis. The study included 24 obese healthy and 16 obese newly diagnozed non-insulin dependent diabetic patients (NIDDM) as well as 20 control healthy subjects, matched in age. RESULTS: Total plasma antioxidative capacity, erythrocyte and plasma reduced glutathione level were significantly decreased in obese diabetic patients, but also in obese healthy subjects, compared to the values in controls. The plasma lipid peroxidation products and protein carbonyl groups were significantly higher in obese diabetics, more than in obese healthy subjects, compared to the control healthy subjects. The increase of erythrocyte lipid peroxidation at basal state was shown to be more pronounced in obese daibetics, but the apparent difference was obtained in both the obese healthy subjects and obese diabetics, compared to the control values, after exposing of erythrocytes to oxidative stress induced by H2O2. Positive correlation was found between the malondialdehyde (MDA) level and index of insulin sensitivity (FIRI). CONCLUSION: Increased oxidative stress together with the decreased antioxidative defence seems to contribute to decreased insulin sensitivity and impaired insulin secretory response in obese diabetics, and may be hypothesized to favour the development of diabetes during obesity. PMID- 17687944 TI - Effect of tadalafil on erectile dysfunction in male patients with diabetes mellitus. AB - BACKGROUND/AIM: [corrected] During the first 10 years over 50% of diabetes patients develop erectile dysfunction (ED). It is more severe and resistant to therapy than in male patients with normal glucoregulation. The purpose of this pilot study was to estimate the tadalafil (Cialis) efficacy and safety in male patients with diabetes mellitus (DM), together with moderate to severe ED. METHODS: The study included 30 male patients with diagnozed type 1 or type 2 DM together with ED. ED was estimated through the International Index of Erectile Function (IIEF-6), Sexual Encounter Profile (SEP) questionnaire and prostaglandin test, at the beginning of the research and three months after the 20 mg tadalafil therapy initiation, once a week (on Fridays). Glycosylated haemoglobin in blood (HbAlc) values were also monitored. According to the ED severity (IIEF values at the beginning of the therapy) the patients were divided into 2 groups. The previous experience with sildenafil citrate (Viagra) and prostaglandin E1 intracavernous therapy was recorded. RESULTS: Tadalafil significantly improved ED (p < 0.001) for 7.40 points of the IIEF score, i.e. for 58% and 60% towards SEP2 and SEP3 questionnaire, respectively. Compared to the previous ED therapy subjectively better tadalafil experience was recorded. Each group experienced a significant improvement in IIEF score (p < 0.001), more significantly in the group 2 (8.26+/-1.49 points) compared with the medium improvement in the group 1 (6.27+/-1.35 points). After three months HbA1c values decreased for 2.26+/-1.62 (p < 0.001). CONCLUSION: Tadalafil is an effective tool for treating ED in diabetes patients. In some situations tadalafil application could replace prostaglandin test. The sexual sphere motivation leads to the improvement of glucoregulation in DM patients. PMID- 17687945 TI - Seven steps of gradual cessation of smoking--an example from India. AB - BACKGROUND/AIM: [corrected] One sixth of smokers in the world live in India. The National Family Health Survey showed that individuals with no education were 2.69 times more likely to smoke and chew tobacco than those with postgraduate education. Whether the physicians' interaction with public can cause the smoking cessation or habit by detailing the harmful effects as well as benefits of cessation without any withdrawal effects? Our aim was, therefore, to help people to stop smoking step by step. METHODS: The study was conducted at the University Student Health Care Centre, Banaras Hindu University, Varanasi, India, from June 2004 to February 2005. A total of 1,200 students smokers (graduate, post graduate or research scholars) participated. They were from 17 to 32 years old (mean age, 26 years). All were male sex. Each and every student was explained in details risks and hazards, and benefits of cessation, focusing this latter on immediate and substantial benefits at any sex and age; their every question and quarries were explained. All were told that either they should stop smoking immediately or minimized step by step. The seven steps were explained to them. RESULTS: The smoking duration was one year and more in all the participants ranging from one to 15 years; the average period of smoking was five years and six months; the number of smoked cigarettes per day was 12 on average (5-20). In 450/1200 (37.50%) students, either of any family members were smoking while 200 (16.66%) students have been inspired from their friends. The majority of 780/1200 (65%) gave-up smoking at any step as advised. The followup could not be done in 80/1200 (6.6%) students who did not report at any of the stages. Finally, 340/1200 (28.0%) students either reduced the number or failed to give-up smoking. CONCLUSION: The results of the study are very encouraging. Such interaction type of doctors with smokers will not only help to the concerned person but also to the society. PMID- 17687946 TI - [Ethical considerations of patients video monitoring]. PMID- 17687947 TI - [Ecthyma gangrenosum in a patient with non-Hodgkin lymphoma]. AB - INTRODUCTION: Ecthymagangrenosum is a rare disease of the skin that causes the localized necrosis of the skin and subcutaneous fat tissue, leading to the multiple ulcerations surrounded by local hyperaemia. The ulcerations are usually localized in groins, and perianal area. In the majority of cases ecthyma is caused by a Pseudomonas aeruginosa sepsis. The disease usually appears in immunocompromized, most frequently hematological patients. CASE REPORT: We presented a 78-year-old woman who had been treated for non-Hodgkin lymphoma for the last 18 years. She had recently been given cytotoxics which led to neutropenia. The patient suddenly developed high fever, chill and diarrhea, followed by ecthyma gangrenosum cutaneous lesions in groins, axillas, right side of the neck and umbilicus. Pseudomonas aeruginosa and Proteus mirabilis, that were sensitive to several antibiotics were isolated. The treatment included rehydratation, antibiotics, surgical debridement and regular dressing with antiseptics. The healing of all lesions was achieved after sixteen weeks of the treatment. CONCLUSION: If haemorrhagic-necrotic lesions of the skin are developed in immunocompromised, usually haematologic patients, an Ecthyma gangrenosum has to be considered immediately, material for identification of a cause has to be taken, followed by immediate administration of antibiotics effective against Pseudomonas aeruginosa. Surgical debridement and other therapeutic modalities are to be considered in some patients. PMID- 17687948 TI - Endoscopically removed giant submucosal lipoma. AB - BACKGROUND: Although uncommon, giant submucosal colon lipomas merit attention as they are often presented with dramatic clinical features such as bleeding, acute bowel obstruction, perforation and sometimes may be mistaken for malignancy. There is a great debate in the literature as to how to treat them. CASE REPORT: A patient, 67-year old, was admitted to the Clinic due to a constipation over the last several months, increasing abdominal pain mainly localized in the left lower quadrant accompanied by nausea, vomiting and abdominal distension. Physical examination was unremarkable and the results of the detailed laboratory tests and carcinoembryonic antigen remained within normal limits. Colonoscopy revealed a large 10 cm long, and 4 to 5 cm in diameter, mobile lesion in his sigmoid colon. Conventional endoscopic ultrasound revealed 5 cm hyperechoic lesion of the colonic wall. Twenty MHz mini-probe examination showed that lesion was limited to the submucosa. Since polyp appeared too large for a single transaction, it was removed piecemeal. Once the largest portion of the polyp has been resected, it was relatively easy to place the opened snare loop around portions of the residual polyp. Endoscopic resection was carried out safely without complications. Histological examination revealed the common typical histological features of lipoma elsewhere. The patient remained stable and eventually discharged home. Four weeks later he suffered no recurrent symptoms. CONCLUSION: Colonic lipomas can be endoscopically removed safely eliminating unnecessary surgery. PMID- 17687949 TI - [Influence of perioperative administration of amino acids on thermoregulation response in patients underwent colorectal surgical procedures]. AB - BACKGROUND: Hypothermia in the surgical patients can be the consequence of long duration of surgical intervention, general anesthesia and low temperature in operating room. Postoperative hypothermia contributes to a number of postoperative complications such as arrythmia, myocardial ischemia, hypertension, bleeding, wound infection, coagulopathy, prolonged effect of muscle relaxants. External heating procedures are used to prevent this condition, but some investigations reported that infusion of aminoacids during surgery can induce thermogenesis and prevent postoperative hypothermia. CASE REPORT: We reported two males who underwent major colorectal surgery for rectal carcinoma. One patient recived Aminosol 15% solution, 125 ml/h, while the other did not. The esophageal temperatures in both cases were measured every 30 minutes during the operation and 60 minutes after in Intensive Care Unit. We were monitoring blood pressure, heart rate, ECG, and shivering. Patient who received aminoacids showed ameliorated postoperative hypothermia without hypertension, arrythmia, or shivering, while the other showed all symptoms mentioned above. CONCLUSION: According to literature data, as well as our findings, we can conclude that intraoperative intravenous treatment with amino acid solution ameliorates postoperative hypothermia along with its complications. PMID- 17687950 TI - [Cessation of epileptic seizures series using peroral valproate in an adult patient with partial epilepsy]. AB - INTRODUCTION: Golden rule for the initiation of antiepileptic therapy in the majority of epileptic syndromes is "start low and go slow", a principle after the second unprovoked seizure. There are certain clinical situations however when fast titration of antiepileptic medication is needed. CASE REPORT: We present a case of the 48-year-old man referred for further management of uncontrolled partial seizures. At the age of 37 years, he had subarachnoid haemorrhage, due to aneurysm rupture of the left internal carotid artery, with consecutive vasospasm and right haemiparesis. Since that time he had received phenobarbital 100 mg nocte. On examination he had a right sided upper motor neuron weakness affecting the arm more than the leg, and mild dysarthria, EEG investigation showed frequent transitory spikewaves discharges above the left hemisphere with the fast contralateral propagation with generalised discharges and CT showed old infarction in distribution of left medial cerebral artery. Valproate therapy was initiated with the retard form in the loading dose of 2000 mg. Seizures stopped in 7th hours after the treatment initiation. Laboratory parameters (liver function tests, blood count, level of antiepileptic drugs) were monitored every day. No further seizures were recorded. The patient was discharged from the hospital after 15 days in excellent condition. CONCLUSION: In selected clinical conditions it is possible to apply the protocol for valproate loading and switch off from the previous antiepileptic drugs to valproate monotherapy. Adverse effects are rare and mild but potentially serious, and close monitoring of clinical and laboratory parameters is necessary. Hence, a rapid switch to valproate monotherapy can be done safely only in an inpatient setting. PMID- 17687951 TI - Do we need more dental schools? PMID- 17687952 TI - An aboriginal and Torres Strait Islander oral health curriculum framework: development experiences in Western Australia. AB - Indigenous oral health is widely acknowledged as paralleling the significant issues faced in general health. It is recognized that as part of the process of addressing these issues, practitioners need to be aware of the complex nature of working in an Indigenous social and cultural context, including issues beyond direct health care services. It is against this backdrop that collaborators from The University of Western Australia's (UWA) Centre for Rural and Remote Oral Health (CRROH) and Centre for Aboriginal Medical and Dental Health (CAMDH) developed a comprehensive, integrated Indigenous Oral Health Curriculum Framework for the Bachelor of Dental Science (BDSc) course. This development was based on the existing framework developed by the Committee of Deans of Australian Medical Schools (CDAMS) for medical education but was tailored to the specific issues and needs of oral health. Additional consultation with the Oral Health Centre of Western Australia (OHCWA), the School of Indigenous Studies (SIS) as well as Indigenous Australian groups occurred to ensure the development process was inclusive. The inclusion of an Indigenous Oral Health Curriculum Framework in the BDSc will enable UWA dental graduates to practise dentistry in a culturally appropriate manner. The framework provides the structure for students to develop and demonstrate an understanding of Indigenous histories, cultures and social experiences and how these impact on Indigenous peoples' health. It is anticipated that this will foster more positive and culturally secure patient-practitioner interactions between UWA dental graduates and Indigenous Australians, thereby making it more likely for Indigenous Australians to present for treatment. The increased awareness of Indigenous oral health issues will hopefully encourage more graduates to become involved in the treatment of Indigenous peoples. The combination of these factors could lead to an improvement in oral health outcomes for Australia's Indigenous peoples and a concomitant positive impact on the general health of Indigenous Australians. PMID- 17687953 TI - Factors influencing oral colonization of mutans streptococci in young children. AB - This paper aims to critically review current knowledge about the key factors involved in oral colonization of the cariogenic group of bacteria, mutans streptococci (MS) in young children. MS, consisting mainly of the species Streptococcus mutans and Streptococcus sobrinus, are commonly cultured from the mouths of infants, with prevalence of infection ranging from around 30 per cent in 3 month old predentate children to over 80 per cent in 24 month old children with primary teeth. MS is usually transmitted to children through their mothers, and the risk of transmission increases with high maternal salivary levels of MS and frequent inoculation. Factors that affect the colonization of MS may be divided into bacterial virulence, host-related and environmental factors. Complex interaction among these factors determine the success and timing of MS colonization in the child. As clinical studies have shown that caries risk is correlated with age at which initial MS colonization occurred, strategies for the prevention of dental caries should include timely control of colonization of the cariogenic bacteria in the mouths of young children. PMID- 17687954 TI - Laser-activated fluoride treatment of enamel against an artificial caries challenge: comparison of five wavelengths. AB - BACKGROUND: Laser-activated fluoride (LAF) therapy with 488 nm laser energy has been shown previously to increase the resistance of human enamel and dentine to acid dissolution in laboratory models of dental caries. The aims of this study were to examine whether LAF therapy, conducted using a range of wavelengths in the visible and near infrared regions, can protect human dental enamel from an artificial cariogenic challenge. MATERIALS AND METHODS: Buccal and lingual surfaces of extracted sound, molar and premolar teeth were used to prepare matched pairs of enamel slabs (N=10 per group). After application of neutral sodium fluoride gel (12300 ppm F ion), slab surfaces were lased (energy density 15 J/cm2; spot size 5mm, wavelength 532, 633, 670, 830 or 1064nm), then exposed to an artificial cariogenic challenge for a period of seven days. The Vicker's hardness number (VHN) was recorded before and after laser treatment and again following the cariogenic challenge. Negative controls did not receive laser exposure. RESULTS: All wavelengths of laser light examined provided an effective LAF effect, compared with the unlased negative control surfaces. CONCLUSION: Using this in vitro model, we conclude that the action spectrum of the LAF effect extends across the visible and near-infrared regions of the spectrum. PMID- 17687955 TI - Recruitment and standardization of a group of Australian dentists for a multipractice study on dental caries prevention. AB - BACKGROUND: This introductory paper details the recruitment and standardization of a group of dentists participating in a clinical trial. The trial is being undertaken to determine the cost-effectiveness of a structured preventive programme compared to standard care within private dental practices. We recruited private dental practitioners from a variety of locations in New South Wales (NSW) and the Australian Capital Territory (ACT). We sought to quantify the diagnostic reliability of dentists involved, and to define, quantify, and analyse standard care. METHODS: This is a multi-centre, clustered randomized controlled trial, where dentists are allocated to an intervention preventive or control group. Recruitment was facilitated with the support of key stakeholders and included oral presentations at divisional meetings of the Australian Dental Association, NSW Branch (ADA). A detailed time-in-motion study of 426 dental procedures was undertaken in order to define the parameters of standard care. The reliability study involved each dentist reading a set of 12 pairs of bitewing radiographs that had been produced and reviewed under standardized conditions. The reliability analysis was undertaken blind to allocation status of the dentist. RESULTS: Recruitment ceased three months into the planned six-month recruitment period, 31 practices having approached the researchers. Eight suburban, five Central Business District (CBD), five rural (in fluoridated communities), and four rural (in non-fluoridated communities) practices have been recruited. Standard care did not differ significantly between intervention and control practices (Mann-Whitney U: z = -0.50; P = 0.6). Diagnostic reliability was substantial (Kappa = 0.79 [range 0.73-0.811 and 0.78 [range 0.72-0.82]) in relation to the intervention and control practices, respectively; P = 0.6. CONCLUSION: The involvement of private dental practices in research is feasible and well supported by the profession. Standard care does not differ significantly between intervention and control practices. Inter- and intra-observer reliability was substantial, and not statistically different between the two arms of the trial. PMID- 17687956 TI - Volumetric contraction in some tooth-coloured restorative materials. AB - BACKGROUND: Much of the concern about the setting contraction of tooth-coloured restorative materials has been focused on the composite resins. This study investigated setting contraction of a range of glassionomer materials and included, for comparison, products from other groups of restorative materials. METHODS: A deflecting disk method was used to determine the volumetric contraction of three conventional (non-light cured) glass-ionomer cements (GICs), two restorative, one "lining" consistency and one adhesive/lining consistency resin-modified glass-ionomers (RMGIs), two resin adhesives, three restorative composite resins and two compomers. The influence of powder:liquid ratio on two hand-mixed materials was also examined. RESULTS: The light-cured materials (including RMGIs) showed substantially greater per cent contraction at 5 minutes than did the three conventional GICs (not light cured) and a substantially greater proportion of the 30-minute contraction had occurred at 5 minutes for these light-cured materials. Their further contraction after 1 hour was generally less than 5 per cent of the 1 hour contraction. CONCLUSION: Although the conventional GICs contract more slowly in the first 5 minutes, by 30 minutes the current restorative GICs and RMGIs exhibit a volumetric setting contraction that is comparable with the composite resins and compomers and is generally in the range of 2-3 per cent. PMID- 17687957 TI - Antimicrobial action of calcium hydroxide, chlorhexidine and their combination on endodontic pathogens. AB - BACKGROUND: The common recovery of Candida albicans and Enterococcus faecalis from failed root canals of teeth in which previous treatment has failed is notable. These organisms have been shown to be resistant to antimicrobial action of calcium hydroxide but are sensitive to chlorhexidine gluconate. The aim of the present in vitro study was to investigate the antimicrobial efficacy of calcium hydroxide paste, 2% chlorhexidine gel and their combination against Candida albicans and Enterococcus faecalis. METHODS: Inoculae of these organisms were used to make lawn cultures on Sabouraud's dextrose agar and blood agar plates. Wells were prepared with these lawn cultures and filled with calcium hydroxide paste, 2% chlorhexidine gel and their combination. The agar plates were kept overnight for incubation at 37 degrees C and the zone of inhibition was examined after 24 and 72 hours. RESULTS: The results suggest that 2% chlorhexidine gel alone is more effective at 72 hours than calcium hydroxide paste alone or in combination with 2% chlorhexidine gel against both the organisms, even though calcium hydroxide showed better antifungal efficacy against Candida albicans at 24 hours. CONCLUSION: In failed root canal treatments, 2% chlorhexidine gel may be a more effective intracanal medicament than calcium hydroxide paste or their combination against Candida albicans and Enterococcus faecalis. PMID- 17687958 TI - Caries experience among 45-54 year olds in Adelaide, South Australia. AB - BACKGROUND: Middle-aged adults are an important focus of dental policy with increasing retention of teeth and use of dental services. The aims of the study were to describe the caries experience of 45-54 year olds by dental visit pattern, dental behaviour, socio-demographics and socio-economic status. METHODS: A random sample of 45-54 year olds from Adelaide, South Australia was surveyed by self-complete questionnaire during 2004-2005 with up to four follow-up mailings to non-respondents (n=879, response rate = 43.8 per cent). Oral examinations were performed by calibrated dentists on 709 persons (completion rate = 80.7 per cent). RESULTS: The mean number (95% CI) of decayed teeth was 0.39 (0.31-0.47), with 5.25 (4.92-5.58) missing teeth, 11.0 (10.62-11.32) filled teeth, and DMFT was 16.61 (16.21-17.01). Multivariate regressions of caries experience by dental visit pattern, dental behaviour, socio-demographics and socio-economic status found: time since last visit of less than 12 months was related (P < 0.05) to fewer decayed teeth (beta = -0.40), more filled teeth (beta = 1.55) and a higher DMFT (beta = 1.24); a last visit for relief of pain was related to more decayed teeth (beta = 0.56); tooth brushing 8+ times per week was related to fewer decayed (beta = -0.36), and missing teeth (beta = -1.13), and lower DMFT (beta = 1.58); not cleaning between teeth was related to more missing teeth (beta = 0.94); males had fewer missing teeth (beta = -0.76); having a diploma/degree was related to fewer missing teeth (beta = -1.07) and lower DMFT (p = -1.27); card holder status was related to more missing teeth (beta= 1.26); and household income of $80,000+ was related to fewer missing teeth (beta= -0.96) and a lower DMFT (beta= -1.35). CONCLUSIONS: Dental visit pattern, dental behaviour, socio demographics and socio-economic status were all related to caries experience. Overall DMFT was lower for those who brushed more frequently, had higher levels of education and higher household income. PMID- 17687959 TI - Electron probe microanalysis of ion exchange of selected elements between dentine and adhesive restorative materials. AB - BACKGROUND: There have been numerous attempts to demonstrate the phenomenon of ion exchange between auto cure glass ionomer cements (GICs) and dentine. The purpose of this study was to employ an electron probe microanalysis (EPMA) technique to examine the interchange of elements between non-demineralized dentine and two types of restorative material, auto cure GICs and a resin composite. METHODS: Restorations of auto cure GICs (Riva Fast, Fuji IX Fast, Ketac Molar Quick and Fuji VII) and a bonded composite resin were placed in each of 10 recently extracted human third molar teeth. After two weeks the restorations were sectioned and prepared for EPMA. Percentage weights of calcium, phosphorus aluminum, strontium and fluoride were calculated in the restorations 200 microm from the restorative interface and 200 microm into the dentine at 5 microm intervals. RESULTS: There was evidence of calcium and phosphorus in all five auto cure GICs to a depth of 50 microm. Aluminum and strontium ions were also present in dentine except subjacent to Ketac Molar restorations. There was evidence of element transfer into composite resin and resin-bonded dentine. CONCLUSIONS: The findings of this paper support the concept of ion exchange as a bonding mechanism between auto cure GIC and dentine. Element penetration into tooth structure and GIC exceeded beyond the "ion exchange layer" observed in scanning electron microscopy studies. Penetration of calcium and phosphorus into composite resin from dentine likely occurred as a result of the self-etching process dissolving calcium and phosphorus and incorporating these elements into the hybrid layer. The presence of Al and Sr ions in dentine were likely to be associated with resin tags extending into the dentine. PMID- 17687960 TI - Resin bonding using an all-etch or self-etch adhesive to enamel after carbamide peroxide and/or CPP-ACP treatment. AB - BACKGROUND: Limited evidence exists regarding the effect of carbamide peroxide and casein phosphopeptide amorphous calcium phosphate (CPP-ACP) on composite enamel bonding. Microshear bond strengths, using either a total-etch or self etching adhesive, to enamel treated with carbamide peroxide and/or CPP-ACP were investigated. MATERIALS AND METHODS: Twenty-six extracted human third molars were sectioned into four parts, each being allocated into one of the four groups (n=26): bleach (Polanight, 16% carbamide peroxide), CPP-ACP (GC Tooth Mousse), bleach and then CPP-ACP, or untreated (control). The surfaces were bonded with a total-etch bonding system (Single Bond) or a self-etching primer system (Clearfil SE Bond) and tested using a microshear test. RESULTS: A significant difference in bond strength was found between bonding systems. SE Bond showed the highest bond strength to untreated enamel (p < 0.05). The microshear bond strength of SE Bond decreased when the enamel was treated with carbamide peroxide, CPP-ACP or both (p < 0.05). Only combined use of carbamide peroxide and CPP-ACP significantly affected microshear bond strength with Single Bond. CONCLUSION: These findings suggest the shear bond strength of resin to enamel using a self-etching priming adhesive may be affected if the enamel is treated with a bleaching agent or CPP ACP. PMID- 17687961 TI - Baby boomer retirement and the future of dentistry. AB - BACKGROUND: The dental workforce, like the Australian population, is ageing. As the large baby boomer cohort retires dental shortages will likely increase. METHODS: Australian Bureau of Statistics census data from 1986 to 2001 were used to examine ageing of the dental workforce and attrition of dentists aged 50 years and over. The number of dentists to retire was projected over the next 20 years. RESULTS: Since 1986, the dental workforce has aged significantly (p < 0.01). About half of the current dental workforce is projected to retire by 2026. Generation X dentists are significantly less likely to work long hours than the baby boomer cohort of dentists (p < 0.01). This is partly due to an increase in the proportion of women in the dental workforce and male Generation X dentists being less likely to work long hours (>41 per week) than male baby boomer dentists (p < 0.01). CONCLUSIONS: Ageing of the workforce will have an impact on dentistry later than on some other professions due to the 35 per cent of dentists who work beyond 65 years of age. Nonetheless, existing dental shortages are likely to be exacerbated over the short term by the 22 per cent of dentists projected to retire over the next 10 years. PMID- 17687962 TI - Dentition of addiction in Queensland: poor dental status and major contributing drugs. AB - BACKGROUND: Although it is said that drug addiction is associated with poor dental health, there is little research in this area. In particular, there is little work comparing the effects of the different drugs of addiction. METHODS: A cross-sectional patient survey of dental health was undertaken in a family practice comparing opiate and other drug addicts (DA) with non-addicts (NA). The age range was restricted to 19-45 years. Damaged teeth were counted and a semi quantitative score applied to severity to allow the calculation of an overall dental index. A medical review only was undertaken; recognized dental diagnostic criteria were not applied. RESULTS: There were 233 and 47 respondents in the DA and NA groups, respectively. The mean ages and gender ratios were similar in both groups. DA used more addictive drugs than NA (all P < 0.001). DA had more absent, traumatized, major cavitated and extracted teeth (all P < 0.05). Addicts had a worse severity index (P < 0.02) and dental index (13.13 + 24.00 vs. 4.74 +/- 16.03; P < 0.005). Furthermore, dental pathology developed in DA at younger ages than in NA with 56.8% vs. 5.4% of patients younger than 38 years having dental indices more than 10 respectively (OR = 22.98, 95% CI = 5.57-200.65, P < 0.0000001). At multivariate analysis age, gender, and dose and/or duration of tobacco, methadone, morphine, and alcohol were significantly associated with these pathologies. CONCLUSION: These data are consistent with published dental reports and basic science information that drug addiction has a deleterious effect on dental health, that in addiction this effect is rapid and severe, and that tobacco, methadone, morphine and alcohol contribute importantly to these changes. PMID- 17687963 TI - Supernumerary tooth with associated dentigerous cyst in an infant. A case report and review of differential diagnosis. AB - This paper reviews the topic of dental structures present at birth or erupting prior to the deciduous incisor teeth. A literature review shows a prevalence of one in every 2000 live births. At this rate of occurrence it is likely that the general dental practitioner may be called upon to offer advice. This review is supported by the presentation of an unusual case of a supernumerary maxillary incisor tooth with the hallmarks of a neonatal tooth and the development of a soft tissue dentigerous cyst. The differential diagnosis of soft and hard tissue swellings in infants is also presented together with rare syndromal associations of natal and neonatal teeth. PMID- 17687964 TI - Decline of the edentulism epidemic in Australia. PMID- 17687965 TI - Argon beam electrosurgery. PMID- 17687966 TI - Are you ready for quality-based payment? PMID- 17687967 TI - An investor's view of the mental health coverage issue. PMID- 17687968 TI - The competitive value of healthcare IT. AB - The competitive advantage that an IT system provides for healthcare organizations does not result from the application system itself; rather, it depends on three factors: How the organization implements the system. Whether the organization is able to develop means to implement IT faster or cheaper than its competitors. The strengths of the organization's IT staff and technical platform. PMID- 17687969 TI - Managed care: a pothole in the road to medical malpractice insurance reform? AB - Rising liability insurance premiums are due in significant part to the growth of managed care. Failure to address managed care abuses will not lead to effective solutions for controlling liability costs. PMID- 17687970 TI - The next generation of revenue cycle management. AB - The revenue cycle management environment is dynamic. Revenue cycle leaders are now responsible for additional functional areas and have to deal with new financing arrangements that expose the organization to greater financial risk. Financial managers can use key performance indicators and the suggested practice processes checklist to determine whether their revenue cycle operations are in good shape or need shaping up. PMID- 17687971 TI - A disciplined approach to capital: today's healthcare imperative. AB - BJC HealthCare's experience exemplifies several basic principles of a finance based approach to capital. Organizations that adopt this approach look to improve processes first, remove costs second, and spend capital last. Multiyear planning is required to quantitatively identify the profitability and liquidity requirements of strategic initiatives and address essential funding and financing issues. PMID- 17687972 TI - Lining up your service lines. AB - Steps in implementing a service line approach include: Defining the service line. Allocating service line revenue and expense. Analyzing service line contribution margin and profitability. Determining the value of other factors. Creating standards for investment decisions, benchmarking, and ranking. PMID- 17687973 TI - Healthcare reform initiatives: the new wave. AB - THE TOP LINE: There is a serious push for healthcare reform at the state and federal level. THE BOTTOM LINE: The reform proposals in the political pipeline differ from those in the policy analysis pipeline in that they are focused on providing coverage for the uninsured. If enacted, they will be very helpful but will still leave several widely acknowledged market dysfunctions in place. THE IMPLICATIONS: There is a danger of raising unrealistic expectations. Also, the impacts can be expected to vary substantially from market to market and from organization to organization. PMID- 17687974 TI - "reCreate Jackson": a turnaround tale. AB - Jackson Health System's "reCreate Jackson" project had six key goals: Improve revenue. Optimize care delivery. Establish a lean infrastructure and support expense. Create effective management. Achieve a balance in clinical delivery and academic missions. Ensure appropriate supply and service expense. PMID- 17687975 TI - Health care: we must get it right. AB - Our healthcare system is largely fragmented and dysfunctional. Healthcare organization leaders need to stop applying solutions to symptoms of problems and instead look for the root causes. After identifying the root causes, they can develop new processes based on best practices. Only then can real progress be achieved. PMID- 17687977 TI - Where is your organization going? PMID- 17687976 TI - Telling the story of community benefit. PMID- 17687978 TI - Retail clinics: here to stay. PMID- 17687979 TI - Rocky investments: have extreme risk takers taken over the market? PMID- 17687980 TI - Impact of disproportionate share payments on Medicare payment. PMID- 17687981 TI - Consequences of non-neurological injury in children. PMID- 17687982 TI - Facially disfigured children--dedicated approach and rehabilitation. AB - Facial disfigurement following congenital anomalies or acquired defects due to accidents or scars results in mental trauma and other related consequences. A multidisciplinary team approach with special importance to rehabilitation is required in handling such patients. PMID- 17687983 TI - Can't they like me as I am? Psychological interventions for children and young people with congenital visible disfigurement. AB - This paper describes the psychological challenges for children and young people with a congenital visible disfigurement. These challenges are outlined in a developmental framework and case histories are used to illustrate a range of interventions. The model underlying assessment and intervention moves away from dysfunction and disability and outcomes are defined by psychological strengths, resilience and coping strategies. For those living with a visible disfigurement, who needs rehabilitation? PMID- 17687984 TI - Visible difference amongst children and adolescents: issues and interventions. AB - Whether present at birth or acquired later in life, a visible difference (disfigurement) can have considerable psychological ramifications for children and adolescents. Whilst many young people adapt to the demands placed upon them and appear relatively unaffected, others report difficulties including adverse effects on body image, quality of life, self-esteem and difficulty with social encounters. This review examines the issues experienced by those affected, summarizes the factors identified as exacerbating or ameliorating any difficulties, then considers the particular pressures associated with developmental stages and the issues for family members. The current provision of care, the potential benefit of psychosocial interventions and the challenges faced by researchers in this area are explored. PMID- 17687985 TI - Adjustment to appearance changes resulting from meningococcal septicaemia during adolescence: a qualitative study. AB - STATEMENT OF PURPOSE: Meningococcal Septicaemia (ms) is an acute, life threatening illness characterized by rapid progression and if not treated swiftly can result in death within hours. Those who survive may require skin grafting or amputation of digits and limbs, and be left with severe scarring. Despite the trauma associated with ms, surprisingly little research has been conducted to determine its psychosocial impact. This study therefore explored the impact of ms during adolescence, with an emphasis on adjustment to a permanently altered appearance following a life-threatening illness. METHODS USED: Eleven in-depth, semi-structured interviews were conducted with adolescents (7 female) and analysed using Interpretative Phenomenological Analysis (IPA). RESULTS: Interviews highlighted the life-altering nature of the experience and the impact this had on finding meaning, life evaluation and adjustment to an altered appearance. Participants spoke at length about differences in themselves, 'pre and post ms', how they assimilated their altered self into life after ms, and the symbolisation attributed to their scars. Issues relating to healthcare provision also arose as a significant theme. DISCUSSION: Participants demonstrated a high degree of resilience in response to their experiences. The means by which this has been achieved, including social comparison are examined in detail and offer a fertile area for further research. PMID- 17687986 TI - "Ur skin is the thing that everyone sees and you cant change it!": exploring the appearance-related concerns of young people with psoriasis. AB - PURPOSE: The failure of research to capture the qualitative experiences of young people who have chronic skin conditions means that their psychosocial needs are poorly understood. Using a grounded theory approach, this study facilitated group discussions between adolescents with psoriasis in order to rapidly identify themes about their support needs. METHODS: Three online focus groups were hosted in a real time forum. In total, 8 young people aged 11-18 years were recruited through the websites of psoriasis support organizations. Focus groups lasted an average of 1 hour and data was analysed using grounded theory techniques. RESULTS: Appearance-related concerns are central to the experiences of young people with psoriasis. Participants constructed their individual struggle (It and Me) in physical, emotional, motivational and intellectual terms. A strong sense of Us developed as participants recognized the value of meeting peers with psoriasis. This enabled groups to blame Them for their negative social experiences. DISCUSSION: The findings are discussed in the context of literature around adolescence and appearance. It is suggested that the experience of negative social encounters in adolescence may have long-term implications for appearance anxiety specifically and self-esteem generally. The potential of peer support to improve these outcomes is considered. PMID- 17687987 TI - The psychological and social impact of disfigurement to the hand in children and adolescents. AB - Hand disfigurement creates potential problems for the developing child. Parental adjustment to the hand is of prime importance in the child's ability to accept and integrate the disfigurement. Self-consciousness follows a developmental path because of internal and external factors in the child's development. This paper presents a research study carried out in order to examine the decision-making process in toe-to-hand transfers. 34 families were assessed of whom 27 decided to proceed with surgery following the decision-making process. Factors which influenced that decision included the way the surgeon communicated information. Those who decided against surgery tended to have more positive beliefs about the role of the disfigured hand in the child's psychological development. The process of decision-making allowed families and the older children to engage in a therapeutic approach. PMID- 17687988 TI - The challenge of evaluating rehabilitative activity holidays for burn-injured children: qualitative and quantitative outcome data from a Burns Camp over a five year period. AB - Specialized holidays for burn-injured children are currently considered an important part of their rehabilitation. These holidays, or Camps, aim to help children face the challenges of their burn injury and treatment in a fun and supportive environment. Manchester Children's Burns Camps have been run by professionals from the Burns Unit at Booth Hall Children's Hospital together with volunteers since 1983. Formal evaluation has been a crucial component of these Camps since 1999. The purpose of this study was to summarize the findings of the evaluation process over the last 5 years, and to discuss any issues raised by the results. Standardized measures were administered to 97 children and their parents over this time period. These measures, designed to assess self-esteem, social relationships and general emotional and behavioural well-being, were completed before and after the children attended the Camp. The quantitative data showed little consistent evidence of change on these measures over the 5 years. However, the qualitative data shows consistent themes of increased confidence and improved coping with the burn injury, amongst others. The discrepancy between the quantitative and qualitative results is discussed, and implications and challenges for further evaluation of Burns Camps are raised. PMID- 17687989 TI - The psychological sequelae of thermal injury on children and adolescents: Part 1. AB - The psychological effects of thermal injury and children and their mothers were investigated in a three-part study; Part 1 is concerned with group comparisons regarding the psychological effects of thermal injury on children; Part 2 with aspects of the thermally injured group and Part 3 with psychological effects on their mothers. A total of 44 thermally injured (aged 11-16 years) injured 3-14 years previously, were matched according to age, sex, burn percentage and site of injury. In-depth interviewing and questionnaire responses on measures of psychological disturbance indicated that thermally injured children were differentiated in terms of psychopathology from matched Fracture Controls and Normal Controls. Such differences embraced many aspects of social and recreational functioning, and group differences emphasised depression, anxiety (particularly situational anxiety) and anti-social disorder as being particularly prominent in the thermally injured group. Therapeutic approaches are briefly discussed. PMID- 17687990 TI - The psychological effects of sex, age at burn, stage of adolescence, intelligence, position and degree of burn in thermally injured adolescents: Part 2. AB - A total of 44 thermally injured children (22 boys and 22 girls), currently aged 11-16 years old, who had been injured 3-14 years previously, stratified by age, sex, degree of burn (1-9%, 10-19%, 20%+) and position of burn (those whose burns included the face and those not burned facially) were selected from a sample pool of 394 previously hospitalized cases. Extent of psychological disturbance experienced by thermally injured adolescents and their mothers indicated that significant effects were evident regarding the sex of the child, age at the time of burn, stage of adolescence, intelligence and by the position and degree of burn. PMID- 17687991 TI - The psychological sequelae on mothers of thermally injured children and adolescents: future directions: Part 3. AB - Part 3 of this study focused on maternal psychopathology and relationship with their children in three groups, assessed in Parts 1 and 2. Evidence of greater psychopathology in the mothers of burned children was supported by findings of both interview and self-report data, which indicated more symptoms of worry, depression, tension, anxiety, lack of energy, lower self confidence with other people and guilt, compared with mothers of Fracture Clinic and Normal Controls. Marital and social functioning and adverse life events did not differentiate groups, with the exception of a significantly higher divorce rate in the parents of burned children, following thermal injury. PMID- 17687992 TI - Identifying influencing factors on paved roads silt loading. AB - The factors that influence the increase or decrease of silt loadings on paved roadways have not been fully quantitatively investigated. They were identified in this study based on the quarterly silt loading sampling data collected from 20 sites by the Clark County Department of Air Quality and Environmental Management in Southern Nevada for the period from 2000 to 2003. The silt loading and associated data collected over these years at one sampling site may inherently possess site-specific characteristics that can be better incorporated by using panel data models. The factors that are identified as significant are the presence of curbs and gutters, shoulder type, pavement conditions, and the presence of construction activities in the vicinity of roadways. The presence of curbs and gutters, stabilized shoulders, and good pavement conditions would result in decreased silt loadings. Conversely, the presence of construction activities within the immediate vicinity of sampled areas would result in increases of silt loadings on the roadway surfaces. Based on the analysis of the results, it was recommended that constructing curbs, gutters and stabilized shoulders, preventing or reducing construction track-out from construction activity, and improving pavement conditions be the preferred control measures to reduce silt loading on paved roadways. PMID- 17687993 TI - Short-term effects of gaseous pollutants on cause-specific mortality in Wuhan, China. AB - In Asia, limited studies have been published on the association between daily mortality and gaseous pollutants of nitrogen dioxide (NO2), ozone (O3), and sulfur dioxide (SO2). Our previous studies in Wuhan, China, demonstrated long term air pollution effects. However, no study has been conducted to determine mortality effects of air pollution in this region. This study was to determine the acute mortality effects of the gaseous pollutants in Wuhan, a city with 7.5 million permanent residents during the period from 2000 to 2004. There are approximately 4.5 million residents in Wuhan who live in the city's core area of 201 km2, where air pollution levels are highest, and pollution ranges are wider than the majority of the cities in the published literature. We used the generalized additive model to analyze pollution, mortality, and covariate data. We found consistent NO2 effects on mortality with the strongest effects on the same day. Every 10-microg/m3 increase in NO2 daily concentration on the same day was associated with an increase in nonaccidental (1.43%; 95% confidence interval [CI]: 0.87-1.99%), cardiovascular (1.65%; 95% CI: 0.87-2.45%), stroke (1.49%; 95% CI: 0.56-2.43%), cardiac (1.77%; 95% CI: 0.44-3.12%), respiratory (2.23%; 95% CI: 0.52-3.96%), and cardiopulmonary mortality (1.60%; 95% CI: 0.85-2.35%). These effects were stronger among the elderly than among the young. Formal examination of exposure-response curves suggests no-threshold linear relationships between daily mortality and NO2, where the NO2 concentrations ranged from 19.2 to 127.4 microg/m3. SO2 and O3 were not associated with daily mortality. The exposure response relationships demonstrated heterogeneity, with some curves showing nonlinear relationships for SO2 and O3. We conclude that there is consistent evidence of acute effects of NO2 on mortality and suggest that a no-threshold linear relationship exists between NO2 and mortality. PMID- 17687994 TI - Evaluation of quicklime incorporation in bench-scale and full-scale lime stabilized biosolids using a flat surface pH electrode. AB - Uniform lime incorporation into sewage sludge is critical for biosolid lime stabilization processes. There is no class B biosolids regulation for lime incorporation. The slurry method is currently used to evaluate the pH of limed biosolids, but this method homogenizes the biosolids and potentially masks poor lime mixing. In this study, a flat-surface pH electrode was used in bench-scale and full-scale experiments to measure the pH of lime-stabilized biosolids without creating slurries. The standard deviation of 15 pH measurements at different locations in a biosolid sample was used to assess mixing quality. The bench-scale experimental study showed that well-mixed limed biosolids had consistently high pHs (approximately 12) with low standard deviations (< 0.5 pH units), whereas poorly mixed biosolids had areas with low pH (< 10) and high standard deviations (> 2 pH units). Poorly mixed biosolids exhibited rapid and marked pH reduction, as well as offensive odor generation, whereas well-mixed biosolids resisted pH reduction and offensive odor generation. The full-scale study aimed at improving lime incorporation and biosolids quality confirmed the use of a flat surface pH electrode to capture low pH regions in biosolids that were masked by the current slurry method. PMID- 17687995 TI - Refinery evaluation of optical imaging to locate fugitive emissions. AB - Fugitive emissions account for approximately 50% of total hydrocarbon emissions from process plants. Federal and state regulations aiming at controlling these emissions require refineries and petrochemical plants in the United States to implement a Leak Detection and Repair Program (LDAR). The current regulatory work practice, U.S. Environment Protection Agency Method 21, requires designated components to be monitored individually at regular intervals. The annual costs of these LDAR programs in a typical refinery can exceed US$1,000,000. Previous studies have shown that a majority of controllable fugitive emissions come from a very small fraction of components. The Smart LDAR program aims to find cost effective methods to monitor and reduce emissions from these large leakers. Optical gas imaging has been identified as one such technology that can help achieve this objective. This paper discusses a refinery evaluation of an instrument based on backscatter absorption gas imaging technology. This portable camera allows an operator to scan components more quickly and image gas leaks in real time. During the evaluation, the instrument was able to identify leaking components that were the source of 97% of the total mass emissions from leaks detected. More than 27,000 components were monitored. This was achieved in far less time than it would have taken using Method 21. In addition, the instrument was able to find leaks from components that are not required to be monitored by the current LDAR regulations. The technology principles and the parameters that affect instrument performance are also discussed in the paper. PMID- 17687996 TI - Source identifications of airborne fine particles using positive matrix factorization and U.S. Environmental Protection Agency positive matrix factorization. AB - The widely used source apportionment model, positive matrix factorization (PMF2), has been applied to various air pollution data. Recently, U.S. Environmental Protection Agency (EPA) developed EPA positive matrix factorization (PMF), a version of PMF that will be freely distributed by EPA. The objectives of this study were to conduct source apportionment studies for particulate matter less than 2.5 microm in aerodynamic diameter (PM(2.5)) speciation data using PMF2 and EPA PMF (version 1.1) and to compare identified sources between the two models. In the present study, ambient PM(2.5) compositional datasets of 24-hr integrated samples collected at EPA Speciation Trends Network monitoring sites in Chicago, IL, and Portland, OR, were analyzed. Both PMF2 and EPA PMF extracted eight sources for the Chicago data and 10 sources for the Portland data. The model resolved source profiles were similar between two models for both datasets. However, in several sources, the average contributions did not agree well and the time series contributions were not highly correlated. The differences between PMF2 and EPA PMF solutions were caused by the different least-square algorithm and the different nonnegativity constraints. Most of the average source contributions resolved by both models were within 5-95% uncertainty provided by EPA PMF, indicating that the sources resolved by both models were reproducible. PMID- 17687997 TI - Encapsulation behaviors of metals in slags containing various amorphous volume fractions. AB - In this study, a melting process with addition of SiO2 was applied to treat incinerator fly ash. To describe the encapsulation behaviors of metals quantitatively, the amorphous volume fraction (AVF) of slags was initially determined. Vitrification appeared to reduce the mobility of Cr, Cu, Mn, and Ni instead of significantly immobilizing Cd, Pb, and Zn. It was verified that SiO2 enhanced the formation of an amorphous glassy structure. With the increase of SiO2, the crystalline phases would gradually diminish and transform into a higher silica-connected species. During the formation of slag matrix, Al, Ca, and Mg could modify the glass network, and consequently the encapsulation behaviors of these species would noticeably affect the chemical stability of slags. Significant immobilization of crust metals could be achieved only when a more compact and interconnected amorphous glass network was formed. Hence, it indicated that a higher AVF silica-based slag had a better potential to resist acid attack. In conclusion, for environmental protection, it is important to investigate the correlation between the encapsulation behaviors of metals and the crystalline characteristics of slag structure. PMID- 17687998 TI - A continuous collection system for household pharmaceutical wastes: a pilot project. AB - A 5-month "self-serve" pilot project was implemented to properly dispose of old and unwanted prescription and nonprescription medications. Obstacles encountered during the program included reluctance by major drug store chains to participate, regulatory and legal restrictions on pharmaceutical handling, and collection of detailed data from participants. Despite these difficulties, a total weight of 305 lb of discarded pharmaceuticals was collected during the pilot program period from an estimated 500 participants. A survey of participants indicated that discard of pharmaceuticals to the sanitary sewer, a newly discovered environmental hazard, is commonplace, with approximately 50% of participants using this method previously. The average age of the patients using the disposed medication was approximately 64 yr old, with the large majority being above 50 yr in age. The majority of participants learned of the program through newspaper advertisement. The average age or time after purchase of the medication was approximately 3 yr, and the primary purpose cited for its disposal was that the medication had exceeded its expiration date. PMID- 17687999 TI - Field evaluation of digital optical method to quantify the visual opacity of plumes. AB - Visual Determination of the Opacity of Emissions from Stationary Sources (Method 9) is a reference method established by U.S. Environmental Protection Agency (EPA) to quantify plume opacity. However, Method 9 relies on observations from humans, which introduces subjectivity. In addition, it is expensive to teach and certify personnel to evaluate plume opacity on a semiannual basis. In this study, field tests were completed during a "smoke school" and a 4-month monitoring program of plumes emitted from stationary sources with a Method 9 qualified observer to evaluate the use of digital photography and two computer algorithms as an alternative to Method 9. This Digital Optical Method (DOM) improves objectivity, costs less to implement than Method 9, and provides archival photographic records of the plumes. Results from "smoke school" tests indicate that DOM passed six of eight tests when the sun was located in the 140 degrees sector behind one of the three cameras, with the individual opacity errors of 15% or less and average opacity errors of 7.5% or less. DOM also passed seven of the eight tests when the sun was located in the 216 degrees sector behind another camera. However, DOM passed only one of the eight tests when the sun was located in the 116 degrees sector in front of the third camera. Certification to read plume opacity by a "smoke reader" for 6 months requires that the "smoke reader" pass one of the smoke school tests during smoke school. The average opacity errors and percentage of observations with individual opacity errors above 15% for the results obtained with DOM were lower than those obtained by the smoke school trainees with the sun was located behind the camera, whereas they were higher than the smoke school trainee results with the sun located in front of the camera. In addition, the difference between plume opacity values obtained by DOM and a Method 9 qualified observer, as measured in the field for two industrial sources, were 2.2%. These encouraging results demonstrate that DOM is able to meet Method 9 requirements under a wide variety of field conditions and, therefore, has potential to be used as an alternative to Method 9. PMID- 17688000 TI - Trends in the elemental composition of fine particulate matter in Santiago, Chile, from 1998 to 2003. AB - Santiago, Chile, is one of the most polluted cities in South America. As a response, over the past 15 yr, numerous pollution reduction programs have been implemented by the environmental authority, Comision Nacional del Medio Ambiente. This paper assesses the effectiveness of these interventions by examining the trends of fine particulate matter (PM(2.5)) and its associated elements. Daily fine particle filter samples were collected in Santiago at a downtown location from April 1998 through March 2003. Additionally, meteorological variables were measured continuously. Annual average concentrations of PM(2.5) decreased only marginally, from 41.8 microg/m3 for the 1998-1999 period to 35.4 microg/m3 for the 2002-2003 period. PM(2.5) concentrations exceeded the annual U.S. Environmental Protection Agency standard of 15 microg/m3. Also, approximately 20% of the daily samples exceeded the old standard of 65 microg/m3, whereas approximately half of the samples exceeded the new standard of 35 microg/m3 (effective in 2006). Mean PM(2.5) levels measured during the cold season (April through September) were three times higher than those measured in the warm season (October through March). Particulate mass and elemental concentration trends were investigated using regression models, controlling for year, month, weekday, wind speed, temperature, and relative humidity. The results showed significant decreases for Pb, Br, and S concentrations and minor but still significant decreases for Ni, Al, Si, Ca, and Fe. The larger decreases were associated with specific remediation policies implemented, including the removal of lead from gasoline, the reduction of sulfur levels in diesel fuel, and the introduction of natural gas. These results suggest that the pollution reduction programs, especially the ones related to transport, have been effective in reducing various important components of PM(2.5). However, particle mass and other associated element levels remain high, and it is thus imperative to continue the efforts to improve air quality, particularly focusing on industrial sources. PMID- 17688001 TI - Evaluation of a sequential extraction process used for determining mercury binding mechanisms to coal combustion byproducts. AB - Leaching of mercury from coal combustion byproducts is a concern because of the toxicity of mercury. Leachability of mercury can be assessed by using sequential extraction procedures. Sequential extraction procedures are commonly used to determine the speciation and mobility of trace metals in solid samples and are designed to differentiate among metals bound by different mechanisms and to different solid phases. This study evaluated the selectivity and effectiveness of a sequential extraction process used to determine mercury binding mechanisms to various materials. A six-step sequential extraction process was applied to laboratory-synthesized materials with known mercury concentrations and binding mechanisms. These materials were calcite, hematite, goethite, and titanium dioxide. Fly ash from a full-scale power plant was also investigated. The concentrations of mercury were measured using inductively coupled plasma (ICP) mass spectrometry, whereas the major elements were measured by ICP atomic emission spectrometry. The materials were characterized by X-ray powder diffraction and scanning electron microscopy with energy dispersive spectroscopy. The sequential extraction procedure provided information about the solid phases with which mercury was associated in the solid sample. The procedure effectively extracted mercury from the target phases. The procedure was generally selective in extracting mercury. However, some steps in the procedure extracted mercury from nontarget phases, and others resulted in mercury redistribution. Iron from hematite and goethite was only leached in the reducible and residual extraction steps. Some mercury associated with goethite was extracted in the ion exchangeable step, whereas mercury associated with hematite was extracted almost entirely in the residual step. Calcium in calcite and mercury associated with calcite were primarily removed in the acid-soluble extraction step. Titanium in titanium dioxide and mercury adsorbed onto titanium dioxide were extracted almost entirely in the residual step. PMID- 17688002 TI - Loading effect correction for real-time aethalometer measurements of fresh diesel soot. AB - In this study, a correction was developed for the aethalometer to measure real time black carbon (BC) concentrations in an environment dominated by fresh diesel soot. The relationship between the actual mass-specific absorption coefficient for BC and the BC-dependent attenuation coefficients was determined from experiments conducted in a diesel exposure chamber that provided constant concentrations of fine particulate matter (PM; PM(2.5); PM < 2.5 microm in aerodynamic diameter) from diesel exhaust. The aethalometer reported BC concentrations decreasing with time from 48.1 to 31.5 microg m(-3) when exposed to constant PM(2.5) concentrations of 55 +/- 1 microg m(-3) and b(scat) = 95 +/- 3 Mm(-1) from diesel exhaust. This apparent decrease in reported light-absorbing PM concentration was used to derive a correction K(ATN) for loading of strong light-absorbing particles onto or into the aethalometer filter tape, which was a function of attenuation of light at 880 nm by the embedded particles. PMID- 17688003 TI - Controversies in childhood bipolar disorders. PMID- 17688004 TI - Does bipolar disorder exist in children? A selected review. AB - Although there is increasing recognition that a substantial proportion of patients with bipolar disorder (BD) experience an onset of illness in adolescence, significant controversy remains over the validity of the diagnosis in very young children. In careful studies of adult patients dating from Kraepelin, first mood episodes not uncommonly occurred during adolescence. Some of these early-onset patients experienced subthreshold mood disturbances or predisposing temperaments earlier in childhood. Earlier onsets of BD have been reported in more recent clinical and community samples of children. Several factors possibly contributed to these earlier onsets, including exposure to psychotropics, bias in favour of a mood rather than a psychotic diagnosis, and recognition of softer-spectrum BDs. However, the validity of the diagnosis of BD in impulsive, irritable, labile, or behaviourally dysregulated children remains to be proven. Studies of high-risk children of well-characterized parents with BD have demonstrated that BD most often debuts as a depressive episode in mid to late adolescence and that activated episodes are rare prior to age 12 years. Some children manifest antecedent nonspecific psychopathology in early childhood. Therefore, as currently diagnosed, BD does not manifest as such typically until at least adolescence. PMID- 17688005 TI - Adult bipolar disorder is continuous with pediatric bipolar disorder. AB - Considerable debate exists regarding the continuity of bipolar disorder (BD) in children and adolescents. Do affected children continue to have BD as adults? Are pediatric forms of BD distinct from adult forms of the disorder? Here, I argue that, in fact, strictly defined BD I and II in children and adolescents is continuous with adult BD. First, if we take developmental differences into account, children and adults share similar symptoms, since they are both diagnosed according to DSM-IV criteria. Next, retrospective studies indicate that 50% to 66% of adults with BD had onset of their disorder before age 19 years. Early prospective data indicate that adolescents with BD progress to become young adults with BD. Further, family studies of pediatric BD probands find high rates of BD in adult relatives, and pediatric offspring of parents with BD have elevated rates of BD, compared with control subjects. Finally, biological characteristics of pediatric BD (such as treatment response, neurobiology, and genetics) are either shared with adults having BD or fit logically into developmental models of BD. Thus, while not conclusive, a preponderance of data support the hypothesis that pediatric BD is continuous with adult BD. Prospective studies incorporating phenomenological and biological assessment are needed to decisively address this issue. PMID- 17688006 TI - Geographical variation in the prevalence of problematic substance use in Canada. AB - OBJECTIVE: The prevalence of substance-related problems has been shown to vary between Canadian provinces, but little else is known about the pattern of geographical differences. In this study, we modelled these differences, using methods of spatial analysis, and attempted to determine whether they are explained by known risk factors. METHODS: We used data from Cycle 1.2 of the Canadian Community Health Survey. We tested interprovincial differences, before and after adjustment for covariates, and also examined differences between urban areas. We then used interpolation techniques to model variation in prevalence without reference to administrative boundaries. Finally, we performed a spatial cluster scan for areas of heightened prevalence. RESULTS: The prevalence of problematic substance use is lower in Ontario and Quebec than in the rest of the country. This pattern is due principally to low prevalence in Toronto, Montreal, and surrounding areas. Prevalence is higher in mid-sized cities than in larger ones or in rural areas. Problematic substance use shows a fairly high degree of spatial clustering, especially within major cities. Interprovincial differences and clustering are generally not explained by known risk factors. CONCLUSIONS: The pattern of large-scale differences is consistent with existing research and is probably part of a larger disparity among regions of Canada. The persistence of variation after adjustment for covariates suggests the influence of unmeasured, geographically varying factors, of which there are several candidates, including latitude and immigrant settlement patterns. PMID- 17688007 TI - Recurrent depressive symptomatology and physical health: a 10-year study of informal caregivers of persons with dementia. AB - OBJECTIVE: To examine the degree to which recurrent depressive symptomatology predicts the decline in the health status of a randomly derived national sample of caregivers of persons with dementia. METHOD: Individuals with dementia and their caregivers were recruited from each Canadian province as part of a national epidemiologic study of dementia prevalence and the health and welfare of care providers. Both patients and caregivers were assessed at 3 points over a 10-year period. Cohabiting family members who shared the same residence as care recipients were selected for the current study (n = 96 pairs). We computed a repeated measures analysis of variance to compare the health of caregivers who were consistently asymptomatic for depression, of those symptomatic at 1 of 3 points of measurement, and of those symptomatic at 2 of 3 points. RESULTS: As hypothesized, caregivers presenting with elevated depressive symptomatology at multiple points of measurement reported poorer and worsening physical health over time. CONCLUSIONS: The results of this study support the assertion that depressive symptomatology significantly predicts the decline in health status of caregivers of persons with dementia. Concerted effort to treat depression in this population is warranted to forestall this trajectory of decline and premature patient institutionalization. PMID- 17688008 TI - Depression literacy in Alberta: findings from a general population sample. AB - OBJECTIVE: To assess the public's knowledge about depression, attitudes toward treatments for depression, perceived causal factors for depression, and reported prognoses of depression, overall and by sex. METHODS: We conducted a cross sectional telephone survey in Alberta between February and June 2006. We used a random phone number selection procedure to identify a sample of adults in the community (n = 3047). Participants were presented with a vignette describing an individual with depression and then asked questions to assess recognition of depression, attitudes toward mental health treatments, possible causal factors for depression, and prognosis of depression. RESULTS: The response rate was 75.2 %. Among the final participants, 75.6% could correctly recognize depression described in a case vignette. General practitioners or family doctors were considered as being the best help for depression. Of the participants, 35% were in complete agreement with health professionals about appropriate interventions for depression, 28% believed in dealing with depression alone, and 43% thought that "weakness of character" was a likely cause of depression. Men had poorer mental health literacy than women and were more likely to endorse the use of alcohol to cope. CONCLUSIONS: Mental health promotion and education efforts are needed to improve the general public's mental health literacy and to clarify misunderstanding about depression. Men need to be a particular target of these efforts. PMID- 17688009 TI - Impairment of autonoetic awareness for emotional events in schizophrenia. AB - OBJECTIVE: To investigate the subjective states of awareness accompanying recognition of emotional events in patients with schizophrenia. METHOD: During the learning phase, a set of neutral pictures associated with emotional sentences was presented to 24 patients with schizophrenia and 24 healthy control subjects. During the test phase, participants had to recognize target pictures and valence and to report their subjective state of awareness (Remember, Know, or Guess) associated with recognition of pictures and valence. RESULTS: Patients with schizophrenia exhibited poor recognition of pictures and emotional valence. The frequency of Remember responses associated with recognition of pictures and of valence was lower in patients than in control subjects. CONCLUSIONS: Autonoetic awareness for emotional events is reduced in schizophrenia, with patients presenting difficulties in consciously recollecting the specific details that make events emotional. PMID- 17688010 TI - Clozapine-induced seizures: recognition and treatment. AB - OBJECTIVES: To inform clinicians about the types of seizures that can be induced by clozapine and to provide recommendations for treatment. METHODS: We identified articles on clozapine-induced seizures from a MEDLINE search of the English language literature from 1978 to July 2006. The frequency of each type of seizure and the dosages of clozapine associated with seizures were compiled. In addition to this review, we report a new case illustrating the challenge of diagnosing subtle seizure activity. RESULTS: The tonic-clonic variety is the most frequently described clozapine-induced seizure. Myoclonic and atonic seizures together constitute about one-quarter of the reported seizures. The mean dosage of clozapine associated with seizures is not high (less than 600 mg daily). CONCLUSIONS: It may be difficult for clinicians to recognize subtle types of clozapine-induced seizures, such as myoclonic, atonic, or partial seizures. Clinicians should not place excessive reliance on the plasma level of clozapine or electroencephalogram findings to predict the occurrence of seizures. When a first seizure occurs, it is recommended that the dosage of clozapine be reduced or an alternative antipsychotic agent be employed. If a second seizure occurs, an anticonvulsant drug should be started. Special attention should be paid when commencing or discontinuing concurrent medication that may affect the plasma level of clozapine. PMID- 17688011 TI - Benefits of enriched intervention compared with standard care for patients with recent-onset psychosis: a metaanalytic approach. AB - OBJECTIVE: To assess the effectiveness of enriched intervention (EI) on symptomatic and functional outcomes, compared with standard care (SC). METHOD: Studies were retrieved from search engines and, using a metaanalytic approach, we compared El trials with SC trials. Eleven EI sample trials (1053 patients) and 6 SC sample trials (500 patients), totalling data from 1553 patients (69% male), were examined. We calculated the effect sizes (ESs) of both symptomatic and functional improvement over a follow-up period of about 1 year. RESULTS: Significant differences between El and SC were observed at follow-up for the improvement of both positive and negative symptoms, respectively: positive, EI = 1.54 (95%CI, -1.63 to -1.45 ) and SC = -1.07 (95%CI, -1.19 to -0.94) (Qbetween = 40.3, df 1, P < 0.001); negative, EI= -0.44 (95%CI, -0.53 to -0.35) and SC = 0.18 (95%Cl, -0.31 to -0.05) (Qbetween = 10.6, df 1, P < 0.01). We also observed a significant difference between the El and the SC groups for functional improvement over the follow-up period with mean EI = 1.11 (95%CI, 0.99 to 1.23) and SC = 0.63 (95%CI, 0.49 to 0.77) (Qbetween = 24.5, df 1, P < 0.001). CONCLUSIONS: There is now quantitative evidence across multiple studies and sites to indicate that Els for patients with recent-onset psychosis are significantly more effective than SC for symptomatic and functional improvement over a period of about 1 year. PMID- 17688012 TI - Cannabis-induced psychosis among Aboriginal people in the Northwest Territories. PMID- 17688013 TI - Publicity for children's oral health: a perfect storm. PMID- 17688014 TI - Enough with "evidence based" titled articles. PMID- 17688015 TI - Sleep disordered breathing in infants and children: a review of the literature. AB - The objective of this report was to review the etiology, diagnosis, and treatment of sleep disordered breathing (SDB) in children and infants. English peer reviewed SDB literature identified by MEDLINE and a manual search conducted between 1999 and 2006 was selected. The keywords used for the search included: (1) children; (2) sleep disorder; (3) snoring; and (4) obstructive sleep apnea. A total of 153 manuscripts was identified. A delay in treatment of SDB children may be caused by several factors and may result in serious but generally reversible problems, including: (1) impaired growth; (2) neurocognitive and behavioral dysfunction; and (3) cardiorespiratory failure. Adenotonsillectomy is the treatment of choice, and continuous positive airway pressure may be an option for patients who are not candidates for surgery or who do not respond to surgery. Minimal information is available concerning the dental treatment of these disorders. With the devastating effects sleep disorders can have on children and their families, dentists must recognize obvious symptoms and refer these patients for management by physicians. PMID- 17688016 TI - Risk factors for early childhood caries in Canadian preschool children seeking care. AB - PURPOSE: The purpose of this study was to determine family characteristics, beliefs, and habits that contribute to early and severe caries in young children in Canada. METHODS: A survey was administered to: (1) parents of 139 children diagnosed with early childhood caries (ECC) in 5 pediatric dentistry practices in Canada over a 33-month period (group 1); and (2) parents of all normal referrals (carious and noncarious children) in one of the practices over a 3 month period (group 2). Group 2 prevented studying an exclusive or polarized population, and allowed direct comparison between children with decoy and without decoy. The survey responses were compared with caries rates in the children, determined by dental examination, to detect important correlations of family and child factors with the disease level. Chi-square and logistic regression analyses described the strength of the relationships. RESULTS: Parent responses provided information on: (1) demographics; (2) economic status; (3) birth order; (4) parental education; (5) payment methods; (6) feeding and weaning history; (7) fluoride history; (8) food habits; (9) hygiene; (10) behavior; and (11) medication use. Caries presence and severe caries was linked to: (1) leaving the bottle with a child while sleeping; (2) having problems brushing a child's teeth; (3) prolonged holding of liquids in the mouth; and (4) being Caucasian. The authors did find that bottle use in general and having a difficult child were protective influences against decay. CONCLUSIONS: The factors providing the most caries risk are: (1) being left with a bottle while sleeping; (2) parents having problems brushing the child's teeth; (3) holding liquids in the mouth for prolonged times; and (4) ethnicity. PMID- 17688017 TI - Dental screening of preschool children using teledentistry: a feasibility study. AB - PURPOSE: The purpose of this study was to assess the feasibility and reliability of using intraoral cameras and telehealth communication technology to screen preschool children for oral disease, in particular early childhood caries (ECC). METHODS: The authors used the existing infrastructure of the Health-e-Access telehealth Network to: (1) assess the diagnostic quality of dental images using the Dr. Camscope intraoral camera; and (2) compare the resulting images to a traditional oral examination. A calibrated dental examiner observed 50 preschool children 4 to 6 years old who were enrolled in an inner-city childcare center. Following the oral examination, images of the children's teeth were obtained by a trained telehealth assistant and transmitted to the remote site computer; identifiers were removed and the images were randomized. After a 2-week washout period, the images were read by the same examiner. RESULTS: A complete set of dental images was obtained from all 50 children in the study. A greater proportion of children examined using the intraoral camera were observed to have caries (42%) compared to children examined visually (28%). Furthermore, a greater number of carious teeth were detected from the images than from the visual examinations. The mean teledentistry dfs score was 2.10, and the oral examination 1.50 (P > .05). The kappa agreement was 61 (kappa = 0.61; 95% CI = 039-0.89). CONCLUSIONS: There was no statistically significant difference between a visual examination and an examination using an intraoral camera, thus suggesting that the intraoral camera is a feasible and potentially cost-effective alternative to a visual oral examination for caries screening, especially early childhood caries, in preschool children attending childcare centers. PMID- 17688018 TI - Analysis of the demographic characteristics of pediatric dental practice sites. AB - PURPOSE: The purposes of this study were to: (1) investigate the demographic characteristics of pediatric dental practice sites in the United States; and (2) develop a model that identifies practice site characteristics commonly associated with pediatric dental practices. METHODS: Demographic data and pediatric dental practices were organized by zip codes and analyzed using discriminant analysis. The demographic characteristics associated with zip codes that contained a pediatric dental practice were determined. RESULTS: The resulting model correctly classified 92% of the 30,134 zip code areas, based upon the presence or absence of a pediatric dental practice. The variables most closely associated with a zip code containing a pediatric dental practice included: (1) number of dental practices (general practice); (2) percent of the adult population with a college degree; and (3) population size. CONCLUSIONS: Demographic characteristics are predictive of sites with or without a pediatric dental practice. Zip codes with large, urban populations that have positive socioeconomic characteristics, such as high income and education levels, are the most likely to have a pediatric dental practice. There are a significant number of zip codes in the United States (1,712) that have the demographic characteristics associated with a pediatric dental practice site but do not have a pediatric dentist in them. PMID- 17688019 TI - Use of restraint and management style as parameters for defining sedation success: a survey of pediatric dentists. AB - PURPOSE: The purpose of this study was to identify factors that may influence current American Academy of Pediatric Dentistry (AAPD) members' definitions of a successful oral sedation. METHODS: Surveys were electronically mailed to all AAPD members with registered e-mail addresses, and printed surveys were sent via postal mail to all other members. The survey included: (1) items on demographic variables; and (2) questions on sedation methods and definition of success. RESULTS: The following response rates were recorded: (1) electronic survey = 26%; (2) printed = 45%; and (3) diplomate = 53%. The majority of members (55%) characterized their patient management style as being authoritarian. Sixty-seven percent agreed that the need to employ restraints when using sedation does not necessarily indicate that sedation is inadequate or unacceptable. When asked if such a sedation outcome could be defined as being successful, however, the agreement dropped to 47%. When defined as optimal, the respondents' agreement was further reduced to 36%. CONCLUSIONS: The practitioner's management style and use of restraint significantly influence how a dentist defines a successful sedation. PMID- 17688020 TI - Ultrastructural and microbiological analysis of the dentin layers affected by caries lesions in primary molars treated by minimal intervention. AB - PURPOSE: The purpose of this in vivo study of primary teeth was to analyze the ultrastructure and microbiology of dentin layers affected by caries lesions before and after restorations with resin-modified glass ionomer. METHODS: Samples of carious dentin from primary teeth removed prior to restoration placement (baseline-0 day) were compared with samples taken after 30 and 60 days. Dentin from 8 primary molars was analyzed by scanning electron microscopy (SEM) and dentin from 22 primary molars was examined microbiologically to compare bacteria (total of viable counts, Streptococcus spp, Streptococcus mutans, Lactobacillus spp, and Actinomyces spp) before and after treatment (30 and 60 days). RESULTS: Baseline caries samples had enlarged dentinal tubules with bacteriol invasion. SEM samples after treatment suggest better tissue organization, with more compact collagen fibers arrangement and narrower dentinal tubules. The number of bacteria decreased in all samples at both 30 (98%) and 60 (96%) days, with all bacteria species showing similar trends. CONCLUSIONS: The minimal intervention approach is very effective to promote beneficial changes in the lesion environment and favorable conditions for the healing process in primary teeth. PMID- 17688021 TI - The transpalatal arch: an alternative to the Nance appliance for space maintenance. AB - The loss of multiple primary molars in the primary or transitional dentition will, in many instances, lead to disturbances of the developing dentition. To prevent this, an appliance can be constructed to maintain the relationship of the remaining teeth and to guide the eruption of the developing teeth. Traditionally, the treatment of choice for maxillary loss is the placement of a Nance appliance. An alternative appliance that may be considered for use is the transpalatal arch or bar. The purpose of this clinical report was to describe the transpalatal arch appliance and present its advantages over the more common Nance appliance, thus encouraging clinicians to prescribe its use in certain clinical situations. PMID- 17688022 TI - Characteristics of a pediatric patient with a capillary hemangioma of the palatal mucosa: a case report. AB - The purpose of this study was to report the case of a capillary hemangioma in a 12-month-old female. The lesion appeared: (1) erythematous to deep purple in appearance; (2) dome-shaped; (3) partially blanched with pressure; and (4) rapidly enlarged in the oropharyngeal region. Magnetic resonance imaging studies demonstrated the affected area and adjacent soft tissues. The lesion was diagnosed as a capillary hemangioma through histopathology. Early detection and biopsy is necessary to determine the clinical behavior of the tumor and potential dentoalveolar complications. PMID- 17688023 TI - Toothbrush bristle wear and adherence of Streptococcus mutans. AB - PURPOSE: The purpose of this study was conducted to determine if bristle wear impacts the adherence of Streptococcus mutans on toothbrushes and to evaluate whether it affects the extent of adherence at 0, 8, and 24 hours after air drying. METHODS: Sixty toothbrushes--composed of 20 each from 3 different groups and defined by brand, brush trim, and head shape--were used in this study. Bristle wear on half of the toothbrushes was achieved using an orthodontic typodont with metal bonds and brackets and evaluated by 4 independent observers. New and worn toothbrushes were inoculated with 5 mutans, rinsed in tap water, and air-dried for 0, 8, and 24 hours. Four tufts were removed from the brush heads at each time point, placed in saline and vortexed to remove bacteria. Bacteria were aerobically grown on Mitis Salivarius Agar plates until colony-forming units could be counted. RESULTS: The toothbrush group impacts adherence of 5 mutans on both new and worn toothbrushes at 0, 8, and 24 hours after air-drying, with new toothbrushes harboring significantly more S mutans than worn toothbrushes at 0 hours. CONCLUSIONS: The results have implications for the design of toothbrush tufts as well as storage of toothbrushes in the home. PMID- 17688024 TI - Oral and dental findings in children with Fanconi anemia. AB - PURPOSE: The purpose of this study was to investigate the oral and dental findings in children with Fanconi anemia (FA). METHODS: The study included 26 FA patients who came to the hospital (Hacettepe University Faculty of Medicine, Pediatric Hematology Unit) from the central region of Anatolia (17 [65%] mole, 9 [35%] female; mean age = 10.0 +/- 5.2 years (range = 2-18; median = 9 years]). Oral and radiological examinations and salivary collection were performed at the Department of Pediatric Dentistry of Hacettepe University Faculty of Dentistry. RESULTS: Among 26 FA children: (a) 16 (62%) had never visited a dentist; (b) 6 (23%) had visited a dentist once; and (c) 4 (15%) had visited a dentist regularly. Furthermore: (a) only 5 children (19%) brushed their teeth regularly; (b) 7 (27%) had never brushed their teeth previously; and (c) the other 14 (54%) had brushed their teeth rarely. The prevalence of dental caries was 35% in this study's patients. Gingival examination revealed that 9 (35%) children had gingivitis and the other 17 (65%) had normal gingival health status. Examination of the oral cavity revealed that: (a) 3 children (12%) had a coated tongue; and (b) 1 (4%) had papillary atrophy. No leukoplakia or other precancerous lesion was detected in this patient group. Salivary flow rate was less than 0.7 ml/minute in 56% of the patients. No patients had a salivary pH less than 5. Salivary buffering capacity of less than 5, however, was detected in 5 patients (33%). Radiological evaluation revealed that the most common congenital dental abnormalities were: (1) microdontia (44%); (2) congenitally missing teeth (26%); (3) transposition (9%); and (4) supernumerary teeth (4%). CONCLUSION: These results demonstrate that poor oral hygiene, dental decay, gingivitis, and congenital dental abnormalities--including generalized microdontia, supernumerary teeth, transposition, and congenitally missing teeth--are common oral and dental findings in this group of Turkish children with Fanconi anemia. PMID- 17688025 TI - Recall rates and caries experience of patients undergoing general anesthesia for dental treatment. AB - PURPOSE: The purpose of this study was to evaluate the recall rate and caries experience of children seen under general anesthesia (GA) at The University of Iowa Hospitals and Clinics. METHODS: After a retrospective chart review, information from 217ASA (American Society of Anesthesiologists) 1 patients undergoing GA between 1998 and 2002 was gleaned regarding: (1) date of GA; (2) age at time of GA; (3) follow-up (recall) visits; (4) referral status; (5) new caries experience; and (6) treatment of new/recurrent lesions. A 19-question survey was also mailed to parents/legal guardians for satisfaction. RESULTS: Survey data were not reported in this study due to the poor (25%) return rate after several attempts: 41% of the patients were referrals; 54% returned for a 2 week postoperative visit, but only 13% returned for a 6-month recall, with subsequent recoils being even lower; 72% were insured by Medicaid; and 25% had recurrent or new lesions at follow-up appointments. CONCLUSION: Recall rates after general anesthesia for dental treatment at a university hospital are very low, and new or recurrent caries experience is high. PMID- 17688026 TI - [Chondrofibrosis of adolescent hip]. AB - Authors present 420 hips with slipped capital epiphysis treated in the IOHB "Banjica", during the period between 1970 and 2005. Research includes the analysis of incidence, diagnostics and causes which contribute to the genesis of hip chondrofibrosis. Risk factors are shown, as well as the approach to eliminate them. 39 hips in which this complication occured were individually analyzed. Every hip was separately studied with intent to determine the cause of the condition's genesis, it's evolution, treatment and it's final functionality result. Synovia biopsy was performed in 7 cases, as well as the biopsy of the capsule, articular hyaline cartilage and subchondral bone of the femoral head, which enabled detailed description of both microscopic and macroscopic changes that follow this condition. Regardless of still hypothetical comprehension of the inception of chondrofibrosis, authors clearly state all the risky procedures during treatment that can contribute to the development of chondrofibrosis. The importance of early diagnostics and well-timed treatment are highlighted in this article, for they are crucial. Results of treated hip chondrofibrosis presented here give hope for the destiny of the ill joint, which was considered highly uncertain for a long time. PMID- 17688027 TI - [Developmental dislocation of the hip is still important problem--therapeutic guidelines]. AB - The authors are describing currently important problem--developmental dislocation of the hip. Guidelines for the treatment have been given according to literature date and upon their own experience. Therapeutic suggestions for the first twelve months of life are based on the ultrasound typing--it is advised to perform nonoperative treatment (abduction devices, "over head" traction, Pavlik harnesses). During the second year of life a pause in the treatment should be adviced in order to avoid postreduction avascular hip necrosis as a very important complication. After that period surgical treatment has to be done (open reduction, pelvic and femoral osteotomies). Special suggestions have been given for the treatment of consecutive leg length inequality and the deformities caused by postreduction avascular hip necrosis. PMID- 17688028 TI - [Choice of operative procedures to correct equinus deformity in patients with cerebral palsy]. AB - Equinus deformity of the foot presents a great number of difficulties to ambulant patients with cerebral palsy. Non-operative treatment of the incorrectible - fixed equinus is not successful. Many procedures are applied to treat it operatively, so its not clear which procedure at what age is the most successful. The purpose of this manuscript. is to clarify the issue. The results of four procedures are analyzed: aponeurectomny of m. gastrocnemius, Achilles tendon lengthening by z-plasty, a combination of these two procedures and sliding elongation of m. triceps surae. The analysis was based on 417 operations in 291 patients of the average age of 9 years (1-64). The average followup was 7 years. The assesment of the results was based on the visual evaluation of the gait, on pedoscope prints and on comparison of ankle movements before and after operation. The analysis shows that the best results were achieved by sliding elongation of m. triceps surae after the age of 7. PMID- 17688029 TI - [The treatment of infected diaphyseal femoral defects by lengthening one of the bone fragments by Ilizarov]. AB - We analyzed 30 patients with infected diaphyseal defect of femur, which have been treated by lengthening one of the bone fragments with Ilizarov apparatus. The mean length of the bone defect was 6 cm. Substitution of the defect, bone healing and elimination of the infection was achieved in 27 patients. The mean time of apparatus fixation was 10 months. According to Palley scoring system, 10 patients had excellent functional results. PMID- 17688030 TI - [Differences in the rehabilitation period following two methods of anterior cruciate ligament replacement: semitendinosus/gracilis tendon vs ligamentum patellae]. AB - In this study we have analyzed outcome during the early rehabilitation period phase following two different methods of anterior cruciate ligament (ACL) reconstruction: ligamentum patellae (LP) and semitendonosus/gracilis tendon (SG) based reconstruction. This study included 40 patients treated by each method, examined 6 weeks and 3, 6 and 12 months after surgery. Patients in the SG group showed significantly better Lysholm scores at 6 and 12 months, Tegner Activity Scale scores at 3 months, and pain profile assessments at 6 weeks and 3 months than those in the LP group. Significant differences were observed in LP group in range-of-motion at 6 weeks and 3 and 6 months post-surgery. Stability tests revealed no significant differences between patients in the two groups. SG-based reconstruction of the ACL thus demonstrated advantages over LP-based reconstruction regarding pain and function, while LP-based reconstruction was associated with an earlier return of motion. PMID- 17688031 TI - [Anterior cruciate ligament reconstruction: comparison of male and female athletes using the patellar tendon and hamstring autografts]. AB - Few authors have studied the effects of gender on the outcome of ACL reconstruction in athletes. This retrospective-prospective study compared the treating results using the patellar tendon (LP) and hamstring (StG) techniques in men and women. We followed 40 athletes (23 males, 17 females) from population of 120 patients operated at Institute for Orthopaedic Surgery Banjica. There were 13 males and 7 females in the LP group and 11 males and 9 females in the StG group. Patients were operated by the same surgeons within 6 month from injury and underwent the same rehabilitation program. After an average of 24 months they were assesed by clinical evaluation, knee laxity analysis and standard knee scores. Among LP patients there were no significant differences between males and females regarding knee evaluation form, laxity or functional tests. Females in the hamstring group had significantly grater laxity and significantly higher deficit in flexion and extension. We suggest further studies on the clinical significance of these findings, particularly on their ramifications of return to sports and rehabilitation of female athletes. PMID- 17688032 TI - [Effect of resection of the lateral retinaculum of the knee in surgical treatment of symptomatic patello-femoral incongruency]. AB - Biomechanical malfunction of the knee extensor mechanism in the patello femoral joint is regarded as patella malalignment but major patients complaints are anterior knee pain and patellar slipping. Lateral retinacular release is one of the basic surgical procedures in the treatment of patellar malalignment. The aim of the study was to estimate the achievements of the lateral retinacular release in solving particular biomechanical disorders of the patello femoral joint, as well as individual patients complaints. Evaluation of objective parameters x-ray and clinical findings before and after the operation, shows statistically highly significant difference, thus confirming implementation of the fore mentioned surgical procedure. Despite the fact that anterior knee pain subsided postoperatively in the number of patients, statistically significant values, comparing to the preoperative findings, could not be obtained. Incidence of the patellar slipping has shown statistically significant reduction two years following the surgery. Achieving proper biomechanical alignment of the patello femoral joint is obviously not sufficient to provide relief of subjective complaints, especially concerning anterior knee pain, although considerable improvements were registered in the number of patients. PMID- 17688033 TI - Low back pain--differential diagnosis, prognosis and treatment. AB - From January 2002 to February 2003, 137 patients complaining of low back pain were treated at the Institute for Orthopedic Surgery "Banjica", Belgrade, Serbia. There were 89 male and 48 female patients aged 13 to 77, mean age 42.2. Their condition was diagnosed through use of radiography, CT, MRI, EMNG, standard battery of neurological tests, and laboratory analyses (urine and blood analysis). Surgical treatment was performed on 39 patients; all other patients received some form of non-surgical care (physical therapy, medication or corset). Treatment efficacy was evaluated by use of the visual analog scales (VAS) and the Oswestry index, before and after treatment. The use Wilcoxon's pair test revealed statistically significant difference between before and after treatment data on VAS and Oswestry index for all patients. PMID- 17688034 TI - [Minimal incision total hip joint arthroplasty]. AB - "Minimaly-invasive" total joint arthroplasty have been widely introduced to the orthopaedic community several years ago. The concept has received a great attention and has been greeted variably with enthusiasm, concern, and skepticism. Numerous meetings, scientific exibits, symposia and congreses has been taking place all around the world. Whether this represents the future of orthopaedic surgery or just a fad, the term "minimaly-invasive" or "minimaly-incision" are yet to be clear and establish. Our intention is to present 72 of first 100 cases of total hip arthroplasty performed by "minimaly-incision" surgery. In our opinion first results are positve and we intend to continue with this kind of surgery. PMID- 17688035 TI - [Antebrachial reverse island flap of the posterior interosseus artery pedicle for reconstruction of thumb defects]. AB - Fasciocutaneous lobe on AIP ( a. interossea posterior) is characterized by thin skin, good texture and satisfactory pedicle lenght, which enables the repair of numerous hand defects. It can be either loose or reversed on the pedicle. We present here 2 neglected cases of thumb injury in which there was a need to compensate the full thickness of the skin. We believe that thumb defects can be repaired with both functionally and esthetically good effects using AIP lobe. PMID- 17688036 TI - [Treatment of unreduced posterior dislocations of the shoulder]. AB - Unreduced posterior dislocations of the shoulder are rare and difficult to treat. Treatment depends of defect of the humeral head. Since 1997 to 2002 eleven patients were referred to us for treatment unreduced posterior dislocations of shoulder with impressed fracture of the humeral head. Dislocations have lasted between two to eight months. All patients were treated with open reduction. Allograft reconstruction of the defect was used in six and hemiarthroplasty in two cases. As assessed with the scoring system of Constant, patients were rated excellent (9), satisfactory (1), unsatisfactory (1). Allograft reconstruction is the optimal choice for defects involving 20% to 45% of the humeral head. Prosthetic replacement is preferred for larger defects. Reconstruction of the defects involving less than 20% of the humeral head is not necessary. The observation is only ment to serve as a guide during decision making. The surgeon must make his own surgical choice based on the individual patient factors and on the intraoperative findings. PMID- 17688037 TI - [Treatment of resistant frozen shoulder by manipulation under anesthesia, intermittent interscalene blocks and protocol of kinesitherapy (Banjica)]. AB - Treatment of frozen shoulder resistant to conservative therapy is complex problem. Manipulation under anesthesia is undertaken if at least 3 months of physical therapy fails to improve mobility of the shoulder. Maintaining the increased range of montion after manipulation is not easy to acheive. The main reaxon is the pain, which prohibits optimal physical therapy were treated between 2001 and 2003. The treatment consisted of manipulation in conjunction with intermittent interscalene blocks followed by protocol of kinesitherapy named Banjica. At final follow up, 95% of the elevation and 81% of the external rotation achieved intraoperatively were maintained. PMID- 17688038 TI - [Posterior femoral cortex perforation unrecognised during arthroscopic LCA reconstructive surgery]. AB - One of the most important technical demands in ACL surgery is good fixation of the graft. Integrity of the posterior femoral cortex is necessary for Interference screws fixation. The femoral tunnel, placed as posterior as possible, is also mandatory for good graft position and potentially leads to violation of the cortex. The divergence between screw and tunnel could result in perforation of the posterior wall. Without intraoperative x-ray it is difficult to be sure that position of the screw is correct, even with good graft tension. Still, the problem exists with absorbable screws. The aim of the study is to show results of 6 patients with this complication treated without revision of the femoral fixation with mean follow up of 1.5 year. Potential pitfall in ACL reconstruction is posterior cortex breakout and loss of fixation. If it is recognized during surgery changing the type of fixation can solve the problem, but if not, in the early phase of rehabilitation and weight bear, graft failure is feasible. The tibia tunnel angle and length, the footprint of femoral tunnel reamer and hyper flexion of the knee during screw insertion are methods for preventing the breakout of the posterior wall and screw-tunnel divergence. Modification of the early postoperative treatment and less aggressive rehabilitation protocol reduced the need for revision surgery. Even with best surgical technique, skill and experience this complication is possible to occur. PMID- 17688039 TI - [Influence of morphometric intercondylar notch parameters in ACL ruptures]. AB - The most important anatomic risk factors in ACL lesions are the morphometric parameters of intercondylar notch. In the morphometric studies index of notch width and index of notch shape (NWI and NSI) are commonly used. The certain morphologic parameters of distal femoral part are used in calculation. Beside standard parameters we measured the maximal width of intercondylar notch and distal part of femur, which we used for calculation of maximal index of notch width and maximal index of notch shape (NWI max and NSI max). We compared two different methods of calculation of intercondylar notch indexes to find out which one represent anatomic risk factor and influence the ACL lesions. The indexes were measured in the two groups of patients (33) who have the history of knee injuries, the first group has document of ACL injuries and the second without ACL injuries (control one). The important difference between two groups was founded in NWI (p < 0.01) and NSI (p < 0.05). NWImax and NSImax do not show the difference (p > 0.05). The NWI and NSI importance is higher in males, and smaller in females. There is no difference in NWImax and NSImax (p > 0.05) comparing to the gender. PMID- 17688040 TI - [Orthopedic injuries in polytrauma]. AB - Trauma is one of the leading causes of mortality in the world. Traumatic injury has a significant impact on the patient, socially, functionally and financially. Orthopaedic injuries are generally not life-threatening unless they result in significant hemodynamic instability. The outcome of the orthopaedic injuries might lead to mild or severe disability and lost quality of life. Therefore, the orthopaedic surgeon has significant role in treatment of trauma patient. In order to control and prevent traumatic injuries, to improve quality of trauma treatment and outcome, including the costs the National trauma registry is essential. The aim of the study was to collect the datas about the frequency of orthopaedic injuries in polytraumatised patients who were treated in intensive care unit of Emergency Center of Serbia in last two years. There were significant number of orthopaedic injuries (53.2%) in polytraumatised patients. The major cause of the injuries is traffic (78.6%) and most patients were between 30-50 years (30%). PMID- 17688041 TI - [Massive hemorrhage and mechanisms of coagulopathy in trauma]. AB - Trauma is disease of the young, mainly affecting people between 15-40 years of age. Uncontrolled massive bleeding is the leading cause of early in-hospital mortality, within 48h of admission, and the second leading cause of prehospital death in victims of both military and civilian trauma, accounting for 40-45% of the total fatalities. Coagulopathy develops early after injury and is present in 25-36% of trauma victims upon admission to the emergency department. Coagulopathy correlates to the severity of trauma and is associated with an increased risk of mortality. The aim of this paper is to explain pathophysiology of developing coagulopathy in trauma. The coagulopathy in the trauma patient is complex and multifactorial. It includes: dilutional coagulopathy, hypothermia, acidosis, hyperfibrinolysis, anemia and consumption coagulopathy. When the patient develops the so called "lethal triad" of hypothermia, acidosis and coagulopathy, surgical restoration of vascular integrity may be insufficient to achieve a deffinitive control of blood loss and non-mechanical bleeding from small vessels, usually terminated by spontaneous coagulation, becomes a life-threatening condition. PMID- 17688042 TI - [Validity of clinical and ultrasound findings in relation to arthroscopic findings of new injuries of the anterior cruciate ligament of the knee]. AB - Injuries of anterior cruciate ligament are constantly present in sports, but also in common life activities. Diagnostic procedures which are available today in diagnosis and estimation of severity of intraarticular knee structures, are numerous, but they are not available, plausibile and valid in the same manner. Aim of this study was to compare diagnostic validity of clinic and ultrasound examination related to arthroscopy in "fresh trauma: of anterior cruciate ligament This prospective study contains analysis 205 hospitalised patients treated from 2004 to 2006 at IOS "Banjica" Beograd and SOSH "Decedra" Beograd in matter of arthroscopy. Before the arthroscopy, clinical and ultrasound examination was performed. Values of sensitivity(87.1%), specificity(97.7%), positive (98.2%) and negative predictive value (84.3%) of ultrasound examination are affirmative in high reliability of this diagnostic procedure in a diagnosis of fresh lesions of anterior cruciate ligament. PMID- 17688043 TI - [Digital video technology in orthopedics]. AB - Digital video technologies are new and powerful tools with wide applications in orthopaedics. Already integral to several common medical devices, digital images can be used for case documentation and presentation as well for diagnostic and surgical patient care information. Digital technologies allow easy manipulation of photographic, video and graphic materials in ways that were impossible with conventional techniques. Educational presentation has been transformed by use of computers and digital projectors. Understanding the basic foundations of digital imaging technology is important for effectively creating digital images, videos and presentations. In this review, we are going to discuss some of the issues that are raised by digital imaging in orthopaedics, digital image processing, as well as, we are giving some recommendations for good quality of pre-, post- and intra-operative photographs in clinical use. PMID- 17688044 TI - [Functional and radiographic results in partial unipolar hip joint arthroplasty after 6-15 years]. AB - Due to extreme conditions during civil war in early 1990's we were forced to deviate from accepted guidelines in treatment of intracapsular fractures of the femoral neck. Therefore, majority of patients were treated non-operatively. In those that were subjected to surgery, unipolar hemiarthroplasty was treatment of choice, since conditions permitted us to attempt osteofixation in very few, youngest of our patients. As a result of this practice born of necessity, we can now look back and learn from this unique experience. PMID- 17688045 TI - [Our experience of postoperative saving of drainage blood in orthopaedic surgery]. AB - Postoperative saving of drainage blood presents postoperative autologous transfusion and that means group of action of collection patients blood and its late reinfision. The conditions of orthopaedic surgery join with arthroplasty of coxae and knee are connected with signicifant loss of blood (800-1200 ml). With the aim of reducing the need for use of heterologous blood and elimination of potentional risks because of her application, we investigate the possibility of application the system of posteoperative saving of drainage blood in the study group of 48 patients in relation of control group of 25 patients. Postoperative blood saving has been derived after the first 4-8 hours, after the and of surgical operation. In the study group only 4 patients (8%) need additional heterologous transfusions. Postoperative blood saving and its reinfusion have not significant effect at hemostasis and sistem of coagulation. During six months postoperative, no patients in the study group have not any complication after orthopaedic surgery. PMID- 17688046 TI - [Primary total hip arthroplasty in patients with rheumatoid arthritis]. AB - Total hip arthroplasty has become a successful way of treating the painful and destroyed hip joint in the patient with rheumatoid arthritis (RA). Two hundred twenty (135 cemented and 85 noncemented) total hip arthroplasties were performed in 180 patients with rheumatoid arthritis. The average age was 48.61 years and the average follow-up was 8.4 years. Clinical evaluation was based on a Harris hip score that showed significant improvement in pain and function preoperatively compared with pain and function at followup. There were two deep infections requiring removal of the prosthesis. Four cemented acetabular cups and one cemented femoral component were revised due to aseptic loosening. Three acetabular rings were revised due to aseptic loosening. The relatively inferior results of total hip arthroplasty among RA patients is due not only to fixation method, but also to the poorer bone quality and weakening musculature. The results in these patients suggest that cementless total hip arthroplasty might become a successful way of treating the destroyed hip joint in the patient with rheumatoid artritis. PMID- 17688047 TI - [Arthroscopy of the hip--surgical treatment of synovial osteochondromatosis]. AB - The hip arthroscopy is an efficient procedure in treatment of synovial chondromatosis in selected patients. The advantages compared to open procedures are lesser operative moribidity and faster postoperative recovery. PMID- 17688048 TI - [Indications for nonoperative and operative treatment of intra-articular fractures of the calcaneus]. AB - Historically, intra-articular calcaneal fractures have been managed, as a rule, nonsurgically, although surgical treatment has more advocates in the past 20 years. Even today many high specialized orthopedic surgeons have a lot of controversies relating the indications fields of nonsurgical and operative treatment of these fractures. For getting correct decision adequate preoperative evaluation of fracture type, overall patients health and his Generally, elderly patients with sedentary habits, without or with minimal fracture displacement, might be treated successfully with nonsurgical management. Good result after surgical treatment might be predicted in patients younger than 40 years, with a simple fracture pattern and high probability of achieving anatomic reduction. Highly precise and good surgical technique is necessary for getting a good final result with a long learning curve of the surgeon. Smoking, diabetes, chronic medical illness, peripheral vascular disease as well workers compensation claim (!) markedly increase the risk of surgical complications. PMID- 17688049 TI - Occipitocervical fusion with rigid internal fixation: long-term follow-up data in 69 patients. AB - OBJECT: Instability of the occipitocervical junction may result from degenerative disease, infection, tumor, and trauma. Surgical stabilization involving screw fixation and rigid implants has been found to be biomechanically superior to wire based implants. To evaluate the long-term results in a large and diverse patient population, the authors prospectively studied a consecutive group of 69 patients. METHODS: All patients underwent occipitocervical fusion in which rigid posterior instrumentation included either plates or rods and screws. Patients ranged in age from 11 to 90 years (mean 51.4 years); there were 34 female and 35 male patients. The mean follow-up duration was 37 months (range 6-66 months). Fifty-seven (83%) of the 69 patients had long-standing occipitocervical anomalies, whereas the remainder presented with acute instability. Basilar invagination was present in 20 patients. RESULTS: Correction of a severe cervical kyphotic deformity was accomplished in six patients. There were no fatalities or medical complications associated with the procedures. During the follow-up period, 87% of the patients exhibited improvement in their myelopathic symptoms; in 13% the symptoms were unchanged. Complications were minimal. Stability was demonstrated on flexion/extension studies in all cases. There were no treatment-related deaths, although four patients died within the follow-up period, all due to progression of metastatic disease. CONCLUSIONS: The authors found that rigid internal fixation of the occipitocervical complex was safe, effective, and technically possible for spine surgeons familiar with occipital bone anatomy and lateral mass fixation. PMID- 17688050 TI - Dysphonia and dysphagia after anterior cervical decompression. AB - OBJECT: In this paper, the authors investigate the effects of anterior cervical decompression (ACD) on swallowing and vocal function. METHODS: The study comprised 114 patients who underwent ACD. The early group (50 patients) was examined immediately pre- and postoperatively, and the late group (64 patients) was examined at only 3 to 9 months postoperatively. Fifty age- and sex-matched patients from the Department of Otorhinolaryngology-Head and Neck Surgery who had not been intubated in the previous 5 years were used as a control group. All patients in the early and control groups were examined by a laryngologist; patients in the late group were examined by a laryngologist and a neurosurgeon. Videolaryngostroboscopy was performed in all members of the patient and control groups, and the function of the ninth through 12th cranial nerves were clinically evaluated. Data were collected concerning swallowing, voice quality, surgery results, and health-related quality of life. Patients with persistent dysphonia were referred for phoniatric evaluation and laryngeal electromyography (EMG). Those with persistent dysphagia underwent transoral endoscopic evaluation of swallowing function and videofluorography. RESULTS: Sixty percent of patients in the early group reported dysphonia and 69% reported dysphagia at the immediate postoperative visit. Unilateral vocal fold paresis occurred in 12%. The prevalence of both dysphonia and dysphagia decreased in both groups 3 to 9 months postoperatively. All six patients with vocal fold paresis in the early group recovered, and in the late group there were two cases of vocal fold paresis. The results of laryngeal EMG were abnormal in 14 of 16 patients with persistent dysphonia. Neither intraoperative factors nor age or sex had any effect on the occurrence of dysphonia, dysphagia, or vocal fold paresis. Most patients were satisfied with the surgical outcome. CONCLUSIONS: Dysphonia, dysphagia, and vocal fold paresis are common but usually transient complications of ACD. Recurrent laryngeal nerve damage detected by EMG is not rare. Pre-and postoperative laryngeal examination of ACD patients should be considered. PMID- 17688051 TI - Factors influencing segmental range of motion after lumbar total disc replacement using the ProDisc II prosthesis. AB - OBJECT: The purpose of this prospective controlled study was to evaluate possible factors that could affect postoperative segmental range of motion (ROM) after lumbar total disc replacement (TDR) using the ProDisc II prosthesis. METHODS: Thirty-two consecutive patients with intractable discogenic pain underwent lumbar TDR using the ProDisc II prosthesis, 30 of whom were followed up for at least 24 months. Segmental ROM was assessed preoperatively and every 6 months postoperatively using dynamic x-ray films. Segmental ROM at the reference level was assessed in relation to patient age, sex, body mass index (BMI), levels with implants, preoperative ROM, prosthesis size, and prosthesis position. RESULTS: At the last follow-up visit, mean ROM of the disc prostheses was significantly increased from 4.23 +/- 3.12 degrees to 6.81 +/- 3.76 degrees at L3-4, and from 3.66 +/- 2.47 degrees to 6.09 +/- 2.11 degrees at L4-5. Mean ROM at L5-S1, however, was decreased from 3.12 +/- 1.56 degrees to 2.86 +/- 1.26 degrees (p > 0.05). This difference in the changes in postoperative ROM between L5-S1 and the other operated levels was the only statistically significant factor (p = 0.025) among the variables related to the postoperative ROM that the authors assessed, but other factors such as patient age, sex, BMI, disc height, and the size and position of the prosthesis were not related to segmental ROM. CONCLUSIONS: The data demonstrate that after TDR using the ProDisc II prosthesis, ROM of the prosthesis at L5-S1 is significantly lower compared with ROM at the other levels. In preserving ROM, the advantage of lumbar TDR using the ProDisc II might be minimal at L5-S1. Among the variables related to postoperative ROM, the level at which the ProDisc II prosthesis was implanted was the only one found to be statistically significant. PMID- 17688052 TI - New prognostic factors for adjacent-segment degeneration after one-stage 360 degrees fixation for spondylolytic spondylolisthesis: special reference to the usefulness of pelvic incidence angle. AB - OBJECT: The purpose of this study was to evaluate the correlation between adjacent-segment degeneration (ASD) and pelvic parameters in the patients with spondylolytic spondylolisthesis. Sagittal balance is the most important risk and prognostic factor in the development of ASD. The pelvic incidence angle (PIA) is an important anatomical parameter in determining the sagittal curvature of the spine and in the individual variability of the sacral slope and the lordotic curve. Thus, the authors evaluated the relationship between the pelvic parameters and the ASD. Methods. Among 132 patients with spondylolytic spondylolisthesis who underwent surgery at their institution, the authors selected patients in whom a one-stage, single-level, 360 degrees fixation procedure was performed for Grade I spondylolisthesis and who underwent follow-up for more than 1 year. Parameters in 34 patients satisfied these conditions. Of the 34 patients, seven had ASD (Group 1) and 27 patients did not have ASD (Group 2). The investigators measured degree of spondylolisthesis, lordotic angle, sacral slope angle (SSA), pelvic tilt angle (PTA), PIA, and additional parameters pre-and postoperatively. The radiographic data were reviewed retrospectively. Results. The population consisted of nine men and 25 women whose mean age was 48.9 +/- 9 years (+/- standard deviation) (range 28-65 years). Seven patients developed ASD after undergoing fusion. Of all the parameters, pre- and postoperative degree of spondylolisthesis, segmental lordosis, lordotic angle, SSA, preoperative PTA, and preoperative PIA did not differ significantly between the two groups; only postoperative PTA and PIA were significantly different. Conclusions. The development of ASD is closely related to postoperative PIA and PTA, not preoperative PIA and PTA. The measurement of postoperative PIA can be used as a new indirect method to predict the ASD. PMID- 17688053 TI - Percutaneous fibrin glue therapy for meningeal cysts of the sacral spine with or without aspiration of the cerebrospinal fluid. AB - OBJECT: The authors assessed the efficacy of computed tomography (CT)-guided percutaneous injection of fibrin glue to treat meningeal cysts of the sacral spine in patients with back pain, and evaluated the necessity for cerebrospinal fluid (CSF) aspiration before glue injection. METHODS: Of the 31 patients in this study, 15 underwent injection of fibrin glue under CT guidance after aspiration of more than 15 ml of CSF (Group A), and 16 patients were treated with the glue but without CSF aspiration (Group B). Clinical results were evaluated after an average of 23 months of follow-up, and changes on the imaging studies were also evaluated. The clinical outcome and postoperative complications were analyzed. RESULTS: All 31 patients experienced resolution or marked improvement of symptoms for as long as 28 months after fibrin glue therapy. No patient experienced recurrence of symptoms during the follow-up interval. The postoperative pain relief was statistically significant (p < 0.001) according to evaluations in which a 100-mm visual analog pain scale was used. There were no statistical differences between the two groups (p > 0.05). CONCLUSIONS: Percutaneous CT guided fibrin glue therapy for sacral arachnoid cysts may be a definitive therapy. It is unnecessary to aspirate the CSF before injection of the fibrin glue. PMID- 17688054 TI - Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure. AB - OBJECT: The authors report data concerning the safety, effectiveness, and patterns of failure obtained in a Phase I/II study of stereotactic body radiotherapy (SBRT) for spinal metastatic tumors. METHODS: Sixty-three cancer patients underwent near-simultaneous computed tomography-guided SBRT. Spinal magnetic resonance imaging was conducted at baseline and at each follow-up visit. The National Cancer Institute Common Toxicity Criteria 2.0 assessments were used to evaluate toxicity. RESULTS: The median tumor volume of 74 spinal metastatic lesions was 37.4 cm3 (range 1.6-358 cm3). No neuropathy or myelopathy was observed during a median follow-up period of 21.3 months (range 0.9-49.6 months). The actuarial 1-year tumor progression-free incidence was 84% for all tumors. Pattern-of-failure analysis showed two primary mechanisms of failure: 1) recurrence in the bone adjacent to the site of previous treatment, and 2) recurrence in the epidural space adjacent to the spinal cord. Grade 3 or 4 toxicities were limited to acute Grade 3 nausea, vomiting, and diarrhea (one case); Grade 3 dysphagia and trismus (one case); and Grade 3 noncardiac chest pain (one case). There was no subacute or late Grade 3 or 4 toxicity. CONCLUSIONS: Analysis of the data obtained in the present study supports the safety and effectiveness of SBRT in cases of spinal metastatic cancer. The authors consider it prudent to routinely treat the pedicles and posterior elements using a wide bone margin posterior to the diseased vertebrae because of the possible direct extension into these structures. For patients without a history of radiotherapy, more liberal spinal cord dose constraints than those used in this study could be applied to help reduce failures in the epidural space. PMID- 17688055 TI - Motion in the unstable cervical spine: comparison of manual turning and use of the Jackson table in prone positioning. AB - OBJECT: The purpose of this study was to compare manual maneuvering with the use of a Jackson table when moving patients with cervical spine instability from the supine to the surgically appropriate prone position. METHODS: The range of motion (ROM) of the cervical spine of a fresh cadaver was measured. A ligamentous instability was created at the C5-6 level, and the increased ROM was confirmed. Sensors for an electromagnetic motion analysis device were fixed to the anterior portions of the C-5 and C-6 vertebral bodies (VBs) using machined polyethylene mounts and carbon fiber rods that were inserted into the VBs. The sensors were used to measure cervical flexion, lateral bending, and axial rotation during the two transfer procedures. The cadaver was then moved from the supine position on a hospital bed to the prone position for surgery. The manual technique was performed by four trained individuals who moved the cadaver from the hospital bed while rotating it 180 degrees axially onto the surgical table. In using the Jackson table, the cadaver was moved from the bed to the table in the supine position and then the Jackson table rotated the cadaver to the prone position. The two techniques were tested with and without the use of a collar and were repeated five times. RESULTS: Analysis of the data indicated that when moving a patient into the prone surgical position, the use of a cervical collar and the Jackson table significantly reduced the cervical motion in all angular planes compared with that of manual transfer. CONCLUSIONS: The use of a cervical collar and the Jackson table may reduce the possibility of further spinal cord compromise. Because manual transfers are performed routinely, this warrants further study. PMID- 17688056 TI - Wear simulation of the ProDisc-L disc replacement using adaptive finite element analysis. AB - OBJECT: An understanding of the wear potential of total disc replacements (TDRs) is critical as these new devices are increasingly introduced into clinical practice. The authors analyzed the wear potential of a ProDisc-L implant using an adaptive finite element (FE) technique in a computational simulation representing a physical wear test. METHODS: The framework for calculating abrasive wear, first validated using a model of a total hip replacement (THR), was then used to model the ProDisc-L polyethylene component that is fixed to the inferior endplate and articulates with the rigid superior endplate. Proposed standards for spine wear testing protocols specified the inputs of flexion-extension (6/-3 degrees), lateral bending (+/- 2 degrees), axial twist (+/- 1.5 degrees), and axial load (200-1750 N or 600-2000 N) applied to the model through 10 million simulation cycles. The model was calibrated with a wear coefficient determined from an experimental wear test. Implicit FE analyses were then performed for variations in coefficient of friction, polyethylene elastic modulus, radial clearance, and polyethylene component thickness to investigate their effects on wear. RESULTS: Using the initial loading protocol (single-peaked axial load profile of 300-1750 N) from the experimental wear test, the polyethylene wear rate was 9.82 mg per million cycles. When a double-peaked loading profile (600-2000 N) was applied, the wear rate increased to 11.77 mg per million cycles. Parametric design variations produced only small changes in wear rates for this simulation. CONCLUSIONS: The chosen design variables had little effect on the resultant wear rates. The comparable wear rate for the THR validation analysis was 16.17 mg per million cycles, indicating that, using this framework, the wear potential of the TDR was equivalent to, if not better, than the THR using joint-specific loading standards. PMID- 17688057 TI - Ossification of the posterior longitudinal ligament of the cervical spine: histopathological findings around the calcification and ossification front. AB - OBJECT: The authors studied the histological and immunohistochemical features of ossified posterior longitudinal ligament (PLL) of the cervical spine, especially in the calcification and ossification front. METHODS: Samples of en bloc ossified PLL plaque obtained in 31 patients were stained with H & E and immunohistochemically prepared for collagens (types I and II), vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-beta, and bone morphogenetic protein (BMP)-2, and by terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick-end labeling method for apoptosis. RESULTS: Enchondral ossification was evident between the ligamentous enthesis and deep layer of the ligament, with irregularly disorganized arrangement of elastic fibers in association with advancement of the degenerative process. In the ossification front, many hypertrophic metaplastic chondrocytes were noted in the ossifying plaque immediately contiguous to the ligament fibers, together with a considerable degree of neovascularization. Both TGFbeta and BMP-2 were highly expressed in metaplastic hypertrophic chondrocytes in the ossification front, and BMP-2 was also expressed in fibroblastic cells near the ossified PLL plaque. Expression of type I collagen was significant in the matrix of the ossified PLL lesion, whereas that of type II was marked in metaplastic chondrocytes in the ossification front. Apoptotic hypertrophic chondrocytes were observed mainly in the fibrocartilaginous area near the calcification front. CONCLUSIONS: The enchondral ossification process in the ossified PLL was closely associated with degenerative changes of elastic fibers and cartilaginous cartilage formation, together with the appearance of metaplastic hypertrophic cartilage cells and neovascularization. The authors also found that VEGF-positive metaplastic chondrocytes in the ossification front and different expression patterns of collagens probably play some role in the extension of the ossified PLL from the ossification front. PMID- 17688058 TI - Thoracic ossification of the human ligamentum flavum: histopathological and immunohistochemical findings around the ossified lesion. AB - OBJECT: The object of this study was to histopathologically and immunohistochemically characterize ossification of the ligamentum flavum (OLF) in samples of the thoracic spine harvested en bloc during surgery and to enhance the understanding of the ossifying process, particularly calcification and ossification. METHODS: Samples of OLF plaque were obtained en bloc from 43 patients who underwent posterior decompression. The histopathological findings were correlated with radiological subtypes using computed tomography. The expression of type I and type II collagens, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)beta, and bone morphogenetic protein (BMP)-2 was investigated. RESULTS: Surgical decompression using the posterior floating and en bloc resection technique resulted in neurological improvement in 40 of 43 patients. Progression of the OLF lesion longitudinally and medially was associated with significant degeneration of elastic fibers, fiber bundle derangement, decrements in fiber diameter, and fragmentation. Calcification and ossification paralleled the degeneration of the elastic fibers, extended more medially, and fused in the central area. Expression of BMP-2, TGFbeta, and VEGF was significant in chondrocytes in the calcified cartilage and fibrocartilage layers, especially around the calcified front. CONCLUSIONS: Histopathologically, the progress of calcification and ossification was closely associated with the degeneration of elastic fibers and with significant expression of BMP-2, TGFbeta, and VEGF in the ossification front. PMID- 17688059 TI - Local delivery of oncogel delays paresis in rat metastatic spinal tumor model. AB - OBJECT: Spinal column metastatic disease clinically affects thousands of cancer patients every year. Local chemotherapy represents a new option in the treatment of metastatic disease of the spine. Despite the clinical impact of metastatic spine disease, the literature currently lacks an accurate animal model for the effective dosing of local chemotherapeutic agents within the vertebral column. METHODS: Female Fischer 344 rats, weighing 150 to 200 g each, were used in this study. After induction of anesthesia, a transabdominal approach to the ventral vertebral body of L-6 was performed. A small hole was drilled and 5 microL of ReGel (blank polymer), OncoGel (paclitaxel and ReGel) 1.5%, OncoGel 3.0%, or OncoGel 6.0% were immediately injected to determine drug toxicity. Based on these results, efficacy studies were performed by intratumoral injection of 5 microL of ReGel, OncoGel 3.0%, and OncoGel 6.0% on Day 6 in a CRL- 1666 breast adenocarcinoma metastatic spine tumor model. Hind limb function was tested pre- and postoperatively using the Basso-Beattie-Bresnahan rating scale. Histological analysis of the spinal cord and vertebral column was performed when the animal died or was killed. RESULTS: There were no signs of toxicity observed in association with any of the agents under study. No increased benefit was seen in the blank polymer group compared with the control group (tumor only). OncoGel 3.0% and OncoGel 6.0% were effective in delaying the onset of paralysis in the respective study groups. CONCLUSIONS: These findings demonstrate the potential benefit of OncoGel in cases of subtotal resections of metastatic spinal column tumors. OncoGel 6.0% is the most efficacious drug concentration and offers the best therapeutic option in this experimental model. These results provide promise for the development of local chemotherapeutic means to treat spinal metastases. PMID- 17688060 TI - A comparison of single and incremental impact approaches for producing experimental thoracolumbar burst fractures. AB - OBJECT: Experimental burst fracture models are often developed by using either single or incremental impacts. In both protocols, the weight-drop technique produces the impact. However, to the authors' knowledge in no study have researchers attempted to compare the equivalence of the spine burst fracture produced using the different impact protocols. This study was performed to investigate whether the single and incremental trauma approaches produce equivalent degrees of severity in thoracolumbar burst fractures. METHODS: Twenty bovine thoracolumbar spines comprising three vertebrae were divided evenly into the single impact and incremental impact groups. The specimens in the incremental impact group were subjected to three axial compressive impacts of increasing energy (78.4, 107.8, and 137.2 J), whereas specimens in the other group were subjected to a single impact (137.2 J). Before and after the final trauma, multidirectional flexibility of each specimen was measured under flexion/extension, right/left lateral bending, and right/left axial rotation, thus quantifying the instability of the fracture. The flexibility parameters were then compared between the two groups. RESULTS: A significant increase in flexibility parameters was found after the final trauma in both groups, indicating the instability of the spine (p < 0.01). No significant differences in flexibility parameters were observed in either intact status or injured status between the two groups (p > 0.05). CONCLUSIONS: In this study the authors have confirmed that the single and incremental impact protocols produced a similar degree of severity in producing an in vitro bovine burst fracture. The results of this study support the use of the incremental impact protocol in future experimental biomechanical studies. PMID- 17688061 TI - Spinal cord injury-induced expression of the antiangiogenic endostatin/collagen XVIII in areas of vascular remodelling. AB - OBJECT: Spinal cord injury (SCI) induces the disruption of neural and vascular structures. In contrast to the emerging knowledge of mechanisms regulating the onset of the postinjury angiogenic response, little is known about counterregulatory signals. METHODS: Using immunohistochemical methods, the authors investigated the expression of the endogenous angiogenic inhibitor endostatin/collagen XVIII during the tissue remodeling response to SCI. RESULTS: After SCI, endostatin/collagen XVIII+ cells accumulated at the lesion site, in pannecrotic regions (especially in areas of cavity formation), at the lesion margin/areas of ongoing secondary damage, and in perivascular Virchow-Robin spaces. In remote areas (> 0.75 cm from the epicenter) a more modest accumulation of endostatin/collagen XVIII+ cells was observed, especially in areas of pronounced Wallerian degeneration. The numbers of endostatin/collagen XVIII+ cells reached their maximum on Day 7 after SCI. The cell numbers remained elevated in both, the lesion and remote regions, compared with control spinal cords for 4 weeks afterwards. In addition to being predominantly confined to ED1+ activated microglia/macrophages within the pannecrotic lesion core, endostatin/collagen XVIII expression was frequently detected by the endothelium/vessel walls. Numbers of lesional endostatin/collagen XVIII+ endothelium/vessel walls were found to increase early by Day 1 postinjury, reaching their maximum on Day 3 and declining subsequently to enhanced (above control) levels 30 days after SCI. CONCLUSIONS: The authors detected that in comparison to the early expression of neoangiogenic factors, there was a postponed lesional expression of the antiangiogenic endostatin/collagen XVIII. Furthermore, the expression of endostatin/collagen XVIII was localized to areas of neovascular pruning and retraction (cavity formation). The expression of endostatin/collagen XVIII by macrophages in a "late" activated phagocytic mode suggests that this factor plays a role in counteracting the preceding "early" neoangiogenic response after SCI. PMID- 17688062 TI - Angiographically occult spinal dural arteriovenous fistula located using selective computed tomography angiography. Case report. AB - Spinal dural arteriovenous fistula (DAVF) is the most common type of spinal arteriovenous malformation and may cause progressive myelopathy but is usually treatable in the early stages by direct surgery or intravascular embolization. Selective spinal angiography has been the gold standard for diagnosis, but angiographically occult DAVF is not uncommon. A 67-year-old man presented with a 2-year history of progressive paraparesis. Magnetic resonance (MR) imaging demonstrated segmental atrophy of the spinal cord and dilated coronary veins on the dorsal surface of the spinal cord. A DAVF was suspected, but repeated selective angiography failed to demonstrate the fistula. Findings from spoiled gradient echo MR imaging suggested that the draining vein flowed into the dilated venous plexus at the T-9 level. Selective computed tomography (CT) angiography of the right T-9 intercostal artery confirmed the location of the fistula. The authors successfully occluded the draining vein through surgery, and they observed that the fistula was low flow. The patient exhibited improvement in his symptoms, and postoperative MR imaging confirmed closure of the fistula. Selective CT angiography is useful in locating the draining vein of angiographically occult DAVF and therefore minimizing the extent of the surgical procedure. PMID- 17688063 TI - Extension of contained rupture of an abdominal aortic aneurysm into a lumbar intervertebral disc. Case report. AB - Chronic contained rupture of an abdominal aortic aneurysm (AAA) is a rare event, making its diagnosis difficult. A delayed diagnosis and delayed surgical repair compromise the outcome. In this paper the authors report the case of a chronic contained rupture of an AAA causing spinal destruction, in which diagnosis was difficult because the lesion produced symptoms mimicking those of pyogenic spondylitis. PMID- 17688064 TI - Iatrogenic splenic injury during anterior thoracolumbar spinal surgery. Case report. AB - The proximity of major abdominal structures encountered in the approach for an anterior thoracolumbar spinal operation makes patients vulnerable to potential intraoperative complications. The spleen, in particular, can be easily injured during manipulation or from being under retractors for a number of hours, although it is a rarely reported phenomenon in the literature. The authors report on a 52-year-old man who suffered a spleen laceration following anterior L1-2 corpectomy and fusion for osteomyelitis of the lumbar spine. The patient required an emergency splenectomy, but he made a full recovery. PMID- 17688065 TI - Dural damage due to a loosened hydroxyapatite intraspinous spacer after spinous process-splitting laminoplasty. Report of two cases. AB - Excellent results from laminoplasty for cervical spinal myelopathy have been reported in many studies. Nevertheless, C-5 nerve root palsy or axial pain such as neck and shoulder pain after laminoplasty are known postoperative complications. To the authors' knowledge, dural damage from dislocation of the hydroxyapatite intraspinous spacer due to absorption of the tip of the spinous process has not been reported. Two cases of dural damage from dislocation of the hydroxyapatite intraspinous spacer after laminoplasty are described. Radiographs, computed tomography myelography, and magnetic resonance (MR) imaging revealed the dislocation of the hydroxyapatite intraspinous spacer, the absorption of the tip of the spinous process, and dural sac compression due to the hydroxyapatite intraspinous spacer. In one patient, the MR imaging studies revealed liquorrhea around the hydroxyapatite intraspinous spacers. Both patients underwent removal of the hydroxyapatite intraspinous spacer and attained good neurological recovery. In patients with dislocation of the hydroxyapatite intraspinous spacer associated with absorption of the tip of the spinous process after spinous process-splitting laminoplasty, each case should be evaluated for aggravating symptoms of myelopathy, dural damage, and liquorrhea around the spacer. PMID- 17688066 TI - Intramedullary inclusion cysts of the cervicothoracic junction. Report of two cases in adults and review of the literature. AB - Intramedullary inclusion cysts are extremely rare within the rostral spinal cord. In this case report the authors outline the clinical features and surgical treatment of one dermoid cyst and one epidermoid cyst of the cervicothoracic junction. The authors also include a relevant literature discussion regarding the treatment and the embryological origin of these lesions. PMID- 17688067 TI - Atlantoaxial subluxation-induced myelopathy in cleidocranial dysplasia. Case report. AB - The authors describe the clinical course and treatment of a patient with cleidocranial dysplasia in whom spastic myelopathy developed due to atlantoaxial subluxation. This 27-year-old woman with cleidocranial dysplasia and a history of atlantoaxial subluxation presented with spastic myelopathy. Surgery was performed twice for cervical myelopathy and atlantoaxial subluxation, including laminectomy at the atlas and cervicooccipital fusion in which the Luque rod system was used, as well as C1-2 fusion via the transpharyngeal route. Solid bone fusion was achieved by 7 months postsurgery. Postoperative magnetic resonance imaging studies demonstrated that spinal cord compression was relieved, but atrophy persisted. At 2 years postsurgery there was no neurological disease progression, but spasticity persisted. The patient could walk with a cane. Cleidocranial dysplasia is an extremely rare cause of myelopathy in patients with atlantoaxial subluxation; the authors know of only two reports of this condition. When managing cleidocranial dysplasia, the practitioner should always be aware that atlantoaxial subluxation may be the cause of cervical myelopathy. PMID- 17688068 TI - Pigmented villonodular synovitis associated with pathological fracture of the odontoid and atlantoaxial instability. Case report and review of the literature. AB - Pigmented villonodular synovitis (PVNS) is a proliferative disorder of the synovium with a predisposition for the appendicular skeleton. Rarely PVNS can arise from the spine, where this disorder usually presents with localized or radicular pain secondary to involvement of the posterior elements. The authors report the case of an 82-year-old woman who presented with long-standing neck pain and acute upper-extremity numbness and weakness. Computed tomography imaging revealed a mixed sclerotic and lucent lesion affecting the dens and right lateral mass of C-2. There was also a pathological fracture at the base of the dens with 8 mm of anterior dens displacement. Magnetic resonance imaging demonstrated a diffusely infiltrative process that was nonenhancing. Because of instability, the patient underwent transarticular screw fixation, and a biopsy of the lesion was also performed at this time. Histopathological analysis was consistent with a diagnosis of PVNS. To the authors' knowledge, this is the first report of PVNS involving the C-2 vertebra or causing a pathological fracture. PMID- 17688069 TI - Multiple filum terminale hemangioblastomas symptomatic during pregnancy. Case report. AB - Hemangioblastomas are low-grade, highly vascular tumors commonly associated with von Hippel-Lindau (VHL) syndrome and most often appearing in the cerebellum. They very rarely occur in the spinal nerve roots, and an origin in the filum terminale is exceptional with no instances of multiple hemangioblastomas of the filum terminale reported in the literature. Because of their vascular nature, these lesions can enlarge and become symptomatic in the context of the changes that take place during pregnancy, as has been noted with cerebellar hemangioblastomas. In any case, the evolution of spinal hemangioblastomas during pregnancy is not well known given its rarity. The conjunction of both processes--that is, multiple hemangioblastomas arising in the filum terminale and pregnancy--is unique. The authors describe the case of a 41-year-old woman with multiple hemangioblastomas of the filum terminale and no other evidence of VHL syndrome, in whom pregnancy precipitated symptoms. The interruption of gestation led to a remission of the symptoms. The literature concerning filum terminale hemangioblastomas and pregnancy is also reviewed. PMID- 17688070 TI - A huge presacral Tarlov cyst. Case report. AB - Perineural cysts have become a common incidental finding during lumbosacral magnetic resonance (MR) imaging. Only some of the symptomatic cysts warrant treatment. The authors describe the successful operative treatment of a patient with, to the best of their knowledge, the largest perineural cyst reported to date. A 29-year-old woman had been suffering from long-standing constipation and low-back pain. During an obstetric investigation for infertility, the clinician discovered a huge presacral cystic mass. Computed tomography myelography showed the lesion to be a huge Tarlov cyst arising from the left S-3 nerve root and compressing the ipsilateral S-2 nerve. The cyst was successfully treated by ligation of the cyst neck together with sectioning of the S-3 nerve root. Postoperative improvement in her symptoms and MR imaging findings were noted. Identification of the nerve root involved by the cyst wall, operative indication, operative procedure, and treatment of multiple cysts are important preoperative considerations. PMID- 17688071 TI - Use of intraoperative sodium tetradecyl sulfate for the treatment of a spinal epidural hemangioma. Technical note. AB - Spinal hemangiomas can be categorized into three different groups based on location. Vertebral body (VB) hemangiomas are frequent incidental findings on magnetic resonance (MR) imaging. There is a subdivision of these with spinal epidural extension that have been reported in the literature. Spinal hemangiomas can also be epidural without VB involvement; these are extremely rare with few reported cases in the thoracic epidural spinal column. The diagnosis and imaging characteristics as well as the surgical tools used in gross-total resection of spinal epidural hemangioma are not well understood. The authors present a detailed characterization of a spinal epidural hemangioma in a 30-year-old woman who presented with complaints of gradual onset of low-back pain that worsened over 1 year. The MR imaging findings indicated a large L2-S1 epidural spinal mass causing thecal sac compression. The patient underwent an L2-S1 laminectomy, and a vascular extradural mass was noted on the posterior aspect of the dura mater. Preoperative spinal angiography as well as intraoperative angiography was performed. Total resection of the tumor was achieved using intraoperative embolization with sodium tetradecyl sulfate and microscopic dissection. The postoperative MR imaging findings and clinical outcome were excellent. The findings and use of sodium tetradecyl sulfate in gross-total resection are discussed. The authors also review treatment modalities and demonstrate the utility and effectiveness of intraoperative sodium tetradecyl sulfate in grosstotal resection of large difficult spinal epidural hemangiomas. PMID- 17688072 TI - Lateral intramuscular planar approach to the lumbar spine and sacrum. Technical note. AB - The goal of this study was to establish a much less invasive method for access to the lateral lumbar spine for posterolateral fusion and pedicle screw (PS) placement. The technique was developed through knowledge of the anatomy literature and the author's clinical experience in more than 90 completed cases. The lateral intramuscular planar approach provides a much less invasive access to the lateral aspect of the lumbar spine and sacrum. An invariant intramuscular plane, poorly described in the anatomical literature, is ideal for posterolateral fusion and/or PS placement from L-3 caudally. The approach requires essentially no resection of the multifidus muscle, or of the pars thoracis of the erector spinae. PMID- 17688073 TI - Changed phosphodiesterase selectivity and enhanced in vitro efficacy by selective deuteration of sildenafil. AB - In order to explore whether selective deuteration of sildenafil affects selectivity and efficacy of the drug, the inhibitory activity of sildenafil (1-[4 ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5 yl)phenyl-sulfonyl] -4-methylpiperazine citrate, CAS 139755-83-2) and three deuterated sildenafil derivatives, D8-piperazine-sildenafil (BDD-10402), D3 methyl-D8-piperazine-sildenafil (BDD-10403) and D5-ethoxy-Sildenafil (BDD-10406) against phosphodiesterases 1-6 was compared. Furthermore, the relaxant effect of sildenafil and its deuterated derivatives in a contractility assay on rabbit corpus cavernosum strips from New Zealand rabbits was investigated. BDD-10406 exhibits a 2-fold higher selectivity for phosphodiesterase 5 versus phosphodiesterase 6 than sildenafil. BDD-10406 and sildenafil inhibited cGMP formation with IC50 values of 6 nmol/L and 9 nmol/L, respectively. The corresponding IC80 values for BDD-10406 and Sildenafil were 33 nmol/L and 40 nmol/L, respectively. Sildenafil, BDD-10402, BDD-10403 and BDD-10406 relaxed the rabbit corpus cavernosum strips in a dose-dependent manner with ED50 values of 245 nmol/L, 91 nmol/L, 121 nmol/L and 85 nmol/L, respectively. Deuteration of sildenafil on the ethoxy group (BDD-10406) leads to enhanced selectivity for phosphodiesterase 5 versus phosphodiesterase 6 and higher efficacy in vitro. This is the first example of a deuteration effect on the inhibitory activity of a reversible enzyme inhibitor. PMID- 17688074 TI - [Intraurethrally applicated alprostadil for the treatment of organic erectile dysfunction in practice: a multicenter clinical monitoring study (noninterventional investigation)]. AB - In a multicenter clinical monitoring study (observation of use investigation according to 67.6 of the German Drug Law), which was conducted between 2003 and 2005 in 105 urological practices in 314 patients with organic erectile dysfunction (ED), efficacy, safety, convenience and acceptance of intraurethral administered alprostadil (CAS 745-65-3; MUSE - Medicated Urethral System for Erection) was studied. 306 patients could statistically be evaluated. The patients were 61.3 +/- 9.2 years old (median+/- SD) (181 patients between 60 and 80 y). The time of ED was from 2 to 120 months with a mean duration of 21.5 +/- 22 months (median+/-SD. Genesis of the ED was in 55 % of the patients a local damage, which followed in 42.8 % a prostate cancer surgery. 46 % of the patients had vascular, 28 % metabolic diseases including diabetes and 11% neural damages. In 51.3% of the patients drugs, which were known to induce ED, were suspected to have caused or partially caused the impairment. The degree of the disturbance was in 93 % of the cases moderate to severe. Alprostadil (MUSE) was applicated three times in doses of 250, 500 or 1000 microg. The dosage of 1000 microg was used for the third application by 65 % of the patients. Very good and good efficacy increased from 45.8% of the patients after the first through 63.7 % after the second to 69.3 % after the third application. In patients after surgery because of prostate cancer very good and good efficacy improved in comparison to the first application about 20% and concerned 53.9 % of the patients after the third application. Sexual intercourse was possible by 67% of the patients after the first, 83 % after the second and 87 % after the third use. Tolerability of alprostadil (MUSE) was very good and good in 90% of the patients. 81.1% intended to continue the treatment. The handling of alprostadil (MUSE) was assessed very good and good by 75%, the acceptance was very good and good in 96% of the patients. In a retrospective comparison with other drugs for the treatment of ED intracavernosal alprostadil ("SKAT") was slightly more effective than intraurethral alprostadil (MUSE) (32.1% vs 25 %), but alprostadil (MUSE) was assessed more useful by 82.1% and preferred by 78.6% of the patients. In comparison to phosphodiesterase-5- (PDE-5)-inhibitors alprostadil (MUSE) was more effective in 77.7 %, and 79.6 % of the patients preferred it. In comparison to apomorphin 94.1% preferred alprostadil (MUSE). 98 % of the patients reported better efficacy of alprostadil (MUSE), and 94.1% preferred it. Five adverse events were reported (slight urethral pain). No patient dropped out. In this non interventional investigation the good efficacy and tolerability of intraurethral applicated alprostadil (MUSE) as a second-line therapy after failure or minor efficacy of PDE-5 inhibitors and other oral drugs was comparable with the results of the clinical trials. The patients in the urological practices assessed handling and acceptance of the system high. PMID- 17688075 TI - Bioequivalence of two enteric coated formulations of pantoprazole in healthy volunteers under fasting and fed conditions. AB - PURPOSE: To compare the bioavailability of two pantoprazole (CAS 102625-70-7) formulations (40 mg pantoprazole enteric coated tablets) under fasted and fed conditions as well as to evaluate the dissolution profile in biorelevant media. METHODS: The subjects received either 40 mg of the reference or of test formulation in fasting (n = 28) and fed (n=70) condition. The studies were conducted according to a single dose and randomized crossover design. Blood samples were collected up to 12 h after drug administration in fasting condition and up to 48 h in fed condition. Plasma concentrations of pantoprazole were determined by LC-MS/MS. Pharmacokinetic parameters were calculated from the observed plasma concentration-time profiles. Bioequivalence between the formulations in fasting and fed condition was assessed considering 90% confidence intervals for the ratio of means for lnCmax and lnAUC(0-t) within 0.8-1.25. Dissolution profiles were evaluated in biorelevant media [Fasting State Simulating Intestinal Fluid (FaSSIF) and Fed State Simulating Intestinal Fluid (FeSSIF)]. The sameness of the dissolution curves was assessed by f2 values between 50 and 100. RESULTS: Under fasting condition the 90% confidence interval for the ratio of means for the lnCmax, (0.94-1.03) and lnAUC(0-t) (0.89-0.99) was within the guideline range of bioequivalence (0.80-1.25). However, the data for lnCmax (0.51-0.76) and lnAUC(0-t) (0.68-0.90) under fed condition were not within the bioequivalence range. The postprandial study demonstrated a high intra subject variability and in some subjects pantoprazole could not be detected for up to 24 h, although the dissolution profile of reference and test formulations presented a similar disposition in FaSSIF and FeSSIF as confirmed by the values of f2 higher than 50. CONCLUSION: The results demonstrated that the test formulation was bioequivalent to the reference in fasting condition but not in postprandial state. The dissolution profile in FaSSIF indicates that this biorelevant medium was more adequate to discriminate the in vivo disposition of pantoprazole than FeSSIF. Furthermore, the fed condition study had shown a pronounced influence of food in the absorption of pantoprazole after single oral dose administration. PMID- 17688076 TI - Pharmacokinetics and bioequivalence study of ranitidine film tablets in healthy male subjects. AB - The aim of the present study was to compare the bioavailability of ranitidine (CAS 66357-35-5) from two different ranitidine hydrochloride (CAS 66357-59-3) film tablets (Ranitab 150 mg film tablets as test preparation and 150 mg film tablets of the originator product as reference preparation). The study was conducted according to an open-label, randomised two-period cross-over design with a wash-out phase of 9 days. Blood samples for pharmacokinetic profiling were taken up to 24 h post-dose, and ranitidine plasma concentrations were determined with a validated HPLC method with UV-detection. Maximum plasma concentrations (Cmax) of 461.8 ng/ml (test) and 450.6 ng/ ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC (0-infinity) of 2,488.6 ng . h/ml (test) and 2,528.8 ng . h/ml (reference) were calculated. The median tmax was 2.83 h (test) and 3.04 h (reference). Plasma elimination half-lives (t1/2) of 2.78 h (test) and 2.89 h (reference) were determined. Both primary target parameters AUC(0-infinity) and Cmax were tested parametrically by analysis of variance (ANOVA) and the 90% confidence intervals were between 91.93 %-106.98 % (AUC (0-infinity) and 92.34%-118.85% (Cmax). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and Cmax the 90 % confidence intervals of the T/R ratios of logarithmically transformed data were in the generally accepted range of 80 %-125 %. PMID- 17688077 TI - Effect of targeting janus kinase 3 on the development of intestinal tumors in the adenomatous polyposis coli(min) mouse model of familial adenomatous polyposis. AB - Familial adenomatous polyposis (FAP) is associated with germ-line mutations in the tumor suppressor gene, adenomatous polyposis coli (APC) located on chromosome 5q21. Multiple intestinal neoplasia (Min) in mice resembles FAP in humans, resulting from a single point mutation in the murine homolog of the APC gene. The effects of the rationally-designed Janus kinase 3 (JAK3) inhibitor JANEX-1 (4-(4' hydroxyphenyl) amino-6,7-dimethoxy-quinazoline, WHI-P131, CAS 202475-60-3) on the development of intestinal tumors in the APC (min/+) mouse model of FAP were examined. The Min mice were fed with rodent chow or chow supplemented with JANEX 1 once a week starting at 1.5 months of age. The cumulative proportions of mice remaining alive at 7 months were 13 +/- 6% for control mice versus 72 +/-12% for JANEX-1 treated mice (P<0.0002). In contrast, Compound DDE24, a synthetically activated genistein, an inhibitor of Epidermal Growth Factor receptor (EGF-R), cellular homologue of oncogene product from Raus Avian sarcoma virus (SRC) and Syk tyrosine kinases, which Thus, selective targeting of JAK3 was highly effective in preventing development of intestinal tumors in Min mice resulting in markedly improved survival outcomes. JAK3 inhibitors may therefore be useful in the prevention of colorectal cancer in individuals with FAP. PMID- 17688078 TI - Large-scale synthesis of GMP grade N'- [2-(2-thiophene) ethyl]-N'- [2- (5 bromopyridyl)] -thiourea (HI-443), a new anti-HIV drug candidate. AB - The thiourea compound N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (HI-443, CAS 258340-15-7), was found to be a potent anti-HIV agent with remarkable activity against nucleoside analog reverse transcriptase (NRT) resistant, non-nucleoside analog reverse transcriptase (NNRT)-resistant, as well as multidrug-resistant HIV. Now the method of producing HI-443 under current Good Manufacturing Practice (cGMP) conditions on the scale of kilograms is reported. The availability of GMP-grade HI-443 will promote the preclinical and clinical development efforts aimed at making this new drug candidate available to HIV infected persons. PMID- 17688079 TI - Comparative acute systemic toxicity of several quinoxaline 1,4-di-N-oxides in Wistar rats. AB - The acute toxicity of six quinoxaline 1,4-di-N-oxides has been evaluated in an attempt to determine: a) the feasibility of testing systemic toxicity of these compounds in a very preliminary phase without an adequate formulation for in vivo administration, b) the LD50 range and the toxic target organ of these compounds in order to have an approximation of the structure-activity relationship. Quinoxaline 1,4-di-N-oxides have shown a great variety of biological activities with potential therapeutic application in cancer, malaria, etc. Problems of toxicity hinder the progression of these compounds to clinical phases. The compounds dissolved in DMSO at their solubility limit were administered i.v. to female Wistar rats (8 weeks, 160 g), using an infusion pump (300 microL; 20 microl/min). Animals were observed for a period of 14 days. This dose of the vehicle (1.7 ml/kg) was well tolerated by the animals. The LD50 could not be determined, but a marked hypoactivity was induced by the treatment. The same compounds were also injected intraperitoneally, suspended in 0.01% Tween 80/0.09 % saline, and the animals that did not die were observed for a period of 14 days. The LD50 could be estimated to be in a range between 30 and 120 mg/kg, except for one of the compounds. A decrease in the evolution of body weight and hypoactivity were the principal symptoms induced by the treatment. In both assays, histopathologic study of heart, liver, kidney, lung, spleen and ovaries indicated that the target organs may be heart and spleen. In conclusion, the i.v. route is not adequate for estimating the LD50 of these compounds due to solubility problems; by i.p. route, the LD50 interval is between 30 and 120 mg/kg. The data did not permit the deduction of any specific structure-activity relationship. PMID- 17688080 TI - Pharmacokinetics and bioequivalence study of doxycycline capsules in healthy male subjects. AB - The aim of the present study was to compare the bioavailability of doxycycline (CAS 564-25-0) from two different doxycycline hyclate (CAS 24390-14-5) capsules (Monodoks 100 mg capsule as test preparation and 100 mg capsule of the originator product as reference preparation) in 24 healthy male subjects. The study was conducted according to an open-label, randomised two-period cross-over design with a wash-out phase of 16 days. Blood samples for pharmacokinetic profiling were taken up to 72 h post-dose, and doxycycline plasma concentrations were determined with a validated HPLC method with UV-detection. Maximum plasma concentrations (Cmax) of 1,715.1 ng/ml (test) and 1,613.3 ng/ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity)) of 28,586.5 ng x h/ml (test) and 29,047.5 ng x h/ml (reference) were calculated. The median tmax was 1.88 h (test) and 2.00 h (reference). Plasma elimination half lives (t1/2) of 16.49 h (test) and 16.75 h (reference) were determined. Both primary target parameters AUC(0-infinity) and Cmax were tested parametrically by analysis of variance (ANOVA) and the 92.39 %-103.53% (AUC(0-infinity)) and 98.45% 111.74% (Cmax). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and Cmax the 90% confidence intervals of the T/R ratios of logarithmically transformed data were in the generally accepted range of 80 0%-125%. PMID- 17688081 TI - Social collaboration, inhibition and context. AB - This experiment investigated whether the exchange of information in social recall situations produced an inhibitory effect comparable to that observed in part-set cuing studies. 112 participants solved anagrams either individually or with a partner, then after a brief interference task recalled the words alone. Following delay participants attempted to recall the words a second time either alone or with a partner. Pairs recalled more words on second recall than those alone. This difference was due to pooling; there was no evidence of collaborative facilitation. Individuals who encoded individually and recalled as a pair forgot more items than those who encoded and recalled individually. PMID- 17688082 TI - An analysis of audit scores of adolescent offenders in two Midwestern counties. AB - The Alcohol Use Disorder Identification Test provides an accurate measure of risk associated with alcohol-related problems across sex, age, and cultures. As a recommended screening tool to detect patients who are appropriate candidates for brief, preventive alcohol interventions, it was given to 78 adolescents in a diversion program for drunk drivers in two southeastern Nebraska counties during routine alcohol-dependency evaluations. The subjects were grouped by age (18 and younger and over 18 years) and by sex. Based on a previous study, it was hypothesized that the responses to the first three AUDIT questions, related to alcohol consumption, would reflect sex and age differences. A 2 x 2 analysis of variance of scores on separate items indicated significant main effects for age (F1,74= 10.40, p<.002) for Question 1 with older boys' and girls' groups reporting they have drinks containing alcohol more frequently, for sex (F1,74= 14.65, p<.001) on Question 2 with the older boys' group reporting more frequent drinking on a typical day, and for age (F1,74 = 7.74, p>.01), and sex (F1,74= 4.12, p< .05) on Question 3 with the older boys' group indicating that they more frequently consumed six or more drinks on one occasion. It is recommended that the AUDIT-C be included in drug and alcohol assessments with adolescents similar to those tested here, and professionals be alert to the possibilities of sex and age differences in response to questions related to consumption. PMID- 17688083 TI - What does the Wonderlic Personnel Test measure? AB - The present investigation examined the concurrent validity of the Wonderlic Personnel Test and Woodcock-Johnson-Revised Tests of Cognitive Ability which were administered to 37 college students, 27 women and 10 men, who ranged in age from 18 to 54 years (M=27.1, SD=8.7). Analysis yielded significant correlation coefficients between the Wonderlic Total score and the score for the WJ-R Broad Cognitive Ability Standard Battery (r = .55) and the Comprehensive Knowledge score (r= .34). Performance on the Wonderlic was not significantly correlated with fluid reasoning skills (r=.26) but was most strongly associated with overall intellectual functioning, as measured by the Woodcock-Johnson Standard Battery IQ score. While scores on the Wonderlic were more strongly associated with crystallized than fluid reasoning abilities, the Wonderlic test scores did not clearly show convergent and divergent validity evidence across these two broad domains of cognitive ability. PMID- 17688084 TI - False recall of critical lures in students with diagnosed learning disabilities. AB - 40 students (M age = 13.5 yr., SD = 1) from a rural south Georgia school system participated. 20 participants (11 boys, 9 girls) were receiving special education services for diagnosed learning disabilities, and 20 were general education students (10 boys, 10 girls). Students attempted to memorize a list of 15 words in 1 min., tried to recall the words, and then repeated the process for each of 10-word lists. As predicted, students with diagnosed learning disabilities recalled fewer words overall and fewer critical lures than did the general education students. PMID- 17688085 TI - Neuroticism, extraversion, and paralinguistic expression. AB - The purpose of this study was to test the associations among neuroticism, extraversion, and paralinguistic expression. The relevant literature provides ample information on the association between personality traits and voice intensity, pitch, pace of speaking, frequency of pauses, slips of the tongue, and other speech impediments. The author attempted to verify and supplement work reported previously. Scores for 100 persons (56 women, 44 men; M age =21.5 yr., SD= 1.5) were analyzed with respect to two aspects of personality, neuroticism and introversion-extraversion. To analyze the paralinguistic properties of speech, elicited oral messages were examined, i.e., a fairy tale told by the examinees. While the analysis did not give unambiguous evidence that the assumptions were correct, it indicated singular and statistically significant relations of introversion and neuroticism with speech fluency impediments. PMID- 17688086 TI - A content analysis of the Japanese interpretation of "eating a balanced diet" . AB - The purpose of this study was to examine how Japanese workers (n= 391) think about "eating a balanced diet" daily. Respondents were 263 men and 128 women whose mean age was 43.1 yr. (SD= 10.9). Content analysis was used to analyze qualitatively responses to a survey. Responses were categorized into Eating a variety of foods, Different types of foods, and Nutritional components. The category, Eating a variety of foods, contained unique behaviors, such as "not continually eating the same foods" rather than eating specific foods or for nutrition. Because interpretations of what "eating a balanced diet" means varied, nutrition professionals should rephrase their advice into language which specifies more clearly practices for daily life. PMID- 17688087 TI - Parenting styles and adolescents' self-esteem in Brazil. AB - This study explored the relationship between parenting styles and self-esteem among 1,239 11- to 15-yr.-old Brazilian adolescents (54% girls; M age= 13.4 yr., SD= 1.4). Teenagers' families were classified into 1 of 4 groups (Authoritative, Authoritarian, Indulgent, or Neglectful) based on adolescents' answers to the ESPA29 Parental Socialization Scale. Participants completed the AF5 Multidimensional Self-Esteem Scale which appraises five dimensions: Academic, Social, Emotional, Family, and Physical. Analyses showed that Brazilian adolescents from Indulgent families scored equal (Academic and Social) or higher (Family) in Self-esteem than adolescents from Authoritative families. Adolescents from Indulgent families scored higher than adolescents from Authoritarian and Neglectful families in four Self-esteem dimensions, Academic, Social, Family, and Physical. Adolescents from Authoritative families scored higher than adolescents from Authoritarian and Neglectful families in three Self-esteem dimensions, Academic, Social, and Family. These results suggest that Authoritative parenting is not associated with optimum self-esteem in Brazil. PMID- 17688088 TI - Using the Megargee system among Belgian prisoners: cross-cultural prevalence of the MMPI-2 based types. AB - On the basis of the Minnesota Multiphasic Personality Inventory, and later the MMPI-2, E. I. Megargee and colleagues empirically developed a classification system to enhance management and treatment of offenders throughout the criminal justice system. This preliminary study extended the application of the MMPI-2 based system for the first time to a non-U.S. prison sample and classified the MMPI-2 profiles of 1,636 male inmates from Belgian federal prisons. The typology was capable of classifying most of the subjects and all 10 Megargee types were represented. Compared to American prevalence data, types Delta and Charlie were overrepresented and type George was underrepresented. Issues that warrant further investigation are discussed. PMID- 17688089 TI - Death depression and death obsession: are they different constructs? AB - This study examined the dimensional structure of Templer, et al.'s Death Depression Scale-Revised and Abdel-Khalek's Death Obsession Scale. The responses of 353 Spanish undergraduates, 261 women and 92 men (M age= 19 yr., SD= 3.1), to the Spanish forms of both scales were evaluated by means of a principal axis factoring with oblimin rotation. Three significant factors were identified: (1) Death Sadness, (2) Death Obsession, and (3) Death Anergia and Anhedonia. The distribution of the factor loadings for the items of both scales supported discriminant validity and capacity to evaluate aspects of human reactions to death. PMID- 17688090 TI - Sex and grade differences in verbal creative thinking among Iranian middle-school children. AB - The relations of sex and grade with verbal originality of 407 boys and 479 girls (M age= 12.7 yr., SD=.9) in Iranian middle schools (Grades 6 through 8) were investigated. The Sounds and Images test, one of the components of Thinking Creatively with Sounds and Words, was administered to measure verbal originality. Analysis showed boys scored significantly higher than girls on verbal originality and Grade 6 children scored significantly higher than Grade 7 children. The results were discussed in terms of sociocultural factors. PMID- 17688091 TI - Nonsupportive disclosure in child sexual abuse: confidants' characteristics and reactions. AB - In a sample of 856 South African child victims of sexual abuse (M age= 10.2 yr., SD=4.2), 26% experienced nonsupportive reactions at initial disclosure, with nonsupportive reactions taking two forms, ignoring the child (16% of cases) and punishing or silencing the child (10% of cases). Nonsupportive disclosure was equally likely when the confidant was a nonoffending guardian (OR= 1.00), another family member (OR= 0.84), or a professional person (OR= 1.07) but significantly more likely in cases where the confidant was a community member (OR=3.41). PMID- 17688092 TI - Psychometric properties of the Child Behavior Checklist/2-3 in an Arab population. AB - Child Behavior Checklist 2-3 is a parents' report questionnaire whose psychometric properties are known in the Western setting, but no studies have investigated this in an Arabic culture. In this study, the psychometric properties of the Arabic translation were studied using a sample of 694 children age 3 yr., ascertained as part of a community-based epidemiological study in the United Arab Emirates. The item-total correlations for items were satisfactory, ranging from .16 to .58. Cronbach alpha values for reliability ranged from .70 to .88 for the subscales and .93 for the Total score. The test-retest reliability coefficient for the Total score was .83. The validity was also high as 94.1% of those who scored above the cut-off point were classified correctly by a blind clinical interview. The results suggest that Child Behavior Checklist 2-3 is a reliable and valid checklist for use in the Arabic culture. PMID- 17688094 TI - Evaluating appreciation of measures attending to pupil diversity (EMAD). AB - Evaluating appreciation of measures attending to pupil diversity (EMAD) is a scale for evaluating the understanding of measures describing pupils' cultural and diversity needs among the staff responsible for such measures in Spanish primary schools. Its 9 Likert-scale items correspond to the various types of action in this area that are currently being promoted in Spain. The principal objective of this study was to assess the scale's factor structure and internal consistency, to which end the scale was completed by the heads of the Departments of Orientation of 140 Spanish primary schools. Corrected item-total correlations and Cronbach alpha (.91) indicated adequate scale homogeneity. Principal components analysis followed by varimax rotation indicated two factors jointly accounting for 71.4% of total variance, one associated with actions involving modification of syllabuses, and the other with actions not requiring such changes. Cronbach alphas were .89 and .79 for the two factors. PMID- 17688093 TI - Psychiatric nurses' reactions to assault upon them by inpatients: a survey in Taiwan. AB - 106 nurses (M age=28.9, SD=6.7 yr.) employed by two mental hospitals in northern Taiwan were surveyed about their reactions to assault by inpatients. 84% of the participants reported having been assaulted. "Body soreness in the area where hit" was the most common somatic reaction, "anger" was the most common emotional reaction, and "fear of the patient who assaulted me" was the most common social reaction to assault. Duration of occupational experience, older age, and increased social support were significantly correlated with less severe reactions to assault. Results are similar to those of prior studies of American nurses. PMID- 17688095 TI - Religious coping, family support, and negative affect in college students. AB - To understand the influence that religion may have on mental health, the present study examined influences of religious coping and family support on anxiety and depression in 190 college students (women=67.4%; M age=21.7 yr., SD= 4.9). Subjects were recruited as volunteers from undergraduate psychology courses and completed the Ways of Religious Coping Scale, the General Functioning subscale of the Family Assessment Device, the Anxiety Scale of the Personality Assessment Inventory, and the Beck Depression Inventory-Second Edition. Analyses indicated greater family support was significantly associated with less anxiety and depression, whereas religious coping was not significantly correlated with anxiety and depression. Overall findings suggest that family emotional support may provide a stronger source of support for college students than religious coping. PMID- 17688096 TI - Psychometric properties of the Brand Personality Scale: evidence from a business school. AB - The Brand Personality Scale has received considerable attention and has been frequently used and cited in the branding literature. This paper describes an investigation of the psychometric characteristics of the Brand Personality Scale in a business school context where umbrella branding is used. A sample (N=262) of students attending the MBA program of a major business school in eastern USA completed the scale. Results indicate problems with the scale's dimensionality, poor reliability, convergent and nomological validity of the Ruggedness dimension, and lack of support for discriminant validity. Managerial and research implications and limitations are noted. PMID- 17688097 TI - Self-assessments of risk tolerance by women and men. AB - A convenience sample of 1,741 Internet users completed a 12-item financial risk tolerance questionnaire. They also rated themselves on their tolerance for financial risk using a 4-point rating scale. The 12-item summated rating score was used to predict the self-rating. The residual between actual and predicted self-rating was compared by sex. The residual for males was positive, indicating that men tended to overestimate their proclivity for taking risks. Conversely, the residual for females was negative, suggesting that women underestimate their tolerance for risk. The relationship held when controlling for other factors linked to risk tolerance, i.e., age, household income, marital status, and education. It was also noted that risk tolerance was overestimated by younger respondents and those with a graduate education. PMID- 17688098 TI - Some factors in perceived unwanted transparency. AB - The feeling experienced when another person seemingly notices something about them that they would rather conceal from others is referred to as a sense of unwanted transparency. Effects of perception of others on one's sense of unwanted transparency were investigated. Participants, after being led to believe that they had performed poorly on an important ability test, interacted with an instructor who was apparently unaware of their poor performance. Participants' perception of the instructor was manipulated by the self-introduction of the instructor, either as a person who perceived the participants' inner selves or as a person who did not. Analysis indicated that participants interacting with an instructor who they believed could perceive their inner selves rated the sense of unwanted transparency higher than those interacting with an instructor who they believed could not perceive their inner selves. PMID- 17688099 TI - Facts and myths about seasonal variation in suicide. AB - The prevalence of suicide presents a universal seasonal pattern. In the Northern hemisphere, suicides peak during spring and early summer and the trough occurs during winter. This peculiar pattern might be counterintuitive for everyday reasoning. Data from 1,093 medical and psychology undergraduates from Austria (382 men and 711 women; M age 25.0 yr., SD=6.6) indicated an almost perfectly reversed pattern of beliefs about suicide seasonality compared with the actual seasonal distribution. The vast majority of respondents believed the peak to be located in late autumn and early winter and the trough occurring in late spring and the summer months. Implications for education and practice are discussed. PMID- 17688100 TI - Application of ecological models to risks related to being overweight among nurses. AB - This paper provides a discussion of environmental strategies to improve health behaviors of nurses. Behavioral choices, partly due to social and environmental factors, influence risk of chronic disease. Strategies that modify environments are critical components of public health interventions, particularly those concerned with improving diet and physical activity. Nurses' health behaviors may be especially important, due to their influence as models when caring for patients. Modifications in work environments may enable nurses to acquire and maintain healthy behaviors. PMID- 17688101 TI - Effect of perceived benefits on reluctance to trade. AB - People often tend to be reluctant to trade an owned object for an alternative object. This concept of reluctance to trade is generally called "endowment effect". Loss aversion, which denotes that losses are weighted more heavily than gains, has been applied to interpret the endowment effect. Specifically, no "reluctance to trade" will occur when no loss is involved. In this research, 172 (90 women, 82 men; M age=21 yr., SD= 1.2) and 152 (82 women, 70 men; M age=21 yr., SD= 1.8) undergraduates voluntarily participated in two experiments, respectively. Results of both experiments indicated that participants were willing to trade an owned object for an alternative object when both objects were of the same benefit type and were reluctant to trade when objects were different. Clearly, an exchange was perceived as lower loss when the owned object and the alternative object were of the same benefit type, leading to no reluctance to trade. PMID- 17688102 TI - Can child self-report measures of depression and anxiety be used in college samples? AB - Depression and anxiety are typically measured in college samples using adult scales. However, some child and adolescent versions of internalizing symptoms may be appropriate for use with college samples. Child versions may be appropriate to use with college samples when multi-sample designs are utilized, e.g., both children and adults are assessed. To explore this possibility, 149 college students (M age=21.9 yr., SD=6.3; 43 men, 106 women) were assessed on child and adolescent versions and adult scales of anxiety, i.e., the Revised Children's Manifest Anxiety Scale and the Beck Anxiety Inventory, and depression, i.e., the Children's Depression Inventory and the Beck Depression Inventory. Both sets of depression scores were highly correlated (r = .81), which suggests that the children's measure can be used in college samples. Although scores on the two anxiety scales were also significantly correlated, these scales shared less common variance. An exploratory factor analysis provided evidence that a single factor composed of all items for depression was an optimal solution. It was concluded that the Children's Depression Inventory can be used with college samples; however, the Revised Children's Manifest Anxiety Scale should not. PMID- 17688103 TI - Word comprehension in a second language: a direct or an indirect route to meaning? AB - For bilingual persons, comprehension of a word in a second language (L2 word) could be achieved via an indirect route, in which the L2 word is first translated into the first language (L1) before meaning is accessed, or via a direct route, in which an L2 word directly activates its meaning. To test these two accounts, proficient Dutch-English bilinguals were asked to translate and to categorize L2 words of high and low familiarity. These L2 words were accompanied by a Dutch context word that was either phonologically related or unrelated to its Dutch translation equivalent. The results showed a clear phonological facilitation effect in the translation task but no phonological facilitation in the categorization task. This result was taken as evidence for a "direct route" from the L2 word to its meaning. PMID- 17688104 TI - A meta-analysis of the 2004 campaign polls: an analogy to practice and publication in psychology. AB - The current practice of relying on single sample null hypothesis tests is being re-evaluated in the behavioral sciences. To highlight the issues raised by both sides of this discussion, a meta-analysis of The Gallup Organization's most recent U.S. Presidential election polling data was conducted. During the 2004 Presidential campaign, most pre-election polling percentages reported Bush ahead of Kerry, although the differences between the voters' preferences were typically within the margin of error. The meta-analyses used in this study showed significant differences between the two candidates' polling percentages, thus yielding a more accurate prediction than the conventional analysis which was based on single samples. These improved predictions provide support for a continued discussion about potential changes in statistical approaches to psychology. PMID- 17688105 TI - Perceived social loafing and anticipated effort reduction among young football (soccer) players: an achievement goal perspective. AB - This study investigated the relationship between motivational climates, personal achievement goals, and three different aspects of social loafing in football (soccer). 170 male competitive football players completed questionnaires assessing perceived motivational climate, achievement goal, and measures of perceived social loafing (anticipation of lower effort amongst their teammates and themselves). The results indicated a marginal but significant positive relationship between an ego-oriented achievement goal and perceived social loafing. In addition, a mastery climate was negatively associated with perceived social loafing and anticipation of lower effort of team members, particularly for athletes who also strongly endorsed a task-oriented achievement goal. A performance climate, in contrast, related positively with these two aspects of social loafing. A mastery climate also related negatively to the third aspect of social loafing, i.e., players' readiness to reduce their own effort in response to their perception of social loafing among their teammates. PMID- 17688106 TI - Cognitive impairment and quality of life among stroke survivors in Nigeria. AB - The study investigated cognitive impairment and quality of life (QOL) among 109 consecutive stroke survivors and 109 normal controls. Each group comprised 64 (58.7%) men and 45 (41.3%) women. The modified Mini Mental State Examination (mMMSE) and the WHO Quality of Life Questionnaire (WHOQOL-Bref) indicated that 19 (17.4%) stroke survivors had cognitive deficits (mMMSE score <16) compared with 5 (4.6%) control participants (chi1(2)=4.27, p<.05). Control participants performed significantly better on orientation, language comprehension, laterality, and the WHOQOL-Bref. Being GHQ-30 positive predicted poor performance on the mMMSE among the stroke survivors and reduced QOL on three of the four domains of the WHOQOL Bref. In addition, previous psychiatric illness, paresis, low education, and shorter time elapsed after a stroke predicted reduced QOL on one or more domains of the WHOQOL-Bref but age and sex of the stroke survivors were not associated with quality of life, and not with cognitive function. PMID- 17688107 TI - Psychometric properties of the brief version of the Fear of Negative Evaluation Scale in a Turkish sample. AB - The purpose of the study was to report initial data on the psychometric properties of the Brief Fear of Negative Evaluation Scale. The scale was applied to a nonclinical sample of 250 (137 women, 113 men) Turkish undergraduate students selected randomly from Middle East Technical University. Their mean age was 20.4 yr. (SD= 1.9). The factor structure of the Turkish version, its criterion validity, and internal reliability coefficients were assessed. Although maximum likelihood factor analysis initially indicated that the scale had only one factor, a forced two-factor solution accounted for more variance (61%) in scale scores than a single factor. The straightforward items loaded on the first factor, and the reverse-coded items loaded on the second factor. The total score was significantly positively correlated with scores on the Revised Cheek and Buss Shyness Scale and significantly negatively correlated with scores on the Rosenberg Self-Esteem Scale. Factor 1 (straightforward items) correlated more highly with both Shyness and Self-esteem than Factor 2 (reverse-coded items). Internal consistency estimate was .94 for the Total scores, .91 for the Factor 1 (straightforward items), and .87 for the Factor 2 (reverse-coded items). No sex differences were evident for Fear of Negative Evaluation. PMID- 17688108 TI - Some sex differences in sentencing severity for a mock crime scenario. AB - Canadian undergraduates (84 women, 65 men) read one of two crime vignettes which varied in how justified a murder was perceived to be, then made sentencing recommendations. Men were more likely than women to recommend capital punishment, but men and women did not differ on recommendation of execution method or prison sentence and parole. PMID- 17688109 TI - Spirituality and resilience in families in which a parent has died. AB - This preliminary study explored the prevalence of spirituality in family resilience in the adaptation process after the loss of a parent. Twenty-five families who lost a parent between one and six years previously were identified by four postgraduate students in their respective neighborhoods in Cape Town, South Africa. Each of the single parents (M age=48.3 yr., SD=7.7), 19 women and six men, were asked to indicate verbally in what way spirituality or religion had contributed to family adaptation after the death of the spouse. The semistructured interviews supplied evidence that a relationship between spirituality and family resilience does indeed exist. PMID- 17688110 TI - Developing attitude statements toward illegal immigration: transcultural reliability and utility. AB - This is a report on the utility of a scale measuring attitudes toward illegal immigrants in two samples from nations that have more people moving out of the country than moving into the country. The Attitude toward Illegal Immigrants Scale was administered to 219 undergraduates from Sofia University in Bulgaria, and 179 undergraduates from Hanoi State University in Vietnam. Results yielded a scale with no sex differences, and acceptable alpha coefficients. Item analysis identified the most contributory and least contributory items, with considerable overlap in the two samples. A principal component analysis with varimax rotation was carried out to examine the structure. PMID- 17688111 TI - Disabled children in special education programs in Taiwan: use of mental health services and unmet needs. AB - Despite national health insurance coverage in Taiwan, many health care needs remain unmet. In the current study, the behavior and emotional problems of 1,042 disabled children in special education programs were evaluated using the Chinese version of the Child Behavior Checklist (CBCL-C) and the Teacher's Report Form (TRF). Using the 60th percentile on the two tests as a cutoff representing a clinical indication, students who reached this cutoff point but did not receive mental health services in the past six months were considered to have "unmet mental health needs." Of the special education students in the study 73.9% reached clinical indications, but did not receive mental health care. PMID- 17688112 TI - Notes on problems of "validity generalization" and situational specificity. AB - This note provides additional research findings, using the Tiffany Control Scales, to re-emphasize that behavior typically changes when situations change. These and other findings reiterate the fact that many psychological tests should reflect situational differences and their effect on behavioral variance. PMID- 17688113 TI - Positive mood as a mediator of the relations among musical preference, postconsumption product evaluation, and consumer satisfaction. AB - This study of how positive mood mediates the influences of musical preference and postconsumption product evaluation on consumer satisfaction focuses specifically on a model in which positive mood fully mediates the influences. The proposed model is compared with two competing models, and a structural equation model is used to test and compare the three theory-driven models. This study sampled 247 students majoring in management at a single university. They had mean age of 23 yr. (SD=2.5). This study used questionnaires to measure subjects' evaluations of a cup of coffee, preference for the music broadcast in the coffee shop, positive mood, and satisfaction after they had the coffee. Analysis indicated that the proposed model outperformed the two competing models in describing the data using chi-square difference tests. Positive mood was identified as a full mediator of the relationship between musical preference and consumer satisfaction. Moreover, the results demonstrate for service managers the importance of creating positive consumer mood. PMID- 17688114 TI - Intention to be physically active: a theory-guided study in Italian teenagers. AB - This study investigated the relationship of self-efficacy, outcome expectancies, and risk perception on intention to increase physical activity in a group of adolescents. The 833 participants (M age= 16.2 yr., SD= 1.5) completed a Survey of Health Behavior anonymously. 88% of the sample said that they engaged in physical activity; 42.1% said that they spent 4 hours per week exercising. Boys appeared to be more active than girls. The results indicated self-efficacy, outcome expectancies, and risk perception as key factors in explaining behavioural intention in teenagers. As regards outcome expectancies, it seems that adolescents are effectively motivated by objectives which affect them closely, such as maintaining the right weight, and which may influence their everyday life. PMID- 17688115 TI - Sex differences and learners' autonomy toward e-learning based on surveys in UK and Taiwan. AB - A questionnaire was designed to investigate attitudes toward e-learning of 102 university students from the United Kingdom and 130 from Taiwan who completed the questionnaire on an intranet. The statistical analyses showed sex differences in users' attitudes toward computers and e-learning. Also, learners' autonomy in use of e-learning was affected by perceived enjoyment of e-learning multimedia, perceived usefulness of e-learning interaction, and quality of e-learning interaction and functions. PMID- 17688116 TI - Empirical comparison of Equity Preference Questionnaire and Equity Sensitivity Instrument in relation to work outcome preferences. AB - Until the development of the Equity Preference Questionnaire in 2000, the only measure of equity sensitivity available was the Equity Sensitivity Instrument. However, only one out of nine empirical studies conducted since 2000 has used this questionnaire, perhaps given the concerns about its applicability to earlier equity sensitivity research findings. This paper empirically examined both measures in relation to work outcome preferences based on the previous study by Miles, Hatfield, and Huseman in 1994 and finds that the two questionnaires produce comparable results. PMID- 17688117 TI - A psychometric assessment of the self-reported Youth Resiliency: Assessing Developmental Strengths questionnaire. AB - As opposed to the problem-based approach of dealing with specific at-risk behaviors, the objective of the self-reported Youth Resiliency: Assessing Developmental Strengths questionnaire is to provide a statistically sound and research-based approach to understanding the factors that contribute to the development of adolescent resiliency. The study of protective factors, or the more recent attempts at conceptualizing the phenomena of individual resiliency, has been prevalent in the social and health sciences research for decades. In this study, the psychometric characteristics of the Youth Resiliency questionnaire, based on a large urban sample of Grades 7 to 9 adolescents (N= 2,291), are presented. The findings from this study present a potential framework for understanding the construct and function of resiliency as it pertains to both the extrinsic and intrinsic factors of adolescent development. PMID- 17688118 TI - Development and initial validation of a cognitive-based work-nonwork conflict scale. AB - Current research related to work and life outside work specifies three types of work-nonwork conflict: time, strain, and behavior-based. Overlooked in these models is a cognitive-based type of conflict whereby individuals experience work nonwork conflict from cognitive preoccupation with work. Four studies on six different groups (N=549) were undertaken to develop and validate an initial measure of this construct. Structural equation modeling confirmed a two-factor, nine-item scale. Hypotheses regarding cognitive-based conflict's relationship with life satisfaction, work involvement, work-nonwork conflict, and work hours were supported. The relationship with knowledge work was partially supported in that only the cognitive dimension of cognitive-based conflict was related to extent of knowledge work. Hypotheses regarding cognitive-based conflict's relationship with family demands were rejected in that the cognitive dimension correlated positively rather than negatively with number of dependent children and perceived family demands. The study provides encouraging preliminary evidence of scale validity. PMID- 17688119 TI - Motivational analysis of academic help-seeking: self-determination in adolescents' friendship. AB - The purpose of this study was to investigate the role that friendship motivation plays in academic help-seeking based on self-determination theory. The relations among self-determined friendship motivation, academic help-seeking, and feeling of satisfaction were examined among high school students (N= 670) in Japan. Analyses showed that self-determined friendship motivation was associated with the academic help-seeking, which in turn was related to the feeling of satisfaction with academic learning and friendship. The role of friendship motivation in the academic setting is discussed. PMID- 17688120 TI - Construction and preliminary validation of the Barcelona Immigration Stress Scale. AB - In the study of mental health and migration, an increasing number of researchers have shifted the focus away from the concept of acculturation towards the stress present in the migratory experience. The bulk of research on acculturative stress has been carried out in the United States, and thus the definition and measurement of the construct has been predicated on that cultural and demographic context, which is of dubious applicability in Europe in general, and Spain in particular. Further, some scales have focused on international students, which down-played the importance of the migratory process, because it deals with a special subset of people who are not formally immigrating. The Barcelona Immigration Stress Scale was developed to measure acculturative stress appropriate to immigrants in Spain, using expert and focus group review and has 42 items. The scale shows acceptable internal validity, and, consistent with other scales, suggests that immigration stress is a complex construct. PMID- 17688121 TI - Assessment of an abstinence-oriented, outpatient drug addiction service in Greece. AB - The 'Athena' service is an abstinence-oriented, outpatient substance addiction unit in Greece. To appraise the operation of the service, 459 clients who contacted the unit during a 3-yr. period were assessed in terms of treatment retention and situation upon discharge from the program; 182 of them had four or more appointments with the service and were thoroughly assessed using a battery of measures pertaining to their situation at discharge and their patterns of abuse and related problems. Most help-seekers were single, unemployed, young men who regularly used heroin (89%) intravenously (35%). From those who got involved in the therapeutic process (40%), 72% had positively modified their drug abuse by the time of discharge from the program (mean duration of treatment: approx. three months); the largest improvement (42%) was recorded in their psychological condition. Treatment retention was significantly higher for cannabis abusers than heroin addicts; longer treatment duration was significantly associated with a positive situation at discharge, while higher education was associated with a less favorable outcome regarding the abuse of the principal substance. These findings suggest that such outpatient programs may help a significant number of individuals who get involved in the therapeutic process and should be considered effective for treatment of substance abuse among the diversity of treatment modalities. PMID- 17688122 TI - Entropy and environmental mystery. AB - Two studies are reported regarding the effects of entropy, lighting, and occlusion on impressions of mystery in physical environments. The theoretical context of this study was the "informational theory" of environmental preference, which, among other claims, holds that mystery can be measured by the extent to which people perceive a promise of more information if they move deeper into an environment. Entropy, in the context of this article, is visual diversity as measured using information theory. Mystery was measured by a semantic differential scale. The definition of mystery was left up to each individual participant. Entropy of occluded objects was used to obtain an objective, experimentally manipulatable and operational definition of "promise of more information." Exp. 1 had 12 stimuli and 15 participants. Exp. 2 had 12 stimuli and 16 participants. Entropy of occluded objects ranged from 0 to 6 bits. Entropy of occluded objects was used to measure the promise that there would be more information if one moved deeper into an environment. Overall, amount of light had the strongest effect on responses of mystery (r = -.63, darker was more mysterious), followed by occlusion (r = .26, occluding objects made a scene seem more mysterious), and by the promise of more information if one moved about in the scene (r = .13), the more entropy in occluded objects, the greater the impression of mystery). The theoretical contribution of this work is that a relationship between subjective impressions of mystery and an objective measure of "promise of more information" was found. PMID- 17688123 TI - Relative age and fast tracking of elite major junior ice hockey players. AB - Investigations in a variety of chronologically grouped team sports have reported that elite young athletes were more likely born in the early months of the selection year, a phenomenon known as the relative age effect. The present study investigated the birth dates and developmental paths of 238 (15 to 20 years old) Major Junior 'A' hockey players from the Ontario Hockey League to determine if a relative age effect still exists in elite junior hockey and if the path to elite sport was accelerated (i.e., fast tracked). The results identified a relative age effect in elite hockey although it is only apparent among individuals who fast track. PMID- 17688124 TI - Perception of linear and nonlinear trends: using slope and curvature information to make trend discriminations. AB - This study investigated several factors influencing the perception of nonlinear relationships in time series graphs. To model real-world data, the graphed data represented different underlying trends and included different sample sizes and amounts of variability. Six trends (increasing and decreasing linear, exponential, asymptotic) were presented on four graph types (histogram, line graph, scatterplot, suspended bar graph). The experiment assessed how these factors affect trend discrimination, with the overall goal of judging what types of graphs lead to better discrimination. Six participants (two psychology professors, four psychology graduate students) viewed graphs on a computer screen and identified the underlying trend. All participants were familiar with the types of trends presented and were aware of the purpose of the experiment. Analysis indicated higher accuracy when variability was lower and sample size was higher. Choice accuracy was higher for nonlinear trends and was highest when line graphs were used. PMID- 17688125 TI - Field dependence-independence and physical activity of black and white adolescents. AB - Self-administered Physical Activity Checklist and portable rod-and-frame test were administered to 47 black and 66 white adolescents in a middle school. One way multivariate analysis of variance indicated that, relative to the group of white adolescents, the black adolescent group scored significantly more field dependent and reported significantly fewer minutes of physical activity participation, although no significant difference was noticed on three other physical activity variables. This group of black adolescents' relatively field dependent scores were weakly associated with fewer mean total minutes of physical activity. PMID- 17688126 TI - Development of a metabolic equation for elliptical crosstrainer exercise. AB - The purpose of this study was to develop an accurate metabolic prediction equation for elliptical crosstrainer (ECT) exercise. Male and female (n= 40) subjects (M+/- SD, age: 30+/-7 yr.; height: 173 +/- 11 cm; weight: 72.3 +/- 13.8 kg; body composition: 18.3 +/- 6.9%) completed two randomized testing sessions. Steady-state oxygen uptake (VO2) was measured, while subjects exercised on the ECT at nine separate workloads each testing session. Multiple regression analysis to predict steady-state VO2 from ECT resistance, ECT cadence, and subjects' body mass resulted in the following model (R2= .783): Steady-state VO2=3.5+/-0.15 (Cadence) + 1.22 (Resistance) - 0.11 (Weight). Both the standard error of the estimate (SEE) and total error (TE) for the prediction of steady-state VO2 under all ECT workload conditions combined were 2.8 mL/kg/min. The SEE and TE values are similar to those previously reported in the literature regarding the accuracy of metabolic equations for other exercise modalities. These findings support the use of the equation developed in the present study to predict steady-state VO2 for ECT exercise. PMID- 17688127 TI - Body mass index of 23 or more is a risk factor for hypertension and hyperlipidemia in Japanese workers. AB - In comparison with western populations, body mass index (BMI) of the Japanese population is typically lower. In this study, the relationship between BMI and other metabolic risk factors was examined in 1,130 male manufacturing workers surveyed from 2000 to 2003. The association between the BMI and the relative risk of hypertension was evaluated in a cross-sectional design using logistic regression analysis. The mean BMI in the subjects was 23.6 (SD=3.2). Of the total number of subjects, 26.6% and 3.3% were classified as pre-obese and obese, respectively. Multivariate analysis indicated that BMI of 23 or greater was significantly associated with an increased risk of hypertension and/or hyperlipidemia. Health education of weight control of borderline obesity of workers is important for the primary prevention of hypertension and hyperlipidemia in Japan. PMID- 17688128 TI - Retrieval by a patient with apraxia of sensorimotor information from visually presented objects. AB - Motor representations are reported to be implicitly evoked when one observes manipulatable objects (action potentiation). The relationship was examined between action potentiation and pantomime deficit in apraxia. Participants responded to line drawings of manipulatable objects with either the left or right hand, according to the color of the stimulus. In normal participants (N= 10, four women, six men, M age = 28.5 yr., SD = 5.6), responses were faster when the orientation of the stimulus was compatible with the response-hand grasp. However, the apraxic patient did not exhibit this compatibility effect. On a control task in which a nonobject (circle) was presented, all participants exhibited the compatibility effect. These results indicated that the apraxic patient was impaired in evoking motor representation associated with objects. Thus, in some cases, apraxic disorders may be attributable to a deficit in retrieving object specific information for manipulation. PMID- 17688129 TI - Time perception, estimation paradigm, and temporal relevance. AB - 52 women and 20 men (M age = 25.3 yr., SD = 4.1) reproduced one of three durations (15, 30, and 45 sec.) of a uniform visual stimulus in either a prospective or a retrospective estimation paradigm. In contrast to the prospective conditions, the participants in the retrospective conditions did not know that time estimation would be required subsequently. However, temporal relevance in the retrospective conditions was raised explicitly by instructing the participants to wait for the termination of a visual stimulus and to press a button immediately after the stimulus had disappeared. The results contrasted with most findings of comparisons between prospective and retrospective duration judgments: there were no differences between the conditions regarding their mean estimates. However, intersubject variability of temporal judgments was higher in the retrospective conditions than in the prospective conditions. The results were interpreted within the framework of attentional models of temporal information processing. PMID- 17688130 TI - Recognition memory for concrete, regular abstract, and diverse abstract pictures. AB - Based on previous research by Goldstein and Chance in which poor recognition memory for abstract visual patterns was reported, this study compared recognition memory for pictures of everyday concrete objects, regular abstract stimuli as employed by Goldstein and Chance, and diverse abstract stimuli. A (3) x 2 design (stimulus type x test order) analysis of variance design was used. The subjects (N = 31) first viewed 30 target stimuli, followed by an immediate recognition test in which for 30 paired target and distractor stimuli shown they indicated which one they had seen previously. Concrete pictures were recognized with near perfect accuracy, and above the level for diverse abstract pictures; these in turn were better identified than regular abstract items, on which performance resembled that found by Goldstein and Chance. It is concluded that stimulus discriminability, rather than representational meaningfulness, may be crucial in picture recognition. PMID- 17688131 TI - Relationships between visual-motor and cognitive abilities in intellectual disabilities. AB - The neurobiological hypothesis supports the relevance of studying visual perceptual and visual-motor skills in relation to cognitive abilities in intellectual disabilities because the defective intellectual functioning in intellectual disabilities is not restricted to higher cognitive functions but also to more basic functions. The sample was 102 children 6 to 16 years old and with different severities of intellectual disabilities. Children were administered the Wechsler Intelligence Scale for Children, the Bender Visual Motor Gestalt Test, and the Developmental Test of Visual Perception, and data were also analysed according to the presence or absence of organic anomalies, which are etiologically relevant for mental disabilities. Children with intellectual disabilities had deficits in perceptual organisation which correlated with the severity of intellectual disabilities. Higher correlations between the spatial subtests of the Developmental Test of Visual Perception and the Performance subtests of the Wechsler Intelligence Scale for Children suggested that the spatial skills and cognitive performance may have a similar basis in information processing. Need to differentiate protocols for rehabilitation and intervention for recovery of perceptual abilities from general programs of cognitive stimulations is suggested. PMID- 17688132 TI - Resampling permutation probability values for six measures of qualitative variation. AB - An algorithm and associated FORTRAN program are provided for six common measures of ordinal association: Kendall's taua and taub, Stuart's tauc, Goodman and Kruskal's gamma, and Somers' dyx and dxy. Program ROMA reports the observed data table, the values for the six test statistics, and the resampling upper- and lower-tail probability values associated with each test statistic. PMID- 17688133 TI - Relations of pitch matching, pitch discrimination, and otoacoustic emission suppression in individuals not formally trained as musicians. AB - Research has yielded a relationship between pitch matching and pitch discrimination. Good pitch matchers tend to be good pitch discriminators and are often judged to be vocally talented. Otoacoustic emission suppression measures the function of the efferent auditory system which may affect accuracy for pitch matching and pitch discrimination. Formally trained musicians show pitch matching and pitch discrimination superior to those of nonmusicians and have greater efferent otoacoustic emission suppression than nonmusicians. This study investigated the relationship among pitch matching, pitch discrimination, and otoacoustic emission suppression in individuals with no formal musical training and who showed varied pitch matching and pitch discrimination. Analysis suggested a significant relationship between pitch matching and pitch discrimination but not between otoacoustic emission suppression and pitch matching and pitch discrimination. Findings are presented in the context of previous research indicating a significant relationship between otoacoustic emission suppression and musical talent in trained musicians. PMID- 17688134 TI - Nonequivalence of computerized and paper-and-pencil versions of Trail Making Test. AB - A computerized version of the Trail Making Test, an adaptation of the classical paper-and-pencil form, was compared with the paper-and-pencil form. The testee must connect targets on the screen with the cursor using the mouse instead of a sheet of paper and a pen. The participants were 68 healthy adolescents and young adults. The comparison of scores on the two versions showed that they cannot be considered equivalent; the difference between the two parts of the test (Parts A and B) was greater in the paper-and-pencil version; correlations between the two versions of Part A and of Part B were significant, but too low to consider the two versions parallel. Both versions were accepted by participants. As expected, mean scores were different in Parts A and B in both versions and magnitude of differences was large. PMID- 17688135 TI - Hand preference consistency and simple rhythmic bimanual coordination in preschool children. AB - This study examined whether strength of hand preference is associated with rhythmic bimanual coordination. 27 preschool children ages 4 to 6 years, identified as 10 right-, 8 left-, and 9 mixed-handed, were evaluated on accuracy and stability with a bimanual tapping task requiring intermodal matching. The primary hypothesis was that consistent right- and left-handers would have an advantage over mixed-handers given higher hemispheric maturation, possibly the corpus callosum, which may be the main interhemispheric communication conduit. A significant difference was noted among the three groups, with right-handers having higher accuracy and stability. This finding suggests that bimanual coordination in young children may be influenced by handedness, which may also be related to the development of interhemispheric communication. PMID- 17688136 TI - Effects of september 11th terrorism stress on estimated duration. AB - Previous research has suggested that the duration of stressful video material is estimated to be longer than one containing less stressful material. The current study sought to examine what effects viewing news coverage of the September 11th 2001 terrorist attacks might have on estimated duration of exposure. 16 participants were recruited from Saint Joseph's College of Maine psychology courses and viewed two 3-min. video clips. One clip contained coverage of the 9 11 terrorist attacks; the other, a nonstressful control, was taken from a familiar segment of The Wizard of Oz. Participants estimated the length of the clip and rated stress experienced while viewing the clip. Analysis showed the September 11th footage was rated as more stressful and was estimated as longer than the control clip. PMID- 17688137 TI - On the elusive nature of the Letters from the Heart effect. AB - The Letters from the Heart effect described by Van den Bergh, Vrana, and Eelen in 1990 is the finding that, in a forced-choice affective evaluation paradigm, typists prefer nonmeaningful letter combinations typed with different fingers over those typed with the same finger, whereas no such preference is evident for nontypists. Typists' dislike of same-finger letter combinations may arise through subconscious activation of motor-behavior memory in affective evaluation tasks, which in turn may create conflicting qualities for same-finger letter combinations given the motor incompatibilities associated with these. Although the effect is cited in the literature, the original finding has never been replicated. The present research attempted to replicate the effect in a series of five studies, involving new sets of letter combinations and a total of 134 typists and 152 nontypists. The effect was not dearly replicated in these studies and thus seems to be elusive. The consistent nonreplication is discussed in terms of a lack of necessary boundary conditions for the effect to emerge reliably and in differences in analysis between the original investigation and the present re- PMID- 17688138 TI - Visual imaging capacity and imagery control in Fine Arts students. AB - This study investigated relationships between visual imaging abilities (imaging capacity and imagery control) and academic performance in 146 Fine Arts students (31 men, 115 women). Mean age was 22.3 yr. (SD= 1.9; range 20-26 yr.). All of the participants who volunteered for the experiment regularly attended classes and were first, second, or third year students. For evaluation of imaging abilities, the Spanish versions of the Gordon Test of Visual Imagery Control, the Vividness of Visual Imagery Questionnaire, the Verbalizer-Visualizer Questionnaire, and Betts' Questionnaire Upon Mental Imagery were used. Academic performance was assessed in four areas, Drawing, Painting, Sculpture, and Complementary Subjects, over a three-year period. The results indicate that imagery control was associated with academic performance in Fine Arts. These findings are discussed in the context of previous studies, and new lines of research are proposed. PMID- 17688139 TI - Relationship between visual and motor imagery. AB - The relationship between visual and motor imagery was investigated by administering a battery of visual and motor imagery measures to a sample of 101 men (n=49) and women (n=52), who ranged in age from 18 to 59 (M=34.5, SD= 12.6). A principal components analysis applied to the correlation matrix indicated four underlying components, which explained 62.9% of the variance. The components were named Implicit Visual Imagery Ability, Self-report of Visual and Motor Imagery, Implicit Motor Imagery Ability, and Explicit Motor Imagery Ability. These results suggested a dissociation between visual and motor imagery although visual and motor imagery were associated as self-reports and there were correlations among particular measures. PMID- 17688140 TI - High school physical education and physical activity in young women. AB - This study assessed if high school physical education experiences were related to physical activity behaviors of young women in college. Undergraduate women from three universities (N = 949) were surveyed concerning their experiences in high school physical education and their physical activity in six areas, aquatics, individual activities, physical conditioning, outdoor adventure, rhythmic activities, and team activities. Analysis indicated that women who completed courses with a diverse curriculum containing content from four of the six categories investigated reported significantly more cardiovascular endurance activities and individual/team sports participation than respondents who completed courses with low curriculum diversity. Results indicate that providing diverse curricular experiences for girls in high school physical education is associated with higher physical activity as young adults. PMID- 17688141 TI - Tolerance of ambiguity: text analytic vs self-report measures in two nonclinical groups. AB - Avoidance of ambiguity can be examined by both text analytic and self-report methods. In previous studies using text analytic methods, clinical groups showed a higher avoidance of ambiguity than nonclinical subjects. In nonclinical subjects, however, higher avoidance of ambiguity did not correlate with emotional processes. In these studies, higher avoidance of ambiguity was assessed by a text analytic method (DoTA), which was applied to the Holtzman Inkblot Technique. However, the Inkblot Technique may not activate those cognitive-affective structures in nonclinical subjects required to elicit higher avoidance of ambiguity. Thus, the following discrepant results can be predicted: in nonclinical subjects, DoTA indicators of higher avoidance of ambiguity based on Holtzman Inkblot Technique do not show correlations with self-report measures of higher avoidance of ambiguity such as the Ambiguity Tolerance Questionnaire, the Inventory for the Measurement of Tolerance of Ambiguity (Reis inventory), or self report measures of related traits of personality such as the Giessen Test. Self report measures of higher avoidance of ambiguity should show such correlations. Two studies were carried out to test these hypotheses. In Study 1, 80 nonclinical subjects (48 women, M age = 34.5 yr.) were examined using the DoTA text analytic method, the Ambiguity Tolerance Questionnaire-14 and the Giessen Test. In Study 2, 82 nonclinical subjects (43 women, M age = 34.0 yr.) were tested using the Reis inventory. The results obtained in these subjects are consistent with the hypothe- PMID- 17688142 TI - Persons with multiple disabilities and minimal motor behavior using small forehead movements and new microswitch technology to control environmental stimuli. AB - Persons with multiple disabilities and minimal motor behavior may be unable to use available microswitch technology to control environmental stimuli. For these persons, one may need to rely on small motor expressions (as responses) and new, matching microswitch technology to ensure a successful outcome. In the present study, a small movement of the forehead skin was selected as the response for two participants (ages 6.5 and 14.2 years) with profound multiple disabilities. The microswitch technology included (a) an optic sensor, i.e., barcode reader, (b) a small tag with horizontal bars attached to the participants' forehead, and (c) an electronic control system which activated stimuli in relation to response occurrence. Movement of the forehead skin shifted up or down the tag with bars and this shifting, if greater than a preset limit and therefore recorded as a response, led to the activation of the control system. Each participant received an ABAB sequence, in which A represented baseline and B intervention phases, and a 6-wk. postintervention check. Analysis showed both participants increased their responding during the intervention phases and maintained that responding at the postintervention check. Implications of the findings were discussed. PMID- 17688143 TI - Brief commentary on "perceived verbal aggressiveness of coaches in volleyball and basketball: a preliminary study". AB - This note contains a brief critical commentary of Bekiari, et al.'s 2006 paper on perceived verbal aggressiveness of coaches. Corrections are made to the description of Lemieux, et al.'s 2002 research, and a weakness in Bekiari, et al's study is identified. PMID- 17688144 TI - Visual memory transformations in dyslexia. AB - Representational Momentum refers to observers' distortion of recognition memory for pictures that imply motion because of an automatic mental process which extrapolates along the implied trajectory of the picture. Neuroimaging evidence suggests that activity in the magnocellular visual pathway is necessary for representational momentum to occur. It has been proposed that individuals with dyslexia have a magnocellular deficit, so it was hypothesised that these individuals would show reduced or absent representational momentum. In this study, 30 adults with dyslexia and 30 age-matched controls were compared on two tasks, one linear and one rotation, which had previously elicited the representational momentum effect. Analysis indicated significant differences in the performance of the two groups, with the dyslexia group having a reduced susceptibility to representational momentum in both linear and rotational directions. The findings highlight that deficits in temporal spatial processing may contribute to the perceptual profile of dyslexia. PMID- 17688145 TI - Psychological profile of Turkish rock climbers: an examination of climbing experience and route difficulty. AB - The purpose of this study was to examine sensation seeking, physical self perception, and intrinsic and extrinsic motives of rock climbers and to compare these psychological constructs with respect to their years of climbing experience and the difficulty of their climbing routes. 64 climbers (M age=29.1 yr., SD=6.4) voluntarily participated in this study. The Arnett Inventory of Sensation Seeking (AISS), Physical Self-Description Questionnaire (PSDQ), and Sport Motivation Scale (SMS) were administered to the rock climbers. Analysis indicated that the mean score of rock climbers on the Novelty subscale of the Sensation Seeking Scale was 33.9 (SD= 3.6) and mean value on the Intensity subscale was 29.2 (SD=5.2). The mean scores of rock climbers on the PSDQ ranged between 3.9 (SD= 1.0, Physical Activity) and 5.1 (SD= 1.1, Body Fat). Descriptive analysis indicated that the highest mean score of rock climbers on the SMS was obtained in Intrinsic motivation to Experience Stimulation (5.7, SD= 0.9). The independent sample t test showed no significant differences in sensation seeking, physical self-perception, and sport motivation with regard to years of climbing experience and route difficulty (p>.05). It may be concluded that sensation seeking in climbers is high, and they have internal motivational orientation and positive physical self-perception; their competence in climbing has no obvious relationship to these variables. PMID- 17688146 TI - Rhythmic ability in children and the effects of age, sex, and tempo.. AB - The aim of the study was to investigate the differentiation, if any, of young children's rhythmic ability that movement frequency (tempo), sex, and age produce. Rhythmic ability was analyzed into its two components, namely, rhythmic accuracy and rhythmic maintenance. The study compared the effect of two tempos, sex, and age on rhythmic accuracy and rhythmic maintenance and examined the association between them. The sample was 170 children (85 boys and 85 girls) between 6 to 9 years old (M= 7.9, SD= 0.9), who were attending the first three grades of public elementary schools in Athens, Greece, and had no extracurricular sports experience. There were no significant differences in performance on rhythmic accuracy and rhythmic maintenance between boys and girls for fast and slow tempos, while age was a significant differentiating factor at the slow tempo but not at the fast tempo. Rhythmic and rhythmic maintenance performances were better at the fast tempo than at the slow one. Rhythmic accuracy performance was better than rhythmic maintenance performance at both tempos. These findings lead to the conclusion that further examination of rhythmic ability performance is required, focusing on aspects of rhythmic maintenance under different tempos and across all children's ages, with varying motor experience. PMID- 17688147 TI - Relationship between perfectionism and social physique anxiety among male and female college student exercisers. AB - The purpose of this study was to examine the relationships between two constructs, social physique anxiety and perfectionism, both conceptually linked to exercise behavior. A secondary purpose was to examine sex differences. Men (n = 80) and women (n = 106) university students who exercised regularly at the campus fitness center completed the Brief Multiple Perfectionism Scale and the Social Physique Anxiety Scale immediately prior to their exercise session. A small but significant correlation was found between the two measures through the Brief Multiple Perfectionism Scale Doubts about Actions. It was concluded that the overall relationship between social physique anxiety and perfectionism is weak. PMID- 17688148 TI - Emotional intelligence and psychological health in a sample of Kuwaiti college students. AB - This summary investigated correlations between emotional intelligence and psychological health amongst 191 Kuwaiti undergraduate students in psychology, 98 men and 93 women (M age=20.6 yr., SD=2.8). There were two measures of emotional intelligence, one based on the ability model, the Arabic Test for Emotional Intelligence, and the other on the mixed model, the Emotional Intelligence Questionnaire. Participants' psychological health was assessed using scales from the Personality Assessment Inventory. A weak relationship between the two types of emotional intelligence was found. A correlation for scores on the Emotional Intelligence Questionnaire with the Personality Assessment Inventory was found but not with those of the Arabic Test for Emotional Intelligence. Regression analysis indicated scores on Managing Emotions and Self-awareness accounted for most of the variance in the association with the Personality Assessment Inventory. Significant sex differences were found only on the Arabic Test for Emotional Intelligence; women scored higher than men. On Emotional Intelligence Questionnaire measures, men had significantly higher means on Managing Emotions and Self-motivation. However, no significant differences were found between the sexes on the Total Emotional Intelligence Questionnaire scores. PMID- 17688149 TI - Approach-avoidance individual differences in changing students' responses to physical education. AB - The purpose of this report was to examine the effects of physical education acrobatic activities as a function of individual differences on approach avoidance tendencies for acrobatics. The data of a study conducted by Robazza, Bortoli, Carraro, and Bertollo (2006) were analyzed after having classified students as high- or low-avoiders. Approach-avoidance tendencies and idiosyncratic emotions related to acrobatic tasks and adventurous sports were originally assessed for 72 Italian male high school students. Experimental participants engaged in acrobatic tasks of physical education for 12 lessons, while control participants were involved in team sports. Analysis showed that high-avoiders changed their emotions positively toward physical education tasks more than low-avoiders, whereas the latter modified their attitudes for adventurous sports. Approach-avoidance tendencies can be expected to moderate involvement in challenging physical activities. PMID- 17688150 TI - Driving Anger Scale, French adaptation: further evidence of reliability and validity. AB - This study was conducted to provide further evidence of reliability and validity for the Driving Anger Scale, French version. A sample of 202 drivers, ages 18-25 years, completed the scale and the general Trait Anger scale from NEO Personality Inventory-Revised. Factor analysis indicated five factors similar to those found in the original U.S. version. The 'Traffic Obstructions' and 'Slow Driving' factors have been slightly modified, and 'Discourtesy' was abandoned. Positive correlations were observed between scores on the Trait-Anger scale from the NEO Personality Inventory-Revised and the Driving Anger Scale (r = .41) and with its factors (from .24 to .38), except for 'Illegal Driving'. The internal consistency of the Driving Anger Scale was acceptable for the total score (alpha = .82) and for factors ranged from .74 to .80. This French version can be preliminarily recommended for the assessment of driving anger in France among young drivers. PMID- 17688151 TI - Preliminary report of a validation study of Instrumental Activities of Daily Living in a Greek sample. AB - To validate the Instrumental Activities of Daily Living in Greek, 44 men (M age=70.5 yr., SD=7.2) and 58 women (M age= 68.4, SD=9.2), outpatients of memory clinics, were studied. Sex differences in the item responses were evaluated. Reliability assessed as Cronbach alpha was .84, while validity was assessed by correlation of .77 with the Mini-Mental State Examination. 21 men and 20 women had moderate to severe dementia, with Mini-Mental State Examination scores <20. The results show that this Greek language version can be effectively used in Greece. PMID- 17688152 TI - Analysis of the efficacy of possessions in boys' 16-and-under basketball teams: differences between winning and losing teams. AB - The purpose of this study was to analyze the ball possessions of winning and losing basketball teams in formative years (16 years and under). The sample was 3,897 ball possessions from 24 games of the boys' 16-and-under finals of the Andalusion Championship, Spain. The variables studied were game outcome, participation, and the initiation and end of each ball possession. Winning teams used more fast breaks and fewer set offenses in their ball possessions. Winning teams had shorter ball possessions and more passes and participating players. Dynamic game styles are necessary in youth basketball, focusing on continuously off-balancing the opponent through fast breaks and a high number of passes in set offenses. PMID- 17688153 TI - Relationship between home and school adjustment: children's experiences at ages 10 and 14. AB - 773 children (359 girls, 414 boys) of two age groups, 10 years and 14 years, completed a questionnaire about subjective experiences of home and school. Children who reported getting along well with their parents and finding it easy to communicate with them also reported being more satisfied with themselves, enjoying school more, feeling less lonely, being less bullied by others, and also bullying others less. Boys reported bullying more than girls and more satisfaction with themselves than girls. Girls reported enjoying school more, feeling lonelier, sometimes having trouble falling asleep, and having headaches more often than boys. Girls at age 14 reported experiencing a prominent increase in headaches and parental complaints about their eating habits. PMID- 17688154 TI - Omni scale rating of perceived exertion at ventilatory breakpoint by direct observation of children's kinematics. AB - Direct kinematic observation was used to measure ratings of perceived exertion at the ventilatory breakpoint (RPE-Vpt) in 10- to 14-yr.-old girls (n=22) and boys (n=22). RPE for the overall body, legs, and chest were simultaneously estimated by a trained observer and self-rated by a subject during treadmill exercise using the Children's OMNI-Walk/Run Scale. Subjects' heart rate and oxygen consumption were measured during each minute of exercise. Vpt for the girls and boys, respectively, were 64.2 and 66.5% VO2 max. RPE-Vpt ranged from 6.0 to 6.5 Overall, 7.1 to 7.6 Legs, and 5.0 to 5.5 Chest for both the observation and self rating procedures. Responses indicated (a) RPE-Vpt (Overall, Legs, Chest) did not differ (p>.05) between the observer and self-rating procedures and (b) Observer RPE-Vpt-Legs was greater (p<.05) than RPE-Vpt-Chest. Findings validated direct kinematic observation to code group-normalized RPE-Vpt for girls and boys performing treadmill exercise. PMID- 17688155 TI - Testing the Finno-Ugrian suicide hypothesis: replication and refinement with regional suicide data from eastern Europe. AB - Multiple lines of evidence indicate specific genetic contributions to suicidal behavior. In particular, geographic studies support the Finno-Ugrian Suicide Hypothesis, i.e., genetic differences between populations may partially account for geographic patterns of suicide prevalence. Specifically, within Europe the high suicide-rate nations constitute a contiguous J-shaped belt. The present research replicated and extended 2003 findings of Voracek, Fisher, and Marusic with new data. Across 37 European nations, an interaction term of squared latitude multiplied with longitude (quantifying the J-shaped belt) accounted for 32% of the cross-national variance in total suicide rates alone, while latitude accounted merely for 18% of variance over and above those. Refined analysis included regional data from countries critical for testing the hypothesis (89 regions of Belarus, western Russia, and the Ukraine) and yielded an even more clear-cut pattern (56% and 3.5%, respectively). These results are consistent with the Finno-Ugrian Suicide Hypothesis. Study limitations and directions for further research are discussed. PMID- 17688156 TI - Contextual interference effects in learning volleyball skills. AB - The aim of this study was to examine the contextual interference effect on learning three volleyball skills. Participants were 26 novice female volleyball players (M age= 12.4 yr., SD= 1.2). They were assigned into two groups, Low Interference (n = 13) and High Interference (n = 13). Two practice schedules were used: blocked (Low Interference) and random (High Interference). The training period lasted for 10 weeks and included 2 training sessions of 75 min. each per week. The pretest was performed before the first training session, the posttest was performed after the completion of the last training period, and the retention test was performed two weeks after the posttest. A 2 (Groups) x 3 (Measurement Periods) analysis of variance with repeated measures indicated significant improvement in performance between pre- and posttests for both High Interference and Low Interference groups for the three skills included in this study. There was no significant main effect of group or interaction effect of group and measure. These findings suggest that either blocked or random practice could be effectively used in learning of volleyball skills by unskilled children. PMID- 17688157 TI - Self-controlled use of a perceived physical assistance device during a balancing task. AB - The nature of the relationship between self-controlled conditions and the participant's perception of when and how to use a physical assistance device while practicing a balancing task was examined. Participants in the Self-control group (n= 9) were allowed to decide when to use a balance pole while performing the task, while the Yoked group (n= 9) had no choice regarding pole usage. The Self-control group had immediate performance benefits that persisted on a delayed retention task. Questionnaire results indicated that the Self-control group predominately used the balance pole when attempting a new performance strategy, while the Yoked group reported they would have preferred use of the pole when attempting a new strategy. Results lend support to the assertion that self controlled conditions facilitate learning because participants can make decisions regarding assistance based on self-generated performance strategy-as relating to their perception of successful movement execution--to a greater extent than under externally controlled conditions. PMID- 17688158 TI - Parents' and teachers' attitudes regarding school involvement in education that extends beyond the traditional academic core. AB - In a survey conducted with 1,107 parents (590 mothers, M age=38.8 yr., SD=5.8; 517 fathers, M age=41.3 yr., SD=6.0) and 123 teachers (82 women, M age=41.1 yr., SD=9.2; 41 men, M age=41.3 yr., SD=9.1) in coastal rural Southern Ostrobothnia, Finland, an assessment of the relative responsibility of the family in comparison with that of school in the teaching of various skills to children was made. Parents and teachers agreed that the school carries 30-40% of the responsibility for the teaching of socio-emotional skills, such as conflict resolution, norms and values, self-esteem, sense of justice and responsibility, and close human relations. They also agreed that school carries 50% of the responsibility for providing information about sexuality and drugs. Fathers opined that school carried a greater responsibility in teaching skills than mothers did. PMID- 17688159 TI - College students' perceptions of sexual orientation and gender given job descriptions and titles for interior decoration, interior design, and architecture. AB - To examine perceptions of design professionals, this study was designed to examine possible gender-bias based on job title and description and whether there is a relationship between the two perceptions. A respondent's sex was significantly related to perceptions of a design professional's sex. Both respondents' sex and the perceived sex of the design professional had significant effects on the perceived sexual orientation of the design professionals. Furthermore, the results also indicated that if the design professional was perceived to be male, there was a higher tendency that he would be perceived as homosexual, especially by a male respondent. PMID- 17688160 TI - Small hand-closure movements used as a response through microswitch technology by persons with multiple disabilities and minimal motor behavior. AB - This study assessed small hand-closure movements as a potential response for microswitch activation with two participants with profound multiple disabilities of 5.2 and 20.6 yr. of age. The microswitch consisted of a two-membrane thin pad fixed to the palm of the hand and a control system. The outer membrane (the one facing the fingers) was a touch-sensitive layer; the inner membrane was activated if the participant applied a pressure of over 20 gm. The activation of either membrane triggered an electronic control system, which in turn activated one or more preferred stimuli for 6 sec. except in baseline phases. Each participant received an ABAB sequence, in which A represented baseline and B intervention phases, and a 1-mo. postintervention check. Analysis showed both participants increased their responding during the intervention phases and maintained that responding at the postintervention check. Implications of the findings are discussed. PMID- 17688161 TI - A pilot study of a possible effect from a motor task on reading performance. AB - This pilot study examined the influence of participation in a 6-week bimanual coordination program on Grade 5 students' reading achievement. Twenty Grade 5 students participated in a bimanual activity (sport stacking) and were tested whether reading achievement scores were significantly different from the scores for 21 control students. The experimental group consisted of 20 students (11 boys, 9 girls) from one intact classroom cohort; the control group consisted of 21 students (12 boys, 9 girls) from one intact classroom cohort. Students in both groups ranged in age from 10 to 11 years. The intact classroom cohorts were randomly assigned to experimental and control groups. Reading achievement was measured by differences in pre- and posttest scores from the GMRT-4 Decoding and Comprehension skill subtests. Group by sex analyses of covariance, using pretest scores as covariates, indicated that there were no significant differences by group or sex for decoding skills. A significant increase was found for the experimental group on Comprehension skills. Therefore, participation in a bimanual coordination program, using sport stacking as the activity, may improve Grade 5 students' reading comprehension skills, regardless of sex. PMID- 17688162 TI - Correlates of a Taoist orientation among Korean students. AB - Associations of .35 and -.34, respectively, were found for a measure of having a Taoist orientation to life with death anxiety and the perception that one's self is unified (versus fragmented) in samples of 41 Korean high school and 145 Korean university students. PMID- 17688163 TI - Dimensional stability of alginate impression material over a four hours time frame. AB - OBJECTIVE: To determine the dimensional stability of alginate impressions poured at varying time intervals in a tropical environment. MATERIALS AND METHODS: Alginate impressions of a master model of truncated metal cones were made and poured at varying time intervals of 5 minutes, 30 minutes, 1 hour, 2 hours and 4hours. The liner dimensional differences between the master cast and stone casts of alginate impressions poured at varying time intervals was determined. RESULTS: Although, there was observed increasing percentage differences with increasing length of time before pouring of the cast for all the inter-abutment distances measured, there was no statistical significant difference in dimension of the cast at ten minutes for all the distances measured except distance D with mean 50.23 and p value 0.010 while there were statistical significant changes observed at all the other time groups and distances. CONCLUSION: Alginate impressions should be cast within 10 minutes although, casts obtained from impressions stored by covering with wet gauze as is commonly done, for not more than 30 minutes will be clinically usable. PMID- 17688164 TI - Anabolic effect of Hibiscus rosasinensis Linn. leaf extracts in immature albino male rats. AB - Many plants remedies have been employed in solving man's health needs especially the nutritive value which enhances health living. Aphrodisiac plants are plants with anabolic properties i.e. they help in protein synthesis and enhances sexual abilities in males. They are also known as androgenic plants because their properties are similar to that of androgen a male hormone. Cold aqueous extract of Hibiscus rosasinensis leaves is reported by local traditional practioners in Western Nigeria to be aphrodisiac. OBJECTIVE: To investigate the anabolic properties of Hibiscus rosasinensis. MATERIALS AND METHOD: Three groups (8/group) of immature male rats of known weights were administered equal doses of aqueous (cold and hot) and alcoholic extracts of Hibiscus rosasinensis leaves for 8 weeks. The gain in body and isolated sexual organs (testis, epididymis, seminal vesicle and prostate) weights were determined after treatment and compared to the value obtained from a fourth untreated group which served as the control. Section through the testes of both the treated and untreated rats were also examined microscopically and displayed as a photomicrograph for comparism. All data were statistically analysed and displaced in graphic form. RESULTS: Over the 8 weeks of treatment, the control, the cold aqueous extract dosed, hot aqueous extract dosed and alcoholic extract dosed rats gained 8%, 15%, 18% and 22% in body weights respectively. The increase in the weight of testis, epididymis, seminal vesicle and prostate of the alcoholic extract dosed rats was 19%, 30%, 31% and 40% respectively. CONCLUSION: The anabolic effect of the leaf extracts of H. rosasinensis is hereby established. More work needs to be done on these leaf extracts to know their effect on the gonadotrophin hormones which regulate the activity of the androgens in relation to spermatogenesis. PMID- 17688165 TI - Public and professional perception of oral and maxillofacial surgery (a pilot study). AB - BACKGROUND: In the advanced countries, the awareness of Oral and maxillofacial surgery by both the public and medical specialties has led to rapid development and expansion of Oral and Maxillofacial surgery specialty with management of diverse and complex problems within a well defined anatomical region. In the developing countries like Nigeria, the trends are slow and this explains why majority of our patients present at very late stage when only palliative measures are the option. OBJECTIVE: The study aims to assess the level of public and professional (GMP and GDP) knowledge and awareness of oral and Maxillofacial surgery specialty. DESIGN: A questionnaire was devised to assess the knowledge and awareness about the specialty of oral and maxillofacial surgery . Ninety one members of the public who were office workers, civil servants, hospital worker in Yaba local government area of Lagos state were the public respondents. The inclusion criteria was that all respondents had attained at least secondary school educational level. They were randomly chosen and had the questionnaires applied to them. Additionally, 40 General medical practitioners and 40 General dental practitioners were picked randomly from 7 local government areas of Lagos state (Yaba, Ebutte Meta, Surulere, Lagos Island, Shomolu, Kosofe and Ikeja) and the questionnaire was applied to them. RESULTS: Only 5.4% of the public had heard of oral and maxillofacial surgeon before. By comparison, the corresponding figures for ENT and plastic surgeons were 40.0% and 23.1% respectively. Only 4.4% of the public had a prior treatment by an oral and maxillofacial surgeon while 86.2% did not know what a maxillofacial surgeon does. The professionals (GMP and GDP) are quite aware of who a maxillofacial surgeon is, but are less knowledgeable of new areas/subspecialties of maxillofacial surgery such as cleft lip and palate surgery, cosmetic and orthognathic surgery, implantology, craniofacial surgery. Also general Medical Practitioners (60%) views of maxillofacial surgeons work are mainly dento-alveolar in horizon. CONCLUSION: These figures are low and it is an indication of low awareness of the specialty by the public and the professionals. While regular auditing ,publications, flow of information, leaflets about oral and maxillofacial surgery to the public, health service personnel, providers and government will improve the trends, continuous professional development Programmes (CPDP) for GDP and GMP will keep them abreast of developments in the specialty. PMID- 17688166 TI - Effect of chloroquine on strips of non-pregnant and pregnant mice uteri in-vitro. AB - Chloroquine (CQ) remains the household drug for the treatment of malaria especially among pregnant women. However, there are reports that CQ inhibits the contractile process in non-pregnant rat's uterus. The aim of this study is to compare responses to CQ between non-pregnant and pregnant mice and identify some mechanisms involved. Experiments were carried out in non-pregnant and pregnant mice pretreated 24 hours before with 1.5 mg/kg-body weight stilboesterol given orally. Strips of uterine smooth muscle, approximately 5 mm in diameter, were mounted in a 20 ml organ bath containing De Jalon solution bubbled with a 95% O2 5% CO2 gas mixture. Responses of the strips to graded concentration of acetylcholine (ACh) (10(-9) to 10(-5) mol/L), oxytocin (OXY) (10(-5) to 10(-2) IU/ml) and CQ (10(-6) to 4 x 10(-4) mol/L) were investigated. The strips were then incubated in 4 x 10(-4) mol/L CQ for 15 mins and the cumulative dose responses for OXY were repeated. To investigate mechanism of action, the strips were incubated for 15 mins in N(w)-nitro L-arginine methyl ester (L-NAME) and the cumulative responses to CQ repeated. Each investigation was carried out in fresh tissue mounted on Grass Model FT03 force transducer coupled unto a 4-channel Grass Model 7D Polygraph. CQ (low to moderate level), ACh and OXY led to increases in contractile responses in the uteri. There were greater contractile responses in non-pregnant than pregnant mice to CQ and ACh. At high doses, CQ had an inhibitory effect on the uterine contraction. Incubating in CQ led to abolition of contractile responses to OXY and ACh. In the presence of L-NAME, inhibitory effect of CQ at high doses was attenuated in pregnant mice only. The results suggest that CQ at high doses inhibits contractile responses in non pregnant and pregnant mice. Enhanced nitric oxide bioactivity attenuated this inhibitory effect. PMID- 17688167 TI - Factors governing the choice of dentifrices by patients attending the Dental Centre, Lagos University Teaching Hospital. AB - OBJECTIVE: To investigate what influences the choice of dentifrice used by patients attending a dental clinic. METHOD: Self-administered questionnaire on patients attending oral diagnosis clinic. Data analyzed for descriptIve statistics using EPI- info 2004 software. RESULTS: Two hundred and three patients comprising of 105 (51.7%) females and 98 (48.3%) males, were involved in this study. Toothpaste with toothbrush was the most common form of oral hygiene practice (90.6%). Cost of the dentifrice (32.5%), the taste of the dentifrice (51.7%), the presence of fluoride (53.7%), availability of the dentifrice (54.7%) and the recommendation of a dental health professional (32.5%) were some of the factors governing choice. CONCLUSION: The choice of dentifrices by patients is governed by factors other than the efficacy of the dentifrice and dental education is important to reverse this trend. PMID- 17688168 TI - Brand variations in the physicochemical properties of metronidazole tablets. AB - This study investigated possible variations in the physiochemical properties of seven brands of metronidazole tablets obtained from different retail pharmacy outlets in Nigeria. The different brands were subjected to various tests such as uniformity of weight, crushing strength, friability, disintegration and dissolution. Chemical assays were also carried out on the tablets. Five of the seven brands of metronidazole tablets passed all British Pharmacopoeia tests; while brand G failed the chemical assay test and brand A failed both the chemical assay and test for friability. Brand A also had the lowest crushing strength which was below the recommended minimum. There was a significant difference (p < 0.001) in the values obtained for the crushing strength of the various brands while no significant difference (p > 0.05) in the friability values. The results show that five of the seven brands are physically and chemically equivalent and could be interchanged irrespective of the brands, while two cannot. The study reinforces the need for constant monitoring of different brands of the same product to ensure quality and consequent efficacy. PMID- 17688169 TI - Impacted mandibular third molars: presentation and postoperative complications at the Lagos University Teaching Hospital. AB - AIM: Surgical extraction of impacted Mandibular third molar is one of the commonest dentoalveolar surgeries. This study aims to investigate the pattern of presentation of impacted Mandibular third molars, the indications for extraction and the post operative complications after this procedure at the Lagos University Teaching Hospital. PATIENTS AND METHODS: A prospective study of patients who required surgical extraction of impacted Mandibular third molars between October 2003 and May 2006 at the Lagos University Teaching Hospital (LUTH) was carried out. Data collected included Patients' age, sex, indication for extraction, tooth/teeth extracted. Also collected were the types of impactions and surgical morbidity (postoperative complications). The data collected were evaluated using the SPSS for windows (version 11.0: SPSS Inc, Chicago, IL) descriptive analysis was used as appropriate. RESULTS: Three hundred and thirty one (331) Mandibular third molars were extracted from 329 patients. The ages ranged from 17 to 55 years with a mean of 26.63 (+/- 7.39). There were 153 males and 176 females; with male to female ratio was 1:1.15. Recurrent Pericoronitis was the most common indication for extraction (209 extractions; 63.1%), while the mesioangular impaction was the most common angulation (117 impactions; 53.4%). 47 (14.2%) of the extractions had postoperative complications and dry socket which occurred in 25 (53.2%) cases was most common. CONCLUSION: The pattern of presentation of impacted Mandibular third molars is similar to earlier reports. The morbidity is however higher than the average value in the literature, it however does not seem to increase with increasing age. PMID- 17688170 TI - Comparison of the effects of tens and sodium salicylate iontophoresis in the management of osteoarthritis of the knee. AB - The aim of this study was to compare the effects of transcutaneous electrical nerve stimulation (TENS) and sodium salicylate Iontophoresis on pain and functional disability in patients with osteoarthritis of the knee. Twenty (20) subjects participated in this study. Their ages ranged from 40-65 years. They were assigned to either the TENS or Iontophoresis group. The application of TENS was done using an EV 904 unit made by. Electro-medical supplies, while Iontophoresis treatment was delivered using a Galvanic current machine by F.W. Read and Sons London. The subjects levels of pain and functional disability prior to commencement of treatment and after the 6 weeks of treatment was taken using the Visual Analogue Scale (VAS) and Disability Index Questionnaire for patients with osteoarthritis of the knee joint(s). Analysis of data obtained was done using the Mann-Whitney U test and level of significance was set at (P < 0.05). The statistical analysis of the result showed a statistically significant reduction in pain and functional disability in both groups (P < 0.05). Patients treated with Sodium salicylate iontophoresis had a more statistically significant reduction of pain and functional disability in comparison with TENS group (P < 0.05). It is hereby suggested that the use of sodium salicylate iontophoresis and TENS be included in treatment of osteoarthritis to enhance pain relief and functional activity. PMID- 17688171 TI - Analgesic, antipyretic and anti-inflammatory properties of Mezoneuron benthamianum Baill (Caesalpiniaceae). AB - The analgesic, antipyretic and anti-inflammatory effects of the aqueous extract of Mezoneuron benthamianum (MB) were evaluated in mice, rats and rabbits using the mouse writhing, tail flick, hot plate and formalin-induced pain tests; 2-4 Dinitrophenol (DNP), D-Amphetamine and E-coli Lipopolysaccharide-induced pyrexia and carrageenan, egg albumin and xylene-induced oedema. The extract (400-1600 mg/kg) and acetylsalicylic acid (100 mg/ kg) produced a significant (P < 0.05) inhibition of the second phase response in the formalin pain model, while only the highest dose (1600 mg/kg) of the extract showed a comparable antinociceptive effect in the first phase. The extract also showed a dose-dependent inhibition of acetic acid induced abdominal writhing. The tail flick latency and the hot plate pain threshold were dose dependently enhanced by the extract but these were significantly lower than that produced by morphine (2 mg/kg). The 2,4-DNP and D Amphetamine (10 and 5 mg/kg, i.p.respectively) increased the rectal temperatures of rats within 30 minutes of their administration. The extract at doses of 400,800 and 1600 mg/kg produced significant lowering of the elevated body temperature in rats. The extract (800 mg/ kg) administered orally to rabbits passaged with E. coil lipopolysacharride was able to relieve the pyrogen induced fever. The antipyretic effect produced by the extract was comparable to a standard antipyretic drug, aspirin. The extract (400-1600 mg/kg) administered 1h after carrageenan-induced paw swelling did not inhibit the oedema. No inhibitions were observed with the egg albumin and xylene induced oedema models. Phytochemical analysis revealed the presence of flavonoids, tannins, cardiac glycosides, anthraquinones, and saponins. Administration of the extract up to 2 g/kg (orally) did not produce any toxic effect in the acute toxicity studies in mice. The LD50 of the extract when administered intraperitoneally was 1021.31 mg/kg. The data obtained show that MB extract possesses analgesic and antipyretic activities but lacks an anti-inflammatory property. PMID- 17688172 TI - Biochemical markers, extracellular components in liver fibrosis and cirrhosis. AB - Liver fibrosis and cirrhosis are common sequelae to diverse liver injuries in the tropics or Nigeria. The development of hepatic fibrosis or cirrhosis is due to increased synthesis, deposition, and possibly reduced degradation of hepatic extracellular matrix components, especially collagens, such as interstitial type I and III, basement membrane type IV, microfibrillar type VI, and pericellular type V, non-collagenous proteins, such as laminin, fibronectin, undulin, etc., and various types of proteoglycans, such as hyaluronan, etc. In Nigeria, the common approach for diagnosing or assessing the activity of connective tissue in this organ is the histological examination of a biopsy, if one is performed by a specialist physician. The liver biopsy provides a static picture of the changes that have already taken place in the liver. Another possible method is (where the facilities are available) a quantitative assessment of the liver biopsy by biochemical determination of total collagen via hydroxyproline. Biopsy is an invasive method and cannot be repeated often enough in the bid to ensuring an intensive follow-up of the changes taking place during the course of antifibrotic treatment or therapy. Thus, serum or other biological fluid assays for connective tissue proteins, such as the aminoterminal propeptide of type III Procollagen PIIINP, or the dimeric carboxyterminal domain of type IV collagen known as NCl or PIVCP, laminin, and others are essentially non-invasive and can be carried out repeatedly. In addition, the measurement of certain enzymes of connective tissue proteins in serum may the reflect activity of liver fibrogenesis. They offer the potential for diagnosis and therapeutic control. However, it is very important to note that circulating biochemical markers of fibrogenesis, fibrolysis or both may not reflect hepatic fibrosis or cirrhosis, since they are not liver-specific. Thus, the best diagnostic approach would be the identification and measurement in serum of the driving force of fibrogenic process. PMID- 17688173 TI - Effect of Five Alive fruit juice on the dissolution and absorption profiles of ciprofloxacin. AB - OBJECTIVE: To determine the effect of interaction of five Alive fruit juice on the dissolution and absorption profiles of ciprofloxacin tablets using urinary excretion. METHODS: In-vitro dissolution of ciprofloxacin 500 mg tablets was studied using US Pharmacopoeia dissolution apparatus II. This was conducted using 0.1N HCl and equal volumes of the fruit juice and 0.1N HCL. Samples were collected at predetermined time intervals for two hours. For the in-vivo study, eleven (5 males and 6 females) healthy volunteers participated in an open, single dose, cross-over randomized trial. After an overnight fasting, each volunteer either ingested a 500 mg ciprofloxacin tablet with 250 ml table water or with the fruit juice. Total urine voided was collected for 72 hrs after each dose of ciprofloxacin. Dissolution and urine samples were assayed using a controlled and validated UV spectrophotometric analysis. RESULTS: A lag time of 5 minutes was observed in dissolution profile of ciprofloxacin in the juice. The percent dissolved of ciprofloxacin in 0.1NHCl and fruit juice were found to be dissimilar (f2 =18.2) using similarity factor. There was statistical difference between the K(el) (elimination constant), K(e) (excretion rate) and X(u) (cumulative amount excreted unchanged) of subjects on water (0.1759 +/- 0.0144; 12.81 +/- 1.36; 375.5 +/- 41.2) and that of fruit juice (0.1250 +/- 0.0161; 7.6 +/- 1.07; 241.6 +/- 34.0). However, there was no difference between the t(1/2) of the subjects (4.2 +/- 0.3; 5.5 +/- 0.8). There was a decrease in relative availability of the drug by 35.75%. CONCLUSION: We conclude that the absorption of ciprofloxacin can be reduced by concomitant ingestion of the juice containing calcium carbonate and grape. Therefore to avoid drug therapeutic failures and subsequent bacterial resistance as a result of subtherapeutic level of the drug in the systemic circulation, ingestion of the juice with ciprofloxacin should be discouraged. PMID- 17688174 TI - Host genetic factors in resistance and susceptibility to malaria. PMID- 17688175 TI - The influence of genetic innate resistance and acquired immunity on drug treatment outcome of uncomplicated Plasmodium falciparum malaria in Tanzania. PMID- 17688176 TI - How genetics and biology helped humanity to survive falciparum malaria. PMID- 17688177 TI - Genetic diversity and population history of Plasmodium falciparum and Plasmodium vivax. PMID- 17688179 TI - At the interface between parasite and host: the salivary glands of the African malaria vector Anopheles gambiae. PMID- 17688178 TI - Comparative analysis of molecular variation in Plasmodium falciparum and P. reichenowi maebl gene. PMID- 17688180 TI - Spatial and long term temporal distribution of the Anopheles maculipennis complex species in Italy. PMID- 17688181 TI - Global undernutrition during gestation influences learning during adult life. AB - Intrauterine growth restriction can lead to significant long-term health consequences such as metabolic and cardiovascular disorders, but less is known about its effects on choice and behavioral adaptation in later life. Virgin Wistar rats were time mated and randomly assigned to receive either ad-libitum access to chow or 30% of that level of nutrition during pregnancy to generate growth-restricted offspring. At 60 days of age, 6 female offspring from each group were trained on concurrent variable-interval schedules. Sessions consisted of seven randomly arranged concurrent-schedule components, each with a different reinforcer ratio that varied from 27:1 to 1:27, and each component lasting for 10 reinforcer deliveries. Behavioral change across reinforcers in components, measured by sensitivity to reinforcement, was consistently lower for offspring of undernourished mothers, showing that their behavior was less adaptable to environmental change. These results provide direct experimental evidence for a link between prenatal environmental conditions and reduced behavioral adaptability--learning--in later life. PMID- 17688182 TI - Learning of colonial odor in the ant Cataglyphis niger (Hymenoptera; Formicidae). AB - Ants learn the odors of members of their colony early in postnatal life, but their ability to learn to recognize noncolony conspecifics and heterospecifics has never been explored. We used a habituation-discrimination paradigm to assess individual recognition in adult Formicine ants, Cataglyphis niger. Pairs of workers from different colonies were placed together for repeated trials, and their ability to discriminate the ant that they encountered from another familiar or unfamiliar ant was observed. Some ants were isolated between encounters, and others were returned to their home colonies. Our results suggest for the first time in ants that C. niger adults learn about individual ants that they have encountered and recognize them in subsequent encounters. Ants are less aggressive toward non-nestmates after they are familiar with one another, but they are aggressive again when they encounter an unfamiliar individual. Learning about non nestmates does not interfere with an ant's memory of members from its own colony. PMID- 17688183 TI - Maintenance of responding when reinforcement becomes delayed. AB - In four experiments with rats, we examined the persistence of behavior when reinforcement was switched from immediate to delayed. In Experiment 1, lever pressing elicited by instrumental training with immediate reinforcement continued when a 20-sec delay of reinforcement was introduced (easy-to-hard condition), whereas when the delay condition was introduced from the start (hard-to-hard condition), responding remained low throughout. A similar result was obtained in Experiment 2, in which lever pressing was elicited by a classical conditioning (autoshaping) procedure. In Experiment 3, rats initially trained with delayed reinforcement continued to respond at a low rate when switched to immediate reinforcement (hard-to-easy condition). By measuring magazine entry (goal tracking) as well as lever pressing (sign tracking) in Experiment 4, we confirmed that such transfer effects at least partly involve the persistence of whatever type of behavior was initially dominant. PMID- 17688184 TI - Resurgence of behavior during extinction depends on previous rate of response. AB - In two experiments, food-deprived rat subjects leverpressed for food in three successive training phases. In the first phase of both experiments, rats were exposed to a multiple schedule, one component of which produced a high rate of response, and the other of which produced a lower rate of response (multiple random ratio [RR], random interval [RI] in Experiment 1, and multiple differential reinforcement of high rate, differential reinforcement of low rate in Experiment 2). Rats were then transferred to a multiple fixed interval (FI; 60 sec, 60-sec) schedule, until the effects of the first phase on response rate were no longer apparent and their response rates did not differ from those of rats responding on a multiple FI 60-sec, FI 60-sec schedule without previously experiencing a multiple RR, RI schedule. During the third stage oftraining, all rats were placed into extinction. During extinction, rates of responding were higher in the component previously associated with the high rate of responding in Phase 1, and they were lower in the component previously associated with low rates of responding in Phase 1. These results suggest that resurgence effects, like other history effects, are controlled by previous rates of responding. PMID- 17688185 TI - Pigeons' memory for sequences of light flashes when gap duration is an unreliable discriminative cue. AB - In Experiment 1, pigeons were trained with a 1-sec dark and a 1-sec houselight illuminated delay interval to discriminate between sequences of two and four flashes of light (feeder illumination). The sequences could be discriminated on the basis of the number of flashes, the number of gaps, or the duration of the gap between flashes. A choose-few bias was obtained at extended dark delays, but not at extended illuminated delays. Pigeons appeared to confuse long dark delays with the longer gap between flashes on few-sample trials. In Experiment 2, additional sample sequences were included that made gap duration an unreliable cue for discriminating between the few and many samples. A significant choose many bias was obtained at extended dark delay intervals, but no biased forgetting was found at extended illuminated delays. The pigeons appeared to discriminate light flash sequences by relying on multiple temporal features of a sequence rather than using an event switch to count flashes. The biased-forgetting effects observed appear to be due to instructional ambiguity that results from the similarity of the delay interval to features of the flash sequences. PMID- 17688186 TI - Temporal generalization and peak shift in humans. AB - Three experiments investigated temporal generalization in humans. In Experiment 1, a peak shift effect was produced when participants were given intradimensional discrimination training. In Experiment 2, after training with a standard S+ and generalization testing with an asymmetrical series of durations, generalization gradients moved toward the prevailing adaptation level. In Experiment 3, generalization gradients showed acentral tendency shift and moved away from the S+ and toward the mean of the test series (of 11 stimulus durations) after participants received training with S+ and S- durations that in one condition were the 2nd and 4th and in another condition were the 4th and 2nd stimuli in the series, respectively. The results were inconsistent with an absolute account of peak shift but were consistent with an adaptation level account of peak shift. PMID- 17688187 TI - Beat shock proteins and atrial fibrillation. AB - In this mini-review, the role of heat shock proteins in susceptability to induction of atrial fibrillation (AF) or in the process of AF is discussed. AF is the most common arrhythmia in humans, is self-perpetuating in nature and hence tends to become more persistent in time. Some studies show a correlation between high Hsp70 (HspA1A) expression in cardiac tissue and a reduced susceptability to induction of postoperative AF. Expression of Hsp70, Hsc70 (HspA8), Hsp40 (DnaJB1), Hsp60 (HspD1), Hsp90 (HspC1) was not associated with progression of AF. However, both correlative studies in human and experimental studies suggest that Hsp27 (HspB1) may delay progression of AF to the more permanent forms and hence Hsp27 might be referred to as a "Beat shock protein". PMID- 17688188 TI - Cellular accumulation of heat shock protein (Hsp) 72i in fetuses of trained rats. AB - Forty-five Sprague-Dawley rats (60-80 days old) were randomly placed into one of three groups: sedentary pregnant control (PC); prepregnancy trained animals that exercised throughout pregnancy (PR); and nonpregnant trained animals (NPR). Each exercising animal ran at approximately 60-70% aerobic capacity (VO2max) for 1 hour/day up to and including day 18 of gestation (term = 21 days). On day 20 of gestation, fetuses were excised from each pregnant animal and scrutinized for gross abnormalities. In 3 randomly chosen fetuses from each litter, brain, heart, kidney, hind limb, and placental tissues were removed to assess the accumulation of the inducible isoform of the 70-kilodalton heat shock protein (Hsp 72i). No significant differences were detected between fetal hearts, hind limbs, or placental tissues of PC or PR groups. No Hsp 72i signal could be detected in fetal kidney or brain tissues from either pregnant group. Results indicate that maternal core temperature did not reach the threshold that would induce either gross fetal abnormalities or a fetal heat shock protein response. However, fetal and placental growth was reduced by the exercise protocol. PMID- 17688189 TI - Investigating cellular stress responses--a multidisciplinary approach from basic science to therapeutics--report on the EuroSciCon (European Scientific Conferences) meeting. AB - The meeting on "Investigating cellular stress responses--a multidisciplinary approach from basic science to therapeutics" was held in London on 13 October 2006. The purpose of this 1-day meeting was to bring together European scientists investigating the immune biology of stress proteins and their potential clinical applications. The main topics included: the role of heat shock proteins (Hsps) in bacterial infections; the role of Hsps with a molecular mass of about 70 kDa in cancer therapy and in prediction of the clinical outcome following allogeneic hematopoietic stem cell transplantation; the quality and duration of stress as a danger signal for the initiation of a stress response; the mechanism of Hsp protein interaction; and Hsp export from tumor cells in secretory granules. PMID- 17688190 TI - Diversity of physiological cell reactivity to heat shock protein 60 in different mouse strains. AB - Heat shock proteins (Hsp) are families of highly conserved molecules and immunodominant antigens in some infections and in autoimmune diseases. Some reports suggest that different regions of the Hsp60 molecule induce distinct immune responses. However, there are no reports comparing physiological T-cell reactivity to Hsp60 in mice. In this study, we have analyzed T-cell proliferation and cytokine production induced by Hsp60, under physiological conditions, in three mouse strains bearing distinct major histocompatibility complex (MHC) backgrounds. Proliferative response predominantly was found in C57BL/6 mice, mostly induced by N-terminal and intermediate Hsp60 peptides (P < 0.0001). Interferon-gamma (IFNgamma) production was broadly induced by different regions of Hsp60 in all three mouse strains, although response was focused in different peptide groups in each strain. We did not observe an exclusive Th1 or Th2 cytokine profile induced by any particular region of Hsp60. However, we identified a strain hierarchy in IL-10 production induced by Hsp60 peptides from different regions, mostly detected in C3H/HePas, and in BALB/c, but not in C57BL/6 mice. In contrast, IL-4 production only was induced by the intermediate and C-terminal region peptides in both C3H/HePas and BALB/c mice. Our data give original information on physiological cellular reactivity to Hsp60. We also have identified peptides with the capacity to induce the production of anti inflammatory cytokines, bringing perspectives for their use in immunotherapy of chronic inflammatory diseases and allograft rejection. PMID- 17688191 TI - Homologous cpn60 genes in Rhizobium leguminosarum are not functionally equivalent. AB - Many bacteria possess 2 or more genes for the chaperonin GroEL and the cochaperonin GroES. In particular, rhizobial species often have multiple groEL and groES genes, with a high degree of amino-acid similarity, in their genomes. The Rhizobium leguminosarum strain A34 has 3 complete groE operons, which we have named cpn.1, cpn.2 and cpn.3. Previously we have shown the cpn. 1 operon to be essential for growth, but the two other cpn operons to be dispensable. Here, we have investigated the extent to which loss of the essential GroEL homologue Cpn60.1 can be compensated for by expression of the other two GroEL homologues (Cnp60.2 and Cpn60.3). Cpn60.2 could not be overexpressed to high levels in R. leguminosarum, and was unable to replace Cpn60.1. A strain that overexpressed Cpn60.3 grew in the absence of Cpn60.1, but the complemented strain displayed a temperature-sensitive phenotype. Cpn60.1 and Cpn60.3, when coexpressed in Escherichia coli, preferentially selfassembled rather than forming mixed heteroligomers. We conclude that, despite their high amino acid similarity, the GroEL homologues of R. leguminosarum are not functionally equivalent in vivo. PMID- 17688192 TI - Heat stress inhibits skeletal muscle hypertrophy. AB - Heat shock proteins (Hsps) are molecular chaperones that aid in protein synthesis and trafficking and have been shown to protect cells/tissues from various protein damaging stressors. To determine the extent to which a single heat stress and the concurrent accumulation of Hsps influences the early events of skeletal muscle hypertrophy, Sprague-Dawley rats were heat stressed (42 degrees C, 15 minutes) 24 hours prior to overloading 1 plantaris muscle by surgical removal of the gastrocnemius muscle. The contralateral plantaris muscles served as controls. Heat-stressed and/or overloaded plantaris muscles were assessed for muscle mass, total muscle protein, muscle protein concentration, Type I myosin heavy chain (Type I MHC) content, as well as Hsp72 and Hsp25 content over the course of 7 days following removal of the gastrocnemius muscle. As expected, in non-heat stressed animals, muscle mass, total muscle protein and MHC I content were significantly increased (P < 0.05) following overload. In addition, Hsp25 and Hsp72 increased significantly after 2 and 3 days of overload, respectively. A prior heat stress-elevated Hsp25 content to levels similar to those measured following overload alone, but heat stress-induced Hsp72 content was increased significantly greater than was elicited by overload alone. Moreover, overloaded muscles from animals that experienced a prior heat stress showed a lower muscle mass increase at 5 and 7 days; a reduced total muscle protein elevation at 3, 5, and 7 days; reduced protein concentration; and a diminished Type I MHC content accumulation at 3, 5, and 7 days relative to nonheat-stressed animals. These data suggest that a prior heat stress and/or the consequent accumulation of Hsps may inhibit increases in muscle mass, total muscle protein content, and Type I MHC in muscles undergoing hypertrophy. PMID- 17688193 TI - Expression of heat shock proteins in myocardium of patients with atrial fibrillation. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia. Because heat shock proteins (Hsp) can protect cells from stress, we compared the levels of Hsp60, Hsp72, Hsc73, and Hsp27 in atrial myocardium from 17 patients with AF (8 paroxysmal and 9 persistent) and 7 controls in sinus rhythm (SR). Hsp60, Hsp72, and Hsc73 levels were not significantly different among the 3 groups. Hsp27 expression was slightly higher in paroxysmal AF than in SR and in persistent AF, and a borderline significant difference (P = 0.064) was seen between the paroxysmal and persistent AF subgroups. Hsp60 levels in the moderate, severe, and profound myolysis groups were significantly lower than the light myolysis group, but no differences were found in other Hsps. In summary, the data indicate that expression of Hsp27 and Hsc73 may be associated with different stages of AF and that Hsp60 also may be associated with the degree of atrial myolysis. PMID- 17688195 TI - Analysis of the alphaB-crystallin domain responsible for inhibiting tubulin aggregation. AB - The cytoskeleton has a unique property such that changes of conformation result in polymerization into a filamentous form. alphaB-Crystallin, a small heat shock protein (sHsp), has chaperone activities for various substrates, including proteins constituting the cytoskeleton, such as actin; intermediate filament; and tubulin. However, it is not clear whether the "alpha-crystallin domain" common to sHsps also has chaperone activity for the protein cytoskeleton. To investigate the possibility that the C-terminal alpha-crystallin domain of alpha-crystallin has the aggregation-preventing ability for tubulin, we constructed an N-terminal domain deletion mutant of alphaB-crystallin. We characterized its structural properties and chaperone activities. Far-ultraviolet (UV) circular dichroism measurements showed that secondary structure in the alpha-crystallin domain of the deletion mutant is maintained. Ultracentrifuge analysis of molecular masses indicated that the deletion mutant formed smaller oligomers than did the full length protein. Chaperone activity assays demonstrated that the N-terminal domain deletion mutant suppressed heat-induced aggregation of tubulin well. Comparison of chaperone activities for 2 other substrates (citrate synthase and alcohol dehydrogenase) showed that it was less effective in the suppression of their aggregation. These results show that alphaB-crystallin recognizes a variety of substrates and especially that alpha-crystallin domain binds free cytoskeletal proteins. We suggest that this feature would be advantageous in its functional role of holding or folding multiple proteins denatured simultaneously under stress conditions. PMID- 17688194 TI - Characterizing the role of Hsp90 in production of heat shock proteins in motor neurons reveals a suppressive effect of wild-type Hsf1. AB - Induction of heat shock proteins (Hsps) is under investigation as treatment for neurodegenerative disorders, yet many types of neurons, including motor neurons that degenerate in amyotrophic lateral sclerosis (ALS), have a high threshold for activation of the major transcription factor mediating stress-induced Hsp upregulation, heat shock transcription factor 1 (Hsf1). Hsf1 is tightly regulated by a series of inhibitory checkpoints that include sequestration in multichaperone complexes governed by Hsp90. This study examined the role of multichaperone complexes in governing the heat shock response in motor neurons. Hsp90 inhibitors induced expression of Hsp70 and Hsp40 and transactivation of a human inducible hsp70 promoter-green fluorescent protein (GFP) reporter construct in motor neurons of dissociated spinal cord-dorsal root ganglion (DRG) cultures. On the other hand, overexpression of activator of Hsp90 adenosine triphosphatase ([ATPase 1], Aha1), which should mobilize Hsf1 by accelerating turnover of mature, adenosine triphosphate-(ATP) bound Hsp90 complexes, and death domain associated protein (Daxx), which in cell lines has been shown to promote transcription of heat shock genes by relieving inhibition exerted by interactions between nuclear Hsp90/multichaperone complexes and trimeric Hsf1, failed to induce Hsps in the absence or presence of heat shock. These results indicate that disruption of multichaperone complexes alone is not sufficient to activate the neuronal heat shock response. Furthermore, in motor neurons, induction of Hsp70 by Hsp90-inhibiting drugs was prevented by overexpression of wild-type Hsfl, contrary to what would be expected for a classical Hsf1-mediated pathway. These results point to additional differences in regulation of hsp genes in neuronal and nonneuronal cells. PMID- 17688196 TI - Comparative genomic analysis of the Hsp70s from five diverse photosynthetic eukaryotes. AB - We have identified 24 members of the DnaK subfamily of heat shock 70 proteins (Hsp70s) in the complete genomes of 5 diverse photosynthetic eukaryotes. The Hsp70s are a ubiquitous protein family that is highly conserved across all domains of life. Eukaryotic Hsp70s are found in a number of subcellular compartments in the cell: cytoplasm, mitochondrion (MT), chloroplast (CP), and endoplasmic reticulum (ER). Although the Hsp70s have been the subject of intense study in model organisms, very little is known of the Hsp70s from early diverging photosynthetic lineages. The sequencing of the complete genomes of Thalassiosira pseudonana (a diatom), Cyanidioschyzon merolae (a red alga), and 3 green algae (Chlamydomonas reinhardtii, Ostreococcus lucimarinus, Ostreococcus tauri) allow us to conduct comparative genomics of the Hsp70s present in these diverse photosynthetic eukaryotes. We have found that the distinct lineages of Hsp70s (MT, CP, ER, and cytoplasmic) each have different evolutionary histories. In general, evolutionary patterns of the mitochondrial and endoplasmic reticulum Hsp70s are relatively stable even among very distantly related organisms. This is not true of the chloroplast Hsp70s and we discuss the distinct evolutionary patterns between "green" and "red" plastids. Finally, we find that, in contrast to the angiosperms Arabidopsis thaliana and Oryza sativa that have numerous cytoplasmic Hsp70, the 5 algal species have only 1 cytoplasmic Hsp70 each. The evolutionary and functional implications of these differences are discussed. PMID- 17688197 TI - Nuclear translocation of 2-amino-3-ketobutyrate coenzyme A ligase by cold and osmotic stress. AB - Cells are continuously exposed to environmental stresses and respond to them to maintain cellular homeostasis. Failure to respond to these stresses may cause pathological states such as renal failure, complications of diabetes, and autoimmune diseases. Signal transduction induced by osmotic and cold stresses is not fully understood. In addition, mechanisms of these stress responses are yet to be elucidated. Activation of many signaling pathways induces translocation of proteins into the nucleus to transduce signals and regulate nuclear functions. By using inducible translocation trap (ITT), a reporter gene-based screening technique, nuclear translocation of 2-amino-3-ketobutyrate coenzyme A ligase (KBL) was detected in response to cold and osmotic stresses. Rapid nuclear translocation of KBL was confirmed by biochemical analysis and fluorescent microscopy. A large region of KBL was required for stress-induced nuclear translocation. The KBL reporter system will be a useful tool for the investigation of cold and osmotic stress responses. PMID- 17688198 TI - Identification of the PP2A-interacting region of heat shock transcription factor 2. AB - Previous work in our laboratory demonstrated the existence of an association between heat shock transcription factor 2 (HSF2) and the serine/threonine phosphatase 2A, which is mediated by interaction between HSF2 and the A subunit (also called PR65) of this protein phosphatase. In light of the importance of HSF2-PP2A association for HSF2 cellular function, in this study, we have sought to dissect the sequences within HSF2 that are important for interaction with the A subunit of PP2A. The results of these experiments indicate that the HSF2 region comprising amino acids 343-363 is important for A subunit interaction. This region includes part of the C-terminal leucine zipper motif of HSF2 called heptad repeat C (HR-C). The results of transfection/immunoprecipitation experiments also show that deletion of the 6 amino acids from 343 to 348 from HSF2 (HSF2 (delta343 348)), is sufficient to prevent HSF2 from interacting with PP2A. These data provide insight into a new functional domain of HSF2, the PP2A A subunit interacting region. PMID- 17688199 TI - Reduced-complexity delayed-decision algorithm for context-based image processing systems. AB - It is well known that the performance of context-based image processing systems can be improved by allowing the processor (e.g., an encoder or a denoiser) a delay of several samples before making a processing decision. Often, however, for such systems, traditional delayed-decision algorithms can become computationally prohibitive due to the growth in the size of the space of possible solutions. In this paper, we propose a reduced-complexity, one-pass, delayed-decision algorithm that systematically reduces the size of the search space, while also preserving its structure. In particular, we apply the proposed algorithm to two examples of adaptive context-based image processing systems, an image coding system that employs a context-based entropy coder, and a spatially adaptive image-denoising system. For these two types of widely used systems, we show that the proposed delayed-decision search algorithm outperforms instantaneous-decision algorithms with only a small increase in complexity. We also show that the performance of the proposed algorithm is better than that of other, higher complexity, delayed decision algorithms. PMID- 17688200 TI - Interconversion between truncated Cartesian and polar expansions of images. AB - In this paper, we propose an algorithm for lossless conversion of data between Cartesian and polar coordinates, when the data is sampled from a 2-D real-valued function (a mapping: R2 --> R) expressed as a particular kind of truncated expansion. We use Laguerre functions and the Fourier basis for the polar coordinate expression. Hermite functions are used for the Cartesian coordinate expression. A finite number of coefficients for the truncated expansion specifies the function in each coordinate system. We derive the relationship between the coefficients for the two coordinate systems. Based on this relationship, we propose an algorithm for lossless conversion between the two coordinate systems. Resampling can be used to evaluate a truncated expansion on the complementary coordinate system without computing a new set of coefficients. The resampled data is used to compute the new set of coefficients to avoid the numerical instability associated with direct conversion of the coefficients. In order to apply our algorithm to discrete image data, we propose a method to optimally fit a truncated expression to a given image. We also quantify the error that this filtering process can produce. Finally the algorithm is applied to solve the polar-Cartesian interpolation problem. PMID- 17688201 TI - Robust image watermarking based on multiband wavelets and empirical mode decomposition. AB - In this paper, we propose a blind image watermarking algorithm based on the multiband wavelet transformation and the empirical mode decomposition. Unlike the watermark algorithms based on the traditional two-band wavelet transform, where the watermark bits are embedded directly on the wavelet coefficients, in the proposed scheme, we embed the watermark bits in the mean trend of some middle frequency subimages in the wavelet domain. We further select appropriate dilation factor and filters in the multiband wavelet transform to achieve better performance in terms of perceptually invisibility and the robustness of the watermark. The experimental results show that the proposed blind watermarking scheme is robust against JPEG compression, Gaussian noise, salt and pepper noise, median filtering, and ConvFilter attacks. The comparison analysis demonstrate that our scheme has better performance than the watermarking schemes reported recently. PMID- 17688202 TI - Time-reversal MUSIC imaging of extended targets. AB - This paper develops, within a general framework that is applicable to rather arbitrary electromagnetic and acoustic remote sensing systems, a theory of time reversal "MUltiple Signal Classification" (MUSIC)-based imaging of extended (nonpoint-like) scatterers (targets). The general analysis applies to arbitrary remote sensing geometry and sheds light onto how the singular system of the scattering matrix relates to the geometrical and propagation characteristics of the entire transmitter-target-receiver system and how to use this effect for imaging. All the developments are derived within exact scattering theory which includes multiple scattering effects. The derived time-reversal MUSIC methods include both interior sampling, as well as exterior sampling (or enclosure) approaches. For presentation simplicity, particular attention is given to the time-harmonic case where the informational wave modes employed for target interrogation are purely spatial, but the corresponding generalization to broadband fields is also given. This paper includes computer simulations illustrating the derived theory and algorithms. PMID- 17688203 TI - Statistical reconstruction for cosmic ray muon tomography. AB - Highly penetrating cosmic ray muons constantly shower the earth at a rate of about 1 muon per cm2 per minute. We have developed a technique which exploits the multiple Coulomb scattering of these particles to perform nondestructive inspection without the use of artificial radiation. In prior work [1]-[3], we have described heuristic methods for processing muon data to create reconstructed images. In this paper, we present a maximum likelihood/expectation maximization tomographic reconstruction algorithm designed for the technique. This algorithm borrows much from techniques used in medical imaging, particularly emission tomography, but the statistics of muon scattering dictates differences. We describe the statistical model for multiple scattering, derive the reconstruction algorithm, and present simulated examples. We also propose methods to improve the robustness of the algorithm to experimental errors and events departing from the statistical model. PMID- 17688204 TI - Segmentation and quantification of human vessels using a 3-D cylindrical intensity model. AB - We introduce a new approach for 3-D segmentation and quantification of vessels. The approach is based on a 3-D cylindrical parametric intensity model, which is directly fitted to the image intensities through an incremental process based on a Kalman filter. Segmentation results are the vessel centerline and shape, i.e., we estimate the local vessel radius, the 3-D position and 3-D orientation, the contrast, as well as the fitting error. We carried out an extensive validation using 3-D synthetic images and also compared the new approach with an approach based on a Gaussian model. In addition, the new model has been successfully applied to segment vessels from 3-D MRA and computed tomography angiography image data. In particular, we compared our approach with an approach based on the randomized Hough transform. Moreover, a validation of the segmentation results based on ground truth provided by a radiologist confirms the accuracy of the new approach. Our experiments show that the new model yields superior results in estimating the vessel radius compared to previous approaches based on a Gaussian model as well as the Hough transform. PMID- 17688205 TI - Hierarchical dynamic range coding of wavelet subbands for fast and efficient image decompression. AB - An image coding algorithm, Progressive Resolution Coding (PROGRES), for a high speed resolution scalable decoding is proposed. The algorithm is designed based on a prediction of the decaying dynamic ranges of wavelet subbands. Most interestingly, because of the syntactic relationship between two coders, the proposed method costs an amount of bits very similar to that used by uncoded (i.e., not entropy coded) SPIHT. The algorithm bypasses bit-plane coding and complicated list processing of SPIHT in order to obtain a considerable speed improvement, giving up quality scalability, but without compromising coding efficiency. Since each tree of coefficients is separately coded, where the root of the tree corresponds to the coefficient in LL subband, the algorithm is easily extensible to random access decoding. The algorithm is designed and implemented for both 2-D and 3-D wavelet subbands. Experiments show that the decoding speeds of the proposed coding model are four times and nine times faster than uncoded 2 D-SPIHT and 3-D-SPIHT, respectively, with almost the same decoded quality. The higher decoding speed gain in a larger image source validates the suitability of the proposed method to very large scale image encoding and decoding. In the Appendix, we explain the syntactic relationship of the proposed PROGRES method to uncoded SPIHT, and demonstrate that, in the lossless case, the bits sent to the codestream for each algorithm are identical, except that they are sent in different order. PMID- 17688206 TI - Joint source-channel rate allocation in parallel channels. AB - A fast rate-optimal rate allocation algorithm is proposed for parallel transmission of scalable images in multichannel systems. Scalable images are transmitted via fixed-length packets. The proposed algorithm selects a subchannel, as well as a channel code rate for each packet, based on the signal to-noise ratios (SNRs) of the subchannels. The resulting scheme provides unequal error protection of source bits and significant gains are obtained over equal error protection schemes. An application of the proposed algorithm to JPEG2000 transmission shows the advantages of exploiting differences in SNRs between subchannels. Multiplexing of multiple sources is also considered, and additional gains are achieved by exploiting information diversity among the sources. PMID- 17688207 TI - Spatially variant apodization for squinted synthetic aperture radar images. AB - Spatially variant apodization (SVA) is a nonlinear sidelobe reduction technique that improves sidelobe level and preserves resolution at the same time. This method implements a bidimensional finite impulse response filter with adaptive taps depending on image information. Some papers that have been previously published analyze SVA at the Nyquist rate or at higher rates focused on strip synthetic aperture radar (SAR). This paper shows that traditional SVA techniques are useless when the sensor operates with a squint angle. The reasons for this behaviour are analyzed, and a new implementation that largely improves the results is presented. The algorithm is applied to simulated SAR images in order to demonstrate the good quality achieved along with efficient computation. PMID- 17688208 TI - Accurate calculation of image moments. AB - Image moments have been extensively used as feature descriptors. However, the quantization error introduced in discrete signals presents problems, especially when dealing with small-size images. This results in the fact that the invariant properties of moments are compromised. In this paper, we present a technique suitable for the calculation of moments from a continuous signal, derived by piecewise polynomial interpolation of the corresponding discrete one. The computed moments exhibit significantly increased accuracy while requiring trivial computational effort. Zernike moments are then computed using the proposed scheme and are shown to display increased stability to geometrical transformations. PMID- 17688209 TI - Motion estimation in the 3-D Gabor domain. AB - Motion estimation methods can be broadly classified as being spatiotemporal or frequency domain in nature. The Gabor representation is an analysis framework providing localized frequency information. When applied to image sequences, the 3 D Gabor representation displays spatiotemporal/spatiotemporal-frequency (st/stf) information, enabling the application of robust frequency domain methods with adjustable spatiotemporal resolution. In this work, the 3-D Gabor representation is applied to motion analysis. We demonstrate that piecewise uniform translational motion can be estimated by using a uniform translation motion model in the st/stf domain. The resulting motion estimation method exhibits both good spatiotemporal resolution and substantial noise resistance compared to existing spatiotemporal methods. To form the basis of this model, we derive the signature of the translational motion in the 3-D Gabor domain. Finally, to obtain higher spatiotemporal resolution for more complex motions, a dense motion field estimation method is developed to find a motion estimate for every pixel in the sequence. PMID- 17688211 TI - A novel fast and reduced redundancy structure for multiscale directional filter banks. AB - The multiscale directional filter bank (MDFB) improves the radial frequency resolution of the contourlet transform by introducing an additional decomposition in the high-frequency band. The increase in frequency resolution is particularly useful for texture description because of the quasi-periodic property of textures. However, the MDFB needs an extra set of scale and directional decomposition, which is performed on the full image size. The rise in computational complexity is, thus, prominent. In this paper, we develop an efficient implementation framework for the MDFB. In the new framework, directional decomposition on the first two scales is performed prior to the scale decomposition. This allows sharing of directional decomposition among the two scales and, hence, reduces the computational complexity significantly. Based on this framework, two fast implementations of the MDFB are proposed. The first one can maintain the same flexibility in directional selectivity in the first two scales while the other has the same redundancy ratio as the contourlet transform. Experimental results show that the first and the second schemes can reduce the computational time by 33.3%-34.6% and 37.1%-37.5%, respectively, compared to the original MDFB algorithm. Meanwhile, the texture retrieval performance of the proposed algorithms is more or less the same as the original MDFB approach which outperforms the steerable pyramid and the contourlet transform approaches. PMID- 17688210 TI - Optimal approach for fast object-template matching. AB - This paper proposes a novel algorithm for an optimal reduction of object description for object matching purposes. Our aim is to decrease the computation needs by considering simplified objects, thus reducing the number of pixels involved in the matching process. We develop the appropriate theoretical background based on centroidal Voronoi tessellations. Its use within the chamfer matching framework is also discussed. We present experimental results regarding the performance of this approach for 2-D contour and region-like object matching. As a special case, we investigate how the snake based representation of target objects can be employed in chamfer matching. The experimental results concern the use of object part matching for recognizing humans and show how the proposed simplification leads to valid replacements of the original templates. PMID- 17688212 TI - A new approach to image copy detection based on extended feature sets. AB - Conventional image copy detection research concentrates on finding features that are robust enough to resist various kinds of image attacks. However, finding a globally effective fealure is difficult and, in many cases, domain dependent. Instead of imply extracting features from copyrighted images directly, we propose a new framework called the extended feature set for detecting copies of images. In our approach, virtual prior attacks are applied to copyrighted images to generate novel features, which serve as training data. The copy-detection problem can be solved by learning classifiers from the training data, thus, generated. Our approach can be integrated into existing copy detectors to further improve their performance. Experiment results demonstrate that the proposed approach can substantially enhance the accuracy of copy detection. PMID- 17688213 TI - Image denoising by sparse 3-D transform-domain collaborative filtering. AB - We propose a novel image denoising strategy based on an enhanced sparse representation in transform domain. The enhancement of the sparsity is achieved by grouping similar 2-D image fragments (e.g., blocks) into 3-D data arrays which we call "groups." Collaborative filtering is a special procedure developed to deal with these 3-D groups. We realize it using the three successive steps: 3-D transformation of a group, shrinkage of the transform spectrum, and inverse 3-D transformation. The result is a 3-D estimate that consists of the jointly filtered grouped image blocks. By attenuating the noise, the collaborative filtering reveals even the finest details shared by grouped blocks and, at the same time, it preserves the essential unique features of each individual block. The filtered blocks are then returned to their original positions. Because these blocks are overlapping, for each pixel, we obtain many different estimates which need to be combined. Aggregation is a particular averaging procedure which is exploited to take advantage of this redundancy. A significant improvement is obtained by a specially developed collaborative Wiener filtering. An algorithm based on this novel denoising strategy and its efficient implementation are presented in full detail; an extension to color-image denoising is also developed. The experimental results demonstrate that this computationally scalable algorithm achieves state-of-the-art denoising performance in terms of both peak signal-to-noise ratio and subjective visual quality. PMID- 17688214 TI - Active contour external force using vector field convolution for image segmentation. AB - Snakes, or active contours, have been widely used in image processing applications. Typical roadblocks to consistent performance include limited capture range, noise sensitivity, and poor convergence to concavities. This paper proposes a new external force for active contours, called vector field convolution (VFC), to address these problems. VFC is calculated by convolving the edge map generated from the image with the user-defined vector field kernel. We propose two structures for the magnitude function of the vector field kernel, and we provide an analytical method to estimate the parameter of the magnitude function. Mixed VFC is introduced to alleviate the possible leakage problem caused by choosing inappropriate parameters. We also demonstrate that the standard external force and the gradient vector flow (GVF) external force are special cases of VFC in certain scenarios. Examples and comparisons with GVF are presented in this paper to show the advantages of this innovation, including superior noise robustness, reduced computational cost, and the flexibility of tailoring the force field. PMID- 17688215 TI - A topdown algorithm for computation of level line trees. AB - We introduce an optimal topdown algorithm for computing and representing level line trees of 2-D intensity images. The running time of the algorithm is O(n + t), where n is the size of the input image and t is the total length of all level lines. The properties of level line trees are also investigated. The efficiency of the algorithm is illustrated by experiments on images of different sizes and scenes. PMID- 17688216 TI - Text extraction and document image segmentation using matched wavelets and MRF model. AB - In this paper, we have proposed a novel scheme for the extraction of textual areas of an image using globally matched wavelet filters. A clustering-based technique has been devised for estim ating globally matched wavelet filters using a collection of groundtruth images. We have extended our text extraction scheme for the segmentation of document images into text, background, and picture components (which include graphics and continuous tone images). Multiple, two class Fisher classifiers have been used for this purpose. We also exploit contextual information by using a Markov random field formulation-based pixel labeling scheme for refinement of the segmentation results. Experimental results have established effectiveness of our approach. PMID- 17688217 TI - Real-time decentralized articulated motion analysis and object tracking from videos. AB - In this paper, we present two new articulated motion analysis and object tracking approaches: the decentralized articulated object tracking method and the hierarchical articulated object tracking method. The first approach avoids the common practice of using a high-dimensional joint state representation for articulated object tracking. Instead, we introduce a decentralized scheme and model the interpart interaction within an innovative Bayesian framework. Specifically, we estimate the interaction density by an efficient decomposed interpart interaction model. To handle severe self-occlusions, we further extend the first approach by modeling high-level interunit interaction and develop the second algorithm within a consistent hierarchical framework. Preliminary experimental results have demonstrated the superior performance of the proposed approaches on real-world videos in both robustness and speed compared with other articulated object tracking methods. PMID- 17688218 TI - Fast template matching with polynomials. AB - Template matching is widely used for many applications in image and signal processing. This paper proposes a novel template matching algorithm, called algebraic template matching. Given a template and an input image, algebraic template matching efficiently calculates similarities between the template and the partial images of the input image, for various widths and heights. The partial image most similar to the template image is detected from the input image for any location, width, and height. In the proposed algorithm, a polynomial that approximates the template image is used to match the input image instead of the template image. The proposed algorithm is effective especially when the width and height of the template image differ from the partial image to be matched. An algorithm using the Legendre polynomial is proposed for efficient approximation of the template image. This algorithm not only reduces computational costs, but also improves the quality of the approximated image. It is shown theoretically and experimentally that the computational cost of the proposed algorithm is much smaller than the existing methods. PMID- 17688219 TI - Iterative cross section sequence graph for handwritten character segmentation. AB - The iterative cross section sequence graph (ICSSG) is an algorithm for handwritten character segmentation. It expands the cross section sequence graph concept by applying it iteratively at equally spaced thresholds. The iterative thresholding reduces the effect of information loss associated with image binarization. ICSSG preserves the characters' skeletal structure by preventing the interference of pixels that causes flooding of adjacent characters' segments. Improving the structural quality of the characters' skeleton facilitates better feature extraction and classification, which improves the overall performance of optical character recognition (OCR). Experimental results showed significant improvements in OCR recognition rates compared to other well-established segmentation algorithms. PMID- 17688220 TI - Estimating planar surface orientation using bispectral analysis. AB - In this correspondence, we propose a direct method for estimating the orientation of a plane from a single view under perspective projection. Assuming that the underlying planar texture has random phase, we show that the nonlinearities introduced by perspective projection lead to higher order correlations in the frequency domain. We also empirically show that these correlations are proportional to the orientation of the plane. Minimization of these correlations, using tools from polyspectral analysis, yields the orientation of the plane. We show the efficacy of this technique on synthetic and natural images. PMID- 17688221 TI - Waiting for Gordon. PMID- 17688222 TI - A change for the better. Interview by Lynne Pearce. PMID- 17688223 TI - Getting to grips with practice based commissioning. PMID- 17688224 TI - Cruel intentions? PMID- 17688225 TI - Seeing is believing. PMID- 17688226 TI - Ten steps to improving team leadership. PMID- 17688227 TI - The transformation of care in the Republic of Ireland. PMID- 17688228 TI - Nurse leaders as teachers. PMID- 17688229 TI - The business of nephrology--a brave new world? PMID- 17688230 TI - Serum albumin, protein, and malnutrition: a different approach. PMID- 17688231 TI - Renal care in Cuba: challenges and opportunities. Part 3. PMID- 17688232 TI - A lesson from the EPO mess: stop the cost shifting. PMID- 17688233 TI - Has economics overshadowed our clinical approaches to EPO? PMID- 17688234 TI - Variants of chemokine receptor 2 and interleukin 4 receptor, but not interleukin 10 or Fas ligand, increase risk of cervical cancer. AB - Cervical cancer is caused by persistent infection of oncogenic human papillomavirus (HPV). Most infected women clear the virus without developing cervical lesions and it is likely that immunological host factors affect susceptibility to cervical cancer. The impact of the human leukocyte antigen (HLA) locus on the risk of cervical cancer is established and several other genes involved in immunological pathways have been suggested as biologically plausible candidates. The aim of this study was to examine the potential role of polymorphisms in 4 candidate genes by analysis of 1,306 familial cervical cancer cases and 288 controls. The following genes and polymorphisms were studied: Chemokine receptor 2 (CCR-2) V64I; Interleukin 4 receptor alpha (IL-4R) I75V, S503P and Q576R; Interleukin 10 (IL-10) -592; and Fas ligand (FasL) -844. The CCR 2 64I variant was associated with decreased risk of cervical cancer; homozygote carriers of the 64I variant had an odds ratio of 0.31 (0.12-0.77). This association was detected in both carriers and noncarriers of the HLA DQB1*0602 cervical cancer risk allele. The IL-4R 75V variant was associated with increased risk of cervical tumors, cases homozygote for 75V had an odds ratio of 1.91 (1.27 2.86) with a tendency that the association was stronger in noncarriers of the DQB1*0602 allele. We did not find any association for IL-10 -592, or FasL -844, previously reported to be associated with cervical cancer in the Dutch and Chinese populations, respectively. PMID- 17688235 TI - Targeting BCL-2 family proteins to overcome drug resistance in non-small cell lung cancer. AB - Cytotoxic chemotherapies are standard of care for patients suffering from advanced non-small cell lung cancer (NSCLC). However, objective responses are only achieved in 20% of cases and long-term survival is rarely observed. Clinically applied anticancer drugs exert at least some of their activities by inducing apoptosis. A critical step in apoptotic signal transduction is the permeabilization of the mitochondrial outer membrane (MOM), which is regulated by the BCL-2 family of proteins. Hence, therapeutic targeting of BCL-2 proteins is a promising approach to increase the drug-sensitivity of cancers. To this end we have assessed the impact of conditional expression of the proapoptotic multidomain (BH1-2-3) protein BAK, which directly permeabilizes the MOM, and the BH3-mimetic ABT-737, which acts indirectly by derepressing BH1-2-3 proteins, on apoptosis and drug sensitivity of NSCLC cells. Conditionally expressed BAK sensitized resistant NSCLC cells to drug-induced apoptosis. In contrast, ABT-737 was ineffective in those NSCLC cells expressing high levels of the anti-apoptotic MCL-1 protein. Tissue microarray analysis of tumor samples from 84 chemotherapy naive NSCLC patients revealed MCL-1 expression in 56% of cases, thus supporting the relevance of this resistance factor in a clinical setting. Enforced expression of the BH3-only protein NOXA, which targets MCL-1, overcame resistance to ABT-737. Moreover, combining conditionally expressed BAK with ABT-737 enhanced apoptosis in NSCLC cells independently of their MCL-1 status. In conclusion, the heterogeneity of apoptosis defects observed in drug-resistant NSCLC demands individually tailored molecular therapies. Targeting the MOM permeabilizer BAK appears to have a broader apoptogenic activity than the BH3-only mimetic ABT-737. PMID- 17688236 TI - Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer. AB - A total of 283 epithelial ovarian cancer families from the United Kingdom (UK) and the United States (US) were screened for coding sequence changes and large genomic alterations (rearrangements and deletions) in the BRCA1 and BRCA2 genes. Deleterious BRCA1 mutations were identified in 104 families (37%) and BRCA2 mutations in 25 families (9%). Of the 104 BRCA1 mutations, 12 were large genomic alterations; thus this type of change represented 12% of all BRCA1 mutations. Six families carried a previously described exon 13 duplication, known to be a UK founder mutation. The remaining six BRCA1 genomic alterations were previously unreported and comprised five deletions and an amplification of exon 15. One of the 25 BRCA2 mutations identified was a large genomic deletion of exons 19-20. The prevalence of BRCA1/2 mutations correlated with the extent of ovarian and breast cancer in families. Of 37 families containing more than two ovarian cancer cases and at least one breast cancer case with diagnosis at less than 60 years of age, 30 (81%) had a BRCA1/2 mutation. The mutation prevalence was appreciably less in families without breast cancer; mutations were found in only 38 out of 141 families (27%) containing two ovarian cancer cases only, and in 37 out of 59 families (63%) containing three or more ovarian cancer cases. These data indicate that BRCA1 and BRCA2 are the major susceptibility genes for ovarian cancer but that other susceptibility genes may exist. Finally, it is likely that these data will be of clinical importance for individuals in families with a history of epithelial ovarian cancer, in providing accurate estimates of their disease risks. PMID- 17688237 TI - Mitochondria and ageing: winning and losing in the numbers game. AB - Mitochondrial dysfunction has long been considered a key mechanism in the ageing process but surprisingly little attention has been paid to the impact of mitochondrial number or density within cells. Recent reports suggest a positive association between mitochondrial density, energy homeostasis and longevity. However, mitochondrial number also determines the number of sites generating reactive oxygen species (ROS) and we suggest that the links between mitochondrial density and ageing are more complex, potentially acting in both directions. The idea that increased density, especially when combined with mitochondrial dysfunction, might accelerate ageing is supported by a negative correlation between mitochondrial density and maximum longevity in an interspecies comparison in mammals, and by evidence for an intimate interconnection between cellular ROS levels, mitochondrial density and cellular ageing. Recent data suggest that retrograde response, which activates mitochondrial biogenesis, accompanies cellular ageing processes. We hypothesise that increased mitochondrial biogenesis, and possibly also impaired degradation and segregation of mitochondria, if occurring as adaptation to pre-existing mitochondrial dysfunction, might aggravate ROS production and thus actively contribute to ageing. PMID- 17688238 TI - Approaches to evaluation of treatment effect in randomized clinical trials with genomic subset. AB - With the advances in human genomic/genetic studies, the clinical trial community gradually recognizes that phenotypically homogeneous patients may be heterogeneous at the genomic level. The genomic technology brings a possible avenue for developing a genomic (composite) biomarker to predict a genomically responsive patient subset that may have a (much) higher likelihood of benefiting from a treatment. Randomized controlled trial is the mainstay to provide scientifically convincing evidence of a purported effect a new treatment may demonstrate. In conventional clinical trials, the primary clinical hypothesis pertains to the therapeutic effect in all patients who are eligible for the study defined by the primary efficacy endpoint. The aspect of one-size-fits-all surrounding the conventional design has been challenged, particularly when the diseases may be heterogeneous due to observable clinical characteristics and/or unobservable underlying the genomic characteristics. Extension from the conventional single population design objective to an objective that encompasses two possible patient populations will allow more informative evaluation in the patients having different degrees of responsiveness to medication. Building in conventional clinical trials, an additional genomic objective can generate an appealing conceptual framework from the patient's perspective in addressing personalized medicine in well-controlled clinical trials. There are many perceived benefits of personalized medicine that are based on the notion of being genomically proactive in the identification of disease and prevention of disease or recurrence. In this paper, we show that an adaptive design approach can be constructed to study a clinical hypothesis of overall treatment effect and a hypothesis of treatment effect in a genomic subset more efficiently than the conventional non-adaptive approach. PMID- 17688239 TI - Replacing animal experiments: choices, chances and challenges. AB - Replacing animal procedures with methods such as cells and tissues in vitro, volunteer studies, physicochemical techniques and computer modelling, is driven by legislative, scientific and moral imperatives. Non-animal approaches are now considered as advanced methods that can overcome many of the limitations of animal experiments. In testing medicines and chemicals, in vitro assays have spared hundreds of thousands of animals. In contrast, academic animal use continues to rise and the concept of replacement seems less well accepted in university research. Even so, some animal procedures have been replaced in neurological, reproductive and dentistry research and progress is being made in fields such as respiratory illnesses, pain and sepsis. Systematic reviews of the transferability of animal data to the clinical setting may encourage a fresh look for novel non-animal methods and, as mainstream funding becomes available, more advances in replacement are expected. PMID- 17688240 TI - The underestimated potential of the immune system in prevention of Alzheimer's disease pathology. AB - Genetic and environmental factors leading to Alzheimer's disease (AD) converge in a pathogenic pathway that leads to the accumulation of mis-folded amyloid peptide (Abeta) in the brain. Removal of Abeta from the brain has thus been the focus of academic and industrial research in the last decade. The concept of immunization therapy could be proven in animal models mimicking amyloid pathology but a multicenter clinical trial in which AD patients were vaccinated with aggregated Abeta has resulted in somewhat unanticipated and partially conflicting results. The occurrence of meningoencephalitis in 6% of vaccinated individuals forced the discontinuation of the clinical study, preventing the generation of sufficient data for an unequivocal statement about the effectiveness of such a therapy approach. This study, however, clearly showed that vaccination induced the production of antibodies against Abeta in some immunized patients. Moreover, circulating anti-Abeta antibodies are found in healthy humans suggesting a protective role of such physiological antibodies. Nonetheless, the physiological role of the immune system in preventing AD is not fully understood. This article summarizes crucial animal and clinical data underscoring the potential of the immune system for AD treatment. PMID- 17688241 TI - Biomedical research funding: when the game gets tough, winners start to play. AB - Extramural funding provides major support for biomedical research in academia, and National Institutes of Health (NIH) grants often constitute direct evaluation criteria for promotions and tenure. Therefore, NIH budget trends influence long term scientific strategies and career decisions, as well as the progress of science itself. Our analysis of the last 37 years of NIH awards, however, reveals that the success rate of grant applications submitted for funding is negatively related to the total yearly amount of (inflation-adjusted) NIH extramural expenditure. Instead, as might be expected, the ratio between available funding and the number of submission directly predicts the probability of winning support in any given year. We purport that the considerable success rate variability can be parsimoniously explained by a proportional but delayed reaction of the number of applications to budget fluctuations. As a counterintuitive consequence, grant proposals conceived during lean periods might stand the best chance of success. PMID- 17688242 TI - The regulatory genome: Eric Davidson at 70. PMID- 17688243 TI - Self-crosslinkable hydrogels composed of partially oxidized hyaluronan and gelatin: in vitro and in vivo responses. AB - Self-crosslinkable hydrogels had been formulated from two precursors, partially oxidized hyaluronan (oHA) and gelatin. The physicochemical properties of the resulting hydrogels have been elucidated by instrumental analyses (FTIR, SEM, and rheometry). These hydrogels were highly porous with an average pore size of 60 microm, and evidently, accommodative to cell infiltration. Increasing the oxidation degree of oHA resulted in corresponding increases in hydrogels' storage moduli and decreases in water uptake. Dermal fibroblasts were used to study the cell-hydrogel interactions in vitro. Both the hydrogels and their degradation byproducts are biocompatible as indicated by long-term cell viability assay. In addition, significant amount of cells migrated into the hydrogels and they aligned into highly organized arrays. When cultured with cells, the hydrogels underwent degradation within 4 weeks depending on composition with obvious loss of cohesiveness over time. The good biocompatibility and biodegradability of oHA/gelatin hydrogel were further demonstrated in mice subdermal implantations. Lastly, in vitro and in vivo depositions of extracellular matrix in hydrogels by cells were demonstrated by SEM analyses. PMID- 17688244 TI - Biomechanical response of condylar cartilage-on-bone to dynamic shear. AB - Shear stress can result in fatigue, damage, and irreversible deformation of the mandibular condylar cartilage. However, little information is available on its dynamic properties in shear. We tested the hypothesis that the dynamic shear properties of the condylar cartilage depend on the frequency and amplitude of shear strain. Ten porcine mandibular condyles were used for dynamic shear tests. Two cartilage-bone plugs were dissected from each condyle and tested in a simple shear sandwich configuration under a compressive strain of 10%. Sinusoidal shear strain was applied with an amplitude of 1.0, 2.0, and 3.0% and a frequency range between 0.01 and 10 Hz. The magnitudes of the shear dynamic moduli were found to be dependent on the frequency and the shear strain amplitude. They increased with shear strain. tan delta ranged from 0.2 to 0.4, which means that the cartilage is primarily elastic in nature and has a small but not negligible viscosity. In conclusion, the present results show that the shear behavior of the mandibular condylar cartilage is dependent on the frequency and amplitude of the applied shear strain. The observed shear characteristics suggest a significant role of shear strain on the interstitial fluid flow within the cartilage. PMID- 17688245 TI - Incorporation of growth factor containing Matrigel promotes vascularization of porous PLGA scaffolds. AB - In tissue engineering, rapid ingrowth of blood vessels into scaffolds is a major prerequisite for the survival of three-dimensional tissue constructs. In the present study, we investigated whether the vascularization of implanted poly-D,L lactic-co-glycolic acid (PLGA) scaffolds may be accelerated by incorporation of Matrigel. For this purpose, we investigated in the aortic ring assay the proangiogenic properties of growth factor reduced Matrigel (GFRM) and growth factor containing Matrigel (GFCM), which were then incorporated into the pores of PLGA scaffolds. Subsequently, we analyzed vascularization, biocompatibility, and incorporation of these scaffolds during 14 days after implantation into dorsal skinfold chambers of balb/c mice by means of intravital microscopy, histology, and immunohistochemistry. Matrigel-free scaffolds served as controls. In the aortic ring assay, GFCM stimulated the development of a network of tubular vessel structures with a significantly increased sprout area and density when compared with GFRM. Accordingly, GFCM accelerated and improved in vivo the ingrowth of new blood vessels into scaffolds, resulting in the formation of a pericyte-coated vascular network with an increased functional capillary density in comparison to the GFRM and control group. Besides, analysis of leukocyte-endothelial cell interaction in host tissue venules located in close vicinity to the scaffolds showed no marked differences in numbers of rolling and adherent leukocytes between the observation groups, indicating that incorporation of Matrigel did not affect biocompatibility of PLGA scaffolds. These findings demonstrate that the combination of proangiogenic extracellular matrices with solid scaffold biomaterials may represent a novel approach to accelerate adequate vascularization of tissue engineering constructs. PMID- 17688246 TI - Cellular compatibility of bone-like apatite containing silicon species. AB - A calcium carbonate/siloxane-containing poly-(lactic acid) composite (Si-CCPC) was prepared by a sol-gel method. Si-CCPC was immersed in simulated body fluid for 3 days, resulting in the formation of bone-like hydroxyapatite layer containing silicon species (b-HA(Si)) on Si-CCPC. The b-HA(Si) was estimated in the cellular compatibility by culture tests using osteoblast-like cells (MC3T3-E1 cells), human mesenchymal stem cells (MSCs) and human osteoblasts (HOBs). Cellular number of MC3T3-E1 cells and alkaline phosphatase activity of MSCs on the b-HA(Si) increased significantly more in comparison with that on the conventional b-HA (without silicon species). Cellular spreading of MC3T3-E1 cells after 1 day of culturing was enhanced on the layer with and without silicon species. The b-HA(Si) was expected to enhance cellular proliferation and osteogenic differentiation, and the b-HA layer was believed to play the important role for cellular spreading. After 14 and 21 days of HOBs-culturing, bone nodules formation was observed on the b-HA(Si). The b-HA(Si) has great potential in use as scaffolds for bone tissue engineering. PMID- 17688247 TI - Structural evolution and adhesion of titanium oxide film containing phosphorus and calcium on titanium by anodic oxidation. AB - This study investigated the microstructure evolution and defects of the titanium oxide layer containing calcium (Ca) and phosphorus (P) formed by anodic oxidation in a solution containing Ca and P compounds. Results show that the anodic film exhibited a two-layer structure: a pore-containing amorphous titanium oxide layer dispersed with nano-sized crystallites formed prior to sparking, and a porous overlay dotted with craters formed after sparking. Ca and P were predominantly incorporated in the porous overlay, in which the amorphous region contained more Ca and P than the crystalline region regardless of the anodizing voltages. Moreover, the ratio of amorphous to crystalline regions in the porous overlay changed insignificantly with anodizing voltage. Increasing anodizing voltage enhanced the incorporation of Ca and P in the anodic film, but deteriorated the adhesion of the anodic film to the substrate. This deterioration was related to two inherent adhesive weaknesses: the aligned pores in the titanium oxide layer and the craters in the major overlay, signifying that a new anodic oxidation process that can produce high Ca- and P-containing oxide film at relatively-low anodizing voltages, i.e. approximately 200 V, is a necessity. PMID- 17688248 TI - Self-setting properties and in vitro bioactivity of Ca3SiO5/CaSO4.1/2H2O composite cement. AB - In this study, a biphasic injectable bone substitute, based on tricalcium silicate (Ca(3)SiO(5)) and plaster (CaSO(4).1/2H(2)O), is presented. The addition of CaSO(4).1/2H(2)O could accelerate the hydration of Ca(3)SiO(5), decrease the setting time, and improve the strength of the cement. The workable Ca(3)SiO(5)/CaSO(4).1/2H(2)O pastes with a liquid to powder (L/P) ratio of 0.8 1.0 mL g(-1) could be injected for 2-20 min (nozzle diameter 2.0 mm) and enabled initial setting times of 9-60 min. The setting process yielded cellular structures with compressive strength of 12.4-31.5 MPa after 2-28 days. The in vitro bioactivity of the paste was investigated by soaking in simulated body fluid (SBF) for 7 days. The result showed that although large amount of CaSO(4).1/2H(2)O (30%) was added, the paste showed good ability to induce the formation of hydroxyapatite (HA). Furthermore, the Ca(3)SiO(5)/CaSO(4).1/2H(2)O paste could degrade in Ringer's solution, and the dissolution extracts of the paste also had a stimulatory effect on L929 cell growth in certain concentration range. Our results indicated that Ca(3)SiO(5)/CaSO(4).1/2H(2)O paste was bioactive and degradable, and showed excellent mechanical properties after self setting. Therefore, it may be a potential candidate for further investigation as injectable tissue repairing substitute. PMID- 17688249 TI - Gonadal differentiation and hormonal sex reversal in Arctic charr (Salvelinus alpinus). AB - The purpose of this study was to develop a practical protocol for the production of female populations of Arctic charr (Salvelinus alpinus). Achieving this required knowledge of the timing of gonadal differentiation. Undifferentiated gonads were observed microscopically to be present by 194 degrees C-days post hatch and definitive germ cells by 346 degrees C-days post-hatch, where " degrees C-days" denote acquired thermal units calculated as the product of temperature and days. Some of the gonads had developed a lumen by 510 degrees C-days post hatch, and by 681 degrees C-days post-hatch anatomical divergence into two types of gonads was clear. Two protocols (immersion and feeding) were tested for hormonal sex reversal of genotypic females using the synthetic androgen 17alpha methyldihydrotestosterone (MDHT). Six-hour MDHT immersions (0.5, 1, 3, 5 and 10 mg/L) were carried out weekly from hatch to first feeding (140 degrees C-days post-hatch), whereas daily feeding treatments (0.5 mg/kg) went from 140 to 600 degrees C-days post-hatch. The sex ratios of all immersion experimental groups were significantly different from the control, with the proportion of presumptive males increasing as MDHT concentration increased. The highest immersion treatment, 10 mg/L, yielded a population of 90% presumptive males and 10% with atypical gonads. However, the most effective treatment, yielding a population of 90% presumptive males and no fish with atypical gonads, was the feeding treatment. Given that female salmonid fishes are homogametic, sex-reversed (masculinized) genotypic females produced in this way can serve as broodstock for the creation of all-female charr populations for aquaculture. PMID- 17688250 TI - Myo1 localizes to phagosomes, some of which traffic to the nucleus in a Myo1 dependent manner in Tetrahymena thermophila. AB - Myo1 is one of 13 myosins in Tetrahymena thermophila. Initially, twelve of the myosins in Tetrahymena were assigned to Class XX in the myosin superfamily but recently re-assigned to a subclass within Class XIV. In a previous study, we reported that genomic knockout of MYO1 affected phagocytosis and macronuclear amitosis. These two phenotypes have appeared disparate because a possible mechanism linking phagocytosis and amitosis was unknown. In the present study, Myo1 localization was investigated in order to further link machinery for phagocytosis and amitosis. Antibodies directed against the Myo1 motor domain detected an immunospecific polypeptide at 175-180 kDa on immunoblots of wild-type proteins. The 175-180 kDa polypeptide was not detected on immunoblots of proteins from the knockout strain. For immunofluorescence microscopy, cells were allowed to internalize fluorescent beads as markers for phagosomes. In wild-type cells, anti-Myo1 and anti-actin antibodies co-localized to the periphery of phagosomes and the macronucleus. In the MYO1-knockout strain only background fluorescence was observed with anti-Myo1 antibody. Confocal x-z series through macronuclei revealed fluorescent beads within the nucleoplasm. Statistical analysis showed a significant difference between the mean distributions of fluorescent beads in the nucleoplasm of wild-type and MYO1-knockout cells. A fluorescent dye was used to label plasma membrane in living cells. Dye-labeled vacuoles trafficked to the macronucleus. Trafficking of phagosomes to the macronucleus in a myosin-dependent manner is a novel finding and a possible mechanism for targeting myosin and actin to the nucleus. PMID- 17688251 TI - The development of boys' preferential pleasure in physical aggression. AB - A large body of literature on physical aggression focuses on its maladaptive nature and causes. The current study of 335 children (209 boys, 126 girls), aged 4-, 5-, 6-, and 9-years, examined a different facet of harmful physical aggression-the development of the pleasure it provides to boys. Two samples of children were included, first 89 boys, then an additional 120 boys and 126 girls. For the first two free response measures, all 209 boys and 126 girls were asked to describe how they played with their three favorite toys and their three favorite playmates, and these descriptions were coded for the presence of physical aggression. Twelve additional structured measures were administered to the second sample of 120 boys and 126 girls. These children were asked to rate how much they enjoyed enacting and viewing on television physical aggression, non physically aggressive male sex-typed roles, and ambiguously sex-typed roles. Results demonstrated that approximately 50% of boys at all four age levels (and less than 10% of girls) reported that at least one of their three favorite toys was used for inflicting harm through physical aggression on an animate being. Further, with increasing age, boys rated physical aggression in play activities and on television as more enjoyable than alternative male sex-typed play and television content. Results suggest that advancing understanding of the development of physical aggression requires acknowledging the pleasure it provides to males. PMID- 17688252 TI - DNA nanoparticles encapsulated in 3D tissue-engineered scaffolds enhance osteogenic differentiation of mesenchymal stem cells. AB - In this study, we enhanced the expression of a plasmid DNA in mesenchymal stem cells (MSC) by the combination of three-dimensional (3D) tissue-engineered scaffold and nonviral gene carrier. To function as an enhanced delivery of plasmid DNA, acetic anhydride was reacted with polyethylenimine (PEI) to acetylate 80% of the primary and 20% of the secondary amines (PEI-Ac(80)). This acetylated PEI has been demonstrated to show enhanced gene-delivery efficiency over unmodified PEI. Collagen sponges reinforced by incorporating of poly(glycolic acid) (PGA) fibers were used as the scaffold material. DNA nanoparticles formed through simple mixing of plasmid DNA encoding bone morphogenetic protein-2 (BMP-2) and PEI-Ac(80) solutions were encapsulated within these scaffolds. MSC were seeded into each scaffold and cultured for several weeks. Within these scaffolds, the level of BMP-2 expression by transfected MSC was significantly enhanced compared to MSC transfected by DNA nanoparticles in solution (in 2D tissue culture plates). Homogeneous bone formation was histologically observed throughout the sponges seeded with transfected MSC by using DNA nanoparticles after subcutaneous implantation into the back of rats. The level of alkaline phosphatase activity and osteocalcin content at the implanted sites of sponges seeded with transfected MSC by using DNA nanoparticles were significantly higher when compared with those seeded with other agents. PMID- 17688253 TI - RNA takes center stage. PMID- 17688254 TI - Synthesis, characterization, and hydrolytic degradation behavior of a novel biodegradable pH-sensitive hydrogel based on polycaprolactone, methacrylic acid, and poly(ethylene glycol). AB - In this work, a new kind of biodegradable pH-sensitive hydrogel was successfully synthesized by UV-initiated free radical polymerization. The obtained hydrogel was characterized by (1)H NMR and FTIR. Swelling behavior in different aqueous media and pH responsivity of the hydrogels were studied in detail as well. With increase in pH from 1.2 to 7.2, swelling ratio of the hydrogel increased. The morphology was observed by scanning electron microscopy, and the hydrolytic degradation behavior was also investigated in this work. PMID- 17688255 TI - Proliferative capacity and osteogenic potential of novel dura mater stem cells on poly-lactic-co-glycolic acid. AB - The rational design of biomimetic structures for the regeneration of damaged or missing tissue is a fundamental principle of tissue engineering. Multiple variables must be optimized, ranging from the scaffold type to the selection and properties of implanted cell(s). In this study, the osteogenic potential of a novel stem cell was analyzed on biodegradable poly(lactic-co-glycolic acid) (PLGA) biomaterials as a step toward creating new cell-materials constructs for bony regeneration. Dura mater stem cells (DSCs), isolated from rat dura mater, were evaluated and compared to bone marrow stem cells (BMSCs) for proliferative and differentiative properties in vitro. Experiments were carried out on both tissue culture plastic (TCP) and 2D planar films of PLGA. Proliferation of DSCs on both TCP and PLGA films increased over 21 days. Positive fold inductions in all five bone marker genes were observed at days 7, 14, 21 in all experimental samples compared with day 0 controls. DSCs demonstrated greater cell coverage and enhanced matrix staining on 2D PLGA films when compared with BMSCs. These cells can be isolated and expanded in culture and can subsequently attach, proliferate, and differentiate on both TCP and PLGA films to a greater extent than BMSCs. This suggests that DSCs are promising for cell-based bone tissue engineering therapies, particularly those applications involving regeneration of cranial bones. PMID- 17688256 TI - Fretting wear properties of hydroxyapatite, alumina containing high density polyethylene biocomposites against zirconia. AB - Considering the importance of wear on the materials performance in biomedical applications, the major objective of the present work is to investigate the friction and fretting wear behavior of various HDPE-based composites against zirconia counterbody, both in air and simulated body fluid (SBF) environment. Both Al(2)O(3) and/or HAp fillers (upto 40 vol %) have been incorporated in HDPE to improve the hardness and elastic modulus of HDPE. The fretting wear study indicates that extremely low COF (approximately 0.055-0.075) as well as higher wear resistance (wear rate in the order of approximately 10(-6) mm(3)/N m) can be achieved with the newly developed composites in SBF. A low wear depth of 3-7 microm is recorded, irrespective of fretting environment. Besides reporting the phenomenological tribological data, major focus has been on to understand the underlying mechanism of material removal at fretting contacts. Such understanding has been established in discussing the wear mechanisms in terms of deformation of polymer matrix, tribolayer formation, and wear debris generation. PMID- 17688257 TI - Biodegradable PCL scaffolds with an interconnected spherical pore network for tissue engineering. AB - A technique for producing controlled interconnected porous structures for application as a tissue engineering scaffold is presented in this article. The technique is based on the fabrication of a template of interconnected poly(ethyl methacrylate) (PEMA) microspheres, the introduction of a biodegradable polymer, poly-epsilon-caprolactone (PCL), and the elimination of the template by a selective solvent. A series of PCL scaffolds with a porosity of 70% and pore sizes up to 200 microm were produced and characterized (both thermally and mechanically). Human chondrocytes were cultured in monolayer on bulk PCL disks or seeded into porous PCL scaffolds. Cell adhesion, viability, proliferation, and proteoglycan (PG) synthesis were tested and compared with monolayer cultures on tissue-treated polystyrene or pellet cultures as reference controls. Cells cultured on PCL disks showed an adhesion similar to that of the polystyrene control (which allowed high levels of proliferation). Stained scaffold sections showed round-shaped chondrocyte aggregates embedded into porous PCL. PG production was similar to that of the pellet cultures and higher than that obtained with monolayer postconfluence cultures. This shows that the cells are capable of attaching themselves to PCL. Furthermore, in porous PCL, cells maintain the same phenotype as the chondrocytes within the native cartilage. These results suggest that PCL scaffolds may be a suitable candidate for chondrocyte culture. PMID- 17688258 TI - N-halamine-based chitosan: preparation, characterization, and antimicrobial function. AB - Upon chlorine bleach treatment, amino groups in chitosan were transformed into N halamine structures. The transformation was confirmed by UV/VIS, XPS, DSC, and TGA evaluation and iodimetric titration. The N-halalmine-based chitosan provided total kill of 10(8)-10(9) colony forming units (CFU/mL) of E. coli (gram-negative bacteria) and S. aureus (gram-positive bacteria) in 10 and 60 min, respectively. SEM observations demonstrated that the chlorinated chitosan effectively prevented the formation of bacterial biofilms. The antimicrobial activity and bio film controlling function were stable for longer than 1 month; when the functions were lost due to extensive use and/or prolonged storage, they could be readily recharged by another bleach treatment. The antimicrobial mechanism was also discussed. PMID- 17688259 TI - The biodegradability of poly(Pro-Hyp-Gly) synthetic polypeptide and the promotion of a dermal wound epithelialization using a poly(Pro-Hyp-Gly) sponge. AB - Collagens are widely used in medical applications, but animal-derived collagens have several drawbacks, such as low thermal stability, nonspecific cell attachment, and susceptibility to contamination by infectious pathogens, such as prions, which may transfect humans. We have previously reported the chemical synthesis of polypeptides consisting of a Pro-Hyp-Gly sequence and the high thermostability of their triple-helical structure. To clarify the biomaterial characteristics of the poly(Pro-Hyp-Gly) polypeptide, we assessed its biodegradability and its capability for skin regeneration. Eight weeks after implantation, a poly(Pro-Hyp-Gly) freeze-dried sponge embedded subcutaneously into a rat dorsal area degraded at the same rate as Terudermis, which is made from bovine type I atelocollagen and is used as an artificial dermis. Surprisingly, compared with Terudermis, the poly(Pro-Hyp-Gly) sponge significantly promoted epithelialization of a full-thickness wound on a rabbit's ear pad. This chemically synthesized polypeptide may be useful as a scaffold for tissue engineering and tissue regeneration. PMID- 17688260 TI - Differentiation stage alters matrix control of stem cells. AB - Cues from the material to which a cell is adherent (e.g., adhesion ligand presentation, substrate elastic modulus) clearly influence the phenotype of differentiated cells. However, it is currently unclear if stem cells respond similarly to these cues. This study examined how the overall density and nanoscale organization of a model cell adhesion ligand (arginine-glycine-aspartic acid [RGD] containing peptide) presented from hydrogels of varying stiffness regulated the proliferation of a clonally derived stem cell line (D1 cells) and preosteoblasts (MC3T3-E1). While the growth rate of MC3T3-E1 preosteoblasts was responsive to nanoscale RGD ligand organization and substrate stiffness, the D1 stem cells were less sensitive to these cues in their uncommitted state. However, once the D1 cells were differentiated towards the osteoblast lineage, they became more responsive to these signals. These results demonstrate that the cell response to material cues is dependent on the stage of cell commitment or differentiation, and these findings will likely impact the design of biomaterials for tissue regeneration. PMID- 17688261 TI - Fibrinogen adsorption onto 316L stainless steel under polarized conditions. AB - Adsorption of the plasma protein fibrinogen onto electrically polarized 316L stainless steel was observed and quantified using both in situ and ex situ atomic force microscopy (AFM) techniques. Significant differences in fibrinogen adsorption were observed across voltages. Ex situ studies showed significantly lower area coverage (theta) and height of adsorbed Fb on cathodically polarized surfaces when compared to anodically polarized surfaces. Conformational differences in the protein may explain the distinctions in Fb surface area coverage (theta) and height between the anodic and cathodic cases. In situ studies showed significantly slower kinetics of Fb adsorption onto surfaces below -100 mV (vs. Ag/AgCl) compared to surfaces polarized above -100 mV. Electrochemical current density data showed large charge transfer processes (approximately 1 x 10(-5) to 1 x 10(-4) A/cm(2)) taking place on the 316L SS surfaces at voltages below -100 mV (vs. Ag/AgCl). These relatively large current densities point to flux of ionic species away from the surface as a major source of the reduction in adsorption kinetics rather than just hydrophilic or electrostatic effects. PMID- 17688262 TI - Considering the zebrafish in a comparative context. AB - This article introduces a special issue on zebrafish biology that attempts to integrate developmental genetics with comparative studies of other fish species. For zebrafish researchers, comparative work offers a better understanding of the evolutionary history of their model system. Comparative biologists can gain many insights from the developmental and genetic mechanisms revealed in zebrafish that have contributed to the huge range of morphological variation among fishes that has arisen over millions of years. These ideas are considered here in various contexts, including systematics, genome organization and the development of the nervous system, pigmentation, craniofacial skeleton and dentition. Studies of the zebrafish in phylogenetic context provide an opportunity for synergy between communities using these two fundamentally different approaches. PMID- 17688263 TI - Composites of poly(DL-lactide-co-glycolide) and calcium carbonate: in vitro evaluation for use in orthopedic applications. AB - Biodegradable materials utilized in current orthopedic sports medicine fixation devices are required to maintain mechanical properties for at least 12 weeks to facilitate tissue healing and then ideally degrade with eventual replacement by surrounding tissue (bone). Current materials exhibit excessive longevity, which limit the potential for bone replacement, an ideal outcome in clinical procedures where revisions are a possibility. This study investigates material property modification of poly(DL-lactide-co-glycolide) (PLGA) by calcium carbonate. Modification of the degradation rate of PLGA by calcium carbonate (16, 36, 51% w/w) was demonstrated and the percentage of calcium carbonate within the polymer optimized at 36% (w/w). The optimized formulation was molded into a fixation screw and in vitro degradation demonstrated a gradual loss in molecular weight but with a pull-out strength retention beyond 12 weeks. Significant mass loss then occurred after 26 weeks. Physical testing, insertion torque, and failure torque indicated that this composite also had sufficient initial mechanical properties required for screw in type fixation devices. The combination of mechanical properties and degradation behavior suggests that this material may have potential to be utilized in orthopedic fixation devices that are placed in bone. PMID- 17688264 TI - Closing capacity of segmental radius defects in rabbits. AB - In the research of synthetic bone graft substitutes, the relevance for bone regeneration can be confirmed in a critical-sized model. In this study the rabbit radial defect was investigated as an ingenious model of critical size, due to its defect immobilizing intact ulna. In addition, the influence of poly(DL-lactic-co glycolic acid) (PLGA) on bone regeneration was determined. Sixteen, 4-month-old rabbits received bilateral segmental radial defects of 15 or 20 mm. The osteotomy ends were marked with small titanium pins. Half of the group received injected PLGA microparticle/carboxymethylcellulose implants. Implantation time was 12 weeks. Evaluation consisted of radiographs after surgery and sacrifice, microcomputed tomography and histology. The radiographs revealed that the created defects were significantly smaller after sacrifice. Further a number of radii showed fibrocartilaginous interposition. Both findings indicated instability of the created defect. All evaluation techniques revealed that 15 and 20 mm were not of critical size, as most defects were more or less regenerated. PLGA microparticles did not influence bone regeneration significantly. In conclusion, 15- and 20-mm radius defects in 4-month-old rabbits were not a suitable model for bone regeneration as these defects were neither critical size nor stable. PLGA microparticle degradation did not influence bone regeneration. PMID- 17688265 TI - Silicone elastomer uptake method for determination of free 1-alkyl-2-pyrrolidone concentration in micelle and hydroxypropyl-beta-cyclodextrin systems used in skin transport studies. AB - Previous investigations in our laboratory demonstrated how the polar head group and alkyl chain of amphiphilic chemical skin permeation enhancers contribute to enhancer potency. In those studies enhancers with n-alkyl chain lengths of eight or less were investigated. In order to investigate enhancers with longer n-alkyl chain lengths, enhancer-solubilizing agents should be considered. Corticosterone (CS) flux enhancement along the lipoidal pathway of hairless mouse skin (HMS) was determined with the enhancers 1-hexyl- (HP), 1-octyl- (OP), 1-decyl- (DP), and 1 dodecyl-2-pyrrolidone (DoP) solubilized in 1,2-distearoyl-sn-glycero-3 phosphatidylethanolamine-N-[methoxy(polyethylene glycol-2000] (DSPE) micelles or in hydroxypropyl-beta-cyclodextrin (HPbetaCD). The free CS, HP, OP, DP, and DoP aqueous concentrations in the DSPE micelle and HPbetaCD systems were determined using a partitioning method. Comparisons of the enhancer potencies based on the free concentration of the enhancers revealed a nearly semi-logarithmic linear relationship between enhancer potency and the carbon number of the alkyl chain length with a slope of approximately 0.55. The observed n-alkyl chain length dependency in the aqueous phase is consistent with the hydrophobic effect. This study shows that longer chain enhancers may be studied by employing a solubilizing system, and free enhancer concentration in these systems can be determined with the aid of the silicone elastomer uptake method. PMID- 17688266 TI - Time-dependent electrochemical characterization of the corrosion of a magnesium rare-earth alloy in simulated body fluids. AB - The electrochemistry of the corrosion process of a magnesium rare-earth-alloy is studied in detail in simulated body fluid (m-SBF) over the first 5 days. The aim is to investigate the corrosion mechanism under in vitro conditions. For this purpose we also used electrolytes that contain only some of the components of SBF, they were compared to SBF to investigate the influence of the different ions in SBF. The influence of albumin on the corrosion process was studied with a solution containing m-SBF and albumin in physiological concentration. For this study, impedance spectroscopy series measurements were performed. Additional results were gained from polarization curves. We conclude from the study that the corrosion resistance is significantly lower in m-SBF than in simple isotonic NaCl solution. Albumin may form a blocking layer on the surface in the first hours of exposure. The formed corrosion layers consisting of amorphous apatite have only a low protective ability. Further results show that the corrosion processes in SBFs follow a linear time-law. The results elucidate critical factors and mechanisms of the electrochemical corrosion process of magnesium rare-earth alloys in SBFs, this understanding is crucial for a successful application of Mg alloys in biomedical applications. PMID- 17688267 TI - Enhanced osteoblast functions on anodized titanium with nanotube-like structures. AB - Previous studies have demonstrated increased osteoblast (bone-forming cells) adhesion on titanium and Ti-6Al-4V anodized to possess nanometer features compared with their unanodized counterparts. In this study, osteoblast long-term functions (specifically, synthesis of intracellular proteins, synthesis of intracellular collagen, alkaline phosphatase activity, and deposition of calcium containing minerals) were determined on titanium anodized to possess either heterogeneous nanoparticles or ordered nanotubes. Titanium was anodized in dilute hydrofluoric acid at 20 V for 20 min to possess nanotubes, while titanium was anodized at 10 V for 20 min to possess nanoparticles. Most importantly, results showed that calcium deposition significantly increased on anodized titanium with nanotube-like structures compared with unanodized titanium and anodized titanium with nanoparticulate structures after 21 days of osteoblast culture. In this manner, the results of the present in vitro study indicated that anodization might be a promising quick and inexpensive method to modify the surface of titanium-based implants to induce better bone cell functions important for orthopedic applications. PMID- 17688268 TI - Increased osteoblast adhesion on nanoparticulate calcium phosphates with higher Ca/P ratios. AB - The biological properties of calcium phosphate-derived materials are strongly influenced by changes in Ca/P stoichiometry and grain size, which have not yet been fully elucidated to date. For this reason, the objective of this in vitro study was to understand osteoblast (bone forming cells) adhesion on nanoparticulate calcium phosphates of various Ca/P ratios. A group of calcium phosphates with Ca/P ratios between 0.5 and 2.5 were obtained by adjusting the Ca/P stoichiometry of the initial reactants necessary for calcium phosphate precipitation. For samples with 0.5 and 0.75 Ca/P ratios, tricalcium phosphate (TCP) and Ca(2)P(2)O(7) phases were observed. In contrast, for samples with 1.0 and 1.33 Ca/P ratios, the only stable phase was TCP. For samples with 1.5 Ca/P ratios, the TCP phase was dominant, however, small amounts of the hydroxyapatite (HA) phase started to appear. For samples with 1.6 Ca/P ratios, the HA phase was dominant. Last, for samples with 2.0 and 2.5 Ca/P ratios, the CaO phase started to appear in the HA phase, which was the dominant phase. Moreover, the average nanometer grain size, porosity (%), and the average pore size decreased in general with increasing Ca/P ratios. Most importantly, results demonstrated increased osteoblast adhesion on calcium phosphates with higher Ca/P ratios (up to 2.5). In this manner, this study provided evidence that Ca/P ratios should be maximized (up to 2.5) in nanoparticulate calcium phosphate formulations to increase osteoblast adhesion, a necessary step for subsequent osteoblast functions such as new bone deposition. PMID- 17688269 TI - Scaffold permeability as a means to determine fiber diameter and pore size of electrospun fibrinogen. AB - The purpose of this study was to construct a flowmeter that could accurately measure the hydraulic permeability of electrospun fibrinogen scaffolds, providing insight into the transport properties of electrospun scaffolds while making the measurement of their topographical features (fiber diameter and pore size) more accurate. Three different concentrations of fibrinogen were used (100, 120, and 150 mg/mL) to create scaffolds with three different fiber diameters and pore sizes. The fiber diameters and pore sizes of the electrospun scaffolds were first analyzed with scanning electron microscopy and image analysis software. The permeability of each scaffold was measured with the flowmeter and used to calculate permeability-based fiber diameters and pore sizes, which were compared to values obtained through image analysis. Permeability measurement revealed scaffold permeability to increase with fibrinogen concentration, much like average fiber diameter and pore size. Comparison between the two measurement methods demonstrated the efficacy of the flowmeter as a way to measure scaffold features. PMID- 17688270 TI - Micro- and nanostructuring of freestanding, biodegradable, thin sheets of chitosan via soft lithography. AB - A technique for imparting micro- and nanostructured topography into the surface of freestanding thin sheets of chitosan is described. Both micro- and nanometric surface structures have been produced using soft lithography. The soft lithography method, based on solvent evaporation, has allowed structures approximately 60 nm tall and approximately 500 x 500 nm(2) to be produced on freestanding approximately 0.5 mm thick sheets of the polymer when cured at 293 K, and structures approximately 400 nm tall and 5 x 5 microm(2) to be produced when cured at 283 K. Nonstructured chitosan thin sheets (approximately 200 microm thick) show excellent optical transmission properties in the visible portion of the electromagnetic spectrum. The structured sheets can be used for applications where optical microscopic analysis is required, such as cell interaction experiments and tissue engineering. PMID- 17688271 TI - Influence of nanohydroxyapatite patterns deposited by electrohydrodynamic spraying on osteoblast response. AB - Electrohydrodynamic spraying has been used to produce patterns of line width up to 100 microm in size on glass discs, using nanohydroxyapatite (nHA). A human osteoblast (HOB)-like cell model was then used to study the interaction between the HOB cells and nHA patterns in vitro. Growth of the cells was significantly increased (p < 0.05) on the nHA surfaces. In addition, HOBs attached and spread well, secreting extracellular matrix. It was found that a confluent, aligned cell layer was achieved on nHA patterns by day 9. Immunofluorescent staining indicated that these cells showed elongated nuclei, enhanced adhesion (vinculin adhesion plaques) and a well-aligned cytoskeleton (actin stress fibres). This work suggests that this type of spraying may provide a route for the production of nanoscale features on implants for biomedical applications. PMID- 17688272 TI - Different regulation of hepatocyte behaviors between natural extracellular matrices and synthetic extracellular matrices by hepatocyte growth factor. AB - The roles of growth factors and extracellular matrices (ECMs) in regulation of hepatocyte behaviors are very important for the establishment of liver-tissue engineering. Especially, collaboration between growth factors and ECMs is a big concern for liver-tissue engineering. In this study, the hepatocyte responses by hepatocyte growth factor (HGF) were compared between natural ECMs and a synthetic galactose-carrying polymer: poly(N-p-vinylbenzyl-4-O-beta-D-galactopyranosyl-D gluconamide) (PVLA). Hepatocytes underwent proliferation on type I collagen- and fibronectin-coated surfaces in the presence of HGF, whereas hepatocytes formed spheroid on laminin-1-, PVLA-, and poly-L-lysine (PLL)-coated surfaces in the presence of HGF without the activation of proliferation. HGF accelerated ECM deposition, especially laminin-10/11, beneath the hepatocytes cultured on PVLA- and PLL-coated surfaces and the deposited laminin-10/11 activated integrin signaling to collaborate with HGF signaling. Therefore, the deposited ECM molecules should be focused to clear the mechanism of hepatocyte behaviors in the presence of HGF. PMID- 17688273 TI - Modeling of electric-stimulus-responsive hydrogels immersed in different bathing solutions. AB - By reformulation of the fixed charge density and consideration of finite deformation, a previous model simulating the pH-sensitive hydrogels is refined in this paper for extension to simulating the electric-sensitive hydrogels, which is termed the refined multi-effect-coupling electric-stimulus (rMECe) model. The rMECe model is based on the assumptions: (a) the hydrogel is isotropic and macroscopically homogeneous, (b) all the three phases are incompressible, including the polymeric solid matrix, interstitial water and mobile ions, (c) the effect of electro-osmosis is neglected, (d) bath solution is ideal so that the variation of the activity coefficients with ionic strength can be negligible, i.e., its effect on the concentration profiles is negligible, (e) the smart hydrogel is immersed in an unstirred solution in vibration-free experimental device; the bulk flow of fluid or hydrodynamic velocity can thus be eliminated and subsequently the convective flux is neglected, and (f) the pore of the present hydrogel is narrow enough so that the diffusion dominates the transmission of flux. The model consists of nonlinear coupled partial differential governing equations with the coupling effects of chemo-electro mechanical multi-energy domains and the fixed charge density with the effect of externally applied electric-field. By comparing the simulating results with experimental data extracted from literature, a very good agreement is achieved and thus this validates the computing accuracy and stability of model. The present rMECe model shows the capability of efficiently predicting the ionic transport and the performance of the hydrogels when they are immersed in a bath solution subject to externally applied electric voltage. The model is used for quantitative analysis of the electric-sensitive hydrogels and for discussion of the influences of several physical parameters on the response of the hydrogels, including the externally applied electric voltage, the initially fixed charge density, and the ionic strength and valence of surrounding solution. PMID- 17688274 TI - Fabrication of porous substrates: a review of processes using pore forming agents in the biomaterial field. AB - This paper is a review of solid and casting manufacturing processes able to create porous materials, mainly in the biomaterial field. The considered methods are based on pore forming agents that are removed either by heating or by dissolution. All techniques lead to products presenting pores with amount, size, and shape are close to those of the initial pore formers. Porosities up to 90% with pores ranging from 1 to 2000 microm are reported. Major differences concern macrointerconnections that are more frequently obtained using foams, or porogens which undergo a melting stage during firing. Casting methods combined with solid free form fabrication are promising for the design of porous network through the manufacturing of 3D scaffolds corresponding to the desired porosity. PMID- 17688275 TI - MicroCT analysis of hydroxyapatite bone repair scaffolds created via three dimensional printing for evaluating the effects of scaffold architecture on bone ingrowth. AB - Recent studies have shown that it is now possible to construct tissue-engineered bone repair scaffolds with tight pore size distributions and controlled geometries using 3-D Printing techniques (3DP). This study evaluated two hydroxyapatite (HA) 8-mm diameter discs with controlled architectures in a rabbit trephine defect at 8 and 16 weeks using a 2 x 2 factorial design. Input parameters were time and scaffold void volume at two levels. Three output variables were extracted from MicroCT data: bone volume ingrowth with respect to total region of interest, bone volume ingrowth with respect to available ingrowth volume, and soft tissue volume. The experiment measured two groups--Group 1: 500 microm x 500-microm channels parallel to the scaffold's long axis and penetrating up 3-mm from the bottom. Group 2: 800-microm x 800-microm struts spaced 500 microm apart set perpendicularly to each other in each printed layer. Rendered 3 dimensional MicroCT scans and undecalcified histological slides of implants revealed good integration with the surrounding tissue, and a sizeable amount of bone ingrowth into the device. Factorial analysis revealed that the effects of time were the greatest determinant of soft tissue ingrowth, while time and its interaction with void volume were the greatest determinants of bone volume ingrowth with respect to both total and available volume. PMID- 17688276 TI - miRNA, piRNA, siRNA -- Kleine Wiener Ribonukleinsauren. PMID- 17688277 TI - Characterization of Staphylococcus aureus strains in a rabbit model of osseointegrated pin infections. AB - Staphylococcus aureus is a common infecting agent of many surgical sites. As a commensal organism to humans and rabbits, the infection process may occur due to native or exogenous S. aureus. We applied exogenous S. aureus ATCC 49230 once weekly to the surgical site of an osseointegrated pin in 20 New Zealand white rabbits. Clinical signs of infection resulted in euthanasia and at necropsy samples were collected from putatively infected sites. The predominant organism cultured was S. aureus. We observed various beta-hemolysis patterns of S. aureus on culture media and used pulsed field gel electrophoresis (PFGE) to determine whether there were distinct strains of S. aureus collected from various sites of the rabbits. On the basis of PFGE results, we found that the exogenous S. aureus ATCC 49230 was not the S. aureus cultured during necropsy, but that S. aureus native to the rabbits was in fact the infecting agent. We conclude that this rabbit model for S. aureus infection, which has not been described previously, may contribute to understanding the pathogenesis of S. aureus infections in future studies with simulated osseointegrated pin infections secondary to S. aureus. PMID- 17688278 TI - Oxidized NiTi surfaces enhance differentiation of osteoblast-like cells. AB - A new oxidation treatment (OT) on NiTi shape memory alloys was developed in a previous work. This OT treatment significantly decreases Ni ion release into the exterior medium, and therefore is thought to be beneficial for NiTi cytocompatibility. As to confirm this expectation, the in vitro response of MG63 osteoblast-like cells cultured on untreated and oxidized NiTi surfaces was studied. An adhesion test at 1, 4, and 8 h of incubation was performed. Statistical differences were evidenced at 1 h of adhesion depending on the surface treatment and chemical composition of the substrate. However, at larger times of study, there were no statistically significant differences between untreated and oxidized surfaces. The proliferation test (until 9 days) showed that untreated and oxidized NiTi surfaces are not cytotoxic for MG63 cells. The differences of adhesion at short times did not affect the proliferation of MG63 cells. However, after 48 h of stimulation with ascorbic acid and dexamethasone, the MG63 cells cultured on oxidized surfaces showed higher alkaline phosphatase activity and osteocalcin levels. The improvement of osteoblast differentiation due to OT treatment could accelerate bone formation, and, therefore, could allow earlier loading of NiTi devices used in dental and orthopedic applications. PMID- 17688279 TI - Behaviour of polysorbate 20 during dialysis, concentration and filtration using membrane separation techniques. AB - During formulation development of a therapeutic protein, combinations of buffers, pH and excipients need to be tested. As the protein bulk solution used for formulation development usually contains a buffer component at a defined pH and potentially one or more excipients already, this bulk requires to be processed. In case low concentrations of non-ionic surfactants, for example polysorbate 20, are already present in the bulk, the surfactant needs to be removed in lab-scale for further development use. The scope of the work was to study the behaviour of low concentrations of polysorbate 20 during membrane separation processes. The first part focuses on evaluating the behaviour of polysorbate 20 during a dialysis process, whereas the second part analyses concentration changes of polysorbate during a membrane concentration process using a stirred cell. The third part analyses potential membrane absorption of polysorbate at sterilizing grade filters. In conclusion, it was found that polysorbate could not be significantly reduced during a dialysis process and accumulated during a membrane concentration process in unreproducable manner. During sterile filtration, no significant influence on the concentration of polysorbate was measurable. In any case, it is recommendable to quantify the concentration of polysorbate during critical membrane process steps in pharmaceutical industry. PMID- 17688280 TI - Mechanical properties of calcium phosphate scaffolds fabricated by robocasting. AB - The mechanical behavior under compressive stresses of beta-tricalcium phosphate (beta-TCP) and hydroxyapatite (HA) scaffolds fabricated by direct-write assembly (robocasting) technique is analyzed. Concentrated colloidal inks prepared from beta-TCP and HA commercial powders were used to fabricate porous structures consisting of a 3-D tetragonal mesh of interpenetrating ceramic rods. The compressive strength and elastic modulus of these model scaffolds were determined by uniaxial testing to compare the relative performance of the selected materials. The effect of a 3-week immersion in simulated body fluid (SBF) on the strength of the scaffolds was also analyzed. The results are compared with those reported in the literature for calcium phosphate scaffolds and human bone. The robocast calcium phosphate scaffolds were found to exhibit excellent mechanical performances in terms of strength, especially the HA structures after SBF immersion, indicating a great potential of this type of scaffolds for use in load bearing bone tissue engineering applications. PMID- 17688281 TI - Both ionically and enzymatically crosslinkable alginate-tyramine conjugate as materials for cell encapsulation. AB - The swelling behavior of the structural material of cell-enclosing capsules is a key factor for the successful transplantation of these capsules in the treatment of diseases. The present study aimed to develop cell-enclosing capsules displaying minimal swelling under physiological conditions. We investigated the use of an alginate-tyramine conjugate synthesized by a carbodiimide/active-ester coupling reaction. The conjugate gel crosslinked by calcium ions and peroxidase catalyzed oxidative coupling of phenols swelled less in saline than in unmodified alginate. The degree of swelling could be controlled by conjugate preparation conditions. The conjugate gel showed no obvious cytotoxicity for cells, including the process of oxidative coupling generation. Further, encapsulated cells could be cultured for up to 2 months and achieve approximately 5.2-fold greater mitochondrial activity after 51 days of encapsulation than after 1 day. These results show that this alginate-tyramine conjugate is a promising material for use in cell-enclosing capsules for cell therapy. PMID- 17688282 TI - Adduction of amiloride hydrochloride in urea through a modified technique for the dissolution enhancement. AB - Amiloride hydrochloride is a potassium-sparing diuretic since it favors sodium excretion and potassium reabsorption. In the present study, urea, a well-known adductor for linear compounds was successfully employed for inclusion of amiloride hydrochloride-a substituted cyclic organic compound through a modified technique. Formation of urea inclusion compounds was confirmed by FTIR, DSC and XRD. The minimum amount of rapidly adductible endocyte (RAE) required for adduction of amiloride hydrochloride in urea was estimated by a modified Zimmerschied calorimetric method. Urea-AH-RAE inclusion compounds containing varying proportions of guests were prepared and their thermal behavior studied by DSC. The inclusion compounds were also found to exhibit high content uniformity and markedly improved dissolution profile as demonstrated by increased dissolution efficiency. Studies reveal the possibility of exploiting co-inclusion of the drug in urea host lattice for the dissolution enhancement. PMID- 17688283 TI - Enhancement of cellular binding efficiency and cytotoxicity using polyethylene glycol base triblock copolymeric nanoparticles for targeted drug delivery. AB - Folate (FA) conjugated tri-block copolymers were prepared by bioconjugation of poly epsilon-caprolactonediol and various molecular weights of diamine polyethylene glycol. The synthetic tri-block copolymers were characterized by 1H NMR. Three types of nanoparticles were prepared by nanoprecipitation. Their size and morphology were verified by laser scattering and transmission electron microscopy, respectively. The colloidal stability of the nanoparticles was evaluated by turbidity test. The anticancer drug doxorubicin (DOX) was encapsulated in the nanoparticles during preparation. Drug loading amounts and release behavior from prepared nanoparticles were investigated. Fluorescent activated cell sorting analysis and epi-fluorescencic microscopic imaging of prepared nanoparticles exhibited good cellular uptake against target cells. FA receptor expressed OVCAR3 cells that showed higher mean fluorescence intensity than FA receptor defect A549 cells at specific polyethylene glycol chain lengths. The cell cytotoxicity of prepared nanoparticles was evaluated for receptor mediated drug delivery. PMID- 17688284 TI - Role of nanotechnology in pharmaceutical product development. AB - A number of new molecular entities (NMEs) selected for full-scale development based on their safety and pharmacological data suffer from undesirable physicochemical and biopharmaceutical properties, which lead to poor pharmacokinetics and distribution after in vivo administration. An optimization of the preformulation studies to develop a dosage form with proper drug delivery system to achieve desirable pharmacokinetic and toxicological properties can aid in the accelerated development of these NMEs into therapies. Nanoparticulate drug delivery systems show a promising approach to obtain desirable druglike properties by altering the biopharmaceutics and pharmacokinetics properties of the molecule. Apart from the advantages of enhancing potential for systemic administration, nanoparticulate drug delivery systems can also be used for site specific delivery, thus alleviating unwanted toxicity due to nonspecific distribution, improve patient compliance, and provide favorable clinical outcomes. This review summarizes some of the parameters and approaches that can be used to evaluate nanoparticulate drug delivery systems in early stages of formulation development. PMID- 17688286 TI - CD38 regulates oxytocin secretion and complex social behavior. AB - The peptide hormone oxytocin plays a critical role in regulating affiliative behaviors including mating, pair-bond formation, maternal/parenting behavior, social recognition, separation distress and other aspects of attachment. Jin and colleagues recently reported intriguing findings that CD38, a transmembrane receptor with ADP-ribosyl cyclase activity, plays a critical role in maternal nurturing behavior and social recognition by regulating oxytocin secretion. This research may have implications for understanding disorders marked by deficits in social cognition and social functioning, including autism, social anxiety disorder, borderline personality disorder and schizophrenia. PMID- 17688285 TI - Differential osteogenic activity of osteoprogenitor cells on HA and TCP/HA scaffold of tissue engineered bone. AB - Biomaterial, an essential component of tissue engineering, serves as a scaffold for cell attachment, proliferation, and differentiation; provides the three dimensional (3D) structure and, in some applications, the mechanical strength required for the engineered tissue. Both synthetic and naturally occurring calcium phosphate based biomaterial have been used as bone fillers or bone extenders in orthopedic and reconstructive surgeries. This study aims to evaluate two popular calcium phosphate based biomaterial i.e., hydroxyapatite (HA) and tricalcium phosphate/hydroxyapatite (TCP/HA) granules as scaffold materials in bone tissue engineering. In our strategy for constructing tissue engineered bone, human osteoprogenitor cells derived from periosteum were incorporated with human plasma-derived fibrin and seeded onto HA or TCP/HA forming 3D tissue constructs and further maintained in osteogenic medium for 4 weeks to induce osteogenic differentiation. Constructs were subsequently implanted intramuscularly in nude mice for 8 weeks after which mice were euthanized and constructs harvested for evaluation. The differential cell response to the biomaterial (HA or TCP/HA) adopted as scaffold was illustrated by the histology of undecalcified constructs and evaluation using SEM and TEM. Both HA and TCP/HA constructs showed evidence of cell proliferation, calcium deposition, and collagen bundle formation albeit lesser in the former. Our findings demonstrated that TCP/HA is superior between the two in early bone formation and hence is the scaffold material of choice in bone tissue engineering. PMID- 17688287 TI - Epigenetic "bivalently marked" process of cancer stem cell-driven tumorigenesis. AB - Silencing of tumor suppressor genes (TSGs), by DNA methylation, is well known in adult cancers. However, based on the "stem cell" theory of tumorigenesis, the early epigenetic events arising in malignant precursors remain unknown. A recent report demonstrates that, while pluripotent embryonic stem cells lack DNA methylation and possess a "bivalent" pattern of activating and repressive histone marks in numerous TSGs, analogous multipotent malignant cells derived from germ cell tumors (embryonic carcinoma cells) gain additional silencing modifications to those same genes. These results suggest a possible mechanism by which aberrant differentiation, mediated by histone and DNA methylation, instigates tumor progression. PMID- 17688289 TI - Connective-tissue responses to defined biomaterial surfaces. II. Behavior of rat and mouse fibroblasts cultured on microgrooved substrates. AB - Surface microgeometry strongly influences the shapes, orientations, and growth characteristics of cultured cells, but in-depth, quantitative studies of these effects are lacking. We investigated several contact guidance effects in cells within "dot" colonies of primary fibroblasts and in cultures of a transformed fibroblast cell line, employing titanium-coated, microgrooved polystyrene surfaces that we designed and produced. The aspect ratios, orientations, densities, and attachment areas of rat tendon fibroblasts (RTF) colony cells, in most cases, varied (p < 0.01) by microgroove dimension. We observed profoundly altered cell morphologies, reduced attachment areas, and reduced cell densities within colonies grown on microgrooved substrates, compared with cells of colonies grown on flat, control surfaces. 3T3 fibroblasts cultured on microgrooved surfaces demonstrated similarly altered morphologies. Fluorescence microscopy revealed that microgrooves alter the distribution and assembly of cytoskeletal and attachment proteins within these cells. These findings are consistent with previous results, and taken together with the results of our in vivo and cell colony growth studies, enable us to propose a unified hypothesis of how microgrooves induce contact guidance. PMID- 17688288 TI - High-strength, in situ-setting calcium phosphate composite with protein release. AB - The aim of this study was to develop a mechanically-strong calcium phosphate cement (CPC) with protein release. Chitosan was used to strengthen CPC and control protein release. Mass fraction of protein release = mass of released protein/mass of total protein incorporated into the specimen. Flexural strength (mean +/- sd; n = 6) of CPC containing 100 ng/mL of protein increased from 8.0 +/ 1.4 MPa with 0% chitosan, to 19.8 +/- 1.4 MPa with 15% chitosan (p < 0.05). The latter exceeded the reported strengths of sintered porous hydroxyapatite implants and cancellous bone. When the chitosan mass fraction was increased from 0% to 10% and 15%, protein release varied from 0.60 +/- 0.03 to 0.41 +/- 0.04, and to 0.23 +/- 0.07, respectively (p < 0.05). When powder:liquid ratio increased from 2:1 to 3:1 and 4:1, protein release changed from 0.89 +/- 0.10 to 0.41 +/- 0.04, and to 0.23 +/- 0.07, respectively p < 0.05. Therefore, chitosan content and powder:liquid ratio successfully controlled the protein release. The protein release mass fraction, M, was related to CPC porosity P by: M = 16.9 P(4.5). In summary, a mechanically-strong CPC with controlled protein release was formulated. Protein release was proportional to CPC porosity. The in situ hardening, nano-apatite composite may have potential for bone tissue engineering, especially when both mechanical strength and controlled release of therapeutic/bioactive agents are needed. PMID- 17688290 TI - Connective-tissue responses to defined biomaterial surfaces. I. Growth of rat fibroblast and bone marrow cell colonies on microgrooved substrates. AB - Surface microgeometry plays a role in tissue-implant surface interactions, but our understanding of its effects is incomplete. Substrate microgrooves strongly influence cells in vitro, as evidenced by contact guidance and cell alignment. We studied "dot" colonies of primary fibroblasts and bone marrow cells that were grown on titanium-coated, microgrooved polystyrene surfaces that we designed and produced. Rat tendon fibroblast and rat bone marrow colony growth and migration varied (p < 0.01) by microgroove dimension and slightly by cell type. We observed profoundly altered morphologies, reduced growth rates, and directional growth in colonies grown on microgrooved substrates, when compared with colonies grown on flat, control surfaces (p < 0.01). The cells in our colonies grown on microgrooved surfaces were well aligned and elongated in the direction parallel to the grooves and colonies. Our "dot" colony is an easily reproduced, easily measured and artificial explant model of tissue-implant interactions that better approximates in vivo implant responses than culturing isolated cells on biomaterials. Our results correlate well with in vivo studies of titanium dioxide coated polystyrene, titanium, and titanium alloy implants with controlled microgeometries. Microgrooves and other surface features appear to directionally or spatially organize cells and matrix molecules in ways that contribute to improved stabilization and osseointegration of implants. PMID- 17688291 TI - Beta-CaSiO3/beta-Ca3(PO4)2 composite materials for hard tissue repair: in vitro studies. AB - In this study, a series of beta-CaSiO(3) (CS)/beta-Ca(3)(PO(4))(2) (TCP) composites with different ratios were prepared to produce new bioactive and biodegradable biomaterials for potential bone repair. The mechanical properties of CS-TCP composites increased steadily with the increase of TCP amounts in composites. Formation of bone-like apatite on a range of CS-TCP composites with CS weight percentage ranging from 0 to 100 has been investigated in simulated body fluid (SBF). The presence of bone-like apatite layer on the composite surface after soaking in SBF was demonstrated by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), and fourier transform infrared reflection spectroscopy (FTIR). The results showed that the apatite formation ability of the CS-TCP composite was enhanced with increasing CS content in the composites. For composites with more than 50% CS contents, the samples were completely covered by a layer of dense bone-like apatite just after 3 days immersion. Dissolution tests in Tris-HCl buffer solution showed obvious differences with different CS contents in composites. The dissolution rate increased with the increase of CS content, which suggested that the solubility of biphasic composites could be tailored by adjusting the initial CS/TCP ratio. In vitro cell experiments showed that higher content of CS phase in composites promoted cell proliferation and differentiation. When the CS amount in the composite increased to 50%, the proliferation rate and ALP activities of osteoblast-like cells showed significant difference compared with pure TCP (p < 0.05). Results of the study suggested that the CS-TCP composites with more than 50% CS content might be promising bone repair materials. PMID- 17688292 TI - Preparation of bone-like apatite-collagen nanocomposites by a biomimetic process with phosphorylated collagen. AB - By imitating in vivo bone mineralization, bone-like apatite-collagen nanocomposites were prepared by chemical phosphorylation of collagen and subsequent biomimetic growth of bone-like nanoapatite on collagen nanofibers. Two steps were employed in the composites preparation. First, the collagen was phosphorylated by chemical treatment, which provides the nucleation sites for bone-like apatite mineralization. The subsequent growth of bone-like nanoapatite on the phosphorylated collagen nanofibers was performed in simulated body fluid (SBF). The characterization of the composites showed that the composites were composed of nanoapatite mineralized collagen nanofibers that exhibit similarity to natural bone in composition and crystal morphology. PMID- 17688293 TI - A novel, tissue occlusive poly(ethylene glycol) hydrogel material. AB - The use of guided bone regeneration (GBR) techniques requires new materials meeting the needs of clinical application. Design criteria for GBR devices are biocompatibility, tissue occlusion, space provision, and clinical manageability. This study evaluates a novel biodegradable poly (ethylene glycol) (PEG) based material as tissue occlusive membrane. A subcutaneous implant model in rats was developed to test the barrier function of the PEG hydrogels over time. Fourteen rats received three membrane implants and two positive controls each. Explants were collected over a period of 7 months. Histological analysis revealed that for at least 4 months cellular infiltration in the membrane explants was lower than 1% of that of the positive controls. Therefore, the PEG based hydrogel can be regarded as tissue occlusive during this period of time. A barrier function seems to be maintained for up to 6 months. In vitro degradation studies performed with the same PEG constructs confirm the in vivo result. In conclusion, our results indicate that this novel PEG-based material has potential for use as a GBR barrier membrane. PMID- 17688296 TI - The involvement of oxidative stress in ochratoxin A and fumonisin B1 toxicity in rats. AB - The aim of this study was to find out whether very low doses of nephrotoxic and hepatotoxic mycotoxins ochratoxin A (OTA) and fumonisin B1 (FB1) induce oxidative stress in rat kidney and liver and whether their effect is synergistic. Rats were treated orally with OTA (5 ng/kg b.w. and 50 microg/kg b.w.) and FB1 (200 ng/kg b.w. and 50 microg/kg b.w.), or their combinations. Malondialdehyde (MDA) and protein carbonyls (PCs) concentration in kidney was affected with lower dose of OTA than in liver (p<0.05). FB1 did not affect MDA and PCs concentrations in the liver, while in the kidney both FB1 doses increased MDA concentration (p<0.05). The combination of the lower doses of OTA+FB1 increased the MDA and PCs concentration both in the liver and the kidney, compared to controls and animals treated with respective doses of mycotoxins (p<0.05). The combinations of mycotoxins reduced the catalase activity only in the kidney when compared to controls (p<0.05). In contrast to the increased kidney concentrations of MDA and PCs even with very low doses of OTA and FB1, the activity of catalase and SOD does not change. Combinations of OTA+FB1 affected almost all parameters, which indicates their potential to produce oxidative damage. PMID- 17688297 TI - Common tea formulations modulate in vitro digestive recovery of green tea catechins. AB - Epidemiological evidence suggests a role for tea catechins in reduction of chronic disease risk. However, stability of catechins under digestive conditions is poorly understood. The objective of this study was to characterize the effect of common food additives on digestive recovery of tea catechins. Green tea water extracts were formulated in beverages providing 4.5, 18, 23, and 3.5 mg per 100 mL epicatechin (EC), epigallocatechin (EGC), epigallocatechin-gallate (EGCG), and epicatechin-gallate (ECG), respectively. Common commercial beverage additives; citric acid (CA), BHT, EDTA, ascorbic acid (AA), milk (bovine, soy, and rice), and citrus juice (orange, grapefruit, lemon, and lime) were formulated into finished tea beverages at incremental dosages. Samples were then subjected to in vitro digestion simulating gastric and small intestinal conditions with pre- and post-digestion catechin profiles assessed by HPLC. Catechin stability in green tea was poor with <20% total catechins remaining post-digestion. EGC and EGCG were most sensitive with less, not double equals 10% recovery. Teas formulated with 50% bovine, soy, and rice milk increased total catechin recovery significantly to 52, 55, and 69% respectively. Including 30 mg AA in 250 mL of tea beverage significantly (p<0.05) increased catechin recovery of EGC, EGCG, EC, and ECG to 74, 54, 82, and 45% respectively. Juice preparation resulted in the highest recovery of any formulation for EGC (81-98%), EGCG (56-76%), EC (86-95%), and ECG (30-55%). These data provide evidence that tea consumption practices and formulation factors likely impact catechin digestive recovery and may result in diverse physiological profiles. PMID- 17688298 TI - Radioactivity measurements and radiation dose evaluation in tap waters of Central Italy. AB - Consumption of drinking water is very important for human nutrition and its quality must be strictly controlled. A study of radioactivity content in tap water samples collected in the Central Italy was performed in order to check the compliance with recent European regulations. Gross alpha and beta activity, 226Ra, 238U and 234U concentrations were measured. Gross alpha and beta activities were determined by standard ISO 9696 and ISO 9697; for 226Ra determination liquid scintillation was used. 238U and 234U concentrations were determined by alpha spectrometry after separation from matrix by extraction chromatography and electroplating. Recommended WHO guideline activity concentrations for drinking water (0.1 and 1.0 Bq/L for gross alpha and gross beta activity, respectively) are exceeded in two cases for gross alpha activity and are not exceeded in any case for gross beta activity. The concentrations (mBq/L) of 226Ra, 238U and 234U ranged from <1.70 to 15.3, 0.65 to 48.8 and 0.780 to 51.5, respectively. Effective dose due to the uranium isotopes and radium was calculated for children and adults using the dose coefficients reported by EC Directive 96/29 EURATOM and annual water intake. For all class ages, the doses are quite similar and much lower than 0.1 mSv/year. PMID- 17688299 TI - Resolution of beta-amino acids on a high performance liquid chromatographic doubly tethered chiral stationary phase containing N-CH3 amide linkage based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. AB - A doubly tethered chiral stationary phase (CSP) containing N-CH(3 )amide linkage based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid was applied to the resolution of various beta-amino acids. The chiral recognition behaviors for the resolution of beta-amino acids on the doubly tethered CSP were consistent with those on the corresponding singly tethered CSP while the chiral recognition ability of the doubly tethered CSP was generally greater in terms of both the separation (alpha) and the resolution factors (R(S)) than that of the corresponding singly tethered CSP. From these results, it was concluded that attaching the second tethering group to silica gel through a carbon atom of the first tethering group of the CSP improves the chiral recognition ability for the resolution of beta-amino acids without any change in the chiral recognition mode. The retention factors (k(1)) on the doubly tethered CSP were larger than those on the corresponding singly tethered CSP and these retention factors were found to be controllable with the variation of the type and the content of the organic and/or acidic modifier in the aqueous mobile phase without significant change in the separation and the resolution factors. PMID- 17688300 TI - Experimental design optimization of the capillary electrophoresis separation of leucine enkephalin and its immune complex. AB - To optimize the capillary electrophoretic separation conditions for leucine enkephalin (LE) and the immune complex of the LE and anti-LE reaction, an analysis using a three-level, three-factorial Box-Behnken design was performed. Three separation parameters, buffer pH (X(1)), buffer concentration (X(2)), and applied voltage (X(3)), were chosen to observe the effect on separation responses. The responses were theoretical plate number, migration time of the LE peak, and resolution between the peaks. The optimum conditions and process validation were determined using statistical regression analysis and surface plot diagrams. The capillary electrophoresis optimum separation conditions were established to be 75 mM phosphate buffer at pH 7.00 with an applied separation voltage of 15 kV. By using the analysis technique, the prediction of responses was satisfactory and process verification yielded values within the +/-5% range of the predicted efficiency. PMID- 17688301 TI - Multidimensional gas chromatographic determination of naphthenes, paraffins, olefins, and aromatics in reformed gasolines. AB - Increasing demand for gasoline, changing regulations concerning the reduction of environmental impact, and new refining technologies have led to the refinement of its composition. Nowadays, gasoline is a complex mixture of different fractions deriving from processes of reforming, cracking, isomerization, and alkylation, with the addition of both oxygenated compounds and butanes. There are regulations governing the mixing of various fractions and it is necessary to analyse the composition of these fractions to ensure that the final composition of commercial gasoline satisfies the required specifications. Moreover, analysis of the composition of each fraction enables the technological process of the fraction examined to be modified as appropriate. In this work some reformed gasolines were analysed by multidimensional gas chromatography. This technique allows good separation of the hydrocarbon types in a single analysis and gives the carbon number distribution within each hydrocarbon type. PMID- 17688302 TI - Nano-LC-MS/MS for the monitoring of angiotensin IV in rat brain microdialysates: limitations and possibilities. AB - To broaden our knowledge about the central role of the angiotensin IV (Ang IV) peptide, we aimed to monitor its extracellular concentration in the brain using in vivo microdialysis. Ang IV was measured in the dialysates using a previously developed nano-LC-MS/MS assay with an LOD of 50 pM. Using this assay, baseline levels of Ang IV in dialysates from different brain structures were undetectable. However, immediately after microdialysis probe insertion, Ang IV could be detected in a concentration that varied between 120 and 187 pM. Using the zero net-flux method, the extracellular levels of Ang IV in the striatum were estimated at 46 pM. These data may indicate that Ang IV is mainly present intracellularly. In addition, Ang IV was clearly measurable after striatal perfusion of Ang II. On the other hand, our nano-LC-MS/MS method was successful for the detection of Met-enkephalin and neurotensin in dialysates from the rat. In conclusion, the nano-LC-MS/MS method coupled with microdialysis is well suited to monitor the biologically significant conversion between Ang II and Ang IV in vivo, but physiological extracellular levels of Ang IV appear too low to be detected. PMID- 17688303 TI - Placental vascularization measured by three-dimensional power Doppler ultrasound at 11 to 13 + 6 weeks' gestation in normal and aneuploid fetuses. AB - OBJECTIVE: To establish the potential role of three-dimensional (3D) power Doppler evaluation of the placental circulation in aneuploidy screening at 11 to 13 + 6 weeks of gestation. METHODS: 3D power Doppler ultrasound examination of the placenta was performed in 25 pregnancies with fetuses with abnormal karyotype and in 100 control pregnancies at 11 to 13 + 6 weeks of gestation. Using the same pre-established settings for all cases, the vascularization index (VI), flow index (FI) and vascularization flow index (VFI) were calculated for the whole placenta. RESULTS: In the chromosomally normal group all the vascular indices increased significantly with advancing gestation between 11 and 13 + 6 weeks (VI: r = 0.482, P < 0.001; FI: r = 0.295, P = 0.0029; VFI, r = 0.484, P < 0.001). In the chromosomally abnormal group, the flow indices were not significantly different from normal in cases with trisomy 21 (13 cases), but they were significantly reduced compared with normal in cases with trisomies 13 and 18 (VI: t = 8.321, P < 0.0001: FI: t = 12.934, P < 0.0001; VFI: t = 7.608, P < 0.0001). CONCLUSIONS: 3D power Doppler evaluation of the placental circulation is not useful in screening for trisomy 21, and unlikely to further increase the already high detection rate for trisomies 13 and 18. However, we provide normal ranges of placental vascular indices between 11 + 0 and 13 + 6 weeks of gestation, which may be useful in future research on placental vascularity in certain at-risk pregnancies. PMID- 17688305 TI - Sonographic visualization of the middle phalanx of the fetal fifth digit between 13 and 17 weeks of gestation. AB - OBJECTIVE: To assess in utero visualization of the middle phalanx of the fifth digit (MPFD) between 13 and 17 weeks of gestation. METHODS: This was a prospective cross-sectional study in which women attending for fetal sonographic examination between 13 + 0 and 17 + 6 weeks of gestation were evaluated for the presence of the middle phalanx of the fifth digit (MPFD). A total of 682 fetuses with normal findings on first-trimester anatomical examination were recruited. Using transvaginal multifrequency 4-8 and 5-9 MHz probes, the fifth finger was examined in both axial and lateral views until optimal visualization of the MPFD was achieved. RESULTS: The MPFD was visualized in 14.3% (2/14) of cases at 13 weeks, 70.3% (154/219) at 14 weeks, 82.2% (240/292) at 15 weeks, 97.4% (111/114) at 16 weeks and 100% (43/43) at 17 weeks of gestation. CONCLUSIONS: Ultrasound visualization of the MPFD gradually increases during the 13- to 17-week period. This emphasizes the limited role of non-ossification of the MPFD as a sonographic marker of Down syndrome before 17 weeks of gestation. PMID- 17688304 TI - Ultrasound assessment of endometrial morphology and vascularity to predict endometrial malignancy in women with postmenopausal bleeding and sonographic endometrial thickness >or= 4.5 mm. AB - OBJECTIVES: To determine which endometrial morphology characteristics as assessed by gray-scale ultrasound and which endometrial vessel characteristics as assessed by power Doppler ultrasound are useful for discriminating between benign and malignant endometrium in women with postmenopausal bleeding (PMB) and sonographic endometrial thickness >or= 4.5 mm and to develop logistic regression models to calculate the individual risk of endometrial malignancy in women with PMB, endometrial thickness >or= 4.5 mm, good visibility of the endometrium and detectable Doppler signals in the endometrium. METHODS: Of 223 consecutive patients with PMB and sonographic endometrial thickness >or= 4.5 mm, 120 fulfilled our inclusion criteria. They underwent transvaginal gray-scale and power Doppler ultrasound examination, which was videotaped for later analysis by two examiners with more than 15 years' experience in gynecological ultrasonography. They independently assessed endometrial morphology and vascularity using predetermined criteria. Their agreed-upon description was compared with the histological diagnosis. Univariate and multivariate logistic regression analyses were used. The best diagnostic test was defined as the one with the largest area under the receiver-operating characteristics curve (AUC). RESULTS: Thirty (25%) endometria were malignant. Inter-observer agreement for the description of endometrial morphology and vascularity was moderate to good (Kappa 0.49-0.78). The best ultrasound variables to predict malignancy were heterogeneous endometrial echogenicity (AUC 0.83), endometrial thickness (AUC 0.80), and irregular branching of endometrial blood vessels (AUC 0.77). A logistic regression model including endometrial thickness and heterogeneous endometrial echogenicity had an AUC of 0.91. Its mathematically best risk cut-off yielded a positive likelihood ratio of 4.4, and a negative likelihood ratio of 0.1. Adding Doppler information to the model improved diagnostic performance marginally (AUC 0.92). CONCLUSIONS: In selected high-risk women with PMB and an endometrial thickness of >or= 4.5 mm, calculation of the individual risk of endometrial malignancy using regression models including gray-scale and Doppler characteristics can be used to tailor management. These models would need to be tested prospectively before introduction into clinical practice. PMID- 17688306 TI - Molecular piracy: manipulation of the ubiquitin system by Kaposi's sarcoma associated herpesvirus. AB - Ubiquitination, one of several post-translational protein modifications, plays a key role in the regulation of cellular events, including protein degradation, signal transduction, endocytosis, protein trafficking, apoptosis and immune responses. Ubiquitin attachment at the lysine residue of cellular factors acts as a signal for endocytosis and rapid degradation by the 26S proteasome. It has recently been observed that viruses, especially oncogenic herpesviruses, utilise molecular piracy by encoding their own proteins to interfere with regulation of cell signalling. Kaposi's sarcoma- associated herpesvirus (KSHV) manipulates the ubiquitin system to facilitate cell proliferation, anti-apoptosis and evasion from immunity. In this review, we will describe the strategies used by KSHV at distinct stages of the viral life-cycle to control the ubiquitin system and promote oncogenesis and viral persistence. PMID- 17688307 TI - A diffusion-weighted template for gestational age-related apparent diffusion coefficient values in the developing fetal brain. AB - OBJECTIVE: To determine the pattern of apparent diffusion coefficient (ADC) values in the normal fetal brain obtained with diffusion-weighted images (DWI) on magnetic resonance imaging (MRI) as a template for normal brain development throughout gestation. METHODS: This was a prospective study of 46 fetuses without suspicion of brain pathology undergoing a total of 66 ultrasound examinations between 17 and 37 weeks of gestation. At T2-weighted MRI, four left and four right brain regions were delineated on transverse slices of the native DWI using a b-value of 0 s/mm2 (b0 images). We examined native b-value images and calculated ADC(avg), ADC(low) and ADC(high) in the basal ganglia, cerebellar hemisphere, frontal parenchyma and occipital parenchyma. Linear regression analysis was used to assess the relationship between gestational age and b0 values as well as the calculated ADC values. RESULTS: Delineations were successful in all fetuses for all regions except for the cerebellar hemispheres in four fetuses. There was a negative correlation between gestational age and b0 values in all examined anatomical regions (P<0.002). For ADC(avg), there were no significant changes in the basal ganglia with increasing gestational age, a positive correlation in the frontal (P<0.0001) and occipital (P=0.03) parenchyma and a negative correlation in the cerebellar hemispheres (P=0.01). For ADC(low), there was a negative correlation between gestational age and the cerebellum (P=0.0002) and basal ganglia (P=0.047), but no correlation for the frontal or occipital parenchyma. For ADC(high), there was a positive correlation with gestational age for the frontal parenchyma (P=0.004), occipital parenchyma (P=0.02) and basal ganglia (P=0.03) but there was no correlation for the cerebellum. CONCLUSIONS: DWI b0 values decreased in the left and right basal ganglia, cerebellar hemisphere, frontal parenchyma and occipital parenchyma between 17 and 37 weeks of gestation and ADC(avg) values increased in two out of four cerebral regions. It remains to be determined to what extent these observations differ in fetuses with suspicion of brain anomalies and whether such measurements will be useful and more predictive of outcome compared with standard MRI sequences. PMID- 17688308 TI - Prospective evaluation of the risk of pre-eclampsia using logistic regression analysis. AB - OBJECTIVES: To calculate the risk of developing pre-eclampsia (PET) in a consecutive series of low-risk women at 18-24 weeks' gestation, using recently published logistic regression models. METHODS: This was a prospective study, with complete follow-up, in a consecutive series of unselected low-risk singleton pregnancies. Uterine artery pulsatility index as well as a combination of maternal factors were recorded at 18-24 weeks' gestation. The distribution of the estimated risks for the 16 PET patients was compared with that obtained for 136 women who had a normal pregnancy, as assessed by routine testing. A receiver operating characteristics (ROC) curve was plotted to evaluate the detection rate at fixed false-positive rates (FPRs) of 5%, 10% and 20% and the corresponding odds cut-offs. RESULTS: Just 1/16 (6.2%) women with PET developed the disease before the 34(th) week of gestation. Using the 'All PET' logistic regression model, for 16 PET cases the overall median odds was 1 : 1454, higher compared with that of 1 : 41635 estimated for controls. Using the 'PET >or= 34 weeks' model, the median odds of the 15 women who developed PET late was 1 : 3405, compared with 1 : 40785 for controls. In the case of PET before 34 weeks, the risk was 1 : 426373 vs. 1 : 4159823126 estimated for controls ('PET < 34 weeks' model). Detection rates for the All PET model were 18%, 50% and 62% at a FPR of 5%, 10% and 20%, respectively. For the PET >or= 34 weeks model these detection rates were 6%, 46% and 60%, respectively. CONCLUSION: Even though the individual odds estimation is too low to represent the real risk of PET, the recently published logistic regression models detected more than 60% of PET at a FPR of 20% for both All PET and PET >or= 34 weeks models. Using these models in clinical practice does not seem to give any significant improvement over Doppler alone in the prediction of PET, but the use of a PET-specific odds instead of an actual Doppler value alone seems to be useful for clinical management. PMID- 17688310 TI - An effective data mining technique for reconstructing gene regulatory networks from time series expression data. AB - Recent development in DNA microarray technologies has made the reconstruction of gene regulatory networks (GRNs) feasible. To infer the overall structure of a GRN, there is a need to find out how the expression of each gene can be affected by the others. Many existing approaches to reconstructing GRNs are developed to generate hypotheses about the presence or absence of interactions between genes so that laboratory experiments can be performed afterwards for verification. Since, they are not intended to be used to predict if a gene in an unseen sample has any interactions with other genes, statistical verification of the reliability of the discovered interactions can be difficult. Furthermore, since the temporal ordering of the data is not taken into consideration, the directionality of regulation cannot be established using these existing techniques. To tackle these problems, we propose a data mining technique here. This technique makes use of a probabilistic inference approach to uncover interesting dependency relationships in noisy, high-dimensional time series expression data. It is not only able to determine if a gene is dependent on another but also whether or not it is activated or inhibited. In addition, it can predict how a gene would be affected by other genes even in unseen samples. For performance evaluation, the proposed technique has been tested with real expression data. Experimental results show that it can be very effective. The discovered dependency relationships can reveal gene regulatory relationships that could be used to infer the structures of GRNs. PMID- 17688309 TI - Computerized fetal heart rate analysis, Doppler ultrasound and biophysical profile score in the prediction of acid-base status of growth-restricted fetuses. AB - OBJECTIVE: To investigate the performance of non-stress test (NST), computerized fetal heart rate analysis (cCTG), biophysical profile scoring (BPS) and arterial and venous Doppler ultrasound investigation in the prediction of acid-base status in fetal growth restriction. METHODS: Growth-restricted fetuses, defined by abdominal circumference < 5(th) percentile and umbilical artery (UA) pulsatility index > 95(th) percentile, were tested by NST, cCTG, BPS, and UA, middle cerebral artery (MCA), ductus venosus (DV) and umbilical vein (UV) Doppler investigation. The short-term variation (STV) of the fetal heart rate was calculated using the Oxford Sonicaid 8002 cCTG system. Relationships between antenatal test results and cord artery pH < 7.20 were investigated, using correlation, parametric and non-parametric tests. RESULTS: Fifty-six of 58 patients (96.6%) received complete assessment of all variables. All were delivered by pre-labor Cesarean section at a median gestational age of 30 + 6 weeks. The UA pulsatility index (PI) was negatively correlated with the cCTG STV (Pearson correlation - 0.29, P < 0.05). The DV PI was negatively correlated with the pH (Pearson correlation - 0.30, P < 0.02). The cCTG mean minute variation and pH were not significantly correlated (Pearson correlation 0.13, P = 0.34). UV pulsations identified the highest proportion of neonates with a low birth pH (9/17, 53%), the highest number of false positives among patients with an abnormal BPS, abnormal DV Doppler and a STV < 3.5 ms, and also stratified false negatives among patients with an equivocal or normal BPS. Abnormal DV Doppler correctly identified false positives among patients with an abnormal BPS. cCTG reduced the rate of an equivocal BPS from 16% to 7.1% when substituted for the traditional NST. Elevated DV Doppler index and umbilical venous pulsations predicted a low pH with 73% sensitivity and 90% specificity (P = 0.008). CONCLUSION: In fetal growth restriction with placental insufficiency, venous Doppler investigation provides the best prediction of acid-base status. The cCTG performs best when combined with venous Doppler or as a substitute for the traditional NST in the BPS. PMID- 17688311 TI - Transmembrane structure predictions with hydropathy index/charge two-dimensional trajectories of stochastic dynamical systems. AB - A novel algorithm is proposed for predicting transmembrane protein secondary structure from two-dimensional vector trajectories consisting of a hydropathy index and formal charge of a test amino acid sequence using stochastic dynamical system models. Two prediction problems are discussed. One is the prediction of transmembrane region counts; another is that of transmembrane regions, i.e. predicting whether or not each amino acid belongs to a transmembrane region. The prediction accuracies, using a collection of well-characterized transmembrane protein sequences and benchmarking sequences, suggest that the proposed algorithm performs reasonably well. An experiment was performed with a glutamate transporter homologue from Pyrococcus horikoshii. The predicted transmembrane regions of the five human glutamate transporter sequences and observations based on the computed likelihood are reported. PMID- 17688312 TI - Assessing the quality of the homology-modeled 3D structures from electrostatic standpoint: test on bacterial nucleoside monophosphate kinase families. AB - In this study, we address the issue of performing meaningful pK(a) calculations using homology modeled three-dimensional (3D) structures and analyze the possibility of using the calculated pK(a) values to detect structural defects in the models. For this purpose, the 3D structure of each member of five large protein families of a bacterial nucleoside monophosphate kinases (NMPK) have been modeled by means of homology-based approach. Further, we performed pK(a) calculations for the each model and for the template X-ray structures. Each bacterial NMPK family used in the study comprised on average 100 members providing a pool of sequences and 3D models large enough for reliable statistical analysis. It was shown that pK(a) values of titratable groups, which are highly conserved within a family, tend to be conserved among the models too. We demonstrated that homology modeled structures with sequence identity larger than 35% and gap percentile smaller than 10% can be used for meaningful pK(a) calculations. In addition, it was found that some highly conserved titratable groups either exhibit large pK(a) fluctuations among the models or have pK(a) values shifted by several pH units with respect to the pK(a) calculated for the X ray structure. We demonstrated that such case usually indicates structural errors associated with the model. Thus, we argue that pK(a) calculations can be used for assessing the quality of the 3D models by monitoring fluctuations of the pK(a) values for highly conserved titratable residues within large sets of homologous proteins. PMID- 17688313 TI - Incorporating homologues into sequence embeddings for protein analysis. AB - Statistical and learning techniques are becoming increasingly popular for different tasks in bioinformatics. Many of the most powerful statistical and learning techniques are applicable to points in a Euclidean space but not directly applicable to discrete sequences such as protein sequences. One way to apply these techniques to protein sequences is to embed the sequences into a Euclidean space and then apply these techniques to the embedded points. In this work we introduce a biologically motivated sequence embedding, the homology kernel, which takes into account intuitions from local alignment, sequence homology, and predicted secondary structure. This embedding allows us to directly apply learning techniques to protein sequences. We apply the homology kernel in several ways. We demonstrate how the homology kernel can be used for protein family classification and outperforms state-of-the-art methods for remote homology detection. We show that the homology kernel can be used for secondary structure prediction and is competitive with popular secondary structure prediction methods. Finally, we show how the homology kernel can be used to incorporate information from homologous sequences in local sequence alignment. PMID- 17688314 TI - A hidden Markov model for predicting protein interfaces. AB - Protein-protein interactions play a defining role in protein function. Identifying the sites of interaction in a protein is a critical problem for understanding its functional mechanisms, as well as for drug design. To predict sites within a protein chain that participate in protein complexes, we have developed a novel method based on the Hidden Markov Model, which combines several biological characteristics of the sequences neighboring a target residue: structural information, accessible surface area, and transition probability among amino acids. We have evaluated the method using 5-fold cross-validation on 139 unique proteins and demonstrated precision of 66% and recall of 61% in identifying interfaces. These results are better than those achieved by other methods used for identification of interfaces. PMID- 17688315 TI - Parallel stochastic simulation of macroscopic calcium currents. AB - This work introduces MACACO, a macroscopic calcium currents simulator. It provides a parameter-sweep framework which computes macroscopic Ca(2+) currents from the individual aggregation of unitary currents, using a stochastic model for L-type Ca(2+) channels. MACACO uses a simplified 3-state Markov model to simulate the response of each Ca(2+) channel to different voltage inputs to the cell. In order to provide an accurate systematic view for the stochastic nature of the calcium channels, MACACO is composed of an experiment generator, a central simulation engine and a post-processing script component. Due to the computational complexity of the problem and the dimensions of the parameter space, the MACACO simulation engine employs a grid-enabled task farm. Having been designed as a computational biology tool, MACACO heavily borrows from the way cell physiologists conduct and report their experimental work. PMID- 17688316 TI - Prediction of transcription factor binding sites using genetical genomics methods. AB - In this paper, we wanted to test whether it is possible to use genetical genomics information such as expression quantitative trait loci (eQTL) mapping results as input to a transcription factor binding site (TFBS) prediction algorithm. Furthermore, this new approach was compared to the more traditional cluster based TFBS prediction. The results of eQTL mapping are used as input to one of the top ranking TFBS prediction algorithms. Genes with observed expression profiles showing the same eQTL region are collected into eQTL groups. The promoter sequences of all the genes within the same eQTL group are used as input in the transcription factor binding site search. This approach is tested with a real data set of a recombinant inbred line population of Arabidopsis thaliana. The predicted motifs are compared to results obtained from the conventional approach of first clustering the gene expression values and then using the promoter sequences of the genes within the same cluster as input for the transcription factor binding site prediction. Our eQTL based approach produced different motifs compared to the cluster based method. Furthermore the score of the eQTL based motifs was higher than the score of the cluster based motifs. In a comparison to already predicted motifs from the AtcisDB database, the eQTL based and the cluster based method produced about the same number of hits with binding sites from AtcisDB. In conclusion, the results of this study clearly demonstrate the usefulness of eQTL to predict transcription factor binding sites. PMID- 17688317 TI - Research on parameterized algorithms of the individual haplotyping problem. AB - The individual haplotyping problem is a computing problem of reconstructing two haplotypes for an individual based on several optimal criteria from one's fragments sequencing data. This paper is based on the fact that the length of a fragment and the number of the fragments covering a SNP (single nucleotide polymorphism) site are both very small compared with the length of a sequenced region and the total number of the fragments and introduces the parameterized haplotyping problems. With m fragments whose maximum length is k(1), n SNP sites and the number of the fragments covering a SNP site no more than k(2), our algorithms can solve the gapless MSR (Minimum SNP Removal) and MFR (Minimum Fragment Removal) problems in the time complexity O(nk(1)k(2) + m log m + nk(2) + mk(1)) and O(mk(2)(2) + mk(1) k(2) + m log m + nk(2) + mk(1))respectively. Since, the value of k(1) and k(2) are both small (about 10) in practice, our algorithms are more efficient and applicable compared with the algorithms of V. Bafna et al. of time complexity O(mn(2)) and O(m(2)n + m(3)), respectively. PMID- 17688318 TI - Counterion free colorimetric metal cation sensor array. PMID- 17688319 TI - Surface modification of poly(L-lactic acid) membrane via layer-by-layer assembly of silver nanoparticle-embedded polyelectrolyte multilayer. AB - The improvement of hydrophilicity, antibacterial activity, hemocompatibility, and cytocompatibility of poly(L-lactic acid) (PLLA) membrane was developed via polyelectrolyte multilayer (PEM) immobilization. Colloidal silver nanoparticles were prepared by using dextran sulfate (DS) as a stabilizer to precede chemical reduction by dextrose. The polysaccharide PEMs, including chitosan (CH) and dextran sulfate (DS)-stabilized silver nanosized colloid (DSS), were successfully deposited on the aminolyzed PLLA membrane in a layer-by-layer (LBL) self-assembly manner. The obtained results showed that the contact angle of PLLA membranes decreased with PEMs grafting layers and reached a steady value after four bilayers of coating, hence suggesting that full coverage was achieved. The PLLA PEM membranes with DSS as the outermost layer could resist platelet adhesion and human plasma fibrinogen (HPF) adsorption, while prolonging the blood coagulation time. The PLLA-PEM membranes could possess antibacterial activity against Methicilin-resistant Staphylococus aureus (MRSA). In addition, the proliferation and viability of human endothelial cells (ECs) on PLLA-PEM membranes could be significantly improved. Overall results demonstrated that such a fast, easy processing and shape-independent method for an antithrombogenic coating can be used for applications in hemodialysis devices. PMID- 17688321 TI - Efficient synthesis of linear multifunctional poly(ethylene glycol) by copper(I) catalyzed Huisgen 1,3-dipolar cycloaddition. AB - Poly(ethylene glycol) (PEG) is a versatile biocompatible polymer. Improvement of its limited functionality (two chain termini) may significantly expand its current applications. In this communication, a simple and yet highly efficient strategy for the synthesis of linear multifunctional PEGs with "click" chemistry is reported. A short acetylene-terminated PEG was linked by 2,2 bis(azidomethyl)propane-1,3-diol using Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition in water at room temperature. High-molecular-weight PEGs with pendant hydroxyl groups were obtained and characterized by 1H NMR and size exclusion chromatography. A prototype bone-targeting polymeric drug delivery system was also successfully synthesized based on this new method. It demonstrates strong biomineral-binding ability and the ease of incorporating therapeutic agents into the delivery system. This simple "click" reaction approach provides a useful tool for the development of novel functional polymers and their conjugates for biomedical applications. PMID- 17688320 TI - Self-organized nanogels responding to tumor extracellular pH: pH-dependent drug release and in vitro cytotoxicity against MCF-7 cells. AB - The principal objective of this study was to fabricate doxorubicin-loaded self organized nanogels composed of hydrophobized pullulan (PUL)-Nalpha-Boc-L histidine (bHis) conjugates. Their responses to tumor extracellular pH (pHe) were determined, and they were also evaluated with regard to their anticancer efficacy against breast cancer cell lines (MCF-7). bHis was grafted to a PUL-deoxycholic acid (DO) conjugate (PUL-DO) via an ester linkage. PUL-DO/bHis conjugates with two different degrees of bHis substitutions (PUL-DO/bHis36 and PUL-DO/bHis78) were synthesized. PUL-DO/bHis nanogels formed via dialysis at a pH of 8.5 evidenced larger particle sizes (<140 nm) and lower critical aggregation concentrations (CACs) than did the PUL-DO nanogels (90 nm). The pH-dependent CAC of PUL-DO/bHis78 changed dramatically, from 1.2 microg/mL at pH 8.5, to 10 at 7.0, and to 660 at 6.2. A similar tendency in pH-dependent size was also noted. The ionization of the imidazole ring in bHis is principally responsible for pH dependency. The bHis moieties function as a switching tool responding to external pH. Doxorubicin (DOX)-loaded nanogels were assessed for pH-dependent releasing kinetics. The release rate of DOX from the PUL-DO/bHis78 nanogels increased significantly with reductions in pH. This resulted in increased cytotoxicity (30% cell viability at a dose of 10 microg/mL DOX equivalent) against sensitive MCF-7 cells at a pH of 6.8 and low cytotoxicity at pH 7.4 (65% cell viability at an identical dose). The results show that PUL-DO/bHis nanogels may potentially be employed as anti-tumor drug carriers. PMID- 17688322 TI - Lactate and sequential lactate-glucose sensing using surface-enhanced Raman spectroscopy. AB - Lactate production under anaerobic conditions is indicative of human performance levels, fatigue, and hydration. Elevated lactate levels result from several medical conditions including congestive heart failure, hypoxia, and diabetic ketoacidosis. Real-time detection of lactate can therefore be useful for monitoring these medical conditions, posttrauma situations, and in evaluating the physical condition of a person engaged in strenuous activity. This paper represents a proof-of-concept demonstration of a lactate sensor based on surface enhanced Raman spectroscopy (SERS). Furthermore, it points the direction toward a multianalyte sensing platform. A mixed decanethiol/mercaptohexanol partition layer is used herein to demonstrate SERS lactate sensing. The reversibility of the sensor surface is characterized by exposing it alternately to aqueous lactate solutions and buffer without lactate. The partitioning and departitioning time constants were both found to be approximately 30 s. In addition, physiological lactate levels (i.e., 6-240 mg/dL) were quantified in phosphate-buffered saline medium using multivariate analysis with a root-mean-square error of prediction of 39.6 mg/dL. Finally, reversibility was tested for sequential glucose and lactate exposures. Complete partitioning and departitioning of both analytes was demonstrated. PMID- 17688323 TI - Multiway partial least-squares coupled to residual trilinearization: a genuine multidimensional tool for the study of third-order data. Simultaneous analysis of procaine and its metabolite p-aminobenzoic acid in equine serum. AB - A new third-order multivariate calibration approach, based on the combination of multiway-partial least-squares with a separate procedure called residual trilinearization (N-PLS/RTL), is presented and applied to multicomponent analysis using third-order data. The proposed chemometric algorithm is able to predict analyte concentrations in the presence of unexpected sample components, which require strict adherence to the second-order advantage. Results for the determination of procaine and its metabolite p-aminobenzoic acid in equine serum are discussed, based on kinetic fluorescence excitation-emission four-way measurements and application of the newly developed multiway methodology. Since the analytes are also the reagent and product of the hydrolysis reaction followed by fast-scanning fluorescence spectroscopy, the classical approach based on parallel factor analysis is challenged by strong linear dependencies and multilinearity losses. In comparison, N-PLS/RTL appears an appealing genuine multiway alternative that avoids the latter complications, yielding analytical results that are statistically comparable to those rendered by related unfolded algorithms, which are also able to process four-way data. Prediction was made on validation samples with a qualitative composition similar to the calibration set and also on test samples containing unexpected equine serum components. PMID- 17688324 TI - Probing the beta-chain hole of fibrinogen with synthetic peptides that differ at their amino termini. AB - In a recent report, we showed that alanine can replace glycine at the amino terminus of synthetic B-knobs that bind to human fibrin(ogen). We now report a survey of 13 synthetic peptides with the general sequence XHRPYam, all tested with regard to their ability to delay fibrinolysis in an in vitro system activated by t-PA, the results being used as measures of binding affinity to the betaC hole. Unexpectedly, some large and bulky amino acids, including methionine and arginine, are effective binders. Amino acids that branch at the beta carbon (valine, isoleucine, and threonine) do not bind effectively. Crystal structures were determined for two of the peptides (GHRPYam and MHRPYam) complexed with fibrin fragment D-dimer; the modeling of various other side chains showed clashing in the cases of beta-carbon substituents. The two crystal structures also showed that the enhanced binding observed with pentapeptides with carboxyl terminal tyrosine, compared with that of their tetrapeptide equivalents, is attributable to an interaction between the tyrosine side chain and a guanidino group of a nearby arginine (beta406). The equivalent position in gamma-chains of human fibrin(ogen) is occupied by a lysine (gamma338), but in chicken and lamprey fibrin(ogen), it is an arginine, just as occurs in beta chains. Accordingly, the peptides GPRPam and GPRPYam, which are surrogate A-knobs, were tested for their influence on fibrin polymerization with fibrinogen from lamprey and humans. In lampreys, GPRPYam is a significantly better inhibitor, but in humans, it is less effective than GPRPam, indicating that in the lamprey system the same tyrosine arginine interaction can also occur in the gamma-chain setting. PMID- 17688325 TI - Regiospecific solid-phase strategy to N7-substituted purines and its application to 8-azapurines and [I]-condensed purines. AB - A highly regioselective and traceless solid-phase route to 1,7,8-trisubstituted purines has been developed. This methodology could be extended to the preparation of 8-azapurines and [i]-condensed purines. A representative set of 17 purines, azapurines, and [i]-condensed purines was synthesized. This paper also describes a mild method to prepare the p-benzyloxybenzylamine (BOBA) resin. PMID- 17688326 TI - Butterfly structure: signature of vibrational flopping in dissociative acetylene. AB - We report experimental evidence for molecular deformation due to a vibrationally active transition state of multiply charged acetylene molecules under the impact of low energy Ar8+ projectiles. "Butterflylike" structures are observed in the experimental coincidence spectra between hydrogen and carbon ionic fragments. Such structures can be generated by numerical simulations and are found to originate from the bending motion of the dissociating molecule. Angular distributions for dissociation products from triply charged C2H2 ion are reported. PMID- 17688327 TI - Hybrid approach for free energy calculations with high-level methods: application to the SN2 reaction of CHCl3 and OH- in water. AB - We present an approach to calculate the free energy profile along a condensed phase reaction path based on high-level electronic structure methods for the reactive region. The bulk of statistical averaging is shifted toward less expensive descriptions by using a hierarchy of representations that includes molecular mechanics, density functional theory, and coupled cluster theories. As an application of this approach we study the reaction of CHCl3 with OH- in aqueous solution. PMID- 17688328 TI - Range separated hybrid density functional with long-range Hartree-Fock exchange applied to solids. AB - We report a plane wave-projector augmented wave implementation of the recently proposed exchange-only range separated hybrid (RSHX) density functional [Gerber and Angyan, Chem. Phys. Lett. 415, 100 (2005)] and characterize its performance in the local density approximation (RSHXLDA) for a set of archetypical solid state systems, as well as for some transition metal oxides. Lattice parameters, bulk moduli, band gaps, and magnetic moments of the transition metal oxides have been calculated at different values of the range separation parameter and compared with results obtained with standard local density approximation (LDA), gradient corrected (PBE), and hybrid (HSE) functionals. The RSHX functional, which has the main feature of providing a correct asymptotic behavior of the exchange potential, has a tendency to improve the description of structural parameters with respect to local and generalized gradient approximations. The band gaps are too strongly opened by the presence of the long-range Hartree-Fock exchange in all but wide-gap systems. In the difficult case of transition metal oxides, the gap is overestimated, while magnetic moments and lattice constants are slightly underestimated. The optimal range separation parameter has been found around 0.4 a.u., slightly lower than the value of 0.5 a.u., recommended earlier for molecular systems. PMID- 17688329 TI - Numerically stable optimized effective potential method with balanced Gaussian basis sets. AB - A solution to the long-standing problem of developing numerically stable optimized effective potential (OEP) methods based on Gaussian basis sets is presented by introducing an approach consisting of an exact exchange OEP method with an accompanying construction and balancing scheme for the involved auxiliary and orbital Gaussian basis sets that is numerically stable and that properly represents an exact exchange Kohn-Sham method. The method is a purely analytical method that does not require any numerical grid, scales like Hartree-Fock or B3LYP procedures, is straightforward to implement, and is easily generalized to take into account orbital-dependent density functionals other than the exact exchange considered in this work. Thus, the presented OEP approach opens the way to the development and application of novel orbital-dependent exchange correlation functionals. It is shown that adequately taking into account the continuum part of the Kohn-Sham orbital spectrum is crucial for numerically stable Gaussian basis set OEP methods. Moreover, it is mandatory to employ orbital basis sets that are converged with respect to the used auxiliary basis representing the exchange potential. OEP calculations in the past often did not meet the latter requirement and therefore may have led to erroneously low total energies. PMID- 17688330 TI - Linear-scaling method for calculating nuclear magnetic resonance chemical shifts using gauge-including atomic orbitals within Hartree-Fock and density-functional theory. AB - Details of a new density matrix-based formulation for calculating nuclear magnetic resonance chemical shifts at both Hartree-Fock and density functional theory levels are presented. For systems with a nonvanishing highest occupied molecular orbital-lowest unoccupied molecular orbital gap, the method allows us to reduce the asymptotic scaling order of the computational effort from cubic to linear, so that molecular systems with 1000 and more atoms can be tackled with today's computers. The key feature is a reformulation of the coupled-perturbed self-consistent field (CPSCF) theory in terms of the one-particle density matrix (D-CPSCF), which avoids entirely the use of canonical MOs. By means of a direct solution for the required perturbed density matrices and the adaptation of linear scaling integral contraction schemes, the overall scaling of the computational effort is reduced to linear. A particular focus of our formulation is to ensure numerical stability when sparse-algebra routines are used to obtain an overall linear-scaling behavior. PMID- 17688331 TI - Rapid motion capture of mode-specific quantum wave packets selectively generated by phase-controlled optical pulses. AB - Rapid motion capture of phase-controlled wave packets was realized using a sensitive wave-packet spectrometer, which was previously developed by the present authors. Two-dimensional Fourier-transformed spectrograms obtained by the wave packet spectrometer provide us full information about the wave-packet motion on both excited- and ground-state potential surfaces. Vibrational wave packet associated with a twisting mode in a DTTCI molecule was observed to be dependent on the pulse chirp, and was generated in the excited state preferably with negatively chirped excitation. The result indicates that the excited-state wave packet can be driven along a favorable configuration coordinate by using phase controlled femtosecond pulses. The present method is essential to adaptive coherent-control application. PMID- 17688332 TI - Quantum molecular dynamics of hydrogen bonded complexes of rigid molecules using the semiclassical initial value representation in Cartesian coordinates. AB - Semiclassical initial value representation calculations are performed for the constrained water dimer in Cartesian coordinates. The study represents the first application of a previously reported method [Issak and Roy, J. Chem. Phys. 123, 084103 (2005); 126, 024111 (2007)] to a molecular cluster. Bound state energies are calculated for a dimer of rigid water molecules (H2O)2 as well as its deuterated form (D2O)2. The results show that the approach fares well with respect to accuracy in capturing quantum effects in intermolecular interactions. PMID- 17688333 TI - How tight is the Lieb-Oxford bound? AB - Density-functional theory requires ever better exchange-correlation (xc) functionals for the ever more precise description of many-body effects on electronic structure. Universal constraints on the xc energy are important ingredients in the construction of improved functionals. Here we investigate one such universal property of xc functionals: the Lieb-Oxford lower bound on the exchange-correlation energy, Exc[n]>or=-Cintegrald3rn4/3, where CXe+HCl+ is comparable to that for XeH+ formation, but at higher energies, it is larger by a factor of 2. The cross section of the XeCl+ formation is an order of magnitude smaller than that of XeH+. For both XeH+ and XeCl+ formations, the reaction threshold is approximately 2 eV. The XeH+ formation takes place immediately following the turning point in a direct-mode mechanism, whereas an indirect-mode mechanism operates in the formation of XeCl+. Both XeH+ and XeCl+ formations come mainly from the perpendicular configuration, Xe+...HCl, at the turning point. Product vibrational excitation is found to be strong in both XeH+ and XeCl+. PMID- 17688338 TI - Rotational spectra of the van der Waals complexes of molecular hydrogen and OCS. AB - The a- and b-type rotational transitions of the weakly bound complexes formed by molecular hydrogen and OCS, para-H2-OCS, ortho-H2-OCS, HD-OCS, para-D2-OCS, and ortho-D2-OCS, have been measured by Fourier transform microwave spectroscopy. All five species have ground rotational states with total rotational angular momentum J=0, regardless of whether the hydrogen rotational angular momentum is j=0 as in para-H2, ortho-D2, and HD or j=1 as in ortho-H2 and para-D2. This indicates quenching of the hydrogen angular momentum for the ortho-H2 and para-D2 species by the anisotropy of the intermolecular potential. The ground states of these complexes are slightly asymmetric prolate tops, with the hydrogen center of mass located on the side of the OCS, giving a planar T-shaped molecular geometry. The hydrogen spatial distribution is spherical in the three j=0 species, while it is bilobal and oriented nearly parallel to the OCS in the ground state of the two j=1 species. The j=1 species show strong Coriolis coupling with unobserved low lying excited states. The abundance of para-H2-OCS relative to ortho-H2-OCS increases exponentially with decreasing normal H2 component in H2He gas mixtures, making the observation of para-H2-OCS in the presence of the more strongly bound ortho-H2-OCS dependent on using lower concentrations of H2. The determined rotational constants are A=22 401.889(4) MHz, B=5993.774(2) MHz, and C=4602.038(2) MHz for para-H2-OCS; A=22 942.218(6) MHz, B=5675.156(7) MHz, and C=4542.960(7) MHz for ortho-H2-OCS; A=15 970.010(3) MHz, B=5847.595(1) MHz, and C=4177.699(1) MHz for HD-OCS; A=12 829.2875(9) MHz, B=5671.3573(7) MHz, and C=3846.7041(6) MHz for ortho-D2-OCS; and A=13 046.800(3) MHz, B=5454.612(2) MHz, and C=3834.590(2) MHz for para-D2-OCS. PMID- 17688339 TI - Ab initio study of the reaction of propionyl (C2H5CO) radical with oxygen (O2). AB - The reaction of propionyl radical with oxygen has been studied using the full coupled cluster theory with the complete basis set. This is the first time to gain a conclusive insight into the reaction mechanism and kinetics for this important reaction in detail. The reaction takes place via a chemical activation mechanism. The barrierless association of propionyl with oxygen produces the propionylperoxy radical, which decomposes to form the hydroxyl radical and the three-center alpha-lactone predominantly or the four-center beta-propiolactone. The oxidation of propionyl radical to carbon monoxide or carbon dioxide is not straightforward rather via the secondary decomposition of alpha-lactone and beta propiolactone. Kinetically, the overall rate constant is almost pressure independent and it approaches the high-pressure limit around tens of torr of helium. At temperatures below 600 K, the rate constant shows negative temperature dependence. The experimental yields of the hydroxyl radical can be well reproduced, with the average energy transferred per collision -DeltaE=20-25 cm( 1) at 213 and 295 K (helium bath gas). At low pressures, together with the hydroxy radical, alpha-lactone is the major product, while beta-propiolactone only accounts for about one-fifth of alpha-lactone. At the high-pressure limit, the production of the propionylperoxy radical is dominant together with a fraction of the isomers. The infrared spectroscopy or the mass spectroscopy techniques are suggested to be employed in the future experimental study of the C2H5CO+O2 reaction. PMID- 17688340 TI - High resolution vacuum ultraviolet emission spectrum of D2: the B' 1Sigmau+-->X 1Sigmag+ band system. AB - In this work, we have extended our previous high resolution study of the vacuum ultraviolet emission spectrum of the D2 molecule [M. Roudjane, et al. J. Chem. Phys. 125, 214305 (2006)] up to 124.2 nm in order to investigate the B' 1Sigmau+- >X 1Sigmag+ band system. The analysis of the spectrum has been carried out by means of a complex spectrum visual identification code IDEN [V. I. Azarov, Phys. Scr. 44, 528 (1991); 48, 656, (1993)] and supported by theoretical calculations using ab initio data [L. Wolniewicz, J. Chem. Phys. 103, 1792 (1995); 99, 1851 (1993); G. Staszewska and L. Wolniewicz, J. Mol. Spectrosc. 212, 208 (2002); L. Wolniewicz and G. Staszewska, 220, 45 (2003)] which provided level energies and transition probabilities. More than 1480 new emission lines have been observed and 109 bands belonging to the B' 1Sigmau+-->X 1Sigmag+ system have been identified between 84.1 and 121.6 nm. Except for the upsilon'-0 bands that were reported in absorption [I. Dabrowski and G. Herzberg, Can. J. Phys. 52, 1110 (1974)], all the upsilon'-upsilon" bands are reported here for the first time. The analysis led to the determination of 111 rovibronic energy levels in the B' 1Sigmau+ state, of which 31 with higher rotational numbers J are new. Observed perturbations are accounted for through a set of coupled equations involving the four excited electronic states B 1Sigmau+, B' 1Sigmau+, C 1Piu, and D 1Piu and including nonadiabatic couplings. The solution of this set provides the percent contribution of these four states to each of the observed rovibronic level. PMID- 17688341 TI - Density functional analysis of the structural evolution of Gan (n=30-55) clusters and its influence on the melting characteristics. AB - Recent experimental results have reported surprising variations in the shapes of the heat capacity curves and melting temperatures of gallium clusters in the size range of 30-55 atoms [G. A. Breaux et al., J. Am. Chem. Soc. 126, 8628 (2004)]. In the present work, we have carried out an extensive density functional investigation on ten selected clusters in the above mentioned size range. In particular, we have analyzed the ground state geometry and the nature of bonding in these clusters using electron localization function. We demonstrate that the existence or otherwise of a large island of atoms bonded with similar strength (i.e., the local order) in the ground state geometry is responsible for the variation in the shape of the heat capacity curve. We attribute the observed higher melting temperatures of some of the clusters (viz., Ga45-Ga48) to the presence of a distinct core and strong covalent bonds between the core and surface atoms. The present work clearly demonstrates that it is possible to understand the general trends observed in the heat capacity curves across the entire series on the basis of the analysis of their ground state. PMID- 17688342 TI - Unraveling the structure of hydrogen bond stretching mode infrared absorption bands: an anharmonic density functional theory study on 7-azaindole dimers. AB - The structure of the linear infrared absorption spectrum of the N-H stretching mode in 7-azaindole dimers is analyzed by quartic anharmonic vibrational force field calculations based on density functional theory. It is demonstrated that a multiple Fermi resonance model including contributions from 12 fingerprint vibrational modes, most of them containing considerable contributions of N-H bending motions, combined with a single low-frequency mode satisfactorily explains the complex line shape of N-H stretching mode absorption band. PMID- 17688343 TI - Phase diagram of model anisotropic particles with octahedral symmetry. AB - The phase diagram for a system of model anisotropic particles with six attractive patches in an octahedral arrangement has been computed. This model for a relatively narrow value of the patch width where the lowest-energy configuration of the system is a simple cubic crystal. At this value of the patch width, there is no stable vapor-liquid phase separation, and there are three other crystalline phases in addition to the simple cubic crystal that is most stable at low pressure. First, at moderate pressures, it is more favorable to form a body centered-cubic crystal, which can be viewed as two interpenetrating, and almost noninteracting, simple cubic lattices. Second, at high pressures and low temperatures, an orientationally ordered face-centered-cubic structure becomes favorable. Finally, at high temperatures a face-centered-cubic plastic crystal is the most stable solid phase. PMID- 17688344 TI - Effective separation of forces in a mode coupling theory of self-diffusion. AB - A mode coupling theory (MCT) expression for the self-diffusion coefficient follows simply when the soft fluctuating intermolecular forces are projected along a collective densitylike variable. The projected forces separate into two parts: from the gradient of the direct correlation function (dcf), and from the short range forces. The time correlation function of the dcf-derived forces is related to the excess entropy, as shown by Ali [J. Chem. Phys. 124, 144504 (2006)], and this relationship is evaluated for two variations of MCT. As for hard spheres, the derivation of an analogous MCT is beset by a number of singularities that kinetic theory could not remove. A justifiable MCT for hard sphere fluids may not exist. PMID- 17688345 TI - Self-diffusion of reversibly aggregating spheres. AB - Reversible diffusion limited cluster aggregation of hard spheres with rigid bonds was simulated and the self-diffusion coefficient was determined for equilibrated systems. The effect of increasing attraction strength was determined for systems at different volume fractions and different interaction ranges. It was found that the slowing down of the diffusion coefficient due to crowding is decoupled from that due to cluster formation. The diffusion coefficient could be calculated from the cluster size distribution and became zero only at infinite attraction strength when permanent gels are formed. It is concluded that so-called attractive glasses are not formed at finite interaction strength. PMID- 17688346 TI - Comparison between the Landau-Teller and flux-flux methods for computing vibrational energy relaxation rate constants in the condensed phase. AB - The calculation of vibrational energy relaxation (VER) rate constants in the condensed phase is usually based on the Landau-Teller formula, which puts them in terms of the Fourier transform, at the vibrational frequency, of the autocorrelation function of the force exerted on the relaxing mode by the bath modes. An alternative expression for the VER rate constant puts it in terms of the autocorrelation function of the vibrational energy flux. In this paper, we compare the predictions obtained via those two methods in the case of iodine in liquid xenon. We find that the computational cost underlying both methods is comparable and that they predict similar VER rates. However, while the calculation of the VER rate via the Landau-Teller formula is somewhat more direct, the predictions obtained via the flux-flux formula are in somewhat better agreement with the VER rates obtained from nonequilibrium molecular dynamics simulations. PMID- 17688347 TI - Water properties and potential of mean force for hydrophobic interactions of methane and nanoscopic pockets studied by computer simulations. AB - We consider model systems consisting of a methane molecule and hemispherical pockets of subnanometer radii whose walls are made of hydrophobic material. The potential of mean force for process of translocation of the methane molecule from bulk water into the pockets' interior is obtained, based on an explicit solvent molecular dynamics simulations. Accompanying changes in water density around the interacting objects and spatial distribution of solvent's potential energy are analyzed, allowing for interpretation of details of hydrophobic interactions in relation to hydrophobic hydration properties. Applicability of surface area-based models of hydrophobic effect for systems of interest is also investigated. A total work for the translocation process is not dependent on pocket's size, indicating that pocket desolvation has little contribution to free energy changes, which is consistent with the observation that solvent density is significantly reduced inside "unperturbed" pockets. Substantial solvent effects are shown to have a longer range than in case of a well investigated methane pair. A desolvation barrier is present in a smaller pocket system but disappears in the larger one, suggesting that a form of a "hydrophobic collapse" is observed. PMID- 17688348 TI - van der Waals forces in presence of free charges: an exact derivation from equilibrium quantum correlations. AB - We study interatomic forces in a fluid consisting of a mixture of free charges and neutral atoms in the framework of the quantum many-body problem at nonzero temperature and nonzero density. Of central interest is the interplay between van der Waals forces and screening effects due to free charges. The analysis is carried out in a partially recombined hydrogen plasma in the Saha regime. The effective potentials in the medium between two atoms, or an atom and a charge, or two charges, are determined from the large-distance behavior of equilibrium proton-proton correlations. We show, in a proper low-temperature and low-density scaling limit, that those potentials all decay as r(-6) at large distance r, while the corresponding amplitudes are calculated exactly. In particular, the presence of free charges only causes a partial (nonexponential) screening of the atomic potential, and it does not modify its typical r(-6) decay. That potential reduces to the standard van der Waals form for two atoms in vacuum when the temperature is driven to zero. The analysis is based on first principles: it does not assume preformed atoms and takes into account in a coherent way all effects, quantum mechanical binding, ionization, and collective screening, which originate from the Coulomb potential. Our method relies on the path integral representation of the quantum Coulomb gas. PMID- 17688349 TI - Spin amplification in solution magnetic resonance using radiation damping. AB - The sensitive detection of dilute solute spins is critical to biomolecular NMR. In this work, a spin amplifier for detecting dilute solute magnetization is developed using the radiation damping interaction in solution magnetic resonance. The evolution of the solvent magnetization, initially placed along the unstable z direction, is triggered by the radiation damping field generated by the dilute solute magnetization. As long as the radiation damping field generated by the solute is larger than the corresponding thermal noise field generated by the sample coil, the solute magnetization can effectively trigger the evolution of the water magnetization under radiation damping. The coupling between the solute and solvent magnetizations via the radiation damping field can be further improved through a novel bipolar gradient scheme, which allows solute spins with chemical shift differences much greater than the effective radiation damping field strength to affect the solvent magnetizations more efficiently. Experiments performed on an aqueous acetone solution indicate that solute concentrations on the order of 10(-5) that of the solvent concentration can be readily detected using this spin amplifier. PMID- 17688350 TI - Scheme of detecting microscopic inhomogeneity in binary liquid mixtures utilizing resonantly coupled vibrational modes. AB - Influence of microscopic inhomogeneity in binary liquid mixtures on their vibrational spectra is studied by doing calculations on a model liquid system. The concentration dependence of the noncoincidence effect (NCE), which is a feature of vibrational bands related to the intermolecular resonant coupling of vibrational modes, is analyzed. It is suggested that observation of convex behavior of the NCEs for the vibrational bands of both species, especially that of the less polar species, in a binary liquid mixture is an indication of the occurrence of microscopic inhomogeneity. PMID- 17688351 TI - Density functional theory of inhomogeneous liquids. I. The liquid-vapor interface in Lennard-Jones fluids. AB - A simple model is proposed for the direct correlation function (DCF) for simple fluids consisting of a hard-core contribution, a simple parametrized core correction, and a mean-field tail. The model requires as input only the free energy of the homogeneous fluid, obtained, e.g., from thermodynamic perturbation theory. Comparison to the DCF obtained from simulation of a Lennard-Jones fluid shows this to be a surprisingly good approximation for a wide range of densities. The model is used to construct a density functional theory for inhomogeneous fluids which is applied to the problem of calculating the surface tension of the liquid-vapor interface. The numerical values found are in good agreement with simulation. PMID- 17688352 TI - Dielectric response of one-dimensional polar chains. AB - We propose a theory for the dielectric constant of materials made of parallel infinite one-dimensional chains of dipoles. Each dipole is allowed to rotate in three dimensions. Monte Carlo simulations show that the Kirkwood factor of the chain grows with increasing dipole moment much faster than in the case of three dimensional polar fluids. With increasing dipole moment or cooling the one dimensional chain undergoes a continuous order-disorder transition to the ferroelectric phase, in which the dielectric constant is limited by the size of ferroelectric domains along the chain. PMID- 17688353 TI - Molecular simulation of pressure-driven fluid flow in nanoporous membranes. AB - An extended nonequilibrium molecular dynamics technique has been developed to investigate the transport properties of pressure-driven fluid flow in thin nanoporous membranes. Our simulation technique allows the simulation of the pressure-driven permeation of liquids through membranes while keeping a constant driving pressure using fluctuating walls. The flow of argon in the liquid state was simulated on applying an external pressure difference of 2.4x10(6) Pa through the slitlike and cylindrical pores. The volume flux and velocity distribution in the membrane pores were examined as a function of pore size, along with the interaction with the pore walls, and these were compared with values estimated using the Hagen-Poiseuille flow. The calculated velocity strongly depends on the strength of the interaction between the fluid and the atoms in the wall when the pore size is approximately<20sigma. The calculated volume flux also shows a dependence on the interaction between the fluid and the atoms in the wall. The Hagen-Poiseuille law overestimates or underestimates the flux depending on the interaction. From the analysis of calculated results, a good linear correlation between the density of the fluid in the membrane pores and the deviation of the flux estimated from the Hagen-Poiseuille flow was found. This suggests that the flux deviation in nanopore from the Hagen-Poiseuille flow can be predicted based on the fluid density in the pores. PMID- 17688354 TI - Efficient and accurate three-dimensional Poisson solver for surface problems. AB - We present a method that gives highly accurate electrostatic potentials for systems where we have periodic boundary conditions in two spatial directions but free boundary conditions in the third direction. These boundary conditions are needed for all kinds of surface problems. Our method has an O(N log N) computational cost, where N is the number of grid points, with a very small prefactor. This Poisson solver is primarily intended for real space methods where the charge density and the potential are given on a uniform grid. PMID- 17688355 TI - Layer-by-layer growth of polar MgO(111) ultrathin films. AB - By alternate deposition of Mg and exposure of O2, layer-by-layer growth, polar MgO(111) ultrathin films with Mg-terminated or O-terminated surfaces have been successfully fabricated on Mo(110) substrate. The surface geometric structure and electronic structures of the polar MgO(111) films were investigated using surface analysis techniques including low-energy electron diffraction and photoelectron emission and electron energy loss spectroscopies. The results indicate that the O terminated surface is of an insulating character, while for Mg-terminated surface, a prominent new surface state at 2-3 eV and appreciable density of states near Fermi level have been observed. The polar oxide films provide ideal model surfaces for further investigation of support-particle system. PMID- 17688356 TI - Enhanced flow in smooth single-file channel. AB - We investigate the flux of particles in a smooth single-file channel where particles cannot cross each other as well as in wider channels of varying cross section where particles execute normal diffusion. All the channels are connected to an infinite reservoir at one end and the flux of particles is measured at the other open end. We perform random walk Monte Carlo simulation using lattice model. The flux decreases monotonically as the channel cross section is increased from single-file channel to wider channel and finally reaches a constant value for a sufficiently wide channel. The observation of enhanced flux in single-file channel as compared to a wider channel can be tested for efficient separation of particles through smooth nanochannels. PMID- 17688357 TI - Adsorption of Janus particles to curved interfaces. AB - We investigate the adsorption of a spherical Janus particle to a spherically curved liquid-liquid interface. We show that the equilibrium contact angle is determined by the geometry of the particle, its wettability, and also the interfacial curvature. In contrast with a homogeneous particle, there is a preferred interfacial curvature (spontaneous curvature) due to the Janus particle when the particle satisfies certain conditions. PMID- 17688358 TI - Analysis of rapid chain dynamics in isochronal dielectric measurements of polymers. AB - Fast dynamics within the microwave frequency range (approximately gigahertz) in polymer systems as a function of temperature (in the range from 20 to 190 degrees C) were studied using high frequency dielectric spectroscopy. The frequency of radiation was varied from 0.5 to 18 GHz. The isochronal dielectric loss data were taken to eliminate the complexity arising from the frequency-independent, temperature-dependent background loss in the condensed phase. These studies were conducted for poly(caprolactone) (PCL), poly(ethylene oxide) (PEO), poly(ethylene oxide) with methoxy end group (PEO-CH3), PLA-b-PEO-b-PLA triblock copolymers, and several polymers with high glass transition temperatures. These polymers possess glass temperatures ranging from -62 degrees C (PCL) to 110 degrees C (PMMA). One broad relaxation process was found only for polymers (PCL, PEO, and PLA-b-PEO-b PLA) with low glass transition temperatures. The effect due to end groups was investigated by comparing the results of PEO with hydroxy versus methoxy end groups. The measured relaxation process was determined not to be associated with end groups. The results from temperature-dependent dielectric spectroscopy indicate that the relaxation process follows an Arrhenius T dependence suggesting that it is due to local motions. The activation energy of the relaxation process was measured and investigated based on the coupling model. The results suggest that the observed relaxation process behaves as a Johari-Goldstein beta relaxation. PMID- 17688359 TI - Kinetics of the shear-induced isotropic-to-lamellar transition of an amphiphilic model system: a nonequilibrium molecular dynamics simulation study. AB - The shear-induced isotropic-to-lamellar phase transition in the amphiphilic systems in the vicinity of the quiescent order-to-disorder transition point is investigated by the large-scale parallel nonequilibrium molecular dynamics simulations of simple amphiphilic model systems. There is a shear-induced upward shift of the ordering temperature. The initial isotropic phase orders into a lamellar phase perpendicular to the shear vorticity. The phase diagram as a function of temperature and shear rate is established. The dependency of the ordering transition on interaction strength and shear rate is rationalized by the competition between shear rate and chain relaxation. The time evolution of morphology reveals that the shear-induced ordering proceeds via nucleation and growth, a signature of a first-order phase transition. At low shear rate, a single ordered domain grows after an incubation period. With increasing shear rate ordering speeds up, but eventually develops in a lamellar system with disordered shear bands. The time dependence of the order parameter follows that of the mean-squared end-to-end distance, shear viscosity, and bulk pressure, and follows an Avrami scheme with an Avrami exponent between 2 and 4. PMID- 17688360 TI - Density dependent potentials: structure and thermodynamics. AB - Local density dependent potentials constitute a family of many body potentials which have been recently introduced in mesoscopic modeling of simple and complex fluids. We construct a field theory for these potentials and calculate the structure factor of the fluid through a saddle point expansion. We propose also an integral equation for local density potentials which shows quantitative agreement both for the correlation functions and thermodynamic properties of such potentials, even close to binodals where the simpler saddle point approximation fails. Contrary to the limitations of global density dependent potentials, there is no ambiguity in the expression of thermodynamics quantities such as the pressure. PMID- 17688361 TI - Diffusion and segmental dynamics of rodlike molecules by fluorescence correlation spectroscopy. AB - The dynamics of weakly bending polymers is analyzed on the basis of a Gaussian semiflexible chain model and the fluorescence correlation spectroscopy (FCS) correlation function is determined. Particular attention is paid to the influence of the rotational motion on the decay of the FCS correlation function. An analytical expression for the correlation function is derived, from which the averaged segmental mean square displacement can be determined independent of any specific model for the polymer dynamics. The theoretical analysis exhibits a strong dependence of the correlation function on the rotational motion for semiflexible polymers with typical lengths and persistence lengths of actin filaments or fd viruses. Hence, FCS allows for a measurement of the rotational motion of such semiflexible polymers. The theoretical results agree well with experimental measurements on actin filaments and confirm the importance of large relaxation times. PMID- 17688362 TI - Solvation dynamics in protein environments: comparison of fluorescence upconversion measurements of coumarin 153 in monomeric hemeproteins with molecular dynamics simulations. AB - The complexes of the fluorescence probe coumarin 153 with apomyoglobin and apoleghemoglobin are used as model systems to study solvation dynamics in proteins. Time-resolved Stokes shift experiments are compared with molecular dynamics simulations, and very good agreement is obtained. The solvation of the coumarin probe is very rapid with approximately 60% occurring within 300 fs and is attributed to interactions with water (or possibly to the protein itself). Differences in the solvation relaxation (or correlation) function C(t) for the two proteins are attributed to differences in their hemepockets. PMID- 17688363 TI - Calculation of the band structure of polyguanilic acid in the presence of water and Na+ ions. AB - Using the Hartree-Fock crystal orbital method with a combined symmetry (helix) operation, the band structure of polyguanilic acid was calculated in the presence of water and Na(+) ions. The water structure was optimized with the help of molecular mechanics. The obtained band structure shows that both the valence and conduction bands are purely guanine type. The three impurity bands in the 10.66 eV large gap are close to the conduction band and therefore cannot play any role in the assumed hole conduction of the system. Namely, according to detailed x-ray diffraction investigations of the nucleosomes in chromatin, there are possibilities of charge transfer from the negative sites of DNA to the positive ones in histones. Therefore most probably there is a hole conduction in DNA and an electronic one in the histone proteins. PMID- 17688364 TI - Erratum: "influence of an electric field on the non-Newtonian response of a hybrid-aligned nematic cell under shear flow" [J. Chem. Phys. 126, 204905 (2007)]. PMID- 17688365 TI - A karyometric study on ageing and butyrate or imatinib treated human leukemic myeloblasts represented by K562 cells originated from chronic myeloid leukaemia. AB - The present study was undertaken to provide more information on nuclear diameter in leukemic granulocytic early precursors myeloblasts. These cells represented by K562 myeloblasts originated from the blastic phase of the chronic myeloid leukaemia (CML) carry characteristic bcr-abl fusion gene. They represent a convenient model for in vitro studies of CML myeloblasts and are sensitive to various agents which may induce ageing, differentiation and cell death. Mean nuclear diameter (MNuD) and largest nuclear diameter (Mx NuD) in stained cytospins of these cells were measured at a high light microscopic magnification by means of computer programme. Starving cultures were used for induction of ageing without preceding differentiation, sodium butyrate was used as a cytostatic agent or differentiation inducer and imatinib mesylate represented a cytostatic agent for CML. The largest shift of MNuD to smaller values was noted in ageing cultures or cultures treated with butyrate. The decrease of MNuD was less apparent in resistant cells treated with imatinib. This drug, however, produced a very large incidence of necrotic or apoptotic cells or bodies. From the methodical point of view it should be mentioned that values of maximal nuclear diameter (MxNuD) followed similar trends as MNuD and thus provided similar information. The measurement of both nuclear diameters, i.e. MNuD and MxNuD might be a complementary and simple tool to evaluate the cell state in cytological preparations because of their decrease in ageing cells or cells treated with antiproliferative drugs of different mode of action. PMID- 17688366 TI - The antioxidative role of selenium in pathogenesis of cancer of the female reproductive system. AB - Selenium, as a component of few antioxidant enzymes, participates indirectly in elimination of reactive oxygen species and in antioxidative defense of the organism. There is a correlation between the concentration of selenium, activity of glutathione peroxidases (GSH-Px), and other parameters of antioxidative defense in blood components. The above mentioned factors were suggested to play an important role in etiopathogenesis of neoplastic diseases. Therefore, the aim of our present study was to compare the selenium status and GSH-Px activity in the plasma of 22 healthy women, 50 individuals suffering from cancer of uterine cervix, uterine corpus or ovary, and 49 women diagnosed with benign neoplasia of the uterine corpus or ovary. In addition, the selenium concentration was measured in postoperative cancer tissues, benign tumors, and histopatologically healthy surgical margins of the aforementioned patients. An average selenium concentration and GSH-Px activity in blood plasma of cancer patients and benign neoplasia patients was significantly lower than in the plasma of healthy women. It suggests that lower overall selenium status and lower selenium-dependent antioxidative capacity of the organism might partly contribute to development of neoplastic diseases of reproductive system. Postoperative tissues of patients revealed significantly higher selenium concentrations in cancer tissues of uterine cervix and corpus, and benign tumors of uterine corpus, as compared to corresponding healthy tissue margins. Higher accumulation of selenium in these neoplastic tissues might reflect a compensatory up-regulation of antioxidant defense systems in tumors that often undergo a persistent oxidative stress. PMID- 17688367 TI - Tissue detection of natural killer cells in laryngeal carcinoma. AB - Natural Killer (NK) cells have gained much attention as potential cells in antitumor immune defense mechanisms. In a group of 31 patients with surgically treated squamous cell laryngeal carcinoma, NK cell presence was semiquantitatively assessed by means of immunohistochemistry. A panel of three monoclonal antibodies including anti-CD16, was applied on frozen tissue sections. High CD 16+ cell presence was more frequently detected in poorly differentiated carcinomas (in 6 out of 14 cases) by comparison to carcinomas of high to moderate degrees of differentiation (in 1 out of 16 cases, p=0.031). No other clinicopathological variable appeared to influence NK cell presence in the examined specimens. No relation between NK cell detection and relapse-free survival emerged. Poorly differentiated laryngeal cancer cells appear to trigger off a greater NK cell tissue response than well and moderately differentiated cancer cells; however, the potential prognostic impact of this observation remains to be established. PMID- 17688368 TI - Semiquantitative RT-PCR evaluation of the MDR1 gene expression in patients with acute myeloid leukemia. AB - Resistance to chemotherapy is one of the major obstacles to effective treatment in acute myeloid leukemia (AML). The most extensively studied protein involved in multidrug resistance (MDR) is the transmembrane glycoprotein P (P-gp), the product of the multidrug resistance gene 1 (MDR1). MDR1/P-gp overexpression is frequently observed in hematological malignancies, especially in acute leukemia, and has been reported to correlate with poor prognosis in acute myeloid leukemia (AML). The aim of this study was to evaluate the level of MDR1 gene expression in bone marrow and/or peripheral blood samples in 92 AML patients in relation to their prognosis. The analyzed group was stratified according to presence or absence of prognostically favorable aberrations (PFAs), such as t(15;17) with PML/RARalpha fusion gene, t(8;21) with AML1/ETO fusion gene or inv(16)/ t(16;16) with CBFbeta/MYH11 fusion gene. These prognostically favorable aberrations were detected by RT-PCR and/or standard cytogenetic techniques. MDR1 expression was detected by semiquantitative comparative RT-PCR using software-based evaluation. The levels of MDR1 expression in the bone marrow predicted induction of complete remission in the whole group of analyzed patients (P = 0.032). They were significantly lower in PFA negative patients who achieved complete remission compared to those who failed to achieve complete remission (P = 0.008). In PFA negative patients, MDR1 expression was higher when compared to PFA positive patients (P = 0.055). No such difference was found when analyzing peripheral blood samples. Our experiments showed no impact of MDR1 expression in bone marrow or peripheral blood cells on overall survival (P = 1.000 and P = 0.903 respectively). In summary, the present study shows the prognostic impact of MDR1 expression on induction of complete remission in AML patients. We confirmed that MDR1 overexpression is an unfavorable prognostic factor in AML, which may help to stratify the risk rate of PFA negative patients. In future studies, quantitative detection of MDR1 expression might be a valuable tool to predict prognosis in this patient subset. PMID- 17688369 TI - The role of clinical criteria, genetic and epigenetic alterations in Lynch syndrome diagnosis. AB - Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC) represents 1-3% of all diagnosed colorectal cancers (CRCs). This study aimed to evaluate the benefit of clinical criteria and several molecular assays for diagnosis of this syndrome. We examined tumors of 104 unrelated clinically characterized colorectal cancer patients for causal mismatch repair (MMR) deficiency by several methods: microsatellite instability (MSI) and loss of heterozygosity (LOH) presence, MMR protein absence, hypermethylation of MLH1 promoter and germline mutation presence. Twenty-five (24%) patients developed CRCs with a high level of MSI (MSI H). Almost all (96%) had at least one affected relative, while this simple criterion was satisfied in only 22% (17/79) of individuals with low level MSI or stable cancers (MSI-L, MSS). Using strict Amsterdam criteria, the relative proportion of complying individuals in both sets of patients (MSI-H vs. MSI-L and MSS) decreased to 68% and 9%, respectively. The right-sided tumors were located in 54% of MSI-H persons when compared to 14% of cancers found in MSI-L or MSS patients. In 16 MSI positive patients with identified germline mutation by DNA sequencing, the gene localization of mutation could be indicated beforehand by LOH and/or immunohistochemistry (IHC) in four (25%) and 14 cases (88%), respectively. The IHC findings in MSI-H cancers with methylation in distal or both regions of MLH1 promoter have not confirmed the epigenetic silencing of the MLH1 gene. None of the patients with MSIL or MSS tumors was a carrier of the MLH1 del616 mutation, despite seven of them meeting Amsterdam criteria. The effective screening algorithm of Lynch-syndrome-suspected patients consists of evaluation of Bethesda or Revised Bethesda Guidelines fulfilling simultaneous MSI, LOH and IHC analyses before DNA sequencing. Variable methylation background in MLH1 promoter does not affect gene silencing and its role in Lynch-syndrome tumorigenesis is insignificant. PMID- 17688370 TI - Germline VHL gene mutations in three Serbian families with von Hippel-Lindau disease. AB - Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited cancer predisposition syndrome due to germline mutations in the VHL tumor suppressor gene which is associated with virtually complete penetrance. The VHL syndrome has a highly variable phenotypic expressivity including retinal and CNS haemangioblastomas, pheochromocytomas, renal clear cell carcinomas, and multifocal cysts. In order to establish VHL gene testing, we analyzed three families affected by VHL disease, using SSCP mutation screening and DNA sequencing. Among 18 family members with and without clinical manifestations, eight cases with germline VHL mutations were detected. In family A, a c.490G>T/ p.Gly93Cys substitution was found. In family B, with pheochromocytoma only phenotype, we detected a previously not described c.463G>A/p.Val84Met replacement. Within this family, a prenatal diagnosis was also performed. Affected members of the third family with a VHL type 1 disease carried a c.475T>C/p.Trp88Arg exchange. All these mutations were located in exon 1 of the VHL tumor suppressor gene. Alterations in this hydrophobic region of the core beta domain of the VHL protein are known to have a variety of phenotypic consequences. We observed also intrafamiliar variation in time of onset and severity of the disease. PMID- 17688371 TI - Long-term outcome with interstitial brachytherapy boost in the treatment of women with early-stage breast cancer. AB - Breast conserving surgery followed by adjuvant radiotherapy and eventually by systemic treatment represent the current trend in therapy of the early-stage breast carcinoma. Local control and the final cosmetic effect are important factors in breast conserving therapeutic approaches. We evaluated 215 patients who underwent breast conserving surgery (BCS) followed by adjuvant radiotherapy (RT) in our institute between October 1996 and February 2004. External beam radiotherapy (EBRT) was performed using a Cobalt- 60 or linear accelerator (LINAC), the boost was administered via high dose rate interstitial brachytherapy (HDR BRT) employing the Gammamed afterloading system. Patient survival was evaluated using the Kaplan-Meier method (disease-free survival DFS, overall survival OS). Late radiotherapy effects were evaluated using the LENT scales. The cosmetic effect (CE) was rated on a 4-grade scale by the patient and a committee; the Breast Retraction Assessment (BRA) was used to objectively assess the extent of the breast deformation and areolar deviation. The median follow-up in our group of patients was 70 months (from 20 to 136 months). Local control of the disease after 5 years was achieved in 98.5% of the patients, DFS was 88.7%, the distant disease-free survival (DDFS) was 89.9% and the overall 5-year survival was 91,8%. Medium vs. heavy fibrosis were recorded in 31.2% vs. 4.2% of the patients, medium vs. heavy teleangiectasia in 11.2% vs. 14.0% of the patients, and medium vs. heavy pigmentations in 6.5% vs. 3.3% of the patients, respectively. In all other cases none or minimal late radiotherapy effects occurred. The total CE was significantly influenced by the extent of the surgery (smaller deformations following tumorectomy < 65 cm3), by the type and orientation of the surgical incision (better results with discontinuous scars then with radial continuous scars), by the depth of the applied HDR BRT needles, by the rate of intermediate and severe postradiation late effects, plus by the value of the objective BRA parameters. Our data show that the HDR interstitial brachytherapy boost offers both excellent local control and favorable cosmetic effect to the patient, as long as the indications are followed closely. This therapeutic approach is suitable for treatment of tumors localized deeper than 2.8 cm under the surface and in patients with voluminous breasts. PMID- 17688372 TI - Establishing the method of chimerism monitoring after allogeneic stem cell transplantation using multiplex polymerase chain reaction amplification of short tandem repeat markers and Amelogenin. AB - We describe the implementation, optimization, sensitivity determination and first clinical results of polymerase chain reaction (PCR) amplification of polymorphic short tandem repeat (STR) markers and Amelogenin locus coupled with fluorescent detection and capillary electrophoresis in chimerism monitoring of patients transplanted at three different transplant centers using a commercially available multiplex microsatellite assay. The chimerism analysis was performed with genomic DNA extracted from unselected peripheral blood leukocytes of one hundred pediatric and adult patients, who underwent allogeneic stem cell transplantation (SCT) from human leukocyte antigen (HLA) matched or one antigen mismatched related or unrelated donors for malignant (70 patients) and non-malignant (30 patients) diseases. Tested were 79 donor recipient pairs for 15 STR systems and identified an informative marker in all but one of them (98,7%), using 6 selected systems out of these fifteen, that appeared highly informative in our patients population. In 21 sex-mismatched donor recipient pairs we used the Amelogenin locus to distinguish the X and Y chromosome. In sixty-three out of these 100 patients chimerism was regularly analyzed from blood samples taken at various time points after SCT with the median follow up of 17 months. Complete chimerism (CC), maintained over the whole follow-up period, was detected in 24 (38, 1%), stable and decreasing mixed chimerism (MC) in 28 (44, 4%) and increasing MC in 11 patients (17, 5%). Patients with CC, stable and decreasing MC showed a significantly better (p 0,005) overall survival rate (0, 81), compared to those with increasing MC (0, 24). These results demonstrate that STR-based chimerism monitoring with sensitivity above 1% and high informativity (98, 7% of donor recipient pairs) is necessary in establishing the origin of engrafted cells after an allogeneic SCT, in detecting graft rejection and that it may contribute in identifying patients with imminent leukemia relapse. PMID- 17688373 TI - How can we help patients with refractory chronic graft versus host disease- single centre experience. AB - Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality in long-term survivors of allogeneic haematopoietic stem cell transplantation (alloHSCT). Ocular involvement as well as dermal sclerosis, joint contractures and pathological changes in oral cavity are often refractory to treatment. This kind of patients require complex aggressive immunosuppressive therapy. We are still waiting for drugs against cGVHD, characterized by decreased infectious complications, encouraging efficacy and rare and reversible side effects. We describe eight patients who developed extensive chronic graft versus host disease with eye involvement after alloHSCT. All had ocular manifestations, which were refractory to the first and second line of systemic immunosuppressive therapy. All patients responded to the topical cyclosporine therapy, but clinical improvement was seen only since the fifth month of starting treatment. Topical cyclosporine was well tolerated. Other four patients with sclerodermoid type of skin changes, refractory to second line systemic immunosuppressive therapy, were treated with clofazimine. Clofazimine is a drug used to treat leprosy. Because of its anti-inflammatory effects, clofazimine is used also as a second or third line therapy for various skin disorders including: pyoderma gangrenosum, lupus erythematosus, palmoplantar pustulosis and chronic graft versus host disease. All patients,who received clofazimine due to dermal sclerosis, joint contractures and oral manifestations, achieved partial or complete responses and were able to reduce other immunosuppressive drugs. Clofazimine was generally well tolerated. PMID- 17688374 TI - Nonseminomatous germ cell testicular tumors clinical stage I: differentiated therapeutic approach in comparison with therapeutic approach using surveillance strategy only. AB - Surveillance after orchiectomy alone becomes popular for the management of clinical stage I nonseminomatous germ cell testicular tumors (CS I NSGCTT). Effort to identify patients at high risk of relapse leads to searching for risk factors of CS I NSGCTT. The aim of the study was to analyse own long-term experiences with different therapeutic approaches in CS I NSGCTT patients according to risk factors of the disease progression and to correlate these results with the group of patients who were treated with surveillance strategy only. From 11/1984 to 12/1991 a total of 145 patients with CS I NSGCTT were treated with surveillance strategy only (group A) and were followed-up to 1/2007. Patients, who had the disease progression, were treated with systemic chemotherapy. The disease progression was experienced in 52 patients (35.9 %). The overall survival rate of the patients in this group was 130/145 (89.7 %). From 1/1992 to 1/2007 a total of 323 patients with CS I NSGCTT were stratified to different risk-adapted therapeutic approaches (groups B1-3) according to histopathologic findings of primary tumor removed by inguinal orchiectomy. 111 patients (group B1) with vascular invasion and majority of embryonal carcinoma component in the primary tumor were treated with adjuvant chemotherapy (2 cycles of BEP). Disease progression developed in two patients (1.9 %). Other patients live without evidence of disease (NED). None of them died. Among 11 patients (group B2) with vascular invasion and majority with teratomatous elements in the primary tumor underwent primary retroperitoneal lymph node dissection (RPLND), 9 were found to be pathological stage I. The disease progression was observed in two patients (18.2 %), they died 87-122 months following orchiectomy. Two patients (18.2 %) with pathological stage II received adjuvant chemotherapy. Other 7 patients live with NED following RPLND. 201 patients (group B3) without vascular invasion have been followed after orchiectomy alone. They were kept under close surveillance, consisting of regular follow-up with tumor markers, chest x-ray and CT of the retroperitoneum. The disease progression was observed in 39 patients (19.4 %), who were treated with BEP chemotherapy. Three of them (7.7 %) died after a mean follow-up of 32.7 months following orchiectomy. The overall survival rate of all patients in group B1-3 was 98.4 %. Introduction of different therapeutic approaches in CS I NSGCTT patients according to risk factors of the disease progression might reduce the overall relapse rate of these patients from 35.9 % (group A) to 19.4 % (group B3) (P< 0.001). Surveillance procedure is recommended only in patients without vascular invasion in the primary tumor. PMID- 17688376 TI - Preoperative radiotherapy and concomitant capecitabine treatment induce thymidylate synthase and thymidine phosphorylase mRNAs in rectal carcinoma. AB - This work is intended to study the effect of preoperative capecitabine and radiotherapy treatment on the levels of thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) mRNAs in rectal carcinoma. 55 patients with locally advanced rectal carcinoma (cT3-4, N0, M0 or cT2-4,N+, M0) were treated with capecitabine 825 mg/m2 twice a day and pelvic radiotherapy 1,8 Gy daily up to cumulative dose of 45 Gy, boosting up to 50,4 Gy. Patients underwent surgery 6th week after the completion of chemoradiotherapy. Biopsies of rectal carcinoma were taken before starting therapy and 14 days after its cesation. Biopsies were examined for TS, DPD and TP mRNA levels. CEA in serum was examined to monitor relapses. Both TP and TS mRNA increase two weeks after starting therapy (p<0,001). TP mRNA median levels were elevated 2,3x after starting therapy. Moreover responders exhibit 1,5x higher induction than non responders both before and after starting therapy, but difference is significant before therapy only (p=0,017). Non-responders have most frequent TS induction. Complete remission was observed in 17% and substantial responses with microscopic residuum only in additional 19% of cases were achieved. The pathologic downstaging rate was 76%. Our data show that TS and TP mRNA are induced by preoperative chemoradiotherapy in both responders and nonresponders. TP induction is in accordance with the expected role of TP in the activation of capecitabine and the known promoting role of TP in tissue fibrosis frequently associated with tumor regression. PMID- 17688375 TI - Reduced-intensity conditioning for allogeneic stem cell transplantation in patients with chronic myeloid leukemia is associated with better overall survival but inferior disease-free survival when compared with myeloablative conditioning a retrospective study of the Czech National Hematopoietic Stem Cell Transplantation Registry. AB - Allogeneic stem cell transplantation (AlloSCT) has been currently recommended in the treatment of patients with chronic myeloid leukemia (CML) as a second option after imatinib failure or in selected group of patients with high-risk CML and low risk for transplant-related mortality. The actual role of reduced-intensity conditioning (RIC) before AlloSCT in CML patients has not been yet conclusively established. The Czech National Hematopoietic Stem Cell Transplantation Registry has conducted a retrospective analysis of all patients (n=29) transplanted after RIC from the Registry database containing 295 patients with CML transplanted in the Czech Republic in years 1988-2005 and compared them with patients at comparable age (median age 48.3 and 50.6 years, respectively; p=0.587) transplanted during the same period of time using conventional myeloablative conditioning (n=26). Survival advantage of patients transplanted after RIC has been confirmed by log rank test (p=0.036) despite the fact that the relapse rate was significantly higher in RIC group (44.8% versus 0%). Both groups did not differ significantly in the use of voluntary unrelated donors, type of the grafts and in incidence of acute graft versus host disease (GVHD). However, there were trends for higher risk of CML and higher use of unrelated donors in the myeloablative group while peripheral stem cell grafts and chronic GVHD were observed more frequently in the RIC group. Transplant-related mortality was the leading cause of death in both groups of patients. Our results should be interpreted with caution because they may be influenced by small groups of subjects and also the impact of patients with high EBMT risk score on inferior survival in the myeloablative group cannot be fully eliminated. More retrospective and prospective studies are needed to elucidate the actual role of RIC before AlloSCT for CML. PMID- 17688377 TI - Pharmacists' views on Indigenous health: is there more that can be done? AB - INTRODUCTION: Our previous study explored the views of Aboriginal health workers (AHWs) in mid western New South Wales (NSW), Australia, in relation to pharmacy and the access to, and use of medicines by Indigenous Australians. That study also explored suggestions made by AHWs to improve the situation. This research aimed to ascertain the readiness and willingness of community pharmacists in rural and remote NSW to take on a greater role in relation to Indigenous health by exploring their knowledge and opinions about Indigenous health, their current interaction with Indigenous people, and their views as to feasible and achievable ways to help. Pharmacists' views were compared with those of the AHWs elicited in the previous study and any differences in perceptions noted. METHODS: Twenty seven semi-structured, face-to-face, in-depth interviews were carried out with NSW community pharmacists working in areas with an Indigenous population. All except one of the 27 pharmacists were based in a rural or remote setting. A qualitative research method was used and the concepts explored in the interviews included pharmacists' current knowledge of Indigenous health, views on the feasibility of proposed new programs from the previous study, and any other ideas that may improve Indigenous health. The interviews were audio recorded, transcribed verbatim, then thematically content analysed. RESULTS: Pharmacists identified chronic diseases as the main health concerns and many felt their Indigenous customers experienced these at a high rate, at a young age of onset and generally had poor management of the condition. They were aware that AHWs were available in their community but interaction varied. Almost all pharmacists felt that Indigenous people were comfortable shopping in their pharmacies, and identified lack of money as the major barrier to access to medicines. Many pharmacists felt that Indigenous patients would be best served in the pharmacy if medications were available at no charge; however, they seemed to be unaware that Indigenous people often feel uncomfortable entering their pharmacies. The majority felt the AHWs' ideas, such as periodically having an AHW in the pharmacy, cultural awareness training and increased collaboration between pharmacists and AHWs, may be of benefit. CONCLUSION: Despite the potential for expansion of the role of the pharmacist in Indigenous health, the majority of participants in this study were reluctant to commit themselves more than at present unless the financial barriers were removed. In addition, although they expressed an openness to undergoing training in cultural safety, and a willingness to have a greater understanding of Indigenous culture, they were very conscious of a lack of time to do so, a situation generally resulting from a shortage of pharmacists. Their awareness of and current interactions with AHWs were limited, but all participants could see the potential value of working more closely with these important members of the healthcare team. If the proposed extension of Section 100 of the Australian Pharmaceutical Benefits Scheme goes ahead and financial barriers are removed, it then remains for pharmacists to take up the challenge to increase their own understanding of Indigenous health issues and form collaborative partnerships with their AHW counterparts. Then a real change for the better in mainstream pharmacy services may be achieved. PMID- 17688378 TI - Acetaminophen safety and hepatotoxicity--where do we go from here? AB - Acetaminophen has been widely used for > 50 years in the treatment of pain and fever and provides for the safe and effective relief of these symptoms. In a small minority of patients, however, acetaminophen is responsible for life threatening liver injury and accounts for up to 50% of all adult cases of acute liver failure in the US. Although approximately two-thirds of adult overdoses are associated with suicide attempts, many are inadvertent, often due to the use of multiple acetaminophen formulations over many days. Additionally, some individuals appear to experience acetaminophen toxicity at 'therapeutic' doses of < 4 g/day, for reasons unknown. In pediatric populations, the overwhelming majority of acetaminophen overdoses are due to unintentional overdoses, except for the predominance of suicidal ingestions in the teenage population. This article seeks to review the mechanism and metabolism of acetaminophen and the features of toxicity in adults, pediatric and special populations. Additionally, expert opinion is presented herein to aid in reducing the frequency and severity of liver injury from acetaminophen. PMID- 17688379 TI - The safety of antidepressant drugs during pregnancy. AB - This article discusses known or suspected effects of maternal use of antidepressants during pregnancy on pregnancy outcome. It is unlikely that any marked teratogenic effect occurs with the possible exception of an increased risk for cardiovascular defects after maternal use of clomipramine or paroxetine. An increased risk for preterm birth is seen. Transient neonatal symptoms are common after the use of antidepressants in late pregnancy. Few firm data are available on the possible impact on the long-term neuropsychological development of the infants. The magnitude of the actual contribution from drug therapy is unclear; it is likely that the underlying pathology of the mother explains part of the anomalies. Selective serotonin re-uptake inhibitor drugs seem to represent a smaller hazard than tricyclic antidepressants. Further research to separate the effects of the drug and underlying pathology is urgently needed as are large scale studies on long-term development. When a pregnant woman has a major depressive disease and non-pharmacological treatments are not enough, the relatively small risk with drug therapy has to be weighed against the considerable risk for a relapse of the disease if therapy is interrupted. PMID- 17688380 TI - Depression as a side effect of the contraceptive pill. AB - Millions of women worldwide use the combined oral contraceptive pill as an effective form of contraception. However, the focus on its side effects to date has mainly been on physical aspects, even though the most commonly stated reason for discontinuation is depression. There are surprisingly few large studies investigating depression related to oral contraceptive use. A pilot study was conducted showing that women using the combined oral contraceptive pill were significantly more depressed than a matched group who were not. More research is needed to better inform women and doctors about depression related to oral contraceptive use, and clinical guidelines are needed regarding the different types of oral contraceptives and their potential depressogenic properties. PMID- 17688381 TI - Lithium: a novel treatment for Alzheimer's disease? AB - Lithium is an alkali metal. First described as a mood stabilizer in 1949, it remains an efficacious treatment for bipolar disorders. Recent emerging evidence of its neuroprotective and neurogenic effects alludes to lithium's potential therapeutic use in stroke and neurodegenerative diseases. One intriguing clinical application is in the treatment of Alzheimer's disease. Ongoing clinical trials are evaluating lithium's abilities to lower tau and beta-amyloid levels in cerebrospinal fluid in Alzheimer's patients. This review summarizes the supporting evidence and safety profiles of lithium's use in the treatment of neurological diseases, especially Alzheimer's disease. PMID- 17688382 TI - Side effects of using nitrates to treat heart failure and the acute coronary syndromes, unstable angina and acute myocardial infarction. AB - Nitrates are potent venous dilators and anti-ischemic agents. They are widely used for the relief of chest pain and pulmonary congestion in patients with acute coronary syndromes and heart failure. Nitrates, however, do not reduce mortality in patients with acute coronary syndromes. Combination of nitrates and hydralazine when given in addition to beta-blockers and angiotensin-converting enzyme (ACE) inhibitors reduce mortality and heart failure hospitalizations in patients with heart failure due to left ventricular systolic dysfunction who are of African-American origin. Side effects during nitrate therapy are common but are less well described in the literature compared with the reported side effects in patients with stable angina pectoris. The reported incidence of side effects varies highly among different studies and among various disease states. Headache is the most commonly reported side effect with an incidence of 12% in acute heart failure, 41-73% in chronic heart failure, 3-19% in unstable angina and 2-26% in acute myocardial infarction. The reported incidence of hypotension also differs: 5-10% in acute heart failure, 20% in chronic heart failure, 9% in unstable angina and < 1-48% in acute myocardial infarction, with the incidence being much higher with concomitant nitrate therapy plus angiotensin-converting enzyme inhibitors. Reported incidence of dizziness is as low as 1% in patients with acute myocardial infarction to as high as 29% in patients with heart failure. Severe headaches and/or symptomatic hypotension may necessitate discontinuation of nitrate therapy. Severe life threatening hypotension or even death may occur when nitrates are used in patients with acute inferior myocardial infarction associated with right ventricular dysfunction or infarction, or with concomitant use of phosphodiesterase-5 inhibitors or N-acetylcysteine. Despite the disturbing observational reports in the literature that continuous and prolonged use of nitrates may lead to increased mortality and recurrent myocardial infarction in patients with stable coronary artery disease, no such adverse effects of nitrates have been reported in the large randomized trials in patients with acute myocardial infarction or chronic heart failure. PMID- 17688383 TI - The direct thrombin inhibitor ximelagatran/melagatran: a systematic review on clinical applications and an evidence based assessment of risk benefit profile. AB - The direct thrombin inhibitor, ximelagatran, and its active form, melagatran (X/M), have been compared against conventional anticoagulant therapy (CAT) in many clinical settings. Their risk-benefit profile drove large debate until withdrawal by the manufacturer. A systematic review of all published randomized trials has been performed and a meta-analysis of randomised controlled trial (RCT) of X/M versus CAT. Major medical databases were searched for RCTs. Major adverse events (MAE: all cause death, nonfatal myocardial infarction, nonfatal thromboembolic stroke, pulmonary embolism), major bleeds (MB), minor bleeds and the rate of hepatotoxicity (HT) were compared. In terms of efficacy, X/M was at least as effective as, or even superior to, CAT. In terms of safety, the overall risk of MAE, MB, minor bleeds and HT was not significantly different for X/M compared with CAT. According to individual clinical settings, X/M was associated with a lower risk of MB but a prohibitive higher risk of HT in those clinical settings requiring prolonged treatment. PMID- 17688384 TI - Safety and efficacy of albumin administration in trauma. AB - Albumin is one of the oldest known and studied human proteins. It is characterised by diverse physiological and biochemical properties that render it relevant to many aspects of the disordered vascular and cellular functions after trauma. Apart from the ability to maintain the colloid oncotic pressure, human serum albumin has multiple effects, including antioxidant activity and binding affinity for drugs and toxic substances, inhibition of apoptosis and modulation of trauma-induced inflammatory response. According to the current state of knowledge, there are conflicting results regarding the benefits of albumin administration in critically ill patients. Further investigations are warranted to resolve the continued uncertainty about the safety and efficacy of human serum albumin in specific clinical circumstances and selected populations of severely injured patients. PMID- 17688385 TI - Safety and adverse effects associated with GLP-1 analogues. AB - The incretin mimetics are an emerging class of agents for the treatment of diabetes. So far, exenatide is licensed for use in the US and also became available in the UK in May 2007. Within development and Phase III trials, liraglutide may also be made available within the next 2 years. These agents enhance glucose-dependent insulin secretion and exhibit other antihyperglycaemic actions, which are of particular benefit to overweight patients with Type 2 diabetes. This article reviews the profile of adverse effects for these agents in relation to their current (exenatide) and anticipated (liraglutide) role in the management of Type 2 diabetes. PMID- 17688386 TI - Safety of sildenafil in the treatment of erectile dysfunction in patients with obstructive sleep apnoea. AB - Obstructive sleep apnoea, characterised by repetitive occlusion of the upper airway during sleep, is recognised as a risk or even an aetiological factor for erectile dysfunction. On the other hand, sleep-disordered breathing has been reported by many patients with erectile dysfunction. Sildenafil, a very commonly used erectile dysfunction treatment, could, at least theoretically, exacerbate sleep apnoea by interfering with pharyngeal muscle tone, nasal patency and gas exchange in the lung. A recent safety study suggested a detrimental effect of oral sildenafil on respiratory events in patients with obstructive sleep apnoea. Given the inconclusiveness of evidence on pathophysiological mechanisms and the paucity of relevant clinical data the safety risk of sildenafil administration in patients with obstructive sleep apnoea should be questioned. More clinical trials are needed to clarify this issue. PMID- 17688387 TI - Drug-induced photoallergic and phototoxic reactions. AB - Drug-induced photosensitivity involves reactions to medication triggered by exposure of the skin to ultraviolet light. Medications that trigger reactions can be topical or oral. Following interaction of ultraviolet radiation with a chemical present in sufficient amounts in the skin, one of the several reactions may occur in susceptible patients, most commonly photoallergy or phototoxicity. These reactions can be diagnosed separately based on pathogenesis, clinical characteristics and histopathology. Phototoxic disorders have a higher incidence than photoallergic disorders. The action spectra for most photoallergens and phototoxins lie in the ultraviolet A range. Subtypes of drug-induced photosensitivity include dyschromia, pseudoporphyria, photo onycholysis, and lichenoid and telangiectatic reactions. PMID- 17688388 TI - Safety considerations with mycophenolate sodium. AB - Following 10 years of clinical use of mycophenolate mofetil (MMF), a prodrug of mycophenolic acid, the FDA has approved enteric-coated mycophenolate sodium (EC MPS). EC-MPS was developed to reduce the upper-gastrointestinal (GI) effects of MMF. Unlike oral MMF, where absorption starts in the stomach, EC-MPS releases MPA in the small intestine. Along with the pharmacology and pharmacokinetics, three randomized, controlled clinical trials in solid-organ transplantation, comparing MMF and EC-MPS, are reviewed. Disappointingly, EC-MPS was similar to MMF in efficacy and safety and did not significantly improve the GI side effects. Moreover, bioequivalence dosing has only been established with concomitant ciclosporin. The pharmacokinetic characteristics must be studied in greater detail. EC-MPS is a safe and effective immunosuppressive agent approved for use in the prevention of acute rejection after renal transplantation. However, the anticipated improvement of GI side effects has not been forthcoming. PMID- 17688389 TI - Signal detection methodologies to support effective safety management. AB - The increased focus on the safety of medical products, as well as the growing volume of available safety information, has created a need for objective quantitative approaches to supplement the medical review of individual case safety reports. Statistical algorithms can be used to identify trends and relationships in both clinical and postmarketing safety databases in support of safety signal detection. Powerful data visualization tools facilitate the medical review of the complex information generated by these methods. In addition, all these approaches need to be integrated into the daily practice of clinical safety and postmarketing pharmacovigilance. PMID- 17688390 TI - Using pharmacokinetic/pharmacodynamic modelling in safety pharmacology to better define safety margins: a regional workshop of the Safety Pharmacology Society. AB - This meeting was convened to encourage the incorporation of empirical and mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modelling into safety pharmacology to improve the predictability of nonclinical investigations for human outcomes. These technologies make use of mathematical expressions relating measured variables to derive essential parameters for describing responses and predicting the behaviour of biological systems to a drug. Hence, empirical PK/PD modelling is intended to define the in vivo interrelationship between three basic entities: time; drug concentrations; and drug effects. The most widely applied equation relating drug bioresponses to plasma concentrations is the Hill sigmoidal E(max) model, which allows the calculation of drug potency (EC(50)) and intrinsic activity (E(max)). However, since the latter parameters depend on attributes of the drug and on the biological system itself, this approach can fail to accurately foretell drug concentration-effect behaviour, particularly between species. A particular phenomenon of PK/PD analysis is hysteresis, which refers to the delay of the bioresponse time-course with respect to exposure time course, as this provides valuable information on the direct or indirect nature of the drug mechanism of action. The application of these concepts to the examination of the QT interval prolongation produced by dofetilide was discussed. A development surmounting the limitations of empirical PK/PD models is mechanism based PK/PD modelling because its toolkits integrate specific mathematical expressions replicating the drug (e.g., affinity, intrinsic efficacy), and the physiological system (e.g., nonlinear, time-dependent, transduction processes), properties that play a crucial role in the cascade of biological events culminating in bioresponses. The usefulness of this approach was illustrated by a thorough analysis of nonclinical respiratory depressant and antinociceptive data on buprenorphine and fentanyl for successfully predicting the human safety and efficacy of these analgesic agents. Thus, PK/PD models can be viewed as in silico clones of drug and biological system activities that provide high-level knowledge that can avoid inappropriate attrition, and hasten the progress, of novel drugs, along the entire critical path of pharmaceutical development. PMID- 17688391 TI - The impact of perceived hypertension status on anxiety and the white coat effect. AB - BACKGROUND: The white coat effect can lead to overdiagnosis of hypertension and unnecessary pharmacologic treatment. Mechanisms underlying the white coat effect remain poorly understood but are critical to improving the accuracy of clinic blood pressure measurement. PURPOSE: This study investigated whether perceived hypertension status was associated with state anxiety levels during a clinic visit and the magnitude of the white coat effect, independent of true blood pressure status. METHODS: This observational study included 214 normotensive and mildly hypertensive participants who were 18 to 80 years old, had no cardiac history, and were willing to discontinue antihypertensive medications for 8 weeks. Participants underwent 36 hr ambulatory blood pressure monitoring and physician blood pressure measurement. Outcome measures were state anxiety reported during the clinic visit and the white coat effect. RESULTS: An analysis of covariance indicated that participants who perceived themselves as hypertensive reported greater state anxiety (p<.001) and showed larger white coat effects (ps<.01) compared with those who perceived themselves as normotensive. True hypertension status based on ambulatory blood pressure was not related to either outcome. Anxiety accounted for approximately 19% of the association between perceived hypertension status and the white coat effect. CONCLUSIONS: These findings suggest that the perception of being hypertensive is associated with greater anxiety during clinic blood pressure measurement and a larger white coat effect, independent of the true blood pressure level. Anxiety appears to be a mechanism by which perceived hypertension status contributes to the white coat effect. PMID- 17688392 TI - Lessons from white coat hypertension: comment on Spruill et al. "The impact of perceived hypertension status on anxiety and the white coat effect". AB - The Implications of White Coat Hypertension by Spruill et al. (2007) are multiple and extend well beyond the domain of hypertension and cardiovascular risk. First, their excellent study indicates that theory and research need to treat emotional reactions as situation-specific events. Although traits such as Anxiety can be easily and reliably measured, their assessment may not detect the situation specific mechanisms that link emotional responses to health risks. Second, patients' self perceptions, whether they label themselves as having a chronic disease, give meaning to the situational cues that elicit emotional reactions. Third, as Spruill et al. indicate, health behavioral research needs to examine how the clinical setting and social and cultural frameworks affect self-labeling. We add to their clinical concerns by questioning whether a clinician's words, i.e., whether they suggest a condition is related to stress, can in our contemporary culture, lead patients to treat a condition as acute rather than chronic, and how the clinicians' behavior, e.g., attention to specific areas of the body during a clinical examination, may shape the perceived cause of symptoms. The implications of this excellent study extend well beyond its focus on white coat hypertension. PMID- 17688393 TI - Education, psychosocial resources, and metabolic syndrome variables in Latinas. AB - BACKGROUND: Individuals with low socioeconomic position (SEP) and Latino ethnicity are at high risk for the metabolic syndrome. In part, this may reflect that these populations benefit from fewer resilient resources to manage stressful environments, resulting in accentuated psychological and physiological costs (1). PURPOSE: We examined the direct effects of educational attainment (an indicator of SEP) and psychosocial resources on metabolic syndrome variables, and tested indirect effects of education, via resources. METHODS: Participants were 145 middle-aged (M=47.07 years) Latinas recruited from health clinics along the California-Mexico border. Women completed assessments of demographics and resilient resources; metabolic syndrome variables were measured (blood pressure [BP], waist circumference [WC]) or abstracted from medical charts (lipids, glucose). RESULTS: Women with less education reported fewer psychosocial resources (DeltaR2=.14, p<.0001) and showed a higher risk profile on measures of BP, WC, and plasma glucose (3-7% of variance explained, all ps<.05), relative to those with more education. Resources independently predicted lower WCs (DeltaR2=.07, p<.05). Education exerted an indirect effect (p<.05) through resources on WC, a core factor underlying the metabolic syndrome. CONCLUSIONS: Additional research is warranted to further explore the roles of resilient resources in relationships among SEP, metabolic risk factors, and chronic disease processes. PMID- 17688394 TI - Interpretations of ambiguous social situations and cardiovascular responses in adolescents. AB - BACKGROUND: Previous research has documented effects of ambiguous outcome social situations on individual differences in cardiovascular reactivity in laboratory contexts. PURPOSE: This study tested whether interpretations of ambiguous social situations are associated with daily life cardiovascular responses using ambulatory approaches. METHODS: There were 206 high school adolescents assessed on interpretations of ambiguous social situations in the laboratory who then completed ambulatory monitoring of blood pressure (BP) and heart rate (HR) for 2 days. RESULTS: Adolescents who perceived threat during ambiguous situations exhibited higher systolic BP when talking to others compared to occasions of not talking with anyone, whereas the opposite was true for those with low threat perception. For high-threat adolescents, higher systolic BP was found when interacting with friends, whereas for low threat adolescents, lower systolic BP was found when interacting with parents. Greater threat interpretations were also associated with elevated HR at night. CONCLUSIONS: Understanding how adolescents perceive social interactions may help in gauging their daily cardiovascular responses. PMID- 17688395 TI - Psychosocial health problems increase risk for HIV among urban young men who have sex with men: preliminary evidence of a syndemic in need of attention. AB - BACKGROUND: Young men who have sex with men (YMSM) experience disparities in HIV rates and potentially in mental health, substance abuse, and exposure to violence. PURPOSE: We assessed the extent to which these psychosocial health problems had an additive effect on increasing HIV risk among YMSM. METHODS: An urban sample of 310 ethnically diverse YMSM reported on psychosocial health problems, sexual risk behaviors, and HIV status. A count of psychosocial health problems was calculated to test the additive relationship to HIV risk. RESULTS: The prevalence of psychosocial health problems varied from 23% for regular binge drinking to 34% for experiencing partner violence. Rates of sexual risk behaviors were high and 14% of YMSM reported receiving a HIV+ test result. Psychosocial health problems cooccurred, as evidenced by significant bivariate odds ratios (ORs) between 12 of the 15 associations tested. Number of psychosocial health problems significantly increased the odds of having multiple anal sex partners (OR=1.24), unprotected anal sex (OR=1.42), and an HIV-positive status (OR 1.42), after controlling for demographic factors. CONCLUSIONS: These data suggest the existence of cooccurring epidemics, or "syndemic," of health problems among YMSM. Disparities exist not only in the prevalence of HIV among YMSM but also in research to combat the epidemic within this vulnerable population. Future research is needed to identify risk and resiliency factors across the range of health disparities and develop interventions that address this syndemic. PMID- 17688396 TI - Physical symptoms, beliefs about medications, negative mood, and long-term HIV medication adherence. AB - BACKGROUND: Near-perfect levels of HIV medication adherence are necessary for treatment to be successful. However, many patients continue to report nonadherence to HIV treatment. PURPOSE: This study examines the relationship between symptoms of HIV and medication adherence and evaluates beliefs about HIV medications and negative mood states as potential mediators of this relationship. METHODS: These relationships were tested with structural equation modeling using a 15-month longitudinal design. The ethnically diverse convenience sample included 325 HIV-infected men who have sex with men and women prescribed Highly Active Antiretroviral Therapy (HAART). RESULTS: Results showed that a greater number of symptoms were associated with poorer medication adherence, and this relationship was partially mediated by increases in concerns about HAART. Contrary to expectations, negative mood states were not directly related to medication adherence. In the final model, concerns about HAART and general distrust of medications each predicted poorer HAART adherence. Necessity beliefs about HAART and level of educational attainment each predicted better adherence. The final model accounted for approximately 24% of the variance in HAART adherence. CONCLUSIONS: The results of this study suggest that Horne's (1) necessity-concerns framework can be successfully applied to identify beliefs about medication that are important predictors of adherence to HAART over time. These findings have relevance for developing interventions to improve medication adherence among HIV-infected patients. PMID- 17688397 TI - Adolescent expectancies, parent-adolescent communication and intentions to have sexual intercourse among inner-city, middle school youth. AB - BACKGROUND: The incidence and prevalence of pregnancy and sexually transmitted infections among American adolescents remain unacceptably high. PURPOSE: This research examines adolescent intentions to have sexual intercourse, their expectancies about having sexual intercourse, and maternal communication about the expectancies of engaging in sexual intercourse. METHODS: Six hundred sixty eight randomly selected inner-city middle school students and their mothers completed self-administered questionnaires. Adolescents reported their intentions to have sexual intercourse and the perceived positive and negative expectancies of doing so. Both mothers and adolescents reported on the frequency of communication about these expectancies. RESULTS: Boys reported higher intentions, more positive expectancies, and lower levels of maternal communication than did girls. Expectancies statistically significantly associated with intentions focused on the positive physical, social, and emotional advantages of having sex rather than on concerns about pregnancy and HIV/AIDS. With some exceptions, maternal communication was associated with adolescents expectancies about engaging in sexual intercourse. However, only modest correlations between maternal and adolescent reports of communication were observed. CONCLUSIONS: Results indicate that intervention programs should address the positive expectancies youth have about having sex, not just the threat of pregnancy and HIV/AIDS, and should address potential gender differences in expectancies between boys and girls. PMID- 17688398 TI - Testing the effectiveness of the exercise plus program in older women post-hip fracture. AB - BACKGROUND: Exercise is an important strategy with potential to improve recovery in older adults following a hip fracture. PURPOSE: The purpose of this study was to test the impact of a self-efficacy based intervention, the Exercise Plus Program, and the different components of the intervention, on self-efficacy, outcome expectations, and exercise behavior among older women post-hip fracture. METHODS: Participants were randomized to one of four groups: exercise plus, exercise only, plus only (i.e., motivation), or routine care. Data collection was done at baseline (within 22 days of fracture), 2, 6, and 12 months post-hip fracture. RESULTS: A total of 209 women were recruited with an average age of 81.0 years (SD=6.9). The majority was White (97.1%), was widowed (57.2%), and had a high school education (66.7%). Generalized Estimating Equations were used to perform repeated measures analyses. No differences in trajectories of recovery were observed for self-efficacy or outcome expectations. A statistically significant difference in the overall trajectory of time in exercise was seen (p<.001), with more time spent exercising in all three treatment groups. CONCLUSIONS: The study demonstrated that it was possible to engage these women in a home-based exercise program and that the plus only, exercise only, and the exercise plus groups all increased exercise. PMID- 17688399 TI - Elucidating the relationship between negative affectivity and symptoms: the role of illness-specific affective responses. AB - BACKGROUND: More than 20 years of research confirm a positive association of trait negative affect (NA) with reports of physical symptoms. As the mechanisms underlying the association of trait NA and symptom reporting have not been identified, the meaning of the association remains unclear. PURPOSE: We attempted to clarify the processes underlying this association by examining the relationship of trait NA and illness-specific worry to both vague, general symptoms and illness-specific symptoms. We tested the hypothesis that trait NA has both a "biasing" effect when ambiguous symptoms are interpreted as a sign of physical illness and an "accuracy" effect on the reports of illness-specific symptoms mediated by illness-specific worry. METHOD: We examined the relationship of trait and state NA to symptoms reports in both cross-sectional and longitudinal data from inner-city adults with moderate and severe asthma. RESULTS: Whereas high levels of trait NA were associated with reports of both asthma and nonasthma symptoms, only the relationship of trait NA to symptoms specific to asthma was mediated by asthma worry. In addition, these data showed that trait NA was not associated with the misattribution of symptoms to disease. CONCLUSIONS: We concluded that NA motivates individuals, through asthma worry, to be more aware of illness-specific symptoms and correctly report and attribute these symptoms to asthma. PMID- 17688400 TI - Psychological symptom clusters, psychiatric comorbidity and poor self-reported health status following myocardial infarction. AB - BACKGROUND: Depression is a risk factor for adverse outcomes following myocardial infarction (MI). However, the importance of various other psychological factors is less well established. PURPOSE: The purpose is (a) explore the degree to which self-reported psychological symptoms in post-MI patients represent one or more underlying dimensions and (b) examine whether psychological symptom profiles based on these dimensions are differentially associated with major depressive disorder (MDD) and anxiety disorder (AD), and impaired health status. METHODS: Two months post-MI, the Beck Depression Inventory, State-Trait Anxiety Inventory, and Global Mood Scale were used to measure symptoms of depression, anxiety, and mood status in 324 patients. The Composite International Diagnostic Interview was administered to diagnose DSM-IV MDD and AD. Health status was assessed by the Seattle Angina Questionnaire. RESULTS: Principal component analysis revealed 4 essential features of post-MI distress: depressed affect, anxious apprehension, positive affect, and emotional exhaustion. Cluster analysis using these components identified 3 subgroups with different symptom profiles: A no distress subgroup (high positive affect, low on the remaining components), a first increased distress subgroup (ID1; elevated anxious apprehension/emotional exhaustion scores and decreased positive affect, p<.001, but absence of depressed affect, p=.56), and a second increased distress subgroup (ID2; decreased positive affect and elevated scores on the other components, all p<.001). Both increased distress subgroups were more likely to have psychiatric disorder (ID1: odds ratio [OR]=5.4, 95% confidence interval [CI]=1.3-22.1, p=.018; ID2: OR=27.1, 95% CI=6.4 114.7, p<.0001) and worse health status (ID1: -.38 DMC >> crocin. PMID- 17688405 TI - Differential p63 and p53 expression in human keloid fibroblasts and hypertrophic scar fibroblasts. AB - The p63 gene belongs to the p53 gene family and encodes for sequence-specific transcription factors. p63 has been characterized primarily in the context of epidermis where is implicated in the establishment of keratinocyte cell fate and in maintenance of epithelial self-renewal. DeltaNp63 isoform has been showed to be involved in several kinds of human tumors of epidermal origin, even nonmalignant, for the neoplastic and proliferative potential. Here, we report the differential expression and the cellular localization of the DeltaNp63 isoform in fibroblasts isolated from human keloids and hypertrophic scars compared to normal skin. Differently from hypertrophic scar, our results show that DeltaNp63 has a nuclear localization and is overexpressed only in keloid fibroblasts, suggesting an essential role of DeltaNp63 in vivo in human keloids. Consistent with our results, we hypothesize that DeltaNp63 overexpression may be oncogenic because of its ability to block the activity of p53 since p53 is underexpressed in fibroblasts from keloids. PMID- 17688406 TI - Transition from chromatin bodies to linear chromosomes in nuclei of murine PreB cells synchronized in S phase. AB - Chromatin structures and individual interphase chromosomes escaping nuclei of reversibly permeabilized cells were analyzed in a cell cycle-dependent manner. Cells were synchronized by counterflow centrifugal elutriation. Individual interphase chromosomes became visible as distinct fibrous chromatin bodies from mid-S-phase, turning to elongated chromosomes by the end of S phase. Major interphase chromosomal forms include (1) mid-S-phase chromatin bodies at 3.0 C value, (2) elongated chromatin bodies later in mid-S-phase (3.25 C-value), (3) chromatin bodies with head and leg portions later in S phase (3.5 C-value), (4) supercoiled ribbons later in S phase seen as twisted prechromosomes (3.7 C value), and (5) end-S-phase elongated, bent prechromosomal structures (3.9 C value). The first karyotype analysis of the earliest forms of chromosomes referred to as chromatin bodies was performed. PMID- 17688407 TI - Sequence-variable mosaics: composites of recurrent transposition characterizing the genomes of phylogenetically diverse phytoplasmas. AB - Phytoplasmas are cell wall-less prokaryotes characterized by small, AT-rich genomes that encode capabilities for obligate, transkingdom parasitism and pathogenicity in plants and insect vectors. Inability to isolate and characterize phytoplasmas in pure culture has led to adoption of the 'Candidatus species' convention to refer to distinct phytoplasma lineages. In this study, we provide evidence that multiple, sequence-variable mosaics (SVMs) of clustered genes and repetitive extragenic palindromes are characteristic features of phytoplasma genome architecture in phylogenetically diverse species. The findings suggest that the origin of SVMs was an ancient event in evolution of the phytoplasma clade, while current forms of SVMs are results of dramatic and more recent events. Sequence diversity of hypervariable regions indicated rapid evolution possibly involving capture of mobile elements recurrently targeted to SVMs. Multiple events of targeted mobile element attack, recombination, and rearrangement conceivably account for the composite structure of SVMs. Proteins encoded by the highly variable region included a lysophospholipase and other putatively secreted and/or transmembrane, cell surface-interacting proteins potentially significant in phytoplasma-host interactions. PMID- 17688408 TI - Schizosaccharomyces pombe Rad4/Cut5 protein modification and chromatin binding changes in DNA damage. AB - The Schizosaccharomyces pombe Rad4/Cut5 protein is essential for DNA replication and checkpoint control. We have analyzed the behavior of the protein during unperturbed DNA replication, in different replication and checkpoint mutant backgrounds and in response to DNA-damaging agents. In an unperturbed cell cycle, Rad4 is chromatin bound and the mobility of the protein is not altered. Rad4 protein level and thus chromatin binding are dependent on a functional DNA polymerase epsilon. In response to replication arrest and DNA damage, the protein is modified in a Rad3-dependent manner. These data indicate that Rad4 undergoes diverse forms of regulation that are distinct in both DNA replication and checkpoint response. PMID- 17688409 TI - Transcription factors GATA-1 and Fli-1 regulate human HOXA10 expression in megakaryocytic cells. AB - HOXA10 is a member of the HOX family of regulatory genes that are involved in hematopoiesis. Its role in megakaryopoiesis has been suggested by its expression in immature megakaryocytes and by the proliferation of megakaryocyte-primitive blast colonies upon HOXA10 overexpression. We sought to understand the role of HOXA10 in megakaryopoiesis better, by investigating its transcriptional regulation. Analysis of the 5' untranslated region and transfection of promoter/plasmids into human tissue culture cell lines identified transcriptionally active sequences that contain GATA-1 and Ets-1 sites and a putative binding site for its neighboring gene, HOXA11. Gel shift assays confirmed protein-DNA interactions at these sites. Mutation of the GATA-1 and the Ets-1 motifs amplified the expression of HOXA10 in HEL and K562 cells, confirming the importance of these cis-acting elements in regulating HOXA10 expression in megakaryocytic cells. Chromatin immunoprecipitation (ChIP) and chloramphenicol acetyl transferase (CAT) assays confirm that HOXA11 binds to the putative binding site, resulting in repression of HOXA10 expression. These data taken together give insight into the regulation of HOXA10 expression in megakaryocytic differentiation. PMID- 17688410 TI - The Wilms' tumor gene 1 (WT1) induces expression of the N-myc downstream regulated gene 2 (NDRG2). AB - The Wilms' tumor gene 1 (WT1) protein is a transcriptional regulator that is highly expressed in immature hematopoietic progenitor cells and in the majority of patients with acute and chronic myeloid leukemia. However, it is still unclear how WT1 exerts its function(s) in hematopoietic cells. The aim of this work was to investigate the function of WT1 as a transcription factor in human hematopoietic progenitor cells. To this end, an oligonucleotide array approach was used to study the gene expression in CD34(+) cells from human cord blood retrovirally transduced with WT1 or a control vector. We found that the expression of the putative tumor suppressor gene N-myc downstream regulated gene 2 (NDRG2) mRNA was induced by WT1 in CD34(+) cells and also in leukemic U937 cells. Furthermore, a novel transcription start site in the NDRG2 gene was identified in WT1-transduced cells, in addition to two previously reported transcription start sites. These results show that the expression of the NDRG2 gene is directly or indirectly induced by WT1, and provide the first insights into transcriptional regulation of the NDRG2 gene, including demonstration of a novel splice variant. PMID- 17688411 TI - GFP expression alters osteosarcoma cell biology. AB - Green fluorescent protein (GFP) expression is widely used for tracking of cells in vivo. Three human osteosarcoma cell lines were transfected with GFP and analyzed for expression of tissue markers and physiology. GFP-mediated increased tumor aggression in vivo in one cell line was corroborated by altered expression of bone markers and osteoblast-like cell biology in vitro as a result of transfection. The use of GFP for cell tracking in osteosarcoma animal models should therefore be used with caution. PMID- 17688412 TI - Homocysteine-mediated expression of SAHH, DNMTs, MBD2, and DNA hypomethylation potential pathogenic mechanism in VSMCs. AB - Homocysteine (Hcy) is a well-established risk factor for atherosclerosis and may cause dysregulation of gene expression, but the characteristics and the key links involved in its pathogenic mechanisms are still poorly understood. The aim of this study was to explore (i) the effects of Hcy on DNA methylation in vascular smooth muscle cells (VSMCs) and (ii) the underlying mechanism of Hcy-induced changes in DNA methylation patterns in relation to atherosclerosis. We examined the levels of gDNA methylation, namely, the Alu and line-1 element sequences, which can serve as a surrogate marker for gDNA methylation, and also investigated the effects of Hcy on the intracellular S-adenosylmethionine (SAM) and S adenosylhomocysteine (SAH) concentrations as well as the expressions of SAH hydrolase (SAHH), DNA methyltransferase3a (DNMT3a), DNMT3b, and methyl-CpG binding domain 2 (MBD2). We found that clinically relevant levels of Hcy (0-500 microM) induced elevation of SAH, declination of SAM and SAM/SAH ratio, and reduction in expression of SAHH and MBD2, but increased the activity of DNMT3a and DNMT3b compared to the control group (p < 0.05). We found also that the genome-wide hypomethylation is a common feature of gDNA in the VSMCs cultured with Hcy. In conclusion, these results suggest that Hcy-induced DNA methylation may be an important potential pathogenic mechanism in the development of atherosclerosis, and may become a therapeutic target for preventing Hcy-induced atherosclerosis. PMID- 17688413 TI - Genetic polymorphisms of the interleukin-18 gene and risk of prostate cancer. AB - Genetic factors are known to be important in the development of prostate cancer. Interleukin-18 (IL-18) is a multifunctional cytokine that induces interferon gamma secretion and plays an important role in antitumor immunity. Variations in the DNA sequence in the IL-18 gene promoter may lead to altered IL-18 production and/or activity, and so this can modulate an individual's susceptibility to prostate cancer. To test this hypothesis, we investigated the relationship of IL 18 gene promoter -137 G/C and -607 C/A polymorphisms and their haplotypes with the risk of prostate cancer. We analyzed two single nucleotide polymorphisms of IL-18 gene promoter -137 G/C and -607 C/A in 265 patients with prostate cancer and 280 age- and sex-matched controls, using sequence-specific primers-polymerase chain reaction strategy. There were significant differences in the genotype and allele distribution of -137 G/C polymorphism of the IL-18 gene among cases and controls. The -137 GC and CC genotypes were associated with a significantly increased risk of prostate cancer as compared with the -137 GG genotypes [odds ratio (OR) = 1.721; 95% confidence interval (CI): 1.187-2.496; p = 0.004, and OR = 2.181; 95% CI: 1.034-4.603; p = 0.037, for GC and CC, respectively]. Consistent with the results of the genotyping analyses, the -137C/-607A haplotype was associated with a significantly increased risk of prostate cancer as compared with the -137G/-607C haplotype (OR = 1.544; 95% CI, 1.137-2.096; p = 0.005). This study shows for the first time an association between IL-18 gene promoter -137 G/C polymorphism and prostate cancer in a Chinese population. PMID- 17688414 TI - Effects of chronic heat stress on immune responses of the foot-and-mouth disease DNA vaccination. AB - The main purpose of this study was to assess the effects of chronic heat stress (CHS) on humoral and cellular responses of DNA vaccination. Mice with the CHS were exposed to a temperature set at 38 +/- 1 degrees C, 2h per day, for 35 days, and mice with thermoneutral (TN) temperature were maintained at 24 +/- 1 degrees C for the same period of time. Both groups of mice were immunized with a DNA vaccine-expressed viruscapsid protein 1 (VP1) of foot-and-mouth disease virus (FMDV), and we tested their antigen-specific humoral and cellular responses during the treatments. Compared with the TN group, titers of total Imunoglobulin G (IgG) and IgG1 and expression of interleukin 4 (IL-4) in CD4(+) cells of CHS group were not affected significantly. In contrast, the levels of IgG2a, T cell proliferations, and expression of interferon-gama (IFN-gamma) in both CD4(+) and CD8(+) cells were suppressed significantly, and cytotoxic T-lymphocyte (CTL) responses in vivo were also weakened by the CHS condition. These results indicate that the CHS treatment has negatively affected the immune responses of DNA vaccination and particularly impaired to the cell-mediated responses. It suggests that vaccination in animals is affected by the changes of ambient temperature. PMID- 17688416 TI - Pediatric eye/vision screening. Referral criteria for the pedia vision plus optix s 04 photoscreener compared to visual acuity and digital photoscreening. Kindergarten computer photoscreening. AB - BACKGROUND AND PURPOSE: Carefully interpreted photoscreen programs yield high predictive value and favorable sensitivity for amblyopia in pre-school children, but most require a long learning curve. The new PediaVision photoscreener appears to offer advantages and is evaluated in caparison with other established screening methods. METHODS: The Plus Optix S04 (PediaVision) computer interpreted, infrared photoscreener was compared to digital physician-interpreted (Gateway DV-S20) photoscreening and patched Surround HOTV acuity testing in Kindergarten students. RESULTS: The estimated sensitivity and predictive value and speed of the objective photoscreeners exceeded visual acuity testing. The PediaVision photoscreener, in addition, allowed a practical range of referral refractive criteria to be determined and utilized. CONCLUSION: The PlusOptix allows user-chosen, age-related, referral criteria and a quick, child friendly, photoscreening technique that should be ideal for many Kindergarten and preschool eye/vision screening programs. PMID- 17688417 TI - High AC/A accommodative esotropia strabismus treated with contact lenses: a single case design (N=1) study. AB - BACKGROUND AND PURPOSE: The purpose was to determine the efficacy of two types of contact lenses (spherical disposable and aplanatic) as treatment in a patient with esotropia with a high Accommodative Convergence/Accommodation Ratio (AC/A). Due to the possibility of the appearance of accommodative insufficiency in this kind of patient, (i.e., following many years of bifocal glasses use), the elimination of the plus addition lens is advisable. Nevertheless, in some patients, this change leads to the appearance of a residual angle of esodeviation in near vision. It was expected that monofocal aplanatic contact lenses could achieve, due to their optical characteristics, an accurate and orthotropic binocular alignment, without aggravating an undesirable manifestation of the accommodative insufficiency. METHODS: An experimental design of a single case (N=1) was used in which the subject acted as his own control. With bifocal glasses the subject displayed stability in his binocular and accommodative system at every distance of vision for the past three years. We compared the efficacy of two different types of hydrophilic contact lenses to control the angle of deviation, both at distance and at near vision. RESULTS: Neither of the two contact lenses produced the results of stability and the correct binocular alignment that had been achieved with bifocal glasses. This subject experienced a worse manifest esodeviation in distance vision with aplanatic lenses than with the disposable ones. CONCLUSIONS: These monofocal contact lenses did not create acceptable binocular alignment and stability in a subject with a high AC/A accommodative esotropia. PMID- 17688418 TI - Retinally-induced aniseikonia. AB - PURPOSE: To show that retinally-induced aniseikonia may vary as a function of visual field angle (i.e., field-dependent aniseikonia), how this could be explained, and what implications this has for managing the aniseikonia. DESIGN: Observational case series. METHOD: Self-administration using software that can be assumed the predecessor of the Aniseikonia Inspector version 2. Aniseikonia was tested in the vertical nd horizontal direction. In each direction aniseikonia was tested for visual field angles of 0.5 to 8 degrees. PATIENTS: Three patients with different retinal conditions: an epiretinal membrane (ERM), a retinal detachment (RD), and a retinoschisis. RESULTS: All patients had field- dependent aniseikonia, with aniseikonia variations of up to 20% over the measured visual field. The aniseikonia for the ERM patient was similar in the vertical and horizontal direction, while this was not the case for the RD patient and the retinoschisis patient. The retinoschisis patient even had negative aniseikonia in one direction and positive aniseikonia in the other direction. CONCLUSIONS: When reporting the aniseikonia of patients with retinal conditions, one cannot speak of 'the' aniseikonia(i.e., a single value or a single value for each direction), because it is most likely field-dependent. It is also important to use a test that only measures static aniseikonia (direct comparison tests with long viewing times may be less suitable). Correction of field- dependent aniseikonia is relatively difficult, because an optical correction is field-independent. Nevertheless, optically correcting the aniseikonia for part of the visual filed often improves the vision comfort considerably. If necessary, an optical correction could be augmented with a unilateral partial transparency occlusion or a unilateral partial field occlusion for more vision comfort. PMID- 17688419 TI - Ultrasound biomicroscopy (UBM) characteristics of scleral tunnels created with suture needles commonly used during strabismus surgery. AB - PURPOSE: To enhance the safety and efficacy of surgical treatment of strabismus, we sought to measure and determine the ultrasound biomicroscopy (UBM) profile of scleral tunnels created with needles commonly used during strabismus surgery, to determine which needles are less likely to create the complication of scleral perforation. METHODS: Adult cadaver eyes were secured in a styrofoam head. Intraocular pressure was maintained between 15 and 21 mm Hg. Then S14, S24, S28 and TG100 needles were used to create scleral tunnels simulating those created during routine strabismus surgery. Ten scleral tunnels were created with each needle type at 3 different sites on the globe, for a total of 120 passes. The thickness of the sclera and the maximum depth and length of each scleral tunnel were measured using UBM. RESULTS: The mean tunnel depth below the scleral surface (+/- SD) was 0.43 +/-0.11 mm, 0.37 +/-0.09, 0.40 +/-0.08 and 0.34 +/-0.07 mm, for the S14, S24, S28 and TG100 needles, respectively (P=0.002, One way ANOVA). For both the S14 and S28 needles, there was a "statistically significant" P 0.05) linear trend of an increase in the depth of the pass as the length of the pass increased (P=0.01 for the S14 and P=0.02 for the S28 {Pearson Correlation 2 tailed test}). A similar trend was found with the S24 needle but the trend was not "statistically significant" (P=0.35). No such trend was found with the TG100 needle. CONCLUSIONS: Needle design had a definite impact on the characteristics of scleral tunnels created to simulate those made during strabismus surgery and may influence needle selection by the surgeon for different or various surgical circumstances, but the differences were not such as to predicate for or against the general use of any of these four needles for strabismus surgery. PMID- 17688420 TI - Normal-sodium diet compared with low-sodium diet in compensated congestive heart failure: is sodium an old enemy or a new friend? AB - The aim of the present study was to evaluate the effects of a normal-sodium (120 mmol sodium) diet compared with a low-sodium diet (80 mmol sodium) on readmissions for CHF (congestive heart failure) during 180 days of follow-up in compensated patients with CHF. A total of 232 compensated CHF patients (88 female and 144 male; New York Heart Association class II-IV; 55-83 years of age, ejection fraction <35% and serum creatinine <2 mg/dl) were randomized into two groups: group 1 contained 118 patients (45 females and 73 males) receiving a normal-sodium diet plus oral furosemide [250-500 mg, b.i.d. (twice a day)]; and group 2 contained 114 patients (43 females and 71 males) receiving a low-sodium diet plus oral furosemide (250-500 mg, b.i.d.). The treatment was given at 30 days after discharge and for 180 days, in association with a fluid intake of 1000 ml per day. Signs of CHF, body weight, blood pressure, heart rate, laboratory parameters, ECG, echocardiogram, levels of BNP (brain natriuretic peptide) and aldosterone levels, and PRA (plasma renin activity) were examined at baseline (30 days after discharge) and after 180 days. The normal-sodium group had a significant reduction (P<0.05) in readmissions. BNP values were lower in the normal-sodium group compared with the low sodium group (685+/-255 compared with 425+/-125 pg/ml respectively; P<0.0001). Significant (P<0.0001) increases in aldosterone and PRA were observed in the low-sodium group during follow-up, whereas the normal-sodium group had a small significant reduction (P=0.039) in aldosterone levels and no significant difference in PRA. After 180 days of follow up, aldosterone levels and PRA were significantly (P<0.0001) higher in the low sodium group. The normal-sodium group had a lower incidence of rehospitalization during follow-up and a significant decrease in plasma BNP and aldosterone levels, and PRA. The results of the present study show that a normal-sodium diet improves outcome, and sodium depletion has detrimental renal and neurohormonal effects with worse clinical outcome in compensated CHF patients. Further studies are required to determine if this is due to a high dose of diuretic or the low-sodium diet. PMID- 17688421 TI - MARCKS-like protein, a membrane protein identified for its expression in developing neural retina, plays a role in regulating retinal cell proliferation. AB - Membrane proteins are expressed in a specific manner in developing tissues, and characterization of these proteins is valuable because it allows them to be used as cell surface markers. Furthermore, they are potentially important for the regulation of organogenesis because some may participate in signal transduction. In the present study, we used proteomics to examine the comprehensive protein expression profile of the membrane fraction in the embryonic and adult mouse retina. We purified the retinal membrane fraction by sucrose-density-gradient centrifugation and analysed total proteins using shotgun analysis on a nanoflow LC-MS/MS (liquid chromatography tandem MS) system. Approximately half of the 326 proteins from the adult retina and a quarter of the 310 proteins from the embryonic retina (day 17) appeared to be membrane-associated proteins. Among these, MLP [MARCKS (myristoylated alanine-rich C-kinase substrate)-like protein], which shares approx. 50% amino acid identity with MARCKS, was selected for further characterization. The mRNA and surface protein expression of MLP decreased as retinal development progressed. Overexpression of MLP by retrovirus mediated gene transfer enhanced the proliferation of retinal progenitor cells without affecting differentiation or cell migration in a retinal explant culture system. In contrast, MLP overexpression did not promote proliferation in fibroblasts (NIH 3T3 cells). Mutation analysis of MLP demonstrated that myristoylation was necessary to promote proliferation and that phosphorylation inhibited proliferation, indicating the functional importance of membrane localization. PMID- 17688422 TI - Identification of a responsible promoter region and a key transcription factor, CCAAT/enhancer-binding protein epsilon, for up-regulation of PHGPx in HL60 cells stimulated with TNF alpha. AB - In the present study we investigated promoter regions of the PHGPx [phospholipid hydroperoxide GPx (glutathione peroxidase)] gene and transcription factors involved in TNFalpha (tumour necrosis factor alpha)-induced up-regulation of PHGPx in non-differentiated HL60 cells. Non-differentiated HL60 cells displayed up-regulation of non-mitochondrial and mitochondrial PHGPx mRNA in response to TNFalpha stimulation. The promoter activity was up-regulated by TNFalpha stimulation in cells transfected with a luciferase reporter vector encoding the region from -282 to -123 of the human PHGPx gene compared with the non-stimulated control. The up-regulated promoter activity was effectively abrogated by a mutation in the C/EBP (CCAAT/enhancer-binding protein)-binding sequence in this region. ChIP (chromatin immunoprecipitation) assays demonstrated that C/EBPepsilon bound to the -247 to -34 region in HL60 cells, but C/EBPalpha, beta, gamma and delta did not. The binding of C/EBPepsilon to the promoter region was increased in HL60 cells stimulated with TNFalpha compared with that of the non stimulated control. An increased binding of nuclear protein to the C/EBP-binding sequence was observed by EMSA (electrophoretic mobility-shift assay) in cells stimulated with TNFalpha, and it was inhibited by pre-treatment with an anti C/EBPepsilon antibody, but not with other antibodies. The C/EBPepsilon mRNA was expressed in PMNs (polymorphonuclear cells), non-differentiated HL60 cells and neutrophil-like differentiated HL60 cells displaying TNFalpha-induced up regulation of PHGPx mRNA, but not in macrophage-like differentiated HL60 cells, HEK-293 cells (human embryonic kidney-293 cells) and other cell lines exhibiting no up-regulation. The up-regulation of PHGPx mRNA, however, was detected in HEK 293 cells overexpressing C/EBPepsilon as a result of TNFalpha stimulation. These results indicate that C/EBPepsilon is a critical transcription factor in TNFalpha induced up-regulation of PHGPx expression. PMID- 17688423 TI - DGA1 (diacylglycerol acyltransferase gene) overexpression and leucine biosynthesis significantly increase lipid accumulation in the Deltasnf2 disruptant of Saccharomyces cerevisiae. AB - We previously found that SNF2, a gene encoding a transcription factor forming part of the SWI/SNF (switching/sucrose non-fermenting) chromatin-remodelling complex, is involved in lipid accumulation, because the Deltasnf2 disruptant of Saccharomyces cerevisiae has a higher lipid content. The present study was conducted to identify other factors that might further increase lipid accumulation in the Deltasnf2 disruptant. First, expression of LEU2 (a gene encoding beta-isopropylmalate dehydrogenase), which was used to select transformed strains by complementation of the leucine axotroph, unexpectedly increased both growth and lipid accumulation, especially in the Deltasnf2 disruptant. The effect of LEU2 expression on growth and lipid accumulation could be reproduced by adding large amounts of leucine to the culture medium, indicating that the effect was not due to Leu2p (beta-isopropylmalate dehydrogenase) itself, but rather to leucine biosynthesis. To increase lipid accumulation further, genes encoding the triacylglycerol biosynthetic enzymes diacylglycerol acyltransferase (DGA1) and phospholipid:diacylglycerol acyltransferase (LRO1) were overexpressed in the Deltasnf2 disruptant. Overexpression of DGA1 significantly increased lipid accumulation, especially in the Deltasnf2 disruptant, whereas LRO1 overexpression decreased lipid accumulation in the Deltasnf2 disruptant. Furthermore, the effect of overexpression of acyl-CoA synthase genes (FAA1, FAA2, FAA3 and FAA4), which each supply a substrate for Dga1p (diacylglycerol acyltransferase), was investigated. Overexpression of FAA3, together with that of DGA1, did not further increase lipid accumulation in the Deltasnf2 disruptant, but did enhance lipid accumulation in the presence of exogenous fatty acids. Lastly, the total lipid content in the Deltasnf2 disruptant transformed with DGA1 and FAA3 overexpression vectors reached approx. 30%, of which triacylglycerol was the most abundant lipid. Diacylglycerol acyltransferase activity was significantly increased in the Deltasnf2 disruptant strain overexpressing DGA1 as compared with the wild-type strain overexpressing DGA1; this higher activity may account for the prominent increase in lipid accumulation in the Deltasnf2 disruptant with DGA1 overexpression. The strains obtained have a lipid content that is high enough to act as a model of oleaginous yeast and they may be useful for the metabolic engineering of lipid production in yeast. PMID- 17688425 TI - Dendrimers and their applications in immunoassays and clinical diagnostics. AB - Unlike other synthetic polymeric materials, Starburst (Dendritic Nanotechnologies Inc., Mount Pleasant, MI, USA.) dendrimers are a unique class of nanoscopic synthetic macromolecules. They allow controlled architecture, low polydispersity and defined molecular mass. These molecules contain a very large number of reactive terminal functional groups that have been utilized to covalently couple a large variety of molecules, including proteins. The unique properties associated with these dendrimer-coupled protein complexes have been exploited in the development of sensitive immunoassays for a variety of clinically significant biochemical markers. In addition, dendrimer-coupled antibody reagents have been utilized in the Stratus CS system, an automated clinical analyser available commercially since 1998. The present review provides an overview of the synthesis and properties of these dendrimers, preparation of dendrimer-coupled protein reagents and their applications in development of immunoassays. PMID- 17688424 TI - Investigation of the redox centres of periplasmic selenate reductase from Thauera selenatis by EPR spectroscopy. AB - Periplasmic SER (selenate reductase) from Thauera selenatis is classified as a member of the Tat (twin-arginine translocase)-translocated (Type II) molybdoenzymes and comprises three subunits each containing redox cofactors. Variable-temperature X-band EPR spectra of the purified SER complex showed features attributable to centres [3Fe-4S]1+, [4Fe-4S]1+, Mo(V) and haem-b. EPR monitored redox-potentiometric titration of the SerABC complex (SerA-SerB-SerC, a hetero-trimetric complex of alphabetagamma subunits) revealed that the [3Fe-4S] cluster (FS4, iron-sulfur cluster 4) titrated as n=1 Nernstian component with a midpoint redox potential (E(m)) of +118+/-10 mV for the [3Fe-4S]1+/0 couple. A [4Fe-4S]1+ cluster EPR signal developed over a range of potentials between 300 and -200 mV and was best fitted to two sequential Nernstian n=1 curves with midpoint redox potentials of +183+/-10 mV (FS1) and -51+/-10 mV (FS3) for the two [4Fe-4S]1+/2+ cluster couples. Upon further reduction, the observed signal intensity of the [4Fe-4S]1+ cluster decreases. This change in intensity can again be fitted to an n=1 Nernstian component with a midpoint potential (E(m)) of about -356 mV (FS2). It is considered likely that, at low redox potential (E(m) less than -300 mV), the remaining oxidized cluster is reduced (spin S=1/2) and strongly spin-couples to a neighbouring [4Fe-4S]1+ cluster rendering both centres EPR-silent. The involvement of both [3Fe-4S] and [4Fe-4S] clusters in electron transfer to the active site of the periplasmic SER was demonstrated by the re oxidation of the clusters under anaerobic selenate turnover conditions. Attempts to detect a high-spin [4Fe-4S] cluster (FS0) in SerA at low temperature (5 K) and high power (100 mW) were unsuccessful. The Mo(V) EPR recorded at 60 K, in samples poised at pH 6.0, displays principal g values of g3 approximately 1.999, g2 approximately 1.996 and g1 approximately 1.965 (g(av) 1.9867). The dominant features at g2 and g3 are not split, but hyperfine splitting is observed in the g1 region of the spectrum and can be best simulated as arising from a single proton with a coupling constant of A1 (1H)=1.014 mT. The presence of the haem-b moiety in SerC was demonstrated by the detection of a signal at g approximately 3.33 and is consistent with haem co-ordinated by methionine and lysine axial ligands. The combined evidence from EPR analysis and sequence alignments supports the assignment of the periplasmic SER as a member of the Type II molybdoenzymes and provides the first spectro-potentiometric insight into an enzyme that catalyses a key reductive reaction in the biogeochemical selenium cycle. PMID- 17688426 TI - Transcriptional regulatory networks via gene ontology and expression data. AB - Transcriptional regulatory network (TRN) discovery using information from a single source does not seem feasible due to lack of sufficient information, resulting in the construction of spurious or incomplete TRNs. A methodology, TRND, that integrates a preliminary TRN, gene expression data and gene ontology is developed to discover TRNs. The method is applied to a comprehensive set of expression data on B cell and a preliminary TRN that included 1,335 genes, 443 transcription factors (TFs) and 4032 gene/TF interactions. Predictions were obtained for 443 TFs and 9,589 genes. 14,616 of 4,247,927 possible gene/TF interactions scored higher than the imposed threshold. Results for three TFs, E2F 4, p130 and c-Myc, were examined in more detail to assess the accuracy of the integrated methodology. Although the training sets for E2F-4 and p130 were rather limited, the activities of these two TFs were found to be highly correlated and a large set of coregulated genes is predicted. These predictions were confirmed with published experimental results not used in the training set. A similar test was run for the c-Myc TF using the comprehensive resource www.myccancergene.org. In addition, correlations between expression of genes that encode TFs and TF activities were calculated and showed that the assumption of TF activity correlates with encoding gene expression might be misleading. The constructed B cell TRN, and scores for individual methodologies and the integrated approach are available at systemsbiology.indiana.edu/trndresults. PMID- 17688427 TI - MOVE: a multi-level ontology-based visualization and exploration framework for genomic networks. AB - Among the various research areas that comprise bioinformatics, systems biology is gaining increasing attention. An important goal of systems biology is the unraveling of dynamic interactions between components of living cells (e. g., proteins, genes). These interactions exist among others on genomic, transcriptomic, proteomic and metabolomic levels. The levels themselves are heavily interconnected, resulting in complex networks of different interacting biological entities. Currently, various bioinformatics tools exist which are able to perform a particular analysis on a particular type of network. Unfortunately, each tool has its own disadvantages hampering it to be used consistently for different types of networks or analytical methods. This paper describes the conceptual development of an open source extensible software framework that supports visualization and exploration of highly complex genomic networks, like metabolic or gene regulatory networks. The focus is on the conceptual foundations, starting from requirements, a description of the state of the art of network visualization systems, and an analysis of their shortcomings. We describe the implementation of some initial modules of the framework and apply them to a biological test case in bacterial regulation, which shows the relevance and feasibility of the proposed approach. PMID- 17688428 TI - In silico analysis of p53 using the p53 knowledgebase: mutations, polymorphisms, microRNAs and pathways. AB - P53 is probably the most important tumor suppressor known. Over the years, information about this gene has increased dramatically. We have built a comprehensive knowledgebase of p53, which aims to facilitate wet-lab biologists to formulate their experiments and new-comers to learn whatever they need about the gene and bioinformaticians to make new discoveries through data analysis. Using the information curated, including mutation information, transcription factors, transcriptional targets, and single nucleotide polymorphisms, we have performed extensive bioinformatics analysis, and made several new discoveries about p53. We have identified point missense mutations that are over-represented in cancers, but lack of functional studies. By assessing the capability of six p53 transcriptional targets' tag SNPs selected from HapMap to capture SNPs obtained from National Institute of Environmental Health Sciences (NIEHS) Environmental Genome project and vice versa, we conclude that NIEHS data is a better source for tagSNP selections of these genes in future association studies. Analysis of microRNA regulation in the transcriptional network of the p53 gene reveals potentially important regulatory relationships between oncogenic microRNAs and transcription factors of p53. By mapping transcription factors of p53 to pathways involved in cell cycle and apoptosis, we have identified distinctive transcriptional controls of p53 in these two physiological states. PMID- 17688429 TI - Evolved cellular automata for protein secondary structure prediction imitate the determinants for folding observed in nature. AB - We demonstrate the first application of cellular automata to the secondary structure predictions of proteins. Cellular automata use localized interactions to simulate global phenomena, which resembles the protein folding problem where individual residues interact locally to define the global protein conformation. The protein's amino acid sequence was input into the cellular automaton and rules for updating states were evolved using a genetic algorithm. An optimized accuracy (Q3) for the RS126 and CB513 dataset of 58.21% and 56.51%, respectively, could be obtained. Thus, the current work demonstrates the applicability of a rather simple algorithm on a problem as complex as protein secondary structure prediction. PMID- 17688430 TI - Prediction of 3-dimensional structure of salivary odorant-binding protein-2 of the mosquito Culex quinquefasciatus, the vector of human lymphatic filariasis. AB - Olfaction of insects is currently recognized as the major area of research for developing novel control strategies to prevent mosquito-borne infections. A 3 dimensional model (3D) was developed for the salivary gland odorant-binding protein-2 of the mosquito Culex quinquefasciatus, a major vector of human lymphatic filariasis. A homology modeling method was used for the prediction of the structure. For the modeling, two template proteins were obtained by mGenTHERADER, namely the high-resolution X-ray crystallography structure of a pheromone-binding protein (ASP1) of Apis mellifera L., [1R5R:A] and the aristolochene synthase from Penicillium roqueforti [1DI1:B]. By comparing the template protein a rough model was constructed for the target protein using MODELLER, a program for comparative modelling. The structure of OBP of the mosquito Culex quinquefasciatus resembles the structure of pheromone-binding protein ASP1 of Apis mellifera L., [1R5R:A]. From Ramachandran plot analysis it was found that the portion of residues falling into the most favoured regions was 86.0%. The predicted 3-D model may be further used in characterizing the protein in wet laboratory. PMID- 17688431 TI - In Silico analysis of the lateral organ junction (LOJ) gene and promoter of Arabidopsis thaliana. AB - A T-DNA based promoter trapped mutant has led to the identification of a novel lateral organ junction specific promoter upstream of the pentatricopeptide repeat (PPR) protein coding gene LOJ in Arabidopsis thaliana by our laboratory. Various in silico based prediction tools are employed to characterize the upstream sequence of the LOJ gene. Out of numerous cis-elements detected in the LOJ promoter a few are considered important based on the expression pattern of the LOJ gene. These elements would provide a basis for designing experiments for more accurate promoter function annotation. A comparative search for conserved elements in the 5'-upstream region of a few genes involved in lateral organ development and meristem related expression reveals a few common relevant regulatory motifs. The coding region of the LOJ gene is intron-less and contains 19 PPR units. Based on in silico analysis, LOJ protein is predicted to be hydrophobic in nature and targeted to mitochondria. A partial 3D model of LOJ protein has been suggested using a homology-based modeling program. PMID- 17688432 TI - Improved prediction of allergenicity by combination of multiple sequence motifs. AB - The identification and validation of protein allergens have become more important nowadays as more and more transgenic proteins are introduced into our food chains. Current allergen prediction algorithms focus on the identification of single motif or single allergen peptide for allergen detection. However, an analysis of the 575 allergen dataset shows that most allergens contain multiple motifs. Here, we present a novel algorithm that detects allergen by making use of combinations of motifs. Sensitivity of 0.772 and specificity of 0.904 were achieved by the proposed algorithm to predict allergen. The specificity of the proposed approach is found to be significantly higher than traditional single motif approaches. The high specificity of the proposed algorithm is useful in filtering out false positives, especially when laboratory resources are limited. PMID- 17688433 TI - GUIMACS - a Java based front end for GROMACS. AB - Molecular dynamics simulations have gained importance due to their ability to provide valuable insights into understanding structure-function relationships of biological macromolecules. With increasing computational speeds there has been a substantial demand for optimization of simulation algorithms to obtain results even faster. With this on one hand, the need for ease of operation lies on the other. GUI front end programs are important appurtenances to ease the use of command line programs. Effective use of command line based programs requires basic knowledge of the UNIX shell and at least one of the UNIX based text editors, making it difficult for pure biologists to use them efficiently. GROMACS, a widely used suite of molecular dynamics simulation and analysis programs, is no exception to this. As a matter of fact, the increasing dependency of experimental procedures on computational methods for accentuating certain key experimental findings increases the need for interactivity in use of command-line based packages. PMID- 17688434 TI - LyM: a tool to reach the best factor in gene expression comparison. AB - We developed a Perl-based tool called LyM to determine the best factor for changes in the expression level for each transcript across two sets of expression libraries. LyM includes a Bayesian framework that analyzes the prior and posterior probability density function for each transcript considering the size of the libraries. To find out the best factor for change in each distribution, LyM was implemented with a binary search. In this work we aimed to validate the performance of LyM tool using SAGE libraries from different human tissues. The results were compared with those generated by DGED (Digital Gene Expression Displayer), which worked as the gold standard, on the same data set, to assess accuracy. SAGE libraries were selected from CGAP for the following tissues (normal versus tumor): breast, colon, lung and stomach, consisting of eight SAGE libraries and 381,569 tags. DGED analyses were performed with five arbitrary factors for gene expression in two expression libraries: 2, 4, 8, 16 and 32. The results were confronted using the ratio between LyM and DGED factors and were quantitatively well-matched. LyM was capable of retrieving the best value of F, a factor that represents the fold difference in the expression of a specific gene between two expression libraries, represented by its SAGE tags. However, the optimal value of F is only shown in DGED output after multiple manual interactions. As a result, there was a significant economy of time with the LyM binary search algorithm. In some anecdotal cases we observed that the differential expression levels reached values above 100-fold for a fixed value of P = 0.05, an information that initially remained hidden in DGED. Finally, LyM proved to be relatively fast, portable to the standard workstation present in the molecular biology laboratory, assisting accurate and convenient gene search in expression experiments with minimal user interactions. PMID- 17688435 TI - Coding potential prediction in Wolbachia using artificial neural networks. AB - Ab initio coding potential prediction in a bacterial genome is an important step in determining an organism's transcriptional regulatory function. Extensive studies of genes structure have been carried out in a few species such as Escherichia coli, fewer resources exist in newly sequenced genomes like Wolbachia. A model of gene prediction trained on one species may not reflect the properties of other, distantly related prokaryotic organisms. These issues were encountered in the course of predicting genes in the genome of Wolbachia, very important gramnegative bacteria that form intracellular inherited infections in many invertebrates. We describe a coding potential predictor based on artificial neural networks and we compare its performance by using different architectures, learning algorithms and parameters. We rely on a dataset of positive samples constructed from coding sequences and on a negative dataset consisted of all the intergenic regions that were not located between the genes of an operon. Both datasets, positive and negative, were output as fasta formatted files and were used for neural network training. The fast, adaptive, batch learning algorithm Resilient propagation, exhibits the best overall performance on a 64input 10hidden-1output nodes multi-layer perceptron neural network. PMID- 17688436 TI - In silico identification and characterization of a putative phosphatidylinositol 4-phosphate 5-kinase (PIP5K) gene in Eimeria tenella. AB - Phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) play diverse roles in the cellular biology of many organisms, including signal transduction, secretion and vesicular trafficking, and regulation of cytoskeleton assembly. Discovery of the PIP5K gene in Eimeria tenella may shed light on its role in the biology of this avian protozoan, and afford further understanding of the cell-host interaction, particularly during the invasion process. In this study, we report the identification of the PIP5K coding region in the genome sequence of Eimeria tenella using in silico gene prediction approaches. Prediction of the PIP5K coding sequence was confirmed by mapping the full-length cDNA sequence, generated via the Rapid Amplification of cDNA Ends (RACE) method, to the genomic sequence. The putative PIP5K gene of Eimeria tenella is located on the complementary strand of the E1080B12.b1 contig, and comprises 12 exons. Further analysis showed that the coding region spans from exon 1 to exon 7, with all exons obeying the adopted 'gt...ag' splicing rule of intronic sequences. Consensus of the hexameric 5' donor-splice site was deduced as GTRDBB... and the consensus for the 3' acceptor splice sites as ...BHDYAG. The gene encodes a 252-amino acid residue protein. Domain search and protein fold recognition analyses provide compelling evidences that the deduced protein is a PIP5K. PMID- 17688437 TI - Elementary mode analysis to study the preculturing effect on the metabolic state of Lactobacillus rhamnosus during growth on mixed substrates. AB - Quantification of metabolism through elementary modes offers insights into the working of a metabolic network. We have determined the fluxes of elementary modes through linear optimization using the stoichiometry of the elementary modes as a constraint. We apply this methodology to obtain insights into the effect of preculturing on growth of Lactobacillus rhamnosus on medium containing mixed substrates. L. rhamnosus, a microaerophilic organism, produces flavor compounds such as diacetyl and acetoin during growth on glucose and citrate. The uptake of citrate has been shown to be sensitive to preculturing states of the cells. Elementary modes demonstrated that citrate was utilized by the organism as a sole carbon source. Further, both glucose and citrate was catabolized by this organism through aerobic and anaerobic routes. The flux analysis indicated that only 21 elementary modes were operational during growth of L. rhamnosus on glucose and citrate. Glucose specifically accounted for 6 elementary modes, while the remaining 15 involved citrate as substrate. The modes associated with glucose were mainly operational when cells were precultured on glucose. It was observed that all the 21 modes contributed to the fluxes when the cells were precultured on citrate. The NADH recycling through lactate formation and oxygen uptake were dependent on the preculturing state. The analysis also demonstrated that preculturing on citrate yielded better productivity of diacetyl and acetoin. PMID- 17688438 TI - eXpanda: an integrated platform for network analysis and visualization. AB - Analysis and visualization of biological networks, such as protein-protein and protein-DNA interactions, are crucially important toward obtaining a thorough understanding of living systems. Here, we present an integrative software platform, eXpanda, which enables an analysis of a very broad range of biological networks, with a special focus on the extraction of characteristic topologies which potentially function as units in the networks. eXpanda is provided as a Perl library which gives full-automatic connections to various biological databases via a Perl programmable interface and can perform topological analysis based on graph theory. The results of these analyses are visualizable by vector graphics. eXpanda is under GNU General Public License. Software package, detailed documentations, source codes, and some sample scripts are downloadable at http://medcd.iab.keio.ac.jp/expanda/. PMID- 17688439 TI - DomainDraw: a macromolecular feature drawing program. AB - Visualization of functional and structural features of biological macromolecules is an important aspect of communicating and analyzing biological data, for example the presence of a transmembrane domain in relation to a nucleotide binding site or the organization of transcription factor binding sites in a promoter. However, this is not necessarily a trivial task especially when the feature information is complex or lengthy. While there are some tools available that can create these images, none have been implemented for the specific purpose of automating the generation of presentation-quality graphics for displaying feature information. We have implemented DomainDraw, a visualization tool that can be used to generate schematic diagrams of biological macromolecules for the purpose of representing the relative position and range of user-specified domains or motifs. The user specifies the name, position, and range of the domains of interest and DomainDraw generates the image based on these parameters. Optional parameters include domain color and shape, image size, and whether to align multiple proteins using a particular domain. DomainDraw is publicly available as a web server and can be accessed at http://domaindraw.imb.uq.edu.au. The executable may be obtained by contacting the authors. PMID- 17688440 TI - Deep metazoan phylogeny. AB - We reconstructed a robust phylogenetic tree of the Metazoa, consisting of almost 1,500 taxa, by profile neighbor joining (PNJ), an automated computational method that inherits the efficiency of the neighbor joining algorithm. This tree supports the one proposed in the latest review on metazoan phylogeny. Our main goal is not to discuss aspects of the phylogeny itself, but rather to point out that PNJ can be a valuable tool when the basal branching pattern of a large phylogenetic tree must be estimated, whereas traditional methods would be computationally impractical. PMID- 17688441 TI - Frameshift signals in genes associated with the circular code. AB - Three sets of 20 trinucleotides are preferentially associated with the reading frames and their 2 shifted frames of both eukaryotic and prokaryotic genes. These 3 sets are circular codes. They allow retrieval of any frame in genes (containing these circular code words), locally anywhere in the 3 frames and in particular without start codons in the reading frame, and automatically with the reading of a few nucleotides. The circular code in the reading frame, noted X, which can deduce the 2 other circular codes in the shifted frames by permutation, is the information used for analysing frameshift genes, i. e. genes with a change of reading frame during translation. This work studies the circular code signal around their frameshift sites. Two scoring methods are developed, a function P based on this code X and a function Q based both on this code X and the 4 trinucleotides with identical nucleotides. They detect a significant correlation between the code X and the -1 frameshift signals in both eukaryotic and prokaryotic genes, and the +1 frameshift signals in eukaryotic genes. PMID- 17688442 TI - Efficient shape descriptors for feature extraction in 3D protein structures. AB - Structural Genomics initiatives are generating an increasing number of protein structures with very limited biochemical characterization. Characterization of a protein's function and understanding the specific nature of a protein's binding is a critical part of both protein engineering and structure-based drug discovery. The accurate detection of binding site in these protein structures can be valuable in determining its function. As shape plays a crucial role in bimolecular recognition and function, the development of shape analysis techniques is important for understanding protein structure-function relationships. This paper describes the use of the continuous wavelet transforms (CWT) for characterizing shape features of 3D protein structures. The goal is to explore the CWT as a multiscale tool to generate rotation- and translation invariant shape features. PMID- 17688443 TI - In silico detection of binding mode of J-superfamily conotoxin pl14a with Kv1.6 channel. AB - A novel conotoxin pl14a containing 25 amino acid residues with an amidated C terminus from vermivorous cone snail, Conus planorbis belongs to J-conotoxin superfamily and this is the first conotoxin, which inhibits both nicotinic acetylcholine receptor subtypes and Kv1.6 channel. We have attempted through bioinformatics approaches to elucidate the extent of specificity of pl14a towards Kv1 channel subtypes (Kv1.1-Kv1.6). Our work provides rationale for the relatively high specificity and binding mode of pl14a to Kv1.6 channel. The pl14a peptide contains two types of structural elements, namely the putative dyad (Lys18 and Tyr19) and basic residue ring constituted of arginine residues. We have carried out in silico docking studies so as to assess the contribution of one or combination of both structural elements of pl14a in blocking of Kv1.6 channel. For this purpose, we have built by homology modelling, the theoretical 3D structure of Kv1.6 channel based on the available crystal structure of mammalian shaker Kv1.2 channel. Docking studies suggest that positively charged residues ring may be involved in the blocking mechanism of Kv1.6 channel. The models suggest that the peptide interacts with negatively charged extracellular loops and pore-mouth of the potassium channel and blocks the channel by covering the pore as a lid, akin to previously proposed blocking mechanism of kappaM conotoxin RIIIK from Conus radiatus to Tsha1 potassium channel. The newly detected pharmacophore for pl14a interacting with Kv1.6 channel provides a pointer to experimental work to validate the observations made here. Based on differences in the number and distribution of the positively-charged residues in other conopeptides from the J-superfamily, we hypothesize different selectivity profiles against subtypes of the potassium channels for these conopeptides. PMID- 17688444 TI - ISN1 nucleotidases and HAD superfamily protein fold: in silico sequence and structure analysis. AB - cN-II class of 5' purine nucleotidases exhibit specificity for IMP/GMP and belong to the HAD (haloacid dehalogenase) superfamily of hydrolases. The recently identified ISNI class of IMP specific 5'-nucleotidases occurring in yeast, fungi and certain Plasmodia lack sequence homology with the cN-II class of enzymes. We show from analysis of motif and fold conservation that ISN1s also belong to the HAD superfamily. This identification adds a new novel member to this superfamily. PMID- 17688445 TI - nWayComp: a genome-wide sequence comparison tool for multiple strains/species of phylogenetically related microorganisms. AB - The increasing number of whole genomic sequences of microorganisms has led to the complexity of genome-wide annotation and gene sequence comparison among multiple microorganisms. To address this problem, we have developed nWayComp software that compares DNA and protein sequences of phylogenetically-related microorganisms. This package integrates a series of bioinformatics tools such as BLAST, ClustalW, ALIGN, PHYLIP and PRIMER3 for sequence comparison. It searches for homologous sequences among multiple organisms and identifies genes that are unique to a particular organism. The homologous gene sets are then ranked in the descending order of the sequence similarity. For each set of homologous sequences, a table of sequence identity among homologous genes along with sequence variations such as SNPs and INDELS is developed, and a phylogenetic tree is constructed. In addition, a common set of primers that can amplify all the homologous sequences are generated. The nWayComp package provides users with a quick and convenient tool to compare genomic sequences among multiple organisms at the whole-genome level. PMID- 17688446 TI - Microsatellite motifs with moderate GC content are clustered around genes on Arabidopsis thaliana chromosome 2. AB - Microsatellites, arrays of 1-6 bp sequences, are abundant in almost all the eukaryotic genomes. Their distribution in the genome is widely accepted to be differential and non random along the axis of the chromosomes. Arabidopsis thaliana genome is dominated by mononucleotide repeats, (A)n being the most abundant motif. In total, 39 microsatellite motifs extended to more than 100 bp in length. Of these, 8 loci are devoid of any gene in their proximity. (AG)n is the most abundant motif among longer repeats. The non-random distribution of microsatellite in the genome is reflected as occurrence of microsatellite clusters in the genome. In total, 3400 microsatellite clusters have been identified in the Arabidopsis genome. Chromosome 2, which is 19.7 Mb long, harbors 550 clusters accommodating 29% of all the microsatellites present on this chromosome. Further, 409 of the 6239 genes on chromosome 2 are associated with 323 microsatellite clusters. Motifs like (AGG)n and (ACT)n, show preferential accommodation in clusters that overlap with genes. Among all the microsatellite clusters that show an overlap with genes, 80% of the clusters show an overlap in such a way that the cluster ends beyond the 3'-end of the gene or starts before the 5'-end of a gene. Genes with diverse functions show association with the clusters. However, not all members of a gene family show similar associations. PMID- 17688447 TI - Analysis of secondary structure predictions of dengue virus type 2 NS2B/NS3 against crystal structure to evaluate the predictive power of the in silico methods. AB - Multiple sequence alignment was performed against eight proteases from the Flaviviridae family using ClustalW to illustrate conserved domains. Two sets of prediction approaches were applied and the results compared. Firstly, secondary structure prediction was performed using available structure prediction servers. The second approach made use of the information on the secondary structures extracted from structure prediction servers, threading techniques and DSSP database of some of the templates used in the threading techniques. Consensus on the one-dimensional secondary structure of Den2 protease was obtained from each approach and evaluated against data from the recently crystallised Den2 NS2B/NS3 obtained from the Protein Data Bank (PDB). Results indicated the second approach to show higher accuracy compared to the use of prediction servers only. Thus, it is plausible that this approach is applicable to the initial stage of structural studies of proteins with low amino acid sequence homology against other available proteins in the PDB. PMID- 17688448 TI - Correlation between the structural stability and aggregation propensity of proteins. AB - Protein aggregation, being an outcome of improper protein folding, is largely dependent on the folding kinetics of a protein. Previous studies have reported a positive correlation between the stability of the secondary structural elements of a protein and their rate of folding/unfolding. In this in silico study, the secondary and tertiary structures of proteins a) that form inclusion bodies on overexpression in Escherichia coli, b) that form amyloid fibrils and c) that are soluble on overexpression in E. coli are analyzed for certain features that are known to be associated with structural stability. The study revealed that the soluble proteins seem to have a higher rate of folding (based on contact order) and a lower percentage of exposed hydrophobic residues as compared to the inclusion body forming or amyloidogenic proteins. The soluble proteins also seem to have a more favored helix and strand composition (based on the known secondary structural propensities of amino acids). The secondary structure analyses also reveal that the evolutionary pressure is directed against protein aggregation. This understanding of the positive correlation between structural stability and solubility, along with the other parameters known to influence aggregation, could be exploited in the design of mutations aimed at reducing the aggregation propensity of the proteins. PMID- 17688457 TI - Mania matters! PMID- 17688458 TI - Depot antipsychotic medications in bipolar disorder: a review of the literature. AB - OBJECTIVE: To review the literature on the efficacy and safety of depot formulations of first- and second-generation antipsychotic medications (FGAs and SGAs) in patients with bipolar disorder. METHOD: We conducted a computer-aided MEDLINE search using the search terms 'depot antipsychotic', 'bipolar disorder' and 'compliance.' RESULTS: We identified eight published reports in bipolar patients regarding the use of depot FGAs, and six preliminary reports on the use of depot SGAs. These studies suggest that depots FGAs are efficacious in preventing manic episodes during the maintenance treatment of bipolar disorder. Several studies, however, indicate that depot FGAs may be associated with increased time with depressive symptoms, particularly in patients with a predominantly depressive course of illness. Preliminary data on the role of depot formulations of SGAs suggest that they reduce the frequency of both manic and depressive episodes during maintenance treatment, and are well tolerated by patients. CONCLUSION: After a careful risk-benefit analysis, depot antipsychotics may be considered for the long-term control of mood episodes in bipolar patients who have relapsed due to medication non-adherence or who have failed to respond to standard therapies. Depot FGAs should be avoided in patients with a high burden of illness from depressive symptoms and particularly in those judged to be at high risk of suicide. The available data on depot formulations of SGAs indicate that they are efficacious in the maintenance treatment of bipolar illness without increasing the burden of the depressive pole of the illness, but further systematic studies are required to definitively assess this. PMID- 17688459 TI - Neuropsychological functioning in euthymic bipolar disorder: a meta-analysis. AB - OBJECTIVE: Although cognitive deficits are prominent in symptomatic patients with bipolar disorder, the extent and pattern of cognitive impairment in euthymic patients remain uncertain. METHOD: Neuropsychological studies comparing euthymic bipolar patients and healthy controls were evaluated. Across studies, effect sizes reflecting patient-control differences in task performance were computed for the 15 most frequently studied cognitive measures in the literature. RESULTS: Across the broad cognitive domains of attention/processing speed, episodic memory, and executive functioning, medium-to-large performance effect size differences were consistently observed between patients and controls, favoring the latter. Deficits were not observed on measures of vocabulary and premorbid IQ. CONCLUSION: Meta-analytic findings provide evidence of a trait-related neuropsychological deficit in bipolar disorder involving attention/processing speed, memory, and executive function. Findings are discussed with regard to potential moderators, etiologic considerations, limitations, and future directions in neuropsychological research on bipolar disorder. PMID- 17688460 TI - Adjunctive treatment of acute mania: a clinical overview. AB - OBJECTIVE: To provide an overview of the available high quality evidence-base of studies of adjunctive pharmacologic treatment for acute mania. METHOD: Double blind controlled trials with adequate samples (n > 100) were identified through search of PubMed/MEDLINE and computerized abstracts from 2004-2006 meetings of the American Psychiatric Association, International Conference on Bipolar Disorder, and Collegium Internationale Neuro-Psychopharmacolium using key words mania, adjunct, and combination. RESULTS: Placebo-controlled studies with positive results support the adjunctive use of five agents including valproate, olanzapine, risperidone, quetiapine, and haloperidol. Agents with only negative or failed placebo-controlled studies included carbamazepine, gabapentin, lamotrigine, topiramate, oxcarbazepine, and ziprasidone. We found no placebo controlled study of many commonly used agents including lithium, aripiprazole, and clozapine. No studies explicitly excluded subjects, based on prior treatment with the monotherapy being offered and several studies limited randomization to patients with documented inadequate response to the monotherapy arm. CONCLUSION: The available placebo-controlled randomized clinical trials support adjunctive therapy combining lithium or valproate with olanzapine, risperidone, haloperidol or quetiapine. The additional increment of antimanic efficacy of these combinations over monotherapy was similar in magnitude to that seen for the same agents as monotherapy in comparison with placebo. These additive benefits enhanced the tolerability of adverse effects sufficiently to allow a higher proportion of subjects receiving combination therapies to complete the studies than monotherapy treated patients. The available data has several shortcomings and the available studies are inadequate to conclusively determine whether combination treatment is more efficacious than monotherapy when used by subjects naive to both treatments. Nevertheless, adjunctive treatment, which combines agents with proven antimanic efficacy, offers an attractive option for patients with acute mania. PMID- 17688461 TI - Vascular mania: an old concept in danger of sclerosing? A clinical overview. AB - OBJECTIVE: To review the evidence for an association between vascular disease and mania, and in this context, to assess the suitability of previously proposed diagnostic criteria. METHOD: Relevant articles were retrieved and reviewed with the aid of search engines [MEDLINE, PsychInfo and EMBASE from 1996 to 2006] using pertinent search terms. Because of the paucity of data, systematic criteria for levels of evidence could not be applied. RESULTS: The literature is limited by the preponderance of case reports or case series, the use of overlapping terms, such as secondary mania, disinhibition syndrome and poststroke mania, and variable definitions of mania per se. There is general support for a tentative association between mania and vascular risk factors, and also between mania and cerebrovascular disease. Such associations seem best described by the term vascular mania for the sake of clinical utility, although it erroneously conveys causality. Proposed diagnostic criteria have defined a late-age at onset (50 years +) sub-type of mania, with associated neuroimaging and neuropsychological changes which are not specific to this age group. CONCLUSION: Further studies are needed to determine whether mania associated with vascular disease is a specific and separate sub-type with a late-age at onset. An alternative framework for considering vascular mania is proposed. PMID- 17688462 TI - Dopamine dysregulation syndrome: implications for a dopamine hypothesis of bipolar disorder. AB - OBJECTIVE: Rational therapeutic development in bipolar is hampered by a lack of pathophysiological model. However, there is a wealth of converging data on the role of dopamine in bipolar disorder. This paper therefore examines the possibility of a dopamine hypothesis for bipolar disorder. METHOD: A literature search was conducted using standard search engines Embase, PyschLIT, PubMed and MEDLINE. In addition, papers and book chapters known to the authors were retrieved and examined for further relevant articles. RESULTS: Collectively, in excess of 100 articles were reviewed from which approximately 75% were relevant to the focus of this paper. CONCLUSION: Pharmacological models suggest a role of increased dopaminergic drive in mania and the converse in depression. In Parkinson's disease, administration of high-dose dopamine precursors can produce a 'maniform' picture, which switches into a depressive analogue on withdrawal. It is possible that in bipolar disorder there is a cyclical process, where increased dopaminergic transmission in mania leads to a secondary down regulation of dopaminergic receptor sensitivity over time. This may lead to a period of decreased dopaminergic transmission, corresponding with the depressive phase, and the repetition of the cycle. This model, if verified, may have implications for rational drug development. PMID- 17688463 TI - A 6-month randomized open-label comparison of continuation of oral atypical antipsychotic therapy or switch to long acting injectable risperidone in patients with bipolar disorder. AB - OBJECTIVE: To determine the safety and effectiveness of long-acting injectable risperidone (LAI-ris) add-on in bipolar patients. METHOD: A 6-month, open-label, randomized, pilot trial enrolled 49 bipolar out-patients who were taking a mood stabilizer and an atypical antipsychotic (AAP). Patients were maintained on a mood stabilizer and were randomized to continuation of their current AAP or switched to LAI-ris treatment. Safety outcomes included adverse events and changes in vital signs, laboratory tests and extrapyramidal symptoms (EPS). Effectiveness measures included Clinical Global Impression-Severity, scales assessing mania, depression, anxiety, resource utilization, quality of life, subject satisfaction with treatment, and time to intervention. RESULTS: Twenty three subjects were randomized to LAI-ris and 26 to oral AAP. There were no significant differences between the groups in adverse events, EPS change scores, weight or other safety measures. LAI-ris group had significant reductions in symptoms as measured by changes in Clinical Global Impression-Severity scores and Young Mania Rating Scale at endpoint relative to baseline and oral AAP group had reductions in Hamilton Anxiety Rating Scale scores relative to baseline but no significant differences were noted between the groups on any of the efficacy measures. CONCLUSION: LAI-ris demonstrated similar effectiveness, safety and tolerability compared to oral AAP in this 6 month pilot trial. PMID- 17688464 TI - Measuring mania metabolites: a longitudinal proton spectroscopy study of hypomania. AB - OBJECTIVE: Using single-voxel proton spectroscopy we aimed to investigate changes in metabolite levels in key brain regions during hypomania and euthymia in patients with bipolar disorder (BD). METHOD: Nine patients with a diagnosis of BD and nine age, sex, education, and handedness-matched comparison subjects underwent magnetic resonance proton spectroscopy (H(1)-MRS) using a 1.5 T magnet. Patients were assessed whilst hypomanic and euthymic. Metabolite (N-acetyl asparTate, NAA; myo-inositol, mI; choline, Cho) levels in the basal ganglia (BG), anterior cingulate cortex (AC), and frontal cortex (FC) were compared both between groups and within the patient group. RESULTS: Multivariate analysis revealed significant complex relationships between metabolite levels and brain regions with significant differences observed both between bipolar patients (hypomanic and euthymic) and controls, and across the two mood states. Hypomanic patients had lower mean metabolite levels when averaged across the AC and FC regions, compared with the controls. They also had a smaller difference in mean metabolite levels between the BG and FC than the control group. Euthymic patients were also found to have a smaller difference in the level of NAA between the BG and AC than the control group. CONCLUSION: This exploratory study of BD demonstrates significant differences in metabolite levels that vary both with respect to brain region and mood state. Not withstanding the confounding effects of medication and the limitation of small sample size the findings are important as they demonstrate that a longitudinal approach is a useful design especially in the context of a long-term phasic illness. PMID- 17688465 TI - Roles of leptin in prenatal and perinatal brain development. AB - Leptin is a hormone that reduces food intake and increases energy expenditure by acting on the arcuate nucleus in the hypothalamus. Recent studies indicated that the neuronal circuit related to food intake in the hypothalamus is formed in the neonatal period and that leptin is necessary for the formation of this circuit. Our studies have further suggested that leptin may act on the fetal cerebral cortex, including the cingulate cortex, which is involved in motor and cognitive processes, and that leptin may affect maintenance and differentiation of neural stem cells, glial-restricted progenitor cells and/or neuronal lineage cells. These recent studies showed that leptin not only has homeostatic functions in adults, but also regulates brain development in the prenatal and neonatal periods. These findings suggest that leptin is related to formation of the normal brain structure and regenerative potency of neural cells as well as the predisposition to homeostatic dysfunction, low locomotor activity or impairment of cognitive function. PMID- 17688466 TI - Hyperthermia in utero due to maternal influenza is an environmental risk factor for schizophrenia. AB - A hypothesis is presented that the association between maternal influenza and other causes of fever during the second trimester of pregnancy and the subsequent development of schizophrenia in the child is due to the damage caused by hyperthermia to the developing amygdalohippocampal complex and associated structures in the fetal brain. Hyperthermia is a known cause of congenital defects of the central nervous system and other organs after sufficiently severe exposures during early organogenesis. The pathogenic mechanisms include death of actively dividing neuroblasts, disruption of cell migration and arborization and vascular damage. In experimental studies, hyperthermia during later stages of central nervous system development also caused damage to the developing brainstem that was associated with functional defects. This damage usually results in hypoplasia of the parts undergoing active development at the time of exposure. Recent studies have shown no evidence of direct invasion of the fetus by the influenza virus. Factors that might interact with hyperthermia include familial liability to schizophrenia, season of birth, maternal nutrition, severe stress and medications used to alleviate the symptoms of fevers. The time of the development of the fetal amygdalohippocampal complex and the changes found in its structure and associated areas of the brain are compatible with the known effects of hyperthermia. PMID- 17688467 TI - Prevention of ochratoxin A-induced neural tube defects by folic acid in the genetic polydactyly/arhinencephaly mouse, Pdn/Pdn. AB - The gene responsible for the polydactyly/arhinencephaly (Pdn/Pdn) mouse, which exhibits polysyndactyly and arhinencephaly and has a 13.2% risk of neural tube defects (NTD), has been identified as Gli3. Ochratoxin A (OTA) is a teratogen causing NTD in mice. When Pdn/Pdn embryos were exposed to 2 mg/kg of OTA on day 7.5, the incidence of NTD in Pdn/Pdn fetuses increased to 51.6%. Pre-treatment with folinic acid (FA), metabolically the most active form of folic acid, before OTA-treatment decreased the incidence of NTD to 20.8%. We investigated the effect of OTA and FA on gene expression in day 9 embryos using whole-mount in situ hybridization and real-time PCR. Over-expression of Fgf8 was observed at the anterior neural ridge (ANR) in the non-treated Pdn/Pdn. Over-expression at the ANR expanded in the OTA-treated Pdn/Pdn, and it was ameliorated by pretreatment with FA. Emx2 signal was observed in the dorsal forebrain in the non-treated +/+, but disappeared in the OTA-treated +/+, and was recovered by FA. The Emx2 signal was pale and the expression amount was depressed in the non-treated and OTA treated Pdn/Pdn embryos. It was suggested that down-regulation of Gli3 induced the over-expression of Fgf8 at the ANR, that OTA treatment accelerated the over expression, and that pretreatment with FA ameliorated the OTA-induced over expression of Fgf8 in the Pdn/Pdn. It was also suggested that down-regulation of Gli3 induced the down-regulation of Emx2 in the Pdn/Pdn. It was further speculated that the over-expression of Fgf8 at the ANR and down-regulation of Emx2 in the dorsal forebrain may contribute to NTD induction. PMID- 17688468 TI - Pattern of chromosomal inversions identified by a birth defects registry, Hawaii, 1986-2002. AB - The aim of the investigation was to describe chromosomal inversions identified by a birth defects registry with respect to chromosomes involved, pregnancy outcome, method of diagnosis, inheritance, sex and diagnosis of major structural birth defects. Cases were derived from a population-based birth defects registry in Hawaii and comprised all infants and fetuses with chromosomal deletions delivered during 1986-2002. A total of 68 cases were identified through a statewide birth defects registry in Hawaii during 1986-2002. The chromosomes involved in the greatest proportion of inversions were chromosomes 6 (18%) and 9 (18%). Live births accounted for 62 (91%) of the cases. Diagnosis was made by amniocentesis or chorionic villus sampling in 60 (88%) of the cases. Of the 43 cases with known inheritance, the inversion was inherited in 40 (93%) and de novo in three (7%). Males accounted for 31 (46%) and females for 37 (54%) of the cases. Major structural birth defects were identified in 12 (18%) of the cases. Inversions diagnosed among infants and fetuses in Hawaii do not appear to affect all chromosomes equally. Most detected inversions occurred among live births and were inherited conditions. Infants and fetuses with inversions are not frequently associated with major structural birth defects. PMID- 17688469 TI - First trimester diagnosis of iniencephaly associated with fetal malformations and trisomy 18: report of a new case and gene analysis on folate metabolism in parents. AB - Iniencephaly is a rare congenital malformation consisting of a complex alteration of the embryonic development occurring around the third post-fertilization week and characterized by a hyper-retroflexion of the cephalic pole. We report a case of iniencephaly associated with acrania-encephalocele, spina bifida and abnormal ductus venosus in a fetus with trisomy 18 diagnosed at 12 week's gestation in a 41-year-old woman. A co-occurrence between aneuploidy and iniencephaly was documented and polymorphisms on folate metabolism-related genes were investigated in the parents to assess possible etiologic factors and recurrence risk for neural tube defects (NTD). An homozygous state for the MTRR polymorphism was diagnosed in the mother, identifying a clinical risk for NTD. Once iniencephaly or any other NTD are suspected, genetic analysis, second level ultrasound and fetal karyotype are recommended. Autopsy should also be performed in all cases of early ultrasound-based diagnosis of fetal malformations. PMID- 17688470 TI - Trichorhinophalangeal syndrome type II without the chromosome 8 deletion that resembled metachondromatosis. AB - We describe a 5-year-old girl with features resembling Trichorhinophalangeal syndrome, type I (sparse scalp hair, bushy eyebrows, bulbous nose, long philtrum, cone-shaped epiphyses, clinobrachydactyly, epiphyseal changes in the femoral head and short stature), and appendicular exostoses similar to trichorhinophalangeal syndrome, type II. However, despite physical resemblance to the trichorhinophalangeal syndrome variants, cytological analysis showed a structurally normal chromosome 8 and no mental deficiency was apparent. In addition, morphological congruities between multiple exostoses and metachondromatosis was indicated from radiographic findings. PMID- 17688471 TI - Characteristics of Kbl:Dutch rabbits in prenatal development in comparison with Kbl:New Zealand white rabbits. AB - Prenatal development of Kbl:Dutch rabbits was studied in comparison with Kbl:New Zealand white rabbits. Significantly accelerated ossification of the 5th and 6th sternebrae and a low incidence of fetuses with a 13th rib were characteristic features in the prenatal development of Kbl:Dutch rabbits in comparison with Kbl:New Zealand white rabbits. These characteristics were largely consistent with earlier studies of Dutch rabbits from different suppliers and are notable when Kbl:Dutch rabbits are used for the evaluation of skeletal ossification. PMID- 17688473 TI - Understanding the role of knowledge in the practice of expert nephrology nurses in Australia. AB - This paper, which is abstracted from a larger study into the acquisition and exercise of nephrology nursing expertise, aims to explore the role of knowledge in expert practice. Using grounded theory methodology, the study involved 17 registered nurses who were practicing in a metropolitan renal unit in New South Wales, Australia. Concurrent data collection and analysis was undertaken, incorporating participants' observations and interviews. Having extensive nephrology nursing knowledge was a striking characteristic of a nursing expert. Expert nurses clearly relied on and utilized extensive nephrology nursing knowledge to practice. Of importance for nursing, the results of this study indicate that domain-specific knowledge is a crucial feature of expert practice. PMID- 17688474 TI - Effect of single and multi-joint lower extremity muscle strength on the functional capacity and ADL/IADL status in Japanese community-dwelling older adults. AB - Forty-seven community-dwelling older adults aged >70 years participated in this Japanese cross-sectional study to determine the relationship between the isometric lower extremity muscle strength measured during knee extension (KE) in single-joint and total leg extension (TLE) in multi-joint tasks, physical performance tests, and functional status. The physical performance was determined by KE and TLE muscle strength, walking capacity, and balance performance tests, while the functional status was evaluated by interview using basic activities of daily living (ADL) and instrumental activities of daily living (IADL) tools. The results indicated that the TLE muscle strength was significantly related to all the other performance tests, while the KE muscle strength was not correlated with the balance test. Also, the bilateral TLE muscle strength was significantly associated with IADL status compared with the KE muscle strength. In conclusion, multi-joint muscle strength testing might be superior to single-joint muscle strength testing for the screening of the functional impairments of older adults. PMID- 17688475 TI - Comparison of the body fluid levels in healthy individuals and those with schizophrenia in Japan: using the bioelectrical impedance method. AB - Polydipsia and water intoxication have been found to be care problems in people with schizophrenia in many countries. This Japanese study measured the body fluid distribution and body fat of 80 males with long standing schizophrenia and compared this to that of 64 healthy males, using bioelectrical impedance spectrum analysis (BIS). Participants with schizophrenia exhibited significantly lower percentages of intracellular fluid and total body fluid, and significantly higher percentages of fat. Moreover, the percentage of extracellular fluid was distributed over a wider range. When the percentage body fluid was compared between the two groups by matching body mass index and body fat, intracellular fluid was significantly lower for those participants with schizophrenia. There findings suggest that nurses and other health professionals need to be very cautious when attempting to modify the excessive drinking of fluids by patients with schizophrenia. In mistakenly trying to prevent water intoxication, they may in fact be contributing to dehydration. PMID- 17688476 TI - Patient advocacy in the USA: key communication role functions. AB - Researchers have long documented the importance of patient advocacy programs as a means of providing customer service in health-care organizations. Yet, while effective communication is often acknowledged as key to effective patient advocacy, knowledge of the specific communication role functions enacted by patient advocates remains limited, as does our understanding of the function of patient advocacy at the organizational level. This qualitative investigation not only provides a typology of communication roles enacted by patient advocates while solving problems on behalf of patients and their family members, but also integrates scholarly research on "boundary-spanning" as a means of theoretically contextualizing the advocacy role at the organizational level. PMID- 17688477 TI - Predictors of family caregivers' burden and quality of life when providing care for a family member with schizophrenia in the People's Republic of China. AB - Limited research has been undertaken regarding family caregivers' burden and quality of life (QOL) when providing care for a family member with schizophrenia in the People's Republic of China. This study examined the following in Chinese families caring for a member with schizophrenia: (i) the level of family caregivers' burden and QOL; (ii) the relationships among the demographic characteristics of family caregivers, the demographic characteristics of family members with schizophrenia, and family caregivers' burden and QOL; and (iii) the best predictors of family caregivers' burden and QOL. The findings suggest that family caregivers suffer a high level of burden when caring for a family member with schizophrenia. Numerous significant correlations were found among the variables. The best predictor of family caregivers' burden was found to be their level of education, while the best predictors of family caregivers' QOL were physical health and household income. PMID- 17688478 TI - Coping strategies and predictors of general well-being in women with breast cancer in the People's Republic of China. AB - The presence of breast cancer has been a great challenge to women's health for decades. However, limited information exists about how Chinese women with breast cancer cope with the stressors of the illness and which factors predict their sense of general well-being. Therefore, the purposes of this study of women with breast cancer from the People's Republic of China were to identify the coping strategies being used and to identify which demographic characteristics and coping strategies were the best predictors of general well-being. The sample consisted of 100 newly diagnosed women with breast cancer, located within one city in the People's Republic of China. Each woman completed three paper-and pencil questionnaires that measured demographics, coping strategies, and general well-being. The findings indicated planning, positive reframing, and self distraction were the most commonly used coping strategies. The best predictors of general well-being were employment status and the coping method, self-blame. PMID- 17688479 TI - The psychosocial work environment and burnout among Swedish registered and assistant nurses: the main, mediating, and moderating role of empowerment. AB - The aim of the present study was to explore: the main effect of empowerment on burnout; empowerment as a mediator between the work environment and burnout; and empowerment as a moderator of the association between the work environment and burnout. In order to explore these effects, multiple regression analyses were performed on questionnaire data from 838 registered nurses and 518 assistant nurses in Sweden. The analyses showed that: empowerment has a negative association to burnout; empowerment has a mediating effect between the work environment (especially for control and social support) and burnout; and the moderating effect of empowerment on the association between the work environment and burnout was weak. The results suggest that: empowerment explains variation with regard to burnout over and above what can be explained by established work situation dimensions; the improvement of the work environment is associated with a higher sense of empowerment which, in turn, is related to lower degrees of burnout; and individual and group differences should be considered in workplace health promotion. PMID- 17688480 TI - Iranian nurses' perceptions of theoretical knowledge transfer into clinical practice: a grounded theory approach. AB - Since nursing education was transferred to universities in Iran, the public and health administrators have criticized Iranian nurses because of poor-quality patient care. It seems that nurses are not able to transfer the taught theoretical knowledge in academia into practice. This paper attempts to provide an insider view of why the taught theoretical knowledge in academia might be difficult to enact in the clinical setting. Using the grounded theory approach, individual in-depth interviews and participant observation were undertaken with a purposive and theoretical sample of 26 participants in Tehran University of Medical Sciences. The data were analyzed using the constant comparative method. The findings showed that, in spite of increased academic input into nursing education, clinical behaviors in both the education and practice settings were perceived as "traditional routine-based". PMID- 17688481 TI - Nursing competency and organizational climate as perceived by staff nurses in a Chinese university hospital. AB - Nursing competency is important to ensure patient safety and improve the quality of nursing care. Based on competency-based human resource management strategies, the organizational climate can positively influence nursing competency. However, a review of the literature indicated that there were no studies about the relationship between nursing competency and organizational climate in the People's Republic of China. This descriptive, correlational study examined the relationship between nursing competency and the organizational climate. The sample consisted of 243 staff nurses who completed the questionnaire worked at one university hospital in Liao Ning Province. The findings showed that there was a significantly moderate positive relationship between nursing competency and organizational climate. The study results suggested that Chinese nurse managers should maintain and provide a positive organizational climate to improve nursing competency. PMID- 17688482 TI - Health status, trends, and issues in Sri Lanka. AB - It is widely recognized that better health is a prerequisite for the overall economic and social development of a nation. Sri Lanka, like many other countries experiencing the epidemiological transition, will have to make effective decisions on health-care service management and the development of education and training programs for health-care professionals. This paper provides a comprehensive review of current health service administration, health status, trends and issues, and health financing and resource allocation in Sri Lanka. The review revealed that Sri Lanka has achieved a relatively high health status given a low level of spending on its health-care services; however, Sri Lanka still experiences vital health problems in all stages of the life cycle, mainly related to lifestyle and the epidemiological transition associated with widespread societal and economic crises. PMID- 17688484 TI - The pedigree of the International Biometric Society. AB - On the 60th anniversary of the International Biometric Society, a look back is taken to the view of biometry held by the first president, R. A. Fisher, as reflected in notes taken in a lecture course he gave in 1935-1936. PMID- 17688485 TI - Marginalized models for moderate to long series of longitudinal binary response data. AB - Marginalized models (Heagerty, 1999, Biometrics 55, 688-698) permit likelihood based inference when interest lies in marginal regression models for longitudinal binary response data. Two such models are the marginalized transition and marginalized latent variable models. The former captures within-subject serial dependence among repeated measurements with transition model terms while the latter assumes exchangeable or nondiminishing response dependence using random intercepts. In this article, we extend the class of marginalized models by proposing a single unifying model that describes both serial and long-range dependence. This model will be particularly useful in longitudinal analyses with a moderate to large number of repeated measurements per subject, where both serial and exchangeable forms of response correlation can be identified. We describe maximum likelihood and Bayesian approaches toward parameter estimation and inference, and we study the large sample operating characteristics under two types of dependence model misspecification. Data from the Madras Longitudinal Schizophrenia Study (Thara et al., 1994, Acta Psychiatrica Scandinavica 90, 329 336) are analyzed. PMID- 17688486 TI - Prospective accuracy for longitudinal markers. AB - In this article we focus on appropriate statistical methods for characterizing the prognostic value of a longitudinal clinical marker. Frequently it is possible to obtain repeated measurements. If the measurement has the ability to signify a pending change in the clinical status of a patient then the marker has the potential to guide key medical decisions. Heagerty, Lumley, and Pepe (2000, Biometrics 56, 337-344) proposed characterizing the diagnostic accuracy of a marker measured at baseline by calculating receiver operating characteristic curves for cumulative disease or death incidence by time t. They considered disease status as a function of time, D(t) = 1(Tor= 0, after the baseline time) can discriminate between people who become diseased and those who do not in a subsequent time interval [s, t]. We assume the disease status is derived from an observed event time T and thus interest is in individuals who transition from disease free to diseased. We seek methods that also allow the inclusion of prognostic covariates that permit patient-specific decision guidelines when forecasting a future change in health status. Our proposal is to use flexible semiparametric models to characterize the bivariate distribution of the event time and marker values at an arbitrary time s. We illustrate the new methods by analyzing a well-known data set from HIV research, the Multicenter AIDS Cohort Study data. PMID- 17688487 TI - Simultaneous inference for semiparametric nonlinear mixed-effects models with covariate measurement errors and missing responses. AB - Semiparametric nonlinear mixed-effects (NLME) models are flexible for modeling complex longitudinal data. Covariates are usually introduced in the models to partially explain interindividual variations. Some covariates, however, may be measured with substantial errors. Moreover, the responses may be missing and the missingness may be nonignorable. We propose two approximate likelihood methods for semiparametric NLME models with covariate measurement errors and nonignorable missing responses. The methods are illustrated in a real data example. Simulation results show that both methods perform well and are much better than the commonly used naive method. PMID- 17688488 TI - Two-stage functional mixed models for evaluating the effect of longitudinal covariate profiles on a scalar outcome. AB - The Daily Hormone Study, a substudy of the Study of Women's Health Across the Nation (SWAN) consisting of more than 600 pre- and perimenopausal women, includes a scalar measure of total hip bone mineral density (BMD) together with repeated measures of creatinine-adjusted follicle stimulating hormone (FSH) assayed from daily urine samples collected over one menstrual cycle. It is of scientific interest to investigate the effect of the FSH time profile during a menstrual cycle on total hip BMD, adjusting for age and body mass index. The statistical analysis is challenged by several features of the data: (1) the covariate FSH is measured longitudinally and its effect on the scalar outcome BMD may be complex; (2) due to varying menstrual cycle lengths, subjects have unbalanced longitudinal measures of FSH; and (3) the longitudinal measures of FSH are subject to considerable among- and within-subject variations and measurement errors. We propose a measurement error partial functional linear model, where repeated measures of FSH are modeled using a functional mixed effects model and the effect of the FSH time profile on BMD is modeled using a partial functional linear model by treating the unobserved true subject-specific FSH time profile as a functional covariate. We develop a two-stage nonparametric regression calibration method using period smoothing splines. Using the connection between smoothing splines and mixed models, we show that a key feature of our approach is that estimation at both stages can be conveniently cast into a unified mixed model framework. A simple testing procedure for constant functional covariate effect is also proposed. The proposed methods are evaluated using simulation studies and applied to the SWAN data. PMID- 17688489 TI - Nonparametric estimation of the joint distribution of a survival time subject to interval censoring and a continuous mark variable. AB - This article considers three nonparametric estimators of the joint distribution function for a survival time and a continuous mark variable when the survival time is interval censored and the mark variable may be missing for interval censored observations. Finite and large sample properties are described for the nonparametric maximum likelihood estimator (NPMLE) as well as estimators based on midpoint imputation (MIDMLE) and coarsening the mark variable (CMLE). The estimators are compared using data from a simulation study and a recent phase III HIV vaccine efficacy trial where the survival time is the time from enrollment to infection and the mark variable is the genetic distance from the infecting HIV sequence to the HIV sequence in the vaccine. Theoretical and empirical evidence are presented indicating the NPMLE and MIDMLE are inconsistent. Conversely, the CMLE is shown to be consistent in general and thus is preferred. PMID- 17688490 TI - Bayesian modeling of multiple episode occurrence and severity with a terminating event. AB - An individual's health condition can affect the frequency and intensity of episodes that can occur repeatedly and that may be related to an event time of interest. For example, bleeding episodes during pregnancy may indicate problems predictive of preterm delivery. Motivated by this application, we propose a joint model for a multiple episode process and an event time. The frequency of occurrence and severity of the episodes are characterized by a latent variable model, which allows an individual's episode intensity to change dynamically over time. This latent episode intensity is then incorporated as a predictor in a discrete time model for the terminating event. Time-varying coefficients are used to distinguish among effects earlier versus later in gestation. Formulating the model within a Bayesian framework, prior distributions are chosen so that conditional posterior distributions are conjugate after data augmentation. Posterior computation proceeds via an efficient Gibbs sampling algorithm. The methods are illustrated using bleeding episode and gestational length data from a pregnancy study. PMID- 17688491 TI - A joint frailty model for survival and gap times between recurrent events. AB - Therapy for patients with a recurrent disease focuses on delaying disease recurrence and prolonging survival. A common analysis approach for such data is to estimate the distribution of disease-free survival, that is, the time to the first disease recurrence or death, whichever happens first. However, treating death similarly as disease recurrence may give misleading results. Also considering only the first recurrence and ignoring subsequent ones can result in loss of statistical power. We use a joint frailty model to simultaneously analyze disease recurrences and survival. Separate parameters for disease recurrence and survival are used in the joint model to distinguish treatment effects on these two types of events. The correlation between disease recurrences and survival is taken into account by a shared frailty. The effect of disease recurrence on survival can also be estimated by this model. The EM algorithm is used to fit the model, with Markov chain Monte Carlo simulations in the E-steps. The method is evaluated by simulation studies and illustrated through a study of patients with heart failure. Sensitivity analysis for the parametric assumption of the frailty distribution is assessed by simulations. PMID- 17688492 TI - Regression models for the mean of the quality-of-life-adjusted restricted survival time using pseudo-observations. AB - In this research we develop generalized linear regression models for the mean of a quality-of-life-adjusted restricted survival time. Parameter and standard error estimates could be obtained from generalized estimating equations applied to pseudo-observations. Simulation studies with moderate sample sizes are conducted and an example from the International Breast Cancer Study Group Ludwig Trial V is used to illustrate the newly developed methodology. PMID- 17688493 TI - Testing goodness of fit of a uniform truncation model. AB - Several goodness-of-fit tests of a lifetime distribution have been suggested in the literature; many take into account censoring and/or truncation of event times. In some contexts, a goodness-of-fit test for the truncation distribution is of interest. In particular, better estimates of the lifetime distribution can be obtained when knowledge of the truncation law is exploited. In cross-sectional sampling, for example, there are theoretical justifications for the assumption of a uniform truncation distribution, and several studies have used it to improve the efficiency of their survival estimates. The duality of lifetime and truncation in the absence of censoring enables methods for testing goodness of fit of the lifetime distribution to be used for testing goodness of fit of the truncation distribution. However, under random censoring, this duality does not hold and different tests are required. In this article, we introduce several goodness-of-fit tests for the truncation distribution and investigate their performance in the presence of censored event times using simulation. We demonstrate the use of our tests on two data sets. PMID- 17688494 TI - A semiparametric odds ratio model for measuring association. AB - We propose a semiparametric odds ratio model to measure the association between two variables taking discrete values, continuous values, or a mixture of both. Methods for estimation and inference with varying degrees of robustness to model assumptions are studied. Semiparametric efficient estimation and inference procedures are also considered. The estimation methods are compared in a simulation study and applied to the study of associations among genital tract bacterial counts in HIV infected women. PMID- 17688495 TI - A parallel phase I/II clinical trial design for combination therapies. AB - The use of multiple drugs in a single clinical trial or as a therapeutic strategy has become common, particularly in the treatment of cancer. Because traditional trials are designed to evaluate one agent at a time, the evaluation of therapies in combination requires specialized trial designs. In place of the traditional separate phase I and II trials, we propose using a parallel phase I/II clinical trial to evaluate simultaneously the safety and efficacy of combination dose levels, and select the optimal combination dose. The trial is started with an initial period of dose escalation, then patients are randomly assigned to admissible dose levels. These dose levels are compared with each other. Bayesian posterior probabilities are used in the randomization to adaptively assign more patients to doses with higher efficacy levels. Combination doses with lower efficacy are temporarily closed and those with intolerable toxicity are eliminated from the trial. The trial is stopped if the posterior probability for safety, efficacy, or futility crosses a prespecified boundary. For illustration, we apply the design to a combination chemotherapy trial for leukemia. We use simulation studies to assess the operating characteristics of the parallel phase I/II trial design, and compare it to a conventional design for a standard phase I and phase II trial. The simulations show that the proposed design saves sample size, has better power, and efficiently assigns more patients to doses with higher efficacy levels. PMID- 17688496 TI - Application of the principal stratification approach to the Faenza randomized experiment on breast self-examination. AB - In this article we present an extended framework based on the principal stratification approach (Frangakis and Rubin, 2002, Biometrics 58, 21-29), for the analysis of data from randomized experiments which suffer from treatment noncompliance, missing outcomes following treatment noncompliance, and "truncation by death." We are not aware of any previous work that addresses all these complications jointly. This framework is illustrated in the context of a randomized trial of breast self-examination. PMID- 17688497 TI - Demystifying optimal dynamic treatment regimes. AB - A dynamic regime is a function that takes treatment and covariate history and baseline covariates as inputs and returns a decision to be made. Murphy (2003, Journal of the Royal Statistical Society, Series B 65, 331-366) and Robins (2004, Proceedings of the Second Seattle Symposium on Biostatistics, 189-326) have proposed models and developed semiparametric methods for making inference about the optimal regime in a multi-interval trial that provide clear advantages over traditional parametric approaches. We show that Murphy's model is a special case of Robins's and that the methods are closely related but not equivalent. Interesting features of the methods are highlighted using the Multicenter AIDS Cohort Study and through simulation. PMID- 17688498 TI - Sensitivity analysis for m-estimates, tests, and confidence intervals in matched observational studies. AB - Huber's m-estimates use an estimating equation in which observations are permitted a controlled level of influence. The family of m-estimates includes least squares and maximum likelihood, but typical applications give extreme observations limited weight. Maritz proposed methods of exact and approximate permutation inference for m-tests, confidence intervals, and estimators, which can be derived from random assignment of paired subjects to treatment or control. In contrast, in observational studies, where treatments are not randomly assigned, subjects matched for observed covariates may differ in terms of unobserved covariates, so differing outcomes may not be treatment effects. In observational studies, a method of sensitivity analysis is developed for m-tests, m-intervals, and m-estimates: it shows the extent to which inferences would be altered by biases of various magnitudes due to nonrandom treatment assignment. The method is developed for both matched pairs, with one treated subject matched to one control, and for matched sets, with one treated subject matched to one or more controls. The method is illustrated using two studies: (i) a paired study of damage to DNA from exposure to chromium and nickel and (ii) a study with one or two matched controls comparing side effects of two drug regimes to treat tuberculosis. The approach yields sensitivity analyses for: (i) m-tests with Huber's weight function and other robust weight functions, (ii) the permutational t-test which uses the observations directly, and (iii) various other procedures such as the sign test, Noether's test, and the permutation distribution of the efficient score test for a location family of distributions. Permutation inference with covariance adjustment is briefly discussed. PMID- 17688499 TI - Accounting for variability in sample size estimation with applications to nonadherence and estimation of variance and effect size. AB - We consider sample size calculations for testing differences in means between two samples and allowing for different variances in the two groups. Typically, the power functions depend on the sample size and a set of parameters assumed known, and the sample size needed to obtain a prespecified power is calculated. Here, we account for two sources of variability: we allow the sample size in the power function to be a stochastic variable, and we consider estimating the parameters from preliminary data. An example of the first source of variability is nonadherence (noncompliance). We assume that the proportion of subjects who will adhere to their treatment regimen is not known before the study, but that the proportion is a stochastic variable with a known distribution. Under this assumption, we develop simple closed form sample size calculations based on asymptotic normality. The second source of variability is in parameter estimates that are estimated from prior data. For example, we account for variability in estimating the variance of the normal response from existing data which are assumed to have the same variance as the study for which we are calculating the sample size. We show that we can account for the variability of the variance estimate by simply using a slightly larger nominal power in the usual sample size calculation, which we call the calibrated power. We show that the calculation of the calibrated power depends only on the sample size of the existing data, and we give a table of calibrated power by sample size. Further, we consider the calculation of the sample size in the rarer situation where we account for the variability in estimating the standardized effect size from some existing data. This latter situation, as well as several of the previous ones, is motivated by sample size calculations for a Phase II trial of a malaria vaccine candidate. PMID- 17688500 TI - Confidence intervals and P-values for meta-analysis with publication bias. AB - We study publication bias in meta-analysis by supposing there is a population (y, sigma) of studies which give treatment effect estimates y approximately N(theta, sigma(2)). A selection function describes the probability that each study is selected for review. The overall estimate of theta depends on the studies selected, and hence on the (unknown) selection function. Our previous paper, Copas and Jackson (2004, Biometrics 60, 146-153), studied the maximum bias over all possible selection functions which satisfy the weak condition that large studies (small sigma) are as likely, or more likely, to be selected than small studies (large sigma). This led to a worst-case sensitivity analysis, controlling for the overall fraction of studies selected. However, no account was taken of the effect of selection on the uncertainty in estimation. This article extends the previous work by finding corresponding confidence intervals and P-values, and hence a new sensitivity analysis for publication bias. Two examples are discussed. PMID- 17688501 TI - Bayesian hierarchical modeling for time course microarray experiments. AB - Time course microarray experiments designed to characterize the dynamic regulation of gene expression in biological systems are becoming increasingly important. One critical issue that arises when examining time course microarray data is the identification of genes that show different temporal expression patterns among biological conditions. Here we propose a Bayesian hierarchical model to incorporate important experimental factors and to account for correlated gene expression measurements over time and over different genes. A new gene selection algorithm is also presented with the model to simultaneously identify genes that show changes in expression among biological conditions, in response to time and other experimental factors of interest. The algorithm performs well in terms of the false positive and false negative rates in simulation studies. The methodology is applied to a mouse model time course experiment to correlate temporal changes in azoxymethane-induced gene expression profiles with colorectal cancer susceptibility. PMID- 17688502 TI - Protein bioinformatics and mixtures of bivariate von Mises distributions for angular data. AB - A fundamental problem in bioinformatics is to characterize the secondary structure of a protein, which has traditionally been carried out by examining a scatterplot (Ramachandran plot) of the conformational angles. We examine two natural bivariate von Mises distributions--referred to as Sine and Cosine models- which have five parameters and, for concentrated data, tend to a bivariate normal distribution. These are analyzed and their main properties derived. Conditions on the parameters are established which result in bimodal behavior for the joint density and the marginal distribution, and we note an interesting situation in which the joint density is bimodal but the marginal distributions are unimodal. We carry out comparisons of the two models, and it is seen that the Cosine model may be preferred. Mixture distributions of the Cosine model are fitted to two representative protein datasets using the expectation maximization algorithm, which results in an objective partition of the scatterplot into a number of components. Our results are consistent with empirical observations; new insights are discussed. PMID- 17688503 TI - An empirical Bayes method for estimating epistatic effects of quantitative trait loci. AB - The genetic variance of a quantitative trait is often controlled by the segregation of multiple interacting loci. Linear model regression analysis is usually applied to estimating and testing effects of these quantitative trait loci (QTL). Including all the main effects and the effects of interaction (epistatic effects), the dimension of the linear model can be extremely high. Variable selection via stepwise regression or stochastic search variable selection (SSVS) is the common procedure for epistatic effect QTL analysis. These methods are computationally intensive, yet they may not be optimal. The LASSO (least absolute shrinkage and selection operator) method is computationally more efficient than the above methods. As a result, it has been widely used in regression analysis for large models. However, LASSO has never been applied to genetic mapping for epistatic QTL, where the number of model effects is typically many times larger than the sample size. In this study, we developed an empirical Bayes method (E-BAYES) to map epistatic QTL under the mixed model framework. We also tested the feasibility of using LASSO to estimate epistatic effects, examined the fully Bayesian SSVS, and reevaluated the penalized likelihood (PENAL) methods in mapping epistatic QTL. Simulation studies showed that all the above methods performed satisfactorily well. However, E-BAYES appears to outperform all other methods in terms of minimizing the mean-squared error (MSE) with relatively short computing time. Application of the new method to real data was demonstrated using a barley dataset. PMID- 17688504 TI - Statistical tests for clonality. AB - Cancer investigators frequently conduct studies to examine tumor samples from pairs of apparently independent primary tumors with a view to determine whether they share a "clonal" origin. The genetic fingerprints of the tumors are compared using a panel of markers, often representing loss of heterozygosity (LOH) at distinct genetic loci. In this article we evaluate candidate significance tests for this purpose. The relevant information is derived from the observed correlation of the tumors with respect to the occurrence of LOH at individual loci, a phenomenon that can be evaluated using Fisher's exact test. Information is also available from the extent to which losses at the same locus occur on the same parental allele. Data from these combined sources of information can be evaluated using a simple adaptation of Fisher's exact test. The test statistic is the total number of loci at which concordant mutations occur on the same parental allele, with higher values providing more evidence in favor of a clonal origin for the two tumors. The test is shown to have high power for detecting clonality for plausible models of the alternative (clonal) hypothesis, and for reasonable numbers of informative loci, preferably located on distinct chromosomal arms. The method is illustrated using studies to identify clonality in contralateral breast cancer. Interpretation of the results of these tests requires caution due to simplifying assumptions regarding the possible variability in mutation probabilities between loci, and possible imbalances in the mutation probabilities between parental alleles. Nonetheless, we conclude that the method represents a simple, powerful strategy for distinguishing independent tumors from those of clonal origin. PMID- 17688505 TI - MICE: multiple-peak identification, characterization, and estimation. AB - MICE--multiple-peak identification, characterization, and estimation--is a procedure for estimating a lower bound of the number of frequency peaks and for estimating the frequency peak parameters. The leading application is protein structure determination using nuclear magnetic resonance (NMR) experiments. NMR frequency data are multiple-peak data, where each frequency peak corresponds to two connected atoms in the three-dimensional protein structure. We analyze the NMR frequency data through a series of steps: a preliminary step for separating the signal from the background followed by identification of local maxima up to a noise-level-dependent threshold, estimation of the frequency peak parameters using an iterative algorithm, and detection of mixtures of peaks using hypothesis testing. PMID- 17688506 TI - Spatial cluster detection for censored outcome data. AB - While numerous methods have been proposed to test for spatial cluster detection, in particular for discrete outcome data (e.g., disease incidence), few have been available for continuous data that are subject to censoring. This article provides an extension of the spatial scan statistic (Kulldorff, 1997, Communications in Statistics 26, 1481-1496) for censored outcome data and further proposes a simple spatial cluster detection method by utilizing cumulative martingale residuals within the framework of the Cox's proportional hazards models. Simulations have indicated good performance of the proposed methods, with the practical applicability illustrated by an ongoing epidemiology study which investigates the relationship of environmental exposures to asthma, allergic rhinitis/hayfever, and eczema. PMID- 17688507 TI - Second-order analysis of inhomogeneous spatial point processes using case-control data. AB - Methods for the statistical analysis of stationary spatial point process data are now well established, methods for nonstationary processes less so. One of many sources of nonstationary point process data is a case-control study in environmental epidemiology. In that context, the data consist of a realization of each of two spatial point processes representing the locations, within a specified geographical region, of individual cases of a disease and of controls drawn at random from the population at risk. In this article, we extend work by Baddeley, Moller, and Waagepetersen (2000, Statistica Neerlandica54, 329-350) concerning estimation of the second-order properties of a nonstationary spatial point process. First, we show how case-control data can be used to overcome the problems encountered when using the same data to estimate both a spatially varying intensity and second-order properties. Second, we propose a semiparametric method for adjusting the estimate of intensity so as to take account of explanatory variables attached to the cases and controls. Our primary focus is estimation, but we also propose a new test for spatial clustering that we show to be competitive with existing tests. We describe an application to an ecological study in which juvenile and surviving adult trees assume the roles of controls and cases. PMID- 17688508 TI - Hierarchical spatiotemporal matrix models for characterizing invasions. AB - The growth and dispersal of biotic organisms is an important subject in ecology. Ecologists are able to accurately describe survival and fecundity in plant and animal populations and have developed quantitative approaches to study the dynamics of dispersal and population size. Of particular interest are the dynamics of invasive species. Such nonindigenous animals and plants can levy significant impacts on native biotic communities. Effective models for relative abundance have been developed; however, a better understanding of the dynamics of actual population size (as opposed to relative abundance) in an invasion would be beneficial to all branches of ecology. In this article, we adopt a hierarchical Bayesian framework for modeling the invasion of such species while addressing the discrete nature of the data and uncertainty associated with the probability of detection. The nonlinear dynamics between discrete time points are intuitively modeled through an embedded deterministic population model with density-dependent growth and dispersal components. Additionally, we illustrate the importance of accommodating spatially varying dispersal rates. The method is applied to the specific case of the Eurasian Collared-Dove, an invasive species at mid-invasion in the United States at the time of this writing. PMID- 17688509 TI - A class of latent Markov models for capture-recapture data allowing for time, heterogeneity, and behavior effects. AB - We propose an extension of the latent class model for the analysis of capture recapture data which allows us to take into account the effect of a capture on the behavior of a subject with respect to future captures. The approach is based on the assumption that the variable indexing the latent class of a subject follows a Markov chain with transition probabilities depending on the previous capture history. Several constraints are allowed on these transition probabilities and on the parameters of the conditional distribution of the capture configuration given the latent process. We also allow for the presence of discrete explanatory variables, which may affect the parameters of the latent process. To estimate the resulting models, we rely on the conditional maximum likelihood approach and for this aim we outline an EM algorithm. We also give some simple rules for point and interval estimation of the population size. The approach is illustrated by applying it to two data sets concerning small mammal populations. PMID- 17688510 TI - Models for circular-linear and circular-circular data constructed from circular distributions based on nonnegative trigonometric sums. AB - Johnson and Wehrly (1978, Journal of the American Statistical Association 73, 602 606) and Wehrly and Johnson (1980, Biometrika 67, 255-256) show one way to construct the joint distribution of a circular and a linear random variable, or the joint distribution of a pair of circular random variables from their marginal distributions and the density of a circular random variable, which in this article is referred to as joining circular density. To construct flexible models, it is necessary that the joining circular density be able to present multimodality and/or skewness in order to model different dependence patterns. Fernandez-Duran (2004, Biometrics 60, 499-503) constructed circular distributions based on nonnegative trigonometric sums that can present multimodality and/or skewness. Furthermore, they can be conveniently used as a model for circular linear or circular-circular joint distributions. In the current work, joint distributions for circular-linear and circular-circular data constructed from circular distributions based on nonnegative trigonometric sums are presented and applied to two data sets, one for circular-linear data related to the air pollution patterns in Mexico City and the other for circular-circular data related to the pair of dihedral angles between consecutive amino acids in a protein. PMID- 17688511 TI - Boosted regression trees with errors in variables. AB - In this article, we consider nonparametric regression when covariates are measured with error. Estimation is performed using boosted regression trees, with the sum of the trees forming the estimate of the conditional expectation of the response. Both binary and continuous response regression are investigated. An approach to fitting regression trees when covariates are measured with error is described, and the boosting algorithms consist of its repeated application. The main feature of the approach is that it handles situations where multiple covariates are measured with error. Some simulation results are given as well as its application to data from the Framingham Heart Study. PMID- 17688512 TI - Random effects modeling approaches for estimating ROC curves from repeated ordinal tests without a gold standard. AB - Estimating diagnostic accuracy without a gold standard is an important problem in medical testing. Although there is a fairly large literature on this problem for the case of repeated binary tests, there is substantially less work for the case of ordinal tests. A noted exception is the work by Zhou, Castelluccio, and Zhou (2005, Biometrics 61, 600-609), which proposed a methodology for estimating receiver operating characteristic (ROC) curves without a gold standard from multiple ordinal tests. A key assumption in their work was that the test results are independent conditional on the true test result. I propose random effects modeling approaches that incorporate dependence between the ordinal tests, and I show through asymptotic results and simulations the importance of correctly accounting for the dependence between tests. These modeling approaches, along with the importance of accounting for the dependence between tests, are illustrated by analyzing the uterine cancer pathology data analyzed by Zhou et al. (2005). PMID- 17688513 TI - ROC graphs for assessing the ability of a diagnostic marker to detect three disease classes with an umbrella ordering. AB - Receiver operating characteristic (ROC) curves and the area under these curves are commonly used to assess the ability of a continuous diagnostic marker (e.g., DNA methylation markers) to correctly classify subjects as having a particular disease or not (e.g., cancer). These approaches, however, are not applicable to settings where the gold standard yields more than two disease states or classes. ROC surfaces and the volume under the surfaces have been proposed for settings with more than two disease classes. These approaches, however, do not allow one to assess the ability of a marker to differentiate two disease classes from a third disease class without requiring a monotone order for the three disease classes under study. That is, existing approaches do not accommodate an umbrella ordering of disease classes. This article proposes the construction of an ROC graph that is applicable for an umbrella ordering. Furthermore, this article proposes that a summary measure for this umbrella ROC graph can be used to summarize the classification accuracy, and corresponding variance estimates can be obtained using U-statistics theory or bootstrap methods. The proposed methods are illustrated using data from a study assessing the ability of a DNA methylation marker to correctly classify lung specimens into three histologic classes: squamous cell carcinoma, large cell carcinoma, and nontumor lung. PMID- 17688514 TI - On models for binomial data with random numbers of trials. AB - A binomial outcome is a count s of the number of successes out of the total number of independent trials n=s+f, where f is a count of the failures. The n are random variables not fixed by design in many studies. Joint modeling of (s, f) can provide additional insight into the science and into the probability pi of success that cannot be directly incorporated by the logistic regression model. Observations where n= 0 are excluded from the binomial analysis yet may be important to understanding how pi is influenced by covariates. Correlation between s and f may exist and be of direct interest. We propose Bayesian multivariate Poisson models for the bivariate response (s, f), correlated through random effects. We extend our models to the analysis of longitudinal and multivariate longitudinal binomial outcomes. Our methodology was motivated by two disparate examples, one from teratology and one from an HIV tertiary intervention study. PMID- 17688515 TI - A note on simplifying likelihoods for site occupancy models. AB - We show how a simple reparameterization can reduce the number of parameters that need to be estimated by numerical maximum likelihood in site occupancy models. Three examples are provided. PMID- 17688531 TI - Evolution in human-altered environments: a summit to translate science into policy. PMID- 17688532 TI - The tails of two geckos tell the story of dispersal in a fragmented landscape. AB - The fragmentation of habitat is a major cause of biodiversity loss. However, while numerous studies have suggested that reducing the size of populations and isolating them on fragments leads ultimately to the extinction of a species (small isolated populations are extinction prone), the evidence has been rather conjectural. This is because dispersal is so difficult to measure and isolation difficult to confirm. In past studies, evidence that populations become small and isolated on fragments, leading to declines, has relied on spatial patterns of distribution and abundance. Thus, a species not trapped in the matrix in which fragments are embedded might be assumed isolated on fragments, and if low in abundance on fragments compared to continuous habitat is assumed to have declined on fragments due to this isolation. However, without accurately measuring the degree of isolation, it is difficult to distinguish the role of isolation from other important causes of population decline that are correlated with fragment and population size, such as habitat degradation. Developments in molecular techniques and statistical methods now make it possible to measure isolation. Refreshingly, in this issue Hoehn et al. analyse microsatellite DNA with a suite of statistical methods to show convincingly that a declining species of gecko suffers from greater isolation on habitat fragments than a contrasting gecko that is able to disperse between fragments and hence persist in the severely fragmented wheatbelt of Western Australia. PMID- 17688533 TI - The temporal development in a hybridizing population of wild and cultivated chicory (Cichorium intybus L.). AB - Hybridization and its possible impacts is a subject of increased attention in connection with the risk of unintended gene flow from cultivated (including genetically modified) plants to wild relatives. Whether such gene flow by hybridization is likely to take place depends among other things on the persistence of the hybrids in a natural environment over time. To evaluate this, we studied an experimental hybridizing population of wild and cultivated chicories (Cichorium intybus) relative to a previous study on the same population 2 years earlier. We compared the genetic composition, morphology and fitness traits of plants from 2004 to the plants in the same plot in 2002. The majority of the plants in 2004 was more morphologically and genetically intermediate than in 2002. This indicates that no selection towards being wild-like or cultivar like was present over the period of 2 years. Furthermore, no distinct fitness differences existed between the plants of 2004, probably due to most of the plants being intermediate. No hybridization barriers appeared to be present between wild and cultivated chicories beyond the F1 generation, since F2 hybrids and backcrosses were in abundance; in fact, hybrids of probably fourth or fifth generation were present. In conclusion, all results indicate that no barriers exist to the temporal persistence of chicory hybrids in a natural environment. PMID- 17688534 TI - The tales of two geckos: does dispersal prevent extinction in recently fragmented populations? AB - Although habitat loss and fragmentation threaten species throughout the world and are a major threat to biodiversity, it is apparent that some species are at greater risk of extinction in fragmented landscapes than others. Identification of these species and the characteristics that make them sensitive to habitat fragmentation has important implications for conservation management. Here, we present a comparative study of the population genetic structure of two arboreal gecko species (Oedura reticulata and Gehyra variegata) in fragmented and continuous woodlands. The species differ in their level of persistence in remnant vegetation patches (the former exhibiting a higher extinction rate than the latter). Previous demographic and modelling studies of these two species have suggested that their difference in persistence levels may be due, in part, to differences in dispersal abilities with G. variegata expected to have higher dispersal rates than O. reticulata. We tested this hypothesis and genotyped a total of 345 O. reticulata from 12 sites and 353 G. variegata from 13 sites at nine microsatellite loci. We showed that O. reticulata exhibits elevated levels of structure (FST=0.102 vs. 0.044), lower levels of genetic diversity (HE=0.79 vs. 0.88), and fewer misassignments (20% vs. 30%) than similarly fragmented populations of G. variegata, while all these parameters were fairly similar for the two species in the continuous forest populations (FST=0.003 vs. 0.004, HE=0.89 vs. 0.89, misassignments: 58% vs. 53%, respectively). For both species, genetic structure was higher and genetic diversity was lower among fragmented populations than among those in the nature reserves. In addition, assignment tests and spatial autocorrelation revealed that small distances of about 500 m through fragmented landscapes are a barrier to O. reticulata but not for G. variegata. These data support our hypothesis that G. variegata disperse more readily and more frequently than O. reticulata and that dispersal and habitat specialization are critical factors in the persistence of species in habitat remnants. PMID- 17688535 TI - Delimiting species boundaries and the conservation genetics of the endangered maritime ringlet butterfly (Coenonympha nipisiquit McDunnough). AB - Species delimitation is a difficult problem that has implications across organismal biology, yet no single method has proved wholly satisfactory. We tested the utility of combining species-delimitation methods based on phylogeny and gene flow statistics using two parapatric members of the Coenonympha tullia group as an example: the endangered maritime ringlet butterfly (Coenonympha nipisiquit McDunnough) and the common inornate ringlet butterfly (Coenonympha inornata Edwards). We reconstructed the phylogeny of the nearctic C. tullia-group taxa from mitochondrial DNA (mtDNA) sequences (cytochrome oxidase I and mitochondrial control region) to explore the ancestry of the C. nipisiquit lineage within the group. We investigated the extent of gene flow between the two taxa with F-statistics using 587 nuclear amplified fragment length polymorphism markers, accounting for the effect of potential scoring 'collisions' where a marker may represent more than one DNA fragment. Combining species-delimitation methods was especially effective because it uncovered both historical and recent evolutionary patterns. Phylogenetic analysis of mtDNA revealed the early divergence of C. nipisiquit from other C. tullia-group taxa, including the morphologically similar C. inornata. F-statistics and gene-by-gene introgression profiles demonstrated clear isolation between the two taxa and revealed strong population structure within C. nipisiquit. C. nipisiquit is the first taxon in the nearctic C. tullia group showing strong evidence of genetic isolation. The methods we used are relatively inexpensive and can be widely used to delimit taxonomic boundaries near the species level, both generally and in particular for taxa that may be targets of conservation efforts. PMID- 17688536 TI - Population genetics of the wood-decay fungus Phlebia centrifuga P. Karst. in fragmented and continuous habitats. AB - The basidiomycete Phlebia centrifuga is a wood-decay fungus characteristic for unmanaged old-growth forests of spruce, a habitat that has become increasingly fragmented due to forest management. The aim of this study was to investigate the genetic population structures of P. centrifuga in both continuous and fragmented habitats, and estimate the potential impact of fragmentation on the genetic diversity of the fungus. Three hundred fifteen single spore isolates (representing 47 spore families and 33 single isolates) from eight populations across northern Europe (Russia, Finland, and Sweden) were screened with seven microsatellite markers and arbitrary primed polymerase chain reaction with the M13 minisatellite. The two molecular methods generally gave the same pattern for the genetic population structure. There were no significant differences between the observed and the expected heterozygosities, and the inbreeding coefficient (FIS) did not indicate any inbreeding. The fixation index (FST) revealed a general pattern with little to moderate genetic differentiation for the majority of populations, while the southernmost Swedish population Norra Kvill was the only one showing high differentiation from about half of the other populations. Swedish population Fiby with the shortest distance to the continuous habitat was moderately differentiated from most of the others and to the largest extent differed from geographically closest population of Norra Kvill. The results indicate that the fragmentation of old-growth forest in Russia and Finland is more recent than the fragmentation in Sweden, and the genetic population structures of P. centrifuga in northern Europe might be related to differences in forest landscape dynamics between the two areas. PMID- 17688537 TI - Phylogeography and population structure of the Yunnan snub-nosed monkey (Rhinopithecus bieti) inferred from mitochondrial control region DNA sequence analysis. AB - Rhinopithecus bieti, the Yunnan snub-nosed monkey, is the nonhuman primate with the highest altitudinal distribution and is also one of the 25 most globally endangered primate species. Currently, R. bieti is found in forests between 3000 and 4500 m above sea level, within a narrow area on the Tibetan Plateau between the Yangtze and Mekong rivers, where it is suffering from loss of habitat and shrinking population size (approximately 1500). To assess the genetic diversity within this species, its population structure and to infer its evolutionary history, we sequenced 401 bp of the hypervariable I (HVI) segment from the mitochondrial DNA control region (CR) for 157 individuals from 11 remnant patches throughout the fragmented distribution area. Fifty-two variable sites were observed and 30 haplotypes were defined. Compared with other primate species, R. bieti cannot be regarded as a taxon with low genetic diversity. Phylogenetic analysis partitioned haplotypes into two divergent haplogroups (A and B). Haplotypes from the two mitochondrial clades were found to be mixed in some patches although the distribution of haplotypes displayed local homogeneity, implying a strong population structure within R. bieti. Analysis of molecular variance detected significant differences among the different geographical regions, suggesting that R. bieti should be separated into three management units (MUs) for conservation. Based on our results, it can be hypothesized that the genetic history of R. bieti includes an initial, presumably allopatric divergence between clades A and B 1.0-0.7 million years ago (Ma), which might have been caused by the Late Cenozoic uplift of the Tibetan Plateau, secondary contact after this divergence as a result of a population expansion 0.16-0.05 Ma, and population reduction and habitat fragmentation in the very recent past. PMID- 17688538 TI - Asian origin and rapid global spread of the destructive dry rot fungus Serpula lacrymans. AB - The dry rot fungus Serpula lacrymans (Basidiomycota) is the most damaging destroyer of wood construction materials in temperate regions. While being a widespread aggressive indoor biodeterioration agent, it is only found in a few natural environments. The geographical source of spread and colonization by this fungus in human environments is thus somewhat of an enigma. Employing genetic markers (amplified fragment length polymorphisms, DNA sequences and microsatellites) on a worldwide sample of specimens, we show that the dry rot fungus is divided into two main lineages; one nonaggressive residing naturally in North America and Asia (var. shastensis), and another aggressive lineage including specimens from all continents, both from natural environments and buildings (var. lacrymans). Our genetic analyses indicate that the two lineages represent well-differentiated cryptic species. Genetic analyses pinpoint mainland Asia as the origin of the aggressive form var. lacrymans. A few aggressive genotypes have migrated worldwide from Asia to Europe, North and South America and Oceania followed by local population expansions. The very low genetic variation in the founder populations indicate that they have established through recent founder events, for example by infected wood materials transported over land or sea. A separate colonization has happened from mainland Asia to Japan. Our data also indicate that independent immigration events have happened to Oceania from different continents followed by admixture. PMID- 17688540 TI - Delimiting cohesion species: extreme population structuring and the role of ecological interchangeability. AB - Species exhibiting morphological homogeneity and strong population structuring present challenging taxonomic problems: morphology-based approaches infer few species, whereas genetic approaches often indicate more. Morphologically cryptic, yet genetically divergent species groups require alternative approaches to delimiting species that assess adaptive divergence and ecological interchangeability of lineages. We apply such an approach to Promyrmekiaphila, a small genus (three nominal taxa) of trapdoor spiders endemic to northern California to define cohesion species (lineages that are genetically exchangeable and ecologically interchangeable). Genetic exchangeability is evaluated using standard phylogeographical techniques (e.g. nested clade analysis); ecological interchangeability is assessed using two GIS-based approaches. First, climatic values are extracted from layer data for each locality point and utilized in a principal components analysis followed by MANOVA. Second, niche-based distribution models of genetically divergent lineages are created using a maximum entropy modelling approach; the amount of overlap among lineages is calculated and evaluated against a probability distribution of null overlap. Lineages that have significant amounts of predicted overlap are considered ecologically interchangeable. Based on a synthetic evaluation of ecological interchangeability, geographical concordance, and morphological differentiation, we conclude that Promyrmekiaphila comprises six cohesion species, five of which are cryptic (i.e. undetectable by conventional means). PMID- 17688539 TI - Comparative phylogeography of Trypanosoma rangeli and Rhodnius (Hemiptera: Reduviidae) supports a long coexistence of parasite lineages and their sympatric vectors. AB - To make reliable interpretations about evolutionary relationships between Trypanosoma rangeli lineages and their insect vectors (triatomine bugs of the genus Rhodnius) and, thus, about the determinant factors of lineage segregation within T. rangeli, we compared phylogenies of parasite isolates and vector species. Sixty-one T. rangeli isolates from invertebrate and vertebrate hosts were initially evaluated in terms of polymorphism of the spliced-leader gene (SL). Further analysis based on SL and SSUrRNA sequences from 33 selected isolates, representative of the overall phylogenetic diversity and geographical range of T. rangeli, supported four phylogenetic lineages within this species. By comparing the phylogeny of Rhodnius species with that inferred for T. rangeli isolates and through analysis of the geographical range of the isolates, we showed that there is a very significant overlap in the distribution of Rhodnius species and T. rangeli lineages. Congruence between phylogeographical analysis of both T. rangeli lineages and complexes of Rhodnius species are consistent with the hypothesis of a long coexistence of parasites and their vectors, with lineage divergence associated with sympatric species of Rhodnius apparently without association with particular vertebrate hosts. Separation of T. rangeli isolates from vectors of distinct complexes living in sympatry favours the absence of gene flow between the lineages and suggests evolution of T. rangeli lineages in independent transmission cycles, probably associated to specific Rhodnius spp. ecotopes. A polymerase chain reaction assay based on SL intergenic sequences was developed for simultaneous identification and lineage genotyping of T. rangeli in epidemiological surveys. PMID- 17688541 TI - Phylogeography of a northeast Asian spruce, Picea jezoensis, inferred from genetic variation observed in organelle DNA markers. AB - Range-wide genetic variation of the widespread cold-temperate spruce Picea jezoensis was studied throughout northeast Asia using maternally inherited mitochondrial DNA and paternally inherited chloroplast DNA markers. This study assessed 33 natural populations including three varieties of the species in Japan, Russia, China, and South Korea. We depicted sharp suture zones in straits around Japan in the geographical distribution pattern of mitochondrial haplotypes (GST=0.901; NST=0.934). In contrast, we detected possible extensive pollen flow without seed flow across the straits around Japan during the past population history in the distribution pattern of chloroplast haplotypes (GST=0.233; NST=0.333). The analysis of isolation by distance of the species implied that by acting as a barrier for the movement of seeds and pollen, the sharp suture zones contributed considerably to the level of genetic differentiation between populations. Constructed networks of mitochondrial haplotypes allowed inference of the phylogeographical history of the species. We deduced that the disjunction with Kamchatka populations reflects range expansion and contraction to the north of the current distribution. Within Japan, we detected phylogeographically different types of P. jezoensis between Hokkaido and Honshu islands; P. jezoensis in Honshu Island may have colonized this region from the Asian continent via the Korean peninsula and the species in Hokkaido Island is likely to have spread from the Asian continent via Sakhalin through land bridges. Japanese endemism of mitochondrial haplotypes in Hokkaido and Honshu islands might have been promoted by separation of these islands from each other and from the Asian continent by the straits during the late Quaternary. PMID- 17688542 TI - Phylogeography of the olive sea snake, Aipysurus laevis (Hydrophiinae) indicates Pleistocene range expansion around northern Australia but low contemporary gene flow. AB - Pleistocene sea-level fluctuations profoundly changed landmass configurations around northern Australia. The cyclic emergence of the Torres Strait land bridge and concomitant shifts in the distribution of shallow-water marine habitats repeatedly sundered east and west coast populations. These biogeographical perturbations invoke three possible scenarios regarding the directions of interglacial range expansion: west to east, east to west, or bidirectional. We evaluated these scenarios for the olive sea snake, Aipysurus laevis, by exploring its genetic structure around northern Australia based on 354 individuals from 14 locations in three regions (Western Australia, WA; Gulf of Carpentaria, GoC; Great Barrier Reef, GBR). A 726-bp fragment of the mitochondrial DNA ND4 region revealed 41 variable sites and 38 haplotypes, with no shared haplotypes among the three regions. Population genetic structure was strong overall, phiST=0.78, P<0.001, and coalescent analyses revealed no migration between regions. Genetic diversity was low in the GBR and GoC and the genetic signatures of these regions indicated range or population expansions consistent with their recent marine transgressions around 7000 years ago. By contrast, genetic diversity on most WA reefs was higher and there were no signals of recent expansion events on these reefs. Phylogenetic analyses indicated that GBR and GoC haplotypes were derived from WA haplotypes; however, statistical parsimony suggested that recent range expansion in the GBR-GoC probably occurred from east coast populations, possibly in the Coral Sea. Levels of contemporary female-mediated gene flow varied within regions and reflected potential connectivity among populations afforded by the different regional habitat types. PMID- 17688543 TI - Contrasting patterns of mitochondrial and microsatellite genetic structure among Western European populations of tawny owls (Strix aluco). AB - A recent study of mitochondrial phylogeography of tawny owls (Strix aluco) in western Europe suggested that this species survived the Pleistocene glaciations in three allopatric refugia located in Iberia, Italy, and the Balkans, and the latter was likely the predominant source of postglacial colonization of northern Europe. New data from seven microsatellite loci from 184 individual owls distributed among 14 populations were used to assess the genetic congruence between nuclear and mitochondrial DNA (mtDNA) markers. Microsatellites corroborated the major phylogeographical conclusions reached on the basis of the mtDNA sequences, but also showed important differences leading to novel inferences. Microsatellites corroborated the three major refugia and supported the Balkan origin of northern populations. When corrected for differences in effective population size, microsatellites and mtDNA yielded generally congruent overall estimates of population structure (N*ST=0.12 vs. RST=0.16); however, there was substantial heterogeneity in the RST among the seven nuclear loci that was not correlated with heterozygosity. Populations representing the Balkans postglacial expansion interact with populations from the other two refugia forming two clines near the Alps and the Pyrenees. In both cases, the apparent position of the contact zones differed substantially between markers due to the genetic composition of populations sampled in northern Italy and Madrid. Microsatellite data did not corroborate the lower genetic diversity of northern, recently populated regions as was found with mtDNA; this discrepancy was taken as evidence for a recent bottleneck recovery. Finally, this study suggests that congruence among genetic markers should be more likely in cases of range expansion into new areas than when populations interact across contact zones. PMID- 17688544 TI - Mediterranean populations of the lesser white-toothed shrew (Crocidura suaveolens group): an unexpected puzzle of Pleistocene survivors and prehistoric introductions. AB - An earlier study revealed the strong phylogeographical structure of the lesser white-toothed shrew (Crocidura suaveolens group) within the northern Palaearctic. Here, we aim to reconstruct the colonization history of Mediterranean islands and to clarify the biogeography and phylogeographical relationships of the poorly documented Middle East region with the northern Palaearctic. We performed analyses on 998-bp-long haplotypes of the mitochondrial cytochrome b gene of 143 samples collected around the Mediterranean basin, including islands and the Middle East. The analyses suggest that the Cypriot shrew belongs to the rare group of relict insular Pleistocene mammal taxa that have survived to the present day. In contrast, the Cretan, Corsican and Menorcan populations were independently introduced from the Middle East during the Holocene. The phylogeographical structure of this temperate Palaearctic species within the Middle East appears to be complex and rich in diversity, probably reflecting fragmentation of the area by numerous mountain chains. Four deeply divergent clades of the C. suaveolens group occur in the area, meaning that a hypothetical contact zone remains to be located in central western Iran. PMID- 17688545 TI - Phylogeographical structure in the subterranean tuco-tuco Ctenomys talarum (Rodentia: Ctenomyidae): contrasting the demographic consequences of regional and habitat-specific histories. AB - In this work we examined the phylogeography of the South American subterranean herbivorous rodent Ctenomys talarum (Talas tuco-tuco) using mitochondrial DNA (mtDNA) control region (D-loop) sequences, and we assessed the geographical genetic structure of this species in comparison with that of subterranean Ctenomys australis, which we have shown previously to be parapatric to C. talarum and to also live in a coastal sand dune habitat. A significant apportionment of the genetic variance among regional groups indicated that putative geographical barriers, such as rivers, substantially affected the pattern of genetic structure in C. talarum. Furthermore, genetic differentiation is consistent with a simple model of isolation by distance, possibly evidencing equilibrium between gene flow and local genetic drift. In contrast, C. australis showed limited hierarchical partitioning of genetic variation and departed from an isolation-by-distance pattern. Mismatch distributions and tests of neutrality suggest contrasting histories of these two species: C. talarum appears to be characterized by demographic stability and no significant departures from neutrality, whereas C. australis has undergone a recent demographic expansion and/or departures from strict neutrality in its mtDNA. PMID- 17688546 TI - Historical and ecological determinants of genetic structure in arctic canids. AB - Wolves (Canis lupus) and arctic foxes (Alopex lagopus) are the only canid species found throughout the mainland tundra and arctic islands of North America. Contrasting evolutionary histories, and the contemporary ecology of each species, have combined to produce their divergent population genetic characteristics. Arctic foxes are more variable than wolves, and both island and mainland fox populations possess similarly high microsatellite variation. These differences result from larger effective population sizes in arctic foxes, and the fact that, unlike wolves, foxes were not isolated in discrete refugia during the Pleistocene. Despite the large physical distances and distinct ecotypes represented, a single, panmictic population of arctic foxes was found which spans the Svalbard Archipelago and the North American range of the species. This pattern likely reflects both the absence of historical population bottlenecks and current, high levels of gene flow following frequent long-distance foraging movements. In contrast, genetic structure in wolves correlates strongly to transitions in habitat type, and is probably determined by natal habitat-biased dispersal. Nonrandom dispersal may be cued by relative levels of vegetation cover between tundra and forest habitats, but especially by wolf prey specialization on ungulate species of familiar type and behaviour (sedentary or migratory). Results presented here suggest that, through its influence on sea ice, vegetation, prey dynamics and distribution, continued arctic climate change may have effects as dramatic as those of the Pleistocene on the genetic structure of arctic canid species. PMID- 17688547 TI - High quantitative and no molecular differentiation of a freshwater snail (Galba truncatula) between temporary and permanent water habitats. AB - We investigate the variation in quantitative and molecular traits in the freshwater snail Galba truncatula, from permanent and temporary water habitats. Using a common garden experiment, we measured 20 quantitative traits and molecular variation using seven microsatellites in 17 populations belonging to these two habitats. We estimated trait means in each habitat. We also estimated the distributions of overall genetic quantitative variation (QST), and of molecular variation (FST), within and between habitats. Overall, we observed a lack of association between molecular and quantitative variance. Among habitats, we found QST>FST, an indication of selection for different optima. Individuals from temporary water habitat matured older, at a larger size and were less fecund than individuals from permanent water habitat. We discuss these findings in the light of several theories for life-history traits evolution. PMID- 17688548 TI - Population genetics of Plasmodium resistance genes in Anopheles gambiae: no evidence for strong selection. AB - Anopheles mosquitoes are the primary vectors for malaria in Africa, transmitting the disease to more than 100 million people annually. Recent functional studies have revealed mosquito genes that are crucial for Plasmodium development, but there is presently little understanding of which genes mediate vector competence in the wild, or evolve in response to parasite-mediated selection. Here, we use population genetic approaches to study the strength and mode of natural selection on a suite of mosquito immune system genes, CTL4, CTLMA2, LRIM1, and APL2 (LRRD7), which have been shown to affect Plasmodium development in functional studies. We sampled these genes from two African populations of An. gambiae s.s., along with several closely related species, and conclude that there is no evidence for either strong directional or balancing selection on these genes. We highlight a number of challenges that need to be met in order to apply population genetic tests for selection in Anopheles mosquitoes; in particular the dearth of suitable outgroup species and the potential difficulties that arise when working within a closely-related species complex. PMID- 17688549 TI - Identity versus role confusion: who will we be tomorrow? PMID- 17688551 TI - Catchers in the rye: treatment foster parents as a system of care. AB - PROBLEM: Similar to the children in J. D. Salinger's novel, The Catcher in the Rye, youth in foster care face the specter of "going over the cliff." METHODS: The empirical basis for "treatment foster care" is reviewed, concluding that treatment foster care is both a clinically and cost-effective form of community based treatment. FINDINGS: Treatment foster parents prevent the fall of foster youth into the chasm of school failure, involvement with juvenile justice, and dependent living as adults. CONCLUSION: Treatment foster care is an evidence based approach that is less restrictive and offers troubled youth an opportunity to engage and grow within a family setting. PMID- 17688552 TI - Psychosocial care for adult and child survivors of the tsunami disaster in India. AB - OBJECTIVES: The tsunami disaster in South Asia affected the mental health and livelihoods of thousands of child and adult survivors, but psychological aspects of rehabilitation efforts are frequently neglected in public health initiatives. METHODS: Professional teams from the National Institute of Mental Health and Neurosciences in Bangalore, India, traveled to the worst-affected areas in South India and implemented a mental health program of psychosocial care for child and adult survivors. This descriptive report is based on observations of child and adult survivors in Tamil Nadu State of India during January-March 2005. OBSERVATIONS: Symptoms of emotional distress were observed in child and adult survivors. A train-the-trainer community-based model was implemented for teachers and community-level workers to respond to the emotional needs of children and adults. CONCLUSION: In resource-poor settings with few trained mental health professionals, community workers were taught basic mental health interventions by teams of psychiatrists, nurses, and social workers. This train-the-trainer, community-based approach has implications for natural and man-made disasters in developed and developing countries. PMID- 17688553 TI - Looking for child psychiatric nursing--Vietnam 2005. AB - In Vietnam, child health services are primarily focused on nutritional and developmental concerns. Child mental health issues, including homelessness, adolescent suicide, and sex trafficking of children, are not currently governmental priorities. PMID- 17688554 TI - Conducting a children's divorce group: one approach. AB - The disruptive period around the time of the divorce can shatter a child's entire living milieu. An 8-week experiential children's group incorporating art and creative activities as well as a concurrent parent group is described. The aim of treatment was to bolster children's abilities to communicate with parents and other caretakers. Overall, participants were observed to effectively release painful affect, communicate more openly, and identify strengths in their family systems. Yalom's therapeutic group factors were incorporated into the treatment model. The research of Davies and Cummings related to children in the context of family therapy was also considered. Group leaders included advance practice registered nurses. Follow-up objective data collected from participants might provide further information about the efficacy of the interventions. PMID- 17688555 TI - Respiratory assessment in child and adolescent residential treatment settings: reducing restraint-associated risks. AB - TOPIC: Crisis situations of youth in treatment settings may require restraints. Restraints should only be used in situations where there is imminent danger to the child and when there is no alternative. They are meant to maintain the child's safety, but there is risk for respiratory compromise. PURPOSE: Nursing care of children in restraints must include respiratory assessment and, when indicated, immediate intervention to prevent disastrous outcomes. SOURCES: Review using PubMed and established texts confirms that clinical skills and knowledge is essential to child and adolescent psychiatric nursing. CONCLUSIONS: Clinical assessment and awareness of risks in physical restraints is essential for the safety and well-being of the child. PMID- 17688556 TI - What are the watchdogs for children planning for 2007? Part II. PMID- 17688557 TI - Risperidone approved for the treatment of serious behavioral problems in children with autism. PMID- 17688558 TI - The crisis of nurse migration in developing countries. PMID- 17688560 TI - Leading and managing professional development - improving patient care. PMID- 17688561 TI - Managing and leading the infection prevention initiative. AB - AIM: To review the national response to health care-associated infection and that of nurses in particular. BACKGROUND: Health care-associated infections have emerged as a significant threat to quality care and preventing it is now a national priority. EVALUATION: This paper considers the key government initiatives to address health care-associated infection. KEY ISSUES: The government has adopted a multifaceted approach to tackle this problem, the most crucial of which was to develop the evidence base to support practice. Now that is established, education and training have become the next priority. CONCLUSION: While health care-associated infection remains a government priority, trusts will find it difficult to meet the demands of the Code of Practice and fulfil other government priorities. IMPLICATIONS FOR NURSING MANAGEMENT: Managers need to be aware of the extent of the problem, its causes and the initiatives both nationally and locally to address the situation so that they can maintain support for these initiatives. PMID- 17688562 TI - Educating advanced midwife practitioners: a collaborative venture. AB - AIM: To describe the collaborative development of an MSc course preparing Ireland's first advanced midwife practitioners. BACKGROUND: Ireland has 55 advanced nurse practitioner posts, but, as yet, no advanced midwife practitioners. METHODS: A consultative, collaborative process involving 38 midwives across Ireland generated the philosophy, aims and content of the course. RESULTS: Participants stated that candidates should be committed to the conceptual uniqueness of midwifery; the advanced midwife practitioner role should be clearly defined and supported by the candidate's sponsors; programme content should emphasize normal midwifery, be practice led, and encourage reflective, evidence-based, women-centred care. CONCLUSION: The collaborative process used to develop this programme ensures that it will meet individual students' needs, thus enhancing the education of Ireland's first advanced midwife practitioners. IMPLICATIONS FOR MIDWIFERY MANAGEMENT: The emphasis on normality rather than specialization is a message that could be assimilated by managers in other countries to the benefit of childbearing women across the world. PMID- 17688563 TI - Helping or hindering: the role of nurse managers in the transfer of practice development learning. AB - AIM: This paper reports selected findings from a recent PhD study exploring how graduates from a BSc Specialist Nursing programme, with an NMC-approved Specialist Practitioner Qualification, engage in practice development during their subsequent careers. BACKGROUND: The UKCC (1998) defines specialist practice as requiring higher levels of judgement, discretion and decision-making, with leadership in clinical practice development forming a core dimension of this level of practice. However, there is little evidence in the published literature that describes or evaluates the practice development role of graduate specialist practitioners. METHODS: This study applied a modified Glaserian approach to grounded theory methods. A preliminary descriptive survey questionnaire was posted to all graduates from the programme, response rate of 45% (n=102). From these respondents, theoretical sampling decisions directed the selection of 20 participants for interview, permitting data saturation. RESULTS: The grounded theory generated by this study discovered a basic social process labelled 'making a difference', whereby graduate specialist practitioners are increasingly able to impact in developing patient care at a strategic level by coming to own the identity of an expert practitioner (Currie, 2006). Contextual factors strongly influence the practitioner journey, with organizational position and other people presenting enabling or blocking conditions. IMPLICATIONS FOR NURSING MANAGEMENT: The line manager plays a crucial role in helping or hindering graduate specialist practitioners to transfer their learning to the clinical setting and become active in practice development. Recommendations to enhance managerial support for the practice development role of graduate specialist practitioners are proposed. ADDING TO CURRENT KNOWLEDGE: This work adds to currently limited knowledge of the graduate specialist practitioners' role in the leadership of clinical practice development. In addition, the findings emphasize the potential influence of the workplace environment by analyzing organizational factors in the specific context of the graduate specialist practitioner attempting to develop practice. PMID- 17688564 TI - The constancy of work-related empowerment. AB - OBJECTIVE: This study describes experiences of work empowerment among staff members at the Rheumatism Foundation Hospital in Helsinki, Finland. METHODS: The data were collected on two occasions in 2004 and 2005 using a structured questionnaire with background variables and items concerning verbal, behavioural and outcome empowerment. The questionnaires were sent to all (n1=115, n2=112) members of multidisciplinary teams at the Rheumatism Foundation Hospital, with the exception of physicians, departmental secretaries and administrative personnel. The response rate at both data collections was 58%. The data were analysed by statistical methods. RESULTS: No statistically significant differences were seen in work empowerment between the two data collections. Perceptions of work-related empowerment were relatively strong. CONCLUSIONS: Work related empowerment appears to be relatively constant and independent of changes in the organization. Indeed there is good reason to ask whether work empowerment is primarily a function of the individual employee's strengths and competencies. PMID- 17688565 TI - Effect of web-based assertion training for stress management of Japanese nurses. AB - AIM AND BACKGROUND: The purpose of this study was to examine the effects of web based assertion training programmes for Japanese hospital nurses based on their assertion knowledge, attitude and behaviour, job stress and depression. Job stress has been reported to be high among Japanese hospital nurses, and it is thought that assertion, one type of communication skill, could help nurses to better manage their job stress. METHOD: Twenty-five nurses from an urban tertiary hospital in western Japan completed the 70-minute assertion programme during 3 weeks. The changes between pretraining and post-training and between pretraining and 1 month after the training were tested. RESULT: Results showed that assertion knowledge and voluntary behaviour in assertive behaviour had increased at post training and remained higher a month later. With regard to job stress, mental workload decreased. CONCLUSION: The results show the effects of web-based assertion training on assertion skills and stress management for Japanese hospital nurses. PMID- 17688566 TI - Sexual harassment in the workplace: it is your problem. AB - AIM: Sexual harassment and hostile work environments are explored. Managerial roles are discussed, including taking a proactive approach and dealing appropriately with an employee's claim. BACKGROUND: Nurse managers must confront the issue of sexual harassment as complaints continue to develop throughout the industry. Because managers are responsible for employees' actions, it is essential that they familiarize themselves with what constitutes the act and how to handle a claim. EVALUATION: Sexual harassment is defined by US Civil Rights Acts (1964 and 1991), US Equal Employment Opportunity Commission, UK's Equal Opportunities Commission, American Nurses Association and the Royal College of Nursing. Frederick Herzberg's Two-Factor Theory of Motivation is also related to workplace sexual harassment. KEY ISSUES: Sexual harassment is a widespread problem within the industry, claiming both men and women as its victims. Managers can be held responsible for sexual harassment even if they are unaware of the existence of behaviour. PMID- 17688567 TI - The impact of ongoing continuing professional development for nurses in the Republic of Ireland. AB - AIM: The aim of this study was to explore and describe the stressors experienced by a group of 70 students who were undertaking a part-time degree in an Irish University. BACKGROUND: Within the literature on stress, part-time nursing students, who are undertaking continuing education programmes, appear to have received little attention. Stress amongst nurses is evident within the nursing literature but little information is available on the specific stressors that affect Registered Nurses who attend further academic study. Furthermore, there is little attention given to comparisons across faculty or between different institutions. METHOD: The authors used quantitative methods to gather a large amount of data on the topic. Data were collected using questionnaires distributed to two groups of students in a classroom setting. RESULTS: The top ranking stressor was 'preparing an assignment for submission'. Nursing students were predominantly exposed to stressors associated with assignment completion/submission and balancing work and family commitments. Differences emerged between the groups with regard to the intensity of perceived stressors in relation to academic portions of the programme and also finance. Nine major factors emerged from factor analysis that may form the basis for future studies in this area. Areas related to lectures, relationships with lecturers and the course process were not identified as stressors. CONCLUSION: The results of this study identified common student stressors across two universities, and confirmed the findings of an initial small exploratory study. The intensity of perceived stress is such that both educators and nurse managers need to be informed of both its magnitude and its possible impact upon clinical practice. In addition, additional student support structures are clearly required within the university setting particularly with regards to writing skills and assignment construction. PMID- 17688568 TI - Continuing professional development: investment or expectation? AB - AIM: The aim of this study was to explore the reason for nurses' participation in postregistration education. BACKGROUND: The study was located in one third level institution in Ireland and prospective candidates who applied to undertake a programme of studies were invited to complete the postal questionnaire and return it to the college anonymously in advance of commencing their studies. METHOD: A descriptive survey research design was adopted with the use of a questionnaire for data collection. The respondents had an opportunity to make additional comments in a questionnaire, which generated some qualitative data. RESULTS: A total of 243 questionnaires were returned which represented a 46.7% response rate. The major reasons for participating in postregistration education were 'to obtain promotion to a higher grade/position' (99%) and 'to enable me extend my clinical role' (98%). CONCLUSION: Investment in nursing education should take into account the reasons for participation in continuing education and professional development as identified in this study and in other studies so as to focus efforts that improve planning for long-term continuing education and professional development. The adoption of such a strategic approach by employers will ensure more precise targeting of scarce continuing education and professional development resources. Equally, expectation without adequate investment is not realistic if the profession wants to move forward in this era of rapid change in the delivery of health care. PMID- 17688569 TI - Impact of primary care management on nursing documentation. AB - AIM: The aim was to investigate whether perceptions of electronic nursing documentation and its performance differed because of primary health care management. BACKGROUND: Success in leading people depends on the manager's personality, the context and the people who are led. Close proximity to clinical work, with manager and personnel sharing the same profession, promotes the authority to carry out changes. METHODS: This study comprised a postal questionnaire to district nurses and an audit of nursing records from two primary health care organizations, one with a uniprofessional (nursing) organization, and one with multidisciplinary health care centres with general practitioners and/or another profession as managers. RESULTS: Uniprofessional nurse management increased district nurses' positive perceptions of nursing documentation but did not affect documentation performance, which was inadequate regardless of management type. CONCLUSIONS: Positive perceptions of nursing documentation are bases for further development to a nursing documentation including a holistic view of the patient. PMID- 17688570 TI - Should nurses be leaders of integrated health care? AB - AIM(S): To examine the role of nurses within integrated health care. BACKGROUND: Healthcare planners are overly concerned with the treatment of diseases and insufficiently focused on social cohesion vertical rather than horizontal integration of healthcare effort. These domains need to be better connected, to avoid medicalization of social problems and socialisation of medical problems. EVALUATION: Published literature, related to theories of whole system integration. *When conceptualizing whole system integration it helps to consider research insights to be snapshots of more complex stories-in-evolution, and change to be the result of ongoing community dance where multiple players adapt their steps to each other. *One image that helps to conceptualize integration is that of a railway network. Railway tracks and multiple journeys are equally needed; each requiring a different approach for success. *Traditional nursing values make nurses more attuned to the issues of combined vertical and horizontal integration than medical colleagues. CONCLUSION(S): Nurses should lead integration at the interface between horizontal and vertical activities. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing managers and universities should support the development of nurses as leaders of whole system integration, in partnership with local healthcare organizations. PMID- 17688571 TI - How commitment and involvement influence the development of strategic consensus in health care organizations: the multidisciplinary approach. AB - AIM: The aim of this study was to describe how clinician and non-clinician managers achieved consensus of strategy in hospitals. This was the first empirical study undertaken that investigated the impact of organizational commitment on the strategic involvement-strategic consensus relationship. BACKGROUND: Clinicians and non-clinician managers hold a pivotal role in health care management from the strategic perspective. The importance of multidisciplinary collaboration is recognized, yet how strategic consensus is achieved amongst health service managers, has not been previously researched. KEY ISSUES: The focus of the professional is often on local concerns rather on the broader organizational strategy. This orientation has led to the charge by health service management that clinicians are not interested in, or do not seek to be involved in strategy development. As half of the clinician group in this study were registered nurses and midwives it is important, for multidisciplinary and interdisciplinary collaboration and for strategic development that this group has an awareness of the importance of strategic involvement and organizational commitment in the attainment of strategic consensus. CONCLUSION: A descriptive study was undertaken and quantitative data were generated through the survey method. The aims of the study were articulated through hypotheses. Almost 400 middle manager heads of department, working in acute care not-for-profit health service organizations, in the Republic of Ireland, responded. Findings indicated that a stronger relationship existed between consensus and commitment than between involvement and commitment. In addition, when present in the organization, involvement and commitment together were better predictors of consensus than each of those factors on its own, but significantly commitment had a greater impact in predicting consensus than involvement had. PMID- 17688572 TI - Rate, causes and reporting of medication errors in Jordan: nurses' perspectives. AB - AIM: The aim of the study was to describe Jordanian nurses' perceptions about various issues related to medication errors. BACKGROUND: This is the first nursing study about medication errors in Jordan. METHODS: This was a descriptive study. A convenient sample of 799 nurses from 24 hospitals was obtained. Descriptive and inferential statistics were used for data analysis. RESULTS: Over the course of their nursing career, the average number of recalled committed medication errors per nurse was 2.2. Using incident reports, the rate of medication errors reported to nurse managers was 42.1%. Medication errors occurred mainly when medication labels/packaging were of poor quality or damaged. Nurses failed to report medication errors because they were afraid that they might be subjected to disciplinary actions or even lose their jobs. In the stepwise regression model, gender was the only predictor of medication errors in Jordan. CONCLUSIONS: Strategies to reduce or eliminate medication errors are required. PMID- 17688575 TI - Specifying self-recognition: peptides lead the way. PMID- 17688576 TI - Tobacco genomes quickly go up in smoke. PMID- 17688577 TI - Holy alliances? PMID- 17688578 TI - Predicting the impact of changing CO(2) on crop yields: some thoughts on food. AB - Recent breakthroughs in CO(2) fumigation methods using free-air CO(2) enrichment (FACE) technology have prompted comparisons between FACE experiments and enclosure studies with respect to quantification of the effects of projected atmospheric CO(2) concentrations on crop yields. On the basis of one such comparison, it was argued that model projections of future food supply (some of which are based on older enclosure data) may have significantly overestimated the positive effect of elevated CO(2) concentration on crop yields and, by extension, food security. However, in the comparison, no effort was made to differentiate enclosure study methodologies with respect to maintaining projected CO(2) concentration or to consider other climatic changes (e.g. warming) that could impact crop yields. In this review, we demonstrate that relative yield stimulations in response to future CO(2) concentrations obtained using a number of enclosure methodologies are quantitatively consistent with FACE results for three crops of global importance: rice (Oryza sativa), soybean (Glycine max) and wheat (Triticum aestivum). We suggest, that instead of focusing on methodological disparities per se, improved projections of future food supply could be achieved by better characterization of the biotic/abiotic uncertainties associated with projected changes in CO(2) and climate and incorporation of these uncertainties into current crop models. PMID- 17688579 TI - S cysteine-rich (SCR) binding domain analysis of the Brassica self incompatibility S-locus receptor kinase. AB - Brassica self-incompatibility, a highly discriminating outbreeding mechanism, has become a paradigm for the study of plant cell-cell communications. When self pollen lands on a stigma, the male ligand S cysteine-rich (SCR), which is present in the pollen coat, is transmitted to the female receptor, S-locus receptor kinase (SRK). SRK is a membrane-spanning serine/threonine receptor kinase present in the stigmatic papillar cell membrane. Haplotype-specific binding of SCR to SRK brings about pollen rejection. The extracellular receptor domain of SRK (eSRK) is responsible for binding SCR. Based on sequence homology, eSRK can be divided into three subdomains: B lectin-like, hypervariable, and PAN. Biochemical analysis of these subdomains showed that the hypervariable subdomain is responsible for most of the SCR binding capacity of eSRK, whereas the B lectin-like and PAN domains have little, if any, affinity for SCR. Fine mapping of the SCR binding region of SRK using a peptide array revealed a region of the hypervariable subdomain that plays a key role in binding the SCR molecule. We show that residues within the hypervariable subdomain define SRK binding and are likely to be involved in defining haplotype specificity. PMID- 17688580 TI - Signalling mechanisms in the regulation of vacuolar ion release in guard cells. AB - Pharmacological agents were used to investigate the possible involvement of actin in signalling chains associated with abscisic acid (ABA)-induced ion release from the guard cell vacuole, a process which is absolutely essential for stomatal closure. Effects on the ABA-induced transient stimulation of tonoplast efflux were measured, using (86)Rb in isolated guard cells of Commelina communis, together with effects on stomatal apertures. In the response to 10 microm ABA (triggered by Ca(2+) influx rather than internal Ca(2+) release), jasplakinolide (stabilizing actin filaments) and latrunculin B (depolymerizing actin filaments) had opposite effects. Both closure and the vacuolar efflux transient were inhibited by jasplakinolide but enhanced by latrunculin B. At 10 microm ABA prevention of mitogen-activated protein (MAP) kinase activation by PD98059 partially inhibited closure and reduced the efflux transient. By contrast, latrunculin B inhibited the efflux transient at 0.1 microm ABA (involving internal Ca(2+) release rather than Ca(2+) influx). The results suggest that 10 microm ABA activates Ca(2+)-dependent vacuolar ion efflux via a Ca(2+)-permeable influx channel which is maintained closed by interaction with F-actin. A MAP kinase is also involved, in a chain similar to that postulated for Ca(2+) dependent gene expression in cold acclimation. PMID- 17688581 TI - Hyperaccumulator Alyssum murale relies on a different metal storage mechanism for cobalt than for nickel. AB - The nickel (Ni) hyperaccumulator Alyssum murale has been developed as a commercial crop for phytoremediation/phytomining Ni from metal-enriched soils. Here, metal co-tolerance, accumulation and localization were investigated for A. murale exposed to metal co-contaminants. A. murale was irrigated with Ni-enriched nutrient solutions containing basal or elevated concentrations of cobalt (Co) or zinc (Zn). Metal localization and elemental associations were investigated in situ with synchrotron X-ray microfluorescence (SXRF) and computed-microtomography (CMT). A. murale hyperaccumulated Ni and Co (> 1000 microg g(-1) dry weight) from mixed-metal systems. Zinc was not hyperaccumulated. Elevated Co or Zn concentrations did not alter Ni accumulation or localization. SXRF images showed uniform Ni distribution in leaves and preferential localization of Co near leaf tips/margins. CMT images revealed that leaf epidermal tissue was enriched with Ni but devoid of Co, that Co was localized in the apoplasm of leaf ground tissue and that Co was sequestered on leaf surfaces near the tips/margins. Cobalt-rich mineral precipitate(s) form on leaves of Co-treated A. murale. Specialized biochemical processes linked with Ni (hyper)tolerance in A. murale do not confer (hyper)tolerance to Co. A. murale relies on a different metal storage mechanism for Co (exocellular sequestration) than for Ni (vacuolar sequestration). PMID- 17688582 TI - Cadmium-induced inhibition of photosynthesis and long-term acclimation to cadmium stress in the hyperaccumulator Thlaspi caerulescens. AB - Acclimation of hyperaccumulators to heavy metal-induced stress is crucial for phytoremediation and was investigated using the hyperaccumulator Thlaspi caerulescens and the nonaccumulators T. fendleri and T. ochroleucum. Spatially and spectrally resolved kinetics of in vivo absorbance and fluorescence were measured with a novel fluorescence kinetic microscope. At the beginning of growth on cadmium (Cd), all species suffered from toxicity, but T. caerulescens subsequently recovered completely. During stress, a few mesophyll cells in T. caerulescens became more inhibited and accumulated more Cd than the majority; this heterogeneity disappeared during acclimation. Chlorophyll fluorescence parameters related to photochemistry were more strongly affected by Cd stress than nonphotochemical parameters, and only photochemistry showed acclimation. Cd acclimation in T. caerulescens shows that part of its Cd tolerance is inducible and involves transient physiological heterogeneity as an emergency defence mechanism. Differential effects of Cd stress on photochemical vs nonphotochemical parameters indicate that Cd inhibits the photosynthetic light reactions more than the Calvin-Benson cycle. Differential spectral distribution of Cd effects on photochemical vs nonphotochemical quenching shows that Cd inhibits at least two different targets in/around photosystem II (PSII). Spectrally homogeneous maximal PSII efficiency (F(v)/F(m)) suggests that in healthy T. caerulescens all chlorophylls fluorescing at room temperature are PSII-associated. PMID- 17688583 TI - Coordination of anthocyanin decline and photosynthetic maturation in juvenile leaves of three deciduous tree species. AB - Juvenile leaves in high-light environments commonly appear red as a result of anthocyanin pigments, which play a photoprotective role during light-sensitive ontogenetic stages. The loss of anthocyanin during leaf development presumably corresponds to a decreased need for photoprotection, as photosynthetic maturation allows leaves to utilize higher light intensities. However, the relationship between photosynthetic development and anthocyanin decline has yet to be quantitatively described. In this study, anthocyanin concentration was measured against photopigment content, lamina thickness, anatomical development, and photosynthetic CO(2) exchange in developing leaves of three deciduous tree species. In all species, anthocyanin disappearance corresponded with development of c. 50% mature photopigment concentrations, c. 80% lamina thickness, and differentiation of the mesophyll into palisade and spongy layers. Photosynthetic gas exchange correlated positively with leaf thickness and chlorophyll content, and negatively with anthocyanin concentration. Species with more rapid photosynthetic maturation lost anthocyanin earliest in development. Chlorophyll a/b ratios increased with leaf age, and were lower than those of acyanic species, consistent with a shading effect of anthocyanin. These results suggest that anthocyanin reassimilation is linked closely with chloroplast and whole-leaf developmental processes, supporting the idea that anthocyanins protect tissues until light processing and carbon fixation have matured to balance energy capture with utilization. PMID- 17688584 TI - Diversity of hydraulic traits in nine Cordia species growing in tropical forests with contrasting precipitation. AB - Inter- and intraspecific variation in hydraulic traits was investigated in nine Cordia (Boraginaceae) species growing in three tropical rainforests differing in mean annual precipitation (MAP). Interspecific variation was examined for the different Cordia species found at each site, and intraspecific variation was studied in populations of the widespread species Cordia alliodora across the three sites. Strong intra- and interspecific variation were observed in vulnerability to drought-induced embolism. Species growing at drier sites were more resistant to embolism than those growing at moister sites; the same pattern was observed for populations of C. alliodora. By contrast, traits related to hydraulic capacity, including stem xylem vessel diameter, sapwood specific conductivity (K(s)) and leaf specific conductivity (K(L)), varied strongly but independently of MAP. For C. alliodora, xylem anatomy, K(s), K(L) and Huber value varied little across sites, with K(s) and K(L) being consistently high relative to other Cordia species. A constitutively high hydraulic capacity coupled with plastic or genotypic adjustment in vulnerability to embolism and leaf water relations would contribute to the ability of C. alliodora to establish and compete across a wide precipitation gradient. PMID- 17688585 TI - Evidence for post-translational regulation of NrtA, the Aspergillus nidulans high affinity nitrate transporter. AB - Here, influx and efflux of (13)NO(3)(-), and net fluxes of (14)NO(3)(-) and (14)NO(2)(-), were measured in Aspergillus nidulans mutants niaD171 and niiA5, devoid of nitrate reductase (NR) and nitrite reductase (NiR) activities, respectively. Transcript and protein abundances of NrtA, the A. nidulans principal high-affinity NO(3)(-) transporter, were determined using semiquantitative reverse transcription-polymerase chain reaction and western blots, respectively. (13)NO(3)(-) influx in niaD171 was negligible relative to wild-type values, whereas efflux to influx ratios increased nine-fold. Nevertheless, NrtA mRNA and NrtA protein were expressed at levels more than two fold and three-fold higher, respectively, in niaD171 than in the wild-type strain. This is the first demonstration of diminished high-affinity NO(3)(-) influx associated with elevated transporter levels, providing evidence that, in addition to transcriptional regulation, control of NrtA expression operates at the post-translational level. This mechanism allows for rapid control of NO(3)(-) transport at the protein level, reduces the extent of futile cycling of NO(3)(-) that would otherwise represent a significant energy drain when influx exceeds the capacity for assimilation or storage, and may be responsible for the rapid switching between the on and off state that is associated with simultaneous provision of NH(4)(+) to mycelia absorbing NO(3)(-). PMID- 17688586 TI - Long-distance movement of Cauliflower mosaic virus and host defence responses in Arabidopsis follow a predictable pattern that is determined by the leaf orthostichy. AB - Long-distance virus transport takes place through the vascular system and is dependent on the movement of photoassimilates. Here, patterns of symptom development, virus movement and gene expression were analysed in Arabidopsis following inoculation with Cauliflower mosaic virus (CaMV) on a single leaf. Virus accumulation and expression of markers for the salicylic acid (SA) and ethylene/jasmonate (Et/JA) defence pathways, PR-1 and PDF1.2, were analysed on a leaf-by-leaf basis by real-time reverse transcription polymerase chain reaction (qRT-PCR). Virus spread followed a strictly defined pattern identical to that of a source-sink relationship. This was exploited to study differences between local and systemic defence responses in a developmental and spatial manner. In infected plants, PR-1 transcripts accumulated primarily but not exclusively in leaves with a direct vascular connection to the inoculated leaf. Abundances fell significantly as virus accumulated. By contrast, PDF1.2 transcripts were significantly lower than in controls in all leaves at early stages of infection, but recovered as virus accumulated. Virus and PR-1 transcript abundances are negatively correlated, and SA- and Et/JA-mediated signalling of gene expression occurs independently of the presence of virus. Although SA-dependent signalling responses were mainly linked to the orthostichy, Et/JA-dependent responses were independent of vascular connections. PMID- 17688587 TI - Only an early nitric oxide burst and the following wave of secondary nitric oxide generation enhanced effective defence responses of pelargonium to a necrotrophic pathogen. AB - Participation of nitric oxide (NO) in cross-talk between ivy pelargonium (Pelargonium peltatum) leaves and Botrytis cinerea was investigated using electrochemical and biochemical approaches. In response to the necrotroph, leaves initiated a near-immediate NO burst, but the specificity of its generation was dependent on the genetic makeup of the host plant. In the resistant cultivar, a strong NO burst was followed by a wave of secondary NO generation, shown by bio imaging with DAF-2DA. The epicentre of NO synthesis was located in targeted cells, which exhibited a TUNEL-positive reaction. Soon after the challenge, an elevated concentration of hydrogen peroxide (H(2)O(2)) was correlated with a reversible inhibition of catalase (CAT), ascorbate peroxidase (APX), and suppression of ethylene synthesis. The induced NO generation initially expanded and then gradually disappeared on successive days, provoking noncell-death associated resistance with an enhanced pool of antioxidants, which finally favoured the maintenance of homeostasis of surrounding cells. By contrast, in the susceptible pelargonium, a weak NO burst was recorded and further NO generation increased only as the disease progressed, which was accompanied by very intensive H(2)O(2) and ethylene synthesis. The pathogen colonizing susceptible cells also acquired the ability to produce considerable amounts of NO and enhanced nitrosative and oxidative stress in host tissues. PMID- 17688588 TI - Role of the cyclic lipopeptide massetolide A in biological control of Phytophthora infestans and in colonization of tomato plants by Pseudomonas fluorescens. AB - Pseudomonas strains have shown promising results in biological control of late blight caused by Phytophthora infestans. However, the mechanism(s) and metabolites involved are in many cases poorly understood. Here, the role of the cyclic lipopeptide massetolide A of Pseudomonas fluorescens SS101 in biocontrol of tomato late blight was examined. Pseudomonas fluorescens SS101 was effective in preventing infection of tomato (Lycopersicon esculentum) leaves by P. infestans and significantly reduced the expansion of existing late blight lesions. Massetolide A was an important component of the activity of P. fluorescens SS101, since the massA-mutant was significantly less effective in biocontrol, and purified massetolide A provided significant control of P. infestans, both locally and systemically via induced resistance. Assays with nahG transgenic plants indicated that the systemic resistance response induced by SS101 or massetolide A was independent of salicylic acid signalling. Strain SS101 colonized the roots of tomato seedlings significantly better than its massA mutant, indicating that massetolide A was an important trait in plant colonization. This study shows that the cyclic lipopeptide surfactant massetolide A is a metabolite with versatile functions in the ecology of P. fluorescens SS101 and in interactions with tomato plants and the late blight pathogen P. infestans. PMID- 17688589 TI - The mycorrhiza helper Pseudomonas fluorescens BBc6R8 has a specific priming effect on the growth, morphology and gene expression of the ectomycorrhizal fungus Laccaria bicolor S238N. AB - The mycorrhiza helper Pseudomonas fluorescens BBc6R8 promotes the presymbiotic survival and growth of the ectomycorrhizal fungus Laccaria bicolor S238N in the soil. An in vitro fungal-bacterial confrontation bioassay mimicking the promoting effects of the bacteria on fungal growth was set up to analyse the fungal morphological and transcriptional changes induced by the helper bacteria at three successive stages of the interaction. The specificity of the P. fluorescens BBc6R8 effect was assessed in comparison with six other rhizobacterial strains possessing mycorrhiza helper or pathogen antagonistic abilities. The helper BBc6R8 strain was the only strain to induce increases in the radial growth of the colony, hyphal apex density and branching angle. These morphological modifications were coupled with pleiotropic alterations of the fungal transcriptome, which varied throughout the interaction. Early stage-responsive genes were presumably involved in recognition processes and transcription regulation, while late stage-responsive genes encoded proteins of primary metabolism. Some of the responsive genes were partly specific to the interaction with P. fluorescens BBc6R8, whereas others were mutually regulated by different rhizobacteria. The results highlight the fact that the helper BBc6R8 strain has a specific priming effect on growth, morphology and gene expression of its fungal associate L. bicolor S238N. PMID- 17688590 TI - Sequence of events leading to near-complete genome turnover in allopolyploid Nicotiana within five million years. AB - Analyses of selected bacterial artificial chromosomes (BACs) clones suggest that the retrotransposon component of angiosperm genomes can be amplified or deleted, leading to genome turnover. Here, Nicotiana allopolyploids were used to characterize the nature of sequence turnover across the whole genome in allopolyploids known to be of different ages. Using molecular-clock analyses, the likely age of Nicotiana allopolyploids was estimated. Genomic in situ hybridization (GISH) and tandem repeat characterization were used to determine how the parental genomic compartments of these allopolyploids have diverged over time. Paternal genome sequence losses, retroelement activity and intergenomic translocation have been reported in early Nicotiana tabacum evolution (up to 200,000 yr divergence). Here it is shown that within 1 million years of allopolyploid divergence there is considerable exchange of repeats between parental chromosome sets. After c. 5 million years of divergence GISH fails. This GISH failure may represent near-complete genome turnover, probably involving the replacement of nongenic sequences with new, or previously rare sequence types, all occurring within a conserved karyotype structure. This mode of evolution may influence or be influenced by long-term diploidization processes that characterize angiosperm polyploidy-diploid evolutionary cycles. PMID- 17688591 TI - Asexuality and the coexistence of cytotypes. AB - Reproductive isolation via apomixis is one way for newly created cytotypes to persist and coexist with other cytotypes. Arnica cordifolia (Asteraceae) has both triploid and tetraploid cytotypes co-occurring in many locations. The rate of apomixis in each cytotype was explored as a mechanism for the maintenance of sympatric cytotypes. Flow cytometry was used on both adults and seeds from mixed cytotype populations to estimate reproductive mode and to evaluate the relationship between cytotype frequency and reproductive success. Flowering time was surveyed to look for temporal reproductive isolation between cytotypes. Both triploids and tetraploids can be asexual. Apomixis in A. cordifolia is usually autonomous, not pseudogamous as previously thought. Sexual reproduction appears to be uncommon. The minority cytotype in each population does not produce fewer seeds, confirming that minority cytotype exclusion is unlikely to occur via reproductive disadvantage. Triploids flowered earlier than tetraploids, but with much overlap. Asexual reproduction is an important factor promoting the coexistence of cytotypes in this system. Other mechanisms maintaining populations of sympatric cytotypes are not well studied or understood and warrant further investigation. PMID- 17688592 TI - Evolutionary ecology of resistance to herbivory: an investigation of potential genetic constraints in the multiple-herbivore community of Solanum carolinense. AB - As part of a study of the ecological and evolutionary dynamics of herbivore resistance in Solanum carolinense (horsenettle), potential genetic constraints to the evolution of resistance to 11 of its most common herbivores were investigated. Leaf, flower, fruit, and stem herbivory were measured in a field experiment involving 24 ramets of each of 40 horsenettle genets. The experimental plant population contained significant genetic variation for resistance to all 11 species of herbivore. For only one species was there an indication of a genotype by-environment interaction in the expression of resistance that might constrain its evolution. Genetic correlations in resistance to different species were common but not universal, with seven negative and 12 positive correlations out of the 55 pairwise species comparisons. Correlations were independent of plant part fed upon. The evolution of the resistance of horsenettle to most of its diverse community of herbivores does not appear to be prevented by a lack of genetic variation or by genotype-by-environment interactions in resistance. Negative genetic correlations in resistance to different herbivores may play a small role in slowing the evolution of resistance, but positive correlations may play at least as large a role in facilitating its evolution. PMID- 17688593 TI - A method for quantifying rotational symmetry. AB - Here, a new approach for quantifying rotational symmetry based on vector analysis was described and compared with information obtained from a geometric morphometric analysis and a technique based on distance alone. A new method was developed that generates a polygon from the length and angle data of a structure and then quantifies the minimum change necessary to convert that polygon into a regular polygon. This technique yielded an asymmetry score (s) that can range from 0 (perfect symmetry) to 1 (complete asymmetry). Using digital images of Geranium robertianum flowers, this new method was compared with a technique based on lengths alone and with established geometric morphometric methods used to quantify shape variation. Asymmetry scores (s) more clearly described variation in symmetry and were more consistent with a visual assessment of the images than either comparative technique. This procedure is the first to quantify the asymmetry of radial structures accurately, uses easily obtainable measures to calculate the asymmetry score and allows comparisons among individuals and species, even when the comparisons involve structures with different patterns of symmetry. This technique enables the rigorous analysis of polysymmetric structures and provides a foundation for a better understanding of symmetry in nature. PMID- 17688596 TI - Spermatozoal RNA as reservoir, marker and carrier of epigenetic information: implications for cloning. AB - The mammalian male gamete is transcriptionally silent as a consequence of the highly condensed architecture of its chromatin and there is also little or no cytoplasm capable of supporting translation; however, we now understand that under certain conditions, spermatozoa can translate their mRNAs de novo and that spermatozoal RNA can potentially affect phenotypic traits in offspring. This epigenetic phenomenon may involve the transmission of extra-chromosomal episomal elements. Recent evidence indicates that spermatozoal RNA may play a role in the progressive shutdown of transcription during spermiogenesis. The presence of RNA in the sperm nucleus and its potential as a carrier of epigenetic information to the egg may prove insightful with regard to the abysmal success rates for cloning of domestic species by somatic nuclear transfer procedures. PMID- 17688597 TI - Mechanisms of regulation of litter size in pigs on the genome level. AB - Improvement in litter size has become of great interest in pig industry as good fecundity is directly related to a sow's productive life. Genetic regulation of litter size is complex and the main component traits so far defined are ovulation rate, embryonic survival, uterus capacity, foetal survival and pre-weaning losses. Improvements using concepts of the quantitative genetics let expect only slow genetic progress due to its low heritability of approximately 0.09 for number of piglets born alive. Marker assisted selection allows to dissect litter size in its component traits and using molecular genetic markers for the components of litter size traits promises more progress and advantages in optimum balancing of the different physiological mechanisms influencing litter size. In this review, efforts being made to unravel the genetic determinants of litter size are accounted and discussed. For litter size traits, more than 50 quantitative trait loci (QTL) were mapped and in more than 12 candidate genes associations confirmed. The number of useful candidate genes is much larger as shown by expression profiles and in addition, much more QTL can be assumed. These functional genomic approaches, both QTL mapping and candidate gene analysis, have to be merged for a better understanding of a wider application across different pig breeds and lines. Newly developed tools based on microarray techniques comprising DNA variants or expressed tags of many genes or even the whole genome appear useful for in depth understanding of the genetics of litter size in pigs. PMID- 17688599 TI - Reproduction in the water buffalo. AB - In this paper, an account of various aspects related to buffalo reproduction are given. Fundamental concepts of the reproductive physiology as well as manipulation of the reproductive function will be presented. This will include an overview of the most recent developments of the oestrous cycle and the ovulation control, new strategies of reproductive management for the improvement of genetic gain and the application of newly developed reproductive technologies, such as in vitro embryo production, embryo and sperm sexing and cloning. PMID- 17688600 TI - Assisted reproduction in female rhinoceros and elephants--current status and future perspective. AB - Over the last few decades, rhinoceroses and elephants became important icons in the saga of wildlife conservation. Recent surveys estimate the wild Asian (Elephas maximus) and African (Loxodonta africana) elephant populations to be, at most, 50 250 and 637 600 respectively. For the five rhinoceros species, black (Diceros bicornis), white (Ceratotherium simum), Indian (Rhinoceros unicornis), Javan (Rhinoceros sondaicus) and Sumatran rhinoceros (Dicerorhinus Sumatrensis), the population estimates of 3610, 11 330, 2400, 60 and 300, respectively, are of even greater concern. Protected against habitat loss, poaching and left undisturbed, rhinoceros and elephants reproduce well in the wild. But small and decreasing populations make successful captive management of these taxa increasingly important. In captivity, however, most populations face possible 'extinction' because of historically poor reproductive performance. From the first descriptions of the reproductive anatomy and the oestrous cycle (Laws 1969; Kassam and Lasley 1981; Balke et al. 1988a,b; Plotka et al. 1988; Godfrey et al. 1991) to the present use of advanced assisted reproduction technologies, researchers have strive to understand the function and dysfunction of the reproductive biology of these charismatic species. This paper reviewed the current knowledge on rhinoceros and elephant reproduction biology, reproductive cycle, gestation, dystocia, reproductive pathology, oestrous induction and artificial insemination, sperm sexing, IVF and contraception, and how this knowledge is or might be used to aid species conservation for maximal reproductive efficiency and enhancement of genetic management. PMID- 17688598 TI - The high-producing dairy cow and its reproductive performance. AB - There is evidence that the reproductive performance of dairy cows has declined as milk yields have increased over the last 40 years. Identifying the precise cause(s) of this problem may provide focused solutions. Intensive genetic selection for very high yields has reduced fertility, due mainly to an increase in postpartum clinical problems, poor expression of oestrus, defective oocytes/embryos and uterine infections. It is a challenge to solve the problem by getting enough food into these cows to meet the high demands of peak milk yields in early lactation, as well as providing the considerable veterinary attention required in the early period after calving. Both these aspects also pose welfare issues. A better solution would be to make genetic and management changes to increase the persistency of lactations to reduce the number and intensity of clinical risk periods throughout a cow's life without compromising milk output. PMID- 17688601 TI - The horse genome project--sequence based insights into male reproductive mechanisms. AB - The growing knowledge on physiology, cell biology and biochemistry of the reproductive organs has provided many insights into molecular mechanisms that are required for successful reproduction. Research directed at the investigation of reproduction physiology in domestic animals was hampered in the past by a lack of species-specific genomic information. The genome sequences of dog, cattle and horse have become publicly available in 2005, 2006 and 2007 respectively. Although the gene content of mammalian genomes is generally very similar, genes involved in reproduction tend to be less conserved than the average mammalian gene. The availability of genome sequences provides a valuable resource to check whether any protein that may be known from human or mouse research is present in cattle and/or horse as well. Currently there are more than 200 genes known that are involved in the production of fertile sperm cells. Great progress has been made in the understanding of genetic aberrations that lead to male infertility. Additionally, the first genetic mechanisms are being discovered that contribute to the quantitative variation of fertility traits in fertile male animals. Here, I will review some selected aspects of genetic research in male fertility and offer some perspectives for the use of genomic sequence information. PMID- 17688602 TI - Application of Doppler ultrasonography in cattle reproduction. AB - The development of Doppler processing extended the scope of sonographic imaging from an anatomical to a physiological basis. This technique became established as a clinical tool in human gynaecology. For example, it has been discussed that the implantation of an embryo is influenced by the uterine blood flow. In cows, this uterine blood flow was investigated, using surgically implanted Doppler ultrasonic or electromagnetic blood flow probes prior to the introduction of colour Doppler sonography in bovine medicine. Therefore, the aims of our studies were to use transrectal Doppler sonography for the non-invasive measurement of uterine and ovarian blood flow in cows and to determine changes in genital perfusion during the oestrous cycle, pregnancy and puerperium, respectively. The results of our studies show that transrectal flow imaging can be used to obtain blood flow velocity waveforms from the uterine arteries at any time during the oestrous cycle, pregnancy and puerperium. During all these phases, characteristic changes in the uterine blood flow could be observed. This uterine blood flow was low during diestrus and high during proestrus and oestrus. During pregnancy, an exponential rise in uterine blood supply could be detected. There was a positive relationship between the uterine blood flow volume (BFV) at the end of gestation and the birth weight of calves. During puerperium, the uterine BFV declined tremendously, especially during the first week after birth. In cows, with pathological disturbances of the pueperium a delayed decrease in the uterine BFV was observed. Characteristic alterations occurred also in the luteal blood flow during the oestrous cycle, which were highly related to those of the progesterone levels. Furthermore, it has been detected by the colour Doppler technique that there is no decrease, but an increase of the luteal blood flow at the beginning of luteolysis in cows. Another group has found that there are close relationships between the LH-surge and the follicular blood flow before ovulation. In conclusion, these studies show that transrectal colour Doppler sonography is a useful technique for the investigation of the genital blood flow and provides new information about physiological changes of the genital organs during, all reproductive phases. The influence of the genital blood flow on fertility in cows needs to be examined further in future studies. PMID- 17688604 TI - Abstracts of the 21st Biennial Meeting of the International Society for Neurochemistry and the 38th Annual Meeting of the American Society for Neurochemistry, Cancun, Mexico, 19-24 August 2007. PMID- 17688605 TI - TNF-alpha from monocyte of patients with pre-eclampsia-induced apoptosis in human trophoblast cell line. AB - OBJECTIVE: In pre-eclampsia, fetal growth restriction is frequently observed, and the possible involvement of inhibitory substances on trophoblast cell proliferation and differentiation has been suggested. The objective of this study was to investigate the effects humoral factors, such as cytokines, produced in immune cells on proliferation of an immortalized trophoblastic cell line (TCL) that we established. METHODS: Serum and lymphocyte layers were isolated from the blood of normal pregnant and preeclamptic women. The lymphocyte layer was further fractionated into different immune cell populations by the Stem Sep method. Immortalized trophoblastic cells were cultured with the sera diluted. The cytokine concentrations in the supernatants of lymphocyte cultures were compared between normal pregnancy and pre-eclampsia. The number, DNA content and induced apoptosis were examined on the immortalized trophoblastic cells at the end of culture. RESULTS: The sera from preeclamptic women significantly inhibited the immortalized trophoblastic cell proliferation in comparison with those from normal pregnancy. Among the lymphocyte fractions, monocytes significantly inhibited the immortalized trophoblastic cell proliferation. The monocytes from preeclamptic women were found to produce higher levels of tumor necrosis factor alpha (TNF-alpha) in the culture supernatant than those from normal pregnant women. The coculture with the monocytes from preeclamptic women increased the frequency of TUNEL-positive TCL cells. TNF-alpha inhibited immortalized trophoblastic cell proliferation in a dose-dependent manner and induced apoptosis. CONCLUSION: The present results suggest that monocytes are activated and that cytokines, such as TNF-alpha, which is produced by monocytes, induce apoptosis and inhibit proliferation of trophoblast cells in pre-eclampsia. PMID- 17688606 TI - Re-evaluation of the true rate of hepatitis C virus mother-to-child transmission and its novel risk factors based on our two prospective studies. AB - OBJECTIVE: To re-evaluate the true hepatitis C virus (HCV) mother-to-child transmission (MTCT) rate and its novel risk factors. STUDY DESIGN: A comparative study based on our own two prospective studies done during the two periods, 'early' (1989-1994) and 'recent' (1995-2004). RESULTS: All carrier infants became HCV RNA-positive within 3 months after birth. The MTCT and de-carrier rates were, respectively, higher (14.2%) and lower (16.7%) in the recent period, although liver dysfunction of carrier infants was found very frequently (66.7%) in both groups. MTCT occurred significantly when the maternal viral load, serum alanine aminotransferase (sALT) levels and blood loss at delivery were, respectively, more than 10(5) copies/mL, 110 IU/L, and 500 g. No MTCT was found when elective cesarean section was done. CONCLUSIONS: The true HCV MTCT and de-carrier rates were found to be much higher and lower than those reported previously. The maternal liver dysfunction (sALT >or=110 IU/mL) and blood loss (>or=500 g) at delivery are the next risk factors to maternal viral load (>or=10(5) copies/mL) for MTCT. PMID- 17688607 TI - Single inherited thrombophilias and adverse pregnancy outcomes. AB - INTRODUCTION: Inherited thrombophilia is believed to be a multiple gene disease with more than one defect. We aimed to determine the association between single thrombophilic patterns and a variety of pregnancy diseases. METHODS: 284 pregnant women were recruited for the present study and were divided in two groups: A group (176 controls) and B group (108 cases). Patients belonging to the B group had one of the following: severe pre-eclampsia, hemolysis, hepatic enzymes increase, hypertension and low platelet count (HELLP) syndrome, gestational hypertension, fetal growth restriction, intrauterine death, abruptio placentae and disseminated intravascular coagulopathy. To detect methylenetetrahydrofolate reductase (MTHFR) A1298C, MTHFR C677T, factor V Leiden, PAI-1, mutant prothrombin G20210A, an inverse hybridization technology was used. Plasma homocysteine, antithrombin (AT) III and protein S were determined. A modified functional activated protein C resistance was detected. RESULTS: MTHFR C677T and hyperhomocysteinemia were more prevalent than other thrombophilias. Deficiency in AT III was significantly linked with pre-eclampsia (relative risk 0.88; 95% CI 0.83-0.94). Activated protein C resistance (APCR) was significantly related to the abruptio placentae (relative risk 0.71; 95% CI 0.61-0.82). COMMENTS: Apart from the linkage between AT III deficiency and the occurrence of pre-eclampsia, and apart from the increased risk of abruptio placentae in pregnant women with altered APCR, we obtained findings in contrast with some of the published literature. In our case series, no association of pre-eclampsia with factor V Leiden or with prothrombin gene mutation was found. PMID- 17688608 TI - Antenatal diagnosis of placenta previa accreta in patients with previous cesarean scar. AB - AIM: To determine the accuracy of transabdominal and transvaginal gray-scale and color Doppler in diagnosing placenta previa accreta in patients with previous cesarean sections. METHODS: Twenty-one patients who had undergone previous cesarean sections and were confirmed to have partial or total placenta previa in the current pregnancy were subjected to ultrasound examinations after the 28th week of gestation. Specific ultrasound features were looked for on gray-scale ultrasound and color Doppler examination of the placenta and its interphase with the uterus and the bladder. RESULTS: Seven of the 21 patients had ultrasound evidence of placenta accreta and all were later confirmed to have placenta previa accreta intraoperatively. The gray-scale positive findings were present in six out of the seven patients. The most prominent gray scale feature to suggest placenta accreta was the presence of multiple lakes that represent dilated vessels extending from the placenta through the myometrium. All seven patients had features of placenta accreta when examined with color Doppler. The most prominent color Doppler feature present in all seven patients was the presence of interphase hypervascularity with abnormal vessels linking the placenta to the bladder. The sensitivity and specificity of antenatal ultrasound diagnosis of placenta previa accreta was 100%. CONCLUSION: Antenatal diagnosis of placenta previa accreta can be made with a thorough ultrasound examination of the placenta in patients with previous cesarean scar and placenta previa. PMID- 17688609 TI - Maternal negative attitudes towards pregnancy as an independent risk factor for low birthweight. AB - AIM: Recently, Japan has witnessed an increase in the number of low-birthweight (LBW) infants. LBW children face a variety of social and medical risk factors. Thus, besides reducing infant mortality, preventing LBW would have many other important health benefits. Emotional status during pregnancy is stated as one of the important risk factors for LBW. This study aims to clarify the relationship between maternal emotions and low birthweight (LBW) after adjusting the effects of other well-known factors that influence LBW. METHODS: This community-based case-control study involved 145 newborns with LBW (cases) and 213 newborns with normal weight (controls). They were born in the municipalities that fall within the jurisdiction of the Yoshida public health center between 1st January 2003 and 30th September 2004. Participants' mothers were interviewed using a simple, structured questionnaire to collect general data on mother and infant, hazardous habits and maternal socioeconomic, occupational and psychological factors. The odds ratio with a 95% confidential interval of delivering LBW infants was calculated using logistic multivariable regression analysis based on maternal and infant factors. RESULTS: In the multivariable regression model, the second-born or subsequent infant was unlikely to be LBW. On the contrary, maternal smoking habit during pregnancy, mothers who kept house by themselves and maternal negative attitudes towards pregnancy during the early stages promoted LBW incidence. CONCLUSION: Maternal negative attitude towards pregnancy during the early stages was an independent LBW risk factor and our simple questionnaire can be used to estimate maternal psychological status in early pregnancy. PMID- 17688610 TI - Development of risk scoring scheme for prediction of cesarean delivery due to cephalopelvic disproportion in Lamphun Hospital, Thailand. AB - AIM: To develop a simple risk scoring scheme for the prediction of cesarean delivery due to cephalopelvic disproportion (CPD) in Lamphun Hospital, Thailand. METHODS: A case-control study was conducted including 116 pregnant women with cesarean delivery due to CPD and 307 pregnant women delivering by normal labor. Obstetric information was retrieved from medical records. Risk indicators measurable at the time of admission were analyzed by a stepwise logistic regression to obtain a set of statistically significant predictors. Regression coefficients were transformed into item scores and added up to a total score. Risk of cesarean delivery due to CPD was analyzed using total scores as the only predictor. RESULTS: A risk scoring scheme was developed from five obstetric predictors: maternal age, height, parity, pregnancy weight gain and symphysis fundal height. Item scores ranged from 0 up to 3.5 and the total score from 0 14.5. The scheme explained, by the area under the receiver operating characteristic curve, 88% of cesarean delivery due to CPD. The likelihood of cesarean delivery due to CPD in pregnant women with low risk (scores below 5), moderate risk (scores 5-9.5) and high risk (scores 10 and over) were 0.09, 0.86 and 10.11, respectively. CONCLUSIONS: The risk of cesarean delivery due to CPD may be forecasted by a simple scoring scheme using five predictors that correctly identified women with low, moderate and high risk. This scheme may be applicable to physicians and midwives for identifying high-risk pregnant women in order to take appropriate action. PMID- 17688611 TI - Nitric oxide donor isosorbide mononitrate for pre-induction cervical ripening at 41 weeks' gestation: A randomized controlled trial. AB - OBJECTIVE: Nitric oxide donors have been shown to cause cervical ripening. The aim of this study was to determine whether sustained release isosorbide mononitrate (ISMN-SR) 60 mg administered vaginally is effective for pre induction cervical ripening at 41 weeks' gestation. METHODS: A double-blind randomised controlled trial was carried out at the University Obstetric Unit, Galle, Sri Lanka for a period of 9 months, commencing 1st August 2003. One hundred and fifty six consecutive women with uncomplicated singleton pregnancies at 41 weeks' gestation with a modified Bishop Score <5 were allocated by stratified (primip/multip) block randomization to receive either ISMN-SR 60 mg (n = 78) or vitamin C 100 mg (n = 78) vaginally. Modified Bishop Score at 41 weeks + 2 days' gestation and the proportions establishing spontaneous labor or becoming favorable for induction of labor (IOL) by 41 weeks + 2 days' gestation were evaluated in each group. RESULTS: At the commencement of the study there were no differences between the mean age, parity or modified Bishop Score of the two groups. In the ISMN-SR group, there was a marked increase in the proportion establishing spontaneous labor (28% vs 7.5%, P < 0.01) and being favorable for IOL (40% vs 9% P < 0.001), 2 days after therapy. In the ISMN-SR group, there was a significantly higher increase in the mean modified Bishop Score (3.8, 95% CI 2.3-5.3 vs 1.3, 95% CI 0.3-2.2, P < 0.01) and a marked decrease in the proportion of subjects requiring further ripening of the cervix with a Foley catheter. (32% vs 79%, P < 0.001). The cesarean section rates were similar in both groups. CONCLUSION: Sustained release ISMN administered vaginally is effective for preinduction cervical ripening. PMID- 17688612 TI - Pregnancy outcome in hyperemesis gravidarum and the effect of laboratory clinical indicators of hyperemesis severity. AB - OBJECTIVE: To determine pregnancy outcome in hyperemesis gravidarum and the effect of metabolic, biochemical, hematological and clinical indicators of disease severity on outcome. STUDY DESIGN: A retrospective study based on 166 women hospitalized for confirmed hyperemesis gravidarum from January 2004 to January 2005. For each woman, three controls matched for age, parity and ethnicity were obtained from our 2004 birth register. The effects of laboratory indicators of hyperemesis severity were separately analyzed within the hyperemesis gravidarum study group. Outcome measures include stillbirths, Apgar score, mode of delivery, low birthweight, preterm delivery, labor induction, pregnancy induced hypertension and gestational diabetes. Analysis was by t-test, Fisher's exact test and multivariable logistic regression analysis. RESULTS: Women with hyperemesis had similar pregnancy outcome compared to controls. In the analysis of laboratory indicators of hyperemesis severity and pregnancy outcomes, hypokalemia (adjusted odds ratio [AOR] 2.7: 95% confidence interval [CI] 1.0-6.8) was associated with emergency operative delivery, high creatinine (odds ratio 4.4: 95% CI 1.3-15) with labor induction and raised gamma glutamyltransferase (AOR 7.5: 95% CI 1.2-46) with the development of gestational diabetes. CONCLUSIONS: Hyperemesis gravidarum per se was not associated adverse pregnancy outcome. Hypokalemia, high creatinine and raised gamma glutamyltransferase in women with hyperemesis gravidarum were associated with adverse pregnancy outcome. PMID- 17688613 TI - Decrease and dysfunction of endothelial progenitor cells in umbilical cord blood with maternal pre-eclampsia. AB - BACKGROUND: The pre-eclampsia is characterized by placental defective angiogenesis and maternal vascular/endothelial dysfunction. Recently, the decrease and senescence of endothelial progenitor cells (EPC) has been observed in maternal circulation with pre-eclampsia. Given the essential involvement of EPC in neovascularization and reendothelialization, we investigate whether or not the depletion of EPC is existent in placental/fetal circulation with maternal pre eclampsia. METHODS: Samples of venous cord blood were collected during the labor of preeclamptic mothers (n = 14) and normotensive controls (n = 10). Circulating EPC were enumerated as AC133+/KDR+ cells via fluorescence-activated cell sorting (FACS) analysis. Additionally, EPC were expanded in vitro and identified by DiI acLDL uptake and lectin staining by direct fluorescent staining under a laser scanning confocal microscope. EPC proliferation, migration and vasculogenesis activities were determined by MTT, modified Boyden chamber assay and in vitro vasculogenensis assay. RESULT: The placental/fetal circulating EPC numbers were significantly decreased in the pre-eclampsia group compared with the control (median, 200; range, 100-440 cells/mL vs 390; 270-440 cells/mL, P < 0.001), and after in vitro cultivation the numbers of EPC also decreased in pre-eclampsia group (19.5; 5.0-32.0 vs 39.5; 31.2-52.0 EPC/x200 field; P < 0.001). Both circulating EPC and cultivated EPC were inversely correlated with cord blood level of soluble fms-like tyrosine kinase 1 (sFlt-1). In addition, the EPC from patients with pre-eclampsia were significantly impaired in their proliferation, migration and vasculogenesis capacities. CONCLUSION: The present study documented the decrease and dysfunction of placental/fetal circulating EPC in patients with pre-eclampsia. The alteration is probably associated with the increased sFlt-1 levels in the umbilical cord blood. PMID- 17688614 TI - Does a change in obstetric management influence the incidence of traumatic birth lesions in mature, otherwise healthy newborn infants? AB - AIM: The incidence of lesions due to birth trauma can be generally regarded as a characteristic of obstetric management; since obstetric management has changed through the years, one might expect a decrease or increase of lesions due to birth trauma in mature newborn infants. METHODS: In a retrospective study, the incidence of lesions due to birth trauma was recorded in the year 2000. In 1989, an identical study had already been carried out in the same department, employing the same criteria. The new findings were compared with the historical data. RESULTS: In the year 1989 24.6% and in 2000 13.2% showed lesions due to obstetric trauma. The episiotomy rate and lesions due to birth trauma had significantly decreased. A decline regarding the traumas per se was noticed in caput succedaneum traumas, in hematomas due to birth trauma and in clavicle fracture. The cesarean section rate among the study group increased. The cesarean section rate among the traumatized newborns decreased. CONCLUSION: Episiotomy does not prevent newborns from traumatic lesions. Gestational age and birthweight have not significantly changed throughout the years; therefore an increase in the cesarean section rate must have contributed to the decrease of birth traumas. Even during abdominal operative delivery, obstetric traumas in newborns do occur. However, an increase in cesarean sections alone can not thoroughly explain the reduction of birth lesion among newborns. Improvement in prenatal diagnostic tools and procedures, respectively, and a goal-oriented use of labor induction might also play a major role. PMID- 17688615 TI - Comparative study of four candidate strategies to detect cervical cancer in different health care settings. AB - AIM: Considering the differing but potentially supplementary properties of visual inspection of the cervix with acetic acid (VIA) and the cytological examination (CYTO) of cervical smears for the screening of cervical cancers, we examined the performance of these two tests and their combinations for the screening of cervical cancer in different health care settings. METHODS: In this cross sectional diagnostic test performance evaluation study of 4235 female subjects in the reproductive age group, we assessed the screening performance of four strategies: VIA alone, CYTO alone, VIA and CYTO combined in a parallel fashion, and VIA and CYTO combined in tandem. Subjects were recruited from three settings: Hospital, Urban Community and Rural Community. Colposcopy was used as the reference standard. Screening performance was assessed using sensitivity, specificity, post-test probabilities and likelihood ratios (LR), diagnostic odds, area under receiver operating characteristic curve and LR chi(2). RESULTS: Both VIA and CYTO when used alone had a low sensitivity but high specificity, especially in the Rural Community setting. A combination of the results of VIA and CYTO improved the diagnostic accuracy but the strategy using a parallel combination of VIA and CYTO was the most accurate. In general, all screening strategies using VIA and CYTO showed a modest screening performance. CONCLUSIONS: In the settings of varying levels of health care and low resources, caution is needed for a generalized use of VIA for cervical cancer screening. Further evaluation of the cost-effective ways of combining VIA and CYTO is needed in these circumstances. PMID- 17688616 TI - Cytokine profiles in serum and peritoneal fluid from infertile women with and without endometriosis. AB - OBJECTIVE: To study the serum and peritoneal fluid cytokine profiles in infertile women with minimal/mild active endometriosis. METHODS: Fifty-seven consecutive infertile women undergoing laparoscopy for unexplained infertility had peritoneal fluid and serum samples obtained at the time of laparoscopy. The levels of interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-1 beta (IL-1 beta), vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF alpha), monocyte chemotatic protein-1 (MCP-1), RANTES, platelet derived growth factor (PDGF), soluble Fas (sFas), and soluble Fas Ligand (sFasL) in peritoneal fluid and serum were measured to compare the concentration in both biological fluids, in women who have minimal/mild red endometriosis using women with no endometriosis as controls. RESULTS: Peritoneal fluid levels of MCP-1, IL-8 and IL 6 were significantly higher in the endometriosis group (P < 0.012, P = 0.003, and P = 0.015, respectively). There was no significant difference in the peritoneal fluid levels of IL-1 beta, TNF-alpha, RANTES, VEGF, PDGF, sFas and sFasL in the two groups. Although serum levels of IL-8 were higher in women with endometriosis, the difference was not significant (P = 0.07). Serum levels of PDGF, IL-6, RANTES, IL-1 beta, TNF-alpha, and sFas, were not significantly different in the two groups. CONCLUSION: The elevated levels of MCP-1, IL-6, and IL-8 in peritoneal fluid but not serum may indicate the importance of local macrophage activating factors in the pathogenesis of endometriosis. PMID- 17688617 TI - Hypersensitivity to aeroallergens in patients with recurrent vulvovaginitis of undetermined etiology. AB - AIM: Recent findings show that the vaginal mucosa can develop an allergic response to environmental allergens and there is a strong association between atopy and some recurrent vulvovaginal infections. In this study, we investigated prospectively the rate of atopy in patients with recurrent vulvovaginitis of undetermined etiology (RVV). MATERIAL AND METHODS: After being investigated by a gynecologist, 35 patients with RVV who were considered as undetermined etiology formed the study group. The control group consisted of 150 healthy females. Study and control groups were investigated for atopy by means of skin prick test for common aeroallergens. Associated allergic disease and familial atopy history of the subjects were recorded. RESULTS: The rate of atopy (11/35; 31.4% vs 9/150; 6%) was significantly higher (P < 0.001) in the study group than in the controls. Familial history of atopy was significantly more frequent in the study group than in the controls (10/35; 28.6% vs 8/150; 5.3%, P < 0.05). RVV in atopics is more associated with seasonal rhinitis than in nonatopics (5/11; 45.4% vs 2/24; 8.3%, P < 0.05). CONCLUSION: We concluded that a significant number of RVV is associated with atopy. Although the exact mechanism(s) of this relationship remains to be investigated atopy might be a causative and/or contributing factor in the pathogenesis of RVV. PMID- 17688618 TI - Establishment of criteria for elective single embryo transfer at day 2 or day 3 by analyzing cases with successful implantation of all embryos transferred. AB - AIM: Elective transfer of two good-quality embryos has been used to avoid triplet or high-order multiple pregnancies. However, the rate of twin pregnancies has remained fairly unchanged. In the present study, criteria for elective single embryo transfer (eSET) at day 2 or day 3 were established by analyzing cases with successful implantation of all embryos transferred. METHODS: A total of 685 fresh or frozen-thawed embryo transfers following in vitro fertilization/intracytoplasmic sperm injection between April 2002 and March 2006 were performed. Only embryo transfers at day 2 or day 3, but not at blastocyst stage, were included. Successful implantation of all embryos transferred was obtained in 17 pregnancy cycles. RESULTS: Thirty-one gestational sacs with fetal heartbeats were obtained by a total of 31 embryo transfers in 17 infertile women. The average age was 32.6 years (23-38), and 14 (82.3%) of the 17 women were <36 years old. Fifteen (88.2%) of the 17 pregnancies were established at the first attempt of assisted reproductive technology (ART). Of the 17 women, eight (47.1%) women were multigravida and four (23.5%) women were multipara. The indications for ART or insemination methods did not seem to be related to the pregnancy results. Twenty-nine (93.5%) of 31 embryos implanted were considered good-quality embryos. Of the 17 fresh embryos transferred at day 2, 15 were at the 4-cell stage and two were at the 5-cell stage. Of the 11 fresh embryos transferred at day 3, one was at the 6-cell stage, two were at the 7-cell stage and eight were at the 8-cell stage. CONCLUSION: The criteria for eSET at day 2 or day 3 were established as follows: <36 years of age, a first treatment cycle and more than two good-quality embryos developed at least to the 4-cell stage at day 2, or 6 cell stage at day 3. Additionally, the past history of pregnancy or delivery should be considered, as patients positive for such history might have better implantation ability. eSET can be highly recommended to avoid twin pregnancies in subjects with the established criteria. PMID- 17688619 TI - Uterine artery embolization should not be recommended without careful consideration in the treatment of symptomatic uterine fibroids. AB - AIM: To evaluate convalescence and the incidence of adverse symptoms associated with uterine artery embolization (UAE) in the treatment of uterine fibroids, several parameters after UAE were compared with those after laparoscopic surgery. METHODS: For the treatment of uterine fibroids, 78 patients underwent UAE and 58 received laparoscopic surgery (31 were laparoscopic myomectomy [LM] and 27 were laparoscopy-assisted myomectomy [LAM]) during the period July 2001 to July 2004. The length of hospitalization, and the periods until the beginning of a normal daily life, work and exercise, long-term follow up data in the UAE and laparoscopy groups were compared, and the incidence of adverse symptoms after each procedure was compared. RESULTS: The length of hospitalization for the UAE group 2.1 +/- 0.1 (mean +/- S.E) was significantly shorter than those for the LM and LAM groups (2.6 +/- 0.1 and 3.8 +/- 0.2 days, respectively; P < 0.0001 and P < 0.0001). The period until beginning of normal daily life and work were similar between the UAE and LM groups. The degree of improved symptoms after each procedure were similar among the three groups, but the incidence of adverse symptoms after UAE was significantly higher than after laparoscopic surgery. CONCLUSIONS: The UAE group showed a significantly shorter period of hospitalization, but the convalescence of the UAE group was similar to the LA group, with a higher incidence of adverse symptoms than laparoscopic surgeries. Therefore, UAE should not be recommended without careful consideration, in the treatment of symptomatic uterine fibroids. PMID- 17688620 TI - Retrospective study of the success rates and complications associated with total laparoscopic hysterectomy. AB - AIMS: Laparoscopic techniques are being used increasingly more in gynecologic surgery and the introduction of modern laparoscopic instruments has allowed complex operations to be performed laparoscopically. The aim of this study is to evaluate our surgical technique with regard to the success of total laparoscopic hysterectomy (TLH) for the removal of the uterus, by analyzing its intraoperative and postoperative surgical outcomes and complications in the hope of reducing their occurrence. METHODS: A retrospective observational study was carried out at KK Hospital, Singapore, based on TLH operations performed from January 2001 to June 2005. The KOH Colpotomizer System and the RUMI Uterine Manipulator were the surgical methods used. RESULTS: 435 women consented for a TLH. 427 women (98.2%) had a successful TLH with three mini-laparotomy and five laparotomy conversions (1.8% failure rate). Injuries included bowel injury (four), bladder base bleeding (one), uterine perforation (one), uterovaginal fistula (one) and vaginal laceration (four). 21 women (4.8%) encountered major complications (defined as laparotomy conversion, excessive bleeding requiring blood transfusion, hemorrhage >or=1000 mL, ureteric injury, bowel injury and pulmonary embolus), which compares favorably with previous reports (4.0-11.0%) of laparoscopic hysterectomy. Our mean operating time, mean estimated blood loss, mean hospital stay and readmission rate are similarly comparable. CONCLUSION: TLH is associated with a high success rate, and low morbidity with few complications. PMID- 17688621 TI - Surgical morbidity associated with total laparoscopic hysterectomy in women with prior diagnostic excision of the cervix. AB - AIMS: To evaluate the feasibility, safety, and complications of total laparoscopic hysterectomy (TLH) in women undergoing prior diagnostic excision of the cervix. METHODS: A retrospective study (Canadian Task Force classification II 2) was conducted in a tertiary care university hospital. The medical records of women undergoing TLH between June 2003 and September 2004 were reviewed. RESULTS: Twenty-six women with stage IA1 cervical cancer (19) and persistent high grade cervical neoplasia (7) underwent TLH after diagnostic cervical excision. The operation was successfully performed in all cases without conversion to laparotomy. The mean age of the patients was 47.0 +/- 8.64 years (95% CI 43.5 50.5). 19 patients had previous loop electrosurgical excision procedure (LEEP), one had cold knife conization. Six patients underwent repeated LEEP for positive endocervical margin. The mean operating time was 253.0 +/- 66.7 min (95% CI 226.0 279.9). The median blood loss was 300 mL (range 50-1000 mL). Only one patient needed 1 unit of blood transfusion. The median post-operative hospital stay was 3 days (range 2-6 days). All hysterectomy specimens had negative surgical margins. Two patients had major complications, one with bladder injury requiring laparoscopic repair. The remaining one had ureteral injury detected 9 days after the operation requiring subsequent ureteroneocystostomy. Both complications occurred in the first four cases of this series. No significant morbidity was noted in 2 years of follow-up. CONCLUSION: TLH appears to be feasible and safe in patients with prior diagnostic excision of the cervix. Careful separation of the bladder from the cervix and identification of both ureters are recommended to minimize morbidity associated with this operation. PMID- 17688622 TI - Total vaginal reconstruction with combined 'Split Labia Minora Flaps' and full thickness skin grafts. AB - PURPOSE: Vaginal reconstruction with split-thickness skin grafts is the most common method for total vaginal reconstruction. Although it has disadvantages like contraction of the graft, foreshortening, donor site morbidity and long lasting periods of vaginal standing; its easy surgical technique makes it popular. A new method using split labia minora (LM) flaps and full-thickness skin graft is discussed in this study. METHOD: A 19-year-old female was presented with amenorrhea. A total absence of vagina was present and the patient underwent a total vaginal reconstruction for possible sexual intercourse. RESULTS: We observed no contraction and no foreshortening with a patent vaginal cavity up to 11 cm and 4.5 cm width. The need for continuous standing period was as short as 4 weeks and for intermittent standing up to 4 months. Sexual intercourse was encouraged after 4 weeks. During sexual intercourse no external lubrication was reported to be needed. There was no need for further reconstructive intervention. CONCLUSION: Vaginal reconstruction in congenital vaginal agenesis with split LM flaps and full-thickness skin grafts is a simple and effective method, which shortens the standing period and decreases the contraction in neovagina. Total vaginal reconstruction with split LM flaps could also be possible; to achieve this goal, expansion of LM flaps could be a further alternative. PMID- 17688623 TI - Impact of use of combined oral contraceptive pill on the quality of life of Japanese women. AB - AIM: To evaluate the impact of combined oral contraceptive pill (OC) use on quality of life (QOL) among Japanese women, we performed a prospective study using the Japanese version of the World Health Organization Quality of Life (WHOQOL) questionnaire. METHODS: Women who consulted Chayamachi Lady's Clinic to get a prescription for OC for the first time were recruited for our questionnaire study and asked to complete the WHOQOL questionnaire twice, before taking OC and more than 3 months after beginning OC use. Two hundred and seventeen women responded to our questionnaire before taking OC and 110 patients completed the questionnaire. The patients were divided into six groups based on the reason they wanted to take OC: contraception, relaxation of dysmenorrhea, regulation of menstrual cycles, improvement of acne, remission of menorrhagia, and improvement of premenstrual tension syndrome (PMS). RESULTS: WHOQOL scores showed significant improvement in all domains of the dysmenorrhea group, all domains but the social of over all participants, the social and overall domain of the irregular cycle group, physical, environmental, and overall domain of the acne group, and psychological and overall domain of the PMS group. The WHOQOL score worsened in the social domain of the contraception group; however, the score in the overall domain of that group improved. CONCLUSIONS: These results indicate that OC can provide higher QOL for women with problems involving menstrual pain and/or hormonal abnormalities. However, those using OC for contraception only were found to be unsatisfied with taking OC in a relationship with their partners. PMID- 17688624 TI - Cervical varix with placenta previa totalis. AB - A cervical varix during pregnancy is a very rare complication. It can lead to hemorrhage and may result in significant morbidity. Furthermore, appropriate management has not yet been established. We present a case of a cervical varix with placenta previa totalis. A 30-year-old woman with placenta previa totalis also had a cervical varix without bleeding. At 32 weeks' gestation, massive hemorrhage from the cervical varix occurred. A vaginal pack controlled the bleeding, and a cesarean section was subsequently carried out because of uncontrollable uterine contractions. A 1655 g female infant was delivered; the estimated blood loss was 1814 mL. The cervical varix decreased dramatically in size. In conclusion, presented herein is a rare case of a cervical varix, which had a successful outcome. PMID- 17688625 TI - Posterior leukoencephalopathy syndrome as a cause of reversible blindness during pregnancy. AB - Cortical blindness is a rare and dramatic complication of pre-eclampsia. The precise nature of the pathogenesis of this condition has not previously been understood. Three preeclamptic patients with unremarkable previous medical history presented with acute blindness between the 28th and 33rd weeks of pregnancy. They were all diagnosed as posterior leukoencephalopathy syndrome (PLES). In all these patients, MRI study revealed the typical feature of gray white matter edema localized to the temporo-parieto-occipital areas. Vision and MRI findings were restored in all patients after delivery. Although PLES has been described as a puerperal clinicoradiologic entity, it may be seen in preeclamptic eclamptic patients during the pregnancy. Therefore neuro-imaging studies should be carried out in pregnant patients with visual disturbances in order to exclude PLES. Prompt diagnosis, immediate control of blood pressure, and elimination of possible causes resolves clinical and imaging findings. PMID- 17688626 TI - Abducens nerve palsy in pre-eclampsia after delivery: An unusual case report. AB - The common neurological manifestations of pre-eclampsia include headache, confusion, and visual disturbance; while isolated abducens nerve palsy in pre eclampsia is very rare. We report one case of a severe pre-eclampsia with abducens nerve palsy at 39 weeks' gestation. There was no specific pathology, except hypertension, and the palsy resolved spontaneously. PMID- 17688627 TI - Blue rubber bleb nevus syndrome: Report of a patient with hemangiomas of the vaginal portion of the cervix appearing during pregnancy. AB - Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder showing venous malformations in the skin and gastrointestinal tract, and other internal organs. We encountered a patient with BRBNS in whom hemangiomas of the uterine cervix appeared during pregnancy. This was apparently the first reported occurrence. To avoid unexpected bleeding from hemangiomas, patients with BRBNS should be examined repeatedly for hemangiomas of the birth canal, and special care should be taken in deciding the mode of delivery. PMID- 17688628 TI - Mechanical ileus in a pregnant woman at term pregnancy accompanied by labor pains. AB - Intestinal obstruction in pregnancy is a rare, but serious complication of pregnancy with significant maternal and fetal mortality. We herein report a case of intestinal strangulation in a pregnant woman with a history of pelvic surgery due to an ectopic pregnancy. Epigastric pain occurred at term pregnancy with concomitant onset of labor pains. The epigastric pain disappeared transiently, and she gave a birth to a healthy child. However, the pain appeared again after the vaginal delivery. She immediately underwent ileo-ileostomy with a diagnosis of mechanical ileus, and the postoperative course was uneventful. Mechanical ileus should be considered when examining epigastric pain in a pregnant woman with a history of abdominal or pelvic surgery even after the onset of labor pains. PMID- 17688629 TI - Fulminant type 1 diabetes during pregnancy: A case report and review of the literature. AB - Fulminant type 1 diabetes, classified as a subtype of nonautoimmune type 1 diabetes, may result in severe complications for both mother and fetus due to the sudden onset of diabetic ketoacidosis. Little is known about the clinical features of pregnancy with fulminant type 1 diabetes. We present a case of fulminant type 1 diabetes during pregnancy, along with a review of the published literature. A 31-year-old Japanese woman presented with sudden onset of nausea and vomiting at 36 weeks' gestation and was provisionally diagnosed with acute gastroenteritis. She was referred to us for investigation of exaggerated general fatigue and intrauterine fetal death. Based on blood and urinary examinations, she was diagnosed with diabetic ketoacidosis, caused by fulminant type 1 diabetes. Although her ketoacidosis was improved, insulin therapy was needed. Awareness of this disease can lead to prompt diagnosis and treatment and consequently, improved maternal and fetal prognosis. PMID- 17688630 TI - B-Lynch suture after the failure of hypogastric artery ligation to control post partum hemorrhage due to placenta increta in a patient with the factor V Leiden mutation. AB - Post-partum hemorrhage may be a life-threatening condition. A case of a patient receiving antithrombotic therapy for the factor V Leiden mutation, in whom post partum hemorrhage had occurred due to placenta increta, is described. In this case, the post-partum hemorrhage did not respond to bilateral hypogastric artery ligation, while the B-Lynch surgical technique was successful in obtaining hemostasis. PMID- 17688631 TI - Massive pericardial effusion in an early gestational fetus having intrapericardial diaphragmatic hernia. AB - Intrapericardial diaphragmatic hernia is a very rare phenotype of congenital diaphragmatic hernia. Twelve cases of this condition have been reported under the age of 1 year since 1981, and in only four cases were abnormal findings observed antenatally. We report a case of a fetus with this disease in which pericardial effusion was noted in an earlier gestational age than any other previously reported cases. A 35-year-old pregnant woman was referred to our center at 16 weeks' gestation. Ultrasound revealed that the bilateral lungs of the fetus were very small due to the compression by massive pericardial effusion. Pregnancy was terminated at 18 weeks, and autopsy of the stillborn baby revealed intrapericardial diaphragmatic hernia and cardiac aneurysm of the right ventricle. In conclusion, when pericardial effusion is observed in a fetus, intrapericardial diaphragmatic hernia, a very rare type of congenital diaphragmatic hernia, must be included in a differential diagnosis. PMID- 17688632 TI - Iniencephaly: Prenatal diagnosis with postmortem findings. AB - Iniencephaly is a rare but almost always lethal neural tube defect with the following cardinal features: occipital bone defect, partial or total absence of cervicothoracal vertebrae and fetal retroflexion. Iniencephaly is associated with malformations of the central nervous system, gastrointestinal and cardiovascular system. Prenatally diagnosed cases of iniencephaly are rare because careful and early ultrasonographic evaluation is necessary. The present cases of iniencephaly were found to carry associated malformations such as atrioventricular septal defect and club foot. We present an iniencephaly prenatally diagnosed by sonography, in which therapeutic abortion was induced, with a review of the published literature. PMID- 17688633 TI - Dichorionic twin fetuses with VACTERL association. AB - Although prenatal diagnosis of VACTERL (vertebral defects, anal atresia, cardiac anomaly, tracheal-esophageal fistula with esophageal atresia, renal defects, and radial limb dysplasia) association is not always possible, ultrasonography and magnetic resonance imaging can visualize some of the characteristic findings of this condition. Because infants with this condition usually require significant surgical treatment and care, prenatal detection with those imaging modalities should assist in proper planning for delivery and anticipated care of the neonate. In this report, we present dichorionic twin fetuses, both of whom were found postnatally to have this condition, and suggest the possible relationship between this disorder and intracytoplasmic sperm injection. As far as we know, this is the first report of twin fetuses affected by VACTERL association. PMID- 17688634 TI - Mixed epithelial and stromal tumor of the kidney in a puerperal woman. AB - Puerperal pyrexia is still rampant, especially in third world countries, and is usually due to puerperal sepsis, urinary tract infections, upper respiratory infection, and breast infection. Rarely, in third world countries like India, it may be due to tuberculosis, malaria, typhoid, and so on, which are also rampant in the general population. Mixed epithelial and stromal tumor of the kidney (MESTK) is a recently recognized subset of renal tumors composed mainly of smooth muscle cells in which epithelial structures are embedded. It usually occurs in middle aged and older women. In the present case report, a 36-year-old woman presented with puerperal pyrexia, possibly due to tuberculosis and with an incidental mixed epithelial and stromal tumor of the kidney causing complex ascitis and fever, which required nephrectomy that was followed by full recovery. This case report highlights the importance of keeping MESTK in mind even in younger women with asymptomatic renal mass. It also highlights the importance of keeping renal tumors in mind as a possibility and to perform proper investigations for adequate treatment and recovery. PMID- 17688635 TI - Metastasis of lobular breast carcinoma to the cervix. AB - Breast cancers without previous dissemination occasionally result in hematogenous metastases in gynecologic organs, particularly in the cervix. This case report examines a multimodally treated lobular breast cancer patient who was 52 months later diagnosed with malignancy in the uterus. After a tumor was detected at the endocervical and isthmic part of the uterus, a complete hysterectomy with bilateral salpingo-oophorectomy was carried out. The malignant cells were highly positive for carcino-embrional antigen and gross cystic disease fluid protein-15, sensitive breast cancer markers. In conclusion, as breast carcinoma can metastasize to atypical places (cervix, endometrium, etc.), regular surveillance of patients should include gynecologic control. PMID- 17688636 TI - Ligneous inflammation involving the female genital tract. AB - Ligneous inflammation is a rare disease characterized by progressive growth of ligneous plaques on mucosal surfaces. Involvement of the female genital tract is an unusual condition. We present a patient with multifocal ligneous inflammation involving her genital tract, oral mucosa and conjunctiva. Plasminogen functional activity was 18% of normal (reference: 55-145%). Molecular analysis exhibited that her genetic status is homozygous for a combination of three polymorphisms. But no true mutation could be found in all 19 exons of the plasminogen gene. We did not observe any clinical changes, although plasminogen activity has improved in the course of 5 months of oral contraceptive therapy Most gynecologists are unfamiliar with this diagnosis and pathologists with wide experience in gynecology are unaware of this disease. However, the histology of lesions is characteristic and a diagnosis can be made quite easily once it has been considered. PMID- 17688637 TI - Severe ovarian hyperstimulation syndrome in a twin pregnancy after intracytoplasmic sperm injection. AB - A 35-year-old woman developed bilateral jugular thrombosis in the seventh gestational week in a twin pregnancy after severe ovarian hyperstimulation syndrome (OHSS) and intracytoplasmic sperm injection (ICSI). Due to progressive thrombosis and further complications despite anticoagulation therapy, the pregnancy was terminated in the ninth gestational week. Thromboembolic events are a serious complication associated with OHSS after assisted reproduction techniques. In these cases, a pregnancy can usually be protected by administering anticoagulation therapy, but our case shows that there may be exceptions to this. Screening for thrombophilia should be considered in patients who are at risk for OHSS and deep vein thrombosis. PMID- 17688638 TI - Definitive diagnosis of primary adenocarcinoma of the appendix by laparoscopic appendectomy. AB - We report a 62-year-old woman with a primary adenocarcinoma of the appendix mimicking ovarian tumor. We had diagnosed it definitively by laparoscopic appendectomy, and additional surgery was required in this case. However, the present case suggests that, in some cases, if cancer of the appendix can be diagnosed early, laparotomy can be avoided and the cancer treated with minimally invasive laparoscopic surgery alone. PMID- 17688639 TI - Intrauterine contraceptive device-related actinomycosis infection presenting as an incarcerated inguinal hernia. AB - We report an unusual case of an intrauterine contraceptive device (IUCD)-related pelvic actinomyces infection presenting as an incarcerated inguinal hernia. An emergency laparotomy showed the presence of pyometra with large abscesses, involving both fallopian tubes and the right ovary with pyometra tracking down the left psoas into the groin, giving a clinical and radiological appearance of an incarcerated hernia. Subsequent results obtained from investigations showed the presence of actinomyces-like organisms on the patient's smear related to an IUCD. PMID- 17688640 TI - Do human papillomavirus vaccines have any role in newborns and the prevention of recurrent respiratory papillomatosis in children? PMID- 17688641 TI - Human rights and child health. AB - Human rights are those basic standards without which people cannot live in dignity. Children are at risk of human rights violations because of their vulnerability in society. The Convention on the Rights of the Child (CRC), a United Nations (UN) treaty acknowledges that addressing children's human rights requires special attention. In Australia groups such as children seeking asylum, Aboriginal and Torres Strait Islander children, children with disabilities, children in care and children living in poverty are identified to be at particular risk. As individuals and collectively, we have had a long history of gathering information, advocacy and tailoring training to improve children's health and well-being. A human rights approach and the use of the CRC provide an additional framework to do this. PMID- 17688642 TI - DTPa-HBV-IPV vaccine for primary vaccination of infants. AB - AIM: Combined vaccines have an increasingly important role to play in delivering these antigens acceptably. We describe the immunogenicity and reactogenicity of a combined DTPa-HBV-IPV vaccine (diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus (DTPa-HBV-IPV: Infanrix penta) ) when administered for the primary vaccination of infants resulting from a study where the primary objective was to demonstrate non-inferiority of the immune response induced by DTPa-HBV-IPV using an industrial-scale IPV production process. METHODS: Three hundred and fourteen infants received primary immunisation with DTPa-HBV-IPV at 2, 4 and 6 months of age. Routine Haemophilus influenzae immunisation was performed at 2 and 4 months of age at a separate injection site. Blood samples were taken at 2 and 7 months of age. Reactogenicity was assessed using diary cards for 7 days after each dose. RESULTS: One month after the primary course, at least 98.9% of subjects achieved seroprotective antibody concentrations/titres against diphtheria, tetanus, hepatitis-B and polio types 1, 2 and 3. More than 97% had a vaccine response to pertussis antigens. The incidence of local injection site reactions after DTPa-HBV-IPV was similar to that for the Haemophilus influenzae vaccine site. General reactions of Grade 3 intensity were uncommon. CONCLUSIONS: The DTPa-HBV-IPV vaccine is a new combination of vaccines previously available separately, with established effectiveness and safety profiles. Combined vaccines reduce storage requirements and minimise the number of injections required, thereby reducing distress for infants and parents. DTPa-HBV-IPV was immunogenic with an acceptable safety profile and could replace separate administration of DTPa, HBV and IPV vaccines in infants. PMID- 17688643 TI - Responses to immunisation with Hib conjugate vaccine in Australian breastfed and formula-fed infants. AB - OBJECTIVE: There are conflicting reports as to whether breastfed infants respond with higher antibody levels to conjugate Haemophilus influenzae type b (Hib) vaccine compared with formula-fed infants. These observations prompted us to investigate the effect of feeding method on the antibody concentration to Hib polyribosylribitol (PRP) both prior to and 3 months after the primary course of immunisation with Hib (PRP-OMP). METHODS: We measured plasma concentrations of IgG antibody to Hib PRP by enzyme-linked immunosorbent assay in blood samples from a total of 272 breastfed and formula-fed infants prior to immunisation (7 weeks of age, n = 82 and n = 148, respectively) and again 3 months after completion of the primary course of immunisation with Hib PRP-OMP (7 months of age, n = 88 and n = 132, respectively). RESULTS: Breastfeeding was associated with lower plasma antibody titres at both times (P < 0.01, T-test) with 49% of breastfed infants having anti-PRP concentrations below 1.0 microg/mL at age 7 months. There was no reported invasive Hib disease in this cohort of infants, and nationally the effectiveness of the Hib vaccination programme remains high. CONCLUSIONS: These data suggest that breastfeeding may be associated with immunomodulation of infant Hib immunisation responses with this immunisation regime. Further research is needed to determine whether differences in antibody concentration described here are primarily determined by factors directly attributed to breastfeeding or whether other environmental factors may play a significant role. PMID- 17688644 TI - Infants who drink cows milk: a cohort study. AB - AIM: The aim of this study was to document current practice in an Australia city regarding the introduction of whole cows milk to children under the age of 12 months. METHODS: A cohort study of mothers and infants, recruited at birth was undertaken in Perth, Australia. A total of 587 mothers were interviewed on seven occasions over a period of 12 months using a structured questionnaire. At each interview infant feeding methods were recorded in detail. At 12 months 453 mothers (78%) remained in the study. RESULTS: In this study the median age of introduction of cows milk was 41.5 weeks, a behaviour that has not changed in the past 8 years. Infants who were given solids earlier than 4 months were more likely to be introduced to cows milk before 12 months (odds ratio (OR) 2.06, confidence interval (CI) 1.4-3.1). Mothers who had a lower score on the IOWA Infant Feeding Attitudes Scale were more likely to give cows milk earlier (OR 1.83, CI 1.21-1.77). Where fathers did not support breastfeeding or were ambivalent infants were more likely to be given cows milk (OR 1.70, CI 1.23-2.58) CONCLUSIONS: Despite recommendations that cows milk should not be given before 12 months of age, the majority of infants were given cows milk before this age. This suggests the need for further education programs. PMID- 17688645 TI - 'Evidence-based implementation' of paediatric asthma guidelines in a rural emergency department. AB - AIM: To determine if an evidence-based implementation (EBI) could lead to improved compliance with guidelines for acute asthma in children aged 1-15 years presenting to a large rural emergency department. METHODS: Pre-intervention, post intervention and 12-month follow-up audits were performed to determine the impact of an EBI strategy used to increase compliance with current asthma guidelines. The pre-intervention audit was conducted from 1 April to 30 June 2004, and follow up data were collected from 1 September to 30 November 2004. The 12-month follow up audit was conducted from 1 August to 31 October 2005. All audits were chart reviews. The intervention was an EBI strategy that was devised and then used to implement established guidelines for the emergency department management of paediatric asthma. RESULTS: There were 51 presentations pre-intervention, 66 post intervention and 68 at 12-month follow-up with no differences noted in the severity of asthma between the groups. At 12-month follow-up, there were significant increases in the documentation of asthma severity (45% to 90%, P < 0.001), use of spirometry (32% to 66%, P = 0.012), use of spacers (5% to 53%, P < 0.001) and use of written short-term asthma management plans (16% to 69%, P < 0.001). There was a reduction in the use of ipratropium bromide in mild asthma (31% to 3%, P < 0.001). There was no significant change in the use of systemic steroids (74% to 62%, P = 0.29) or antibiotic use in afebrile patients (15% to 6%, P = 0.175). For the seven clinical indicators (CIs) combined, compliance with the guideline increased from 47% to 79% (P < 0.001). Positive changes in clinical behaviour occurred immediately and compliance with all seven CIs was 83% immediately post intervention before falling, non-significantly, to 79% at 12 month follow-up (P = 0.142). CONCLUSIONS: The pre-intervention audit identified a low rate of compliance with current asthma guidelines across seven CIs of asthma care. The intervention significantly increased compliance with five of the CIs and for the seven CIs aggregated. Positive changes in clinical behaviour were immediate and the gains were sustained at 12 months. PMID- 17688646 TI - Identification of Aboriginal infants at an urban hospital. AB - AIM: This study explored the accuracy of identification of Aboriginal infants at an urban hospital. METHODS: Data on the Aboriginal status of all infants who were delivered at the hospital to mothers who resided in the surrounding Local Government Area during 2002 were extracted from the Obstetrics Data Package (ODP). These data were supplemented with local health worker knowledge about the Aboriginal status of infants and compared with NSW Birth Register data held by the Australian Bureau of Statistics. RESULTS: There were 1739 deliveries at the hospital to mothers from the Local Government Area. Our study showed that 71.4% (n = 90) of Aboriginal and 77.5% (n = 1649) of non-Aboriginal infants identified through ODP were included in the Birth Register. The proportion of Aboriginal infants identified through the ODP was 5.2% and the Birth Register was 5.6%. The 90 Aboriginal infants included 38 with an Aboriginal mother, 34 with an Aboriginal father, and 18 with two Aboriginal parents. CONCLUSIONS: This was the first use of these data to examine the accuracy of identification of Aboriginal infants born at this facility. The study highlighted the importance of systematically seeking information on the Aboriginal status of both parents by antenatal services; of providing opportunities for timely feedback on the data quality to maternity service providers; and ensuring that the data are used to inform development of culturally appropriate services. As a result of this study, services have implemented strategies to routinely identify infants with an Aboriginal father as well as those with an Aboriginal mother. PMID- 17688647 TI - Outcome and hospital cost for infants weighing less than 500 grams: a tertiary centre experience in Taiwan. AB - AIM: To determine the outcome and hospital cost for infants weighing < or =500 g at a tertiary centre in Taiwan. METHODS: We retrospectively reviewed the medical records of infants who were born alive with birthweight < or =500 g at the National Taiwan University Hospital from 1997 to 2004. Their outcome and hospital cost were analysed. RESULTS: A total of 168 infants were included for analysis that 146 of them died after compassionate care in the delivery room and 22 received postnatal resuscitation. The infants who received resuscitation were more likely to have higher birthweights, older gestational ages and multiple births compared with those who received compassionate care. After resuscitation, five of the infants died and 17 were admitted to neonatal intensive care unit (NICU) for further management. Subsequently, 12 infants died and five infants survived to discharge. Two infants were discharged against advice and died within days. After exclusion of those receiving compassionate care, the NICU survival rate was 22.7% and the long-term survival rate was 13.6%. The most common early morbidities were respiratory distress syndrome, intraventricular haemorrhage and patent ductus arteriosus, whereas the late morbidities included cholestatic jaundice, retinopathy of prematurity and chronic lung disease. The average total hospital costs for the NICU survivors with birthweight < or =500 g was US $42,411 and the average hospital cost per day was US $350. CONCLUSION: Exclusive compassionate care was given to the majority of the infants weighing < or =500 g in Taiwan. The survival rate remained low in these marginally viable infants. PMID- 17688648 TI - alpha1-Antitrypsin deficiency is not an important cause of childhood liver diseases in a multi-ethnic Southeast Asian population. AB - AIM: We conducted a prospective study to determine the role of alpha1-antitrypsin (alpha1AT) deficiency in the pathogenesis of neonatal cholestasis and other childhood liver diseases in a multi-ethnic Southeast Asian population. METHODS: Prospective patients with neonatal cholestasis (group 1), other liver diseases (group 2) and children with other medical conditions (group 3) referred to the Paediatric Unit, University of Malaya Medical Centre, Malaysia, from May 2002 to June 2005, were screened for alpha1AT level and phenotype. alpha1AT level below 80 mg/dL was considered as low. RESULTS: Of the 114 patients (group 1, n = 53; group 2, n = 42; group 3, n = 19) screened, seven patients (6% of total; group 1, n = 1; group 2, n = 4; group 3, n = 2) had a alpha1AT level below 80 mg/dL. All had marginally low level (range 57-79 mg/dL), but none had a clinical diagnosis of alpha1AT deficiency. One patient had PiZ- heterozygous phenotype (alpha1AT level 217 mg/dL) while another patient had PiMS heterozygous. CONCLUSIONS: alpha1AT deficiency is not an important cause of neonatal cholestasis and childhood liver diseases in Malaysian children. In Malaysian children with neonatal cholestasis or other liver diseases, routine assay for alpha1AT phenotype is not recommended if there is no family history of neonatal cholestasis of uncertain aetiology, or if alpha1AT level is above 80 mg/dL. PMID- 17688649 TI - Thrombotic thrombocytopenic purpura in childhood: an uncommon but life threatening cause of thrombocytopenia. AB - Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder characterised by microangiopathic haemolytic anaemia, thrombocytopenia and signs of ischaemic organ dysfunction such as neurological or renal impairment and fever. The diagnosis of TTP should be considered in any child presenting with thrombocytopenia, in particular those children with microangiopathic haemolysis, atypical immune thrombocytopenia purpura or Evan's syndrome. Distinguishing TTP from haemolytic uraemic syndrome is difficult, but where there is doubt about the diagnosis, a presumptive diagnosis of TTP should be made to allow potentially life-saving therapy with therapeutic plasma exchange. Recent advances in the molecular basis of the disease have resulted in assays for ADAMTS-13 activity, inhibitor levels and ADAMTS-13 mutation analysis. These assays help to distinguish TTP from haemolytic uraemic syndrome. However, the performance characteristics of these assays in the diagnosis and management of TTP are yet to be defined. PMID- 17688650 TI - Early intervention for the ocular and neurodevelopmental sequelae of Fetal Valproate Syndrome. AB - The established teratogenicity of antiepileptic drugs raises important issues in women of child-bearing age. While the association between neural tube defects and antiepileptic drugs is well recognised, other congenital malformations are known to occur. We report two siblings with characteristic craniofacial features of Fetal Valproate Syndrome who also had associated ocular and neurodevelopmental problems which would benefit from early recognition and intervention. PMID- 17688651 TI - Twin pregnancy with a coexisting hydatiform mole and liveborn infant: complicated by maternal hyperthyroidism and neonatal hypothyroidism. AB - A twin pregnancy with a coexisting complete hydatiform mole and a healthy fetus is rare. Associated with this condition are potentially serious maternal and fetal complications. We describe a case of a woman, 23/40 pregnant, who was diagnosed with a twin pregnancy complicated by a hydatiform mole, vaginal bleeding, hyperthyroidism and preterm labour at 26/40. Her hyperthyroidism was successfully treated with propylthiouracil. The preterm labour resulted in the livebirth of a healthy male infant. The baby developed biochemical hypothyroidism post-natally. The baby's thyroid function tests were unexpected, revealing a low T4 and a low-normal thyroid stimulating hormone. This is the first case reported in the literature to describe an infant's clinical and biochemical thyroid status after gestational trophoblastic disease complicated by hyperthyroidism. PMID- 17688652 TI - Marked obesity in infancy and relationship to sudden infant death. PMID- 17688653 TI - Poliomyelitis: acute flaccid paralysis and stool virology. PMID- 17688655 TI - Agent orange: your new look JGH (the improvements go deeper than the cover). PMID- 17688656 TI - Is the constipated Asian male more common than we think? PMID- 17688657 TI - Cyclooxygenase-2 (COX-2): does it matter in patients with HCV-related liver cirrhosis? PMID- 17688658 TI - Growth factors as indicators of prognosis in liver failure. PMID- 17688659 TI - Effect of tegaserod on colonic transit time in male patients with constipation predominant irritable bowel syndrome. AB - BACKGROUND AND AIMS: Tegaserod is approved for the treatment of constipation predominant irritable bowel syndrome (C-IBS) in females. The aim of this study was to evaluate the effect of tegaserod on colonic transit time (CTT) and symptoms in male patients with C-IBS. METHODS: Forty-four males with C-IBS (Rome II) were enrolled. After a baseline washout period of 2 weeks, 40 patients were randomized to 6 mg twice daily of tegaserod or placebo for 12 weeks. Daily bowel habits and weekly satisfactory relief of symptoms were recorded. Total and segmental CTT were measured using radiopaque markers at baseline and after treatment. RESULTS: The mean +/- SD for the total colonic, right colonic, left colonic and rectosigmoid transit time (in hours) were 18.96 +/- 3.92, 7.74 +/- 1.55, 5.64 +/- 1.51 and 5.58 +/- 2.2 in the tegaserod group compared to 22.47 +/- 3.73, 9.69 +/- 2.33, 6.6 +/- 1.32 and 6.18 +/- 2.22 in the placebo group at the end of 12 weeks. There was a statistically significant difference in the total, right and left CTT in the tegaserod group (P < 0.05) at the end of treatment. Global satisfactory relief at the end of 12 weeks was 75% in the tegaserod group and 50% in the placebo group (P > 0.05). Greater stool frequency occurred in the tegaserod group (P > 0.05). There was a significant decrease in the stool consistency at the end of 12 weeks in patients treated with tegaserod (P < 0.05). CONCLUSIONS: Tegaserod causes significant acceleration of CTT in male patients with C-IBS. Although there was a trend towards improvement in bowel symptoms in the treated group, this effect was not statistically significant. PMID- 17688660 TI - High dose probiotic and prebiotic cotherapy for remission induction of active Crohn's disease. AB - BACKGROUND: Clinical trials of probiotic treatment for Crohn's disease (CD) have yielded conflicting results. This study assessed the clinical usefulness of combined probiotic and prebiotic therapy in the treatment of active CD. METHOD: Ten active CD outpatients without history of operation for CD were enrolled. Their mean (+/-SD) age was 27 +/- 7 years and the main symptoms presented were diarrhea and abdominal pain. Patients' initial therapeutic regimen of aminosalicylates and prednisolone failed to achieve remission. Patients were thus initiated on a synbiotic therapy, consisting of both probiotics (75 billion colony forming units [CFU] daily) and prebiotics (psyllium 9.9 g daily). Probiotics mainly comprised Bifidobacterium and Lactobacillus. Patients were free to adjust their intake of probiotics or prebiotics throughout the trial. Crohn's disease activity index (CDAI), International Organization for the Study of Inflammatory Bowel Disease (IOIBD) score and blood sample variables were evaluated and compared before and after the trial. RESULTS: The duration of the trial was 13.0 +/- 4.5 months. By the end of therapy, each patient had taken a 45 +/- 24 billion CFU daily probiotic dose, with six patients taking an additional 7.9 +/- 3.6 g daily psyllium dose. Seven patients had improved clinical symptoms following combined probiotic and prebiotic therapy. Both CDAI and IOIBD scores were significantly reduced after therapy (255-136, P = 0.009; 3.5-2.1, P = 0.03, respectively). Six patients had a complete response, one had a partial response, and three were non-responders. Two patients were able to discontinue their prednisolone therapy, while four patients decreased their intake. There were no adverse events. CONCLUSION: High-dose probiotic and prebiotic cotherapy can be safely and effectively used for the treatment of active CD. PMID- 17688661 TI - Endoscopic management of traumatic hepatobiliary injuries. AB - BACKGROUND: Non-surgical treatment has become the therapeutic method of choice in hemodynamically stable patients with liver trauma. There are a few reports of endoscopic management of traumatic hepatobiliary injuries in such patients; however, the optimal intervention is not known. METHODS: Twenty patients with traumatic hepatobiliary injuries from May 1997 to November 2005 were retrospectively evaluated. RESULTS: There were 18 male and two female patients with a mean age of 21.45 +/- 10.17 years (range 7-42 years). Seven patients were children. Patients presented 19.4 +/- 17.04 days following trauma. Computed tomography (CT) revealed hepatic laceration in right lobe in 14 (70%) and in left lobe in six (30%) patients. Endoscopic retrograde cholangiopancreatography (ERCP) revealed biliary leak in right duct in 14 (70%) and in left duct in six (30%) patients. Five patients also had bilhemia and one had hemobilia. Thirteen patients (65%) were treated by endoscopic sphincterotomy with nasobiliary drainage and seven (35%) were treated by nasobiliary drainage alone, which enabled fistula closure in 15.76 +/- 4.22 days and 12.14 +/- 3.93 days, respectively (P > 0.05). One patient in sphincterotomy group died due to multiple bony injuries and fat embolism. Two patients developed fever following ERCP, which responded to antibiotic treatment. CONCLUSIONS: Endoscopic treatment with nasobiliary drainage without sphincterotomy is the optimal method of management of traumatic hepatobiliary injuries in hemodynamically stable patients. PMID- 17688662 TI - Endoscopic retrograde cholangiopancreatography in patients with Billroth II gastroenterostomy. AB - BACKGROUND AND AIM: Endoscopic retrograde cholangiopancreatography (ERCP) is more complicated in patients with Billroth II gastroenterostomy (B II GE) especially in those associated with Braun anastomosis (BA). The aim of the present study was to review experience of ERCP in patients with B II GE. METHODS: The records of patients with B II GE who had undergone an ERCP within the last 2.5 years were retrospectively evaluated. RESULTS: Fifty-two patients with simple B II GE and seven with additional BA underwent ERCP within this period. The probability of common bile duct cannulation and success of endoscopic treatment was 43/52 (83%) and 2/7 (29%) in the respective groups. The reasons for failure were long afferent loop in patients with BA; for the nine patients with B II GE the reasons for failure were tumoral infiltration at the orifice of afferent loop in one patient, peripapillary tumoral invasion in two patients, failure of entrance to the afferent loop due to angulation in two patients, and long afferent loop in the remaining four patients. Overall, perforation developed in 10.2% (6/59 of the patients. Two of these patients died (2/59, 3.4%) and one (1/59, 1.7%) had concomitant pancreatitis. CONCLUSIONS: Although ERCP is successful in a large proportion of patients with B II GE, it carries significant risks such as perforation. ERCP must be performed by experienced endoscopists at institutions that have suitable facilities to manage endoscopy-related complications. PMID- 17688663 TI - Applicability of MELD as a short-term prognostic indicator in patients with chronic liver disease: an Indian experience. AB - BACKGROUND: The model for end-stage liver disease (MELD), which employs objective variables, statistical weighting and a continuous scale, has replaced the Child Turcotte-Pugh (CTP) classification as the scoring system of choice in several liver transplant centers. However, the predictive ability of MELD has never been prospectively evaluated in India. The aim of this study was to examine the MELD score, the CTP score and the recently proposed modified CTP score in Indian patients with liver cirrhosis to determine their correlation and compare their prognostic significance for short-term survival. METHODS: A total of 76 patients with cirrhosis (mean age 46.97 years) were prospectively evaluated and followed up for 6 months. MELD score, CTP score and modified CTP score were calculated at baseline. The correlation between variables was evaluated by Pearson's correlation test. Receiver-operating characteristic (ROC) curves were used to determine the cutoff values for each score with the best sensitivity and specificity in discriminating between patients who survived and those who died. RESULTS: Alcoholic liver disease was the most common (50%) etiology of cirrhosis. MELD score and CTP score showed very good correlation (Pearson correlation r = 0.983). ROC curve showed area under curve (c-statistics) for MELD score, CTP score and modified CTP score as 0.764, 0.804 and 0.817, respectively. CONCLUSION: The MELD score was not found to be superior to CTP score and modified CTP score for short-term prognostication of patients with cirrhosis in this study. PMID- 17688664 TI - Role of meal carbohydrate content for the imbalance of plasma amino acids in patients with liver cirrhosis. AB - BACKGROUND AND AIM: Imbalance of circulating branched chain amino acids (BCAA) versus aromatic amino acids (AAA) and hyperinsulinemia are common metabolic alterations in patients with liver cirrhosis. The aim of this study was to characterize the effect of the carbohydrate component of a protein-rich mixed meal on postprandial plasma concentrations of 21 amino acids, insulin and C peptide in patients with compensated liver cirrhosis. Furthermore, the effect of a dietary intervention on the metabolic alterations in cirrhotic patients was examined. METHODS: Eighteen patients with cirrhosis and 12 healthy volunteers received a protein-rich meal (pork filet 200 g) with or without carbohydrates (bread 50 g, glucose 20 g). A subgroup of four cirrhotic patients received an isoenergetic (117 kJ/kg bw) carbohydrate-enriched (60%) and -restricted (20%) diet for 7 days each. RESULTS: In the cirrhotic patients, basal plasma insulin and C-peptide concentrations were significantly elevated. The ingestion of a protein-rich meal without additional carbohydrates led to a significantly greater increase of insulin and C-peptide in the cirrhotic patients compared to controls. Postprandial increases of leucine and isoleucine were reduced, whereas those of phenylalanine were higher in cirrhotic patients. The addition of carbohydrates led to higher insulin and C-peptide plasma concentrations in cirrhotic patients. Postprandial BCAA increases were more impaired in the cirrhotic group after additional carbohydrate ingestion (46%vs 82%). After the carbohydrate-restricted diet for 7 days BCAA plasma levels increased but the BCAA/AAA ratio remained unaltered. CONCLUSIONS: The carbohydrate content of a meal enhances reduction of BCAA plasma concentrations in clinically stable cirrhotic patients. An imbalanced BCAA/AAA ratio cannot be avoided by a carbohydrate-reduced diet alone, supporting mandatory BCAA supplementation. PMID- 17688665 TI - Overexpressed cyclo-oxygenase-2 in the background liver is associated with the clinical course of hepatitis C virus-related cirrhosis patients after curative surgery for hepatocellular carcinoma. AB - BACKGROUND: The probable role of cyclo-oxygenase-2 (COX-2) in the development of hepatocellular carcinoma (HCC) in patients with chronic liver diseases has been accepted to be relevant. The purpose of the present study was to determine whether overexpressed COX-2 in the background liver affects the clinical course of hepatitis C virus (HCV)-related cirrhosis patients after curative surgery for HCC. METHODS: Twenty-nine clinical stage I HCC patients with HCV-related cirrhosis, who underwent curative surgery, were enrolled in the present study (22 men and seven women, age range 53-73 years; follow-up period; range 22-159 months, median 61 months). The COX-2 expression in the cirrhotic liver was examined by immunohistochemistry using the avidin-biotin-peroxidase complex technique on paraffin-embedded formalin-fixed tissue. The COX-2 expression was scored, then correlated with monitored alanine aminotransferase (ALT) levels during the follow-up period after surgery, response to alternative therapy aiming to improve elevated ALT levels, and recurrence/survival after surgery. RESULTS: The COX-2 expression scores were significantly higher in the high-ALT group than in the low-ALT group (Mann-Whitney, P = 0.010), and were significantly higher in non-responders to the alternative therapy than in responders (Mann-Whitney, P = 0.028). The higher COX-2 expression in the cirrhotic liver was the significant independent risk factor for residual liver recurrence (Cox multivariate analysis, P = 0.014), but not for survival. CONCLUSIONS: Overexpressed COX-2 in the background liver may play an important role in prolonged acceleration of necroinflammation, resistance to the alternative therapy, and recurrence/new development of HCC in HCV-related cirrhosis patients. PMID- 17688666 TI - Up-regulated eotaxin plasma levels in chronic liver disease patients indicate hepatic inflammation, advanced fibrosis and adverse clinical course. AB - BACKGROUND AND AIMS: Recent studies highlight the role of chemokines for the attraction of inflammatory cells in liver injury and fibrogenesis. The CC chemokine ligand 11, eotaxin (CCL11), is up-regulated in senescent human hepatic stellate cells and crucial in animal models of T-cell mediated hepatitis. The aim of this study was to analyze the role of eotaxin in chronic liver disease. METHODS: Plasma eotaxin levels of 111 patients with chronic liver disease were correlated with clinical presentation, laboratory parameters, liver histology and clinical course in a 6-year follow-up. RESULTS: Eotaxin concentrations were significantly up-regulated in patients with liver cirrhosis and increased according to Child-Pugh and model of end-stage liver disease (MELD) score. Eotaxin correlated with the hepatic biosynthetic capacity and other inflammatory cytokines. High eotaxin was associated with hepatic necroinflammation and fibrosis in liver histology. In patients with typical clinical complications of cirrhosis, eotaxin was found to be increased. High eotaxin indicated an unfavorable prognosis in 6-year follow-up. CONCLUSIONS: High eotaxin expression may be involved in the pathogenesis of chronic liver diseases. Plasma eotaxin levels correlate with the degree of liver cirrhosis and could serve as an additional biomarker indicating histological hepatic necroinflammation and fibrosis as well as an adverse clinical course. PMID- 17688667 TI - Serum levels of stem cell factor and thrombopoietin are markedly decreased in fulminant hepatic failure patients with a poor prognosis. AB - BACKGROUND AND AIM: Hematopoietic growth factors including stem cell factor (SCF), thrombopoietin (TPO) and granulocyte colony stimulating factor (G-CSF) have a potential role in inducing bone marrow hematopoietic stem cells to move into the circulation, and the association of these factors with liver regeneration has received a lot of attention recently. The aim of this study was to determine the serum levels of such factors in patients with acute liver injury. METHODS: The subjects were 25 patients with acute hepatitis (AH) who had a favorable prognosis and 26 patients with fulminant hepatitis (FH), of whom 11 were alive and 15 had died. Sixty-six healthy subjects matched for age and sex served as controls. Serum samples were collected before treatment, and the levels of SCF, TPO and G-CSF were measured using enzyme-linked immunosorbant assays. RESULTS: The levels of SCF and TPO were significantly lower in FH patients than in AH patients and the controls, and were also significantly lower in the FH patients who died, compared to the surviving patients. The G-CSF levels did not differ among them. CONCLUSIONS: These results suggest that low serum levels of SCF and TPO may be linked to poor prognosis in patients with severe liver injury. PMID- 17688668 TI - Inhibition of sympathetic pathways restores postoperative ileus in the upper and lower gastrointestinal tract. AB - BACKGROUND AND AIM: Postoperative ileus (POI) is a transient bowel dysmotility following abdominal surgery. The effects of adrenergic blocking agents and celiac ganglionectomy were studied in rats to investigate the possible involvement of the adrenergic pathway in whole gastrointestinal (GI) transit in the early and late phases of POI. METHODS: After laparotomy, the terminal ileum was manipulated for 10 min. (51)Cr was administered into the stomach or colon immediately after surgery. In another group, (51)Cr was administered 24 h after surgery. Three hours after (51)Cr was administered, the rats were killed, and GI and colonic transit was calculated as a geometric center (GC). RESULTS: Gastrointestinal transit was significantly delayed 3 h after intestinal manipulation, compared with GI transit in rats that had anesthesia only. Three hours after intestinal manipulation, guanethidine (5 mg/kg) and yohimbine (3 mg/kg) significantly improved delayed GI transit. Celiac ganglionectomy also significantly improved delayed GI transit. Twenty-seven hours after intestinal manipulation, guanethidine, yohimbine and celiac ganglionectomy improved delayed GI transit induced by intestinal manipulation. Colonic transit was delayed 3 h after intestinal manipulation, and delayed colonic transit was partially restored within 27 h of intestinal manipulation. Guanethidine, yohimbine and celiac ganglionectomy improved delayed colonic transit 3 h and 27 h after intestinal manipulation. CONCLUSIONS: Adrenoceptors activated by intestinal manipulation impair the motility of the entire GI tract in both the early and the late phase of POI. PMID- 17688669 TI - Serum granulysin level as a novel prognostic marker in patients with gastric carcinoma. AB - BACKGROUND: Granulysin is a cytolytic molecule present in human cytotoxic T cells and natural killer cell granules, and plays a key role in the cell-mediated immunity against tumor and infection. However, few studies have estimated serum granulysin concentrations in patients with solid or hematological malignancies. METHODS: Peripheral blood samples were taken from patients with gastric carcinoma preoperatively and from healthy volunteers. Serum and tumor tissue granulysin concentrations were measured using a granulysin-specific ELISA kit in order to assess its prognostic value. RESULTS: Both serum and tumor tissue granulysin concentrations were higher in patients with stage II or III gastric cancer and lower in patients with stage IV disease as compared to healthy controls. The low preoperative granulysin levels were associated with more frequent hepatic and peritoneal metastases, and with a poor outcome of the curative gastrectomy. CONCLUSIONS: Preoperative serum granulysin levels reflect the status of cell mediated immunity in patients with gastric carcinoma. It has significance as a prognostic determinant following a curative resection. PMID- 17688670 TI - Education and Imaging. Gastrointestinal: buried bumper syndrome. PMID- 17688671 TI - Education and Imaging. Hepatobiliary and pancreatic: extended directional power Doppler ultrasonography in liver transplantation. PMID- 17688672 TI - Education and Imaging. Gastrointestinal: ileal ulcers induced by non-steroidal anti-inflammatory drugs. PMID- 17688673 TI - Education and Imaging. Gastrointestinal: peritoneal hydatidosis. PMID- 17688674 TI - Education and Imaging. Hepatobiliary and pancreatic: spontaneous cystogastric fistula. PMID- 17688675 TI - Dieulafoy's disease as a possible cause of gallbladder hemorrhage. PMID- 17688676 TI - The effect of Pseudomonas aeruginosa virulence factor, pyocyanin, on the liver sinusoidal endothelial cell. PMID- 17688677 TI - Modeling longitudinal data in acute illness. AB - Biomarkers of sepsis could allow early identification of high-risk patients, in whom aggressive interventions can be life-saving. Among those interventions are the immunomodulatory therapies, which will hopefully become increasingly available to clinicians. However, optimal use of such interventions will probably be patient specific and based on longitudinal profiles of such biomarkers. Modeling techniques that allow proper interpretation and classification of these longitudinal profiles, as they relate to patient characteristics, disease progression, and therapeutic interventions, will prove essential to the development of such individualized interventions. Once validated, these models may also prove useful in the rational design of future clinical trials and in the interpretation of their results. However, only a minority of mathematicians and statisticians are familiar with these newer techniques, which have undergone remarkable development during the past two decades. Interestingly, critical illness has the potential to become a key testing ground and field of application for these emerging modeling techniques, given the increasing availability of point-of-care testing and the need for titrated interventions in this patient population. PMID- 17688678 TI - Mammary stem cell number as a determinate of breast cancer risk. AB - The 'cancer stem cell hypothesis' posits that cancers, including breast cancer, arise in tissue stem or progenitor cells. If this is the case, then it follows that the risk for developing breast cancer may be determined in part by the number of breast stem/progenitor cells that can serve as targets for transformation. Stem cell number may be set during critical windows of development, including in utero, adolescence, and pregnancy. The growth hormone/insulin-like growth factor-1 axis may play an important role in regulating breast stem cell number during these developmental windows, suggesting an important link between this signaling pathway and breast cancer risk. PMID- 17688679 TI - The Opossum genome reveals further evidence for regulatory evolution in mammalian diversification. AB - The sequencing of the euchromatic genome of a marsupial, the opossum Monodelphis domestica, identifies shared and unique features of marsupial and placental genomes and reveals a prominent role for the evolution of non-protein-coding elements. PMID- 17688680 TI - Analysis of KLF transcription factor family gene variants in type 2 diabetes. AB - BACKGROUND: The Kruppel-like factor (KLF) family consists of transcription factors that can activate or repress different genes implicated in processes such as differentiation, development, and cell cycle progression. Moreover, several of these proteins have been implicated in glucose homeostasis, making them candidate genes for involvement in type 2 diabetes (T2D). METHODS: Variants of nine KLF genes were genotyped in T2D cases and controls and analysed in a two-stage study. The first case-control set included 365 T2D patients with a strong family history of T2D and 363 normoglycemic individuals and the second set, 750 T2D patients and 741 normoglycemic individuals, all of French origin. The SNPs of six KLF genes were genotyped by Taqman SNP Genotyping Assays. The other three KLF genes (KLF2, 15 and -16) were screened and the identified frequent variants of these genes were analysed in the case-control studies. RESULTS: Three of the 28 SNPs showed a trend to be associated with T2D in our first case-control set (P < 0.10). These SNPs, located in the KLF2, KLF4 and KLF5 gene were then analysed in our second replication set, but analysis of this set and the combined analysis of the three variants in all 2,219 individuals did not show an association with T2D in this French population. As the KLF2, -15 and -16 variants were representative for the genetic variability in these genes, we conclude they do not contribute to genetic susceptibility for T2D. CONCLUSION: It is unlikely that variants in different members of the KLF gene family play a major role in T2D in the French population. PMID- 17688681 TI - Avoiding the danger that stop smoking services may exacerbate health inequalities: building equity into performance assessment. AB - BACKGROUND: The UK is the only developed country to have established a nation wide stop smoking treatment service. Apart from addressing tobacco dependence, which is the leading preventable cause of ill health and premature death, smoking cessation has been identified by the UK department of health as a service priority for reducing gaps in health between disadvantaged groups and the country as a whole. However smoking cessation tends to be more successful among affluent than disadvantaged groups. This means that for stop smoking services there is a trade-off to be had in terms of maximising the number of quitters and reducing socioeconomic inequalities in smoking prevalence. Current performance targets for the national stop smoking services in the UK are set only in terms of numbers of quitters, which does not encourage the adoption of strategies to reduce socioeconomic inequalities in smoking prevalence. DISCUSSION: This paper proposes an assessment framework, which allows the two dimensions of overall reduction in smoking prevalence and reductions of inequalities in smoking prevalence to be assessed together. The framework is used to assess the performance over time of a stop smoking service in Derwentside, a former Primary Care Trust in the North East of England, both in terms of meeting targets for the overall number of quitters and in terms of reducing socioeconomic inequalities in smoking prevalence. The example demonstrates how the proposed assessment framework can be applied in practice given existing records kept by stop smoking services in England and the available information on smoking prevalence at small area level. For Derwentside it is shown that although service expansion was successful in increasing the overall number of quitters, the service continued to exacerbate inequality in smoking prevalence between deprived and affluent wards. SUMMARY: The Secretary of State for Health in the UK has warned about the dangers of health promotion services and messages being taken up more readily by the better off, thus exacerbating health inequalities. Because smokers from affluent backgrounds are more successful at quitting than those living in deprived circumstances, it is important to build an equity element into the monitoring of individual stop smoking services. Otherwise the danger highlighted by the Secretary of State for Health will go undetected and unaddressed. PMID- 17688682 TI - Identification of diarrheagenic Escherichia coli isolated from infants and children in Dar es Salaam, Tanzania. AB - BACKGROUND: Relatively few studies have been done in Tanzania to detect and classify diarrheagenic Escherichia coli (DEC) strains among children with diarrhea. This study aimed at investigating DEC among children in Dar es Salaam aged less than five years hospitalized due to acute/persistent diarrhea. METHODS: DEC were isolated from stool samples collected from two hundred and eighty children with acute/persistent diarrhea at Muhimbili National Hospital and Ilala and Mwananyamala Municipal Hospitals in Dar es Salaam. A multiplex PCR system method was used to detect a species specific gene for E.coli and ten different virulence genes for detection of five pathogroups of DEC namely enteroaggregative (EAEC), enteropathogenic- (EPEC), enterotoxigenic- (ETEC), enteroinvasive- (EIEC) and enterohemorghagic- Escherichia coli (EHEC). RESULTS: Sixty-four patients (22.9%) harbored DEC. Forty-one of them (14.6%) were categorized as EAEC. Most of the EAEC (82.9%) were classified as typical EAEC possessing the aggR gene, and 92.6% carried the aat gene. Isolates from thirteen patients were EPEC (4.6%) and most of these (92.3%) were typical EPEC with both eae and bfpA genes. Ten isolates were identified as ETEC (3.6%) with only the heat stable toxin; either st1a or st1b but not both. Age wise, EAEC and EPEC were significantly more prevalent among the age group 0-6 months (p < 0.05). Genes for EHEC (stx1 and stx2) and EIEC (ial) were not detected in this study group. CONCLUSION: The results show a high proportion of DEC among Tanzanian children with diarrhea, with typical EAEC and typical EPEC predominating. The use of primers for both variants of ST1 (st1a and st1b) increased the sensitivity for detection of ETEC strains. PMID- 17688684 TI - Cophenetic correlation analysis as a strategy to select phylogenetically informative proteins: an example from the fungal kingdom. AB - BACKGROUND: The construction of robust and well resolved phylogenetic trees is important for our understanding of many, if not all biological processes, including speciation and origin of higher taxa, genome evolution, metabolic diversification, multicellularity, origin of life styles, pathogenicity and so on. Many older phylogenies were not well supported due to insufficient phylogenetic signal present in the single or few genes used in phylogenetic reconstructions. Importantly, single gene phylogenies were not always found to be congruent. The phylogenetic signal may, therefore, be increased by enlarging the number of genes included in phylogenetic studies. Unfortunately, concatenation of many genes does not take into consideration the evolutionary history of each individual gene. Here, we describe an approach to select informative phylogenetic proteins to be used in the Tree of Life (TOL) and barcoding projects by comparing the cophenetic correlation coefficients (CCC) among individual protein distance matrices of proteins, using the fungi as an example. The method demonstrated that the quality and number of concatenated proteins is important for a reliable estimation of TOL. Approximately 40-45 concatenated proteins seem needed to resolve fungal TOL. RESULTS: In total 4852 orthologous proteins (KOGs) were assigned among 33 fungal genomes from the Asco- and Basidiomycota and 70 of these represented single copy proteins. The individual protein distance matrices based on 531 concatenated proteins that has been used for phylogeny reconstruction before 14 were compared one with another in order to select those with the highest CCC, which then was used as a reference. This reference distance matrix was compared with those of the 70 single copy proteins selected and their CCC values were calculated. Sixty four KOGs showed a CCC above 0.50 and these were further considered for their phylogenetic potential. Proteins belonging to the cellular processes and signaling KOG category seem more informative than those belonging to the other three categories: information storage and processing; metabolism; and the poorly characterized category. After concatenation of 40 proteins the topology of the phylogenetic tree remained stable, but after concatenation of 60 or more proteins the bootstrap support values of some branches decreased, most likely due to the inclusion of proteins with lowers CCC values. The selection of protein sequences to be used in various TOL projects remains a critical and important process. The method described in this paper will contribute to a more objective selection of phylogenetically informative protein sequences. CONCLUSION: This study provides candidate protein sequences to be considered as phylogenetic markers in different branches of fungal TOL. The selection procedure described here will be useful to select informative protein sequences to resolve branches of TOL that contain few or no species with completely sequenced genomes. The robust phylogenetic trees resulting from this method may contribute to our understanding of organismal diversification processes. The method proposed can be extended easily to other branches of TOL. PMID- 17688683 TI - Gastrointestinal permeability in ovarian cancer and breast cancer patients treated with paclitaxel and platinum. AB - BACKGROUND: Combination of platinum derivatives with paclitaxel is currently the standard front line regimen for patients with epithelial ovarian carcinoma, and represents also an active regimen in patients with metastatic breast or unknown primary carcinomas. Measurement of intestinal permeability represents one of the potential methods of noninvasive laboratory assessment of gastrointestinal mucositis induced by chemotherapy, but little is known about intestinal permeability in patients treated with paclitaxel or platinum. METHODS: Intestinal permeability was assessed in 36 breast and ovarian cancer patients treated with paclitaxel/platinum combination by measuring, using capillary gas chromatography, urinary sucrose, lactulose, xylose and mannitol after oral challenge. The significance of differences during the therapy compared to pre-treatment values was studied by Wilcoxon paired test. The differences between groups of patient were studied by Mann-Whitney U test. Fisher exact test was used to compare the frequency in different subgroups. RESULTS: After administration of the first dose, a significant (p < 0.05) decrease in xylose absorption and increased lactulose/mannitol, sucrose/mannitol, lactulose/xylose and sucrose/xylose ratios were observed, but these parameters returned subsequently to pre-treatment levels. Patients who experienced serious (grade 3 or 4) toxicity had at baseline significantly lower percentages of xylose, mannitol and sucrose, and higher lactulose/mannitol ratio. Nine of 13 (69%) patients with baseline lactulose/mannitol ratio 0.070 or above experienced serious toxicity compared to 4 out of 23 patients (17%) with the ratio below 0.070 (p = 0.002). Post-treatment lactulose, lactulose/mannitol, sucrose/mannitol and lactulose/xylose ratios were significantly increased in patients with serious toxicity. CONCLUSION: A transient significant increase in lactulose/monosaccharide and sucrose/monosaccharide ratios was observed in ovarian and breast cancer patients treated with paclitaxel and platinum. Increased lactulose absorption, lactulose/mannitol, sucrose/mannitol and lactulose/xylose ratios were evident in patients with grade 3 or 4 toxicity, and increased baseline lactulose/mannitol ratio predicted serious toxicity. PMID- 17688685 TI - Sensitivity and specificity of the Major Depression Inventory in outpatients. AB - BACKGROUND: The Major Depression Inventory (MDI) is a new, brief, self-report measure for depression based on the DSM-system, which allows clinicians to assess the presence of a depressive disorder according to the DSM-IV, but also to assess the severity of the depressive symptoms. METHODS: We examined the sensitivity, specificity, and psychometric qualities of the MDI in a consecutive sample of 258 psychiatric outpatients. Of these patients, 120 had a mood disorder (70 major depression, 49 dysthymia). A total of 139 subjects had a comorbid axis-I diagnosis, and 91 subjects had a comorbid personality disorder. RESULTS: Crohnbach's alpha of the MDI was a satisfactory 0.89, and the correlation between the MDI and the depression subscale of the SCL-90 was 0.79 (p < .001). Subjects with major depressive disorder (MDD) had a significantly higher MDI score than subjects with anxiety disorders (but no MDD), dysthymias, bipolar, psychotic, other neurotic disorders, and subjects with relational problems. In ROC analysis we found that the area under the curve was 0.68 for the MDI. A good cut-off point for the MDI seems to be 26, with a sensitivity of 0.66, and a specificity of 0.63. The indication of the presence of MDD based on the MDI had a moderate agreement with the diagnosis made by a psychiatrist (kappa: 0.26). CONCLUSION: The MDI is an attractive, brief depression inventory, which seems to be a reliable tool for assessing depression in psychiatric outpatients. PMID- 17688686 TI - Malaria mosquito control using edible fish in western Kenya: preliminary findings of a controlled study. AB - BACKGROUND: Biological control methods are once again being given much research focus for malaria vector control. This is largely due to the emerging threat of strong resistance to pesticides. Larvivorous fish have been used for over 100 years in mosquito control and many species have proved effective. In the western Kenyan highlands the larvivorous fish Oreochromis niloticus L. (Perciformes: Cichlidae) (formerly Tilapia nilotica) is commonly farmed and eaten but has not been previously tested in the field for malaria mosquito control. METHODS: This fish was introduced into abandoned fishponds at an altitude of 1,880 m and the effect measured over six months on the numbers of mosquito immatures. For comparison an untreated control pond was used. During this time, all ponds were regularly cleared of emergent vegetation and fish re-stocking was not needed. Significant autocorrelation was removed from the time series data, and t-tests were used to investigate within a pond and within a mosquito type any differences before and after the introduction of O. niloticus. Mulla's formula was also used on the raw data to calculate the percentage reduction of the mosquito larvae. RESULTS: After O. niloticus introduction, mosquito densities immediately dropped in the treated ponds but increased in the control pond. This increase was apparently due to climatic factors. Mulla's formula was applied which corrects for that natural tendency to increase. The results showed that after 15 weeks the fish caused a more than 94% reduction in both Anopheles gambiae s.l. and Anopheles funestus (Diptera: Culicidae) in the treated ponds, and more than 75% reduction in culicine mosquitoes. There was a highly significantly reduction in A. gambiae s.l. numbers when compared to pre-treatment levels. CONCLUSION: This study reports the first field trial data on O. niloticus for malaria mosquito control and shows that this species, already a popular food fish in western Kenya, is an apparently sustainable mosquito control tool which also offers a source of protein and income to people in rural areas. There should be no problem with acceptance of this malaria control method since the local communities already farm this fish species. PMID- 17688687 TI - Influence of degree correlations on network structure and stability in protein protein interaction networks. AB - BACKGROUND: The existence of negative correlations between degrees of interacting proteins is being discussed since such negative degree correlations were found for the large-scale yeast protein-protein interaction (PPI) network of Ito et al. More recent studies observed no such negative correlations for high-confidence interaction sets. In this article, we analyzed a range of experimentally derived interaction networks to understand the role and prevalence of degree correlations in PPI networks. We investigated how degree correlations influence the structure of networks and their tolerance against perturbations such as the targeted deletion of hubs. RESULTS: For each PPI network, we simulated uncorrelated, positively and negatively correlated reference networks. Here, a simple model was developed which can create different types of degree correlations in a network without changing the degree distribution. Differences in static properties associated with degree correlations were compared by analyzing the network characteristics of the original PPI and reference networks. Dynamics were compared by simulating the effect of a selective deletion of hubs in all networks. CONCLUSION: Considerable differences between the network types were found for the number of components in the original networks. Negatively correlated networks are fragmented into significantly less components than observed for positively correlated networks. On the other hand, the selective deletion of hubs showed an increased structural tolerance to these deletions for the positively correlated networks. This results in a lower rate of interaction loss in these networks compared to the negatively correlated networks and a decreased disintegration rate. Interestingly, real PPI networks are most similar to the randomly correlated references with respect to all properties analyzed. Thus, although structural properties of networks can be modified considerably by degree correlations, biological PPI networks do not actually seem to make use of this possibility. PMID- 17688688 TI - Predicting active site residue annotations in the Pfam database. AB - BACKGROUND: Approximately 5% of Pfam families are enzymatic, but only a small fraction of the sequences within these families (<0.5%) have had the residues responsible for catalysis determined. To increase the active site annotations in the Pfam database, we have developed a strict set of rules, chosen to reduce the rate of false positives, which enable the transfer of experimentally determined active site residue data to other sequences within the same Pfam family. DESCRIPTION: We have created a large database of predicted active site residues. On comparing our active site predictions to those found in UniProtKB, Catalytic Site Atlas, PROSITE and MEROPS we find that we make many novel predictions. On investigating the small subset of predictions made by these databases that are not predicted by us, we found these sequences did not meet our strict criteria for prediction. We assessed the sensitivity and specificity of our methodology and estimate that only 3% of our predicted sequences are false positives. CONCLUSION: We have predicted 606110 active site residues, of which 94% are not found in UniProtKB, and have increased the active site annotations in Pfam by more than 200 fold. Although implemented for Pfam, the tool we have developed for transferring the data can be applied to any alignment with associated experimental active site data and is available for download. Our active site predictions are re-calculated at each Pfam release to ensure they are comprehensive and up to date. They provide one of the largest available databases of active site annotation. PMID- 17688689 TI - Pattern and determinants of hospitalization during heat waves: an ecologic study. AB - BACKGROUND: Numerous studies have investigated mortality during a heatwave, while few have quantified heat associated morbidity. Our aim was to investigate the relationship between hospital admissions and intensity, duration and timing of heatwave across the summer months. METHODS: The study area (Veneto Region, Italy) holds 4577408 inhabitants (on January 1st, 2003), and is subdivided in seven provinces with 60 hospitals and about 20000 beds for acute care. Five consecutive heatwaves (three or more consecutive days with Humidex above 40 degrees C) occurred during summer 2002 and 2003 in the region. From the regional computerized archive of hospital discharge records, we extracted the daily count of hospital admissions for people aged >or=75, from June 1 through August 31 in 2002 and 2003. Among people aged over 74 years, daily hospital admissions for disorders of fluid and electrolyte balance, acute renal failure, and heat stroke (grouped in a single nosologic entity, heat diseases, HD), respiratory diseases (RD), circulatory diseases (CD), and a reference category chosen a priori (fractures of the femur, FF) were independently analyzed by Generalized Estimating Equations. RESULTS: Heatwave duration, not intensity, increased the risk of hospital admissions for HD and RD by, respectively, 16% (p < .0001) and 5% (p < .0001) with each additional day of heatwave duration. At least four consecutive hot humid days were required to observe a major increase in hospital admissions, the excesses being more than twofold for HD (p < .0001) and about 50% for RD (p < .0001). Hospital admissions for HD peaked equally at the first heatwave (early June) and last heatwave (August) in 2004 as did RD. No correlation was found for FF or CD admissions. CONCLUSION: The first four days of an heatwave had only minor effects, thus supporting heat health systems where alerts are based on duration of hot humid days. Although the finding is based on a single late summer heatwave, adaptations to extreme temperature in late summer seem to be unlikely. PMID- 17688690 TI - When is a drug-related death not a drug-related death? Implications for current drug-related death policies in the UK and Europe. AB - BACKGROUND: Drug-related death (DRD) figures, published by the national performance management framework, are used to monitor the performance of Drug (and Alcohol) Action Teams (D[A]ATs) in England and Wales with respect to reducing DRDs among drug abusers. To date, no investigation has been made into the types of death included in these figures, the demographic and drug profile of those who died, nor the likelihood of individuals included in DRD figures interacting with services designed to assist drug abusers. The aim of this work was to examine the characteristics of deaths classified as drug-related and to explore their applicability to performance-monitor drug-related services. Liverpool was chosen because it was reported by the national DRD monitoring system to have the highest number of DRDs in 2004. METHODS: Information was retrieved from the Liverpool coroner's records and established monitoring systems on individuals reported by the national performance monitoring system as a DRD between 1st January 2004 and 30th June 2005 (n = 70). Analyses assessed differences between those categorised by the national performance monitoring system as 'drug abusers/dependents' and 'non-drug abusers/dependents' using chi2, Fisher's exact test and Mann-Whitney U. RESULTS: Non-drug abusers were significantly older (median age 53.59 vs. 38.23), had no recent contact with drug related agencies (cv. 31.6% of abusers who had treatment contact) and had different post mortem drug profiles than drug abusers. A significantly greater proportion of non-drug abusers died from drug toxicity - predominantly through anti-depressants, anti-psychotics and analgesics. CONCLUSION: Our findings suggest that the national DRD performance monitoring system includes deaths of people who are not drug abusers - individuals who are not the current focus of drug prevention, treatment or harm minimisation services. This raises concerns regarding the applicability of these figures to performance monitor D(A)ATs. Furthermore, using the more compact definitions used to monitor trends in DRDs across England, Wales and Europe fails to include a proportion of deaths attributable to drug misuse - such as those attributable blood-borne viruses. Current definitions used to monitor DRDs locally, nationally and across Europe fail to capture the true burden of drug-related mortality. PMID- 17688691 TI - Catabolic cytokine expression in degenerate and herniated human intervertebral discs: IL-1beta and TNFalpha expression profile. AB - Low back pain is a common and debilitating disorder. Current evidence implicates intervertebral disc (IVD) degeneration and herniation as major causes, although the pathogenesis is poorly understood. While several cytokines have been implicated in the process of IVD degeneration and herniation, investigations have predominately focused on Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNFalpha). However, to date no studies have investigated the expression of these cytokines simultaneously in IVD degeneration or herniation, or determined which may be the predominant cytokine associated with these disease states. Using quantitative real time PCR and immunohistochemistry we investigated gene and protein expression for IL-1beta, TNFalpha and their receptors in non-degenerate, degenerate and herniated human IVDs. IL-1beta gene expression was observed in a greater proportion of IVDs than TNFalpha (79% versus 59%). Degenerate and herniated IVDs displayed higher levels of both cytokines than non-degenerate IVDs, although in degenerate IVDs higher levels of IL-1beta gene expression (1,300 copies/100 ng cDNA) were observed compared to those of TNFalpha (250 copies of TNFalpha/100 ng cDNA). Degenerate IVDs showed ten-fold higher IL-1 receptor gene expression compared to non-degenerate IVDs. In addition, 80% of degenerate IVD cells displayed IL-1 receptor immunopositivity compared to only 30% of cells in non-degenerate IVDs. However, no increase in TNF receptor I gene or protein expression was observed in degenerate or herniated IVDs compared to non-degenerate IVDs. We have demonstrated that although both cytokines are produced by human IVD cells, IL-1beta is expressed at higher levels and in more IVDs, particularly in more degenerate IVDs (grades 4 to 12). Importantly, this study has highlighted an increase in gene and protein production for the IL-1 receptor type I but not the TNF receptor type I in degenerate IVDs. The data thus suggest that although both cytokines may be involved in the pathogenesis of IVD degeneration, IL-1 may have a more significant role than TNFalpha, and thus may be a better target for therapeutic intervention. PMID- 17688692 TI - Restaurant outbreak of Legionnaires' disease associated with a decorative fountain: an environmental and case-control study. AB - BACKGROUND: From June to November 2005, 18 cases of community-acquired Legionnaires' disease (LD) were reported in Rapid City South Dakota. We conducted epidemiologic and environmental investigations to identify the source of the outbreak. METHODS: We conducted a case-control study that included the first 13 cases and 52 controls randomly selected from emergency department records and matched on underlying illness. We collected information about activities of case patients and controls during the 14 days before symptom onset. Environmental samples (n = 291) were cultured for Legionella. Clinical and environmental isolates were compared using monoclonal antibody subtyping and sequence based typing (SBT). RESULTS: Case-patients were significantly more likely than controls to have passed through several city areas that contained or were adjacent to areas with cooling towers positive for Legionella. Six of 11 case-patients (matched odds ratio (mOR) 32.7, 95% CI 4.7-infinity) reported eating in Restaurant A versus 0 controls. Legionella pneumophila serogroup 1 was isolated from four clinical specimens: 3 were Benidorm type strains and 1 was a Denver type strain. Legionella were identified from several environmental sites including 24 (56%) of 43 cooling towers tested, but only one site, a small decorative fountain in Restaurant A, contained Benidorm, the outbreak strain. Clinical and environmental Benidorm isolates had identical SBT patterns. CONCLUSION: This is the first time that small fountain without obvious aerosol generating capability has been implicated as the source of a LD outbreak. Removal of the fountain halted transmission. PMID- 17688693 TI - Altered mental status, an unusual manifestation of early disseminated Lyme disease: A case report. AB - Early disseminated Lyme disease can have a myriad of central nervous system manifestations. These run the gamut from meningitis to radiculopathy and cranial neuropathy. Here we present a case that manifested with only acute mental status change in the setting of central nervous system involvement with Lyme disease. A paucity of other central nervous system manifestations is rare, especially with positive serum and cerebrospinal fluid markers. This article underscores the importance of a high index of clinical suspicion in detection of Lyme disease related manifestations in endemic areas. PMID- 17688694 TI - Could increased axial wall stress be responsible for the development of atheroma in the proximal segment of myocardial bridges? AB - BACKGROUND: A recent model describing the mechanical interaction between a stenosis and the vessel wall has shown that axial wall stress can considerably increase in the region immediately proximal to the stenosis during the (forward) flow phases, so that abnormal biological processes and wall damages are likely to be induced in that region. Our objective was to examine what this model predicts when applied to myocardial bridges. METHOD: The model was adapted to the hemodynamic particularities of myocardial bridges and used to estimate by means of a numerical example the cyclic increase in axial wall stress in the vessel segment proximal to the bridge. The consistence of the results with reported observations on the presence of atheroma in the proximal, tunneled, and distal vessel segments of bridged coronary arteries was also examined. RESULTS: 1) Axial wall stress can markedly increase in the entrance region of the bridge during the cardiac cycle. 2) This is consistent with reported observations showing that this region is particularly prone to atherosclerosis. CONCLUSION: The proposed mechanical explanation of atherosclerosis in bridged coronary arteries indicates that angioplasty and other similar interventions will not stop the development of atherosclerosis at the bridge entrance and in the proximal epicardial segment if the decrease of the lumen of the tunneled segment during systole is not considerably reduced. PMID- 17688695 TI - Heterogeneity of autoantibodies in 100 patients with autoimmune myositis: insights into clinical features and outcomes. AB - The objective of this study was to determine the prevalence, mutual associations, clinical manifestations, and diagnoses associated with serum autoantibodies, as detected using recently available immunoassays, in patients with autoimmune myositis (AIM). Sera and clinical data were collected from 100 patients with AIM followed longitudinally. Sera were screened cross-sectionally for 21 autoantibodies by multiplex addressable laser bead immunoassay, line blot immunoassay, immunoprecipitation of in vitro translated recombinant protein, protein A assisted immunoprecipitation, and enzyme-linked immunosorbent assay. Diagnoses were determined using the Bohan and Peter classification as well as recently proposed classifications. Relationships between autoantibodies and clinical manifestations were analyzed by multiple logistic regression. One or more autoantibodies encompassing 19 specificities were present in 80% of the patients. The most common autoantibodies were anti-Ro52 (30% of patients), anti Ku (23%), anti-synthetases (22%), anti-U1RNP (15%), and anti-fibrillarin (14%). In the presence of autoantibodies to Ku, synthetases, U1RNP, fibrillarin, PM-Scl, or scleroderma autoantigens, at least one more autoantibody was detected in the majority of sera and at least two more autoantibodies in over one-third of sera. The largest number of concurrent autoantibodies was six autoantibodies. Overall, 44 distinct combinations of autoantibodies were counted. Most autoantibodies were unrestricted to any AIM diagnostic category. Distinct clinical syndromes and therapeutic responses were associated with anti-Jo-1, anti-fibrillarin, anti U1RNP, anti-Ro, anti-Ro52, and autoantibodies to scleroderma autoantigens. We conclude that a significant proportion of AIM patients are characterized by complex associations of autoantibodies. Certain myositis autoantibodies are markers for distinct overlap syndromes and predict therapeutic outcomes. The ultimate clinical features, disease course, and response to therapy in a given AIM patient may be linked to the particular set of associated autoantibodies. These results provide a rationale for patient profiling and its application to therapeutics, because it cannot be assumed that the B-cell response is the same even in the majority of patients in a given diagnostic category. PMID- 17688696 TI - Extensive variation in synonymous substitution rates in mitochondrial genes of seed plants. AB - BACKGROUND: It has long been known that rates of synonymous substitutions are unusually low in mitochondrial genes of flowering and other land plants. Although two dramatic exceptions to this pattern have recently been reported, it is unclear how often major increases in substitution rates occur during plant mitochondrial evolution and what the overall magnitude of substitution rate variation is across plants. RESULTS: A broad survey was undertaken to evaluate synonymous substitution rates in mitochondrial genes of angiosperms and gymnosperms. Although most taxa conform to the generality that plant mitochondrial sequences evolve slowly, additional cases of highly accelerated rates were found. We explore in detail one of these new cases, within the genus Silene. A roughly 100-fold increase in synonymous substitution rate is estimated to have taken place within the last 5 million years and involves only one of ten species of Silene sampled in this study. Examples of unusually slow sequence evolution were also identified. Comparison of the fastest and slowest lineages shows that synonymous substitution rates vary by four orders of magnitude across seed plants. In other words, some plant mitochondrial lineages accumulate more synonymous change in 10,000 years than do others in 100 million years. Several perplexing cases of gene-to-gene variation in sequence divergence within a plant were uncovered. Some of these probably reflect interesting biological phenomena, such as horizontal gene transfer, mitochondrial-to-nucleus transfer, and intragenomic variation in mitochondrial substitution rates, whereas others are likely the result of various kinds of errors. CONCLUSION: The extremes of synonymous substitution rates measured here constitute by far the largest known range of rate variation for any group of organisms. These results highlight the utility of examining absolute substitution rates in a phylogenetic context rather than by traditional pairwise methods. Why substitution rates are generally so low in plant mitochondrial genomes yet occasionally increase dramatically remains mysterious. PMID- 17688697 TI - The psychometric properties of Beck Depression Inventory for adolescent depression in a primary-care paediatric setting in India. AB - BACKGROUND: There is increasing interest in identifying adolescents with depression in primary care settings by paediatricians in India. This article studied the diagnostic accuracy, reliability and validity of Beck Depression Inventory (BDI) while used by paediatricians in a primary care setting in India. METHODS: 181 adolescents attending 3 schools were administered a back translated Tamil version of BDI by a paediatrician to evaluate its psychometric properties along with Children's Depression Rating Scale (CDRS-R) for convergent validity. Clinical diagnosis of depressive disorders, for reference standard, was based on ICD-10 interview by an independent psychiatrist who also administered the Impact of Event Scale (IES) for divergent validity. Appropriate analyses for validity and diagnostic accuracy both at the item and scale levels were conducted. RESULTS: A cut-off score of >or= 5 (Sn = 90.9%, Sp = 17.6 %) for screening and cut-off score of >or= 22 (Sn = 27.3%, Sp = 90%) for diagnostic utility is suggested. The 4 week test - retest reliability was good (r = 0.82). In addition to the adequate face and content validity, BDI has very good internal consistency (alpha = 0.96), high convergent validity with CDRS-R (r = 0.72; P = 0.001), and high discriminant validity with IES (r = 0.26; P = 0.23). There was a moderate concordance rate with the reference standard (54.5%) in identifying depression among the adolescents. Factor analysis replicated the 2-factor structure explaining 30.5 % of variance. CONCLUSION: The BDI proved to be a psychometrically sound measure for use by paediatricians in a primary care setting in India. The possibility of screening for depressive disorders through the use of BDI may be helpful in identifying probable cases of the disorder among adolescents. PMID- 17688698 TI - Endogenous TGF-beta activation by reactive oxygen species is key to Foxp3 induction in TCR-stimulated and HIV-1-infected human CD4+CD25- T cells. AB - BACKGROUND: CD4+CD25+ T regulatory cells (Tregs) play an important role in regulating immune responses, and in influencing human immune diseases such as HIV infection. It has been shown that human CD4+CD25+ Tregs can be induced in vitro by TCR stimulation of CD4+CD25- T cells. However, the mechanism remains elusive, and intriguingly, similar treatment of murine CD4+CD25- cells did not induce CD4+CD25+Foxp3+ Tregs unless exogenous TGF-beta was added during stimulation. Thus, we investigated the possible role of TGF-beta in the induction of human Tregs by TCR engagement. We also explored the effects of TGF-beta on HIV-1 infection mediated induction of human Tregs since recent evidence has suggested that HIV-1 infection may also impact the generation of Tregs in infected patients. RESULTS: We show here that endogenous TGF-beta is key to TCR induction of Foxp3 in human CD4+CD25- T cells. These events involve, first, the production of TGF-beta by TCR and CD28 stimulation and the activation of latent TGF-beta by reactive oxygen species generated from the activated T cells. Biologically active TGF-beta then engages in the induction of Foxp3. Neutralization of active TGF beta with anti-TGF-beta antibody or elimination of ROS with MnTBAP abrogated Foxp3 expression. HIV-1 infection enhanced Foxp3 expression in activated CD4+CD25 T cells; which was also abrogated by blockade of endogenous TGF-beta. CONCLUSION: Several conclusions can be drawn from this work: (1) TCR and CD28 induced Foxp3 expression is a late event following TCR stimulation; (2) TGF-beta serves as a link in Foxp3 induction in human CD4+CD25- T cells following TCR stimulation, which induces not only latent, but also active TGF-beta; (3) the activation of TGF-beta requires reactive oxygen species; (4) HIV infection results in an increase in Foxp3 expression in TCR-activated CD25- T cells, which is also associated with TGF-beta. Taken together, our findings reinforce a definitive role of TGF-beta not only in the generation of Tregs with respect to normal immune responses, but also is critical in immune diseases such as HIV-1 infection. PMID- 17688699 TI - Near-highway pollutants in motor vehicle exhaust: a review of epidemiologic evidence of cardiac and pulmonary health risks. AB - There is growing evidence of a distinct set of freshly-emitted air pollutants downwind from major highways, motorways, and freeways that include elevated levels of ultrafine particulates (UFP), black carbon (BC), oxides of nitrogen (NOx), and carbon monoxide (CO). People living or otherwise spending substantial time within about 200 m of highways are exposed to these pollutants more so than persons living at a greater distance, even compared to living on busy urban streets. Evidence of the health hazards of these pollutants arises from studies that assess proximity to highways, actual exposure to the pollutants, or both. Taken as a whole, the health studies show elevated risk for development of asthma and reduced lung function in children who live near major highways. Studies of particulate matter (PM) that show associations with cardiac and pulmonary mortality also appear to indicate increasing risk as smaller geographic areas are studied, suggesting localized sources that likely include major highways. Although less work has tested the association between lung cancer and highways, the existing studies suggest an association as well. While the evidence is substantial for a link between near-highway exposures and adverse health outcomes, considerable work remains to understand the exact nature and magnitude of the risks. PMID- 17688700 TI - Structural footprinting in protein structure comparison: the impact of structural fragments. AB - BACKGROUND: One approach for speeding-up protein structure comparison is the projection approach, where a protein structure is mapped to a high-dimensional vector and structural similarity is approximated by distance between the corresponding vectors. Structural footprinting methods are projection methods that employ the same general technique to produce the mapping: first select a representative set of structural fragments as models and then map a protein structure to a vector in which each dimension corresponds to a particular model and "counts" the number of times the model appears in the structure. The main difference between any two structural footprinting methods is in the set of models they use; in fact a large number of methods can be generated by varying the type of structural fragments used and the amount of detail in their representation. How do these choices affect the ability of the method to detect various types of structural similarity? RESULTS: To answer this question we benchmarked three structural footprinting methods that vary significantly in their selection of models against the CATH database. In the first set of experiments we compared the methods' ability to detect structural similarity characteristic of evolutionarily related structures, i.e., structures within the same CATH superfamily. In the second set of experiments we tested the methods' agreement with the boundaries imposed by classification groups at the Class, Architecture, and Fold levels of the CATH hierarchy. CONCLUSION: In both experiments we found that the method which uses secondary structure information has the best performance on average, but no one method performs consistently the best across all groups at a given classification level. We also found that combining the methods' outputs significantly improves the performance. Moreover, our new techniques to measure and visualize the methods' agreement with the CATH hierarchy, including the threshholded affinity graph, are useful beyond this work. In particular, they can be used to expose a similar composition of different classification groups in terms of structural fragments used by the method and thus provide an alternative demonstration of the continuous nature of the protein structure universe. PMID- 17688701 TI - Positive end-expiratory pressure at minimal respiratory elastance represents the best compromise between mechanical stress and lung aeration in oleic acid induced lung injury. AB - INTRODUCTION: Protective ventilatory strategies have been applied to prevent ventilator-induced lung injury in patients with acute lung injury (ALI). However, adjustment of positive end-expiratory pressure (PEEP) to avoid alveolar de recruitment and hyperinflation remains difficult. An alternative is to set the PEEP based on minimizing respiratory system elastance (Ers) by titrating PEEP. In the present study we evaluate the distribution of lung aeration (assessed using computed tomography scanning) and the behaviour of Ers in a porcine model of ALI, during a descending PEEP titration manoeuvre with a protective low tidal volume. METHODS: PEEP titration (from 26 to 0 cmH2O, with a tidal volume of 6 to 7 ml/kg) was performed, following a recruitment manoeuvre. At each PEEP, helical computed tomography scans of juxta-diaphragmatic parts of the lower lobes were obtained during end-expiratory and end-inspiratory pauses in six piglets with ALI induced by oleic acid. The distribution of the lung compartments (hyperinflated, normally aerated, poorly aerated and non-aerated areas) was determined and the Ers was estimated on a breath-by-breath basis from the equation of motion of the respiratory system using the least-squares method. RESULTS: Progressive reduction in PEEP from 26 cmH2O to the PEEP at which the minimum Ers was observed improved poorly aerated areas, with a proportional reduction in hyperinflated areas. Also, the distribution of normally aerated areas remained steady over this interval, with no changes in non-aerated areas. The PEEP at which minimal Ers occurred corresponded to the greatest amount of normally aerated areas, with lesser hyperinflated, and poorly and non-aerated areas. Levels of PEEP below that at which minimal Ers was observed increased poorly and non-aerated areas, with concomitant reductions in normally inflated and hyperinflated areas. CONCLUSION: The PEEP at which minimal Ers occurred, obtained by descending PEEP titration with a protective low tidal volume, corresponded to the greatest amount of normally aerated areas, with lesser collapsed and hyperinflated areas. The institution of high levels of PEEP reduced poorly aerated areas but enlarged hyperinflated ones. Reduction in PEEP consistently enhanced poorly or non-aerated areas as well as tidal re-aeration. Hence, monitoring respiratory mechanics during a PEEP titration procedure may be a useful adjunct to optimize lung aeration. PMID- 17688702 TI - Emergency contraception among Finnish adolescents: awareness, use and the effect of non-prescription status. AB - BACKGROUND: Adolescents need to be aware that there is a method of preventing pregnancy even after an unprotected intercourse. Limited information is available on the awareness of young adolescents and the effects of selling emergency contraception (EC) over-the-counter, and the findings are controversial. The aims of this study were to investigate awareness and use of EC among Finnish girls aged 12-18 years in 1999-2003, and to assess the effect of the 2002 non prescription status on the use. METHODS: A self-administered questionnaire was sent to a population-based sample of 12-18-year-olds girls in 1999, 2001, and 2003. Response rate was 83% in 1999 (N = 4,369), 79% in 2001 (N = 4,024) and 77% in 2003 (N = 3,728), altogether N = 12,121. Logistic regression model was used to examine the association of unawareness and use of EC with socio-economic background and health behaviour. RESULTS: In 2001, nearly all 14-18-year-olds and a majority of 12-year-olds were aware of EC. Among 12-14-year-olds, a slight increase in awareness between 1999 and 2003 was observed but this was not related to non-prescription status. Health-compromising behavior (alcohol use, smoking), dating and having good school achievement were related to higher awareness of EC.Nine percent of 14-18-year-olds had used EC once and 1% three times or more. No statistically significant change in EC use was found after non-prescription status. EC use increased with increasing alcohol consumption, particularly at age 14. Smoking, dating, and poor school achievement were related to increased use as well as not living in nuclear family. A lower use was observed if living in rural area or father's education was high. Mother's education was not related to use. CONCLUSION: Adolescent girls were well aware of the existence of emergency contraception even before the non-prescription status. Over-the-counter selling did not increase the use. PMID- 17688703 TI - Psychoimmunological effects of dioscorea in ovariectomized rats: role of anxiety level. AB - BACKGROUND: Anxiety levels in rats are correlated with interleukin-2 (IL-2) levels in the brain. The aim of the present study was to investigate the effects of dioscorea (wild yam), a Chinese medicine, on emotional behavior and IL-2 levels in the brain of ovariectomized (OVX) rats. METHODS: One month after ovariectomy, female Wistar rats were screened in the elevated plus-maze (EPM) test to measure anxiety levels and divided into low anxiety (LA) and high anxiety (HA) groups, which were then given dioscorea (250, 750, or 1500 mg/kg/day) by oral gavage for 27 days and were tested in the EPM on day 23 of administration and in the forced swim test (FST) on days 24 and 25, then 3 days later, the brain was removed and IL-2 levels measured. RESULTS: Compared to sham-operated rats, anxiety behavior in the EPM was increased in half of the OVX rats. After chronic dioscorea treatment, a decrease in anxiety and IL-2 levels was observed in the HA OVX rats. Despair behavior in the FST was inhibited by the highest dosage of dioscorea. CONCLUSION: These results show that OVX-induced anxiety and changes in neuroimmunological function in the cortex are reversed by dioscorea treatment. Furthermore, individual differences need to be taken into account when psychoneuroimmunological issues are measured and the EPM is a useful tool for determining anxiety levels when examining anxiety-related issues. PMID- 17688704 TI - Classical sickle beta-globin haplotypes exhibit a high degree of long-range haplotype similarity in African and Afro-Caribbean populations. AB - BACKGROUND: The sickle (betas) mutation in the beta-globin gene (HBB) occurs on five "classical" betas haplotype backgrounds in ethnic groups of African ancestry. Strong selection in favour of the betas allele - a consequence of protection from severe malarial infection afforded by heterozygotes - has been associated with a high degree of extended haplotype similarity. The relationship between classical betas haplotypes and long-range haplotype similarity may have both anthropological and clinical implications, but to date has not been explored. Here we evaluate the haplotype similarity of classical betas haplotypes over 400 kb in population samples from Jamaica, The Gambia, and among the Yoruba of Nigeria (Hapmap YRI). RESULTS: The most common betas sub-haplotype among Jamaicans and the Yoruba was the Benin haplotype, while in The Gambia the Senegal haplotype was observed most commonly. Both subtypes exhibited a high degree of long-range haplotype similarity extending across approximately 400 kb in all three populations. This long-range similarity was significantly greater than that seen for other haplotypes sampled in these populations (P < 0.001), and was independent of marker choice and marker density. Among the Yoruba, Benin haplotypes were highly conserved, with very strong linkage disequilibrium (LD) extending a megabase across the betas mutation. CONCLUSION: Two different classical betas haplotypes, sampled from different populations, exhibit comparable and extensive long-range haplotype similarity and strong LD. This LD extends across the adjacent recombination hotspot, and is discernable at distances in excess of 400 kb. Although the multi-centric geographic distribution of betas haplotypes indicates strong subdivision among early Holocene sub-Saharan populations, we find no evidence that selective pressures imposed by falciparum malaria varied in intensity or timing between these subpopulations. Our observations also suggest that cis-acting loci, which may influence outcomes in sickle cell disease, could lie considerable distances away from beta-globin. PMID- 17688705 TI - Dietary fat intakes for pregnant and lactating women. AB - Dietary fat intake in pregnancy and lactation affects pregnancy outcomes and child growth, development and health. The European Commission charged the research project PERILIP, jointly with the Early Nutrition Programming Project, to develop recommendations on dietary fat intake in pregnancy and lactation. Literature reviews were performed and a consensus conference held with international experts in the field, including representatives of international scientific associations. The adopted conclusions include: dietary fat intake in pregnancy and lactation (energy%) should be as recommended for the general population; pregnant and lactating women should aim to achieve an average dietary intake of at least 200 mg DHA/d; intakes of up to 1 g/d DHA or 2.7 g/d n-3 long chain PUFA have been used in randomized clinical trials without significant adverse effects; women of childbearing age should aim to consume one to two portions of sea fish per week, including oily fish; intake of the DHA precursor, alpha-linolenic acid, is far less effective with regard to DHA deposition in fetal brain than preformed DHA; intake of fish or other sources of long-chain n-3 fatty acids results in a slightly longer pregnancy duration; dietary inadequacies should be screened for during pregnancy and individual counselling be offered if needed. PMID- 17688706 TI - Comparison of azithromycin and moxifloxacin against bacterial isolates causing conjunctivitis. AB - OBJECTIVE: To examine in vitro resistance to azithromycin and moxifloxacin in bacterial conjunctivitis isolates. METHODS: MIC90s (Minimum Inhibitory Concentration) and resistance rates to azithromycin and moxifloxacin were determined based upon microtiter broth dilution and/or antimicrobial gradient test strips in a multicenter phase III study and confirmed externally. RESULTS: The most common isolates collected from bacterial conjunctivitis patients in the phase III study were Haemophilus influenzae (40.6%), followed by Staphylococcus epidermidis (19.3%), Propionibacterium acnes (17.3%), Streptococcus pneumoniae (16.8%), and Staphylococcus aureus (0.06%). MIC90s for all of these organisms were well below established resistance breakpoints for moxifloxacin, indicating no bacterial resistance. On the other hand, the MIC90 for H. influenzae was 3 fold higher than the resistance breakpoint for azithromycin, > or = 128-fold higher for S. epidermidis, 16-fold higher for S. pneumoniae and > or = 128-fold higher for S. aureus, indicating moderate to very high bacterial resistance to azithromycin. CONCLUSIONS: Resistance to azithromycin is more common than resistance to moxifloxacin in clinical isolates causing bacterial conjunctivitis. PMID- 17688707 TI - Colocutaneous fistula complicating therapeutic mesenteric embolisation. AB - Percutaneous embolotherapy has now assumed an important role in the management of massive colonic haemorrhage. However, this therapeutic option is associated with a significant risk of irreversible segmental colonic ischaemia. We present a case where distal segmental ischaemia led to a colocutaneous fistula, a complication not reported so far in the literature. PMID- 17688708 TI - Endovascular treatment of bleeding external iliac artery pseudo-aneurysm following control of haemorrhage with Sengstaken tube during revision total hip arthroplasty. AB - We report a case of false aneurysm of the external iliac artery and compression of the external iliac vein, which subsequently caused deep venous thrombosis in a 63-year-old female patient with a revised total hip arthroplasty. This is the first case of control of life-threatening intraoperative haemorrhage of an external iliac pseudo-aneurysm by Sengstaken tube which allowed time for successful management of the external iliac artery pseudo-aneurysm with endovascular covered stent. Recognition of delayed vascular injury following revision of total hip arthroplasty and the need of pre-operative imaging should be considered in revision hip arthroplasty. PMID- 17688709 TI - Popliteal artery pseudo-aneurysm secondary to femoral osteochondroma: a case report and literature review. AB - A case of pseudo-aneurysm of the popliteal artery secondary to an osteochondroma of the femur in a young adult is described. PMID- 17688710 TI - Ischaemic lumbosacral plexopathy following aorto-iliac bypass graft: case report and review of literature. AB - A 77-year-old man had aorto-iliac bypass for an abdominal aortic aneurysm (AAA). This was complicated by occlusion that needed extension of the graft to the right femoral artery. He was unable to move his right leg with numbness after surgery. This was caused by extensive lumbosacral plexopathy on the right side. Lumbosacral plexopathy is uncommon because the plexus has a rich blood supply. The incidence of ischaemic lumbosacral plexopathy is higher with re-operative and emergency AAA reconstruction. This may predispose the lumbosacral plexus to ischaemic injury. Consideration should be given to maintaining retrograde perfusion of the internal iliac artery. PMID- 17688711 TI - A rare cause of abdominal pain. AB - Pacemaker migration is a rare, but important, complication of pacemaker insertion mainly documented in children. We report the case of a 60-year-old woman who was admitted with right iliac fossa pain thought to be caused by appendicitis. She was noted to have both an epicardial and endocardial pacemaker in situ. Imaging and laparoscopy revealed migration of the epicardial pacemaker to the right iliac fossa. We describe the possible mechanisms of pacemaker migration. PMID- 17688712 TI - Unusual squamous cell carcinoma of the scrotum arising from a well healed, innocuous scar of an infertility procedure: a case report. AB - A novel case of squamous cell carcinoma of scrotum that developed in a well healed, uncomplicated scar following an infertility procedure. PMID- 17688713 TI - Pneumothorax, pneumomediastinum, pneumoperitoneum, pneumoretroperitoneum and subcutaneous emphysema following diagnostic colonoscopy. AB - Colonic perforation is an unusual complication of colonoscopy. We present a case of pneumothorax, pneumomediastinum, pneumoperitoneum and extensive subcutaneous emphysema resulting from a diagnostic colonoscopy. To our knowledge, only two such cases have been described previously. PMID- 17688714 TI - The problem surgical colleague. AB - The surgical profession, more than any other medical specialty, is constantly in the limelight. Frequently, concerns are expressed about our colleagues. The concerns may be personality clashes rather than failure in behaviour or performance. Most concerns can be addressed locally with support from the Royal College Invited Review Mechanism of the National Clinical Assessment Service. Unfortunately, if the concern is sufficiently serious or repetitive it may warrant referral to the General Medical Council (GMC) who alone has the right to withdraw a surgeon's medical registration. The surgeon will then be unable to work in the medical profession in this country. The procedures the the surgeon must undergo if referred to the GMC are stressful and protracted. Even if successful the surgeon will probably be expected to undergo a period of retraining that will prove difficult to arrange. New proposals to modify the GMC procedures will reduce the standard of proof to one of 'balance of probabilities'. The surgical profession should be accountable to its patients and colleagues. Will our Royal College rise to the challenge to establish itself as the bulwark of the surgical profession? PMID- 17688716 TI - Popliteal aneurysms: from John Hunter to the 21st century. AB - Popliteal aneurysms are rare and tend to occur in older men with significant co morbidity. Historically, management of popliteal aneurysms can be considered in three broad groups: (i) the technique of Antyllus; (ii) techniques relying upon a collateral circulation; and (iii) techniques involving maintenance or restoration of circulation. Bypass and exclusion is currently been challenged by endovascular techniques which show promise in selected cases. Current controversies in popliteal aneurysms management are: when to repair asymptomatic aneurysms, what operation to do and how to manage acute thrombosis. These have been addressed by studying, prospectively, 73 patients presenting with 116 popliteal aneurysms. Diameter greater than 2 cm is often stated as being an indication for elective operation in asymptomatic popliteal aneurysms. However, distortion of the aneurysm appears to be at least as important as size in determining whether symptoms are likely to develop. Of 17 popliteal aneurysms followed for a median of 34 months with a diameter 2-3 cm and distortion less than 45 degrees , none thrombosed. This is no worse than patency following elective bypass (P = 0.064). Popliteal aneurysms greater than 3 cm in diameter in patients who are unfit or who declined an operation were significantly more likely to develop thrombosis or any other symptom (P = 0.01 and P = 0.004, respectively). Popliteal aneurysms less than 3 cm in diameter with distortion less than 45 degrees can safely be managed by ultrasound surveillance. Popliteal aneurysms with greater diameter or distortion are best operated upon. Bypass, combined with proximal and distal ligation of the aneurysm, resulted in 5-year graft patency of 78% and 65% for popliteal aneurysms originally patent or thrombosed, respectively, with good long term exclusion of the aneurysm. In addition to the general complications of intra arterial thrombolysis, acute deterioration of the limb during lysis appears to be a particular problem when dealing with thrombosed popliteal aneurysms. It occurs in about 13% of cases which compares with 2% when dealing with thrombosed grafts or native arteries. Intra-arterial thrombolysis for thrombosed popliteal aneurysms is associated with unacceptably high numbers of complications and thrombolysis should be reserved for intra-operative use only. PMID- 17688718 TI - Mesh repairs in hiatal surgery. The case against mesh repairs in hiatal surgery. PMID- 17688717 TI - Modern perspectives in the treatment of chronic anal fissures. AB - INTRODUCTION: Anal fissures are commonly encountered in routine colorectal practice. Developments in the pharmacological understanding of the internal anal sphincter have resulted in more conservative approaches towards treatment. Simple measures are often effective for early fissures. Glyceryl trinitrate is well established as a first-line pharmacological therapy. The roles of diltiazem and botulinum, particularly as rescue therapy, are not well understood. Surgery has a defined role and should not be discounted completely. METHODS: Data were obtained from Medline publications citing 'anal fissure'. Manual cross-referencing of salient articles was conducted. We have sought to highlight various controversies in the management of anal fissures. FINDINGS: Acute fissures may heal spontaneously, although simple conservative measures are sufficient. Idiopathic chronic anal fissures need careful evaluation to decide what therapy is suitable. Pharmacological agents such as glyceryl trinitrate (GTN), diltiazem and botulinum toxin have been subjected to most scrutiny. Though practices in the UK vary, GTN or diltiazem would be suitable as first-line therapy with botulinum toxin used as rescue treatment. Sphincterotomy is indicated for unhealed fissures; fissurectomy has been revisited and advancement flaps have a role in patients in whom sphincter division is not suitable. PMID- 17688719 TI - Should we pursue patients who fail to attend colorectal clinics? A 9-year study. AB - INTRODUCTION: No uniform protocol exists on how to deal with patients who fail to attend colorectal clinics. Our aim was to identify whether the tendency to 'failure to attend' (FTA) in the colorectal clinic was associated with FTA in other clinics and also whether FTA patients have serious pathology. PATIENTS AND METHODS: This was a retrospective study of a prospectively recorded list of FTA patients, in colorectal urgent or two-week wait clinics from 1996-2004. RESULTS: A total of 151 patients, who failed to attend their first appointment, were included in the study. Of these, 61 (40.4%) were colorectal referrals, 76 (50.3%) were general surgical referrals, and for 14 (9.3%) case notes were not available. There were 59 FTA episodes in 61 colorectal patients associated with 59 FTA episodes in other clinics (Pearson correlation: r = 0.411; P = 0.01, two-tailed, SPSS v.12). Of 58 colorectal outcomes, five (8.6%) colorectal cancers (CRC) were diagnosed, 23 (39.6%) were persistent non-attendees, 16 (27.5%) had benign colorectal pathology, two (3.4%) benign non-colorectal outcomes and 12 (20.6%) normal outcomes. CONCLUSIONS: Tendency to FTA is habitual. Care needs to be exercised in the management of FTAs to avoid delayed presentation of colorectal cancer. PMID- 17688720 TI - Is patient outcome affected by the administration of intravenous fluid during bowel preparation for colonic surgery? AB - INTRODUCTION: We have previously shown that Picolax bowel preparation causes a significant dehydrating effect, which can be minimised by administering a calculated volume of intravenous fluid. The aim of this prospective study was to assess whether peri-operative outcome is affected by administering a calculated volume of intravenous fluid during bowel preparation. PATIENTS AND METHODS: Patients having bowel preparation (Picolax: Ferring Pharmaceuticals Ltd, Middlesex, UK) prior to colonic surgery were prospectively randomised to receive no intravenous fluid (group 1) or calculated intravenous crystalloid based on their body weight (group 2), during preparation. In both groups, transfusion was protocol-driven. Outcome variables measured included intra-operative and postoperative intravenous fluid requirement, hourly recorded urine output for 24 h, number of patients transfused, number of units of blood transfused, time to the passage of flatus, time to having their bowels open, time until tolerating a full diet, complications and length of stay in hospital. RESULTS: Thirty-three patients were recruited - group 1 (n = 18) and group 2 (n = 15). There were 24 men and 9 women, median age 69 years (range, 29-86 years). There was no significant difference between the groups with respect to age, sex, weight, ASA grade, pre-operative haemoglobin concentration, duration or type of operation. The total number of patients receiving a transfusion (P = 0.026) and the number of units of blood transfused (P = 0.017) was significantly greater in group 1. The number of units of blood transfused intra-operatively was significantly greater in group 1 (P = 0.029). Significantly fewer patients had a urine output < 30 ml/h in the first 24-h after operation (P = 0.046) in group 2. There was no difference between groups in other outcomes measures. CONCLUSIONS: This study indicates that a calculated volume of intravenous fluid administered during bowel preparation improves patient outcomes with respect to blood transfusion and postoperative oliguria. We advocate calculated intravenous fluid administration in all patients undergoing bowel preparation prior to colonic surgery. PMID- 17688721 TI - Giant haemangioma of the liver: is enucleation better than resection? AB - INTRODUCTION: Haemangioma is the most common liver tumour. Treatment is indicated for symptomatic tumours, rapid increase in size, rupture or doubt in diagnosis. There is continuing debate regarding the ideal method of surgical treatment for liver haemangiomas, with some surgeons favouring enucleation over liver resection. PATIENTS AND METHODS: Retrospective analysis of prospectively compiled database of patients who were surgically treated for liver haemangioma. RESULTS: Between 1987 and 2003, we operated on 21 patients with liver haemangioma. Pre operative diagnosis on imaging was made in 16 patients (13 symptomatic, 3 had progressive increase in size). In five patients, the indication of surgery was uncertain diagnosis. Enucleation was performed in 9 patients and liver resection in 12. The size of the haemangioma was similar in the enucleation and resection groups (8.9 cm versus 10 cm; P = 0.85). The mean intra-operatiive blood loss was significantly less in the enucleation group (400 ml versus 1330 ml; P = 0.004). The mean operative time was significantly less in the enucleation group as compared to the resection group (170 min versus 230 min; P = 0.035). Five patients had major postoperative morbidity in the resection group as compared to none in the enucleation group (P = 0.045). The duration of hospital stay was significantly longer in the resection group.(9.9 days versus 5.6 days; P = 0.005). CONCLUSIONS: Enucleation of liver haemangiomas is safer, quicker and associated with less morbidity than liver resection. Except for some situations, such as uncertain diagnosis or total replacement of a lobe, we recommend enucleation as the surgical procedures of choice for the treatment of hepatic haemangiomas. PMID- 17688722 TI - Ultrasound-guided, vacuum-assisted excision in the diagnosis and treatment of clinically benign breast lesions. AB - INTRODUCTION: Ultrasound-guided, vacuum-assisted biopsy has a definitive role in the diagnosis of breast lesions. Its role in the treatment of benign breast lesions like fibroadenomas has not been established. PATIENTS AND METHODS: This is a retrospective review of patients undergoing ultrasound-guided, vacuum assisted biopsy for clinically benign breast lesions. The procedures were performed in all cases by two consultant radiologists with special interest in breast radiology between February 2002 and January 2004. Patients were followed up in the clinic 6 weeks after the procedure. RESULTS: Seventy-six patients had ultrasound-guided, vacuum-assisted excision of clinically benign breast lesions during this 2-year period. Mean age of the patients was 31 years. Altogether, 86 procedures were performed. Six patients with larger lesions (> 2 cm) had two procedures on separate sitting and 4 patients had separate lesions excised on a later date. Fifty-six patients were identified to have fibroadenomas and had complete excisions as evidenced on scan. Three out of nine patients identified with equivocal disease on fine needle aspiration cytology (FNAC) were found to have cancer following ultrasound-guided, vacuum-assisted excision. One patient who was diagnosed with cancer on FNAC, proved to be fibroadenoma on final histopathology. Four patients developed haematomas following ultrasound-guided, vacuum-assisted excision and all were managed conservatively. CONCLUSIONS: Our study shows that ultrasound-guided, vacuum-assisted excision can play an efficient role in the diagnosis of benign breast lesions and is a safe and successful alternative in treatment of fibroadenomas. PMID- 17688723 TI - Inguinal hernia repair: local or general anaesthesia? AB - INTRODUCTION: Specialist hernia centres and public hospitals with a dedicated hernia service (Plymouth Hernia Service) have achieved remarkable results for inguinal hernia repair with the use of local anaesthesia and set the standards for groin hernia surgery. There is minimal data in the literature as to whether such results are reproducible in the National Health Service in the UK. PATIENTS AND METHODS: A retrospective analysis of all inguinal hernia repairs performed in one district general hospital over a 9-year period was performed. The outcome measures were type of anaesthesia used, early and late postoperative complications and recurrence. A postal questionnaire survey was conducted to obtain satisfaction rates. In addition, a postal questionnaire survey of consultant surgeons in Wales was performed to determine the use of local anaesthesia and day-case rates for inguinal hernia repair. RESULTS: A total of 577 hernia repairs were performed during the study period. Of these, 369 (64%) repairs were performed under local anaesthesia (LA) and 208 (36%) under general anaesthesia (GA). Day-case repair was achieved in 70% (400) of cases. The day case rates were significantly higher under LA compared to GA (82.6% versus 42.6%; P < 0.05). Patients operated under LA had lower postoperative analgesic requirements and lower incidence of urinary retention compared with the GA group (P < 0.05). There were 7 (1.2%) recurrences at a median follow-up of 5.1 years (range, 10.3-2.5 years). Postal questionnaire revealed higher satisfaction rates with LA compared to GA repair. Only 15% of surgeons in Wales offer the majority of their patients local anaesthetic repair. CONCLUSIONS: The use of LA results in increased day-case rates, lesser postoperative analgesic requirements and fewer micturition problems. The excellent results obtained by specialist hernia centres can be reproduced by district general hospitals by increasing the use of LA to repair inguinal hernias. PMID- 17688724 TI - Managing osteoporosis in patients with fragility fractures: did the British Orthopaedic Association guidelines have any impact? AB - INTRODUCTION: The incidence of fragility fractures could double in the next 50 years. Effective treatments for osteoporosis exist and the British Orthopaedic Association (BOA) has guidelines governing how to manage underlying osteoporosis in patients with fragility fractures. This study assessed how well two trauma units treat underlying osteoporosis and whether the BOA guidelines made any impact. PATIENTS AND METHODS: Case notes of patients with a fracture of their proximal femur admitted during January and February in 2003, 2004 and 2005 were reviewed. The results were analysed for differences between site and year. RESULTS: A total of 602 case notes were reviewed. There was a significant difference in the number of patients discharged on osteoporosis medication between the two sites (27% at LRI, 8% at KGH; P < 0.001), but not between 2003 and 2005 (22% and 16%; P = 0.16). Of the patients started on treatment, 83% were started on calcium and/or vitamin D(3) supplements. CONCLUSIONS: The number of patients who had their underlying osteoporosis addressed was low and the type of treatment sub-optimal. This suggests the BOA guidelines have not made an impact and further work is required to improve the management of these patients. PMID- 17688726 TI - Ponseti treatment in the management of clubfoot deformity - a continuing role for paediatric orthopaedic services in secondary care centres. AB - INTRODUCTION: The Ponseti technique is a well-proven way of managing paediatric clubfoot deformity. We describe a management set-up which spreads the care between secondary and tertiary care with no loss of quality. PATIENTS AND METHODS: In our audit of the first 2 years of Ponseti casting in the treatment of idiopathic congenital talipes equinovarus (CTEV, clubfoot) deformity, we identified 77 feet having been treated in 50 patients. Forty-nine feet were treated primarily in Oswestry, a tertiary referral centre for paediatric orthopaedic conditions, and 13 feet were treated in conjunction with the physiotherapy department at one of the region's district general hospitals (Leighton Hospital, Crewe, Cheshire). RESULTS: Similar good results and low requirement for surgical interventions other than Achilles tenotomy, which forms part of the Ponseti regimen, were found in both cohorts. CONCLUSIONS: This 'hub and-spoke' approach would appear to be efficient in terms of resource utilisation. Additional benefits for patients and their carers include ease of access to services and reduced financial and transport burdens. PMID- 17688727 TI - Helicopter Emergency Ambulance Service (HEAS) transfer: an analysis of trauma patient case-mix, injury severity and outcome. AB - INTRODUCTION: A retrospective review of all patients transferred by helicopter ambulance to the Great Western Hospital over a 20-month period between January 2003 and September 2004 was undertaken to establish the case-mix of patients (trauma and non-trauma) transferred and the outcome. PATIENTS AND METHODS: Details of all Helicopter Emergency Ambulance Service (HEAS) transfers to this unit in the study time period were obtained from the three HEAS providers in the area and case notes were reviewed. RESULTS: There were 156 trauma patients transferred (total 193) in the study period with 111 cases identified for analysis with a mean age of 33 years (range, 1-92 years). Average Injury Severity Score on admission was 12 (range, 1-36). Forty-five patients were discharged home from the emergency department, 24 cases had operation, 10 patients required ICU care and 2 were pronounced dead in the emergency department. Average hospital stay following HEAS transfer was 2.97 days (range, 0-18 days). DISCUSSION: Helicopter ambulance transfer in the acute setting is of debated value. Triage criteria are at fault if as many as 41% of patients transferred are being discharged home from casualty having incurred the financial cost of helicopter transfer. We suggest that the triage criteria for helicopter emergency transfer should be reviewed. PMID- 17688728 TI - Mortality following hip fracture surgery in patients with recent myocardial infarction. AB - INTRODUCTION: In an elective setting, surgery is best avoided for at least 6 months following myocardial infarction. However, in the presence of a femoral neck fracture, this would most probably lead to significant complications in relation to prolonged immobilisation. There is no published mortality data for patients undergoing surgery for hip fracture following a recent myocardial infarction. The aim of this retrospective study was to assess the mortality of hip fracture patients with a recent myocardial infarction that have undergone surgery at our institution. PATIENTS AND METHODS: Between January 2003 and October 2005, 2270 patients were admitted to our unit with a proximal femoral fracture. Of these, 11 patients were found to have a recent myocardial infarction. RESULTS: Of these 11 patients, 8 were female. The average age was 78.2 years (range, 59-90 years). Average delay from the time of infarction to operation was 11.2 days (range, 3-23 days). Mortality at 1 and 6 months was 45.4% and 63.5%, respectively. DISCUSSION: This is much higher than the overall reported mortality following proximal femur fracture. This information may be useful when planning future peri-operative care and discussing overall prognosis with patients and their relatives. PMID- 17688729 TI - Day-case rigid and flexible ureteroscopy. AB - INTRODUCTION: The aim of this study was to evaluate the feasibility of rigid and flexible ureteroscopy as a day-surgery procedure. PATIENTS AND METHODS: All patients requiring elective ureteroscopy from March 2004 were considered for a day-surgery procedure. The standard day-surgery exclusions existed but there were no urological criteria for exclusion. A single consultant urologist performed or supervised all procedures. RESULTS: A total of 64 patients underwent 50 rigid and 14 flexible procedures. Six diagnostic ureteroscopies were performed. There was a 96% stone clearance rate. Five patients required an unplanned admission within the first 2 weeks' postoperatively. Three of these patients were admitted on the day of surgery, two for pain and one for social reasons. Two patients were admitted at 24 h and 48 h, respectively, for urinary retention. CONCLUSIONS: Ureteroscopy, both rigid and flexible, is a safe procedure for the day-surgery setting. Routine use of prophylactic antibiotics, intravenous non-steroidal anti inflammatory drugs resulted in an acceptable re-admission rate. PMID- 17688734 TI - The practical application of a method of assessing defective theatre scissors. PMID- 17688735 TI - MRSA contamination. PMID- 17688736 TI - Limitation of sling distraction in ankle arthroscopy. PMID- 17688737 TI - Scissor efficacy. PMID- 17688738 TI - Cutting with scissors. PMID- 17688739 TI - Fine needle aspiration cytology. PMID- 17688740 TI - MP3 users beware. PMID- 17688741 TI - Laparoscopic management of non-viable bowel following reduction en masse. PMID- 17688742 TI - Characteristics of calcium sulfate/gelatin composite biomaterials for bone repair. AB - A novel hybrid biomaterial composed of calcium sulfate (CS) and gelatin (GEL) was prepared with the potential of being used as bone filler or scaffold owing to its osteoconduction. Such composite biomaterial, cross-linked or un-cross-linked, could provide a suitable absorbing rate and prevent the CS crystals migrating from the implant for tissue engineering. The structure of the composite was analyzed with infrared (IR) spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy (SEM). The results indicated that the crystal pattern of CS was affected by the addition of GEL. The GEL part affected the development of the CS dihydrate (CSD) crystal by slowing the conversion from CS hemihydrate (CSH) to CSD; thus, the composite actually contained CSD, CSH and GEL. The compressive strength of the CS/CLGEL composite was also investigated. The compressive strength was correlated to the weight proportions of CS in the CS/cross-linked GEL (CS/CLGEL) composite, and the highest compressive strength of 82 MPa was obtained for the composite containing 40 wt% CS. The in vitro absorption test and the SEM results showed that a porous scaffold was formed in situ with the absorption of CS in the CS/CLGEL composite in a certain time. Therefore, the CS/CLGEL composite material can be used as an in situ porous scaffold with a high initial mechanical strength, and the remaining porous GEL scaffold will enable further in-growth of cells. Human osteoblasts were cultured in contact with the CS/CLGEL composite and the primary results suggested that human osteoblasts could attach and spread on the surface of CS/CLGEL films. The preliminary animal model experiment was operated for assessing the potential of the CS/CLGEL composite as a biodegradable bone substitute. The primary results showed that the CS/CLGEL composite filler could promote new bone in-growth, which will stimulate further study. PMID- 17688743 TI - Characterization of new biodegradable bone cement compositions based on functional polysuccinates and methacrylic anhydride. AB - New biodegradable poly(3-allyloxy-1,2-propylene)succinate-based materials were obtained by cross-linking poly(3-allyloxy-1,2-propylene)succinate (PSAGE) with methyl methacrylate (MMA) and methacrylic anhydride (MAAH). The aim of this study was to examine the influence of MAAH/MMA ratio and incorporation of biphasic calcium phosphate (BCP) filler on the maximum curing temperature, setting time, compressive strength and modulus of the cured materials, as well as on their hydrolytic degradation. The latter was characterized by determination of the weight loss and observation of changes in samples morphology by SEM. The maximum temperature during cross-linking was found to decrease with increasing MAAH content. The setting time was affected strongly by the concentration of double bonds and was rapidly shortened with its increase. The compressive strength and compressive modulus values increased with increasing MAAH/MMA ratio. Moreover, addition of bioactive mineral filler (BCP) improves significantly mechanical properties of these materials. On the other hand, it slows down their hydrolytic degradation. PMID- 17688745 TI - Enhanced proliferation and osteogenic differentiation of rat mesenchymal stem cells in collagen sponge reinforced with different poly(ethylene terephthalate) fibers. AB - The objective of this study was to investigate the feasibility of collagen sponges mechanically reinforced by the incorporation of poly(ethylene terephthalate) (PET) fibers in stem cell culture. A collagen solution with homogeneously dispersed PET fibers was freeze-dried, followed by dehydrothermal cross-linking to obtain the collagen sponge incorporating PET fibers. By scanning electron microscopy observation, the collagen sponges exhibited isotropic and interconnected pore structures with an average size of 200 microm, irrespective of PET fiber incorporation. As expected, PET fibers incorporation significantly enhanced the compression strength of collagen sponge. When used for rat mesenchymal stem cells (MSC), the collagen sponge incorporating PET fibers was superior to the original collagen sponge without PET fibers incorporation in terms of the initial attachment, proliferation and osteogenic differentiation of cells, irrespective of the amount and diameter of fibers incorporated. The shrinkage of sponges during cell culture was significantly suppressed by the fiber incorporation. It is possible that the shrinkage suppression maintains the three-dimensional inner pore structure of collagen sponges without impairing the cell compatibility, resulting in the superior MSC attachment and the subsequent osteogenic differentiation in the sponge incorporating PET fiber. PMID- 17688744 TI - Influence of cross-linking degree of a biodegradable genipin-cross-linked gelatin guide on peripheral nerve regeneration. AB - We evaluated peripheral nerve regeneration using biodegradable genipin-cross linked gelatin nerve conduits (GGCs) with three different cross-linking degrees, 24, 36 and 51%. Biocompatibility and biodegradability of the GGC and its efficiency as a guidance channel were examined based on the repair process of a 10-mm gap in the rat sciatic nerve. From this pilot study we concluded that GGCs with a mean cross-linking degree of 36% can ensure nerve regeneration with a more mature structure, as demonstrated by better developed epineural and perineural organisation and axonal development, as well as better-recovered electrophysiology with a relatively positive sciatic functional index and a shorter latency of the muscle action potential curve. Regenerated nerves in the GGCs with mean cross-linking degrees of 24 and 51% were less favourable, due to irritation caused by degradation material and compression by the remaining tube walls, respectively. PMID- 17688746 TI - Expression profile of plasmid DNA obtained using spermine derivatives of pullulan with different molecular weights. AB - The objective of this study was to prepare a novel gene carrier from pullulan, a polysaccharide with an inherent affinity for the liver, and evaluate the feasibility in gene transfection. Pullulan with different molecular weights was cationized by chemical introduction of spermine. The cationized pullulan derivative was complexed with a plasmid DNA and applied to HepG2 cells for in vitro gene transfection. The level of gene expression depended on the molecular weight of cationized pullulan derivatives and the highest level was observed for the cationized pullulan derivative with a molecular weight of 47.3 x 10(3). Pre treatment of cells with asialofetuin decreased the level of gene expression by the complexes. These findings indicate that the cationized pullulan derivative is a promising non-viral carrier of plasmid DNA which is internalized in a receptor mediated fashion. PMID- 17688747 TI - Partially biodegradable temperature- and pH-responsive poly(N isopropylacrylamide)/dextran-maleic acid hydrogels: formulation and controlled drug delivery of doxorubicin. AB - A new family of partially biodegradable temperature- and pH-responsive hydrogels, poly(N-isopropylacrylamide)/dextran-maleic acid (PNIPAAm/Dex-MA), was synthesized and its application as a drug carrier was investigated. The PNIPAAm/Dex-MA hydrogels were synthesized by UV cross-linking over a wide range of mixed solvent ratios of dimethyl formamide (DMF) to water. PNIPAAm and Dex-MA precursors were chosen as thermo-sensitive and pH-sensitive components, respectively. Dex-MA was also used as a cross-linker. An anti-tumor drug, doxorubicin, was used to examine the effects of network structures of PNIPAAm/Dex-MA hydrogels on the release of drug. These PNIPAAm/Dex-MA hybrid hydrogels exhibited a wide range of porous network structures and sizes due to the effect of the mixed solvent during the gelation reaction. This variation in porous network structure of NDF hydrogels led to a wide range of swelling, deswelling and biodegradation processes. The distinctive porous structure of the PNIPAAm/Dex-MA hydrogels was correlated to the release of doxorubicin from the hydrogels. A larger and faster release of doxorubicin was found in those hydrogels having a large pore size. This new family of PNIPAAm/Dex-MA hydrogels may have a great potential as drug carriers because of their combined stimuli-response capability, as well as partial biodegradability. PMID- 17688748 TI - In vivo evaluation of an ultra-thin polycaprolactone film as a wound dressing. AB - The use of ultra-thin films as dressings for cutaneous wounds could prove advantageous in terms of better conformity to wound topography and improved vapour transmission. For this purpose, ultra-thin poly(epsilon-caprolactone) (PCL) films of 5-15 microm thickness were fabricated via a biaxial stretching technique. To evaluate their in vivo biocompatibility and feasibility as an external wound dressing, PCL films were applied over full and partial-thickness wounds in rat and pig models. Different groups of PCL films were used: untreated, NaOH-treated, untreated with fibrin, NaOH-treated with perforations, and NaOH treated with fibrin and S-nitrosoglutathione. Wounds with no external dressings were used as controls. Wound contraction rate, histology and biomechanical analyses were carried out. Wounds re-epithelialized completely at a comparable rate. Formation of a neo-dermal layer and re-epithelialization were observed in all the wounds. A lower level of fibrosis was observed when PCL films were used, compared to the control wounds. Ultimate tensile strength of the regenerated tissue in rats reached 50-60% of that in native rat skin. Results indicated that biaxially-stretched PCL films did not induce inflammatory reactions when used in vivo as a wound dressing and supported the normal wound healing process in full and partial-thickness wounds. PMID- 17688751 TI - Access to primary care: advanced... or smart? PMID- 17688752 TI - Chronic musculoskeletal pain. PMID- 17688753 TI - Dementia: still muddling along? PMID- 17688754 TI - Impact of Advanced Access on access, workload, and continuity: controlled before and-after and simulated-patient study. AB - BACKGROUND: Case studies from the US suggest that Advanced Access appointment systems lead to shorter delays for appointments, reduced workload, and increased continuity of care. AIM: To determine whether implementation of Advanced Access in general practice is associated with the above benefits in the UK. DESIGN OF STUDY: Controlled before-and-after and simulated-patient study. SETTING: Twenty four practices that had implemented Advanced Access and 24 that had not. METHOD: Anonymous telephone calls were made monthly to request an appointment. Numbers of appointments and patients consulting were calculated from practice records. Continuity was determined from anonymised patient records. RESULTS: The wait for an appointment with any doctor was slightly shorter at Advanced Access practices than control practices (mean 1.00 day and 1.87 days respectively, adjusted difference -0.75; 95% confidence interval [CI] = -1.51 to 0.004 days). Advanced Access practices met the NHS Plan 48-hour access target on 71% of occasions and control practices on 60% of occasions (adjusted odds ratio 1.61; 95% CI = 0.78 to 3.31; P = 0.200). The number of appointments offered, and patients seen, increased at both Advanced Access and control practices over the period studied, with no evidence of differences between them. There was no difference between Advanced Access and control practices in continuity of care (adjusted difference 0.003; 95% CI = -0.07 to 0.07). CONCLUSION: Advanced Access practices provided slightly shorter waits for an appointment compared with control practices, but performance against NHS access targets was considerably poorer than officially reported for both types of practice. Advanced Access practices did not have reduced workload or increased continuity of care. PMID- 17688755 TI - Does Advanced Access improve access to primary health care? Questionnaire survey of patients. AB - BACKGROUND: General practices in England have been encouraged to introduce Advanced Access, but there is no robust evidence that this is associated with improved access in ways that matter to patients. AIM: To compare priorities and experiences of patients consulting in practices which do or do not operate Advanced Access. DESIGN OF STUDY: Patient questionnaire survey. SETTING: Forty seven practices in 12 primary care trust areas of England. METHOD: Questionnaire administered when patients consulted. RESULTS: Of 12,825 eligible patients, 10,821 (84%) responded. Most (70%) were consulting about a problem they had had for at least 'a few weeks'. Patients obtained their current appointment sooner in Advanced Access practices, but were less likely to have been able to book in advance. They could usually see a doctor more quickly than those in control practices, but were no more satisfied overall with the appointment system. The top priority for patients was to be seen on a day of choice rather than to be seen quickly, but different patient groups had different priorities. Patients in Advanced Access practices were no more or less likely to obtain an appointment that matched their priorities than those in control practices. Patients in both types of practice experienced problems making contact by telephone. CONCLUSION: Patients are seen more quickly in Advanced Access practices, but speed of access is less important to patients than choice of appointment; this may be because most consultations are about long-standing problems. Appointment systems need to be flexible to accommodate the different needs of different patient groups. PMID- 17688756 TI - Influence of magnetic resonance of the knee on GPs' decisions: a randomised trial. AB - BACKGROUND: Magnetic resonance imaging (MRI) of the knee for meniscus and ligament injuries is an accurate diagnostic test. Early and accurate diagnosis of patients with knee problems may prevent the onset of chronic problems such as osteoarthritis, a common cause of disability in older people consulting their GP. AIM: To assess the effect of early access to MRI, compared with referral to an orthopaedic specialist, on GPs' diagnoses and treatment plans for patients with knee problems. DESIGN OF STUDY: A multi-centre, pragmatic, randomised controlled trial. SETTING: Five hundred and fifty-three patients with knee problems were recruited from 163 general practices across the UK from November 2002 to October 2004. METHOD: Eligible patients were randomised to MRI or consultation with an orthopaedic specialist. GPs made a concomitant provisional referral to orthopaedics for patients who were allocated to imaging. GPs recorded patients' diagnoses, treatment plans, and their confidence in these decisions at trial entry and follow-up. Data were analysed as intention to treat. RESULTS: There was no significant difference between MRI and orthopaedic groups for changes in diagnosis (P = 0.79) or treatment plans (P = 0.059). Significant changes in diagnostic and therapeutic confidence were observed for both groups with a greater increase in diagnostic confidence (P<0.001) and therapeutic confidence (P = 0.002) in the MRI group. There was a significant increase in within-group changes in diagnostic and therapeutic confidence. CONCLUSION: Access to MRI did not significantly alter GPs' diagnoses or treatment plans compared with direct referral to an orthopaedic specialist, but access to MRI significantly increased their confidence in these decisions. PMID- 17688757 TI - Health risk appraisal in older people 3: prevalence, impact, and context of pain and their implications for GPs. AB - BACKGROUND: Pain is a common experience in later life. There is conflicting evidence of the prevalence, impact, and context of pain in older people. GPs are criticised for underestimating and under-treating pain. AIM: To assess the extent to which older people experience pain, and to explore relationships between self reported pain and functional ability and depression. DESIGN OF STUDY: Secondary analysis of baseline data from a randomised controlled trial of health risk appraisal. SETTING: A total of 1090 community-dwelling non-disabled people aged 65 years and over were included in the study from three group practices in suburban London. METHOD: Main outcome measures were pain in the last 4 weeks and the impact of pain, measured using the 24-item Geriatric Pain Measure; depression symptoms captured using the 5-item Mental Health Inventory; social relationships measured using the 6-item Lubben Social Network Scale; Basic and Instrumental Activities of Daily Living and self-reported symptoms. RESULTS: Forty-five per cent of women and 34% of men reported pain in the previous 4 weeks. Pain experience appeared to be less in the 'oldest old': 27.5% of those aged 85 years and over reported pain compared with 38-53% of the 'younger old'. Those with arthritis were four times more likely to report pain. Pain had a profound impact on activities of daily living, but most of those reporting pain described their health as good or excellent. Although there was a significant association between the experience of pain and depressed mood, the majority of those reporting pain did not have depressed mood. CONCLUSION: A multidimensional approach to assessing pain is appropriate. Primary care practitioners should also assess the impact of pain on activities of daily living. PMID- 17688758 TI - A case-control study of presentations in general practice before diagnosis of coeliac disease. AB - BACKGROUND: Delay in the diagnosis of coeliac disease prolongs morbidity and may increase mortality. Little is known about presentations in general practice that may predict a subsequent diagnosis of coeliac disease. AIM: To examine presentations in general practice during the 5 years prior to diagnosis of coeliac disease. DESIGN OF STUDY: A case-control study with each biopsy-proven coeliac disease case matched by age, sex, and general practice to an average of two controls. SETTING: Thirty-seven general practices in south-east Wales. METHOD: Cases were identified via a secondary care clinic and controls recruited from the general practices of cases. General practice clinical records of both cases and controls were analysed to determine frequency of consultations, presenting symptoms, diagnoses, referrals, and investigations during the 5 years prior to diagnosis. RESULTS: Cases (n = 68) had an increased number of consultations compared with controls (n = 160) during the 5 years prior to diagnosis (mean difference five consultations, P = 0.001). Three clinical features were independently associated with subsequent diagnosis of coeliac disease: depression and/or anxiety (odds ratio [OR] = 2.5, 95% confidence interval [CI] = 1.1 to 5.7, P = 0.031); diarrhoea (OR = 4.5, 95% CI = 2.0 to 10.0, P <0.001); and anaemia (OR = 26.3, 95% CI = 5.7 to 120.6, P <0.001). Both diarrhoea and anaemia remained associated even when data for the year prior to diagnosis was excluded from the analysis. CONCLUSION: [corrected] GPs should consider testing for coeliac disease when patients present often, especially with diarrhoea and/or who are discovered to be anaemic. Further research is required to clarify the role of depression and/or anxiety in the diagnosis of coeliac disease. PMID- 17688759 TI - Health locus of control and use of conventional and alternative care: a cohort study. AB - BACKGROUND: Health locus of control influences health-related behaviour, but its association with healthcare use is unclear. AIM: To investigate the association between individuals' health locus of control and the use of conventional and alternative health care. DESIGN OF STUDY: Prospective cohort study. SETTING: A nationally representative random sample of community-dwelling adult households in Japan. METHOD: Health locus of control, symptom-related visits to physicians, and the use of dietary and physical complementary and alternative medicine (CAM) was measured. Dietary CAM included supplements, such as herbs and vitamins. Physical CAM included manipulations, such as acupuncture and acupressure. RESULTS: Of the 2453 adult participants studied, 2103 (86%; 95% CI [confidence interval] = 84 to 88%) developed at least one symptom during the 31-day study period. Of these symptomatic adults, 639 visited physicians (30%; 95% CI = 28 to 32%), 480 used dietary CAM (23%; 95% CI = 21 to 25%), and 156 (7%; 95% CI = 6 to 9%) used physical CAM. The likelihood of visiting a physician was not related significantly to individuals' health locus of control. Increased use of dietary CAM was weakly associated with control by spiritual powers (P = 0.028), internal control (P = 0.013), and less control by professionals (P = 0.020). Increased use of physical CAM was significantly associated with control by spiritual powers (P = 0.009) indicating a belief that supernatural forces control individuals' health status. CONCLUSION: The likelihood of visiting a physician is not affected by individuals' health locus of control. Control by spiritual powers is involved with increased CAM use. Internal control is weakly associated with greater use of dietary CAM; professional control is weakly associated with less use of dietary CAM. PMID- 17688760 TI - Diagnosing depression in primary care using self-completed instruments: UK validation of PHQ-9 and CORE-OM. AB - There is increased emphasis on routine assessment of depression in primary care. This report is the first UK validation of two self-completed measures: the Patient Health Questionnaire (PHQ-9) and the Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM). Optimum cut-off points were established against a diagnostic gold standard in 93 patients. PHQ-9 sensitivity = 91.7% (95% confidence interval [CI] = 77.5 to 98.3%) and specificity 78.3% (95% CI = 65.8 to 87.9%). CORE-OM sensitivity = 91.7% (95% CI = 77.5 to 98.2%) and specificity = 76.7% (95% CI = 64.0 to 86.6%). Brief self-rated questionnaires are as good as clinician-administered instruments in detecting depression in UK primary care. PMID- 17688761 TI - Predictive value of tonometry with Tono-pen XL in primary care. AB - This is a descriptive study designed to assess the predictive value of intraocular pressure (IOP) measurement in GPs' offices in an urban healthcare site using Tono-pen XL. A total of 2044 patients, aged > or =40 years, were enrolled by consecutive sampling from patients visiting the GP. Those participants who had IOP > or =21 mmHg were referred to the ophthalmologist. Of the 226 then tested, ocular hypertension was confirmed in 100 participants (4.89%, 95% CI [confidence interval] = 3.93 to 5.85%). Predictive value was 44.2%. These results suggest the validity of using Tono-pen XL in the GP's office to detect ocular hypertension. PMID- 17688763 TI - Shoulder adhesive capsulitis: systematic review of randomised trials using multiple corticosteroid injections. AB - BACKGROUND: Adhesive capsulitis is a common, painful, and disabling condition that has been managed with corticosteroid injections for over 50 years. There is debate over the use of single or multiple injections, but no systematic review has investigated the effects of administering multiple injections. AIM: To assess the efficacy of treating adhesive capsulitis of the shoulder with multiple corticosteroid injections. DESIGN OF STUDY: Systematic review. METHOD: An English language search for randomised controlled trials was conducted from: MEDLINE, EMBASE, CINAHL, PEDro, SIGLE, National Technical Information Service, British National Bibliography, Index of Scientific and Technical Proceedings databases, and the Cochrane Library. Randomised controlled trials were identified from reference lists of review and eligible articles. The studies were assessed using a recognised rating system of methodological trial quality. The conclusions and results of the identified studies, based on their main outcome measures, were then summarised. RESULTS: Nine randomised controlled trials were identified and four studies were rated as high quality. Three high quality studies showed a beneficial effect for the use of multiple corticosteroid injections with outcome measures of pain reduction, improved function, and increased range of shoulder movement. CONCLUSION: The evidence suggested that multiple injections were beneficial until 16 weeks from the date of the first injection. Up to three injections were beneficial, with limited evidence that four to six injections were beneficial. No evidence was found to support giving more than six injections. PMID- 17688764 TI - OOH care and locum doctors. PMID- 17688762 TI - Prognostic factors for musculoskeletal pain in primary care: a systematic review. AB - BACKGROUND: Estimating the future course of musculoskeletal pain is an important consideration in the primary care consultation for patients and healthcare professionals. Studies of prognostic indicators tend to have been viewed in relation to each site separately, however, an alternative view is that some prognostic indicators may be common across different sites of musculoskeletal pain. AIM: To identify generic prognostic indicators for patients with musculoskeletal pain in primary care. DESIGN OF STUDY: Systematic review. SETTING: Observational cohort studies in primary care. METHOD: MEDLINE, EMBASE, PsychINFO and CINAHL electronic databases were searched from inception to April 2006. Inclusion criteria were that the study was a primary care-based cohort, published in English and contained information on prognostic indicators for musculoskeletal conditions. RESULTS: Forty-five studies were included. Eleven factors, assessed at baseline, were found to be associated with poor outcome at follow up for at least two different regional pain complaints: higher pain severity at baseline, longer pain duration, multiple-site pain, previous pain episodes, anxiety and/or depression, higher somatic perceptions and/or distress, adverse coping strategies, low social support, older age, higher baseline disability, and greater movement restriction. CONCLUSION: Despite substantial heterogeneity in the design and analysis of original studies, this review has identified potential generic prognostic indicators that may be useful when assessing any regional musculoskeletal pain complaint. However, Its unclear whether these indicators, used alone, or in combination, can correctly estimate the likely course of individual patients' problems. Further research is needed, particularly in peripheral joint pain and using assessment methods feasible for routine practice. PMID- 17688766 TI - Vitamin D deficiency. PMID- 17688767 TI - QOF. PMID- 17688768 TI - Screening for peripheral vascular disease. PMID- 17688772 TI - Essay - Family medicine education and training in China: past, present and future. PMID- 17688774 TI - Diagnostic testing: the importance of context. PMID- 17688775 TI - The end of the road for the campaign against MMR. PMID- 17688781 TI - [Results of psychoanalytic long-term therapy in specific diagnostic groups: improvement in symptoms and interpersonal relationships]. AB - OBJECTIVES: In the present paper, data from four German studies on the efficacy of outpatient psychoanalytic long-term psychotherapy were examined for symptom reduction (SCL-90-R) and reduction of interpersonal problems (IIP-D). Specifically, the research question addressed the efficacy of long-term therapy in specific diagnostic groups and was was compared with that of a parallel group who underwent shorter-term psychodynamic therapy. METHODS: Data from four German studies addressing the efficacy of outpatient psychoanalytic long-term therapy were collected. Evaluation of these data was carried for specific diagnostic groups allowing for comorbid diagnoses. The effects of psychoanalytic therapy were assessed by pre-post and pre-follow-up comparisons using paired t-tests. Additionally, effect sizes were calculated. Psychoanalytic long-term psychotherapy and shorter-term psychodynamic therapy were compared by using a repeated measure ANOVA: Pretreatment vs. posttreatment/follow-up (two-levels) with the between subject factor "therapy conditions" (two levels). RESULTS: The results showed that in terms of improvement of symptoms and interpersonal problems, psychoanalytic long-term therapy was at least as effective as shorter term psychodynamic therapy with regard to the following ICD-10 diagnostic groups: affective disorders (F3), anxiety disorders (F40; F41; F42), personality disorders (F60; F61; F62), and a group of mixed neurotic disorders (F43; F50; F51; F1; F55). Effect sizes were large and remained stable at follow-up. CONCLUSIONS: The authors emphasize the clinical relevance of the examined diagnostic groups and relatively large effects achieved by the psychoanalytic treatment. Furthermore, the occurrence of comorbid diagnoses and their consequences are discussed. The authors stress that the specific effects of psychoanalytic therapy can only be very insufficiently tapped by the outcome measures referring to symptoms and interpersonal problems. PMID- 17688782 TI - [Validation of the "Assessment of DSM-IV Personality Disorders (ADP-IV)" Questionnaire]. AB - OBJECTIVES: The "Assessment of DSM-IV Personality Disorders (ADP-IV)" represents a 94-item questionnaire that allows for a categorical and dimensional assessment of the DSM-IV personality disorders. METHODS: Psychometric properties of the German ADP-IV were investigated in 400 psychotherapy outpatients and a community sample of 385 persons. The SCID-II interview and a standardised expert consensus rating were employed for the assessment of concurrent validity. RESULTS: The ADP IV showed satisfactory reliability; the median Cronbach's alpha for the subscales was .76 (range .65-.87), the median retest reliability .79 (range .37-.88). Factor analysis revealed an 11-factor solution that explained 49.4% of the variance. The median correlation of the dimensional ADP-IV subscale scores with the SCID-II and the expert consensus ratings were .51 (range: .34-.72) and .44 (range: .27-.62), respectively. The kappas for the chance corrected agreement of categorical ADP-IV diagnoses with the SCID-II diagnoses and the expert ratings were .35 and .29 for any personality disorder and a median of .37 and .30 for the specific personality disorders. CONCLUSIONS: The ADP-IV shows satisfactory reliability and a validity that is comparable and partly superior to other self rating instruments. The advantages of the instrument are its brevity, the inclusion of distress ratings, and the dimensional scoring that allows for the construction of detailed profiles of personality pathology. Moreover it is freely available in the internet: (http://zmkweb.uni muenster.de/einrichtungen/proth/dienstleistungen/psycho/diag/index.html). PMID- 17688783 TI - [The effectiveness of psychoanalytic-interactional therapy in borderline personality disorder: a study of clinical data]. AB - OBJECTIVES: Different methods are available for the psychotherapeutic treatment of patients with severe structural mental disorders. Psychoanalytic-interactional therapy is among those methods which have been clinically proven to be effective for many years. Psychoanalytic-interactional therapy was derived from analytic psychotherapy specifically to allow for the treatment of severely disturbed patients, e.g. patients with borderline personality disorders, prepsychotic disorders, addictions and perversions. METHODS: In a naturalistic study, the effectiveness of psychoanalytic-interactional therapy was tested in a sample of patients with borderline personality disorders (N = 132). The patients were treated at the Clinic Tiefenbrunn near Goettingen, Germany. Standardized, reliable and valid diagnostic instruments were used to study the treatment effects. RESULTS: Psychoanalytic-interactional therapy was found to significantly improve target symptoms, general symptoms, interpersonal problems and life satisfaction. DISCUSSION: The results are discussed with regard to the treatment of severely disturbed patients. PMID- 17688784 TI - [How do conflict and structure present themselves in relationships?]. AB - It is argued that the approaches used up to now for analyzing dysfunctional relationship patterns are more or less explicitly based on a conflict model and therefore not adequate for describing relationships characterized by structural impairments of a patient's personality. Using the concepts of conflict and structure as derived from the Operationalized Psychodynamic Diagnostic system (OPD-2), four principles of a dysfunctional relationship formation are discussed. It is shown that the differentiation of conflict- and structure-related pathology is highly significant with regard to the selection of an appropriate psychotherapeutic strategy. Furthermore, the connections between the OPD axes relationship, conflict, and structure are conceptualized. PMID- 17688785 TI - [Influence of personality variables on perceived help and stress by group therapy and fellow patients in multimodal psychodynamic inpatient psychotherapy]. AB - OBJECTIVE: The aim of the study was to investigate whether dimensional traits of personality disorder and other aspects of personality had an influence on perceived help and stress by the subsettings of a multimodal psychodynamic inpatient psychotherapy. METHODS: 89 patients of a psychodynamic psychotherapy clinic were investigated. Symptom severity was measured using SCL-R-90 symptom check list and BSS (Impairment Score). A questionnaire for patients' assessment of perceived help and stress by each subsetting of the therapy program was administered weekly. Personality assessment included (1) personality traits related to specific personality disorder as defined by SCID-II interview and questionnaire, (2) interpersonal problems as measured by the IIP, (3) self related affiliation as measured by SASB-INTREX questionnaire (Introjekt), and (4) psychotrauma as determined by the Childhood Trauma Questionnaire (CTQ). Therapy outcome measures were: change of SCL-90-R, change of BSS, perceived change in VEV. RESULTS: Perceived help and stress by the total setting, by inpatient group therapy and by fellow patients were shown to be primarily influenced by personality traits related to DSM-IV clusters of personality disorders, particularly by Cluster-A-related traits. Interpersonal dominance and trauma history had an influence as well. CONCLUSION: Perceived help and stress by subsettings of inpatient psychotherapy can be predicted on the basis of several aspects of personality. PMID- 17688786 TI - [Fast-track surgery deserves more attention]. PMID- 17688787 TI - [Hepatic surgery in the era of liver transplantation]. PMID- 17688788 TI - [Diagnosis and treatment of rare hepatic benign and malignant occupying lesions in 42 cases]. AB - OBJECTIVE: To sum up the experience of diagnosis and treatment of rare hepatic benign and malignant occupying lesion (OL) in 42 cases. METHODS: The clinical data of 42 cases of rare hepatic benign and malignant OL were reviewed retrospectively. RESULTS: Accordance rate of the imaging diagnosis with pathological result was 23.8%; the diagnostic accuracies of ultrasound B, CT and MRI were 14.3%, 19.4% and 22.2%, respectively. All cases were followed up for 1 - 5 years, no recurrence was found in 32 cases of benign OL post operation, 2 patients with malignant OL has survived for 18 and 36 months respectively, other 5 survived an average time of 7.5 months. CONCLUSIONS: It's difficult to make a confirmed diagnosis of rare hepatic benign and malignant OL before operation, combined examination of ultrasound B, CT and MRI can improve accuracy in diagnosis, no recurrence occurred in benign OL after operation, surgery can prolong survival in malignant OL. PMID- 17688789 TI - [Role of post-operative transcatheter arterial chemoembolization in hepatocellular carcinoma with different pathological characteristics]. AB - OBJECTIVE: To evaluate the efficacy of transcatheter arterial chemoembolization (TACE) on postoperative recurrence of hepatocellular carcinoma. METHODS: A total of consecutive 823 patients with hepatocellular carcinoma from October 1996 to September 2001 were included in this study. All patients underwent curative liver resection and 126 patients (15.3%) received TACE post operation. The effects of postoperative TACE on the recurrence of hepatocellular carcinoma with different pathological characteristics such as tumor size, tumor capsule, number of nodules, vascular invasion and surgical margin was analyzed. RESULTS: Postoperative TACE had not decreased the recurrence rate in patients with a tumor diameter less than 3 cm. Postoperative TACE increased the disease-free survival for patients with tumor diameter of 3 - 10 cm, positive in alpha fetoprotein (AFP), presented vascular invasion or patients with tumor diameter larger than 10 cm, positive in AFP, multi-nodular, presented vascular invasion, resection margin less than 1 cm. CONCLUSIONS: Postoperative TACE can decrease recurrence rate and prolong the survival of hepatocellular carcinoma patients with high risk factors for recurrence. PMID- 17688790 TI - [Comparative study of selective hepatic vascular exclusion and Pringle maneuver in hepatectomy involving the second porta hepatis]. AB - OBJECTIVE: To compare the effects of selective hepatic vascular exclusion (SHVE) and Pringle maneuver in resecting the liver tumors involving the second porta hepatis. METHODS: From January 2000 to October 2005, 2100 liver tumors were resected, among which 235 tumors adhered to or were very close to one or more hepatic veins. Both SHVE and Pringle maneuver were used to control the blood loss during the hepatectomy. They were divided into two groups: SHVE group (125 cases) and Pringle group (110 cases). Data regarding the intra-operative and postoperative courses of the patients were analyzed. SHVE group included total SHVE (clamping of the porta hepatis and all major hepatic veins) in 25 cases and partial SHVE (clamping of the porta hepatic and one or two hepatic veins) in 100 cases. Three methods were used to occlude hepatic veins: be ligated with suture, be encircled and occluded with tourniquets and be clamped with Shatinsky clamps directly. RESULTS: There was no difference between the 2 groups regarding the age, sex, tumor size, cirrhosis and HBsAg positive rate, ischemia time and operating time (P > 0.05). Intra-operative blood loss and transfusion requirements were decreased significantly in the SHVE group. Hepatic veins ruptured with massive blood loss in 14 and air embolism in 3 in Pringle group, but there was no massive blood loss and air embolism in SHVE group. Postoperative bleeding, reoperation, liver function failure and mortality rate were higher in Pringle group (P < 0.05), ICU stay and hospital stay were longer in Pringle group (P < 0.05). CONCLUSIONS: SHVE is much more effective than Pringle maneuver for controlling intraoperative bleeding. It can prevent massive blood loss and air embolism resulting from hepatic veins ruptured and can reduce the postoperative complications rate and mortality rate. Clamping the hepatic veins with Shatinsky clamp is safer and easier than encircled and occluded with tourniquets. PMID- 17688791 TI - [Identification of a naturally presented MAGE-A3 epitope on the surface of HLE cell line by mass spectrometry]. AB - OBJECTIVE: To identify a naturally presented HLA-A2-restricted epitope of MAGE-A3 antigen, FLWGPRALV (MAGE-A3(271 - 279)), on the surface of a human hepatocellular carcinoma (HCC) cell line HLE. METHODS: Synthetic peptide FLWGPRALV, served as positive control target, was analyzed by HPLC and HPLC-ESI-TOF-MSMS, in order to determine its HPLC elution time, mass-spectrometric characteristics and the lowest detection limitation by the two approaches. 3 x 10(9) HLE cells were collected, peptides naturally presented by major histocompatibility complex (MHC) molecules on the cell surface were isolated by mild acid elution, and concentrated by lyophilization, then the mixtures of peptides were fractioned by HPLC. The ingredient ranged from 2 min before the elution time determined by the synthetic peptide to 2 min after that was collected, concentrated by lyophilization, and analyzed by HPLC-ESI-TOF-MSMS, to identify the existence of the MAGE-A3(271 - 279) peptide. RESULTS: The HPLC-ESI-TOF-MSMS detection provided an evidence for the existence of a doubly charged ion of (m/z)(2) 529.9, which was further analyzed by collision induced dissociation. The doubly charged ion was ultimately identified as the MAGE-A3(271 - 279) peptide, its amino sequence was FLWGPRALV and its molecular weight was 1058.4 Da. CONCLUSIONS: MAGE-A3(271 - 279) epitope could be naturally presented by HLA-A2 molecules to the surface of HCC cell line and MAGE-A3(271 - 279) peptide may have potential immunotherapeutic value in HCC patients. PMID- 17688792 TI - [The tracking of allogenic grafted rat bone marrow stem cells in rat liver and their role on repairing injured liver]. AB - OBJECTIVE: To study the location, immigration of allogenic grafted Feridex labeled rat bone marrow stem cells (BMSCs) in chemically-induced acute injured livers and their role on repairing the injured liver function. METHODS: The rat models of chemically-induced acute hepatic injury established with CCl4 Feridex labeled BMSCs were injected into the injured livers. Magnetic resonance imaging (MRI) examination was conducted on rat livers, the levels of ALT, AST and Fe3+ in the serum and hepatic tissues were studied 6 h before and 6 h, 1 w and 5 w after injection. RESULTS: Cellular necrosis, congestion in the hepatic sinusoid and infiltration of inflammatory cells were seen in the model livers. Above 90 percent of the cells were Feridex-labeled BMSCs positive by prussian blue staining and iron particles were found in their endochylema through electron microscopy. MRI examination at the sequence of SE-T2WI showed remarkably low signal changes 6 h after injecting Feridex-labeled BMSCs and the site with signal changes gradually expanded 1 and 5 w after injection. Comparatively, the changes of low signal images at each time point in the injured livers were more obvious than those of the controls at all time points, respectively. Simultaneously, pathological injuries in the livers were ameliorated and the levels of ALT and AST in serums declined: these changes in the Feridex-labeled BMSCs group were more obvious than those in the non-Feridex-labeled BMSCs group. Uniformly, there were no significant differences between the Feridex-labeled BMSCs group and the non-Feridex-labeled BMSCs group in view of histopathological examination and serological examination (including ALT, AST, Fe3+ levels) at all time points. CONCLUSIONS: The liver function in the model of chemically-induced acutely injured liver may be repaired by BMSCs implantation. Traced by MRI, BMSCs in the injured liver of rats disperse at a higher rate than in the normally fed ones. PMID- 17688793 TI - [TNF-alpha induced reversal of multidrug resistance in human hepatocellular carcinoma cells]. AB - OBJECTIVE: To investigate the reversal of multidrug resistance in the cell line HepG2/ADM induced by TNF-alpha. METHODS: HepG2/ADM cells were incubated with different concentrations of TNF-alpha (100, 500 and 2500 U/ml) for 72 h. Real time PCR was performed to compare the mRNA levels of MDR1 with PPAR-alpha in the different concentrations of TNF-alpha treated cells. The Annexin V assay was used to check cell apoptosis induced by 0.5 mg/L adriamycin. Rhodamine 123 efflux assay and MTT assay were used to study P-gp activity and drug resistance in each group, respectively. RESULTS: TNF-alpha could induce down-regulation of MDR1 and up-regulation of PPAR-alpha. Meanwhile, it could enhance cell cytotoxicity and cell apoptosis induced by 0.5 mg/L adriamycin. CONCLUSIONS: TNF-alpha could partially reverse the multidrug resistance of HepG2/ADM cells by down-regulating the expression of MDR1 and up-regulating the expression of PPAR-alpha. PMID- 17688794 TI - [Study of mesenchymal stem cells transfected with oncogenes differentiate into hepatocellular carcinoma of rats]. AB - OBJECTIVE: To investigate the effect of rat mesenchymal stem cells (MSCs) transfected with different oncogenes differentiate into hepatocellular carcinoma (HCC) in vitro. METHODS: MSCs, transfected with different oncogenes c-myc, K-ras, c-myc and K-ras and amplified in vitro, were infused into rats via vena portae. The recipient rats were divided into the hepatic impairment group, which were fed with tetrachloromethane and the healthy control group. At day 7, 14, 21, 28 and 42 following grafting, the complete livers were obtained and examined using fluorescence detection, conventional pathology and immunohistochemistry detection of GFP, c-kit and AFP to study the colonization and distribution of stem cells in rat liver. RESULTS: No immunological rejection occurred after grafting of allogenic MSCs. The infused MSCs colonized in the recipient rat liver. Liver tumors were present in 6 rats grafted with MSCs that were transfected with K-ras, K-ras and c-myc, and the protein expression of AFP was detected using immunocytochemistry at day 7. Rats grafted with MSCs that were transfected with c myc gene had no obvious tuberosity or tumor. Small oval cells were found microscopically in the periphery of vena portae, and immunohistochemistry staining of AFP was negative. Immunohistochemical staining of c-kit was positive in all livers of rats that were transfected with MSCs. CONCLUSIONS: Hepatocellular carcinoma may derive from genetically mutated MSCs. PMID- 17688795 TI - [Three-dimensional assessment of the remnant hepatic function following surgery using single photon emission computed tomography in an animal model]. AB - OBJECTIVE: The predictive value of postoperative hepatic function evaluated by liver functional imaging combined with single photon emission computed tomography (SPECT) technique was appraised in the present study. METHODS: Twenty New Zealand white rabbits were divided randomly into two groups, including the Hepatic Fibrosis with Carcinoma Group (FC-Group, n = 10) and the Control Group (C-Group, n = 10). All the rabbits underwent the resection of outer-right lobe of the liver. The whole hepatic function indexes, such as HCI(5), HLI(5) and Ex(15), and the hepatic function remnant indexes, including HCI(5P), HLI(5P) and Ex(15P), were calculated by 99mTc-EHIDA liver imaging. RESULTS: Ex(15) of FC-Group was lower than that of C-Group (P < 0.05). HCI(5) and HLI(5) of FC-Group had the trends to increase compared with the C-Group. Ex(15) was positively correlated with ALB, and negatively correlated with TBil and GGT (P < 0.05). HCI(5) had a positive correlation with CHE (P < 0.05), while HLI(5) had a negative correlation with A/G (P < 0.05). HLI(5P) had the negative correlation with postoperative A/G (P < 0.05), and Ex(15P) had the negative correlation with postoperative TBil and GGT (P < 0.05). CONCLUSIONS: This study has established a method of 3-D liver function evaluation system on an animal model. Among the indexes, Ex(15) can exactly represent the whole liver function while Ex(15P) and HLI(5P) can predict the liver function after the liver resection. The results may help the future clinical use of this technique to evaluate the risk of operation. PMID- 17688797 TI - [Surgical treatment of profunda femoral vein insufficiency]. AB - OBJECTIVE: To study the role and curative effect of encircling construction of the popliteal vein and ligation of the profunda femoral vein (PFV) to treat profunda femoral vein insufficiency (PFVI). METHODS: Thirty-four patients were diagnosed as having PFVI through phlebography and color ultrasound system. (CEAP clinical scale: C(4) 31, C(5) 1, C(6) 2). The forms of the profunda femoral veins (PFV) were Raju grouping, type II: 22, type III: 10, type IV: 2. Thirty-two patients' popliteal veins were annularly constructed in the distal communication of the PFV and the popliteal vein, and in the abouchement of gastrocnemius vein into the popliteal vein. The other two PFV trunks were ligated at the communication of PFV trunk and the popliteal vein. RESULTS: Thirty-one patients (91.1%), 4, 6-year follow-up in average, threw off their aching pain in the leg. Pigmentation from the ankle to the middle of the leg subsided; the ulcers were healed and did not relapse. The postoperative ambulatory venous pressure detected was distinguishable from the preoperative data (P < 0.01), venous pressure recovery time > 22 seconds. A standing position (60 degrees from the vertical) is used in the postoperative phlebography. And the development time of the contrast media reaching the superior margin of patellar level, together with the regurgitation volume per minute of the popliteal vein detected through color ultrasound system in a standing position, was recorded. The patients' physical status had been greatly improved after the surgery (P < 0.01). CONCLUSIONS: The back flow caused by PFVI has a deep impact on the hemodynamics of the lower limb. In the popliteal fossa, it is operable and effective to use encircling construction of popliteal vein and the ligation of the PFV to treat PFVI. PMID- 17688798 TI - [Study on culture, identification and differentiation of CD133+ endothelial progenitor cells from human umbilical cord blood]. AB - OBJECTIVE: To study the isolation, culture and identification of CD133+ endothelial progenitor cells (EPCs) from human umbilical cord blood in vitro. METHODS: EPC separation was performed with density gradient centrifugation and MACS separation. Purity of EPCs was determined by flow cytometry. EPC was cultured with EBM-2 to study the cultivate features of EPC. Uptake test of Dil LDL and FITC-Lectin and immunohistochemistry were performed. RESULTS: According to flow cytometry, (1.13 +/- 0.10)% of mono-nuclear cells were CD133+ and the purities of CD133+ EPCs were (91.45 +/- 1.04)% on average. CD133+ EPCs became adherent, spindle-shaped and formed cluster during culture. Uptake test of Dil LDL and FITC-Lectin were positive. (95.83 +/- 1.72)% of CD133+ cells were found positive in both uptake tests. The positive rates of immunostaining of cell markers CD34 and factor VIII were (95.83 +/- 2.23)% and (95.92 +/- 1.43)% after cultured for one week, which showed no significant differences between CD133+ EPCs and human umbilical vein endothelial cells. Capillary structures were formed by CD133+ EPCs after cultured for 4 and 7 d in vitro. CONCLUSIONS: High purity of CD133+ EPCs can be obtained by MACS separation. CD133+ EPCs can differentiate into mature endothelial cells with the effects of stimulating factors. PMID- 17688799 TI - [Separation of gastrothoracopagus conjoined twins: 2 cases report]. AB - OBJECTIVE: To investigate reasonable surgical therapy for conjoined twins. METHODS: Two pairs of gastrothoracopagus were admitted in July 2004 and April 2005 respectively. The first pair was separated by emergency surgery for the rupture of umbilical hernia resulting in the exposure of intestines. The thoracic and abdominal wall was repaired with local skin flaps, and the secondary wound was covered with artificial skin. Skin expanders were embedded in thoracic and abdominal wall 2 months after birth in the second pair. The surgical separation was performed one month after. The deficiencies of pericardium, sternum and abdominal wall were reconstructed by allogenic grafting of pericardium, porous polyethylene implant and monofilament polypropylene patch respectively. The thoracic and abdominal wall was repaired with expanded rotation skin flap. RESULTS: The first twins died of respiratory failure and circulatory and respiratory failure 2 hours and 39 hours after the separation respectively. Both of the second pair survived and were discharge after healing. CONCLUSIONS: The separation of gastrothoracopagus should be performed after skin expansion in the interest of the closure of wound. It's better to use porous polyethylene implant and monofilament polypropylene patch to reconstruct the sternum and abdominal wall respectively. PMID- 17688800 TI - [Research of rat small intestinal mesentery lymphoid tissue stimulating allograft mixed lymphocyte reaction]. AB - OBJECTIVE: To evaluate the effect of the small intestinal mesenteric lymphoid tissues stimulating mixed lymphocyte reaction with dendritic cells (DC) and peripheral blood monocyte cells (PBMC), and observe the changes of the MHC molecular expression on DC. METHODS: DC, PBMC and mixed lymphocyte were separated to culture from SD rats. Lymphoid tissue suspension was adopted from small intestinal mesentery of Wistar rats. In the mixed lymphocyte reaction (MLR), the cellular proliferation of small intestinal mesenteric lymphoid tissue antigen act on DC and PBMC was detected with cell counting of CCK-8 assay, the same assay used in small intestinal mesenteric lymphoid tissue antigen and ovalbumin (OVA) acting on DC. FACS analysis was performed after lymphoid tissue suspension stimulating DC to observe the MHC molecular expression. RESULTS: In the lymphoid tissue suspension, 91% of the cells was lymphocyte, others including granulocyte, plasmocyte, epithelium. The effect of stimulating mixed lymphocyte proliferation were higher in DC groups than in PBMC groups with the small intestinal mesenteric lymphoid tissue (P < 0.05). In the proportion of DC and mixed lymphocyte >or= 1:100 groups, the mixed lymphocyte proliferation were higher in the small intestinal mesenteric lymphoid tissues groups than in the OVA groups (P < 0.05). After stimulated by the small intestinal mesenteric lymphoid tissue, DC expressed higher MHC-I and -II molecules than control groups. CONCLUSIONS: The small intestinal mesenteric lymphoid tissue has high antigenicity; the antigen presenting ability of DC was much stronger than granulocytes; DC expresses high MHC-I and MHC-II molecules after stimulated by mixed lymphoid tissue suspension. PMID- 17688811 TI - [Principles and related consideration on the treatment of primary malignant bone tumor]. PMID- 17688812 TI - [New concept on surgical treatment of esophageal achalasia]. PMID- 17688813 TI - [Current status of esophageal surgery in China]. PMID- 17688814 TI - [Endoprosthetic reconstruction after resection of the tumor of the proximal femur]. AB - OBJECTIVE: To evaluate the outcome and complications of endoprosthetic reconstruction after wide tumor excision on the patients with neoplasms at the proximal femur. METHODS: Between July 1998 and July 2005, 81 patients with tumor of the proximal femur were treated by wide excision and endoprosthetic reconstruction. Nine cases received devitalized bone and prosthesis composite reconstruction (among them, 3 patients of fibrous dysplasia had long stem bipolar hip replacement) and 5 cases had allograft prosthesis composite replacement. Two cycles of neoadjuvant chemotherapy were given to all the cases of osteosarcoma and Ewing sarcoma. The functional outcomes were evaluated by MSTS 93 score. RESULTS: Among the 30 patients with metastatic tumor, because all of them were transferred to related department to receive chemotherapy or radiotherapy after surgery, the follow-up was not doing well and the rate of local recurrence was not confirmed. Five patients with metastatic tumors died in 3 months after surgery. Most patients had excellent or good function postoperatively, the average MSTS 93 score was 25 in 6 months after surgery. Among the 51 patients with primary tumor, 2 patients had chronic infection and 2 patients had loosening of the prosthesis during the following time. Allograft bone and host bone nonunion were seen in 2 cases. Two patients with bipolar hip replacement had severe acetabulum abrasion. The other 3 patients also received total hip replacement for hip pain after walk. Five patients had local recurrence 6 months to 2 years postoperatively. CONCLUSIONS: Because of low complication rate and good postoperative function, endoprosthetic replacement is a good option for reconstruction of the proximal femur after tumor resection. PMID- 17688815 TI - [Total femoral prosthesis replacement in management of femoral malignant bone tumor]. AB - OBJECTIVE: To discuss the indications of reconstruction with total femoral prosthesis for the patients with a majority of femur infiltrated by malignant bone tumor, and to evaluate the functional outcome and complication. METHODS: Between October 1996 and October 2002, 17 patients with malignant bone tumor were treated with total femoral prosthesis replacement. The patients included 8 males and 9 females, whose age was from 12 to 34 years, with the average of 16 years. The lesions were located in the proximal femur metaphysis in 1, the distal femur metaphysis in 6, the femur shaft in 10, pathologic fracture in 2, skip lesions in 3. The extent of lesions was 23-28 cm (a majority of femur infiltrated by malignant bone tumor). Preoperative pathologic diagnosis were established by open biopsy (2 cases) or needle biopsy (15 cases). All patients were osteosarcoma. According to Enneking surgical staging system, the cases were 12 IIB and 5 IIIB. Seventeen cases received preoperative chemotherapy and 15 cases received postoperative chemotherapy. RESULTS: Seventeen cases were followed up with a mean time of 45 months (range 9-120 months). Local recurrence was observed in 3 (17.6%) after operation 6-14 months. In 12 IIB cases, 4 cases (33%) developed pulmonary metastasis and died. Eight cases remained continuously disease-free for average 75 months (range 50-120 months). In 5 IIIB cases, all with a mean survived term of 13 months (range 9-20 months) died. Fifteen patients (88%) could walk. The patients had maintained average 74% (range 40% - 93%) limb function scores evaluated by ISOLS criteria. Four cases had complications of paralysis of common peroneal nerve (3 cases) and dislocation of hip joint (2 case). No infection took place. CONCLUSIONS: Total femoral prosthesis replacement could be used in the treatment of the patients with a majority of femur infiltrated by malignant bone tumor and could effectively recover their limb function to a great extent. The procedure can effectively improve the quality of life for the patients with malignant bone tumor staging IIIB. PMID- 17688816 TI - [Endoprosthetic reconstruction after wide resection of primary bone tumor around the knee]. AB - OBJECTIVE: To evaluate the effect and complication of the endoprosthetic reconstruction after wide resection of primary bone tumor around the knee. METHODS: The retrospective analysis was performed on 83 patients undergoing the prosthetic reconstruction after the resection of the primary tumor around the knee between December 1995 and December 2005. All the diagnoses were pathologically confirmed (58 patients with osteosarcoma, 2 with osteosarcomatosis, 1 with parosteal osteosarcoma, 4 with malignant fibrous histiocytoma, 13 with giant cell tumor of bone, 1 with leiomyosarcoma, 2 with Ewing's sarcoma, 2 with chondrosarcoma). The distal femur group was involved in 44 patients, proximal tibia group in 34 (including 33 deficit in proximal tibia, 1 deficit both in proximal tibia and distal femur), total femur replacement group in 5. After operation, the Musculoskeletal Tumor Society (MSTS) score was used to evaluate the recovery of their corresponding functions. RESULTS: The follow-up for 12 - 130 months (with a median of 41 months) revealed that the 3-year survival rate of the prosthesis was 88.2%, and the 5-year survival rate was 82.1%. As for the complications, local recurrence developed in 6 patients, peri prosthesis infection in 2 patients, aseptic loosening in 2 patients. The mean MSTS core was 25.0 (19.0 - 29.0) in the distal femur group, 24.4 (17.0 - 28.0) in the proximal tibia group, and 19.0 (16.0 - 21.0) in the total femur replacement group. As to the statistical analysis, the function of the former two groups were greater than the latter one (F = 11.666, P < 0.001), however, there was no significant difference between the former 2 groups (F = 0.813, P = 0.370). CONCLUSIONS: Taken together, the tumor prosthesis gives a satisfactory functional outcome after the tumor around the knee is removed with a lower incidence of complication. PMID- 17688817 TI - [Limb salvage surgery for osteosarcoma around the knee in children and adolescent patients]. AB - OBJECTIVE: To discuss the reconstruction methods and treatment effects of osteosarcoma around the knee in skeletal immature children and adolescent patients. METHODS: Between October 1996 and December 2005, 89 children and adolescent patients with osteosarcoma around the knee received limb salvage surgery. The average age was 13 years old. Tumor involved distal femur in 52 cases, proximal tibia in 36 cases, and both parts in one patient. Different limb salvage methods, including tumor recycle bone reimplantation (n = 20), partial endoprosthesis (n = 19) and total knee megaprosthesis replacement (n = 50) were chosen according to both the age of the patient and the skeletal. Expandable and special designed pediatric prosthesis some times might also be considered. RESULTS: After average follow up of 42 months, 4 cases of local recurrence and 11 of metastasis occurred in tumor recycle bone group; 1 case of local recurrence and 4 of metastasis in partial endoprosthesis group; another 4 cases of local recurrence and 9 patients died of disease in total knee megaprosthesis group. The five-year survival rate was 47.1%, 71.7% and 68.2% in 3 groups respectively. There were 3 deep infections in all the cases, 2 subluxations and 1 amputation after operation for limb ischemia in partial endoprosthesis group. The average functional score of MSTS 93 was 21.43 point, 23.40 point and 25.32 point; and the average leg length discrepancy was 5.48, 4.50 and 3.12 cm in 3 groups respectively. CONCLUSIONS: Partial-joint prosthesis or other methods which can avoid injury of the opposite epiphysis should be used to decrease the possibility of limb length discrepancy and ease the following revised arthroplasty. For patient with almost mature skeletal, total knee megaprosthesis may be a proper choice for better function result. PMID- 17688818 TI - [Application of the proximal tibiofibular joint resection on the limb salvage for osteosarcoma of the proximal tibia]. AB - OBJECTIVE: To evaluate the proximal tibiofibular joint resection on the limb salvage for osteosarcoma of the proximal tibia. METHODS: Between August 1995 and January 2004, 11 patients with osteosarcoma of proximal tibia and tibiofibular joint involved underwent resection and endoprosthetic proximal tibial replacement. Seven patients were male and 4 were female. The patients ranged in age from 14 to 23 years (mean 18 years). The surgical stage were IIB. RESULTS: The follow-up period varied from 2 to 9 years (mean 59 months). Three patients died of pulmonary metastases, 1 patient was still alive with pulmonary metastasis, 1 patient underwent amputation for local recurrence. There was 1 early skin necrosis, 2 transient palsy of the common peroneal nerve, and 2 thrombus of lower limb vein. The mean postoperative Musculoskeletal Tumor Society score of the knee joint was 70% (range 55% - 86%), the mean postoperative range of motion was 85 degrees (range 0 degrees - 120 degrees ), and the extensor lag varied from 0 degrees to 20 degrees . CONCLUSIONS: Limb salvage for osteosarcoma of the proximal tibia with proximal tibiofibular joint resection and custom-made prosthesis reconstruction has had excellent results, however, the prevention and treatment of relevant complications should be given more attention. PMID- 17688819 TI - [Massive allograft replacement in management of bone tumors]. AB - OBJECTIVE: To evaluate the functional outcome and the complications of allograft replacement in management of bone tumors. METHODS: Between March 1992 and September 2002 164 patients underwent bone tumor resection and massive allograft reconstruction of bone defects. The length of the resected part ranged from 5 - 35 cm. The resections were classified as marginal or wide resections of the tumor on the basis of the Musculoskeletal Tumor Society staging system. Fresh-frozen allografts were employed as osteoarticular grafts (n = 95), hemi-condylar (n = 15), massive (n = 23), allograft-prosthesis composite (n = 12), intercalary grafts (n = 15) or hemi-pelvic grafts (n = 4). Most of the lesions were osteosarcoma and giant cell tumor of bone and located in proximal and distal femur, proximal tibia and humerus. RESULTS: At a median follow-up of 47 months (range, 12 to 168 months) after the operation, 154 of the patients in the study were free of disease and 10 died of disease. Twenty-one (12.8%) patients had local recurrence and 38 (23.2%) nonunion. Late complications included 11 (6.7%) fractures of the allograft and 18 (11.0%) infections of the graft. Instability of the joint in the form of subluxation was noted in 13 (7.9%) patients. Ten extremities were amputated due to local recurrence or severe infection. CONCLUSIONS: Allografts can be used for reconstruction of bony defects after tumor resection. Allograft has nearly similar shape, strength, osteo-conduction and osteo-induction with host bone. Allograft implantation is a high complication reconstruction method, and the risk of recurrence increases when less surgical margin achieves. PMID- 17688820 TI - [Surgical treatment of primary esophageal adenocarcinoma]. AB - OBJECTIVE: To summarize the surgical treatment and clinical bio-characteristics of primary esophageal adenocarcinoma (PEAC). METHODS: Clinical data of 43 cases with PEAC who had undergone operation from February 1980 to December 2000 in Linzhou City Esophageal Tumor Hospital were retrospectively analyzed. RESULTS: Forty-three cases PEAC were reported in this study, which were 0.8% out of 5638 cases pathologically confirmed esophageal carcinoma treated during this period. Twelve cases (27.9%) were in the middle 1/3 of esophagus, thirty-one cases (72.1%) in the lower 1/3, which were significantly different from esophageal squamous cell carcinoma (ESCC). Fourteen cases were pure esophageal adenocarcinoma (32.6%), twenty-nine cases were adenosquamous cell carcinoma and adenoacanthoma cell carcinoma (67.4%). The ratio of lymph node metastasis of PEAC was higher than that of ESCC (65.1% vs. 31.6%, P < 0.001). The overall survival rates of 1, 3 and 5-year of PEAC were 81.4%, 46.5% and 28.2%, respectively, which were lower than those of ESCC (89.7%, 68.2% and 39.4%, respectively; chi 2 = 4.846, P = 0.028). CONCLUSIONS: Compared with ESCC, PEAC, mainly located in the inferior 1/3 of esophagus, is a malignant disease with higher frequency of lymph node metastasis and poor prognosis. Surgical resection should be the first choice of treatment. Early diagnosis and early treatment as well as curative operation could improve prognosis. The long-term survival may be increased by adjunct multi modality treatment. PMID- 17688821 TI - [Outcome of Nissen fundoplication using intraoperative manometry]. AB - OBJECTIVE: Through reviewing the surgical experience in the treatment of sliding hiatus hernia, the effectiveness of Nissen fundoplication using intraoperative oesophageal manometry has been evaluated. METHODS: There were 84 undergoing the transabdominal surgery who have been divided into three groups: 27 patients were in the Nissen group, 39 in the floppy Nissen group, 18 in the intraoperative oesophageal-manometry group. RESULTS: There is no postoperative death. Complications occurred in 5 patients within one month after operation: in the Nissen group, 2 patients suffered from severe dysphagia and 1 from regurgitation; In the floppy Nissen group, 2 patients had regurgitation; In the intraoperative oesophageal-manometry group, there were no one suffering severe dysphagia or regurgitation. During the long-term follow-up, excellent functional results were also observed in the intraoperative-oesophageal-manometry group, whereas 2 patients suffered from severe dysphagia and 1 from nausea in the Nissen group and 1 patient recurred in the floppy Nissen group. CONCLUSIONS: The Nissen fundoplication (NF) should be suitable to be done in patients with sliding hiatus hernia. But if there are possibilities to perform intraoperative oesophageal manometry during the operation of anti-reflux, side effects can be decreased to the least. Intraoperative manometry is useful in standardizing the tightness of the wrap in NF. And it will contribute to reducing or avoiding the happening of complications. PMID- 17688822 TI - [A prospective longitudinal study examining the impact on short term quality of life of hand video-assisted thoracoscopic surgical esophagectomy in patients with esophageal cancer]. AB - OBJECTIVE: To evaluate the impact of hand video-assisted thoracoscopic surgery (HVATS) and Ivor-Lewis surgery on short term quality of life (QL) of patients with esophageal cancer. METHODS: Thirty-nine consecutive patients with esophageal cancer were classified into HVATS group (n = 21) and Ivor-Lewis group (n = 18) randomly, all patients completed the Chinese versions of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and QLQ-OES18 before treatment and at regular intervals until 6 months after operation. MEAN scores were calculated for every patient. RESULTS: Baseline functional and symptom QL MEAN scores were similar in both groups. All patients reported worse functional, symptom and global QL scores (QOL) within 6 months after operation than before. HVATS group gained higher functional, global QL scores and lower symptom scores than Ivor-Lewis group, moreover, patients' QL scores of HVATS group returned to preoperative levels more quickly than those patients in Ivor-Lewis group. Significant differences were found in global health (QOL), physical functioning, fatigue and pain scales between groups. In both groups, QLQ-OES18 dysphagia scales were improved after surgery,but no significant differences were found at scales respect to esophageal cancer. CONCLUSIONS: HVATS esophagectomy is a safe procedure which has a low disturbance to patients' short term Quality of Life compared with Ivor-Lewis esophagectomy. It might seem reasonable to choose HVATS esophagectomy for patients with early stage esophageal cancer. PMID- 17688826 TI - [Clinical analysis of 1434 cases of frameless stereotactic operation]. AB - OBJECTIVE: Stereotactic operations were performed using a frameless stereotactic instrument manufactured by CAS-R-2 instead of traditional stereotactic frame. The aim of this study was to assess the clinical usefulness, accuracy and safety of frameless stereotactic instrument. METHODS: The clinical data of 1434 patients was retrospectively reviewed. The mean age was 30.7 years (from 0.2 to 89.0 years). Each patient underwent frameless CT/MRI image-guided stereotactic surgery by this robot system from January 1997 to January 2006. The accuracy of position and improvement of symptom were observed. The averaged period of followed-up was 24 months (from 3 to 48 months). RESULTS: The surgical procedures were performed successfully in all cases. All targets were pointed accurately at first time during the operation. The total effective rate was 93.3% without serious operation related complications. CONCLUSIONS: Compared with the traditional stereotactic operations, this method has some advantages, such as releasing the patient's pain, convenience the doctors, extending the range of indications and increasing the safety and effective of operation. PMID- 17688827 TI - [Treatment of multisegmental intramedullary cervical spinal cord ependymomas]. AB - OBJECTIVE: To discuss the possibility of microneurosurgery techniques in the treatment of multisegmental intramedullary cervical spinal cord ependymomas. METHODS: The clinical data of 26 cases of multisegmental intramedullary cervical spinal cord ependymomas patients was reviewed and analyzed. RESULTS: There were 14 cases of cervical spinal cord ependymomas, 12 cases of cervical and thoracic spinal cord ependymomas. 4.5 spinal cord segments were involved in average. Incompletely inferior paraplegia was in 18 cases, incompletely high paraplegia in 8 cases, dyspnea in 6 cases, sphincter dysfunction in 10 cases. MRI detected syringomyelia formation in 24 cases. Vertebral lamina reposition were done in 20 cases. Muscle strength recovered in 21 cases, no change in 4 cases, aggravated in 1 case. All cases had total resection and 1 cases vertebral had instability in MRI. CONCLUSIONS: Total resection of intramedullary cervical spinal cord ependymomas can be achieved by microneurosurgery. Most of the symptoms can be released after microsurgical treatment. After multisegmental laminotomy, the vertebral plate reposition should be done to ensure the stability. PMID- 17688828 TI - [Total knee arthroplasty and perioperative management of hemophilic arthritis]. AB - OBJECTIVE: To evaluate the clinical results and perioperative management of primary total knee arthroplasty (TKA) in hemophilic patients. METHODS: From February 1997 to February 2006, the data of 6 total knee arthroplasty performed in 4 hemophilic patients was reviewed retrospectively. The values of coagulation factor were maintained at suitable level by monitoring the activity of the factors and their inhibitors during perioperative period. The mean follow-up time was 4.4 years, knee society score and the last postoperative radiographs were recorded. RESULTS: After TKA, the hemophilic patients felt pain of knee relieved, the knee function was improved, but the range of motion increased limitedly. At the early post-operative stage, 3 knees in 2 patients with hemarthrosis or muscle bleeding, 1 of the 2 patients complicated with formation of inhibitor of factor VIII and healing problem in 1 knee after TKA, 1 patient with transient paralysis of the common peroneal nerve, 1 patient with venous circulation insufficiency crisis, but no compartment syndrome. In the late stage after TKA, 1 patient with hemarthrosis of both elbows, but no late infection, loosening, displacement and fracture of the prosthesis in the 6 knees. CONCLUSIONS: Total knee arthroplasty could alleviate knee pain and improve joint function in advanced severe hemophilic arthritic patients. It is important to monitor the activity and inhibitors of coagulation factor VIII or IX, which could decrease the early and late postoperative complications. PMID- 17688834 TI - Immunogenicity of biologic agents: a new concern for the practicing rheumatologist? PMID- 17688835 TI - Inflammatory muscle disease: clinical presentation and assessment of patients. AB - Muscle weakness and muscle fatigue are the most common manifestations in patients with idiopathic inflammatory myopathies (ie, myositis), but other organs are frequently involved such as skin, lungs, joints, and the heart. These could occur before, simultaneously with, or after the onset of muscle symptoms. One tool to structure outcome measure is the International Classification of Functioning, Disability, and Health. Measures of "disability" can be divided into impairment and activity limitation/participation restriction. Most of the available outcome measures for myositis could be classified as measures of impairment, such as muscle strength, serum levels of muscle enzymes, and pulmonary function tests. Measures of activity limitation/participation restriction are also important, such as the myositis activities profile, the visual analog scale to assess impact on general well-being, and the generic short form-36 to capture impact on health related quality of life. PMID- 17688836 TI - Advances in the immunopathophysiology of the idiopathic inflammatory myopathies: not as simple as suspected. AB - In the past three decades, not much has changed in the pathophysiologic concepts of dermatomyositis and polymyositis. However, in the past couple of years, many changes have occurred reflecting the extremely complex nature of the immune response in general. New pathophysiologic models are needed, but at present, none of them encompasses all the recent findings. The changing concepts of dermatomyositis and polymyositis offer new opportunities for unraveling these diseases and developing better strategies for prevention and treatment. This article discusses the most important developments and their methodologic short comings. PMID- 17688837 TI - Cytokine response in inflammatory myopathies. AB - After background information about pathologic findings, this review focuses on the cytokine response in the pathogenesis of polymyositis and dermatomyositis. Cytokines are important mediators of the immune response and play a key role in these diseases by acting on inflammatory immune cells, muscle cells, and vessel cells. Various cytokines are found in myositis samples, in particular interleukin 1 and tumor necrosis factor-alpha, which are associated with the migration, differentiation, and maturation of inflammatory cells. Recent advances indicate that the muscle cell itself could participate in the inflammatory process. Cytokines promote changes in muscle metabolism resulting in a self-sustaining inflammatory response. Accordingly, cytokines may represent new targets for therapies. PMID- 17688838 TI - Advances in the immunobiology and treatment of inflammatory myopathies. AB - The clinical spectrum and immunopathogenesis of inflammatory myopathies are summarized with an update on possible triggering factors, cell degeneration, and emerging new therapies. PMID- 17688839 TI - Intravenous pulsed corticosteroid therapy for primary treatment of Kawasaki disease. PMID- 17688840 TI - Small-vessel vasculitis. AB - Small-vessel vasculitis is a convenient descriptor for a wide range of diseases characterized by vascular inflammation of the venules, capillaries, and/or arterioles with pleomorphic clinical manifestations. The classical clinical phenotype is leukocytoclastic vasculitis with palpable purpura, but manifestations vary widely depending upon the organs involved. Histopathologic examination in leukocytoclastic vasculitis reveals angiocentric segmental inflammation, fibrinoid necrosis, and a neutrophilic infiltrate around the blood vessel walls with erythrocyte extravasation. The etiology of small-vessel vasculitis is unknown in many cases, but in others, drugs, post viral syndromes, malignancy, primary vasculitis such as microscopic polyarteritis, and connective tissue disorders are associated. The diagnosis of small-vessel vasculitis relies on a thorough history and physical examination, as well as relevant antibody testing including antinuclear antibody and antineutrophil cytoplasmic antibody, hepatitis B and C serologies, assessment of complement, immunoglobulins, blood count, serum creatinine, liver function tests, urinalysis, radiographic imaging, and biopsy. PMID- 17688841 TI - Urticarial vasculitis. AB - Urticarial vasculitis can present in a variety of ways, ranging from a primarily cutaneous disease consisting of chronic urticaria to a lupus-like disease with severe cardiopulmonary disease. Low complement levels and positive anti-C1q antibodies are markers of more severe disease. Care must be taken to look for an underlying condition. The mainstay of therapy is treatment of any underlying condition. Therapies most often employed include corticosteroids, antihistamine, and dapsone, but many others have been utilized. PMID- 17688842 TI - Imaging studies in the diagnosis and management of vasculitis. AB - The term vasculitis encompasses a number of distinct clinicopathologic disease entities. Final diagnosis should be supported by histologic study in most cases. However, different imaging modalities offer the potential for an early visualization of inflammatory vascular abnormalities, provide some diagnostic clues, and allow for an adequate assessment of therapeutic response. This review discusses recent advances in imaging techniques and refinements in vascular imaging methods, as well as a brief mention of research modalities that are increasingly used in studies of pathogenesis or in the assessment of disease progression. PMID- 17688843 TI - Small-vessel vasculitis: therapeutic management. AB - Small-vessel vasculitis is defined by the presence of blood vessel inflammation involving the arterioles, venules, or capillaries. This can be seen in a broad spectrum of settings, but it is most commonly associated with Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. Although prednisone combined with cyclophosphamide induces remission and prolongs survival in these diseases, this regimen is toxic and does not prevent relapse. Current therapeutic approaches seek to minimize cyclophosphamide exposure through the use of staged induction-maintenance regimens or cyclophosphamide alternatives for induction of nonsevere disease. Emerging trials with biologic agents are exploring new treatment options. PMID- 17688845 TI - [Importance of time delay in selecting reperfusion therapy]. PMID- 17688844 TI - Kawasaki disease: 40 years after the original report. AB - The cause of Kawasaki disease (KD) remains unknown, although a number of epidemiologic and clinical observations suggest it is triggered by one or more infectious agents, each of which can result in the clinical manifestation of the disease. Advances have been made in the management of the disease with the introduction of aspirin and intravenous immunoglobulin (IVIG), which have had a significant impact on lowering the rate of coronary artery aneurysms and death from the disease. Questions remain regarding the management of those patients who fail to respond to IVIG. It appears that some patients with severe KD who are resistant to IVIG may benefit from IV pulse steroid therapy or infliximab infusion. However, a recent multicenter, randomized, controlled trial did not support the addition of a pulsed dose of intravenous methylprednisolone to the conventional IVIG therapy for the primary treatment of KD. It remains to be seen whether other anti-inflammatory agents such as immunosuppressive therapies or new biologics will play a role in the management of patients with KD. PMID- 17688846 TI - [Investigation of angiographically moderate lesions in the left main coronary artery. A clinical indication for intracoronary ultrasound]. PMID- 17688847 TI - [C-reactive protein in the emergency department: has it found a clinical application?]. PMID- 17688848 TI - [Treatment of acute myocardial infarction by primary angioplasty on-site compared with treatment following interhospital transfer: short- and long-time clinical outcomes]. AB - INTRODUCTION AND OBJECTIVES: Primary angioplasty is the treatment of first choice for patients with ST-segment elevation acute myocardial infarction. However, its use is limited as the majority of patients present at hospitals without a catheterization laboratory. The objective of this study was to determine short- and long-term outcomes of systematically implementing a primary angioplasty program at two hospitals, one of which did not have a catheterization laboratory. METHODS: This prospective observational study involved consecutive patients with acute myocardial infarction and an indication for reperfusion therapy who were admitted to the two participating hospitals (Hospital 1 had a catheterization laboratory, while Hospital 2 did not) between January 2000 and April 2001. Clinical follow-up was performed at 1, 6 and 12 months. RESULTS: The study included 222 patients: 158 in Hospital 1 and 64 in Hospital 2. The median (interquartile range) delays from door to angiography at Hospital 1 and Hospital 2 were 49.5 min (30.0-88.0 min) and 62.5 min (53.5-93.7 min), respectively (P=.001), and from symptoms to angiography, 162.5 min (105.0-247.5 min) and 187.5 min (131.2-288.7 min), respectively (P=.04). In-hospital and 1-year mortality rates were 12.2% and 15.3%, respectively, with no difference between the hospitals. The hospital of origin was not a determinant of either in-hospital mortality (odds ratio [OR]=1.42, 95% confidence interval [CI], 0.3-7.8) or 1-year mortality (HR=2.04, 95% CI, 0.74-5.61). CONCLUSIONS: Patients with ST-segment elevation acute myocardial infarction who require interhospital transfer for primary angioplasty have a similar clinical outcome to those who are admitted to a hospital at which the procedure is available, provided transfer is undertaken under optimal conditions (i.e., with a suitable means of transport and a short transfer time). PMID- 17688849 TI - [Prospective use of an intravascular ultrasound-derived minimum lumen area cut off value in the assessment of intermediate left main coronary artery lesions]. AB - BACKGROUND AND OBJECTIVES: Angiographic assessment of the severity of intermediate lesions in the left main coronary artery (LMCA) is subject to significant limitations. Intravascular ultrasound (IVUS) can provide accurate measurement, but there is no agreement on the minimum lumen cross-sectional area (MLA) that indicates significant disease. The aim of this study was to determine the long-term safety of applying a cut-off value of 6 mm2 for the MLA in the LMCA. METHODS: The study included patients with intermediate lesions (i.e., 25 50%) in unprotected LMCAs, with no previous evidence of associated ischemia. An IVUS examination was carried out and revascularization was indicated when the MLA was < or =6 mm2. RESULTS: In total, 79 patients were recruited between 2000-2005. In 31 (39%), the MLA was < or =6 mm2, and they underwent LMCA revascularization; in the remaining 48 (61%), the MLA was >6 mm2, and patients either underwent angioplasty for other lesions (n=37) or continued medical treatment (n=11). In a follow-up period of 40 [17] months, four patients (8.3%) died from heart disease, all of whom had an MLA between 9-10 mm2 in the baseline study. Revascularization of the LMCA was necessary in only two patients (4.2%), both of whom had elective surgery more than 2 years after the initial study. CONCLUSIONS: Intravascular ultrasound assessment of intermediate LMCA lesions using an MLA cut-off value of 6 mm2 appears safe over the long term provided the clinical and angiographic criteria applied to patient selection are similar to those used in this study. PMID- 17688850 TI - [Evaluation of patients with acute chest pain of uncertain origin by means of serial measurement of high-sensitivity C-reactive protein]. AB - INTRODUCTION AND OBJECTIVES: We investigated the usefulness of taking two serial measurements of the high-sensitivity C-reactive protein (hs-CRP) level for evaluating acute chest pain in patients with non-diagnostic ECG findings and normal levels of markers of myocardial cell injury (i.e., an inconclusive diagnosis). We hypothesized that the C-reactive protein concentration would be raised if symptoms were due to coronary endothelial damage or arteriosclerotic plaque rupture. METHODS: The study involved 468 consecutive patients who presented to the emergency department with acute chest pain, 191 of whom had an inconclusive diagnosis. In this patient group, we determined the hs-CRP level on emergency admission and at 24 hours. Standard guidelines on managing acute chest pain of suspected coronary origin were followed. Any increase in hs-CRP level between baseline and 24 hours was regarded as a positive result. RESULTS: In total, 38 (20%) patients were diagnosed with chest pain due to coronary disease. Measurement of the hs-CRP level differential (i.e., the hs-CRP level at 24 hours minus the baseline level at emergency admission) had a sensitivity of 95% (95% confidence interval [CI] 81-98%), a specificity of 40% (95% CI, 32-47%), a positive likelihood ratio of 1.57 (95% CI, 1.33-1.83), a negative likelihood ratio of 0.13 (95% CI, 0.04-0.44), and an area under the receiver operating characteristic curve of 0.77 (95% CI, 0.69-0.85). By 30-day follow-up, no cardiac event had occurred in patients with a negative hs-CRP level differential. CONCLUSIONS: Measurement of the hs-CRP level differential is diagnostically useful in patients with acute chest pain of likely coronary origin. A negative result is associated with a low risk of ischemic heart disease and would allow patients to be discharged safely from the emergency department. PMID- 17688851 TI - [Blood pressure findings in Spanish dyslipidemic primary-care patients. LIPICAP PA Study]. AB - BACKGROUND AND OBJECTIVES: Despite the well-known significant relationship between blood pressure and cardiovascular mortality, few data are available on the blood pressure characteristics of dyslipidemic patients. The aims of this study were to determine the blood pressure characteristics of dyslipidemic patients being treated in primary care, and to identify factors associated with poor blood pressure control. METHODS: This multicentre cross-sectional study involved patients of both sexes aged > or =18 years who were diagnosed with dyslipidemia (i.e., hypercholesterolemia, hypertriglyceridemia, mixed dyslipidemia, or a low high-density lipoprotein cholesterol level) in the 17 Spanish autonomous regions. Blood pressure was measured according to standard procedures, and was considered well-controlled if it was <140/90 mm Hg (or <130/80 mm Hg in patients with diabetes, nephropathy or cardiovascular disease). RESULTS: In total, 7054 patients were studied (mean age 61.3 [11.2] years, 50.8% male). Mean systolic and diastolic blood pressures were 134.6 [14.2]/79.8 [8.9] mm Hg, with significant differences (P< .001) between hypertensives (140.8 [14.6]/82.8 [9.0] mmHg) and normotensives (128.5 [10.7]/76.9 [7.7] mm Hg). Good blood pressure control was observed in 47.4% (95% confidence interval, 46.3 48.5%) of subjects overall, in 29.3% of hypertensives, and in 12.8% of hypertensive diabetics. Poor control was associated with an increased cardiovascular disease risk (hazard ratio [HR]=2.89), poor control of low-density lipoprotein cholesterol (HR=1.43), a higher body mass index (HR=1.06), and older age (HR=1.02). CONCLUSIONS: Fewer than half of dyslipidemic primary-care patients in Spain had good blood pressure control. Poor control was associated, in particular, with increased cardiovascular risk and poor control of the low density lipoprotein cholesterol level. PMID- 17688852 TI - [Pulmonary atresia with intact ventricular septum. Perforation and pulmonary valvuloplasty using a modified mechanical technique. Medium-term follow-up]. AB - INTRODUCTION AND OBJECTIVES: In patients with pulmonary atresia with intact ventricular septum (PAIVS), radiofrequency-assisted perforation of the valve is the most widely used initial therapy when the anatomy is favorable. We report our experience with a modified mechanical technique that gave good results. METHODS: Between November 2001 and October 2006, valve opening was carried out successfully in 11 consecutive neonates with a favorable anatomy (i.e., Alwi groups A and B, and tricuspid valve Z-score -1.1 [1.3]). The technique involved snare-assisted anterograde or retrograde perforation with the soft tip of a special guidewire used for chronic total coronary artery occlusions, use of an arteriovenous loop, and progressive balloon dilatation from a diameter of 2 mm to a maximum diameter of 9.6 [1.2] mm. RESULTS: Valve opening was achieved in all patients, and right ventricular (RV) systolic pressure fell from 97 [17] mmHg to 48 [13] mmHg (P< .001). No pericardial effusion or cardiac tamponade was observed, though one neonate died 24 hours after the procedure due to pulmonary embolism. Six patients (54%) were discharged without any further intervention, while 4 (36%) required an additional increase in pulmonary blood flow. During the follow-up period of 25 [21] months, two patients died. Eight (72%) survived and were in New York Heart Association functional class 1. Two required additional surgery on the outflow tract, one of whom also needed a one-and-a-half ventricular repair. Data indicate that the valves remain open as RV structures grow, though without any change in the tricuspid valve Z-score. CONCLUSIONS: Pulmonary valvuloplasty using a mechanical technique proved effective in patients with PAIVS. Modification of the standard mechanical technique by using the soft tip of a special guidewire used for chronic total coronary artery occlusions was less aggressive and improved results. In patients with a favorable anatomy, results were comparable to those obtained using the radiofrequency technique. PMID- 17688853 TI - [Epidemiology and new predictors of atrial fibrillation after coronary surgery]. AB - INTRODUCTION AND OBJECTIVES: Postoperative atrial fibrillation (PAF) is a frequent complication of coronary artery bypass grafting (CABG). Our aims were to study its epidemiology and to identify predictors in everyday clinical practice, while taking into account statin use, extracorporeal circulation, and new biomarkers of inflammation and ventricular stress. METHODS: The study included 102 consecutive patients (65 [9] years, 72% male) who were undergoing CABG. Blood samples were taken the day before surgery to determine baseline levels of C reactive protein (CRP) and N-terminal probrain natriuretic peptide (NT-proBNP). Details of baseline clinical characteristics, preoperative treatment and surgery were recorded. The end-point was PAF at 30 days. RESULTS: The incidence of PAF was 23% (n=23; 3.2 [2.9] days, range 1-15 days). Its appearance was associated with a longer stay in the intensive care unit (+ 1 day; P=.019), but not with an increased total hospital stay (P=.213). Among patients with PAF, 4.3% had an embolism and 8.6% remained in atrial fibrillation at discharge. Moreover, PAF was associated with a longer duration of ischemia (28.5 [22.3] vs 18.0 [27.9]; P=.045) and a lower statin pretreatment rate (39% vs 66%; P=.022). Multivariate analysis showed that the only factor associated with a higher risk of PAF was the absence of statin pretreatment (odds ratio = 4.31, 95% confidence interval 1.33 13.88; P=.015). There was no association between either extracorporeal circulation or the baseline CRP or NT-proBNP level and an increased risk of PAF. CONCLUSION: In everyday clinical practice, PAF is a frequent complication. Statin pretreatment could have a protective effect against its appearance. PMID- 17688854 TI - [Anemia in heart failure: pathophysiology, pathogenesis, treatment, and incognitae]. AB - Although anemia now occupies an important place in our present understanding of the pathogenesis of heart failure, the condition is surrounded in mystery. Anemia is highly prevalent in patients with heart failure and is of great clinical significance. However, the treatment targets for anemia in patients with heart failure have still not been accurately defined. The present article reviews of the clinical and pathophysiological characteristics of anemia in this context. Particular emphasis has been placed on cellular and molecular regulatory mechanisms, and their implications for treatment. PMID- 17688855 TI - [Internal carotid artery revascularization]. AB - Carotid endarterectomy remains the standard revascularization technique for the prevention of ischemic stroke resulting from severe carotid stenosis. Surgery is highly beneficial in patients with a symptomatic stenosis of 70% or greater that is not a total or near-total occlusion. The benefit becomes more diluted in patients with a symptomatic 50-69% stenosis, and surgery has no effect, or even increases the risk of stroke, in those with a less than 50% stenosis. Surgery has also been shown to reduce the risk of stroke in asymptomatic patients with a 60 99% stenosis, but the absolute benefit is only 1% per year. There is no clear evidence that surgery benefits asymptomatic women at 5-year follow-up, and the benefit is unknown in asymptomatic patients aged over 75 years. Decision-making must take individual factors into consideration, particularly in patients with an asymptomatic (60-99%) or a moderate (50-69%) symptomatic carotid stenosis, so that the risk-benefit ratio of surgery can be optimized. Current data do not support the preferential use of carotid stenting over carotid endarterectomy in patients with a symptomatic or asymptomatic carotid stenosis who are good candidates for surgery. In those who are not good surgical candidates, carotid stenting might be equivalent to surgery, but whether or not any form of carotid revascularization is superior to medical treatment alone remains unknown. PMID- 17688856 TI - [Endomyocardial fibrosis. Diagnosis by imaging: late gadolinium enhancement]. PMID- 17688857 TI - [Heart failure units in Spain: state of the art]. AB - Heart failure is a huge public health problem. Heart failure units provide better care for patients with this condition. The establishment of such units in hospitals varies greatly between countries. To date, no specific data are available on the current situation with these units in Spain. A short questionnaire was used to evaluate the present-day implementation and characteristics of heart failure units in Spanish hospitals. Of the 110 hospitals surveyed, 45 (41%) had a heart failure unit. The percentage varied significantly with the technological sophistication of the hospital: level 1 (lowest) 8%, level 2 38%, and level 3 (highest) 76%. Some 91% of units were run by cardiology departments. In 78% of the units surveyed, nurses were involved in patient care, though only on a part-time basis in the majority (63%). Their task was primarily patient education, although, in 34%, they only performed basic support tasks (i.e., ECG and monitoring vital signs). PMID- 17688858 TI - [Clinical experience with levosimendan in the emergency department of a tertiary care hospital]. AB - The efficacy and safety of levosimendan administration in patients with acute heart failure admitted to intensive care units has been well established. However, no information is available on the drug's beneficial effects in emergency departments. We studied 40 patients with acute heart failure who showed no or only partial improvement after conventional treatment and who received levosimendan during the period 2005-2006. The patients' mean age was 76 (9) years. The most common etiology was ischemic heart disease, and 85% of patients were in New York Heart Association (NYHA) class III or IV. The clinical response was favorable in 82% of patients, while adverse effects occurred in 18%. Some 70% were admitted to the emergency department short-stay unit. These findings indicate that levosimendan can be used safely and effectively in hospital emergency departments. PMID- 17688859 TI - [Stent pseudorestenosis due to annular calcification]. PMID- 17688860 TI - [Idiopathic chylopericardium. A case in point]. PMID- 17688861 TI - [Collateral circulation due to persistent myocardial sinusoids]. PMID- 17688862 TI - [Surgical treatment of a massive pulmonary embolism after a double cardiac arrest]. PMID- 17688863 TI - [Influence of biopsychosocial assessment on degree of doctor-patient empathy in a cohort of patients with multiple diseases]. AB - INTRODUCTION: The biopsychosocial factors that affect or influence empathy in the doctor-patient with multiple disease (PMD) relationship are unknown. This study aimed to determine the patient's own and external factors (from a biopsychosocial point of view) associated to a better empathic relation with health professionals in a multicenter cohort obtained from a population basis. MATERIAL AND METHODS: The multicenter cohort was obtained from four basic health zones, 3 urban and one periurban, from the province of Seville (Southwestern Spain). Empathy was measured with the Likert scale (1-5), by means of an interview (differentiating between family doctor, family nurse and reference internist), by a member of the research team who was not related with patient's care. After that, a factorial analysis was performed, obtaining global empathy as a factor (maximum likelihood method, the summarized three variable matrix, ranging from 0.44 to 0.85). The possible predictive factors of global empathy were chosen from clinical demographic care features of PMD. Comparisons between groups were performed with the Student's t and ANOVA tests. Correlations were with Pearson correlation quotient. Finally a multivariant analysis was done by linear regression and p < 0.05 was considered statistically significant. RESULTS: Four hundred and sixty (69%) of 662 eligible PMD from the cohort answered the interview. Empathy with family doctor, family nurse and reference internist was 4.39 +/- 0.98; 4.49 +/- 0.87 and 4.48 +/- 0.48, respectively. The median of the global empathy factor was 0.33 (-4.7-1.2). Global empathy was associated to having telephone access to the family doctor (0.56 vs 0.22; p < 0.0001) and to the family nurse (0.58 vs 0.24, p = 0.05), and was inversely correlated with global Gijon scale (r -0.100; p = 0.031) and with two of its dimensions: support (r -0.145; p = 0.002), and income (r -0.167; p < 0.0001). In the multivariant analysis, social evaluation measured by the Gijon index (p = 0.001) and number of drugs prescribed (p = 0.004) independently predicted global empathy. CONCLUSION: In the PMD multicenter cohort, both empathy level with the different health professionals and global empathy were high. The latter was associated with having telephone access to the family doctor and nurse, with number of drugs prescribed and with a good social and family support status. PMID- 17688864 TI - [High frequency of anemia in COPD patients admitted in a tertiary hospital]. AB - INTRODUCTION: Anemia is related to chronic and inflammatory diseases. Moreover, it is a factor of worse outcome in heart failure or myocardial infarction. Despite the importance of hemoglobin as a globular oxygen carrying protein, there are few studies on anemia and chronic obstructive pulmonary disease (COPD). OBJECTIVE: To determine the frequency and the characteristics of the anemia in COPD patients admitted to a tertiary hospital within a one year period. METHODS: Anthropometric and clinical data, tobacco habit, lung function tests, arterial blood gases and a basic study of anemia (BSA) were collected from digital clinical files. RESULTS: A total of 177 patients were enrolled. Mean age was 70 (range 44-95), FEV1 was 35 (15%) and hemoglobin (Hb) 136(22) g/dl. Sixty-six (37%) patients had chronic respiratory failure (CRF) and 59 (33%) were receiving long-term oxygen therapy. A total of 56 (31%) had anemia (Hb < 130 g/dl in men or < 120 g/dl in women) with a mean Hb of 111(13). Anemia was normocytic normochromic in 32 cases (58%). BSA was obtained in 24 patients (42.85%) and showed that 10 patients (41%) had anemia of chronic disease, 6 patients (25%) had iron deficiency and 8 (34%) had other causes. It should be mentioned that 35 patients (53%) had CRF had anemia but only 8 patients had erythrocytosis (4.5%). CONCLUSION: Anemia was frequent in these patients and was an underdiagnosed comorbidity. PMID- 17688865 TI - [Effect of surveillance on surgical site infection rate in knee and hip arthroplasty]. AB - OBJECTIVE: To determine whether continuous surveillance of hospital-associated infections with regular feedback to the staff reduces the infection rate in orthopedic surgery. MATERIAL AND METHODS: Prospective surveillance in two periods of time in an orthopedic surgery department at a Spanish university hospital. Two infection control nurses and an epidemiologist surveyed all patients over a 3 year period for infections and potential risk factors. After an initial 24-month period (period A), surveillance for 12 months was conducted (period B). Between these periods, adherence to recommendations was reinforced. RESULTS: A total of 1,088 patients were surveyed. In period A, 3.3% of all operations were followed by an infection, compared with 2.0% in period B (p = 0.14). Adherence to recommended schedule of surgical prophylaxis increased from 8.7% in the first year to 32,7% in the last year (p = 0.001). We also determined the NNIS (National Nosocomial Infections Surveillance) index risk in 383 patients, with the NNIS index-risk 2 as more frequent in period A (16.8%) than the period B (5.4%) (p < 0.001). Renal failure frequency was higher in period A (3.4% vs. 1.6%; p = 0.04). However, diabetes and neoplasms were the same in both periods. In period B, chronic obstructive pulmonary disease (14.6 vs. 11.0; p = 0.05) and obesity (12.8 vs. 10.3; p = 0.12) predominated. The means for surgical intervention, hospital stay, and age, were very similar in both periods. CONCLUSIONS: Surveillance of hospital-associated infections including regular feedback to the staff is accompanied by a reduction in infection rates, possibly with lower cost and more patient safety. Thus, such a surveillance program for orthopedic surgery department seems to be beneficial. PMID- 17688866 TI - [Collagenous colitis. Clinicopathological study of 18 cases]. AB - INTRODUCTION: Collagenous colitis (CC) is an uncommon disease with a favorable prognosis. It is included in the group of chronic watery diarrheas. OBJECTIVE: To study epidemiological and clinical characteristics of CC, as well as its course and response to the treatment. MATERIAL AND METHODS: This is a descriptive, retrospective study of the endoscopic colon biopsies performed in Hospital de Leon during 5 years. Those biopsies that fulfilled the histological criteria of CC were selected. RESULTS: A total of 18 cases with an incidence of 1.25/10(5) inhabitants/year was obtained. Mean age was 66.7 years. There was no difference between both genders. The period of time to diagnosis was long (10 months). A possible association with intake of some drugs, as non-steroidal antiinflammatory drugs (46%) and lansoprazole (42.8%), and smoking (41.6%), as well as autoimmune disease (30.7%) was found. There was a good response to the treatment with mesalazine in 2 of 3 patients who received this treatment. The clinical course was also favorable for the 2 patients treated with budesonide. CONCLUSION: It is important to take multiple biopsies of the colon in order to diagnose CC when there is a case of chronic watery diarrhea even when the colonoscopy is normal. Certain drugs and autoimmune diseases may be involved in the etiology. PMID- 17688867 TI - [Febrile syndrome in a 22-year old male]. PMID- 17688868 TI - [A 34-year old woman with gait instability]. PMID- 17688869 TI - [A 23-year old woman with hypertensive episode]. PMID- 17688870 TI - [Meningovascular neurosyphilis]. PMID- 17688871 TI - [Disseminated granulomatous disease: sarcoidosis or tuberculosis?]. PMID- 17688872 TI - [Pharmacological recommendations in the daily metabolic control of diabetes mellitus type 2. The role of the new insulins]. AB - The epidemic of type 2 diabetes in the latter part of the 20th and early 21st centuries and the recognition that achieving specific glycemic goals can substantially reduce morbidity, have made effective treatment of hyperglycemia a top priority. In addition, strict control of the multiple, classical and emergent cardiovascular risk factors are also important. Diabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. The development of new classes of blood glucose-lowering medications such as glitazones to supplement the classical therapies such as sulfonylureas and metformin has increased oral treatment options for type 2 diabetes. Combined therapy of two oral agents is the essential axis of type 2 diabetic patients. Early insulin therapy in combined therapy is presently an option according to ADA 2007 Standards. PMID- 17688873 TI - [Reflections in regard to health care management]. AB - The evolution of management models in the health care centers has often been motivated by an initial change in the head manager of the site and parallelly to an increase in their area of business interest. This way of promoting change is subjected to the risk of detaining and discouraging the human team responsible for attaining good results in the final product of the health care sector. There are signs and symptoms in the organization that make it possible to detect the separation of interests between directors and non-directors in order to avoid an evolution to a non-efficient organization. PMID- 17688875 TI - [Erlotinib (Tarceva) induced severe exanthema]. PMID- 17688874 TI - [Soluble CD40 ligand: a potential marker of cardiovascular risk]. AB - Recombinant human soluble CD40 ligand, also named CD145 or gp 39, is a 16.3 kD glycoprotein containing 149 aa residues comprising the receptor binding TNF-like domain of CD40 ligand. It is expressed on antigen-presenting cells such as B cells, macrophages, dendritic cells and thymic epithelial cells and it constitutes the nexus between the inflammatory system and the vascular thrombotic processes. Its gene is located in the long arm of the human X chromosome. Prognostic evaluation of the residual fixed atherosclerotic plaque is insufficient to predict clinical course. Currently, studies have been done that demonstrate the participation of the immunoinflammatory system in the genesis and complications of the atherosclerotic condition. In the future, the most specific biomarkers of vulnerability will be very useful in the daily practice (interleukins, CD40, etc.). The soluble CD40 ligand together with its CD40 receptor are overexpressed in experimental and human atherosclerotic lesions. This leads to an increase of mediators for the development of atherosclerosis. Both significantly contribute to the inflammatory processes that leads to atherosclerosis and thrombosis. PMID- 17688876 TI - [Gynecomastia as first manifestation of hyperthyroidism]. PMID- 17688877 TI - [Intake of very foreign bodies]. PMID- 17688878 TI - [Behcet's disease in treatment with cyclosporine and seizures: diagnostic dilemma]. PMID- 17688879 TI - [Rhabdomyolysis associated to combined ezetimibe-statin treatment]. PMID- 17688880 TI - Platelets Strongly Induce Hepatocyte Proliferation with IGF-1 and HGF In Vitro. AB - BACKGROUND: It is well known that platelets have a thrombotic effect. However, platelets play an important role not only in hemostasis but also in wound healing and tissue regeneration. Platelets have been reported to accumulate in the liver and promote liver regeneration after an extended hepatectomy, but the mechanism is unclear. The present study was designed to clarify the mechanism by which platelets have a direct proliferative effect on hepatocytes in vitro. MATERIALS AND METHODS: Hepatocytes obtained from male BALB/c mice by collagenase digestion and immortalized hepatocytes (TLR2) were used. To elucidate the mechanism of the proliferative effect of platelets, DNA synthesis of hepatocytes was measured under various conditions and the related cellular signals were analyzed. Chromatographic analysis was also performed to clarify which elements of platelets have mitogenic activity. RESULTS: DNA synthesis significantly increased in the hepatocytes cultured with platelets (P < 0.001). However, when the platelets and hepatocytes were separated, the platelets did not have a proliferative effect. Whole disrupted platelets, the supernatant fraction, and fresh isolated platelets had a similar proliferative effect, while the membrane fraction did not. After the addition of platelets, both Akt and extracellular signal-regulated kinases ERK1/2 were activated, but extracellular signal regulated kinase STAT3 was not activated. Some mitogenic fractions were obtained from the platelet extracts by gel exclusion chromatography; the fractions were rich in hepatocyte growth factor and IGF-1. CONCLUSIONS: Direct contact between platelets and hepatocytes was necessary for the proliferative effect. The direct contact initiated signal transduction involved in growth factor activation. Hepatocyte growth factor, vascular endothelial growth factor, and insulin-like growth factor-1, rather than platelet-derived growth factor, mainly contributed to hepatocyte proliferation. PMID- 17688881 TI - Losartan attenuates ventilator-induced lung injury. AB - BACKGROUND: Accumulating evidence shows that angiotensin II (ANG II) can be generated locally in the lung tissue and may have autocrine and/or paracrine actions on the cellular level. In addition, ANG II precursor, angiotensinogen, as well as ANG II type 1 receptor (AT(1)), are also expressed in the lung tissue. Recent studies revealed that ANG II promoted acute lung injury induced by acid aspiration or sepsis, and that ANG II receptor blockade had a protective effect against acute lung injury. Therefore, the authors hypothesized that ventilator induced lung injury might also be exacerbated by local ANG II action, and that ANG II receptor blockade would protect the lung from ventilator-induced lung injury. MATERIALS AND METHODS: Forty Sprague Dawley rats weighing 300-350 g were randomly divided into the following experimental groups (10 rats in each group): (1) control group: rats were unventilated; (2) LVT (low volume ventilation) group: rats were ventilated with 8 mL/kg tidal volume room air for 2 h; (3) HVT (high volume ventilation) group: rats were ventilated with 40 mL/kg tidal volume room air for 2 h; (4) HVT + Losartan group: rats were pretreated with Losartan (30 mg/kg, i.p.) prior to high volume ventilation. The samples of pulmonary tissue and lung lavage fluid were collected after experiments. The expression of angiotensinogen and AT(1) receptor mRNA in lung tissue was measured by reverse transcriptase-polymerase chain reaction. Apoptosis of the lung cells was assayed with terminal deoxynucleodityl transferase-mediated nick-end labeling method. Lung pathological changes were examined with optical microscopy. Total protein, wet/dry ratios (W/D), myeloperoxidase (MPO) activity, and neutrophil counts of the lung tissue or lavage fluid were measured with corresponding methods. RESULTS: Compared with control or LVT, HVT caused significant ventilator-induced lung injury and increased the expression of angiotensinogen and AT(1) receptor mRNA in the lung. Total protein, the number of apoptotic cells, W/D ratio, MPO activity, and neutrophil counts were significantly higher in the HVT group than in the LVT or control group. Pretreatment with Losartan attenuated ventilator induced lung injury and prevented the increase in total protein, the number of apoptotic cells, W/D ratio, MPO, and neutrophil counts caused by high volume ventilation. CONCLUSION: Our study indicates that HVT causes remarkable lung injury and up-regulates angiotensinogen and AT(1) receptor expression of in the lung, and that Losartan, a selective inhibitor of subtype AT(1) receptors for angiotensin II, can relieve acute lung injury caused by high volume ventilation. PMID- 17688882 TI - Basement membrane proteins play an important role in the invasive processes of human pancreatic cancer cells. AB - BACKGROUND: The invasive interaction between cells and their matrix has important roles in tumor cell invasion. This study investigated modulation of basement membrane (BM) proteins, especially collagen IV (Coll IV), laminin, and fibronectin (FN), in invasion of human pancreatic cancer cells. Furthermore, we examined the roles of beta(1)-integrins and arginine-glycine-aspartic (RGD) containing oligopeptide in cell-matrix interactions. MATERIALS AND METHODS: Expression of integrins were examined by reverse transcriptase-polymerase chain reaction and flow-cytometric analysis in three human pancreatic cancer cell lines (BxPC-3, PANC-1, and SW1990), respectively. To determine the effect of BM proteins, invasion assays were performed. Western blot analysis for extracellular signal-regulated kinase (ERK) was performed to investigate the involvement of ERK1/2 signaling pathways. RESULTS: BM proteins significantly enhanced the invasive behavior of pancreatic cancer cells. Pretreatment with anti-beta(1) integrin antibody suppressed invasion into Matrigel, but RGD-containing peptide inhibited invasion, which was enhanced by Coll IV and FN, not laminin. Treatment with both RGD-containing peptide and beta(1)-integrin antibody inhibited ERK1/2 phosphorylation activated by Coll IV and FN. CONCLUSIONS: BM proteins have positive actions on the processes of pancreatic cancer cell invasion and cross talk between BM proteins and beta(1)-integrins widely participates in the multistep processes of pancreatic cancer invasion and metastasis formation. PMID- 17688883 TI - Patterns of correlation of plasma ceruloplasmin in sepsis. AB - BACKGROUND: In sepsis, plasma ceruloplasmin (Cp, mg/L) is known to increase as part of the acute phase response. However, there is poor knowledge of the patterns of increase and correlation with changes in other biochemical variables, and our study has been performed to investigate this aspect. MATERIALS AND METHODS: A total of 213 simultaneous measurements of Cp and other acute phase proteins, biochemical variables, and amino acids were performed on nine patients with severe sepsis, and processed by regression analysis. RESULTS: Mean Cp was 478 +/- 119 mg/L (median 488, range 242-784). Significant direct correlations between Cp and C-reactive protein, alpha-1-antitrypsin and alpha-2-macroglobulin (P < 0.001 for all) were all simultaneously influenced by the level of alkaline phosphatase, which was an independent determinant of increased Cp (P < 0.001). Cp increased further with decreasing plasma pH and increasing triglyceride, taurine levels, and distance from the onset of sepsis (P < 0.001 for all). The maximum increases in Cp were associated with the presence of cholestasis, increasing triglyceride levels, and metabolic acidosis. With regard to septic liver dysfunction, while signs of cholestasis were mostly reflected in greater increases in Cp, increasing bilirubin in the presence of normal alkaline phosphatase was mostly correlated with abnormal increases in cyst(e)ine, cystathionine, and tyrosine levels. CONCLUSIONS: These data characterize the patterns of correlation of Cp within the biochemical abnormalities of sepsis, and may provide new insights into the pathophysiology of septic hepatobiliary dysfunction. PMID- 17688884 TI - Clinical significance of ghrelin concentration of plasma and tumor tissue in patients with gastric cancer. AB - BACKGROUND: The nutritional status of gastric cancer patients is an important factor determining the outcome after a gastrectomy. Ghrelin is produced primarily in the gastrointestinal tract including the stomach, and has been reported to reflect the nutritional status and control homeostasis by influencing the level of food intake and adiposity. This study examined the difference in the plasma and tissue ghrelin levels according to the clinicopathological features and the extent of a gastric resection in gastric cancer patients who underwent a gastrectomy. PATIENTS AND METHODS: Eighty patients over a 3 mo-period were divided into two groups according to the degree of preoperative weight loss (weight loss > or = 5% or < 5%) and the extent of the gastrectomy (subtotal or total gastrectomy). Blood samples were collected from all patients preoperatively and on postoperative day 7. The gastric tissues samples, including the tumor and normal tissues, were obtained from the resected stomach. The ghrelin levels in the plasma and tissue were measured using a commercial enzyme-linked immunosorbent assay kit. RESULTS: There were no significant differences in the clinical characteristics and ghrelin levels in the plasma, gastric tumor tissue, and normal tissue according to the degree of weight loss. There was no correlation between the ghrelin levels in the plasma and tumor tissue. However, the ghrelin level in the tumor tissue was significantly lower than that in the normal tissue. There was an association between the degree of cellular differentiation and ghrelin production. A gastrectomy decreased the plasma ghrelin levels and nutritional index such as the body mass index, triceps skin fold, mid-arm muscle circumference, and biochemical markers regardless of the extent of the gastric resection. CONCLUSIONS: Gastric cancer affects the production of ghrelin in the gastric mucosa. Moreover, ghrelin is produced mainly in the stomach even though it might be partially covered by the endogenous ghrelin produced by other organs after gastrectomy. However, more study will be needed to determine if there are other factors that have an impact on energy consumption, ghrelin secretion, and the changes in the ghrelin level after a gastrectomy. PMID- 17688886 TI - HTLV-1 infection and the viral etiology of multiple sclerosis. AB - The HTLV-1 virus produces a progressive inflammatory, and then degenerative, myelopathy which evolves progressively from onset. HTLV-1 in endemic in populations which are recognized as having low risk of multiple sclerosis . Multiple sclerosis generally evolves as a relapsing-remitting disease and affects predominantly Caucasians. In Caucasians, HAM/TSP can be marked by fluctuations as well as relapses. In Asians MS affects preferentially the spinal cord. The author hypothesizes that population selection through environmental factors has pushed the immune response of Caucasians towards generating relapsing-remitting disease and that of Primordial populations towards progressive disease. HTLV-1 endemicity being the marker of Primordial populations and its absence that of Caucasians. PMID- 17688885 TI - Intestinal ischemia-reperfusion injury alters purinergic receptor expression in clinically relevant extraintestinal organs. AB - BACKGROUND: Intestinal ischemia-reperfusion (IIR) injury is known to initiate the systemic inflammatory response syndrome, which often progresses to multiple organ failure. We investigated changes in purinoceptor expression in clinically relevant extra-intestinal organs following IIR injury. MATERIALS AND METHODS: Anesthetized adult male BalbC mice were randomized to sham laparotomy (control, n = 5), or 15 min of superior mesenteric artery occlusion. Experimental ischemia was followed by a period of reperfusion [1 min (n = 6) or 1 h (n = 6)]. Mice were then sacrificed and lung, kidney, and intestinal tissues were harvested. Following RNA extraction, purinoceptor mRNA expression for P2Y2, A3, P2X7, A2b, P2Y4, and P2Y6 was analyzed using real-time RT-PCR. RESULTS: Significant differences in purinoceptor expression were observed in the lungs and kidneys of mice exposed to IIR injury when compared to controls. Pulmonary P2Y2 receptor expression was increased in the 1 h IIR group when compared to control, while pulmonary A3 receptor expression was incrementally elevated following IIR injury. In the kidney, P2Y2 receptor expression was increased in the 1 h IIR group compared to both 1 min IIR and control, and A3 receptor expression was decreased in the 1 h IIR group compared to the 1 min IIR group. No significant changes were observed in the intestinal purinoceptor profiles. CONCLUSION: Purinoceptor expression is altered in the murine lung and kidney, but not intestine following experimental IIR injury. These findings may implicate extracellular nucleotides and purinoceptors as possible mediators of the extra-intestinal organ dysfunction associated with IIR injury. PMID- 17688887 TI - Stochastic approach to molecular interactions and computational theory of metabolic and genetic regulations. AB - The underlying molecular mechanisms of metabolic and genetic regulations are computationally identical and can be described by a finite state Markov process. We establish a common computational model for both regulations based on the stationary distribution of the Markov process with the aim of establishing a unified, quantitative model of general biological regulations. Various existing results regarding intracellular regulations are derived including the classical Michaelis-Menten equation and its generalization to more complex allosteric enzymes in a systematic way. The notion of probability flow is introduced to distinguish the equilibrium stationary distribution from the non-equilibrium one; it plays a crucial role in the analysis of stationary state equations. A graphical criterion to guarantee the existence of an equilibrium stationary distribution is derived, which turns out to be identical to the classical Wegscheider condition. Simple graphical methods to compute the equilibrium and non-equilibrium stationary distributions are derived based crucially on the probability flow, which dramatically simplifies the classical methods still used in enzymology. PMID- 17688888 TI - Malnutrition enhances cardiovascular responses to chemoreflex activation in awake rats. AB - Several studies in the literature suggest that low-protein intake is associated with increases in sympathetic efferent activity and cardiovascular disease. Among the possible mechanisms, changes in the neurotransmission of cardiovascular reflexes have been implicated. Therefore, the present study comprised the evaluation of chemoreflex responsiveness in rats subjected to a low-protein diet during the 35 days after weaning. As a result, we observed that malnourished rats presented higher levels of baseline mean arterial pressure and heart rate and exhibited a mild increase in the pressor response to chemoreflex activation. They also exhibited a massive bradycardic response to chemoreflex activation. Interestingly, bilateral ligature of the carotid body arteries further increased baseline mean arterial pressure and heart rate in malnourished animals. The data suggest severe autonomic imbalance and/or change in the central interplay between neural and cardiovascular mechanisms. PMID- 17688889 TI - Calcium antagonists cause dry mouth by inhibiting resting saliva secretion. AB - Ca2+ antagonists cause dry mouth by inhibiting saliva secretion. The present study was undertaken to elucidate the mechanism by which Ca2+ antagonists cause dry mouth. Since the intracellular Ca2+ concentration ([Ca2+]i) is closely related to saliva secretion, [Ca2+]i was measured with a video-imaging analysis system by using human submandibular gland (HSG) cells as the material. The Ca2+ antagonist, nifedipine, inhibited the elevation in [Ca2+]i induced by 1-10 microM carbachol (CCh), but had no inhibitory effect on that induced by 30 and 100 microM CCh. The other kinds of Ca2+ antagonists, verapamil (10 microM), diltiazem (10 microM), and the inorganic Ca2+ channel blocker, CdCl2 (50 microM), also inhibited the [Ca2+]i elevation induced by 10 microM CCh. The Ca2+ channel activator, Bay K 8644 (5 microM), significantly enhanced the CCh (10 microM) induced [Ca2+]i elevation. Endothelin-1 and norepinephrine also increased the CCh (10 microM)-induced [Ca2+]i elevation. SKF-96365 reversed the enhancement of the CCh (10 microM)-induced [Ca2+]i elevation caused by AlF4- and phenylephrine. The phospholipase Cbeta (PLCbeta) inhibitor, U-73122 (5 microM), significantly inhibited the [Ca2+]i elevation induced by 100 microM CCh compared with that induced by 10 microM CCh, while the PLCbeta activator, m-3M3FBS (20 microM), significantly increased the [Ca2+]i elevation induced by 100 microM CCh compared with that induced by 10 microM CCh. We therefore conclude that non-selective cation and voltage-dependent Ca2+ channels are involved in resting salivation and that Ca2+ antagonists depress H2O secretion by blocking the Ca2+ channels and thereby cause dry mouth. PMID- 17688890 TI - A novel method for mapping the heterogeneity in blood supply to normal and malignant tissues in the mouse dorsal window chamber. AB - A novel first-pass imaging method for studying blood flow in tumors and normal tissues in mouse dorsal window chamber preparations is reported in this study. A fluorescence-labeled macromolecule is administered i.v. as a bolus dose, and the signal generated by the bolus is detected as the bolus passes through the vascular network. The sensitivity of the method is sufficiently high that the bolus can be detected in any tumor or normal tissue microvessel. The method is particularly useful for measuring the velocity and direction of blood flow in individual vessel segments of normal and malignant tissues and the blood supply time (BST) of individual tumor vessel segments; i.e., the time required for arterial blood to flow from a supplying tumor artery to a downstream microvessel segment. Since all vessels within a window chamber preparation can be studied simultaneously in a single imaging sequence, a significant benefit of the method is that it can be used to produce maps of velocity of blood flow and BST of the entire microvascular network of xenografted tumors. PMID- 17688892 TI - Controlling attention through action: observing actions primes action-related stimulus dimensions. AB - Previous findings suggest that planning an action "backward-primes" perceptual dimension related to this action: planning a grasp facilitates the processing of visual size information, while planning a reach facilitates the processing of location information. Here we show that dimensional priming of perception through action occurs even in the absence of active action planning. Subjects watched video clips showing a grasping or reaching action before detecting size- or location-defined deviants in visual stimulus sequences. Size deviants were detected faster after seeing a grasp and location deviants were detected faster after seeing a reach. This supports the assumption that perceptual codes and action plans share a common representational medium, and that "attention to action" controls "attention to stimuli". PMID- 17688891 TI - Brain levels of neuropeptides in human chronic methamphetamine users. AB - Animal data show that neuropeptide systems in the dopamine-rich brain areas of the striatum (caudate, putamen, and nucleus accumbens) are influenced by exposure to psychostimulants, suggesting that neuropeptides are involved in mediating aspects of behavioral responses to drugs of abuse. To establish in an exploratory study whether levels of neuropeptides are altered in brain of human methamphetamine users, we measured tissue concentrations of dynorphin, metenkephalin, neuropeptide Y, neurotensin, and substance P in autopsied brains of 16 chronic methamphetamine users and 17 matched control subjects. As expected, levels of most neuropeptides were enriched in dopamine-linked brain regions such as the nucleus accumbens and striatum of normal human brain. In contrast to animal findings of increased neuropeptide levels following short-term methamphetamine exposure, striatal neuropeptide concentrations were either normal or moderately decreased in the methamphetamine users. In other examined dopamine poor cortical and subcortical brain areas, neuropeptide levels were generally either normal or variably reduced. Although the neuropeptide differences might be explained by methamphetamine-induced damage to neuropeptide-containing neurons, our human data are consistent with the possibility that, at least in the human striatum, long-term methamphetamine exposure leads to an adaptive process that is distinct from that which increases neuropeptide levels after acute methamphetamine exposure. PMID- 17688893 TI - Neuroleptics reverse attentional effects in schizophrenia patients. AB - Patients with schizophrenia show attention deficit characterized by a larger validity effect (fast responses to cued than uncued stimuli) in the right visual field than in the left visual field. In addition, schizophrenia patients do not show inhibition of return (IOR--a mechanism that enables efficient visual search), unless attention is summoned back to the center after the peripheral cue. The present study examined the short-term effect of neuroleptic medications on these two components of visual spatial attention in schizophrenia patients. In order to do this we tested schizophrenia patients that were treated with long acting neuroleptic medication. These patients were treated once a month, which allowed us to test them with either low or high levels of medication. Here we show that neuroleptic medications reverse the attentional hemispheric asymmetry. In the group with a high level of medication fast RTs to cued trials were found in the right visual field, while in the group with a low level of medication the opposite pattern was found - fast RTs to cued trials were found in the left visual field. In addition, level of medication did not influence IOR - regardless of the level of medication, IOR was observed only when attention was summoned back to the center, unlike control group. These finding suggest an imbalance in dopaminergic activity, possibly in subcortical structures such as the basal ganglia. This study also shows a dissociation between the two components of visual orienting of attention and suggests that facilitation and inhibition are independent processes. PMID- 17688894 TI - Antifungal rosane diterpenes and other constituents of Hugonia castaneifolia. AB - The rosane diterpenoids hugorosenone [3beta-hydroxyrosa-1(10),15-dien-2-one], 18 hydroxyhugorosenone and 18-hydroxy-3-deoxyhugorosenone, and 12-hydroxy-13 methylpodocarpa-8,11,13-trien-3-one were isolated as antifungal constituents of H. castaneifolia Engl. root bark, together with the previously reported di podocarpanoids hugonone A and hugonone B that were weakly active, and 1(10),15 rosadiene-2beta,3beta-diol (hugorosenol), 4alpha-methoxyhimachal-10-en-5beta-ol (hugonianene B) and 2-hydroxyhenpentacont-2-enal, and the known compounds tetracosyl-(E)-ferrulate and caryophyllene oxide, all of which were inactive. Hugorosenone also exhibited activity against Anopheles gambiae mosquito larvae. Structural determination was achieved based on spectroscopic data. PMID- 17688895 TI - [Nasal sequels of unilateral clefts: analysis and management]. AB - Usually, the nasal sequels of unilateral cleft patient are just considered as an esthetic problem to be addressed after the growth spurt of adolescence. This very narrow vision has led the cleft lip and palate treatment to a deadend. Actually, nasal sequels are the worst in terms of consequence on facial growth. 75% of complete unilateral cleft children are more oral than nasal breathers. Today, we know about the bad consequences of oral breathing on facial growth. It is not surprising to observe a high rate of small maxilla with cleft maxilla scars. In the fetus, the unilateral cleft nose deformities are well explained by the rupture of the facial envelope and the ventilatory dynamics of the amniotic fluid. Every step of the primary treatment threatens the nasal air way patency, whether when repairing lip and nose, suturing the hard palate that is the floor of the nose, or closing the alveolar cleft which controls the width of the piriform aperture. The functional and esthetic nasal sequels reflect the initial deformity, but are also the surgeon's skill and protocol choice. Before undertaking treatment, we must analyze the deformity at every level. Usually, the best option is to reopen the cleft completely to perform a combined revision of the lip, nose, and alveolar cleft after an adequate anterior maxillary expansion. If nasal breathing is necessary for an adequate facial growth, 25 years of experience showed us that it was very difficult to erase the cortical imprint of an early oral breathing pattern. So it is essential to establish a normal nasal breathing mode at the initial surgery. When the initial surgery is efficient and/or the secondary repair is successful, the final esthetic rhinoplasty, when indicated, is just performed for the sake of harmonization, with a classic internal approach and a few refinements. PMID- 17688896 TI - [Maxillary sequels in labial-alveolar-velopalatine clefts. The role of orthognathic surgery]. AB - Maxillary hypoplasia is a common sequel in cleft lip and palate deformities. After primary surgery to close lip and palate, patients routinely need extensive treatment particularly orthodontic management. With this type of approach, maxillary hypoplasia is less frequent and severe and subsequent orthognathic surgery is efficient in most cases. Without the proper management maxillary hypoplasia may be severe and patients will need a modified management and specific revision. At the end of maxillar growth, the first aim of treatment is to achieve continuity of the maxillary arch with gingivoperiosteoplasty. The transversal insufficiency can then be treated by distraction osteogenesis. Orthodontic treatment should leave place for missing teeth. PMID- 17688897 TI - [Oronasal fistula in sequels of labialalveolarvelopalatine clefts]. AB - Labial and palatine maxillary clefts are treated by surgery, as for oronasal fistula. One of the most important parts of management is the timing of primary surgery in order to avoid growth disturbance. The authors describe the various possibilities to close secondary oronasal fistula. The timing and choice of surgical techniques are still debated and being improved. Various surgical techniques are available, from mucoperiosteal palatal flap to a free flap. Nevertheless, the mucoperiosteal palatal flap is the most commonly used. In some cases mucoperiosteal flaps are impossible to perform, so other options for extreme cases are discussed. PMID- 17688898 TI - Human polymer-based cartilage grafts for the regeneration of articular cartilage defects. AB - The use of autologous chondrocyte implantation (ACI) and its further development combining autologous chondrocytes with bioresorbable matrices may represent a promising new technology for cartilage regeneration in orthopaedic research. Aim of our study was to evaluate the applicability of a resorbable three-dimensional polymer of pure polyglycolic acid (PGA) for the use in human cartilage tissue engineering under autologous conditions. Adult human chondrocytes were expanded in vitro using human serum and were rearranged three-dimensionally in human fibrin and PGA. The capacity of dedifferentiated chondrocytes to re-differentiate was evaluated after two weeks of tissue culture in vitro and after subcutaneous transplantation into nude mice by propidium iodide/fluorescein diacetate (PI/FDA) staining, scanning electron microscopy (SEM), gene expression analysis of typical chondrocyte marker genes and histological staining of proteoglycans and type II collagen. PI/FDA staining and SEM documented that vital human chondrocytes are evenly distributed within the polymer-based cartilage tissue engineering graft. The induction of the typical chondrocyte marker genes including cartilage oligomeric matrix protein (COMP) and cartilage link protein after two weeks of tissue culture indicates the initiation of chondrocyte re-differentiation by three-dimensional assembly in fibrin and PGA. Histological analysis of human cartilage tissue engineering grafts after 6 weeks of subcutaneous transplantation demonstrates the development of the graft towards hyaline cartilage with formation of a cartilaginous matrix comprising type II collagen and proteoglycan. These results suggest that human polymer-based cartilage tissue engineering grafts made of human chondrocytes, human fibrin and PGA are clinically suited for the regeneration of articular cartilage defects. PMID- 17688900 TI - Cytolytic peptides belonging to the brevinin-1 and brevinin-2 families isolated from the skin of the Japanese brown frog, Rana dybowskii. AB - Peptidomic analysis of an extract of the skins of specimens of Dybowski's brown frog Rana dybowskii Gunther, 1876, collected on Tsushima Island, Japan led to the identification of 10 peptides with differential antibacterial and hemolytic activities. The primary structures of these peptides identified them as belonging to the brevinin-1 (5 peptides) and brevinin-2 (5 peptides) families of antimicrobial peptides. A peptide (FIGPIISALASLFG.NH(2)) with structural similarity to members of the temporin family was also isolated but this component lacked cytolytic activity. Phylogenetic relationships among the Japanese brown frogs (R. dybowskii, R. japonica, R. okinavana, R. ornativentris, R. pirica, R. sakuraii, R. tagoi, and R. tsushimensis) are only incompletely understood. Cladograms based upon maximum parsimony analyses of the brevinin-1 and brevinin-2 amino acid sequences provide strong support for a sister-group relationship between R. dybowskii and R. pirica and somewhat weaker support for a sister-group relationship between R. okinavana and R. tsushimensis. These conclusions are consistent with previous analyses based upon allozyme variations and comparisons of the nucleotide sequences of mitochondrial genes. PMID- 17688899 TI - Genistein genotoxicity: critical considerations of in vitro exposure dose. AB - The potential health benefits of soy-derived phytoestrogens include their reported utility as anticarcinogens, cardioprotectants and as hormone replacement alternatives in menopause. Although there is increasing popularity of dietary phytoestrogen supplementation and of vegetarian and vegan diets among adolescents and adults, concerns about potential detrimental or other genotoxic effects persist. While a variety of genotoxic effects of phytoestrogens have been reported in vitro, the concentrations at which such effects occurred were often much higher than the physiologically relevant doses achievable by dietary or pharmacologic intake of soy foods or supplements. This review focuses on in vitro studies of the most abundant soy phytoestrogen, genistein, critically examining dose as a crucial determinant of cellular effects. In consideration of levels of dietary genistein uptake and bioavailability we have defined in vitro concentrations of genistein >5 microM as non-physiological, and thus "high" doses, in contrast to much of the previous literature. In doing so, many of the often-cited genotoxic effects of genistein, including apoptosis, cell growth inhibition, topoisomerase inhibition and others become less obvious. Recent cellular, epigenetic and microarray studies are beginning to decipher genistein effects that occur at dietarily relevant low concentrations. In toxicology, the well accepted principle of "the dose defines the poison" applies to many toxicants and can be invoked, as herein, to distinguish genotoxic versus potentially beneficial in vitro effects of natural dietary products such as genistein. PMID- 17688901 TI - Identification, cloning and sequencing of two major venom proteins from the box jellyfish, Chironex fleckeri. AB - Two of the most abundant proteins found in the nematocysts of the box jellyfish Chironex fleckeri have been identified as C. fleckeri toxin-1 (CfTX-1) and toxin 2 (CfTX-2). The molecular masses of CfTX-1 and CfTX-2, as determined by SDS-PAGE, are approximately 43 and 45 kDa, respectively, and both proteins are strongly antigenic to commercially available box jellyfish antivenom and rabbit polyclonal antibodies raised against C. fleckeri nematocyst extracts. The amino acid sequences of mature CfTX-1 and CfTX-2 (436 and 445 residues, respectively) share significant homology with three known proteins: CqTX-A from Chiropsalmus quadrigatus, CrTXs from Carybdea rastoni and CaTX-A from Carybdea alata, all of which are lethal, haemolytic box jellyfish toxins. Multiple sequence alignment of the five jellyfish proteins has identified several short, but highly conserved regions of amino acids that coincide with a predicted transmembrane spanning region, referred to as TSR1, which may be involved in a pore-forming mechanism of action. Furthermore, remote protein homology predictions for CfTX-2 and CaTX-A suggest weak structural similarities to pore-forming insecticidal delta endotoxins Cry1Aa, Cry3Bb and Cry3A. PMID- 17688902 TI - Expression of the Arabidopsis Xrn4p 5'-3' exoribonuclease facilitates degradation of tombusvirus RNA and promotes rapid emergence of viral variants in plants. AB - Rapid RNA virus evolution is a major problem due to the devastating diseases caused by human, animal and plant-pathogenic RNA viruses. A previous genome-wide screen for host factors affecting recombination in Tomato bushy stunt tombusvirus (TBSV), a small monopartite plant virus, identified Xrn1p 5'-3' exoribonuclease of yeast, a model host, whose absence led to increased appearance of recombinants [Serviene, E., Shapka, N., Cheng, C.P., Panavas, T., Phuangrat, B., Baker, J., Nagy, P.D., (2005). Genome-wide screen identifies host genes affecting viral RNA recombination. Proc. Natl. Acad. Sci. U. S. A. 102 (30), 10545-10550]. In this paper, we tested if over-expression of Xrn1p in yeast or expression of the analogous Xrn4p cytoplasmic 5'-3' exoribonuclease, which has similar function in RNA degradation in Arabidopsis as Xrn1p in yeast, in Nicotiana benthamiana could affect the accumulation of tombusvirus RNA. We show that over-expression of Xrn1p led to almost complete degradation of TBSV RNA replicons in yeast, suggesting that Xrn1p is involved in TBSV degradation. Infection of N. benthamiana expressing AtXrn4p with Cucumber necrosis tombusvirus (CNV) led to enhanced viral RNA degradation, suggesting that the yeast and the plant cytoplasmic 5'-3' exoribonuclease play similar roles. We also observed rapid emergence of novel CNV genomic RNA variants formed via deletions of 5' terminal sequences in N. benthamiana expressing AtXrn4p. Three of the newly emerging 5' truncated CNV variants were infectious in N. benthamiana protoplasts, whereas one CNV variant caused novel symptoms and moved systemically in N. benthamiana plants. Altogether, this paper establishes that a single plant gene can contribute to the emergence of novel viral variants. PMID- 17688903 TI - Structural basis for the binding of the neutralizing antibody, 7D11, to the poxvirus L1 protein. AB - Medical countermeasures to prevent or treat smallpox are needed due to the potential use of poxviruses as biological weapons. Safety concerns with the currently available smallpox vaccine indicate a need for research on alternative poxvirus vaccine strategies. Molecular vaccines involving the use of proteins and/or genes and recombinant antibodies are among the strategies under current investigation. The poxvirus L1 protein, encoded by the L1R open reading frame, is the target of neutralizing antibodies and has been successfully used as a component of both protein subunit and DNA vaccines. L1-specific monoclonal antibodies (e.g., mouse monoclonal antibody mAb-7D11, mAb-10F5) with potent neutralizing activity bind L1 in a conformation-specific manner. This suggests that proper folding of the L1 protein used in molecular vaccines will affect the production of neutralizing antibodies and protection. Here, we co-crystallized the Fab fragment of mAb-7D11 with the L1 protein. The crystal structure of the complex between Fab-7D11 and L1 reveals the basis for the conformation-specific binding as recognition of a discontinuous epitope containing two loops that are held together by a disulfide bond. The structure of this important conformational epitope of L1 will contribute to the development of molecular poxvirus vaccines and also provides a novel target for anti-poxvirus drugs. In addition, the sequence and structure of Fab-7D11 will contribute to the development of L1 targeted immunotherapeutics. PMID- 17688904 TI - Predicting visual fixations on video based on low-level visual features. AB - To what extent can a computational model of the bottom-up visual attention predict what an observer is looking at? What is the contribution of the low-level visual features in the attention deployment? To answer these questions, a new spatio-temporal computational model is proposed. This model incorporates several visual features; therefore, a fusion algorithm is required to combine the different saliency maps (achromatic, chromatic and temporal). To quantitatively assess the model performances, eye movements were recorded while naive observers viewed natural dynamic scenes. Four completing metrics have been used. In addition, predictions from the proposed model are compared to the predictions from a state of the art model [Itti's model (Itti, L., Koch, C., & Niebur, E. (1998). A model of saliency-based visual attention for rapid scene analysis. IEEE Transactions on Pattern Analysis and Machine Intelligence 20(11), 1254-1259)] and from three non-biologically plausible models (uniform, flicker and centered models). Regardless of the metric used, the proposed model shows significant improvement over the selected benchmarking models (except the centered model). Conclusions are drawn regarding both the influence of low-level visual features over time and the central bias in an eye tracking experiment. PMID- 17688905 TI - Interaction between binocular rivalry and depth in plaid patterns. AB - Binocular rivalry was studied using plaids which were the sum of orthogonal diagonal gratings plus identical vertical gratings in the two eyes. The rivalry alternations sped up as the spatial frequency difference between the vertical and diagonal gratings was increased above about one octave, but slowed down for smaller differences. The interaction between depth and rivalry was studied using similar plaids but with depth introduced in the vertical components. Depth and rivalry coexisted when the spatial frequency difference between the vertical and diagonal gratings was greater than about one octave, but rivalry slowed down and depth perception was reduced for smaller differences. Plaids consisting of square wave gratings were used to compare: (1) added gratings; (2) vertical gratings superimposed on (i.e. occluding) diagonal gratings; (3) diagonal gratings superimposed on vertical gratings. Rivalry alternations were fastest in condition (3), indicating that grouping effects played a role. The final experiment indicated that depth and rivalry coexisted within a spatial frequency band if the orientation difference between the vertical and diagonal components was 60-70 degrees . These results place constraints on models of stereopsis and rivalry, indicating that depth and rivalry can coexist in different spatial frequency and orientation bands but that each interferes with the other in the same band. PMID- 17688906 TI - Receptive field properties of neurons in the primary visual cortex under photopic and scotopic lighting conditions. AB - Knowledge of the physiology of the primate visual cortex (area V-1) comes mostly from studies done in photopic conditions, in which retinal cones are active and rods play little or no part. Conflicting results have come from research into the effects of dark adaptation on receptive field organization of cells in the retina and the lateral geniculate nucleus. These studies claim either that the effect of the surround disappears with dark adaptation or that it does not. The current study has as its objective a comparison of responses of V-1 cells in awake-alert macaque monkeys under conditions of light and dark adaptation. We reasoned that basic receptive field properties of V-1 cells such as orientation selectivity, direction selectivity, and end-stopping should be preserved in scotopic conditions if the receptive field organization of antecedent cells is maintained in dim light. Our results indicate that dark adaptation does not alter basic V-1 receptive field characteristics such as selectivity for orientation, direction, and bar length. PMID- 17688907 TI - Optimisation of sludge disruption by sonication. AB - This study presents an examination on the correlation of sonication operating condition, sludge property, formation and behaviour of cavitation bubbles in sludge disruption under low-frequency ultrasound sonication. The influence of sonication time, sonication density, type of sludge and solids content on the disruption was evaluated. The most vigorous particle disruption was achieved in the initial period of sonication, which subsided subsequently. The explosive effect was likely due to the rapid cavitation arising from powerful transient bubbles generated in fractions of microseconds. A rating for the type of sludge was derived based on the finding that particles in secondary sludge were more readily disrupted than both primary sludge and mixed sludge. While sonication density exhibited the most significant role in cavitation bubble formation and behaviour, particle disruption could be optimised for energy input by sonicating at higher sonication density and shorter sonication time. Based on theoretical consideration, it was deduced that within an optimum sludge solids content ranging between 2.3% and 3.2%, superior particle disruption could be accomplished within a minute for secondary sludge sonicated at a density of 0.52 W/mL. Useful guidelines for sonication system installation, equipment protection and process reliability could be established from knowledge derived from a good understanding on the influence of solids content on sludge sonication. PMID- 17688908 TI - Occurrence and distribution of novel botryococcene hydrocarbons in freshwater wetlands of the Florida Everglades. AB - A high abundance of isoprenoid hydrocarbons, the botryococcenes, with carbon numbers from 32 to 34 were detected in the Florida Everglades freshwater wetlands. These compounds were present in varying amounts up to 106microg/gdw in periphyton, 278microg/gdw in floc, and 46microg/gdw in soils. Their structures were determined based on comparison to standards, interpretation of their mass spectra and those of their hydrogenation products, and comparison of Kovats indexes to those reported in the literature. A total of 26 cyclic and acyclic botryococcenes with 8 skeletons were identified, including those with fewer degrees of unsaturation, which are proposed as early diagenetic derivatives from the natural products. This is the first report that botryococcenes occur in the Everglades freshwater wetlands. Their potential biogenetic sources from green algae and cyanobacteria were examined, but neither contained botryococcenes. Thus, the source implication of botryococcenes in this ecosystem needs further study. PMID- 17688909 TI - Organochlorine and mercury contamination in fish tissues from the River Nestos, Greece. AB - Polychlorinated biphenyls (PCBs), hexachlorocyclohexane (HCH) isomers, dichlorodiphenyltrichloroethane (DDT) and its metabolites, other organochlorine pesticides such as hexachlorobenzene (HCB), chlordane compounds (CHLs, including trans-chlordane and cis- and trans-nonachlor) and the heavy metal mercury were quantified in muscle and liver of the European chub (Leuciscus cephalus, Linnaeus, 1758) and in the muscle of the barbel (Barbus cyclolepis, Heckel, 1837) at two sampling sites of the River Nestos, Greece. PCBs in muscle and DDTs in the liver tissues were the predominant organochlorinated contaminants. Among the PCBs, congeners 47 (up to 9.60 ng g(-1) wet wt.), 180 (up to 1.15 ng g(-1) wet wt.) and 190 (up to 1.50 ng g(-1) wet wt.) were the most frequent and abundant. The contamination degree by the sum of PCBs on the fish tissue samples from the River Nestos is lower or similar to PCB levels found in other ecosystems. Among the organochlorine pesticides, essentially only p,p'-DDD, p,p'-DDE and alpha-, beta- and gamma-HCH were found, with the former appearing at mean levels up to 30.71 ng g(-1) wet wt. From a public health standpoint, residue organochlorine pesticide levels from our work are considerably lower than the recommended tolerance limits. Finally, mean values of Hg in chub were significant lower (up to 31.04 ng g(-1) wet wt.) compared to those detected on barbel (up to 169.27 ng g(-1) wet wt.). The concentrations of Hg in fresh water fish from the River Nestos did not exceed WHO and US EPA health guidelines, and were suitable for human consumption. PMID- 17688910 TI - Evolutionary reversals of limb proportions in early hominids? Evidence from KNM ER 3735 (Homo habilis). AB - Upper-to-lower limb proportions of Homo habilis are often said to be more ape like than those of its reputed ancestor, Australopithecus afarensis. Such proportions would either imply multiple evolutionary reversals or parallel development of a relatively short upper limb in A. afarensis and later Homo. However, assessments of limb proportions are complicated by the fragmentary nature of the two known H. habilis skeletons, OH 62 and KNM-ER 3735. Initially, KNM-ER 3735 was compared to A.L. 288-1 (A. afarensis) using a single modern human and chimpanzee as reference. Here, based on a larger comparative sample, we find that the relative size of the distal humerus, radial head, and shaft of both KNM ER 3735 and A.L. 288-1 lie within the range of variation of modern humans, whereas their sacra are small as is the case for all early hominids. In addition, their manual phalanges are similar in having a gracile base but robust midshaft. Contrary to earlier studies, the fossils are not differentiable from each other statistically with respect to all features listed above. On the other hand, they differ in robusticity of the scapular spine and relative length of the radial neck. An exact randomization test suggests only a very low probability of finding a similar degree of difference within a single species of extant hominoids. In contrast to the consensus view, we conclude that A.L. 288-1 had a short, human like forearm, whereas KNM-ER 3735 possessed a distinctly longer forearm and more powerful shoulder girdle. This interpretation fits with earlier conclusions that suggested human-like humerofemoral proportions but chimpanzee-like brachial proportions for Homo habilis. Thus, the scenario of a unidirectional, progressive change in limb proportions within the hominid lineage is not supported by our work. PMID- 17688911 TI - Genetic variation for life span, resistance to paraquat, and spontaneous activity in unselected populations of Drosophila melanogaster: implications for transgenic rescue of life span. AB - Genetic variation in adult life span, resistance to paraquat, resistance to DDT, and spontaneous flying activity were measured in 138 recombinant inbred lines of Drosophila melanogaster. We find that the phenotypic correlation between life span and resistance to an exogenous oxidizing agent is positive, though weak, and that there is little correlation between the two traits at the level of quantitative trait loci (QTLs). The sign of the life span-resistance correlation is haplotype-specific, suggesting a high degree of statistical interaction and dependence on genetic background. Because of the genotype-specificity in the relationship between life span and resistance phenotypes, interventions to extend life span by overexpression of antioxidant enzymes are likely to produce strain specific results. These observations are in general agreement with the "genetic rescue" hypothesis of Sohal et al. [Sohal, R.S., Mockett, R.J., Orr, W.C., 2002. Mechanisms of aging: an appraisal of the oxidative stress hypothesis. Free Radic. Biol. Med. 33, 575-586.], though we emphasize that such statistical interaction is a normal feature of standing genetic variation, and does not imply that some genotypes are pathological. Ad hoc observation of spontaneous flying activity 5 days after emergence proved to be a much better predictor of life span than resistance to an exogenous oxidant in these populations. PMID- 17688912 TI - Age-related BM-MNC dysfunction hampers neovascularization. AB - Although ischemia-induced neovascularization is reportedly impaired with aging, the effect of aged-bone marrow mononuclear cells (BM-MNCs) on neovascularization has not been investigated. The neovascularization capacity of BM-MNCs obtained from 8-week-old mice (young) was compared to those obtained from 18-month-old mice (old), both in vivo and in vitro. Neovascularization in ischemic limbs was significantly impaired in old mice. Whereas transplantation of young BM-MNCs significantly improved blood perfusion, tissue capillary density, and vascular endothelial growth factor (VEGF) production in transplanted ischemic limbs, no such effects were observed with old BM-MNCs. Old BM-MNCs also showed a significant impairment of in vitro VEGF production and migratory capacity in response to VEGF. The number of Dil/lectin-positive cells was significantly lower in old mice, but there was no difference in the number of AC133(+)/CD34(+) and CD34(+)/VEGF-R2(+) positive cells between young and old BM-MNCs. Transplantation of young BM-MNCs improved neovascularization and VEGF production in the ischemic limbs of old recipients, with results that were similar to those obtained in young recipients. These results indicate that the neovascularization capacity of transplanted BM-MNCs is impaired with aging. However, aging does not hamper the revitalization of neovascularization in the murine host in response to transplantation of young BM-MNCs. PMID- 17688913 TI - Organochlorine pesticide contamination in three bird species of the Embalse La Florida water reservoir in the semiarid midwest of Argentina. AB - Organochlorine pesticides (OCs) have a variety of acute and chronic pathological effects on animals, are persistent in the environment and are accumulated in adipose tissue of animals. In Argentina there are few studies reporting the OC contamination in the fauna. Moreover, no data are available for an ecologically relevant region, the arid-semiarid midwest region of Argentina. Recently, it was reported OC contamination in the water of an important artificial water reservoir of this area, the Embalse La Florida in the San Luis province. The present study aims to provide OC baseline data for birds of Embalse La Florida and to evaluate the potential risk of OC contamination for the local avifauna. We selected two fish-eating species, Podiceps major (great grebe) and Phalacrocorax brasilianus (neotropic cormorant) and one omnivore species, Pitangus sulphuratus (great kiskadee) to evaluate OC contamination. Alpha-, beta-, delta- and gamma hexachlorocyclohexane (SigmaHCH), p,p'-DDT, p,p'-DDD, p,p'-DDE and methoxychlor (SigmaDDT), aldrin, dieldrin, endrin and endosulfan (SigmaALD) and, cis chlordane, trans-chlordane, heptachlor, heptachlor epoxide(SigmaCHL) were measured in adipose tissue of two male great grebes, six neotropic cormorant (3 of each sex) and four great kiskadees (2 of each sex). We detected all OC pesticides assayed [SigmaHCH range: ND to 3168.41 ng/g fat, SigmaCHL range: ND to 4961.66 ng/g fat, SigmaALD range: 287.07 to 9161.70 ng/g fat, SigmaDDT range: 1068.98 to 6479.84 ng/g fat], with the exception of p,p'-DDT. Summed OC concentration in all bird species ranged from 2684.91 to 19231.91 ng/g fat. The omnivore had significantly greater concentrations of SigmaCHLs than fish-eating species. Females of the neotropic cormorant had significantly higher amounts of SigmaHCH and SigmaCHL than males. The OC concentrations detected in birds were lower than those reported in the literature that are associated with deleterious effects on survival or reproduction in others species of birds. This study is the first report of OC contamination in birds of the midwest region of Argentina and constitutes a starting point for future studies that evaluate temporal changes of OCs in birds in this region. PMID- 17688914 TI - Synthetic reactive dye wastewater treatment by narrow-leaved cattails (Typha angustifolia Linn.): effects of dye, salinity and metals. AB - Narrow-leaved cattails were studied in synthetic reactive dye wastewater (SRDW) under caustic conditions. The effects of the toxic dye were expressed in terms of relative plant growth rate and the appearance of symptoms such as necrosis, and chronic or acute wilting. The dye toxicity was 25.33 mg l(-1) which was close to approximate the concentration of dye residue from the textile effluent in the public stream. The system pH and % color removal were decreased, indicating that narrow-leaved cattail can treat wastewater. The average system pH decreased from 9 to 7. The maximum color removal was approximately 60% when cultured under soil conditions. The SEM image of narrow-leaved cattail root after treatment with SRDW indicated that the root cortex was damaged and the crystalline sodium salts deposited in the root cells which caused evaporation and transpiration decreased in SRDW. The salinity under caustic conditions also affects the growth of the plants. The maximum sodium removal was approximately 44% and was found in the SRDW under soil conditions within 14 days. A small amount of sodium could enhance the relative growth rate. However, the sodium removal of the plants was limited after the third week of treatment. It should be noted that narrow-leaved cattails are known to avoid the textile dye and salt stress conditions during SRDW treatment through special mechanisms such as salt accumulation in the roots or shedding of older leaves. In addition, elements such as silicon, calcium and iron in plants might help the plant to detoxify by forming complexes with dye molecules. PMID- 17688915 TI - Correlation between production amounts of DEHP and daily intake. AB - It is shown that the daily intake of DEHP in German university students is strictly and almost perfectly correlated with the industrial production of DEHP in Germany yielding a correlation coefficient of >0.9. PMID- 17688916 TI - Impaired elasticity of aorta in patients with erectile dysfunction. AB - OBJECTIVES: The close relationship between the elasticity of the aorta and cardiovascular disease has aroused the interest of investigators in performing studies related to aortic stiffness parameters. We investigated the aortic stiffness parameters in patients with erectile dysfunction (ED) without known cardiovascular disease and diabetes were investigated. METHODS: The study included 40 men with ED (aged 56 +/- 8 years) according to the Doppler penile ultrasound findings and the five-item version of the International Index of Erectile Function score (group 1) and 25 healthy men (aged 53 +/- 5 years; group 2) underwent fasting serum glucose and lipid level determination. Echocardiography (using a 3.75-MHz transducer) and exercise treadmill test were performed. The diameter change, pulse pressure, aortic strain index, and distensibility index as aortic stiffness parameters were investigated in patients with ED and compared with those of healthy subjects. RESULTS: The average International Index of Erectile Function-5 score of those with ED (group 1) and the control groups (group 2) was 11.2 and 23.2, respectively. Body mass index, age, fasting serum glucose, and lipid profile were not significantly different between the two groups. All patients had negative results on the exercise stress test; and the echocardiography parameters were similar. The percentage of aortic strain (group 1, 4.64 +/- 2.43 versus group 2, 10.21 +/- 5.13, P = 0.021) and the value of the distensibility index (group 1, 0.21 +/- 0.15 versus group 2, 0.51 +/ 0.20 cm2/dyn/10(-3), P <0.001 were significantly lower in the ED group than were those of the control group. CONCLUSIONS: The results of our study have shown that the aortic strain index and distensibility index are impaired in patients with ED. This suggests that ED is a generalized vessel disease rather than a disorder peculiar to the penile arteries. PMID- 17688917 TI - Expression of S100A2 and S100A4 predicts for disease progression and patient survival in bladder cancer. AB - OBJECTIVES: To determine the expression patterns and prognostic value of S100A2 and S100A4 in surgical specimens from radical cystectomy for transitional cell carcinoma of the urinary bladder. METHODS: Immunohistochemical staining for S100A2 and S100A4 was performed in 92 archived radical cystectomy and 38 normal specimens. The immunoreactivity of these proteins was stratified on a 0 to 6 scale and then correlated with the pathologic features and clinical outcome. RESULTS: S100A2 expression was significantly decreased in the bladder cancer specimens compared with the controls (P <0.0001), and S100A4 expression was significantly greater in the bladder cancer specimens (P = 0.03). The loss of expression of S100A2 and increased expression of S100A4 were associated with muscle invasion (P <0.05). These alterations in expression were also associated with a greater risk of disease progression and a decreased chance of cancer specific survival at a median follow-up of 25.3 months (P <0.0001 for both). After adjusting for the effects of the pathologic findings, S100A4 expression remained a significant predictor of disease progression (P <0.0001) and cancer specific survival (P <0.0001). CONCLUSIONS: S100A4 appeared to be an independent predictor for the treatment outcome in bladder cancer. The expression patterns of S100A2 and S100A4 correlated well with the pathologic stage, disease progression, and cancer-specific mortality. This finding could aid in identifying more biologically aggressive cancers and thus patients who might benefit from more intensive adjuvant therapy. PMID- 17688918 TI - Impact of retraction of vas deferens in postradical prostatectomy inguinal hernia. AB - OBJECTIVES: The incidence of inguinal hernia after radical retropubic prostatectomy (RRP) is high. We speculated that retraction of the vasa deferentia with a retractor might cause stretch injury of the myopectineal orifice and lead to inguinal hernia. In testing this hypothesis, we performed RRP with a modified technique and followed up patients prospectively. METHODS: From 1993 to 2002, 171 patients underwent RRP with a retrograde approach, in which the vasa deferentia were cut after the prostate and seminal vesicles were finally exposed. From 2003 to 2005, 150 patients were followed up prospectively who had undergone RRP with a modified technique, in which the bilateral vasa deferentia and surrounding tissues were dissected before placing a retractor so as not to retract them and injure the myopectineal orifice. The incidence rates of inguinal hernia in the two groups were compared. In addition, for the entire group of 321 patients, we determined the risk factors for inguinal hernia after RRP using multivariate analysis. RESULTS: Of the 150 patients in the modified method group, 22 (14.7%) developed an inguinal hernia during follow-up, and 42 (24.6%) of the 171 patients did so in the previous method group. No significant difference was noted between the two groups in terms of the hernia-free rate. Multivariate analysis revealed a body mass index of less than 23 kg/m2 and a history of previous inguinal hernia repair were significant risk factors for postoperative inguinal hernia. CONCLUSIONS: We found that retraction of the vasa deferentia with a retractor did not affect the high incidence of postoperative inguinal hernia after RRP. PMID- 17688919 TI - Continuing or discontinuing low-dose aspirin before transrectal prostate biopsy: results of a prospective randomized trial. AB - OBJECTIVES: To determine whether the incidence and duration of bleeding complications after transrectal prostate biopsy (PB) in patients not discontinuing low-dose aspirin (LDA) are greater than in those discontinuing it. METHODS: A total of 200 consecutive subjects taking chronic LDA were enrolled in a prospective trial and were randomly assigned to undergo transrectal PB while continuing LDA (group 1, n = 67), replacing LDA with low-molecular-weight heparin (group 2, n = 67), or discontinuing LDA (group 3, n = 66). The incidence and duration of hematuria, rectal bleeding, and hematospermia for each group were assessed with a self-administered questionnaire. On days 14 and 30 after PB, all men were evaluated with an outpatient visit and a telephone interview, respectively. RESULTS: The cohort comprised 196 assessable subjects. The median number of biopsy cores taken was 10 (range 6 to 10). The overall bleeding rate was 78.5%, 69.7%, and 81.5% in groups 1, 2, and 3, respectively (P = 0.26). No significant difference was found for hematuria, rectal bleeding, or hematospermia among the groups. No severe bleeding complications occurred. The median duration of hematuria and rectal bleeding was significantly greater statistically in groups 1 and 2 compared with group 3 (6, 4, and 2 days versus 3, 2, and 1 days, respectively; P <0.0001). The proportion of men still reporting hematospermia at 30 days after PB was 21.4%, 18.5%, and 9.3% in groups 1, 2, and 3, respectively (P = 0.2). CONCLUSIONS: The continued use of LDA in men undergoing transrectal PB did not increase the incidence of mild bleeding complications, although it prolonged the duration of self-limiting hematuria and rectal bleeding. Its effect, however, on severe bleeding remains to be determined. PMID- 17688920 TI - Modified posterior sagittal transanorectal approach in repair of urogenital sinus anomalies. AB - INTRODUCTION: To describe the operative details and results of a modified posterior sagittal transanorectal approach for the reconstruction of urogenital sinus (UGS) anomalies. TECHNICAL CONSIDERATIONS: Six children with UGS anomalies underwent surgery using this technique. In a prone jack-knife position, a midline incision was continued to the puborectalis muscle. A plane of dissection was created circumferentially around the rectum separating it from the underlying UGS. Circumferential transanal mucosectomy and a transanal dissection was carried proximally for 5 to 10 cm. The mucosal tube with the serosal wall was resected, exposing the proximal part of the UGS. The posterior and anterior sphincters, anus, and perineal body were then divided in the midline, completely exposing the UGS. Reconstruction of the urethra and vagina was done. At completion of UGS reconstruction, an endoanal pull through of the rectal tube and a low coloanal anastomosis were performed. The muscle complex and perineal body were closed in layers. The modified technique of posterior sagittal transanorectal approach allowed excellent exposure in all 6 patients. None developed any complications related to suture line leak. Fecal and urinary continence was preserved in patients who were continent before the operation. CONCLUSIONS: The modified posterior sagittal transanorectal approach is a safe and effective technique in the treatment of UGS anomalies and can be performed without the need for a protective colostomy. PMID- 17688921 TI - Comparative diagnostic value of urine cytology, UBC-ELISA, and fluorescence in situ hybridization for detection of transitional cell carcinoma of urinary bladder in routine clinical practice. AB - OBJECTIVES: Fluorescence in situ hybridization (FISH) has been reported to have much better sensitivity for the detection of bladder transitional cell carcinoma (TCC) than urine cytology. We comparatively tested cytology, FISH, and the cytokeratin-detection test of urinary bladder cancer (UBC) in routine clinical practice. METHODS: In a prospective study, FISH, the urinary bladder cancer test (UBC-enzyme-linked immunosorbent assay [ELISA]), and cytology were used in 166 patients. Of the 166 patients, 62 had primary TCC (group 1), 71 had undergone transurethral resection of primary TCC before routine secondary transurethral resection (group 2), and 33 control had not undergone TCC (group 3). All patients with false-positive test results were followed up for a mean follow-up time of 22 months. RESULTS: The overall sensitivity of FISH, UBC-ELISA, and cytology was 53.2% (95% confidence interval 40% to 66%), 40.3% (95% confidence interval 28% to 53%), and 71.0% (95% confidence interval 59% to 83%), respectively (P <0.05). For grade 3 TCC, both FISH and cytology reached a sensitivity of 93.3%. In the 104 patients without TCC, the specificity of FISH, UBC-ELISA, and cytology was 74.0%, 75.0%, and 83.7%, respectively. During follow-up, 33.3% of patients with a false positive FISH result developed recurrence, as did 23.1% with false-positive UBC results and 29.4% with false-positive cytology findings (P >0.05). Receiver operating characteristic analysis showed an area under the curve for FISH, UBC, and cytology of 0.636, 0.577, and 0.773, respectively. Only cytology and FISH were significantly predictive of a TCC finding on histologic examination (P <0.001 and P = 0.003, respectively). CONCLUSIONS: In routine clinical practice, conventional cytology in experienced hands can be superior to FISH. False positive results with all three test systems used warrant a high suspicion of subclinical precursor lesions of TCC recurrence. PMID- 17688922 TI - Comparison of two different artificial neural networks for prostate biopsy indication in two different patient populations. AB - OBJECTIVES: Different artificial neural networks (ANNs) using total prostate specific antigen (PSA) and percentage of free PSA (%fPSA) have been introduced to enhance the specificity of prostate cancer detection. The applicability of independently trained ANN and logistic regression (LR) models to different populations regarding the composition (screening versus referred) and different PSA assays has not yet been tested. METHODS: Two ANN and LR models using PSA (range 4 to 10 ng/mL), %fPSA, prostate volume, digital rectal examination findings, and patient age were tested. A multilayer perceptron network (MLP) was trained on 656 screening participants (Prostatus PSA assay) and another ANN (Immulite-based ANN [iANN]) was constructed on 606 multicentric urologically referred men. These and other assay-adapted ANN models, including one new iANN based ANN, were used. RESULTS: The areas under the curve for the iANN (0.736) and MLP (0.745) were equal but showed no differences to %fPSA (0.725) in the Finnish group. Only the new iANN-based ANN reached a significant larger area under the curve (0.77). At 95% sensitivity, the specificities of MLP (33%) and the new iANN based ANN (34%) were significantly better than the iANN (23%) and %fPSA (19%). Reverse methodology using the MLP model on the referred patients revealed, in contrast, a significant improvement in the areas under the curve for iANN and MLP (each 0.83) compared with %fPSA (0.70). At 90% and 95% sensitivity, the specificities of all LR and ANN models were significantly greater than those for %fPSA. CONCLUSIONS: The ANNs based on different PSA assays and populations were mostly comparable, but the clearly different patient composition also allowed with assay adaptation no unbiased ANN application to the other cohort. Thus, the use of ANNs in other populations than originally built is possible, but has limitations. PMID- 17688923 TI - The role of multi-modality adjuvant chemotherapy and radiation in women with advanced stage endometrial cancer. AB - OBJECTIVE: : The optimal adjuvant therapy for women with stages III and IV endometrial cancer following surgical staging and cytoreductive surgery is controversial. We sought to determine the outcome of patients with advanced stage endometrial cancer treated with postoperative chemotherapy+/-radiation to determine whether there was an advantage to combining treatment modalities. METHODS: : A retrospective analysis of patients with surgical stages III and IV endometrial cancer from 1975 to 2006 was conducted at Duke University and the University of North Carolina. Inclusion criteria were comprehensive staging procedure including hysterectomy, bilateral salpingo-oophorectomy, +/-selective pelvic/aortic lymphadenectomy, surgical debulking, and treatment with adjuvant chemotherapy and/or radiotherapy. Progression-free (PFS) and overall survival (OS) were analyzed using Kaplan-Meier method and Cox proportional hazards model. RESULTS: : 356 Patients with advanced stage endometrial cancer were identified who received postoperative adjuvant therapies; 48% (n=171) radiotherapy alone, 29% (n=102) chemotherapy alone, 23% (n=83) chemotherapy and radiation. The median age was 66 years; 38% had endometrioid tumors; and 83% were optimally debulked. There was a significant difference between the adjuvant treatment groups for both OS and PFS (p<0.001), with those receiving chemotherapy alone having poorer 3 year OS (33%) and PFS (19%) compared to either radiotherapy alone (70% and 59%) or combination therapy (79% and 62%). After adjusting for stage, age, grade, and debulking status the hazard ratio (HR) for OS was 1.60 (95% CI, 0.88 to 2.89; p=0.122) for chemotherapy alone and 2.01 (95% CI, 1.17 to 3.48; p=0.012) for radiotherapy alone, compared to combination therapy. When the analysis was restricted to optimally debulked patients the adjusted HR for patients who were treated with either chemotherapy or radiation alone indicated a significantly higher risk for disease progression [HR=1.84 (95% CI, 1.03 to 3.27; p=0.038); HR=1.80 (95% CI, 1.10 to 2.95; p=0.020)] and death [HR=2.33 (95% CI, 1.12 to 4.86; p=0.024); HR=2.64 (95% CI, 1.38 to 5.07; p=0.004)], respectively, compared to patients who received combination therapy. CONCLUSION: : Combined adjuvant chemotherapy and radiation was associated with improved survival in patients with advanced stage disease compared to either modality alone. Future clinical trials are needed to prospectively evaluate multi-modality adjuvant therapy in women with advanced staged endometrial cancer to determine the appropriate sequencing and types of chemotherapy and radiation. PMID- 17688924 TI - Heparanase expression correlates with metastatic capability in human choriocarcinoma. AB - OBJECTIVE: In this report, we studied the role of Hpa in metastatic capability of human choriocarcinoma. At the same time, we investigated the effect of Hpa antisense oligodeoxynucleotide (ASODN) on inhibition of invasiveness of human choriocarcinoma. METHODS: The different invasion ability between JEG-3 and JAR cell lines was proved by Matrigel invasion assay in vitro. Reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot analyses were carried out respectively to determine Hpa gene and protein expression; the localization of this molecule was demonstrated by immunohistochemistry. Finally, Hpa antisense oligodeoxynucleotide (ASODN) was transfected into JEG-3 cells and Hpa mRNA and protein were quantified by RT-PCR and Western blot. The effect of ASODN on the metastatic capability of JEG-3 was evaluated by Matrigel invasion assay. RESULTS: (1) We proved that the invasion ability of JEG-3 cell line was stronger than that of JAR cell line (P<0.05). (2) We found that the Hpa gene and protein in JEG-3 and JAR cell lines were significantly higher than those in normal chorion (P<0.05). On the other hand, we detected that JEG-3 expressed much more Hpa than JAR (P<0.05). (3) Both in JEG-3 cell and in JAR cell, we found that Hpa protein express in cytoplasm. (4) After transfection of Hpa ASODN, Hpa mRNA and protein expression in JEG-3 cell decreased 4- and 5-fold. At the same time, we also observed that the invasion ability of JEG-3 cell was weakened than before (P<0.05). CONCLUSION: The current study demonstrated that the expression of Hpa plays an important role in metastatic capability of human choriocarcinoma and reducing the expression of Hpa can help weaken the invasion ability of human choriocarcinoma. PMID- 17688925 TI - A phase I study of gemcitabine followed by cisplatin concurrent with whole pelvic radiation therapy in locally advanced cervical cancer: a Gynecologic Oncology Group study. AB - PURPOSE: To determine the maximum tolerated dose (MTD) of gemcitabine followed by cisplatin that can be administered weekly during pelvic radiation therapy in patients with locally advanced cervical cancer. METHODS: A phase I and feasibility study with dose escalation of gemcitabine in cohorts of three to six patients to determine the MTD (the dose level at which no more than one of six patients experienced a acute dose-limiting toxicity) was conducted. RESULTS: Thirteen patients were entered on the phase I trial. Acute dose-limiting toxicity occurred with weekly cisplatin at a dose of 40 mg/m(2) and gemcitabine at a dose of 100 mg/m(2). The study was modified, decreasing the dose of cisplatin to 30 mg/m(2) in an effort to dose escalate gemcitabine. Acute dose-limiting toxicity occurred again with weekly cisplatin at a dose of 30 mg/m(2) and gemcitabine at a dose of 75 mg/m(2) (dose level 3). In addition to acute hematologic and acute and late non-hematologic toxicities, late grade 3 and 4 GI and GU toxicities have occurred in two of six patients at dose level 3. Twelve of thirteen patients remained disease-free following treatment. CONCLUSION: The MTD found in this chemoradiation study was weekly gemcitabine 50 mg/m(2) followed by cisplatin 40 mg/m(2). The alternative drug sequence has been reported by others to allow higher doses of gemcitabine. However, at this dose level chronic toxicity was observed. Further expansion of the feasibility cohort of this study was suspended pending the efficacy and toxicity results of a large trial which has recently been completed. PMID- 17688926 TI - Role of systematic lymphadenectomy and adjuvant therapy in stage I uterine papillary serous carcinoma. AB - OBJECTIVE: To assess surgical staging with systematic lymphadenectomy (LND) and adjuvant therapy in patients with stage I uterine papillary serous carcinoma (UPSC). METHODS: A single-institution, retrospective review was conducted of all surgically treated patients with primary UPSC between 1982 and 2005. RESULTS: 42 patients (IA=15, IB=21, IC=6) were stage I. 81% (n=34) underwent LND (median 40 nodes), 69% omentectomy, and 45% peritoneal biopsies. Median follow-up was 39 months. The 5-year overall survival (OS) and progression free survival (PFS) rates were 85% and 78%. The substage 5-year OS was: IA 100%, IB 89%, IC 60%. No lymphatic recurrences (LR) were observed in 34 patients who had LND compared to 1 LR in 8 who did not undergo LND (p=NS). No recurrences were detected among the 15 patients with stage IA UPSC, irrespective of post-operative therapy. None of the 20 IB and IC patients who received radiation therapy (RT) had vaginal recurrences (VR) compared to 2 of the 7 (29%) who did not receive RT (p=0.02). A systematic LND (>20 lymph nodes) was performed in 19 stage IB and IC patients. No hematological or peritoneal recurrence (HPR) was detected in the 6 patients who received chemotherapy. In contrast, HPR were observed in 3 (23%) of 13 patients who did not receive chemotherapy. DISCUSSION: Observation is an option for patients with stage IA UPSC confirmed by systematic LND. Patients with comprehensively staged IB and IC UPSC are candidates for chemotherapy and vaginal brachytherapy to prevent HPR and VR. PMID- 17688927 TI - Intraperitoneal cisplatin and paclitaxel versus intravenous carboplatin and paclitaxel chemotherapy for Stage III ovarian cancer: a cost-effectiveness analysis. AB - OBJECTIVE: To evaluate the cost-effectiveness of intraperitoneal cisplatin and paclitaxel chemotherapy as front-line treatment for patients with Stage III epithelial ovarian cancer following optimal primary cytoreductive surgery. METHODS: Based on Gynecologic Oncology Group protocols #172 and #158, a decision analysis model was created to compare two treatment strategies for patients with optimal residual disease Stage III ovarian cancer: (1) inpatient intravenous paclitaxel (24 h) and intraperitoneal cisplatin plus outpatient intraperitoneal paclitaxel chemotherapy (IP/IV), and (2) outpatient intravenous paclitaxel (3 h) and carboplatin chemotherapy (IV/IV). The cost-effectiveness of each strategy was evaluated from the perspective of society. RESULTS: Cost-effectiveness analysis revealed that the strategy of IP/IV chemotherapy had an overall cost per patient of $39,861 and effectiveness of 5.16 QALYs compared to $18,822 and 4.59 QALYs for IV/IV chemotherapy. The IP/IV chemotherapy strategy was associated with an additional 0.56 QALYs at an incremental cost of $21,039. The incremental C/E ratio for IP/IV chemotherapy was $37,454/QALY. Inpatient treatment accounted for 43.2% of the cost of IP/IV chemotherapy. Sensitivity analysis testing confirmed the robustness of the model. CONCLUSIONS: In this model, IP/IV chemotherapy was associated with a modest extension in quality-adjusted survival time but was also more costly than IV/IV chemotherapy. On balance, the IP/IV strategy can be considered a good healthcare value. However, these data also suggest that efforts to reduce the cost of IP/IV chemotherapy, such as through development of an ambulatory regimen with equivalent therapeutic efficacy but an improved toxicity profile, would improve the overall value of this adjuvant treatment program. PMID- 17688928 TI - Psilocybin-induced stimulus control in the rat. AB - Although psilocybin has been trained in the rat as a discriminative stimulus, little is known of the pharmacological receptors essential for stimulus control. In the present investigation rats were trained with psilocybin and tests were then conducted employing a series of other hallucinogens and presumed antagonists. An intermediate degree of antagonism of psilocybin was observed following treatment with the 5-HT(2A) receptor antagonist, M100907. In contrast, no significant antagonism was observed following treatment with the 5-HT(1A/7) receptor antagonist, WAY-100635, or the DA D(2) antagonist, remoxipride. Psilocybin generalized fully to DOM, LSD, psilocin, and, in the presence of WAY 100635, DMT while partial generalization was seen to 2C-T-7 and mescaline. LSD and MDMA partially generalized to psilocybin and these effects were completely blocked by M-100907; no generalization of PCP to psilocybin was seen. The present data suggest that psilocybin induces a compound stimulus in which activity at the 5-HT(2A) receptor plays a prominent but incomplete role. In addition, psilocybin differs from closely related hallucinogens such as 5-MeO-DMT in that agonism at 5 HT(1A) receptors appears to play no role in psilocybin-induced stimulus control. PMID- 17688929 TI - Premenopausal risk factors for coronary and aortic calcification: a 20-year follow-up in the healthy women study. AB - OBJECTIVE: It is important to understand the early development of subclinical cardiovascular disease (CVD) in women to prevent costly morbidity and mortality associated with CVD events. METHODS: 363 Women enrolled in the Healthy Women Study, Allegheny County, PA, had electron beam tomography measures of coronary (CaC) and aortic (AC) calcification on average 14.6 years after study entry in 1983; 267 had a second EBT 6.4 years later, by 2006. Risk factors were assessed when women were premenopausal and 5 years after the menopause. RESULTS: Step-wise logistic regression analyses showed that the independent premenopausal predictors of CaC > or = 100 14.6 years later were low-density lipoprotein cholesterol, OR=1.15 (1.03-1.29 for 10 mg/dl) and current smoker, OR=2.72, 1.29-5.71. The same premenopausal risk factors were predictors of AC > or = 500, in addition to premenopausal systolic blood pressure (SBP). Similar results were obtained for predicting calcification 20.6 years later. Postmenopausal risk factors measured 5 years prior to the initial scans were unrelated to CaC and AC, after the significant premenopausal risk factors were taken into account, except for postmenopausal SBP being related to AC. CONCLUSION: Premenopausal risk factors are strong predictors of postmenopausal CaC and AC. Clinical trials should test if reduction of premenopausal levels of risk factors reduces the risk of early calcification. PMID- 17688930 TI - Watching children watch food advertisements on TV. PMID- 17688932 TI - Cytotoxicity of resin composites as a function of interface area. AB - OBJECTIVES: The standardization protocols for biomaterial cytotoxicity testing require fine tuning for oral biomaterials to obtain international comparability as the basis for risk assessment. The principal aims were specifically to evaluate the effect of (i) relative interface area (ratio of specimen surface to cell layer surface) and (ii) volume of cell culture medium on cytotoxicity as a potential modification of ISO 10993-5. METHODS: ISO 10993-5 was followed with an interface area of 12.5%, as recommended, using primary human gingival fibroblasts and L-929 mouse fibroblasts. In another series of experiments (using L-929 cells) the interface area was varied between 12.5% and 0.71%. For each relative interface area, three conditions for affecting the cure of the resin composite were investigated by using three mould materials: white, transparent and black moulds. In addition, the volume of cell culture medium was varied. Composite specimens (Herculite XRV) were added to the cultures immediately after production or preincubation for 1, 2, 7 days or 6 weeks under cell culture conditions. Specimens were incubated with fibroblasts for 72 h and cell numbers determined by flow cytometry. Glass specimens resembling composite specimens in diameter and height were used as negative controls. RESULTS: Cytotoxicity results with primary gingival fibroblasts were comparable to results with the cell line L-929. An effect from the color/material of the specimen moulds was found. Different ratios of specimen sizes to cell culture parameters (cell layer surface, volume of cell culture medium) produced different results. Three out of four differently designed specimens showed the same behavior in cell culture. SIGNIFICANCE: Cytotoxicity tests should be further standardized in line with existing standards with regard to specimen production protocols to ensure results are internationally comparable to validate these tests as tools for risk assessment. PMID- 17688931 TI - In vitro wear, surface roughness and hardness of propanal-containing and diacetyl containing novel composites and copolymers based on bis-GMA analogs. AB - OBJECTIVE: To evaluate the effect of two additives, aldehyde or diketone, on the wear, roughness and hardness of bis-GMA-based composites/copolymers containing TEGDMA, propoxylated bis-GMA (CH(3)bis-GMA) or propoxylated fluorinated bis-GMA (CF(3)bis-GMA). METHODS: Fifteen experimental composites and 15 corresponding copolymers were prepared combining bis-GMA and TEGDMA, CH(3)bis-GMA or CF(3)bis GMA, with aldehyde (24 mol% and 32 mol%) or diketone (24 mol% and 32 mol%) totaling 30 groups. For composites, hybrid treated filler (barium aluminosilicate glass/pyrogenic silica; 60 wt%) was added to monomer mixtures. Photopolymerization was affected by 0.2 wt% each of camphorquinone and N,N dimethyl-p-toluidine. Wear (W) test was conducted in a toothbrushing abrasion machine (n=6) and quantified using a profilometer. Surface roughness (R) changes, before and after abrasion test, were determined using a rugosimeter. Microhardness (H) measurements were performed for dry and wet samples using a Knoop microindenter (n=6). Data were analyzed by one-way ANOVA and Tukey's test (alpha=0.05). RESULTS: Incorporation of additives led to improved W and H values for bis-GMA/TEGDMA and bis-GMA/CH(3)bis-GMA systems. Additives had no significant effect on the W and H changes of bis-GMA/CF(3)bis-GMA. With regard to R changes, additives produced decreased values for bis-GMA/CH(3)bis-GMA and bis-GMA/CF(3)bis GMA composites. Bis-GMA/TEGDMA and bis-GMA/CH(3)bis-GMA copolymers with additives became smoother after abrasion test. SIGNIFICANCE: The findings correlate with additives ability to improve degree of conversion of some composites/copolymers thereby enhancing mechanical properties. PMID- 17688933 TI - Acrylophosphonic acid reactivity with calcium ions and biological apatite. AB - OBJECTIVES: Acrylophosphonic acid (H(2)L) was reacted with biological apatite originating from dental enamel powder in order to identify and study the reaction products formed during the use of self-etch monomers. Nuclear magnetic resonance spectroscopy (NMR) showed the formation of brushite and a calcium salt of acrylophosphonic acid. This Ca salt was further synthesized and characterized by NMR, Fourier transform-infrared (FT-IR) and chromatography coupled with potentiometric analysis. The results reveal that calcium ions form a compound with two mono-deprotonated acrylophosphonate anions at physiological pH values. Thus, dissolution of the biological apatite by the acid-etch releases phosphate and calcium ions that combine to form brushite. The remaining dissolved Ca neutralize the acrylophosphonic acid to form an ionic salt of formula Ca(HL)(2). SIGNIFICANCE: The stoichiometry of this calcium salt allows us to conclude that, following a self-etch procedure, dissolved Ca ions participate in the formation of crosslinks in the complex photopolymerized copolymer composite network of the hybrid layer. PMID- 17688934 TI - Two-body wear of resin and ceramic denture teeth in comparison to human enamel. AB - OBJECTIVES: To evaluate the two-body wear resistance of different artificial denture teeth when opposed to steatite ceramic balls in a dual-axis chewing simulator. METHODS: Artificial denture teeth including the ceramic tooth Bonartic CT, the composite resin tooth Condyloform II NFC, the acrylic resin teeth Bonartic TCR, Orthognath, Polystar Selection, SR Orthotyp DCL, and Vitapan Cuspiform, and human maxillary premolars were tested in a chewing simulator. Wear resistance was analyzed measuring vertical substance loss and volume loss using profilometry and an optical macroscope after various chewing cycles (49N, up to 1,200,000 cycles). Data were statistically analyzed using one-way analysis of variance (ANOVA) followed by the Fisher test (LSD) at p< or =0.05. RESULTS: After 1,200,000 chewing cycles the mean vertical substance loss and volume loss for the composite resin teeth (117microm and 0.144mm3) were significantly lower than for all acrylic resin teeth (149-166microm and 0.220-0.292mm3) (p< or =0.05), but higher than for ceramic teeth (36microm and 0.029mm3) and for enamel (56microm and 0.033mm3) (p< or =0.05). No significant differences were found among the acrylic resin teeth for both parameters (p>0.05). SIGNIFICANCE: The composite resin showed improved in vitro two-body wear resistance compared to modern acrylic resin denture teeth; however, it showed less wear resistance than ceramic teeth and human enamel. Ceramic teeth should be preferred over natural teeth when occlusal stability is considered a high priority. PMID- 17688935 TI - Influence of thermal and mechanical cycling on the flexural strength of ceramics with titanium or gold alloy frameworks. AB - OBJECTIVES: The aim of this study was to evaluate the effect of thermal and mechanical cycling alone or in combination, on the flexural strength of ceramic and metallic frameworks cast in gold alloy or titanium. METHODS: Metallic frameworks (25 mm x 3 mm x 0.5 mm) (N=96) cast in gold alloy or commercial pure titanium (Ti cp) were obtained using acrylic templates. They were airborne particle-abraded with 150 microm aluminum oxide at the central area of the frameworks (8 mm x 3 mm). Bonding agent and opaque were applied on the particle abraded surfaces and the corresponding ceramic for each metal was fired onto them. The thickness of the ceramic layer was standardized by positioning the frameworks in a metallic template (height: 1 mm). The specimens from each ceramic metal combination (N=96, n=12 per group) were randomly assigned into four experimental fatigue conditions, namely water storage at 37 degrees C for 24h (control group), thermal cycling (3000 cycles, between 4 and 55 degrees C, dwell time: 10s), mechanical cycling (20,000 cycles under 10 N load, immersion in distilled water at 37 degrees C) and, thermal and mechanical cycling. A flexural strength test was performed in a universal testing machine (crosshead speed: 1.5 mm/min). Data were statistically analyzed using two-way ANOVA and Tukey's test (alpha=0.05). RESULTS: The mean flexural strength values for the ceramic-gold alloy combination (55+/-7.2MPa) were significantly higher than those of the ceramic-Ti cp combination (32+/-6.7 MPa) regardless of the fatigue conditions performed (p<0.05). Mechanical and thermo-mechanical fatigue decreased the flexural strength results significantly for both ceramic-gold alloy (52+/-6.6 and 53+/-5.6 MPa, respectively) and ceramic-Ti cp combinations (29+/-6.8 and 29+/-6.8 MPa, respectively) compared to the control group (58+/-7.8 and 39+/-5.1 MPa, for gold and Ti cp, respectively) (p<0.05) (Tukey's test). While ceramic-Ti cp combinations failed adhesively at the metal-opaque interface, gold alloy frameworks exhibited a residue of ceramic material on the surface in all experimental groups. SIGNIFICANCE: Mechanical and thermo-mechanical fatigue conditions decreased the flexural strength values for both ceramic-gold alloy and ceramic-Ti cp combinations with the results being significantly lower for the latter in all experimental conditions. PMID- 17688936 TI - On-and off-field antisocial and prosocial behavior in adolescent soccer players: a multilevel study. AB - This study investigated to what extent team membership predicts on- and off-field antisocial and prosocial behavior in (pre)adolescent athletes. Effects of team membership were related to characteristics of the team environment, such as relational support from the coach towards team members, fair play attitude and sociomoral reasoning within the team, and sociomoral climate. The sample consisted of N=331 male soccer players. Multilevel analyses revealed that 21% of the variance in off-field antisocial behavior, and 8% and 14% of the variance in on-field antisocial and prosocial behavior, respectively, could be attributed to characteristics of the sporting environment, including relational support from the coach, exposure to high levels of sociomoral reasoning about sports dilemmas, and positive team attitude toward fair play. The results highlight the importance of contextual factors in explaining both antisocial and prosocial behavior in adolescent athletes and emphasize the role of organized youth sports as a socialization context. PMID- 17688937 TI - Adolescents' transitions to behavioral autonomy after German unification. AB - The present study examined the timing of behavioral autonomy transitions in two same-aged cohorts of East German adolescents assessed in 1991 and 1996. An earlier timing of autonomy privileges was associated with higher deviant behavior. A later timing of autonomy privileges and responsibilities was linked to structural constraints, specifically, to parental unemployment. Between 1991 and 1996 significant timing differences were observed for some autonomy transitions in the East, implying an adaptation to Western timetables. Our findings illustrate the plasticity of autonomy transitions under conditions of social change. PMID- 17688938 TI - Purification and partial characterization of myosin II from rat testis. AB - The intent, in this work, was to isolate rat testis myosin II. Testis 40,000 x g x 40' supernatant was frozen at -20 degrees C for 48 h and, after it was thawed and centrifuged. The precipitate, after washed twice, was enriched in three polypeptides bands: p205, p43 and one that migrated together with the front of the gel. These polypeptides were solubilized in pH 10.8 at 27 degrees C and separated in Sephacryl S-400 column. Three low weight polypeptides co-eluted together with p205. The p205 was marked with anti-myosin II, possess actin stimulated Mg-ATPase activity and co-sedimented with F-actin in the absence, but not in the presence, of ATP. In the present study, we have been developing a method for purification of myosin II from rat testis. PMID- 17688939 TI - Prosthetic vascular grafts: wrong models, wrong questions and no healing. AB - In humans, prosthetic vascular grafts remain largely without an endothelium, even after decades of implantation. While this shortcoming does not affect the clinical performance of large bore prostheses in aortic or iliac position, it contributes significantly to the high failure rate of small- to medium-sized grafts (SMGs). For decades intensive but largely futile research efforts have been under way to address this issue. In spite of the abundance of previous studies, a broad analysis of biological events dominating the incorporation of vascular grafts was hitherto lacking. By focusing on the three main contemporary graft types, expanded polytetrafluoroethylene (ePTFE), Dacron and Polyurethane (PU), accumulated clinical and experimental experience of almost half a century was available. The main outcome of this broad analysis-supported by our own experience in a senescent non-human primate model-was twofold: Firstly, inappropriate animal models, which addressed scientific questions that missed the point of clinical relevance, were largely used. This led to a situation where the vast majority of investigators unintentionally studied transanastomotic rather than transmural or blood-borne endothelialization. Given the fact that in patients transanastomotic endothelialization (TAE) covers only the immediate perianastomotic region of sometimes very long prostheses, TAE is rather irrelevant in the clinical context. Secondly, transmural endothelialization seems to have a time window of opportunity before a build-up of an adverse microenvironment. In selecting animal models that prematurely terminate this build-up through the early presence of an endothelium, the most significant 'impairment factor' for physiological tissue regeneration in vascular grafts remained ignored. By providing insight into mechanisms and experimental designs which obscured the purpose and scope of several decades of vascular graft studies, future research may better address clinical relevance. PMID- 17688940 TI - The drug loading, cytotoxicty and tumor vascular targeting characteristics of magnetite in magnetic drug targeting. AB - Chemotherapy is a popular treatment approach against cancer but significant uptake of drugs by normal tissues is still a major limitation. Magnetic drug targeting (MDT) has been used to improve localized drug delivery to interstitial tumor targets. MDT is now being developed to improve drug delivery to tumor vessels. We thus seek to understand the role of magnetite (MAG-C) in drug loading, influence on cytotoxicity and vascular targeting characteristics. The inclusion of MAG-C at lower concentrations (0.5 mg/ml) in cationic liposomes did not alter the efficiency of loading etoposide, but at higher concentrations (2.5 mg/ml) incorporation decreased from 80+/-3.4% to 44+/-4.26%. MAG-C reduced the incorporation of dacarbazine. The incorporation was significantly lower compared to liposomal etoposide, both in the presence and absence of MAG-C. The incorporation efficiency of vinblastine sulfate in cationic liposomes was similar for low and relatively high MAG-C content; values for incorporation were 21+/ 0.11 and 23+/-2, respectively. Polyethylene-glycol improved the efficiency of loading chemotherapeutic agents regardless of drug type. Additionally, cytotoxicity and tumor vascular targeting characteristics of liposome therapeutics were not influenced by MAG-C. The components used to prepare magnetic liposomes for MDT should be optimized for maximum therapeutic benefit. PMID- 17688941 TI - In vitro biological evaluation of high molecular weight hyperbranched polyglycerols. AB - Low molecular weight hyperbranched polyglycerols are highly water soluble and biocompatible polyether polyols, which can be synthesized in a controlled manner with narrow polydispersity. Recently we reported the synthesis and characterization of very high molecular weight (Mn up to 700,000) and narrowly polydispersed polyglycerols which could be potentially used as alternatives to high generation dendrimers which are difficult to make. A detailed biocompatibility testing of these polymers conducted in vitro is reported here. The in vitro studies include hemocompatibility testing for effects on coagulation (prothrombin time (PT), activated partial thromboplastin time (APTT), plasma recalcification time (PRT), thrombelastograph parameters (TEG)), complement activation, platelet activation, red blood cell aggregation and cytotoxicity. Results from these studies show that these high molecular weight polyglycerols are highly biocompatible and are potential candidates for various applications in nanobiotechnology and in nanomedicine. Moreover these polymers are thermally and oxidatively stable. PMID- 17688942 TI - Bioengineering skin using mechanisms of regeneration and repair. AB - The development and use of artificial skin in treating acute and chronic wounds has, over the last 30 years, advanced from a scientific concept to a series of commercially viable products. Many important clinical milestones have been reached and the number of artificial skin substitutes licensed for clinical use is growing, but they have yet to replace the current "gold standard" of an autologous skin graft. Currently available skin substitutes often suffer from a range of problems that include poor integration (which in many cases is a direct result of inadequate vascularisation), scarring at the graft margins and a complete lack of differentiated structures. The ultimate goal for skin tissue engineers is to regenerate skin such that the complete structural and functional properties of the wounded area are restored to the levels before injury. New synthetic biomaterials are constantly being developed that may enable control over wound repair and regeneration mechanisms by manipulating cell adhesion, growth and differentiation and biomechanics for optimal tissue development. In this review, the clinical developments in skin bioengineering are discussed, from conception through to the development of clinically viable products. Central to the discussion is the development of the next generation of skin replacement therapy, the success of which is likely to be underpinned with our knowledge of wound repair and regeneration. PMID- 17688943 TI - Distribution of neuroendocrine cells in the small and large intestines of the one humped camel (Camelus dromedarius). AB - The distribution and relative frequency of neuroendocrine cells in the small and large intestines of one-humped camel were studied using antisera against 5 hydroxytryptamine (5-HT), cholecystokinin (CCK-8), somatostatin (SOM), peptide tyrosine tyrosine (PYY), gastric inhibitory polypeptide (GIP), neuronal nitric oxide synthase (nNOS), gastrin releasing peptide (GRP), substance P (SP), and neurokinin A (NKA). Among these cell types, CCK-8 immunoreactive (IR) cells were uniformly distributed in the mucosa, while others showed varied distribution in the villi or crypts of the small intestine. Immunoreactive cells like 5HT, CCK-8, and SOM showed peak density in the villi and crypts of the small intestine and in the colonic glands of the large intestine, while cells containing SP were discerned predominately in the crypts. 5-HT, CCK-8 and SOM cells were mainly flask-shaped and of the open-variety, while PYY and SP immunoreactive cells were mainly rounded or basket-shaped and of the closed variety. Basically the distribution pattern of the endocrine cells in the duodenum, jejunum and colon of the one-humped camel is similar to that of other mammals. Finally, the distribution of these bioactive agents may give clues as to how these agents aid in the function of the intestinal tract of this desert animal. PMID- 17688944 TI - Alterations of BDNF and NT-3 genes expression in the nucleus paragigantocellularis during morphine dependency and withdrawal. AB - Locus coeruleus (LC) plays a key role in opioid dependence and withdrawal. Chronic morphine administration induces neurochemical adaptations in the noradrenergic system. The nature of signal responsible for opiate-induced adaptations of noradrenergic neurons in LC is not well defined. Neurotrophins signaling pathways such as brain derived neurotrophic factor (BDNF) and Neurotrophin-3 (NT-3) play a key role for regulating the noradrenergic response of LC neurons to opiates. The nucleus paragigantocellularis (PGi) is one of the two major afferents to LC. The present study was designed to evaluate the expression of BDNF and NT-3 in the context of opiate dependence and withdrawal in PGi. Such data are important because they could reveal the role of PGi as an additional source of BDNF and NT-3 in the neurochemical plasticity of LC neurons. Opiate dependence was induced by a progressive intraperitoneal treatment of morphine. In morphine dependent group PGi nucleus was extracted for gene expression assay 6h after the last injection of morphine. In spontaneous withdrawal, rats received the same chronic treatment as morphine group. PGi was extracted for gene expression assay 24, 48 and 72 h after the last injection of morphine. PGi nucleus was assayed for the expression of BDNF and NT-3 using semi quantitative RT-PCR normalized to beta-actin gene expression. Results showed that chronic administration of morphine significantly increased BDNF and NT-3 gene expression in PGi. In spontaneous withdrawal, BDNF/NT-3 genes expression were high in comparison to control group. It seems that BDNF/NT-3 -signaling pathway originating from PGi is essential for opiate-induced adaptations of the LC neurons. PMID- 17688945 TI - Identification of a novel, transactivation-defective splicing variant of p53 gene in patients with chronic lymphocytic leukemia. AB - p53 is implemented in many processes controlling cell fate. Recently it has been reported that besides post-translational modifications and regulation of protein protein interactions, the activity of p53 is also substantially controlled at transcriptional level. In 109 out of 127 (86%) patients with chronic lymphocytic leukemia (CLL) we have identified a novel p53 splicing variant, lacking the whole coding sequence of exon 6. This splicing p53 isoform ("delta ex6") is devoid of transactivational activity and is differentially expressed in CLL patients as compared to healthy controls. The overexpression of "delta ex6" p53 variant in CLL patients supports the recent evidence on dysregulation of p53 splicing pattern in malignancies. PMID- 17688946 TI - Isolated thrombocytosis as first sign of chronic myeloid leukemia with e6a2 BCR/ABL fusion transcript, JAK2 negativity and complete response to imatinib. AB - Since very few unusual BCR/ABL fusion transcripts in chronic myeloid leukemia have been reported, no clear evidence exists concerning their clinical and prognostic implications. We describe here a CML case with normal karyotype at standard cytogenetics and an atypical e6a2 BCR/ABL fusion transcript, presenting at diagnosis isolated thrombocytosis and mild leukopenia; the patient, who was tested negative for JAK2 mutation, obtained a complete response to imatinib. The few previous observations from literature are also reviewed. PMID- 17688947 TI - A novel shRNA vector that enables rapid selection and identification of knockdown cells. AB - Small interference RNA (siRNA) is a powerful tool for disrupting expression of specific genes in a variety of cells. We have developed a vector, piMARK, which mediates expression of both small hairpin RNA (shRNA) and the blasticidin resistance (Bsr) protein fused with enhanced green fluorescent protein (EGFP), enabling rapid selection and identification of knockdown cells. Using this vector, we targeted Ect2, a gene encoding a guanine nucleotide exchange factor for several small GTPases, in human cell lines. Incubation in the presence of 10 microg/ml blasticidin S rapidly killed untransfected cells, so that after 24 h >90% of surviving HeLa S3 cells emitted green fluorescence and >70% were binucleate as a result of the frequent failure of cell division. The GFP-Bsr fluorescence enabled easy identification of individual knockdown cells under a fluorescence microscope, which in turn enabled unambiguous assessment of the morphological consequences of silencing Ect2. Moreover, because untransfected cells rapidly died and detached from the substrate, they were easily removed by simply rinsing the culture dishes. It thus should be possible to analyze the biochemical consequences of gene silencing en masse in the absence of a background of untransfected cells. PMID- 17688948 TI - What neuroimaging tells us about sensory substitution. AB - A major question in the field of sensory substitution concerns the nature of the perception generated by sensory substitution prostheses. Is the perception determined by the nature of the substitutive modality or is it determined by the nature of the information transmitted by the device? Is it a totally new, amodal, perception? This paper reviews the recent neuroimaging studies which have investigated the neural bases of sensory substitution. The detailed analysis of available results led us to propose a general scheme of the neural mechanisms underlying sensory substitution. Two different main processes may be responsible for the visual area recruitment observed in the different studies: cross-modality and mental (visual) imagery. Based on our results analysis, we propose that cross modality is the predominant process in early blind subjects whereas mental imagery is predominant in blindfolded sighted subjects. This model implies that, with training, sensory substitution mainly induces visual-like perception in sighted subjects and mainly auditory or tactile perception in blind subjects. This framework leads us to make some predictions that could easily be tested. PMID- 17688949 TI - Effects of travel mode on exposures to particulate air pollution. AB - Monitoring was carried out of particulate concentrations whilst simultaneously walking and driving 48 routes in London, UK. Monitoring was undertaken during May and June 2005. Route lengths ranged from 601 to 1351 m, and most routes were travelled in both directions. Individual journey times ranged from 1.5 to 15 min by car (average 3.7 min) and 7.3 to 30 min (average 12.8 min) whilst walking; car trips were therefore repeated up to 5 times for each single walking trip and the results averaged for the route. Car trips were made with windows closed and the ventilation system on a moderate setting. Results show that mean exposures while walking are greatly in excess of those while driving, by a factor 4.7 for the coarse particle mass (PM10-PM2.5), 2.2 for the fine particle mass (PM2.5-PM1), 1.9 for the very fine particle mass ( or = 7, 25 (22%) had PCa tumor volume > 0.5 cc, and 15 (13%) had extracapsular extension. On multivariable analysis, only increasing age was significantly associated with PCa (odds ratio=1.3, p=0.046). Of the 77 with PUC, 28 (36%) had in situ disease only, while 49 (64%) had prostatic stromal invasion. Bladder tumor location in the trigone/bladder neck (p<0.001) and bladder carcinoma in situ (p<0.001) was strongly associated with PUC in the final specimen. Overall, 158 (67%) had either PCa or PUC in the prostate. CONCLUSIONS: PCa and/or PUC is present in a majority of RCP specimens. Current preoperative staging and tumor characteristics are not adequate for determining who can safely be selected for prostate-sparing cystectomy. PMID- 17689004 TI - Re: Michael Mittenberger, Germar M. Pinggera, Rainer Marksteiner, Eva Margreiter, Raffael Plattner, Gunter Klima, Georg Bartsch and Hannes Strasser. Functional and histological changes after myoblast injections in the porcine rhabdosphincter. Eur urol 2007;52:1736-43. PMID- 17689005 TI - Thromboembolism prophylaxis and total prostatectomy: is pharmacologic therapy required? PMID- 17689006 TI - Synthesis of polyamine flocculants and their potential use in treating dye wastewater. AB - Polyamine flocculants were synthesized by the polycondensation of dimethylamine and epichlorohydrin, in which organic amines, e.g. 1,2-diaminoethane, were used as modifying agents. Different products were obtained by varying the reaction parameters, such as the molar ratio of epichlorohydrin to dimethylamine, the amount of 1,2-diaminoethane and reaction temperature. The polyamine flocculants were characterized by transmission electron microscope (TEM). Their flocculation performance was evaluated with simulated dye liquor and actual printing and dyeing wastewater. The behavior of the flocculants was compared with that of inorganic coagulant, polyaluminum chloride (PAC). The experimental results show that polyamine with the highest viscosity and cationicity could be prepared under following conditions: an epichlorohydrin to dimethylamine molar ratio of 1.5, a reaction temperature of 70 degrees C, a 3% content of 1,2-diaminoethane in the total reaction monomers and a reaction time of 7h. Polyamine polymers can, as flocculants for treating simulated and actual dye wastewater, remove color and COD efficiently. The rate of color removal from reactive red liquor, reactive blue liquor and reductive yellow liquor reached as high as 96%, 97% and 96%, respectively. The highest efficiency of color removal and COD removal from polyamine for treating dye wastewater was 90% and 89%, respectively. PMID- 17689007 TI - The clathrate hydrate process for post and pre-combustion capture of carbon dioxide. AB - One of the new approaches for capturing carbon dioxide from treated flue gases (post-combustion capture) is based on gas hydrate crystallization. The basis for the separation or capture of the CO(2) is the fact that the carbon dioxide content of gas hydrate crystals is different than that of the flue gas. When a gas mixture of CO(2) and H(2) forms gas hydrates the CO(2) prefers to partition in the hydrate phase. This provides the basis for the separation of CO(2) (pre combustion capture) from a fuel gas (CO(2)/H(2)) mixture. The present study illustrates the concept and provides basic thermodynamic and kinetic data for conceptual process design. In addition, hybrid conceptual processes for pre and post-combustion capture based on hydrate formation coupled with membrane separation are presented. PMID- 17689008 TI - Photocatalytic degradation for methylene blue using zinc oxide prepared by codeposition and sol-gel methods. AB - Zinc oxide nanoparticle was obtained by zinc hydrate deposited on the silica nanoparticle surface and zinc hydrate was dispersed in starch gel. The structure of zinc oxide particle was characterized by nitrogen adsorption-desorption and XRD, the morphology was observed by TEM. The result showed that the zinc oxide nanoparticle deposited on the silica nanoparticle surface was well-dispersed and less than 50nm, displayed higher photocatalytic activity for methylene blue degradation. However, the zinc oxide nanoparticle in a size of 60nm was derived from starch gel and showed poorer photocatalytic activity. It provided a simple and effective route to prepare zinc oxide nanoparticle with higher photocatalytic activity through depositing zinc oxide on the silica particle surface, moreover, the catalyst is easier to recover due to its higher density. PMID- 17689009 TI - The formation and distribution of haloacetic acids in copper pipe during chlorination. AB - The formation and distribution of HAAs in copper pipe during chlorination was investigated. To determine the material influence of copper pipe, parallel experiments were performed in glass pipe. Results showed that there was no obvious difference between the sum of haloacetic acids (HAAs) and trihalomethanes (THMs) produced in copper pipe compared to that produced in glass pipe over a 12h period. However, significant differences were observed about the distribution of five haloacetic acids in copper pipe and in glass pipe. Relatively less trichloroacetic acid (TCAA) and more monochloroacetic acid (MCAA), dichloroacetic acid (DCAA), dibromoacetic acid (DBAA) and trihalomethanes (THMs) were produced in copper pipe than those in glass pipe. Corrosion scale on the wall of copper pipe was analyzed using X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM) and energy dispersive spectroscopy (EDS). The results showed the scales on the pipe surface mainly consisted of Cu2O, CuO and Cu (OH)2 or CuCO3. During 24h stagnation, copper released gradually from copper pipe. The influences of copper (II) and copper oxides on the distribution of HAAs were investigated in designed experiments. Results showed that less amount of TCAA, more amounts of DCAA and MCAA were formed with increasing concentration of copper (II). It was because the accelerative effect of copper (II) on the depletion of chlorination restricted the formation of TCAA precursor and the further formation of TCAA. Owing to the transformation of DCAA precursor to TCAA precursor was limited, more DCAA precursor could yield DCAA. The influences of Cu2O and CuO on the distribution of TCAA and DCAA were the result of copper released at higher content. PMID- 17689010 TI - Remediation of PAH-contaminated sediments by chemical oxidation. AB - The aim of this experimental investigation was to assess the feasibility of using chemical oxidation to degrade sorbed polycyclic aromatic hydrocarbons (PAHs) in case of old date sediment contamination. For this purpose several bench scale laboratory tests were performed, with the following liquid reactants: hydrogen peroxide, modified Fenton's reagent, activated sodium persulfate, potassium permanganate, as well as a combination of potassium permanganate and hydrogen peroxide, and a combination of activated sodium persulfate and hydrogen peroxide. The main target of the study was to find out what liquid oxidant was more effective in reducing the pollutant content and to assess the optimal reactant doses. The initial total PAH concentration in sediment samples was about 2800mg/kgSS (light PAHs about 1600mg/kgSS, heavy PAHs about 1200mg/kgSS) and a 95% degradation was required to meet the remediation goals. Based on the results of this study, chemical oxidation proved to be an effective remediation technology, amenably applicable for the ex situ remediation of the sediments of concern. Different reactants resulted however in different removal efficiencies. The best remediation performances were achieved with the use of modified Fenton's reagent, hydrogen peroxide and potassium permanganate, with oxidant dosages about 100mmols per 30g sediment sample. In all these cases the residual heavy PAH concentration in the treated samples was below 100mg/kgSS. The optimal oxidant dosages determined in this study were quite high, as sorbed PAH mineralization requires very vigorous oxidation conditions, especially for soils and sediments with high organic matter content. The results indicated that the optimal oxidant dose must be carefully determined under site-specific conditions. In fact, if the oxidation conditions are not strong enough, the reactants cannot be able to attack the most recalcitrant compounds, while also too high oxidant doses can result in a decrease in the oxidation efficiency, thus failing in meeting the remediation goals. PMID- 17689012 TI - Biosorption of chromium species by aquatic weeds: kinetics and mechanism studies. AB - In this paper, we have presented the results of Cr(VI) and Cr(III) removal from aqueous phase by different aquatic weeds as biosorbents. Batch kinetic and equilibrium experiments were conducted to determine the adsorption kinetic rate constants and maximum adsorption capacities of selected biosorbents. In most of the cases, adsorption followed a second-order kinetics. For Cr(III), maximum adsorption capacity was exhibited by reed mat (7.18mg/g). In case of Cr(VI), mangrove leaves showed maximum removal/reduction capacity (8.87mg/g) followed by water lily (8.44mg/g). There was a significant difference in the concentrations of Cr(VI) and total chromium removed by the biosorbents. In case of Cr(VI) removal, first it was reduced to Cr(III) with the help of tannin, phenolic compounds and other functional groups on the biosorbent and subsequently adsorbed. Acid treatment significantly increased Cr(VI) removal capacity of the biosorbents whereas, alkali treatment reduced the Cr(VI) removal capacities of the biosorbents. FTIR spectrum showed the changes in functional groups during acid treatment and biosorption of Cr(VI) and Cr(III). Aquatic weeds seem to be a promising biosorbent for the removal of chromium ions from water environment. PMID- 17689011 TI - In situ reductive dechlorination of chlorinated ethenes in high nitrate groundwater. AB - In situ bioremediation using carbohydrate was evaluated as an in situ treatment alternative for trichloroethene (TCE) and cis-1,2-dichloroethene (cDCE) in groundwater containing high nitrate concentrations. Upon addition of carbohydrate to groundwater, sequential reduction of electron acceptors was observed, where nitrate was reduced early in the pilot test, followed by sulfate and TCE. Reduction of cDCE to vinyl chloride and ethene occurred in conjunction with increased iron and manganese, and increased methane concentrations, approximately 7 months into the evaluation period, following depletion of nitrate and sulfate. TCE, cDCE, and vinyl chloride concentrations decreased from approximately 500 to >10 microg/L within 21 months of operation. PMID- 17689013 TI - Appendix to "Coulomb interactions in Ga LMIS" by Radlicka and Lencova. AB - This appendix comments on the input data and simulation results of Radlicka and Lencova (RL), reported in the preceding paper. These simulations relate to the effects of space-charge on the full-width at half-maximum (FWHM) of the ion energy distribution from a gallium liquid metal ion source (LMIS), and on its virtual source size. Corrections are necessary to the input data, relating to LMIS shape, that were supplied by the present author. It is clear from RL's work that their simulations, when applied to the corrected shape data, would generate very good agreement between experimental results and numerical simulations concerning the FWHM. This work confirms that an inappropriate hydrodynamic condition has been used in past modelling programmes for LMIS shapes and current/voltage characteristics; consequently, some quantitative results from these old programmes must be considered unreliable in detail, especially at low emission currents, although qualitative trends have been correctly exhibited. PMID- 17689014 TI - Treatment of natural infestations of the biting louse (Werneckiella equi) on horses using triflumuron, a benzoylurea derivative insect growth regulator. AB - The horse biting louse (Werneckiella equi) is a common global equine ectoparasite. To our knowledge, benzoyl(phenyl)urea insecticides (triflumuron, diflubenzuron) commonly used as sheep lousicides, have not been evaluated for efficacy against W. equi. The aim of this study was to determine louse control efficacy, general wellness and dermal safety following triflumuron application as a backline pour-on to horses. Two efficacy trials using 25 adult naturally infested lousy horses, and a dermal safety trial using 10 adult louse-free horses were conducted over a 14-month period. Lousy animals were selected by assessment of their lice status prior to treatment. For the efficacy trial, the triflumuron product was applied at a dose of 2.5mg triflumuron per kg bodyweight (1 mL product per 10 kg bodyweight). For the safety study, triflumuron was applied at a 3x clinical dose of 7.5 mg triflumuron per kg bodyweight (3 mL product per 10 kg bodyweight). In our first efficacy trial, 100% lousicidal efficacy was achieved by day 44 post-treatment. In our second trial, no lice were identified on horses by day 71 post-treatment. In the safety trial, no adverse effects were seen. Results of this study demonstrate that the off-label, experimental pour-on application of triflumuron at 2.5 mg/kg bodyweight is convenient, highly effective and safe (at 3x the clinical dose) for the treatment of the horse biting louse, W. equi. PMID- 17689015 TI - Babesiosis in free-ranging chamois (Rupicapra r. rupicapra) from Switzerland. AB - Pathological examination of five adult chamois (Rupicapra r. rupicapra) found dead in two different regions from the Swiss Alps revealed pale mucous membranes and musculature, swollen spleen and haemoglobinuria. Histologically, haemosiderosis in the spleen and centrilobular hepatic necrosis were the predominant findings. On blood smears, small (approximately 0.84-1.47 microm), round to pyriform, peripherally located inclusions were present in the erythrocytes. PCR followed by sequencing of DNA extracted from blood or spleen of the infected animals revealed 99-100% identity of the amplified part of the 18S rRNA gene with GenBank entries attributed to Babesia divergens/Babesia capreoli. This is the first report of fatal Babesia infections in chamois raising the question of an emerging disease in this species. PMID- 17689016 TI - Transplantation of cultured human keratinocytes in single cell suspension: a comparative in vitro study of different application techniques. AB - Transplantation of autologous cultured keratinocytes in single cell suspension is useful in the treatment of burns. The reduced time needed for culture, and the fact that keratinocytes in suspension can be transported from the laboratory to the patient in small vials, thus reducing the costs involved and be stored (frozen) in the clinic for transplantation when the wound surfaces are ready, makes it appealing. We found few published data in the literature about actual cell survival after transplantation of keratinocytes in single cell suspension and so did a comparative in vitro study, considering commonly used application techniques. Human primary keratinocytes were transplanted in vitro in a standard manner using different techniques. Keratinocytes were counted before and after transplantation, were subsequently allowed to proliferate, and counted again on days 4, 8, and 14 by vital staining. Cell survival varied, ranging from 47 to >90%, depending on the technique. However, the proliferation assays showed that the differences in numbers diminished after 8 days of culture. Our findings indicate that a great number of cells die during transplantation but that this effect is diminished if cells are allowed to proliferate in an optimal milieu. A burned patient's wounds cannot be regarded as the optimal milieu, and using less harsh methods of transplantation may increase the take rate and wound closing properties of autologous keratinocytes transplanted in a single cell suspension. PMID- 17689017 TI - 22R-Hydroxycholesterol induces differentiation of human NT2 precursor (Ntera2/D1 teratocarcinoma) cells. AB - Recently, we have shown that 22R-hydroxycholesterol, a steroid intermediate in the pathway of pregnenolone formation from cholesterol, is present at lower levels in Alzheimer's disease (AD) hippocampus and frontal cortex tissue specimens than in age-matched controls, and that this substance protects against cell death induced by amyloid beta-peptide in both rat sympathetic nerve pheochromocytoma (PC12) and differentiated human Ntera2/D1 teratocarcinoma neurons. Herein we report that 22R-hydroxycholesterol inhibits the proliferation of human Ntera2/D1 teratocarcinoma precursor cells (NT2) and induces these cells to differentiate into "neuron-like" or "astrocyte-like" cells. 22R Hydroxycholesterol-induced differentiation of NT2 cells is associated with increases in the expression of neurofilament protein NF200, the cytoskeletal proteins microtubule-associated protein type II (MAP2) a and MAP2b, glial fibrillary acidic protein (GFAP) and glial cell line-derived neurotrophic factor receptor-alpha 2 (GFRalpha2). These effects of 22R-hydroxycholesterol are considered to be stereospecific because its enantiomer 22S-hydroxycholesterol and other steroids failed to induce differentiation of NT2 cells. 22R Hydroxycholesterol was found to lack specific binding for numerous receptors, including all steroid receptors tested. However, using a cholesterol protein binding blot assay we demonstrated the presence of a 22R-hydroxycholesterol binding protein in NT2 cells distinct from the human oxysterol receptors liver X receptor LXRalpha and beta. PMID- 17689018 TI - Cortisol awakening response in abstinent alcohol-dependent patients as a marker of HPA-axis dysfunction. AB - Hypothalamo-pituitary-adrenocorticoid (HPA)-axis reactivity to psychosocial or pharmacological stimulants is diminished in alcohol-dependent patients during early abstinence but recovers after several months of abstention. In order to assess the physiological reactivity in the morning we used the cortisol awakening response (CAR) in saliva to compare 24 early abstainers (mean 21.9+/-7.6, range 10-36 days) with 12 alcohol-dependent patients with longer abstention periods (mean 116.8+/-45.7, range 59-230 days) and looked for an association with sleep, especially rapid eye movement (REM) sleep of the preceding night. Both groups did not differ with respect to age, duration of alcohol dependence, daily drinking dosage before detoxification, body mass index, depressivity, level of anxiety, daily cigarette consumption or sleep quality during the preceding 14 days. Sleep in the night before cortisol assessment did not differ with respect to total sleep time (412.4+/-35.9 vs. 407.0+/-38.7 min). Immediately upon awakening and 15, 30, 45 and 60 min later, specimens of salivary cortisol were collected. While starting from equal levels upon awakening longer abstaining patients with alcohol dependence showed a stronger CAR (ANOVA with repeated measurement, time x group effect: F=4.33, p<0.01) with distinctly higher cortisol levels 45 and 60 min after awakening (T=3.79, p<0.001 and T=3.06, p<0.005, respectively). Across both groups the time spent in REM-sleep only correlated with cortisol levels upon awakening (r=0.33, p<0.05). Our data indicate that CAR is a useful tool for investigating alterations in the HPA-axis regulation in abstaining alcohol dependent patients. PMID- 17689019 TI - Cognitive impairment and increased brain neurosteroids in adult rats perinatally exposed to low millimolar blood alcohol concentrations. AB - Epidemiological evidence suggests that adolescents and adults perinatally exposed to alcohol, even at low doses, show high prevalence of cognitive impairment and social behavior deficits, which may be in part related to alcohol-induced changes of the gamma-aminobutyric acid (GABA)ergic neurotransmission. The endogenous neurosteroid 3alpha-hydroxy,5alpha-pregnan-20-one (3alpha,5alpha tetrahydroprogesterone/3alpha,5alpha-THP), a potent positive allosteric modulator of GABA(A) receptor function, is implicated in the physiological tuning of GABA mediated fast inhibition and in various alcohol's actions in the brain. This study was undertaken to determine whether perinatal exposure to low millimolar blood alcohol concentrations alters cognitive skills (social discrimination and inhibitory avoidance tests), emotional reactivity (elevated plus maze test), and neurosteroid content in brain cortex and hippocampus of adult male offspring. Dams had access to a 3% alcohol solution or to an equicaloric sucrose solution from gestational day 15 to postnatal day 9. Eighty-day old alcohol-exposed male offspring exhibited impaired social recognition memory, but unchanged inhibitory avoidance performance and normal behavior on the elevated-plus maze. The concentrations of 3alpha,5alpha-THP and its precursor progesterone were more than doubled in brain cortex and hippocampus of alcohol-exposed rats, whereas in plasma only progesterone was increased. Thus, exposure to low millimolar blood alcohol concentrations has a long-lasting impact on the developing brain as it causes an impairment of social recognition as well as an increase of brain neurosteroid content in mature animals. The latter may be consequent to altered expression/activity of brain steroidogenic enzymes, as reflected by the enduring increase of the GABA(A) receptor-active neurosteroid 3alpha,5alpha-THP in brain cortex and hippocampus, but not in plasma. It is speculated that, by inducing a greater amplification of GABA(A) receptor function, the elevation of 3alpha,5alpha-THP brain content contributes to the cognitive impairment exhibited by adult alcohol-exposed offspring. PMID- 17689020 TI - Osteocyte: the impresario in the electrical stimulation for bone fracture healing. AB - Delayed healing and nonunions of bone fracture are critical problems in orthopedic surgery. Electrical stimulation has been used as a therapeutic method for enhancing bone healing for a long time. Despite unanimous clinical success, the underlying mechanism concerning bone tissue in response to electrical stimulation remains poorly understood. In the meantime, emerging evidences suggest that osteocytes, with their unique location and morphologies, play an important role in regulating the behaviors of other bone cells, including osteoblasts, osteoclasts and their progenitor cells. In this paper, we hypothesize that osteocytes are the sensory cells for the electrical stimulation, and they orchestrate the whole process of new bone formation and remodeling in the electrotherapy for bone fracture. The postulated electrosensory transduction pathway might be a coupling effect of osteoblasts and osteoclasts, which is regulated by the biochemical signals expressed from osteocytes after sensing the membrane potential changes. It is believed that better understanding of this mechanism would facilitate optimizing the electrotherapy for bone disorders and assist in solving these clinical problems. PMID- 17689021 TI - The fibrosis and atrial fibrillation: is the transforming growth factor-beta 1 a candidate etiology of atrial fibrillation. AB - Atrial fibrillation (AF) is the most commonly occurring arrhythmia in clinical practice, however, the mechanism of atrial fibrillation is not well explained. It has been considered that myocardial fibrosis plays a role in atrial fibrillation. Within the heart, this fibrosis is thought to be mediated by transforming growth factor-beta 1 (TGF-beta 1), a potent stimulator of collagen-producing cardiac fibroblasts. Recent studies indicate that atrial fibrillation is associated with elevated serum concentrations of TGF-beta 1 and C-terminal propeptide of procollagen type I (a marker of collagen type I synthesis). TGF-beta 1 was not only associated with the presence of atrial fibrillation but may also predict patients at increased risk for future development of atrial fibrillation. Why TGF beta 1 in atrial fibrillation is high is a puzzling problem. We hypothesized that TGF-beta 1 is a possible cause of atrial fibrillation by initiating fibrosis response. Atrial interstitial fibrosis has been seen in patients with CHF and in animal models of pacing-induced heart failure. It was demonstrated that TGF-beta 1 levels were increased in the atria after the development of congestive heart failure in dogs. In a similar study, mice with increased expression of TGF-beta 1 were prone to atrial fibrillation development as a result of raised levels of atrial fibrosis. If the hypothesis is confirmed, administration of TGF-beta 1 monoclonal antibodies may be used to eliminate the etiology. It will be a new target point to treat atrial fibrillation. PMID- 17689022 TI - Impaired innate immunity of ocular surface is the key bridge between extended contact lens wearing and occurrence of Acanthamoeba keratitis. AB - Acanthamoeba keratitis is a progressive, sight-threatening corneal disease. Extended wearing contact lens is one of predisposed factors. Early studies mostly focused on "improper contact-lens hygiene", which described that contact lens wearers have more opportunities to contact with pathogens directly and prone to get A. keratitis. However, improper contact-lens hygiene can not explain the phenomenon that Acanthamoeba protozoon were found in normal individuals' lens cases. So there might be other factors related with A. keratitis. Recently, more attention has been paid on the influence of extended wearing contact lens on the innate immunity of ocular surface. It has been proven that in contact lens wearers the reactivity of polymorphonuclear leucocytes (PMNs) and the concentration of certain inflammatory mediators were significantly altered compared with that in non-lens wearers. Moreover, other studies showed the important contributions of innate immunity on occurrence and development of A. keratitis. With the contribution of extended wearing contact lens on immunity and the relation between innate immunity and Acanthamoeba, we suggest that the impaired innate immunity of ocular surface may be a key bridge between extended wearing contact lens and A. keratitis. With the impaired innate immunity caused by extended contact-lens wearing, the Acanthamoeba trophozoites and cysts could not be easily killed, therefore A. keratitis was occurred and aggravated. Understanding the immunological mechanism of extended contact lens wearing on the A. keratitis may give more contributions on the research of the disease, and facilitate the production of contact lens with much higher biocompatibility. PMID- 17689023 TI - A phase I-II study of postoperative capecitabine-based chemoradiotherapy in gastric cancer. AB - BACKGROUND: The Intergroup 0116 randomized study showed that postoperative 5 fluorouracil-based chemoradiotherapy improved locoregional control and overall survival in patients with gastric cancer. We hypothesized that these results could be improved further by using a more effective, intensified, and convenient chemotherapy schedule. Therefore, this Phase I-II dose-escalation study was performed to determine the maximal tolerated dose and toxicity profile of postoperative radiotherapy combined with concurrent capecitabine. PATIENTS AND METHODS: After recovery from surgery for adenocarcinoma of the gastroesophageal junction or stomach, all patients were treated with capecitabine monotherapy, 1,000 mg/m2 twice daily for 2 weeks. After a 1-week treatment-free interval, patients received capecitabine (650-1,000 mg/m2 orally twice daily 5 days/week) in a dose-escalation schedule combined with radiotherapy on weekdays for 5 weeks. Radiotherapy was delivered to a total dose of 45 Gy in 25 fractions to the gastric bed, anastomoses, and regional lymph nodes. RESULTS: Sixty-six patients were treated accordingly. Two patients went off study before or shortly after the start of chemoradiotherapy because of progressive disease. Therefore, 64 patients completed treatment as planned. During the chemoradiotherapy phase, 4 patients developed four items of Grade III dose-limiting toxicity (3 patients in Dose Level II and 1 patient in Dose Level IV). The predefined highest dose of capecitabine, 1,000 mg/m2 twice daily orally, was tolerated well and, therefore, considered safe for further clinical evaluation. CONCLUSIONS: This Phase I-II study shows that intensified chemoradiotherapy with daily capecitabine is feasible in postoperative patients with gastroesophageal junction and gastric cancer. PMID- 17689024 TI - Postmastectomy electron beam chest wall irradiation in women with breast cancer: a clinical step toward conformal electron therapy. AB - PURPOSE: Electron beam radiotherapy of the chest wall with or without lymph node irradiation has been used at the Institut Curie for >20 years. The purpose of this report was to show the latest improvements of our technique developed to avoid hot spots and improve the homogeneity. METHODS AND MATERIALS: The study was split into two parts. A new electron irradiation technique was designed and compared with the standard one (dosimetric study). The dose distributions were calculated using our treatment planning software ISIS (Technologie Diffusion). The dose calculation was performed using the same calculation parameters for the new and standard techniques. Next, the early skin toxicity of our new technique was evaluated prospectively in the first 25 patients using Radiation Therapy Oncology Group criteria (clinical study). RESULTS: The maximal dose found on the five slices was 53.4 +/- 1.1 Gy for the new technique and 59.1 +/- 2.3 Gy for the standard technique. The hot spots of the standard technique plans were situated at the overlap between the internal mammary chain and chest wall fields. The use of one unique field that included both chest wall and internal mammary chain volumes solved the problem of junction. To date, 25 patients have been treated with the new technique. Of these patients, 12% developed Grade 0, 48% Grade 1, 32% Grade 2, and 8% Grade 3 toxicity. CONCLUSIONS: This report describes an improvement in the standard postmastectomy electron beam technique of the chest wall. This new technique provides improved target homogeneity and conformality compared with the standard technique. This treatment was well tolerated, with a low rate of early toxicity events. PMID- 17689025 TI - Outcomes in treatment for intradural spinal cord ependymomas. AB - PURPOSE: Spinal cord ependymomas are rare tumors, accounting for <2% of all primary central nervous system tumors. This study assessed the treatment outcomes for patients diagnosed with spinal cord ependymomas within the Southern California Kaiser Permanente system. METHODS AND MATERIALS: We studied 23 patients treated with surgery with or without external beam radiotherapy (EBRT). The local and distant control rates and overall survival rates were determined. RESULTS: The overall local control, overall recurrence, and 9-year overall survival rate was 96%, 17.4%, and 63.9%, respectively. CONCLUSIONS: The results of our study indicate that en bloc gross total resection should be the initial treatment, with radiotherapy reserved primarily for postoperative cases with unfavorable characteristics such as residual tumor, anaplastic histologic features, or piecemeal resection. Excellent local control and overall survival rates can be achieved using modern microsurgical techniques, with or without local radiotherapy. PMID- 17689026 TI - Customized dose prescription for permanent prostate brachytherapy: insights from a multicenter analysis of dosimetry outcomes. AB - PURPOSE: To investigate the biochemical control rate in patients undergoing permanent prostate brachytherapy as a function of the biologically effective dose (BED) and risk group. METHODS AND MATERIALS: Six centers provided data on 3,928 permanent brachytherapy patients with postimplant dosimetry results. The mean prostate-specific antigen level was 8.9 ng/mL. (125)I was used in 2,293 (58%), (103)Pd in 1,635, and supplemental external beam radiotherapy in 882 (22.5%) patients. The patients were stratified into low- (n = 2,188), intermediate- (n = 1,188), and high- (n = 552) risk groups and into three BED groups of < 140 Gy (n = 524), 140-200 Gy (n = 2284), and >200 Gy (n = 1,115). Freedom from biochemical disease progression (biochemical freedom from failure [bFFF]) was determined using the American Society for Therapeutic Radiology Oncology and Phoenix definitions and calculated using the Kaplan-Meier method, with factors compared using the log-rank test. RESULTS: The 10-year prostate-specific antigen bFFF rate for the American Society for Therapeutic Radiology Oncology and Phoenix definitions was 79.2% and 70%, respectively. The corresponding bFFF rates for the low-, intermediate-, and high-risk groups was 84.1% and 78.1%, 76.8% and 63.6%, and 64.4% and 58.2%, respectively (p < 0.0001). The corresponding bFFF rate for the three BED groups was 56.1% and 41.4%, 80% and 77.9%, and 91.1% and 82.9% (p < 0.0001). The corresponding bFFF rate for the low-risk patients by dose group was 69.8% and 49.8%, 86% and 85.2%, and 88.1% and 88.3% for the low-, intermediate, and high-dose group, respectively (p <0.0001). The corresponding bFFF rate for the intermediate-risk patients by dose group was 52.9% and 23.1%, 74.1% and 77.7%, and 94.3% and 88.8% for the low-, intermediate-, and high-dose group, respectively (p < 0.0001). The corresponding bFFF rate for high-risk patients by dose group was 19.2% and 41.7%, 61.8% and 53.2%, and 90% and 69.6% for the low-, intermediate-, and high-dose group, respectively (p < 0.0001). CONCLUSIONS: These data suggest that permanent brachytherapy dose prescriptions can be customized to risk status. In low-risk patients, achieving a BED of >or=140 Gy might be adequate for prostate-specific antigen control. However, high-risk disease might require a BED dose of >or=200 Gy. PMID- 17689027 TI - Improving the capture of adverse event data in clinical trials: the role of the International Atomic Energy Agency. AB - PURPOSE: To report meetings of the Applied Radiation Biology and Radiotherapy section of the International Atomic Energy Agency (IAEA), organized to discuss issues surrounding, and develop initiatives to improve, the recording of adverse events (AE) in clinical trials. METHODS AND MATERIALS: A first meeting was held in Atlanta, GA (October 2004). A second meeting was held in Denver, CO (October 2005) and focused on AE data capture. The National Cancer Institute Common Terminology Criteria for Adverse Events, version 3 (CTCAE) was suggested during the first meeting as the preferred common platform for the collection and reporting of AE data in its clinical trials. The second meeting identified and reviewed the current weaknesses and variations in the capture of AE data, and proposals to improve the quality and consistency of data capture were discussed. RESULTS: There is heterogeneity in the collection of AE data between both institutions and individual clinicians. The use of multiple scoring systems hampers comparisons of treatment outcomes between centers and trials. There is often insufficient detail on normal tissue treatment effects, which leads to an underestimate of toxicity. Implementation of improved data capture was suggested for one of the ongoing IAEA clinical trials. CONCLUSIONS: There is a need to compare the quality and completeness of data between institutions and the efficacy of structured/directed vs. traditional passive data collection. Data collection using the CTCAE (with or without a questionnaire) will be investigated in an IAEA multinational trial of radiochemotherapy and high-dose-rate brachytherapy in cervical cancer. PMID- 17689028 TI - Image-guided intensity-modulated photon radiotherapy using multifractionated regimen to paraspinal chordomas and rare sarcomas. AB - PURPOSE: Image-guided intensity-modulated radiotherapy enables delivery of high dose radiation to tumors close to the spinal cord. We report our experience with multifractionated regimens using image-guided intensity-modulated radiotherapy to treat gross paraspinal disease to doses beyond cord tolerance. METHODS AND MATERIALS: We performed a retrospective review of 27 consecutive patients with partially resected or unresectable paraspinal tumors irradiated to >5,300 cGy in standard fractionation. RESULTS: The median follow-up was 17.4 months (range, 2.1 47.3). Eighteen sarcomas, seven chordomas, and two ependymomas were treated. The median dose to the planning target volume was 6,600 cGy (range, 5,396-7,080) in 180- or 200-cGy fractions. The median planning target volume was 164 cm3 (range, 29-1,116). Seven patients developed recurrence at the treatment site (26%), and 6 of these patients had high-grade tumors. Three patients with recurrence had metastatic disease at the time of radiotherapy. The 2-year local control rate was 65%, and the 2-year overall survival rate was 79%. Of the 5 patients who died, 4 had metastatic disease at death. Twenty-three patients (84%) reported either no pain or improved pain at the last follow-up visit. Sixteen patients discontinued narcotic use after treatment (62.5%). Twenty-three patients (89%) had a stable or improved American Spine Injury Association score at the last follow-up visit. No patient experienced radiation-induced myelopathy. CONCLUSIONS: The dose to paraspinal tumors has traditionally been limited to respect cord tolerance. With image-guided intensity-modulated radiotherapy, greater doses of radiation delivered in multiple fractions can be prescribed with excellent target coverage, effective palliation, and acceptable toxicity and local control. PMID- 17689029 TI - Use of palliative radiotherapy among patients with metastatic non-small-cell lung cancer. AB - PURPOSE: Radiotherapy (RT) is known to effectively palliate many symptoms of patients with metastatic non-small-cell lung cancer (NSCLC). Anecdotally, RT is believed to be commonly used in this setting, but limited population-based data are available. The objective of this study was to examine the utilization patterns of palliative RT among elderly patients with Stage IV NSCLC and, in particular, to identify factors associated with its use. METHODS AND MATERIALS: A retrospective population-based cohort study was performed using linked Surveillance, Epidemiology and End Results (SEER)-Medicare data to identify 11,084 Medicare beneficiaries aged > or =65 years who presented with Stage IV NSCLC in the 11 SEER regions between 1991 and 1996. The primary outcome was receipt of RT. Logistic regression analysis was used to identify factors associated with receipt of RT. RESULTS: A total of 58% of these patients received RT, with its use decreasing over time (p = 0.01). Increasing age was negatively associated with receipt of treatment (p <0.001), as was increasing comorbidities (p <0.001). Factors positively associated with the receipt of RT included income (p = 0.001), hospitalization (p <0.001), and treatment with chemotherapy (p <0.001). Although the use varied across the SEER regions (p = 0.001), gender, race/ethnicity, and distance to the nearest RT facility were not associated with treatment. CONCLUSIONS: Elderly patients with metastatic NSCLC frequently receive palliative RT, but its use varies, especially with age and receipt of chemotherapy. Additional research is needed to determine whether this variability reflects good quality care. PMID- 17689030 TI - Squamous cell carcinoma antigen in follow-up of cervical cancer treated with radiotherapy: evaluation of cost-effectiveness. AB - PURPOSE: The squamous cell carcinoma (SCC) antigen is still considered the most accurate serologic tumor marker in cervical carcinoma. We assessed the contribution of the SCC assay to the detection of recurrences in patients treated with radiotherapy. METHODS AND MATERIALS: The pattern of recurrence and follow-up data were prospectively recorded for 135 patients. Of the 135 patients, 103 (76.3%) had primary cervical carcinoma and 32 (23.7%) had already experienced disease recurrence that had been successfully treated with surgery (n = 2), surgery plus radiotherapy (n = 2), radiotherapy (n = 5), or concomitant chemoradiotherapy (n = 23). The follow-up evaluations (chest X-ray, abdominopelvic magnetic resonance imaging, gynecologic examination with colposcopy, Papanicolaou smear, and SCC assay) were performed at 6-month intervals; the evaluation was done earlier if recurrent disease was suspected. The median follow-up time was 29 months (range, 6-131). The SCC serum levels were assayed, and a cost analysis was done. RESULTS: A total of 481 SCC determinations were performed. Of the 135 patients, 43 (31.8%) experienced disease recurrence. The SCC levels were higher in those with recurrent disease than in the disease free patients. Elevation of SCC was documented in 34 (79.1% sensitivity) of 43 recurrences before symptoms appeared. Of the 38 patients with serum SCC elevation, 34 developed a recurrence (positive predictive value, 89.5%). Of the 97 patients with negative SCC serum levels, 88 had negative findings at the clinicoradiologic evaluation (negative predictive value, 90.7%). A simplified approach (SCC plus gynecologic examination) was evaluated. Compared with the complete follow-up program, the rate of missed recurrence was 2.2%. The total projected cost per patient for 5 years of follow-up for the simplified procedure was approximately 12.2-fold lower than the standard approach. CONCLUSIONS: Our results have shown that a simplified diagnostic approach, including the SCC assay and gynecologic examination, can detect a high rate of recurrence from cervical cancer, with a very favorable cost-effective profile. PMID- 17689031 TI - Long-term outcomes for synovial sarcoma treated with conservation surgery and radiotherapy. AB - PURPOSE: To evaluate prognostic factors and treatment outcomes in patients with localized synovial sarcoma treated with conservation surgery and radiotherapy (RT). METHODS AND MATERIALS: Between 1960 and 2003, 150 patients with nonmetastatic synovial sarcoma were treated with conservation surgery and RT. The majority of patients (81%) were aged >20 years. Sixty-eight percent received postoperative RT, and 32% received preoperative RT. Forty-eight percent received adjuvant chemotherapy. RESULTS: Median follow-up was 13.2 years. Overall survival (OS) rates at 5, 10, and 15 years were 76%, 57%, and 51%, respectively. Corresponding disease-free survival (DFS) rates were 59%, 52%, and 52%, respectively. Tumor size >5 cm predicted worse OS, DFS, disease-specific survival (DSS), and higher rate of distant metastases (DM). Age >20 years predicted worse DFS and DSS but not OS. Local control (LC) was 82% at 10 years. Positive or unknown resection margins predicted inferior LC rates. Forty-four percent developed DM by 10 years. Only 1% developed nodal metastases. Analysis of outcomes by treatment decade showed no significant differences with respect to LC and DM rates. CONCLUSIONS: Synovial sarcoma is adequately controlled at the primary site by conservation surgery and RT. Elective nodal irradiation is not indicated. Rates of development of DM and subsequent death from disease remain high, with no significant improvement in outcomes for this disease in the past four decades. PMID- 17689032 TI - Duodenal adenocarcinoma: patterns of failure after resection and the role of chemoradiotherapy. AB - PURPOSE: To report patterns of disease recurrence after resection of adenocarcinoma of the duodenum and compare outcomes between patients undergoing surgery only vs. surgery with concurrent chemotherapy and radiation therapy (CT RT). METHODS AND MATERIALS: This was a retrospective analysis of all patients undergoing potentially curative therapy for adenocarcinoma of the duodenum at Duke University Medical Center and affiliated hospitals between 1975 and 2005. Overall survival (OS), disease-free survival (DFS), and local control (LC) were estimated using the Kaplan-Meier method. Univariate regression analysis evaluated the effect of CT-RT on clinical endpoints. RESULTS: Thirty-two patients were identified (23 M, 9 F). Median age was 60 years (range, 32-77 years). Surgery alone was performed in 16 patients. An additional 16 patients received either preoperative (n = 11) or postoperative (n = 5) CT-RT. Median RT dose was 50.4 Gy (range, 12.6-54 Gy). All patients treated with RT also received concurrent 5 fluorouracil-based CT. Two patients treated preoperatively had a pathologic complete response (18%), and none had involved lymph nodes at resection. Five year OS, DFS, and LC for the entire group were 48%, 47%, and 55%, respectively. Five-year survival did not differ between patients receiving CT-RT vs. surgery alone (57% vs. 44%, p = 0.42). However, in patients undergoing R0 resection, CT RT appeared to improve OS (5-year 83% vs. 53%, p = 0.07). CONCLUSIONS: Local failure after surgery alone is high. Given the patterns of relapse with surgery alone and favorable outcomes in patients undergoing complete resection with CT RT, the use of CT-RT in selected patients should be considered. PMID- 17689033 TI - Reduction of overall treatment time in patients irradiated for more than three brain metastases. AB - PURPOSE: Patients with multiple brain metastases usually receive whole brain radiotherapy (WBRT). A dose of 30 Gy in 10 fractions (10 x 3 Gy) in 2 weeks is the standard treatment in many centers. Regarding the poor survival of these patients, a shorter RT regimen would be preferable if it provides a similar outcome as that with 10 x 3 Gy. This study compared 20 Gy in five fractions (5 x 4 Gy) within 5 days to 10 x 3 Gy. METHODS AND MATERIALS: Data from 442 patients treated with WBRT for multiple brain metastases were retrospectively analyzed. Survival and local control within the brain of 232 patients treated with 5 x 4 Gy were compared with the survival and local control within the brain of 210 patients treated with 10 x 3 Gy. Seven additional potential prognostic factors were investigated: age, gender, Karnofsky performance score, tumor type, interval from tumor diagnosis to RT, extracranial metastases, and recursive partitioning analysis class. RESULTS: On univariate analysis, the WBRT program was not associated with survival (p = 0.29) or local control (p = 0.07). On multivariate analyses, improved survival was associated with a lower recursive partitioning analysis class (p < 0.001), age or=70 (p = 0.015), and the absence of extracranial metastases (p = 0.005). Improved local control was associated with a lower recursive partitioning analysis class (p < 0.001), Karnofsky performance score >or=70 (p < 0.001), and breast cancer (p = 0.043). Grade 3 acute toxicity rates were not significantly different between 5 x 4 Gy and 10 x 3 Gy. CONCLUSIONS: Shorter course WBRT with 5 x 4 Gy was associated with similar survival and local control as "standard" WBRT with 10 x 3 Gy in patients with more than three brain metastases. The 5 x 4-Gy regimen appears preferable for most of these patients, because it is less time consuming and more convenient for patients than the 10 x 3-Gy regimen. PMID- 17689034 TI - Boron neutron capture therapy in the treatment of locally recurred head and neck cancer. AB - PURPOSE: Head and neck carcinomas that recur locally after conventional irradiation pose a difficult therapeutic problem. We evaluated safety and efficacy of boron neutron capture therapy (BNCT) in the treatment of such cancers. METHODS AND MATERIALS: Twelve patients with inoperable, recurred, locally advanced (rT3, rT4, or rN2) head and neck cancer were treated with BNCT in a prospective, single-center Phase I-II study. Prior treatments consisted of surgery and conventionally fractionated photon irradiation to a cumulative dose of 56-74 Gy administered with or without concomitant chemotherapy. Tumor responses were assessed using the RECIST (Response Evaluation Criteria in Solid Tumors) criteria and adverse effects using the National Cancer Institute common toxicity grading v3.0. Intravenously administered boronophenylalanine-fructose (BPA-F, 400 mg/kg) was used as the boron carrier. Each patient was scheduled to be treated twice with BNCT. RESULTS: Ten patients received BNCT twice; 2 were treated once. Ten (83%) patients responded to BNCT, and 2 (17%) had tumor growth stabilization for 5.5 and 7.6 months. The median duration of response was 12.1 months; six responses were ongoing at the time of analysis or death (range, 4.9 19.2 months). Four (33%) patients were alive without recurrence with a median follow-up of 14.0 months (range, 12.8-19.2 months). The most common acute adverse effects were mucositis, fatigue, and local pain; 2 patients had a severe (Grade 3) late adverse effect (xerostomia, 1; dysphagia, 1). CONCLUSIONS: Boron neutron capture therapy is effective and safe in the treatment of inoperable, locally advanced head and neck carcinomas that recur at previously irradiated sites. PMID- 17689036 TI - A new 2-arylbenzofuran from the root bark of Chinese Morus cathayana. AB - A new 2-arylbenzofuran, sanggenofuran B (3',5'-dihydroxy-6-methoxy-4'-prenyl-2 arylbenzofuran), from the root bark of Chinese Morus cathayana is reported. PMID- 17689035 TI - A nomogram to predict radiation pneumonitis, derived from a combined analysis of RTOG 9311 and institutional data. AB - PURPOSE: To test the Washington University (WU) patient dataset, analysis of which suggested that superior-to-inferior tumor position, maximum dose, and D35 (minimum dose to the hottest 35% of the lung volume) were valuable to predict radiation pneumonitis (RP), against the patient database from Radiation Therapy Oncology Group (RTOG) trial 9311. METHODS AND MATERIALS: The entire dataset consisted of 324 patients receiving definitive conformal radiotherapy for non small-cell lung cancer (WU = 219, RTOG 9311 = 129). Clinical, dosimetric, and tumor location parameters were modeled to predict RP in the individual datasets and in a combined dataset. Association quality with RP was assessed using Spearman's rank correlation (r) for univariate analysis and multivariate analysis; comparison between subgroups was tested using the Wilcoxon rank sum test. RESULTS: The WU model to predict RP performed poorly for the RTOG 9311 data. The most predictive model in the RTOG 9311 dataset was a single-parameter model, D15 (r = 0.28). Combining the datasets, the best derived model was a two parameter model consisting of mean lung dose and superior-to-inferior gross tumor volume position (r = 0.303). An equation and nomogram to predict the probability of RP was derived using the combined patient population. CONCLUSIONS: Statistical models derived from a large pool of candidate models resulted in well-tuned models for each subset (WU or RTOG 9311), which did not perform well when applied to the other dataset. However, when the data were combined, a model was generated that performed well on each data subset. The final model incorporates two effects: greater risk due to inferior lung irradiation, and greater risk for increasing normal lung mean dose. This formula and nomogram may aid clinicians during radiation treatment planning for lung cancer. PMID- 17689037 TI - Mesencephalic neurodegeneration in the orally administered bisphenol A-caused hyperactive rats. AB - Since an emerging body of evidence is accumulating that endocrine disruptors exert their effects on the central nervous system, their neuronal risk assessment is now required. A previous study showed that a single intracisternal administration of bisphenol A, an endocrine disruptor, into neonatal rats caused hyperactivity. To evaluate the neural risk assessment of bisphenol A, it is very important to test the potential of the chemical via an environmental exposure route. In this study, we tested the hypothesis that oral exposure to bisphenol A would exhibit effects observed previously with direct instillation. Oral administration of 600mug/pup/day bisphenol A into male Wistar rats aged 5 days-3 weeks caused significant hyperactivity at 4-5 weeks of age. Treated rats were about 1.3 times as active in the nocturnal phase as were vehicle-treated control rats (p<0.005). The long-term effects of the chemical resulted in a large reduction of immunoreactivity for tyrosine hydroxylase in the midbrain at 7 weeks of age, where terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells were detected. Furthermore, bisphenol A decreased gene expression levels of dopamine transporter in adult rats. PMID- 17689038 TI - In vitro embryo development and blastocyst hatching rates following vitrification of river buffalo embryos produced from oocytes recovered from slaughterhouse ovaries or live animals by ovum pick-up. AB - The present study was undertaken to determine whether the source of oocytes (ovum pick up versus slaughterhouse ovaries) affected in vitro embryo production and embryo survival (as measured by blastocyst hatching rates) following vitrification in buffaloes (Bubalus bubalis). Oocytes recovered from live buffaloes (n=6) by ovum pick up (OPU) and by manual aspiration from slaughterhouse ovaries were in vitro matured, fertilized and cultured to blastocyst stage under same culture conditions. Vitrification of blastocysts was carried out in two steps at 24 degrees C. Embryos were equilibrated in 10% EG+10% DMSO+0.3 M sucrose in base medium for 4 min. Subsequently, the embryos were transferred into 25% EG+25% DMSO+0.3 M sucrose in base medium for 45 s and then the embryos were loaded into straws and immersed in liquid nitrogen. Following warming, blastocysts were cultured in vitro for 48 h to assess hatching. Oocytes derived from live animals by OPU resulted in a significantly higher blastocyst yield then those derived from slaughterhouse ovaries (30.6+/-4.3 versus 18.5+/ 1.8). Blastocyst hatching rates following vitrification of buffalo embryos produced from the oocytes collected from live animals by OPU was significantly higher than the oocytes collected from slaughterhouse ovaries (52.8+/-4.2 versus 40.2+/-4.4). In conclusion, the present study showed that source of oocytes (OPU versus slaughterhouse ovaries) affects the in vitro embryo development and blastocyst hatching rates following vitrification of embryos in buffaloes. PMID- 17689039 TI - Psychiatric morbidity in murder and attempted murder crime convicts: a Turkey study. AB - In the present, the morbidity of psychiatric disorders of homicide/attempted homicide crime convicts imprisoned in Turkey, Sivas maximum security prison was investigated. Seventy imprisoned homicide/attempted homicide crime convicts included in this study. Sociodemographic information form, structured clinical interview for DSM-IV Axis-I disorders and structured clinical interview for DSM III-R personality disorders applied to the participants. Most commonly diagnosed disorders among those convicts were current Axis-I disorders, depressive disorders (7.1%) and anxiety disorders (5.7%). Among Axis-I disorders, the most diagnosed one was the substance use disorders (45.7%). The most diagnosed Axis-II disorder was found as to be antisocial personality disorder (48.6%). The rate of convicts who were diagnosed as having both Axis-I and Axis-II disorders was 51.4%. The most prevalently accompanying lifetime Axis-I disorders to antisocial personality disorder with respect to Axis-I, and Axis-II comorbidity was substance use disorders. As a result, it was thought that the substance use disorders and antisocial personality disorder among the homicide/attempted homicide crime convicts were the most prevalent lifetime psychiatric disorders. PMID- 17689040 TI - Cardiovascular risk factors in centenarians. AB - Several studies have shown that centenarians have better cardiovascular risk profiles compared to younger old people. Some reports have revealed that cardiovascular diseases (i.e. hypertension, diabetes, angina and/or myocardial infarction) are less common in centenarians respect to 70 and 80 years old persons. In order to explain this evidence, there is a growing number of hypothesis that consider a combination of genetic factors and lifestyle aspects to elucidate the exceptional longevity of centenarians, able to overcome the most frequent mortality cause, which is a cardiovascular event. It has been suggested that a role on this better cardiovascular risk profile may be played by the increasing use of pharmacologic treatments in the elderly population (specially for hypertension and dyslipidemia), but the contribution of drug treatments to promote extreme longevity is not confirmed. Furthermore, centenarians in general have needed fewer drugs at younger ages due to a healthy lifestyle. The importance of the genetic contribution is demonstrated by the inheritance of low risk cardiovascular profiles in centenarian offspring and lower prevalence of cardiovascular diseases in this population as compared with their spouses or with age-matched subjects without centenarian parents. Another advantage in centenarians' offspring seems to be a delay in the onset for cardiovascular diseases, respect to age- and sex-matched controls. Cardiovascular risk factors mirror the factors that contribute to longevity. Hence, it is not surprising that these risk factors are less prevalent in centenarians when compared to younger old individuals. PMID- 17689041 TI - Regulation of life history determines lifespan of worker honey bees (Apis mellifera L.). AB - Life expectancy of honey bees (Apis mellifera L.) is of general interest to gerontological research because its variability among different groups of bees is one of the most striking cases of natural plasticity of aging. Worker honey bees spend their first days of adult life working in the nest, then transition to foraging and die between 4 and 8 weeks of age. Foraging is believed to be primarily responsible for the early death of workers. Three large-scale experiments were performed to quantitatively assess the importance of flight activity, chronological age, extrinsic mortality factors and foraging specialization. Forager mortality was higher than in-hive bee mortality. Most importantly however, reducing the external mortality hazards and foraging activity did not lead to the expected strong extension of life. Most of the experimental effects were attributable to an earlier transition from hive tasks to foraging. This transition is accompanied by a significant mortality peak. The age at the onset of foraging is the central variable in worker life-history and behavioral state was found more important than chronological age for honey bee aging. However, mortality risk increased with age and the negative relation between pre-foraging and foraging lifespan indicate some senescence irrespective of behavioral state. Overall, honey bee workers exhibit a logistic mortality dynamic which is mainly caused by the age-dependent transition from a low mortality pre-foraging state to a higher mortality foraging state. PMID- 17689042 TI - Active listening in medical consultations: development of the Active Listening Observation Scale (ALOS-global). AB - OBJECTIVE: Active listening is a prerequisite for a successful healthcare encounter, bearing potential therapeutic value especially in clinical situations that require no specific medical intervention. Although generally acknowledged as such, active listening has not been studied in depth. This paper describes the development of the Active Listening Observation Scale (ALOS-global), an observation instrument measuring active listening and its validation in a sample of general practice consultations for minor ailments. METHODS: Five hundred and twenty-four videotaped general practice consultations involving minor ailments were observed with the ALOS-global. Hypotheses were tested to determine validity, incorporating patients' perception of GPs' affective performance, GPs' verbal attention, patients' self-reported anxiety level and gender differences. RESULTS: The final 7-item ALOS-global had acceptable inter- and intra-observer agreement. Factor analysis revealed one homogeneous dimension. The scalescore was positively related to verbal attention measured by RIAS, to patients' perception of GPs' performance and to their pre-visit anxiety level. Female GPs received higher active listening scores. CONCLUSION: The results of this study are promising concerning the psychometric properties of the ALOS-global. More research is needed to confirm these preliminary findings. PRACTICE IMPLICATIONS: After establishing how active listening differentiates between health professionals, the ALOS-global may become a valuable tool in feedback and training aimed at increasing listening skills. PMID- 17689043 TI - Liver resection for HCC with cirrhosis: surgical perspectives out of EASL/AASLD guidelines. AB - EASL/AASLD guidelines clearly define indications for liver surgery for HCC: patients with single HCC and completely preserved liver function without portal hypertension. These guidelines exclude from operation many patients that could benefit from radical resection and that are daily scheduled for hepatectomy in surgical centers. Patients with large tumors or with portal vein thrombosis cannot be transplanted or treated by interstitial treatments. In selected cases liver resection may obtain good long-term outcomes, significantly better than non curative therapies. In cases of multinodular HCC, liver transplantation is the treatment of choice within Milan criteria; patients beyond these limits can benefit from liver resection, especially if only two nodules are diagnosed: even if they have a worse prognosis, survival results after liver surgery are better than those reported after TACE or conservative treatments. EASL/AASLD guidelines excluded from operating patients with portal hypertension but data about this topic are not conclusive and further studies are necessary. Selected patients with mild portal hypertension could probably be scheduled for liver resection and, considering the shortage of donors, listing for transplantation could be avoided. In conclusion, guidelines for HCC treatment should consider good results of liver resection for advanced HCC, and indications for hepatectomy should be expanded in order not to exclude from radical therapy patients that could benefit from it. PMID- 17689044 TI - [Maajoun poisoning]. PMID- 17689045 TI - [Continuous intraosseous epinephrine infusion in adults: its interest when haemodynamics is poor]. PMID- 17689046 TI - Co-infection of the cotton rat (Sigmodon hispidus) with Staphylococcus aureus and influenza A virus results in synergistic disease. AB - Bacterial super-infection of influenza patients is the primary cause of excess mortality during influenza pandemics, with Staphylococcus aureus (S. aureus) having the highest fatality rate. The cotton rat (Sigmodon hispidus) is an excellent model for both influenza and S. aureus pathogenesis, and therefore a potential tool to model co-infection. We compared physiologic and pathologic changes in cotton rats infected with both S. aureus and influenza A/Wuhan/359/95 (H3N2), with animals infected with each pathogen alone. Co-infected cotton rats demonstrated significantly higher mortality, lower temperatures on 2 and 3 days post-inoculation (p.i.), higher levels of bacteremia and pulmonary bacterial load 4 days p.i., and worse pathology 7 days p.i. Early indicators of exacerbated disease coincided with higher pulmonary mRNA levels for IL-1beta, IL-6, IL-10 and IFNy, supporting the idea that these may contribute to disease severity. Our results demonstrate that the cotton rat is a good model of influenza and S. aureus co-infection, with increased mortality and hypothermia as well as prolonged bacterial duration indicative of synergistic disease that may be the result of increased induction of both pro- and anti-inflammatory cytokines. PMID- 17689047 TI - Spontaneous conversion between mutL and 6 bpDeltamutL in Salmonella typhimurium LT7: association with genome diversification and possible roles in bacterial adaptation. AB - Previously, we reported the phenomenon of genome diversification in Salmonella typhimurium LT7, i.e., individual strains derived from LT7 kept changing the genome structure by inversions, translocations, duplications, and mutations. To elucidate the genetic basis, we sequenced selected genes of the mismatch repair (MMR) system for correlations between MMR defects and genome diversification. We chose S. typhimurium LT7 mutants 8111F2 and 9052D1 for mut gene sequence analyses and found that both mutants had a deletion of one of three tandem 6-bp repeats, GCTGGC GCTGGC GCTGGC, within mutL, which was designated 6 bpDeltamutL. mutS and mutH genes were unchanged in the mutants analyzed. Some sublines of 8111F2 and 9052D1 spontaneously stopped the genome diversification process at certain stages during single-colony restreaking passages, and in these strains the 6 bpDeltamutL genotype also became wild-type mutL. We conclude that conversion between mutL and 6 bpDeltamutL occurs spontaneously and that transient defects of mutL facilitate genome diversification without leading to the accumulation of multiple detrimental genetic changes. Spontaneous conversion between mutL and 6 bpDeltamutL may be an important mechanism used by bacteria to regulate genetic stability in adaptation to changing environments. PMID- 17689048 TI - Plant cytosine-5 DNA methyltransferases: structure, function, and molecular evolution. AB - A detailed analysis of the structure and function, along with evolutionary aspects, of the main plant cytosine-5 DNA methyltransferases (C5-MTases) is presented. The evolutionary relationships between the already known and four candidate plant C5-MTases identified in this work were investigated using the distance, maximum-parsimony, and maximum-likelihood approaches. The topologies of the trees were overall congruent: four monophyletic groups corresponding to the four plant C5-MTase families were clearly distinguished. In addition, sequence analyses of the plant C5-MTase target recognition domain sequences were performed and phylogenetic trees were reconstructed showing that there is good conservation among but not within the plant C5-MTase families. Furthermore, a conserved dipeptide that plays an important role in flipping the target base into the catalytic site of the C5-MTases was identified in all plant C5-MTases under study. PMID- 17689049 TI - Neuroimmune mechanisms of opioid-mediated conditioned immunomodulation. AB - Morphine administration elicits pronounced effects on the immune system, including decreases in natural killer (NK) cell activity and lymphocyte mitogenic responsiveness. These immune alterations can become conditioned to environmental stimuli that predict morphine as a result of Pavlovian conditioning processes. Prior work in our laboratory has shown that acute morphine exposure produces dopamine-dependent reductions of NK cell activity that are mediated peripherally by neuropeptide Y Y1 receptors. The present study examined the involvement of dopamine D1 and neuropeptide Y Y1 receptors in the conditioned immunomodulatory effects of morphine. Rats received two conditioning sessions during which an injection of morphine was paired with a distinctive environment which served as the conditioned stimulus (CS). The results show that systemic administration of the D1 antagonist SCH-23390 prior to CS re-exposure prevented the conditioned suppression of splenic NK activity but did not alter conditioned decreases in mitogen-induced lymphocyte proliferation. Furthermore, bilateral microinjections of SCH-23390 directly into the nucleus accumbens shell fully blocked conditioned changes in NK activity. In a subsequent manipulation, subcutaneous injection of the Y1 receptor antagonist BIBP3226 prior to CS re-exposure was also shown to prevent conditioned effects on NK activity. Collectively, these findings provide evidence that the nucleus accumbens shell plays an important role in conditioned immunomodulation and further suggest that the conditioned and unconditioned immunomodulatory effects of opioids involve similar receptor mechanisms. PMID- 17689050 TI - Chaotic pattern transitions in pulse neural networks. AB - In models of associative memory composed of pulse neurons, chaotic pattern transitions where the pattern retrieved by the network changes chaotically were found. The network is composed of multiple modules of pulse neurons, and when the inter-module connection strength decreased, the stability of pattern retrieval changed from stable to chaotic. It was found that the mixed pattern of stored patterns plays an important role in chaotic pattern transitions. PMID- 17689051 TI - Successful transcatheter closure of a postmyocardial infarction ventricular septal rupture in a patient rejected for cardiac surgery: usefulness of transesophageal echocardiography. AB - Acute ventricular septal rupture is a high-risk complication of myocardial infarction. Although early surgical treatment improves the prognosis of this condition, hospital mortality after emergency surgery ranges from 10% to 60%. Transcatheter closure is an established method of treating selected congenital septal defects; less experience exists regarding its usefulness for postmyocardial infarction ventricular septal defect. We report a case of successful transcatheter closure of a postmyocardial infarction ventricular septal defect with a septal occluder in a 71-year-old patient rejected for surgery. PMID- 17689052 TI - Live-wire-based segmentation using similarities between corresponding image structures. AB - A live-wire-based segmentation method that exploits similarities of corresponding object contours is presented. The method accelerates the segmentation process transferring anchor points of segmented reference contours to unsegmented target slices automatically. The target contours are created using the live-wire algorithm trained by features of the reference contours. An automatic contour correction improves the segmentation. Only few user interactions with an intuitive contour editor are necessary. The evaluation using intra- and interpatient transfer shows that 51-73% of interaction time can be saved compared to normal live-wire preserving the segmentation quality. PMID- 17689053 TI - Lack of support for the inability to taste phenylthiocarbamide as an endophenotypic marker in patients with schizophrenia and their first-degree relatives. AB - OBJECTIVE: This study sought to replicate recent findings that both patients and relatives are significantly more likely to be phenylthiocarbamide (PTC) nontasters than healthy controls, and that within the patient group, nontasters have more severe positive and/or negative symptoms than tasters. Associations between PTC-tasting status and olfactory identification scores also were examined. METHOD: PTC perception and olfactory identification were assessed in 48 patients with schizophrenia or schizoaffective disorder, 28 first-degree relatives, and 32 healthy volunteers. RESULTS: The three groups did not differ in PTC taste sensitivity. Findings did not change after: a sensitivity analysis that re-categorized participants who "possibly" tasted PTC, excluding Caucasian participants, or restricting the sample of patients to only those with schizophrenia. Among the patients, tasters and nontasters did not differ with regard to positive, negative, or general psychopathology symptoms. In the combined sample and the three groups separately, there were no associations between PTC-tasting status and olfactory identification scores. CONCLUSIONS: This study, conducted specifically as an attempt to replicate previously reported findings, failed to provide support for PTC perception as an endophenotypic marker for schizophrenia. Further research is warranted. PMID- 17689054 TI - What aspects of emotional functioning are impaired in schizophrenia? AB - Disturbances in emotional functioning are a major cause of persistent functional disability in schizophrenia. However, it is not clear what specific aspects of emotional functioning are impaired. Some studies have indicated diminished experience of positive affect in individuals with schizophrenia, while others have not. The current study assessed emotional responses by 34 individuals with schizophrenia and 35 demographically matched healthy participants to 131 images sampling a wide range of emotional arousal and valence levels. Ratings of affective response elicited by individual images were highly correlated across the groups (r's>.90), indicating similar emotional experiences at the moment of stimulus exposure. However, the data did not indicate strong relationships between ratings of the emotional impact of the images and most measures of day-to day emotional processing. These results demonstrate that individuals with schizophrenia report "normal" emotional responses to emotional stimuli, and thus suggests that deficits in emotional functioning associated with the disorder are likely to occur further downstream, and involve the effective integration of emotion and cognition for adaptive functioning in areas such as goal-setting, motivation, and memory. PMID- 17689055 TI - Flavonolignans from Silybum marianum moderate UVA-induced oxidative damage to HaCaT keratinocytes. AB - BACKGROUND: UV radiation from sunlight is a very potent environmental risk factor in the pathogenesis of skin cancer. Exposure to UV light, especially the UVA part, provokes the generation of reactive oxygen species (ROS), which induce oxidative stress in exposed cells. Topical application of antioxidants is a successful strategy for protecting the skin against UV-caused oxidative damage. OBJECTIVE: In this study, silybin (SB) and 2,3-dehydrosilybin (DS) (1-50 micromol/l), flavonolignan components of Silybum marianum, were tested for their ability to moderate UVA-induced damage. METHODS: Human keratinocytes HaCaT were used as an appropriate experimental in vitro model, to monitor the effects of SB and DS on cell viability, proliferation, intracellular ATP and GSH level, ROS generation, membrane lipid peroxidation, caspase-3 activation and DNA damage. RESULTS: Application of the flavonolignans (1-50 micromol/l) led to an increase in cell viability of irradiated (20 J/cm(2)) HaCaT keratinocytes. SB and DS also suppressed intracellular ATP and GSH depletion, ROS production and peroxidation of membrane lipids. UVA-induced caspases-3 activity/activation was suppressed by treatment with SB and DS. Lower concentrations of both compounds (10 micromol/l) significantly reduced cellular DNA single strand break formation. CONCLUSION: Taken together, the results suggest that these flavonolignans suppress UVA-caused oxidative stress and may be useful in the treatment of UVA-induced skin damage. PMID- 17689056 TI - Tricho-rhino-phalangeal type I syndrome and mental retardation: identification of a novel mutation in the TRPS1 gene. PMID- 17689057 TI - Paradoxical (REM) sleep genesis: the switch from an aminergic-cholinergic to a GABAergic-glutamatergic hypothesis. AB - In the middle of the last century, Michel Jouvet discovered paradoxical sleep (PS), a sleep phase paradoxically characterized by cortical activation and rapid eye movements and a muscle atonia. Soon after, he showed that it was still present in "pontine cats" in which all structures rostral to the brainstem have been removed. Later on, it was demonstrated that the pontine peri-locus coeruleus alpha (peri-LCalpha in cats, corresponding to the sublaterodorsal nucleus, SLD, in rats) is responsible for PS onset. It was then proposed that the onset and maintenance of PS is due to a reciprocal inhibitory interaction between neurons presumably cholinergic specifically active during PS localized in this region and monoaminergic neurons. In the last decade, we have tested this hypothesis with our model of head-restrained rats and functional neuroanatomical studies. Our results confirmed that the SLD in rats contains the neurons responsible for the onset and maintenance of PS. They further indicate that (1) these neurons are non cholinergic possibly glutamatergic neurons, (2) they directly project to the glycinergic premotoneurons localized in the medullary ventral gigantocellular reticular nucleus (GiV), (3) the main neurotransmitter responsible for their inhibition during waking (W) and slow wave sleep (SWS) is GABA rather than monoamines, (4) they are constantly and tonically excited by glutamate and (5) the GABAergic neurons responsible for their tonic inhibition during W and SWS are localized in the deep mesencephalic reticular nucleus (DPMe). We also showed that the tonic inhibition of locus coeruleus (LC) noradrenergic and dorsal raphe (DRN) serotonergic neurons during sleep is due to a tonic GABAergic inhibition by neurons localized in the dorsal paragigantocellular reticular nucleus (DPGi) and the ventrolateral periaqueductal gray (vlPAG). We propose that these GABAergic neurons also inhibit the GABAergic neurons of the DPMe at the onset and during PS and are therefore responsible for the onset and maintenance of PS. PMID- 17689058 TI - Lifestyle during and after cancer treatment. AB - The aim of this overview was to examine the evidence for links between lifestyle during and after cancer treatment and quality of life, risk of treatment side effects, rate of progression and prevention of relapse. The reviewed studies were divided into categories according to the role lifestyle plays in progression, during treatment, and in relapse prevention. The evaluated evidence was utilised to show potential lifestyle interventions to facilitate well-being and quality-of life initiatives. There is now persuasive evidence that dietary choice and exercise can improve the physical and psychological function of patients with cancer. There is also persuasive evidence that lifestyle choice can prevent cancer or the reoccurrence of cancer in susceptible individuals, and possibly improve survival. PMID- 17689059 TI - Effects of carvacrol upon the liver of rats undergoing partial hepatectomy. AB - The present study aims to investigate the possible effects of carvacrol obtained from origanum oil upon the regenerative feature of the liver subsequent to partial hepatectomy in rats. Male Wistar Albino rats, weighing 230+/-30g, were divided into three experiment groups. Group I (n=8) were used as sham operation group. Group II (n=8) were applied saline solution and hepatectomy. Carvacrol and hepatectomy (73mg/kg) were applied to Group III (n=8). One dose of test material was injected 1h before 68% partial hepatectomy. At the end of the experiments, blood and organs were removed. The liver regeneration rate of the rats was calculated measuring the weights of their liver before and after the hepatectomy. Hematoxylin and eosin, interleukin-6 (IL-6) and proliferating cell nuclear antigen (PCNA) treatments were applied to liver sections. Aspartate transaminase (AST), alanine transaminase (ALT), tumor necrosis factor-alpha (TNF-alpha) and IL 6 levels were determined in serum samples. The liver regeneration, mitotic index and PCNA index increased significantly in rats of Group III over the Group II at the 72nd hour after partial hepatectomy. Histological evaluations were also similar with these results of PCNA and mitotic indexes. In AST, ALT, TNF-alpha and IL-6 levels, there was no statistically significant difference. According to these results, it is concluded that carvacrol increases the liver regeneration rate. PMID- 17689060 TI - Chondroitin sulfate based niches for chondrogenic differentiation of mesenchymal stem cells. AB - Bone marrow-derived mesenchymal stem cells (MSCs) have strong potential in regeneration of musculoskeletal tissues including cartilage and bone. The microenvironment, comprising of scaffold and soluble factors, plays a pivotal role in determining the efficacy of cartilage tissue regeneration from MSCs. In this study, we investigated the effect of a three-dimensional synthetic biological composite hydrogel scaffold comprised of poly (ethylene glycol) (PEG) and chondroitin sulfate (CS) on chondrogenesis of MSCs. The cells in CS-based bioactive hydrogels aggregated in a fashion which mimicked the mesenchymal condensation and produced cartilaginous tissues with characteristic morphology and basophilic extracellular matrix production. The aggregation of cells resulted in an enhancement of both chondrogenic gene expressions and cartilage specific matrix production compared to control PEG hydrogels containing no CS-moieties. Moreover, a significant down-regulation of type X collagen expression was observed in PEG/CS hydrogels, indicating that CS inhibits the further differentiation of MSCs into hypertrophic chondrocytes. Overall, this study demonstrates the morphogenetic role of bioactive scaffold-mediated microenvironment on temporal pattern of cartilage specific gene expressions and subsequent matrix production during MSC chondrogenesis. PMID- 17689061 TI - Testing the organization of the immunological synapse. PMID- 17689062 TI - Allergic bronchopulmonary aspergillosis' diagnosis remains a challenge. AB - INTRODUCTION: Allergic bronchopulmonary aspergillosis (ABPA) is a complex disease, triggered by a hypersensitivity reaction to the allergens of Aspergillus fumigatus, a fungus that opportunistically colonizes the lungs of patients with asthma. The diagnosis of ABPA is difficult. A major problem is the lack of standardized allergens used in the determination of specific IgE, but the use of recombinant allergens has been proposed to overcome this. The aim of the present study is to evaluate whether serological tests for IgE specific to recombinant allergens of A. fumigatus (rAsp) can aid in the detection of sensitization to this fungus and in the diagnosis of ABPA. METHODS: This was an observational, cross-sectional study. The diagnosis of ABPA, using classical criteria, was searched in 65 asthmatics patients with immediate cutaneous reactivity to A. fumigatus. After that, serum titers of IgE against rAsp f 1, rAsp f 2, rAsp f 3, rAsp f 4 and rAsp f 6 were determined. In order to compare the differences between patients with confirmed and excluded diagnosis of ABPA, the two-tailed Fisher's exact test was used. RESULTS: Although 19 of 65 patients had IgE against at least one recombinant, the disease was diagnosed in only six patients by classical criteria. One of them had IgE against all recombinant allergens tested and another one had antibody against Asp f 3. DISCUSSION: The determination of serum IgE against recombinant A. fumigatus allergens in this group was not helpful to make the diagnosis of ABPA, neither to detect sensitization to fungus. PMID- 17689063 TI - Organellar proteomics to create the cell map. AB - The elucidation of a complete, accurate, and permanent representation of the proteome of the mammalian cell may be achievable piecemeal by an organellar based approach. The small volume of organelles assures high protein concentrations. Providing isolated organelles are homogenous, this assures reliable protein characterization within the sensitivity and dynamic range limits of current mass spec based analysis. The stochastic aspect of peptide selection by tandem mass spectrometry for sequence determination by fragmentation is dealt with by multiple biological replicates as well as by prior protein separation on 1-D gels. Applications of this methodology to isolated synaptic vesicles, clathrin coated vesicles, endosomes, phagosomes, endoplasmic reticulum, and Golgi apparatus, as well as Golgi-derived COPI vesicles, have led to mechanistic insight into the identity and function of these organelles. PMID- 17689065 TI - Selection of infectious medical waste disposal firms by using the analytic hierarchy process and sensitivity analysis. AB - While Taiwanese hospitals dispose of large amounts of medical waste to ensure sanitation and personal hygiene, doing so inefficiently creates potential environmental hazards and increases operational expenses. However, hospitals lack objective criteria to select the most appropriate waste disposal firm and evaluate its performance, instead relying on their own subjective judgment and previous experiences. Therefore, this work presents an analytic hierarchy process (AHP) method to objectively select medical waste disposal firms based on the results of interviews with experts in the field, thus reducing overhead costs and enhancing medical waste management. An appropriate weight criterion based on AHP is derived to assess the effectiveness of medical waste disposal firms. The proposed AHP-based method offers a more efficient and precise means of selecting medical waste firms than subjective assessment methods do, thus reducing the potential risks for hospitals. Analysis results indicate that the medical sector selects the most appropriate infectious medical waste disposal firm based on the following rank: matching degree, contractor's qualifications, contractor's service capability, contractor's equipment and economic factors. By providing hospitals with an effective means of evaluating medical waste disposal firms, the proposed AHP method can reduce overhead costs and enable medical waste management to understand the market demand in the health sector. Moreover, performed through use of Expert Choice software, sensitivity analysis can survey the criterion weight of the degree of influence with an alternative hierarchy. PMID- 17689064 TI - Ubiquitin-dependent sorting of integral membrane proteins for degradation in lysosomes. AB - The pathways that deliver newly synthesized proteins that reside in lysosomes are well understood on comparison with our knowledge of how integral membrane proteins are sorted and delivered to the lysosome for degradation. Many membrane proteins are sorted to lysosomes following ubiquitination, which provides a sorting signal that can operate for sorting at the TGN (trans-Golgi network), at the plasma membrane or at the endosome for delivery into lumenal vesicles. Candidate multicomponent machines that can potentially move ubiquitinated integral membrane cargo proteins have been identified, but much work is still required to ascertain which of these candidates directly recognize ubiquitinated cargo and what they do with cargo after recognition. In the case of the machinery required for sorting into the lumenal vesicles of endosomes, other functions have also been determined including a link between sorting and movement of endosomes along microtubules. PMID- 17689066 TI - Use of cardiac markers to assess the toxic effects of anthracyclines given to children with cancer: a systematic review. AB - AIM: To evaluate the effectiveness of cardiac markers to quantify anthracycline induced cardiotoxicity in children with cancer. METHODS: Systematic review using a priori methods. RESULTS: Seven studies, all with methodological limitations, were identified. One RCT suggests that cardiac troponin can be used to assess the effectiveness of the cardio-protective agent dexrazoxane. Cohort studies suggest that atrial natriuretic peptide and brain (B-type) natriuretic peptide are elevated in some subgroups of patients compared with healthy children; NT-pro-BNP levels are significantly elevated in children with cardiac dysfunction compared with those without; serum lipid peroxide is higher in children who have received doxorubicin compared with children not receiving doxorubicin; there are no differences in carnitine levels between children treated with doxorubicin and a healthy control group. CONCLUSIONS: The limited evidence makes conclusions difficult. Research is needed to fill this important evidence gap and link short term changes in cardiac markers to longer-term cardiac damage. PMID- 17689067 TI - S100A2-S100P expression profile and diagnosis of non-small cell lung carcinoma: impairment by advanced tumour stages and neoadjuvant chemotherapy. AB - Early and correct diagnosis of non-small cell lung carcinoma (NSCLC) is essential for the choice of an appropriate anti-cancer therapy. Besides the histopathological diagnosis, molecular profiling by detection of the tumour associated gene expression might play an upcoming role. As proteins of the S100 gene family show a distinct cell type-specific expression profile, our study focused on the relevance of the S100 family for identification and classification of NSCLCs. Among the S100 members, we identified the expression of S100A1, S100A2, S100A4, S100A6, S100A9 and S100P in human lung carcinoma cells (H358(p53 ), A549(p53+)) or NSCLC tissues. Distinct S100 members are increased in NSCLCs compared with control lung specimens depending on the histopathological subtype. In particular, S100A2 was upregulated in squamous cell carcinomas, whereas S100P was mainly increased in adenocarcinomas. The upregulation of either S100A2 or S100P was detected in early but less in advanced tumour stages and not at all in NSCLC patients who had received neoadjuvant chemotherapy. In conclusion, our study indicates an important role of the S100A2-S100P expression profile for molecular diagnosis of NSCLCs at early and, therefore, prognostically more favourable tumour stage. As the S100A2-S100P profile also allows the histopathological classification, it might significantly support the conventional tumour diagnostics. PMID- 17689068 TI - Pregnancy in women who had cancer in childhood. AB - The majority of female cancer survivors will have normal reproductive function and would be expected to have a successful pregnancy. For the minority of young women who have received significant cytotoxic insult to the reproductive organs and yet still manage to conceive, pregnancy must be considered a high risk condition and these patients should be managed by a multidisciplinary specialist team. Female survivors of childhood cancer who are able to become pregnant carry an excess risk of preterm delivery and low birth weight baby. This restricted foetal growth and inability of the uterus to carry the foetus to term is associated with radiation-induced damage to the uterus. Chemotherapy does not appear to be associated with adverse pregnancy outcomes. However, prospective follow-up of cohorts of patients treated with contemporary therapies, frequently involving more intensive therapies are required to determine the risk. A number of large multi-centre studies, are underway and will provide new insights into pregnancy outcomes in survivors of childhood cancer. PMID- 17689069 TI - PSA and other tissue kallikreins for prostate cancer detection. AB - Prostate cancer is the most common neoplasia of middle-aged men. Prostate specific antigen (PSA) is the first FDA-approved tumour marker for early detection of cancer and it is now in widespread clinical use. The discovery of different PSA molecular forms in serum (free PSA, PSA complexed with various protease inhibitors) in the early 1990s renewed clinical research to enhance the specificity of PSA. Also, the use of a homologous prostate-localised antigen, human glandular kallikrein 2 (KLK2) may further reduce the number of unnecessary prostate biopsies. More recently, promising data is emerging regarding molecular forms of free PSA (proPSA, BPSA, 'intact' PSA) and other members of the expanded human kallikrein family. These new findings may add substantial clinical information for early detection of prostate cancer. PMID- 17689070 TI - Translation procedures for standardised quality of life questionnaires: The European Organisation for Research and Treatment of Cancer (EORTC) approach. AB - BACKGROUND: The European Organisation for Research and Treatment of Cancer quality of life (EORTC QL) questionnaires are used in international trials and therefore standardised translation procedures are required. This report summarises the EORTC translation procedure, recent accomplishments and challenges. METHODS: Translations follow a forward-backward procedure, independently carried out by two native-speakers of the target language. Discrepancies are arbitrated by a third consultant, and solutions are reached by consensus. Translated questionnaires undergo a pilot-testing. Suggestions are incorporated into the final questionnaire. Requests for translations originate from the module developers, physicians or pharmaceutical industry, and most translations are performed by professional translators. The translation procedure is managed and supervised by a Translation Coordinator within the EORTC QL Unit in Brussels. RESULTS: To date, the EORTC QLQ-C30 has been translated and validated into more than 60 languages, with further translations in progress. Translations include all major Western, and many African and Asian languages. The following translation problems were encountered: lack of expressions for specific symptoms in various languages, the use of old-fashioned language, recent spelling reforms in several European countries and different priorities of social issues between Western and Eastern cultures. The EORTC measurement system is now registered for use in over 9000 clinical trials worldwide. CONCLUSIONS: The EORTC provides strong infrastructure and quality control to produce robust translated questionnaires. Nevertheless, translation problems have been identified. The key to improvements may lie in the particular features and strengths of the group, consisting of researchers from 21 countries representing 25 languages and include the development of simple source versions, the use of advanced computerised tools, rigorous pilot-testing, certification procedures and insights from a unique cross-cultural database of nearly 40,000 questionnaire responses. PMID- 17689072 TI - An experimental and theoretical approach to 5alpha-cholestan-6-spiro-1',2',4' triazolidine-3'-one. AB - The 5alpha-cholestan-6-one semicarbazone (1) on reaction with hydrogen peroxide at 0 degrees C affords selectively 5alpha-cholestan-6-spiro-1',2',4'-triazolidine 3'-one. (2) The structural assignment of the product was confirmed on the basis of its elemental, analytical and spectral analysis. The Hartree-Fock method using 6-31G* basis set was employed in order to explore the reaction mechanism. The results of the computational study show that the reaction proceeds through two radical intermediates formation. The different characteristics involved during the reaction were explained, firstly, the lower energy conformation of each molecule using total energy, hardness and dipole moment, and secondly, the explanation of the free radical mechanism, using frontier molecular orbital (FMO) theory, encoded electrostatic potential, spin electronic density and atomic charges. The localization of highest occupied molecular orbital (HOMO) or alpha HOMO, lowest unoccupied molecular orbital (LUMO) or alpha-LUMO and the flow of atomic charges are in good agreement to support the present mechanism of the reaction. Stability and feasibility of all the optimized structures were supported by their respective fundamental frequencies and energy minima. PMID- 17689071 TI - Human 3beta-hydroxysteroid dehydrogenase types 1 and 2: Gene sequence variation and functional genomics. AB - The 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4) isomerase isoenzymes 1 and 2 (HSD3B1 and HSD3B2) are membrane-bound enzymes that play essential roles in the biosynthesis of steroid hormones. Therefore, variation in the HSD3B1 and HSD3B2 genes might play a role in the pathophysiology of steroid hormone-related disease. We set out to systematically identify common polymorphisms and haplotypes in human HSD3B1 and HSD3B2. We identified 17 single nucleotide polymorphisms (SNPs) in HSD3B1 and 9 in HSD3B2 - the majority of which were not present in public databases - by resequencing human HSD3B1 and HSD3B2 using 240 DNA samples from four different ethnic groups (60 samples per group). Functional genomic studies of the five non-synonymous cSNPs in HSD3B1 and the one observed in HSD3B2 showed that two of these polymorphisms resulted in significant decreases in the quantity of enzyme protein expressed. However, none of the three non-synonymous SNPs located in areas encoding putative membrane-binding domains altered subcellular localization of the enzyme as determined by immunofluorescence microscopy. Finally, common variant haplotypes in the 5' flanking regions of these genes showed significant cell line-dependent variation in their ability to drive transcription. In aggregate, these results provide a basis for study of the possible role in human disease of common genetic variation in HSD3B1 and HSD3B2. PMID- 17689073 TI - Wilms tumor: progress and considerations for the surgeon. AB - Wilms tumor (WT) or nephroblastoma is the most common tumor of renal origin found in children. It accounts for 6% of all pediatric tumors and is the second most frequent intrabdominal solid organ tumor found in children. Initial survival rates in the early part of the last century was only 30%, but now long-term survival in both North America and European trials is approaching 85% with many low-stage tumors significantly higher. Treatment is now progressing towards "risk based management"- based not only on stage and histology but also incorporating genetic markers [Dome JS, Grundy PE, Perlman EJ, Ehrlich PF, et al. Protocols for the renal tumors study. Childrens Oncology Group. [www.childrensoncologygroup.org. 2007.]. Within the multidisciplinary treatment team the surgeon plays a critical role in the diagnosis, staging and the surgeon's technical skills and judgment directs therapy and impacts outcome. The next generation of treatment for children with WT will focus on identifying subsets of patients who can be defined by some criterion as having a different outcome than their similar stage peers and who therefore require a variation in management. These include children with WT that have unsatisfactory long-term survival (less then 75%), patients of good survival but high potential for late effects and a final challenge are those children with both a poor survival and a high potential for late effects. This article presents a review of the most recent treatment considerations for WT with a focus on the surgeon's role to ensure a good outcome. PMID- 17689074 TI - The manufacture of particleboards using mixture of peanut hull (Arachis hypoqaea L.) and European Black pine (Pinus nigra Arnold) wood chips. AB - This research was conducted to investigate the suitability of peanut hull to produce general purpose particleboards. A series of panels were produced using peanut hull and mixture of peanut hull and European Black pine wood chips. Particleboards were manufactured using various hull ratios in the mixture (0%, 25%, 50%, 75% and 100%). Urea formaldehyde adhesive was utilized in board production and boards were produced to target panel's density of 0.7 g/cm3. Panels were tested for some physical (water absorption and thickness swelling), chemical (holocellulose content, lignin content, alcohol-benzene solubility, 1% NaOH solubility, hot water solubility and cold water solubility) and mechanical (modulus of rupture, modulus of elasticity and internal bond) properties. The main observation was that increase in peanut hull in the mixture resulted in a decrease in mechanical and physical properties of produced panels and panel including 25% hull in the mixture solely met the standard required by TS-EN 312 standard. Conclusively, a valuable renewable natural resource, peanut hull could be utilized in panel production while it has been mixed to the wood chips. PMID- 17689075 TI - Pentamer is the minimum structure for oligomannosylpeptoids to bind to concanavalin A. AB - Enzyme-linked lectin assay (ELLA) was performed for oligomannosylpeptoids, which were immobilized on microtiter plates through a streptavidin-biotin interaction. The other immobilization methods, a hydrophobic adsorption and a covalent attachment, were found inapplicable to the oligomannosylpeptoids. Penta- and hexamannosylpeptoids with a shorter or longer spacer were found to be significantly recognized by concanavalinA (ConA), while the smaller peptoids showed no bindings. A proportional relationship between the amount of bound ConA and the peptoid density on the microtiter plate was observed, indicating the absence of both cluster and overdense effects that would assist or inhibit the binding increasingly with the ligand density. PMID- 17689076 TI - Synthesis and antibacterial activity of some novel chiral fluorophoric biscyclic macrocycles. AB - Synthesis of chiral permanent fluorophoric biscyclic macrocycles incorporating anthraquinone and (S)-BINOL core is described. Interestingly, the biscyclic macrocycle 1 exhibited remarkable antibacterial activity against most of the pathogenic bacteria in the tested concentrations as compared to the other three compounds 2, 14 and 17 as well as the test control, tetracycline. Further biscyclophanes 1 and 2 exhibited permanent fluorescence sensing property even under highly acidic conditions. PMID- 17689077 TI - Identification of Sansalvamide a analog potent against pancreatic cancer cell lines. AB - Thirty-one Sansalvamide A peptide derivatives were synthesized. (3)H thymidine inhibition assays were performed using two pancreatic cancer cell lines (PL45 and BxPC-3). Six compounds possess 140-fold increased differential selectivity for cancer cell lines over normal cell lines (WS1, skin fiberblasts) and are 140 times more active against pancreatic cancer cell lines than compounds used clinically to treat these cancers (e.g., 5-FU). Structure-activity relationship studies show the inclusion of a single N-methyl and/or d-amino acid appears to be critical for presenting the active conformation of the six San A peptide derivatives to their biological target(s). PMID- 17689078 TI - Pyrazolo[3,4-d]pyrimidines as potent inhibitors of the insulin-like growth factor receptor (IGF-IR). AB - A high throughput screen of Abbott's compound repository revealed that the pyrazolo[3,4-d]pyrimidine class of kinase inhibitors possessed moderate potency for IGF-IR, a promising target for cancer chemotherapy. The synthesis and subsequent optimization of this class of compounds led to the discovery of 14, a compound that possesses in vivo IGF-IR inhibitory activity. PMID- 17689079 TI - Dual acting antioxidant A1 adenosine receptor agonists. AB - Herein we report the synthesis and biological evaluation of some potent and selective A(1) adenosine receptor agonists, which incorporate a functionalised linker attached to an antioxidant moiety. N(6)-(2,2,5,5-Tetramethylpyrrolidin-1 yloxyl-3-ylmethyl)adenosine (VCP28, 2e) proved to be an agonist with high affinity (K(i)=50nM) and good selectivity (A(3)/A(1) > or = 400) for the A(1) adenosine receptor. N(6)-[4-[2-[1,1,3,3-Tetramethylisoindolin-2-yloxyl-5 amido]ethyl]phenyl]adenosine (VCP102, 5a) has higher binding affinity (K(i)=7 nM), but lower selectivity (A(3)/A(1)= approximately 3). All compounds bind weakly (K(i)>1 microM) to A(2A) and A(2B) receptors. The combination of A(1) agonist activity and antioxidant activity has the potential to produce cardioprotective effects. PMID- 17689080 TI - Cyclonatsudamine A, a new vasodilator cyclic peptide from Citrus natsudaidai. AB - A new cyclic heptapeptide, cyclonatsudamine A (1), cyclo (-Gly-Tyr-Leu-Leu-Pro Pro-Ser-), has been isolated from the peels of Citrus natsudaidai and the structure was elucidated by 2D NMR analysis and chemical degradation. Cyclonatsudamine A (1) relaxed norepinephrine-induced contractions of rat aorta, which may be mediated through the increased release of NO from endothelial cells. PMID- 17689081 TI - Inter-professional working in the RAF Critical Care Air Support Team (CCAST). AB - OBJECTIVE: To understand working relationships between doctors and nurses in the (UK) Royal Air Force (RAF). METHODS: Qualitative, semi-structured interviews. SAMPLE: Six nurses and five anaesthetists from the RAF Critical Care Air Support Team were interviewed. FINDINGS: A variety of factors had an effect on inter professional dynamics between anaesthetists and nurses within CCAST. DISCUSSION: The military setting makes this relationship different from that which has been observed in the National Health Service (NHS) and reported in the literature. An area which had not been analysed before in terms of doctor-nurse relationships debate is the issue of personality. This research shows it to be a significant issue in this relationship, for both groups of professionals. PMID- 17689082 TI - Health is yearning--experiences of being conscious during ventilator treatment in a critical care unit. AB - The aim of this study was to investigate experiences of being conscious during ventilator treatment in the ICU from a patient perspective. Hermeneutic, phenomenological methods were used. Eight patients who had received ventilator treatment were interviewed. The time on a ventilator varied from 1 day to several months. Some patients had been more heavily sedated during the acute phase while some were only lightly sedated and others had no sedation at all. The motor activity assessment scale was used to rate the sedation level. The patients had been sufficiently conscious to communicate with the help of the alphabet board, by means of facial expression or by nodding or shaking their head. The results show that the experience of care by patients who were conscious during ventilator treatment was described under the headings of: memories, mastering the situation and individual consequences. Health in the ICU is associated with yearning. The patient undergoes different stages of yearning as part of his or her recovery process. The patient who is conscious during ventilator treatment views him/herself and his/her worth on the basis of the attitude and behaviour of the caregivers, where the value of caring consists of the holistic confirmation of individual suffering. PMID- 17689083 TI - Connectivity of an effective hypothalamic surgical target for cluster headache. AB - The purpose of this study was to look at the connectivity of the posterior inferior hypothalamus in a patient implanted with a deep brain stimulating electrode using probabilistic tractography in conjunction with postoperative MRI scans. In a patient with chronic cluster headache we implanted a deep brain stimulating electrode into the ipsilateral postero-medial hypothalamus to successfully control his pain. To explore the connectivity, we used the surgical target from the postoperative MRI scan as a seed for probabilistic tractography, which was then linked to diffusion weighted imaging data acquired in a group of healthy control subjects. We found highly consistent connections with the reticular nucleus and cerebellum. In some subjects, connections were also seen with the parietal cortices, and the inferior medial frontal gyrus. Our results illustrate important anatomical connections that may explain the functional changes associated with cluster headaches and elucidate possible mechanisms responsible for triggering attacks. PMID- 17689084 TI - Angiotensinogen gene polymorphism as a risk factor for ischemic stroke. AB - While gene polymorphism for angiotensinogen (AGT) is reported to contribute to the regulation of blood pressure and salt sensitivity, its effect on the risk of ischemic stroke remains controversial. We hypothesized that polymorphism of the AGT gene could be a risk factor for ischemic stroke. Major clinical risk factors and the AGT gene M235T polymorphism were examined in 147 consecutive stroke patients and 133 healthy age-matched controls. All patients were categorized into four stroke types (single lacuna, multiple lacunae, large-artery atherosclerosis and branch atheromatous disease in brainstem) and two vascular groups (large and perforating arterial lesions). The AGT gene M allele significantly increased the risk of single lacuna, multiple lacunae and small arterial lesions, in male patients (p=0.029, 0.031 and 0.026, respectively). Synergistic effects of the AGT gene polymorphism and clinical risks were not observed. In conclusion, AGT M allele may present a risk of lacunar infarctions in Japanese men, independent of hypertension. PMID- 17689085 TI - Combined autologous chondrocyte implantation and allogenic meniscus transplantation: a biological knee replacement. AB - Meniscus deficient knees develop early osteoarthritis in the knee. Autologous Chondrocyte Implantation has provided a new dimension to the treatment of chondral defects in the knee, with 85% good to excellent results and a long-term durable outcome of up-to 11 years. However, it is contraindicated in meniscus deficient knees. Allogenic Meniscus Transplantation gives good symptomatic relief in meniscus deficient knees, with a success rate of 89%. However, it is contraindicated in advanced cartilage degeneration. We hypothesized that combination of these two might be a solution for bone-on-bone arthritis in young individuals. We studied a consecutive series of eight patients, with mean age of 43 years, presenting with large kissing chondral defects, secondary to the previous meniscectomy. All the patients were treated with a combination of Autologous Chondrocyte Implantation and Allogenic Meniscus Transplantation. Mean pre-operative Lysholm score was 49, which rose to mean of 66 at 1 year, an average increase by 16.4 points. Six patients showed significant improvement at one year. MRI scans showed good integration of the menisci with the capsule, without any rejection. Histology confirmed the integration. All the patients could lead an active life-style. Five patients maintained the improvement at a mean follow-up of 3.2 years. We could not find any deleterious effects of the combination of these two techniques. So we conclude that the combination of these two techniques together may act a one step towards a true biological knee replacement. PMID- 17689086 TI - QSAR studies on the activation of the human carbonic anhydrase cytosolic isoforms I and II and secretory isozyme VI with amino acids and amines. AB - The first QSAR study on the activation of the human secretory isoform of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), CA VI, with a series of amines and amino acids is reported. A large set of topological indices have been used to obtain several tri-/tetra-parametric models. We compared the CA VI activating QSAR models with those calculated for activation of the cytosolic human isozymes hCA I and hCA II. In addition, the effect of D- and L-amino acids as activators of hCA I, hCA II and of hCA VI as compared to those of structurally related biogenic amines was investigated for obtaining statistically significant and predictive QSAR equations. The obtained models are discussed using a variety of statistical parameters. The best models were obtained for hCA II activation, followed by hCA I, whereas the QSAR models for the activation of hCA VI were statistically weaker. PMID- 17689087 TI - Microscopical investigations of nisin-loaded nanoliposomes prepared by Mozafari method and their bacterial targeting. AB - Nanoencapsulation may improve activity of protein or polypeptide antimicrobials against a variety of microorganisms. In this study, nanoliposomes prepared from different lipids (Phospholipon 90H, Phospholipon 100H, dipalmitoylphosphatidylcholine (DPPC), stearylamine (SA), dicetyl phosphate (DCP) and cholesterol) by a new, non-toxic and scalable method, were tested for their capacity to encapsulate nisin Z and target bacteria (Bacillus subtilis and Pseudomonasaeruginosa). Factors affecting the entrapment efficiency (charge and cholesterol concentration in the vesicles) and stability of nanoliposomes were assessed. The nanoliposomes and their bacterial targeting were visualised, using different microscopes under air and liquid environments. Nisin was entrapped in different nanoliposomes with encapsulation efficiencies (EE) ranging from 12% to 54%. Anionic vesicles possessed the highest EE for nisin while increase in cholesterol content in lipid membranes up to 20% molar ratio resulted in a reduction in EE. Stability of nanoliposome-encapsulated nisin was demonstrated for at least 14 months at 4 degrees C (DPPC:DCP:CHOL vesicles) and for 12 months at 25 degrees C (DPPC:SA:CHOL vesicles). PMID- 17689088 TI - Inducible NO synthase expression in endomyocardial biopsies after heart transplantation in relation to the postoperative course. AB - OBJECTIVE: Ischemia and reperfusion during heart transplantation cause damage to cardiomyocytes and endothelial cells and may initiate later acute rejection. Free oxygen radicals generated by iNOS are widely accepted to be responsible for ischemic injury. Increased iNOS expression on cardiac tissue may represent a more intensive tissue injury during ischemia and reperfusion in heart transplantation. The aim of this study was, therefore, to test the hypothesis that increased iNOS expression in early postoperative endomyocardial biopsies correlates with rejection or infection episodes in the later postoperative course. PATIENTS AND METHODS: Right ventricular endomyocardial biopsies were obtained from heart transplantation recipients at transplantation and during the first 2 weeks postoperatively. The recipients were divided into three groups depending on the postoperative course during the first year after transplantation: patients in group 1 had an uncomplicated postoperative course, patients in group 2 developed significant signs of postoperative infection, while patients in group 3 presented with acute rejection (< or =grade 2R ISHLT). The expression was analyzed in a semi-quantitative score. RESULTS: iNOS expression was found in cardiomyocytes, endothelial cells, infiltrating cells, and vascular smooth muscle cells. At the time of heart transplantation, the expression was significantly increased in the rejection group compared to the other groups. This increase was even more pronounced in week 2. CONCLUSIONS: The present study shows that an increased iNOS expression at the time of heart transplantation could precede an acute rejection in the later postoperative course. Thus, measurements of iNOS expression may be of predictive value for an increased rejection risk and therefore offer the possibility of earlier therapeutic intervention. PMID- 17689089 TI - The external reinforcement of the aortic wall: a futile attempt. PMID- 17689090 TI - Tracheoesophageal fistula and tracheo-subclavian artery fistula after tracheostomy. AB - Tracheoesophageal fistula and tracheo-arterial fistula are both uncommon but life threatening complications after a tracheostomy. The most common source of a major hemorrhage is from the tracheo-innominate artery fistula. Most tracheo-arterial fistulas occur within the first 3 weeks after tracheostomy. We describe a very rare case of a patient who developed both a tracheoesophageal fistula and massive hemorrhage from a tracheo-left subclavian artery fistula 4 months after a tracheostomy procedure. PMID- 17689091 TI - Ascending-to-descending aortic extra-anatomic graft. PMID- 17689092 TI - Increased level of cytokines and matrix metalloproteinases in osteoarthritic subchondral bone. AB - OBJECTIVE: The aim of this study was to investigate the expression of several cytokines, matrix metalloproteinases (MMPs), and tissue inhibitor of matrix metalloproteinases (TIMP)-1 in osteoarthritis (OA) and control sera and different joint tissues. METHODS: Serum, synovial fluid, cartilage, synovial and subchondral bone tissues were examined in OA and control subjects. The protein level of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, IL-8, IL-10 and MMP-2, MMP-3, MMP-9, and TIMP-1 were measured by immunoanalysis. RESULTS: Serum levels of TNF-alpha, MMP-3 and -9 were significantly higher in OA patients than in controls. Conversely, serum IL-10 was decreased in OA patients. CRP was elevated when compared to healthy controls and decreased significantly 6 months after the surgery. In contrast to control samples, OA cartilage and synovium revealed significantly higher MMP-2, -3, -9 and IL-10. IL-1alpha was significantly higher in OA cartilage and IL-8 in OA synovium. Interestingly, MMP 3, -9, TIMP-1 and all tested cytokines were up-regulated in OA subchondral bone. DISCUSSION: This study demonstrates pro-inflammatory condition of OA pathology and supports the idea that vascularized subchondral region may increase the synthesis of cytokines and MMPs leading to degradation of adjacent cartilage. PMID- 17689093 TI - A systematic evaluation of chip-based nanoelectrospray parameters for rapid identification of proteins from a complex mixture. AB - HPLC-MS/MS is widely used for protein identification from gel spots and shotgun fractions. Although HPLC has well recognized benefits, this type of sample infusion also has some undesirable attributes: relatively low sample throughput, potential sample-to-sample carryover, time-varying sample composition, and no option for longer sample infusion for longer MS analyses. An automated chip-based ESI device (CB-ESI) has the potential to overcome these limitations. This report describes a systematic evaluation of the information-dependant acquisition (IDA) and sample preparation protocols for rapid protein identification from a complex mixture using a CB-ESI source compared with HPLC-ESI (gradient and isocratic elutions). Cytochrome c and a six-protein mixture (11-117 kDa) were used to develop an IDA protocol for rapid protein identification and to evaluate the effects of sample preparation protocols. MS (1-10 s) and MS/MS (1-60 s) scan times, sample concentration (50-500 fmol/microL), and ZipTipC(18) cleanup were evaluated. Based on MOWSE scores, protein coverage, experimental run time, number of identified proteins, and reproducibility, a 12.5 min experiment (22 cycles, each with one 3 s MS and eight 10 s MS/MS scans) was determined to be the optimal IDA protocol for CB-ESI. This work flow yielded up to 220% greater peptide coverage compared with gradient HPLC-ESI and provided protein identifications with up to a 2-fold higher throughput rate than either HPLC-ESI approach, whilst employing half the amount of sample over the same time frame. The results from this study support the use of CB-ESI as a rapid alternative to the identification of protein mixtures. PMID- 17689094 TI - Reaction of naphthalene-2,3-dicarboxaldehyde with enkephalins for LC-fluorescence and LC-MS analysis: conformational studies by molecular modeling and H/D exchange mass spectrometry. AB - A new labeling method compatible with both laser-induced fluorescence (LIF) and MS detection for enkephalins, which uses naphthalene-2,3-dicarboxaldehyde (NDA) and a new nucleophilic agent (N,N-dimethylaminoethanethiol) is described. When the derivative is separated via reverse phase HPLC and detected via MS, two different peaks with similar exact mass but different fluorescence and fragmentation properties are obtained. To interpret these results, molecular modeling and H/D exchange mass spectrometry studies were investigated to test the hypothesis that the peak obtained by LC/LIF/MS analysis depends on the site of protonation of the labeled enkephalins. The peptides labeled with NDA and N,N dimethylaminoethanethiol were separated on a reverse phase C18 column with a gradient of aqueous 0.1% formic acid and acetonitrile. In mass spectrometry, two peaks are observed with the same exact mass for each molecule while only one peak is detected using fluorescence. Tandem mass spectrometry experiments of ion m/z 809.5 were performed on each chromatographic peak; the first peak (which is not observed by LIF detection) gives a fragment corresponding to the loss of the aminothiol side chain while no fragmentation is observed on the second peak, which was detected by fluorescence. The hypothesis is that each peak represents the labeled enkephalin with different sites of protonation. According to this hypothesis, three fundamental conformations that were closed to the unlabeled leucine-enkephalin were obtained by molecular modeling: a beta-turn like conformation with two hydrogen bonds, a 3(10)-helix with an H bond, and finally, the extended form without any intramolecular interactions. H/D exchange mass spectrometry experiments with D(2)O and d(2-)formic acid as eluent was used to determine which conformation is involved in each peak. PMID- 17689095 TI - Peptide Shifter: enhancing separation reproducibility using correlated expression profiles. AB - Chromatographic protein and peptide separation technologies enable comprehensive proteomic analysis of plasma and other complex biological samples by mass spectrometry. However, as the number of separations and/or fractions increases, so does the number of peptides split across fraction boundaries. Irreproducibility of peptide chromatographic separation results in peptides on or near the boundary moving partially or entirely into adjacent fractions. Peptide shifting across fraction boundaries increases the variability of measured peptide abundance, and so there is a trade-off between proteomic comprehensiveness using separation technologies and accurate quantitative proteomic measurements. In this paper, a method for detecting and correcting split peptides, called Peptide Shifter, is introduced and evaluated. An essential component of Peptide Shifter is a global peptide expression profile analysis that allows the inference of the underlying peptide shift pattern without the use of peptide labeling or internal standards. A controlled proteomic analysis of plasma samples demonstrates a 34% decrease in peptide intensity variability after the application of Peptide Shifter. PMID- 17689096 TI - Mechanisms for the proton mobility-dependent gas-phase fragmentation reactions of S-alkyl cysteine sulfoxide-containing peptide ions. AB - Mechanisms for the gas-phase fragmentation reactions of singly and multiply protonated precursor ions of the model S-alkyl cysteine sulfoxide-containing peptides GAILCGAILK, GAILCGAILR, and VTMGHFCNFGK prepared by reaction with iodomethane, iodoacetamide, iodoacetic acid, acrylamide, or 4-vinylpyridine, followed by oxidation with hydrogen peroxide, as well as peptides obtained from an S-carboxyamidomethylated and oxidized tryptic digest of bovine serum albumin, have been examined using multistage tandem mass spectrometry, hydrogen/deuterium exchange and molecular orbital calculations (at the B3LYP/6-31 + G(d,p) level of theory). Consistent with previous reports, CID-MS/MS of the S-alkyl cysteine sulfoxide-containing peptide ions resulted in the dominant "non-sequence" neutral loss of an alkyl sulfenic acid (XSOH) from the modified cysteine side chains under conditions of low proton mobility, irrespective of the alkylating reagent employed. Dissociation of uniformly deuterated precursor ions of these model peptides determined that the loss of alkyl sulfenic acid in each case occurred via a "charge-remote" five-centered cis-1,2 elimination reaction to yield a dehydroalanine-containing product ion. Similarly, the charge state dependence to the mechanisms and product ion structures for the losses of CO(2), CO(2) + H(2)O and CO(2) + CH(2)O from S-carboxymethyl cysteine sulfoxide-containing peptides, and for the losses of CH(2)CHCONH(2) and CH(2)CHC(5)H(4)N, respectively, from S amidoethyl and S-pyridylethyl cysteine sulfoxide-containing peptide ions have also been determined. The results from these studies indicate that both the proton mobility of the peptide precursor ion and the nature of the S-alkyl substituent have a significant influence on the abundances and charge states of the product ions resulting from the various competing fragmentation pathways. PMID- 17689097 TI - Atmospheric pressure photoionization proton transfer for complex organic mixtures investigated by fourier transform ion cyclotron resonance mass spectrometry. AB - To further clarify the role of dopant solvent in proton transfer in atmospheric pressure photoionization (APPI), we employ ultrahigh-resolution FT-ICR mass analysis to identify M(+*), [M + H](+), [M - H](-), and [M + D](+) species in toluene or perdeuterotoluene for an equimolar mixture of five pyrrolic and pyridinic nitrogen heterocyclic model compounds, as well as for a complex organic mixture (Canadian Athabasca bitumen middle distillate). In the petroleum sample, the protons in the [M + H](+) species originate primarily from other components of the mixture itself, rather than from the toluene dopant. In contrast to electrospray ionization, in which basic (e.g., pyridinic) species protonate to form [M + H](+) positive ions and acidic (e.g., pyrrolic) species deprotonate to form [M - H](-) negative ions, APPI generates ions from both basic and acidic species in a single positive-ion mass spectrum. Ultrahigh-resolution mass analysis (in this work, m/Deltam(50%) = 500,000, in which Deltam(50%) is the mass spectral peak full width at half-maximum peak height) is needed to distinguish various close mass doublets: (13)C versus (12)CH (4.5 mDa), (13)CH versus (12)CD (2.9 mDa), and H(2) versus D (1.5 mDa). PMID- 17689098 TI - HLA-G expression in malignant melanoma. AB - Both, the expression of HLA-G (a non-classical HLA class I molecule) and the loss of classical HLA class I molecules enable tumor cells to evade from immunosurveillance of the host. Whereas HLA-G down-modulates the immune functions of all cells participating in the immune defence mechanisms, defects on HLA class I expression result in the resistance of tumor cells to cytotoxic T lymphocytes attacks. This contribution reviews the HLA-G expression pattern in malignant melanoma lesions, its correlation to the loss of classical HLA class I antigens, and new aspects of HLA-G regulation. PMID- 17689099 TI - Expression in periplasmic space of Shewanella oneidensis. AB - A Shewanella expression system has been used for an overproduction of c-type multiheme proteins. The proteins were exported to the periplasmic space for the maturation. Since the periplasmic expression system is attractive, especially for protease-sensitive proteins, an expression vector containing a signal peptide was constructed for expressions in the periplasmic space of Shewanella oneidensis. To evaluate the system, two eukaryotic proteins which originally do not have signal sequences and are difficult to express in Escherichia coli, were selected. The first is human cytochrome c. Properties of the recombinant cytochrome c were identical to those previously reported, indicating the protein is intact. The other was potato calcium-dependent protein kinase. The protein was expressed in periplasmic space. These results indicated that the system is generally applicable for any protein expression including c-type cytochromes, protease sensitive proteins and those with multi-disulfide bonds because of transportation to the periplasmic space. PMID- 17689100 TI - The multisensory perception of flavor. AB - Following on from ecological theories of perception, such as the one proposed by [Gibson, J. J. (1966). The senses considered as perceptual systems. Boston: Houghton Mifflin] this paper reviews the literature on the multisensory interactions underlying the perception of flavor in order to determine the extent to which it is really appropriate to consider flavor perception as a distinct perceptual system. We propose that the multisensory perception of flavor may be indicative of the fact that the taxonomy currently used to define our senses is simply not appropriate. According to the view outlined here, the act of eating allows the different qualities of foodstuffs to be combined into unified percepts; and flavor can be used as a term to describe the combination of tastes, smells, trigeminal, and tactile sensations as well as the visual and auditory cues, that we perceive when tasting food. PMID- 17689101 TI - WSPM: wavelet-based statistical parametric mapping. AB - Recently, we have introduced an integrated framework that combines wavelet-based processing with statistical testing in the spatial domain. In this paper, we propose two important enhancements of the framework. First, we revisit the underlying paradigm; i.e., that the effect of the wavelet processing can be considered as an adaptive denoising step to "improve" the parameter map, followed by a statistical detection procedure that takes into account the non-linear processing of the data. With an appropriate modification of the framework, we show that it is possible to reduce the spatial bias of the method with respect to the best linear estimate, providing conservative results that are closer to the original data. Second, we propose an extension of our earlier technique that compensates for the lack of shift-invariance of the wavelet transform. We demonstrate experimentally that both enhancements have a positive effect on performance. In particular, we present a reproducibility study for multi-session data that compares WSPM against SPM with different amounts of smoothing. The full approach is available as a toolbox, named WSPM, for the SPM2 software; it takes advantage of multiple options and features of SPM such as the general linear model. PMID- 17689102 TI - Electrophysiological neural mechanisms for detection, configural analysis and recognition of faces. AB - Despite ample explorations the nature of neural mechanisms underlying human expertise in face perception is still undetermined. Here we examined the response of two electrophysiological signals, the N170 ERP and induced gamma-band activity (>20 Hz), to face orientation and familiarity across two blocks, one in which the face identity was task-relevant and one in which it was not. N170 amplitude to inverted faces was higher than to upright faces and was not influenced by face familiarity or its task relevancy. In contrast, induced gamma activity was higher for upright than for inverted faces and for familiar than unfamiliar faces. The effect of face inversion was found in lower gamma frequency band (25-50 Hz), whereas familiarity affected amplitudes in higher gamma frequency band (50-70 Hz). For gamma, the relevance of face identity to the task modulated both inversion and familiarity effects. These findings pinpoint three functionally dissociated neural mechanisms involved in face processing, namely, detection, configural analysis, and recognition. PMID- 17689103 TI - Comprehension of implicit meanings in social situations involving irony: a functional MRI study. AB - To understand implicit social meanings, the interaction of literal meanings and relevant information in a situational context is important. However, previous studies have not investigated such contextual interactions. Using functional magnetic resonance imaging (fMRI), we investigated cortical mechanisms underlying the processing of implicit meanings, particularly irony, in realistic social situations, focusing on contextual interactions. Healthy subjects were shown pictures depicting daily communicative situations during judgment tasks involving situational appropriateness and literal correctness. The left medial prefrontal cortex showed significantly greater activation during tasks involving situational judgments than during literal judgments. The right temporal pole was activated task-independently during irony-specific processing. The medial orbitofrontal cortex was activated task-dependently during irony processing in situational judgment tasks. These regions have been reported to be involved in theory of mind, and have not been implicated in previous studies on the linguistic processing of implicit meanings. This suggests that the intentional assessment of situational appropriateness for task execution is carried out in the left medial prefrontal cortex, whereas irony is processed in the right temporal pole by assessing situational context automatically, and is judged based on the situational context in the medial orbitofrontal cortex. Our results show that the processing of implicit meanings and irony in contextually rich situations depends on brain mechanisms involved in the "theory of mind," based on processing relevant information in a situational context, and suggest different functions in each region. PMID- 17689104 TI - MR diffusion changes correlate with ultra-structurally defined axonal degeneration in murine optic nerve. AB - Diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI) are widely used to investigate central nervous system (CNS) white matter structure and pathology. Changes in principal diffusivities parallel and perpendicular to nerve fibers or axonal tracts have been associated with axonal pathology and de/dysmyelination respectively. However, the ultra-structural properties and the pathological alterations of white matter responsible for diffusivity changes have not been fully elucidated. We examined the relationship between the directional diffusivities and ultra-structural properties in mouse optic nerve using healthy animals, and mice with optic neuritis (ON) that exhibited marked inflammatory changes and moderately severe axonal pathology. Progressive axonal degeneration in ON resulted in a 23% reduction of parallel diffusivity as detected by diffusion MRI (P<10(-5)), but no change in perpendicular diffusivity. Parallel diffusion changes were highly correlated with the total axolemmal cross-sectional area in the pre-chiasmal portion of the optic nerve (r=0.86, P<0.001). This study provides quantitative evidence that reduced parallel diffusivity in the optic nerve correlates significantly with axolemmal cross-sectional area reductions. MRI-based assessment of axonal degeneration in murine ON is feasible and potentially useful for monitoring of neuro-protective therapies in preclinical trials in animals. PMID- 17689105 TI - Regional grey matter abnormalities in juvenile myoclonic epilepsy: a voxel-based morphometry study. AB - Visual assessment of structural MRI is, by definition, normal in patients with juvenile myoclonic epilepsy (JME), a major subsyndrome of idiopathic generalized epilepsy (IGE). However, recent quantitative MRI studies have shown structural abnormalities in cortical and thalamic grey matter (GM) in JME. Voxel-based morphometry (VBM) is a fully automated, unbiased, operator-independent MRI analysis technique that detects regionally specific differences in brain tissue composition on a voxel-wise comparison between groups of subjects. Using VBM, we examined structural differences in cortical and subcortical GM volume (GMV) between 25 JME patients (15 women, mean age=22.7+/-5.1 years) and age- and sex matched 44 control subjects (27 women, mean age=23.1+/-4.3 years). We also performed a correlation analysis to delineate a possible relationship between the GMV increases or reductions and the increasing duration of epilepsy. Group comparison showed GMV increases in the superior mesiofrontal region bilaterally and GMV reductions in the thalamus bilaterally in JME patients (P<0.05, corrected for multiple comparisons using false discovery rate). Correlation analysis revealed that bilateral thalamic GMV had negative correlations with the duration of epilepsy (P<0.05, corrected for multiple comparisons after small volume corrections; P<0.05, Pearson correlation test). Our findings of GMV increases in the superior mesiofrontal regions and progressive thalamic atrophy could further support the pathophysiological concept of the functional abnormalities in thalamocortical circuit in JME. PMID- 17689106 TI - Large, well-established departments who carry out paediatric work on a daily basis did not receive the questionnaire. PMID- 17689108 TI - Protective role of carnitine in breast cancer via decreasing arginase activity and increasing nitric oxide. AB - Breast cancer remains one of the most common types of cancer. High levels of arginase and ornithine in different carcinomas may indicate their relation to cancer. Carnitine is a cofactor required for the transformation of free long chain fatty acids into acetyl-carnitines. We have examined the protective effect of carnitine and the possibility that it disturbs arginase-nitric oxide (NO) interaction. Histopathological examination, arginase activity, ornithine and NO levels were determined in tumour tissues. Mitotic cells significantly decreased in the treatment group. Tissue arginase activity and ornithine levels decreased significantly with carnitine. NO levels were significantly higher in the treatment group. One of the possible mechanisms of carnitine's protective role in tumour progression might be its promotion of NO. This mechanism could decrease the production of tumour-promoting agents, polyamines, and increase the production of NO, thereby exerting a protective effect on cancer development. PMID- 17689109 TI - In vivo dedifferentiation of human epidermal cells. AB - Consistent with our previous study, we herein offer further evidence to demonstrate the dedifferentiation of differentiating epidermal cells into stem cells or stem cells -like in vivo. The epidermal sheets eliminated of basal cells were labeled with 6-diamidino-2-phenylindole (DAPI), and then were transplanted onto the full-thickness skin wounds nude mice. Immunohistochemical examination of the survival sheets showed that some cells were positive for both DAPI and either cytokeratins (CK19, CK14) or beta1 integrin in spinous and granular layers at day 7 after transplantation. Furthermore, there was a significant increase in the percentages of both alpha6briCDdim and alpha6briCD71bri populations in survival epidermal sheet grafts 7 d after transplantation compared with those before xenotransplantation (P<0.05), as determined by flow cytometry. The results collectively indicated that some of the differentiated cells in engrafted epidermal sheets dedifferentiated into stem cells or stem cells-like in vivo, which offer us new evidence and insights into the dedifferentiation. PMID- 17689110 TI - Culture of osteogenic cells from human alveolar bone: a useful source of alkaline phosphatase. AB - The aim of this study was to obtain membrane-bound alkaline phosphatase from osteoblastic-like cells of human alveolar bone. Cells were obtained by enzymatic digestion and maintained in primary culture in osteogenic medium until subconfluence. First passage cells were cultured in the same medium and at 7, 14, and 21 days, total protein content, collagen content, and alkaline phosphatase activity were evaluated. Bone-like nodule formation was evaluated at 21 days. Cells in primary culture at day 14 were washed with Tris-HCl buffer, and used to extract the membrane-bound alkaline phosphatase. Cells expressed osteoblastic phenotype. The apparent optimum pH for PNPP hydrolysis by the enzyme was pH 10.0. This enzyme also hydrolyzes ATP, ADP, fructose-1-phosphate, fructose-6-phosphate, pyrophosphate and beta-glycerophosphate. PNPPase activity was reduced by typical inhibitors of alkaline phosphatase. SDS-PAGE of membrane fraction showed a single band with activity of approximately 120 kDa that could be solubilized by phospholipase C or Polidocanol. PMID- 17689111 TI - Operative intervention for carotid restenosis is safe and effective. AB - Carotid stenting has been proposed as an alternative to reoperative carotid endarterectomy (rCEA) for recurrent carotid stenosis. The purpose of this study is to prove the safety, effectiveness and durability of reoperation in long term follow up of 18 years in a community hospital setting. From March 1988 to April 2005 80 patients, 46 men and 34 women (mean age: 64.1 years) underwent a total of 83 operations. Symptomatic recurrent stenosis (>70%) was the indication in 32, asymptomatic high-grade stenosis (>80%) in 49, intimal flap in one and fibromuscular dysplasia (F.M.D), in one. The initial operation was carotid endarterectomy with primary closure in 60 and prosthetic patch in 23. The mean recurrences were at 23.3 months in 33 with myointimal hyperplasia, 105.4 months in 29 with recurrent atherosclerosis, 61.4 months in 19 with both hyperplasia and atherosclerosis, 2 months in one with intimal flap and 8 months in one with F.M.D bands. Reoperation utilized primary closure (3), vein patch (14), prosthetic patch (55), Gore-Tex interposition grafts (7), vein interposition grafts (3) and intraoperative dilation (1). No perioperative strokes or deaths occurred. One patient died from cardiac complications following combined rCEA and coronary artery bypass grafting. Operative morbidity consisted of reversible nerve injury (5), irreversible recurrent laryngeal nerve injury (1) and hematoma requiring evacuation (3). During follow up (3-153 months; mean: 50.9) carotid occlusion resulted in mild ipsilateral stroke in one patient, and one non-hemispheric stroke. There were 26 late deaths due to all causes, one due to CVA. Eight patients required reoperation (mean 53.4 months). Seven of these were hypertensive. Kaplan-Meier analysis of long-term follow up shows relatively high stroke free rates; at 153 months (12.75 years) the hemispheric stroke free rate was 98.67% and the all-stroke free rate was 95.85%. The survival estimate following redo surgery was 69.97% at 5 years and 40.23% at 10 years. We found that individuals on statin therapy (p-value=0.0042), and those on combination of statin and aspirin (p-value=0.0320), had significantly increased interval between primary and secondary operation. Increased age was correlated to a decreased time to redo surgery (p-value=<0.0001). We conclude that reoperation for recurrent carotid stenosis using standard vascular techniques is safe, effective, durable and cost effective. It should continue to be the mainstay of treatment when secondary intervention is required. Statins have a salutary effect on durability of the procedure and should be used when indicated. PMID- 17689112 TI - Effects of percutaneous transluminal angioplasty and endovascular brachytherapy on vascular remodeling of human femoropopliteal artery: 2 years follow-up by noninvasive magnetic resonance imaging. AB - OBJECTIVES: We aimed to assess in vivo the long-term effects of percutaneous transluminal angioplasty (PTA) and endovascular brachytherapy (EVBT) on vessel wall by serial MRI. METHODS: Twenty patients with symptomatic stenosis of the femoropopliteal artery were randomly assigned to PTA (n=10) or PTA+EVBT (n=10, 14Gy by gamma-source). High-resolution MRI was performed prior, at 24-hours, 3 months, and 24-months after intervention. MRI data were analyzed by an independent, blinded observer. RESULTS: The effects of both procedures on vessel wall at 24-hours and 3-months have been reported. Despite similar percent decrease in lumen area between 3- and 24-months in both groups (-8% for PTA and 11% for PTA+EVBT), at 24-months lumen area gain compared to baseline was +30% in PTA versus +82% in PTA+EVBT (p<0.05). Total vessel area, which was increased at 24-hours and 3-months, returned to pre-treatment value in both groups. CONCLUSIONS: We demonstrated non-invasively that restenosis and inward remodeling after PTA are delayed by EVBT. At 24-months, patients treated with brachytherapy have larger lumen than those treated with PTA alone. The decrease in luminal and total vessel area between 3- and 24-months after EVBT indicates that the restenotic and remodeling process is not abolished but delayed with this therapy. PMID- 17689113 TI - Long term outcome for extra-anatomic arch reconstruction. An analysis of 143 procedures. AB - PURPOSE: With the FDA approval of thoracic endografts, extra-anatomic reconstruction of the aortic arch has allowed for more suitable proximal landing zones and increased applicability of thoracic endovascular procedures. We evaluated our short term and long term results of extra-anatomic reconstruction of the carotid and subclavian vessels. METHODS: One hundred and forty three (143) procedures were performed for extra-anatomic carotid and subclavian reconstruction. Of these 143 operations: 85 were carotid subclavian reconstructions, 22 were carotid crossover bypasses, 30 were subclavian carotid reconstructions and 6 were carotid subclavian transpositions. Sixty (42%) were male, 20 (14%) were diabetic, and 63 (44%) were current smokers. Mean age was 63 (SD +/- 12.3). Indication for surgery was primarily for occlusive or embolic disease (97%). In those patients undergoing bypass graft, prosthetic (ePTFE) was used in 93%. Follow-up was performed at 3 and 6 month intervals by ultrasound and pulse volume recordings where indicated. Life table analyses were used to analyze patency. RESULTS: Of the 143 reconstructions operative mortality was 1 (0.7%). Non-fatal complications included 3 (2.1%) for bleeding, 1 (0.7%) wound infection, 2 (1.4%) TIA, 1 (0.7%) suffered a non-fatal stroke, 2 (1.4%) had postoperative myocardial infarctions, and 6 (4.3%) late (>30-day) occlusions. Follow-up was 1 to 124 months (mean: 39 months). Primary patency at 1 year was 98%, 3 years 96%, and 5 years was 92%. CONCLUSION: Extra-anatomic arch reconstruction can be performed safely and appears to be durable over long term follow-up. Its use with endovascular grafting should provide a durable reconstruction for patients who require aortic "debranching" prior endovascular thoracic aortic aneurysm repair. PMID- 17689114 TI - Misdiagnosed fibrosarcoma of the mandible mimicking temporomandibular disorder: a rare condition. AB - The jawbones can be sites of various neoplastic conditions. Given the variety of processes affecting this particular anatomical area, formulation of a precise diagnosis can be challenging to clinicians. Limited jaw movement, pain, and facial asymmetry are common signs among patients, especially those with temporomandibular disorder (TMD). This paper reports a case of primary fibrosarcoma affecting the mandible and surrounding structures in a 14-year-old girl presenting signs and symptoms similar to TMD. Her condition was misdiagnosed, and she was treated for TMD over an extended period before the correct diagnosis was made for fibrosarcoma. The patient underwent surgical resection with postsurgical radiotherapy and chemotherapy and now is being followed up. Although malignant lesions are rare in the temporomandibular joint (TMJ) region, dentists are advised to be aware of the condition and to keep in mind that patients who are admitting for TMD can also possibly be affected from neoplasms. Hence, those patients have to be examined meticulously to avoid misdiagnosis and mistreatment. PMID- 17689116 TI - Trigeminal autonomic cephalalgias. Part 3: short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. AB - Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) is a syndrome characterized by severe, strictly unilateral short-lasting (between 5 and 240 seconds) pain localized to orbital, supraorbital, and temporal areas, accompanied by ipsilateral conjunctival injection and lacrimation. It represents 1 of 3 primary headaches classified as trigeminal autonomic cephalalgias (TACs). Although its prevalence is extremely small, SUNCT patients may present at dental offices seeking relief for their pain. It is important for oral health care providers to recognize SUNCT and render an accurate diagnosis. This will avoid the pitfall of implementing unnecessary and inappropriate traditional dental treatments in hopes of alleviating this neurovascular pain. The following article is part 3 of a review on TACs and focuses on SUNCT. Aspects of SUNCT, including epidemiology, genetics, pathophysiology, clinical presentation, classification and variants, diagnosis, medical management, and dental considerations are discussed. PMID- 17689115 TI - Duration-dependent susceptibility of endodontic pathogens to calcium hydroxide and chlorhexidene gel used as intracanal medicament: an in vitro evaluation. AB - The aim of this study was to evaluate the effective duration of antimicrobial activity of a calcium hydroxide-based medicament (Apex Cal) and 2% chlorhexidene gluconate gel against selected endodontic pathogens (Enterococcus faecalis, Candida albicans, Porphyromonas gingivalis, and Prevotella intermedia). The agar diffusion test was used to determine the antimicrobial activity. Chlorhexidene gluconate gel showed the largest inhibitory zones. The antimicrobial action of both medicaments decreased significantly with time, with calcium hydroxide showing no antimicrobial action after 72 hours. In conclusion, 2% chlorhexidene gel showed better antimicrobial activity than calcium hydroxide, and the effective antimicrobial action of both medicaments decreased after 48 hours. PMID- 17689117 TI - Assessment of mandibular buccal and lingual cortical bones in postmenopausal women. AB - OBJECTIVE: Correlations between the widths of mandibular cortical bones and the bone mineral density (BMD) of the spine were analyzed to evaluate the influence of the general bone condition. STUDY DESIGN: Thirty postmenopausal women were enrolled in this investigation. The widths of cortical bones in sites of the mental foramen and the BMD of the mandibular cancellous bone were measured using multislice computerized tomography (CT) images. The BMD of the lumbar spine was measured using dual-energy x-ray absorptiometry, and the ratio to the young adult mean (YAM) was obtained. RESULTS: A weak correlation between the widths of cortical bones and the ratio to the YAM was observed. Also, correlations between the widths of cortical bones and the BMD of the mandible were noted. CONCLUSION: The widths of buccal and lingual cortical bones in the mesial and distal sites of the mental foramen measured on axial CT images do not serve as a reliable examination for the BMD of the lumbar spine. PMID- 17689118 TI - An application of virtual microscopy in the teaching of an oral and maxillofacial pathology laboratory course. AB - OBJECTIVE: The aim of this study is to share the experience of establishing a virtual microscope and telepathology system for the oral and maxillofacial pathology laboratory course in a dental school. STUDY DESIGN: A dot-slide system has been used to generate digitized microscopic slides, which are placed on an image server that is available online. RESULTS: Using software that is available as a free download (OlyVIA), students are able to select a teaching slide record, view at magnifications comparable with those of a conventional microscope, and navigate to any area on the matching virtual slide image that is stored on the image server database. Before class, the students can review the findings of the virtual teaching slides at any time or any place via broadband internet by using the instructions available on DVD. During class, students report and discuss the histological findings of the virtual teaching slides with tutors who evaluate, test, and make constructive comments on the presentations in a Web-based computer classroom. After class, students can revise the histological findings of the microscopic virtual slides available on the server. CONCLUSIONS: Virtual microscopy has many advantages over real microscopy in oral and maxillofacial pathology education. Furthermore, telepathology could also be applied in other pathological services, such as intraoperative frozen sections, routine surgical pathology, and subspecialty consultation. PMID- 17689120 TI - Chronotherapeutics in a psychiatric ward. AB - Psychiatric chronotherapeutics is the controlled exposure to environmental stimuli that act on biological rhythms in order to achieve therapeutic effects in the treatment of psychiatric conditions. In recent years some techniques (mainly light therapy and sleep deprivation) have passed the experimental developmental phase and reached the status of powerful and affordable clinical interventions for everyday clinical treatment of depressed patients. These techniques target the same brain neurotransmitter systems and the same brain areas as do antidepressant drugs, and should be administered under careful medical supervision. Their effects are rapid and transient, but can be stabilised by combining techniques among themselves or together with common drug treatments. Antidepressant chronotherapeutics target the broadly defined depressive syndrome, with response and relapse rates similar to those obtained with antidepressant drugs, and good results are obtained even in difficult-to-treat conditions such as bipolar depression. Chronotherapeutics offer a benign alternative to more radical treatments of depression for the treatment of severe depression in psychiatric wards, but with the advantage of rapidity of onset. PMID- 17689119 TI - The role of STAT, AP-1, E-box and TIEG motifs in the regulation of hepcidin by IL 6 and BMP-9: lessons from human HAMP and murine Hamp1 and Hamp2 gene promoters. AB - Hepcidin, the principal regulator of the iron metabolism, is up-regulated in response to inflammatory stimuli, bone morphogenic proteins (BMPs) and iron excess. There are two murine hepcidin genes: hepcidin-1 (Hamp1) and hepcidin-2 (Hamp2). Hamp1 gene responds to both IL-6 and BMPs while Hamp2 responds to neither. We replaced the putative functional regulatory motifs of the Hamp1 promoter with the corresponding putative "non-functional" Hamp2 motifs and vice versa in reporter constructs. Conversion of the Hamp1 STAT site into the Hamp2 site reduced the basal level of reporter expression but did not affect IL-6 and BMP responsiveness; replacing Hamp2 site with the Hamp1 site only resulted in partial responsiveness. These data are in contrast to the role of the STAT site in the human hepcidin promoter which is important in both basal level and IL-6 inducible promoter activity. The murine AP1, E-box and TIEG motifs were found to neither influence the basal level of expression of Hamp1 and HAMP promoters nor play a critical role in the IL-6 and BMP-9 induced response. Our data suggest that the STAT site (nt -148 to -130) is important for the regulation of basal level expression of Hamp1 but there are additional regions that are responsible for the IL-6 and BMP-9 responsiveness within the Hamp1 promoter. PMID- 17689121 TI - On NUFFT-based gridding for non-Cartesian MRI. AB - For MRI with non-Cartesian sampling, the conventional approach to reconstructing images is to use the gridding method with a Kaiser-Bessel (KB) interpolation kernel. Recently, Sha et al. [L. Sha, H. Guo, A.W. Song, An improved gridding method for spiral MRI using nonuniform fast Fourier transform, J. Magn. Reson. 162(2) (2003) 250-258] proposed an alternative method based on a nonuniform FFT (NUFFT) with least-squares (LS) design of the interpolation coefficients. They described this LS_NUFFT method as shift variant and reported that it yielded smaller reconstruction approximation errors than the conventional shift-invariant KB approach. This paper analyzes the LS_NUFFT approach in detail. We show that when one accounts for a certain linear phase factor, the core of the LS_NUFFT interpolator is in fact real and shift invariant. Furthermore, we find that the KB approach yields smaller errors than the original LS_NUFFT approach. We show that optimizing certain scaling factors can lead to a somewhat improved LS_NUFFT approach, but the high computation cost seems to outweigh the modest reduction in reconstruction error. We conclude that the standard KB approach, with appropriate parameters as described in the literature, remains the practical method of choice for gridding reconstruction in MRI. PMID- 17689122 TI - Changes in beta 2-adrenoceptor and other signaling proteins produced by chronic administration of 'beta-blockers' in a murine asthma model. AB - BACKGROUND: We have previously reported that chronic treatment with certain 'beta blockers' reduces airway hyperresponsiveness (AHR) to methacholine in a murine model of asthma. METHODS: Airway resistance was measured using the forced oscillation technique in ovalbulmin-sensitized and ovalbulmin-challenged mice treated with several beta-adrenoceptor (beta-AR) ligands. We used the selective beta 2-AR ligand ICI 118,551 and the preferential beta 1-AR ligand metoprolol to investigate the receptor subtype mediating the beneficial effect. Expression of beta-ARs was evaluated using immunofluorescence. We evaluated several signaling proteins by western blot using lung homogenates, and measured the relaxation of the isolated trachea produced by EP2 and IP receptor agonists. RESULTS: Four findings were associated with the decreased AHR after chronic beta-blocker treatment: (1) the highly selective beta 2-AR antagonist/inverse agonist, ICI 118,551 produced the bronchoprotective effect; (2) beta 2-AR up-regulation resulted from chronic 'beta-blocker' treatment; (3) reduced expression of certain proteins involved in regulating bronchial tone, namely, Gi, phosphodiesterase 4D and phospholipase C-beta 1; and (4) an enhanced bronchodilatory response to prostanoid agonists for the IP and EP2 receptors. CONCLUSIONS: These data suggest that in the murine model of asthma, several compensatory changes associated with either increased bronchodilator signaling or decreased bronchoconstrictive signaling, result from the chronic administration of certain 'beta-blockers'. PMID- 17689123 TI - Stable isotope variability in tissues of the Eurasian perch Perca fluviatilis. AB - Stable isotope analysis is frequently used as a complementary method of dietary analysis, to describe trophic relationships and assess food-web structure. These studies allow a precise determination, based on the calculation of a diet-tissue fractionation factor. The fractionation factor, determined for whole organisms or specific tissues, may vary substantially in natura. In the present study, delta13C and delta15N were assessed in lipid-free tissues (spleen, liver, viscera, scales, gills, spine, white muscle, brain) and in available energy reserves (proteins, glycogen, lipids) of Eurasian perch (Perca fluviatilis) reared under controlled conditions and fed for 4 months with the same artificial diet. Some discrepancies in delta15N and delta13C data were observed among tissues, respectively up to 3.43 per thousand and 2.54 per thousand for delta15N and delta13C. The 15N signature in organs depends on their metabolic activity. Despite a significant delta13C enrichment from feed to tissues, the lipids in spine, liver and viscera exhibit a certain stability. PMID- 17689124 TI - The role of the type I insulin-like growth factor receptor (IGF-IR) in glomerular integrity. AB - Insulin-like growth factors (IGFs) have been implicated in normal mammalian kidney development. To confirm a role for the IGF system in podocyte and glomerular integrity, we generated a transgenic mouse that expresses a dominant negative type 1 IGF receptor (IGF-IR) and determined the structural and functional consequences. Using a 4.25kb fragment of the murine nephrin promoter, the dominant-negative construct was expressed exclusively in the kidney, confirmed by Southern blot and RT-PCR analysis. IGF-Ir486(FLAGstop) protein localized specifically to the glomerular podocyte based on FLAG immunohistochemistry and on co-localization with nephrin and podocin. Wild type and transgenic glomeruli expressed both the alpha- and beta-subunits of the endogenous IGF-IR, with normal expression of both nephrin and podocin. Although the animals were viable and phenotypically normal, histological analysis of the kidneys revealed abnormal and small glomeruli with dilated glomerular capillaries and condensed podocyte nuclei, while ultra-structural examination revealed diffuse but segmental podocyte foot process broadening, fusion, and effacement. Explanted glomeruli from transgenic animals demonstrated a significant inhibition of podocyte cell outgrowth when compared to controls. These studies suggest that IGF signaling is essential for maintaining the integrity of the podocyte and that alterations of IGF signaling may play a role in progressive glomerular disease. PMID- 17689125 TI - Glycogen storage disease type IX: High variability in clinical phenotype. AB - Glycogen storage disease type IX (GSD type IX) results from a deficiency of hepatic phosphorylase kinase activity. The phosphorylase kinase holoenzyme is made up of four copies of each of four subunits (alpha, beta, gamma and delta). The liver isoforms of the alpha-, beta- and gamma-subunits are encoded by PHKA2, PHKB and PHKG2, respectively. Mutation within these genes has been shown to result in GSD type IX. The diagnosis of GSD type IX is complicated by the spectrum of clinical symptoms, variation in tissue specificity and severity, and its inheritance, either X-linked or autosomal recessive. We investigated 15 patients from 12 families with suspected GSD type IX. Accurate diagnosis had been hampered by enzymology not being diagnostic in five cases. Clinical symptoms included combinations of hypoglycaemia, hepatosplenomegaly, short stature, hepatopathy, weakness, fatigue and motor delay. Biochemical findings included elevated lactate, urate and lipids. We characterised causative mutations in the PHKA2 gene in ten patients from eight families, in PHKG2 in two unrelated patients and in the PHKB gene in three patients from two families. Seven novel mutations were identified in PHKA2 (p.I337X, p.P498L, p.P869R, p.Y116_T120dup, p.R1070del, p.R916W and p.M113I), two in PHKG2 (p.L144P and p.H48QfsX5) and two in PHKB (p.Y419X and c.2336+965A>C). There was a severe phenotype in patients with PHKG2 mutations, a mild phenotype with patients PHKB mutations and a broad spectrum associated with PHKA2 mutations. Molecular analysis allows accurate diagnosis where enzymology is uninformative and identifies the pattern of inheritance permitting counselling and family studies. PMID- 17689126 TI - Prognostic factors in metastatic nasopharyngeal carcinoma. AB - BACKGROUND: The current retrospective study aimed to identify some determinants of survival in metastatic NPC. METHODS: The study concerned 95 patients with metastatic nasopharyngeal carcinoma treated between 1993 and 2001. Statistical comparison between patients subgroups survival was carried out employing the log Rank test (statistical significance was defined as p45 years and25 years), gender, performance status at diagnosis of metastatic disease (PS 0-1 or 2-3), time of metastasis diagnosis(at presentation or later), number of metastatic sites (single or multiple), specific metastatic sites(bone, liver, lung, distant nodes), number of bone metastasis (single or multiple), disease free survival (DFI) (6 months), prior chemotherapy, radiotherapy of metastatic sites. RESULTS: Negative prognostic factors in univariate analysis were: poor PS (>or=1), multiple metastatic sites, multiple bone metastasis, previous chemotherapy, visceral or node metastasis and non irradiated metastasis. Poor PS, multiple metastatic sites, and prior chemotherapy were independently significant negative prognostic factors in multivariable analysis. CONCLUSIONS: In this study we identified new prognostic factors in univariate and multivariate analysis. A regular and careful follow-up of patients treated for NPC is then recommended in order to detect early metastatic dissemination (with minimal localizations) while patients have still a good PS. PMID- 17689128 TI - Serum ghrelin levels but not GH, IGF-1 and IGFBP-3 levels are altered in patients with fibromyalgia syndrome. AB - INTRODUCTION: Both hypothalamo-pituitary-insulin-like growth factor-1 (IGF-1) axis and ghrelin levels may be altered in fibromyalgia syndrome (FMS) due to increased somatostatin tone. The aim of this study is to compare hypothalamo pituitary-IGF-1 axis, ghrelin concentrations and their relations in premenopausal women with FMS and premenopausal healthy controls. METHODS: Seventy-five women (47 FMS and 28 healthy women) were enrolled in the study. Fasting plasma glucose, serum growth hormone (GH), insulin, C-peptide, IGF-1, insulin-like growth factor binding protein-3 (IGFBP-3) and ghrelin levels were measured. Depressive symptoms were assessed using beck depression inventory. Pain intensity and sleep disturbance were recorded on a visual analog scale. The activity of daily living was assessed by fibromyalgia impact questionnaire. RESULTS: There were no significant differences in GH, IGF-1, IGFBP-3, glucose, insulin, and C-peptide levels between patients and controls (p>0.05), whereas ghrelin levels were significantly lower in patients than controls (p<0.05). Ghrelin levels were not correlated with GH, IGF-1, IGFBP-3, glucose, insulin, and C-peptide levels while they were positively correlated with tender point score and sleep disturbance score and negatively correlated with pain intensity score. CONCLUSION: Our results suggest that low levels of ghrelin in FMS are not related to the changes in hypothalamo-pituitary-IGF-1 axis but may be related to some symptoms of FMS. Our results need to be clarified by further studies. PMID- 17689127 TI - [Expression of c-kit in North African nasopharyngeal carcinomas: correlation with age and LMP1]. AB - PURPOSE: To determine the level and prognostic significance of c-kit expression in the two age groups of North African nasopharyngeal carcinomas. PATIENTS AND METHODS: A retrospective study of 99 NPC specimens from Tunisian patients was investigated by immunohistochemistry. Immunohistochemical data were correlated with Epstein-Barr virus LMP1 expression and pathological, clinical and survival parameters. RESULTS: c-kit was detected in 79% of the cases for patients under 30 years of age (juvenile form) but in only 56% of specimens in patients over 30 years (P=0.039) and was significantly over-expressed for patients with lymph node involvement (P=0.015). LMP1 score was 5.78 (+/-1.84) for c-kit negative tumors compared to 8,23 (+/-2.39) for c-kit positive tumors (P=0.002). Multivariate analysis including age, lymph nodes involvement and LMP1 expression as co variables, showed that only age (P=0.027) and LMP1 expression (P=0.005) were significantly correlated to the c-kit expression. CONCLUSION: c-kit is highly expressed in the juvenile form of North African nasopharyngeal carcinomas. There is a significant association between LMP1 and c-kit expression. The contrasted levels of C-kit expression in the two age groups strengthen the hypothesis that these clinical forms result from distinct oncogenic mechanisms. PMID- 17689129 TI - [Why the placenta should not be too quickly discarded]. PMID- 17689130 TI - Glucose regulated proteins 78 protects insulinoma cells (NIT-1) from death induced by streptozotocin, cytokines or cytotoxic T lymphocytes. AB - Endoplasmic reticulum stress-mediated apoptosis plays an important role in the destruction of pancreatic beta-cell, and contributes to the development of type 1 diabetes. The chaperone molecule, glucose regulated proteins 78 (GRP78), is required to maintain ER function during toxic insults. In this study, we investigated the effect of GRP78 on the beta-cell apoptosis. We first measured GRP78 protein expression in different phase of streptozotocin-affected beta-cell by immunoblotting analysis. An insulinoma cell line, NIT-1, transfected with GRP78 was established, named NIT-GRP78, and used to study apoptosis, which was induced by streptozotocin or inflammatory cytokines. Apoptosis of NIT-1 or NIT GRP78 cells was detected by flow cytometry, the transcription of C/EBP homologous protein (CHOP) was monitored by real-time PCR, the concentration of nitric oxide and the activity of superoxide dismutase were measured by colorimetric method. We found that, in comparison to NIT-1 cells, NIT-GRP78 cells responded to the streptozotocin or cytokines treatments with decreased concentration of nitric oxide, but increased activity of superoxide dismutase. In addition, the level of CHOP was also decreased in the NIT-GRP78 cells, which may mediate the resistance of the GRP78 overexpressed NIT-1 cells from apoptosis. Finally, we found that NIT GRP78 cells were also more resistant than NIT-1 cells to cytotoxic T lymphocyte (CTL) specific killing detected by flow cytometry through target cells expressing green fluorescent protein cultured with effector cells and finally stained with propidium iodide. The data suggest that modulating GRP78 expression could be useful in preventing pancreatic beta-cell from the immunological destruction in type 1 diabetes individuals. PMID- 17689131 TI - The mitogen-activated protein kinase p38 regulates activator protein 1 by direct phosphorylation of c-Jun. AB - The involvement of p38 in fundamental physiological processes and the fact that deregulation often leads to disease indicates the potential impact of p38 dependent mechanisms. Here we demonstrate a new pathway that includes the induction of the mitogen activated protein kinase p38 by protein kinase C and results in a specific phosphorylation of c-Jun in T-lymphocytes. P38 directly phosphorylates c-Jun within its transactivation domain at serine 63 and serine 73 and thus posttranscriptionally affects the presence of DNA-bound phosphorylated c Jun, a prerequisite for activator protein 1 dependent gene transcription. Moreover, DNA-binding activity of c-Fos, FosB, and JunB were also dependent on the p38 protein kinase activity, whereas JunD, Fra-1 and Fra-2 were not affected. Although we show that stress induced mitogen activated protein kinases share c Jun as a substrate for phosphorylation, p38 mediated effects could not be rescued by the c-Jun N-terminal kinases. This demonstrates that the protein kinase p38 plays a unique and non-redundant role in posttranslational c-Jun regulation. The induction of a p38 dependent c-Jun phosphorylation was comparable in both CD4(+) and CD8(+) T-cells, proposing a ubiquitous pathway that is not linked to T-cell subtype and effector function. In contrast, ATF-2 was predominantly phosphorylated in CD8(+) T-cells. Different cell lines show p38-dependent c-Jun phosphorylation upon phorbol ester induction but there is evidence that the simian virus 40 large T-antigen may interfere with this pathway. PMID- 17689133 TI - The application of a computerised videokeratography (CVK) based contact lens fitting software programme on irregularly shaped corneal surfaces. AB - PURPOSE: To explore the success of the application of a computerised videokeratography (CVK) software system for the fitting of rigid gas permeable (RGP) contact lenses (CLs) on irregular corneal surfaces and compare it to the standard diagnostic fitting procedure. METHODS: This was a comparative prospective study, over a 1-year period (2004-2005). It included 41 RGP CL wearers (68 eyes) with irregular corneal surfaces. Of these, 51 (75%) had keratoconus, 7 (10%) corneal scarring (infectious or traumatic), 6 (6.82%) corneal transplants, 2 (2.9%) astigmatism, and 2 (2.9%) aphakia. Each eye was being re-fitted with a new RGP CL based on a topographical measurement in conjunction with a CL fitting software programme. The performance of the CLs was evaluated regarding visual outcome, fitting characteristics, and efficiency of the fitting procedure. RESULTS: Of the 68 eyes, 53 (77.94%) chose the CL fitted using the CVK software system, 9 (13.24%) chose the CL fitted using the standard procedure, and 6 (8.82%) showed no preference for either CL. There was a statistically significant improvement regarding visual outcome [contrast sensitivity at the spatial frequencies of 0.66 (p=0.029), 3.40 (p=0.008), and 17 (p=0.032), subjective vision (p=0.009)], fitting characteristics [grading scale (p=0.00), lens comfort (p=0.00) and daily wearing time (p=0.002)], and efficiency [number of trial lenses required (p=0.00)] with the CL fitted using the CVK software system. Correlating factors for the likely preference for the CL fitted using the CVK software system were subjective vision (p=0.004), lens comfort (p=0.009), and convenience of the fitting procedure (p=0.023). CONCLUSION: The application of a CVK software system for the fitting procedure of RGP CLs on irregular corneal surfaces was a safe procedure and shown to be more successful and efficient than the standard diagnostic fitting method. PMID- 17689132 TI - Viral defense, carcinogenesis and ISG15: novel roles for an old ISG. AB - Recent studies have established that type I interferon modulates expression of large number of cellular genes. While the proteins encoded by some of these genes have a direct antiviral activity, the functions of the majority of the others have not yet been determined. One of the first identified IFN stimulated gene, encodes ubiquitin like protein ISG15 that is also expressed in response to different stress stimuli. Although it was shown that ISG15 functions as protein modifier, it has been only recently that the targets of ISG15 conjugation were identified. Recent studies have also revealed mechanism of ISG15 conjugation and its interaction with the ubiquitin conjugation pathway. This review is focused on the possible role of ISG15 in the antiviral response, regulation of cell growth and carcinogenesis. PMID- 17689134 TI - Promoter hypermethylation of CCNA1, RARRES1, and HRASLS3 in nasopharyngeal carcinoma. AB - In search for putative tumor suppressor genes critical of nasopharyngeal carcinoma (NPC), we analyzed the available information from the expression profiling in conjunction with the comprehensive alleotyping published data relevant to this malignancy. Integration of this information suggested eight potential candidate tumor suppressor genes, CCNA1, HRASLS3, RARRES1, CLMN, EML1, TSC22, LOH11CR2A and MCC. However, to confirm the above observations, we chose to investigate if promoter hypermethylation of these candidate genes would be one of the mechanisms responsible for the de-regulation of gene expression in NPC in addition to the loss of genetic materials. In this study, we detected consistent hypermethylation of the 5' element of CCNA1, RARRES1, and HRASLS in NPC tissues with prevalence of 48%, 51%, and 17%, respectively. Moreover, we found a similar profile of promoter hypermethylation in primary cultured NPC cells but none in normal nasopharyngeal epithelium or leukocytes, which further substantiate our hypothesis. Our data indicate that CCNA1, RARRES1, and HRASLS3 may be the putative tumor suppressor genes in NPC. PMID- 17689135 TI - Ameloblastic fibroma: a review of published studies with special reference to its nature and biological behavior. AB - To further elucidate confusions with respect to the nature and biological behavior of ameloblastic fibroma (AF), available English-language literature since its first description in 1891 was reviewed. A total number of 123 cases with well-documented follow-up data were retrieved to evaluate various clinical, pathological and behavioral aspects of this tumor. AF tends to occur in the first two decades (89/123; 72.4%), but patients older than 22 years are not uncommon (30 cases). An overall recurrence rate of 33.3% (41 cases) is identified in reported cases who were treated by conservative (91.5%) and radical (8.5%) methods. Malignant transformation is evident in 14 recurrent tumors with an overall transformation rate of 11.4%. These data support the view that majority of AFs are true neoplasms. However, a small number of AFs occurring in childhood may represent the primitive stage of a developing odontoma, as three of the reported recurrent AFs do show further maturation with formation of dental hard tissues. A significantly longer recurrence-free survival was noted in patients treated by radical procedures in comparison to those treated by conservative methods and the age of patients at the first presentation was significantly related to malignant transformation of AF. As we are unable, at present, to differentiate a hamartomatous lesion from a neoplasm among this group of lesions merely on histologic grounds, age of the patients should be an important consideration when choosing therapeutic methods. Radical surgery should not be employed for the treatment of AFs in young people. PMID- 17689136 TI - Inhibition of doxorubicin-induced mutagenicity by Baccharis dracunculifolia. AB - Baccharis dracunculifolia DC (Asteraceae), a native plant from Brazil, have been used as an antipyretic, stomachic and health tonic in Brazil. The objective of the present study was to investigate the potential mutagenic effect of B. dracunculifolia ethyl acetate extract (Bd-EAE) and its influence on the mutagenicity induced by the chemotherapeutic agent doxorubicin (DXR) using the rat bone marrow and peripheral blood micronucleus test. Wistar rats were divided into 10 treatment groups. Five groups received DXR (90 mg/kg body weight, b.w., intraperitoneally) to induce mutagenicity and three of these groups received a single oral dose of Bd-EAE at a concentration of 6, 12 or 24 mg/kg b.w. prior to DXR administration. A vehicle-treated control group and Bd-EAE control groups were also included. The results showed that Bd-EAE itself was not mutagenic, in the rat micronucleus assay. In animals treated with Bd-EAE and DXR, the number of MNPCEs was significantly decreased compared to animals receiving DXR alone. HPLC analysis of the extract obtained permitted the identification of the following phenolic compounds: caffeic acid, p-coumaric acid, aromadendrin-4'O-methyl ether, 3-prenyl-p-coumaric acid (drupanin), 3,5-diprenyl-p-coumaric acid (artepillin C) and baccharin. The putative antioxidant activity or the interference of one or more of the active compounds of Bd-EAE with mutagenic metabolic pathways may explain its effect on DXR mutagenicity. PMID- 17689137 TI - Genotoxic effects and induction of phytochelatins in the presence of cadmium in Vicia faba roots. AB - This study investigates different effects in roots of Vicia faba (broad bean) after exposure to cadmium. Genotoxic effects were assessed by use of the well known Vicia root tip micronucleus assay. Cytotoxic effects were evaluated by determining the mitotic index in root tip cells. Finally, molecular induction mechanisms were evaluated by measuring phytochelatins with HPLC. After hydroponical exposure of V. faba roots to a range of cadmium concentrations and during different exposure times, the results of this approach showed large variations, according to the endpoint measured: after 48 h of exposure, genotoxic effects were found between 7.5 x 10(-8) and 5 x 10(-7)M CdCl(2), and cytotoxic effects were observed between 2.5 x 10(-7) and 5 x 10(-7)M CdCl(2). Statistically significant phytochelatin (PC) concentrations were measured at >or=10(-6)M CdCl(2) for PC(2), and at >or=10(-5)M CdCl(2) for PC3 and PC4. PMID- 17689138 TI - Growth, structural, optical and thermal properties of gamma-glycine crystal. AB - Single crystals of gamma-glycine were grown from a mixture of glycine, water and lithium bromide. Single crystal X-ray diffraction analysis confirmed the growth of gamma-glycine phase. Presence of various functional groups of gamma-glycine was identified by FTIR spectrum. Optical absorbance spectrum recorded in the wavelength range of UV-vis-NIR revealed that this crystal has good optical transparency in the range 250-1500 nm. Vickers microhardness values were estimated on the prominent (100) face. Thermogravimetric and differential scanning calorimetric analyses were carried out to study the thermal properties of gamma-glycine. Second harmonic generation efficiency of the crystal measured by Kurtz's powder method using Nd:YAG laser is about three times that of KDP. PMID- 17689139 TI - Central African Republic is part of the West-African hepatitis B virus genotype E crescent. AB - BACKGROUND: Recent studies have shown that Hepatitis B virus (HBV) genotype E predominates in a vast crescent in West-Africa spanning from Senegal to Angola. OBJECTIVES: To determine whether HBV strains in the Central African Republic (CAR) belong predominately to the homogeneous West-African genotype E or whether they are more closely related to genotypes found in East Africa. STUDY DESIGN: Serum samples were randomly collected from 196 patients admitted with symptoms of acute or chronic hepatitis to the Central Hospital in Bangui. Thirty complete and 36 partial sequences of HBV strains were obtained. RESULTS: Ninety-four percent (62/66) of the strains belonged to genotype E, while genotype A1, most closely related to a strain from Tanzania and genotype D were detected in only one and three samples, respectively. One strain presented a recombination between the S and X gene of a genotype E precursor and a partial PreC/C gene of a genotype D precursor. CONCLUSIONS: Genotype E is predominant in CAR with little overlap with genotypes from Eastern Africa, extending the West-African HBV genotype E crescent further to the East. PMID- 17689140 TI - Multiple plasma membrane receptors but not NPC1L1 mediate high-affinity, ezetimibe-sensitive cholesterol uptake into the intestinal brush border membrane. AB - We compared cholesterol uptake into brush border membrane vesicles (BBMV) made from the small intestines of either wild-type or Niemann-Pick C1-like 1 (NPC1L1) knockout mice to elucidate the contribution of NPC1L1 to facilitated uptake; this uptake involves cholesterol transport from lipid donor particles into the BBM of enterocytes. The lack of NPC1L1 in the BBM of the knockout mice had no effect on the rate of cholesterol uptake. It follows that NPC1L1 cannot be the putative high-affinity, ezetimibe-sensitive cholesterol transporter in the brush border membrane (BBM) as has been proposed by others. The following findings substantiate this conclusion: (I) NPC1L1 is not a brush border membrane protein but very likely localized to intracellular membranes; (II) the cholesterol absorption inhibitor ezetimibe and its analogues reduce cholesterol uptake to the same extent in wild-type and NPC1L1 knockout mouse BBMV. These findings indicate that the prevailing belief that NPC1L1 facilitates intestinal cholesterol uptake into the BBM and its interaction with ezetimibe is responsible for the inhibition of this process can no longer be sustained. PMID- 17689141 TI - Protein kinase C-dependent antilipolysis by insulin in rat adipocytes. AB - Recently, we have shown that protein kinase C (PKC) activated by phorbol 12 myristate 13-acetate (PMA) attenuates the beta1-adrenergic receptor (beta1-AR) mediated lipolysis in rat adipocytes. Stimulation of cells by insulin, angiotensin II, and alpha1-AR agonist is known to cause activation of PKC. In this study, we found that lipolysis induced by the beta1-AR agonist dobutamine is decreased and is no longer inhibited by PMA in adipocytes that have been treated with 20 nM insulin for 30 min followed by washing out insulin. Such effects on lipolysis were not found after pretreatment with angiotensin II and alpha1-AR agonists. The rate of lipolysis in the insulin-treated cells was normalized by the PKCalpha- and beta-specific inhibitor Go 6976 and PKCbeta-specific inhibitor LY 333531. In the insulin-treated cells, wortmannin increased lipolysis and recovered the lipolysis-attenuating effect of PMA. Western blot analysis revealed that insulin slightly increases membrane-bound PKCalpha, betaI, and delta, and wortmannin decreases PKCbetaI, betaII, and delta in the membrane fraction. These results indicate that stimulation of insulin receptor induces a sustained activation of PKC-dependent antilipolysis in rat adipocytes. PMID- 17689143 TI - Risk for sleep-disordered breathing and executive function in preschoolers. AB - BACKGROUND: Pediatric sleep-disordered breathing is known to negatively impact cognitive development. While a theoretical basis has been proposed for the developmental effect of pediatric sleep-disordered breathing on executive function specifically, this had not been directly examined among preschool-age children. This population may be particularly vulnerable if school-readiness is compromised. The purpose of the current study was to use a multi-dimensional approach to assessing executive function among preschool-age children at risk for sleep-disordered breathing. METHODS: Thirty-nine preschool children were administered executive function tasks assessing the dimensions of inhibition, working memory, and planning as part of a larger study. A parent or guardian completed a validated questionnaire concerning the child's snoring and other behaviors indicating risk for sleep-disordered breathing. RESULTS: After controlling for age in a series of regressions, higher parent-reported risk for sleep-disordered breathing was associated with substantially lower performance on each executive function dimension. In comparing the group means of children at high and low risk for sleep-disordered breathing, the single snoring frequency item also showed that children who snored frequently or almost always had lower performance on each executive function dimension. CONCLUSIONS: The results suggest that sleep-disordered breathing may be associated with impaired executive function in preschoolers, with its strongest impact on the inhibition dimension, further emphasizing the importance of early intervention for sleep-disordered breathing in this early age group. PMID- 17689142 TI - Enhancement of sleep stability with Tai Chi exercise in chronic heart failure: preliminary findings using an ECG-based spectrogram method. AB - OBJECTIVE: To assess the effects of a 12-week Tai Chi exercise program on sleep using the sleep spectrogram, a method based on a single channel electrocardiogram (ECG)-derived estimation of cardiopulmonary coupling, previously shown to identify stable and unstable sleep states. METHODS: We retrospectively analyzed 24-h continuous ECG data obtained in a clinical trial of Tai Chi exercise in patients with heart failure. Eighteen patients with chronic stable heart failure, left ventricular ejection fraction or=4.0) developed within 5 years in 15 (13%) of the 120 children for whom EDSS score was available. 23 (17%) had impaired academic performance, which was associated with increasing disease duration (p=0.02). Over 108 (86%) of the children with MS, irrespective of geographical residence, were seropositive for remote EBV infection, compared with only 61 (64%) of matched controls (p=0.025, adjusted for multiple comparisons). Children with MS did not differ from controls in seroprevalence of the other childhood viruses studied, nor with respect to month of birth, sibling number, sibling rank, or exposure to young siblings. INTERPRETATION: Paediatric MS is a relapsing-remitting disease, with presenting features that vary by age at onset. MS in children might be associated with exposure to EBV, suggesting a possible role for EBV in MS pathobiology. PMID- 17689149 TI - Establishment of ELISA for murrel vitellogenin and choriogenin, as biomarkers of potential endocrine disruption. AB - Vitellogenin (Vg) and choriogenin (Chg) are sensitive biomarkers for testing endocrine disruption in fish. Therefore, we have developed immunoassays for Vg and Chg in the Indian freshwater murrel, Channa punctatus. Vg is a known precursor of egg-yolk proteins, whereas Chg contributes to the formation of egg envelope. Vg and Chg were induced in male murrel by administration of estradiol 17beta. Chg had an apparent native molecular mass of 180 kDa. It consisted of a single peptide with a molecular mass of 110 kDa, whereas native Vg protein (530 kDa) contained 175 kDa peptide. Highly specific polyclonal antibodies against purified plasma proteins, Vg and Chg, were employed for developing competitive enzyme linked immunosorbent assays (ELISAs). The sensitivity of Vg assay was 3.9 ng/mL (working range 15-500 ng/mL) and of Chg assay was 1.56 ng/mL (working range 6-200 ng/mL). The inter- and intra-assay variations were well within acceptable limits. The two antisera did not cross-react with male plasma proteins. Antiserum to Vg did not cross-react with Chg. Similarly, antiserum to Chg showed no correlation with Vg. Further, immunofluorescence and Western blotting confirmed the specificity of Vg and Chg antisera. PMID- 17689150 TI - Histamine in Macaca mulatto monkey cardiac sympathetic nerve system: a morphological and functional assessment. AB - Our previous study demonstrated the co-localization of histamine with norepinephrine (NE) within superior cervical ganglia (SCG), and the release of histamine from sympathetic nerve endings of guinea pig evoked by stimulations. We have now further investigated that whether the histamine can be synthesized, stored and released from the sympathetic nerve systems of Macaca mulatto monkey, and investigated the modulation of the sympathetic endogenous histamine release through histamine H(3) receptor in the monkey cardiac sympathetic nerve system. Double-labeled immunofluorescence technique was applied to investigate co localization of histamine and NE in SCG of Macaca mulatto monkey. The cardiac sympathetic nerve terminals (synaptosomes) of Macaca mulatto monkey was prepared and depolarized with 50 mmol/L K(+). Histamine released from synaptosomes was detected by spectrofluorometer and regulations of histamine release through Ca(2+), Ca(2+)-channel blockers, H(3)-receptor agonist (R)-alpha-methylhistamine and histamine H(3)-receptor antagonist, thioperamide were observed. Co localization of histamine and NE was identified within the same neuron of SCG. Release of histamine was Ca(2+)-dependent and inhibited by N-type Ca(2+)-channel blocker omega-conotoxin, but not affected by the L-type Ca(2+)-channel blocker lacidipine. Compound 48/80, a mast cell releaser, did not affect cardiac synaptosome histamine exocytosis. Cardiac synaptosome histamine release was augmented by the enhanced synthesis of histamine or the inhibition of histamine metabolism. Histamine H(3)-receptor activation by (R)-alpha-methylhistamine inhibited high K(+)-evoked histamine release and thioperamide blocked the effects of (R)-alpha-methylhistamine. These results firstly showed that histamine co existed with NE within sympathetic neurons of monkey and the exocytosis of histamine from sympathetic terminals could be regulated by presynaptic histamine H(3) receptors. Sympathetic histamine may act as a neurotransmitter to modulate sympathetic neurotransmission. PMID- 17689151 TI - Ion transport in tumors under electrochemical treatment: in vivo, in vitro and in silico modeling. AB - The electrochemical treatment of cancer (EChT) consists in the passage of a direct electric current through two or more electrodes inserted locally in the tumor tissue. The extreme pH changes induced have been proposed as the main tumor destruction mechanism. Here, we study ion transport during EChT through a combined modeling methodology: in vivo modeling with BALB/c mice bearing a subcutaneous tumor, in vitro modeling with agar and collagen gels, and in silico modeling using the one-dimensional Nernst-Planck and Poisson equations for ion transport in a four-ion electrolyte. This combined modeling approach reveals that, under EChT modeling, an initial condition with almost neutral pH evolves between electrodes into extreme cathodic alkaline and anodic acidic fronts moving towards each other, leaving the possible existence of a biological pH region between them; towards the periphery, the pH decays to its neutral values. pH front tracking unveils a time scaling close to t(1/2), signature of a diffusion controlled process. These results could have significant implications in EChT optimal operative conditions and dose planning, in particular, in the way in which the evolving EChT pH region covers the active cancer cells spherical casket. PMID- 17689152 TI - Analysis of Rev1p and Pol zeta in mitochondrial mutagenesis suggests an alternative pathway of damage tolerance. AB - Ultraviolet light is a potent DNA damaging agent that induces bulky lesions in DNA which block the replicative polymerases. In order to ensure continued DNA replication and cell viability, specialized translesion polymerases bypass these lesions at the expense of introducing mutations in the nascent DNA strand. A recent study has shown that the N-terminal sequences of the nuclear translesion polymerases Rev1p and Pol zeta can direct GFP to the mitochondrial compartment of Saccharomyces cerevisiae. We have investigated the role of these polymerases in mitochondrial mutagenesis. Our analysis of mitochondrial DNA point mutations, microsatellite instability, and the spectra of mitochondrial mutations indicate that these translesion polymerases function in a less mutagenic pathway in the mitochondrial compartment than they do in the nucleus. Mitochondrial phenotypes resulting from the loss of Rev1p and Pol zeta suggest that although these polymerases are responsible for the majority of mitochondrial frameshift mutations, they do not greatly contribute to mitochondrial DNA point mutations. Analysis of spontaneous mitochondrial DNA point mutations suggests that Pol zeta may play a role in general mitochondrial DNA maintenance. In addition, we observe a 20-fold increase in UV-induced mitochondrial DNA point mutations in rev deficient strains. Our data provides evidence for an alternative damage tolerance pathway that is specific to the mitochondrial compartment. PMID- 17689153 TI - A sensitive immunoassay for determination of hepatitis B surface antigen and antibody in human serum using capillary electrophoresis with chemiluminescence detection. AB - A sensitive and homogeneous immunoassay (IA) based on capillary electrophoresis (CE) with enhanced chemiluminescence (CL) detection has been developed for the determination of hepatitis B surface antigen (HBsAg) and antibody (HBsAb) in human serum. The conditions for the CL reaction and electrophoresis were investigated in detail using horseradish peroxidase (HRP) labeled HBsAg (HBsAg*) as a marker because of its catalytic effects on the luminol-hydrogen peroxide reaction. The CL reaction was enhanced by para-iodophenol and the CL detector was designed uniquely without any dead volume or diluents effect. The present method has been used for assaying HBsAg and HBsAb in human serum using a competitive format and a non-competitive format, respectively. Under the optimal conditions, the linear ranges were from 1 to 400 pmol/L (R=0.9988) for HBsAg and 2 to 200 mIU/mL (R=0.9981) for HBsAb. The detection limits were 0.4 pmol/L and 1 mIU/mL for HBsAg and HBsAb, respectively. The relative standard deviations of peak area were 4.2% and the errors of it were from -0.03% to +0.05% for 80 pmol/L HBsAg* (n=7). In this study, the free HBsAg* and the bound HBsAg* (HBsAg*-HBsAb) were separated in the separation capillary within 6 min using a borate run buffer. To verify the experimental reliability, the result was comparable with that of enzyme linked immunosorbent assay (ELISA) and demonstrated the feasibility of the CE-CL immunoassay method for clinical diagnosis. PMID- 17689154 TI - Purification and analysis of a 5kDa component of enamel matrix derivative. AB - High performance liquid chromatography (HPLC) methods were used to analyse a 5kDa component purified from enamel matrix derivative (EMD), the active ingredient in Emdogain, a commercial product for periodontal tissue regeneration. After initial purification by size-exclusion chromatography (SEC) on a 100 cm x 5 cm column (Bio-Gel P-30 Fine, 280 nm), collected fractions were analysed by size-exclusion HPLC (SE HPLC; TSK-Gel Super SW2000, 220 nm). The fractions containing only the 5kDa component were analysed by reversed-phase high-pressure chromatography (RP HPLC; YMC-Pack ODS-A, 200 nm), revealing four peaks of the 5kDa component. From 1200 mg of EMD (of which 9% is the 5kDa component), approximately 65 mg of lyophilised 5kDa component were obtained, corresponding to a recovery of 60%. The SE HPLC method was mainly suitable for qualitative analysis, whereas the RP HPLC method was appropriate for both qualitative and quantitative analysis. PMID- 17689155 TI - Variation in relative substrate specificity of bifunctional beta-D xylosidase/alpha-L-arabinofuranosidase by single-site mutations: roles of substrate distortion and recognition. AB - To probe differential control of substrate specificities for 4-nitrophenyl-alpha l-arabinofuranoside (4NPA) and 4-nitrophenyl-beta-d-xylopyranoside (4NPX), residues of the glycone binding pocket of GH43 beta-d-xylosidase/alpha-l arabinofuranosidase from Selenomonas ruminantium were individually mutated to alanine. Although their individual substrate specificities (kcat/Km)(4NPX) and (kcat/Km)(4NPA) are lowered 330 to 280,000 fold, D14A, D127A, W73A, E186A, and H248A mutations maintain similar relative substrate specificities as wild-type enzyme. Relative substrate specificities (kcat/Km)(4NPX)/(kcat/Km)(4NPA) are lowered by R290A, F31A, and F508A mutations to 0.134, 0.407, and 4.51, respectively, from the wild type value of 12.3 with losses in (kcat/Km)(4NPX) and (kcat/Km)(4NPA) of 18 to 163000 fold. R290 and F31 reside above and below the C4 OH group of 4NPX and the C5 OH group of 4NPA, where they can serve as anchors for the two glycone moieties when their ring systems are distorted to transition state geometries by raising the position of C1. Thus, whereas R290 and F31 provide catalytic power for hydrolysis of both substrates, the native residues are more important for 4NPX than 4NPA as the xylopyranose ring must undergo greater distortion than the arabinofuranose ring. F508 borders C4 and C5 of the two glycone moieties and can serve as a hydrophobic platform having more favorable interactions with xylose than arabinofuranose. PMID- 17689156 TI - Functional motifs outside the kinase domain of yeast Srb10p. Their role in transcriptional regulation and protein-interactions with Tup1p and Srb11p. AB - Several derivatives of the native Srb10 proteins from Saccharomyces cerevisiae and Kluyveromyces lactis, with removed selected motifs, have been constructed in order to test their role in Srb10p function. It has been demonstrated that the ATP binding site is necessary for repression of FLO11, CYC7 and SPI1. Yeast Srb10p specific motifs CM-I and CM-II, outside the kinase domain, are also necessary to complement two mutant phenotypes in S. cerevisiae Deltasrb10 strains, the failure to growth in galactose at 37 degrees C and flocculation. They are also required to keep transcriptional repression of FLO11 in non flocculants, and for aerobic repression of CYC7 and SPI1. Two-hybrid analyses revealed that, in Srb10p derivatives, the absence of these motifs decreases the interaction of Srb10p with its cyclin partner Srb11p and with the component Tup1p of the general co-repressor complex Tup1p-Ssn6p. PMID- 17689157 TI - Re: weight-bearing exercise and bone mineral accrual in children and adolescents: a review of controlled trials. PMID- 17689159 TI - The influence of lipid-extraction method on the stiffness of articular cartilage. AB - BACKGROUND: One of the known characteristics of osteoarthritis is the loss of articular cartilage lipids. Therefore, it is important to study how lipids influence the functions of the tissue. This can only be done successfully by indirect analysis involving the extraction of lipids and subsequent assessment of the delipidized matrix. Therefore, for accuracy, the procedure for lipid extraction must not induce any other modification in the samples to be assessed. Hence, we compare three rinsing agents and methods in this study. METHODS: Normal and delipidized articular cartilage samples were tested under compressive loading at 4 loading velocities to obtain and compare their stiffness values. FINDINGS: Chloroform rinsing resulted in a 45% decrease in the stiffness of cartilage at low strain-rates (10(-2)/s and 10(-1)/s) on average with a corresponding increase of 55% at higher strain-rate of 10/s relative to the normal. Ethanol rinsed cartilage exhibited a corresponding decrease of 40% at the low strain-rates while exhibiting an increase of about 20% at the highest loading rates. Propylene glycol rinsing resulted in a decrease of approximately 20% in stiffness, while an increase of up to 5% at high rates of loading. INTERPRETATION: The loss of lipids modifies the stiffness of articular cartilage at all loading rates. The relatively larger deviation of the stiffness of chloroform-rinsed samples relative to the normal is probably a consequence of the drying process involved in rinsing protocol. It is probable that the results of milder rinsing agents, used without vacuum drying, are more reflective of physiological delipidization effects on the tissue. Consequently, we recommend propylene glycol and its associated protocol for extracting lipids from articular cartilage. PMID- 17689160 TI - Elemental levels in tree-bark and epiphytic-lichen transplants at a mixed environment in mainland Portugal, and comparisons with an in situ lichen. AB - Samples of Platanus hybrida Brot. bark and Flavoparmelia caperata (L.) Hale thalli, from a clean area in northern Portugal (Baiao), were transplanted into an exposure location at the south-western Atlantic coast, impacted by urban industrial emissions (Sines), for a 10-month long experiment. Bark pieces were confined into nylon bags (2-mm mesh), and lichen thalli kept with their bark substrate (Pinus pinaster (Ait.) Sol.). Every two months, a double set of transplants (one for bark, one for lichens) was brought back into the laboratory, together with native samples of Evernia prunastri (L.) Ach. Following suitable cleansing and preparation procedures, field samples were put through INAA for elemental assessment. The results indicate that, regardless of signal magnitude, (1) concentrations in bark and lichen transplants are significantly correlated with atmospheric deposition for an appreciable number of elements; (2) there are a number of significant correlations between transplanted and native samples, and again between the latter and the deposition; and (3) the elements with biological patterns that follow the deposition in either transplanted or native samples (Co, V) are the very ones whose bioaccumulation seems to benefit from an alternation of wet-dry periods, which fits the precipitation record of the test site during the exposure term. PMID- 17689161 TI - The response of epiphytic lichens to air pollution and subsets of ecological predictors: a case study from the Italian Prealps. AB - We investigated the response of epiphytic lichens to air pollution, against the background of other ecological predictors in a prealpine heterogeneous area, using Non-Parametric Multiplicative Regression (NPMR). The best NPMR model for total lichen diversity according to N environmental predictors at tree level has a cross R(2)=0.709. It includes 10 variables, belonging to three different subsets of factors: two pollution-related factors (distance in meters from the road and from the cement factory); four stand-related (habitat, heat index, LAI and elevation) and four substrate-related factors (inclination, circumference and texture and tree species). Considering separately the effects of each subset on lichen diversity, substrate- and stand-related factors produce good models with similar cross R(2) (0.490 and 0.500, respectively), whereas pollution-related factors produce a model with a lower cross R(2) (0.340). Hence, we provide information to investigate the applicability of lichen biomonitoring to complex heterogeneous areas where standardized protocols are not reliable. PMID- 17689162 TI - Determinants of prostate cancer stage in northern New England: USA Franco American contextual effects. AB - Despite screening for prostate cancer, mortality in the United States remains substantial. In northern New England, we know little about either determinants of stage at diagnosis--an important predictor of survival--or health outcomes for Franco-Americans, the region's largest ethnic minority. The objective of this investigation was to identify predictors of late prostate cancer stage in a rural, predominantly white state with a large Franco-American population. The Maine Cancer Registry provided incident cases from 1995 to 1998. We modeled individual-level variables (age, sex, race, French ethnicity by surname, and payer) and contextual/town-level variables (socioeconomic measures, population density, Franco ancestry proportion, distance to health care, and weather severity) with multiple logistic regression for late stage. We found that age categories 50-64, 65-74, and 75-84 years--but not 40-49 years--(versus 85+) were protective for late stage, as was residence in higher snowfall areas. Diagnosis in the earlier years of the study, particularly for French-surnamed men, and residence in a high-Franco area conferred greater risk for late disease. However, in a two-way interaction, residence in towns with high Franco ancestry proportion protected French-surnamed men (OR=0.09, type 3 p<0.0593). Using an established framework for social network theory we explore the potential reasons for this interaction, including: high social cohesion, a wide range of strong ties of long duration, and frequent contact, which might have facilitated access to resources as well as social support and normative influences toward health care seeking. The absence of an association of cancer stage with socioeconomic variables may stem from the mixed sociodemographic profiles in rural and urban regions of Maine. We feel that further research should therefore refine these and other contextual measures to elucidate effects on preventable morbidity and mortality; expand our knowledge of Franco-American health outcomes and social networks; and evaluate the utility of assigning French ethnicity by surname. PMID- 17689163 TI - Framework for Aboriginal-guided decolonizing research involving Metis and First Nations persons with diabetes. AB - This paper documents the process of implementing an Aboriginal-guided research approach to examining the lived experiences of Metis and First Nations peoples with diabetes in Winnipeg, Manitoba, Canada. A newly developed Aboriginal oriented process framework for decolonizing research includes, in order of application, the six processes of rationalizing, enabling, facilitating, experiencing, accepting, and enacting decolonizing research. We review the key methodological elements of our research as a basis for discussing this decolonizing process framework that challenges traditional western ways of doing research, and requires the reformulation of underlying assumptions and methods. Aboriginal-grounded decolonizing research processes have implications for health researchers and health service providers who work with Indigenous peoples worldwide and are particularly useful for developing culturally grounded, community-based health promotion programs for Indigenous peoples suffering from health-related problems, including diabetes. PMID- 17689164 TI - Olanzapine withdrawal/discontinuation-induced hyperthermia in rats. AB - In female rats olanzapine (4 mg/kg b.i.d., i.p.) induced acute hypothermia, followed by very rapid full tolerance. With more prolonged treatment (over > 10 days) the hypothermic effect of olanzapine was reinstated. Subsequent withdrawal after 18 days of treatment induced very rapid onset (within 1 day) hyperthermia, which was time limited, dissipating completely over 3-4 days. These findings are similar to previous findings with clozapine [Goudie A Smith J Robertson A Cavanagh C (1999). Clozapine as a drug of dependence. Psychopharmacology; 142: 369-374.]. Although the mechanism(s) involved in the secondary hypothermic effect of olanzapine are, at present, unclear; the withdrawal hyperthermia observed represents the first report of a clear discontinuation effect of olanzapine. Such discontinuation effects are probably observed with many antipsychotic drugs. Since they have been suggested to facilitate relapse to psychosis and to interfere with subsequent clinical responses to antipsychotics, they merit further detailed analysis in both clinical and preclinical studies. PMID- 17689165 TI - The protective effect of erdosteine against cyclosporine A-induced cardiotoxicity in rats. AB - Cyclosporine A (CsA) is a frequently used immunosuppressive agent in transplant medicine to prevent rejection and in the treatment of autoimmune diseases. However, CsA generates reactive oxygen species, which causes nephrotoxicity, hepatotoxicity and cardiotoxicity. The use of antioxidants reduces the adverse effects of CsA. The aim of this study is to determine the protective effects of erdosteine on CsA-induced heart injury through tissue oxidant/antioxidant parameters and light microscopic evaluation in rats. CsA cardiotoxicity was induced by administrating an oral dose of 15mg/kg CsA daily for 21 days. The rats were divided into four groups: control group (n=4), CsA administrated group (15mg/kg, n=5), CsA+erdosteine administrated group (10mg/kg day orally erdosteine, n=4) and only erdosteine administrated group (10mg/kg day orally n=5). CsA treated rats showed increase in the number of infiltrated cells and disorganization of myocardial fibers with interstitial fibrosis. The number of infiltrated cells, disorganization of myocardial fibers and interstitial fibrosis was diminished in the hearts of CsA-treated rats given erdosteine. The malondialdehyde, the protein carbonyl content and nitric oxide levels were increased in the cyclosporine A group in comparison with the control and CsA plus erdosteine groups. The activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were higher in CsA plus erdosteine group than CsA group. However, the CAT, GSH-Px and SOD activities were significantly lower in CsA group than in control group and erdosteine group. These results suggest that erdosteine has protective effect against CsA-induced cardiotoxicity. PMID- 17689166 TI - Neuronal structures involved in the induction and propagation of seizures caused by nerve agents: implications for medical treatment. AB - In epilepsy research, studies have been made to identify brain areas critical for triggering and/or controlling propagated seizure activity. The purpose of the present study was to focus on a similar approach in nerve agent research by reviewing relevant literature to map potential trigger sites and propagation pathways for seizures. The piriform cortex and medial septal area emerge as prime target areas for soman-induced seizures. The cholinergic hyperactivation in the latter structures seems to induce increased glutamatergic activity in the piriform, entorhinal, and perirhinal cortices along with the hippocampal region. For prophylactic or early treatment, mapping of muscarinic subreceptors in the piriform cortex and medial septum would be guiding for designing anticholinergic drugs with optimal properties. Sustained seizures governed by glutamatergic over activity may primarily be terminated by drugs with optimal glutamatergic antagonism primarily in the piriform, entorhinal, and perirhinal cortices. Studies of radiolabeled ligands to map subreceptors may provide specification of wanted drug properties to guide the choice among existing agents or to synthesize novel ones. PMID- 17689168 TI - Do contaminated dental unit waterlines pose a risk of infection? AB - OBJECTIVES: To review the evidence that the dental unit waterlines are a source of occupational and healthcare acquired infection in the dental surgery. DATA: Transmission of infection from contaminated dental unit waterlines (DUWL) is by aerosol droplet inhalation or rarely imbibing or wound contamination in susceptible individuals. Most of the organisms isolated from DUWL are of low pathogenicity. However, data from a small number of studies described infection or colonisation in susceptible hosts with Legionella spp., Pseudomonas spp. and environmental mycobacteria isolated from DUWL. The reported prevalence of legionellae in DUWL varies widely from 0 to 68%. The risk from prolonged occupational exposure to legionellae has been evaluated. Earlier studies measuring surrogate evidence of exposure to legionellae in dental personnel found a significant increase in legionella antibody levels but in recent multicentre studies undertaken in primary dental care legionellae were isolated at very low rate and the corresponding serological titres were not above background levels. Whereas, a case of fatal Legionellosis in a dental surgeon concluded that the DUWL was the likely source of the infection. The dominant species isolated from dental unit waterlines (DUWL) are Gram-negative bacteria, which are a potent source of cell wall endotoxin. A consequence of indoor endotoxin exposure is the triggering or exacerbation of asthma. Data from a single large practice-based cross-sectional study reported a temporal association between occupational exposure to contaminated DUWL with aerobic counts of >200cfu/mL at 37 degrees C and development of asthma in the sub-group of dentists in whom asthma arose following the commencement of dental training. SOURCES: Medline 1966 to February 2007 was used to identify studies for this paper. STUDY SELECTION: Design criteria included randomised control trials, cohort, and observational studies in English. CONCLUSIONS: Although the number of published cases of infection or respiratory symptoms resulting from exposure to water from contaminated DUWL is limited, there is a medico-legal requirement to comply with potable water standards and to conform to public perceptions on water safety. PMID- 17689167 TI - Evaluating the objectivity of caries removal with a caries detector dye using color evaluation and PCR. AB - OBJECTIVES: This laboratory study evaluated the objectivity of caries removal with a caries detector dye by color and bacterial evaluations. METHODS: In 41 cases of dentin caries (32 extracted human molars), carious tissues were removed using a caries detector dye. Images of dentin surfaces with color-matching stickers were acquired using a CCD camera, and dentinal tissue samples were collected with new round burs. Corrected L*, a* and b* values (CIE 1976 L*a*b* color system) of dentin surfaces were calculated from the sticker color changes. In addition, bacterial DNA in dentinal tissues was detected by the polymerase chain reaction. RESULTS: The intra-class correlation coefficient of the corrected L*, a* and b* values was 0.34, 0.30 and 0.49, respectively. There were significant inter-operator differences (P<0.05). Seventeen of 41 specimens contained bacterial DNA after caries removal. CONCLUSIONS: Results showed that objectivity of caries removal using the caries detector dye with visual inspection was low. PMID- 17689169 TI - Biochemical characterization of a novel beta-1--3, 1--4 glucan 4-glucanohydrolase from Thermomonospora sp. having a single active site for lichenan and xylan. AB - A bifunctional high molecular weight (Mr, 64,500 Da) beta-1-3, 1-4 glucan 4 glucanohydrolase was purified to homogeneity from Thermomonospora sp., exhibiting activity towards lichenan and xylan. A kinetic method was used to analyze the active site that hydrolyzes lichenan and xylan. The experimental data was in agreement with the theoretical values calculated for a single active site. Probing the conformation and microenvironment at active site of the enzyme by fluorescent chemo-affinity label, OPTA resulted in the formation of an isoindole derivative with complete inactivation of the enzyme to hydrolyse both lichenan and xylan confirmed the results of kinetic method. OPTA forms an isoindole derivative by cross-linking the proximal thiol and amino groups. The modification of cysteine and lysine residues by DTNB and TNBS respectively abolished the ability of the enzyme to form an isoindole derivative with OPTA, indicating the participation of cysteine and lysine in the formation of isoindole complex. PMID- 17689170 TI - The impact of avalanche rescue devices on survival. AB - BACKGROUND: Within Europe and North America, the median annual mortality from snow avalanches between 1994 and 2003 was 141. There are two commonly used rescue devices: the avalanche transceiver, which is intended to speed up locating a completely buried person, and the avalanche airbag, which aims to prevent the person from being completely buried. OBJECTIVE: This retrospective study aimed to evaluate whether these avalanche rescue devices had an effect on mortality. METHODS: The study population was 1504 persons who were involved in 752 avalanches either in Switzerland from 1990 to 2000 and from 2002 to 2003 (1296 persons, 86.2%) or in Austria from 1998 to 2004 (208 persons, 13.8%). RESULTS: Persons equipped with an avalanche airbag had a lower chance of dying (2.9% versus 18.9%; P=0.026, OR 0.09, n=1504). In persons who were completely buried, without visible or audible signs at the surface and who did not rescue themselves (n=317), we found a lower median duration of burial (25min versus 125min; P<0.001) and mortality (55.2% versus 70.6%; P<0.001, OR 0.26) in those using an avalanche transceiver than in those not using the device. CONCLUSIONS: Our data showed that both the avalanche airbag and the avalanche transceiver reduce mortality. However, to improve the evaluation of rescue devices in the future, the data collection procedures should be reviewed and prospective trials should be considered, as the reliability of retrospective studies is limited. PMID- 17689171 TI - Effects of rescuer position on the kinematics of cardiopulmonary resuscitation (CPR) and the force of delivered compressions. AB - BACKGROUND: Depending on the clinical setting, rescuers may provide CPR from a kneeling (if the patient is on the ground) or standing (if the patient is in a bed) position. The rescuer position may affect workload, and hence rate of fatigue and quality of CPR. PURPOSE: This study evaluates how three common rescuer positions affect the kinematics of CPR and the force of delivered compressions. METHODS: Subjects were 18 health care providers experienced in CPR. Each participant performed CPR from three different positions: kneeling beside the Resusci Anne manikin placed on the floor (F); standing beside the manikin placed on a Table 63 cm in height (H), and standing beside the manikin placed on a Table 37 cm in height (L). The compression to ventilation ratio was 15:2. CPR duration was 5 min for each position, with a rest period of 50 min in-between. The order of position was randomised. The manikin was equipped with a six-axial force load cell to collect 3D compression forces at a sampling rate of 1000 Hz. An eight-camera Motion Analysis Digital System was adopted to collect 3D trajectory information. Data were compared using crossover-design analysis of variance (p<0.05 was regarded as statistically significant). Ratings of Perceived Exertion (RPE) were measured by modified Borg scale. RESULTS: Significant differences were observed in the head, shoulder, lower trunk, hip and knee angles between the three methods. Lower trunk flexion angle (degrees) for H, L, and F were -14.52+/-1.13, -28.83+/-1.75, and 14.39+/-1.14, respectively. Hip flexion angle for H, L, and F were -16.21+/-3.30, -42.59+/-4.75, and -47.39+/-4.36, respectively. However, compression force (N) in H, L, and F were 455.8+/-17.6, 455.7+/-14.0, 461.5+/-13.5, respectively (p>0.05). Compression depths (mm) were: 43.5+/-3.4, 42.0+/-5.4, 44+/-5.2, respectively (p>0.05). Compression frequencies (times/min) were: 117.9+/-12.4, 116.6+/-13.4, 108.8+/-11.7, respectively (p>0.05). No differences were found between the three positions for RPE. CONCLUSIONS: In this study, while the kinematics of CPR differed significantly with varying rescuer position, these differences did not affect the compression force, depth and frequency as performed by experienced providers. PMID- 17689172 TI - Is the relationship between frontal EEG alpha asymmetry and depression mediated by implicit or explicit self-esteem? AB - A robust physiological finding is a higher relative left sided activity in the prefrontal cortex during the experience of positive approach related emotions and a higher relative right sided activity during the experience of negative withdrawal related emotions. Since self-esteem can be conceptualized within a framework of approach/withdrawal tendencies, the present study aimed at investigating if the relation between frontal EEG alpha asymmetry and depressive symptoms is mediated by implicit or explicit self-esteem. Self-esteem was measured by questionnaires (explicit) and in an indirect way (implicit). The mediation analyses showed that only explicit self-esteem acted as a partial mediator in the path from EEG alpha asymmetry to depression. PMID- 17689173 TI - Effects of carbohydrates on brain tryptophan availability and stress performance. AB - Although glucose intake has been associated with enhanced mental performance, this does not follow a clear synchronized relationship and findings are inconsistent. Given the brain's need for glucose during demanding conditions, glucose intake may be beneficial for stress performance. Brain serotonin may be involved as a postprandial mechanism initiated by increases in plasma tryptophan to the sum of the other large neutral amino acids (Trp/LNAA ratio). We tested whether carbohydrate drinks compared to placebo drinks increase the plasma Trp/LNAA ratio and improve stress performance and mood. Thirty-seven healthy subjects were monitored in a double-blind placebo-controlled study for performance when continuously exposed to cold pressor stress; 2h after carbohydrate- or placebo-intake. Cold pressor stress significantly increased cortisol and reduced mood and cognitive performance, whereas carbohydrates significantly increased plasma Trp/LNAA and positively influenced performance and mood under stress. PMID- 17689174 TI - The role of leptin in fetal growth: a short review from conception to delivery. AB - Abnormally high- or low-serum maternal levels and/or levels in placental, umbilical blood, and fetus/neonate are associated with a wide spectrum of complicated pregnancies. Whereas the state of knowledge about mechanisms and pathways involving secondary or tertiary modulators is far from complete, the role of leptin from ovulation and implantation and throughout pregnancy underscores its importance in normal and abnormal states. PMID- 17689175 TI - Community involvement in marine protected areas: the case of Puerto Morelos reef, Mexico. AB - The case of Puerto Morelos reef marine protected area (MPA) provides an example of a community-based marine conservation initiative to protect a coral reef ecosystem. The establishment and maintenance of this MPA had five stages: (a) identification of community leaders who would participate in the project; (b) generation of consensus on the need to protect the reef through discussions among local stakeholders, NGOs and reef scientists; (c) involvement of government agencies in establishing the status of a MPA; (d) take-over of decision-making by centralized governmental agencies; and (e) continuous problem-solving process between the government and stakeholders. Over a 9-year period, the control of the MPA was taken over by government and stakeholders' participation downgraded from a decision-making to an advice-giving role. Government shortcomings to manage this MPA could be circumvented via collaborative co-management. Given the small population size of the community and strong sense of ownership, there was a high level of participation in the decision-making processes and scientific advisors are present in the area. PMID- 17689176 TI - Evans blue staining of cardiomyocytes induced by myocardial contrast echocardiography in rats: evidence for necrosis instead of apoptosis. AB - High mechanical index (MI) echocardiography with contrast agent has been shown to induce Evans blue staining of cardiomyocytes, seen 1 d after exposure, in addition to contraction band necrosis, seen immediately after exposure. This research examined the roles of necrosis vs. apoptosis in these bioeffects. Myocardial contrast echocardiography at high MI with 1:4 electrocardiogram triggering was performed in anesthetized rats at 1.5 MHz. Histologically observable cell injury was accumulated by infusing a high dose of 50 microL/kg ultrasound contrast media via tail vein for 5 min at the start of 10 min of scanning. Evans blue dye or propidium iodide was injected as an indicator of cardiomyocyte plasma membrane integrity. Histologic sections were stained using the terminal dUTP nick-end labeling (TUNEL) method for labeling nuclei with DNA degradation (e.g., apoptosis). Evans blue fluorescent cells were counted on frozen sections or on hematoxylin-stained and TUNEL-labeled paraffin sections. In addition, transmission electron microscopy was used to assess potential apoptotic nuclei. Hypercontraction and propidium iodide staining were observed immediately after imaging exposure. Although TUNEL-positive cells were evident after 4 h, these also had indications of contraction band necrosis, and features of apoptosis were not confirmed by electron microscopy. Inflammatory cell infiltration was evident after 24 h. A second, more subtle injury was recognized by Evans blue staining, with minimal inflammatory cell infiltration at the morphologically intact stained cells after 24 h. Apoptosis was not detected by the TUNEL method in the cardiomyocytes stained with Evans blue at 24 h. However, Evans blue-stained cell numbers declined after 48 h, with continued inflammatory cell infiltration. The initial insult for Evans blue-stained cardiomyocytes apparently induced partial permeability of the plasma membrane, which led to gradual degeneration (but not apoptosis) and necrosis after 24 to 48 h. PMID- 17689177 TI - Saline infusion sonohysterography and the risk of malignant extrauterine spread in endometrial cancer. AB - The aim of this study was to evaluate the incidence of tumor cell dissemination after saline infusion sonohysterography (SIS) in patients with endometrial cancer (EC). A retrospective study was conducted on 173 patients with EC in whom one of the following methods were performed: dilation and curettage (D&C, n = 120) and D&C followed by SIS (n = 53). No selection or randomization of patients was applied to both groups. The presence of positive peritoneal cytology, as well as adnexal or abdominal metastases was considered the endpoint of this analysis. Positive peritoneal cytology was present in one patient (0.8%) after D&C and in one patient (1.9%) after D&C followed by SIS (chi(2) = 0.030; p > 0.05). Adnexal metastases were present in nine (7.5%) patients after D&C and in three (5.7%) patients after D&C followed by SIS (chi(2) = 0.013; p > 0.05). Metastases to abdominal cavity were found in three (2.5%) patients after D&C and in two (3.8%) patients after D&C followed by SIS (chi(2) = 0.001; p > 0.05). Upstaged because of positive cytology, adnexal or abdominal metastases were 13 patients (10.8%) after D&C and six patients (11.3%) after D&C followed by SIS (chi(2) = 0.029; p > 0.05). These data show that SIS does not increase the risk of malignant cell dissemination in patients with EC. PMID- 17689178 TI - Isovolumic relaxation flow propagation velocity: a promising load-independent relaxation parameter in hemodialysis patients. AB - The aim of this study is to evaluate whether isovolumic relaxation flow propagation velocity (IRFPV), a newly proposed relaxation parameter, is independent of load alterations. Thirty-nine uremic patients (21 men; age 62 +/- 10 y) who underwent echocardiography 1 h before and 1 h after hemodialysis (HD) were included. After HD, body weight, systolic blood pressure, early transmitral filling wave velocity (E), early diastolic mitral annular velocity (Ea) and early diastolic inflow propagation velocity (EPV) decreased significantly (p or=2.5 kg, E (p < 0.001), Ea (p = 0.001) and EPV (p = 0.001) decreased significantly but IRFPV (p = 0.715) was still constant after HD. In conclusion, IRFPV may be a load independent parameter in assessing left ventricular diastolic function. However, Ea and EPV are load-independent only at minor load alterations. In evaluating left ventricular diastolic function in HD patients whose loading conditions frequently vary with time, IRFPV seems to be more adequate than Ea and EPV. PMID- 17689179 TI - Two-dimensional ultrasound measurement of thyroid gland volume: a new equation with higher correlation with 3-D ultrasound measurement. AB - This study aimed to develop a new two-dimensional (2-D) ultrasound thyroid volume estimation equation using three-dimensional (3-D) ultrasound as the standard of reference, and to compare the thyroid volume estimation accuracy of the new equation with three previously reported equations. 2-D and 3-D ultrasound examinations of the thyroid gland were performed in 150 subjects with normal serum thyrotropin (TSH, thyroid-stimulating hormone) and free thyroxine (fT4) levels (63 men and 87 women, age range: 17 to 71 y). In each subject, the volume of both thyroid lobes was measured by 3-D ultrasound. On 2-D ultrasound, the craniocaudal (CC), lateromedial (LM) and anteroposterior (AP) dimensions of the thyroid lobes were measured. The equation was derived by correlating the volume of the thyroid lobes measured with 3-D ultrasound and the product of the three dimensions measured with 2-D ultrasound using linear regression analysis, in 75 subjects without thyroid nodule. The accuracy of thyroid volume estimation of the new equation and the three previously reported equations was evaluated and compared in another 75 subjects (without thyroid nodule, n = 30; with thyroid nodule, n = 45). It is suggested that volume of thyroid lobe may be estimated as: volume of thyroid lobe = 0.38.(CC.LM.AP) + 1.76. Result showed that the new equation (16.9% to 36.1%) had a significantly smaller thyroid volume estimation error than the previously reported equations (20.8% to 54.9%) (p < 0.05). There was a significantly larger thyroid volume estimation error when thyroid glands with nodules were examined (p < 0.05). With the use of the appropriate thyroid volume equation, 2-D ultrasound can be a useful alternative in thyroid volume measurement when 3-D ultrasound is not available. PMID- 17689180 TI - Regional variation in the measured apparent ultrasonic backscatter of mid gestational fetal pig hearts. AB - The goal of this study was to characterize and compare regional backscatter properties of fetal hearts through measurements of the apparent integrated backscatter. Sixteen excised, formalin-fixed fetal pig hearts, representing an estimated 53 to 63 days of gestation, were investigated. Spatially localized measurements of integrated backscatter from these specimens were acquired using a 50 MHz single-element transducer. The apparent integrated backscatter measurements demonstrate different patterns of backscatter from the myocardium of the right ventricle compared with that of the left ventricle. These backscatter measurements appear to be consistent with the anisotropy of the fiber orientation observed in histologic assessment of the same specimens. For each of the 16 hearts, the apparent integrated backscatter from the right ventricular myocardium was larger than that from the left ventricular myocardium, exhibiting mean apparent backscatter values of -35.9 +/- 2.0 dB and -40.1 +/- 1.9 dB (mean +/- standard deviation; n = 16; p < 0.001), respectively. This study suggests that the intrinsic ultrasonic properties of the left and right ventricular myocardium are distinct in fetal pig hearts at mid-gestation. PMID- 17689181 TI - Three-dimensional ultrasonography can detect the modulation of kidney volume in two-kidney, one-clip hypertensive rats. AB - As volume changes are a typical finding in the two-kidney, one-clip hypertensive rat model (2K1C), it is of interest to investigate within what time frame these volume changes occur and their relation to hypertension. Kidney volume changes in Wistar rats were measured by three-dimensional (3D) ultrasonography (USG). Clipped induced stenosis was applied to the left renal artery in 11-wk-old animals (n = 8), using age-matched nonclipped rats as controls (n = 7). Ultrasonographic recordings were made before clipping and, thereafter, weekly with corresponding systolic blood pressure and body weight measurements. The nonclipped kidney showed increased volume at week 2, 5 and 7. Three wk after clipping, clipped kidneys were smaller than the nonclipped kidneys (0.47 +/- 0.11 mL versus 1.28 +/- 0.07 mL). No difference was found between the left and right kidney in the control group at any week. Blood pressure was significantly higher in the 2K1C hypertensive group 4 weeks after clipping (201 +/- 16 versus 139 +/- 4 mm Hg) with stable blood pressure thereafter. Three-dimensional USG showed that clipping caused a decrease in kidney volume from week 3 in the clipped kidney and a volume increase in the nonclipped kidney at week 2. A significant increase in blood pressure appeared after week 4. PMID- 17689182 TI - Kinetic and equilibrium study for the sorption of cadmium(II) ions from aqueous phase by eucalyptus bark. AB - The efficiency of eucalyptus bark as a low cost sorbent for removing cadmium ions from aqueous solution has been investigated in batch mode. The equilibrium data could be well described by the Langmuir isotherm but a worse fit was obtained by the Freundlich model. The five linearized forms of the Langmuir equation as well as the non-linear curve fitting analysis method were discussed. Results show that the non-linear method may be a better way to obtain the Langmuir parameters. Maximum cadmium uptake obtained at a temperature of 20 degrees C was 14.53mgg( 1). The influence of temperature on the sorption isotherms of cadmium has been also studied. The monolayer sorption capacity increased from 14.53 to 16.47 when the temperature was raised from 20 to 50 degrees C. The DeltaG degrees values were negative, which indicates that the sorption was spontaneous in nature. The effect of experimental parameters such as contact time, cadmium initial concentration, sorbent dose, temperature, solution initial pH, agitation speed, and ionic strength on the sorption kinetics of cadmium was investigated. Pseudo second-order model was evaluated using the six linear forms as well as the non linear curve fitting analysis method. Modeling of kinetic results shows that sorption process is best described by the pseudo-second-order model using the non linear method. The pseudo-second-order model parameters were function of the initial concentration, the sorbent dose, the solution pH, the agitation speed, the temperature, and the ionic strength. PMID- 17689183 TI - NO reduction by propene or CO over alkali-promoted Pd/YSZ catalysts. AB - The catalytic activity and selectivity of Pd dispersed on 8mol% yttria stabilized zirconia (YSZ) support for the reduction of NO by propene or CO is strongly promoted by alkalis in a wide temperature range 200-500 degrees C. Rate increases by up to one order of magnitude are achievable, accompanied with significant improvement in N(2)-selectivity for the alkali promoted catalysts. The promoting effect of alkalis on both the activity and selectivity can be understood in terms of the effect of alkali promoter on the relative adsorption strengths of reactant species. These achievements could be very useful for the formulation of modern lower cost automotive catalytic converters, capable of controlling automotive emissions more efficiently. PMID- 17689184 TI - Arsenate removal by zero valent iron: batch and column tests. AB - This study investigates the efficiency of zero valent iron (ZVI) to remove arsenate from water. Batch experiments were carried out to study the removal kinetics of arsenate under different pH values and in the presence of low and high concentrations of various anions (chloride, carbonate, nitrate, phosphate, sulphate and borate), manganese and dissolved organic matter. Borate and organic matter, particularly at higher concentrations, inhibited the removal of arsenic. Column tests were carried out to investigate the removal of arsenate from tap water under dynamic conditions. The concentrations of arsenic and iron as well as the pH and Eh were measured in treated water. Efficient removal of arsenate was observed resulting at concentrations below the limit of 10 microg/L in treated waters. PMID- 17689185 TI - Complete dechlorination of DDT and its metabolites in an alcohol mixture using NaOH and Pd/C catalyst. AB - DDT (1,1-bis(4-chlorophenyl)-2,2,2-trichloroethane) was dechlorinated in 2 propanol/methanol (99:1v/v) by means of stoichiometric reaction with NaOH and subsequent catalytic dechlorination over Pd/C catalyst. When DDT was treated with a molar excess of NaOH ([NaOH]/[DDT]=9) in the alcohol mixture at room temperature, DDT disappeared within 15min. The reaction of DDT produced an equimolar amount of HCl to yield DDE (1,1-bis(4-chlorophenyl)-2,2 dichloroethylene). The produced DDE was successfully dechlorinated to a chlorine free product (1,1-diphenylethane, 97% yield) by addition of Pd/C to the alkaline solution and heating at 40 degrees C for 4h. DDD (1,1-bis(4-chlorophenyl)-2,2 dichloroethane) was also dechlorinated to 1,1-diphenylethane in a similar manner. Possible dechlorination pathways for DDT, DDE, and DDD were investigated by observation of the partially dechlorinated intermediates by means of gas chromatography/mass spectrometry (GC/MS). PMID- 17689186 TI - Biosorption of Pb(II) and Cd(II) from aqueous solution using green alga (Ulva lactuca) biomass. AB - The biosorption characteristics of Pb(II) and Cd(II) ions from aqueous solution using the green alga (Ulva lactuca) biomass were investigated as a function of pH, biomass dosage, contact time, and temperature. Langmuir, Freundlich and Dubinin-Radushkevich (D-R) models were applied to describe the biosorption isotherm of the metal ions by U. lactuca biomass. Langmuir model fitted the equilibrium data better than the Freundlich isotherm. The monolayer biosorption capacity of U. lactuca biomass for Pb(II) and Cd(II) ions was found to be 34.7mg/g and 29.2mg/g, respectively. From the D-R isotherm model, the mean free energy was calculated as 10.4kJ/mol for Pb(II) biosorption and 9.6kJ/mol for Cd(II) biosorption, indicating that the biosorption of both metal ions was taken place by chemisorption. The calculated thermodynamic parameters (DeltaG degrees , DeltaH degrees and DeltaS degrees ) showed that the biosorption of Pb(II) and Cd(II) ions onto U. lactuca biomass was feasible, spontaneous and exothermic under examined conditions. Experimental data were also tested in terms of biosorption kinetics using pseudo-first-order and pseudo-second-order kinetic models. The results showed that the biosorption processes of both metal ions followed well pseudo-second-order kinetics. PMID- 17689187 TI - Ouabain does not impair reconsolidation following a reminder of passive avoidance learning in the day-old chick. AB - This study investigated the effect of ouabain, an inhibitor of NA(+) and K(+) ATPase, on consolidation and reconsolidation of a passive avoidance learning task in the day-old chick. In the consolidating trace, ouabain is thought to inhibit an intermediate-term memory phase, some aspects of which acts as a "trigger" for long-term stabilisation of the trace by new protein synthesis. It was hypothesised that a similar process may initiate the protein synthesis observed following reminder-activated reconsolidation in the young chick. Chicks were trained on a single trial passive avoidance task. A dose of 0.2 ug/kg ouabain was administered intracranially either 5 min post-training (consolidation processes) or 5 min post-reminder (reconsolidation processes). Consistent with previous research, ouabain administration induced a memory deficit following the initial learning trial. However, contrary to expectation, ouabain did not disrupt memory processing post-reactivation. This finding provides further evidence for the notion that consolidation and reconsolidation are associated with similar, but distinct, stages of processing. PMID- 17689188 TI - Atropine, a muscarinic cholinergic receptor antagonist increases serotonin, but not dopamine levels in discrete brain regions of mice. AB - We investigated the effects of atropine, a muscarinic acetylcholine (ACh) receptor antagonist, on the level of serotonin in discrete brain regions, the nucleus raphe dorsalis (NRD), nucleus caudatus putamen (NCP), cerebral cortex and the cerebellum. Biogenic amines were assayed employing HPLC electrochemistry in these regions 30 min following different doses of atropine (5, 10, 25mg/kg; i.p.), and at various time points (15, 30, 60, 120 min) after 25mg/kg of the drug. The cholinergic receptor antagonist caused a dose-dependent alteration in the level of serotonin in NRD, but the increase was not dose-dependent for other regions studied. The metabolite of serotonin, 5-hydroxyindoleacetic acid was unaffected. Atropine did not affect the levels of dopamine or its metabolites dihydroxyphenyl acetic acid and homovanillic acid. The present study suggests significant effect of this antimuscarinic agent on the synthesis of serotonin in the central serotoninergic pathways, which may have clinical relevance. PMID- 17689189 TI - Dose-dependent neuroprotection of delta opioid peptide [D-Ala2, D-Leu5] enkephalin in neuronal death and retarded behavior induced by forebrain ischemia in rats. AB - Cerebral ischemic insult, mainly induced by cardiovascular disease, is one of the most severe neurological diseases in clinical. There's mounting evidence showing that delta opioid agonist [D-Ala2, D-Leu5] enkephalin (DADLE) has a tissue protective effect. However, whether this property is effective to prevent neuronal death induced by forebrain ischemia is not clear. This study was aimed to investigate whether intracerebroventricular (ICV) administration of DADLE has a neuroprotective effect against forebrain ischemia in rats. We found in our study that administration of DADLE 45 min before forebrain ischemia had significant protective effect against CA1 neuronal lose. Further more, we found that DADLE had a dose-dependent protection for improving behavioral retardation revealed by Morris water maze and motor score test, while naltrindole, the antagonist of delta opioid receptor, partially abolished neuroprotective effect of DADLE, which implicated that both opioid and non-opioid systems are involved in ischemic insults and neuroprotection. PMID- 17689190 TI - The characteristics of chronic central pain after traumatic brain injury. AB - Central pain following traumatic brain injury (TBI) has not been studied in depth. Our purpose was to conduct a systematic study of patients with TBI suffering from chronic central pain, and to describe the characteristics of the central pain. Groups were TBI patients with (TBIP) and without central pain (TBINP) and healthy controls. TBI patients with other pain mechanisms were excluded from the study. Participants underwent quantitative somatosensory testing in the painful and pain-free body regions. Thresholds for warmth, cold, heat-pain, touch and graphesthesia were measured and pathologically evoked pain (allodynia, hyperpathia and wind-up pain) evaluated. Chronic pain was mapped and characterized. Chronic pain developed at a relatively late onset (6.6+/-9 months) was almost exclusively unilateral and reported as pricking, throbbing and burning. Although both TBIP and TBINP exhibited a significant reduction in thermal and tactile sensations compared to controls, thermal sensations in the painful regions of TBIP were significantly more impaired than pain-free regions in the same patients (p<0.01) and in TBINP (p<0.01). Painful regions also exhibited very high rates of allodynia, hyperpathia and exaggerated wind-up. The characteristics of the chronic pain resembled those of other central pain patients although TBIP displayed several unique features. The sensory profile indicated that damage to the pain and temperature systems is a necessary but not sufficient condition for the development of chronic central pain following TBI. Neuronal hyperexcitability may be a contributing factor to the chronic pain. PMID- 17689191 TI - IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats. AB - Although it has been shown that pro-inflammatory cytokines such as interleukin 1beta (IL-1beta) facilitate perception of noxious inputs at the spinal level, the mechanisms have not been understood. This study determined the cell type that produces IL-1beta, the co-localization of IL-1 receptor type I (IL-1RI) and Fos and NR1 in the spinal cord, and the effects of IL-1 receptor antagonist (IL-1ra) on NR1 phosphorylation and hyperalgesia in a rat model of inflammatory pain. Phosphorylation of NR1, an essential subunit of the NMDA receptor (NMDAR), is known to modulate NMDAR activity and facilitate pain. Hyperalgesia was induced by injecting complete Freund's adjuvant (CFA, 0.08ml, 40microg Mycobacterium tuberculosis) into one hind paw of each rat. Paw withdrawal latency (PWL) was tested before CFA (-48h) for baseline and 2 and 24h after CFA to assess hyperalgesia. IL-1ra was given (i.t.) 24h before CFA to block the action of basal IL-1beta and 2h prior to each of two PWL tests to block CFA-induced IL-1beta. Spinal cords were removed for double immunostaining of IL-1beta/neuronal marker and IL-1beta/glial cell markers, IL-1RI/Fos and IL-1RI/NR1, and for Western blot to measure NR1 phosphorylation. The data showed that: (1) astrocytes produce IL 1beta, (2) IL-1RI is localized in Fos- and NR1-immunoreactive neurons within the spinal dorsal horn, and (3) IL-1ra at 0.01mg/rat significantly increased PWL (P<0.05) and inhibited NR1 phosphorylation compared to saline control. The results suggest that spinal IL-1beta is produced by astrocytes and enhances NR1 phosphorylation to facilitate inflammatory pain. PMID- 17689192 TI - Hypnosis in the management of persistent idiopathic orofacial pain--clinical and psychosocial findings. AB - This controlled and patient blinded study tested the effect of hypnosis on persistent idiopathic orofacial pain (PIOP) in terms of clinical and psychosocial findings. Forty-one PIOP were randomized to active hypnotic intervention or simple relaxation as control for five individual 1-h sessions. Primary outcome was average pain intensity scored three times daily in a pain diary using visual analogue scale (VAS). Secondary outcome measures were pain quality assessed by McGill pain questionnaire (MPQ), psychological symptoms assessed by symptom check list (SCL), quality of life assessed by SF36, sleep quality, and consumption of analgesic. Data were compared between groups before and after treatment using ANOVA models and paired t-tests. The change in VAS pain scores from baseline to the last treatment (t4) was (33.1+/-7.4%) in the hypnosis group and (3.2+/-5.4%) in the control group (P<0.03). In the hypnosis group, highly hypnotic susceptible patients had greater decreases in VAS pain scores (55.0+/-12.3%) when compared to less susceptible patients (17.9+/-6.7%) (P<0.02). After the last treatment there were also statistically significant differences between groups in perceived pain area (MPQ) and the use of weak analgesics (P<0.03). There were no statistically significant changes in SCL or SF36 scores from baseline to t4. In conclusion, hypnosis seems to offer clinically relevant pain relief in PIOP, particularly in highly susceptible patients. However, stress coping skills and unresolved psychological problems need to be included in a comprehensive management plan in order also to address psychological symptoms and quality of life. PMID- 17689193 TI - Use of ELISA employing Leishmania (Viannia) braziliensis and Leishmania (Leishmania) chagasi antigens for the detection of IgG and IgG1 and IgG2 subclasses in the diagnosis of American tegumentary leishmaniasis in dogs. AB - American tegumentary leishmaniasis (ATL) shows a reduced humoral response in dogs and levels of specific antibodies may therefore not be detected by indirect immunofluorescence. Although the sensitivity of enzyme-linked immunosorbent assay (ELISA) is higher than that of indirect immunofluorescence, the best antigen for the diagnosis of ATL in dogs has not been defined. The detection of IgG subclasses represents an alternative to increase the efficiency of the serological diagnosis. In Rio de Janeiro, sporotrichosis is the main differential diagnosis of ATL in dogs, and a sensitive, specific and little invasive method that permits the discrimination of the two diseases is desired. In the present study, 69 serum samples, 34 obtained from dogs with ATL and 35 from dogs with sporotrichosis, all of them with a confirmed etiological diagnosis, were tested. The samples were analyzed by ELISA using Leishmania (Viannia) braziliensis and L. (L.) chagasi antigens for the detection of anti-Leishmania IgG, IgG1 and IgG2. The use of L. (V.) braziliensis antigens for the detection of IgG and IgG2 yielded the best results. Using L. (L.) chagasi antigen, the sensitivity and specificity for the detection of IgG were 82.4% and 100%, respectively, whereas both sensitivity and specificity were 97.1% with the L. (V.) braziliensis antigen. No improvement in the performance of the test was observed when IgG2 was analyzed separately. The IgG1 assays presented low accuracy, irrespective of the antigen used: sensitivity and specificity of 58.8% and 60% for L. (V.) braziliensis and of 64.7% and 77.1% for L. (L.) chagasi, respectively. The present results suggest that IgG ELISA using the L. (V.) braziliensis shows the best performance for the diagnosis of ATL, permitting the discrimination between cases of ATL and sporotrichosis in dogs. PMID- 17689194 TI - Possibility of Neospora caninum infection by venereal transmission in CB-17 scid mice. AB - CB-17 scid and BALB/c male mice were inoculated intraperitoneally with Neospora caninum to examine the possibility of its venereal transmission. Some of these mice were killed on days 7 and 20 post-inoculation to examine the genital organs for presence of the parasite. The remaining scid male mice were housed with non infected female mice from day 7 p.i. and kept with them for 14 days. These scid mice died between days 28 and 35 p.i. N. caninum DNA was detected in the testis of mice on days 7 and 20 p.i. by PCR and tachyzoite viability was determined by bioassay conducted by means of mouse inoculation. Microscopically, fewer tachyzoites were detected in the testis obtained on day 20 p.i., than in other organs. The inoculated BALB/c male mice survived until the end of the experiment with no clinical signs and N. caninum DNA was detected in the testis on day 7 p.i. but not on day 14 p.i. Five of eight female scid mice housed with infected males became pregnant. Tachyzoites were detected in three of these mice and their neonates (n=3, 5 and 13, respectively). In three non-pregnant mice, no parasite was detected. Two of the four female BALB/c mice housed with infected male scid mice became pregnant but the parasite was not detected in them or in the neonates (n=3 and 13, respectively). These results indicate that the tachyzoites were present in the genital organs of the immunodeficient mice from day 7 p.i. and suggest that transmission may occur through mating with male mice. PMID- 17689195 TI - World distribution of Trichinella spp. infections in animals and humans. AB - The etiological agents of human trichinellosis show virtually worldwide distribution in domestic and/or wild animals, with the exception of Antarctica, where the presence of the parasite has not been reported. This global distribution of Trichinella and varying cultural eating habits represent the main factors favouring human infections in industrialised and non-industrialised countries. Human trichinellosis has been documented in 55 (27.8%) countries around the world. In several of these countries, however, trichinellosis affects only ethnic minorities and tourists because the native inhabitants do not consume uncooked meat or meat of some animal species. Trichinella sp. infection has been documented in domestic animals (mainly pigs) and in wildlife of 43 (21.9%) and 66 (33.3%) countries, respectively. Of the 198 countries of the world, approximately 40 (20%) are small islands far from the major continents, or city-states where Trichinella sp. cannot circulate among animals for lack of local fauna (both domestic and wild). Finally, information on the occurrence of Trichinella sp. infection in domestic and/or wildlife is still lacking for 92 countries. PMID- 17689196 TI - The impact of assessing simulated bad news consultations on medical students' stress response and communication performance. AB - Seventy second-year medical students volunteered to participate in a study with the aim of evaluating the impact of the assessment of simulated bad news consultations on their physiological and psychological stress and communication performance. Measurements were taken of salivary cortisol, systolic and diastolic blood pressure, heart rate, state anxiety and global stress using a Visual Analogue Scale. The subjects were asked to take three salivary cortisol samples on the assessment day as well as on a quiet control day, and to take all other measures 5 min before and 10 min after conducting the bad news consultation. Consultations were videotaped and analyzed using the information-giving subscale of the Amsterdam Attitude and Communication Scale (AACS), the Roter Interaction Analysis System (RIAS), and the additional non-verbal measures, smiling, nodding and patient-directed gaze. MANOVA repeated measurements were used to test the difference between the cortisol measurements taken on the assessment and the control day. Linear regression analysis was used to determine the association between physiological and psychological stress measures and the students' communication performance. The analyses were restricted to the sample of 57 students who had complete data records. In anticipation of the communication assessment, cortisol levels remained elevated, indicating a heightened anticipatory stress response. After the assessment, the students' systolic blood pressure, heart rate, globally assessed stress level and state anxiety diminished. Pre-consultation stress did not appear to be related to the quality of the students' communication performance. Non-verbal communication could be predicted by pre-consultation physiological stress levels in the sense that patient-directed gaze occurred more often the higher the students' systolic blood pressure and heart rate. Post-consultation heart rate remained higher the more often the students had looked at the patient and the more information they had provided. However, the heart rate appeared to diminish the more often the students had reassured the patient. These findings suggest that in evaluating students' communication performance there is a need to take their stress levels into account. PMID- 17689197 TI - Eosinophil-induced prognosis improvement of solid tumors could be enabled by their vesicle-mediated barrier permeability induction. AB - Eosinophils are multifunctional cells, which contain and produce many biologically active substances. Generally, eosinophilia is associated with parasitic infections or allergic disorders, while according to recent studies eosinophil infiltration is also present in target tissues of both physiological and pathological processes, such as angiogenesis, embryogenesis, immune regulation, different infections or neoplasies, leading to tissue damage or remodeling. Reflecting on prognosis improvement in the case of solid tumors after eosinophilic infiltration of their capsules, it could be hypothesized that eosinophils are not tumoricidal per se; rather they can perforate such barriers through their vesicles' content, whereas the tumoricidal cytokines such as interleukin 4 (IL-4) fulfill the tumoral necrosis. This scenario can be supported by the fact that IL-4 originated from macrophages and lymphocytes fails to mediate tumor necrosis in vitro conditions in absence of eosinophils. In addition, the requirement of eosinophil-mediated increasing permeability among diverse biologic barriers and tissues may explain the eosinophils' introduction in capsules of cysts, mucosal membrane of respiratory and gastroenteric systems, hemato-encephalic barrier, in embryos, as well as in bacterial and parasitic membranes. Thus, in some situations rather than being multifunctional effectors per se, eosinophils, due to induction of target barrier dysfunction, may assure the host-required action, mediated by various kinds of leucocytes and their biologic effectors. Consequently, a better understanding of physiology and patho physiology of this enigmatic cell will lead to new clinical strategies. PMID- 17689198 TI - Could chronic wounds not heal due to too low local copper levels? AB - Copper is an essential trace element involved in numerous human physiological and metabolic processes. It plays a key role in many of the processes that together comprise wound healing, including induction of endothelial growth factor, angiogenesis and expression and stabilization of extracellular skin proteins. We hypothesize that in individuals with diabetic ulcers, decubitus, peripheral vascular, or other wounds which might have compromised circulation to the wound site, that part of the incapacity of the wounds to heal is due to low local copper levels. Contamination of wounds is also an important factor causing impaired wound healing. Importantly, copper has potent broad biocidal properties. In contrast, the risk of adverse skin reactions due to exposure to copper is extremely low. We thus hypothesize that introducing copper into wound dressings would not only reduce the risk of wound and dressing contamination, as silver does but, more importantly, would stimulate faster wound repair directly. This would be done by the release of copper from the wound dressings directly into the wound site inducing angiogenesis and skin regeneration. PMID- 17689199 TI - Is uric acid itself a player or a bystander in the pathophysiology of chronic heart failure? AB - Uric acid (UA) is the end product of purine metabolism in humans. Hyperuricemia is often found in patients with chronic heart failure (CHF). The increase of serum UA level is inversely associated with disease severity, cardiac function and prognosis of CHF. Some researchers found that UA had detrimental impact on the cardiovascular system, including mediating immune response upon cell injury, increasing endotoxin-stimulated tumor necrosis factor-alpha production and hence proinflammatory immune activation, increasing blood pressure, and so on. Other researchers found that UA had important antioxidant properties by scavenging various reactive oxygen species. So far, there is no evidence suggest that UA has detrimental effect on the pathophysiology of CHF. Xanthine oxidase (XO) is an enzyme that produces uric acid during purine metabolism. XO activity is up regulated in failing heart, and serum UA levels reflect the degree of XO activation in CHF. XO plays an important role in the pathophysiology process of CHF, including myocyte apoptosis, endothelial dysfunction and cardiac mechanoenergetic uncoupling. The therapeutic effect of long-term XO inhibition has been confirmed in animal models and partly in human bodies. We hypothesize that UA itself is not a player but a bystander associated with the activation of XO in the pathophysiology of CHF. PMID- 17689200 TI - Fetal death repetition: the event memory hypothesis. AB - Fetal death recurrence is an important problem in reproductive health that is poorly understood. Based on preliminary epidemiologic evidence, we propose an "event memory" hypothesis which posits that when fetal death occurs the event is retained (memorized) as a program that is replayed in future pregnancies. We describe a pathway through which excessive programmed death (apoptosis) that mediates fetal demise in an initial pregnancy gets stored as an apoptotic cascade program that is replayed in a subsequent pregnancy regardless of the cause of the initial pregnancy loss. We propose an innovative method by which this hypothesis could be tested. If proven, the hypothesis will potentially represent a shift in paradigm in the field of epidemiology by introducing a new dimension (memory recall) to the cause--effect inference model; it will create a new intervention concept in prevention science, and will positively influence inter-conceptional care for mothers with a previous fetal death. PMID- 17689201 TI - Irreversible and reversible components in the genesis of hypertension by sodium chloride (salt). AB - Despite the abundant studies and overwhelming evidences demonstrating the essential role of salt (sodium chloride) for developing "essential" hypertension (EH), the controversies about salt-hypertension (HT) relations are still continuing. One of important mistakes in this topic is assuming that the HT producing effect of salt is reversible. The present paper explains the complex nature of salt-HT relations. The deduction was made basing on the studies which investigate the relations between salt and HT. Animal experiments show that HT producing effect of salt contains irreversible and reversible components. The existence of irreversible component manifests itself in this way: the blood pressure (BP) does not recede to the natural values despite removing of salt exposure. The proportion of BP decreasing after salt exposure termination belongs to the reversible component. Available evidences indicate that the irreversible component is developed in utero, during suckling and, generally, in prepubertal period secondary to salt exposure, however, if the salt exposure extends over more than one period, the HT may be intensified. The consequences of salt exposure during early life of human beings have not been investigated as detailed as in experimental animals, however, there are some clinical trials and epidemiological observations indicating that, similar to experimental animals, irreversible and reversible components are also developed in man during the genesis of HT. By the introduction of irreversible and reversible components notion, some obscured items on salt-HT relations can be clarified. For example, some intervention studies could not find dramatic relations between salt and HT, because these interventions modify only the reversible component, but irreversible component remains unchanged. As a result, salt exposure is detrimental for each period of life. For eradication of HT, it is prerequisite to prevent all individuals (especially pregnant or lactating women, and children) from salt exposure. In this condition, the new generation will be free from HT. PMID- 17689202 TI - Recent advance and possible future in TREK-2: a two-pore potassium channel may involved in the process of NPP, brain ischemia and memory impairment. AB - TREK-2, a new member of the mechanosensitive tandem-pore K+ channel family, share 65% amino acid sequence identity and some similar basic electrophysiological and pharmacological properties with TREK-1. It also has some specific regulatory pathway and tissue distribution contrasted with TREK-1 and TRAAK. TREK-2 distributes extensively in CNS and periphery tissue. It can be regulated by G protein-coupled receptor (GPCR) and may involve in several of physiological and pathophysiological conditions. The long-chain unsaturated free fatty acids such as arachidonic acid (AA), PHi, pressure and temperature can increase the activity of TREK-2. The purpose of this review is to present the recent study and possible importance of TREK-2 in neuropathic pain, thereby emphasizing TREK-2 as one of the important mechanisms underlying. This information should be very useful and prospective for effective chronic pain therapy and future analgesic drug development. This review also further predicts the role of TREK-2 in brain ischemia, memory and other tissue. The specific location and function of TREK-2 in these tissues need further study. PMID- 17689203 TI - TLRs are important inflammatory factors in atherosclerosis and may be a therapeutic target. AB - Inflammation and immune reactions are implicated in atherogenesis and plaque disruption. The precise triggers for inflammation in atherosclerosis are not fully understood but may include hypercholesterolemia, modified lipoproteins and local or distant infections. TLRs play an important role in the innate and inflammatory signaling responses to microbial agents. Evidence from diverse sources has suggested that TLRs can affect atherosclerosis in multiple ways. Several reports have documented the expression of TLRs in atherosclerotic lesions and suggested that the TLR-NF-kappa B pathway is activated in the lesion, resulting in the transcription of a variety of genes involved in the inflammatory and proliferative responses of cells critical to atherogenesis and ultimately leading to the synthesis and release of antimicrobial peptides and inflammatory cytokines that provide a critical link to adaptive immunity. Moreover, TLR4 expression in macrophages is up-regulated by oxidized LDL, which suggests a potential mechanism for the synergistic effects of hypercholesterolemia and infection in acceleration of atherosclerosis. These findings indicate that TLRs provide additional new insights into the link among lipids, infection/inflammation and atherosclerosis, thus may be effective therapeutic target molecules. We speculate that TLRs are important for the development and progression of atherosclerosis, and hence blocking the expression of TLRs may serve as new targets for antiatherogenic therapy. PMID- 17689204 TI - The proportion of fixed interval trials to probe trials affects acquisition of the peak procedure fixed interval timing task. AB - A common procedure for studying the ability of animals to time is the peak procedure. With the peak procedure, animals are first trained on a fixed interval schedule (i.e., 30s). After the animals have been well trained on the fixed interval schedule, probe trials are introduced. On probe trials, the stimulus is presented longer (i.e., 90s) and the animal does not receive reinforcement for responding. When animals are first presented with probe trials responding remains flat following the point that reinforcement normally occurs on fixed interval trials. The descending slope that eventually emerges is acquired with experience with probe trials. The present experiments manipulated the percentage of probe trials compared to FI trials across groups of rats. It was hypothesized that the descending limb of peak responding would be acquired more quickly when there were many probe trials per session as this might facilitate extinction of responding beyond the interval that reinforcement normally occurs. It was found, however, that acquisition of peak responding occurred best when there were few probe trials per session. PMID- 17689206 TI - The tree of life might be rooted in the branch leading to Nanoarchaeota. AB - It is suggested that the tree of life might be rooted in the domain of the Archaea, in the branch leading to the phylum of Nanoarchaeota. This hypothesis seems to be corroborated by the uniqueness and ancestrality of some traits possessed by Nanoarchaeum equitans, such as split genes separately codifying for the 5' and 3' halves of the tRNA molecule. These half genes are the oldest ancestral form of gene we have ever seen. This, along with the absence of operons from the genome of N. equitans, would seem to indicate that this genome is a molecular fossil of the evolutionary stage which the ancestral genomes had reached when the first lines of divergence were established. Moreover, the late appearance of DNA coinciding with the rooting of the universal phylogenetic tree would make the genome of N. equitans a witness to this fundamental event. PMID- 17689205 TI - Ethnic differences in alcohol treatment outcomes and the effect of concurrent smoking cessation treatment. AB - The Timing of Alcohol and Smoking Cessation (TASC) Study tested the optimal timing of smoking cessation treatment in an alcohol-dependent population. Previously reported results suggest that providing concurrent smoking cessation treatment adversely affects alcohol outcomes. The purpose of this analysis was to investigate whether there are ethnic differences in alcohol and tobacco outcomes among a diverse sample of alcohol-dependent smokers using data from the TASC trial in which 499 participants were randomized to either concurrent (during alcohol treatment) or delayed (6 months later) smoking intervention. This analysis focused on smokers of Caucasian (n=381) and African American (n=78) ethnicity. Alcohol outcomes included 6 months sustained alcohol abstinence rates and time to first use of alcohol post-treatment. Tobacco outcomes included 7-day point prevalence smoking abstinence. Random effects logistic regression analysis was used to investigate intervention group and ethnic differences in the longitudinally assessed alcohol outcomes. Alcohol abstinence outcomes were consistently worse in the concurrent group than the delayed group among Caucasians, but this was not the case for African Americans. No significant ethnic differences were observed in smoking cessation outcomes. Findings from this analysis suggest that concurrent smoking cessation treatment adversely affects alcohol outcomes for Caucasians but not necessarily for African Americans. PMID- 17689207 TI - Protective effects of kahweol and cafestol against hydrogen peroxide-induced oxidative stress and DNA damage. AB - There is an increasing evidence that oxidative stress is implicated in the processes of inflammation and carcinogenesis. It has been shown that kahweol and cafestol, coffee-specific diterpenes, exhibit chemoprotective effects. This study investigated the effects of kahweol and cafestol, coffee-specific diterpenes, on the hydrogen peroxide (H(2)O(2))-induced oxidative stress and DNA damage in NIH3T3 cells. When the cells were treated with kahweol or cafestol, cytotoxicity, lipid peroxidation, and reactive oxygen species production induced by H(2)O(2) were markedly reduced in a dose-dependent manner. Moreover, kahweol and cafestol were shown to be highly protected against H(2)O(2)-induced oxidative DNA damage as determined by the Comet (single cell gel electrophoresis) assay and the measurement of 8-oxoguanine content in NIH3T3 cells. Kahweol and cafestol also protected hydroxyl radical-induced 2-deoxy-d-ribose degradation by ferric ion nitrilotriacetic acid and H(2)O(2). In addition, kahweol and cafestol efficiently removed the superoxide anion generated from the xanthine/xanthine oxidase system. These results suggest that kahweol and cafestol are effective in protecting against H(2)O(2)-induced oxidative stress and DNA damage, probably via scavenging free oxygen radicals, and that kahweol and cafestol act as antioxidants. PMID- 17689208 TI - Expression of STAT3 and Bcl-6 oncoprotein in sodium arsenite-treated SV-40 immortalized human uroepithelial cells. AB - Arsenic is widely distributed in the environment, and it is a proven toxic and carcinogenic agent. On the southwest coast of Taiwan, an endemic occurrence of chronic arsenical poisoning due to a high concentration of arsenic in artesian well water has been reported. However, the mechanisms of its carcinogenic action are still unclear. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is an essential cascade for mediating normal functions of different cytokines in the development of the hematopoietic and immune systems. In this study, the substantial morphological changes observed in SV-40 immortalized human uroepithelial cells (SV-HUC-1) after treatment of various concentrations of arsenite were examined, and the expression of Bcl-6, Jak-2 and p-STAT3 (Tyr 705) were evaluated by immunocytochemistry and Western blotting. Our results showed that the expression of Bcl-6 increased dose dependently in arsenite-treated urothelial cells. Sodium arsenite treatment reduced Jak-2 protein expression in a dose-dependent manner. However, treatment of SV-HUC-1 cells with arsenite at concentration ranges from 2 and 4microM for 48h dramatically increased p-STAT3 (Tyr 705), but the levels decreased at 8 40microM of arsenite. Our data suggest that arsenic-mediated inactivation of the JAK-STAT signaling pathway might be caused by Bcl-6 interaction with JAK tyrosine kinase or STAT. In conclusion, our findings indicate that arsenic inhibits JAK tyrosine kinase protein expression and suggest the interference in the JAK-STAT pathway might be through Bcl-6 playing an important role in arsenic-associated carcinogenesis. PMID- 17689209 TI - Early pregnancy loss in sows after low dose, deep uterine artificial insemination with sex-sorted, frozen-thawed sperm. AB - Recent developments in reproductive technologies have enabled the production of piglets of a predetermined sex via non-surgical, low dose artificial insemination. The practical application of sex-sorting technology to the pig is made challenging by the large numbers of sperm required for successful insemination of sows. One way of overcoming the time required for sex-sorting may be to create a bank of cryopreserved, sex-sorted sperm, thus making available appropriate doses as sows require insemination. To date, little success has been achieved with non-surgical inseminations of sex-sorted boar sperm. This study attempted to achieve litters of a predetermined sex after a double insemination of sows with 160x10(6) sex-sorted, frozen-thawed sperm. Sows were synchronised and sperm were non-surgically inseminated into the proximal third of the uterine horn at 36 and 42 h after hCG administration. Sows inseminated with sex-sorted sperm achieved similar pregnancy rates to those receiving an equal dose of unsorted, frozen-thawed sperm. However, all sows conceiving after insemination with sex-sorted sperm returned to oestrus within 57 days of insemination. This was a higher rate of pregnancy loss than observed for sows inseminated with unsorted sperm (37.5%; P=0.031). A combination of low sperm numbers and potentially compromised developmental capability of embryos derived from sex sorted sperm may have resulted in this early stage loss of pregnancy. PMID- 17689210 TI - Controlled dual release of basic fibroblast growth factor and indomethacin from heparin-conjugated polymeric micelle. AB - This work describes the development of heparinized polymeric micelle as a novel injectable carrier for the dual drug delivery that can simultaneously release basic fibroblast growth factor (bFGF) and indomethacin (IMC), which can promote the regeneration of damaged tissue and prevent the inflammatory response after implantation. Tetronic-PCL-heparin for the preparation of heparinized polymeric micelle was synthesized by introducing PCL as a biodegradable linkage on Tetronic, following the conjugation of heparin. The mean diameter of the formed TCH micelle was around 114 nm and increases in the micelle size after single and dual drug loading were observed. Loading efficiencies of IMC and bFGF were 30.9% and 70.5%, respectively. In vitro dual drug release profiles from TCH micelles were investigated. IMC was more slowly released from dual drug-loaded micelle over 3 weeks as compared with single drug-loaded one. bFGF was released over 2 months in a controlled manner. Therefore, the release profile results support that TCH micelle could not only incorporate a hydrophobic drug into the core but also bind with bFGF to heparin that exists on its outer shell. The TCH micelle will have enhanced therapeutic effects on the target site which may be required the multi-function of drugs to use. PMID- 17689211 TI - Unified compaction curve model for tensile strength of tablets made by roller compaction and direct compression. AB - A model that describes the relationship between roller-compaction conditions and tablet strength is proposed. The model assumes that compaction is cumulative during roller compaction and subsequent granule compaction, and compact strength (ribbon and tablet) is generated irreversibly as if strength is controlled by plastic deformation of primary particles only. Roller-compaction is treated as a compaction step where the macroscopic ribbon strength is subsequently destroyed in milling. This loss in strength is irreversible and tablets compressed from the resulting granulation are weaker than those compressed by direct compression at the same compression force. Roller-compacted ribbons were produced at a range of roll forces for three formulations and subsequently milled and compacted into tablets. Once the total compaction history is taken in account, the compaction behavior of the uncompacted blends and the roller-compacted granules ultimately follow a single master compaction curve--a unified compaction curve (UCC). The model successfully described the compaction behavior of DC grade starch and formulations of lactose monohydrate with 50% or more microcrystalline cellulose, and may be more generally applicable to systems containing significant proportions of any plastically deforming material, including MCC and starch. PMID- 17689212 TI - Enhancement of the dissolution rate and gastrointestinal absorption of pranlukast as a model poorly water-soluble drug by grinding with gelatin. AB - The effect of grinding with gelatin on the dissolution behavior and gastrointestinal absorption of a poorly water-soluble drug was evaluated using the antiasthmatic agent, pranlukast, as a model poorly water-soluble drug. A ground pranlukast-gelatin mixture was prepared by grinding equal quantities of pranlukast and gelatin. In the dissolution testing, the dissolution rate of pranlukast in the suspension of the ground pranlukast-gelatin mixture under conditions of pH 3.0, 5.0 and 7.0 was markedly faster than that in the suspension of pranlukast. According to powder X-ray diffractometry (PXRD) and differential scanning calorimetry (DSC) analysis, the enhanced dissolution rate of pranlukast produced by grinding with gelatin was caused by changing the crystalline state of pranlukast into an amorphous state. In an animal experiment, the bioavailability of pranlukast following oral administration of the ground pranlukast-gelatin mixture to rats was threefold greater than that following administration of pranlukast. In the in vitro permeation experiment, the amount of permeated pranlukast through Caco-2 cell monolayers after application of the ground pranlukast-gelatin mixture was greater than that after application of pranlukast. These results suggest that the enhancement of the gastrointestinal absorption of pranlukast by grinding with gelatin is due to enhancement of the dissolution rate. Grinding a poorly water-soluble drug with gelatin is a useful method of enhancing its gastrointestinal absorption. PMID- 17689213 TI - Study growth kinetics in fluidized bed granulation with at-line FBRM. AB - In this study, a novel at-line focused beam reflectance measurement (FBRM) technique was developed to investigate granule growth in a fluidized bed granulation (FBG). The chord length distribution (CLD) measured by the FBRM was used to represent granule particle size distribution (PSD). Through a systematic study, it was proved that the trends of the chord length measured by the at-line FBRM technique were identical to those measured by a laser diffraction instrument and sieve analysis in spite of different measurement mechanisms. The portable at line FBRM technique was successfully applied to a granule growth kinetics study for a fluidized bed granulation performed in a Glatt GPCG-1 granulator. Granule size evolution was clearly exhibited by the at-line FBRM. Spray rate was found to be the most significant factor on the granule growth compared with the other two factors: binder solution concentration and intra- to extra-granular microcrystalline cellulose (MCC) ratio for the formulation studied in this work. The CLD evolution measured by the FBRM confirmed that the granule agglomeration was mainly dominated by the binder on the granule surface. The at-line FBRM enables us to select appropriate process parameters and effectively control the fluid bed granulation process. PMID- 17689214 TI - Fractal-feature distance as a substitute for observer performance index in contrast-detail examination. AB - PURPOSE: To assess whether or not the fractal-feature distance using the box counting algorithm can be a substitute for observer performance index. METHODS AND MATERIALS: Contrast-detail (C-D) phantom images were obtained at various mAs values (0.5-4.0 mAs) and 140 kV(p) with a Fuji computed radiography system, and the reference image was acquired at 50 mAs; all cylindrical targets in the C-D phantom were visualized on this image. The C-D images were converted to binary images using the profile curves around the smallest cylindrical target images on the reference images. The fractal analysis was conducted using the box-counting algorithm for these binary images. The fractal-feature distances between the low dose and reference images were calculated using the fractal dimension and the complexity. Furthermore, we performed the C-D analysis in which ten radiologists participated, and compared the fractal-feature distances with the image quality figures (IQF) derived from the C-D analysis with Markov chain. RESULTS: For all C D phantom radiographs, the relationship between the length of the square boxes and the number of boxes to cover the positive pixels of the binary image was linear on a log-log scale (r>or=0.999). A strong linear correlation was found between the fractal-feature distance and IQF (r=0.990). CONCLUSION: We have shown that the binary image of C-D phantom can be analyzed by the box-counting algorithm and its fractal-feature distance increases as the radiation dose decreases. Furthermore, we have shown that the fractal-feature distances will be equivalent to IQFs in C-D analysis. PMID- 17689215 TI - Use of ultrasmall superparamagnetic iron oxide in lymph node MR imaging in prostate cancer patients. AB - A macrophage-specific magnetic resonance (MR) contrast agent allows the detection of small and otherwise undetectable lymph node metastases in patients with prostate cancer. This has an important clinical impact, as the diagnosis will be more precise and less invasive to obtain. Subsequently, this will reduce morbidity and health care costs. However, thorough knowledge of sequence parameters and planes, lymph node anatomy, appearance of normal and abnormal nodes, is essential when using this technique. This will be elaborated in this review. PMID- 17689216 TI - Osteoid osteoma treated with percutaneous radiofrequency ablation: MR imaging follow-up. AB - PURPOSE: We evaluated follow-up magnetic resonance (MR) images for osteoid osteoma treated with percutaneous radiofrequency ablation (RFA). MATERIALS AND METHODS: Sixteen patients with osteoid osteoma treated with RFA underwent follow up MR imaging. The protocol included T1, T2 and contrast-enhanced (CE) T1 weighted images with fat saturation at each visit immediately for 17 months after the treatment. MR images were jointly reviewed by two radiologists, regarding the appearance of treated areas, presence of complications, and the best sequence for visualization of signal intensity (SI) changes. The therapeutic response was evaluated to be a clinical success with the relief of pain. RESULTS: The treated areas had a target-like appearance on MR images: a central ablated zone (Z1) surrounded by a band (Z2), and a peripheral area (Z3). Z1 was a non-enhancing, hypointense core on T1, T2WI. Z2 was a well-enhancing, hyperintense rim on T2WI. Z3 was less hyperintense and less enhanced than Z2. All nidi were within Z1. This appearance became evident from 1 week to 1 and 2 months. Following up after 2 months, Z2 showed progressive inward enhancement from the periphery, resulting in almost complete enhancement of Z1 and Z2 with a diminishing size. Z3 gradually showed a decrease in signal change and enhancement. No complications were found. CE-T1WI was the best for visualizing SI changes. The clinical success was achieved in all patients except for one patient with a recurrence at 17 months following treatment that had a second ablation. CONCLUSION: MR imaging demonstrated a characteristic appearance and subsequent changes of treated areas for osteoid osteoma following RFA. PMID- 17689217 TI - Comparison of observer performance on soft-copy reading of digital chest radiographs: high resolution liquid-crystal display monitors versus cathode-ray tube monitors. AB - The purpose of this study is to compare observer performance for detection of abnormalities on chest radiographs with 5-megapixel resolution liquid-crystal displays (LCD) and 5-megapixel resolution cathode-ray tube (CRT) monitors under bright and subdued ambient light conditions. Six radiologists reviewed a total of 254 digital chest radiographs under four different conditions with a combination of two types of monitors (a 5-megapixel resolution LCD and a 5-megapixel resolution CRT monitor) and with two types of ambient light (460 and 50 lux). The abnormalities analyzed were nodules, pneumothorax and interstitial lung disease. For each reader, the detection performance using 5-megapixel LCD and 5-megapixel CRT monitors under bright and subdued ambient light conditions were compared using multi-case and multi-modality ROC analysis. For each type of ambient light, the average detection performance with the two types of monitors was also compared. For each reader, the observer performance of 5-megapixel LCD and 5 megapixel CRT monitors, under both bright and subdued ambient light conditions, showed no significant statistical differences for detecting nodules, pneumothorax and interstitial lung disease. In addition, there was no significant statistical difference in the average performance when the two monitor displays, under both bright and subdued ambient light conditions, were compared. PMID- 17689218 TI - Transrectal high-intensity focused ultrasound ablation of prostate cancer: effective treatment requiring accurate imaging. AB - Transrectal HIFU ablation has become a reasonable option for the treatment of localized prostate cancer in non-surgical patients, with 5-year disease-free survival similar to that of radiation therapy. It is also a promising salvage therapy of local recurrence after radiation therapy. These favourable results are partly due to recent improvements in prostate cancer imaging. However, further improvements are needed in patient selection, pre-operative localization of the tumor foci, assessment of the volume treated and early detection of recurrence. A better knowledge of the factors influencing the HIFU-induced tissue destruction and a better pre-operative assessment of them by imaging techniques should improve treatment outcome. Whereas prostate HIFU ablation is currently performed under transrectal ultrasound guidance, MR guidance with real-time operative monitoring of temperature will be available in the near future. If this technique will give better targeting and more uniform tissue destruction, its cost effectiveness will have to be carefully evaluated. Finally, a recently reported synergistic effect between HIFU ablation and chemotherapy opens possibilities for treatment in high-risk or clinically advanced tumors. PMID- 17689219 TI - Development of LC/MS/MS assay for the determination of 5-ethyl-2-{5-[4-(2 hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-7-propyl-3,5 dihydropyrrolo[3,2-d]pyrimidin-4-one (SK3530) in human plasma: application to a clinical pharmacokinetic study. AB - 5-Ethyl-2-{5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-7-propyl 3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one (SK3530) is a new phosphodiesterase type 5 inhibitor currently undergoing a Phase III investigation for the treatment of male erectile dysfunction. This study first describes a rapid and sensitive LC/MS/MS assay method for the quantification of SK3530 and its major metabolite, SK3541, in human plasma. The assay was validated to demonstrate the specificity, linearity, recovery, lower limit of quantification (LLOQ), accuracy, and precision. The multiple reaction monitoring was based on the transition of m/z=532.5-->99.1 for SK3530, 488.6-->295.5 for SK3541, and 520.3-->99.1 for SK3304 (internal standard). The assay utilized a single liquid-liquid extraction and isocratic elution, and the LLOQ was 1 ng/ml using 0.2 ml human plasma. The assay was linear over a range from 1 to 1000 ng/ml for both SK3530 and SK3541, with correlation coefficients >0.9999. The mean intra- and inter-day assay accuracy ranged from 94.7 to 101.6% and 96.8 to 101.1% for SK3530 and 92.6-105.7% and 97.4-107.8% for SK3541, respectively. The mean intra- and inter-day precision was between 7.2-12.1% and 5.7-7.4% for SK3530 and 4.6-13.2% and 5.0-14.1% for SK3541, respectively. The developed assay was applied to a clinical pharmacokinetic study after oral administration of SK3530 in healthy male volunteers (dose 100 mg). PMID- 17689220 TI - Zinc-dependent cytoadherence of Legionella pneumophila to human alveolar epithelial cells in vitro. AB - Microbial adherence to host cells is an early key step in the establishment of infection. During the course of Legionnaire's disease, Legionella interactions with host cells are best documented for resident macrophages. However, L. pneumophila can also replicate within type I and type II pneumocytes, which cover almost the entire alveolar surface. In the presence of zinc, we observed a significant and concentration-dependent increase in L. pneumophila adherence to and invasion of type II pneumocytes. The zinc-dependent adherence mechanism seemed to be host-cell-independent, as a similar increase in cytoadherence was observed with macrophages. We also found that zinc-dependent adherence of L. pneumophila appears to involve recognition of zinc-binding pneumocyte receptors by a bacterial adhesin, and heparan-sulfated host cell receptors, but not type IV pili. PMID- 17689221 TI - Detection of antibodies against the Mycoplasma bovis glyceraldehyde-3-phosphate dehydrogenase protein in beef cattle. AB - Diseases caused by Mycoplasma bovis are an important source of financial losses for beef and dairy cattle producers. Antigenic variation in M. bovis hinders the production of effective vaccines and although there are few vaccines available, they are prepared from bacteria obtained from few isolates potentially limiting their effectiveness. Thus, to develop a vaccine that protects against all M. bovis isolates, it is necessary to use a common antigen that shows less or no antigenic variation. We have isolated the gap gene of M. bovis encoding for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and showed that cattle colonized with M. bovis were able to mount an immune response to GAPDH. Using restriction fragment length polymorphism (RFLP) of several M. bovis gap genes amplified by PCR, we were able to detect small intragenic variations that allowed us to classify the genes into two groups without changing the antigenic makeup of the proteins. The immune responses detected in cattle combined with the antigenic conservation of the proteins suggest that the M. bovis GAPDH protein could be a potential target for development of a more effective vaccine against all M. bovis isolates. PMID- 17689222 TI - Characterization of N-butanoyl-L-homoserine lactone (C4-HSL) deficient clinical isolates of Pseudomonas aeruginosa. AB - In the opportunistic pathogen Pseudomonas aeruginosa, the production of several virulence factors such as elastase, rhamnolipids and pyocyanin depends on cell-to cell signaling or quorum sensing (QS) involving N-acylhomoserine lactone (AHL) signal molecules. In vitro studies with laboratory strains and virulence studies in animals with these same strains have demonstrated the contribution of QS to the pathogenesis of P. aeruginosa. However, the importance of P. aeruginosa QS systems in the development of human infections is not clearly known. In order to determine if deficiency within the QS system compromises the ability of P. aeruginosa to cause infections in humans, we collected 50 P. aeruginosa clinical isolates. Phenotypic characterization showed that isolates I-457, I-458, I-459 and I-461 were defective in the production of N-butanoyl-l-homoserine lactone (C4 HSL) signaling molecule and virulence factors elastase, protease, pyocyanin and rhamnolipids. Analysis of the sequences of the lasR, lasI, rhlR and rhlI genes of these four isolates showed that two of the four isolates had mutational defects in both rhlR and rhlI genes while other two isolates were only mutated in the rhlI gene. The combination of rhlR and rhlI mutations or only rhlI mutation probably explains their C4-HSL and virulence factors deficiencies. These observations suggest that QS deficient P. aeruginosa clinical isolates are able to cause infections and that in addition to known virulence factors, factors yet unidentified may contribute to the pathogenesis of P. aeruginosa. PMID- 17689223 TI - Development of a non-linear weighted hybrid cone-beam CT reconstruction for circular trajectories. AB - We investigated an image reconstruction algorithm to reduce cone-beam artifacts in cone-beam CT. Our new algorithm to reduce such artifacts features: (1) a change in weighting with respect to projection data obtained at different projection angles; (2) distribution of correction coefficients so that they are larger near the center of the detector, while taking individual channel data for the detector into account, and smaller near the edges; (3) three-dimensional back projection of corrected projection data. These findings confirmed that this algorithm reduces cone-beam artifacts and generates high-quality reconstruction images. PMID- 17689224 TI - Detection and quantification of the parenchymal abnormalities in emphysema using pulmo-CT. AB - We aimed to determine the degree and extent of parenchymal abnormalities on pulmo CT in patients with emphysema. The study group consisted of 29 patients (18 male, 11 female; mean age 57.9+/-13). The diagnosis was based on clinical symptoms, pulmonary function tests (PFT) values, and chest CT findings. All of the patients CT scans were obtained during suspended deep inspiration from the apices to the costophrenic angles. The mean lung attenuation (MLD) and parenchymal abnormalities related to emphysema were quantitatively calculated with tables, histograms and graphics at the whole lung. The lung density measurements revealed a mean density of -898.48+/-51.37 HU in patients with emphysema and -825.1+/-25.5 HU in control group. In addition, mean percentage of subthreshold attenuation values was found as 12.03+/-15.75 and 1.07+/-0.83 in patients with emphysema and control group, respectively. Compared with control group, the patients with emphysema had a significantly lower inspiratory MLD (p<0.05). Additionally, statistically significant correlations were seen between the MLD and percentage of subthreshold values (r=0.44, p<0.05). In contrast, there was poor correlation between PFT measurements and the subthreshold values. In conclusion, pulmo-CT is a quick, simple method for quantitative confirmation of the presence of parenchymal abnormalities of lung as mosaic attenuation and should be used in combination with other radiological methods and PFT as it gives additional information to routine examinations in patients with emphysema. PMID- 17689225 TI - Multiple pathways regulating the anti-apoptotic protein clusterin in breast cancer. AB - Cancer chemotherapy inhibits tumor growth, in part, by triggering apoptosis, and anti-apoptotic proteins reduce the effectiveness of chemotherapy. Clusterin, a chaperone-like protein that binds to apoptotic and DNA repair proteins, is induced by chemotherapy and promotes tumor cell survival. Histone deacetylase inhibitors (HDIs) such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) are pharmacological agents that induce differentiation and apoptosis in cancer cells by altering chromatin structure, and we have found that combinations of chemotherapeutic drugs such as doxorubicin and HDIs efficiently induce apoptosis, even though they paradoxically induce high levels of clusterin. The hyper-expressed form of clusterin localizes to mitochondria, inhibits cytochrome c release, and is inhibited by the proteasome. When HDIs are used as single agents, clusterin suppresses cytochrome c release and apoptosis. However, doxorubicin/HDI-induced apoptosis is not inhibited by clusterin, and clusterin resistant apoptosis corresponds with markers of the extrinsic/receptor-mediated apoptotic pathway. Thus, chemotherapy-HDI combinations are capable of overcoming an innate anti-apoptotic pathway of tumor cells, suggesting that chemotherapy-HDI combinations have potential for treating advanced stage breast cancer. PMID- 17689226 TI - A decision-support tool for the formulation of orally active, poorly soluble compounds. AB - Physicochemical data for a set of potentially poorly soluble compounds was analysed in relation to suitable formulations for these compounds. Physical chemistry was found to be a key determinant of formulation class expressed in terms of conventional, solid dispersion, lipidic/surfactant, and crystalline nanoparticle systems. This relationship was used to build a decision-support tool aimed to guide formulation selection for poorly soluble compounds during product development. Tool components included a user interface, a database of compound cases together with known formulations, and predictive modules based on statistics, decision trees, and case-based reasoning. The tool was tested and exhibited significant and consistent predictive ability across testing conditions. This type of tool has the potential to improve the efficiency and predictability of the formulation development process. PMID- 17689227 TI - A nonlinear feedback model capturing different patterns of tolerance and rebound. AB - The objectives of the present analysis are to disect a class of turnover feedback models that have proven to be flexible from a mechanistic and empirical point of view, for the characterization of the onset, intensity and duration of response. Specifically, this class of models is designed so that it has the following properties: (I) Stimulation of the production term, which raises the steady state R(ss), causes an overshoot and a rebound upon return to baseline. (II) Stimulation of the loss term, which lowers the steady state R(ss), causes an overshoot which is negligible vis-a-vis the rebound upon the return to baseline. (III) Inhibition of the loss term, which raises the steady state R(ss), causes an overshoot which is larger than the rebound upon the return to the baseline. These models are then anchored in three datasets corresponding to the cases (I), (II) and (III). The objectives of this paper are to analyze the behavior of these turnover models from a mathematical/analytical point of view and to make simulations with different parameter settings and dosing regimens in order to highlight the intrinsic behavior of these models and draw some general conclusions. We also expand the analysis with two different extensions of the basic feedback model: one with a transduction step in the moderator and one which captures nonlinear phenomena (triggering mechanisms) caused by different drug input rates. A related objective is to come up with recommendations about experimental design and model building techniques in situations of feedback systems from a drug discovery point of view. PMID- 17689228 TI - Isolation and functional expression of the bop gene from Halobiforma lacisalsi. AB - A novel bop gene was described from Halobiforma lacisalsi strain AJ5(T), an extremely halophilic archaeon isolated from Ayakekum Lake, China. Following six rounds of PCR amplification based on the conserved fragment of the bop gene, the complete sequence of the bop gene, including the 5' and 3' flanking regions of the conserved fragment, was obtained by the ligation-mediated PCR amplification (LPA) approach. The data presented provide us with further insight into the distribution of bop-like genes in the family Halobacteriaceae. This is the first example of a bop-like gene in halophiles found in the high-pH environment. Alignment and hydropathy analysis of the deduced amino acid sequence identified the conserved functional sites as well as some variations compared with other bacterio-opsins. Molecular phylogenetic analysis revealed the position of the bacterio-opsin of strain AJ5, which is closest to that of Haloterrigena sp. arg-4 with 85% identity. In the presence of all-trans retinal, recombinant Escherichia coli cells expressing the gene turned dark purple. The purple membrane from the recombinant E. coli showed maximal absorption at 540 nm. PMID- 17689229 TI - Iron-dependent growth of and siderophore production by two heterotrophic bacteria isolated from brackish water of the southern Baltic Sea. AB - Iron is indispensable to the growth and metabolism of all marine organisms, including bacteria. In this work, we investigated and compared the influence of iron(III) concentration on the growth of and siderophore production by two heterotrophic bacteria--Micrococcus luteus and Bacillus silvestris. Our results showed that the iron concentration strongly influences the growth of both species. The growth curves were different for each iron concentration and each strain. M. luteus grew more rapidly than B. silvestris, but produced a roughly four times smaller quantity of siderophores. Both M. luteus and B. silvestris secreted hydroxamate-type siderophores and alpha-keto/alpha-hydroxy acids, but did not produce catecholates. This paper is probably the first to report on siderophore production by B. silvestris and M. luteus isolated from seawater. Moreover, the influence of different iron concentrations on the growth of and siderophore production in these bacteria has been documented. This provides further evidence indicating iron bioavailability as the actual reason for siderophore release by biota. PMID- 17689230 TI - Antiplatelet effects of acidamides isolated from the fruits of Piper longum L. AB - The inhibitory effects of four acidamides, piperine, pipernonaline, piperoctadecalidine, and piperlongumine, isolated from the fruits of Piper longum L. on washed rabbit platelet aggregation were examined. All of the four tested acidamides showed dose-dependent inhibitory activities on washed rabbit platelet aggregation induced by collagen, arachidonic acid (AA), and platelet-activating factor (PAF), except for that induced by thrombin. Piperlongumine, in particular, showed stronger inhibitory effects than other acidamides to rabbit platelet aggregation induced by collagen, AA and PAF. PMID- 17689231 TI - Antinociceptive effect of Russelia equisetiformis leave extracts: identification of its active constituents. AB - This study examines the antinociceptive effect of the whole plant extracts of Russelia equisetiformis. The result shows the ethylacetate fraction to be the most active, while the dichloromethane fraction exhibited least activity. The major isolated compound from the ethylacetate showed a tremendous activity on acetic acid induced writhing with less activity on tail-flick response in mice. The structures of the two compounds were assigned on the basis of spectroscopic data. Occurrence of these compounds in Russelia is reported here for the first time, and the results confirm the traditional uses of R. equisetiformis in the treatment of inflammation and pain. PMID- 17689232 TI - Inhibitory effect of Erigeron breviscapus extract and its flavonoid components on GABA shunt enzymes. AB - Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter, is metabolized by the successive action of GABA transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH). Inhibition of both enzymes in brain tissues increases the GABA level and may have therapeutic applications in neurological diseases. Erigeron breviscapus ethanol extract was evaluated for their effect on both enzymes. This extract, its ethyl acetate fraction and aqueous fraction, significantly inhibited them at >100 microg/ml. Flavonoid components of E. breviscapus potently and noncompetitively inhibited both enzymes, and the different structure-activity relations were observed with respect to inhibition of both enzymes. Baicalein was the most potent inhibitor for GABA-T with an IC50 value of 12.8+/-1.2 microM, and scutellarein exhibited the best inhibitory effect on SSADH with an IC50 value of 7.20+/-0.9 microM. The present results may imply new pharmacological actions of E. breviscapus and contribute partially to the beneficial effect of the herb and flavonoids on the central nervous system. PMID- 17689233 TI - Serotonin mediates beneficial effects of Hypericum perforatum on nicotine withdrawal signs. AB - Antidepressants may be effective treatment for smoking cessation and new evidence on relationship between smoking and depression is emerging. Extracts of the plant Hypericum perforatum possess antidepressant activity in humans and reduce nicotine withdrawal signs in mice. Both nicotine and H. perforatum administration elicit changes in serotonin (5-HT) formation in the brain. On this basis, we investigated the possible involvement of 5-HT in the beneficial effects of H. perforatum on nicotine withdrawal signs. With the aim to induce nicotine dependence, nicotine (2 mg/kg, four intraperitoneal injections daily) was administered for 14 days to mice (NM). Saline (controls, M) or H. perforatum extract (Ph 50, 500 mg/kg) were orally administered immediately after the last nicotine injection for 30 days after nicotine withdrawal. Another group of animals treated with nicotine (14 days) and successively with H. perforatum extract was intraperitoneally co-administered with selective 5-HT receptorial antagonist WAY 100635 (WAY) (1 mg/kg). All animals were evaluated for locomotor activity and abstinence signs, 24 after nicotine withdrawal. Brain 5-HT metabolism was evaluated in the cortex of mice sacrificed 30 days after nicotine withdrawal through evaluation of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and 5 HIAA/5-HT ratio. After nicotine withdrawal measurement of 5-HT metabolism in the cortex showed a reduction of 5-HT content while animals treated only with Hypericum extract showed a significant reduction of total abstinence score compared to controls. WAY inhibited the reduction of total abstinence score induced by H. perforatum. Moreover, 5-HT1A expression has been evaluated 30 days after nicotine withdrawal. Our results, show a significant increase of cortical 5 HT content in NM treated with H. perforatum, with a concomitant significant increase of 5-HT1A receptor. So, it is possible to suggest an involvement of 5-HT in beneficial effects of H. perforatum on suffering produced by nicotine withdrawal in dependent mice. PMID- 17689234 TI - The economic consequences of asthma among adults in Sweden. AB - OBJECTIVES: Asthma is a common disease in most countries. The objective of this study was to estimate the societal costs for subjects with asthma. METHODS: Telephone interviews regarding resource utilization were made in a representative sample of 115 randomly selected subjects with asthma derived from a large population study of obstructive airway diseases. Direct and indirect costs were measured, and the costs were also transformed with the estimated prevalence of asthma in Sweden. RESULTS: Average annual costs were SEK 15919 (USD 1592; EUR 1768) per subject with asthma in the ages between 25 and 56 years. The direct and indirect costs were SEK 4931 (31.0%) and SEK 10988 (69.0%), respectively, and were highly dependent of age and disease severity. Assuming that the prevalence is representative for Sweden as a whole, the asthmatics would amount to 226000 in the ages between 25 and 56 years, corresponding to an overall prevalence in Sweden of 6-7%. The total costs of asthma for the society amounted thus to SEK 3.7 billion in these ages. CONCLUSIONS: The total costs of asthma for the society could be estimated at 3.7 billion SEK in the age range of 25-56 years, and thus approximately twice as high in the whole population of Sweden. The costs were strongly dependent on disease severity and increasing age. PMID- 17689235 TI - Skeletal muscle dysfunction in patients with idiopathic pulmonary arterial hypertension. AB - Dyspnea and exercise limitation are common in patients with idiopathic pulmonary arterial hypertension (IPAH). Recently, a reduction in inspiratory and expiratory muscle strength has been observed in IPAH. However, it has not been investigated whether this respiratory muscle weakness might be part of a general muscle dysfunction as observed in congestive left heart failure. Therefore, in 24 consecutive IPAH patients (16 female; age 58.7+/-16.2; WHO class II-III; systolic pulmonary artery pressure during echocardiography at rest (sPAP) 65.0+/-20.6 mmHg, and 6-min-walk test (6-MWT) 473.6+/-127.7 m), the maximal isometric forearm muscle strength (best of three hand grip manoeuvres), maximal inspiratory and expiratory mouth occlusion pressures (Pimax, Pemax) were prospectively evaluated. The isometric forearm muscle strength was significantly lower in IPAH patients (281.7+/-102.6N) than in matched 24 healthy controls (397.1+/-116.8 N; p=0.03). In IPAH patients, there was a correlation between maximal isometric forearm muscle strength and 6-MWT (r=0.67; p=0.0007) and both, Pimax (r=0.69; p=0.0003) and Pemax (r=0.63; p=0.01), respectively. There was no correlation between forearm muscle strength and sPAP (r=0.30; p=0.16). The present skeletal muscle dysfunction is a novel finding in patients with IPAH. The correlation with respiratory muscle dysfunction and severity of disease might indicate a generalised "myopathy" in IPAH. PMID- 17689236 TI - Prognostic value of mouth occlusion pressure in patients with chronic ventilatory failure. AB - BACKGROUND: Mouth occlusion pressure measurement is widely used for assessment of respiratory muscle function, particularly in patients with respiratory failure. However, its predictive value for long-term survival remains largely unexplored. METHODS: In 464 patients with chronic hypercapnic respiratory failure (CHRF) due to various underlying disorders and receiving non-invasive ventilation (NIV), maximal inspiratory mouth pressure (PI(max)), mouth occlusion pressure at 100 ms during quiet breathing (P(0.1)) and the ratio P(0.1)/PI(max) were assessed prior to and after treatment including NIV. Baseline data and changes at follow-up were used to evaluate their predictive value for long-term survival. RESULTS: Overall, median (quartiles) P(0.1) was 177.0 (109.2;287.0) %pred, PI(max) 35.0 (24.0;47.0) %pred, and P(0.1)/PI(max) 564.0 (275.7;1082.3) %pred. In multivariate analyses, P(0.1) was related to airflow obstruction, lung hyperinflation, haemoglobin (Hb) and leukocytes, and PI(max) to airflow obstruction and hyperinflation (p<0.05 each). All-cause mortality during follow-up (median 31.6 months) was 31.5%. Survival was associated with age, body-mass index (BMI), lung function, leukocytes, Hb, PI(max), P(0.1) and P(0.1)/PI(max) (p<0.01 each, univariate). Among these multivariate Cox regression identified age, BMI, FEV(1), leukocytes and P(0.1)/PI(max) as independent predictors (p<0.05 each). Furthermore, the decrease of P(0.1)/PI(max) at follow-up was associated with improved survival in patients with high baseline P(0.1)/PI(max) (>50th or 75th percentile; p<0.05). CONCLUSIONS: In patients with CHRF and current NIV therapy, P(0.1)/PI(max) was an independent predictor of long-term survival, in addition to previously established risk factors. Moreover, a decrease in P(0.1)/PI(max) after treatment including NIV was associated with an improved survival in patients with high baseline P(0.1)/PI(max) values. PMID- 17689237 TI - At identical isowork rates, ageing influences cardiorespiratory adaptations in COPD out-patients. AB - PURPOSE: To determine the extent to which younger COPD patients improve their cardiorespiratory function during exercise in comparison with older COPD patients, as a result of exercise training. METHODS: Thirty-nine COPD patients underwent an exercise program. They were divided into two groups: a younger group (57.2+/-1.0 years, n=18 patients) and an older group (68.8+/-0.6 years, n=21 patients). Forced expiratory volume in 1s was lower than 55% of the predicted value for all patients. RESULTS: After training, VO2 symptom-limited significantly improved by 10.3% and 8.4% for the younger and older COPD patients, respectively (P<0.05). Peak power significantly improved by 25.2% and 17.8% in the younger and older groups, respectively (P<0.05) with a greater improvement for the younger group (P<0.05). At submaximal exercise, ventilation and heart rate significantly decreased after training in the younger COPD patients (P<0.05) with no significant modification in the older COPD patients. CONCLUSIONS: The results suggest that all patients with COPD benefit from exercise rehabilitation at maximal exercise workload, however, according to their age, submaximal cardiorespiratory adaptations were greater in younger patients. PMID- 17689238 TI - Mitosis controls the Golgi and the Golgi controls mitosis. AB - In mammals, the Golgi complex is structured in the form of a continuous membranous system composed of up to 100 stacks connected by tubular bridges, the 'Golgi ribbon'. During mitosis, the Golgi undergoes extensive fragmentation through a multistage process that allows its correct partitioning and inheritance by daughter cells. Strikingly, this Golgi fragmentation is required not only for inheritance but also for mitotic entrance itself, since its block results in the arrest of the cell cycle in G2. This is called the 'Golgi mitotic checkpoint'. Recent studies have identified the severing of the ribbon into its constituent stacks during early G2 as the precise stage of Golgi fragmentation that controls mitotic entry. This opens new ways to elucidate the mechanism of the Golgi checkpoint. PMID- 17689239 TI - Patterned gallium surfaces as molecular mirrors. AB - An entirely new means of printing molecular information on a planar film, involving casting nanoscale impressions of the template protein molecules in molten gallium, is presented here for the first time. The metallic imprints not only replicate the shape and size of the proteins used as template. They also show specific binding for the template species. Such a simple approach to the creation of antibody-like properties in metallic mirrors can lead to applications in separations, microfluidic devices, and the development of new optical and electronic sensors, and will be of interest to chemists, materials scientists, analytical specialists, and electronic engineers. PMID- 17689240 TI - Logic of gene regulatory networks. AB - Regulatory networks of transcription factors and signaling molecules lie at the heart of development. Their architecture implements logic functions whose execution propels cells from one regulatory state to the next, thus driving development forward. As an example of a subcircuit that translates transcriptional input into developmental output, we consider a particularly simple case, the regulatory processes underlying pigment cell formation in sea urchin embryos. The regulatory events in this process can be represented as elementary logic functions. PMID- 17689242 TI - Highly thermostable, thermophilic, alkaline, SDS and chelator resistant amylase from a thermophilic Bacillus sp. isolate A3-15. AB - A thermostable alkaline alpha-amylase producing Bacillus sp. A3-15 was isolated from compost samples. There was a slight variation in amylase synthesis within the pH range 6.0 and 12.0 with an optimum pH of 8.5 (8mm zone diameter in agar medium) on starch agar medium. Analyses of the enzyme for molecular mass and amylolytic activity were carried out by starch SDS-PAGE electrophoresis, which revealed two independent bands (86,000 and 60,500 Da). Enzyme synthesis occurred at temperatures between 25 and 65 degrees C with an optimum of 60 degrees C on petri dishes. The partial purification enzyme showed optimum activity at pH 11.0 and 70 degrees C. The enzyme was highly active (95%) in alkaline range of pH (10.0-11.5), and it was almost completely active up to 100 degrees C with 96% of the original activity remaining after heat treatment at 100 degrees C for 30 min. Enzyme activity was enhanced in the presence of 5mM CaCl2 (130%) and inhibition with 5mM by ZnCl2, NaCl, Na-sulphide, EDTA, PMSF (3mM), Urea (8M) and SDS (1%) was obtained 18%, 20%, 36%, 5%, 10%, 80% and 18%, respectively. The enzyme was stable approximately 70% at pH 10.0-11.0 and 60 degrees C for 24h. So our result showed that the enzyme was both, highly thermostable-alkaline, thermophile and chelator resistant. The A3-15 amylase enzyme may be suitable in liquefaction of starch in high temperature, in detergent and textile industries and in other industrial applications. PMID- 17689241 TI - Progesterone regulates catechol-O-methyl transferase gene expression in breast cancer cells: distinct effect of progesterone receptor isoforms. AB - There is strong evidence that catechol-O-methyl transferase (COMT) protects breast cells against estrogen-induced cancer by detoxifying catecholestrogens, the carcinogenic estrogen metabolites. COMT gene expression is controlled by two promoters - a proximal promoter (COMTP1) and a distal promoter (COMTP2) - that regulate the expression of soluble (S-COMT) and membrane-bound (MB-COMT) isoforms, respectively. We investigated the transcriptional regulation of the COMT gene by progesterone/progesterone receptors in breast cancer cells. Our results indicated that progesterone (P4) downregulates COMT gene expression in breast cancer cell lines. In addition, the COMTP1 and COMTP2 harbor several progesterone response elements (PREs). Electrophoretic mobility shift assay (EMSA) indicated that nuclear extracts of T47D cells bind to the identified PREs in COMTP1. Site-directed mutagenesis of PREs in COMTP1 not only reversed the P4 induced inhibition of COMTP1, but also increased its basal activity. The two progesterone receptor isoforms, PR-A and PR-B, were found to have opposite effects on the regulation of P4 in COMT expression; PR-A is associated with P4 induced upregulation of COMT, while PR-B is associated with P4-induced downregulation of COMT. In summary, our data demonstrated that P4 downregulates the COMT gene expression through multiple PREs in the COMT promoters and that different progesterone receptor isoforms have distinctive effects on COMT gene expression. PMID- 17689243 TI - Growth of bedding plants in commercial potting substrate amended with vermicompost. AB - Vermicompost has been promoted as a viable alternative container media component for the horticulture industry. The purpose of this research was to investigate the use of vermicompost at different points in the production cycle of tomato, marigold, pepper, and cornflower. The incorporation of vermicompost of pig manure origin into germination media up to 20% v/v enhanced shoot and root weight, leaf area, and shoot:root ratios of both tomato and French marigold seedlings; however amendment with vermicompost had little influence on pepper and cornflower seedling growth. Moreover there was no effect on the germination of seed of any species. When seedlings of tomato, French marigold, and cornflower were transplanted into 6-cell packs there was greater plant growth in media amended with vermicompost compared to the control media, and the greatest growth when vermicompost was amended into both the germination and transplant media. This effect was increased when seedlings in the transplant media were irrigated with water containing fertilizer. PMID- 17689244 TI - Recycling of waste products in the induction of biofilms to remediate the visual impact generated by quartz mining. AB - The present study was undertaken to investigate the viability of the use of two waste products, cheese whey and composted organic waste, as nutrient sources in the induction of biological films on quartz surfaces, with the final aim of reducing the visual impact generated by quartz mining. Experiments were carried in laboratory in which quartz samples were colonized with microorganisms (mainly cyanobacteria) forming biofilms. Previous studies have shown that a nutritional supplement must be added for good development of biofilms and, therefore, application of the two waste products was compared with application of the chemical nutrient medium on which these types of microorganisms are usually cultivated. Both products provided better results than the culture medium, in terms of the speed of formation of the biofilm, faster with the waste products, and the degree of cover of the brilliant white colour of the quartz, better masked by the biofilms formed when the waste products were applied as a darker biofilm was obtained. PMID- 17689245 TI - Biosorption of chromium(VI) using a Sargassum sp. packed-bed column. AB - Chromium(VI) is present in several industrial wastewaters and it can cause health and environmental hazards above certain concentrations. Equilibrium studies have shown the feasibility of using Sargassum sp. algae for chromium removal from aqueous solutions by biosorption. However, for the design and operation of chromium biosorption processes, dynamic flow studies are required. The objective of the study was to examine chromium(VI) removal from an aqueous solution using a packed-bed column with Sargassum sp. algae as a biosorbent. The dynamic behavior of the biosorption column was investigated through experiments and the influence of operating conditions, such as initial chromium concentration, flow rate and amount of biosorbent, on the column removal capacity have been analyzed using the factorial design methodology. The capacity of removal obtained at optimum conditions was 19.06 mg of metal/g biosorbent. PMID- 17689246 TI - Design and evaluation of a potential mutagen for Hepatitis C virus. AB - Pyrrolopyrimidine nucleoside 1 was designed and synthesized as a potential mutagen for HCV. An in vitro HCV NS5B enzymatic assay indicated that pyrrolopyrimidine triphosphate acts as a CTP analog rather than a UTP analog. The SATE-prodrug of pyrrolopyrimidine monophosphate showed a weak inhibitory activity in an HCV replicon system (EC(50)=60 microM) and did not exhibit cytotoxicity (CC(50)>100 microM). Investigation of phosphorylation events using nucleoside kinases and LC-MS analysis revealed that the second phosphorylation step, from monophosphate ester to diphosphate ester, is unfavorable. PMID- 17689247 TI - Nursing activities score (NAS): a proposal for practical application in intensive care units. AB - For over 30 years in an attempt to demonstrate the cost-benefit ratio of the intensive care unit (ICU) a variety of tools have been developed to measure not only the severity of illness of the patient but also to capture the true cost of nursing workload. In this context, the nursing activities score (NAS) was developed as a result of modifications to the therapeutic interventions scoring system-28 (TISS-28). The NAS is a tool to measure nursing workload ICU and it has been shown to be twice as effective in measuring how nurses spend their time caring for critically ill patients than the TISS-28. This paper discuss the introduction of the NAS into everyday use in an intensive care unit in Brazil and highlights the challenges of standardisation of operational definitions, training requirements and accurate completion of the documentation when using such a tool. The rationale and steps undertaken to achieve this are outlined and the benefits of such a process are highlighted. PMID- 17689248 TI - Pathophysiology of acid base balance: the theory practice relationship. AB - There are many disorders/diseases that lead to changes in acid base balance. These conditions are not rare or uncommon in clinical practice, but everyday occurrences on the ward or in critical care. Conditions such as asthma, chronic obstructive pulmonary disease (bronchitis or emphasaemia), diabetic ketoacidosis, renal disease or failure, any type of shock (sepsis, anaphylaxis, neurogenic, cardiogenic, hypovolaemia), stress or anxiety which can lead to hyperventilation, and some drugs (sedatives, opioids) leading to reduced ventilation. In addition, some symptoms of disease can cause vomiting and diarrhoea, which effects acid base balance. It is imperative that critical care nurses are aware of changes that occur in relation to altered physiology, leading to an understanding of the changes in patients' condition that are observed, and why the administration of some immediate therapies such as oxygen is imperative. PMID- 17689249 TI - Pain related to tracheal suctioning in awake acutely and critically ill adults: a descriptive study. AB - The purpose of this secondary data analysis of findings from a larger procedural pain study was to examine several factors related to pain during tracheal suctioning. In addition to tracheal suctioning, other procedures studied included turning, wound drain removal, femoral catheter removal, placement of a central venous catheter, and wound dressing change. A total of 755 patients underwent the tracheal suctioning procedure that was performed primarily in intensive care units (93%). A 0-10 numeric rating scale, a behavioural observation tool, and a modified McGill Pain Questionnaire-Short Form were used for pain assessment. Pain intensity scores were significantly greater during the tracheal suctioning procedure (M=3.96, S.D.=3.3) than prior to (M=2.14, S.D.=2.8) or after (M=1.98, S.D.=2.7) tracheal suctioning. Few patients received analgesics prior to or during the procedure. Surgical, younger, and non-white patients reported higher pain intensities. Although mean pain intensity during tracheal suctioning was mild, almost the half of the patients reported moderate-to-severe pain. Individualized pain management must be performed by healthcare providers in order to respond to patients' needs as they undergo painful procedures such as tracheal suctioning. PMID- 17689250 TI - Good nursing care to ICU patients on the edge of life. AB - Critically ill patients are admitted to intensive care units (ICUs) to receive advanced technological and medical treatment. Some patients seem not to benefit from the treatment, and sometimes questions are raised as to whether treatment should be withheld or withdrawn. This study was conducted using ICU nurses' experiences with the aim of acquiring a deepened understanding of what good nursing care is for these patients. The study was performed at an adult ICU in Norway, where 14 ICU female nurses were included as participants. The research design was based on interpretative phenomenology and data was collected by group interviews inspired by focus-group methodology. The participants were divided into two groups and each group was interviewed four times. Colaizzi's model was used in the process of analysis. The results show that good nursing care depended on several basic conditions: continuity, knowledge, competence and cooperation, and included clear goals to give appropriate life-saving -- or end-of-life treatment and care. Cornerstones in good nursing care were nurses' verbal communication and nurses' use of their hands. The study emphasises several consequences for future ICU nursing practice and education to enhance good nursing care to patients on the edge of life. PMID- 17689251 TI - Fingernail polish does not influence pulse oximetry to a clinically relevant dimension. PMID- 17689252 TI - Synthesis, antiproliferative, and antiplatelet activities of oxime- and amide containing quinolin-2(1H)-one derivatives. AB - Certain oxime- and amide-containing quinolin-2(1H)-one derivatives were synthesized and evaluated for their antiproliferative and antiplatelet activities. These compounds were synthesized via alkylation of hydroxyl precursors followed by the reaction with NH(2)OH or NaN(3) (Schmidt reaction). The preliminary assays indicated that amide derivatives are either weakly active or inactive while the oxime counterparts exhibited potent inhibitory activities against platelet aggregation induced by collagen, AA (arachidonic acid), and U46619 (the stable thromboxan A(2) receptor agonist). Among them, (Z)-6-[2-(4 methoxyphenyl)-2-hydroxyiminoethoxy]quinolin-2(1H)-one (7c) was the most active against AA induced platelet aggregation with an IC(50) of 0.58microM and was inactive against cell proliferation. For the inhibition of U46619 induced aggregation, 7a and 8a-c exhibited very potent activities with IC(50) values in a range between 0.54 and 0.74microM. For the antiproliferative evaluation, N (biphenyl-4-yl)-2-(2-oxo-1,2-dihydroquinolin-7-yloxy)acetamide (11d) was the most potent with GI(50) values of <10, 10.8, and <10microM against the growth of MT-2, NCI-H661, and NPC-Tw01, respectively, and possessed only a weak antiplatelet activity. Further evaluation of 11d as a potential anticancer agent is on-going. PMID- 17689254 TI - Role of alpha-synuclein in synaptic glutamate release. AB - Defective mobilization of dopamine from the reserve pool has been reported in both alpha-synuclein knockout mice (KO) and pPrp-A30P transgenic mice. The present study extends these findings to glutamate release. Standard hippocampal slices were prepared from KO, pPrp-A30P, and C57BL/6J wild type (WT1) mice, as well as from mice with transgenic overexpression of wild type human alpha synuclein (pSyn-hASY) and their negative littermates (WT2), and field responses were measured in CA3 in response to mossy fiber stimulation. The input/output curves indicated no differences in basal synaptic transmission between groups. Paired-pulse facilitation was significantly weaker in both transgenic alpha synuclein lines and KO mice compared to their controls. High-frequency stimulation induced LTP only in transgenic mice. Frequency-facilitation was absent in KO mice and different from other mouse lines. These findings support the idea that lack of alpha-synuclein impairs mobilization of glutamate from the reserve pool. However, transgenic expression of A30P mutated or wild type alpha synuclein does not appear to prevent endogenous mouse alpha-synuclein to carry out this function. PMID- 17689255 TI - The coronary collaterals to the chronically occluded right coronary artery. PMID- 17689256 TI - Human embryonic stem cells: current technologies and emerging industrial applications. AB - The efficiency and accuracy of the drug development process is severely restricted by the lack of functional human cell systems. However, the successful derivation of pluripotent human embryonic stem (hES) cell lines in the late 1990s is expected to revolutionize biomedical research in many areas. Due to their growth capacity and unique developmental potential to differentiate into almost any cell type of the human body, hES cells have opened novel avenues both in basic and applied research as well as for therapeutic applications. In this review we describe, from an industrial perspective, the basic science that underlies the hES cell technology and discuss the current and future prospects for hES cells in novel and improved stem cell based applications for drug discovery, toxicity testing as well as regenerative medicine. PMID- 17689257 TI - Circannual prolactin rhythms: calendar-like timer revealed in the pituitary gland. AB - Although photoperiodic regulation of annual rhythms in reproduction and other functions has been well characterized, the basis for the endogenous generation of circannual rhythms during exposure to constant conditions has not been elucidated. Lincoln and colleagues have recently reported that circannual prolactin rhythms in rams persist after hypothalamo-pituitary disconnection, but not after pinealectomy. Does the pars tuberalis, the site of pituitary gland melatonin receptors, generate circannual rhythms and integrate photoperiodic signals mediated by melatonin? PMID- 17689258 TI - Generation of human innate immune responses towards membrane macrophage colony stimulating factor (mM-CSF) expressing U251 glioma cells within immunodeficient (NIH-nu/beige/xid) mice. AB - The response of human peripheral blood mononuclear cells (PBMC) to cloned human HLA-A2+ U251 glioma cells (U251-2F11/TK) expressing membrane macrophage colony stimulating factor (mM-CSF) was investigated in vitro and in vivo. Enriched human monocytes derived from cancer patients produced a respiratory burst following 20min of interaction with mM-CSF expressing U251 glioma cells. This respiratory burst response was not observed in the enriched human monocytes following similar exposure to the viral vector control U251 (U251-VV) cells. Reactive oxygen species such as H(2)O(2) and HOCl produced death of the U251 cells. The U251 2F11/TK cells failed to grow in severely compromised combined immunodeficient (NIH-bg-nu-xidBR) mice that were depleted of murine monocyte/macrophages then reconstituted with human HLA-A2+ PBMC. Reactive oxygen species (ROS) were produced by PBMC, both in vitro and in vivo in response tomM-CSF expressing U251 cells. U251-2F11/TK cells failed to form subcutaneous tumors in macrophage depleted mice reconstituted with human PBMC; whereas, progressive growth of such tumors was observed with the U251-VV cells. U251-2F11/TK tumors formed if the initial inoculums of PBMC were depleted of monocytes. From this work it can be concluded that mM-CSF transduced U251-2F11/TK glioma cells can safely stimulate human innate immune responses in vivo. PMID- 17689259 TI - Risk factors for group B streptococcal colonization: potential for different transmission systems by capsular type. AB - PURPOSE: Group B Streptococcus (GBS) is a common inhabitant of the bowel and vaginal flora, with known transmission routes including sexual contact and vertical transmission from mother to infant. Food-borne transmission is also possible, as GBS is a known fish and bovine pathogen. We conducted a prospective cohort study in order to identify risk factors for acquisition. METHODS: We identified risk factors for GBS acquisition among college women (n = 129) and men (n = 128) followed at 3-week intervals for 3 months. RESULTS: A doubling in sex acts significantly increased incidence of GBS capsular type V by 80% (95% confidence interval [CI]: 1.19, 2.58), and other non-Ia or -Ib types combined by 40% (95% CI: 1.00, 2.06; incidence of capsular type Ia (odds ratio [OR] = 1.2; 95% CI: 0.71, 1.88; p = 0.57) and Ib (OR = 1.5, 95% CI: 0.75, 2.86; p = 0.27) were elevated, although not significantly. After adjustment for sexual activity and sexual history, gender, and eating venue, fish consumption increased risk of acquiring capsular types Ia and Ib combined 7.3 fold (95% CI: 2.34, 19.50), but not of acquiring other capsular types. Beef and milk were not associated with GBS incidence. CONCLUSIONS: Different GBS capsular types may have different transmission routes. PMID- 17689260 TI - End-stage liver disease in a state prison population. AB - OBJECTIVES: Information on the epidemiology of end-stage liver disease (ESLD) in US correctional populations is limited. We examined the prevalence, mortality and clinical characteristics of ESLD in the nation's second largest state prison system. METHODS: We collected and analyzed medical and demographic data from 370,511 offenders incarcerated in Texas' prison system during a 3.5-year period. RESULTS: ESLD was diagnosed in 484 inmates (131/100,000); 213 (57/100,000) died of ESLD. Offenders who were Hispanic, 30-49 years of age, > or =50 years of age, HIV monoinfected, hepatitis C virus (HCV) monoinfected, or HIV/HCV coinfected had elevated ESLD prevalence and mortality rates. CONCLUSIONS: ESLD mortality in Texas' prison population is approximately 3 times higher than that of the general population, reflecting elevated rates of HCV and HIV/HCV coinfection among prisoners. Ultimately, the only viable treatment option for many prisoners with ESLD will be liver transplantation. The enormous costs of organ transplantation and immunosuppressive therapy are staggering and have the potential to decimate the healthcare budgets of most prison systems. Consequently, it is imperative that correctional healthcare programs expand HCV treatment and prevention strategies. PMID- 17689261 TI - The impact of HIPAA authorization on willingness to participate in clinical research. AB - PURPOSE: This study systematically examined the impact of inclusion of Health Insurance Portability and Accountability Act (HIPAA) authorization on the willingness of African Americans of diverse sociodemographic characteristics to participate in a clinical research study and explored reasons for nonparticipation. METHODS: For a purposive sample of 384 African American outpatients at four metropolitan primary care clinics from August 2005 through May 2006, willingness to participate in a hypothetic clinical research study of an antihypertensive medication under one of two experimental conditions was compared. Interviewees were randomly assigned to undergo informed consent alone (control group) or informed consent with HIPAA authorization (HIPAA group). They were asked whether they would participate and reasons for their decisions. RESULTS: A smaller proportion of interviewees in the HIPAA group were willing to enroll in the study (27% vs. 39%; p = 0.02), with an adjusted odds ratio of 0.56 (95% confidence interval = 0.36-0.91). Those in the HIPAA group were more likely to give reasons related to privacy (p < 0.001), poor understanding of the form (p = 0.01), and mistrust or fear of research (p = 0.04) for nonparticipation. CONCLUSIONS: The inclusion of HIPAA authorization within the informed consent process may adversely affect the willingness of African Americans to participate in clinical research and may raise concerns about privacy, understanding the forms, and mistrust or fear of research. PMID- 17689262 TI - Maternal exposures to hazardous waste sites and industrial facilities and risk of neural tube defects in offspring. AB - PURPOSE: We examined the relationship between maternal proximity to hazardous waste sites and industrial facilities and neural tube defect (NTD) risk. METHODS: Texas Birth Defects Registry cases were linked with their birth or fetal death certificates; controls (without defects) were randomly selected from birth certificates. Distances from maternal addresses at delivery to National Priority List (NPL) and state superfund sites and Toxic Release Inventory (TRI) facilities were determined for 655 cases and 4368 controls. RESULTS: Living within 1 mile of an NPL or state superfund site was not related to NTD risk (adjusted odds ratio [OR] = 1.0; 95% confidence intervals [CI] = 0.6, 1.7). Living within 1 mile of a TRI facility carried a slight risk (adjusted OR = 1.2; 95% CI = 1.0, 1.5). The effect was highest among mothers 35 years and older (OR = 2.7; 95% CI = 1.4, 5.0) and among non-Hispanic white mothers (OR = 1.8; 95% CI = 1.1, 2.8). CONCLUSIONS: Hazardous waste sites posed little risk for NTDs in offspring. Close proximity to industrial facilities with chemical air emissions was associated with NTD risk in some subgroups. Further investigation is needed to determine if the effects are real or due to unresolved confounding or bias. PMID- 17689263 TI - On the feasibility of visualizing ultrasmall gold labels in biological specimens by STEM tomography. AB - Labeling with heavy atom clusters attached to antibody fragments is an attractive technique for determining the 3D distribution of specific proteins in cells using electron tomography. However, the small size of the labels makes them very difficult to detect by conventional bright-field electron tomography. Here, we evaluate quantitative scanning transmission electron microscopy (STEM) at a beam voltage of 300 kV for detecting 11-gold atom clusters (Undecagold) and 1.4 nm diameter nanoparticles (Nanogold) for a variety of specimens and imaging conditions. STEM images as well as tomographic tilt series are simulated by means of the NIST Elastic-Scattering Cross-Section Database for gold clusters embedded in carbon. The simulations indicate that the visibility in 2D of Undecagold clusters in a homogeneous matrix is maximized for low inner collection semi angles of the STEM annular dark-field detector (15-20 mrad). Furthermore, our calculations show that the visibility of Undecagold in 3D reconstructions is significantly higher than in 2D images for an inhomogeneous matrix corresponding to fluctuations in local density. The measurements demonstrate that it is possible to detect Nanogold particles in plastic sections of tissue freeze substituted in the presence of osmium. STEM tomography has the potential to localize specific proteins in permeabilized cells using antibody fragments tagged with small heavy atom clusters. Our quantitative analysis provides a framework for determining the detection limits and optimal experimental conditions for localizing these small clusters. PMID- 17689264 TI - The spatiality of situation: comment on Legrand et al. PMID- 17689265 TI - Cell-oriented analysis in vivo using diffusion tensor imaging for normal appearing brain tissue in multiple sclerosis. AB - There have been several methods proposed so far using diffusion tensor imaging (DTI) for the assessment of normal-appearing brain tissue (NABT) injury in multiple sclerosis (MS). However, for these methods, the analyses of the NABT injury at the cellular level, wherein histological examinations can be used, still present challenging problems. We developed a method of segregating NABT into the following anatomical structures using lambda chart analysis associated with a two-dimensional Gaussian deconvolution of diffusion characteristic functions: 1) structures primarily composed of small neurons and glia; 2) structures primarily composed of large neurons; 3) structures primarily composed of short axons; and 4) structures primarily composed of long axons. Each segregated structure that had a distinctive diffusion characteristic was subjected to the statistical inference of DTI-derived parameters for 14 patients with conventional relapsing-remitting MS (RRMS) and 20 age-matched healthy volunteers. In all of the structures, the trace values were significantly higher and the fractional anisotropy values were significantly lower in the RRMS patients than in the healthy volunteers. Furthermore, the volume fractions of the structures primarily composed of short axons markedly decreased, whereas those of the structures primarily composed of small neurons and glia markedly increased. These results suggest that axonal loss and glial proliferation predominantly occurred in the subcortical white matter and adjacent deep cortical layer, namely, the juxtacortical region. This cell-oriented analysis of NABT injury using DTI confirmed in vivo the histological observation that the juxtacortical region is the most vulnerable site in MS. PMID- 17689266 TI - Conjunction group analysis: an alternative to mixed/random effect analysis. AB - We address the problem of testing in every brain voxel v whether at least u out of n conditions (or subjects) considered shows a real effect. The only statistic suggested so far, the maximum p-value method, fails under dependency (unless u=n) and in particular under positive dependency that arises if all stimuli are compared to the same control stimulus. Moreover, it tends to have low power under independence. For testing that at least u out of n conditions shows a real effect, we suggest powerful test statistics that are valid under dependence between the individual condition p-values as well as under independence and other test statistics that are valid under independence. We use the above approach, replacing conditions by subjects, to produce informative group maps and thereby offer an alternative to mixed/random effect analysis. PMID- 17689267 TI - Positive correlations between corpus callosum thickness and intelligence. AB - Callosal morphology is thought to reflect the capacity for inter-hemispheric communication and thus, in addition to other cerebral characteristics, may serve as a neuroanatomical substrate of general intellectual capacity. We applied novel computational mesh-based methods to establish the presence and direction of correlations between intelligence and callosal thickness at high spatial resolution while removing the variance associated with overall brain size. Within healthy subjects (n=62), and within males (n=28) and females (n=34) separately, we observed significant positive correlations between callosal morphology and intelligence measures (full-scale, performance, and verbal). These relationships were pronounced in posterior callosal sections and were confirmed by permutation testing. Significant negative correlations were absent. Positive associations between intelligence and posterior callosal thickness may reflect a more efficient inter-hemispheric information transfer, positively affecting information processing and integration, and thus intellectual performance. At the same time, regional variations in callosal size might also partly reflect the underlying architecture of topographically connected cortical regions relevant for processing higher-order cognitive information. Our findings emphasize the importance of incorporating posterior (callosal) regions into the theories and models proposed to explain the anatomical substrates of intelligence. PMID- 17689269 TI - Partitioned Bayesian analyses, dispersal-vicariance analysis, and the biogeography of Chinese toad-headed lizards (Agamidae: Phrynocephalus): a re evaluation. AB - The toad-headed lizards of genus Phrynocephalus are distributed from northwestern China to Turkey and are one of the major components of the central Asian desert fauna. To date, published morphological and molecular phylogenetic hypotheses of Phrynocephalus are only partially congruent, and the relationships within the genus are still far from clear. We re-analyzed published mitochondrial gene sequence data (12S, 16S, cyt b, ND4-tRNA(Leu)) by employing partition-specific modeling in a combined DNA analysis to clarify existing gaps in the phylogeny of Chinese Phrynocephalus. Using this phylogenetic framework, we inferred the genus' historical biogeography by using weighted ancestral-area analysis and dispersal vicariance analysis in combination with a Bayesian relaxed molecular-clock approach and paleogeographical data. The partitioned Bayesian analyses support the monophyly of Phrynocephalus and its sister-group relationship with Laudakia. An earlier finding demonstrating the monophyly of the viviparous group is corroborated. However, our hypothesis of internal relationships of the oviparous group differs from a previous hypothesis as our results do not support monophyly of the oviparous taxa. Instead, the viviparous taxa form a clade with many oviparous taxa exclusive of P. helioscopus and P. mystaceus. Our results also suggest that: (1) P. putjatia is a valid species, comprising populations from Guide, Qinghai Province and Tianzhu, Gansu Province; (2) P. hongyuanensis is not a valid species, synonymized instead with P. vlangalii; (3) P. zetangensis is not a valid species and should be included in P. theobaldi; (4) the population occurring in Kuytun, Xinjiang Uygur Autonomous Region is recognized as P. guttatus instead of P. versicolor; and (5) the Lanzhou population of P. frontalis is part of P. przewalskii. Congruent with previous hypotheses, the uplift of the Tibetan Plateau played a fundamental role in the diversification of Phrynocephalus. An evolutionary scenario combining aspects of vicariance and dispersal is necessary to explain the distribution of Phrynocephalus. Bayesian divergence-time estimation suggests that Phrynocephalus originated at the Middle Late Miocene boundary (15.16-10.4 Ma), and diversified from Late Miocene to Pleistocene from a center of origin in Central Asia, Tarim Basin, and Junggar Basin temperate desert, followed by several rapid speciation events in a relatively short time. The proposed biogeographic scenarios also indicate that the Tarim Basin desert may be the secondary diversification center, followed by Junggar Basin temperate desert and Alashan Plateau temperate desert. In the viviparous group, the allopatric speciation of P. theobaldi and P. vlangalii may have been caused by the uplifting of Tanggula Mountain Ranges. In addition, the results of this study make an important contribution to understanding the uplift of the Tibetan Plateau and Tian Shan Mountains and the biogeography of the entire region. PMID- 17689270 TI - Comparison of the QT interval response during sinus and paced rhythm in conscious and anesthetized beagle dogs. AB - INTRODUCTION: The aim of the present study was to compare sensitivity in detecting the drug-induced QT interval prolongation in three dog models: conscious telemetered at sinus rhythm and conscious and anesthetized dogs during atrial pacing. The test substances used represent different chemical classes with different pharmacological and pharmacokinetic profiles. METHOD: Dofetilide and moxifloxacin were tested in all models, whereas cisapride and terfenadine were tested in the conscious telemetered and paced models. All substances were given as two consecutive 1.5-h intravenous infusions (infusions 1 and 2). The individual concentration-time courses of dofetilide, moxifloxacin, and cisapride were linked to the drug-induced effects on the QT interval and described with a pharmacokinetic-pharmacodynamic model to obtain an estimate of the unbound plasma concentrations at steady state that give a 10- and 20-ms drug-induced QT interval prolongation (CE10ms and CE20ms). RESULTS: In the conscious telemetered, conscious paced, and anesthetized dog models, the mean CE10ms values were 1.4, 4.0, and 2.5 nM for dofetilide and 1300, 1800, and 12,200 nM for moxifloxacin. For cisapride, the CE10ms values were 8.0 and 4.4 nM in the conscious telemetered and conscious paced dog models. The drug-induced QT interval prolongation during the last 30 min of infusions 1 and 2 was comparable in the conscious models, but smaller in the anesthetized dog model. Terfenadine displayed a marked delay in onset of response, which could only be detected by the extended ECG recording. DISCUSSION: All dog models investigated detected QT interval prolongation after administration of the investigated test substances with similar sensitivity, except for a lower sensitivity in the anesthetized dogs following moxifloxacin administration. The conscious telemetered dog model was favorable, mainly due to the extended continuous ECG recording, which facilitated detection and quantification of delayed temporal differences between systemic exposure and drug induced QT interval prolongation. PMID- 17689271 TI - Development of psychogenic non-epileptic seizures in response to auditory hallucinations. AB - Psychogenic non-epileptic seizures can co-exist with epileptic seizures. Differentiating between the two is central to appropriate management. We report the case of a patient with established focal epilepsy who developed psychogenic non-epileptic seizures in direct response to second-person auditory hallucinations. To our knowledge, this is the first description of such an occurrence. These non-epileptic seizures improved with treatment of the underlying psychosis. The relationship between epilepsy and psychosis is outlined, and the possible causes and nosology of these psychogenic non-epileptic seizures are discussed. PMID- 17689268 TI - Human cortical representations for reaching: mirror neurons for execution, observation, and imagery. AB - We used functional magnetic resonance imaging (fMRI) to map the cortical representations of executed reaching, observed reaching, and imagined reaching in humans. Whereas previous studies have mostly examined hand actions related to grasping, hand-object interactions, or local finger movements, here we were interested in reaching only (i.e. the transport phase of the hand to a particular location in space), without grasping. We hypothesized that mirror neuron areas specific to reaching-related representations would be active in all three conditions. An overlap between executed, observed, and imagined reaching activations was found in dorsal premotor cortex as well as in the superior parietal lobe and the intraparietal sulcus, in accord with our hypothesis. Activations for observed reaching were more dorsal than activations typically reported in the literature for observation of hand-object interactions (grasping). Our results suggest that the mirror neuron system is specific to the type of hand action performed, and that these fronto-parietal activations are a putative human homologue of the neural circuits underlying reaching in macaques. The parietal activations reported here for executed, imagined, and observed reaching are also consistent with previous functional imaging studies on planned reaching and delayed pointing movements, and extend the proposed localization of human reach-related brain areas to observation as well as imagery of reaching. PMID- 17689272 TI - Inflammatory response in patients undergoing hip surgery due to osteoarthrosis or different types of hip fractures. AB - OBJECTIVE: Hip surgery represents a major intervention associated with significant inflammatory response. The objective of our study was to compare markers of systemic inflammation and soluble adhesive molecules in patients undergoing elective hip replacement to those with hip fracture either intracapsular (IC) or extracapsular (EC). DESIGN: We included 65 consecutive patients undergoing hip surgery--17 patients with elective hip replacement (EL group), 29 patients with EC fracture (EC group) and 11 patients with IC fracture (IC group). Fibrinogen (FBG), orosomucoid (ORM), C-reactive protein (CRP), transferrin (TRF) and white blood cells count (WBC), sP-selectin, sE-selectin, and soluble intercellular adhesion molecule-1 (sICAM-1) were measured before surgery 4h, 48h, and 7 days after surgery. RESULTS: IC patients had preoperatively highest values of inflammatory markers including FBG, CRP, ORM, WBC and lowest values of TRF, as compared to intermediate values found in EC and lowest values in EL groups. The surgery has led in all three subgroups to significant elevation in CRP, ORM and decrease in TRF. In IC group, the subsequent recovery of inflammatory markers was very slow. We noted a significant suppression of sP-selectin and sE-selectin values in all subgroups after surgery. The decrease of sE-selectin but not of sP-selectin correlated with changes in hemoglobin and blood transfusions' administration. CONCLUSIONS: Hip surgery is associated with significant inflammatory reaction. In patients with hip fractures, inflammatory markers are elevated already preoperatively, more so in IC than in EC fractures. The unexpected observation of a significant postoperative decrease in sE-selectin and sP-selectin will require further research for elucidation. PMID- 17689273 TI - Interleukin-10 inhibits the down-regulation of ATP binding cassette transporter A1 by tumour necrosis factor-alpha in THP-1 macrophage-derived foam cells. AB - It is suggested that cholesterol efflux mediated by ATP binding cassette transporter A1 (ABCA1) plays an important role in anti-atherogenesis. However, the effects of inflammatory cytokines on ABCA1 expression and cholesterol accumulation in foam cells are little known. This study investigates the effects of tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) on ABCA1 expression and cholesterol content in THP-1 macrophage-derived foam cells. ABCA1mRNA and protein levels were determined by RT-PCR and Western blot, respectively. The total cholesterol content in THP-1 macrophage-derived foam cells was detected by the zymochemistry method. Results revealed that TNF-alpha could increase cholesterol content by down-regulating ABCA1 expression in a time dependent manner in THP-1 macrophage-derived foam cells, which may contribute to its pro-atherosclerotic effect. In addition IL-10 time-dependently decreased cholesterol accumulation by up-regulating ABCA1 expression and inhibited the down regulation of ABCA1 by TNF-alpha in THP-1 macrophage-derived foam cells, which may be one of the mechanisms of IL-10 contributing to its anti-atherosclerotic action. PMID- 17689274 TI - Endovascular repair of spontaneous infrarenal aortic dissection presenting as severe lower extremity ischaemia. AB - We report a 90-year old man who presented with severe lower extremity ischaemia due to spontaneous dissection of a non-aneurysmal infrarenal abdominal aorta. The aortic lesion was treated using an aorto-uni-iliac stent-graft with contralateral common iliac artery occlusion and femoro-femoral cross-over bypass. The patient underwent digital amputation and debridement of the foot four weeks post operatively. At 12 months follow-up, he remains symptom-free with an excluded dissection, patent reconstruction and healed foot. PMID- 17689275 TI - Oromandibular dystonia. AB - Oromandibular dystonia (OMD) is a rare neuromuscular disorder characterized by involuntary repetitive muscular contraction affecting different parts of the oromandibular region. Its various physical manifestations can be extremely debilitating and socially disabling to affected patients. To date, there is no commonly accepted set of diagnostic criteria nor well-defined management pathways. This paper aims to discuss some aspects of clinical manifestations, diagnostic criteria, neurological mechanisms, and treatment options for OMD, with illustrations from 6 clinical cases. PMID- 17689276 TI - Impact of live cell imaging on coated vesicle research. AB - The role of membrane traffic is to transfer cargo between distinct subcellular compartments. Each individual trafficking event involves the creation, transport and fusion of vesicular and tubular carriers that are formed and regulated via cytoplasmic coat protein complexes. The dynamic nature of this process is therefore highly suitable for studying using live cell imaging techniques. Although these approaches have raised further questions for the field, they have also been instrumental in providing essential new information, in particular relating to the morphology of transport carriers and the exchange kinetics of coat proteins and their regulators on membranes. Here, we present an overview of live cell-imaging experiments that have been used in the study of coated-vesicle transport, and provide specific examples of their impact on our understanding of coat function. PMID- 17689277 TI - Activation and silencing of matrix metalloproteinases. AB - Matrix metalloproteinases (MMPs) were first described as proteases that act on protein components of the extracellular matrix. However, subsequent studies of MMP function in vivo have revealed that these proteinases also cleave numerous non-ECM protein substrates. Because their substrates are diverse in functions, MMPs are involved in variety of homeostatic functions, such as tissue repair and immunity, as well as pathological processes, including cancer, fibroses and inflammation. Essential steps in regulating MMP proteolysis are conversion of the zymogen into an active proteinase and subsequent inactivation. A number of mechanisms including proteolysis, allosteric interactions, oxidative modification, pericellular compartmentalization, interaction with tissue inhibitor of metalloproteinases (TIMPs), endocytosis, and more have been proposed to control the activation and inactivation of MMPs. In this paper, we discuss these and other mechanisms, and their relevance to in vivo control of MMP mediated functions. PMID- 17689278 TI - A novel approach to the simulation of nitroxide spin label EPR spectra from a single truncated dynamical trajectory. AB - A simple effective method for calculation of EPR spectra from a single truncated dynamical trajectory of spin probe orientations is reported. It is shown that an accurate simulation can be achieved from the small initial fraction of a dynamical trajectory until the point when the autocorrelation function of re orientational motion of spin label has relaxed. This substantially reduces the amount of time for spectra simulation compared to previous approaches, which require multiple full length trajectories (normally of several microseconds) to achieve the desired resolution of EPR spectra. Our method is applicable to trajectories generated from both Brownian dynamics and molecular dynamics (MD) calculations. Simulations of EPR spectra from Brownian dynamical trajectories under a variety of motional conditions including bi-modal dynamics with different hopping rates between the modes are compared to those performed by conventional method. Since the relatively short timescales of spin label motions are realistically accessible by modern MD computational methods, our approach, for the first time, opens the prospect of the simulation of EPR spectra entirely from MD trajectories of real proteins structures. PMID- 17689279 TI - Nuclear spin resonance of (129)Xe doped with O(2). AB - Spin-lattice relaxation of (129)Xe nuclei in solid natural xenon has been investigated in detail over a large range of paramagnetic O(2) impurity concentrations. Direct measurements of the ground state magnetic properties of the O(2) are difficult because the ESR (electron spin resonance) lines of O(2) are rather unstructured, but NMR measurements in the liquid helium temperature region (1.4-4 K) are very sensitive to the effective magnetic moments associated with the spin 1 Zeeman levels of the O(2) molecules and to the O(2) magnetic relaxation. From these measurements, the value of the D[Sz(2)-(1/3)S(2)] spin Hamiltonian term of the triplet spin ground state of O(2) can be determined. The temperature and magnetic field dependence of the measured paramagnetic O(2) induced excess line width of the (129)Xe NMR signal agree well with the theoretical model with the spin-Hamiltonian D=0.19 meV (2.3 K), and with the reasonable assumption that the E[S(x)(2)-S(y)(2)] spin-Hamiltonian term is close to 0 meV. An anomalous temperature dependence between 1.4 K and 4.2K of the (129)Xe spin-lattice relaxation rate, T(1n)(-1)(T), is also accounted for by our model. Using an independent determination of the true O(2) concentration in the Xe-O(2) solid, the effective spin lattice relaxation time (which will be seen to be transition dependent) of the O(2) at 2.3 K and 0.96 T is determined to be approximately 1.4 x 10(-8)s. The experimental results, taken together with the relaxation model, suggest routes for bringing highly spin-polarized (129)Xe from the low temperature condensed phase to higher temperatures without excessive depolarization. PMID- 17689280 TI - Cloning, expression, purification, and characterization of arginine kinase from Locusta migratoria manilensis. AB - Arginine kinase (AK) is a phosphotransferase that plays a critical role in energy metabolism in invertebrates. The gene encoding Locusta migratoria manilensis AK was cloned and expressed in Escherichia coli by two prokaryotic expression plasmids, pET-30a and pET-28a. The recombinant protein was expressed as inclusion bodies using pET-30a. After denaturation, the recombinant AK was successfully renatured and confirmed to be enzymatically active. Addition of Tween-20 and SDS to the dilution system led to higher renaturation efficiency. Using another expression plasmid, pET-28a, and changing the expression conditions resulted in a soluble and functional form of AK, which was purified by an improved method using Sephadex G-75 chromotography to a final yield of 358 mg L(-1) of LB medium. Some parameters for the renatured and soluble forms of AK, including Km, Kd, specific activity, electrophoretic mobility and isoelectric focusing, were identical with those of AK obtained directly from L. migratoria manilensis leg muscle. Comparison of kinetic constants with those of AKs from other sources indicated that L. migratoria manilensis AKs have the highest kcat and stronger synergistic substrate binding. The first report of a concise purification method enables the enzyme to be prepared in large quantities. This research should enable further detailed investigations of the enzymatic mechanism by site directed mutagenesis techniques. PMID- 17689281 TI - Tripolar-cuff deviation from ideal model: assessment by bioelectric field simulations and saline-bath experiments. AB - Ideally, interference in neural measurements due to signals from nearby muscles can be completely eliminated with the use of tripolar cuffs, in combination with appropriate amplifier configurations, such as the quasi-tripole (QT) and the true tripole (TT). The operation of these amplifiers, is based on the theoretical property of the nerve cuff to produce a linear relationship of potential versus distance along its length, internally, when external potentials appear between its ends. Thus, in principle, electroneurogram (ENG) recordings from an ideal tripolar cuff would be free from electromyogram (EMG) interference generated by nearby muscles. However, in practice the cuff exhibits non-ideal behaviour leading to "cuff imbalance". The main focus of this paper is to investigate the causes of cuff imbalance, to demonstrate that it should be incorporated as a main parameter in the theoretical ENG-recording cuff electrode model. In addition to cuff asymmetry and tissue growth, the proximity of the interference source to the cuff is shown to result in cuff imbalance. The influence of proximity imbalance on the performance of the QT and TT amplifiers is also considered. Proximity imbalance is studied using bioelectric field simulations and saline-bath experiments. Variation is observed with both distance (40 mm and 70 mm was examined) and orientation (0-180 degrees), with the latter causing a more severe effect especially when the source dipole and the cuff are vertical to each other. The simulations and measurements are in close agreement. Tissue growth imbalance and asymmetry imbalance are also investigated in vitro. Finally, the signal-to interference ratio (SIR; ENG/EMG) of the QT and TT amplifiers is examined in the presence of cuff imbalance. It is shown that proximity imbalance results in their SIR to peak only at certain cuff orientation values. This important finding offers an insight as to why in practice ENG recordings using these amplifiers have been widely reported to be degraded by EMG interference. PMID- 17689282 TI - Roles of mitogen-activated protein kinase signal-integrating kinases 1 and 2 in oxidant-mediated eIF4E phosphorylation. AB - Oxidative stress alters cellular metabolic processes including protein synthesis. The eukaryotic initiation factor, eIF4E, acts in the rate-limiting steps of initiation and promotes nuclear export. Phosphorylation of eIF4E by mitogen activated protein kinase signal-integrating kinases 1 and 2 (Mnk) influences the affinity of eIF4E for the 5'-mRNA cap and fosters nuclear export activity. Although phosphorylation of eIF4E on Ser209 is observed following oxidant exposure, the contribution of Mnk isoforms and the significance of phosphorylation remain elusive. Using a Mnk inhibitor and fibroblasts derived from Mnk knockout mice, we demonstrate that that H2O2 enhances eIF4E phosphorylation in cells containing Mnk1. In contrast, cells containing only Mnk2 show little change or a decrease in eIF4E phosphorylation in response to H2O2. H2O2 also shifted eIF4GI protein from the nucleus to the cytoplasm suggesting that the increases in eIF4E phosphorylation may reflect enhanced substrate availability to cytoplasmic Mnk1. In Mnk1(+/+) cells, H2O2 also enhanced eIF4E phosphorylation in the nucleus to a greater degree than in the cytoplasm, an effect not observed in cells containing Mnk2. In response to H2O2, all MEFs showed increased eIF4E:4E-BP1 and 4E-BP2:eIF4E binding and reduced eIF4E:eIF4GI binding. We also observed a dramatic increase in the amount of Mnk1 associated with eIF4E following affinity chromatography. These changes coincided with a smaller reduction in global protein synthesis in response to H2O2 in the DKO cells. These findings suggest that changes in eIF4GI distribution may enhance eIF4E phosphorylation and that the presence of either Mnk1 or 2 or any degree of eIF4E phosphorylation negatively regulates global protein synthesis in response to oxidant stress. PMID- 17689284 TI - A novel method to study fluorescein staining of the ocular surface using the fluorescein angiogram setting of the fundus camera. AB - We present a case of a failed penetrating keratoplasty (PKP), comparing the fluorescein staining of the cornea with the conventional technique, and the new technique using the fluorescein filters of a standard fundus camera. PMID- 17689283 TI - Augmentation of effects of interferon-stimulated genes by reversal of epigenetic silencing: potential application to melanoma. AB - Increased expression of genes, silenced by methylation of their promoters, could have relevance for increasing effects of not only interferons (IFNs) but also APO2L/TRAIL, cytotoxics and immunotherapeutics for melanoma and other malignancies. A resistant melanoma cell line, A375, lacked APO2L/TRAIL or apoptosis induction by either IFN-alpha2 or IFN-beta. However, apoptosis was induced by IFNs in A375 cells by 5-aza,2'-deoxycytidine (5-Aza-dC), evaluated based upon the postulate that promoter methylation might be silencing pro apopoptotic IFN-stimulated genes (ISGs). RASSF1A, commonly methylated at high frequency in many tumors including melanoma, which we discovered to be also an IFN-regulated gene, was increased by 5-Aza-dC. RASSF1A was important in enhancing apoptotic effects of not only IFNs and APO2L/TRAIL but also cisplatin. Unraveling epigenetic regulatory mechanisms, as yet only partially identified, will result in new biological insights and improved strategies for therapeutic use of IFNs or ISGs such as APO2L/TRAIL. PMID- 17689285 TI - Epidermal growth factor receptor inhibitors enhance susceptibility to Fas mediated apoptosis in oral squamous cell carcinoma cells. AB - Molecular inhibition of epidermal growth factor receptor (EGFR) signaling is a promising cancer treatment strategy. We examined whether inhibition of EGFR signaling would affect the susceptibility of oral squamous cell carcinoma (OSCC) cells to Fas-mediated apoptosis. Treatment of OSCC cells with an anti-EGFR monoclonal antibody, C225, and an EGFR tyrosine kinase inhibitor, AG1478, which target the extracellular and intracellular domains of the receptor, respectively, inhibited phosphorylation of EGFR and its downstream effector molecule Akt and amplified the induction of Fas-mediated apoptosis. In OSCC cells treated with EGFR inhibitors, Fas-mediated apoptosis was accompanied by caspase-8 activation but not Bid cleavage. Caspase-3 and -8 inhibitors reduced the effect of EGFR inhibitors on Fas-mediated apoptosis in OSCC cells, but a caspase-9 inhibitor did not. These results indicate that the pro-apoptotic activity of EGFR inhibitors in OSCC cells depends on the extrinsic pathway of the caspase cascade. Although EGFR inhibitors did not affect the expression of Fas, the Fas-associated death domain protein, or procaspase-8 in OSCC cells, the inhibition downregulated cellular FLICE-inhibitory protein (c-FLIP). Moreover, knockdown of c-FLIP in HSC-2 cells with a small interfering RNA strongly enhanced Fas-mediated apoptosis. These results suggest that the EGFR signaling pathway may, in part, regulate Fas mediated apoptosis in OSCC cells through c-FLIP expression. PMID- 17689286 TI - Tumour cell proliferation under hypoxic conditions in human head and neck squamous cell carcinomas. AB - Two mechanisms of radiotherapy resistance of major importance in head and neck cancer are tumour cell repopulation and hypoxia. Hypoxic tumour cells that retain their clonogenic potential can survive radiation treatment and lead to local recurrences. The aim of this study was to quantify this cellular population in a cohort of human head and neck carcinomas and to investigate the prognostic significance. The proliferation marker iododeoxyuridine (IdUrd) and the hypoxia marker pimonidazole were administered intravenously prior to biopsy taking in patients with stage II-IV squamous cell carcinoma of the head and neck. Triple immunohistochemical staining of blood vessels, IdUrd and pimonidazole was performed and co-localization of IdUrd and pimonidazole was quantitatively assessed by computerized image analysis. The results were related with treatment outcome. Thirty-nine biopsies were analyzed. Tumours exhibited different patterns of proliferation and hypoxia but generally the IdUrd signal was found in proximity to blood vessels whereas pimonidazole binding was predominantly at a distance from vessels. Overall, no correlations were found between proliferative activity and oxygenation status. The fraction of IdUrd-labelled cells positive for pimonidazole ranged from 0% to 16.7% with a mean of 2.4% indicating that proliferative activity was low in hypoxic areas and occurring mainly in the well oxygenated tumour compartments. IdUrd positive cells in hypoxic areas made up only 0.09% of the total viable tumour cell mass. There were no associations between the magnitude of this cell population and local tumour control or survival. Co-localization between proliferating cells and hypoxia in head and neck carcinomas was quantified using an immunohistochemical triple staining technique combined with a computerized simultaneous analysis of multiple parameters. The proportion of cells proliferating under hypoxic conditions was small and no correlation with treatment outcome could be found. PMID- 17689287 TI - Reasons of different colors in the ignimbrite lithology: micro-XRF and confocal Raman spectrometry method. AB - Medium to large volume ignimbrites usually show vertical changes in terms of color, mineral components, texture and geochemistry. Determination of vertical changes in single extensive ignimbrite flow unit is difficult and requires careful studies. Color changes in ignimbrite flow units are very important for earth scientists. This may cause to identify the same ignimbrite series with different definition. Incesu ignimbrite has a wide distribution in the Central Anatolian Volcanic Province (CAVP). It is classified into three levels as lower, middle and upper according to color and welding degree. There is a sharp contact between the lower and middle level. The lower level is dark brown to black in color and the middle level has pinkish red to red color. The present paper focuses on the investigation of color changes between the ignimbrite levels by using micro-XRF and confocal Raman spectrometry. Micro-XRF and Raman spectrometry studies were performed on the polished thin sections of the lower and middle levels with different compositions. These differences were because of the compositional changes of K and slightly Fe elements distribution within the matrix. The dark brown to black color of the lower level was related to the high concentration of the K and Fe relatively to the middle level. Confocal Raman spectrometry investigations exhibited the matrix of the lower level mainly composed of anorthoclase, supporting the results of the micro-XRF. PMID- 17689288 TI - Atomic absorption spectroscopic, conductometric and colorimetric methods for determination of some fluoroquinolone antibacterials using ammonium reineckate. AB - Three accurate, rapid and simple atomic absorption spectrometric (AAS), conductometric and colorimetric methods were developed for the determination of gatifloxacin (GTF), moxifloxacin (MXF) and sparfloxacin (SPF). The proposed methods depend upon the reaction of ammonium reineckate with the studied drugs to form stable precipitate of ion-pair complexes, which was dissolved in acetone. The pink coloured complexes were determined either by AAS or colorimetrically at lambda(max) 525 nm directly using the dissolved complex. Using conductometric titration, the studied drugs could be evaluated in 50% (v/v) acetone. The optimizations of various experimental conditions were described. Optimum concentration ranges for the determination of GTF, MXF and SPF were 5.0-150, 40 440 microg mL(-1) and 0.10-1.5 mg mL(-1) using atomic absorption (AAS), conductometric and colorimetric methods, respectively. Detection and quantification limits are ranges from 1.5 to 2.3 microg mL(-1) using AAS method or 30-45 microg mL(-1) using colorimetric method. The proposed procedures have been applied successfully to the analysis of these drugs in pharmaceutical formulations and the results are favourably comparable to the reference methods. PMID- 17689289 TI - Novel pharmacological applications of G-protein-coupled receptor-G protein fusions. AB - Single, bi-functional polypeptides consisting of a G-protein-coupled receptor (GPCR) linked directly to a G protein alpha subunit have been employed for a number of years to study many aspects of signal initiation, including the roles of post-translational modifications, effects of mutations in both receptor and G protein and in the de-orphanisation of novel G-protein-coupled receptors. Recently, they have been used to improve signal-to-background in ligand assay screens and to study both agonist-directed signal trafficking and distinct conformational states of receptors. As well as such novel concepts in pharmacology, G-protein-coupled receptor-G protein fusions have recently been employed to examine receptor homo-dimerisation and hetero-dimerisation and are beginning to be used to explore allosteric effects within GPCR hetero-dimers. PMID- 17689290 TI - Interleukin-10 and the pathogenesis of human visceral leishmaniasis. AB - The mechanisms underlying the failure to control the growth and systemic spread of Leishmania parasites in human visceral leishmaniasis (VL) are not well understood. Although the absence of antigen-specific Th1 responses in the peripheral blood mononuclear cells from VL patients is thought to be causally related to disease progression, the finding that these patients also express elevated interferon-gamma mRNA in lesional tissue, as well as elevated serum levels of proinflammatory cytokines, suggests that their immunological defect cannot be explained simply by immune tolerance or Th2 polarization. As a possible homeostatic mechanism to control persistent infection-induced inflammation, elevated levels of the regulatory cytokine interleukin (IL)-10 have been reported repeatedly in clinical studies of VL. Here, we review the studies with relevance to immune responses in human VL and highlight the central role that IL-10 might have in the pathogenesis of VL and as a target for immune-based therapy. PMID- 17689291 TI - The emergence of neurotransmitters as immune modulators. AB - Initially, the idea that neurotransmitters could serve as immunomodulators emerged with the discovery that their release and diffusion from nervous tissue could lead to signaling through lymphocyte cell-surface receptors and the modulation of immune function. It is now evident that neurotransmitters can also be released from leukocytes and act as autocrine or paracrine modulators. Here, we review the data indicating that leukocytes synthesize and release 'neurotransmitters' and we also discuss the diverse effects that these compounds exert in a variety of immune cells. The role of neurotransmitters in immune related diseases is also reviewed succinctly. Current and future developments in understanding the cross-talk between the immune and nervous systems will probably identify new avenues for treating immune-mediated diseases using agonists or antagonists of neurotransmitter receptors. PMID- 17689292 TI - Tissue Doppler echocardiography reliably reflects severity of iron overload in pediatric patients with beta thalassemia. AB - AIMS: Tissue Doppler imaging has been recently used to evaluate ventricular function in patients with beta thalassemia. In clinical practice, serum ferritin is commonly used to assess the severity of iron overload. The aim of this study was to determine which Doppler findings correlated with serum ferritin. METHODS AND RESULTS: Thirty-one pediatric patients with transfusion-dependent beta thalassemia with normal LVFS were evaluated. Seven patients with serum ferritin <2500 ng/ mL, 13 patients with serum ferritin 2500-5000 ng/mL, and 11 patients with serum ferritin >5000 ng/mL were studied. Diastolic dysfunction was absent in all patients with serum ferritin <2500 ng/mL, and was present in all patients with serum ferritin >5000 ng/mL. Deceleration time (DT) has a significant correlation with serum ferritin (r = -0.59, p < 0.0001). Difference of pulmonary vein atrial reversal flow and mitral valve A wave duration (PVAR - MVA) and early ventricular filling velocity to early diastolic myocardial velocity ratio (E/Em) significantly correlated with serum ferritin (r = 0.49, p = 0.006; r = 0.56, p = 0.001, respectively). CONCLUSION: Decreased DT, increased PVAR-MVA duration, and increased E/Em ratio reliably reflected severe iron overload in pediatric patients with beta thalassemia. Systolic and diastolic LV function is preserved in patients who have serum ferritin <2500 ng/mL. PMID- 17689293 TI - The left atrial function index: a rhythm independent marker of atrial function. AB - AIMS: This study evaluates a simple echocardiographic rhythm independent expression of left atrial (LA) function, 'the left atrial function index' (LAFI). BACKGROUND: Quantitation of LA function is challenging and often established parameters including peak A are limited to sinus rhythm (SR). We hypothesized that atrial function could be characterized independent of rhythm by combining analogues of LA volume, reservoir function and LV stroke volume. METHODS: Seventy two patients with chronic atrial fibrillation (CAF) were followed for six months post cardioversion (CV). Thirty-seven age matched healthy subjects were controls. The LAFI = LAEF x LVOT-VTI/LAESVI (LAEF = LA emptying fraction, LAESVI = maximal LA volume indexed to BSA, LVOT-VTI = outflow tract velocity time integral). RESULTS: The LAFI pre-CV in the CAF group was depressed vs controls (0.10 +/- 0.05 vs 0.54 +/- 0.17; P = 0.0001). Post-CV, LAFI was lower in persistent AF than in those restored to SR (AF vs SR: 0.08 +/- 0.03 vs 0.15 +/- 0.08; P = 0.0001), improved progressively in SR and was unchanged when AF persisted. CONCLUSION: The LAFI, a simple, rhythm independent expression of atrial function, appears sensitive to differences between individuals in AF and those restored to SR and justifies clinical and investigative applications. PMID- 17689294 TI - Racial/ethnic differences in patient experiences with and preferences for computed tomography colonography and optical colonoscopy. AB - BACKGROUND & AIMS: Racial/ethnic minorities are less likely than whites to undergo colorectal cancer (CRC) screening. Although computed tomography colonography (CTC) is a less invasive alternative to optical colonoscopy (OC), it is not known whether CTC will increase acceptance of CRC screening in minorities. METHODS: Patients undergoing OC for clinically indicated reasons had CTC followed by same-day OC. After the sedation from the OC had worn off, a questionnaire was administered to assess pain, discomfort, bloating, embarrassment, anxiety, and patient satisfaction using a 10-point scale (1 = least, 10 = greatest). RESULTS: Of the 272 patients enrolled, there were 134 whites, 71 blacks, 53 Hispanics, and 14 who self-identified their race/ethnicity as other. Although the proportion of subjects who preferred CTC over OC was not significantly different (52.9% vs 47.1%, P = .36), racial/ethnic minorities were significantly less likely than whites to prefer CTC over OC (whites, 65.7%; blacks, 45.1%; Hispanics, 35.8%; and other, 35.7%; P < .001). Racial/ethnic minorities were less satisfied with CTC (whites, 8.4 +/- 1.7; blacks, 7.8 +/- 1.7; Hispanics, 7.4 +/- 1.8; and other, 7.5 +/- 2.1; P = .001) and were significantly less willing to undergo CTC again in the future (whites, 95.5%; blacks, 80.3%; Hispanics, 84.9%; and other, 85.7%; P = .006). CONCLUSIONS: Compared with white patients, OC is better tolerated and is preferred over CTC for evaluation of the colon among racial/ethnic minorities. Although CTC is less invasive than OC, our findings suggest that CTC is unlikely to overcome racial/ethnic disparities in CRC screening. PMID- 17689295 TI - Effect of precut sphincterotomy on biliary cannulation based on the characteristics of the major duodenal papilla. AB - BACKGROUND & AIMS: Therapeutic endoscopic retrograde cholangiopancreatography requires selective cannulation of the relevant ductal system. The aim of this study was to evaluate the efficacy and safety of 3 different precutting techniques for difficult bile duct access on the basis of the characteristics of the major duodenal papilla (MDP). METHODS: The patients were classified into small MDP, large MDP, or swollen MDP groups on the basis of the characteristics of the MDP. The precutting technique was based on MDP characteristics: transpancreatic sphincterotomy for small MDPs, needle-knife precut sphincterotomy for large MDPs, and needle-knife fistulotomy for swollen MDPs. The success rate of bile duct cannulation and the complication rates were compared. RESULTS: A total of 86 patients (58 men; mean age, 76 years) with difficult bile duct cannulation required precutting technique; 48 had transpancreatic sphincterotomy, 30 had needle-knife precut sphincterotomy, and 8 had needle-knife fistulotomy. With precutting, the procedure was successful in 46 of 48 (96%), 27 of 30 (90%), and 8 of 8 patients (100%), respectively. The overall success rate of biliary cannulation after 2 endoscopic retrograde cholangiopancreatography attempts was 100%. The overall complication rate was 4.7% (4 of 86) (2 mild bleeding and 2 mild pancreatitis). CONCLUSIONS: Selection of the precutting technique on the basis of the characteristics of the MDP resulted in a high degree of success and a low complication rate in cases of difficult bile duct cannulation. PMID- 17689297 TI - In vivo histopathology for detection of gastrointestinal neoplasia with a portable, confocal miniprobe: an examiner blinded analysis. AB - BACKGROUND & AIMS: Confocal fluorescence microscopy (CFM) has been mentioned to be a promising tool for in vivo histology. Recently, a portable confocal miniprobe has been developed. Our aim was to evaluate the potential benefit of CFM for detection of gastrointestinal neoplasia. METHODS: A total of 47 patients with known or suspected neoplasia in the upper (n = 34) or lower gastrointestinal tract (n = 13) were examined with standard endoscopes. After mucolyis with 5-10 mL of acetic acid 1.5%, chromoendoscopy with 2-5 mL cresyl violet 0.25% was performed, with the substance also being used as a fluorophore for CFM. Real-time video sequences were recorded. Thereafter, biopsies were taken or mucosectomy/polypectomy was performed from the same examined area. All stored sequences were put into a random order and assessed by a pathologist and a gastroenterologist both blinded to any data. RESULTS: A total of 119 CFM video sequences were recorded of 85 benign or 34 neoplastic areas. Quality of CFM images was regarded too low in 24 (pathologist) and 14 sequences (gastroenterologist). For the pathologist, accuracy of CFM detecting neoplasia was 92.6% (suitable images) and 73.9% (intention to diagnose). The respective accuracy values for the gastroenterologist were 92.4% (suitable images) and 81.5% (intention to diagnose). Agreement between CFM and histopathology was excellent (kappa values, 0.821 and 0.817). CONCLUSIONS: We have demonstrated that CFM with a miniprobe has the potential to diagnose neoplasia during ongoing endoscopy. This system has the advantage that it can be used with standard endoscopes. Further studies are warranted for validation. PMID- 17689296 TI - Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study. AB - BACKGROUND & AIMS: Intrahepatic and extrahepatic cholangiocarcinomas are rare and highly malignant cancers of the bile duct. Although the incidence of extrahepatic cholangiocarcinoma (ECC) has remained constant, the incidence of intrahepatic cholangiocarcinoma (ICC) has increased in the United States. Because the etiology of both tumors is poorly understood, a population-based case-control study was conducted to examine the association of ECC and ICC with preexisting medical conditions. METHODS: Medical conditions among 535 ICC patients, 549 ECC patients (diagnosed 1993-1999), and 102,782 cancer-free controls were identified by using the Surveillance, Epidemiology and End Results-Medicare databases. Logistic regression analysis was used to calculate adjusted odds ratios. RESULTS: In addition to established risk factors (choledochal cysts, cholangitis, inflammatory bowel disease), several other conditions were significantly associated with ECC and ICC: biliary cirrhosis (ECC, ICC: P < .001), cholelithiasis (ECC, ICC: P < .001), alcoholic liver disease (ECC, P < .001; ICC, P = .01), nonspecific cirrhosis (ECC, ICC: P < .001), diabetes (ECC, ICC: P < .001), thyrotoxicosis (ECC, P = .006; ICC, P = .04), and chronic pancreatitis (ECC, ICC: P < .001). Conditions only associated with ICC were obesity (ECC, P = .71; ICC, P = .01), chronic nonalcoholic liver disease (ECC, P = .08; ICC, P = .02), HCV infection (ECC, P = .67; ICC, P = .01), and smoking (ECC, P = .07; ICC, P = .04). CONCLUSIONS: Several novel associations with ECC and ICC were identified. HCV infection, chronic nonalcoholic liver disease, and obesity, all of which are increasing in incidence, and smoking were associated only with ICC, suggesting that these conditions might explain the divergent incidence trends of the tumors. PMID- 17689298 TI - Tuberculosis transmission in a high incidence area: a retrospective molecular epidemiological study of Mycobacterium tuberculosis in Casablanca, Morocco. AB - Like in most developing countries, tuberculosis represents a major public health problem in Morocco. This paper describes the first study combining molecular and conventional epidemiology of tuberculosis in Casablanca, the economic capital of this country. Molecular fingerprinting of the genomic DNA recovered from cultures of sputum of 150 patients was performed by MIRU-VNTR. This molecular marker revealed that 53.1% of the total cases were clustered. These cases were classified into 23 clusters ranging in size from 2 to 13 patients, suggesting a rate of 37% of recent transmission in the sample under study. In a multivariate analysis, there were no independent predictors of clustering. However, the clinical form was associated with drug resistance (odds ratio=9.9; P value=0.0006). The phylogenetic analysis showed that the heterogeneity found in this population includes also the members from a same patient family, and that the 2 major families distributed in Casablanca were the Latin-American Mediterranean (LAM) and Haarlem families. All the results of this work allow to understand better the tuberculosis transmission in Casablanca, and suggest that different clones of M. tuberculosis seem to circulate in this city, and that the reactivation of latent infections would be mainly responsible for the endemic situation of this disease. These findings indicate also that the transmission of TB in Morocco is not optimally controlled, and that efforts for control strategies should be sustained in all developing countries where the incidence of TB is high and still raising. PMID- 17689299 TI - Alveolar epithelial transport in the adult lung. AB - The alveolar surface comprises >99% of the internal surface area of the lungs. At birth, the fetal lung rapidly converts from a state of net fluid secretion, which is necessary for normal fetal lung development, to a state in which there is a minimal amount of alveolar liquid. The alveolar surface epithelium facing the air compartment is composed of TI and TII cells. The morphometric characteristics of both cell types are fairly constant over a range of mammalian species varying in body weight by a factor of approximately 50,000. From the conservation of size and shape across species, one may infer that both TI and TII cells also have important conserved functions. The regulation of alveolar ion and liquid transport has been extensively investigated using a variety of experimental models, including whole animal, isolated lung, isolated cell, and cultured cell model systems, each with their inherent strengths and weaknesses. The results obtained with different model systems and a variety of different species point to both interesting parallels and some surprising differences. Sometimes it has been difficult to reconcile results obtained with different model systems. In this section, the primary focus will be on aspects of alveolar ion and liquid transport under normal physiologic conditions, emphasizing newer data and describing evolving paradigms of lung ion and fluid transport. We will highlight some of the unanswered questions, outline the similarities and differences in results obtained with different model systems, and describe some of the complex and interweaving regulatory networks. PMID- 17689300 TI - Capillary electrophoresis with laser-induced fluorescence and pre-column derivatization for the analysis of illicit drugs. AB - In the current paper, we report the development of a new capillary electrophoresis method using pre-column derivatization and laser-induced fluorescence detection for the determination of ephedrine and amphetamine drugs. Our new method allows for the identification and quantification of six commonly used illicit drugs namely pseudoephedrine, ephedrine, amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, and 3,4 methylenedioxymethylamphetamine, respectively, as well as propafenone (internal standard). Following derivatization with fluorescein isothiocyanate, a total of six amphetamine drugs and the internal standard could readily be separated using a fused-silica 75 micromID x 60 cm length (effective length: 50.2 cm) capillary column. The mobile phase consisted of buffer containing 20mM borate (pH 12, adjusted with sodium hydroxide). Samples were injected in pressure mode with the capillary being operated at 25kV/25 degrees C, and the detection of the derivatized compounds was sought using a laser-induced fluorescence (LIF) detector (lambda(ex)=488 nm and lambda(em)=520 nm), with a run-time of 20 min. The current method was validated with regard to precision (relative standard deviation, RSD), accuracy, sensitivity, linear range, limit of detection (LOD) and limit of quantification (LOQ). In human blood and urine samples, detection limits were 0.2 ngmL(-1), and the linear range of the calibration curves was 0.5 100 ngmL(-1). The intra-day and inter-day precisions were both less than 13.22%. PMID- 17689301 TI - Preparative separation of punicalagin from pomegranate husk by high-speed countercurrent chromatography. AB - Punicalagin, the main ingredient of pomegranate (Punica granatum L.) husk, is a high molecular weight polyphenolic compound. It has shown remarkable pharmacological activities attributed in the presence of dissociable OH groups. To isolate punicalagin, previous methods included labor intensive and expensive solid phase extractions by column chromatography (C-18, polyamides, dellulose, Sephadex Lipophilic LH-20, Diaion HP20). High-speed countercurrent chromatography (HSCCC) was used for isolation and purification of punicalagin from pomegranate husk. Using preparative HSCCC about a 350 mg amount of the crude extract was separated, yielding 105 mg of punicalagin at a high-purity of over 92%. Eighty milligrams of gallic acid was simultaneously separated as another product, at a purity of 75%. PMID- 17689302 TI - Simultaneous determination of flavonoid and alkaloid compounds in Citrus herbs by high-performance liquid chromatography-photodiode array detection-electrospray mass spectrometry. AB - The major active biological constituents in Citrus herbs are flavonoids, especially hesperidin, naringin and alkaloids, mainly synephrine, with beneficial medical effects on human health. They are used as the markers to control the quality of Citrus herbs. In this paper, a new ion pairing chromatographic method was developed to exclude the most polar solute (synephrine) from the viod volume and to maintain selectivity between the two other solutes (hesperidin and naringin). Perfluorinated carboxylic acids, which are appropriate for MS detection due to their volatility, were used as ion-pairing agents. The problems of the synephrine separation, such as band tailing and low retention, were solved successfully by using perfluorinated carboxylic acids. The effect of heptafluorobutyric acid (HFBA) was the best in the three investigated perfluorinated carboxylic acids. For the flavanone glycosides, the influence of the perfluorinated acids on retention time was rather weak. The two different kinds of the analytes were separated satisfactorily in one run using an isocratic eluent and the total analysis time takes less than 10 min. The abundance of pseudomolecular ions was recorded using selected ion monitoring (SIM) mode of m/z 135.1, 273.1 and 303.1 for synephrine, naringin and hesperidin, respectively. The contents of hesperidin, naringin and synephrine in several Citrus herbs were simultaneously determined by the proposed method. PMID- 17689303 TI - Multi-component plasma quantitation of anti-hyperglycemic pharmaceutical compounds using liquid chromatography-tandem mass spectrometry. AB - Type-2 diabetes is a disorder characterized by disrupted insulin production leading to high blood glucose levels. To control this disease, combination therapy is often used. Hypoglycemic agents such as metformin, glipizide, glyburide, repaglinide, rosiglitazone, nateglinide, and pioglitazone are widely prescribed to control blood sugar levels. These drugs provide the basis for the development of a quantitative multianalyte bioanalytical method. As an example, a highly sensitive and selective multi-drug method based on liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed. This rapid, automated method consists of protein precipitation of 20 microL of plasma coupled with gradient HPLC elution of compounds using 10 mM ammonium formate buffer and 0.1% formic acid in acetonitrile as the mobile phases. MS/MS detection was performed using turbo ion spray in the positive ion multiple reaction monitoring (SRM) mode. A lower limit of quantitation (LLQ) in a range of 1.0-5.0 ng/mL was achieved for all analytes. The linearity of the method was observed over a 500-fold dynamic range. Drug recoveries ranged from 86.2 to 94.2% for all analytes of interest. Selectivity, sample dilution, intra-day and inter-day accuracy and precision, and stability assessment were evaluated for all compounds. PMID- 17689304 TI - Simultaneous determination of rivanol and mifepristone in human plasma by a HPLC UV method with solid-phase extraction. AB - A HPLC method with UV detection was developed and validated for the simultaneous determination of rivanol and mifepristone in human plasma. Norethisterone was used as the internal standard. Separation was performed by a C18 reversed-phase column maintained at 20 degrees C. The mobile phase was a mixture of methanol acetonitrile-0.05% sodium dodecylsulfonate in a 0.05 M phosphate buffer with the pH adjusted to 3.0 (30:30:40, v/v/v) at a flow rate of 0.8 ml/min. Dual wavelength mode was used, with mifepristone monitored at UV 302 nm, while rivanol and norethisterone at 272 nm. A reliable biological sample pre-treatment procedure by means of solid-phase extraction was used, which allowed to obtain good extraction efficiency (>93%) for both of the analytes and the internal standard. The calibration curves were both linear with the correlation coefficient r equal to 0.9999. For rivanol, the assay gave CV% values for precision always lower than 7.8% and mean accuracy values higher than 95.3%. As to mifepristone, precision was always lower than 10.1% and mean accuracy values were higher than 93.8%. The limit of detection for the assay of rivanol and mifepristone was 1.1 and 3 ng/ml, respectively. The method is simple, sensitive and accurate, and allow for simultaneous determination of nanogram levels of rivanol and mifepristone in human plasma. It could be applied to assess the plasma level of rivanol and mifepristone in women undergoing polypharmacy with the two drugs. PMID- 17689305 TI - Determination of scopoletin in rat plasma by high performance liquid chromatographic method with UV detection and its application to a pharmacokinetic study. AB - A rapid and simple high-performance liquid chromatographic (HPLC) method has been developed and validated for determination of scopoletin in rat plasma using psoralen as internal standard. Chromatographic separation was achieved on a C(18) column using methanol and distilled water (49:51, v/v) containing 0.05% (v/v) phosphoric acid as mobile phase. The UV detector was set at 345 nm. The calibration curve was linear over the range of 0.165-9.90 microg/ml with a correlation coefficient of 0.9994. The recovery for plasma samples of 0.165, 1.32 and 6.60 microg/ml was 93.2%, 95.9% and 95.5%, respectively. The RSD of intra- and inter-day assay variations was less than 6.7%. This HPLC assay is a precise and reliable method for the analysis of scopoletin in pharmacokinetic studies. PMID- 17689306 TI - Aggregation and fibrillation of bovine serum albumin. AB - The all-alpha helix multi-domain protein bovine serum albumin (BSA) aggregates at elevated temperatures. Here we show that these thermal aggregates have amyloid properties. They bind the fibril-specific dyes Thioflavin T and Congo Red, show elongated although somewhat worm-like morphology and characteristic amyloid X-ray fiber diffraction peaks. Fibrillation occurs over minutes to hours without a lag phase, is independent of seeding and shows only moderate concentration dependence, suggesting intramolecular aggregation nuclei. Nevertheless, multi exponential increases in dye-binding signal and changes in morphology suggest the existence of different aggregate species. Although beta-sheet content increases from 0 to ca. 40% upon aggregation, the aggregates retain significant amounts of alpha-helix structure, and lack a protease-resistant core. Thus BSA is able to form well-ordered beta-sheet rich aggregates which nevertheless do not possess the same structural rigidity as classical fibrils. The aggregates do not permeabilize synthetic membranes and are not cytotoxic. The ease with which a multidomain all-alpha helix protein can form higher-order beta-sheet structure, while retaining significant amounts of alpha-helix, highlights the universality of the fibrillation mechanism. However, the presence of non-beta-sheet structure may influence the final fibrillar structure and could be a key component in aggregated BSA's lack of cytotoxicity. PMID- 17689307 TI - Technique for the control of spheroid diameter using microfabricated chips. AB - This paper describes a new technique for the control of spheroid diameter in liver-derived cell lines using microfabricated chips that were prepared by combining microfabrication with chemical surface modification. The chip possesses multicavities in a triangular arrangement in the central region (10 mm x 10 mm) of a polymethylmethacrylate (PMMA) plate (24 mm x 24 mm), and the surface of the chip was modified with polyethylene glycol, thereby producing a surface that is non-adhesive to cells. HepG2 cells, a model liver-derived cell line, inoculated onto the chip were trapped within each cavity and proliferated to gradually form spheroids with smooth surfaces and high circularity. Although the spheroid diameters increased with cell proliferation during the initial 10 days of culture, they remained constant thereafter. The spheroid diameters were dependent on the scales of the multicavities on the chip, and the spheroid configuration with uniform diameter was maintained for at least 1 month. In particular, it was demonstrated using chips of various designs that the cavity diameter and the pitch between cavities were effective factors in controlling the spheroid diameter. Furthermore, the protein secretion activities of the spheroid formed on the chip were higher than those of the monolayers for at least 1 month of culture. These results indicate that this chip is a useful technique for the control of spheroid diameter and for the mass preparation of uniform spheroids. PMID- 17689308 TI - 'Prefabricated' and 'prelaminated' flaps: two very different techniques. PMID- 17689309 TI - Effects of multiple stakeholders in identifying and interpreting perceived needs. AB - The participation of diverse groups is advocated for planning and implementing needs assessment (NA) procedures. While the involvement of varied constituencies is important, obtaining it requires more effort from the needs assessor and therefore is less commonly employed [Witkin, B.R. (1994). Needs assessment since 1981: The state of the practice. Evaluation Practice, 15(1), 17-27]. In this paper the perspectives held by two groups of stakeholders in an NA were obtained, compared, and when disparate, the groups were queried as to why they were different. A mixed-method design, a quantitative approach followed by a qualitative one, was utilized. Self-report data were collected from the two groups. Group effects, although not strong, were apparent for some items. Understanding the reasons for such differences contributes to a fuller and more meaningful interpretation of needs. PMID- 17689310 TI - Structural equation model for the evaluation of national funding on R&D project of SMEs in consideration with MBNQA criteria. AB - Financial support on the R&D in Science & Technology for SMEs at the governmental level plays a crucial role on the improvement of the national competitiveness. Korea Science & Engineering Foundation (KOSEF) has supported the R&D projects of SMEs with the competitive technology ability by way of the Science and Technology Promotion Fund. In this paper, we propose a structural equation model (SEM) to evaluate the performance of such a funding program in terms of three aspects: output, outcome and impact under given funding inputs, R&D environment of a recipient company, and external evaluation programs of funding organization. We adopt Malcolm Baldrige National Quality Award (MBNQA) criteria to assess the R&D environmental factors of recipient companies. In addition, we test the effect of interim evaluation of the funded project. The proposed model is applied to the real case and is used to identify the best practices as well as to provide feedback information for the improvement of the government funding programs of the R&D projects of SMEs. PMID- 17689311 TI - A use-and-transformation model for evaluating public R&D: illustrations from polycystic ovarian syndrome (PCOS) research. AB - Evaluating federally funded research and development (R&D) presents unique challenges to both federal science agencies and evaluators. Often focusing only on outcome evaluative measures (such as productivity or economic value) can shortchange the true value of the federal investment. For example, program directors at the National Science Foundation (NSF) and National Institutes of Health (NIH) talk about the "value added" of the new interdisciplinary science centers that they have funded-and they hope to be able to capture how funding can generate increased capacity for new cutting-edge research in the future. The purpose of this paper is to present a use-and-transformation model for evaluating public R&D, which explicitly focuses on measuring capacity-based metrics for evaluation instead of outcome-based metrics. The theory for the model presented here explicitly uses the concept of a Knowledge Value Collective that was introduced by Bozeman and Rogers [Bozeman, B., & Rogers, J. D. (2002). A churn model of scientific knowledge value: Internet researchers as a knowledge value collective. Research Policy, 31(5), 769-794; Rogers, J. D., & Bozeman, B. (2001). "Knowledge value alliances": An alternative to the R&D project focus in evaluation. Science Technology & Human Values, 26(1), 23-55]. PMID- 17689312 TI - Determinates of youth and parent satisfaction in usual care psychotherapy. AB - OBJECTIVE: Client satisfaction with mental health services is used commonly as an indicator of the quality of care, but there is minimal research on the construct of client satisfaction in youth services, and the extent to which satisfaction is related to improvements in clinical functioning versus other determinants. We examined the relationship between parent and youth satisfaction with youth services, and tested for significant determinants of satisfaction across three major domains: (1) change in youth clinical functioning; (2) youth/family service entry characteristics; (3) treatment/therapist characteristics. METHOD: The participants were 143 youths receiving community-based outpatient care. Youths and parents were interviewed at service entry and six months later using well established measures of clinical functioning and service satisfaction. RESULTS: Youths and parents reported generally high satisfaction, but the correlation between them was low. Despite testing for many potential predictors of satisfaction, very few significant effects were found. In regression analyses of significant predictors of satisfaction, higher youth satisfaction was significantly associated with Caucasian ethnicity and more positive youth expectations about treatment. Higher parent satisfaction was associated with lower caregiver strain at service entry, increased number of sessions, and improvement in youth-reported functional impairment. CONCLUSIONS: Client satisfaction remains a rather elusive construct, but it is not necessarily a strong indicator of service effectiveness. PMID- 17689313 TI - Developing the Learning Door: a case study in youth participatory program planning. AB - This article presents the results of a case study in youth participatory program planning conducted in the context of a nonformal technology-education program in eastern Finland. The purpose of the program was to have youth, university, and business stakeholders work together to create the Learning Door, a door that would meet the needs of older people and people with disabilities. The participatory program planning process that was used involved clarifying the mission, roles, and modes of collaboration as well as creating stakeholder matrices, logic models, program plans, and implementation plans. It was found that the observed program planning process was similar to the intended planning process and that the process was well received by the planning participants. The lessons learned include clarifying the nature of collaboration before the program gets underway, reviewing program planning steps often, and making clear distinctions between logic models and implementations plans. PMID- 17689314 TI - Monitoring and evaluation under the PRSP: solid rock or quicksand? AB - Over the last few years a shift has taken place in the aid instruments advocated for low-income countries, characterised by a conversion from project to more programme-oriented aid and by the inclusion of 'broad-based civil society participation' as an aid conditionality. Poverty Reduction Strategy Papers (PRSPs) constitute a new framework for policy negotiations with the recipient government as well as a new set of rules for aid implementation. So far scant attention has been paid to strengthening monitoring and evaluation. This paper contributes to this under-exploited field of research by stocktaking and assessing different aspects of M&E systems for a selected number of Sub-Saharan African countries. Findings of our desk study confirm that M&E is among the weaker parts of the new aid architecture. The PRSP approach seeks improvements in M&E, but its unrealistic ambitions put embryonic national M&E systems under undue stress. PMID- 17689315 TI - Implementation and evaluation of an HIV/STD intervention in Peru. AB - This paper presents the lessons learned through a process evaluation (PE) after 1 year of implementation of a 2-year community intervention in Lima, Peru. The intervention consisted of training and motivating community popular opinion leaders (CPOLs) for three marginal population segments to disseminate prevention messages among their peers. PE data included: observations, qualitative interviews with CPOLS, conversations and messages delivered by CPOLs, training facilitators' perceptions about implementation, and a survey of CPOLs. The PE helped to document and enhance the intervention. CPOLs were motivated to talk to their peers. CPOLs perceived that their participation had an effect on their own risk behaviors and saw their role as beneficial to their community. The PE was helpful in examining training delivery and the feasibility and acceptability of the intervention in order to assess the elements related to program success necessary to replicate the CPOL model. PMID- 17689316 TI - Beyond the limitations of best practices: how logic analysis helped reinterpret dual diagnosis guidelines. AB - The co-occurrence of mental health and substance use disorders is becoming increasingly recognized as a single problem, and professionals recognize that both should be addressed at the same time. Medical best practices recommend integrated treatment. However, criticisms have arisen, particularly concerning the difficulty of implementing integrated teams in specific health-care contexts and the appropriateness of the proposed model for certain populations. Using logic analysis, we identify the key clinical and organizational factors that contribute to successful implementation. Building on both the professional and organizational literatures on integrated services, we propose a conceptual model that makes it possible to analyze integration processes and places integrated treatment within an interpretative framework. Using this model, it becomes possible to identify key factors necessary to support service integration, and suggest new models of practice adapted to particular contexts. PMID- 17689317 TI - Analysis of strategic plans to assess planning for sustainability of comprehensive community initiatives. AB - In order to achieve the intended impact on a community, comprehensive community initiatives must sustain programs once they have been implemented. However, planning for sustainability is challenging and is rarely incorporated in the planning process of an initiative. The current study examined 19 5-year plans developed during the planning phase of the Comprehensive Strategy for Serious, Violent and Chronic Juvenile Offenders. Quantitative and qualitative methods were employed to assess the extent to which the construct of sustainability was incorporated. The plan analysis was supplemented with results from other components of the complex evaluation design implemented as part of the process evaluation of Comprehensive Strategy. Results suggested that sustainability was not accounted for during the planning phase of this initiative. The implications of these findings, including the importance of planning for sustainability in order to achieve sustainability, are discussed. PMID- 17689318 TI - Key considerations for logic model development in research partnerships: a Canadian case study. AB - Community-academic partnership research is a fairly new genre of community-based participatory research. It has arisen in part, from recognition of the potential role of alliances in the development and translation of applied knowledge and the elimination of health disparities. This paper reports on the learning process of academic and community members who worked together in developing a logic model for a research program focusing on partnerships with vulnerable populations. The Partners in Community Health Research is a 6-year training program that seeks to combine research, training, and practice through the work of its "learning clusters". As these types of partnerships proliferate, the articulation and exploration of clear models will assist in their implementation. The authors, coming from both academia and community agencies, present a logic model meant to facilitate program management. Key considerations in the model's development are discussed in the context of an ongoing research partnership; namely, the complexity of the research partnership, power and accountability, alignment with health promotion policy, and the iterative nature of program design. Recommendations challenge academics, policy-makers, service providers, and community members to reflect on the elements needed to support and manage research partnerships and the tools necessary to ensure continued collaboration. PMID- 17689319 TI - The use of concept mapping for scale development and validation in evaluation. AB - Evaluators often make key decisions about what content to include when designing new scales. However, without clear conceptual grounding, there is a risk these decisions may compromise the scale's validity. Techniques such as concept mapping are available to evaluators for the specification of conceptual frameworks, but have not been used as a fully integrated part of scale development. As part of a multi-site evaluation of family support programs, we integrated concept mapping with traditional scale-development processes to strengthen the creation of a scale for inclusion in an evaluation instrument. Using concept mapping, we engaged staff and managers in the development of a framework of intended benefits of program participation and used the information to systematically select the scale's content. The psychometric characteristics of the scale were then formally assessed using a sample of program participants. The implications of the approach for supporting construct validity, inclusion of staff and managers, and theory driven evaluation are discussed. PMID- 17689320 TI - The relationship between implementation fidelity and educational outcomes in a school-based family support program: development of a model for evaluating multidimensional full-service programs. AB - There is increasing recognition of the need for evaluations that identify program processes or mediators and assess degree of program implementation rather than focusing solely on outcome evaluation. This paper describes the application of complementary qualitative and quantitative evaluation procedures to assess the degree of implementation of multi-component family support programs for improving educational outcomes for at risk youth, and to assess the relationship between program implementation and outcomes. The qualitative evaluation involved prolonged engagement to identify common program domains or mediators. Using a method called Innovation Configuration Analysis, levels of implementation of program domains were explicated as well as an overall Implementation Fidelity Index. Strong positive relationships were found between overall program implementation and program-level outcomes achieved by student participants. PMID- 17689321 TI - Assessing the relevance of higher education courses. AB - The establishment of the European Higher Education Area has involved specifying lists of professional competencies that programs are expected to develop, and with this the need for procedures to measure how every course within a higher education program is aligned with the program's competencies. We propose an instrument for characterizing this alignment, a process that we call assessing the relevance of a course. Using information from the course syllabus (objectives, contents and assessment scheme), our instrument produces indicators for characterizing the syllabus in terms of a competence list and for assessing its coherence. Because assessment involves quality, the results obtained can also be used to revise and improve the course syllabus. We illustrate this process with an example of a methods course from a mathematics teacher education program at a Spanish university. PMID- 17689322 TI - Implications of nested designs in school-based mental health services research. AB - Evaluating school-based mental health services for children and youth with emotional disturbance (ED) has been a challenge for researchers. One particular challenge is the study design of using the student as the statistical unit of analysis, which in certain cases may lead to a violation of the "independence of error" assumption. However, the alternative to this nested design, including fewer students and more schools, can be costly and administratively complex. This study examines data from two national studies including 314 students with ED and served in special education programs and their caregivers from 24 schools in the US to identify the extent to which nesting or design effects occur in this population. The results show that variables focusing on psychopathology are less affected by nesting but school-related variables such as academic functioning are more affected. Design effects varied by grade level, suggesting that grade should be considered when designing such evaluations. PMID- 17689323 TI - Quasi-experimental evaluation of a national primary school HIV intervention in Kenya. AB - This study examined the impact of a primary-school HIV education initiative on the knowledge, self-efficacy and sexual and condom use activities of upper primary-school pupils in Kenya. A quasi-experimental mixed qualitative quantitative pre- and 18-month post-design using 40 intervention and 40 matched control schools demonstrated significant program impact on targeted objectives of (1) adequate program delivery and, for standard 6 and 7 pupils (ages 11-16 years), (2) increased HIV-related knowledge; (3) increased communication with parents and teachers about HIV and sexuality; (4) increased assistance to fellow pupils to avoid sexual activity; (5) increased self-efficacy related to abstinence and condom use; (6) decreased exposure to HIV through delayed first intercourse, decreased sexual activity and increased condom. Results support the conclusions that the existing infrastructure is adequate for national roll-out of the program; that the program has its most beneficial effect on sexually inexperienced youth and should therefore be implemented with the youngest age groups possible; and that gains are gender specific, with boys reporting increased condom use while girls are more likely to decrease or delay sexual activity. Based on these results, the program began national roll-out to all primary schools in 2005. By June 2006, the program was operating in 11,000 of the country's nearly 19,000 schools. PMID- 17689324 TI - Predictors of short-term treatment outcomes among California's Proposition 36 participants. AB - California's voter-initiated Proposition 36 offers non-violent drug offenders community-based treatment as an alternative to incarceration or probation without treatment. This article reports short-term treatment outcomes subsequent to this major shift in drug policy. Data are from 1104 individuals randomly selected from all Proposition 36 participants assessed for treatment in five California counties during 2004. The overall study sample was 30% female, 51% white, 18% Black, 24% Hispanic, and 7% other racial/ethnic groups. The mean+/-SD age was 37+/-10 years. Counties varied considerably in participant characteristics, treatment service intensity, treatment duration, urine testing, and employment and recidivism outcomes, but not in drug use at 3-month follow-up. Controlling for county, logistic regression analysis showed that drug abstinence was predicted by gender (female), employment at baseline (full or part-time), residential (vs. outpatient) stay, low psychiatric severity, frequent urine testing by treatment facility, and more days in treatment. Recidivism was predicted only by shorter treatment duration. Employment predictors included age (younger), gender (male), baseline employment, and lower psychiatric severity. The study findings support drug testing to monitor abstinence and highlight the need to address employment and psychiatric problems among Proposition 36 participants. PMID- 17689325 TI - Measuring risk and protection in communities using the Communities That Care Youth Survey. AB - The Communities That Care Youth Survey measures risk and protective factors shown in prior studies to predict adolescent problem behaviors such as drug use, delinquency, and violence. This paper describes the development and validation of cut points for the risk and protective factor scales in the Communities That Care Youth Survey that distinguish youths at higher risk for involvement in problem behaviors from those at lower risk. Using these cut points, populations surveyed with this instrument can be described in terms of the proportions of youths experiencing risk and the proportions experiencing protection on each predictor. This facilitates communities' prioritization of specific factors for attention. This paper compares different cut points, and evaluates the discriminant validity of selected cut points. Results indicate that cut points with sufficient sensitivity and selectivity can be established for each of the scales, and that risk and protective factors can be profiled as prevalence rates. Implications of these findings for prevention planning are discussed. PMID- 17689326 TI - Degrees of freedom and degrees of certainty: a developmental model for the establishment of evidence-based youth care. AB - There are many psychosocial interventions for children and adolescents. The effects of these interventions in day-to-day practice are nevertheless often unclear. Researchers typically take the randomized controlled trial (RCT) as the "gold standard" for the supply of evidence regarding the effectiveness of an intervention. However, such trials are rarely performed in youth care practice because they are difficult to conduct and sometimes meet with ethical objections. RCTs may also be prematurely and thus unnecessarily conducted on interventions that are not yet fully developed or interventions that have yet to be accepted into actual practice. In this article, a four-stage model for the classification and development of effective interventions carried out in actual youth care practice is presented. Stage 1 (potential interventions) requires specification of the core elements of an intervention (e.g., objectives, target groups, activities) and may involve both descriptive and implementation studies. Stage 2 (plausible interventions) requires the explication of an underlying intervention theory (e.g., what works with whom and why) and may involve both literature reviews and techniques to elicit the knowledge of experts. Stage 3 (functional interventions) requires preliminary evidence that the intervention works in actual practice and may involve client satisfaction studies, goal attainment studies, pre-post test studies, quality control studies, benchmark studies, correlational studies, and quasi-experimental studies. Stage 4 (efficacious interventions) requires clear evidence that the intervention is responsible for the observed effects and may involve RCTs and well-designed repeated case studies. PMID- 17689328 TI - Building evaluation capacity: definitional and practical implications from an Australian case study. AB - Internationally, evaluation capacity-building activities have mushroomed as demands have increased for government-funded programs to demonstrate that they are effective and efficient. Despite this, there is a lack of clarity in the way in which evaluation capacity-building is defined and conceptualized. The current paper presents a case study of a national evaluation capacity building exercise that we are in the midst of conducting in Australia, and discusses the findings in relation to definitional, conceptual and practical issues. Specifically, we describe an evaluation capacity building exercise involving over 100 mental health projects, detailing the methods that we employ, some of the challenges that we have faced, and the benefits we feel we are achieving. Our key message is that definitions of evaluation capacity-building should not only make reference to equipping organizations to routinely conduct evaluations, but should also stress the varied uses to which evaluation findings can be put. In addition, such definitions should acknowledge some of the valuable by-products of evaluation capacity building activities, such as the development of shared understandings of the program or project being evaluated. PMID- 17689329 TI - Organizational capacity building: addressing a research and practice gap. AB - The purpose of this article is to address the gap between evaluation research, and the practice of capacity building with nonprofits. This study describes a 5 year capacity building initiative with grassroots organizations including a longitudinal evaluation of the implementation and outcomes achieved. Formative processes yielded many lessons that were used to improve the capacity building model of services. The results show that the majority of groups met a priori expectations for participation success. Organizational staff valued technology, consultants, and program funding the most. Increases were found in board membership and perceptions of visibility of the organization were enhanced. Executive directors reported greater awareness of needs and improved management knowledge. These small organizations fill many unmet needs and more capacity building evaluation studies are needed to understand the mechanisms that support their efforts and the impact on their sustainability. PMID- 17689330 TI - Evaluating school capacity to implement new programs. AB - An eight-factor survey-based Bayesian model (Bridge-It) for assessing school capacity to implement health and education programs was tested in secondary analyses of data from 47 schools in the Texas Tobacco Prevention Initiative (TTPI). Bridge-It was used during the pre-implementation phase and again at mid course of the TTPI 2 years later. Achieved implementation status was evaluated in follow-up almost 4 years after the start of the TTPI. The Bridge-It score aggregated across all eight of the capacity factors predicted both quality of adherence to the Guidelines for School Programs to Prevent Tobacco Use and Addiction and quantity of implementing activity. The school-based leadership factor was an independent predictor of quality of adherence whereas the facilitation processes factor predicted quantity of implementing activity. Integration of Bridge-It, or comparable multi-attribute tools, into the planning and evaluation of school-centered programs can increase understanding of factors that influence implementation and provide guidance for capacity building. PMID- 17689331 TI - Problems in needs assessment data: discrepancy analysis. AB - Needs assessment (NA) is generally based on the discrepancy between two conditions-the desired and present states. To date, there has not been an extensive research regarding a number of subtle problems in discrepancy analysis. One such example is missing data for one or both the two states. This leads to highly varied item n's for calculating discrepancy scores. Concerns like this arose in a NA study of minority students in science, technology, engineering, and mathematics programs in universities. A number of problems observed in this context are discussed as well as possible solutions for them. The results should be valuable to needs assessors and evaluators responsible for assessing needs. PMID- 17689332 TI - Theory-based evaluation of a comprehensive Latino education initiative: an interactive evaluation approach. AB - Latino student access to higher education has received significant national attention in recent years. This article describes a theory-based evaluation approach used with ENLACE of Hillsborough, a 5-year project funded by the W.K. Kellogg Foundation for the purpose of increasing Latino student graduation from high school and college. Theory-based evaluation guided planning, implementation as well as evaluation through the process of developing consensus on the Latino population of focus, adoption of culturally appropriate principles and values to guide the project, and identification of strategies to reach, engage, and impact outcomes for Latino students and their families. The approach included interactive development of logic models that focused the scope of interventions and guided evaluation designs for addressing three stages of the initiative. Challenges and opportunities created by the approach are discussed, as well as ways in which the initiative impacted Latino students and collaborating educational institutions. PMID- 17689333 TI - Translating research into practice: using concept mapping to determine locally relevant intervention strategies to increase physical activity. AB - PURPOSE: To translate intervention strategies to increase physical activity interventions recommended by the Community Guide for higher and lower income African-American adults living in an urban, Midwestern community. METHOD: Structured interviews were conducted with a stratified random sample of African American men and women from high- and low-income groups. Data were analyzed using concept mapping, a six-step process that incorporates qualitative and quantitative analysis. RESULTS: The results suggest differences among men and women, high and low income, in the conceptualization of factors associated with physical activity behavior. The different conceptualizations suggest different intervention strategies and action steps may be necessary for subgroups of a population. CONCLUSION: Concept mapping is a participatory method that community members and health practitioners can use to develop locally defined intervention strategies. From the strategies and action steps identified, evidence-based interventions can be developed in light of the optimal characteristics necessary within a community. PMID- 17689334 TI - Measuring changes in interagency collaboration: an examination of the Bridgeport Safe Start Initiative. AB - This paper describes the evaluation of interagency collaboration in a network of child-serving providers as part of the evaluation of the Bridgeport Safe Start Initiative (BSSI). In line with the system of care approach, the objectives of BSSI included reducing fragmentation of efforts and delivering integrated services to families of young children exposed to or at risk of exposure to family violence. Interagency collaboration was examined via social network and focus group data collected at three time points starting at baseline. Network analysis findings suggest that over time the network structure became consistent with BSSI's vision of an ideal collaborative network structure. Focus group findings, however, present a more complex picture of the status of collaboration. This paper sheds light on approaches and challenges to measuring interagency collaboration in a service delivery system and communicating social network analysis findings to stakeholders in a way that is accessible and useful. PMID- 17689335 TI - Linking structure, process, and outcome to improve group home services for foster youth in California. AB - The California Youth Connection obtained funding from two foundations to evaluate the performance of group homes serving foster youth in Alameda County, California, in order to inform state policy-making. The evaluation team initially included 14 foster youth that personally experienced group home living. Three inter-related aspects of service were studied: structure, process, and client outcomes, specifically residents' increase in developmental assets leading to the ability to transition successfully to independent living by the age of 18 years. Data were collected at 32 group homes from 127 residents and 72 staff members using three questionnaires. Both structural and process aspects of services influenced residents' satisfaction with services. However, only the process of care predicted changes in residents' developmental assets. State-level regulatory agencies learned from these results that auditing only structural aspects of services was not sufficient to promote effective services. Further, one structure item and two process items were identified as less consistently occurring in the group homes: timely distribution of clothing allowances, healthy communication between staff and youth, and staff support of regular exercise for the residents. Focusing on these aspects of service first should promote more change in outcomes and satisfaction for foster youth residing in group homes. PMID- 17689338 TI - Drug consumption rooms: an overdue extension to harm reduction policy in the UK? AB - This commentary examines the drug policy context of drug consumption rooms (DCRs) in the UK and describe the conclusions of an Independent Working Group (IWG) that was set up to evaluate the evidence of need in the UK, the international evaluation literature and legal, political and ethical concerns. Having considered this evidence, the IWG produced its report in May 2006, recommending a trial of DCRs in the UK, on the basis that DCRs offer a unique and promising way to work with problematic drug users in order to reduce the risk of overdose, improve their health and lessen the damage and costs to society. However, despite support for the idea from a number of quarters, the UK Government has rejected this recommendation, citing previously deployed arguments that do not appear to be carry much weight in 2007. PMID- 17689337 TI - Drug use settings: an emerging focus for research and intervention. PMID- 17689339 TI - Public perceptions of public drug use in four UK urban sites. AB - At the local level, proposals for regeneration are often put forwards as solutions to social and health problems associated with poverty, drug use and crime. Debates about establishing drug consumption rooms (DCRs) are also concerned with providing services to drug use-related environmental problems. However, conflicts may exist between interventions aiming to reduce drug-related harm to discriminated communities and wider regeneration aims to support corporate development. This commentary draws on data from a rapid assessment study which examined the experience of 100 people living and working in four British neighbourhoods where public drug use is common. Primary data were gathered in semi-structured interviews and during local walk-about tours. These were triangulated with secondary sources of information on local policies and indicators of public drug use. Public awareness of the impacts of environmental regeneration projects including loss of amenity, 'fortress mentality' and displacement effects were found at all study sites. However, comparative area analyses suggest that whether communities welcome these changes depends on how close-to-home they perceive the competitions for urban space. Cohesive communities may direct environmental regeneration in pursuit of general social improvement rather than the narrower aims of either DCRs or corporate developers. PMID- 17689340 TI - Fools rush in where angels fear to tread Playing God with Vancouver's Supervised Injection Facility in the political borderland. AB - Healthcare does not exist in a social vacuum. Nowhere is this more obvious than in the case of people living with active addiction who are treated as social lepers: feared, despised and socially banished from the wider human family. People with addictions, and their families, fight for survival in the moral borderland between two competing understandings of their condition. According to one understanding, addiction is a concern for the criminal justice system while according to the other it is primarily a population health issue. In one orientation, addicts are troublesome offenders, while in the other they are wounded persons in need of medical attention. These competing values form a cultural web of belief that extends far beyond healthcare to the highest political office of Canadian society. This paper examines the politics of addiction over a 6-year period beginning at the municipal level in Vancouver and culminating with a confrontation between the Prime Minister of Canada and the tiny neighbourhood that provides a home for North America's only Supervised Injection Facility. Not wanting to let the medical facts get in the way of a political stand, Prime Minister Stephen Harper and his Health Minister, Tony Clement, played God this summer by playing politics with the lives of people in the shadows of Canadian society. PMID- 17689341 TI - Public injection settings in Vancouver: physical environment, social context and risk. AB - While epidemiological investigations have documented elevated health harms associated with public injecting, further ethnographic research focused specifically on public injecting settings is required to develop greater understanding of how these environments influence the production of drug-related harm. We undertook preliminary ethnographic research, incorporating a structured environmental survey, observations and interviews with 50 local injectors, in Vancouver's Downtown Eastside (DTES). Our study aimed to document the physical locations and social context of public injecting settings, exploring how such venues interplay with injection-related health risks. Findings show that DTES public injecting locations comprise a large network of alleyways, which are often unsanitary and constrain efforts to inject in a hygienic fashion. Due to fears of being intercepted by the police, physically assaulted, or robbed, injectors are preoccupied with "hurrying and worrying" when injecting in public. Although individuals are concerned with matters of hygiene and avoiding infections associated with injecting, the perceived risks of public injection settings are primarily related to the presence of street predators and the police. Ecological features of public injecting environments serve to complicate the task of injecting, encourage 'rushing' during the injection process, and decrease the likelihood that public injectors will employ safer injecting practices. Future interventions must specifically target these micro risk environments. Innovative strategies are urgently needed to ensure that police operations in the open drug scene do not compromise public injectors' efforts to protect their health. Additionally, structural factors which perpetuate the large public injecting scene should be addressed through policy interventions that increase access to housing and public toilets as well as expanding the scope and capacity of the local drug consumption facilities. PMID- 17689342 TI - A micro-environmental intervention to reduce the harms associated with drug related overdose: evidence from the evaluation of Vancouver's safer injection facility. AB - BACKGROUND: Conventional drug overdose prevention strategies have been criticised for failing to address the macro- and micro-environmental factors that shape drug injecting practices and compromise individual ability to reduce the risks associated with drug-related overdose. This in turn has led to calls for interventions that address overdose risks by modifying the drug-using environment, including the social dynamics within them. Safer injection facilities (SIFs) constitute one such intervention, although little is known about the impact of such facilities on factors that mediate risk for overdose. METHODS: Semi-structured qualitative interviews were conducted with fifty individuals recruited from a cohort of SIF users in Vancouver, the Scientific Evaluation Of Supervised Injecting (SEOSI). Audio recorded interviews elicited injection drug users' (IDU) accounts of overdoses as well as perspectives regarding the impact of SIF use on overdose risk and experiences of overdose. Interviews were transcribed verbatim and a thematic analysis was conducted. RESULTS: Fifty IDU, including 21 women, participated in this study. The perspectives of participants suggest that the Vancouver SIF plays an important role in mediating various risks associated with overdose. In particular, the SIF addresses many of the unique contextual risks associated with injection in public spaces, including the need to rush injections due to fear of arrest. Further, SIF use appears to enable overdose prevention by simultaneously offsetting potential social risks associated with injecting alone and injecting in the presence of strangers. The immediate emergency response offered by nurses at the SIF was also valued highly, especially when injecting adulterated drugs and drugs of unknown purity and composition. CONCLUSION: The perspectives of IDU participating in this study suggest that SIFs can address many of the micro-environmental factors that drive overdose risk and limit individual ability to employ overdose prevention practices. Although challenges related to coverage remain in many settings, SIFs may play a unique role in managing overdoses, particularly those occurring within street-based drug scenes. PMID- 17689343 TI - Five years on: what are the community perceptions of drug-related public amenity following the establishment of the Sydney Medically Supervised Injecting Centre? AB - BACKGROUND AND OBJECTIVES: There is currently limited evidence on medium to long term community perceptions of public amenity where supervised injecting centres operate (SIC). Our objective was to investigate if community perceptions of public amenity have changed over time, comparing data collected prior to the establishment of the Sydney Medically Supervised Injecting Centre (MSIC), after 18 months and then following four and a half years of operation. METHODS: Telephone surveys were conducted among random samples of local residents and business operators in the vicinity of the MSIC at baseline, in the short term (following 18 months of operation) and in the medium term (following four and a half years of operation). Respondents were asked about their perceptions of drug use and its consequences in their neighbourhood, and to describe what they saw as advantages and disadvantages of the Sydney MSIC. Responses were compared over time and according to demographic characteristics of the survey participants. RESULTS: The survey was completed by 515, 540 and 316 residents and 269, 207 and 210 businesses in the 3 years respectively, with response rates generally above 75%. There was a significant decrease in the proportion of residents and business operators who reported having witnessed public injecting and publicly discarded injecting equipment, in the last month, with no significant change in proportions offered drugs for purchase. Residents were less likely to have seen public injecting in the last month if they were female, retired, lived over 500m from the MSIC or participated in the survey in 2005. Business operators who had witnessed public injecting or discarded needles and syringes in the last month were less likely to report either if located over 500m from the MSIC. Those businesses operating for over 5 years were more likely to have seen publicly discarded needles and syringes than those who had opened within the last year. Approximately 90% of both samples reported at least one advantage of the MSIC located in their area, citing the control of HIV/AIDS and hepatitis C and reduced overdose risk for injecting drug users among potential advantages. CONCLUSION: While the Sydney MSIC continues to attract political controversy, local residents and business operators perceived significant improvements in public amenity indicators since the opening of the service. Community members appear to be cognizant of both public health (potential reduction in blood borne virus transmission and overdose among injecting drug users) and public amenity benefits of the service. PMID- 17689344 TI - Public opinion towards supervised injection facilities and heroin-assisted treatment in Ontario, Canada. AB - In recent years, controversial interventions such as 'heroin-assisted treatment' (HAT) and 'supervised injection facilities' (SIFs) have been established in attempts to minimise the high morbidity and mortality consequences of illicit drug use. This paper examines public opinion towards HAT and SIF using data from the 2003 Centre for Addiction and Mental Health (CAMH) Monitor, a representative population survey conducted among adults residing in Ontario, Canada. Data relating specifically to SIFs and HAT were isolated from the main database (n=885); agreement scores were collapsed to create a scale and analysed using independent sample t-tests and ANOVAs. Results revealed that 60 percent (n=530) of the sample agreed that SIFs should be made available to injection drug users, while 40 percent (n=355) disagreed. When asked about the provision of HAT, a similar pattern emerged. Variables significantly associated with positive opinions toward SIFs and HAT were: income; higher education; the use of cocaine or cannabis within the last 12 months; being in favour of cannabis decriminalisation; support of needle exchange in prison; view of illicit drug users as ill people; and agreement that drug users are in need of public support. Given the current political climate and the tentative position of SIFs and HAT in Canada, understanding the public's opinion is crucial for the feasibility and long-term sustainability of these interventions. PMID- 17689345 TI - Public injecting and willingness to use a drug consumption room among needle exchange programme attendees in the UK. AB - This study examines the prevalence of public injecting and willingness to use drug consumption rooms (DCRs) among UK needle exchange programme (NEP) attendees. Three hundred and one injecting drug users (IDUs) were surveyed using a brief questionnaire across five NEPs in London and Leeds between April and June 2005. Injection in a public place in the past week was reported by 55% of the sample and 84% reported willingness to use a DCR if it was available. Public injecting was positively associated with insecure housing (AOR=2.1, CI 1.2-3.5, p=0.009), unsafe needle and syringe disposal in the past month (AOR=3.6, CI 1.9-6.9, p<0.001) and willingness to use DCR (AOR=2.7, CI 1.3-5.4, p=0.006). Public injecting was negatively associated with being aged more than 30 years (AOR=0.4, CI 0.3-0.7, p=0.003) and living in close proximity (within 0.5 miles/0.8 km) of the usual place of drug purchase (AOR=0.6, CI 0.3-0.9, p=0.02). Our findings suggest that recent public injecting is prevalent among UK NEP attendees and the majority would be willing to use DCRs if available. It is also probable that if such services were located close to key drug markets they would engage vulnerable IDU sub-populations such as young people and the insecurely housed and reduce their levels of public injecting and unsafe needle/syringe disposal. Targeted pilot implementation of DCRs in the UK is recommended. PMID- 17689346 TI - "Harm reduction--coming of age": a local movement with global impact. PMID- 17689347 TI - Tobacco harm reduction: how rational public policy could transform a pandemic. AB - Nicotine, at the dosage levels smokers seek, is a relatively innocuous drug commonly delivered by a highly harmful device, cigarette smoke. An intensifying pandemic of disease caused or exacerbated by smoking demands more effective policy responses than the current one: demanding that nicotine users abstain. A pragmatic response to the smoking problem is blocked by moralistic campaigns masquerading as public health, by divisions within the community of opponents to present policy, and by the public-health professions antipathy to any tobacco control endeavours other than smoking cessation. Yet, numerous alternative systems for nicotine delivery exist, many of them far safer than smoking. A pragmatic, public-health approach to tobacco control would recognize a continuum of risk and encourage nicotine users to move themselves down the risk spectrum by choosing safer alternatives to smoking--without demanding abstinence. PMID- 17689348 TI - Strengthening drug policy and practice through ethics engagement: an old challenge for a new harm reduction. AB - Harm reduction proponents aim to identify and support policies and programmes that moderate or decrease the deleterious consequences of illicit drug use. While harm reduction is clearly a value-based response to drugs, for many, 'ethics' merely represent institutional research and professional practice regulations to be satisfied, subjective moral claims, or philosophy that is too abstract to offer tangible benefits in keeping with the pragmatism of harm reduction. In this paper we revisit the relationship between harm reduction and ethics, reframe ethics as a pragmatic concern for all of harm reduction, and argue that greater attention to the actual values and beliefs underpinning harm reduction can help to enhance policy, practice and research outcomes. Examples are given of early progress in this area to illustrate possible features of ethics engagement in harm reduction, and existing ethics materials are highlighted as suitable supporting resources for applied ethical decision-making in this field. PMID- 17689349 TI - How the harm reduction movement contrasts itself against punitive prohibition. AB - On the basis of the harm reduction movement's founding texts from the beginning of the 1990s, this paper reflects the movement's self-understanding in contrasting itself with the system of punitive prohibition. Following this is a discussion of the implications for drug users of harm reduction claims-making. The paper concludes that the principles of the harm reduction movement resonate extremely well with the moral sensibilities of our contemporary societies, and but that the movement's claims for an amoral, rational, just, and emancipating approach to drug use are to be seen rather as a powerful rhetorical intervention in the highly moralised landscape of drug debate than something that would be achieved in practice. PMID- 17689350 TI - Using words: the harm reduction conception of drug use and drug users. PMID- 17689351 TI - Coverage of HIV prevention programmes for injection drug users: confusions, aspirations, definitions and ways forward. AB - The concept of coverage first emerged in the 1960s as a key indicator for measuring the proportion of populations that were covered by health care. In the area of HIV interventions among injecting drug users, the term "coverage" has been used for widely different aspects of reach and effectiveness of programmes. This paper reviews an array of ways of thinking about coverage from the scientific and grey literature and discusses methods of estimating coverage, finding that some measures of coverage refer to individuals, others to populations and others to populations covered by services. Nomenclature for these various types of "coverage" are discussed and recommendations are provided for future attempts to measure coverage of harm reduction interventions. PMID- 17689352 TI - The children of mama coca: coca, cocaine and the fate of harm reduction in South America. AB - The paper reviews the main findings from substance misuse research carried out over the last two decades in South America looking at the main initiatives aimed at reducing drug related harm and curbing the spread of HIV/AIDS and other sexually transmitted and blood-borne diseases. The current challenges faced by harm reduction in the region are analysed from the perspective of the history of coca and its different uses in South America. Except in Brazil and Argentina, the implementation of initiatives to reduce drug related harm in South America has been very cautious. The paper aims to link the analysis of harms associated with the use of illicit substances, with the often paradoxically harmful effects of supply-side drug policies in the world's largest coca/cocaine producing area. Despite the undeniable success of many initiatives, the broader context of harm maximization through structural violence and entrenched corruption acts as a major disincentive for the comprehensive adoption of sound public health policies. PMID- 17689353 TI - Harm reduction theory: users' culture, micro-social indigenous harm reduction, and the self-organization and outside-organizing of users' groups. AB - This paper discusses the user side of harm reduction, focusing to some extent on the early responses to the HIV/AIDS epidemic in each of four sets of localities New York City, Rotterdam, Buenos Aires, and sites in Central Asia. Using available qualitative and quantitative information, we present a series of vignettes about user activities in four different localities in behalf of reducing drug-related harm. Some of these activities have been micro-social (small group) activities; others have been conducted by formal organizations of users that the users organized at their own initiative. In spite of the limitations of the methodology, the data suggest that users' activities have helped limit HIV spread. These activities are shaped by broader social contexts, such as the extent to which drug scenes are integrated with broader social networks and the way the political and economic systems impinge on drug users' lives. Drug users are active agents in their own individual and collective behalf, and in helping to protect wider communities. Harm reduction activities and research should take note of and draw upon both the micro-social and formal organizations of users. Finally, both researchers and policy makers should help develop ways to enable and support both micro-social and formally organized action by users. PMID- 17689354 TI - Rapid scale up of harm reduction in China. AB - In the last 20 years, China has seen a resurgence in drug use, particularly heroin, and with it a growing epidemic of HIV/AIDS. Faced with this dual epidemic, the government has begun testing harm reduction strategies in recent years. These have included methadone maintenance treatment (MMT) programmes, needle-syringe programmes (NSP), outreach, and increasing access to HIV testing. MMT and NSP have moved from the pilot stage to scale-up, with 320 MMT clinics and 93 NSPs now open. Both will number more than 1000 by the end of 2008. There are some good examples of outreach programmes in some areas, however more needs to be done to facilitate greater involvement from non-government organizations. Similarly, HIV testing for drug users is widely available, but novel approaches to increasing its uptake need to be explored. Management of scale-up and reaching China's vast and dispersed drug-using population remain key challenges. The introduction of harm reduction has been a massive turn-around in thinking by the government, particularly law enforcement agencies, and achieving this has required considerable cooperation and understanding between the Ministries of Health, Public Security, and Justice, and the Food and Drug Administration. With their support, rapid scale-up to effectively reach a majority of drug users can be achieved in the coming years. PMID- 17689355 TI - Implementation of harm reduction in Central and Eastern Europe and Central Asia. AB - Harm reduction (HR) interventions began in Central-Eastern Europe and Central Asia in the mid-1980s with the establishment of substitution treatment (ST) in Yugoslavia. In the mid-1990s, the first needle and syringe programmes (NSPs) opened in selected countries following the outbreaks of HIV among injecting drug users (IDUs). The number of NSPs continues to increase via a combination of international and state funding with large expansions made possible via the Global Fund to Fight AIDS, Tuberculosis and Malaria. While ST is still unaccepted in several countries, others have made some progress which is especially visible in South Eastern and Central Europe and the Baltic States. Development of regional networking including Central and Eastern European HR Network and a number of national networks helped to coordinate joint advocacy effort and in some cases sustain HR services. Activism of drug users and people living with HIV (PLWH) increased in the region in the last several years and helped to better link HR with the affected communities. Still a number of challenges remain important for the movement today such as repressive drug policies; stigma and discrimination of IDUs, PLWH, sex workers and inmates, including poor access to prevention and treatment; lack of important components of HR work such as naloxone distribution and hepatitis B vaccination, prevention in prisons; issues of quality control; sustaining services after finishing of major international projects; reaching of adequate coverage and others. PMID- 17689356 TI - Malaysia and harm reduction: the challenges and responses. AB - In Malaysia the response to illicit drug use has been largely punitive with the current goal of the Malaysian government being to achieve a drug-free society by 2015. This paper outlines the results of a desk-based situation assessment conducted over a 3-week period in 2004. Additional events, examined in 2005, were also included to describe more recent policy developments and examine how these came about. Despite punitive drug policy there has been a substantial rise in the number of drug users in the country. Over two-thirds of HIV/AIDS cases are among injecting drug users (IDUs) and there has been an exponential rise in the number of cases reported. Further, data suggest high risk drug use practices are widespread. Harm reduction initiatives have only recently been introduced in Malaysia. The successful piloting of substitution therapies, in particular methadone and buprenorphine, is cause for genuine hope for the rapid development of such interventions. In 2005 the government announced it will allow methadone maintenance programmes to operate beyond the pilot phase and needle and syringe exchange programmes will be established to serve the needs of IDUs. PMID- 17689357 TI - Merseyside, the first harm reduction conferences, and the early history of harm reduction. AB - In the mid 1980s, Liverpool implemented pioneering approaches to dealing with the problems caused by the use of drugs. The Mersey Harm Reduction Model concentrated on reducing the harms rather than, as previously was the case, trying to reduce drug use itself. This policy was given great impetus by the emergence of HIV and the danger of infection from using contaminated injection equipment. It became imperative to reduce this kind of risk behaviour by providing clean injecting equipment, prescribing methadone (and in a small percentage of cases, heroin) and by using outreach workers to go into the community and help people where they lived and to attract them into services. The police played a key role. Service uptake was rapid and included many who had never had previous contact with services. An HIV epidemic did not happen amongst injecting drug users in Mersey. In 1991, the approach was applied to the new phenomenon of the use of MDMA with the publication of the leaflet 'Chill Out'. The First International Conference on the Reduction of Drug Related Harm took place in Liverpool in 1990 as a response to the interest shown in what was happening in the region and the International Harm Reduction Association was born out of these conferences. PMID- 17689358 TI - The Latin American harm reduction network (RELARD): successes and challenges. PMID- 17689359 TI - The role and development of the Asian Harm Reduction Network. AB - In Asia, the future of harm reduction in the response to HIV and AIDS is truly uncertain. An overview of the regional situation would reveal many gaps and the small steps of progress. Reviewing the role and development of the Asian Harm Reduction Network in that context will demonstrate that the organisation's mission has been achieved through networking, information sharing, advocacy, capacity building and service delivery activities. Indeed, AHRN has been recognised both as a strong and consistent advocate and a responsive leader in the advancement of harm reduction in Asia in the context of the growing HIV and AIDS epidemic. Yet it is increasingly clear that additional support will be required to turn back the tide of HIV and AIDS. PMID- 17689360 TI - Harm reduction in the Mersey Region. PMID- 17689361 TI - Harm reduction in Tanzania: an urgent need for multisectoral intervention. PMID- 17689362 TI - Do medical cannabis laws encourage cannabis use? AB - Medical cannabis is a contentious issue in the United States, with many fearing that introduction of state laws will increase use among the general population. The present study examined whether the introduction of such laws affects the level of cannabis use among arrestees and emergency department patients. Using the Arrestee Drug Abuse Monitoring system, data from adult arrestees for the period 1995-2002 were examined in three cities in California (Los Angeles, San Diego, San Jose), one city in Colorado (Denver), and one city in Oregon (Portland). Data were also analysed for juvenile arrestees in two of the California cities and Portland. Data on emergency department patients from the Drug Abuse Warning Network for the period 1994-2002 were examined in three metropolitan areas in California (Los Angeles, San Diego, San Francisco), one in Colorado (Denver), and one in Washington State (Seattle). The analysis followed an interrupted time-series design. No statistically significant pre-law versus post-law differences were found in any of the ADAM or DAWN sites. Thus, consistent with other studies of the liberalization of cannabis laws, medical cannabis laws do not appear to increase use of the drug. One reason for this might be that relatively few individuals are registered medical cannabis patients or caregivers. In addition, use of the drug by those already sick might "de glamorise" it and thereby do little to encourage use among others. PMID- 17689363 TI - Differential responses to cannabis potency: a typology of users based on self reported consumption behaviour. AB - AIMS: To determine whether a classification of cannabis users into different types can help to clarify the relationship between cannabis potency and consumption behaviour, harmful physical effects and psychological dependency. METHODS: A field sample of 388 respondents was recruited who had smoked cannabis at least once in the past month. They were contacted and interviewed in 28 cannabis coffee shops located in five Dutch cities. Data were collected with an assisted self-completion questionnaire. Cluster analysis was performed using the k-means method. FINDINGS: Various ways were observed in which cannabis users in natural settings adjusted their intake to the potency of the drug. Cluster analysis identified three broad types of cannabis users. The strongest high type was the youngest, consumed the highest monthly dose, inhaled higher-potency cannabis more deeply, and scored highest on psychological cannabis dependency. The consistent high type preferred milder cannabis, consumed the lowest monthly dose, and compensated for stronger cannabis by inhaling less deeply and smoking less. The steady quantity type was the oldest, usually smoked alone, consumed an intermediate monthly dose, and did not tend to adjust the depth of inhalation to the potency of the cannabis. The results suggest that this typology might also reflect three successive stages in the careers of continuing cannabis users. CONCLUSIONS: Laboratory studies to assess the effects of higher THC concentrations on external and internal exposure to cannabis should allow for the possibility that the types of users studied can affect the results. PMID- 17689364 TI - Creating the cannabis user: a post-structuralist analysis of the re classification of cannabis in the United Kingdom (2004-2005). AB - In January 2004 the British government announced that cannabis would be reclassified from Classes B to C, taking into account its level of harmfulness for human health and considering the penalties for possession and supplying. It was argued by the Government, that cannabis reclassification would save some resources and stop the criminalisation of otherwise law-abiding citizens. One year later, in 2005 the discussion about cannabis reclassification shifted from the argument about efficiency in the use of resources toward a debate about the effects of cannabis on mental health. The purpose of this article is to determine what happened between these two moments, and how the discussion originally formulated in terms of public management and efficiency became a matter of both mental health and criminality. Using a post-Structuralist approach, based on selected ideas from the French philosopher Michel Foucault, and supported by extensive research, this article proposes that the political decision regarding cannabis reclassification can be understood as part of the re-definition of the 'cannabis problem' and hence, the creation of a new type of 'cannabis user'. Although the debate took place in the United Kingdom, the main arguments can be extended to other reforms on cannabis legislation in other European countries. PMID- 17689365 TI - Individual dollar expenditure and earnings from cannabis in the New Zealand population. AB - INTRODUCTION: : High spending on illegal drug use can potentially provide insight into a range of drug related harm such as poor health, financial hardship, loss of opportunity, family neglect and income generating crime. Assessing the impact of high spending on drug use is complicated by the fact that many heavy drug users support their high expenditure on drug use through selling drugs. The aim of this paper is to estimate individual dollar expenditure and dollar earnings from cannabis in New Zealand. METHODS: : As part of the 2003 New Zealand national household drug survey, detailed data were collected on cannabis use and purchasing in the previous 12 months. Those who had purchased cannabis in the previous year were divided into two groups for further analysis: 'cannabis buyers' (i.e. those who only purchased sufficient cannabis for their own personal consumption needs); and 'cannabis dealers' (i.e. those who purchased large surpluses of cannabis for re-sale on to others). RESULTS: : Seventy-two percent of those who had purchased cannabis in the previous year were 'cannabis buyers' only. Cannabis buyers spent a mean of $817 (NZD) each on cannabis in the previous year (median $120). Cannabis dealers spent a mean of $5988 each on cannabis in the preceding year (median $1250). Once we accounted for projected earnings from selling surplus cannabis, half of the cannabis dealers achieved a mean net annual financial gain of $2739, and the remaining half were left with a mean net annual financial loss of only $350 over a year. Overall, 81% of all those who had purchased cannabis in the previous year had spent less than 5% of their gross annual personal income on cannabis, with 14% of these making a net financial gain. The proportion of income spent on cannabis was highest among those in the two lowest income earning groups, where approximately 8% spent 20% or more of their income on cannabis. Both cannabis buyers and cannabis dealers spending 10% or more of their income on cannabis were four times more likely to be unemployed than the wider population. CONCLUSIONS: : For the vast majority of those who had purchased cannabis in the previous year, spending on cannabis had only a small impact on their total annual income levels. High spending on cannabis can potentially be substantially offset by earnings from selling surplus cannabis. High spending on cannabis had its greatest impact among low income earning groups where approximately one in 13 low income cannabis spenders were spending high proportions of their income on cannabis. There appeared to be some relationship between high cannabis spending and unemployment and this warrants further investigation. PMID- 17689366 TI - Improving health and social care relationships for harm reduction. AB - This paper explores elements of the relationships that develop between people who use illicit drugs and people who provide services to them. It focuses on expectations people who use drugs and service providers have of health and social care relationships for harm reduction, as well as facilitators and barriers to effective and ineffective interactions, and to what governments might better do to help strengthen interactions. Prior to Canada's inaugural national harm reduction conference, informal discussion groups were organized to source local views regarding policy reform for harm reduction. One component of these discussion groups focused upon improving health and social care relationships for harm reduction. Community-based organizations providing services for harm minimisation were consulted to help develop themes and questions. Discussion groups conducted in French or English were held in 10 cities across Canada. Groups were audio-recorded, transcribed and thematically analysed. Disjuncture between understandings of the nature of health and social care relationships for harm reduction were found. Interpersonal and structural factors functioned both for and against the development of effective interactions. Differences in expectation sets held by illicit drug users and service providers may reflect the fluid experience of boundaries as a population on society's margins moves between harm-causing and harm-reducing behaviours and identities. The research described in this paper targeted those most directly involved in receiving, developing and delivering harm reduction programmes across a very diverse nation. It did so by including representatives of those most directly involved in utilizing and providing services within the research process itself. By incorporating a process that was community-based, user-driven, and which strived to be non-judgmental, the research was able to explore suggestions for improving health and social care relationships for harm reduction proffered by professionals actively providing services, as well as a variety of users, including some isolated or structurally excluded from service access by geography, illiteracy and/or street-involvement. PMID- 17689367 TI - Minimal uptake of sterile drug preparation equipment in a predominantly cocaine injecting population: implications for HIV and hepatitis C prevention. AB - OBJECTIVE: To identify factors associated with using sterile drug injection equipment by injection drug users (IDUs). METHODS: 275 IDUs were recruited from syringe exchange programs in Montreal, Canada in 2004-2005. A structured, interviewer-administered questionnaire collected information about demographics, drug injection practices, self-reported HIV and hepatitis C virus (HCV) status, and harm reduction behaviours. Logistic regression was used to model variables in relation to the use of sterile syringes, containers, filters, and drug preparation water. RESULTS: Sterile syringes, containers, filters, and water were used for at least half of injecting episodes by 95%, 23%, 23%, and 75% of subjects, respectively. In multivariate analysis, users of sterile syringes had higher odds of being older and injecting alone, and were less likely to report problems obtaining sterile syringes and requiring or providing help with injecting. Using sterile filters was associated with having at least high school education, injecting heroin, and injecting alone. In addition to the factors associated with filters, users of sterile containers were more likely to be HCV negative and older. Using sterile water was associated with daily injecting and being HCV-negative. CONCLUSIONS: Improving the uptake of sterile drug preparation equipment among IDUs could be aided by considering drug-specific risks, such as drug of choice and injecting context, while reinforcing existing messages on safer injecting. The association between sterile equipment use and HCV-negative status may be representative of an established subgroup of safer injectors who have remained free of infection because of consistent safe injecting practices. PMID- 17689368 TI - Beyond 'peer pressure': rethinking drug use and 'youth culture'. AB - The study of drug use by young people in the West has been transformed over the last decade by the development of sociological approaches to drug use which take serious account of the cultural context in which young people encounter drugs. One consequence is that the notion of 'peer pressure', as the primary articulation of the engagement between youth culture and drug use, has been displaced by that of 'normalisation', which envisages 'recreational' drug use as one expression of consumer-based youth cultural lifestyles. In stark contrast, academic discussion of drug use in Russia remains primarily concerned with the prevalence and health consequences of (intravenous) drug use while explanations of rising rates of drug use focus on structural factors related to the expansion of drugs supply and, to a lesser extent, post-Soviet social and economic dislocation. In this article, original empirical research in Russia is used to develop an understanding of young people's drug use that synthesises structural and cultural explanations of it. It does this by situating young people's narratives of their drugs choices in the context of local drugs markets and broader socio-economic processes. However, it attempts to go beyond seeing structural location as simply a 'constraint' on individual choice by adopting an understanding of 'youth culture' as a range of youth cultural practices and formations that simultaneously embody, reproduce and negotiate the structural locations of their subjects. PMID- 17689369 TI - 'There is no profile it is just everyone': the challenge of targeting hepatitis C education and prevention messages to the diversity of current and future injecting drug users. AB - This paper investigates drug use, knowledge of hepatitis C, and risk minimisation amongst participants of the Sydney inner city dance party/club scene. The aim is to identify factors that contribute to the limited success of hepatitis C education and prevention efforts in Australia and to suggest ways in which they might be improved. The method used was a thematic analysis of 31 semi-structured qualitative interviews with people drawn from the Sydney inner city dance party/club scene. This is a scene where the consumption of recreational drugs is normalised, and where the practice of injecting takes place, albeit less commonly to other routes of administration. In the material presented here, drugs are seen as sources of enjoyment and experimentation, but are not seen as necessary to the functioning of daily life. Indeed, dependency on drugs is largely seen as undesirable. Most participants consider themselves to be both well informed about the drugs they use, and in control of their drug use. Whilst participants in this scene are generally well informed about drugs (and deploy harm reduction strategies to avoid such things as overdose), their knowledge of hepatitis C is limited and vague. The marginal and stigmatised status of injecting both inside and outside the scene appears to contribute to an absence of information and communication about safer injecting and hepatitis C within the scene. Often information about safe injecting is perceived to lack relevance to scene participants and to be aimed at 'other' injecting drug users (IDU). The material discussed confirms the diversity of IDU and the crossover between social, sexual and drug networks. Whilst this poses challenges for education and prevention, the exploration of these networks or scenes has the potential to inform the content of education and prevention materials as well as identifying contexts for dissemination. PMID- 17689370 TI - Positive and negative aspects of participation in illicit drug research: implications for recruitment and ethical conduct. AB - Improved understanding of incentives and barriers to drug user research participation may improve study recruitment, retention and outcomes and enhance the ethical acceptability of illicit drug research. In Melbourne, Australia during 2001-2004, 507 injecting drug users were recruited from Needle and Syringe Programs and asked to nominate the 'best' and 'worst' things about research. Commonly reported positive aspects of drug research were its capacity to provide valid information about drug use (39%), the potential to improve drug-related policies and practices (20%) and benefits to the community (14%). Reported negative aspects of drug research included concerns about lack of, or negative impact of research findings (31%), and personal dislikes about research projects, such as discomfort (27%), inconvenience (21%) and risk (9%). IDU may participate in non-intervention research because of expected benefits for themselves and others, and may be discouraged from involvement by personal discomfort, inconvenience and risk, or a perceived lack of impact or benefit. To enhance recruitment to non-intervention research and fulfil ethical obligations investigators should (1) actively consider how best to minimise the IDU-defined negative aspects of research, and (2) clarify for prospective participants the intended impact of the research on policy and practice. PMID- 17689371 TI - Universal access to HIV/AIDS treatment for injecting drug users: keeping the promise. PMID- 17689372 TI - Paradoxes in antiretroviral treatment for injecting drug users: access, adherence and structural barriers in Asia and the former Soviet Union. AB - Offered proper support, injection drug users (IDUs) can achieve the same levels of adherence to and clinical benefit from antiretroviral treatment (ARV) as other patients with HIV. Nonetheless, in countries of Asia and the former Soviet Union where IDUs represent the largest share of HIV cases, IDUs have been disproportionately less likely to receive ARV. While analysis of adherence amongst IDUs has focused on individual patient ability to adhere to medical regimens, HIV treatment systems themselves are in need of examination. Structural impediments to provision of ARV for IDUs include competing, vertical systems of care; compulsory drug treatment and rehabilitation services that often offer neither ARV nor effective treatment for chemical dependence; lack of opiate substitution treatments demonstrated to increase adherence to ARV; and policies that explicitly or implicitly discourage ARV delivery to active IDUs. Labeling active drug users as socially untrustworthy or unproductive, health systems can create a series of paradoxes that ensure confirmation of these stereotypes. Needed reforms include professional education and public campaigns that emphasize IDU capacity for health protection and responsible choice; recognition that the chronic nature of injecting drug use and its links to HIV infection require development of ARV treatment delivery that includes active drug users; and integrated treatment that strengthens links between health providers and builds on, rather than seeks to bypass, IDU social networks and organizations. PMID- 17689373 TI - Antiretroviral HIV treatment and care for injecting drug users: an evidence-based overview. AB - AIDS-related mortality and the rate of progression to AIDS have dramatically decreased since the advent of highly active antiretroviral treatment (HAART). The overall benefit from antiretroviral HIV treatment has, however, been lesser in HIV-infected injecting drug users (IDUs) than in other patient groups (e.g. men who have sex with men). Poorer outcomes in HIV-infected IDUs are related to a variety of factors, including increased rates of non-HIV-related deaths, hepatitis C, delayed access to effective treatment, lower adherence to care and treatment regimens, continuation of illicit drug use, depression and negative life events. The available evidence strongly suggests the need for the large scale implementation of comprehensive treatment and care strategies for IDUs that include both treatment of drug dependence and HAART. PMID- 17689374 TI - Adherence to HIV treatment among IDUs and the role of opioid substitution treatment (OST). AB - In the era of highly effective anti-retroviral therapy (ART), data show a significant difference in treatment outcomes between injecting drug users (IDUs) and non-IDUs. Factors that may contribute to suboptimal treatment outcomes in IDUs include delayed access to ART, competing comorbid diseases, psychosocial barriers and poor long-term adherence to ART. This review describes and compares several studies on adherence to ART and its correlates in HIV-infected individuals in general, then IDUs and finally those IDUs on opioid substitution treatment (OST). It highlights how ongoing drug use or OST can modify the pattern of these correlates. The aim is to extend all the experience acquired from these studies in order to optimise both access to care and adherence in those countries where HIV infection is mainly driven by IDUs and where ART and OST are only starting to be scaled up. The role of OST in fostering access to care and adherence to ART together with the promising results achieved to date using modified directly observed therapy (DOT) programs for patients taking methadone, allow us to emphasize the efficacy of a comprehensive care model which integrates substance dependence treatment, psychiatric treatment, social services, and medical treatment. The review concludes by suggesting areas of future research targeted at improving the understanding of both the role of perceived toxicity and patient-provider relationship for patients on ART and OST. PMID- 17689375 TI - Access to highly active antiretroviral therapy (HAART) for injecting drug users in the WHO European Region 2002-2004. AB - Providing equitable access to highly active antiretroviral treatment (HAART) to injecting drug users (IDUs) is both feasible and desirable. Given the evidence that IDUs can adhere to HAART as well as non-IDUs and the imperative to provide universal and equitable access to HIV/AIDS treatment for all who need it, here we examine whether IDUs in the 52 countries in the WHO European Region have equitable access to HAART and whether that access has changed over time between 2002 and 2004. We consider regional and country differences in IDU HAART access; examine preliminary data regarding the injecting status of those initiating HAART and the use of opioid substitution therapy among HAART patients, and discuss how HAART might be better delivered to injecting drug users. Our data adds to the evidence that IDUs in Europe have poor and inequitable access to HAART, with only a relatively small improvement in access between 2002 and 2004. Regional and country comparisons reveal that inequities in IDU access to HAART are worst in eastern European countries. PMID- 17689376 TI - Directly observed therapy programmes for anti-retroviral treatment amongst injection drug users in Vancouver: access, adherence and outcomes. AB - The introduction of highly active anti-retroviral therapy (HAART) has produced dramatic reductions in HIV associated morbidity and mortality. However, this success has not been replicated amongst injection drug users (IDUs) and other marginalised groups largely due to reduced uptake and lower rates of access and adherence to anti-retrovirals (ARVs). Multi-disciplinary programmes have been developed to help support ARV treatment and HIV care amongst IDUs. We retrospectively analysed the rates of adherence and plasma viral load suppression amongst participants in two clinic-based programmes that began enrollment in 1998. Of the 297 clients, the mean age was 40.5 years, 73% were males, 44% were of Aboriginal ethnicity, and 85% were Hepatitis C co-infected. One hundred and forty-two (47%) started therapy with a CD4 count below 200 mm(-3), and baseline plasma viral load was over 100,000 copies/ml in 73 (25%). Treatment interruptions of greater than 2 weeks occurred in 41% of the participants during follow-up. The overall rate of adherence to treatment was 84.5% during periods when known interruptions were not considered. Plasma viral load suppression was attained by 29% during the first ARV regimen, although 83% had at least one fully suppressed plasma viral load recorded during follow-up. All cause mortality was 21% during the period of observation. The programmes initiated in Vancouver demonstrate the positive impact that a comprehensive DOT programme can have on ARV adherence, as well as highlight the challenges that remain. PMID- 17689377 TI - Self-reported side-effects of anti-retroviral treatment among IDUs: a 7-year longitudinal study (APROCO-COPILOTE COHORT ANRS CO-8). AB - The introduction of potent anti-retroviral treatment (ART) has transformed HIV disease into a chronic condition with the prospect, for the patient, of strict adherence to effective but life-long treatments. Within this framework, a major issue that can negatively affect adherence is the side-effects of the treatment. To date, studies documenting how individuals HIV-infected through drug injection (IDUs) experience ART-related side effects are sparse. Longitudinal data collected from the APROCO-COPILOTE cohort have been used to compare the experience of ART-related side-effects who have been HIV-infected via injecting drug use and non-IDU patients. A 20-item list was used to collect self-reported side-effects over a 7-year follow up period. Of 922 patients, 15% were IDUs. At any given visit, IDUs reported a significantly higher number of side-effects and had approximately twice the risk of reporting any side effect than non-IDUs. Most commonly reported side-effects were dry skin, fatigue, vomiting, bone troubles, insomnia. After adjustment for social conditions, depressive symptoms, use of sleeping pills and time since HIV diagnosis, IDUs reported experiencing significantly more side-effects than non-IDUs. Whether or not this is related to sensitivity to pain or to other comorbidities is difficult to establish. Further research is needed to understand how substitution treatment can mediate the relationship between exposure to opioids and side-effects. Providing appropriate care to reduce side-effects, thereby increasing adherence to ART in this population, remains a major challenge especially in those countries scaling up ART. Incorporating symptom management and improving access to analgesic medications within a model of comprehensive care for HIV-infected IDUs, could reduce the impact of drug-related and HIV-related harms and induce better long term treatment outcomes and quality of life. PMID- 17689378 TI - Scaling up HIV treatment, care and support for injecting drug users in Vietnam. AB - BACKGROUND: People living with HIV/AIDS (PLWHA) in developing countries are rarely consulted about ways to promote their health and well-being. This study sought to identify and understand, from the perspective of PLWHA, challenges and opportunities for improving access to HIV treatment, care and support in Vietnam, a resource-limited setting with an epidemic driven by injecting drug use. METHODS: PLWHA trained in participatory research methods completed fieldwork and data collection and co-facilitated focus groups with injecting drug users (IDUs) in Ho Chi Minh City. Qualitative data were analysed in Vietnamese and English using an inductive approach to code and compare content and identify key themes. RESULTS: Results suggest considerable barriers to scaling up in this setting. Against a backdrop of punitive government policies, including mandatory detention of IDUs and sex workers, and widespread stigma and discrimination, many PLWHA lived with the fear of discovery and the threat of abandonment. Lack of confidentiality, limited financial resources and restricted access to essential medications provided powerful disincentives to health service utilisation. CONCLUSIONS: Opportunities for scaling up lie firstly in expanding access to confidential HIV counselling and testing. However, in the absence of affordable, quality care and access to anti-retroviral therapy, IDUs are unlikely to see testing as worthwhile. Efforts to scale up also need to address structural barriers including stigma and discrimination, poverty and institutional capacity. Finally, PLWHA in Vietnam are a significant but underutilised resource and consideration should be given to overcoming barriers to building confidence and capacity within affected communities. PMID- 17689379 TI - Integration and co-location of HIV/AIDS, tuberculosis and drug treatment services. AB - Injection drug use (IDU) plays a critical role in the HIV epidemic in several countries throughout the world. In these countries, injection drug users are at significant risk for both HIV and tuberculosis, and active IDU negatively impacts treatment access, adherence and retention. Comprehensive strategies are therefore needed to effectively deliver preventive, diagnostic and curative services to these complex patient populations. We propose that developing co-located integrated care delivery systems should become the focus of national programmes as they continue to scale-up access to antiretroviral medications for drug users. Existing data suggest that such a programme will expand services for each of these diseases; increase detection of tuberculosis (TB) and HIV; improve medication adherence; increase entry into substance use treatment; decrease the likelihood of adverse drug events; and improve the effectiveness of prevention interventions. Key aspects of integration programmes include: co-location of services convenient to the patient; provision of effective substance use treatment, including pharmacotherapies; cross-training of generalist and specialist care providers; and provision of enhanced monitoring of drug-drug interactions and adverse side effects. Central to implementing this agenda will be fostering the political will to fund infrastructure and service delivery, expanding street-level outreach to IDUs, and training community health workers capable of cost effectively delivering these services. PMID- 17689380 TI - Obstacles in provision of anti-retroviral treatment to drug users in Central and Eastern Europe and Central Asia: a regional overview. AB - Central and Eastern Europe and Central Asia is currently the region with the fastest growing HIV epidemic, mainly among injecting drug users (IDUs). This study explored access to anti-retroviral (ARV) treatment among IDUs and evaluated obstacles to gaining access to treatment. Semi-structured questionnaires were collected from 21 countries from agencies which deliver services to IDUs (N=55), including AIDS centres, drug treatment institutions and Non-governmental Organisations. Results showed that there was poor access to ARV treatment for IDUs. The major obstacles reported were: limited range of institutions for the provision of ARVs, lack of treatment due to high cost of ARVs, lack of clear policies and regulations in providing treatment for IDUs, lack of infrastructure and trained staff to provide treatment, and in some countries, absence of mechanisms such as methadone substitution programmes to support IDUs receiving ARV. There is a need for human and capital resources to bring ARV treatment to IDU populations in the region. Regulations and treatment protocols need to be developed to address this particular group of HIV positive clients to insure better adherence and monitoring of clients with HCV co-infection. Integration of provision of ARV treatment with drug treatment and low-threshold services is advised. Substitution therapy should be advocated for in countries where it is not available or where access is limited. Finally, more research needs to be conducted to understand what will work best in each country, region or setting. PMID- 17689381 TI - Access, adherence, quality and impact of ARV provision to current and ex injecting drug users in Manipur (India): an initial assessment. AB - OBJECTIVES: This study aims to understand who is obtaining anti-retroviral therapy (ART) in Manipur, and to determine adherence, access, and impact amongst those who use it. It also explores the quality of these services, their impact and the level of user satisfaction. METHODS: A mixed method approach was used for this assessment involving direct observations, analysis of service statistics, and a semi-structured survey (n=226). RESULTS: Less than 5% of current injecting drug users (IDUs) were accessing ART (despite IDUs making up the single largest category affected by HIV in Manipur). Self-reported treatment adherence amongst patients is poor. Major factors influencing adherence are current alcohol use, the cost of ART, having attending any counselling in the last 6 months, income levels of below Indian Rupees (INR) 2000 and negative experience of side effects. Client satisfaction is associated with: duration of time spent with doctors, waiting time and how staff treat the patients. Service quality also requires improvement. A quarter of patients on ART perceive that it has benefited their health and report feeling well. Side effects were experienced by 61% of those on ART. Greater efforts to bring more active IDUs into treatment, whilst improving the manner in which ART is delivered in Manipur are required. PMID- 17689382 TI - HIV treatment access and scale-up for delivery of opiate substitution therapy with buprenorphine for IDUs in Ukraine--programme description and policy implications. AB - BACKGROUND: Injection drug use (IDU) accounts for 70 percent of HIV cases in Ukraine. Until buprenorphine maintenance therapy (BMT) was introduced, few effective strategies aimed at achieving reduction in illicit drug use were available as a conduit to anti-retroviral therapy (ARV) among IDUs. DESCRIPTION: In October 2005, BMT was scaled-up using Global Fund resources in six regions within Ukraine. Entry criteria included opioid dependence, HIV-1 seropositivity, age >or=18 years and reported interest in BMT. All sites included a multidisciplinary team. To date, 207 patients have been initiated on BMT. LESSONS LEARNED: The existing infrastructure allows for further scale-up of and administration of BMT and the possibility of co-administration with ARV. The process for prescription and administration of buprenorphine and ARV is at times cumbersome and constrained by current regulations. RECOMMENDATIONS: More IDU need BMT to improve overall health outcomes. Central to expanding access will be legislative changes to existing drug policy. Moreover, the cost of buprenorphine is prohibitively expensive. Sustainable substitution therapy in Ukraine requires lower negotiated prices for buprenorphine, the addition of methadone, or both to the existing formulary for HIV+ drug users. PMID- 17689383 TI - Case study: accessible primary health care--a foundation to improve health outcomes for people who inject drugs. AB - ISSUE: Injecting drug users (IDUs) represent a large part of the population with HIV globally, however, IDUs continue to have less access to HIV treatment than non-IDUs. While IDUs with HIV potentially fare as well on anti-retroviral therapy (ART) as non-IDUs in terms of HIV disease progression, ART adherence is critical. Opioid dependent IDUs may experience lifestyle instability affecting ART adherence. IDUs often have a range of complex health and social welfare needs beyond HIV. THE APPROACH: Opioid agonist pharmacotherapies such as methadone maintenance treatment, improve overall health and psychosocial stability among opioid-dependent IDUs. The integration of pharmacotherapies into primary health care settings also allows the direct observation of the concomitant administration of HIV treatments. This dual treatment approach maximises HIV treatment adherence and enables the timely management of other clinical issues. Where relevant, sexual and reproductive, infant and maternal health services should also be incorporated alongside HIV and hepatitis B and C prevention services. Services should be anonymous and confidential, and be provided by a multidisciplinary team in a non-judgemental way. Involvement of IDUs in service planning should also be promoted to ensure the acceptability of the model to the target population. A CASE STUDY: The Kirketon Road Centre (KRC) in Kings Cross, Australia, is an example of a community-based primary health care service delivery model that comprehensively addresses a range of complex health and social welfare needs IDUs may have. Established in 1987 to prevent HIV/AIDS and other transmissible infections among "at risk" young people, IDUs and commercial sex workers, the KRC model has also proven versatile in upscaling to meet hepatitis C and other emerging health needs of IDUs in a timely way. CONCLUSION: Integrated primary health care models should be promoted more widely as a foundation to improve the health outcomes of IDUs. PMID- 17689384 TI - Should routine echocardiography be performed in all patients with stroke? AB - BACKGROUND: Cardiogenic embolism accounts for 15% to 30% of ischemic strokes. Echocardiography is frequently being used as a screening test for sources of cardiac embolism in patients with stroke. However, the value of routine use of echocardiography for this task remains controversial. We evaluated the diagnostic yield of echocardiography in unselected patients with acute ischemic stroke. METHODS: Consecutive patients with ischemic stroke or a transient ischemic attack were included in the study. Transthoracic echocardiography was performed in all patients, complemented by transesophageal echocardiography in selected patients. RESULTS: In all, 807 echocardiographic examinations (743 transthoracic and 64 transesophageal) were performed in 775 consecutive patients. A potential cardiac source of embolism (CSE) was found in 144 (18%) of the patients. The most frequent potential causes of cardiac embolism included atrial fibrillation (7%) and patent foramen ovale (6%). Results were more likely to have impact on therapeutic decisions in younger patients. Numbers needed to test for detection of CSE increased 10-fold from 6 in patients younger than 50 years to 62 in patients aged 70 years and older. CONCLUSION: Echocardiography may provide important information on the cause of ischemic stroke. However, echocardiographic screening for a CSE is not warranted in all patients. In patients with younger than 50 years with stroke, echocardiography has a higher diagnostic yield and should routinely be performed. In older patients routine echocardiography results in a high rate of unspecific findings, and should be applied selectively, targeted at specific clinical questions. PMID- 17689385 TI - Home monitoring with a modified automatic sphygmomanometer to detect recurrent atrial fibrillation. AB - OBJECTIVES: Detecting asymptomatic atrial fibrillation would help identify patients who would benefit from anticoagulation. This study examined the application of a modified blood pressure monitor to screen for episodes of atrial fibrillation. METHODS: A modified sphygmomanometer was designed to detect atrial fibrillation. The device has a sensitivity near 100% and a specificity of up to 91%. Therefore, this device can be expected to detect all episodes of atrial fibrillation. However, the lower specificity may result in false-positive readings that could prompt unnecessary clinic visits for electrocardiogram confirmation of the rhythm. Outpatients in sinus rhythm with a history of atrial fibrillation were given the device to monitor their pulse regularity once daily to detect atrial fibrillation. Patients with irregular readings were evaluated with an electrocardiogram. RESULTS: Nineteen patients were monitored at home for a period ranging from 5 days to 5 months. Seven patients had recurrent atrial fibrillation identified by the monitor. Nine patients had no irregular readings for a mean of 82 +/- 40 days. Of 19 patients, 3 had false-positive irregular readings that were a result of sinus arrhythmia or ectopy. CONCLUSIONS: The device had an acceptably low false-positive rate allowing 16 of 19 patients to use it at home for long-term atrial fibrillation monitoring. This device may help prevent strokes by identifying patients with prolonged episodes of asymptomatic atrial fibrillation who are candidates for anticoagulation. PMID- 17689386 TI - Increased intima media thickness and atherosclerotic plaques in the carotid artery as risk factors for silent brain infarcts. AB - The presence of silent cerebral infarcts (SCIs), defined as lesions > or = 3 mm in diameter on magnetic resonance imaging (MRI), is considered a predictor of symptomatic cerebrovascular disorders (CVDs). Similarly, SCI-like lesions < 3 mm in diameter, lesions which often occur in the deep white matter and basal ganglia, also may be a risk factor for CVD. This study evaluated the relationships between SCI and SCI-like brain lesions, as defined by MRI, and 2 findings on extracranial carotid ultrasonography: intima-media thickness (IMT) and atherosclerotic plaque. We studied data obtained by carotid ultrasonography and cerebral MRI in 448 consecutive subjects without a history of stroke who had undergone comprehensive brain screening (mean age, 51.1 years). The subjects were classified into 4 groups according to the presence of increased (> or = 1 mm) IMT (I) and plaque (P). A total of 110 subjects demonstrated increased IMT (24.6%), and 54 subjects had increased plaque (12.1%). SCI-like lesions were found in 38 subjects (8.5%); single SCI, in 24 (5.4%); and multiple SCIs, in 51 (11.4%). Frequencies of SCI-like lesion(s), single SCI, and multiple SCIs were 6.1%, 12.2%, and 8.7%, respectively, in the I(-)P(-) group; 14.6%, 22.0%, and 13.4% in the I(+)P(-) group; 7.7%, 30.8%, and 26.9% in the I(-)P(+) group; and 17.9%, 39.3%, and 21.4% in the I(+)P(+) group. Multivariate analysis found that the presence of carotid plaques was significantly associated with (1) SCI-like lesion(s) and SCI (odds ratio [OR] = 2.20; 95% confidence interval [CI] = 1.17 4.34), (2) single and multiple SCI (OR = 2.33; 95% CI = 1.16-4.67), and (3) multiple SCIs (OR = 2.31; 95% CI = 1.06-5.03). However, the presence of increased carotid IMT was not significantly associated with any of these 3 categories. Coexistence of increased IMT and plaque was more strongly correlated with SCI than with either lesion alone. PMID- 17689387 TI - Predictors for recanalization after intravenous thrombolysis in acute ischemic stroke. AB - OBJECTIVE: The purpose of this study was to evaluate clinical aspects of recanalization and to assess variables associated with early recanalization. METHODS: In all, 27 consecutive patients treated with intravenous thrombolysis were examined with the National Institutes of Health Stroke Scale (NIHSS) and transcranial Doppler ultrasound at presentation and at 2 and 24 hours after treatment. RESULTS: Recanalization less than 24 hours after treatment was found in 70% of patients. Patients who recanalized had lower NIHSS score on presentation (P = .01) and significant improvement in NIHSS score at 0 to 2 hours (P = .042) and 0 to 24 hours (P = .002) compared with those who did not recanalize. Atrial fibrillation (P = .04), higher serum glucose values on presentation (P = .05), and more traditional risk factors (P = .05) were associated with no recanalization. CONCLUSIONS: Recanalization is associated with clinical improvement. High NIHSS score, atrial fibrillation, high serum glucose, and higher number of risk factors indicate a reduced probability for recanalization. PMID- 17689388 TI - Circumstances, activities, and events precipitating aneurysmal subarachnoid hemorrhage. AB - Medical records of 513 patients with aneurysmal subarachnoid hemorrhage were reviewed to analyze the factors precipitating aneurysmal rupture. There was no seasonal difference in incidence. A significantly higher incidence was observed during 6:00 AM to 9:00 AM and 6:00 PM to 9:00 PM when engaging in daily routines such as defecation/micturition, brushing teeth/washing face/dressing, eating/drinking, and taking a bath. These activities are associated with a Valsalva maneuver that results in sudden pressure changes across the aneurysmal wall precipitating aneurysmal rupture. Aneurysmal rupture occurred most frequently during talking, chatting, watching television, or staying home without any strenuous physical activity. Considering the time spent, the highest incidence rate was found during defecation/micturition. There was no significant difference between men and women or between younger and older age groups regarding activities or events preceding aneurysmal rupture. Hypertension was the most common pre-existing medical problem. The main results are the same as those of the previous study except for aging of the patients. PMID- 17689389 TI - Cerebral microbleeds and intracerebral hemorrhages in patients on maintenance hemodialysis. AB - Cerebrovascular and cardiovascular diseases are the leading causes of death in patients undergoing maintenance hemodialysis. Recently, it has become clear that the appearance of cerebral microbleeds (MBs) on T2*-weighted magnetic resonance imaging (MRI) is closely related to intracerebral hemorrhage. The present study investigated the incidence of MBs in patients undergoing chronic dialysis and the effect of maintenance hemodialysis on the appearance of MBs. A total of 80 patients (34 males and 46 females) with chronic renal failure, mean age 62.9 +/- 11.4 years, were examined by MRI. The mean duration of hemodialysis was 7.8 +/- 6.3 years. MBs were found in 28 patients (35%) by T2*-weighted MRI. The duration of hemodialysis did not significantly affect the appearance of the MBs. Old intracerebral hemorrhages were seen in 7 of the patients, 5 of whom (71%) had MBs. The frequency of old intracerebral hemorrhages was significantly higher in the patients with MBs than in those without MBs (P = .048), and the patients with old intracerebral hemorrhages had significantly more MBs than the patients without them (P = .0065). This study found a high incidence of MBs in patients on maintenance hemodialysis, a correlation between MBs and intracerebral hemorrhage, but no correlation between the duration of hemodialysis and the appearance of MBs. The high ratio of patients with MBs was considered to have been caused not by maintenance hemodialysis, but by other factors, such as hypertension. PMID- 17689390 TI - Sex differences in stroke severity, symptoms, and deficits after first-ever ischemic stroke. AB - OBJECTIVE: The purpose of the study was to assess whether there were sex differences in stroke severity, infarct characteristics, symptoms, or the symptoms-deficit relationship at the time of acute stroke presentation. METHODS: In a prospective study of 505 patients with first-ever ischemic stroke (the Ischemic Stroke Genetics Study), stroke subtype was centrally adjudicated and infarcts were characterized by imaging. Deficits were assessed by National Institutes of Health Stroke Scale (NIHSS) and stroke symptoms were assessed using a structured interview. Kappa statistics were generated to assess agreement between the NIHSS and the structured interview, and a Chi square test was used to assess agreement between the NIHSS and the structured interview by sex. RESULTS: In all, 276 patients (55%) were men and 229 (45%) were women. Ages ranged from 19 to 94 years (median, 65 years). The mean (+/-SD) NIHSS score of 3.8 (+/-4.5) for men and 4.3 (+/-5.2) for women was similar (P = .15). No sex difference was observed for the symptoms of numbness, visual deficits, or language. Weakness occurred in a greater proportion of women (69%) than men (59%) (P = .03). Stroke subtype did not differ significantly between sexes (P = .79). Infarct size and location were similar for each sex. The association between symptoms and neurologic deficits did not differ by sex. CONCLUSIONS: We found no sex difference in stroke severity, stroke subtype, or infarct size and location in patients with incident ischemic stroke. A greater proportion of women presented with weakness; however, similar proportions of men and women presented with other traditional stroke symptoms. PMID- 17689391 TI - Peculiar geometric alopecia and trigeminal nerve dysfunction in a patient after Guglielmi detachable coil embolization of a ruptured aneurysm. AB - Neuroendovascular treatment is increasingly being used for treatment of intracranial aneurysms. Postradiation alopecia, commonly seen weeks after radiation for other diseases such as brain tumors, is rarely reported after neuroendovascular procedures for benign lesions because of their delayed manifestations. Although the morbidity and mortality is less compared with surgery, adverse effects related to radiation are probably understated, underreported, and/or often attributed to prolonged bed rest, heparinization, or poor nutrition. We present a case with a delayed onset of a graphic but peculiar geometric alopecia associated with trigeminal nerve pattern dysfunction, which was related to the fluoroscopic radiation for coil embolization of an anterior communicating artery aneurysm. PMID- 17689392 TI - Acute loss of vision with hypoplasia of the contralateral carotid artery. AB - We report a case of a young woman with acute loss of vision of the left eye. The first diagnosis of hypoplasia of the common carotid artery, internal carotid artery, and vertebral artery on the right side was made by means of magnetic resonance angiography. The ischemic optic nerve lesion was caused by a steal phenomenon from the left internal carotid artery to the right cerebral hemisphere with consecutive hypoperfusion of the left ophthalmic artery. Anomalies of the cerebrovascular system should be included in the differential diagnosis of acute loss of vision, even in young patients without cerebrovascular risk factors. PMID- 17689393 TI - The impact of subarachnoid hemorrhage on regional cerebral blood flow and large vessel diameter in the canine model of chronic vasospasm. AB - OBJECTIVE: The aim of this study was to correlate changes in regional cerebral blood flow (rCBF) to the degree of cerebral vasospasm in the canine two hemorrhage model of subarachnoid hemorrhage (SAH). METHODS: SAH was induced in 13 adult beagle dogs using the two-hemorrhage model. Eleven beagle dogs served as controls. Angiography of the basilar artery and measurements of rCBF with colored microspheres were performed on days 1 and 8. Diameter of the basilar artery was calculated at equidistant points from the angiogram. RESULTS: In controls, basilar artery diameter (mm) and rCBF (mL/min/g) were equal on days 1 and 8. In the SAH group, basilar artery diameter decreased significantly (1.27 +/- 0.17 [mean +/- SD]-0.84 +/- 0.15 mm). rCBF decreased significantly (P < .05) in the cerebrum (1.69 +/- 0.54 [mean +/- SD]-1.06 +/- 0.45 mL/min/g), cerebellum (1.18 +/- 0.40-0.80 +/- 0.32 mL/min/g), and brain stem (0.81 +/- 0.33-0.51 +/- 0.21 mL/min/g). However, decrements in CBF were not correlated to the reduction in vessel caliber in the corresponding vascular territory. CONCLUSION: Induced SAH in the canine model produces a significant impairment in rCBF irrespective of the degree of vasospasm of large cerebral vessels. The findings support the presumptive role of the microvasculature in regard to delayed cerebral ischemia after SAH. PMID- 17689394 TI - Morphologic assessment of middle cerebral artery aneurysms for endovascular treatment. AB - BACKGROUND: Aneurysms of the middle cerebral artery (MCA) trifurcation region are underrepresented in large series of endovascularly treated aneurysms. The purpose of our study was to evaluate the incidence of specific morphologic features of MCA bifurcation aneurysms that may affect suitability for endovascular treatment. METHODS: We evaluated 53 consecutive patients with 58 bifurcation or trifurcation MCA aneurysms seen for angiographic evaluation during a 4-year period at our institution. All angiograms were reviewed for: aneurysm size (largest dimension, dome and neck size), branch vessels originating from the aneurysm sac, straightening of the aneurysm wall to suggest intramural thrombus, calcification in the region of the aneurysm, stenosis of the parent vessel, and presence of daughter sacs. RESULTS: Of 58 aneurysms, 51 (88%) had a dome to neck ratio less than 2:1. Branch vessel incorporation in the aneurysm sac was seen in 23/58 (40%), straightening suggestive of thrombus in 14/58 (24%), calcification in 2/58 (3%), parent vessel stenosis in 1/58 (2%), and daughter sacs in 4/58 (7%). CONCLUSIONS: The majority of MCA aneurysms have morphologic features such as a dome to neck ratio less than 2:1 or branch vessel incorporation that may make them unsuitable for endovascular treatment using conventional intra-aneurysmal coiling. PMID- 17689395 TI - Acute physiologic predictors of mortality and functional and cognitive recovery in hemorrhagic stroke: 1-, 3-, and 6-month assessments. AB - This study was conducted to evaluate the prognostic values of acute physiologic parameters of mortality and functional and cognitive recovery. We studied 108 patients with hemorrhagic stroke admitted within 24 hours after stroke onset to a neurologic intensive care department. Details concerning potential physiologic predictors were collected (i.e., systolic and diastolic blood pressure, pulse rate, respiration rate, body temperature, hematocrit, Pao(2), Paco(2) and serum osmolality, pH, cholesterol, and glucose levels) at admission. As outcome variables, mortality and functional and cognitive recovery at 1, 3, and 6 months were measured. Results showed that blood pressure, serum pH, and Pao(2) on admission are significant predictors of mortality; that respiratory rate and hematocrit on admission are significant predictors of functional recovery; and that respiratory rate, Pao(2), and heart rate on admission predict cognitive recovery. It appears that the physiologic predictors of hemorrhagic stroke are remarkably dependent on outcome definitions (i.e., mortality, functional disability, or cognitive ability), but not with recovery times. PMID- 17689396 TI - Acute ischemic stroke lesion measurement on diffusion-weighted imaging--important considerations in designing acute stroke trials with magnetic resonance imaging. AB - BACKGROUND: In acute ischemic stroke, magnetic resonance diffusion-weighted imaging (DWI) is increasingly used to select patients for inclusion or as a surrogate outcome marker in clinical trials, or in routine practice. Little is known of what factors might affect DWI lesion size measurement. We examined morphologic factors that might affect DWI lesion measurement. METHODS: On DWI obtained less than 24 hours after stroke, we categorized lesions according to DWI appearance (solitary or multifocal; well-defined or ill-defined edges), lesion size (5 cm(3)), and time to imaging (<6, 6-12, and 12-24 hours). Two observers (senior neuroradiologist; less-experienced imaging neuroscientist) measured all lesions. In 4 representative cases we assessed DWI lesion volume using two apparent diffusion coefficient thresholds (0.55 and 0.65 x 10(-3) mm(2)/s). RESULTS: Among 63 patients (33% imaged < 6 hours after stroke), the neuroradiologist measured larger lesion volumes than the imaging neuroscientist (median 4.29 v 3.50 cm(3), respectively, P < .01). Differences between observers were greatest in patients scanned within 6 hours of stroke, in multifocal ill defined or large lesions (all P < .01). Both apparent diffusion coefficient thresholds underestimated lesion extent and included remote normal tissue, particularly in multifocal ill-defined large lesions. CONCLUSION: DWI lesion characteristics influence lesion volume measurement. Large, multifocal, ill defined DWI lesions obtained in less than 6 hours have the greatest variability. Trials using DWI should account for this in their study design. PMID- 17689397 TI - Cognitive and behavioral aspects affecting early referral of acute stroke patients to hospital. AB - Successful management of acute ischemic stroke is dependent on early referral for thrombolysis. We explored the key motivational factors affecting stroke sufferers and bystanders and their cognitive and behavioral responses, especially those that would affect prompt management of stroke. This study comprised a structured interview survey of patients and bystanders admitted to a stroke unit in an area where thrombolysis for acute stroke had not yet been introduced. Outcome measures (eg, knowledge of stroke, health beliefs, self-efficacy, and self-care responses) were recorded. Only 41% of the patients correctly assessed their symptoms to be stroke; 44% perceived their symptoms to be mild; and 59% would wait to see whether their symptoms would improve spontaneously. About 61% of the patients and 80% of the bystanders worried about troubling other people with their problem. The bystander was a relative in 68% of cases. Of the bystanders, 65% correctly assessed the symptoms as stroke; only 42% perceived the patient's symptoms as severe. About 25% of the bystanders took a passive approach and would wait and see whether symptoms improved spontaneously; 93% did not find it difficult to ask for assistance. To promote early referral to a hospital, educational strategies must address the public's knowledge and information base and seek to address the cognitive and behavioral processes involved so as to overcome barriers to action. Effective treatment for stroke must be emphasized. PMID- 17689399 TI - Changes in diffusion-weighted magnetic resonance imaging findings in the acute and subacute phases of anoxic encephalopathy. AB - We report serial magnetic resonance imaging findings in a case of anoxic encephalopathy (AE). Diffusion-weighted images clearly showed early development of lesions in the cerebellum, cerebral cortex, and caudate putamen, along with delayed manifestation of lesions in the hippocampus, corpus callosum, and white matter. The present case is the first to demonstrate delayed development of postischemic changes in the hippocampus and deep white matter after AE on neuroimaging. PMID- 17689398 TI - Sensitive reduction in 14C-acetate uptake in a short-term ischemic rat brain. AB - 14C-acetate is preferentially taken up by astrocytes, and is a useful tool for measurement of glial metabolism. The aim of this study was to determine the effects of short-term ischemia on 14C-acetate uptake in the rat brain. The middle cerebral artery was occluded for 3, 10, or 30 minutes. Five minutes after reperfusion, rats were injected with 14C-acetate and decapitated 5 minutes later. Radioactivity concentrations in striatum and cerebral cortex were determined by autoradiography. Cerebral blood flow was also measured using 14C-iodoamphetamine. Neuronal cell death was measured by Nissl staining, and expression of monocarboxylate transporter-1 was examined by immunohistochemical staining. A significant reduction of 14C-acetate uptake was observed in striatum by 3 minutes of occlusion. The degree of reduction of 14C-acetate uptake and reduction area were increased with occlusion period. In contrast, within the same region the regional blood flow was increased by 10 minutes of occlusion, suggesting that uptake of 14C-acetate was independent of blood flow. No neural cell death was detected, and no significant alteration of monocarboxylate transporter-1 expression was observed by 30 minutes of occlusion. These results indicate that 14C-acetate uptake is a sensitive marker for glial metabolism in the ischemic rat brain. PMID- 17689400 TI - Basilar trunk aneurysms with associated fenestration treated by using Guglielmi detachable coils: two cases reports. AB - Basilar trunk saccular aneurysms associated with fenestration are infrequent. Surgical treatment of a basilar trunk aneurysm is difficult because of its anatomic environment and complicated surgical exposure. We experienced two cases of basilar fenestration aneurysm, and the patients were treated using Guglielmi detachable coils. The usefulness of 3-dimensional digital subtraction angiography and efficacy of endovascular treatment for basilar trunk aneurysms with associated fenestration is discussed in this article, and the relevant literature is reviewed. PMID- 17689401 TI - Paradoxical cerebral embolism as the initial symptom in a patient with ovarian cancer. AB - This report concerns a 37-year-old patient with ovarian cancer and a paradoxical cerebral embolism as the initial symptom. She developed acute onset of left quadrantic hemianopia during coughing. Brain magnetic resonance imaging showed an acute multiple infarction, and a simultaneous acute pulmonary embolism was observed. Transesophageal echocardiography showed a patent foramen ovale, multidetector row computed tomography an ovarian tumor and infarction of the spleen, whereas multidetector row computed tomography venography showed right iliac vein compression by the ovarian tumor. The diagnosis was stage Ic ovarian cancer. Because blood stasis of the pelvic vein is a major risk factor for venous thrombosis, the presence of a patent foramen ovale should alert physicians to examine not only veins in the lower extremities but also the pelvic and intra abdominal veins as a source paradoxical embolism. PMID- 17689402 TI - Stratified age-period-cohort analysis of stroke mortality in Japan, 1960 to 2000. AB - BACKGROUND: Although stroke mortality has been decreasing in Japan, in 2000 it was still the third leading cause of death among Japanese of either sex. Elucidation of stroke mortality trends among age, calendar year, and birth cohorts should improve stroke prevention efforts. The objective of this study was to clarify the age, period, and cohort effects on stroke mortality in Japan from 1960 to 2000 by using stratified age-period-cohort models with improved goodness of fit. METHODS: Death and population from the Vital Statistics of Japan and the National Statistics Bureau, respectively, were tabulated among 12 age groups (30 34, 35-39, 40-44, 45-49, 50-54, 55-59, 60-64, 65-69, 70-74, 75-79, 80-84, and 85 89) and 9 quinquennials (1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, and 2000), which yielded 20 birth cohorts (midyears of 1873, 1878, 1883, 1888, 1893, 1898, 1903, 1908, 1913, 1918, 1923, 1928, 1933, 1938, 1943, 1948, 1953, 1958, 1963, and 1968). A stratified model (age-periods-cohort model) with 7 age classes (30-44, 45-54, 55-64, 65-69, 70-74, 75-79, and 80-89 years) was applied under the assumption that the number of deaths has an extra-Poisson variation. RESULTS: The stratified model showed that: (1) middle-aged groups (40-64 years in men and 40 59 years in women) had higher mortality than their linear age trends; (2) young (30-44 years) and middle-aged (45-64 years) groups showed different patterns than those of the elderly (65-89 years) age groups: the two younger groups had higher nonlinear period effects than their linear trends between 1970 and 1990, and the trend of decreasing began later (in 1975 in men and 1980 in women, respectively) than it did for the elderly (1970); and (3) the nonlinear cohort effects indicated 4 patterns in each sex, and the effects increased in post-1948 cohort in men and in post-1958 cohort in women. CONCLUSION: Young and middle age (30-59 years) boosted the mortality, suggesting that this age range should be targeted for increased stroke prevention efforts. PMID- 17689403 TI - Relation of postischemic delayed hypoperfusion and cerebral edema after transient forebrain ischemia. AB - Postischemic delayed hypoperfusion (PDH) is based on the imbalance between local vasodilators and vasoconstrictors. We evaluated the time course of cerebral blood flow and cerebral specific gravity representing cerebral edema after transient forebrain ischemia induced by bilateral occlusion of the common carotid arteries in anesthetized gerbils to determine whether PDH is a significant factor in development of cerebral edema. PDH appeared 45 minutes after reperfusion followed by the increase of cerebral edema. Thereafter, the local cerebral blood flow recovered from PDH 24 hours after reperfusion in spite of the stable cerebral specific gravity. Furthermore, cerebral specific gravity established a linear correlation with the local cerebral blood flow 120 minutes after reperfusion in the 3 different durations of cerebral ischemia (30, 60, and 90 minutes). It is suggested that cerebral edema is not the cause in PDH development, but PDH may cause cerebral edema. PMID- 17689404 TI - Clinical investigation of acute spontaneous subdural hematoma cases. AB - BACKGROUND: Acute spontaneous subdural hematomas of arterial origin without any traumatic history or vascular anomaly are rarely reported. Here, we report our series of 6 patients with acute spontaneous subdural hematoma. METHODS: All patients with acute spontaneous subdural hematoma were surgically treated at our hospital between January 1994 and December 2003. Each patient's constitution, medical history, clinical findings, intraoperative findings, complications, and outcomes were reviewed. RESULTS: The patients were 5 men and 1 woman with a mean age of 53.0 years (range 32-82). Two of the 6 patients had histories of head injury with onset more than 10 years earlier. Other medical histories included hepatitis C, dementia, alcoholism, and hypertension in one patient each. Initial symptoms were rapidly progressive disturbance of consciousness in 5 patients. Surgical operation was performed in all patients, and the bleeding points were identified as ruptures of cortical arteries located near the sylvian fissure. One patient completely recovered, one had a moderate deficit, two had severe deficits, one fell into a vegetative state, and one died (mortality was 16.7%). CONCLUSION: In many cases, the patients suddenly fell into a serious disturbance of consciousness at the onset, and the outcomes were poor. We emphasize that a very early operation is required for a good outcome. PMID- 17689405 TI - Signs and symptoms of sleep apnea and acute stroke severity: is sleep apnea neuroprotective? AB - BACKGROUND: In animal models, brief periods of hypoxemia render the brain tolerant to subsequent ischemic insults. Sleep apnea leads to frequent episodes of nocturnal hypoxemia and may induce ischemic tolerance. Snoring and daytime sleepiness are cardinal symptoms of sleep apnea. We undertook this study to determine differences in stroke severity and early neurologic course in patients at risk for sleep apnea as determined by a sleep questionnaire. METHODS: Patients admitted with acute ischemic stroke completed the Berlin questionnaire. The Berlin questionnaire examines habitual snoring, daytime sleepiness, presence of hypertension, and body mass index (BMI) and classifies patients into a high or low risk for sleep apnea group. National Institutes of Health Stroke Scale (NIHSS) score was determined on admission and day 5 of hospitalization. Age, sex, cardiovascular risk factors, BMI, and stroke mechanism were determined prospectively. RESULTS: We enrolled 190 patients with a mean age of 60 years and 53% were men. The Berlin questionnaire classified 103 patients (54%) at high risk for sleep apnea. The median NIHSS score on admission and day 5 of hospitalization did not differ between the two groups after multivariate analysis. Examined separately, we found no effect of snoring, daytime sleepiness, or BMI on acute stroke severity and outcome. CONCLUSION: We found that a large number of patients admitted with acute ischemic stroke were at high risk for having sleep apnea. We were not able to show that a constellation of symptoms and features highly suggestive of sleep apnea influenced stroke severity or early neurologic course after acute ischemic stroke. PMID- 17689406 TI - Metabolic syndrome among ethnic South Asian patients with ischemic stroke and comparison with ethnic Chinese patients: the Singapore General Hospital experience. AB - BACKGROUND: South Asians are the largest ethnic group in the world, yet there are no data on metabolic syndrome (MetS) among ethnic South Asian patients with ischemic stroke. Ethnic differences in the prevalence of MetS are known to exist. METHODS: We studied 126 consecutive ethnic South Asian patients and 126 age-, sex , and diabetes-matched ethnic Chinese patients admitted with acute ischemic stroke. RESULTS: The prevalence of MetS among ethnic South Asian patients, at 61%, was significantly higher than among ethnic Chinese patients (47%) (P < .001). Of note, mean high-density lipoprotein was lower among ethnic South Asian compared with ethnic Chinese patients (P = .002). CONCLUSION: We describe a high burden of MetS among ethnic South Asian patients, which was significantly greater than that found among ethnic Chinese patients. PMID- 17689407 TI - Circuit training in community-living "younger" men after stroke. AB - OBJECTIVES: We sought to assess a training program focused on muscle strength and endurance in persons with prior stroke. METHODS: Thirty men with a slight hemiparesis caused by a first occurrence of stroke at least 6 months earlier were included with an average age of 54 years. The following was assessed before and after an 8-week period: muscle strength, endurance, work capacity, and activity level. The training group consisted of 21 persons and 9 served as control subjects. There were no differences between the groups in the various assessments from the start. The training was set up as circuit training with 5 stations aiming to strengthen the muscles and increase endurance in the bilateral lower limbs. The session lasted for 45 minutes, 3 times per week, for 8 weeks. On eligible persons in the training group, double-sided muscle biopsies were also performed before and after. RESULTS: There was significance in improved muscle strength and improved peak oxygen uptake for the paretic leg, which was reflected in the muscle enzymes. The nonparetic side also showed improvement, but to a lesser extent. The control group remained unchanged. CONCLUSIONS: Stroke survivors can improve muscle strength, endurance, and work capacity in both the paretic and nonparetic leg with a circuit training program. PMID- 17689408 TI - Fibromuscular dysplasia with carotid artery dissection presenting as an isolated hemianopsia. AB - BACKGROUND: Internal carotid artery (ICA) dissection is a well-known cause of anterior circulation stroke, but its association with posterior circulation stroke has been less commonly reported. The latter situation can arise when there is persistent fetal circulation of the posterior cerebral artery and has, to our knowledge, never been reported in the setting of fibromuscular dysplasia (FMD) involving the ICA. METHODS: A 52-year-old man awoke with severe headache and noted visual loss. Examination confirmed a congruous left homonymous hemianopsia. A head computed tomography scan revealed an acute right posterior parietal infarct. Carotid ultrasonography demonstrated complete occlusion of the right ICA. Conventional angiography confirmed this and was diagnostic of FMD with dissection. A right-sided persistent fetal circulation was also noted. Magnetic resonance imaging revealed right parietal and right occipital infarctions. RESULTS: The patient received ASA and clopidogrel and his visual deficit resolved within days. One year later, he remained asymptomatic and there was no suggestion of FMD in other vascular beds. CONCLUSIONS: Although infrequently reported, carotid disease, including dissection, can be responsible for posterior circulation infarcts. Cervical artery dissection can be related to underlying arteriopathies such as FMD, which must be differentiated from vasculitis and vasospasm. PMID- 17689409 TI - Decreased contribution from afferent feedback to the soleus muscle during walking in patients with spastic stroke. AB - We investigated the contribution of afferent feedback to the soleus (SOL) muscle activity during the stance phase of walking in patients with spastic stroke. A total of 24 patients with hemiparetic spastic stroke and age-matched healthy volunteers participated in the study. A robotic actuator attached to the foot and leg was used to apply 3 types of ankle perturbations during treadmill walking. First, fast dorsiflexion perturbations were applied to elicit stretch reflexes in the SOL muscle. The SOL short-latency stretch reflex was facilitated in the patients (1.4 +/- 0.3) compared with the healthy volunteers (1.0 +/- 0.3, P = .05). Second, fast plantar flexion perturbations were applied during the stance phase to unload the plantar flexor muscles, thus, removing the afferent input from these muscles to the SOL motoneurons. These perturbations produced a distinct decrease in SOL activity that was significantly smaller in the patients (-30 +/- 3%) compared with the control subjects (-43 +/- 4%, P = .03). Third, slow-velocity, small-amplitude ankle trajectory modifications mimicking small deviations in the walking surface were applied to evaluate the afferent-mediated amplitude modulation of the locomotor SOL electromyogram (EMG). In the healthy volunteers these perturbations generated gradual increments and decrements on the SOL EMG; however, in the patients the SOL EMG modulation was significantly depressed (P = .04). Moreover, this depression was related to the spasticity level measured by the Ashworth score. These results indicate that although the stretch reflex response is facilitated during spastic gait, the contribution of afferent feedback to the ongoing locomotor SOL activity is depressed in patients with spastic stroke. PMID- 17689410 TI - Lack of association between infectious burden and carotid atherosclerosis in Japanese patients. AB - Several infectious agents, such as Chlamydia pneumoniae, cytomegalovirus (CMV), herpes simplex virus (HSV), and Helicobacter pylori, have been implicated in the pathogenesis of atherosclerosis; however, but the contribution of infection may vary among races and geographic conditions. The present study investigates the association between the presence of these pathogens and carotid atherosclerosis and examines the relevance of an infectious burden during atherogenesis in Japanese patients undergoing carotid endarterectomy. We investigated a total of 50 carotid atherosclerotic plaques resected during carotid endarterectomy by polymerase chain reaction (PCR) for C. pneumoniae, CMV, HSV, and H. pylori and by immunocytochemistry (ICC) for C. pneumoniae. We also examined the presence of antibodies to IgG and/or IgA for each pathogen in blood samples. We detected HSV DNA in 2 specimens (4%) and positive ICC for C. pneumoniae in 8 (16%). The results of PCR, ICC, or serum antibodies, as well as the number of seropositive antibodies, did not correlate with severely stenotic, ulcerative, or symptomatic plaques. Our findings indicate that the detection rate of infectious agents within atherosclerotic plaques was significantly lower in our patients than that in other studies. Thus, an inflammatory mechanism might not correlate with the pathogenesis of carotid atherosclerosis among Japanese patients with severe carotid artery stenosis. PMID- 17689411 TI - Association of PAI-1 4G/5G and -844G/A gene polymorphism and changes in PAI-1/tPA levels in stroke: a case-control study. AB - Mutations in the plasminogen activator inhibitor-1 (PAI-1) gene, along with altered PAI-1 and tissue-type plasminogen activator (tPA) levels, have been implicated in stroke pathogenesis. We investigated the association of PAI-1 and tPA levels with stroke as a function of PAI-1 4G/5G and -844G/A genotypes, as well as the link between these PAI-1 gene variants and stroke risk, in a case control study of 135 ischemic stroke patient, diagnosed according to clinical and radiologic findings and confirmed by computed tomography scan. Controls (n = 118) were age- and sex-matched and had no personal/family history of stroke. PAI-1 4G/5G and -844G/A genotyping were done by polymerase chain reaction-restriction fragment length polymorphism, and PAI-1 and tPA levels were measured by enzyme immunoassay. Significant elevation in PAI-1 and marked reduction in tPA levels were seen in stroke patients and were correlated with 4G/5G, but not with 844G/A, PAI-1 variants. Whereas the frequencies of 4G or -844A alleles were comparable between patients and controls, 4G/4G carriers had reduced risk of stroke compared with other genotypes (odds ratio [OR] = 0.54; 95% confidence interval [CI] = 0.31-0.95). The 4G/-844A haplotype also was more closely associated with reduced stroke risk (OR = 0.43; 95% CI = 0.20-0.97) than 5G/-844A or 4G/-844G haplotypes. Regression analysis demonstrated that 4G homozygosity (OR = 0.176), hypertension (OR = 6.288), and body mass index (OR = 1.325) were independent predictors of stroke. The protective effect of 4G allele against stroke suggests involvement of PAI-1 4G/5G polymorphism in stroke through a mechanism not related to fibrinolysis, possibly involving altered plaque stabilization, and/or through antagonism of tPA effects. PMID- 17689412 TI - Association of apolipoprotein E gene polymorphism with ischemic stroke involving large-vessel disease and its relation to serum lipid levels. AB - A relationship between apolipoprotein E (Apo E) genotype and stroke was previously suggested, but with inconsistent results. We investigated the relationships among serum lipid levels, Apo E alleles and genotypes, and stroke risk factors in 216 stroke patients and 282 age- and sex-matched controls. Fasting blood samples were collected for total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride level determination and for genomic DNA extraction. Apo was genotyped by polymerase chain reaction-restriction fragment length polymorphism (Cfo I) analysis. Increasing levels of total cholesterol, LDL-C, HDL-C, and triglycerides were associated with elevated stroke risk and was more pronounced in Apo E4-carrying subjects than in E3- and/or E2-carrying subjects. Apo 3 was significantly lower (0.546 vs 0.736; P < .001), whereas Apo 4 was higher in the stroke patients (0.370 vs 0.181; P < .001); Apo 2 was present at low but comparable frequencies. The prevalence of E3/E3 was lower and that of E4 containing phenotypes (E3/E4 and homozygous E4/E4) was higher in the stroke patients. The prevalence of the E4-containing phenotypes were significantly higher in ischemic versus hemorrhagic (P < .001) and in small-vessel versus large vessel stroke cases (P < .001), and was associated with increased need for statin drugs (P = .040). Logistic regression models, after adjusting for potentially confounding variables including lipid profile, age, and sex, showed an significant association of apo 4 genotype with risk of stroke (P = .033). Our findings indicate that Apo 4 is an independent risk factor associated with an altered lipid profile in this study population. PMID- 17689413 TI - A new device for the treatment of thromboembolic strokes. AB - We present data concerning the design and testing of a new clot-sucking device for possible use in the extraction of blood clots that arise during thromboembolic strokes. Our data indicate that a jelly-like mass of 0.02 g (of an artificial clot) can be removed from plastic tubing using this vortex-creating device, which has an optimal diameter of 1 mm, in conjunction with a 6F arterial catheter that is 110-cm long and using applied suction pressures of about 50 cm Hg. PMID- 17689414 TI - The PAI-1 4G/5G gene polymorphism and ischemic stroke: an association study and meta-analysis. AB - To investigate whether the 4G/5G polymorphism of plasminogen activator inhibitor type 1 (PAI-1) and the -7351 C/T polymorphism of tissue-type plasminogen activator (t-PA) are associated with ischemic stroke, we conducted a case-control study of 190 hospital cases of first-ever ischemic stroke and 185 community-based controls. Our findings do not indicate any association between the PAI-1 or t-PA polymorphisms and risk of stroke. Adding our PAI-1 results to previous studies in a meta-analysis indicated a strong association between this polymorphism and ischemic stroke (P = .0002), with no publication bias but with extreme heterogeneity. There was evidence of stroke association with the PAI-1 4G/5G locus. Strong heterogeneity indicates the need to address other issues, including association with particular stroke subtypes or linkage disequilibrium (LD) with another causative allele. The results also sound a cautionary note that varying LD structure across populations may obscure the relationship with a causative locus, and that future meta-analyses need to look beyond a simple pooled estimate. PMID- 17689416 TI - Amphetamine-associated ischemic stroke: clinical presentation and proposed pathogenesis. AB - We report a young lady with acute left middle cerebral artery infarction after acute intake of amphetamine. This is the first case report of amphetamine-induced ischemic stroke with serial angiography and transcranial color-coded Doppler studies. The temporal sequence of stenosis of at least 3 weeks with subsequent complete resolution by 3 months and a "beaded" appearance on angiography support vasculitis or vasospasm as the pathogenesis of ischemic stroke in this patient. The presence of microembolic signals supports acute thrombosis at the site of vasculitis/vasospasm with distal embolism. PMID- 17689415 TI - Early recovery and functional outcome are related with causal stroke subtype: data from the tinzaparin in acute ischemic stroke trial. AB - INTRODUCTION: Baseline severity and causal subtype are predictors of outcome in ischemic stroke. We used data from the Tinzaparin in Acute Ischemic Stroke Trial (TAIST) to further assess the relationship among stroke subtype, early recovery, and outcome. METHODS: Patients with ischemic stroke (<48 hours ictus) and enrolled into TAIST were included. Severity was measured prospectively as the Scandinavian Neurological Stroke Scale (SNSS) at days 0, 4, 7, and 10. Causal subtype as large artery atherosclerosis (LAA), cardioembolism (CE), or small vessel occlusion (SVO) was assigned after standard investigations. The rate of recovery was calculated as the change in SNSS at each time point. Functional outcome was assessed using the modified Rankin Scale (mRS) and Barthel Index at day 90. RESULTS: Analyses were performed on the 1190 patients in TAIST who met criteria for LAA, CE, and SVO. The largest change in SNSS score occurred between baseline and day 4 and was greatest in SVO (median improvement 4 U), compared with LAA (median improvement 2 U) and CE (median improvement 2 U) (P < .0001). If no improvement in SNSS had occurred by day 4, irrespective of subgroup, then early recovery (median SNSS improvement by day 10: 2) and functional outcome (mRS 4) tended to be limited; patients who recovered early tended to continue to improve (median SNSS improvement by day 10: 11) and had a better outcome at day 90 (median, mRS 2). CONCLUSIONS: Recovery is related to causal subtype. In all subtypes most recovery occurred by day 4, and was predictive of longer-term functional outcome. PMID- 17689417 TI - The realities of a nurse led Randomised Control Trial (RCT). PMID- 17689418 TI - Supernumerary status--an unrealised ideal. AB - Supernumerary status, for pre-registration student nurses, should have fundamentally changed the way they learn in practice. Research suggests, however, that for many students the apprenticeship model still exists and that supernumerary status has created new challenges for learning in practice. Common themes found in the literature on supernumerary status are: confusion over the meaning of supernumerary status, the effect of supernumerary status on becoming part of the team, importance of the mentor, power relationships and operationalising supernumerary status. These themes are explored further with reference to the international literature and recommendations made as to how nurse education can respond to the challenges posed in order to ensure the quality of student learning in practice. PMID- 17689419 TI - Interprofessional learning in practice for pre-registration health care: interprofessional learning occurs in practice--is it articulated or celebrated? AB - This paper summarises the issues involved in promoting interprofessional learning in practice both on campus and within placement areas with reference to one particular university. National drivers of Interprofessional Learning (IPL) are outlined and then explored in relation to the portfolio of pre qualifying programmes within a large, multiprofessional School of Health and Social Care. In this particular context, rapid development of campus based IPL require equally robust developments in practise based learning. Integration of IPL across the whole curriculum is considered in the light of current practice based learning initiatives and projects. From this discussion an approach to integration emerges, built on the need to explicitly articulate examples of interprofessional collaboration as they arise in every placement. These interprofessional learning opportunities need to inform assessment strategies both on campus and in practice. Inherent in this approach is the assumption that IPL does occur in practice but is not explicitly articulated or celebrated. PMID- 17689420 TI - A collaborative approach to developing "learning synergy" in primary health care. AB - Supporting and enhancing clinical learning for pre registration nursing students continues to be a challenge for nurse educators. The drive of recent and contemporary nurse education policy in the United Kingdom (UK) has re-emphasised the need for nurse educators to be instrumental in the support and development of clinical learning [United Kingdom Central Council for Nursing, Midwifery and Health Visiting (UKCC), 1999. Fitness for Practice (The Peach Report). UKCC, London; Department of Health, 1999. Making a Difference. Strengthening the Nursing, Midwifery and Health Visiting Contribution to Health and Healthcare, DOH, HMSO]. This paper presents a preliminary study of an action research project, identifying how nurse educators can facilitate new ways of learning in practice. Predominantly, a first person inquiry approach is adopted, supplemented by qualitative approaches, reflecting the journey of the author in relation to her role as nurse educator in practice. This was enriched by engaging with students and mentors from the author's clinical link area, who had participated in a new initiative to develop small tutorial groups designed for students undertaking their primary health care placement, within year two of a Fitness for Practice programme within the UK. Students' and mentors' experiences and stories, were appraised using qualitative and self-reflexive techniques. The role of the nurse educator in clinical practice is demonstrated, as is the importance of successful collaboration between educators and practitioners to establish high quality learning environments for students. PMID- 17689421 TI - Exploring bullying: Implications for nurse educators. AB - This article examines briefly the issue of workplace violence and bullying in the hospital environment, but more importantly how the same and different styles of bullying and intra-staff bullying are emerging in nurse education. The content describes the aetiology of violence and bullying and their place in the National Health Service (NHS) including nursing. It explores bullying as the principle form of intimidation in nurse education, the different types and subtle forms of bullying, why individuals become bullies, dealing with and the consequences of bullying. The legislation, guidelines, policies are part of the recommendations for practice. PMID- 17689422 TI - Student nurses as peer-mentors: collegiality in practice. AB - Mentoring is promoted as a key strategy for supporting nursing students and new practitioners in clinical settings. However, mentoring is also a complex process, requiring the development of bounded and purposeful relationships underpinned by knowledge, experience and opportunities for reflection. This paper reports the findings of an evaluation by second-year nursing student mentors and first-year mentee students of a short peer-mentoring programme. The main objective of the programme was to support students making the transition to the university and nursing. At a more focused professional level, the programme also provided the opportunity for students to be a mentor or to be mentored, as a learning precursor to being mentored in the clinical setting. The programme provided rich learning opportunities for the development of the qualities and skills required for mentoring roles and was a vehicle for encouraging collegial interaction and learning. The students' evaluation of the programme also demonstrated that formal mentoring programmes require considerable organisational investment and ongoing commitment in educational and clinical settings. Mentors and mentees require time for face-to-face meetings and discussion, effective and on-going communication channels, and adequate role preparation. PMID- 17689423 TI - Using clinical nurses as preceptors to teach leadership and management to senior nursing students: a qualitative descriptive study. AB - The preceptor model of clinical education uses nurses to fulfill the role of 'teacher' in a one-on-one relationship with students. The current nursing shortage, however, places increased demands on nurses and threatens their continuation in this role. The purpose of this qualitative descriptive study was to gain a better understanding of the nurse preceptor's experience. Five themes evolved during data analysis: (1) making it worthwhile for the nurse, (2) making a difference, (3) engaging in the process, (4) "I love being a preceptor, but..., and (5) accepting the role, taking responsibility. Making it worthwhile for the nurse included how nurses saw personal and professional rewards and benefits in precepting. Making a difference described how nurses felt they made a difference in student learning. Engaging in the process described how nurses created learning opportunities for students by being a good role model and protecting students from negative experiences. "I love being a preceptor, but..." identified aspects of the precepting role that were difficult. Accepting the role, taking responsibility identified the different people involved in the complex precepting experience; the preceptor, nursing faculty, students, and the nurse manager that all had to work together if students were to have a good experience. Findings can be used to develop better support for preceptors as well as more structured and consistent orientation to the role. PMID- 17689424 TI - Critical thinking and clinical competence: results of the implementation of student-centered teaching strategies in an advanced practice nurse curriculum. AB - The nursing profession has advanced dramatically over the past 50 years. People are living longer, technology is advancing at a rapid rate, and patients are presenting more critically ill. The recent move in the US and other countries away from secondary and tertiary care towards primary care will have a dramatic impact on the practice of nursing as the focus of treatment is aimed at prevention and maintenance of health. Budgetary constraints and a shrinking nursing workforce have added additional strain on the ability of nurses to remain clinically competent in this fast-paced healthcare environment. In addition, the demographics of students have shifted, with more adult and ethnically diverse students entering various nursing programs. These changes have compelled schools of nursing worldwide to revise their approach to student education to keep up with the challenge associated with these influences. Terms such as problem-based learning, critical thinking, evidence-based practice, and student-centered teaching strategies have replaced traditional terminology typically linked with education and practice. However, it appears that not all centers of nursing education have embraced the need to change to new methods of teaching and continue to teach as they were taught. This article will detail the approach used to develop and implement problem-based learning in an advanced practice nurse curriculum in the US. The results and recommendations for implementation are discussed based upon student and nurse educator feedback. PMID- 17689425 TI - Are all doctorates equal or are some "more equal than others"? An examination of which ones should be offered by schools of nursing. AB - This paper examines the typical and varying routes to doctoral degrees in the UK and other developed countries. It raises the important question of whether university schools of nursing should offer a whole range of options with the potential for sub-optimal higher degree training and therefore "mediocre" academics, or resist the "path of least resistance" and offer more limited pathways that ensure that only the highest quality training and candidates are associated with what should be the pinnacle of the profession. As such, it seeks to clarify which of the commonly offered routes to doctoral degrees might be most suited to the academic integrity and value of the profession to our patients and the health care system. PMID- 17689426 TI - Problem-based learning in clinical nursing education: integrating theory and practice. AB - Over the last few decades, nursing education in Sweden has undergone many changes in its length, content, and academic level. Pedagogical developments have occurred, but not as much change has taken place in the clinical part of education. Therefore, a project was initiated to improve students' integrated learning, ability to actively search for knowledge, reflect critically, and to improve the clinical learning environment, during the clinical training part of the undergraduate nursing program at a Swedish university. This was accomplished through applying problem-based learning (PBL), supporting reflection, applying a new model for supervision, and supporting nursing preceptors. The project was carried out during clinical studies in acute care in the second year of a nursing undergraduate program. The aim of this study was to describe nursing students' and their preceptors' experiences of problem-based learning and a new model for supervision in clinical education. A total of 45 students and 30 preceptors participated by answering a questionnaire and an interview. The findings showed that the project overall was perceived positively by students and preceptors. The possibility for supervised reflection was perceived as positive by both students and preceptors, although it sometimes was difficult for preceptors to set aside time. Research-based knowledge was rarely used in clinical teaching. PMID- 17689427 TI - Engaging with peer assessment in post-registration nurse education. AB - The use of student Peer Assessment within the sphere of Higher Education is both innovative and intriguing. The accolades associated with this mechanism of assessment are clearly articulated as promoting a deep approach to learning and the development of astute self-appraisal skills. Within the context of both nurse education and professional nursing practice, these attributes are firmly endorsed as essential transferable skills. The platform for this discussion on Peer Assessment within Post-Registration Education is contextualised within the Community Nursing Specialist Practitioner Qualification, whose framework is predetermined by the Nursing and Midwifery Council [Nursing & Midwifery Council, 2001. Post Registration Standards for Specialist Education and Practice. NMC, London]. This degree level programme aims to prepare first level nurses to develop the knowledge, skills and attributes commensurate with Specialist Practice, defined as the capacity to exercise higher levels of judgement, discretion and decision making in clinical practice. Whilst engaging with Peer Assessment within this context was unquestionably challenging, the experience proved to be a viable approach to supporting and developing student learning. PMID- 17689428 TI - Nursing practice problems in private hospitals in Jordan: students' perspectives. AB - This paper grew from an exploration of clinical practice problems in a private hospital in Jordan. Senior nursing students in a governmental university studied these issues while focusing on leadership and management issues. The private sector is of a secondary focus in nursing research. In Jordan, nursing studies that explore the nursing profession and its related issues have been limited in the literature. A student assignment in the "Nursing Leadership and Management" course required the students to work in groups to identify a nursing practice problem, and its contributing causes and suggested solutions. The nursing shortage; job dissatisfaction; burnout; and turnover were the identified nursing practice problems. Causes and solutions of these problems were explored. PMID- 17689429 TI - A collaborative endeavor to educate community nurses in Guangzhou, China. AB - A collaborative endeavor was initiated between a Hong Kong school of nursing and a school of health in Guangzhou to develop a prevention-focused community nursing educational program. The collaboration aims were to increase the ability and confidence of Guangzhou nurses in performing their community healthcare roles and to train local community health nursing trainers in Guangzhou. The collaborating parties participated in a series of review for planning the teaching team, the taught subjects in the curriculum, the education approach, the student assessment and the train the trainer scheme for the program. The program was developed after the review, planning and implementation phases. This collaboration provided the groundwork for the education of community nurses in Guangzhou and developed local trainers in community health nursing; it enhanced understanding of the present status of community health nursing for both the school of health and the students; and it provided a reference for others that may collaborate with institutions in the People's Republic of China to initiate or strengthen educational programs to build up community health nursing. PMID- 17689430 TI - Expansive learning in the university setting: the case for simulated clinical experience. AB - This paper argues that simulated practice in the university setting is not just a second best to learning in the clinical area but one which offers the potential for deliberation and deep learning [Eraut, M., 2000. Non-formal learning, implicit learning and tacit knowledge in professional work. Journal of Educational Psychology, 70, 113-136]. The context of student learning in an undergraduate midwifery programme is analysed using human activity theory [Engestrom, Y., 2001. Expansive learning at work: toward an activity theoretical reconceptualization. Journal of Education and Work, 14, 133-156]. The advantages of this approach to student learning as opposed to situated learning theory and the concept of legitimate peripheral participation [Lave, J., Wenger, E., 1991. Situated Learning: Legitimate Peripheral Participation. Cambridge University Press, New York] are discussed. An activity system changes as a result of contradictions and tensions between what it purports to produce and the views of stakeholders (multi-voicedness) as well as its historical context (Historicity of activity). A focus group with students highlights their expressed need for more simulated practice experience. The views of midwifery lecturers are sought as an alternative voice on this tension in the current programme. Qualitative differences in types of simulated experience are explored and concerns about resources are raised in the analysis. Discussion considers the value of well planned simulations in encouraging the expression of tacit understanding through a group deliberative learning process [Eraut, M., 2000. Non-formal learning, implicit learning and tacit knowledge in professional work. Journal of Educational Psychology, 70, 113-136]. PMID- 17689431 TI - The CCARE model of clinical supervision: bridging the theory-practice gap. AB - Clinical supervision of nursing students is a key component of nursing education. The clinical setting provides students with an opportunity to develop a professional identity, knowledge base, and the ability to transfer classroom knowledge to the clinical setting. This paper suggests a model of clinical supervision that will address how to bridge the pre-existing theory-practice gap in nursing education through an attitude of caring and the utilization of caring behaviours based on Leininger's theory of culture care. Key concepts included in this model are: communication, collaboration, application, reflection and evaluation, these concepts comprise the CCARE model of clinical supervision. PMID- 17689432 TI - Facilitating reflective practice and self-assessment of competence through the use of narratives. AB - Reflective practice is a skill that is central to nursing students' professional development. Although there is an abundance of literature on the value of reflective practice there are few concrete methods that facilitate self assessment of competence through the use of reflective practice. One such method is narrative reflection. A nursing narrative is a brief recount of an actual situation or episode in clinical practice that is significant because it resulted in new learning and/or new understanding. Narratives provide important opportunities for uncovering nursing practices that often go unnoticed and a new appreciation of the knowledge and skills of clinical practice. Nursing narratives reveal the richness of the clinical knowledge embedded in practice and provide a way for knowledge and practice to be linked together in meaningful dialogue, promoting interpretive analysis and reflection. A narrative approach contextualises knowledge and values and builds upon the clinical experiences of the student. Narratives afford opportunities for nursing students to: Learn from practice through reflection. Describe and critically analyse episodes of their clinical practice. Illuminate and assess their own level of competence by applying competency standards as a benchmark. Identify areas of strength and those requiring development. Develop practice-driven clinical learning objectives. Narratives have proven to be a successful means of developing students' ability to reflect upon and assess competence in a clinically relevant and motivating way. This paper will explore the possibilities that narratives hold for developing clinical acumen, promoting reflective practice, and assessing competence. It will provide an overview of narrative writing, and discuss some of the challenges encountered in the implementation of this clinical learning innovation at the author's university in Australia. PMID- 17689433 TI - What does the Cooksey report hold for nursing research in the UK? PMID- 17689434 TI - Nursing scholarship and the asymmetrical professor. AB - A recent editorial by David Thompson and Roger Watson prompted the question 'Nursing professors: what do they profess?', with the stated intention of stimulating thought about the role of professors and their scholarly endeavours. This paper has been written in response to their challenge, and outlines a scholarly role for the professor of nursing which is very different from Thompson and Watson's 'pipe dream' of the university without students. In particular, I argue for a fully-rounded 'symmetrical professor' whose role is not predominantly to conduct research, but rather to 'profess the profession'. PMID- 17689435 TI - Evaluation of moving and handling training for pre-registration nurses and its application to practice. AB - This paper describes preliminary questionnaire survey work in a research programme exploring M&H training for student nurses (n=106) and its application to practice. The aim of the study was to provide evidence of the students' experiences of M&H in the clinical setting to inform future educational development. The students were able to distinguish between acceptable and unacceptable practice they observed. Good practice comprised planning and coordination within the nursing team and careful reassurance of the patient. Regarding poor practice, the students identified that equipment was unavailable or not used and that staff demonstrated poor posture in this work or used condemned techniques thought to be detrimental to the staff and the patients. Fewer students had observed: risk assessments, equipment safety checks and use of a hoist for lifting fallen patients, than had seen other accepted M&H procedures. Contrary to the Manual Handling Operations Regulations (HSE. 1992; 1998. Manual Handling Operations Regulations. HMSO, London.) and hospital 'no-lifting' policies, 71% of the respondents had been asked to participate in a manoeuvre that they thought was wrong and a similar number had been asked to physically lift patients without using recommended equipment. Perceived injuries to both staff and patients were also described. PMID- 17689436 TI - Using reflective models to enhance learning: experiences of staff and students. AB - In this paper we reflect on a quality activity undertaken with students enrolled in a Bachelor of Nursing course who were required to write a 3000-word reflective paper for a unit called 'Nursing People Experiencing Long Term Illnesses.' Students were required to select one chronic illness from a list of five suggested by the teaching team. Having made their choice, they developed their paper in two parts. Students were first required to briefly discuss the pathophysiology of the illness, and its psychosocial effects on the individual and family. Second, they were required to use a model of reflection to discuss how knowledge they gained could be applied when working with a person with this condition, within the hospital and the community. Highlighted in this paper are the voices of 10 students who accepted an invitation to be involved in a focus group discussion which elicited their views, experiences and concerns regarding this assessment. Analysis revealed that students found the assignment topic to be challenging, rewarding and an appropriate vehicle to unveil what they learned. However, completion of the assessment was not without its difficulties. In this paper, insights gained in using this teaching and learning strategy are shared. PMID- 17689437 TI - Opening up pre-registration education for nurses (the OPEN Project): a partnership approach. AB - METHODS: Using a combination of focus groups and questionnaires, data were obtained from 20 health care assistants/pre-registration nursing students taking part in the OPEN Project, their 20 respective clinical mentors, three National Health Service Trust-based facilitators and three University Tutors. The aim was to evaluate development and delivery of the project by: Data were analysed using a combination of Framework Technique and descriptive statistics. RESULTS: The three main emergent themes were: Personal, Professional and Organisational learning. Through a combination of predominantly work based learning, teaching and assessment methods, students were able to demonstrate how they transformed existing knowledge into a usable tool on which to build further learning, while challenging previous assumptions about practice arising from their health care assistant role. Familiarity with the workplace while in the dual role of student/health care assistant allowed them to explore practice issues and implement changes while also gaining the credit to step onto year two of the Diploma in Nursing Science/Registered Nurse Programme. The main recommendations related to the issues of role identity for the students and infrastructure development in the Trusts and informed further similar projects. PMID- 17689438 TI - Being a real nurse--concepts of caring and culture in the clinical areas. AB - In this paper we discuss the issues of caring and culture in practice settings and how they affect student nurses in their endeavours to learn how to be a 'real nurse'. Drawing upon differing conceptions of 'caring' we discuss the notion as a pivotal factor in becoming a nurse. We examine the degree to which boundaries are changing, not least those in which students seem currently to define the bedrock of physical and emotional care as belonging to health care support workers whom they will merely supervise. Complicating this picture are developments in medical and nursing boundaries which may, or may not help to 'professionalise' nursing. We conclude by arguing that complex cultural norms and the negotiated order of health care need to be properly recognised by curriculum developers if, within contemporary higher education nurses are to be fit for purpose and practice. PMID- 17689439 TI - You have no credibility: nursing students' experiences of horizontal violence. AB - Horizontal violence is a significant issue confronting the nursing profession both in Australia and internationally. The term horizontal violence is used to describe bullying and aggression involving inter-group conflict. Some evidence suggests that nursing students commonly experience this during clinical placement(s). Despite the current shortage of nurses and the fact that clinical placement experiences may influence whether students remain in the nursing profession, there has been little research undertaken on this topic. This study used a questionnaire to investigate 152 second and third year nursing student's experiences of horizontal violence (either directly experienced or witnessed). Analysis identified five major themes: humiliation and lack of respect; powerlessness and becoming invisible; hierarchical nature of horizontal violence; coping strategies; and future employment choices. More than half of the sample indicated that they had experienced or witnessed horizontal violence; importantly, most of these (51% of the total sample) also indicated that it would impact on their future career and/or their employment choices. Strategies are discussed that could be implemented to reduce the effect of horizontal violence, including giving a higher priority to debriefing within a supportive university environment, and teaching assertiveness and conflict resolution skills within the Bachelor of Nursing Degree. PMID- 17689440 TI - So what is so good about clinical experience? A mental health nursing perspective. AB - The available literature suggests that undergraduate nursing students generally do not have positive attitudes towards working in the mental health field but that clinical experience is the most important factor influencing the development of a more favourable outlook. Despite this there is very little attention paid to the factors that contribute to a positive clinical experience. The aim of this paper is to examine the level of, and factors contributing to, undergraduate nursing students' satisfaction with clinical experience. A survey was administered to undergraduate nursing students (n=146). The findings support the available literature in suggesting that the provision of support and the ability to become actively involved in patient care are the two most important factors affecting the perceived quality of clinical placements. However, this study contradicts the findings of earlier research in demonstrating a higher degree of satisfaction with clinical experience in inpatient settings. This reflected the view that there was less opportunity for patient care involvement within the community environment. Given the increased emphasis on community care, it is important that students are actively engaged in the care and treatment process in order that they have the opportunity to meet learning objectives in the mental health field. PMID- 17689441 TI - Holistic health promotion: putting the art into nurse education. AB - The role of the arts in health care and health promotion is enjoying belated attention as a way of promoting people's mental health and well-being. Canterbury Christ Church University offers a course which examines how nurses can use the arts to enhance the health care experience for both staff and patients. The Holistic Health Promotion course is compulsory for all final year pre registration Bachelor degree students in Adult and Child Nursing. The content and process of the course are described, and the findings from the evaluation data are discussed. Through the use of autobiographical literature, active learning in the classroom, visiting speakers and visits within the local community, the course provides a positive learning experience for many students and broadens their perceptions of how to carry out mental, emotional and spiritual health promotion. PMID- 17689442 TI - Storytelling: a clinical application for undergraduate nursing students. AB - Faculty from Creighton University School of Nursing participating in a grant set out to design and implement a model for teaching health care management in community-based settings. The goal of the grant was to cross-educate acute care faculty on how to provide holistic care to patients transitioning between acute care and the community with a focus on underserved and vulnerable populations and to incorporate this into acute care clinical experiences with students. One of the recurring topics during grant discussions was the importance of getting to know the patient's story and how it impacts the nurse-patient relationship. Key themes related to storytelling that emerged during grant meetings were listening, partnership, reciprocity, and solidarity. Grant participants identified various methods in which stories could be obtained and shared with others for educational purposes. Various storytelling techniques were implemented in the classroom and clinical settings as a means for teaching and learning. Examples of specific techniques implemented included case studies, journals, stories from practice, life reviews, and reminiscence therapy. The aim of the storytelling projects was to get students to gather information from multiple sources and to put it into a cohesive story in order to provide comprehensive, holistic, and individualized care. PMID- 17689443 TI - Mistaken, misshapen and mythical images of nurse education: creating a shared identity for clinical nurse educator practice. AB - The hospital-based clinical nurse educator is pivotal to the integration of formal learning and clinical practice. Clinical nurse educators are generally considered to be expert nurses within a particular clinical environment; however, many of those who are expert clinicians suffer some loss of identity when assuming clinical teaching roles. It is necessary to facilitate the expression of identity in order to foster collective agency and to empower individuals and groups. In a health care system that is awash with change, the importance of this may often be overlooked. This paper reports on the process and outcomes of a series of workshops with clinical nurse educators in a New South Wales area health service that sought to create a shared identity and role for clinical nurse educators within the health service. Challenges in role demarcation and delineation of the roles and functions of clinical nurse educators clinical nurse specialists, clinical nurse consultants, practice development facilitators and nurse educators have been reported. Each of these has overlapping and complementary roles to support learning, however, the primary focus and area of responsibility varies among each of these groups. PMID- 17689444 TI - Taking the wrong turns: ensuring the legacy of the nursing workforce in England. PMID- 17689445 TI - The theory-practice relationship in nursing: a debate. AB - The dispute surrounding the existence or not of a gap between the theory and practice of nursing is one that has occupied and at times polarised the profession for decades. The authors of this article, one from England and the other from New Zealand, met during a break between sessions at a research conference held in Surfers Paradise Australia. Karen Ousey is convinced of the existence of a gap and Peter Gallagher resolute that the notion of a gap is axiomatic and ultimately a false dichotomy. As the authors live in the Southern and Northern hemispheres the debate was eventually conducted via email. What follows is the content of that debate. PMID- 17689446 TI - Exploring the transition and professional socialisation from health care assistant to student nurse. AB - BACKGROUND: Minimal research is available examining the socialisation process from the perspective of students with health care knowledge who prior to undertaking their training worked as a health care assistant (HCA). The transition and professional socialisation process undertaken by students is an important factor in contributing to the successful completion of a pre registration nursing programme. Despite this, limited empirical research explores the impact prior health care knowledge plays in this process. OBJECTIVE: The studies aim was to determine the transitional processes associated with moving from a HCA to Student Nurse. DESIGN: A descriptive qualitative study undertaken over an 8-month period at a university in the northeast of England. POPULATION, SAMPLE, SETTING: A homogeneous sample of 14 students with previous experience as a HCA within the field of adult nursing was used. METHODS: Data were collected through 4 focus group interviews and analysed using [Burnard, P., 1991. A method of analysing interview transcripts in qualitative research. Nurse Education Today 11, 461-466.] thematic content analysis. FINDINGS: The main themes that emerged around culture shock and clinical issues identified both positive and negative perceptions upon this process. Equally a new concept is introduced from the findings, that of 'the comfort zone', which explores the intentional reversal into the HCA role by the participants of the study. From the findings a framework for the transition and professional socialisation from HCA to student nurse is provided. The findings will assist the university and others in identifying, addressing and aiding the socialisation needs of these students into their new role as a student nurse. PMID- 17689447 TI - Exploring the assessors' and nurses' experience of formal assessment of clinical competency in the administration of blood components. AB - Blood transfusion, clinical competency, assessment, evaluation The change in nurse education from apprenticeship training to the higher education setting, has raised concerns about the lack of practical skills newly qualified nurses have on registration. Every practitioner must be able to administer blood components safely however, the Serious Hazards of Transfusion (SHOT) scheme have consistently demonstrated that 'wrong blood' incidents are the major cause of morbidity and mortality related to transfusion in the United Kingdom. As a result the SHOT working group have recommended that all practitioners should have their clinical competency formally assessed. This paper describes the development and evaluation of a tool for assessing clinical competency for staff involved in transfusing blood. The evaluation used a triangulated approach of phenomenology and survey. The tool was piloted in two different clinical settings by four registered nurses who each assessed two nurses. Individual semi-structured interviews were conducted to collate the nurses' and the assessors' experience of the process. The study participants were of the opinion that assessing clinical competency using a criterion-referenced tool gave practitioners the opportunity to relate theory to practice, promote best practice and encourage adherence to hospital transfusion policies. Formal assessment of clinical competency is therefore, a vehicle that could be used to promote safe transfusion practice, ensuring the safety of patients is paramount. PMID- 17689448 TI - Evaluation of a teaching pack designed for nursing students to acquire the essential knowledge for competent practice in blood transfusion administration. AB - This article describes the evaluation of a teaching pack designed for nursing students to acquire the knowledge required for safe administration of blood transfusions. The Serious Hazards of Transfusion (SHOT) Committee is a confidential reporting body, which gathers data from the United Kingdom and reports the serious sequelae of blood transfusion. The SHOT reports have repeatedly identified that errors in blood transfusions are wholly avoidable. Nurses, as the health care professionals ultimately responsible for the bedside check, have the final opportunity to prevent a mis-transfusion [Nursing and Midwifery Council, 2004a. The NMC code of professional conduct: standards for conduct, performance and ethics. NMC, London; Serious Hazards of Transfusion, 2002. SHOT Annual Report 2001-2002. SHOT Scheme, Manchester]. The educational strategies implemented will be explained and evidence that applying structured learning programmes in the undergraduate nursing curriculum can improve students' knowledge presented. A structured questionnaire was employed to assess students' knowledge of the process for transfusing blood components pre- and post-teaching and evaluate the effectiveness of the teaching pack. The results will be presented and discussed. PMID- 17689449 TI - Clinical learning environments for student nurses: key indices from two studies compared over a 25 year period. AB - In 1978, a longitudinal study commenced in England to illuminate criteria for the evaluation of hospital wards as clinical learning environments for student nurses. It derived measures to quantify the clinical learning experienced by 71 students in three cohorts in three training hospitals over their entire programme. In 2003, a second study, based in one English School of Health Studies, using clinical placements in three NHS trusts, employed a retrospective, cross-sectional, analytic survey design with anonymised, self-completion questionnaires, to map the clinical learning of 272 students as part of a quality assurance and enhancement initiative. This paper explores changes over time by comparing data based on five key indices, devised in the first study and revisited in the second. Concepts of clinical learning and supervision are reviewed as part of this changing context and background together with limitations implicit in the comparison. The findings suggest an average 20% improvement in the quality of hospital based clinical learning environments over a 25 year period, based mainly on trained staff personally supervising students more extensively, testing their theoretical knowledge more frequently and spending more time performing practical procedures with them. However, unacceptable variations in clinical learning opportunities persist for some students. PMID- 17689450 TI - Designing and delivering clinical risk management education for graduate nurses: an Australian study. AB - In order to enhance their capabilities in clinical risk management (CRM) and to be integrated into safe and effective patient safety organisational processes and systems, neophyte graduate nurses need to be provided with pertinent information on CRM at the beginning of their employment. What and how such information should be given to new graduate nurses, however, remains open to question and curiously something that has not been the subject either of critique or systematic investigation in the nursing literature. This article reports the findings of the third and final cycle of a 12 month action research (AR) project that has sought to redress this oversight by developing, implementing and evaluating a CRM education program for neophyte graduate nurses. Conducted in the cultural context of regional Victoria, Australia, the design, implementation and evaluation of the package revealed that it was a useful resource, served the intended purpose of ensuring that neophyte graduate nurses were provided with pertinent information on CRM upon the commencement and during their graduate nurse year, and enabled graduate nurses to be facilitated to translate that information into their everyday practice. PMID- 17689451 TI - Establishing library 'key skill' confidence levels amongst a cohort of nursing students at an English university. AB - This article presents the findings of a small-scale preliminary survey of one cohort of students studying towards a Diploma/BSc in Nursing. The survey sought to establish student characteristics and indicate their confidence levels using identified key library facilities. From questionnaires (N=64), the data confirmed the 'typicality' of the student group illuminating a breadth of prior experiences in terms of students' prior learning and perceived confidence in using library resources. Whilst a number of respondents indicated confidence using identified library resources, a significant number of students (typically over one third n=14+) indicated that they lacked confidence in and did not utilise library facilities. This suggests that they may not be using the resources to full advantage. Over half of the respondents (53% n=23) had not attended library skills training within the last two years and 9% (n=4) had not used the library although they were completing assignments. This survey points to gaps in student confidence, and by implication, use of key library skills, particularly those involving electronic resources. At a time of widening participation and the explosion of information technology, this survey is a timely reminder of the need to revisit key skill development for nursing students studying in higher education. PMID- 17689452 TI - Learning in practice--practice educator role. AB - Learning in practice is increasingly becoming the focus of attention for higher education institutions, commissioners of health care education and the National Health Service in the United Kingdom. This article describes an evaluation of an initiative to provide specific support for pre qualifying nursing students in the practice environment. The initiative was the establishment of a new role, titled practice educator. The aim of the study was to evaluate the effectiveness of the practice educator role from the perspective of the three main constituent groups, practice educators themselves, mentors and students. Both qualitative and quantitative methods were used. The views of all three groups were that the role of practice educator was an important link between the University and practice providers. The issue of high credibility, accessibility and approachability was highlighted by post holders and reinforced by both students and mentors. The study indicates that practice educators are seen as supportive to both mentors and students and are perceived as a vital link between the University and practice environment. PMID- 17689453 TI - Nursing at the cross roads? PMID- 17689454 TI - Spirituality as a universal concept: student experience of learning about spirituality through the medium of art. AB - Precise definitions of spirituality can be elusive (McSherry, 2000). This factor together with the increasing class sizes for undergraduate nursing students render the teaching and learning of spirituality in nursing a challenge for both lecturers and students alike (McSherry, 2000). This paper reports on the design, delivery and evaluation of an innovative spirituality program for second year nursing students attending a Bachelor of Science degree at a university in the Republic of Ireland. This teaching program was introduced in 2005 to enhance nursing students' engagement with the concept of spirituality. The program consisted of a series of lectures on the topic, followed by a visit to the National Gallery of Ireland. The latter involved a structured visit, whereby the students (n=100) were divided into ten small groups and asked to wander through a section of the gallery and choose a piece of art work that they perceived to be spiritual in nature. Students were then asked to write their subjective impressions and reasons for their choice of painting. A list of themes related to spirituality was provided to the students as a prompt. Students later visited the paintings with both a lecturer and an art gallery guide and their chosen paintings were discussed within the group. Later that day, purposive sampling was used, whereby a selection of nursing students participating in the Gallery visit (n=21) partook in four recorded focus group interviews following the Gallery visit. Themes emerging from the interviews pertained to the universal and individual nature of spirituality. In keeping with Mc Sherry's (2000:27) definition of spirituality as a "universal concept relevant to all individuals", students in the study revealed their surprise at the uniqueness of their colleague's interpretations. The teaching methodology offered them an opportunity to reflect upon their own understandings and develop a deeper awareness of the meaning of spirituality. It also allowed many of them to understand how spirituality transcends traditional religions and permitted many of them to verbalize their feelings on spirituality for the first time. PMID- 17689455 TI - Questioning: a tool in the nurse educator's kit. AB - Effective questioning is one of the most important teaching techniques and plays a crucial role in creating an effective learning environment. Yet, in nurse education little has been written about this technique or its importance. Most literature refers to the need for lecturers to be skilled in questioning, but less is written about how to develop this essential technique. Being skilled in questioning is an important fundamental step towards becoming an effective lecturer. Developing the skills necessary to help students draw on and apply acquired knowledge in new, unique situations requires the skilled use of questioning. Most experienced lecturers use both written and verbal questioning, but evidence suggests that the majority of their questioning is posed at lower cognitive levels of description. Quality teaching requires students to be engaged with the content of learning tasks designed to reach understanding. Using questioning appropriately facilitates the learning process by requiring the student to participate in the process and to achieve higher comprehension skills by acquiring deep, elaborate understanding of the subject. To acquire and develop this skill, the lecturer is required to understand questioning, to select the tool appropriately and to use questions that are varied, planned, appropriate and humanely posed. The functions of questioning, types of questions and the key skills required for the effective use of this teaching strategy are outlined in this article. PMID- 17689456 TI - A systematic review of tobacco smoking among nursing students. AB - This study was conducted to systematically and critically evaluate the large number of academic publications which have investigated tobacco smoking among nursing students in recent years. It was performed as a state-of-the-art examination of all modern literature published in peer-reviewed, English-language journals since 1990. Although smoking appears to be fairly common among nursing students, its prevalence and distribution varies widely depending on the country of study and time period during which the research was undertaken. Although there is some evidence to suggest that smoking rates increase by year of study in the nursing course, not all research has shown a clear association in this regard. Similarly, the value of anti-smoking interventions for nursing students appears to be limited, based on currently available information. Given these conflicting issues, further research which helps to ascertain why student nurses do not wish to give up their habit is clearly needed both locally and internationally. The development of an international smoking questionnaire may also be useful to help standardize future research on tobacco usage among this vulnerable demographic. PMID- 17689457 TI - Critical thinking: a two-phase framework. AB - This article provides a comprehensive review of how a two-phase framework can promote and engage nurses in the concepts of critical thinking. Nurse education is required to integrate critical thinking in their teaching strategies, as it is widely recognised as an important part of student nurses becoming analytical qualified practitioners. The two-phase framework can be incorporated in the classroom using enquiry-based scenarios or used to investigate situations that arise from practice, for reflection, analysis, theorising or to explore issues. This paper proposes a two-phase framework for incorporation in the classroom and practice to promote critical thinking. Phase 1 attempts to make it easier for nurses to organise and expound often complex and abstract ideas that arise when using critical thinking, identify more than one solution to the problem by using a variety of cues to facilitate action. Phase 2 encourages nurses to be accountable and responsible, to justify a decision, be creative and innovative in implementing change. PMID- 17689458 TI - Clinical education: a review of the literature. AB - In 2005, the University of Sheffield was commissioned to research the role, function and perceived impact of the clinical nurse educator role in a National Health Service Primary Care Trust. This paper presents the results of Phase I of the study, a review of the literature on clinical education and the series of research questions that were indicated. The importance of clinical education for quality nursing care has long been agreed but has gained increasing attention over the last two decades. This increased attention is the result of policy directives that place work based learning at the centre of health and social care practice. The literature is less equivocal, however, concerning the responsibility for clinical education and asserts various roles including; the lecturer employed by the University; joint appointments; mentors; ward sister; specialist and advanced practitioners including the nurse consultant; and more recently the clinical nurse educator. Clinical educators have reported to have been introduced to meet the professional educational needs of the workforce but there is little empirical or theoretical evidence to support or refute this. This paper is an attempt to begin to address this. PMID- 17689459 TI - Learning to nurse in China--structural factors influencing professional development in practice settings: a phenomenological study. AB - This paper describes findings from a stratified phenomenological investigation into Chinese nursing students' experiences of learning in practice placements. The investigation was undertaken in China whilst studying at an English University for a post-graduate degree. With the transition of Chinese nursing education into higher education institutions, clinical nursing experience remains a fundamental factor in students' preparation for qualification. This small phenomenological study sought to understand the kinds of experiences students encounter, the factors that supported or inhibited their learning and the ways in which learning in practice could be enhanced. This paper concentrates on the structural factors that influenced students' learning. These structural factors included; the opportunities available for students to learn, students' participation in clinical nursing activities; the relationship that placement staff were willing to engage in with the students and the prevailing learning climate of the placement setting. PMID- 17689460 TI - The professional self-concept of new graduate nurses. AB - The purposes of this study were to: (1) describe the level of professional self concept among new graduate nurses working in critical care and general medical surgical unit six months after completing a nursing program, (2) examine the professional self-concept in relation to age, marital status, and educational level of new graduate nurses, and (3) examine graduate nurses' perceptions of their nursing educational preparation for their clinical area. One hundred thirty two (n=132) new graduate nurses completed the professional self-concept nurses instrument (PSCNI) and answered two open ended questions focused on their educational preparation. Scores on the PSCNI ranged 58-106 with an overall mean of 83. There was a positive correlation between age and level of professional self-concept. Single factor ANOVA showed no statistical differences between levels of professional self-concept, marital status (p=0.43), and educational level (p=0.09). New graduate nurses identified themes as they assessed their educational preparation for their work experiences. PMID- 17689461 TI - Student nurse practitioners--a rite of passage? The universality of Van Gennep's model of social transition. AB - Whilst much has been written on the competence and clinical effectiveness of qualified nurse practitioners, the literature reveals little on the educational experience of student nurse practitioners. This paper reviews an ethnography that examined, over a two-year period, the experiences of student nurse practitioners undertaking a clinical degree programme (B.Sc. (Hons) Nurse Practitioner). The findings revealed the student nurse practitioner experience as a composite of social and cultural transitions, and subsequently Van Gennep's (Van Gennep, A., 1960. The Rites of Passage (Trans). Routledge & Kegan Paul, London) rite of passage model was found to have similarity with this emergent model. Finally, it was noted that, whilst social transition is modelled in the literature in many ways, the stages of a rite of passage had universal application. PMID- 17689462 TI - Framework for teaching pharmacology to prepare graduate nurse for prescribing in New Zealand. AB - The place of nurse prescribing and the preparation for this role is an educational challenge that has been heavily debated in New Zealand and overseas for the past 10 years. Nurse prescribing is relatively new in New Zealand and is related to the expanding roles and opportunities for nurses in health care. Opposition to nurse prescribing in New Zealand has been marked and often this has been linked to concerns over patient safety with the implication that nurses could not be adequately prepared for safe prescribing. The educational framework used to teach pharmacology to nurses by one university in New Zealand is presented, along with early findings on the effectiveness of this approach. Further research is required to confirm that nurse prescribers in New Zealand are well prepared and able to utilise effective decision-making processes for safe prescribing. PMID- 17689463 TI - Estimation of 24-h aldosterone secretion in the dog using the urine aldosterone:creatinine ratio. AB - OBJECTIVES: One potential method of evaluating renin-angiotensin-aldosterone system (RAAS) activation involves the quantification of urinary aldosterone excretion. While blood concentrations of aldosterone are easily obtained, results may be misleading because of minute-to-minute variation in aldosterone secretion and subsequent blood concentrations. Urinary aldosterone concentration measurement represents a more consistent "pooled" index of aldosterone secretion, but obtaining 24-h urine samples is time-consuming, difficult, and fraught with potential error. We postulated that the urinary aldosterone:creatinine ratio, measured from spot urine samples, would correlate well with 24-h urinary aldosterone excretion, and would provide a simple index of aldosterone excretion that would eliminate the need for 24-h urine collection. ANIMALS, MATERIALS AND METHODS: After validating an assay for aldosterone in canine urine, 24-h urinary aldosterone excretion was determined by radioimmunoassay from 8 normal, male beagle dogs under control conditions, after RAAS stimulation with amlodipine administration, and after RAAS attenuation with the addition of enalapril to amlodipine administration. Spot urine samples, each obtained at the same time of day, were used to determine the aldosterone:creatinine ratio during control conditions, RAAS stimulation, and RAAS attenuation. RESULTS: The aldosterone:creatinine ratio from spot-checked urine samples correlated well with 24-h urinary aldosterone excretion (r=0.77, P<0.0001). CONCLUSIONS: A spot urinary aldosterone:creatinine ratio might be substituted for 24-h urinary aldosterone determination. PMID- 17689464 TI - Systolic anterior motion of the mitral valve associated with right ventricular systolic hypertension in 9 dogs. AB - OBJECTIVES: To describe the zoographic and echocardiographic characteristics of canine patients in which systolic anterior motion of the mitral valve (SAM) was identified in association with right ventricular systolic hypertension (RVSH). ANIMALS, MATERIALS AND METHODS: Medical records and digitally recorded echocardiographic examinations were reviewed for RVSH and two-dimensional (2DE) or M-mode echocardiographic evidence of SAM. RESULTS: SAM was identified in association with RSVH in 9 patients; 5 had pulmonic stenosis, 2 had tetralogy of Fallot and 2, pulmonary hypertension. Relative to body weight, the end-diastolic and end-systolic left ventricular dimensions were subnormal in all patients. Hyperdynamic left ventricular systolic performance was identified in 8 of 9 patients. In 5 of the 9 patients, SAM was mild or moderate in degree. Left ventricular outflow tract (LVOT) obstruction and mitral valve regurgitation were documented by Doppler studies in only 3 of the 4 patients with marked SAM. However, late systolic acceleration within the LVOT was recorded in 2 additional patients for whom peak velocities were normal. CONCLUSIONS: In the cases described here, the presence of SAM is likely explained by alterations in left ventricular geometry and function associated with diminished pulmonary venous return together with sympathetic activation resulting from subnormal stroke volume. Although the hemodynamic consequences were apparently minor, the association of SAM with right-sided heart disease might be of interest to those engaged in the practice of veterinary echocardiography. PMID- 17689465 TI - Contrast echocardiography in Boxer dogs with and without aortic stenosis. AB - OBJECTIVES: The aim of this study was to investigate whether contrast echocardiography could enhance the subcostal Doppler signal for aortic flow measurements and achieve myocardial opacification, in Boxer dogs with and without AS. BACKGROUND: In evaluating dogs for aortic stenosis (AS) subcostal Doppler echocardiography was used for measurement of the aortic flow velocity, a measurement that can sometimes be difficult to perform in Boxer dogs. ANIMALS, MATERIALS, AND METHODS: Cardiac auscultation, phonocardiographic and echocardiographic examinations, including a contrast study with Optison, were performed on 29 Boxer dogs selected based on previous examinations. RESULTS: The initial subcostal Doppler signal was weak in 66% of the dogs and a marked improvement was seen in all dogs after contrast injection. The peak aortic flow velocity increased 5% from 2.58+/-1.42 m/s before contrast to 2.71+/-1.54 m/s after contrast (p=0.003). This corresponds to a 2.8 mmHg increase in the pressure gradient from 26.6 mmHg before to 29.4 mmHg after contrast. A dose of 0.05-0.1 mL of Optison administered intravenously resulted in approximately 4 min of Doppler signal enhancement. With the present technique contrast echocardiography did not achieve myocardial opacification. CONCLUSIONS: Single use of the contrast agent Optison can be recommended for enhancement of the subcostal Doppler signal in dogs, in which plain Doppler signals are difficult to obtain. Albeit statistically significant, the mild increase in peak aortic flow velocity after contrast was not considered biologically or clinically significant. PMID- 17689466 TI - The patch clamp technique: principles and technical considerations. AB - The development of techniques that allow the high fidelity measurement of small scale ionic currents ushered in a new era of investigation into the role of ion channels in the physiologic and pathophysiologic function of excitable tissue. Based upon the formation of a high resistance (gigaohm) seal with the membrane of the cell being studied, these "patch clamp" techniques have improved our understanding of a wide variety of cardiac disease states with respect to diagnosis, treatment and prognosis. This review outlines the basic principles underlying the patch clamp technique, including the properties of biological membranes and ion channels, and provides an elementary summary of its application to the recording of cardiac ionic currents, with a particular focus on issues related to myocyte isolation, electrode manufacturing and the voltage clamp configuration. PMID- 17689467 TI - Increased chymase-like activity in a dog with congenital pulmonic stenosis. AB - OBJECTIVES: This study was intended to compare the tissue chymase-like activity and angiotensin converting enzyme (ACE) activity in the right and left ventricles of a dog with congenital pulmonic stenosis (PS), with normal dogs, and to discuss the potential clinical implications of these findings. ANIMALS, MATERIALS AND METHODS: Study subjects included a one-year-old Beagle dog with spontaneous PS and six clinically normal Beagles. Chymase-like and ACE activities were determined in all hearts by high pressure liquid chromatography. RESULTS: In the PS dog right ventricular (RV) chymase-like activity (49.79 nmol/min/g tissue) and left ventricular (LV) chymase-like activity (36.85 nmol/min/g tissue) were elevated vs normal Beagle dogs (mean+/-standard deviation, RV: 20.17+/-5.24 nmol/min/g, LV: 19.03+/-3.27 nmol/min/g). CONCLUSIONS: Activation of the tissue RAA system was detected in a dog with congenital PS. This interesting finding should be pursued with further studies to validate this result, and to explore whether pharmacological blockade of chymase, or the angiotensin II receptor, represents a useful strategy to prevent myocardial remodeling in this condition. PMID- 17689468 TI - Persistent truncus arteriosus in a cat. AB - A 5-month-old male domestic cat presented with a history of rapid, heavy breathing and cyanosis after exercise. Physical examination showed an abnormal respiratory pattern with an increased rate and stress-induced cyanosis. Auscultation revealed tachycardia and a grade 5/6 systolic murmur best heard over the left base. Radiographs showed evidence of right atrial and ventricular enlargement with distended pulmonary vessels and an enlarged ascending aorta. An echocardiographic examination revealed a dilated right atrium, eccentric right ventricular hypertrophy and an overriding aorta associated with a large ventricular septal defect (VSD). The pulmonary trunk could not be identified by echocardiography. Doppler and saline contrast studies showed large right-to-left shunting through the VSD. These findings were compatible with persistent truncus arteriosus, which was confirmed at necropsy. PMID- 17689469 TI - Cranial vena cava aneurysm in a dog. AB - A 1.5-year-old mixed breed dog was presented for evaluation of arrhythmia and a cranial mediastinal density was noted on thoracic radiographs. The density was determined to be a cranial vena cava aneurysm based on ultrasonographic and angiographic testing. No treatment was initiated and the dog remains asymptomatic for the cranial vena cava aneurysm at 6 years of age. Although rare, cranial vena cava aneurysm should be a differential diagnosis for dogs with cranial mediastinal abnormalities on thoracic radiographs. PMID- 17689470 TI - Third degree atrioventricular block and sudden death secondary to acute myocarditis in a dog. AB - Third degree atrioventricular (AV) block in dogs is thought to be most frequently characterized by non-specific fibrotic changes in the AV node. However, it may occur secondary to an undiagnosed inflammatory process. We report a case of third degree AV block in a dog, secondary to acute lymphocytic-plasmacytic myocarditis that resulted in sudden death. This dog had cardiac troponin I levels of 44.65 ng/mL (normal <0.11 ng/mL). The serum cardiac troponin I level was five times higher than any other AV block patient measured in our laboratory, and was also substantially higher than in dogs with chronic valve disease or dilated cardiomyopathy. The severe myocardial necrosis observed at necropsy correlated with the degree of cardiac troponin I elevation. This report suggests that measurement of cardiac troponin I may be an indicated test before pacemaker implantation in dogs with third degree AV block. PMID- 17689471 TI - Double aortic arch with a hypoplastic left arch and patent ductus arteriosus in a dog. PMID- 17689472 TI - Unmasking other pituitary deficits during growth hormone replacement therapy. PMID- 17689473 TI - [Use and abuse of anabolic steroids and glucocorticoids in sport]. PMID- 17689474 TI - L-T4 and L-T3 combined treatment vs L-T4 alone. PMID- 17689475 TI - Expanding use of recombinant hTSH. AB - The clinical benefits of recombinant human thyroid-stimulating hormone (rhTSH; Thyrogen, Genzyme Corp., Cambridge, MA, USA) are well established as an alternative stimulation procedure to thyroid hormone withdrawal in the follow-up of thyroid cancer patients. rhTSH has the advantage to avoid both hypothyroidism, with a major impact on the quality of life, and the side effects on tumor growth related to the long-lasting TSH increase. More recently, alternative uses have been proposed, including treatment of nodular goiter, TSH stimulation to enhance PET scanning and chemotherapy treatment, and differential diagnosis of congenital hypothyroidism. In benign thyroid diseases, rhTSH administration increases thyroid uptake resulting in a more homogeneous distribution of the tracer, and allows to reduce the dose of 131I maintaining the same effects on thyroid shrinkage. Moreover, rTSH stimulation improves the detectability of occult thyroid metastases with FDG-PET, and promising results have been obtained in the response rate of poorly differentiated thyroid cancer submitted to chemotherapy after rhTSH stimulation. Finally, rhTSH testing has been proved to be safe and to lead, in association with ultrasound, to the differential diagnosis of congenital hypothyroidism during L-thyroxine, allowing the appropriate clinical/genetic management of the disease and thus representing a valuable alternative to L thyroxine withdrawal. PMID- 17689476 TI - [rhGH replacement therapy in adults]. PMID- 17689477 TI - Metabolic syndrome: a contemporary fuel excess syndrome and its specific impact in women. PMID- 17689478 TI - DHEA: why, when, and how much--DHEA replacement in adrenal insufficiency. AB - In recent years it has been demonstrated that current replacement therapy with glucocorticoids and mineralocorticoids fails to fully restore health-related quality of life in patients with adrenal insufficiency (AI). Accordingly, replacement of zona reticularis function by DHEA is of considerable interest. Available studies have demonstrated beneficial effects of DHEA on health perception, vitality, fatigue, and (in women) sexuality. DHEA restores low circulating androgens in women into the normal range and increases IGF-1 levels. Side effects are mostly mild and related to androgenic activity of DHEA in women and include increased sebum production, facial acne, and changes in hair status. Replacement consists of a single oral dose of 25-50 mg DHEA in the morning. However, not all investigators have found effects of DHEA on well-being, most likely because of small sample size and short duration of treatment. Thus, to fully explore the role of DHEA in the treatment of AI large trials for 12-24 months are still urgently needed. Until the results of such trials are available DHEA cannot be considered part of standard replacement in AI, but compassionate use of DHEA in individual patients with AI and impaired well-being may be justified. PMID- 17689479 TI - Non thyroidal illness: to treat or not to treat? AB - In critically ill patients, pronounced alterations in the hypothalamic-pituitary thyroid axis occur without any evidence for thyroid disease. T3 decreases and rT3 increases within a few hours of the onset of disease. Severity and duration of disease are related to the magnitude of these changes. This manuscript discusses whether these changes in thyroid hormone levels during critical illness should be treated, and was in part published elsewhere. PMID- 17689480 TI - [Corticotropic axis in septic shock]. PMID- 17689481 TI - Hormonal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. AB - During childhood, the main aims of the medical treatment of congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency, are to prevent salt loss and virilization and to achieve normal stature and normal puberty. As such, there is a narrow therapeutic window through which the intended results can be achieved. In adulthood, the clinical management has received little attention, but recent studies have shown the relevance of long-term follow-up of these patients. Indeed, long-term evaluation of adult CAH patients enables the identification of multiple clinical, hormonal and metabolic abnormalities as bone mineral density alteration, overweight and disturbed reproductive functions. In women with classic CAH, low fertility rate is reported, and is probably the consequence of multiple factors, including neuroendocrine and hormonal factors, feminizing surgery, and psychological factors. Men with CAH may present hypogonadism either through the effect of adrenal rests or from suppression of gonadotropins resulting in infertility. These patients should therefore be carefully followed-up, from childhood through to adulthood, to avoid these complications and to ensure treatment compliance and tight control of the adrenal androgens, by multidisciplinary teams who have knowledge of CAH. PMID- 17689482 TI - Androgen replacement in women. PMID- 17689483 TI - [Diffuse cervical cellulites and descending necrotizing mediastinitis]. AB - OBJECTIVES: To give a report on the progress in physical examination, investigations and treatment of diffuse cervical cellulites (DCC) associated with descending necrotizing mediastinitis. MATERIALS AND METHODS: A Retrospective study (1995-2005) of patients presenting DCC with mediastinitis was made. All had a cervical and thoracic Computed tomography (CT) scan. The references were collected by a Medline search. RESULTS: Six men and 2 women, average ages 53 years were treated. Four had an immunodeficient status. Two had had an anti inflammatory drug treatment without antibiotic treatment. The average for diagnosis and treatment was 4 days. In 2 cases we found a dental origin and in 6 cases a pharyngeal origin. The most frequently identified germs were streptococcus beta haemolytic group A and Prevotella. In 4 cases, no physical sign of mediastinitis was noted. The diagnosis of mediastinitis was made thanks to the thoracic CT scan. All the patients were treated by broad-spectrum antibiotic therapy. All had cervical and thoracic surgical drainage. Mediastinal drainage was made by cervical way in 3 cases and by thoracotomy in 5 cases. One patient died. CONCLUSIONS: The DCC with mediastinum extension are serious infectious emergencies with a high mortality rate. Clinical diagnosis of mediastinitis is difficult. A thoracic CT scan should be performed systematically. Performing thoracotomy best controls mediastinal drainage. PMID- 17689484 TI - Mechanism of the antioxidant to pro-oxidant switch in the behavior of dehydroascorbate during LDL oxidation by copper(II) ions. AB - Oxidised low density lipoprotein (LDL) may be involved in the pathogenesis of atherosclerosis. We have therefore investigated the mechanisms underlying the antioxidant/pro-oxidant behavior of dehydroascorbate, the oxidation product of ascorbic acid, toward LDL incubated with Cu(2+) ions. By monitoring lipid peroxidation through the formation of conjugated dienes and lipid hydroperoxides, we show that the pro-oxidant activity of dehydroascorbate is critically dependent on the presence of lipid hydroperoxides, which accumulate during the early stages of oxidation. Using electron paramagnetic resonance spectroscopy, we show that dehydroascorbate amplifies the generation of alkoxyl radicals during the interaction of copper ions with the model alkyl hydroperoxide, tert butylhydroperoxide. Under continuous-flow conditions, a prominent doublet signal was detected, which we attribute to both the erythroascorbate and ascorbate free radicals. On this basis, we propose that the pro-oxidant activity of dehydroascorbate toward LDL is due to its known spontaneous interconversion to erythroascorbate and ascorbate, which reduce Cu(2+) to Cu(+) and thereby promote the decomposition of lipid hydroperoxides. Various mechanisms, including copper chelation and Cu(+) oxidation, are suggested to underlie the antioxidant behavior of dehydroascorbate in LDL that is essentially free of lipid hydroperoxides. PMID- 17689485 TI - Characterization of cynomolgus monkey cytochrome P450 (CYP) cDNAs: is CYP2C76 the only monkey-specific CYP gene responsible for species differences in drug metabolism? AB - Cynomolgus monkey CYP2C76 does not have a corresponding ortholog in humans, and it is at least partly responsible for differences in drug metabolism between monkeys and humans. To determine if CYP2C76 is the only monkey-specific CYP gene, we identified cynomolgus monkey cDNAs for CYP2A23, CYP2A24, CYP2E1, CYP2J2, CYP3A5, CYP3A8, CYP4A11, CYP4F3, CYP4F11, CYP4F12, and CYP4F45. These CYP cDNAs showed a high sequence identity (93-96%) to the homologous human CYP cDNAs. The monkey CYPs were preferentially expressed in liver among the analyzed tissues. Moreover, all five analyzed monkey CYPs (CYP2A23, CYP2A24, CYP2E1, CYP3A5, and CYP3A8) metabolized typical substrates for human CYPs in the corresponding subfamilies. These results suggest that these 11 monkey CYP cDNAs are closely related to the human CYP cDNAs and thus, unlike CYP2C76, are not apparent monkey specific cDNAs. PMID- 17689486 TI - Cloning and functional characterization of a novel mitochondrial N-ethylmaleimide sensitive glycerol-3-phosphate acyltransferase (GPAT2). AB - Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the initial and rate limiting step in glycerolipid synthesis. Several mammalian GPAT activities have been recognized, including N-ethylmaleimide (NEM)-sensitive isoforms in microsomes and mitochondria and an NEM-resistant form in mitochondrial outer membrane (GPAT1). We have now cloned a second mitochondrial isoform, GPAT2 from mouse testis. The open-reading frame encodes a protein of 798 amino acids with a calculated mass of 88.8kDa and 27% amino acid identity to GPAT1. Testis mRNA expression was 50-fold higher than in liver or brown adipose tissue, but the specific activity of NEM-sensitive GPAT in testis mitochondria was similar to that in liver. When Cos-7 cells were transiently transfected with GPAT2, NEM sensitive GPAT activity increased 30%. Confocal microscopy confirmed a mitochondrial location. Incubation of GPAT2-transfected Cos-7 cells with trace (3 microM; 0.25 microCi) [1-(14)C]oleate for 6h increased incorporation of [(14)C]oleate into TAG 84%. In contrast, incorporation into phospholipid species was lower than in control cells. Although a polyclonal antibody raised against full-length GPAT1 detected an approximately 89-kDa band in liver and testis from GPAT1 null mice and both 89- and 80-kDa bands in BAT from the knockout animals, the GPAT2 protein expressed in Cos-7 cells was only 80 kDa. In vitro translation showed a single product of 89 kDa. Unlike GPAT1, GPAT2 mRNA abundance in liver was not altered by fasting or refeeding. GPAT2 is likely to have a specialized function in testis. PMID- 17689487 TI - Mechanism and energetics of proton translocation by the respiratory heme-copper oxidases. AB - Recent time-resolved optical and electrometric experiments have provided a sequence of events for the proton-translocating mechanism of cytochrome c oxidase. These data also set limits for the mechanistic, kinetic, and thermodynamic parameters of the proton pump, which are analysed here in some detail. The analysis yields limit values for the pK of the "pump site", its modulation during the proton-pumping process, and suggests its identity in the structure. Special emphasis is made on side-reactions that may short-circuit the pump, and the means by which these may be avoided. We will also discuss the most prominent proton pumping mechanisms proposed to date in relation to these data. PMID- 17689488 TI - A Sveinsson's chorioretinal atrophy-associated missense mutation in mouse Tead1 affects its interaction with the co-factors YAP and TAZ. AB - Sveinsson's chorioretinal atrophy (SCRA) is an autosomal dominant eye disease characterized by bilateral chorioretinal degeneration. A missense mutation in the gene encoding the transcription factor TEAD1/TEF-1 (Y421H) is genetically linked to SCRA, but the mechanisms of pathology remain unclear. To study the molecular mechanisms underlying SCRA, a missense mutation corresponding to Y421H in human TEAD1 was introduced into mouse Tead1 (Y410H), and a functional analysis of the mutant protein was performed in RPE-J cells. The missense mutation reduced the ability of Tead1 to interact with the co-factors YAP and TAZ, but not with the co factors Vgl-1, -2, and -3, in a mammalian two-hybrid assay. A GST pull-down assay showed that the direct interaction between Tead1 and YAP or TAZ was lost owing to the mutation. Amino acid substitutions at position 410 of Tead1 revealed the essentiality of this tyrosine residue to the interaction. The Y410H mutation also abolished the transcriptional activity of Tead1 under the co-expression of YAP or TAZ. These results suggest that SCRA pathogenesis may be due to a loss-of function of TEAD1 affecting the regulation of its target genes. PMID- 17689489 TI - Functional role of stromal interaction molecule 1 (STIM1) in vascular smooth muscle cells. AB - We investigated the functional role of STIM1, a Ca(2+) sensor in the endoplasmic reticulum (ER) that regulates store-operated Ca(2+) entry (SOCE), in vascular smooth muscle cells (VSMCs). STIM1 was mainly localized at the ER and plasma membrane. The knockdown of STIM1 expression by small interfering (si) RNA drastically decreased SOCE. In contrast, an EF-hand mutant of STIM1, STIM1(E87A), produced a marked increase in SOCE, which was abolished by co-transfection with siRNA to transient receptor potential canonical 1 (TRPC1). In addition, transfection with siRNA against STIM1 suppressed phosphorylation of cAMP responsive element binding protein (CREB) and cell growth. These results suggest that STIM1 is an essential component of SOCE and that it is involved in VSMC proliferation. PMID- 17689490 TI - Binase induces apoptosis of transformed myeloid cells and does not induce T-cell immune response. AB - Microbial RNases along with such animal RNases as onconase and BS-RNase are a promising basis for developing new antitumor drugs. We have shown that the Bacillus intermedius RNase (binase) induces selective apoptosis of transformed myeloid cells. It attacks artificially expressing activated c-Kit myeloid progenitor FDC cells and chronic myelogenous leukemia cells K562. Binase did not induce apoptosis in leukocytes of healthy donors and in normal myeloid progenitor cells. The inability of binase to initiate expression of activation markers CD69 and IFN-gamma in CD4+ and CD8+ T-lymphocytes testifies that enzyme is devoid of superantigenic properties. Altogether, these results demonstrate that binase possesses therapeutic opportunities for treatment of genotyped human neoplasms expressing activated kit. PMID- 17689491 TI - Suppression of gross chromosomal rearrangements by a new alternative replication factor C complex. AB - Defects in DNA replication fidelity lead to genomic instability. Gross chromosomal rearrangement (GCR), a type of genomic instability, is highly enhanced by various initial mutations affecting DNA replication. Frequent observations of GCRs in many cancers strongly argue the importance of maintaining high fidelity of DNA replication to suppress carcinogenesis. Recent genome wide screens in Saccharomyces cerevisiae identified a new GCR suppressor gene, ELG1, enhanced level of genome instability gene 1. Its physical interaction with proliferating cell nuclear antigen (PCNA) and complex formation with Rfc2-5p proteins suggest that Elg1 functions to load/unload PCNA onto DNA during a certain DNA metabolism. High level of DNA damage accumulation and enhanced phenotypes with mutations in genes involved in cell cycle checkpoints, homologous recombination (HR), or chromatin assembly in the elg1 strain suggest that Elg1p Rfc2-5p functions in a fundamental DNA metabolism to suppress genomic instability. PMID- 17689492 TI - Treadmill exercise enhances ABCA1 expression in rat liver. AB - ATP-binding cassette transporters (ABCs) belong to a large family and include 49 mammalian transmembrane transporters that transfer a variety of substrates across the lipid bilayers in an energy-dependent manner. ABCA1 is a member of this family which plays a crucial role in plasma HDL-C remodeling. The purpose of this study was to investigate liver ABCA1 expression and plasma HDL level in response to treadmill running program in rats. Ten adult Wistar male rats (12-14weeks old, 200-220g) were used for this study. Animals were divided into control (Con, n=5) and Training (TR, n=5) groups. Training group was given exercise on a motor driven treadmill at 25m/min (0% grade) for 90min/day, 5 days/week for 6 weeks. Rats were sacrificed 24h after the last session of exercise portion of the liver was excised, immediately washed in ice-cold saline, and frozen in liquid nitrogen for extraction of ABCA1 mRNA. Plasma was collected for HDL-C, LDL, TC, TG, and VLDL-C measurements. Liver ABCA1 mRNA expression was significantly (P<0.001) higher in trained rats compared to control rats. Plasma HDL-C, LCAT, pre-beta-HDL concentrations were significantly higher (P<0.01, P<0.001, P<0.028, respectively) in trained rats at the end of treadmill exercise. However, plasma lipids, other lipoproteins and TC/HDL and LDL/HDL ratio were unchanged. In conclusion, a treadmill running-induced elevated plasma HDL-C concentration was accompanied with a higher liver ABCA1 mRNA expression and increased in LCAT and pre-beta-HDL levels. PMID- 17689493 TI - Isw2 regulates gene silencing at the ribosomal DNA locus in Saccharomyces cerevisiae. AB - Three heterochromatin-like domains have been identified in Saccharomyces cerevisiae that are refractory to transcription by Pol II, the silent mating-type loci, telomeres and the ribosomal DNA. Previous work has shown that chromatin remodelers can regulate silent chromatin. Here, we report the findings of an investigation into the role of ISW2 in transcriptional silencing at the rDNA. We show that the levels of retrotransposition and mRNA from a genetically marked Ty1 element located in the rDNA were increased significantly in isw2Delta cells, while transcript levels from Ty1 elements outside of the rDNA were not increased in cells lacking ISW2. Additionally, we show that Isw2 is not required for silencing at a telomere. Our findings demonstrate that Isw2 is required for transcriptional silencing at the rDNA and emphasize the differences in the regulation of transcriptional silencing at silent loci in S. cerevisiae. PMID- 17689494 TI - Novel anisotropic engineered cardiac tissues: studies of electrical propagation. AB - The goal of this study was to engineer cardiac tissue constructs with uniformly anisotropic architecture, and to evaluate their electrical function using multi site optical mapping of cell membrane potentials. Anisotropic polymer scaffolds made by leaching of aligned sucrose templates were seeded with neonatal rat cardiac cells and cultured in rotating bioreactors for 6-14 days. Cells aligned and interconnected inside the scaffolds and when stimulated by a point electrode, supported macroscopically continuous, anisotropic impulse propagation. By culture day 14, the ratio of conduction velocities along vs. across cardiac fibers reached a value of 2, similar to that in native neonatal ventricles, while action potential duration and maximum capture rate, respectively, decreased to 120ms and increased to approximately 5Hz. The shorter culture time and larger scaffold thickness were associated with increased incidence of sustained reentrant arrhythmias. In summary, this study is the first successful attempt to engineer a cm(2)-size, functional anisotropic cardiac tissue patch. PMID- 17689495 TI - Heparanase induces Akt phosphorylation via a lipid raft receptor. AB - The endoglycosidase heparanase is the predominant enzyme that degrades heparan sulfate side chains of heparan sulfate proteoglycans, activity that is strongly implicated in tumor metastasis. Apart of its well characterized enzymatic activity, heparanase was noted to exert also enzymatic-independent functions. Among these is the induction of Akt/PKB phosphorylation noted in endothelial- and tumor-derived cells. Protein domains of heparanase required for signaling were not identified to date, nor were identified heparanase binding proteins/receptors capable of transmitting heparanase signals. Here, we examined the possible function of mannose 6-phosphate receptor (MPR) and low-density lipoprotein receptor related protein (LRP), recently implicated in cellular uptake of heparanase, as heparanase receptors mediating Akt phosphorylation. We found that heparanase addition to MPR- and LRP-deficient fibroblasts elicited Akt activation indistinguishable from control fibroblasts. In contrast, disruption of lipid rafts abrogated Akt/PKB phosphorylation following heparanase addition. These results suggest that lipid raft-resident receptor mediates heparanase signaling. PMID- 17689496 TI - CAPE (caffeic acid phenethyl ester) stimulates glucose uptake through AMPK (AMP activated protein kinase) activation in skeletal muscle cells. AB - Caffeic acid phenethyl ester (CAPE), a flavonoid-like compound, is one of the major components of honeybee propolis. In the present study, we investigated the metabolic effects of CAPE in skeletal muscle cells and found that CAPE stimulated glucose uptake in differentiated L6 rat myoblast cells and also activated AMPK (AMP-activated protein kinase). In addition, the inhibition of AMPK blocked CAPE induced glucose uptake, and CAPE activated the Akt pathway in a PI3K (phosphoinositide 3-kinase)-dependent manner. Furthermore, CAPE enhanced both insulin-mediated Akt activation and glucose uptake. In summary, our results suggest that CAPE may have beneficial roles in glucose metabolism via stimulation of the AMPK pathway. PMID- 17689497 TI - Regulation of synaptic transmission and plasticity by neuronal nicotinic acetylcholine receptors. AB - Nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout the central nervous system and participate in a variety of physiological functions. Recent advances have revealed roles of nAChRs in the regulation of synaptic transmission and synaptic plasticity, particularly in the hippocampus and midbrain dopamine centers. In general, activation of nAChRs causes membrane depolarization and directly and indirectly increases the intracellular calcium concentration. Thus, when nAChRs are expressed on presynaptic membranes their activation generally increases the probability of neurotransmitter release. When expressed on postsynaptic membranes, nAChR-initiated calcium signals and depolarization activate intracellular signaling mechanisms and gene transcription. Together, the presynaptic and postsynaptic effects of nAChRs generate and facilitate the induction of long-term changes in synaptic transmission. The direction of hippocampal nAChR-mediated synaptic plasticity - either potentiation or depression - depends on the timing of nAChR activation relative to coincident presynaptic and postsynaptic electrical activity, and also depends on the location of cholinergic stimulation within the local network. Therapeutic activation of nAChRs may prove efficacious in the treatment of neuropathologies where synaptic transmission is compromised, as in Alzheimer's or Parkinson's disease. PMID- 17689499 TI - Upregulation of sodium-dependent vitamin C transporter 2 expression in adrenals increases norepinephrine production and aggravates hyperlipidemia in mice with streptozotocin-induced diabetes. AB - The hyperglycemia and hyperoxidation that characterize diabetes lead to reduced vitamin C (L-ascorbic acid, AA) levels in diabetic humans and animals. We examined the possibility that diabetes-induced low plasma AA levels impair AA distribution to various tissues and that these changes are closely related to the development of diabetic complications. AA levels were markedly decreased in the plasma and increased in the adrenals of mice with streptozotocin (STZ)-induced diabetes. Consistently with these results, in [1-(14)C]AA accumulation assays, the efficiency of [1-(14)C]AA accumulation was significantly higher in the adrenals (which had the greatest ability to accumulate [1-(14)C]AA) of diabetic mice than in those of controls. Expression of sodium-dependent vitamin C transporter (SVCT)-2, a transporter of AA, was upregulated in diabetic adrenals. Furthermore, increased AA incorporation into the diabetic adrenals by SVCT-2 led to increased plasma norepinephrine, triglyceride and free fatty acid levels in mice with STZ-induced diabetes. Therefore, oversupplementation with AA could be deleterious in diabetic patients, because overexpression of adrenal SVCT-2 in diabetes could lead to excessive AA uptake, thus enhancing norepinephrine production and exacerbating some diabetic complications. Interestingly, however, treatment with AA dose-dependently abolished the increased expression of adrenal SVCT-2 and normalized the abovementioned plasma parameters in diabetic mice. These results suggest SVCT-2-mediated increases in AA uptake by the adrenals followed by excessive production of plasma norepinephrine may play a pivotal role in the development of diabetic complications. PMID- 17689498 TI - Neuronal nicotinic receptor agonists for the treatment of attention deficit/hyperactivity disorder: focus on cognition. AB - Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioral disorder in children and adolescents, and in about half of these patients, significant symptomology continues into adulthood. Although impulsivity and hyperactivity are the most salient features of ADHD, cognitive deficits, particularly impairments in attention and executive function, are an important component, particularly in adolescents and adults, with over 90% of adults seeking treatment for ADHD manifesting cognitive dysfunction. Currently available medications treat the core ADHD symptoms but typically do not adequately address cognitive aspects of ADHD, underscoring the need for new therapeutics. Dopamine and norepinephrine are hypothesized to be particularly important in ADHD, but there is emerging evidence that cholinergic neurotransmission, particularly involving neuronal nicotinic acetylcholine receptors (nAChRs), may play a role in the pathophysiology of ADHD. Nicotine has demonstrated procognitive effects in both humans and experimental animals and has produced signals of efficacy in small proof-of-concept adult ADHD trials. Although adverse effects associated with nicotine preclude its development as a therapeutic, a number of novel nAChR agonists with improved safety/tolerability profiles have been discovered. Of these, ABT-418 and ABT-089 have both demonstrated signals of efficacy in adults with ADHD. Notably, tolerability issues that might be expected of a nAChR agonist, such as nausea and emesis, were not observed at efficacious doses of ABT 089. Further understanding of the effects of novel neuronal nAChR agonists on specific aspects of cognitive functioning in ADHD is required to assess the full potential of this approach. PMID- 17689500 TI - Is gray matter volume an intermediate phenotype for schizophrenia? A voxel-based morphometry study of patients with schizophrenia and their healthy siblings. AB - BACKGROUND: Shared neuropathological characteristics of patients with schizophrenia and their siblings might represent intermediate phenotypes that could be used to investigate genetic susceptibility to the illness. We sought to discover previously unidentified gray matter volume differences in patients with schizophrenia and their siblings with optimized voxel-based morphometry. METHODS: We studied 169 patients with schizophrenia, 213 of their unaffected siblings, and 212 healthy volunteers from the Clinical Brain Disorders Branch/National Institute of Mental Health Genetic Study of Schizophrenia with magnetic resonance imaging. RESULTS: Patients with schizophrenia had significant regional gray matter decreases in the frontal, temporal, and parietal cortices compared with healthy volunteers. Their unaffected siblings tended to share gray matter decreases in the medial frontal, superior temporal, and insular cortices, but these decreases were not significant after correction for multiple comparisons, even when we looked at a subgroup of siblings with a past history of mood disorder. As an exploratory analysis, we estimated heritability with regions of interest from the VBM analysis as well as from the hippocampus. Hippocampal volume was significantly correlated within sibling-pairs. CONCLUSIONS: Our findings confirm and extend previous voxel-based morphometry analyses in ill subjects with schizophrenia. Furthermore, these data argue that although siblings might share some regional gray matter decreases with their affected siblings, the pattern of regional differences might be a weak intermediate phenotype for schizophrenia. PMID- 17689501 TI - Increased autophagy in transgenic mice with a G93A mutant SOD1 gene. AB - Autophagy, like the ubiquitin-proteasome system, is considered to play an important role in preventing the accumulation of abnormal proteins. Rat microtubule-associated protein 1 light chain 3 (LC3) is important for autophagy, and the conversion from LC3-I into LC3-II is accepted as a simple method for monitoring autophagy. We examined a SOD1G93A transgenic mouse model for amyotrophic lateral sclerosis (ALS) to consider a possible relationship between autophagy and ALS. In our study we analyzed LC3 and mammalian target of rapamycin (mTOR), a suppressor of autophagy, by immunoassays. The level of LC3-II, which is known to be correlated with the extent of autophagosome formation, was increased in SOD1G93A transgenic mice at symptomatic stage compared with non-transgenic or human wild-type SOD1 transgenic animals. Moreover, the ratio of phosphorylated mTOR/Ser2448 immunopositive motor neurons to total motor neurons was decreased in SOD1G93A-Tg mice. The present data show the possibility of increased autophagy in an animal model for ALS. And autophagy may be partially regulated by an mTOR signaling pathway in these animals. PMID- 17689502 TI - Changes in the alpha and beta amplitudes of the central EEG during the onset, continuation, and offset of long-duration repetitive hand movements. AB - Electroencephalographic alpha and beta activities recorded from central electrodes are known to display movement-related suppression or enhancement. We investigated whether the suppression that is known to occur during the onset of a single movement would persist or otherwise habituate when the movement is continuously repeated for a long period of time. Fourteen subjects took part in the experiments. They performed repetitive simultaneous extension-flexions of the fingers II-V in one hand, continuously for a period of at least 30 s. They then stopped this self-paced movement and rested for at least 30 s. Bipolar recording was made from C3-Cz and C4-Cz. Patterns of amplitude changes in the alpha and beta bands were calculated against a resting baseline. Following a bilateral alpha and beta suppression at the movement onset, alpha amplitude gradually but not fully recovered towards the baseline during the 30 s post-onset. Habituation of afferences and transfer of the cortical function were discussed as the two alternative explanations for this gradual recovery. Beta amplitude, however, displayed no recovery as long as the movement continued. Considering the relatively rapid beta recovery reported for sustained movements, this finding demonstrated that the sustained and continuous movements are conducted through quite different processes. A transient contralateral beta rebound was observed only after the end of the long movement period, strengthening the viewpoint that links the beta rebound with the closure of the cortical processes running throughout a motor sequence. Modulation of the beta amplitude, rather than the changes in alpha amplitude, appeared to be more closely correlated with the execution of a continuous movement. PMID- 17689503 TI - Promoter analysis of human glutamate carboxypeptidase II. AB - The expression of glutamate carboxypeptidase II (GCP II) is reduced in selective brain regions in schizophrenic patients. To investigate transcriptional mechanisms regulating the human GCP II gene, a 3460 bp DNA fragment comprised of the proximal 3228 bp of 5' untranscribed sequence and first 232 bp of 5' UTR portion of this gene was cloned into the mammalian luciferase reporter gene vector pGL3-Basic. Transfection assays in human astrocyte-derived SVG and human prostate tumor-derived LNCaP cells demonstrated that constructs with 3460, 1590 and 761 bp portions of 5' region of human GCP II gene were able to drive the luciferase reporter gene. Additional deletion constructs showed that in the SVG cell line, constructs with 511 and 411 bp of GCP II gene fragments yielded highest transcriptional activity, with declining activity upon further removal of 5' sequences. 15 bp of the promoter 5' to a 225 bp GCP II fragment were essential for luciferase expression. Thus, in the SVG cells, the proximal 240 bp of the human GCP II promoter (232 bp of the 5' UTR and 8 bp of 5' untranscribed sequences) may represent the core promoter. Further, while a LyF-1 site lies within and overlaps a transcription start site in the 15 bp sequence, site directed mutagenesis shows that LyF-1 is not the transcription initiator for the "TATA and CAAT" box lacking GCP II gene in the SVG cells. Finally, pattern differences in GCP II gene promoter expression in SVG and LNCaP cells suggest that sequences beyond 240 bp may be important for tissue-specific GCP II expression. PMID- 17689504 TI - Impact of individual cognitive profile on visuo-motor reorganization in relapsing remitting multiple sclerosis. AB - BACKGROUND: In multiple sclerosis (MS), relationships between disease-related MRI changes, cognitive function and brain responses are complex and still unclear. This study addresses the relative effects of cognitive impairment and brain atrophy on the cortical reorganization associated with a visuo-motor task. METHODS: Multivariate analysis was applied to compare functional MRI brain responses of 28 relapsing-remitting (RR) MS patients (16 cognitively preserved and 12 cognitively impaired) to that of 35 matched healthy controls during the execution of visuo-motor integration task. Regression analysis was performed to test for linear effects of structural variables (grey matter (GM) and white matter (WM) volumes) and cognitive profiles--and their combined effect--on the same response. RESULTS: Compared to preserved MS patients or normal controls, cognitively impaired MS patients showed significant decreases of brain parenchymal and GM volumes, but only a trend for lower WM volume. Multivariate analysis showed that cognitive profile, GM and WM atrophy independently contributed to the activation of parieto-premotor cortices. Baseline cognition predicted the greatest response of the entire network, whereas WM and GM losses predicted selective responses of parietal and premotor regions. CONCLUSIONS: Visuo-motor function in MS is associated with altered patterns of brain activation that vary as a function of cognitive decline. This is confirmed by a larger effect size of the individual cognitive profile compared to the structural damage. Both effects contribute in an additive way to cortical reorganization, which is primarily driven by such a cognitive gradient in RR-MS patients. PMID- 17689505 TI - Preceding weak noise sharpens the frequency tuning and elevates the response threshold of the mouse inferior collicular neurons through GABAergic inhibition. AB - In acoustic communication, animals must extract biologically relevant signals that are embedded in noisy environment. The present study examines how weak noise may affect the auditory sensitivity of neurons in the central nucleus of the mouse inferior colliculus (IC) which receives convergent excitatory and inhibitory inputs from both lower and higher auditory centers. Specifically, we studied the frequency sensitivity and minimum threshold of IC neurons using a pure tone probe and a weak white noise masker under forward masking paradigm. For most IC neurons, probe-elicited response was decreased by a weak white noise that was presented at a specific gap (i.e. time window). When presented within this time window, weak noise masking sharpened the frequency tuning curve and increased the minimum threshold of IC neurons. The degree of weak noise masking of these two measurements increased with noise duration. Sharpening of the frequency tuning curve and increasing of the minimum threshold of IC neurons during weak noise masking were mostly mediated through GABAergic inhibition. In addition, sharpening of frequency tuning curve by the weak noise masker was more effective at the high than at low frequency limb. These data indicate that in the real world the ambient noise may improve frequency sensitivity of IC neurons through GABAergic inhibition while inevitably decrease the frequency response range and sensitivity of IC neurons. PMID- 17689507 TI - A water-soluble glucan isolated from an edible mushroom Termitomyces microcarpus. AB - A water-soluble glucan was isolated from an edible mushroom, Termitomyces microcarpus. On the basis of total acid hydrolysis, methylation analysis, periodate oxidation and NMR studies ((1)H, (13)C, TOCSY, DQF-COSY, NOESY and HSQC), the repeating unit of the polysaccharide is established as -->4)-alpha- Glcp-(1-->3)-beta--Glcp-(1--> PMID- 17689506 TI - Daily cocaine self-administration under long-access conditions augments restraint induced increases in plasma corticosterone and impairs glucocorticoid receptor mediated negative feedback in rats. AB - Cocaine addiction appears to be associated with a drug-induced dysregulation of stressor responsiveness that may contribute to further cocaine use. The present study examined alterations in stressor-induced activation of the hypothalamic pituitary-adrenal (HPA) axis in rats provided daily access to cocaine for self administration (SA) under long-access conditions (1.0 mg/kg/infusion; 6 hx14 days). Cocaine self-administering rats displayed reduced basal plasma corticosterone (CORT) levels but showed an augmented restraint-induced percent increase response from baseline compared to saline self-administering controls when measured 24 days after SA testing. This augmented CORT response may have been attributable to impaired glucocorticoid receptor (GR)-mediated feedback regulation of HPA function, since cocaine self-administering rats were also less susceptible to dexamethasone (0.01 mg/kg, i.p.) suppression of plasma CORT levels. GR protein expression measured using Western blot analysis was significantly reduced in the dorsomedial hypothalamus (including the paraventricular nucleus [PVN]) but not in the pituitary gland, ventromedial hypothalamus, dorsal hippocampus, ventral subiculum, medial prefrontal cortex or amygdala in cocaine self-administering rats. Surprisingly, basal corticotropin releasing hormone (CRH) mRNA or post-restraint increases in CRH mRNA measured at a single (90 min) time-point in the PVN using in situ hybridization did not differ between groups. The findings suggest that cocaine use produces persistent changes in individual responsiveness to stressors that may contribute to the addiction process. PMID- 17689508 TI - Synthesis of glycosyl-triazole linked 1,2,4-oxadiazoles. AB - The synthesis of four different types of oxadiazoles containing a terminal acetylenic group is described. Reaction of these oxadiazoles with various azidoglycosides via a copper-catalyzed [3+2] cycloaddition ('click chemistry') afforded the corresponding glycosyl-triazole linked 1,2,4-oxadiazoles in good yields. PMID- 17689509 TI - Effects of tetrahydrobiopterin on coronary vascular reactivity in atherosclerotic human coronary arteries. AB - OBJECTIVES: Reduced nitric oxide (NO) bioavailability is a key mechanism in the development of endothelial dysfunction. The NO synthase cofactor, tetrahydrobiopterin (BH4), increases NO availability, yet its effect in the human coronary circulation, particularly following PCI, remains uncertain. This study was designed to evaluate the effects of intracoronary BH4 in human coronary arteries with non-critical coronary artery disease or following percutaneous coronary intervention (PCI). METHODS: The study group consisted of 57 stable patients, 10 of which were controls. Active drug was administered in 47 patients, with either de novo non-critical coronary disease (non-stent group; n=25) or following PCI (stent group; n=22). Coronary blood flow (CBF) was measured (0.014 inch Doppler flow wire) in each of these groups in response to sequential intracoronary infusions of acetylcholine (Ach, 10(-7) & 10(-6) M), BH4 (250 microg/min & 500 microg/min) and a co-infusion of BH4 (500 microg/min) and Ach (10(-7) & 10(-6) M). The primary endpoint evaluated the % change in CBF to Ach compared to co-infusion of Ach and BH4. RESULTS: Mean age was 60+/-10 years (M 45:F 12). Regarding the primary hypothesis, no difference was observed between Ach response compared to co-infusion of BH4 and Ach in the % change in CBF in either the non-stent group (Ach 97+/-122%, Ach/BH4 87+/-95%) or the stent group (Ach 77+/-105%, Ach/BH4 55+/-97%). CONCLUSIONS: In native non-critical coronary artery disease or following PCI, coronary microvascular endothelial function is not improved by co-administration of Ach and BH4. PMID- 17689510 TI - Adventitial fibroblast reactive oxygen species as autacrine and paracrine mediators of remodeling: bellwether for vascular disease? AB - The importance of the vascular adventitia is increasingly being recognized not only in vascular disease but also in normal maintenance and homeostasis of vessels. Activation of the adventitia and its resident fibrocytic cells in response to injury, stretch, cytokines, and hormones has been shown to stimulate differentiation, collagen deposition, migration, and proliferation. Importantly, the effects of adventitial fibroblasts are increasingly being ascribed to reactive oxygen species (ROS) produced by adventitial fibroblast NAD(P)H oxidases. Much historical and recent evidence suggests that fibroblast NAD(P)H oxidase) is a harbinger and initiator of vascular disease and remodeling. Data from our laboratory indicate that adventitial fibroblast NAD(P)H oxidase plays a direct and/or paracrine role in neointimal hyperplasia as well as a paracrine role in medial smooth muscle hypertrophy in vivo. We propose that adventitial NAD(P)H oxidase-derived cell-permeant hydrogen peroxide or a byproduct of its oxidation of lipids activates signaling mechanisms in medial smooth muscle leading to the growth response. This review will address the potential role of this adventitial ROS in vascular inflammation and cytokine release to potentiate smooth muscle hypertrophy. We will also survey other signaling pathways involving adventitial NAD(P)H oxidase ultimately leading to changes in vascular phenotype. PMID- 17689511 TI - Reference values for plasma concentrations of asymmetrical dimethylarginine (ADMA) and other arginine metabolites in men after validation of a chromatographic method. AB - BACKGROUND: Owing to the growing number of reports in the literature on ADMA as a possibly useful marker of endothelial health, its use in the clinical laboratory is of increasing interest. Age dependency and the small, but statistically significant differences between healthy subjects and disease groups are difficult to interpret. Additionally, levels of ADMA in comparable patient groups of different studies vary widely, even when similar methods have been used. METHODS: After analytical evaluation of a chromatographic method according to international guidelines, we analysed asymmetrical (ADMA) and symmetrical dimethyl arginine (SDMA), homo-arginine and arginine in EDTA plasma of 292 healthy males aged 20 to 75 years (y) who had passed strict inclusion/exclusion criteria. For statistical analysis, 4 age groups were formed. Group differences were identified with the non-parametric Kruskal-Wallis test. RESULTS: Calibration curves were linear throughout the selected ranges; the standard deviation for the regression line, recovery, imprecision, and accuracy results were all highly satisfactory. The reference ranges of ADMA for the 4 age groups are presented as age (mean+/-SD of age group, y); number of subjects; median, 2.5th-97.5th percentile: group <35 y: 26.7+/-4.0 y; n=78; 0.58, 0.43-0.69 micromol/L; group 35 49 y: 41.6+/-4.0 y; n=93; 0.59, 0.45-0.73 micromol/L; group 50-65 y: 57.5+/-4.2 y; n=82; 0.61, 0.46-0.78 micromol/L; and group >65 y: 69.6+/-3.3 y; n=39; 0.64, 0.54-0.79 micromol/L. CONCLUSIONS: Only highly precise methods are able to detect small differences between groups. The application of an evaluated method to a well defined group of healthy subjects should provide a basis for comparison of ADMA concentrations in different patient populations of future studies. PMID- 17689512 TI - Advances in nucleic acid-based diagnostics of bacterial infections. AB - Methods for rapid detection of infectious bacteria and antimicrobial-resistant pathogens have evolved significantly over the last decade. Many of the new procedures are nucleic acid-based and replace conventional diagnostic methods like culturing which is time consuming especially with fastidious and slow growing microorganisms. The widespread use of antibiotics has resulted in an increased number of cases with resistant microorganisms such as methicillin resistant Staphylococcus aureus, vancomycin resistant enterococci, and multidrug resistant Mycobacterium tuberculosis. Rapid detection of these pathogens is important to isolate patients and prevent further spreading of the diseases. Newly developed diagnostic procedures are superior with respect to turnaround time, sensitivity and specificity. Methods like multiplex real time PCR and different array-based technologies offer the possibility of multiparameter assays where several pathogens and antibiotic resistance genes can be detected simultaneously. PMID- 17689513 TI - Measurement of coenzyme Q10 in clinical practice. PMID- 17689514 TI - Electrolytes and pH changes in pre-eclamptic rats. AB - BACKGROUND: Intracellular free calcium [Ca2+]i and magnesium [Mg2+]i ions play major roles in the mechanism of vascular smooth muscle (VSM) contraction. Although essential hypertension and abnormal intracellular homeostasis of these ions have long been recognized as major icons in the pathogenesis of pre eclampsia, the underlying mechanism(s) remain poorly understood. METHODS: Alterations of vascular smooth muscle and platelet intracellular cations [Ca2+]i, [Mg2+]i and [H+]i relative to plasma concentrations of these ions in nitric oxide synthase (NOS) blockade-induced models of pre-eclampsia have been evaluated in the present study. RESULTS: Pregnant rats injected with the NOS inhibitor, NG nitro-L-arginine methyl ester (L-NAME) developed a significantly elevated arterial blood pressure, proteinuria and other clinical parameters characteristic of pre-eclampsia compared to age-matched pregnant and non-pregnant rat controls that received the L-NAME vehicle only. Plasma total calcium concentration was significantly lower in pre-eclamptic rat models compared to normal pregnant rats (10.29+/-0.08 vs 10.67+/-0.18 mg/dl, p<0.05). A significant increase in plasma calcium was observed in pregnant controls compared to non-pregnant rats (10.67+/ 0.18 vs 10.14+/-0.09 mg/dl, p<0.01). Plasma Ca2+ levels in pre-eclamptic rats were consistently lower than those of pregnant controls (5.69+/-0.09 vs 5.98+/ 0.06 mg/dl, p<0.05). Resting levels of [Ca2+]i was significantly higher in pre eclamptic rats than in pregnant controls. (351+/-45.2 vs 196+/-23.2 nmol/l, p<0.01). Blood pH was significantly increased in pre-eclamptic rats as compared to pregnant controls (7.16+/-0.02 vs 7.05+/-0.03, p<0.05). There was no significant difference in plasma and intracellular magnesium concentrations between the three rat groups. CONCLUSIONS: These findings suggest that a significantly decreased plasma level of Ca2+ coupled with a concomitant increase in VSM [Ca2+]i concentrations and an altered blood pH are associated with pre eclampsia in the pregnant rat. Routine monitoring of serum pH, Ca2+ and Mg2+ especially in the late third trimester, may have potential in the early detection of patients at risk for pre-eclampsia, and monitoring the progress of diverse therapeutic regimens during clinical management. PMID- 17689515 TI - An imbalance in antioxidant enzymes and stress proteins in childhood asthma. AB - OBJECTIVES: The study was undertaken to examine antioxidant status and level of the major intracellular heat shock proteins (Hsps) in healthy children and children with mild and moderate asthma. DESIGN AND METHODS: Native gel assays were performed to estimate activities of copper/zinc (CuZn) and manganese (Mn) superoxide dismutase (SOD), and catalase (CAT) in peripheral blood mononuclear cells (PBMC) of healthy and asthmatic children. Hsp70 and Hsp90 protein levels in PBMCs were assessed by Western blot analysis. RESULTS: Moderate asthmatics displayed higher CuZnSOD/CAT activity ratio compared to healthy children, and increased Hsp90 level compared to mild asthmatics and healthy children. CONCLUSIONS: With regard to the imbalance in the antioxidant enzyme activities children with moderate asthma differ from healthy children, while an increased Hsp90 expression could be associated with the disease severity, as well. PMID- 17689516 TI - Automated monitoring of C2 and C0 blood levels of mycophenolic acid and cyclosporine on the Abbott Architect c8000. AB - OBJECTIVES: Evaluation of the performance of the EMIT 2000 Cyclosporin assay using 2 sets of assay calibrators and the EMIT 2000 mycophenolic acid assay to measure C0 and C2 concentrations on the Abbott Architect c8000 analyzer. DESIGN AND METHODS: Imprecision studies were performed. Cyclosporin concentration was assayed by EMIT on the c8000, by ACMIA on the Dimension and by LC-MS/MS while mycophenolic acid was analyzed by EMIT on c8000 and on Dimension and by HPLC. RESULTS: Agreement between cyclosporin and mycophenolic acid concentrations assayed on the c8000 and on the Dimension was very good. Method comparison between the c8000 and LC-MS/MS resulted in a relative bias of 15.7% for C0 and 11.5% for C2 concentrations. Relative bias of the mycophenolic acid concentrations assayed on the c8000 and the HPLC was 37.7%. CONCLUSIONS: When reported properly to the clinician mycophenolic acid and cyclosporine blood levels can be monitored using the EMIT assays on the c8000 consolidating standard routine workflow and reducing reagent costs significantly. PMID- 17689517 TI - Indirect estimation of pediatric Health Related Limits for serum thyrotropin using the ADVIA Centaur analyzer. AB - OBJECTIVES: To determine pediatric reference values for thyrotropin using Advia Centaur analyzer. DESIGN AND METHODS: The study was conducted in a large regional hospital on TSH results obtained from 5741 females and 4332 males aged 0-17 years. After the exclusion of the results outside 4 standard deviations, we calculated the Health Related Limits (HRLs) following the indirect Kairisto's procedure and using the software GraphROC. RESULTS: The lower HRL of TSH concentration was 0.70 mU/L in the years 0-11 and 0.50 mU/L in the following years. The upper TSH HRL was 6.9 mU/L in males vs. 5.7 mU/L in females in the first year and 6.7 mU/L vs. 5.3 in the period 1-2 years. The upper HRLs in females and males were similar in the following years and the upper HRL in the 13 17 years class was 3.8 mU/L. CONCLUSIONS: The indirect methods appear reliable for calculating the pediatric HRLs for TSH. PMID- 17689518 TI - From diagnostics to therapy: prospects of quantum dots. AB - Quantum dots (QDs) are among the most promising items in the nanomedicine toolbox. These nanocrystal fluorophores have several potential medical applications including nanodiagnostics, imaging, targeted drug delivery, and photodynamic therapy. The diverse potential applications of QDs are attributed to their unique optical properties including broad-range excitation, size-tunable narrow emission spectra, and high photostability. The size and composition of QDs can be varied to obtain the desired emission properties a makes them amenable for simultaneous detection of multiple targets. Also, numerous surface functionalizations can be used to adapt QDs to the needed application. Recent reports have shown successful use of QDs in various medical applications. With respect to in vivo applications, caution must be exercised with QDs due to their toxic components. Development of appropriate health and safety regulations and resolution of intellectual property issues are necessary for commercialization. In light of these obstacles however, QDs appear to be too valuable to nanomedicine to dismiss, and will eventually come into routine practical use. PMID- 17689519 TI - The presence of apolipoprotein epsilon4 and epsilon2 alleles augments the risk of coronary artery disease in type 2 diabetic patients. AB - OBJECTIVE: It has been suggested that there is a relationship between apolipoprotein E polymorphism and the severity of coronary artery disease in type II diabetes mellitus (T2DM). The current study specifically aimed to examine whether APOE polymorphism in association with serum lipids-lipoproteins level is a risk factor for developing coronary artery disease (CAD) in diabetic patients living in western of Iran. METHODS: The APOE genotypes were detected by PCR-RFLP in 152 angiographically documented diabetic CAD patients, 262 non-diabetic (ND) individuals with CAD and 300 unrelated controls (normal coronary artery cases without diabetes) and serum lipid level was measured enzymatically. RESULTS: The APOE-epsilon4 and epsilon2 allele frequencies were significantly higher in the CAD/T2DM and CAD/ND patients than in the control group (p<0.001). Our study demonstrated a significant association between APOE polymorphism and the level of plasma lipids with CAD/T2DM (p=0.001) and CAD/ND (p=0.026) patients. The CAD subjects with T2DM and ND patients carrying APOE-epsilon4 allele had lower plasma HDL-C level (p<0.001), (p=0.008) but had higher plasma LDL-C (p=0.01), total cholesterol (p=0.002), (p=0.03) and TG (p<0.001), (p=0.042) than that of the APOE epsilon3 carriers, respectively. However, carriers of APOE-epsilon2 had significantly higher levels of plasma TG only. OR of APOE-epsilon4 and epsilon2 alleles in CAD/T2DM and CAD/ND patients were found to be 2.98 (p=0.001),1.86 (p=0.001), 2 (p=0.001), and 1.65 (p=0.001), respectively. CONCLUSIONS: The major finding of the present case-control study is that T2DM patients carrying APOE epsilon2 and epsilon4 alleles have a higher risk of developing CAD than ND patients in the western population of Iran, with APOE-epsilon4 being more closely associated with CAD than the APOE-epsilon2 allele. These results indicated that carriers of APOE-epsilon4 allele have a distinct plasma lipids profile and carrier of this allele with low levels of HDL-C and with high levels of LDL-C may be susceptible to CAD and myocardial infarction specially in diabetic patients. This suggests that a therapeutic modality should be considered for these patients. PMID- 17689520 TI - The azimuth projection for the display of 3-D EEG data. AB - Electroencephalogram (EEG) is a scalp record of the neural electric activities of the brain. There are many kinds of methods to display the EEG data, such as a projective plane or the realistic head surface. In this work, one of the atlas projection methods, azimuth conformal projection, was tested and recommended as a new way of a planar EEG display. The method details are given and numerically compared with the normal projective plane display. The results indicate that the azimuth projection has many advantages: the transform is simple, convenient, and it can keep all the information. It shows all the information in the 3-D data within a projective plane without distinct shape change. Therefore, it can help to analyze the data effectively. PMID- 17689521 TI - Mutation of the Apc1 homologue shattered disrupts normal eye development by disrupting G1 cell cycle arrest and progression through mitosis. AB - The shattered1 (shtd1) mutation disrupts Drosophila compound eye structure. In this report, we show that the shtd1 eye defects are due to a failure to establish and maintain G1 arrest in the morphogenetic furrow (MF) and a defect in progression through mitosis. The observed cell cycle defects were correlated with an accumulation of cyclin A (CycA) and String (Stg) proteins near the MF. Interestingly, the failure to maintain G1 arrest in the MF led to the specification of R8 photoreceptor cells that undergo mitosis, generating R8 doublets in shtd1 mutant eye discs. We demonstrate that shtd encodes Apc1, the largest subunit of the anaphase-promoting complex/cyclosome (APC/C). Furthermore, we show that reducing the dosage of either CycA or stg suppressed the shtd1 phenotype. While reducing the dosage of CycA is more effective in suppressing the premature S phase entry in the MF, reducing the dosage of stg is more effective in suppressing the progression through mitosis defect. These results indicate the importance of not only G1 arrest in the MF but also appropriate progression through mitosis for normal eye development during photoreceptor differentiation. PMID- 17689522 TI - Control of morphogenetic cell movements in the early zebrafish myotome. AB - As the vertebrate myotome is generated, myogenic precursor cells undergo extensive and coordinated movements as they differentiate into properly positioned embryonic muscle fibers. In the zebrafish, the "adaxial" cells adjacent to the notochord are the first muscle precursors to be specified. After initially differentiating into slow-twitch myosin-expressing muscle fibers, these cells have been shown to undergo a remarkable radial migration through the lateral somite, to populate the superficial layer of slow-twitch muscle of the mature myotome. Here we characterize an earlier set of adaxial cell behaviors; the transition from a roughly 4x5 array of cuboidal cells to a 1x20 stack of elongated cells, prior to the migration event. We find that adaxial cells display a highly stereotypical series of behaviors as they undergo this rearrangement. Furthermore, we show that the actin regulatory molecule, Cap1, is specifically expressed in adaxial cells and is required for the progression of these behaviors. The requirement of Cap1 for a cellular apical constriction step is reminiscent of similar requirements of Cap during apical constriction in Drosophila development, suggesting a conservation of gene function for a cell biological event critical to many developmental processes. PMID- 17689524 TI - Mechanisms involved in the vasodilator effect induced by diosgenin in rat superior mesenteric artery. AB - The aim of this study was to investigate the vasorelaxant effect induced by diosgenin in superior mesenteric rings. In rings pre-contracted with phenylephrine (10 microM), diosgenin caused concentration-dependent relaxations [EC(50) = (3.3 +/- 1.2) x 10(- 4)M, E(max) = 94.2 +/- 2.6 %]. Vascular relaxation induced by diosgenin was significantly inhibited after removal of the endothelium (E(max) = 46 +/- 8.8%, p < 0.001) or after pre-treatment of the rings with N nitro-L-arginine methyl esther (l-NAME) 100 or 300 microM (E(max) = 35.3 +/- 4%; 28.1 +/- 3.3%, respectively, p < 0.001), atropine 1 microM (E(max) = 24.6 +/- 3.4%, p < 0.001), hydroxocobalamin 30 microM (E(max) = 54.0 +/- 9.6%, p < 0.001), 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) 10 microM (E(max) = 46.0 +/- 8.0%, p < 0.001) or indomethacin 1 microM (E(max) = 22.6 +/- 11.8%, p < 0.001). Vasorelaxation evoked by diosgenin was significantly inhibited after pre treatment of preparations with both selective and non-selective inhibitors of large conductance Ca(2+)-activated K(+) (BK(Ca)) channels, iberiotoxin 100 nM or tetraethylammonium (TEA) 1mM, respectively (E(max) = 62.5 +/- 9.1%; 65.7 +/- 1.1%, p < 0.001). Conversely, in endothelium-denuded vessels, none of BK(Ca) channel blockers modified the relaxant effect induced by diosgenin. In mesenteric endothelial cells loaded with FURA-2 diosgenin was able to increase intracellular calcium concentrations, which were significantly decreased by atropine 1 microM. In addition, in isolated mesenteric rings, diosgenin induced marked increase in nitric oxide (NO) levels, which was completely abolished after functional endothelium removal. The results obtained here demonstrated that diosgenin induced relaxation appears to involve endothelial muscarinic receptor activation with increase in intracellular calcium concentrations and consequent release of endothelium-derived relaxing factors (EDRFs), mainly NO and cyclooxygenase derivatives, which activate BK(Ca) channels. Nevertheless, further studies are necessary to clearly elucidate residual endothelium-independent relaxation induced by diosgenin. PMID- 17689523 TI - Zebrafish Naked1 and Naked2 antagonize both canonical and non-canonical Wnt signaling. AB - Wnt signaling controls a wide range of developmental processes and its aberrant regulation can lead to disease. To better understand the regulation of this pathway, we identified zebrafish homologues of Naked Cuticle (Nkd), Nkd1 and Nkd2, which have previously been shown to inhibit canonical Wnt/beta-catenin signaling. Zebrafish nkd1 expression increases substantially after the mid blastula transition in a pattern mirroring that of activated canonical Wnt/beta catenin signaling, being expressed in both the ventrolateral blastoderm margin and also in the axial mesendoderm. In contrast, zebrafish nkd2 is maternally and ubiquitously expressed. Overexpression of Nkd1 or Nkd2a suppressed canonical Wnt/beta-catenin signaling at multiple stages of early zebrafish development and also exacerbated the cyclopia and axial mesendoderm convergence and extension (C&E) defect in the non-canonical Wnt/PCP mutant silberblick (slb/wnt11). Thus, Nkds are sufficient to antagonize both canonical and non-canonical Wnt signaling. Reducing Nkd function using antisense morpholino oligonucleotides resulted in increased expression of canonical Wnt/beta-catenin target genes. Finally, reducing Nkd1 function in slb mutants suppressed the axial mesendoderm C&E defect. These data indicate that zebrafish Nkd1 and Nkd2 function to limit both canonical and non-canonical Wnt signaling. PMID- 17689526 TI - MDMA ("Ecstasy") suppresses the innate IFN-gamma response in vivo: a critical role for the anti-inflammatory cytokine IL-10. AB - Here we demonstrate that the widely abused drug methylenedioxymethamphetamine (MDMA; "Ecstasy") suppresses innate interferon (IFN)-gamma production in mice following an in vivo lipopolysaccharide (LPS) challenge. IFN-gamma signalling was also impaired by MDMA, as indicated by reduced phosphorylation of signal transducer and activator of transcription-1 (STAT1) and reduced expression of interferon-gamma inducible protein 10 (IP-10/CXCL10); a chemokine induced by IFN gamma. MDMA also suppressed production of interleukin (IL)-12 and IL-15; two cytokines that induce IFN-gamma production. Our results demonstrate that in vitro exposure to MDMA does not mimic the suppression of innate IFN-gamma observed in vivo, indicating that observed suppression is most likely due to the release of endogenous immunomodulatory substances following drug administration. In this regard, we previously demonstrated that MDMA increases production of the anti inflammatory cytokine IL-10 in vivo, an event that is mediated by beta adrenoceptor activation on immune cells. Considering that increased IL-10 production precedes suppression of IFN-gamma induced by MDMA, and also considering that IL-10 can inhibit IL-12 and IFN-gamma production, we examined the possibility that IL-10 was an essential mediator of the suppressive effect of MDMA on the IFN-gamma response. By pre-treating mice with an anti-IL-10 receptor antibody we demonstrate that IL-10 is a critical mediator of MDMA-induced suppression of IFN- gamma production and signalling. Consistent with a role for beta-adrenoceptor activation in the immunosuppressive actions of MDMA, pre treatment with the beta-adrenoceptor antagonist nadolol blocked the MDMA-induced increase in IL-10, and also inhibited the suppressive action of MDMA on the innate IFN-gamma response. The potential clinical significance of these findings for MDMA users is discussed. PMID- 17689525 TI - Nicotinic and dopamine D2 receptors mediate nicotine-induced changes in ventral tegmental area neurotensin system. AB - Neuropeptides have been implicated in the psychopathology of stimulants of abuse. Neurotensin is a neuropeptide associated with the regulation of the nigrostriatal and mesolimbic dopamine pathways. In addition, the ventral tegmental area, a midbrain region implicated in the rewarding effects of most, if not all, addictive drugs, appears to be a particularly critical target for nicotine action. Because neurotensin has been linked with both mesolimbic and mesocortical dopamine function, we examined the impact of nicotine treatment on central nervous neurotensin systems by measuring changes in neurotensin tissue content because it has been shown that such changes reflect alterations in release and activity of this peptide system. Male Sprague-Dawley rats received multiple administrations of (+/-) nicotine 4.0 mg/kg/day (0.8 mg/kg, i.p.; 5 x 2-h intervals) in the presence or absence of selective dopamine receptor antagonists (dopamine D(1); SCH 23390 or dopamine D(2); eticlopride) or two doses of the non selective nicotinic acetylcholine receptor antagonist (mecamylamine; 3.0 and 6.0 mg/kg, s.c.). The nicotine treatment significantly decreased neurotensin-like immunoreactivity content in the ventral tegmental area, as well as related regions such as prefrontal cortex, substantia nigra, and anterior striatal region 12-18 h after drug treatment, but not the nucleus accumbens. The nicotine mediated decrease in the neurotensin-like immunoreactivity of the ventral tegmental area was selectively blocked by a specific dopamine D(2), but not a dopamine D(1), receptor antagonist, while mecamylamine attenuated at the low (3.0 mg/kg) and completely blocked at high (6.0 mg/kg) dose this nicotine effect. These findings with previous studies, suggest that nicotine-mediated dopamine release activates D(2) receptors which in turn increases neurotensin release, turnover and acutely reduces tissue levels in the ventral tegmental area and other limbic and basal ganglia structures. PMID- 17689527 TI - Antagonism of endothelin action normalizes altered levels of VEGF and its signaling in the brain of stroke-prone spontaneously hypertensive rat. AB - Stroke-prone spontaneously hypertensive rats (SHRSP) often suffer from spontaneous stroke, in part, due to abnormalities in the cerebrovasculature. Here, we investigate the profile of key angiogenic factors and their basic signaling molecules in the brain of SHRSP during the age-dependent stages of hypertension. The profile of VEGF and its receptor, Flk-1, was dependent on age and stage of hypertension (i.e., down regulated at pre-hypertensive and malignant hypertensive stages, but up regulated at typical hypertensive stage), while that of its downstream components, pAkt and eNOS, were down regulated in a time dependent manner in the frontal cortex of SHRSP compared to age-matched genetic control, normotensive WKY rats. On the other hand, the expression of endothelin-1 and its type A receptor (endothelin ETA receptor) were up regulated, depending on age and stage of hypertension. In contrast, levels of endothelin type B receptor were down regulated. The regional cerebral blood flow decreased during the development of malignant hypertension. Thus, subsequent experiments were designed to investigate whether endothelin-1 receptor antagonism, using endothelin-A/-B dual receptor antagonist SB209670, could normalize the molecular profile of these factors in SHRSP brain. Interestingly, blockage of endothelin-1 receptor restored to normal, levels of cerebral endothelin-1, endothelin ETA receptor and endothelin ETB receptor; VEGF and Flk-1; endothelial nitric oxide synthase (eNOS) and pAkt, in SHRSP, compared to age-matched WKY. Endothelin receptor blocker might be important to prevent the progression in the defect in VEGF and its angiogenic signaling cascade in the pathogenesis of hypertension-induced vascular remodeling in frontal cortex of SHRSP rats. PMID- 17689528 TI - Cysteinyl leukotriene receptor antagonist MK-571 alters bronchoalveolar lavage fluid proteome in a mouse asthma model. AB - Cysteinyl leukotriene receptor type 1 (leukotriene CysLT(1) receptor) antagonist is one of the most effective anti-inflammatory agents for asthma. The spectrum of protein targets that can be regulated by leukotriene CysLT(1) receptor antagonist in asthma is not fully understood. The present study tried to identify novel protein targets of a selective leukotriene CysLT(1) receptor antagonist MK-571 in allergic airway inflammation by analyzing the proteome of mouse bronchoalveolar lavage fluid. BALB/c mice sensitized and challenged with ovalbumin showed increased pulmonary inflammatory cell infiltration, airway mucus production and serum ovalbumin-specific IgE level. MK-571 inhibited all these allergic airway inflammation endpoints. Lavage fluid proteins were resolved by two-dimensional gel electrophoresis and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The level of fourteen bronchoalveolar lavage fluid protein spots was markedly altered by MK-571. A family of chitinases (Ym1, Ym2 and acidic mammalian chitinase), lungkine, surfactant protein-D and gamma actin have been found for the first time to be down-regulated by leukotriene CysLT(1) receptor antagonist in mouse allergic airways. Some of the down regulatory effects were confirmed with reverse transcription-polymerase chain reaction analyses. Taken together, we have identified novel protein targets that can be regulated by leukotriene CysLT(1) receptor antagonist in mouse allergic airway inflammation, and our findings reveal additional pharmacological actions of leukotriene CysLT(1) receptor antagonist in the treatment of asthma. PMID- 17689529 TI - Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro 2H-pyridin-4-yl}-6-chloro-1H-indole), a dopamine D4 receptor antagonist and serotonin reuptake inhibitor: characterisation of its in vitro profile and pre clinical antipsychotic potential. AB - The present study describes the pharmacological profile of the putative antipsychotic drug Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3 yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole). The in vitro receptor profile of Lu 35-138 revealed high affinity (K(i)=5 nM) and competitive antagonism (K(b)=8 nM) at dopamine D(4) receptors combined with potent 5-HT uptake inhibition (IC(50)=3.2 nM) and moderate alpha(1)-adrenoceptor affinity (K(i)=45 nM). In vivo, Lu 35-138 selectively counteracted hyperlocomotion induced by d-amphetamine (0.5 mg/kg; ED(50)=4.0 mg/kg, s.c.) in rats and phencyclidine (PCP; 2.5 mg/kg; ED(50)=13 mg/kg, s.c.) in mice. Lu 35-138 was unable to affect hyperlocomotion induced by a high dose of d-amphetamine (2.0 mg/kg), which indicates a preferential action on limbic versus striatal structures. A similar limbic selectivity of Lu 35-138 was indicated in voltammetric measure of dopamine output in the core and shell subdivisions of the nucleus accumbens in rats. Furthermore, a relatively large dose of Lu 35-138 (18 mg/kg, s.c.) counteracted d amphetamine-induced disruption of pre-pulse inhibition in rats and repeated administration of Lu 35-138 (0.31 or 1.25 mg/kg, p.o. once daily for 3 weeks) reduced the number of spontaneously active dopamine neurones in the ventral tegmental area, underlining its antipsychotic-like profile. Lu 35-138 failed to induce catalepsy in rats or dystonia in Cebus apella monkeys and did not deteriorate spatial memory in rats as assessed by water maze performance. Collectively, these results suggest that Lu 35-138 possesses antipsychotic activity combined with a low extrapyramidal and cognitive side effect liability. PMID- 17689530 TI - Cdc6 is a rate-limiting factor for proliferative capacity during HL60 cell differentiation. AB - The DNA replication (or origin) licensing pathway represents a critical step in cell proliferation control downstream of growth signalling pathways. Repression of origin licensing through down-regulation of the MCM licensing factors (Mcm2-7) is emerging as a ubiquitous route for lowering proliferative capacity as metazoan cells exit the cell division cycle into quiescent, terminally differentiated and senescent "out-of-cycle" states. Using the HL60 monocyte/macrophage differentiation model system and a cell-free DNA replication assay, we have undertaken direct biochemical investigations of the coupling of origin licensing to the differentiation process. Our data show that down-regulation of the MCM loading factor Cdc6 acts as a molecular switch that triggers loss of proliferative capacity during early engagement of the somatic differentiation programme. Consequently, addition of recombinant Cdc6 protein to in vitro replication reactions restores DNA replication competence in nuclei prepared from differentiating cells. Differentiating HL60 cells over-expressing either wild type Cdc6 or a CDK phosphorylation-resistant Cdc6 mutant protein (Cdc6A4) exhibit an extended period of cell proliferation compared to mock-infected cells. Notably, differentiating HL60 cells over-expressing the Cdc6A4 mutant fail to down-regulate Cdc6 protein levels, suggesting that CDK phosphorylation of Cdc6 is linked to its down-regulation during differentiation and the concomitant decrease in cell proliferation. In this experimental model, Cdc6 therefore plays a key role in the sequential molecular events leading to repression of origin licensing and loss of proliferative capacity during execution of the differentiation programme. PMID- 17689531 TI - Long-term EGF/serum-treated human thyrocytes mimic papillary thyroid carcinomas with regard to gene expression. AB - Constitutive activation of the RAS/RAF/MAPK pathway has been found in different tumor types including papillary thyroid carcinomas (PTCs). To get more insight into genes primarily regulated in the human tumor cells, an in vitro model was developed in which primary cultures of human thyrocytes were treated for different times with epidermal growth factor and serum (EGF/serum), which stimulate the MAPK cascade. Gene expression profiles were obtained by microarrays and compared to the expression profiles of PTCs. An evolution from short-term to long-term EGF/serum-treated cells was found, i.e., a program change showing a distinction between gene expression profiles of short-term and long-term EGF/serum-treated cells. The late pattern of EGF/serum stimulated cells converges to the pattern of PTCs. Comparison of these two types of cells with cAMP activated cells, from thyroid-stimulating hormone-treated thyrocytes and autonomous adenomas, showed distinct gene expression profiles for the two pathways. For the two models, an overlap was found in a number of genes which were early induced in vitro but down-regulated later in vitro and in the in vivo tumors. Thus, long-term stimulated human primary cultures demonstrate a clear relation with the tumor in vivo and could therefore be used as models for the disease. PMID- 17689532 TI - A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder. AB - We compared the binding profiles of medications potentially useful in the treatment of involuntary emotional expression disorder at twenty-six binding sites in rat brain tissue membranes. Sites were chosen based on likelihood of being target sites for the mechanism of action of the agents in treating the disorder or their likelihood in producing side effects experienced by patients treated with psychoactive agents. We used radioligand binding assays employing the most selective labeled ligands available for sites of interest. Concentrations of labeled ligand were used at or below the K(i) value of the ligand for the target site. Compounds were initially screened at 1 muM. For compounds that competed for greater than 20-30% of specific binding at target sites of interest, full concentration curves were constructed. Dextromethorphan, amitriptyline and fluoxetine competed for binding to sigma(1) receptors and to serotonin transporters with high to moderate affinity. Of the target sites tested, these are the most likely to contribute to the therapeutic benefit of the various agents. In addition, all three drugs showed some activity at alpha(2) and 5-HT(1B/D) sites. Of the drugs tested, dextromethorphan bound to the fewest sites unlikely to be target sites. Although the mechanism of action of dextromethorphan or any drug that has been used in the treatment of involuntary emotional expression disorder is currently unknown, our data support that the affinity of the drug for sigma(1) receptors is consistent with its possible action through this receptor type in controlling symptoms of the disorder. PMID- 17689533 TI - The importance of transgene and cell type on the regeneration of adult retinal ganglion cell axons within reconstituted bridging grafts. AB - When grafted onto the cut optic nerve, chimeric peripheral nerve (PN) sheaths reconstituted with adult Schwann cells (SCs) support the regeneration of adult rat retinal ganglion cell (RGC) axons. Regrowth can be further enhanced by using PN containing SCs transduced ex vivo with lentiviral (LV) vectors encoding a secretable form of ciliary neurotrophic factor (CNTF). To determine whether other neurotrophic factors or different cell types also enhance RGC regrowth in this bridging model, we tested the effectiveness of (1) adult SCs transduced with brain-derived neurotrophic factor (BDNF) or glial cell line-derived neurotrophic factor (GDNF), and (2) fibroblasts (FBs) genetically modified to express CNTF. SCs transduced with LV-BDNF and LV-GDNF secreted measurable and bioactive amounts of each of these proteins, but reconstituted grafts containing LV-BDNF or LV-GDNF transduced SCs did not enhance RGC survival or axonal regrowth. LV-BDNF modified grafts did, however, contain many pan-neurofilament immunolabeled axons, many of which were also immunoreactive for calcitonin gene-related peptide (CGRP) and were presumably of peripheral sensory origin. Nor-adrenergic and cholinergic axons were also seen in these grafts. There were far fewer axons in LV-GDNF engineered grafts. Reconstituted PN sheaths containing FBs that had been modified to express CNTF did not promote RGC viability or regeneration, and PN reconstituted with a mixed population of SCs and CNTF expressing FBs were less effective than SCs alone. These data show that both the type of neurotrophic factor and the cell types that express these factors are crucial elements when designing bridging substrates to promote long-distance regeneration in the injured CNS. PMID- 17689534 TI - The protonation state of the catalytic aspartates in plasmepsin II. AB - Assigning the correct protonation state to the catalytic residues is essential for a realistic modelling of an enzyme's active site. Plasmepsins are pharmaceutically relevant aspartic proteases involved in haemoglobin degradation by Plasmodium spp. In aspartic proteases, one of the two catalytic aspartates is protonated, while the other is negatively charged. Here, multiple explicit-water molecular dynamics simulations of plasmepsin II, uncomplexed and with a hydroxypropylamine peptidomimetic inhibitor, indicate that protonation of Asp214 favours a stable active site structure. Moreover, the protonation state of the catalytic aspartate has a strong influence on a linear chain of hydrogen bonds with the adjacent side chains. PMID- 17689535 TI - The interaction between endogenous calcineurin and the plasma membrane calcium dependent ATPase is isoform specific in breast cancer cells. AB - Plasma membrane calcium/calmodulin-dependent ATPases (PMCAs) are high affinity calcium pumps that extrude calcium from the cell. Emerging evidence suggests a novel role for PMCAs as regulators of calcium/calmodulin-dependent signal transduction pathways via interaction with specific partner proteins. In this work, we demonstrate that endogenous human PMCA2 and -4 both interact with the signal transduction phosphatase, calcineurin, whereas, no interaction was detected with PMCA1. The strongest interaction was observed between PMCA2 and calcineurin. The domain of PMCA2 involved in the interaction is equivalent to that reported for PMCA4b. PMCA2-calcineurin interaction results in inhibition of the calcineurin/nuclear factor of activated T-cells signalling pathway. PMID- 17689536 TI - Eukaryotic initiation factor 2alpha kinase is a nitric oxide-responsive mercury sensor enzyme: potent inhibition of catalysis by the mercury cation and reversal by nitric oxide. AB - The activity of one of the eukaryotic initiation factor 2alpha kinases, heme regulated inhibitor (HRI), is modulated by heme binding. Here, we demonstrate for the first time that Hg2+ strongly inhibits the function of HRI (IC50=0.6 microM), and nitric oxide fully reverses this inhibition. Other divalent metal cations, such as Fe2+, Cu2+, Cd2+, Zn2+ and Pb2+, also significantly inhibit kinase activity with IC50 values of 1.9-8.5 microM. Notably, inhibition by cations other than Hg2+ is not reversed by nitric oxide. Our present data support dual roles of Hg2+ and nitric oxide in the regulation of protein synthesis during cell emergency states. PMID- 17689537 TI - CAMTAs: calmodulin-binding transcription activators from plants to human. AB - Recently, a novel family of calmodulin-binding transcription activators (CAMTAs) was reported in various eukaryotes. All CAMTAs share a similar domain organization, with a novel type of sequence-specific DNA-binding domain (designated CG-1). This domain could bind DNA directly and activate transcription, or interact with other transcription factors, not through DNA binding, thus acting as a co-activator of transcription. Investigations of CAMTAs in various organisms imply a broad range of functions from sensory mechanisms to embryo development and growth control, highlighted by the apparent involvement of mammalian CAMTA2 in cardiac growth, and of CAMTA1 in tumor suppression and memory performance. PMID- 17689538 TI - E-cadherin expression in cervical epithelial cells of postmenopausal women: association with hormone therapy, tibolone, and raloxifene. AB - This study assesses the possible associations between postmenopausal therapy (hormone therapy, raloxifene, and tibolone) and E-cadherin expression in normal cervical Papanicolaou smears (squamous, glandular, and metaplastic cells). E cadherin immunostaining was less intense in metaplastic cells of women on tibolone, whereas hormone therapy and raloxifene were not associated with altered E-cadherin expression. PMID- 17689539 TI - Osteochondroma of the phalanx: a late Roman case. AB - Accounting for 20-50% of all benign forms, solitary osteochondromae are the most common kind of bone tumour. The long bones of the lower extremity are the most frequently affected; the small bones of the hands and feet, the pelvis, the scapula, and the spine are less usual locations. This paper describes an osteochondroma in a proximal phalanx of the hand of a female aged between 17 and 25 years buried in a Late Roman necropolis from SE Spain. The bone displayed a solitary osteochondroma, which was confirmed by macroscopic and radiographic examination. This is the first palaeopathological example of a solitary sessile osteochondroma of the hand. PMID- 17689540 TI - Betaine supplementation improves the atherogenic risk factor profile in a transgenic mouse model of hyperhomocysteinemia. AB - OBJECTIVE: To investigate the lipotropic action of betaine on plasma lipoproteins and tissue lipids. METHODS AND RESULTS: Adult mice, wild type (+/+) or heterozygous (+/-) for a disruption of the methylenetetrahydrofolate reductase (Mthfr) gene, were supplemented with betaine for 1 year and compared with mice on control diets. Outcome measures were plasma homocysteine and lipoprotein levels, aortic and liver morphology, and liver staining for 3-nitrotyrosine (oxidative stress marker) and Apolipoprotein A-I (ApoA-I). We also investigated short-term effects of supplemental betaine on plasma lipoproteins in Mthfr +/+ and +/- mice. Both genotypes showed significantly lower plasma homocysteine after long-term betaine supplementation, and lower plasma triglycerides and higher HDL cholesterol after both short- and long-term betaine. Lipid accumulation in liver and aortic wall tended to be lower in Mthfr+/+ compared to Mthfr+/- mice and in betaine-supplemented compared to unsupplemented mice. Nitrotyrosine staining was higher and ApoA-I staining was lower in livers of Mthfr+/- compared to Mthfr+/+ mice. Betaine did not affect staining of nitrotyrosine but increased ApoA-I staining. A significant negative correlation was observed between plasma homocysteine and liver ApoA-I. CONCLUSIONS: Mild MTHFR deficiency in mice is associated with increased risk for atherosclerotic disease. Betaine has a lipotropic effect, which is associated with a reduction in homocysteine, an increase in ApoA-I and an amelioration of the atherogenic risk profile. PMID- 17689541 TI - A biomechanical model of artery buckling. AB - The stability of arteries under blood pressure load is essential to the maintenance of normal arterial function and the loss of stability can lead to tortuosity and kinking that are associated with significant clinical complications. However, mechanical analysis of arterial bent buckling is lacking. To address this issue, this paper presents a biomechanical model of arterial buckling. Using an elastic cylindrical arterial model, the mechanical equations for arterial buckling were developed and the critical buckling pressure was found to be a function of the wall stiffness (Young's modulus), arterial radius, length, wall thickness, and the axial strain. Both the model equations and experimental results demonstrated that the critical pressure is related to the axial strain. Arteries may buckle and become tortuous due to reduced (subphysiological) axial strain, hypertensive pressure, and a weakened wall. These results are in accordance with, and provide a possible explanation to the clinical observations that hypertension and aging are the risk factors for arterial tortuosity and kinking. The current model is also applicable to veins and ureters. PMID- 17689542 TI - Highly efficient monolithic silica capillary columns modified with poly(acrylic acid) for hydrophilic interaction chromatography. AB - Monolithic silica capillary columns for hydrophilic interaction liquid chromatography (HILIC) were prepared by on-column polymerization of acrylic acid on monolithic silica in a fused silica capillary modified with anchor groups. The products maintained the high permeability (K=5 x 10(-14)m(2)) and provided a plate height (H) of less than 10 microm at optimum linear velocity (u) and H below 20 microm at u=6mm/s for polar solutes including nucleosides and carbohydrates. The HILIC mode monolithic silica capillary column was able to produce 10000 theoretical plates (N) with column dead time (t(0)) of 20s at a pressure drop of 20 MPa or lower. The total performance was much higher than conventional particle-packed HILIC columns currently available. The gradient separations of peptides by a capillary LC-electrospray mass spectrometry system resulted in very different retention selectivity between reversed-phase mode separations and the HILIC mode separations with a peak capacity of ca. 100 in a 10 min gradient time in either mode. The high performance observed with the monolithic silica capillary column modified with poly(acrylic acid) suggests that the HILIC mode can be an alternative to the reversed-phase mode for a wide range of compounds, especially for those of high polarity in isocratic as well as gradient elution. PMID- 17689543 TI - Synergistic effects in competitive adsorption of carbohydrates on an ion-exchange resin. AB - Adsorption of the three carbohydrates sucrose, glucose and fructose from aqueous solutions was investigated on an ion-exchange resin. The adsorption equilibrium of single components, binary and ternary mixtures was quantified by frontal analysis and the adsorption-desorption method. The experiments covered a concentration range up to 600 g/L at 60 degrees C and 80 degrees C. Within this range the adsorption isotherms of carbohydrates exhibited anti-Langmuirian behavior. Data of mixture adsorption revealed reversed competitive (synergistic or cooperative) effects, i.e., an increase of the concentration of one component of the mixture enhanced the adsorption of others. To model such an adsorption behavior the anti-Langmuir model has been used. The isotherm parameters determined for single components were used to simulate the competitive adsorption equilibria through the IAS (ideal adsorbed solution) theory. Finally, dynamic concentration profiles of multicomponent mixtures have been recorded. The shapes of adsorption and desorption curves confirmed the observed competitive effects found in the equilibrium studies. The breakthrough curves measured were simulated using the equilibrium theory as well as a numerical solution of the equilibrium dispersive model. PMID- 17689544 TI - Analysis of p-chlorobenzoic acid in water by liquid chromatography-tandem mass spectrometry. AB - para-Chlorobenzoic acid (p-CBA) is typically used as a probe compound to indirectly quantify hydroxyl radicals formed during advanced oxidation processes used in drinking water and wastewater treatment. A method has been developed for the sensitive analysis of p-CBA in water using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A reporting limit in water of 100 ng/L was determined for the method, which is 40-fold lower than the 4.0 microg/L reporting limit of the widely used liquid chromatography with UV detection (LC-UV) method. The method was found to be robust in difficult matrices such as wastewater and highly selective, unlike LC-UV which relies on non-specific detection at 234 nm. The detection of p-CBA below 1 microg/L during bench-scale ozonation of wastewater after hydrogen peroxide addition was demonstrated. Duplicate samples were analyzed by LC-MS/MS and LC-UV and results were found to be comparable at concentrations quantifiable by both methods. PMID- 17689545 TI - Evaluation of a solid-phase extraction dual-layer carbon/primary secondary amine for clean-up of fatty acid matrix components from food extracts in multiresidue pesticide analysis. AB - The use of dual-layer solid-phase extraction (SPE), a primary-secondary amine (PSA) in combination with graphitized carbon black (GCB), was evaluated for sample clean-up during multiresidue pesticide screening of agricultural and food products. The retention of fatty acids by the PSA sorbent was quantified and the effect of the elution solvent on the retention of fatty acid on the SPE cartridge was evaluated. The use of stronger elution solvents to elute certain pesticides from graphitized carbon was shown to interfere with the capacity of PSA to bind fatty acids. A suitable protocol was tested using GCB/PSA dual-layer SPE to clean up several food matrices and to simultaneously screen multiple fortified pesticides with a wide range of physico-chemical properties. With a few exceptions, pesticide recoveries were between 85% and 110%, and sample-to-sample differences of less than 5% were achieved, demonstrating the versatile suitability of the dual-layer SPE to sample clean-up. PMID- 17689546 TI - Nonionic surfactant-capped gold nanoparticles as postcolumn reagents for high performance liquid chromatography assay of low-molecular-mass biothiols. AB - Gold nanoparticles (GNPs) have been stabilized with nonionic surfactant ligands, i.e., Brij 35, and their aggregation could be induced rapidly and selectively by biologically active low-molecular-mass thiols including sulphydryl-containing amino acids (cysteine and homocysteine) and small peptides (glutathione, cysteinylglycine, and glutamylcysteine). A new postcolumn detection method has been developed for high-performance liquid chromatography (HPLC) assay of these small biothiols based on the analyte-induced aggregation of the GNPs. Compared with conventional thiol-reactive probes, the GNP colloids are easier to prepare, much more stable in aqueous solution over a wide pH range and at ambient temperature, and exhibit relatively high selectivity toward small biothiols. The analysis of human urine samples demonstrated that the proposed method is promising in HPLC assay of the small thiol molecules in biological fluids. PMID- 17689547 TI - Synthesis of biomorphological mesoporous TiO2 templated by mimicking bamboo membrane in supercritical CO2. AB - A new approach is presented for preparing biomorphological mesoporous TiO2 templated by mimicking bamboo inner shell membrane via supercritical CO2 (SCCO2) transportation through titanium tetrabutyloxide (TTBO). The analysis of wide angle X-ray powder diffraction (XRD) showed the prepared TiO2 in phase of anatase, and the small-angle XRD revealed the presence of mesopores without periodicity. The product exhibited the shape of crinkled films and extended in two dimensions up to centimeters. The electron microscopic observation showed that the TiO2 films were around 200 nm in thickness, and across the films there were numerous round or ellipse-shaped mesopores, being 10-50 nm in diameter, which were formed by the close packing of TiO2 particles. High-resolution transmission electron microscope (HRTEM) displayed that the single TiO2 particle size was about 12.5 nm. The UV-vis absorption spectrum was transparent in the wavelength of 320-350 nm for suspensions of the prepared mesoporous TiO2 in ethanol at the concentration of 5.0 mg/l. The mesoporous TiO2 prepared with the aid of SCCO2 exhibited an obvious blue shift compared with the TiO2 prepared by sol-gel infiltration. The possible mechanism for the formation of the mesoporous TiO2 is summarized into a biomimetic mineralization pathway. First, TTBO was transported to the membrane surface via SCCO2, and then condensed. Hydrolysis reactions between the functional groups of organic membrane and TTBO took place to form the nuclear TiO2, and the TiO2 seeds grew around the organic membrane into TiO2 mesoporous materials. The approach provides a low-cost and efficient route for the production of ceramics nanomaterials with unique structural features, which may have potential application in designing UV-selective shielding devices [S. Zhao, X.H. Wang, S.B. Xin, Q. Jiang, X.P. Liang, Rare Metal Mater. Eng. 35 (2006) 508-510]. PMID- 17689548 TI - Adsorption studies on the removal of Vertigo Blue 49 and Orange DNA13 from aqueous solutions using carbon slurry developed from a waste material. AB - Waste material (carbon slurry), from fuel oil-based generators, was used as adsorbent for the removal of two reactive dyes from synthetic textile wastewater. The study describes the results of batch experiments on removal of Vertigo Blue 49 and Orange DNA13 from synthetic textile wastewater onto activated carbon slurry. The utility of waste material in adsorbing reactive dyes from aqueous solutions has been studied as a function of contact time, temperature, pH, and initial dye concentrations by batch experiments. pH 7.0 was found suitable for maximum removal of Vertigo Blue 49 and Orange DNA13. Dye adsorption capacities of carbon slurry for the Vertigo Blue 49 and the Orange DNA13 were 11.57 and 4.54 mg g(-1) adsorbent, respectively. The adsorption isotherms for both dyes were better described by the Langmuir isotherm. Thermodynamic treatment of adsorption data showed an exothermic nature of adsorption with both dyes. The dye uptake process was found to follow second-order kinetics. PMID- 17689549 TI - Surface plasmon resonance spectroscopy study of interfacial binding of thrombin to antithrombin DNA aptamers. AB - We have applied surface plasmon resonance (SPR) spectroscopy, in combination with one-step direct binding, competition, and sandwiched assay schemes, to study thrombin binding to its DNA aptamers, with the aim to further the understanding of their interfacial binding characteristics. Using a 15-mer aptamer that binds thrombin primarily at the fibrinogen-recognition exosite as a model, we have demonstrated that introducing a DNA spacer in the aptamer enhances thrombin binding capacity and stability, as similarly reported for hydrocarbon linkers. The bindings are aptamer surface coverage and salt concentration dependent. When free aptamers or DNA sequences complementary to the immobilized aptamer are applied after the formation of thrombin/aptamer complexes, bound thrombin is displaced to a certain extent, depending on the stability of the complexes formed under different conditions. When the 29-mer aptamer (specific to thrombin's heparin-binding exosite) is immobilized on the surface, its affinity to thrombin appears to be lower than the immobilized 15-mer aptamer, although the 29-mer aptamer is known to have a higher affinity in the solution phase. These findings underline the importance of aptamers' ability to fold into intermolecular structures and their accessibility for target capture. Using a sandwiched assay scheme followed by an additional signaling step involving biotin-streptavidin chemistry, we have observed the simultaneous binding of the 15- and 29-mer aptamers to thrombin protein at different exosites and have found that one aptamer depletes thrombin's affinity to the other when they bind together. We believe that these findings are invaluable for developing DNA aptamer-based biochips and biosensors. PMID- 17689550 TI - Adhesion maps of spheres corrected for strength limit. AB - Present understanding of adhesion is mostly due to the well-known contact theories for spheres, including JKR (Johnson-Kendall-Roberts), DMT (Derjaguin Muller-Toporov) and MD (Maugis-Dugdale). Since most of the models exhibit their optimal applicability only in a specific regime, an adhesion map has been developed [K.L. Johnson, J.A. Greenwood, J. Colloid Interface Sci. (1997)] to guide the selection among different models. In the JG (Johnson-Greenwood) map, however, an important physical fact has been neglected that the adhesion strength must not exceed the theoretical strength; thereby the applicability of the classical adhesion models is overestimated and misguidance may arise from the JG map. To avoid this limitation, in this paper we introduce the strength limit into the adhesion map and find that the selection of adhesion models depends not only on the Tabor number but also on the ratio of the theoretical strength to the stiffness. Given this ratio, there exists a critical Tabor number or the size of the sphere, below which adhesion is dominated by the limiting strength and the classical adhesion models are no longer appropriate for spheres. These results eventually lead to a corrected adhesion map for spheres. PMID- 17689551 TI - Reactive two-dimensional layered material with regular chlorine groups. AB - A novel reactive layered two-dimensional molecular space material [layered chloroacetamide phenyl silica (CAAPhS)] with regular chlorine groups was synthesized by grafting chlorine groups into the layer structure of layered aminophenyl silica. The reactive activity of chlorine groups regularly arranged in the layer structure of layered CAAPhS was confirmed through a substitution reaction with n-butylamine. Layered CAAPhS showed potential as a starting material for the formation of a series of two-dimensional layered materials with various regular functional molecules and organic-inorganic composite materials. PMID- 17689552 TI - Encephalitis in a stone marten (Martes foina) after natural infection with highly pathogenic avian influenza virus subtype H5N1. AB - Recent outbreaks of disease in different avian species, caused by the highly pathogenic avian influenza virus (HPAIV), have involved infection by subtype H5N1 of the virus. This virus has also crossed species barriers and infected felines and humans. Here, we report the natural infection of a stone marten (Martes foina) from an area with numerous confirmed cases of H5N1 HPAIV infection in wild birds. Histopathological examination of tissues from this animal revealed a diffuse nonsuppurative panencephalitis with perivascular cuffing, multifocal gliosis and neuronal necrosis. Additionally, focal necrosis of pancreatic acinar cells was observed. Immunohistochemically, lesions in these organs were associated with avian influenza virus antigen in neurons, glial cells and pancreatic acinar cells. Thus, the microscopical lesions and viral antigen distribution in this stone marten differs from that recently described for cats naturally and experimentally infected with the same virus subtype. This is the first report of natural infection of a mustelid with HPAIV H5N1. PMID- 17689553 TI - Expanded murine regulatory T cells: analysis of phenotype and function in contact hypersensitivity reactions. AB - Regulatory T cells (Treg) exert suppressive functions in the periphery of the body for the maintenance of tolerance. The functional analysis of Treg is hampered by the fact that only small numbers (5%-10% among the CD4(+) T cells) of Treg exist in peripheral blood and tedious isolation methods further reduce the yield of high-purity Treg. We therefore set out to expand isolated murine Treg in ex vivo cultures with help of anti-CD3/anti-CD28 antibodies in the presence of IL 2. Our expansion-protocol described herein resulted in a 200-fold expansion of Treg and does not involve feeder cells, beads or other cellular compounds that would interfere with further in vivo use of the expanded cells. Expanded Treg could even be stored in liquid nitrogen and thawed without loss of function. Functional analysis revealed that expanded Treg are superior suppressors of T cell functions in vitro and in vivo and when applied in a model for contact hypersensitivity reactions, Treg were able to suppress the ear swelling reaction significantly. Thereby the expanded Treg home to secondary lymphoid organs in similar manner as observed for freshly isolated Treg. Accordingly, the expansion procedure does not effect the expression of specific homing markers. Thus, this protocol will facilitate the production of Treg as an "off-the-shelf reagent" and offers the possibility to explore the application of Treg as a cellular therapeutic in several allergic and autoimmune diseases. PMID- 17689554 TI - Murine CTLL-2 cells respond to mIL12: prospects for developing an alternative bioassay for measurement of murine cytokines IL12 and IL18. AB - Cell line-based bioassays are becoming increasingly popular for assessment of biological activities of cytokines primarily because these are easy to perform and are not subject to donor variation. A well characterised cell line with world wide availability would further minimise the inter-assay variations. C57BL/6 mice derived T cell line; CTLL-2 fits this criterion. We explored the potential of CTLL-2 cells to develop a bioassay to detection of murine (m) IL12 and mIL18. Both cytokines have shown significant activity against a number of cancers and importantly, act synergistically via mutual upregulation of each other's receptors. The preliminary flow cytometric analyses of immunostained CTLL-2 cells showed that approximately 65% expressed mIL12 and approximately 5% expressed mIL18 receptors suggesting that these may respond to mIL12. As predicted, cells incubated with different doses of mIL12 or mIL18 for 72 h were responsive to mIL12 and not to mIL18. However, when pre-treated with mIL12 for 24 h prior to incubation with mIL18, there was a significant enhancement in response. The sensitivity of the response was comparable to that obtained using the conventional splenocyte-based IFNgamma release assay. The cytokine specificity of the response was proven unequivocally when significant reduction in CTLL-2 response was observed in the presence of the relevant neutralising antibodies. Finally, we could successfully detect lowest doses of approximately 0.1 pg/microL mIL12 or 40 pg/mL of mIL18 in cell supernatants in a cytokine specific manner, which is lower than the resting levels of these cytokines in mouse sera. Again the sensitivity was comparable to that observed in the conventional IFNgamma release assay. Hence, we have demonstrated the potential of CTLL-2-based bioassay to detect biologically active mIL12 and mIL18 in biological samples accurately and reproducibly. PMID- 17689555 TI - Cellular co-localization of intron-4 containing mRNA and HLA-G soluble protein in melanoma analyzed by fluorescence in situ hybridization. AB - HLA-G5, -G6, and -G7 soluble isoforms of the immunosuppressive HLA-G molecule are produced from the splice variants of the primary HLA-G mRNA transcript containing intron-4 that encodes a specific 21 amino acids tail. In particular, HLA-G5 interacts with the inhibitory ILT2/4 and KIR2DL4 receptors that are expressed on immune cells. Acquisition of soluble HLA-G in the microenvironment may turn a HLA G non-expressing cell into a HLA-G-bearing one. To address the question of how to distinguish cells that express soluble HLA-G generated by alternative splicing from those that have acquired HLA-G, we have developed a method capable of detecting intron-4 containing mRNA and protein in situ simultaneously. M8 melanoma cell line either transfected or not with HLA-G5 cDNA was analyzed by indirect immunofluorescence confocal microscopy using double staining with a HLA G intron-4 digoxygenin labeled probe along with a monoclonal antibody directed against the 21 amino acid tail. The combined fluorescence in situ hybridization was also used on the HLA-G-positive choricarcinoma cell line JEG-3. This method would be helpful to follow-up bona fide HLA-G expression in a heterogeneous cell population and to elucidate the mechanisms underlying soluble HLA-G mediated immune modulation in physiological conditions such as pregnancy and pathophysiological situations such as cancer. PMID- 17689556 TI - Do food protein and carbohydrate content influence the pattern of feeding and the tendency to explore of forest tent caterpillars? AB - This study examines whether the ratio of protein to carbohydrate affects the timing of meals and the propensity to explore of forest tent caterpillars (Malacosoma disstria). The behavior of fourth instar caterpillars was observed on three semi-defined artificial diets varying in protein (p)-carbohydrate (c) ratio. These diets were (a) p14:c28, (b) p28:c14, and (c) p35:c7. The probability of initiating feeding at first contact with the food and the duration of the first feeding event did not vary across diets, suggesting not much difference in phagostimulatory power. There was also no difference in the total time spent eating, at rest and in motion between diets. However, the timing and duration of meals varied significantly; more short meals were observed on the carbohydrate biased diet. The duration of pauses between meals also increased with food protein content. Furthermore, caterpillars on the carbohydrate-biased diet were more likely to leave the trail leading to the known food source and to discover a second food source, suggesting that protein deprivation promotes exploration. These findings shed insight into the physiological responses to protein and carbohydrate ingestion and demonstrate how post-ingestive effects can favor consumption of foods containing protein without invoking an explicit mechanism of independent nutrient regulation, but simply by influencing the pattern of feeding and the propensity to explore. PMID- 17689558 TI - Susceptibility of legume pod borer (LPB), Maruca vitrata to delta-endotoxins of Bacillus thuringiensis (Bt) in Taiwan. AB - Baseline susceptibility of legume pod borer (LPB) to the insecticidal crystal proteins (ICPs) from Bacillus thuringiensis, viz, Cry1Aa, Cry1Ab, Cry1Ac, Cry1Ca and Cry2Aa was assessed in Taiwan. Insect bioassays were performed by incorporating the Bt delta-endotoxins into the LPB artificial diet. The efficacy of different Bt delta-endotoxins against second instar larvae of LPB showed that the toxin Cry1Ab was the most potent toxin (LC(50) 0.207ppm), followed by Cry1Ca, Cry1Aa, Cry2Aa and Cry1Ac in descending order, with LC(50)s 0.477ppm, 0.812ppm, 1.058ppm and 1.666ppm, respectively. Hence, Cry1Ab and/or Cry1Ca toxins would provide effective control of early larval stages of LPB. PMID- 17689557 TI - Fate of blood meal iron in mosquitoes. AB - Iron is an essential element of living cells and organisms as a component of numerous metabolic pathways. Hemoglobin and ferric-transferrin in vertebrate host blood are the two major iron sources for female mosquitoes. We used inductively coupled plasma mass spectrometry (ICP-MS) and radioisotope labeling to quantify the fate of iron supplied from hemoglobin or as transferrin in Aedes aegypti. At the end of the first gonotrophic cycle, approximately 87% of the ingested total meal heme iron was excreted, while 7% was distributed into the eggs and 6% was stored in different tissues. In contrast, approximately 8% of the iron provided as transferrin was excreted and of that absorbed, 77% was allocated to the eggs and 15% distributed in the tissues. Further analyses indicate that of the iron supplied in a blood meal, approximately 7% appears in the eggs and of this iron 98% is from hemoglobin and 2% from ferric-transferrin. Whereas, of iron from a blood meal retained in body of the female, approximately 97% is from heme and <1% is from transferrin. Evaluation of iron-binding proteins in hemolymph and egg following intake of (59)Fe-transferrin revealed that ferritin is iron loaded in these animals, and indicate that this protein plays a critical role in meal iron transport and iron storage in eggs in A. aegypti. PMID- 17689559 TI - Differences in inflammation, MMP activation and collagen damage account for gender difference in murine cardiac rupture following myocardial infarction. AB - Cardiac rupture remains a fatal complication of acute myocardial infarction (MI) with its mechanism partially understood. We hypothesized that damage to the collagen matrix of infarcted myocardium is the central mechanism of rupture and therefore responsible for the difference in the incidence of rupture between genders. We examined left ventricular (LV) remodeling during the acute phase post MI in 129sv mice. Following induction of MI, we monitored rupture events and assessed the extent of LV remodeling by echocardiography. Muscle tensile strength, content of insoluble and soluble collagen, expression and activity of matrix metalloproteinases (MMPs) and density of inflammatory cells were determined in the infarcted and non-infarcted myocardium. We then tested the effects of MMP inhibition on rupture. Compared to female mice, males with MI displayed greater extent of LV remodeling, reduced muscle tensile strength, loss of insoluble collagen, local inflammatory response and MMP-9 activation, changes associated with a 3 times higher incidence of rupture than in females. MMP-9 expression by circulating blood mononuclear cells was also increased in male mice with acute MI. Treatment of male mice with an MMP inhibitor reduced MMP activity and halved rupture incidence. Our findings demonstrate that the differences in the severity of inflammation, MMP activation and damage to collagen matrix account for gender difference in cardiac rupture. Our study illustrates the breakdown of fibril collagen as a central mechanism of cardiac rupture. PMID- 17689560 TI - Aerobic interval training enhances cardiomyocyte contractility and Ca2+ cycling by phosphorylation of CaMKII and Thr-17 of phospholamban. AB - Cardiac adaptation to aerobic exercise training includes improved cardiomyocyte contractility and calcium handling. Our objective was to determine whether cytosolic calcium/calmodulin-dependent kinase II and its downstream targets are modulated by exercise training. A six-week aerobic interval training program by treadmill running increased maximal oxygen uptake by 35% in adult mice, whereupon left ventricular cardiomyocyte function was studied and myocardial tissue samples were used for biochemical analysis. Cardiomyocytes from trained mice had enhanced contractility and faster relaxation rates, which coincided with larger amplitude and faster decay of the calcium transient, but not increased peak systolic calcium levels. These changes were associated with reduced phospholamban expression relative to sarcoplasmic reticulum calcium ATPase and constitutively increased phosphorylation of phospholamban at the threonine 17, but not at the serine 16 site. Calcium/calmodulin-dependent kinase IIdelta phosphorylation was increased at threonine 287, indicating activation. To investigate the physiological role of calcium/calmodulin-dependent kinase IIdelta phosphorylation, this kinase was blocked specifically by autocamtide-2 related inhibitory peptide II. This maneuver completely abolished training-induced improvements of cardiomyocyte contractility and calcium handling and blunted, but did not completely abolish the training-induced increase in Ca(2+) sensitivity. Also, inhibition of calcium/calmodulin-dependent kinase II reduced the greater frequency-dependent acceleration of relaxation that was observed after aerobic interval training. These observations indicate that calcium/calmodulin-dependent kinase IIdelta contributes significantly to the functional adaptation of the cardiomyocyte to regular exercise training. PMID- 17689561 TI - The folding pathway of an FF domain: characterization of an on-pathway intermediate state under folding conditions by (15)N, (13)C(alpha) and (13)C methyl relaxation dispersion and (1)H/(2)H-exchange NMR spectroscopy. AB - The FF domain from the human protein HYPA/FBP11 folds via a low-energy on-pathway intermediate (I). Elucidation of the structure of such folding intermediates and denatured states under conditions that favour folding are difficult tasks. Here, we investigated the millisecond time-scale equilibrium folding transition of the 71-residue four-helix bundle wild-type protein by (15)N, (13)C(alpha) and methyl(13)C Carr-Purcell-Meiboom-Gill (CPMG) NMR relaxation dispersion experiments and by (1)H/(2)H-exchange measurements. The relaxation data for the wild-type protein fitted a simple two-site exchange process between the folded state (F) and I. Destabilization of F in mutants A17G and Q19G allowed the detection of the unfolded state U by (15)N CPMG relaxation dispersion. The dispersion data for these mutants fitted a three-site exchange scheme, U<-->I<- >F, with I populated higher than U. The kinetics and thermodynamics of the folding reaction were obtained via temperature and urea-dependent relaxation dispersion experiments, along with structural information on I from backbone (15)N, (13)C(alpha) and side-chain methyl (13)C chemical shifts, with further information from protection factors for the backbone amide groups from (1)H/(2)H exchange. Notably, helices H1-H3 are at least partially formed in I, while helix H4 is largely disordered. Chemical shift differences for the methyl (13)C nuclei suggest a paucity of stable, native-like hydrophobic interactions in I. These data are consistent with Phi-analysis of the rate-limiting transition state between I and F. The combination of relaxation dispersion and Phi data can elucidate whole experimental folding pathways. PMID- 17689562 TI - Nitration of a critical tyrosine residue in the allosteric inhibitor site of muscle glycogen phosphorylase impairs its catalytic activity. AB - Muscle glycogen phosphorylase (GP) is a key enzyme in glucose metabolism, and its impairment can lead to muscle dysfunction. Tyrosine nitration of glycogen phosphorylase occurs during aging and has been suggested to be involved in progressive loss of muscle performance. Here, we show that GP (in its T and R form) is irreversibly impaired by exposure to peroxynitrite, a biological nitrogen species known to nitrate reactive tyrosine residues, and to be involved in physiological and pathological processes. Kinetic and biochemical analysis indicated that irreversible inactivation of GP by peroxynitrite is due to the fast (k(inact)=3 x 10(4) M(-1) s(-1)) nitration of a unique tyrosine residue of the enzyme. Endogenous GP was tyrosine nitrated and irreversibly inactivated in skeletal muscle cells upon exposure to peroxynitrite, with concomitant impairment of glycogen mobilization. Ligand protection assays and mass spectrometry analysis using purified GP suggested that the peroxynitrite-dependent inactivation of the enzyme could be due to the nitration of Tyr613, a key amino acid of the allosteric inhibitor site of the enzyme. Our findings suggest that GP functions may be regulated by tyrosine nitration. PMID- 17689563 TI - Quantification of the elevated rate of domain rearrangements in metazoa. AB - Most eukaryotic proteins consist of multiple domains created through gene fusions or internal duplications. The most frequent change of a domain architecture (DA) is insertion or deletion of a domain at the N or C terminus. Still, the mechanisms underlying the evolution of multidomain proteins are not very well studied. Here, we have studied the evolution of multidomain architectures (MDA), guided by evolutionary information in the form of a phylogenetic tree. Our results show that Pfam domain families and MDAs have been created with comparable rates (0.1-1 per million years (My)). The major changes in DA evolution have occurred in the process of multicellularization and within the metazoan lineage. In contrast, creation of domains seems to have been frequent already in the early evolution. Furthermore, most of the architectures have been created from older domains or architectures, whereas novel domains are mainly found in single-domain proteins. However, a particular group of exon-bordering domains may have contributed to the rapid evolution of novel multidomain proteins in metazoan organisms. Finally, MDAs have evolved predominantly through insertions of domains, whereas domain deletions are less common. In conclusion, the rate of creation of multidomain proteins has accelerated in the metazoan lineage, which may partly be explained by the frequent insertion of exon-bordering domains into new architectures. However, our results indicate that other factors have contributed as well. PMID- 17689564 TI - Efficacy of direct electrical current therapy and laser-induced interstitial thermotherapy in local treatment of hepatic colorectal metastases: an experimental model in the rat. AB - BACKGROUND: Local antitumoral therapy of metastases is an important tool in the palliative treatment of advanced colorectal cancer. Several authors have recently reported on successful local treatment of different malignant diseases with low level direct current therapy. The aim of the present study was to compare the effectiveness of direct current therapy with the established laser-induced thermotherapy (LITT) on experimental colorectal liver metastases. MATERIALS AND METHODS: Colorectal metastases were induced in 49 BD IX rats by injection of colon cancer cells beneath the liver capsule. Three weeks after induction, tumor volumes and sizes were estimated with magnetic resonance imaging and by manual measurement of the largest tumor diameter, and two treatment groups and two control groups were established. Direct current (80 C/cm(3)) versus LITT (2 W; 5 to 10 min) was locally applied via laparotomy. Control groups were sham treated. Tumor growth was analyzed 5 wk after therapy by manual measurement of the maximal diameter and histopathological examination was performed. RESULTS: Measurement of tumor sizes 5 wk after therapy confirmed a significant antitumoral effect of direct current (1.6-fold tumor enlargement) and of LITT (1.3-fold tumor enlargement), compared with controls (2.8-fold and 2.9-fold tumor enlargement). However, after 5 wk, LITT was significantly more effective in limiting tumor growth than direct current treatment (P 0.05). Geometric means (GM) are similar, ranging from 1040 to 1380 Bq m(-3), whereas geometric standard deviations (GSD) for both the retrospective methods are greater than for the CONT method, showing reasonable agreement between VT, ST and CONT measurements. A regression analysis, with respect to the lognormal distribution of each data set, shows that for VT-ST the correlation coefficient r is 0.85, for VT-CONT r is 0.82 and for ST-CONT r is 0.73. Comparison of retrospective and contemporary radon concentrations with regard to supposed long-term indoor radon changes further supports the principal agreement between the retrospective and conventional methods. PMID- 17689590 TI - Osmium in environmental samples from Northeast Sweden. Part II. Identification of anthropogenic sources. AB - Osmium (Os) concentrations and (187)Os/(188)Os isotope abundance ratios measured in epiphytic lichens from Northeast Sweden have been used for the identification of anthropogenic emission sources of this element. Based on isotope abundance ratios and similarities in spatial distributions between Os and chromium, smelters operated on chromium ores from Kemi deposits have shown to be the most important factor affecting the airborne Os burden in the region. The extent of the exposure is reflected by lichen concentrations near the source exceeding those from remote areas by a factor of 1000. Contributions from metal foundries processing iron, copper, lead and zinc ores can also be seen, though, because of lower Os concentrations in the feedstock, on a considerably lower scale. Masked by these industrial emissions in the studied area, the impact of Os originating from automotive catalytic converters cannot be resolved at present. PMID- 17689591 TI - Polycyclic aromatic hydrocarbon (PAH) content of soil and olives collected in areas contaminated with creosote released from old railway ties. AB - Simple sample preparation procedures involving sonication and solid phase extraction (SPE), followed by reversed-phase high performance liquid chromatography (HPLC) and spectrofluorometric detection, were used to analyse polycyclic aromatic hydrocarbons (PAHs) in soil and olives collected in areas contaminated with creosote-treated railway ties. Very high PAH contents (with amounts ranging from 114.7 to 2157.2 and from 167.3 to 3121.8 microg kg(-1) dry weight for total light PAHs and total heavy PAHs, respectively) were found in soil sampled up to 1 m from the source of contamination. The PAH load decreased rapidly with the distance from the railway ties. High amounts of light PAHs, up to 6359.9 microg kg(-1), were also found in oil extracted from olives collected in a rural area where old railway ties were stored. No appreciable transfer of heavy PAHs and benzo[a]pyrene was observed in oil samples. PMID- 17689592 TI - Mapping ecological risk of agricultural pesticide runoff. AB - A screening approach for the EU-scale is introduced and validated that predicts pesticide runoff and related ecological risk for aquatic communities in small agricultural streams. The approach is based on the runoff potential (RP) of stream sites, by a spatially explicit calculation based on pesticide use, precipitation, topography, land use and soil characteristics in the near-stream environment. The underlying simplified model complies with the limited availability and resolution of data at larger scales. RP is transformed to ecological risk by means of a runoff-response relationship between RP and invertebrate community composition that results from a large-scale investigation and considers the influence of landscape-mediated recovery pools. Community composition is expressed as abundance of SPEcies At Risk (SPEAR) i.e. species that are potentially affected by pesticides because of physiological sensitivity to organic pollutants and ecological traits. The SPEAR concept was applied because it provides powerful community descriptors that are independent of habitat parameters and support comparison of pesticide effects between different geographical regions. Raster maps for the EU before the 2004 enlargement indicate that ecological risk from pesticide runoff is potentially low for streams in 34% of the grid cells with non-irrigated arable land (mostly northern countries, predicted effects at < or = 20% of the streams per cell). In contrast, ecological risk is very high in 19% of the grid cells (central and southern countries, predicted effects at >90% of the streams per cell). Field investigations showed that the screening approach produced appropriate estimates of ecological risk from pesticide runoff for selected regions in Finland, France and Germany. PMID- 17689593 TI - Fertility-sparing surgery in 101 women with adenocarcinoma in situ of the cervix. AB - OBJECTIVES: Cervical adenocarcinoma in situ (AIS) is a precursor of invasive disease that is increasing in incidence primarily among reproductive-age women of low parity. Conization is an alternative to hysterectomy that allows future pregnancy, but has an inherent risk of residual AIS. The purpose of this study was to determine the outcomes of patients treated by this fertility-sparing strategy over an extended period of surveillance. METHODS: Women diagnosed with cervical AIS who underwent primary fertility-sparing surgery with either loop excision or cold knife conization between 1993 and 2001 were identified at three institutions. A retrospective medical record review was performed. Patients 40 years of age and older and those undergoing hysterectomy within 12 months of diagnosis were excluded. RESULTS: A total of 101 women underwent cone biopsy and expectant management. The median age was 29 years. Fifty-seven percent were nulliparous and 23% primiparous. Cold knife conization was most commonly performed (69 vs. 32 procedures) and had a higher efficacy of achieving negative margins (72% vs. 47%; P=0.036). Thirty-five women had a total of 49 pregnancies during a mean follow-up of 51 months. Thirty-five gestations were delivered at term. There were two preterm births, eight spontaneous miscarriages, three elective terminations, and one ectopic pregnancy. Thirty-six patients had a repeat cone biopsy. Five ultimately underwent hysterectomy. No invasive cervical adenocarcinomas were observed during the study interval. CONCLUSION: Fertility sparing surgery enables women with cervical AIS to achieve pregnancy with minimal risk of developing invasive disease during surveillance. PMID- 17689594 TI - Continent ileocolonic urinary diversion (Rome pouch) for gynecologic malignancies: technique and feasibility. AB - OBJECTIVE: To describe the technique, feasibility and early complications of "Rome pouch" urinary diversion. METHODS: Thirty-five consecutive patients affected by advanced or recurrent gynecological cancers who required anterior or total pelvectomy entered the study. Rome pouch technique starts with the transection of terminal ileum about 12 cm from the ileocecal valve; the large colon is transected 15-20 cm distal to the hepatic flexure. The intestinal wall tension and internal pressure are reduced using 5-8 transverse teniamyotomies of the cecum. The efferent segment of the pouch is created either with the appendix or with the distal ileum. Operative data, intra- and early postoperative complications were recorded. RESULTS: Between February 2000 and March 2006, an ileocolonic urinary diversion (Rome pouch) was carried out in 35 patients affected by advanced or recurrent gynecologic malignancies. The average operative time to complete the anterior and total exenteration including reconstruction procedure was 285 (range, 230-350) and 320 (range 280-415) min, respectively. The average time in performing the Rome pouch technique was 60 min (range, 45-90). Overall postoperative complication rate (major and minor complications) was 82% (29 patients). Febrile morbidity occurred in 26 patients (74%). Wound complications and pelvic collection were found in 7 (20%) and 6 (17%) patients, respectively. CONCLUSION: Our experience demonstrated that Rome pouch technique represents a valid alternative in gynecology oncology for continent urinary diversion. This technique showed low rate of medical and early urologic complications. The simplicity of performing the procedure and the reduced operating time are the best goals reached by Rome pouch technique. Future comparative trials will better define the role that the Rome pouch will have in these patients. PMID- 17689595 TI - Protective effect of Schistosoma mansoni infection on allergic airway inflammation depends on the intensity and chronicity of infection. AB - BACKGROUND: Population studies have suggested that chronic and intense helminth infections, in contrast to acute and mild helminth infections, might suppress allergic airway inflammation. OBJECTIVE: We sought to address the question of how the chronicity and intensity of helminth infections affect allergic airway inflammation in a well-defined experimental model. METHODS: C57/Bl6 mice were infected with Schistosoma mansoni, followed by sensitization and challenge with ovalbumin (OVA), and different stages and intensities of infection were studied. To this end, mice were analyzed at 8, 12, or 16 weeks, representing the acute, intermediate, or chronic phases of infection, respectively. RESULTS: Lung lavage eosinophilia, peribronchial inflammation, and OVA-induced airway hyperresponsiveness were increased during acute infection but significantly decreased when infection progressed into chronicity. Decreases in lung lavage eosinophilia were parasite density-dependent. Similar levels of OVA-specific IgE were found during all phases of infection, whereas both OVA-specific and parasite specific T(H)2 cytokine levels were significantly reduced during chronic infection. Inhibition of airway inflammation could be transferred to OVA sensitized recipient mice by B cells and CD4(+) T cells from spleens of chronically, but not acutely, infected mice. This suppression was IL-10 dependent. CONCLUSION: During chronic, but not acute, helminth infections, suppressive mechanisms are induced that regulate immune reactions to inhaled allergens. These data confirm human epidemiologic observations in a well controlled animal model. CLINICAL IMPLICATIONS: Characterization of chronic helminth infection-induced regulatory mechanisms will help in the development of future therapeutics to treat or prevent allergic disease. PMID- 17689596 TI - Peanut allergy: emerging concepts and approaches for an apparent epidemic. AB - Peanut allergy is typically lifelong, often severe, and potentially fatal. Because reactions can occur from small amounts, the allergy presents patients with significant obstacles to avoid allergic reactions. In North America and the United Kingdom, prevalence rates among schoolchildren are now in excess of 1%, framing an increasing public health concern and raising research questions about environmental, immunologic, and genetic factors that may influence outcomes of peanut allergy. This review focuses on recent observations that continue to question the influences of maternal and infant diet on outcomes of peanut allergy, and explore how peanut may be uniquely suited to induce an allergic response. We highlight studies that affect current diagnosis, management, and the nature of advice that can be provided to patients, including the utility of diagnostic tests, doses that elicit reactions, characteristics of reactions from exposure, issues of cross-reactivity, concerns about peanut contamination of manufactured goods, and the natural course of the allergy. Clinical, molecular, and immunologic advances are reviewed, highlighting research discoveries that influence strategies for improved diagnosis, prevention, and treatment. Among the therapeutic strategies reviewed are sublingual and oral immunotherapy, anti-IgE, Chinese herbal medicine, and vaccine strategies. PMID- 17689597 TI - Transmembrane activator and calcium modulator and cyclophilin ligand interactor enhances CD40-driven plasma cell differentiation. AB - BACKGROUND: Transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) is a receptor used by B cell-activating factor of the TNF family and a proliferation-inducing ligand (APRIL) to induce isotype switching independently of CD40 and is mutated in patients with common variable immunodeficiency. OBJECTIVE: We sought to determine whether TACI and CD40 cooperate in inducing class switch recombination and immunoglobulin production. METHODS: Naive mouse B cells were stimulated with suboptimal concentrations of anti-CD40 plus IL-4 in the presence or absence of APRIL or anti-TACI. IgG(1) and IgE production was measured by means of ELISA. mRNA for Cgamma(1) and Cepsilon germ-line transcripts, activation-induced cytidine deaminase, and mature gamma(1) and epsilon transcripts were measured by means of RT-PCR. Plasmablasts were enumerated by using syndecan-1/CD138 staining. Interferon regulatory factor 4, B lymphocyte-induced maturation protein 1, and IL6 mRNA expression was measured by using quantitative PCR. RESULTS: TACI ligation enhanced IgG(1) and IgE secretion by naive murine B cells stimulated by anti-CD40 plus IL-4, with little effect on B-cell proliferation or class switch recombination. In contrast, TACI ligation of anti-CD40 plus IL-4-stimulated B cells induced a significant increase in syndecans-1/CD138-positive cells. TACI ligation caused a modest but significant increase in the expression of interferon regulatory factor 4, with no detectable change in B lymphocyte-induced maturation protein 1 expression. CONCLUSION: TACI and CD40 signaling converge to promote B-cell differentiation into plasmablasts. CLINICAL IMPLICATIONS: Our data suggest that TACI dysfunction could contribute to the impaired antibody response to T-dependent antigens in common variable immunodeficiency. PMID- 17689598 TI - Low IFN-gamma production in the first year of life as a predictor of wheeze during childhood. AB - BACKGROUND: Diminished cytokine production in infancy has been associated with an increased risk for allergen sensitization and early-life wheeze. OBJECTIVE: We sought to assess the effect of low cytokine production in the first year of life on the development of wheeze through age 13 years. METHODS: Cytokine production (IFN-gamma and IL-2) by mitogen-stimulated mononuclear cells was determined from peripheral blood samples (9.4 months, n = 118) in a subset of healthy infants enrolled in the Tucson Children's Respiratory Study. The occurrence of wheeze during the previous year was ascertained at ages 2, 3, 6, 8, 11, and 13 years by means of questionnaire. Relative risk for wheeze was computed with generalized estimating equations. RESULTS: The risk of wheezing between 2 and 13 years was significantly higher for subjects with low 9-month IFN-gamma production (relative risk, 2.29; 95% CI, 1.35-3.89) and borderline significant for those with intermediate IFN-gamma production (relative risk, 1.59; 95% CI, 0.95-2.68) compared with those who produced high levels of IFN-gamma (P value for linear association = .002). Nine-month IL-2 production was unrelated to wheeze. In relation to complex wheezing phenotypes, 9-month IFN-gamma production was inversely related to toddler wheeze (occurring only before age 6 years, P = .03) and chronic wheeze (occurring before and after age 6 years, P = .007) but not school-age wheeze (occurring only after age 6 years, P = .06). CONCLUSION: The results suggest that characteristics of the immune system present during the first year of life can anticipate the likelihood of development of episodes of airway obstruction characterized by wheezing. CLINICAL IMPLICATIONS: Immune susceptibility to asthma is established very early during postnatal life. PMID- 17689599 TI - Evolutionary biology of plant food allergens. AB - The majority of plant food allergens can be grouped into just 4 protein families. This review summarizes the evolutionary relationships of allergenic and nonallergenic members of these families. Proteins from the prolamin superfamily have been described in vascular plants. This superfamily contains several allergenic (2S albumins, nonspecific lipid transfer proteins, and cereal amylase and protease inhibitors) and nonallergenic (hybrid proline-rich proteins, cereal indolines, and alpha-globulins) member families. The cupin superfamily comprises numerous functionally highly diverse protein families from all groups of organisms. However, allergenicity within the cupins is confined to the vicilin and legumin seed storage proteins. Profilins are ubiquitous eukaryotic proteins that are nonallergenic, with the exception of profilins from flowering plants. Finally, the Bet v 1 superfamily contains the pathogenesis-related proteins 10 family, the family of major latex proteins and ripening-related proteins, the norcoclaurine synthases, and the cytokinin-binding proteins, with pathogenesis related proteins 10 family members from certain taxa being the only allergenic members. The study of the distribution of allergenic and nonallergenic members of protein families will provide new insights into the evolution of allergenicity and the factors that make proteins allergenic. PMID- 17689600 TI - Preference-based electronic decision aid to promote colorectal cancer screening: results of a randomized controlled trial. AB - OBJECTIVE: Despite the burden of colorectal cancer and improved health care outcomes with early detection and treatment, screening rates among eligible adults are low. We previously developed through a series of studies an interactive electronic tool, Colorectal Web, to promote colorectal cancer screening. METHOD: From May 2002 to December 2003, we conducted a randomized controlled trial of Colorectal Web compared to a standard Web site on colorectal cancer screening in urban, suburban, and rural communities in Michigan with high colorectal cancer burden. Study participants were age 50 years and older, with no previous colorectal cancer screening. Major outcome was screened for colorectal cancer by 24 weeks post-intervention. RESULTS: 174 eligible adults were randomized and participated. Immediately post-intervention, Colorectal Web participants were significantly more likely to have a preferred colorectal cancer screening method, but this difference did not persist at subsequent follow-up. Eighty-nine participants had been screened for colorectal cancer by 24 weeks post intervention. The probability of being screened for the Colorectal Web intervention study arm compared to the control is OR=3.23 (2.73-3.50 95% Confidence Interval). CONCLUSION: Colorectal Web is more effective than a standard colorectal cancer Web site at prompting previously unscreened individuals to choose a preferred colorectal cancer screening test and to be screened for colorectal cancer. PMID- 17689601 TI - School teachers can effectively manage primary prevention of adult cardiovascular disease. The Stradella Project. AB - OBJECTIVE: To determine whether school teachers educated about Primary Prevention of Adult Cardiovascular Disease (PPCVD) could help their students improve their blood lipid profile. METHOD: Five teachers voluntarily received training about PP CVD. Thirteen classes of a single high school in Stradella (north Italy) were randomized to receive a 2-month course on PP-CVD (PP-classes; 150 pupils) by their teachers or to a control group (control classes; 130 pupils) during 2004. In all students body weight and fasting venous blood concentrations of total cholesterol (TC), HDL-CHOL, LDL-CHOL, and triglycerides were determined before and 6 months after the completion of the PP-CVD course. RESULTS: Six months after the PP-CVD course, males had significant improvements of all baseline lipid parameters whereas females had improved HDL-CHOL and TC/HDL ratio. No improvements were observed in the control class students. Body weight was unchanged in both groups of students 6 months after the PP-CVD course or the control course. CONCLUSION: This investigation shows that well-trained school teachers are able to manage PP-CVD education so that students can really improve their lipid profile as a consequence of autonomous changes in dietary habits. PMID- 17689602 TI - Smoking status and adiponectin in healthy Japanese men and women. AB - BACKGROUND: Recent studies promisingly indicate that adiponectin plays an important and fundamental role in the development and progression of metabolic and atherosclerosis disorders. Smoking is known as one of the most important risk factors of atherosclerosis, and its relation with metabolic disorders has also been reported. We therefore investigated the association between cigarette smoking and adiponectin concentration in a large sample of Japanese men and women. METHOD: The cross-sectional study was carried out in 2002. The subjects were 3260 men and 953 women local government workers aged 35 to 59 in Japan. Lifestyle-related variables including detailed smoking history were inquired in a self-administered questionnaire. RESULTS: Significant differences in adiponectin levels related to smoking status were observed in both men and women (p=0.001). A dose-dependent association was found between the intensity of smoking and adiponectin levels in current smokers, and was statistically significant in men (p for trend=0.006 in the multivariate-adjusted model). Men who quit smoking for more than 20 years and women for more than 10 years had an adiponectin concentration similar to that observed in non-smokers. CONCLUSION: We not only revealed that current smoking habit was associated with low adiponectin level but also found a dose-dependent association between smoking intensity and adiponectin level in current smokers. The present finding may provide further evidence of the importance of a causal relationship between smoking status and adiponectin concentrations. PMID- 17689603 TI - Follicular development and plasma concentrations of LH and prolactin in anestrous female dogs treated with the dopamine agonist cabergoline. AB - The effect of a daily administration of a dopamine agonist (cabergoline, 5 microg/kg) for 4 weeks, starting about 95 days after the end of estrus on follicular development and its relationship with LH and prolactin secretion has been investigated in two groups of anestrous bitches (Beagles and Greyhounds). Pro-estrus was detected in 80% (8/10) of beagles and 50% (3/6) of treated greyhounds. The mean inter-estrus interval of treated animals was 132+/-5.0 and 169+/-7.0 days for beagles and greyhounds, respectively, and in both this differed significantly from the cycle preceding treatment (192+/-9.0 and 198+/ 12.0 days) and from that in untreated bitches (194+/-11.0 and 196+/-11.0 days for beagles and greyhounds, respectively (all comparisons at P<0.001). The interval from the beginning of treatment to pro-estrus in responding animals was 13.3+/ 1.90 days in beagles and 20.3+/-1.70 days in greyhounds. Cabergoline increased (P<0.001) the length of pro-estrus (10.6+/-0.50 and 11.7+/-0.50 days) in the treated estrus cycle compared to the previous estrus cycle (8.4+/-0.30 and 8.8+/ 0.40 days for in beagles and greyhound, respectively). Ovarian enlargement and follicle development was detected by ultrasound in 90% of treated beagles and in 83% of greyhound between the second and third weeks of treatment, but only 80% of beagles and 66% of treated greyhound displayed pro-estrus and estrus. In the treated bitches, mean plasma LH increased (P<0.001) before pro-estrus. There was high variability in mean plasma prolactin levels between animals. These data indicate that the administration of the dopamine agonist cabergoline to anestrous bitches increases mean LH plasma levels and induces follicular development shortly before pro-estrus but this activity is not always followed by pro-estrus and estrus. Finally, prolactin per se does not have a prominent role in the control of folliculogenesis in the bitch. PMID- 17689604 TI - Production of non-canonical sentences in agrammatic aphasia: limits in representation or rule application? AB - The study reported here compares two linguistically informed hypotheses on agrammatic sentence production, the TPH [Friedmann, N., & Grodzinsky, Y. (1997). Tense and agreement in agrammatic production: Pruning the syntactic tree. Brain and Language, 56, 397-425.] and the DOP [Bastiaanse, R., & van Zonneveld, R. (2005). Sentence production with verbs of alternating transitivity in agrammatic Broca's aphasia. Journal of Neurolinguistics, 18, 59-66]. To explain impaired production of non-canonical sentences in agrammatism, the TPH basically relies on deleted or pruned clause structure positions in the left periphery, whereas the DOP appeals to limitations in the application of movement rules. Certain non canonical sentences such as object-questions and object-relative clauses require the availability of nodes in the left periphery as well as movement to these nodes. In languages with relatively fixed word order such as English, the relevant test cases generally involve a coincidence of left periphery and movement, such that the predictions of the TPH and the DOP are identical although for different reasons. In languages with relatively free word order such as German, on the other hand, it is possible to devise specific tests of the different predictions due to the availability of scrambling. Scrambled object sentences, for example, do not involve the left periphery but do require application of movement in a domain below the left periphery. A study was conducted with German agrammatic subjects which elicited canonical sentences without object movement and non-canonical scrambled sentences with object movement. The results show that agrammatic speakers have a particular problem with the production of scrambled sentences. Further evidence reported in the study from spontaneous speech, elicitation of object relatives, questions and passives and with different agrammatic subjects confirms that non-canonical sentences are generally harder to produce for agrammatics. These findings provide evidence in favor of the DOP and it will be argued that a cross-modal explanation of agrammatic deficits is possible if two factors--movement and canonicity--are taken into consideration. PMID- 17689605 TI - Light transmission on dental resin composites. AB - OBJECTIVES: The purposes of this study was: (1) to examine the light transmittance characteristics of two light-cured resin composites, for different thickness, (2) to correlate the light transmittance through the resin composites and the filler contents, and (3) to determine the penetration depth of the light as a function of the wavelength. METHODS: Two resin composites (Filtek Z250, shade A2 and Filtek Supreme XT, shade A2E) were used. Specimens of six different thicknesses (0.15, 0.25, 0.30, 0.36, 0.47 and 0.75 mm) were prepared (n=3). The transmittance at wavelengths from 400 to 800 nm was measured using a UV-visible spectrophotometer, before and after light polymerization. RESULTS AND SIGNIFICANCE: Significant differences were found in the wavelength dependence of transmittance between the two materials, and between the unpolymerized and polymerized stages of each resin composite. At lower wavelengths, the light transmittance of the Filtek Supreme XT resin composite was lower than the Filtek Z250. At the higher wavelengths, however, Filtek Supreme XT presented higher light transmittance. For both resin composites, the penetration depth was higher after polymerization. However, Filtek Supreme XT showed a higher gain in transmittance at the 0.15 mm thickness. The difference in light transmittance characteristics of the resin composites may affect their depth of polymerization. PMID- 17689606 TI - Morphology and structure of electrospun mats from regenerated silk fibroin aqueous solutions with adjusting pH. AB - In this paper, regenerated silk fibroin (SF) aqueous solutions were adjusted to a pH of 6.9 by mimicing the condition in the posterior division of silkworm's gland and rheological behavior of solutions was investigated. The electrospinning technique was used to prepare fibers, and non-woven mats of regenerated B. mori silk fibroin were successfully obtained. The effects of electrospinning parameters on the morphology and diameter of regenerated silk fibers were investigated by orthogonal design. Statistical analysis showed that voltage, the concentration of regenerated SF solutions and the distance between tip and collection plate were the most dominant parameters to fiber morphology, diameter and diameter distribution, respectively. An optimal electrospinning condition was obtained in producing uniform cylindrical fibers with an average diameter of 1300nm. It was as follows: the concentration 30%, voltage 40kV, distance 20cm. The structure of electrospun mats was characterized by Raman spectroscopy (RS), wide-angle X-ray diffraction (WAXD) and modulated differential scanning calorimetry (MDSC). It was found that electrospun mats were predominantly random coil/silk I structure, and the transition to silk II (beta-sheet) rich structure should be further explored. PMID- 17689607 TI - Cell-based therapies: from basic biology to replacement, repair, and regeneration. AB - A series of meetings in the last 6 months has afforded an extraordinary opportunity to assess the progress that has been made in the development of cell based therapeutic approaches and the issues that still need to be addressed. Even though real progress has been made, it has become clear that the key to success will come from a better understanding of the basic biology so as to be able to deliver the right biological signals at the right place and at the right time. Beyond the basic biology, there are some other key issues. These include the selection of cell source, the development of "smart", instructive biomaterials that can be used to deliver the biological signals, and the development of bioreactors for the expansion of cells and the growth of tissues, ones that can be scaled up for clinical studies. Tissue engineering and regenerative medicine, though still very much in a fledgling state, continues to offer the promise to address clinical needs where today there are no treatment options available. To do this, however, will require a better understanding of the biology and the development of key technologies. Long-term clinical therapies and treatments must move beyond the replacement of tissues and organs to the harnessing of the intrinsic repair and regenerative potential of the human body. PMID- 17689609 TI - Release of cytochrome c from mitochondria precedes Bax translocation/activation in Triton X-100-induced apoptosis. AB - The precise mechanisms by which sublytic concentrations of detergents induce apoptosis remain unclear. Recent studies reported the ability of nonionic detergents such as Triton X-100 to induce conformational change of Bax to the active form in vitro. Here we investigated whether activation of Bax might play a role in Triton X-100-induced apoptosis in cells. Although Bax translocation/activation was inhibited by caspase inhibitors, cytochrome c release from mitochondria was not affected in Triton X-100-induced apoptosis in U 937 cells. These results demonstrate that translocation/activation of Bax occurs downstream of cytochrome c release and caspase activation in Triton X-100-induced apoptosis. PMID- 17689608 TI - The catastrophe revisited: blood compatibility in the 21st Century. AB - The biomaterials community has been unable to accurately assign the term "blood compatible" to a biomaterial in spite of 50 years of intensive research on the subject. There is no clear consensus as to which materials are "blood compatible." There are no standardized methods to assess blood compatibility. Since we use millions of devices in contact with blood each year, it is imperative we give serious thought to this intellectual catastrophe. In this perspective, I consider five hypotheses as to why progress has been slow in evolving a clear understanding of blood compatibility: Hypothesis 1-It is impossible to make a blood compatible material. Hypothesis 2-We do not understand the biology behind blood compatibility. Hypothesis 3-We do not understand how to test for or evaluate blood compatibility. Hypothesis 4-Certain materials of natural origin seem to show better blood compatibility but we do not know how to exploit this concept. Hypothesis 5-We now have better blood compatible materials but the regulatory and economic climate prevent adoption in clinical practice. PMID- 17689610 TI - The morphological subcategories of acute monocytic leukemia (M5a and M5b) share similar immunophenotypic and cytogenetic features and clinical outcomes. AB - Acute monocytic leukemia (M5) is a subtype of acute myeloid leukemia (AML) with two distinct morphologic subcategories, M5a and M5b. We compared the immunophenotype, cytogenetics and clinical outcome of AML M5 with non-M5 AML and also compared M5a with M5b. One hundred and twelve M5 (76 M5a, 36 M5b) and 726 non-M5 cases were identified and treated on protocols at our institution. There were no significant differences in immunophenotype between M5a and M5b. Translocation 11q23 was the sole abnormality in 18.6% of M5 and 3.2% of non-M5 (p<0.001). Trisomy 8 was also more prevalent in M5 (16.9%) than in non-M5 (8.7%; p=0.03). There was no significant difference in karyotypes between M5a and M5b. The complete remission rate was 70% for AML M5 and 57% for non-M5 AML (p=0.03). There was no significant difference in median overall survival or disease free survival for patients with M5 versus non-M5, M5a versus M5b. Our data indicate that the prognosis of AML M5 is similar to non-M5 AML and that M5a and M5b do not differ in immunophenotype, cytogenetics or clinical outcome. PMID- 17689611 TI - Large-scale survey of porcine endogenous retrovirus in Chinese miniature pigs. AB - We conducted a large-scale survey on the existence and expression status of porcine endogenous retrovirus (PERV) in seven breeds of Chinese miniature pigs. Genotyping of PERV was examined by PCR using type-specific primers according to the env genotyping method. The presence and expression status of viral gag, pol and env genes were further analyzed in Wuzhishan pigs (WZSP) and Bama minipigs (BMP). The results showed that PERV existed in all 348 genomic DNA samples. The genotype distribution was subtype A-74.43%, subtype B-95.40% and subtype C 30.46%. No expression of subtype C was found in WZSP and BMP. This research obtained an adequate level of information on the molecular epidemiology of PERV in China. The results indicated that it is possible to monitor pig herds for individuals with the lowest PERV prevalence, especially lacking PERV-C. PMID- 17689612 TI - Retinal blood flow response to posture change in glaucoma patients compared with healthy subjects. AB - PURPOSE: To characterize the retinal vascular autoregulatory response to ocular perfusion pressure (OPP) changes in patients with glaucoma and in healthy control subjects. DESIGN: Observational cohort study. PARTICIPANTS: Eighteen patients with open-angle glaucoma (OAG) and 8 control subjects, all females ages 40 to 60 years, were studied. Only subjects with known maximum intraocular pressure less than 22 mmHg in both eyes were included. METHODS: Arterial diameter and blood speed in the inferior temporal retinal artery of the left eye were measured simultaneously at baseline while sitting, while reclining for approximately 30 minutes, and once again sitting using a retinal laser Doppler instrument. Blood flow rate was computed automatically. Brachial artery blood pressure and heart rate also were measured. MAIN OUTCOME MEASURE: Change in blood flow rate while reclining for approximately 30 minutes compared with baseline blood flow rate measured while seated. RESULTS: In control subjects, arterial diameter decreased by 7.5+/-3.4% (P = 0.0003) and blood speed increased by 24.6+/-10.8% (P = 0.004) while reclining compared with baseline. The concomitant change in the blood flow rate (6.5+/-12.0%; P = 0.15) compared with baseline was not statistically significant. In contrast, OAG patients showed a much broader range of blood flow changes in response to posture change (14.9+/-37.7%; P = 0.086) compared with baseline. Although there were no significant differences in the flow changes compared with baseline in either group, there was a significant difference in the variance of the blood flow changes in the OAG patients compared with the controls (P = 0.0025). Division of the OAG patients into subgroups revealed a significant (P = 0.031) association between baseline OPP and the retinal blood flow response to posture change. CONCLUSIONS: The authors describe the hemodynamic details of retinal vascular autoregulation in response to posture-induced changes in OPP in healthy subjects and document the lack of such autoregulation in a selected group of patients with OAG. PMID- 17689613 TI - Copper conjugates of nimesulide Schiff bases targeting VEGF, COX and Bcl-2 in pancreatic cancer cells. AB - Copper conjugates of Schiff base derivatives of nimesulide (1), a well-known cyclooxygenase-2 (COX-2) inhibitor, were synthesized, structurally characterized and evaluated for their COX selectivity indices and cytotoxicities on pancreatic tumor, BxPC-3 (COX-2 positive) and MiaPaCa (COX-2 negative) cell lines. Copper conjugates exhibit distorted square planar geometries as revealed by the single crystal X-ray structure determination of Cu(L1)(2) and show significant growth inhibition in both cell lines (IC50 values 3-26 microM for COX-2 positive and 5-9 microM for COX-2 negative cell line) than the parent nimesulide (35 microM for COX-2 positive and >100 microM for COX-2 negative cell line). The mechanistic pathway for the biological activity involves inhibition of vascular endothelial growth factor (VEGF) and COX inhibition, as well as down regulation of antiapoptotic Bcl-2 and Bcl-(XL) proteins. PMID- 17689614 TI - Comparative studies of coordination properties of puromycin and puromycin aminonucleoside towards copper(II) ions. AB - Protonation equilibria of puromycin (PM) and puromycin aminonucleoside (PAN) and their coordination by copper(II) ion were studied in solution by potentiometry, electronic absorption spectroscopy (UV-Vis), circular dichroism (CD), electron paramagnetic resonance (EPR) and mass spectrometry. For puromycin four mononuclear complexes were found, with stoichiometries Cu(PM)2+, CuH(-1)(PM)+, CuH(-2)(PM) and CuH(-3)(PM)(-). In each of them the Cu(II) ion was bound in the peptidic-like manner, the differences of stoichiometries are a consequence of subsequent deprotonations of the sugar C2'-OH group and the coordinated water molecule. The coordination mode for puromycin aminonucleoside was aminosugar like. Two dimeric complexes, Cu2H(-1)(PAN)2(2+) and Cu2H(-2)(PAN)2+, and one monomeric CuH(-2)(PAN)2 were found. The N6,N6-dimethyladenine moiety of PAN was not involved in the coordination process due to steric hindrance. PMID- 17689615 TI - Solution studies of some new oxamides - co-ordination behaviour towards Cu(II) ions. AB - The co-ordination chemistry of some new oxamides towards Cu(II) ions was studied using various techniques: potentiometry, voltammetry, spectroscopy (UV-Vis, CD and EPR) and ESI-MS spectrometry. All tested compounds chelate the copper(II) ions with formation of 1:1 and 1:2 (metal-to-ligand ratio) complexes. The Cu(II) ions are bound by 1N, 2N or 3N nitrogen donor systems. Additionally, an unusual co-ordination to amide N-atoms without additional anchoring site is suggested. The (14)N hyperfine splitting observed for the system ox6-Cu(II) above pH 10 clearly indicates the involvement of at least three N donor atoms in the copper ion binding. Moreover, the surrounding by three amide-N and one carbonyl-O stabilizes the high oxidation state of copper(III), although such complexes are very unstable in solution. PMID- 17689616 TI - New Pd(II) and Pt(II) complexes with N,S-chelated pyrazolonate ligands: molecular and supramolecular structure and preliminary study of their in vitro antitumoral activity. AB - New Pd(II) and Pt(II) complexes [ML2] (HL=a substituted 2,5-dihydro-5-oxo-1H pyrazolone-1-carbothioamide) have been synthesized by reacting K2MCl4 (M=Pd, Pt) or Pd(OAc)2 with beta-ketoester thiosemicarbazones. The structures of seven of these complexes were determined by X-ray diffraction. Although all exhibit a distorted square-planar coordination with trans- or (in one case) cis-[MN2S2] kernels, their supramolecular arrangements vary widely from isolated molecules to 3D-networks. The in vitro antitumoral assays performed with two HL ligands and their metal complexes showed significant cytostatic activity for the latter, with the most active [ML2] derivative (a palladium complex) being about sixteen times more active than cis-DDP against the cisplatinum-resistant cell line A2780cisR. PMID- 17689617 TI - Balanced ROC analysis (BAROC) protocol for the evaluation of protein similarities. AB - Identification of problematic protein classes (domain types, protein families) that are difficult to predict from sequence is a key issue in genome annotation. ROC (Receiver Operating Characteristic) analysis is routinely used for the evaluation of protein similarities, however its results - the area under curve (AUC) values - are differentially biased for the various protein classes that are highly different in size. We show the bias can be compensated for by adjusting the length of the top list in a class-dependent fashion, so that the number of negatives within the top list will be equal to (or proportional with) the size of the positive class. Using this balanced protocol the problematic classes can be identified by their AUC values, or by a scatter diagram in which the AUC values are plotted against positive/negative ratio of the top list. The use of likelihood-ratio scoring (Kajan et al, Bioinformatics,22, 2865-2869, 2007) the bias caused by class imbalance can be further decreased. PMID- 17689619 TI - Successful pregnancy with the use of nitric oxide donors and heparin after recurrent severe preeclampsia in a woman with scleroderma. AB - We report the case of a woman with scleroderma who had severe, early-onset preeclampsia on 2 consecutive pregnancies. With a treatment that included aspirin, heparin, and a nitric oxide donor, her third pregnancy ended with a healthy neonate at term. Nitric oxide donors and heparin may play a preventive role on placental dysfunction in scleroderma. PMID- 17689620 TI - Cognitive dysfunction with tolterodine use. AB - This is the first case of a 65 year old healthy woman developing de novo mental confusion during treatment with 2 mg tolterodine twice daily. It is a rare complication of therapy for overactive bladder and resolved when dosage was reduced to 1 mg, although overactive bladder symptoms were still controlled. PMID- 17689621 TI - Subgroup analysis in obstetrics clinical trials. AB - Although clinical trials report results in the aggregate, clinicians often wish to tailor treatments that are based on demographic, historic, clinical, or laboratory characteristics of their patients and are interested therefore in trial results that are presented separately according to such characteristics. Unfortunately, such subgroup analysis often are done incorrectly and often are misinterpreted, even when done correctly. Only subgroups that are defined by characteristics that are determined at or before the moment of randomization are valid. It is incorrect to determine whether treatment is effective among a subgroup of patients according to the probability value in that particular subgroup. The correct method uses a formal test for interaction. However, even when done correctly, most subgroup differences in treatment effectiveness prove to be spurious. A priori definition of the subgroup, strong supporting rationale, and, ultimately, replication in other studies increase confidence that subgroup differences are valid. PMID- 17689622 TI - To the point: Medical education review of the RIME method for the evaluation of medical student clinical performance. AB - This article, the sixth in the ongoing To The Point Series produced by the Association of Professors of Gynecology and Obstetrics Undergraduate Medical Education Committee, reviews the Reporter-Interpreter-Manager-Educator (RIME) method for the evaluation of student clinical performance on the obstetrics and gynecology rotation. This article discusses the inherent challenges of descriptive narrative evaluation and the superiority of the RIME method in producing meaningful evaluation of and feedback for students. The use of the method to fulfill Liaison Committee on Medical Education standards and implementation of the method are described. PMID- 17689623 TI - Transdermal hormonal contraception: benefits and risks. AB - Transdermal drug delivery systems have been available in the United States for >20 years. Since the introduction of the first transdermal patch (scopolamine) for the treatment of motion sickness, >35 transdermal patch products have been approved by the US Food and Drug Administration for a variety of indications that include hormone replacement therapy, nicotine replacement therapy, chronic pain (fentanyl), angina (nitroglycerin), hypertension (clonidine), and more recently, overactive bladder (oxybutynin), and contraception (ethinyl estradiol/norelgestromin). Clinical data demonstrated the efficacy and safety of the contraceptive patch; however, concerns regarding estrogen levels and reports of venous thromboembolism led to the development of 2 epidemiologic studies and, subsequently, revised product labeling. Despite this, the contraceptive patch may be an appropriate option for some patients. PMID- 17689624 TI - Body composition during treatment with conjugated estrogens with and without medroxyprogesterone acetate: analysis of the women's Health, Osteoporosis, Progestin, Estrogen (HOPE) trial. AB - OBJECTIVE: The objective of the study was to determine the effects of several doses of conjugated estrogens (CE) and CE plus medroxyprogesterone acetate (MPA) on body composition (BC). STUDY DESIGN: This was a randomized, double-blind, placebo-controlled substudy of the Women's Health, Osteoporosis, Progestin, Estrogen (HOPE) trial. Healthy women (n = 822, 1-4 years after menopause) were randomly assigned to receive the following treatments daily for 2 years: CE, 0.625 mg; CE, 0.625 mg, and MPA, 2.5 mg; CE, 0.45 mg; CE, 0.45 mg, and MPA, 2.5 mg; CE, 0.45 mg, and MPA, 1.5 mg; CE, 0.3 mg; CE, 0.3 mg, and MPA, 1.5 mg; or placebo. Body weight (BW) was assessed every 3-4 cycles and fat body mass (FBM), lean body mass (LBM), and percent body fat (PBF) at cycles 6, 13, 19, and 26. RESULTS: In the placebo group, BW, FBM, and PBF increased at each visit during the study. Changes in these parameters were smaller in the active groups. These effects were independent of CE dose and the presence of MPA. Changes in LBM were small and comparable across groups. CONCLUSION: Treatment with CE or CE and MPA for up to 2 years does not affect BC. PMID- 17689625 TI - Long-term use of postmenopausal estrogen and progestin hormone therapies and the risk of endometrial cancer. AB - OBJECTIVE: The purpose of this study was to assess whether endometrial cancer risk among long-term users of (1) sequential estrogen plus progestin 10-24 days per month exceeds that of nonusers and (2) daily estrogen plus progestin (continuous combined hormone therapy) is below that of nonusers. STUDY DESIGN: In this population-based case-control study with 1038 endometrial cancer cases diagnosed in 1985-1999 and 1453 control subjects, exclusive users of a single form of hormone therapy were compared with never users of hormone therapy. RESULTS: For sequential therapy, only long-term use (> or = 6 years) was associated with increased risk (odds ratio, 2.0; 95% CI, 1.2-3.5). Continuous combined therapy was associated with decreased risk (odds ratio, 0.59; 95% CI, 0.40-0.88), with no increased risk among long-term users (odds ratio, 0.77; 95% CI, 0.45-1.3). CONCLUSION: These results support the hypotheses that continuous combined therapy does not increase (and may decrease) endometrial cancer risk and that long-term sequential therapy can lead to a modest increased risk. However, the collective results of all studies of these questions and their clinical implications remain unclear. PMID- 17689626 TI - Adolescent cervical dysplasia: histologic evaluation, treatment, and outcomes. AB - OBJECTIVE: The purpose of this study was to evaluate histologic findings and outcomes among adolescents with cervical dysplasia. STUDY DESIGN: Patient charts (2001-2005) were reviewed. Prevalence of cervical intraepithelial neoplasia (CIN) grades 2 and 3 and progression and regression were recorded. RESULTS: Five hundred one patients were identified. On biopsy, 324 patients (65%) had CIN 1 or less, and 177 patients (35%) had CIN > or = 2. Twenty-nine percent of the patients with CIN 2 opted for conservative treatment vs excision. Over 18 months, the condition of 65% of the patients regressed; the condition of 20% of the patients was stable, and the condition of 5% of the patients progressed without cancer. Of the patients who underwent excision (follow-up median, 26 months), 84% experienced regression of their condition; the condition of 11% was persistent, and 5% progressed with no cancer. CONCLUSION: CIN > or = 2 is present in 35% of our cohort. Most had CIN 2, and most experienced regression. Our observation supports continued vigilance in the evaluation of adolescents but suggests that less intervention for CIN 2 may be acceptable. PMID- 17689627 TI - A randomized trial of the intrauterine contraceptive device vs hormonal contraception in women who are infected with the human immunodeficiency virus. AB - OBJECTIVE: The purpose of this study was to determine whether the intrauterine contraceptive device (IUD) is effective and safe among women who are infected with the human immunodeficiency virus (HIV). STUDY DESIGN: We randomly assigned 599 postpartum, HIV-infected women in Zambia to receive either a copper IUD or hormonal contraception and followed them for at least 2 years. RESULTS: Women who were assigned randomly to hormonal contraception were more likely to become pregnant than those who were assigned randomly to receive an IUD (rate, 4.6/100 vs 2.0/100 woman-years; hazards ratio, 2.4; 95% CI, 1.3-4.7). One woman who was assigned to the IUD experienced pelvic inflammatory disease (crude rate, 0.16/100 woman-years; 95% CI, 0.004-868); there was no pelvic inflammatory disease among those women who were assigned to hormonal contraception. Clinical disease progression (death or CD4+ lymphocyte count dropping below 200 cells/microL) was more common in women who were allocated to hormonal contraception (13.2/100 woman years) than in women who were allocated to the IUD (8.6/100 woman-years; hazard ratio, 1.5; 95% CI, 1.04-2.1). CONCLUSION: The IUD is effective and safe in HIV infected women. The unexpected observation that hormonal contraception was associated with more rapid HIV disease progression requires urgent further study. PMID- 17689628 TI - Neurodevelopmental outcome at 5 years after operative delivery in the second stage of labor: a cohort study. AB - OBJECTIVE: The purpose of this study was to compare the neurodevelopmental outcome of children at 5 years of age after instrument vaginal delivery and cesarean delivery in the second stage of labor. STUDY DESIGN: This prospective cohort study was comprised of women with term, singleton, cephalic pregnancies who needed operative delivery in the operating room during the second stage of labor from February 1999 to February 2000. Data were collected with postal questionnaires and review of medical records. The primary outcome measure was the neurodevelopment of children at 5 years of age. RESULTS: A total of 393 women required operative delivery, of whom 264 women (67%) completed questionnaires at 5 years. A total of 66 children (17%) had been born in poor condition (Apgar score <7 at 5 minutes, umbilical artery pH <7.10, significant trauma, sepsis, or special care baby unit admission). Medical records were available for all 66 children. Rates of neurodevelopmental morbidity were low, with no significant differences between delivery groups. Two children had significant neurodevelopmental morbidity, but this was unlikely to relate to the mode of delivery. CONCLUSION: In this cohort, the rates of neurodevelopmental morbidity were low overall and comparable, irrespective of the mode of delivery. PMID- 17689629 TI - Primary human immunodeficiency virus infection during pregnancy detected by repeat testing. AB - OBJECTIVE: The purpose of this study was to describe characteristics of pregnant women with newly acquired human immunodeficiency virus (HIV) infection that was identified by repeat testing. STUDY DESIGN: The Centers for Disease Control and Prevention-sponsored Mother-Infant Rapid Intervention at Delivery (MIRIAD) study, which was conducted in 6 US cities, encouraged repeat HIV testing during pregnancy to identify primary infections. RESULTS: Fifty-four HIV-infected women were identified. Four primary HIV infections were recognized, with median estimated seroconversion at 22 weeks of gestation. All 4 women denied new sex partners, alcohol, and illegal drug use during pregnancy. Three of the 4 mother infant pairs received antiretroviral medications. One infant was infected perinatally, with positive HIV DNA polymerase chain reaction at birth. Questionnaire data identified 2 additional women with HIV that was likely acquired during pregnancy (identified by rapid testing at labor and delivery), which suggests that 6 of 54 HIV-infected women (11%) in the MIRIAD study had primary infection during pregnancy. CONCLUSION: Repeat HIV testing in pregnancy can identify opportunities for antiretroviral prophylaxis and should be used in areas of high HIV prevalence. PMID- 17689630 TI - Paternal race is a risk factor for preterm birth. AB - OBJECTIVE: The purpose of this study was to test the hypothesis that paternal race influences the risk for preterm birth. STUDY DESIGN: We conducted a population-based cohort study to examine the association of paternal race with preterm birth using the Missouri Department of Health's birth registry from 1989 1997. Birth outcomes were analyzed in 4 categories: white mother/white father, white mother/black father, black mother/white father, and black mother/ black father. RESULTS: We evaluated 527,845 birth records. The risk of preterm birth at <35 weeks of gestation increased when either parent was black (white mother/black father: adjusted odds ratio, 1.28 [95% CI, 1.13, 1.46], black mother/white father: adjusted odds ratio, 2.10 [95% CI, 1.68, 2.62], and black mother/black father: adjusted odds ratio, 2.28 [95% CI, 2.18, 2.39]) and was even higher for extreme preterm birth (<28 weeks of gestation) in pregnancies with a nonwhite parent. CONCLUSION: Paternal black race is associated with an increased risk of preterm birth in white mothers, which suggests a paternal contribution to fetal genotype that ultimately influences the risk for preterm delivery. PMID- 17689631 TI - Planned vs emergent cesarean hysterectomy. AB - OBJECTIVE: The aim of this study was to compare operative and postpartum outcomes between planned and emergent cesarean hysterectomy. STUDY DESIGN: In this multicenter retrospective review over a 5-year period, 65 cases of cesarean hysterectomy (30 planned vs 35 emergent) were identified. Demographic, operative, and postoperative data were extracted and stratified by group (planned vs emergent). RESULTS: Patients who underwent an emergent cesarean hysterectomy were more likely to have higher estimated blood loss (2597.1 +/- 1369.4 mL vs 1963.3 +/- 1180.2 mL; P = .05), have transfusion (66% vs 33%; P = .02), and require greater quantities of packed red blood cells (4.49 +/- 4.7 x10(12)/L vs 1.6 +/- 3.1 x10(12)/L; P = .006) compared with the planned cesarean hysterectomy group. Patients who underwent emergent cesarean hysterectomy had higher overall complication rates (37% vs 66%; P = .03) and more intensive care unit admissions (7% vs 29%; P = .03). CONCLUSION: After planned cesarean hysterectomy, patients had a significantly lower rate of blood loss, less need for blood transfusions, and fewer complications compared with patients who underwent an emergent cesarean hysterectomy. PMID- 17689632 TI - Pattern and degree of forces applied during simulation of shoulder dystocia. AB - OBJECTIVE: The objective of the study was to determine the level and pattern of forces applied during simulated shoulder dystocia. STUDY DESIGN: One hundred forty staff (95 midwives, 45 obstetricians) were randomized from 6 UK hospitals. Applied delivery force was measured during a standardized simulated shoulder dystocia. Maximum, average, total, and applied force gradients were calculated for each delivery. RESULTS: There was a wide range for all force variables: geometric mean maximum applied force 106 newtons (N) (range 6 to more than 250, n = 113), maximum force gradient 45 N/s (range 2-249, n = 113), total applied force 2954 N/s (range 33 to 14,197, n = 108), and average applied force 16 N (range 0 68, n = 108). CONCLUSIONS: Despite participants managing the same scenario, there was great variation in the pattern and degree of traction used. High forces were applied during two thirds of simulations. Training must emphasize that maneuvers should be used to overcome shoulder dystocia while minimizing iatrogenic applied force. PMID- 17689633 TI - Psychosocial impact of early-onset hypertensive disorders and related complications in pregnancy. AB - OBJECTIVE: The objective of the study was to examine the psychosocial impact of severe hypertensive disorders during pregnancy. STUDY DESIGN: All women (n = 216) in a prospective study cohort with severe hypertensive disorders of pregnancy were invited at term age, 3 months, and 1 year postterm to complete the 90-item Symptom Check List (SCL-90) questionnaire for assessment of their psychosocial condition. The association of hypothesized determinants was tested by binary logistic analysis. RESULTS: Psychosocial impact decreased over time in all women (P < .01). Women with an adverse infant outcome had a worse score at term age (P = .04). The only parameter relating significantly to SCL-90 score in multivariate analysis was gestational age at inclusion. One year postterm, 72% resumed work and 9% were still on sick leave. CONCLUSION: Severe hypertensive disorders of pregnancy have a high psychological impact, especially when gestational age at onset of disease is below 30 weeks or if adverse infant outcome occurs. PMID- 17689634 TI - Frontomaxillary facial angles in screening for trisomy 21 at 14-23 weeks' gestation. AB - OBJECTIVE: The objective of the study was to investigate the potential value of the frontomaxillary facial (FMF) angle in second-trimester ultrasound screening for trisomy 21. METHODS: We examined stored images of fetal profiles taken before amniocentesis at 14-24 weeks from 100 euploid fetuses and 34 with trisomy 21. The FMF angles between the upper surface of the upper palate and the frontal bone (FMF(bone)) and the skin over the forehead (FMF(skin)) were measured. RESULTS: In the euploid group the FMF angles decreased with gestation. In the fetuses with trisomy 21, the FMF(bone) and FMF(skin) angles were 79.4% and 87.9% above the 95th percentile for gestation of the respective values from the euploid group. In trisomy 21 fetuses, there was no significant difference in FMF angles between those with nasal bone hypoplasia (n = 19) and those without (n = 15). CONCLUSION: The FMF angle is substantially higher in trisomy 21 than euploid fetuses. Measurement of the FMF angles is likely to prove a useful method in prenatal screening for trisomy 21 in the second trimester. PMID- 17689635 TI - Blood pressure dynamics during pregnancy and spontaneous preterm birth. AB - OBJECTIVE: The objective of the study was to examine whether blood pressure in early pregnancy and its rise in the second half of gestation are associated with spontaneous preterm birth in healthy, normotensive, nulliparous women. STUDY DESIGN: We included 5167 women with singleton gestation who participated in the World Health Organization Calcium Supplementation for the Prevention of Preeclampsia Trial. Systolic, diastolic, and mean arterial blood pressure and pulse pressure at baseline (12-19 weeks of gestation) and at the midthird trimester (30-34 weeks) were calculated. Rise in blood pressure was the difference between the midthird trimester and baseline. Preterm birth was defined as early preterm (less than 34 completed weeks) and late preterm birth (34-36 weeks). RESULTS: Women experiencing early or late preterm birth had over 10 mm Hg and 3 mm Hg higher rise, respectively, in systolic, diastolic, and mean arterial blood pressure than women delivering at term. A rise in systolic pressure over 30 mm Hg or diastolic pressure over 15 mm Hg was associated with a statistically significant 2- to 3-fold increase in risk of spontaneous preterm birth. CONCLUSION: An excessive rise in either systolic or diastolic blood pressures from early pregnancy to the midthird trimester is associated with spontaneous preterm birth in a dose-response pattern. PMID- 17689636 TI - Systemic and vaginal biomechanical properties of women with normal vaginal support and pelvic organ prolapse. AB - OBJECTIVE: The objective of the study was to compare the biomechanical properties of vaginal and systemic skin in women with and without pelvic organ prolapse. STUDY DESIGN: In this cross-sectional study, 25 women with pelvic organ prolapse and 23 age-matched women with normal pelvic support were recruited from an office setting. A Cutometer MPA 580 and DermaLab skin probe were used to measure systemic biomechanical parameters and a 1.5 mm offset DermaLab skin probe was used for vaginal biomechanical measurements. RESULTS: There were no significant differences in the baseline demographic, obstetrical, or gynecologic information between the 2 groups. There were no significant differences in the systemic biomechanical parameters between the 2 groups. Women with pelvic organ prolapse had significantly more extensible vaginal skin than women with normal pelvic support (initial stiffness index 7.3 vs 10.9 kpa, final stiffness index 5.9 vs 10.7 kpa; all P values less than .01). Furthermore, vaginal extensibility was related to pelvic organ prolapse quantification stage in a linear fashion. CONCLUSION: Our findings suggest that local, rather than systemic, alterations in biomechanical skin properties are associated with pelvic organ prolapse. PMID- 17689637 TI - Incidence and remission of urinary incontinence in middle-aged women. AB - OBJECTIVE: The objective of the study was to describe changes in urinary incontinence in middle-aged women. STUDY DESIGN: A prospective analysis of 64,650 women aged 36-55 years in the Nurses' Health Study II. Participants reported urine leaking in 2001 and 2003. Two-year incidence and remission proportions were estimated. RESULTS: The 2-year incidence of incontinence was 13.7%. Incidence generally increased through age 50 years and then declined slightly in older women. Among women with incident incontinence at least weekly, the incidence of stress incontinence increased through age 50 years (2-year incidence 1.7%), and the incidence of urge incontinence was stable across age groups (2-year incidence 0.4%). Also, a minority (38%) mentioned leaking to their physician. Complete remission of symptoms occurred in 13.9% of women with incontinence at baseline. CONCLUSION: We found that incontinence occurs frequently in middle-aged women. Yet few women mentioned incontinence to their physicians; thus, it may be important to initiate conversations about urinary symptoms even among younger patients. PMID- 17689638 TI - Effect of biofilm phenotype on resistance of Gardnerella vaginalis to hydrogen peroxide and lactic acid. AB - OBJECTIVE: Bacterial vaginosis is the most common vaginal disorder worldwide. Certain lactobacilli produce H2O2 and lactic acid, which normally suppress growth of anaerobes; however, in bacterial vaginosis, Gardnerella vaginalis and other anaerobes proliferate, and the number of lactobacilli decreases. G. vaginalis colonizes the vaginal epithelium as a biofilm, which likely plays a role in colonization and relapsing infection. STUDY DESIGN: We developed an in vitro model for G. vaginalis biofilm formation and compared susceptibilities of biofilms vs planktonic cultures to H2O2 and lactic acid. The structure and composition of the biofilm matrix were studied in order to design a method for biofilm dissolution. RESULTS: Biofilms tolerated 5-fold and 4-8 fold higher concentrations of H2O2 and lactic acid (respectively) than planktonic cultures. Proteolytic dissolution of biofilms reduced sensitivity to H2O2 and lactic acid. CONCLUSION: Increased tolerance to H2O2 and lactic acid suggests that biofilm formation contributes to the survival of G. vaginalis in the presence of lactobacilli. PMID- 17689639 TI - Flat square knots: are 3 throws enough? AB - OBJECTIVE: The objective of the study was to determine the integrity of flat square knots. STUDY DESIGN: Three sutures were used in both 0 and 2-0 suture gauges: poliglecaprone 25 (Monocryl), polyglactin 910 (Vicryl), and silk. For each, flat square knots were tied with either 3 or 5 throws. Knots were tested to failure. The major outcome measured was the proportion of 3 throw knots untying, compared with that of 5 throw knots. RESULTS: There were high rates of untying for the poliglecaprone 25 and for the polyglactin 910 with both suture gauges when tied with only 3 throws. The failure rate decreased significantly when the throws were increased. There was no statistical benefit to increasing the number of throws for silk. CONCLUSION: Knot failure is decreased by increasing the number of throws for poliglecaprone 25 and polyglactin 910. However, there is no advantage to increasing the number of throws from 3 to 5 for silk. PMID- 17689640 TI - Soluble endoglin as a second-trimester marker for preeclampsia. AB - OBJECTIVE: The objective of this investigation was to characterize soluble endoglin (sEng) concentrations in second-trimester serum of women who either develop preeclampsia or have a normal pregnancy. STUDY DESIGN: Single second trimester serum samples obtained from healthy, nonsmoking women who subsequently developed severe preeclampsia (n = 48) or from healthy nonsmoking women who experienced a normal pregnancy (n = 56) were measured by enzyme-linked immunosorbent assay. Data were reported as mean +/- standard deviation. RESULTS: Maternal age or gestational age at time of sample was not different between the 2 groups. Patients who later developed preeclampsia delivered earlier, had smaller infants, and had a higher mean arterial pressure than controls. Patients who later developed severe preeclampsia had elevated sEng, compared with those with normal pregnancy (6.19 +/- 2.1 vs 5.00 +/- 1.0 ng/mL, P = .02). CONCLUSION: Soluble endoglin is elevated in second-trimester maternal serum in patients destined to develop severe preeclampsia. PMID- 17689641 TI - Circulating concentrations of soluble endoglin (CD105) in fetal and maternal serum and in amniotic fluid in preeclampsia. AB - OBJECTIVE: We explored whether concentrations of soluble endoglin in fetal serum and amniotic fluid and in maternal serum were elevated in preeclampsia. STUDY DESIGN: Umbilical vein serum, amniotic fluid, and maternal serum from 42 preeclamptic and 43 uncomplicated pregnancies that were delivered by cesarean section were analyzed by enzyme-linked immunosorbent assay for soluble endoglin. RESULTS: Median maternal serum and amniotic fluid soluble endoglin concentrations were elevated in preeclampsia, compared with control pregnancies (66.9 ng/mL vs 15.1 ng/mL; P < .001, and 1.9 ng/mL vs 0.6 ng/mL; P < .001). Low concentrations of soluble endoglin were found in fetal circulation, which did not differ between preeclampsia and control pregnancies (5.0 ng/mL vs 4.7 ng/mL; P = .2). Maternal serum soluble endoglin levels correlated with circulating soluble fms-like tyrosine kinase 1 concentrations. CONCLUSION: We confirmed elevated soluble endoglin in maternal circulation in preeclampsia, which correlated with soluble fms-like tyrosine kinase 1 concentrations and soluble fms-like tyrosine kinase 1/placental growth factor ratio. The fetus appears not to contribute to elevated circulating maternal soluble endoglin concentrations in preeclampsia. PMID- 17689642 TI - Dose-dependent lipopolysaccharide-induced fetal brain injury in the guinea pig. AB - OBJECTIVE: This study determined whether a lipopolysaccharide (LPS) dose dependent increase in fetal brain injury occurs to further characterize the relationship between maternal inflammation and fetal brain injury. STUDY DESIGN: Pregnant guinea pigs (n = 59) at 70% gestation were injected intraperitoneally with 1, 5, 25, 50, 100, 200, or 300 microg LPS per kilogram of maternal body weight or an equivalent volume of vehicle. Animals were killed 7 days later. Maternal serum and amniotic fluid samples were assayed for proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 using enzyme-linked immunosorbent assay kits. Fetal brains (n = 72) were stained for evidence of cell death with NeuroTACS stain. RESULTS: Seven days after LPS injections, cytokine concentrations in maternal serum and amniotic fluid were not different (P > .05) from controls. Levels of cell death in all brain regions examined were highest following the maternal administration of 300 mug/kg LPS (P < .05). The dose effect was brain region-dependent (P < .05). CONCLUSION: A threshold of maternal infection/inflammation exists, beyond which demonstrable fetal brain injury may result. PMID- 17689643 TI - Screening for structural fetal anomalies during the nuchal translucency ultrasound examination. AB - OBJECTIVE: The purpose of this study was to evaluate the ability to screen for structural fetal anomalies during the nuchal translucency (NT) ultrasound examination, without performing a complete anatomic fetal scan, by using the sagittal views of the fetus. STUDY DESIGN: In a prospective study, we evaluated all the suspected structural findings observed during the NT examinations performed in our Division of Maternal-Fetal Medicine in 2004-2005. The purpose of the examination was to screen for fetal chromosome abnormalities by using the fetal NT measurements. However, the sonographers were instructed to pay attention to any abnormality observed while obtaining the sagittal views of the fetus. Other views were not to be obtained and fetal anatomy scan was performed only if a structural fetal anomaly was suspected when viewing the fetus in sagittal planes. When a structural fetal anomaly was suspected, a fetal anatomy scan was performed, and then a diagnosis was established at 14-16 weeks' gestation or later. RESULTS: We performed 1723 NT examinations during the study period. The sonographers suspected structural fetal anomalies in 22 cases (1.3%), most of them performed between 11.2 and 13 weeks' gestation. Further evaluation of these cases diagnosed 9 fetuses (0.52%) with structural anomalies including: acrania, holoprosencephaly, Dandy-Walker syndrome, cerebellar agenesis, prune belly syndrome, 2 cases of omphalocele, and 2 cases of cleft lip. The NT was abnormal (greater than 3 mm) in only 1 case (omphalocele). None of the additional 8 cases diagnosed with structural anomalies had a positive maternal serum screening result for trisomy 21. Eight of these 9 fetal structural anomalies were sonographically confirmed at 14-16 weeks' gestation and the remaining 1 was confirmed at 20 weeks' gestation. An additional 13 noncardiac structural anomalies were detected in the study group during routine fetal anatomy scan performed at 14-16 or at 18-24 weeks' gestation. Four of these 9 fetal cardiac defects (44%) were diagnosed by an early fetal echocardiography performed for an increased fetal NT. CONCLUSION: In addition to chromosomal anomalies and congenital cardiac defects, the NT examination can provide an opportunity to screen for structural fetal anomalies when viewing within the sagittal planes of the fetus. The NT examination can be used as a screening test for those who require an early fetal anatomy scan without performing an additional early anatomy scan to all patients. PMID- 17689644 TI - The future is behind us! PMID- 17689645 TI - Sonographic cervical assessment to predict the success of labor induction: a systematic review with metaanalysis. AB - OBJECTIVE: The purpose of this investigation was to review the literature that evaluates sonographic cervical assessment to predict successful induction of labor. STUDY DESIGN: Published prospective trials that measured sonographic cervical length before labor induction was initiated were evaluated. Trials were excluded if they contained data presented in later articles or did not contain extractable data. The total analysis included 20 trials with 3101 aggregate participants. RESULTS: Cervical length predicted successful induction (likelihood ratio of positive test, 1.66; 95% confidence interval [CI], 1.20-2.31) and failed induction (likelihood ratio of negative test, 0.51; 95% CI, 0.39-0.67). Cervical length did not predict any specific outcome (eg, mode of delivery). The assessment of cervical wedging proved to be a useful diagnostic test, with a likelihood ratio of a positive test result of 2.64 and a likelihood ratio of a negative test result of 0.64. CONCLUSION: Sonographic cervical length was not an effective predictor of successful labor induction. Further evaluation of cervical wedging in the prediction of labor induction appears warranted. PMID- 17689646 TI - Intrauterine device use in a high-risk population: experience from an urban university clinic. AB - OBJECTIVE: The purpose of this study was to evaluate the acceptability, efficacy, and complication rates of the ParaGard intrauterine device (IUD; Duramed Pharmaceuticals Inc, Cincinnati, OH) and the Mirena intrauterine system (IUS; Berlax Laboratories, Wayne, NJ) in a cohort of women who attended an urban university-based obstetrics and gynecology resident clinic. STUDY DESIGN: A retrospective chart review was conducted for 194 women who had an IUD/IUS inserted between January 2000-December 2005. RESULTS: One-third of the women who received an IUD had a history of sexually transmitted disease before the insertion. No differences were found between women with an IUD or an IUS regarding demographics and obstetric and gynecologic history before IUD insertion. The IUD was associated with significantly higher rates of herpes simplex and Neisseria gonorrhea infections, complaints of expulsion, and unintended pregnancy after the insertion. No increased risk of pelvic inflammatory disease was associated with IUD use. CONCLUSION: IUD/IUS use appears to be safe, acceptable, and feasible in high-risk patients. The IUS had lower rates of complications and greater acceptability than the IUD. PMID- 17689647 TI - Cervical adenocarcinoma in situ: the predictive value of conization margin status. AB - OBJECTIVE: We evaluated the impact of conization margin status on outcomes of patients diagnosed with cervical adenocarcinoma in situ. STUDY DESIGN: A retrospective chart review identified patients at a University hospital from 1988 2006 with adenocarcinoma in situ (AIS) on conization. RESULTS: Seventy-four patients were included. Median follow-up was 26 months. Twenty-two of 74 patients (30%) had positive margins, 46 patients (62%) had negative margins, and 6 patients had indeterminate margins. Of patients with positive margins, 55% (12/22) were diagnosed with residual or recurrent disease, including 3 patients diagnosed with adenocarcinoma on hysterectomy. Thirteen percent of patients with negative conization margins (6/46) were diagnosed with residual or recurrent disease, including 2 patients diagnosed with adenocarcinoma during follow-up. Cold knife conization resulted in a significantly higher number of negative margins compared to other conization procedures (P = .013). CONCLUSIONS: Even with negative conization margins, women still face a risk of residual, recurrent, or invasive disease. PMID- 17689648 TI - The "Hispanic paradox": an investigation of racial disparity in pregnancy outcomes at a tertiary care medical center. AB - OBJECTIVE: The purpose of this study was to examine racial disparities and the "Hispanic paradox" in pregnancy outcomes at a tertiary-care medical center. STUDY DESIGN: A cross-sectional study of pregnancy events was performed with information from the Duke University birth database. The latter includes data on birth outcomes, cost, and health services factors. The final sample included 10,755 women with Medicaid insurance, who gave birth during calendar years 1994 2004. Pregnancy comorbidities and outcome measures were identified by International Classification of Diseases, 9th revision, and Current Procedural Terminology (CPT) codes. Univariate and multivariate analyses were performed to compare racial/ethnic groups. RESULTS: African-American women were younger and more likely to be employed, to have a medical comorbidity, to remain in the hospital for >4 days, and to have hospital charges of >$7500. African-American women had higher rates of preterm birth, small-for-gestational-age infants, preeclampsia, and stillbirths. There were no differences by race for gestational diabetes mellitus. With the use of white women as the reference group, Hispanic women had lower odds for preterm birth (odds ratio, 0.66; 95% CI, 0.54-0.80), and African-American women had greater odds for preeclampsia (odds ratio, 1.30; 95% CI, 1.07-1.58) and small-for-gestational-age infants (odds ratio, 1.74; 95% CI, 1.29-2.36). With the use of African-American women as the reference, Hispanic women were less likely than African-American women to experience any adverse pregnancy event, with the exception of gestational diabetes mellitus. CONCLUSION: Poverty and insurance status does not explain differences in adverse pregnancy outcomes between African-American women and Hispanic women with Medicaid insurance. PMID- 17689649 TI - Use of cisplatin without desensitization after carboplatin hypersensitivity reaction in epithelial ovarian and primary peritoneal cancer. AB - OBJECTIVE: The purpose of this study was to evaluate the results of substituting cisplatin for carboplatin in women who experienced a carboplatin-associated hypersensitivity reaction while undergoing treatment for gynecologic cancers. STUDY DESIGN: Using a comprehensive data repository, we identified all epithelial ovarian cancer and primary peritoneal cancer patients who experienced a documented significant hypersensitivity reaction to carboplatin and were subsequently treated with cisplatin at our institution from 1995 to the present. We also performed a review of published case reports of similar patient management. RESULTS: We identified a total of 24 patients who met inclusion criteria. Eighteen patients (75%) tolerated cisplatin without any adverse events. Six patients (25%) eventually developed a reaction to cisplatin; none was life threatening, and only 1 required hospitalization. Twenty-three of the 24 patients (96%) tolerated at least 1 cycle of cisplatin. Of the 5 patients who initially tolerated cisplatin but eventually experienced a reaction, the mean number of cycles tolerated was 3.4. CONCLUSION: The use of cisplatin without desensitization is a reasonable approach for continuing platinum-based chemotherapy in patients with a significant carboplatin hypersensitivity reaction. Patients should be advised of risks and closely monitored, given published case reports of anaphylaxis. PMID- 17689650 TI - The Mother's House: a new concept in antepartum care. AB - OBJECTIVE: High-risk antepartum patients often require long and costly hospitalization. The Mother's House facility has been used to house antepartum women on hospital property as an alternative to inpatient management. This study looked at the cost effectiveness of this facility. STUDY DESIGN: A retrospective chart review on occupants (n = 111) of the Mother's House from 2003-2005 was performed. Admission, discharge, and outcome data were collected. A comparison of the cost of management at the Mother's House with the estimated cost of inpatient management was then performed. RESULTS: A cost savings of $2.1 million was seen over a 3-year period with the use of the Mother's House. Demographic data show that patients with positive drug screens are more likely to fail Mother's House management. CONCLUSION: The Mother's House is a cost effective alternative to inpatient management of some antepartum patients. Admission criteria should be modified to exclude patients with positive drug screens. PMID- 17689651 TI - The role of vaginal hysterectomy in the treatment of endometrial cancer. AB - OBJECTIVE: The objective of the study was to evaluate the role of vaginal hysterectomy in the treatment of endometrial cancer. STUDY DESIGN: Medical records were retrospectively reviewed for patients undergoing vaginal hysterectomy for endometrial cancer at the University of South Florida. The medical data were reviewed for medical comorbidities, preoperative and postoperative diagnosis, hospital course, surgical and postoperative complications, adjuvant treatments, and follow-up. RESULTS: Sixty-three women underwent vaginal hysterectomy for endometrial carcinoma between May 1987 September 2006. Mean age was 62.1 years and body mass index [BMI] was 40; 73% of patients were obese (BMI > or = 30 or greater). Medical comorbidities included hypertension (76.2%), cardiovascular disease (34.9%), diabetes mellitus (31.7%), and pulmonary disease (28.6%). Eighty-one percent of patients had at least 2 and 55.5% had 3 or more comorbid surgical risk factors. Postoperative complications included infection (4.8%), blood transfusion (11.1%), and prolonged hospital stay (6.3%). Of patients with intrauterine pathology, 89.5% had endometrioid adenocarcinoma. CONCLUSION: Vaginal hysterectomy may be appropriate treatment of endometrial carcinoma for select patients. PMID- 17689652 TI - Concurrent carboplatin and paclitaxel with pelvic radiation therapy in the primary treatment of cervical cancer. AB - OBJECTIVE: The objective of the study was to determine the feasibility of weekly carboplatin/paclitaxel with radiation therapy (RT) in the primary treatment of cervical cancer. STUDY DESIGN: Women diagnosed with stage IB-1 to stage IVA untreated primary cervical cancer were eligible. Carboplatin (area under the curve = 2.0) and paclitaxel 40 mg/m2 were administered weekly for 6 weeks with pelvic RT. Brachytherapy was completed after pelvic RT. Acute toxicities and response to treatment were assessed. RESULTS: Twenty-two evaluable patients were enrolled. The median duration of follow-up was 23 months. Carboplatin (mean dose 245 mg) and paclitaxel (mean dose 70 mg) were successfully administered in 97% and 90% of planned treatments, respectively. Median time to complete external radiation therapy was 36.6 days (25-57 days). Grade 3/4 hematologic or gastrointestinal toxicity was unusual. The complete response rate 3 months after completion of therapy was 91%. The estimated 3-year progression-free survival is 70% and overall survival is 65%. CONCLUSION: Weekly carboplatin/paclitaxel and RT is a reasonable treatment regimen for cervical cancer. PMID- 17689653 TI - A comparison of 3 criteria of oligohydramnios in identifying peripartum complications: a secondary analysis. AB - OBJECTIVE: The objective of the study was to ascertain the diagnostic accuracy of 3 criteria of oligohydramnios in identifying 4 peripartum complications. STUDY DESIGN: The 3 definitions of oligohydramnios were amniotic fluid index (AFI) 5.0 cm or less and AFI <5% for gestational age (GA) using nomograms by Moore and Cayle or Magann et al. Likelihood ratio (LR) and guidelines by the Evidence-Based Medicine Working Group were used in the secondary analysis of previously published reports. AFI obtained during antepartum and intrapartum periods were analyzed separately. RESULTS: The 95% confidence intervals for the prevalence of oligohydramnios using the 3 criteria are significantly different in the antepartum or intrapartum analysis. The LR was <6 for ante- and intrapartum AFI to identify cesarean delivery for nonreassuring fetal heart rate tracing, Apgar score 3 or less at 5 minutes, umbilical arterial pH <7.00, and newborns' weight 5% or less for GA. CONCLUSION: The 3 criteria for determining the adequacy of amniotic fluid are not fungible, and they are not useful diagnostic tests for identifying peripartum complications because LR is <10. PMID- 17689654 TI - Extended cytoreduction of intraabdominal metastatic ovarian cancer in the left upper quadrant utilizing en bloc resection. AB - OBJECTIVE: The objective of the study was to describe the development of and experience with a technique for en bloc resection of left upper quadrant intraperitoneal metastatic ovarian cancer. STUDY DESIGN: From May 7, 2002-August 14, 2004, 6 women underwent en bloc resection of extensive tumor contiguously involving the omentum, colon, gastrocolic ligament and spleen. This represents about 5% of all cytoreductive operations performed during that time. Four of the 6 had received neoadjuvant chemotherapy. RESULTS: A description of the technique is included in the text. Two women required partial gastrectomy and partial pancreatectomy. Separate segmental resection or subtotal colectomy was performed in 3 women. Cytoreduction was optimal in all 6 cases. Significant complications occurred in 3 of the women. Disease-free survival ranged from 2-12 months. CONCLUSION: In highly selected patients undergoing cytoreductive surgery for ovarian cancer, en bloc resection of extensive left upper quadrant intraabdominal tumor may be a reasonable method for accomplishing optimal cytoreduction. PMID- 17689655 TI - Second-trimester angiogenic factors as biomarkers for future-onset preeclampsia. AB - OBJECTIVE: The purpose of this study was to determine whether second-trimester soluble fms-like tyrosine kinase-1 and placenta growth factor (PlGF) are altered in patients who have preeclampsia develop compared with controls. Furthermore, soluble fms-like tyrosine kinase-1 and placenta growth factor levels in patients with chronic hypertension are described. STUDY DESIGN: With the use of a research database, 21 patients who had severe preeclampsia develop, 34 controls, and 9 patients with chronic hypertension were enrolled. Placenta growth factor and soluble fms-like tyrosine kinase-1 serum levels were determined by enzyme-linked immunosorbent assay. Appropriate statistical tests were used and results were reported as median (quartile 1-quartile 3) in picograms per milliliter. RESULTS: Placenta growth factor was significantly lower in patients in the second trimester who later had severe preeclampsia develop but soluble fms-like tyrosine kinase-1 was unchanged compared with healthy pregnancies. In patients with chronic hypertension, placenta growth factor and soluble fms-like tyrosine kinase 1 levels were not different compared with controls. CONCLUSION: Second-trimester placenta growth factor levels are altered in patients who had severe preeclampsia develop. PMID- 17689656 TI - Long-term postmenopausal hormone therapy and endometrial cancer risk: a study by Doherty et al. PMID- 17689657 TI - Postpartum peril. PMID- 17689658 TI - Planned cesarean vs planned vaginal delivery at term. PMID- 17689661 TI - References revisited. PMID- 17689662 TI - Pathogenesis of amniotic band syndrome. PMID- 17689664 TI - Novel biomechanical quantification methodology for lumbar intraforaminal spinal nerve adhesion in a laminectomy and disc injury rat model. AB - Spinal nerve fibrosis following injury or surgical intervention may play an important role in the pathophysiology of chronic back pain. In this current study, we demonstrate the role of biomechanical quantification of lumbar intraforaminal spinal nerve adhesion and tethering in the analysis of the post laminectomy condition and describe a direct methodology to make this measurement. Twenty age-matched Sprague-Dawley male rats were divided into operative and non operative (control) groups. Operative animals underwent a bilateral L5-L6 laminectomy with right-side L5-6 disc injury, a post-laminectomy pain model previously published by this lab. At eight weeks, animals were sacrificed and the strength of adhesion of the L5 intraforaminal spinal nerve to surrounding structures was quantified using a novel biomechanical methodology. Operative animals were found to have a significantly greater load to displace the intact right L5 spinal nerve through the intervertebral foramen when compared to control animals. The findings show that the post-laminectomy condition creates quantifiable fibrosis of the spinal nerve to surrounding structures and supports the conclusion that this fibrosis may play a role in the post-laminectomy pain syndrome. PMID- 17689665 TI - Segmentation of cultured neurons using logical analysis of grey and distance difference. AB - The molecular and cellular bases of neuronal cell death that underpin a wide range of neurodegenerative disorders are still not well understood. One approach to investigating neuronal death is through systematic studies of the changing morphology of cultured brain neurons in response to cellular challenges. Image segmentation methods developed to date to analyze such changes have been limited by the low contrast of cells in unstained neuronal cultures and the unimodal histograms generated by these analyses. In this paper we present new algorithms based on logical analysis of grey and distance difference of images that successfully circumvent these problems. Two key parameters of this analysis, window width and logical threshold, are automatically extracted for use in logical level technique, and spurious regions are detected and removed through use of a hierarchical window filter. The efficacy of the developed algorithms is demonstrated here through an analysis of cultured brain neurons from newborn mice. PMID- 17689666 TI - Child-specific and family-wide risk factors using the retrospective Childhood Experience of Care & Abuse (CECA) instrument: a life-course study of adult chronic depression - 3. AB - BACKGROUND: An earlier paper [Brown, G.W., Craig, T.K.J., Harris, T.O., Handley, R.V., Harvey, A.L., 2007a-this issue. Development of a retrospective interview measure of parental maltreatment using the Childhood Experience of Care & Abuse (CECA) instrument - a life-course study of adult chronic depression - 1. J. Affect. Disord. doi:10.1016/j.jad.2007.05.022] documented an association between parental maltreatment and risk of adult chronic depression. This paper explores the contribution of other child-specific factors (e.g. conduct problems) and family-wide factors (e.g. parental discord). METHODS: Data are derived from an enquiry of 198 women largely comprising of adult sister pairs. Data was collected by semi-structured interviews covering a wide range of parental behaviour and childhood behaviour. RESULTS: Parental maltreatment emerged as channelling the effect of family-wide factors on risk of adult chronic depression, but with a child's conduct problems and shame-withdrawal partly mediating this link. A child's depression before 17, although correlated with parental maltreatment, did not appear to play a significant role in adult depression. This core model is supplemented by analyses exploring the mechanisms involved. A mother's rejection/physical abuse and her depression via her lax control, for example, account for the link of parental maltreatment with conduct problems. Also 'rebelliousness' of a child relates to the chances of her low affection moving to rejection. "Rebelliousness" also appears to play a role in why the paired sisters so often had a different experience of maltreatment. LIMITATIONS: The data is collected retrospectively - but see [Brown, G.W., Craig, T.K.J., Harris, T.O., Handley, R.V., Harvey, A.L., 2007b-this issue. Validity of retrospective measures of early maltreatment and depressive episodes using the Childhood Experience of Care and Abuse (CECA) instrument - A life-course study of adult chronic depression - 2. J. Affect. Disord. doi:10.1016/j.jad.2007.06.003]. CONCLUSIONS: Child-specific factors play a major role in the origins of adult chronic depressive episodes. This, however, is fully consistent with an equally significant contribution from family-wide factors. The crucial point is that the link of the latter with such depression appears to be indirect and mediated very largely by parental maltreatment. PMID- 17689667 TI - Internet administration of the Edinburgh Depression Scale. AB - BACKGROUND: Internet-based screening for depression is becoming increasingly important. The aim of this study is to validate the Edinburgh Depression Scale (EDS) for internet administration. METHODS: In 407 participants (64% women; 36% men) with subthreshold depression (mean age=55 years; S.D.=4.9) positive predictive values for a syndromal CIDI diagnosis of clinical depression were calculated and compared to those from paper and pencil validation studies. At one year follow-up, internal consistency and convergent validity of the internet based EDS were determined in 177 participants by Cronbach's alpha and correlations with the internet-administered BDI and SCL-90 subscales depression and anxiety. RESULTS: Positive predictive values ranged between 29% and 33% at cut-off scores of 12 to 14. Cronbach's alpha for the internet-administered EDS was 0.87. The EDS correlated significantly with the internet-administered BDI (r=.75; p<.001) and two internet-administered subscales of the SCL-90: depression (r=.77; p<.001) and anxiety (r=.72; p<.001). A major limitation is that the study was conducted without a control group of healthy subjects. CONCLUSION: The psychometric properties of the internet-administered EDS are comparable to those of the paper and pencil EDS. PMID- 17689669 TI - Global infections--avian influenza and other significant emerging pathogens: an overview. PMID- 17689670 TI - Avian influenza: the next pandemic? PMID- 17689671 TI - ITGA4 polymorphisms and susceptibility to multiple sclerosis. AB - In multiple sclerosis (MS), alpha(4)beta(1) integrin, also known as Very Late Antigen 4 (VLA4), facilitates migration of leukocytes across the blood brain barrier. Several studies suggest that expression of alpha(4) integrin may be increased in MS patients compared to controls, and down-regulation or antagonism of alpha(4) integrin may be associated with immunomodulatory treatment success. We analysed association of 13 single nucleotide polymorphisms (SNPs) in the gene encoding alpha(4) integrin (ITGA4) with susceptibility to MS in two distinct populations comprising cases and controls from the Basque Country in northern Spain (352 patients; 235 controls) and Nordic countries (1119 patients; 1235 controls). Carriage of the C allele of the ITGA4 promoter SNP rs1449263 was independently and weakly increased in MS patients from each population compared to respective controls (P = 0.037 in Basque; and P = 0.042 in Nordic cohorts), though these associations were lost upon application of permutation correction. Meta-analysis of rs1449263*C carriage revealed a Mantel-Haenszel common OR of 1.26 (95% CI 1.06-1.49; P = 0.0069). Though our data only modestly argue for a role of ITGA4 in determining susceptibility to MS, we suggest that further examination of this gene, particularly the promoter region, is warranted. PMID- 17689672 TI - A bench-scale, cost effective and simple method to elicit Lycopersicon esculentum cv. PKM1 (tomato) plants against Cucumber mosaic virus attack using ozone mediated inactivated Cucumber mosaic virus inoculum. AB - Studies were undertaken to evaluate ozone for inactivation of Cucumber mosaic virus present in the inoculum and to stimulate Lycopersicon esculentum cv. PKM1 (tomato) plants against Cucumber mosaic virus infection by using the inactivated Cucumber mosaic virus inoculum. Application of a T(4) (0.4mg/l) concentration of ozone to the inoculum containing Cucumber mosaic virus resulted in complete inactivation of the virus. The inactivated viral inoculum was mixed with a penetrator (delivery agent), referred to as T(4) preparation, and it was evaluated for the development of systemic acquired resistance in the tomato plants. Application of a T(4) preparation 5 days before inoculation with the Cucumber mosaic virus protected tomato plants from the effects of Cucumber mosaic virus. Among the components of the inactivated virus tested, coat protein subunits and aggregates were responsible for the acquired resistance in tomato plants. In field trials, the results of enzyme-linked immunosorbent assay revealed that, Cucumber mosaic virus accumulation was significantly less for all the test plants (16%) sprayed with the T(4) preparation than untreated control plants (89.5%) at 28 days postinoculation (dpi). A remarkable increase in the activities of the total soluble phenolics (10-fold) and salicylic acid (16-fold) was detected 5 days after the treatment in foliar extracts of test plants relative to untreated control plants. The results showed that treatment of tomato plants with inactivated viral inoculum led to a significant enhancement of protection against Cucumber mosaic virus attack in a manner that mimics a real pathogen and induces systemic acquired resistance. PMID- 17689673 TI - Retinoid X receptor gene expression and protein content in tissues of the rock shell Thais clavigera. AB - To elucidate the role of retinoid X receptor (RXR) in the development of imposex caused by organotin compounds in gastropod molluscs, we investigated RXR gene expression and RXR protein content in various tissues of male and female wild rock shells (Thais clavigera). Quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry with a commercial antibody against human RXR alpha revealed that RXR gene expression was significantly higher in the penises of males and imposex-exhibiting females than in the penis-forming areas of normal females (P<0.01 and P<0.05, respectively). Western blotting demonstrated that the antibody could detect rock shell RXR and showed that the male penis had the highest content of RXR protein among the analyzed tissues of males and normal females. Immunohistochemical staining revealed nuclear localization of RXR protein in the epithelial and smooth muscle cells of the vas deferens and in the interstitial or connective tissues and epidermis of the penis in males and imposex-exhibiting females. RXR could be involved in the mechanism of induction of male-type genitalia (penis and vas deferens) by organotin compounds in female rock shells. PMID- 17689674 TI - Census, molecular characterization and developmental expression of Leucine-Rich Repeat proteins in Plasmodium falciparum. AB - The capacity of Leucine-Rich Repeat or LRR proteins to interact with many ligands enables them to contribute to important cellular functions ranging from the regulation of the cell cycle to protein trafficking and signal transduction. In Plasmodium falciparum, little is known about the expression of these LRR proteins. Here, we identified the PfLRR genes and determined their transcriptional expression during the intraerythrocytic parasite life cycle. Exhaustive analysis of the P. falciparum genome revealed 14 potential genes encoding LRR-containing proteins, designated from PfLRR1 to PfLRR14. Molecular cloning and sequencing of the corresponding cDNA indicated that all PfLRRs contain 4-10 LRR motifs. Real-time quantitative PCR revealed that most of genes are highly expressed in late intraerythrocytic stages, including late trophozoites and schizonts. The ability of P. falciparum to express LRR containing proteins will enable further investigations into the parasite interactome and create opportunities for discovering candidate drug targets. PMID- 17689675 TI - Purification and cDNA cloning of a new heat-stable allergen from Anisakis simplex. AB - The nematode Anisakis simplex is a representative parasite for marine animals and occasionally causes not only anisakiasis but also allergic reactions in sensitized subjects. Besides the known allergens, a number of unidentified allergens have been suggested to still exist in A. simplex. In this study, a new heat-stable allergen of 15kDa (named Ani s 8) was purified from the third stage larvae of A. simplex by gel filtration on Sephacryl S-300, anion-exchange HPLC on Mono Q and reverse-phase HPLC on TSKgel Phenyl-5PW RP. Analysis by fluorescence ELISA showed that 7 of 28 Anisakis-allergic patients had elevated serum levels of IgE to Ani s 8. On the basis of the determined partial amino acid sequence, the complete sequence of Ani s 8 (composed of 150 amino acid residues) was elucidated by cDNA cloning, in which as many as 32 homologs of the cDNA encoding 10 isoforms of Ani s 8 were detected. Ani s 8 shares amino acid sequence homology (up to 36%) with several members of the SXP/RAL-2 protein family, including Ani s 5 (15kDa) previously identified as an A. simplex allergen. Inhibition ELISA data demonstrated the IgE cross-reactivity between Ani s 8 and Ani s 5. PMID- 17689676 TI - Gnothi se auton: SUS Presidential Address. PMID- 17689677 TI - Clinicopathologic features of re-resected cases of intraductal papillary mucinous neoplasms (IPMNs). AB - BACKGROUND: We analyzed the clinical characteristics and patterns of recurrence of intraductal papillary mucinous neoplasms (IPMNs) from 100 consecutive surgical cases. METHODS: The average age was 62 +/- 12 years. The tumor was located in the head in 65 patients, body in 25 patients, and tail in 10 patients. Sixty-seven patients had benign IPMNs, and 33 patients had malignant IPMNs. Malignant IPMNs were observed more frequently in the head (42%) as compared with the body (20%) or tail (10%) (P < .05). During the follow-up period, 5 patients recurred and underwent second operation. In the first operation, 1 patient underwent pancreatoduodenectomy for the head tumor and the other 4 patients underwent distal pancreatectomy for the body and/or tail tumor. RESULTS: Although histopathologic findings in the first operation were adenoma in 2 and carcinoma in 3 patients, all patients developed carcinoma by the time of the second operation. No hyperplasia developed recurrence. The overall recurrence rate for the head tumors was 1.5% (1 out of 65), whereas that for the body and tail tumors was 11.4% (4 out of 35) (P < .05). Metachronous multicentric recurrence was suspected in 4 cases. CONCLUSIONS: These results indicate that adenomatous or carcinomatous IPMNs, especially originated from the body or tail, should be carefully observed even with a histologically negative surgical margin. PMID- 17689678 TI - The creation of an infrarenal aneurysm within the native abdominal aorta of swine. AB - BACKGROUND: Models of native abdominal aortic aneurysms (AAA) have been created in rodents using elastase and calcium chloride perfusion. These models, however, do not permit the evaluation of endovascular devices. This study describes the use of mechanical and enzymatic techniques to create native AAA in swine. METHODS: Surgically exposed abdominal aortas of ten male Yorkshire swine (25-35 kg) were dilated, then perfused for 20 min with a 50-mL solution of elastase (30 units) and collagenase (8000 units). Serial magnetic resonance imaging (MRI) at 1, 3, and 6 wk was used to evaluate postoperative aortic diameter. Animals were euthanized at 24 h, 48 h and 1, 2, and 6 wk for histological evaluation. RESULTS: MRI demonstrated an increase in mean aortic diameter by 73.3% +/- 30.2% (33.3 116.7%), which gradually increased postoperatively. Partial endothelial loss, mural neutrophil infiltrate, and elastin disruption were evident (1, 3, and 7 days). Smooth muscle cell attrition occurred within the inner tunica media (7 days). Collagen deposition, limited SMC repopulation and luminal reendothelialization appeared at 3-6 wk. Elastin injury persisted. CONCLUSIONS: The creation of an infrarenal aneurysm is possible within the native aorta of swine. After aneurysm creation, progressive increase in aortic diameter was detectable. Further evaluation will be necessary to more completely characterize the nature and extent of elastase-induced porcine aortic aneurysmal degeneration. PMID- 17689679 TI - Real-time monitoring of cardiac metabolism using biosensors shows myocardial protection during ischemia-reperfusion injury with glucose-insulin-potassium administration. AB - BACKGROUND: Systemic infusion of glucose-insulin-potassium (GIK) is thought to confer myocardial protection during ischemia-reperfusion injury. Our laboratory has experience with real-time monitoring of glucose and pH levels using needle mounted biosensors. We tested the hypothesis that GIK enhances myocardial metabolism as displayed by real-time myocardial metabolic monitoring. METHODS: A total of 40 kg male swine were randomized to receive GIK (n = 7) or lactated Ringer's (n = 7) solution intravenously at 1.5 mL/kg/hour. Ischemia was induced in the left anterior distribution (LAD) by 20 minutes LAD occlusion, followed by 20 minutes reperfusion. Hearts were instrumented anteriorly and posteriorly with continuously recording myocardial pH and glucose biosensors. Biopsies from the LAD distribution were taken at baseline, maximum ischemia, and after reperfusion to assess cardiac adenosine triphosphate (ATP) levels. RESULTS: GIK animals had less myocardial pH decrease than controls during both ischemia (pH decrease -0.03 vs -0.37, P = .04) and reperfusion (pH decrease -0.10 vs -0.44, P = .05). Neither ATP (74% vs 73% decrease from baseline) nor glucose (27% vs 33% decrease from baseline) varied significantly between groups during ischemia. GIK animals had faster normalization of ATP (100% vs 79% increase from ischemia) and glucose (69% vs 28% increase from ischemia) during reperfusion. CONCLUSIONS: Real-time myocardial metabolic monitoring shows that cardiac pH is improved by GIK during ischemia-reperfusion injury; however, ATP and glucose levels were not significantly enhanced. GIK animals trended toward earlier recovery during reperfusion. Mediators of this metabolic enhancement need to be explored. PMID- 17689680 TI - Stat1 acetylation inhibits inducible nitric oxide synthase expression in interferon-gamma-treated RAW264.7 murine macrophages. AB - BACKGROUND: We hypothesized that acetylation of the Stat1 regulates interferon gamma (IFN-gamma) mediated macrophage expression of inducible nitric oxide synthase (iNOS). METHODS: RAW 264.7 iNOS expression was induced with IFN-gamma. Deacetylase inhibitors trichostatin A (TSA) or valproic acid (VPA) were added. Stat1 and iNOS mRNA and protein were measured. Acetylated Stat1 was determined by immunoprecipitation. Chromatin immunoprecipitation assessed in vivo binding of Stat1 to the iNOS promoter. RESULTS: IFN-gamma significantly increased nitrite, iNOS protein and iNOS mRNA, and iNOS promoter activation. (P < .01 vs control for nitrite, protein, and mRNA). TSA-mediated acetylation decreased these to levels that were not different from controls. IFN-gamma increased acetylated Stat1 by 5 fold (P < .02 vs control); TSA + IFN-gamma caused an additional 4-fold increase in acetylated Stat1 (P < .05 vs IFN alone). Stat1 binding to the iNOS promoter increased 8-fold with IFN-gamma (P < .01 vs control). In TSA + IFN-gamma, Stat1 binding was not different from controls. Although less potent than TSA, VPA also significantly decreased nitrite, iNOS protein, iNOS mRNA, Stat1 acetylation, and Stat1 binding. CONCLUSIONS: Acetylation of Stat1 protein correlates with decreased Stat1 binding to the iNOS promoter with resultant inhibition of IFN gamma-mediated iNOS expression. Acetylation of the Stat1 protein may downregulate iNOS expression in proinflammatory states. PMID- 17689681 TI - Sp1 regulates osteopontin expression in SW480 human colon adenocarcinoma cells. AB - BACKGROUND: Osteopontin (OPN) mediates cancer metastasis. Mechanisms regulating OPN expression in human colorectal cancer are unknown. Using SW480 colon adenocarcinoma cells, we hypothesized that transcription determines OPN expression. METHODS: SW480 constitutively express OPN. Transient transfection and deletion analysis of human OPN promoter (full-length 2.1 kb)-luciferase constructs identified cis-regulatory regions. Gelshift and chromatin immunoprecipitation (ChIP) assays identified the trans-regulatory nuclear protein. Using in vitro adhesion, migration, and invasion studies, siRNA was used to determine the functional effect of decreased nuclear protein expression. RESULTS: A cis-regulatory promoter region, nt-80 to nt-108, upregulated OPN transcription. Gelshift assays demonstrated specific binding of nuclear proteins. Competition with unlabeled mutant oligonucleotides indicated that the region, nt 94 to nt-104 (TGGGCTGGGC), was essential for protein binding in gelshift assays. Confirmatory ChIP assays showed the corresponding nuclear protein to be Sp1. Sp1 expression was ablated with siRNA (si-Sp1), resulting in decreased OPN-dependent adhesion, migration, and invasion by 50%, 70%, and 65%, respectively. Exogenous addition of OPN to si-Sp1 cells restored adhesion, migration, and invasion indices. CONCLUSIONS: In SW480 human colon cancer cells, we conclude that Sp1 mediated expression of the tumor metastasis protein, OPN, regulates in vitro functional correlates of tumor metastasis. PMID- 17689682 TI - Norepinephrine suppresses wound macrophage phagocytic efficiency through alpha- and beta-adrenoreceptor dependent pathways. AB - BACKGROUND: The systemic response to injury is characterized by massive release of norepinephrine (NE) into the circulation as a result of global sympathetic activation. We have recently demonstrated that NE modulates the recruitment of macrophages to the cutaneous wound. We hypothesized that NE suppresses wound macrophage phagocytic function through canonical adrenergic signaling pathways. METHODS: Murine wound macrophages were harvested at 5 days after injury and treated with physiologic and pharmacologic dose norepinephrine. Phagocytosis of green fluorescent protein-labeled Escherichia coli was assayed by flow cytometry. The signaling pathways mediating NE modulation of wound macrophage phagocytosis were interrogated by pharmacologic manipulation of alpha- and beta adrenoreceptors (ARs), intracellular cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA). Tissue specificity was determined by comparison of wound macrophages to splenic macrophages. RESULTS: Both physiologic and pharmacologic dose NE suppressed wound macrophage phagocytic efficiency. This effect was mediated by alpha- and beta-ARs in a dose-dependent fashion. Direct stimulation of cAMP-suppressed phagocytic efficiency and blockade of PKA signaling prevented NE-mediated suppression of phagocytic efficiency. Splenic macrophage phagocytic efficiency was less than that of wound macrophages and was not altered by NE. CONCLUSIONS: NE has a profound immunosuppressive effect on wound macrophage function that is tissue specific and appears to be mediated through adrenergic receptors and their canonical downstream signaling pathway. Attenuation of post injury immunosuppression represents another potential mechanism by which beta-AR blockade may reduce morbidity and mortality after severe injury. PMID- 17689683 TI - The ACGME competencies in the operating room. AB - BACKGROUND: In 1999, the ACGME introduced the 6 competencies that have become the basis for resident education. Since the operating room (OR) has traditionally been the major focus for resident teaching in surgery, we performed an observational study to determine whether it is an appropriate setting for the teaching and/or assessment of the competencies. METHODS: A 3-person team observed 11 operations and recorded all teaching events. Observers then determined whether each event involved the teaching of a competency by faculty or demonstration of a competency by residents. Frequency counts, mean times, and ranges were calculated for each competency taught and demonstrated. RESULTS: The Patient Care competency was both the most commonly taught and demonstrated. Faculty spent an average of 33% of operative time instructing in patient care, and residents demonstrated it 65% of the time. The Interpersonal/Communication Skills (4%) and Practice-Based Learning/Improvement (4%) competencies were also occasionally demonstrated by residents. The remaining competencies were addressed less frequently. CONCLUSIONS: OR teaching was primarily devoted to the Patient Care competency. The OR was also an appropriate setting for evaluating resident performance in this area. New approaches to OR teaching or educational efforts in other settings such as the clinic are necessary for teaching and assessing the remaining competencies. PMID- 17689684 TI - Bortezomib inhibits angiogenesis and reduces tumor burden in a murine model of neuroblastoma. AB - BACKGROUND: Bortezomib is a proteasome inhibitor with pleiotropic antitumor activity. Here we investigate the antiangiogenic and antitumor efficacy of bortezomib against neuroblastoma both in vitro and in a murine model of localized and disseminated disease. METHODS: In vitro activity of bortezomib was assessed by evaluating its effect on cell proliferation and cell cycle status. Localized tumor burden was followed with caliper measurements and total-body bioluminescence in mice with disseminated disease. The antiangiogenic activity was evaluated with immunohistochemistry and human vascular endothelial growth factor (VEGF) enzyme-linked immunosorbent assay on tumor protein extracts. RESULTS: Bortezomib treatment resulted in dose and time-dependent decreases in cell proliferation and resulted in cell cycle arrest. In vivo, bortezomib restricted tumor growth in a model of localized disease and decreased bioluminescence in mice with disseminated disease. That decreased bioluminescence reflected decreased tumor burden was confirmed at necropsy by assessing disease in specific organs. In addition, treatment resulted in a decrease in intratumoral vessel counts and reduced tumor VEGF expression. CONCLUSION: Bortezomib shows significant activity against neuroblastoma in vitro, and it inhibits tumor growth and angiogenesis in vivo. These results suggest that clinical studies of bortezomib are warranted for the treatment of this difficult disease. PMID- 17689685 TI - MAPK signaling contributes to rotaviral-induced cholangiocyte injury and viral replication. AB - BACKGROUND: Biliary atresia is a disease of newborns that results in obliteration of the biliary tree. Infection of mice with rhesus rotavirus (RRV) results in a cholangiopathy mirroring human disease. The Mitogen Associated Protein Kinase (MAPK) signaling pathway can be activated by viral binding to cell-surface receptors. We hypothesized that RRV infection of cholangiocytes results in activation of MAPK signaling. METHODS: Extrahepatic bile ducts from BALB/c pups or immortalized cholangiocytes subjected to RRV infection or control were analyzed, using Western blots, for phosphorylated members of the MAPK family: p38, ERK 1/2, JNK 1/2, and downstream transcription factors. Inhibitors of the MAPK were used to downregulate activity. Viral replication and cytolysis in cholangiocytes were evaluated post-MAPK inhibition. RESULTS: Phosphorylation of all MAPK increased in RRV-infected mice and cholangiocytes. Several downstream transcription factors had increased activity in vitro. Inhibition of p38 and ERK 1/2 resulted in decreased viral replication. ERK 1/2 inhibition decreased cytolysis without affecting viral entry or binding. CONCLUSIONS: RRV infection of cholangiocytes resulted in increased MAPK signaling. Inhibition of p38 and ERK 1/2 influenced the ability of rotavirus to replicate. These novel findings provide insight into the signaling cascade involved in RRV-induced cholangiocyte injury. PMID- 17689686 TI - Limited feedback and video tutorials optimize learning and resource utilization during laparoscopic simulator training. AB - BACKGROUND: The purpose of this study was to determine the impact of instructor feedback and video tutorials on skill acquisition during proficiency-based laparoscopic suturing training. METHODS: Performance data from a prospectively maintained database were reviewed for three groups of novices (n = 34 medical students) who completed the same proficiency-based laparoscopic suturing curriculum on a Fundamentals of Laparoscopic Surgery-type videotrainer model as part of two separate institutional review board-approved, randomized controlled trials. Group I (n = 9) watched the video tutorial once and received intense feedback during each training session; Group II (n = 13) watched the video tutorial once and received limited feedback (<10 min per session); Group III (n = 12) watched the video tutorial several times and also received limited feedback (<10 min per session). Feedback was given by the same instructor and was quantified on a 0 (none) to 4 (extensive) Likert scale. RESULTS: Baseline characteristics were similar for all groups. All participants achieved the proficiency level (512) on two consecutive attempts. Group III required the shortest training time and number of repetitions to reach proficiency, with statistically significant differences compared with Group I (P < 0.02). This strategy led to a cost savings of $139 per trainee. CONCLUSIONS: Limited instructor feedback appears to be superior to intense feedback during proficiency based laparoscopic simulator training. Coupled with video tutorials, this type of feedback may accelerate learning and improve resource utilization by minimizing the need for instructor involvement. PMID- 17689687 TI - Laparoscopic surface scanning and subsurface targeting: implications for image guided laparoscopic liver surgery. AB - Segmental liver resection and locoregional ablative therapies are dependent upon accurate tumor localization to ensure safety as well as acceptable oncologic results. Because of the liver's limited external landmarks and complex internal anatomy, such tumor localization poses a technical challenge. Image guided therapies (IGT) address this problem by mapping the real-time, intraoperative position of surgical instruments onto preoperative tomographic imaging through a process called registration. Accuracy is critical to IGT and is a function of: 1) the registration technique, 2) the tissue characteristics, and 3) imaging techniques. The purpose of this study is to validate a novel method of registration using an endoscopic Laser Range Scanner (eLRS) and demonstrate its applicability to laparoscopic liver surgery. Six radiopaque targets were inserted into an ex-vivo bovine liver and a computed tomography (CT) scan was obtained. Using the eLRS, the liver surface was scanned and a surface-based registration was constructed to predict the position of the intraparenchymal targets. The target registration error (TRE) achieved using our surface-based registration was 2.4 +/- 1.0 mm. A comparable TRE using traditional fiducial-based registration was 2.6 +/- 1.7 mm. Compared to traditional fiducial-based registration, laparoscopic surface scanning is able to predict the location of intraparenchymal liver targets with similar accuracy and rate of data acquisition. PMID- 17689688 TI - In the adult mesenchymal stem cell population, source gender is a biologically relevant aspect of protective power. AB - BACKGROUND: Acute treatment with bone marrow mesenchymal stem cells (MSC) reduces myocardial infarct size by multiple mechanisms, including the paracrine release of protective growth factors. Female MSCs produce more growth factor when stressed; therefore, we hypothesized that myocardial protection provoked by female MSCs would be greater than that elicited by male MSCs. METHODS: Hearts were subjected to 25 min of warm global ischemia, 40 min of reperfusion, and randomly assigned into one of three groups: (1) vehicle treated; (2) male MSC treated; and (3) female MSC treated. Myocardial function was continuously recorded and in separate experiments, male and female MSC growth factor production was assessed by ELISA. RESULTS: All indices of functional recovery were significantly higher in the stem cell infused rat heart compared with control hearts. Interestingly, female MSC treated rat hearts demonstrated significantly greater recovery of left ventricular developed pressure, +dP/dT, and -dP/dT than male MSC treated hearts at end reperfusion. In addition, male MSCs produced significantly greater tumor necrosis factor alpha, and significantly less vascular endothelial growth factor than female MSCs. CONCLUSIONS: This study is the first to demonstrate that, in the adult mesenchymal population, source gender is a biologically relevant aspect of ultimate stem cell function in the heart. PMID- 17689689 TI - A del T poly T (8) mutation in the 3' untranslated region (UTR) of the CDK2-AP1 gene is functionally significant causing decreased mRNA stability resulting in decreased CDK2-AP1 expression in human microsatellite unstable (MSI) colorectal cancer (CRC). AB - BACKGROUND: We have previously published results indicating that decreased expression of CDK2-AP1 in MSI human colorectal cancer is associated with deletion mutations in the poly (T) 8 repeat sequence within the 3'-UTR of the CDK2-AP1 gene. In this study, we test the hypothesis that the del T mutation results in decreased CDK2-AP1 expression by causing reduced mRNA stability. METHODS: We introduced wild-type and mutant 3'-UTR sequences fused to a green fluorescent protein (GFP) gene separately into human CRC cell lines and quantified the expression of the GFP gene. Native CDK2-AP1 mRNA stability was measured in human CRC cell lines, using an actinomycin D assay and the mRNA structure folding software mfold 3.2. RESULTS: Mutant GFP-3'-UTR samples demonstrated significantly reduced GFP expression compared with wild-type GFP-3'-UTR as measured by both FACS and real-time PCR. Both the actinomycin D assay and mfold software demonstrated significantly reduced mRNA stability for the del T poly (T) 8 transcript compared with the wild type. CONCLUSIONS: In summary, these novel results support our hypotheses that the del T poly (T) 8 observed in the 3'-UTR of the CDK2-AP1 gene in human MSI CRC is functionally significant and results in decreased CDK2-AP1 expression. The results also indicate the mechanism of this decreased expression is caused at least in part by decreased mRNA stability. PMID- 17689690 TI - Ezetimibe ameliorates cholecystosteatosis. AB - BACKGROUND: Cholecystosteatosis is the accumulation of gallbladder wall fats leading to decreased gallbladder emptying. Ezetimibe inhibits intestinal fat absorption and prevents murine gallstone formation. However, the influence of ezetimibe on gallbladder emptying and cholecystosteatosis has not been studied. Therefore, we tested the hypothesis that ezetimibe would improve gallbladder motility by preventing the buildup of fats in the gallbladder wall. METHODS: Forty lean female mice were fed either a control diet or a lithogenic diet for 6 weeks. Half of the mice on each diet received ezetimibe. At 11 weeks of age, all mice were fasted overnight and underwent gallbladder ultrasonography to determine ejection fraction. One week later, the mice were fasted and underwent cholecystectomy. Bile was examined for cholesterol crystals. The gallbladders were snap-frozen for lipid analysis. RESULTS: The lithogenic diet significantly (P < 0.05) increased serum cholesterol, biliary crystals, gallbladder wall cholesterol and cholesterol/phospholipid ratio, and decreased gallbladder ejection fraction. All of these abnormalities were reversed (P < 0.05) by the addition of ezetimibe to the diet. CONCLUSIONS: These data suggest that ezetimibe lowers serum cholesterol, prevents biliary crystals, and normalizes gallbladder wall fat and function. We conclude that ezetimibe ameliorates cholecystosteatosis and may be an effective agent for gallstone prevention. PMID- 17689691 TI - Heparin-binding EGF-like growth factor preserves mesenteric microcirculatory blood flow and protects against intestinal injury in rats subjected to hemorrhagic shock and resuscitation. AB - BACKGROUND: The gut is highly susceptible to injury after hemorrhagic shock and resuscitation (HS/R) because of progressive mesenteric hypoperfusion. The aim of the current study was to evaluate the effect of heparin-binding EGF-like growth factor (HB-EGF) on mesenteric microcirculatory blood flow and intestinal injury in rats subjected to HS/R. METHODS: HS/R was induced in adult rats, with some rats receiving HB-EGF (600 mug/kg) IV at the onset of resuscitation (HS/R+HB-EGF) and others receiving vehicle only (HS/R). FITC-dextran was administered intra arterially to evaluate mesenteric microcirculation, and intestinal damage and restitution were evaluated histologically. Data were expressed as mean +/- SE, with P < .05 considered statistically significant. RESULTS: Microcirculatory blood flow was significantly reduced 1 hour after HS/R. HS/R+HB-EGF rats had significantly increased microcirculatory flow compared with HS/R rats at 1 hour (4.5 +/- 0.43 vs 2.64 +/- 0.46, P < .05) and 3 hours (8.04 +/- 1.58 vs 2.89 +/- 0.63, P < .05) after HS/R. HS/R+HB-EGF rats had significantly less intestinal damage compared with HS/R rats 3 hours after resuscitation (2.04 +/- 0.5 vs 3.08 +/- 0.5, P < .05), along with significantly fewer incompetent (nonresurfaced, nonhealed) villi, which is indicative of improved restitution. CONCLUSIONS: HB EGF significantly improved postresuscitation microcirculatory blood flow in rats subjected to HS/R, associated with significantly decreased intestinal damage and increased restitution. These results suggest that HB-EGF may be a useful therapeutic agent that improves intestinal blood flow in patients with intestinal injury secondary to hemorrhagic shock. PMID- 17689692 TI - Protein kinase C alpha modulates microvascular reactivity in the human coronary and skeletal microcirculation. AB - BACKGROUND: Cardioplegic arrest (CP) and cardiopulmonary bypass (CPB) can lead to dysfunction in the coronary and skeletal microcirculation leading to impaired tissue perfusion. alpha-Adrenergic signaling pathways acting on these microcirculatory beds are thought to involve protein kinase C (PKC). We investigate here the role of the conventional PKCs in microvascular function in the setting of CP/CPB. METHODS: Atrial and skeletal muscle was harvested from 30 patients undergoing cardiac surgery before and after CP/CPB. Microvessels were used for Western blotting and immunofluorescent staining against conventional PKCs. Microvascular constriction was assessed in pre- and post-CP/CPB samples in response to alpha-adrenergic stimulation with phenylephrine, with and without a PKC-alpha inhibitor or PKC-alpha activator. PKC activity was assessed in isolated microvessels. RESULTS: Western blotting and immunostaining demonstrated only PKC alpha in coronary and skeletal microvessels. CP/CPB diminished contractile responses to phenylephrine in coronary and skeletal samples. Inhibition of PKC alpha reduced phenylephrine induced vasoconstriction in coronary and skeletal microvessels, whereas activation of PKC-alpha-augmented phenylephrine induced responses. PKC activity was decreased in coronary microvessels and to an even greater degree in skeletal microvessels after CP/CPB. CONCLUSIONS: PKC-alpha is the predominant conventional PKC present in the human coronary and skeletal microcirculation. It likely plays a key role in alpha-adrenergic signaling in microvessels and in the vasomotor dysfunction after CP/CPB. PMID- 17689693 TI - Polymicrobial sepsis enhances clearance of apoptotic immune cells by splenic macrophages. AB - BACKGROUND: Macrophage phagocytosis of apoptotic cells induces an anti inflammatory macrophage phenotype. Immune cell apoptosis is widespread in sepsis; however, it is unknown whether sepsis alters the capacity of macrophages to clear this expanded population. We hypothesize that sepsis will enhance splenic macrophage phagocytosis of apoptotic immune cells, potentially contributing to immunosuppression. METHODS: Sepsis was induced in C57BL/6J mice by cecal ligation and puncture (CLP). Apoptosis was induced in mouse thymocytes by dexamethasone incubation. At multiple time points after CLP/sham, splenic and peritoneal macrophages were isolated, plated on glass coverslips, co-incubated with apoptotic thymocytes, and fixed and the coverslips were then Giemsa stained. Splenic macrophages were also isolated 48 hours after CLP/sham, stained with the red fluorescent dye PKH26, and co-incubated with green fluorescent dye CFSE stained apoptotic thymocytes and then coverslips were fixed and counterstained with DAPI. The macrophage phagocytic index (PI) was calculated for both staining methods. RESULTS: The PI of CLP splenic macrophages was significantly higher than sham by 24 hours, and this difference was sustained through 48 hours. CONCLUSIONS: Studies suggest that apoptotic cell clearance leads to an anti inflammatory macrophage condition, which together with our findings in septic macrophages, may point at a process that contributes to septic immune suppression. PMID- 17689694 TI - Effectiveness of siRNA uptake in target tissues by various delivery methods. AB - BACKGROUND: RNA interference offers clinical potential as a therapeutic modality for a variety of diseases; the efficacy of in vivo delivery remains poorly understood. The purpose of our study was to compare and contrast short interfering RNA (siRNA) uptake in vivo using various delivery techniques. METHODS: DY547- and rhodamine-labeled siRNA was administered to mice by one of four delivery methods: (1) hydrodynamic intravenous tail vein injection, (2) standard intravenous tail vein injection, (3) intraperitoneal injection, and (4) rectal administration. Mice were killed over a time course; representative tissue samples were collected and analyzed using fluorescent microscopy to determine siRNA uptake. RESULTS: siRNA uptake was noted in the liver, kidney, pancreas, spleen, and bone marrow by both hydrodynamic and standard IV injection. siRNA uptake was detected in the spleen, liver, and bone marrow after intraperitoneal administration. Rectal administration resulted in siRNA uptake in the spleen, bone marrow, and colon. CONCLUSION: Our results demonstrate differential siRNA uptake depending on delivery technique. Importantly, our results demonstrate the potential of siRNA as a systemic therapeutic option in vivo for selected disease processes. PMID- 17689695 TI - A novel suicide gene therapy targeting the overexpression of eukaryotic initiation factor 4E improves survival in a rat peritoneal carcinomatosis model. AB - BACKGROUND: Eukaryotic Initiation Factor 4E (eIF4E) is pivotal in translating mRNAs with complex 5' un-translated regions (UTRs). A target-specific gene therapy was developed by splicing a complex 5'UTR upstream of the herpes simplex virus thymidine kinase (TK) gene in an adenovirus vector (Ad-HSV-UTK). Translation of the suicide TK gene is restricted to cells that overexpress eIF4E. We investigated the efficacy of this novel therapy in a rat peritoneal carcinomatosis (PC) model. METHODS: A PC model was developed by implanting a syngeneic 0.25 cm(3) tumor into Fisher 344 rats' omentum. Rats were grouped as follow: No surgery (O CS), cytoreductive surgery alone (CS), and CS + Ad-HSV-UTK + gancyclovir (GCV). 10(9) Ad-HSV-UTK was injected intraperitoneally (i.p.) and GCV (50 mg/kg) was administered i.p. every other day, beginning on postoperative day 2. The Kaplan-Meier survival method and log-rank test were statistical tests used. RESULTS: Treated rats had a significantly longer median and overall survival than the O CS and CS groups (P = .012). The median survivals for the treated rats, O CS, CS were 18 days, 9 days, and 11 days, respectively. CONCLUSIONS: Treatment with a novel suicide gene therapy following cytoreductive surgery prolonged survival in a rat peritoneal carcinomatosis model. PMID- 17689696 TI - The effects of a novel resuscitation strategy combining pentoxifylline and hypertonic saline on neutrophil MAPK signaling. AB - BACKGROUND: The combination of hypertonic saline (HS) and pentoxifylline (PTX) has been shown to synergistically downregulate neutrophil oxidative burst in vitro. We investigated the effects of HS/PTX on human neutrophil mitogen activated protein kinase (MAPK) signaling and the role of Protein kinase A (PKA) in this process. METHODS: Isolated neutrophils were treated with PTX (2 mmol/L), HS10 (10 mmol/L above isotonicity), and HS40 (40 mmol/L above isotonicity) alone or in combination for determination of intracellular cyclic adenosine monophosphate (cAMP) concentrations. Human neutrophils were stimulated with f methionyl-leucyl-phenylalanine (fMLP) (1 micromol/L) before the treatments above in both the presence and the absence of PKA inhibition for Western blot analysis of MAPK p38 and extracellular signal-related kinase 1/2 (ERK 1/2) phosphorylation. RESULTS: Concomitant exposure to HS/PTX results in an additive increase in intracellular cAMP. fMLP-induced ERK 1/2 phosphorylation was synergistically attenuated by HS/PTX. Both PTX and HS reduced p38MAPK phosphorylation. No additive effect was observed with combined treatment. Although PKA inhibition abrogated the effects of PTX, HS retained some capacity to attenuate MAPK phosphorylation. CONCLUSION: HS/PTX is more effective in attenuating neutrophil ERK signaling than either component alone, whereas both components alone or in combination produced comparable results with p38MAPK. Although PTX functions primarily through PKA activation, HS may suppress neutrophils through a partially PKA-independent mechanism. PMID- 17689697 TI - Deletion of CCR2 but not CCR5 or CXCR3 inhibits aortic aneurysm formation. AB - BACKGROUND: Microscopic analysis of abdominal aortic aneurysms (AAAs) demonstrates an abundance of infiltrating leukocytes. The chemokine receptors CCR2, CCR5, and CXCR3 are associated with pathways implicated previously in aneurysm pathogenesis. We hypothesized that genetic deletions of CCR2, CCR5, and CXCR3 would limit leukocyte infiltration and aneurysm formation in a mouse model of AAA. METHODS: CCR2(-/-), CCR5(-/-), CXCR3(-/-), and control mice of the same genetic background were subject to periaortic application of calcium chloride. Aortic diameters were measured before aneurysm induction and at harvest 6 weeks later. Diameters were compared using the Mann-Whitney test. Aortas were stained with H&E and trichrome for histologic analysis. Aortic MMP-2 and MMP-9 activities were measured using zymography. RESULTS: Aneurysm formation was attenuated in CCR2(-/-) mice with the final mean aortic diameter less than that of the control mice (P < .01). Histology revealed preservation of the lamellar architecture and decreased inflammatory cells. Aortic MMP-2 and MMP-9 levels were decreased in CCR2(-/-) mice. CCR5(-/-) and CXCR3(-/-) mice demonstrated no protection from aneurysm formation, which was corroborated by the tissue histology showing similar inflammatory cell infiltration and elastin degradation. CONCLUSIONS: The CCR2 receptor is involved directly in AAA formation, whereas the CCR5 and CXCR3 receptors are not. PMID- 17689698 TI - Hemoglobin-based oxygen carrier induces hepatic heme oxygenase 1 expression in Kupffer cells. AB - BACKGROUND: Kupffer cells (liver macrophages) are a key initiator of inflammation following hepatic insults such as infection, ischemia/reperfusion, and rejection. Heme oxygenase 1 (HO-1) is protective against inflammatory injury. A hemoglobin based oxygen carrier (HBOC) has been shown to prevent organ inflammation from hemorrhagic shock as well as induce HO-1 at the cellular level. Therefore, we hypothesize that HBOC can induce Kupffer cell HO-1 production. METHODS: Mice administered 20% blood volume HBOC or saline intravenously were sacrificed at 0, 12, 24, 48 hours (n = 4-6/group). Hepatic protein underwent Western blotting for HO-1 and heat shock protein 72. Hepatic frozen sections underwent immunofluorescent staining for HO-1/CD68. RESULTS: Following HBOC injection, hepatic HO-1 fold change peaked at 12 hours (7.3 +/- 0.8) (p < .01), remained increased at 24 hours (4.7 +/- 0.4) (p < .01), and returned to baseline by 48 hours. HSP72 expression was unaffected in all groups. Twleve-hour liver section immunostaining confirmed significant induction of HO-1 by HBOC. Double staining for HO-1 and CD68 identified Kupffer cells as the majority of cells expressing HO 1. CONCLUSION: HBOC induces hepatic HO-1 expression in Kupffer cells without heat shock protein response. These data provide the basis for further investigation into a clinical therapy to induce Kupffer cell HO-1 expression with the goal of attenuating the hepatic immunoresponse to various insults. PMID- 17689699 TI - Phosphatidylinositol 3-kinase pathway regulates hypoxia-inducible factor-1 to protect from intestinal injury during necrotizing enterocolitis. AB - BACKGROUND: Hypoxia is an important risk factor for development of necrotizing enterocolitis (NEC) in premature infants. Hypoxia-inducible factor (HIF)-1 is a transcription factor that plays a critical role in cellular responses to hypoxia and can be induced by phosphatidylinositol 3-kinase (PI3-K) pathway. Activation of the PI3-K and regulation of HIF-1 during NEC have not been elucidated. METHODS: NEC was induced in 3-day-old neonatal mice using hypoxia and artificial formula feedings. Mice were divided into 3 treatment groups: (1) NEC alone, (2) NEC with insulin-like growth factor (IGF)-I, or (3) NEC with Akt1 siRNA treatment. Animals were sacrificed, and intestinal sections were harvested for protein analysis, H&E, and immunohistochemical staining. RESULTS: In vivo model of NEC produced intestinal injury associated with increased protein expression of HIF-1alpha, pAkt, PARP, and caspase-3 cleavage. Pretreatment with IGF-1 attenuated an HIF-1alpha response. In contrast, targeted inhibition of Akt1 completely abolished NEC-induced expression of pAkt and upregulated HIF-1alpha activation. CONCLUSIONS: NEC activates important protective cellular responses to hypoxic injury such as HIF-1alpha and PI3-K/Akt in neonatal gut. Hypoxia-mediated activation of pro-survival signaling during NEC may be modulated with growth factors, which thus suggests a potential therapeutic option in the treatment of neonates with NEC. PMID- 17689700 TI - Defining service and education: the first step to developing the correct balance. AB - BACKGROUND: Service and education activities have not been well defined or studied. The purpose of this study is to describe how attendings and residents categorize common resident activities on a service-education continuum. METHODS: A web-based survey was designed to categorize resident activities. A panel of residents and surgical educators reviewed the survey for content validity. Residents and attendings categorized 27 resident activities on a 5-point scale from 1 (pure service) to 5 (pure education). Data analysis was performed using SPSS ver.12. RESULTS: 125 residents and 71 attendings from eight residency programs participated. 66% of residents and 90% of attendings were male. On average, attendings had practiced 14.3 years. Residents' post-graduate year ranged from PGY-1 to PGY-6 (mean of 2.78). Attendings and residents agreed on the categorization of most activities. Residents felt more time should be devoted to pure education than did attendings. Forty percent of residents felt that more than half of their time was spent in pure service versus 10% of attendings. Twenty-five percent of residents and 23% of attendings were dissatisfied with the service-education balance. CONCLUSIONS: The Residency Review Committee mandates that education is the central purpose of the surgical residency without clearly defining the balance between education and service. Attendings and residents agree on the educational value of most activities and that the balance between education and service is acceptable. When compared with attendings, residents feel they need significantly more time in education. Adequate learning can be facilitated by the development of clear definitions of service and education and guidelines for the distribution of resident time. PMID- 17689701 TI - Myocardial infarction with huge mural thrombus due to spontaneous coronary artery dissection detected by 64-multidetector computed tomography. AB - A 28-year-old man without medical history of cardiovascular disease came to the clinic to have the cause of his ECG abnormalities and chest discomfort evaluated. Echocardiogram showed regional wall motion abnormality of the anteroseptum and inferoseptum from the upper mid-left ventricle to apex with aneurysm and anterior wall from the mid-left ventricle to apex. It also showed huge and broad mural thrombus (5.2x1.4 cm in size) harboring in the left ventricle. Coronary angiography revealed a middle part of left anterior descending coronary artery (LAD) dissection with good distal flow. ECG gated 64-multidetector computed tomography (MDCT) demonstrated the proximal and middle part of LAD dissection. There has been no observation of myocardial infarction with huge mural thrombi complicating a spontaneous coronary artery dissection in which MDCT allowed an accurate and non-invasive diagnosis. PMID- 17689702 TI - Can we finally get a coronary angiography with the least amount of dye? AB - The incidence of adverse events complicating coronary angiography is still considerably high. Founded concerns about risks of coronary angiography, and mainly its inherent invasiveness, have favored the increasing request for noninvasive techniques to evaluate the coronary anatomy, such as multislice computed tomography (MSCT). Nonetheless, it has to be kept in mind that several risks and complications are the same both for MSCT and conventional coronary angiography. Rotational angiography has been shown to be a powerful imaging tool for the evaluation of coronary anatomy resulting in the use of less contrast media and less radiation, without losing the possibility to obtain a precise, efficient and fast characterization of obstructive coronary artery disease. It is likely that in the next future the overall performance, taking into account both the diagnostic accuracy and the risk of exposure to radiation and contrast media, of MSCT techniques will have to be compared to that of rotational angiography, especially when the latter is coupled with minimally invasive approaches. PMID- 17689703 TI - Cardioplegic ischemia or reperfusion: which is a main trigger for tumor necrosis factor production? AB - BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) is a key cytokine in the pathogenesis of ischemia-reperfusion injury (I/R) that also possesses negative inotropic and direct cardiotoxic effects. We investigated whether myocardial ischemia and/or reperfusion is the trigger for TNF-alpha synthesis and whether TNF-alpha release is time dependent. METHODS: Isolated rat hearts undergoing 30 min of coronary perfusion with modified Krebs-Henseleit solution followed by cardioplegic arrest for 60 min of global cardioplegic normothermic ischemia (GCI) and 30 min of reperfusion using a modified Langendorff model. Myocardial TNF-mRNA expression and TNF-alpha protein levels in effluent from the coronary sinus were measured at baseline and then after 15, 30, and 60 min of GCI and after 10 and 30 min of reperfusion. RESULTS: GCI induced myocardial TNF-alpha mRNA expression and elevation protein TNF-alpha levels in a time-dependent manner after 30 min of ischemia from 78+/-17 pg/ml to 915+/-287 pg/ml after 60 min (p<0.0015). Reperfusion did not cause time-dependent increase of TNF-alpha synthesis and release but was accompanied by progressive decrease of left ventricular (LV) function. There was a correlation between TNF-alpha protein levels and depression of LV function immediately after GCI but not with TNF-alpha protein levels at 30 min of reperfusion. CONCLUSION: This study demonstrated that myocardial ischemia rather than reperfusion is the main trigger for time-dependent TNF-alpha synthesis. Depression of LV function during reperfusion correlated significantly only with TNF-alpha levels at the end of GCI. PMID- 17689704 TI - Anomalous origin of the right coronary artery: depiction at whole-heart coronary magnetic resonance angiography. AB - Anomalous origin of the right coronary artery (RCA) is a rare congenital anomaly, which may cause myocardial ischemia and sudden death. Whole-heart coronary magnetic resonance angiography (MRA) was performed in a 61-year-old woman who had exercise-induced myocardial ischemia. MRA revealed that the RCA originated from the left sinus of Valsalva, separately from the left main coronary artery and it coursed between the ascending aorta and pulmonary artery. There was acute angle take-off of the RCA from the aorta. This is the first report describing whole heart coronary MRA findings of the anomalous origin of the RCA. PMID- 17689705 TI - Cardiac troponins after a downhill marathon. PMID- 17689706 TI - Right ventricular dysfunction is an independent predictor of survival in patients with dilated chronic Chagas' cardiomyopathy. AB - BACKGROUND: Right ventricular (RV) involvement is a typical feature of Chagas' disease. In patients with congestive heart failure of other etiologies, RV dysfunction is a strong indicator of poor prognosis. However, the prognostic value of RV dysfunction in patients with Chagas' cardiomyopathy has not been reported. This study sought to investigate the prognostic value of RV dysfunction, apart from other well established risk factors, in patients with Chagas' cardiomyopathy. METHODS: The study enrolled 158 patients (99 men; mean age of 48+/-12 years) from a tertiary center for Chagas' disease. Patients were selected if found to have both the diagnosis of Chagas' disease and cardiomyopathy. All patients underwent a comprehensive Doppler echocardiogram and the global RV function was quantitatively assessed using the RV index of myocardial performance (Tei index). RESULTS: Most of the patients were in NYHA classes I and II (79%). During a mean follow up of 34+/-23 months, 44 patients (28%) died: 24 (55%) patients died of progressive heart failure and 16 (36%) of sudden death. RV Tei index emerged as an independent predictor of survival (hazard ratio 5.75, 95% confidence interval 1.69 to 19.51). Kaplan-Meier survival curves showed a higher cumulative mortality among patients in the highest quartile of RV Tei index, compared with other 3 quartiles (log-rank statistic 21.87, p<0.001). After adjustment for clinical data and LV ejection fraction, RV Tei index in the highest quartile (>0.56) remained a significant predictor of death (hazard ratio 5.29, 95% confidence interval 2.43 to 11.52). CONCLUSIONS: RV function assessed by the Tei index added significant prognostic information, incremental to the NYHA clinical classification and to the standard echocardiographic evaluation of LV systolic function. A simple measure of a Doppler index, which allows analysis of both systolic and diastolic function of the RV, appears to be a useful non-invasive tool for risk stratification in patients with dilated chronic Chagas' cardiomyopathy. PMID- 17689707 TI - Chronic dissection of internal mammary artery graft. AB - We report a case of internal mammary artery graft dissection. Cardiac catheterization showed a spiral dissection in the anastomotic site of internal mammary artery graft with TIMI 3 flow. Percutaneous stenting for native coronary artery lesions was performed. Cardiac catheterization, performed 2 years after the stenting, showed no change in the internal mammary artery dissection. This is the first case of unhealed chronic dissection of internal mammary artery graft. PMID- 17689708 TI - Comparison of fluoroscopic coronary angiography and multi-slice coronary angiography in the characterization of anomalous coronary artery. AB - Anomalous coronary arteries with an inter-arterial course are associated with sudden cardiac death. We reported a study comparing the accuracy of fluoroscopic coronary angiography (FCA) with that of multi-slice computed tomography (MSCT) coronary angiography in determining the proximal course of anomalous coronary arteries. Twelve patients with thirteen anomalous coronary arteries had both FCA and MSCT coronary angiography were included in this study. Twelve cardiologists individually reviewed FCAs of anomalous coronary arteries and determined the proximal course of anomalous coronary arteries as retro-aortic, inter-arterial or ante-pulmonary. Their diagnoses were compared with MSCT coronary angiography which was regarded as the reference standard in this study. On MSCT coronary angiography, there were six anomalous left circumflex arteries with a retro aortic course, five anomalous right coronary arteries and one anomalous left anterior descending artery with inter-arterial courses, and a single anomalous left main artery with an ante-pulmonary course. The percentage of correct diagnosis made by 12 cardiologists based on FCA findings was 93/156 or 60%. None of the cardiologists was correct in determining the proximal course of all anomalous coronary arteries. The median number of anomalous coronary arteries with their proximal courses correctly identified by the cardiologists was 7.5 (range 3-12). In conclusion, FCA was limited in delineating the proximal course of anomalous coronary arteries in comparison with MSCT coronary angiography. PMID- 17689709 TI - Alterations of an average heart rate change heart rate variability due to mathematical reasons. AB - In the article, we demonstrate how the mathematical rules may bias the results of heart rate variability analysis. We also propose the way how to get rid of this problem. PMID- 17689710 TI - Pulmonary hypertension in rheumatoid arthritis--relation with the duration of the disease. AB - Isolated pulmonary hypertension with clinical implication is rare in rheumatoid arthritis. We sought to study the prevalence of pulmonary arterial hypertension in an unselected population of 45 patients with rheumatoid arthritis (classified according to the ARA criteria) without cardiac disease and corresponding age and sex matched controls by Doppler echocardiography. The pulmonary artery systolic pressure was higher in patients with Rheumatoid Arthritis (27.49+/-12.66 mm Hg) than in controls (20.40+/-8.88) (p=0.003). Incidence of pulmonary artery systolic pressure>30 mm Hg suggesting pulmonary hypertension was significantly higher in patients with RA (26.7% versus 4.5% in controls; p=0.03) and 20% of patients had pulmonary hypertension without lung disease or cardiac disease evident on pulmonary function testing, and echocardiogram respectively. There was also a strong correlation between the pulmonary artery pressure and the disease duration (r=0.68, p<0.0001) suggesting a subclinical involvement of the pulmonary vasculature with disease progression and may be relevant to the high incidence of cardiovascular deaths observed in patients with Rheumatoid Arthritis. PMID- 17689711 TI - Clinical in-stent restenosis with bare metal stents: is it truly a benign phenomenon? AB - OBJECTIVE: In-stent restenosis (ISR) remains an important problem following percutaneous coronary intervention (PCI). Although it is generally believed that patients with ISR present with stable angina, this has not been well characterized. The aim of this study was to define the incidence, predictors, timing and clinical presentation of patients with ISR requiring repeat catheterization. DESIGN: Using a multiregion prospective database which captures all patients undergoing cardiac catheterization and revascularization in the Province of Alberta, Canada, consecutive bare metal stent (BMS) implantations from January 1, 1998 to December 31, 2002 were analyzed. All patients with a repeat angiogram within one year of the index PCI were reviewed for evidence of clinical-ISR (CISR), defined as ISR as the cause for clinical presentation at angiography. RESULTS: Of the 12,492 consecutive PCI patients reviewed, 2521 had repeat angiography and 744 patients (6.0%) had CISR by study definition. The mean time to repeat angiography in CISR patients was 5.4+/-2.7 months and multivariate analysis identified female gender, diabetes mellitus, and prior PCI as predictors. The majority of patients presented with an acute coronary syndrome: 52.2% unstable angina/non-ST elevation myocardial infarction and 18.5% ST elevation myocardial infarction. Only 25.3% presented with stable exertional angina. CONCLUSION: Although the incidence of CISR within one year after BMS was relatively low, the recurrent clinical event in the majority of cases was a high risk coronary syndrome. Thus, careful consideration of the risks of ISR to a specific patient against the cost implications of novel and expensive means to decrease its occurrence is required. PMID- 17689712 TI - Electrocardiographic characteristics of patients with inferior myocardial infarction but angiographically normal coronary arteries. AB - Normal coronary arteries were found in 22 (5.8%) of 379 patients presented with acute inferior myocardial infarction. These patients were significantly younger, had less cardiovascular risk factors, better systolic heart function, and lower cardiac enzymes level. Electrocardiography significantly showed more (1) ratio of ST-segment elevation in II/ III>or=1; (2) isoelectric ST-segment in I; (3) ST segment elevation in I; and less (4) paroxysmal atrial fibrillation; (5) ST segment depression in I; and (6) ST-segment elevation in V4R. In conclusion, this subset of patients had clinical features suggestive of smaller infarct size compared with those suffering from atherosclerotic disease. They may have more left circumflex artery involvement and distal right coronary artery occlusion, as deduced from electrocardiography. PMID- 17689713 TI - Staphylococcus lugdunensis endocarditis following cardiac catheterisation. AB - We report the case of a 77 year old with Staphylococcus lugdunensis endocarditis following cardiac catheterisation via a femoral approach. We underline the association between this pathogen and inguinal skin breaks, and discuss the potential diagnostic pitfalls in clinical and laboratory diagnosis. PMID- 17689714 TI - Artifacts and noise removal in electrocardiograms using independent component analysis. AB - Independent component analysis (ICA) is a novel technique capable of separating independent components from electrocardiogram (ECG) complex signals. The purpose of this analysis is to evaluate the effectiveness of ICA in removing artifacts and noise from ECG recordings. ICA is applied to remove artifacts and noise in ECG segments of either an individual ECG CSE data base file or all files. The reconstructed ECGs are compared with the original ECG signal. For the four special cases discussed, the R-Peak magnitudes of the CSE data base ECG waveforms before and after applying ICA are also found. In the results, it is shown that in most of the cases, the percentage error in reconstruction is very small. The results show that there is a significant improvement in signal quality, i.e. SNR. All the ECG recording cases dealt showed an improved ECG appearance after the use of ICA. This establishes the efficacy of ICA in elimination of noise and artifacts in electrocardiograms. PMID- 17689715 TI - Recanalization of peripheral arteries by interventional cardiologists: rationale and results. AB - The coexistence of peripheral artery disease (PAD) and multilevel atherosclerosis increases death and stroke rates in patients with coronary artery disease (CAD). These patients are often treated conservatively without revascularisation of inferior limbs. We included 66 consecutive patients with complex CAD diagnosed by coronary angiography. All patients underwent percutaneous coronary intervention (PCI) for non-ST elevation acute coronary syndrome (NSTEACS) before or simultaneously with peripheral angioplasty (PTA). Major adverse cardiac and cerebrovascular events (MACCE) during long-term follow-up were assessed. There were 3 deaths, one myocardial infarction, two urgent PCIs, two ischaemic strokes and two TIAs, 8 repeated PTAs in previously treated peripheral lesions, 7 elective PTAs of other vessels after the index procedure in different hospitalisations and no amputation. Patients with concomitant CAD and PAD could safely undergo percutaneous cardiovascular interventions with promising long-term follow-up. PMID- 17689716 TI - Early cardiac damage after subarachnoid hemorrhage in rats. PMID- 17689717 TI - Spontaneous coronary dissection of the left main stem after intense physical activity--regression under conservative strategy. AB - Spontaneous coronary dissection usually occurs in middle-aged women, during pregnancy and postpartum. Proposed management strategies are most often based on invasive procedures such as percutaneous transluminal intervention with stenting, or surgical revascularization. We report a case of coronary dissection of the main stem artery occurring after intensive exercise, showing a rapid regression under conservative medical treatment. This case and the review of the literature emphasize that in case of non-occlusive coronary dissection, a conservative approach with a careful follow-up may be a strategy to consider. PMID- 17689718 TI - Percutaneous mitral valvuloplasty in patients with low cardiac output at high surgical risk. AB - Among 1146 patients undergoing percutaneous mitral valvuloplasty for symptomatic mitral stenosis, 8 (4 men and women) were at high risk for surgery on the basis of the New York Heart Association functional class IV (n=8), severe pulmonary hypertension (n=5). All these patients aged 30+/-23.6 years had signs of right heart failure, high echocardiographic score (9.6+/-3.6) and low mitral valve area (0.50+/-0.19 cm(2)). The procedure resulted in an increase in mitral valve area (1.55+/-0.17 cm(2)) with a concomitant reduction in pulmonary artery systolic pressure (58.7+/-9.9 mm Hg) and decrease in tricuspid regurgitation. At follow-up (mean 14+/-3 months), one patient with renal failure... presented with a mitral restenosis is scheduled for mitral valve replacement, two patients with severe tricuspid regurgitation required tricuspid annuloplasty. In conclusion, percutaneous mitral valvuloplasty is feasible and safe in patients at high surgical risk and can be considered as an acceptable alternative to surgery. PMID- 17689719 TI - Reversible 18-FDG-uptake defects on myocardial PET: Is this myocardial resurrection? AB - Because it can accurately detect preserved glucose metabolism even in the hypoperfused or stunned myocardium, 18-FDG-PET is considered as the gold standard of myocardial viability assessment. In tako-tsubo cardiomyopathy, a presumed condition of stunning, absence of glucose metabolism however is not a marker of death. This sheds a critical light on 18-FDG-PET as a gold standard for viability. PMID- 17689720 TI - Giant right atrial aneurysm: a case report. AB - Giant right atrial aneurysm is a very rare congenital heart defect. We report a case which was diagnosed during fetal life and operated on at 4 months of age with excision of the aneurysmal part and pericardial patch closure. Early repair is recommended to prevent late complications such as arrhythmias and thromboembolic phenomena. PMID- 17689721 TI - Adenosine-induced atrial fibrillation during pharmacologic stress testing: report of eight cases and review of the literature. AB - Adenosine-induced atrial fibrillation has been described in the setting of treatment of supraventricular tachycardia, but has been rarely reported during adenosine infusion for pharmacologic stress testing. We present 8 patients who developed atrial fibrillation during adenosine stress testing. The incidence of this arrhythmia was 0.41% in our laboratory. Atrial fibrillation was often preceded by frequent atrial premature beats and/or AV block, and the duration ranged from 15 seconds to 6 hours. All patients converted spontaneously to normal sinus rhythm. Atrial fibrillation is a relatively rare arrhythmic complication of adenosine infusion, and can be managed expectantly, without need of cardioversion. PMID- 17689722 TI - Surgical treatment of arrhythmias in adults with congenital heart defects. AB - BACKGROUND: Supraventricular and ventricular arrhythmias are a major cause of morbidity and mortality in adult patients with congenital heart disease (CHD). Intraoperative ablation offers an alternative to the complex surgical Cox-Maze procedure for these patients. We present the results of our preliminary experience with intraoperative monopolar irrigated radiofrequency ablation (IRA) in adults with CHD undergoing elective cardiac surgery. METHODS: Since September 2002, 50 adults with a mean age of 39 years with CHD underwent IRA during cardiac surgery. We performed 31 right-sided Maze procedures, 13 Cox-Maze III procedures and 6 right ventricular ablations. In addition, we implanted a pace-maker into 14 patients. RESULTS: Two patients died (2 of 50; 4%) of causes not related to the intraoperative ablation. Over an average follow-up period of 28 months the remaining 48 patients are alive in NYHA class I or II. All patients were discharged on antiarrhythmic oral treatment for 3 months. All patients underwent Holter testing 3 and 6 months after the ablation procedure and five underwent programmed ventricular tachycardia stimulation 6 months postoperatively. Forty three patients are still in spontaneous sinus rhythm, two are in sinus rhythm on chronic oral antiarrhythmic treatment for recurrence of atrial fibrillation, two are in stable atrial fibrillation, and one has pacemaker rhythm. There were no complications from the IRA. CONCLUSIONS: Intraoperative IRA is a safe and effective procedure to control arrhythmic problems in adults with CHD. This procedure should be taken into consideration when transcatheter ablation fails or when elective cardiac surgery is planned. PMID- 17689724 TI - Atrial mechanical remodeling and new onset atrial fibrillation in chronic Chagas' heart disease. AB - Atrial fibrillation (AF) is a common arrhythmia, mechanistically linked to underlying heart disease. AF affects about one fifth of subjects with Chagas' heart disease and is a harbinger of poor prognosis. In a retrospective longitudinal analysis, 50 subjects were investigated in long-term follow-up for the first documented atrial fibrillation (AF) episode. During a follow-up of (mean+/-SD) 84.2+/-39.0 months, nine subjects developed AF (incidence: 3.3+/ 1.0%/year). Five subjects had nonfatal embolic stroke and nine died due to cardiac causes. The relative risk of AF for stroke was 3.0 (p=0.22) and for cardiac death was 3.6 (p=0.04). A faster left atrial diameter (LAD) enlargement during follow-up was tracked in subjects with more severe cardiac damage at presentation, and large LAD was detected at both presentation (p=0.02) and end of follow-up (p=0.002) in subjects who experienced AF. Atrial remodeling in chronic Chagas' disease is associated with severity of underlying heart disease at presentation and impacts AF incidence in this population. PMID- 17689725 TI - Two cases of dilated cardiomyopathy with right ventricular wall degeneration demonstrated by late gadolinium enhanced MRI. AB - Right heart failure is prominent in some patients with dilated cardiomyopathy (DCM). In this article, we present right ventricular wall degeneration and fibrosis demonstrated by late gadolinium enhanced magnetic resonance imaging (MRI) in patients with DCM. PMID- 17689726 TI - Total anomalous pulmonary venous return and Mayer-Rokitansky-Kuster-Hauser syndrome. AB - We present an adult woman with total anomalous pulmonary venous return (TAPVR) and Mayer-Rokitansky-Kuster-Hauser syndrome that was diagnosed intraoperatively during a planned atrial secundum defect closure. Surgical repair of TAPVR was performed with good outcome. PMID- 17689727 TI - Mechanical support availability in pediatric cardiac surgery: program size should not matter. AB - Intractable heart failure may require Extracorporeal Life Support (ECLS) techniques for rescue therapy. Nevertheless, in many small to middle-sized centers in Europe, this valuable resource is not available. In our University pediatric intensive care unit 0.9% of 1360 open-heart surgical patients required mechanical assistance over the latest 9 years with a survival rate of 69.2% and low residual morbidity. This favorable overall outcome suggests that regardless of the program size, it is possible to ensure the availability of efficient mechanical assistance that appears to be fundamental in a center performing surgery for complex congenital or acquired cardiac diseases. PMID- 17689728 TI - Multiple involvements of cardiac sarcoidosis in both left and right ventricles and papillary muscles detected by delayed-enhanced magnetic resonance imaging. AB - Cardiac sarcoidosis may cause various cardiac symptoms including congestive heart failure, arrhythmias, conduction disturbances and sudden death, depending upon the extent and sites of cardiac involvement. We describe a patient presenting with ventricular tachycardia and congestive heart failure. Magnetic resonance imaging revealed multiple delayed-enhanced areas in the left and right ventricles and papillary muscles. PMID- 17689729 TI - QT interval prolongation and torsade de pointes. AB - Torsade de pointes is a form of polymorphic ventricular tachycardia occurring in a setting of prolonged QT interval on surface electrocardiogram. Several drugs have been shown to prolong cardiac repolarization predisposing to torsade de pointes ventricular tachycardia. We present a case of torsade de pointes in a 72 year-old Italian woman in treatment with sotalol, sertraline, digoxin and acenocumarine. PMID- 17689730 TI - Comprehensive recognition of double-site dynamic obstruction in hypertrophic cardiomyopathy by cardiac magnetic resonance and Doppler echocardiography. AB - The noninvasive assessment of the mechanisms that lead to left ventricular outflow obstruction in hypertrophic cardiomyopathy allows the correct clinical management and the most suitable medical or surgical treatment for these patients. We report the case of a male patient affected by hypertrophic obstructive cardiomyopathy, where an uncommon variety of double-site dynamic obstruction was recognized by an integrated evaluation with high-resolution Doppler echocardiography and cardiac magnetic resonance. PMID- 17689731 TI - Simultaneous subacute stent thrombosis after implantation of sirolimus-eluting stent and bare-metal stent. AB - Simultaneous multivessel stent thrombosis is a rare, but can cause catastrophic clinical results. We report a case occurred ST simultaneously in DES and BMS. Our case demonstrated that the use of multiple stents, irrespective of stent type, in multiple coronary artery lesions should be undertaken with great attention in the patient who has multiple adverse clinical predictors such as AMI. PMID- 17689732 TI - The effect of double dose of omeprazole on the course of angina pectoris and treadmill stress test in patients with coronary artery disease--a randomised, double-blind, placebo controlled, crossover trial. AB - BACKGROUND: Gastroesophageal reflux (GER) and coronary artery disease (CAD) frequently overlap, making the proper diagnosis of chest pain more difficult. GER symptoms may mistake anginal chest pain, and oesophageal acidification may induce myocardial ischaemia both in the rest and in the effort. Increase of oesophageal pH should prevent these conditions. AIM: To estimate the effect of double omeprazole dose on the course of angina pectoris and treadmill stress test in patients with coronary artery disease (CAD), using double-blind, crossover randomised, placebo-controlled study design. METHODS: We studied 48 patients with angina pectoris symptoms and significant narrowing of coronary vessels in angiography. After baseline examination and treadmill stress test all subjects were randomised to treat either with omeprazole (20 mg b.i.d.) or placebo for 14 days, using a double-blind, crossover placebo controlled design. RESULTS: Seventeen (35%) subjects reported more than by half decrease in symptoms severity after omeprazole and 6 (12%) after placebo (p=0,01). Omeprazole significantly decreased the number of chest pain episodes and number of nitroglycerin doses taken in the second week of both study phases, as well as the percentage of subjects with significant decrease of ST interval during the stress test (64% vs. 73%, p<0,05). However majority of other stress test parameters (i.e. test duration, DUKE index) have improved both after omeprazole and placebo administration (by 9-38%). CONCLUSION: Double dose of omeprazole significantly decreased symptoms severity in 35% of patients with CAD, as well as frequency of some electrocardiographic signs of myocardial ischaemia during stress test. PMID- 17689733 TI - Coronary artery embolisation. AB - In the setting of an acute inferior myocardial infarction undergoing primary stent implantation, we could document a macroscopic embolus moving along the right coronary artery. Coronary embolisation is a well known drawback of percutaneous coronary interventions and dedicated devices can be used in order to minimize myocardial damage. Nonetheless, unexpected macroscopic embolisation after the first manual contrast injection through a diagnostic catheter remains a possible complication and may lead to unsatisfactory results when the upstream pharmacological therapy is not appropriate. PMID- 17689734 TI - Impaired isotonic contractility and structural abnormalities in the diaphragm of congestive heart failure rats. AB - BACKGROUND: Metabolic alterations and decreased isometric force generation have been demonstrated in different animal models for congestive heart failure (CHF). However, as few morphological examinations have been performed on the CHF diaphragm, it is unknown if structural abnormalities comprise a substrate for diaphragm dysfunction in CHF. Therefore, we investigated CHF diaphragm isometric and isotonic contractility together with the presence of structural abnormalities. METHODS: Isometric twitch (P(t)) and maximal (P(o)) force, shortening velocity and power generation were determined in diaphragm bundles from rats with CHF, induced by myocardial infarction, and sham-operated rats. Immunofluorescence staining of myosin and sarcolemmal components fibronectin, laminin and dystrophin was performed on diaphragm cryosections. Electron microscopy was used to study the ultrastructure of diaphragm fibres. RESULTS: P(t) and P(o) were respectively approximately 30% and approximately 20% lower in CHF diaphragm bundles than sham. Maximal shortening velocity was reduced by approximately 20% and maximal power generation by approximately 35%. Structural abnormalities were frequently observed in CHF diaphragm fibres and were mainly marked by focal degradation of sarcomeric constituents and expansion of intermyofibrillar spaces with swollen and degenerated mitochondria. Immunofluorescence microscopy showed reduced staining intensities of myosin in CHF diaphragm fibres compared to sham. No differences were found regarding the distribution of fibronectin, laminin and dystrophin, indicating an intact sarcolemma in both groups. CONCLUSION: This study demonstrates impaired isometric and isotonic contractility together with structural abnormalities in the CHF diaphragm. The sarcolemma of CHF diaphragm fibres appeared to be intact, excluding a role for sarcolemmal injuries in the development of CHF diaphragm dysfunction. PMID- 17689735 TI - Uncorrected tetralogy of Fallot: adult presentation in the 61st year of life. AB - Tetralogy of Fallot (TOF) is the commonest form of cyanotic congenital heart defect after infancy [Brickner ME, Hillis LD, Lange RA. Congenital Heart Disease in Adults-Second of Two Parts. NEJM 2000; 342(5):334-342.]. There are few studies assessing the risk of surgical correction in adult patients and long-term survival into the fourth decade of life is rare. The case history is described of a 61-year old female presenting with probable viral myocarditis. Subsequent investigations revealed an underlying diagnosis of tetralogy of Fallot. The patient remains asymptomatic despite persistent hypoxia. Potential factors contributing to longevity in this case are relatively good pulmonary blood flow via large branch pulmonary arteries, and the possible gradual development of right ventricular outflow tract obstruction over a long time period. PMID- 17689736 TI - Echocardiographic diagnosis of syndrome of left ventricular-right atrial shunt (Gerbode defect). AB - Left ventricular-to-right atrial communications are rare types of ventricular septal defect known collectively as the Gerbode defect. These defects are usually congenital and they have also been reported after bacterial endocarditis and after acute myocardial infarction. Echocardiography is the most useful diagnostic method. We describe a case of echocardiographic diagnosis of Gerbode defect in a 68-year-old Italian woman. PMID- 17689737 TI - Functional result following direct coronary artery stenting with drug eluting stents in chronic stable angina is similar to stenting after balloon predilatation. AB - BACKGROUND: The safety and efficacy of direct coronary artery stenting without predilatation using drug eluting stents has not been firmly established. Concerns have been raised that this technique may be associated with increased risk of immediate and short term complications. METHODS: 68 consecutive patients with chronic stable angina and angiographically proven single vessel disease were randomised to undergo either direct coronary artery stenting or stenting after balloon predilation. All patients underwent Pressure Wire directed percutaneous coronary intervention (PCI) and drug eluting stents were deployed. Pre and post PCI fractional flow reserve (FFR) was assessed following administration of intravenous adenosine. Post-procedure troponin I (TNI) and creatine kinase-MB (CK MB) were compared. 51 of the 68 patients successfully completed a 6 month treadmill exercise test. RESULTS: There were no significant differences in the demographic, risk factor or angiographic profiles between the two groups except for hyperlipedemia and statin therapy. Drug eluting stents were deployed in all patients. Majority of the lesions were relatively simple (all lesions were either type A or B1). The pre-procedure FFR [mean(SD)]was marginally lower in the pre dilatation group compared to the direct stenting group [0.57(0.17) versus 0.64(018); p=0.04]. The post-procedure FFR was similar in both groups [0.97(0.05) versus 0.98(0.03); p=0.26]. There was no difference in the post-procedure rise of either TNI or CK-MB in both groups. At 6 months, no major adverse cardiac events (death, MI or revascularisation) were observed in all patients. A positive exercise test was seen in 5 patients (10%) and there was no difference between the two groups. CONCLUSION: A strategy of direct stenting of appropriate coronary lesions with drug eluting stents in patients with chronic stable angina is associated with similar functional results as balloon predilatation followed by stenting. PMID- 17689738 TI - Conduction disturbances and paroxysmal atrial fibrillation during acute inferior myocardial infarction. AB - Associated symptoms and conduction disturbances are reported during acute inferior myocardial infarction. Differentiation of right coronary artery from left circumflex artery occlusion may be difficult since both can present an electrocardiographic pattern of inferior myocardial infarction. Paroxysmal atrial fibrillation is considered a frequent complication of acute myocardial infarction and the patients with paroxysmal atrial fibrillation probably should be targeted for earlier and more aggressive treatment. These patients in the thrombolytic era have a better overall outcome than counterparts in the prethrombolytic era. We describe a case of conduction disturbances and paroxysmal atrial fibrillation in a 51-year-old Italian man with acute inferior myocardial infarction and right coronary artery stenosis. PMID- 17689740 TI - Does homocysteine-lowering treatment improve cardiovascular outcomes in patients with acute coronary syndromes? What we have learned from clinical trials? PMID- 17689739 TI - Waist circumference, metabolic syndrome and coronary artery disease in a Pakistani cohort. AB - BACKGROUND: Metabolic syndrome (M-IRS) is common in Asians. This study investigated the relationship of two definitions of M-IRS to atherosclerosis in Indian Asians with suspected coronary arterial disease (CAD). METHODS: 400 patients with chest pain selected for the presence or absence of angiographic disease were recruited from a tertiary referral centre in Pakistan into a prospective case-control study. Patients were categorized by the National Cholesterol Education Program adult treatment panel 3 (NCEP) and International Diabetes Federation (IDF) definitions of the metabolic syndrome and the relationship of these to the presence of CAD and extent of atheroma burden was investigated. RESULTS: M-IRS was present in 53% by IDF criteria and in 44% using the Asian criteria for NCEP. The 2 populations identified were only 69% concordant. No relationship existed between the presence of NCEP M-IRS and atheroma burden. In contrast, the presence of IDF M-IRS was associated with CAD (65 vs. 34%; RR=1.88; p<0.001) and angiographic disease burden (28 [0-224] vs. 0 (0-198); RR=1.83; p<0.001). This association persisted (beta=18.4; p<0.001) after correction for C-reactive protein (beta=8.67; p<0.001), lipoprotein (a) (beta=8.14; p=0.002), and estimated glomerular filtration rate (beta=-0.22; p=0.01). Differences in presumed underlying factors were found in the 2 populations identified by the definitions though both agreed on the separate weightings given to blood pressure and HDL-C/apolipoprotein A1. CONCLUSIONS: The specific Asian IDF and NCEP definitions of M-IRS show limited concordance in Pakistanis. The IDF criteria in contrast to the NCEP criteria are associated with the presence of CAD even after allowing for other risk factors identified in this population. PMID- 17689741 TI - Methylated arginines in stable and acute patients with coronary artery disease before and after percutaneous revascularization. AB - BACKGROUND: Impairment of the nitric oxide synthase (NOS) pathway independently predicts cardiovascular events. We investigated whether plasma levels of the NOS inhibitor asymmetric dimethylarginine (ADMA), of symmetric dimethylarginine (SDMA) and of the nitrogen oxide substrate l-arginine can serve as additional staging biomarkers in stable coronary artery disease, non-ST-segment myocardial infarction (NSTEMI) and ST-segment myocardial infarction (STEMI). MATERIALS AND METHODS: Consecutive patients referred for percutaneous coronary intervention (PCI) were studied. Peripheral blood samples were drawn immediately before, immediately after and 24 h following PCI and analyzed by means of high performance liquid chromatography. RESULTS: Seventy-four patients were studied: 27 patients with stable angina pectoris (7 women, 61.4+/-1.9 years), 23 NSTEMI patients (9 women, 61.8+/-2.3 years) and 24 STEMI patients (7 women, 61.3+/-2.8 years). Plasma concentrations of ADMA and SDMA were elevated following PCI compared to before PCI but there were no differences in concentrations between STEMI, NSTEMI and stable angina patients. Plasma concentrations of l-arginine rose after PCI but remained lower in patients with STEMI than in those with NSTEMI or in stable angina patients. Medication might influence l-arginine concentrations and the use of HMG CoA reductase inhibitors and beta-adrenoceptor antagonists at study inclusion was significantly less common in STEMI patients compared to NSTEMI and stable angina patients. CONCLUSION: l-arginine levels were lower in patients with STEMI and we found changes in ADMA levels over shorter time periods than previously considered possible. We speculate that these variations may be related to the natural history of myocardial infarction or to peri-procedural stress related to PCI. PMID- 17689742 TI - A broken heart--or anguish in top-sport in antiquity. AB - Cardiovascular disease is a major determinant of sudden death. Nevertheless the impact of autonomic dysregulation is grossly underestimated not to say ignored. The limited life expectancy of retired gladiators is a fine example of the interactive influence of an occupational- and socio-cultural hazard at the time. Possibly the fate of retired athletes in antiquity is sealed by autonomic dysregulation, cardiac adaptation and noxious exposure in fatal interaction. Observations like these could be helpful in the understanding of complex pathofysiological mechanisms, and may have implications in medical practice. PMID- 17689743 TI - Free floating right atrial thrombus leading to acute pulmonary embolism. AB - The presence of right heart thrombi appears to increase the risk of mortality compared to the presence of pulmonary thromboemboli alone. The increased use of two-dimensional echocardiography has led to increased detection of these thromboemboli, particularly in patients with suspected or confirmed pulmonary emboli. The optimal management of the right heart thromboemboli remains unclear, but thrombolytic therapy with rt-PA appears to be rapidly effective in most patients resulting with complete resolution of the thrombus and improvement of pulmonary perfusion. Here, we present a case of free floating, worm-like thrombus in the right atrium which was lysed successfully by fibrinolytic therapy in a patient presenting with acute massive pulmonary embolism. PMID- 17689744 TI - The culprit artery in acute myocardial infarction in different environmental physical activity levels. AB - BACKGROUND: The timing of acute coronary events may be related to endogenous and exogenous--environmental--factors. AIM: To check if daily levels of geomagnetic activity (GMA) and/or cosmic ray activity (CRA) measured by neutron activity (imp/min) on the Earth's surface are related by timing with specific culprit artery of AMI. PATIENTS AND METHODS: Data of PCI for AMI (n=904, 696 men) from 01/2000 to 02/2006 (2251 days) were used for analysis. Daily GMA (I-IV levels) and neutron activity in imp/min were compared with localization of the culprit artery in AMI (LAD, RCA, CRX and Diagonal). The principal consideration was concentrated in the most frequent lesions of LAD (n=422) and RCA (n=332). The cosmophysical data were derived from USA, Russia and Finland. RESULTS: Similar to the whole 2251 days, the PCI were inversely related to GMA (p=0.03) and show a strong tendency to increase at higher CRA (p=0.07). Comparing data on two high (III, IV) and low (I, II) levels of GMA shows that, at high GMA, RCA and LAD lesions were equal; at the more often low daily levels of GMA, accompanied by higher CRA (neutron) activity (p<0.0001), LAD lesions were higher by 30% (chi(2)= 4.064, p=0.04). CONCLUSION: At higher daily levels of GMA, RCA/LAD culprit lesions in AMI are equal; at low GMA and higher CRA (neutron) activity, LAD lesions are predominant. PMID- 17689745 TI - Postprandial lipemia: an under-recognized atherogenic factor in patients with diabetes mellitus. AB - Atherosclerotic disease is the leading cause of both morbidity and mortality in patients with type 2 diabetes. In these patients, postprandial dyslipidemia include not only quantitative but also qualitative abnormalities of lipoproteins which are potentially atherogenic and seems to be a significant risk factor for cardiovascular disease since there is evidence that it results in endothelial dysfunction and enhanced oxidative stress. The most common pattern of postprandial dyslipidemia in diabetes consists of high concentrations of triglycerides, higher VLDLs production by the liver and a decrease in their clearance, a predominance of small dense LDL particles, and reduced levels of HDL. The cause of this postprandial dyslipidemia in diabetes is complex and involves a variety of factors including hyperinsulinemia, insulin resistance, hyperglycemia and disturbed fatty acid metabolism. Numerous clinical studies have shown that postprandial dyslipidemia is associated with endothelial dysfunction in type 2 diabetes and with alterations in other surrogate markers in the cascade of atherosclerosis. Current published guidelines indicate that in diabetics the primary lipid target is LDL<100 mg/dL (70 mg/dL in very high-risk patients) and the most appropriate class of drugs are statins although the issue of postprandial dyslipidemia has not been specifically addressed so far. Moreover, several other classes of medications (fibrates, niacin and antidiabetic drugs) as well as non-pharmacological interventions (i.e. diet, smoking cessation and exercise) can be used to treat lipid and lipoprotein abnormalities associated with insulin resistance and type 2 diabetes. These type of interventions may be more appropriate to ameliorate postprandial dyslipidemia. However, this remains to be confirmed on clinical grounds. PMID- 17689746 TI - Acute myocardial infarction induced increases in plasma tumor necrosis factor alpha and interleukin-10 are associated with the activation of poly(ADP-ribose) polymerase of circulating mononuclear cell. AB - Systemic inflammatory response to acute myocardial infarction (AMI) is detrimental to heart function. In this study, we proved that poly(ADP-ribose) polymerase (PARP) activity of circulating mononuclear cell (MNC) increased significantly in post-AMI patients. MNC PARP activity was correlated positively with plasma tumor necrosis factor-alpha (TNF-alpha) level, interleukin-10 (IL-10) level and the ratio of plasma TNF-alpha/IL-10 respectively. On the contrary, MNC PARP activity was correlated negatively with left ventricular ejection fraction and left ventricular fractional shortening which were measured with echocardiography in the same day when blood sample was collected. These results implicated that activation of PARP in MNC contributes to the increases in plasma TNF-alpha and IL-10 and is associated with systolic dysfunction of heart after AMI. PMID- 17689747 TI - Can kinetics of oxygen uptake at onset of exercise identify contractile reserve in patients with ischemic left ventricular dysfunction? PMID- 17689748 TI - Intraventricular obstruction in a patient with tako-tsubo cardiomyopathy. AB - We describe a case of a 70-year-old woman who developed chest pain and shortness of breath not related to a stress. The patient, with history of hypertension, presented T-wave inversion and prolonged QTc interval at admission electrocardiogram, peak troponin I level was normal, and no signs of myocarditis were found. Angiography demonstrated the "apical ballooning" without any obstructive coronary artery disease; on pullback of the pigtail catheter from the left ventricular apex to the basal tract, a 35 mm Hg gradient was observed. The echocardiographic evaluation showed asymmetric septal wall thickening of 19 mm, systolic anterior motion of the anterior mitral leaflet, juxtaposition of the septum to the mitral chordal apparatus, no significant left ventricular outflow tract gradient, moderate-to-severe mitral regurgitation and a pulmonary systolic pressure of 40 mm Hg. Rest (201)tallium myocardial perfusion scintigraphy SPECT showed a perfusion defect in the left ventricular apex. At 1-month echocardiographic and scintigraphic follow-up, left ventricular wall motion and myocardial perfusion returned completely normal. Nine months after the acute event the patient remained asymptomatic. We hypothesize that septal ventricular hypertrophy and intraventricular obstruction could be related to the development of some of the cases of tako-tsubo cardiomyopathy. PMID- 17689749 TI - Usefulness of Doppler echocardiography guidance during balloon aortic valvuloplasty for the treatment of congenital aortic stenosis. AB - INTRODUCTION: Few data exist regarding the potential benefits of continuous echocardiographic guidance during balloon aortic valvuloplasty (BAV) for the treatment of congenital aortic stenosis (AS). The objectives of this study were 1) to prospectively evaluate, in a series of consecutive patients with severe AS, the efficacy of BAV guided by Doppler echocardiography (DE) in relieving AS while preventing the appearance of significant aortic regurgitation (AR), and 2) to compare the results obtained by BAV-DE with those obtained in a historical series of patients who underwent BAV without echocardiographic guidance (BAV guided by angiography, BAV-A). METHODS: From 1995 to 2006 a total of 36 consecutive patients with AS (median age 6 years, range, 1 day to 26 years) underwent BAV in our center, with systematic application of continuous DE guidance since 2003. BAV DE consisted of measuring the aortic annulus, choosing balloon diameters and evaluating the results of each balloon dilation on the basis of DE. RESULTS: Seventeen patients underwent BAV-DE (transthoracic and transesophageal DE in 3 and 14 patients, respectively) with successful transaortic gradient relief in 88% of them. None of the patients complicated with moderate or severe AR. At 17+/-13 months follow-up there had been 3 cardiac events (18%), all of them related to aortic restenosis. BAV-A was associated with longer fluoroscopic times (35 min vs 16 min, p=0.005 after adjusting for age and weight differences between groups) and a higher degree of AR following BAV (>or=2 degrees increase in AR, 32% vs 0%, p=0.045 after adjusting for age and weight). Angiographic measurements of the aortic annulus were higher than those obtained by DE (mean overestimation+2.5+/ 1.8 mm, range 0 to +6 mm, p<0.0001). CONCLUSION: BAV-DE provides successful gradient relief of severe AS with lower fluoroscopy time and a lower degree of AR compared to BAV-A. Overestimation of aortic annulus diameters by angiographic measurements might partially explain the high rate of significant AR associated with BAV in the absence of echocardiographic guidance. PMID- 17689750 TI - Homocysteine-lowering vitamins and cardiovascular mortality: are they really effective? AB - In the light of current data obtained from prospective outcome studies, we believe that it is premature to support the use of homocysteine-lowering vitamins including folic acid in patients with established coronary artery disease in order to improve cardiovascular outcomes. We think that future large-scale epidemiological trials with very long-term follow-up periods will probably solve this dilemma. PMID- 17689751 TI - Acute ST elevation myocardial infarction with angiographically normal coronary arteries: causes and outcomes. AB - A minority of patients presenting with ST elevation myocardial infarction (STEMI) have angiographically normal coronary arteries. We aimed to assess its incidence, identify possible aetiologies and determine long-term prognosis. We retrospectively analysed 714 consecutive patients presenting with STEMI over a 10 year period (1995 to 2005), and identified 41 patients with angiographically normal coronary arteries. Mean age was 44+/-15 years; the majority were male. Specific diagnoses were made in 13/41 (32%) patients, including peri-myocarditis (11/41) and Takotsubo cardiomyopathy (2/41). No specific diagnosis was made in the remainder and these were considered cryptogenic AMI's. At a mean follow-up of 44+/-30 months, 1 patient with cryptogenic AMI had a non-cardiovascular death and 1 patient required pacing. In conclusion, there is a small but definite incidence of angiographically normal coronary arteries in patients presenting with STEMI. While the eventual aetiology remains uncertain in most patients, long-term outcomes appear favourable. PMID- 17689752 TI - Bone mineral density, bone remodeling and osteoprotegerin in patients with acute coronary syndrome. AB - The objective of this study was to evaluate the relationship between coronary disease and osteoporosis and determine the effect of osteoprotegerin (OPG) on bone remodeling and bone mineral density (BMD) in a group of patients with acute coronary syndrome. Eighty-three patients (52 males and 31 women) with acute coronary syndrome (75 patients with acute myocardial infarction and 8 with unstable angina) with an average age of 61+/-10 years were studied. Levels of osteocalcin, urinarydeoxypyridinoline, OPG and the receptor activator of nuclear factor-kappaB ligand (RANKL) were determined during the hospital stay. Femoral neck, trochanter and lumbar spine densitometry was carried out using a DXA densitometer. Thirty percent of patients presented osteoporosis (39% of females and 26% of males). Osteoporotic patients were older and had a lower weight and height and elevated serum levels of osteocalcin (3.6+/-2.25 2.63 versus +/-1.55, p=0.05). Levels of OPG and RANKL were similar in both groups and showed no relationship with BMD. In conclusion, no relationship was observed between the OPG/RANKL system and BMD in these patients. PMID- 17689753 TI - Echocardiographic and right heart catheterization techniques in patients with pulmonary arterial hypertension. AB - BACKGROUND: The cardiovascular assessment of patients with suspected pulmonary arterial hypertension (PAH) involves Doppler echocardiography and often subsequent confirmation by right heart catheterization (RHC). However, there appears to be limited consensus on the appropriate technique(s) for assessing PAH, and thus no clear, comprehensive guidelines exist for assessment of PAH. The aim of this paper is to review the Doppler echocardiographic and RHC techniques for the diagnosis and/or assessment of PAH. METHOD: We searched Medline (1966 to August 2006) and EMBASE (1980 to August 2006) bibliographic databases to allow identification of all potentially relevant studies and review articles. In addition, the reference lists of included articles were scanned to identify relevant references and unpublished reports missed by the search strategy. RESULTS: Our findings show that recommendations for the echocardiographic assessment of PAH at rest or with exercise are heterogeneous. Clinical practice guidelines provide limited details. Although more specific information regarding echocardiographic techniques can be obtained from individual research articles, the techniques employed and the methods used to calculate specific hemodynamic variables do not appear to be consistent throughout the literature. RHC techniques for the confirmation of PAH are more consistent, albeit less frequently reported. The literature search identified several articles where indications and considerations for the catheterization of patients with PAH are discussed, together with safety considerations and principles for the accurate assessment of hemodynamic variables. CONCLUSION: Although clinical practice guidelines and numerous research studies provide details of echocardiographic measures in patients with PAH, greater consensus and standardisation of measurement techniques is required. A minimum dataset for the evaluation of PAH by these techniques is suggested. PMID- 17689754 TI - Abnormal aortic elastic properties in adults with congenital valvular aortic stenosis. AB - BACKGROUND: Abnormalities of the aortic root are common in patients with a bicuspid aortic valve. Our aim was to investigate the elastic properties of the aortic root in patients with congenital aortic valvular stenosis (AS) in comparison with age- and gender-matched controls, and to investigate the influence of stenosis severity and aortic size on aortic root elasticity. METHODS: Thirty-two adults (mean age 30.4+/-7.5 years, 22 men) with congenital AS without previous cardiovascular surgery were prospectively studied. Aortic root elasticity indices such as aortic stiffness index (ASI), aortic root distensibility (ARD), and aortic strain were calculated with the use of M-mode echocardiography. RESULTS: ASI was significantly higher in patients compared to controls, 8.5+/-8.4 versus 4.0+/-1.4, respectively (P<0.01). Other indices of aortic root elasticity were similar between patients and controls: ARD was 4.2+/ 3.6 versus 4.3+/-1.9 x 10(-6) cm(2)/dynes, respectively, and aortic strain was 12.4+/-9.6 versus 13.5+/-5.0%, respectively (P=NS for all). Correlations were found between aortic size and indices of aortic elasticity (i.e., aortic strain and ARD), denoting that an increased aortic dimension is associated with a stiffer aorta. Interestingly, no correlations were found between indices of severity of AS and aortic elasticity, suggesting that an abnormal aortic elasticity is independent of stenosis severity. CONCLUSIONS: Congenital AS results in abnormal aortic elastic properties, independent of stenosis severity. Furthermore, there seems to be a relationship between aortic dimensions and aortic stiffness. PMID- 17689755 TI - Relaxation effects of lavender aromatherapy improve coronary flow velocity reserve in healthy men evaluated by transthoracic Doppler echocardiography. AB - PURPOSE: It has been reported that mental stress is an independent risk factor for cardiovascular events and impairs coronary circulation. Lavender aromatherapy, one of the most popular complementary treatments, is recognized as a beneficial mental relaxation therapy. However, no study has examined the effect of this therapy on coronary circulation. We aimed to assess the effect of lavender aromatherapy on coronary circulation by measuring coronary flow velocity reserve (CFVR) with noninvasive transthoracic Doppler echocardiography (TTDE). MATERIAL AND METHODS: We enrolled 30 young healthy men (mean age 34+/-4.7 years, range 24-40 years). Coronary flow velocities in the left anterior descending coronary artery were recorded by TTDE at rest and during hyperemia induced with an intravenous infusion of adenosine triphosphate (ATP). CFVR was calculated as the ratio of hyperemic to basal mean diastolic flow velocity. CFVR was assessed at baseline and immediately after lavender aromatherapy (four drops of essential oil diluted with 20 ml of hot water and inhaled for 30 min). Simultaneously, serum cortisol was measured as a marker of stress hormones. To exclude the relaxation effects of rest, the same measurements were repeated in the same volunteers without aromatherapy as a control study. RESULTS: CFVR measurements were obtained in all volunteers (100%). Blood pressure and heart rate responses to ATP infusion were not affected by lavender aromatherapy. Serum cortisol significantly decreased after lavender aromatherapy (8.4+/-3.6 to 6.3+/-3.3, p<0.05), but remained unchanged in controls (9.1+/-3.5 to 8.1+/-3.9, p=ns). In addition, CFVR significantly increased after lavender aromatherapy (3.8+/-0.87 to 4.7+/-0.90, p<0.001), but not in controls (3.9+/-0.8 to 3.9+/-0.8, p=ns). CONCLUSIONS: Lavender aromatherapy reduced serum cortisol and improved CFVR in healthy men. These findings suggest that lavender aromatherapy has relaxation effects and may have beneficial acute effects on coronary circulation. PMID- 17689756 TI - Are fractures due to anticoagulants or the disease necessitating the treatment? PMID- 17689757 TI - A surviving case of mitochondrial cardiomyopathy diagnosed from the symptoms of multiple organ dysfunction syndrome. AB - A 49-year-old female cardiomyopathic patient with heart, hepatic, and renal failure and lactic acidosis was transferred to the intensive care unit without a unifying diagnosis. She was of short stature (145 cm tall), had difficulty in hearing, a past history of complete atrioventricular block, and had received a permanent pacemaker. She had been diagnosed and treated as dilated cardiomyopathy by her primary doctor. Treatment in the intensive care unit for 21 days including plasma exchange, continuous hemodiafiltration, artificial ventilation, and administration of catecholamine, carperitide, and a large amount of coenzyme Q10 (210 mg/day) improved the symptoms. Genetic analysis using mitochondrial DNA from leukocytes and sternocleidomastoid muscle revealed a 3243A>G mutation in the mitochondrial tRNA(Leu (UUR)) gene, which is related to mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). The patient recovered through intensive care and could be discharged from hospital without any sequelae. This case was mitochondrial cardiomyopathy diagnosed from the symptoms of multiple organ dysfunction syndrome. Cardiomyopathy due to the mutation of mitochondrial DNA is not a common disease. However, it should be considered as a possible cause of heart failure. PMID- 17689758 TI - Is it possible to predict which patients need distal protection during primary angioplasty? AB - BACKGROUND: Although the benefit of distal protection (DP) during primary percutaneous coronary intervention (PCI) remains questionable, there appears to be efficacy in some clinical situations. We sought to identify in patients with ST-segment elevation acute myocardial infarction (STEMI) which clinical and angiographic characteristics might indicate the patient who will benefit from the use of a DP device. METHODS: A series of 103 consecutive patients with STEMI undergoing primary PCI using DP were compared with 98 consecutive patients treated by primary PCI alone. RESULTS: The overall rates of thromboembolic complications and achievement of optimal reperfusion (myocardial blush grade >/=2 and ST-segment resolution >/=70%), and infarct size, were similar between the 2 groups. However, DP use was associated with higher rates of optimal reperfusion in patients with right coronary artery (RCA) lesions (OR 2.45; 95% CI, 1.07 to 5.59; P=0.034), thrombus score >/=4 (OR 2.64; 95% CI, 1.07 to 6.50; P=0.034) or infarct-related artery (IRA) of >/=3.5 mm in diameter (OR 4.09; 95% CI, 1.02 to 16.40; P=0.047). In this population (RCA location, thrombus score >/=4, or IRA >/=3.5 mm), DP use reduced the risk of thromboembolic complications (64%, P=0.012, 45%, P=0.035 and 54%, P=0.050, respectively), resulting in a smaller infarct size (8.0+/-5.1 vs. 11.7+/-7.5, P=0.028, 13.1+/-8.8 vs. 17.4+/-10.0, P=0.026 and 15.5+/-10.8 vs. 22.1+/-10.1, P=0.042, respectively). CONCLUSIONS: The use of a DP during primary PCI may lead to a reduction of thromboembolic complications, subsequent higher rates of optimal reperfusion and reduced infarct size in patients with RCA culprit lesions, a large thrombus, or large IRA. PMID- 17689759 TI - Impact of metabolic syndrome on left ventricular mass: is the same in all ethnic groups and in men and women? PMID- 17689760 TI - Accumulation of risk factors enhances the prothrombotic state in atrial fibrillation. AB - BACKGROUND: The present study was conducted to investigate the relation between the accumulation of the risk factors of thromboembolism and the levels of hemostatic markers in patients with nonvalvular atrial fibrillation (NVAF). METHODS: Five hundred ninety-one NVAF patients and 129 control subjects were categorized into low, moderate or high risk of thromboembolism, according to CHADS(2) index. One point each was given to patients with advanced age (> or =75 years), hypertension, congestive heart failure, and diabetes mellitus, and 2 points, to those with prior ischemic stroke or transient ischemic attack. Patients with CHADS(2) score of 0, 1 or 2, and > or =3 were classified as low, moderate and high risk, respectively. Levels of hemostatic markers (platelet factor 4, beta-thromboglobulin, prothrombin fragment F1+2 and D-dimer) were determined. RESULTS: Of 591 patients with NVAF, 302 were treated with warfarin (mean international normalized ratio 1.88). D-dimer levels increased as the risk level increased irrespective of warfarin use. Particularly, NVAF patients without receiving warfarin (n=289) had significantly higher D-dimer levels than control patients (e.g., for high risk patients, 175+/-144 vs 75+/-87 ng/ml, p<0.001), while NVAF patients receiving warfarin had intermediate levels (136+/-156 ng/ml). F1+2 levels increased as the risk level increased, and were significantly suppressed by warfarin. Levels of markers of platelet activation (platelet factor 4 and beta-thromboglobulin) were increased in NVAF patients but not affected by the risk level. CONCLUSION: Coagulation and fibrinolytic activity is increased along with the accumulation of the risk factors of thromboembolism in NVAF patients. PMID- 17689761 TI - Surgically palliated double-inlet left ventricle with transposition of the great arteries mistaken for aortic aneurysm with dissection. AB - We report a 23-year-old male with history of double-inlet single ventricle with transposition of the great arteries who is s/p pulmonary artery banding, a Damus Kaye-Stanzel anastomosis, and Fontan procedure during infancy and childhood who now presents with chest pain. A chest CTA at an outside hospital was thought concerning for the presence of a thoracic aortic aneurysm with dissection, prompting immediate transfer to our institution. However, repeat chest CTA at our institution revealed the predicted anastomoses based on his surgical procedures, which was misinterpreted as aortic aneurysm and dissection. An understanding of the physiology of his surgically repaired congenital heart disease is critical in interpreting his subsequent chest CTA and arriving at the appropriate clinical conclusion. PMID- 17689762 TI - Elevated CA-125 level in acute heart failure due to Toxoplasma gondii perimyocarditis. PMID- 17689763 TI - Gender and age related predictive value of walk test in heart failure: do anthropometrics matter in clinical practice? AB - BACKGROUND: The six-minute walk test (6 WT) is a valid and reliable predictor of morbidity and mortality in chronic heart failure (CHF) patients, frequently used as an endpoint or target in clinical trials. As opposed to spiroergometry, improvement of its prognostic accuracy by correction for height, weight, age and gender has not yet been attempted comprehensively despite known influences of these parameters. METHODS: We recorded the 6 WT of 1035 CHF patients, attending clinic from 1995 to 2005. The 1-year prognostic value of 6 WT was calculated, alone and after correction for height, weight, BMI and/or age. Analysis was performed on the entire cohort, on males and females separately and stratified according to BMI (<25, 25-30 and >30 kg/m(2)). RESULTS: 6 WT weakly correlated with age (r=-0.32; p<0.0001), height (r=0.2; p<0.0001), weight (r=0.11; p<0.001), not with BMI (r=0.01; p=ns). The 6 WT was a strong predictor of 1-year mortality in both genders, both as a single and age corrected parameter. Parameters derived from correction of 6 WT for height, weight or BMI did not improve the prognostic value in univariate analysis for either gender. Comparison of the receiver operated characteristics showed no significant gain in prognostic accuracy from any derived variable, either for males or females. CONCLUSION: The six-minute walk test is a valid tool for risk prediction in both male and female CHF patients. In both genders, correcting 6 WT distance for height, weight or BMI alone, or adjusting for age, does not increase the prognostic power of this tool. PMID- 17689764 TI - Hierarchical and spatial analyses of pneumonia-lesion prevalence at slaughter in New Zealand lambs. AB - We recorded lesions of moderate-to-severe pneumonia (>or=10% lung surface area affected; "pneumonia") in 1,899,556 lambs submitted to three New Zealand abbatoirs between December 2000 and September 2001. The average prevalence of pneumonia ranged between 7 and 13%, by abbatoir. We ran a two-level mixed-effects binomial logistic-regression model with the prevalence of pneumonia as the outcome, and adjusting for abbatoir and month. The intracluster correlations for batch (slaughter lambs from the same farm sent at the same time) and farm were 31.3 and 12.4%, respectively. (We also noted threefold differences in odds across abbatoirs, and >30-fold differences among slaughter months.) Case flocks (those in the upper quintile of pneumonia prevalence) generally were not clustered in the spatial incidence-risk analysis (after adjusting for flock-level and batch level effects, and as compared to flocks in the lower two quintiles). We therefore concluded that the risk of moderate-to-severe pneumonia-lesion prevalence detectable at slaughter of lambs was determined at the flock and batch level, rather than at the spatial level. PMID- 17689765 TI - Comparison of different electrophoretic parameters of Pulse-Field Gel Electrophoresis for Vibrio cholerae subtyping. AB - Molecular subtyping is used to distinguish pathogenic bacterial strains during epidemiological surveys of infectious diseases and the discovery of novel pathogens. There is a need to standardize protocols involving Pulse-Field Gel Electrophoresis (PFGE), a crucial method in molecular subtyping, to make inter laboratory results comparable and information exchange possible. The PFGE pattern varies with electrophoretic parameters (EPs), so it is important to select the parameter that can distinguish the patterns better. To optimize EPs of PFGE for Vibrio cholerae, we analyzed 24 isolates of V. cholerae O1 biotype El Tor and 26 isolates of O139 by PFGE with Not|. We used four different EPs and compared the similarity coefficients from the four groups by Friedman test. Based on the principle that the electrophoretic parameter producing smaller similarity in the PFGE patterns has higher level of discriminatory power, the one producing the smallest similarity coefficients is considered to be optimal. This method could be applied to determine the optimal molecular subtyping protocol for other bacteria. PMID- 17689766 TI - Polymerase chain reaction detection of Pneumocystis jiroveci: evaluation of 9 assays. AB - Various polymerase chain reaction (PCR) amplification strategies have been described for detecting Pneumocystis jiroveci in clinical specimens. Different combinations of primer/target and platforms have been reported to yield varying PCR detection rates. PCR was evaluated on clinical specimens using internal transcribed spacer regions of the rRNA nested, dihydropteroate synthase single and nested, dihydrofolate reductase nested, major surface glycoprotein heminested, mitochondrial large subunit rRNA (mtLSUrRNA) single and nested, 18S rRNA 1-tube nested, and real-time 5S rRNA PCR. The most sensitive PCR was subsequently compared with routine diagnostic immunofluorescence (IF) microscopy. Discrepant PCR and IF results were resolved after review of clinical and histology/cytology records. Major discrepancies were observed among the methods investigated. mtLSUrRNA nested PCR was the most sensitive, produced less false negative results, and displayed the highest degree of concordance with histology. Direct comparison of mtLSUrRNA nested PCR versus IF yielded low sensitivity and specificity, which were improved for PCR and lowered for IF on review of clinical and laboratory records. PMID- 17689767 TI - Effects of simultaneous EEG recording on MRI data quality at 1.5, 3 and 7 tesla. AB - Although the focus of attention on data degradation during simultaneous MRI/EEG recording has to date largely been upon EEG artefacts, the presence of the conducting wires and electrodes of the EEG recording system also causes some degradation of MRI data quality. This may result from magnetic susceptibility effects which lead to signal drop-out and image distortion, as well as the perturbation of the radiofrequency fields, which can cause local signal changes and a global reduction in the signal to noise ratio (SNR) of magnetic resonance images. Here, we quantify the effect of commercially available 32 and 64 electrode caps on the quality of MR images obtained in scanners operating at magnetic fields of 1.5, 3 and 7 T, via the use of MR-based, field-mapping techniques and analysis of the SNR in echo planar image time series. The electrodes are shown to be the dominant source of magnetic field inhomogeneity, although the localised nature of the field perturbation that they produce means that the effect on the signal intensity from the brain is not significant. In the particular EEG caps investigated here, RF inhomogeneity linked to the longer ECG and EOG leads causes some reduction in the signal intensity in images obtained at 3 and 7 T. Measurements of the standard deviation of white matter signal in EPI time series indicates that the introduction of the EEG cap produces a small reduction in the image signal to noise ratio, which increases with the number of electrodes used. PMID- 17689768 TI - Inactivation of Escherichia coli inoculated into cloudy apple juice exposed to dense phase carbon dioxide. AB - The inactivation of Escherichia coli in cloudy apple juice by dense phase carbon dioxide (DPCD) was investigated. With CO2 at 20 MPa and 37 degrees C or at 30 MPa and 42 degrees C, the inactivation of E. coli significantly increased (p<0.05) when increasing the exposure time, which conformed to a fast-to-slow two-stage kinetics. The two stages were well fitted to first-order reactions. Higher temperature or pressure significantly enhanced the bactericidal effect of DPCD (p<0.05), the maximum reduction was 7.66 log CFU at 45 MPa and 52 degrees C for 30 min. The survival curves against temperature or pressure were fitted using a linear equation with high regression coefficients (R2>0.94). The temperature inactivation rate (kT) and pressure inactivation rate (kP) were obtained. Higher kT or kP indicated higher susceptibility of E. coli to temperature or pressure. Moreover, there was good linear correlation of kT with pressure (R2=1.00). Also, kP increased with increasing temperature except for 37 degrees C. Greater inactivation of E. coli was obtained with 99.9% CO2 than with 99.5% CO2 or with the initial number of 10(5) CFU/mL than with that of 10(8) CFU/mL at 20 MPa and 37 degrees C. PMID- 17689769 TI - Thromboembolism in patients undergoing total knee arthroplasty with epidural analgesia. AB - We retrospectively reviewed the charts of 381 consecutive patients who underwent primary unilateral or bilateral total knee arthroplasty with regional anesthesia between 1995 and 2002. All operations in this study were performed at the Cleveland Clinic Foundation by the senior author. Calf-high intermittent pneumatic compression stockings were used in all patients, and routine ultrasound examinations were performed at an average of 3 days after surgery. We compared the early postoperative rates of venous thromboembolism between patients with indwelling epidural catheters and no chemoprophylaxis and those with spinal anesthesia combined with low-molecular-weight heparin. We found no significant difference between the 2 groups. PMID- 17689771 TI - Presence of medical comorbidities in patients with infected primary hip or knee arthroplasties. AB - Many older patients undergoing primary hip or knee joint arthroplasty surgery have multiple medical problems. In this retrospective case-control study, the authors examined the individual and cumulative effects of various types of medical comorbidities on the risk of developing prosthetic joint infection after surgery. Case and control patients were matched by age, sex, and procedure. Analysis was undertaken using crude odds ratios (ORs) and multiple logistic regression analysis. Fifty-one patients with 52 joint infections were identified. Both diabetes mellitus (OR, 3.91; P = .04) and total number of medical conditions (OR, 1.35; P = .005) were associated with higher risk of infection. This information allows the orthopedic surgeon to inform patients more fully regarding the risks of surgery, and promotes the reduction and optimization of medical comorbidities before surgery. PMID- 17689770 TI - Low-dose warfarin coupled with lower leg compression is effective prophylaxis against thromboembolic disease after hip arthroplasty. AB - Consecutive patients having elective total hip arthroplasty were prescribed 1 mg of warfarin for 7 days preceding surgery, variable doses while in hospital (target international normalized ratio, 1.5-2.0), and discharged to rehabilitation center or home taking 1 mg daily until 4-week to 6-week follow-up visit. Lower leg pneumatic compression was used postoperatively and elastic compression stockings after discharge. Hospital and clinic charts plus auxiliary sources were reviewed for evidence of thromboembolic diseases (TED). Of 1003 consecutive patients studied, 3 (0.3%, 95% CI 0.0-0.6%) had symptomatic TED, including 2 with deep venous thrombosis and 1 with nonfatal pulmonary embolus. Follow-up rate was 99.1%. Complications from warfarin were minimal. Very-low-dose warfarin coupled with lower leg compression is effective prophylaxis against TED after elective hip arthroplasty when prescribed as described. PMID- 17689772 TI - Intramedullary step-cut osteotomy for revision total hip arthroplasty with allograft-host bone size mismatch. AB - Eleven revision total hip arthroplasties were treated with proximal segmental femoral allograft reconstruction in which the diameter of the distal host bone was larger than the largest long-stem femoral component which could fit into the segmental allograft. A long, lateral step-cut osteotomy of the allograft was used with placement of the lateral cortical allograft inside the distal host bone. All allograft-host bone junctions healed. The average time to union was 6.7 months. The long step-cut osteotomy provides stability of the allograft-host bone junction when the diameter of the host bone is larger than the allograft. The osteotomy also provides a large surface area of contact between the allograft and host bone. PMID- 17689773 TI - The use of total femoral arthroplasty as a limb salvage procedure: the Sheffield experience. AB - Over the last 25 years, 14 patients have undergone total femoral arthroplasty (TFA) after complications of revision arthroplasty surgery. These patients had previously undergone extensive surgery, which had failed, and required salvage surgery. The alternatives would have been amputation or hip disarticulation. A retrospective review of medical records and radiographs was undertaken, and clinical outcome was evaluated using the Musculoskeletal Tumour Society criteria. Before TFA, all patients had previously undergone multiple operations (range, 2 10). In 88% of cases, reconstructive options were not only limited by the availability of minimal host bone but also by deep sepsis. Results were encouraging, with most of the patients having greater mobility and less pain after surgery. A third of the patients achieved a 75% improvement in function. We believe that TFA has a definite role in the management of complex problems after extensive hip and knee revision arthroplasty surgery. PMID- 17689774 TI - Tibial component fixation in total knee arthroplasty: a comparison of pegged and stemmed designs. AB - This study compares midterm radiographic, functional, and quality-of-life outcomes in patients receiving a cemented tibial component that has either a short intramedullary stem or one that has a pegged tibial component. A cohort of 181 patients received 225 NexGen cruciate-retaining implants (84 stemmed, 141 pegged) during total knee arthroplasty, with annual follow-up examinations for up to 7 years. Both types of tibial components were associated with excellent radiographic and clinical results with no radiographic evidence of implant loosening or osteolysis. Clinical outcomes included improvement in joint function and patient function, as well as quality of life. Survival analysis showed 98% survival at 7 years with both implants. Pegged tibial components offered comparable midterm radiographic, functional, and quality-of-life results to stemmed components. PMID- 17689775 TI - Free vascularized fibular grafting following failed core decompression for femoral head osteonecrosis. AB - The results of treatment of femoral head osteonecrosis with free vascularized fibular grafting (FVFG) following failed core decompression (core decompression FVFG [CD-FVFG] group: 32 hips) were reviewed and compared with those of a control group that underwent FVFG only (54 hips). Outcome was considered unsuccessful if total hip arthroplasty was subsequently performed. Total hip arthroplasty was performed in 15 and 20 hips of the CD-FVFG and control groups, respectively. When considering age, sex, and presence of bilateral disease, patients with previous core decompression did not have a significantly different failure rate from patients with FVFG only. However, patients with preoperative stage V osteonecrosis or corticosteroid use had worse outcomes after vascularized fibular grafting if they had a previous core decompression of the femoral head. PMID- 17689776 TI - Periprosthetic changes in bone mineral density in 5 stem designs 5 years after cemented total hip arthroplasty. No relation to stem migration. AB - Changes in bone mineral density (BMD) at the proximal femur were evaluated in 83 cemented total hip arthroplasties (THAs) 5 years after surgery. The BMD changes were compared among 5 stem designs and were related to the stem migration. A greater BMD decrease was found in Scientific Hip Prosthesis (Biomet, Bridgend, UK) and SPII CoCr stems (Link, Hamburg, Germany) than in Exeter (Howmedica, London, UK), Spectron (Smith & Nephew, Memphis, Tenn), and SPII Titanium stems (P < .05), and the stiffer SPII CoCr stems (Link) had a larger bone loss than the SPII Titanium stems (Link). However, no overall relationship was found between the BMD changes and stem migration or stem stiffness. PMID- 17689777 TI - Cementless hip arthroplasty in Paget's disease at medium-term follow-up (average of 6.7 years). AB - We performed 33 cementless total hip arthroplasties for arthritis in 27 patients with an established diagnosis of Paget's disease on the acetabular or femoral side of the hip. There were 3 revisions. One stem for aseptic loosening at 55 months, and 2 stems after periprosthetic fractures at 9 and 70 months. Twenty three cases were available for follow-up at an average of 6.7 years (range, 2-14 years). Harris hip score improved from 56/100 preoperatively (16-98/100) to 90/100 postoperatively (78-100/100). All surviving components were radiographically bone ingrown. Based on our findings, it appears that a cementless total hip arthroplasty can have a good outcome in Paget's disease. PMID- 17689778 TI - The Biomet Bi-Metric total hip arthroplasty and universal acetabular cup: high polyethylene failure rate in the medium term. AB - We report on the medium-term results of the Bi-Metric (Biomet UK Ltd, Bridgend, UK) uncemented total hip arthroplasty system used with the Universal acetabular cup and polyethylene liner secured with the Ringloc (Biomet UK Ltd) mechanism. Fifty-eight total hip arthroplasties in 49 patients (mean age at implantation, 57.1 years) were identified, with 45 hips followed up at a mean of 7.6 years (range, 5-13 years). Of those hips not requiring revision, the mean Harris hip score was 89, 87% of the hips were judged to be very good or good according to d'Aubigne and Postel (J Bone and Joint Surgery 1954;36A:451), and the radiographic criteria by Engh et al (Clin Orthop Relat Res 1990;257:107) demonstrated the femoral components to be well fixed. Six patients required a revision procedure at a mean of 6.2 years postsurgery, with all failures attributed to marked wear of the polyethylene liner. PMID- 17689779 TI - The role of blood cultures in the acute evaluation of postoperative fever in arthroplasty patients. AB - The use of blood cultures to work up fever in postarthroplasty patients was studied retrospectively. Four hundred fifty-three patients done consecutively with a diagnosis-related group 209 discharge diagnosis were studied. One hundred patients (22%) had blood cultures drawn for fever greater than 101 degrees F. Specifically, there were 240 total knee arthroplasty patients with 40 blood cultures drawn. There were 124 total hip arthroplasty patients with 31 blood cultures drawn. One patient with a total knee arthroplasty had positive cultures as did one patient with a total hip arthroplasty. Both were thought to be contaminants, and neither had any sequelae. Blood cultures are expensive and do not add relevant information in the care of postarthroplasty patients. PMID- 17689780 TI - Midterm results of "thrust plate" prosthesis. AB - The aim of this investigation was to analyze the midterm results obtained with the metaphyseal fixation principle of the thrust plate prosthesis (TPP). Survival of 214 implants in 204 patients was analyzed. Clinical (Harris hip score) and radiologic examinations were carried out on 157 of 190 TPP with a postimplantation follow-up period of at least 5 years. Failure rate was 7.0% (9 aseptic and 6 septic loosening). Harris hip score increased from 36.9 +/- 13.5 points preoperatively to 91.2 +/- 13.1 points at follow-up. Eleven TPPs showed radiolucent lines not indicating prosthetic loosening. Thrust plate prosthesis is not an alternative to stemmed endoprostheses. It may be rarely indicated in very young patients where, because of their age, several revision operations can be expected. PMID- 17689781 TI - Fatigue failure of the GAP ring. AB - This study reports the results and early failures using the Graft Augmentation Prosthesis ring in the reconstruction of acetabular defects encountered during total hip arthroplasty. Seventeen consecutive Graft Augmentation Prosthesis rings were used during 7 complex primary and 10 revision hip arthroplasties. Five patients died during the follow-up period. Of the remaining 12 patients, 7 had been revised at an average of 5 years follow-up. Five cases were revised because of fatigue failure of the implant associated with allograft resorption. Two cases were revised for recurrent dislocations. Because of this high mechanical failure rate (5 of 12 cases at only 5 years follow-up), we have abandoned this device in favor of implants with more mechanical strength. PMID- 17689782 TI - Difference between 2 measurement methods of version angles of the acetabular component. AB - We evaluated the relationship and the difference between measurements of version angles (VAs) of the acetabular components in total hip arthroplasty taken using 2 different methods. One VA was measured on an anteroposterior radiograph of the hip joint (VAP) and the other on a cross-table lateral radiograph (VCL) in 97 hips after surgery (clinical data) and 6 sawbone pelvic models (model data). There was a positive correlation between VAP and VCL for both data. Mean and standard deviation of the differences (VCL - VAP) between the 2 measurements were 5 degrees +/- 4.2 degrees in clinical data and -0.01 degrees +/- 0.32 degrees in model data. These differences on clinical data should be taken into consideration when comparing VAs in the literature using different measuring methods. PMID- 17689783 TI - In vivo oxidation of gamma-barrier-sterilized ultra-high-molecular-weight polyethylene bearings. AB - gamma-Barrier packaging is shown to be effective in preventing oxidation of polyethylene during shelf storage and in addressing the problem of early fatigue failure seen in gamma-air-sterilized bearings with long shelf-storage before implantation. The series of gamma-barrier retrievals studied suggests that oxidation occurs in the body via the same mechanism as seen in gamma-air sterilized bearings. A critical oxidation level is identified above which polyethylene bearings are susceptible to fatigue damage after sufficient cycles of use. Although critical oxidation was not reached in the majority of the retrieved gamma-barrier bearings studied, in vivo oxidation appears to follow an exponential increase with time. The result of in vivo oxidation is expected to be loss of mechanical properties, and susceptibility of polyethylene bearings to eventual fatigue failure. PMID- 17689784 TI - Cementation of a polyethylene liner into a metal shell. AB - As the number of revision hip arthroplasties continues to increase, alternative reconstructive options may be necessary. Cementation of a polyethylene liner into a well-fixed metal acetabular shell has previously been reported to save bone stock and enhance the pullout strength. This study analyzed whether cementation of various types of mechanically modified or nonmodified liners into a metal shell altered wear characteristics when compared with noncemented modular liners. The authors used nonirradiated and highly cross-linked polyethylene liners that were mechanically modified or left unmodified. Wear in both nonirradiated and highly cross-linked liners was not affected by the cementing process. Wear of the highly cross-linked polyethylene liners was significantly less when compared with the nonirradiated liners. This laboratory study provides quantitative data supporting previous qualitative studies of cementing a polyethylene liner into a metal-backed acetabular shell. Based on this study, cementation of a mechanically modified liner did not affect wear in this study, which simulated 3 years of activity. PMID- 17689785 TI - In vitro pressurization of the acetabular cement mantle: the effect of a flange. AB - A model was developed to assess the effect of an acetabular flange on pressure within different zones of the cement mantle during insertion. Two prosthetic designs were assessed in 3 different sizes. Flanged components produced significantly higher mean pressures than unflanged ones (P < .01). The effect of a flange was more pronounced at the rim than at the pole. Delayed insertion resulted in a further significant rise in mean pressure (P < .01), but this did not compensate for the lack of a flange. This experimental model supports the use of a flange to increase pressure within the cement mantle on component insertion. The beneficial effect is more marked in the area that is most likely to show deficiency in the cement-bone interface on postoperative radiographs. PMID- 17689786 TI - Factors affecting the impingement angle of fixed- and mobile-bearing total knee replacements: a laboratory study. AB - Maximum flexion-or impingement angle-is defined as the angle of flexion when the posterior femoral cortex impacts the posterior edge of the tibial insert. We examined the effects of femoral component placement on the femur, the slope angle of the tibial component, the location of the femoral-tibial contact point, and the amount of internal or external rotation. Posterior and proximal femoral placement, a more posterior femoral-tibial contact point, and a more tibial slope all increased maximum flexion, whereas rotation reduced it. A mobile-bearing knee gave results similar to those of the fixed-bearing knee, but there was no loss of flexion in internal or external rotation if the mobile bearing moved with the femur. In the absence of negative factors, a flexion angle of 150 degrees can be reached before impingement. PMID- 17689787 TI - Unilateral tibial polyethylene liner failure in bilateral total knee arthroplasty -bilateral retrieval analysis at 8 years. AB - This is a report of a unique case of bilateral simultaneous total knee arthroplasties in which one tibial liner failed dramatically, whereas the other liner showed minimal evidence of wear. This unique case allows isolation of component factors as the primary contributing etiology to failure. The differentiating characteristic was the method of sterilization and the shelf life of the polyethylene liner. The insert that showed minimal wear was sterilized with gamma radiation in a barrier package and had a shelf life of less than 1 year, whereas the insert that failed dramatically was sterilized in air and had a shelf life of more than 5 years. This case provides a dramatic example of the potential detrimental effects of manufacturing details on the performance of orthopedic implants, particularly polyethylene inserts. PMID- 17689788 TI - Infected total hip arthroplasty after intravesical bacillus Calmette-Guerin therapy. AB - An infected total hip arthroplasty remains one of the most challenging problems faced by orthopedic surgeons. We present the case of a 76-year-old man with an unusual infected total hip arthroplasty. Four years before presenting to our service, the patient was treated for vesical transitional cell carcinoma with intravesical administration of bacille Calmette-Guerin. The patient presented with groin pain, radiographic loosening of the hip implant, and elevated erythrocyte sedimentation rate and C-reactive protein. He underwent irrigation and debridement of the hip with removal of components. Cultures isolated bacille Calmette-Guerin necessitating treatment with antituberculosis chemotherapy. Bone cultures obtained under computed tomography guidance were negative, and reimplantation surgery was performed with a successful outcome. Pathway of infection spread, diagnosis, and treatment of this rare infection are discussed with review of the literature. PMID- 17689789 TI - Insufficiency fracture in the medial wall of the acetabulum after total hip arthroplasty. AB - Insufficiency fracture following total hip arthroplasty (THA) frequently occurs in the superior and inferior pubic ramus, the puboischial rami, or the ischium around the obturator foramen, while it rarely occurs in the medial wall of the acetabulum. Here, we report three cases showing insufficiency fracture in the medial wall of the acetabulum following THA. In our three cases, two fractures resulted from the development of bone fragility due to osteolysis at the prosthesis site, and the convergence of mechanical stress on the acetabular load bearing point due to loosening of the cup. We consider it appropriate to describe these fractures as another entity of stress fracture, namely, osteolytic fracture, rather than either pathologic fracture or insufficiency fracture. PMID- 17689790 TI - Insufficiency fracture of the acetabular medial wall. AB - Acetabular insufficiency fractures are much less common than acetabular fractures associated with trauma. They most commonly occur in postmenopausal women with a history of rheumatoid arthritis or pelvic irradiation. We present the case of a 93-year-old man with an atraumatic pelvic insufficiency fracture of the fossa acetabuli. The patient had 2 predisposing risk factors: osteoporosis and lower extremity reconstructive surgery. PMID- 17689791 TI - Charcot's arthropathy of the hip joints: a late manifestation of tabes dorsalis successfully treated by total joint arthroplasty. report of 2 cases. AB - This article describes 2 cases of Charcot's arthropathy of the hip joints successfully treated with cemented total hip arthroplasty. Follow-up at 10 and 9.5 years confirmed the success of the treatment. This article also includes a review of current publications on the topic. PMID- 17689792 TI - Damage of oxinium femoral heads subsequent to hip arthroplasty dislocation three retrieval case studies. AB - Oxinium exhibits 4900 times less volumetric wear and 640 times less deep scratches in laboratory wear testing compared with traditional cobalt-chromium alloys. Despite the superior wear resistance because of the thin ceramic surface, the zirconium alloy substrate is relatively soft (Hv = 285) when compared with cobalt-chrome alloy femoral heads (ISO 5832-12; Hv = ~420,) and may deform in contact with acetabular shell materials (ISO5832-3; Hv = 350) in the case of dislocation. Three retrieval cases highlight the damage that may occur during dislocation and/or when performing closed reduction maneuvers. It is recommended that closed reduction be attempted with caution because significant head damage can occur. This may lead to accelerated polyethylene wear. In the case of successful reduction, close patient follow-up is recommended. Open reduction with femoral head inspection and exchange may be preferable if difficulty is encountered in closed reduction maneuvers. PMID- 17689793 TI - Fatigue fracture of a proximally modular, distally tapered fluted implant with diaphyseal fixation. AB - We report and analyze the causes of a fracture in a proximally modular, distally tapered fluted MP stem in a 48-year-old woman (168 cm, 67 kg) with severe proximal bone deficiency. Evidence of fatigue failure with striations initiated laterally was observed in the laser etching of the tensile aspect of the prosthesis. However, metallurgical analysis suggested that laser engraving did not alter the microstructure of the stem. Stress due to the absence of proximal femoral bone support may have been sufficiently high to put this particular stem at risk for fatigue fracture. This important complication should be addressed when choosing this therapeutic option in cases with substantial proximal femoral bone loss. Strut allograft support should be recommended in such cases. PMID- 17689794 TI - Vascularity of the femoral head after Birmingham hip resurfacing. A technetium Tc 99m bone scan/single photon emission computed tomography study. PMID- 17689796 TI - The effect of posterior tibial slope on range of motion after total knee arthroplasty. PMID- 17689798 TI - Response of fluxome and metabolome to temperature-induced recombinant protein synthesis in Escherichia coli. AB - The response of the central carbon metabolism of Escherichia coli to temperature induced recombinant production of human fibroblast growth factor was studied on the level of metabolic fluxes and intracellular metabolite levels. During production, E. coli TG1:plambdaFGFB, carrying a plasmid encoded gene for the recombinant product, revealed stress related characteristics such as decreased growth rate and biomass yield and enhanced by-product excretion (acetate, pyruvate, lactate). With the onset of production, the adenylate energy charge dropped from 0.85 to 0.60, indicating the occurrence of a severe energy limitation. This triggered an increase of the glycolytic flux which, however, was not sufficient to compensate for the increased ATP demand. The activation of the glycolytic flux was also indicated by the readjustment of glycolytic pool sizes leading to an increased driving force for the reaction catalyzed by phosphofructokinase. Moreover, fluxes through the TCA cycle, into the pentose phosphate pathway and into anabolic pathways decreased significantly. The strong increase of flux into overflow pathways, especially towards acetate was most likely caused by a flux redirection from pyruvate dehydrogenase to pyruvate oxidase. The glyoxylate shunt, not active during growth, was the dominating anaplerotic pathway during production. Together with pyruvate oxidase and acetyl CoA synthase this pathway could function as a metabolic by-pass to overcome the limitation in the junction between glycolysis and TCA cycle and partly recycle the acetate formed back into the metabolism. PMID- 17689799 TI - Enzymatic synthesis of galactosyl lactic ethyl ester and its polymer for use as biomaterials. AB - Lactate-based chemicals and polymers including poly(lactic acid) (PLA) are highly valuable materials for biomedical, food and general-purpose applications. Chemical synthesis, albeit the high reaction velocities achieved with it, often leaves chemical residues that are subject to health and safety concerns. Alternative biosynthesis is preferred in order to overcome these problems. Herein we report a novel enzymatic synthesis for the preparation of beta-d-galactosyl-l lactic acid ethyl ester (GLAEE). Such a product, which may find applications in food and personal care products, is generally difficult to synthesize via traditional chemical routes because the reactions have to be highly selective due to the multiple hydroxyl groups of sugars. We further explore the enzymatic polymerization of GLAEE to form a unique biopolymer, poly(beta-d-galactoside-co-l lactic acid) (PGLA). Novozyme 435 was found efficient in catalyzing the polymerization reaction in acetone with a conversion yield of 60% within 100 h. The molecular weight of the polymer product ranged from about 800-2000 as analyzed by using ESI-MS. It is expected that a variety of sugar-hydroxyl acids copolymers can be prepared through the same approach and a new class of biomaterials can thus be developed. PMID- 17689800 TI - Simultaneous biosynthesis of (+)-geodin by a lovastatin-producing fungus Aspergillus terreus. AB - The simultaneous biosynthesis of lovastatin (mevinolinic acid) and (+)-geodin by Aspergillus terreus ATCC 20542 with regard to the medium composition, i.e. the concentrations of carbon and nitrogen source, was described in this paper. A. terreus is a lovastatin producer but the formation of lovastatin was accompanied by the significant amounts of (+)-geodin, when the elevated concentration of carbon source (lactose) was still present in the medium in the idiophase and nitrogen source (yeast extract) was deficient. It was observed for runs, in which the higher (above 20 g l(-1)) initial lactose concentration was applied or when the nitrogen deficiency led to the decrease of biomass content in the system. In contrast to lovastatin, there was not optimum initial concentration of yeast extract, as its lowest tested initial concentration (2 g l(-1)) led to the highest (+)-geodin volumetric formation rates and final yield. What is more, even higher final (+)-geodin concentrations were achieved at elevated initial lactose concentration (40 g l(-1)) and in the lactose-fed fed-batch run. In the fed-batch run lovastatin concentration increased significantly too, as this metabolite formation is also carbon source dependent. Finally, (+)-geodin occurred to be a metabolite, whose formation, in contrast to lovastatin, is non-growth associated. PMID- 17689801 TI - The need for reappraisal of AIDS score weight of Charlson comorbidity index. AB - OBJECTIVE: To discuss the need for reappraisal of AIDS score weight of the Charlson comorbidity index. STUDY DESIGN AND SETTING: This article is a comment on Charlson comorbidity index. RESULTS: This article shows that the weight assigned for AIDS in the original cohort of Charlson score may be higher considering the dramatic improvement in the prognosis of such patients after the advent of highly active antiretroviral therapy. Only a few exceptions among HIV related diseases are still strongly associated with high mortality rates within 1 year. This might lead to an inaccurate measurement of the impact of Charlson score on mortality rate, particularly in cohorts with high relative number of AIDS patients. CONCLUSION: Charlson comorbidity index should be reassessed in cohorts with higher proportions of AIDS patients, taking into account the current prognosis of the disease. A stratification of AIDS-related category may be required to improve Charlson score accuracy in predicting mortality or adjusting for confounding. PMID- 17689802 TI - Systematic reviewers neglect bias that results from trials stopped early for benefit. AB - OBJECTIVE: To examine how authors of systematic reviews that include randomized clinical trials (RCTs) that are stopped early for benefit (truncated RCTs-tRCTs) address the potential for overestimation of treatment effects and to determine the weight of the tRCTs on pooled results. STUDY DESIGN AND SETTING: We searched the Cochrane Library and MEDLINE and evaluated systematic reviews that include at least one tRCT. We documented approaches that authors used to address potential overestimates of treatment effect introduced by including tRCTs. We assessed the impact of tRCTs in meta-analyses on the outcomes that led to their early termination. RESULTS: Of 96 systematic reviews that included at least one tRCT, 44 (46%) included >1 tRCT, 68 (71%) did not mention truncation at all, and 2 (2%) documented early stopping for benefit as a criterion for methodological quality. Of 47 meta-analyses in which authors reported, or we could calculate the contribution of the tRCTs to the pooled result, the tRCTs contributed more than 40% of the weight in 16/47 (34%). CONCLUSION: Most systematic reviews and meta analyses including tRCTs fail to consider the possible overestimates of effect that may result from early stopping for benefit. We recommend safeguards that address this possibility. PMID- 17689803 TI - Relative risks and confidence intervals were easily computed indirectly from multivariable logistic regression. AB - OBJECTIVE: To assess alternative statistical methods for estimating relative risks and their confidence intervals from multivariable binary regression when outcomes are common. STUDY DESIGN AND SETTING: We performed simulations on two hypothetical groups of patients in a single-center study, either randomized or cohort, and reanalyzed a published observational study. Outcomes of interest were the bias of relative risk estimates, coverage of 95% confidence intervals, and the Akaike information criterion. RESULTS: According to simulations, a commonly used method of computing confidence intervals for relative risk substantially overstates statistical significance in typical applications when outcomes are common. Generalized linear models other than logistic regression sometimes failed to converge, or produced estimated risks that exceeded 1.0. Conditional or marginal standardization using logistic regression and bootstrap resampling estimated risks within the [0,1] bounds and relative risks with appropriate confidence intervals. CONCLUSION: Especially when outcomes are common, relative risks and confidence intervals are easily computed indirectly from multivariable logistic regression. Log-linear regression models, by contrast, are problematic when outcomes are common. PMID- 17689804 TI - Probabilistic record linkage is a valid and transparent tool to combine databases without a patient identification number. AB - OBJECTIVE: To describe the technical approach and subsequent validation of the probabilistic linkage of the three anonymous, population-based Dutch Perinatal Registries (LVR1 of midwives, LVR2 of obstetricians, and LNR of pediatricians/neonatologists). These registries do not share a unique identification number. STUDY DESIGN AND SETTING: A combination of probabilistic and deterministic record linkage techniques were applied using information about the mother, delivery, and child(ren) to link three known registries. Rewards for agreement and penalties for disagreement between corresponding variables were calculated based on the observed patterns of agreement and disagreements using maximum likelihood estimation. Special measures were developed to overcome linking difficulties in twins. A subsample of linked and nonlinked pairs was validated. RESULTS: Independent validation confirmed that the procedure successfully linked the three Dutch perinatal registries despite nontrivial error rates in the linking variables. CONCLUSIONS: Probabilistic linkage techniques allowed the creation of a high-quality linked database from crude registry data. The developed procedures are generally applicable in linkage of health data with partially identifying information. They provide useful source date even if cohorts are only partly overlapping and if within the cohort, multiple entities and twins exist. PMID- 17689805 TI - Combining ratings from multiple physician reviewers helped to overcome the uncertainty associated with adverse event classification. AB - OBJECTIVES: Adverse events (AEs) are poor patient outcomes, resulting from medical care. We performed this study to quantify the misclassification rate obtained using current AE detection methods and to evaluate the effect of combining physician AE ratings. STUDY DESIGN AND SETTING: Three physicians independently rated poor patient outcomes. We used latent class analysis to obtain estimates for AE prevalence and reviewer accuracy. These estimates were used as a base case for four simulations of 10,000 cases rated independently by five reviewers. We assessed the effect of AE prevalence, reviewer accuracy, and the number of agreeing reviewers on the probability that cases were correctly classified as an AE. RESULTS: Reviewer sensitivity and specificity for AE classification were 0.86 and 0.94, respectively. When prevalence was 3%, the positive predictive value that an AE occurred when a single reviewer classified the case as such was 31%, whereas when 2/3 reviewers did so it was 51%. The positive predictive values of ratings for AE occurrence increased with AE prevalence, reviewer accuracy, and the number of reviewers. CONCLUSION: Current methods of AE detection overestimate the risk of AE. Uncertainty regarding the presence of an AE can be overcome by increasing the number of reviews. PMID- 17689806 TI - The use of imperfect diagnostic tests had an impact on prevalence estimation. AB - OBJECTIVE: Problems arising with the estimation of sensitivity and specificity when two imperfect diagnostic tests are applied are widely discussed. Effects on the estimation of prevalence may be of importance as well. Different methods of dealing with two or more imperfect tests and unknown reference standard are contrasted with regard to their implications on prevalence estimation: discrepant analysis, composite reference standards, and latent class models. STUDY DESIGN AND SETTING: Prospective epidemiological multicenter study to determine the prevalence of respiratory syncytial virus in children with lower respiratory tract infections. A subsample of 1,003 patients from a hospital population and from a practice population is considered. Virus isolation, polymerase chain reaction, and rapid antigen test had been applied. RESULTS: Prevalence estimates obtained under various assumptions ranged from 0.263 to 0.386 in the hospital population and from 0.214 to 0.277 in the practice population. CONCLUSION: Estimation procedures involving a resolver test applied to some but not all cells are at risk of introducing a serious bias in prevalence estimation as well as in the estimation of test accuracy parameters. Estimation via latent class modeling may be more useful, but care should be taken regarding the underlying assumptions. PMID- 17689808 TI - The Postoperative Morbidity Survey was validated and used to describe morbidity after major surgery. AB - OBJECTIVES: To describe the reliability and validity of the Postoperative Morbidity Survey (POMS). To describe the level and pattern of short-term postoperative morbidity after major elective surgery using the POMS. STUDY DESIGN AND SETTING: This was a prospective cohort study of 439 adults undergoing major elective surgery in a UK teaching hospital. The POMS, an 18-item survey that address nine domains of postoperative morbidity, was recorded on postoperative days 3, 5, 8, and 15. RESULTS: Inter-rater reliability was perfect for 11/18 items (Kappa=1.0), with Kappa=0.94 for 6/18 items. A priori hypotheses that the POMS would discriminate between patients with known measures of morbidity risk, and predict length of stay were generally supported through observation of data trends, and there was statistically significant evidence of construct validity for all but the wound and neurological domains. POMS-defined morbidity was present in 325 of 433 patients (75.1%) remaining in hospital on postoperative day 3 after surgery, 231 of 407 patients (56.8%) on day 5, 138 of 299 patients (46.2%) on day 8, and 70 of 111 patients (63.1%) on day 15. Gastrointestinal (47.4%), infectious (46.5%), pain-related (40.3%), pulmonary (39.4%), and renal problems (33.3%) were the most common forms of morbidity. CONCLUSION: The POMS is a reliable and valid survey of short-term postoperative morbidity in major elective surgery. Many patients remain in hospital without any morbidity as recorded by the POMS. PMID- 17689807 TI - Observed association between antidepressant use and pneumonia risk was confounded by comorbidity measures. AB - OBJECTIVE: A prior study suggested that antidepressants might increase the risk of hospitalization for pneumonia in the elderly. This study sought to confirm or refute this hypothesis. STUDY DESIGN AND SETTING: Case-control study of persons aged 65 and above nested in the UK General Practice Research Database. RESULTS: We identified 12,044 cases of the hospitalization for pneumonia (the primary outcome) and 48,176 controls. The odds ratio (OR) for any antidepressant use, adjusting for age, sex, and calendar year was 1.61 (95% confidence interval 1.46 1.78). After further adjustment for comorbidity measures, the OR was 0.89 (0.79 1.00). We also identified 159 cases of hospitalization for aspiration pneumonia (the secondary outcome) and 636 controls. The OR for any antidepressant use, adjusted for age, sex, and calendar year was 1.45 (0.65-3.24). After further adjustment for comorbidity measures, the OR was 0.63 (0.23-1.71). CONCLUSION: These findings refute the prior hypothesis that use of antidepressants by elderly patients increases the risk of hospitalization for pneumonia or for aspiration pneumonia. Decisions regarding use of antidepressants in elderly persons should not be affected by concern about pneumonia risk. Data-derived hypotheses should be independently confirmed before being acted upon. PMID- 17689809 TI - Probabilistic threshold technique showed that patients' preferences for specific trade-offs between pain relief and each side effect of treatment in osteoarthritis varied. AB - OBJECTIVES: Therapeutic decisions in osteoarthritis (OA) often involve trade-offs between accepting risks of side effects and gaining pain relief. Our objectives were (1) to determine patients' maximum acceptable risk increments (MARI) for different adverse effects from OA medication and (2) to identify the predictors of these preferences. STUDY DESIGN AND SETTING: MARI were measured with a probabilistic threshold technique (TT). Risk and pain levels in the TT scenarios were controlled for in a 2x2 randomized factorial design. Clinical, sociodemographic, and psychological characteristics (decisional conflict and locus of control) of the participants were assessed using a self-administered questionnaire. RESULTS: For 196 subjects, MARI varied by type of adverse effect, level of pain relief, and baseline risk. Mean MARI ranged from 3% to 5% for heart attack/stroke, 5% to 8% for stomach bleed, 13% to 21% for hypertension, 22% to 33% for fluid retention, and 23% to 35% for dyspepsia. Age, gender, education, physical and mental health, pain, disability, and locus of control were not associated with MARI. CONCLUSION: Participants varied widely in the level of risk they would accept, but their clinical, sociodemographic, and psychological characteristics did not explain this variation. These observations are important for the development of practice guidelines for physicians and patients' decision aids that can foster individualized, evidence-based yet preference-sensitive care for patients with OA. PMID- 17689810 TI - Statistically significant papers in psychiatry were cited more often than others. AB - OBJECTIVE: Citations by other researchers are important in the dissemination of research findings. We aimed to investigate whether preferential citation of statistically significant articles exists in the psychiatric literature. STUDY DESIGN AND SETTINGS: We analyzed all original research papers published in 1996 in four psychiatric journals. Using a standardized questionnaire, from each paper, we extracted the primary outcome and its statistical significance. The number of citations, excluding authors' "self-citations," received by April 2005 was obtained. Regression analysis was used to relate citation frequency to statistical significance, adjusting for confounders. RESULTS: Of 448 extracted papers, 368 used statistical significance testing and 287 (77.8%) reported P<0.05. The median number of citations for papers reporting "significant" and "nonsignificant" results was 33 vs. 16. After adjustment for journal, study design, reporting quality, whether outcome confirmed previous findings and study size, the ratio of the number of citations per article for articles reporting "P<0.05" on the primary outcome to those reporting "P>0.05" was 1.63 (95% confidence interval [CI]: 1.32, 2.02, P<0.001). CONCLUSION: Authors cite studies based on their P-value rather than intrinsic scientific merit. This practice skews the research evidence. Systematic study registration and inclusion in meta analysis should be encouraged. PMID- 17689811 TI - Good generalizability of a prediction rule for prediction of persistent shoulder pain in the short term. AB - OBJECTIVE: To evaluate the generalizability of recently developed clinical prediction rules for the prognosis of shoulder pain in general practice. STUDY DESIGN AND SETTING: A large research program, consisting of a prognostic cohort study and three randomized controlled trials with 6 months follow-up, was carried out in The Netherlands. The clinical prediction rules were derived from the results of the prognostic cohort study (n=587). The main outcome measure was persistent symptoms at 6 weeks or 6 months. The control groups of the trials who received usual care were merged (n=212), and used to validate the prediction rules by studying calibration and discrimination. RESULTS: The prediction rule for short-term outcome showed reasonable calibration and discriminative ability in this validation cohort. The area under the receiver operating characteristic curve (AUC) was 0.72 compared to 0.74 in the derivation cohort. The prediction rule for long-term outcome performed less well. Discriminative ability (AUC) decreased to 0.56 in the validation cohort compared to 0.67 in the derivation cohort. CONCLUSION: The prediction rule for the short-term (6 weeks) prognosis showed good generalizability. The prediction rule for the long-term prognosis showed poor generalizability. PMID- 17689812 TI - Educational intervention toward preventive home visitors reduced functional decline in community-living older women. AB - OBJECTIVE: To investigate whether immediate effects of a 3-year educational intervention in primary health care were confirmed 18 months after the end of the intervention. STUDY DESIGN AND SETTING: A controlled 3-year intervention study in 34 Danish municipalities with randomization and intervention at municipality level. The 17 intervention municipality visitors received regular education, and GPs were introduced to a short assessment program. The effect was measured at the individual level by questions about functional ability at the end of the intervention period and 1(1/2) years later; 4,060 older adults living in the municipalities participated. We adopt the approach introduced by Dufouil et al. (2004) and treat dropouts due to death differently from dropouts from other reasons. RESULTS: Educational intervention to primary care professionals was associated with better functional ability in surviving women at the end of the intervention (odds ratio [OR]: 1.24, 95% confidence interval [CI]=1.07-1.45), from the end of the intervention until 1(1/2) years later (OR: 1.21, 95% CI=1.03 1.44) and during the total study period (OR: 1.22, 95% CI=1.06-1.42). No effects were seen in men. CONCLUSION: The effect of a brief, feasible educational intervention for primary care professionals is sustained in women 1(1/2) years after the end of the intervention. PMID- 17689813 TI - Pain and depression in caregivers affected their perception of pain in stroke patients. AB - OBJECTIVES: Informal caregivers often serve as proxy raters of Health-Related Quality of Life (HRQL) when patients cannot report on their own behalf. Caregiver depression has been associated with bias in proxy ratings, but few studies have examined the role of caregiver pain. The aim of this study was to determine if caregiver depressive symptoms and/or pain systematically affected patient-proxy agreement on patient HRQL after stroke. STUDY DESIGN AND SETTINGS: Secondary data analysis of 95 stroke patients and their caregivers (dyads) at 6 months poststroke. Caregiver depressive symptoms were measured by Center for Epidemiologic Studies Depression Rating Scale, and pain was measured using EQ-5D. Using multivariate regression, we examined the effect of caregiver depressive symptoms and pain on patient-proxy difference scores on Health Utilities Index 3 (HUI3) attributes and Short Form-36 domains of vitality and social functioning. RESULTS: Caregiver depressive symptoms and pain were associated with significant differences in patient-proxy scores on HUI3 pain (P<0.05). Depressed caregivers underestimated pain experienced by patients, and caregivers with pain overestimated patient pain. Additionally, an interaction between caregiver depressive symptoms and pain was identified. CONCLUSION: Presence of pain and depressive symptoms in caregivers can significantly affect perceptions of pain in stroke patients. Results suggest that caregivers with pain and/or depression may provide more biased proxy assessments of pain. PMID- 17689814 TI - ICD-10 adaptations of the Ontario acute myocardial infarction mortality prediction rules performed as well as the original versions. AB - OBJECTIVE: To derive and validate an International Classification of Diseases-10 (ICD-10) version of the Ontario Acute Myocardial Infarction (AMI) mortality prediction rules, used to adjust for case-mix differences in studies of AMI patients using administrative data. STUDY DESIGN AND SETTING: We linked the records of all Ontario patients admitted with AMI (2002-2004) with mortality data. The original ICD-9 codes were mapped to ICD-10-CA (Canada) codes using both a translation produced by coding experts and a manual search of codes; the final codes were determined by consensus. Comorbidity prevalence and mortality rates were calculated. Multivariable logistic regression models were used to predict 30 day and 1-year mortality and the C-statistic was used to evaluate the discrimination of the models. RESULTS: We identified 37,271 AMI patients. The most common comorbidities were heart failure and dysrhythmias; 30-day and 1-year mortality rates were 12.3% and 21.8%, respectively; and mortality rates were highest among patients with shock, cancer, and acute renal failure. The C statistics were 0.77 and 0.80, compared with 0.78 and 0.79 in the ICD-9 version, for 30-day and 1-year mortality, respectively. CONCLUSION: An ICD-10 version of the AMI mortality prediction rules predicted 30-day and 1-year mortality as well as the original ICD-9 version. PMID- 17689815 TI - A simple method to correct for the design effect in systematic reviews of trials using paired dichotomous data. AB - BACKGROUND AND OBJECTIVES: In systematic reviews of interventions of studies where randomization was done by individual but data are paired (such as eyes, ears), it is necessary to account for the natural clustering present. The Cochrane Handbook suggests treating these as examples of cluster randomized trials. An incorrect analysis (without adjustment) would usually overestimate the precision of the estimate. We discuss a simple method of adjustment that deals with this problem. METHODS: From a cross-tabulation of the event being present on the "left" and "right" body part, we estimate the design effect which is a measure of the inflation on the variance due to clustering. This estimate is then used to obtain an adjusted effect size per trial by reducing the number of events and the sample size in each intervention group. RESULTS: In a systematic review on Auto-inflation for Glue Ear, data on improvement were obtained for pairs of ears. The design effect obtained from these data was 1.25. In a meta-analysis, the weights given to the trials changed after adjustment from 33% to 11% in one case. CONCLUSION: In a systematic review, when dealing with paired data, it is possible to give adequate weighting to each trial using a simple adjusting method. PMID- 17689816 TI - Imputation is beneficial for handling missing data in predictive models. PMID- 17689817 TI - Effectiveness and stability of heterologous proteins expressed in plants by Turnip mosaic virus vector at five different insertion sites. AB - The N-terminal (NT) regions of particular protein-coding sequences are generally used for in-frame insertion of heterologous open reading frames (ORFs) in potyviral vectors for protein expression in plants. An infectious cDNA clone of Turnip mosaic virus (TuMV) isolate YC5 was engineered at the generally used NT regions of HC-Pro and CP, and other possibly permissive sites to investigate their effectiveness to express the GFP (jellyfish green fluorescent protein) and Der p 5 (allergen from the dust mite, Dermatophagoides pteronyssinus) ORFs. The results demonstrated the permissiveness of the NT regions of P3, CIP and NIb to carry the ORFs and express the translates as part of the viral polyprotein, the processing of which released free-form proteins in the host cell milieu. However, these sites varied in their permissiveness to retain the ORFs intact and hence affect the heterologous protein expression. Moreover, strong influence of the inserted ORF and host plants in determining the permissiveness of a viral genomic context to stably carry the alien ORFs and hence to support their prolonged expression was also noticed. In general, the engineered sites were relatively more permissive to the GFP ORF than to the Der p 5 ORF. Among the hosts, the local lesion host, Chenopodium quinoa Willd. showed the highest extent of support to TuMV to stably carry the heterologous ORFs at the engineered sites and the protein expression therefrom. Among the systemic hosts, Nicotiana benthamiana Domin proved more supportive to TuMV to carry and express the heterologous ORFs than the Brassica hosts, whereas the protein expression levels were significantly higher and more stable in the plants of Brassica campestris L. var. chinensis and B. campestris L. var. ching-geeng than those in the plants of B. juncea L. and B. campestris L. var. pekinensis. PMID- 17689818 TI - Randomized trials or population-based registries. PMID- 17689819 TI - Alteration of the VRK1-p53 autoregulatory loop in human lung carcinomas. AB - Human VRK1 (vaccinia-related kinase 1) is a novel serine-threonine kinase that regulates several transcription factors, including p53, ATF2 and c-Jun; and its loss results in defects of cell proliferation. VRK1 stabilizes p53 and the accumulated p53 downregulates VRK1 forming an autoregulatory loop. Wild-type p53, but not mutant p53, was able to downregulate VRK1 in the A549 lung carcinoma cell line. VRK1 expression has been studied in human lung carcinomas. VRK1 protein level was significantly higher in squamous cell lung carcinomas than in adenocarcinomas, and inversely correlated with p16. Tumours with p53 mutations have a positive trend with those having very high levels of VRK1 protein, particularly in squamous cell lung carcinomas. These data indicate that the VRK1 p53 autoregulatory loop was not functional in a group of lung carcinomas. The accumulation of VRK1 in tumours with mutant p53 could result in stimulation of other signalling pathways that can contribute to tumour growth and progression in addition to those resulting from loss of p53 function. PMID- 17689820 TI - Quantification of biotransformation of chlorinated hydrocarbons in a biostimulation study: added value via stable carbon isotope analysis. AB - Stable carbon isotope analysis of chlorinated aliphatic compounds was performed at an in situ biostimulation pilot test area (PTA) at a site where 1,2 dichloroethane (1,2-DCA) and trichloroethene (TCE) were present in groundwater. Chlorinated products of TCE reductive dechlorination (cis-dichloroethene (cDCE) and vinyl chloride (VC)) were present at concentrations of 17.5 to 126.4 micromol/L. Ethene, a potential degradation product of both 1,2-DCA dihaloelimination and TCE reductive dechlorination was also present in the PTA. Emulsified soybean oil and lactate were added as electron donors to stimulate anaerobic dechlorination in the PTA. Stable carbon isotope analysis provided evidence that dechlorination was occurring in the PTA during biostimulation, and a means of monitoring changes in dechlorination efficiency over the 183 day monitoring period. Stable carbon isotope analysis was also used to determine if ethene production in the PTA was due to dechlorination of TCE, 1,2-DCA, or both. Fractionation factors (alpha) were determined in the laboratory during anaerobic biotransformation of 1,2-DCA via a dihaloelimination reaction in four separate enrichment cultures. These alpha values (as well as the previously published ranges of alpha for the dechlorination of TCE, cDCE and 1,2-DCA) were used, along with isotopic values measured during the pilot test, to derive quantitative estimates of biotransformation during the pilot test. Dechlorination was found to account for 10.7 to 35.9%, 21.9 to 74.9%, and 54.4 to 67.8% of 1,2-DCA, TCE and cDCE concentration loss respectively in the PTA. Stable carbon isotope analysis indicates that dechlorination of 1,2-DCA, TCE and cDCE were all significant processes during the pilot test, while ethene production during the pilot test was dominated by 1,2-DCA dihaloelimination. This study demonstrates how stable carbon isotope analysis can provide more conservative estimates of the extent of biotransformation than do conventional protocols. In addition, in a complex mixed plume such as this, compound specific isotope analysis is shown to be one of the few methods available for clarifying dominant biotransformation pathways where breakdown products are non-exclusive (i.e. ethene). PMID- 17689821 TI - Functional brain imaging--the missing link? PMID- 17689822 TI - Pediatric ophthalmology and strabismus of the future. PMID- 17689823 TI - Rates of strabismus surgery in the United States: implications for manpower needs in pediatric ophthalmology. AB - PURPOSE: To investigate rates of strabismus surgery and population projections in the United States and to consider whether a sufficient number of pediatric ophthalmologists are being trained to meet future needs. METHODS: Review of online data from Series 13 reports from the National Center for Health Statistics for the period 1965 to 1996, including reports from the National Hospital Discharge Survey and the National Survey of Ambulatory Surgery. Population data were obtained from the U.S. Census Bureau. RESULTS: The current rate of strabismus surgery for children under 15 years of age is 80 per 100,000 persons in the United States. This rate would generate an additional 389 strabismus cases annually, based on the predicted growth of the pediatric population. On average, today's pediatric ophthalmologist performs about 114 strabismus procedures annually. CONCLUSIONS: If the current rates and trends remain stable over the coming years, it is not likely that there will be a shortage of pediatric ophthalmologists in the United States. PMID- 17689824 TI - Recruitment and manpower in pediatric ophthalmology and strabismus. AB - PURPOSE: Many have observed what appears to be declining interest on the part of ophthalmology graduates in pediatric ophthalmology and strabismus (PO&S) as a career. Four questions might address this concern: (1) Has there been a decline in the number of fellowship positions filled in the period 2000 to 2005? (2) Why do graduates choose other career paths? (3) Assuming there has been a decrease in interest in PO&S, does it reflect dissatisfaction on the part of pediatric ophthalmologists in their field? (4) What can be done to enhance the appeal of the subspecialty? METHODS: Data from the San Francisco Matching Programs covering the years 2000 through 2005 included the numbers of ophthalmology graduates, their subspecialty choices, the number of applicants to PO&S and other subspecialty fellowships, and the number of fellowship positions offered. Supplemental surveys assessed positions filled outside the match and international fellows. Factors influencing residents' career choices and the job satisfaction of pediatric ophthalmologists were analyzed in separate surveys. RESULTS: The number of fellowship positions in PO&S increased from 41 to 50 between 2000 and 2004. The number of graduates participating in the match has varied but remained the same (38) in 2005 as in 2000. Graduates were discouraged from PO&S by inadequate mentoring, by aversion to children, and by higher compensation in other fields. Pediatric ophthalmologists generally are highly satisfied in their careers, although financial compensation is a concern for many. CONCLUSIONS: Pediatric ophthalmologists should remain optimistic about recruitment but could enhance the appeal of PO&S by teaching more effectively and by promoting the field. PMID- 17689825 TI - Babies Count: the national registry for children with visual impairments, birth to 3 years. AB - INTRODUCTION: Information about the prevalence of visual impairment in children is not collected systematically. Further, little information is available about children under age 6. Babies Count is a national registry of children with visual impairment in the United States, aged birth to 3 years. METHODS: Data were collected on 2,155 children at the point of entry into specialized early intervention programs. Data include patient diagnosis, functional vision, age, gender, ethnicity, and family characteristics. Concurrent visual pathology and systemic disabilities were also documented. RESULTS: Of the sample of 2,155 children, 1,167 (54%) were boys; approximately 40% of the children were legally blind, and 68% had disabilities in addition to visual impairment. Cortical visual impairment, retinopathy of prematurity (ROP), and optic nerve hypoplasia (ONH) were the three most prevalent visual conditions. In children with these three conditions, those with ROP were diagnosed the earliest (mean, 3.4 months), and those with cortical visual impairment were diagnosed latest (mean, 7.6 months). There was on average a 4.5 month mean lag between the diagnosis of children's visual impairment and referral for services. ONH carried a poorer visual outcome when compared with other diagnoses, including CVI, ROP, and albinism. CONCLUSIONS: Prevalent visual conditions in children in the United States differ from those found in developing countries and in adults with visual impairment. Babies Count is a comprehensive set of data that may affect our understanding of the epidemiology of visual impairment in the United States. In an era of preventive and outcome-based medicine, and with competition for health care and research funding, these data provide a valuable means for understanding the impact of these disorders on society. PMID- 17689828 TI - Monocanalicular silastic intubation for the initial correction of congenital nasolacrimal duct obstruction. PMID- 17689829 TI - Subpopulations of human dendritic cells display a distinct phenotype and bind differentially to proteins of the extracellular matrix. AB - CD1a(pos) dendritic cells (DCs) and Langerhans cells (LCs) are highly specialized antigen-presenting cells mainly localized in the skin. Various cells have been identified as precursors of cutaneous DCs, but the definitive precursor subpopulations remain to be defined and characterized in detail. In this study, DCs were generated in vitro from monocytes (monocyte-derived DCs, MoDCs) and from CD34(pos) stem cells (CD34(pos) cell-derived DCs, CD34DCs). By virtue of their CD14 and CD1a expression, four CD34DC subpopulations were characterized while MoDCs contain three different subpopulations. Of these, CD14-expressing cells are considered to be precursors of fully differentiated DCs, which themselves are CD14(neg)CD1a(pos). Both, MoDCs and CD34DCs expressed the alpha integrins LFA-1, Mac-1, CR4, VLA-4, VLA-5 and the beta2 integrin CD18. CD34DCs and MoDCs were negative for VLA-3, whereas MoDCs, but not CD34DCs expressed VLA-6. Phenotypic and functional characterization of the cells generated herein at earlier time points revealed that DCs at day 3 of culture may reflect the in vivo situation more closely than at day 7. Adhesion of DC precursors to endothelial cells and to components of the extracellular matrix is a prerequisite for their migration towards the epidermis. To this end, we investigated adhesion of CD34DCs and MoDCs to components of the cutaneous extracellular matrix. Distinct DC subsets showed a differential binding pattern to proteins of the extracellular matrix. MoDCs and CD34DCs bound preferentially to laminin 332 via CD49f and to fibronectin via CD49e, but only weakly to laminin 111 or to collagens. While CD14(pos) cells preferentially bound to laminin 332, CD1a(pos) cells adhered to fibronectin. In summary, subpopulations of CD34DCs and MoDCs are phenotypically related to each other, but not identical and display differential binding to components of the extracellular matrix. PMID- 17689830 TI - Infection of maize leaves with Ustilago maydis prevents establishment of C4 photosynthesis. AB - The Basidiomycete fungus Ustilago maydis is the common agent of corn smut and is capable of inducing gall growth on infected tissue of the C4 plant maize (Zea mays). While U. maydis is very well characterized on the genetic level, the physiological changes in the host plant in response to U. maydis infection have not been studied in detail, yet. Therefore, we examined the influence of U. maydis infection on photosynthetic performance and carbon metabolism in maize leaf galls. At all stages of development, U. maydis-induced leaf galls exhibited carbon dioxide response curves, CO2 compensation points and enzymatic activities that are characteristic of C3 photosynthesis, demonstrating that the establishment of C4 metabolism is prevented in infected tissue. Hexose contents and hexose/sucrose ratio of leaf galls remained high at 6 days post infection, while a shift in free sugar metabolism was observed in the uninfected controls at that time point. Concomitantly, transitory starch production and sucrose accumulation during the light period remained low in leaf galls. Given that U. maydis is infectious on young developing tissue, the observed changes in carbohydrate metabolism suggest that the pathogen manipulates the developing leaf tissue to arrest sink-to-source transition in favor of maintaining sink metabolism in the host cells. Furthermore, evidence is presented that carbohydrate supply during the biotrophic phase of the pathogen is assured by a fungal invertase. PMID- 17689831 TI - PPARs special issue: anchoring the present to explore the future. PMID- 17689832 TI - Evaluating the role of recombinant erythropoietin in nephrogenic systemic fibrosis. PMID- 17689833 TI - Information about infantile hemangiomas on the Internet: how accurate is it? AB - OBJECTIVES: We sought to measure the type, content, and quality of World Wide Web sites retrieved when conducting an Internet search for infantile hemangiomas. METHODS: Fifty World Wide Web sites from a Google search for "hemangioma" were examined. Relevant sites were characterized, and content was evaluated by 8 pediatric dermatologists. RESULTS: The most accurate subjects were the description of risk factors and natural history, whereas the least accurate areas were photographic representation of the disease and presentation of treatment options. Four sites were considered accurate, and the majority of raters would recommend these sites to parents. LIMITATIONS: Internet sites and search results change. CONCLUSIONS: An Internet search for information about infantile hemangiomas yields few sites that accurately depict the full disease spectrum from innocuous to severe. Online educational resources containing a broader overview of the real disease spectrum of infantile hemangiomas are needed. Such sites should include large numbers of photographs, evidence-based content, and resources for parental support. PMID- 17689834 TI - Re: sequential medication strategies for postherpetic neuralgia: a cost effectiveness analysis. PMID- 17689835 TI - Structure-function studies of peptides for cell adhesion inhibition: identification of key residues by alanine mutation and peptide-truncation approach. AB - Blockage of the interaction of CD2 with its ligand CD58 is expected to bring out potential therapeutic value for autoimmune diseases and organ transplantation. Three series of peptides (cVL, cIL and cAQ series) were designed from ratCD2 and humanCD2 to modulate CD2-CD58 interaction. To determine the specific segments in parent peptides responsible for inhibitory activity as lead sequence, we generated shorter fragments of the parent peptides and evaluated their biological activity with cell adhesion assay. The structure-activity relationship studies indicated that small cyclic peptides derived from CD2 ligand binding epitopes could mimic native beta-turn structure, and thus modulate CD2-CD58 interaction. PMID- 17689836 TI - Towards predictive inhibitor design for the EGFR autophosphorylation activity. AB - Inhibition of the epidermal growth factor receptor (EGFR) tyrosine kinase is one among the pivotal targets for the treatment of cancer. The structural investigation directly halting the EGFR autophosphorylation is expected to give insights into alternatively blocking the aberrant activity of EGFR. The three dimensional quantitative structure-activity relationship (3D-QSAR) models were developed from the systematic search conformer-based alignment method. Models derived from the training set of 95 compounds showed superior CoMFA as compared with CoMSIA (CoMFA: q(2)=0.50, r(2)=0.74, N=5, F=48.83, r(2)(pred)=0.56 while CoMSIA: q(2)=0.48, r(2)=0.62, N=2, F=72.70, r(2)(pred)=0.51). Validation of the models by test set prediction of 26 compounds was in good agreement with the experimental results. Further validation by molecular docking superimposition into the 3D-QSAR contour maps was found in agreement with each other. We identified that the structural modification of compound 19 by attachment of a bulky group on pyrrole ring along with an electronegative group on quinazoline ring and a hydrogen-bond donor on methyl formate opens a new avenue towards the optimization of novel chemical entities to develop potent inhibitors for EGFR autophosphorylation. PMID- 17689837 TI - Synthesis of novel 4,6-disubstituted quinazoline derivatives, their anti inflammatory and anti-cancer activity (cytotoxic) against U937 leukemia cell lines. AB - In view of the link between use of NSAIDs and altered cancer incidence and a growing evidence of COX-II implication in angiogenesis, a novel series of 4,6 disubstituted quinazoline derivatives have been synthesized starting from anthranilic acid derivatives 1 through conventional methods. Initially acylation followed by cyclisation to obtain benz-oxazinones 2 which on further treatment with ammonia yielded the crucial intermediate, 2-substituted benzamide (3). The products were subsequently cyclised to obtain quinazolones 4, chlorinated 5, then hooked to various optically pure alpha-amino acids to have 4,6-disubstituted quinazoline derivatives 6. All the derivatives 6 are screened for anti inflammatory and anti-cancer activity against U937 leukemia cell lines. Some of the compounds exhibited promising anti-cancer activity with reference to standard drug Etoposide. PMID- 17689838 TI - [Systemic granulomatosis--in perspective]. PMID- 17689839 TI - WITHDRAWN: A diet enriched in eicosapentanoic acid, gamma-linolenic acid and antioxidants in the prevention of new pressure ulcer formation in critically ill patients with lung injury: A randomized, prospective, controlled study. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published in Clin. Nutr., doi:10.1016/j.clnu.2007.06.015. The duplicate article has therefore been withdrawn. PMID- 17689840 TI - Short-term alanyl-glutamine dipeptide pretreatment in liver ischemia-reperfusion model: effects on microcirculation and antioxidant status in rats. AB - BACKGROUND & AIMS: Ischemia-reperfusion (I-R) injury is responsible for the morbidity associated with liver surgery. Production of toxic free radicals influences the microcirculation. The aim of our study was to examine the effect of glutamine (Gln) supplementation--adminstered in alanyl-glutamine dipeptide form--on liver function, immuno/histopathology and the oxidative state of the liver after injury. METHODS: Two-hundred and fifty grams male Wistar rats underwent normothermic, 60 min, segmental liver ischemia followed by 6 h of reperfusion. The animals (n = 45) were divided into three groups: sham operated, I-R and parenteral Gln pretreatment. Hepatic microcirculation was monitored by laser Doppler flowmetry. At the 6 h of reperfusion, histological alterations, TUNEL reaction, active caspase-3 reaction, serum and liver tissue antioxidant levels, serum ALAT, ASAT and TNF-alpha levels were measured. RESULTS: Upon reperfusion, the Gln group had significantly (p<0.05) higher flow rates than the I-R group and, at the end of the 6h of reperfusion, significantly (p<0.05) lower serum ALAT and ASAT levels. The liver chemiluminescent intensity was lower, free SH-groups were elevated, while the reducing power was decreased in the Gln pretreated group. Positive staining for caspase-3 after Gln pretreatment was significantly increased in contrast to the control tissues. CONCLUSION: Glutamine pretreatment is beneficial in supporting hepatic microcirculation and can prevent hepatocellular necrosis in liver reperfusion injury. PMID- 17689841 TI - A novel strategy to mimic discontinuous protective epitopes using a synthetic scaffold. AB - Although vaccines have been used for a long time and different types of vaccines have been developed, as yet no fully synthetic vaccines have been produced. The production of fully synthetic vaccines has probably not been realized so far due to the structural limitations of linear synthetic peptides to mimic the native shape of protein fragments which is often needed to induce protective antibodies. In this report we used the Bordetella pertussis protein pertactin as a model and show that a novel synthetic scaffold can be used to mimic structurally defined epitopes by confined presentation of several different peptide arms. Guided by modelling a construct was synthesized that induced protective antibodies directed towards a discontinuous epitope. This approach opens up the possibility to the design of new and fully synthetic vaccines that can induce protective antibodies. PMID- 17689842 TI - In vitro interactions between macrophages and aluminum-containing adjuvants. AB - Intramuscular administration of aluminum-adjuvanted vaccines induces an infiltration of aluminum-containing macrophages between muscle fibers. In vitro stimulation of human monocyte-derived macrophages with aluminum hydroxide (AlOOH) induces similar intracellular crystalline inclusions as well as phenotypical and functional modifications. We compared in this study the ability of other adjuvants to exert similar changes in macrophages in vitro. All mineral salts, i.e. aluminic (AlOOH, AlPO(4)) and non-aluminic mineral adjuvants (CaPO(4), FePO(4)) but not emulsion were able to increase macrophages capacity to potentiate autologous memory T lymphocyte proliferation, while only aluminic adjuvants induced CD83 expression and increased CD86 on macrophages. All together, this suggests that aluminic and non-aluminic adjuvants exerted their immunoactivities by distinct mechanisms on macrophages. PMID- 17689844 TI - Access to the frontal sinus and zygomatico frontal suture through the supratarsal fold. AB - Precise repositioning of a fractured zygoma is difficult. The traditional approach is through an eyebrow incision, but it can produce a scar that causes aesthetic and psychological problems for the patient. We describe the supratarsal fold approach to expose the frontozygomatic suture and to reduce small displacements of frontal sinus anterior wall; it gives good access and excellent aesthetic results. PMID- 17689845 TI - Accumulation of cyanobacterial toxins in freshwater "seafood" and its consequences for public health: a review. AB - This review summarizes and discusses the current understanding of human exposure to cyanobacterial toxins in "seafood" collected from freshwater and coastal areas. The review consists of three parts: (a) the existing literature on concentrations of cyanobacterial toxins in seafood is reviewed, and the likelihood of bioaccumulation discussed; (b) we derive cyanotoxin doses likely to occur through seafood consumption and propose guideline values for seafood and compare these to guidelines for drinking water; and (c) we discuss means to assess, control or mitigate the risks of exposure to cyanotoxins through seafood consumption. This is discussed in the context of two specific procedures, the food specific HACCP-approach and the water-specific Water Safety Plan approach by the WHO. Risks of exposure to cyanotoxins in food are sometimes underestimated. Risk assessments should acknowledge this and investigate the partitioning of exposure between drinking-water and food, which may vary depending on local circumstances. PMID- 17689846 TI - Risk perception and decision processes underlying informed consent to research participation. AB - According to the rational choice model, informed consent should consist of a systematic, step-by-step evaluation of all information pertinent to the treatment or research participation decision. Research shows that people frequently deviate from this normative model, however, employing decision-making shortcuts, or heuristics. In this paper we report findings from a qualitative study of 32 adolescents and (their) 31 parents who were recruited from two Northeastern US hospitals and asked to consider the risks of and make hypothetical decisions about research participation. The purpose of this study was to increase our understanding of how diabetic and at-risk adolescents (i.e., those who are obese and/or have a family history of diabetes) and their parents perceive risks and make decisions about research participation. Using data collected from adolescents and parents, we identify heuristic decision processes in which participant perceptions of risk magnitude, which are formed quickly and intuitively and appear to be based on affective responses to information, are far more prominent and central to the participation decision than are perceptions of probability. We discuss participants' use of decision-making heuristics in the context of recent research on affect and decision processes, and we consider the implications of these findings for researchers. PMID- 17689847 TI - Going to scale with community-based primary care: an analysis of the family health program and infant mortality in Brazil, 1999-2004. AB - This article assesses the effects of an integrated community-based primary care program (Brazil's Family Health Program, known as the PSF) on microregional variations in infant mortality (IMR), neonatal mortality, and post-neonatal mortality rates from 1999 to 2004. The study utilized a pooled cross-sectional ecological analysis using panel data from Brazilian microregions, and controlled for measures of physicians and hospital beds per 1000 population, Hepatitis B coverage, the proportion of women without prenatal care and with no formal education, low birth weight births, population size, and poverty rates. The data covered all the 557 Brazilian microregions over a 6-year period (1999-2004). Results show that IMR declined about 13 percent from 1999 to 2004, while Family Health Program coverage increased from an average of about 14 to nearly 60 percent. Controlling for other health determinants, a 10 percent increase in Family Health Program coverage was associated with a 0.45 percent decrease in IMR, a 0.6 percent decline in post-neonatal mortality, and a 1 percent decline in diarrhea mortality (p<0.05). PSF program coverage was not associated with neonatal mortality rates. Lessons learned from the Brazilian experience may be helpful as other countries consider adopting community-based primary care approaches. PMID- 17689848 TI - Thermal balneotherapy induces changes of the platelet serotonin transporter in healthy subjects. AB - Although the beneficial effects of balneotherapy have been recognized since a long time, a few information is available on the biological mechanisms underlying them and the subjective feelings of increased well-being and mood. The links between the serotonin (5-HT) system and mood prompted us to investigate the 5-HT platelet transporter (SERT), which is considered a reliable, peripheral marker of the same structure present in presynaptic neurons, in 20 healthy volunteers before (t0) and 30 min after (t1) thermal balneotherapy with ozonized water of Montecatini spa, as compared with a similar group who underwent a bath in non mineral water. The SERT was evaluated by means of the specific binding of (3)H paroxetine ((3)H-Par) to platelet membranes. Equilibrium-saturation binding data, the maximal binding capacity (Bmax) and the dissociation constant (Kd), were obtained by means of the Scatchard analysis. The results showed that, while Bmax values did not change in both groups, the Kd values decreased significantly at t1 only in those subjects who bathed in ozonized water. The results of this study, while showing a decrease of the dissociation constant (Kd) which is the inverse of affinity constant, of (3)H-Par binding to SERT in all subjects after balneotherapy and not in those bathing in normal water, suggest that SERT modifications may be related to a specific effect of ozonized water and, perhaps, also to the increased sense of well-being. PMID- 17689849 TI - The analytical epidemiology of obsessive-compulsive disorder: risk factors and correlates. AB - In this qualitative systematic review, we evaluate studies of the demographic, innate, and environmental risk factors and correlates associated with the development of Obsessive-Compulsive Disorder (OCD) in epidemiological samples. We found that a significant proportion of the studies indicate that late adolescence is a period of increased vulnerability for the development of OCD; that OCD affects predominantly female adults and male children and adolescents; that those who are unmarried or abusing drugs are more likely to present with OCD; that OCD is a familial and genetic disorder, particularly when one considers symptom dimensions instead of categorical diagnosis and when the disorder begins at an early age; and that individuals with OCD from the community, like those seen in clinical settings, may be especially prone to present psychiatric conditions such as mood and anxiety disorders. Although there are plenty of data on the correlates and risk factors of OCD in epidemiological samples, more research is needed on other potential risk factors, including obstetrical and pregnancy problems, pre-morbid neurocognitive functioning, and streptococcal infections, among others. PMID- 17689850 TI - Dietary isoflavones in the prevention of cardiovascular disease--a molecular perspective. AB - The Food and Drugs Administration has approved a health claim for soy based on clinical trials and epidemiological data indicating that high soy consumption is associated with a lower risk of coronary artery disease. Soy products contain a group of compounds called isoflavones, with genistein and daidzein being the most abundant. A number of cardioprotective benefits have been attributed to dietary isoflavones including a reduction in LDL cholesterol, an inhibition of pro inflammatory cytokines, cell adhesion proteins and inducible nitric oxide production, potential reduction in the susceptibility of the LDL particle to oxidation, inhibition of platelet aggregation and an improvement in vascular reactivity. There is increasing interest in the use of nutrigenomic methods to understand the mechanisms by which isoflavones induce these changes, and in the use of nutrigenetics to understand why the effects vary between individuals. Nutrigenomics is a rapidly growing field making use of molecular biology methodologies, such as microarray technology and proteomics, to study how specific nutrients or diets affect gene expression and cellular protein levels. The analysis of differential gene expression and protein levels in endothelial cells, macrophages and smooth muscle cells is critical to elucidating the sequence of events leading to the formation of atherosclerotic lesions, and to understanding the potential anti-atherogenic properties of soy isoflavones. An increasing number of studies demonstrate a significant impact of genetic variation on changes in cardiovascular risk factors in response to dietary intervention. Nutrigenetic effects of this type have recently been reported for dietary isoflavones, and may help to explain some of the disparities in the current literature concerning isoflavones and cardiovascular health. PMID- 17689851 TI - Tiered toxicity testing: evaluation of toxicity-based decision triggers for human health hazard characterization. AB - A set of biologically-based toxicity testing decision triggers was developed and analyzed within a tiered testing and decision-making framework for evaluating potential human health hazards and risks associated with chemical exposures. The proposed three-tiered toxicity testing approach starts from a base set of toxicity studies (acute toxicity, in vitro genetic toxicity, in vitro cytogenetics, repeat dose/subchronic toxicity, developmental toxicity, reproductive toxicity) and then uses the toxicity triggers to identify which specific additional tests are needed to adequately characterize a substance's hazard potential. The toxicity triggers were initially evaluated using published information for eight chemicals, representing diverse classes. A retrospective validation study was then conducted using seven chemicals which had completed the USEPA's Voluntary Children's Chemical Evaluation Program (VCCEP). The toxicity triggers were shown to identify appropriate higher tier tests and to be reasonably predictive of the results expected in higher tiered tests. Employing these toxicity triggers within a tiered testing framework could lead to a reduction in the number of laboratory animals without diminishing the degree of scientific certainty necessary for hazard evaluations. The toxicity triggers appear to be suitable for identifying which specific endpoints and tests warrant further evaluation, and which do not, and for documenting the scientific basis for such decisions. PMID- 17689852 TI - Context-dependent enhancement of declarative memory performance following acute psychosocial stress. AB - Studies on how acute stress affects learning and memory have yielded inconsistent findings, with some studies reporting enhancing effects while others report impairing effects. Recently, Joels et al. [Joels, M., Pu, Z., Wiegert, O., Oitzl, M.S., Krugers, H.J., 2006. Learning under stress: how does it work? Trends in Cognitive Sciences, 10, 152-158] argued that stress will enhance memory only when the memory acquisition phase and stressor share the same spatiotemporal context (i.e., context-congruency). The current study tested this hypothesis by looking at whether context-congruent stress enhances declarative memory performance. Undergraduates were assigned to a personality stress group (n=16), a memory stress group (n=18), or a no-stress control group (n=18). While being exposed to the acute stressor or a control task, participants encoded personality- and memory-related words and were tested for free recall 24h later. Relative to controls, stress significantly enhanced recall of context-congruent words, but only for personality words. This suggests that acute stress may strengthen the consolidation of memory material when the stressor matches the to-be-remembered information in place and time. PMID- 17689853 TI - Planned vaginal delivery of fetuses in breech presentation at term: prenatal determinants predictive of elevated risk of cesarean delivery during labor. AB - OBJECTIVE: Identify the prenatal determinants associated with cesarean delivery during labor of term breech presentation for which vaginal delivery is planned. STUDY DESIGN: Prospective study of 174 French and Belgian maternity units. Relations between cesarean and prenatal determinants were estimated with a multilevel logistic model and expressed as adjusted ORs. A prediction score for cesarean section was proposed and diagnostic values were estimated for different cutoff values. RESULTS: Of 2,478 women meeting the inclusion criteria, 705 (28.5%) had cesarean deliveries. Nulliparity, complete breech, rupture of membranes before labor, fetal weight > or = 3800 g, biparietal diameter > 95 mm and university and public non-teaching hospital maternity units were significantly associated with cesarean delivery during labor. The rate of cesarean during labor was significantly higher in establishments where more than 80% of women had planned cesareans and in cases where mode of delivery had not been decided before labor. The prediction score values ranged from 9 to 21.4 (10th, 50th and 90th percentiles corresponded to 10.1, 12.2 and 14.7). The cesarean rate was 43% in women whose score was greater than the cutoff point of 12.9, and 15% for women whose score was below this value. CONCLUSION: Our findings indicate that once vaginal delivery has been decided upon, the risk of cesarean delivery during labor for breech presentation at term depends not only on the progress of labor, but also on prenatal determinants both maternal and obstetrical. It also depends on some characteristics of the maternity units. Obstetricians should either plan cesarean delivery or define stringent rules for indications of cesarean during labor. PMID- 17689854 TI - Assessing hydrological impact of potential land use change through hydrological and land use change modeling for the Kishwaukee River basin (USA). AB - We connected a cellular, dynamic, spatial urban growth model and a semi distributed continuous hydrology model to quantitatively predict streamflow in response to possible future urban growth at a basin scale. The main goal was to demonstrate the utility of the approach for informing public planning policy and investment choices. The Hydrological Simulation Program-Fortran (HSPF) was set up and calibrated for the Kishwaukee River basin in the Midwestern USA and was repeatedly run with various land use scenarios generated either by the urban growth model (LEAMluc) or hypothetically. The results indicate that (1) the land use scenarios generated by LEAMluc result in little changes in total runoff but some noticeable changes in surface flow; (2) the argument that low flows tend to decrease with more urbanized areas in a basin was confirmed in this study but the selection of indicators for low flows can result in misleading conclusions; (3) dynamic simulation modeling by connecting a distributed land use change model and a semi-distributed hydrological model can be a good decision support tool demanding reasonable amount of efforts and capable of long-term scenario-based assessments. PMID- 17689855 TI - Characterization of an abdominal aortic velocity waveform in patients with abdominal aortic aneurysm. AB - Haemodynamics studies of abdominal aortic aneurysm require data on the velocity in the normal section of the aorta. Centreline velocity waveforms were measured in abdominal aortic aneurysm patients proximal to the aneurysm using spectral Doppler ultrasound. Characteristic points were automatically found on 21 of the waveforms and their parameters were used to create an archetypal centreline velocity waveform. The maximum velocity was 45 +/- 13 cm s(-1), the minimum velocity was -15 +/- 11 cm s(-1) and the maximum diastolic velocity was 2.7 +/- 4.7 cm s(-1). The velocity wave is suitable for use as an input to in vitro or in silico investigations of abdominal aortic aneurysm haemodynamics. PMID- 17689856 TI - Crosstalk between the glucocorticoid receptor and other transcription factors: molecular aspects. AB - Glucocorticoids (GCs) regulate cell fate by altering gene expression via the glucocorticoid receptor (GR). Ligand-bound GR can activate the transcription of genes carrying the specific GR binding sequence, the glucocorticoid response element (GRE). In addition, GR can modulate, positively or negatively, directly or indirectly, the activity of other transcription factors (TFs), a process referred to as "crosstalk". In the indirect crosstalk, GR interferes with transduction pathways upstream of other TFs. In the direct crosstalk, GR and other TFs modulate each other's activity when bound to the promoters of their target genes. The multiplicity of molecular actions exerted by TFs, particularly the GR, is not only fascinating in terms of molecular structure, it also implies that the TFs participate in a wide range of regulatory processes, broader than anticipated. This review focuses on the molecular mechanisms involved in the crosstalk, on both current ideas and unresolved questions, and discusses the possible significance of the crosstalk for the physiologic and therapeutic actions of GCs. PMID- 17689857 TI - Characterization of Tusc5, an adipocyte gene co-expressed in peripheral neurons. AB - Tumor suppressor candidate 5 (Tusc5, also termed brain endothelial cell derived gene-1 or BEC-1), a CD225 domain-containing, cold-repressed gene identified during brown adipose tissue (BAT) transcriptome analyses was found to be robustly expressed in mouse white adipose tissue (WAT) and BAT, with similarly high expression in human adipocytes. Tusc5 mRNA was markedly increased from trace levels in pre-adipocytes to significant levels in developing 3T3-L1 adipocytes, coincident with several mature adipocyte markers (phosphoenolpyruvate carboxykinase 1, GLUT4, adipsin, leptin). The Tusc5 transcript levels were increased by the peroxisome proliferator activated receptor-gamma (PPARgamma) agonist GW1929 (1microg/mL, 18h) by >10-fold (pre-adipocytes) to approximately 1.5-fold (mature adipocytes) versus controls (p<0.0001). Taken together, these results suggest an important role for Tusc5 in maturing adipocytes. Intriguingly, we discovered robust co-expression of the gene in peripheral nerves (primary somatosensory neurons). In light of the marked repression of the gene observed after cold exposure, these findings may point to participation of Tusc5 in shared adipose-nervous system functions linking environmental cues, CNS signals, and WAT BAT physiology. Characterization of such links is important for clarifying the molecular basis for adipocyte proliferation and could have implications for understanding the biology of metabolic disease-related neuropathies. PMID- 17689858 TI - Genistein sensitizes TRAIL-resistant human gastric adenocarcinoma AGS cells through activation of caspase-3. AB - The cytotoxic effect of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is limited in some cancer cells, including AGS gastric adenocarcinoma cells. However, treatment with TRAIL in combination with subtoxic concentrations of genistein sensitizes TRAIL-resistant AGS cells to TRAIL mediated apoptosis. Combined treatment with genistein and TRAIL-induced chromatin condensation and sub-G1 phase DNA content. These indicators of apoptosis are correlated with the activation of death receptors (DR5) and induction of caspase 3 activity, which results in the cleavage of poly(ADP-ribose)polymerase. Both the cytotoxic effect and apoptotic characteristics induced by combined treatment were significantly inhibited by z-DEVD-fmk, a caspase-3 inhibitor, which demonstrates the important role of caspase-3 in the observed cytotoxic effect. These results indicate that caspase-3 is a key regulator of apoptosis in response to combined genistein and TRAIL in human gastric adenocarcinoma AGS cells through the activation of DR5 and mitochondrial dysfunction. PMID- 17689859 TI - CHM-1 inhibits hepatocyte growth factor-induced invasion of SK-Hep-1 human hepatocellular carcinoma cells by suppressing matrix metalloproteinase-9 expression. AB - Clinical observations suggest that hepatocyte growth factor (HGF) can promote invasion and metastasis in hepatocellular carcinoma. In this study, we found that HGF-stimulated invasion of SK-Hep-1 cells, together with increased expression of matrix metalloproteinase (MMP)-9. CHM-1 was identified from 2-phenyl-4-quinolone derivatives to potently inhibit HGF-induced cell invasion, proteolytic activity, and expression of MMP-9. CHM-1 significantly inhibited tyrosine autophosphorylation of c-Met induced by HGF. CHM-1 also suppressed HGF-induced Akt phosphorylation, and NF-kappaB activation, the downstream regulators of HGF/c Met signaling, resulting in the inhibition of MMP-9. Thus, we suggest that CHM-1 is a potential therapeutic agent against tumor invasion. PMID- 17689860 TI - Application of titanate nanotubes for dyes adsorptive removal from aqueous solution. AB - The potential of adsorptive removal of basic dyes with titanate nanotubes (TNTs) and acid dyes with surfactant (hexadecyltrimethylammonium (HDTMA) chloride) modified TNTs were investigated. TNTs were prepared via a hydrothermal method and subsequently washed with HCl aqueous solutions of different concentrations. The prepared TNTs were then mediated by the HDTMA ions through the cation exchange process. Effects of acid washing and HDTMA-modified process on the revolution of microstructure and surface chemistry characteristics of TNTs were characterized with XRD, nitrogen adsorption-desorption isotherms, and FTIR. The adsorption capacities of two basic dyes (two acid dyes) on TNTs (their HDTMA-modified version) at initial dye concentration of 2000 mg/L were measured. It was experimentally concluded that if the amount of Na(+) in the TNTs was not very low, the TNTs and their HDTMA-modified version might be a good adsorbent for the removal of basic and acid dyes from aqueous solution through the cation and anion exchange mechanism, respectively. The adsorption capacity for basic and acid dyes could reach 380 and 400 mg/g, respectively. PMID- 17689861 TI - Mobility of copper in greenhouse soils. AB - The mobility of copper (Cu) was studied in 13 soil samples from greenhouses in Falasarna, northwestern Crete, Greece. The spatial variability of Cu concentration in greenhouse soils and their physicochemical characteristics were examined. The results showed that the concentrations varied considerably, between 15 and 4900 ppb. Sorption and leaching experiments--kinetic and equilibrium--were conducted in uncontaminated and contaminated soils, respectively. Both leaching and sorption equilibrium experiments were performed as a function of pH. The leaching experiment results indicated that the total dissolved Cu concentration was between 10 and 15 ppb at a pH of 7.5, which is below the drinking water standards. The results suggest that the kinetics of Cu leaching were fast and the leachate concentration was relatively low, whereas Cu sorption kinetics were rapid and the sorbed concentrations were significant. PMID- 17689862 TI - A membrane-based co-treatment strategy for the recovery of print- and beck-dyeing textile effluents. AB - This paper describes the final part of a study on the recovery of print- and beck dyeing wastewaters of the carpet manufacturing industry by membrane processes. These wastewaters had been previously treated separately where the print dyeing wastewaters were recovered by chemical precipitation followed by nanofiltration (NF) and beck-dyeing wastewaters were subjected to microfiltration (MF) and pH neutralization prior to NF. In this study, a co-treatment scheme after separate pre-treatment stages was adopted to simplify the overall process. The effect of mixing ratio on membrane fouling was also investigated. The co-treatment strategy was found advantageous since the number of NF units was minimized and the pH neutralization step in separate treatment of beck-dyeing wastewaters was eliminated, providing a reduction of chemical usage. PMID- 17689864 TI - Removal of Acid Violet 17 from aqueous solutions by adsorption onto activated carbon prepared from sunflower seed hull. AB - The adsorption of Acid Violet 17 (AV17) was carried out using various activated carbons prepared from sunflower seed hull (SSH), an agricultural solid waste by product. The effect of parameters such as agitation time, initial dye concentration, adsorbent dosage, pH and temperature were studied. The Langmuir and Freundlich isotherm models were applied and the Langmuir model was found to best report the equilibrium isotherm data. Langmuir adsorption capacity was found to be 116.27 mg/g. Kinetic data followed pseudo-second-order kinetics. Maximum colour removal was observed at pH 2.0. It was observed that the rate of adsorption improves with increasing temperature and the process is endothermic. The adsorbent surface was analysed with a scanning electron microscope. The results indicate that activated sunflower seed hull could be an attractive option for colour removal from dilute industrial effluents. PMID- 17689866 TI - Clinical course of chronic pelvic pain in women. AB - A follow-up study on a cohort of women with chronic pelvic pain (CPP) was conducted, to evaluate the clinical course and to identify factors associated with outcome. Participants were over 18 years of age and had initially visited a multidisciplinary CPP-team of a Gynaecological Department of a University Hospital. The course of chronic pelvic pain was evaluated using the Life Chart Interview (LCI) method. All participants completed questionnaires covering demographic and clinical characteristics, pain (McGill) and psychological distress (SCL-90) at baseline and follow up. The response rate was 60%. A survival analysis was conducted. After a mean follow-up period of 3.4 years, 18 women (25%) of the study sample (N=72) reported recovery from pelvic pain (i.e. pelvic pain for less than 3 months per year). Eight of these 18 women (11% of the total sample) reported no pain at all at follow up. Relapse of symptoms was not encountered. Not any demographic, clinical or pain related variable measured at baseline, nor any intervention between baseline and follow up, was associated with outcome. Our results indicate that chronic pelvic pain in women in secondary care is a longstanding condition. Further research is recommended to identify risk factors for persistence of symptoms. PMID- 17689865 TI - Population-based cohort study of incident and persistent arm pain: role of mental health, self-rated health and health beliefs. AB - To investigate whether somatising tendency, low mood and poor self-rated health (SRH) predict incident arm pain, and whether these factors and beliefs about causation and prognosis predict symptom persistence, we conducted an 18-month postal follow-up in 1798 working-aged subjects, sampled from the registers of five British general practices. At baseline questions were asked about pain in the arm (lasting >or=1day in the prior 12months), mental health (Short-Form 36 (SF-36MH)), somatising tendency (the Brief Symptom Inventory (BSI)), SRH, and beliefs about causation and prognosis. At follow-up we asked about arm pain in the last four weeks, and whether it had been present on >or=14days. Associations with incidence and persistence were explored using logistic regression. The 1256 participants (70% response) comprised 613 free of, and 643 with, arm pain initially. Among the former, 21% reported new pain at follow-up, while 53% of the latter reported symptom persistence. The odds of both incident and persistent arm pain were significantly raised (1.7- to 4-fold) in the least vs. most favourable bands of SF-36MH, BSI and SRH. Even stronger associations were found for arm pain on >or=14days. Persistent pain was significantly more common among those who attributed their pain to work or stress, and in those who expected symptoms still to be a problem in 12months. Thus, SRH and mental health indices were strong predictors of incident and persistent arm pain in adults from the community, while persistence was also predicted by beliefs about causation and prognosis. PMID- 17689867 TI - Multivariate statistical analysis of electron energy-loss spectroscopy in anisotropic materials. AB - Recently, an expression has been developed to take into account the complex dependence of the fine structure in core-level electron energy-loss spectroscopy (EELS) in anisotropic materials on specimen orientation and spectral collection conditions [Y. Sun, J. Yuan, Phys. Rev. B 71 (2005) 125109]. One application of this expression is the development of a phenomenological theory of magic-angle electron energy-loss spectroscopy (MAEELS), which can be used to extract the isotropically averaged spectral information for materials with arbitrary anisotropy. Here we use this expression to extract not only the isotropically averaged spectral information, but also the anisotropic spectral components, without the restriction of MAEELS. The application is based on a multivariate statistical analysis of core-level EELS for anisotropic materials. To demonstrate the applicability of this approach, we have conducted a study on a set of carbon K-edge spectra of multi-wall carbon nanotube (MWCNT) acquired with energy-loss spectroscopic profiling (ELSP) technique and successfully extracted both the averaged and dichroic spectral components of the wrapped graphite-like sheets. Our result shows that this can be a practical alternative to MAEELS for the study of electronic structure of anisotropic materials, in particular for those nanostructures made of layered materials. PMID- 17689868 TI - Treating retardation effects in valence EELS spectra for Kramers-Kronig analysis. AB - Retardation effects such as Cerenkov losses and waveguide modes alter the valence electron energy-loss spectrum of semiconductors and insulators as soon as the speed of the probing electron exceeds the speed of light inside the probed medium. This leads to the dilemma, that optical properties from these media cannot be determined correctly using electron energy-loss spectrometry (EELS) if no corrections are applied. In this work we present two ways out of this dilemma: a reduction of the beam energy and the application of an off-line correction. We demonstrate the accuracy of these two methods by using two similar layers of Si(x):H having slightly different refractive indices and discuss the impact of the normalization parameter during Kramers-Kronig analysis (KKA) on the obtained dielectric properties. We further demonstrate that KKA can be applied without the use of standard specimens, if thickness determination using transmission electron microscopy and EELS is accurate enough. PMID- 17689869 TI - Seroprevalence of Toxoplasma gondii antibodies in wild carnivores from Spain. AB - Serum samples from 282 wild carnivores from different regions of Spain were tested for antibodies to Toxoplasma gondii by the modified agglutination test using a cut-off value of 1:25. Antibodies to T. gondii were found in 22 of 27 (81.5%) of Iberian lynx (Lynx pardinus), 3 of 6 European wildcats (Felis silvestris), 66 of 102 (64.7%) red foxes (Vulpes vulpes), 15 of 32 (46.9%) wolves (Canis lupus), 26 of 37 (70.3%) Eurasian badgers (Meles meles), 17 of 20 (85.0%) stone martens (Martes foina), 4 of 4 pine martens (Martes martes), 6 of 6 Eurasian otters (Lutra lutra), 4 of 4 polecats (Mustela putorius), 1 of 1 ferret (Mustela putorius furo), 13 of 21 (61.9%) European genets (Genetta genetta), and 13 of 22 (59.1%) Egyptian mongooses (Herpestes ichneumon). Serological results indicated a widespread exposure to T. gondii among wild carnivores in Spain. The high T. gondii seroprevalence in Iberian lynx and the European wildcat reported here may be of epidemiologic significance because seropositive cats might have shed oocysts. PMID- 17689870 TI - The effect of dietary protein supplementation on the pathophysiology of Haemonchus contortus infection in West African Dwarf goats. AB - The effect of dietary protein on the pathophysiology of Haemonchus contortus infection in reproducing first pregnancy West African Dwarf (WAD) goats was studied. Eighteen 10-12-month-old pubertal female WAD goats divided into two equal groups were used and confined separately. One group was maintained on high protein diet (HPD) while the other was maintained on low-protein diet (LPD) from day 1 of pregnancy up to week 6 post-partum. Each animal was infected with 600 infective larvae of H. contortus weekly for 4 weeks and blood collected by jugular venipuncture for the determination of packed cell volume and serum proteins. The results of the study showed that improved protein nutrition significantly enhanced the level of serum albumin (p<0.05). It also significantly lowered the level of serum globulin (p<0.05) that otherwise would be high in haemonchosis. However, improvement in the dietary protein level appeared not to have any effect on the packed cell volume and total serum protein level. PMID- 17689871 TI - Engineering the enantioselectivity of glutathione transferase by combined active site mutations and chemical modifications. AB - Based on the crystal structure of human glutathione transferase M1-1, cysteine residues were introduced in the substrate-binding site of a Cys-free mutant of the enzyme, which were subsequently alkylated with 1-iodoalkanes. By different combinations of site-specific mutations and chemical modifications of the enzyme the enantioselectivity in the conjugation of glutathione with the epoxide containing substrates 1-phenylpropylene oxide and styrene-7,8-oxide were enhanced up to 9- and 10-fold. The results also demonstrate that the enantioselectivity can be diminished, or even reversed, by suitable modifications, which can be valuable under some conditions. The redesign of the active-site structure for enhanced or diminished enantioselectivities have divergent requirements for different epoxides, calling for a combinatorial approach involving alternative mutations and chemical modifications to optimize the enantioselectivity for a targeted substrate. This approach outlines a general method of great potential for fine-tuning substrate specificity and tailoring stereoselectivity of recombinant enzymes. PMID- 17689872 TI - Tandir burns: a severe cause of burns in rural Turkey. AB - Tandir is the name given to an oven used for baking bread in the eastern and south-eastern part of Anatolia. Tandir burn is a special kind of burns in which primarily women and small children fall in it and have deep extensive burns (TBSA %). The records of 60 patients with tandir burn who were treated in our Burn Center from September 1999 to January 2006 were reviewed. The patients consisted of 9.2% of all burned patients. The mean age was 17.10 years (1-60 years) and 61.50% of the patients were female. The mean total body surface area (TBSA) burned was 21.09% (6-58) and 88% of the patients had third-degree burns. Eight of the patients underwent amputation of an extremity, 10 had fasciotomies, and 25 partial thickness skin grafts. The mean hospitalization period was 31.64 days (3 73 days). Fifteen patients (25%) died. Tandir burn is a severe kind of burn with a higher morbidity and mortality. PMID- 17689873 TI - Cortisol secretory activity in older people in relation to positive and negative well-being. AB - Secretion of the hormone cortisol, a physiological correlate of affect, has been studied mostly in relation to negative states, especially stress. By contrast, policy initiatives aimed at older populations now routinely emphasise well-being and a 'positive ageing' perspective. In this study, we examined diurnal salivary cortisol profiles from 50 active seniors recruited into a wider community research project (mean age 74 years; 34 F/16 M). Participants' wrist activity was continuously monitored by actimeters in their homes over a 48 h period. During this time two diurnal cycles of cortisol data were collected (8 samples per day); with actimeter data providing a compliance check in regard to timing of self administered saliva collections. Prior to the trial, participants had completed the GHQ-30 which was scored separately to yield both positive and negative well being scores which matched closely normative data from over 6000 cases in a large survey. Our data suggest that positive and negative psychological well-being are quite strongly and inversely correlated. However, neither on their own was associated with basal levels of cortisol. Rather, for cortisol secretion in the 45-min period following awakening, but not during the rest of the day, we found a significant interaction between positive and negative well-being (p<0.024). Further analysis of this interaction showed that among participants low on negative well-being, higher positive well-being was significantly associated with lower cortisol; equally, among participants high on positive well-being, lower negative well-being was significantly associated with lower cortisol. Thus, a powerful synergy seemed to be operating in this early morning period such that cortisol secretion was 27% lower in participants with both higher-than-average positive well-being and lower-than-average negative well-being (comprising 34% of the sample). We conclude that cortisol secretion in the first 45 min following awakening is distinct from the rest of the day and most able to discriminate well being states. PMID- 17689874 TI - Bullying and fighting among adolescents--do drinking motives and alcohol use matter? AB - The present study investigates the direct and indirect links (through alcohol use) between adolescents' drinking motives and violent behaviors (i.e. bullying and fighting). Structural equation models were estimated based on a national representative sample of 5419 8th to 10th graders in Switzerland (mean age 15.0, SD=.86). Results demonstrate that enhancement motives were only indirectly linked (through alcohol use) to violent behaviors, whereas coping motives were both directly and indirectly linked, particularly among girls. No consistent link was found for social motives. Despite the negative indirect link (through alcohol use), conformity motives were the strongest predictor of bullying and fighting among boys, and even stronger than alcohol use itself. To conclude, drinking motives have a bearing on other problem behaviors besides excessive drinking, and may be useful for early identification and intervention for students who are likely to experience a variety of problems. PMID- 17689875 TI - Predicting violence among cocaine, cannabis, and alcohol treatment clients. AB - In this study, the relationship between the use of various substances, selected psychosocial characteristics, and violence was examined. Groups of subjects in treatment for a primary problem with cocaine (n=300), cannabis (n=128), alcohol (n=110), other drugs (33), tobacco (n=249) or gambling (n=199) completed a self administered questionnaire. The questionnaire included questions on various psychosocial scales (i.e., aggressive personality, chronic stress, sleep problems, impulsivity, disrespect for the law and social supports), frequency of drug and alcohol use, and violence in the past year. For the univariate analyses, all of the drug and psychosocial variables were significantly related to violence. In the multivariate analyses, frequency of cocaine and alcohol use, disrespect for the law, aggressive personality, age and sex were significantly related to violence. The findings point to multi-causal explanations; however, both alcohol and cocaine use appear to play a significant role in explaining violence. PMID- 17689876 TI - Nutrient-sensitive, antagonistically pleiotropic genes and their contribution to malignant behavior. AB - Recent evidence from microarray data argues that much of the malignant potential of neoplastic cells is a result of either somatic initiating mutations or constitutional polymorphisms present in normal tissue. Consequently, we reasoned that the initiating genetic lesions seen in some of the Phakomatoses, disorders associated with predominantly benign neoplasms, may somehow fundamentally limit malignant behavior (invasion and metastasis). The function of these genes reveals a consistent pattern of antagonistic pleiotropy; they inhibit proliferation but are critical for motility. We argue that inactivating mutations in these genes (labeled RPPMs: repressors of proliferation/promoters of motility) results in predominantly benign growths because, while such mutations promote unconstrained proliferation, they limit the ability of neoplastic cells to migrate and invade. Such pleiotropy may represent an evolutionarily conserved strategy designed to limit the spread of nascent neoplasias. When not inactivated, we show how selective pressures in the tumor microenvironment would suppress mutation in these genes during progression and how wild-type RPPMs may function synergistically with oncogenes to promote malignant behavior. Finally, we explore how this model may help to explain oncogene addiction, tumor dormancy, and spontaneous regression. PMID- 17689877 TI - A Darwinian approach to Huntington's disease: subtle health benefits of a neurological disorder. AB - Huntington's disease (HD) is a neurodegenerative disorder that, unlike most autosomal dominant disorders, is not being selected against. One explanation for the maintenance of the mutant HD allele is that it is transparent to natural selection because disease symptoms typically occur subsequent to an individual's peak reproductive years. While true, this observation does not explain the population-level increase in HD. The increase in HD is at least partly the result of enhanced fitness: HD+ individuals have more offspring than unaffected relatives. This phenomenon has previously been explained as the result of elevated promiscuity of HD+ individuals. For this to be true, disease symptoms must be expressed during the otherwise asymptomatic peak reproductive years and promiscuity must increase offspring production; however, neither prediction is supported by data. Instead, new data suggest that the mutant HD allele bestows health benefits on its carriers. HD+ individuals show elevated levels of the tumor suppressor protein p53 and experience significantly less cancer than unaffected siblings. We hypothesize that the mutant HD allele elevates carriers' immune activity and thus HD+ individuals are, on average, healthier than HD- individuals during reproductive years. As health and reproductive output are positively related, data suggest a counterintuitive relationship: health benefits may lead to an increased prevalence of Huntington's disease. PMID- 17689878 TI - Keloids do not harbor EBV or HHV8. PMID- 17689879 TI - Hemochromatosis: a Neolithic adaptation to cereal grain diets. AB - The Neolithic period in Europe marked the transition from a hunter-gatherer diet rich in red meat to an iron-reduced cereal grain diet. This dietary shift likely resulted in an increased incidence of iron deficiency anemia, especially in women of reproductive age. I propose that hereditary hemochromatosis and in particular the common HFE C282Y mutation may represent an adaptation to decreased dietary iron in cereal grain-based Neolithic diets. Both homozygous and heterozygous carriers of the HFE C282Y mutation have increased iron stores and therefore possessed an adaptive advantage under Neolithic conditions. An allele age estimate places the origin of the HFE C282Y mutation in the early Neolithic period in Northern Europe and is thus consistent with this hypothesis. The lower incidence of this mutation in other agrarian regions (the Mediterranean and Near East) may be due to higher dietary intakes of the iron uptake cofactor vitamin C in those regions. The HFE C282Y mutation likely only became maladaptive in the past several centuries as dietary sources of iron and vitamin C improved in Northern Europe. PMID- 17689880 TI - Variation in adherence to external beam radiotherapy quality measures among elderly men with localized prostate cancer. AB - PURPOSE: To characterize the variation in adherence to quality measures of external beam radiotherapy (EBRT) for localized prostate cancer and its relation to patient and provider characteristics in a population-based, representative sample of U.S. men. METHODS AND MATERIALS: We evaluated EBRT quality measures proposed by a RAND expert panel of physicians among men aged >or=65 years diagnosed between 2000 and 2002 with localized prostate cancer and treated with primary EBRT using data from the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare program. We assessed the adherence to five EBRT quality measures that were amenable to analysis using SEER-Medicare data: (1) use of conformal RT planning; (2) use of high-energy (>10-MV) photons; (3) use of custom immobilization; (4) completion of two follow-up visits with a radiation oncologist in the year after therapy; and (5) radiation oncologist board certification. RESULTS: Of the 11,674 patients, 85% had received conformal RT planning, 75% had received high-energy photons, and 97% had received custom immobilization. One-third of patients had completed two follow-up visits with a radiation oncologist, although 91% had at least one visit with a urologist or radiation oncologist. Most patients (85%) had been treated by a board-certified radiation oncologist. CONCLUSIONS: The overall high adherence to EBRT quality measures masked substantial variation in geography, socioeconomic status in the area of residence, and teaching affiliation of the RT facility. Future research should examine the reasons for the variations in these measures and whether the variation is associated with important clinical outcomes. PMID- 17689881 TI - Clinical evaluation of targeting accuracy of gamma knife radiosurgery in trigeminal neuralgia. AB - PURPOSE: The efficiency of radiosurgery is related to its highly precise targeting. We assessed clinically the targeting accuracy of radiosurgical treatment with the Leksell Gamma Knife for trigeminal neuralgia. We also studied the applied radiation dose within the area of focal contrast enhancement on the trigeminal nerve root following radiosurgery. METHODS AND MATERIALS: From an initial group of 78 patients with trigeminal neuralgia treated with gamma knife radiosurgery using a 90-Gy dose, we analyzed a subgroup of 65 patients for whom 6 month follow-up MRI showed focal contrast enhancement of the trigeminal nerve. Follow-up MRI was spatially coregistered to the radiosurgical planning MRI. Target accuracy was assessed from deviation of the coordinates of the intended target compared with the center of enhancement on postoperative MRI. Radiation dose delivered at the borders of contrast enhancement was evaluated. RESULTS: The median deviation of the coordinates between the intended target and the center of contrast enhancement was 0.91 mm in Euclidean space. The radiation doses fitting within the borders of the contrast enhancement of the trigeminal nerve root ranged from 49 to 85 Gy (median value, 77 +/- 8.7 Gy). CONCLUSIONS: The median deviation found in clinical assessment of gamma knife treatment for trigeminal neuralgia is low and compatible with its high rate of efficiency. Focal enhancement of the trigeminal nerve after radiosurgery occurred in 83% of our patients and was not associated with clinical outcome. Focal enhancement borders along the nerve root fit with a median dose of 77 +/- 8.7 Gy. PMID- 17689882 TI - Radiation therapy for cutaneous squamous cell carcinoma involving the parotid area lymph nodes: dose and volume considerations. AB - PURPOSE: The intraparotid and periparotid lymph nodes are the most commonly involved when skin cancer of the head and neck metastasizes beyond the primary site. We sought to report the clinical outcome of patients treated with radiation therapy for parotid-area metastases from cutaneous squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: The records of 36 patients treated with radiation therapy for cutaneous squamous cell carcinoma involving the parotid area lymph nodes were reviewed. All patients had clinically N0 necks and were without evidence of distant disease. Thirty patients (83%) were treated postoperatively after gross total tumor resection. Median dose to the parotid area was 60 Gy (range, 50-72 Gy). Treatment of clinically N0 necks consisted of surgical dissection (7 patients), irradiation (15 patients), and observation (14 patients). RESULTS: The 5-year estimate of local (parotid) control was 86% in patients treated using surgery with postoperative therapy and 47% in patients treated using radiation therapy alone. Three of 4 patients with tumors that relapsed locally after surgery and postoperative radiation received a dose of less than 60 Gy. Elective neck irradiation decreased the incidence of subsequent nodal failures from 50% to 0% and significantly improved neck control (p < 0.001). The 5-year overall survival rate was 63%. CONCLUSIONS: Surgery followed by radiation therapy to doses of at least 60 Gy results in effective local control for patients with parotid area metastasis from cutaneous squamous cell carcinoma. Routine irradiation of the clinically N0 neck is recommended. PMID- 17689883 TI - Prognostic value of abnormal p53 expression in locally advanced prostate cancer treated with androgen deprivation and radiotherapy: a study based on RTOG 9202. AB - PURPOSE: The goal of this study was to verify the significance of p53 as a prognostic factor in Radiation Therapy Oncology Group 9202, which compared short term androgen deprivation (STAD) with radiation therapy (RT) to long-term androgen deprivation + RT in men with locally advanced prostate cancer (Pca). METHODS AND MATERIALS: Tumor tissue was sufficient for p53 analysis in 777 cases. p53 status was determined by immunohistochemistry. Abnormal p53 expression was defined as 20% or more tumor cells with positive nuclei. Univariate and multivariate Cox proportional hazards models were used to evaluate the relationships of p53 status to patient outcomes. RESULTS: Abnormal p53 was detected in 168 of 777 (21.6%) cases, and was significantly associated with cause specific mortality (adjusted hazard ratio [HR] = 1.89; 95% confidence interval (CI) 1.14 - 3.14; p = 0.014) and distant metastasis (adjusted HR = 1.72; 95% CI 1.13-2.62; p = 0.013). When patients were divided into subgroups according to assigned treatment, only the subgroup of patients who underwent STAD + RT showed significant correlation between p53 status and cause-specific mortality (adjusted HR = 2.43; 95% CI = 1.32-4.49; p = 0.0044). When patients were divided into subgroups according to p53 status, only the subgroup of patients with abnormal p53 showed significant association between assigned treatment and cause-specific mortality (adjusted HR = 3.81; 95% CI 1.40-10.37; p = 0.0087). CONCLUSIONS: Abnormal p53 is a significant prognostic factor for patients with prostate cancer who undergo short-term androgen deprivation and radiotherapy. Long-term androgen deprivation may significantly improve the cause-specific survival for those with abnormal p53. PMID- 17689884 TI - TGFB1 single nucleotide polymorphisms are associated with adverse quality of life in prostate cancer patients treated with radiotherapy. AB - PURPOSE: To investigate whether the presence of single nucleotide polymorphisms (SNPs) located within TGFB1 might be predictive for the development of adverse quality-of-life outcomes in prostate cancer patients treated with radiotherapy. METHODS AND MATERIALS: A total of 141 prostate cancer patients treated with radiotherapy were screened for SNPs in TGFB1 using DNA sequencing. Three quality of-life outcomes were investigated: (1) prospective decline in erectile function, (2) urinary quality of life, and (3) rectal bleeding. Median follow-up was 51.3 months (range, 12-138 months; SD, 24.4 months). RESULTS: Those patients who possessed either the T/T genotype at position -509, the C/C genotype at position 869 (pro/pro, codon 10) or the G/C genotype at position 915 (arg/pro, codon 25) were significantly associated with the development of a decline in erectile function compared with those who did not have these genotypes: 56% (9 of 16) vs. 24% (11 of 45) (p = 0.02). In addition, patients with the -509 T/T genotype had a significantly increased risk of developing late rectal bleeding compared with those who had either the C/T or C/C genotype at this position: 55% (6 of 11) vs. 26% (34 of 130) (p = 0.05). CONCLUSIONS: Possession of certain TGFB1 genotypes is associated with the development of both erectile dysfunction and late rectal bleeding in patients treated with radiotherapy for prostate cancer. Therefore, identification of patients harboring these genotypes may represent a means to predict which men are most likely to suffer from poor quality-of-life outcomes after radiotherapy for prostate cancer. PMID- 17689885 TI - Health-related quality-of-life outcomes following IMRT versus conventional radiotherapy for oropharyngeal squamous cell carcinoma. AB - PURPOSE: To compare health-related quality-of-life (HRQOL) outcomes of patients with oropharyngeal squamous cell carcinoma treated using intensity-modulated radiotherapy (IMRT) vs. conventional radiotherapy (CRT). PATIENTS AND METHODS: Patients with oropharyngeal squamous cell carcinoma were extracted from the database of an ongoing longitudinal Outcome Assessment Project. Eligible criteria included (1) treated with definitive radiation, and (2) provided 12-month posttreatment HRQOL data. Excluded were 7 patients who received IMRT before October 1, 2002, during this institution's developmental phase of the IMRT technique. The HRQOL outcomes of patients treated with IMRT were compared with those of patients who received CRT. RESULTS: Twenty-six patients treated using IMRT and 27 patients treated using CRT were included. Patients in the IMRT group were older and had more advanced-stage diseases and more patients received concurrent chemotherapy. However, the IMRT group had higher mean Head and Neck Cancer Inventory scores (which represent better outcomes) for each of the four head-and-neck cancer-specific domains, including eating, speech, aesthetics, and social disruption, at 12 months after treatment. A significantly greater percentage of patients in the CRT group had restricted diets compared with those in the IMRT group (48.0% vs. 16.0%, p = 0.032). At 3 months after treatment, both groups had significant decreases from pretreatment eating scores. However, the IMRT group had a significant improvement during the first year, but the CRT group had only small improvement. CONCLUSIONS: Proper delivery of IMRT can improve HRQOL for patients with oropharyngeal cancer compared with CRT. PMID- 17689886 TI - Failure to achieve a PSA level or=2 months of neoadjuvant luteinizing hormone releasing hormone agonist therapy in patients scheduled to undergo external beam radiotherapy for localized prostate carcinoma is associated with reduced biochemical failure-free survival. METHODS AND MATERIALS: A retrospective case note review of consecutive patients with intermediate- or high-risk localized prostate cancer treated between January 2001 and December 2002 with neoadjuvant hormonal deprivation therapy, followed by concurrent hormonal therapy and radiotherapy was performed. Patient data were divided for analysis according to whether the PSA level in Week 1 of radiotherapy was 1 ng/mL in 52. At a median follow-up of 49 months, the 4-year actuarial biochemical failure-free survival rate was 84% vs. 60% (p = 0.0016) in favor of the patients with a PSA level after neoadjuvant hormonal deprivation therapy of 1 ng/mL at the beginning of external beam radiotherapy after >or=2 months of neoadjuvant luteinizing hormone-releasing hormone agonist therapy have a significantly greater rate of biochemical failure and lower survival rate compared with those with a PSA level of 0.999) within test ranges. The developed method showed good repeatability for the quantification of six investigated nucleobases in Cordyceps with intra- and inter day variations of less than 9.0 and 9.1%, respectively. The validated method was successfully applied to quantify bio-available nucleosides in natural and cultured Cordyceps, which is helpful to control their quality. PMID- 17689910 TI - Analysis of cephalosporin antibiotics. AB - A comprehensive review with 276 references for the analysis of members of an important class of drugs, cephalosporin antibiotics, is presented. The review covers most of the methods described for the analysis of these drugs in pure forms, in different pharmaceutical dosage forms and in biological fluids. PMID- 17689911 TI - [Chryseobacterium indologenes bacteremia in a patient with systemic corticosteroid therapy]. PMID- 17689912 TI - [Is it necessary to reevalue the risk of a gas embolism complicating an intervention with carbon dioxide insufflation?]. PMID- 17689913 TI - One shot spinal is not a good solution for pain relief during labor. PMID- 17689914 TI - [Respiratory distress revealing a diaphragmatic hernia during a caesarean section]. PMID- 17689915 TI - [Peripheral nerve block in orthopaedic surgery: multicentric evaluation of practicing professionals and impact on the activity of the recovery room]. AB - OBJECTIVES: Since the last national survey on evaluation of professional practice in France, many peripheral nerve blocks techniques were developed. The aim of this study was to assess the place of such techniques and their impact on the stay in recovery room after orthopaedic surgery. STUDY DESIGN: Prospective, multicentric study. PATIENTS AND METHODS: Consecutive patients receiving a regional anaesthetic technique for orthopaedic surgery over a 15-day period were included in this multicenter study (four private clinics, two non-university and three university hospitals). Characteristics of blocks, duration of stay and activity of nurses in post-anaesthetic care unit (PACU) were recorded for each patient. RESULTS: A total of 289 blocks performed in 283 patients were analyzed. A regional anaesthetic technique was performed alone or associated with a light sedation (58 and 8% respectively) or with a general anaesthesia (44%). A continuous peripheral nerve block (mainly for femoral and iliofascial blocks) was performed in 25% of patients, mostly in university hospital and private clinics (35 and 26% respectively), but only in 3% of cases in non-university hospital. Mean duration of PACU stay was 64+/-67 minutes. This time was longer when regional anaesthesia was associated to or performed after general anaesthesia. Workload of nurses was a simple supervision in 47% of the cases (in 61% of patients receiving regional anaesthesia alone vs 21% in those with general anaesthesia, p<0.05). CONCLUSION: This survey confirms that peripheral nerve block became widely used in orthopaedic surgery. This decreases the medical workload in PACU, especially for distal upper limb surgery. Regional anaesthetic techniques must be well taught during formation cursus of residents. PMID- 17689916 TI - [Assessment of management practices for women with early-stage breast cancer]. AB - OBJECTIVE: To improve management of patients with breast cancer by providing healthcare professionals with a discussion tool based on an assessment of their local practices compared with national guidelines. METHOD: Retrospective survey assessing the medical files of all patients who had surgery for ductal carcinoma of the breast (maximum diameter<2 cm) in any Strasbourg hospital during the second quarter of 2002. Cases were identified from the central medical database (PMSI). Procedures were compared with national guidelines and results discussed with the healthcare professionals involved. RESULTS: In all, 154 women were referred to 19 surgeons at 8 hospitals (public: 3; private: 5) between April 1 and June 30, 2002. The number of procedures per surgeon during this period ranged from 1 to 33. Surgery occurred within the recommended time from radiologic diagnosis (i.e.<4 weeks) in only 26% of cases. There was no preoperative diagnostic staging for 14%, and no preliminary discussion at multidisciplinary team meetings for 36%. In 36% of standard axillary lymph node dissections, fewer than 10 lymph nodes were cleared. Intraoperative radiography was not mentioned for 42% of subjects with microcalcifications. The pTNM status was not reported in 44% of histology reports from 15 experienced pathologists, surgical margins were not documented in 13%, and information on vascular invasion was missing from 54%. Finally, 30% of patients received lower doses of radiation therapy than recommended. CONCLUSION: Important differences between hospitals showed the need for improvement of several processes. Better coordination between surgeons and pathologists is essential. The results of this survey point out the value of external evaluation processes to sensitize professionals and improve the overall management of patients with breast cancer. PMID- 17689917 TI - Aeromonas hydrophila AH-3 AexT is an ADP-ribosylating toxin secreted through the type III secretion system. AB - We cloned and sequenced an ADP-ribosylating toxin (AexT) from a mesophilic Aeromonas hydrophila strain AH-3 with a type III secretion system (T3SS). This toxin only showed homology, in genes and proteins, with the first half of A. salmonicida AexT. The A. hydrophila AexT showed ADP-ribosyltransferase activity, translocation through the T3SS system, and this A. hydrophila T3SS system is inducible under calcium-depleted conditions. The A. hydrophila aexT mutant showed a slight reduction in their virulence assayed by several methods when compared to the wild-type strain, while an A. hydrophila T3SS mutant is highly reduced in virulence on the same assays. The A. hydrophila AexT is the first described and the smallest T3SS effector toxin found in mesophilic Aeromonas with a functional T3SS. PMID- 17689918 TI - mtDNA evidence: genetic background associated with related populations at high risk for esophageal cancer between Chaoshan and Taihang Mountain areas in China. AB - There are three major geographic regions in China known for their high incidences of esophageal cancer (EC): the Taihang Mountain range of north-central China, the Minnan area of Fujian province, and the Chaoshan plain of Guangdong province. Historically, waves of great population migrations from north-central China through coastal Fujian to the Chaoshan plain were recorded. To study the genetic relationship among the related EC high-risk populations, we analyzed mitochondrial DNA (mtDNA) haplogroups based on 30 EC patients from Chaoshan and used control samples from the high-risk populations, including 48, 73, and 89 subjects from the Taihang, Fujian, and Chaoshan areas, respectively. The principal component of all haplogroups, correlation analysis of haplogroup frequency distributions between populations, and haplogroup D network analysis showed that compared with other Chinese populations, populations in the three studied areas are genetically related. The highest haplogroup frequency shared by all studied populations was haplogroup D, with much higher frequency in the Chaoshan area EC patients. The majority of haplogroup D individuals among the Chaoshan area EC patients belonged to subhaplogroups D4a and D5a, with the total frequency of these two haplogroups significantly higher than that in the high risk population in the same area (chi(2)=9.017, p<0.01). In conclusion, EC high risk populations in these three areas share a similar matrilineal genetic background, and D4a and D5a might be candidate genetic markers for screening populations susceptible to EC in the Chaoshan area. Ours is the first report to show the association between mtDNA haplogroups (D4a and D5a) and esophageal cancer. PMID- 17689919 TI - Bisphenol-A and chlorinated derivatives in adipose tissue of women. AB - Bisphenol-A (BPA) and chlorinated derivatives (Cl(x)BPA) were investigated in adipose tissue of women in Southeast Spain. BPA was above limit of detection (LOD) in 11 out of 20 samples (55%). Among Cl(x)BPA, Cl(2)BPA was the most frequent (80%) and abundant, constituting 94.6% of total chlorinated BPA in adipose tissue. Mean +/- S.D. of BPA, monochloro-BPA (ClBPA), dichloro-BPA (Cl(2)BPA), and trichloro-BPA (Cl(3)BPA) were 5.83 +/- 3.48, 3.05 +/- 0.28, 9.21 +/- 9.26, and 0.74 +/- 0.15 ng/g of adipose tissue, respectively. No tetrachloro BPA (Cl(4)BPA) was found above LOD. There are no published data on BPA in human adipose tissue or on Cl(x)BPA in adipose tissue or blood, limiting comparisons. BPA levels were similar (w/w) to findings in blood (w/v) in other populations and below levels reported in placenta tissue (w/w). Because of the estrogen mimicking effects of BPA and its Cl(x)BPA, further research is needed to explore their combined effects on human health and trends in human exposure. PMID- 17689920 TI - Acquisition of uncharacterized sequences from Candidatus liberibacter, an unculturable bacterium, using an improved genomic walking method. AB - An effective PCR-based genomic walking approach is described to discover previously unknown flanking genomic DNA sequences from Candidatus Liberibacter asiaticus, an unculturable, phloem-limited bacterium. Using this technique, 8564bp of new DNA sequences were obtained from three genomic loci; tufB-secE-nusG rplKAJL-rpoBC gene cluster, omp gene (outer membrane protein, Omp) and 16/23S rRNA gene in Ca. L. asiaticus. These, together with publicly available Ca. Liberibacter sequences, are clustered into five contigs and two singlets representing 24,477 non-redundant base pairs. BLAST annotation predicts 12 full length genes, two partial genes and one pseudogene among these sequences. The sequences obtained in this study provide new genome information about Ca. Liberibacter that will facilitate development of new genome-based detection tools. The technique described here can also be employed to acquire new genomic information for other unculturable or fastidious organisms for which available sequences are limited or for filling sequence gaps between known flanking genomic DNA sequences. PMID- 17689921 TI - Baseline behavior, but not sensitivity to stimulant drugs, differs among spontaneously hypertensive, Wistar-Kyoto, and Sprague-Dawley rat strains. AB - Deficits in temporal processing are implicated in Attention Deficit Hyperactivity Disorder (ADHD) for which the most common rodent model is the Spontaneously Hypertensive Rat (SHR). To assess strain differences in temporal processing, males and females of the SHR, Wistar-Kyoto (WKY), and Sprague-Dawley (SD) strains were compared on two timing tasks: one requiring maintenance of a lever press for 10-14 s (TRD, temporal response differentiation) and the other requiring withholding of a lever press for 10-14 s (DRL, differential reinforcement of low rates). Performance of the progressive ratio (PR) task more directly assessed food-motivated behavior. Strains did not differ in task acquisition; however, steady state TRD and DRL performance of the SHR and WKY strains was less accurate which was related to increased burst (non-timing related) responses in those strains relative to the SD. PR performance demonstrated that the SHR and WKY strains exhibited higher response rates and breakpoints than the SD. Subsequently, methylphenidate (1, 3.25, 4.50, 7.50, and 12.0 mg/kg) and d amphetamine (0.1, 0.25, 0.65, 1.0, and 2.0 mg/kg) were administered intraperitoneally pre-testing. Both drugs disrupted TRD and DRL performances by increasing burst response frequency; however, the strains were not differentially sensitive to either drug. Strain differences were generally maintained throughout the drug and extinction portions of the study. These results indicate increased similarity between the SHR and WKY strains relative to the SD in performance of timing and motivation tasks. Further, the current results do not support continued use of the SHR as a model for ADHD. PMID- 17689922 TI - Rapid bioprosthetic valve degeneration resulting in severe mitral stenosis. AB - A 61-year-old man presented 9 months after bioprosthetic mitral valve implantation with progressive exertional dyspnea. Transesophageal echocardiography revealed severe mitral stenosis with diffuse leaflet thickening but no calcification. Subsequent pathologic examination of the valve demonstrated infiltrating fibroconnective tissue and chronic inflammation. Careful echocardiographic follow-up of this valve type may be warranted, especially in patients with early recurrent symptoms. PMID- 17689923 TI - Reliability of tarsal bone segmentation and its contribution to MR kinematic analysis methods. AB - The purpose of this study was to determine the reliability of tarsal bone segmentation based on magnetic resonance (MR) imaging using commercially available software. All tarsal bones of five subjects were segmented five times each by two operators. Volumes and second moments of volume were calculated and used to determine the intra- as well as interoperator reproducibility. The results show that these morphological parameters had excellent interclass correlation coefficients (>0.997) indicating that the presented tarsal bone segmentation is a reliable procedure and that operators are in fact interchangeable. The consequences on differences in MR kinematic analysis methods of segmentation due to repetition were also determined. It became evident that one analysis method--fitting surface point clouds--was considerable less affected by repeated segmentation (cuboid: up to 0.2 degrees, other tarsal bones up to 0.1 degrees) compared to a method using principal axes (cuboid up to 6.7 degrees, other tarsal bones up to 0.8 degrees). Thus, the former method is recommended for investigations of tarsal bone kinematics by MR imaging. PMID- 17689925 TI - Sprouty2 binds Grb2 at two different proline-rich regions, and the mechanism of ERK inhibition is independent of this interaction. AB - Sprouty2 has been widely implicated in the negative regulation of the fibroblast growth factor receptor-extracellular regulated kinase (ERK) pathway. Sprouty2 directly interacts with the adapter protein Grb2, member of the receptor tyrosine kinase-induced signaling pathways. In considering the functional role of Grb2, we investigated whether the interaction with this protein was responsible for ERK pathway inhibition. We found that the binding between Sprouty2 and Grb2 is constitutive, independent of Sprouty2 tyrosine phosphorylation, although it is increased when fibroblast growth factor receptor is activated. This connection is mediated by the N-terminal SH3 domain of Grb2 and two Sprouty2 proline-rich stretches (residues 59-64 and 303-307). Most importantly, a double Sprouty2 mutant (hSpry2 P59AP304A), which is unable to bind Grb2, developed at a similar inhibition level of fibroblast growth factor receptor-ERK pathway than that which originated from Sprouty2 wt. These results are evidence that the Sprouty2 mechanism of ERK inhibition is independent of Grb2 binding. PMID- 17689924 TI - Lysophosphatidic acid modulates c-Met redistribution and hepatocyte growth factor/c-Met signaling in human bronchial epithelial cells through PKC delta and E-cadherin. AB - Previously we demonstrated that ligation of lysophosphatidic acid (LPA) to G protein-coupled LPA receptors induces transactivation of receptor tyrosine kinases (RTKs), such as platelet-derived growth factor receptor beta (PDGF-Rbeta) and epidermal growth factor receptor (EGF-R), in primary cultures of human bronchial epithelial cells (HBEpCs). Here we examined the role of LPA on c-Met redistribution and modulation of hepatocyte growth factor (HGF)/c-Met pathways in HBEpCs. Treatment of HBEpCs with LPA-induced c-Met serine phosphorylation and redistribution to plasma membrane, while treatment with HGF-induced c-Met internalization. Pretreatment with LPA reversed HGF-induced c-Met internalization. Overexpression of dominant negative (Dn)-PKC delta or pretreatment with Rottlerin or Pertussis toxin (PTx) attenuated LPA-induced c-Met serine phosphorylation and redistribution. Co-immnuoprecipitation and immunocytochemistry showed that E-cadherin interacted with c-Met in HBEpCs. LPA treatment induced E-cadherin and c-Met complex redistribution to plasma membranes. Overexpression of Dn-PKC delta attenuated LPA-induced E-cadherin redistribution and E-cadherin siRNA attenuated LPA-induced c-Met redistribution to plasma membrane. Furthermore, pretreatment of LPA attenuated HGF-induced c-Met tyrosine phosphorylation and downstream signaling, such as Akt kinase phosphorylation and cell motility. These results demonstrate that LPA regulates c Met function through PKC delta and E-cadherin in HBEpCs, suggesting an alternate function of the cross-talk between G-protein-coupled receptors (GPCRs) and RTKs in HBEpCs. PMID- 17689926 TI - Regulation of myostatin signaling by c-Jun N-terminal kinase in C2C12 cells. AB - Myostatin, a member of the transforming growth factor beta (TGF-beta) superfamily, is a negative regulator of skeletal muscle growth. We found that myostatin could activate c-Jun N-terminal kinase (JNK) signaling pathway in both proliferating and differentiating C2C12 cells. Using small interfering RNA (siRNA) mediated activin receptor type IIB (ActRIIB) knockdown, the myostatin induced JNK activation was significantly reduced, indicating that ActRIIB was required for JNK activation by myostatin. Transfection of C2C12 cells with TAK1 specific siRNA reduced myostatin-induced JNK activation. In addition, JNK could not be activated by myostatin when the expression of MKK4 was suppressed with MKK4-specific siRNA, suggesting that TAK1-MKK4 cascade was involved in myostatin induced JNK activation. We also found that blocking JNK signaling pathway by pretreatment with JNK specific inhibitor SP600125, attenuated myostatin-induced upregulation of p21 and downregulation of the differentiation marker gene expression. Furthermore, it was also observed that the presence of SP600125 almost annulled the growth inhibitory role of myostatin. Our findings provide the first evidence to reveal the involvement of JNK signaling pathway in myostatin's function as a negative regulator of muscle growth. PMID- 17689927 TI - Transgenic fruit-flies expressing a FRET-based sensor for in vivo imaging of cAMP dynamics. AB - 3'-5'-cyclic adenosine monophosphate (cAMP) is a ubiquitous intracellular second messenger that mediates the action of various hormones and neurotransmitters and influences a plethora of cellular functions. In particular, multiple neuronal processes such as synaptic plasticity underlying learning and memory are dependent on cAMP signalling cascades. It is now well recognized that the specificity and fidelity of cAMP downstream effects are achieved through a tight temporal as well as spatial control of the cAMP signals. Approaches relying on real-time imaging and Fluorescence Resonance Energy Transfer (FRET)-based biosensors for direct visualization of cAMP changes as they happen in intact living cells have recently started to uncover the fine details of cAMP spatio temporal signalling patterns. Here we report the generation of transgenic fruit flies expressing a FRET-based, GFP-PKA sensor and their use in real-time optical recordings of cAMP signalling both ex vivo and in vivo in adult and developing organisms. These transgenic animals represent a novel tool for understanding the physiology of the cAMP signalling pathway in the context of a functioning body. PMID- 17689928 TI - Localization of the serotonergic terminal fields modulating seizures in the genetically epilepsy-prone rat. AB - Serotonin (5-HT) has been shown to exert antiepileptic effects in a variety of generalized convulsive seizure models, particularly the genetically epilepsy prone rat (GEPR). The present study was designed to identify the region/site(s) where 5-HT exerts anticonvulsant effects in the GEPR-9, a model in which sound evoked generalized tonic-clonic seizures (GTCS) are highly sensitive to manipulations in 5-HT concentration. Because the 5-HT reuptake inhibitor, fluoxetine, was known to exert anticonvulsant effects in GEPR-9s via a 5-HT dependent mechanism, we utilized selective regional 5-HT depletion in combination with systemic fluoxetine administration to find the site where a 5-HT deficit would prevent the anticonvulsant action of fluoxetine. Widespread destruction of serotonergic terminal fields or regionally specific terminal field destruction was achieved using intracerebroventricular and more target specific infusions of 5,7-dihydroxytryptamine. The capacity of fluoxetine to suppress seizures in GEPR 9s following a loss of 5-HT was then examined. The present findings show the anticonvulsant action of fluoxetine is markedly attenuated following the loss of midbrain 5-HT, particularly in the region of the superior colliculus, while forebrain and spinal cord 5-HT do not appear to play a role in the action of fluoxetine. The importance of the deep layers of the SC was confirmed by demonstrating that direct microinfusion of fluoxetine into the SC can suppress seizures in rats pretreated with the 5-HT(1A) receptor antagonist pindolol. PMID- 17689929 TI - Tobacco, alcohol and cannabis use in Tunisian patients with schizophrenia. PMID- 17689930 TI - Trends in psychiatric hospitalisation of people with schizophrenia: a register based investigation over the last three decades. AB - The number of psychiatric beds has declined considerably in many countries over the past decades. Long-term studies on the impact of these health care changes for the severely mentally ill, however, are still scarce. This epidemiological study investigates the use of inpatient psychiatric services by people with schizophrenia, compared to that by people with other mental disorders. We used psychiatric register data of the Swiss canton Zurich to establish the annual treatment prevalence in the period 1977-2004. For patients with psychoses, the length of inpatient episodes decreased by half. The annual number of inpatient admissions doubled. The proportion of schizophrenia patients, which accounted for 36%-41% of all inpatient treatments up to 1993, dropped to 20% in 2004, while that of other psychoses remained about the same (8%-10%) throughout the study period. This contrasts with a 2-3 fold increase in other patient groups. The annual treatment prevalence for people with schizophrenia declined from 7.3 to 2.2 per 10000 population since the 1990s and affected patients of all ages and of both sexes equally. The treatment prevalence for other psychoses remained virtually unchanged (1.3 per 10000). For all other mental disorders, there was an up to twofold increase. The study suggests that the downsizing of psychiatric hospitals has resulted in a far-reaching redistribution of overall inpatient treatment resources. The considerable decrease in inpatient treatment for people with schizophrenia emphasizes the need to further investigate the current state of coverage for and the appropriateness of health care available to this patient group. PMID- 17689931 TI - Treatment of negative symptoms of schizophrenia using repetitive transcranial magnetic stimulation in a double-blind, randomized controlled study. AB - OBJECTIVE: To verify whether high-frequency rTMS applied above the area of the left prefrontal cortex in 15 stimulation sessions with maximum stimulation intensity is able to modify negative symptoms of schizophrenia in a double-blind, randomized controlled study. METHODS: Twenty-two patients with schizophrenia stabilized on antipsychotic medication with prominent negative symptoms were included in the trial. They were divided into two groups: eleven were treated with effective rTMS and eleven with ineffective "sham" rTMS. The ineffectiveness of the sham rTMS was achieved through the stimulation coil position. Stimulation was applied to the left dorsolateral prefrontal cortex. The stimulation frequency was 10 Hz. Stimulation intensity was 110% of the motor threshold intensity. Each patient received 15 rTMS sessions on 15 consecutive working days. Each daily session consisted of 15 applications of 10-second duration and 30-second intervals between sequences. There were 1500 stimuli per session. RESULTS: During real rTMS treatment a statistically significant decrease of negative symptoms was found (approximately 29% reduction in the PANSS negative symptom subscale and 50% reduction in the SANS). No adverse events occurred during therapy except for a mild headaches. In sham rTMS treatment a decrease of negative symptoms was also identified, but to a lesser extent than in real rTMS (about 7% in negative subscale PANSS and 13% in SANS). The change in SANS achieved statistical significance. Mutual comparison revealed a greater decrease of negative symptoms in favor of real rTMS in contrast to sham rTMS. CONCLUSION: The augmentation of rTMS enabled patients to experience a significant decrease in the severity of the negative symptoms. Our results support the therapeutic potential of rTMS at higher frequency for negative symptoms of schizophrenia. PMID- 17689932 TI - Targeting TNFalpha rapidly reduces density of dendritic cells and macrophages in psoriatic plaques with restoration of epidermal keratinocyte differentiation. AB - BACKGROUND: The cytokine network theory for psoriasis postulates a key role for TNFalpha in mediating inflammation and altered epidermal differentiation. OBJECTIVE: This study defines responses following administration of adalimumab, a TNFalpha inhibitor, in pre-psoriatic skin (PN) and lesional psoriatic plaques (PP) skin. METHODS: PN and PP skin before and after treatment were biopsied at days 2, 7, 28 and 84 (n=6 different patients). Cryosections were immunohistochemically stained to detect TNFalpha and other relevant markers in epidermal and dermal compartments. Detection of apoptosis utilized antibody specific for activated caspase 3. Semiquantitative assessments and statistical analysis was performed for each staining profile. RESULTS: TNFalpha+ cells were increased in PP skin. PP skin was also characterized by a four-fold increase in number of CD68+ macrophages as well as eight-fold increase in CD11c+ dermal dendritic cells (DCs) compared to PN skin. By two-color immunofluorescence staining, both CD68+ cells as well as CD11c+ cells expressed TNFalpha. Following initiation of adalimumab therapy, CD11c+ cells, significantly decreased in PP skin at days 7, 28, and 84, while CD68+ and CD14+ cells decreased at days 28 and 84. Other markers for DCs (CD83, CD86) showed decreases at days 7, 28, and 84. Reduction in DCs, macrophages or T cells was not accompanied by increased activated caspase 3-positive cells. When a keratinocyte terminal differentiation marker was examined, adalimumab triggered rapid restoration of loricrin expression (beginning on day 2), with loss of aberrant differentiation marker, keratin 17 (K17). CONCLUSION: Adalimumab impacts dermal-based immunocytes, and the epidermal compartment also responds by restoration of normal differentiation without detectable apoptosis. PMID- 17689933 TI - Bacteraemia in febrile neutropenic cancer patients. AB - A total of 2142 patients with febrile neutropenia resulting from cancer chemotherapy were registered in two observational studies and followed prospectively in different institutions. There were 499 (23%) patients with bacteraemia who are reviewed here. The relative frequencies of Gram-positive, Gram-negative and polymicrobial bacteraemias were 57%, 34% and 10% with respective mortality rates of 5%, 18% and 13%. Mortality rates were significantly higher in bacteraemic patients than in non-bacteraemic patients; a trend for higher mortality was observed (without reaching statistical significance) in those patients in whom bacteraemia was associated with a clinical site of infection compared to bacteraemic patients without any clinical documentation. Prophylactic antibiotics but not granulopoiesis stimulating factors were associated with a lower incidence of Gram-negative bacteraemia; however, neither prophylactic approach influenced the subsequent rate of complications in the patients who developed bacteraemia. The present study also confirms that the MASCC scoring system can identify a group of bacteraemic patients with a relatively low risk of complications and death (MASCC >/=21). On the other hand, in patients with very low levels of the MASCC score (<15), and then with predicted very unfavourable risk, the rate of complications and death was dramatically high, irrespective of the microbiological nature of the bacteraemia. PMID- 17689934 TI - Persistent regional frontotemporal hypoactivity in violent offenders at follow up. AB - Since cross-sectional brain-imaging studies demonstrating frontotemporal cerebral hypoactivity in violent offenders have generally been carried out around the time of trial and sentencing, the findings might be influenced by the stressful situation of the subjects. It seems that no group of offenders with this finding has yet been followed longitudinally. We have re-examined nine offenders convicted of lethal or near-lethal violence in whom single photon emission tomography (SPECT) previously had demonstrated frontotemporal hypoperfusion. The mean interval between the initial and the follow-up examination was 4 years. The initially observed hypoactivity was found to have remained virtually unchanged at follow-up: no mean change in the group exceeded 5% in 12 assessed regions of interest. Although preliminary due to the small sample size, this study suggests that frontotemporal brain hypoactivity is a trait rather than a state in perpetrators of severe violent crimes. PMID- 17689935 TI - Construction of cDNA library of cotton mutant Xiangmian-18 library during gland forming stage. AB - Gossypol, a secondary metabolite stored in the glands of cotton, protecting cottonseed from consumption of human and monogastric animal. This ability is unique to the tribe Gossypieae. Although the relationship between gossypol and pigment gland has been studied for a long time, the development mechanism of pigment gland has not been investigated at molecular level. Here we described a simple and efficient method for constructing a normalized cDNA library from a cotton mutant, Xiangmian-18, during its pigments gland forming stage. It combined switching mechanism at 5'-end of RNA transcript (SMART) technique and duplex specific nuclease (DSN) normalization methods. In a model experiment, double stranded cDNAs were synthesized from mRNAs, processed by normalization and Sfi I restriction endonuclease, and finally the cDNAs were ligated to pDNR-LIB vector. The ligation mixture was transformed into E. coli JM109 by electroporation. Counting the number of colonies, the titer of the original library was 5.86x10(5)cfu/ml in this library. Electrophoresis gel results indicated the fragments ranged from 800bp to 2kb, with the average size of 1400bp. Random picking clones showed that the recombination rate was 94%. The results showed that the cDNA library constructed successfully was a full-length library with high quality, and could be used to screen the genes related to development of pigments gland cottons. PMID- 17689936 TI - Acute and chronic consequences of non-pulsatile blood flow pattern in long-term total artificial heart experiment. AB - Vessel pulsation is presumably a key physiological function for the optimal supply of peripheral tissues and vital organs by oxygen and nutrients. The absence of pulsatility might impair the peripheral perfusion stability and trigger microvascular dysfunction of vital organs. The main purpose of this study was to investigate the influence of non-pulsatile flow on the microcirculation in experimental goat with implanted undulation pump total artificial heart (UPTAH). A microscopic system (Keyence, Japan) for the direct observation of the microcirculation of bulbar conjunctiva was used. Following the acute flow pattern change (from pulsatile to non-pulsatile one), the number of perfused capillaries decreased significantly (from 34.7+/-6.3 to 19.7+/-4.1 number of capillaries/mm; P<0.05). The velocity of erythrocytes dropped (from 526+/-83 to 132+/-41mum/s; P<0.05). The velocity of erythrocytes and capillary density were only partly recovered, when the pulsatile flow mode was restored. Histopathological analysis after 33 days of pumping in non-pulsatile mode revealed the presence of chronic venostasis, tissue edema, hemorrhages, hypoxia and ischemic necroses in the tissue samples from liver, kidneys and lung. These findings could be regarded as a direct effect of the chronic non-pulsatile pumping mode and inadequate blood supply. We conclude that the presence of pulsatile flow should be considered as a vital condition for a successful long-term survival after total artificial heart implantation. PMID- 17689937 TI - Particle radiotherapy in the UK. PMID- 17689938 TI - Polymer coating of quantum dots--a powerful tool toward diagnostics and sensorics. AB - The use of quantum dots for biological and biomedical applications is one of the fastest moving fields of nanotechnology today. The unique optical properties of these nanometer-sized semiconductor crystals make them an exciting fluorescent tool for in-vivo and in-vitro imaging as well as for sensoric applications. To apply them in biological fluids or aqueous environment it is essential to modulate the chemical nature of quantum dot surfaces to alter their solubility and add additional chemical functionalities. By employing different coating technologies they cannot only be rendered water soluble but also functionalized to fulfill different tasks, like receptor targeting or sensing of low molecular weight substances. To achieve this goal different polymeric coatings are applied to provide solubility in water and additional functional groups for attachment. Taken together the versatile modifications described in this review make quantum dots a promising alternative to conventional fluorescent dyes and may offer possibilities for new future developments. PMID- 17689939 TI - Resveratrol enhances proliferation and osteoblastic differentiation in human mesenchymal stem cells via ER-dependent ERK1/2 activation. AB - In the present study, we investigated the in vitro effect of resveratrol (RSVL), a polyphenolic phytoestrogen, on cell proliferation and osteoblastic maturation in human bone marrow-derived mesenchymal stem cell (HBMSC) cultures. RSVL (10(-8) 10(-5) M) increased cell growth dose-dependently, as measured by [(3)H]-thymidine incorporation, and stimulated osteoblastic maturation as assessed by alkaline phosphatase (ALP) activity, calcium deposition into the extracellular matrix, and the expression of osteoblastic markers such as RUNX2/CBFA1, Osterix and Osteocalcin in HBMSCs cell cultures. Further studies found that RSVL (10(-6)M) resulted in a rapid activation of both extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) signaling in HBMSCs cultures. The effects of RSVL were mimicked by 17beta-estrodial (10(-8) M) and were abolished by estrogen receptor (ER) antagonist ICI182780. An ERK1/2 pathway inhibitor, PD98059, significantly attenuated RSVL-induced ERK1/2 phosphorylation, consistent with the reduction of cell proliferation and osteoblastic differentiation as well as expression of osteoblastic markers. In contrast, SB203580, a p38 MAPK pathway blocker, blocked RSVL-induced p38 phosphorylation, but resulted in an increase of cell proliferation and a more osteoblastic maturation. These data suggest that RSVL stimulates HBMSCs proliferation and osteoblastic differentiation through an ER-dependent mechanism and coupling to ERK1/2 activation. PMID- 17689940 TI - Comparison of the estrogenic potencies of standardized soy extracts by immature rat uterotrophic bioassay. AB - Soy phytoestrogens, isoflavones, are a primary class of plant-based estrogen alternatives being sold over the counter nowadays. Genistein, daidzein and glycitein are the major isoflavones found in soybeans, as aglycones and glycosides. Each isoflavone shows distinctive estrogenic activity and pharmacokinetics. Soy dry extracts, employed as pharmaceutical raw material for manufacturing isoflavone supplements, are standardized to contain 40% of total isoflavones, but the amount of each isoflavone is highly diverse. The influence of these compositional differences on the estrogenic potency of soy extracts was evaluated by uterotrophic bioassay. Five commercial samples of standardized soy dry extract, homogeneously suspended in arachis oil, were administered per os in serial doses (125-4150 mg/kg bw/day) to immature female rats for 3 days. Soy extract samples with considerable diversity in isoflavone composition revealed different estrogenic potencies. Our results indicate a need of standardization of the individual isoflavone content in soy extracts. PMID- 17689941 TI - Antidyslipidemic activity of polyprenol from Coccinia grandis in high-fat diet fed hamster model. AB - Ethanol extract of Coccinia grandis (L.) Voigt showed significant triglyceride (TG) and cholesterol-lowering effects in dyslipidemic hamster model. Ethanolic extract was fractionated into chloroform, n-butanol and water-soluble fractions and were evaluated. Activity was proved to be concentrated in chloroform-soluble fraction. Chloroform-soluble fraction containing active component was subjected to repeated column chromatography, furnished a polyprenol characterized as C(60) polyprenol (1) isolated for the first time from this plant. It significantly decreased serum TG by 42%, total cholesterol (TC) 25% and glycerol (Gly) 12%, accompanied HDL-C/TC ratio 26% in high-fat diet (HFD)-fed dyslipidemic hamsters at the dose of 50mg/kg body weight. Results are comparable to standard drug fenofibrate at the dose of 108 mg/kg. Based on these investigations, it was concluded that the compound polyprenol (1) isolated from leaves of C. grandis possess marked antidyslipidemic activity. PMID- 17689942 TI - Umbelliprenin from Ferula szowitsiana inhibits the growth of human M4Beu metastatic pigmented malignant melanoma cells through cell-cycle arrest in G1 and induction of caspase-dependent apoptosis. AB - Metastatic malignant melanoma have a bad prognosis (median survival: 6-8 months) mainly due to the development of lung, hepatic and brain metastases. In this study we have used the resazurin reduction test and FACS analysis to assess the cytostatic and cytotoxic effect of umbelliprenin from Ferula szowitsiana (Apiaceae) on human solid cancer cells and human primary fibroblasts. We have observed that the cell susceptibility to umbelliprenin decreases in the order M4Beu (metastatic pigmented malignant melanoma)>A549 (nonsmall cell lung carcinoma) approximately PC3 (androgen-resistant prostate carcinoma)>PA1 (ovary teratocarcinoma)>human primary fibroblasts approximately MCF7 (breast adenocarcinoma)>DLD1 (colon adenocarcinoma). M4Beu cell-proliferation is inhibited through cell-cycle arrest in G1 and induction of caspase-dependent apoptosis. The finding that the cytotoxic effect of umbelliprenin is markedly more pronounced in M4Beu cells than in primary fibroblasts, suggests a therapeutic margin. As M4Beu cell proliferation is more potently inhibited by umbelliprenin (IC50 12.3 microM) than by the citrus coumarin auraptene (7 geranyloxycoumarin, IC50 17.1 microM) previously reported capable of inhibiting the prevalence of lung metastasis in mice bearing B16BL6 murine melanoma, our data suggest that umbelliprenin orally administered and foods and folk medicines containing this coumarin, may afford protection against the development and early recurrence of malignant melanoma. In vivo investigations are needed to test these hypotheses. PMID- 17689943 TI - The gastric ulcer protective and healing role of cysteine proteinases from Carica candamarcensis. AB - Latex from Caricaceae contains proteolytic enzymes localized in the fruit, which are used ethnopharmacologically to treat digestive disorders. Some of these proteins display proliferative properties when probed with mammalian cells, suggesting a role in the reconstruction of wounded tissue. We tested the efficacy of a proteolytic fraction derived from Carica candamarcensis, designated as P1G10 in experimental rodent models, to protect and heal chemically induced gastric ulcers. The protective effect of oral administration of P1G10 fraction was analyzed in indomethacin-treated Wistar animals. The healing effect of P1G10 was studied following sub-serous injection of acetic acid in a Wistar rat model. The results show that P1G10 between 0.1 and 10 mg/kg protect indomethacin but not ethanol-induced gastric ulcers. The maximal protection attained was 67% with 10 mg/kg of P1G10. The healing rate by 10 mg/kg of P1G10 using the acetic acid ulcerogenic model is similar to that of omeprazole (10 mg/kg) or ranitidine (100 mg/kg). The effect of P1G10 at 10 mg/kg seems to be mediated by an increase in the mucus content by 25% and stimulation of angiogenesis by 64% in a manner similar to growth factors. These results confirm the protective and healing role of proteinases from C. candamarcensis. PMID- 17689944 TI - Ginseng modifies the diabetic phenotype and genes associated with diabetes in the male ZDF rat. AB - Asian ginseng (Panax ginseng) and its close relative North American ginseng (Panax quinquefolius) are perennial aromatic herbs that are widely used in Oriental medicine and have been acclaimed to have various health benefits including diabetes treatment. In this study, we compared the effects of a diet containing rosiglitazone to a diet containing ginseng (Panax quinquefolius) in male Zucker diabetic fatty (ZDF) rats. Animals were assigned to one of three diets: control, rosiglitazone (0.1 g/1 kg diet), or ginseng (10 g/1 kg diet). During the 11-week study, body weight, food intake, organ weight, blood glucose, plasma cholesterol, and plasma triglyceride levels were evaluated. Animals treated with rosiglitazone or ginseng exhibited increased body weight (p<0.05) and decreased kidney weight (p<0.05) compared to control animals. The rosiglitazone group demonstrated decreased food intake and plasma triglyceride levels versus the other groups (p<0.05). The ginseng group revealed decreased cholesterol levels relative to the control group (p<0.05). Furthermore, ginseng and rosiglitazone had marked effects on the expression of genes involved in PPAR actions and triglyceride metabolism compared to controls. In conclusion, ginseng modified the diabetic phenotype and genes associated with diabetes in the male ZDF rat. These data are encouraging, and warrant further research to determine the therapeutic value of this medicinal herb in treating human diabetes. PMID- 17689945 TI - Piper longum Linn. Extract inhibits TNF-alpha-induced expression of cell adhesion molecules by inhibiting NF-kappaB activation and microsomal lipid peroxidation. AB - Recruitment of specific leukocyte subpopulations at the site of inflammation requires a series of cell adhesion molecule (CAM)-mediated interactions. The major CAMs, viz., intercellular adhesion molecule-1 (ICAM-1), VCAM-1 and E selectin are expressed on endothelium in response to various cytokines or bacterial LPS. Here, we have evaluated the effect of Piper longum chloroform extract (PlCE) on TNF-alpha-induced expression of ICAM-1 on endothelial cells and on NADPH-catalyzed rat liver microsomal lipid peroxidation with a view to identify modulators for the expression of CAMs. We demonstrate that PlCE inhibits adhesion of neutrophils to endothelial monolayer. This inhibition is due to the ability of PlCE to significantly block the TNF-alpha-induced expression of CAMs, i.e. ICAM-1, VCAM-1 at 17.5 microg/ml concentration and E-selectin at 15 microg/ml concentration on human umbilical vein endothelial cells. The inhibition of ICAM-1, VCAM-1 and E-selectin by PlCE is mediated through inhibition of NF kappaB in endothelial cells. To demonstrate the antioxidant activity of PlCE, we showed that PlCE inhibited the NADPH-catalyzed rat liver microsomal lipid peroxidation significantly. These results suggest a possible mechanism of anti inflammatory as well as antioxidant activity of PlCE. PMID- 17689946 TI - Increased degradation of extracellular matrix structures of lacrimal glands implicated in the pathogenesis of Sjogren's syndrome. AB - Lacrimal glands (LGs) of male non-obese diabetic (NOD) mice display many features of human LGs in patients afflicted with the autoimmune disease Sjogren's syndrome (SS), including the loss of secretory functions and a lymphocytic infiltration into the glands by 4 months of age. So far, research has mainly focused on the intracellular events that are involved in initiating LG dysfunction; however, the impact of SS on extracellular matrix (ECM) structures of the diseased LGs has not yet been determined. In this study we identified and compared LG ECM formation and integrity of age-matched male healthy (BALB/c) and diseased (NOD) mice. LG tissues were examined using routine histological, biochemical, immunohistochemical and gene expression analysis. Multiphoton imaging and second harmonic generation (SHG) microscopy permitted the non-invasive analysis of major LG ECM structures including collagen- and elastin-containing fibers. Biochemical testing demonstrated a significant loss of collagen, glycosaminoglycans and desmosine in NOD LGs when compared to healthy BALB/c LGs. Immunohistochemical staining and gene expression analysis confirmed this disease-related alteration of LG ECM structures. Furthermore, laser-induced autofluorescence and SHG microscopy revealed dramatic changes in the structural organization of most collagenous and elastic fibers of the diseased LG tissues that were more pronounced than those displayed by histological analysis. Our results clearly show an enhanced degradation of ECM proteins accompanied by the severe disorganization and deformation of ECM structures of diseased LG tissues. These new insights into the involvement of ECM degradation in SS may lead to novel therapies for patients suffering from dry eye disease. PMID- 17689947 TI - Initiation of maintenance treatment with salmeterol/fluticasone propionate 50/100 microg bd versus fluticasone propionate 100 microg bd alone in patients with persistent asthma: integrated analysis of four randomised trials. AB - OBJECTIVES: To identify the asthma patients, on short-acting beta2-agonists alone, who would benefit from initial maintenance therapy (IMT) with salmeterol/fluticasone (SFC) propionate 50/100 microg bd compared with fluticasone propionate (FP) 100 microg bd alone. The results of an integrated analysis of data from four previous trials are presented. METHODS: The four original trials were randomised, double-blind, parallel group studies and included patients who had received IMT with SFC 50/100 microg bd or FP 100 microg bd. Patients were >or=12 years with a 6 month history of asthma and >or=15% reversibility in FEV1. Patients had either not received inhaled corticosteroids in the preceding month or were steroid naive. Patients were assessed to determine whether any GINA-defined asthma characteristics or combination of asthma characteristics could predict those individuals who would achieve well controlled asthma status with IMT with SFC rather than with inhaled steroid alone. Patients with persistent asthma were assessed based on GINA-defined baseline asthma characteristics and well controlled asthma status in response to each treatment was investigated according to combinations of these baseline features. Subsequently, a further range of endpoints, including asthma symptoms, rescue medication use and asthma control, were analysed over weeks 1-12 for the combinations of features where the treatment difference in well controlled asthma status was greatest. RESULTS: The results of the initial analyses demonstrated that patients exhibiting two or three features of uncontrolled asthma at baseline were more likely to achieve well controlled asthma when treated with SFC than with FP alone, the most significant difference being observed in patients with three baseline features (odds ratio 2.60, 95% CI: 1.87, 3.62, p<0.001). Patients with one baseline feature showed no difference between the FP and SFC groups. Further analyses on data from patients with two or three baseline asthma features, showed that treatment with SFC resulted in significantly greater improvements in mean morning PEF, percentage symptom-free days, nights with no awakenings and rescue-free days compared with FP. In addition, asthma control was achieved earlier in patients in the SFC group. SFC and FP were well tolerated as shown previously in the four individual trials. CONCLUSIONS: Patients on short acting beta2-agonists alone with two or three features of uncontrolled asthma (moderate to severe airflow limitation/daily symptoms/daily rescue medication use) are most likely to achieve better control, earlier, with SFC 50/100 microg bd initial maintenance treatment compared with FP 100 microg bd alone. PMID- 17689948 TI - Supervised high intensity continuous and interval training vs. self-paced training in COPD. AB - BACKGROUND: Endurance training is an effective component of pulmonary rehabilitation in COPD. Controversy exists regarding whether different modalities of supervised exercise training (continuous (C) or interval (I)) or self-paced (S) programs are equally beneficial. METHODS: Seventy-one patients with COPD (average FEV(1)=55% predicted) were assigned to 8 weeks of C, I or S training, 45 min/session, 3 times/week. Group C (n=22) exercised at 80% of pre-training peak work rate in an incremental cycle ergometer test. In group I (n=17), training consisted of 30 min of cycling 2 min at 90% followed by 1 min at 50% peak work rate bracketed by 7.5 min at 50% peak work rate. The S group (n=32) was instructed to cycle, climb stairs and walk in their home with the same periodicity and time intervals. RESULTS: Improvement in incremental test peak work rate was significant in both C and I groups, but not in S. Peak oxygen uptake and lactic acidosis threshold improved significantly in the supervised groups, but differences among groups did not achieve significance. Scores in an activity questionnaire improved in all groups without significant differences among groups. CONCLUSIONS: In COPD patients, continuous and interval training have similar physiologic effects; by some measures of endurance exercise performance, they are superior to self-paced training. However, all were effective in improving patient-perceived activity. PMID- 17689949 TI - Outcome and severity of adult onset asthma--report from the obstructive lung disease in northern Sweden studies (OLIN). AB - BACKGROUND: Studies of longitudinal changes in severity and the long-term outcome of asthma in epidemiological settings are uncommon. AIM: To assess the outcome of incident asthma in a cohort of subjects who developed asthma after the age of 20 years. METHODS: This is a prospective study of the outcome of 309 subjects with incident asthma being included in a case-referent study based on all adults aged 20-60 years living in three municipalities/towns in Northern Sweden. The subjects fulfilled the criteria for incident asthma defined as onset of symptoms common in asthma within 12 months prior to the study and a verified bronchial variability. In 2003, 250 (81%) of the subjects with asthma were re-examined with structured interview, lung-function test and methacholine test. RESULTS: At follow-up, 237 (95%) subjects still had an active asthma, i.e. they had symptoms or used asthma medicines. Among those with active asthma, 65% were using inhaled cortico steroids. Severity grading (GINA 2000) showed that 21% had mild intermittent asthma, 30% mild persistent, 44% moderate persistent, and 5% severe asthma, contrasting to 75% with moderate or severe asthma at entry. Higher age, higher BMI and low lung function were associated with greater asthma severity. Twelve subjects (5%) were in remission. Predictors for remission were non-sensitisation and a normal lung function. Age, sex, BMI, and smoking habits were not significantly different between those in remission and those not. CONCLUSIONS: Remission of adult onset asthma was low. Severity of asthma changed considerably over time, however, the overall change was towards a milder disease probably as a result of treatment. PMID- 17689950 TI - Optimizing the collection of used paper from small businesses through GIS techniques: the Leganes case (Madrid, Spain). AB - This article deals with a methodology for the design of routes for the "bin to bin" (BTB) collection of paper and cardboard waste (PCB) from small businesses, as well as with the new location and calculation of the number of containers needed in the streets for both commercial and non-commercial use due to the large amount of PCB deposited in them. This study was carried out in five shopping areas of the city of Leganes (Community of Madrid, Spain). One of the characteristics of the area is a high density of population and urban traffic. The tool used is the Geographical Information System (GIS-Arc-View). With it we can generate PCB points of high population density in commercial streets based on territorial analysis. We placed the special routes and the new container locations within a distance of 60 m of these collection points (CPT). The system calculates and optimizes six routes according to different urban restrictions. Finally, we provided service to 59% of the shops, which generate almost 82% of the PCB waste, using 160 min per day to collect 1027 kg of high quality PCB. If we compare the system with the system in place previously, we can conclude that the "bin to bin" (BTB) system improves the quality of the PCB in the containers, avoiding overflow and reducing the percentage of rejected material. PMID- 17689951 TI - Mobility of organic carbon from incineration residues. AB - Dissolved organic carbon (DOC) may affect the transport of pollutants from incineration residues when landfilled or used in geotechnical construction. The leaching of dissolved organic carbon (DOC) from municipal solid waste incineration (MSWI) bottom ash and air pollution control residue (APC) from the incineration of waste wood was investigated. Factors affecting the mobility of DOC were studied in a reduced 2(6-1) experimental design. Controlled factors were treatment with ultrasonic radiation, full carbonation (addition of CO2 until the pH was stable for 2.5h), liquid-to-solid (L/S) ratio, pH, leaching temperature and time. Full carbonation, pH and the L/S ratio were the main factors controlling the mobility of DOC in the bottom ash. Approximately 60 weight-% of the total organic carbon (TOC) in the bottom ash was available for leaching in aqueous solutions. The L/S ratio and pH mainly controlled the mobilization of DOC from the APC residue. About 93 weight-% of TOC in the APC residue was, however, not mobilized at all, which might be due to a high content of elemental carbon. Using the European standard EN 13 137 for determination of total organic carbon (TOC) in MSWI residues is inappropriate. The results might be biased due to elemental carbon. It is recommended to develop a TOC method distinguishing between organic and elemental carbon. PMID- 17689952 TI - From response to stimulus: adaptive sampling in sensory physiology. AB - Sensory systems extract behaviorally relevant information from a continuous stream of complex high-dimensional input signals. Understanding the detailed dynamics and precise neural code, even of a single neuron, is therefore a non trivial task. Automated closed-loop approaches that integrate data analysis in the experimental design ease the investigation of sensory systems in three directions: First, adaptive sampling speeds up the data acquisition and thus increases the yield of an experiment. Second, model-driven stimulus exploration improves the quality of experimental data needed to discriminate between alternative hypotheses. Third, information-theoretic data analyses open up novel ways to search for those stimuli that are most efficient in driving a given neuron in terms of its firing rate or coding quality. Examples from different sensory systems show that, in all three directions, substantial progress can be achieved once rapid online data analysis, adaptive sampling, and computational modeling are tightly integrated into experiments. PMID- 17689953 TI - Orthostatic intolerance in survivors of childhood cancer. AB - PURPOSE: To compare the prevalence and severity of orthostatic intolerance in survivors of childhood cancer and in healthy controls, and to correlate results of self-reported measures of health status with orthostatic testing in survivors of childhood cancer. PATIENT AND METHODS: Thirty-nine survivors of childhood cancer and 56 controls were recruited for this study. Each cancer survivor completed standardised self-report measures and all participants underwent a standing test (5 min supine, 10 min of motionless standing leaning against a wall, followed by another 2 min supine). The main outcomes of the standing test were orthostatic tachycardia (OT), defined as a heart rate increase of at least 30 beats per minute (bpm) during standing, and neurally mediated hypotension (NMH), defined as a drop in systolic blood pressure of at least 25 mmHg. RESULTS: OT developed in 22/39 (56%) cancer survivors versus 17/56 (30%) controls (P=.01). Cancer survivors had a higher baseline and maximum standing heart rate (both P<.001) and a more rapid onset of significant OT (P=.005). No significant difference in scores on self-report measures was found between cancer survivors with or without OT. CONCLUSION: This study provides preliminary evidence of a higher rate of orthostatic intolerance in childhood cancer survivors. Further study is warranted to better define whether this is a modifiable risk factor for fatigue in this population, and how orthostatic intolerance interacts with other known risk factors for lowered quality of life. PMID- 17689954 TI - Medical exposure to ionising radiation and the risk of brain tumours: Interphone study group, Germany. AB - BACKGROUND: The role of exposure to low doses of ionising radiation in the aetiology of brain tumours has yet to be clarified. The objective of this study was to investigate the association between medically or occupationally related exposure to ionising radiation and brain tumours. METHODS: We used self-reported medical and occupational data collected during the German part of a multinational case-control study on mobile phone use and the risk of brain tumours (Interphone study) for the analyses. RESULTS: For any exposure to medical ionising radiation we found odds ratios (ORs) of 0.63 (95% confidence interval (CI)=0.48-0.83), 1.08 (95% CI=0.80-1.45) and 0.97 (95% CI=0.54-1.75) for glioma, meningioma and acoustic neuroma, respectively. Elevated ORs were found for meningioma (OR 2.32, 95% CI: 0.90-5.96) and acoustic neuroma (OR 6.45, 95% CI: 0.62-67.16) for radiotherapy to the head and neck regions. CONCLUSION: We did not find any significant increased risk of brain tumours for exposure to medical ionising radiation. PMID- 17689955 TI - Health-related quality of life and health care utilisation among older long-term cancer survivors: a population-based study. AB - BACKGROUND: The consequences of cancer and its treatment on health-related quality of life (HRQL) and health care utilisation among elderly long-term cancer survivors have rarely been studied. However, the impact can be different for older compared to younger patients due to the higher prevalence of comorbid diseases, a higher risk of treatment-related complications and because they often receive different therapies compared to younger patients. Therefore, this study addressed the following questions; do HRQL and health care utilisation differ between younger and elderly cancer survivors, and are those differences age or disease related. METHODS: A population-based, cross-sectional survey among 1893 long-term survivors of endometrial cancer, prostate cancer and non-Hodgkin's lymphoma was conducted using a cancer registry. HRQL was measured by the SF-36 and health care utilisation was measured with a self-reported questionnaire. Results were compared to a normative population. Patients with disease progression were excluded resulting in a total number of 1112 patients to be analysed. RESULTS: Young non-Hodgkin lymphoma survivors (<70 years) reported lower vitality, bodily pain and general health compared to the normative population while older (70 years) survivors did not differ from the norm. Young lymphoma survivors experienced better physical functioning compared to older survivors. Young endometrial cancer survivors experienced less bodily pain compared to the normative population while older survivors did not differ from the norm. Young endometrial cancer survivors experienced better physical and role functioning compared to older survivors. Young prostate cancer survivors reported less bodily pain compared to the norm while older survivors did not. Young prostate cancer survivors reported higher scores on physical functioning compared to older survivors. Age, comorbid diseases, educational level and current occupation influenced HRQL significantly. Both younger and older cancer survivors visited their medical specialist, but not their GP, significantly more often compared to the age-matched general Dutch population. Both younger and older cancer survivors only sporadically used additional care services after cancer treatment. DISCUSSION: HRQL of older and younger survivors is comparable, with the exception of physical functioning which is lower in older survivors. This difference in physical functioning was probably not caused by cancer because physical functioning among cancer survivors did not differ much compared to an age-matched normative population. Both younger and older long-term cancer survivors visited their medical specialist often but only sporadically used additional care services after cancer treatment. PMID- 17689957 TI - Pediatric surgical oncology: management of rhabdomyosarcoma. AB - A malignant tumor of striated muscle origin, Rhabdomyosarcoma (RMS) is a childhood tumor that has benefited from 30 years of multimodality therapeutic trials culminating in a greater than 70% overall current 5-year survival. Prognosis for RMS is dependent on anatomic primary tumor site, age, completeness of resection, presence and number of metastatic sites, histology and biology of the tumor cells. Multimodality treatment is based on risk stratification according to pretreatment stage, postoperative group, histology and site. Therefore, pretreatment staging is vital for assessment and is dependent on primary tumor site, size, regional lymph node status, and presence of metastases. Unique to RMS is the concept of postoperative clinical grouping that assesses the completeness of disease resection and takes into account lymph node evaluation both at the regional and metastatic basins. At all sites, if operative resection of all disease is accomplished, including microscopic disease, survival is improved. Therefore, the surgeon plays a vital role in determining risk stratification for treatment and local control of the primary tumor for RMS. PMID- 17689956 TI - Estrogen-like effect of a Cimicifuga racemosa extract sub-fraction as assessed by in vivo, ex vivo and in vitro assays. AB - Black cohosh (Cimicifuga racemosa) is used in the treatment of painful menstruation and menopausal symptoms. Data about the nature of the active compounds and mechanism(s) of action are still controversial, chiefly with respect to its estrogenic activity. This work aimed to assess the possible estrogenic activity of a commercial dry hydro-alcoholic extract of C. racemosa and its hydrophilic and lipophilic sub-fractions on in vivo, ex vivo, and in vitro assays. In a yeast estrogen screen, only the lipophilic sub-fraction was able to activate the human estrogen receptor alpha, with a lower potency but comparable efficacy to that of 17 beta-estradiol. Neither the total extract nor the lipophilic sub-fraction showed an in vivo uterotrophic effect in 21-day-old rats. Uterine tissues obtained ex vivo from C. racemosa treated animals were generally much less sensitive to oxytocin, prostaglandin F(2alpha,) and bradykinin than tissues obtained from estradiol valerate treated rats. The lipophilic sub-fraction, instead, induced a dose-dependent inhibitory activity on the in vitro response to oxytocin, prostaglandin F(2alpha,) and bradykinin of uterine horns from naive 28-day-old rats, with a potency rate close to 1:30 of that of 17 beta-estradiol. Reported results confirm the effectiveness of C. racemosa in menstrual distress and further emphasize the possibility that lipophilic constituents bind to an as yet not identified estrogen receptor, likely inversely involved in inflammation. PMID- 17689958 TI - Interventional radiology and the care of the pediatric oncology patient. AB - Interventional radiology has become increasingly involved in the diagnosis and management of the pediatric oncology patient. Percutaneous biopsy and needle aspiration can be performed for solid and liquid lesions with image guidance, both for the primary diagnosis and for management of sequelae of cancer therapy. Therapeutic options also can be performed with image guidance, including radiofrequency ablation and transarterial chemoembolization. When surgical resection is required, image guided tumor localization can be used to aid in identifying small lesions. PMID- 17689959 TI - DSAS-6 organizes a tube-like centriole precursor, and its absence suggests modularity in centriole assembly. AB - Centrioles are microtubule-based cylindrical structures that exhibit 9-fold symmetry and facilitate the organization of centrosomes, flagella, and cilia [1]. Abnormalities in centrosome structure and number occur in many cancers [1, 2]. Despite its importance, very little is known about centriole biogenesis. Recent studies in C. elegans have highlighted a group of molecules necessary for centriole assembly [1, 3]. ZYG-1 kinase recruits a complex of two coiled-coil proteins, SAS-6 and SAS-5, which are necessary to form the C. elegans centriolar tube, a scaffold in centriole formation [4, 5]. This complex also recruits SAS-4, which is required for the assembly of the centriolar microtubules that decorate that tube [4, 5]. Here we show that Drosophila SAS-6 is involved in centriole assembly and cohesion. Overexpression of DSAS-6 in syncitial embryos led to the de novo formation of multiple microtubule-organizing centers (MTOCs). Strikingly, the center of these MTOCs did not contain centrioles, as described previously for SAK/PLK4 overexpression [6]. Instead, tube-like structures were present, supporting the idea that centriolar assembly starts with the formation of a tube like scaffold, dependent on DSAS-6 [5]. In DSAS-6 loss-of-function mutants, centrioles failed to close and to elongate the structure along all axes of the 9 fold symmetry, suggesting modularity in centriole assembly. We propose that the tube is built from nine subunits fitting together laterally and longitudinally in a modular and sequential fashion, like pieces of a layered "hollow" cake. PMID- 17689960 TI - RSC functions as an early double-strand-break sensor in the cell's response to DNA damage. AB - The detection of a DNA double-strand break (DSB) is necessary to initiate DSB repair. Several proteins, including the MRX/N complex, Tel1/ATM (ataxia telangiectasia mutated), and Mec1/ATR (ATM and Rad3 related), have been proposed as sensors of DNA damage, yet how they recognize the breaks is poorly understood. DSBs occur in the context of chromatin, implicating factors capable of altering local and/or global chromatin structure in the cellular response to DNA damage, including DSB sensing. Emerging evidence indicates that ATP-dependent chromatin remodeling complexes function in DNA repair. Here we describe an important and novel early role for the RSC ATP-dependent chromatin remodeler linked to DSB sensing in the cell's DNA-damage response. RSC is required for full levels of H2A phosphorylation because it facilitates the recruitment of Tel1/ATM and Mec1/ATR to the break site. Consistent with these results, we also show that Rsc2 is needed for efficient activation of the Rad53-dependent checkpoint, as well as for Cohesin's association with the break site. Finally, Rsc2 is needed for the DNA damage-induced changes in nucleosome structure surrounding the DSB site. Together, these new findings functionally link RSC to DSB sensing, highlighting the importance of ATP-dependent chromatin-remodeling factors in the cell's early response to DNA damage. PMID- 17689961 TI - Toward resolving the eukaryotic tree: the phylogenetic positions of jakobids and cercozoans. AB - Resolving the global phylogeny of eukaryotes has proven to be challenging. Among the eukaryotic groups of uncertain phylogenetic position are jakobids, a group of bacterivorous flagellates that possess the most bacteria-like mitochondrial genomes known. Jakobids share several ultrastructural features with malawimonads and an assemblage of anaerobic protists (e.g., diplomonads and oxymonads). These lineages together with Euglenozoa and Heterolobosea have collectively been designated "excavates". However, published molecular phylogenies based on the sequences of nuclear rRNAs and up to six nucleus-encoded proteins do not provide convincing support for the monophyly of excavates, nor do they uncover their relationship to other major eukaryotic groups. Here, we report the first large scale eukaryotic phylogeny, inferred from 143 nucleus-encoded proteins comprising 31,604 amino acid positions, that includes jakobids, malawimonads and cercozoans. We obtain compelling support for the monophyly of jakobids, Euglenozoa plus Heterolobosea (JEH group), and for the association of cercozoans with stramenopiles plus alveolates. Furthermore, we observe a sister-group relationship between the JEH group and malawimonads after removing fast-evolving species from the dataset. We discuss the implications of these results for the concept of "excavates" and for the elucidation of eukaryotic phylogeny in general. PMID- 17689962 TI - Individual differences in white-matter microstructure reflect variation in functional connectivity during choice. AB - The relation between brain structure and function is of fundamental importance in neuroscience. Comparisons between behavioral and brain-imaging measures suggest that variation in brain structure correlates with the presence of specific skills. Behavioral measures, however, reflect the integrated function of multiple brain regions. Rather than behavior, a physiological index of function could be a more sensitive and informative measure with which to compare structural measures. Here, we test for a relationship between a physiological measure of functional connectivity between two brain areas during a simple decision-making task and a measure of structural connectivity. Paired-pulse transcranial magnetic stimulation indexed functional connectivity between two regions important for action choices: the premotor and motor cortex. Fractional anisotropy (FA), a marker of microstructural integrity, indexed structural connectivity. Individual differences in functional connectivity during action selection show highly specific correlations with FA in localized regions of white-matter interconnecting regions, including the premotor and motor cortex. Probabilistic tractography, a technique for identifying fiber pathways from diffusion-weighted imaging (DWI), was used to reconstruct the anatomical networks linking the component brain regions involved in making decisions. These findings demonstrate a relationship between individual differences in functional and structural connectivity within human brain networks central to action choice. PMID- 17689964 TI - Prediction of mechanical efficiency from heart rate during stair-climbing in children with cerebral palsy. AB - Measuring mechanical efficiency (ME) is potentially useful to assess motor performance in individuals with physical disabilities. The purpose of this study was to determine the accuracy of predicting ME from heart rate (HR) during a self paced stair-climbing test in children with a range of motor abilities. The participants were 12 normally developed children (ND) and 24 with cerebral palsy (CP), ranging in age from 5 to 15 years (mean: 8 years). Five were at level II, 11 at level III and 8 at level IV according to the gross motor function classification system. ME was calculated as the ratio of external work to O(2) uptake (VO(2) ml/min) measured or predicted from HR. The absolute values of VO(2) and HR during stair-climbing were not significantly correlated. However, the correlation between values above resting (dVO(2) and dHR) was significant (r=0.61). Furthermore, when including body weight as a second variable the prediction of dVO(2) was significantly improved (r=0.85). This resulted in a high correlation (r=0.96) between measured and predicted net ME (ME(net)). Predicted ME(net) for 25 stair-climbing tests repeated after an average of 6 months resulted in an r-value of 0.92 with predicted ME(net) of the first test. This study demonstrates that ME(net) during stair-climbing can be predicted in children with a broad range of motor abilities from dHR and may be a simple tool to help define developmental stages or evaluating intervention efficacy. PMID- 17689963 TI - Biomechanics of recumbent cycling in adolescents with cerebral palsy with and without the use of a fixed shank guide. AB - New stationary cycles can decrease motion in the frontal and transverse planes with a shank guide. However, there are no studies comparing cycling with and without this guide. The purpose of this study was to compare cycling with and without a shank guide for adolescents with cerebral palsy (CP). Three males and seven females (15.6+/-1.8 years) with CP, classified as levels III and IV with the Gross Motor Functional Classification System, underwent biomechanical analysis of stationary recumbent cycling with and without a shank guide at 30 and 60 rpm if able. Data collected included three-dimensional lower extremity joint kinematics using motion analysis, surface electromyography of eight lower extremity muscles, cocontraction of six agonist/antagonist pairings, efficiency (power output divided by oxygen consumption), and perceived exertion (OMNI Scale of Perceived Exertion). Non-circular data were analyzed via ANOVAs, and circular data were analyzed using circular t-tests. The shank guide altered joint kinematics in all three planes (p<0.008), had a minor impact on muscle activity (p<0.006), and had no impact on cocontraction (p>0.008), efficiency (p=0.920), or perceived exertion (p=0.318). The results suggest that a shank guide during cycling may be beneficial for individuals with CP to decrease the amount of hip and knee frontal and transverse plane motion. Knee movement in these planes has been associated with pain in healthy adults; therefore the guide may help to prevent long-term complications from cycling for adolescents with CP. PMID- 17689965 TI - Repeatability and variation of quantitative gait data in subgroups of patients with stroke. AB - We aimed to determine the repeatability and variation of quantitative gait data in patients with stroke and to compare the subgroups in terms of gait variability. Time-distance and kinematic characteristics of gait were evaluated in 90 inpatients (30 women) with hemiparesis (mean+/-S.D. age 57.7+/-12.5 years and time since stroke 5.99+/-6.46 months). Subgroups were based on "gender", "side of paresis", "lesion type", "motor recovery level", "sensory status", "time since stroke" and "walking velocity". Repeatability was adequate to excellent in all stroke subgroups (ICC range 0.48-0.98). Walking velocity was the most repeatable gait parameter after stroke. Variation in step length was significantly higher in women than in men (CV 16% versus 9%, p<0.05). Slow walkers (walking velocity <0.34 m/s) had a higher variation than fast walkers in step length (CV 12.5% versus 7.5%, p<0.01), single support time (CV 11.9% versus 6.3%, p<0.05), peak hip extensions in stance (CV 11.5% versus 3.7%, p<0.01) and knee flexion in swing (CV 11.8% versus 6.5%, p<0.05). In our stroke patients, their age, time since injury, lesion characteristics, impaired proprioception or level of motor recovery had no effect on gait variability. For better interpretation of quantitative gait data, clinicians should consider that variation in step length, single support time, peak hip extension in stance and knee flexion in swing differs according to walking velocity after stroke. PMID- 17689966 TI - Identification of psoralen loaded PLGA microspheres in rat skin by light microscopy. AB - Drug delivery systems involving the use of polymers are widely studied and discovery of biocompatible polymers has become the focus of research in this area. Psoralen loaded poly(DL-lactide-co-glycolide) (PLGA) microspheres to be used in PUVA therapy (psoralen and UVA irradiation (ultraviolet A, 320-400 nm) of psoriasis were identified in paraffin sections by histological analysis. The psoralen loaded PLGA microspheres were prepared using the solvent evaporation technique. They were spherical and possessed an external smooth surface as observed by scanning electron microscopy (SEM) analysis. This study describes a modification in the routine preparation of microsphere samples for examination by light microscopy. The changes involved fixative agents and/or stains allowing the identification of microspheres containing a non-fluorescent material. The preservation and identification of microspheres in tissues for histological processing in paraffin was greatly improved by these modifications as proven by our results. PMID- 17689967 TI - Monte Carlo analysis of tagged neutron beams for cargo container inspection. AB - Fast neutrons produced via D+T reactions and tagged by the associated particle technique have been recently proposed to inspect cargo containers. The general characteristics of this technique are studied with Monte Carlo simulations by determining the properties of the tagged neutron beams as a function of the relevant design parameters (energy and size of the deuteron beam, geometry of the charged particle detector). Results from simulations, validated by experiments, show that the broadening of the correlation between the alpha-particle and the neutron, induced by kinematical as well as geometrical (beam and detector size) effects, is important and limits the dimension of the minimum voxel to be inspected. Moreover, the effect of the container filling is explored. The material filling produces a sizeable loss of correlation between alpha-particles and neutrons due to scattering and absorption. Conditions in inspecting cargo containers are discussed. PMID- 17689968 TI - Glycopeptide pharmacokinetics in current paediatric cardiac surgery practice. AB - OBJECTIVE: To examine the evolution of serum concentrations of prophylactic glycopeptides administered during state-of-the-art cardiopulmonary bypass (CPB) and vigorous haemodiafiltration in paediatric patients undergoing cardiac surgery. METHODS: We enrolled infants and children <3 years of age who, based on the preoperative microbiological screening, age and surgical complexity, were at high risk of methicillin-resistant Staphylococcus aureus (MRSA) infection. Antimicrobial prophylaxis with glycopeptides was administered to 22 patients, randomly assigned to vancomycin (VAN; n=11) versus teicoplanin (TEC; n=11). Fixed doses of each drug (15 mg/kg for VAN and 8 mg/kg for TEC) were administered immediately before the operation, at the time of priming of the extracorporeal circuit, upon admission to the intensive care unit and for 48 h thereafter, q. 8 h for VAN, and once daily for TEC. Vigorous haemodiafiltration was applied during and briefly after CPB. RESULTS: The second dose of drug added to the prime prevented a fall in serum drug concentrations at the onset of CPB in both groups. A 77% decrease in VAN, versus 53% in TEC concentrations, was observed after the conclusion of CPB. Serum concentrations of TEC>10 microg/ml were observed throughout the treatment period in 91% of patients, while 55% of patients assigned to VAN had serum concentrations consistently >5 microg/ml (p=0.08). Therapeutic serum concentrations were maintained throughout the intraoperative period, particularly with TEC, administered before the first surgical incision, followed by a supplemental bolus in the priming fluid of CPB. Postoperative surgical wound infections occurred in neither group. CONCLUSIONS: The prophylactic use of glycopeptides in paediatric patients at high risk of MRSA infection undergoing cardiac surgery was safe and effective. TEC might be the drug of choice, since stable, therapeutic serum concentrations were easily maintained throughout the treatment period. PMID- 17689969 TI - The impact of symptom severity on cardiac reoperative risk: early referral and reoperation is warranted. AB - BACKGROUND: Operative mortality is comparatively higher for coronary artery bypass grafting (CABG) or valve reoperations. Studies of reoperative risk have focussed on surgical techniques. We sought to determine the risk and predictors of poor outcome in current practice, and the influence of preoperative symptoms. METHOD: For every redo patient (n=289), we selected the best-matched pair of patients who underwent a primary operation (n=578) between 1998 and 2006. Matching variables were age, gender, left ventricular ejection fraction (LVEF) and type of operation. Poor outcome was defined as operative mortality or major morbidity. RESULT: Median age was 68 (interquartile range 62-73) years and 28% were female for both groups. Severe symptoms and cardiac morbidity dominated the presentation of redo patients. CABG (53%), valve repair/replacement (34%) and combined CABG and valve (12%) were performed with overall operative mortality of 6.6% (median additive EuroScore 7.0) for redo versus 1.6% (median additive EuroScore 4.0) for primary groups (p<.0001). Whereas no significant difference was observed between primary (1.6%) and redo CABG (3.9%, p=.19), valve reoperations had higher operative mortality (9.6% vs 1.5%, p<.0001). Major complications occurred more frequently after redo valve compared to primary valve operations (28% vs 14%, p=.001). Reoperation (odds ratio [OR] 1.26, 95% confidence interval [CI] 0.66-2.42, p=.48) was not a predictor of major adverse event after CABG or valve surgery. Determinants of poor outcome after valve reoperations were New York Heart Association class III/IV (OR 6.86, 95% CI 2.29 12.11, p=.03), duration of extracorporeal circulation (OR 1.17, 95% CI 1.02-1.35, p=.03) and mitral valve replacement (OR 4.07, 95% CI 1.83-36.01, p=.04). The predictors of major adverse events after redo CABG were congestive heart failure (OR 1.85, 95% CI 1.04-8.98, p=.006) chronic obstructive pulmonary disease (OR 17.5, 95% CI 1.87-35.21, p=.05) and interval from prior surgery (OR 1.37, 95% CI 1.09-1.92, p=.01). CONCLUSION: In the current era, redo CABG is nearly as safe as the primary operation. A valve reoperation, on the contrary, is higher risk due, partly, to severe symptoms at presentation. Patients should be referred and operated on early before they develop severe symptoms. PMID- 17689970 TI - Multiple coronary artery-left ventricular fistulae: a pattern of anomalous coronary microvascularization. PMID- 17689971 TI - Endovascular treatment for mobile thrombus of the thoracic aorta. AB - Detection levels of mobile thrombus of the thoracic aorta have greatly increased after any embolic event. Although the indication for treatment remains controversial, there is a growing interest about the etiopathogenesis of this rare entity and to define proper diagnostic and therapeutic approaches. We present a case of mobile thrombus of the thoracic aorta causing recurrent peripheral emboli managed with endovascular stent graft. PMID- 17689972 TI - Right-left atrium by-pass as salvage treatment for graft failure after heart transplantation. AB - Chronic functional pulmonary hypertension (FPH) secondary to end-stage cardiomyopathy constitutes a risk factor for graft right ventricular failure (RVF) after orthotopic heart transplantation (HTx). A novel form of mechanical assist circuit, the extracorporeal right to left atrium bypass (ECRLAB), has been proposed. Since 1998, at our institution, a total of six patients with FPH who experienced graft RVF after HTx, as ischemic end-stage cardiomyopathy, during the effort to wean from cardiopulmonary bypass, underwent ECRLAB support. There were five men and one woman with a mean age of 55+/-3.5 years (49-59 years). The Jostra Rota Flow pump was used in five patients and the Bio-Medicus in one. Mean duration of support was 94.3+/-17.5 h (75-126 h). All (100%) patients were successfully weaned from ECRLAB support. Hemodynamic parameters improved in all patients. Two patients died from cerebral haemorrhage. Four (66.6%) patients were successfully discharged home. ECRLAB could be proposed during HTx in patients with increased preoperative transpulmonary gradient to promote the functional adaptation of the graft and avoid graft RVF, until the decline of pulmonary resistances. PMID- 17689973 TI - Left ventricular mass: impact on left ventricular contractile function and its reversibility in patients undergoing aortic valve replacement. AB - BACKGROUND: We examined the relationships of left ventricular (LV) contractile state with LV geometry and hypertrophy in patients with aortic valve disease, and investigated the reversibility of LV hypertrophy and contractility following aortic valve replacement. METHODS: Preoperative data from quantitative cineangiography and pressure measurements in 132 patients with chronic aortic valve disease, of whom 82 aortic regurgitation (AR), 41 aortic stenosis (AS), and 9 had mixed stenosis and regurgitation (AS-AR), were reviewed. Late after surgery, 59 of the patients (39 with AR, 20 with AS) were studied to elucidate the postoperative reversibility of LV performance and regression of LV hypertrophy. RESULTS: Preoperatively, multiple comparison tests found significant changes in the variables of LV volumes and dimensions in relation to LV contractile state. In stepwise regression analysis, the LV mass index was initially incorporated into a multivariate regression model as an important correlate of LV contractile state. LV geometric variables showed either no or a poor correlation with contractile state. Following aortic valve replacement, improvement of LV contractile dysfunction and regression of LV hypertrophy were limited in many of the patients who had severe preoperative hypertrophy (LV mass index 200% of normal or greater). Further, a close association between LV hypertrophy and LV contractility persisted postoperatively. CONCLUSION: Our results suggest that the development of LV hypertrophy in terms of an increase in LV mass index, in contrast to changes in geometric patterns, is significantly associated with deterioration in contractile function. LV hypertrophy may become irreversible and pathological at equivalent degrees of hypertrophy (LV mass index >/=200% of normal), regardless of the type of aortic valve lesion. PMID- 17689974 TI - Influence of the IL-6 -572C>G polymorphism on inflammatory markers according to cigarette smoking in Korean healthy men. AB - We investigated whether smoking would interact with the interleukin-6 (IL-6) polymorphisms (-174G>C and -572C>G, -597G>A and -1363G>T) in determining circulating levels of inflammatory markers and its consequence to oxidative stress. The G/G genotype (n=26) of the -572C>G in nonsmokers (n=376) was associated with higher IL-6 (P=0.028), fibrinogen (P=0.007) and ox-LDL (P=0.006) than those with C/C (n=209) or C/G (n=141). Results were similar for nonsmokers and smokers (n=268), but in smokers, the -572G/G genotype was associated with a greater difference in levels of IL-6 (P=0.031), fibrinogen (P=0.001), ox-LDL (P=0.037) and PGF(2alpha) (P=0.050). IL-6 had positive relations with CRP, fibrinogen, ox-LDL and PGF(2alpha). There was no evidence of an effect of -572C>G genotype on CRP levels in nonsmokers, however, this polymorphism was associated with a highly significant effect on CRP in smokers (P<0.001) (genotype-smoking interaction P=0.04, adjusted for age, BMI and IL-6). The C allele frequency at the -174 promoter region of IL-6 was very rare (<0.01) and -597G>A and -1363G>T were monomorphic in this study. Our results suggest that IL-6 -572C>G has a greater response over time to the inflammatory effects of smoking and this may result in smokers having higher oxidative stress in subjects with G/G compared to C/C or C/G. PMID- 17689975 TI - Dynamic alteration of soluble serum biomarkers in healthy aging. AB - Dysbalanced production of inflammatory cytokines is involved in immunosenescence in aging. The age-related changes of the levels of circulating inflammatory mediators and their clinical importance have not been investigated until recently. Still, little is known about the influence of aging on circulating levels of many cytokines, chemokines, growth factors, and angiogenic factors. In the present study, we evaluated the effect of aging on 30 different serum biomarkers involved in pro- and anti-inflammatory responses using multianalyte LabMAP Luminex technology. The simultaneous measurement of serological markers has been done in 397 healthy subjects between 40 and 80 years old. We demonstrated an increase in serum interferon-gamma-inducible chemokines (MIG and IP-10), eotaxin, chemoattractant for eosinophils, and soluble TNFR-II with advancing age. Serum levels of EGFR and EGF, important regulators of cell growth and differentiation, were decreased with age in healthy donors. These data suggest novel pathways, which may be involved in age-associated immunosenescence. PMID- 17689976 TI - Light-induced recruitment of INAD-signaling complexes to detergent-resistant lipid rafts in Drosophila photoreceptors. AB - Here, we reveal a novel feature of the dynamic organization of signaling components in Drosophila photoreceptors. We show that the multi-PDZ protein INAD and its target proteins undergo light-induced recruitment to detergent-resistant membrane (DRM) rafts. Reduction of ergosterol, considered to be a key component of lipid rafts in Drosophila, resulted in a loss of INAD-signaling complexes associated with DRM fractions. Genetic analysis demonstrated that translocation of INAD-signaling complexes to DRM rafts requires activation of the entire phototransduction cascade, while constitutive activation of the light-activated channels resulted in recruitment of complexes to DRM rafts in the dark. Mutations affecting INAD and TRP showed that PDZ4 and PDZ5 domains of INAD, as well as the INAD-TRP interaction, are required for translocation of components to DRM rafts. Finally, selective recruitment of phosphorylated, and therefore activatable, eye PKC to DRM rafts suggests that DRM domains are likely to function in signaling, rather than trafficking. PMID- 17689977 TI - Identification and characterization of a novel phosphorylation site on the GluR1 subunit of AMPA receptors. AB - Phosphorylation of various AMPA receptor subunits can alter synaptic transmission and plasticity at excitatory glutamatergic synapses in the central nervous system. Here, we identified threonine-840 (T840) on the GluR1 subunit of AMPA receptors as a novel phosphorylation site. T840 is phosphorylated by protein kinase C (PKC) in vitro and is a highly turned-over phosphorylation site in the hippocampus. Interestingly, the high basal phosphorylation of T840 in the hippocampus is maintained by a persistent activity of a protein kinase, which is counter-balanced by a basal protein phosphatase activity. To study the function of T840, we generated a line of mutant mice lacking this phosphorylation site using a gene knock-in technique. The mice generated lack T840, in addition to two previously identified phosphorylation sites S831 and S845. Using this mouse, we demonstrate that T840 may regulate synaptic plasticity in an age-dependent manner. PMID- 17689978 TI - The neuronal Ca(2+) -binding protein 2 (NECAB2) interacts with the adenosine A(2A) receptor and modulates the cell surface expression and function of the receptor. AB - Heptaspanning membrane also known as G protein-coupled receptors (GPCR) do interact with a variety of intracellular proteins whose function is regulate receptor traffic and/or signaling. Using a yeast two-hybrid screen, NECAB2, a neuronal calcium binding protein, was identified as a binding partner for the adenosine A(2A) receptor (A(2A)R) interacting with its C-terminal domain. Co localization, co-immunoprecipitation and pull-down experiments showed a close and specific interaction between A(2A)R and NECAB2 in both transfected HEK-293 cells and also in rat striatum. Immunoelectron microscopy detection of NECAB2 and A(2A)R in the rat striatopallidal structures indicated that both proteins are co distributed in the same glutamatergic nerve terminals. The interaction of NECAB2 with A(2A)R modulated the cell surface expression, the ligand-dependent internalization and the receptor-mediated activation of the MAPK pathway. Overall, these results show that A(2A)R interacts with NECAB2 in striatal neurones co-expressing the two proteins and that the interaction is relevant for A(2A)R function. PMID- 17689979 TI - Evidence for distinct leptomeningeal cell-dependent paracrine and EGF-linked autocrine regulatory pathways for suppression of fibrillar collagens in astrocytes. AB - A unique and unresolved property of the central nervous system is that its extracellular matrix lacks fibrillar elements. In the present report, we show that astrocytes secrete triple helices of fibrillar collagens type I, III and V in culture, while no astroglial collagen expression could be detected in vivo. We discovered two inhibitory mechanisms that could underlie this apparent discrepancy. Thus, we uncover a strong inhibitory effect of meningeal cells on astrocytic collagen expression in coculture assays. Furthermore, we present evidence that EGF-receptor activation downregulates collagen expression in astrocytes via an autocrine loop. These investigations provide a rational framework to explain why the brain is devoid of collagen fibers, which is a unique feature that characterizes the structure of the neural extracellular matrix. Moreover, fibrillar collagens were found transiently upregulated in a laser-induced cortical lesion, suggesting that these could contribute to the glial scar that inhibits axonal regeneration. PMID- 17689980 TI - Formalization of Damasio's theory of emotion, feeling and core consciousness. AB - This paper contributes an analysis and formalization of Damasio's theory on core consciousness. Three important concepts in this theory are 'emotion', 'feeling' and 'feeling a feeling' (or core consciousness). In particular, a simulation model is described of the dynamics of basic mechanisms leading via emotion and feeling to core consciousness, and dynamic properties are formally specified that hold for these dynamics at a more global level. These properties have been automatically checked for the simulation model. Moreover, a formal analysis is made of relevant notions of representation used by Damasio. As part of this analysis, specifications of representation relations have been verified and confirmed against the simulation model. PMID- 17689982 TI - Isolating physiologic noise sources with independently determined spatial measures. AB - To properly account for the presence of physiologic noise in fMRI data, parallel measurement of pulse and respiratory data is necessary. In some cases, this parallel measurement is difficult or impossible due to the experimental paradigm or lack of available monitoring equipment. We present a robust method for determining the direct-sampled pulse and respiratory data for a subject from the fMRI data itself, utilizing an independently determined spatial weighting matrix. It is shown that temporal independent component analysis can reliably separate the spatial and temporal patterns of physiologic noise through correlation if the parallel measurement is made. The spatial patterns thus determined can be applied to a separate scan of the same subject to produce the temporal pattern specific to this independent scan. The robustness of this method leads to the more general method of creating spatial weight matrices in standard brain space averaged over multiple subjects in order to acquire the physiologic signals without the necessity of any (further) parallel measurements. The resulting cardiac and respiratory estimators can effectively be used in a manner similar to that of a direct-sampled physiologic signal, e.g., direct input to retrospective correction methods, evaluation of cardiac and respiratory effects of tasks, etc. Spatial mixing matrices for estimating cardiac and respiratory sources for the acquisition protocols described here (and others as they are developed) are offered to investigators and can be obtained through e-mail from the corresponding author. PMID- 17689981 TI - Contrast responsivity in MT+ correlates with phonological awareness and reading measures in children. AB - There are several independent sets of findings concerning the neural basis of reading. One set demonstrates a powerful relationship between phonological processing and reading skills. Another set reveals a relationship between visual responses in the motion pathways and reading skills. It is widely assumed that these two findings are unrelated. We tested the hypothesis that phonological awareness is related to motion responsivity in children's MT+. We measured BOLD signals to drifting gratings as a function of contrast. Subjects were 35 children ages 7-12 years with a wide range of reading skills. Contrast responsivity in MT+, but not V1, was correlated with phonological awareness and to a lesser extent with two other measures of reading. No correlation was found between MT+ signals and rapid naming, age or general IQ measures. These results establish an important link between visual and phonological processing in children and suggest that MT+ responsivity is a marker for healthy reading development. PMID- 17689983 TI - Inter-relationships between attention, activation, fMR adaptation and long-term memory. AB - fMR adaptation in the ventral visual pathway reflects information processing that may contribute to implicit and explicit memory. In experiments that employed <1 s repetition lag, we found that attention increases adaptation for repeated objects in brain regions at the top of the visual processing hierarchy (anterior fusiform and parahippocampal gyri) but that it can still appear with minimal attention in most of the fusiform bilaterally. Of the ventral visual regions showing adaptation, the parahippocampal region and LOC showed the strongest correlation between adaptation magnitude and recognition memory across subjects. Although there was some overlap, regions showing correlations between adaptation and priming lay more posteriorly within the fusiform region. The positive association between encoding-related activation and adaptation suggests that over an entire test set, memory performance can be determined by neural events occurring in the peristimulus period. This may reflect stronger engagement of attention at encoding. PMID- 17689984 TI - AFM combines functional and morphological analysis of peripheral myelinated and demyelinated nerve fibers. AB - Demyelination of the myelinated peripheral or central axon is a common pathophysiological step in the clinical manifestation of several human diseases of the peripheral and the central nervous system such as the majority of Charcot Marie-Tooth syndromes and multiple sclerosis, respectively. The structural degradation of the axon insulating myelin sheath has profound consequences for ionic conduction and nerve function in general, but also affects the micromechanical properties of the nerve fiber. We have for the first time investigated mechanical properties of rehydrated, isolated peripheral nerve fibers from mouse using atomic force microscopy (AFM). We have generated quantitative maps of elastic modulus along myelinated and demyelinated axons, together with quantitative maps of axon topography. This study shows that AFM can combine functional and morphological analysis of neurological tissue at the level of single nerve fibers. PMID- 17689985 TI - Impact of the COMT Val108/158 Met and DAT genotypes on prefrontal function in healthy subjects. AB - Two limiting factors of dopamine activity are the catechol-o-methyltransferase (COMT) and the dopamine transporter (DAT), which terminate dopamine activity by degradation and uptake, respectively. Genetic variants of COMT and DAT have been related to the enzymatic activity and protein availability, respectively. The Met allele of the COMT Val108/158 Met polymorphism has been associated to lower enzymatic activity and the 9-repeat allele of the DAT 40 base-pair (bp) variable number of tandem repeat (VNTR) polymorphism has been related to lower protein availability. Genotypes for COMT and DAT were determined in a sample of 75 healthy subjects, who underwent functional magnetic resonance imaging (fMRI) while performing an N-back task. To further assess the effects of the genotypes on cognition, subjects were administered the Wisconsin Card Sorting Test (WCST) and the Continuous Performance Test (CPT). Analysis of fMRI data revealed an additive effect of these two genes on brain activation in an N-back task, with subjects homozygous for the Val and the 9-repeat alleles showing the highest activation for the same level of performance. Moreover, the Val allele was related to higher number of perseverative errors on the WCST and with a higher number of commission errors on the CPT. The 10-repeat allele was associated with faster reaction times but also with a higher number of commission errors. Our results support a role of the COMT Val108/158 Met and the DAT 40 bp VNTR in both brain activation and cognition. PMID- 17689986 TI - Timing of V1/V2 and V5+ activations during coherent motion of dots: an MEG study. AB - In order to study the temporal activation course of visual areas V1 and V5 in response to a motion stimulus, a random dots kinematogram paradigm was applied to eight subjects while magnetic fields were recorded using magnetoencephalography (MEG). Sources generating the registered magnetic fields were localized with Magnetic Field Tomography (MFT). Anatomical identification of cytoarchitectonically defined areas V1/V2 and V5 was achieved by means of probabilistic cytoarchitectonic maps. We found that the areas V1/V2 and V5+ (V5 and other adjacent motion sensitive areas) exhibited two main activations peaks at 100-130 ms and at 140-200 ms after motion onset. The first peak found for V1/V2, which corresponds to the visual evoked field (VEF) M1, always preceded the peak found in V5+. Additionally, the V5+ peak was correlated significantly and positively with the second V1/V2 peak. This result supports the idea that the M1 component is generated not only by the visual area V1/V2 (as it is usually proposed), but also by V5+. It reflects a forward connection between both structures, and a feedback projection to V1/V2, which provokes a second activation in V1/V2 around 200 ms. This second V1/V2 activation (corresponding to motion VEF M2) appeared earlier than the second V5+ activation but both peaked simultaneously. This result supports the hypothesis that both areas also generate the M2 component, which reflects a feedback input from V5+ to V1/V2 and a crosstalk between both structures. Our study indicates that during visual motion analysis, V1/V2 and V5+ are activated repeatedly through forward and feedback connections and both contribute to m-VEFs M1 and M2. PMID- 17689987 TI - Cytonuclear discordance across a leopard frog contact zone. AB - We conducted a genetic analysis of the extent of hybridization within and outside a contact zone between two North American leopard frogs, Rana blairi and Rana pipiens by comparing distribution patterns of mitochondrial and nuclear haplotypes. The contact zone, located between South Dakota, Nebraska, and Iowa, USA, was previously examined using morphological data in the 1970s, leading to the conclusion that hybridization was rare between R. pipiens and R. blairi. Our genetic analysis of 51 populations (611 samples) shows strong cytonuclear discordance. Mitochondrial-haplotype distribution matches the same pattern as the documented species spatial distributions based on morphology. However, the geographic distribution of the nuclear haplotypes reveals asymmetrical swamping of the R. pipiens nuclear haplotypes by R. blairi haplotypes. Phylogenetic analyses of both mitochondrial and nuclear markers provide strong evidence for the presence of R. blairi-R. pipiens introgression for the nuclear marker. A pattern of mitochondrial isolation with nuclear introgression is extremely unusual, and predicted to occur much less often than the reverse. PMID- 17689988 TI - Early hemispherectomy in catastrophic epilepsy: a neuro-cognitive and epileptic long-term follow-up. AB - The authors report their experience about a neuro-cognitive and epileptic long term follow-up of children with catastrophic epilepsy treated with hemispherectomy in the first 5 years of life. Nineteen children with resistant epilepsy that significantly interfered with their neuro-cognitive development underwent hemispherectomy within 5 years of life (mean: 2 years, 3 months; range: 5 months to 5 years). All patients were assessed before surgery and after, at least at the end of the follow-up (mean: 6 years and 6 months; range: 2-11 years and 2 months) with a full clinical examination including motor ability and functional status evaluation as well as behaviour observation, neuroimaging and an ictal/interictal prolonged scalp video-EEG. A seizure-free outcome was obtained in 73.7% of patients. Gross motility generally improved and cognitive competence did not worsen, with an evident progress in two cases. Consistently with previous reports, evolution was worse in cortical dysplasia than in progressive or acquired vascular cerebropathies. The excellent epileptic outcome and the lack of developmental deterioration in comparison with other more aged series seem to suggest a possible better evolution in earlier surgery treatment. To confirm this suggestion, however, further experience with larger series is needed. PMID- 17689989 TI - On how degeneration influences load-bearing in the cartilage-bone system: a microstructural and micromechanical study. AB - OBJECTIVE: This study investigated the microanatomical response to compression of intact and degenerate cartilage-on-bone samples with the aim of elucidating the functional consequences of articular surface disruption and related matrix changes. METHOD: Two groups of mature bovine patellae were identified at the time of harvest; those with intact cartilage and those with cartilage exhibiting mild to severe degeneration. Cartilage-on-bone samples were statically compressed (7 MPa) to near-equilibrium using an 8-mm diameter cylindrical indenter, and then formalin-fixed in this deformed state. Following mild decalcification full-depth cartilage-bone sections, incorporating the indentation profile and beyond, were studied in their fully hydrated state using differential interference contrast optical microscopy (DIC). RESULTS: Differences in matrix texture, degree of disruption of the articular surface layer (or its complete absence), number of tidemarks and absence or presence of vascularization of the calcified cartilage zone were all observable features that provided clear differentiation between the normal and degenerate tissues. Under load a chevron-type shear discontinuity characterized those samples in which the strain-limiting surface layer was still largely intact. The extent to which this shear discontinuity advanced into the adjacent non-directly loaded cartilage continuum was influenced by the integrity of the cartilage general matrix. For those tissues deficient in a strain-limiting articular surface there was no shear discontinuity, the cartilage deformation field was instead shaped primarily by its osteochondral attachment and a laterally-directed compressive collapse of a much weakened matrix. In the degenerate samples the altered matrix textures associated with different regions of the deformation field are interpreted in terms of an intrinsic fibrillar architecture that is weakened by two fundamental processes: (1) a de-structuring resulting from a reduction in connectivity between fibrils and (2) subsequent aggregation of these now disconnected fibrils. CONCLUSION: DIC microscopy provides a high-resolution description of the integrated osteochondral tissue system across the full continuum of matrices, from normal to severely degenerate. Our study demonstrates the important functional role played by the strain limiting articular surface, the consequences associated with its disruption, as well as the loss of effective stress transmission associated with a 'de structured' general matrix. The study also provides new insights into the integration of cartilage with both its subchondral substrate and the wider continuum of non-directly loaded cartilage. PMID- 17689990 TI - Significance of eIF4E expression in skin squamous cell carcinoma. AB - Cutaneous squamous cell carcinoma (SCC) is a malignant tumour of keratinising epidermal cells. This type of skin cancer is the second leading cause of death after melanoma, and it is the second most common type of non-melanoma skin cancer after basal cell carcinoma. The cellular and molecular events involved in the progression of skin cancers are largely unknown. Increased protein synthesis is necessary for the transition of cells from quiescence to proliferation. Translational control is critical for the proper regulation of the cell cycle, tissue induction and growth. Eukaryotic initiation factor eIF4E, an important regulator of translation, plays critical roles in neo-plastic transformation and cancer progression. We investigated eIF4E expression in 49 skin samples (six normal tissues, eight Bowen diseases, seven stage I, 10 stage II, 13 stage III and five stage IV SCCs). Results obtained demonstrated that all SCC samples, evaluated by SDS-PAGE, Western blotting and cap-affinity chromatography using m7GTP-sepharose, presented eIF4E expression (13.6+/-1.2), whereas, starting from stage 0 (4.1+/-0.9) to stage I (7.4+/-1.4), stage II (12.1+/-2.4), stage III (18.1+/-3.0) and stage IV (26.2+/-3.8) SCCs, a constant and significant increase of protein over expression (P<0.001) was observed. A high expression of eIF4E is correlated with advanced stages. The results presented in this study demonstrate a possible role of eIF4E in SCC. PMID- 17689991 TI - Molecular characterization of type 3 (neuronopathic) Gaucher disease in Thai patients. AB - Gaucher disease is an autosomal recessive lysosomal storage disorder due to deficiency of the lysosomal enzyme glucocerebrosidase. Three clinical phenotypes, type 1, nonneuronopathic; and types 2 and 3, acute and subacute neuronopathic are recognized. The incidence of Gaucher disease in the Thai population is unknown, but likely under-diagnosed. We performed molecular analysis in four patients, from three sibships, with type 3 Gaucher disease. Four mutant glucocerebrosidase (GBA) alleles were identified including two novel splice site mutations, IVS6 1G>C and IVS9-3C>G; both are predicted to result in truncated protein products, p.F255fsX256, and p.K464fsX487 and p.S463fsX480, respectively. One patient, homozygous for the L444P point mutation, had a "Norbottnian-like" phenotype, with more severe visceral involvement, kyphosis, barreled chest, and no neurological involvement other than supranuclear gaze palsy. These molecular studies of neuronopathic Gaucher disease will provide additional genotype-phenotype correlation particularly in non-Caucasian population. PMID- 17689992 TI - Some commonly fed herbs and other functional foods in equine nutrition: a review. AB - Most herbs and functional foods have not been scientifically tested; this is especially true for the horse. This paper reviews some of the literature pertinent to herbal supplementation in horses and other species. Common supplements like Echinacea, garlic, ginger, ginseng, and yucca are not regulated, and few studies have investigated safe, efficacious doses. Ginseng has been found to exert an inhibitory effect on pro-inflammatory cytokines and cyclooxygenase-2 expression. Equine studies have tested the anti-inflammatory effects of a single dose of ginger, post-exercise. Echinacea has been reported to have anti inflammatory and antioxidant properties. Yucca contains steroid-like saponins, which produce anti-inflammatory, antioxidant, and anti-spasmodic effects. However, some herbs have drug-like actions that interact with dietary components and may contain prohibited substances like salicylates, digitalis, heroin, cocaine and marijuana. Horses fed garlic at >0.2g/kg per day developed Heinz body anaemia. Drug-herb interactions are common and caution needs to be taken when implementing 'natural product' usage. PMID- 17689993 TI - Applicability of a rapid chromatographic immunoassay for analysis of the distribution of PrPBSE in confirmed BSE cases. AB - The Prionics-Check PrioSTRIP is a rapid chromatographic immunoassay for bovine spongiform encephalopathy (BSE) approved by the European Union in 2004. In this study, the PrioSTRIP was used to analyse PrP(BSE) in 16 different brain areas of nine confirmed BSE cases. The levels of PrP(BSE) in the different brain areas were plotted to give the brain PrP(BSE) distribution curve (BPDC) and compared with the BPDC obtained previously by Western blotting and enzyme-linked immunosorbent assay (ELISA) methods on the same samples. The distribution of PrP(BSE) in different areas of the brain was similar, irrespective of the test applied, indicating that each test could be used for the characterisation of BSE cases. PMID- 17689994 TI - Comparative QSTR studies for predicting mutagenicity of nitro compounds. AB - Mutagenicity and carcinogenicity are toxicological endpoints which pose a great concern being the major determinants of cancers and tumours. Nitroarenes possess genotoxic properties as they can form various electrophilic intermediates and adducts with biological systems. Different QSTR techniques were employed to develop models for the prediction of mutagenicity of nitroarenes using a diverse set of 197 nitro aromatic and hetero aromatic molecules. The 2D and 3D QSTR methods used for model development gave statistically significant results. The alignment for 3D methods was obtained by maximum common substructures (MCS) approach, by taking the most mutagenic molecule of the dataset as the template. All the QSTR models were developed with the same set of training and test set molecules. The 3D contours and 2D contribution maps along with molecular fingerprints provide useful information about the mutagenic potentials of the molecules. The GFA based model shows thermodynamic and topological descriptors play an important role in characterizing mutagenicity of nitroarenes. Atomic level thermodynamic descriptor namely AlogP throws light on hydrophobic features and helps to understand the bilinear model. Topological aspects of these classes of compounds were depicted by the fragment fingerprints and Balaban indices obtained from HQSAR and GFA models, respectively. The predictive abilities of 2D and 3D QSTR models may be useful as a vibrant predictive tool to screen out mutagenic nitroarenes and design safer non-mutagenic nitro compounds. PMID- 17689995 TI - Characterization of the hemoglobins of the adult brushtailed possum, Trichosurus vulpecula (Kerr) reveals non-genetic heterogeneity. AB - The hemoglobins contained within the red blood cells of the adult brushtail possum exhibited cooperative (n=2.6) oxygen binding curves with an associated p50 of 38 mm Hg at pH 7.4 and a large Bohr effect (-0.60). Stripped hemolysate showed a Bohr effect of -0.27, and was sensitive to added DPG (K=56 micromol L(-1)), ATP (K=130 micromol L(-1)), and chloride ions. Four isoforms of hemoglobin were identified using isoelectric focusing. Mass spectrometry indicated that all four isoforms most likely represent the same gene products which have differentially undergone post-translational deamidation and glutathionylation. The oxygen binding characteristics of three isolated isohemoglobins have been determined. PMID- 17689996 TI - New insights into fish ion regulation and mitochondrion-rich cells. AB - Compared to terrestrial animals, fish have to cope with more-challenging osmotic and ionic gradients from aquatic environments with diverse salinities, ion compositions, and pH values. Gills, a unique and highly studied organ in research on fish osmoregulation and ionoregulation, provide an excellent model to study the regulatory mechanisms of ion transport. The present review introduces and discusses some recent advances in relevant issues of teleost gill ion transport and functions of gill ionocytes. Based on accumulating evidence, a conclusive model of NaCl secretion in gills of euryhaline teleosts has been established. Interpretations of results of studies on freshwater fish gill Na+/Cl- uptake mechanisms are still being debated compared with those for NaCl secretion. Current models for Na+/Cl- uptake are proposed based on studies in traditionally used model species. Many reported inconsistencies are claimed to be due to differences among species, various experimental designs, or acclimation conditions. Having the benefit of advanced techniques in molecular/cellular biology, functional genomics, and model animals, several new notions have recently been raised concerning relevant issues of Na+/Cl- uptake pathways. Several new windows have been opened particularly in terms of molecular mechanisms of ionocyte differentiation and energy metabolite transport between gill cells during environmental challenge. PMID- 17689997 TI - Three peptidoglycan recognition protein (PGRP) genes encoding potential amidase from eri-silkworm, Samia cynthia ricini. AB - Three cDNA clones encoding peptidoglycan recognition proteins (PGRP-B, -C and -D) were isolated from larval fat body of immunized Samia cynthia ricini. The deduced amino acid sequences show high homology to each other and also to Drosophila PGRP LB, but rather lower homology to all of the known lepidopteran PGRPs including Samia PGRP-A, a receptor-type PGRP. The three PGRPs conserve the five amino acid residues which form the catalytic site of N-acetylmuramoyl L-alanine amidase as in Drosophila LB. The PGRP-C and -D genes were silent in naive larvae, but strongly induced in fat body by an injection of peptidoglycan. PGRP-B gene, in contrast, constitutively expressed at high levels in naive midgut, and the gene was weakly induced in fat body after injection of peptidoglycan. PMID- 17689998 TI - Influence of antibody formation on reduction of globotriaosylceramide (GL-3) in urine from Fabry patients during agalsidase beta therapy. AB - Two recombinant human agalsidase preparations are available for treatment of Fabry disease. We assayed urinary GL-3 (uGL-3) concentration in seronegative and seropositive patients receiving agalsidase beta (1mg/kg). Antibody formation and residual enzyme activity were strongly correlated. Normalization of uGL-3 was achieved more efficiently in seronegatives. But different from previous reports, reduction of uGL-3 level was observed in some seropositive patients. PMID- 17689999 TI - Transient multiple acyl-CoA dehydrogenation deficiency in a newborn female caused by maternal riboflavin deficiency. AB - A newborn female presented on the first day of life with clinical and biochemical findings consistent with multiple acyl-CoA dehydrogenase deficiency (MADD). Riboflavin supplementation corrected the biochemical abnormalities 24 h after commencing the vitamin. In vitro acylcarnitine profiling in intact fibroblasts both in normal and riboflavin depleted media showed normal oxidation of fatty acids excluding defects in electron transfer flavoprotein (ETF), or ETF ubiquinone oxidoreductase (ETF:QO), or a genetic abnormality in flavin metabolism. In addition, sequencing of the genes encoding ETF and ETF:QO in the proband did not reveal any pathogenic mutations. Determination of the maternal riboflavin status after delivery showed that the mother was riboflavin deficient. Repeat testing done two years after the infant's birth and while on a normal diet showed that the mother was persistently riboflavin deficient and showed a typical MADD profile on plasma acylcarnitine testing. A possible genetic defect in riboflavin transport of metabolism in the mother is postulated to be the cause of the transient MADD seen in the infant. Sequencing of the SLC16A12, RFK and FLAD1 genes encoding key enzymes in riboflavin transport of metabolism in the mother did not identify any pathogenic mutations. The underlying molecular basis of the mother's defect in riboflavin metabolism remains to be established. PMID- 17690000 TI - Retroperitoneal fibrosis: a rare vascular and immune entity disclosed by chronic lombalgia. AB - Retroperitoneal fibrosis is a rare inflammatory and fibrotic process in the retroperitoneal peri-aortic tissues, associated with ureters and other abdominal organs' entrapment. Here we report an original observation of a 55-year-old patient presenting with chronic lombalgia disclosing idiopathic retroperitoneal fibrosis. After one-year follow-up, treatment with corticosteroids led to a complete clinical, biological, and radiological response. Pathogenesis and therapeutic options in idiopathic retroperitoneal fibrosis are discussed. PMID- 17690001 TI - Simulation of high tensile Poisson's ratios of articular cartilage with a finite element fibril-reinforced hyperelastic model. AB - Analyses with a finite element fibril-reinforced hyperelastic model were undertaken in this study to simulate high tensile Poisson's ratios that have been consistently documented in experimental studies of articular cartilage. The solid phase was represented by an isotropic matrix reinforced with four sets of fibrils, two of them aligned in orthogonal directions and two oblique fibrils in a symmetric configuration respect to the orthogonal axes. Two distinct hyperelastic functions were used to represent the matrix and the fibrils. Results of the analyses showed that only by considering non-orthogonal fibrils was it possible to represent Poisson's ratios higher than one. Constrains in the grips and finite deformations played a minor role in the calculated Poisson's ratio. This study also showed that the model with oblique fibrils at 45 degrees was able to represent significant differences in Poisson's ratios near 1 documented in experimental studies. However, even considering constrains in the grips, this model was not capable to simulate Poisson's ratios near 2 that have been reported in other studies. The study also confirmed that only with a high relation between the stiffness of the fibers and that of the matrix was it possible to obtain high Poisson's ratios for the tissue. Results suggest that analytical models with a finite number of fibrils are appropriate to represent main mechanical effects of articular cartilage. PMID- 17690003 TI - Geometrical regularization of displacement fields for histological image registration. AB - This article tackles the registration of 2-D biomedical images (histological sections, autoradiographs, cryosections, etc.). Our goal is to adequately match anatomical features of interest without inducing biologically improbable tissue distortions. We observe that the large variety of registration applications--3-D volume reconstruction, multimodal molecular mapping, etc.--induce a no less diverse set of requirements in terms of accuracy and robustness. In turn, these directly translate into regularization constraints on the deformation model, which should ideally be specifiable by the user. We propose an adaptive regularization approach where the rigidity constraints are informed by the registration application at hand and whose support is controlled by the geometry of the images to be registered. For each site of a sparse lattice over which a displacement field has been computed, our algorithm estimates, in a robust fashion, a rigid or affine transformation within a circular neighbourhood cut to fit the local geometry around the site. We investigate the behaviour of this technique and discuss its sensitivity to the rigidity parameter. PMID- 17690002 TI - Neovascular glaucoma. AB - Neovascular glaucoma (NVG) is a severely blinding, intractable disease. The objective of this review is to provide detailed information on its basic and clinical aspects, to enable us to manage it logically. Therefore, its causes, pathogenesis and pathology, methods of early diagnosis and management are discussed. To prevent or reduce the extent of visual loss caused by NVG, the first essential is to have a high index of suspicion of its development. The most common diseases responsible for development of NVG are ischemic central retinal vein occlusion (CRVO), diabetic retinopathy and ocular ischemic syndrome. In the management strategy, the first priority should be to try to prevent its development by appropriate management of the causative diseases. If NVG develops, early diagnosis is crucial to reduce the extent of visual loss. Management of NVG primarily consists of controlling the high IOP by medical and/or surgical means to minimize the visual loss. Currently, we still do not have a satisfactory means of treating NVG and preventing visual loss in the majority, in spite of multiple modes of medical and surgical options advocated over the years and claims made. This review discusses the pros and cons for the various advocated treatments. PMID- 17690004 TI - Hierarchical statistical shape analysis and prediction of sub-cortical brain structures. AB - In this paper, we describe how two multivariate statistical techniques can be used to investigate how different structures within the brain vary statistically relative to each other. The first of these techniques is canonical correlation analysis which extracts and quantifies correlated behaviour between two sets of vector variables. The second technique is partial least squares regression which determines the best factors within a first set of vector variables for predicting a vector variable from a second set. We applied these techniques to 178 sets of 3D MR images of the brain to quantify and predict correlated behaviour between 18 sub-cortical structures. Pairwise canonical correlation analysis of the structures gave correlation coefficients between 0.51 and 0.67, with adjacent structures possessing the strongest correlations. Pairwise predictions of the structures using partial least squares regression produced an overall sum squared error of 4.26 mm2, compared with an error of 6.75 mm2 produced when using the mean shape as the prediction. We also indicate how the correlation strengths between structures can be used to inform a hierarchical scheme in which partial least squares regression is combined with a model fitting algorithm to further improve prediction accuracy. PMID- 17690005 TI - Keratoconus contact lens fitting: what do we really know? (... and where do we learn it?). PMID- 17690006 TI - Adenovirus-mediated expression of dominant negative c-myb induces apoptosis in head and neck cancer cells and inhibits tumor growth in animal model. AB - The recent demonstration of aberrant expression of the c-myb proto-oncogene in various cancers suggests that c-myb plays an important role in the development of cancer. On this basis, it has been proposed that ablation of c-myb function might be an effective approach for therapy of c-myb dependent malignancies. We previously used a dominant negative c-myb (DN-myb) construct to induce apoptosis in K562 cells. In this study, DN-myb was expressed in an adenovirus-mediated gene delivery system and introduced into head and neck squamous cell carcinoma cells (HNSCC) in vitro and in vivo to examine its tumor suppressive function and its potential in HNSCC gene therapy. Over expression of DN-myb in HNSCC cells inhibited in vitro cell proliferation, expression of growth factors such as IGF I, -II, IGF-1R, and VEGF, inhibited Akt/PKB pathway activation, and enhanced induction of apoptosis. Similarly, in vivo administration of DN-myb retarded tumor-growth. Our results support a role for DN-myb in inducing apoptosis and tumor suppression, and, furthermore, suggest that DN-myb gene therapy might provide a powerful tool for treatment of c-myb dependent malignancies such as HNSCC. PMID- 17690007 TI - A study on photochemical behavior of lysozyme-bromophenol blue complex and its analytical application. AB - It was found that macromolecular complexes were formed between lysozyme and bromophenol blue (BPB) with the electrostatic attraction in acetate medium (pH 6.5). The binding constant and the number of binding site for lysozyme-BPB complex were obtained, and the thermodynamic parameters were given. In addition, a remarkable enhancement of resonance light scattering (RLS) intensity for the macromolecular complex was observed with a scattering peak at 336 nm. And the increment of RLS intensity was proportional to the concentration of lysozyme in the range of 5 ng ml(-1) to 10.0 microg ml(-1). The influence of experimental conditions including pH, BPB concentration, and ionic strength on RLS system were tested, especially the effect of temperature was examined in detail. The proposed method was successfully applied to determine lysozyme in human saliva and tear samples without any special pretreatment. Compared with other methods the proposed method is of higher sensitivity and wider linear range. PMID- 17690008 TI - Synthesis of new oxamide-based ligand and its coordination behavior towards copper(II) ion: spectral and electrochemical studies. AB - A new ligand N,N'-bis{3-(2-formyl-4-methyl-phenol)-6-iminopropyl}oxamide (L) and its mono- and binuclear copper(II) complexes have been synthesized and characterized. The ligand shows absorption maxima at 249 and 360 with a weak transition at 455 nm. The ligand was found to be fluorescent and shows an emission maximum at 516 nm on excitation at 360 nm. The electronic spectra of the mono- and binuclear Cu(II) complexes exhibited a d-d transition in the region 520 560 nm characteristic of square planar geometry around Cu(II) ion. The ESR spectrum of the mononuclear complex showed four lines with nuclear hyperfine splitting. The binuclear complex showed a broad ESR spectrum with g=2.10 due to antiferromagnetic interaction between the two Cu(II) ions. The room-temperature magnetic moment values (micro(eff)) for the mono- and binuclear Cu(II) complexes are found to be 1.70 micro(B) and 1.45 micro(B), respectively. The electrochemical studies of the mononuclear Cu(II) complex showed a single irreversible one-electron wave at -0.70 V (E(pc)) and the binuclear Cu(II) complex showed two irreversible one-electron reduction waves at -0.75 V (E(pc)(1)) and -1.27 V (E(pc)(2)) in the cathodic region. PMID- 17690009 TI - A single red InGaN-based light-emitting diode with a europium (III) ternary complex as mono-phosphor. AB - A novel europium (III) ternary complex, Eu(TPBDTFA)(3)Phen, was designed and synthesized. Photoluminescence measurements show that the energy absorbed by the organic ligands was efficiently transferred to the central Eu(3+) ions, and the complex exhibits strongly red emission due to the (5)D(0)-(7)F(j) transitions of Eu(3+) ions with appropriate CIE (Commission Internationale de l'Eclairage, International Commission on Illumination) chromaticity coordinates (x=0.66, y=0.33) under 310-420 nm light excitation. The luminescence quantum yield for the Eu(3+) complex is 0.18. Thermogravimetric analysis (TGA) confirms a high thermal stability of the complex with a decomposition temperature of 341 degrees C. All the characteristics indicate that the Eu(3+) complex is a highly efficient red phosphor suitable to be excited by near UV light. An intense red-emitting LED was fabricated by combining the mono-phosphor Eu(TPBDTFA)(3)Phen with a approximately 395 nm emitting InGaN chip. PMID- 17690011 TI - Statins and foam cell formation: impact on LDL oxidation and uptake of oxidized lipoproteins via scavenger receptors. AB - The uptake of oxidized lipoproteins via scavenger receptors and the ensuing formation of foam cells are key events during atherogenesis. Foam cell formation can be reduced by treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). The efficacy of statins is evidently due not only to their cholesterol-lowering properties, but also to lipid-independent pleiotropic effects. This review focuses on lipid-independent pleiotropic effects of statins that influence foam cell formation during atherogenesis, with special emphasis on oxidative pathways and scavenger receptor expression. PMID- 17690010 TI - Evaluation of global clustering patterns and strain variation over an extended ORF26 gene locus from Kaposi's sarcoma herpesvirus. AB - BACKGROUND: Small 233-bp or 330-bp DNA fragments of the ORF26 gene of human Kaposi's sarcoma herpesvirus (KSHV) have been used extensively to identify KSHV by PCR in clinical samples; to associate KSHV with novel diseases and to correlate KSHV strain differences with pathogenicity. OBJECTIVES: We evaluated the nature, extent and source of nucleotide sequence variability among a large and diverse set of known KSHV-positive DNA samples. STUDY DESIGN: Direct DNA PCR sequencing was carried out on 136 distinct Kaposi's sarcoma and primary effusion lymphoma-related samples from different geographic locations. RESULTS: The presence of 26 diagnostic nucleotide polymorphisms across an expanded 965-bp PCR locus define eight distinct ORF26E genotypes, three being of Eurasian origin, one from the Pacific Rim, and five from Sub-Saharan Africa. Previous ambiguities between some genotype patterns in the 330-bp locus data are fully resolved. CONCLUSIONS: This analysis provides an expanded database for understanding and evaluating ORF26 polymorphisms. In particular, the eight genotype clusters correlated with specific ethnic and geographic origins of the patients. Furthermore, the very low level of additional sporadic nucleotide variation found permits detection of spurious sequence errors or contamination present in some published data. PMID- 17690012 TI - External qigong for pain conditions: a systematic review of randomized clinical trials. AB - The aim of this systematic review was to assess the clinical evidence of external qigong as a treatment option for pain conditions. Databases were searched up to January 2007. Randomized, clinical trials (RCTs) testing external qigong in patients with pain of any origin assessing clinical outcomes were considered. Trials using any type of control group were included. The selection of studies, data extraction, and validation were performed independently by at least 2 reviewers. One hundred forty-one potentially relevant studies were identified and 5 RCTs could be included. All RCTs of external qigong demonstrated greater pain reductions in the qigong groups compared with control groups. Meta-analysis of 2 RCTs showed a significant effect of external qigong compared with general care for treating chronic pain (Pain 100 mm VAS; weighted main differences, 36.3 mm; 95% CI, 22.8 to 49.8; P < .001; heterogeneity: chi(2) = 1.79, P = .18, I(2) = 44.0%, n = 80). The evidence from RCTs testing the effectiveness of external qigong for treating pain is encouraging. Further studies are warranted. PERSPECTIVE: This review of clinical studies focused on the efficacy of qigong, an energy-healing intervention used to prevent and cure ailments. A meta-analysis shows that evidence for the effectiveness of external qigong is encouraging, though further studies are warranted. PMID- 17690013 TI - Hyperbaric oxygen treatment is comparable to acetylsalicylic acid treatment in an animal model of arthritis. AB - Approximately 1 in 5 adults in the United States are affected by the pain, disability, and decreased quality of life associated with arthritis. The primary focus of treatment is on reducing joint inflammation and pain through a variety of pharmacotherapies, each of which is associated with various side effects. Hyperbaric oxygen therapy is an alternative treatment that has been recommended to treat a variety of inflammatory diseases, ranging from chronic brain injury to exercise induced muscle soreness. The purpose of this set of experiments was to explore the effect of hyperbaric oxygen therapy on joint inflammation and mechanical hyperalgesia in an animal model of arthritis, and compare these effects to treatment with aspirin. Hyperbaric oxygen therapy significantly reduced both joint inflammation and hyperalgesia. As compared with aspirin treatment, hyperbaric treatment was equally as effective in decreasing joint inflammation and hyperalgesia. PERSPECTIVE: This article reports that hyperbaric oxygen treatment decreases pain and inflammation in an animal model of arthritis. The effect of hyperbaric oxygen treatment is very similar in magnitude to the effect of acetylsalicylic acid treatment. Potentially, hyperbaric oxygen could be used to treat pain and inflammation in patients with arthritis. PMID- 17690014 TI - A systematic review of measures used to assess chronic musculoskeletal pain in clinical and randomized controlled clinical trials. AB - There are many types of pain assessments available to researchers conducting clinical trials, ranging from simple, single-item Visual Analog Scale (VAS) questions through extensive, multidimensional inventories. The primary question addressed in this survey of top-tier medical journals was: Which pain assessments are most commonly used in trials? Articles addressing chronic musculoskeletal pain in clinical trials were identified in 7 major medical journals for the year 2003. A total of 50 studies (1476 total original research articles reviewed) met selection criteria, and from these we identified 28 types of pain assessments. Selected studies were classified according to the dimensions of pain assessed, the type of scale and descriptors/anchors used, and the reporting period specified. The most frequently used assessments were the single-item VAS and the Numeric Rating Scale; multidimensional inventories were used infrequently. There was considerable variability in the instructions patients received about the period to consider when evaluating their pain, and many studies provided only cursory information about their assessments in the methods. Overall, it appears that clinical trials use simple measures of pain and that there is no widely accepted standard for clinical pain assessment that would facilitate comparison of outcomes across trials. PERSPECTIVE: This review highlights the heterogeneity of pain outcome measures used and the abundance of single-item measures in clinical trials. Although there are many pain outcome measures available to clinical researchers, more consistency in the field should be encouraged so that results between studies can be compared. PMID- 17690015 TI - Contribution of myofascial trigger points to migraine symptoms. AB - This study evaluated the contribution of myofascial trigger points (TrPs) to migraine pain. Seventy-eight migraine patients with cervical active TrPs whose referred areas (RAs) coincided with migraine sites (frontal/temporal) underwent electrical pain threshold measurement in skin, subcutis, and muscle in TrPs and RAs at baseline and after 3, 10, 30, and 60 days; migraine pain assessment (number and intensity of attacks) for 60 days before and 60 days after study start. Fifty-four patients (group 1) underwent TrP anesthetic infiltration on the 3rd, 10th, 30th, and 60th day (after threshold measurement); 24 (group 2) received no treatment. Twenty normal subjects underwent threshold measurements in the same sites and time points as patients. At baseline, all patients showed lower than normal thresholds in TrPs and RAs in all tissues (P < .001). During treatment in group 1, all thresholds increased progressively in TrPs and RAs (P < .0001), with sensory normalization of skin/subcutis in RAs at the end of treatment; migraine pain decreased (P < .001). Threshold increase in RAs and migraine reduction correlated linearly (.0001 < P < .006). In group 2 and normal subjects, no changes occurred. Cervical TrPs with referred areas in migraine sites thus contribute substantially to migraine symptoms, the peripheral nociceptive input from TrPs probably enhancing the sensitization level of central sensory neurons. PERSPECTIVE: This article shows the beneficial effects of local therapy of active myofascial trigger points (TrPs) on migraine symptoms in patients in whom migraine sites coincide with the referred areas of the TrPs. These results suggest that migraine pain is often contributed to by myofascial inputs that enhance the level of central neuronal excitability. PMID- 17690016 TI - An exploration of the psychometric properties of the PASS-20 with a nonclinical sample. AB - The Pain Anxiety Symptoms Scale-20 (PASS-20) assesses 4 factorially distinct components of pain-related anxiety (ie, cognitive, fear, escape/avoidance, physiological). The PASS-20 has good factor stability, reliability, and internal consistency in clinical samples. Psychometric data for nonclinical populations are not yet established. This study had 4 purposes: (1) To assess the factor structure of the PASS-20 with a nonclinical sample; (2) to assess concurrent validity of PASS-20 subscales with related self-report instruments; (3) to compare our results with findings of a similar study using a clinical pain sample; and (4) to suggest a preliminary cut-off score to identify individuals with significantly elevated pain-related anxiety. A sample of 155 undergraduates completed the PASS-20 as part of a larger study. Confirmatory factor analysis supported the existing 4-factor model, and internal consistencies for total and subscale scores were comparable with previous research. PASS-20 total and subscale scores were moderately correlated with other related measures, providing evidence of concurrent validity. On all PASS-20 subscales the nonclinical sample had significantly lower (P < .01) scores than those for a clinical pain sample. The majority of individuals classified as having high pain-related anxiety had PASS-20 total scores greater than 30. Implications and future research directions are discussed. PERSPECTIVE: A nonclinical sample is used to explore the psychometric properties of the PASS-20. Confirmatory factor analysis, comparisons with a clinical pain sample, and preliminary cut-off scores indicative of high levels of pain-related anxiety are discussed. Pain-related anxiety is identified as a continuous construct, robust across both clinical and nonclinical samples. PMID- 17690017 TI - A randomized clinical trial of targeted cognitive behavioral treatment to reduce catastrophizing in chronic headache sufferers. AB - This randomized clinical trial (RCT) examined the efficacy of a cognitive behavioral treatment (CBT) specifically targeted toward reducing pain catastrophizing for persons with chronic headache. Immediate treatment groups were compared with wait-list control groups. Differential treatment gains based on the order of presentation of 2 components of CBT (cognitive restructuring and cognitive/behavioral coping) and the role of catastrophizing in treatment outcome were examined. Thirty-four participants enrolled in a 10-week group treatment and 11 completed a wait-list self-monitoring period. Participants reported significant reductions in catastrophizing and anxiety and increased self-efficacy compared with wait-list control subjects, and these were maintained at follow-up. Although we did not find overall differences in the reduction of headache frequency or intensity compared with wait-list control subjects, calculation of clinical significance on headache indicators suggest that approximately 50% of treated participants showed meaningful changes in headache indices as well. Order of treatment modules was not related to gains during treatment or at follow-up; however, almost all changes occurred during the second half of treatment, suggesting that duration of treatment participation is important. PERSPECTIVE: Cognitive-behavioral treatment targeting reduction of catastrophizing for chronic headache pain reduced negative cognitive and affective variables associated with recurrent headache, increased headache management self-efficacy, and in half of the participants, produced clinically meaningful reductions in headache indicators. Length of treatment is an important factor to consider when providing CBT for chronic pain. PMID- 17690018 TI - Calcimimetic, AMG 073, induces relaxation on isolated rat aorta. AB - Calcimimetics are a class of compounds that positively modulate the calcium sensing receptor (CaR) by allosterically increasing the affinity of the receptor for extracellular Ca(2+). In this study we have investigated the effects of the clinically used calcimimetic, AMG 073, on contractility of the rat aorta by wire myography. AMG 073 elicited a concentration-dependent vasodilatation of the precontracted aorta. Inhibition of endothelium function by L-NAME and indomethacin reduced AMG 073-induced relaxation of the vessel precontracted with phenylephrine, but not with 125 mM K(+). The vasodilatory effect could be mediated by the CaR or/and a direct action on the ion channels. Intriguingly, CaR agonists, neomycin and gadolinium, did not have any effect on the contractility of the aorta. Immunohistochemical staining of the aorta with two CaR specific antibodies demonstrated the presence of the CaR protein, predominantly in endothelial and adventitial layers. PMID- 17690019 TI - Confocal endomicroscopy in ulcerative colitis: differentiating dysplasia associated lesional mass and adenoma-like mass. AB - BACKGROUND & AIMS: The management of dysplasia-associated lesional mass (DALM) and adenoma-like mass (ALM) in chronic ulcerative colitis (CUC) differs radically, involving total pan-proctocolectomy vs endoscopic resection and surveillance. Such lesions cannot be reliably differentiated using conventional colonoscopy. Confocal laser scanning imaging enables in vivo surface and subsurface cellular resolution imaging during ongoing video endoscopy. The aim of this study was to prospectively assess the clinical applicability and predictive power of the Pentax EC3870K endomicroscope for the in vivo differentiation of ALM and DALM in CUC during ongoing videocolonoscopy. METHODS: Patients were recruited who had a diagnosis of ALM or DALM within the previous 16 weeks. Confocal laser endomicroscopic (CLE) imaging of the circumscribed lesion and 4 adjacent mucosal segments was performed. Targeted biopsy with and without tissue sampling with endoscopic mucosal resection was performed and compared with conventional histopathology as the gold standard. RESULTS: Thirty-six patients with 36 lesions fulfilled the study entry criteria. Using modified Mainz criteria for the in vivo diagnosis of ALM and DALM, the kappa coefficient of agreement between CLE and histopathologic evaluation was 0.91, and accuracy was 97% (95% confidence interval = 86%-99%). CONCLUSIONS: This is the first study addressing the novel application of the Pentax EC3870K endomicroscopy system for the in vivo differentiation of ALM and DALM during ongoing video colonoscopy in CUC. We have shown that ALM and DALM can be differentiated with a high overall accuracy, enabling the safe selection of patients suitable for endoluminal resection versus immediate referral for pan-proctocolectomy. PMID- 17690020 TI - Gastric band technique. PMID- 17690021 TI - Accessing the common bile duct after Roux-en-Y gastric bypass. AB - We report on the clinical course of 2 patients who underwent laparoscopic Roux-en Y gastric bypass for obesity and subsequently presented with biliary complications of choledocholithiasis in 1 case and sphincter of Oddi dysfunction in the other. The approach to these complex problems is described. Both patients underwent percutaneous transhepatic access to the common bile duct (CBD) for balloon sphincteroplasty. In 1 patient, percutaneous choledochoscopy was used for endoluminal visualization of the CBD. A literature review of the management of biliary problems after gastric bypass is presented. Although access to the CBD is limited, the options include percutaneous transhepatic instrumentation of the CBD, percutaneous or laparoscopic transgastric endoscopic retrograde cholangiopancreatography (ERCP), transenteric endoscopic cholangiopancreatography, ERCP using specialized endoscopes, and laparoscopic or open CBD exploration. Bile duct pathology after laparoscopic gastric bypass can be safely and effectively managed using a variety of techniques. PMID- 17690022 TI - Identification of a novel endochitinase from a marine bacterium Vibrio proteolyticus strain No. 442. AB - Chitin binding proteins prepared from Vibrio proteolyticus were purified and the N-terminal amino-acid sequence of a protein from a 110-kDa band on SDS-PAGE was found to be 85-90% identical to the 22nd-41st residues of the N-termini of chitinase A precursor proteins from other vibrios. We cloned the corresponding gene, which encodes a putative protein of 850 amino acids containing a 26-residue signal sequence. The chitinase precursor from V. proteolyticus was 78-80% identical to those from Vibrio parahaemolyticus, Vibrio alginolyticus and Vibrio carchariae. However, the proteolytic cleavage site for C-terminal processing between R597 and K598 in the chitinase precursor of other vibrios was not observed in the amino acid sequence of V. proteolyticus, which instead had the sequence R600 and A601. Subsequently, full-length and truncated chitinases were generated in Escherichia coli. The specific activity of full-length chitinase expressed in E. coli was 17- and 20-folds higher for colloidal and alpha-chitins (insoluble substrate), respectively, than that of the C-terminal truncated enzyme. However, both recombinants showed similar hydrolysis patterns of hexa-N acetyl-chitohexaose (soluble substrate), producing di-N-acetyl-chitobiose as major product on TLC analysis. We showed that the C-terminus of the V. proteolyticus chitinase A was important for expression of high specific activity against insoluble chitins. PMID- 17690023 TI - Kinetic analysis of butyrylcholinesterase-catalyzed hydrolysis of acetanilides. AB - The aryl-acylamidase (AAA) activity of butyrylcholinesterase (BuChE) has been known for a long time. However, the kinetic mechanism of aryl-acylamide hydrolysis by BuChE has not been investigated. Therefore, the catalytic properties of human BuChE and its peripheral site mutant (D70G) toward neutral and charged aryl-acylamides were determined. Three neutral (o-nitroacetanilide, m nitroacetanilide, o-nitrophenyltrifluoroacetamide) and one positively charged (3 (acetamido) N,N,N-trimethylanilinium, ATMA) acetanilides were studied. Hydrolysis of ATMA by wild-type and D70G enzymes showed a long transient phase preceding the steady state. The induction phase was characterized by a hysteretic "burst". This reflects the existence of two enzyme states in slow equilibrium with different catalytic properties. Steady-state parameters for hydrolysis of the three acetanilides were compared to catalytic parameters for hydrolysis of esters giving the same acetyl intermediate. Wild-type BuChE showed substrate activation while D70G displayed a Michaelian behavior with ATMA as with positively charged esters. Owing to the low affinity of BuChE for amide substrates, the hydrolysis kinetics of neutral amides was first order. Acylation was the rate-determining step for hydrolysis of aryl-acetylamide substrates. Slow acylation of the enzyme, relative to that by esters may, in part, be due suboptimal fit of the aryl acylamides in the active center of BuChE. The hypothesis that AAA and esterase active sites of BuChE are non-identical was tested with mutant BuChE. It was found that mutations on the catalytic serine, S198C and S198D, led to complete loss of both activities. The silent variant (FS117) had neither esterase nor AAA activity. Mutation in the peripheral site (D70G) had the same effect on esterase and AAA activities. Echothiophate inhibited both activities identically. It was concluded that the active sites for esterase and AAA activities are identical, i.e. S198. This excludes any other residue present in the gorge for being the catalytic nucleophile pole. PMID- 17690024 TI - A simple technique to support the paralysed face with Gore-tex sutures using drain trocars under local anaesthetic. PMID- 17690025 TI - Effects of continuous dexamethasone treatment on differentiation capabilities of bone marrow-derived mesenchymal cells. AB - Human bone marrow-derived mesenchymal cells (hBMMCs) originate from cell populations in the bone marrow and are capable of differentiating along multiple mesenchymal lineages. To differentiate hBMMCs into osteoblasts, adipocytes and chondrocytes, dexamethasone has been used as a differentiation reagent. We hypothesized that dexamethasone would augment the responsiveness of BMMCs to other differentiation reagents and not define the lineage. This study investigated the effect of continuous treatment with 100 nM dexamethasone on the differentiation of BMMCs into three different lineages. hBMMCs cultured with continuous dexamethasone treatment (100 nM) exhibited higher mRNA expression levels of osteogenic markers and higher positive rates of colony forming unit assays for osteogenesis compared to hBMMCs treated with dexamethasone only during the differentiation culture. Furthermore, continuous dexamethasone treatment augmented bone formation capability of monkey-derived BMMCs in a bone induction experimental model at an extra skeletal site. In addition, continuously dexamethasone-treated hBMMCs formed larger chondrogenic pellets and expressed SOX9 at higher level than the control BMMCs. Likewise, continuous dexamethasone treatment facilitated adipogenic differentiation based on mRNA level and colony forming unit analysis. To investigate the mechanism of the augmentation of differentiation, further studies on apoptosis were conducted. The studies indicated that dexamethasone selectively induced apoptosis of some populations of hBMMCs which were thought to have poor differentiation capability. PMID- 17690026 TI - The use of fractography to supplement analysis of bone mechanical properties in different strains of mice. AB - Fractography has not been fully developed as a useful technique in assessing failure mechanisms of bone. While fracture surfaces of osteonal bone have been explored, this may not apply to conventional mechanical testing of mouse bone. Thus, the focus of this work was to develop and evaluate the efficacy of a fractography protocol for use in supplementing the interpretation of failure mechanisms in mouse bone. Micro-computed tomography and three-point bending were performed on femora of two groups of 6-month-old mice (C57BL/6 and a mixed strain background of 129SV/C57BL6). SEM images of fracture surfaces were collected, and areas of "tension", "compression" and "transition" were identified. Percent areas of roughness were identified and estimated within areas of "tension" and "compression" and subsequently compared to surface roughness measurements generated from an optical profiler. Porosity parameters were determined on the tensile side. Linear regression analysis was performed to evaluate correlations between certain parameters. Results show that 129 mice exhibit significantly increased bone mineral density (BMD), number of "large" pores, failure strength, elastic modulus and energy to failure compared to B6 mice (p<0.001). Both 129 and B6 mice exhibit significantly (p<0.01) more percent areas of tension (49+/-1%, 42+/-2%; respectively) compared to compression (26+/-2%, 31+/-1%; respectively). In terms of "roughness", B6 mice exhibit significantly less "rough" areas (30+/ 4%) compared to "smooth" areas (70+/-4%) on the tensile side only (p<0.001). Qualitatively, 129 mice demonstrate more evidence of bone toughening through fiber bridging and loosely connected fiber bundles. The number of large pores is positively correlated with failure strength (p=0.004), elastic modulus (p=0.002) and energy to failure (p=0.041). Percent area of tensile surfaces is positively correlated with failure strength (p<0.001), elastic modulus (p=0.016) and BMD (p=0.037). Percent area of rough compressive surfaces is positively correlated with energy to failure (p=0.039). Evaluation of fracture surfaces has helped to explain why 129 mice have increased mechanical properties compared to B6 mice, namely via toughening mechanisms on the compressive side of failure. Several correlations exist between fractography parameters and mechanical behavior, supporting the utility of fractography with skeletal mouse models. PMID- 17690027 TI - Early post-operative complications in living donor liver transplantation: prevention, detection and management. PMID- 17690028 TI - Regulating regulatory T cells to achieve transplant tolerance. AB - BACKGROUND: Regulatory T cells (Tregs) play crucial roles in both induction and maintenance of tolerance. This active immune regulation may contribute not only to the control of immune responses to self-antigens and thereby prevent autoimmune diseases, but also the control of responses to non-self molecules in adaptive immunity. Numerous experimental and clinical studies indicate that manipulating the balance between regulatory and responder T cells is an effective strategy to control immune responsiveness after transplantation. DATA SOURCES: Literature search was conducted using PubMed on the related subjects. Part of the material was based on the most recent work in the authors' laboratory. RESULTS: We propose some new strategies to achieve transplant tolerance in rodent animals via manipulating Treg function, including using histone deacetylase (HDAC) inhibitor to regulate Foxp3 transcription and enhance Treg suppression, induction of Treg-sparing apoptosis via Nur77, and identification of the co-inhibitory molecule herpes virus entry mediator (HVEM) as an effector molecule for Treg function. CONCLUSION: Regulation of Treg function will definitely provide us very promising tools to achieve clinical tolerance in the future. PMID- 17690029 TI - Management of the middle hepatic vein and its tributaries in right lobe living donor liver transplantation. AB - BACKGROUND: Left liver graft from a small donor will not meet the metabolic demands of a larger adult recipient. To overcome the problem of graft size insufficiency, living donor liver transplantation (LDLT) using the right lobe has become a standard method for adult patients. As the drainage of the median sector (segments V, VIII and IV) is mainly by the middle hepatic vein (MHV), the issue of whether the MHV should or should not be taken with the graft or whether the MHV tributaries (V5, V8) should be reconstructed in the recipient remains to be settled. DATA SOURCES: An English-language literature search was conducted using MEDLINE (1985-2006) on right lobe living donor liver transplantation, middle hepatic vein, vein graft, hepatic venoplasty and other related subjects. RESULTS: Some institutions had proposed their policy for the management of the MHV and its tributaries. Dominancy of the hepatic vein, graft-to-recipient weight ratio, and remnant liver volume as well as the donor-to-recipient body weight ratio, the volume of the donor's right lobe to the recipient's standard liver volume and the size of MHV tributaries are the major elements for the criteria of inclusion of the MHV, while for the policy of MHV tributaries reconstruction, the proportion of congestive area and the diameter of the tributaries are the critical elements. Optimal vein grafts such as recipient's portal vein and hepatic venoplasty technique have been used to obviate hepatic congestion and venous drainage disturbance. CONCLUSIONS: Taking right liver grafts with the MHV trunk (extended right lobe grafts) or performing the MHV tributaries reconstruction in modified right lobe grafts, according to the criteria proposed by the institutions with rich experience, can solve the congestion problem of the right paramedian sector and help to improve the outcomes of the patients. The additional use of optimal vein grafts and hepatic venoplasty also can guarantee excellent venous drainage. PMID- 17690030 TI - Multi-slice spiral CT angiography in evaluating donors of living-related liver transplantation. AB - BACKGROUND: During the past years, the number of liver transplantation has increased greatly, but the number of available organs has not increased. In view of the critical shortage of organs, the indications for living-related liver transplantation (LRLT) have broadened since experience with the procedure has been achieved. This study was undertaken to assess the value of multi-slice spiral CT (MSCT) angiography in evaluating the hepatic arterial and veinous anatomy of potential donors for LRLT. METHODS: MSCT was performed after intravenous injection of contrast material at 3 ml/s. The total dose was calculated as 2 ml/kg. Twenty LRLT donors (2 men and 18 women) were subjected to MSCT angiography of hepatic blood vessels. These were generated by volume rendering and maximum intensity projection, while curved planar reformation was added in 5 patients. RESULTS: We identified 10 important hepatic vascular variants in 9 of the 20 donors (4 arterial, 4 venous, and 2 portal venous variants). In hepatic arterial variants, two had a replaced right hepatic artery arising from the superior mesenteric artery, an accessory right hepatic artery from the superior mesenteric artery and a replaced left hepatic artery arising from the left gastric artery. In hepatic venous variants, three had an accessory inferior right hepatic vein and one had two accessory inferior right hepatic veins. In hepatic portal venous variants, two had trifurcation of the main portal vein. CONCLUSIONS: As a non-invasive and reliable method, MSCT angiography is of value in the clinical evaluation of LRLT donors. MSCT angiography should be recommended as a routine preoperative examination for potential LRLT donors. PMID- 17690031 TI - Recombinant anti-HBsAg Fab blocks hepatitis B virus infection after orthotopic liver transplantation. AB - BACKGROUND: Recurrence of hepatitis B virus (HBV) after orthotopic liver transplantation is very common in the absence of adequate prophylaxis and is often associated with poor prognosis because of the development of cirrhosis, fibrosing cholestatic hepatitis, or fulminant hepatitis. Therefore it is important to study the prevention of HBV reinfection after liver transplantation. METHODS: Recombinant Fab (rFab) was constructed to evaluate gene therapy for post transplantation HBV reinfection. Hepatocytes were divided into three groups: HBV infection, rFab-blocked HBV-infection, and control. The inhibition of HBsAg adsorption test, the micro-cytotoxicity assay, and the blockade test of HBV infection were carried out. The HBsAg adsorption rate, the hepatocyte death rate and the HBV infection rate were statistically analyzed. RESULTS: The HBsAg adsorption rate blocked by rFab in the HBsAg adsorption test was 0.3%. The hepatocyte death rate was 98.8% induced by rFab in the micro-cytotoxicity assay, 1.3% in the rFab-blocked HBV-infected group and 77% in the HBV-infected group in the blockade test of HBV. CONCLUSIONS: We found that rFab effectively blocked HBV infection in human hepatocytes. This provides an attractive alternative for hepatitis B prophylaxis. PMID- 17690032 TI - Sirolimus as primary immunosuppressant for calcineurin inhibitor-related renal insufficiency after liver transplantation. AB - BACKGROUND: Calcineurin inhibitor-related renal toxicity affects patient and graft survival in transplant recipients. This study aimed to determine whether sirolimus is effective and safe in treating renal insufficiency related to tacrolimus after liver transplantation. METHODS: Tacrolimus for primary immunosuppression was used in 16 patients after liver transplantation. Patients with a creatinine level higher than 132.6 micromol/L were eligible for conversion to sirolimus. Simultaneously, the dose of tacrolimus was decreased to half. Blood urea nitrogen, creatinine, tacrolimus level, liver function and rejection episodes were monitored dynamically. RESULTS: All patients showed improvement of renal function after conversion to sirolimus. Blood creatinine level was reduced from 146.8+/-92.4 to 105.3+/-71.3 micromol/L (P<0.05). One patient had an acute rejection episode that was successfully treated with pulsed corticosteroids and low-dose tacrolimus. The side-effects of sirolimus included hyperlipidemia (4 patients) and leukocytopenia (2). CONCLUSION: Sirolimus can be safely used in liver transplant recipients suffering from tacrolimus-related renal insufficiency. PMID- 17690033 TI - Donor denervation and elimination of Kupffer cells affect expression of P selectin and ICAM-1 in liver graft. AB - BACKGROUND: The non-function and dysfunction of primary liver graft likely involves dependence on Kupffer cells and hepatic innervation. The present experiment was designed to study the expression of P-selectin and intercellular adhesion molecule-1 (ICAM-1) mRNA in liver graft and to elucidate the role of Kupffer cells and the sympathetic nerve of the liver in down-regulating this expression. METHODS: Donor rats were given hexamethonium, a sympathetic ganglionic blocking agent, and/or gadolinium chloride, an inhibitor of Kupffer cells. Then the changes of graft P-selectin and ICAM-1 mRNA expression were measured after liver transplantation. RESULTS: The expressions of P-selectin and ICAM-1 mRNA were increased after liver transplantation, and down-regulated by liver denervation and elimination of Kupffer cells. CONCLUSIONS: Live donor denervation and elimination of Kupffer cells down-regulated the expressions of P selectin and ICAM-1 mRNA in grafts. This may decrease graft ischemia/reperfusion injury. PMID- 17690034 TI - Postoperative jaundice after cardiac surgery. AB - BACKGROUND: The frequency and pattern of hyperbilirubinemia after open-heart surgery and its severe perioperative complications are not well clarified. The purpose of this study was to investigate the incidence and nature of postoperative jaundice in patients undergoing cardiac operation, to analyze the determinants, and to identify the clinical significance of this complication with regard to the associated morbidity and mortality. METHODS: A prospective observational study was made during the period of 2003-2004 in a Surgical Intensive Care Unit of a Cardiac Surgery Center, Athens. One hundred twenty-eight adult patients for open heart surgery were divided into three groups. Group A included 50 patients who underwent coronary artery bypass crafting (CABG), group B 31 patients who were subjected to aortic valve replacement (AVR)+CABG and group C 47 patients who underwent mitral valve replacement (MVR)+CABG. Aminotransferases, alkaline phosphatase, gamma-glutamyl-transpeptidase and both types of bilirubin were determined at admission, 24 hours after the operation and thereafter according to clinical evolution. The presence of jaundice was associated with elevated serum bilirubin above 3 mg/dl. RESULTS: Hyperbilirubinemia developed in 34 patients (26.5%). The incidence of postoperative jaundice was higher in patients who were subjected to MVR+CABG than to CABG and AVR+CABG. Hyperbilirubinemia was correlated with prolonged cardiopulmonary by-pass time (P<0.001), aortic cross-clamping time (P<0.001), the use of intra aortic balloon pumping (P<0.001), the administration of inotrops and the number of blood and plasma transfusions. Postoperative jaundice resulted mainly from an increase in conjugated bilirubin. CONCLUSIONS: Although hyperbilirubinemia seems to be multifactorial, the type of operation, the preoperative hepatic dysfunction due to advanced heart failure (NYHA II-III) and the decreased hepatic flow during the operation seem to determine the incidence of jaundice. PMID- 17690035 TI - Isolated liver perfusion for regional chemotherapy in rats. AB - BACKGROUND: In the isolated liver perfusion (ILP) technique, the liver is temporarily isolated from the systemic circulation in order to infuse large doses of chemotherapeutic agents through the hepatic inflow. The hepatic tissue can show a drug concentration higher than that after systemic chemotherapy, and a general toxic reaction from chemotherapeutic agent is avoided. In a modified ILP model in rats, we explored the distribution of the chemotherapeutic agent, fluorouracil (5-FU) in the systemic circulation and in the hepatic tissue, and assessed the pathological changes in the liver. METHODS: 306 Sprague-Dawley rats were randomly divided into 4 groups: control, ILP without 5-FU, ILP with 5-FU at different doses, and infusion of 5-FU through the portal vein. All animals were subjected to modified ILP, and 5-FU concentrations in the hepatic tissue and the systemic blood were determined at different time points. Levels of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), and changes in hepatic function, pathology and liver enzymes were assessed. RESULTS: ILP through the portal vein at three dosages (25, 50 and 100 mg/kg) resulted in significantly higher 5-FU concentrations in the liver tissue for 50 and 100 mg/kg and there was only a small leakage of 5-FU from the perfusion system into the systemic circulation. The pathological findings revealed that the liver tissue tolerated ILP below the maximum tolerance dose (MTD) of 5-FU. If the 5-FU dose exceeded the MTD the ultrastructure and the enzymatic activity of hepatocytes were clearly affected. The change of TXB2 and PGF1alpha balance were closely related to the injury of hepatic tissue caused by ILP with 5-FU doses greater than the MTD. CONCLUSIONS: Hepatic tissue sustains a higher drug concentration using ILP than that from systemic chemotherapy, and avoids a general toxic reaction to the drug entering into the systemic circulation. Evident injury may not occur in hepatocytes, and the changes of liver function are slight and transient by using ILP with no more than the MTD of 5-FU. PMID- 17690036 TI - Human multi-drug resistant hepatocellular carcinoma induced in nude mice by B ultrasonographically-directed orthotopic implantation: a new experimental model. AB - BACKGROUND: Present studies on the reversal of multi-drug resistance (MDR) are almost entirely limited to in vitro systems, and are seldom carried out in vivo. In order to study MDR under the in vivo situation, a MDR cell strain was used to establish a model in nude mice via orthotopic implantation directed by B ultrasonography. This model is expected to provide a good platform for evaluating strategies to reverse the phenomenon of primary hepatocellular carcinoma (HCC) MDR. METHODS: An orthotopic MDR1 hepatoma was obtained by injecting the cell lines HepG2 and HepG2/ADM subserosally into the liver of nude mice (10 control and 20 MDR mice). The injections were made under B-ultrasonographic direction. Ultrasonography and laparotomy were used to assess tumor growth, and the long chain PCR technique was applied to sequence the MDR1 gene from multi-drug resistant human HCC cells, HepG2/ADM, and corresponding implanted tumor tissues. Furthermore, MDR1 mRNA and P-gp protein expression were evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemical methods. RESULTS: The success rates of tumor implantation and induction of MDR were 100% (30/30) and 95% (19/20), respectively. The 3.8kbp MDR1 gene band was detected from the HepG2/ADM cell line and the corresponding implanted tumor tissues, and the MDR1 gene sequence coincided with that reported in GenBank. The expressions of MDR1 mRNA and P-gp protein in MDR mice were significantly higher than those in the control group. There was a significant difference in P-gp protein expression between MDR and control mice. CONCLUSION: A MDR model has been successfully established in nude mice via orthotopic implantation of multi-drug resistant human HCC cells directed by ultrasonography. PMID- 17690037 TI - The role and mechanism of fatty acids in gallstones. AB - BACKGROUND: Cholelithiasis is a common entity in China, but its etiology and pathogenesis have not been fully elucidated. Pigment stones of the intrahepatic and extrahepatic bile duct still form a high proportion in China, while they are rare in Europeans. To date, reports on fatty acids in stones remain few. We analyzed the quantity of fatty acids in different stones from Chinese and Japanese cases and discussed the role and mechanism of fatty acids in the formation of pigment stones. METHODS: Clinical data from 18 Chinese and 37 Japanese patients with different types of stones were analyzed using the procedure for extracting fatty acids from gallstones and high performance liquid chromatography. RESULTS: The total fatty acid and free fatty acid contents of pigment stones were markedly higher than those in black or cholesterol stones. The ratio of free saturated to free unsaturated fatty acids was highest in intrahepatic and less in extrahepatic pigment stones, which were significantly different from the other two kinds of stones. CONCLUSIONS: This indicates that phospholipase participates in the course of pigment stone formation. The action of phospholipase A1 is more important than phospholipase A2. PMID- 17690038 TI - Two-dimensional electrophoresis for comparative proteomic analysis of human bile. AB - BACKGROUND: Proteomic analysis of bile fluid holds promise as a method to identify biomarkers of bile tract diseases, especially for tumors. Two dimensional electrophoresis (2-DE) is a popular and proven separation technique for proteome analysis, but using this strategy for bile fluid analysis is still not fully developed. This study was undertaken to (a) establish a reliable method for general clean-up to make bile fluid samples suitable for 2-DE; (b) obtain 2-D biliary maps with high reproducibility and resolution; and (c) identify protein patterns present in 2-D biliary maps for potential tumor biomarker discovery, with the intention of distinguishing malignant from benign causes of bile duct obstruction. METHODS: Bile fluid samples were obtained from two patients suffering from malignant and benign bile tract obstruction (one patient with cholangiocarcinoma as the experimental case, the other with cholelithiasis as control). A variety of sample preparation options, including delipidation, desalination and nucleic acid removal, were adopted to remove contaminants that affect 2-DE results. After that, each 350 microg purified sample was loaded onto nonlinear IPG strips (18 cm, pH 3-10 and pH 4-7) for first-dimension isoelectric focusing, and 12.5% SDS-PAGE electrophoresis for second dimension separation. Then 2-D maps were visualized after silver staining and analyzed with the Image Master 2-D software. RESULTS: A large number of protein spots were separated in 2 D maps from the experimental and control groups, with means of 250 and 216 spots on pH 3-10 IPG strips, and 182 and 176 spots on pH 4-7 strips, respectively. Approximately 16 and 23 spots were differentially expressed in matched pairs from the experimental and control cases using pH 3-10 and pH 4-7 strips. CONCLUSIONS: This study established a reliable sample preparation process suitable for 2-DE of bile fluid. By this method, 2-D biliary maps with high reproducibility and resolution were obtained. The differentially displayed proteomes in the 2-D biliary maps from the experimental and control groups indicated the potential application for bile fluid analysis to identify disease-associated biomarkers, especially for biliary tract tumors. PMID- 17690039 TI - Promoter hypermethylation of death-associated protein kinase gene in cholangiocarcinoma. AB - BACKGROUND: Death-associated protein kinase (DAPK) is a Ca2+/calmodulin-regulated Ser/Thr kinase which is involved in apoptosis. The aberrant methylation of its promoter region CpG islands may be one of the important mechanisms of carcinogenesis. We studied the relationship of methylation status and expression of the DAPK gene with the clinical findings in cholangiocarcinoma. METHODS: Target DNA was modified by sodium bisulfite, coverting all unmethylated, but not methylated, cytosines to uracil, and subsequently detected by methylation specific PCR. Moreover, mRNA expression of the DAPK gene was assessed by RT-PCR. RESULTS: Aberrant methylation of the DAPK gene was detected in 11 (30.6%) of 36 tissue specimens of cholangiocarcinoma, and in 2 (5.6%) of 36 specimens of adjacent normal tissues. DAPK mRNA was not expressed in tumor and adjacent tissues with hypermethylation of the DAPK promoter. There were no statistical differences in the extent of differentiation and invasion, lymph node metastasis or pathologic type between the methylated and unmethylated tissues. CONCLUSIONS: The frequency of DAPK gene methylation in cholangiocarcinoma is high and it may offer an effective means for earlier auxiliary diagnosis of the malignancy. The DAPK gene is probably suppressed by methylation, and it could become resistant to apoptosis and immunological surveillance. The DAPK gene epigenetically affected by methylation may be associated with the carcinogenesis of cholangiocarcinoma. PMID- 17690040 TI - Expression of c-erbB-2 proto-oncogene in extrahepatic cholangiocarcinoma and its clinical significance. AB - BACKGROUND: Many investigators have indicated that overexpression and amplification of the human proto-oncogene c-erbB-2 is an independent prognostic factor for primary tumors. We studied expression of c-erbB-2 protein in tissues from extrahepatic cholangiocarcinoma, tissues peripheral to the carcinoma and normal bile ducts, and discussed the occurrence and development of extrahepatic cholangiocarcinoma. Another aim was to explore possible application of the c-erbB 2 gene for clinical diagnosis, pathological differentiation and treatment of extrahepatic cholangiocarcinomas. METHODS: The c-erbB-2 expression levels from 75 samples of extrahepatic cholangiocarcinoma, 48 samples of tissues peripheral to the carcinoma and 9 samples from normal bile ducts were assayed by immunohistochemical streptavidinbiotin complex (SABC). RESULTS: The rates of c erbB-2 expression in extrahepatic cholangiocarcinomas, tissues peripheral to the carcinomas, and normal bile ducts were 80% (60/75), 56% (27/48), and 0% (0/9), respectively. In the extrahepatic cholangiocarcinomas, the expression of c-erbB-2 was directly proportional to the malignant grade and tumor metastasis. The expression rate of c-erbB-2 in tumors with nerve infiltration was significantly higher than in those without nerve infiltration. The expression rates of c-erbB-2 in tumors with histological grade III/IV were significantly higher than in those with histological grade I. The expression of c-erbB-2 was not correlated with the size or position of tumors, blood vessel infiltration or patients' sex or age. CONCLUSIONS: c-erbB-2 was only expressed in extrahepatic cholangiocarcinomas and tissues peripheral to the carcinomas but not in normal bile ducts, indicating that c-erbB-2 may play an important role in the occurrence and development of extrahepatic cholangiocarcinoma. The fact that the expression level of c-erbB-2 was highly correlated with differentiation grade and metastasis of the tumor suggests potential clinical importance of c-erbB-2 as a tumor biomarker in the diagnosis, treatment and prognosis of extrahepatic cholangiocarcinoma. PMID- 17690041 TI - Chylous ascites after pancreatico-duodenectomy cholangiocarcinoma xenografts in nude mice. AB - BACKGROUND: Chylous ascites (CA) following pancreatico-duodenectomy (PD) is a rare complication secondary to disruption of the lymphatics during extended retroperitoneal lymph node dissection. The majority of cases do not develop CA, possibly due to patency of the proximal thoracic duct and good collaterals. CA may be due to a consequence of occult obstruction of the proximal thoracic duct by malignant infiltration or tumor embolus. This study was to report the incidence of CA and its outcomes of management. METHODS: A retrospective search of our liver database was performed using the key words "pancreatico duodenectomy", "chylous ascites" from January 2000 to December 2005. The medical records of CA patients and their management and outcome were reviewed. RESULTS: In 138 patients who had undergone PD in our centre for pancreatic malignancy, 3 were identified with CA and managed by abdominal paracentesis. CA resolved in 2 patients with low fat medium chain triglyceride diet alone and 1 patient had total parenteral nutrition (TPN) for persistent CA. Resolution of CA occurred in these 3 patients at a median follow-up of 4 weeks (range 4-12 weeks). Histologically, resected specimen confirmed pancreatic adenocarcinoma in all the patients. Two patients developed loco-regional recurrences at a median follow up of 8 months (range 6-10 months). And the other was currently disease free at a 10 month follow up. CONCLUSIONS: CA as an uncommon postoperative complication requires frequent paracentesis, prolonged hospital stay, and delayed adjuvant chemotherapy. CA is treated with low fat medium chain triglyceride diet or occasionally TPN is required. PMID- 17690042 TI - Intra-abdominal pressure monitoring in predicting outcome of patients with severe acute pancreatitis. AB - BACKGROUND: Severe acute pancreatitis (SAP) is a serious disease with many complications, high mortality and poor prognosis. It is characterized by rapid deterioration and poses one of the most difficult challenges in clinical practice. Previous investigations suggest that SAP is one of the main causes of intra-abdominal pressure (IAP) increase. The aim of this study was to evaluate the utility of IAP-monitoring in predicting the severity and prognosis of SAP. METHODS: Eighty-nine patients with SAP who had been treated from February 2001 to December 2005 were studied. Since bladder pressure accurately reflects IAP, we measured it instead of IAP. Bladder pressure was measured at the time of admission and every 12 hours in the course of the disease, 9 consecutive times in all. The APACHE II scores of all patients were obtained within 24 hours after admission. According to a maximum bladder pressure <10 cmH2O, all patients were divided into two groups, mildly-elevated and severely-elevated. Mortality and mean APACHE II scores in the two groups were calculated. In addition, the mean bladder pressure and APACHE II scores in survivors were compared with those in deaths. RESULTS: Sixty-eight of the 89 patients were in the severely-elevated group. Mortality and mean APACHE II scores in this group were much higher than those in the mildly-elevated group (mortality, 39.71% vs. 9.52%; mean APACHE II score, 23.15+/-7.42 vs. 15.95+/-5.35, P<0.01). The mean bladder pressures and APACHE II scores in deaths were significantly greater than those in survivors (mean bladder pressure, 14.1+/-3.8 vs. 9.2+/-2.3 cmH2O, P<0.01; mean APACHE II score, 27.83+/-4.87 vs. 18.37+/-6.74, P<0.01). CONCLUSION: It is suggested that IAP may be used as a marker of the severity and prognosis of SAP. PMID- 17690043 TI - PDX-1 expression and proliferation of duct epithelial cells after partial pancreatectomy in rats. AB - BACKGROUND: The pancreas has a strong regeneration potential in mammals. Previous studies suggested that pancreas regeneration is correlated with proliferation and differentiation of pancreatic stem cells, but the field of pancreatic stem cells is still in its infancy. This study was undertaken to detect the expression of pancreas/duodenal homeobox-1 (PDX-1) and proliferation of pancreatic duct epithelial cells in remnant pancreas during regeneration after partial pancreatectomy in rats, and characterize the source of pancreatic stem cells. METHODS: Partial pancreatectomy (90%) was performed on four- to five-week-old Sprague-Dawley rats, and duct epithelial cells and acinar cells were detected by immunohistochemical staining and scored using the 5-bromo-2-deoxyuridine (BrdU) labelling index at various time points. Western blotting and reverse transcriptase-polymerase chain reaction (RT-PCR) were used to assess the expression of PDX-1 protein and mRNA, respectively. RESULTS: At 24 hours after partial pancreatectomy, proliferation started in the main, large and small duct cells, and persisted in small duct cells to day 5. The experimental and control groups were significantly different (P<0.001). BrdU-positive acinar cells were greatly increased and reached a peak on day 5. PDX-1 protein was only faintly detectable in pancreatic ductal cells on day 1 after partial pancreatectomy. On days 2 and 3, a 2-3 fold increase in PDX-1 protein was observed, corresponding to the characteristic 42 kD protein in Western blotting. The operated and sham operated groups also differed significantly (P<0.05). PDX-1 protein expression on days 5 and 7 after operation did not differ from that of the control group. RT PCR revealed that PDX-1 mRNA expression did not significantly differ between the operated group and the sham-operated group at various time points. CONCLUSIONS: Pancreatic stem cells in pancreatic ductal epithelial cells are involved in the regeneration of remnant pancreas and the expression of PDX-1 in ductal cells is due to posttranscriptional regulation. PMID- 17690044 TI - Precise hepatectomy guided by the middle hepatic vein. AB - The middle hepatic vein (MHV) lies in the midplane of the liver. The classical teaching of right or left hepatectomy is transection of liver 1 cm to the right or left wall of the MHV in order to avoid bleeding. However, guidance of liver transection is lost if the course of the MHV is not known. By exposing the MHV early in the phase of liver transection and following its course to the inferior vena cava, a precise liver transection plane could be obtained. Such technique has the potential of achieving adequate tumor-free resection margin, avoiding damage to intrahepatic portal pedicles, preserving venous drainage and functional liver tissue, and less postoperative infection. PMID- 17690045 TI - Amiodarone hepatotoxicity complicating obstructive jaundice due to ampullary cancer. AB - BACKGROUND: The presence of dual pathology can cause diagnostic dilemmas. We present a case of adenocarcinoma of the ampulla of Vater with concurrent amiodarone hepatotoxicity. METHODS: Painless jaundice associated with a palpable gallbladder was investigated clinically, radiologically, endoscopically and via liver biopsy. RESULTS: Liver biopsy showed amiodarone hepatotoxicity. Endoscopic biopsy identified an ampullary adenoma. However, the endoscopic ultrasound and intra-operative findings suggested a malignancy, which was confirmed postoperatively. CONCLUSIONS: While the classic findings of Courvoisier's Law are borne out in this case, the etiology of jaundice is twofold. Although dual pathology is uncommon it should always be considered. PMID- 17690046 TI - Coexistence of Mirizzi syndrome with adenomyomatosis in the gallbladder: report of a case. AB - BACKGROUND: Mirizzi syndrome is a rare complication of cholelithiasis. Adenomyomatosis is a common tumor-like lesion of the gallbladder. METHODS: A 52 year-old man was admitted to our hospital complaining of right hypochondriac pain and jaundice. Ultrasonography and computed tomography revealed stones in the gallbladder and dilation of the intrahepatic bile ducts. Magnetic resonance cholangiopancreatography revealed narrowing of the common bile duct caused by compression of the gallbladder. Laparotomy revealed type II Mirizzi syndrome. RESULTS: Partial cholecystectomy with a Roux-en-Y hepaticojejunostomy reconstruction was performed. Histologically, Rokitansky-Aschoff sinus proliferation, hypertrophy of smooth muscles, and fibrosis were seen in the gallbladder. A segmental type of adenomyomatosis of the gallbladder was diagnosed. CONCLUSIONS: The pathogenic link between the two peculiar entities is unclear. A possible explanation is considered that the pathogenesis of Mirizzi syndrome is resulted from chronic inflammation due to adenomyomatosis. PMID- 17690047 TI - Segmental liver incarceration through a recurrent incisional lumbar hernia. AB - BACKGROUND: Lumbar hernia is a rare congenital or acquired defect of the posterior abdominal wall. The acquired type is more common and occurs mainly as an incisional defect after flank surgery. Incarceration or strangulation of hernia contents is uncommon. METHOD: Segmental liver incarceration through a recurrent incisional lumbar defect was diagnosed in a 58 years old woman by magnetic resonance imaging. RESULTS: The patient underwent an open repair of the complicated hernia. An expanded polytetraflouoroethylene (e-PTFE) mesh was fashioned as a sublay prosthesis. She had an uncomplicated postoperative course. Follow-up examinations revealed no evidence of recurrence. CONCLUSIONS: Although lumbar hernia rarely results in incarceration or strangulation, early repair is necessary because of the risks of complications and the increasing difficulty in repairment as it enlarges. Surgical repair is often difficult and challenging. PMID- 17690048 TI - Comparison of current U.S. and Canadian cigarette pack warnings. AB - Cigarette smoking is the single most preventable cause of death in the United States. From 1985 to date, one of four mandatory cigarette warnings proposed by the Comprehensive Smoking Education Act of 1984 has been displayed on cigarette packages. In addition to cigarette warnings, states like California, Massachusetts, Arizona, Oregon and Maine have implemented "Tobacco Control Programs" (TCP) to reduce the overall number of smokers. However, the decline in the rate of smoking is not occurring fast enough to meet the national health objective by 2010. The present U.S. cigarette warnings are verbal in form and provide information, which is inadequate but appropriate to make it legally adequate. On the other hand, warnings in other countries such as Canada and Brazil are more descriptive and specific and are accompanied by vivid and sometimes gruesome pictures. In the present study, six pictorial Canadian labels and four U.S. verbal labels were analyzed for potential effectiveness among eighty subjects using a survey questionnaire. The survey findings are compared with recent Canadian smoking data. It is concluded that placing pictorial labels on cigarette packages in the U.S. will allow the product to carry warnings that potentially provide better results than current verbal messages and less TCP funds will need to be used. PMID- 17690049 TI - Gender equity and HIV/AIDS prevention: comparing gender differences in sexual practice and beliefs among Zimbabwe university students. AB - We assess gender differences in HIV prevention knowledge, attitudes and practices with a focus on cultural, sociological, and economic variables. A randomized cross-sectional study was used in order to achieve high participation and broad comparative assessment. An eight-page questionnaire was administered to 933 randomly selected students at the University of Zimbabwe. Survey items addressed sexual decision-making, condom use, limiting sexual partners, cultural power dynamics and access to HIV testing. We found marked gender differences with men reporting beliefs of entitlement to dominate women, an assumed leadership in decision-making concerning condom use and an attitude that when a woman says "no" to sex, really, "it depends." Women acknowledged gender-based cultural attitudes but are much more likely to support women's rights to sexual expression. A multi faceted approach to gender equity training is needed to challenge men and women to change attitudes and increase social awareness that respects cultural traditions while still inspiring both men and women to champion justice and equality between genders. PMID- 17690050 TI - Relationships between factors affecting contraception and fertility in Bangladesh. AB - Using the data derived from the 1989 Bangladesh Fertility Survey, the 1993-94 and 1996-97 Bangladesh Demographic and Health surveys, this study attempts to find the relationships between the factors affecting contraception and fertility among currently married women by using a linear recursive path model which provides direct and indirect relationships between the variables. The results suggest that women's status had a significant negative effect on childbearing and it had a significant positive effect on the use of contraception. It was also observed that higher incidence of child mortality led to a higher level of fertility. PMID- 17690051 TI - Road safety practices among commercial motorcyclists in a rural town in Nigeria: implications for health education. AB - This cross-sectional, community-based study was carried out among commercial motorcyclists in Igboora. All the commercial motor parks in Igboora were visited and all the commercial motorcyclists who consented to participate in the study were interviewed. Information on the respondents' socio-demographic characteristics, and the practice of road safety measures was collected using an interviewer administered questionnaire. A total of 299 motorcyclists were interviewed. All (100%) of them were males. The mean age of the respondents was 27.4 +/- 7.4 years. One hundred eighty-two (60.7%) of the motorcyclists had the correct knowledge of the purpose of Highway Code. Only 70 (23.3%) could recognize more than half of the currently used road safety codes and 47 (15.7%) obey these road safety codes more than half of the time they see it. Only 183 (61.2%) of them had a driving license and 72 (24.1%) were able to produce these licenses on demand. All (100%) of the respondents did not use any protective helmet. Those who have longer years of working experience, higher level of education and higher knowledge of the safety codes practice it more regularly (r = 0.198, p = 0.001, chi2= 9.31, p = 0.025, and r = 0.28, p = 0.001 respectively). One hundred thirty six (45.5%) have been involved in at least one accident in the preceding year. The overall incidence of road traffic accident was 2.16 per 1,000. There was however on statistically significant association between the practice of road safety codes and the occurrence of road traffic accidents (chi2= 0.176, p = 0.916). The study shows that the practice of road safety measures was low in this rural Nigerian community and was not associated with the incidence of road traffic accidents. Introducing road safety education particularly targeted at educating the motorcyclists on the importance and practice of road safety measures would lead to an increase in the practice of the safety measures and hopefully a reduction in the incidence of road traffic accidents. PMID- 17690052 TI - A comparison of falls efficacy among older United States adults living independently and in group dwellings: health education implications. AB - The objective was to examine the relationship between a community based balance measure and perceptions of balance among individuals from different elderly living environments. The research was a cross-sectional between groups comparison design. Data collection was conducted in a community setting, in both older adult group housing facilities and in older adult community centers. Data analysis was conducted on a sample of 74 older adults that included independent and group dwellers. Instruments used to collect information from the older adults were the Berg Balance Scale and the Tinetti Falls Efficacy Scale. Results indicate that significant differences (p < .05) in Falls Efficacy by location were found (t(72) = 2.04, p = .044). Many group dwelling older adults believe their ability to perform activities of daily living (ADLs) is compromised simply as a result of their living situation. This research indicates that this fear may be unfounded. In the future, we suggest that health educators working with older adults focus their efforts on education designed to increase senior falls efficacy. PMID- 17690053 TI - A health educator's guide to theories of health behavior. AB - Numerous health behavior theories (HBTs), each which attempt to explain why individuals engage in (or fail to engage in) health-related behaviors, exist in the literature. While much attention has been devoted to testing individual theories, little attention has been paid to issues that arise in the selection of theories. The current article has three goals. First, to describe some of the most widely used individual-level HBTs. Second, to discuss the application of these theories to successful health promotion efforts. And finally, to compare and contrast numerous HBTs and provide an example for how a selected theory might be applied to a health education program. The overriding goal is to provide guidance to researchers, health educators and other interventionists with regard to the important decision of which theory to use as a basis for one's health promotion efforts. PMID- 17690054 TI - Eliminating human tuberculosis in the twenty-first century. AB - Recognizing that tuberculosis (TB) is still the leading cause of human death from a curable infection, the international health community has set ambitious targets for disease control. One target is to eliminate TB by 2050; that is, to cut the annual incidence of new cases to less than 1 per million population. National TB control programmes are working to eliminate TB mainly by intensifying efforts to find and cure patients with active disease. Here, we use mathematical modelling to show that, while most TB patients can be cured with present drug regimens, the 2050 target is far more likely to be achieved with a combination of diagnostics, drugs and vaccines that can detect and treat both latent infection and active disease. We find that the coupling of control methods is particularly effective because treatments for latent infection and active disease act in synergy. This synergistic effect offers new perspectives on the cost-effectiveness of treating latent TB infection and the impact of possible new TB vaccines. Our results should be a stimulus to those who develop, manufacture and implement new technology for TB control, and to their financial donors. PMID- 17690055 TI - The Leeuwenhoek lecture 2006. Microscopy goes cold: frozen viruses reveal their structural secrets. AB - The electron microscope provides a powerful tool for investigating the structure of biological complexes such as viruses. A modern instrument is fully capable of atomic resolution on suitable non-biological specimens, but biological materials are difficult to preserve, owing to their fragility, and to image, owing to their radiation, sensitivity. The act of imaging the specimen severely damages it. Originally, samples were prepared by staining with a heavy metal salt, which provides a stable specimen but limits the amount of details that can be retrieved. Now particulate specimens, such as viruses, are prepared by rapid freezing of unstained material and observed in a frozen state with low doses of electrons. The resulting images require extensive computer processing to extract fully detailed three-dimensional information about the specimen. The whole process is referred to as single-particle electron cryomicroscopy. Using this approach, the structure of the human hepatitis B virus core was solved at the level of the protein fold. By comparing maps of RNA- and DNA-containing cores, it was possible to propose a model for the maturation and control of the envelopment of the virus during assembly. These examples show that cryomicroscopy offers great potential for understanding the structure and function of complex biological assemblies. PMID- 17690056 TI - Neurodevelopmental outcome after severe traumatic brain injury in very young children: role for subcortical lesions. AB - Traumatic brain injury is a major cause of mortality and morbidity in children younger than 15 years of age. To evaluate the role of subcortical lesions on neurodevelopmental outcomes, long-term outcomes of 50 children with severe traumatic brain injury before 4 years of age (accidental injury, n = 21, nonaccidental injury, n = 29) were reviewed retrospectively and compared with late magnetic resonance imaging (MRI) findings: no visible lesions, cortical lesions, or subcortical lesions. Subcortical lesions occurred in both accidental and nonaccidental traumatic brain injuries. Traumatic brain injury severity (initial Glasgow Coma Scale or coma duration) was significantly associated with subcortical lesions. Long-term motor or visual deficiencies occurred in one third of patients and cognitive deficiencies in 52.1%. Although deficiencies occurred without visible MRI lesions, global outcome scores, motor delay, visual impairment, head growth slowing, global intellectual quotients, and planning performances were significantly worse in patients with subcortical lesions. An alarming deterioration in intellectual quotient over time was noted. It was concluded that neurodevelopmental outcomes are worrisome after severe traumatic brain injury in young children, and subcortical lesions affect the prognosis. PMID- 17690057 TI - Prospective open-label clinical trial of trihexyphenidyl in children with secondary dystonia due to cerebral palsy. AB - Although trihexyphenidyl is used clinically to treat both primary and secondary dystonia in children, limited evidence exists to support its effectiveness, particularly in dystonia secondary to disorders such as cerebral palsy. A prospective, open-label, multicenter pilot trial of high-dose trihexyphenidyl was conducted in 23 children aged 4 to 15 years with cerebral palsy judged to have secondary dystonia impairing function in the dominant upper extremity. All children were given trihexyphenidyl at increasing doses over a 9-week period up to a maximum of 0.75 mg/kg/d. Trihexyphenidyl was subsequently tapered off over the next 5 weeks. Objective motor assessments were performed at baseline, 9 weeks, and 15 weeks. The primary outcome measure was the Melbourne Assessment of Unilateral Upper Limb Function, tested in the dominant arm. Tolerability and safety were monitored closely throughout the trial. Of the 31 children who agreed to participate in the study, 5 failed to meet entry criteria and 3 withdrew due to nonserious adverse events (chorea, drug rash, and hyperactivity). Three children required a dosage reduction because of nonserious adverse events but continued to participate. The 23 children who completed the study showed a significant improvement in arm function at 15 weeks (P = .045) but not at 9 weeks (P = .985). Post hoc analysis showed that a subgroup (n = 10) with hyperkinetic dystonia (excess involuntary movements) worsened at 9 weeks (P = .04) but subsequently returned to baseline following taper of the medicine. The authors conclude that scientific evidence for the clinical use of trihexyphenidyl in cerebral palsy remains equivocal. Trihexyphenidyl may be a safe and effective for treatment for arm dystonia in some children with cerebral palsy if given sufficient time to respond to the medication. Post hoc analyses based on the type of movement disorder suggested that children with hyperkinetic forms of dystonia may worsen. A larger, randomized prospective trial stratified by the presence or absence of hyperkinetic movements is needed to confirm these results. PMID- 17690058 TI - Differential stimulant response on attention in children with comorbid anxiety and oppositional defiant disorder. AB - Attention-deficit hyperactivity disorder (ADHD) affects 3% to 7% of school-age children. Approximately 30% of the children with ADHD also have comorbid anxiety or oppositional defiant disorder. Methylphenidate is the drug of choice for the medical treatment of such cases. When compared with children with ADHD alone, children with comorbid anxiety or oppositional defiant disorder may show worsening of the global attention score in response to methylphenidate and not only a "reduced response," as reported in previous studies. This study included 1122 children diagnosed as ADHD, of which 174 were diagnosed with comorbid anxiety and 141 with comorbid oppositional defiant disorder. All patients performed the Test of Variables of Attention before and after methylphenidate administration. A normal distribution (Gaussian distribution) of reaction to methylphenidate, as measured by the global ADHD score in children diagnosed as pure ADHD, was found. These findings were in contrast to children with ADHD and comorbid anxiety or oppositional defiant disorder who showed a bimodal distribution and hence represent a distinct population. In both groups with comorbid disorders, there was a larger subgroup in which significant worsening of global ADHD score occurred after methylphenidate administration (P < .05). Children with ADHD and comorbid anxiety or oppositional defiant disorder might represent clinically distinct populations in which inattention is secondary to those disorders; therefore, methylphenidate may be an inappropriate treatment for such children. PMID- 17690059 TI - Poor penmanship in children correlates with abnormal rhythmic tapping: a broad functional temporal impairment. AB - Timing is crucial for proficient motor tasks; temporal impairments may lead to dysfunctional motor activities. Although much research has been dedicated to the study of movement timing, clinical examination often overlooks temporal impairment of motor activity. The authors hypothesize that some children have a global temporal impairment leading to dysfunctional motor skills. This article checks whether temporal abnormalities detected on a simple tapping task correlate with temporal dysfunction during complex motor skills such as handwriting. Twenty three school-aged children, 8-14 years (11.1 +/- 1.3 years), underwent tests to assess finger tapping and cursive handwriting. Handwriting samples were rated by experienced teachers. Children with abnormal tapping had lower handwriting rating scores. Temporal features were similar in both tasks; variability on the tapping test correlated with handwriting variability. Temporal variability was not significantly higher for children with poor penmanship as a whole but rather specific to the subgroup of children with a tapping abnormality. Poor penmanship could be attributed in certain children to global temporal impairment reflected as variable finger tapping and handwriting. Evaluation of dysfunctional motor performance should include temporal aspects, and further studies are needed to better delineate and address treatment of "dysrhythmia." PMID- 17690060 TI - Sydenham's chorea: a clinical follow-up of 65 patients. AB - Sydenham's chorea, the neurological manifestation of rheumatic fever, is the most common acquired chorea of childhood. In this retrospective study, the authors aim to present the clinical and laboratory findings of 65 Sydenham's chorea patients, followed up in a clinic over less than 7 years. The mean age at the onset of the symptoms was 11.7 +/- 2.6 years (range, 6-17 years). Of the patients, 63% were female and 37% were male (male/female: 1.7/1). Chorea was generalized in 78.5% of the patients, right hemichorea in 12.3%, and left hemichorea 9.2%. There was a history of rheumatic fever in 30.8% of the patients. Echocardiographic study showed cardiac valve involvement in 70.5% of 61 patients. Brain magnetic resonance imaging, which was performed on only 18 patients, was evaluated as normal in all. Electroencephalography was also performed on only 18 patients and showed abnormal waves in 50% of them. Pimozide was mostly the first choice of drug therapy. Nevertheless, drug therapy was not needed in 18.5% of the patients. The recovery period of the first attack of the chorea was 1 to 6 months in 51.7% of the patients. The recurrence rate was 37.9%. In conclusion, Sydenham's chorea is still an important health problem in Turkey with respect to its morbidity. PMID- 17690061 TI - Late-infantile neuronal ceroid lipofuscinosis (CLN2/Jansky-Bielschowsky type) in Oman. AB - This study was conducted to see the pattern of neuronal ceroid lipofuscinosis in Oman. Eleven children (10 male) with late-infantile neuronal ceroid lipofuscinosis were seen in 5 families. Most of the patients, 9 of 11 (81.8%), were CLN2 type (late-infantile neuronal ceroid lipofuscinosis or Jansky Bielschowsky), and 2 patients were the atypical type. Five children were seen in 1 extended family. All children had onset with seizures except in 1 family. The majority had onset between ages 1 to 4 years. Nine and of the 11 children had onset with myoclonic seizures. Neuroregression and microcephaly were noted in all. All children had brain volume reduction and typical cerebellar atrophy. Ophthalmological examination was abnormal in all. Clinical features, histological findings, and genetic study reveal that CLN2 type is the most common form of neuronal ceroid lipofuscinosis. There is male predominance of 90.1% in this part of the Arab world. PMID- 17690062 TI - Current treatment of West syndrome in Japan. AB - About 10 years have passed since a previous survey on the treatment of West syndrome in Japan. To elucidate current practice, a questionnaire was sent to 113 institutes. It included (1) the drugs used for the treatment, (2) their dosage, and (3) the dosage and the schedule of adrenocorticotropic hormone therapy. Response rate was 51.3%. Adrenocorticotropic hormone, valproic acid, vitamin B(6), and zonisamide were frequently used. Vitamin B(6) was used most frequently as the first-choice drug followed by valproic acid, zonisamide, and adrenocorticotropic hormone. The most frequently used dose of synthetic adrenocorticotropic hormone-Z was 0.0125 mg/kg/d. Adrenocorticotropic hormone was administered every day for 2 weeks and then tapered off in more than 80% of the institutes. Although therapeutic strategy and drug usage have not changed largely during these 10 years, 2 alterations were observed: an increased use of zonisamide and a shortened duration of adrenocorticotropic hormone therapy. PMID- 17690063 TI - Long-term enzyme replacement therapy for pompe disease with recombinant human alpha-glucosidase derived from chinese hamster ovary cells. AB - Pompe disease is a rare autosomal recessive myopathy due to the deficiency of lysosomal acid alpha-glucosidase. Clinical phenotypes range from the severe classic infantile form (hypotonia and hypertrophic cardiomyopathy), to milder late onset forms (skeletal myopathy and absence of significant heart involvement). Enzyme replacement therapy with recombinant human alpha-glucosidase derived from either rabbit milk or Chinese hamster ovary cells has been introduced and is undergoing clinical trials. Reported is a long-term follow-up of 3 Pompe patients presenting without cardiomyopathy, treated with recombinant human alpha-glucosidase derived from Chinese hamster ovary cells. This study suggests that enzyme replacement therapy can lead to significant motor and respiratory improvement in the subgroup of patients who start the therapy before extensive muscle damage has occurred. The recombinant enzyme derived from Chinese hamster ovary cells, administered at doses significantly higher than previously reported, appears to have the same safety as the drug derived from rabbit milk. PMID- 17690064 TI - Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability. AB - Autism and Pervasive Developmental Disorder Not Otherwise Specified are common developmental problems often seen by child neurologists. There are currently no cures for these lifelong and socially impairing conditions that affect core domains of human behavior such as language, social interaction, and social awareness. The etiology may be multifactorial and may include autoimmune, genetic, neuroanatomic, and possibly excessive glutaminergic mechanisms. Because memantine is a moderate affinity antagonist of the N-methylD-aspartic acid (NMDA) glutamate receptor, this drug was hypothesized to potentially modulate learning, block excessive glutamate effects that can include neuroinflammatory activity, and influence neuroglial activity in autism and Pervasive Developmental Disorder Not Otherwise Specified. Open-label add-on therapy was offered to 151 patients with prior diagnoses of autism or Pervasive Developmental Disorder Not Otherwise Specified over a 21-month period. To generate a clinician-derived Clinical Global Impression Improvement score for language, behavior, and self-stimulatory behaviors, the primary author observed the subjects and questioned their caretakers within 4 to 8 weeks of the initiation of therapy. Chronic maintenance therapy with the drug was continued if there were no negative side effects. Results showed significant improvements in open-label use for language function, social behavior, and self-stimulatory behaviors, although self-stimulatory behaviors comparatively improved to a lesser degree. Chronic use so far appears to have no serious side effects. PMID- 17690066 TI - Childhood epilepsy with occipital paroxysms: difficulties in distinct segregation into either the early-onset or late-onset epilepsy subtypes. AB - The Commission on Classification and Terminology of the International League Against Epilepsy Childhood rigidly segregated epilepsy with occipital paroxysms into 2 separate syndromes with different predominant seizure types: early-onset seizure susceptibility type consisting of prolonged infrequent, nocturnal autonomic seizures and accompanied by eye deviation and ictal vomiting and late onset with short diurnal frequent seizures and visual ictal manifestations along with throbbing headaches. Epileptic clinical manifestations and electroencephalographic data were analyzed in 28 patients with suspected occipital lobe epilepsy in an attempt to segregate them into either the early or late forms according to the International League Against Epilepsy classification. Electroencephalography in 25 children demonstrated occipital epileptiform paroxysms compatible with the suspected epileptic syndrome. Only 14 (50%) children complied with the rigid criteria of either early-onset or late-onset presentations. The other 14 (50%) children presented with mixed diverse epileptic phenomena such as short-lived seizures in infancy or prolonged seizures during childhood, not complying with either rigid syndrome (ie, short-lived epileptic blindness at an early age or vomiting during later childhood). Despite present attempts to rigidly segregate childhood epilepsy with occipital paroxysms into 2 distinct epileptic syndromes, a high percentage of children still present with various mixed clinical phenomena. Therefore, clinicians should be aware of possible unique and unusual presentations of occipital lobe epilepsy at various ages. PMID- 17690065 TI - Neurodevelopmental outcome of children with intrauterine growth retardation: a longitudinal, 10-year prospective study. AB - One hundred twenty-three children with intrauterine growth retardation were prospectively followed from birth to 9 to 10 years of age in order to characterize their specific neurodevelopmental and cognitive difficulties and to identify clinical predictors of such difficulties. Perinatal biometric data and risk factors were collected. Outcome was evaluated at age 9 to 10 by neurodevelopmental, cognitive, and school achievement assessments. Sixty-three children served as controls who were appropriate for gestational age. Significant differences in growth (P < .001), neurodevelopmental scores (P < .001), intelligence quotient (IQ) (P < .0001), and school achievements measured by the Kaufmann Assessment Battery for Children (P < .001) were found between the children with intrauterine growth retardation and controls. Children with intrauterine growth retardation demonstrated a specific profile of neurocognitive difficulties at school age, accounting for lower school achievements. The best perinatal parameter predictive of neurodevelopment and IQ was the Cephalization Index (P < .001). Somatic catch-up growth at age 2 and at age 9 to 10 correlated with favorable outcome at 9 to 10 years of age. PMID- 17690067 TI - Familial risk factors in autism. AB - Familial history risk factors in relation to autism were examined in a cohort of 164 autistic children referred to The Autism Center at New Jersey Medical School University of Medicine and Dentistry of New Jersey, Newark, over a 2-year period (2001-2003). Information related to familial history was obtained from each family and reviewed by a clinician. It is shown that these families carry a higher overall burden of psychiatric and developmental illnesses compared to reported national levels. These families also carry a relatively high incidence of medical disorders, independently of developmental and psychiatric disorders. This work supports the underlying presence of genetic factors in the etiology of autism. PMID- 17690068 TI - Factors associated with epilepsy in children with periventricular leukomalacia. AB - Children with cerebral palsy associated with periventricular leukomalacia frequently develop unprovoked epileptic seizures. This article reports an analysis of risk factors for epilepsy in children with radiologically confirmed periventricular leukomalacia. This cohort was screened for epilepsy and for an array of clinical and demographic factors. Of 154 subjects with radiologically confirmed periventricular leukomalacia, 40 (26.0%) had epilepsy. In the epileptic group, radiologic pathology other than periventricular leukomalacia was uncommon. Significant associations were found between epilepsy and cerebral palsy patterns other than spastic diparesis, mental handicap, cortical visual impairment, neonatal seizures, and severe periventricular leukomalacia. Only the presence of neonatal seizures was significantly associated with epilepsy once other risk factors were controlled in the regression model. Some previous studies have shown an association between neonatal seizures and later epilepsy for cerebral palsy in general. This is the first report of such an association for a single predominant type of cerebral pathology. PMID- 17690069 TI - The pediatric neurotransmitter disorders. AB - The pediatric neurotransmitter disorders represent an enlarging group of neurological syndromes characterized by abnormalities of neurotransmitter synthesis and breakdown. The disorders of dopamine and serotonin synthesis are aromatic amino acid decarboxylase deficiency, tyrosine hydroxylase deficiency, and disorders of tetrahydrobiopterin synthesis. Amino acid decarboxylase, tyrosine hydroxylase, sepiapterin reductase, and guanosine triphosphate cyclohydrolase (Segawa disease) deficiencies do not feature elevated serum phenylalanine and require cerebrospinal fluid analysis for diagnosis. Segawa disease is characterized by dramatic and lifelong responsiveness to levodopa. Glycine encephalopathy is typically manifested by refractory neonatal seizures secondary to a defect of the glycine degradative pathway. gamma-amino butyric acid (GABA) metabolism is associated with several disorders, including glutamic acid decarboxylase deficiency with nonsyndromic cleft lip/ palate, GABA transaminase deficiency, and succinic semialdehyde dehydrogenase deficiency. The latter is characterized by elevated gamma-hydroxybutyric acid and includes a wide range of neuropsychiatric symptoms as well as epilepsy. Pyridoxine-dependent seizures have now been associated with deficiency of alpha-aminoadipic semialdehyde dehydrogenase, as well as a new variant requiring therapy with pyridoxal-5-phosphate, the biologically active form of pyridoxine. PMID- 17690070 TI - Impact of recent seizures on cerebral blood flow in patients with sturge-weber syndrome: study of 2 cases. AB - Patients with refractory seizures, including those with Sturge-Weber syndrome, undergo functional studies in preparation for surgery. Perfusion studies in Sturge-Weber syndrome by single photon emission computed tomography and positron emission tomography generally demonstrate hypoperfusion in the diseased tissue. We report perfusion-weighted magnetic resonance imaging results in 2 cases of Sturge-Weber syndrome with recent seizures. The affected cerebral tissue showed increased relative cerebral blood flow and volume with prolonged mean transit time and time to peak. Elevated relative cerebral blood flow could be attributed to seizures, whereas increased relative cerebral blood volume might have resulted from vasodilation due to seizure activity or chronic ischemia. These findings point to the variable results of functional studies in Sturge-Weber syndrome that might lead to miscalculations of the lesion area before surgery. PMID- 17690071 TI - Neuropsychological symptoms of juvenile-onset batten disease: experiences from 2 studies. AB - Juvenile neuronal ceroid lipofuscinosis (Batten disease) is a progressive and fatal autosomal-recessive inherited lysosomal storage disorder of childhood. Core symptoms include vision loss, seizures, and mental and motor decline. This article presents data from 2 studies of neuropsychological function in juvenile neuronal ceroid lipofuscinosis. In the first cross-sectional pilot study, 15 children with genetic or clinicopathologic confirmation of juvenile neuronal ceroid lipofuscinosis completed a brief test of attention (mean age = 14.3 +/- 2.9 years, range = 8.75-18.74 years; 7 males, 8 females). Average attention performances were significantly below age-expected normative data. A second longitudinal study was then initiated to study neuropsychological function in greater depth, including change in function over time. The authors have enrolled 18 children to date (mean age = 12.88 +/- 3.59 years, range = 6.26-18.65; 11 males, 7 females). Of these, 5 children have completed a second (annual) re evaluation. Results thus far indicate significant impairment in domains of auditory attention, memory, estimated verbal intellectual function, and verbal fluency. Neuropsychological impairment was significantly correlated with disease duration and with motor function as assessed by a disease-specific clinical neurologic rating scale. There was no significant difference between males and females in neuropsychological test performance. Neuropsychological function was worse among children with a positive seizure history. Juvenile neuronal ceroid lipofuscinosis-affected children exhibited significant and pervasive impairments on tests of auditory attention, verbal memory and repetition, verbal fluency, and an estimate of verbal intellectual ability. Preliminary follow-up data from an annual reassessment showed progressive declines in cognitive function, in particular on a task of working memory. Neuropsychological deficits are pervasive and progressive. Future research will focus on clarifying the relationship among disease duration, motor function, and neuropsychological performances, including the relative sensitivity of neuropsychological testing at different stages of motor impairment or disease duration. PMID- 17690072 TI - Levetiracetam-induced diffuse interstitial lung disease. AB - The authors report the first case of levetiracetam-induced diffuse interstitial lung disease. The patient is a 9-year-old girl who was admitted to the pediatric intensive care unit for aspiration pneumonia. She has a history of epilepsy, cerebral palsy, mental retardation, asthma, and repeated hospitalizations for presumed aspiration pneumonia, which resolved with conventional medical treatment. She has been on low-dose levetiracetam for her epilepsy over the past 2 years, and the dosage was increased just prior to this admission. However, this time, with conventional treatment, the patient's aspiration pneumonia did not improve, which led to a lung biopsy. The biopsy demonstrated a diffuse interstitial process of relatively recent onset, with features consistent with diffuse lung disease. Levetiracetam was implicated in the pathogenesis of the interstitial pneumonitis. The patient improved clinically after the discontinuation of levetiracetam and with the treatment of steroids. PMID- 17690073 TI - Persistence of suppression-bursts in a patient with Ohtahara syndrome. AB - Early infantile epileptic encephalopathy, or Ohtahara syndrome, is characterized by tonic spasms and a suppression-burst pattern on the electroencephalography (EEG). The EEG demonstrates a suppression-burst pattern during waking and sleeping states that often evolves into hypsarrhythmia and followed later by a diffuse slow spike-wave pattern. In other patients, the EEG evolves into focal spike discharges or multiple independent spike foci. We report a 5-year-old girl with Ohtahara syndrome that persistently demonstrated tonic spasms and suppression-burst on multiple EEGs. Over her lifetime, neither hypsarrhythmia nor diffuse slow spike-wave pattern were seen. This suggests that in Ohtahara syndrome, a suppression-burst pattern can persist over a long period of time. PMID- 17690074 TI - Methylation status in females with rett syndrome. AB - The authors studied methionine and creatine metabolism in females with Rett syndrome. Plasma metabolites (including methionine, homocysteine, guanidinoacetate) and urine creatine/creatinine ratios in 29 females with Rett syndrome were within the age-appropriate range. Although the authors have not been able to identify any abnormalities, it can be speculated that patients with Rett syndrome may benefit from dietary intervention to increase the supply of labile methyl groups to affected tissues. PMID- 17690075 TI - Levetiracetam in nonconvulsive status epilepticus in childhood: a case report. AB - The authors report the case of a child with cerebral palsy and refractory epilepsy who developed nonconvulsive status epilepticus without acute medical cause treated successfully with levetiracetam. In accordance with other studies whose authors hypothesized that aggressive treatment may worsen the prognosis in elderly patients with nonconvulsive status epilepticus, the present authors successfully used a more conservative approach to the treatment of nonconvulsive status epilepticus in their patient. This case suggests that levetiracetam is a useful option for the treatment of nonconvulsive status epilepticus in childhood, in accordance with some authors who have described the anticonvulsant effects of levetiracetam in experimental status epilepticus and in status epilepticus in adults and in children with continuous spike waves during slow sleep. PMID- 17690076 TI - Lamotrigine overdose in a child. AB - The purpose of this article is to describe an unusual presentation of lamotrigine toxicity in an epileptic child treated on a lower than previously reported dosage. This is a case description of a 5-year-old epileptic girl on lamotrigine monotherapy, which caused toxicity. The child presented with ataxia, drowsiness, and acute confusion after ingesting 500 mg (25 mg/kg/d) in two 250-mg doses 12 hours apart. This was followed by vomiting and seizure exacerbation. Discontinuing lamotrigine, intravenous fluids and observation were the mainstays of therapy. Until now, the reported minimum dose of lamotrigine causing toxicity was 800 mg. In this patient, toxic manifestation occurred after the initial 250 mg. This case report demonstrates the low safety margin in children treated with lamotrigine. PMID- 17690077 TI - Progressive multicystic encephalopathy: is there more than hypoxia-ischemia? AB - Progressive multicystic encephalopathy following prenatal or perinatal hypoxia ischemia is a well-described phenomenon in the literature. The authors report on a term infant with a devastating encephalopathy and severe neuronal dysfunction immediately after delivery without a known antecedent of prenatal or perinatal hypoxia or distress. Clinical and paraclinical findings in the patient are compared with those described in the literature. The authors focus on the specific results guiding to the final diagnosis of progressive multicystic encephalopathy and the timing of morphologic changes. As in this case, if the criteria of an acute hypoxic event sufficient to cause neonatal encephalopathy are not met, then factors other than hypoxia-ischemia may be leading to progressive multicystic encephalopathy. PMID- 17690078 TI - Costello syndrome: cognitive and proton magnetic resonance spectroscopy findings- a case report. AB - The authors describe a girl with Costello syndrome who showed cerebral palsy and neurosensorial deafness. Brain computer tomography and magnetic resonance findings were normal. Multivoxel proton magnetic resonance spectroscopy showed a lowering of the peak of choline with a reduced choline/creatine ratio at the level of the centrum semiovale. These findings might be due to a congenital dysmyelinating or hypomyelinating condition. A complete neuroimaging study can play a relevant role to better clarify the pathogenesis of brain involvement in Costello syndrome. PMID- 17690079 TI - Merosin-negative congenital muscular dystrophy: diffusion-weighted imaging findings of brain. AB - Merosin-negative congenital muscular dystrophy is a rare genetic disease of childhood involving the central and peripheral nervous system. There were high signal intensities throughout the centrum semiovale, periventricular, and sub cortical white matters on T2-weighted images in a 4-year-old girl with merosin negative congenital muscular dystrophy. An apparent diffusion coefficient map revealed increased signal intensity and apparent diffusion coefficient values in the periventricular and deep white matters. It may be attributable to increased water content in the white matter because of an abnormal blood-brain barrier rather than to decreased or abnormal myelination. PMID- 17690080 TI - Headache as a sole manifestation in nonconvulsive status epilepticus. AB - Nonconvulsive status epilepticus may present with several manifestations, and many of them may not be obvious. The most important for the diagnosis of nonconvulsive status epilepticus is the electroencephalogram pattern. This is a case report of a 9-year-old boy with severe and continuous headache. He received chemotherapy for histiocytosis that was diagnosed when he was 3 years, 6 months years old. He had no evidence of central nervous system histiocytosis involvement or drug toxicity. He was diagnosed with nonconvulsive status epilepticus. The headache and electroencephalogram anomaly disappeared completely when anticonvulsant therapy began. Headache and seizure disorder may coexist, but this may be the first report of nonconvulsive status epilepticus with headache as a sole manifestation. PMID- 17690082 TI - Overview: definitions and classifications of seizure emergencies. AB - Seizure emergencies are potentially life-threatening events that are under recognized. Status epilepticus is associated with considerable rates of morbidity and mortality. Experts currently believe that any episode of seizure activity lasting 5 minutes or longer should be considered status epilepticus. Treatment should be initiated as early as possible; evidence has shown that once seizures persist for 5 to 10 minutes, they are unlikely to stop on their own in the subsequent few minutes. Prehospital treatment with benzodiazepines has been shown to reduce seizure activity significantly compared with seizures that remain untreated until the patient reaches the emergency department. The consequences of delayed treatment of status epilepticus include a serious risk of subsequent prolonged seizure activity or epileptogenesis, memory deficits, and learning difficulties. The importance of timely intervention in generalized tonic-clonic status epilepticus must be emphasized. Recent research has found that emergency department personnel fail to recognize the condition in children in 34% of cases. PMID- 17690083 TI - Who is at risk for prolonged seizures? AB - This article reviews how long seizures last and how frequently seizures are prolonged, risk factors for prolonged seizures, and a conceptual framework that links them. These data are derived from studies of patients with a first unprovoked seizure, studies of children with febrile seizures, studies of population-based and community-based cohorts with newly diagnosed epilepsy and patients with refractory epilepsy, and treatment trials. Prolonged seizures that exceed 5 to 10 minutes are relatively common, and the key factor in the identification of those at risk is a history of a prior prolonged seizure. A subgroup of patients with seizures is predisposed to prolonged although not necessarily frequent seizures, which are associated with increased morbidity, increased emergency department visits, and a decreased quality of life. This article also addresses criteria used to justify treatment of a seizure once it has continued longer than 5 minutes and the rationale for such treatment. PMID- 17690084 TI - Do seizures affect the developing brain? Lessons from the laboratory. AB - Laboratory models of prolonged seizures and status epilepticus in developing animals demonstrate age- and model-dependent propensity for brain injury. Even in models without overt brain injury, plasticity, which leads to epileptogenicity as well as to behavioral and cognitive effects, has been demonstrated. Brief, recurrent seizures in the neonatal period not only appear to exhibit plasticity that can be anatomically and physiologically meaningful but also seem to produce cognitive deficits. Translation of these findings into clinical practice is limited by the effects chronic therapy may have on brain development. There is little evidence that available treatments can effectively alter epileptogenesis. However, it is widely agreed that prolonged seizures and status epilepticus can carry negative consequences. Preventing epileptogenesis remains an important goal to modify the development of comorbidities, and it represents an area of research in need of much progress. For now, prevention of prolonged seizures with early intervention is important and is the most effective available option to minimize the potential short- and long-term adverse effects of prolonged seizures and optimize patient outcomes. PMID- 17690085 TI - First aid for seizures: the importance of education and appropriate response. AB - In most circumstances, first aid for seizures aims to protect the individual from harm during a seizure. Many people harbor misconceptions about or simply do not know how to respond to a seizure. Guidelines for seizure first aid from the Epilepsy Foundation are readily available and widely distributed, yet data from surveys and studies illustrate a deep unmet need in seizure first aid education. Lack of knowledge increases the potential for inappropriate or inadequate responses by parents, teachers, coworkers, and the public at large to repetitive or prolonged seizures, and the associated discomfort about how to provide first aid also can contribute to the general stigma associated with epilepsy. Clinicians play a key role in educating patients, parents, caregivers, and the community about how to respond to an individual who is having a seizure. This article reviews the data regarding seizure first aid knowledge among the various groups that may be called on to respond to a repetitive or prolonged seizure, highlights important goals of seizure first aid (including the prevention of status epilepticus) that should be relayed to these groups, and discusses the positive impact of seizure first aid education. PMID- 17690086 TI - Designing practical evidence-based treatment plans for children with prolonged seizures and status epilepticus. AB - The adverse effects of prolonged seizures and status epilepticus can be reduced through appropriate, prompt, and aggressive intervention. Because most prolonged seizures and status epilepticus episodes begin outside the hospital, it is important to design treatment interventions that can be rendered at home or in school that do not rely entirely on intervention by emergency medical personnel. Factors that make this new approach possible include the use of evidence-based guidelines to inform treatment decisions and the successful development, and government approval, of new formulations of commonly used medications, including rectal diazepam gel and the phenytoin prodrug fosphenytoin. A useful plan should be initiated at the 5-minute to 10-minute mark (not the 30-minute mark) and contain clear, easy-to-read directions that can be implemented by family, school personnel, or emergency medical services who have varying levels of medical sophistication. Four scenarios illustrating these considerations are included and provide examples of plans that fulfill these criteria. PMID- 17690087 TI - Pharmacologic considerations in the treatment of repetitive or prolonged seizures. AB - Seizure emergencies are relatively common; however, in-hospital emergency care often is delayed by a variety of factors. Home-based treatment is effective at interrupting prolonged or repetitive seizures, but this option is underused despite its wide availability. The choice of agent used to treat seizure emergencies will depend chiefly on differences among the properties of the available drugs, particularly with regard to route of administration, lipid solubility, formulation characteristics, and the relative size of the absorptive surface area. These factors also can play a part in the decision to use one route of administration over another. Intravenous administration is the fastest and most reliable method of drug delivery, but alternative methods of drug delivery include oral, intramuscular, buccal, nasal, and rectal routes. PMID- 17690088 TI - Special issues in the management of young children, older adults, and the developmentally disabled. AB - The very young, the very old, and those with developmental disability have an increased risk of both epilepsy and prolonged and repetitive seizures. The special issues that affect their management are reviewed. Polypharmacy that occurs because of comorbid illnesses requiring chronic medication can result in dangerous drug-drug interactions. The antiepileptic drug's pharmacokinetic profile must be factored when treating young children and older adults. Patients who have taken an older enzyme-inducing antiepileptic drug for years may have a markedly induced hepatic enzyme system that may alter drug metabolism. Overdose or toxicity may occur in older adults who may metabolize and clear antiepileptic drugs more slowly than younger patients. Benzodiazepines are the most rapidly effective acute therapy for repetitive or prolonged seizures. It is important to have a plan for management of prolonged and repetitive seizures. Long-term therapy should be managed in a manner that will eliminate the need for rescue therapies and visits to the emergency department. PMID- 17690089 TI - The personal and financial impact of repetitive or prolonged seizures on the patient and family. AB - Individuals with epilepsy consistently report diminished quality of life. The clinical characteristics of seizures and the unpredictable nature of seizure occurrences are some factors that affect quality of life. Prolonged or repetitive seizures can impose psychologic comorbidities, social issues, and lifestyle restrictions that can affect quality of life of patients and their caregivers and family members, who also bear the considerable indirect costs of seizures, including time away from work or school, and even loss of employment. The availability and use of an at-home medication to terminate prolonged or repetitive seizures or in seizure emergencies improves quality of life for patients and their families. Fewer visits to the emergency department are associated with a reduction in the financial burden to families and the health care system. This article discusses factors that contribute to the personal and financial impact of prolonged seizures on adult and pediatric patients, their families, and caregivers. PMID- 17690090 TI - Conclusion: having a plan to manage seizure emergencies. PMID- 17690091 TI - Enzymatic transition state theory and transition state analogue design. PMID- 17690092 TI - Glutathione depletion down-regulates tumor necrosis factor alpha-induced NF kappaB activity via IkappaB kinase-dependent and -independent mechanisms. AB - Reduced glutathione (GSH) plays a crucial role in hepatocyte function, and GSH depletion by diethyl maleate was shown previously to inhibit expression of NF kappaB target genes induced by tumor necrosis factor alpha (TNFalpha) and sensitize primary cultured mouse hepatocytes to TNF-mediated apoptotic killing. Here we demonstrate in the same system that GSH depletion down-regulates TNF induced NF-kappaB transactivation via two mechanisms, depending on the extent of the depletion. With moderate GSH depletion (approximately 50%), the down regulation is IkappaB kinase (IKK)-independent and likely acts on NF-kappaB transcriptional activity because TNF-induced IKK activation, IkappaBalpha phosphorylation and degradation, NF-kappaB nuclear translocation, NF-kappaB DNA binding in vitro, and NF-kappaB subunit RelA(p65) recruitment to kappaB sites of target gene promoters all appear unaltered. On the other hand, with profound GSH depletion (approximately 80%), the down-regulation also is IKK-dependent, and a timeline is established linking the inhibition of polyubiquitination of receptor interacting protein 1 in TNF receptor 1 complex to partial blockage of IKK activation, IkappaBalpha phosphorylation and degradation, and NF-kappaB nuclear translocation. Of note, pretreatment with antioxidant trolox protects against the inhibitory effect of profound GSH depletion on IKK activation and NF-kappaB nuclear translocation but fails to restore expression of NF-kappaB target genes, revealing both IKK-dependent and -independent inhibition. These findings provide new insights into the complex effects of oxidative stress and redox perturbations on the NF-kappaB pathway. PMID- 17690093 TI - Discovery of the true peroxy intermediate in the catalytic cycle of terminal oxidases by real-time measurement. AB - The sequence of the catalytic intermediates in the reaction of cytochrome bd terminal oxidases from Escherichia coli and Azotobacter vinelandii with oxygen was monitored in real time by absorption spectroscopy and electrometry. The initial binding of O(2) to the fully reduced enzyme is followed by the fast (5 micros) conversion of the oxy complex to a novel, previously unresolved intermediate. In this transition, low spin heme b(558) remains reduced while high spin heme b(595) is oxidized with formation of a new heme d-oxygen species with an absorption maximum at 635 nm. Reduction of O(2) by two electrons is sufficient to produce (hydro)peroxide bound to ferric heme d. In this case, the O-O bond is left intact and the newly detected intermediate must be a peroxy complex of heme d (Fe (3+)(d)-O-O-(H)) corresponding to compound 0 in peroxidases. The alternative scenario where the O-O bond is broken as in the P(M) intermediate of heme-copper oxidases and compound I of peroxidases is not very likely, because it would require oxidation of a nearby amino acid residue or the porphyrin ring that is energetically unfavorable in the presence of the reduced heme b(558) in the proximity of the catalytic center. The formation of the peroxy intermediate is not coupled to membrane potential generation, indicating that hemes d and b(595) are located at the same depth of the membrane dielectric. The lifetime of the new intermediate is 47 micros; it decays into oxoferryl species due to oxidation of low spin heme b(558) that is linked to significant charge translocation across the membrane. PMID- 17690094 TI - 1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. AB - We have shown that 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) down-regulates renin expression. To explore the molecular mechanism, we analyzed the mouse Ren 1c gene promoter by luciferase reporter assays. Deletion analysis revealed two DNA fragments from -2,725 to -2,647 (distal fragment) and from -117 to +6 (proximal fragment) that are sufficient to mediate the repression. Mutation of the cAMP response element (CRE) in the distal fragment blunted forskolin stimulation as well as 1,25(OH)(2)D(3) inhibition of the transcriptional activity, suggesting the involvement of CRE in 1,25(OH)(2)D(3)-induced suppression. EMSA revealed that 1,25(OH)(2)D(3) markedly inhibited nuclear protein binding to the CRE in the promoter. ChIP and GST pull-down assays demonstrated that liganded VDR blocked the binding of CREB to the CRE by directly interacting with CREB with the ligand-binding domain, and the VDR-mediated repression can be rescued by CREB, CBP, or p300 overexpression. These data indicate that 1,25(OH)(2)D(3) suppresses renin gene expression at least in part by blocking the formation of CRE-CREB-CBP complex. PMID- 17690095 TI - Ammonium scanning in an enzyme active site. The chiral specificity of aspartyl tRNA synthetase. AB - D-amino acids are largely excluded from protein synthesis, yet they are of great interest in biotechnology. Aspartyl-tRNA synthetase (AspRS) can misacylate tRNA(Asp) with D-aspartate instead of its usual substrate, L-Asp. We investigate how the preference for L-Asp arises, using molecular dynamics simulations. Asp presents a special problem, having pseudosymmetry broken only by its ammonium group, and AspRS must protect not only against D-Asp, but against an "inverted" orientation where the two substrate carboxylates are swapped. We compare L-Asp and D-Asp, in both orientations, and succinate, where the ammonium group is removed and the ligand has an additional negative charge. All possible ammonium positions on the ligand are thus scanned, providing information on electrostatic interactions. As controls, we simulate a Q199E mutation, obtaining a reduction in binding free energy in agreement with experiment, and we simulate TyrRS, which can misacylate tRNA(Tyr) with D-Tyr. For both TyrRS and AspRS, we obtain a moderate binding free energy difference DeltaDeltaG between the L- and D-amino acids, in agreement with their known ability to misacylate their tRNAs. In contrast, we predict that AspRS is strongly protected against inverted L-Asp binding. For succinate, kinetic measurements reveal a DeltaDeltaG of over 5 kcal/mol, favoring L-Asp. The simulations show how chiral discriminations arises from the structures, with two AspRS conformations acting in different ways and proton uptake by nearby histidines playing a role. A complex network of charges protects AspRS against most binding errors, making the engineering of its specificity a difficult challenge. PMID- 17690096 TI - Cloning and characterization of two human VIP1-like inositol hexakisphosphate and diphosphoinositol pentakisphosphate kinases. AB - Eukaryotes possess numerous inositol phosphate (IP) and diphosphoinositol phosphate (PP-IPs or inositol pyrophosphates) species that act as chemical codes important for intracellular signaling pathways. Production of IP and PP-IP molecules occurs through several classes of evolutionarily conserved inositol phosphate kinases. Here we report the characterization of a human inositol hexakisphosphate (IP6) and diphosphoinositol pentakisphosphate (PP-IP5 or IP7) kinase with similarity to the yeast enzyme Vip1, a recently identified IP6/IP7 kinase (Mulugu, S., Bai, W., Fridy, P. C., Bastidas, R. J., Otto, J. C., Dollins, D. E., Haystead, T. A., Ribeiro, A. A., and York, J. D. (2007) Science 316, 106 109). Recombinant human VIP1 exhibits in vitro IP6 and IP7 kinase activities and restores IP7 synthesis when expressed in mutant yeast. Expression of human VIP1 in HEK293T cells engineered to produce high levels of IP7 results in dramatic increases in bisdiphosphoinositol tetrakisphosphate (PP2-IP4 or IP8). Northern blot analysis indicates that human VIP1 is expressed in a variety of tissues and is enriched in skeletal muscle, heart, and brain. The subcellular distribution of tagged human VIP1 is indicative of a cytoplasmic non-membrane localization pattern. We also characterized human and mouse VIP2, an additional gene product with nearly 90% similarity to VIP1 in the kinase domain, and observed both IP6 and IP7 kinase activities. Our data demonstrate that human VIP1 and VIP2 function as IP6 and IP7 kinases that act along with the IP6K/Kcs1-class of kinases to convert IP6 to IP8 in mammalian cells, a process that has been found to occur in response to various stimuli and signaling events. PMID- 17690097 TI - Glutathione binding to the Bcl-2 homology-3 domain groove: a molecular basis for Bcl-2 antioxidant function at mitochondria. AB - Bcl-2 protects cells against mitochondrial oxidative stress and subsequent apoptosis. However, the mechanism underlying the antioxidant function of Bcl-2 is currently unknown. Recently, Bax and several Bcl-2 homology-3 domain (BH3)-only proteins (Bid, Puma, and Noxa) have been shown to induce a pro-oxidant state at mitochondria (1-4). Given the opposing effects of Bcl-2 and Bax/BH3-only proteins on the redox state of mitochondria, we hypothesized that the antioxidant function of Bcl-2 is antagonized by its interaction with the BH3 domains of pro-apoptotic family members. Here, we show that BH3 mimetics that bind to a hydrophobic surface (the BH3 groove) of Bcl-2 induce GSH-sensitive mitochondrial dysfunction and apoptosis in cerebellar granule neurons. BH3 mimetics displace a discrete mitochondrial GSH pool in neurons and suppress GSH transport into isolated rat brain mitochondria. Moreover, BH3 mimetics and the BH3-only protein, Bim, inhibit a novel interaction between Bcl-2 and GSH in vitro. These results suggest that Bcl-2 regulates an essential pool of mitochondrial GSH and that this regulation may depend upon Bcl-2 directly interacting with GSH via the BH3 groove. We conclude that this novel GSH binding property of Bcl-2 likely plays a central role in its antioxidant function at mitochondria. PMID- 17690098 TI - Acetylation of lysine 56 of histone H3 catalyzed by RTT109 and regulated by ASF1 is required for replisome integrity. AB - In budding yeast, acetylation of histone H3 lysine 56 (H3-K56) is catalyzed by the Rtt109-Vps75 histone acetyltransferase (HAT) complex, with Rtt109 being the catalytic subunit, and histone chaperone Asf1 is required for this modification. Cells lacking Rtt109 are susceptible to perturbations in DNA replication. However, how Asf1 regulates acetylation of H3-K56 and how loss of H3-K56 acetylation affects DNA replication are unclear. We show that at low concentrations the Rtt109-Vps75 HAT complex acetylates H3-K56 in vitro when H3/H4 is complexed with Asf1, but not H3/H4 tetramers, recapitulating the in vivo requirement of Asf1 for H3-K56 acetylation using recombinant proteins. Moreover, the Rtt109-Vps75 complex interacts with Asf1-H3/H4 but not Asf1. In vivo, the Rtt109-Asf1 interaction is also dependent on the ability of Asf1 to bind H3/H4. Furthermore, the Rtt109 homolog in Schizosaccharomyces pombe (SpRtt109) also displayed an Asf1-dependent H3-K56 HAT activity in vitro. These results indicate that Asf1 regulates H3-K56 acetylation by presenting histones H3 and H4 to Rtt109 Vps575 for acetylation, and this mechanism is likely to be conserved. Finally, we have shown that cells lacking Rtt109 or expressing H3-K56 mutants exhibited significant reduction in the association of three proteins with stalled DNA replication forks and hyper-recombination of replication forks stalled at replication fork barriers of the ribosomal DNA locus compared with wild-type cells. Taken together, these studies provide novel insight into the role of Asf1 in the regulation of H3-K56 acetylation and the function of this modification in DNA replication. PMID- 17690099 TI - Mitochondrial regulation of caspase activation by cytochrome oxidase and tetramethylphenylenediamine via cytosolic cytochrome c redox state. AB - Cytochrome c release from mitochondria induces caspase activation in cytosols; however, it is unclear whether the redox state of cytosolic cytochrome c can regulate caspase activation. By using cytosol isolated from mammalian cells, we find that oxidation of cytochrome c by added cytochrome oxidase stimulates caspase activation, whereas reduction of cytochrome c by added tetramethylphenylenediamine (TMPD) or yeast lactate dehydrogenase/cytochrome c reductase blocks caspase activation. Scrape-loading of cells with this reductase inhibited caspase activation induced by staurosporine. Similarly, incubating intact cells with ascorbate plus TMPD to reduce intracellular cytochrome c strongly inhibited staurosporine-induced cell death, apoptosis, and caspase activation but not cytochrome c release, indicating that cytochrome c redox state can regulate caspase activation. In homogenates from healthy cells cytochrome c was rapidly reduced, whereas in homogenates from apoptotic cells added cytochrome c was rapidly oxidized by some endogenous process. This oxidation was prevented if mitochondria were removed from the homogenate or if cytochrome oxidase was inhibited by azide. This suggests that permeabilization of the outer mitochondrial membrane during apoptosis functions not just to release cytochrome c but also to maintain it oxidized via cytochrome oxidase, thus maximizing caspase activation. However, this activation can be blocked by adding TMPD, which may have some therapeutic potential. PMID- 17690100 TI - Mutations designed to destabilize the receptor-bound conformation increase MICA NKG2D association rate and affinity. AB - MICA is a major histocompatibility complex-like protein that undergoes a structural transition from disorder to order upon binding its immunoreceptor, NKG2D. We redesigned the disordered region of MICA with RosettaDesign to increase NKG2D binding. Mutations that stabilize this region were expected to increase association kinetics without changing dissociation kinetics, increase affinity of interaction, and reduce entropy loss upon binding. MICA mutants were stable in solution, and they were amenable to surface plasmon resonance evaluation of NKG2D binding kinetics and thermodynamics. Several MICA mutants bound NKG2D with enhanced affinity, kinetic changes were primarily observed during association, and thermodynamic changes in entropy were as expected. However, none of the 15 combinations of mutations predicted to stabilize the receptor-bound MICA conformation enhanced NKG2D affinity, whereas all 10 mutants predicted to be destabilized bound NKG2D with increased on-rates. Five of these had affinities enhanced by 0.9-1.8 kcal/mol over wild type by one to three non-contacting substitutions. Therefore, in this case, mutations designed to mildly destabilize a protein enhanced association and affinity. PMID- 17690101 TI - Raft-dependent endocytosis of autocrine motility factor is phosphatidylinositol 3 kinase-dependent in breast carcinoma cells. AB - Autocrine motility factor (AMF) is internalized via a receptor-mediated, dynamin dependent, cholesterol-sensitive raft pathway to the smooth endoplasmic reticulum that is negatively regulated by caveolin-1. Expression of AMF and its receptor (AMFR) is associated with tumor progression and malignancy; however, the extent to which the raft-dependent uptake of AMF is tumor cell-specific has yet to be addressed. By Western blot and cell surface fluorescence-activated cell sorter (FACS) analysis, AMFR expression is increased in tumorigenic MCF7 and metastatic MDA-231 and MDA-435 breast cancer cell lines relative to dysplastic MCF10A mammary epithelial cells. AMF uptake, determined by FACS measurement of protease insensitive internalized fluorescein-conjugated AMF, was increased in MCF7 and MDA-435 cells relative to MCF-10A and caveolin-1-expressing MDA-231 cells. Uptake of fluorescein-conjugated AMF was dynamin-dependent, methyl-beta-cyclodextrin- and genistein-sensitive, reduced upon overexpression of caveolin-1 in MDA-435 cells, and increased upon short hairpin RNA reduction of caveolin-1 in MDA-231 cells. Tissue microarray analysis of invasive primary human breast carcinomas showed that AMFR expression had no impact on survival but did correlate significantly with expression of phospho-Akt. Phospho-Akt expression was increased in AMF-internalizing MCF7 and MDA-435 breast carcinoma cells. AMF uptake in these cells was reduced by phosphatidylinositol 3-kinase inhibition but not by regulators of macropinocytosis such as amiloride, phorbol ester, or actin cytoskeleton disruption by cytochalasin D. The raft-dependent endocytosis of AMF therefore follows a distinct phosphatidylinositol 3-kinase-dependent pathway that is up-regulated in more aggressive tumor cells. PMID- 17690102 TI - Microsomal triglyceride transfer protein activity is not required for the initiation of apolipoprotein B-containing lipoprotein assembly in McA-RH7777 cells. AB - We previously demonstrated that the N-terminal 1000 amino acid residues of human apolipoprotein (apo) B (designated apoB:1000) are competent to fold into a three sided lipovitellin-like lipid binding cavity to form the apoB "lipid pocket" without a structural requirement for microsomal triglyceride transfer protein (MTP). Our results established that this primordial apoB-containing particle is phospholipid-rich (Manchekar, M., Richardson, P. E., Forte, T. M., Datta, G., Segrest, J. P., and Dashti, N. (2004) J. Biol. Chem. 279, 39757-39766). In this study we have investigated the putative functional role of MTP in the initial lipidation of apoB:1000 in stable transformants of McA-RH7777 cells. Inhibition of MTP lipid transfer activity by 0.1 microm BMS-197636 and 5, 10, and 20 microm of BMS-200150 had no detectable effect on the synthesis, lipidation, and secretion of apoB:1000-containing particles. Under identical experimental conditions, the synthesis, lipidation, and secretion of endogenous apoB100 containing particles in HepG2 and parental untransfected McA-RH7777 cells were inhibited by 86-94%. BMS-200150 at 40 microm nearly abolished the secretion of endogenous apoB100-containing particles in HepG2 and parental McA-RH cells but caused only 15-20% inhibition in the secretion of apoB: 1000-containing particles. This modest decrease was attributable to the nonspecific effect of a high concentration of this compound on hepatic protein synthesis, as reflected in a similar (20-25%) reduction in albumin secretion. Suppression of MTP gene expression in stable transformants of McA-RH7777 cells by micro-interfering RNA led to 60-70% decrease in MTP mRNA and protein levels, but it had no detectable effect on the secretion of apoB:1000. Our results provide a compelling argument that the initial addition of phospholipids to apoB:1000 and initiation of apoB containing lipoprotein assembly occur independently of MTP lipid transfer activity. PMID- 17690103 TI - Determination of dual effects of parathyroid hormone on skeletal gene expression in vivo by microarray and network analysis. AB - Parathyroid hormone (PTH) stimulates bone formation when injected daily but causes severe bone loss with continuous infusion. The mechanism of its paradoxical effects is still elusive. In this study, we compared changes in the gene expression profile in bone induced by intermittent or continuous treatment with three different PTH peptides, PTH-(1-34), -(1-31), and -(3-34), in Sprague Dawley female rats. PTH-(1-34) regulated numerous genes (approximately 1,000), but differentially, in both regimes. PTH-(1-31) regulated a similar number of genes in the intermittent regimen but fewer in the continuous regimen, consistent with its less potent catabolic effect. PTH-(3-34) regulated very few genes in both regimes, which suggests the protein kinase C pathway plays a limited role in mediating the dual effects of PTH, whereas the cAMP-dependent protein kinase A pathway appears to predominate. In the intermittent treatment, many genes encoding signaling mediators, transcription factors, cytokines, and proteases/protease inhibitors are regulated rapidly and cyclically with each PTH injection; genes associated with skeletal development show a slowly accruing pattern of expression. With continuous treatment, some genes are regulated from 6 h, and the mRNA levels are sustained with a longer infusion, whereas others show a kinetic decrease and then increase later. Significant up-regulation of genes stimulating osteoclastogenesis in the anabolic regime suggests a provocative and paradoxical theme for the anabolic effect of PTH that a full anabolic response requires a transient up-regulation of genes classically associated with a resorptive response. Ingenuity pathway analysis was performed on the microarray data. A novel signaling network was established that is differentially regulated in the two PTH treatment regimes. Key regulators are suggested to be AREG, CCL2, WNT4, and cAMP-responsive element modulator. PMID- 17690104 TI - Enzymes responsible for synthesis of corneal keratan sulfate glycosaminoglycans. AB - Keratan sulfate glycosaminoglycans are among the most abundant carbohydrate components of the cornea and are suggested to play an important role in maintaining corneal extracellular matrix structure. Keratan sulfate carbohydrate chains consist of repeating N-acetyllactosamine disaccharides with sulfation on the 6-O positions of N-acetylglucosamine and galactose. Despite its importance for corneal function, the biosynthetic pathway of the carbohydrate chain and particularly the elongation steps are poorly understood. Here we analyzed enzymatic activity of two glycosyltransferases, beta1,3-N acetylglucosaminyltansferase-7 (beta3GnT7) and beta1,4-galactosyltransferase-4 (beta4GalT4), in the production of keratan sulfate carbohydrate in vitro. These glycosyltransferases produced only short, elongated carbohydrates when they were reacted with substrate in the absence of a carbohydrate sulfotransferase; however, they produced extended GlcNAc-sulfated poly-N-acetyllactosamine structures with more than four repeats of the GlcNAc-sulfated N-acetyllactosamine unit in the presence of corneal N-acetylglucosamine 6-O sulfotransferase (CGn6ST). Moreover, we detected production of highly sulfated keratan sulfate by a two-step reaction in vitro with a mixture of beta3GnT7/beta4GalT4/CGn6ST followed by keratan sulfate galactose 6-O sulfotransferase treatment. We also observed that production of highly sulfated keratan sulfate in cultured human corneal epithelial cells was dramatically reduced when expression of beta3GnT7 or beta4GalT4 was suppressed by small interfering RNAs, indicating that these glycosyltransferases are responsible for elongation of the keratan sulfate carbohydrate backbone. PMID- 17690105 TI - Enzymatic characterization of dihydrolipoamide dehydrogenase from Streptococcus pneumoniae harboring its own substrate. AB - This study describes the enzymatic characterization of dihydrolipoamide dehydrogenase (DLDH) from Streptococcus pneumoniae and is the first characterization of a DLDH that carries its own substrate (a lipoic acid covalently attached to a lipoyl protein domain) within its own sequence. Full length recombinant DLDH (rDLDH) was expressed and compared with enzyme expressed in the absence of lipoic acid (rDLDH(-LA)) or with enzyme lacking the first 112 amino acids constituting the lipoyl protein domain (rDLDH(-LIPOYL)). All three proteins contained 1 mol of FAD/mol of protein, had a higher activity for the conversion of NAD(+) to NADH than for the reaction in the reverse direction, and were unable to use NADP(+) and NADPH as substrates. The enzymes had similar substrate specificities, with the K(m) for NAD(+) being approximately 20 times higher than that for dihydrolipoamide. The kinetic pattern suggested a Ping Pong Bi Bi mechanism, which was verified by product inhibition studies. The protein expressed without lipoic acid was indistinguishable from the wild-type protein in all analyses. On the other hand, the protein without a lipoyl protein domain had a 2-3-fold higher turnover number, a lower K(I) for NADH, and a higher K(I) for lipoamide compared with the other two enzymes. The results suggest that the lipoyl protein domain (but not lipoic acid alone) plays a regulatory role in the enzymatic characteristics of pneumococcal DLDH. PMID- 17690106 TI - Ligand binding rapidly induces disulfide-dependent dimerization of glycoprotein VI on the platelet plasma membrane. AB - Thrombus formation in hemostasis or thrombotic disease is initiated by adhesion of circulating platelets to damaged blood vessel walls. Exposed subendothelial collagen interacting with platelet glycoprotein (GP) VI leads to platelet activation and integrin alpha(IIb)beta(3)-mediated aggregation. We previously showed that ligand binding to GPVI also induces metalloproteinase-dependent shedding, generating an approximately 55-kDa soluble ectodomain fragment and an approximately 10-kDa membrane-associated remnant. Here, treatment of platelets with collagen or the GPVI-targeting rattlesnake toxin convulxin also induces rapid (10-30 s) formation of a high molecular weight GPVI complex (GPVIc) under nonreducing conditions, as detected by immunoblotting with anti-GPVI antibodies. The appearance of an approximately 20-kDa remnant detectable using a polyclonal antibody against the GPVI cytoplasmic tail under nonreducing, but not reducing, conditions after ectodomain shedding and nonreduced/reduced two-dimensional SDS polyacrylamide gel analysis of biotinylated platelets confirmed that that GPVIc was a homodimer. Formation of disulfide-linked GPVIc was prolonged in the presence of metalloproteinase inhibitor GM6001 and was independent of GPVI signaling because it was unaffected by inhibitors of Src kinases, Syk, or phosphoinositide 3-kinase. To identify the thiol involved in disulfide bond formation, wild-type or mutant GPVI, where two available sulfhydryls (Cys-274 and Cys-338) were individually mutated to serine, was expressed in rat basophilic leukemia cells. Dimerization of wild-type and C274S GPVI, but not the C338S mutant, was observed after treating cells with convulxin. We conclude that (i) a subpopulation of GPVI forms a constitutive dimer on the platelet surface, facilitating rapid disulfide cross-linking, (ii) convulxin or other GPVI agonists induce disulfide-linked GPVI dimerization independent of GPVI signaling, and (iii) the penultimate residue of the GPVI cytoplasmic tail, Cys-338, mediates disulfide-dependent dimer formation. PMID- 17690107 TI - Polyamine-dependent regulation of spermidine-spermine N1-acetyltransferase mRNA translation. AB - Spermidine-spermine N(1)-acetyltransferase (SSAT) is induced in response to an elevation in intracellular polyamine pools. The increased enzyme activity is the result of an increase in gene transcription, mRNA translation, and protein stability. Induction of SSAT by polyamine analogues can lead to intracellular polyamine depletion and apoptosis. The mechanism by which polyamines alter the translational efficiency of SSAT mRNA is not well understood. In this study, we investigated the regulation of SSAT translation by the polyamine analogue N(1),N(11)-diethylnorspermine (DENSPM). DENSPM induced expression of both FLAG tagged SSAT and SSAT fused to Renilla luciferase in a time- and concentration dependent manner. This effect was not inhibited by actinomycin D indicating that changes in gene transcription did not explain the enhanced expression in the presence of DENSPM. Furthermore, because FLAG-SSAT did not contain the 5'- or 3' untranslated regions of SSAT, translational regulation involved the coding sequence only. By contrast, cycloheximide completely inhibited induction by DENSPM, indicating a requirement for new protein synthesis. Deletion constructs identified two regions of the SSAT protein-coding RNA sequence that conferred polyamine responsiveness. Using these regions as probes in RNA electrophoretic mobility shift assays, we observed specific binding of a cytoplasmic protein. In addition, we found that the interaction between the RNA probes and the binding protein could be inhibited by DENSPM in a concentration-dependent manner. These results suggest that polyamines regulate SSAT mRNA translational efficiency by inhibiting a repressor protein from binding to regions of the coding sequence of the SSAT transcript. PMID- 17690108 TI - Parathyroid hormone stimulates osteoblastic expression of MCP-1 to recruit and increase the fusion of pre/osteoclasts. AB - The clinical findings that alendronate blunted the anabolic effect of human parathyroid hormone (PTH) on bone formation suggest that active resorption is involved and enhances the anabolic effect. PTH signals via its receptor on the osteoblast membrane, and osteoclasts are impacted indirectly via the products of osteoblasts. Microarray with RNA from rats injected with human PTH or vehicle showed a strong association between the stimulation of monocyte chemoattractant protein-1 (MCP-1) and the anabolic effects of PTH. PTH rapidly and dramatically stimulated MCP-1 mRNA in the femora of rats receiving daily injections of PTH or in primary osteoblastic and UMR 106-01 cells. The stimulation of MCP-1 mRNA was dose-dependent and a primary response to PTH signaling via the cAMP-dependent protein kinase pathway in vitro. Studies with the mouse monocyte cell line RAW 264.7 and mouse bone marrow proved that osteoblastic MCP-1 can potently recruit osteoclast monocyte precursors and facilitate receptor activator of NF-kappaB ligand-induced osteoclastogenesis and, in particular, enhanced fusion. Our model suggests that PTH-induced osteoblastic expression of MCP-1 is involved in recruitment and differentiation at the stage of multinucleation of osteoclast precursors. This information provides a rationale for increased osteoclast activity in the anabolic effects of PTH in addition to receptor activator of NF kappaB ligand stimulation to initiate greater bone remodeling. PMID- 17690109 TI - Regulation of mesodermal differentiation of mouse embryonic stem cells by basement membranes. AB - Basement membranes (BMs) have been implicated in cell fate determination during development. Embryoid bodies (EBs) derived from mouse embryonic stem cells deficient in the laminin gamma1 chain are incapable of depositing a BM, resulting in failure of primitive ectoderm epithelialization. To elucidate the mechanisms involved in this phenomenon, we compared the gene expression profiles of EBs with or without a BM to identify the genes showing BM-dependent expression. We found that the expressions of marker genes for the epithelial-mesenchymal transition (EMT), including the transcription factor Snai2, were up-regulated in LAMC1(-/-) EBs, whereas restoration of a BM to LAMC1(-/-) EBs suppressed the up-regulation of these genes. Overexpression of Snai2 induced the EMT in control EBs by molecular and morphological criteria, suggesting that suppression of the EMT regulatory genes is involved in BM-dependent epithelialization of primitive ectoderm. Despite the failure of primitive ectoderm epithelialization in BM deficient EBs, mesodermal differentiation was not compromised, but rather accelerated. Furthermore, at later stages of control EB differentiation, the BM was disrupted at the gastrulation site where mesodermal markers were strongly expressed only in cells that had lost contact with the BM. Taken together, these results indicate that the BM prevents the EMT and precocious differentiation of primitive ectoderm toward mesoderm in EBs, implying that BMs are important for the control of mammalian gastrulation. PMID- 17690110 TI - Role of p14ARF in TWIST-mediated senescence in prostate epithelial cells. AB - Recently, TWIST, a basic helix-loop-helix transcription factor, is suggested to be an oncogene because of its over-expression in many types of human cancer and its positive role in promoting cell survival. The aim of this study was to investigate the role of TWIST on the growth of human epithelial cells. Using two immortalized human prostate epithelial cell lines, we demonstrated that inactivation of TWIST by small RNA technology led to the promotion of cellular senescence and growth arrest, suggesting that TWIST plays a key role in the continuous proliferation of immortalized cells. Over-expression of TWIST, in contrast, resulted in suppression of cellular senescence in response to genotoxic damage and promotion of cell proliferation with DNA damage accumulation, indicating that TWIST promotes genomic instability. In addition, we also found that the TWIST-mediated cellular senescence was regulated through its negative effect on p14(ARF) and subsequent suppression of MDM2/p53 and Chk1/2 DNA damage response pathways. Our results suggest that over-expression of TWIST results in down-regulation of p14(ARF), which leads to the impairment of DNA damage checkpoint in response to genotoxic stress. This negative effect of TWIST on DNA damage response facilitates uncontrolled cell proliferation with genomic instability and tumorigenesis in non-malignant cells. PMID- 17690111 TI - Binary PAH mixtures cause additive or antagonistic effects on gene expression but synergistic effects on DNA adduct formation. AB - Polycyclic aromatic hydrocarbons (PAHs) cover a wide range of structurally related compounds which differ greatly in their carcinogenic potency. PAH exposure usually occurs through mixtures rather than individual compounds. Therefore, we assessed whether the effects of binary PAH mixtures on gene expression, DNA adduct formation, apoptosis and cell cycle are additive compared with the effects of the individual compounds in human hepatoma cells (HepG2). Equimolar and equitoxic mixtures of benzo[a]pyrene (B[a]P) with either dibenzo[a,l]pyrene (DB[a,l]P), dibenzo[a,h]anthracene (DB[a,h]A), benzo[b]fluoranthene (B[b]F), fluoranthene (FA) or 1-methylphenanthrene (1-MPA) were studied. DB[a,l]P, B[a]P, DB[a,h]A and B[b]F dose-dependently increased apoptosis and blocked cells cycle in S-phase. PAH mixtures showed an additive effect on apoptosis and on cell cycle blockage. DNA adduct formation in mixtures was higher than expected based on the individual compounds, indicating a synergistic effect of PAH mixtures. Equimolar mixtures of B[a]P and DB[a,l]P (0.1, 0.3 and 1.0 microM) were assessed for their effects on gene expression. Only at 1.0 microM, the mixture showed antagonism. All five compounds were also tested as a binary mixture with B[a]P in equitoxic concentrations. The combinations of B[a]P with B[b]F, DB[a,h]A or FA showed additivity, whereas B[a]P with DB[a,l]P or 1-MPA showed antagonism. Many individual genes showed additivity in mixtures, but some genes showed mostly antagonism or synergism. Our results show that the effects of binary mixtures of PAHs on gene expression are generally additive or slightly antagonistic, suggesting no effect or decreased carcinogenic potency, whereas the effects on DNA adduct formation show synergism, which rather indicates increased carcinogenic potency. PMID- 17690112 TI - Meat intake, preparation methods, mutagens and colorectal adenoma recurrence. AB - Red meat intake has been shown to be associated with higher risk of colorectal cancer. Though the exact mechanisms responsible for this association remain unknown, several tumorigenic properties of meat have been proposed. One well supported biologic mechanism is elevated exposure to the genotoxic formation of heterocyclic amines (HCAs), which occur when meat is cooked at high temperatures for a long period of time. We prospectively assessed the relation between type of meat, meat preparation method, doneness, a metric of HCAs and other mutagens and colorectal adenoma recurrence among 869 participants in a chemoprevention trial of ursodeoxycholic acid. Unconditional logistic regression analyses were used to estimate odds ratios (ORs) and associated 95% confidence intervals (CIs). Most meat variables assessed were positively but weakly associated with recurrence of any adenoma. In contrast, recurrence of advanced or multiple adenomas was more strongly associated with a number of the meat exposure variables evaluated. For recurrence of advanced lesions, significant associations were detected among individuals in the highest when compared with the lowest tertile of intake for pan-fried red meat (OR = 1.85; 95% CI = 1.10-3.13) and well/very well done red meat (OR = 1.71; 95% CI = 1.02-2.86). Significant positive associations were shown for recurrence of multiple adenomas and the following variables: processed meat (OR = 1.83; 95% CI = 1.10-3.04), pan-fried red meat (OR = 1.63; 95% CI = 1.01-2.61), well/very well done red meat (OR = 1.68; 95% CI = 1.03-2.74), 2-amino 3,4,8-trimethylimidazo[4,5,-f]quinoxaline (OR = 1.74; 95% CI = 1.07-2.82) and 2 amino-3,8-dimethylimidazo[4,5-f]quinoxaline (OR = 1.68; 95% CI = 1.03-2.75). Our results support a meat mutagen exposure hypothesis as a potential mechanism for recurrence of clinically significant adenomatous polyps. PMID- 17690113 TI - Identification and characterization of a novel germ line p53 mutation in familial gastric cancer in the Japanese population. AB - Germ line mutations of the p53 gene are known to cause Li-Fraumeni syndrome, and a germ line p53 mutation has recently been reported in a small subset of familial gastric cancer (FGC) in Europe and Korea. Although the incidence of gastric cancer is very high in Japan and familial clustering is not uncommon, there has been little information on the genetic factors of FGC. Therefore, to determine the role of germ line p53 mutations in FGC in the Japanese population in this study, we used sequencing analysis to examine 80 individuals from 35 Japanese FGC families without germ line CDH1 mutations for germ line p53 mutations. One missense (c.91G>A: p.Val31Ile) and two intronic germ line mutations were found, and transcriptional activity of the Ile31 mutant on p53-responsive genes was examined to determine the functional effect of the novel p.Val31Ile germ line mutation. A luciferase reporter assay showed that the transcriptional activity of p21 (CDKN1A) and MDM2 promoters but not of the BAX promoter was significantly lower in the Ile31-type p53 than in the wild-type (wt) p53. Next, doxycycline regulated p53-inducible H1299 cell lines were established by applying a retrovirus-mediated gene transfer system to a p53-null human H1299 cell line. Under similar p53 expression conditions shown by western blot and immunofluorescence analyses, a cell proliferation assay showed that the Ile31 type p53 had significantly lower cell proliferation suppressing activity than wt p53. These results suggest that Ile31-type p53 may be partly involved in FGC because of its low transcriptional activity and low cell proliferation suppressing activity. PMID- 17690114 TI - Modulation of tumor induction and progression of oncogenic K-ras-positive tumors in the presence of TGF- b1 haploinsufficiency. AB - Oncogenic K-ras is one of the most common genetic alterations in human lung adenocarcinomas. In addition, inactivation of clusters of tumor suppressor genes is required to bring about classical characteristics of cancer including angiogenesis as a prelude to invasion and metastasis. Transforming growth factor beta (TGF-beta) 1 is a tumor suppressor gene that is implicated in lung cancer progression. Although in vitro studies have shown that TGF-beta1 and Ras pathways cooperate during tumorigenesis, the biology of interaction of TGF-beta1 and Ras has not been studied in in vivo tumorigenesis. We hypothesized that inactivation of TGF-beta1 in addition to oncogeneic activation of K-ras would lead to early initiation and faster progression to lung adenocarcinoma and invasion and metastasis. Heterozygous (HT) TGF-beta1 mice were mated with latent activatable (LA) mutated K-ras mice to generate TGF-beta1(+/+), K-ras LA (wild-type (WT)/LA) and TGF-beta1(+/-), K-ras LA (HT/LA) mice. Both HT/LA and WT/LA mice developed spontaneous lung tumors, but HT/LA mice progressed to adenocarcinomas significantly earlier compared with WT/LA mice. In addition, WT/LA adenocarcinomas had significantly higher angiogenic activity compared with HT/LA adenocarcinomas. Thus, while oncogenic K-ras mutation and insensitivity to the growth regulatory effects of TGF-beta1 is essential for initiation and progression of mouse lung tumors to adenocarcinoma, a full gene dosage of TGF beta1 is required for tumor-induced angiogenesis and invasive potential. This study identifies a number of genes not previously associated with lung cancer that are involved in tumor induction and progression. In addition, we provide evidence that progression to invasive angiogenic lesions requires TGF-beta1 responsiveness in addition to Ras mutation. PMID- 17690115 TI - Phospho-epitope binding by the BRCT domains of hPTIP controls multiple aspects of the cellular response to DNA damage. AB - Human (h)PTIP plays important but poorly understood roles in cellular responses to DNA damage. hPTIP interacts with 53BP1 tumour suppressor but only when 53BP1 is phosphorylated by ATM after DNA damage although the mechanism(s) and significance of the interaction of these two proteins are unclear. Here, we pinpoint a single ATM-phosphorylated residue in 53BP1--Ser25--that is required for binding of 53BP1 to hPTIP. Binding of phospho-Ser25 to hPTIP in vitro and in vivo requires two closely apposed pairs of BRCT domains at the C-terminus of hPTIP and neither pair alone can bind to phospho-Ser25, even though one of these BRCT pairs in isolation can bind to other ATM-phosphorylated epitopes. Mutations in 53BP1 and in hPTIP that prevent the interaction of the two proteins, render cells hypersensitive to DNA damage and weaken ATM signalling. The C-terminal BRCT domains of hPTIP are also required for stable retention of hPTIP at sites of DNA damage but this appears to be independent of binding to 53BP1. Thus, the BRCT domains of hPTIP play important roles in the cellular response to DNA damage. PMID- 17690116 TI - Cdc18/CDC6 activates the Rad3-dependent checkpoint in the fission yeast. AB - A screen for genes that can ectopically activate a Rad3-dependent checkpoint block over mitosis in fission yeast has identified the DNA replication initiation factor cdc18 (known as CDC6 in other organisms). Either a stabilized form of Cdc18, the Cdc18-T6A phosphorylation mutant, or overexpression of wild type Cdc18, activate the Rad3-dependent S-M checkpoint in the apparent absence of detectable replication structures and gross DNA damage. This cell cycle block relies on the Rad checkpoint pathway and requires Chk1 phosphorylation and activation. Unexpectedly, Cdc18-T6A induces changes in the mobility of Chromosome III, affecting the size of a restriction fragment containing rDNA repeats and producing aberrant nucleolar structures. Recombination events within the rDNA appear to contribute at least in part to the cell cycle delay. We propose that an elevated level of Cdc18 activates the Rad3-dependent checkpoint either directly or indirectly, and additionally causes expansion of the rDNA repeats on Chromosome III. PMID- 17690117 TI - Daily mood as a mediator or moderator of the pain-sleep relationship in children with sickle cell disease. AB - OBJECTIVE: To investigate mood as a mediator or moderator of the pain-sleep relationship in children with sickle cell disease (SCD). METHOD: Children with SCD (n = 20; aged 8-12 years) completed daily diaries assessing mood, sleep, and pain for up to 2 months. Data was analyzed using multilevel modeling. Results Results indicate that negative mood partially mediates the relationship between high daily pain and poor sleep that night as well the relationship between poor sleep and high daily pain the following day. The impact of poor sleep on high pain the following day was weakened at increasing levels of positive mood. CONCLUSION: Research is needed to fully explore the ways positive and negative mood may relate to pain and sleep characteristics. This information may be beneficial for developing more effective pain management and sleep interventions. PMID- 17690118 TI - In vivo behavior of zirconia hydroxyapatite (ZH) ceramic implants in dogs: a clinical, radiographic, and histological study. AB - The main goal of this study is to evaluate potential applications of two zirconia hydroxyapatite composites, Z4H6 and Z6H4, as bone substitutes. Composite plugs were implanted into the distal femoral metaphysis and also onto the longissimus dorsi of 18 adult mixed-breed dogs in order to assess in vivo biocompatibility by immediate clinical and radiographic evaluation 30, 90, and 120 days after implantation. Radiographic examination revealed radiolucency on the defect site. However, a progressive increase in bone density was observed over time, reaching a radiopacity similar to that of bone 120 days after implantation. Histological study revealed that a thin layer of fibroblasts was observed at the implant-bone interface in addition to osteoblastic activity 30 days after implantation, whereas bone neoformation around the implants was detected for the subsequent implantation times (90 and 120 days). Otherwise, the histological evaluation of the implant-muscle interface showed the presence of an initially thick fibrous tissue layer 30 days after implantation, which decreased with longer investigation times (90 and 120 days). The numbers of plasmocytes, lymphocytes, and macrophages gradually reduced as a function implantation time, being completely absent 120 days after implantation with a resulting complete osteointegration process. The zirconia phase content did not affect the bioactive behavior of the implants investigated and did not induce bone formation when implanted into muscle either. PMID- 17690119 TI - Discrimination of exudative pleural effusions based on multiple biological parameters. AB - Pleural effusion is a common complication of various diseases. Conventional methods are not always capable of establishing the cause of pleural effusion, so alternative tests are needed. The aim of this study was to explore means of discriminating between different pleural effusion groups, malignant, parapneumonic and tuberculous, based on the combined function of seven biological markers. Adenosine deaminase (ADA), interferon-gamma, C-reactive protein (CRP), carcinoembryonic antigen, interleukin-6, tumour necrosis factor-alpha and vascular endothelial growth factor concentration levels were measured in pleural fluid from 45 patients with malignant, 15 with parapneumonic and 12 with tuberculous pleural effusion. Receiver operating characteristic curve analysis, multinomial logit modelling and canonical variate analysis were applied to discriminate the pleural effusion groups. The three groups could be discriminated successfully using the measured markers. The most important parameters for discrimination were ADA and CRP concentration levels. An individual with an ADA concentration level of >45 U.L(-1) and a CRP concentration of <4 mg.dL(-1) was more likely to belong to the tuberculous pleural effusion group, whereas one with an ADA concentration level of <40 U.L(-1) and a CRP concentration of >6 mg.dL(-1) was more likely to belong to the parapneumonic pleural effusion group, and one with a CRP concentration of <4 mg.dL(-1) to the malignant pleural effusion group. The combination of adenosine deaminase and C-reactive protein levels might be sufficient for discriminating between the three different groups of exudative pleural effusion: malignant, tuberculous and parapneumonic. PMID- 17690120 TI - Premature discontinuation of patients: a potential bias in COPD clinical trials. AB - Premature discontinuation from clinical trials may bias results against effective therapies. In the present study mortality rates were retrospectively reviewed in a 6-month, randomised, placebo-controlled trial in which tiotropium 18 mug daily was shown to decrease chronic obstructive pulmonary disease exacerbations. Patients participated for 6 months even if trial medication was prematurely discontinued. Exposure-adjusted incidence rates (IRs) were calculated for randomisation-end trial, randomisation-end trial drug (0-ED) and end trial drug end trial (ED-ET). Of 1,829 patients (forced expiratory volume in one second 1.04 L (36% predicted), mean age 68 yrs, 99% male), 16% tiotropium and 27% placebo patients prematurely stopped trial medication. The number of fatal events for the entire cohort was: 62 all cause, including 16 cardiac and 16 lower respiratory. IRs for fatal events per 100 patient-yrs were higher in the discontinued period: 1.9 (0-ED) versus 23.0 (ED-ET) in the tiotropium group and 1.8 versus 19.0 in the placebo group. Respective IRs for fatal cardiac events were 0.7 versus 2.8 (tiotropium) and 0.5 versus 6.2 (placebo); for fatal lower respiratory events were 0.7 versus 2.8 (tiotropium) and 0.8 versus 5.4 (placebo). Rate ratios (tiotropium/placebo) for fatal events were lower in the discontinued period: 1.4 versus 0.5 for cardiac and 0.9 versus 0.5 for lower respiratory. Higher incidence rates of fatal events occurred following premature discontinuation of study medication. Incomplete information from rate ratios occurs as a result of failure to consider outcomes of patients who discontinue early from clinical trials. PMID- 17690121 TI - Clinical and operational value of the extensively drug-resistant tuberculosis definition. AB - Currently, no information is available on the effect of resistance/susceptibility to first-line drugs different from isoniazid and rifampicin in determining the outcome of extensively drug-resistant tuberculosis (XDR-TB) patients, and whether being XDR-TB is a more accurate indicator of poor clinical outcome than being resistant to all first-line anti-tuberculosis (TB) drugs. To investigate this issue, a large series of multidrug-resistant TB (MDR-TB) and XDR-TB cases diagnosed in Estonia, Germany, Italy and the Russian Federation during the period 1999-2006 were analysed. Drug-susceptibility testing for first- and second-line anti-TB drugs, quality assurance and treatment delivery was performed according to World Health Organization recommendations in all study sites. Out of 4,583 culture-positive TB cases analysed, 361 (7.9%) were MDR and 64 (1.4%) were XDR. XDR-TB cases had a relative risk (RR) of 1.58 to have an unfavourable outcome compared with MDR-TB cases resistant to all first-line drugs (isoniazid, rifampicin ethambutol, streptomycin and, when tested, pyrazinamide), and an RR of 2.61 compared with "other" MDR-TB cases (those susceptible to at least one first line anti-TB drug among ethambutol, pyrazinamide and streptomycin, regardless of resistance to the second-line drugs not defining XDR-TB). The emergence of extensively drug-resistant tuberculosis confirms that problems in tuberculosis management are still present in Europe. While waiting for new tools which will facilitate management of extensively drug-resistant tuberculosis, accessibility to quality diagnostic and treatment services should be urgently ensured and adequate public health policies should be rapidly implemented to prevent further development of drug resistance. PMID- 17690123 TI - Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension. AB - For chronic thromboembolic pulmonary hypertension not amenable to pulmonary endarterectomy, effective medical therapy is desired. In an open-label uncontrolled clinical trial, 104 patients (mean +/- sem age 62 +/- 11 yrs) with inoperable chronic thromboembolic pulmonary hypertension were treated with 50 mg sildenafil t.i.d. At baseline, patients had severe pulmonary hypertension (pulmonary vascular resistance 863 +/- 38 dyn.s.cm(-5)) and a 6-min walking distance of 310 +/- 11 m. Eight patients were in World Health Organization functional class II, 76 in class III and 20 in class IV. After 3 months' treatment, there was significant haemodynamic improvement, with reduction of pulmonary vascular resistance to 759 +/- 62 dyn.s.cm(-5). The 6-min walking distance increased significantly to 361 +/- 15 m after 3 months' treatment, and to 366 +/- 18 m after 12 months' treatment. A subset of 67 patients received a single dose of 50 mg sildenafil during initial right heart catheterisation. The acute haemodynamic effect of this was not predictive of long-term outcome. In this large series of patients with inoperable chronic thromboembolic pulmonary hypertension, open-label treatment with sildenafil led to significant long-term functional improvement. The acute effect of sildenafil may not predict the long term outcome of therapy. PMID- 17690122 TI - Anti-inflammatory effects of high-dose inhaled fluticasone versus oral prednisone in asthma exacerbations. AB - The objective of the present study was to investigate the kinetics of high doses of inhaled steroid fluticasone in comparison with oral steroid prednisone on plasma protein leakage and bronchial eosinophilia in adults with moderate asthma exacerbations. The study design was a randomised, double-blind, placebo controlled prospective trial. In total, 45 patients treated at the emergency department for moderate asthma exacerbations were recruited and 39 were assigned to receive fluticasone and placebo of prednisone (19 patients), or prednisone and placebo of fluticasone (20 patients). Medication was administered to all patients via a metered-dose inhaler and spacer (16 puffs; 4,000 microg.day(-1) or placebo) plus one pill (prednisone 30 mg.day(-1) or placebo). Spirometry and induced sputum for differential cell counts, albumin and alpha(2)-macroglobulin levels and blood eosinophils, interleukin-5 and granulocyte-macrophage colony stimulating factor levels were obtained before treatment and at 2, 6 and 24 h after treatment. Symptoms clearly improved after 24 h in both groups. No differences were seen between groups in peak expiratory flow or forced expiratory flow in one second, which improved progressively but then decayed slightly after 24 h. Eosinophil counts in sputum also improved over time in both groups. The effect was faster with fluticasone than with prednisone, but was partially lost at 24 h. However, plasma proteins in sputum and eosinophil count in blood both decreased until 24 h, with no significant differences between groups. There was no correlation between eosinophil counts and plasmatic protein levels. In conclusion, both treatments improved symptoms, airway obstruction and inflammation, and plasma protein leakage at 24 h. Prednisone reduced blood eosinophil counts, while fluticasone reduced airway eosinophil counts, suggesting that the anti-inflammatory performance of fluticasone is exerted locally. PMID- 17690124 TI - Chemotherapy improves low performance status lung cancer patients. AB - The aim of the present study was to determine the potential benefit of conventional cisplatin-based chemotherapy on patients with advanced nonsmall cell lung cancer (NSCLC) and poor performance status (PS), defined as 60-70 on the Karnofsky scale. Retrospective analysis was carried out of a randomised trial performed in advanced NSCLC where 485 patients received three courses of gemcitabine+ifosfamide+cisplatin induction chemotherapy. Of the patients, 80% had good PS (Karnofsky 80-100) and 20% poor PS. Response rates were 38 and 28%, respectively. Clinical improvement, defined as achieving a good PS during chemotherapy, was observed overall in 25% of the poor PS patients, with rates of 38, 20 and 14%, respectively, in case of response, no change and progression. PS improved more quickly in the responders. Survival of patients with poor PS was significantly worse, but survival of responders was similar, irrespective of the initial poor or good PS. Although nonfatal toxicity was almost similar, there were more toxic deaths (including vascular and cardiac fatalities) in the poor PS patients (9.2 versus 2.1%). In conclusion, combination chemotherapy is associated with clinical improvement in a substantial number of patients with advanced nonsmall cell lung cancer of poor performance status. PMID- 17690125 TI - Effects of systemic steroids in patients with severe community-acquired pneumonia. AB - The benefit of systemic steroids as adjunctive treatment in patients with severe community-acquired pneumonia (CAP) remains unclear. The present study aimed to evaluate the impact of corticosteroid treatment on mortality in patients with severe CAP. A retrospective, observational study of a cohort of patients hospitalised with severe CAP, classes IV and V of the Prognostic Severity Index score, was carried out. Information on epidemiological, clinical and laboratory data, and 30-day mortality was collected from medical charts. Of the 308 patients evaluated, 238 (77%) were treated with standard antimicrobial therapy and 70 (23%) received both antibiotics and systemic steroids. Clinical characteristics were similar between steroid and nonsteroid groups, except in the prevalence of male sex and the presence of chronic obstructive pulmonary disease. Systemic steroids were independently associated with a decreased mortality (odds ratio 0.287; 95% confidence interval 0.113-0.732), while severity of CAP (2.923; 1.262 6.770) was the only independent factor associated with increased mortality. Mortality decreased in the patients with severe CAP who received simultaneous administration of systemic steroids along with antibiotic treatment. Severity of community-acquired pneumonia remains the most important risk factor associated with increased mortality. PMID- 17690126 TI - Isolated right ventricular dysfunction in systemic sclerosis: latent pulmonary hypertension? AB - Right ventricular function is frequently abnormal in patients with systemic sclerosis, but whether this is related to pulmonary vascular complications of the disease is unclear. Standard echocardiography with tissue Doppler imaging was performed at rest and during exercise for the study of right ventricular function and pulmonary circulation in 25 consecutive systemic sclerosis patients and in 13 age-matched healthy controls. When compared with the controls, the patients had no difference in systolic right ventricular pressure gradient, but a decreased pulmonary flow acceleration time, and increased right ventricular free wall thickness and end-diastolic dimensions. At the tricuspid annulus, the E maximal velocity was decreased (8.9 +/- 4 versus 11.7 +/- 2.3 cm.s(-1)) and the isovolumic relaxation time corrected to RR interval was increased (6.5 +/- 2.9 versus 4.5 +/- 2.5%). The tissue Doppler imaging profile at the mitral annulus was similar in both groups. At exercise, 18 patients had a decreased maximum workload and cardiac output, no change in systolic right ventricular pressure gradient, but an increase in the slope of pulmonary artery pressure/flow relationships. These results suggest that patients with systemic sclerosis may present with latent pulmonary hypertension as a likely cause of right ventricular diastolic dysfunction, as revealed by stress echocardiography and tissue Doppler imaging. PMID- 17690127 TI - Is air travel safe for those with lung disease? AB - Airlines commonly report respiratory in-flight emergencies; flight outcomes have not been examined prospectively in large numbers of respiratory patients. The current authors conducted a prospective, observational study of flight outcomes in this group. UK respiratory specialists were invited to recruit patients planning air travel. Centres undertook their usual pre-flight assessment. Within 2 weeks of returning, patients completed a questionnaire documenting symptoms, in flight oxygen use and unscheduled healthcare use. In total, 616 patients were recruited. Of these, 500 (81%) returned questionnaires. The most common diagnoses were airway (54%) and diffuse parenchymal lung disease (23%). In total, 12 patients died, seven before flying and five within 1 month. Pre-flight assessment included oximetry (96%), spirometry (95%), hypoxic challenge (45%) and walk test (10%). Of the patients, 11% did not fly. In those who flew, unscheduled respiratory healthcare use increased from 9% in the 4 weeks prior to travel to 19% in the 4 weeks after travel. However, when compared with self-reported data during the preceding year, medical consultations increased by just 2%. In patients flying after careful respiratory specialist assessment, commercial air travel appears generally safe. PMID- 17690128 TI - Respiratory impedance in children with cystic fibrosis using forced oscillations in clinic. AB - Measurement of lung function is an important component of clinical management in cystic fibrosis (CF), but has been difficult in young children. The present study aimed to characterise the utility of the forced oscillation technique for measurement of lung function in preschool-aged children with CF in a routine clinical setting. Lung function was assessed in 56 young children (aged 2-7 yrs) with CF. Respiratory system resistance (R(rs)) and reactance (X(rs)) at 6, 8 and 10 Hz were measured and expressed as Z-scores. Children were classified as asymptomatic or symptomatic based on an administered respiratory questionnaire and physical examination at the time of testing. Between-test repeatability was assessed in 25 children. Measurement of lung function using the forced oscillation technique was feasible in the CF clinic. The children with CF, as a group, had Z-scores for R(rs) at 6 Hz (R(rs,6)) R(rs,8), R(rs,10), X(rs) at 6 Hz (X(rs,6)) and X(rs,8) that were significantly different from zero. Children with current symptoms showed significantly decreased X(rs) and increased R(rs,6) compared with asymptomatic children. Measurement of lung function using the forced oscillation technique is feasible in young children with cystic fibrosis in a clinical setting. The technique has the potential to improve knowledge concerning early cystic fibrosis lung disease. PMID- 17690129 TI - Population health and the health system: a comparative analysis of avoidable mortality in three nations and their world cities. AB - BACKGROUND: Access to timely and effective medical services can reduce rates of premature mortality attributed to certain conditions. We investigate rates of total and avoidable mortality (AM) and the percentage of avoidable deaths in France, England and Wales and the United States, three wealthy nations with different health systems, and in the urban cores of their world cities, Paris, Inner London and Manhattan. We examine the association between AM and an income related variable among neighbourhoods of the three cities. METHODS: We obtained mortality data from vital statistics sources for each geographic area. For two time-periods, 1988-90 and 1998-2000, we assess the correlation between area of residence and age- and gender-adjusted total and AM rates. In our comparison of world cities, regression models are employed to analyse the association of a neighbourhood income-related variable with AM. RESULTS: France has the lowest mortality rates. The US exhibits higher total, but similar AM rates compared to England and Wales. Rates of AM are lowest in Paris and highest in London. Avoidable mortality rates are higher in poor neighbourhoods of all three cities; only in Manhattan is there a correlation between the percentage of deaths that are avoidable and an income related variable. CONCLUSIONS: Beyond the well-known association of income and mortality, persistent disparities in AM exist, particularly in Manhattan and Inner London. These disparities are disturbing and should receive greater attention from policy makers. PMID- 17690130 TI - Pontine tegmental cap dysplasia: a novel brain malformation with a defect in axonal guidance. AB - Four unrelated children are described with an identical brainstem and cerebellar malformation on MRI. The key findings are: vermal hypoplasia, subtotal absence of middle cerebellar peduncles, flattened ventral pons, vaulted pontine tegmentum, molar tooth aspect of the pontomesencephalic junction and absent inferior olivary prominence. Peripheral hearing impairment is present in all. Variable findings are: horizontal gaze palsy (1/4), impaired swallowing (2/4), facial palsy (3/4), bilateral sensory trigeminal nerve involvement (1/4), ataxia (2/4). Bony vertebral anomalies are found in 3/4. Additional MR studies in one patient using diffusion tensor imaging (DTI) with colour coding and fibre tracking revealed an ectopic transverse fibre bundle at the site of the pontine tegmentum and complete absence of transverse fibres in the ventral pons. The combined findings indicate an embryonic defect in axonal growth and guidance. Phenotypic analogy to mice with homozygous inactivation of Ntn1 encoding the secreted axonal guidance protein netrin1, or Dcc encoding its receptor Deleted in Colorectal Cancer led us to perform sequence analysis of NTN1 and DCC in all the patients. No pathogenic mutations were found. For the purpose of description the name 'pontine tegmental cap dysplasia' (PTCD) is proposed for the present malformation, referring to its most distinguishing feature on routine MRI. PMID- 17690131 TI - Cell cycle activation contributes to post-mitotic cell death and secondary damage after spinal cord injury. AB - Spinal cord injury (SCI) causes delayed secondary biochemical alterations that lead to tissue loss and associated neurological dysfunction. Up-regulation of cell cycle proteins occurs in both neurons and glia after SCI and may contribute to these changes. The present study examined the role of cell cycle activation on secondary injury after severe SCI in rat. SCI caused cell cycle protein up regulation associated with neuronal and oligodendroglial apoptosis, glial scar formation and microglial activation. Treatment with the cell cycle inhibitor flavopiridol reduced cell cycle protein induction and significantly improved functional recovery versus vehicle-treated controls at 21 and 28 days post injury. Treatment also significantly reduced lesion volume, as measured by MRI and histology, decreased astrocytic reactivity, attenuated neuronal and oligodendroglial apoptosis and reduced the production of factors associated with microglial activation. Thus, flavopiridol treatment improves outcome after SCI by inhibiting cell cycle pathways, resulting in beneficial multifactorial actions on neurons and glia. PMID- 17690133 TI - The PPAR alpha-humanized mouse: a model to investigate species differences in liver toxicity mediated by PPAR alpha. AB - To determine the impact of the species difference between rodents and humans in response to peroxisome proliferators (PPs) mediated by peroxisome proliferator activated receptor (PPAR)alpha, PPAR alpha-humanized transgenic mice were generated using a P1 phage artificial chromosome (PAC) genomic clone bred onto a ppar alpha-null mouse background, designated hPPAR alpha PAC. In hPPAR alpha PAC mice, the human PPAR alpha gene is expressed in tissues with high fatty acid catabolism and induced upon fasting, similar to mouse PPAR alpha in wild-type (Wt) mice. Upon treatment with the PP fenofibrate, hPPAR alpha PAC mice exhibited responses similar to Wt mice, including peroxisome proliferation, lowering of serum triglycerides, and induction of PPAR alpha target genes encoding enzymes involved in fatty acid metabolism in liver, kidney, and heart, suggesting that human PPAR alpha (hPPAR alpha) functions in the same manner as mouse PPAR alpha in regulating fatty acid metabolism and lowering serum triglycerides. However, in contrast to Wt mice, treatment of hPPAR alpha PAC mice with fenofibrate did not cause significant hepatomegaly and hepatocyte proliferation, thus indicating that the mechanisms by which PPAR alpha affects lipid metabolism are distinct from the hepatocyte proliferation response, the latter of which is only induced by mouse PPAR alpha. In addition, a differential regulation of several genes, including the oncogenic let-7C miRNA by PPs, was observed between Wt and hPPAR alpha PAC mice that may contribute to the inherent difference between mouse and human PPAR alpha in activation of hepatocellular proliferation. The hPPAR alpha PAC mouse model provides an in vivo platform to investigate the species difference mediated by PPAR alpha and an ideal model for human risk assessment PPs exposure. PMID- 17690132 TI - Disrupted prediction-error signal in psychosis: evidence for an associative account of delusions. AB - Delusions are maladaptive beliefs about the world. Based upon experimental evidence that prediction error-a mismatch between expectancy and outcome--drives belief formation, this study examined the possibility that delusions form because of disrupted prediction--error processing. We used fMRI to determine prediction error-related brain responses in 12 healthy subjects and 12 individuals (7 males) with delusional beliefs. Frontal cortex responses in the patient group were suggestive of disrupted prediction-error processing. Furthermore, across subjects, the extent of disruption was significantly related to an individual's propensity to delusion formation. Our results support a neurobiological theory of delusion formation that implicates aberrant prediction-error signalling, disrupted attentional allocation and associative learning in the formation of delusional beliefs. PMID- 17690134 TI - Glucocorticoid-enhanced expression of dioxin target genes through regulation of the rat aryl hydrocarbon receptor. AB - The aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR) are ligand activated transcription factors and members of the basic helix-loop-helix Period aryl hydrocarbon nuclear translocator-single minded and nuclear hormone receptor superfamilies, respectively. Besides their individual role as activators of specific gene transcription, also interplay between both transcription factors can be an important mechanism of regulation. In this study, we report that GR can strongly activate AhR-mediated transcription and consequent gene expression in rat H4IIe cells. Reporter gene assays showed an enhanced effect of dexamethasone on the dioxin response mediated by GR in rat H4IIe cells and mouse Hepa 1c1c7 cells, but not in human HepG2 cells and human T47D cells. These deviations between the rodent and human cell lines were confirmed by CYP1A1 enzyme activities. In addition, quantitative reverse transcription-PCR showed enhanced GR-mediated effects of dexamethasone on endogenous 2,3,7,8-tetrachlorodibenzo-[p] dioxin target genes as well in rat H4IIe cells, but not in human HepG2 and human T47D cells. Surprisingly, AhR itself was upregulated by combined dioxin/glucocorticoid exposure in rat H4IIe cells but not in the human cells which could be explained by the presence of two putative glucocorticoid response elements in the rat AhR promoter, but not in the human AhR promoter. This GR mediated expression of dioxin target genes through upregulation of the AhR in rat but not in human cells opens the possibility that dioxin responses in rodent based models for toxicity differ from humans and provides new insight into the interactions of stress-related pathways, biological effects of dioxin-like compounds and may possibly have implications for risk assessment. PMID- 17690135 TI - Meta-analysis of studies of passive smoking and lung cancer: effects of study type and continent. AB - BACKGROUND: To calculate a pooled estimate of relative risk (RR) of lung cancer associated with exposure to passive smoking in never smoking women exposed to smoking spouses. This study is an updated meta-analysis that also assesses the differences between estimated risks according to continent and study type using meta-regression. METHODS: From a total of 101 primary studies, 55 studies are included in this meta-analysis, of which, 7 are cohort studies, 25 population based case-control and 23 non-population-based case-control studies. Twenty previously published meta-analyses are also reviewed. Fixed and random effect models and meta-regression are used to obtain pooled estimates of RR and P-value functions are used to demonstrate consistency of results. RESULTS: The pooled RR for never-smoking women exposed to passive smoking from spouses is 1.27 (95% CI 1.17-1.37). The RR for North America is 1.15 (95% CI 1.03-1.28), Asia, 1.31 (95% CI 1.16-1.48) and Europe, 1.31 (1.24-1.52). Sequential cumulative meta-analysis shows no trend. There is no strong evidence of publication bias. CONCLUSIONS: The abundance of evidence, consistency of finding across continent and study type, dose-response relationship and biological plausibility, overwhelmingly support the existence of a causal relationship between passive smoking and lung cancer. PMID- 17690136 TI - The secret lives of voltage sensors. PMID- 17690137 TI - Variation in time and space: what is the resolution? PMID- 17690138 TI - Saccades and pursuit: two outcomes of a single sensorimotor process. AB - Saccades and smooth pursuit eye movements are two different modes of oculomotor control. Saccades are primarily directed toward stationary targets whereas smooth pursuit is elicited to track moving targets. In recent years, behavioural and neurophysiological data demonstrated that both types of eye movements work in synergy for visual tracking. This suggests that saccades and pursuit are two outcomes of a single sensorimotor process that aims at orienting the visual axis. PMID- 17690139 TI - Expression of interleukin-15 in human skeletal muscle effect of exercise and muscle fibre type composition. AB - The cytokine interleukin-15 (IL-15) has been demonstrated to have anabolic effects in cell culture systems. We tested the hypothesis that IL-15 is predominantly expressed by type 2 skeletal muscle fibres, and that resistance exercise regulates IL-15 expression in muscle. Triceps brachii, vastus lateralis quadriceps and soleus muscle biopsies were obtained from normally physically active, healthy, young male volunteers (n = 14), because these muscles are characterized by having different fibre-type compositions. In addition, healthy, normally physically active male subjects (n = 8) not involved in any kind of resistance exercise underwent a heavy resistance exercise protocol that stimulated the vastus lateralis muscle and biopsies were obtained from this muscle pre-exercise as well as 6, 24 and 48 h post-exercise. IL-15 mRNA levels were twofold higher in the triceps (type 2 fibre dominance) compared with the soleus muscle (type 1 fibre dominance), but Western blotting and immunohistochemistry revealed that muscle IL-15 protein content did not differ between triceps brachii, quadriceps and soleus muscles. Following resistance exercise, IL-15 mRNA levels were up-regulated twofold at 24 h of recovery without any changes in muscle IL-15 protein content or plasma IL-15 at any of the investigated time points. In conclusion, IL-15 mRNA level is enhanced in skeletal muscles dominated by type 2 fibres and resistance exercise induces increased muscular IL-15 mRNA levels. IL-15 mRNA levels in skeletal muscle were not paralleled by similar changes in muscular IL-15 protein expression suggesting that muscle IL-15 may exist in a translationally inactive pool. PMID- 17690140 TI - Cell tracking using magnetic resonance imaging. AB - Cell tracking by in vivo magnetic resonance imaging (MRI) requires strategies of labelling the cells with MRI contrast agents. The principal routes to achieve efficient cell labelling for neurological applications are discussed with methodological advantages and caveats. Beyond temporo-spatial localization of labelled cells, the investigation of functional cell status is of great interest to allow studies of functional cell dynamics. The two major approaches to reach this goal, use of responsive contrast agents and generation of transgenic cell lines, are discussed. PMID- 17690141 TI - Blockade of phosphodiesterase Type 5 enhances rat neurohypophysial excitability and electrically evoked oxytocin release. AB - Phosphodiesterase type 5 (PDE5) acts specifically on cyclic guanosine monophosphate (cGMP) and terminates cGMP-mediated signalling. PDE5 has a well established role in vascular smooth muscle, where specific inhibitors of PDE5 such as sildenafil correct erectile dysfunction by augmenting cGMP-mediated vascular relaxation. However, the role of PDE5 outside of the vasculature has received little attention. The present study tested PDE5 inhibitors on the cGMP mediated modulation of K(+) channels in the neurohypophysis (posterior pituitary). Photolysis of caged-cGMP enhanced current through Ca(2+)-activated K(+) channels, and this enhancement recovered in about 2 min. Sildenafil essentially eliminated this recovery, suggesting that the reversal of K(+) current enhancement depends on cGMP breakdown. Activation of nitric oxide synthase during trains of activity in pituitary nerve terminals enhances excitability. When trains of stimulation were applied at regular intervals, sildenafil enhanced the excitability of neurohypophysial nerve terminals and increased the action potential firing probability. T-1032, a compound with high specificity for PDE5 over PDE6, had a similar action. Voltage imaging in intact neurohypophysis with a voltage sensitive absorbance dye showed that T-1032 reduced the failure of propagating action potentials during trains of activity. This indicates that PDE5 activity limits action potential propagation in neurohypophysial axons. Immunoassay of oxytocin, a neuropeptide hormone secreted by the posterior pituitary, demonstrated that sildenafil increased electrically evoked release. Thus, PDE5 plays an important role in the regulation of neurohypophysial function, and blockade of this enzyme can enhance the use dependent facilitation of neurohypophysial secretion. PMID- 17690142 TI - Compartmentalized NMDA receptor signalling to survival and death. AB - The ability of Ca(2+) influx through the N-methyl d-aspartate subclass of glutamate receptor (NMDA receptor) to both kill neurons and to promote survival under different circumstances is well established. Here we discuss the signal pathways that mediate this dichotomous signalling, and the factors that influence whether an NMDA receptor-dependent Ca(2+) signal results in a net pro-survival or pro-death effect. The magnitude of NMDA receptor activation, be it intensity or duration, is of course very important in determining the nature of the response to an episode of NMDA receptor activity, with excitotoxic death pathways requiring higher levels than survival pathways. However, the NMDA receptor is not merely a conduit for Ca(2+) influx: the consequences of NMDA receptor activity can be influenced by signalling molecules that physically associate with the NMDA receptor or indeed the location (synaptic versus extrasynaptic) of the receptor. Furthermore, we discuss the possibility that the Ca(2+) effectors of survival and death are in different subcellular locations, and thus depend on the spatial characteristics of the Ca(2+) transient. A greater understanding of these issues may point to ways of selectively blocking pro-death signalling in neurological disorders such as stroke, where global NMDA receptor antagonists have proved ineffective. PMID- 17690143 TI - Altered potassium channel function in the superficial dorsal horn of the spastic mouse. AB - The spastic mouse has a naturally occurring glycine receptor (GlyR) mutation that disrupts synaptic input in both motor and sensory pathways. Here we use the spastic mouse to examine how this altered inhibitory drive affects neuronal intrinsic membrane properties and signal processing in the superficial dorsal horn (SDH), where GlyRs contribute to pain processing mechanisms. We first used in vitro patch clamp recording in spinal cord slices (L3-L5 segments) to examine intrinsic membrane properties of SDH neurones in spastic and age-matched wildtype controls ( approximately P23). Apart from a modest reduction ( approximately 3 mV) in resting membrane potential (RMP), neurones in spastic mice have membrane and action potential (AP) properties identical to wildtype controls. There was, however, a substantial reorganization of AP discharge properties in neurones from spastic mice, with a significant increase (14%) in the proportion of delayed firing neurones. This was accompanied by a change in the voltage sensitivity of rapid A-currents, a possible mechanism for increased delayed firing. To assess the functional consequences of these changes, we made in vivo patch-clamp recordings from SDH neurones in urethane anaesthetized (2.2 g kg(-1), i.p.) spastic and wildtype mice ( approximately P37), and examined responses to innocuous and noxious mechanical stimulation of the hindpaw. Overall, responses recorded in wildtype and spastic mice were similar; however, in spastic mice a small population of spontaneously active neurones ( approximately 10%) exhibited elevated spontaneous discharge frequency and post-pinch discharge rates. Together, these results are consistent with the altered intrinsic membrane properties of SDH neurones observed in vitro having functional consequences for pain processing mechanisms in the spastic mouse in vivo. We propose that alterations in potassium channel function in the spastic mouse compensate, in part, for reduced glycinergic inhibition and thus maintain normal signal processing in the SDH. PMID- 17690144 TI - Development of gerbil medial superior olive: integration of temporally delayed excitation and inhibition at physiological temperature. AB - The sensitivity of medial superior olive (MSO) neurons to tens of microsecond differences in interaural temporal delay (ITD) derives in part from their membrane electrical characteristics, kinetics and timing of excitatory and inhibitory inputs, and dendrite structure. However, maturation of these physiological and structural characteristics are little studied, especially in relationship to the onset of auditory experience. We showed, using brain slices at physiological temperature, that MSO neurons exhibited sensitivity to simulated temporally delayed (TD) EPSCs (simEPSC), injected through the recording electrode, by the initial phase of hearing onset at P10, and TD sensitivity was reduced by block of low threshold potassium channels. The spike generation mechanism matured between P10 and P16 to support TD sensitivity to adult-like excitatory stimuli (1-4 ms duration) by P14. IPSP duration was shorter at physiological temperature than reported for lower temperatures, was longer than EPSP duration at young ages, but approached the duration of EPSPs by P16, when hearing thresholds neared maturity. Dendrite branching became less complex over a more restricted time frame between P10 and P12. Because many physiological and structural properties approximated mature values between P14 and P16, we studied temporal integration of simEPSCs and IPSPs at P15. Only a narrow range of relative onset times (< 1 ms) yielded responses showing sensitivity to TD. We propose that shaping of excitatory circuitry to mediate TD sensitivity can begin before airborne sound is detectable, and that inhibitory inputs having suboptimal neural delays may then be pruned by cellular mechanisms activated by sensitivity to ITD. PMID- 17690145 TI - Multiple vesicle recycling pathways in central synapses and their impact on neurotransmission. AB - Short-term synaptic depression during repetitive activity is a common property of most synapses. Multiple mechanisms contribute to this rapid depression in neurotransmission including a decrease in vesicle fusion probability, inactivation of voltage-gated Ca(2+) channels or use-dependent inhibition of release machinery by presynaptic receptors. In addition, synaptic depression can arise from a rapid reduction in the number of vesicles available for release. This reduction can be countered by two sources. One source is replenishment from a set of reserve vesicles. The second source is the reuse of vesicles that have undergone exocytosis and endocytosis. If the synaptic vesicle reuse is fast enough then it can replenish vesicles during a brief burst of action potentials and play a substantial role in regulating the rate of synaptic depression. In the last 5 years, we have examined the impact of synaptic vesicle reuse on neurotransmission using fluorescence imaging of synaptic vesicle trafficking in combination with electrophysiological detection of short-term synaptic plasticity. These studies have revealed that synaptic vesicle reuse shapes the kinetics of short-term synaptic depression in a frequency-dependent manner. In addition, synaptic vesicle recycling helps maintain the level of neurotransmission at steady state. Moreover, our studies showed that synaptic vesicle reuse is a highly plastic process as it varies widely among synapses and can adapt to changes in chronic activity levels. PMID- 17690146 TI - Priming of intracellular calcium stores in rat CA1 pyramidal neurons. AB - Repetitive synaptic stimulation evokes large amplitude Ca(2+) release waves from internal stores in many kinds of pyramidal neurons. The waves result from mGluR mobilization of IP(3) leading to Ca(2+)-induced Ca(2+) release. In most experiments in slices, regenerative Ca(2+) release can be evoked for only a few trials. We examined the conditions required for consistent release from the internal stores in hippocampal CA1 pyramidal neurons. We found that priming with action potentials evoked at 0.5-1 Hz for intervals as short as 15 s were sufficient to fill the stores, while sustained subthreshold depolarization or subthreshold synaptic stimulation lasting from 15 s to 2 min was less effective. A single episode of priming was effective for about 2-3 min. Ca(2+) waves could also be evoked by uncaging IP(3) with a UV flash in the dendrites. Priming was necessary to evoke these waves repetitively; 7-10 spikes in 15 s were again effective for this protocol, indicating that priming acts to refill the stores and not at a site upstream to the production of IP(3). These results suggest that normal spiking activity of pyramidal neurons in vivo should be sufficient to maintain their internal stores in a primed state ready to release Ca(2+) in response to an appropriate physiological stimulus. This may be a novel form of synaptic plasticity where a cell's capacity to release Ca(2+) is modulated by its average firing frequency. PMID- 17690147 TI - The effect of lung volume on the co-ordinated recruitment of scalene and sternomastoid muscles in humans. AB - The human scalenes are obligatory inspiratory muscles that have a greater mechanical advantage than sternomastoid, an accessory muscle. This study determined scalene and sternomastoid recruitment during voluntary inspiratory tasks, and whether this activity varied with lung volume, when feedback from the lungs and inspiratory muscles would differ. If afferent feedback has a major role in determining the recruitment of the scalenes and sternomastoid, then at each lung volume, activity would be altered. Intramuscular EMG from scalene and sternomastoid muscles, and oesophageal pressure were recorded while subjects (n = 7) performed inspiratory isovolumetric ramps to maximal inspiratory pressure (MIP) and dynamic inspirations from functional residual capacity (FRC) to total lung capacity (TLC). The static inspiratory ramps were repeated at three lung volumes: FRC, FRC + tidal volume, and TLC. To determine the profile of inspiratory activation, i.e. the initial and ongoing recruitment of the muscles, the root mean square of the EMG was measured throughout the tasks. Scalene was recruited early, and EMG increased with pressure, reaching a plateau at 80% MIP. In contrast, sternomastoid activity began later, but then increased with pressure from 20 to 100% MIP. Similar profiles of activation occurred at all three lung volumes (n.s.). The ratio of sternomastoid to scalene EMG was also the same irrespective of the initial lung volume (n.s.). In dynamic inspirations, scalene and sternomastoid activation had similar stereotypical profiles to the static tasks, but scalene EMG was 15-40% greater (P < 0.05). Sternomastoid activation was the same in both tasks (n.s.). These results suggest that in voluntary tasks, scalene and sternomastoid are recruited in the order of their mechanical advantages, and that alterations in feedback related to changes in lung volume failed to alter their activation. Thus, in humans, the mechanism responsible for the differential activation of these two inspiratory muscles has an element that is preset. PMID- 17690148 TI - Human cerebrovascular and ventilatory CO2 reactivity to end-tidal, arterial and internal jugular vein PCO2. AB - This study examined cerebrovascular reactivity and ventilation during step changes in CO(2) in humans. We hypothesized that: (1) end-tidal P(CO(2)) (P(ET,CO(2))) would overestimate arterial P(CO(2)) (P(a,CO(2))) during step variations in P(ET,CO(2)) and thus underestimate cerebrovascular CO(2) reactivity; and (2) since P(CO(2)) from the internal jugular vein (P(jv,CO(2))) better represents brain tissue P(CO(2)), cerebrovascular CO(2) reactivity would be higher when expressed against P(jv,CO(2)) than with P(a,CO(2)), and would be related to the degree of ventilatory change during hypercapnia. Incremental hypercapnia was achieved through 4 min administrations of 4% and 8% CO(2). Incremental hypocapnia involved two 4 min steps of hyperventilation to change P(ET,CO(2)), in an equal and opposite direction, to that incurred during hypercapnia. Arterial and internal jugular venous blood was sampled simultaneously at baseline and during each CO(2) step. Cerebrovascular reactivity to CO(2) was expressed as the percentage change in blood flow velocity in the middle cerebral artery (MCAv) per mmHg change in P(a,CO(2)) and P(jv,CO(2)). During hypercapnia, but not hypocapnia, P(ET,CO(2)) overestimated P(a,CO(2)) by +2.4 +/- 3.4 mmHg and underestimated MCAv-CO(2) reactivity (P < 0.05). The hypercapnic and hypocapnic MCAv-CO(2) reactivity was higher ( approximately 97% and approximately 24%, respectively) when expressed with P(jv,CO(2)) than P(a,CO(2)) (P < 0.05). The hypercapnic MCAv-P(jv,CO(2)) reactivity was inversely related to the increase in ventilatory change (R(2) = 0.43; P < 0.05), indicating that a reduced reactivity results in less central CO(2) washout and greater ventilatory stimulus. Differences in the P(ET,CO(2)), P(a,CO(2)) and P(jv,CO(2)) MCAv relationships have implications for the true representation and physiological interpretation of cerebrovascular CO(2) reactivity. PMID- 17690149 TI - Defective interaction between dual oscillators for respiratory rhythm generation in Na+,K+-ATPase {alpha}2 subunit-deficient mice. AB - The current concept regarding the respiratory centre in mammals is that it is composed of two distinct rhythm-generating neuronal networks in the ventrolateral medulla. These two rhythm generators can be active independently but are normally coupled in newborn and juvenile rats. Detailed characteristics of each generator and the neuronal mechanisms of coupling during development remain to be elucidated. Here, we report a knockout mouse (Na(+),K(+)-ATPase alpha2 subunit gene (Atp1a2) knockout) that may be defective in functional coupling between the two respiration-related rhythm generators. We investigated respiration-related neuron activity in an en bloc brainstem-spinal cord preparation isolated from embryonic day 18.5 Atp1a2(-/)(-) mouse fetuses. In the presence of adrenaline, two different types of rhythm generators were identified. One produced inspiratory burst activity that correlated with C4 inspiratory activity and was thought to be the inspiratory rhythm generator on the basis of its location and sensitivity to a mu-opiate receptor agonist, [d-Ala2, N-Me-Phe4, Gly5-ol] enkephalin (DAMGO). The other was presumed to be the preinspiratory rhythm generator because it was insensitive to DAMGO and correlated with facial nerve activity. Coupling between these rhythm generators did not function in the normal manner in Atp1a2(-/)(-) mice, as shown by disruption of the linkage between the preinspiratory burst and the inspiratory burst. Coupling was partially restored by repeated activation of the neurons within the networks, suggesting the involvement of an activity-dependent process in the prenatal development of this coupling. PMID- 17690151 TI - The effect of quadriceps muscle fatigue on position matching at the knee. AB - This is a report of the effects of exercise on position matching at the knee. Young adult subjects were required to step down a set of stairs (792 steps), representing eccentric-biased exercise of the quadriceps muscle, or step up them, concentric-biased exercise. Immediately after eccentric exercise subjects showed a mean force drop of 28% (+/- 6%, s.e.m.) of the control value in their exercised quadriceps muscle, which was accompanied by 4.8 deg (+/- 0.8 deg) of error between reference and matching legs in a position matching task at the knee. Similarly concentric exercise was followed by a force drop of 15% (+/- 3%) and matching errors of 3.7 deg (+/- 0.4 deg). These effects were significant. The direction of the errors suggested that subjects perceived their exercised muscles to be longer that they actually were. This finding was not consistent with the hypothesis that the increase in effort required to support the leg after fatigue from exercise was responsible for the errors. It is hypothesized that position sense in an unsupported leg arises, in part, from operation of an internal forward model. When the motor command is increased to compensate for the effects of fatigue, the comparison between predicted and actual feedback from quadriceps leads to the impression that the muscle is longer than it actually is. The exercise effects on proprioception may have implications for sports injuries and for evaluation of the factors leading to falls in the elderly. PMID- 17690150 TI - Acute regulation of mouse AE2 anion exchanger requires isoform-specific amino acid residues from most of the transmembrane domain. AB - The widely expressed anion exchanger polypeptide AE2/SLC4A2 is acutely inhibited by acidic intracellular (pH(i)), by acidic extracellular pH (pH(o)), and by the calmodulin inhibitor, calmidazolium, whereas it is acutely activated by NH(4)(+). The homologous erythroid/kidney AE1/SLC4A1 polypeptide is insensitive to these regulators. Each of these AE2 regulatory responses requires the presence of AE2's C-terminal transmembrane domain (TMD). We have now measured (36)Cl(-) efflux from Xenopus oocytes expressing bi- or tripartite AE2-AE1 chimeras to define TMD subregions in which AE2-specific sequences contribute to acute regulation. The chimeric AE polypeptides were all functional at pH(o) 7.4, with the sole exception of AE2((1-920))/AE1((613-811))/AE2((1120-1237)). Reciprocal exchanges of the large third extracellular loops were without effect. AE2 regulation by pH(i), pH(o) and NH(4)(+) was retained after substitution of C-terminal AE2 amino acids 1120-1237 (including the putative second re-entrant loop, two TM spans and the cytoplasmic tail) with the corresponding AE1 sequence. In contrast, the presence of this AE2 C-terminal sequence was both necessary and sufficient for inhibition by calmidazolium. All other tested TMD substitutions abolished AE2 pH(i) sensitivity, abolished or severely attenuated sensitivity to pH(o) and removed sensitivity to NH(4)(+). Loss of AE2 pH(i) sensitivity was not rescued by co-expression of a complementary AE2 sequence within separate full-length chimeras or AE2 subdomains. Thus, normal regulation of AE2 by pH and other ligands requires AE2-specific sequence from most regions of the AE2 TMD, with the exceptions of the third extracellular loop and a short C-terminal sequence. We conclude that the individual TMD amino acid residues previously identified as influencing acute regulation of AE2 exert that influence within a regulatory structure requiring essential contributions from multiple regions of the AE2 TMD. PMID- 17690152 TI - Chronic hypoxia up-regulates alpha1H T-type channels and low-threshold catecholamine secretion in rat chromaffin cells. AB - alpha(1H) T-type channels recruited by beta(1)-adrenergic stimulation in rat chromaffin cells (RCCs) are coupled to fast exocytosis with the same Ca(2+) dependence of high-threshold Ca(2+) channels. Here we show that RCCs exposed to chronic hypoxia (CH) for 12-18 h in 3% O(2) express comparable densities of functional T-type channels that depolarize the resting cells and contribute to low-voltage exocytosis. Following chronic hypoxia, most RCCs exhibited T-type Ca(2+) channels already available at -50 mV with the same gating, pharmacological and molecular features as the alpha(1H) isoform. Chronic hypoxia had no effects on cell size and high-threshold Ca(2+) current density and was mimicked by overnight incubation with the iron-chelating agent desferrioxamine (DFX), suggesting the involvement of hypoxia-inducible factors (HIFs). T-type channel recruitment occurred independently of PKA activation and the presence of extracellular Ca(2+). Hypoxia-recruited T-type channels were partially open at rest (T-type 'window-current') and contributed to raising the resting potential to more positive values. Their block by 50 microm Ni(2+) caused a 5-8 mV hyperpolarization. The secretory response associated with T-type channels could be detected following mild cell depolarizations, either by capacitance increases induced by step depolarizations or by amperometric current spikes induced by increased [KCl]. In the latter case, exocytotic bursts could be evoked even with 2-4 mm KCl and spike frequency was drastically reduced by 50 microm Ni(2+). Chronic hypoxia did not alter the shape of spikes, suggesting that hypoxia recruited T-type channels increase the number of secreted vesicles at low voltages, without altering the mechanism of catecholamine release and the quantal content of released molecules. PMID- 17690153 TI - MPTP-induced deficits in striatal synaptic plasticity are prevented by glial cell line-derived neurotrophic factor expressed via an adeno-associated viral vector. AB - This study determined the consequences of dopamine denervation of the striatum on synaptic plasticity and prevention of these changes with gene therapy using an adeno-associated viral vector (AAV) expressing glial cell line-derived neurotrophic factor (GDNF). C57BL6/J mice were injected with the neurotoxin 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP); long-term depression (LTD) or potentiation (LTP) were measured in vitro. Fast-scan cyclic voltammetry measured electrically released dopamine from a functionally relevant pool in these same striatal slices. After MPTP, dopamine release and uptake were greatly diminished, and LTP and LTD were blocked in the striatal slices. The loss of plasticity resulted directly from the loss of dopamine since its application rescued synaptic plasticity. Striatal GDNF expression via AAV, before MPTP, significantly protected against the loss of dopamine and prevented the blockade of corticostriatal LTP. These data demonstrate that dopamine plays a role in supporting several forms of striatal plasticity and that GDNF expression via AAV prevents the loss of dopamine and striatal plasticity caused by MPTP. We propose that impairment of striatal plasticity after dopamine denervation plays a role in the symptomology of Parkinson's disease and that AAV expression of neurotrophic factors represents a tenable approach to protecting against or slowing these neurobiological deficits. PMID- 17690154 TI - Prevention and restoration of lactacystin-induced nigrostriatal dopamine neuron degeneration by novel brain-permeable iron chelators. AB - Dysfunction of the ubiquitin-proteasome system (UPS) and accumulation of iron in substantia nigra (SN) are implicated in the pathogenesis of Parkinson's disease (PD). UPS dysfunction and iron misregulation may reinforce each other's contribution to the degeneration of dopamine (DA) neurons. In the present study, we use a new brain-permeable iron chelator, VK-28 [5-(4-(2-hydroxyethyl) piperazin-1-yl (methyl)-8-hydroxyquinoline], and its derivative M30 [5-(N-methyl N-propargyaminomethyl)-8-hydroxyquinoline] in vivo to test their neuroprotective and neurorestorative properties against proteasome inhibitor (lactacystin) induced nigrostriatal degeneration. Bilateral microinjections of lactacystin (1.25 microg/side) into the mouse medial forebrain bundle were performed. Administration of VK-28 (5 mg/kg, once a day) or M30 (5 mg/kg, once a day) was applied intraperitoneally 7 days before or after the lactacystin microinjection until the mice were sacrificed 28 days after microinjection. We found that VK-28 and M30 both significantly improved behavioral performances and attenuated lactacystin-induced DA neuron loss, proteasomal inhibition, iron accumulation, and microglial activation in SN. In addition, M30 restored the Bcl-2 level, which was suppressed after lactacystin injection. These findings suggest that brain permeable iron chelators can improve DA neuron survival under UPS impairment. Furthermore, M30, a derivative of VK-28 and neuroprotective agent rasagiline, may serve as a better neuroprotective therapy for PD. PMID- 17690155 TI - The role of pre-replicative complex (pre-RC) components in oncogenesis. AB - Normal DNA replication is stringently regulated to ensure a timely occurrence no more than once per cell cycle. Abrogation of the exquisite control mechanisms that maintain this process results in detrimental gains and losses of genomic DNA commonly seen in cancer and developmental defects. Replication initiation proteins, known as prereplicative complex (pre-RC) proteins, serve as a primary level of regulation, controlling when DNA replication can begin. Unsurprisingly, several pre-RC proteins are overexpressed in cancer and serve as good tumor markers. However, their direct correlation with increasing tumor grade and poor prognosis has posed a long-standing question: Are pre-RC proteins oncogenic? Recently, a growing body of data indicates that deregulation of individual pre-RC proteins, either by overexpression or functional deficiency in several organismal models, results in significant and consistently perturbed cell cycle regulation, genomic instability, and, potentially, tumorigenesis. In this review, we examine this broad range of evidence suggesting that pre-RC proteins play roles during oncogenesis that are more than simply indicative of proliferation, supporting the notion that pre-RC proteins may potentially have significant diagnostic and therapeutic value. PMID- 17690156 TI - Left atrial remodelling early after mitral valve repair for degenerative mitral regurgitation. AB - OBJECTIVE: Left atrial (LA) size is an important predictor of outcome after mitral valve replacement in patients with symptomatic chronic mitral regurgitation (MR). Data on LA remodelling after mitral valve repair (MVr) for chronic non-ischaemic MR are scarce. The aim of this study was to assess changes in LA size early after MVr for chronic severe degenerative MR and to identify clinical and echocardiographic correlates of those changes. METHODS: The study analysed 225 consecutive patients who underwent MVr and were echocardiographically evaluated in our hospital within 1 month before and 1-6 months after surgery. Patients with MR aetiology other than degenerative, associated aortic valve replacement, or congenital heart disease were excluded. The remaining 79 patients (aged 60 (SD 12) years, 55 men) with isolated chronic severe degenerative MR formed the study group. LA reverse remodelling was defined as a decrease in LA volume index (LAVi) > or = 15%. RESULTS: LA dimensions significantly decreased after MVr (p<0.001). Mean LAVi reduction was 29% (SD 18%). LA reverse remodelling was observed in 63 patients (80%). Correlates of LAVi reduction were preoperative LAVi (p = 0.008), systolic and diastolic blood pressure (p = 0.032, p = 0.009), postoperative transmitral mean pressure gradient (p = 0.001) and residual MR (p = 0.043). LAVi reduction was lower in patients > 45 years (p = 0.008) and in hypertensive patients (p = 0.031). CONCLUSION: LA reverse remodelling is common early after MVr for chronic severe degenerative MR. Preoperative LAVi, blood pressure, postoperative transmitral mean pressure gradient, residual MR and age > 45 are related to LAVi reduction. The prognostic value of LA reduction in this setting needs further study. PMID- 17690157 TI - Hypocalcaemia and vitamin D deficiency: an important, but preventable, cause of life-threatening infant heart failure. AB - BACKGROUND: In recent large paediatric cardiomyopathy population studies from North America and Australia, vitamin D deficiency was not identified as a cause of infant heart failure. However, rickets is resurgent in developed countries. OBJECTIVE: To review the prevalence of this cardiomyopathy in paediatric cardiology units of southeast England and determine the prognosis. METHODS AND RESULTS: A retrospective review from 2000 to 2006 in southeast England. Sixteen infants (6 Indian subcontinent, 10 black ethnicity) were identified: median (range) age at presentation was 5.3 months (3 weeks-8 months). All had been breast fed. Ten presented at the end of the British winter (February-May). Median shortening fraction was 10% (range 5-18%) and median left ventricular end diastolic dimension z score was 4.1 (range 3.1-7.0). Six had a cardiac arrest; three infants died. Eight were ventilated, two required mechanical circulatory support and 12 required intravenous inotropic support. Two were referred for cardiac transplantation. Median (range) of biochemical values on admission was: total calcium 1.5 (1.07-1.74) mmol/l; alkaline phosphatase 646 (340-1057) IU/l; 25-hydroxyvitamin D 18.5 (0-46) nmol/l (normal range >35) and parathyroid hormone 34.3 (8.9-102) pmol/l (normal range <6.1). The clinical markers and echocardiographic indices of all survivors have improved. The mean time from diagnosis to achieve normal fractional shortening was 12.4 months. CONCLUSIONS: Vitamin D deficiency and consequent hypocalcaemia are seen in association with severe and life-threatening infant heart failure. That no infant or mother was receiving the recommended vitamin supplementation highlights the need for adequate provision of vitamin D to ethnic minority populations. PMID- 17690158 TI - Abnormal papillary muscle morphology is independently associated with increased left ventricular outflow tract obstruction in hypertrophic cardiomyopathy. AB - BACKGROUND: Abnormal papillary muscles (PM) are often found in hypertrophic cardiomyopathy (HCM). OBJECTIVE: To assess the relationship between morphological alterations of PM in patients with HCM and left ventricular outflow tract (LVOT) obstruction, using magnetic resonance imaging (MRI) and echocardiography. METHODS: Fifty-six patients with HCM (mean age 42 years (interquartile range 27, 51), 70% male) and 30 controls (mean age (42 (30, 53) years, 80% male) underwent MRI on a 1.5 T scanner (Siemens, Erlangen, Germany). Standard cine images were obtained in short-axis (base to apex), along with two-, three- and four-chamber views. The presence of bifid PM (none, one or both) and anteroapical displacement of anterolateral PM was recorded by MRI and correlated with resting LVOT gradients obtained by echocardiography. RESULTS: Double bifid PM (70% vs 17%) and anteroapical displacement of anterolateral PM (77% vs 17%) were more prevalent in patients with HCM than in controls (p<0.001). Subjects with anteroapically displaced PM and double bifid PM had higher resting LVOT gradients than controls (45 (6, 81) vs 12 (0, 12) mm Hg (p<0.01) and 42 (6, 64) vs 11 (0, 17) mm Hg (p = 0.02), respectively. In patients with HCM, the odds ratio of having significant (>or=30 mm Hg) peak resting gradient was 7.1 (95% CI 1.4 to 36.7) for anteroapically displaced anterolateral PM and 10.4 (95% CI 1.2 to 91.2) for double bifid PM (both p = 0.005), independent of septal thickness, use of beta blockers and/or calcium blockers and resting heart rate. CONCLUSIONS: Patients with HCM with abnormal PM have a higher degree of resting LVOT gradient, which is independent of septal thickness. PMID- 17690159 TI - Trends for coronary heart disease and stroke mortality among migrants in England and Wales, 1979-2003: slow declines notable for some groups. AB - OBJECTIVE: To examine trends in coronary heart disease and stroke mortality in migrants to England and Wales. DESIGN: Cross-sectional. OUTCOME MEASURES: Age standardised and sex-specific death rates and rate ratios 1979-83, 1989-93 and 1999-2003. RESULTS: Coronary mortality fell among migrants, more so in the second decade than the first. Rate ratios for coronary mortality remained higher for men and women from Scotland, Northern Ireland, Republic of Ireland and South Asia, and lower for men from Jamaica, other Caribbean countries, West Africa, Italy and Spain. Rate ratios increased for men from Jamaica (1979-83: 0.45, 0.40 to 0.50; 1999-2003: 0.81, 0.73 to 0.90), Pakistan (1979-83: 1.14, 1.04 to 1.25; 1999-2003: 1.93, 1.81 to 2.06), Bangladesh (1979-83: 1.36, 1.15 to 1.60; 1999-2003: 2.11, 1.90 to 2.34), Republic of Ireland (1979-1983: 1.18, 1.15 to 1.21; 1999-2003: 1.45, 1.39 to 1.52) and Poland (1979-83: 1.17, 1.09 to 1.25; 1999-2003: 1.97, 1.57 to 2.47), and for women from Jamaica (1979-83: 0.63, 0.52 to 0.77; 1999 2003: 1.23, 1.06 to 1.42) and Pakistan (1979-83: 1.14, 0.88 to 1.47; 1999-2003: 2.45, 2.19 to 2.74), owing to smaller declines in death rates than those born in England and Wales. Rate ratios for stroke mortality remained higher for migrants. As a result of smaller declines, rate ratios increased for men from Pakistan (1979-1983: 0.99, 0.76 to 1.29; 1999-2003: 1.58, 1.35 to 1.85), Scotland (1979 1983: 1.11, 1.04 to 1.19; 1999-2003: 1.30, 1.19 to 1.42) and Republic of Ireland (1979-1983: 1.27, 1.19 to 1.36; 1999-2003: 1.67, 1.52 to 1.84). CONCLUSION: For groups with higher mortality than people born in England and Wales, mortality remained higher. Smaller declines led to increasing disparities for some groups and to excess coronary mortality for women from Jamaica. Maximising the coverage of prevention and treatment programmes is critical. PMID- 17690160 TI - Raised interleukin-10 is an indicator of poor outcome and enhanced systemic inflammation in patients with acute coronary syndrome. AB - OBJECTIVES: To re-evaluate the relation between plasma interleukin-10 (IL-10) concentration at hospital admission and outcome and to investigate the impact of single nucleotide polymorphisms (SNP) in the IL-10 gene in patients with non-ST elevation acute coronary syndrome (ACS). DESIGN: Determination of IL-10 plasma concentrations and genotyping of SNPs in the IL-10 gene in a prospective trial of patients with ACS and in a group of healthy controls. PATIENTS: 3179 patients in the Fragmin and fast revascularisation during InStability in Coronary artery disease II (FRISC II) trial and 393 healthy controls. MAIN OUTCOME MEASURES: Mortality and incidence of myocardial infarction (MI) at 12 months. RESULTS: The median and interquartile ranges of IL-10 were 0.8 (0.5-1.0) pg/ml in healthy controls and 1.1 (0.7-1.9) pg/ml in patients (p<0.001). In patients, IL-10 predicted a crude risk increase of death/MI, with the highest risk observed in the fourth quartile (adjusted odds ratio 1.7 (95% confidence interval 1.2 to 2.3)). Adjustment for common risk indicators, including C-reactive protein and interleukin-6, weakened the association to a non-significant level. The 1170 CC genotype weakly predicted increased plasma concentrations of IL-10 in patients (p = 0.04) and in controls (p = 0.03), which was consistent with the modest association of this variant with coronary disease (p = 0.01). CONCLUSION: In contrast with some previous reports, we conclude that IL-10 reflects a proinflammatory state in patients with ACS and we therefore suggest that IL-10 is as effective a biomarker for the risk prediction of future cardiovascular events as other markers of systemic inflammation. PMID- 17690161 TI - Progesterone, but not estrogen, stimulates vessel maturation in the mouse endometrium. AB - The human endometrium undergoes regular periods of growth and regression, including concomitant changes in the vasculature, and is one of the few adult tissues where significant angiogenesis and vascular maturation occurs on a routine, physiological basis. The aim of this study was to investigate the effects of estrogen and progesterone on endometrial vascular maturation in mice. Endometrial tissues were collected from early pregnant mice (d 1-4) and ovariectomized mice given a single 17beta-estradiol (100 ng) injection 24 h before dissection (short-term estrogen regime) or three consecutive daily injections of progesterone (1 mg) with/without estrogen priming (progesterone regime). Experiments were then repeated with the inclusion of mice treated concurrently with progesterone and either RU486 or a vascular endothelial growth factor-A antiserum. Proliferating vascular mural cells (PVMC) were observed on d 3-4 of pregnancy, corresponding with an increase in circulating progesterone. A significant increase in PVMC and alpha-smooth muscle actin (labels mural cells) coverage of vessel profiles were observed in mice treated with progesterone in comparison to controls; no significant change was noted in mice treated with estrogen or with vascular endothelial growth factor antiserum. RU486 treatment did not inhibit the progesterone-induced increases in PVMC and mural cell coverage, although progesterone-induced changes in endothelial and epithelial cell proliferation were inhibited. These results show that progesterone, but not estrogen, stimulates vessel maturation in the mouse endometrium. The work illustrates the relevancy of the mouse model for understanding endometrial vascular remodeling during the menstrual cycle and in response to the clinically important progesterone receptor antagonist RU486. PMID- 17690162 TI - Lovastatin enhances the replication of the oncolytic adenovirus dl1520 and its antineoplastic activity against anaplastic thyroid carcinoma cells. AB - Anaplastic thyroid carcinoma (ATC) is one of the most aggressive solid tumors and shows morphological features of a highly malignant, undifferentiated neoplasm. Patients with ATC have a poor prognosis with a mean survival time of 2-6 months; surgery, radiotherapy, and chemotherapy do not improve survival. Gene therapy approaches and oncolytic viruses have been tested for the treatment of ATC. To enhance the antineoplastic effects of the oncolytic adenovirus dl1520 (Onyx-015), we treated ATC cells with lovastatin (3-hydroxy-methylglutaryl-CoA reductase inhibitor), a drug used for the treatment of hypercholesterolemia, which has previously been reported to exert growth-inhibitory and apoptotic activity on ATC cells. Lovastatin treatment significantly increased the effects of dl1520 against ATC cells. The replication of dl1520 in ATC cells was enhanced by lovastatin treatment, and a significant increase of the expression of the early gene E1A 13 S and the late gene Penton was observed in lovastatin-treated cells. Furthermore, lovastatin treatment significantly enhanced the effects of dl1520 against ATC tumor xenografts. Lovastatin treatment could be exploited to increase the efficacy of oncolytic adenoviruses, and further studies are warranted to confirm the feasibility of the approach in ATC patients. PMID- 17690163 TI - Contribution of noradrenergic and adrenergic cell groups of the brainstem and agouti-related protein-synthesizing neurons of the arcuate nucleus to neuropeptide-y innervation of corticotropin-releasing hormone neurons in hypothalamic paraventricular nucleus of the rat. AB - CRH-synthesizing neurons in the hypothalamic paraventricular nucleus (PVN) integrate neuronal and hormonal inputs and serve as a final common pathway to regulate the hypothalamic-pituitary-adrenal axis. One of the neuronal regulators of CRH neurons is neuropeptide Y (NPY) contained in axons that densely innervate CRH neurons. The three main sources of NPY innervation of the PVN are the hypothalamic arcuate nucleus and the noradrenergic and adrenergic neurons of the brainstem. To elucidate the origin of the NPY-immunoreactive (NPY-IR) innervation to hypophysiotropic CRH neurons, quadruple-labeling immunocytochemistry for CRH, NPY, dopamine-beta-hydroxylase, and phenylethanolamine-N-methyltransferase was performed. Approximately 63% of NPY-IR varicosities on the surface of CRH neurons were catecholaminergic (22% noradrenergic and 41% adrenergic), and 37% of NPY-IR boutons were noncatecholaminergic. By triple-labeling immunofluorescence detection of NPY, CRH, and agouti-related protein, a marker of NPY axons projecting from the arcuate nucleus, the noncatecholaminergic, NPY-ergic axon population was shown to arise primarily from the arcuate nucleus. When NPY was administered chronically into the cerebral ventricle of fed animals, a dramatic reduction of CRH mRNA was observed in the PVN (NPY vs. control integrated density units, 23.9 +/- 2.7 vs. 77.09 +/- 15.9). We conclude that approximately two thirds of NPY-IR innervation to hypophysiotropic CRH neurons originates from catecholaminergic neurons of the brainstem, whereas the remaining one third arises from the arcuate nucleus. The catecholaminergic NPY innervation seems to modulate the activation of CRH neurons in association with glucoprivation and infection, whereas the NPY input from the arcuate nucleus may contribute to inhibition of CRH neurons during fasting. PMID- 17690164 TI - Effects of maternal levels of thyroid hormone (TH) on the hypothalamus-pituitary thyroid set point: studies in TH receptor beta knockout mice. AB - A level of thyroid hormone (TH) in agreement with the tissue requirements is essential for vertebrate embryogenesis and fetal maturation. In this study we evaluate the immediate and long-term effects of incongruent intrauterine TH levels between mother and fetus using the TH receptor (TR) beta(-/-) knockout mouse as a model. We took advantage of the fact that the TRbeta(-/-) females have elevated serum TH but are not thyrotoxic due to resistance to TH. We used crosses between heterozygotes with wild-type phenotype (TRbeta(+/-)) males and TRbeta(-/ ) females, with a hyperiodothyroninemic (high T(4) and T(3) levels) intrauterine environment (TH congruent with the TRbeta(-/-) fetus and excessive for the TRbeta(+/-) fetus), and reciprocal crosses between TRbeta(-/-) males and TRbeta(+/-) females, providing a euiodothyroninemic intrauterine environment. We found that TRbeta(-/-) dams had reduced litter sizes and pups with lower birth weight but preserved the mendelian TRbeta(-/-) to TRbeta(+/-) ratio at birth, indicating that the incongruous TH levels did not decrease intrauterine survival of a specific genotype. The results of studies in newborns demonstrate that TRbeta(+/-) pups born to TRbeta(-/-) dams have persistent suppression of serum TSH without a peak. On the other hand, TRbeta(-/-) pups born to TRbeta(+/-) dams have lower serum TSH at birth and a tendency to peak higher, compared with TRbeta(-/-) pups born to TRbeta(-/-) dams. The studies in the adult progeny demonstrate that TRbeta(+/-) mice born to TRbeta(-/-) dams and, thus, exposed to higher intrauterine TH levels, have greater resistance to TH at the level of the pituitary when stimulated with TRH. On the other hand, TRbeta(-/-) mice born to TRbeta(+/-) dams and, thus, deprived of TH in uterine life, were more sensitive to TH when similarly stimulated with TRH. Thus, TH exposure in utero has an effect on the regulatory set point of the hypothalamus-pituitary-thyroid axis, which can be seen early in life and persists into adulthood. PMID- 17690165 TI - Differential accessibility of circulating leptin to individual hypothalamic sites. AB - Hypothalamic neurons expressing the long form of the leptin receptor (LRb) mediate important leptin actions. Although it has been suggested that leptin crosses the blood-brain barrier (BBB) via a specific transport system, we hypothesized the existence of a population of hypothalamic arcuate nucleus (ARC) neurons that senses leptin independently of this transport system. Indeed, endogenous circulating leptin results in detectable levels of baseline activated signal transducer and activator of transcription 3 (STAT3) phosphorylation in a population of ARC/LRb neurons, consistent with increased sensing of circulating leptin in these neurons compared with other LRb neurons. Furthermore, a population of ARC/LRb neurons that responds more rapidly and sensitively to circulating leptin compared with other hypothalamic LRb neurons detected by leptin activated phosphorylated STAT3. In addition, peripheral application of the BBB-impermeant retrograde tracer fluorogold revealed a population of ARC/LRb neurons that directly contact the circulation (e.g. via neuronal processes reaching outside the BBB). Taken together, these data suggest that a population of ARC/LRb neurons directly contacts the circulation and displays increased sensitivity to circulating leptin compared with neurons residing entirely behind the BBB elsewhere in the hypothalamus. PMID- 17690166 TI - Human placental development is impaired by abnormal human chorionic gonadotropin signaling in trisomy 21 pregnancies. AB - Placental development is markedly abnormal in women bearing a fetus with trisomy 21, with defective syncytiotrophoblast (ST) formation and function. The ST occurs from cytotrophoblast (CT) fusion and plays an essential role by secreting human chorionic gonadotropin (hCG), which is essential to placental development. In trisomy of chromosome 21 (T21) pregnancies, CTs do not fuse and differentiate properly into STs, leading to the secretion of an abnormal and weakly bioactive hCG. In this study we report for the first time, a marked decrease in the number of mature hCG receptor (LH/CG-R) molecules expressed at the surface of T21 affected CTs. The LH/CG-R seems to be functional based on sequencing that revealed no mutations or deletions and binding of recombinant hCG as well as endogenous hCG. We hypothesize that weakly bioactive hCG and lower LH/CG-R expression may be involved in the defect of ST formation. Interestingly, the defective ST formation is mimicked in normal CT cultures by using LH/CG-R small interfering RNA, which result in a lower hCG secretion. Furthermore, treatment of T21-affected CTs with recombinant hCG overcomes in vitro the T21 phenotype, allowing CTs to fuse and form a large ST. These results illustrate for the first time in trisomy 21 pathology, how abnormal endogenous hCG signaling impairs human placental development. PMID- 17690167 TI - Proteasome-dependent down-regulation of activated nuclear hippocampal glucocorticoid receptors determines dynamic responses to corticosterone. AB - Timing is a critical factor in neuroendocrinology. Despite this, the temporal aspects of glucocorticoid signaling in the regulation of in vivo targets have been largely overlooked. Here, we present data showing that plasma glucocorticoid levels differ greatly from the constant signal predominantly used in cell culture experiments. Using an automated blood sampling system, we found that under basal conditions in nonstressed rats, corticosterone release occurs in discrete pulses of various amplitudes dependent on the circadian cycle. This basal pattern changes to a prolonged elevated nonpulsatile release in response to stressful stimuli. We have been able to recapitulate these different patterns of corticosterone presentation (short pulse vs. prolonged elevation) in adrenalectomized rats, and show that each pattern results in differential activation of hippocampal glucocorticoid and mineralocorticoid receptors. Finally, we provide evidence for a rapid proteasome-dependent clearance of activated glucocorticoid receptors, but not mineralocorticoid receptors, as a novel mechanism to allow dynamic interaction with rapidly changing physiological and environmental conditions. PMID- 17690168 TI - Expression and role of the corticotropin-releasing hormone/urocortin-receptor binding protein system in the primate corpus luteum during the menstrual cycle. AB - CRH/urocortin-receptor-binding protein (CRH/UCN-R-BP) mRNAs are dynamically expressed in the primate ovary during the menstrual cycle. Therefore, studies were designed to localize CRH/UCN-R-BP mRNAs to ovarian cell types, quantitate protein expression during the corpus luteum (CL) lifespan, and investigate the role of this system in the macaque ovary at midcycle. Monkey ovaries were removed during the preovulatory phase and through the luteal phase to localize CRH/UCN-R BP mRNAs by in situ hybridization and determine their protein levels in CL by Western blotting. Also, vehicle or a CRH receptor antagonist (astressin) was injected into the preovulatory follicle; daily serum samples were analyzed for hormone levels, and ovaries were removed on d 9 of the luteal phase for histological analysis. There was minimal ligand mRNA staining, whereas receptor and CRHBP was detected in the granulosa and theca cells of the preovulatory follicle. However, ligand and receptor mRNA staining was appreciable in luteal cells of the CL during the early luteal phase (ECL) and diminished in the late luteal phase (LCL). CRHBP staining was low in the ECL and increased markedly in the LCL. Ligand and receptor protein expression was also highest during ECL, whereas CRHBP expression was highest at the LCL. Although astressin injection did not prevent follicle rupture, progesterone levels were significantly less by the mid-luteal phase, and estradiol levels never increased above baseline during the CL lifespan. Histological indices of cell degeneration were observed in the astressin-treated CL. Thus, CRH/UCN-R-BP components are expressed in an ovarian cell-specific manner. The expression pattern and results from antagonist injection are consistent with the hypothesis that CRH/UCN-R activation promotes luteal development and/or structure-function in monkeys during the menstrual cycle. PMID- 17690169 TI - Coxsackievirus and adenovirus receptor is up-regulated in migratory germ cells during passage of the blood-testis barrier. AB - The coxsackievirus and adenovirus receptor (CAR) is a cell adhesion molecule expressed in epithelial tight junctions and other cell-cell contacts. Using indirect immunofluorescence, quantitative RT-PCR, and Western blots, the expression and distribution of CAR in developing and adult testis are examined. CAR is highly expressed in both Sertoli and germ cells during perinatal and postnatal development, followed by a rapid down-regulation of both mRNA and protein levels. Interestingly, we find that CAR is a previously unknown downstream target for FSH because CAR mRNA levels were induced in primary cultures of FSH-stimulated Sertoli cells. In contrast to other epithelia, CAR is not a general component of tight junctions in the seminiferous epithelium, and Sertoli cells in the adult testis do not express CAR. Instead, CAR expression is stage dependent and specifically found in migratory germ cells. RT-PCR also demonstrated the presence of junctional adhesion molecule-like (JAML) in the testis. JAML was previously reported by others to form a functional complex with CAR regulating transepithelial migration of leukocytes. The expression of JAML in the testis suggests that a similar functional complex might be present during germ cell migration across the blood-testis barrier. Finally, an intermediate compartment occupied by CAR-positive, migrating germ cells and flanked by two occludin-containing junctions is identified. Together, these results implicate a function for CAR in testis morphogenesis and in migration of germ cells across the blood-testis barrier during spermatogenesis. PMID- 17690170 TI - Angiotensin II-induced mitogen-activated protein kinase phosphatase-1 expression in bovine adrenal glomerulosa cells: implications in mineralocorticoid biosynthesis. AB - Angiotensin II (AngII) stimulates aldosterone biosynthesis in the zona glomerulosa of the adrenal cortex. AngII also triggers the MAPK pathways (ERK1/2 and p38). Because ERK1/2 phosphorylation is a transient process, phosphatases could play a crucial role in the acute steroidogenic response. Here we show that the dual specificity (threonine/tyrosine) MAPK phosphatase-1 (MKP-1) is present in bovine adrenal glomerulosa cells in primary culture and that AngII markedly increases its expression in a time- and concentration-dependent manner (IC(50) = 1 nm), a maximum of 548 +/- 10% of controls being reached with 10 nm AngII after 3 h (n = 3, P < 0.01). This effect is completely abolished by losartan, a blocker of the AT(1) receptor subtype. Moreover, this AngII-induced MKP-1 expression is reduced to 250 +/- 35% of controls (n = 3, P < 0.01) in the presence of U0126, an inhibitor of ERK1/2 phosphorylation, suggesting an involvement of the ERK1/2 MAPK pathway in MKP-1 induction. Indeed, shortly after AngII-induced phosphorylation of ERK1/2 (220% of controls at 30 min), MKP-1 protein expression starts to increase. This increase is associated with a reduction in ERK1/2 phosphorylation, which returns to control values after 3 h of AngII challenge. Enhanced MKP-1 expression is essentially due to a stabilization of MKP-1 mRNA. AngII treatment leads to a 53-fold increase in phosphorylated MKP-1 levels and a doubling of MKP 1 phosphatase activity. Overexpression of MKP-1 results in decreased phosphorylation of ERK1/2 and aldosterone production in response to AngII stimulation. These results strongly suggest that MKP-1 is the specific phosphatase induced by AngII and involved in the negative feedback mechanism ensuring adequate ERK1/2-mediated aldosterone production in response to the hormone. PMID- 17690171 TI - Differential regulation of cholera toxin-inhibited Na-H exchange isoforms by butyrate in rat ileum. AB - Electroneutral Na absorption occurs in the intestine via sodium-hydrogen exchanger (NHE) isoforms NHE2 and NHE3. Bicarbonate and butyrate both stimulate electroneutral Na absorption through NHE. Bicarbonate- but not butyrate-dependent Na absorption is inhibited by cholera toxin (CT). Long-term exposure to butyrate also influences expression of apical membrane proteins in epithelial cells. These studies investigated the effects of short- and long-term in vivo exposure to butyrate on apical membrane NHE and mRNA, protein expression, and activity in rat ileal epithelium that had been exposed to CT. Ileal loops were exposed to CT in vivo for 5 h and apical membrane vesicles were isolated. 22Na uptake was measured by using the inhibitor HOE694 to identify NHE2 and NHE3 activity, and Western blot analyses were performed. CT reduced total NHE activity by 70% in apical membrane vesicles with inhibition of both NHE2 and NHE3. Reduced NHE3 activity and protein expression remained low following removal of CT but increased to control values following incubation of the ileal loop with butyrate for 2 h. In parallel there was a 40% decrease in CT-induced increase in cAMP content. In contrast, NHE2 activity partially increased following removal of CT and was further increased to control levels by butyrate. NHE2 protein expression did not parallel its activity. Neither NHE2 nor NHE3 mRNA content were affected by CT or butyrate. These results indicate that CT has varying effects on the two apical NHE isoforms, inhibiting NHE2 activity without altering its protein expression and reducing both NHE3 activity and protein expression. Butyrate restores both CT inhibited NHE2 and NHE3 activities to normal levels but via different mechanisms. PMID- 17690172 TI - Impaired deglutitive EGJ relaxation in clinical esophageal manometry: a quantitative analysis of 400 patients and 75 controls. AB - Assessing deglutitive esophagogastric junction (EGJ) relaxation is an essential focus of clinical manometry. Our aim was to apply automated algorithmic analyses to high-resolution manometry (HRM) studies to ascertain the optimal method for discriminating normal from abnormal deglutitive EGJ relaxation. All 473 subjects (73 controls) were studied with a 36-channel solid-state HRM assembly during water swallows. Patients were classified as: 1) achalasia, 2) postfundoplication, 3) nonachalasia with normal deglutitive EGJ relaxation, or 4) functional obstruction (preserved peristalsis with incomplete EGJ relaxation). Automated computer programs assessed the adequacy of EGJ relaxation by using progressively complex analysis routines to compensate for esophageal shortening, crural diaphragm contraction, and catheter movement, all potential confounders. The single-sensor method of assessing EGJ relaxation had a sensitivity of only 52% for detecting achalasia. Of the automated HRM analysis paradigms tested, the 4-s integrated relaxation pressure using a cutoff of 15 mmHg performed optimally with 98% sensitivity and 96% specificity in the detection of achalasia. We also identified a heterogeneous group of 26 patients with functional EGJ obstruction attributed to variant achalasia and other diverse pathology. Although further clinical experience will ultimately judge, it is our expectation that applying rigorous methodology such as described herein to the analysis of HRM studies will improve the consistency in the interpretation of clinical manometry and prove useful in guiding clinical management. PMID- 17690173 TI - An overlapping binding site in the CYP7A1 promoter allows activation of FXR to override the stimulation by LXRalpha. AB - The aim of this study was to explore why in rabbits activation of farnesoid X receptor (FXR) is dominant over activated liver X receptor-alpha (LXRalpha) in the regulation of CYP7A1. We cloned the rabbit CYP7A1 promoter and found a fetoprotein transcription factor (FTF) binding element embedded within the LXRalpha binding site (LXRE). Gel shift assays demonstrated that FTF competes with LXRalpha for binding to LXRE. Short heterodimer partner (SHP) enhances the competitive ability of FTF. Studies in HepG2 cells showed that SHP combined with FTF had more powerful effect to offset the stimulation of CYP7A1 by LXRalpha. Gel shift and chromatin immunoprecipitation assays demonstrated that SHP with FTF diminished LXRalpha binding to the CYP7A1 promoter. In vivo studies in rabbits fed cholesterol for 10 days showed that hepatic expression of SHP but not FTF rose and LXRalpha-bound LXRE decreased. We propose that the SHP/FTF heterodimer occupies LXRE via the embedded FTF binding element and blocks LXRalpha from recruiting to LXRE. Therefore, activation of FXR, which upregulates SHP expression, will eliminate the stimulatory effect of LXRalpha on the CYP7A1 promoter because increased levels of SHP combined with FTF diminish the recruitment of LXRalpha to CYP7A1 promoter. PMID- 17690174 TI - Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver. AB - Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (CIH) during sleep. OSA is associated with nonalcoholic steatohepatitis (NASH) in obese individuals and may contribute to progression of nonalcoholic fatty liver disease from steatosis to NASH. The purpose of this study was to examine whether CIH induces inflammatory changes in the liver in mice with diet-induced hepatic steatosis. C57BL/6J mice (n = 8) on a high-fat, high-cholesterol diet were exposed to CIH for 6 mo and were compared with mice on the same diet exposed to intermittent air (control; n = 8). CIH caused liver injury with an increase in serum ALT (461 +/- 58 U/l vs. 103 +/- 16 U/l in the control group; P < 0.01) and AST (637 +/- 37 U/l vs. 175 +/- 13 U/l in the control group; P < 0.001), whereas alkaline phosphatase and total bilirubin levels were unchanged. Histology revealed hepatic steatosis in both groups, with mild accentuation of fat staining in the zone 3 hepatocytes in mice exposed to CIH. Animals exposed to CIH exhibited lobular inflammation and fibrosis in the liver, which were not evident in control mice. CIH caused significant increases in lipid peroxidation in serum and liver tissue; significant increases in hepatic levels of myeloperoxidase and proinflammatory cytokines IL-1beta, IL-6, and CXC chemokine MIP-2; a trend toward an increase in TNF-alpha; and an increase in alpha1(I)-collagen mRNA. We conclude that CIH induces lipid peroxidation and inflammation in the livers of mice on a high-fat, high-cholesterol diet. PMID- 17690175 TI - Flexibility of the hepatic zonation of carbon and nitrogen fluxes linked to lactate and pyruvate transformations in the presence of ammonia. AB - It has been proposed that key enzymes of ureagenesis and the alanine aminotransferase activity predominate in periportal hepatocytes. However, ureagenesis from alanine, when measured in the perfused liver, did not show periportal predominance and even the release of the direct products of alanine transformation, lactate and pyruvate, was higher in perivenous cells. An alternative way of analyzing the functional distributions of alanine aminotransferase and the urea cycle along the hepatic acini would be to measure alanine and urea production from precursors such as lactate or pyruvate plus ammonia. In the present work these aspects were investigated in the bivascularly perfused rat liver. The results of the present study confirm that gluconeogenesis and the associated oxygen uptake tend to predominate in the periportal region. Alanine synthesis from lactate and pyruvate plus ammonia, however, predominated in the perivenous region. Furthermore, no predominance of ureagenesis in the periportal region was found, except for conditions of high ammonia concentrations plus oxidizing conditions induced by pyruvate. These observations corroborate the view that data on enzyme activity or expression alone cannot be extrapolated unconditionally to the living cell. The current view of the hepatic ammonia detoxifying system proposes that the small perivenous fraction of glutamine synthesizing perivenous cells removes a minor fraction of ammonia that escapes from ureagenesis in periportal cells. However, since urea synthesis occurs at high rates in all hepatocytes with the possible exclusion of those cells not possessing carbamoyl-phosphate synthase, it is probable that ureagenesis is equally important as an ammonia-detoxifying mechanism in the perivenous region. PMID- 17690176 TI - Concise review: hematopoietic stem cells and tissue stem cells: current concepts and unanswered questions. AB - The term hematopoietic stem cells has at times been used to include a miscellany of precursor cells ranging from multipotential self-generating cells to lineage restricted progenitors with little capacity for self-generation. It is probable that the stem cells of other tissues also vary widely in their multipotentiality and proliferative capacity. This review questions several dogmas regarding the self-generative capacity of various hematopoietic cells, the single episodic origin of hematopoietic cells, and the irreversible nature of progressive mature cell formation in individual hematopoietic lineages. Disclosure of potential conflicts of interest is found at the end of this article. PMID- 17690177 TI - Concise review: human umbilical cord stroma with regard to the source of fetus derived stem cells. AB - Human umbilical cord (UC) has been a tissue of increasing interest in recent years. Many groups have shown the stem cell potency of stromal cells isolated from the human UC mesenchymal tissue, namely, Wharton's jelly. Since UC is a postnatal organ discarded after birth, the collection of cells does not require an invasive procedure with ethical concerns. Stromal cells, as the dominant cells of this fetus-derived tissue, possess multipotent properties between embryonic stem cells and adult stem cells. They bear a relatively higher proliferation rate and self-renewal capacity. Although they share common surface markers with bone marrow-derived MSCs, they also express certain embryonic stem cell markers, albeit in low levels. Without any spontaneous differentiation, they can be successfully differentiated into mature adipocytes, osteoblasts, chondrocytes, skeletal myocytes, cardiomyocytes, neurons, and endothelial cells. While causing no immunorejection reaction, they effectively function in vivo as dopaminergic neurons, myocytes, and endothelial cells. Given these characteristics, particularly the plasticity and developmental flexibility, UC stromal cells are now considered an alternative source of stem cells and deserve to be examined in long-term clinical trials. This review first aims to document the published findings so far regarding the nature of human UC stroma with special emphasis on the spatial distribution and functional structure of stromal cells and matrix, which serves as a niche for residing cells, and, secondly, to assess the in vitro and in vivo experiments in which differential stem cell potencies were evaluated. PMID- 17690178 TI - Donor-derived human bone marrow cells contribute to solid organ cancers developing after bone marrow transplantation. AB - Bone marrow-derived stem cells have been shown to participate in solid organ repair after tissue injury. Animal models suggest that epithelial malignancies may arise as aberrant stem cell differentiation during tissue repair. We hypothesized that if bone marrow stem cells participate in human neoplasia, then solid organ cancers developing after allogeneic bone marrow transplantation (ABMT) might include malignant cells of donor origin. We identified four male patients who developed solid organ cancers (lung adenocarcinoma, laryngeal squamous cell carcinoma, glioblastoma, and Kaposi sarcoma) after myeloablation, total body irradiation, and ABMT from female donors. Donor-derived malignant cells comprised 2.5%-6% of the tumor cellularity The presence of donor-derived malignant cells in solid organ cancers suggests that human bone marrow-derived stem cells have a role in solid organ cancer's carcinogenesis. However, the nature of this role is yet to be defined. PMID- 17690179 TI - Genetically manipulated human embryonic stem cell-derived dendritic cells with immune regulatory function. AB - Genetically manipulated dendritic cells (DC) are considered to be a promising means for antigen-specific immune therapy. This study reports the generation, characterization, and genetic modification of DC derived from human embryonic stem (ES) cells. The human ES cell-derived DC (ES-DC) expressed surface molecules typically expressed by DC and had the capacities to stimulate allogeneic T lymphocytes and to process and present protein antigen in the context of histocompatibility leukocyte antigen (HLA) class II molecule. Genetic modification of human ES-DC can be accomplished without the use of viral vectors, by the introduction of expression vector plasmids into undifferentiated ES cells by electroporation and subsequent induction of differentiation of the transfectant ES cell clones to ES-DC. ES-DC introduced with invariant chain-based antigen-presenting vectors by this procedure stimulated HLA-DR-restricted antigen specific T cells in the absence of exogenous antigen. Forced expression of programmed death-1-ligand-1 in ES-DC resulted in the reduction of the proliferative response of allogeneic T cells cocultured with the ES-DC. Generation and genetic modification of ES-DC from nonhuman primate (cynomolgus monkey) ES cells was also achieved by the currently established method. ES-DC technology is therefore considered to be a novel means for immune therapy. PMID- 17690180 TI - Unique glycerophospholipid signature in retinal stem cells correlates with enzymatic functions of diverse long-chain acyl-CoA synthetases. AB - Lipidomics is an emerging research field that comprehensively characterizes lipid molecular species and their metabolic regulation and biological roles. We performed the first lipidomics study on glycerophospholipids (GPLs) in adult mammalian retinal stem cells (RSCs) and non-RSC control cells. A unique GPL signature identified by electrospray ionization tandem mass spectrometry showed new prominent peaks of 16:0 (sn-1)-18:0 (sn-2) or 16:0-16:0 saturated fatty acids, instead of 18:0-20:4 or 18:0-22:6 polyunsaturated essential fatty acids, at 720 m/z of phosphatidylethanolamine, 764 m/z of phosphatidylserine, and 809 m/z of phosphatidylinositol in RSCs (sphere colony RSCs and enriched RSCs), but not in non-RSCs (retinal cells, ciliary cells, sphere colony-derived retinal cells, and nonretinal cells). To seek whether the GPL signature was associated with long-chain acyl-CoA synthetase (LACS), a potential modulator of fatty acid profiles in de novo GPL synthesis, we analyzed gene expression, catabolic activity, substrate selectivity, and inhibitor sensitivity of diverse LACSs. LACSs in RSCs mediated less utilization by GPLs of polyunsaturated essential fatty acids, including arachidonic acid (20:4 [n-6], a second messenger in cell signaling), which was accompanied by lower plasma membrane fluidity in proliferating RSCs compared with differentiated non-RSCs. These novel findings suggest that LACS-associated GPL signature and cell membrane fluidity may participate in regulating proliferation versus differentiation in RSCs and, perhaps, other types of stem cells. PMID- 17690181 TI - Administration of granulocyte colony-stimulating factor after myocardial infarction enhances the recruitment of hematopoietic stem cell-derived myofibroblasts and contributes to cardiac repair. AB - The administration of granulocyte colony-stimulating factor (G-CSF) after myocardial infarction (MI) improves cardiac function and survival rates in mice. It was also reported recently that bone marrow (BM)-derived c-kit(+) cells or macrophages in the infarcted heart are associated with improvement of cardiac remodeling and function. These observations prompted us to examine whether BM derived hematopoietic cells mobilized by G-CSF administration after MI play a beneficial role in the infarct region. A single hematopoietic stem cell from green fluorescent protein (GFP)-transgenic mice was used to reconstitute hematopoiesis in each experimental mouse. MI was then induced, and the mice received G-CSF for 10 days. In the acute phase, a number of GFP(+) cells showing the elongated morphology were found in the infarcted area. Most of these cells were positive for vimentin and alpha-smooth muscle actin but negative for CD45, indicating that they were myofibroblasts. The number of these cells was markedly enhanced by G-CSF administration, and the enhanced myofibroblast-rich repair was considered to lead to improvements of cardiac remodeling, function, and survival rate. Next, G-CSF-mobilized monocytes were harvested from the peripheral blood of GFP-transgenic mice and injected intravenously into the infarcted mice. Following this procedure, GFP(+) myofibroblasts were observed in the infarcted myocardium. These results indicate that cardiac myofibroblasts are hematopoietic in origin and could arise from monocytes/macrophages. MI leads to the recruitment of monocytes, which differentiate into myofibroblasts in the infarct region. Administration of G-CSF promotes this recruitment and enhances cardiac protection. PMID- 17690182 TI - Noninvasive tracking of cardiac embryonic stem cells in vivo using magnetic resonance imaging techniques. AB - Despite rapid advances in the stem cell field, the ability to identify and track transplanted or migrating stem cells in vivo is limited. To overcome this limitation, we used magnetic resonance imaging (MRI) to detect and follow transplanted stem cells over a period of 28 days in mice using an established myocardial infarction model. Pluripotent mouse embryonic stem (mES) cells were expanded and induced to differentiate into beating cardiomyocytes in vitro. The cardiac-differentiated mES cells were then loaded with superparamagnetic fluorescent microspheres (1.63 microm in diameter) and transplanted into ischemic myocardium immediately following ligation and subsequent reperfusion of the left anterior descending coronary artery. To identify the transplanted stem cells in vivo, MRI was performed using a Varian Inova 4.7 Tesla scanner. Our results show that (a) the cardiac-differentiated mES were effectively loaded with superparamagnetic microspheres in vitro, (b) the microsphere-loaded mES cells continued to beat in culture prior to transplantation, (c) the transplanted mES cells were readily detected in the heart in vivo using noninvasive MRI techniques, (d) the transplanted stem cells were detected in ischemic myocardium for the entire 28-day duration of the study as confirmed by MRI and post-mortem histological analyses, and (e) concurrent functional MRI indicated typical loss of cardiac function, although significant amelioration of remodeling was noted after 28 days in hearts that received transplanted stem cells. These results demonstrate that it is feasible to simultaneously track transplanted stem cells and monitor cardiac function in vivo over an extended period using noninvasive MRI techniques. PMID- 17690183 TI - Early axonopathy preceding neurofibrillary tangles in mutant tau transgenic mice. AB - Neurodegenerative diseases characterized by brain and spinal cord involvement often show widespread accumulations of tau aggregates. We have generated a transgenic mouse line (Tg30tau) expressing in the forebrain and the spinal cord a human tau protein bearing two pathogenic mutations (P301S and G272V). These mice developed age-dependent brain and hippocampal atrophy, central and peripheral axonopathy, progressive motor impairment with neurogenic muscle atrophy, and neurofibrillary tangles and had decreased survival. Axonal spheroids and axonal atrophy developed early before neurofibrillary tangles. Neurofibrillary inclusions developed in neurons at 3 months and were of two types, suggestive of a selective vulnerability of neurons to form different types of fibrillary aggregates. A first type of tau-positive neurofibrillary tangles, more abundant in the forebrain, were composed of ribbon-like 19-nm-wide filaments and twisted paired helical filaments. A second type of tau and neurofilament-positive neurofibrillary tangles, more abundant in the spinal cord and the brainstem, were composed of 10-nm-wide neurofilaments and straight 19-nm filaments. Unbiased stereological analysis indicated that total number of pyramidal neurons and density of neurons in the lumbar spinal cord were not reduced up to 12 months in Tg30tau mice. This Tg30tau model thus provides evidence that axonopathy precedes tangle formation and that both lesions can be dissociated from overt neuronal loss in selected brain areas but not from neuronal dysfunction. PMID- 17690184 TI - Neutrophil elastase converts human immature dendritic cells into transforming growth factor-beta1-secreting cells and reduces allostimulatory ability. AB - During microbial infection, neutrophils (polymorphonuclear leukocytes; PMNs) activate dendritic cells (DCs). However, early reports illustrated that neutrophil-derived mediators may suppress responses to mitogens. In the present study, we investigated the mechanism used by PMNs to modulate the immunostimulatory ability of DCs. Autologous syngeneic PMNs decreased T-cell proliferation induced by allogeneic DCs. Culture supernatant (CS) derived from PMNs also decreased allostimulation ability of immature DCs and increased the expression of transforming growth factor (TGF)-beta1 on DCs. A TGF-beta1 monoclonal antibody, a CD40 monoclonal antibody, or a serine protease inhibitor reversed the effect of PMN CS on DC allostimulatory ability. Furthermore, elastase reproduced the inhibitory effect of PMN CS on DC allostimulatory ability and the TGF-beta1 production. The role of elastase was confirmed by examining PMN CS from two patients with cyclic neutropenia, a disease due to mutations in the neutrophil elastase gene. These PMN CS samples had reduced elastase activity and were unable to increase DC TGF-beta1 production. Moreover, elastase and PMN CS induced IkappaBalpha degradation in DCs. We conclude that PMNs decrease DC allostimulatory ability via production of elastase leading to a switch of immature DCs into TGF-beta1-secreting cells. PMID- 17690185 TI - Dexamethasone inhibits interleukin-1beta-induced corneal neovascularization: role of nuclear factor-kappaB-activated stromal cells in inflammatory angiogenesis. AB - Dexamethasone, a synthetic corticosteroid, is widely used as a potent anti inflammatory drug in various diseases including corneal angiogenesis. However, dexamethasone's impact on interleukin (IL)-1beta-dependent inflammatory angiogenesis is unknown. Here, we show that dexamethasone inhibits IL-1beta induced neovascularization and the expression of the angiogenesis-related factors, vascular endothelial growth factor-A, KC, and prostaglandin E(2) in the mouse cornea 2 days after IL-1beta implantation. IL-1beta caused IkappaB-alpha phosphorylation in corneal stromal cells but not in infiltrated CD11b(+) cells 2 days after IL-1beta implantation. In contrast, both cell types were positive for phosphorylated IkappaB-alpha 4 days after IL-1beta implantation. Dexamethasone significantly inhibited IkappaB-alpha phosphorylation 2 and 4 days after IL-1beta implantation. Furthermore, dexamethasone inhibited IL-1beta-induced expression of vascular endothelial growth factor-A, KC, and prostaglandin E(2), and signaling of nuclear factor (NF)-kappaB in corneal fibroblasts in vitro. A selective NF kappaB inhibitor attenuated IL-1beta-induced corneal angiogenesis. These findings suggest that NF-kappaB activation in the corneal stromal cells is an important early event during IL-1beta-induced corneal angiogenesis and that dexamethasone inhibits IL-1beta-induced angiogenesis partially via blocking NF-kappaB signaling. PMID- 17690186 TI - c-Jun NH2 terminal kinase activation and decreased expression of mitogen activated protein kinase phosphatase-1 play important roles in invasion and angiogenesis of urothelial carcinomas. AB - We here examined whether c-Jun NH(2) terminal kinase (JNK) might be involved in the progression of urothelial carcinomas. In vitro and in vivo invasion assays using Matrigel and chick embryo chorioallantoic membrane approaches showed constitutive activation of JNK to significantly increase two processes, invasion and angiogenesis, in the human urothelial carcinoma cell line kU-7, this being suppressed by a JNK inhibitor, SP600125, or cell-permeable peptides. In addition, we found that mitogen-activated protein kinase phosphatase (MKP)-1 functions as an endogenous inhibitor of JNK-mediated signals in urothelial carcinoma cells: chorioallantoic membrane assays showed UMUC14 cells with low MKP-1 expression to be more invasive and have pronounced angiogenesis compared to UMUC6 cells with high MKP-1. Furthermore, knockdown of the MKP-1 gene by siRNA transfection enhanced JNK activation in UMUC6 cells to the UMUC14 level. Immunohistochemically, JNK was found to be highly phosphorylated in high-grade and invasive carcinomas (>/=pT2) as well as carcinoma in situ but not in low grade and noninvasive phenotypes (pTa, pT1). In contrast, MKP-1 was much more expressed in low-grade/noninvasive cancers than with the high-grade/invasive phenotype, reversely correlating with phosphorylated JNK. Taken together, JNK activation and decreased expression of MKP-1 may play important roles in progression of urothelial carcinoma. PMID- 17690187 TI - Sustained secretion of immunoglobulin by long-lived human tonsil plasma cells. AB - Immunoglobulin-secreting cells comprise both short-lived proliferating plasmablasts and long-lived nonproliferating plasma cells. To determine the phenotype and functional activity of Ig-secreting cells in human lymphoid tissue, we used a tonsillar organ culture model. A significant proportion of IgA and IgG secretion was shown to be mediated by long-lived, nonproliferating plasma cells that coexpressed high levels of CD27 and CD38. The presence of such cells was further corroborated by the finding of enhanced expression in the CD19(+) B-cell population of XBP-1, IRF-4, and particularly Blimp-1 genes involved in the differentiation of plasma cells. Intact tissue seemed to be necessary for optimal functional activity of plasma cells. A strong correlation was found between concentrations of interleukin-6 and IgA or IgG, but not IgM, in culture supernatants suggesting a role for interleukin-6 in the survival of long-lived plasma cells. Taken together, the present study demonstrates that human lymphoid tissue harbors a population of nonproliferating plasma cells that are dependent on an intact microenvironment for ongoing Ig secretion. PMID- 17690188 TI - BMP7: a new bone metastases prevention? PMID- 17690189 TI - Salmonella effector AvrA regulation of colonic epithelial cell inflammation by deubiquitination. AB - AvrA is a newly described bacterial effector existing in Salmonella. Here, we test the hypothesis that AvrA is a deubiquitinase that removes ubiquitin from two inhibitors of the nuclear factor-kappaB (NF-kappaB) pathway, IkappaBalpha and beta-catenin, thereby inhibiting the inflammatory responses of the host. The role of AvrA was assessed in intestinal epithelial cell models and in mouse models infected with AvrA-deficient and -sufficient Salmonella strains. We also purified AvrA and AvrA mutant proteins and characterized their deubiquitinase activity in a cell-free system. We investigated target gene and inflammatory cytokine expression, as well as effects on epithelial cell proliferation and apoptosis induced by AvrA-deficient and -sufficient bacterial strains in vivo. Our results show that AvrA blocks degradation of IkappaBalpha and beta-catenin in epithelial cells. AvrA deubiquitinates IkappaBalpha, which blocks its degradation and leads to the inhibition of NF-kappaB activation. Target genes of the NF-kappaB pathway, such as interleukin-6, were correspondingly down-regulated during bacterial infection with Salmonella expressing AvrA. AvrA also deubiquitinates and thus blocks degradation of beta-catenin. Target genes of the beta-catenin pathway, such as c-myc and cyclinD1, were correspondingly up-regulated with AvrA expression. Increased beta-catenin further negatively regulates the NF-kappaB pathway. Our findings suggest an important role for AvrA in regulating host inflammatory responses through NF-kappaB and beta-catenin pathways. PMID- 17690190 TI - Expression patterns of atrogenic and ubiquitin proteasome component genes with exercise: effect of different loading patterns and repeated exercise bouts. AB - Unaccustomed exercise is known to produce strength loss, soreness, and myocellular disruption. With repeated application of exercise stimuli, the appearance of these indexes of muscle damage is attenuated, the so-called "repeated bout effect." No direct connection has been established between this repeated bout effect and exercise-induced increases in protein turnover, but it appears that a degree of tolerance is developed toward exercise for both. The present study sought to investigate markers of protein degradation by determining the expression of components related to the ubiquitin-proteasome system (UPS) with repeated exercise bouts. Healthy men carried out 30 min of bench stepping, performing eccentric work with one and concentric work with the other leg (n = 14), performing a duplicate exercise bout 8 wk later. A nonexercising control group was included (n = 6). RNA was extracted from muscle biopsies representing time points preexercise, +3 h, +24 h, and +7 days, and selected mRNA species were quantified using Northern blotting. The exercise model proved sufficient to produce a repeated bout effect in terms of strength and soreness. For forkhead box O transcription factor 1 (FOXO1) and muscle RING finger protein-1 (MURF1), strong upregulations were seen exclusively with concentric loading (P < 0.001), while atrogin-1 displayed a strong downregulation exclusively in response to eccentric exercise (P < 0.001). For MURF1 transcription, the first bout produced a downregulation that persisted until the second bout (P < 0.01). In conclusion, the UPS is modulated differentially in response to varying loading modalities and with different time frames in a way that to some extent reflects changes in protein metabolism known to take place with exercise. PMID- 17690191 TI - Performance of runners and swimmers after four weeks of intermittent hypobaric hypoxic exposure plus sea level training. AB - This double-blind, randomized, placebo-controlled trial examined the effects of 4 wk of resting exposure to intermittent hypobaric hypoxia (IHE, 3 h/day, 5 days/wk at 4,000-5,500 m) or normoxia combined with training at sea level on performance and maximal oxygen transport in athletes. Twenty-three trained swimmers and runners completed duplicate baseline time trials (100/400-m swims, or 3-km run) and measures for maximal oxygen uptake (VO(2max)), ventilation (VE(max)), and heart rate (HR(max)) and the oxygen uptake at the ventilatory threshold (VO(2) at VT) during incremental treadmill or swimming flume tests. Subjects were matched for sex, sport, performance, and training status and divided randomly between hypobaric hypoxia (Hypo, n = 11) and normobaric normoxia (Norm, n = 12) groups. All tests were repeated within the first (Post1) and third weeks (Post2) after the intervention. Time-trial performance did not improve in either group. We could not detect a significant difference between groups for a change in VO(2max), VE(max), HR(max), or VO(2) at VT after the intervention (group x test interaction P = 0.31, 0.24, 0.26, and 0.12, respectively). When runners and swimmers were considered separately, Hypo swimmers appeared to increase VO(2max) (+6.2%, interaction P = 0.07) at Post2 following a precompetition taper and increased VO(2) at VT (+8.9 and +12.1%, interaction P = 0.007 and 0.006, at Post1 and Post2). We conclude that this "dose" of IHE was not sufficient to improve performance or oxygen transport in this heterogeneous group of athletes. Whether there are potential benefits of this regimen for specific sports or training/tapering strategies may require further study. PMID- 17690192 TI - Modified activity-stress paradigm in an animal model of the female athlete triad. AB - The exercising woman with nutritional deficits and related menstrual irregularities is at risk of compromising long-term bone health, i.e., the female athlete triad. There is no animal model of the female athlete triad. The purpose of this study was to examine long-term energy restriction in voluntary wheel running female rats on estrous cycling, bone mineral content, and leptin levels. Twelve female Sprague-Dawley rats (age 34 days) were fed ad libitum and given access to running wheels during an initial 14-wk period, providing baseline and age-related data. Daily collection included dietary intake, body weight, estrous cycling, and voluntary running distance. At 4 mo, rats were randomized into two groups, six restrict-fed rats (70% of ad libitum intake) and six rats continuing as ad libitum-fed controls. Energy intake, energy expenditure, and energy availability (energy intake - energy expenditure) were calculated for each animal. Serum estradiol and leptin concentrations were measured by RIA. Femoral and tibial bone mineral density and bone mineral content (BMC) were determined by dual-energy X-ray absorptiometry. Restrict-fed rats exhibited a decrease in energy availability during Weight Loss and Anestrous phases (P = 0.002). Compared with controls after 12 wk, restrict-fed rats showed reduced concentrations of serum estradiol (P = 0.002) and leptin (P = 0.002), lower ovarian weight (P = 0.002), and decreased femoral (P = 0.041) and tibial (P = 0.05) BMC. Decreased energy availability resulted in anestrus and significant decreases in BMC, estrogen and leptin levels, and body weight. Finally, there is a critical level of energy availability to maintain estrous cycling. PMID- 17690193 TI - Acquired and innate cardioprotection. PMID- 17690194 TI - PGC-1beta is downregulated by training in human skeletal muscle: no effect of training twice every second day vs. once daily on expression of the PGC-1 family. AB - We hypothesized that the peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) family of transcriptional coactivators (PGC-1alpha, PGC 1beta, and PRC) is differentially regulated by training once daily vs. training twice daily every second day and that this difference might be observed in the acute response to endurance exercise. Furthermore, we hypothesized that expression levels of the PGC-1 family differ with muscular fiber-type composition. Thus, before and after 10 wk of knee extensor endurance training, training one leg once daily and the other leg twice daily every second day, keeping the total amount of training for the legs equal, skeletal muscle mRNA expression levels of PGC-1alpha, PGC-1beta, and PRC were determined in young healthy men (n = 7) in response to 3 h of acute exercise. No significant difference was found between the two legs, suggesting that regulation of the PGC 1 family is independent of training protocol. Training decreased PGC-1beta in both legs, whereas PGC-1alpha was increased, but not significantly, in the leg training once daily. PRC did not change with training. Both PGC-1alpha and PRC were increased by acute exercise both before and after endurance training, whereas PGC-1beta did not change. The mRNA levels of the PGC-1 family were examined in different types of human skeletal muscle (triceps, soleus, and vastus lateralis; n = 7). Only the expression level of PGC-1beta differed and correlated inversely with percentage of type I fibers. In conclusion, there was no difference between training protocols on the acute exercise and training response of the PGC-1 family. However, training caused a decrease in PGC-1beta mRNA levels. PMID- 17690195 TI - Brain stem NO modulates ventilatory acclimatization to hypoxia in mice. AB - The objective of our study was to assess the role of neuronal nitric oxide synthase (nNOS) in the ventilatory acclimatization to hypoxia. We measured the ventilation in acclimatized Bl6/CBA mice breathing 21% and 8% oxygen, used a nNOS inhibitor, and assessed the expression of N-methyl-d-aspartate (NMDA) glutamate receptor and nNOS (mRNA and protein). Two groups of Bl6/CBA mice (n = 60) were exposed during 2 wk either to hypoxia [barometric pressure (PB) = 420 mmHg] or normoxia (PB = 760 mmHg). At the end of exposure the medulla was removed to measure the concentration of nitric oxide (NO) metabolites, the expression of NMDA-NR1 receptor, and nNOS by real-time RT-PCR and Western blot. We also measured the ventilatory response [fraction of inspired O(2) (Fi(O(2))) = 0.21 and 0.08] before and after S-methyl-l-thiocitrulline treatment (SMTC, nNOS inhibitor, 10 mg/kg ip). Chronic hypoxia caused an increase in ventilation that was reduced after SMTC treatment mainly through a decrease in tidal volume (Vt) in normoxia and in acute hypoxia. However, the difference observed in the magnitude of acute hypoxic ventilatory response [minute ventilation (Ve) 8% - Ve 21%] in acclimatized mice was not different. Acclimatization to hypoxia induced a rise in NMDA receptor as well as in nNOS and NO production. In conclusion, our study provides evidence that activation of nNOS is involved in the ventilatory acclimatization to hypoxia in mice but not in the hypoxic ventilatory response (HVR) while the increased expression of NMDA receptor expression in the medulla of chronically hypoxic mice plays a role in acute HVR. These results are therefore consistent with central nervous system plasticity, partially involved in ventilatory acclimatization to hypoxia through nNOS. PMID- 17690196 TI - Body size and human energy requirements: reduced mass-specific resting energy expenditure in tall adults. AB - Two observations favor the presence of a lower mass-specific resting energy expenditure (REE/weight) in taller adult humans: an earlier report of height (H) related differences in relative body composition; and a combined model based on Quetelet and Kleiber's classic equations suggesting that REE/weight proportional, variantH(-0.5). This study tested the hypothesis stating that mass-specific REE scales negatively to height with a secondary aim exploration of related associations between height, weight (W), surface area (SA), and REE. Two independent data sets (n = 344 and 884) were evaluated, both with REE measured by indirect calorimetry and the smaller of the two including fat estimates by dual energy X-ray absorptiometry. Results support Quetelet's equation (W proportional, variantH(2)), but Kleiber's equation approached the interspecific mammal form (REE proportional, variantW(0.75)) only after adding adiposity measures to weight and age as REE predictors. REE/weight scaled as H( approximately (-0.5)) in support of the hypothesis with P values ranging from 0.17 to <0.001. REE and SA both scaled as H( approximately 1.5), and REE/SA was nonsignificantly correlated with height in all groups. These observations suggest that adiposity needs to be considered when evaluating the intraspecific scaling of REE to weight; that relative to their weight, taller subjects require a lower energy intake for replacing resting heat losses than shorter subjects; that fasting endurance, approximated as fat mass/REE, increases as H(0.5); and that thermal balance is maintained independent of stature by evident stable associations between resting heat production and capacity of external heat release. These observations have implications for the modeling of adult human energy requirements and associate with anthropological concepts founded on body size. PMID- 17690197 TI - Age-related neuromuscular function during drop jumps. AB - Muscle- and movement-specific fascicle-tendon interaction affects the performance of the neuromuscular system. This interaction is unknown among elderly and consequently contributes to the lack of understanding the age-related problems on neuromuscular control. The present experiment studied the age specificity of fascicle-tendon interaction of the gastrocnemius medialis (GM) muscle in drop jump (DJ) exercises. Twelve young and thirteen elderly subjects performed maximal squat jumps and DJs with maximal rebound effort on a sledge apparatus. Ankle and knee joint angles, reaction force, and electromyography (EMG) from the soleus (Sol), GM, and tibialis anterior (TA) muscles were measured together with the GM fascicle length by ultrasonography. The results showed that the measured ankle joint stiffness (AJS) during the braking phase correlated positively with the rebound speed in both age groups and that both parameters were significantly lower in the elderly than in young subjects. In both groups, the AJS correlated positively with averaged EMG (aEMG) in Sol during the braking phase and was further associated with GM activation (r = 0.55, P < 0.01) and TA coactivation (TA/GM r = -0.4 P < 0.05) in the elderly subjects. In addition, compared with the young subjects, the elderly subjects showed significantly lower GM aEMG in the braking phase and higher aEMG in the push-off phase, indicating less utilization of tendinous tissue (TT) elasticity. These different activation patterns are in line with the mechanical behavior of GM showing significantly less fascicle shortening and relative TT stretching in the braking phase in the elderly than in the young subjects. These results suggest that age-specific muscle activation patterns as well as mechanical behaviors exist during DJs. PMID- 17690198 TI - beta-Alanine supplementation augments muscle carnosine content and attenuates fatigue during repeated isokinetic contraction bouts in trained sprinters. AB - Carnosine (beta-alanyl-l-histidine) is present in high concentrations in human skeletal muscle. The ingestion of beta-alanine, the rate-limiting precursor of carnosine, has been shown to elevate the muscle carnosine content. We aimed to investigate, using proton magnetic resonance spectroscopy (proton MRS), whether oral supplementation with beta-alanine during 4 wk would elevate the calf muscle carnosine content and affect exercise performance in 400-m sprint-trained competitive athletes. Fifteen male athletes participated in a placebo-controlled, double-blind study and were supplemented orally for 4 wk with either 4.8 g/day beta-alanine or placebo. Muscle carnosine concentration was quantified in soleus and gastrocnemius by proton MRS. Performance was evaluated by isokinetic testing during five bouts of 30 maximal voluntary knee extensions, by endurance during isometric contraction at 45% maximal voluntary contraction, and by the indoor 400 m running time. beta-Alanine supplementation significantly increased the carnosine content in both the soleus (+47%) and gastrocnemius (+37%). In placebo, carnosine remained stable in soleus, while a small and significant increase of +16% occurred in gastrocnemius. Dynamic knee extension torque during the fourth and fifth bout was significantly improved with beta-alanine but not with placebo. Isometric endurance and 400-m race time were not affected by treatment. In conclusion, 1) proton MRS can be used to noninvasively quantify human muscle carnosine content; 2) muscle carnosine is increased by oral beta-alanine supplementation in sprint-trained athletes; 3) carnosine loading slightly but significantly attenuated fatigue in repeated bouts of exhaustive dynamic contractions; and 4) the increase in muscle carnosine did not improve isometric endurance or 400-m race time. PMID- 17690199 TI - Age-related resistance to skeletal muscle fatigue is preserved during ischemia. AB - During voluntary contractions, the skeletal muscle of healthy older adults often fatigues less than that of young adults, a result that has been explained by relatively greater reliance on muscle oxidative metabolism in the elderly. Our aim was to investigate whether this age-related fatigue resistance was eliminated when oxidative metabolism was minimized via ischemia induced by cuff (220 mmHg). We hypothesized that 1) older men (n = 12) would fatigue less than young men (n = 12) during free-flow (FF) contractions; 2) both groups would fatigue similarly during ischemia; and 3) reperfusion would reestablish the fatigue resistance of the old. Subjects performed 6 min of intermittent, maximal voluntary isometric contractions of the ankle dorsiflexors under FF and ischemia-reperfusion (IR) conditions. Ischemia was maintained for the first 3 min of contractions, followed by rapid cuff deflation and reperfusion for 3 additional minutes of contractions. Central activation, peripheral activation, and muscle contractile properties were measured at 3 and 6 min of contractions. Older men fatigued less than young men during FF (P 90% were unchanged in expression. Noteworthy was the up-regulation of several tight junction-related proteins, including MUPP1 (multi-PDZ protein-1), ZO1 (zonula occludens 1), and Af6. The most robustly up-regulated protein under hypertonic conditions was MUPP1 (7.2x, P < 0.001). Changes in expression for MUPP1 were verified by quantitative PCR for message and Western blot for protein. In mouse kidney tissues, MUPP1 expression was substantial in the papilla and was absent in the cortex. Furthermore, MUPP1 expression increased 253% (P < 0.01) in the papilla upon 36 h of thirsting. Localization of MUPP1 protein expression was confirmed by immunocytochemical analysis demonstrating only minor staining under isotonic conditions and the substantial presence in chronically adapted cells at the basolateral membrane. Message and protein half-life in IMCD3 cells were 26.2 and 17.8 h, respectively. Osmotic initiators of MUPP1 expression included NaCl, sucrose, mannitol, sodium acetate, and choline chloride but not urea. Stable IMCD3 clones silenced for MUPP1 expression used the pSM2-MUPP1 vector. In cell viability experiments, clones silenced for MUPP1 demonstrated only a minor loss in cell survival under acute sublethal osmotic stress compared with empty vector control cells. In contrast, a 24% loss (P < 0.02) in transepithelial resistance for monolayers of MUPP1-silenced cells was determined as compared with controls. These results suggest that MUPP1 specifically, and potentially tight junction complexes in general, are important in the renal osmoadaptive response. PMID- 17690247 TI - Meiotic crossover hotspots contained in haplotype block boundaries of the mouse genome. AB - Fertility requires successful chromosome segregation in meiosis, which in most sexual organisms depends on the formation of appropriately placed crossovers. The nonrandom genome-wide distributions of meiotic recombination events have been examined at the molecular level experimentally in yeast and by inference from linkage disequilibrium patterns in humans. Thus far, no method has existed for pinpointing sites of crossing-over on a genome-wide scale in an experimentally tractable animal whose genome size and complexity models that of humans. Here, we present a genomic approach to identify mouse crossover hotspots, based on targeting haplotype block boundaries. This represents a previously undescribed method potentially applicable to large-scale mouse hotspot identification. Using this method, we have successfully predicted the location of two previously uncharacterized crossover hotspots in male mice. As increasing amounts of single nucleotide polymorphism data emerge, this approach will be useful for investigating the recombination landscape of the mouse genome. PMID- 17690248 TI - The AKAP Yu is required for olfactory long-term memory formation in Drosophila. AB - Extensive neurogenetic analysis has shown that memory formation depends critically on cAMP-protein kinase A (PKA) signaling. Details of how this pathway is involved in memory formation, however, remain to be fully elucidated. From a large-scale behavioral screen in Drosophila, we identified the yu mutant to be defective in one-day memory after spaced training. The yu mutation disrupts a gene encoding an A-kinase anchoring protein (AKAP). AKAPs comprise a family of proteins, which determine the subcellular localization of PKAs and thereby critically restrict cAMP signaling within a cell. Further behavioral characterizations revealed that long-term memory (LTM) was disrupted specifically in the yu mutant, whereas learning, short-term memory and anesthesia-resistant memory all appeared normal. Another independently isolated mutation of the yu gene failed to complement the LTM defect associated with the yu mutation, and this phenotypic defect could be rescued by induced acute expression of a yu(+) transgene, suggesting that yu functions physiologically during memory formation. AKAP Yu is expressed preferentially in the mushroom body (MB) neuroanatomical structure, and expression of a yu(+) transgene to the MB, but not to other brain regions, is sufficient to rescue the LTM defect of the yu mutant. These observations lead us to conclude that proper localization of PKA by Yu AKAP in MB neurons is required for the formation of LTM. PMID- 17690249 TI - Mechanism of and requirement for estrogen-regulated MYB expression in estrogen receptor-positive breast cancer cells. AB - MYB (the human ortholog of c-myb) is expressed in a high proportion of human breast tumors, and that expression correlates strongly with estrogen receptor (ER) positivity. This may reflect the fact that MYB is a target of estrogen/ER signaling. Because in many cases MYB expression appears to be regulated by transcriptional attenuation or pausing in the first intron, we first investigated whether this mechanism was involved in estrogen/ER modulation of MYB. We found that this was the case and that estrogen acted directly to relieve attenuation due to sequences within the first intron, specifically, a region potentially capable of forming a stem-loop structure in the transcript and an adjacent poly(dT) tract. Secondly, given the involvement of MYB in hematopoietic and colon tumors, we also asked whether MYB was required for the proliferation of breast cancer cells. We found that proliferation of ER(+) but not ER(-) breast cancer cell lines was inhibited when MYB expression was suppressed by using either antisense oligonucleotides or RNA interference. Our results show that MYB is an effector of estrogen/ER signaling and provide demonstration of a functional role of MYB in breast cancer. PMID- 17690250 TI - Nuclear targeting of the growth hormone receptor results in dysregulation of cell proliferation and tumorigenesis. AB - Growth hormone receptor (GHR) has been demonstrated to be nuclear localized both in vivo and in vitro, but the significance of this observation has remained elusive. Here we show that nuclear GHR is strongly correlated with proliferative status in vivo by using a liver regeneration model. In vitro, nuclear translocation of the GH receptor is GH-dependent and appears to be mediated by the Importin system. Constitutive nuclear targeting of GHR in murine pro-B cells is associated with constitutive activation of STAT5, a transforming agent in lymphoma and other cell types. This activation is abrogated by inhibition of JAK2 and appears to be driven by autocrine murine GH action coupled with enhanced nuclear uptake of phospho-STAT5. Nuclear targeting induces dysregulated cell cycle progression in the pro-B cell line, associated with constitutive up regulation of the proliferation inducers Survivin and Mybbp, the metastasis related Dysadherin, and other tumor markers. GHR nuclear-targeted cells generate aggressive metastatic tumors when injected into nude mice, which display nuclear localized GHR strikingly similar to that seen in human lymphomas. We conclude that aberrant nuclear localization of GHR is a marker of high proliferative status and is sufficient to induce tumorigenesis and tumor progression. PMID- 17690251 TI - Pharmacology and antitussive efficacy of 4-(3-trifluoromethyl-pyridin-2-yl) piperazine-1-carboxylic acid (5-trifluoromethyl-pyridin-2-yl)-amide (JNJ17203212), a transient receptor potential vanilloid 1 antagonist in guinea pigs. AB - Transient receptor potential vanilloid 1 (TRPV1) plays an integral role in modulating the cough reflex, and it is an attractive antitussive drug target. The purpose of this study was to characterize a TRPV1 antagonist, 4-(3 trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid (5-trifluoromethyl pyridin-2-yl)-amide (JNJ17203212), against the guinea pig TRPV1 receptor in vitro followed by a proof-of-principle study in an acid-induced model of cough. The affinity of JNJ17203212 for the recombinant guinea pig TRPV1 receptor was estimated by radioligand binding, and it was functionally characterized by antagonism of low-pH and capsaicin-induced activation of the ion channel (fluorometric imaging plate reader and electrophysiology). The nature of antagonism was further tested against the native channel in isolated guinea pig tracheal rings. Following pharmacokinetic characterization of JNJ17203212 in guinea pigs, pharmacodynamic and efficacy studies were undertaken to establish the antitussive efficacy of the TRPV1 antagonist. The pK(i) of JNJ17203212 for recombinant guinea pig TRPV1 was 7.14 +/- 0.06. JNJ17203212 inhibited both pH (pIC(50) of 7.23 +/- 0.05) and capsaicin (pIC(50) of 6.32 +/- 0.06)-induced channel activation. In whole-cell patch clamp, the pIC(50) for inhibition of guinea pig TRPV1 was 7.3 +/- 0.01. JNJ17203212 demonstrated surmountable antagonism in isolated trachea, with a pK(B) value of 6.2 +/- 0.1. Intraperitoneal administration of 20 mg/kg JNJ17203212 achieved a maximal plasma exposure of 8.0 +/- 0.4 microM, and it attenuated capsaicin evoked coughs with similar efficacy to codeine (25 mg/kg). Last, JNJ17203212 dose-dependently produced antitussive efficacy in citric acid-induced experimental cough in guinea pigs. Our data provide preclinical support for developing TRPV1 antagonists for the treatment of cough. PMID- 17690252 TI - Conversion of phosphodiesterase-5 (PDE5) catalytic site to higher affinity by PDE5 inhibitors. AB - Phosphodiesterase-5 (PDE5) specifically hydrolyzes cGMP, thereby contributing to modulation of intracellular levels of this nucleotide. In the present study, preincubation with cGMP increased PDE5 catalytic activity for cGMP degradation, and it converted the PDE5 catalytic site to a form that was more potently inhibited by each of the three PDE5 catalytic site-specific inhibitors: sildenafil, vardenafil, and tadalafil. These results implied that elevated cGMP initiates a physiological negative feedback on the cGMP pathway by increasing the affinity of the PDE5 catalytic site for cGMP. This increase in catalytic site activity or affinity for inhibitors could be caused by binding of cGMP to either the PDE5 allosteric sites, catalytic site, or both. Whether occupation of the catalytic site alone could mediate the effect was examined using radiolabeled PDE5 inhibitors in the absence of cGMP. Exchange-dissociation of [(3)H]sildenafil (Viagra), [(3)H]vardenafil (Levitra), or [(3)H]tadalafil (Cialis) from full length PDE5 or isolated catalytic domain revealed two kinetic components (slow and fast). Extended preincubation of full-length PDE5, but not isolated catalytic domain, with (3)H inhibitors converted the biphasic pattern to a single slow (high-affinity) component. Studies of amino-terminally truncated PDE5 established that full-length mammalian GAF-B (cGMP-binding phosphodiesterase, Anabaena adenylyl cyclases, Escherichia coli FhlA) subdomain conjoined with the catalytic domain was sufficient for this conversion. In conclusion, binding of substrate or substrate analogs such as PDE5 inhibitors to the catalytic site converts a fast (low-affinity) inhibitor dissociation component of the PDE5 catalytic site to a slow (high-affinity) inhibitor dissociation component. This effect is predicted to improve the substrate affinity or inhibitory potencies of these compounds in intact cells. PMID- 17690253 TI - The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling. AB - Anaplastic large cell lymphomas (ALCLs) are highly proliferating tumors that commonly express the AP-1 transcription factor JunB. ALK fusions occur in approximately 50% of ALCLs, and among these, 80% have the t(2;5) translocation with NPM-ALK expression. We report greater activity of JunB in NPM-ALK-positive than in NPM-ALK-negative ALCLs. Specific knockdown of JUNB mRNA using small interfering RNA and small hairpin RNA in NPM-ALK-expressing cells decreases cellular proliferation as evidenced by a reduced cell count in the G2/M phase of the cell cycle. Expression of NPM-ALK results in ERK1/2 activation and transcriptional up-regulation of JUNB. Both NPM-ALK-positive and -negative ALCL tumors demonstrate active ERK1/2 signaling. In contrast to NPM-ALK-negative ALCL, the mTOR pathway is active in NPM-ALK-positive lymphomas. Pharmacological inhibition of mTOR in NPM-ALK-positive cells down-regulates JunB protein levels by shifting JUNB mRNA translation from large polysomes to monosomes and ribonucleic particles (RNPs), and decreases cellular proliferation. Thus, JunB is a critical target of mTOR and is translationally regulated in NPM-ALK-positive lymphomas. This is the first study demonstrating translational control of AP-1 transcription factors in human neoplasia. In conjunction with NPM-ALK, JunB enhances cell cycle progression and may therefore represent a therapeutic target. PMID- 17690254 TI - Histone H2B as a functionally important plasminogen receptor on macrophages. AB - Plasminogen (Plg) facilitates inflammatory cell recruitment, a function that depends upon its binding to Plg receptors (Plg-Rs). However, the Plg-Rs that are critical for cell migration are not well defined. Three previously characterized Plg-Rs (alpha-enolase, annexin 2, and p11) and a recently identified Plg-R (histone H2B [H2B]) were assessed for their contribution to Plg binding and function on macrophages. Two murine macrophage cell lines (RAW 264.7 and J774A.1) and mouse peritoneal macrophages induced by thioglycollate were analyzed. All 4 Plg-Rs were present on the surface of these cells and showed enhanced expression on the thioglycollate-induced macrophages compared with peripheral blood monocytes. Using blocking Fab fragments to each Plg-R, H2B supported approximately 50% of the Plg binding capacity, whereas the other Plg-Rs contributed less than 25%. Anti-H2B Fab also demonstrated a major role of this Plg-R in plasmin generation and matrix invasion. When mice were treated intravenously with anti-H2B Fab, peritoneal macrophage recruitment in response to thioglycollate was reduced by approximately 45% at 24, 48, and 72 hours, with no effect on blood monocyte levels. Taken together, these data suggest that multiple Plg-Rs do contribute to Plg binding to macrophages, and among these, H2B plays a very prominent and functionally important role. PMID- 17690255 TI - Treatment with GITR agonistic antibody corrects adaptive immune dysfunction in sepsis. AB - Apoptosis of CD4(+) T cells and T(H)2 polarization are hallmarks of sepsis induced immunoparalysis. In this study, we characterized sepsis-induced adaptive immune dysfunction and examined whether improving T-cell effector function can improve outcome to sepsis. We found that septic mice produced less antigen specific T-cell-dependent IgM and IgG(2a) antibodies than sham-treated mice. As early as 24 hours after sepsis, CD4(+) T cells proliferated poorly to T-cell receptor stimulation, despite normal responses to phorbol myristate acetate and ionomycin, and possessed decreased levels of CD3zeta. Five days following immunization, CD4(+) T cells from septic mice displayed decreased antigen specific proliferation and production of IL-2 and IFN-gamma but showed no difference in IL-4, IL-5, or IL-10 production. Treatment of mice with anti-GITR agonistic antibody restored CD4(+) T-cell proliferation, increased T(H)1 and T(H)2 cytokine production, partially prevented CD3zeta down-regulation, decreased bacteremia, and increased sepsis survival. Depletion of CD4(+) T cells but not CD25(+) regulatory T cells eliminated the survival benefit of anti-GITR treatment. These results indicate that CD4(+) T-cell dysfunction is a key component of sepsis and that improving T-cell effector function may be protective against sepsis-associated immunoparalysis. PMID- 17690256 TI - Kupffer cell heterogeneity: functional properties of bone marrow derived and sessile hepatic macrophages. AB - Kupffer cells form a large intravascular macrophage bed in the liver sinusoids. The differentiation history and diversity of Kupffer cells is disputed; some studies argue that they are derived from blood monocytes, whereas others support a local origin from intrahepatic precursor cells. In the present study, we used both flow cytometry and immunohistochemistry to distinguish 2 subsets of Kupffer cells that were revealed in the context both of bone marrow transplantation and of orthotopic liver transplantation. One subset was radiosensitive and rapidly replaced from hematogenous precursors, whereas the other was relatively radioresistant and long-lived. Both were phagocytic but only the former population was recruited into inflammatory foci in response to CD8(+) T-cell activation. We propose the name "sessile" for the radioresistant Kupffer cells that do not participate in immunoinflammatory reactions. However, we found no evidence that these sessile Kupffer cells arise from immature intrahepatic precursors. Our conclusions resolve a long-standing controversy and explain how different experimental approaches may reveal one or both of these subsets. PMID- 17690257 TI - Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to event results of the APEX trial. AB - Initial analysis of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of relapsed multiple myeloma patients showed significantly longer time to progression, higher response rate, and improved survival with single-agent bortezomib versus high-dose dexamethasone. In this updated analysis (median follow-up: 22 months), survival was assessed in both arms, and efficacy updated for the bortezomib arm. Median survival was 29.8 months for bortezomib versus 23.7 months for dexamethasone, a 6-month benefit, despite substantial crossover from dexamethasone to bortezomib. Overall and complete response rates with bortezomib were 43% and 9%, respectively; among responding patients, 56% improved response with longer therapy beyond initial response, leading to continued improvement in overall quality of response. Higher response quality (100% M-protein reduction) was associated with longer response duration; response duration was not associated with time to response. These data confirm the activity of bortezomib and support extended treatment in relapsed multiple myeloma patients tolerating therapy. PMID- 17690258 TI - LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. AB - Tricyclic antidepressants exert their pharmacological effect-inhibiting the reuptake of serotonin, norepinephrine, and dopamine-by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters. PMID- 17690259 TI - Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. AB - Glaucoma is a leading cause of irreversible blindness. A genome-wide search yielded multiple single-nucleotide polymorphisms (SNPs) in the 15q24.1 region associated with glaucoma. Further investigation revealed that the association is confined to exfoliation glaucoma (XFG). Two nonsynonymous SNPs in exon 1 of the gene LOXL1 explain the association, and the data suggest that they confer risk of XFG mainly through exfoliation syndrome (XFS). About 25% of the general population is homozygous for the highest-risk haplotype, and their risk of suffering from XFG is more than 100 times that of individuals carrying only low risk haplotypes. The population-attributable risk is more than 99%. The product of LOXL1 catalyzes the formation of elastin fibers found to be a major component of the lesions in XFG. PMID- 17690260 TI - Land-use allocation protects the Peruvian Amazon. AB - Disturbance and deforestation have profound ecological and socioeconomic effects on tropical forests, but their diffuse patterns are difficult to detect and quantify at regional scales. We expanded the Carnegie forest damage detection system to show that, between 1999 and 2005, disturbance and deforestation rates throughout the Peruvian Amazon averaged 632 square kilometers per year and 645 square kilometers per year, respectively. However, only 1 to 2% occurred within natural protected areas, indigenous territories contained only 11% of the forest disturbances and 9% of the deforestation, and recent forest concessions effectively protected against clear-cutting. Although the region shows recent increases in disturbance and deforestation rates and leakage into forests surrounding concession areas, land-use policy and remoteness are serving to protect the Peruvian Amazon. PMID- 17690261 TI - 20th-century industrial black carbon emissions altered Arctic climate forcing. AB - Black carbon (BC) from biomass and fossil fuel combustion alters chemical and physical properties of the atmosphere and snow albedo, yet little is known about its emission or deposition histories. Measurements of BC, vanillic acid, and non sea-salt sulfur in ice cores indicate that sources and concentrations of BC in Greenland precipitation varied greatly since 1788 as a result of boreal forest fires and industrial activities. Beginning about 1850, industrial emissions resulted in a sevenfold increase in ice-core BC concentrations, with most change occurring in winter. BC concentrations after about 1951 were lower but increasing. At its maximum from 1906 to 1910, estimated surface climate forcing in early summer from BC in Arctic snow was about 3 watts per square meter, which is eight times the typical preindustrial forcing value. PMID- 17690262 TI - Leptin regulates striatal regions and human eating behavior. AB - Studies of the fat-derived hormone leptin have provided key insights into the molecular and neural components of feeding behavior and body weight regulation. An important challenge lies in understanding how the rewarding properties of food interact with, and can override, physiological satiety signals and promote overeating. We used functional magnetic resonance imaging to measure brain responses in two human patients with congenital leptin deficiency who were shown images of food before and after 7 days of leptin replacement therapy. Leptin was found to modulate neural activation in key striatal regions, suggesting that the hormone acts on neural circuits governing food intake to diminish the perception of food reward while enhancing the response to satiety signals generated during food consumption. PMID- 17690263 TI - Geochemistry. "C"ing Arctic climate with black ice. PMID- 17690264 TI - Dan Koshland: a retrospective. PMID- 17690265 TI - Biosecurity. U.K. labs suspected as source of foot-and-mouth outbreak. PMID- 17690266 TI - Human evolution. New fossils challenge line of descent in human family tree. PMID- 17690267 TI - Genetics. High-risk glaucoma gene found in Nordic studies. PMID- 17690268 TI - U.S. science policy. Congress passes massive measure to support research, education. PMID- 17690269 TI - U.S. science policy. New DOE agency sparks an energetic debate. PMID- 17690270 TI - AIDS research. Feud over AIDS vaccine trials leads prominent Italian researchers to court. PMID- 17690271 TI - Paleoanthropology. The fellowship of the hobbit. PMID- 17690272 TI - Medicine. The big chill. PMID- 17690273 TI - Climate change. Humans and nature duel over the next decade's climate. PMID- 17690274 TI - Retraction of an interpretation. PMID- 17690275 TI - The dangers of advocacy in science. PMID- 17690277 TI - A clarification on centrifugal force. PMID- 17690276 TI - Controversy over EmrE structure. PMID- 17690278 TI - Environment: globalization of conservation: a view from the south. PMID- 17690279 TI - Neuroscience. Shining light on depression. PMID- 17690280 TI - Evolution. An embarrassment of switches. PMID- 17690281 TI - Chemistry. Molecules take the heat. PMID- 17690282 TI - Philosophy of science. The Cha-Cha-Cha Theory of Scientific Discovery. PMID- 17690283 TI - Applied physics. How to strum a nanobar. PMID- 17690285 TI - The future of attosecond spectroscopy. AB - Attoscience is the study of physical processes that occur in less than a fraction of a cycle of visible light, in times less than a quadrillionth of a second. The motion of electrons inside atoms and molecules that are undergoing photoionization or chemical change falls within this time scale, as does the plasma motion that causes the reflectivity of metals. The techniques to study motion on this scale are based on careful control of strong-field laser-atom interactions. These techniques and new research opportunities in attosecond spectroscopy are reviewed. PMID- 17690286 TI - Attosecond control and measurement: lightwave electronics. AB - Electrons emit light, carry electric current, and bind atoms together to form molecules. Insight into and control of their atomic-scale motion are the key to understanding the functioning of biological systems, developing efficient sources of x-ray light, and speeding up electronics. Capturing and steering this electron motion require attosecond resolution and control, respectively (1 attosecond = 10(-18) seconds). A recent revolution in technology has afforded these capabilities: Controlled light waves can steer electrons inside and around atoms, marking the birth of lightwave electronics. Isolated attosecond pulses, well reproduced and fully characterized, demonstrate the power of the new technology. Controlled few-cycle light waves and synchronized attosecond pulses constitute its key tools. We review the current state of lightwave electronics and highlight some future directions. PMID- 17690287 TI - Harnessing attosecond science in the quest for coherent X-rays. AB - Modern laser technology has revolutionized the sensitivity and precision of spectroscopy by providing coherent light in a spectrum spanning the infrared, visible, and ultraviolet wavelength regimes. However, the generation of shorter wavelength coherent pulses in the x-ray region has proven much more challenging. The recent emergence of high harmonic generation techniques opens the door to this possibility. Here we review the new science that is enabled by an ability to manipulate and control electrons on attosecond time scales, ranging from new tabletop sources of coherent x-rays to an ability to follow complex electron dynamics in molecules and materials. We also explore the implications of these advances for the future of molecular structural characterization schemes that currently rely so heavily on scattering from incoherent x-ray sources. PMID- 17690288 TI - Rapid population growth of a critically endangered carnivore. AB - Reintroductions of endangered species are controversial because of high costs and frequent failures. However, the population of black-footed ferrets descended from animals released in Shirley Basin, Wyoming, from 1991 to 1994 has grown rapidly after a decline to a low of five animals in 1997. Beginning around 2000, the population grew rapidly to an estimated 223 (95% confidence interval is 192 to 401) individuals in 2006. Matrix population modeling shows the importance of survival and reproduction during the first year of life, reflecting an uncommon life history for an endangered mammalian carnivore. Recovery of the species may benefit from more opportunistic and widespread releases. PMID- 17690289 TI - Multifunctional nanomechanical systems via tunably coupled piezoelectric actuation. AB - Efficient actuation is crucial to obtaining optimal performance from nanoelectromechanical systems (NEMS). We employed epitaxial piezoelectric semiconductors to obtain efficient and fully integrated NEMS actuation, which is based on exploitation of the interaction between piezoelectric strain and built in charge depletion. The underlying actuation mechanism in these depletion mediated NEMS becomes important only for devices with dimensions approaching semiconductor depletion lengths. The induced actuation forces are controlled electrically, and resonant excitation approaching single-electron efficiency is demonstrated. The fundamental electromechanical coupling itself can be programmed by heterostructure band engineering, externally controllable charge depletion, and crystallographic orientation. These attributes are combined to realize a prototype, mechanically based, exclusive-or logic element. PMID- 17690290 TI - Ultrafast flash thermal conductance of molecular chains. AB - At the level of individual molecules, familiar concepts of heat transport no longer apply. When large amounts of heat are transported through a molecule, a crucial process in molecular electronic devices, energy is carried by discrete molecular vibrational excitations. We studied heat transport through self assembled monolayers of long-chain hydrocarbon molecules anchored to a gold substrate by ultrafast heating of the gold with a femtosecond laser pulse. When the heat reached the methyl groups at the chain ends, a nonlinear coherent vibrational spectroscopy technique detected the resulting thermally induced disorder. The flow of heat into the chains was limited by the interface conductance. The leading edge of the heat burst traveled ballistically along the chains at a velocity of 1 kilometer per second. The molecular conductance per chain was 50 picowatts per kelvin. PMID- 17690291 TI - Direct synthesis of amides from alcohols and amines with liberation of H2. AB - Given the widespread importance of amides in biochemical and chemical systems, an efficient synthesis that avoids wasteful use of stoichiometric coupling reagents or corrosive acidic and basic media is highly desirable. We report a reaction in which primary amines are directly acylated by equimolar amounts of alcohols to produce amides and molecular hydrogen (the only products) in high yields and high turnover numbers. This reaction is catalyzed by a ruthenium complex based on a dearomatized PNN-type ligand [where PNN is 2-(di-tert-butylphosphinomethyl)-6 (diethylaminomethyl)pyridine], and no base or acid promoters are required. Use of primary diamines in the reaction leads to bis-amides, whereas with a mixed primary-secondary amine substrate, chemoselective acylation of the primary amine group takes place. The proposed mechanism involves dehydrogenation of hemiaminal intermediates formed by the reaction of an aldehyde intermediate with the amine. PMID- 17690292 TI - Improved surface temperature prediction for the coming decade from a global climate model. AB - Previous climate model projections of climate change accounted for external forcing from natural and anthropogenic sources but did not attempt to predict internally generated natural variability. We present a new modeling system that predicts both internal variability and externally forced changes and hence forecasts surface temperature with substantially improved skill throughout a decade, both globally and in many regions. Our system predicts that internal variability will partially offset the anthropogenic global warming signal for the next few years. However, climate will continue to warm, with at least half of the years after 2009 predicted to exceed the warmest year currently on record. PMID- 17690293 TI - Mechanism of Na+/H+ antiporting. AB - Na+/H+ antiporters are central to cellular salt and pH homeostasis. The structure of Escherichia coli NhaA was recently determined, but its mechanisms of transport and pH regulation remain elusive. We performed molecular dynamics simulations of NhaA that, with existing experimental data, enabled us to propose an atomically detailed model of antiporter function. Three conserved aspartates are key to our proposed mechanism: Asp164 (D164) is the Na+-binding site, D163 controls the alternating accessibility of this binding site to the cytoplasm or periplasm, and D133 is crucial for pH regulation. Consistent with experimental stoichiometry, two protons are required to transport a single Na+ ion: D163 protonates to reveal the Na+-binding site to the periplasm, and subsequent protonation of D164 releases Na+. Additional mutagenesis experiments further validated the model. PMID- 17690294 TI - Augmented Wnt signaling in a mammalian model of accelerated aging. AB - The contribution of stem and progenitor cell dysfunction and depletion in normal aging remains incompletely understood. We explored this concept in the Klotho mouse model of accelerated aging. Analysis of various tissues and organs from young Klotho mice revealed a decrease in stem cell number and an increase in progenitor cell senescence. Because klotho is a secreted protein, we postulated that klotho might interact with other soluble mediators of stem cells. We found that klotho bound to various Wnt family members. In a cell culture model, the Wnt klotho interaction resulted in the suppression of Wnt biological activity. Tissues and organs from klotho-deficient animals showed evidence of increased Wnt signaling, and ectopic expression of klotho antagonized the activity of endogenous and exogenous Wnt. Both in vitro and in vivo, continuous Wnt exposure triggered accelerated cellular senescence. Thus, klotho appears to be a secreted Wnt antagonist and Wnt proteins have an unexpected role in mammalian aging. PMID- 17690295 TI - Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. AB - The regenerative potential of skeletal muscle declines with age, and this impairment is associated with an increase in tissue fibrosis. We show that muscle stem cells (satellite cells) from aged mice tend to convert from a myogenic to a fibrogenic lineage as they begin to proliferate and that this conversion is mediated by factors in the systemic environment of the old animals. We also show that this lineage conversion is associated with an activation of the canonical Wnt signaling pathway in aged myogenic progenitors and can be suppressed by Wnt inhibitors. Furthermore, components of serum from aged mice that bind to the Frizzled family of proteins, which are Wnt receptors, may account for the elevated Wnt signaling in aged cells. These results indicate that the Wnt signaling pathway may play a critical role in tissue-specific stem cell aging and an increase in tissue fibrosis with age. PMID- 17690296 TI - International conservation policy delivers benefits for birds in Europe. AB - Conservation of the planet's biodiversity will depend on international policy intervention, yet evidence-based assessment of the success of such intervention is lacking. Poor understanding of the effectiveness of international policy instruments exposes them to criticism or abandonment and reduces opportunities to improve them. Comparative analyses of population trends provide strong evidence for a positive impact of one such instrument, the European Union's Birds Directive, and we identify positive associations between the rate of provision of certain conservation measures through the directive and the response of bird populations. The results suggest that supranational conservation policy can bring measurable conservation benefits, although future assessments will require the setting of quantitative objectives and an increase in the availability of data from monitoring schemes. PMID- 17690297 TI - Adaptive mutations in bacteria: high rate and small effects. AB - Evolution by natural selection is driven by the continuous generation of adaptive mutations. We measured the genomic mutation rate that generates beneficial mutations and their effects on fitness in Escherichia coli under conditions in which the effect of competition between lineages carrying different beneficial mutations is minimized. We found a rate on the order of 10(-5) per genome per generation, which is 1000 times as high as previous estimates, and a mean selective advantage of 1%. Such a high rate of adaptive evolution has implications for the evolution of antibiotic resistance and pathogenicity. PMID- 17690298 TI - Divergence of transcription factor binding sites across related yeast species. AB - Characterization of interspecies differences in gene regulation is crucial for understanding the molecular basis of both phenotypic diversity and evolution. By means of chromatin immunoprecipitation and DNA microarray analysis, the divergence in the binding sites of the pseudohyphal regulators Ste12 and Tec1 was determined in the yeasts Saccharomyces cerevisiae, S. mikatae, and S. bayanus under pseudohyphal conditions. We have shown that most of these sites have diverged across these species, far exceeding the interspecies variation in orthologous genes. A group of Ste12 targets was shown to be bound only in S. mikatae and S. bayanus under pseudohyphal conditions. Many of these genes are targets of Ste12 during mating in S. cerevisiae, indicating that specialization between the two pathways has occurred in this species. Transcription factor binding sites have therefore diverged substantially faster than ortholog content. Thus, gene regulation resulting from transcription factor binding is likely to be a major cause of divergence between related species. PMID- 17690299 TI - Characterizing the limits of human visual awareness. AB - Momentary awareness of a visual scene is very limited; however, this limitation has not been formally characterized. We test the hypothesis that awareness reflects a surprisingly impoverished data structure called a labeled Boolean map, defined as a linkage of just one feature value per dimension (for example, the color is green and the motion is rightward) with a spatial pattern. Features compete with each other, whereas multiple locations form a spatial pattern and thus do not compete. Perception of the colors of two objects was significantly improved by successive compared with simultaneous presentation, whereas perception of their locations was not. Moreover, advance information about which objects are relevant aided perception of colors much more than perception of locations. Both results support the Boolean map hypothesis. PMID- 17690303 TI - Transcriptional interference: an unexpected layer of complexity in gene regulation. AB - Much of the genome is transcribed into long untranslated RNAs, mostly of unknown function. Growing evidence suggests that transcription of sense and antisense untranslated RNAs in eukaryotes can repress a neighboring gene by a phenomenon termed transcriptional interference. Transcriptional interference by the untranslated RNA may prevent recruitment of the initiation complex or prevent transcriptional elongation. Recent work in yeast, mammals, and Drosophila highlights the diverse roles that untranslated RNAs play in development. Previously, untranslated RNAs of the bithorax complex of Drosophila were proposed to be required for its activation. Recent studies show that these untranslated RNAs in fact silence Ultrabithorax in early embryos, probably by transcriptional interference. PMID- 17690300 TI - Immunization by avian H5 influenza hemagglutinin mutants with altered receptor binding specificity. AB - Influenza virus entry is mediated by the receptor binding domain (RBD) of its spike, the hemagglutinin (HA). Adaptation of avian viruses to humans is associated with HA specificity for alpha2,6- rather than alpha2,3-linked sialic acid (SA) receptors. Here, we define mutations in influenza A subtype H5N1 (avian) HA that alter its specificity for SA either by decreasing alpha2,3- or increasing alpha2,6-SA recognition. RBD mutants were used to develop vaccines and monoclonal antibodies that neutralized new variants. Structure-based modification of HA specificity can guide the development of preemptive vaccines and therapeutic monoclonal antibodies that can be evaluated before the emergence of human-adapted H5N1 strains. PMID- 17690304 TI - Necessity of inositol (1,4,5)-trisphosphate receptor 1 and mu-calpain in NO induced osteoclast motility. AB - In skeletal remodeling, osteoclasts degrade bone, detach and move to new locations. Mechanical stretch and estrogen regulate osteoclast motility via nitric oxide (NO). We have found previously that NO stimulates guanylyl cyclase, activating the cGMP-dependent protein kinase 1 (PKG1), reversibly terminating osteoclast matrix degradation and attachment, and initiating motility. The PKG1 substrate vasodilator-stimulated protein (VASP), a membrane-attachment-related protein found in complexes with the integrin alphavbeta3 in adherent osteoclasts, was also required for motility. Here, we studied downstream mechanisms by which the NO-dependent pathway mediates osteoclast relocation. We found that NO stimulated motility is dependent on activation of the Ca(2+)-activated proteinase mu-calpain. RNA interference (RNAi) showed that NO-dependent activation of mu calpain also requires PKG1 and VASP. Inhibition of Src kinases, which are involved in the regulation of adhesion complexes, also abolished NO-stimulated calpain activity. Pharmacological inhibition and RNAi showed that calpain activation in this process is mediated by the inositol (1,4,5)-trisphosphate receptor 1 [Ins(1,4,5)P(3)R1] Ca(2+) channel. We conclude that NO-induced motility in osteoclasts requires regulated Ca(2+) release, which activates mu calpain. This occurs via the Ins(1,4,5)P(3)R1. PMID- 17690305 TI - A FRET map of membrane anchors suggests distinct microdomains of heterotrimeric G proteins. AB - The standard model of heterotrimeric G protein signaling postulates a dissociation of Galpha and Gbetagamma subunits after activation. We hypothesized that the different combination of lipid-modifications on Galpha and Galphabetagamma subunits directs them into different microdomains. By characterizing rapidly and at high sensitivity 38 fluorescence resonance energy transfer (FRET) pairs of heterotrimeric-G-protein constructs, we defined their microdomains in relation to each other, free from the constraints of the raft/non raft dualism. We estimated that in a cell approximately 30% of these membrane anchored proteins are mostly clustered in 3400-16,200 copies of 30-nm microdomains. We found that the membrane anchors of Galpha and Galphabetagamma subunits of both the G(i/o) and G(q) family co-cluster differently with microdomain markers. Moreover, anchors of the Galpha(i/o) and Galpha(q) subunits co-clustered only weakly, whereas constructs that contained the anchors of the corresponding heterotrimers co-clustered considerably, suggesting the existence of at least three types of microdomain. Finally, FRET experiments with full length heterotrimeric G proteins confirmed that the inactive, heterotrimerized Galpha subunit is in microdomains shared by heterotrimers from different subclasses, from where it displaces upon activation into a membrane-anchor- and subclass-specific microdomain. PMID- 17690306 TI - Hemicraniectomy: a second chance on life for patients with space-occupying MCA infarction. PMID- 17690307 TI - Migraine with aura and ischemic stroke: which additional factors matter? PMID- 17690308 TI - Probable migraine with visual aura and risk of ischemic stroke: the stroke prevention in young women study. AB - BACKGROUND AND PURPOSE: Migraine with aura is associated with ischemic stroke, but few studies have investigated the clinical and anatomic features of this association. We assessed the association of probable migraine with and without visual aura with ischemic stroke within subgroups defined by stroke subtype, vascular territory, probable migraine characteristics, and other clinical features. METHODS: Using data from a population-based, case-control study, we studied 386 women ages 15 to 49 years with first ischemic stroke and 614 age- and ethnicity-matched controls. Based on their responses to a questionnaire on headache symptoms, subjects were classified as having no migraine, probable migraine without visual aura, or probable migraine with visual aura (PMVA). RESULTS: Women with PMVA had 1.5 greater odds of ischemic stroke (95% CI, 1.1 to 2.0); the risk was highest in those with no history of hypertension, diabetes, or myocardial infarction compared to women with no migraine. Women with PMVA who were current cigarette smokers and current users of oral contraceptives had 7.0 fold higher odds of stroke (95% CI, 1.3 to 22.8) than did women with PMVA who were nonsmokers and non-oral contraceptive users. Women with onset of PMVA within the previous year had 6.9-fold higher adjusted odds of stroke (95% CI, 2.3 to 21.2) compared to women with no history of migraine. CONCLUSIONS: PMVA was associated with an increased risk of stroke, particularly among women without other medical conditions associated with stroke. Behavioral risk factors, specifically smoking and oral contraceptive use, markedly increased the risk of PMVA, as did recent onset of PMVA. PMID- 17690309 TI - US multicenter experience with the Wingspan stent system for the treatment of intracranial atheromatous disease: periprocedural results. PMID- 17690310 TI - Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery (DESTINY): a randomized, controlled trial. AB - BACKGROUND AND PURPOSE: Decompressive surgery (hemicraniectomy) for life threatening massive cerebral infarction represents a controversial issue in neurocritical care medicine. We report here the 30-day mortality and 6- and 12 month functional outcomes from the DESTINY trial. METHODS: DESTINY (ISRCTN01258591) is a prospective, multicenter, randomized, controlled, clinical trial based on a sequential design that used mortality after 30 days as the first end point. When this end point was reached, patient enrollment was interrupted as per protocol until recalculation of the projected sample size was performed on the basis of the 6-month outcome (primary end point=modified Rankin Scale score, dichotomized to 0 to 3 versus 4 to 6). All analyses were based on intention to treat. RESULTS: A statistically significant reduction in mortality was reached after 32 patients had been included: 15 of 17 (88%) patients randomized to hemicraniectomy versus 7 of 15 (47%) patients randomized to conservative therapy survived after 30 days (P=0.02). After 6 and 12 months, 47% of patients in the surgical arm versus 27% of patients in the conservative treatment arm had a modified Rankin Scale score of 0 to 3 (P=0.23). CONCLUSIONS: DESTINY showed that hemicraniectomy reduces mortality in large hemispheric stroke. With 32 patients included, the primary end point failed to demonstrate statistical superiority of hemicraniectomy, and the projected sample size was calculated to 188 patients. Despite this failure to meet the primary end point, the steering committee decided to terminate the trial in light of the results of the joint analysis of the 3 European hemicraniectomy trials. PMID- 17690311 TI - Sequential-design, multicenter, randomized, controlled trial of early decompressive craniectomy in malignant middle cerebral artery infarction (DECIMAL Trial). AB - BACKGROUND AND PURPOSE: There is no effective medical treatment of malignant middle cerebral artery (MCA) infarction. The purpose of this clinical trial was to assess the efficacy of early decompressive craniectomy in patients with malignant MCA infarction. METHODS: We conducted in France a multicenter, randomized trial involving patients between 18 and 55 years of age with malignant MCA infarction to compare functional outcomes with or without decompressive craniectomy. A sequential, single-blind, triangular design was used to compare the rate of development of moderate disability (modified Rankin scale score < or =3) at 6 months' follow-up (primary outcome) between the 2 treatment groups. RESULTS: After randomization of 38 patients, the data safety monitoring committee recommended stopping the trial because of slow recruitment and organizing a pooled analysis of individual data from this trial and the 2 other ongoing European trials of decompressive craniectomy in malignant MCA infarction. Among the 38 patients randomized, the proportion of patients with a modified Rankin scale score < or =3 at the 6-month and 1-year follow-up was 25% and 50%, respectively, in the surgery group compared with 5.6% and 22.2%, respectively, in the no-surgery group (P=0.18 and P=0.10, respectively). There was a 52.8% absolute reduction of death after craniectomy compared with medical therapy only (P<0.0001). CONCLUSIONS: In this trial, early decompressive craniectomy increased by more than half the number of patients with moderate disability and very significantly reduced (by more than half) the mortality rate compared with that after medical therapy. PMID- 17690312 TI - Novel thyroxine derivatives, thyronamine and 3-iodothyronamine, induce transient hypothermia and marked neuroprotection against stroke injury. AB - BACKGROUND AND PURPOSE: Mild hypothermia confers profound neuroprotection in ischemia. We recently discovered 2 natural derivatives of thyroxine, 3 iodothyronamine (T(1)AM) and thyronamine (T(0)AM), that when administered to rodents lower body temperature for several hours without induction of a compensatory homeostatic response. We tested whether T(1)AM- and T(0)AM-induced hypothermia protects against brain injury from experimental stroke. METHODS: We tested T(1)AM and T(0)AM 1 hour after and 2 days before stroke in a mouse model of focal ischemia. To determine whether T(1)AM and T(0)AM require hypothermia to protect against stroke injury, the induction of hypothermia was prevented. RESULTS: T(1)AM and T(0)AM administration reduced body temperature from 37 degrees C to 31 degrees C. Mice given T(1)AM or T(0)AM after the ischemic period had significantly smaller infarcts compared with controls. Mice preconditioned with T(1)AM before ischemia displayed significantly smaller infarcts compared with controls. Pre- and postischemia treatments required the induction of hypothermia. T(1)AM and T(0)AM treatment in vitro failed to confer neuroprotection against ischemia. CONCLUSIONS: T(1)AM and T(0)AM, are potent neuroprotectants in acute stroke and T(1)AM can be used as antecedent treatment to induce neuroprotection against subsequent ischemia. Hypothermia induced by T(1)AM and T(0)AM may underlie neuroprotection. T(1)AM and T(0)AM offer promise as treatments for brain injury. PMID- 17690313 TI - Does the prevention of complications explain the survival benefit of organized inpatient (stroke unit) care?: further analysis of a systematic review. AB - BACKGROUND AND PURPOSE: Systematic reviews have shown that organized inpatient (stroke unit) care reduces the risk of death after stroke. However, it is unclear how this is achieved. We tested whether stroke unit care could reduce deaths by preventing complications. METHODS: We updated a collaborative systematic review of 31 controlled clinical trials (6936 participants) to include reported interventions and complications during early hospital care plus the certified cause of death during follow up. Each secondary analysis used data from between 7 and 17 studies (1652 to 3327 participants). Complications were grouped as physiological, neurological, cardiovascular, complications of immobility, and others. Bayesian hierarchical models were used to estimate odds ratios for features occurring in stroke units versus conventional care. RESULTS: Based on the data of 17 trials (3327 participants), organized (stroke unit) care reduced case fatality during scheduled follow up (OR: 0.75; 95% credible intervals: 0.59 to 0.92), in particular deaths certified as attributable to complications of immobility (0.59; 0.41 to 0.86). Stroke unit care was associated with statistically significant increases in the reported use of oxygen (2.39; 1.39 to 4.66), measures to prevent aspiration (2.42; 1.36 to 4.36), and paracetamol (2.80; 1.14 to 4.83) plus a nonsignificant reduction in the use of urinary catheterization. Stroke units were associated with statistically significant reductions in stroke progression/recurrence (0.66; 0.46 to 0.95) and in some complications of immobility: chest infections (0.60; 0.42 to 0.87), other infections (0.56; 0.40 to 0.84), and pressure sores (0.44; 0.22 to 0.85). There were no significant differences in cardiovascular, physiological, or other complications. CONCLUSIONS: Organized inpatient (stroke unit) care appears to reduce the risk of death after stroke through the prevention and treatment of complications, in particular infections. PMID- 17690314 TI - Transforming growth factor activity is a key determinant for the effect of estradiol on fatty streak deposit in hypercholesterolemic mice. AB - OBJECTIVE: Whereas estradiol prevents fatty streak deposit in immunocompetent apoE-/- or LDLr-/- mice, it is totally ineffective in immunodeficient mice, underlining the key role of immunoinflammation in this effect. In the present work, the role of several major pro- and antiinflammatory cytokines involved in the atheromatous process was evaluated in the effect of estradiol on fatty streak constitution. METHODS AND RESULTS: The preventive effect of estradiol was fully maintained in LDLr-/- mice grafted with bone marrow from either IFN-gamma or interleukin (IL)-12-deficient mice, showing that this beneficial effect was not mediated through a specific decrease in the production of these 2 proinflammatory cytokines. Furthermore, IL-10-/- apoE-/- mice remained protected by estradiol, excluding a significant contribution of this antiinflammatory cytokine. In contrast, the protective effect of estradiol was (1) associated with enhanced aortic expression of TGF-beta1 in apoE-/- mice during early steps of atherogenesis; (2) abolished and even reversed in apoE-/- mice administered with a neutralizing anti-TGF-beta antibody; (3) abolished in LDLr-/- mice grafted with bone marrow from Smad3-deficient mice. CONCLUSIONS: The status of the TGF-beta pathway crucially determines the antiatherogenic effect of estradiol in hypercholesterolemic mice, whereas neither IFN-gamma, IL-12, nor IL-10 are specifically involved in this protection. PMID- 17690315 TI - Defective leptin/leptin receptor signaling improves regulatory T cell immune response and protects mice from atherosclerosis. AB - OBJECTIVE: Obesity is a major risk factor for atherosclerosis and is associated with increased cardiovascular morbidity and mortality. However, the precise molecular pathways responsible for this close association remain poorly understood. METHODS AND RESULTS: In this study, we report that leptin-deficiency (ob/ob) in low-density lipoprotein receptor knockout (ldlr(-/-)) mice induces an unexpected 2.2- to 6-fold reduction in atherosclerotic lesion development, compared with ldlr(-/-) mice having similar total cholesterol levels. Ldlr(-/ )/ob/ob mice show reduced T cell helper type 1 (Th1) response, enhanced expression of Foxp3, the specification transcription factor of regulatory T (Treg) cells, and improved Treg cell function. Leptin receptor-deficient (db/db) mice display marked increase in the number and suppressive function of Treg cells. Supplementation of Treg-deficient lymphocytes with Treg cells from db/db mice in an experimental model of atherosclerosis induces a significant reduction of lesion size and a marked inhibition of interferon (INF)-gamma production, compared with supplementation by Treg cells from wild-type mice. CONCLUSIONS: These results identify a critical role for leptin/leptin receptor pathway in the modulation of the regulatory immune response in atherosclerosis, and suggest that alteration in regulatory immunity may predispose obese individuals to atherosclerosis. PMID- 17690316 TI - The problem of passenger genes in transgenic mice. PMID- 17690317 TI - Fatty liver: a novel component of the metabolic syndrome. AB - Although the epidemic of obesity has been accompanied by an increase in the prevalence of the metabolic syndrome, not all obese develop the syndrome and even lean individuals can be insulin resistant. Both lean and obese insulin resistant individuals have an excess of fat in the liver which is not attributable to alcohol or other known causes of liver disease, a condition defined as nonalcoholic fatty liver disease (NAFLD) by gastroenterologists. The fatty liver is insulin resistant. Liver fat is highly significantly and linearly correlated with all components of the metabolic syndrome independent of obesity. Overproduction of glucose, VLDL, CRP, and coagulation factors by the fatty liver could contribute to the excess risk of cardiovascular disease associated with the metabolic syndrome and NAFLD. Both of the latter conditions also increase the risk of type 2 diabetes and advanced liver disease. The reason why some deposit fat in the liver whereas others do not is poorly understood. Individuals with a fatty liver are more likely to have excess intraabdominal fat and inflammatory changes in adipose tissue. Intervention studies have shown that liver fat can be decreased by weight loss, PPARgamma agonists, and insulin therapy. PMID- 17690318 TI - Ubiquitin carboxyl-terminal hydrolase L1, a novel deubiquitinating enzyme in the vasculature, attenuates NF-kappaB activation. AB - OBJECTIVE: We identified a ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) gene, which encodes a deubiquitinating enzyme and is expressed in the vasculature, by functional screening of a human endothelial cell (EC) cDNA library. UCHL1 is expressed in neurons, and abnormalities in UCHL1 are responsible for inherited Parkinson's disease via its effects on the ubiquitin-proteasome system. Therefore, the goal of present study was to clarify the role of the UCHL1 gene in vascular remodeling by evaluating nuclear factor-kappaB (NF-kappaB) inactivation in ECs and vascular smooth muscle cells (VSMCs). METHODS AND RESULTS: From Northern blot and immunohistochemical analysis, the UCHL1 gene was endogenously expressed in vascular ECs, VSMCs, and brain tissue. Expression of UCHL1 was markedly increased in the neointima of the balloon-injured carotid artery and was also present in atherosclerotic lesions from human carotid arteries. Overexpression of the UCHL1 gene significantly attenuated tumor necrosis factor (TNF)-alpha-induced NF-kappaB activity in vascular cells and increased inhibitor of kappa B-alpha (IkappaB-alpha), possibly through the attenuation of IkappaB alpha ubiquitination, leading to decreased neointima in the balloon-injured artery. In contrast, knockdown of UCHL1 by small interfering RNA resulted in increased NF-kappaB activity in VSMCs. CONCLUSIONS: These data suggest that UCHL1 may partially attenuate vascular remodeling through inhibition of NF-kappaB activity. PMID- 17690319 TI - Multiple sclerosis: hyperintense lesions in the brain on nonenhanced T1-weighted MR images evidenced as areas of T1 shortening. AB - PURPOSE: To retrospectively document hyperintense lesions on nonenhanced T1 weighted magnetic resonance (MR) images in patients with multiple sclerosis (MS) and study their relationship to physical disability, disease course, and other MR markers of tissue damage (brain atrophy). MATERIALS AND METHODS: Institutional review board approval was obtained; informed consent was waived for this HIPAA compliant study, with 145 patients with MS (mean age, 43 years). Patients had relapsing-remitting (RR) (n=92) or secondary-progressive (SP) (n=49) MS; clinical course was unknown in four. Mean Expanded Disability Status Scale (EDSS) score was 3.5. T1 lesions were compared with normal white matter on nonenhanced images and judged hyperintense. Spearman rank correlation, Wilcoxon rank sum, and Fisher exact probability tests and analysis of variance and analysis of covariance (ANCOVA) were employed. RESULTS: At least one T1 hyperintense lesion was found in 113 patients (total, 340 lesions). Two-thirds of lesions had hyperintense rim; others were uniformly hyperintense. Lesions were more common in patients with SP MS (P=.003, Wilcoxon test) and correlated with EDSS score (Spearman rho=0.19, P=.04) and brain atrophy measures (total cortical atrophy, Spearman rho=0.42, P<.001; third ventricular width, Spearman rho=0.40, P<.001) but not disease duration (Spearman rho=0.038, P=.69). Lesions were more likely multiple in the SP versus RR group (P<.001, Fisher test). After adjustment for disease course, T1 hyperintense lesions remained associated with brain atrophy (Por=.50). Area under the ROC curve for the diagnosis of breast cancer was 0.64 for standard gray-scale US and power Doppler US, 0.67 for contrast-enhanced power Doppler US, 0.76 for mammography, and 0.78 for SHI (P>.20). Contrast enhancement was better with SHI than with power Doppler (100% vs 44% of lesions with good or excellent enhancement; P=.004). CONCLUSION: SHI appears to improve the diagnosis of breast cancer relative to conventional US and mammography, albeit on the basis of results in a very limited number of subjects. PMID- 17690325 TI - Reinventing radiology in a digital and molecular age: summary of proceedings of the Sixth Biannual Symposium of the International Society for Strategic Studies in Radiology (IS3R), August 25 27, 2005. PMID- 17690326 TI - Interleukin-5 priming of human eosinophils alters siglec-8 mediated apoptosis pathways. AB - Previously, we have identified the sequential activation of reactive oxygen species (ROS), mitochondria, and caspase-3, -8, and -9, in Siglec-8-mediated eosinophil apoptosis. Cytokine priming, which normally prolongs eosinophil survival, paradoxically potentiated this proapoptotic effect. The mechanisms of Siglec-8-mediated apoptosis after priming were therefore explored. Using IL-5 as the priming stimulus, the rate of Siglec-8-induced eosinophil apoptosis was found to be enhanced compared with unprimed cells, and mechanisms differed after IL-5 priming in that neither a pan-caspase inhibitor, nor a specific caspase-3 inhibitor, could override apoptosis. IL-5 priming also accelerated Siglec-8 mediated dissipation of mitochondrial membrane potential. Finally, both the mitochondrial electron transport inhibitor rotenone, and the ROS inhibitors diphenyleneiodonium and antimycin, completely inhibited Siglec-8-mediated apoptosis, even after IL-5 priming. These data demonstrate that IL-5 priming enhances Siglec-8-mediated mitochondrial and ROS-dependent eosinophil apoptosis and eliminates caspase dependence. The potential clinical implication of these findings is that cytokine priming, as often occurs in vivo in asthma and other hypereosinophilic disorders, may render eosinophils from such patients especially susceptible to the proapoptotic effects of a Siglec-8-engaging therapeutic agent. PMID- 17690327 TI - Macrophage Turnover Kinetics in the Lungs of Mice Infected with Streptococcus pneumoniae. AB - Streptococcus pneumoniae is the most prevalent cause of community-acquired pneumonia and is known to induce apoptosis and necrosis in macrophages in vivo. We analyzed the kinetics of alveolar and lung parenchymal macrophage replacement by newly recruited exudate macrophages in vehicle-treated and S. pneumoniae challenged bone marrow chimeric CD45.1 mice. After lethal irradiation, CD45.1 alloantigen-expressing recipient mice were transplanted with bone marrow cells from CD45.2 alloantigen-expressing donor mice. After only 24 hours of low-dose S. pneumoniae infection, approximately 60% of CD45.1(pos) recipient-type alveolar macrophages (AM) were replaced by CD45.2(pos) donor-type exudate AM in bronchoalveolar lavage fluid, and this increased to more than 80% on Day 7 of infection. In contrast, lung parenchymal macrophages of S. pneumoniae-infected chimeric CD45.1 mice were replaced by only about 10% by 24 hours, although this increased to over 80% by Days 3 to 7 of infection. This dramatic macrophage turnover was accompanied by early induction of apoptosis/necrosis in donor-type exudate AM peaking at 6 hours after infection, whereas peak apoptosis/necrosis induction in recipient-type AM was delayed until Day 7. Collectively, these data for the first time demonstrate that S. pneumoniae infection of the lung triggers a brisk turnover of both resident and recruited mononuclear phagocyte subsets, and suggest an important role of exudate but not resident macrophages in re establishing alveolar and lung homeostasis. PMID- 17690328 TI - Carbonic anhydrase II and alveolar fluid reabsorption during hypercapnia. AB - Carbonic anhydrase II (CAII) plays an important role in carbon dioxide metabolism and intracellular pH regulation. In this study, we provide evidence that CAII is expressed in both type I (AECI) and type II (AECII) alveolar epithelial cells by RT-PCR and Western blotting in freshly isolated rat cells. These results were further confirmed by double immunostaining with CAII antibodies and AECI- or AECII-specific markers in freshly isolated alveolar epithelial cells and rat lung tissues. Inhibition of CAII by acetazolamide or methazolamide delayed the decrease in the intracellular pH observed during hypercapnia in cultured AECI, AECII, and AECI-like cells. In an isolated-perfused rat lung model, alveolar fluid reabsorption significantly decreased during high CO(2) exposure, which was not prevented by carbonic anhydrase inhibition. Thus, we provide evidence that CAII is expressed in rat alveolar epithelial cells and does not regulate lung alveolar fluid reabsorption during hypercapnia. PMID- 17690329 TI - IL10 polymorphisms are associated with airflow obstruction in severe alpha1 antitrypsin deficiency. AB - Severe alpha(1)-antitrypsin (AAT) deficiency is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD), especially in individuals who smoke. There is marked variability in the development of lung disease in individuals homozygous (PI ZZ) for this autosomal recessive condition, suggesting that modifier genes could be important. We hypothesized that genetic determinants of obstructive lung disease may be modifiers of airflow obstruction in individuals with severe AAT deficiency. To identify modifier genes, we performed family-based association analyses for 10 genes previously associated with asthma and/or COPD, including IL10, TNF, GSTP1, NOS1, NOS3, SERPINA3, SERPINE2, SFTPB, TGFB1, and EPHX1. All analyses were performed in a cohort of 378 PI ZZ individuals from 167 families. Quantitative spirometric phenotypes included forced expiratory volume in one second (FEV(1)) and the ratio of FEV(1)/forced vital capacity (FVC). A qualitative phenotype of moderate-to-severe COPD was defined for individuals with FEV(1) or = 119 nM, and six isolates had low IC(50)s (five wild-type or mixed dhfr, 0.04-1.37 nM; one triple mutant, 6.4 nM). Of 194 isolates, only 7 had the wild-type dhfr and 187 were mutants. The results of the two methods were highly concordant and indicated a significant increase (P < 0.05) in the prevalence of mutant, pyrimethamine-resistant P. falciparum between 1994 and 2005. The addition of probenecid or sulfinpyrazone to pyrimethamine resulted in a slight-to-moderate decrease in the level of in vitro pyrimethamine resistance without rendering the parasites susceptible to pyrimethamine. Analysis of molecular markers may be useful for the long-term surveillance of antifolate-resistant malaria. PMID- 17690391 TI - Prevalence and predictors of maternal peripheral malaria parasitemia in central Mozambique. AB - Malaria infection during pregnancy (MiP) is heterogeneously distributed even in malaria-endemic countries. Program planners require data to facilitate identification of highest-priority populations for MiP control. Using data from two cross-sectional studies of 5,528 pregnant women in 8 neighboring sites in Mozambique, we described factors associated with maternal peripheral parasitemia by using logistic regression. Principal multivariate predictors of maternal peripheral parasitemia were gravidity (odds ratio [OR] = 2.29, 95% confidence interval [CI] = 1.60-3.26 for primigravidae and OR = 1.61, 95% CI = 1.29-2.01 for secundigravidae compared with gravidity > or = 3); age (OR = 0.96 per year, 95% CI = 0.94-0.99); study site (OR = 1.45, 95% CI = 1.34-1.56 to 5.32, 95% CI = 4.92 5.75) for comparison with the reference site; and no maternal education (OR = 1.38, 95% CI = 1.15-1.66) compared with any education. Other predictors (in subgroups) were bed net use (OR = 0.49, 95% CI = 0.48-0.50); preventive sulfadoxine-pyrimethamine doses (OR = 0.25, 95% CI = 0.24-0.25); and infection with human immunodeficiency virus (HIV) (OR = 1.49, 95% CI = 1.11-2.00). Programmatic priorities should respond to heterogeneous distribution of multiple risk factors, including prevalence of malaria and infection with HIV, and maternal socioeconomic status. PMID- 17690392 TI - Therapeutic efficacy and effects of artemether-lumefantrine and amodiaquine sulfalene-pyrimethamine on gametocyte carriage in children with uncomplicated Plasmodium falciparum malaria in southwestern Nigeria. AB - The treatment efficacy and effects of artemether-lumefantrine (AL) and amodiaquine-sulfalene-pyrimethamine (ASP) on gametocyte carriage were evaluated in 181 children < or = 10 years of age with uncomplicated Plasmodium falciparum malaria randomized to receive either drug combination. All children recovered clinically. Fever clearance times were similar. The rate of P. falciparum reappearance (recrudescence or re-infection) between two and six weeks after the start of therapy was significantly higher in AL-treated children (P = 0.01). Parasite clearance was significantly faster in children treated with AL (mean +/- SD = 1.7 +/- 0.6 days, 95% confidence interval = 1.58 - 1.83, P = 0.0001) but the polymerase chain reaction-corrected cure rate (90 of 91 versus 84 of 90) and the rate of resolution of malaria-related anemia two weeks after treatment began (45 of 50 versus 33 of 46) were higher in children treated with ASP. Gametocyte carriage rates were similar. Both regimens were well tolerated. Artemether lumefantrine clears parasitemia more rapidly than ASP but both combinations are effective in treatment of uncomplicated P. falciparum malaria in Nigerian children. PMID- 17690393 TI - Effects of anticoagulants on Plasmodium vivax oocyst development in Anopheles albimanus mosquitoes. AB - Artificial membrane feeding (AMF) assays are used to determine malaria transmission-blocking activity in Anopheles. The purpose of this study was to determine the effect of the most widely used anticoagulants, EDTA and heparin, on development of the Plasmodium vivax sporogonic cycle. Blood samples collected from 60 patients carrying P. vivax infections were used to feed An. albimanus using AMF. Seven days after feeding, mosquitoes were dissected to assess mosquito infection. Mosquitoes fed with blood containing EDTA showed a lower mean oocyst number as compared with those fed blood with heparin. However, this effect was minimized upon reduction of EDTA concentrations in the serum. This result may be explained by the fact that microgametocytes require Ca(2+), Mn(2+), and Mg(+2) to activate enzymes important for exflagellation process and for motility of ookinetes. We therefore recommend that heparin be used as the anticoagulant of choice for blood used in AMF assays. PMID- 17690394 TI - Parasite prevalence: a static measure of dynamic infections. AB - The intensity of malaria transmission is often measured by looking at the fraction of individuals infected at a given point in time. However, malaria infections in individuals are dynamic, leading to uncertainty about whether a cross-sectional survey that represents a single snapshot in time is a useful representation of a temporally complex process. In this analysis, we examine the impact of parasite density fluctuations on the measurement of parasite prevalence. Our results show that parasite prevalence may be underestimated by 20% or more, depending on the sensitivity of parasite detection. PMID- 17690395 TI - A polymerase chain reaction/ligase detection reaction fluorescent microsphere assay to determine Plasmodium falciparum MSP-119 haplotypes. AB - The merozoite surface protein-1 (MSP-1) is a blood stage antigen currently being tested as a vaccine against Plasmodium falciparum malaria. Determining the MSP 1(19) haplotype(s) present during infection is essential for assessments of MSP-1 vaccine efficacy and studies of protective immunity in human populations. The C terminal fragment (MSP-1(19)) has four predominant haplotypes based on point mutations resulting in non-synonymous amino acid changes: E-TSR (PNG-MAD20 type), E-KNG (Uganda-PA type), Q-KNG (Wellcome type), and Q-TSR (Indo type). Current techniques using direct DNA sequencing are laborious and expensive. We present an MSP-1(19) allele-specific polymerase chain reaction (PCR)/ligase detection reaction-fluorescent microsphere assay (LDR-FMA) that allows simultaneous detection of the four predominant MSP-1(19) haplotypes with a sensitivity and specificity comparable with other molecular methods and a semi-quantitative determination of haplotype contribution in mixed infections. Application of this method is an inexpensive, accurate, and high-throughput alternative to distinguish the predominant MSP-1(19) haplotypes in epidemiologic studies. PMID- 17690396 TI - Metabolic acidosis and other determinants of hemoglobin-oxygen dissociation in severe childhood Plasmodium falciparum malaria. AB - Metabolic acidosis is a common complication of severe malaria caused by Plasmodium falciparum. The factors contributing to the acidosis were assessed in 62 children with severe falciparum malaria (cases) and in 29 control children who had recently recovered from mild or moderate malaria. The acidosis was largely caused by the accumulation of both lactic and 3-hydroxybutyric acids. The determinants of oxygen release to the tissues were also examined; although there was no difference between cases and controls in respect of 2,3 bisphosphoglycerate and mean corpuscular hemoglobin concentration, there was a marked increase in P(50) in the cases, caused by pyrexia, low pH, and base deficit. There was substantial relative or actual hypoglycemia in many cases. The relationship of these observations to therapeutic strategy is discussed. PMID- 17690397 TI - Adaptation of a multi-drug resistant strain of Plasmodium falciparum from Peru to Aotus lemurinus griseimembra, A. nancymaae, and A. vociferans monkeys. AB - A strain of Plasmodium falciparum from Peru was adapted to splenectomized Aotus nancymaae and Aotus vociferans monkeys. The Peru 134/CDC strain of P. falciparum was shown to be resistant to treatment with chloroquine in monkeys and partially resistant to mefloquine and malarone. Genetic mutations in crt, dhfr, dhps, and cytochrome b genes conferring drug resistance were also determined for this Peruvian strain of P. falciparum. PMID- 17690398 TI - Treatment of mucosal leishmaniasis in Latin America: systematic review. AB - Mucosal leishmaniasis (ML) is an important endemic disease and public-health problem in underdeveloped countries because of its significant morbidity and mortality. Increases in ecological tourism have extended this problem to developed countries. This form of leishmaniasis, caused by reactivation after primary cutaneous lesion, has a natural history of progressive destruction of the nasal septa and soft and hard palates, causing facial disfiguration and leading to respiratory disturbances. Treatment of ML, based on several therapies, depends on use of toxic compounds, and few drugs have emerged over the past 40 years. Drug resistance has increased, and the cure rate is no better than 70% in the largest studies. Despite these data, there has been no systematic review of therapies used to treat this important tropical disease. The aim of this study is to determine the best drug management for treatment of ML in Latin America based on the best studies offered by the medical literature. The MEDLINE, LILACS, EMBASE, Web of Science, and Cochrane Library databases were searched to identify articles related to ML and therapy. The studies were independently selected by 2 authors. Articles with sufficient data for cure and treatment failures, internal and external validity information, and > 4 patients in each treatment were included. Validation of this systematic review was based on guidelines to guarantee quality; 22 articles met our inclusion criteria. Stibogluconate achieved a 51% cure rate (76/150 patients), and 88% of patients treated with meglumine were cured (121 patients). Pentamidine and amphotericin were as effective as meglumine. Use of itraconazole and other therapies (pentoxifylline, allopurinol, or interferon-gamma) was controversial, and numbers of patients in some studies were insufficient for statistical analysis. Meglumine may be the drug of choice in the treatment of ML, as it offers similar cure rates when compared with amphotericin B and pentamidine. Cost, adverse effects, local experience, and availability of drugs to treat ML are strong points to be considered before determining the best management of this disease, especially in developing countries. PMID- 17690399 TI - Kala-azar outbreak in Libo Kemkem, Ethiopia: epidemiologic and parasitologic assessment. AB - In May 2005, visceral leishmaniasis (VL) was recognized for the first time in Libo Kemkem, Ethiopia. In October 2005, a rapid assessment was conducted using data from 492 patients with VL treated in the district health center and a household survey of 584 residents of four villages. One subdistrict accounted for 71% of early cases, but the incidence and number of affected subdistricts increased progressively throughout 2004-2005. In household-based data, we identified 9 treated VL cases, 12 current untreated cases, and 19 deaths attributable to VL (cumulative incidence, 7%). Thirty percent of participants were leishmanin skin test positive (men, 34%; women, 26%; P = 0.06). VL was more common in men than women (9.7% versus 4.5%, P < 0.05), possibly reflecting male outdoor sleeping habits. Molecular typing in splenic aspirates showed L. infantum (six) and L. donovani (one). Local transmission resulted from multiple introductions, is now well established, and will be difficult to eradicate. PMID- 17690400 TI - Evidence that the 45-kD glycoprotein, part of a putative dengue virus receptor complex in the mosquito cell line C6/36, is a heat-shock related protein. AB - Dengue virus (DENV) is transmitted to humans by mosquitoes of the genus Aedes. Although several molecules have been described as part of DENV receptor complex in mosquito cells, none of them have been identified. Our group characterized two glycoproteins (40 and 45 kD) as part of the DENV receptor complex in C6/36 cells. Because identification of the mosquito cell receptor has been unsuccessful and some cell receptors described for DENV in mammalian cells are heat-shock proteins (HSPs), the role of HSPs in DENV binding and infection in C6/36 cells was evaluated. Our results indicate that gp45 and a 74-kD molecule (p74), which interact with DENV envelope protein, are immunologically related to HSP90. Although p74 is induced by heat shock, gp45 apparently is not. However, these proteins are relocated to the cell surface after heat-shock treatment, causing an increase in virus binding without any effect on virus yield. PMID- 17690401 TI - Chest radiographic presentation in patients with dengue hemorrhagic Fever. AB - There has been no previously reported case series study regarding chest radiographic (CXR) presentations in dengue hemorrhagic fever (DHF) patients. We retrospectively studied 363 DHF patients from June to December 2002 in southern Taiwan, and a total of 468 CXRs were obtained and reviewed. More than 50% of these showed abnormalities after the 3rd day, with infiltration only and small pleural effusion as the major findings. Progressive changes during the first week and improvements during the second week were observed in these abnormal CXRs. The CXR presentation was also significantly correlated with laboratory findings (white blood cell count, platelet levels, activated partial thromboplastin time, and alanine aminotransferase and albumin levels), as well as the clinical course (renal insufficiency, liver function impairment, upper gastrointestinal bleeding, combination bacterial infection, and duration of admission) and outcome (mortality). The CXR may therefore be a modality for evaluating the clinical course of DHF and should be made during first week after the onset of illness. PMID- 17690402 TI - Implications of dynamic changes among tumor necrosis factor-alpha (TNF-alpha), membrane TNF receptor, and soluble TNF receptor levels in regard to the severity of dengue infection. AB - Tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptors (sTNFR1 and sTNFR2) have been implicated in infectious diseases. We investigated dynamic changes among TNF-alpha, membrane TNF receptors (mTNFR1 and mTNFR2), and sTNFR1 and sTNFR2 levels for patients with dengue hemorrhagic fever (DHF) and those not infected during a DEN-2 outbreak in southern Taiwan in 2002-2003. Patients with DHF showed the lowest levels of mTNFR1 and mTNFR2 expression. Multivariate analysis showed that a decrease in levels of mTNFR1 expression was the only factor significantly different between patients with DHF and those with dengue fever. Moreover, lower mTNFR1 expression was significantly correlated with higher plasma TNF-alpha levels, but not with sTNFR1 levels in patients with DHF. This finding suggests that a lower level of mTNFR1 expression in response to a higher plasma TNF-alpha level may be a pathogenic marker for early detection of DHF. PMID- 17690403 TI - Low gene flow of Aedes aegypti between dengue-endemic and dengue-free areas in southeastern and southern Brazil. AB - We present a population genetic study of Aedes aegypti in Brazil using isoenzyme markers. Four polymorphic loci were used to examine 11 mosquito collections at four periods in 2003. Samples from a dengue-endemic area (southeastern region) and a dengue-free area (southern region) connected by an important network of roads and railways were analyzed. The degree of genetic differentiation observed between populations is consistent with limited gene flow between them. There was no evidence of passive dispersion of Ae. aegypti by vehicles among the different routes linking metropolitan areas. PMID- 17690404 TI - Analysis of the population genetic structure of the malaria vector Anopheles sinensis in South Korea based on mitochondrial sequences. AB - The population genetics of Anopheles sinensis, a major malaria vector in South Korea, was studied based on the nucleotide sequences of a 238-bp variable region of the mitochondrial control region. Three features of genetic variance were observed. First, the Taebaek and Sobaek mountain ranges may function as genetic barriers between the Northern Group (NG) and the Southern Group (SG). These mountain ranges are associated with the subdivision of the population, and significant and unique population differentiation was observed in the examined area. Second, the genetic cohesiveness observed within each group may have been caused by a recent expansion in the population rather than recurrent gene flow. Third, a marked dissimilarity in the genetic diversity between the two groups may also have resulted from several factors that caused a difference in the effective population sizes. PMID- 17690405 TI - Spatial and temporal genetic structure of Anopheles arabiensis in Southern Zambia over consecutive wet and drought years. AB - No studies have addressed the spatial complexity of Anopheles arabiensis populations in Zambia or the effects of drought on the genetic structure of this species. We genotyped approximately 420 An. arabiensis at 12 microsatellite loci representing 18 collections from the Southern Province of Zambia. Collections spanned three transmission seasons and covered a wet year-drought year-wet year cycle. Anopheles arabiensis within the 2,000 km(2) of the Macha study region were panmictic, with high gene flow between Macha and Namwala, Zambia, which are 80 km apart. There was little evidence for genetic structuring among years, with no significant shifts in allele frequency distributions or observed heterozygosity, and no evidence for a genetic bottleneck despite a drastic reduction in mosquito numbers during the drought year. Anopheles arabiensis in southern Zambia has a large deme size, and the regional genetic structure of this species was little affected by an extended drought period. PMID- 17690406 TI - Establishment of a mass screening method of sand fly vectors for Leishmania infection by molecular biological methods. AB - Surveillance of the prevalence of Leishmania and its vector, sand fly species, in endemic and surrounding areas is important for prediction of the risk and expansion of leishmaniasis. In this study, a method for the mass screening of sand flies for Leishmania infection was established. This method was applied to 319 field-captured specimens, and 5 positive sand flies were detected. Sand fly species were identified by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) of the18S rRNA gene, and all the positive flies were Lu. hartmanni. Furthermore, cytochrome b (Cyt b) gene sequence analyses identified all the parasites as Endotrypanum species including a probable novel species. Because the method requires minimum effort and can process a large number of samples at once, it will be a powerful tool for studying the epidemiology of leishmaniasis. PMID- 17690407 TI - Confirmation of elimination of lymphatic filariasis by an IgG4 enzyme-linked immunosorbent assay with urine samples in Yongjia, Zhejiang Province and Gaoan, Jiangxi Province, People's Republic of China. AB - A sensitive and specific IgG4 enzyme-linked immunosorbent assay (ELISA) with urine samples has been reported. To confirm elimination of bancroftian filariasis, the ELISA was used in a study conducted in Yongjia County and Gaoan City, People's Republic of China, where filariasis elimination was declared, with 10,409 students 5-16 years of age. The antibody positive rates were 0.08% in Yongjia and 0.34% in Gaoan. All positive samples were re-examined and found to be negative. Our results show that this ELISA is practical and useful for confirmation of the elimination of filariasis. If similar results are obtained in different filariasis-endemic countries, this method may be useful in global filariasis elimination programs. PMID- 17690408 TI - Elimination of Onchocercia volvulus transmission in the Santa Rosa focus of Guatemala. AB - To eliminate transmission of Onchocerca volvulus, semiannual mass treatment with ivermectin (Mectizan; donated by Merck & Co) has been underway in Guatemala since 2000. We applied the 2001 World Health Organization (WHO) elimination criteria in the Santa Rosa focus of onchocerciasis transmission in Guatemala (10,923 persons at risk). No evidence of parasite DNA was found in 2,221 Simulium ochraceum vectors (one-sided 95% confidence interval [CI], 0-0.086%), and no IgG4 antibody positives to recombinant antigen OV16 were found in a sample of 3,232 school children (95% CI, 0-0.009%). We also found no evidence of microfilariae in the anterior segment of the eye in 363 area residents (95% CI, 0-0.08%). Our interpretation of these data, together with historical information, suggest that transmission of O. volvulus is permanently interrupted in Santa Rosa and that ivermectin treatments there can be halted. PMID- 17690409 TI - Taeniasis in Mongolia, 2002-2006. AB - Survey on secondary data of taeniasis/cysticercosis was carried out in Mongolia in 2002-2006. A total of 118 taeniid proglottids, a diphyllobothriid segment, and 59 serum samples from 118 taeniasis cases were collected at National Center for Communicable Diseases, Ulaanbaatar, Mongolia. In 2006, 14 serum samples were collected from local people who had histories of epileptic seizures in Selenge Province where pig husbandry was the main business. The 118 proglottids were confirmed to be Taenia saginata by mitochondrial DNA analysis using cytochrome c oxidase subunit 1 and cytochrome b genes. T. saginata taeniasis was widely distributed at least in 10 of 21 provinces. No variation in the nucleotide sequences of the two genes was observed among T. saginata isolates from Mongolia. There was no evidence of Taenia solium taeniasis/cysticercosis or Taenia asiatica taeniasis. A diphyllobothriid segment was confirmed to be Diphyllobothrium latum by mitochondrial DNA analysis. PMID- 17690410 TI - A probable case of human neurotrichinellosis in the United States. AB - Human neurotrichinellosis is seldom reported. This is likely the result of the low incidence of parasites from the genus Trichinella in the United States domestic food supply, as well as difficulties in diagnosing the disease, especially when neither the organism nor the source of the infection are readily available. Although trichinellosis from domestic food supplies has been decreasing for many years, a resurgence has occurred in cases derived from the consumption of wild game. We report a rare case of neurotrichinellosis in the United States and implicate wild game as the source of the infection. These results suggest that clinicians should consider the potential for Trichinella infection in cases where wild game is common in the diets of the patients. PMID- 17690411 TI - Voriconazole as therapy for systemic Penicillium marneffei infections in AIDS patients. AB - The objective of this study was to evaluate the triazole anti-fungal agent, voriconazole, as therapy for systemic Penicillium marneffei infections in patients with advanced HIV infection. Patients with systemic P. marneffei infection were enrolled into a study of voriconazole for the treatment of less common, emerging, or refractory fungal infections. Patients were eligible for inclusion in the study on the basis that no anti-fungal agents have received regulatory approval specifically for P. marneffei infections. Patients were treated in the hospital setting with intravenous voriconazole (6 mg/kg every 12 hours on Day 1 and then 4 mg/kg every 12 hours for at least 3 days, after which patients could switch to oral therapy at 200 mg twice a day) or as outpatients with oral voriconazole (400 mg twice a day on Day 1 and then 200 mg twice a day) for a maximum of 12 weeks. Eleven patients received treatment with voriconazole. Two received short courses of intravenous therapy followed by the oral formulation; nine were treated with oral voriconazole only. At the end of therapy, eight of the nine evaluable patients had favorable response to therapy, based on mycological and clinical findings. There were no relapses of P. marneffei infection in the six patients who were seen at follow-up within 4 weeks of the end of therapy. Treatment with voriconazole was well tolerated, with no discontinuations caused by drug-related adverse events. The results of this study suggest that voriconazole is an effective, well-tolerated, and convenient option for the treatment of systemic infections with P. marneffei. PMID- 17690412 TI - Seroprevalence of antibodies to parvovirus B19 among children in Papua New Guinea. AB - Parvovirus B19 (B19) is a common childhood infection that has recently been found to be associated with severe anemia in Papua New Guinean children. Population surveys were performed in 15 villages in Maprik district, East Sepik Province, Papua New Guinea in 2005. Plasma samples collected from children less than 10 years of age were tested for IgM and IgG antibodies to B19 by enzyme immunoassay. The prevalence of IgG antibody to B19 was 53.8% and ranged from 20% in those less than one year of age to 85.5% in those nine years of age. Considerable variation in IgG prevalence was observed between study areas, indicating complex patterns of transmission. Prevalence of IgM antibody to B19 was 1.5%. This study confirms that B19 infection is common among children in this tropical area. With 19.5% of children one year of age showing evidence of previous infection, any preventive measures should be targeted at the very young. PMID- 17690413 TI - Serologic evidence of West Nile virus infections in wild birds captured in Germany. AB - To assess the risk of acquiring a West Nile virus (WNV) infection in Germany, we investigated samples from migrating and from resident birds. Because of their stay in or migration through WNV-endemic regions, these birds are at risk to become infected with WNV. Blood samples from 3,399 birds, representing 87 bird species, were collected in Germany in 2000 and in 2002-2005. Overall, 53 birds belonging to 5 species had WNV-neutralizing antibodies. Fifty-nine birds belonging to 9 species were reactive by WNV immunofluorescence assay, and 8 birds had neutralizing antibodies against Usutu virus. Because of maternal antibody transfer via egg yolk, WNV-antibody titers in white stork nestlings were generally lower than those in adults. Despite a relatively high percentage of stork nestlings with antibodies, no viral genomes were detectable by polymerase chain reaction. In Germany, the prevalence of antibodies to WNV in migrating birds wintering in Africa or southern Europe is comparatively low. PMID- 17690414 TI - A newly emergent genotype of West Nile virus is transmitted earlier and more efficiently by Culex mosquitoes. AB - Studies examining the evolution of West Nile virus since its introduction into North America have identified the emergence of a new dominant genotype (WN02) that has displaced the introduced genotype (NY99). The mechanistic basis for this displacement, however, remains obscure. Although we found no detectable difference in vitro between the genotypes in either replication or fitness, there were significant differences in vivo in Culex mosquitoes. After peroral infection, the extrinsic incubation period (EIP) of the WN02 genotype was up to 4 days shorter than the EIP of the NY99 genotype; however, after intrathoracic inoculation, there was no difference in EIP between the genotypes, suggesting that differences in genotype interaction with the mosquito midgut are likely to play a role in this phenotype. These results suggest a model for the displacement of the NY99 genotype, where earlier transmission of WN02 viruses leads to higher WN02 infection rates in avian reservoir hosts. PMID- 17690415 TI - Prevalence of anti-hantavirus antibodies in patients with hypertransaminemia in Madrid (Spain). AB - The hantaviruses are involved in a number of clinical syndromes of different severity and prognosis. Hantaviruses are widely distributed around the world, but the spectrum of illnesses they cause outside recognized endemic areas is unclear. A retrospective analysis was performed to detect anti-hantavirus antibodies in the serum of patients with hypertransaminemia of unknown etiology and in that of healthy members of the general population of Madrid (Spain). Antibodies were detected by indirect immunofluorescence and enzyme immunoassay; positive results were confirmed by Western blotting. Of the 182 patients with hypertransaminemia, 11 (6%) were positive for anti-hantavirus IgG antibodies; Western blotting using recombinant Puumala virus N antigen showed one of these patients to have hantavirus-specific IgM antibodies. Among the 146 healthy subjects from the general population, 3 (2%) were positive for anti-hantavirus IgG antibodies. These results show that anti-hantavirus antibodies are more commonly detected in patients with hypertransaminemia than in healthy people. PMID- 17690416 TI - Detection of Rickettsia africae in Rhipicephalus (Boophilus) decoloratus ticks from the Republic of Botswana, South Africa. AB - A total of 53 engorged adult ticks belonging to the species Rhipicephalus (Boophilus) decoloratus (N = 9), Rhipicephalus evertsi evertsi (N = 27), Rhipicephalus appendiculatus (N = 9), Amblyomma hebraeum (N = 5), and Hyalomma marginatum turanicum (N = 3), were removed from oryx in Botswana (South Africa). They were tested for the presence of spotted fever group (SFG) Rickettsia and Anaplasma phagocytophilum using polymerase chain reaction (PCR). Seventy-seven percent of R. decoloratus as well as twenty percent of A. hebraeum were positive for ompA, gltA and 16S rRNA SFG Rickettsia PCR assays. All nucleotide sequences were homologous to Rickettsia africae, the agent of African tick-bite fever (ATBF). None of the tested ticks was positive for 16S rRNA A. phagocytophilum PCR assays. These results suggest for the first time that R. decoloratus ticks may be reservoirs of R. africae, and support the ATBF risk in this area. PMID- 17690417 TI - Prevalence of antibodies against spotted fever group rickettsiae in a rural area of Colombia. AB - We recently rediscovered Rocky Mountain spotted fever in Villeta, Colombia, near the same locality (Tobia) where it was first recognized in 1937. To have a better idea of the magnitude of this problem, sera from 392 randomly recruited healthy adults from Villeta were analyzed by indirect immunofluorescent antibody assay to detect IgG against Rickettsia rickettsii as antigen. The seropositivity rate for spotted fever group rickettsiae was 40.3%. We did not find any association between the presence of antibodies to spotted fever group rickettsiae and several demographic and epidemiologic variables, which could be a reflection of unique features of this area. PMID- 17690418 TI - Experience with intravenous metronidazole to treat moderate-to-severe amebiasis in Japan. AB - Twenty-eight cases of either intestinal amebiasis, amebic liver abscess, or both, most of which were of moderate-to-severe intensity, were treated with intravenous metronidazole, pioneered by the Research Group on Chemotherapy of Tropical Diseases, Japan. This study was not conducted as a formal clinical trial, and all patients either underwent colectomy for intestinal amebiasis, received oral metronidazole, or both. Despite these limitations, intravenous metronidazole was shown to be well tolerated and seemed to be very effective. This agent should be more widely recommended than previously thought for treating moderate-to-severe amebiasis, especially its intestinal form. PMID- 17690419 TI - Signs and symptoms predictive of respiratory failure in patients with foodborne botulism in Thailand. AB - We conducted a clinical study of 137 patients with home-canned bamboo shoot botulism at Nan Hospital, northern Thailand. The median age of the patients was 44 years (range = 14-74 years) and 36.2% were male. The median incubation period was 2 days (range = 1-8 days). Forty-three patients (31.4%) developed respiratory failure, but there were no deaths. Patients who did not have either nausea or vomiting and did not have urinary retention that required Foley catheterization was less likely to develop respiratory failure. This clinical predictor rule had a sensitivity of 75.5% and a specificity of 90.7%. The clinical syndrome most predictive of respiratory failure was nausea or vomiting and any cranial neuropathy with urinary retention or difficulty swallowing. This clinical syndrome had a sensitivity of 69.8% and a specificity of 93.6%. These clinical characteristics could help triage large numbers of patient in the event of a future outbreak. PMID- 17690420 TI - Concurrent infections in acute febrile illness patients in Egypt. AB - We report the occurrence of concurrent infections with multiple acute febrile illness (AFI) pathogens during an ongoing prospective laboratory-based surveillance in four infectious disease hospitals in urban and rural areas of Egypt from June 2005 to August 2006. Patients were screened for Leptospira, Rickettsia typhi, Brucella, or Salmonella enterica serogroup Typhi by various methods including serology, culture, and PCR. One hundred eighty-seven of 1,510 patients (12.4%) evaluated had supporting evidence for the presence of co infections; 20 (1%) of these patients had 2 or more pathogens based upon confirmatory 4-fold rise in antibody titer, culture, and/or PCR. Most coinfected patients lived or worked in rural agricultural areas. The high coinfection rates suggest that defining the etiologies of AFI is imperative in guiding proper disease treatment, prevention, and control strategies in Egypt. PMID- 17690421 TI - Use of handheld computers with global positioning systems for probability sampling and data entry in household surveys. AB - We introduce an innovative method that uses personal digital assistants (PDAs) equipped with global positioning system (GPS) units in household surveys to select a probability-based sample and perform PDA-based interviews. Our approach uses PDAs with GPS to rapidly map all households in selected areas, choose a random sample, and navigate back to the sampled households to conduct an interview. We present recent field experience in two large-scale nationally representative household surveys to assess insecticide-treated bed net coverage as part of malaria control efforts in Africa. The successful application of this method resulted in statistically valid samples; quality-controlled data entry; and rapid aggregation, analyses, and availability of preliminary results within days of completing the field work. We propose this method as an alternative to the Expanded Program on Immunization cluster sample method when a fast, statistically valid survey is required in an environment with little census information at the enumeration area level. PMID- 17690422 TI - Tetanus-induced acute kidney injury in a renal transplant recipient. AB - A 48-year-old renal transplant recipient who developed tetanus 6 years after transplantation is described. His immunosuppressive protocol was mofetil mycophenolate, sirolimus, and prednisone. The patient presented symptoms of severe tetanus with autonomic dysfunction, requiring ICU care and mechanical ventilation. His clinical course was marked by development of tetanus-induced acute kidney injury and sepsis. He was discharged after 37 days of hospitalization with recovered renal function. Tetanus is a preventable disease associated with a high fatality rate. Its treatment is difficult and requires specialized and intensive care. This case highlights the crucial importance of following adequate immunization guidelines in transplant recipients. PMID- 17690423 TI - Analysis of liquid structure without construction of any structure models by the X-ray scattering method. AB - A simple approach for determining a liquid structure using X-ray scattering data, in which a liquid structure is uniquely evaluated without construction of any plausible structure models, has been applied to liquid acetonitrile, acetone and cyclohexane. For a pair of molecules, a given point within a molecule is located at the origin with a given molecular orientation. The site of the given point of another molecule is defined by the polar coordinates and the molecular orientation is treated by three Eulerian angles. These parameters are optimized by a non-linear least-squares calculation applied to X-ray scattering data. The reliability of the method was examined by determining the liquid structure of polar acetonitrile and the obtained intermolecular interatomic distances are in good agreement with the previously reported values. The method was then successfully applied to the determination of the liquid structure of acetone and cyclohexane. Especially for nonpolar cyclohexane, the construction of a variety of plausible structural models is very difficult. It was revealed that acetone has an ordered liquid arrangement similar to that found in its crystal, although the intermolecular distances in liquid acetone are different from those in the crystal. On the other hand, the liquid structure of cyclohexane is disordered. PMID- 17690424 TI - Quantitative structure-property relationship study of the solvent polarity using wavelet neural networks. AB - Quantitative structure-property relationship (QSPR) studies based on artificial neural network (ANN) and wavelet neural network (WNN) techniques were carried out for the prediction of solvent polarity. Experimental S' values for 69 solvents were assembled. This set included saturated and unsaturated hydrocarbons, solvents containing halogen, cyano, nitro, amide, sulfide, mercapto, sulfone, phosphate, ester, ether, etc. Semi-empirical quantum chemical calculations at AM1 level were used to find the optimum 3D geometry of the studied molecules and different quantum-chemical descriptors were calculated by the HyperChem software. A stepwise MLR method was used to select the best descriptors and the selected descriptors were used as input neurons in neural network models. The results obtained by the two methods were compared and it was shown that in WNN, the convergence speed was faster and the root mean square error of prediction set was also smaller than ANN. The average relative error in WNN was 7.9 and 6.8% for calibration and prediction set, respectively, and the results showed the ability of the WNN developed here to predict solvent polarity. PMID- 17690425 TI - Photoreactivity of amino acids: tryptophan-induced photochemical events via reactive oxygen species generation. AB - Tryptophan (Trp), an aromatic amino acid, is a constituent of peptides/proteins and is also a precursor of serotonin, kynurenine derivatives, and nicotinamide adenine dinucleotides. There have been a number of reports on photochemical reactions involving peptides/proteins which contain Trp that showed significant photodegradation, dimerization, and photoionization. The photochemical properties of Trp have not been fully elucidated, and this would provide novel insight into the handling of Trp-containing peptides/proteins. Consequently, we have been trying to evaluate the photochemical properties of Trp, as well as other essential amino acids, focusing on their photosensitivity, photodegradation, and their ability to induce lipid peroxidation. Among all the essential amino acids tested, Trp exhibited the maximal level of superoxide anion generation under 18 h of light exposure (30000 lux). UV spectral analysis of Trp suggested the absorbability of UVA/B light, and exposure of Trp, in both solid and solution states, to UVA/B light resulted in significant photodegradation (t(0.5): 18 h) and gradual color changes. In addition, photoirradiated Trp generated lipoperoxidant, a causative agent of photoirritation, and this might be associated with ROS generation. PMID- 17690426 TI - Selective determination of tryptophan-containing peptides through precolumn derivatization and liquid chromatography using intramolecular fluorescence resonance energy transfer detection. AB - A selective and sensitive fluorometric determination method for native fluorescent peptides has been developed. This method is based on intramolecular fluorescence resonance energy transfer (FRET) detection in a liquid chromatography (LC) system following precolumn derivatization of the amino groups of tryptophan (Trp)-containing peptides. In this detection process, we monitored the FRET from the native fluorescent Trp moieties (donor) to the derivatized fluorophore (acceptor). From a screening study involving 10 fluorescent reagents, we found that o-phthalaldehyde (OPA) generated FRET most effectively. The OPA derivatives of the native fluorescent peptides emitted OPA fluorescence (445 nm) through an intramolecular FRET process when they were excited at the excitation maximum wavelength of the Trp-containing peptides (280 nm). The generation of FRET was confirmed through comparison with the analysis of a non-fluorescent peptide (C-reactive protein fragment (77 - 82)) performed using LC and a three dimensional fluorescence detection system. We were able to separate the OPA derivatives of the Trp-containing peptides when performing LC on a reversed-phase column. The detection limits (signal-to-noise ratio = 3) for the Trp-containing peptides, at a 20-microL injection volume, were 41 - 180 fmol. The sensitivity of the intramolecular FRET-forming derivatization method is higher than that of the system that takes advantage of the conventional detection of OPA derivatives. Moreover, native non-fluorescent amines and peptides in the sample monitored at FRET detection are weaker than those of conventional fluorescence detection. PMID- 17690427 TI - Qualitative and quantitative assessment of the HPLC fingerprints of Ginkgo biloba extract by the involution similarity method. AB - In this paper, we develop a new method for evaluating chromatographic fingerprints of traditional Chinese medicine (TCM) by the average involution similarity and the quantitative involution similarity. To validate this novel approach, we studied the chromatographic fingerprints of Ginkgo biloba extract by the new similarity parameters. The results were compared with those of the cosine of vectorial angle (S(F)), the correlative coefficient (r) and some other quantitative parameters, such as the apparent quantitative similarity of fingerprint R% and the average mass percentage M%. The approach represented in this paper was proved to well reflect the similarity alteration of each batch of Ginkgo biloba extract and the quantitative differences of the extracted constituents. The S(gxq) and S(gxsq) are the best qualitive and quantitative similarity parameters of all those mentioned in this paper; they can be profitably used for the qualitative and quantitative assessments of TCM chromatographic fingerprints. Through this study, the quality evaluation of TCM can be simplified by using only one parameter of with the qualitive and quantitative functions proposed in this paper. PMID- 17690428 TI - Selective determination of cadmium(II) from divalent metal ions in environmental samples by capillary electrophoresis using in-capillary complexation with a lacunary Keggin-type [PW11O39]7- complex. AB - A novel capillary electrophoretic (CE) method, based on in-capillary complexation with [PW(11)O(39)](7-), was developed for the determination of cadmium(II) in natural water samples. When a sample solution is injected into a capillary containing 0.20 mM [PW(11)O(39)](7-) and 0.10 M malonate buffer (pH 3.0), the ternary Keggin-type complex, [P(Cd(II)W(11))O(39)](5-), which possesses high molar absorbtivities in the UV region, is formed in the capillary, and its migration toward the anode gives a well-defined migration peak in the electropherogram. An advantage of this method is that many divalent metal ions do not interfere. The proposed method was successfully applied to the determination of Cd(II) in environmental samples. The detection limits were 1 x 10(-7) and 5 x 10(-7) M for river-water and seawater samples, respectively (signal-to-noise ratio = 3). PMID- 17690429 TI - Strong molecular aggregation of neutral carriers bearing perfluoroalkyl chains in liquid-crystalline ion-sensor membranes. AB - A liquid-crystalline benzocrown ether, 4'-[(4''-1,1,2,2 tetrahydroperfluorooctyloxy)biphenyloxycarbonyl]benzo-15-crown-5, was used as a neutral carrier of ion-selective electrodes (ISEs) to elucidate the effect of highly ordered assembling of the neutral carrier on the sensor properties through fluorophilic interactions. The properties for the membrane and the resulting ISEs based on a benzocrown ether bearing a perfluoroalkyl chain were compared with those based on the corresponding crown ether bearing an alkyl chain. Atomic force microscopy and fluorescence measurements suggested that the neutral carrier bearing a perfluoroalkyl chain formed highly aggregational states in the membranes of ISEs. PMID- 17690430 TI - Overoxidized polypyrrole doped with 4,5-dihydroxy-3-(p-sulfophenylazo)-2,7 naphthalene disulfonic acid as a selective and regenerable film for the stripping detection of copper(II). AB - A conducting polymer modified electrode based on the incorporation of 4,5 dihydroxy-3-(p-sulfophenylazo)-2,7-naphthalene disulfonic acid, SPADNS, as an anionic complexing ligand into polypyrrole film during electropolymerization was prepared. The electroanalysis of copper(II) in this modified electrode was achieved by medium exchange and differential pulse voltammetry. Copper ions were accumulated from ammonia buffer on the electrode surface by the formation of a chemical complex at open circuit. The resulting electrode with complexed Cu(2+) was then transferred to an acetate buffer and subjected to anodic stripping voltammetry. The analytical performance was evaluated and, finally, linear calibration graphs were obtained in the concentration range of 2 - 250 ng ml(-1) for Cu(II). The detection limit was found to be 1.1 ng ml(-1) and RSD was obtained at 3.1 and 1.9% for two different concentrations. Many coexisting metal ions had little or no effect on the determination of copper. The developed method was applied to Cu(II) determination in natural water and human hair samples. Also, the rapid and convenient regeneration of electrode allows the use of a single modified electrode in multiple analyses. PMID- 17690431 TI - A single-bead analysis on a disk-shaped microfluidic device using an antigen immobilized bead. AB - A disk-shaped microfluidic device (lab-on-a-Disk) was developed to allow the evaluation of mental stress. As a standard sample, secretory immunoglobulin A (sIgA), which is a candidate marker of mental stress, was measured by a heterogeneous enzyme immunoassay (EIA) on the lab-on-a-Disk. Centrifugal force provided a microfluidic control on the lab-on-a-Disk. We examined the relationship between the rotational speed, the channel profile, and the position of the microfluidic chambers from the center of rotation to manipulate sample solutions into each reaction reservoir through microchannels sequentially, i.e., retain in a reservoir or flow into a subsequent reservoir. A single glass bead with immobilized sIgA on its surface was injected into a reservoir for a competitive antigen-antibody reaction, and applied to a specific surface in a heterogeneous assay. It is expected that the lab-on-a-Disk would be suitable for miniaturization and automation of the processes in EIA compared with a conventional EIA using a titer plate. PMID- 17690432 TI - Novel nitrite sensing using a palladium-polyphenosafranine nano-composite. AB - A novel palladium-polyphenosafranine nano-composite (PPS-Pd) was synthesized by electrochemical co-deposition at a glassy carbon electrode (GCE) for fabrication of a nitrite sensor, PPS-Pd/GCE. This PPS-Pd film was characterized by X-ray photoelectron spectroscopy (XPS) and field emission scanning electron microanalysis (SEM). It was found that the PPS-Pd nano-composite consisted of Pd nanoparticles smaller than 10 nm in diameter which stick together due to the polymer, forming a Pd-embedded PPS layer structure. The sensing ability was investigated by cyclic voltammetry (CV), differential pulse voltammetry (DPV) and differential pulse amperometry (DPA). The PPS-Pd/GCE had excellent catalytic activity toward the oxidation of nitrite: high current sensitivity of 0.365 A/M cm(-2), good reproducibility, good stability and fast response. In neutral solutions, a linear concentration range of 1.0 x 10(-6) to 1.1 x 10(-3) M (R(2) = 0.999) with the detection limit (s/n = 3) of 3 x 10(-7) M nitrite was obtained for DPV determination. PMID- 17690433 TI - Determination of oxygenated volatile organic compounds in ambient air using canister collection-gas chromatography/mass spectrometry. AB - This research attempts to establish a method to measure 11 kinds of oxygenated volatile organic compound (OVOC) in ambient air by using the canister collection gas chromatography/mass spectrometry (GC/MS) method. Since several compounds such as acetone exhibited high blank concentrations due to their laboratory use, stringent quality control was conducted for the VOC-free added water and the VOC free nitrogen gas. In order to prevent the decline of recovery rates due to lack of sufficient relative humidity, it is necessary to add VOC-free water when pressurizing and diluting the air samples. Thus, all the target compounds in ambient air were obtained from the canisters at high recovery rates without significant contamination. Furthermore, the canister collection-GC/MS method makes it possible to apply simultaneous air monitoring of OVOCs as well as volatile hazardous air pollutants without additional sampling. PMID- 17690434 TI - Continuous approach for ultrasound-assisted acid extraction-minicolumn preconcentration of chromium and cobalt from seafood samples prior to flame atomic absorption spectrometry. AB - A rapid and sensitive method has been proposed for the determination of chromium and cobalt in seafood samples by flame atomic absorption spectrometry combined with a dynamic ultrasound-assisted acid extraction and an on-line minicolumn preconcentration. The use of diluted nitric acid as extractant in a continuous mode at a flow rate of 3.5 mL min(-1) and room temperature was sufficient for quantitative extraction of these trace metals from seafoods. A minicolumn containing a chelating resin was an excellent device for the quantitative preconcentration of chromium and cobalt prior to their detection. A flow injection manifold was used as interface for coupling all analytical steps, which allowed the automation of the whole analytical process. A Plackett-Burman experimental design was used as a multivariate strategy for the optimization of both sample preparation and preconcentration steps. The method was successfully applied to the determination of chromium and cobalt in seafood samples. PMID- 17690436 TI - Hydration effect on the ion-pair extraction of lithium picrate by hydrophobic benzo-15-crown-5 ether into various less-polar diluents. AB - The ion-pair formation constant (K(MLA)(0) in mol(-1) dm(3)) for Li(B15C5)(+) with a picrate ion (Pic(-)) in water was determined by potentiometry with a K(+) selective electrode at 25 degrees C and an ionic strength of 0, where B15C5 denotes benzo-15-crown-5 ether. Using the concentration equilibrium constants, K(MLA), estimated from this value, the extraction constants (mol(-2) dm(6) unit) of about ten diluents were re-calculated from previously reported extraction data. Also, the distribution constants of an ion-pair complex, Li(B15C5)Pic, between water and the diluents were re-estimated. A disagreement in the determined K(MLA) value between a solvent-extraction method and potentiometry was explained in terms of the Scatchard-Hildebrand equation; it came from the fact that the hydration of Li(I) in Li(B15C5)Pic was larger than that of free B15C5 in water. Then, the previously determined value by the former method was re estimated using the potentiometric K(MLA) value. PMID- 17690435 TI - ICP-AES determination of trace rare earth elements in environmental and food samples by on-line separation and preconcentration with acetylacetone-modified silica gel using microcolumn. AB - A novel method of online microcolumn separation and preconcentration coupled to inductively coupled plasma atomic emission spectrometry (ICP-AES) with the use of acetylacetone-modified silica gel as packing material was developed for the determination of trace rare earth elements (REEs) in environmental and food samples. The main parameters affecting online separation/preconcentration, including pH, sample flow rate, sample volume, elution and interfering ions, have been investigated in detail. Under the optimized operating conditions, the adsorption capacity values for Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu were 25.65, 23.23, 24.01, 19.40, 22.89, 23.77, 24.40, 23.96, 25.58, 25.15, 24.86, 22.75, 16.05, 24.13, 26.51 and 27.93 mg g(-1), respectively. Detection limits (3sigma) based on three times standard deviations of the blanks by 8 replicates were in the range from 48 pg mL(-1) for Lu to 1003 pg mL(-1) for Sm. With 90 s preconcentration time and 10 s elution time, the enrichment factor was 10 and the sample frequency was 28 h(-1). The precisions (RSDs) obtained by determination of a 250 ng mL(-1) (n = 8) REEs standard solution were in the range from 1.7% for Y to 4.4% for Sm. The proposed method was successfully applied to the determination of trace REEs in pig liver, agaric and mushroom. To validate the proposed method, we analyzed three certified reference materials (GBW07401 soil, GBW07301a sediment, and GBW07605 tea leaves). The determined values were in a good agreement with the certified values. The method is rapid, selective, sensitive and applicable to the determination of trace REEs in biological and environmental samples with complicated matrix effects. PMID- 17690437 TI - Fullerene as a standard sample for adjusting the NMR spectral resolution in multiple-quantum magic-angle-spinning experiments. AB - A method using fullerene for adjusting the NMR spectral resolution for multiple quantum magic angle spinning (MQMAS) experiments is proposed. To observe its (13)C MAS signal, it is not necessary to apply (1)H decoupling, unavailable with single-resonance MQMAS probes. Although (13)C T(1) of fullerene is rather long, a recycle time of 5 s in shimming yields its signal with sufficiently high sensitivity if setting the appropriate Ernst angles corresponding to magnetic fields. It is demonstrated that so-adjusted high resolution is reflected in the (87)Rb MQMAS spectra of RbNO(3). PMID- 17690438 TI - Bidentate and tridentate heterocyclic azo compounds having long alkyl chains as coating reagents for ion chromatography of manganese, zinc, and cadmium ions. AB - Bidentate and tridentate heterocyclic azo compounds with and without a long alkyl chain were prepared and examined for cation exchange chromatography of manganese, zinc, and cadmium; these ions could not be separated by reversed phase HPLC following precolumn derivatization with heterocyclic azo compounds owing to the dissociation of the complexes. The newly prepared azo compounds having a long alkyl chain favorably orientate in the reversed-phase stationary phase such that the coordinating parts of the ligand may make contact with metal ions in the mobile phase. Bidentate ligands showed sharp peaks but almost no resolution of manganese and cadmium. A tridentate ligand strongly retained all the three metal ions, which could be separated within 10 min by a competing ligand and by optimizing the pH. PMID- 17690439 TI - Studies on Neurosteroids XXI: an improved liquid chromatography-tandem mass spectrometric method for determination of 5alpha-androstane-3alpha,17beta-diol in rat brains. AB - A sensitive liquid chromatography-electrospray ionization-tandem mass spectrometric (LC-ESI-MS/MS) method for the determination of the rat brain 5alpha androstane-3alpha,17beta-diol (3alpha,5alpha-Adiol) has been developed and validated. The brain extract was purified using solid-phase extraction cartridges, derivatized with isonicotinoyl azide, and subjected to LC-MS/MS. The method was accurate and reproducible, and the limit of quantitation was 0.1 ng/g tissue when a 100-mg tissue sample was used. The change in the brain 3alpha,5alpha-Adiol level by immobilization stress was also analyzed using the developed method. PMID- 17690440 TI - Rapid coprecipitation technique using yttrium hydroxide for the preconcentration and separation of trace elements in saline water prior to their ICP-AES determination. AB - Yttrium hydroxide quantitatively coprecipitated Be(II), Ti(IV), Cr(III), Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), and Pb(II) at pH 9.6 - 10.0 for seawater and pH 10.5 - 11.4 for a table-salt solution. The coprecipitated elements could be determined by inductively coupled plasma atomic emission spectrometry; yttrium was used as an internal standard element. The detection limits ranged from 0.001(6) microg (Mn(II)) to 0.22 microg (Zn(II)) in 100 mL of sample solutions. The operation time required to separate 11 elements was approximately 30 min. PMID- 17690442 TI - Improved Gateway binary vectors: high-performance vectors for creation of fusion constructs in transgenic analysis of plants. AB - We made a series of improved Gateway binary vectors (pGWBs) for plant transformation. Fifteen different reporters and tags, sGFP, GUS, LUC, EYFP, ECFP, G3GFP, mRFP, 6xHis, FLAG, 3xHA, 4xMyc, 10xMyc, GST, T7, and TAP, were employed. Some vectors carry the 2x35S-Omega promoter for higher-level expression. The kanamycin- and hygromycin-resistant markers are independently available for each of the 43 types of vectors, thus an additional transformation of once-transformed plants can be carried out easily. Their small size and high-copy number in Escherichia coli make possible easier handling at plasmid preparation and sequencing. Improved pGWBs should be a powerful tool for transgenic research in plants. PMID- 17690443 TI - Practical preparation of lacto-N-biose I, a candidate for the bifidus factor in human milk. AB - A one-pot enzymatic reaction to produce lacto-N-biose I (LNB), which is supposed to represent the bifidus factor in human milk oligosaccharides, was demonstrated. Approximately 500 mM of LNB was generated in 10-liter of reaction mixture initially containing 660 mM of sucrose and 600 mM of GlcNAc by the concurrent actions of four enzymes, sucrose phosphorylase, UDP-glucose-hexose-1-phospate uridylyltransferase, UDP-glucose 4-epimerase, and lacto-N-biose phosphorylase, in the presence of UDP-Glc and phosphate, indicating a reaction yield of 83%. LNB was isolated from the mixture by crystallization after yeast treatment. Finally, 1.4 kg of LNB of 99.6% purity was recovered after recrystallization. PMID- 17690444 TI - Action of ascorbic acid on a myosin molecule derived from carp. AB - The influence of L-ascorbic acid at 40 degrees C incubation on the subfragment-1 and rod regions, prepared by chymotryptic digestion of myosin, and myosin was investigated by SDS-polyacrylamide gel electrophoresis and transmission electron microscopy respectively. It was observed that L-ascorbic acid acted more readily on the subfragment-1 region of myosin. Further, circular dichroism measurement indicated that L-ascorbic acid did not affect the structure of myosin. These results suggest that L-ascorbic acid acts more readily on the myosin subfragment 1 region and promotes the gelation of myosin without producing a conformational change in this protein. PMID- 17690445 TI - New buffers to improve the quantitative real-time polymerase chain reaction. AB - Real-time PCR is a potent technique for nucleic acid quantification for research and diagnostic purposes, the wide dynamic range being one of the advantages over other techniques like the microarray. Several additives and enhancers have been studied to expand the PCR dynamic range in order to be more efficient in quantifying low quantities of nucleic acids, increase the yield and improve reaction efficiency. Shown here is that a combination of new buffers with the regularly used Tris buffer makes it possible to expand the real-time PCR dynamic range and to improve the efficiency and correlation coefficient. Mixing HEPES, TEA or MOPS with Tris was more efficient than Tris alone. It was also found that, if the pH value of the Tris buffer was calibrated with phosphoric acid instead of hydrochloric acid, then the dynamic range was significantly improved and low quantities could be detected and quantified more efficiently. Mixing more than one compound with the Tris buffer was also effective for expanding the dynamic range and increasing the efficiency and correlation coefficient in quantitative real-time PCR. PMID- 17690447 TI - Improvement in performance of affinity gels containing Gly-D-Phe as a ligand to thermolysin due to increasing the spacer chain length. AB - The aim of this study was to improve the performance of affinity gels containing glycyl-D-phenylalanine (Gly-D-Phe) as a ligand to thermolysin. Gly-D-Phe was immobilized to the resin through spacers of varying chain lengths. The resulting affinity gels had spacer chain lengths of 2 carbon atoms and 11 and 13 carbon-and oxygen atoms (designated T2, T11, and T13), and were characterized for their binding abilities to thermolysin. Measurement of adsorption isotherms showed that the association constants to thermolysin were in the order T13 > T11 > T2. In affinity column chromatography, in which 5 mg thermolysin was applied onto 1-ml volumes of the gels, the adsorption ratios of thermolysin were also in the order T13 > T11 > T2. These results indicate that the performance of affinity gels is improved by increasing the spacer chain length to 13 carbon-and-oxygen atoms. PMID- 17690446 TI - Biosynthesis of castor oil: effect of polyamines on the acylation of lysophosphatidic acid at the sn-2 position with ricinoleic acid. AB - Polyamines with diamine structures of chain length longer than 3C were essential for the synthesis of phosphatidic acid (PA) from ricinoleoyl-CoA and lysophosphatidic acid (LPA) by the castor LPA acyltransferase reaction, suggesting that polyamines modulate enzyme affinity for the acyl-CoA substrate in vivo. PMID- 17690448 TI - A new ester isolated from Ferula assa-foetida L. AB - A new caffeic acid cinnamyl ester (1) was isolated from the n-hexane-soluble fraction of an MeOH extract of the gum resin of Ferula assa-foetida L. The structure was determined to be (2E)-3,4-dimethoxycinnamyl-3-(3,4 diacetoxyphenyl) acrylate on the basis of spectroscopic data including 1D- and 2D-NMR. Compound 1 showed moderate activity for inhibiting LPS-induced nitric oxide production in murine macrophage RAW264.7 cells, with an IC50 value of 54.9 microm. PMID- 17690449 TI - Three new taxanes with the 10-alkoxy group from the heartwood of Taxus cuspidata. AB - Three novel taxanes with the 10-alkoxy group were isolated from heartwood of Taxus cuspidata. The structures were identified as 2alpha,14beta-diacetoxy-10beta ethoxytaxa-11,4(20)-dien-5alpha-ol (1), 2alpha,14beta-diacetoxy-10beta methoxytaxa-11,4(20)-dien-5alpha-ol (2), and 2alpha-acetoxy-10beta-ethoxytaxa 11,4(20)-diene-5alpha,14beta-diol (3) on the basis of spectroscopic analysis. These are the first taxanes with an alkoxy moiety on the skeleton. PMID- 17690450 TI - Analyses of native disulfide bond formations in the early stage of the folding process in mutant lysozymes where the long-range interactions in the denatured state were modulated. AB - In order to clarify whether modulation of long-range interactions in the denatured state affect native disulfide bond (SS bond) formations of hen egg white lysozyme (HEL) containing a pair of cysteine residues, we examined the extent of SS bond formation among 12 variants containing a pair of cysteines. The loss of clusters 5 and 6 in the denatured state affected the formation of Cys30 Cys115 and Cys6-Cys127 respectively. PMID- 17690451 TI - New lignans from the heartwood of Cunninghamia lanceolata. AB - Two new lignans, including the aryltetralin-type lignan, lanceoline (1), and the diaryl butyrolactone-type lignan, 5-methoxytrachelogenin (2), together with 5 methoxywikstromol (3), were isolated from the low-polar layer of a heartwood extract of Cunninghamia lanceolata as their acetylated derivatives 1a, 2a and 3a, respectively, and were identified by spectroscopic analyses. The (13)C-NMR data for 3a are reported for the first time in this paper. PMID- 17690452 TI - Dietary supplementation with epigallocatechin gallate elevates levels of circulating adiponectin in non-obese type-2 diabetic Goto-Kakizaki rats. AB - Epigallocatechin gallate (EGCG) reportedly enhances plasma adiponectin levels in models of insulin resistance and obesity. In this study, we found that EGCG increases plasma adiponectin levels and decreases plasma triacylglycerol levels in non-obese diabetic Goto-Kakizaki rats with insulin secretory dysfunction. These results suggest that EGCG ameliorates lipid metabolic abnormality even in non-obese rats, probably by increasing adiponectin production. PMID- 17690453 TI - Tryptophol induces death receptor (DR) 5-mediated apoptosis in U937 cells. AB - Tryptophol is a natural component isolated from vinegar produced from the boiled extract of black soybean. We have reported that tryptophol induces apoptosis in U937 cells via activation of caspase-8 followed by caspase-3. Tryptophol, however, did not affect human peripheral blood lymphocytes (PBL). In this study, we found that tryptophol enhances formation of a death-inducing signaling complex including death receptor (DR) 5. Cell viability and induction of apoptosis by tryptophol was reduced by transfection with decoy receptor (DcR) 1. These results indicate that tryptophol induces apoptosis through DR5 and that the resistance of PBL to tryptophol-induced apoptosis might be due to competition from DcR1. PMID- 17690454 TI - Physicochemical properties of succinylated calfskin pepsin-solubilized collagen. AB - Some physicochemical properties of calfskin pepsin-solubilized collagen (PSC) and succinylated PSC (SPSC) were compared. The amino acid profile remained significantly unchanged. Sodium dodecylsulphate-polyacrylamide gel electrophoresis showed that subunits of SPSC migrated less than those of PSC. The denaturation temperatures of PSC and SPSC were 38.4 degrees C and 34.7 degrees C respectively. Succinylation slightly altered the triple-helical conformation of collagen, as determined by circular dichroism. PMID- 17690455 TI - Inhibitory activity of linoleic acid isolated from proso and Japanese millet toward histone deacetylase. AB - Linoleic acid was isolated from both the methanol extracts of proso and Japanese millet as a histone deacetylase inhibitor. It showed uncompetitive inhibitory activity toward histone deacetylase (IC(50)=0.51 mM) and potent cytotoxicity toward human leukemia K562 (IC(50)=68 microM) and prostate cancer LNCaP cells (IC(50)=193 microM). Millet containing linoleic acid might have anti-tumor activity. PMID- 17690456 TI - Assessment of prion inactivation by fenton reaction using protein misfolding cyclic amplification and bioassay. AB - An abnormal isoform of the prion protein, associated with transmissible spongiform encephalopathies, retains infectivity even after undergoing routine sterilization processes. We found that a formulation of iron ions combined with hydrogen peroxide effectively reduced infectivity and the level of abnormal isoforms of the prion protein in scrapie-infected brain homogenates. Therefore, the Fenton reaction has potential for prion decontamination. PMID- 17690457 TI - Functional analysis of a pyoverdine synthetase from Pseudomonas sp. MIS38. AB - Fluorescent Pseudomonas sp. MIS38 produces a cyclic lipopeptide, arthrofactin. Arthrofactin is synthesized by a unique nonribosomal peptide synthetase (NRPS) with dual C/E-domains. In this study, another class of cyclic peptide, pyoverdine, was isolated from MIS38, viz., Pvd38. The main fraction of Pvd38 had an m/z value of 1,064.57 and contained Ala, Glu, Gly, (OHOrn), Ser, and Thr at a ratio of 2:1:1:(1):1:1 in the peptide part, suggesting a new structure compound. A gene encoding NRPS for the chromophore part of Pvd38 was identified, and we found that it contained a conventional E-domain. Gene disruption completely impaired the production of Pvd38, demonstrating that the synthetase is functional. This observation allows us to conclude that different NRPS systems with dual C/E-domains (in arthrofactin synthetase) and a conventional E-domain (in pyoverdine synthetase) are both functional in MIS38. PMID- 17690458 TI - Synthesis of (+/-)-sundiversifolide based on Lewis acid-mediated Claisen rearrangement. AB - A new and concise synthesis of (+/-)-sundiversifolide (1), an allelopathic bisnor sesquiterpene lactone isolated from germinating sunflower (Helianthus annuus L.) seeds, was achieved by employing Lewis acid-mediated Claisen rearrangement as the key step. PMID- 17690459 TI - Slow absorption of conjugated linoleic acid in rat intestines, and similar absorption rates of 9c,11t-conjugated linoleic acid and 10t,12c-conjugated linoleic acid. AB - We have previously shown that the 9c,11t-conjugated linoleic acid (CLA) concentration was always significantly higher than the 10t,12c-CLA concentration following the administration of these compounds to mice and rats, and considered that structural differences between the conjugated double bonds in these isomers affected absorption in the small intestine. This study investigates the absorption of CLA in the rat intestine by a lipid absorption assay of lymph from the thoracic duct. In Study 1, we used safflower oil and a triacylglycerol form of CLA (CLA-TG), while in Study 2, we used 9c,11t-CLA and 10t,12c-CLA. The cumulative recovery of CLA was lower than that of linoleic acid until two hours after sample administration. There was no difference in the extent of lymphatic recovery of 9c,11t-CLA and 10t,12c-CLA after the administration of CLA-TG, 9c,11t CLA, and 10t,12c-CLA to the rats, suggesting that geometrical and positional isomerism of the conjugated double bonds did not influence the absorption. PMID- 17690460 TI - Propionibacterium acnes acts as an adjuvant in in vitro immunization of human peripheral blood mononuclear cells. AB - We have established an in vitro immunization protocol whereby human peripheral blood mononuclear cells (PBMCs) are initially treated with L-leucyl-L-leucine methyl ester (LLME) and subsequently sensitized with antigen in the presence of interleukin (IL)-2, IL-4, and adjuvant. This protocol resulted in the production of antigen-specific antibodies. PBMCs are potentiated to react with exogenous antigens upon treatment with LLME. We are using this system to investigate the immunomodulatory activity of additives. In the present study, we aimed to evaluate the immunomodulatory activity of Propionibacterium acnes (P. acnes), which is known to exhibit various immunomodulatory effects in murine models, using this in vitro immunization protocol. P. acnes was found to augment the production of antigen-specific antibodies by PBMC, possibly through increased production of inflammatory cytokines and/or increased T-B cell interaction. P. acnes hence appears to act as an adjuvant in the antibody response in in vitro immunization. PMID- 17690461 TI - Identification of nucleotide residues essential for RNase P activity from the hyperthermophilic archaeon Pyrococcus horikoshii OT3. AB - Ribonuclease P (RNase P) is involved in the processing of the 5' leader sequence of precursor tRNA (pre-tRNA). We have found that RNase P RNA (PhopRNA) and five proteins (PhoPop5, PhoRpp21, PhoRpp29, PhoRpp30, and PhoRpp38) reconstitute RNase P activity with enzymatic properties similar to those of the authentic ribozyme from the hyperthermophilic archaeon Pyrococcus horikoshii OT3. We report here that nucleotides A40, A41, and U44 at helix P4, and G269 and G270 located at L15/16 in PhopRNA, are, like the corresponding residues in Esherichia coli RNase P RNA (M1RNA), involved in hydrolysis by coordinating catalytic Mg(2+) ions, and in the recognition of the acceptor end (CCA) of pre-tRNA by base-pairing, respectively. The information reported here strongly suggests that PhopRNA catalyzes the hydrolysis of pre-tRNA in approximately the same manner as eubacterial RNase P RNAs, even though it has no enzymatic activity in the absence of the proteins. PMID- 17690462 TI - Production of reactive oxygen species (ROS) by various marine fish species during the larval stage. AB - Previous studies have indicated that the devil stinger produces reactive oxygen species (ROS) during early development from fertilized egg to larva. To determine whether ROS generation is a common feature in marine fish species, we conducted chemiluminescence analysis using ROS specific probe (L012) on larvae of six marine fish species. Marbled rockfish, black rockfish, and devil stinger showed higher levels of chemiluminescence response (CR), whereas the levels of CR of sevenband grouper, tiger puffer, and red seabream were fairly lower. These CRs were inhibited by the addition of superoxide dismutase. Hypersensitive photon counting microscopic observation of black rockfish suggested that ROS production was concentrated in the head area. Our results suggest that the larvae of these six marine fishes produce ROS to considerably different extents depending on species, and that rockfish species, belonging to ovoviviparous fish, tend to produce much higher levels of ROS especially at the later larval stage. PMID- 17690463 TI - Sex pheromone production in the silkworm, Bombyx mori, is mediated by store operated Ca2+ channels. AB - In most female moths, pheromone biosynthesis activating neuropeptide (PBAN) regulates sex pheromone production by stimulating an influx of extracellular Ca(2+). Little is known about the plasma membrane channel or how the PBAN stimulus is communicated to the channel. Fluorescent Ca(2+) imaging techniques confirmed PBAN-induced Ca(2+) influx in the silkworm, Bombyx mori, and showed that the PBAN response is reduced with repeated stimulation. Compounds known to impact Ca(2+) signaling were examined for their effects on sex pheromone production. These experiments demonstrated that the PBAN signal is likely mediated by a store-operated channel (SOC). SOC blockers, SKF-96365 and 2 aminoethoxydiphenyl borate, abolished sex pheromone production, as did flufenamic acid, a blocker of transient receptor potential (TRP) channels. Thapsigargin mimicked the pheromonotropic effects of PBAN. Similar results were seen when PBAN induced lipase activity was assayed. Conversely, 1-oleoyl-2-acetyl-sn-glycerol and arachidonic acid, activators of diacylglycerol-dependent Ca(2+) channels, had no effect on bombykol production. PMID- 17690464 TI - Anti-angiogenic effects of conjugated docosahexaenoic acid in vitro and in vivo. AB - The anti-angiogenic effects of conjugated docosahexaenoic acid (CDHA), which was prepared by an alkaline treatment of docosahexaenoic acid and contained conjugated double bonds, were investigated in vitro and in vivo. CDHA inhibited tube formation by the bovine aortic endothelial cell (BAEC), and also inhibited the proliferation of BAEC at a concentration of CDHA that suppressed tube formation, but did not influence cell migration. The inhibition of BAEC growth caused by CDHA was accompanied by a marked change in cellular morphology. Nuclear condensation and brightness were observed in Hoechst 33342-stained cells treated with CDHA, indicating that CDHA induced apoptosis in BAEC. We also evaluated the angiogenesis inhibition of CDHA in vivo. The vessel formation which was triggered by tumor cells was clearly suppressed in mice orally given CDHA. Our findings suggest that CDHA has potential use as a therapeutic dietary supplement for minimizing tumor angiogenesis. PMID- 17690465 TI - Purification, biochemical characterization, and gene cloning of a new extracellular thermotolerant and glucose tolerant maltooligosaccharide-forming alpha-amylase from an endophytic ascomycete Fusicoccum sp. BCC4124. AB - An endophytic fungus, Fusicoccum sp. BCC4124, showed strong amylolytic activity when cultivated on multi-enzyme induction enriched medium and agro-industry substrates. alpha-Amylase and alpha-glucosidase activities were highly induced in the presence of maltose and starch. The purified target alpha-amylase, Amy-FC1, showed strong hydrolytic activity on soluble starch (kcat/Km=6.47 x 10(3) min( 1)(ml/mg)) and selective activity on gamma- and beta-cyclodextrins, but not on alpha-cyclodextrin. The enzyme worked optimally at 70 degrees C in a neutral pH range with t(1/2) of 240 min in the presence of Ca(2+) and starch. Maltose, matotriose, and maltotetraose were the major products from starch hydrolysis but prolonged reaction led to the production of glucose, maltose, and maltotriose from starch, cyclodextrins, and maltooligosaccharides (G3-G7). The amylase showed remarkable glucose tolerance up to 1 M, but was more sensitive to inhibition by maltose. The deduced protein primary structure from the putative gene revealed that the enzyme shared moderate homology between alpha-amylases from Aspergilli and Lipomyces sp. This thermotolerant, glucose tolerant maltooligosaccharide forming alpha-amylase is potent for biotechnological application. PMID- 17690466 TI - Enzymatic characterization of 5-methylthioribose 1-phosphate isomerase from Bacillus subtilis. AB - The product of the mtnA gene of Bacillus subtilis catalyzes the isomerization of 5-methylthioribose 1-phosphate (MTR-1-P) to 5-methylthioribulose 1-phosphate (MTRu-1-P). The catalysis of MtnA is a novel isomerization of an aldose phosphate harboring a phosphate group on the hemiacetal group. This enzyme is distributed widely among bacteria through higher eukaryotes. The isomerase reaction analyzed using the recombinant B. subtilis enzyme showed a Michaelis constant for MTR-1-P of 138 microM, and showed that the maximum velocity of the reaction was 20.4 micromol min(-1) (mg protein)(-1). The optimum reaction temperature and reaction pH were 35 degrees C and 8.1. The activation energy of the reaction was calculated to be 68.7 kJ mol(-1). The enzyme, with a molecular mass of 76 kDa, was composed of two subunits. The equilibrium constant in the reversible isomerase reaction [MTRu-1-P]/[MTR-1-P] was 6. We discuss the possible reaction mechanism. PMID- 17690467 TI - Mammalian glycerophosphodiester phosphodiesterases. AB - Bacterial glycerophosphodiester phosphodiesterases (GP-PDEs), GlpQ and UgpQ, are well-characterized periplasmic and cytosolic proteins that play critical roles in the hydrolysis of deacylated glycerophospholipids to glycerol phosphate and alcohol, which are utilized as major sources of carbon and phosphate. In contrast, two novel mammalian GP-PDEs, GDE1/MIR16 and GDE3, were recently identified, and were shown to be involved in several physiological functions. GDE1/MIR16 was identified as a membrane protein interacting with RGS16, a regulator of G protein signaling, and found to hydrolyze glycerophosphoinositol preferentially. We have found that expression of GDE3 is significantly up regulated during osteoblast differentiation and is involved in morphological changes of cells. Furthermore, five mammalian GP-PDEs were virtually identified, and very recent studies indicate that retinoic acid-induced expression of GDE2 plays essential roles in neuronal differentiation and neurite outgrowth. Thus mammalian GP-PDEs are likely to be important in controlling numerous cellular events, indicating that the GP-PDE superfamily in mammals might be a pharmacological target in the future. PMID- 17690468 TI - Facile preparation of deuterium-labeled standards of indole-3-acetic acid (IAA) and its metabolites to quantitatively analyze the disposition of exogenous IAA in Arabidopsis thaliana. AB - [2',2'-(2)H(2)]-indole-3-acetic acid ([2',2'-(2)H(2)]IAA) was prepared in an easy and efficient manner involving base-catalyzed hydrogen/deuterium exchange. 1-O ([2',2'-(2)H(2)]-indole-3-acetyl)-beta-D-glucopyranose, [2',2'-(2)H(2)]-2 oxoindole-3-acetic acid, and 1-O-([2',2'-(2)H(2)]-2-oxoindole-3-acetyl)-beta-D glucopyranose were also successfully synthesized from deuterated IAA, and effectively utilized as internal standards in the quantitative analysis of IAA and its metabolites in Arabidopsis thaliana by using liquid chromatography electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). The use of this technique shows that these metabolites were accumulated in the roots of Arabidopsis seedlings. Dynamic changes in the metabolites of IAA were observed in response to exogenous IAA, revealing that each metabolic action was regulated differently to contribute to the IAA homeostasis in Arabidopsis. PMID- 17690469 TI - Identification of the functional periplasmic nitrate reductase (nap) gene cluster from the deep-sea denitrifier Pseudomonas sp. strain MT-1. AB - The nap gene cluster encoding periplasmic nitrate reductase was identified from Pseudomonas sp. strain MT-1, a deep-sea denitrifier isolated from the Mariana Trench. The ORFs identified were highly homologous with those of Pseudomonas stutzeri, but the cluster included only four ORFs (napDABC), less than those in other organisms. For other bacteria, some additional small ORFs (such as napE, napF, napG, napH, and napK) are found in the nap gene cluster, although their physiological function is still unclear. The soluble fraction of MT-1 grown under denitrifying condition showed significant nitrate reductase activity. This observation suggests that the periplasmic nitrate reductase encoded by the gene cluster identified in this study is functional. The activity was highest when the organism was grown under denitrifying conditions, suggesting that the enzyme participates in dissimilatory nitrite reduction. PMID- 17690470 TI - Gender difference in ICER Igamma transgenic diabetic mouse. AB - Few studies have been done to examine gender differences in diabetic mouse models. Here we examined a gender difference in Inducible cAMP Early Repressor (ICER) transgenic (Tg) mice, a diabetic mouse model. Longitudinal changes in diabetes and nephropathy were investigated in male and female Tg mice. Both male and female Tg mice developed severe diabetes early in life due to severely impaired insulin synthesis and decreased beta-cell numbers, but only female Tg mice became less hyperglycemic later in life, and most female Tg mice did not develop diabetic nephropathy. Even some female Tg mice that remained hyperglycemic showed less renal expansion than age-matched male Tg mice. Thus the gender difference in the severity of diabetes and diabetic nephropathy was evident with age in this model. This study indicates that sex hormones may play a role in glucose metabolism in diabetic conditions. PMID- 17690471 TI - Melanogenesis inhibition by an oolong tea extract in b16 mouse melanoma cells and UV-induced skin pigmentation in brownish guinea pigs. AB - To investigate the new physiological functions of oolong tea, the effects on melanogenesis were studied. An oolong tea extract inhibited melanogenesis without affecting cell growth in B16 mouse melanoma cells. However, the oolong tea extract hardly showed any inhibitory effect on mushroom tyrosinase in a cell-free system. The effects of an oolong tea extract on the intracellular tyrosinase level in B16 cells were therefore studied. All the levels of activity, protein and mRNA were decreased in the oolong tea extract-treated cells. We also investigated the inhibitory effects of oolong tea on the pigmentation induced by ultraviolet B (UVB) by using brownish guinea pigs in vivo. The number of 3,4 dihydroxyphenylalanine (DOPA)-positive melanocytes increased by UVB was repressed by an oral administration of oolong tea. These results imply that oolong tea might be effective in whitening and that its inhibitory effect on melanogenesis was involved in the decrease of intracellular tyrosinase at the mRNA level. PMID- 17690472 TI - Site-specific and asymmetric hydrolysis of prochiral 2-phenyl-1,3-propanediol diacetate by a bacterial esterase from an isolated strain. AB - Bacillus cereus 809A and Burkholderia sp. 711C were isolated from soil. These strains demonstrate hydrolysis activity towards prochiral 2-phenyl-1,3 propanediol diacetate and accumulated the corresponding chiral monoacetates into the reaction mixture. When 2-phenyl 1,3-propanediol diacetate was used as a substrate, the produced monoacetates with Burkholderia sp. 711C were obtained in a racemic form but that produced by Bacillus cereus 809A showed an excess of the (S)-form. The resting cell reaction revealed that for Bacillus cereus 809A, there was an enrichment of one of the enantiomers of the monoacetate such that the enantiomeric excess (e.e.) of the (S)-form was over 95%. The purified enzyme from Bacillus cereus 809A hydrolyzed diacetate to monoacetate, and the e.e. value of the (S)-form increased by prolonged reaction in a way similar to the resting cell reaction. From N-terminal amino acids, this esterase is conserved in some strains of Bacillus for which the genomic sequences have been reported. PMID- 17690473 TI - megB1, a novel macroevolutionary genomic marker of the fungal phylum Basidiomycota. AB - Molecular studies on the evolution and systematics of fungi have been established primarily based on the neutral theory by analyzing neutral mutations in some defined segments of housekeeping genes as genetic markers. Such an approach is, however, hardly applicable for analyzing ancient evolutionary radiations. In the present study, we looked for DNA sequences characterizing higher taxa, and discovered a unique macroevolutionary genomic marker, megB1, that specifies the phylum Basidiomycota. megB1 is an approximately 500-bp DNA element, which is defined by terminal sequences and five internal segments conserved throughout the phylum. megB1 resides on the rDNA intergenic spacer 1 (IGS1) from 27 species of 10 Basidiomycota genera examined. While megB1 was not found in IGS1 from the other 92 species of the 27 Basidiomycota genera, several genera representing them carry megB1 in some other genomic regions. No known taxonomic criteria fit into the classification on the basis of whether megB1 resides on rDNA. Neighbor joining analysis of the megB1 sequence, however, properly assigned species to their respective genera. Thus far, megB1 has not been found in any genomic or genetic databases currently available for other phyla. These results suggest that megB1 may have emerged upon the occurrence of Basidiomycota, and that this phylum evolved thereafter leaving this element conserved throughout their further differentiation. megB1 may be a novel genomic marker useful in the analysis of ancient through the latest evolutionary radiation in Basidiomycota. PMID- 17690474 TI - Glioperazine B, as a new antimicrobial agent against Staphylococcus aureus, and glioperazine C: two new dioxopiperazines from Bionectra byssicola. AB - In the course of our screening for new antibacterials from microbial metabolites, two new dioxopiperazine metabolites, glioperazines B (1) and C (2), together with the known compound, glioperazine (3), were isolated from the mycelia of a liquid fermentation culture of the fungus, Bionectra byssicola F120. The structures of compounds 1 and 2 were assigned on the basis of MS and NMR data. Compound 1 is an unusual dioxopiperazine metabolite containing an OMe group at the alpha-carbon of the amino acid residue. Compound 1 showed weak antibacterial activity against various strains of S. aureus, including methicillin-resistant S. aureus (MRSA) and quinolone-resistant S. aureus (QRSA), while 2 and 3 did not show such activity. PMID- 17690475 TI - DPPH radical scavenging and semicarbazide-sensitive amine oxidase inhibitory and cytotoxic activities of Taiwanofungus camphoratus (Chang-chih). AB - Wild, liquid state culture and solid state culture of Taiwanofungus camphoratus (Chang-chih) were sequentially extracted with cold water, methanol, and hot water to get cold water soluble, methanol soluble, and hot water soluble extracts respectively. The extracts from three Chang-chih were used to determine 1,1 diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, semicarbazide sensitive amine oxidase inhibitory, and cytotoxic activities against B16-F10 and HT-1080 cell lines. It was found that extracted fractions from three Chang-chih exhibited the different levels of biological activities. PMID- 17690476 TI - Preventive effects of Moringa oleifera (Lam) on hyperlipidemia and hepatocyte ultrastructural changes in iron deficient rats. AB - The effects of Moringa oleifera (MO), Moringaceae on hyperlipidemia and hepatocyte ultrastructural changes caused by iron deficiency were investigated. Four-week-old male Wistar-strain rats were fed a control diet based on AIN-93G (C), an iron deficient diet (FeD), a FeD + 0.5% MO (FeD-m) diet, or a FeD + MO 1% (FeD-M) diet for 4 weeks. It was found that MO reduced iron-deficient diet induced increases in serum and hepatic lipids with dose-dependent increases of serum quercetin and kaempherol, but did not prevent anemia. By electron microscopy, in iron deficient hepatocytes, slightly swollen mitochondria and few glycogen granules were observed, but glycogen granules increased and mitochondria were normalized by treatment with MO. Furthermore, lipoproteins were observed in the Golgi complex under treatment with MO. These results suggest a possible beneficial effect of MO in the prevention of hyperlipidemia and ultrastructural changes in hepatocytes due to iron-deficiency. PMID- 17690477 TI - Effects of Ala substitution for conserved Cys residues in mouse ileal and hepatic Na+-dependent bile acid transporters. AB - Although ileal and hepatic Na(+)-dependent bile acid transporters (SLC10A2 and SLC10A1 respectively) share structural similarities, the mutation of conserved amino acids often has distinct effects on them. We have identified two Cys residues in mouse Slc10a2 (Cys(51) and Cys(106)) the replacement of which by Ala remarkably reduces taurocholic acid (TCA) transport. Although Cys(51) is conserved in Slc10a1 as Cys(44), Ala substitution gave no apparent difference in TCA uptake. Here, we further analyzed the kinetics of TCA uptake and cell surface localization of these mutants. The C51A and C106A mutants of Slc10a2 showed significantly reduced TCA uptake, while no apparent difference in TCA uptake was observed for the Slc10a1-C44A mutant. The K(m) values for TCA uptake by these mutants were comparable, suggesting that these residues are not involved in the interaction with TCA. PMID- 17690478 TI - A structural and phylogenetic study of the HO gene from Saccharomyces bayanus var. uvarum. AB - A novel HO gene (Uv-HO) was cloned from the Saccharomyces bayanus var. uvarum (abbreviated as S. uvarum in this study) type strain. The coding region of Uv-HO showed relatively high homology (95%) to that of the Sb-HO gene (S. bayanus var. bayanus HO), but not to the HO genes of other Saccharomyces sensu stricto species. However, the 5' and 3' non-coding region of Uv-HO showed less similarity (79% and 76% respectively) even to those of the most homologous gene Sb-HO. Motifs of the mating-type control and the cell-cycle control were conserved in the 5' non-coding region of Uv-HO, but numbers and positions of motifs were different from those of Sb-HO. CHEF-Southern analysis showed that all tested strains of S. bayanus species, including S. uvarum, carried the HO gene on the 1,100-kb chromosome. By HO-typing PCR using mixed primers, which provided a rapid and convenient tool for yeast identification, either the Uv-HO gene or the Sb-HO gene was detected in strains of S. bayanus species, but two strains were found to have both types of HO gene in each genome. These results suggest that S. uvarum has a unique sequence, but might share the same chromosome constitution within S. bayanus species, and that S. bayanus is a heterogeneous species, of which some strains might be natural hybrid. PMID- 17690479 TI - Light represses conidiation in koji mold Aspergillus oryzae. AB - In the filamentous fungus Aspergillus oryzae, there has been no report on photoreaction. Here we investigated the effect of light in A. oryzae and found that conidiation was repressed by white light. This reaction is contrary to that of other Aspergilli, which show abundant conidiation under light. Moreover, red light also caused reduced conidiation. Genome sequencing of A. oryzae indicated the existence of homologs of some light-related genes in other filamentous fungi. To approach the molecular mechanism of this photoresponse, the effect of red light on the expression level of several genes putatively responsible for conidiation or photoperception, i.e., brlA, a gene known to be required for conidiation, AofphA, the putative homolog of the A. nidulans phytochrome gene fphA, and AoveA, the putative homolog of the negative regulator gene in conidiation in A. nidulans, was examined. These three genes showed no significant response to red light at the transcriptional level. The results indicate that A. oryzae perceives and responds to red light in a manner independent of the transcriptional regulation of these genes. PMID- 17690480 TI - Characterization and structure analysis of a novel bacteriocin, lacticin Z, produced by Lactococcus lactis QU 14. AB - A novel bacteriocin, lacticin Z, produced by Lactococcus lactis QU 14 isolated from a horse's intestinal tract was identified. Lacticin Z was purified through a three step procedure comprised of hydrophobic-interaction, cation-exchange chromatography, and reverse-phase HPLC. ESI-TOF MS determined the molecular mass of lacticin Z to be 5,968.9 Da. The primary structure of lacticin Z was found to consist of 53 amino acid residues without any leader sequence or signal peptide. Lacticin Z showed homology to lacticin Q from L. lactis QU 5, aureocin A53 from Staphylococcus aureus A53, and mutacin BHT-B from Streptococcus rattus strain BHT. It exhibited a nanomolar range of MICs against various Gram-positive bacteria, and the activity was completely stable up to 100 degrees C. Unlike many of other LAB bacteriocins, the stability of lacticin Z was emphasized under alkaline conditions rather than acidic conditions. All the results indicated that lacticin Z belongs to a novel type of bacteriocin. PMID- 17690481 TI - Cholesterol and plant sterol efflux from cultured intestinal epithelial cells is mediated by ATP-binding cassette transporters. AB - In this study we analyzed functions of ATP-binding cassette (ABC) transporters involved in sterol transport from Caco-2 cells. Treatment with a synthetic liver x receptor ligand elevated both mRNA and protein levels of ABCG5, G8, and ABCA1. The ligand stimulated cholesterol efflux, suggesting that ABC transporters are involved in it. To identify the acceptors of cholesterol, potential molecules such as apolipoprotein A-I, glycocholic acid, phosphatidylcholine, and bile acid micelles were added to the medium. Apo A-I, a known acceptor of cholesterol transported by ABCA1, elevated cholesterol efflux on the basal side, whereas the others raised cholesterol efflux on the apical side. Moreover, bile acid micelles preferentially augmented plant sterol efflux rather than cholesterol. Finally, in HEK293 cells stably expressing ABCG5/G8, bile acid micelle-mediated sterol efflux was significantly accelerated. These results indicate that ABCG5/G8, unlike ABCA1, together with bile acids should participate in sterol efflux on the apical surface of Caco-2 cells. PMID- 17690482 TI - The effect of cocoa and polydextrose on bacterial fermentation in gastrointestinal tract simulations. AB - Effects of cocoa mass and supplemented dietary fiber (polydextrose) on microbial fermentation were studied by combining digestion simulations of stomach and small intestine with multi-staged colon simulations. During the four phases of digestion, concentrations of available soluble proteins and reducing sugars reflected in vivo absorption of nutrients in small intestine. In colon simulation vessels, addition of polydextrose to digested cocoa mass significantly increased concentrations of total short-chain fatty acids and butyric acid, from 103 to 468 mM (P<0.01) and from 12 to 22 mM (P<0.01), respectively. Long-chain fatty acid concentrations (decreasing from 1,222 to 240 mM) were mainly affected by the presence of digested cocoa mass. Cocoa mass with or without polydextrose addition significantly decreased production of cadaverine (P<0.02) and branched-chain fatty acids compared to control during colon simulations. Results indicate beneficial effects on metabolism of colonic microbiota after digestion of cocoa mass, and even more so with polydextrose addition. PMID- 17690483 TI - Metabolism and calcium antagonism of sodium alginate oligosaccharides. AB - Sodium alginate oligosaccharides (NaAOs) consisting of a mixture of eight oligosaccharides have previously been reported to lower blood pressure. We investigated in this study the excretion of NaAOs into the urine or feces, and attempted to elucidate the mechanism for lowering blood pressure by using isolated mesenteric arteries from the rabbit. The recovery rate of P8, which is the main component of NaAOs, was 5.2% and 58.9% over 48 hours in the urine and feces, respectively. The mechanism for lowering blood pressure appeared to be NaAOs having calcium antagonist activity, especially voltage-operated calcium channels. Our results suggest that NaAOs are substantially excreted into the feces, although some of them may be absorbed internally, exerting antagonist activity towards the calcium channels, especially voltage-operated calcium channels. PMID- 17690484 TI - Rubralactone, rubralides A, B and C, and rubramin produced by Penicillium rubrum. AB - Rubralactone (1), rubralides A, B and C (2-4), rubramin (5), and 2-formyl-3,5 dihydroxy-4-methylbenzoic acid (6), were isolated from Penicillium rubrum, and their structures established by spectroscopic methods including 2D NMR. The effects on plant growth of 1-6 were examined using the lettuce seedling bioassay. Compound 1 promoted root growth. Compounds 2, 3 and 5 inhibited the growth of lettuce seedlings, but 4 and 6 did not have any inhibitory effect on their growth. PMID- 17690485 TI - Clinical effects of a hop water extract on Japanese cedar pollinosis during the pollen season: a double-blind, placebo-controlled trial. AB - The clinical effects of an oral administration of a hop water extract (HWE) on the improvement of Japanese cedar pollinosis (JCPsis) symptoms were investigated. In a double-blind, placebo-controlled trial, 39 subjects took a drink containing either 100 mg of HWE or a placebo for 12 weeks during the pollen season. Nasal symptoms (sneezing attacks, nasal discharge, and nasal obstruction) were assessed from the subjects' diaries. A clinical examination and blood sampling were carried out before and 4, 8 and 12 weeks after the initiation of treatment. As a result, a significant difference was observed in the symptom score and in the symptom-medication score 10 weeks after the intervention in comparison with the placebo group. Improvements were observed in nasal swelling, nasal color, amount of nasal discharge, and characteristics of nasal discharge in the intervention group 12 weeks after the treatment. No significant eosinophil infiltration into the nasal discharge was apparent in the intervention group throughout the study period, although it was observed in the placebo group. These findings indicate that an oral administration of HWE may be effective in alleviating the allergic symptoms related to JCPsis. PMID- 17690486 TI - Isolation of antioxidative phenolic glucosides from lemon juice and their suppressive effect on the expression of blood adhesion molecules. AB - Phenolic glucosides having radical scavenging activity were examined from the fraction eluted with 20% methanol on Amberlite XAD-2 resin applied to lemon (Citrus limon) juice by using reversed phase chromatography. Four phenolic glucosides were identified as 1-feruloyl-beta-D-glucopyranoside, 1-sinapoyl-beta D-glucopyranoside, 6,8-di-C-glucosylapigenin and 6,8-di-C-glucosyldiosmetin by (1)H-NMR, (13)C-NMR, and MS analyses. They exhibited radical scavenging activity for 1,1-diphenyl-2-picrylhydrazyl (DPPH) and superoxide, although the activity was low in comparison with eriocitrin, a potent antioxidant in lemon fruit, and the eriodictyol of its aglycone. The phenolic compounds in lemon juice were examined for their suppressive effect on the expression of blood adhesion molecules by measuring the expression of intercellular adhesion molecule-1 (ICAM 1) in human umbilical vein endothelial cells (HUVECs) induced by necrosis factor alpha (TNF-alpha). 6,8-Di-C-glucosylapigenin, apigenin, and diosmentin of the flavones were found to significantly suppress the expression of ICAM-1 at 10 muM (P<0.05). The phenolic glucosides isolated in this study were contained in comparative abundance in daidai (Citrus aurantium) and niihime (Citrus unshiu x Citrus tachibana) among the sour citrus juices. PMID- 17690487 TI - Thrombin activatable fibrinolysis inhibitor antigen levels are inversely correlated with plasminogen activator inhibitor-1 antigen levels in hyperthyroid patients. AB - Both increased and decreased fibrinolytic activity have been reported in patients with hyperthyroidism. Elevated levels of plasma plasminogen activator inhibitor-1 (PAI-1) antigen have been found in hyperthyroid patients. Thrombin activatable fibrinolysis inhibitor (TAFI) is a novel plasma protein, which inhibits fibrinolysis through removal of C-terminal lysines from partially degraded fibrin. Previously, we showed that plasma TAFI antigen levels were increased in patients with overt and subclinical hypothyroidism. The aim of this study is to investigate plasma levels of TAFI and PAI-1 antigens in hyperthyroid patients. PAI-1 and TAFI antigen levels were measured in the plasma of 29 patients with hyperthyroidism (14 overt hyperthyroid and 15 subclinical hyperthyroid), and 26 healthy individuals. Although there were increased levels of PAI-1 antigen in hyperthyroid patients, plasma TAFI antigen levels were significantly lower compared to controls (80.79 ng/ml vs. 32.42 ng/ml, p = 0.000 for PAI-1; 10.42 microg/ml vs. 12.24 microg/ml, p = 0.009 for TAFI). Elevated PAI-1 antigen levels were positively correlated with free thyroid hormones, although TAFI antigen levels were in negative correlation with free thyroxine. Furthermore, an inverse correlation between PAI-1 and TAFI antigen levels was found. Our study demonstrated that TAFI antigen levels were decreased in patients with hyperthyroidism. Inverse correlation with PAI-1 suggests that the decrease in TAFI antigen levels may be due to activation of TAFI pathway. Further studies evaluating the underlying mechanisms of low TAFI antigen levels in hyperthyroidism should be undertaken. PMID- 17690488 TI - [Animal models of psychiatric disorders: significances, roles, and problems from the behavioral pharmacology point of view]. PMID- 17690489 TI - [Evaluation methods for general and depressive-like behaviors]. PMID- 17690490 TI - [Evaluation for anxiety-related behaviors in rodents]. PMID- 17690491 TI - [Behavioral analyses for learning and memory in mice and rats]. PMID- 17690492 TI - [Behavioral evaluation in animal models of schizophrenia]. PMID- 17690493 TI - [Evaluation method for a pain-like action]. PMID- 17690494 TI - [Evaluation of drug dependence: use of a conditioned place preference paradigm]. PMID- 17690495 TI - [Cannabinoid receptor: its critical role in the CNS]. PMID- 17690496 TI - [Evaluation of latent learning in a water-finding test by using model animals]. PMID- 17690497 TI - [Basis of antiviral agents: anti-HIV agents (anti-AIDS agents)]. PMID- 17690498 TI - [Clinical use of anti-HIV agents]. PMID- 17690499 TI - [Carcinogenicity studies]. PMID- 17690500 TI - [Local irritation studies for evaluation of drug products]. PMID- 17690501 TI - Diagnostic mammography and ultrasonography for palpable and nonpalpable breast cancer in women aged 30 to 39 years. AB - PURPOSE: To investigate the relationship between the tumor size of breast cancer by palpation and the sensitivity of mammography (MMG) and ultrasonography (US), and which modality can detect nonpalpable breast cancer in women aged 30 to 39 years. METHODS: We retrospectively evaluated the tumor size by palpation, breast density, and the sensitivity of MMG and US in 165 patients aged 30 to 39 years. Palpation, US, and MMG were performed with prior knowledge of the results of other modalities. The tumor size on palpation were classified into Tnp; nonpalpable, T1p; 2 cm or less, T2p; more than 2 cm, but not more than 5 cm, and T3p; more than 5 cm. RESULTS: Of 165 patients, 147 patients (89%) showed mammographically dense breasts. Of 165 cancers, 14 (8%) were Tnp, 40 (24%) were T1p, 82 (50%) were T2p, and 29 (18%) were T3p. The sensitivity of MMG was 57% (8 of 14) for Tnp, 78% (31 of 40) for T1p, 90% (74 of 82) for T2p, and 97% (28 of 29) for T3p. The sensitivity of US was 43% (6 of 14) for Tnp and 100% for palpable cancers. Of 14 nonpalpable cancers, 4 (29%), 4 (29%), and 2 (14%) could be detected by only MMG, bloody nipple discharge, and US. CONCLUSIONS: The sensitivity of MMG depends on the tumor size on palpation in this age range. MMG fails to detect relatively large palpable cancers. On the other hand, US can detect all palpable cancers. However, the sensitivity of US declines for nonpalpable cancers. For the detection of nonpalpable cancers, MMG, US, and nipple discharge are complementary modalities. PMID- 17690502 TI - The relationship between FDG uptake in PET scans and biological behavior in breast cancer. AB - BACKGROUND: Positron emission tomography (PET) is a non-invasive imaging modality used in the diagnosis and staging of breast cancer. However, several factors can affect fluoro-deoxyglucose (FDG) uptake by a tumor. To clarify the parameters that most affect FDG accumulation in tumors, the relationship between standardized uptake values (SUVs) and clinicopathological factors and immunohistopathological analysis was investigated in breast cancer. MATERIAL AND METHODS: PET studies were performed preoperatively on 37 patients with breast carcinoma. SUVs were counted at one hour (early phase) and at two hours (delayed phase) after FDG injection. The relationships between SUVs and 13 clinical, pathological and immunohistchemical factors were studied. RESULTS: A significant association was found between FDG accumulation and early and delayed phase mitotic counts (p=0.0018 and 0.0010, respectively), Ki67 positive cell percentage (p=0.0098 and 0.0062, respectively), and nuclear grade (p=0.0232 and 0.0195, respectively). On the other hand, nodal status weakly correlated with the delayed phase (p=0.0907). However, other clinicopathological parameters and immunohistopathological status, which included tumor size, age, histology, estrogen receptor, progesterone receptor and Her2/neu overexpression, did not correlate significantly with FDG uptake. CONCLUSION: Mitotic count and Ki67 reflect cellular aggressiveness. These parameters were strongly correlated with tracer uptake. Thus our data suggested that the biological behavior of breast cancer is reflected in the variation of FDG uptake by the tumor. However, whether FDG uptake is a true prognostic and predictive factor remains to be confirmed in larger studies over an extended period of time. PMID- 17690503 TI - Relation of serum levels of estrogen and dehydroepiandrosterone sulfate to hormone receptor status among postmenopausal women with breast cancer. AB - BACKGROUND: It is hypothesized that breast cancer may consist of heterogeneous diseases with different hormonal environments classified by hormone receptor status. Epidemiologic studies evaluating risk factors for breast cancer by hormone receptor status have supported the hypothesis. However, there are inconsistencies in the risk factor profiles by estrogen receptor (ER) and progesterone receptor (PR) across the studies. To clarify the heterogeneity of the disease, it is necessary to understand not only risk factor profiles but also the biologic characteristics such as the relationships among endogenous sex hormone levels and hormone receptors. METHODS: We measured serum levels of estrone (E1), estradiol (E2), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG) in 142 postmenopausal women aged 50 and over with primary breast cancer who had undergone surgical treatment, and investigated the heterogeneity in the relations of endogenous sex hormone levels to hormone receptor status, using the case-series study method. Subjects were categorized into 3 classes based on tertiles of each hormone level in receptor-negative subjects, and odds ratios (ORs) for receptor-positive status compared with receptor-negative status were computed, taking the lowest category as a reference category. RESULTS: There were clear trends toward higher serum levels of E1, E2, and DHEAS in women with PR+ cancer. The case-series approach revealed that PR+ status might be strongly associated with serum sex hormone levels. In particular, the OR of PR+ was large for a high DHEAS level (OR for the highest category=4.28). No significant association between serum hormone levels and ER status was observed. CONCLUSION: The association of serum sex hormone levels with hormone receptor status may differ by PR status, but not by ER status. This finding suggests that PR status may be related to the heterogeneity in hormonal environments associated with breast cancer risk. PMID- 17690504 TI - Clinicopathologic significance of an immunohistochemical expression of p27 in scirrhous carcinoma of the breast. AB - BACKGROUND: Scirrhous carcinoma has been known to have more aggressive biological behavior than other histologic subtypes of invasive ductal carcinoma of the breast. The significance of expression of p27kip1, which is thought to be a tumor suppressor gene, in breast carcinoma remains controversial. The aim of the current study was to clarify clinicopathologic significance of scirrhous carcinoma of the breast with special reference to p27 expression. METHODS: Clinicopathologic features including immunohistochemical expression of p27 were compared between scirrhous carcinoma (n=42) and non-scirrhous invasive ductal carcinoma (papillotubular and solid-tubular carcinoma, n=63) of the breast. RESULTS: The proportion of pathologic lymph node metastasis among scirrhous carcinomas was significantly higher than that among carcinomas of other histologic types (papillotubular or solid-tubular carcinomas, p=0.029). The proportion of strong expression of p27 among scirrhous carcinomas was significantly lower than that among tumors of other histologic types (p<0.0001). CONCLUSIONS: Biological behavior of scirrhous carcinoma was found to be aggressive. The aggressiveness and poor cellular differentiation of scirrhous carcinoma of the breast might be related to low p27 expression. PMID- 17690505 TI - DCIS showing architectural distortion on the screening mammogram - comparison of mammographic and pathological findings. AB - BACKGROUND: Patients with mammograms showing architectural distortion often have an invasive carcinoma with noticeable fibrosis, such as scirrhous carcinoma or invasive lobular carcinoma. However, architectural distortion is also seen in some cases of ductal carcinoma in situ (DCIS). METHODS: Of the 316 patients operated on in our hospital from October 2003 to June 2004, 54 were histopathologically diagnosed as having DCIS (excluding cases with microinvasion). Of these 54 patients, 5 exhibited architectural distortion on the preoperative mammogram. The aim of this study was to correlate the radiologic and pathologic features of DCIS showing architectural distortion on the mammogram. RESULTS: The mammograms of the 5 patients revealed clusters of calcifications in the architectural distortion. Sclerosis was seen in the interstitium around the DCIS in 3 cases, and DCIS components were found in Cooper's ligament in 4 cases. In 2 cases, sclerosing adenosis was seen in the background of the DCIS. CONCLUSION: It is generally accepted that architectural distortion in DCIS is due to sclerosing adenosis, but sclerosis in the interstitium around the DCIS and presence of DCIS components in Cooper's ligament proved to be the cause of architectural distortion in the cases described here. Since architectural distortion is also seen in DCIS cases, we think that besides the diagnosis of malignancy, the presence or absence of infiltration should be histopathologically established before surgery. PMID- 17690506 TI - Indications for stereotactically-guided vacuum-assisted breast biopsy for patients with category 3 microcalcifications. AB - BACKGROUND: Since microcalcifications classified as category 3 on mammography include not only malignant lesions but also benign lesions, it is difficult to decide whether stereotactic vacuum-assisted breast biopsy (Mammotome(R), MMT) should be performed or the patient should merely be follows. The purpose of this study is to adequately diagnose microcalcifications classified as category 3 and to formulate a correct clinical policy. In addition, we examined the characteristics of the calcifications. METHODS: This study included 51 patients who underwent MMT from July 2003 to October 2004. All the cases were evaluated as category 3, and no abnormal findings were detected on ultrasonography. We classified the pattern of calcifications based on three aspects: 1. density and size, 2. pleomorphic appearance 3. number of calcifications per square centimeter. RESULTS: Of the 51 patients, 14 were histologically diagnosed with ductal carcinoma in situ (DCIS). Heterogeneity in the density and size were observed in 9 of 14 patients (64.3%). The calcifications had a pleomorphic appearance in 6 of 14 patients (42.9%). A large number of calcifications (20/cm(2)) were observed in 8 of 14 patients (57.1%). Better examination characteristics were obtained with heterogeneity in density and size (AUC=0.72 95%C.I: 0.56-0.89) compared with pleomorphic appearance and the number of calcifications per square centimeter. The potential for malignancy was an average of 6 times higher for calcifications with heterogeneity in density and size compared to that for calcifications which were homogeneous in these aspects. CONCLUSION: Attention should be paid to prevent unnecessary mammotome procedures. Heterogeneity in the density and size of calcifications is a reliable criterion for clinical decision-making. PMID- 17690507 TI - Evaluation and indications of ultrasound-guided vacuum-assisted core needle breast biopsy. AB - BACKGROUND: The Mammotome is a diagnostic tool used under stereotactic or with ultrasound guidance. A clear indication for Mammotome use under stereotactic guidance is when a non-palpable microcalcification is a target. However, the indications for the use of the Mammotome under ultrasound guidance vary among institutions, and it is difficult to find a place for the Mammotome among conventional biopsy techniques. The Mammotome biopsy has been available in our hospital since July 1999. We assessed the effectiveness and indications of ultrasound-guided Mammotome biopsy. METHODS: We performed Mammotome biopsies in 433 cases requiring histological diagnosis from July 1999 to September 2006, using an 11-gauge articulated arm-type Mammotome under ultrasound guidance. There were 377 mass lesions including 83 non-palpable cases and 56 hypoechoic lesions. RESULTS: The indications for Mammotome biopsy were 162 cases with inconsistent fine needle aspiration (FNA) and imaging findings, 114 cases indeterminate by FNA, 68 cases of an identified pathological type before neoadjuvant chemotherapy and confirmation of hormone receptor status, 36 inadequate cases by FNA, 20 cases of confirmation of fibroadenoma and other benign tumors, 8 removal cases of fibroadenoma, 8 microcalcification cases, and 17 others. The target lesion was obtained in 99.5% of the cases. CONCLUSIONS: Ultrasound-guided Mammotome biopsy is an accurate and useful diagnostic method that enables sufficient amounts of tissue to be obtained with minimal invasion and few complications. The Mammotome is the first choice for obtaining a definitive pathological diagnosis in breast lesions. PMID- 17690508 TI - Complete remission of recurrent breast cancer with multiple liver metastases after oral capecitabine and injected trastuzumab. AB - A 32-year-old woman underwent modified radical mastectomy for right breast cancer (invasive ductal carcinoma, f, INF beta, v0, ly1, pT2, pN1, M0, Stage II B ER (+/ ), PR (-), Her2 (3+)) in June 2003, and received postoperative systemic adjunctive chemotherapy using epirubicin combined with cyclophosphamide, followed by paclitaxel. In August 2004, after a disease-free interval of 14 months, liver metastasis appeared, and therefore from September 2004, combination chemotherapy with oral capecitabine (2,400 mg/day) and injected trastuzumab (120 mg/week) was started. After 3 cycles, all the metastases responded and this marked response has been maintained for 16 months. This therapy is currently being continued (19 cycles), and no serious side effects have been encountered. Capesitabine and trastuzumab combination therapy is effective for recurrent breast cancer showing overexpression of HER2 and resistance to taxane, and can be considered as a first line therapy for this purpose. It is anticipated that many cases treated with this regimen will be reported and discussed in the near future. PMID- 17690509 TI - A rare case of invasive ductal carcinoma with hyperprolactinemia. AB - We report here a rare form of invasive ductal carcinoma composed of a mass protruding from the tip of the nipple in a 43-year-old woman with hyperprolactinemia. She had been amenorrheic for 15 years following an incomplete pituitary adenomectomy for prolactinoma. She presented with a mass on the left nipple that had been growing for 6 months. Morphologically, the mass resembled adenoma of the nipple. Another mass was located in the subareolar region. She underwent mastectomy after invasive ductal carcinoma was diagnosed. Histopathologically, the tumor of the nipple was invasive ductal carcinoma, which had extended intraductally from another invasive ductal carcinoma in the subareolar region, and had infiltrated the epidermis of the nipple (Paget's disease). MR mammography successfully detected the relationship between the tumors. Postoperatively, the plasma prolactin level was abnormally high, while the plasma estradiol level was quite low, although macro-pituitary adenoma was not detected by MRI. The patient was treated with bromocriptine mesilate, in addition to adjuvant chemotherapy for breast cancer, and the plasma prolactin level has since normalized. PMID- 17690510 TI - Clear cell hidradenoma of the breast: a case report with review of the literature. AB - Clear cell hidradenoma of the breast is rare. A 55-year-old woman demonstrated a left breast tumor during follow-up examination of the right breast. Focal asymmetric density was shown on mammogram, and ultrasonography showed an intracystic tumor. Since the diagnosis was not clear on aspiration cytology, excisional biopsy was performed. The lesion was an intracystic tumor macroscopically. Histological examination demonstrated characteristic histological features of clear cell hidradenoma, such as proliferation of uniform epithelial cells, clear or slightly eosinophilic cytoplasm, and cuboidal cell lined ductal structures. Immunohistochemically, these proliferating epithelial cells were negative for myoepithelial markers, such as alpha-smooth muscle actin, CD10 and anti-muscle actin, but positive for p63. These features were consistent with clear cell hidradenoma. PMID- 17690511 TI - A case of intracystic papillary carcinoma accompanying widespread ductal carcinoma in situ. AB - A 39-year-old Japanese woman noticed a right breast tumor in July 2004. Mammography (MMG) demonstrated an oval tumor without calcification. Dynamic Magnetic Resonance Imaging (D-MRI) demonstrated a high-intensity mass on T2 weighted images, showing mild enhancement during the arterial phase and persistent enhancement during the arterial late phase. Core needle biopsy revealed papillary carcinoma suggestive of Intracystic Papillary Carcinoma (IPC). Auchincloss operation was performed following a partial mastectomy, as the surgical margin after partial mastectomy was positive for carcinoma. Histopathologic mapping of her right breast revealed wide and extensive intraductal spread of DCIS around the IPC. IPC was originally reported to be a localized non-invasive mammary carcinoma. But approximately, half of IPC cases are associated with invasive carcinoma or DCIS beyond the tumor. Careful selection of operative procedure is needed after localized non-invasive IPC or IPC associated with DCIS around the main tumor or invasive carcinoma is diagnosed. PMID- 17690512 TI - Primary diffuse large B-cell lymphoma of the breast. AB - Diffuse large B cell lymphoma (DLBL) of the breast is a rare subtype of breast tumor, the diagnosis of which is based on the cytological and histopathological features of this unique neoplasm. A 28-year-old woman noticed a mass in her right breast. It could not be definitely diagnosed clinically by diagnostic imaging (mammography, ultrasonography), so malignant tumor not otherwise specified was diagnosed. Fine-needle aspiration cytology (FNAC) suggested that it was malignant lymphoma; however it was difficult to distinguish from reactive lymphocytes. Excisional biopsy of the breast mass suggested malignant lymphoma. Based on the diagnosis of malignant lymphoma by FNAC and excisional biopsy, lumpectomy was performed and DLBL was diagnosed histologically according to the World Health Organization classification. DLBL is difficult to distinguish from other types of malignant lymphoma by routine immunohistochemical evaluation. Some previous studies have showed that the octamer-binding transcription factor 2 (Oct2) and coactivator B-cell Oct-binding protein 1 (BOB.1) and the pan-B-cell markers CD20 and CD79a may aid in the diagnosis of malignant lymphoma. In our case, the staining of large atypical lymphocytes for CD20, CD79a, BOB.1 and Oct2 was strongly positive and supports the notion that BOB.1 and Oct2 are also useful immunohistochemical markers for DLBL of the breast. PMID- 17690513 TI - A case of invasive micropapillary carcinoma of the breast. AB - BACKGROUND: Invasive micropapillary carcinoma (IMP) of the breast is uncommon and has only recently been characterized. Knowing the cytological appearance of IMP is important to enable early diagnosis by fine needle aspiration cytology (FNAC). We describe a case of IMP diagnosed by preoperative FNAC. CASE: A 48-year-old menopausal woman presented in 2003 with a mass in her left breast. Mammogram and ultrasound findings indicated that the tumor was malignant. Cytological examination showed papillary clusters of hyperchromatic cells with irregular and crowded nuclei, but lacking papillary cores. No myoepithelial cells were seen. Based on the cytological findings, invasive micropapillary carcinoma was diagnosed. Microscopic findings showed cancer cells with moderate atypia in abundant micropapillary cancer nests without a fibrovascular core. These cancer nests were morula-like, surrounded by empty, clear spaces lined with delicate strands of fibrocollagenous stroma. The polarity of each cancer nest was reversed, with the secretion border facing fibrocollagenous stroma. These pathological features occupied the invasive part of the primary tumor. CONCLUSION: The cytologic features of IMP are distinctive and correlate with histology. FNAC of IMP is important role to confirm the diagnosis. PMID- 17690514 TI - A case of ductal carcinoma with squamous differentiation in malignant phyllodes tumor. AB - Carcinoma derived from the lining epithelial cells in malignant phyllodes tumor is a rare neoplasm of the breast and belongs to the category of carcinosarcoma. We report a case of ductal carcinoma with squamous differentiation arising in malignant phyllodes tumor. A 54-year-old woman was admitted with a rapidly enlarging left breast mass. A breast tumor with a diameter of 6 cm was located mainly in the left outer area of the breast. Mammography revealed a high-density mass with an irregular margin and ultrasound showed a cystic tumor. A pathological diagnosis of ductal carcinoma with squamous differentiation was made by fine needle aspiration and a core needle biopsy. She underwent neoadjuvant chemotherapy followed by a modified radical mastectomy with a skin flap. Histopathological examination revealed that the invasive ductal carcinoma with squamous differentiation originated from the lining epithelial cells in malignant phyllodes tumor and that there was no transition area between the carcinomatous and the sarcomatous component. She experienced lung and facial bone metastases, microscopic features of which were consistent with the sarcomatous component of the original breast carcinosarcoma. This is an extremely rare case of carcinosarcoma and the histopathological findings and review of the literature are discussed. PMID- 17690515 TI - A case of metastatic lobular breast carcinoma with detection of the primary tumor after ten years. AB - Lobular carcinoma of the breast is known to metastasize to unusual sites such as the gastrointestinal tract, peritoneum, and gynecologic organs. We report a patient with intraperitoneal metastases from lobular carcinoma who was originally treated for an unknown primary cancer. Ten years later, a tumor was found in her left breast and the diagnosis was changed to peritoneal metastases from invasive lobular carcinoma. Immunohistochemistry revealed that the metastases were high molecular weight cytokeratin (CK34betaE12) and estrogen receptor-positive, but were E-cadherin-negative. These results assisted in diagnosis. Surgeons should be aware of the characteristics of metastasis lobular carcinoma. PMID- 17690516 TI - Nodular fasciitis of the breast. AB - We report a case of nodular fasciitis of the breast, which is a rare histological type of breast tumor. A 41-year-old woman had noticed a mass in her right breast. The mass was elastic-hard, 15 mm x 15 mm in size, and located mainly in the upper outer quadrant of the right breast. Mammography demonstrated an oval dense mass with spiculation. Ultrasonography revealed a hypoechoic lesion, 8 mm x 10 mm in size. Fine needle aspiration cytology and core needle biopsy showed no evidence of malignancy. Excisional biopsy was performed. The tumor was characterized by a proliferation of fibroblastic cells. Histologically, the excised tumor was consistent with nodular fasciitis of the breast. Nodular fasciitis should be considered in the differential diagnosis of a mass suspicious for breast cancer. PMID- 17690517 TI - Thirteen-week inhalation toxicity of carbon tetrachloride in rats and mice. AB - Subchronic toxicity of carbon tetrachloride (CCl4) was examined by inhalation exposure of F344 rats and BDF1 mice of both sexes to 0, 10, 30, 90, 270 or 810 ppm (v/v) CCl4 vapor for 13 wk (6 h/d and 5 d/wk). In the high exposure levels at 270 and 810 ppm, altered cell foci in the livers of both rats and mice, and fibrosis and cirrhosis in the rat liver were observed. Hematoxylin and eosin stained altered cell foci of rats were recognized as glutathione-S-transferase placental form (GST-P) positive foci, which are preneoplastic lesions of hepatocarcinogenesis. The most sensitive endpoint of CCl4-induced toxicity was fatty change with large droplets in rats of both sexes and male mice, and cytoplasmic globules in male mice, as well as increased relative liver weight in male rats. Those endpoints were manifested at 10 ppm and the LOAEL was determined as 10 ppm for the hepatic endpoints in rats and mice. Enhanced cytolytic release of liver transaminases into plasma in rats and mice and its close association with hepatic collapse in mice were observed at medium and high levels of inhalation exposure. Both CCl4-induced hematotoxicity and nephrotoxicity were observed in both rats and mice, but those toxicities were manifested at higher exposure concentrations than hepatotoxicity. The LOAEL for the hepatic endpoint and the GST-P-stained altered cell foci provide relevant animal data for reconsidering the occupational exposure limit val1ue of 5 ppm for CCl4 and strengthen the evidence of CCl4-induced hepatocarcinogenicity which is used in its carcinogenicity classification. PMID- 17690518 TI - Results of recognition tests on Japanese subjects of the labels presently used in Japan and the UN-GHS labels. AB - The UN-GHS, a globally harmonized system of classifying and labeling chemicals that was recommended by the United Nations in 2003, will be implemented globally in 2008. This system is expected to encourage people to behave in a way that reduces the risk of accidents or diseases caused by chemicals. However, the UN GHS differs significantly from the present Japanese system of classifying and labeling chemicals. In particular, since the Japanese system does not require pictographic labels, ordinary Japanese people are not familiar with the new pictographic labels defined in the UN-GHS. Hence, before introducing the UN-GHS at the Japanese workplace, it is critical to clarify the actual usage conditions and the problems that this labeling system of hazardous chemicals poses, and to manage the related problems. We conducted recognition tests on Japanese subjects of the labels presently used in Japan and the UN-GHS labels. The results revealed that the subjects faced some difficulty in recognizing the meanings of some UN GHS labels. The percentage of questions that were answered correctly with regard to the labels depicting 'cylinder,' 'corrosion,' 'health hazard,' and 'aqueous hazard,' with no accompanying explanatory statements, was less than 60. The results of the answers regarding the labels depicting 'flame' and 'flame over circle' revealed that many subjects were unable to distinguish one from the other. Further, many subjects were unable to clearly distinguish 'skull and crossbones' from 'health hazard.' These results indicate that it is very important to impart correct education regarding these labels. PMID- 17690519 TI - High pallidal T1 signal is rarely observed in obstructive jaundice, but is frequently observed in liver cirrhosis. AB - Although high signal intensities in the globus pallidus are frequently observed in T1-weighted magnetic resonance images (MRI) of patients with liver cirrhosis, it is unclear whether these increases are due to portal-systemic shunt or obstruction of biliary excretion. We therefore studied pallidal signals in 18 cancer patients with bile duct obstruction and marked jaundice (>10 mg/dl). Patients who had fever, leukocytosis or liver cirrhosis were excluded to ensure that jaundice was due to bile duct obstruction. All patients showed a dilated intrahepatic duct on computed tomography (CT) scan. A high pallidal signal was observed in one of 18 biliary obstructive patients whereas high signals were highly prevalent in liver cirrhosis. A portal-systemic shunt rather than an obstruction of biliary excretion may be responsible for the increased blood manganese concentrations and pallidal T1 signals in chronic liver diseases. PMID- 17690520 TI - Work-related respiratory symptoms and ventilatory disorders among employees of a cement industry in Shiraz, Iran. AB - Although the main hazard in cement processing is dust and respiratory tract disorders are the most important group of occupational diseases in this industry, evidence for associations between exposure to cement dust and either respiratory symptoms or functional impairment has not been conclusive. This study was, therefore, undertaken to more thoroughly examine the effects of occupational exposure to cement dust on the respiratory system. The study population consisted of a group of 88, randomly selected, male workers with current exposure to cement dust and 80 healthy male office workers without present or past history of exposure to dust that served as the referent group. Subjects were interviewed and were given respiratory symptom questionnaires to answer. They also underwent chest X-ray and lung function tests. Additionally, personal dust monitoring for airborne inhalable and respirable dust was carried out at nine different worksites. Moreover, X-ray diffraction (XRD) and X-ray fluorescence (XRF) techniques were performed to determine the silica phases and the SiO2 contents of the dust samples. Levels of exposures to inhalable and respirable cement dust were estimated to be 53.4+/-42.6 and 26+/-14.2 mg/m3, respectively (Mean+/-SD). Statistical analysis of the data revealed that symptoms like regular cough, phlegm, wheezing and shortness of breath were significantly (p<0.05) more prevalent among exposed workers. Similarly, chest radiographs of exposed workers showed various degrees of abnormalities including emphysematous changes, old calcified granulomas, emphysematous changes associated with inflammatory processes, evidence of chronic inflammatory processes, focusal calcification of the lungs and infiltrative changes. However, no significant changes were noted in the radiographs of the referent group. Furthermore, exposed workers compared to their referent counterparts showed significant reductions in the parameters of lung function. In conclusions, our data provide corroborative evidence further substantiating the contention that exposure to cement dust is associated with respiratory symptoms and functional impairments. PMID- 17690521 TI - Detection of mutant p53 protein in workers occupationally exposed to benzidine. AB - To investigate the expression of mutant p53 protein in workers occupationally exposed to benzidine, we detected mutant p53 protein by immuno-PCR assay in the serum of 331 benzidine-exposed healthy workers, while we classified exfoliated urothelial cells in urine samples with Papanicoloau's grading (PG). The Papanicoloau's grading classified exfoliated urothelial cells of the subjects from grade I (normal cells) to grade III (suspicious malignant cells). The subjects were also divided into high, medium and low exposure groups according to the exposure intensity index. The results revealed that mutant p53 protein in the medium and high exposure groups were significantly higher than the in low exposure group (p<0.05), and in PG II and III were significantly higher than in the PG I (p<0.05). There was no significant differences among Papanicoloau's gradings strata in the low exposure group on the incidence and quantity of mutant p53 protein. In the medium and high exposure groups, the incidence and/or quantity of mutant p53 protein in the stratum of PG II and/or III were significantly higher than that of PG I (p<0.05). Detection of mutant p53 protein in conjunction with benzidine exposure level and Papanicoloau's gradings of exfoliated urothelial cells could provide more information to help us elevate surveillance efficiency and diagnose bladder cancer in the early period. PMID- 17690522 TI - Hematological follow-up of an intervention program adding rubber glove-wearing to local ventilation for 2-ethoxyethanol acetate-exposed workers. AB - The objective of this study was to evaluate an intervention program, implemented in year 1999, of wearing rubber gloves in addition to engineering control, and to follow-up the hematological effects of 2-ethoxyethanol acetate (2-EEA) exposure among workers in a silk-screening factory. All workers from the printing department with direct exposure to 2-EEA were recruited as the exposed group. Workers from the other departments were recruited as the comparison group. Hematological parameters were measured during health surveys conducted 3 times every two years. Information on personal characteristics and working habits was obtained through a structured questionnaire. More female workers were involved in manual printing resulting in higher exposure to 2-EEA. Hemoglobin and haematocrit levels in female exposed workers were significantly lower than those of female comparison workers in the 1st (1998) health survey, but not in the 2nd (2000) and 3rd (2002) health surveys. No difference was found between male exposed and comparison workers for all three surveys. Longitudinal analysis after adjusting for confounders using the general estimating equation model showed the hemoglobin, haematocrit, and RBC count were significantly higher for 2-EEA exposed workers than comparison workers across the 3 surveys (n=42). The results show that wearing rubber gloves in addition to local ventilation was effective at preventing direct dermal exposure to 2-EEA and ameliorated the hematological effects of 2-EEA exposure. PMID- 17690523 TI - Nurses' expectations, experiences and attitudes towards the intervention of a 'no lifting policy'. AB - The aim of the study was to evaluate expectations and attitudes towards a No Lifting Policy programme, the "No Lift system", among nurses at hospitals where an introduction of the intervention was planned (PreNLS hospitals), and to make a comparison with nurses' experiences and attitudes at one hospital where the intervention had already been implemented (NLS hospital). A cross-sectional study of nurses at two PreNLS hospitals and one NLS hospital was performed. Most nurses at both the PreNLS hospitals and the NLS hospital were positive or very positive to the intervention. The expected and experienced obstacles differed between nurses at the PreNLS hospitals and the NLS hospital; however, there was more agreement concerning benefits. The most frequently expected obstacles at the PreNLS hospitals were organisational issues and obstacles related to the facilities, while most obstacles identified at the NLS hospital concerned specific transfers or were patient-related. A decrease in the number of injuries was the most often considered benefit among most nurses. Nurses at the NLS hospital rated their physical exertion as lower in seven out of nine specific patient transfers compared with nurses at the PreNLS hospitals. They also reported increased well-being at work and an improved ability to manage their daily work. The comprehensive approach and participatory design, including all levels of staff and extensive support from the nurses' own union and management, is probably one important explanation for the positive attitudes and successful introduction of the intervention. PMID- 17690524 TI - A case of acute organotin poisoning. PMID- 17690525 TI - Workplace violence on workers caring for long-term institutionalized schizophrenic patients in Taiwan. AB - It has been noted that workplace violence most frequently occurs in psychiatric settings. The purpose of this study was to explore the workplace violence, including violence situation, victims' feeling, and the prevention strategies, on workers caring for long-term institutionalized schizophrenic patients in Taiwan. We conducted a face-to-face, in-depth, and semi-structured interview with 13 health care workers suffering from physical violence and/or sexual harassment by patients in 2002. First, the interviews were taped and/or paper-notes recorded, then transcribed, organized, and analyzed. Results found that all of the victims alleged they did not receive enough post-incident support, and more than a half of the victims could not call others for help during the violence. To avoid further attack, most victims offered prevention strategies which were considered valuable for establishing guidelines. However, some victims regarded workplace violence as inevitable and part of the job. The most common situations of workplace violence were during routine ward inspections, especially when the victims were alone. The most serious psychological harm was post-traumatic stress disorder (PTSD). In conclusion, we recommended a re-engineering of the organization to a supportive and safe working environment for prevention of workplace violence in the study hospital. PMID- 17690526 TI - Accidental exposure to blood in medical interns of Tehran University of Medical Sciences. AB - Healthcare workers and medical students are at risk of exposure to blood-borne viruses such as HBV, HCV HIV, etc. Here we report the results of a survey of the frequency and causes of cutaneous blood exposure accidents (CBEA) among medical students. Anonymous questionnaires were randomly distributed to 200 interns in their second year of internship in hospitals affiliated to Tehran University of Medical Sciences. A definite exposure was defined as injury by a sharp object causing obvious bleeding, whereas a possible exposure was defined as subtle or superficial injury due to contact with a contaminated instrument or needle but without bleeding, or contamination of an existing wound with blood or other body fluids. One hundred eighty-four subjects (92% of the original sample) responded to the questionnaire. We recorded 121 definite exposures and 259 possible exposures over a mean time interval of 14 months. Needles were the most common objects (41% of exposure episodes) causing CBEAs, while phlebotomy and suturing were the hospital procedures that accounted for the highest percentage of exposure episodes (30 and 28 percent, respectively). Only a minority of students regularly observed basic safety measures (wearing gloves, not recapping used needles and proper disposal of sharp objects). Considering the high incidence of blood exposure in medical interns at Tehran University of Medical Sciences and the ensuing risk of blood-borne infections, the subjects are likely to develop such infections during their internship period. PMID- 17690527 TI - Involvement of intracellular Ca(2+) in the regulatory volume decrease after hyposmotic swelling in MDCK cells. AB - We examined the source of Ca(2+) involved in the volume regulation of Madin-Darby canine kidney (MDCK) cells with confocal microscopy and fluoroprobes. Hyposmosis induced a transient increase in cell volume, as well as cytoplasmic Ca(2+), which peaked at 3 to 5 min and gradually decreased to reach the initial value within about 30 min. This late decrease in cell volume, as well as the transient rise in cytoplasmic Ca(2+), was reduced in Ca(2+)-free solution and was abolished by pretreatment with thapsigargin. In conclusion, Ca(2+) released from the intracellular store contributes to the regulatory volume decrease following hyposmotic swelling in MDCK cells. PMID- 17690529 TI - Regulation of GABA(A)-receptor surface expression with special reference to the involvement of GABARAP (GABA(A) receptor-associated protein) and PRIP (phospholipase C-related, but catalytically inactive protein). AB - GABA(A) receptors are heteropentameric ligand-gated chloride channels composed of a variety of subunits, including alpha1 - 6, beta1 - 3, gamma1 - 3, delta, epsilon, theta, and pi, and play a key role in controlling inhibitory neuronal activity. Modification of the efficacy of the synaptic strength is produced by changes in both the number of neuronal surface receptors and pentameric molecular assembly, leading to differences of sensitivity to neurotransmitters and neuromimetic drugs. Therefore, it is important to understand the molecular mechanisms regulating the so-called "life cycle of GABA(A) receptors" including sequential pentameric assembly at the site synthesized, intracellular transport through the Golgi apparatus and the cytoplasm, insertion into the cell membrane, functional modulation at the cell surface, and finally internalization, followed by either recycling back to the surface membrane or lysosomal degradation. This review is focused on events related to the surface expression of the receptor containing the gamma2 subunit and clathrin/AP2 complex-mediated phospho-regulated endocytosis of the receptor, with special reference to the function of novel GABA(A) receptor modulators, GABARAP (GABA(A) receptor-associated protein) and PRIP (phospholipase C-related, but catalytically inactive protein). PMID- 17690528 TI - Wogonin prevents glucocorticoid-induced thymocyte apoptosis without diminishing its anti-inflammatory action. AB - The effect of wogonin, a flavone highly purified from the roots of Scutellaria baicalensis, on apoptotic cell death was re-evaluated in rat thymocytes. This flavone inhibited glucocorticoid-induced apoptotic changes such as DNA fragmentation, phosphatidylserine translocation, and nuclear condensation in rat thymocytes. Similar inhibition was also observed in apoptosis induced by other inducers such as etoposide. No significant changes of these apoptotic features were observed in rat thymocytes treated with wogonin alone, suggesting that this flavone protects against glucocorticoid-mediated immunosuppression caused by thymocyte apoptosis. Wogonin was reported to possess anti-inflammatory action in some previous studies, but this flavone had no effect on carrageenan-induced paw edema in this study. The simultaneous treatment of wogonin and glucocorticoid neither enhanced nor reduced the anti-inflammatory effect of glucocorticoid. These results indicate that wogonin is likely to prevent the immunosuppression of glucocorticoid without diminishing its drug efficacy as an anti-inflammatory agent. PMID- 17690530 TI - Changes in the peripheral concentrations of inhibin, follicle-stimulating hormone, luteinizing hormone, progesterone and estradiol-17beta during turnover of cystic follicles in dairy cows with spontaneous follicular cysts. AB - Several studies have clarified that the follicular cysts degenerate and are replaced by newly growing follicles that develop into new follicular cysts without ovulation, i.e., turnover of ovarian follicular cysts in cows. However, the relativity of endocrinological changes, including the inhibin profile during turnover of spontaneous follicular cysts in dairy cows, is still unclear. In the present study, the relationship between turnover of follicular cysts and changes in the peripheral blood concentrations of progesterone (P), estradiol-17beta (E(2)), luteinizing hormone (LH), follicle stimulating hormone (FSH) and inhibin were examined in lactating dairy cows. Five cows diagnosed with follicular cysts (follicles of more than 25 mm in diameter in the absence of a corpus luteum) were investigated. Their ovarian dynamics were monitored using ultrasonography, and blood samples were collected at 2- or 3- day intervals throughout the experiment. The day when a follicle fated to become a follicular cyst reached more than 8 mm in diameter was defined as the start of a cystic follicular wave. Four of the 5 cows exhibited a similar patterns of cystic follicular changes and hormone profiles. The data from the 4 cows was used for analysis of the relationships between turnover of cystic follicles and the hormone profiles. Two or three new cystic follicular waves occurred in each cow during the experimental period. The mean diameter of the cystic follicles was more than 25 mm 13 to 15 days after the start of the cystic follicular wave, and it began to decrease 1 to 6 days before the start of the subsequent cystic follicular wave. The levels of E(2) and inhibin tended to decrease for 7 to 9 days before the start of a new cystic follicular wave and to increase concomitantly with new follicular cyst growth. The levels of FSH rose for 1 to 3 days before the start of a new cystic follicular wave. The present study clarified the relationship between FSH and inhibin during turnover of spontaneous follicular cysts in dairy cows and found that it was very similar to previous results for cows. The present results suggest that an increase in FSH secretion following a reduction in inhibin secretion triggers turnover of cystic follicles in cows with spontaneous follicular cysts. PMID- 17690531 TI - Continuous UV-B irradiation induces morphological changes and the accumulation of polyphenolic compounds on the surface of cucumber cotyledons. AB - Sharp-headed and globular-headed trichomes are found on the surface of cucumber (Cucumis sativus L.) cotyledons. Most sharp-headed trichomes consist of three cells. Toluidine blue O stains sharp-headed but not globular-headed trichomes. The effect of continuous ultraviolet-B (UV-B; 290-320 nm) irradiation on the surface of cucumber cotyledons was examined with respect to the two trichome types. Continuous UV-B irradiation induced cell division at or under the basal part of sharp-headed trichomes, resulting in an increase in the number of cell layers from three to six. In parallel, the area stained by toluidine blue O expanded to include epidermal cells surrounding sharp-headed trichomes. Regions of alkali-induced fluorescence due to the presence of polyphenolic compounds coincided with areas stained by toluidine blue O. In contrast, continuous UV-B irradiation did not cause morphological changes in globular-headed trichomes. Thus, continuous UV-B irradiation causes the accumulation of polyphenolic compounds in cucumber cotyledons and induces specific morphological changes in or around sharp-headed trichomes. UV-B exposure also increases lignin content in this tissue. Therefore, continuous UV-B irradiation may induce the specific accumulation of polyphenolic compounds, especially stress lignins, in and near sharp-headed trichomes. PMID- 17690532 TI - Cancer risks and low-level radiation in U.S. shipyard workers. AB - The risks for four cancers, leukemia, lymphopoietic cancers (LHC), lung cancer and mesothelioma, were studied in workers from shipyards involved in nuclear powered ship overhauls. The population represented a sample of all workers based on radiation dose at study termination. The final sample included 28,000 workers with > or = 5.0 mSv, 10,462 workers with < 5.0 mSv and 33,353 non-nuclear workers. Nuclear workers had lower mortality rates for leukemia and LHC than US white males but higher rates of lung cancer and a significant five-fold excess of mesothelioma. Dose-dependent analyses of risks in the high exposure group indicated that for each cancer the risk increased at exposures above 10.0 mSv. An internal comparison of workers with 50.0 mSv exposures to workers with exposures of 5.0-9.9 mSv indicated relative risks for leukemia of 2.41 (95% CI: 0.5, 23.8), for LHC, 2.94 (95% CI: 1.0,12.0), for lung cancer, 1.26 (95% CI: 0.9, 1.9) and for mesothelioma, 1.61 (95% CI: 0.4, 9.7) for the higher exposure group. Except for LHC, these risks are not significant. However, the increasing risk with increasing exposure for these cancers, some of which are known to be related to radiation, suggests that low-level protracted exposures to gamma rays may be associated with these cancers. Other agents such as asbestos, which are common to shipyard work, may play a role especially in the risk of mesothelioma. Future follow up of the population would identify bounds on radiation risks for this population for comparison with similar risks estimated from other populations. PMID- 17690533 TI - Microdosimetric evaluation of secondary particles in a phantom produced by carbon 290 MeV/nucleon ions at HIMAC. AB - Microdosimetric single event spectra as a function of depth in a phantom for the 290 MeV/nucleon therapeutic carbon beam at HIMAC were measured by using a tissue equivalent proportional counter (TEPC). Two types of geometries were used: one is a fragment particle identification measurement (PID-mode) with time of flight (TOF) method without a backward phantom, and the other is an in-phantom measurement (IPM-mode) with a backward phantom. On the PID-mode geometry, fragments produced by carbon beam in a phantom are identified by the DeltaE-TOF distribution between two scintillation counters positioned up- and down-stream relative to the tissue equivalent proportional counter (TEPC). Lineal energy distributions for carbon and five ion fragments (proton, helium, lithium, beryllium and boron) were obtained in the lineal-energy range of 0.1-1000 keV/microm at eight depths (7.9-147.9 mm) in an acrylic phantom. In the IPM-mode geometry, the total lineal energy distributions measured at eight depths (61.9 322.9 mm) were compared with the distributions in the PID-mode. Both spectra are consistent with each other. This shows that the PID-mode measurement can be discussed as the equivalent of the phantom measurement. The dose distribution of the carbon beam and fragments were obtained separately. In the depth dose curve, the Bragg peak was observed. Relative biological effectiveness (RBE) for the carbon beam in the acrylic phantom was obtained based on a biological response function as a lineal-energy. The RBE of carbon beam had a maximum of 4.5 at the Bragg peak. Downstream of the Bragg peak, the RBE rapidly decreases. The RBE of fragments is dominated by Boron particles around the Bragg peak region. PMID- 17690534 TI - Inhibition of potential lethal damage repair and related gene expression after carbon-ion beam irradiation to human lung cancer grown in nude mice. AB - Using cultured and nude mouse tumor cells (IA) derived from a human lung cancer, we previously demonstrated their radiosensitivity by focusing attention on the dynamics of tumor clonogens and the early and rapid survival recovery (potential lethal damage repair: PLD repair) occurring after X-ray irradiation. To the authors' knowledge, this is the first study demonstrating gene expression in association with PLD repair after carbon-ion beam or X-ray irradiation to cancer cells. In this study we tried to detect the mechanism of DNA damage and repair of the clonogens after X-ray or carbon-ion beam irradiation. At first, colony assay method was performed after irradiation of 12 Gy of X-ray or 5 Gy of carbon-ion beam to compare the time dependent cell survival of the IA cells after each irradiation pass. Second, to search the genes causing PLD repair after irradiation of X-ray or carbon-ion beam, we evaluated gene expressions by using semi-quantitative RT-PCR with the selected 34 genes reportedly related to DNA repair. The intervals from the irradiation were 0, 6, 12 and 24 hr for colony assay method, and 0, 3, 18 hr for RT-PCR method. From the result of survival assays, significant PLD repair was not observed in carbon-ion beam as compared to X-ray irradiation. The results of RT-PCR were as follows. The gene showing significantly higher expressions after X-ray irradiation than after carbon-ion beam irradiation was PCNA. The genes showing significantly lower expressions after X-ray irradiation rather than after carbon-ion beam irradiation were RAD50, BRCA1, MRE11A, XRCC3, CHEK1, MLH1, CCNB1, CCNB2 and LIG4. We conclude that PCNA could be a likely candidate gene for PLD repair. PMID- 17690535 TI - Hypointensity on postcontrast MR imaging from compression of the sacral promontory in enlarged uterus with huge leiomyoma and adenomyosis. AB - PURPOSE: In patients with huge leiomyoma and with adenomyosis of the uterus, a peculiar area of hypointensity was occasionally observed on postcontrast magnetic resonance (MR) imaging in the dorsal portion of the enlarged uterus near the sacral promontory. We describe the imaging characteristics of these MR findings and correlate them with histopathological findings to examine whether the areas represent specific pathological changes. METHODS: Ten patients with huge leiomyomas and two with huge adenomyotic lesions whose imaging revealed the hypointensity were enrolled. All had enlarged uteri that extended beyond the sacral promontory. MR findings of the hypointense areas were evaluated and correlated with histopathological findings in 5 patients with leiomyoma and two with adenomyosis who had hysterectomy. RESULTS: The ten patients with leiomyoma showed flare-shaped hypointensity arising from the dorsal surface of the uterine body that extended deep into the tumor. The base of the hypointense areas was narrow in 5 patients with intramural leiomyoma and broad in five with subserosal leiomyoma. Two patients with adenomyosis showed nodular-shaped areas of hypointensity in front of the sacral promontory. Precontrast T(1)- and T(2) weighted MR images showed no signal abnormalities in the portions corresponding to the hypointensity in any of the 12 patients. Pathological examinations showed no specific findings in the portions corresponding to the hypointensity in the 7 patients who had hysterectomy. CONCLUSION: The areas of hypointensity may represent functional changes, such as decreased localized blood flow caused by compression of the sacral promontory. PMID- 17690536 TI - Correction of inhomogeneous RF field using multiple SPGR signals for high-field spin-echo MRI. AB - PURPOSE: To propose a simple and useful method for correcting nonuniformity of high-field (3 Tesla) T(1)-weighted spin-echo (SE) images based on a B1 field map estimated from gradient recalled echo (GRE) signals. METHODS: To estimate B1 inhomogeneity, spoiled gradient recalled echo (SPGR) images were collected using a fixed repetition time of 70 ms, flip angles of 45 and 90 degrees, and echo times of 4.8 and 10.4 ms. Selection of flip angles was based on the observation that the relative intensity changes in SPGR signals were very similar among different tissues at larger flip angles than the Ernst angle. Accordingly, spatial irregularity that was observed on a signal ratio map of the SPGR images acquired with these 2 flip angles was ascribed to inhomogeneity of the B1 field. Dual echo time was used to eliminate T(2)(*) effects. The ratio map that was acquired was scaled to provide an intensity correction map for SE images. Both phantom and volunteer studies were performed using a 3T magnetic resonance scanner to validate the method. RESULTS: In the phantom study, the uniformity of the T(1)-weighted SE image improved by 23%. Images of human heads also showed practically sufficient improvement in the image uniformity. CONCLUSION: The present method improves the image uniformity of high-field T(1)-weighted SE images. PMID- 17690537 TI - Automated MR spectroscopy of intra- and extraventricular neurocytomas. AB - PURPOSE: We evaluated the automated magnetic resonance spectroscopic (MRS) characteristics of intra- and extraventricular neurocytomas. MATERIALS AND METHODS: One extra- and 4 intraventricular neurocytomas were studied. Automated single-voxel proton MRS was performed with a 1.5 T MR scanner. The results of 6 total automated MR spectra were analyzed for each tumor. RESULTS: Lactate resonance was detected as a doublet in 3 MR spectra of 2 intraventricular neurocytomas. A peak corresponding to N-acetylaspartate (NAA) was small in 5 MR spectra of 4 intraventricular neurocytomas. Creatine (Cr) resonance was detected in all 6 MR spectra. Prominent choline (Cho) resonance was found in all 6 MR spectra. The myoinositol (MI) and/or glycine (Gly) peaks were large in 3 MR spectra of 2 intraventricular neurocytomas. CONCLUSION: The presence of the NAA signal and high MI and/or Gly signals may be characteristic features of intraventricular neurocytomas. A combination of prominent Cho resonance and detectable Cr resonance is a common feature of both intra- and extraventricular neurocytomas. PMID- 17690538 TI - Measuring brain tissue oxygenation under oxidative stress by ESR/MR dual imaging system. AB - The in vivo measurement of oxygen in tissues is of great interest because of oxygen's fundamental role in life. Many methods have been developed for such measurement, but all have been limited, especially with regard to repeated measurement, degree of invasiveness, and sensitivity. We describe electron spin resonance (ESR) oximetry with paramagnetic oxygen-sensing probe for in vivo measurement of oxygen in brain tissues by home-made ESR/MR dual imaging spectroscopy. Lithium 5, 9, 14, 18, 23, 27, 32, 36-octa-n-butoxy-2,3 naphthlocyanine (LiNc-BuO) radical was employed as the solid oxygen-sensing probe, and we confirmed its ability to report partial pressure of oxygen (pO(2)) in brain tissues of live animals under normal and pathological conditions for more than a month. pO(2) measurements could also be made repeatedly on the same animal and at the same location. The implantation site of LiNc-BuO in examined rats was verified by 0.5 T magnetic resonance (MR) imaging. Septic-shock rats were used to monitor tissue oxygenation during pathological state. A decline in pO(2) levels from severe hypotension during sepsis was detected, and generation of nitric oxide (NO) in brain tissues was confirmed by NO spin trapping. ESR oximetry using oxygen-sensing probe and NO spin-trapping can be used to monitor pO(2) change and NO production simultaneously and repeatedly at the same site in examined animals. PMID- 17690539 TI - Quantitative perfusion imaging with pulsed arterial spin labeling: a phantom study. AB - PURPOSE: Pulsed arterial spin labeling (PASL) is a magnetic resonance (MR) method for measuring cerebral blood flow. Although several validation studies for PASL in animals and humans have been reported, no reports have detailed the fundamental study of PASL using a flow phantom. We compared the true and theoretical flow rates in a flow phantom to confirm the analytical validity of quantitative perfusion imaging with Q2TIPS sequence. METHODS: We built a flow phantom consisting of a 40-mm diameter plastic syringe filled with plastic beads and small plastic tubes 4 mm in diameter. Gd-DTPA-doped 8L water solution (0.1 mM) was circulated between the syringe and a tank through a plastic tube by a constant flow pump while the flow rate was adjusted between 0 and 2.61 cm/s. Q2TIPS sequence parameters were TI(1)=50 ms and TI(2)=1400 ms. Five imaging slices of 50 subtraction images were acquired sequentially in a distal-to proximal direction using a single-shot echo planar imaging (EPI) technique. The theoretical flow rate calculated based upon the previously reported kinetic model for Q2TIPS was compared with the true flow rate. RESULTS: A good linear relationship was observed between the theoretical, F', and true flow rates, F, in a flow rate range of 1.43 to 1.95 cm/s (F'=1.024*F-1.915, R(2)=0.902). The ratio of theoretical to true flow rate was 92 (+/-) 4%. CONCLUSION: Flow rate was quantified with reasonable accuracy when the entire amount of labeled bolus within the phantom could be recovered. Our experiment confirmed the analytical validity of Q2TIPS and suggested that blood flow measurement may be feasible using the Q2TIPS pulse sequence and kinetic model of the PASL equation. PMID- 17690540 TI - Handedness and the brain: a review of brain-imaging techniques. AB - The author reviewed brain-imaging studies on human handedness reported in major academic journals for the last 12 years, classified them as having anatomical or functional interest, and attempted to determine consensus on findings and limitations among the studies. Present reviews suggest that there have been fewer functional than anatomical examinations into handedness and that findings from those studies have not been necessarily consistent, that participants' degree of handedness has not been consistent between left-handed and right-handed people, and that much more brain-imaging study is anticipated to examine functional and anatomical differences of handedness based on genetic and environmental models. PMID- 17690541 TI - Optimized system design and construction of a compact whole-hand scanner for diagnosis of rheumatoid arthritis. AB - We have developed a compact magnetic resonance (MR) imaging scanner with permanent magnet, gradient coil set, and radiofrequency (RF) coils optimized for whole-hand examination for the diagnosis of rheumatoid arthritis (RA). The system weighs about 600 kg, and installation space is 2 m(2), excluding the shield room. Hand examinations of normal volunteers and patients with RA were performed using a 3D T(1)-weighted gradient-echo (GRE) sequence and short T(I) inversion recovery 3D fast spin-echo (STIR-3DFSE) sequence, and anatomical structures and various lesions of the hand caused by RA were clearly visualized in a 16-min examination. It was concluded that the system could be used for diagnosis of RA in even a small clinic. PMID- 17690542 TI - MR imaging features of solid-pseudopapillary tumor of the pancreas. AB - Solid-pseudopapillary tumor (SPT) of the pancreas is characterized as cystic, necrotic, and hemorrhagic degeneration. In this study, magnetic resonance (MR) findings of 4 cases were reviewed. Patchy or spotty areas of high intensity that suggested hemorrhagic degeneration were constantly detected on fat-suppressed T(1)-weighted images. Dynamic contrast-enhanced MR imaging revealed mild and gradual increase of contrast enhancement in solid portions. Multi-contrast MR imaging that included fat-suppressed T(1)-weighted imaging and dynamic contrast enhanced imaging allowed accurate diagnosis of SPT and its differentiation from other tumors. PMID- 17690543 TI - Assessment of suitability of thrombolysis in middle cerebral artery infarction: a proof of concept study of a stereologically-based technique. AB - BACKGROUND: The extent of cerebral ischemia, assessed by the Alberta Stroke Program Early CT Score (ASPECTS) method and unaided visual determination of the CT Summit Criterion, correlates with increased risk of intracerebral hemorrhage following rt-PA administration. Concerns about the accuracy of the unaided visual assessment in the estimation of infarct size and the conservative nature of the ASPECTS method led us to develop a new method (MCAGrid) based on stereological grid counting and a digital atlas of the middle cerebral artery (MCA) infarct territory. METHODS: We tested the hypotheses that the stereological method increases the accuracy of infarct estimation and that the number of patients deemed eligible for thrombolysis is greater with this method than with existing methods. Four experienced radiologists with extensive neuroradiological experience examined the CT images of 19 patients with MCA territory stroke and determined patient eligibility for thrombolysis by: unaided visual determination of the CT Summit Criterion, MCAGrid, and the ASPECTS score. The chi(2) test was used to compare the differences in the number of patients deemed 'eligible' for thrombolysis by the 3 imaging methods. Further, the unaided visual assessment and MCAGrid were compared with volumes calculated following manual segmentation of infarct, and the sensitivity, specificity and positive and negative likelihood ratios for these techniques were calculated. RESULTS: In general, MCAGrid was better than unaided visual assessment in the prediction of >1/3 involvement of the MCA territory by infarct. The number of patients considered as 'eligible' for thrombolysis based on imaging criteria was significantly lower when ASPECTS criteria (15/76) were used than when unaided visual determination of the CT Summit Criterion (32/76; p < 0.01) or MCAGrid (59/76; p < 0.001) criteria were used. CONCLUSION: The choice of methods for rating infarct extent affects the number of patients 'eligible' for thrombolysis significantly. Furthermore, MCAGrid increased the accuracy with which infarct extent was estimated. These results provide justification for a prospective study of this technique in the setting of acute stroke. PMID- 17690544 TI - Increase of stroke incidence after weekend regardless of traditional risk factors: Takashima Stroke Registry, Japan; 1988-2003. AB - BACKGROUND AND PURPOSE: The study purpose was to identify patterns of variation in stroke incidence among days of the week and examine if it is modified by conventional stroke risk factors: hypertension, diabetes, drinking and smoking. METHODS: Data were obtained from the Takashima Stroke Registry, which covers a stable population of roughly 55,000 residents of Takashima County in central Japan. A total of 1,773 stroke cases (men: 943 and women: 830) occurred between 1988 and 2003. We divided the days into 3 groups: 'weekend', 'after weekend' and 'rest of the week', and calculated stroke incidence rates and incidence rate ratios. To identify the effect of conventional risk factors on the variation, proportion of differences between observed and expected stroke incidences were considered. RESULTS: The stroke incidence for the after weekend group (250.1 per 100,000 person years, 95% CI: 222.0-278.3) was higher than for the other day groups among men. The after weekend increase was observed mainly among older men aged 65 years or more. Among the stroke subtypes, the incidence for cerebral infarction was highest in the after weekend group (857.2, 95% CI: 730.6-983.8) and was 1.37 times (95% CI: 1.12-1.68) higher than in the rest of the week group. Tendency of after weekend increase was observed regardless of the presence or absence of risk factor history. CONCLUSIONS: Week day variation for stroke was observed predominantly among older men regardless of presence and absence of risk factor history. Information about the weekly trend regarding episode of increased stroke incidence can be used as a surrogate predictor for stroke onset and would be helpful in designing more effective insights for preventive strategies. PMID- 17690545 TI - Common carotid artery intima-media thickness and intracranial pulsatility index in non-ST-elevation acute coronary syndromes. AB - BACKGROUND: Common carotid intima-media thickness (CIMT) has been related to cardiovascular risk factors, coronary atherosclerosis and a higher risk of myocardial infarction. Evaluation of intracranial arteries by transcranial Doppler explores the presence of vascular dysfunction at this level. We tested the hypothesis that CIMT and Doppler Pulsatility Index (DPI) can be related to the Thrombolysis in Myocardial Infarction (TIMI) risk score for non-ST-elevation acute coronary syndrome (nST-ACS). The relation to the prognosis after an acute event was also assessed. METHODS: We recruited 126 consecutive patients (80 males; mean age: 66.6 +/- 13.1 years) admitted with nST-ACS. A carotid assessment with bidimensional mode, measuring the CIMT in the posterior wall of the common carotid artery, and a transcranial Doppler assessment of the middle cerebral artery, with measurement of the Pulsatility Index were carried out. Clinical follow-up at 6 months was performed for endpoints (cardiovascular death, recurrent ACS or revascularization). RESULTS: Fifty-nine patients had an abnormal (> or =0.8 mm) CIMT, whilst 70 patients had an abnormal DPI (> or =1.2). CIMT was correlated with TIMI risk score (Pearson r: 0.26; p = 0.004), whilst abnormal DPI was associated with TIMI risk scale (p < 0.001). Using a logistic regression analysis, the presence of an abnormal CIMT was only related to age > or =65 (p = 0.0012) and diabetes mellitus (p = 0.0028). Abnormal DPI was also associated with age > or =65 (p < 0.0001) and diabetes mellitus (p = 0.0466). Neither CIMT nor DPI were related to 6 months' clinical outcome. CONCLUSIONS: Patients with nST ACS have a high prevalence of dates of abnormal DPI, which was associated with increased CIMT. Both variables were related to age and diabetes but not with clinical outcomes. PMID- 17690546 TI - Association between single nucleotide polymorphisms in the lysyl oxidase-like 1 gene and spontaneous cervical artery dissection. AB - BACKGROUND: Spontaneous cervical artery dissection (sCAD) is a common cause of stroke in patients below 55 years. Dermal connective tissue abnormalities have been observed in up to 60% of patients. A chromosomal locus for connective tissue abnormalities associated with sCAD has been mapped to chromosome 15q24 to a candidate region containing the lysyl oxidase-like 1 gene (LOXL1). LOXL1 an excellent candidate susceptibility gene for non-familial sCAD was investigated by mutation analysis and a genetic association study. METHODS: We sequenced the whole coding region of the LOXL1 gene in 15 sCAD patients and performed a genetic association study in 157 sCAD patients using 12 single nucleotide polymorphisms (SNP). RESULTS: The SNP rs3825942 (Gly153Asp) showed marginal association with sCAD on an allele basis and in the dominant genetic model, and intronic SNP rs893817 under a recessive model only. None of the SNP haplotypes was associated with sCAD. CONCLUSIONS: Genetic variation in LOXL1 might play a role as a risk factor for sCAD. PMID- 17690547 TI - Long-term outcome as function of blood pressure in acute ischemic stroke and effects of thrombolysis. AB - BACKGROUND: While baseline blood pressure (BP) is a known predictor of 90-day residual deficit after acute ischemic stroke, the effect of thrombolysis on this relationship has not been described. To study the interaction and to find intervals of prognostic significance, the functional forms of this predictive relationship should be found and compared for recombinant tissue plasminogen activator (rt-PA)- and placebo-treated patients of the first European Cooperative Acute Stroke Study. METHODS: We studied the 615 patients with acute ischemic hemispheric stroke randomized and treated in the first European Cooperative Acute Stroke Study. Endpoints were fatal outcome within and favorable outcome (no or negligible long-term handicap on the modified Rankin Scale scores 0 or 1) after 90 +/- 14 days. Functional relationships with baseline BP were estimated fully nonparametrically as moving averages of occurrences of either outcome among placebo- and rt-PA-treated patients, separately. Visual findings were corroborated by conventionally stratified logistic regression. RESULTS: For favorable outcome, an S-shaped functional relationship with baseline systolic BP (SBP) was found with an averaged incremental rate around 10% per 1 mm Hg increase in baseline SBP between 140 and 160 mm Hg, among rt-PA and placebo patients. Similar results were obtained for diastolic BP (DBP) between 80 and 90 mm Hg. Odds ratios in favor of rt-PA were 1.96 (95% CI: 1.02-3.78) and 2.87 (95% CI: 1.36-6.04) for SBP and DBP in these intervals, respectively. For mortality, visible markedly lower risks in the placebo group between 120 and 140 and between 160 and 180 mm Hg SBP were confirmed with adjusted OR of 2.47 (95% CI: 1.09-5.64) and 9.73 (95% CI: 2.02-46.82), respectively. CONCLUSIONS: Patients benefited from rt-PA in terms of no or negligible handicap after 90 days, without excess risk of death, with baseline SBP between 140 and 160 mm Hg or baseline DBP between 80 and 90 mm Hg. PMID- 17690548 TI - Risk factors of intracranial cerebral atherosclerosis among asymptomatics. AB - BACKGROUND: Little information is available regarding the risk factors for intracranial cerebral atherosclerosis (ICAS), particularly among asymptomatics. METHODS: Data from a consecutive series of 1,208 subjects aged > or =40 years, with no history of stroke, and who had undergone transcranial Doppler ultrasonography (TCD) were collected prospectively. The role of classic risk factors was assessed in the presence and severity of asymptomatic ICAS, which was determined by TCD. RESULTS: Regarding the presence of ICAS, the adjusted odds ratios (95% confidence intervals) were as follows: 1.22 (1.08-1.37) for every 10 year increase in age, 1.44 (1.08-1.91) for hypertension and 1.86 (1.33-2.59) for diabetes mellitus. No significant association was observed with regard to male sex, smoking or hyperlipidemia. CONCLUSION: The findings suggest that age, hypertension and diabetes mellitus are significant risk factors for ICAS in asymptomatic populations. PMID- 17690549 TI - 3-Tesla versus 1.5-Tesla magnetic resonance diffusion and perfusion imaging in hyperacute ischemic stroke. AB - BACKGROUND: Clinical 3-tesla magnetic resonance imaging systems are becoming widespread. No studies have examined differences between 1.5-tesla and 3-tesla imaging for the assessment of hyperacute ischemic stroke (<6 h from symptom onset). Our objective was to compare 1.5-tesla and 3-tesla diffusion and perfusion imaging for hyperacute stroke using optimized protocols. METHODS: Three patients or their surrogate provided informed consent. Diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) was performed sequentially at 1.5 T and 3 T. DWI, apparent diffusion coefficient (ADC) maps and relative time-to-peak (TTP) maps were registered and assessed. DWI contrast-to-noise ratio (CNR) and ADC contrast were measured and compared. The infarct lesion volume (ILV) and thresholded ischemic volume (TIV) were estimated on the ADC and TTP maps, respectively, with the penumbral volume being defined as the difference between these volumes. RESULTS: Qualitatively, the 3-tesla TTP images exhibited greater feature detail. Quantitatively, the DWI CNR and ILV were similar at both field strengths, the ADC contrast was greater at 3 T and the TIV and penumbral volumes were much smaller at 3 T. CONCLUSIONS: Overall, the 3-tesla diffusion and perfusion images were at least as good and in some ways superior to the 1.5-tesla images for assessing hyperacute stroke. The TTP maps showed greater feature detail at 3 T. The ischemic and penumbra volumes were much greater at 1.5 T, indicating a potential difference in the diagnostic utility of the PWI-DWI mismatch between field strengths. PMID- 17690550 TI - Inferior olivary hypertrophy is associated with a lower functional state after pontine hemorrhage. AB - BACKGROUND: Inferior olivary hypertrophy (IOH) may develop after pontine hemorrhage and may become a pacemaker for symptomatic palatal tremor (SPT). However, there is no information available that elucidates how IOH may affect the functional outcome. The purpose of this study was to investigate how frequently IOH was associated with clinical manifestations of involuntary movements, including ocular myoclonus (OM) and SPT, and whether IOH influenced the functional outcome after pontine hemorrhage. METHODS: In 20 consecutive patients undergoing inpatient multidisciplinary rehabilitation after pontine hemorrhage, the location of lesions (tegmental vs. ventral) and the presence of IOH were examined by magnetic resonance imaging, and the functional outcome was assessed by means of Fugl-Meyer scale for neurological impairment and Functional Independence Measure for disability on admission and discharge. RESULTS: In 10 patients, IOH was detected, and the tegmentum was involved in 7 of the 10 patients. OM or SPT was present in 7 of these 10 patients. In the remaining 10 patients, IOH was not detected, and the tegmentum was involved only in 2 of these 10 patients. None of them had OM or SPT. The presence of IOH was associated with a lower functional status on admission and discharge. CONCLUSION: After pontine hemorrhage, IOH may be associated with tegmental lesions with OM or SPT and may impose a detrimental effect on the functional outcome. PMID- 17690551 TI - Diagnostic Performance of Clock Drawing Test by CLOX in an Asian Chinese population. AB - BACKGROUND/AIMS: Clock Drawing Tests are commonly used for cognitive screening, but their clinical utility has not yet been studied in Chinese Singaporeans. We examined the usefulness of a Clock Drawing Test, CLOX, in detecting dementia in our population and explored its performance in the dementia subtypes, Alzheimer's disease (AD), and the vascular composite group (VCG) of AD with cerebrovascular disease and vascular dementia. METHOD: CLOX was administered to 73 subjects (49.3%) with dementia and 75 healthy controls (50.7%). Receiver operating characteristic analysis determined the diagnostic accuracy and optimal cut-off scores, stratified by education. Analysis of Variance was used to compare CLOX scores between AD and VCG. RESULTS: The diagnostic accuracy (area under the curve) was 84 and 85% for CLOX1 and CLOX2, respectively. Cut-offs at 10 for CLOX1 and 12 for CLOX2 yielded sensitivities of 75.3 and 75%, and specificities of 76 and 80%, respectively. The mean CLOX1 but not CLOX2 scores for AD (8.1) and VCG (5.5) remained significantly different (p = 0.002) after adjustment for the covariates age, gender, education, MMSE and dementia stage. CONCLUSION: Our results support CLOX as a valid cognitive screen in Singaporean Chinese with adequate psychometric properties. In addition, CLOX may aid as an adjunct in differentiating AD from dementia with a vascular element, e.g. AD with cerebrovascular disease and vascular dementia. PMID- 17690552 TI - Role of serotonin transporter polymorphisms in the behavioural and psychological symptoms in probable Alzheimer disease patients. AB - BACKGROUND/AIMS: Alzheimer disease (AD) patients commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in AD has been demonstrated. This is an investigation of whether the linked polymorphic region and variable number tandem repeat variants of the serotonin transporter (SERT) are associated with BPSD. METHODS: The longitudinal measures of BPSD of our large cohort of 367 AD patients were assessed by the Neuropsychiatric Inventory. Measures with good evidence of serotonergic involvement (delusions, hallucinations, depression, anxiety, agitation/aggression and irritability) were related to genotype and allele frequencies of the linked polymorphic region and variable number tandem repeat variants. RESULTS: Analysis revealed significant relationships between the linked polymorphic region variant long allele with irritability and the variable number tandem repeat 10-repeat allele with psychosis, but no associations were found with depression, anxiety or agitation/aggression. CONCLUSION: Our data and review of previous studies suggest SERT could play a minor role in development of psychosis and aggressive/irritable tendencies; however, further investigations are required in large, well characterized cohorts. PMID- 17690553 TI - Total tau protein in cerebrospinal fluid and diffusion-weighted MRI as an early diagnostic marker for Creutzfeldt-Jakob disease. AB - BACKGROUND: We have recently begun to doubt the effectiveness of periodic sharp wave complexes observed on electroencephalographs and the detection of 14-3-3 protein in cerebrospinal fluid (CSF) as diagnostic criteria for Creutzfeldt-Jakob disease (CJD). Diffusion-weighted magnetic resonance imaging (DWI) and the detection of total tau (t-tau) protein in CSF may be more sensitive diagnostic criteria. METHODS: Among 44 CJD patients, we selected 21 subjects that suffered from early-stage CJD, which was defined as cases in the 6 weeks following the onset of the disease. The sensitivities of DWI and electroencephalographs, as well as those of t-tau protein, 14-3-3 protein, neuron-specific enolase (NSE), and S-100b protein in CSF were compared as diagnostic markers for early-stage CJD. RESULTS: NSE, S-100b protein, t-tau protein, and 14-3-3 protein were detected in the samples from 57.1, 4.8, 95.2, and 76.2% of the 21 early-stage CJD patients, respectively. Additionally, DWI was used to positively identify 90.5% of these cases. CONCLUSION: We concluded that t-tau protein was the most sensitive of the diagnostic markers for CJD. Moreover, the data in this study showed that detection of t-tau protein combined with DWI identified 98% of the early-stage cases, and these tests should be included as diagnostic criteria for CJD. PMID- 17690554 TI - Symptoms of anxiety and depression in the course of cognitive decline. AB - BACKGROUND/AIMS: Anxiety and depression are common inpatients with cognitive decline and Alzheimer's disease (AD), and recognition and treatment of these symptoms can improve their quality of life. The present study investigates anxiety and depression in different phases of cognitive decline. METHODS: The sample consisted of five groups of elderly people in different phases of cognitive decline; four from a community-based sample (Longitudinal Aging Study Amsterdam), and one group of elderly people diagnosed with AD. ANOVAs were performed to investigate group differences in the severity and prevalence of anxiety and depression, and comorbid anxiety and depressive symptoms. RESULTS: The prevalence rates of anxiety, comorbid anxiety and depressive symptoms and depressive symptoms follow a pattern of an increasing prevalence as cognitive performance declines and a decrease in the prevalence when cognitive functioning is severely impaired. AD patients report fewest anxiety symptoms. CONCLUSION: We found that the prevalence of anxiety symptoms, depressive symptoms and comorbid anxiety and depressive symptoms seems to increase in the early phase of cognitive decline, and decreases as cognitive functioning further declines. Elderly diagnosed with AD report less anxiety as expected, probably due to lack of insight caused by AD. PMID- 17690555 TI - Validity of dementia diagnoses in the Danish hospital registers. AB - BACKGROUND: The validity of dementia diagnoses in the Danish nationwide hospital registers was evaluated to determine the value of these registers in epidemiological research about dementia. METHODS: Two hundred patients were randomly selected from 4,682 patients registered for the first time with a dementia diagnosis in the last 6 months of 2003. The patients' medical journals were reviewed to evaluate if they fulfilled ICD-10 and/or DSM-IV criteria for dementia and specific dementia subtypes. The patients who were still alive in 2006 were invited to an interview. RESULTS: One hundred and ninety-seven journals were available for review and 51 patients were interviewed. A registered diagnosis of dementia was found to be correct in 169 (85.8%) cases. Regarding dementia subtypes, the degree of agreement between the registers and the results of the validating process was low with a kappa of 0.36 (95% CI 0.24-0.48). CONCLUSION: The validity of dementia syndrome in the Danish hospital registers was high and allows for epidemiological studies about dementia. Alzheimer's disease, although underregistered, also had a good validity once the diagnosis was registered. In general, other ICD-10 dementia subtypes in the registers had a low validity and are less suitable for epidemiological research. PMID- 17690556 TI - Incidence and outcome of traumatic brain injury in an urban area in Western Europe over 10 years. AB - INTRODUCTION: Valid epidemiological data on incidence and outcome of traumatic brain injury (TBI) show great variability. A study on incidence, severity and outcome of TBI was conducted in an urban area of one million inhabitants. MATERIALS AND METHODS: 130,000 prehospital emergencies were screened for TBI. INCLUSION CRITERIA: Glasgow Coma Scale (GCS) score or=2 with confirmed TBI via appropriate diagnostics. RESULTS: Annual incidence was 7.3/100,000. Overall mortality rate was 45.8%: 182 (28%) were prehospital deaths, 116 (17.8%) patients died in hospital. Two hundred and fourteen of 352 (60.8%) surviving patients were sufficiently rehabilitated at discharge [Glasgow Outcome Scale (GOS) score = 1], but 138 patients (39.2%) survived with persisting deficits. GOS was associated with initial GCS and AIS(head). CONCLUSION: The incidence of TBI was lower compared to the literature. The overall mortality was high, especially prehospital and early in-hospital mortality rates. PMID- 17690557 TI - Prognoses and prognostic factors of carcinosarcoma, endometrial stromal sarcoma and uterine leiomyosarcoma: a comparison with uterine endometrial adenocarcinoma. AB - AIMS: The aims of this study were to evaluate the factors affecting prognosis in patients with uterine sarcomas and to demonstrate that carcinosarcoma bears a similarity to high-grade endometrial carcinoma in terms of its prognosis and clinicopathological parameters. METHODS: In June 2004, 17 Japanese institutions received questionnaires regarding uterine sarcomas. Study patients had uterine sarcomas initially treated at each institution between January 1990 and May 2004. Survival analyses and comparisons were performed by univariate methods. Patient data of 921 cases of endometrial adenocarcinoma were also analyzed and compared to the data with the uterine sarcomas. RESULTS: One hundred twenty-one patients with uterine sarcomas were identified who met study eligibility criteria. In uterine sarcomas, carcinosarcoma had a worse prognosis than other sarcomas, but the difference was not significant (p = 0.302). In carcinosarcoma, significant differences were observed with age (p = 0.0388), stage (p < 0.01) and surgical procedure (with or without pelvic lymphadenectomy, p = 0.0316). In carcinosarcoma and G3 adenocarcinoma, no significant difference was identified with regard to overall survival in univariate (p = 0.191) and multivariate (p = 0.168) analyses. CONCLUSION: Our results demonstrate that the clinical behavior of carcinosarcoma strongly resembles that of G3 endometrial adenocarcinoma, setting it apart from other 'pure' uterine sarcomas. PMID- 17690558 TI - Apolipoprotein e expression in anaplastic thyroid carcinoma. AB - OBJECTIVES: Apolipoprotein E (Apo E) has been known to play a role in cholesterol transport and metabolism. However, recently the relationship between Apo E and carcinoma progression has been investigated. In this study, we investigated Apo E expression in thyroid carcinoma at both the protein and molecular levels. METHODS: We investigated Apo E expression at the protein and molecular level in 124 thyroid neoplasms. RESULTS: In RT-PCR and in situ hybridization, the Apo E mRNA expression level was very low in papillary and follicular carcinomas as well as normal thyroid, but was dramatically elevated in anaplastic carcinoma. In an immunohistochemical study, 32 of 33 anaplastic carcinomas (97.0%) showed high levels of Apo E expression, but this phenomenon was seen only in 1 of 51 papillary carcinomas (2.0%). None of the follicular carcinomas or adenomas showed high levels of Apo E expression. CONCLUSIONS: These findings suggest that Apo E is one of the typical biological characteristics of anaplastic thyroid carcinoma. PMID- 17690559 TI - Twist expression predicts poor clinical outcome of patients with clear cell carcinoma of the ovary. AB - OBJECTIVES: Twist is a highly conserved basic helix-loop-helix transcription factor that regulates the expression of E-cadherin and promotes the epithelial mesenchymal transition, which is critical for tumor infiltration. We examined the distribution and expression of this molecule in clear cell carcinoma of the ovary (CCC) to elucidate their clinical significance. METHODS: Paraffin sections from CCC tissues (n = 27) were immunostained with Twist antibody and staining intensities were evaluated. Stratified with various clinicopathological factors, overall survival (OS) and progression-free survival (PFS) were evaluated. RESULTS: In the 27 carcinomas, negative Twist immunoexpression was observed in 14 cases (51.9%), and positive immunoexpression in 13 (48.1%). Twist, when categorized into negative versus positive expression, was associated with FIGO stage and peritoneal cytology. In addition, positive Twist expression significantly predicted a poorer OS and PFS compared with negative expression (p < 0.0001). Furthermore, the multivariate analyses revealed that positive Twist expression was an independent prognostic factor for OS and PFS of patients with CCC in this study (p = 0.0077 and 0.0033, respectively). CONCLUSION: The current findings suggest that the assessment of Twist immunoreactivity may be a useful prognostic indicator and that Twist may play a critical role in the progression of CCC. PMID- 17690560 TI - The synergistic effect of 5-aza-2'-deoxycytidine and 5-fluorouracil on drug resistant tumors. AB - PURPOSE: We investigated whether a 5-fluorouracil (5-FU)-resistant tumor could regain chemosensitivity after the administration of 5-aza-2'-deoxycytidine (DAC) as a demethylating agent. METHODS: Human colorectal cancer cells (SW48) are characterized by the hypermethylation of proapoptotic genes. They were transplanted into 20 athymic BALB/c nu/nu mice which were randomly placed into 4 groups (1 = control; 2 = 5-FU alone; 3 = DAC alone; 4 = DAC followed by 5-FU). We evaluated the synergistic effect of DAC and 5-FU on the growth of these xenografts. Reactivation of proapoptotic genes in these cells was analyzed by methylation-specific PCR. Gene expression was determined by a quantitative reverse-transcription PCR assay. RESULTS: Compared with the control group, relative tumor volumes were statistically significantly decreased only in group 4 mice (p = 0.006). In groups 3 and 4, p14, p16 and death-associated protein kinase (DAPK) promoter regions were demethylated and p14 gene expression was gradually increased after DAC administration. CONCLUSION: DAC could be a useful medicine that breaks the silencing of various genes and recovers some expressions. By pretreating with DAC at a nontoxic level, we confirmed the restoration of 5-FU chemosensitivity and apoptosis induction. The combination of demethylating agents and several cytotoxic drugs has potential in clinical practice. PMID- 17690561 TI - Prognosis of occult breast carcinoma presenting as isolated axillary nodal metastasis. AB - Axillary metastasis from an occult breast carcinoma is an uncommon presentation and presents a therapeutic dilemma. The objective of this study is to describe the presenting clinical features, management approach and treatment outcomes for occult breast carcinoma. We conducted a retrospective review of patients who presented with axillary nodal metastases from an occult breast carcinoma between 1997 and 2004 at the Roswell Park Cancer Institute; 2,150 patients were diagnosed and treated for breast cancer during this period. After excluding stage I and IV patients, we identified 642 who had disease metastatic to lymph nodes, 10 of these had no primary tumor in the breast despite a thorough evaluation including bilateral mammography and breast ultrasound. Of these, 7 had undergone breast magnetic resonance imaging as well. All patients underwent axillary nodal dissection. The breast was managed with radiotherapy alone in 8 patients, wide local excision with radiation therapy in 1 patient and 1 patient underwent mastectomy. No patient had a recurrence with a median 57 months of follow-up. Breast conservation with radiation therapy alone can be considered as a management option for women with occult breast cancer presenting with axillary nodal metastasis. PMID- 17690562 TI - Three different bradycardic agents, zatebradine, diltiazem and propranolol, distinctly modify heart rate variability and QT-interval variability. AB - Zatebradine, diltiazem and propranolol are all antiarrhythmic agents, and all induce bradycardia, but each is known to have a different initial molecular mechanism: zatebradine is a channel blocker of the hyperpolarization-activated inward current (I(f)); diltiazem is a blocker of the L-type Ca(2+) channel (I(CaL)), and propranolol is a beta-blocker. To further investigate the mechanisms underlying their clinical effects, we studied their effects on heart rate variability (HRV) and QT-interval variability (QTV). To this end, guinea pigs were treated with either zatebradine (1.5 mg/kg, i.p.), diltiazem (40 mg/kg, i.p.) or propranolol (20 mg/kg, i.p.). A dose of each agent that decreased HR by 20-22% was used in this study. HRV and QTV were analyzed by a fast Fourier and/or a wavelet transform algorithm. Zatebradine, an I(f) channel blocker, had no significant effect on HRV and QTV. Diltiazem, a non-dihydropyridine I(CaL) blocker, increased high frequency (HF) power and decreased the power ratio of the low frequency (LF) range to the HF range (L/H) in HRV, and increased QTV. Propranolol, a non-selective beta-antagonist, decreased LF power and L/H ratios in HRV, and appreciably reduced QTV. These differences in pharmacological action may help us better understand the antiarrhythmic and/or proarrhythmic actions of these agents when they are used clinically for reducing HR. PMID- 17690563 TI - In vitro P-glycoprotein-mediated transport of (R)-, (S)-, (R,S)-methadone, LAAM and their main metabolites. AB - Methadone and L-alpha-acetylmethadol (LAAM) are used as treatment for opiate addiction. Using a cellular model, we aimed to determine if methadone, LAAM and their main metabolites are substrates of the human P-glycoprotein transporter (P gp), which is encoded by the ABCB1 gene, and whether methadone transport exhibits stereoselectivity. Pig kidney epithelial cells (control) and human ABCB1 transfected cells were incubated with methadone, LAAM and their metabolites, and their intra- and extracellular concentrations were measured. The intra- to extracellular ratios of methadone, LAAM and their metabolites were all decreased in ABCB1-transfected cells compared to controls (p < 0.05), thus indicating that they are substrates of P-gp. A weak stereoselectivity in methadone transport was observed towards the (S)-enantiomer. P-gp may therefore affect the pharmacokinetics and pharmacodynamics of methadone and LAAM. PMID- 17690564 TI - Stopping antiretroviral therapy. PMID- 17690565 TI - Levels of antigen processing machinery components in dendritic cells generated for vaccination of HIV-1+ subjects. AB - OBJECTIVE: To evaluate expression of the antigen processing machinery (APM) components and HLA molecules by monocyte-derived dendritic cells (DC) generated from chronically HIV-1 infected subjects on antiretroviral therapy (ART) and to assess their ability to ex vivo induce HIV-1 specific T cells. METHODS: DC generated in 16 HLA-A2 positive patients were matured in cytokines, pulsed with HIV-1 or other viral peptides and tested in interferon (IFN)-gamma ELISPOT assays. Immature (i)DC, mature (m)DC and viral peptide-pulsed DC were studied by multiparameter quantitative flow cytometry for intracellular APM component expression and for HLA class I and II, beta-2 microglobulin and co-stimulatory molecule surface expression. DC from 13 normal donors served as controls. RESULTS: Marked heterogeneity in APM component expression levels in iDC and mDC from HIV-1 positive subjects was observed. Nevertheless, the median levels were comparable to those in iDC and mDC, respectively, from normal donors. Patients' mDC pulsed with the HIV-1, influenza A, cytomegalovirus (CMV) or Epstein-Barr virus peptides induced IFN-gamma production by T cells specific for these peptides in ELISPOT assays. The frequency of T cells responsive to influenza A, cytomegalovirus or Epstein-Barr virus peptides was comparable in the patients and normal donors. CONCLUSIONS: The APM component expression profiles of iDC and mDC were more heterogeneous in subjects with chronic HIV-1 infection on ART, than those in normal donors, although not statistically different. Ex vivo, patients' DC pulsed with HIV-1 peptides induced IFN-gamma production from autologous T cells. Thus, DC obtained from HIV-1 infected subjects on ART were phenotypically and functionally competent. PMID- 17690566 TI - Understanding the diversification of HIV-1 groups M and O. AB - OBJECTIVE: To quantify the similarity (or lack of) between the phylogenetic substructure of HIV-1 groups O and M. METHODS: Two phylogenetic tree statistics- the subtype diversity ratio (SDR) and the subtype diversity variance (SDV)--were used in conjunction with bootstrap replicates on gag, pol and env sequence alignments of group O and M strains. Randomly generated phylogenetic trees were used as a control. RESULTS: We show that, as expected, the established global group M subtypes have a high degree of phylogenetic symmetry in relation to each other in terms of inter- and intra-subtype diversification. They are significantly different from the substructure present amongst the random trees. To the contrary, the group O diversification does not display this highly symmetrical substructure and is not significantly different from the substructure present on randomly generated trees. Phylogenies comprised of group M strains from the epicentre of the HIV/AIDS pandemic, the Democratic Republic of Congo (DRC), exhibit a substructure more similar to group O than to global-group M. CONCLUSIONS: The substructure present within groups O and M is quantifiably different. The well defined clades, the subtypes that characterize group M diversification, are not present in group O or amongst group M strains from the DRC. The group M subtypes are thus unique and a signature of pandemic HIV-1. PMID- 17690567 TI - Identification of a novel hepatitis B virus precore/core deletion mutant in HIV/hepatitis B virus co-infected individuals. AB - OBJECTIVES: Although HAART has resulted in improved health outcomes for most HIV infected individuals, liver failure has emerged as a major cause of morbidity and mortality in people co-infected with hepatitis B virus (HBV). In HBV mono infected individuals, core deletion mutants are associated with more aggressive liver disease. As HIV accelerates HBV liver disease progression, we hypothesized that HIV-HBV co-infected individuals have increased frequency of core mutations including deletions. To test this hypothesis, we have analysed genome-length sequences of HBV DNA from patients both prior to and during antiviral therapy. SETTING: Prospective HIV/HBV co-infected cohort study. METHODS: Genomic length HBV DNA was amplified by PCR from the serum samples of ten HIV/HBV co-infected individuals and five HBV mono-infected individuals prior to the commencement of lamivudine therapy and again after nine to 74 months of treatment. The complete genomes were sequenced and in order to further analyse some mutations, their frequency was determined in additional HIV/HBV co-infected and HBV mono-infected individuals. RESULTS: A novel -1G mutation was identified in the HBV precore and overlapping core genes that truncated the deduced precore/core proteins. The mutant genome was the dominant species in some HIV/HBV co-infected individuals and was more prevalent in HIV/HBV co-infected individuals than HBV mono-infected individuals. The mutation was also associated with high HBV DNA concentrations in HIV/HBV co-infected individuals. Additional mutations were identified in the core/precore and polymerase genes and regulatory regions. CONCLUSION: Mutations in the HBV core and precore genes may be contributing to disease pathogenesis in HIV/HBV co-infected individuals. PMID- 17690568 TI - Pneumocystis jiroveci pneumonia prophylaxis is not required with a CD4+ T-cell count < 200 cells/microl when viral replication is suppressed. AB - OBJECTIVE: To determine the safety of discontinuing Pneumocystis jiroveci pneumonia (PCP) prophylaxis, in patients on effective antiretroviral therapy with CD4+ T-cell counts that have plateaued at < 200 cells/microl. METHODS: We prospectively evaluated a cohort of HIV infected patients at a multidisciplinary HIV clinic with sustained HIV RNA levels < 50 copies/ml and CD4+ T-cell counts that have plateaued at < 200 cells/microl and who have discontinued PCP prophylaxis. RESULTS: Nineteen patients fulfilled the above criteria. Eleven had been taking daily trimethoprim-sulfamethoxazole, seven were receiving monthly aerosolized pentamidine, and one patient never received any prophylaxis. The median CD4+ T-cell count at the time of discontinuation and at the most recent determination were 120 (range, 34-184) and 138 (range, 6-201) cells/microl, respectively. To date, patients have been off PCP prophylaxis for a mean of 13.7 +/- 10.6 months and a median of 9.0 (range 3-39) months for a total of 261 patient-months. To date, no patient has developed PCP. This is significantly different from the risk of developing PCP with a CD4+ T-cell count of < 200 cells/microl in untreated HIV infection (rate difference 9.2%; 95% confidence interval, 5.7 to 12.8%; P < 0.05). CONCLUSION: With sustained suppression of viral replication, PCP prophylaxis may not be necessary, regardless of CD4+ T cell count. This illustrates a degree of immune recovery that occurs with virologic suppression that is not reflected in absolute CD4+ T-cell count or percentage and suggests that guidelines for P. jiroveci pneumonia prophylaxis may need to be re-evaluated. PMID- 17690569 TI - Rate of AIDS diseases or death in HIV-infected antiretroviral therapy-naive individuals with high CD4 cell count. AB - OBJECTIVE: To assess the absolute rate of AIDS and death in antiretroviral therapy (ART)-naive patients with a high CD4 cell count. Such information would be helpful in the design of a trial investigating early initiation of ART. DESIGN: Analysis of data from an ongoing HIV cohort study. METHODS: The rate of (severe) AIDS or death and death alone was evaluated in ART-naive patients according to the current CD4 cell count, focusing on CD4 cell counts > or = 350 cells/microl among patients in the UK CHIC Study. RESULTS: In a total of 30 313 person-years of follow-up, there were 1557 AIDS or death events. The rate of AIDS or death in persons with most recent CD4 cell count 350-499, 500-649 and > 650 cells/microl was 2.49, 1.54 and 0.96 per 100 person-years, respectively. The rate ratio for those with CD4 cell count 500-649 cells/microl compared with those with CD4 cell count > or = 650 cells/microl was 1.55 [95% confidence interval (CI), 1.11-2.17; P = 0.01]. In a Poisson regression model based on person years with CD4 cell count > or = 350 cells/microl , there was a strong effect of CD4 cell count on rate of AIDS or death (rate ratio, 0.84; 95% CI, 0.76-0.93; P = 0.001), independent of viral load and age. CONCLUSIONS: The trend of decreasing rate of AIDS and death with higher CD4 cell count is present throughout the CD4 cell count > or = 350 cells/microl range in ART-naive people. PMID- 17690571 TI - Longitudinal increases in waist circumference are associated with HIV-serostatus, independent of antiretroviral therapy. AB - BACKGROUND: The relative contributions of the different classes of antiretroviral therapy (ART), HIV infection per se, and aging to body shape changes in HIV infected patients have not been clearly defined in longitudinal studies. METHODS: Since September 1999, men enrolled in the Multicenter AIDS Cohort Study have undergone measurements of body mass index (BMI) and body circumferences at each semi-annual visit. The effect of HIV-serostatus and cumulative exposure to the three major ART classes on changes in anthropomorphic measurements occurring between 1999 and 2004 among HIV-infected and HIV-uninfected men were determined using linear mixed effects regression models. RESULTS: At baseline, average BMI and circumference measurements were greater in HIV-uninfected men (n = 392) than HIV-infected men (n = 661) (BMI, 27.3 versus 25.3 kg/m; waist, 96.4 versus 90.2 cm; hip 101.3 versus 95 cm, thigh 54.1 versus 50.8 cm; arm 33.3 versus 31.7 cm, P < 0.001 for each comparison). Cumulative nucleoside reverse transcriptase inhibitor (NRTI) exposure, but not protease inhibitor or non-nucleoside reverse transcriptase inhibitor exposure, was associated with statistically significant changes in BMI (-0.11 +/- 0.04 kg/m per year) and in circumferences of waist ( 0.27 +/- 0.07 cm/year), hip (-0.24 +/- 0.05 cm/year), and thigh (-0.16 +/- 0.03 cm/year) over the 5 years of follow-up. Independent of ART exposure, HIV-infected men had a more rapid increase in waist circumference over the study interval than did the HIV-uninfected men (difference 0.33 +/- 0.15 cm/year, P = 0.02). CONCLUSION: Cumulative NRTI therapy was associated with longitudinal decreases in body circumference measurements, whereas HIV-serostatus was associated with increases in waist circumference independent of ART. PMID- 17690570 TI - Amplified transmission of HIV-1: comparison of HIV-1 concentrations in semen and blood during acute and chronic infection. AB - OBJECTIVES: This study was conducted to compare viral dynamics in blood and semen between subjects with antibody negative, acute HIV-1 infection and other subjects with later stages of infection. DESIGN: A prospective cohort study was embedded within a cross-sectional study of HIV screening in a Lilongwe, Malawi STD clinic. METHODS: Blood samples from HIV antibody negative or indeterminate volunteers were used to detect HIV RNA in plasma using a pooling strategy. Blood and seminal plasma HIV-1 RNA concentrations were measured over 16 weeks. RESULTS: Sixteen men with acute HIV infection and 25 men with chronic HIV infection were studied. Blood viral load in subjects with acute HIV infection was highest about 17 days after infection (mean +/- SE, 6.9 +/- 0.5 log10 copies/ml), while semen viral load peaked about 30 days after infection (4.5 +/- 0.4 log10 copies/ml). Semen viral load declined by 1.7 log10 to a nadir by week 10 of HIV infection. Semen and blood viral loads were more stable in chronically infected subjects over 16 weeks. Higher semen levels of HIV RNA were noted in subjects with low CD4 cell counts. CONCLUSIONS: These results provide a biological explanation for reported increases in HIV transmission during the very early (acute) and late stages of infection. Recognizing temporal differences in HIV shedding in the genital tract is important in the development of effective HIV prevention strategies. PMID- 17690572 TI - Antiretroviral therapy exposure and incidence of diabetes mellitus in the Women's Interagency HIV Study. AB - OBJECTIVE: To determine the incidence of diabetes mellitus (DM) in a nationally representative cohort of HIV-infected women and a comparison group of HIV uninfected women. DESIGN: A prospective study between October 2000 and March 2006 of 2088 participants from the Women's Interagency HIV Study who did not have evidence of DM at enrollment (1524 HIV infected and 564 HIV uninfected). METHODS: Incident DM was defined as either having fasting glucose > or = 1.26 g/l, reporting antidiabetic medication, or reporting DM diagnosis (with subsequent confirmation by fasting glucose > or = 1.26 g/l or reported antidiabetic medication); all were assessed at semi-annual study visits. RESULTS: DM developed in 116 HIV-infected and 36 HIV-uninfected women over 6802 person-years. HIV infected women reporting no recent antiretroviral therapy had a DM incidence rate of 1.53/100 person-years; those reporting HAART containing a protease inhibitor (PI) had a rate of 2.50/100 person-years and those reporting non-PI-containing HAART a rate of 2.89/100 person-years. None of these rates differed from the HIV uninfected women (1.96/100 person-years) substantially or beyond levels expected by chance. Among HIV-infected women, longer cumulative exposure to nucleoside reverse transcriptase inhibitors (NRTI) was associated with an increased risk of DM incidence compared with no NRTI exposure: relative hazard (RH) 1.81 [95% confidence interval (CI), 0.83-3.93] for > 0 to 3 years exposure and RH 2.64 (95% CI, 1.11-6.32) for > 3 years exposure. CONCLUSION: Longer cumulative exposure to NRTI was associated with increased DM incidence in HIV-infected women. Regular DM monitoring is advisable because NRTI form the backbone of effective antiretroviral therapy. PMID- 17690573 TI - Circulating memory B-cell subpopulations are affected differently by HIV infection and antiretroviral therapy. AB - OBJECTIVE: To determine if the depletion of IgM memory B cells might contribute to the increased susceptibility of HIV patients to pneumococcal infection, memory B-cell subpopulations were investigated in HIV patients, including patients receiving antiretroviral therapy (ART). METHODS: Blood B cells with the phenotype of IgM memory B cells (CD27, IgM) and switched memory B cells (CD27, IgM) were measured in antiretroviral-treated (n = 32) and untreated (n = 24) HIV patients and non-HIV controls (n = 35). Serum levels of IgG and IgG2 antibodies to pneumococcal polysaccharides, IgG, IgG subclasses, IgM and IgA were also assayed in HIV patients. RESULT: Switched memory B-cell counts were lower than controls in HIV patients (P < 0.01) irrespective of antiretroviral status and correlated with CD4 T-cell counts (r = 0.56, P = 0.001) in treated patients. In untreated patients, IgM memory B-cell counts correlated with CD4 T-cell counts (r = 0.73, P < 0.0001) reflecting higher values than controls in patients with CD4 T-cell counts greater than 300 cells/microl (P = 0.004) and lower values than controls in patients with CD4 T-cell counts below 300 cells/microl (P = 0.0001). There was no relationship between serum levels of pneumococcal antibodies and IgM or switched memory B cells. CONCLUSION: The depletion of IgM memory B cells in untreated HIV patients with a CD4 T-cell count below 300 cells/microl might be a risk factor for pneumococcal infection. The depletion of switched memory B cells is a complication of HIV infection irrespective of ART and might contribute to impaired IgG antibody responses. Memory B-cell subpopulations might predict the risk of pneumococcal sepsis more accurately than the CD4 T-cell count or pneumococcal antibody levels. PMID- 17690574 TI - African infants' CCL3 gene copies influence perinatal HIV transmission in the absence of maternal nevirapine. AB - BACKGROUND: Individuals with more copies of CCL3L1 (CCR5 ligand) than their population median have been found to be less susceptible to HIV infection. We investigated whether maternal or infant CCL3L1 gene copy numbers are associated with perinatal HIV transmission when single-dose nevirapine is given for prevention. METHOD: A nested case-control study was undertaken combining data from four cohorts including 849 HIV-infected mothers and their infants followed prospectively in Johannesburg, South Africa. Access to antiretroviral drugs for the prevention of perinatal transmission differed across the cohorts. Maternal and infant CCL3L1 gene copy numbers per diploid genome (pdg) were determined by real-time polymerase chain reaction for 79 out of 83 transmitting pairs ( approximately 10% transmission rate) and 235 randomly selected non-transmitting pairs. RESULTS: Higher numbers of infant, but not maternal, CCL3L1 gene copies were associated with reduced HIV transmission (P = 0.004) overall, but the association was attenuated if mothers took single-dose nevirapine or if the maternal viral load was low. Maternal nevirapine was also associated with reduced spontaneously released CCL3 (P = 0.007) and phytohemagglutinin-stimulated CCL3 (P = 0.005) production in cord blood mononuclear cells from uninfected infants. CONCLUSION: We observed a strong association between higher infant CCL3L1 gene copies and reduced susceptibility to HIV in the absence of maternal nevirapine. We also observed a reduction in newborn CCL3 production with nevirapine exposure. Taken together, we hypothesize that nevirapine may have direct or indirect effects that partly modify the role of the CCR5 ligand CCL3 in HIV transmission, obscuring the relationship between this genetic marker and perinatal HIV transmission. PMID- 17690575 TI - Interleukin-10-secreting CD4 cells from aged patients with AIDS decrease in-vitro HIV replication and tumour necrosis factor alpha production. AB - OBJECTIVE: To evaluate the impact of age on the proliferative response, cytokine profile and viral kinetics in AIDS patients treated successfully with antiretroviral drugs. METHODS: Peripheral blood mononuclear cells (PBMC), CD4 cell-depleted PBMC or CD4 T cells from young adult and aged HIV-1-infected patients were activated in vitro with anti-CD3 with or without interleukin (IL) 2. Lymphoproliferation and cytokines were measured after 3 days and in-vitro HIV 1 replication after 7 days. RESULTS: Both lymphoproliferation and cytokine [IL 1beta, tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma)] secretion were higher in younger than in older AIDS patients. In cultures of cells derived from aged patients and activated by anti-CD3, IFN-gamma production was severely damage and IL-10 production was much higher. Although IL-2 addition to activated PBMC elevated IFN-gamma secretion, IL-10 production remained elevated in the aged group. The depletion of CD4 T lymphocytes from these cultures dramatically reduced released IL-10 in the older group but did not alter significantly IFN-gamma production. Interestingly, higher IL-10 levels produced by CD4 T cells were related to lower in-vitro HIV-1 replication, and the blockade of this cytokine by anti-IL-10 monoclonal antibody enhanced virus replication. This effect may be correlated with elevated TNF-alpha secretion. Finally, impaired IFN-gamma secretion detected in activated CD4 T cells obtained from aged patients was not directly correlated with high IL-10 production. CONCLUSIONS: Elevated IL-10 production by aged AIDS patients contributed considerably to control of HIV replication and to inhibition of TNF-alpha secretion but not to the reduced IFN-gamma production. PMID- 17690576 TI - Hormonal contraceptive use, herpes simplex virus infection, and risk of HIV-1 acquisition among Kenyan women. AB - BACKGROUND: Studies of the effect of hormonal contraceptive use on the risk of HIV-1 acquisition have generated conflicting results. A recent study from Uganda and Zimbabwe found that women using hormonal contraception were at increased risk for HIV-1 if they were seronegative for herpes simplex virus type 2 (HSV-2), but not if they were HSV-2 seropositive. OBJECTIVE: To explore the effect of HSV-2 infection on the relationship between hormonal contraception and HIV-1 in a high risk population. Hormonal contraception has previously been associated with increased HIV-1 risk in this population. METHODS: Data were from a prospective cohort study of 1206 HIV-1 seronegative sex workers from Mombasa, Kenya who were followed monthly. Multivariate Cox proportional hazards analyses were used to adjust for demographic and behavioral measures and incident sexually transmitted diseases. RESULTS: : Two hundred and thirty-three women acquired HIV-1 (8.7/100 person-years). HSV-2 prevalence (81%) and incidence (25.4/100 person-years) were high. In multivariate analysis, including adjustment for HSV-2, HIV-1 acquisition was associated with use of oral contraceptive pills [adjusted hazard ratio (HR), 1.46; 95% confidence interval (CI), 1.00-2.13] and depot medroxyprogesterone acetate (adjusted HR, 1.73; 95% CI, 1.28-2.34). The effect of contraception on HIV-1 susceptibility did not differ significantly between HSV-2 seronegative versus seropositive women. HSV-2 infection was associated with elevated HIV-1 risk (adjusted HR, 3.58; 95% CI, 1.64-7.82). CONCLUSIONS: In this group of high risk African women, hormonal contraception and HSV-2 infection were both associated with increased risk for HIV-1 acquisition. HIV-1 risk associated with hormonal contraceptive use was not related to HSV-2 serostatus. PMID- 17690577 TI - Men's circumcision status and women's risk of HIV acquisition in Zimbabwe and Uganda. AB - OBJECTIVE: To assess whether male circumcision of the primary sex partner is associated with women's risk of HIV. DESIGN: Data were analyzed from 4417 Ugandan and Zimbabwean women participating in a prospective study of hormonal contraception and HIV acquisition. Most were recruited from family planning clinics; some in Uganda were referred from higher-risk settings such as sexually transmitted disease clinics. METHODS: Using Cox proportional hazards models, time to HIV acquisition was compared for women with circumcised or uncircumcised primary partners. Possible misclassification of male circumcision was assessed using sensitivity analysis. RESULTS: At baseline, 74% reported uncircumcised primary partners, 22% had circumcised partners and 4% had partners of unknown circumcision status. Median follow-up was 23 months, during which 210 women acquired HIV (167, 34, and 9 women whose primary partners were uncircumcised, circumcised, or of unknown circumcision status, respectively). Although unadjusted analyses indicated that women with circumcised partners had lower HIV risk than those with uncircumcised partners, the protective effect disappeared after adjustment for other risk factors [hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.69-1.53]. Subgroup analyses suggested a non-significant protective effect of male circumcision on HIV acquisition among Ugandan women referred from higher-risk settings: adjusted HR 0.16 (95% CI, 0.02-1.25) but little effect in Ugandans (HR, 1.33; 95% CI, 0.72-2.47) or Zimbabweans (HR, 1.12; 95% CI, 0.65-1.91) from family planning clinics. CONCLUSIONS: After adjustment, male circumcision was not significantly associated with women's HIV risk. The potential protection offered by male circumcision for women recruited from high risk settings warrants further investigation. PMID- 17690578 TI - Effectiveness of the WHO/UNICEF guidelines on infant feeding for HIV-positive women: results from a prospective cohort study in South Africa. AB - BACKGROUND: The World Health Organization (WHO) and UNICEF recommend that HIV positive women should avoid all breastfeeding only if replacement feeding is acceptable, feasible, affordable, sustainable and safe. Little is known about the effectiveness of the implementation of these guidelines in developing country settings. OBJECTIVE: To identify criteria to guide appropriate infant-feeding choices and to assess the effect of inappropriate choices on infant HIV-free survival. METHOD: Prospective cohort study of 635 HIV-positive mother-infant pairs across three sites in South Africa to assess mother to child transmission of HIV. Semistructured questionnaires were used during home visits between the antenatal period and 36 weeks after delivery to collect data concerning appropriateness of infant feeding choices based on the WHO/UNICEF recommendations. RESULTS: Three criteria were found to be associated with improved infant HIV-free survival amongst women choosing to formula feed: piped water; electricity, gas or paraffin for fuel; and disclosing HIV status. Using these criteria as a measure of appropriateness of choice: 95 of 311 women who met the criteria (30.5%) chose to breastfeed and 195 of 289 women who did not meet the criteria (67.4%) chose to formula feed. Infants of women who chose to formula feed without fulfilling these three criteria had the highest risk of HIV transmission/death (hazard ratio, 3.63; 95% confidence interval, 1.48-8.89). CONCLUSIONS: Within operational settings, the WHO/UNICEF guidelines were not being implemented effectively, leading to inappropriate infant-feeding choices and consequent lower infant HIV-free survival. Counselling of mothers should include an assessment of individual and environmental criteria to support appropriate infant-feeding choices. PMID- 17690579 TI - Determinants of adherence to highly active antiretroviral therapy among HIV-1 infected patients in Cote d'Ivoire. AB - OBJECTIVE: To assess adherence to HAART and to determine factors associated with poor adherence among HIV-1-infected patients in Abidjan, Cote d'Ivoire. METHODS: A prospective observational study of 614 consecutive patients attending an HIV/AIDS outpatient clinic. Adherence was measured twice at 3-month intervals by self-report of missing doses over 4 days. An adherence level of less than 95% was defined as poor adherence. We used generalized estimating equation models for binomial distribution with repeated measures for data analysis. RESULTS: Of the 591 subjects who completed the study, 74.3% reported adherence levels of 95% or greater. Six factors were independently related to poor adherence: age less than 35 years [relative risk (RR) 1.45; 95% confidence interval (CI) 1.17-1.79], absence of social support (RR 1.66; 95% CI 1.24-2.24), number of daily pills 10 or more (RR 1.47; 95% CI 1.14-1.91), time of adherence assessment (first versus second time assessment RR 1.36; 95% CI 1.12-1.66), CD4 cell count of 250 cells/mul or greater (RR 1.43; 95% CI 1.10-1.88), and not being less worried about HIV infection now that treatments have improved (RR 1.26; 95% CI 1.01 1.58). Drug supply interruptions in the pharmacies were reported by 10.0% of the non-adherent patients as the reason for missing pills. CONCLUSION: Psychosocial factors were found to impact adherence and should be analysed in more detail by further studies. Scaling up antiretroviral therapy in sub-Saharan Africa should be preceded by reliable drug supply and distribution systems. PMID- 17690580 TI - Risk factors for early mortality in children on adult fixed-dose combination antiretroviral treatment in a central hospital in Malawi. AB - OBJECTIVES: In children aged less than 15 years, to determine the cumulative proportion of deaths occurring within 3 and 6 months of starting split-tablet adult fixed-dose combination antiretroviral therapy (ART) and to identify risk factors associated with early deaths. DESIGN: A retrospective cohort analysis. METHODS: Data were collected and analysed from ART patient master cards and the ART register of all children registered for treatment between July 2004 and September 2006 in the ART clinic at Mzuzu Central Hospital, northern Malawi. RESULTS: A total of 439 children started on ART, of whom 220 (50%) were male; 37 (8%) were aged less than 18 months, 172 (39%) 18 months to 5 years, and 230 (52%) were 6-14 years. By September 2006, 49 children (11%) had died, of whom 35 (71%) died by 3 months and 44 (89%) by 6 months. The cumulative incidence of death at 3, 6, 12 and 24 months after ART was 8, 12, 13 and 15%, respectively. After multivariate analysis, being in World Health Organization clinical stage 4, having severe wasting and severe immunodeficiency were factors significantly associated with 3-month mortality and 6-month mortality, respectively. CONCLUSION: Although children do well on ART, there is high early mortality. Scaling up HIV testing and simple diagnostic tests for infants and children, expanding routine provision of cotrimoxazole prophylaxis, and investigating the role of nutritional interventions are three measures that, if implemented and expanded countrywide, may improve ART outcomes. PMID- 17690581 TI - HCV/HIV co-infection, HCV viral load and mode of delivery: risk factors for mother-to-child transmission of hepatitis C virus? AB - BACKGROUND: Hepatitis C virus (HCV) infection in children is mainly acquired via maternal transmission. Our aim was to identify mother-to-child-transmission (MTC) risk factors, namely those associated with maternal virological characteristics and mode of delivery. METHODS: Women were included between October 1998 and September 2002 in six hospitals in Southern France on the basis of positive HCV serological status. Recorded data included maternal characteristics, circumstances of delivery and laboratory data concerning mother and child. Paediatric follow-up lasted 1 year, and 2 years for children with circulating HCV RNA. RESULTS: A total of 214 mother-and-child pairs were analysed; 55 (26%) were HCV/HIV co-infected. The probability of HCV transmission was three-fold higher for HCV/HIV-co-infected women (P = 0.05). Twelve children were HCV RNA positive at 1 year of age (MTC = 5.6%); three became HCV RNA negative between 12 (M12) and 18 months of age (M18) and recovered normal alanine aminotransferase levels. Circulating HCV RNA was found in 137 (69%) mothers. Mothers of infected children all displayed HCV viraemia (MTC = 8.8%): six children were born of HCV/HIV-co infected HCV RNA positive women (MTC = 13.6%) and six from HCV monoinfected women with positive HCV RNA (MTC = 6.5%). When maternal HCV RNA levels were below 6 log IU/ml, the rate of transmission was significantly higher in the case of HCV/HIV co-infection (odds ratio = 8.3, 95% confidence interval, 1.4-47.5) P = 0.01. This association did not, however, exist for HCV RNA-positive mothers with levels of at least 6 log-IU/ml. Rate of transmission did not differ significantly between children born by vaginal delivery or caesarean section after membrane rupture and those born by elective caesarean section independently of HIV status. PMID- 17690582 TI - Stopping antiretroviral therapy: easier said than done. PMID- 17690583 TI - Treatment for lipoatrophy: facing the real costs. PMID- 17690584 TI - Efficacy of boosted protease inhibitor monotherapy in patients with complex medical problems. AB - The efficacy of boosted protease inhibitor monotherapy (BPIm) in HIV-positive patients with complex medical problems was assessed in ten patients. With BPIm, median (range) HIV viral load reduction was log10 2.15 (1.62-3.1) by 4-8 weeks; in four patients, viral load was < 400 copies/ml. During follow-up, at median (range) = 50 (8-156) weeks, no patient had an opportunistic illness; one patient developed new PI mutations after 48 weeks. These very preliminary data need further confirmation on a larger scale. PMID- 17690585 TI - Are disulfiram-like reactions associated with abacavir-containing antiretroviral regimens in clinical practice? AB - Abacavir is metabolized primarily by two enzymes: alcohol dehydrogenase and gluconyl transferase. Under normal conditions, alcohol is hepatically cleared via alcohol dehydrogenase to acetaldehyde, and subsequently by acetaldehyde dehydrogenase (ACD) to acetic acid. Disulfiram acts as an ACD blocker. Abacavir may also act as an inhibitor of alcohol dehydrogenase, which raises the possibility of disulfiram-like reactions (if complete inhibition occurs) or reduced alcohol tolerance (if partial inhibition occurs) occurring with abacavir therapy. PMID- 17690586 TI - Continuous evidence of fast HIV disease progression related to class-wide resistance to antiretroviral drugs: a 6 year follow-up analysis of a large observational database. AB - Class-wide resistance (CWR) was increasingly associated with a higher risk of HIV progression after 72 months of follow-up among 1392 patients genotypic-tested after failure (AIDS risk 13% for no CWR to 34% for three CWR; AIDS/death risk 21 54%). At multivariate analysis, the detection of two and three CWR was significantly associated with a two and threefold increased risk, respectively, of death and AIDS/death, suggesting that extended resistance is a marker of disease progression in long-term observation. PMID- 17690587 TI - Virological failure and subsequent resistance profiles in individuals exposed to atazanavir. AB - Few data exist regarding the resistance profile in individuals receiving atazanavir. We found that ritonavir-boosted atazanavir is not associated with the development of primary genotypic resistance in individuals failing this combination, without previous protease inhibitor failure. It is rarely associated with the acquisition of primary mutations in individuals with previous protease inhibitor exposure. This is particularly important because of the increasing use of atazanavir monotherapy, and implies that treatment failure is caused by lack of potency. PMID- 17690588 TI - Considerations on the effectiveness of nevirapine in protease inhibitor-based regimen simplification. PMID- 17690589 TI - Response to Berg et al. 'Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review'. PMID- 17690590 TI - Response to Kourtis et al. 'Use of antiretroviral therapy in pregnant HIV infected women and the risk of premature delivery: a meta-analysis'. PMID- 17690591 TI - Vpr from HIV-1 subtypes B and C exhibit significant differences in their ability to transactivate LTR-mediated gene expression and also in their ability to promote apoptotic DNA ladder formation. PMID- 17690592 TI - An HIV-2-infected Japanese man who was a long-term nonprogressor for 36 years. PMID- 17690593 TI - Methylmalonic acidaemia in a 7-month-old following maternal highly active antiretroviral therapy during pregnancy. PMID- 17690594 TI - Factors affecting outcome in schizophrenia and their relevance for psychopharmacological treatment. AB - A major focus of current treatment research in schizophrenia is the determinants of long-term outcome, including functional outcome and general medical well being, rather than just specific domains of psychopathology such as positive and negative symptoms, mood symptoms, and cognitive impairment. This focus does not negate the importance of the latter issues but sees them as factors contributing to long-term outcome to variable extents. A long-term treatment focus facilitates a more clinically relevant assessment of benefits versus risks of available treatments. For instance, atypical antipsychotic drugs as a group have clear advantages for several important domains of efficacy that may influence long-term outcome, but are also more expensive over the long term. Use of some agents may also result in deleterious physical health consequences as well as large additional costs over the long term owing to metabolic adverse effects. The present paper focuses on several key issues in schizophrenia which are important determinants of long-term outcome in schizophrenia, or influence choice of antipsychotic drugs, or both, including: (i) duration of untreated psychosis; (ii) impact of relapse on long-term outcome; (iii) limited efficacy for specific domains of psychopathology of current treatments; (iv) mortality owing to suicide; and (v) mortality owing to other causes (e.g. cardiovascular disease). PMID- 17690595 TI - Open-label escitalopram treatment for pathological skin picking. AB - Pathological skin picking is characterized by dysfunctional, repetitive and excessive manipulation of the skin resulting in noticeable tissue damage. This study sought to assess the effectiveness of escitalopram in treating pathological skin picking. Twenty-nine individuals with pathological skin picking were enrolled in an 18-week, open-label trial of escitalopram. Study measures assessing skin picking severity and impact, anxiety, depression, and quality of life were given at baseline and weeks 2, 4, 6, 10, 14, and 18. The mean maximally tolerated dose was 25.0 mg (standard deviation=8.4). For the 19 study completers, pre-post-treatment analyses revealed significant improvements (P<0.05) on measures of skin picking severity and impact, quality of life, and self-rated anxiety and depression. Completer as well as intent-to-treat analyses indicated that approximately half of the sample satisfied full medication response criteria and one-quarter were partial medication responders. Correlational analyses indicated that changes in depression, anxiety, and quality of life co-occurred with reductions in skin picking severity but not impact. A high percentage of variance in severity, however, remained unexplained. These results suggest that escitalopram can be an effective agent in reducing pathological skin picking. The lack of medication response in a subset of our sample suggests the possibility of pathological skin picking subtypes. PMID- 17690596 TI - The attitude of patients towards antipsychotic depot treatment. AB - In spite of their well known advantages, depot antipsychotics are seldom prescribed in the treatment of schizophrenia. A frequently stated reason is the patient's objection to depot treatment. We questioned 300 patients in nine psychiatric hospitals shortly before their discharge about their preferences in the mode of administration of antipsychotic treatment, taking earlier depot experience into account. 145 patients were naive to depot treatment, 95 had experienced a depot earlier and 60 were currently on a depot medication. Acceptance of depot treatment in relapse prevention was 73% in patients currently being treated with a depot and 45% in depot-experienced patients, compared with 23% in depot-naive participants. Participants, depending on their experience with the formulation, acknowledged suggested potential advantages of depot treatment. Preference of depots as favorable antipsychotic treatment depends on the patient's experience with the formulation. A considerable number of patients would accept a depot drug as a long-term treatment option. The gap between patients' acceptance and the low prescription rates can be narrowed by offering antipsychotic depots to more patients. PMID- 17690597 TI - Severe depression and antidepressants: focus on a pooled analysis of placebo controlled studies on agomelatine. AB - The efficacy of agomelatine in severe depression has been examined in three positive placebo-controlled studies and in a pooled analysis of the data from the three studies in patients treated with 25-50 mg agomelatine (n=357) and placebo (n=360). Agomelatine was significantly more effective than placebo in a subgroup of patients with severe depression with a severity of 25 or more on the Hamilton Depression Rating Scale 17-item scale in each individual study (P<0.05) and in the pooled analysis (P<0.001). Analysis of the pooled data demonstrated that there was an increase in the magnitude of the agomelatine-placebo difference with increasing severity on the baseline Hamilton Depression Rating Scale. When the population was divided into subgroups using increasing cut-off Hamilton Depression Rating Scale values a significant difference between agomelatine and placebo was observed in each subgroup despite the decreasing numbers of patients with higher severity with a difference of 2.06 rising to 4.45 points on the Hamilton Depression Rating Scale. In conclusion, agomelatine is effective in treating severe depression. PMID- 17690598 TI - Benzodiazepine prescribing to the Swiss adult population: results from a national survey of community pharmacies. AB - The purpose of the study was to assess prevalence of benzodiazepine use in the Swiss adult population and to assess on benzodiazepine prescription patterns of physicians in domiciliary practice. STUDY DESIGN: A retrospective, population based cross-sectional study with 520 000 patients covering a 6-month period. METHODS: We estimated the prevalence, amount and duration of benzodiazepine use using a pharmacy dispensing database. RESULTS: Of all patients, 9.1% (n=45 309) received at least one benzodiazepine prescription in the 6-month period. Most persons receiving benzodiazepine prescriptions were women (67%), and half of all patients were aged 65 or older. Of 45 309 patients with benzodiazepine prescriptions, 44% (n=19 954) had one single prescription, mostly for a short period (<90 days) and in lower than the recommended dose range. Fifty-six percent (n=25 354) had repeated benzodiazepine prescriptions, mostly for a long time period (>90 days), and in lower than the recommended or within the recommended dose range. In patients with long-term use (n=25 354), however, 1.6% had benzodiazepine prescriptions in extremely high doses. The sample of patients with repeated prescriptions allowed an estimation of a benzodiazepine use of 43.3 daily defined doses per 1000 inhabitants in Switzerland. CONCLUSIONS: Benzodiazepine prescriptions were appropriate for most patients and thus were prescribed in therapeutic doses, as indicated in the treatment guidelines. On the other hand, our survey showed that 1.6% of the patients had prescriptions for long time periods at very high doses, indicating an abuse or dependence on benzodiazepines in this subgroup. PMID- 17690599 TI - A double-blind, placebo-controlled, randomized study evaluating the effect of paliperidone extended-release tablets on sleep architecture in patients with schizophrenia. AB - The effects of paliperidone extended-release on sleep architecture in patients with schizophrenia-related insomnia were evaluated in this multicenter, double blind, randomized, placebo-controlled study. Patients received paliperidone extended-release 9 mg/day or matching placebo during the 14-day double-blind phase. Sleep architecture and sleep continuity were evaluated using polysomnograms. Subjective sleep measures were evaluated daily using the Leeds Sleep Evaluation Questionnaire. Efficacy and safety were also assessed. Thirty six patients (17 on paliperidone extended-release, 19 on placebo; mean age 32.2 years) completed the study. Paliperidone extended-release treatment vs. placebo resulted in clinically and statistically significant differences in sleep measurements from baseline to endpoint including a reduction in: persistent sleep latency (41 min), sleep onset latency (35 min), number of awakenings after sleep onset (7), time awake in bed (50 min), and stage 1 sleep duration (12 min); prolongation in: total sleep time (53 min), sleep period time (42 min), stage 2 sleep duration (51 min), and rapid eye movement sleep duration (18 min); and an increase in sleep efficiency index (11%). Paliperidone extended-release, compared with placebo, did not exacerbate daytime somnolence and improved symptoms of schizophrenia. Paliperidone extended-release was well tolerated and improved sleep architecture and sleep continuity in patients diagnosed with schizophrenia and concomitant insomnia. PMID- 17690600 TI - Efficacy and safety of antidepressant monotherapy in the treatment of bipolar-II depression. AB - Sparse data exist regarding the risks and benefits of treating bipolar-II depression with antidepressants alone. On the basis of studies of bipolar-I patients, treatment guidelines suggest antidepressants should be augmented with mood stabilizers. Whether these recommendations apply to bipolar-II is unclear. A post-hoc analysis of a double-blind study, which compared the relative efficacy of placebo, imipramine and phenelzine in depressed outpatients. Patients rated 1 ('very much improved') or 2 ('much improved') on the Clinical Global Inventory Scale were considered responders. In an intent to treat analysis, no significant differences between bipolar patients (N=62) and unipolar patients (N=248) in response rates to placebo, imipramine and phenelzine were seen. No patient developed manic symptoms that required medication discontinuation or mood stabilizer augmentation. Antidepressant monotherapy was found to be a safe and effective treatment for bipolar-II depression. PMID- 17690603 TI - Laryngopharyngeal abnormalities in hospitalized patients with dysphagia. AB - OBJECTIVES: To determine the prevalence of laryngopharyngeal (LP) abnormalities in hospitalized patients with dysphagia referred for flexible endoscopic evaluation of swallowing (FEES). STUDY DESIGN: Retrospective, blinded review by two otolaryngologists of 100 consecutive FEES studies performed and video recorded by a speech-language pathologist (SLP). METHODS: Two otolaryngologists reviewed videos of 100 consecutive FEES studies on hospitalized patients with dysphagia for the presence of abnormal LP findings. RESULTS: Sixty-one male and 38 female patients comprised the hospital dysphagia cohort. The mean age was 62. One subject could not be evaluated because of the severity of the retained secretions, leaving 99 subjects in the cohort. Seventy-six percent had been previously intubated, with a mean intubation duration of 13 days. The overall prevalence of abnormal LP findings was 79%. Forty-five percent of the patients presented with two or more findings, which included arytenoid edema (33%), granuloma (31%), vocal fold paresis (24%), mucosal lesions (17%), vocal fold bowing (14%), diffuse edema (11%), airway stenosis (3%), and ulcer (6%). There was a significant difference in LP findings between those individuals who had or had not been intubated. CONCLUSIONS: Hospitalized patients with dysphagia are at high risk for LP abnormalities, particularly if they have been intubated, and may benefit from either 1) an initial joint examination by the SLP and otolaryngologist or 2) an otolaryngologist's review of the recorded examination conducted by the SLP. Such otolaryngology involvement could identify airway stenosis patients at an earlier stage, initiate granuloma treatment sooner, enable earlier biopsy of unexpected lesions, and allow follow-up of mucosal and neuromuscular findings that do not respond to medical management. PMID- 17690604 TI - Tracheal ceramic rings for tracheomalacia: a review after 17 years. AB - BACKGROUND: Despite different support techniques, the surgical management of tracheomalacia is still a challenging problem. Satisfactory results after internal stenting are above 80%, whereas, when performing external stenting using biocompatible ceramic rings, results are reported at over 90%. OBJECTIVE: The purpose of this study was to examine the efficiency of surgical treatment in patients with segmentary tracheomalacia using external ceramic ring grafts. METHODS: In this retrospective study, we collected data from 12 patients who underwent surgery during the last 17 years for symptomatic segmentary tracheomalacia by use of biocompatible aluminum-oxide ceramic rings. All except one patient had undergone previous tracheostomy, six had a history of long-term intubation, two had previous trauma, and two patients had previous cancer treatment including radiotherapy. One of the patients still had an existing tracheostoma, which was closed when a ceramic ring was implanted. Tracheal wall collapse with pseudoglottis formation or flattened anterior-posterior tracheal diameter was documented with fiberoscopy at rest, and both pre- and postoperative airway resistance measurements were performed in all 12 patients using a spirometer. After malacic segments were found to be expandable using rigid tracheoscopy while the patient was under general anesthesia, preparation of the trachea was performed using a midline vertical incision in the neck. Subsequently, the malacic trachea was expanded by placing and suturing proper sized ceramic ring(s) around it. RESULTS: In all patients, surgical expansion of the malacic segment using ceramic rings was successfully carried out without major complications while inspiratory stridor was resolved. Airway resistance decreased significantly from an average of 0.62 to 0.385 kPascal. CONCLUSION: Although the results of applying internal tracheal stents are encouraging, complications such as stent migration, granulation tissue and fistula formation, and mucociliary transport arrest are possible. Biocompatible ceramic rings do not cause foreign body reactions, remain stabile, and, with a proper suturing technique, provide a suitable long-term solution. PMID- 17690605 TI - Nasolacrimal duct orifice cysts in adults: a previously unrecognized, easily treatable cause of epiphora. AB - BACKGROUND: Epiphora is a common problem evaluated by ophthalmologists and otolaryngologists. It is typically the result of obstruction at some level of the nasolacrimal system, either the canaliculi, sac, or duct. Multiple etiologies exist, including scarring from infection or trauma, tumors, or masses. Cysts of the nasolacrimal duct orifice (dacryocystoceles) in the inferior meatus have been described in neonates, usually presenting as obstructive nasal masses shortly after birth. Nasolacrimal duct orifice cysts have not been described in the adult population in the medical literature. PATIENTS: Three patients were identified with epiphora as a result of cysts in the inferior meatus at the opening of the nasolacrimal duct. All patients presented with constant epiphora and were referred for dacryocystorhinostomy by an ophthalmologist or an otolaryngologist. None of the patients had a previous history of nasolacrimal duct (NLD) surgery. One patient had previous endoscopic sinus surgery for nasal polyps. Cysts were identified by nasal endoscopy of the inferior meatus in all patients. RESULTS: All patients underwent endoscopic resection of the inferior meatus cyst to relieve the obstruction of the NLD. Two procedures were performed under general anesthesia and one under intravenous sedation. All patients had complete relief of epiphora and have had no evidence of recurrence of the symptoms or the cyst in 4 to 10 months follow-up. CONCLUSIONS: NLD orifice cysts are easily correctable causes of epiphora. Routine inferior meatus endoscopy should be routinely performed in patients with epiphora to identify whether on not this pathology is present prior to performing dacryocystorhinostomy. PMID- 17690606 TI - Hyaluronan-based scaffolds to tissue-engineer cartilage implants for laryngotracheal reconstruction. AB - OBJECTIVES: Donor site morbidity, including pneumothorax, can be a considerable problem when harvesting cartilage grafts for laryngotracheal reconstruction (LTR). Tissue-engineered cartilage may offer a solution to this problem. This study investigated the feasibility of using Hyalograft C combined with autologous chondrocytes to tissue engineer cartilage grafts for LTR in rabbits. STUDY DESIGN: Animal study. METHODS: Eighteen New Zealand white rabbits underwent LTR: 12 rabbits received autologous tissue-engineered cartilage grafts and 6 animals, serving as a positive control group, native auricular cartilage. To determine any differences in response to the site of implantation and any potential immune response to the scaffold, a second piece of engineered neocartilage and a non cell-loaded scaffold were inserted paralaryngeally into a subset of the rabbits. The rabbits were sacrificed 3, 6, 8, 10, and 12 weeks after the LTR and their larynx examined. RESULTS: None of the 18 rabbits showed signs of respiratory distress. A smooth, noninflammatory scar was visible intraluminally. Histologically, the native auricular cartilage implants showed excellent integration without any signs of inflammation or cartilage degradation. In contrast, all tissue-engineered grafts and empty scaffolds revealed marked signs of an unspecific foreign body reaction, leading to a complete degradation of the neocartilage, whether implanted para- or intralaryngeally. CONCLUSION: In contrast to the success with which Hyalograft C has been applied in articular defect repair, our results indicate that, in rabbits, Hyalograft C initiates a foreign body reaction if implanted intra- or paralaryngeally, leading to cartilage degradation and possible graft failure. These findings suggest limitations on the environment in which Hyalograft C can be applied. PMID- 17690607 TI - Viability of crushed and diced cartilage grafts wrapped in oxidized regenerated cellulose and esterified hyaluronic acid: an experimental study. AB - OBJECTIVES: The objective of this study was to investigate the viability of diced/crushed cartilage grafts wrapped in esterified hyaluronic acid (HYAFF) and oxidized regenerated cellulose (Surgicel) with respect to macroscopic and microscopic parameters. STUDY DESIGN: Experimental study. METHODS: A total of 10 New Zealand rabbits were acquired for the study. Cartilage grafts were harvested from both ears, with the ventral and dorsal perichondrial layers dissected off. There were six comparison groups in this experimental study: 1) bare, diced cartilage, 2) diced cartilage wrapped in Surgicel, 3) diced cartilage wrapped in HYAFF, 4) bare, crushed cartilage, 5) crushed cartilage wrapped in Surgicel, 6) crushed cartilage wrapped in HYAFF. Six cartilage grafts were inserted into the six subcutaneous pockets of the same animal. All the rabbits were sacrificed at the end of 2 months, the samples were collected, and the total specimen was examined histopathologically. The sections were stained with hematoxylin-eosin and Masson trichrome stain and examined under light microscopy. RESULTS: There was a significant difference among the bare, diced cartilage, the Surgicel, and the HYAFF groups with respect to fibrosis, chronic inflammation, cartilage mass, and vascularization. A significant difference was observed among the bare, crushed cartilage, Surgicel, and HYAFF groups with respect to fibrosis, chronic inflammation, and cartilage mass. There was no significant difference among the three groups regarding vascularization. CONCLUSIONS: This study suggests that wrapping cartilage grafts with Surgicel grossly reduces cartilage viability and the regeneration potential of the chondrocytes, leading to fibrosis formation. On the other hand, hyaluronic acid promotes cartilage integrity and survival, thus increasing clinical predictability and avoiding the need for overcorrection. PMID- 17690608 TI - Thyroid cancer in pregnancy. AB - We report a case of papillary thyroid cancer in pregnancy and discuss the various diagnostic and therapeutic challenges inherent to this condition. Several case series are reviewed. In addition, we examine the effect of pregnancy on the development and progression of thyroid malignancy. PMID- 17690609 TI - Predictors of prolonged length of stay after major elective head and neck surgery. AB - OBJECTIVE/HYPOTHESIS: Longer length of stay (LOS) after elective surgery is associated with an increased use of health care resources and higher costs. The objectives of this study were to determine the perioperative factors that predict a prolonged LOS after elective major head and neck operations and to test the hypothesis that factors related to process of care (intra- and postoperative) independently predict prolonged LOS after adjustment for preoperative patient characteristics. STUDY DESIGN: Prospective hospital-based cohort study. METHODS: The National VA Surgical Quality Improvement Program data were accessed for seven head and neck operations: radical neck dissection (RND) (n = 398), modified RND (n = 891), total laryngectomy (n = 431), total laryngectomy with RND (n = 747), hemiglossectomy with unilateral RND (n = 201), composite resection (n = 105), and composite resection with RND (n = 312). Prolonged LOS was defined as exceeding the 75th percentile for the LOS distribution of each operation. Multivariable logistic regression analysis was performed to identify factors that predicted prolonged LOS. RESULTS: Sixty-eight variables were analyzed among 3,050 patients who qualified for inclusion. Preoperative patient characteristics that predicted prolonged LOS were older age, poorer functional status, consumption of more than two drinks of alcohol per day, history of chronic obstructive pulmonary disease, and diabetes mellitus. Intraoperative processes that predicted prolonged LOS were a longer operative time and transfusion of erythrocytes. The postoperative variables that predicted a prolonged LOS were a return to the operating room within 30 days of the index operation and the occurrence of two or more operative complications. CONCLUSION: Several intraoperative processes and postoperative adverse events contributed additional predictive information for prolonged LOS, after consideration of preoperative patient characteristics. PMID- 17690610 TI - Nonpharmacologic effects of botulinum toxin on the life quality of patients with spasmodic dysphonia. AB - OBJECTIVE: Botulinum toxin (BT) injection improves objective and subjective voice measurements in spasmodic dysphonia; however, it is not clear whether the results are entirely caused by the neuromuscular blocking effects of BT or whether other factors (e.g., psychological or emotional) play a part. The aim of this study is to investigate whether nonpharmacologic factors contribute to the changes observed in the quality of life (QoL) after BT treatment of spasmodic dysphonia. STUDY DESIGN: Prospective cohort study. METHODS: Thirty-eight consecutive spasmodic dysphonic patients attending for repeat BT injections were investigated by recording their Voice Handicap Index (VHI) scores at three time points: 1) immediately prior to injection (baseline), 2) 1 day postinjection (when least pharmacologic change is expected), and 3) 2 weeks postinjection (when most pharmacologic change is expected). The changes in the total and domain VHI scores were compared between the two postinjection scores and the baseline value using two-way analysis of variance and the post hoc Bonferroni test. RESULTS: Most of the change in VHI score occurred between the baseline and first postinjection measurement. For two of the domains (total and emotional), the change was statistically significant. The change between the two postinjection assessments was minimal, and no domain showed statistically significant change. CONCLUSIONS: Our data indicate that the early improvements in QoL after BT injection can only in small part be attributed to the neurotoxic effects of the agent. We cannot say whether the reported effects in our study are attributable to a strong placebo response or are a real consequence of the patient's changing emotional state. PMID- 17690611 TI - Infectious complications in pediatric cochlear implants. AB - OBJECTIVES: Infectious complications may cause significant delay in cochlear implant device initiation and programming and be a source of additional morbidity. We reviewed our experience with infectious complications in the pediatric age group to determine specific sources that may not be seen in adults. STUDY DESIGN: A retrospective analysis from a single implant center. METHODS: Cases of pediatric cochlear implants were reviewed for data on infectious complications. Complications were identified as "major" or "minor," "early" or "delayed." Information was gathered regarding any comorbid, chronic health condition. Data related to the causative organism(s) were collected. RESULTS: Two hundred sixty-eight cases of pediatric implants were reviewed. Twenty-two cases were identified (an infection rate of 8.2%), all classified as "major." The majority, 12, were classified as "delayed" complications. Twenty-one cases required explantation with 14 successfully reimplanted. Five cases (in 4 patients) or 23% were associated with a specific chronic pediatric condition including two children with tracheostomies. Among implanted children who had chronic health conditions, 42% developed implant-related infections. Among otherwise healthy implanted children, only 6.6% developed implant-related infections. Resistant bacterial infections were not identified. CONCLUSIONS: Health conditions in the pediatric age group were associated with 23% of our complications, a risk factor not previously identified in the literature. These children, demonstrating seven times the infection rate of healthy children, should be carefully observed postoperatively. Overall, cochlear implantation in children continues to be associated with a low risk of infectious complications. PMID- 17690612 TI - A "fenestration approach" for arytenoid adduction through the thyroid ala combined with type I thyroplasty. AB - OBJECTIVE: To develop and evaluate the voice outcomes of an approach of arytenoid adduction (AA) through a fenestration of the thyroid ala for unilateral vocal cord paralysis. STUDY DESIGN: Twelve consecutive patients with severe unilateral vocal cord paralysis, whose maximum phonation times (MPTs) were less than or equal to 5 seconds, underwent laryngoplasty using an approach of AA performed through a fenestration of the thyroid ala combined with type I thyroplasty. METHOD: Two surgical windows were made in the lower part of the thyroid ala. The anterior window was for typical type I thyroplasty, and the posterior window was for AA. AA was performed by pulling the lateral cricoarytenoid muscle (LCA) (5 patients) or muscular process (7 patients) through the posterior fenestration in the contractile direction of the LCA without releasing the cricoarytenoid joint. The operation was performed under local anesthesia with sedation except in two patients who underwent general anesthesia using a laryngeal mask. The vocal cord medialization was confirmed endoscopically during the operation. For all patients, the MPT and mean airflow rate (MFR) were measured before and after the operation. The postoperative voices were analyzed using shimmer and jitter. RESULT: All patients achieved a MPT of over 12 seconds. The MFR, which ranged from 340 to 1902 mL/second before the operation, improved to less than 200 mL/second, except in one patient whose MFR was 210 mL/second. Shimmer and jitter improved significantly after the operation. Perceptual evaluation using the GRBAS (grade, roughness, breathiness, aesthenia, strain) scale also improved significantly. CONCLUSION: A fenestration-based approach simplified the combination of AA and type I thyroplasty because the two treatments could be performed in the same operating field and provided good voice improvement. Pulling the AA braid in the contractile direction of the LCA and endoscopic vocal cord observation during surgery may have contributed to the positive results. PMID- 17690613 TI - Effect of ototopical medications on tympanostomy tube biofilms. AB - OBJECTIVE: Examine how ototopical medications affect biofilms on fluoroplastic tympanostomy tubes. STUDY DESIGN: In vitro comparison of different ototopical medications against a clinical isolate of Pseudomonas aeruginosa biofilm on tympanostomy tubes treated for 5, 10, 14, and 21 days. METHODS: Under sterile conditions 21 tympanostomy tubes were cut in half. These were attached to pegs of two Calgary Biofilm Devices via rubber cement. Device 1 evaluated microbial growth as colony forming units (CFUs). Device 2 evaluated presence of biofilms. Tubes were prepped for biofilm growth, incubated, and stressed for 72 hours. Afterward, one tube per device was removed and forcefully washed. One was sonificated for 5 minutes, serially diluted, and plated for CFUs. Formalin preserved the other for biofilm evaluation by scanning electron microscopy. Next, tubes were exposed to five drops of Ciprofloxacin, Ciprofloxacin/Dexamethasone, Dexamethasone, Ofloxacin, or saline for 1 hour. Afterward, the ototopicals were removed and sterile broth was placed in the wells as a nutrient. This was repeated every 12 hours for 5, 10, 14, and 21 days of treatment. Prior to the last dose of treatment intervals, a streak plate was performed to evaluate for microbial growth in the wells. The tubes were evaluated for CFUs and biofilms at each interval as previously described. RESULTS: Microbial activity in CFUs decreased by day 5 and continued through day 21 for the antibiotic containing drops. Despite treatment, the biofilm was never eradicated and continued to progress. CONCLUSIONS: Infectivity of the biofilm is neutralized by antibiotic ototopicals; however, the biofilm will progress despite treatment. PMID- 17690614 TI - Surgical management of jugular foramen meningiomas: a series of 13 cases and review of the literature. AB - OBJECTIVE: Primary meningiomas occurring within the jugular foramen are exceedingly rare lesions presumed to originate from arachnoid-lining cells situated within the jugular foramen. The objective of this study is to analyze the management and outcome in a series of 13 primary jugular foramen meningiomas collected at a single center. STUDY DESIGN: Retrospective study. SETTING: Quaternary referral otology and skull base private center. METHODS: Charts belonging to 13 consecutive patients with pathologically confirmed jugular foramen meningioma surgically treated between September 1991 and May 2005 were examined retrospectively. The follow-up of the series ranged from 12 to 120 (mean, 42.8 +/- 27.5) months. RESULTS: Four (28.5%) patients underwent single stage tumor removal through the petro-occipital transigmoid (POTS) approach. In two patients with preoperative unserviceable hearing, a combined POTS translabyrinthine approach was adopted. Two patients underwent a combined POTS transotic approach because of massive erosion of the carotid canal. A modified transcochlear approach type D with posterior rerouting of the facial nerve and transection of the sigmoid sinus and jugular bulb was performed in two patients with a huge cerebellopontine angle tumor component with extension to the prepontine cistern together with massive involvement of the petrous bone and middle ear and encasement of the vertical and horizontal segments of the intrapetrous carotid artery. In one patient with evidence of a dominant sinus on the site of the tumor, a subtotal tumor removal via an enlarged translabyrinthine approach (ETLA) was planned to resect the intradural component of the tumor. Two patients in our series underwent a planned staged procedure on account of a huge tumor component in the neck. One of these patients underwent a first-stage infratemporal fossa approach type A to remove the tumor component in the neck; the second-stage intradural removal of the tumor was accomplished via an ETLA. The last patient underwent a first-stage modified transcochlear type D approach to remove the intradural tumor component followed by a second-stage transcervical procedure for removal of the extracranial component. Gross total tumor removal (Simpson grade I-II) was achieved in 11 (84.6%) cases. Subtotal removal of the tumor was accomplished in two patients. Good facial nerve function (grades I and II) was achieved in 46.1% of cases, whereas acceptable function (grade III) was achieved in the remaining cases 1 year after tumor removal. Hearing was preserved at the preoperative level in all four patients who underwent surgery via the POTS approach. After surgery, no patient recovered function of the preoperatively paralyzed lower cranial nerves. A new deficit of one or more of the lower cranial nerves was recorded in 61.5% of cases. CONCLUSIONS: Surgical resection is the treatment of choice for jugular foramen meningiomas. Among the various surgical techniques proposed for dealing with these lesions, we prefer the POTS approach alone or combined with the translabyrinthine or transotic approaches. Despite the advances in skull base surgery, new postoperative lower cranial nerve deficits still represent a challenge. PMID- 17690615 TI - Atomic force microscopy investigation of vocal fold collagen. AB - OBJECTIVES: Collagen is an important constituent of the vocal fold extracellular matrix and is necessary for providing tensile strength and maintaining tissue geometry. Traditional investigations of vocal fold collagen using light and electron microscopy do not provide information on the organization and mechanical properties of collagen in native topographic state. The primary objective of this study was to use Atomic Force Microscopy (AFM) to examine the surface characteristics and organization of collagen in the deep layer of the lamina propria at nanoscale resolution. STUDY DESIGN: Experimental in vitro design. METHODS: Freshly dissected porcine vocal folds were mounted on AFM discs and imaged under contact and tapping mode to obtain information on topographic distribution of collagen. RESULTS: AFM imaging of the deep layer of the lamina propria revealed dense, abundant collagen fibers with a characteristic banding pattern. The distribution of collagen was heterogeneous, with both hydrophilic and hydrophobic regions within a sample. CONCLUSIONS: AFM offers a useful tool to obtain topographic information about biologic samples at nanoscale resolution with minimal sample preparation. Mapping the topography and mechanical properties of vocal fold collagen is necessary for designing rheologically compatible bioimplants for the treatment of dysphonia resulting from vocal fold scarring and bowing. PMID- 17690616 TI - Influence of polyps on outcomes after endoscopic sinus surgery. AB - OBJECTIVE: To determine clinical and comparative outcomes for endoscopic sinus surgery (ESS) for chronic rhinosinusitis (CRS) with polyposis. METHODS: Two cohorts of adult patients with refractory CRS with and without nasal polyps were prospectively studied before and after ESS (minimum follow-up, 12 months) with the Rhinosinusitis Symptom Inventory (RSI). For the non-polyp and polyp cohorts, RSI symptom domains and medical resource utilization were compared in the preoperative and postoperative states. Corresponding effect sizes were computed and compared between cohorts to determine the effect of polyps on prognosis after ESS. RESULTS: A total of 165 non-polyp and 86 polyp patients were enrolled. Polyps were more common in female patients (2:1, P = .025); age (mean, 42.9 years) and follow-up (18.5 months) were similar between groups. Lund scores were significantly higher for polyp patients (13.7, SD 4.8) vs. non-polyp patients (8.1, SD 5.3, P < .001). At baseline, polyp patients reported lower symptom scores for facial, oropharyngeal, and systemic RSI symptom domains (all P < .012); nasal and total symptom domains were similar between groups. Both non polyp and polyp groups obtained significant symptomatic benefit from ESS with effect sizes for RSI symptom domain improvements ranging from 0.89 to 1.38 and 0.43 to 1.19, respectively (all P < .001). There were no significant differences between groups in symptomatic improvement, excepting oropharyngeal symptoms (better improvement in non-polyp group, P = .024). Non-polyp patients decreased medical resource consumption more significantly than did polyp patients. CONCLUSIONS: Both non-polyp and polyp patients derive similar clinically significant symptomatic improvement after ESS. These similarities suggest that polyp patients do not necessarily have a poorer symptomatic outcome after ESS. PMID- 17690618 TI - Cognition in children with sensorineural hearing loss: etiologic considerations. AB - OBJECTIVES: A considerable amount of literature has documented the impact of hearing impairment on spoken language skills in deaf children referred for cochlear implantation. Critical areas of neurocognitive development in the acquisition of visual (manual) language also appear to be impacted, although the evidence is less robust. The present study focused on the development of visual and fine motor skills in a sample of preschool-age children diagnosed with sensorineural hearing loss with no known neurologic conditions (n=36). STUDY DESIGN: Analysis of data collected as part of a standardized screening process for cochlear implantation at an academic medical center. METHOD: Children underwent a standardized neuropsychological assessment battery. Children were classified into three groups based on the etiology of their deafness (Connexin=15, Structural Malformation=11, and Unknown=10). RESULTS/CONCLUSIONS: Correlational analyses replicated previous research on the reduction in visual reception and fine motor skills as deaf children age. Children with genetic (Connexin) etiology exhibited a significant reduction in fine motor skills with age, whereas those with an etiology of Structural Abnormality exhibited a significant reduction in visual reception skills with age. Results of planned comparisons conducted as part of a multivariate analysis of variance (Skill x Group) indicated that the Connexin group was significantly better than the Unknown group with regard to fine motor skills. Implications for these findings and future studies are discussed. PMID- 17690619 TI - Imaging procedures after bone-anchored hearing aid implantation. PMID- 17690620 TI - Voice outcomes of polyacrylamide hydrogel injection laryngoplasty. AB - OBJECTIVES: Polyacrylamide hydrogel (PAAG, Aquamid) is widely used as permanent facial tissue filler during facial plastic surgery. In this study, we examined the long-term effects and safety aspects of PAAG as a vocal fold augmentation material for patients with permanent unilateral vocal cord paralysis. STUDY DESIGN: Prospective clinical trials. METHODS: PAAG injection laryngoplasty was performed in 34 consecutive patients with permanent unilateral vocal cord paralysis. Percutaneous injection was performed under local anesthesia into the vocalis muscle using disposable 25 gauge long needles. Of the 34 patients, 16 completed acoustic, perceptual, stroboscopic, and subjective evaluations prior to the injection and at 6 and 12 months after the injection. RESULTS: Acoustic and perceptual parameters (GRBAS [Overall grade of dysphonia, Roughness, Breathiness, Aesthenia, Strain], Maximal phonation time [MPT], jitter, and shimmer) were significantly improved (P < .05) after injection and remained stable over 12 months. The grades of mucosal waves and glottic closure were also significantly improved (P < .01). The voice handicap index (VHI), as well as the visual analogue scale (VAS) of hoarseness and aspiration significantly improved over 12 months. No adverse effects were observed except for a decrease in the mucosal wave of one patient, after injection into a superficial area of the vocal fold. CONCLUSION: Based on the preliminary results of this trial, PAAG appears to be a long-lasting and safe injection material that is suitable for the treatment of glottal insufficiency caused by permanent unilateral vocal cord paralysis. PMID- 17690621 TI - Laser-assisted endoscopic submucosal medial arytenoidectomy (LESMA). PMID- 17690622 TI - Reducing intake of trans fatty acids. PMID- 17690623 TI - Probiotics. PMID- 17690624 TI - Bone graft incorporation after reconstruction of bony defects with impacted morselized bone graft. Histology of animals and patients. AB - The major problem in revision total hip surgery is the loss of bone stock, which is induced by various factors: the loosening process itself, osteolysis, infection and manipulations during removal of the prosthesis components and the cement. The instability of the implant leads to progressive bone loss and a vicious cycle is initiated in which a combined central and peripheral cavitary segmental defect may develop in the acetabulum. With the technique of impacted bone grafts and cement, it is possible to replace the loss of bone and to repair normal hip mechanics in combination with a standard hip prosthesis, achieving a long-lasting stable reconstruction. In this paper we present the histological data of patient-material and of various animal experiments to support this technique. From the results of this histology it could be concluded that in animals complete incorporation into a new bony structure took place. After incorporation the newly formed bone structure obeys Wolffs law. In the biopsies of patients, also an almost complete incorporation was found of the impacted morsellized bone graft. Base on the good results of the histology and based on the very good clinical follow-up data in the acetabulum of patients revised with this technique of impaction grafting, we strongly advocate the use of this technique in revision arthroplasty of the acetabulum. PMID- 17690625 TI - [Clinical, diagnostic and surgical aspects of heart space-occupying lesions at children and youths]. AB - Clinical, diagnostic and surgical aspects of primary heart tumors, pseudotumor and morphologically unidentified heart space-occupying lesions were analyzed at 52 childhood and adolescence patients. Difficulty of early diagnosis, more aggressive clinical course in majority cases, and individual approach to the choice of surgical approach has been demonstrated. Principle of oncological determinant has been ensured the success in surgical treatment of patients with non-malignant intracavitary and intramuscular neoplasms, and also with pseudotumor space-occupying lesions. Postoperative lethality was low (2.2%), and there were no true recurrences of disease in long-term period after surgery. PMID- 17690626 TI - [Simultaneous and staged grafting of descending aorta with aorto-coronary bypass]. AB - One hundred and six patients with aneurysm of descending thoracic aorta (ADTA) and thoracoabdominal aneurysm of aorta (TAAA) has been operated, aorto-coronary bypass (ACB) has been performed at 5 (4.7%) of them, including 4 cases of simultaneous and 1 case of staged ACB with grafting of descending and thoracoabdominal aorta. It is demonstrated that If coronary syndrome prevails over other symptoms then surgical revascularization of myocardium through sternotomy can be performed as first stage, and in 2-3 weeks - aorta grafting trough thoracotomy or thoracophrenolaparotomy. PMID- 17690627 TI - [Surgical technique and tools for surgery at aorto-iliac zone from mini approach]. AB - Original method of aorto-bifemoral bypass from mini-approach and special tool kit are described. Surgery from mini-approach (to aorta through 6 cm median minilaparotomy) has been performed at 133 patients. Special tools and surgical technique for main types of aorto-iliac vascular reconstructions (bypass, grafting) are described in detail; main intraoperative parameters (general time of surgery, time of aorta clamping, volume of blood loss) are evaluated. Conversion to standard laparotomy was necessary at 6 from 133 cases. Original tool kit permits to perform surgical manipulations at limited space without technical difficulties. PMID- 17690628 TI - [Results of surgical treatment of patients with nonpalpable non-malignant breast tumors]. AB - Results of surgical treatment of 100 patients with nonpalpable non-malignant breast tumors are analyzed. Correlation between x-ray parameters, risk factors, results of ultrasonic and morphological examinations was studied. It was demonstrated that risk factors have no diagnostic value for specification of breast pathological process. Ultrasonic and x-ray parameters are important for choice of tactics at nonpalpable tumors. Obtained data permit to determine the groups of patients subjected to surgical treatments, and otherwise - to dynamic follow-up. PMID- 17690629 TI - [Elective combined operations - the new problem of geriatric surgery]. AB - Elective combined operations were performed at 228 (10.96%) geriatric patients (aged from 60 to 85 years, 75.3% male, 24.7% female). It is demonstrated that more than 10% patients at specialized geriatric surgical departments require elective simultaneous operations, 86.8% of them are the surgeries of light and middle severity degree. Mini-invasive technologies and differential approach to the anesthetic management choice permit to increase contingent of geriatric patients who can treated with elective simultaneous surgical procedures, that decreases cost in 1.8 times compared with staged surgical treatment and significantly improves life quality of these patients. PMID- 17690630 TI - [Acute colonic pseudoobstruction: Ogilvie's syndrome]. AB - Based on literature and own original clinical data authors conclude that Ogilvie's syndrome is the form of dynamic obstruction of colon due to lesion of retroperitoneal neural nodes, heart failure and intoxication. Ogilvie's syndrome complicates therapeutic and surgical diseases. This syndrome can be manifested with acute abdomen symptoms and at 22% cases may be the cause of surgical treatment. Ogilvie's syndrome is successfully treated with evacuation of intestinal contents, but the risk of recurrence after this treatment is high. Ethiotropic therapy, correction of water-electrolytic balance and tissues oxygenation, administration of acetylcholinesterase inhibitors are the more effective treatment of this syndrome. PMID- 17690631 TI - [Method of postcolectomy syndrome prophylaxis]. AB - Method of prophylaxis of postcolectomy syndrome after colectomy and rectum anterior resection at two-stage surgical treatment of severe forms of nonspecific ulcerative colitis and colon diffuse polyposis has been developed and used at 9 patients. Postoperative complications were seen at 2 (22.2%) of them. This method permits to reduce the symptoms of postcolectomy syndrome after radical stage of surgery (colectomy and anterior resection of rectum) and to improve the clinical course of postoperative period after reconstructive stage of surgery. PMID- 17690632 TI - [Hypothermal enteral sanation at intestinal obstruction]. AB - Results of intensive care of 57 patients (31 male, 26 female, aged from 16 to 82 years) with intestinal obstruction are summarized. All the patients were divided into two groups: 1st (study) group consisted of 27 patients who have been treated with hypothermal enteral sanation, patients of 2nd group (30) have been treated with intestinal decompression only. Results of treatment were compared by clinical and laboratory parameters. It is demonstrated that intestinal intubation and hypothermal sanation at acute intestinal obstruction are effective methods for elimination of toxic intestinal contents, prevent ischemic damage and stimulate peristalsis of intestinum. The positive final results after this treatment are demonstrated. Lethality was 11.1 and 20%. PMID- 17690633 TI - [Treatment of the patients with complications of colon malignant tumors]. AB - Results of treatment of 150 patients with colorectal cancer complicated with obturation intestinal obstruction are analyzed. Rational health care organization has permitted to increase operability and respectability of tumor to 96 and 87% accordingly compared with 73 and 57.5% at control group. Primary anastomosis in study group was used at 68% patients, rate of insufficiency was 4%. Postoperative lethality in study group was 13%, in control group - 23%. Rate of postoperative complications was 21 and 36.5% accordingly. It is concluded that rational organizational approach permits to improve immediate results of treatment of these patients. PMID- 17690635 TI - [Problems of integration in dental implantology]. AB - Actual problems of intraosseous dental implants integration into bone tissue were discussed. The main definitions of integration as a natural phenomenon were given, the significance of integration processes from positions of alive and dead relation for efficacy of widely used in stomatological practice implants was also disclosed. 3 stages of integration process were described, the mechanisms in the background of dental implants osteointegration into bone tissue were revealed. PMID- 17690636 TI - [Biological evaluation of means for chemomechanical removal of carious dentine]. AB - Biological evaluation of the 1st domestically developed and produced preparation for chemomechanical removal of carious dentine Caricleans (firm "VladMiVa", Belgorod) was performed in the CRIS with the use of express techniques of the hemolytic activity (HA) and cytotoxic effect (CTE). It was established that according to HA data both gels of the Caricleans preparation were nontoxic. CTE of 2 gels was also determined on 2 cells lines - LECH (lung embryon cell human) and HeLa; higher sensitivity was received on HeLa cells, the toxic effect of gel #2 of the Caricleans preparation was higher. The received results allowed the authors come to the conclusion that taking into account high sensitivity, high specificity and high cost of the CTE-test not to recommend its use for evaluation of the preparations for short-term action in stomatology. PMID- 17690637 TI - [Principles of galvanic currents determination in oral cavity and their clinical background]. AB - The most important reasons for metal intolerance used for teeth treatment and dental prosthetics are allergic intolerance for the given metals and galvanic currents appearance in the oral cavity. Although they often have similar symptoms their differential diagnostics is very important for determination of correct tactics of treatment and further patient's course. The method of galvanic currents measurement in oral cavity was invented. Basing on data of clinical and laboratory examination of considerable group of human beings the principles of exact determination of galvanic currents in oral cavity including algorithm of determination of the received data clinical significance. PMID- 17690638 TI - [Method for determination of human individual sensitivity to fluoride]. AB - Study for determination of human individual sensitivity to fluoride was performed on 140 patients of CRIS clinics of the age from 20 to 65 years. It was established that even in cases of F-concentrations analogous to high physiological F-concentrations in blood serum (0.19 ppm) in 11.4% of the examined patients the signs of higher F-sensitivity were observed. Human individual sensitivity to fluoride was dependant upon the severity of patient's status. The results received can be used as a base for tactics development of timely and adequate correction of F-dosage. PMID- 17690639 TI - [Influence of the climatic and geographical conditions and industrial factors on the stomatologic status of metallurgical workers in the far north environment]. AB - There was clinically proved negative influence of the climate and geographical conditions of the far north and the industrial factors as well on the stomatologic status of metallurgical workers of Norilsk. There was recommended a set of preventive measures. PMID- 17690640 TI - [pH-metric efficacy evaluation of interdental spaces cleaning from dental plaque by wood toothpicks]. AB - With the help of local pH-metry the degree of interdental spaces cleaning from dental plaque by wood toothpicks was determined in 18 students-volunteers 21-23 years old. Positive effect was achieved of the wood toothpicks use in the group with preliminary stimulation of metabolic activity of acid producing microflora by 47% solution of sucrose and without it. Expressed change of hydrogen ion exponent in patients with high DMFT index and inflammatory periodontal disease was noted. High accuracy of the method allows to use it in the groups with relatively small number of subjects. PMID- 17690641 TI - [Dynamics of morphological changes in the region of dental implants in cases of immediate functional loading in experimental study]. AB - The experimental study was done on macro biomodels (laboratory mini-pigs) in order to estabishe optimal timing (1, 3 and 6.5 months) for functional loading intraosseons implants. It was shown in morphological dynamic studies in the period of time from 1 to 6.5 months connective tissue capsule was formed around implant which was maturing quickly, packing and thinning by reparation osteogenesis. The osseous mass growing was noted on implant surface and alveolar process thickening in the implantation zone under alveolar process as the influence of early functional loads. PMID- 17690642 TI - [Indications and efficiency of various surgical interventions use as treatment of patients with odontogentic antritis caused by moved out filling material into maxillary sinus]. AB - Indications to various surgical interventions methods of treatment of patients with odontogentic antritis caused by moved out filling material into maxillary sinus including endoscopic one were considered. Efficiency and indications to surgical intervention in 52 patients with the use of traditional operative access and in 20 patients with the use of endoscopic technique were analyzed. PMID- 17690643 TI - [Comparative analysis of antimicrobial action of polyhexametylenguanide hydrochloride (Biopag) and chlorhexidine bigluconate upon potential infectious agent of suppurative-inflammatory diseases of maxillo-facial region and neck]. AB - Sensitivity of microflora representatives isolated from inflammatory foci from 40 patients with suppurative-inflammatory diseases of maxillo-facial region and neck to different concentrations of antiseptic preparations of polyhexametylenguanide hydrochloride (Biopag) and chlorhexidine bigluconate was tested. It was determined that 0.05-0.1% solutions of these antiseptics were optimal for these diseases treatment. Biopag had more pronounced fungicidal action, less toxic and more prolonged antimicrobial action and better organoleptic properties when compared with chlorhexidine bigluconate. PMID- 17690644 TI - [Experience in treatment of patients with spacious cysts of jaws]. AB - Experience in operative treatment of 91 patients with spacious cysts of jaws occupying from 1/3 to capital DSE, Macedonian and more of the lower jaw volume was presented. In 36 patients keratocysts were found and in 55 patients teeth containing cysts. In the latter case it is obligatory to remove fully the cyst capsule because its epithelium is capable of metaplasia and neoplastic transformation. Patients were treated with the use of 2 stage method. 1st stage included decompression operation of cystotomy type; 2nd stage was performed 1-2 or more years later (depending upon primary cyst size) and consisted of remaining cyst capsule removal with wound closure. Benefits of 2 stage operation were described. PMID- 17690645 TI - [Experience of vascularized autotransplants use for lower jaw defect substitution after its resection with disarticulation]. AB - To 17 patients after lower jaw resection with disarticulation (on the occasion of neoplasm and traumas) the defects were replaced by vascularized autotransplants of the 2nd radius of pedis and vascularized fibula autotransplants in combination with titanium implants. In all cases positive results were received. The authors consider that microsurgery with vascularized fibula autotransplants in combination with titanium implants was an optimal way to replace lower jaw defects after its resection with disarticulation in TMJ. PMID- 17690646 TI - [Algorithm of comprehensive treatment of adult patients with TMJ ankylosis and concomitant deformations of face skeleton]. AB - There was offered an algorithm of optimal tactics of treatment and rehabilitation of adult patients with TMJ ankylosis and concomitant deformations of face skeleton. PMID- 17690647 TI - [Defects of nasal septum skin part elimination]. AB - Method of elimination of nasal septum skin part defects was offered with creation of full-fledged receptive bed in the defect and cicatricially changed nose tip region with subsequent columella plastic by skin flaps from the region of the bases of nasal wings and upper third of the upper lip. The method allows to fill the defect of nasal septum skin part, to eliminate cicatricial deformity of nose tip, to shift wing of nose curls in right position, to reduce the lower third face height; hence the face becomes more harmonious. PMID- 17690648 TI - [Antimicrobial photodynamic therapy: current view]. AB - Growing resistance of bacteria to wide-spectrum antibiotics gave rise to a search for new approaches to antimicrobial therapy. Photodynamic therapy (PT) was proposed for fighting against infections. It combines effects of a photosensitiser and visible light. PT produces reactive oxygen species able to kill cells. High response to PT was achieved in the treatment of local infections, in particular, in the treatment of pyoinflammatory ENT diseases caused both by gram-positive and gram-negative bacteria, fungi, especially diseases caused by bacteria with antibiotic polyresistance. PMID- 17690649 TI - [Potential of temporal bone CT in the study of external acoustic meatus in health and pathology]. AB - Computed tomography (CT) was used to examine 50 patients (100 temporal bones) aged from 10 days to 60 years with healthy external acoustic meatus (EAM) and 53 patients (62 temporal bones) aged from 4 to 75 years with symptoms of acquired stenosis, atresia or obturation of the external acoustic meatus. Polyposition CT of the temporal bone including axial and coronary projections is the most informative method of visualization of the EAM bone part. In axial projection the assessment covers the anterior and posterior walls of the EAM, in the coronary one - the upper and the lower walls. In the presence of EAM changes, CT is able to characterize them (soft tissue, bone, size, position). In patients with EAM neoplasms CT of the temporal bone detects polyps of the acoustic meatus, glomal tumors, neurinomas of the facial nerve, inherited cholesteatomas, cancer of the temporal bone. The detected alterations in the EAM and other structures of the temporal bone determine further policy of treatment. PMID- 17690650 TI - [Effects of middle-ear surgical interventions of different types on peripheral audio reproduction part of the acoustic analyzer in patients with otitis media purulenta chronica]. AB - Different operations on the middle ear were performed in 86 patients with otitis media purulenta chronica (OMPC). Mean bone hearing thresholds in the high-pitched area (10,000-16,000 Hz) were determined and suprathreshold tests were made in 86 patients on day 10 and 6 months after surgery. Minimal changes seen only in early postoperative period occurred in canal wall up operations with tympanoplasty of type I-II. Canal wall down type of surgery had a negative effect on the function of the cochlear receptor system in the early postoperative period. All "open" types of ear surgery, even with tympanoplasty, provoked hearing deterioration with maximum elevation of the hearing thresholds in the high-pitched area (10,000 16,000 Hz). Middle ear surgery without forming a new tympanic cavity results in progressive deterioration of the peripheral part of the hearing receptor system. PMID- 17690651 TI - [Genetic characteristics of hearing disorders in changes in genes responsible for collagen synthesis]. AB - The latest clinicogenetic studies of different hypoacusis forms associated with defects in collagen synthesis are reviewed. To 2002 in human cochlear the researchers got to know gene expression of 10 types of collagens. Basal membrane of the Corti's organ is formed by collagen of type IV, bone cochlear capsule - by collagen of type I, the tectorial membrane contains collagens of type II, V, IX and XI. Brief clinical and genetic characteristics of Alport syndrome, Stickler syndrome, stapes ankylosis syndrome, OSMED syndrome, osteogenesis imperfecta are provided. The results of the study confirm the fact that collagen, being a basic structural component of the connective tissue, has an essential role in development of normal hearing. Accurate diagnosis of the above syndromes is sure to improve quality of treatment. PMID- 17690652 TI - [Otoprotective effect of argon in exposure to noise]. AB - The trial with participation of 10 healthy volunteers aged 18-25 years was made to assess an otoprotective effect of inert gas argon (Ar) in 1-hour exposure to 85 dB white noise. The condition of the acoustic system was evaluated by findings of pure-tone audiometry, TEOAE, DPOAE, BERA and electrocochleography (EcohG). Breathing with oxygen-nitrogen-argon gas mixture (02 - 16%, N2 - 60%, Ar - 24%) in normobaric pressure provides cochlear defense from noise hazard. The authors believe that argon has otoprotective and neuroprotective effects in all types of existing models of cochlear hair cell affection related to hypoxia, oxidative stress, activation of peroxide radicals, toxic effect of glutamate. The detected defensive effect of argon in experimental human hypoxia and in exposure to noise opens a perspective of a new therapeutic strategy in noise damage to the organ of hearing, ototoxic processes in the cochlea and of a novel trend in the treatment of neurosensory hypoacusis and noise in the ear. PMID- 17690653 TI - [Epidemiological aspects of nasal bones fractures in an industrial city today]. AB - Contemporary epidemiological situation in relation to nasal bone fractures is characterized by a noticeable rise in the incidence rate in population (26.1 to 36.9 per 100,000 according to hospital statistics in an industrial city, and 57 to 61 per 100,000 according to statistics of outpatient clinics) and ENT morbidity (6.3 to 10.1% among inpatients); by stabilization of this incidence rate for the last 3 years and the trend to a decrease in the number of inpatients with nasal bone fractures. However, a high level of traumatism dictates the necessity of perfection of the system of the diagnosis and medical care for patients with nasal bone fractures. PMID- 17690654 TI - [Use of fibrinocollagen complex in surgical treatment of patients with vascular tumors of the ear and external nose (a pilot report)]. AB - A fibrinocollagen complex (TahoComb) has been used in surgical treatment of patients with vascular tumors of the ear and external nose (6 patients with hemangioma of the ear and 6 patients with hemangioma of the external nose). It is shown that TahoComb reduces significantly blood loss in removal of branchy arterial hemangiomas, need in ligation or embolization of afferent vessels, in tight tamponade of the tympanic cavity and external acoustic meatus. PMID- 17690655 TI - [Choice of tools for ambulatory uvulopalatoplasty on the basis of experimental and clinical studies]. AB - We studied interaction of a radiofrequency scalpel and a semiconductor laser with the tissue phantom. The heated part of the phantom can be easily removed and measured for size of the coagulated area. We investigated to what extent the width of the coagulation necrosis along the incision is influenced by the power and speed of each instrument used for incision. As for the laser, the width of the coagulation zone increased with rise of power and slowing of cutting velocity. For the scalpel, this relationship between incision velocity and coagulation effect was much weaker but had the same trend. We compared hemostasis efficiency during uvulopalatoplasty with both instruments. Much more potent hemostatic effect was registered in laser uvulopalatoplasty. PMID- 17690656 TI - [Restoration of voice function in patients without larynx and pharyx: myth or reality?]. AB - The article presents an original technique of voice restoration in patients who have undergone laryngopharyngectomy with resection of esophageal cervical part; analyses mechanism of phonation. Four cases of prosthetic reconstruction are reported. The necessity and feasibility of voice rehabilitation in patients with this severe condition are validated. PMID- 17690657 TI - [Rehabilitation of patients with bilateral laryngeal paralysis in a time aspect]. AB - According to the literature, up to 15% surgical interventions on the neck is accompanied with such complications as paralysis and paresis of the larynx. Rehabilitation of paralysed larynx by staged surgical treatment and prosthesis lasts for years. Late diagnosis of bilateral laryngeal paralysis after cervical surgery entails persistent systemic poststenotic alterations. The authors offer the diagnosis-treatment algorithm for patients with bilateral laryngeal paralysis which allows a significant reduction in duration of rehabilitation. PMID- 17690658 TI - [One-stage laparoscopic resection of colon at primary-multiple cancer]. AB - Results of treatment of one patient with multiple cancer of colon and the efficacy of laparoscopic surgical methods for synchronous tumors of colon are analyzed. It is revealed that laparoscopic technologies for colon resection reduce surgical trauma. Short- and long-term results demonstrate high level of patient's life quality; recurrence-free period was 3 years. It is concluded that mini-invasive technologies are appropriate and effective for the treatment of colorectal cancer. PMID- 17690659 TI - [Treatment of the patients with complications of colon malignant tumors]. AB - Results of surgical treatment of 106 patients with complications of colon malignant tumors are analyzed. Diagnostic and treatment algorithm for these patients has been developed and used in clinical practice. Standardization and use of this algorithm permitted to increase the rate of radical operations from 48.9 to 62.6%, to reduce the rate of purulent complications more in 2 times and postoperative lethality - in 1.6 times. PMID- 17690660 TI - [Cholelithic small bowel obstruction]. AB - Results of treatment of 18 patients with cholelithic small bowel obstruction are analyzed. All of them were female aged 62 to 84 years with severe concomitant diseases. Different variants of clinical manifestation of small bowel obstruction, significance of diagnostic methods, the causes of delayed hospitalization and operation are analyzed in details. Fourteen patients have been operated with diagnosis of intestinal obstruction but only at 3 of them the true cause of disease has been assumed before surgery. Enterolithotomy was performed at 15 patients, resection of small intestine together with gallstone - at 3 patients. Recurrence of cholelithic obstruction was seen at one patient on 8th day after surgery. Postoperative lethality was 27.7%, but only at one case the purulent complications and multiple organ failure was the cause of lethality. Recommendations for improvement of treatment results and prophylaxis of cholelithic small bowel obstruction are given. PMID- 17690661 TI - [Temporary endoscopic stenting of bile ducts]. AB - Experience of endoscopic stenting for preoperative preparation of patients with various diseases of hepatopancreatobiliary zone and high surgical risk is analyzed. Internal drainage (stenting) of bile ducts was performed at 45 (58%) patients, external - at 24 (31.1%), combined external-internal - at 8 (10.4%) patients. Advantages and disadvantages of each stenting type are evaluated, differential indications are determined. Analysis of short-term results demonstrates that the rate of early postoperative complications is lower at patients operated after bile ducts stenting that at ones operated on jaundice peak. It is concluded that endoscopic stenting of bile ducts permits to increase efficacy of preoperative preparation for surgical or endoscopic procedures, and to decrease the risk of their complications. PMID- 17690662 TI - [Results of surgical treatment of benign strictures of extrahepatic bile ducts]. AB - The main reason of benign biliary strictures is the traumatic bile duct injuries during laparoscopic or open cholecystectomy. Although there are growing possibilities of interventional endoscopic treatment of such pathology the definitive operative drainage is in many cases the therapy of choice. There were analyzed the short- and long-term results of surgical reconstruction in 160 patients with of benign strictures of hepaticocholedochus. Complication rate was 12,5%, mortality 2,5%. Median follow-up period was 53,6+/-51,3 month, good and satisfactory long-term results were observed in 76%. There were revealed two factors, predicting poor outcome: biliary fistula (R=0,31; p=0,0053) and reoperations (R=0,309; small er, Cyrillic=0,0058). CONCLUSION: biliodigestive anastomosis is method of choice for treatment of benign biliary strictures of hepaticocholedochus. Hepaticojejunostomy with Roux-en-jejunal limb is more preferable variant of reconstruction for treatment of benign biliary strictures of HC. Good long-term results can be achieved in most part of the patients. In patient with not wide bile ducts and in technically difficult cases transhepatic biliary drainage is acceptable. PMID- 17690663 TI - [Laparoscopy at early postoperative intraabdominal bleedings]. AB - Results of treatment of 46 patients with intraabdominal bleeding as complication of abdominal surgery are analyzed. Laparoscopy and ultrasonic diagnosis assisted with earlier diagnosis of complication. Eleven patients underwent repeated surgery at abdominal bleeding with laparoscopic techniques. Favorable outcome was seen at all the cases. Diagnostic algorithm of early postoperative intraabdominal bleedings is proposed. PMID- 17690664 TI - [Surgical treatment of patients with perforated peptic ulcers]. AB - Results of surgical treatment of 782 patients with perforated gastric and duodenal ulcers are analyzed. Gastric ulcers of I type were diagnosed at 86 (10.9%) patients, prepyloric and pyloric ulcers - at 441 (56.4%), duodenal ulcers - at 255 (32.6%) patients. Perforation was combined with bleeding and stenosis at 24 (3.1%). Palliative operations have been performed at 172 (22.0%) patients, stem vagotomy with ulcer excision and pyloroplasty - at 58 (7.4%), various types of stomach resection - at 54 (6.9%), proximal gastric vagotomy with excision of gastric, pyloric or duodenal ulcer - at 77 (9.8%), proximal gastric vagotomy with excision or suturing of ulcer and pyloro- or duodenoplasty - at 421 (53.8%) patients. The rate of postoperative complications after proximal gastric vagotomy was 3.6%, after stomach resection - 18.2% (p<0.01). Early postoperative complications after vagotomy with ulcer excision and pyloroplasty were diagnosed at 8.3%, after stomach resection - at 18.2% patients (p<0.01). The quality of patients life was higher after organ-saving operations. Proximal gastric vagotomy with excision of ulcer and pyloro- or duodenoplasty should be regarded as operation of choice at perforated duodenal ulcers. PMID- 17690665 TI - [Prediction of surgical infections severity at elderly and old patients]. AB - Clinical and immunological characteristics of generalized peritonitis in different age group at complicated and non-complicated postoperative period were analyzed at 246 patients with abdominal purulent infection. Prognostic criteria of complicated postoperative period at elderly and old patients have been determined. It is concluded that interpretation of immune characteristics permits to determine the prognostic criteria of disease course and outcome at various age group, and to use the rational immunocorrection. PMID- 17690666 TI - [Laparoscopic operations for simple cysts of kidneys at children]. AB - Results of treatment of 62 children aged 1 to 15 years with non-parasitic cysts of kidneys using mini-invasive laparoscopic technologies are analyzed. Laparoscopic operations with original technique have been performed at all the patients with various cysts sizes (from 3 to 13 cm across diameter) and localization (including 12 cases of peripelvic cysts). The time of surgery ranged 25 to 110 min (43 min on average); there were no conversions to open surgery, intraoperative and postoperative complications. The follow-up ranged from 1 to 3 years, there were no cases of cyst recurrence, and the functional and cosmetic results were excellent. It is concluded that laparoscopic method should be regarded as "gold standard" for the treatment of non-parasitic kidneys cysts at children that permits to achieve the stable positive results regardless of patient age, size and localization of cyst. PMID- 17690667 TI - [Anti-Titin-antibodies at the patients with myasthenic and non-myasthenic thymoma]. AB - Serum specimens from 52 myasthenic patients with thymoma of various histological characteristics and 4 patients with thymoma without myasthenia have tested for anti-Titin-antibodies titer. It has been demonstrated that organ-specific thymoma dominated at myasthenic patients, and organ-nonspecific thymoma - at the patients without myasthenia. There was no correlation between severe clinical symptoms and the level of anti-Titin-antibodies. The titer of antibodies at the patients with organ-specific thymoma was higher that at ones with organ-nonspecific thymoma, but there was no correlation between the level of anti-Titin-antibodies and histological type of organ-specific thymoma. PMID- 17690668 TI - [Ultrasonic scalpel in abdominal surgery]. AB - Ultrasonic scalpels and original modified compressing instruments were used in 216 abdominal operations. High efficacy of ultrasonic scalpels both in traditional and endoscopic surgery is demonstrated. PMID- 17690669 TI - [State of hemostasis system at transurethral prostatic resection]. AB - Hemostasis system was examined at 58 patients who underwent transurethral prostate resection due to benign prostatic hyperplasia. All the patients were divided into 2 groups: the study group where the surgery was performed under spinal anesthesia, and control - under intravenous anesthesia. The hemostasis system was examined before surgery and on 1st, 3rd and 5th day after it. It is revealed that the surgery under intravenous anesthesia is associated with increase of coagulation potential and decrease of fibrinolytic activity that is the most marked on 3rd and 5th day. PMID- 17690670 TI - [Functional and anatomic classification in the surgery of combined thoracoabdominal aorta aneurysms]. AB - The functional and anatomic classification of occlusive lesions of arterial system is proposed. This classification permits to evaluate the sate of arterial bed, the bulk and priority of affected arteries revascularization at patients with thoracoabdominal aorta aneurysms, to choice optimal treatment tactics, and to carry out the dynamic evaluation before and after surgery. PMID- 17690671 TI - [Pathogenetic approach to diagnosis and treatment of acute pancreatitis]. AB - Results of examination and treatment of 958 patients with acute pancreatitis are analyzed. The study group consisted of 372 patients treated in accordance with special clinical protocols (2001-2004). The control group consisted of 586 patients treated before these protocols extensive use (1995-2001). The two groups were similar by the main clinical characteristics. It was demonstrated that the treatment according standard protocols permitted to reduce general lethality from 3.9% (control group) to 2.7% (study group), postoperative lethality - from 14.3 to 11.5%. General lethality at severe acute pancreatitis decreased from 18.5 to 12.7%, postoperative lethality - from 26 to 19%. PMID- 17690672 TI - [Azygoportal disconnection at esophageal varicose veins dilatation]. AB - Two original organ-saving surgical technologies are suggested for surgical prophylaxis of bleedings from esophageal and gastric varicose veins dilatation. The azygoportal disconnection surgery has been performed at 42 patients. The rate of bleeding recurrences was 4.8%. This surgical procedure may be regarded as the stage of complex treatment of patients with liver cirrhosis and as the final treatment at the patients with extrahepatic portal hypertension. PMID- 17690673 TI - [Surgical treatment of patients with acute pancreatitis]. AB - Results of treatment of patients with acute pancreatitis are analyzed. Efficacy of staged treatment of patients with acute destructive pancreatitis is demonstrated. The ineffective conservative therapy during 1-3 days is regarded as indication for half-open surgical method (median laparotomy, necrsecvestrectomy, omentopancreatobursostoma and lumbostoma formation). General purulent peritonitis is indication for open method (laparostoma formation). Unitized surgical tactics permitted to reduce lethality from 4.2 to 2.5%. PMID- 17690674 TI - [Clinical course, diagnosis and treatment of cholelithic intestinal obstruction]. AB - Forty-seven cases of intestinal obstruction due to gall-stones are analyzed. All the patients underwent surgery including enterolithotomy with two-layer intestinal closure (40), passage of stone into cecum (3), intestinal resection due to wall necrosis (3). Two patients died due to intestinal perforation with retroperitoneal phlegmon and multiple organ failure. It is concluded that clinical symptoms of cholelithic intestinal obstruction are wave-like. Intestinal X-ray and ultrasonic examinations are the most informative for final diagnosis. PMID- 17690675 TI - [Surgical treatment of the patients with posttraumatic aneurysms of subclavian arteries]. AB - Posttraumatic aneurysm of clavicular artery is the rare pathology (less 1% of all peripheral aneurysms). Experience of surgical treatment of 5 patients with this disease is analyzed. All the patients underwent different surgical procedures depending on aneurysm size and localization. There were no lethal outcomes. Preoperative diagnostic methods, surgical techniques and postoperative complications are described. Review of literature is also available. PMID- 17690676 TI - [Adenocystic bronchial cancer]. AB - Among 4005 patients with lung cancer 26 (0.65%) of them had adenocystic bronchial cancer, including 13 male and 13 female patients aged 13 to 60 years. Overall 33 operations have been performed at 26 patients, 5 of them were operated twice, and 1 patient underwent 3 surgical procedures. The plastic operations on bronchi (10) were the main surgical procedures. Four patients underwent pneumonectomy with resection of tracheal bifurcation, and 2 patients - circular resection of primary bronchus with resection of carine and tracheobronchial angle. One patient died after surgery, postoperative complications were seen at 4 patients including hemothorax (1), bleeding (1) and empyema (2). Twenty-five patients have been discharged, 21 of them were followed-up. Three patients survived more 3 years, 6 patients - more 5 years, 8 - more 10 years, 2 - more 15 years, and 2 - more 20 years. Long-term results of radical surgical treatment argue the efficacy of these surgeries at adenocystic bronchial cancer. PMID- 17690677 TI - [Treatment of thorax wounds]. AB - Results of surgical treatment of 154 patients with thorax injuries are analyzed. Most of the patients (93 ps, 60.4%) had penetrating wounds. X-ray examination remains the open most method of diagnosis. The pleural cavity drainage with prolonged aspiration was the main treatment method for the patients with closed thoracic trauma and open trauma without organs injury. Lethality was 7.8% among all the patients and 12.9% among ones with thoracic penetrating wounds. There were no postoperative lethal outcomes. The rate of postoperative complications was 22.7%. Videothoracoscopy and video-assisted mini-thoracotomy are effective methods for diagnosis and treatment, reduce the rate of postoperative complications and lethal outcomes, limit the indications to wide thoracotomy. PMID- 17690678 TI - [Compressive invaginated ileocolic anastomoses]. AB - Results of treatment of 80 patients with right-half colon diseases are analyzed. New technology of compressive invaginated ileocolic end-to-end and end-to-side anastomoses with special device (nickel-titanium basis with superelasticity and "memory" effect) was used. Early postoperative complications were seen at 3 (3.75%) patients and they were not relating to suture quality. There were no anastomosis complications in 6 months to 5 years after surgery. The scintigraphic assessment of motor-evacuatory function of gastrointestinal tract demonstrated radiopharmaceutical delay at the zone of compressive anastomosis and portion evacuation of chymus into colon. PMID- 17690679 TI - [Prediction of multiple organ failure due to sepsis at the patients with purulo necrotic diseases of soft tissues]. AB - Microcirculatory disorders at sepsis lead to severe tissue perfusion injury and multiple organ dysfunction. Level of decrease of albumin serum concentration may be used as marker of microcirculatory disorders. One hundred and forty patients with purulo-necrotic diseases of soft tissues were examined. It was demonstrated that intensity of systemic inflammatory reaction (SIR) and old age of patients are the independent risk factors of severe sepsis; multiple organ failure is associated with significant decrease of albumin serum concentration with slight symptoms of SIR. Numeric criteria of risk assessment and 3 risk category of sepsis and multiple organ failure are formulated. PMID- 17690680 TI - [Microsurgical techniques for the surgery on colon and ileocecal zone]. AB - Morphometric and microanatomic features of colon wall has been studied. Experimental microsurgical operations demonstrated ability of wounds and anastomoses to primary healing in 4-7 days. It was demonstrated that operations with microsurgical techniques in clinical practice had the advantages over ones without it: primary healing of anastomoses in 6-12 days, decrease of anastomoses insufficiency rate and hospital stay, reduction of indications to proximal colostoma creation, good early functional result, absence of anastomoses stenosis. PMID- 17690681 TI - [Clinical features of surgical diseases at the patients with HIV/AIDS]. AB - Results of treatment of HIV-infected patients with surgical diseases are analyzed. These results are compared with ones at non-infected patients. The standards of surgical operations at HIV-infected patients are that permits to optimize surgical tactics at HIV/AIDS patients and to improve treatment results. PMID- 17690682 TI - [Immuneprophylaxis of purulent and septic complications with Derinat at surgical treatment of calculous cholecystitis]. PMID- 17690683 TI - [Conception of "humid" healing of venous ulcers]. PMID- 17690684 TI - Association of NFKB1 -94ins/del ATTG promoter polymorphism with susceptibility to and phenotype of Graves' disease. AB - Recently, a functional polymorphism in the NFKB1 gene promoter (-94ins/del ATTG) has been identified and associated with chronic inflammatory diseases. The aim of this study was to analyze the association of NFKB1 polymorphism with susceptibility to and phenotype of Graves' disease (GD). The initial case-control association study, performed in a Polish-Warsaw cohort (388 GD patients and 688 controls), was followed by the two replication studies performed in Polish Gliwice and Japanese-Kurume cohorts (198 GD patients and 194 controls, and 424 GD patients and 222 controls, respectively). The frequency of the -94del ATTG (D) allele was increased in GD compared to controls in Warsaw cohort. This finding was replicated in Gliwice cohort. Combining both Polish-Caucasian cohorts showed that the NFKB1 polymorphism was significantly associated with susceptibility to GD with a codominant mode of inheritance (P=0.00005; OR=1.37 (1.18-1.60)). No association with GD was found in Japanese cohort. However, subgroup analysis in Japanese GD patients revealed a correlation between the NFKB1genotype and the development of ophthalmopathy (P=0.009; OR=1.49 (1.10-2.01)), and the age of disease onset (P=0.009; OR=1.45 (1.09-1.91)). Our results suggest that NFKB1 94ins/del ATTG polymorphism may be associated with susceptibility to and/or phenotype of GD. PMID- 17690685 TI - Differential sensitivity of naive and subsets of memory CD4+ and CD8+ T cells to hydrogen peroxide-induced apoptosis. AB - CD4+ and CD8+ memory T cells are identified into central and effector memory subsets, which are characterized by distinct homing patterns and functions. In this investigation, we show that naive and central memory CD4+ and CD8+ T cells are sensitive to hydrogen peroxide (H2O2)-induced apoptosis, whereas effector memory CD4+ and CD8+ T cells are relatively resistant to H2O2-induced apoptosis. Apoptosis in naive and central memory CD4+ and CD8+ is associated with the release of cytochrome c and activation of caspase-9 and caspase-3, upregulation of Bax and voltage-dependent anion channel (VDAC) expression, and decreased intracellular glutathione (GSH). In vitro GSH and a superoxide dismutase mimetic Mn(III) tetrakis (1-methyl-4-pyridyl) porphyrin inhibited H2O2-induced apoptosis in both naive and central memory CD4+ and CD8+ T cells. Furthermore, VDAC inhibitor 4,4'-diisothiocynostilbene-2,2'-disulfonic acid blocked H2O2-induced apoptosis. These data demonstrate that H2O2 induces apoptosis preferentially in human naive and central memory CD4+ and CD8+ T cells via the mitochondrial pathway by regulating intracellular GSH and the expression of Bax and VDAC. PMID- 17690686 TI - Structure of three tandem filamin domains reveals auto-inhibition of ligand binding. AB - Human filamins are large actin-crosslinking proteins composed of an N-terminal actin-binding domain followed by 24 Ig-like domains (IgFLNs), which interact with numerous transmembrane receptors and cytosolic signaling proteins. Here we report the 2.5 A resolution structure of a three-domain fragment of human filamin A (IgFLNa19-21). The structure reveals an unexpected domain arrangement, with IgFLNa20 partially unfolded bringing IgFLNa21 into close proximity to IgFLNa19. Notably the N-terminus of IgFLNa20 forms a beta-strand that associates with the CD face of IgFLNa21 and occupies the binding site for integrin adhesion receptors. Disruption of this IgFLNa20-IgFLNa21 interaction enhances filamin binding to integrin beta-tails. Structural and functional analysis of other IgFLN domains suggests that auto-inhibition by adjacent IgFLN domains may be a general mechanism controlling filamin-ligand interactions. This can explain the increased integrin binding of filamin splice variants and provides a mechanism by which ligand binding might impact filamin structure. PMID- 17690687 TI - LysM domains mediate lipochitin-oligosaccharide recognition and Nfr genes extend the symbiotic host range. AB - Legume-Rhizobium symbiosis is an example of selective cell recognition controlled by host/non-host determinants. Individual bacterial strains have a distinct host range enabling nodulation of a limited set of legume species and vice versa. We show here that expression of Lotus japonicus Nfr1 and Nfr5 Nod-factor receptor genes in Medicago truncatula and L. filicaulis, extends their host range to include bacterial strains, Mesorhizobium loti or DZL, normally infecting L. japonicus. As a result, the symbiotic program is induced, nodules develop and infection threads are formed. Using L. japonicus mutants and domain swaps between L. japonicus and L. filicaulis NFR1 and NFR5, we further demonstrate that LysM domains of the NFR1 and NFR5 receptors mediate perception of the bacterial Nod factor signal and that recognition depends on the structure of the lipochitin oligosaccharide Nod-factor. We show that a single amino-acid variation in the LysM2 domain of NFR5 changes recognition of the Nod-factor synthesized by the DZL strain and suggests a possible binding site for bacterial lipochitin oligosaccharide signal molecules. PMID- 17690688 TI - The candidate tumor suppressor BTG3 is a transcriptional target of p53 that inhibits E2F1. AB - Proper regulation of cell cycle progression is pivotal for maintaining genome stability. In a search for DNA damage-inducible, CHK1-modulated genes, we have identified BTG3 (B-cell translocation gene 3) as a direct p53 target. The p53 transcription factor binds to a consensus sequence located in intron 2 of the gene both in vitro and in vivo, and depletion of p53 by small interfering RNA (siRNA) abolishes DNA damage-induced expression of the gene. Furthermore, ablation of BTG3 by siRNA in cancer cells results in accelerated exit from the DNA damage-induced G2/M block. In vitro, BTG3 binds to and inhibits E2F1 through an N-terminal domain including the conserved box A. Deletion of the interaction domain in BTG3 abrogates not only its growth suppression activity, but also its repression on E2F1-mediated transactivation. We also present evidence that by disrupting the DNA binding activity of E2F1, BTG3 participates in the regulation of E2F1 target gene expression. Therefore, our studies have revealed a previously unidentified pathway through which the activity of E2F1 may be guarded by activated p53. PMID- 17690689 TI - Impaired GABAergic transmission and altered hippocampal synaptic plasticity in collybistin-deficient mice. AB - Collybistin (Cb) is a brain-specific guanine nucleotide exchange factor that has been implicated in plasma membrane targeting of the postsynaptic scaffolding protein gephyrin found at glycinergic and GABAergic synapses. Here we show that Cb-deficient mice display a region-specific loss of postsynaptic gephyrin and GABA(A) receptor clusters in the hippocampus and the basolateral amygdala. Cb deficiency is accompanied by significant changes in hippocampal synaptic plasticity, due to reduced dendritic GABAergic inhibition. Long-term potentiation is enhanced, and long-term depression reduced, in Cb-deficient hippocampal slices. Consistent with the anatomical and electrophysiological findings, the animals show increased levels of anxiety and impaired spatial learning. Together, our data indicate that Cb is essential for gephyrin-dependent clustering of a specific set of GABA(A) receptors, but not required for glycine receptor postsynaptic localization. PMID- 17690690 TI - Structural insights into the transcriptional and translational roles of Ebp1. AB - The ErbB3-binding protein 1 (Ebp1) is an important regulator of transcription, affecting eukaryotic cell growth, proliferation, differentiation and survival. Ebp1 can also affect translation and cooperates with the polypyrimidine tract binding protein (PTB) to stimulate the activity of the internal ribosome entry site (IRES) of foot-and-mouth disease virus (FMDV). We report here the crystal structure of murine Ebp1 (p48 isoform), providing the first glimpse of the architecture of this versatile regulator. The structure reveals a core domain that is homologous to methionine aminopeptidases, coupled to a C-terminal extension that contains important motifs for binding proteins and RNA. It sheds new light on the conformational differences between the p42 and p48 isoforms of Ebp1, the disposition of the key protein-interacting motif ((354)LKALL(358)) and the RNA-binding activity of Ebp1. We show that the primary RNA-binding site is formed by a Lys-rich motif in the C terminus and mediates the interaction with the FMDV IRES. We also demonstrate a specific functional requirement for Ebp1 in FMDV IRES-directed translation that is independent of a direct interaction with PTB. PMID- 17690692 TI - Proteome analyses of the growth inhibitory effects of NCH-51, a novel histone deacetylase inhibitor, on lymphoid malignant cells. AB - Recent reports showing successful inhibition of cancer and leukemia cell growth using histone deacetylase inhibitor (HDACi) compounds have highlighted the potential use of HDACi as anti-cancer agents. However, high incidence of toxicity and low stability in vivo were observed with hydroxamic acid-based HDACi such as suberoylanilide hydroxamic acid (SAHA), thus limiting its clinical applicability. In this study, we found that a novel non-hydroxamate HDACi NCH-51 could inhibit the cell growth of a variety of lymphoid malignant cells through apoptosis induction, more effectively than SAHA. Activation of caspase-3, -8 and -9, but not -7 was detected after the treatment with NCH-51. Gene expression profiles showed that NCH-51 and SAHA similarly upregulated p21 and downregulated anti apoptotic molecules including survivin, bcl-w and c-FLIP. Proteome analysis using two-dimensional electrophoresis revealed that NCH-51 upregulated anti-oxidant molecules including peroxiredoxin 1 and 2 and glutathione S-transferase at the protein level. Interestingly, NCH-51 induced reactive oxygen species (ROS) after 8 h whereas SAHA continuously declined ROS. Pretreatment with an antioxidant, N acetyl-L-cysteine, abolished the cytotoxicity of NCH-51. These findings suggest that NCH-51 exhibits cytotoxicity by sustaining ROS at the higher level greater than SAHA. This study indicates the therapeutic efficacy of NCH-51 and novel insights for anti-HDAC therapy. PMID- 17690691 TI - Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group. AB - We evaluated the efficacy of a treatment strategy in which infants with acute lymphoblastic leukemia (ALL) were stratified by their MLL gene status and then assigned to different risk-based therapies. A total of 102 patients were registered on two consecutive multicenter trials, designated MLL96 and MLL98, between 1995 and 2001. Those with a rearranged MLL gene (MLL-R, n=80) were assigned to receive intensive chemotherapy followed by hematopoietic stem cell transplantation (HSCT), while those with germline MLL (MLL-G, n=22) were treated with chemotherapy alone. The 5-year event-free survival (EFS) rate for all 102 infants was 50.9% (95% confidence interval, 41.0-60.8%). The most prominent late effect was growth impairment, observed in 58.9% of all evaluable patients in the MLL-R group. This plan of risk-based therapy appears to have improved the overall prognosis for infants with ALL, compared with previously reported results. However, over half the events in patients with MLL rearrangement occurred before the instigation of HSCT, and that HSCT-related toxic events comprised 36.3% (8/22) of post-transplantation events, suggesting that further stratification within the MLL-R group and the development of more effective early-phase intensification chemotherapy will be needed before the full potential of this strategy is realized. PMID- 17690693 TI - Overexpression of a hematopoietic transcriptional regulator EDAG induces myelopoiesis and suppresses lymphopoiesis in transgenic mice. AB - Erythroid differentiation-associated gene (EDAG) is a hematopoietic tissue specific gene that is highly expressed in the earliest CD34+ lin- bone marrow (BM) cells and involved in the proliferation and differentiation of hematopoietic cells. To investigate the role of EDAG in hematopoiesis, we established an EDAG transgenic mouse model driven by human CD11a promoter. The transgenic mice showed increased mortality with severe organ infiltration by neutrophils, and the homeostasis of hematopoiesis was broken. The myelopoiesis was enhanced with expansion of myeloid cells in BM, increased peripheral granulocytes and extramedullary myelopoiesis in spleen. In contrast to myeloid cells, the lymphoid commitment was severely impaired with the B lymphopoiesis blocked at the transition from pro/pre-B I to pre-B II stage in BM and T thymocytes development blocked at the most immature stage (DN I). Moreover, we showed that EDAG was a transcriptional regulator which had transactivation activity and regulated the expression of several key transcription factors such as PU.1 and Pax5 in transgenic hematopoietic stem cells. These data suggested that EDAG was a key transcriptional regulator in maintaining the homeostasis of hematopoietic lineage commitment. PMID- 17690694 TI - A novel silver (I) chelate: cytotoxicity and apoptotic mechanism of action on human hematopoietic malignancies. PMID- 17690695 TI - Evidence for the interaction of imatinib at the transport-substrate site(s) of the multidrug-resistance-linked ABC drug transporters ABCB1 (P-glycoprotein) and ABCG2. PMID- 17690696 TI - Expression of MUM1/IRF4 mRNA as a prognostic marker in patients with multiple myeloma. PMID- 17690697 TI - A PDGFRB-positive acute myeloid malignancy with a new t(5;12)(q33;p13.3) involving the ERC1 gene. PMID- 17690698 TI - CD34+/Ph+ cells are still detectable in chronic myeloid leukemia patients with sustained and prolonged complete cytogenetic remission during treatment with imatinib mesylate. PMID- 17690699 TI - Trolox enhances the anti-lymphoma effects of arsenic trioxide, while protecting against liver toxicity. AB - Arsenic trioxide (As2O3) is an effective therapy in acute promyelocytic leukemia (APL), but its use in other malignancies is limited by the higher concentrations required to induce apoptosis. We have reported that trolox, an analogue of alpha tocopherol, increases As2O3-mediated apoptosis in a variety of APL, myeloma and breast cancer cell lines, while non-malignant cells may be protected. In the present study, we extended previous results to show that trolox increases As2O3 mediated apoptosis in the P388 lymphoma cell line in vitro, as evidenced by decrease of mitochondrial membrane potential and release of cytochrome c. We then sought to determine whether this combination can enhance antitumor effects while protecting normal cells in vivo. In BDF1 mice, trolox treatment decreased As2O3 induced hepatomegaly, markers of oxidative stress and hepatocellular damage. In P388 tumor-bearing mice, As2O3 treatment prolonged survival, and the addition of trolox provided a further significant increase in lifespan. In addition, the combination of As2O3 and trolox inhibited metastatic spread, and protected the tumor-bearing mice from As2O3 liver toxicity. Our results suggest, for the first time, that trolox might prevent some of the clinical manifestations of As2O3 related toxicity while increasing its pro-apoptotic capacity and clinical efficacy in hematological malignancies. PMID- 17690700 TI - Nucleophosmin leukaemic mutants contain C-terminus peptides that bind HLA class I molecules. PMID- 17690701 TI - Comparison between two fludarabine-based reduced-intensity conditioning regimens before allogeneic hematopoietic stem-cell transplantation: fludarabine/melphalan is associated with higher incidence of acute graft-versus-host disease and non relapse mortality and lower incidence of relapse than fludarabine/busulfan. AB - Reduced-intensity conditioning (RIC) regimens are increasingly used in allogeneic stem-cell transplantation (SCT). There are no data whether any of these regimens has advantage and in what setting. We retrospectively analyzed SCT outcomes in 151 patients given fludarabine-based RIC for various hematological malignancies; 72 conditioned with fludarabine and intravenous-busulfan (FB) and 79 with fludarabine and melphalan (FM). FM was more myelosuppressive. Grade III-IV organ toxicity occurred in 31 and 53% of FB and FM recipients (P=0.005) and acute graft versus-host disease grade II-IV in 33 and 53%, respectively (P=0.01). Non-relapse mortality rate (NRM) was 16 and 40%, respectively (P=0.003). Active disease (HR 2.2, P=0.003) and prior autologous SCT (HR 1.7, P=0.04) predicted inferior overall survival (OS). Among patients transplanted in remission, OS was 72 and 36% after FB and FM, respectively (P=0.03) due to increased NRM with FM. Similarly, patients transplanted in active disease experienced higher NRM with FM, however lower relapse rates resulted in equivalent OS. In conclusion, there are marked differences in outcome between RIC regimens that are theoretically dose-equivalent. The FM regimen is more myelosuppressive and toxic but controls disease better. FB was associated with improved survival in patients transplanted in remission. These observations merit further study in prospective studies. PMID- 17690702 TI - Childcare in the first 2 years of life reduces the risk of childhood acute lymphoblastic leukemia. PMID- 17690703 TI - Identification of TSC-22 as a potential tumor suppressor that is upregulated by Flt3-D835V but not Flt3-ITD. AB - Transforming growth factor-beta (TGF-beta)-stimulated clone-22 (TSC-22) was originally isolated as a TGF-beta-inducible gene. In this study, we identified TSC-22 as a potential leukemia suppressor. Two types of FMS-like tyrosine kinase 3 (Flt3) mutations are frequently found in acute myeloid leukemia: Flt3-ITD harboring an internal tandem duplication in the juxtamembrane domain associated with poor prognosis and Flt3-TKD harboring a point mutation in the kinase domain. Comparison of gene expression profiles between Flt3-ITD- and Flt3-TKD-transduced Ba/F3 cells revealed that constitutive activation of Flt3 by Flt3-TKD, but not Flt3-ITD, upregulated the expression of TSC-22. Importantly, treatment with an Flt3 inhibitor PKC412 or an Flt3 small interfering RNA decreased the expression level of TSC-22 in Flt3-TKD-transduced cells. Forced expression of TSC-22 suppressed the growth and accelerated the differentiation of several leukemia cell lines into monocytes, in particular, in combination with differentiation inducing reagents. On the other hand, a dominant-negative form of TSC-22 accelerated the growth of Flt3-TKD-transduced 32Dcl.3 cells. Collectively, these results suggest that TSC-22 is a possible target of leukemia therapy. PMID- 17690704 TI - Combined high-resolution array-based comparative genomic hybridization and expression profiling of ETV6/RUNX1-positive acute lymphoblastic leukemias reveal a high incidence of cryptic Xq duplications and identify several putative target genes within the commonly gained region. AB - Seventeen ETV6/RUNX1-positive pediatric acute lymphoblastic leukemias were investigated by high-resolution array-based comparative genomic hybridization (array CGH), gene expression profiling and fluorescence in situ hybridization. Comparing the array CGH and gene expression patterns revealed that genomic imbalances conferred a great impact on the expression of genes in the affected regions. The array CGH analyses identified a high frequency of cytogenetically cryptic genetic changes, for example, del(9p) and del(12p). Interestingly, a duplication of Xq material, varying between 30 and 60 Mb in size, was found in 6 of 11 males (55%), but not in females. Genes on Xq were found to have a high expression level in cases with dup(Xq); a similar overexpression was confirmed in t(12;21)-positive cases in an external gene expression data set. By studying the expression profile and the proposed function of genes in the minimally gained region, several candidate target genes (SPANXB, HMGB3, FAM50A, HTATSF1 and RAP2C) were identified. Among them, the testis-specific SPANXB gene was the only one showing a high and uniform overexpression, irrespective of gender and presence of Xq duplication, suggesting that this gene plays an important pathogenetic role in t(12;21)-positive leukemia. PMID- 17690705 TI - Effective treatment of leukemic cell lines with wt1 siRNA. AB - The expression of wt1 and bcl-2 is considered to have a proliferating and survival supporting effect in leukemia blast cells. Here we describe the use of siRNA against wt1 and bcl-2 in leukemic cell lines for successful growth inhibition. We have used two different sequences designated as siRNA-A and siRNA B corresponding to positions within the wt1 coding sequence to downregulate wt1 and a commercially available siRNA kit to downregulate bcl-2. WT1 and bcl-2 gene expression in transfected leukemic cell lines were evaluated with RT-PCR and western blot analyses. MTT assay was used to measure the cell viability and flow cytometry using annexin V/PI-staining for apoptosis. K562 and HL-60 cell lines transfected with siRNA-A targeted to wt1 had greatly decreased levels of both wt1 mRNA and protein expression. In contrast, siRNA-B and control siRNA led almost to no effect on wt1 mRNA and protein expression. siRNA-A-reduced wt1 mRNA expression was associated with a decreased cell proliferation and increased number of apoptotic cells in K562 and HL-60 cells by 24 and 48 h after transfection. Combined treatment with wt1 siRNA and bcl-2 siRNA simultaneously was not able to override the cell growth and apoptosis effects compared to single treatment with wt1 siRNA. siRNAs targeted against human wt1 might be a valuable tool as antiproliferative agent against wt1 expressing leukemic cells. PMID- 17690706 TI - Different genomic imbalances in low- and high-grade HCV-related lymphomas. PMID- 17690707 TI - Extramedullary BCR-ABL1-negative myeloid leukemia in a patient with chronic myeloid leukemia and synchronous cytogenetic abnormalities in Philadelphia positive and -negative clones during imatinib therapy. PMID- 17690708 TI - Molecular basis for sunitinib efficacy and future clinical development. AB - Sunitinib malate (SU11248/Sutent; Pfizer) is a multitargeted tyrosine kinase inhibitor that has potent anti-angiogenic and antitumour activities. Definitive efficacy has been demonstrated in advanced renal cell carcinoma and in gastrointestinal stromal tumours that are refractory or intolerant to imatinib (Gleevec; Novartis), which has provided the basis for the recent regulatory approvals for these indications. This article summarizes the discovery and development of sunitinib, and discusses key issues for the multitargeted approach in cancer treatment, such as markers of response and development of resistance, and their significance for the future development of sunitinib and other multikinase inhibitors. PMID- 17690709 TI - Translational research in medication development for nicotine dependence. AB - A major obstacle to the development of medications for nicotine dependence is the lack of animal and human laboratory models with sufficient predictive clinical validity to support the translation of knowledge from laboratory studies to clinical research. This Review describes the animal and human laboratory paradigms commonly used to investigate the pathophysiology of nicotine dependence, and proposes how their predictive validity might be determined and improved, thereby enhancing the development of new medications. PMID- 17690710 TI - Screening of microsatellite markers in penile cancer reveals differences between metastatic and nonmetastatic carcinomas. AB - Penile cancer, observed only rarely in the western world, represents a carcinoma that may be cured by resection of primary lesion and in case of lymph node metastasis by early lymph node dissection. This early inguinal lymphadenectomy bares a significant better survival even in cases of nonpalpable lymph nodes, but carries also a high risk of overtreatment, especially in lower tumor stages. Due to the low incidence, only few data are available on the molecular genetic background of this tumor, especially concerning tumor progression and metastasis. Therefore, we studied 62 microsatellite markers in 28 penile carcinomas searching for markers predicting progression or outcome. LOH in more than 25% of primary tumors was found on six different chromosomes, including 2q, 6p, 8q, 9p, 12q and 17p13. Statistically significant correlations could be established in D6S260 to clinical outcome and in markers from chromosomes 6, 9 and 12 to tumor stage and metastasis. These regions are worthy for further analysis concerning tumor suppressor genes and metastasis suppressor genes. PMID- 17690711 TI - deltaN-p73 is a transcriptional target of the PML/RARalpha oncogene in myeloid differentiation. PMID- 17690712 TI - A plant triterpenoid, avicin D, induces autophagy by activation of AMP-activated protein kinase. AB - Avicins, a family of plant triterpene electrophiles, can trigger apoptosis associated tumor cell death, and suppress chemical-induced carcinogenesis by its anti-inflammatory, anti-mutagenic, and antioxidant properties. Here, we show that tumor cells treated with benzyloxycarbonylvalyl-alanyl-aspartic acid (O-methyl) fluoro-methylketone, an apoptosis inhibitor, and Bax(-/-)Bak(-/-) apoptosis resistant cells can still undergo cell death in response to avicin D treatment. We demonstrate that this non-apoptotic cell death is mediated by autophagy, which can be suppressed by chloroquine, an autophagy inhibitor, and by specific knockdown of autophagy-related gene-5 (Atg5) and Atg7. Avicin D decreases cellular ATP levels, stimulates the activation of AMP-activated protein kinase (AMPK), and inhibits mammalian target of rapamycin (mTOR) and S6 kinase activity. Suppression of AMPK by compound C and dominant-negative AMPK decreases avicin D induced autophagic cell death. Furthermore, avicin D-induced autophagic cell death can be abrogated by knockdown of tuberous sclerosis complex 2 (TSC2), a key mediator linking AMPK to mTOR inhibition, suggesting that AMPK activation is a crucial event targeted by avicin D. These findings indicate the therapeutic potential of avicins by triggering autophagic cell death. PMID- 17690713 TI - Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease. AB - The development of safe and effective antigen-specific therapies is needed to treat patients with autoimmune diseases. These therapies must allow for the specific tolerization of self-reactive immune cells without altering host immunity to infectious insults. Experimental models and clinical trials for the treatment of autoimmune disease have identified putative mechanisms by which antigen-specific therapies induce tolerance. Although advances have been made in the development of efficient antigen-specific therapies, translating these therapies from bench to bedside has remained difficult. Here, we discuss the recent advances in our understanding of antigen-specific therapies for the treatment of autoimmune diseases. PMID- 17690714 TI - Sonic hedgehog signalling in T-cell development and activation. AB - The production of mature functional T cells in the thymus requires signals from the thymic epithelium. Here, we review recent experiments showing that one way in which the epithelium controls the production of mature T cells is by the secretion of sonic hedgehog (SHH). We consider the increasing evidence that SHH induced signalling is not only important for the differentiation and proliferation of early thymocyte progenitors, but also for modulating T-cell receptor signalling during repertoire selection, with implications for positive selection, CD4 versus CD8 lineage commitment, and clonal deletion of autoreactive cells. We also review the influence of hedgehog signalling in peripheral T-cell activation. PMID- 17690715 TI - Formation of the entorhino-hippocampal pathway: a tracing study in vitro and in vivo. AB - Objective The entorhino-hippocampal pathway is the major excitatory input from neurons of the entorhinal cortex on both ipsilateral and contralateral hippocampus/dentate gyrus. This fiber tract consists of the alvear path, the perforant path and a crossed commissural projection. In this study, the histogenesis and development of the various subsets of the entorhino-hippocampal projection have been investigated. Methods DiI, DiO and fast blue tracing as well as anti-calretinin immunocytochemistry were carried out with prenatal and postnatal rats at different ages. Results The alvear path and the commissural pathway started to develop as early as embryonic day (E) 16, while the first perforant afferents reached the stratum lacunosum-moleculare of the hippocampus at E17 and the outer molecular layer of dentate gyrus at postnatal day (P) 2, respectively. Retrograde tracing with DiI identified entorhinal neurons in layer II to IV as the origin of entorhino-hippocampal pathway. Furthermore, anti calretinin immunocytochemistry revealed transitory Cajal-Retzius (CR) cells in the stratum lacunosum-moleculare of the hippocampus from as early as E16. DiI labeling of entorhinal cortex fibers and combined calretinin-immunocytochemistry showed a close association between CR cells and entorhinal afferents. Conclusion The subsets of entorhino-hippocampal pathway appear in the developmental hippocampus during E16-P2. The temporal and spatial relationship between CR cell and perforant afferent suggests the role of this cell type as a guiding cue for entorhinal afferents at early cortical development. PMID- 17690716 TI - Effect of ciliary neurotrophic factor on activation of astrocytes in vitro. AB - Objective To observe the activating effect of ciliary neurotrophic factor (CNTF) on astrocyte in vitro. Methods Astrocytes cultured purely from newborn rats. Cerebral cortex was raised in normal and serum deprivation condition with different concentrations (in ng/ml: 0, 2, 20, or 200) of CNTF. After cultured for 24 h, the shape and the cell cycle of astrocytes were examined by immunocytochemistry and flow cytometer, respectively. Results The immunoactivity of glial fibrillary acidic protein (GFAP) and the nuclear size of astrocytes were increased when CNTF was applied, whether cells were cultured in medium with or without serum. CNTF promoted astrocytes to enter the cell cycle in medium with serum, but had no this effect in medium without serum. Conclusion In medium without serum, astrocytes could differentiate into activated state cells with CNTF application, but could not proliferate; in medium with serum, astrocytes could proliferate with aid of CNTF. PMID- 17690717 TI - Effect of adrenomedullin on neuron apoptosis, infarction volume and expression of Egr-1 mRNA after focal ischemia-reperfusion in rats. AB - Objective To observe the influence of adrenomedullin (ADM) on neuron apoptosis, infarction volume of brain, and the expression of early growth response 1 (Egr-1) mRNA in ischemia-reperfusion rats. Methods The arteria cerebri media was tied for 2 h to construct the ischemia model. Infarction volume was detected by triphenltetrazolium chloride (TTC) staining, neuronal apoptosis and necrosis was detected with terminal deoxynucleotidyl transferase nick labeling (TUNEL) method, and the Egr-1 mRNA expression was examined by in situ hybridization (ISH). Results Infarction volume after ischemia-reperfusion is (269 +/- 20) mm(3). Infarction volume after injection of ADM through different ways are femoral vein (239 +/- 17) mm(3) (decreased by 11.2%), arteria carotis (214 +/- 14) mm(3) (by 20.4%) and lateral cerebral ventricle (209 +/- 13) mm(3) (by 22.3%), respectively. The results indicate that injecting ADM through arteria carotis and lateral cerebral ventricle is much more effective than it through femoral vein (P < 0.05). The TUNEL-positive cells in cerebral cortex or hippocampus are few in the sham operation group, but much more in the ischemia-reperfusion group. After being supplied with ADM, especially through arteria carotis interna or lateral cerebral ventricle way, the TUNEL-positive cells decreased obviously. Expression of Egr-1 mRNA was low in the cerebral cortex of the sham operation group rats, enhanced in the ischemia and reperfusion group rats, and enhanced markedly after treatment with ADM, especially through arteria carotis interna or lateral cerebral ventricle way (P < 0.01). Conclusion Injection of ADM through different ways could alleviate neural dysfunction, decrease neuron apoptosis and brain infarction volume, and increase the expression of Egr-1 mRNA. PMID- 17690718 TI - R-apomorphine protects against 6-hydroxydopamine-induced nigrostriatal damage in rat. AB - Objective The aim of the present study was not only to assess the retrograde degenerative changes in the dopaminergic neurons of the substantia nigra (SN) and ventral tegmental area (VTA) after injection of 6-hydroxydopamine (6-OHDA) into the striatum, but also to use this 6-OHDA model of Parkinson's disease to explore the possible neuroprotective effect of R-apomorphine (R-APO). Methods The partial lesion was obtained by intrastriatal administration of 6-OHDA. R-APO administration (10 mg/kg, s.c.) started 15 min prior to lesioning and continued daily for another 22 days post surgery. Testing was carried out 5 weeks after lesioning. We investigated the histology and associated behavior and neurochemical changes. Structural and functional deficits were quantified by tyrosine hydroxylase (TH) / Nissl-staining cell number counting, striatal dopamine (DA) content determination and amphetamine-induced rotation analysis. Results R-APO-treatment attenuated the amphetamine-induced ipsiversive rotation 5 weeks after the lesion induction. R-APO administration for 22 days significantly reduced the size of the lesion at the level of the SN from 50% (control group) to 69%. Moreover, the cell shape resembled that observed in the intact animals. R APO treatment significantly increased the number of cells in both the lesion and the intact sides of VTA by 60%, suggesting selective neurotrophic effect of R-APO in this area. Finally, R-APO-treatment significantly attenuated the 6-OHDA induced striatal DA depletion and normalized dihydroxyphenylacetic acid (DOPAC)/DA ratios. Conclusion We conclude that R-APO has neuroprotective and possible neurotrophic effect on a striatal lesion with 6-OHDA, suggesting that this drug may have rescuing properties in patients with early stage Parkinson's disease. These effects are more pronounced in VTA and enhance with duration of treatment. PMID- 17690719 TI - Computational analysis of genetic loci required for synapse structure and function and their corresponding microRNAs in C. elegans. AB - Objective To elucidate the important functions of microRNAs (miRNAs) in regulating synaptic assembly and function, we performed a computational analysis for the genetic loci required for the synaptic structure and function and their corresponding miRNAs in C. elegans. Methods Total 198 genetic loci required for the synaptic structure and function were selected. Sequence alignment was combined with E value evaluation to investigate and identify the possible corresponding miRNAs. Results Total 163 genes among the 198 genetic loci selected have their possibly corresponding regulatory miRNA (s), which covered most of the important genetic loci required for the synaptic structure and function. Moreover, only 22 genes among the analyzed 38 genetic loci encoding synaptic proteins have more possibility to under the control of non-coding RNA genes. In addition, the distribution of miRNAs along the 3' untranslated region (UTR) of these 22 genes exhibits different patterns. Conclusion Here we provide the computational screen and analysis results for the genetic loci required for synaptic structure and function and their possible corresponding miRNAs. These data will be useful for the further attempt to systematically determine the roles of miRNAs in synaptic assembly and function regulation in worms. PMID- 17690720 TI - Neural pathway for fever generation. AB - Fever is an adaptive host response coordinated by the central nervous system (CNS) during systemic immune challenge. Recent research shed light on the mechanism of fever generation, particularly the underlying neural pathways. In this review, we first briefly summarize current views on the mechanism of sensing microbial infection by the nervous system, and the roles of prostaglandin E2 (PGE2) and its receptors in fever; then we focus on the neural circuits underlying fever generation, particularly their relationship with the distribution of PGE2 receptors within the CNS. At the end, an overall neurochemical model of fever generation is presented, pointing to the direction for future studies. PMID- 17690721 TI - Learning and learning choice in the nematode Caenorhabditis elegans. AB - The nematode Caenorhabditis elegans is an attractive model organism to study the behavioral plasticity for its simple system and ability to respond to diverse environmental stimuli, such as touch, smell, taste and temperature. Learning in C. elegans encompasses both non-associative learning and associative learning. Till now, themotaxis and chemotaxis are two major paradigms for associative learning and there are at least 6 forms of chemotaxis-mediated associative learning. Three research systems have also been explored to study the mechanism of learning choice in worms. This review will discuss the forms, research models, genetic and molecular regulation of learning and learning choice in C. elegans. PMID- 17690722 TI - Clinical application of magnetic resonance neurography in peripheral nerve disorders. AB - Recent advances in the technology of magnetic resonance (MR) imaging (MRI) have made the diagnostic evaluations for peripheral nerve disorders shift from the clinical and physiological examination to the anatomical study. As a sensitive noninvasive tool, MR neurography could directly display high-resolution longitudinal and cross-sectional images of peripheral nerves, including nerve compression, nerve inflammation, nerve trauma, nerve recovery, and systemic neuropathies, thereby the morphology of intraneural and extraneural lesions can be visualized. Thus neurologists, as well as specialist radiologists, should be highly familiar with the various new types of image findings in this steadily advancing field. The purpose of this review is to overview how to evaluate peripheral nerve problems with MR neurography and its current limitations and advances in experimental MR research. The techniques for peripheral nerve MR neurography will also be discussed. PMID- 17690723 TI - Auditory evoked potentials recorded in monkeys with hallucinatory-like behaviors induced by bromocriptine. AB - Objective Bromocriptine and other dopamine D2 receptor agonists can affect a range of behaviors in nonhuman primates, particularly those behaviors associated with motor and mental function, such as suppressant behaviors and hallucinatory like behaviors in monkeys. Besides bromocriptine, the dysfunction of the rapid eye movement sleep (REM) mechanism may also contribute to hallucinations. Dissociation of wakefulness, REM, and non-REM (NREM) can cause a series of psychotic symptoms. Methods We simultaneously recorded auditory evoked potentials (AEP) from five cerebral regions in monkeys during normal and psychotomimetic states to investigate and compare state-dependent changes in AEP. Results Phase reversal of peak-to-baseline amplitude of 250 ms component (PBA250) in dorsolateral prefrontal cortex was common characteristic of hallucinatory-like and REM, and that hallucinatory-like and REM shared the equivalent modulatory orderliness of the PBA250 in dorsolateral prefrontal cortex. This result suggests that hallucinatory-like and REM share an equivalent electrophysiological modulatory in dorsolateral prefrontal cortex. Conclusion These results reveal that emergence of the N250 in dorsolateral prefrontal cortex is an exclusive marker that may help to discern whether hallucinatory-like behaviors is exhibited, which suggests that dorsolateral prefrontal cortex may be the most pivotal region for exhibition of hallucinatory-like behaviors. PMID- 17690724 TI - Environmental cues associated with morphine modulate release of glutamate and gamma-aminobutyric acid in ventral subiculum. AB - Objective To investigate whether environmental cues associated with different properties of morphine could regulate the extracellular levels of glutamate and gamma-aminobutyric acid (GABA) in the hippocampal ventral subiculum, which play a critical role in the reinstatement of drug-seeking behavior induced by environmental cues. Methods Conditioning place preference (CPP) and conditioning place aversion (CPA) models were used to establish environment associated with rewarding and aversive properties of morphine respectively. Microdialysis and high performance liquid chromatography were used to measure the extracelluar level of glutamate and GABA in the ventral subiculum under these environmental cues. Results Exposure to the environmental cues associated with rewarding properties of morphine resulted in a decrease (approximately 11%) of extracellular level of GABA in ventral subiculum, and exposure to the environmental cues associated with aversive properties of morphine resulted in an increase (approximately 230%) of extracellular level of glutamate in ventral subiculum. Conclusion Environmental cues associated with different properties of morphine modulate the release of distinct neurotransmitters in the hippocampal ventral subiculum possibly through different neural circuit. PMID- 17690725 TI - Effects of spinal cord stimulation on cerebrovascular flow: role of sympathetic and parasympathetic innervations. AB - Objective Cervical spinal cord stimulation (SCS) has been found to augment cerebral blood flow (CBF) in a number of animal models. However, the effective use of SCS is hampered by a lack of understanding of its mechanism(s) of action. In this paper, we focus on the sympathetic and parasympathetic effects of SCS on CBF. Method Sprague-Dawley rats were selected for the experimental series.The animals were divided into 5 groups to underwent SCS and laser Doppler flowmeter (LDF) recordings. Control group, the animal underwent SCS and LDF recordings without any surgery of the nerve fibers and ganglia. V1 group, the animal underwent bilateral resection of the nasociliary and post-ganglionic parasympathetic nerve fibbers. SCG group, the animal underwent bilateral resection of supper cervical ganglion. V1 + SCG group, the animal underwent both surgeries as V1- and SCG-group animals did. Sham group, the animal underwent the carotid manipulation with blunt-tipped forceps as well as the dissection of nasociliary and post-ganglionic parasympathetic nerve fibers around the ethmoidal foramen, but without cutting any nerves. Results During the SCS, the LDF was no statistical difference between the V1 or SCG group and the control group. Yet, the effects of SCS on CBF are completely abolished in V1 + SCG group. Conclusions Surgical interruption of both the parasympathetic and sympathetic pathways has the contradict effect on SCS-induced CBF augmentation. PMID- 17690726 TI - Analgesic effects of receptin, a chemically modified cobratoxin from Thailand cobra venom. AB - Objective To investigate the analgesia induced by receptin (REC), a chemically modified cobratoxin (CTX, a long-chain postsynaptic alpha -neurotoxin from Thailand cobra venom), and the effects of atropine and naloxone on antinociceptive activity of REC in rodent pain models. Methods REC was administered intraperitoneally (5 mg/kg, 7.07 mg/kg, or 10 mg/kg, i.p.) or intra cerebral venticularly (62.5 mu g/kg, i.c.v.). The antinociceptive action was determined using the hot-plate test, the acetic acid writhing test and tail flick assay in mice and rats. The involvement of cholinergic and the opioid peptidergic systems in REC-induced analgesia were examined by pretreatment of animals with atropine (Atr; 0.5 mg/kg, i.m. or 10 mg/kg, i.p.) or naloxone (Nal; 3 mg/kg, i.p.). The effect of REC on motor activity was tested using the Animex test in mice. Results REC (5 mg/kg, 7.07 mg/kg or 10 mg/kg, i.p.) exhibited a dose dependent analgesic action in mice as determined with hot-plate test and acetic acid writhing test. The significant analgesia of REC was seen 2 h to 3 h after its administration. In the rat-tail flick assay, the administration of REC at 62.5 mu g/kg (1/160 of systemic dose; i.c.v.) produced marked analgesic effects. Atropine at 0.5 mg/kg (i.m.), 10 mg/kg (i.p.) or naloxone at 3 mg/kg (i.p.) failed to block the analgesic effects of REC. REC at the highest effective dose of 10 mg/kg did not change the spontaneous mobility of mice. Conclusion These results demonstrate that REC has analgesic effect. This activity appears to be mediated through the peripheral nervous system though central nervous system may contribute to REC' s analgesic effects. The central cholinergic system and opioid peptidergic system appear not to be involved in the antinociceptive action of REC. PMID- 17690727 TI - Aniracetam attenuates H2O2-induced deficiency of neuron viability, mitochondria potential and hippocampal long-term potentiation of mice in vitro. AB - Objective It is known that free radicals are involved in neurodegeneration and cognitive dysfunction, as seen in Alzheimer' s disease (AD) and aging. The present study examines the protective effects of aniracetam against H2O2-induced toxicity to neuron viability, mitochondria potential and hippocampal long-term potentiation (LTP). Methods Tetrazolium salt 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide (MTT) was used to detect neuronal viability. MitoTracker Red (CMX Ros), a fluorescent stain for mitochondria, was used to measure mitochondria potential. Electrophysiological technique was carried out to record hippocampal LTP. Results H2O2 exposure impaired the viability of neurons, reduced mitochondria potential, and decreased LTP in the CA1 region of hippocampus. These deficient effects were significantly rescued by pre-treatment with aniracetam (10-100 mu mol/L). Conclusion These results indicate that aniracetam has a strong neuroprotective effect against H2O2-induced toxicity, which could partly explain the mechanism of its clinical application in neurodegenerative diseases. PMID- 17690728 TI - Overexpression of 14-3-3 protein protects pheochromocytoma cells against 1-methyl 4-phenylpyridinium toxicity. AB - Objective To investigate the effects of 14-3-3 protein overexpression on the 1 methyl-4-phenylpyridinium (MPP(+)) induced pheochromocytoma (PC12) cell death and the potential mechanisms. Methods pcDNA3.1(+)-14-3-3 plasmids, which could be expressed in mammalian cell, were constructed and transfected into PC12 cells with Lipofectamine 2000. The expression of 14-3-3 protein, Bcl-2 protein, and BAD protein were determined by western blot. 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide (MTT) assay, microplate reader, and flow cytometric analysis were used to measure cell viability, the caspase activity, and apoptotic ratio respectively. Results (1) The expression of 14-3-3 protein increased significantly three weeks after pcDNA3.1 (+)-14-3-3 plasmids transfected into PC12 cells. (2) MPP(+) caused a decrease of cell viability in a dose-dependent manner. At 100 mu mol/L MPP(+), cell viability reduced approximately 50%. (3) The caspase activity increased along with the MPP(+) concentrations rising and reached its maximum value (0.34 mu mol/mg protein) at 100 mu mol/L MPP(+). However caspase activity decreased significantly when the MPP(+) concentration exceeded 100 mu mol/L. (4) Overexpression of 14-3-3 protein decreased the apoptosis ratio of PC12 cells treated with 100 mu mol/L MPP(+) from 26.5% to 8.6%. (5) Bcl-2 protein tended to decrease but BAD protein tended to increase after treatment of PC12 cells with 100 mu mol/L MPP(+). Overexpression of 14-3-3 protein significantly increased the cellular level of Bcl-2 protein and decreased that of BAD protein. Conclusion Overexpression of 14-3-3 protein may reduce MPP(+)-induced apoptotic cell death in PC12 cells by up-regulating the Bcl-2 expression and down-regulating the BAD expression. These results may provide a promising target for treatment of Parkinson' s disease. PMID- 17690729 TI - alpha-Synuclein redistributed and aggregated in rotenone-induced Parkinson's disease rats. AB - Objective To observe the influence of rotenone on the distribution of alpha synuclein (ASN) in rat model of Parkinson's disease (PD). Methods Wistar rats were randomly divided into two groups and received 2 mg/kg rotenone (s.c.) or sunflower oil (as control group) for about 4 weeks. The hippocampus, substantia nigra and striatum of brain were observed. Hematoxylin and eosin stain were used to observe the Lewy body like inclusion. The expression of tyrosine hydroxylase (TH) or ASN protein was determined by anti-TH or anti-alpha-synuclein immunohistochemistry, respectively. Results In control rats, ASN protein distributed widely in brain, especially in hippocampus, cortex and striatum. Rotenone obviously increased TH positive neurons and fibers loss in substantia nigra and striatum (P < 0.05). In rotenone treated rats, ASN positive cells increased in global brain but not distributed in an even manner. In substantia nigra, ASN positive stuff was found aggregate in both cytoplasm and nucleus, and some formed spherical inclusion; in striatum, ASN positive neurites end aggregated and agglomerated around neurons; and in hippocampus, few dot-like ASN were aggregated in cell body, and no notable change was found in nucleus. Conclusion In rotenone administrated PD rats, ASN protein aggregated in several brain regions but most obviously in striatum and substantia nigra, and the distribution region of ASN was changed from peri-synapse to the cytoplasm and nucleus of dopaminergic neuron. PMID- 17690730 TI - Regulatory genes controlling neural stem cells differentiation into neurons. AB - The recent progress in neural stem cells (NSCs) research has shed lights on possibility of repair and restoration of neuronal function in neurodegenerative diseases using stem cells. Induction of stem cells differentiate into mature neurons is critical to achieve the clinical applications of NSCs. At present, molecular mechanisms modulating NSC differentiation are not fully understood. Differentiation of stem cells into neuronal and glial cells involves an array of changes in expression of transcription factors. Transcription factors then trigger the expression of a variety of central nervous system (CNS) genes that lead NSCs to differentiate towards different cell types. In this paper, we summarized the recent findings on the gene regulation of NSCs differentiation into neuronal cells. PMID- 17690731 TI - Screening for genetic loci affecting the active zone formation in C. elegans. AB - Objective To screen and identify genetic loci affecting the active zone formation in C. elegans. Methods A SYD-2::GFP reporter was constructed and used as an active zone marker for forward genetic screen to identify genetic loci affecting the active zone formation. Results Eight isolated mutant alleles were characterized from 15,000 haploid genomes. The SYD-2::GFP phenotypes of these mutants are mainly reflected as the changes of number, morphology, distribution of puncta and the gaps appearance. Some mutants also exhibit visible behavioral or physical phenotypes, and aldicarb resistant or sensitive phenotypes. Conclusion These mutants provide the opportunity for further systematic research on the active zone formation and the neurotransmission. PMID- 17690732 TI - Aminohydrolases acting on adenine, adenosine and their derivatives. AB - BACKGROUND: Adenine and adenosine-acting aminohydrolases are important groups of enzymes responsible for the metabolic salvage of purine compounds. Several subclasses of these enzymes have been described and given current knowledge of the full genome sequences of many organisms, it is possible to identify genes encoding these enzymes and group them according to their primary structure. METHODS AND RESULTS: This article is a short overview of the enzymes classified as adenine and adenosine deaminase. It summarises knowledge of their occurrence, genetic basis and their catalytic and structural properties. CONCLUSIONS: These enzymes are constitutive components of purine metabolism and their impairment may cause serious medical disorders. In humans, adenosine deaminase deficiency is linked to severe combined immunodeficiency and as such the enzyme has been approved for the first gene therapy trial. The role of these enzymes in plants is unclear, since the activity was has not been detected in extracts and putative genes have not been yet cloned and analyzed. A literature search and amino acid identity comparison show that Ascomycetes contain only adenine deaminase, but not adenosine deaminase, despite the fact that corresponding genes are annotated in databases as the adenosine cleaving enzymes because they share the same conserved domain. PMID- 17690733 TI - WWOX, a new potential tumor suppressor gene. AB - BACKGROUND: WWOX (WW domain-containing oxidoreductase) gene, located on chromosome 16q 23.3-24.1 in the region recognized as the common fragile site FRA16D is considered to be a tumor suppressor gene involved in various cancers: breast, ovarian, prostate, esophageal, lung, pancreatic, gastric and hepatic. The aim of this study was to describe (i) putative protein interactions of WWOX (ii) the molecular mechanisms of tumor suppressor activity (iii) present an overview of WWOX in relation to nervous system and breast, prostate and ovarian cancers. METHODS AND RESULTS: WWOX expression is up-regulated in endocrine organs indicating its importance in these tissues. In many cancers WWOX expression is down-regulated and low WWOX expression is related to poor prognosis. CONCLUSION: All the evidence suggest that WWOX can be considered as a new tumor suppressor gene and target for gene therapy due to the association of high WWOX expression with improved disease free survival. PMID- 17690734 TI - Epidemiology of esophageal cancer--an overview article. AB - BACKGROUND: Esophageal cancer is one of the most serious tumor diseases worldwide, owing to its rapid development and fatal prognosis in most cases. To compare epidemiologic characteristics, data published by the International Agency for Research on Cancer, Lyon, France and data from Masaryk Memorial Cancer Institute, Brno, Czech Republic were used. METHODS: We conducted a search of selected Czech and foreign literature focused on the epidemiology of esophageal cancer and its main risk factors. RESULTS AND CONCLUSION: An overview of esophageal cancer epidemiology is presented. Prevention of esophageal cancer should be based on early detection and surveillance of precancerous lesions, especially of Barrett's esophagus, and attention should also focus on modification of changeable risk factors, including tobacco smoking, alcohol abuse, and ingestion of hot and spicy food. Carefully designed epidemiologic studies, both descriptive and analytical, are required to increase understanding of the complexity of esophageal cancer etiology. PMID- 17690735 TI - Natural compounds of Palestine flora. Comparison analysis by static headspace and steam distillation GC-MS of semivolatile secondary metabolites from leaves of cultivated Palestinian Majorana syriaca. AB - BACKGROUND: A comparative analysis by using static headspace (HS) and steam distillation (SD) GC-MS of the volatile and the semi-volatile secondary metabolites from leaves of cultivated Majorana syriaca. METHODS: The essential oils endogenous to cultivated thyme were isolated and identified by HS-GC-MS technology and compared to those from SD-GC-MS. RESULTS: The HS-GC-MS results showed that the Palestinian cultivated thyme is rich in monoterpene hydrocarbons and phenolic monoterpenes such as alpha-phellandrene, alpha-pinene, beta-myrcene, m-cymene, p-cymene, gamma-terpinene, thymol and carvacrol. In all the samples gamma-terpinene, p-cymene, thymol and carvacrol were the most abundant compounds. CONCLUSIONS: HS and SD-GC-MS have proved that most of the cultivated thyme samples examined has thymol isomer as the major phenolic constituent. PMID- 17690736 TI - Capillary electrophoresis as a verification tool for immunochemical drug screening. AB - BACKGROUND: The aim of this work was to develop a simple capillary electrophoretic method as the verification and confirmation tool in the screening analysis for amphetamines, opiates, benzodiazepines and cocaine and their metabolites for toxicological applications. METHODS: 50 mM phosphate Tris pH 2.0 with 30% (v/v) of methanol was used as a background electrolyte that enabled fast separation of drugs and their metabolites in saliva and urine. Verification of the data from the electrophoretic method was done by High Performance Thin Layer Chromatography (HPTLC) and the immunochemical screening test QuikScreen. RESULTS: The experimental conditions of the Capillary Electrophoresis (CE) were partially optimized (mainly the influence of concentration and types of additives, e.g. cyclodextrines, organic solvents) and validated; the method was used for analysing samples from drug abusers. CONCLUSIONS: The non-instrumental, immunoassay tests could only confirm qualitative addictions and are mainly employed when the emergency detection of drugs is needed. For quantitative analysis and verification of obtained results the confirmation step is strongly recommended. The simple screening capillary zone electrophoresis method allows recognition of the most abused drugs. The agreement of the results from CE, HPTLC and QuikScreen test was more than 95%. PMID- 17690737 TI - Antioxidant capacity of seminal plasma measured by TAS Randox. AB - BACKGROUND: An imbalance between reactive oxygen species (ROS) generation in sperm and antioxidant capacity of seminal plasma has been linked to male infertility. The antioxidant power of biological fluids can be evaluated either by measurement of individual antioxidants or total antioxidant capacity (TAC). The aim of this study was to assess whether TAS Randox can also be used for seminal plasma antioxidant capacity estimation. MATERIAL AND METHODS: Freshly thawed aliquots of seminal plasma and blood serum of 38 males from infertile couples and 24 healthy normospermic controls were simultaneously assayed using TAS Randox reagents on the Hitachi Modular P800 Analyzer. Semen analysis was performed according to WHO guidelines. ROS in fresh sperm suspension in phosphate buffered saline was measured by chemiluminescence immediately after separation of seminal plasma. RESULTS: Semen analysis showed that in our study group only 14 males were normospermic and 24 males had mostly combined pathologies. The medians for ROS production were similar in both the study and the control groups (4850 and 5450 RLU/min, resp). Seminal plasma TAS levels were significantly lower (p<0.02) in the study group while blood serum TAS levels were similar in both groups. A significant positive correlation (p<0.05) between TAS in seminal plasma and serum was found, seminal plasma levels being on average 1.4 times higher. CONCLUSIONS: The TAS Randox kit may be used for clinical studies intended to identify decreased antioxidant power in the seminal fluid of infertile men. PMID- 17690738 TI - Glucan and resveratrol complex--possible synergistic effects on immune system. AB - BACKGROUND: Recent data showing that glucan elicited defense responses in grapevine and induced protection via induction of resveratrol production led us to evaluate the possible synergetic effects of glucan and resveratrol complex on immune reactions. METHODS: We measured phagocytosis using HEMA particles, expression of cell surface markers via fl ow cytometry, expression of cytokines using ELISA, recovery after fluorouracil-induced leucopenia and effects on gene expression via RT-PCR. RESULTS: Our results showed that both glucan and resveratrol complex stimulated phagocytosis of blood leukocytes, caused increase in surface expression of CD(+) splenocytes and showed higher restoration of spleen recovery after experimentally induced leucopenia. In all these cases, strong synergetic effects were observed. When we measured the effects of these substances on expression level of NF-kappaB2, Cdc42 and Bcl-2 in breast cancer cells, upregulation of Cdc42 expression was evident only using both immunomodulators in combination. CONCLUSIONS: In conclusion, our data suggest significant synergy in stimulation of immune reactions and support further studies of these natural immunomodulators. PMID- 17690739 TI - Cytotoxicity of colchicine derivatives in primary cultures of human hepatocytes. AB - BACKGROUND: Colchicine has been used to treat gout for centuries. However, owing to its toxicity it displays a variety of side effects. The replacement of colchicine by less toxic but still active derivatives would solve this drawback. AIM: The aim of this study was to examine the cytotoxicity of 17 colchicine derivatives. METHODS: Primary cultures of human hepatocytes were the model of choice. Prior to testing, we measured the biochemical parameters of liver donors and the toxicological response of the hepatocytes cultures. For toxicity testing, cells were treated for 24 h with tested compounds in concentrations 1-100 microM. We monitored lactate dehydrogenase (LDH) leakage into the medium, mitochondrial activity (MTT test) and secretion of albumin. RESULTS: Our data show that LDH and MTT were less sensitive parameters compared to albumin secretion for monitoring the toxicity of colchicine derivatives. Compounds with lower antimitotic activity displayed lowered toxicity. CONCLUSION: Since human hepatocytes in culture are quiescent cells, they are not as susceptible to tropolone alkaloids as proliferating cells. Screening for colchicine derivatives with lowered cytotoxicity revealed that 10-O-demethylated compounds might be the substances of choice. PMID- 17690740 TI - Huntington's disease and steroid hormone receptors. AB - BACKGROUND: Steroid hormone receptors constitute a special group of receptors having a wide range of efficiency and distribution in the body. Androgen and estrogen receptors, and their expression in the body, are linked with attributes such as reproduction control and sexual behaviour, but their relation with behavioural models, perception, memory and stress remain unclear to date. PURPOSE: In this project we aim to focus on monitoring the expressive influence of steroid hormone receptors on embryonic tissues and subsequently, expand our study to include the expression on adult tissues such as the CNS and to monitor the developmental aspects and relations pertaining to neurodegenerative disorders, such as Huntington's disease. MATERIAL AND METHODS: We shall rely on immuno-histochemistry, immuno-fluorescence and RT-PCR methods for detecting steroid hormone receptors and Huntingtin-associated protein 1 in the embryonic and adult tissue. CONCLUSION: Mapping the expression of steroid receptors during development represents an essential step in the quest for further studies and monitoring of the expression in adult tissues. PMID- 17690741 TI - Novel immunohistochemical markers for the differentiation of lobular and ductal invasive breast carcinomas. AB - AIMS: Invasive ductal and lobular carcinomas are the most common histological types of breast cancer. The loss of E-cadherin expression has been suggested to be the most reliable marker for invasive lobular carcinoma. The aim of our study was to identify the diagnostic usefulness of novel markers in the differentiation of these tumor types. METHODS: We examined tissue microarrays (TMA) which were constructed from surgical specimens of 119 breast cancer patients. TMA consisted of 80 ductal carcinomas, 29 lobular carcinomas and special type cancers. TMA sections were stained using standard immunohistochemical methods. Monoclonal mouse antibodies against E-cadherin, cytokeratin 5/6 and 17, and polyclonal mouse antibodies against EMP1, DDR1, PRKCI and DVL1 were used. RESULTS: E-cadherin was absent in 93.3% of lobular tumors compared with only 15 % of ductal tumors (p<0.0001). EMP1 and DVL1 were overexpressed in lobular tumors (93.1% and 96.5%, respectively), whereas PRKCI and DDR1 were positive in ductal cancers (90% and 96.2%, respectively). Reduced expression or absence of both cytokeratins 5/6 and 17 was found in both tumor tissues in comparison to normal terminal duct lobular units (p<0.0001). CONCLUSIONS: Apart from the well-established marker, E cadherin, proteins examined on TMA slides by immunohistochemistry (EMP1, DVL1, DDR1, PRKCI) may represent novel tissue markers helpful in the differentiation of ductal and lobular breast cancers. Further studies with larger sets of patients are desirable, to verify the complete immunohistochemical profiles of various histological types of breast cancer and determine the prognostic and predictive significance of novel markers. PMID- 17690742 TI - Bioequivalence of two fexofenadine formulations in healthy human volunteers after single oral administration. AB - AIM: A randomized, two-way, crossover, bioequivalence study was conducted in 25 fasting, healthy, male volunteers to compare two brands of fexofenadine 180 mg tablets, FEXOFENADINE 180 mg Film Tablet (Drogsan A.S., Ankara, Turkey) as test and Telfast 180 mg Tablet (Aventis Pharma, Frankfurt am Main, Germany) as a reference product. METHOD: One tablet of either formulation was administered after 10 h of overnight fasting. After dosing, serial blood samples were collected during a period of 48 hours. Plasma samples were analysed for fexofenadine by a validated HPLC method. The pharmacokinetic parameters AUC(0 48), AUC(0-alpha), C(max), T(max), K(el), T(1/2), and CL were determined from plasma concentration-time profiles for both formulations and were compared statistically. RESULTS AND CONCLUSIONS: The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals (CI) fell within the acceptable range, satisfying the bioequivalence criteria of the FDA. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetics profiles and that Drogsan's Fexofenadine is equivalent to Telfast of Aventis Pharma, Frankfurt am Main, Germany. PMID- 17690743 TI - Distribution of nuclear receptors for steroid hormones in the human brain: a preliminary study. AB - BACKGROUND: Expression of the nuclear steroid hormone receptors (SHR) within certain parts of the human brain has been described by many authors. However, a comprehensive analysis of SHR expression in the human brain still has not been performed. AIM: To investigate the expression of SHR in different anatomical areas of the brain, especially within the neocortex. METHOD: Immunohistochemical expression of estrogen receptors (ER), progesterone receptors (PR) and androgen receptors (AR) in different regions of the human brain was examined. RESULTS: Nuclear expression of the AR was found in the mamillary body, praecentral gyrus and hippocampus of males. The same expression in analysed structures of female was not found. The expression of ER and PR was not observed. CONCLUSIONS: The analysis revealed unexpected localization of SHR within the brain cortex, which could be the first step to the explanation of SHR action in brain as an interrelationship to function and behaviour. These results indicate on the possibility of SHR detection in post-mortal brain. PMID- 17690744 TI - A mathematical algorithm for ECG signal denoising using window analysis. AB - BACKGROUND: The presence of parasite interference signals could cause serious problems in the registration of ECG signals and many works have been done to suppress electromyogram (EMG) artifacts noises and disturbances from electrocardiogram (ECG). Recently, new developed techniques based on global and local transforms have become popular such as wavelet shrinkage approaches (1995) and time-frequency dependent threshold (1998). Moreover, other techniques such as artificial neural networks (2003), energy thresholding and Gaussian kernels (2006) are used to improve previous works. This review summarizes windowed techniques of the concerned issue. METHODS AND RESULTS: We conducted a mathematical method based on two sets of information, which are dominant scale of QRS complexes and their domain. The task is proposed by using a varying-length window that is moving over the whole signals. Both the high frequency (noise) and low frequency (base-line wandering) removal tasks are evaluated for manually corrupted ECG signals and are validated for actual recorded ECG signals. CONCLUSIONS: Although, the simplicity of the method, fast implementation, and preservation of characteristics of ECG waves represent it as a suitable algorithm, there may be some difficulties due to pre-stage detection of QRS complexes and specification of algorithm's parameters for varying morphology cases. PMID- 17690745 TI - Postnatal penicillin prophylaxis of early-onset group B streptococcal infection in term newborns. A preliminary study. AB - BACKGROUND: Early-onset group B Streptococcal disease (EOGBSD) is a serious but preventable neonatal infection. Maternal intrapartum antibiotic prophylaxis (IAP) does not prevent all cases of the disease. Management of asymptomatic neonates of GBS colonized mothers is problematic. AIMS: The objective of this prospective study was to determine whether administration of intramuscular penicillin at birth to a strictly defined group of term newborns of GBS colonized mothers is an effective and safe method to prevent EOGBSD. METHODS: A protocol for management of full-term infants born to GBS colonized mothers was created. Either an abnormality of blood count or presence of more than one obstetric risk factor were chosen as the indication criteria for administering postnatal antibiotic prophylaxis (PAP). RESULTS: The study sample consists of 250 newborns (11.5% of all term infants). PAP was administered in 39 cases. Indication criteria included leucocytosis in 37 cases, leucopenia in 1 case and obstetric risk factors in 1 case. There was no case of clinically manifest infection, and no case of sepsis either suspect or proven. CONCLUSIONS: The authors suggest that the strategy of selective PAP using penicillin, may be an effective and safe method in order to reduce morbidity and mortality from streptococcal infections. They recommend a combination of IAP and selective PAP. PMID- 17690746 TI - Percutaneous treatment of benign biliary strictures and biliary manometric perfusion test. AB - BACKGROUND: Benign biliary strictures are usually treated surgically or endoscopically. When these strictures are not accessible by endoscope or when open repair is not possible, percutaneous dilatation treatment is indicated. The efficacy of treatment is usually evaluated by clinical trial which includes leaving a small non-functional catheter in situ and following liver function tests. The evaluation may be effectively done by the biliary manometric perfusion test. AIM: The aim of this paper is to emphasize the importance of percutaneous dilatation treatment of benign biliary strictures with focus on the role of the biliary manometric perfusion test and its future prospects. METHODS AND RESULTS: Based on the literature and our own experience, this article gives a short overview of percutaneous treatment of benign biliary strictures, indications, techniques, complications and results. The treatment of these strictures has an overall success rate between 60 to 90%. This article also explains the biliary manometric test, the technique and its importance in evaluation of treatment success. CONCLUSION: Benign biliary strictures of the hepatic duct junction or bilio-enteric anastomosis are difficult to treat surgically and are endoscopically inaccessible. Percutaneous treatment by balloon dilatation and long term external-internal drainage is feasible in the majority of these patients. It is minimally invasive, safe and effective. The evaluation of the treatment success may be more effectively done by the manometric perfusion test. It is easy, reliable, less time-consuming giving immediate results, and relatively safe. PMID- 17690747 TI - Relation of blood platelet count during carbamazepine and oxcarbazepine treatment with daily dose, and serum concentrations of carbamazepine, carbamazepine-10, 11 epoxide, and 10-hydroxycarbazepine. AB - BACKGROUND: Carbamazepine (CBZ) occasionally causes haematological disorders such as thrombocytopenia, and recently a case of oxcarbazepine (OXCBZ)-induced thrombocytopenia has been described. The aim of our study was blood platelet count determination in epileptic patients treated with CBZ and OXCBZ, and its relationship with the dose and serum levels of these drugs and its metabolites. METHODS: The serum levels of CBZ and its epoxide, and the pharmacologically active monohydroxy derivative of OXCBZ were determined in 137 patients treated with CBZ, and 60 patients treated with OXCBZ. The platelet count, mean platelet volume, and platelet size distribution width were also determined. RESULTS: The difference between the platelet counts of the patient groups treated with CBZ and OXCBZ was not significant. No significant correlations between the platelet count and serum levels of the administered antiepileptic drugs and their metabolites were found. However, significant negative correlations between the platelet count and the daily doses of CBZ and OXCBZ were obtained (p<0.01). In 5 cases (4 treated with CBZ and 1 with OXCBZ) the platelet count was <150 x 10(9)/l. CONCLUSIONS: In accordance with the mean platelet volume and platelet distribution width, the thrombocytopenia observed in some of the patients studied was due to a hyper-destruction of peripheral blood platelets. However, the results obtained suggest that the mechanism of CBZ or OXCBZ-induced thrombocytopenia is not due to a direct toxicity of these drugs or their major metabolites on the circulating platelets. Although, the patients treated with OXCBZ shown a lower prevalence for thrombocytopenia (1.7%) than those treated with CBZ (2.9%), the routine platelet count monitoring in patients treated with both drugs may be recommended. PMID- 17690748 TI - Accidental deep hypothermia with cardiac arrest. Prompt complete recovery after rewarming by extracorporeal circulation. Case report. AB - BACKGROUND: Deep accidental hypothermia (core temperature <28 degrees C) is an uncommon medical emergency requiring rapid active core rewarming. Extracorporeal circulation has become the treatment of choice for deep hypothermic patients with cardiac arrest. CASE REPORT: We report on a 30-year-old patient who suffered from deep accidental hypothermia (core temperature 24.8 degrees C) and cardiac arrest by prolonged exposure to a cold urban environment as a consequence of severe ethylalcohol intoxication. The rewarming with the aid of extracorporeal circulation was initiated shortly after his arrival at the hospital. External cardiac massage was maintained until full ECC fl ow was established. The patient was weaned from extracorporeal circulation after 157 min, awaked 4 hours later and consequently extubated within 16 hours after rewarming with no neurological impairment. At 3-week follow-up, the patient was fully re-integrated in his work and personal life. CONCLUSION: This case demonstrates the excellent prognosis of a young victim in the case of deep accidental hypothermia with cardiac arrest, provided that deep hypothermia precedes the cardiac arrest and rewarming by extracorporeal circulation is immediately applied. Simultaneous ethyl alcohol intoxication can be considered a protective factor improving the patient's outcome. Complete recovery was achieved within 24 hours after the accident. PMID- 17690749 TI - Immunophenotyping--a tool for the differential diagnostics of lymphadenomegaly. AB - BACKGROUND: Flow cytometry is a method that enables the automated quantification of a set of parameters for a large number of cells or cell-like particles. It is also possible to analyze solid tissues after reduction to a single cell suspension. One of the applications of fl ow cytometry is immunophenotyping. AIM: The authors try to introduce the basic physical and biological principles of fl ow-cytometry to the broader public and to prove the benefits of method in lymph nodes assessment. METHOD: A common method of immunophenotyping with the help of labeled monoclonal antibodies applied to lymph node cells was used. RESULTS: Flow cytometry revealed the infiltration of the extirpated lymph node with leukemic cells. CONCLUSIONS: The authors demonstrate fl ow cytometry as a relatively less common but efficient way of lymph node assessment in a patient with an anamnesis of acute lymphoblastic leukemia. They also discuss the contribution of immunophenotyping to the process of the differential diagnostics of lymph nodes enlargement. PMID- 17690750 TI - Peripheral T-cell lymphoma, unspecified--the analysis of the data from the Czech Lymphoma Study Group (CLSG) registry. AB - BACKGROUND: Peripheral T-cell lymphoma, unspecified (PTCL-US) is one of the entities from the infrequent family of nodal mature T-cell lymphomas. The clinical course is aggressive, and despite multiagent chemotherapy, the median survival is about 2 years. Published data are limited to retrospective, mostly single-center studies or reviews and usually include more lymphoma subtypes. AIM: To evaluate the current treatment modalities, clinical outcome and prognostic factors in unselected, new diagnosed patients with PTCL-US in the population of the central european region (Czech Republic). METHOD: Czech Lymphoma Study Group is a national scientific organization which provides an on-line database registry which collects a data about almost all new diagnosed lymphoma patients since year 2000. All diagnostic biopsies were reviewed by a reference pathologist. RESULTS: We analyzed 63 patients with new diagnosis of PTCL-US. The median age was 59 years (25-81), chemotherapy (CHT) was administered in 56 of the 63 patients: anthracyclin-based CHT in 51%, intensive CHT in 21% and non-anthracyclin regimen was applied in 13% of the patients. The overall response rate was 74.4%, (CR in 57.4%). After a median follow-up of 19.6 months, 41% of the patients were in CR, 3.4% in PR or stable disease and 55% of the patients died. The estimated survival probability in 3 years was 36%. Clinical stage (IV) and CR achievement were found to be independent survival predictors in a multivariate analysis. CONCLUSIONS: Although the current treatment modalities are mostly ineffective in PTCL-US, appropriate intensive treatment may lead to prolonged remission but not survival. PMID- 17690751 TI - Relapsed follicular lymphoma sequentially treated with rituximab and 90Y ibritumomab tiuxetan. Case report. AB - BACKGROUND: Monoclonal antibodies have dramatically changed the treatment possibilities for follicular lymphoma. (90)Y-ibritumomab tiuxetan (Zevalin) is the first radioimmunotherapy agent approved for the treatment of relapsed and resistant follicular lymphoma patients. Long-term benefit was observed especially for patients achieving CR after radioimmunotherapy. METHODS AND RESULTS: A 65 year-old female patient with the second relapse of CD20 positive follicular lymphoma and multiple concomitant diseases was treated with four weekly doses of rituximab (375 mg/m(2)). (18)F-fluoro-deoxyglucose positron emission tomography combined with computed tomography (PET-CT) demonstrated only partial response to therapy with persistent PET scan positivity in enlarged abdominal lymph nodes. Therefore, it was decided to treat her with a 1200-MBq (32-mCi) dose of (90)Y ibritumomab tiuxetan radioimmunotherapy. No acute complications were noted afterwards. Hematological nadirs were reached 4 weeks later, with a platelet count of 24 x 10(9)/l that normalized within the next 2 weeks. The patient had neither infection nor bleeding complications. Eight weeks after radioimmunotherapy, the PET-CT scans documented only 3 lymph nodes around the abdominal aorta, maximum size 2 x 1 cm. The PET scan analysis proved no accumulation of (18)F-fluoro-deoxy-glucose in any lymph nodes or other organs and tissues. CONCLUSIONS: Sequential treatment with rituximab and (90)Y-ibritumomab tiuxetan may be an interesting alternative in cases of relapsed follicular or other indolent lymphomas in pretreated or older patients with other concomitant diseases. PMID- 17690752 TI - Spontaneous splenic rupture in two patients with hematologic malignancy. AB - BACKGROUND: Spontaneous splenic rupture (SSR) is a very rare complication described in several hundred patients, mainly as case reports. It is defined as a splenic rupture without antecedent injury. The authors of the present paper describe the only two SSR cases diagnosed at the Hemato-oncology department, coincidentally in one year. PATIENTS: The first patient was admitted to hospital because of planned chemotherapy for relapsed hairy cell leukemia. The second was directed to the Hemato-oncology outpatient department because of anemia and painful splenomegaly diagnosed by a physician. The diagnose of hematologic malignancy (diffuse large B-cell lymphoma) was determined subsequently on the basis of histological examination of the spleen. CONCLUSION: It is necessary to consider SSR not only in patients with known diagnosis of malignant disease but in the patients with negative anamnesis, too. The aim of the paper is to draw attention to the existence of this complication. PMID- 17690753 TI - Evaluation of joint flexibility and cardiovascular efficiency in children and adolescents with haemophilia and their healthy peers. AB - BACKGROUND: Problems concerning treatment of patients with haemophilia are long term and exist even in the present days. Thanks to interdisciplinary complex therapy the results of treatment are constantly better than many years ago. AIM: The goal of this study is to analyse the current state of management of haemophilia and to suggest a comprehensive concept of rational and effective rehabilitation of children with haemophilia. METHOD: In the clinical study, two different measurements were used (goniometry and functional step test) and a special questionnaire. Four different groups of participants were created for the clinical measurements (a set of patients and a control group) and for the questionnaire (a set of patients and a control group). RESULTS: This study concluded that there were no significant differences in the outcomes of the goniometry and the step test, and in the restriction of movement activities between the patients and healthy individuals. CONCLUSIONS: The concept of physiotherapy in patients with coagulopathies in the Czech Republic is comparable with rehabilitation concepts in other European and non-European countries. Current rehabilitation care is of good quality and necessary for effective lifelong therapy of haemophilia, however, it is used insufficiently. PMID- 17690754 TI - Papillary pineocytoma in child: a case report. AB - BACKGROUND: Papillary pineocytoma is an extremely rare tumor usually with a poor outcome. CASE REPORT: We report a case of a 10-year-old-girl with pineal gland tumor and obstructive hydrocephalus diagnosed using MRI. The child was successful treated by insertion of a ventriculoperitoneal shunt and consecutive tumor resection by supracerebellar-infratentorial approach. Histopathological examination showed a papillary structure of the pineocytoma. As such, tumors are considered to be aggressive the child was subjected to radio- and chemotherapy. CONCLUSION: At six year follow-up after surgery, the patient is symptom-free and the MRI shows no tumor recurrence. PMID- 17690755 TI - Combination of two pseudoaneurysms in a patient 6 years after ascending aorta and aortic valve replacement. AB - BACKGROUND: We report successful treatment of a patient 6 years after ascending aorta and aortic valve replacement suffering from a combination of two pseudoaneurysms. The first of them originated from the coronary ostial suture line and the second pseudoaneurysm originated from the distal suture line. METHODS: We performed re-replantation of the left main trunk to the prosthesis and then we resected the pseudoaneurysm originating from the distal suture line and we replaced the entire aorta by a vascular graft. RESULTS: The postoperative convalescence was uneventful, the patient was discharged two weeks after the surgery. The patient is currently in a very good condition one year after the surgery. CONCLUSIONS: Coronary ostial pseudoaneurysm in patients after ascending aorta and aortic valve replacement with the use of "button technique" is a quite rare situation. The combination of two pseudoaneurysms originating from different suture lines in one patient seems to be unique in literature reviews. PMID- 17690756 TI - Autogenous arteriovenous elbow fistula for haemodialysis and upper extremity ischemia. AB - BACKGROUND: The autogenous brachiocephalic or brachiobasilic arteriovenous elbow fistula is not considered to be only the secondary haemodialysis access. In patients with an unsuitable forearm vessel bundle, it is indicated as primary access and it is the method preferred to the fistula creation using a vascular prosthesis. Its rather rare complication is the development of upper extremity ischemia. AIM: To summarise current knowledge of this fistula type and its associated complications METHODS: Review of the literature. RESULTS: The creation and maturation of the fistula and occurrence of the steal syndrome is influenced by a number of factors. The analysis and awareness of such factors will provide for creation of a suitable fistula as well as for timely complication diagnostics and treatment. CONCLUSIONS: The autogenous elbow fistula utilising the brachial artery and the cephalic or basilic vein in the upper extremity represents a high quality haemodialysis access. Its potential complication is the occurrence of the steal syndrome. Its occurrence and manifestations do not constitute indications for ligation of the access. The gathered information shows that a suitable surgical procedure can help meet the basic rule for haemodialysis access- resolving the ischemia and maintaining the access. PMID- 17690757 TI - Methods of imaging in the diagnosis of temporomandibular joint disorders. AB - BACKGROUND: Different methods of temporomandibular joint imaging are presented and discussed. Research reports published from 1979 to 2002 have been evaluated. METHOD AND RESULTS: The aim of this paper is to summarize the main findings from research. Basic X-ray examination is the most readily available method of imaging which usually does not have any contraindication. The use of computer tomography offers all advantages of tomographic scanning in different layers and projections, imaging soft tissues close to the joint and the possibility of "3D" reconstruction of bone structures. In case of joint dysfunctions and internal joint derangement, it is more preferable to use nuclear magnetic resonance for the depiction of the joint structures. To make a diagnosis more efficient, miniinvasive diagnostic methods are becoming necessary. Arthroscopy allows direct visual control of the joint space with the possibility of therapeutic help in cases when conservative treatment has failed. Ultrasonography, as a completely non-invasive procedure, is applied even in diagnosing functional temporomandibular defects. In these cases the diagnostic value of ultrasonography is almost comparable with this of nuclear magnetic resonance. CONCLUSIONS: So it is possible that, together with the improvement of the equipment, development of the diagnostic methods used during the treatment of temporomandibular joint defects could continue in this direction. PMID- 17690758 TI - Evaluation of bone healing in femurs lengthened via the gradual distraction method. AB - BACKGROUND: Treatment of leg length inequality via lengthening of the shorter extremity is an infrequent orthopedic procedure due to the requirement of special distraction devices and possible serious complications. Essential qualitative changes in operative technique development are associated with the name of G. A. Ilizarov, who paved the way for the autoregenerate gradual distraction method in the 1950s. MATERIAL AND METHODS: In the years 1990 through 2006 a total of 57 patients underwent femur lengthening via gradual distraction using various types of external fixators at the Department of Pediatric Surgery, Orthopedics, and Traumatology, Faculty Hospital in Brno. The quality of bone healing was monitored and a number of parameters followed and statistically evaluated using regularly scheduled X-ray examinations. RESULTS: In 11 cases we had to remove the external fixator following the distraction phase, perform an osteosynthesis via a splint and fill the distraction gap via spongioplasty. The bone healing was satisfactory in the remaining 46 patients and the lengthened bone required no other fixation method. The analysis showed statistically significant deceleration in bone healing following distraction in female patients over 12 years of age, and in boys over 14 years of age. Lack of periosteal callus five weeks after surgery always signified serious problems in further healing. Severe complications were recorded in 11 cases during the distraction phase, and in 9 cases after the removal of the distraction apparatus. CONCLUSIONS: The aim of this report was to present the results of our study of distraction gap bone healing using the gradual lengthening approach. PMID- 17690759 TI - Laser Doppler fluxmetry. AB - BACKGROUND: Laser Doppler fluxmetry (LDF) is an extraordinary sensitive noninvasive method of examination. It can be used for monitoring changes in the cutaneous peripheral microcirculation(15). It uses a monochromatic low-energy laser beam. This beam penetrates the tissue and, depending on individual tissue penetration, it is reflected, recorded by a sensitive sensor and subsequently analyzed using the Doppler. Laser Doppler fluxmetry detects movement of cells in the peripheral circulation and microcirculation. METHODS: The light from the laser source is delivered via optical fibers to the tissue. In the tissue the light collides with moving blood elements; after a collision, the wave length of the light changes--this phenomenon is called Doppler shift. Our own method of measurement has already been fully developed. We have a group of patients with physiological findings and also groups of patients with vasoneurosis, patients with type 1 diabetes mellitus, vasculitis patients, and other patient groups. We examine the blood flow on the dorsal side of fingers or toes. There are many protocols for laser Doppler examination. For all the patient groups we used a protocol evaluating an algorithm, developed in the training department of the Perimed company, using provocation tests for the assessment of the vascular wall function in addition to records at rest. USE OF LASER DOPPLER: We have developed a method of use of laser Doppler examination in about 8 years. We have examined several groups of patients. First a patient group with physiological findings was examined, and subsequently groups of patients with vasculitis, vasoneurosis, and a group of patients with type l diabetes mellitus. Recently, monitoring has been performed in patients after cardioversion in chronic atrial fibrillation with sinus rhythm restitution, and also data obtained before and after a varicose vein operation on lower limbs have been compared. CONCLUSION: Clear diagnostic criteria for this method do not exist so far. For the time being this is a rather theoretical method that we used even in practice for the above mentioned diseases. The method provides enough data even for more detailed analyses. The information value of the curve arises after statistical data analysis with the t test. PMID- 17690760 TI - Opinions of medical students on the pre-graduate scientific activities--how to improve the situation? AB - BACKGROUND: The number of medical undergraduates taking part in Student Scientific Activities (SSA) at Jessenius Faculty of Medicine Comenius University in Slovakia remains low. The aim of this study was to discover some of the factors responsible and suggest improvements. METHODS: An anonymous 30-item questionnaire was devised and sent to 245 medical undergraduates (UG) of the 1st, 2nd, 3rd and 5th years. RESULTS: Foreign fellowships, postgraduate research, assistant posts at universities and financial incentives were cited as the main positive motivators for participation in UG student scientific research. Characteristics in tutors that encouraged student research were scientific knowledge, giving time to students and enthusiasm for research while poor infrastructure, tutor lack of time/interest, own time constraints, weak career motivation and lack of information were the strongest discouraging factors. CONCLUSION: Involvement of students in SSA is influenced by many factors. To increase the number of students taking part in SSA, student research and/or continuing to Ph.D and scientific career, these factors need to be addressed by medical schools. PMID- 17690761 TI - The evolutionary ideas of F. M. (Ladimir) Klacel, teacher of Gregor Mendel. AB - Abstract: A philosopher and teacher, F. M. (Ladimir) Klacel (1808-1882), educated in what is now the Czech Republic, developed his own explanation for the origin and interaction of living organisms. Klacel, a member of the Augustinian Monastery in Brno, influenced his younger colleague, Friar Gregor Mendel, who went on to formulate concepts in heredity that are still recognized for their profound insight. A mutual interest in the natural sciences of these two friends provided a basis for their discussions of the relationship between religion, evolution, and society. Klacel's outspoken defense of his proposals caused him to lose favor with both the Church and the authorities, and he immigrated to America in 1869. His failing health and inability to communicate with the English speaking populace, unfortunately, limited his influence in his new environs. In this paper we trace the roots of Klacel's philosophy and elucidate his incorporation of ideas from Hegel, Darwin, and others. An investigation of Klacel's recipe for a successful society reveals his belief in the universality of life and his optimistic hope for human achievement. PMID- 17690764 TI - Benign nerve tumors of the hand and the forearm. AB - We used a hand surgeon's 1978-1994 pathology reports to retrospectively review the incidence, preoperative and postoperative diagnoses, and presenting signs and symptoms of benign nerve tumors. Twenty-four (11.5%) of our series of 208 soft tissue tumors of the hand and the forearm were benign nerve tumors. Nerve tumors were the third most common tumor after giant cell tumors of tendon sheath and inclusion cysts. Correct preoperative diagnosis was made in only 1 (4.2%) of the 24 cases. Schwannomas and neurofibromas were equally distributed (12 each), and 2 cases of neurofibromatosis (8.3%) were documented. Two (16.7%) of the 12 patients with schwannomas and 4 (33.3%) of the 12 patients with neurofibromas had neurologic symptoms. Six (85.7%) of the 7 digital tumors were dorsally located. In the literature, incidence of benign nerve tumors is much lower (ie, 1%-5%), and preoperative diagnosis consistently incorrect in our study. Incidence of neurologic symptoms (numbness, paresthesia) as presenting symptoms was higher in our study than previously documented. Although benign nerve tumors are most often located on the volar surface of the hand, 25% of the lesions we found were on the dorsal surface of the fingers. PMID- 17690765 TI - Recurrent schwannoma with bony erosion of the distal middle finger. PMID- 17690766 TI - Peroneal nerve palsy due to an intraneural ganglion: a case report of a 4 1/2 year-old boy. PMID- 17690767 TI - Distal femoral physeal fractures and peroneal nerve palsy: outcome and review of the literature. PMID- 17690768 TI - Spectroscopic probes of molecular recognition. PMID- 17690769 TI - Carbohydrate molecular recognition: a spectroscopic investigation of carbohydrate aromatic interactions. AB - The physical basis of carbohydrate molecular recognition at aromatic protein binding sites is explored by creating molecular complexes between a series of selected monosaccharides and toluene (as a truncated model for phenylalanine). They are formed at low temperatures under molecular beam conditions, and detected and characterized through mass-selected, infrared ion depletion spectroscopy-a strategy which exploits the extraordinary sensitivity of their vibrational signatures to the local hydrogen-bonded environment of their OH groups. The trial set of carbohydrates, alpha- and beta-anomers of glucose, galactose and fucose, reflects ligand fragments in naturally occurring protein-carbohydrate complexes and also allows an investigation of the effect of systematic structural changes, including the shape and extent of 'apolar' patches on the pyranose ring, removal of the OH on the exocyclic hydroxymethyl group, and removal of the aglycon. Bound complexes invariably form, establishing the general existence of intrinsic intermolecular potential minima. In most of the cases explored, comparison between recorded and computed vibrational spectra of the bound and free carbohydrates in the absence of solvent water molecules reveal that dispersion forces involving CH-pi interactions, which promote little if any distortion of the bound carbohydrate, predominate although complexes bound through specific OH pi hydrogen-bonded interactions have also been identified. Since the complexes form at low temperatures in the absence of water, entropic contributions associated with the reorganization of surrounding water molecules, the essence of the proposed 'hydrophobic interaction', cannot contribute and other modes of binding drive the recognition of sugars by aromatic residues. Excitingly, some of the proposed structures mirror those found in naturally occurring protein carbohydrate binding sites. PMID- 17690770 TI - Laser spectroscopic study on the conformations and the hydrated structures of benzo-18-crown-6-ether and dibenzo-18-crown-6-ether in supersonic jets. AB - The laser-induced fluorescence spectra of jet-cooled benzo-18-crown-6 (B18C6) and dibenzo-18-crown-6 (DB18C6) exhibit a number of vibronic bands in the 35 000-37 000 cm(-1) region. We attribute these bands to monomers and hydrated clusters by fluorescence-detected IR-UV and UV-UV double resonance spectroscopy. We found four and two conformers for bare B18C6 and DB18C6, and the hydration of one water molecule reduces the number of isomers to three and one for B18C6-(H(2)O)(1) and DB18C6-(H(2)O)(1), respectively. The IR-UV spectra of B18C6-(H(2)O)(1) and DB18C6 (H(2)O)(1) suggest that all isomers of the monohydrated clusters have a double proton-donor type (bidentate) hydration. That is, the water molecule is bonded to B18C6 or DB18C6 via two O-H[dot dot dot]O hydrogen bonds. The blue shift of the electronic origin of the monohydrated clusters and the quantum chemical calculation suggest that the water molecule in B18C6-(H(2)O)(1) and DB18C6 (H(2)O)(1) prefers to be bonded to the ether oxygen atoms near the benzene ring. PMID- 17690771 TI - Conformational preferences of chiral molecules: free jet rotational spectrum of 1 phenyl-1-propanol. AB - The rotational spectra of normal and O-d species of the two most stable conformers of chiral 1-phenyl-1-propanol, obtained by free jet millimetre-wave absorption spectroscopy reveal that both conformers are stabilized by a O-H[dot dot dot]pi interaction, and have the Calpha-Cbeta-bond oriented nearly perpendicular to the plane of the benzene ring. The methyl group is trans with respect to the phenyl group for the most stable conformer (T), while it is gauche with respect to the phenyl group and entgegen with respect to the hydroxyl group for the second most stable conformer (GE). The energy difference (E(GE)-E(T)) was estimated to be 50(50) cm(-1) from relative intensity measurements. PMID- 17690772 TI - Electronic and infrared spectroscopy of jet-cooled (+/-)-cis-1-amino-indan-2-ol hydrates. AB - The role of conformational isomerism in molecular interaction has been studied using the example of jet-cooled complexes of (+/-)-cis-1-amino-indan-2-ol with water. The two formerly evidenced conformers of (+/-)-cis-1-amino-indan-2-ol easily form hydrates and dihydrates, which have been studied by means of laser induced fluorescence and IR/UV double resonance spectroscopy, as well as ab initio calculations. All the 1 : 1 and 1 : 2 complexes with water evidenced in this work involve "ring" structures, in which the water monomer or dimer acts as an acceptor from the NH(2) and a donor to the OH groups of (+/-)-cis-1-amino indan-2-ol. However, the water lies externally to the indan frame in the hydrates of conformer I of (+/-)-cis-1-amino-indan-2-ol, which possesses axial NH(2) and equatorial OH groups, and above it for the hydrates with the less stable conformer II, with equatorial NH(2) and axial OH groups. Consequently, the different steric constraints which exist in the two conformers result in different hydrogen bond topologies, with an additional OH[dot dot dot]pi interaction for the hydrates of conformer II. PMID- 17690773 TI - A peptide co-solvent under scrutiny: self-aggregation of 2,2,2-trifluoroethanol. AB - Trifluoroethanol (TFE) and its aggregates are studied via supersonic jet FTIR and Raman spectroscopy as well as by quantum chemistry and simple force field approaches. A multi-slit nozzle is introduced to study collisionally excited clusters. Efforts are made to extract harmonic frequencies from experiment for better comparison to theory. Based on deuteration, the OH stretching anharmonicity changes weakly upon dimerization, but increases for trimers. Among the possible dimer conformations, only an all-gauche, homoconfigurational, compact, OH-F connected structure is observed in an extreme case of chiral discrimination. Quantum tunneling assisted pathways for this surprising helicity synchronization are postulated. The oscillator coupling in hydrogen-bonded trimers is analyzed. Trans conformations of TFE start to become important for trimers and probably persist in the liquid state. Simple force fields can be refined to capture some molecular recognition features of TFE dimer, but their limitations are emphasized. PMID- 17690774 TI - Intramolecular recognition in a jet-cooled short peptide chain: gamma-turn helicity probed by a neighbouring residue. AB - gamma-Turn, the shortest secondary structure of peptides, exists as two helical forms gamma(l) and gamma(d) of opposite handedness. The present gas phase study of capped l-Phe-Xxx peptides (Xxx = l-Ala, d-Ala or Aib: aminoisobutyric acid) provides a unique example of intramolecular chiral recognition of the gamma-turn helicity on Ala or Aib by the neighbouring residue Phe within the chain. With the chiral l- or d-Ala residues, the presence of a side-chain operates a discrimination between the two helical forms: one of them is widely favoured over the other (gamma(l) or gamma(d), respectively). This enables us to validate and calibrate the recognition capabilities of the nearby l-Phe residue. The discriminating interactions have been precisely characterized from their spectroscopic UV and IR signatures and identified by comparison with quantum chemistry calculations. Then, in the case of the non-chiral residue Aib, the two helical forms of the gamma-turn, which are simultaneously observed in the jet, have been discriminated and assigned by comparison with the chiral residues. The relative abundances of the diastereomeric forms l-Phe-Aib(gamma(l)) and l-Phe Aib(gamma(d)) enable us to determine the most efficient recognition configuration. PMID- 17690775 TI - NMR studies of double proton transfer in hydrogen bonded cyclic N,N' diarylformamidine dimers: conformational control, kinetic HH/HD/DD isotope effects and tunneling. AB - Using dynamic NMR spectroscopy, the kinetics of the degenerate double proton transfer in cyclic dimers of polycrystalline (15)N,(15)N'-di-(4-bromophenyl) formamidine (DBrFA) have been studied including the kinetic HH/HD/DD isotope effects in a wide temperature range. This transfer is controlled by intermolecular interactions, which in turn are controlled by the molecular conformation and hence the molecular structure. At low temperatures, rate constants were determined by line shape analysis of (15)N NMR spectra obtained using cross-polarization (CP) and magic angle spinning (MAS). At higher temperatures, in the microsecond time scale, rate constants and kinetic isotope effects were obtained by a combination of longitudinal (15)N and (2)H relaxation measurements. (15)N CPMAS line shape analysis was also employed to study the non degenerate double proton transfer of polycrystalline (15)N,(15)N'-diphenyl formamidine (DPFA). The kinetic results are in excellent agreement with the kinetics of DPFA and (15)N,(15)N'-di-(4-fluorophenyl)-formamidine (DFFA) studied previously for solutions in tetrahydrofuran. Two large HH/HD and HD/DD isotope effects are observed in the whole temperature range which indicates a concerted double proton transfer mechanism in the domain of the reaction energy surface. The Arrhenius curves are non-linear indicating a tunneling mechanism. Arrhenius curve simulations were performed using the Bell-Limbach tunneling model. The role of the phenyl group conformation and hydrogen bond compression on the barrier of the proton transfer is discussed. PMID- 17690776 TI - Molecular recognition in 1 : 1 hydrogen-bonded complexes of oxirane and trans-2,3 dimethyloxirane with ethanol: a rotational spectroscopic and ab initio study. AB - High resolution rotational spectroscopy complemented by ab initio calculations has been used to elucidate the diastereomeric interactions in 1 : 1 complexes of ethanol, a transient chiral alcohol, hydrogen-bonded to oxirane (achiral) or trans-2,3-dimethyloxirane (DMO, 2 stereocenters). Two conformers of oxirane[dot dot dot]ethanol and three conformers of DMO[dot dot dot]ethanol have been identified, and their structures as well as their stability ordering have been determined. This completes, together with previous results on the propylene oxide...ethanol complex (N. Borho and Y. Xu, Angew. Chem., 2007, 119, 2326-2329; Angew. Chem., Int. Ed., 2007, 46, 2276-2279.), the study of a set of model systems with zero, one, and two methyl functional groups at the hydrogen bond acceptor oxirane. The dependence of the observed rotational line intensities on pressure, nozzle temperature, and different carrier gases has been investigated for the case of DMO[dot dot dot]ethanol. This provides insight into the kinetical and thermodynamical influence on the formation of different conformers. Comparison of the subtle energy differences among the complexes and within each set of conformers allows for a detailed analysis of molecular recognition in this benchmark system. PMID- 17690777 TI - Conformational study of 2-phenylethylamine by molecular-beam Fourier transform microwave spectroscopy. AB - The conformational preferences of the simplest amine neurotransmitter 2 phenylethylamine have been investigated using molecular beam Fourier transform microwave (MB-FTMW) spectroscopy. Two new conformers have been observed together with the two previously reported by Godfrey et al. [J. Am. Chem. Soc., 1995, 117, 8204]. The (14)N nuclear quadrupole hyperfine structure has been resolved for all four conformers. Comparison of the experimental rotational and quadrupole coupling constants with those calculated theoretically provides a conclusive test for the identification of all conformers. The two most stable conformers present a gauche (folded) disposition of the alkyl-amine chain and are stabilised by a weak NH...pi interaction between the amino group and the aromatic ring. The other two conformers show an anti (extended) arrangement of the alkyl-amine chain. Tunnelling splittings have been observed in the spectrum of one of the anti conformers. The post expansion relative abundances in the supersonic jet have been also investigated and related to the conformer energies. PMID- 17690778 TI - Raman jet spectroscopy of formic acid dimers: low frequency vibrational dynamics and beyond. AB - The vibrational dynamics of formic acid dimer is quite regular at low fundamental excitation frequencies, whereas it evolves into a complex and irregular vibrational signature in the OH stretching region. This is evidenced by the first Raman investigation of the jet-cooled formic acid dimer and its three deuterated isotopomers. Subtle isotope effects in the inter-monomer stretching mode, which is directly observed for the first time at 194 cm(-1), find an interpretation based on hydrogen bond weakening due to quantum delocalization of the protons. The reported high-frequency jet spectra should provide essential experimental stepping stones towards a more complete understanding of this planar prototype for strong double hydrogen bonding. PMID- 17690779 TI - Infrared spectroscopy of acetic acid and formic acid aerosols: pure and compound acid/ice particles. AB - Acetic acid aerosol particles, formic acid aerosol particles and mixed acid/ice particles were generated in a collisional cooling cell at a temperature of 78 K and investigated using in situ rapid scan Fourier transform infrared spectroscopy. The infrared spectra reveal that the internal structure of the particles critically depends on the particle formation conditions and, especially for the mixed particles, on the composition. The acetic acid particles are likely to have only a partially crystalline structure whereas the formic acid particles are likely to have an overall crystalline structure. The existence of acid in the mixed acid/ice particles prevents the ice from crystallization even at low acid concentrations (less than 10%). Mid-infrared refractive index data were derived from the different particle spectra, which can be helpful for remote sensing of such systems. PMID- 17690780 TI - Selectivity of guest-host interactions in self-assembled hydrogen-bonded nanostructures observed by NMR. AB - We studied the incorporation of various small guest molecules into calix[4]hydroquinone nanotubes and nanoclusters using solid-state proton NMR spectroscopy in combination with quantum chemical calculations. While the molecules exhibit different types of hydrogen bonding and van der Waals interactions, they show different affinities to the nanotube host structures. As the guest molecules are located inside the complexes, they experience a shift in the NMR resonance line caused by screening effects from the aromatic electrons of the host superstructure. The abilities to fill the otherwise empty space within the tubes can hence be measured indirectly by the displacement of the NMR lines relative to the free molecules. In this way, we can probe which guest molecules are recognized by the calix[4]hydroquinones as suitable for filling their nanoporous superstructures. Selective guest-host interactions have been successfully achieved for the three component mixture of water and acetone with either 2-methyl-2-propanol or 2-propanol. In both cases, the alcohols were superior to acetone in filling the CHQ tubes. PMID- 17690781 TI - Molecular recognition in molecular tweezers systems: quantum-chemical calculation of NMR chemical shifts. AB - Quantum-chemical calculations for molecular tweezers systems are presented, where the focus is not only on the recognition process in the host-guest systems, but on the self aggregation of the tweezers host as well. Such intermolecular interactions influence the corresponding NMR spectra strongly by up to 6 ppm for proton chemical shifts, since ring-current effects are particularly important. The quantum-chemical results allow one to reliably assign the spectra and to gain information both on the structure and on the importance of intra- and intermolecular interactions. In addition, we study the accuracy of a variety of density functionals for describing the present host-guest systems, where we observe a considerable underestimation of ring-current effects on (1)H NMR chemical shifts at the density functional theory (DFT) level using smaller basis sets such as 6-31G**, so that larger bases like TZP are required. This stands in contrast to the behavior of the Hartree-Fock scheme, where small basis sets, such as 6-31G**, provide reliable (1)H NMR shieldings for molecular tweezers systems. PMID- 17690782 TI - Molecular recognition in the gas phase. Dipole-bound complexes of benzonitrile with water, ammonia, methanol, acetonitrile, and benzonitrile itself. AB - Described herein are the high resolution fluorescence excitation spectra of 1 : 1 complexes of benzonitrile with water, ammonia, methanol, acetonitrile, and benzonitrile itself in the gas phase. Analyses of these spectra yield the equilibrium geometries of each species in both the ground and excited electronic states, and therefore provide information about the intermolecular interactions that are responsible for holding them together, in the absence of perturbing solvent molecules. In all cases, the determined structure corresponds to the one expected on the basis of interacting dipole moments; in some cases, significant internal motions of one component relative to the other, leading to a time varying dipole field, also has been observed. PMID- 17690783 TI - Vibrational dynamics of carboxylic acid dimers in gas and dilute solution. AB - Ultrafast mid-IR transient absorption spectroscopy has been used to study the vibrational dynamics of hydrogen-bonded cyclic dimers of trifluoroacetic acid and formic acid in both the gas and solution phases (0.05 M in CCl(4)). Ultrafast excitation of the broad O-H cyclic dimer band leads, in the gas phase, to large scale structural changes of the dimer creating a species with a distinct free O-H stretching band on 20 ps and 200 ps timescales. These timescales are assigned to ring-opening and dissociation of the dimer, respectively. In the solution phase, no such structural rearrangement occurs and our results are consistent with previous studies. The gas phase dynamics are insensitive to both the specific excitation energy (over a span of 550 cm(-1)) and the chemical identity of the dimer. PMID- 17690784 TI - IR-UV double resonance spectroscopy of xanthine. AB - We present resonant two-photon ionization (R2PI), UV-UV, and IR-UV double resonance spectra of xanthine seeded in a supersonic jet by laser desorption. We show that there is only one tautomer of xanthine which absorbs in the wavelength range of 36 700 to 37 700 cm(-1). The IR-UV double resonance spectrum shows three strong bands at 3444, 3485, and 3501 cm(-1), all of which we assign as N-H stretching vibrations. Comparison of the IR-UV double resonance spectrum with frequencies and intensities obtained from density functional theory (DFT) and second order Moller Plesset (MP2) calculations suggests that the observed xanthine is the diketo N(7)H tautomer. PMID- 17690785 TI - Secondary structure binding motifs of the jet cooled tetrapeptide model Ac-Leu Val-Tyr(Me)-NHMe. AB - In this paper the structure of the isolated tetrapeptide model Ac-Leu-Val-Tyr(Me) NHMe (Leu = leucine, Val = valine, Tyr = tyrosine) is investigated by mass- and isomer-selective IR/UV double resonance spectroscopy. Two isomers of this peptide are observed and in combination with force field, ab initio, and DFT calculations these structures are assigned to folded arrangements presenting two different secondary structure binding motifs: (a) a combined gamma-turn/beta-turn structure and (b) a triple gamma-turn structure, which is described for the first time for an isolated model system in the gas phase. PMID- 17690786 TI - UV resonance Raman spectroscopic monitoring of supramolecular complex formation: peptide recognition in aqueous solution. AB - The formation of a supramolecular complex between a tetrapeptide and an artificial receptor , is monitored at submillimolar concentrations in water by UV resonance Raman spectroscopy. Using 275 nm excitation, we selectively probe the carboxylate binding site (CBS) within the receptor, a moiety which is very efficient in binding the carboxy terminus of peptides in aqueous media. Complexation of the receptor with the tetrapeptide involves the formation of a H bond enforced ion pair, resulting in significant changes in the corresponding UV resonance Raman spectra. Our qualitative interpretation is based on experimental reference and calculated Raman spectra on model systems. First preliminary calculations show that for a quantitative analysis, also the distinct contributions of multiple CBS conformers must be considered in addition to the H bond induced changes upon complexation. PMID- 17690788 TI - Papillary microcarcinoma and papillary cancer of the thyroid or=100 Gy to all metastases without exceeding 2 Gy to the blood (a surrogate for bone marrow toxicity). We thus determined the absorbed lesion dose per GBq of administered 131I activity (LDpA) based on serial PET (4, 24, 48, 72 and 96 h after oral 124I intake) and PET/computed tomography (25 h after (124)I intake) and the critical blood activity (CBA) based on blood and whole-body radiation counting (2, 4, 24, 48, 72, 96 h after 124I intake). We compared the dosimetry-based interventions with our standard empirical protocol. RESULTS: 25 patients had a total of 126 iodine positive metastases. 18 (72%) of the 25 had solely iodine-avid metastases, while seven (28%) had both iodine-avid and -non-avid metastases. In two patients (8%), none of the iodine-avid metastases could have been practically treated with a sufficient radiation dose. Relative to the empirical protocol, (124)I-PET dosimetry findings changed management in 7 (25%) patients, e.g. allowing application of activities >11 GBq (131)I. Further changes included implementation of hematological back-up in a patient found to be at risk of life-threatening marrow toxicity, and early multimodal therapy in 9 (32%) patients. CONCLUSION: 124I-PET dosimetry is a useful routine procedure in advanced DTC and may allow safer or more effective radioiodine activities and earlier multimodal interventions than do standard empirical protocols. PMID- 17690790 TI - Initial presentation of scintigraphic changes during the first episode of acute pyelonephritis in children: simultaneous evaluation with MAG3 and DMSA. AB - 99mTc-DMSA scintigraphy is generally accepted as the method of choice for detecting renal parenchymal damage in pyelonephritis. 99mTc-MAG3 dynamic scintigraphy is not routinely used for this purpose. The AIM of this study was to evaluate the MAG3 scintigraphic presentation in the acute phase of pyelonephritis in children and re-evaluate them at least 6 months later, as well as to establish whether a MAG3 in the parenchymal phase is as reliable and sensitive in the detection of a renal parenchymal damage as the DMSA. PATIENTS, METHODS: The MAG3 scintigraphic pattern was evaluated during the first episode of acute pyelonephritis in 31 children (median age: 2.5 years) and compared to the DMSA scan. The scintigraphy was performed on the same day with both radiopharmaceuticals. After at least 6 months the whole procedure was repeated on 28 patients. A scoring system was designed to evaluate the parenchymal lesions, and categorize them as positive or equivocal. The findings on the initial scans were compared to those obtained in the follow up studies. RESULTS: When all lesions (equivocal + positive) were analysed, MAG3 sensitivity was 98%, and specificity 78%, while for positive lesions only, the values were 83 and 100%, respectively. The average acute severity score was significantly lower for both MAG3 and DMSA then the follow up score (p < 0.0001). These results corresponded to a clinical convalescence, which was observed in 26/28 children in the follow up. CONCLUSION: With the MAG3 scintigraphy a reliable semi quantitative and qualitative detection of the renal inflammatory lesions can be obtained in acute pyelonephritis, as well as their recovery, thus obviating the need for a DMSA scan. Moreover, the duration of the MAG3 procedure is shorter, enabling the visualization of the entire collecting system as well, while the radiation exposure is approximately a half of that delivered by the DMSA scan. PMID- 17690791 TI - Scintigraphy with 99mTc-labeled heat-altered erythrocytes in diagnosing hyposplenia: prospective comparison to 99mTc-labeled colloids and colour-coded duplex ultrasonography. AB - AIM: Ultrasound may be a cheap alternative to scintigraphic determination of splenic function. We directly compared nanocolloid scintigraphy (NS), scintigraphy with heat-altered erythrocytes (ES), and colour-coded Doppler sonography (DS) in patients with chronic inflammatory bowel disease (CIBD). PATIENTS, METHODS: 35 patients were included into the study. Clearance rates were determined in ES, spleen/liver ratios (SLR) were measured scintigraphically in ES/NS. In DS, spleen size, echogenicity, and vascular resistance indices (RI) were determined. The results were compared to each other, to the clinical activity scores for CIBD, and to the course of the disease. RESULTS: Based on the blood erythrocyte clearance serving as standard, patients had a good (19 patients), impaired (5), or missing splenic function (11). There was a good correlation of the clearance to SLR in ES (0.63, p < 0.01). The 10 min / 45 min ES clearance showed a high correlation (Spearman-Rho 0.87, p < 0.01). The SLR in ES at 2, 5, 10 and 45 min also correlated well with each other (Spearman-Rho > 0.9, p < 0.01; SLR > 3.45 normal splenic function, SLR < 1.22 indicated hyposplenia). There were no correlations between the results of NS, DS, Howell Jolly-bodies, or clinical parameters. Only ES and the erythrocyte clearance correlated well. Howell-Jolly-Bodies detected 1 of 11 patients with hyposplenia while false-positive in 4. CONCLUSION: Ultrasound and colloid scintigraphy show a low correlation with clearance of heat-altered erythrocytes. Only ES shows a good correlation in patients with CIBD. The clearance at 10 min already reliably determines splenic function. SLR may be determined after 10 minutes and is predictive of normal function if above 3.45 while SLR < 1.2 indicated hyposplenia. PMID- 17690792 TI - [3D volume and SUV analysis of oncological PET studies: a voxel-based image processing tool with NSCLC as example]. AB - AIM: The standardized uptake value (SUV) of 18FDG-PET is an important parameter for therapy monitoring and prognosis of malignant lesions. SUV determination requires delineating the respective volume of interest against surrounding tissue. The present study proposes an automatic image segmentation algorithm for lesion volume and FDG uptake quantitation. METHODS: A region growing-based algorithm was developed, which goes through the following steps: 1. Definition of a starting point by the user. 2. Automatic determination of maximum uptake within the lesion. 3. Calculating a threshold value as percentage of maximum. 4. Automatic 3D lesion segmentation. 5. Quantitation of lesion volume and SUV. The procedure was developed using CTI CAPP and ECAT 7.2 software. Validation was done by phatom studies (Jaszczak phantom, various "lesion" sizes and contrasts) and on studies of NSCLC patients, who underwent clinical CT and FDG-PET scanning. RESULTS: Phantom studies demonstrated a mean error of 3.5% for volume quantification using a threshold of 41% for contrast ratios >or=5 : 1 and sphere volumes >5 ml. Comparison between CT- and PET-based volumetry showed a high correlation of both methods (r = 0.98) for lesions with homogeneous FDG uptake. Radioactivity concentrations were underestimated by on average -41%. Employing an empirical threshold of 50% for SUV determination, the underestimation decreased to on average -34%. CONCLUSIONS: The algorithm facilitates an easy and reproducible SUV quantification and volume assessment of PET lesions in clinical practice. It was validated using NSCLC patient data and should also be applicable to other tumour entities. PMID- 17690793 TI - 18F-FDG metabolism in a rat model of chronic infarction: a 17-sector semiquantitative analysis. AB - Strategies to establish the functional benefit of cell therapy in cardiac regeneration and the potential mechanism are needed. AIMS: Development of a semi quantitative method for non invasive assessment of cardiac viability and function in a rat model of myocardial infarction (MI) based on the use of microPET. ANIMALS, METHODS: Ten rats were subjected to myocardial imaging 2, 7, 14, 30, 60 and 90 days after left coronary artery ligation. Intravenous 18F-fluoro-2-deoxy-2 D-glucose (18F-FDG) was administered and regional 18F activity concentrations per unit area were measured in 17 regions of interest (ROIs) drawn on cardiac polar maps. By comparing the differences in 18F uptake between baseline and each of the follow up time points, parametric polar maps of statistical significance (PPMSS) were calculated. Left ventricular ejection fraction (LVEF) was blindly assessed echocardiographically. All animals were sacrificed for histopathological analysis after 90 days. RESULTS: The diagnostic quality of 18F-FDG microPET images was excellent. PPMSS demonstrated a statistically significant decrease in 18F concentrations as early as 48 hours after MI in 4 of the 17 ROIs (segments 7, 13, 16 and 17; p < 0.05) that persisted throughout the study. Semiquantitative analysis of 18F-FDG uptake correlated with echocardiographic decrease in LVEF (p < 0.001). CONCLUSION: The use of PPMSS based on 18F-FDG-microPET provides valuable semi-quantitative information of heart glucose metabolism allowing for non-invasive follow up thus representing a useful strategy for assessment of novel therapies in cardiac regeneration. PMID- 17690794 TI - The role of the GABRA2 polymorphism in multiplex alcohol dependence families with minimal comorbidity: within-family association and linkage analyses. AB - OBJECTIVE: The genes encoding the gamma-aminobutyric acid(A) (GABA(A)) receptor have been the focus of several recent studies investigating the genetic etiology of alcohol dependence. Analyses of multiplex families found a particular gene, GABRA2, to be highly associated with alcohol dependence, using within-family association tests and other methods. Results were confirmed in three case-control studies. The objective of this study was to investigate the GABRA2 gene in another collection of multiplex families. METHOD: Analyses were based on phenotypic and genotypic data available for 330 individuals from 65 bigenerational pedigrees with a total of 232 alcohol-dependent subjects. A proband pair of same-sex siblings meeting Diagnostic and Statistical Manual of Mental Disorders, Third Edition, criteria for alcohol dependence was required for entry of a family into the study. One member of the proband pair was identified while in treatment for alcohol dependence. Linkage and association of GABRA2 and alcohol dependence were evaluated using SIBPAL (a nonparametric linkage package) and both the Pedigree Disequilibrium Test and the Family-Based Association Test, respectively. RESULTS: We find no evidence of a relationship between GABRA2 and alcohol dependence. Linkage analyses exhibited no linkage using affected/affected, affected/unaffected, and unaffected/unaffected sib pairs (all p's < .13). There was no evidence of a within-family association (all p's > .39). CONCLUSIONS: Comorbidity may explain why our results differ from those in the literature. The presence of primary drug dependence and/or other psychiatric disorders is minimal in our pedigrees, although several of the other previously published multiplex family analyses exhibit a greater degree of comorbidity. PMID- 17690795 TI - Random alcohol testing reduced alcohol-involved fatal crashes of drivers of large trucks. AB - OBJECTIVE: This study examined the impact of random alcohol testing, implemented on August 1, 1994, on the likelihood that the driver of a large truck involved in a fatal motor vehicle crash was alcohol-involved. METHOD: Among fatal crashes, the proportion of alcohol-positive large truck drivers (intervention group) was compared with the proportion of alcohol-positive light passenger vehicle drivers (control group). Annual Fatality Analysis Reporting System (FARS) data (1988 2003) were compiled for each of the 50 states and Washington, D.C., for the control and intervention groups. Using these pooled cross-sectional data, logistic regression modeled the likelihood that a driver was alcohol-positive (blood alcohol concentration > 0) before compared with after random alcohol testing. We attributed the difference-in-difference (the difference in likelihoods of being alcohol positive pretesting versus post-testing in large truck versus passenger vehicle drivers) to the impact of random testing. RESULTS: Drivers of large trucks were 18.6% less likely to be alcohol-involved after random testing was implemented than before random testing (odds ratio [OR] = 0.814, 95% confidence interval [CI]: 0.713-0.930). The control group of passenger car drivers was 4.7% less likely to be alcohol-involved after random testing was implemented (OR = 0.953, 95% CI: 0.924-0.983). The net reduction in the odds of alcohol involvement for drivers of large trucks was 14.5% (OR = 0.855, 95% CI: 0.748-0.976). CONCLUSIONS: Controlling for the general declining trend in alcohol involved drivers in fatal crashes, random alcohol testing was correlated with a 14.5% reduction in alcohol involvement among large truck drivers. PMID- 17690796 TI - Cocaine craving as a predictor of treatment attrition and outcomes after residential treatment for cocaine dependence. AB - OBJECTIVE: Whether craving (urge to use) actually predicts drug-use outcomes has had little investigation despite its central role in theories. Pretreatment predictors of within-treatment cocaine urges were investigated, and the urge reports were used as predictors of treatment attrition and outcome while controlling for correlated variables. In addition, urge to use in the patients' first relapse situations was compared with urge reports in the same patients' close-call situations without relapse. METHOD: Cocaine-dependent patients (N = 163) in residential treatment were assessed during the first week of treatment for pretreatment substance use and for urge to use cocaine in simulated high-risk situations. Substance use was assessed at follow-up with urine-confirmed self reports (n = 119 at 3 months, n = 114 at 6 months). Mood and urge ratings just before relapse and in close calls without relapse were assessed. RESULTS: Urge to use cocaine was unrelated to demographics, other substance use, years used, or cocaine-use frequency in the past 6 months but was higher for those who spent more on cocaine before treatment or reported more negative cocaine consequences. Urge did not predict treatment attrition but significantly predicted the amount spent on cocaine during the first 3 months even after covarying the pretreatment amount spent on cocaine. Urge ratings, not mood, were higher just before a relapse than a close call. CONCLUSIONS: Urge to use cocaine predicts early drug use outcomes and is not simply accounted for by the pretreatment quantity of cocaine use. Thus urge is a valid treatment target. PMID- 17690797 TI - Uneven distribution of ethanol in rat brain following acute administration, with the highest level in the striatum. AB - OBJECTIVE: Following acute administration, ethanol has been assumed to be evenly distributed throughout the brain. However, some evidence exists for unequal extracellular levels of ethanol in different areas of the brain, suggesting the existence of locally elevated intracellular levels. The aim of this study was to investigate the relative tissue levels and rates of decline of ethanol in various regions of the brain and in the plasma of rats. METHOD: Adult male Wistar rats (250-300 g) were injected intraperitoneally with a 14% ethanol/water solution at a dose of 1 g/kg of body weight. Brain and plasma samples were analyzed by an enzymatic rate method 30, 60, 90, or 120 minutes after injection for ethanol content. RESULTS: The highest tissue and plasma concentrations of ethanol occurred 30 minutes after administration, with concentrations of ethanol being highest in the striatum. All regions of the brain and plasma followed zero-order kinetics of elimination of ethanol; however, the rate of elimination in the brain declined at a slower rate than in the plasma. The rate remained constant during the 90-minute period. Elimination was slower in the brain than in the plasma. CONCLUSIONS: Ethanol can accumulate to higher levels and can be eliminated more slowly from the brain than from the plasma, thus raising questions about blood alcohol testing as a measure of intoxication. The higher level of ethanol in the striatum, an area implicated in movement regulation and substance addiction, thus may have a significant bearing on the neurological effects and addictive properties of ethanol. PMID- 17690798 TI - Transitions to, and correlates of, suicidal ideation, plans, and unplanned and planned suicide attempts among 3,729 men and women with alcohol dependence. AB - OBJECTIVE: Using a heuristic model of suicidal ideation and behavior, the two objectives were to identify correlates of (1) unique suicide-related outcomes (ideation, planning, planned attempt, unplanned attempt) and (2) specific transitions from one suicide-related category to the next. METHOD: Analyses were conducted with data from the Collaborative Study on the Genetics of Alcoholism (COGA), a six-site family pedigree study of individuals in treatment for alcoholism, their relatives, and control families. There were 3,729 subjects in the analysis; all were age 18 years or older with a diagnosis of current alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised. Lifetime suicidal ideation, planning, and attempts were analyzed retrospectively. Correlates of each lifetime transition were analyzed using a series of multivariate logistic regressions. Multivariate multinomial regression analysis was used to examine correlates of each lifetime outcome. RESULTS: Female gender is uniquely associated with transitions to unplanned and planned attempts. Independent depression and substance-induced depression are associated with transitions to ideation and planning, whereas alcohol-related aggression is correlated with transitions to unplanned attempts. Analyses of suicide-related outcomes show that women are at higher risk for unplanned and planned attempts. Substance use and impairment are related to suicidal plans and attempts but not ideation. Independent and substance-induced depressions are associated with each suicide-related outcome, whereas alcohol related aggression is uniquely related to unplanned attempts. CONCLUSIONS: Data underscore the heterogeneity of suicidal ideation and behavior among alcoholics and indicate the need to make clear distinctions between types of suicidal ideation and behavior in research and prevention efforts. PMID- 17690799 TI - Mechanisms of action in integrated cognitive-behavioral treatment versus twelve step facilitation for substance-dependent adults with comorbid major depression. AB - OBJECTIVE: In a population of veterans with co-occurring substance use disorders and concomitant major depressive disorder, the current study compared mechanisms of change and therapeutic effects relevant to both disorders between integrated, dual disorder-specific cognitive behavioral therapy (ICBT) and twelve-step facilitation (TSF). METHOD: Veterans (N = 148) were given standard pharmacotherapy for depression and were randomly assigned to receive 24 weeks of either TSF or ICBT. Process measures were selected to quantify (1) changes in self-efficacy in ICBT, (2) changes in ability to terminate negative affect in ICBT, (3) twelve-step affiliation (TSA) in TSF, and (4) changes in social support in both conditions. Measures of depression and substance use were administered to all participants before treatment, during treatment, and at the end of treatment. RESULTS: Self-efficacy increased among both TSF and ICBT participants during treatment, whereas self-reported ability to regulate negative affect did not change. Consistent with predictions, TSF participants increased community TSA during treatment, whereas those receiving ICBT reduced TSA. Changes in self efficacy and TSA were associated with improvement in substance use outcomes at the end of treatment. Hypothesized changes in social support were not supported. CONCLUSIONS: Both ICBT and TSF produce improvements in self-efficacy, and these changes are related to substance use outcomes for depressed substance abusers. In TSF, intervention-specific changes in TSA occur during the course of treatment and are related to substance use outcomes. PMID- 17690800 TI - Depressive symptoms and subsequent alcohol use and problems: a prospective study of medical inpatients with unhealthy alcohol use. AB - OBJECTIVE: We sought to determine whether depressive symptoms assessed during hospitalization predicted alcohol use and alcohol-related problems during the subsequent year among medically ill patients. METHOD: The study sample was a cohort of hospitalized medical patients with unhealthy alcohol use who participated in a randomized controlled trial of an alcohol brief intervention. Depressive symptoms at baseline, assessed with the Center for Epidemiologic Studies-Depression Scale (CES-D), were used to predict alcohol use and problems at 3 and 12 months. RESULTS: Of the 341 patients enrolled, 90% (men = 220; women = 88) provided data on at least one follow-up time point during the subsequent year. Gender-stratified longitudinal Pois-son regression models were fit for each alcohol outcome, adjusting for baseline values of age, physical symptoms, randomization group, alcohol outcome, cocaine use, and socioeconomic indicators. Depressive symptoms were significantly associated with drinks per day (men: incidence rate ratio [IRR] = 1.17 per 10-unit increase in CES-D, p < .01; women: IRR = 1.00 per 10-unit increase in CES-D, p = .98) and alcohol-related problems (men: IRR = 1.22 per 10-unit increase in CES-D, p < .001; women: IRR = 1.05 per 10-unit increase in CES-D, p = .39) for men but not for women. They were not significantly associated with the number of days abstinent in men or women. CONCLUSIONS: In hospitalized medical patients with unhealthy alcohol use, depressive symptoms predict subsequent drinks per day and alcohol-related problems among men. These findings suggest that symptoms of depression may be important to consider in treatment planning for male medical patients with unhealthy patterns of drinking. PMID- 17690801 TI - College spring break and alcohol use: effects of spring break activity. AB - OBJECTIVE: This study examined the relationship between spring break vacation and changes in alcohol consumption among college students. Analyses also examined the effects of spring break activity (vacationing with friends, visiting parents, staying in college town, etc.) and selection (i.e., whether heavy drinkers are more likely to vacation with friends) on the spring break/alcohol consumption relationship. METHOD: Participants were 3,720 students (46% male; 90% white; mean age = 17.96) at a large midwestern university. Students were contacted during the fall and spring of their freshman, sophomore, and junior years and were asked to complete online surveys assessing (1) their typical alcohol use, (2) their alcohol use during spring break week, and (3) the activities they engaged in during spring break week. RESULTS: Students who vacationed with friends during spring break dramatically increased their alcohol use. In contrast, students who stayed home or vacationed with parents during spring break were at low risk for excessive alcohol use. CONCLUSIONS: Findings highlight the need for targeted drinking interventions geared specifically toward students taking trips with friends. Findings also highlight the need for further research into both person and environmental variables that predict increases in drinking during spring break. PMID- 17690802 TI - Alcohol-related legal infractions and student retention. AB - OBJECTIVE: The present study employed municipal alcohol-related arrest reports to determine if being arrested/cited reduced the probability of academic retention. METHOD: Alcohol-related legal infraction data implicating 1,310 college students was gathered during a 4-year period. First- through third-year students were identified in the database by cross-checking names in the campus directory. A random sample of nonarrested students functioned as the comparison group (n = 856). Students not appearing in the directory the following year were defined as nonretained students. RESULTS: Retention was not affected by the experience of one alcohol-related legal infraction. Retention odds were 31% lower for students experiencing multiple arrests, however, than for nonarrested or single-arrested students. Gender moderated the association between arrest and retention, with women who had been arrested more likely to return to school than those who had not been arrested. Retention odds were higher for arrested/cited students if they were in their second or third year of college, a fraternity/sorority member, or charged with an offense other than driving under the influence. CONCLUSIONS: Multi-arrested college students are at risk for attrition. Immersion in college life may reduce the odds of attrition among arrested college students. PMID- 17690803 TI - Drinking in conjunction with sexual experiences among at-risk college student drinkers. AB - OBJECTIVE: The primary aim of this article was to examine event-level associations between alcohol use and sexual risk taking across first and repeat oral and vaginal sex encounters among at-risk college student drinkers. METHOD: Participants (n = 221; 51.1% women) provided information on alcohol consumption, sexual activity, and event-level data on their most recent (repeat and first) experiences with oral and vaginal sex. RESULTS: Of the total sample, 80.5% reported ever engaging in oral or vaginal sex. Alcohol use was more likely in new, compared with, repeat sexual partnerships. In addition, for recent vaginal sex experiences with a repeat partner, alcohol use was more likely among those who were less committed to the relationship. For new sexual partnerships, regardless of the type of sex experience, knowing the partner for less time was associated with an increased likelihood of drinking. Alcohol use was also associated with fewer discussions of topics pertinent to safe sexual practices. Finally, there was a tendency for drinking in conjunction with a new vaginal sex experience to be associated with a lower likelihood of contraceptive use. CONCLUSIONS: These findings highlight the need for integrated interventions targeting alcohol use and risky sexual practices among high-risk college students, with a particular focus on alcohol use during new sexual partnerships and the often-overlooked connection between drinking and oral sex experiences. PMID- 17690804 TI - Intimate partner violence perpetration and problem drinking among college students: The roles of expectancies and subjective evaluations of alcohol aggression. AB - OBJECTIVE: The present research examined the effect of alcohol aggression expectancies and subjective evaluations of alcohol's effects on aggression in intimate partner violence (IPV) perpetration among college students. We were interested in determining the extent to which these relationships differed across gender. METHOD: A total of 780 (57.3% female) incoming heavy drinking college freshmen who were between the ages of 18 and 25 years completed self-reported measures of IPV perpetration, alcohol use and problems, and alcohol aggression expectancies and subjective evaluations of those expectancies as part of the baseline assessment for a larger social norms alcohol intervention study. Analyses evaluated the effect of alcohol aggression expectancies and subjective evaluations of those expectancies on IPV perpetration. RESULTS: Results indicated that problem drinking was positively associated with IPV perpetration for those who were lower (beta = .32, p < .001) versus those who were higher (beta = .07, p = ns) in alcohol aggression expectancies. Among men, there was a significantly stronger relationship between problem drinking and IPV perpetration among those who evaluated alcohol's effects on aggression more favorably (beta = .41, p < .001) versus less favorably (beta = .11, p = ns). Among women, there was not a significantly stronger relationship between problem drinking and IPV perpetration at less favorable (beta = .17, p < .05) versus more favorable (beta = .11, p < .06) evaluations of alcohol's effects on aggression. CONCLUSIONS: Findings suggest that, in understanding IPV perpetration, it may not be sufficient to evaluate expected alcohol effects without also including whether those effects are viewed as good or bad. Findings also suggest that the relationship between alcohol problems and IPV perpetration may be stronger and more straightforward for men than for women. PMID- 17690805 TI - Social motives and the interaction between descriptive and injunctive norms in college student drinking. AB - OBJECTIVE: Social norms are a key determinant of young adult drinking, yet little research has evaluated potential interactive effects among different types of norms. The present research was designed to evaluate perceptions of friends' approval of drinking (i.e., injunctive norms) as a moderator of the relationship between perceived prevalence of friends' drinking (i.e., descriptive norms) and personal alcohol consumption. We also evaluated whether social drinking motives further influence this relationship. METHOD: Participants included 1,400 first year college students (61% women) who completed Web-based assessments of descriptive and injunctive norms, personal drinking, and social drinking motives. RESULTS: Results revealed that both descriptive and injunctive norms regarding close friends were uniquely and positively associated with drinking behavior. The relationship between perceived descriptive norms and personal alcohol consumption was stronger among those who also perceived their friends as being more approving of drinking but only among students who reported stronger social motives for drinking. CONCLUSIONS: Descriptive and injunctive norms are distinct constructs and are not interchangeable, having both unique and interactive effects, and vary as a function of social motives. Results are considered in terms of their implications for brief interventions. PMID- 17690806 TI - Alcohol involvement and participation in residential learning communities among first-year college students. AB - OBJECTIVE: Residential learning communities (RLCs) on U.S. college campuses are assumed to build connections between formal learning opportunities and students' living environment. The objective of this longitudinal study was to examine the association between living in RLCs and alcohol misuse among first-year undergraduate students. METHOD: A Web-based survey was self-administered to a stratified random sample of 923 first-year undergraduate students (52.7% women) attending a large Midwestern research university. The sample included 342 students who lived and participated in RLCs (termed RLC) and 581 students who did not participate in RLCs (termed non-RLC). First-year students were asked about their drinking behaviors before college, during their first semester, and approximately 6 months later during their second semester. RESULTS: RLC students reported lower rates of drinking than non-RLC students before college. RLC students reported lower rates of drinking and fewer alcohol-related consequences than non-RLC students during the first and second semesters. Maximum drinks in 1 day increased from precollege to first semester, and this increase was larger among non-RLC students than RLC students. The number of drinks per occasion and alcohol-related consequences increased between first semester and second semester for all students regardless of RLC status. CONCLUSIONS: Lower rates of alcohol misuse among RLC students predate their entrance into college, and the increase in drinking from precollege to first semester is lower in magnitude among RLC students. RLCs' influence involves selection and socialization processes. These findings have implications for prevention and intervention efforts aimed at incoming first-year undergraduate students. PMID- 17690807 TI - Longitudinal differences in alcohol use in early adulthood. AB - OBJECTIVE: Research with college populations suggests that elevated levels of heavy drinking do not generally persist into later adulthood for most individuals. The aims of this study were to determine whether this pattern applies to the population as a whole and to identify those for whom heavy drinking in early adulthood does lead to continued high levels of consumption throughout the life course. METHOD: Patterns of heavy drinking were assessed, and a mixture model was used to evaluate relationships between psychological profiles and trajectories of heavy drinking in early to middle adulthood for race-gender groups. Subjects (N = 5,115; 55% women) were drawn from the longitudinal study of Coronary Artery Risk Development in Young Adults (CARDIA) conducted in four major U.S. cities from 1985 to 1995. RESULTS: Patterns of heavy drinking differed by race and gender, with higher rates observed among whites and men. Heavy drinking was generally most common in the early 20s and dropped sharply thereafter. For a subset with psychological profiles characterized by elevated levels of hostility, anxiety, and depressive symptoms, high rates of heavy drinking persisted into later adulthood; 20% of whites and 50% of blacks in the overall sample were in this subset. Rates of heavy drinking in this group were similar for blacks and whites. CONCLUSIONS: At a population level, heavy drinking in early adulthood tends not to continue into later life. For a subset of psychologically vulnerable individuals, however, early adult heavy drinking persists into the middle adulthood years. PMID- 17690808 TI - Social networks and their influence on drinking behaviors: differences related to cognitive impairment in clients receiving alcoholism treatment. AB - OBJECTIVE: Mechanisms of behavioral change that support positive addiction treatment outcomes in individuals with co-occurring alcohol-use disorders and cognitive impairment remain largely unknown. This article combines person- and variable-centered approaches to examine the interrelated influence of cognitive impairment and social support on stability of and changes in drinking behaviors of Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity) outpatients and aftercare clients (N = 1,726) during the first year after their entry into treatment. METHOD: Latent class analysis identified homogeneous groups of clients based on the nature and extent of social support for abstinence or drinking at treatment entry. Cognitive impairment and drinking outcomes were compared across latent classes, and the interaction between impairment and social support on drinking outcomes was examined using mixture probit regression. RESULTS: Three independent social support classes (frequent positive, limited positive, and negative) were identified. In the outpatient sample, the frequent positive support class had greater cognitive impairment at treatment entry versus other classes, and extent of impairment significantly predicted improved drinking outcomes in this class. In the aftercare sample, the frequent positive and negative support classes had heightened impairment, yet cognitive impairment significantly predicted relatively poorer drinking outcomes in the negative support class only. CONCLUSIONS: Cognitive impairment may increase the influence of the social network on the drinking outcomes of persons receiving treatment for alcohol-use disorders, but more research is needed to understand client characteristics that determine whether this influence is more likely to be manifest as increased salience of helping agents or of hindering agents in the social network. PMID- 17690809 TI - Acute alcohol intoxication impairs controlled search across the visual field. AB - OBJECTIVE: The objective of the two experiments reported was to examine the effects of acute alcohol intoxication and of alcohol expectancies on controlled search across the visual field. METHOD: After receiving an oral dose of 0.5 g/kg alcohol (Experiment 1), an oral dose of 0.7 g/kg alcohol (Experiment 2), or a placebo, participants searched for a target in large arrays of homogeneous distractors that were either highly similar or less similar to the target. Targets were systematically placed at fixation and at visual angles of 2.5 degrees , 5.0 degrees , 7.5 degrees , and 10.0 degrees . RESULTS: Target detection was less accurate in the placebo condition of both experiments than in the no-beverage control group, suggesting that alcohol expectancies had a negative effect on controlled search. The effects of alcohol at the lower dose and of the placebo on visual search were not different (Experiment 1). At the higher dose, the negative effects of target eccentricity on the accuracy of target detection were larger when targets appeared among highly similar distractors, compared with the placebo condition and with a no-beverage control group. Target eccentricity effects on accuracy or speed were not observed at either dose when targets and distractors were dissimilar. CONCLUSIONS: Acute alcohol intoxication at either a low or high dose and placebo-associated intoxication expectancies have a detrimental effect on controlled visual search in large arrays. Acute alcohol intoxication at a high dosage exaggerates the detrimental effects of target eccentricity and of task difficulty on controlled visual search. PMID- 17690810 TI - Contextual influences on alcohol expectancy processes. AB - OBJECTIVE: Context may differentially influence expectancy dimensions, in turn affecting drinking behavior. The present study examined alcohol cue and mood contextual influences on expectancy activation, controlling for more stable self reported expectancy endorsement. We were particularly interested in the specific effects of negative mood on affect-relevant (tension reduction) expectancies. METHOD: Regularly drinking undergraduates (N = 140; 64 female) underwent a mood (stress or neutral) induction procedure and then were presented with alcohol or nonalcohol beverage cues. Participants next completed a computerized expectancy response time task (ETASK), and self-report measures of drinking variables. RESULTS: Individual difference analyses generally replicated previous reports on the inverse relationship between alcohol involvement and ETASK response time. However, examination of contextual effects revealed a different pattern of ETASK responding. Participants exposed to alcohol cues were slower to respond to expectancy items than those in the nonalcohol cue condition. Mood and expectancy type moderated this effect; response time after alcohol cues slowed selectively for those in the stress mood condition and only for tension-reduction expectancy items. CONCLUSIONS: These data highlight the dimensionality of expectancies that comes into relief when contextual factors are considered. Expectancy response times index both facilitation, when examined in the context of drinking expertise, and interference, in response to motivationally relevant stimuli. Our data also support the specificity of contextual effects on those expectancies that are context relevant (i.e., mood). Further consideration of these contextual effects on dynamic expectancy processes may improve prediction of drinking behavior in real-world settings. PMID- 17690811 TI - The validity of the Brief Michigan Alcohol Screening Test (bMAST) as a problem drinking severity measure. AB - OBJECTIVE: The Brief Michigan Alcoholism Screening Test (bMAST) is a 10-item test derived from the 25-item Michigan Alcoholism Screening Test (MAST). It is widely used in the assessment of alcohol dependence. In the absence of previous validation studies, the principal aim of this study was to assess the validity and reliability of the bMAST as a measure of the severity of problem drinking. METHOD: There were 6,594 patients (4,854 men, 1,740 women) who had been referred for alcohol-use disorders to a hospital alcohol and drug service who voluntarily participated in this study. RESULTS: An exploratory factor analysis defined a two factor solution, consisting of Perception of Current Drinking and Drinking Consequences factors. Structural equation modeling confirmed that the fit of a nine-item, two-factor model was superior to the original one-factor model. Concurrent validity was assessed through simultaneous administration of the Alcohol Use Disorders Identification Test (AUDIT) and associations with alcohol consumption and clinically assessed features of alcohol dependence. The two factor bMAST model showed moderate correlations with the AUDIT. The two-factor bMAST and AUDIT were similarly associated with quantity of alcohol consumption and clinically assessed dependence severity features. No differences were observed between the existing weighted scoring system and the proposed simple scoring system. CONCLUSIONS: In this study, both the existing bMAST total score and the two-factor model identified were as effective as the AUDIT in assessing problem drinking severity. There are additional advantages of employing the two factor bMAST in the assessment and treatment planning of patients seeking treatment for alcohol-use disorders. PMID- 17690812 TI - [Antipruritic therapy in atopic eczema]. AB - In patients with atopic eczema, the quality of life is seriously affected by tormenting pruritus. As the pathogenesis of pruritus is not understood, symptomatic measures are the mainstay of treatment along with avoiding aggravating factors. They include emollients, topical and systemic active ingredients and physical therapy (e. g. phototherapy) adjusted to the acuity the disease. Behavioral therapy offers additional support. New treatment modalities, partly still in experimental stage, such as immunomodulators, immunosuppressive agents and opiate antagonists are reserved for nonresponding patients; they too are reviewed. PMID- 17690813 TI - [Guidelines for therapy with fumaric acid ester]. PMID- 17690814 TI - [Guidelines of the Germany Dermatological Society (DDG) for the management of contact allergies with skin tests]. PMID- 17690815 TI - [Comparison of pressure measurements for tubular bandaging material and compression bandages]. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to measure the pressure exerted by a tubular bandaging material developed for the treatment of leg ulcers in vivo in healthy volunteers and to compare the measured values with the pressure exerted by short- or long-stretch medical compression bandages. PATIENTS/METHODS: This was an open, randomized, prospective study on 15 volunteers with healthy veins. Both static pressure and dynamic pressure fluctuations during exercise (10 toe stands) were measured. All volunteers wore tubular bandage on one leg and on the other leg in random order short- or long stretch medical compression bandages. RESULTS: The tubular bandaging material produced a more steady pressure over the 8 hours of usage than both the short- and long-stretch bandages. The test subjects found the tubular bandage more comfortable. CONCLUSIONS: The pressure exerted by the different bandaging materials varied with the experience of the bandager and the material used. The tubular bandage maintains a therapeutically beneficial pressure profile throughout the day and provide the conditions necessary for the reliable prevention of edema, thus promising to be effective in the treatment of venous ulcers. PMID- 17690816 TI - [Lentigo maligna and lentigo maligna melanoma of the cheeks. Analysis of different growth patterns via photographic records]. AB - The dynamics of tumor growth of malignant melanoma may be reconstructed by evaluation of suitable private photographs of the patient. Photohistorical investigations can greatly aid in following the course of development of malignant melanomas and show impressively the slow and protracted growth of initial melanomas. We report on a 90-year-old patient with an in situ melanoma (lentigo maligna) and an invasive lentigo maligna melanoma in the facial region. We were able to obtain complete series of photographs from this patient, which show the different development of the two melanomas over a period of more than 30 years. The first tumor to appear developed very slowly while the later one showed invasive growth after a short time period. Development of multiple primary melanomas is a well recognized phenomenon. The presence of multiple primary melanomas does not appear to be a negative prognostic factor. However, patients with primary melanoma should be made aware of increased risk of development another primary and physicians should do careful total body skin examinations for new primary melanomas as well as for recurrences of the original melanoma. PMID- 17690817 TI - [Ultraviolet-A1 (UVA1) phototherapy in lichen sclerosus et atrophicus]. AB - Two patients, a nine year old girl and a 59 year old woman, presented with extensive and recalcitrant lichen sclerosus et atrophicus (LSA). Both patients were treated with low-dose ultraviolet-A1 (UVA1) phototherapy (340-400 nm) for ten weeks. The cumulative UVA1 dose was 800 J/cm(2), the single UVA1 dose was 20 J/cm(2). After 40 treatment sessions, the previously sclerotic skin lesions had almost completely cleared in both patients. In addition 20-MHz ultrasound examination and histological specimen revealed no further signs of sclerosis. UVA1 phototherapy seems to be a new and effective treatment for LSA with optimal patients' acceptance due to the absence of systemic side effects. UVA1 should be therefore considered as therapeutic option for LSA. PMID- 17690818 TI - [Topical interferon-beta: an additional treatment for ulcerated mycosis fungoides]. AB - The combination of systemic interferon-alpha and systemic photochemotherapy is one of the most effective and most frequently administered treatment regimens for mycosis fungoides. Two patients with mycosis fungoides stage IIb with ulcerated tumors were treated with this regimen. While the plaques responded favorably to the combination therapy, the ulcerated tumors were quite resistant despite treatment for several weeks. When topical interferon-beta in a gel base was added to the regimen, a rapid resolution of the tumors was noticed. This observation suggests topical interferon-beta may be an effective adjuvant strategy to be combined with systemic therapy. PMID- 17690819 TI - [Treatment of plaque-type psoriasis with cream-PUVA therapy]. AB - PUVA-bath therapy has developed into first line topical PUVA therapy in the treatment of psoriasis. Because of logistical and economic problems, bath PUVA may be difficult to administer. Recently, cream-PUVA therapy has been described as an alternative mode of topical therapy. We treated two patients with moderate plaque-type psoriasis with this new topical approach. 0,0006% 8-methoxypsoralen cream was applied for 1 hour, directly followed by increasing doses of UVA. The number of treatments needed for clearance were 34 and 40. The cumulative UVA dosages were 71.6 and 84 J/cm(2) respectively. Our data document that cream-PUVA therapy is an effective and safe variation of topical PUVA therapy, which may develop into first line photochemotherapy for patients with moderate plaque-type psoriasis. PMID- 17690820 TI - [Secondary lymphedema of the hand as a complication of recurrent erysipelas in irritant contact dermatitis]. AB - A 54 year old female hairdresser suffered from occupational irritant contact dermatitis of the hands. As a complication of hand dermatitis, secondary lymphoedema developed following recurrent erysipelas. Fissures occurring in the course of the hand dermatitis presumably enabled entry of streptococci. Treatment of this complication of occupational dermatitis was reimbursed by the Employers Liability Insurance. PMID- 17690821 TI - [A case of corticosteroid allergy]. AB - A 42-year old female patient developed a corticosteroid-induced allergic contact dermatitis. She had severe atopic dermatitis and had received treatment with steroid-containing ointments over a period of decades. After an intra-articular injection with steroids (Predni H-injekt 10((R)), Prednisolone acetate) she developed severe erythema and edema in and around the area of the injection. The allergological assessment revealed a type-IV-sensitivity to group D2 corticosteroids (No methyl substitution on C(16), side chain ester on C(17), possibly a side chain on C(21); according to the latest classification). The occurrence of contact allergy to corticosteroids in Germany ranges between 1.1% and 3.1%. PMID- 17690822 TI - [Successful treatment of angiosarcoma with liposomal-encapsulated doxorubicin]. AB - Cutaneous angiosarcoma is a rare tumor of endothelial origin, often difficult to diagnose and with an unfavorable prognosis. A 85-year-old woman presented with an extensive angiosarcoma involving her right leg. The tumor was not clinically typical but the diagnosis was confirmed histologically. Because of her age and the extent of the tumor, we elected to treat primarily with cobalt-60 irradiation. The tumor unfortunately progressed during radiation therapy, so we decided to begin palliative chemotherapy with liposome-encapsulated doxorubicin. The patient received six cycles of doxorubicin (Caelyx, 15 mg/m(2) i.v. in four week intervals) which was well-tolerated and led to complete regression of angiosarcoma which has lasted for 6 months. Chemotherapy with liposome encapsulated doxorubicin may represent a well-tolerable therapeutic option in cases where surgery and irradiation are not possible or fail. Further studies are necessary to prove the efficacy of doxorubicin therapy in angiosarcoma. PMID- 17690823 TI - [Livedo racemosa with ulcerations. Cyclic therapy with iloprost infusions]. AB - A 43 year old woman suffered from an intermittent painful livedo racemosa at the back since her childhood. Her clinical course was complicated by ulcerations. In careful clinical investigations no signs of an underlying disease could be found, in particular a Sneddon syndrome could be excluded. By means of both conservative and surgical treatments, initial healing of the ulcerations was achieved but relapses occurred. Cyclic infusions of iloprost achieved long-term clearing of the ulcerations and disappearance of the pain. To the best of our knowledge the effectiveness of this treatment has not been described for this disease in the literature. PMID- 17690824 TI - [Injectable silicon--long term sequelae after use in plastic surgery]. AB - The injection of fluid silicone was formerly an acceptable therapy for recontouring post-traumatic or age-related changes of the face and neck. About 20 years after the use of silicone injections, the number of patients presenting with late complications is increasing. Such complications include migration of the silicone, granuloma formation, chronic cellulitis, skin ulcers and and scarring, all of which are difficult to treat medically or surgically. Recent data in the literature support the notion that fluid silicon is a potential carcinogen. These patients require a careful approach combining the limited surgical possibilities with the support needed to live with such a problem. Using a case report as an example, we discuss the diagnostic and therapeutic problems associated with this phenomenon which is relatively uncommon in Europe. PMID- 17690825 TI - [Keloidal granular cell tumor]. AB - A 27-year-old man presented with multiple granular cell tumors of the skin. One tumor presented clinically as a dermatofibrosarcoma or a spontaneous keloid. Histologically, both this tumor and another cutaneous lesion showed striking peritumoral fibrosis. Granular cell tumor should be included in the differential diagnosis of keloidal lesions. The tumors should be removed completely and patients then examined regularly to detect new tumors in a timely fashion. PMID- 17690826 TI - [Centrifugal changing erythrosquamous plaque after a stay in West Africa]. PMID- 17690827 TI - [Indoor allergens]. PMID- 17690829 TI - ["Summa cum laude" / "with distinction". The awards bestowal on the 41st anniversary of the DDG in Berlin, 1-5 May 2001]. PMID- 17690830 TI - [Antimicrobial prophylaxis and therapy of Borrelia burgdorferi infections. New strategic aspects]. PMID- 17690831 TI - Bilateral extraperitoneal uterosacral suspension: a new approach to correct posthysterectomy vaginal vault prolapse. AB - Restoration of apical vaginal support remains a challenging problem for the pelvic reconstructive surgeon. The transvaginal use of the uterosacral-cardinal ligament complex is gaining increasing popularity in the surgical treatment of uterovaginal and posthysterectomy vault prolapse. We describe an extraperitoneal surgical approach using this ligamentous complex to reattach the vaginal apex in women with posthysterectomy vault prolapse and report our surgical experience with this procedure in 123 women over 5 years. The relevant anatomy related to the procedure and risk of ureteric injury with uterosacral suspension is also reviewed. Extraperitoneal vault suspension can be combined with the use of polypropylene mesh if required. The extraperitoneal approach is an alternative procedure in women with vault prolapse with or without concomitant enterocele or where access to the Pouch of Douglas is difficult particularly after previous pelvic surgery. We believe this procedure to have less risk of ureteral injury than the intraperitoneal approach. PMID- 17690832 TI - Toxicity of two pulsed metal exposures to Daphnia magna: relative effects of pulsed duration-concentration and influence of interpulse period. AB - Aquatic organisms living in surface waters experience fluctuating contaminant exposures that vary in concentration, duration, and frequency. This study characterized the role of pulsed concentration, pulsed duration, and the interval between pulses on the toxicity of four metals (Cu, Zn, Se, and As) to Daphnia magna. During 21-d toxicity tests, neonatal D. magna were exposed to single or double pulses. Pulsed concentrations and durations ranged from 32 to 6000 microg/L and 8 to 96 h, respectively. Intervals between two pulses ranged from 24 to 288 h. Mortality, growth, and reproduction were characterized for exposures. For single-pulse exposures of Cu and As, metal concentration had a stronger effect on survival of D. magna than did pulsed duration: pulses with 2X concentration and 1Y duration resulted in more mortality than did pulses with 1X concentration and 2Y duration. In contrast, effects of pulsed duration were stronger than metal concentration for Zn. However, the effects of duration and concentration were similar for Se. The relative effects of pulsed concentration and duration found in the present study revealed that the common method using area under the curve (AUC = concentration x duration) may not always accurately estimate environmental risk from metals (e.g., for Cu, Zn, As). In addition, the occurrence of delayed mortality in the present study revealed that using continuous exposure bioassays might underestimate metal toxicity to aquatic biota. For double-pulse exposures, the toxicity of the second pulse was influenced by the first pulse for all four metals. This influence was dependent on the pulsed concentration and duration and the interval between pulses. Further, toxicity caused by the second pulse decreased as the time between the exposures increased. For all four metals, there existed an interval great enough that the toxicity of the two pulses was independent. This would result in less toxicity for multiple exposures than continuous exposures with the same total exposure duration. The interval time at which the effects of the two pulses were independent increased with increasing concentration. Growth and cumulative reproduction of D. magna over 21 d were not significantly affected by pulsed exposures examined in the present study, indicating recovery of the organisms. PMID- 17690833 TI - Ecotoxicity assessment of river sediments and a critical evaluation of some of the procedures used in the aquatic oligochaete Tubifex tubifex chronic bioassay. AB - Sediment from 27 river sites in Northern Spain were tested with the aquatic oligochaete Tubifex tubifex (Annelida, Clitellata) 28-day chronic bioassay. Sampling sites were chosen from those established by regulatory water agencies for water-quality surveillance networks in rivers of the Basque Country and the Ebro basin. Inclusion of this test in an assessment programme with chemical and benthic community data currently collected by the water agencies will enable a more comprehensive ecotoxicological assessment. Cocoon and adult biomass were used as end points in addition to percent mortality, number of cocoons, young per adult, and percent of hatch end points as proposed in the American Society for Testing and Materials (ASTM) guidelines. Ecotoxicity assessment of the sediments was carried out by comparing mortality, growth, and reproduction in test sediments with their respective experimental control. Cluster analysis resulted in four groups of sediments that were compared using multidimensional scaling ordination (MDS), and the contribution of toxicity end points and the relationship of chemical variables to the MDS ordination space were assessed by principal component correlation (PCC). A gradient of sediments from nontoxic (4 controls and 6 sediments) to severely toxic (8 sediments) was observed, with all of the original biological end points contributing significantly to the ordination. The most toxic sediments could be separated into 2 groups based on the effects of pollutants on mortality (4 sediments) or on reproduction and growth (4 sediments). Remaining sites were grouped together as toxic sediments but showed a variable degree of sublethal effects. The acceptability criteria for validation of the bioassay, as recommended by the ASTM, measured in the control batch of each bioassay were achieved for survival and cocoon production (coefficient of variation [CV] and variability with regard to their average calculated through laboratory control charts). However, the ASTM criteria were found to be strict for the CV for total number of young, and a more realistic criterion is proposed. New criteria are also suggested to improve quality assurance of the bioassay, namely, a minimum number of cocoons per adult in the control group. PMID- 17690834 TI - Effects of HMX-lead mixtures on reproduction of the earthworm Eisenia andrei. AB - High metal (e.g., Pb) concentrations are typically found in explosive contaminated soil, and their presence may increase, decrease, or not influence toxicity predicted on the basis of one explosive alone (e.g., HMX). Nevertheless, few data are available in the scientific literature for this type of multiple exposure. Soil organisms, such as earthworms, are one of the first receptors affected by the contamination of soil. Therefore, a reproductive study was conducted using Eisenia andrei in a forest-type soil. Both HMX and Pb decreased reproduction parameters (number of total cocoons, hatched cocoons, and surviving juveniles) individually. Based on the total number of cocoons, HMX was more toxic in a forest soil than Pb, with EC(50) of 31 mg kg(-1), and 1068 mg kg(-1), respectively. The slope of the concentration-response curve was significantly greater in the case of Pb, which is consistent with the possibility that the two compounds do not act on the same target site. The response-addition model was used to predict the response of earthworms and to test for interaction between the two contaminants. The predicted toxicity was not significantly different than the observed toxicity, implying that Pb and HMX were considered noninteractive compounds. The combined action of Pb-HMX may be described, therefore, as dissimilar-noninteractive joint action in a forest soil. The results illustrate the relevance of considering the presence of metals in the risk assessment of explosive-contaminated sites because metals can add their toxicity to explosives. Extension of this study to other types of soil and other metals would improve the understanding of toxicity at these sites. PMID- 17690835 TI - Dissolution of dead corals by euendolithic microorganisms across the northern Great Barrier Reef (Australia). AB - Spatial and temporal variabilities in species composition, abundance, distribution, and bioeroding activity of euendolithic microorganisms were investigated in experimental blocks of the massive coral Porites along an inshore offshore transect across the northern Great Barrier Reef (Australia) over a 3 year period. Inshore reefs showed turbid and eutrophic waters, whereas the offshore reefs were characterized by oligotrophic waters. The euendolithic microorganisms and their ecological characteristics were studied using techniques of microscopy, petrographic sections, and image analysis. Results showed that euendolithic communities found in blocks of coral were mature. These communities were dominated by the chlorophyte Ostreobium quekettii, the cyanobacterium Plectonema terebrans, and fungi. O. quekettii was found to be the principal agent of microbioerosion, responsible for 70-90% of carbonate removal. In the offshore reefs, this oligophotic chlorophyte showed extensive systems of filaments that penetrated deep inside coral skeletons (up to 4.1 mm) eroding as much as 1 kg CaCO3 eroded m(-2) year(-1). The percentage of colonization by euendolithic filaments at the surface of blocks did not vary significantly among sites, while their depths of penetration, especially that of O. quekettii (0.6-4.1 mm), increased significantly and gradually with the distance from the shore. Rates of microbioerosion (0.1-1.4 kg m(-2) after 1 year and 0.2-1.3 kg m(-2) after 3 years of exposure) showed a pattern similar to the one found for the depth of penetration of O. quekettii filaments. Accordingly, oligotrophic reefs had the highest rates ofmicrobioerosion ofup to 1.3 kg m(-2) year(-1), whereas the development of euendolithic communities in inshore reefs appeared to be limited by turbidity, high sedimentation rates, and low grazing pressure (rates < 0.5 kg m(-2) after 3 years). Those results suggest that boring microorganisms, including O. quekettii, have a significant impact on the overall calcium carbonate budget of coral reef ecosystems, which varies according to environmental conditions. PMID- 17690836 TI - Endophytic bacterial diversity in rice (Oryza sativa L.) roots estimated by 16S rDNA sequence analysis. AB - The endophytic bacterial diversity in the roots of rice (Oryza sativa L.) growing in the agricultural experimental station in Hebei Province, China was analyzed by 16S rDNA cloning, amplified ribosomal DNA restriction analysis (ARDRA), and sequence homology comparison. To effectively exclude the interference of chloroplast DNA and mitochondrial DNA of rice, a pair of bacterial PCR primers (799f-1492r) was selected to specifically amplify bacterial 16S rDNA sequences directly from rice root tissues. Among 192 positive clones in the 16S rDNA library of endophytes, 52 OTUs (Operational Taxonomic Units) were identified based on the similarity of the ARDRA banding profiles. Sequence analysis revealed diverse phyla of bacteria in the 16S rDNA library, which consisted of alpha, beta, gamma, delta, and epsilon subclasses of the Proteobacteria, Cytophaga/Flexibacter/Bacteroides (CFB) phylum, low G+C gram-positive bacteria, Deinococcus-Thermus, Acidobacteria, and archaea. The dominant group was Betaproteobacteria (27.08% of the total clones), and the most dominant genus was Stenotrophomonas. More than 14.58% of the total clones showed high similarity to uncultured bacteria, suggesting that nonculturable bacteria were detected in rice endophytic bacterial community. To our knowledge, this is the first report that archaea has been identified as endophytes associated with rice by the culture independent approach. The results suggest that the diversity of endophytic bacteria is abundant in rice roots. PMID- 17690837 TI - Long-term follow-up of 5 patients with intracranial germinoma initially treated by chemotherapy alone. AB - BACKGROUND: High rates of overall- and event-free survival have been reported in patients with intracranial germinoma treated by radiotherapy. We report the long term results after treatment initially with chemotherapy, but without radiation. PATIENTS AND METHOD: Five patients with an intracranial germinoma were treated with 2 cycles of etoposide and cisplatin, without radiotherapy. All achieved complete remission; 3 suffered recurrence within 2 years and were again treated with 2 cycles of etoposide and cisplatin followed by radiotherapy. RESULTS: At long-term follow-up, each of the 5 patients was in complete remission without further recurrence. Each patient with a neurohypophyseal germinoma who presented with endocrinopathy had initially recovered endocrinological function. CONCLUSION: In a patient with a germinoma chemotherapy, and restriction of radiation to those with recurrence may allow restoration of hypophyseal function damaged by the intracranial germinoma without compromising long term survivial. PMID- 17690838 TI - Complications in subthalamic nucleus stimulation surgery for treatment of Parkinson's disease. Review of 272 procedures. AB - BACKGROUND: Deep brain stimulation (DBS) is a surgical technique used to alleviate symptoms in patients with advanced Parkinson's disease (PD). It is a reversible procedure and its effect is based on electrical modulation of the nervous system and has considerable advantages in morbidity-mortality when compared to lesion techniques such as thalamotomy and/or pallidotomy. The objective was to evaluate the adverse events during the surgical placement of leads in the subthalamic nucleus for the treatment of Parkinson's disease. METHODS: A retrospective data collection was made in a total of 130 patients in whom we performed 272 procedures for the implant of leads in the subthalamic nucleus between May 1998 and December 2005. All the patients were operated by the same surgeon, in the same institution and with the same surgical methodology. The complications under evaluation were: aborted procedure, misplaced leads, intracranial haemorrhage, seizures, hardware complications and other complications. RESULTS: 130 patients were treated (62 women, 68 men; average age 62 (36-74) years). The average duration of disease from the time of diagnosis to operation was 15.3 years (4-28 years) and the mean follow-up was of 37 months (3 93 months). One hundred and twenty four patients were implanted bilaterally and 6 unilaterally. 62% did not present any complications, 30% had one complication, and 8% more than one complication. Aborted procedures amounted to 5.14% of all procedures, misplaced leads 2.2%, intracranial haemorrhage 3.3%, seizures 4.7%, hardware complications 1.8% and other complications 5.1%. CONCLUSION: Deep brain stimulation surgery is an effective and safe method to treat Parkinson's disease with a low incidence of permanent adverse events. PMID- 17690839 TI - Intracellular application of TNF-alpha impairs cell to cell communication via gap junctions in glioma cells. AB - Human gliomas are the most common class of brain neoplasm. In order to better characterize their response to inflammation, we evaluated the influence of tumor necrosis factor alpha (TNF-alpha) on the coupling behaviour and the membrane resting potential (MRP) of glioma cells (F98 glioma cell line) compared to primary astrocytes. In contrast to cultured primary astrocytes which exhibited a profound inhibition of gap junction mediated intercellular communication (GJIC), extracellular exposure of TNF-alpha to F98 glioma cells gained no effect on the functional coupling. Whereas, intracellular application of TNF-alpha into the glioma cells elicited similar effects as those found in primary astrocytes indicating a compromised accessibility of the TNF-alpha receptor in F98 cells. Western blotting, immunocytochemical staining and real time RT PCR analysis revealed a differential expression and distribution of TNF-alpha receptor 1 (TNFR1) in the glioma cells. Connexin 43 (Cx43) is the major astrocytic gap junction protein which when phosphorylated has been shown to reveal altered gating properties. Here we show that TNF-alpha increases the level of phosphorylated Cx43 in primary astrocytes but not in the F98 glioma cells. Our observations could account for the decreased regulatory effects of TNF-alpha on GJIC of F98 glioma cells. PMID- 17690840 TI - Expression of oligodendroglial differentiation markers in pilocytic astrocytomas identifies two clinical subsets and shows a significant correlation with proliferation index and progression free survival. AB - The growth pattern of pilocytic astrocytoma (PAs) is unpredictable. Gene expression profiling has recently demonstrated an inverse relationship between myelin basic protein (MBP) expression and progression free survival (PFS) in PAs. We present here the pattern of expression of oligodendroglial differentiation markers (ODMs) in PAs by immunohistochemistry and their correlation with PI and PFS. Sixty-four cases of PA were reviewed and representative sections were stained for Ki-67 and ODMs, including MBP, platelet-derived growth factor receptor-alpha (PDGFR-alpha), Olig-1, and Olig-2. Sections were graded semi quantitatively for intensity (I: 0-3+) and extent (E: 0-4+) of staining. PI was expressed as a percentage of Ki-67 positive cells. Immunoreactivity of MBP, PDGFR alpha, Olig-1, and Olig-2 was observed in 84, 56, 97, and 75% of cases, respectively. There was a statistically significant inverse correlation between MBP expression and PI (r (2) = .696, p = .014). A positive correlation was observed between PDGFR-alpha and PI (r (2) = .727, p = .011). Further analysis showed a significant difference in PFS between low expressors [I + E score < or = 3] and high expressors (I + E score > or = 4) for PDGFR-alpha with p < .001. Notably, there was a significant difference in PFS between high expressors of MBP and high expressors of PDGFR-alpha with p < .001. These results suggest that expression of ODMs, especially MBP and PDGFR-alpha, may identify two clinical subsets of PA. In addition, we have shown the expression of 4 different ODMs in PAs, which may support the possibility that PAs arise from oligodendrocyte progenitor/precursor cells probably similar to the O2A progenitor cells in the mouse. PMID- 17690841 TI - T-DNA tagged knockout mutation of rice OsGSK1, an orthologue of Arabidopsis BIN2, with enhanced tolerance to various abiotic stresses. AB - T-DNA-tagged rice plants were screened under cold- or salt-stress conditions to determine the genes involved in the molecular mechanism for their abiotic-stress response. Line 0-165-65 was identified as a salt-responsive line. The gene responsible for this GUS-positive phenotype was revealed by inverse PCR as OsGSK1 (Oryza sativa glycogen synthase kinase3-like gene 1), a member of the plant GSK3/SHAGGY-like protein kinase genes and an orthologue of the Arabidopsis brassinosteroid insensitive 2 (BIN2), AtSK21. Northern blot analysis showed that OsGSK1 was most highly detected in the developing panicles, suggesting that its expression is developmental stage specific. Knockout (KO) mutants of OsGSK1 showed enhanced tolerance to cold, heat, salt, and drought stresses when compared with non-transgenic segregants (NT). Overexpression of the full-length OsGSK1 led to a stunted growth phenotype similar to the one observed with the gain-of function BIN/AtSK21 mutant. This suggests that OsGSK1 might be a functional rice orthologue that serves as a negative regulator of brassinosteroid (BR)-signaling. Therefore, we propose that stress-responsive OsGSK1 may have physiological roles in stress signal-transduction pathways and floral developmental processes. PMID- 17690842 TI - Hyponatremia and comparison of NT-pro-BNP concentrations in blood samples from jugular bulb and arterial sites after traumatic brain injury in adults: a pilot study. AB - BACKGROUND: Hyponatremia after traumatic brain injury (TBI) may influence neurological function and treatment. A causal relationship between elevated serum concentrations of Type B natriuretic peptide (BNP) and hyponatremia has been implied after subarachnoid hemorrhage and other neurosurgical disorders, although the source of BNP has not been identified. We evaluated if hyponatremia and increased BNP occur after TBI and if BNP is produced/released by the brain within 24 h after injury. RESULTS: NT-proBNP was measured in concomitant jugular venous and arterial blood samples within 24 h after TBI. NT-proBNP was elevated in both samples in six patients (24%). One patient (4%) showed an increased jugular NT proBNP concentration above a normal arterial concentration, suggesting a brain source. In the other 24 patients the difference between jugular and arterial NT proBNP was not statistically significant. Hyponatremia (< or =136 mEq/l) also occurred in six patients (24%), but only two (8%) had both increased arterial NT proBNP and hyponatremia. In both the urine sodium was slightly elevated above normal, but not statistically different from other patients. The difference in serum sodium between hypo- and normo-natremic groups was significant, but mean NT proBNP and jugular:arterial NT-proBNP differences were not. CONCLUSIONS: In this pilot study BNP is elevated within 24 h after TBI in some patients. However, it does not originate from the brain and increased NT-proBNP concentrations are not consistently associated with hyponatremia or increased urinary sodium loss. PMID- 17690843 TI - To become a pain specialist one has to understand the nervous system, yet the specialists of the nervous system still have a long way to go before understanding pain. PMID- 17690844 TI - Capgras delusion. PMID- 17690845 TI - Different roles of matrix metalloproteinases-2 and -9 after human ischaemic stroke. AB - Accumulating data suggest that matrix metalloproteinases (MMPs), in particular MMP-2 and MMP-9, are deleterious after acute ischaemic stroke. A beneficial effect of MMPs in the repairing phases of cerebral ischaemia has also been proposed. This study investigated the relationship between MMP-2 and MMP-9 and stroke subtypes, clinical recovery and haemorrhagic transformation (HT). We measured MMP-9 and MMP-2 plasma levels in 29 patients with ischaemic stroke at days one and seven. MMP-2 levels increased only in lacunar strokes, whilst MMP-9 increased only in patients with more severe stroke. Basal MMP-2 levels were higher in patients with stable or recovering symptoms whilst MMP-9 values at day seven were correlated with worse clinical outcome. No differences related to the presence of HT were found. This study sustains a different behaviour of MMPs after ischaemic stroke. MMP-2 seems to be expressed early and related to better outcome, whilst MMP-9 seems to be late and related to more severe stroke. PMID- 17690846 TI - Autosomal dominant hereditary spastic paraplegia: report of a large Italian family with R581X spastin mutation. AB - We describe a large kindred with a typical pure form of autosomal dominant hereditary spastic paraplegia (ADHSP). On the basis of maximum LOD score of 1.94 at theta (max)=0 with marker D2S367, we obtained suggestive evidence for linkage of ADHSP to SPG4 locus. Denaturing high-performance liquid chromatography (DHPLC) and direct sequence analysis allowed us to identify a nonsense mutation (1741* C>T) in exon 17 of the Spastin gene. This transition, carried by all the affected family members and two apparently healthy individuals, lead to truncation of the last 36 amino acids in the C-terminus of the protein. These results confirm the existence of mutation in the SPG4 gene with a reduced penetrance, indicating that other genetic or environmental factors are required to trigger full-blown disease. PMID- 17690847 TI - Somatostatin receptor scintigraphy in the follow-up of myasthenia gravis. AB - To evaluate the potential value of somatostatin receptor scintigraphy (SRS) using 111In-DTPA (diethylenetriaminepenta acetic acid)-D-Phe1-octreotide (111In pentetreotide) in patients with recurring or persisting symptoms of myasthenia gravis (MG), 14 consecutive cases with such supplemental receptor imaging during neurological routine follow-up were retrospectively evaluated in this study. All 14 patients underwent SRS in addition to chest computed tomography (CT). Mean follow-up after imaging was 34 months. Eight patients had previous thymectomy, and three patients were referred to surgery after scintigraphy and chest CT. SRS was positive in one of the 14 patients with local recurrence of thymoma and pleural invasion, and negative in the remaining 13 patients. CT was positive for thymoma in three patients, inconclusive in four patients and negative in seven patients. In conclusion, while SRS may be able to detect thymoma lesions including metastases, it seems of limited value in patients with inconspicuous CT findings. Our initial experience fails to point out a benefit of SRS in the management of persisting or recurring MG (with regard to detection of thymic disorders) compared to CT. Whether SRS is useful for differentiating thymoma from non-neoplastic thymic disease may be investigated by larger series. A predominant proportion of patients with unsatisfactory treatment response, however, continue to suffer an unfavourable clinical course despite absent evidence for thymic pathology. PMID- 17690848 TI - Clinical presentation of CADASIL in an Italian patient with a rare Gly528Cys exon 10 NOTCH3 gene mutation. AB - CADASIL is an autosomal dominant arteriopathy characterised by diffuse white matter lesions and small subcortical infarcts on neuroimaging and a variable combination of recurrent cerebral ischaemic episodes, cognitive deficits, migraine with aura and psychiatric symptoms. It is caused by mutations in the NOTCH3 gene encoding a NOTCH3 receptor protein. Here, we describe the genetical, clinical, neuropsychological and neuroimaging findings in an Italian CADASIL patient with a rare mutation in exon 10 leading to a Gly528Cys substitution. PMID- 17690849 TI - A case of unilateral hemispheric encephalitis. AB - Herein we report a case of encephalitis involving the unilateral hemisphere, with a clinical course different from that of Rasmussen syndrome. A 44-year-old man visited us because of headache and language abnormality. Cerebrospinal fluid examination showed lymphocytosis with increased level of protein. Brain MRI showed abnormal findings limited to the unilateral hemisphere. The symptoms and signs improved without any specific antiviral treatment in a week. However, language disturbance and right hemiparesis developed after a week. Steroid therapy was effective. He recovered without any neurologic sequelae. Our case was unusual encephalitis involving the unilateral hemisphere, which was benign and steroid-responsive. PMID- 17690850 TI - The case of lost Wilma: a clinical report of Capgras delusion. AB - This detailed clinical report of a typical Capgras delusion (CD) in a demented patient is presented in order to foster future descriptions in neurological cases. In the framework of a recently developed model of familiar person processing, it is suggested that CD might be due to a dysfunction at the level of Person Identity Nodes. Prefrontal impairment is held to represent a critical factor leading to a failure of belief evaluation. PMID- 17690851 TI - Idiopathic familial trigeminal neuralgia: a case report. AB - Trigeminal neuralgia (TN) is paroxysmal, lancinant pain often described as an "electric wave" by patients, with involvement of the divisions of the fifth cranial nerve. Demyelinating, compressive, ischaemic diseases are involved in the physiopathology of TN, but there are some cases without explanation. Familial TN (FTN) is a rare condition, about 1%-2% of all TN cases, while sporadic cases are the most common. To date, there have been about 126 reports of FTN. We describe the case of a 66-year-old man who had been complaining for 3 years of right-side paroxysmal lancinating pain in the second division of the fifth cranial nerve. A brain MRI with angiographic sequences did not show neurovascular conflicts or other pathological conditions. The patient had a family history of TN, which had been diagnosed in 3 other family members (father, sister and first cousin), who had undergone medical or surgical treatment for TN. There was no family history of hypertension, metabolic disorders, neurological or traumatic diseases. Animal studies have shown a probable involvement of genes codifying for calcium channels as the starting alterations in trigeminal excitability. Our FTN could be a good model to investigate the role of gene mutations in this condition. PMID- 17690852 TI - Progressive myoclonic ataxia with intrathecal immune activation in six patients. AB - In six patients with slowly progressive sporadic cerebellar ataxia and cortical multifocal action myoclonus, cerebrospinal fluid (CSF) IgG index was persistently very high (1.2-6.7) and numerous oligoclonal bands were detected. Progressive cognitive impairment and MRI cerebellar and cerebral atrophy were observed. No serum antibodies were found. Various degenerative, metabolic, inflammatory and systemic diseases were excluded. The cerebellum may be the main target of a degenerative or immune process and releases antigens that, enhancing a compartmentalised (auto)immune response, as suggested by the persistent intrathecal activation, could lead to further cerebellar damage. As the frequency of CSF oligoclonal banding in myoclonic ataxia is unknown, our patients' disease might represent a hitherto unreported entity or a subset of progressive myoclonic ataxia. PMID- 17690853 TI - Clinical and electrodiagnostic follow-up of an adolescent poisoned with thallium. AB - We report a six-year clinical and electrodiagnostic follow-up of an adolescent patient with acute thallium poisoning from attempted suicide. During the acute stage the patient showed gastrointestinal disturbances, alopecia, and clinical and electrodiagnostic signs of severe polyneuropathy. Three years after poisoning, his neurological symptomatology was making progress, and electrophysiologic signs of peripheral neuropathy were mainly confined to lower limbs. Six years after intoxication, he was still complaining of weakness and sensory disturbances at the level of distal lower extremities; his neurologic and electrodiagnostic abnormalities affected mainly the feet. In this case report we underline the importance of early diagnosis and treatment to prevent neurological damage and the role of serial electromyographic and nerve conduction studies in thallium poisoning. These investigations allowed the authors to depict the electrophysiologic course of peripheral nervous system involvement over six years following poisoning. PMID- 17690854 TI - Variable responses to rituximab treatment in neuromyelitis optica (Devic's disease). AB - We have described two cases of Devic's disease patients treated with rituximab with different outcomes. The results indicate that there may be early unresponsiveness in very aggressive cases. Well designed clinical trials are needed to assess treatment effects in such a rare disease. PMID- 17690855 TI - Venous congestive myelopathy in spinal dural arteriovenous fistula mimicking neoplasia. AB - Spinal dural arteriovenous fistulas (SDAVF) are the most common acquired arteriovenous shunts that occur in adults. By increasing venous pressure in the spinal venous system they are a cause of venous congestive myelopathy. We report the case of a patient with a SDAVF mimicking, on magnetic resonance imaging, the presence of a spinal cord tumour due to an unusual pattern of enhancement after gadolinium administration. PMID- 17690856 TI - Ethical questions in the treatment of subjects with dementia. Part I. Respecting autonomy: awareness, competence and behavioural disorders. AB - The document deals with some ethical issues raised by the treatment of demented people. In particular the conceptual and empirical aspects of the assessment of awareness and competence of these patients are analysed, as well as the dilemmas related to the treatment of behavioral disorders. PMID- 17690857 TI - Differentiating between hygromas and haematomas. PMID- 17690858 TI - [Urology in Vienna around 1900. A study of the times]. PMID- 17690859 TI - [Incontinence in elderly patients]. PMID- 17690860 TI - [Clinical experience with a versatile urologic system]. PMID- 17690861 TI - [Analysis of gene expression of human tumor cells in testicular tumor]. PMID- 17690862 TI - [How come? What for? Why? Questions on the topic of "Botulinum toxin in urology"]. PMID- 17690863 TI - [Resveratrol and newly synthetized resveratrol analogs in therapy of prostate carcinoma]. PMID- 17690865 TI - Evaluating benefits and harms in intensive care research. PMID- 17690864 TI - Lack of agreement between thermodilution and electrical velocimetry cardiac output measurements. AB - OBJECTIVE: The modified algorithm for the non-invasive determination of cardiac output (CO) by electrical bioimpedance-electrical velocimetry (EV)-has been reported to give reliable results in comparison with echocardiography and pulmonary arterial thermodilution (PA-TD) in patients either before or after cardiac surgery. The present study was designed to determine whether EV-CO measurements reflect intraindividual changes in CO during cardiac surgery. DESIGN: Prospective, observational study. SETTING: Operating room (OR) and intensive care unit (ICU) of a university hospital. PATIENTS: Twenty-nine patients undergoing elective cardiac surgery. INTERVENTIONS: None. MEASUREMENTS: CO was determined simultaneously by PA-TD and EV after induction of anesthesia (t1) and 4.9+/-3.5 h after ICU admission (t2). RESULTS: TD-CO was 3.9+/-1.4 and 5.4+/-1.1 l/min at t1 and t2 (p < 0.0001). EV-CO was 4.3+/-1.1 and 4.9+/-1.5 l/min at t1 and t2 (p = 0.013). Bland-Altman analysis showed a bias of -0.4 l/min and 0.4 l/min and a precision of 3.2 and 3.6 l/min (34.3% and 67.4%) at t1 and t2, respectively. Analysis of the individual pre- to postoperative changes in CO with both methods revealed bidirectional changes in n = 12 patients and unidirectional changes with a difference greater than 50% and less than 50% in n = 9 and n = 8 patients, respectively. CONCLUSIONS: The disagreement between PA-TD and EV-CO measurements after anesthesia induction and after ICU admission, as well as the fact that thoracic bioimpedance did not adequately reflect pre- to postoperative changes in CO, questions the reliability of EV-CO measurements in cardiac surgery patients and contrasts sharply with previous studies. PMID- 17690866 TI - Mixed effects modeling of weight change associated with placebo and pregabalin administration. AB - OBJECTIVE: To characterize change from baseline weight over time for pregabalin and placebo administration. METHODS: Asymptotic fraction of baseline weight was modeled with a nonmixture model and a mixture model as a function of baseline weight, exposure, time, covariate effects, and subject-specific random effects. Model fit was assessed using standard diagnostic plots. Predictive performance was assessed using both data similar to the original data, and open-label data. RESULTS: The nonmixture model indicated that a typical patient (baseline weight 82 kg) receiving placebo or 300 mg/day pregabalin approached an asymptotic fractional change from baseline weight of [mean (95% prediction interval for typical individual)] 0.7% (-5.5% to 7.4%) or 2.5% (-3.8% to 9.1%), respectively, with a half-life of 17 days. Substantial between-subject variability is observed, with some drug-treated subjects remaining weight neutral or losing weight, at all levels of exposure. Structural fixed effects parameters for the two submodels (mixture model) were in close agreement with each other and with those for the nonmixture model. The mixture model described two subpopulations differing in interindividual variability. No significant interindividual-varying covariates influencing the mixture probabilities were identified other than exposure. Both models had adequate fit; both models performed well during external validation. Predictive performance (nonmixture model) was adequate to ~900 days. CONCLUSIONS: The weight of a typical 82-kg patient receiving placebo or pregabalin (300 mg/day) approaches an asymptotic fractional change from baseline weight of 0.7%, or 2.5%, respectively, with a half-life of 17 days. Substantial between-subject variability remains unexplained. PMID- 17690867 TI - Technical note: the "double eye" technique as a modification of autologous chondrocyte implantation for the treatment of retropatellar cartilage defects. AB - Retropatellar cartilage defects treated with autologous chondrocyte implantation (ACI) are still associated with inferior clinical outcome compared to defects being located on the femoral condyles. This is partly because of the biomechanical characteristics of the patellofemoral section of the joint, in which, in contrast to the medial or lateral compartments of the knee joint, prejudicial shearing forces are dominant. The patellar ridge has a particularly important role in the reduction of these shearing forces. The double eye technique was developed as a modification of ACI with preserving the important patellar ridge for the treatment of retropatellar cartilage defects extending beyond the patellar ridge and involving the medial and lateral retropatellar facets. This technique provides for a separate reconstruction of the medial and the lateral facets by means of ACI, but the ridge region is preserved to maintain the original thickness of cartilage at this point. The present paper describes the "double eye" technique as a modification of autologous chondrocyte transplantation (ACI) for treatment of cartilage defects of the patella, that involve both lateral and medial facets, and gives first clinical results of 11 patients. The average follow-up was 41.6 (+/-15.0) months, and the average age at diagnosis was 40.4 (+/-10.1) years. The Lysholm score, the subjective IKDC score, and the ICRS score were the instruments used to measure the outcome. This paper focuses on the introduction of the double eye technique with preservation of the patella ridge in the treatment of retropatellar cartilage lesion. Nevertheless, first clinical results of 11 patients are given, with an average Lysholm score of 75 (+/-14) points and an average subjective IKDC score of 60 (+/-14). Objective evaluation according to the criteria of the IKDC score showed very good or good treatment results in 9 of the 11 cases, with only 2 poor results. In conclusion, with the double eye modification presented in this paper, the potential for successful results in the treatment of combined cartilage defects of the medial and lateral facets of the patella is high; it takes into account the specific biomechanical properties of the patella ridge. The procedure needs further evaluation in clinical studies involving larger numbers of patients so that the indications can be determined more precisely. PMID- 17690868 TI - Examining the clinical efficacy of bupropion and nortriptyline as smoking cessation agents in a rodent model of nicotine withdrawal. AB - RATIONALE: At present, there is a lack of an established animal model to demonstrate the clinical efficacy of smoking cessation agents in the laboratory. The aim of this study was to compare the effects of the antidepressants bupropion and nortriptyline, clinically proven smoking cessation aids, within a rodent model of a nicotine withdrawal based on somatic measures. MATERIALS AND METHODS: Male hooded Lister rats were chronically exposed to nicotine (3.16 mg kg1 day1) for 7 days via SC implanted ALZET osmotic minipumps. Animals were acutely pre treated with bupropion (10, 30 or 60 mg/kg, IP) or nortriptyline (1.5, 4.7 and 15 mg/kg, IP), and nicotine withdrawal was precipitated by mecamylamine (1 mg/kg). RESULTS: Precipitation of nicotine withdrawal led to an increase in somatic signs including body shakes, chews, eye blinks, foot licks, head shakes and ptosis. Bupropion dose-dependently decreased the total abstinence scores and reduced the occurrence of some individual somatic signs. Pre-treatment with 60 mg/kg bupropion did not result in a significant increase in total abstinence scores or individual somatic signs scores after mecamylamine challenge, compared to the mecamylamine control group, suggesting nicotine withdrawal is fully attenuated at this dose. Similarly, the highest dose of nortriptyline reduced total abstinence scores and some individual somatic signs to the level of the mecamylamine control group. However, nortriptyline was only effective at alleviating somatic measures of withdrawal at doses which also suppressed locomotor activity. CONCLUSION: In concurrence with clinical findings proposing alleviation of withdrawal states as a possible mechanism of bupropion and nortriptyline's smoking cessation action, both drugs were found to ameliorate somatic signs of nicotine withdrawal in rodents. PMID- 17690869 TI - Serotonin transporter binding after recovery from eating disorders. AB - RATIONALE: Several lines of evidence suggest that altered serotonin (5-HT) function persists after recovery from anorexia nervosa (AN) and bulimia nervosa (BN). OBJECTIVES: We compared 11 subjects who recovered (>1 year normal weight, regular menstrual cycles, no binging or purging) from restricting-type AN (REC RAN), 7 who recovered from bulimia-type AN (REC BAN), 9 who recovered from BN (REC BN), and 10 healthy control women (CW). MATERIALS AND METHODS: Positron emission tomography (PET) imaging with [11C]McN5652 was used to assess the 5-HT transporter (5-HTT). For [11C]McN5652, distribution volume (DV) values were determined using a two-compartment, three-parameter tracer kinetic model, and specific binding was assessed using the binding potential (BP, BP=DVregion of interest/DVcerebellum-1). RESULTS: After correction for multiple comparisons, the four groups showed significant (p<0.05) differences for [11C]McN5652 BP values for the dorsal raphe and antero-ventral striatum (AVS). Post-hoc analysis revealed that REC RAN had significantly increased [11C]McN5652 BP compared to REC BAN in these regions. CONCLUSIONS: Divergent 5-HTT activity in subtypes of eating disorder subjects may provide important insights as to why these groups have differences in affective regulation and impulse control. PMID- 17690870 TI - Miniaturized monolithic disks for immunoadsorption of cardiac biomarkers from serum. AB - Immunoadsorbers based on 2.0 x 6.0 mm i.d., epoxy-bearing, methacrylate-based monolithic disks were developed in order to target myoglobin and N-terminal pro natriuretic peptide (NT-proBNP), two biomarkers involved in cardiovascular disease. In both cases, antibodies were successfully coupled to the polymeric disk material. The developed immunoadsorbers permitted the selective isolation of myoglobin and NT-proBNP from human serum. Myoglobin was successfully isolated and detected from serum samples at concentrations down to 250 fmol microL(-1). However, the affinity of the antibodies was not sufficient for the analysis of low-concentration clinical samples. Frontal analysis of anti-NT-proBNP disks revealed the ability of the immunoadsorber to bind up to 250 pmol NT-proBNP, which is more than sufficient for the analysis of clinical samples. Anti-NT proBNP disks showed good stability over more than 18 months and excellent batch to-batch reproducibility. Moreover, anti-NT-proBNP disks permitted the isolation of NT-proBNP at concentrations down to 750 amol microL(-1) in serum, corresponding to concentrations of strongly diseased patients. Using reversed phase trapping columns, the detection of NT-proBNP eluted from immunoadsorbers by mass spectrometry was achieved for concentrations down to 7.8 fmol microL(-1). PMID- 17690871 TI - Collision-induced reporter fragmentations for identification of covalently modified peptides. AB - Collision-induced reporter fragmentations of the currently most important covalent peptide modifications as detected by tandem mass spectrometry are summarized. These fragmentations comprise the formation of reporter ions, which are preferentially immonium ions, immonium ion-derived fragments or side chain fragments. In addition, the reporter neutral loss reactions for covalently modified amino acid residues are summarized. For each individual covalent modification which can be recognized by a reporter fragmentation, the accurate mass shift and the gross formula shift of the modified amino acid residue are given. The same set of data is provided for the reporter fragmentations. Finally, an extensive accurate mass and gross formula list is presented as supplementary material, describing mostly regular and modified y(1) and dipeptide a and b ions, which are helpful for identification of the peptide ends of covalently modified peptides. PMID- 17690872 TI - Head pitch affects muscle activity in the decerebrate cat hindlimb during walking. AB - Our purpose was to quantify the effects of head pitch on muscle activity patterns of the decerebrate cat hindlimb during walking. Five decerebrate cats walked at 0.7 m/s on a treadmill positioned level with the head pitch either parallel to the treadmill, 50% nose down or 50% nose up. We collected electromyography data from six hindlimb muscles. During level walking, after we manipulated head pitch, our results were surprisingly equivalent to the research on slope walking. For instance, muscle activity during level walking with a 50% head pitch nose down mimicked uphill walking. The muscle activity of the iliopsoas and semitendinosus significantly increased. Muscle activity during level walking with a 50% head pitch nose up mimicked downhill walking. Specifically, the biceps femoris and semimembranosus were inactive during the entire step. These alterations in muscle activity occurred within one step of altering head pitch but dissipated as level walking continued. In conclusion, the time course of muscle activity patterns due to modifications in head pitch is immediate and transitory. PMID- 17690874 TI - Non-target flanker effects on movement in a virtual action centred reference frame. AB - Visual selective attention is thought to underly inhibitory control during pointing movements. Accounts of inhibitory control during pointing movements make differential predictions about movement deviations towards or away from highly salient non-target flankers based on their potential cortical activation and subsequent inhibition: (1) Tipper et al. (Vis Cogn 4:1-38, 1997) "response vector model" predicts movements away from highly salient flankers; (2) Welsh and Elliott's (Q J Exp Psychol 57:1031-1057, 2004a and J Mot Behav 36:200-211, 2004b) "response activation model" predicts movements towards highly salient flankers early in the response, that is resolved by a race for inhibition. To eliminate the confounds of physical properties, such as obstacle avoidance and information cues of non-target objects, pointing was conducted in a virtual environment (graphical user interface). Participants were 14 skilled computer users who moved a computer cursor with a mouse to virtual targets. Analysis revealed non-target flankers significantly interfered with movement consistent with action centred selective attention, and reflecting a proximity-to-hand effect. Spatial analysis revealed evidence of highly salient flankers attracting movement, and less salient flankers repelling movement, supporting Welsh and Elliott's response activation model. These effects were achieved in a virtual 2D environment where interference caused by the physical properties of objects was less cogent. PMID- 17690873 TI - Memory and coordination in bimanual isometric finger force production. AB - Isometric force output of the dominant hand has previously been shown to decline when feedback of that output is withdrawn. This effect is more pronounced for higher levels of force output, and appears to rely upon visuomotor memory processes. In the present study these existing findings are extended to a task where subjects produced force output with both the dominant and non-dominant hand, and with both hands together. The results suggested that force change following the withdrawal of feedback follows the same pattern in bimanual conditions as it does in unimanual conditions. In addition it was found that the proportion of the total force contributed by each hand in the bimanual condition varied through a trial, which was achieved without a corresponding drop in force output when feedback was available. Taken together, the results support the idea of a central representation for target force level, which, when available, makes use of visual information to control a mutually redundant pair of effectors. PMID- 17690875 TI - Postural prioritization defines the interaction between a reaction time task and postural perturbations. AB - Concurrent demands for postural and cognitive control processes are now known to induce interference, e.g., information processing speed may decrease during postural adjustment. It is less clear whether postural control may, at least in many situations, take precedence over cognitive control ("postural prioritization"). The purpose of this study was to determine if postural dual task effects are the result of a postural prioritization effect. Twelve young subjects (6 female; 24.1 +/- 4.1) performed a discrete choice reaction time (RT) task in combination with a platform perturbation. To assess the effect of postural prioritization on RT and center of pressure (COP) parameters, destabilizing perturbations were randomly interspersed with non-destabilizing perturbations. Furthermore, stimulus order and the time interval of the RT stimulus relative to the platform perturbation were manipulated. COP and RT data obtained in these manipulations were compared to single-task baseline data. The results suggested that, irrespective of the degree of threat to postural stability, postural task processes are prioritized. Furthermore, anticipation of a postural stimulus negatively affects RT. However, once a perturbation commences subsequent RTs are speeded. Postural reactions were unaffected by a concurrent RT task, however. The RT stimulus acted as a cue to initiate biomechanical adaptations for an upcoming perturbation. PMID- 17690877 TI - Rhabdomyosarcoma of the clitoris. PMID- 17690876 TI - Maintenance of indinavir by dose adjustment in HIV-1-infected patients with indinavir-related toxicity. AB - OBJECTIVE: Treatment with indinavir/ritonavir (IDV/RTV) is very effective but hampered by frequent development of IDV-associated adverse events (mainly nephrotoxicity and skin changes). We tested whether dose reduction of IDV guided by therapeutic drug monitoring resulted in improved tolerability without compromising antiviral efficacy. PATIENTS: HIV-infected patients with any IDV/RTV regimen who suffer from IDV-related adverse events were included. Viral load had to be adequately controlled for at least 2 months prior to inclusion. Dose reduction from 800 mg to 600 or 400 mg IDV b.i.d. followed a specified protocol. IDV-related toxicity and IDV plasma concentrations were monitored for 24 weeks. IDV concentrations were quantified with a validated high performance liquid chromatography method. RESULTS: Twenty patients were included. Reasons for inclusion were: skin abnormalities 11, nephrotoxicity five, metabolic disturbances three, and hypertension one. IDV dose could be lowered to 400 mg b.i.d. in 13, to 600 mg b.i.d. in two patients. Five patients discontinued the treatment. Overall tolerability improved with respect to incidence and severity of adverse events. Median trough concentrations decreased from 1.02 mg/l (range 0.08-7.1) at baseline to 0.48 mg/l (0.11-1.4) after 24 weeks (p = 0.03) and remained above the critical threshold of 0.1 mg/l at any time after dose reduction. There was no change of CD4 cell counts or viral suppression. There were no significant changes in other laboratory parameters (creatinine, bilirubin, triglycerides, cholesterol, blood count, and urinalysis). CONCLUSION: Dose reduction of IDV improved tolerability of IDV-containing highly active antiretroviral treatment (HAART). Sufficient IDV trough concentrations were maintained in all patients as was virologic control. PMID- 17690878 TI - Sequencing and expression analysis of sakacin genes in Lactobacillus curvatus strains. AB - In this study, we focused our investigation on two strains of Lactobacillus curvatus, L442 and LTH1174, which are able to produce bacteriocins. L. curvatus LTH1174 is widely studied for its capability to produce curvacin A, while L. curvatus L442 was isolated from traditional Greek fermented sausages and was shown to possess a strong inhibitory activity toward Listeria monocytogenes. By polymerase chain reaction, we were able to target in both strains the genes for the production of sakacin P and sakacin Q, sppA and sppQ, respectively, both encoded chromosomally. While sppA was found to be conserved when compared with other sakacin P genes, sppQ showed a deletion of about 15 nucleotides when aligned with sequences obtained from Lactobacillus sakei. This difference did not affect the activity of sakacin Q as determined by testing sensitive strains. Expression analysis highlighted that sakacin P was expressed in L. curvatus L442 but not in L. curvatus LTH1174. Curing experiments were performed on L. curvatus LTH1174 to study the effect of the megaplasmid, present in this strain. In the plasmid-cured strain, expression of the sppA gene was detected. sppQ was expressed in both plasmid-cured and wild-type L. curvatus LTH1174, although expression was higher in the plasmid-cured strain. PMID- 17690879 TI - Pseudoaneurysm following vertebral biopsy and treatment with percutaneous thrombin injection. AB - We present a case of a pseudoaneurysm within the lumbar musculature. This occurred following a computed tomography (CT)-guided vertebral biopsy in a 79 year-old male patient and was successfully treated with percutaneous ultrasound guided thrombin injection. The patient initially presented with severe back pain. The plain radiographs and Magnetic resonance imaging (MRI) showed destruction of the L1 and L2 end plates, with marked narrowing of the disc space, suggestive of infective discitis. CT-guided biopsy was performed by the right paravertebral approach. Methicillin-resistant Staphylococcus aureus (MRSA) was grown, following culture of the specimen. Twenty days later, the patient developed a palpable swelling in the right lumbar region, with worsening of the back pain. MRI and ultrasound imaging showed a 3 cm pseudoaneurysm within the right lumbar musculature. The pseudoaneurysm was successfully treated following percutaneous ultrasound-guided injection of thrombin. PMID- 17690880 TI - Phase I study of alpha-galactosylceramide-pulsed antigen presenting cells administration to the nasal submucosa in unresectable or recurrent head and neck cancer. AB - BACKGROUND: Human Valpha24 natural killer T (NKT) cells are activated by the specific ligand, alpha-galactosylceramide (alpha-GalCer), in a CD1d-dependent manner. Potent anti-tumor activity of activated NKT cells has been previously demonstrated. METHODS: We conducted a phase I study with alpha-GalCer-pulsed antigen presenting cells (APCs) administered in the nasal submucosa of patients with head and neck cancer, and evaluated the safety and feasibility of such a treatment. Nine patients with unresectable or recurrent head and neck cancer received two treatments 1 week apart, of 1 x 10(8) of alpha-GalCer-pulsed autologous APCs into the nasal submucosa. RESULTS: During the clinical study period, no serious adverse events (Common Terminology Criteria for Adverse Events version 3.0 greater than grade 3) were observed. After the first and the second administration of alpha-GalCer-pulsed APCs, an increased number of NKT cells was observed in four patients and enhanced natural killer activity was detected in the peripheral blood of eight patients. CONCLUSION: The administration of alpha GalCer-pulsed APCs into the nasal submucosa was found to be safe and induce anti tumor activity in some patients. PMID- 17690881 TI - Disruption of Golgi processing by 2-phenyl benzimidazole analogs blocks cell proliferation and slows tumor growth. AB - PURPOSE: Cancer chemotherapy continues to be challenged by the emergence of resistant tumors, and one organelle entwined in the development of drug resistance is the Golgi apparatus. Recently, we discovered a group of 2 (substituted phenyl)-benzimidazole (2-PB) compounds that displace resident Golgi proteins from the juxtanuclear region resulting in their degradation. These compounds are also potent anti-proliferative agents, which together with their action on the Golgi made a compelling case for testing them against cancer. METHODS: The anti-tumor activity of a group of 2-PB compounds was examined both in vitro and in vivo. The role of the Golgi in the anti-proliferative effect was assessed by comparing the proliferation of individual cell lines with the distribution and total cellular expression of selected resident Golgi proteins. RESULTS: The anti-proliferative activity of 2-PB compounds is partially reversible (time- and concentration-dependent), non-cell-cycle-specific, and translates to tumor growth inhibition in vivo. While 2-PB compounds displace resident Golgi proteins from the juxtanuclear region in all cells, those that are resistant to the anti-proliferative effects differ from sensitive cells in that they have the capacity to protect these Golgi proteins from degradation. CONCLUSIONS: These results illustrate the utility of targeting the Golgi for cancer drug development. They also reveal a cellular strategy for resisting 2-PB drug effects through protection of displaced Golgi proteins from degradation thus allowing their continued function. PMID- 17690882 TI - A randomized trial of anemia correction with two different hemoglobin targets in the first-line chemotherapy of advanced gastric cancer. AB - PURPOSE: To evaluate if raising baseline and maintaining hemoglobin (Hb) levels with red blood cell (RBC) transfusion could improve the outcomes of chemotherapy for advanced gastric cancer (AGC). METHODS: Patients were randomized to receive RBC transfusion to maintain their Hb levels >or=10 g/dl (arm 1) or >or=12 (arm 2) before the start of their 5-fluorouracil-based first-line chemotherapy. Objective response, KPS and quality of life (QOL) data were measured. RESULTS: For 87 patients enrolled, mean baseline Hb was 10.1 g/dl, and 54 patients received RBC prior to chemotherapy initiation. Despite transfusion, we failed to maintain the Hb level above the predefined target range. Eighteen patients experienced brief and reversible adverse events during transfusion, including two patients with acute pulmonary edema. KPS was improved from baseline to post-chemotherapy in both arms. QOL data showed improvement in some symptom scores, but there was no difference in the QOL scores between the two arms at baseline and all four cycles of treatment. Similar response rates were observed in both arms (arm 1, 30%; arm 2, 35%). Both arms showed similar chemotherapy duration (3.8 and 4.1 months, respectively), progression-free survival (4.0 and 4.1 months) and overall survival (9.9 and 9.3 months). CONCLUSIONS: Red blood cell transfusion achieving Hb level above 10 g/dl might contribute to the improvement of the KPS and QOL seen in patients with AGC. The observation of equivalent outcomes at the two target Hb levels supports the feasibility of anemia correction to Hb 10 g/dl, which merits further evaluation. PMID- 17690883 TI - Effect of gastrectomy on the pharmacokinetics of S-1, an oral fluoropyrimidine, in resectable gastric cancer patients. AB - PURPOSE: The effect of gastrectomy on pharmacokinetics after S-1 administration was investigated. PATIENTS AND METHODS: A dose of 40 mg/m(2) of S-1 was administered orally twice daily for 7 days (80 mg/m(2)/day) preoperatively in ten patients with resectable gastric cancer, and the same dose of S-1 was administered for 28 consecutive days after gastrectomy. Plasma concentrations of tegafur, gimeracil, and oteracil potassium, all the components of S-1, and 5-FU were measured on pre- and postoperative days. Concentrations of 5-FU in tumor and normal tissues were also determined. RESULTS: At day 4 from the initial preoperative administration of S-1, the AUC of 5-FU was 1,055 +/- 304 ng h/ml. At day 18, day 28, and day 42 after gastrectomy, it was 1,012 +/- 331, 1,070 +/- 403, and 946 +/- 226 ng h/ml, respectively. No significant differences for plasma 5-FU were observed between pre- and postoperative days. In the resected tumor tissues, concentrations of 5-FU were 242 +/- 83 ng/g around 4.5 h and 91.7 +/- 37.0 ng/g around 20 h after the final administration, respectively. CONCLUSION: Gastrectomy does not affect on pharmacokinetics of 5-FU derived from S-1 regardless of partial or total gastrectomy, indicating that S-1 can be a useful drug in postoperative adjuvant chemotherapy for gastric cancer. PMID- 17690884 TI - The Nodosome: Nod1 and Nod2 control bacterial infections and inflammation. AB - Toll-like receptors (TLRs) and the nucleotide-binding domain, leucine rich repeat containing family (or Nod-like receptors, NLRs) are two important families of microbial sensors that are membrane-associated and cytosolic molecules, respectively. The Nod proteins Nod1 and Nod2 are two NLR family members that trigger immune defense in response to bacterial peptidoglycan. Nod proteins fight off bacterial infections by stimulating proinflammatory signaling and cytokine networks and by inducing antimicrobial effectors, such as nitric oxide and antimicrobial peptides. Nod1 is also critically implicated in shaping adaptive immune responses towards bacterial-derived constituents. In addition, recent evidence has demonstrated that mutations in Nod1 and Nod2 are associated with a number of human inflammatory disorders, including Crohn's disease, Blau syndrome, early-onset sarcoidosis, and atopic diseases. Together, Nod1 and Nod2 represent central players in the control of immune responses to bacterial infections and inflammation. PMID- 17690886 TI - Dramatic progression of skin involvement in systemic sclerosis after the appearance of anti-Scl70 antibody: a case report. AB - The authors describe a young man suffering from systemic sclerosis who showed a dramatic progression of skin involvement after the appearance of anti-Scl70 antibody. PMID- 17690885 TI - TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system. AB - The innate immune system precisely modulates the intensity of immune activation in response to infection. Flagellin is a microbe-associated molecular pattern that is present on both pathogenic and nonpathogenic bacteria. Macrophages and dendritic cells are able to determine the virulence of flagellated bacteria by sensing whether flagellin remains outside the mammalian cell, or if it gains access to the cytosol. Extracellular flagellin is detected by TLR5, which induces expression of proinflammatory cytokines, while flagellin within the cytosol of macrophages is detected through the Nod-like receptor (NLR) Ipaf, which activates caspase-1. In macrophages infected with Salmonella typhimurium or Legionella pneumophila, Ipaf becomes activated in response to flagellin that appears to be delivered to the cytosol via specific virulence factor transport systems (the SPI1 type III secretion system (T3SS) and the Dot/Icm type IV secretion system (T4SS), respectively). Thus, TLR5 responds more generally to flagellated bacteria, while Ipaf responds to bacteria that express both flagellin and virulence factors. PMID- 17690887 TI - Central nervous system involvement as a major manifestation of rheumatoid arthritis. AB - A 58-year-old woman with an 8-year history of seropositive rheumatoid arthritis was admitted with right hemiparesis, history of seizures, fever, weight loss and headaches. Her blood tests revealed the presence of rheumatoid factor, elevated C reactive protein and anti-cyclic citrullinated peptide antibodies (>200 RU/ml). Examination of cerebrospinal fluid demonstrated pleocytosis (118 cells/mm(3), predominantly lymphocytes) with elevated protein level (58 mg/dl); cultures were negative. Magnetic resonance imaging findings were suggestive for meningoencephalitis. Short course of high-dose corticosteroids and cyclophosphamide led to clinical improvement. Rheumatoid vasculitis was probably responsible for neurological symptoms. PMID- 17690888 TI - Gain of function of stomatal movements in rooting Vitis vinifera L. plants: regulation by H(2)O(2) is independent of ABA before the protruding of roots. AB - Reactive oxygen species (ROS), namely superoxide radical (O2(-)) and hydrogen peroxide (H(2)O(2)) are generated when plant tissues endure a variety of environmental stresses, including light stress. The extremely short life times of ROS makes the study of their production in planta very difficult. The use of ROS specific tracer dyes, 3-3' diaminobenzidine and nitroblue tetrazolium, together with high-resolution imaging provides the opportunity to identify sites of photooxidative stress response by ROS accumulation. This technique was applied to grapevine during the first 7 days after transfer from in vitro to ex vitro under an irradiance 4-fold higher than in vitro. ROS accumulation was detected in the first days of analysis, which gradually decreased to levels comparable to greenhouse leaves. (O2(-)) was uniformly distributed while H(2)O(2) accumulated preferentially in veins, wounds and stomatal guard and surrounding cells. To evaluate the role of H(2)O(2 )in stomatal functioning and its crosstalk with abscisic acid (ABA) we focused on the percentage of coloured structures, stomatal aperture and ABA concentration. We propose that the high H(2)O(2) level triggered by increased light is responsible for the activation of a signalling pathway over stomatal cells, in a process apparently irrespective of ABA regulation prior to root protrusion. This could explain the gain of function of a low yet consistent percentage of stomatal cells, essential for plant survival during the ontogenic period in analysis. PMID- 17690889 TI - Biomarkers for prostate cancer. AB - Novel biomarkers for prostate cancer (PCa) are currently being assessed for utility in PCa diagnosis. This article aims to provide concise information on the current findings that impact prostate cancer research. Results of enzyme-linked immunosorbent assays (ELISA) for single biomarkers, quantitative polymerase chain reaction (PCR)-based assays for DNA/RNA markers will be reviewed in addition to high-throughput proteomic profiling of PCa specimens. The advantages/disadvantages of tissue, blood, urine or seminal plasma as sources for potential biomarkers are discussed emphasizing the consequences for PCa diagnosis. In summary, the majority of promising marker candidates available today needs further validation. Some of the identified markers have the potential to yield novel prognostic tools for PCa, provide novel insights into its pathophysiology, and contribute to the establishment of novel treatment strategies. PMID- 17690890 TI - Targeting EGFR in bladder cancer. AB - Expression and overexpression of the epidermal growth factor receptor (EGFR) have been described in several solid tumors including bladder, breast, colorectal, NSCLC, prostate, and ovarian cancers. In addition to gene amplification, point mutations within the kinase domain also occur. Previous reports indicate that the patient's response to gefitinib depends on either the presence of mutations within the kinase domain of EGFR or the expression of the most frequent alteration, the truncated EGFR variant III (EGFRvIII). Therefore, it is important to determine if these EGFR alterations are present in urothelial carcinoma. The kinase domain of EGFR (exons 18-21) from 11 bladder cancer cell lines as well as from 75 patient tumors was analyzed by automated sequencing. No mutations were detected in all samples tested. Furthermore, analysis of EGFRvIII by immunohistochemistry revealed that almost half of all the patient samples expressed this truncation in a urothelial carcinoma tissue microarray. However, there have been previous reports of inconsistencies in detecting EGFRvIII by immunohistochemistry owing to the specificity of the antibodies and the methodologies utilized. Therefore, these results were validated by reverse transcription PCR, real-time PCR and western blot analysis. In these assays, none of the samples tested positive for EGFRvIII. Taken together, these results indicate that mutations within the tyrosine kinase domain of EGFR and expression of EGFRvIII are rare events in bladder cancer and therefore do not contribute to the malignant phenotype of this tumor. These results have clinical implications in selecting tyrosine kinase inhibitors for the therapy of urothelial carcinoma. PMID- 17690891 TI - Protective role of erythropoietin during testicular torsion of the rats. AB - Testicular torsion is an important clinical urgency. Similar mechanisms occurred after detorsion of the affected testis as in the ischemia reperfusion (I/R) damage. This study was designed to investigate the effects of erythropoietin (EPO) treatment after unilateral testicular torsion. Fifty male Sprague-Dawley rats were divided into five groups. Group 1 underwent a sham operation of the right testis under general anesthesia. Group 2 was same as sham, and EPO (3,000 IU/kg) infused i.p., group 3 underwent a similar operation but the right testis was rotated 720 degrees clockwise for 1 h, maintained by fixing the testis to the scrotum, and saline infused during the procedure. Group 4 underwent similar torsion but EPO was infused half an hour before the detorsion procedure, and in group 5, EPO was infused after detorsion procedure. Four hours after detorsion, ipsilateral and contralateral testes were taken out for evaluation. Treatment with EPO improved testicular structures in the ipsilateral testis but improvement was less in the contralateral testis histologically, but EPO treatment decreased germ cell apoptosis in both testes following testicular IR. TNF-alpha, IL-1beta, IL-6 and nitrite levels decreased after EPO treatment especially in the ipsilateral testis. We conclude that testicular I/R causes an increase in germ cell apoptosis both in the ipsilateral and contralateral testes. Erythropoietin has antiapoptotic and anti-inflammatory effects following testicular torsion. PMID- 17690893 TI - Pascual's study may change a mechanical point of view for anal fissure healing. PMID- 17690892 TI - The regulation of thapsigargin-sensitive sarcoendoplasmic reticulum Ca(2+)-ATPase activity in estivation. AB - Estivation (aerobic dormancy) is characterized by sustained metabolic rate depression, which is crucial to survival in the face of unfavorable environmental conditions and enables the preservation of endogenous fuel reserves. Ion pumping is one of the most energetically taxing physiological processes in cells, and ion motive ATPases are likely loci to be differentially regulated in models of metabolic arrest. We proposed that the sarcoendoplasmic reticulum (SER) calcium ATPase (SERCA) would be deactivated in the estivating desert snail Otala lactea, potentially contributing to the overall suppression of metabolism. SERCA kinetic parameters [decreased maximal velocities, increased substrate K (m) values, increased Arrhenius activation energy (E (a))] were indicative of a less active enzyme in the estivated state. Interestingly, the less active SERCA population in dormant snails featured greater kinetic (K (m) Mg.ATP versus temperature) and conformational (resistance to urea denaturation) stability than that in active snails. Western blotting confirmed that SERCA protein content did not change during estivation. In light of this observation, we proposed that estivation dependent changes in SERCA activity was due to changes in SERCA phosphorylation state. In vitro studies promoting specific kinase or phosphatase action indicated that decreased SERCA activity in estivation was linked with endogenous kinase activity whereas reactivation of SERCA was facilitated by endogenous protein phosphatases (PP). PMID- 17690896 TI - External exposure of deciduous tooth enamel to photons: dose conversion coefficients for standard radiation fields. AB - Dose conversion coefficients for teeth of children were computed for external photon sources by means of Monte Carlo methods using a modified MIRD-type mathematical phantom of a 5-year-old child. The tooth region is separated into eight smaller regions that represent incisors, canines, first and second molars. Each of these sub-regions is separated into enamel and dentin parts. Dose conversion coefficients were computed as ratio of absorbed dose in the enamel and air kerma. They are given for unidirectional (AP, PA, RLAT, LLAT), rotational (ROT) and isotropic (ISO) photon sources in the energy range from 10 keV to 10 MeV. All computations were performed with the MCNP4 code including coupled electron-photon transport. The computed coefficients demonstrate a significant non-linearity versus photon energy, which is more pronounced than that observed for adult phantoms. Due to this non-linearity, use of the EPR-measured doses in human teeth requires information on the incident photon fluence spectra. The data presented can be used for assessment of public exposure. PMID- 17690895 TI - Head and neck reconstruction with free flaps: a report on 213 cases. AB - The aim of this retrospective study is to review the experience of our institution in performing microvascular head and neck reconstruction between 2000 and 2004. During this period, 213 free flaps, including 146 radial forearm free flaps, 60 fibular flaps and 7 scapular flaps, were performed. Free flap success rate and complications were reported. The pre-treatment factors influencing these results were subsequently analyzed. Functional and aesthetic outcomes were evaluated by the same clinician. There were 14 free flap failures, giving an overall free flap success rate of 93.4%. Salvage surgery for recurrent cancer was the only factor correlated with a higher risk of free flap failure (P = 0.0004). The local complication rate was 20.9%. High level of comorbidity (P = 0.009), salvage surgery for recurrent cancer (P = 0.03) and hypopharyngeal surgery (P = 0.002) were associated with a higher risk of local complications. An unrestricted oral diet and an intelligible speech were recovered by respectively 76 and 88% of the patients. Microvascular free flaps represent an essential and reliable technique for head neck reconstruction and allow satisfactory functional results. PMID- 17690894 TI - Role of L-glutamine and glycine supplementation on irradiated colonic wall. AB - BACKGROUND AND AIMS: Radiotherapy is frequently used for cancer treatment, but it may be associated with several complications. Thus, this study aimed to evaluate the role of L-glutamine and/or glycine supplementation on the colonic wall in rats submitted to abdominal radiation. MATERIALS AND METHODS: Sixty adult Wistar rats were randomly divided into six groups: I-healthy, II (control)-irradiated rats without amino acid supplementation, III-irradiated rats with glycine supplementation, IV-irradiated rats with L-glutamine supplementation, V irradiated rats with glycine supplementation 7 days before irradiation and with L glutamine supplementation 7 days after irradiation, and VI-irradiated rats with L glutamine supplementation 7 days before irradiation and with glycine supplementation 7 days after irradiation. Abdominal irradiation was employed with a dose of 1,000 cGy on the eighth day of the experiment. All animals underwent laparotomy on the 15th day for resection of a colonic segment for stereologic analysis. Parametric and nonparametric tests were used for statistical analysis, with the level of significance set at p 0.05). It could be concluded that while the application of connective tissue graft with coronally advanced flap is efficient for coverage of Miller's class I and II gingival recession defects, the short-term clinical outcome of this surgical method is not affected by orientation of connective tissue graft. PMID- 17690924 TI - Is there a relation between local bone quality as assessed on panoramic radiographs and alveolar bone level? AB - The aim was to explore the relation between radiographic bone quality on panoramic radiographs and relative alveolar bone level. Digital panoramic radiographs of 94 female patients were analysed (mean age, 44.5; range, 35-74). Radiographic density of the alveolar bone in the premolar region was determined using Agfa Musica software. Alveolar bone level and bone quality index (BQI) were also assessed. Relationships between bone density and BQI on one hand and the relative loss of alveolar bone level on the other were assessed. Mandibular bone density and loss of alveolar bone level were weakly but significantly negatively correlated for the lower premolar area (r = -.27). The BQI did not show a statistically significant relation to alveolar bone level. Radiographic mandibular bone density on panoramic radiographs shows a weak but significant relation to alveolar bone level, with more periodontal breakdown for less dense alveolar bone. PMID- 17690925 TI - CoMFA study of distamycin analogs binding to the minor-groove of DNA: a unified model for broad-spectrum activity. AB - A 3D-QSAR analysis has been carried out by comparative molecular field analysis (CoMFA) on a series of distamycin analogs that bind to the DNA of drug-resistant bacterial strains MRSA, PRSP and VSEF. The structures of the molecules were derived from the X-ray structure of distamycin bound to DNA and were aligned using the Database alignment method in Sybyl. Statistically significant CoMFA models for each activity were generated. The CoMFA contours throw light on the structure activity relationship (SAR) and help to identify novel features that can be incorporated into the distamycin framework to improve the activity. Common contours have been gleaned from the three models to construct a unified model that explains the steric and electrostatic requirements for antimicrobial activity against the three resistant strains. PMID- 17690926 TI - Calculation of binding affinities of HIV-1 RT and beta-secretase inhibitors using the linear interaction energy method with explicit and continuum solvation approaches. AB - The linear interaction energy (LIE) approach has been applied to estimate the binding free energies of representative sets of HIV-1 RT and beta-Secretase inhibitors, using both molecular dynamics (MD) and tethered energy minimization sampling protocols with the OPLS-AA potential, using a range of solvation methodologies. Generalized Born (GB), 'shell' and periodic boundary condition (PBC) solvation were used, the latter with reaction field (RF) electrostatics. Poisson-Boltzmann (PB) and GB continuum electrostatics schemes were applied to the simulation trajectories for each solvation type to estimate the electrostatic ligand-water interaction energy in both the free and bound states. Reasonable agreement of the LIE predictions was obtained with respect to experimental binding free energy estimates for both systems: for instance, 'PB' fits on MD trajectories carried out with PBC solvation and RF electrostatics led to models with standard errors of 1.11 and 1.03 kcal mol(-1) and coefficients of determination, r (2) of 0.76 and 0.75 for the HIV-1 RT and beta-Secretase sets. However, it was also found that results from MD sampling using PBC solvation provided only slightly better fits than from simulations using shell or Born solvation or tethered energy minimization sampling. PMID- 17690927 TI - A survey of the preparedness for an influenza pandemic of general practitioners in the West Midlands, UK. AB - There is a lack of evidence regarding the preparedness of general practitioners (GPs) to respond to pandemic influenza. A postal questionnaire survey was conducted to explore the self-perceived pandemic preparedness of GPs in the West Midlands, United Kingdom, and to determine differences between urban and non urban GPs. The postal questionnaire was sent out to 773 GPs in November 2005, and a reminder was sent in January 2006. In all, 427/773 (55%) questionnaires were returned, and 56% of respondents were aware of influenza pandemic preparedness plans. Approximately one-quarter of respondents (28%, 114/401) thought the response of their practice to a pandemic event would be very poor/poor. Non-urban GPs were significantly more likely to rate the response of their practice to a pandemic as likely to be poor (OR 3.01, 95%CI 1.03-8.76) and were less likely to be aware of pandemic preparedness plans (OR 0.62, 95%CI 0.39-0.99). Non-urban GPs were also significantly more likely to feel less confident in their ability to explain to their patients what to do and why during an influenza pandemic than GPs based in urban areas (OR 4.68, 95%CI 1.78-12.31). GPs rating of the odds of a pandemic affecting the United Kingdom did not differ significantly by geographic location. The results of this paper can be used to inform and influence public health policy and as evidence of a need to provide additional education and training to improve pandemic preparedness among GPs, in particular those in non urban areas. PMID- 17690928 TI - Breakthrough infection of Trichosporon asahii during posaconazole treatment in a patient with acute myeloid leukaemia. AB - A neutropenic patient with acute myeloid leukaemia experienced a breakthrough infection of Trichosporon asahii during posaconazole treatment. After treatment was changed to a combination therapy with voriconazole and liposomal amphotericin B, the infection resolved. Posaconazole works effectively as an antifungal prophylaxis and salvage therapy in rare invasive fungal infections. This case however illustrates that breakthrough infections with T. asahii may occur during posaconazole treatment. PMID- 17690929 TI - Contribution of the extracellular matrix to the viscoelastic behavior of the urinary bladder wall. AB - We previously reported that when the stress relaxation response of urinary bladder wall (UBW) tissue was analyzed using a single continuous reduced relaxation function (RRF), we observed non-uniformly distributed, time-dependent residuals (Ann Biomed Eng 32(10):1409-1419, 2004). We concluded that the single relaxation spectrum was inadequate and that a new viscoelastic model for bladder wall was necessary. In the present study, we report a new approach composed of independent RRFs for smooth muscle and the extracellular matrix components (ECM), connected through a stress-dependent recruitment function. In order to determine the RRF for the ECM component, biaxial stress relaxation experiments were first performed on decellularized extracellular matrix network of the bladder obtained from normal and spinal cord injured rats. While it was assumed that smooth muscle followed a single spectrum RRF, modeling the UBW ECM required a dual-Gaussian spectrum. Experimental results revealed that the ECM stress relaxation response was insensitive to the initial stress level. Thus, the average ECM RRF parameters were determined by fitting the average stress relaxation data. The resulting stress relaxation behavior of whole bladder tissue was modeled by combining the ECM RRF with the RRF for the smooth muscle component using an exponential recruitment function representing the recruitment of collagen fibers at higher stress levels. In summary, the present study demonstrated, for the first time, that stress relaxation response of bladder tissue can be better modeled when divided into the contributions of the extracellular matrix and smooth muscle components. This modeling approach is suitable for prediction of mechanical behaviors of the urinary bladder and other organs that exhibit rapid tissue remodeling (i.e., smooth muscle hypertrophy and altered ECM synthesis) under various pathological conditions. PMID- 17690930 TI - Management of cancer treatment-induced bone loss in early breast and prostate cancer -- a consensus paper of the Belgian Bone Club. AB - Cancer treatment-induced bone loss (CTIBL) is one of the most important side effects of adjuvant antineoplastic treatment in hormone-dependent neoplasms. Chemotherapy, GnRH analogs and tamoxifen can induce marked bone loss in premenopausal women with early breast cancer. Aromatase inhibitors (AIs) are replacing tamoxifen as the preferred treatment for postmenopausal women. As a class effect, steroidal (exemestane) and non-steroidal (anastrozole and letrozole) AIs increase bone turnover and cause bone loss (4%-5% over 2 years). When compared to tamoxifen, the risk of getting a clinical fracture under AI treatment is increased by 35%-50%. In patients with prostate cancer, androgen deprivation therapy (ADT) increases bone turnover, reduces bone mass (4%-5% per year) and increases the fracture rate depending on the duration of therapy. Zoledronic acid can prevent accelerated bone loss induced by goserelin in premenopausal women, by letrozole in postmenopausal women and by ADT in men. More limited data indicate that weekly alendronate or risedronate could also be effective for preventing CTIBL. Initiation of therapy early, prior to the occurrence of severe osteoporosis, rather than after, may be more effective. Bisphosphonate treatment should be considered in osteoporotic but also in osteopenic patients if other risk factor(s) for fractures are present. PMID- 17690931 TI - Distal renal tubular acidosis and ovalocytosis: a case report. AB - A 23-year-old man presented with osteoporosis, revealed by femoral fractures, and a history of nephrolithiasis, short stature, metabolic acidosis, hypokalemia and ovalocytosis, a red blood cell abnormality common in malaria endemic regions. Biological investigations led to the diagnosis of type 1 distal renal tubular acidosis (dRTA). Ovalocytosis and dRTA may co-exist in the same patient, since both can originate in mutations of the anion-exchanger 1 (AE1) gene, which codes for band 3, the bicarbonate/chloride exchanger, present in both the red cell membrane and the basolateral membrane of the collecting tubule alpha-intercalated cell. PMID- 17690932 TI - Computer-aided detection for CT colonography: update 2007. AB - Computed tomographic colonography (CTC) is an emerging technique for polyp detection in the colon. However, lesion detection can be challenging due to insufficient patient preparation, chosen CT technique or reader imperfection. The primary goal of computer-aided detection (CAD) for CTC is locating possible polyps, and presenting the reader with these polyp candidates. Other goals are sensitivity improvement and reduction of reading time and inter-observer variability. The multistep CAD procedure typically consists of segmentation of the colonic wall (e.g. region growing); selection of intermediate polyp candidates (curvature analysis, sphere fitting, normal analysis, slope density function ...); classification of final candidates for detection and listing suspicious polyps (location, size and volume). Remaining task for the radiologist is the validation or rejection of the polyp candidates. State-of-the-art CAD systems should require minimal or even no user interaction for the extraction of the colonic wall, offer a computation time less than 10-20 min and high sensitivity and specificity for different polyp sizes and shapes, with a low number of false positives. These systems have the potential to increase radiologist's performance and to decrease inter-reader variability. Besides CAD key techniques we also discuss new developments in CAD and describe recent applications facilitating CTC. PMID- 17690933 TI - Mortality in perforated peptic ulcer patients after selective management of stratified poor risk cases. AB - INTRODUCTION: Perforated peptic ulcer disease continues to inflict high morbidity and mortality. Although patients can be stratified according to their surgical risk, optimal management has yet to be described. In this study we demonstrate a treatment option that improves the mortality among critically ill, poor risk patients with perforated peptic ulcer disease. METHODS: In our study, two series were retrospectively reviewed: group A patients (n = 522) were treated in a single surgical unit at the Dhaka Medical College Hospital, Dhaka, Bangladesh during the 1980s. Among them, 124 patients were stratified as poor risk based on age, delayed presentation, peritoneal contamination, and coexisting medical problems. These criteria were the basis for selecting a group of poor risk patients (n = 84) for minimal surgical intervention (percutaneous peritoneal drainage) out of a larger group of patients, group B (n = 785) treated at Khulna Medical College Hospital during the 1990s. RESULTS: In group A, 479 patients underwent conventional operative management with an operative mortality of 8.97%. Among the 43 deaths, 24 patients were >60 years of age (55.8%), 12 patients had delayed presentation (27.9%), and 7 patients were in shock or had multiple coexisting medical problems (16.2%). In group B, 626 underwent conventional operative management, with 26 deaths at a mortality rate of 4.15%. Altogether, 84 patients were stratified as poor risk and were managed with minimal surgical intervention (percutaneous peritoneal drainage) followed by conservative treatment. Three of these patients died with an operative mortality of 3.5%. CONCLUSIONS: Minimal surgical intervention (percutaneous peritoneal drainage) can significantly lower the mortality rate among a selected group of critically ill, poor risk patients with perforated peptic ulcer disease. PMID- 17690934 TI - Determinants of complications and adequacy of surgical resection in laparoscopic versus open total gastrectomy for adenocarcinoma. AB - BACKGROUND: The role of laparoscopic total gastrectomy (LTG) in the treatment of gastric cancer is controversial. The present study analyzed the morbidity and adequacy of resection in LTG versus open total gastrectomy (OTG) for gastric adenocarcinoma. METHODS: Between 2003 and 2006, clinical data of 38 consecutive patients who underwent LTG for gastric adenocarcinoma were collected prospectively. The same data-entry form was used for retrospective data collection from 22 consecutive patients who underwent OTG within the same time period. Logistic regression models were used in univariate and multivariate analyses to identify the optimally combined factors related to the occurrence of postoperative complications and to the number of harvested lymph nodes. RESULTS: Postoperative complications occurred in 24 patients with subsequent mortality in two. Median (range) length of hospital stay was 11 (6-73) days and comparable after LTG versus OTG (p = 0.847). The occurrence of postoperative complications was related (p = 0.004) to the first year of surgery and patients' medical condition before surgery [American Society of Anaesthesiologists (ASA) physical status III]. Microscopic tumor-free margins were obtained in all but two patients. The number of harvested lymph nodes was 17 (0-90), and determined by tumor wall penetration (p = 0.001). CONCLUSIONS: The occurrence of complications after total gastrectomy is determined by the patients' medical condition before surgery and the surgical expertise, but not by the approach. LTG and OTG can result in adequate tumor-free resection margins and lymph node yield, which is related to the tumor wall penetration. The role of LTG in gastric cancer needs further evaluation in randomized controlled trials with large patient series. PMID- 17690935 TI - Execution of the SimSET Monte Carlo PET/SPECT simulator in the condor distributed computing environment. AB - SimSET is a package for simulation of emission tomography data sets. Condor is a popular distributed computing environment. Simple C/C++ applications and shell scripts are presented which allow the execution of SimSET on the Condor environment. This is accomplished without any modification to SimSET by executing multiple instances and using its combinebin utility. This enables research facilities without dedicated parallel computing systems to utilize the idle cycles of desktop workstations to greatly reduce the run times of their SimSET simulations. The necessary steps to implement this approach in other environments are presented along with sample results. PMID- 17690936 TI - Robot-assisted vs. conventional laparoscopic rectopexy for rectal prolapse: a comparative study on costs and time. AB - PURPOSE: Laparoscopic rectopexy has become one of the most advocated treatments for full-thickness rectal prolapse, offering good functional results compared with open surgery and resulting in less postoperative pain and faster convalescence. However, laparoscopic rectopexy can be technically demanding. Once having mastered dexterity, with robotic assistance, laparoscopic rectopexy can be performed faster. Moreover, it shortens the learning curve in simple laparoscopic tasks. This may lead to faster and safer laparoscopic surgery. Robot-assisted rectopexy has been proven safe and feasible; however, until now, no study has been performed comparing costs and time consumption in conventional laparoscopic rectopexy vs. robot-assisted rectopexy. METHODS: Our first 14 cases of robot assisted laparoscopic rectopexy were reviewed and compared with 19 patients who underwent conventional laparoscopic rectopexy in the same period. RESULTS: Robot assisted laparoscopic rectopexy did not show more complications. However, the average operating time was 39 minutes longer, and costs were euro 557.29 (or: dollars 745.09) higher. CONCLUSION: Robot-assisted laparoscopic rectopexy is a safe and feasible procedure but results in increased time and higher costs than conventional laparoscopy. PMID- 17690937 TI - Practice parameters for the surgical management of Crohn's disease. PMID- 17690938 TI - One hundred million years of chemical warfare by insects. AB - An important defensive strategy among animals is the use of chemical compounds with toxic or irritating properties. In this paper, we report the discovery of an Early Cretaceous soldier beetle (Coleoptera: Cantharidae) in Burmese amber that seemingly employed a chemical defense response against a potential predator. Six pairs of cuticular vesicles with associated gland reservoirs were extruded from the insect's abdomen, and a secretion released from one of these covers a portion of the antenna of a second insect species, considered to be the perpetrator of the response. This is the earliest fossil record of a putative chemical defense response and suggests that chemical defense mechanisms in beetles have been in existence for at least 100 Ma. PMID- 17690939 TI - Hepatic imaging characteristics predict overall survival in hepatocellular carcinoma. AB - BACKGROUND: Pathologic tumor-related factors, including vascular invasion, remain the only reliable predictor of recurrence and overall survival in hepatocellular cancer (HCC). Other preoperative factors, such as hepatitis status, degree of liver disease (cirrhosis), number of tumors, and size of tumors have been inconsistent in predicting outcome. The aim of this study is to demonstrate that standard radiological imaging characteristics will predict overall survival in HCC. METHODS: We identified 103 HCC treated in our department from January 1999 to June 2005. All images were reviewed by two blinded physicians and classified into one of three radiological characteristics: pusher/mass forming (well encapsulated without parenchymal violation), invader (non-encapsulated with violation of parenchyma), and hanger/pedunculated (encapsulated with a majority of the lesion suspended from segments II, III, IV b, V, and / or VI). RESULTS: The study included 61 males and 31 females with a median age of 61 years (range 23 to 90 years), a median of one lesion (range 1-10), a majority with <25% liver involvement, with a median lesion size of 6 cm (range 1 to 22 cm). Surgical therapy included hepatic resection 34 (33%), RFA 23 (22%), and liver transplantation 21 (20%). The distribution of radiological characteristics at initial evaluation was 54% pushers, 41% invaders, and 4% hangers. Median survival for invaders (8.2 months) and hangers (10.0 months) was significantly lower than for pushers (median 29 months) (p = 0.0007). CONCLUSION: Standard, reproducible radiological characteristics are predictive of outcome in patients with HCC. Greater emphasis on identifying preoperative factors remains imperative to better identify patients' biology and determine which should undergo resection or transplantation. PMID- 17690940 TI - Long term outcome and prognostic factors for large hepatocellular carcinoma (10 cm or more) after surgical resection. AB - BACKGROUND: Surgical resection is the standard treatment for hepatocellular carcinoma (HCC). However, the role of surgery in treatment of large tumors (10 cm or more) is controversial. We have analyzed, in a single centre, the long-term outcome associated with surgical resection in patients with such large tumors. METHODS: We retrospectively investigated 166 patients who had undergone surgical resection between July 1995 and December 2006 because of large (10 cm or more) HCC. Survival analysis was done using the Kaplan-Meier method. Prognostic factors were evaluated using univariate and multivariate analyses. RESULTS: Of the 166 patients evaluated, 80% were associated with viral hepatitis and 48.2% had cirrhosis. The majority of patients underwent a major hepatectomy (48.2% had four or more segments resected and 9% had additional organ resection). The postoperative mortality was 3%. The median survival in our study was 20 months, with an actuarial 5-year and 10-year overall survival of 28.6% and 25.6%, respectively. Of these patients, 60% had additional treatment in the form of transarterial chemoembolization, radiofrequency ablation or both. On multivariate analysis, vascular invasion (P < 0.001), cirrhosis (P = 0.028), and satellite lesions/multicentricity (P = 0.006) were significant prognostic factors influencing survival. The patients who had none of these three risk factors had 5 year and 10-year overall survivals of 57.7% each, compared with 22.5% and 19.3%, respectively, for those with at least one risk factor (P < 0.001). CONCLUSIONS: Surgical resection for those with large HCC can be safely performed with a reasonable long-term survival. For tumors with poor prognostic factors, there is a pressing need for effective adjuvant therapy. PMID- 17690941 TI - Outcomes of pheochromocytoma management in the laparoscopic era. AB - BACKGROUND: Laparoscopic adrenalectomy (LA) is the preferred surgical approach for pheochromocytomas. We have investigated the changes in diagnosis, management and outcome of pheochromocytomas treated since the widespread advent of LA. METHODS: Data were collected retrospectively from 96 patients with pheochromocytomas that had been surgically treated at three tertiary referral centers. RESULTS: There were 53 females. Mean age was 47 years (10-81). Tumors were found incidentally in 40% of patients. Of the 96 patients, 12 (13%) had familial syndromes. CT or MRI localized the adrenal lesion in all patients. MIBG scans obtained from 32 patients were concordant with the CT/MRI in 19, were false negative in 9 and misleading in 1, and altered management in only 3 patients. Mean tumor size was 5.6 cm (1.8-17). There were 92 adrenal pheochromocytomas and 9 paragangliomas. Laparoscopy was successful in 67 of 74 (91%) patients, with 20 of 67 (30%) having tumors of 6 cm or greater in size. Conversions to open procedures were performed in patients with 4 left, 2 right pheochromocytomas and 1 paraganglioma. Of the patients, 22 had an open procedure due to suspicion of malignancy or large tumors. Malignancy was observed in 4 of 92 (4.3%) pheochromocytomas and 4 of 9 (44%) paragangliomas. Average follow-up was 22 months (1-122). There were seven recurrences. Postoperative biochemical tests available in 64 patients were normal in 90%. CONCLUSIONS: The diagnosis of pheochromocytoma was made incidentally in 40% of patients. MIBG is not necessary for unilateral non-hereditary pheochromocytomas localized by CT/MRI. LA is possible with excellent results in most patients, including for treatment of lesions 6 cm or greater in size with no signs of invasion. Laparoscopy should be used cautiously for paragangliomas because of a high rate of malignancy. PMID- 17690943 TI - Update in women's health. PMID- 17690944 TI - Family-based association analysis of functional VNTR polymorphisms in the dopamine transporter gene in migraine with and without aura. AB - Because of the role of dopamine in triggering migraine attacks, genes of the dopamine system are candidates for involvement in migraine. We examined three VNTR polymorphisms in the dopamine transporter, the 5'UTR VNTR, the intron 8 VNTR and the intron 14 VNTR, in a sample of 205 family trios. We used the transmission disequilibirium test (TDT) to examine the transmission of these three markers and their haplotypes to offspring affected by migraine. We found no significant transmission distortion of any marker. Likewise haplotypes of the three markers did not show significant overall or individual association with migraine. Finally we examined migraine with and without aura, and likewise found no association between dopamine transporter VNTRs or their haplotypes and either classification of the disease. We conclude that functional genetic variation in the dopamine transporter does not act as a significant risk factor for migraine. PMID- 17690945 TI - Serotonin transporter gene polymorphism and the phenotypic heterogeneity of adult ADHD. AB - The present study investigates possible associations between the 5-HTT control region polymorphism (5-HTTLPR) with adult ADHD, including subtypes, severity, temperament profile and comorbidities. The polymorphic site was genotyped in 312 adult patients with ADHD and 236 controls, all of them Brazilians of European descent. The interviews followed the DSM-IV criteria, using the K-SADS-E for ADHD and oppositional defiant disorder, SCID-I and MINI for comorbidities and the TCI for temperament dimensions. The 5-HTTLPR polymorphism was not associated with ADHD. Carriers of the S allele presented slightly higher inattention and novelty seeking scores, and a higher frequency of drug dependence. These differences do not persist after correction for multiple comparisons. These results suggest that the 5-HTTLPR polymorphism does not have a direct role in the predisposition to adult ADHD. There is suggestive evidence for a small effect in some behavioral phenotypes related to ADHD. PMID- 17690946 TI - Serum proteomic profiling of dementia with Lewy bodies: diagnostic potential of SELDI-TOF MS analysis. AB - Dementia with Lewy bodies (DLB) is the second most common senile degenerative dementia after Alzheimer's disease (AD). The presentation of overlapping symptoms between these two disorders leads to difficulties in the determination of clinical entities. Serum samples were subjected to surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) analysis in order to identify a diagnostic marker for DLB. Four putative protein peaks (m/z 3,883, 4,964, 7,761 and 10,534) were differentially expressed in DLB patients compared to AD patients and control subjects. Receiver operating characteristics (ROC) analysis of a multivariate logistic model of the combination of three peaks (m/z 3,883, 7,761 and 10,534) exhibited the highest discriminatory ability of DLB subjects from non-DLB subjects with a sensitivity of 83.3%, a specificity of 95.8%, a positive predictive value of 90.9% and a negative predictive value of 92.0%. SELDI-TOF MS profiling, therefore, has revealed a serum signature with high diagnostic potential for DLB. PMID- 17690948 TI - In parkinsonian substantia nigra, alpha-synuclein is modified by acrolein, a lipid-peroxidation product, and accumulates in the dopamine neurons with inhibition of proteasome activity. AB - alpha-Synuclein (alphaSYN) plays a central role in the neural degeneration of Parkinson's disease (PD) through its conformational change. In PD, alphaSYN, released from the membrane, accumulates in the cytoplasm and forms Lewy body. However, the mechanism behind the translocation and conformational change of alphaSYN leading to the cell death has not been well elucidated. This paper reports that in the dopamine neurons of the substantia nigra containing neuromelanin from PD patients, alphaSYN was modified with acrolein (ACR), an aldehyde product of lipid peroxidation. Histopathological observation confirmed the co-localization of protein immunoreactive to anti-alphaSYN and ACR antibody. By Western blot analyses of samples precipitated with either anti-alphaSYN or anti-ACR antibody, increase in ACR-modified alphaSYN was confirmed in PD brain. Modification of recombinant alphaSYN by ACR enhanced its oligomerization, and at higher ACR concentrations alphaSYN was fragmented and polymerized forming a smear pattern in SDS-PAGE. ACR reduced 20S proteasome activity through the direct modification of the proteasome proteins and the production of polymerized ACR modified proteins, which inhibited proteasome activity in vitro. These results suggest that ACR may initiate vicious cycle of modification and aggregation of proteins, including alphaSYN, and impaired proteolysis system, to cause neuronal death in PD. PMID- 17690947 TI - Homovanillic acid (HVA) plasma levels inversely correlate with attention deficit hyperactivity and childhood neglect measures in addicted patients. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) seems to be a risk condition for substance use disorders, possibly in relationship to common neurobiological changes, underlying both addictive and externalising behaviour susceptibility. Although this vulnerability has been primarily attributed to gene variants, previous studies suggest that also adverse childhood experiences may influence neurotransmission, affecting in particular brain dopamine (DA) system and possibly concurring to the development of behavioural disorders. Therefore, we decided to investigate ADHD symptoms and plasma concentrations of the DA metabolite homovanillic acid (HVA) in abstinent addicted patients, in comparison with healthy control subjects, evaluating whether ADHD scores were related with HVA levels, as expression of DA turnover, and whether HVA values, in turn, were associated with childhood emotional neglect. METHODS: Eighty-two abstinent drug dependent patients, and 44 normal controls, matched for age and sex, completed the Wender Utah Rating Scale (WURS), measuring ADHD symptoms, and the Childhood Experience of Care and Abuse Questionnaire (CECA-Q). Blood samples were collected to determine HVA plasma levels. RESULTS: Addicted individuals showed significantly higher ADHD scores and lower HVA levels respect to control subjects. ADHD scores at WURS in addicted patients negatively correlated with plasma HVA values. In turn, plasma HVA levels were inversely associated with childhood neglect measures, reaching statistical significance with "mother antipathy" and "mother neglect" scores. CONCLUSIONS: These findings suggest the possibility that childhood experience of neglect and poor mother-child attachment may have an effect on central dopamine function as an adult, in turn contributing to both ADHD and substance abuse neurobiological vulnerability. PMID- 17690949 TI - Brivaracetam is superior to levetiracetam in a rat model of post-hypoxic myoclonus. AB - In the present study, we evaluated the anti-seizure and anti-myoclonic activity of levetiracetam and brivaracetam in an established rat model of cardiac arrest induced post-hypoxic myoclonus. We found that brivaracetam (0.3 mg/kg, the minimal effective dose) was more potent than levetiracetam (3 mg/kg, the minimal effective dose) against post-hypoxic seizures. The anti-seizure activity of both compounds occurred 30 min following intraperitoneal (i.p.) administration and was maintained over the entire 150 min post-dose observation period. Both brivaracetam and levetiracetam significantly reduced auditory stimulated post hypoxic myoclonus from a dose 0.3 mg/kg. At that dose, the anti-myoclonic activity of brivaracetam was already maximal whereas it continued to increase in a dose-relation manner with levetiracetam, suggesting that brivaracetam is a more potent agent. The onset and the duration of anti-myoclonic activity of both compounds were similar. These findings demonstrate that brivaracetam possesses more potent anti-seizure and anti-myoclonic activity than levetiracetam in an established rat model of cardiac arrest-induced post-hypoxic myoclonus. PMID- 17690950 TI - Dietary amino acid taurine ameliorates liver injury in chronic hepatitis patients. AB - The effect of dietary amino acid taurine on the liver function of chronic hepatitis patients was investigated. The 24 chronic hepatitis patients with 2-5 times over normal activities of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) were selected and equally divided into taurine treatment and control groups. In taurine treatment group, each patient took 2 g taurine 3 times a day for three months, and then stopped treatment for 1 month. Patients taking placebo without taurine for 4 months served as a control group. ALT and AST activities and levels of cholesterol, triglyceride and thiobarbituric acid relative substances of serum plasma in the taurine group were all decreased at the end of three month treatment. The study suggested that dietary amino acid taurine may ameliorate liver injury for chronic hepatitis patients. PMID- 17690951 TI - Strain-dependent effects of cognitive enhancers in the mouse. AB - A series of cognitive enhancers (CEs) have been reported to increase spatial memory in rodents, information on behavioral effects, however, is limited. The aim of the study was therefore to examine the behavioral effects of three CEs in two well-documented inbred mouse strains. C57BL/6J and DBA/2 mice were administered intraperitonial. D-cycloserine (DCS; NMDA receptor agonist), 1-(4 Amino-5-chloro-2-methoxyphenyl)-3-[1-butyl-4-piperidinyl]-1-propanone hydrochloride (RS67333; 5HT4-receptor agonist), and (R)-4-{[2-(1-methyl-2 pyrrolidinyl)ethyl]thio}phenol hydrochloride (SIB-1553A; beta-4-nicotinic receptor agonist) and tested in the open field (OF), elevated plus maze (EPM), neurological observational battery and rota-rod. Cognitive performance was tested in the Morris water maze. All compounds modified behavioral performance in the OF, DCS showed an anxiolytic effect in the EPM, and differences in the observational battery were observed i.e. vestibular drop was decreased by SIB 1553A and RS67333 treatment in C57BL/6J and increased with DCS treatment in DBA/2 mice. In the rota rod SIB-1553A improved motor performance. DCS effects on learning and memory was comparable to controls whereas the other compounds impaired performance in the Morris water maze. In conclusion, behavioral testing of CEs in the mouse revealed significant changes that may have to be taken into account for evaluation of CEs, interpretation of cognitive studies and warrant further neurotoxicological studies. Moreover, strain-dependent differences were observed that in turn may confound results obtained from behavioral and cognitive testing. PMID- 17690952 TI - Depression and treatment with inner city pregnant and parenting teens. AB - BACKGROUND: Between a quarter and half of pregnant adolescents are estimated to be depressed (Beardslee et al. 1988). Two recent open clinical trials found significant drops in depression levels among pregnant and newly parenting inner city teenagers after 12 weeks of Interpersonal Psychotherapy modified for pregnant teenagers (Miller et al. submitted). The current study addresses the nature of and contributors to participants' depression, and the active ingredients in their healing. METHOD: Qualitative analyses of therapy sessions, clinical notes and post hoc interviews of clinicians were integrated with questionnaire data. RESULTS: The most common symptoms of participant depression (n = 80) were anger/irritability and sadness and the cluster of depressive symptoms with the greatest variance was characterized by shame and guilt. Participants attributed symptoms of depression to feeling trapped or wronged, when family members were sad or rejecting and when the symptoms functioned to help participants meet their needs. Experiences associated with symptom relief were validation of pregnancies, successful use of self-advocacy and boundary setting skills and recognition of passage through important transitions. Support from participants' mothers was instrumental. CONCLUSIONS: Interpersonal contexts may be pivotal in contributing, maintaining and/or alleviating depression among poor urban pregnant and newly parenting adolescents. PMID- 17690953 TI - The influence of surface trapping and dark states on the fluorescence emission efficiency and lifetime of CdSe and CdSe/ZnS quantum dots. AB - To investigate the influence of surface trapping and dark states on CdSe and CdSe/ZnS quantum dots (QDs), we studied the absorption, fluorescence intensity and lifetime by using one-and two-photon excitation, respectively. Experimental results show that both one- and two-photon fluorescence emission efficiencies of the QDs enhance greatly and the lifetime increase after capping CdSe with ZnS due to the effective surface passivation. The lifetime of one-photon fluorescence of CdSe and CdSe/ZnS QDs increase with increasing emission wavelength in a supralinear way, which is attributed to the energy transfer of dark excitons. On the contrary, the lifetime of two-photon fluorescence of bare and core-shell QDs decrease with increasing emission wavelength, and this indicates that the surface trapping is the dominant decay mechanism in this case. PMID- 17690954 TI - The phenomenon of spontaneous genetic reversions in the Wiskott-Aldrich syndrome: a report of the workshop of the ESID Genetics Working Party at the XIIth Meeting of the European Society for Immunodeficiencies (ESID). Budapest, Hungary October 4-7, 2006. AB - The Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disease caused by mutations in the Wiskott-Aldrich Protein (WASP) gene, which typically leads to absent WASP protein expression in WAS leukocytes. However, some patients have been found with small populations of WASP-expressing cells caused by reverse or second-site mutations that allow protein expression. An international consortium was established to further investigate these phenomena. This paper summarizes data collected by this consortium that was presented at a workshop held during the XIIth Meeting of the European Society for Immunodeficiencies (ESID), October, 2006. WASP reversions were noted in approximately 11% of 272 patients tested. Many different cell lineages showed reversions. These data form the foundation for further investigation into this phenomenon, which has implications for therapy of this disease. PMID- 17690955 TI - Resetting the adaptive immune system after autologous stem cell transplantation: lessons from responses to vaccines. AB - Autologous stem cell transplantation (ASCT) to treat autoimmune diseases (AID) is thought to reset immunological memory directed against autoantigens. This hypothesis can only be studied indirectly because the exact nature of the pathogenetic autoantigens is unknown in most AID. Therefore, 19 children with juvenile idiopathic arthritis (JIA) or systemic lupus erythematodes (SLE) and 10 adults with multiple sclerosis (MS) were vaccinated with the T-cell-dependent neoantigen rabies and the recall antigen tetanus toxoid after, respectively before, bone marrow harvest. Both vaccinations were repeated after ASCT. All except two of the responders mounted a primary antibody response to rabies after revaccination, and 44% of the responders mounted a primary antibody response to tetanus boost after ASCT. These data show that immunological memory to a neoantigen is lost in most patients with AID after immunoablative pretreatment; however, memory to a recall antigen boosted before bone marrow harvest is only lost in part of the patients. Disease progression was arrested in all patients with JIA/SLE except one, but only in a minority of MS patients. Clinical outcome on a per case basis was not associated with the profile of the immune response toward the vaccination antigens after ASCT. PMID- 17690956 TI - Deception detection expertise. AB - A lively debate between Bond and Uysal (2007, Law and Human Behavior, 31, 109 115) and O'Sullivan (2007, Law and Human Behavior, 31, 117-123) concerns whether there are experts in deception detection. Two experiments sought to (a) identify expert(s) in detection and assess them twice with four tests, and (b) study their detection behavior using eye tracking. Paroled felons produced videotaped statements that were presented to students and law enforcement personnel. Two experts were identified, both female Native American BIA correctional officers. Experts were over 80% accurate in the first assessment, and scored at 90% accuracy in the second assessment. In Signal Detection analyses, experts showed high discrimination, and did not evidence biased responding. They exploited nonverbal cues to make fast, accurate decisions. These highly-accurate individuals can be characterized as experts in deception detection. PMID- 17690957 TI - Moving forward: response to "Studying eyewitness investigations in the field". AB - Field studies of eyewitness identification are richly confounded. Determining which confounds undermine interpretation is important. The blind administration confound in the Illinois study is said to undermine it's value for understanding the relative utility of simultaneous and sequential lineups. Most criticisms of the Illinois study focus on filler identifications, and related inferences about the importance of the blind confound. We find no convincing evidence supporting this line of attack and wonder at filler identifications as the major line of criticism. More debilitating problems impede using the Illinois study to address the simultaneous versus sequential lineup controversy: inability to estimate guilt independent of identification evidence, lack of protocol compliance monitoring, and assessment of lineups quality. Moving forward requires removing these limitations. PMID- 17690958 TI - A practical intervention to increase breastfeeding initiation among Cambodian women in the US. AB - Cambodians have the lowest breastfeeding initiation rate of any racial/ethnic group in Massachusetts. One barrier to breastfeeding is a lack of hospital foods that allow women to follow a traditional diet postpartum. We examined whether a culturally acceptable menu for new Cambodian mothers would increase breastfeeding initiation in the hospital. After a staff training program on breastfeeding, and the creation of a Cambodian menu, initiation rates increased significantly more in Cambodians than in non-Cambodians. Pre intervention, breastfeeding initiation was 16.7% (2/12) among Cambodians, compared to 60.6% (106/175) among non Cambodians (P = 0.003). Post intervention, there was no significant difference between breastfeeding initiation rates among Cambodian women (66.7%; 8/12) compared to non-Cambodians (68.9%; 104/151) (P = 0.874). PMID- 17690959 TI - Prevalence of children with special health care needs in metropolitan and micropolitan statistical areas in the United States. AB - OBJECTIVES: We estimate the prevalence of children with special health care needs (CSHCN) in 70 metropolitan and four micropolitan statistical areas across the United States. METHODS: The data are from the 2001 National Survey of CSHCN, which was sponsored by the Maternal and Child Health Bureau and conducted by the National Center for Health Statistics. Prevalence estimates were generated for 74 metropolitan and micropolitan statistical areas (M/MSAs) and 45 individual counties that were represented by at least 1,000 children in the sample. To generate the estimates, the child-level sample weights (representative at the national and state level) were recalibrated within each M/MSA and county to match Census 2000 counts of the child population by age, sex, and Hispanic ethnicity. RESULTS: M/MSA-level and county-level prevalence of CSHCN are compared with national- and state-level prevalence, and within M/MSAs and counties, prevalence is reported by age, sex and race/ethnicity. Most, but not all, M/MSA- or county level prevalence estimates did not differ significantly from state-level estimates. Some M/MSAs and counties that did not differ from their states in overall prevalence of CSHCN did show some differences in prevalence for certain demographic subgroups. CONCLUSIONS: Metropolitan health departments and Maternal and Child Health agencies that serve urban areas may find these new small area estimates useful for program planning purposes. This study demonstrates the importance of assessing whether state estimates may approximate local area estimates of the prevalence of CSHCN. PMID- 17690960 TI - Correlates of prenatal alcohol use. AB - OBJECTIVE: S: To identify correlates of prenatal alcohol use in a statewide population-based sample. METHODS: A self-reported survey was conducted in 67 prenatal clinics in Minnesota with 4,272 women at their first prenatal visit. Chi squared and multivariate logistic regression analyses were conducted to identify risk markers associated with any prenatal alcohol use. RESULTS: Nearly 27% of the respondents were calculated as having used alcohol during pregnancy. In multivariable analyses, the following were risk markers for prenatal alcohol use: older age, being unmarried, lower gravidity, greater depressed mood, currently smoking, exposure to intrapersonal violence, a history of not remembering things because of alcohol use, and feelings that the respondent should reduce her drinking. Subsequent analyses revealed that the association of intrapersonal violence with prenatal drinking was mediated by whether the woman reported that she did not remember things while drinking or that the woman felt she should reduce her drinking. CONCLUSIONS: The demographic and behavioral correlates reported here are consistent with previous research. The significance of two alcohol behavioral factors (i.e., not remembering things and feeling that she should reduce her drinking) suggest that the women who drank during pregnancy would likely have substance abuse issues. PMID- 17690961 TI - A secondary analysis of race/ethnicity and other maternal factors affecting adverse birth outcomes in San Bernardino County. AB - Objectives Though it is the largest county in the lower United States, minimal attention has been given to the elevated rates of poor perinatal outcomes and infant mortality in San Bernardino County. This study sought to analyze adverse birth outcomes such as low birth weight, and infant mortality as an outcome of specific proxy maternal sociodemographic factors. Methods Data from the California Department of Health Services Office of Vital Statistics birth cohort of mothers delivering between 1999 and 2001 (N = 1,590,876 participants) were analyzed. Of those, 5.5% (n = 86,736) were births in San Bernardino County. Low birth weight, very low birth weight, death in infants less than one year of age, and other maternal sociodemographic factors were explored. All events of low birth weight and deaths among infants less than one year of age were used as significant variables in statistical models. Results Black mothers experienced more than twice the rate of very low birth weight (3.89) than their White counterparts (1.39). The most significant contributors to adverse birth outcomes among Black women were length of gestation and maternal education, whereas the most significant predictor of infant mortality was birth weight. Conclusions This study demonstrates that traditional risk factors such as length of gestation and maternal age only partially explain adverse birth outcomes. These findings highlight the need to advocate for the systematic collection of data on maternal education and length gestation and for the promotion of public health initiatives that address these inequities in our most vulnerable of populations. PMID- 17690962 TI - Poverty and cumulative hospitalization in infancy and early childhood in the Quebec birth cohort: a puzzling pattern of association. AB - OBJECTIVE: We anticipate a negative gradient between income and hospitalization, since income is positively associated with good health. In a previous cross sectional study, we reported an unexpected pattern of association between poverty and hospitalization for 5-month-old infants in Quebec. This study re-examines the poverty-hospitalization relationship within a longitudinal population study of the same birth cohort aged 3.5 years. METHOD: Life table analysis, multivariable proportional hazard regression, and multivariable logistic regression were performed on data from the first four waves of the Quebec Longitudinal Study of Child Development (QLSCD). Probabilities of hospitalization were estimated by poverty status. The hazard ratios (HR) (Cox-regression) for duration of poverty (frequency of insufficient income) and severity of poverty (combining frequency and level of income insufficiency) were estimated, controlling for predisposing, enabling, and need determinants of hospitalization. RESULTS: At 3.5 years, 31% of children had been hospitalized at least once. Compared with children whose families had constantly sufficient income, children with intermittent poverty exhibited higher hospitalization risks (HR = 1.30; 95%CI = 1.04-1.64) while chronically poor children exhibited comparable hospitalization hazards (HR = 0.97; 95%CI = 0.73-1.27). Hospitalization risks for children in the severest poverty group resembled that of the non-poor group (HR = 0.99; 95%CI = 0.66 1.49), while children in less severely poor families were more likely to be hospitalized (HR = 1.26; 95%CI = 0.99-1.60). CONCLUSION: Results suggest hospitalization barriers for children living in chronic and severe poverty. If these barriers exist in a universal health care system, they may originate with primary care service organization or hospital care referral procedures. PMID- 17690963 TI - An enhanced method for identifying obstetric deliveries: implications for estimating maternal morbidity. AB - OBJECTIVES: The accuracy of maternal morbidity estimates from hospital discharge data may be influenced by incomplete identification of deliveries. In maternal/infant health studies, obstetric deliveries are often identified only by the maternal outcome of delivery code (International Classification of Diseases code = V27). We developed an enhanced delivery identification method based on additional delivery-related codes and compared the performance of the enhanced method with the V27 method in identifying estimates of deliveries as well as estimates of maternal morbidity. METHODS: The enhanced and standard V27 methods for identifying deliveries were applied to data from the 1998-2004 Healthcare Cost and Utilization Project Nationwide Inpatient Sample, an annual nationwide representative survey of U.S. hospitalizations. Odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression were used to examine predictors of deliveries not identified using the V27 method. RESULTS: The enhanced method identified 958,868 (3.4%) more deliveries than the 27,128,539 identified using the V27 code alone. Severe complications including major puerperal infections (OR = 3.1, 95% CI 2.8-3.4), hysterectomy (OR = 6.0, 95% CI 5.3-6.8), sepsis (OR = 11.9, 95% CI 10.3-13.6) and respiratory distress syndrome (OR = 16.6, 95% CI 14.4-19.2) were strongly associated with deliveries not identified by the V27 method. Nationwide prevalence rates of severe maternal complications were underestimated with the V27 method compared to the enhanced method, ranging from 9% underestimation for major puerperal infections to 40% underestimation for respiratory distress syndrome. CONCLUSION: Deliveries with severe obstetric complications may be more likely to be missed using the V27 code. Researchers should be aware that selecting deliveries from hospital stay records by V27 codes alone may affect the accuracy of their findings. PMID- 17690964 TI - Infant feeding attitudes and knowledge among socioeconomically disadvantaged women in Glasgow. AB - OBJECTIVES: This study: (1) investigated infant feeding attitudes and knowledge among socioeconomically disadvantaged mothers in an urban community with historically low breastfeeding rates, (2) examined the influence of women's social networks on infant feeding attitudes and decisions, and (3) validated a measure of infant feeding attitudes and knowledge in this population (Iowa Infant Feeding Attitude Scale, IIFAS). METHODS: Women attending a prenatal clinic (n=49) reported on: (1) demographics, (2) infant feeding attitudes and knowledge (IIFAS), (3) feeding intent, (4) opinions about breastfeeding in public, and (5) social networks. Feeding method at discharge was abstracted from hospital charts. Social network members (n=47) identified by the prenatal sample completed interviews covering: (1) demographics, (2) infant feeding attitudes and knowledge (IIFAS), (3) prior infant feeding methods and recommendations, and (4) opinions about breastfeeding in public. RESULTS: Mean IIFAS scores were low in both groups, indicating neutral to negative breastfeeding attitudes; mothers' scores were lower than social network members. Higher maternal IIFAS score was significantly associated with intended and actual breastfeeding. A social network positive towards breastfeeding was significantly associated with mothers' positive attitude towards breastfeeding. Both mothers and social network members support breastfeeding in public. IIFAS internal consistency was robust for both mothers and social network members. Predictive validity was demonstrated by significant positive association between score and intended and actual feeding methods. CONCLUSIONS: Knowledge and attitude predict breastfeeding initiation in this population. Social network members may influence mothers' feeding choices. This research is important because attitudes and knowledge derived from the IIFAS can be used to develop and evaluate breastfeeding promotion programs. PMID- 17690965 TI - The effects of anti-adhesion materials in preventing postoperative adhesion in abdominal cavity (anti-adhesion materials for postoperative adhesions). AB - PURPOSE: The purpose of this study was to compare the effects of anti-adhesion materials in postoperative adhesions. MATERIALS AND METHODS: Rats were assigned to five groups: Group 1: Control. Group 2: chitin layers were used. Group 3: Na hyaluronate / carboxymethylcellulose layers were used. Group 4: Na-hyaluronate gel was poured into the abdomen. Group 5: methylprednisolone was injected. The adhesion frequency and grade were scored according to Granat. Blood was taken for Hb, AST, BUN and albumin levels determination. FINDINGS: The adhesion frequencies (right and left) and grades were as follow in Groups; I: 82%, 91%, 2.63 +/- 1.22; II: 8.3%, 25%, 0.58 +/- 0.66; III: 17%, 33%, 1.08 +/- 1.08; IV: 50%, 58%, 1.41 +/ 1.44; V: 50%, 42%, 1.41 +/- 1.50. The adhesion phase in all study groups was found significantly low compared to control group, p < 0.05. No difference was observed among serologic and hematological parameters in all groups. CONCLUSION: All the materials used significantly lowered the adhesion frequency and grade. PMID- 17690966 TI - A randomized trial comparing effects of radiofrequency and cryoablation on the structural integrity of esophageal tissue. AB - BACKGROUND: Esophageal injury is a rare, but catastrophic complication of radiofrequency (RF) pulmonary vein isolation. It is not known if cryoablation is less likely to injure esophageal tissue. The purpose of this study is to compare the effects of RF and cryoablation on the structural integrity of esophageal tissue. METHODS AND RESULTS: Porcine esophageal tissue was sectioned into 396 strips measuring 3 mm in width by 30 mm in length. Samples were randomly assigned to receive no ablation (149 specimens in the control group), RF ablation (126 specimens) or cryoablation (121 specimens). A single ablation was administered in the center of the tissue sample. A force gauge was used to measure the tensile strength of the tissue sample in Newtons. Groups were compared using ANOVA and a Bonferroni post-test. The mean tensile strength in the control group was 2.19 N (SD, 2.17), 1.66 N (SD, 0.88) for RF ablated tissue and 1.96 N (SD, 1.68) for cryo. RF ablation resulted in a significant reduction in esophageal tensile strength when compared to control (t = 2.59), however cryo did not (t = 1.11). On microscopic evaluation RF ablation disrupted elastic fiber architecture whereas cryoablation did not. CONCLUSIONS: Cryoablation has no significant adverse impact on the structural integrity of esophageal tissue. Cryoablation may be a safer alternative to RF for left atrial ablation and reduce the risk of esophageal injury and atrial-esophageal fistula formation. PMID- 17690967 TI - Using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule with young children with developmental delay: evaluating diagnostic validity. AB - Few studies have focused on the validity of the ADI-R and ADOS in the assessment of preschool children with developmental delay. This study aimed to evaluate the diagnostic validity of the ADI-R and the ADOS in young children. Two-hundred and nine children aged 20-55 months participated in the study, 120 of whom received a diagnosis of autism. ADI-R and ADOS diagnostic classifications were compared to consensus clinical diagnoses. Children with a clinical diagnosis of autism scored significantly higher on all algorithm domains of the ADI-R and ADOS. The ADOS performed better than the ADI-R in comparison to consensus clinical diagnosis. Characteristics of the ADI-R and ADOS false positive and false negative cases are explored. Further research is recommended in terms of examining which items of the ADI-R best predict a diagnosis of autism for very young children with developmental problems. PMID- 17690968 TI - Injury treatment among children with autism or pervasive developmental disorder. AB - This study examined the differences in the frequency and type of injury for children with autism and pervasive developmental disorder (PDD) compared with typically developing peers, when both groups are insured by Medicaid. The relative rate (RR) of emergency/hospital treatment of injury for children with autism or PDD compared to controls was 1.20 [95% Confidence Interval (CI) 1.04 1.39] after controlling for age and gender. Children with autism or PDD had a higher rate for head, face, and neck injuries (RR 1.47, 95% CI 1.13-1.90) and lower rate for sprains and strains (RR 0.54, 95% CI 0.32-0.91). Treatment for poisoning was 7.6 times as frequent, and self-inflicted injury was also 7.6 times as frequent for children with autism or PDD. PMID- 17690969 TI - Medical expenditures for children with an autism spectrum disorder in a privately insured population. AB - This study provides estimates of medical expenditures for a subset of children and adolescents who receive employer-based health insurance and have a medical diagnosis of an autism spectrum disorder (ASD). Data analyzed were from the 2003 MarketScan research databases. Individuals with an ASD had average medical expenditures that exceeded those without an ASD by $4,110-$6,200 per year. On average, medical expenditures for individuals with an ASD were 4.1-6.2 times greater than for those without an ASD. Differences in median expenditures ranged from $2,240 to $3,360 per year with median expenditures 8.4-9.5 times greater. These findings add to a growing body of evidence that children and adolescents with medical diagnoses of an ASD incur elevated medical utilization and costs. PMID- 17690970 TI - Correlates of early overt and covert sexual behaviors in heterosexual women. AB - We used data provided by 417 Kinsey-0 and Kinsey-1 heterosexual women using an anonymous computerized survey to determine the adult correlates of two female female behaviors that occurred before age 18; 25.4% of participants reported engaging in one or both behaviors. Sexual experimentation with females and masturbating using images of females before age 18 were statistically significant predictors of four different female-female behaviors in adulthood: sexual contact with females, masturbating using images of females, preferring a female fantasy partner while having sex with a favorite (male) partner, and voyeurism directed at females; 27.3% of the participants reported engaging in one or more of the latter four behaviors. The analogous early female-male behaviors were not statistically significant predictors of female-female behaviors in adults. Conditioning resulting from participation in these early female-female behaviors might explain the correlations between the two early behaviors and the subsequent four adult same-gender behaviors. The earliest and latest ages that participants engaged in each early behavior and case-by-case analysis showed that the sequence of events leading to the female-female adult behaviors was initial sexual experimentation with similar age females (at a median age of 9 years) followed by masturbating using images of females (at a median age of 15). These results suggest that conditioning and other forms of learning play an important role in establishing coexisting same-gender orientations in heterosexual women. PMID- 17690971 TI - Associations between crystal methamphetamine use and potentially unsafe sexual activity among gay men in Australia. AB - It has been suggested that crystal methamphetamine may have disinhibiting or aphrodisiac effects, which may lead to unsafe sexual behavior and increase the risk of HIV transmission. Using data from two Australian studies, the Sydney Gay Community Periodic Survey study and the Positive Health (PH) cohort study, we examined changes over time in use of crystal, other recreational drugs, and Viagra, and in a range of sex-related behaviors. Compared to non-users, crystal users reported having more sex partners, looking for sex in more types of venues, and being more likely to engage in unprotected anal intercourse with casual partners (UAIC) and in esoteric sex. Crystal users were also more likely to be using other recreational drugs and Viagra than non-users. Crystal use remained significantly associated with UAIC after adjustment for other relevant variables in a log-binomial regression analysis (adjusted prevalence rate ratio=1.26; 95% CI: 1.19-1.34). The other variables (HIV status, number of sex partners, number of types of venue where men looked for sex, Viagra use, other drug use) were independently associated with UAIC, and did not show confounding or mediating effects on the crystal-UAIC association. Nevertheless, these data did not allow reliable attribution of higher levels of these sex-related behaviors among crystal users specifically to the effects of crystal. The prevalence of crystal use among Australian men who have sex with men (MSM) increased between 2002 and 2005 (e.g., from 26% to 39% among HIV-+ MSM). However, the prevalence of UAIC remained stable or decreased over time in various study subgroups, as did the prevalence of other sex-related behaviors, suggesting that crystal use does not necessarily drive unsafe sexual behavior. Crystal use and unsafe sexual behavior can, and should, be considered and addressed separately in health promotion and community education campaigns. PMID- 17690972 TI - Sexual abuse in childhood and physical and mental health in adulthood: an Australian population study. AB - Although childhood sexual abuse (CSA) is associated with a wide range of health problems later in life, there is also evidence of substantial individual differences. This study describes the mental and physical health of a population sample of Australians, randomly selected from the Commonwealth electoral roll, who have reported their CSA histories. Some 58% of those located from the electoral roll agreed to a telephone interview (n=1,784). Health status was measured using the Short Form 36 questionnaire. Men who had experienced non penetrative and penetrative sexual abuse in childhood had 2.25 (95% CI=1.32-3.82) and 5.93 (95% CI=2.72-12.95) times respectively the rate of impaired mental health, but no higher rates of impaired physical health. Women who had experienced non-penetrative and penetrative sexual abuse in childhood had 1.87 (95% CI=1.19-2.95) and 3.15 (95% CI=1.87-5.33) times respectively the rate of impaired mental health and 1.87 (95% CI=1.19-2.92) and 2.31 (95% CI=1.34-3.97) times respectively the rate of impaired physical health. However, participants who had experienced CSA were no less likely than those who had not experienced CSA to be in optimum physical and mental health. None of the possible confounding or moderating variables tested appeared to mitigate the impact of CSA on health outcomes. Those with the highest levels of mental and physical health appear to be unaffected by the experience of CSA. PMID- 17690973 TI - Beliefs about treatments for HIV/AIDS and sexual risk behaviors among men who have sex with men, 1997-2006. AB - Beliefs that HIV treatments reduce HIV transmission risks are related to increases in sexual risk behaviors, particularly unprotected anal intercourse among men who have sex with men (MSM). Changes in unprotected anal intercourse and prevention-related treatment beliefs were recently reported for surveys of mostly white gay men collected in 1997 and 2005. The current study extends this previous research by replicating the observed changes in behaviors and beliefs in anonymous community surveys collected in 2006. Results indicated clear and consistent increases in beliefs that HIV treatments reduce HIV transmission risks and increases in unprotected anal intercourse. These changes were observed for both HIV positive and non-HIV positive men. African American men endorsed the belief that HIV treatments protect against HIV transmission to a greater degree than White men. Results show that HIV prevention messages need to be updated to educate MSM about the realities of HIV viral concentrations and HIV transmission risks. PMID- 17690974 TI - Predictors of risky sexual behavior among adolescents in Tanzania. AB - Studies on sexual behavior among adolescents are fundamental in understanding and fighting against outcomes of unprotected sex that include unplanned/unwanted pregnancies and sexually transmitted diseases. This survey conducted among in- and out-of-schools adolescents measured prevalence of sexual behavior variables, including risky sexual behavior and associated factors. Risky sexual behavior was defined as having first sex before 16 years, inconsistent condom use and having multiple sexual partners. About 30% of adolescents reported being sexually active; a higher proportion being among males than females and 24.5% of sexually active adolescents reported having multiple sexual partners. More males (37%) reported having multiple sexual partners than females (26%). Nearly 48% of unmarried sexually active adolescents reported having used a condom during the most recent sexual intercourse. Predictors of risky sexual behavior were being male, young age (10-14 years) and being inschool. Preventive information and education should take into consideration these factors. PMID- 17690976 TI - Gender and ethnic diversity in NIMH-funded clinical trials: review of a decade of published research. AB - A total of 379 NIMH-funded clinical trials published between 1995 and 2004 in five major mental health journals were assessed on their inclusion of women and racial/ethnic groups in their study recruitment. Findings showed that whereas most of the studies reported gender information and gender representation was balanced across studies, less than half of the studies provided complete racial/ethnic information. All racial/ethnic groups except Whites and African Americans were underrepresented, a pattern that has not improved significantly over the last decade. Less than half of the studies had potential for subgroup analyses by gender and race/ethnicity. PMID- 17690975 TI - The relationship of sexual dyad and personal network characteristics and individual attributes to unprotected sex among young injecting drug users. AB - We examine in the heterosexual partnerships (dyads) of IDUs the correlates of engaging in unprotected sex on three levels: individual attributes, social network characteristics, and dyad characteristics. Unprotected sex was significantly less likely to occur in dyads where the participant injected daily or had high safe-sex attitude scores, and in dyads where both members encouraged each other to use condoms. Unprotected sex was significantly more likely to occur in dyads that smoked crack together, shared needles with each other, and where the participant knew that the sex partner had concurrent sex partners. In the sexual dyads of IDUs there is a combined risk of unsafe injecting and unsafe sex. Both injecting and sexual risk, and their combination need to be addressed in interventions that target the sexual partnerships of IDUs. Such interventions should also aim to reduce injected and non-injected crack and other stimulant use associated with high-risk sex. PMID- 17690977 TI - Genetic support for the dual nature of attention deficit hyperactivity disorder: substantial genetic overlap between the inattentive and hyperactive-impulsive components. AB - OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a common, complex and highly heritable disorder, characterised by inattentive, impulsive and overactive behaviour. Evidence for the heritability of ADHD measures in twin population samples has come from the analysis of total scores that combine inattentive and hyperactive-impulsive symptoms subscales. This study investigated, in a community sample, the aetiology of ADHD-like traits and the aetiological overlap between the two dimensions that define the ADHD disorder. MATERIALS AND METHODS: Parents of 6,222 approximately 8-year-old twin pairs from the Twins Early Development Study (TEDS) population sample completed the two subscales of the Conners' 18-item DSMIV checklist, a screening instrument for ADHD symptoms. RESULTS: Both subscales were highly heritable (hyperactive impulsive: 88%; inattentive: 79%). Bivariate genetic modelling indicated substantial genetic overlap between the two components; however, there were significant independent genetic effects. CONCLUSIONS: These findings suggest that many genes associated with the hyperactivity-impulsivity dimension will also be associated with the inattentive dimension but that there is significant genetic heterogeneity as well. These results provide genetic support for combining the two behavioural dimensions that define ADHD, but also suggest that some symptom specific genes will also be identified. PMID- 17690978 TI - Number of STR repeats as a potential new quantitative genetic marker for complex diseases, illustrated by schizophrenia. AB - It has proved difficult to find strong and replicable genetic linkages for complex diseases, since each susceptibility gene makes only a modest contribution to onset. This is partly because high-efficacy genetic markers are not usually available. The aim of this article is to explore the possibility that the total number of tandem repeats in one STR locus, rather than the frequencies of different alleles, is a higher efficacy quantitative genetic marker. DNA samples were collected from schizophrenic patients and from a control population. Alleles of the short tandem repeats (STR) loci D3S1358, vWA, and FGA were determined using the STR Profiler Plus PCR amplification kit. The two groups did not differ statistically in the frequencies of alleles at the D3S1358, vWA, or FGA loci. However, a significant difference was obtained in the vWA locus when the total number of core unit repeats was compared between the schizophrenia and control groups (33.28+/-2.61 vs. 32.35+/-2.58, P<0.05). It seems that the number of STR repeats may be a new, quantitative, and higher efficacy genetic marker for directly indicating genetic predisposition to complex hereditary diseases such as schizophrenia. PMID- 17690979 TI - A single nucleotide substitution (-107C-->G) in the hMLH1 promoter found in colorectal cancer population reduces transcriptional activity. AB - Inactivation of the DNA mismatch repair gene hMLH1 predisposes one to colorectal cancer. We have identified a C to G nucleotide substitution at position -107 relative to the hMLH1 gene translation initiation site in three of 163 colorectal cancer patients with an allele frequency of 0.0092 (3/326). One of the three 107G alleles occurred in one patient out of five with reduced hMLH1 expression in the tumor tissue. The -107G was not found in 63 healthy individuals. This substitution reduced transcriptional activity by 51% compared with -107C (P<0.01) and impeded the promoter-binding capacity of nuclear proteins. Although the small number of identified -107G alleles is insufficient to evaluate the contribution to the carcinogenesis and clinicopathological properties of the tumors, the effects of -107G on hMLH1 gene transcription and nuclear protein binding to the promoter sequence implicate the site, including -107C, as a crucial element interacting with the activator that maintains hMLH1 gene expression. PMID- 17690980 TI - The organization and financing of end-stage renal disease treatment in Japan. AB - End-stage renal disease (ESRD) affects 230,000 Japanese, with about 36,000 cases diagnosed each year. Recent increases in ESRD incidence are attributed mainly to increases in diabetes and a rapidly aging population. Renal transplantation is rare in Japan. In private dialysis clinics, the majority of treatment costs are paid as fixed fees per session and the rest are fee for service. Payments for hospital-based dialysis are either fee-for-service or diagnosis-related. Dialysis is widely available, but reimbursement rates have recently been reduced. Clinical outcomes of dialysis are better in Japan than in other countries, but this may change given recent ESRD cost containment policies. PMID- 17690983 TI - The effect of regional variations of the trabecular bone properties on the compressive strength of human vertebral bodies. AB - Cancellous centrum is a major component of the vertebral body and significantly contributes to its structural strength and fracture risk. We hypothesized that the variability of cancellous bone properties in the centrum is associated with vertebral strength. Microcomputed tomography (micro-CT)-based gray level density (GLD), bone volume fraction (BV/TV), and finite element modulus (E) were examined for different regions of the trabecular centrum and correlated with vertebral body strength determined experimentally. Two sets of images in the cancellous centrum were digitally prepared from micro-CT images of eight human vertebral bodies (T10-L5). One set included a cubic volume (1 per vertebral centrum, n = 8) in which the largest amount of cancellous material from the centrum was included but all the shell materials were excluded. The other set included cylindrical volumes (6 per vertebral centrum, n = 48) from the anterior (4 regions: front, center, left, and right of the midline of vertebra) and the posterior (2 regions: left and right) regions of the centrum. Significant positive correlations of vertebral strength with GLD (r (2) = 0.57, p = 0.03) and E (r (2) = 0.63, p = 0.02) of the whole centrum and with GLD (r (2) = 0.65, p = 0.02), BV/TV (r (2) = 0.72, p = 0.01) and E (r (2) = 0.85, p = 0.001) of the central region of the vertebral centrum were found. Vertebral strength decreased with increasing coefficient of variation of GLD, BV/TV, and E calculated from subregions of the vertebral centrum. The values of GLD, BV/TV, and E in centrum were significantly smaller for the anterior region than for the posterior region. Overall, these findings supported the significant role of regional variability of centrum properties in determining the whole vertebral strength. PMID- 17690982 TI - Using information technology to evaluate the detection of co-occurring substance use disorders amongst patients in a state mental health system: implications for co-occurring disorder state initiatives. AB - The current study describes a system-wide method of evaluating detection strategies for co-occurring disorders within a state mental health system. Information technology was used to merge administrative datasets from the New Jersey mental health and substance abuse systems and identify individuals treated in both systems. We measured a 53% detection rate of substance use disorders amongst adult patients in the mental health system with particularly low detection rates in acute settings (49.0%) and among female (43.7%), older (36.2%), and psychotic patients (43.6%). The methodology described here could help evaluate critical aspects of ongoing state co-occurring disorder quality improvement initiatives. PMID- 17690984 TI - Neuropsychological consequences of opiate use. AB - Approximately 3.7 million individuals have used heroin and other opiate substances in their lifetime. Despite increasing knowledge of the effects of heroin, it remains the most abused opiate and use among adults has recently increased. The empirical literature examining the neurocognitive effects of acute and chronic opioid use remains limited; however, findings to date suggest that the use of opiates has both acute and long-term effects on cognitive performance. Neuropsychological data indicate deficits in attention, concentration, recall, visuospatial skills and psychomotor speed with both acute and chronic opioid use. The long-term effects of opiate use appear to have the greatest impact on executive functions, including the ability to shift cognitive set and inhibit inappropriate response tendencies. Factors that contribute to addiction and recovery are also discussed, as it is difficult to disentangle the effects of opiate use on cognitive performance from other factors that may affect neurobehavioral measures. PMID- 17690985 TI - The effects of tobacco smoke and nicotine on cognition and the brain. AB - Tobacco smoke consists of thousands of compounds including nicotine. Many constituents have known toxicity to the brain, cardiovascular, and pulmonary systems. Nicotine, on the other hand, by virtue of its short-term actions on the cholinergic system, has positive effects on certain cognitive domains including working memory and executive function and may be, under certain conditions, neuroprotective. In this paper, we review recent literature, laboratory and epidemiologic, that describes the components of mainstream and sidestream tobacco smoke, including heavy metals and their toxicity, the effect of medicinal nicotine on the brain, and studies of the relationship between smoking and (1) preclinical brain changes including silent brain infarcts; white matter hyperintensities, and atrophy; (2) single measures of cognition; (3) cognitive decline over repeated measures; and (4) dementia. In most studies, exposure to smoke is associated with increased risk for negative preclinical and cognitive outcomes in younger people as well as in older adults. Potential mechanisms for smoke's harmful effects include oxidative stress, inflammation, and atherosclerotic processes. Recent evidence implicates medicinal nicotine as potentially harmful to both neurodevelopment in children and to catalyzing processes underlying neuropathology in Alzheimer's Disease. The reviewed evidence suggests caution with the use of medicinal nicotine in pregnant mothers and older adults at risk for certain neurological disease. Directions for future research in this area include the assessment of comorbidities (alcohol consumption, depression) that could confound the association between smoking and neurocognitive outcomes, the use of more specific measures of smoking behavior and cognition, the use of biomarkers to index exposure to smoke, and the assessment of cognition-related genotypes to better understand the role of interactions between smoking/nicotine and variation in genotype in determining susceptibility to the neurotoxic effects of smoking and the putative beneficial effects of medicinal nicotine. PMID- 17690988 TI - The pituitary gland: a brief history. AB - The functions of the pituitary gland as an important constituent of the endocrine system were not understood until the latter part of the nineteenth century and the first half of the 20th century. At one time, the pituitary was deemed to be the "leader of the endocrine orchestra," but more recent studies have shown that its secretions are influenced by external stimuli and that it is largely under the control of the hypothalamus. PMID- 17690987 TI - An audit of treatment outcome in acromegalic patients attending our center at Bergamo, Italy. AB - BACKGROUND: Acromegaly is a chronic disease impacting on morbidity and mortality. Increased mortality is reverted after the achievement of hormonal targets. The relative role of treatment options is still matter of debate. METHODS: A retrospective chart review was performed on all the acromegalic patients attending our center along the last 20 years. RESULTS: Data about 159 patients (83 F) were retrieved and analyzed: 18% had been lost to follow-up, while follow up was >5 years in 79%. Growth hormone (GH) at diagnosis was 24 microg/L (median, range 3-239). Pituitary MRI showed a macro-, micro-adenoma or no lesion in 73.6, 22.9, and 3.5%, respectively. Hyperprolactinemia (hyperPRL) was present in 20.8%. Ninety-six and 29 patients had been treated by neurosurgery (NS) and irradiated (RT), respectively. Drugs had been employed in 149 patients (in 58 as the only treatment). At the last evaluation, 22% of patients were cured (hypopituitarism and GH deficiency in 6.3%), 37.1% were controlled by ongoing pharmacological treatment, 22.6% had discordant GH and Insulin-like growth factor I (IGF-I) values, and 18.2% had still active disease (median follow-up in this last group was 9 months). By evaluating the outcome with a multimodal approach, safe GH and normal IGF-I had been achieved in 78 and 63.5% of the whole series, 80.5 and 59.7% in patients submitted to NS (and adjuvantly treated with drugs), 95.8 and 91.7% in those submitted to NS + RT (and drugs as well), 70.2 and 55.2% in those treated only with drugs (increased to 82.2 and 60.9% if considering only patients treated with modern long-acting drugs). Hypopituitarism had occurred in 25, 66.6, and 13.8% in the three groups, respectively. At multivariate analysis, previous RT and NS were significant positive predictors of cure, whereas previous NS, follow-up, and year of diagnosis were significant positive predictors of control. Diabetes was a negative predictor both of cure and control. Sex, age, baseline GH levels, hyperPRL, tumor size, extrasellar extension, and invasiveness were not independent predictors of either cure or control. CONCLUSION: This series seems to indicate that a multimodal approach can achieve control of disease in most patients. PMID- 17690989 TI - Population genetic structure of three tree species in the mangrove genus Ceriops (Rhizophoraceae) from the Indo West Pacific. AB - Ceriops is a viviparous mangrove with widespread species Ceriops decandra and C. tagal, and an endemic species C. australis. Genetic diversity of the three species was screened in 30 populations collected from 23 locations in the Indo West Pacific (IWP) using Inter-simple sequence repeats (ISSR) and sequences of partial nuclear gene (G3pdh) and chloroplast DNA (trnV-trnM). At the species level, the total gene diversity (Ht) revealed by ISSRs was 0.270, 0.118, and 0.089 in C. decandra, C. tagal, and C. australis, respectively. A total of six haplotypes of G3pdh and five haplotypes of trnV-trnM were recognized among the three species. Only C. decandra was detected containing more than one haplotype from each sequence data set (four G3pdh haplotypes and three trnV-trnM haplotypes). At the population level, genetic diversity of Ceriops was relatively low inferred from ISSRs (He = 0.028, 0.023, and 0.053 in C. decandra, C. tagal, and C. australis, respectively). No haplotype diversity within population was detected from any of the three species. Cluster analysis based on ISSRs identified three major geographical groups in correspond to the East Indian Ocean (EIO), South China Sea (SCS), and North Australia (NA) in both C. decandra and C. tagal. The cladogram from DNA sequences also detected the same three geographical groups in C. decandra. Analysis of molecular variance (AMOVA) revealed that most of the total variation was accounted for by differentiation between the three major geographical regions of both C. decandra and C. tagal. The significant genetic structure may result from the geological events in these regions during the recent Pleistocene glaciations. This study also provided insights into the phylogenetics of Ceriops. PMID- 17690990 TI - Soil salinity evolution and its relationship with dynamics of groundwater in the oasis of inland river basins: case study from the Fubei region of Xinjiang Province, China. AB - Soil salinization is an important worldwide environmental problem, especially in arid and semi-arid regions. Knowledge of its temporal and spatial variability is crucial for the management of oasis agriculture. The study area has experienced dramatic change in the shallow groundwater table and soil salinization during the 20th century, especially in the past two decades. Classical statistics, geostatistics and geographic information system (GIS) were applied to estimate the spatial variability of the soil salt content in relation to the shallow groundwater table and land use from 1983 to 2005. Consumption of reservoir water for agricultural irrigation was the main cause of a rise in the shallow groundwater table under intense evapotranspiration conditions, and this led indirectly to soil salinization. The area of soil salt accumulation was greater in irrigated than in non-irrigated landscape types with an increasing of 40.04% from 1983 to 2005 in cropland at approximately 0.43 t ha(-1) year(-1), and an increase at approximately 0.68 t ha(-1) year(-1) in saline alkaline land. Maps of the shallow groundwater table in 1985 and 2000 were used to deduce maps for 1983 and 1999, respectively, and the registration accuracy was 99%. PMID- 17690991 TI - Estimates of soil erosion using cesium-137 tracer models. AB - The soil erosion was studied by 137Cs technique in Yatagan basin in Western Turkey, where there exist intensive agricultural activities. This region is subject to serious soil loss problems and yet there is not any erosion data towards soil management and control guidelines. During the soil survey studies, the soil profiles were examined carefully to select the reference points. The soil samples were collected from the slope facets in three different study areas (Kirtas, Peynirli and Kayisalan Hills). Three different models were applied for erosion rate calculations in undisturbed and cultivated sites. The profile distribution model (PDM) was used for undisturbed soils, while proportional model (PM) and simplified mass balance model (SMBM) were used for cultivated soils. The mean annual erosion rates found using PDM in undisturbed soils were 15 t ha(-1) year(-1) at the Peynirli Hill and 27 t ha(-1) year(-1) at the Kirtas Hill. With the PM and SMBM in cultivated soils at Kayisalan, the mean annual erosion rates were obtained to be 65 and 116 t ha(-1) year(-1), respectively. The results of 137Cs technique were compared with the results of the Universal Soil Loss Equation (USLE). PMID- 17690986 TI - The neuropsychology of amphetamine and opiate dependence: implications for treatment. AB - Chronic use of amphetamines and/or opiates has been associated with a wide range of cognitive deficits, involving domains of attention, inhibitory control, planning, decision-making, learning and memory. Although both amphetamine and opiate users show marked impairment in various aspects of cognitive function, the impairment profile is distinctly different according to the substance of abuse. In light of evidence showing that cognitive impairment in drug users has a negative impact on treatment engagement and efficacy, we review substance specific deficits on executive and memory function, and discuss possibilities to address these during treatment intervention. PMID- 17690992 TI - Is clinical competence perceived differently for student daily performance on the wards versus clerkship grading? AB - Clinical rotations play an important role in the medical curriculum and are considered crucial for student learning. However, competencies that should be learned can differ from those that are assessed. In order to explore which competencies are considered important for daily performance of student on the wards and to what extent clinical teachers consider the same competencies important for clerkship grading, a survey that consisted of 21 different student characteristics was administered to clinical teachers. Two independent factor analyses using structural equation modeling were conducted to abstract underlying latent relationships among the different student characteristics and to define a clinical competence profile for daily performance of students on the wards and clerkship grading. Differences between the degree of importance for student daily ward performance and clerkship grading are considered and discussed. The results of the survey indicate that the degree of importance of competencies are rated different for daily performance of students on the wards and clerkship grades. Competencies related to the diagnostic process are more important for clerkship grading, whereas interpersonal skills, professional qualities, and motivation are more important for daily ward performance. It is concluded that the components of clinical competence considered important for adequate performance are not necessarily in alignment with what is required for grading. Future research should focus on an explanation why clinical educators think differently about the importance of competencies for student examination in contrast to what is required for adequate daily performance on the wards. PMID- 17690993 TI - Spirodela (duckweed) as an alternative production system for pharmaceuticals: a case study, aprotinin. AB - Aprotinin is a small serine protease inhibitor used in human health. Spirodela were transformed, via Agrobacterium, with a synthetic gene encoding the mature aprotinin sequence and a signal peptide for secretion which was driven by the CaMV 35S promoter. A total of 25 transgenic Spirodela lines were generated and aprotinin production was confirmed by northern and western blot analyses. Expression levels of up to 3.7% of water soluble proteins were detected in the plant and 0.65 mg/l in the growth medium. In addition, immunoaffinity purification of the protein followed by amino acid sequencing confirmed the correct splicing of the aprotinin produced in Spirodela and secreted into the growth medium. PMID- 17690994 TI - Documenting pharmacist's clinical interventions in New Zealand hospitals. AB - OBJECTIVES: To investigate the perceived value and the recording, storage and use of pharmacists' clinical intervention data in New Zealand hospitals. METHODS: A questionnaire-based cross-sectional survey of all pharmacy managers in public and privately funded hospitals employing one or more pharmacists. MAIN OUTCOME MEASURES: The number of hospitals collecting information, the collection and storage systems used, and use of the data. RESULTS: Twenty-nine hospitals responded (94%). All rated data collection as very important (17) or important (12) but five hospitals, of all sizes, did not record interventions. Of those collecting data, 21 hospitals made daily recordings and three periodic. Pre printed forms were the most popular initial collection method (18 hospitals), with notebooks used by three hospitals. Almost all the hospitals using a paper based collection system (15, 83%) transcribed data into an electronic database, but there were unfavourable comments regarding transcription and analysis time. Three hospitals stated they used direct intranet data entry but one also used a backup paper form when ward computer access was limited. Of information frequently recorded, variability in categorising interventions and grading severity, were identified as concerns. The impact on cost savings was not commonly recorded. The most popular uses for intervention data was to provide management activity reports (15), identify pharmacists' impact on patient care (15) and to identify prescribing problems (14); less than half reported use for educational purposes. Five hospitals reported data were underutilised and 15 considered their systems required modification. CONCLUSIONS: The majority of New Zealand hospitals collect pharmacist intervention data on a daily basis. While a high value is placed on intervention data by pharmacy managers, some hospitals did not meet national data collection requirements. Favouring paper-based systems over direct electronic entry may reflect difficulties in computer access in ward areas. The development of a national system is suggested to aid access to data collection for all hospitals, provided issues of categorising and grading can be resolved. Furthermore we recommend that direct-entry technologies be critically evaluated for reliability, efficiency and cost, and that data be used more frequently for hospital staff education. PMID- 17690996 TI - Ethical problems inherent in psychological research based on internet communication as stored information. AB - This paper deals with certain ethical problems inherent in psychological research based on internet communication as stored information. Section 1 contains an analysis of research on Internet debates. In particular, it takes into account a famous example of deception for psychology research purposes. In section 2, the focus is on research on personal data in texts published on the Internet. Section 3 includes an attempt to formulate some ethical principles and guidelines, which should be regarded as fundamental in research on stored information. PMID- 17690995 TI - Characterization of the putative iron sulfur protein IdiC (ORF5) in Synechococcus elongatus PCC 7942. AB - The IdiC protein (iron deficiency induced protein C) is encoded by orf5 (now called idiC), which is part of the iron-responsive idiB operon of Synechococcus elongatus PCC 7942. The 20.5 kDa IdiC protein has a putative transmembrane helix and belongs to the thioredoxin (TRX)-like [2Fe-2S] ferredoxin family. IdiC has the highest similarity to the peripheral subunit NuoE of the Escherichia coli NDH 1 complex. IdiC expression increased under iron starvation and also in the late growth phase, representing growth conditions, which favor photosynthetic cyclic and respiratory electron transport over photosynthetic linear electron transport from water to NADP+. Attempts to insertionally inactivate the idiC gene generated merodiploid mutants with a strongly reduced IdiC content (mutant MuD) but no IdiC free mutant. Thus, IdiC seems to be an essential protein for the viability of S. elongatus under the used experimental conditions. Comparative analyses of S. elongatus wild type (WT) and mutant MuD showed that under iron limitation in WT and MuD the amount of the reaction center proteins PsbA and PsaA/B was highly reduced. MuD had a lower growth rate, chlorophyll content, and photosynthetic O2 evolving activity with bicarbonate as electron acceptor than WT. Immunoblot analyses also showed that in MuD, when grown under iron limitation, the amount of the proteins IdiC and IdiB was greatly reduced as compared to WT. As a consequence of the reduction of the transcription factor IdiB, IdiA and IrpA expression were also decreased. In addition, the IsiA protein concentration was lower in MuD than in WT, although the isiA mRNA was equally high in MuD and WT. Another significant difference was the lower expression of the ferredoxin:NADP+ oxidoreductase in mutant MuD under iron limitation compared to WT. A possible function of the protein IdiC in cyclic electron transport around photosystem I and/or in respiratory electron transport will be discussed. PMID- 17690997 TI - Attention bias for paranoia-relevant visual stimuli in schizophrenia. AB - INTRODUCTION: A number of studies indicate that patients with schizophrenia share a bias for paranoia-relevant material. The presence of an attentional bias for such stimuli would be of utter importance for our pathogenetic understanding of the disorder in view of ample evidence that patients with schizophrenia gather little information before arriving at strong conclusions: A both scarce and affectively biased data selection of available information may heavily distort its inner representation and thus prompt the formation of false beliefs. To date, the profile of this putative attentional bias in schizophrenia (e.g., automatic vs. controlled; hypervigilance towards vs. problems to disengage from such stimuli) is not fully uncovered. METHODS: To shed light on this aspect of information processing in schizophrenia, we administered a novel task based on the inhibition of return paradigm (IOR). Twenty-four schizophrenia patients and thirty-four healthy controls were presented neutral (e.g., cup), anxiety-relevant (e.g., shark), and paranoia-relevant cue pictures (e.g., gun) at either of two possible locations. Subsequent to either a short or long interval, a target appeared at the same or opposite location. Participants were requested to press a spatially corresponding button. RESULTS: Both currently paranoid and nonparanoid schizophrenia patients responded faster to all kinds of targets following paranoia-relevant pictures, that is, such stimuli speeded reaction times irrespective of the cue-target interval and spatial correspondence. CONCLUSIONS: This indicates that paranoia-relevant information generally alerts patients more than other stimuli and facilitates processing of subsequent information. Possible implications of this finding for our understanding of delusion formation and maintenance are outlined. PMID- 17690998 TI - Did I say that word or did you? Executive dysfunctions in schizophrenic patients affect memory efficiency, but not source attributions. AB - INTRODUCTION: Schizophrenic patients have difficulties in recognising previously presented verbal information and identifying its sources. The antecedents of these recognition and source misattributions are, however, largely unknown. The current study examined to what extent schizophrenic patients' lack of memory efficiency, their memory errors, and their source misattributions are related to neurocognitive deficits (i.e., executive dysfunctions). METHODS: 23 schizophrenic patients and 20 healthy controls were administered an adapted version of the Deese/Roediger-McDermott (DRM) task from which parameters of memory efficiency, memory errors, source misattributions, and two-high threshold measures were derived. Furthermore, two neurocognitive tasks tapping executive functions were administered: the Wisconsin Card Sorting Test (WCST) and the Behavioural Assessment of the Dysexecutive Syndrome (BADS). Using multiple linear regression analyses, we examined whether these neurocognitive measures predicted various memory parameters. RESULTS: Patients with schizophrenia showed poorer memory efficiency and were more prone to make internal-external source misattributions with high confidence. However, they did not more often falsely recognise critical lure words than controls. Executive dysfunctions predicted memory efficiency, but not source misattribution performance. CONCLUSION: Our findings provide further evidence that schizophrenic patients' memory impairments are intimately related to fundamental neurocognitive deficits. PMID- 17690999 TI - No effect of donepezil on neurocognition and social cognition in young persons with stable schizophrenia. AB - INTRODUCTION: Cognitive dysfunction is common in schizophrenia and linked with psychosocial dysfunction. We examined the possible effect of a 16-week trial of donepezil on cognition in young persons with stable schizophrenia. METHOD: Twenty six outpatients who met criteria for age, duration of illness, clinical stability, and medications were randomly assigned to 16-week treatment with donepezil or placebo using a double blind design. At beginning and conclusion of the trial, participants completed standardised computerised assessment of neurocognition and social cognition. Symptomatology and functioning were assessed using standard rating scales for negative and positive symptoms, depression and mania, and quality of life. RESULTS: No treatment effects were found on any cognitive functions or clinical symptoms in placebo or donepezil groups. CONCLUSION: Similar to other studies using acetylcholinesterase inhibitors in more heterogeneous and symptomatic groups of patients with schizophrenia, donepezil does not appear to enhance cognitive abilities. Persistent cognitive impairment in schizophrenia with pervasive effects on psychosocial functioning and outcome, urge the search for agents that may offer improvement. PMID- 17691000 TI - Asymmetry in the emotional content of lateralised multimodal hallucinations following right thalamic stroke. AB - The thalamus has been described as a "relay station" for sensory information from most sensory modalities projecting to cortical areas. Therefore injury to the thalamus may result in multimodal sensory and motor deficits. In the present study, a 61-year-old woman suffered a right thalamic cerebral vascular accident (CVA; as evidenced by a computerised tomography [CT] scan). Secondary to this incident, she complained of altered sensations across multiple sensory modalities, including olfactory, visual, auditory, tactile, temperature, and pain sensation. Interestingly, during recovery from the thalamic CVA, the patient reported hallucinations in all the modalities cited above. Multimodal dysaethesias (odd sensations) and hallucinations showed reliable laterality in the affective valence across modalities with positive associations within right hemispace and negative associations within left hemispace. Overall, the results support multimodal role of the thalamus and provide evidence for lateralisation of positive and negative affect within the right and left hemispheres respectively. PMID- 17691001 TI - Comorbid anxiety corresponds with neuropsychological dysfunction in unipolar depression. AB - INTRODUCTION: Unipolar depressives seem apt to show neuropsychological impairment, particularly involving executive function and memory. Yet, not all depressed patients show such deficits. Major depressive illness shares a high rate of comorbid anxiety disorder, and anxiety disorders also tend to correspond with cognitive difficulties. Consequently, depressed individuals with comorbid anxiety disorders may be inclined to demonstrate greater neuropsychological dysfunction than those without anxiety disorders. METHOD: We compared nonpsychotic depressed inpatients with (n=22) and without comorbid anxiety disorders (n=30) to a group of control subjects (n=38) on a brief but broad battery of neuropsychological tests. Patients were tested during an inpatient admission, and data were collected retrospectively from available records. RESULTS: Both groups of depressed patients showed worse memory function than the controls. Yet, executive dysfunction and psychomotor slowing were specific to the depressed group with comorbid anxiety. The comorbid anxiety group also had more impaired scores than either the nonanxious depressed group or the control group. The depressed group without a comorbid anxiety disorder demonstrated no significant slowing compared to the control group. CONCLUSIONS: Major depressive disorder corresponds with significant memory impairment, regardless of comorbid anxiety disorder. Yet, presence of a comorbid anxiety disorder coincides with deficits involving executive function and psychomotor slowing. Clinical and theoretical relevance of the data is discussed. PMID- 17691002 TI - Poor intentional inhibition in individuals predisposed to hallucinations. AB - INTRODUCTION: Intentional inhibition deficits have been found in hallucinating individuals with schizophrenia using the Inhibition of Currently Irrelevant Memories (ICIM) task. This study sought to investigate whether similar difficulties are found in healthy individuals predisposed to hallucinations. METHODS: The Launay-Slade Hallucination Scale-Revised (LSHS-R) was completed by 589 undergraduate students, from which high- and low-predisposed groups were drawn. On the ICIM task, participants were asked to identify within-run picture repetitions, requiring them to inhibit memory traces of the same items seen in previous runs. RESULTS: Compared to the low LSHS-R group, the high LSHS-R group showed significantly increased false alarms on critical "inhibitory" runs (incorrectly identifying previous-run items as within-run repetitions), but no group differences were found in first-run false alarms or in the identification of within-run targets. These results were specific to hallucination predisposition and could not be explained by other schizophrenia-related characteristics. CONCLUSIONS: Individuals predisposed to hallucinations show subtle, though consistent difficulties with intentional inhibition similar to patients with hallucinations. These findings demonstrate a continuity of cognitive processes in individuals predisposed to hallucinations and in patients with schizophrenia who hallucinate, consistent with a common neurodevelopmental pathway. PMID- 17691004 TI - Allergenicity and allergens of amphipods found in nori (dried laver). AB - Gammaridean and caprellid amphipods, crustaceans of the order Amphipoda, inhabit laver culture platforms and, hence, are occasionally found in nori (dried laver) sheets. Amphipods mixed in nori may cause allergic reactions in sensitized patients, as is the case with other crustaceans, such as shrimp and crab, members of the order Decapoda. In this study, dried samples of amphipods (unidentified) found in nori and fresh samples of gammaridean amphipod (Gammarus sp., not accurately identified) and caprellid amphipod (Caprella equilibra) were examined for allergenicity and allergens using two species of decapods (black tiger prawn and spiny lobster) as references. When analyzed by ELISA, sera from crustacean allergic patients reacted to extracts from amphipod samples, although less potently than to the extracts from decapods. In IgE-immunoblotting, a 37-kDa protein was found to be the major allergen in amphipods. Based on the molecular mass and the cross-reactivity with decapod tropomyosin evidenced by inhibition ELISA and inhibition immunoblotting, the 37-kDa protein was identified as amphipod tropomyosin. PMID- 17691005 TI - Investigation of the causes for the occurrence of residues of the anticoccidial feed additive nicarbazin in commercial poultry. AB - Investigations were undertaken to identify causes for the occurrence of high levels of the zootechnical feed additive nicarbazin in broiler liver at slaughter. The first investigation on 32 commercial broiler flocks involved sampling and analysis for nicarbazin (as dinitrocarbanilide, DNC) in liver from birds during a 3-10-day period after withdrawal of nicarbazin from their feed and before commercial slaughter. DNC residues in liver samples of broilers scheduled as being withdrawn from nicarbazin for > or =6 days ranged from 20 to >1600 microg kg(-1) (the specified withdrawal period for nicarbazin is 5 days and the Joint Expert Committee on Food Additives (JECFA) maximum residue limit (MRL) is 200 microg kg(-1) liver). Further on-farm investigations on 12 of these flocks, selected on the basis of the feeding system in use and the levels of DNC residues determined in liver, identified issues in feed management contributing to elevated residues in broiler liver. A significant correlation (0.81, p < 0.01, n = 10) between DNC residues in liver samples and in feed samples from the feeding pans was observed. The second investigation on 12 commercial broiler flocks involved sampling and analysis for DNC in liver samples and feed samples from feeding pans and from the feed mill at the three thinnings of birds for commercial slaughter. In the case of one flock, a clear relationship between nicarbazin in feed from the feed mill (10.5 mg kg(-1) DNC), in feed from the feeding pans (6.6 mg kg(-1) DNC) and in liver (583 microg kg(-1) DNC) at first thinning (9 days scheduled withdrawal from nicarbazin) was observed. Such a clear relationship was not observed in other cases, particularly at second and third thinnings, pointing to re-exposure of birds to nicarbazin late in the flock production cycle, probably from the litter. Guidelines outlining best farm practice to eliminate nicarbazin residues in poultry have been published in booklet and poster format for broiler producers and deal with feed system cleaning, feed bin management, feed deliveries, feed usage and records. PMID- 17691006 TI - Stability studies of the metabolites of nitrofuran antibiotics during storage and cooking. AB - Nitrofuran antibiotics cannot be used in food production within the European Union because of their potential health risks to consumers. The recent discovery of their widespread use in global food industries and the finding of semicarbazide in baby food as a result of packaging contamination have focused attention on the toxicity and stability of these drugs and their metabolites. The stability of the nitrofuran marker residues 3-amino-2-oxazolidinone (AOZ), 3 amino-5-morpholinomethyl-2-oxazolidone (AMOZ), 1-aminohydantoin (AHD) and semicarbazide (SEM) were tested. Muscle and liver of nitrofuran treated pigs were cooked by frying, grilling, roasting and microwaving. Between 67 and 100% of the residues remained after cooking, demonstrating that these metabolites are largely resistant to conventional cooking techniques and will continue to pose a health risk. The concentration of metabolites in pig muscle and liver did not drop significantly during 8 months of storage at -20 degrees C. Metabolite stock and working standard solutions in methanol were also stable for 10 months at 4 degrees C. Only a 10 ng ml(-1) solution of SEM showed a small drop in concentration over this extended storage period. PMID- 17691007 TI - Toxic and essential metals in liver, kidney and muscle of pigs at slaughter in Galicia, north-west Spain. AB - The aims of the study were to evaluate toxic and essential metal concentrations in meat and offal from pigs in north-west Spain to compare these with reported metal concentrations in pigs in other countries and in cattle in this region, and to relate the observed concentrations to maximum acceptable concentrations. Samples from 63 pigs aged 6 months were randomly collected at slaughter. After acid digestion, levels of metals were determined by ICP-OES and ICP-MS. As regards the toxic metals, mean concentrations in liver, kidney and muscle were 0.073, 0.308 and 0.009 mg kg(-1) fresh weight for cadmium, 0.004, 0.008 and 0.003 mg kg(-1) for lead, 0.013, 0.011 and 0.003 mg kg(-1) for arsenic, and 0.001, 0.002 and 0.001 mg kg(-1) for mercury. These concentrations can be considered low, and in general similar to those reported in similar studies in recent years. In addition, maximum admissible concentrations established by the European Union were not exceeded in any sample. As regards the essential metals, concentrations in liver, kidney and muscle were 14.9, 5.63 and 6.85 mg kg(-1) for copper, 81.3, 28.9 and 42.5 mg kg(-1) for zinc, 195, 51.6 and 26.5 mg kg(-1) for iron; 1.17, 2.51 and 0.656 mg kg(-1) for selenium, 3.32, 1.56 and 1.01 mg kg(-1) for manganese, 0.023, 0.027 and 0.003 mg kg(-1) for cobalt, 0.120, 0.077 and 0.131 mg kg(-1) for chromium, 0.009, 0.027 and 0.026 mg kg(-1) for nickel, and 1.62, 0.683 and 0.140 mg kg(-1) for molybdenum. These concentrations are all within the accepted adequate-safe ranges for this animal species, and in general are in line with those previously reported in the literature. PMID- 17691008 TI - Mercury content in Chilean fish and estimated intake levels. AB - The intake of fish products is a major public health concern due to possible methyl mercury exposure, which is especially toxic to the human nervous system. This pilot study (n = 46) was designed to determine mercury concentrations in fish products for national consumption (Chilean jack mackerel, hake, Chilean mussel, tuna) and for export (salmon, Patagonian toothfish, swordfish, southern hake), and to estimate the exposure of the general population. The fish products were collected from markets in Talcahuano, Puerto Montt and Santiago. Samples were analyzed at the National Environmental Center by cold vapor atomic absorption spectrophotometry. Mercury levels in swordfish and one canned tuna sample exceeded levels prescribed by national and international standards. The remaining two export products (Patagonian toothfish, also known as Chilean sea bass, and salmon) complied with international limits, which are more demanding than Chilean regulations. Theoretical estimates of mercury intake varied from 0.08 to 3.8 microg kg(-1) bw day(-1) for high fish consumers, exceeding the provisional tolerable intake for tuna, Chilean seabass, Chilean jack mackerel and swordfish. This group appears to be at the greatest risk from mercury contamination among the Chilean population. PMID- 17691009 TI - Survey of lead and copper in Turkish raisins. AB - Lead and copper levels in various types of Turkish raisins, collected from the most important production centers, were determined by electrothermal atomic absorption spectrometry. Samples were principally the products of 2005; however, two different and important raisin types produced between 2003 and 2006 were also analyzed. To investigate the source of pollution, the lead and copper content of all samples were separately determined after successive treatment with water, then with acetone and, finally, complete decomposition in a HNO(3)/H(2)SO(4)/H(2)O(2) mixture. Metal levels in raisin seeds were also determined. The results were statistically evaluated, indicating that the raisins taken from different regions and years contained a mean (range) of 0.056 (0.012 0.359) mg kg(-1) lead and 2.542 (0.770-4.706) mg kg(-1) copper. Lead concentrations in Turkish raisins were significantly lower than those found in a previous study. PMID- 17691010 TI - Total and organic mercury concentrations in the white muscles of swordfish (Xiphias gladius) from the Indian and Atlantic oceans. AB - A total of 226 swordfish samples collected from Taiwanese fishing vessels in the Indian and Atlantic oceans were examined for total mercury (THg) and organic Hg (OHg). Analysis of 56 pooled white muscle samples showed that THg and OHg concentrations ranged from 0.056 to 3.97 (1.3 +/- 0.97) and from 0.043 to 3.92 (1.01 +/- 0.82) microg g(-1) flesh mass, respectively. These values were similar to those from various previous studies during the past three decades. THg and OHg were significantly linearly correlated with fork length (FL, cm) of the fish from Indian and Atlantic oceans; however, there was no significant OHg%-FL relationship. OHg and THg also were significantly correlated. Fishes with FL < or = 140 cm met the methyl Hg (meHg) regulatory standard set by the European Commission Decision (meHg < or = 1.0); and fish with FL < or = 211 cm met the Taiwanese Food and Hygiene Standard (meHg < or = 2.0). Weekly swordfish consumption rates and amounts are recommended accordingly. PMID- 17691011 TI - Occurrence of ochratoxin A in sweet wines produced in Spain and other countries. AB - A survey for the presence of ochratoxin A (OTA) was undertaken from 2001 to 2005 in 188 samples of sweet wines produced in Spain and in 102 samples originating from other countries: France (n = 49), Austria (9), Chile (9), Portugal (9), Greece (6), Italy (5), Germany (3), Hungary (2), Slovenia (2), Switzerland (2), Canada (1), Japan (1), New Zealand (1), Ukraine (1), South Africa (1) and the USA (1). The analytical method was based on immunoaffinity chromatography clean-up and high-performance liquid chromatography (HPLC) with fluorescence detection. The limit of detection (defined as a signal-noise ratio = 3) was estimated to be 0.01 microg l(-1). The limit of quantification (0.02 microg l(-1)) was checked as being the lowest measurable concentration. OTA was detected in 281 out of 290 samples analysed (96.9% positive) at concentrations ranging from 0.01 to 4.63 microg l(-1). The overall mean and median levels were estimated to be 0.50 and 0.14 microg l(-1), respectively. In Spanish sweet wines OTA was found in 99% of the samples, with mean and median values of 0.65 and 0.19 microg l(-1), respectively. The mean value obtained in this study for OTA in the Spanish sweet wines would result in an intake of about 37.5 and 3.2 ng day(-1) of OTA for regular consumers and for the overall population, respectively. These figures represent a minor contribution to the provisional tolerable weekly intake (PTWI) or TWI established by the Joint Expert Committee on Food Additives (JECFA) and the European Food Safety Authority: 3.8 and 3.1% for regular consumers; and 0.4 and 0.3% for the whole adult population, respectively. PMID- 17691012 TI - Ochratoxin A in liquorice as affected by processing methods. AB - A study of the effect of several processing methods on the concentration of ochratoxin A (OTA) in liquorice and derived products was carried out. The effect of the sorting, washing and peeling of fresh liquorice roots was investigated; as well as the production at a laboratory scale of liquorice extract and block liquorice from dry roots. Finally, the thermal stability of OTA was assessed. The OTA content was analysed by high-performance liquid chromatography-fluorescence and confirmed by methyl ester formation. The OTA level in liquorice extract was stable to heat treatment at 150 degrees C for 60 min. The OTA concentration was unaffected by sorting or washing, but it was much reduced by peeling (a 53.1% reduction). A great reduction in the OTA level was found during the production of liquorice extract (78.6%) and block liquorice (91.8%). PMID- 17691013 TI - Survey of maize from south-western Nigeria for zearalenone, alpha- and beta zearalenols, fumonisin B1 and enniatins produced by Fusarium species. AB - A survey for the natural occurrence of Fusarium mycotoxins in maize for human consumption in four south-western states of Nigeria using High Performance Liquid Chromatography coupled with Mass Spectroscopy (HPLC/MS) showed that 93.4% of the samples were contaminated with zearalenone (ZON), alpha- and beta-zearalenols (alpha- and beta-ZOL), fumonisin B(1) (FB(1)) or enniatins (ENNs). The fractions of contaminated samples were 73% for FB(1) (mean:117 microg kg(-1), range:10-760 microg kg(-1)); 57% for ZON (mean:49 microg kg(-1), range:115-779 microg kg(-1)) and 13% for alpha-ZOL (mean: 63.6 microg kg(-1), range:32-181 microg kg(-1)), while ENNs A1, B and B(1) were present in 3, 7 and 3% of the samples respectively. There was no beta-ZOL present above the quantification limits of 50 microg kg(-1). Only the FB(1) content was significantly different at the 95% confidence level among the four states. The Fusarium species most frequently isolated from maize seeds were F. verticillioides (70%), followed by F. sporotrichioides (42%), F. graminearum (30%), F. pallidoroseum (15%), F. compactum (12%), F. proliferatum (12%), F. equiseti (9%), F. acuminatum (8%) and F. subglutinans (4%). This is the first report of the occurrence of alpha zearalenol and enniatins in Nigerian maize. PMID- 17691014 TI - Effects of electron beam irradiation on deoxynivalenol levels in distillers dried grain and solubles and in production intermediates. AB - Wheat contaminated with deoxynivalenol (DON), and distillers dried grain and solubles (DDGS) obtained after ethanol production from the contaminated wheat, were irradiated to doses ranging from 2.0 to 55.8 kGy using an electron accelerator. Samples of wet distillers grain, distillers solubles and stillage obtained during production of DDGS were also irradiated. All samples were analysed for Fusarium trichothecene mycotoxins by a method involving use of gas chromatography-mass spectrometry (GC-MS). The three production intermediates showed dose-dependent reductions in their DON contents ranging from 47.5 to 75.5% at the highest doses. Electron beam treatment produced a 17.6% reduction in the DON level of wheat at the highest dose used, but had no effect on DON in DDGS. These results indicate that electron beam treatment may provide a method for reducing DON levels in DDGS on an industrial scale. PMID- 17691015 TI - Dioxins, furans and dioxin-like PCBs: occurrence in food and dietary intake in France. AB - PCDD/Fs and DL-PCBs contamination data in food products consumed in France collected from national monitoring programmes (2001-04) and representing analytical results for almost 800 individual food samples were combined with food consumption data from the French national dietary survey to estimate PCDD/Fs and DL-PCBs dietary intakes, expressed as toxic equivalents (WHO-TEQs). The mean PCDD/Fs and DL-PCBs intakes were estimated as 1.8 and 2.8 pg WHO-TEQ kg(-1) b.w. day(-1), respectively, for adults (aged 15 years and over) and children (aged 3 14 years). The main contributors to total intake were fish and milk products for both children and adults (48 and 31% for adults and 34 and 43% for children, respectively). DL-PCBs constituted the largest contributor to contamination in most foodstuffs. A life-long intake estimate showed that a non-negligible part of the French population (between 20 and 28%) had an intake above the tolerable monthly intake for dioxins and dioxin-like PCBs of 70 pg WHO-TEQ kg(-1) b.w. month(-1). PMID- 17691016 TI - Development and application of a simplified clean-up procedure for the determination of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in horse fat by gas chromatography-tandem mass spectrometry (GC MS/MS). AB - A simplified clean-up procedure was developed in combination with gas chromatography-tandem mass spectrometry (GC-MS/MS) for the determination of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in adipose tissue. Clean-up was performed by the successive application of a Mega Bond Elut silica column and a Bond Elut PCB column. Validation of the method was conducted according to European Union Commission Decision 2002/657/EC. In order to evaluate the applicability of the method, 44 horse fat samples were analysed. The total PCB concentration (sum of PCBs 28, 52, 101, 118, 138, 153 and 180) ranged from 5.35 to 140 ng g(-1) lipid weight. The total PBDE concentration (sum of BDEs 28, 47, 99, 100, 153, 154 and 183) ranged from below the decision limit to 6.34 ng g(-1) lipid weight. PMID- 17691017 TI - US FDA's revised consumption factor for polystyrene used in food-contact applications. AB - US FDA's continual effort to evaluate the safety of food-contact materials includes periodically re-examining our established packaging factors, such as consumption and food-type distribution factors. The use of polystyrene in food contact and disposable food-packaging applications has expanded and is expected to continue to increase in the future. Therefore, it is important to revise the polystyrene consumption factor to account for increases in consumer exposure to substances migrating from styrenic food packaging. The currently used consumption factor for polystyrene is 0.1, which is based on market data collected around 1980. US FDA has revised the polystyrene consumption factor utilizing three different sources of market data. Using consumption and population data, US FDA calculated a new consumption factor of 0.14 for polystyrene. This consumption factor has been further subdivided to allow for the refinement of exposure estimates for uses limited to specific subcategories of polystyrene packaging. PMID- 17691019 TI - Identification of genes involved in positive selection of CD4+8+ thymocytes: expanding the inventory. AB - Positive selection of cortical CD4+8+ thymocytes represents crucial and mysterious process in T cell development whereby short-lived precursors are rescued from programmed cell death and induced to differentiate towards long lived CD4 and CD8 T cells. One reason that this process is not fully understood is that the inventory of genes changing their expression in positively selected CD4+8+ thymocytes is not yet complete. In this work Affymetrics GeneChip cDNA microarrays and cDNA-Representational Difference Analysis were used to search for unknown and known genes that were not identified before as being involved in positive selection. Comparison of transcriptosome of nonstimulated with transcriptosome of PMA/ionomycin stimulated thymoma cell line resembling CD4+8+ thymocytes and subtraction of cDNA of extrathymic tissues from cDNA of purified CD4+8+ thymocytes resulted in identification of 36 genes, which have not been previously reported to change their expression during positive selection. One of them represents a novel, third evolutionarily conserved gene within RAG locus. PMID- 17691020 TI - Impact of Helicobacter pylori infection on the humoral immune response to MUC1 peptide in patients with chronic gastric diseases and gastric cancer. AB - Many investigators have demonstrated alteration of gastric mucins in H. pylori infected individuals. The inflammatory environment induced by H. pylori leading to aberrant glycosylation of MUC1 and demasking of core peptide MUC1 epitope could enhance immune responses to MUC1. IgG and IgM immune response to MUC1 in patients with gastric cancer (n = 214) chronic gastroduodenal diseases (n = 160) and healthy blood donors (n = 91) was studied with ELISA using bovine serum albumin-MUC1 60-mer peptide as antigen. H. pylori serologic status was evaluated with ELISA and CagA status by immunoblotting. Gastric mucosa histology was scored according to the Sydney system. Compared to H. pylori seronegative individuals, higher levels of IgG antibody to MUC1 were found in H. pylori seropositive patients with benign gastric diseases (p < 0.01) and blood donors (p < 0.03). Higher MUC1 IgG antibody levels were associated with a higher degree of gastric corpus mucosa inflammation in patients with chronic gastroduodenal diseases (p < 0.0025). There was a positive correlation between the levels of anti-H. pylori IgG and MUC1 IgG antibody levels in blood donors (p = 0.03), and in patients with benign diseases (p < 0.0001). In patients with gastric cancer (n = 214) a significantly higher level of anti-MUC1 IgG than in blood donors was observed (p < 0.001) irrespective of H. pylori status or stage of cancer. MUC1 IgM antibody levels were not related to the H. pylori serology. IgG immune response to tumor associated MUC1 is up regulated in H. pylori infected individuals. This increase is associated with a higher IgG immune response to H. pylori and with a higher degree of gastric mucosa inflammation. High levels of MUC1 IgG antibody irrespective of H. pylori serologic status characterized patients with gastric cancer. The findings suggest that, in some individuals, the H. pylori infection may stimulate immune response to tumor-associated MUC1 peptide antigen thus modulating tumor immunity. PMID- 17691021 TI - Kinetics of B cell response during Yersinia enterocolitica infection in resistant and susceptible strains of mice. AB - In this study we analyze the B-cell response in murine yersiniosis. To this end, we determined whether polyclonal activation of B-lymphocytes occurs during infection of susceptible (BALB/c) and resistant (C57BL/6) mice with Y. enterocolitica O:8 and compared the immunoglobulin (Ig) isotypes produced in response to the infection by the two strains. The number of splenic cells secreting nonspecific and specific immunoglobulins was determined by ELISPOT. The presence of anti-Yersinia antibodies in serum was detected by ELISA. In both strains, the number of specific Ig-secreting cells was relatively low. Polyclonal B-cell activation was observed in both strains of mice, and the greatest activation was observed in the BALB/c mice, mainly for IgG1- and IgG3- secreting cells. The C57BL/6 mice showed a predominance of IgG2a-secreting cells. The peak production of anti-Yersinia IgG antibodies in the sera of BALB/c mice was seen on the 28th day after infection. The greatest increase in IgM occurred on the 14th day. A progressive increase of specific IgG antibodies was observed in C57BL/6 mice up to the 28th day after infection while IgM increased on the 21st day after infection. The production of specific IgA antibodies was not detected in either BALB/c or C57BL/6 mice. We conclude that polyclonal activation of B lymphocytes occurs in both the Yersinia-resistant and Yersinia-susceptible mice and that the more intense activation of B lymphocytes observed in the susceptible BALB/c mice does not enhance their resistance to Y. enterocolitica infection. PMID- 17691022 TI - IL-18 level correlates with development of sepsis in surgical patients. AB - Interleukin 18 may play an important role in sepsis. We measured circulating IL 18 levels in 47 patients with surgical wounds, 27 of them had clinical and laboratory evidences of sepsis. The patients had significantly higher IL-18 levels than healthy control (p1 = 0.001), patients with local infection (p4 = 0.001) and patients with clean surgical wound (p5 = 0.001) both at admission and after 48 hours. Serial observations revealed that in all patients, IL-18 levels increased significantly especially in patients with sepsis after 48 h (p = 0.007). IL-18 levels appeared to correlate significantly with leucocytes counts (p = 0.001) and with C-RP (p = 0.007). These results suggest that IL-18 levels are increased in patients with sepsis and correlate with CRP and leukocyte counts suggesting that IL-18 may play a role in sepsis. We suggest that IL-18 could be used as a collaborative evidence of surgical sepsis. PMID- 17691023 TI - In vitro activation of mononuclear cells by two probiotics: Lactobacillus paracasei I 1688, Lactobacillus salivarius I 1794, and their mixture (PSMIX). AB - BACKGROUND: Most studies on probiotics have described their effects on the human immune system after ingestion of LAB, but little is known about their effect on in vitro stimulation of human immune cells. AIM OF THE STUDY: Evaluate the "in vitro" activity of Lactobacillus paracasei (I 1688), Lactobacillus salivarius (I 1794), and a commercial mix of the two (PSMIX, Proge Farm), on immune cells from healthy individuals. MATERIALS: Two probiotic strains, Lactobacillus salivarius (I 1794; Proge Farm, Italy) and Lactobacillus paracasei (I 1688; Proge Farm, Italy), which are contained in the functional food ENTEROBACILLI, were evaluated for their ability to stimulate peripheral blood mononuclear cells and modulate surface phenotype and cytokine production. RESULTS: All subjects responded to the bacteria, with different levels of response. The cell populations that showed a significant percent increase were CD4+/CD25+ cells (T-helper activated regulatory cells), CD8+/CD25+ (T-suppressor/cytotoxic activated cells), and CD16+/CD56+ (NK cells) (p<0.05). IL-12 and IFN-gamma in vitro production significantly increased with exposure to probiotics (p<0.05 for both). CONCLUSIONS: This study provides the first evidence that Lactobacillus paracasei and Lactobacillus salivarius are capable of inducing a specific immune response that may be useful in the clinical setting for improving innate and adaptive immune responses. PMID- 17691024 TI - Combination of recombinant xenogeneic endoglin DNA and protein vaccination enhances anti-tumor effects. AB - The immunization approaches with DNA vaccine priming and subsequent protein or peptide boosting has been widely tested in various models of infectious diseases. However, these approaches are seldom reported in the areas of cancer immunotherapy. In this study we combined endoglin plasmid DNA and recombinant protein as vaccines and used them to prime and boost, simultaneously, as a vaccine strategy. Our results showed that combination of endoglin DNA and protein vaccines could enhance both protective and therapeutic anti-tumor efficacy in both colon carcinoma and Lewis lung carcinoma models. Significant inhibition of tumor angiogenesis was found in the tumor tissues. The titers of autoantibodies against murine endoglin were significantly increased and the antibody levels lasted longer in the mice with combined endoglin DNA and recombinant protein vaccination. CTL response against endoglin-positive HUVECs, but not against endoglin-negative tumor cells was found in the mice combined DNA with protein vaccination. In addition, combination of endoglin DNA and recombinant protein vaccination significantly induced IFN-gamma secreting cells. These observations suggested that a combination of endoglin DNA and recombinant protein immunization as a vaccine strategy was superior to those using endoglin DNA or recombinant protein alone as vaccines. PMID- 17691025 TI - Suppression of innate immune cytokines and interferon regulatory factor-1 by endogenous interferon-alpha in response to respiratory syncytial virus in neonate mononuclear cells. AB - Respiratory syncytial virus (RSV) infections are extremely common in early childhood but are most severe in infants in the first few months of life. Unresponsive adaptive immunity and hyporesponsive innate immunity were previously found to be the typical responses of neonate mononuclear cells (MCs) to live RSV. Investigating the mechanism of innate immune hyporesponsiveness in neonate MCs to live RSV revealed that in contrast to the previously reported low expression of interferon (IFN)-gamma, IFN-alpha expression in response to live RSV was significantly greater than that observed in adult MCs. Inhibition of live RSV induced IFN-alpha with anti-IFN-alpha antibodies in neonate MCs led to significant increases in innate cytokine [IFN-gamma, interleukin (IL)-12, IL-18 and tumor necrosis factor (TNF)-alpha] but not adaptive immune cytokine [IL-2] production. Although MCs from adults responded to live RSV with upregulation of interferon regulatory factor-1 (IRF-1) mRNA, IRF-1 mRNA in RSV-treated neonate MCs was not detectable. However, in the presence of anti-IFN-alpha antibodies, live RSV induced detectable IRF-1 mRNA expression in neonate MCs. These data support the possibility that the severity of early life RSV-induced illnesses may occur via a mechanism in which live RSV induces IFN-alpha that in turn leads to innate immune suppression in neonate MCs. PMID- 17691026 TI - The role of alveolar macrophages in the pathogenesis of aspiration pneumonitis. AB - RATIONALE: A robust TNFalpha response is seen following aspiration of food particles, while there is only a modest response to acid. OBJECTIVES: To examine the direct effects of acid and particulate components of gastric content on local and systemic macrophages. METHODS: Pathogen-free Long-Evans rats were injured with intratracheal instillation of normal saline (SHAM), low pH saline (ACID), small non-acidic particles (SNAP) or acidified particles (CASP). The alveolar (local) and the peritoneal (systemic) macrophages were harvested following the injury. MEASUREMENTS: We examined the phagocytic activity and TNFalpha release by the alveolar and peritoneal macrophages following in vivo and in vitro exposure to acid and/or food particles. TNFalpha release by macrophages was examined in response to E. coli lipopolysaccharide (LPS) stimulation. MAIN RESULTS: In rats injured with gastric particles, the number of the mononuclear cells was higher than those obtained from acid-injured animals. Both in vivo and in vitro exposure of the alveolar macrophages to SNAP resulted in increased production of TNFalpha within 8 hours. Transient exposure of the alveolar macrophages to a low pH environment suppressed LPS-induced production of this cytokine. Additionally, the phagocytic activity of the alveolar macrophages was inhibited by in vitro exposure of the macrophages to acid. CONCLUSIONS: We conclude that the two components of gastric aspiration have diverse effects on local and systemic macrophages. Although there is a synergy between acid and gastric particulate in producing an acute lung injury, the modulatory effects of these injuries on the alveolar macrophages are averse. PMID- 17691027 TI - Experimental Leishmania (L.) amazonensis leishmaniasis: characterization and immunogenicity of subcellular fractions. AB - A technique developed in Trypanosoma cruzi biochemical studies was successfully used to fractionate Leishmania (Leishmania) amazonensis promastigotes. Ultrastructural analyses revealed a membrane fraction (MF) associated to subpellicular microtubules, a ribosomal-rich microsomal fraction (MicF), and a flagellar fraction (FF) free of associated membrane. All fractions proved to be immunogenic through delayed type hypersensitivity reaction assays. Therefore, a protocol was designed to test whether these fractions could elicit a protective response in mice infected by L. (L), amazonensis. The protocol consisted of a BCG injection (as cellular immunity inducer), followed by cyclophosphamide (once its cytotoxic effect is over, this immunosuppressor can increase the number of circulating leukocytes), then an injection with one of the fractions followed by a challenge. When compared to infected control animals, mice injected with any of the fractions presented a smaller footpad swelling, especially those injected with MicF or FF. Macroscopically, immunized mice under modulation by BCG presented no swelling. Histopathological studies performed on day 120 revealed fewer amastigotes and more intense inflammation in lesions of MicF and FF injected mice. Animals injected with MF presented an intermediate pattern. Parasite quantification corroborated these results. The results show that all fractions are potent immunostimulators, but MicF and FF have the strongest protective ability. PMID- 17691028 TI - Insulin-like growth factor-1 receptor RNA expression in hematopoietic stem cell transplanted patients does not correlate with graft-versus-host disease. AB - In vivo activated T lymphocytes exhibit altered expression of insulin-like growth factor-1 receptor (IGF-1R) compared to the naive T lymphocyte pool. The objective of this study was to investigate the expression of IGF-1R RNA in CD4 and CD8 positive cells after allogeneic hematopoietic stem cell transplantation (HSCT) in patients with and without GVHD. For this purpose we isolated RNA from CD4 and CD8 positive cells, sorted with immunomagnetic beads. We used real-time PCR for RNA quantification. We demonstrate a significantly decreased expression of IGF-1R RNA in both CD4 and CD8 positive cells up to 12 months after HSCT. We could not demonstrate a correlation between the IGF-1R RNA expression and T cell activating processes like GVHD, expansion of CD4 or CD8 populations or virus infections. PMID- 17691029 TI - Rapid HLA-DR fluorotyping based on melting curve analysis. AB - Real-time polymerase chain reaction (PCR) has been used in the study of human leukocyte antigen (HLA) genotyping as a potential alternative for routinely used molecular methods such as PCR-sequence specific primers (PCR-SSP) and PCR sequence specific oligonucleotide probes (PCR-SSO). Combined with fluorescent dye like SYBR GREEN I, it has more advantages such as low cost and consistent background. The aim of this study was to optimize the fluorescent dye-based method and introduce it into the fluorotyping for HLA-DR lotus. 24 pairs of allele-specific primers and 1 pair of internal control were optimized to discriminate HLA-DRB1, -DRB3/B4/B5 alleles. Additionally, conditions of real-time PCR amplifying and melting curve recording had been improved for convenient and clear readout. Forty-two clinical samples previously typed by conventional PCR SSP or sequence based typing (SBT) were tested and all got identical results. With this technique, 15 DNA samples can be assayed in parallel within 2 hours on the Real-time PCR instrument. These data strongly suggest a rapid HLA-DR fluorotyping method based on melting curve analysis, which could be a more economic and automatic alternative for clinical HLA-DR typing. PMID- 17691030 TI - Vision restoration therapy does not benefit from costimulation: A pilot study. AB - Visual field deficits in patients have long been considered to be nontreatable, but in previous studies we have found an enlargement of the intact visual field following vision restoration therapy (VRT). In the present pilot study, we wished to determine whether a double-stimulation approach would facilitate visual field enlargements beyond those achieved by the single-stimulus paradigm used in standard VRT. This was motivated by the findings that following visual cortex injury in animals, the size of receptive fields could be enlarged by systematic costimulation, where two stimuli were used to excite visual cortex neurons (Eysel, Eyding, & Schweigart, 1998). Patients (n = 23) with stable homonymous field deficits after trauma, cerebral ischemia, or hemorrhage (lesion age > 6 months) carried out either (a) standard VRT with a single stimulation (n = 9), or vision therapy with (b) a parallel costimulation (n = 7) or (c) a moving costimulation paradigm (n = 7). Training was carried out twice daily for 30 min over a 3-month period. Before and after therapy, visual fields were tested with 30 degrees and 90 degrees Tubinger automatic perimetry (TAP) and with high resolution perimetry (HRP). Eye movements were recorded with an eye tracking system. When data of all three types of visual field training were pooled, we found significant improvements of stimulus detection in HRP (4.2%) and fewer misses within the central 30 degrees perimetrically (-3.7% right eye, OD, or 4.4% left eye, OS). However, the type of training did not make any difference such that the three training groups profited equally. A more detailed analysis of trained versus untrained visual field areas in 16 patients revealed a superiority of the trained area of only 1.1% in HRP and between 3.5% (OS) and 4.4% (OD) in TAP. Spatial attention and alertness improved significantly in all three groups and correlated significantly with visual field enlargements. While vision training had no influence on the patient's testimonials concerning their visual abilities, the patients significantly improved in a practical paper-and-pencil number tracking task (Zahlen-Verbindungs Test; ZVT). Visual field enlargement does not benefit from a double-stimulation paradigm, but visual attention seems to play an important role in vision restoration. The improvements in trained as well as in untrained areas are explained by top-down attentional control mechanisms interacting with local visual cortex plasticity. PMID- 17691031 TI - Long-term morbidities following self-reported mild traumatic brain injury. AB - The objective of this study was to examine the prevalence of long-term psychiatric, neurologic, and psychosocial morbidities of self-reported mild traumatic brain injury (MTBI). A cross-sectional cohort sample of three groups was examined: those who had not been injured in a motor vehicle accident nor had a MTBI (n = 3,214); those who had been injured in an accident but did not have a MTBI (n = 539); and those who had a MTBI with altered consciousness (n = 254). Logistic regression analyses were used to model odds ratios for the association between group and outcome variables while controlling demographic characteristics, comorbid medical conditions, and early-life psychiatric problems. Compared with uninjured controls, MTBI increased the likelihood of depression and postconcussion syndrome. MTBI also was associated with peripheral visual imperceptions and impaired tandem gait. Similarly, the MTBI group had poorer psychosocial outcomes including an increased likelihood of self-reported disability, underemployment, low income, and marital problems. Results suggest that MTBI can have adverse long-term psychiatric, neurologic, and psychosocial morbidities. PMID- 17691032 TI - Executive function is associated with brain proton magnetic resonance spectroscopy in amnestic mild cognitive impairment. AB - Persons with amnestic mild cognitive impairment (MCI) show deficits on executive function measures, although the neuroanatomic basis of executive function in MCI is unknown. We investigated cognitive correlates of 3-tesla proton magnetic resonance spectroscopy (MRS) of the posterior cingulate gyrus in 26 MCI patients. Posterior cingulate ratio of myo-inositol to creatine (mI/Cr) was negatively correlated (-.51) with spontaneous clock drawing. This relationship was not attenuated after accounting for age, overall cognitive function, or memory performance. This finding suggests a role for the posterior cingulate in executive function in MCI. Proton MRS may offer a means to track neurometabolic changes associated with cognitive impairment in MCI. PMID- 17691033 TI - Decreased false memory for visually presented shapes and symbols among adults on the autism spectrum. AB - Individuals with autism spectrum disorders (ASD) have been shown in some studies to be less susceptible to the verbal "false memory" effect, perhaps due to restricted semantic associative networks. High-functioning individuals with ASD can demonstrate subtle language impairments. However, relative preservation of spatial skills can also be observed. This study investigated false memory in both visual and verbal paradigms to elucidate whether adults with ASD would be more or less prone to illusory recognition in a visual paradigm that contained slides of geometric figures with minimal linguistic and semantic associative representation. In the verbal paradigm, modeled on the Deese-Roediger-McDermott method, those with ASD did not perform significantly better than a matched comparison group. In contrast, in the visual paradigm those with ASD were significantly better able to discriminate true items from lure items and were less likely to falsely recognize the lures. Findings from the visual paradigm provide further evidence of restricted associative networks in ASD, particularly in the spatial domain. PMID- 17691034 TI - Measuring recovery in new learning and memory following traumatic brain injury: a mixed-effects modeling approach. AB - Patterns of recovery from traumatic brain injury (TBI) vary greatly across individuals. Using archival data from the Traumatic Brain Injury Model Systems, recovery of memory following TBI as measured by scores on the Rey Auditory Verbal Learning Test (RAVLT) through 5 years postinjury was examined via mixed-effects modeling. Individual-level variables of age and posttraumatic amnesia duration were significant predictors of 1-year RAVLT total score. None of the variables examined predicted the trajectory of memory recovery after 1 year. Mixed-effects analyses can be helpful in determining the effect of intervention while allowing for missing data across time points. PMID- 17691035 TI - The relationship between executive functioning and dissociation. AB - Although dissociation by definition affects cognition, few studies have used neuropsychological measures to examine dissociative phenomena. This study compared 33 high and 32 low dissociators based on the Dissociative Experiences Scale, on self-report and neuropsychological measures of executive function, including the Dysexecutive Questionnaire, Iowa Gambling Task, Operation Span task, and Wisconsin Card Sorting Test-64. High dissociators endorsed significantly more executive difficulties than did low dissociators, but these difficulties were not related to their performance on neuropsychological measures. Results suggest that dissociative individuals' perceptions of executive impairments may be divorced from objective deficits, revealing an important process underlying the clinical manifestations of dissociation. PMID- 17691036 TI - Neuropsychological evaluation of the treatments applied to intracranial aneurysms in a Spanish sample. AB - Very few studies have examined the neuropsychological differences between the two types of aneurysm treatment, and these studies come from different countries. The purpose of this study is to compare the neuropsychological differences between surgical treatment and endovascular treatment in a Spanish sample of patients who have experienced an aneurysmal subarachnoid hemorrhage. The sample is composed of three groups: 40 patients who underwent surgical intervention, 24 who were treated by means of coiling, and a group of 29 healthy participants. An extensive neuropsychological evaluation was performed. The results presented show that no neuropsychological differences were found between the two types of treatment for aneurysms and that the most affected function was memory. This result coincides with findings from other studies. PMID- 17691037 TI - Auditory feedback does not influence random number generation: Evidence from profoundly deaf adults with cochlear implant. AB - Oral random number generation is a widely used neuropsychological task engaging a number of overlapping neural systems of attention, number representation, response generation, and working memory. Although phonological processing is known to be essential for random number generation no information exists on the significance of the auditory feedback of hearing one's own voice on task performance. We therefore examined the influence of auditory feedback in 15 profoundly deaf adults with cochlear implants in a device-on/off experiment. No significant effects of occluding auditory feedback on random number generation were noted, thus supporting an internal response-monitoring model independent of auditory condition. PMID- 17691038 TI - The relationship between motor programming and executive abilities: constructs measured by the Push-Turn-Taptap task from the Behavioral Dyscontrol Scale Electronic Version. AB - The relationship between executive functioning and three components of motor programming (motor control, motor planning, and motor learning) was examined. Participants were 54 adults aged 18 to 68 years. Instruments included the Push Turn-Taptap task from the Behavioral Dyscontrol Scale-Electronic Version and a battery of traditional neuropsychological measures. The results showed that, after controlling for age, processing speed, and motor speed, all three components of motor programming accounted for additional 12 to 19% of variance in executive functioning. Additionally, task complexity, but not task novelty, accounted for the relationship between executive functioning and motor learning and motor control, but not motor planning. PMID- 17691039 TI - Is there a selective relationship between language functioning and auditory attention in children? AB - This study explores the selectivity of the relationship between auditory attention and language in children. A total of 42 children (16 females) between 7.0 and 10.0 years of age were administered a battery of cognitive, language, and behavioral measures along with 3 auditory and 3 visual continuous performance tests (CPTs). Omission errors on auditory CPTs were related to language skills whereas commission errors on CPTs in both modalities were related to behavioral ratings. The finding of a specific relationship between language functioning and auditory attention indicates that the contribution of auditory attention to language acquisition, processing, and breakdown should be more fully explored. PMID- 17691040 TI - The generalizability of neurocognitive test/retest data derived from a nonclinical sample for detecting change among two HIV+ cohorts. AB - Objective methods for determining clinically relevant neurocognitive change are useful for clinicians and researchers, but the utility of such methods requires validation studies in order to assess their accuracy among target populations. We examined the generalizability of regression equations and reliable change indexes (RCI) derived from a healthy sample to two HIV-infected samples, one similar in demographic makeup to the normative group and the other dissimilar. Measures administered at baseline and follow-up included the Trail Making Test, Controlled Oral Word Association Test (COWAT), Grooved Pegboard, and Digit Span. Frequencies of decline, improvement, or stability were determined for each measure. Among the demographically similar clinical cohort, elevated rates of decline among more immunologically impaired participants were indicated by simple regression method on measures of psychomotor speed and attention, while RCI addressing practice effects (RCI-PE) indicated improvement on most measures regardless of immunostatus. Conversely, among the demographically dissimilar cohort, simple regression indicated high rates of decline across all measures, while RCI-PE indicated elevated rates of decline on psychomotor and attention measures. Thus, the accuracy of the two methods examined for determining clinically significant change among HIV+ cohorts differs depending upon their similarity with the normative sample. PMID- 17691042 TI - New synthesis of two tridentate bipyrazolic compounds and their cytotoxic activity tumor cell lines. AB - Two new tripodal compounds - 4-{bis[(3,5-dimethyl-1H-pyrazole-1 yl)methyl]amino}butane-1-ol (1); ethyl 1-[((2-hydroxyethyl){[3-(ethoxycarbonyl)-5 methyl-1H-pyrazole-1-yl]methyl} amino)methyl]-5-methyl-1H-pyrazole-3-carboxylate (2) were reported. The evaluation of the cytotoxic properties in vitro of these ligands, was examined on two tumor cell lines - P815 (mastocytome murine) and Hep (carcinoma of human larynx). The concentration required to induce 50% of lysis (IC(50)) was more pronounced against P815 cell line (IC(50): 39.42 microg mL(-1) for the compound 1 and 97.74 microg mL(-1) for the compound 2) than the Hep cell line (IC(50): 83.49 microg mL(-1) for compound 1 and 185.30 microg mL(-1) for compound 2). Statistical analysis shows that the compound 1 is two to three folds more cytotoxic than the compound 2 (p < 0.05). Interestingly, the cytotoxic activity depends strongly on both the substituents linked to the aminic nitrogen and pyrazolic rings. PMID- 17691043 TI - A new cytotoxic cholesterol sulfate from marine sponge Halichondria rugosa. AB - A new steroid, 24xi,25-dimethyl-3alpha-hydroxyl-cholest-5-ene-2beta-ol sodium sulfate (1), together with a known steroid, 24xi,25-dimethyl-cholest-5-ene 2beta,3alpha-diol disodium sulfate (2), was isolated from the ethanol extract of marine sponge Halichondria rugosa. Their structures were elucidated on the base of spectroscopic analysis. Both compounds showed cytotoxicity to four human cancer cell lines (BEL-7402, HT-29, SPC-A1 and U-251) with IC(50) values between 6.5 and 23.1 microM. PMID- 17691044 TI - A new triterpenoid from roots of Laportea crenulata and its antifungal activity. AB - A new triterpenoid 2alpha,3beta,21beta,23,28-penta hydroxyl 12-oleanene and two known compounds were isolated from the roots of Laportea crenulata Gaud. The structures of all compounds were elucidated on the basis of various spectroscopic data. The two known compounds beta-sitosterol and beta-sitosterol 3-beta-D glucopyranoside are also the first report of isolation from this plant. The antifungal activity of new triterpenoid was studied against Aspergillus flavus, Aspergillus niger, Candida albicans, and Rhizopus aurizae, and compared with the activity of nystatin (30 microg disc(-1)). This compound has shown moderate activity against tested fungi. PMID- 17691045 TI - Synthesis and insecticidal activities of novel derivatives of podophyllotoxin. AB - In order to find the biorational pesticides, eight novel 4beta-substituted phenoxyaniline derivatives of podophyllotoxin (4a-h) have been synthesized with significant stereoselectivity and improved yields by employing the BF(3).Et(2)O/NaI reagent system and evaluated for insecticidal activity against Pieris rapae as well as for their antifeedant effect against fifth instar larvae of P. rapae. The results showed that all these derivatives of PPT showed delayed insecticidal activity, which is different from the traditional neurotoxic insecticides. Among them, compounds possessing a 4beta-phenoxyaniline moiety substituted at para (CO(2)C(2)H(5), Cl, and OH) position exhibited greater insecticidal activity against P. rapae than podophyllotoxin. Also, the antifeedant activities showed that these compounds exhibited less potency than podophyllotoxin. PMID- 17691046 TI - Seasonal and biological variations of Epidendrum mosenii: quantification of 24 methylenecycloartanol using gas chromatography. AB - Epidendrum mosenii is a Brazilian medicinal plant, traditionally used to treat infective and dolorous processes. The present article reports a comparative study of the chemical and pharmacological aspects of different parts and seasons of this plant. The results demonstrate that 24-methylenecycloartanol (1), one of the main active principles present in this plant, is located practically in all the parts and during all seasons, but it is much more concentrated in the stems when collected in spring and summer. The pharmacological results indicate that dichloromethane extracts collected in spring and summer were the most active when evaluated against the writhing test in mice, being several times more potent than some reference drugs used as comparison. Together, the results strongly suggest that the antinociceptive effect of E. mosenii is related, at least in part, to the presence of compound 1, and this finding could be useful for quality control of phytopreparations based on this plant. PMID- 17691047 TI - Bioassay-guided fractionation of antifertility components of castorbean (Ricinus communis L.) seed extracts. AB - In the present study, the aether extracts of castorbean seed (AEC), which possessed antifertility activity and contraceptive efficacy in female and male rodents, were evaluated for their in vitro inhibitory activity in the primary cultured rat decidual stromal cells (DSC). A bioassay-guided fractionation technique was used to separate active components from crude extracts. A colorless crystal showed a significant inhibitory activity (IC(50) = 63.84 +/- 3.04 microg mL(-1), r = +0.9478). The chemical analysis of the colorless crystal by capillary gas chromatography-mass spectrometry (GC-MS) revealed that the colorless crystal was a mixture of five components: four phytosterols which were ergost-5-en-3-ol (6.10%), stigmasterol (35.80%), gamma-sitosterol (44.77%), and fucosterol (8.40%); and one probucol analog (4.93%). It was presumed that gamma-sitosterol may be the main component contributing to inhibit the viability of DSC. PMID- 17691048 TI - Biological evaluations of fatty acid esters originated during storage of Prasaplai, a Thai traditional medicine. AB - Three fatty acid esters, (E)-4-(3,4-dimethoxyphenyl)but-3-en-1-yl linoleate (1), (E)-4-(3,4-dimethoxyphenyl)but-3-en-1-yl oleate (2), and (E)-4-(3,4 dimethoxyphenyl)but-3-en-1-yl palmitate (3), originated during storage by the interaction of components in Prasaplai, were synthesized. These three artificial esters were subjected to four biological evaluations. All three compounds were active against Mycobacterium tuberculosis H(37)Ra for which compounds 1 and 3 had inhibitory concentration at 200 microg mL(-1) while compound 2 inhibited at 100 microg mL(-1). When all these compounds were subjected to anti-HSV-1 test, compound 2 showed positive activity at 42.6 microg mL(-1) without any cytotoxic activity against human vero cell line while compound 3 had the cytotoxicity to vero cell at IC(50) 38 microg mL(-1). Compound 1 was inactive for this test. PMID- 17691049 TI - Design, synthesis, and biological evaluation of novel spin-labeled derivatives of podophyllotoxin as potential antineoplastic agents. Part XII. AB - Five novel nitroxyl spin-labeled ester derivatives of podophyllotoxin (11a-11e) have been prepared and their structural information on these nitroxyl spin labeled ester derivatives of podophyllotoxin (11a-11e) using (1)HNMR spectroscopy was efficiently obtained by application of the in situ reduction of representative nitroxyl spin-labeled ester derivative of podophyllotoxin 11e with phenylhydrazine for the preparation of N-hydroxylamine 12 in the NMR tube. These novel derivatives were further evaluated for their in vitro cytotoxic activity against five neoplastic cell lines (K562, HL-60, SPCA-1, Lewis, and L-1210) using MTT assay. Most of the target compounds (except for all these compounds against SPCA-1) exhibited more pronounced cytotoxicity against several neoplastic cell lines than that of the prototypical inhibitor etoposide. PMID- 17691050 TI - A novel antiplasmodial 3',5'-diformylchalcone and other constituents of Friesodielsia obovata. AB - Phytochemical investigation of the stem and root barks of Friesodielsia obovata Benth (Annonaceae) afforded new 3',5'-diformyl-2',4',6'-trihydroxychalcone and N formyl-7-hydroxyglaucine together with five known compounds, 3',5'-dimethyl 2',4',6'-trihydroxychalcone, (-)-crotepoxide, demethoxymatteucinol, lawinal, and benzyl benzoate. 3',5'-diformyl-2',4',6'-trihydroxychalcone indicated significant antiplasmodial, cytotoxicity, and larvicidal activities. PMID- 17691051 TI - Novel stilbene glycosides from Pleuropterus ciliinervis. AB - New stilbene glycosides, (E)-resveratrol-3-O-alpha-L-rhamnopyranosyl-(1 --> 2) beta-D-xylopyranoside, was isolated from the MeOH extract of the roots of Pleuropterus ciliinervis Nakai (Polygonaceae). Their structures were determined spectroscopically, particularly by 2D NMR spectroscopic analysis. PMID- 17691052 TI - Two new flavanes and bioactive compounds from Daphne tangutica Maxim. AB - Two new flavanes, named daphneflavan B (1) and daphneflavan C (2), along with two known biflavonoids, daphnodorin D(1) (3) and daphnodorin D(2) (4), were isolated from the roots of Daphne tangutica Maxim. Their structures were established on the basis of chemical, physicochemical, and spectroscopic evidences. Two compounds 3 and 4 were noted to have the most marked antitumor activity in vivo assay. PMID- 17691053 TI - A new cytotoxic and larvicidal himachalenoid, rosanoids and other constituents of Hugonia busseana. AB - A new cytotoxic himachalene sesquiterpenoid 4alpha-methoxy-5,9-oxahimachal-9-ene (hugonianene A) which exhibited moderate activity against Anopheles gambiae mosquito larvae after 24 h at a concentration of 0.237 mg mL(-1), and at 48 h and 72 h contact time causing complete larval mortality up to a concentration as low as 0.01369 mg mL(-1), was isolated as the major constituent of the cytotoxic root bark extract of Hugonia busseana. Hugonianene A was obtained together with the hitherto unreported rosane diterpenoid 18-hydroxyrosane, the known rosane diterpenoid hugorosediol, an inseparable mixture of 12-methoxy-13-methylpodocarpa 8,11,13-trien-3,7-dione and 12-methoxy-13-methylpodocarpa-1,8,11,13-tetraen-3,7 dione, and the di-podocarpanoid hugonone B that was previously obtained from H. castaneifolia. PMID- 17691054 TI - Inhibitory effect of lactone fractions and individual components from three species of the Achillea millefolium complex of Bulgarian origin on the human neutrophils respiratory burst activity. AB - Achillea species are widely used in folk medicine for treatment of inflammatory diseases. The inhibitory effect on the human neutrophils respiratory burst activity of total extracts, their fractions and some main constituents of the flower heads from Achillea asplenifolia, A. collina and A. distans belonging to A. millefolium complex of Bulgarian origin, were tested by the modified method of Tan and Berridge. Seven from the investigated fractions showed activity similar or higher than that of indomethacine and might be evaluated as nonsteroidal anti inflammatory agents. PMID- 17691055 TI - Plaunotol induces apoptosis of gastric cancer cells. AB - Although some isoprenoids, such as taxans and geranylgeraniol (GGOH), have been reported to have strong anticancer activities, the effect of plaunotol, the isoprenoid extracted from the leaves of Plau-noi, on cancer has not yet been evaluated. Here, we aimed to investigate the effect of plaunotol on gastric cancer cell lines. Three gastric cancer cell lines, namely MKN-45, MKN-74 and AZ 521 were used. Plaunotol was tested at 10, 20, 30 and 40 micromol/L. Plaunotol dose-dependently inhibited the growth of all gastric cancer cells, dependent on the induction of apoptosis. Caspases-8, -9 and -3, were found to be activated in the apoptotic cells. The expression of Bax protein was increased, but Bcl-2 and Bcl-xL protein expressions were not significantly affected. Plaunotol should be a promising new antitumor agent, and since it is already available for clinical use in Japan, its anticancer properties should be confirmed in clinical trials. PMID- 17691056 TI - Comparative study on plant latex proteases and their involvement in hemostasis: a special emphasis on clot inducing and dissolving properties. AB - In the present study we compared the clot inducing and dissolving properties of Calotropis gigantea R. Br. (Asclepiadaceae), Synadenium grantii Hook. f. (Euphorbiaceae) and Wrightia tinctoria R. Br. (Apocynaceae) latex extracts. All the three latex extracts hydrolyzed casein, fibrinogen and crude fibrin dose dependently. The proteolytic action on fibrinogen subunity was in the order of Aalpha > Bbeta > gamma. All extracts exhibited procoagulant activity as assayed by re-calcification time. However, thrombin like activity is restricted to C. gigantea. In addition, the extracts dose-dependently hydrolyzed blood and plasma clots. Furthermore, the hydrolyzing pattern of fibrin in the plasma clot was substantiated by SDS-PAGE. The extracts hydrolyzed all the subunits (alpha polymer, alpha-chains, gamma-gamma dimer and beta-chain) of fibrin efficiently. Both fibrinogenolytic and fibrinolytic activity potency of the extracts were in the order of C. gigantea > S. grantii > W. tinctoria. Among the three latices, C. gigantea is toxic with a minimum hemorrhagic dose (MHD) of > 75 microg, whereas S. grantii and W. tinctoria latex extracts were non-toxic and did not induce any hemorrhagic effect at the tested dose (> 200 microg). The proteolytic activity of C. gigantea latex extract on different substrates was inhibited by IAA. On the other hand, the proteolytic activities of S. grantii and W. tinctoria were inhibited by PMSF. Thus, this study provides the basis for the probable action of plant latex proteases to stop bleeding and effect wound healing as exploited in folk medicine. PMID- 17691057 TI - Dendrazawaynes A and B, antifungal polyacetylenes from Dendranthema zawadskii (Asteraceae). AB - Two new C(14) polyacetylenes dendrazawayne A(7) and dendrazawayne B (9) together with known C(13) polyacetylenes (2, 3), C(14) polyacetylenes (1, 4, and 8) and polyacetylene amides (5 and 6) were isolated from the roots of Dendranthema zawadskii. The structures of 7 and 9 were elucidated based on spectroscopic methods including 2D-NMR, HR-TOF-MS, IR, and UV. Compounds 1, 2, 3, 5, and 6 showed moderate activity against tumor cell lines (human small lung cancer cell line A549, melanoma SK-Mel-2, and mouse melanoma B16F1) with IC(50) values in the range of 7.4 - 30 microg/mL. Compounds 7 and 9, including other polyacetylenes, showed strong activity against the fungus Trichophyton (MIC: 5 - 10 microg/mL). PMID- 17691058 TI - Gastroprotective effect and cytotoxicity of semisynthetic jatropholone derivatives. AB - The gastroprotective effect of the diterpenes jatropholone A, jatropholone B and 16 semisynthetic derivatives was assessed in the HCl/ethanol-induced gastric lesion model in mice and the cytotoxicity was determined towards fibroblasts and AGS cells. In a dose-response study, jatropholone B reduced gastric lesions by 65% at 6 mg/kg and jatropholone A by 54% at 100 mg/kg. The jatropholone B derivatives 9 - 14 and the compounds 15 - 18 were compared at a single oral dose of 25 mg/kg while the jatropholone A derivatives 2 - 7 were assessed at 100 mg/kg. A decrease in gastroprotective activity was observed for the ether as well as for the ester derivatives of jatropholone B. The methyl and propyl ethers of jatropholone A were more gastroprotective than the natural product. The placement of an additional methyl group at C-2 in the jatropholone B derivatives led to a loss of selectivity, the methyl and propyl ethers lack a gastroprotective effect. Jatropholone B was not toxic towards AGS cells and fibroblasts. Jatropholone A was active only against AGS cells. The gastroprotective effect of the epimeric jatropholones was selective showing a higher effect for jatropholone B. These results further support that the stereochemistry of the methyl group at C-2 in the jatropholones plays a relevant role in preventing the gastric lesions in mice. The compounds 3, 5 - 7, 10 and 12 - 18 are described for the first time. PMID- 17691059 TI - In vitro activity of 10-deacetylbaccatin III against Leishmania donovani promastigotes and intracellular amastigotes. AB - Current treatments for leishmaniasis are unsatisfactory due to their route of administration, toxicity and expense but, most importantly, to the developed resistance of Leishmania to first-line drugs. Therefore, the identification of new effective targeted drugs is an urgent need. Since many studies have shown that medicinal plants contain compounds active against protozoa we have undertaken a study aiming to determine the antileishmanial activity of the taxoid 10-deacetylbaccatin III, isolated from dried needles and small branches of the European yew tree (Taxus baccata). Interestingly, 10-deacetylbaccatin III was found to selectively inhibit the growth of L. DONOVANI intracellular amastigotes within J774 murine macrophages in vitro at nanomolar concentrations with an IC(50) value of 70 nM. Concentrations of 10-deacetylbaccatin III as high as 5 microM did not affect J774 murine macrophages whereas 20 nM of taxol, used as a control, was toxic to macrophages. The compound also inhibited the growth of L. donovani promastigotes but at higher concentrations with a maximum level of inhibition of 35 %. Taxol inhibited promastigote growth at micromolar concentrations. Comparison of the effect of 10-deacetylbaccatin III to that of taxol on cell cycle progression and cellular morphology showed that their mechanisms of action are different. The 10-deacetylbaccatin III-treated promastigotes were slightly arrested in the G2/M phase whereas taxol-treated cells were blocked in the G2/M phase. In addition 10-deacetylbaccatin III treatment, contrary to taxol, did not affect cellular morphology. PMID- 17691061 TI - Direct repair of canalicular lacerations. AB - Injury and disruption of the canaliculi of the lacrimal excretory system commonly occur from laceration or shearing trauma. This type of injury will likely lead to dysfunction of tear flow from the palpebral sulcus and chronic epiphora. The goal of this article is to give a step-by-step review of canalicular repair. PMID- 17691062 TI - Modified technique and ptosis clamp for surgical correction of congenital pediatric ptosis by anterior levator resection. AB - Congenital ptosis is due to a dysgenesis of the levator complex with the levator muscle being replaced by fatty and fibrous tissue. This dysfunction of the levator muscle gives rise to the classic triad of findings in congenital ptosis, including ptosis in the primary position, lagophthalmos in downgaze, and a poorly formed eyelid crease. There are traditionally two ways to surgically correct congenital ptosis, levator resection and frontalis suspension (by utilizing a myriad of both autogenous and synthetic materials). Although frontalis suspension is the more utilized surgical option for the correction of congenital ptosis, the complication rate due to the use of synthetic materials is not insignificant. Many surgeons feel that the contour and appearance of the eyelid following levator resection is superior to the frontalis suspension technique. Thus, levator resection for congenital ptosis can be one of the most satisfactory and physiologically normal of the ptosis procedures. Surgery for congenital ptosis can however be unpredictable in outcome. We propose a modified technique for levator resection as well as a newly designed and modified Berke ptosis clamp for levator resection surgery. Postoperative results with the modified technique as well as clamp have been very encouraging with excellent postoperative lid contour and height. The author has utilized this clamp and modified technique in over 350 lid surgeries over the past ten years. PMID- 17691063 TI - Noninvasive techniques in periorbital rejuvenation. AB - The combination of noninvasive treatments in the periorbital area can be used to achieve dramatic and long-lasting results. New technologies and current therapies may supplement or even delay traditional surgical procedures. PMID- 17691064 TI - Thyroid-related orbitopathy: concepts and management. AB - Thyroid-related orbitopathy is a disorder related to systemic thyroid dysfunction, which can cause devastating orbital disease affecting nearly all of the orbital tissues. This includes orbital and eyelid abnormalities that may be acute, subacute, or chronic. The disease is complex and difficult to treat due varying activity of the systemic thyroid disease. The resulting morbidity of the disease ranges from mildly abnormal cosmesis and ocular irritation to blindness. A systematic approach to successful management of this disease requires timely medical and surgical interventions. PMID- 17691065 TI - Techniques in midface-lifting. AB - A review of different techniques used in midface-lifting. PMID- 17691066 TI - Management and reconstruction of periocular malignancies. AB - Skin cancers are increasing as the population ages. Basal cell and squamous cell carcinomas are the most commonly occurring lesions. The frozen section techniques and Mohs' techniques are considered to be the gold standard of treatment of periocular carcinomas. Strategies for treatment of these lesions as well as reconstruction of full-thickness eyelid defects and partial-thickness skin defects are discussed. PMID- 17691067 TI - Orbital floor fractures: evaluation, indications, approach, and pearls from an ophthalmologist's perspective. AB - Blunt trauma to the orbital rim is a frequent cause of orbital floor fractures. Although orbital floor fractures often occur in association with other facial trauma, the term "blowout fracture" is reserved for isolated orbital floor fractures with an intact orbital rim. Many surgical specialties--including ophthalmologists, otolaryngologists, maxillofacial specialists, and plastic surgeons--evaluate and treat floor fractures. The wide range of treating physicians means that varying levels of expertise and experience are involved in care of patients with periorbital trauma. Although each subspecialty can offer pearls from their basis of training, the purpose of this article is to offer insights on orbital floor fractures from the ophthalmic plastic and reconstructive surgeon's perspective. Particular emphasis will be placed on ophthalmic portions of the examination and treatment plan; all in an attempt to avoid ophthalmic complications. This review is meant to be a user-friendly guide to the evaluation and treatment of orbital floor fractures from an ophthalmic perspective. PMID- 17691068 TI - The lateral tarsal strip: illustrated pearls. AB - The lateral tarsal strip is a mainstay procedure of oculoplastic surgery. The technique is easy to conceive but difficult to master. Awareness of its many indications and its limitations along with a working knowledge of its proper execution is necessary. PMID- 17691069 TI - Blepharoptosis: evaluation, techniques, and complications. AB - Blepharoptosis (ptosis) is one of the most common eyelid disorders encountered in ophthalmology. A detailed history and exam are crucial in the evaluation of a patient presenting with ptosis. This provides the correct guidelines for surgical planning. The appropriate surgical technique is usually determined by the degree of ptosis and levator function. The surgeon should have an armamentarium of several different techniques for the management of ptosis. This article will detail a modified approach to the traditional tarsomyectomy (Fasenalla-Servat procedure) and also discuss the levator advancement. Despite the proper preoperative evaluation and meticulous attention to technique, the ptosis surgeon may still encounter postoperative complications. The ability to manage the array of possible complications truly distinguishes the ptosis surgeon. PMID- 17691070 TI - The cis/trans isomerization of Cu(II)-bis-(glycinato) complex in solution: a computer aided multifrequency EPR and DFT/PCM calculation study. AB - In this paper the Cu(II)-bis-(glycinato) complex has been analysed in solution by applying a combined approach of multifrequency EPR and DFT/PCM calculations. The accuracy in the determination of magnetic parameters has been reached by the use of a unique simulation program (COSMOS) for the whole range of temperatures analysed and by the error analysis. A change in magnetic parameters was envisaged in the 243-253 K range of temperature, and was interpreted in terms of stabilization, near the freezing point of the solution, of one of the isomers of the complex. A DFT/PCM computational model was crucial in assigning, on the basis of the experimental superhyperfine interaction value, the isomer to the trans form. PMID- 17691072 TI - Sarcomas: genetics, signalling, and cellular origins. Part 1: The fellowship of TET. AB - Sarcomas comprise some of the most aggressive solid tumours that, for the most part, respond poorly to chemo- and radiation therapy and are associated with a sombre prognosis when surgical removal cannot be performed or is incomplete. Partly because of their lower frequency, sarcomas have not been studied as intensively as carcinomas and haematopoietic malignancies, and the molecular mechanisms that underlie their pathogenesis are only beginning to be understood. Even more enigmatic is the identity of the primary cells from which these tumours originate. Over the past 25 years, however, several non-random chromosomal translocations have been found to be associated with defined sarcomas. Each of these translocations generates a fusion gene believed to be directly related to the pathogenesis of the sarcoma in which it is expressed. The corresponding fusion proteins provide a unique tool not only to study the process of sarcoma development, but also to identify cells that are permissive for their putative oncogenic properties. This is the first of two reviews that cover the mechanisms whereby specific fusion/mutant gene products participate in sarcoma development and the cellular context that may provide the necessary permissiveness for their expression and oncogenicity. Part 1 of the review focuses on sarcomas that express fusion genes containing TET gene family products, including EWSR1, TLS/FUS, and TAFII68. Part 2 (J Pathol 2007; DOI: 10.1002/path.2008) summarizes our current understanding of the genetic and cellular origins of sarcomas expressing fusion genes exclusive of TET family members; it also covers soft tissue malignancies harbouring specific mutations in RTK-encoding genes, the prototype of which are gastrointestinal stromal tumours (GIST). PMID- 17691073 TI - Scalaradial, a dialdehyde-containing marine metabolite that causes an unexpected noncovalent PLA2 Inactivation. AB - Several marine terpenoids that contain at least one reactive aldehyde group, such as manoalide and its congeners, possess interesting anti-inflammatory activities that are mediated by the covalent inactivation of secretory phospholipase A(2) (sPLA(2)). Scalaradial, a 1,4-dialdehyde marine terpenoid that was isolated from the sponge Cacospongia mollior, is endowed with a relevant anti-inflammatory profile, both in vitro and in vivo, through selective sPLA(2) inhibition. Due to its peculiar dialdehyde structural feature, it has been proposed that scalaradial exerts its enzymatic inactivation by means of an irreversible covalent modification of its target. In the context of our on-going research on anti PLA(2) natural products and their interaction at a molecular level, we studied scalaradial in an attempt to shed more light on the molecular mechanism of its PLA(2) inhibition. A detailed analysis of the reaction profile between scalaradial and bee venom PLA(2), a model sPLA(2) that shares a high structural homology with the human synovial enzyme, was performed by a combination of spectroscopic techniques, chemical reactions (selective modifications, biomimetic reactions), and classical protein chemistry (such as proteolytic digestion, HPLC and mass spectrometry), along with molecular modeling studies. Unexpectedly, our data clearly indicated the noncovalent forces to be the leading event in the PLA(2) inactivation process; thus, the covalent modification of the enzyme emerges as only a minor side event in the ligand-enzyme interaction. The overall picture might be useful in the design of SLD analogues as new potential anti inflammatory compounds that target sPLA(2) enzymes. PMID- 17691074 TI - Semisynthesis and cytotoxicity of hypothemycin analogues. PMID- 17691075 TI - Thermodynamics of hydrophobic interactions: entropic recognition of a hydrophobic moiety by poly(ethylene oxide)-zinc porphyrin conjugates. AB - The recognition of 4-alkylpyridines by water-soluble poly(ethylene oxide)-zinc porphyrin conjugates was studied with a focus on the thermodynamic parameters of binding. Microcalorimetric studies indicated that binding of the alkyl group of the guest in water is driven by the entropic term (delta DeltaH0 = DeltaH0(4 pentylpyridine) - DeltaH0(4-methylpyridine) = +1.7 kJ mol(-1), deltaT DeltaS0 = TDeltaS0(4-pentylpyridine) - TDeltaS0(4-methylpyridine) = +11.8 kJ mol(-1) at 298 K), thus showing the significance of water reorganization during host-guest interaction. The enthalpy-entropy compensation temperature of binding of 4 alkylpyridines was as low as 38 K; only below this temperature could the enthalpic term be a driving force. The binding affinity was modulated by the addition of cations and by varying the degree of polymerization of poly(ethylene oxide), which suggests that guest binding is coupled with polymer conformation. PMID- 17691076 TI - Treatment with amisulpride and olanzapine improve neuropsychological function in schizophrenia. AB - OBJECTIVES: Although antipsychotic drugs control acute psychotic manifestations of schizophrenia, improving cognitive symptoms is also important for long-term prognosis. METHODS: Three hundred and seventy-seven adult patients with acute psychosis were randomised to either amisulpride (200-800 mg/d) or olanzapine (5 20 mg/d) for 6 months. Neuropsychological performance was assessed at inclusion and after 6 months in a subgroup of 26 subjects (11 treated with amisulpride and 15 with olanzapine) using the Auditory Verbal Learning Test (AVLT), the Trail Making Test (TMT) and the Controlled Oral Word Association Test (COWAT). RESULTS: The improvement in BPRS score was similar in both treatment groups. No significant differences in test performance between groups were observed at inclusion. After 6 months, AVLT scores increased by 8.7 points in the amisulpride group and by 2.3 points in the olanzapine group (p = 0.049). Completion speed in the TMT increased by 17.4 s (amisulpride) and 15.4 s (olanzapine) for Part A and by 39.8 and 48.8 s, respectively for Part B. Performance in the COWAT improved little in both groups. CONCLUSIONS: Both amisulpride and olanzapine produce sustained improvement in certain measures of neuropsychological performance in patients with schizophrenia; a significant improvement in score on the AVLT was observed only with amisulpride. PMID- 17691077 TI - Mediation analysis via potential outcomes models. AB - This paper develops a causal or manipulation model framework for mediation analysis based on the concept of potential outcome. Using this framework, we provide new definitions and measures of mediation. Effects of manipulations are modeled via the linear structural model. Corresponding structural equation models (SEMs), in conjunction with two-stage least-squares estimation and the delta method, are used to perform inference. The methods are applied to data from a study of nursing interventions for postoperative pain. We address the cases of more than two treatment groups, and an interaction among mediators. For the latter, a sensitivity analysis approach to handle unidentified parameters is described. Interpretative advantages of the potential outcomes framework for mediation are emphasized. PMID- 17691078 TI - Season of birth: dementia in Alzheimer's disease in adults with Down Syndrome. PMID- 17691079 TI - Comparing several means of dependent populations of count: a parametric robust approach. AB - We propose a parametric robust procedure for comparing several means of dependent populations of counts. The validity of the proposed method requires no knowledge of the true underlying joint distributions so long as they have finite second moments. The efficacy of this novel technique is demonstrated by simulations and the analysis of a data set from the Taiwan National Health Insurance Research Database. Our new parametric robust method is also compared with the popular semi parametric generalized estimating equations approach. PMID- 17691080 TI - Glucose-induced de novo synthesis of fatty acyls causes proportional increases in INS-1E cellular lipids. AB - Raised concentrations of glucose for extended periods of time have detrimental effects on the insulin-producing beta-cell. As de novo synthesis of lipids has been observed under such conditions, it was hypothesized that newly formed lipids may preferentially contain saturated fatty acids, which in particular have been associated with impaired beta-cell function. Glucose-induced de novo synthesis of fatty acids in INS-1E cells cultured in 5.5, 11, 20 or 27 mM glucose for 5 days was assessed by high-resolution magic-angle-spinning (HR-MAS) NMR spectroscopy and gas chromatography-mass spectrometry (GC-MS). The glucose origin of the increase in fatty acyls was verified by replacing glucose with [1-13C]glucose during culture followed by analysis with two-dimensional 1H-13C NMR spectroscopy. The composition of the fatty acyls was determined by GC-MS. Fatty acyls determined by HR-MAS (1)H NMR spectroscopy were increased fivefold in INS-1E cells cultured in 20 or 27 mM glucose compared with cells cultured in 5.5 mM glucose. The five most abundant fatty acids with their relative percentages in INS-1E cells cultured in 5.5 mM glucose were oleate (33%), palmitate (25%), stearate (19%), octadecenoate (13%) and palmitoleate (4.4%). These proportions were not affected by glucose- induced de novo synthesis in INS-1E cells cultured in 11, 20 or 27 mM glucose. It is concluded that glucose-induced de novo lipid synthesis results in accumulation of both saturated and unsaturated fatty acids in specific proportions that are identical with those present under control conditions. PMID- 17691081 TI - Effect of exposure misclassification on the mean squared error of population attributable risk and prevented fraction estimates. AB - Previous work has considered the effect of exposure misclassification on the bias of population attributable risk (AR) estimates, but little is known about the corresponding effects on their precision or mean squared error (MSE). This paper considers AR estimation in typical scenarios for case-control and cohort studies. The analogous index used when exposure reduces the risk--the prevented fraction (PF)--is also investigated. It is shown, through both theoretical and simulation results, that even with quite modest levels of exposure misclassification, the MSE can increase substantially, relative to the variance of AR estimated without measurement error. When exposure assessment is perfectly sensitive, there is no bias in AR but lack of measurement specificity can still cause a substantial loss of precision. In a few cases, the AR or PF with misclassified exposure can actually have smaller MSE; these exceptional cases arise when sensitivity is poor and the bias in AR or PF is relatively large. We conclude that while bias can be reduced by defining exposure on a highly sensitive basis, one must also consider the deleterious effect on precision by doing so. Loss of precision in the AR and PF estimates can be safely ignored only when the exposure measure is very accurate. PMID- 17691082 TI - Hagfish embryos again: the end of a long drought. AB - Hagfishes have long held a key place in discussions of early vertebrate evolution. Frustratingly, one basis for such discussions -- namely hagfish embryology -- is very incompletely known, because the embryos of these animals are notoriously difficult to obtain. Fortunately, a recent publication on a Far Eastern hagfish describes a workable procedure for obtaining embryos and then uses this precious material to show that the hagfish neural crest arises by cell delamination as in other vertebrates -- and not by epithelial outpouchings from the wall of the neural tube as previously claimed. Importantly, because hagfish embryos should now be available on a regular basis, the way is open for additional morphological and developmental genetic investigations to help evaluate existing evolutionary scenarios and perhaps suggest new ones. PMID- 17691083 TI - Stereoselective synthesis of alpha-allenols by rhodium-catalyzed reaction of alkynyl oxiranes with arylboronic acids. PMID- 17691084 TI - Metalated nitriles: internal 1,2-asymmetric induction. PMID- 17691085 TI - Designing facial amphiphiles for the stabilization of integral membrane proteins. PMID- 17691086 TI - Organocatalytic enantioselective protonation of silyl enolates mediated by cinchona alkaloids and a latent source of HF. PMID- 17691087 TI - Sixty years after wittig: gas-phase synthesis of lithium trimethylammonium methylide, [(CH3)3NCH2Li]+. PMID- 17691088 TI - Geminal bismethylation prevents polyketide oxidation and dimerization in the benastatin pathway. PMID- 17691089 TI - Mechanism of methyl esterification of carboxylic acids by trimethylsilyldiazomethane. PMID- 17691090 TI - Macrocyclic helix-threading peptides for targeting RNA. PMID- 17691091 TI - A practical synthesis of the phytosiderophore 2'-deoxymugineic acid: a key to the mechanistic study of iron acquisition by graminaceous plants. PMID- 17691092 TI - Grafting single-walled carbon nanotubes with highly hybridizable DNA sequences: potential building blocks for DNA-programmed material assembly. PMID- 17691093 TI - Thermodynamic analysis of beta-sheet secondary structure by backbone thioester exchange. PMID- 17691094 TI - The fatty acid factory of yeasts. PMID- 17691095 TI - Spirodiepoxides: heterocycle synthesis and mechanistic insight. PMID- 17691096 TI - Regional differences in the genetic variability of Finno-Ugric speaking Komi populations. AB - The Komi (Komi-Zyryan) people are one of the most numerous ethnic groups belonging to the Finno-Ugric linguistic community. They occupy an extensive territory in north Russia to the west of the Ural Mountains, in the northeast of the East European Plain. This is an area of long-term interactions between Europeans and North Asians. Genetic variability was evaluated in two geographically distinct populations, the Izhemski and Priluzski Komi. We searched for polymorphisms of the TP53 gene (a 16-bp duplication in intron 3 and three RFLPs: for Bsh1236I at codon 72, for MspI in intron 6, and for BamHI in the 3' flanking region) and for variable number tandem repeat (VNTR) polymorphisms of locus D1S80 and of the 3' untranslated region of the gene for apolipoprotein B (ApoB). Some data from our previous studies of TP53, 3'ApoB, and D1S80 variability were involved in the comparison of Komi with other Eastern European populations. Multidimensional scaling analysis of genetic distances was used for the evaluation of genetic relationships between populations. The results revealed some affinity between Priluzski Komi and Eastern Slavonic populations, and significant segregation of Izhemski Komi from other ethnic groups studied. The unique genetic features of Izhemski Komi may have been determined by their ethnogenesis or the pressure of environmental factors, such as special nutrition and adaptation to extreme climatic conditions. PMID- 17691097 TI - Impact of seasonal scarcity on energy balance and body composition in peasant adolescents from Calakmul, Campeche Mexico. AB - A time allocation and anthropometric study were performed on 46 male and 38 female adolescents from 16 peasant households from two different adaptive strategies in the municipio of Calakmul, Campeche Mexico to see if they could maintain energy balance during the annual scarcity season. These strategies were called: "household subsistence agricultural strategy" (HSA) and "household commercial agricultural strategy" (HCA). Each month, from June 2001 to May 2002, adolescents were measured and followed for 24 h. Their activities were recorded at 15 min intervals. Weight for age (W/A), height for age (H/A), body mass index (BMI), arm muscle area, arm fat area, total energy expenditure (TEE), activity energy expenditure (AEE), and basal metabolic rate (BMR) were estimated and the data compared between seasons using a repeated measurements analysis of variance. The results suggest that HCA offers their adolescents better buffering against seasonal scarcity, and that HSA males are better protected than females. HCA adolescents didn't show significant losses of weight, and HCA females lost body fat during the scarcity season. HSA vulnerability was observed in W/A and BMI z score reductions during the scarcity season. It also reflected itself in stunted adolescent males and adolescent females with fewer fat reserves. HSA adolescents reduced their BMR to down regulate their energy expenditure during the scarcity season without reducing TEE and physical activity levels. HSA females lost muscle mass during the scarcity season while HSA males didn't. This difference was associated with a more demanding work schedule throughout the year for females. PMID- 17691098 TI - Growth among Tibetans at high and low altitudes in India. AB - In India, Tibetans have been living at different altitudes for more than 40 years. This study describes physical growth in terms of height, weight, sitting height, skinfold thickness at triceps and upper arm circumference of Tibetans born and raised at three Tibetan refugee settlements (3,521; 970; and 800 m) from the view point of the hypothesis that growth is retarded at high altitude. Samples consist of individuals between the ages of 2 and 40 years. Tibetans at high altitude in India show a growth pattern similar to that previously observed among Tibetans in Tibet. Tibetans at high altitude are taller and heavier compared to Andean highlanders. The general trends show that Tibetan children and adults of both sexes at low altitude in India are advanced in terms of height, weight, skinfold thickness at triceps and upper arm circumference compared to Tibetans at high altitude. Trunk length (sitting height) is similar at the two altitudes but relative sitting height is greater at high altitude. Greater relative sitting height and lesser leg length at high altitude than at low altitudes is discussed in terms of effect of altitude, temperature, and nutritional status. PMID- 17691099 TI - Evolution of global regulatory networks during a long-term experiment with Escherichia coli. AB - Evolution has shaped all living organisms on Earth, although many details of this process are shrouded in time. However, it is possible to see, with one's own eyes, evolution as it happens by performing experiments in defined laboratory conditions with microbes that have suitably fast generations. The longest-running microbial evolution experiment was started in 1988, at which time twelve populations were founded by the same strain of Escherichia coli. Since then, the populations have been serially propagated and have evolved for tens of thousands of generations in the same environment. The populations show numerous parallel phenotypic changes, and such parallelism is a hallmark of adaptive evolution. Many genetic targets of natural selection have been identified, revealing a high level of genetic parallelism as well. Beneficial mutations affect all levels of gene regulation in the cells including individual genes and operons all the way to global regulatory networks. Of particular interest, two highly interconnected networks -- governing DNA superhelicity and the stringent response -- have been demonstrated to be deeply involved in the phenotypic and genetic adaptation of these experimental populations. PMID- 17691100 TI - Breaking the silence: three bHLH proteins direct cell-fate decisions during stomatal development. AB - Stomata are microscopic pores on the surface of land plants used for gas and water vapor exchange. A pair of highly specialized guard cells surround the pore and adjust pore size. Studies in Arabidopsis have revealed that cell-cell communication is essential to coordinate the asymmetric cell divisions required for proper stomatal patterning. Initial research in this area identified signaling molecules that negatively regulate stomatal differentiation. However, genes promoting cell-fate transition leading to mature guard cells remained elusive. Now, three closely related basic helix-loop-helix (bHLH) proteins, SPEECHLESS, MUTE and FAMA have been identified as positive regulators that direct three consecutive cell-fate decisions during stomatal development. The identification of these genes opens a new direction to investigate the evolution of stomatal development and the conserved functions of bHLH proteins in cell type differentiation adopted by plants and animals. PMID- 17691101 TI - Biochemistry and molecular biology of Arabidopsis-aphid interactions. AB - To ensure their survival in natural habitats, plants must recognize and respond to a wide variety of insect herbivores. Aphids and other Hemiptera pose a particular challenge, because they cause relatively little direct tissue damage when inserting their slender stylets intercellularly to feed from the phloem sieve elements. Plant responses to this unusual feeding strategy almost certainly include recognition of aphid salivary components and the induction of phloem specific defenses. Due to the excellent genetic and genomic resources that are available for Arabidopsis thaliana (Arabidopsis), this plant was chosen as a model system to study the metabolic and transcriptional responses to infestation by two aphids, Myzus persicae (green peach aphid, a broad generalist) and Brevicoryne brassicae (cabbage aphid, a crucifer-feeding specialist). Future research on Arabidopsis-aphid interactions will lead to the identification of aphid-specific elicitors, components of the defense-signaling pathway, and additional metabolic responses that are induced by aphid infestation. PMID- 17691102 TI - Small-fiber involvement in spinobulbar muscular atrophy (Kennedy's disease). AB - We assessed the involvement of cutaneous innervation in two subjects with a molecularly confirmed diagnosis of spinobulbar muscular atrophy (SBMA) using antidromic nerve conduction studies, quantitative sensory testing, and sweat tests, as well as immunohistochemical techniques and confocal microscopy of glabrous and hairy skin biopsy. Both patients showed a marked reduction in amplitude of sensory action potentials and moderate or severe abnormalities of tactile thresholds and mechanical pain perception. A severe reduction of sweat drops on the Silastic imprint test and a widespread loss of small myelinated and unmyelinated fibers in hairy skin were also observed. Fiber loss involved either somatic or autonomic fibers and did not show any distal-proximal gradient. These results, together with loss of Meissner corpuscles and their large myelinated afferent fibers in glabrous skin, confirmed the extensive involvement of sensory neurons of large and small size and revealed an autonomic skin denervation in SBMA. PMID- 17691103 TI - Diminished fatigue at reduced muscle length in human skeletal muscle. AB - Understanding muscle fatigue properties at different muscle lengths is essential to improve electrical stimulation applications in which impaired muscle is activated to produce function or to serve as an orthotic assist. This study examined the effects of muscle length on fatigue in human quadriceps muscle. Twelve healthy subjects were tested at short and long muscle lengths (15 degrees and 90 degrees of knee flexion, respectively) before and after a fatigue producing protocol using low-, high-, and variable-frequency testing trains. Greater fatigue was observed at the longer muscle length, supporting the notion that fatigue is largely dependent upon metabolic factors. Fatigue, however, was characterized by greater attenuation of low- than high-frequency responses (i.e., low-frequency fatigue, LFF) at the long length. This observation, accompanied by the fact that variable-frequency trains produced greater augmentations in force production than comparable low-frequency trains at the longer length, suggests that excitation-contraction coupling impairment is also a contributing factor to fatigue and plays a greater role at the more fatigue-susceptible longer muscle length. PMID- 17691104 TI - Fluorophore-labeled myosin-specific antibodies simplify muscle-fiber phenotyping. AB - Skeletal muscles are frequently analyzed for composition of phenotypically distinct myofibers, as a functional determinant. We describe an improved myofiber phenotyping procedure, involving cryosection co-incubation with fluorophore labeled myosin heavy-chain (MyHC)-isoform-specific antibodies. This technique identifies multiple fiber "types" on a single section, thereby reducing reagents and processing, and offers side-by-side comparison of samples from multiple species including mice. These advances are valuable for studying the physiological attributes of skeletal muscle in health and disease. PMID- 17691105 TI - Male pregnancy in seahorses and pipefish: beyond the mammalian model. AB - Pregnancy has been traditionally defined as the period during which developing embryos are incubated in the body after egg-sperm union. Despite strong similarities between viviparity in mammals and other vertebrate groups, researchers have historically been reluctant to use the term pregnancy for non mammals in recognition of the highly developed form of viviparity in eutherians. Syngnathid fishes (seahorses and pipefishes) have a unique reproductive system, where the male incubates developing embryos in a specialized brooding structure in which they are aerated, osmoregulated, protected and likely provisioned during their development. Recent insights into physiological, morphological and genetic changes associated with syngnathid reproduction provide compelling evidence that male incubation in these species is a highly specialized form of reproduction akin to other forms of viviparity. Here, we review these recent advances, highlighting similarities and differences between seahorse and mammalian pregnancy. Understanding the changes associated with the parallel evolution of male pregnancy in the two major syngnathid lineages will help to identify key innovations that facilitated the development of this unique form of reproduction and, through comparison with other forms of live bearing, may allow the identification of a common set of characteristics shared by all viviparous organisms. PMID- 17691106 TI - Getting a first clue about SPRED functions. AB - Spreds form a new protein family with an N-terminal Enabled/VASP homology 1 domain (EVH1), a central c-Kit binding domain (KBD) and a C-terminal Sprouty related domain (SPR). They are able to inhibit the Ras-ERK signalling pathway after various mitogenic stimulations. In mice, Spred proteins are identified as regulators of bone morphogenesis, hematopoietic processes, allergen-induced airway eosinophilia and hyperresponsiveness. They inhibit cell motility and metastasis and have a high potential as tumor markers and suppressors of carcinogenesis. Moreover, in vertebrates, XtSpreds help together with XtSprouty proteins to coordinate gastrulation and mesoderm specification. Here, we give an overview of this new field and summarize the domain functions, binding partners, expression patterns and the cellular localizations, regulations and functions of Spred proteins and try to give perspectives for future scientific directions. PMID- 17691107 TI - Patients with renal cell carcinoma nodal metastases can be accurately identified: external validation of a new nomogram. AB - Outcome of patients with renal cell carcinoma nodal metastases (NM) is substantially worse than that of patients with localized disease. This justifies more thorough staging and possibly more aggressive treatment in those at risk of or with established NM. We developed and externally validated a nomogram capable of highly accurately predicting renal cell carcinoma NM in patients without radiographic evidence of distant metastases. Age, symptom classification, tumour size and the pathological nodal stage were available for 4,658 individuals. The data of 2,522 (54.1%) individuals from 7 centers were used to develop a multivariable logistic regression model-based nomogram predicting the individual probability of NM. The remaining data from 2,136 (45.9%) patients from 5 institutions were used for external validation. In the development cohort, 107/2,522 (4.2%) had lymph node metastases vs. 100/2,136 (4.7%) in the external validation cohort. Symptom classification and tumour size were independent predictors of NM in the development cohort. Age failed to reach independent predictor status, but added to discriminant properties of the model. A nomogram based on age, symptom classification and tumour size was 78.4% accurate in predicting the individual probability of NM in the external validation cohort. Our nomogram can contribute to the identification of patients at low risk of NM. This tool can help to risk adjust the need and the extent of nodal staging in patients without known distant metastases. More thorough staging can hopefully better select those in whom adjuvant treatment is necessary. (c) 2007 Wiley-Liss, Inc. PMID- 17691108 TI - PPARalpha and PP2A are involved in the proapoptotic effect of conjugated linoleic acid on human hepatoma cell line SK-HEP-1. AB - Conjugated linoleic acid (CLA), found in dairy products, in beef and lamb has been demonstrated to possess anticancer properties protecting several tissues from developing cancer. Moreover, it has been shown to modulate apoptosis in several cancer cell lines. The aim of this study was to investigate which signaling transduction pathways were modulated in CLA-induced apoptosis in human hepatoma SK-HEP-1 cells. The cells exposed to CLA were evaluated for PPARalpha, PP2A, pro-apoptotic proteins Bak, Bad and caspases, and anti-apoptotic proteins Bcl-2 and Bcl-X(L). Cells were also treated with okadaic acid, a PP2A inhibitor, or with Wy-14643, a specific PPARalpha agonist. The CLA-induced apoptosis was concomitant to the increase of percentage of cells in the S phase, PPARalpha, PP2A and pro-apoptotic proteins; simultaneously, antiapoptotic proteins decreased. Inhibition of PP2A prevented apoptosis, and PPARalpha agonist showed similar effect as CLA. The increased PP2A could be responsible for the dephosphorylation of Bcl-2 and Bad, permitting apoptotic activity of Bax and Bad. The increase of caspase 8 and 9 suggested that both the intrinsic and extrinsic apoptotic pathways were induced. PP2A was probably increased by PPARalpha, since putative PPRE sequences were found in genes encoding its subunits. In conclusion, CLA induces apoptosis in human hepatoma SK-HEP-1 cells, by increasing PPARalpha, PP2A and pro-apoptotic proteins. PMID- 17691110 TI - Identification of a subset of pericytes that respond to combination therapy targeting PDGF and VEGF signaling. AB - The aim of our study was to further explore the use of anti-angiogenic therapy targeting the vascular endothelial growth factor receptor (VEGFR) on endothelial cells while simultaneously targeting platelet-derived growth factor receptors (PDGFRs) on adjacent pericytes. B16 mouse melanoma tumors exogenously expressing PDGF-BB (B16/PDGF-BB) display higher pericyte coverage on the vasculature compared to the parental B16 tumors (B16/mock). These models were used to investigate the effects of combination therapy targeting VEGFR and PDGFR signaling on size-matched tumors. Combination therapy using 25 mg/kg/day of the VEGFR inhibitor PTK787 and 100 mg/kg/day of the PDGFR inhibitor STI571 decreased the tumor growth rate of both tumor types, but the inhibition was only significant in the B16/PDGF-BB tumors. Combination therapy induced vessel remodeling, primarily by reducing the vessel density in B16/mock tumors, and by reducing the vessel size in B16/PDGF-BB tumors. When analyzing the effects of combination therapy on tumor vessel pericytes, it was found to primarily reduce the subpopulation of alpha-smooth muscle actin and PDGFRbeta-positive pericytes partly detached from the tumor vessels, without affecting the number of pericytes closely attached to the endothelium, which also express desmin. Taken together, these data demonstrate an increased benefit of targeting both VEGFR and PDGFR pathways in B16/PDGF-BB tumors, and demonstrates that the increased tumor growth inhibition in this model is accompanied by a reduction in a specific subset of pericytes, characterized by being loosely attached to endothelial cells and negative for the pericyte marker desmin. PMID- 17691111 TI - Fruit and vegetable intake and esophageal cancer in a large prospective cohort study. AB - Changing patterns of esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) incidence worldwide suggest distinct etiologies. Although associations between fruit and vegetable intake and both ESCC and EAC have been found in multiple ecological and case-control studies, few prospective studies have investigated these associations. We prospectively examined these associations in 490,802 participants of the National Institutes of Health (NIH) AARP Diet and Health Study using Cox models adjusted for age, alcohol intake, body mass index, cigarette smoking, education, physical activity and total energy intake. We present hazard ratios and 95% confidence intervals per serving per 1,000 calories. During 2,193,751 person years of follow-up, 103 participants were diagnosed with ESCC and 213 participants with EAC. We found a significant inverse association between total fruit and vegetable intake and ESCC risk (HR: 0.78, 95% CI: 0.67-0.91), but not EAC risk (0.98, 0.90-1.08). In models mutually adjusted for fruit and vegetable intake, the protective association with ESCC was stronger for fruits (0.73, 0.57-0.93) than for vegetables (0.84, 0.66-1.07). When we examined botanical subgroups, we observed significant protective associations for ESCC and intake of Rosacea (apples, peaches, nectarines, plums, pears and strawberries) and Rutaceae (citrus fruits). A significant inverse association between EAC and Chenopodiaceae (spinach) intake was observed. Results from our study suggest that the relation of fruit and vegetable intake and esophageal cancer risk may vary by histologic type. PMID- 17691112 TI - Epidemiologic findings on serologically defined chronic atrophic gastritis strongly depend on the choice of the cutoff-value. AB - Chronic atrophic gastritis (CAG), a precursor of intestinal gastric cancer, is mostly ascertained noninvasively by serum pepsinogens in epidemiologic studies. However, serological definitions vary widely. We aimed to investigate the impact of this variation on estimated prevalence of CAG and its association with its main risk factors, age and Helicobacter pylori infection. Serum pepsinogen I and II and antibodies against H. pylori were measured by ELISA among 9,444 women and men aged 50-74 years in a population-based cohort study in Saarland/Germany. Application of the various definitions resulted in a wide range of prevalence estimates of CAG prevalence (2.1%-8.2%, with an outlier of 18.8% for one particular definition) and its associations with age and H. pylori infection (age adjusted odds ratios, OR, for CagA positive H. pylori infection: 0.98-4.48). Definitions of CAG based on both pepsinogen I and the pepsinogen I/II ratio or on the pepsinogen I/II ratio only revealed much clearer associations with both age and H. pylori infection than definitions of CAG based on pepsinogen I only (ORs for H. pylori infection: 1.45-4.48 and 0.86-1.30, respectively). Epidemiologic findings on CAG lack comparability due to the heterogeneity in serologic definitions of CAG. The association of age and H. pylori infection with CAG may be strongly underestimated in studies in which CAG is defined by pepsinogen I only. PMID- 17691113 TI - Intratumoral homogeneity of MGMT promoter hypermethylation as demonstrated in serial stereotactic specimens from anaplastic astrocytomas and glioblastomas. AB - Hypermethylation of the DNA repair gene O(6)-methyl-guanine DNA methyltransferase (MGMT) has been linked to prolonged survival in glioblastoma patients treated with alkylating agents. It was aimed to analyze prospectively whether the MGMT status of malignant gliomas could be determined from small-sized stereotactic biopsies (maximum volume: 1 mm(3)). Special attention was directed towards the intratumoral distribution of the MGMT promoter methylation, the MGMT protein expression and potential correlations between both. Twenty-five adult patients were included (20 patients with primary World Health Organisation (WHO) Grade III or IV malignant gliomas, 5 patients with secondary malignant gliomas). About 2-4 biopsy specimens per tumor were collected from different sites within the tumor. Promoter methylation of the MGMT gene was assessed by methylation-specific PCR (MSP) and sodium bisulfite sequencing in each of the collected specimens (overall number of specimens: 69). Both methods were validated for application in small sized tissue samples (1 mm(3)). The MGMT protein expression was analyzed by immunohistochemistry. The overall MGMT promoter methylation rate was 30% in the de novo group and 80% in the tumor progression group. The success rates of MSP and sequencing were 100% and 80%, respectively. Sequence analysis and MSP exhibited 100% concordant findings. No differences in MGMT promoter methylation were detected between the different samples of each individual tumor in 24 of 25 patients. One false negative result was obtained due to the contamination of the biopsy specimen by necrotic tissue. Tissue samples taken from different sites of each individual tumor (13 tumors investigated) exhibited equal or highly similar MGMT protein expression. No correlation between MGMT protein expression and MGMT promoter methylation was observed. The MGMT promoter methylation status of malignant gliomas can be reliably determined from small-sized stereotactic biopsies. The methylation profile, as defined by MSP and sodium bisulfite sequencing, constitutes a homogeneous marker throughout malignant gliomas. The lack of correlation between MGMT status and MGMT protein expression needs further evaluation. PMID- 17691114 TI - Functional and phenotypic characteristics of CD4+CD25highFoxp3+ Treg clones obtained from peripheral blood of patients with cancer. AB - Circulating human CD4(+)CD25(high)Foxp3(+) T cell populations (Treg) may contain activated CD4(+)CD25(+) T cells interfering with Treg evaluation. To gain insights into the phenotypic and functional characteristics of Treg in patients with cancer, we have analyzed CD4(+)CD25(high) populations at the clonal level. Single-cell sorted (SCS) CD4(+)CD25(high) T cells obtained from PBMC of normal controls (NC) or patients with squamous cell carcinoma of the head and neck (HNSCC) were plated at 1 cell/well in 96 well plates and expanded with anti CD3/anti-CD28 Abs and 1,000 IU IL-2/mL in the presence or absence of rapamycin (1 nM). All generated clones were evaluated for the phenotype by flow cyometry and suppressor function in CFSE-based proliferation assays. Clones had heterogeneous CD25 expression levels. Cloning efficiency of CD4(+)CD25(high) T cells was low. CD25(high) clones expressed CTLA-4, Foxp3, CD62L, but little GITR and suppressed proliferation of autologous CD4(+)CD25(-) responder cells. Clones of activated CD4(+)CD25(interm./low) cells expressed intermediate to high levels of GITR and HLA-DR and did not suppress proliferation of responder cells. The number, suppressor phenotype and function of CD25(high) Treg clones were significantly enhanced in HNSCC patients relative to NC (p or = 80% of a panel of elderly able to break, > or = 90% probability) was 34%. Of the 29 studied tablets, 5 complied with all criteria, amongst which were all three oblong tablets that were included in the study. The Summary of Product Characteristics (SmPC) of the tablets was independently evaluated by experts to assess whether their break-mark was needed for the posology. The experts came to a uniform conclusion for only 66% of the tablets. It is concluded that the proposed test procedures for ease of subdivision and loss of mass by subdivision are workable, that the proposed criteria are reasonable and that their inclusion in Ph.Eur. can be considered. From a pharmaceutical-technological point of view, the requirements of Ph.Eur. 5.5 Subdivision of tablets for uniformity of mass of subdivided tablets, and the proposed criteria for ease of subdivision and loss of mass, are all simultaneously attainable. It is also concluded that the majority of the break-mark tablets with a MA in NL do not meet the requirements of Ph.Eur.5.5 Subdivision of tablets, and that they do not fulfill the proposed criterion for ease of subdivision. This is expected to also be the case in other countries. It is proposed that the test Ph.Eur. 5.5 Subdivision of tablets should give instructions on how to handle tablets that cannot be broken, or that crumble upon subdivision. It is also proposed that the criteria Ph.Eur. 5.5 Subdivision of tablets should not be restricted to break-marks needed for the posology, as dosing instructions in SmPCs are open to different interpretations, and that this restriction should be deleted. PMID- 17691209 TI - Establishing standardised methods for comparing aqueous droplet inhalers. AB - Aerosol inhalers are widely used to deliver drug directly to the respiratory system in patients with respiratory disease. Currently available nebulisers only deliver a proportion of the loaded or charged dose to the patient. The proportion of the charged dose received by the patient can be considered as the inhalable dose and is that part of the dose generated during inhalation and breathed in by the patient. As such, it is important to fully characterise the performance of new nebuliser brands to assess the proportion of the charged dose actually delivered to the patient. Despite the large variety of nebulisers, driver units and formulations currently on the market, often little is known about the performance of new nebulisers in terms of inhalable dose under a variety of breathing patterns and with different drug formulations. The results presented here highlight the variation in performance in terms of inhalable dose and droplet distribution of a breath-enhanced jet nebuliser when tested with a number of formulations and under different breathing patterns. Based on the results presented here we propose that a standard protocol for evaluating the performance of established and developmental nebulisers should include breathing patterns appropriate to the intended use and a variety of test formulations to capture those currently available for nebulisation. PMID- 17691210 TI - Determination of the impurity profile of adenosine by means of ion-pair reversed phase chromatography. AB - Production processes of adenosine include condensation of ribose and adenine by means of chemical or biochemical processes, as well as fermentation. Nowadays, adenosine is commonly produced by alkaline hydrolysis of yeast ribonucleic acid, often in the presence of calcium or lead ions, followed by chromatographic separation of the obtained nucleosides adenosine, cytidine, guanosine and uridine. The current Ph. Eur. monograph for adenosine describes a TLC method for determination of related substances that limits the impurities to 1 per cent. To ensure the quality of adenosine, it is proposed to replace the TLC method by a more sensitive and selective HPLC method, in accordance with the current policy for control of impurities as defined by the Ph. Eur. Commission. An HPLC separation system, originally proposed by the USP, using ion-pair reversed-phase chromatography in combination with tetrabutylammonium hydrogen sulphate as an ion pair reagent, has been examined for its suitability to limit guanosine, inosine, uridine and adenine. This article describes the experiments as regards the choice of the most suitable commercial column to obtain an appropriate separation, the column temperature, the establishment of a relevant system suitability criterion, and the determination of correction factors for the individual impurities. PMID- 17691211 TI - Acceptance criteria for levels of hydrazine in substances for pharmaceutical use and analytical methods for its determination. AB - This report includes a brief review of the toxicology of hydrazine and the strategies used to set acceptance criteria. A preliminary examination of a number of approaches to determine hydrazine in pharmaceutical substances susceptible to its presence either as residue from the synthesis or from decomposition are described. PMID- 17691212 TI - A liquid chromatographic method using a reversed-phase hybrid stationary phase to control potential impurities of imipramine hydrochloride. AB - A reversed-phase liquid chromatographic method has been developed for the detection and control of impurities of imipramine hydrochloride at a level of 0.2 microg/ml (corresponding to 0.02 per cent in the procedure described). This method is included in a proposed revision of the monograph (Pharmeuropa 18.4) and replaces the thin-layer chromatographic method currently employed. PMID- 17691213 TI - Disintegration of sublingual tablets: proposal for a validated test method and acceptance criterion. AB - In the Netherlands the market share of isosorbide dinitrate 5 mg sublingual tablets is dominated by 2 products (A and B). In the last few years complaints have been received from health care professionals on product B. During patient use the disintegration of the tablet was reported to be slow and/or incomplete, and ineffectiveness was experienced. In the European Pharmacopoeia (Ph. Eur.) no requirement is present for the disintegration time of sublingual tablets. The purpose of this study was to compare the in vitro disintegration time of products A and B, and to establish a suitable test method and acceptance criterion. A and B were tested with the Ph. Eur. method described in the monograph on disintegration of tablets and capsules as well as with 3 modified tests using the same Ph. Eur. apparatus, but without movement of the basket-rack assembly. In modified test 1 and modified test 2 water was used as medium (900 ml and 50 ml respectively), whereas in modified test 3 artificial saliva was used (50 ml). In addition, disintegration was tested in Nessler tubes with 0.5 and 2 ml of water. Finally, the Ph. Eur. method was also applied to other sublingual tablets with other drug substances on the Dutch market. With modified test 3 no disintegration could be achieved within 20 min. With the Ph. Eur. method and modified tests 1 and 2 product A and B differed significantly (p < 0. 001), with product B having longer disintegration times. These 3 methods were capable of discriminating between products and between batches. The time measured with the Ph. Eur. method was significantly lower compared to modified tests 1 and 2 (p < 0.001) and correlated well with the Nessler tube results. It is concluded that the in vivo complaints on product B could be related to the in vitro data. Furthermore, it is proposed that for immediate release of sublingual tablets the disintegration time should be tested. The Ph. Eur. method is considered suitable for this test. In view of the products currently on the market and taking into consideration requirements in the United States Pharmacopeia and Japanese Pharmacopoeia, an acceptance criterion of not more than 2 min is proposed. PMID- 17691214 TI - Discriminatory power of the different requirements for uniformity of dosage units in the European pharmacopoeia. AB - The discriminatory power of the new and the old requirements are compared on a mathematical basis and by the simulation of data. The probability of passing the requirements of the test for uniformity of dosage units versus the tests for uniformity of content and uniformity of mass are compared by the simulation of different batches. These batches are characterised by a true content and true standard deviation under the prerequisite of normal distribution. Furthermore, a mathematical evaluation of the newly introduced acceptance value AV is presented. PMID- 17691215 TI - Laser diffractometry and cascade impaction for nebulizer product characterization. AB - The techniques of laser diffractometry and multi-stage cascade impaction are widely used in the in vitro characterization of liquid droplet aerosols generated from nebulizing systems. This position paper is a concise summary of key aspects relating to both techniques and is intended to inform the development of the proposed general chapter 2.9.44 "Preparations for Nebulization" for the European Pharmacopeia, as well as assist in the development of a proposed International Standard (ISO 27427) for nebulizing systems. PMID- 17691216 TI - A cylinder-plate method for microbiological assay of clavulanic acid. AB - Clavulanic acid is a natural occurring beta-lactam product of Streptomyces clavuligerus and is a potent inhibitor of bacterial beta-lactamases. The present work reports a microbiological assay based on the cylinder-plate method for determination of clavulanic acid. The assay is based on the inhibitory effect of clavulanic acid in combination with penicillin G upon Escherichia coli ATCC 35218, which is used as the test organism. The correlation between clavulanic acid concentration and the inhibitory effect on E. coli was linear (r > 0.99) and in the range of 8-20 microg/ml. These results indicate that the proposed method is appropriate for the determination of clavulanic acid in commercial samples and can be used in routine quality control. PMID- 17691217 TI - 2005 National Hospital Discharge Survey. AB - OBJECTIVES: This report presents national estimates of the use of nonfederal short-stay hospitals in the United States during 2005 and selected trend data. Numbers and rates of discharges, diagnoses, and procedures are shown by age and sex. Average lengths of stay are presented for all discharges and for selected diagnostic categories by age and by sex. METHODS: The estimates are based on data collected through the 2005 National Hospital Discharge Survey (NHDS). The survey has been conducted annually by NCHS since 1965. Diagnoses and procedures presented are coded using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). RESULTS: Trends in the utilization of nonfederal short-stay hospitals show that the overall average length of a hospital stay has declined significantly. In 2005, the average length of stay for all inpatients was 4.8 days compared with 7.8 days in 1970. Stays for discharges aged 15-44, 45-64 and 65 years and over also declined, but the average lengths of stay for those under 15 years of age were the same in 1970 and 2005. In 2005, there were an estimated 34.7 million hospital discharges, excluding newborn infants. Persons aged 65 years and over comprised 38 percent of all inpatients. One notable trend for elderly people is that their rate of hospitalization for septicemia increased 47 percent from 2000 to 2005. There were 45 million procedures performed on inpatients during 2005. Obstetrical procedures (6.9 million) comprised 25 percent of all procedures performed on females. Cesarean section (18 percent), repair of current obstetric laceration (18 percent), and artificial rupture of membranes (14 percent) accounted for one-half of all obstetrical procedures. Males had more cardiovascular procedures than females (4.1 million compared with 2.9 million), whereas females had more operations on the digestive system than males (3.2 million compared with 2.4 million). PMID- 17691218 TI - Gliomas: association of histology and molecular genetic analysis of chromosomes 1p, 10q, and 19q. AB - The aim of our study was to evaluate the frequencies of loss of heterozygosity (LOH) on chromosomes 1p, 10q, and 19q in gliomas and to correlate them with the histological diagnosis and with patient age and gender. We found deletions within chromosome 1p to be significantly associated with the histological subtype of glial tumor (P < 0.05); frequency of 1p deletions increased from astrocytoma (0%) through glioblastoma (31%) and oligoastrocytoma (57%) to oligodendroglioma (63%). In patients with 1p LOH, the odds for having astrocytoma or glioblastoma were approximately 10-fold and 4-fold lower, respectively, than oligodendroglioma. The odds for having oligoastrocytoma were similar to oligodendroglioma (OR = 1.3). The frequency of 10q LOH in patients with glioblastoma was significantly higher than in patients with oligodendroglioma (89% vs. 36%; P < 0.005). In patients with oligodendroglioma, most cases with LOH on chromosome 1p also had LOH 19q (90%), one case of 1p LOH also had a deletion on 10q. Statistical analyses revealed a significant association between deletions on 1p and 19q (P < 0.05). Our data provide evidence that use of molecular genetic analyses of chromosomes 1p, 19q, and 10q might improve the diagnosis of gliomas. PMID- 17691219 TI - Oxidative DNA damage and level of thiols as related to polymorphisms of MTHFR, MTR, MTHFD1 in Alzheimer's and Parkinson's diseases. AB - Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are accompanied by increased levels of 8-oxo-2'-deoxyguanosine (8 oxo2dG) and alterations in levels of homocysteine (Hcy), methionine (Met), and cysteine (Cys). Hcy may undergo remethylation due to involvement of MTHFR, MTR and MTHFD1 proteins. Present studies are aimed at determination of 8-oxo2dG, Hcy, Met, and Cys in AD and PD patients as well as in control groups, using HPLC/EC/UV, as well as estimation, by restriction analysis, frequency of following gene polymorphisms: MTHFR (C677T, A1298C, G1793A), MTHFD1 (G1958A), and MTR (A2756G). In AD there were significant differences of the levels of only Cys (GG, MTHFR, G1793A) and Met/Hcy (AA, MTHFD1, G1958A) whereas in PD there were more significant differences of the levels of thiols: Hcy [MTHFR: CT (C677T) and GG (G1793A); MTR, AG (A2756G)], Met [MTR, AA (A2756G)], Cys [MTR, AG (A2756G)], and Met/Hcy [MTHFR: CC, CT (C677T) and AA (A1298C), and GG (G1793A); MTHFD1 AA(G1958A); MTR AA(A2756G)]. Significant differences in the levels of Cys/Hcy, MTHFD1 GA (G1958) were varied between AD and PD groups. The results indicate that of the enzymes studied only polymorphisms of folate-dependent enzyme MTHFD1 have pointed to significant differences in intensity of turnover of circulating thiols between AD and PD patients. PMID- 17691220 TI - Plasma Abeta levels as predictors of response to rivastigmine treatment in Alzheimer's disease. AB - Cholinesterase inhibitors are currently the mainstream of symptomatic treatment of patients with Alzheimer's disease. The response to treatment with cholinesterase inhibitors is clinically difficult to predict. Several demographic, clinical and biological variables have been proposed as pretreatment predictors of long-term therapy efficacy. In this paper, consistently with previous reports, we confirm that higher initial disease severity and faster progression of cognitive impairment increase the chance of a clinically meaningful response to cholinesterase inhibitor therapy in a carefully selected population of patients with Alzheimer's disease. Moreover, for the first time we demonstrate the association between the increase in the concentration of plasma Abeta(1-42) peptide after 2 weeks of treatment with an initial dose of rivastigmine and the likelihood of a positive response to treatment after 6 months. A change in plasma Abeta(1-42) level might constitute a novel biochemical predictor of rivastigmine treatment efficacy in Alzheimer's disease. PMID- 17691221 TI - Erythropoietin preconditioning suppresses neuronal death following status epilepticus in rats. AB - Status epilepticus (SE) is a grave condition in which the brain undergoes lasting seizures which can lead to neuronal loss. Our previous study suggested that preconditioning with erythropoietin (Epo) suppressed neuronal apoptosis in hippocampus of rats following SE in vivo by inhibiting caspase-3. In this study, we investigated the mechanisms by which Epo preconditioning may exert its anti apoptotic effects using a lithium-pilocarpine induced SE model in rats. The effects of Epo on neuronal cell death were evaluated using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and the role of the Bcl-2 protein family, which have been shown to be anti- (Bcl-2, Bcl w) or pro- (Bid, Bim) apoptotic, was examined with immunofluorescence. We found Epo preconditioning decreased the total number of TUNEL, Bim and Bid positive cells, but increased the total number of Bcl-w and Bcl-2 positive cells. These results suggest that systemic Epo pretreatment protects neurons in an acute phase of SE and may result in further suppression of neuronal apoptosis in hippocampus by regulating the balance between pro- and anti-apoptotic Bcl-2 family proteins. PMID- 17691222 TI - Evans Blue fluorescence permits the rapid visualization of non-intact cells in the perilesional rim of cold-injured rat brain. AB - A focal cold lesion-induced injury, i.e., a model of focal vasogenic brain edema, enhances the permeability of the blood-brain barrier and cell membrane in the perilesional rim. However, non-intact cells can be detected, e.g. by markers of apoptosis, only hours or even days after the injury. The early membrane dysfunction allows extravasated serum proteins to enter the injured cells, which can be readily visualized if the plasma albumin was previously bound to fluorescent tracers, such as Evans Blue (EB). The aim of this study was to demonstrate injured cells that take up the EB/albumin conjugate in the perilesional rim. This tracer was administered 3.5 h after the induction of the injury and the animals were sacrificed 30 min later. With an excitation wavelength of 530-550 nm, the EB-positive cells emitted bright-red fluorescence at > 590 nm and were easy to count. No positive cells were observed in the controls. This method provides more information than the classical 2,3,5 triphenyltetrazolium chloride reaction, because it permits an assessment of the density and distribution of cells with non-intact cell membranes in the perilesional area following cerebrocortical injury. PMID- 17691223 TI - The P3 produced by auditory stimuli presented in a passive and active condition: modulation by visual stimuli. AB - The aim of this study was to investigate how the processing of auditory stimuli is affected by the simultaneous presentation of visual stimuli. This was approached in an active and passive condition, during which a P3 was elicited in the human EEG by single auditory stimuli. Subjects were presented tones, either alone or accompanied by the simultaneous exposition of pictures. There were two different sessions. In the first, the presented tones demanded no further cognitive activity from the subjects (passive or 'ignore' session), while in the second session subjects were instructed to count the tones (active or 'count' session). The central question was whether inter-modal influences of visual stimulation in the active condition would modulate the auditory P3 in the same way as in the passive condition. Brain responses in the ignore session revealed only a small P3-like component over the parietal and frontal cortex, however, when the auditory stimuli co-occurred with the visual stimuli, an increased frontal activity in the window of 300-500 ms was observed. This could be interpreted as the reflection of a more intensive involuntary attention shift, provoked by the preceding visual stimulation. Moreover, it was found that cognitive load caused by the count instruction, resulted in an evident P3, with maximal amplitude over parietal locations. This effect was smaller when auditory stimuli were presented on the visual background. These findings might support the thesis that available resources were assigned to the analysis of visual stimulus, and thus were not available to analyze the subsequent auditory stimuli. This reduction in allocation of resources for attention was restricted to the active condition only, when the matching of a template with incoming information results in a distinct P3 component. It is discussed whether the putative source of this effect is a change in the activity of the frontal cortex. PMID- 17691224 TI - Active touch does not improve sequential processing in a counting task. AB - Active touch involves tactile and proprioceptive sensory inputs, activation of the motor system and executive functions. It has been shown by the previous literature that active touch facilitates shape recognition. Since both active and passive exploration requires sequential presentation of the tactile inputs, this facilitation may be due to the improvement of the sequential-processing mechanism. The effects of active and passive touch on the sequential processing of tactile inputs were tested at different stimulus-presentation rates in a counting task. Active touch did not improve the performance, which shows that the additional sensory and motor information conveyed by active exploration are not utilized by the sequential-processing mechanism. Therefore, the results cannot be explained by the feature-specific theory of sequential processing. On the other hand, the counting errors were higher than those predicted by the limitation of the minimal inter-stimulus interval, which is suggested by the central-timing theory. Consequently, it is proposed that a mechanism based on the central-timing theory may contribute to tactile sequential processing, but the bottleneck at high presentation rates is probably due to short-term memory. PMID- 17691225 TI - On light as an alerting stimulus at night. AB - Light exposure at night increases alertness; however, it is not clear if light affects nocturnal alertness in the same way that it affects measures of circadian regulation. The purpose of this study was to determine if a previously established functional relationship between light and nocturnal melatonin suppression was the same as that relating light exposure and nocturnal alertness. Four levels of narrow-band blue light at the cornea were presented during nighttime sessions. The ratio of electroencephalographic alpha power density with eyes closed to eyes open (alpha attenuation coefficient, AAC) and the Norris mood scale were used. The AAC and ratings of alertness increased monotonically with irradiance and were highly correlated. Both measures of alertness were highly correlated with model predictions of nocturnal melatonin suppression for the same circadian light stimulus, consistent with the inference that the suprachiasmatic nuclei play an important role in nocturnal alertness as well as circadian regulation. PMID- 17691226 TI - Evidence for differentiation of arousal and activation in normal adults. AB - "Arousal" at a particular time has been defined as the energetic state at that moment, reflected in electrodermal activity and measured by skin conductance level. In contrast, task related "activation" has been defined as the change in arousal from a resting baseline to the task situation. The present study, replicating some aspects of a previous investigation of these ideas in children, aimed to further explore whether the separation of "arousal" and "activation" was useful in describing state effects on the phasic Orienting Response (OR) and behavioral performance. A continuous performance task (CPT) was used with normal adults. It was found that the magnitude of the mean phasic OR to targets was dependent on arousal, but not on task-related activation. A performance measure (reaction time) improved with increasing activation, but not with arousal. These findings support our previous suggestions concerning the value of conceptualizing arousal and activation as separable aspects of the energetics of physiological and behavioral function. PMID- 17691227 TI - Bone marrow stromal cells in traumatic brain injury (TBI) therapy: true perspective or false hope? AB - Recent studies regard bone marrow stromal cells as a potential andidate for cellular therapy of traumatic brain injury and thus as an attractive alternative for embryonic and fetal stem cells. Numerous experiments indicate that bone marrow stromal cells play an important role in the repair of injured brain tissue and also support healing processes. Findings of in vitro and in vivo studies show that these cells have an ability to differentiate into cells of multiple tissues, including neurons and glial cells and to secrete an array of growth factors and cytokines, which have an influence on repair of damaged tissue. In addition, treatment of traumatic brain injury with bone marrow stromal cells promotes functional recovery of injured animals. Taking this into consideration, there is hope for using bone marrow stromal cells in brain injury therapy, which is very difficult because of specific events that occur in the pathological conditions. However, mechanisms responsible for the observed therapeutic potential of bone marrow stromal cells still remain unclear. The review presents achievements in studies on bone marrow stromal cells as a source of therapeutic benefits in treatment of traumatic brain injury and addresses the question of their possible future use in clinical trials. PMID- 17691228 TI - Role of hypercapnia in brain oxygenation in sleep-disordered breathing. AB - Adaptive mechanisms may diminish the detrimental effects of recurrent nocturnal hypoxia in obstructive sleep apnea (OSA). The potential role of elevated carbon dioxide (CO2) in improving brain oxygenation in the patients with severe OSA syndrome is discussed. CO2 increases oxygen uptake by its influence on the regulation of alveolar ventilation and ventilation-perfusion matching, facilitates oxygen delivery to the tissues by changing the affinity of oxygen to hemoglobin, and increases cerebral blood flow by effects on arterial blood pressure and on cerebral vessels. Recent clinical studies show improved brain oxygenation when hypoxia is combined with hypercapnia. Anti-inflammatory and protective against organ injury properties of CO2 may also have therapeutic importance. These biological effects of hypercapnia may improve brain oxygenation under hypoxic conditions. This may be especially important in patients with severe OSA syndrome. PMID- 17691229 TI - Colon cancer screening. PMID- 17691230 TI - Growth curves for normal Jamaican neonates. AB - The aim of this study was to provide standards for the assessment of birthweight, head circumference and crown-heel length for normal, singleton newborns of predominantly West African descent. Data were collected for 10 482 or 94% of all recorded births in Jamaica during the two-month period September 1 to October 31, 1986. After editing procedures, data were available for 6178 (birthweight), 5975 (head circumference), and 5990 (crown-heel length). The data presented in tables and growth curves include birthweight, head circumference and crown-heel length for males and females separately, for gestational ages 30-43 weeks. Data sets from the University Hospital of the West Indies in 1990 and 1999 were used to explore the possibility of secular change over the period 1986-1999. In conclusion, these ethnic and gender-specific growth curves are based on the most extensive dataset currently available in Jamaica for babies of West African descent. PMID- 17691231 TI - Dietary habits, diversity and the indigenous diet of the Turks and Caicos Islands: implications for island-specific nutrition intervention. AB - OBJECTIVE: To describe dietary habits in the Turks and Caicos Islands. DESIGN AND METHODS: Food frequency questionnaires were administered to female-household heads of 144 households randomly selected from three islands' voter's lists (Grand Turk [n = 48], Providenciales [n = 46] and Middle Caicos [n = 50]). Data were collected on the distribution of (a) Households among Levels 0 - 7 of a Food Group Scale, developed using the Cornell Technique of Scaling Dichotomous Data, and based on number of households that consumed seven food groups (meat and legumes, bread/cereals, fruits, vegetables, starchy roots/tubers/fruits; dairy and beverages) weekly; (b) Foods among four categories (common core, island core, occasional or rare) also based on weekly frequency of consumption. RESULTS: Thirty per cent of households on Grand Turk and 37% on Providenciales were at level 7, the most varied and complex diets, compared to 3% for Middle Caicos, which exemplified the indigenous diet of local seafood, beans, and grits (corn) supplemented with imports eg rice and bread/flour Middle Caicos had substantially fewer island core foods ([n = 16] from four food groups) than did Grand Turk (n = 29) and Providenciales (n = 30), which represented the 7-food groups and included 15 (94%) of Middle Caicos' island core foods. CONCLUSION: Providenciales and Grand Turk had more varied and complex diets. Understanding how various islands supplement the indigenous/traditional diet is imperative to develop and evaluate (a) island-specific nutrition intervention eg culturally appropriate nutrition education messages (eg to increase iron consumption); and (b) future research protocols. PMID- 17691232 TI - Ethnicity, body image perception and weight-related behaviour among adolescent Females attending secondary school in Trinidad. AB - OBJECTIVE: The correlates of body image perception among an ethnically diverse group of adolescent females attending secondary school in Trinidad were investigated. METHODS: A cross-sectional survey was carried out among adolescent females from selected secondary schools in Trinidad. Participants completed a self-administered questionnaire consisting of sociodemographic items and standardized psychometric instruments. RESULTS: Two hundred and fifty-one students participated in the survey with an ethnic composition as follows: Indo Trinidadian (35.9%), Afro-Trinidadian (28.7%), Indo-Afro mixed Trinidadian (21.9%) and other (13.5%). The results suggest that 2.4% of the participants reported having a medical diagnosis for an eating disorder Indo-Trinidadians had significantly greater body dissatisfaction than Indo-Afro-mixed Trinidadians but not more than Afro-Trinidadians (p = 0.04). Also, a significantly higher proportion of Indo-Trinidadians engaged in binge eating behaviour compared to the other ethnic groups (p < 0.001). Afro-Trinidadians were more likely to use vomiting as a mean of weight control compared to Indo- and Indo-Afro-mixed Trinidadian (p < 0. 05). Fifty-one per cent of participants had a negative body image perception. Altered body image perception was associated with a significant higher mean Body Shape Questionnaire BSQ 16 score (p < 0.001) and increased likelihood of reporting being diagnosed with an eating disorder (OR = 2.03, 95% CI: 1.78, 2.31; p = 0.01) compared to non-altered body image state. Eating Attitude Test (EAT-26) score was positively correlated with Drive-for-Thinness (p < 0.001) and BSQ16 (p < 0.001) scores and inversely correlated with the Rosenberg self-esteem score (p = 0.012). CONCLUSION: In this group of adolescents, there are ethnic differences in the level of concern over body image and associated eating, and weight-related behaviour. PMID- 17691233 TI - Acute lead poisoning associated with backyard lead smelting in Jamaica. AB - Long-term backyard smelting of lead in a district known as Mona Commons, Kingston, Jamaica, has produced lead burdens as high as 30 000 mg/kg in soils near to the smelter, and indoor dust loadings of 373 microg/f2 in the residents' home. The blood lead levels (BPb) of 107 children from the district were in the range 2.2-202 microg/dL. Fifty-nine per cent of these had BPb levels above 10 microg/dL and the population mean was an unacceptably high 25.1 microg/dL. The highest levels were observed for five siblings, two of whom presented with lead encephalopathy. This severe chronic exposure to lead was exacerbated by a significant history of pica, and chronic nutritional anaemia. Chelation therapy significantly reduced the BPb levels but due to lead storage in other organs, the values after several months were still higher than desirable. This study emphasizes the importance of reducing the exposure of children to lead. PMID- 17691234 TI - The epidemiology of psoriasis in a dermatology clinic in a general hospital in Port-of-Spain, Trinidad and Tobago, West Indies. AB - Psoriasis is a chronic skin disorder which is believed to affect 2% of the world's population. This retrospective study analyzed the frequency of occurrence of psoriasis in the population of a dermatology clinic in a general hospital in the capital city of Trinidad and Tobago. Psoriasis was found to be more common in males and the peak presentation was between 50-59 years. Psoriasis was more common in persons of East Indian descent compared to those of African origin. PMID- 17691235 TI - Hepatic local micro-environmental immune status in hepatocellular carcinoma and cirrhotic tissues. AB - Hepatocellular carcinoma (HCC) is one of the most common malignant tumours in the world, especially in Guangxi, China. The causes and mechanism of its tumourigenesis and development have not been completely clarified Some studies revealed that the hepatic local cellular immune function was one of the factors. In the present study, the local micro-environmental immune status was explored by investigating the number, distribution and function of CD3, CD57, CD20, CD68, and granzyme B (GrB) positive cells in 60 patients with HCC and 62 patients with liver cirrhosis (LC) and its relationship with the prognosis of the patients. The results showed that the number of T and B lymphocytes and natural killer (NK) cells in the liver of HCC patients was significantly higher than that in the LC and normal controls; while the number of macrophages (Mphi) was significantly lower The number of Mphi in the tissues decreased successively with the decrease of HCC differentiation; GrB-expressing cells in the liver predominantly consisted of CD57 positive cells. The number of NK cells, B lymphocytes and GrB-expressing cells in the cancerous tissues of stage I and II was significantly higher than that of stages III and IV. The number of T lymphocytes, NK cells, Mphi, and GrB expressing lymphocytes in HCC cases without metastasis in 15 months was significantly higher than in the metastatic counterparts. The number of T and B lymphocytes, NK cells, and GrB-expressing cells decreased in patients with the progression of the HCC. These results suggest that the number of T and B lymphocytes, NK cells, Mphi and GrB-positive lymphocytes might be important markers in the estimation of hepatic local immune status and be useful factors for predicting the prognosis of HCC patients. PMID- 17691236 TI - Serum leptin levels in children with acute viral hepatitis A. AB - OBJECTIVES: In acute viral hepatitis A (AVH-A), involvement of the liver is through cytotoxic cells and cytokine levels are increased Immune response of the host determines the severity of the disease. Leptin stimulates cytokines, therefore, the authors hypothesized that the relationship between leptin and cellular immunity might cause different clinical presentations of the disease. METHODS: Twenty-eight children with AVH-A and 10 healthy children formed the basis of the study. Serum leptin, C-reactive protein (CRP) and alpha-1 antitrypsin (A1AT) levels were determined RESULTS: There was significant positive correlation between body mass index (BMI) and leptin levels both in patients and controls (p = 0.003 and p = 0.001 respectively). No significant difference in serum leptin, CRP or A1AT levels between patients and controls was detected (p > 0.05). Presence of icterus or fulminant hepatic failure (FHF) did not affect serum leptin level (p > 0.05). Mean A1AT level was significantly higher in children with FHF (p < 0.05). On the 30th day of admission, mean BMI, weight and leptin levels increased (p < 0.01, p < 0.01 and p < 0.05 respectively) and mean A1AT level decreased (p < 0.01). CONCLUSION: Leptin levels are not altered in children with AVH-A. In the convalescence period, leptin increased parallel to BMI. It is suggested that expected increment in leptin due to inflammation might be balanced with the decrease due to loss of appetite during acute illness or it might be entirely due to loss of production. PMID- 17691237 TI - The smoking prevalence and the determinants of smoking behaviour among students in Cukurova University, Southern Turkey. AB - OBJECTIVES: To determine the smoking prevalence and its determinants in students at Cukurova University, Southern Turkey. DESIGN: The sample was selected from the first and final year students of all faculties in Cukurova University. The students who were present on the day of the survey were all included in the study. The students filled in an anonymous questionnaire detailing their sociodemographic characteristics and smoking behaviour A random sample of 2200 students in Cukurova University was enrolled in the study representing a total of 8309 students for this random cross-sectional study. The response rate was 90.9% (n = 2131). A self-administered questionnaire was completed by all students. Outcome measures were smoking prevalence, family and peer smoking, grade, gender and place of living that may be related to smoking. Logistic regression was used to examine the determinants of smoking behaviour RESULTS: Smoking increased between the ages of 13 and 17 years (26.6% and 43.7%, respectively). The smoking behaviour of best friends was the most powerful determinant of smoking, and this was consistent across the age groups. Best friends' attitudes towards smoking and family members' smoking behaviour were also important determinants of smoking. CONCLUSIONS: Smoking prevalence among students in Cukurova University, in Southern Turkey, is high. Effective smoking prevention programmes should take into account the dominant influence of peers on the onset and maintenance of smoking behaviour School-related items had a less important role in predicting smoking behaviour than expected. PMID- 17691238 TI - Femoral lengthening using the Ilizarov technique. AB - The Ilizarov method allows the surgeon to perform extended lengthening of both congenital and acquired short limbs. The technique can be difficult, time consuming and is associated with many complications. Generally, the number of complications and failures of lengthenings increases in proportion to the length of the distraction and the severity of the preoperative problems. The rate of major complications decreases substantially as the experience of the surgeon increases. PMID- 17691239 TI - Validation of the Brief Screen for Depression in a Jamaican cohort. AB - Research on depression in Jamaicans has been limited by the absence of a psychometrically sound measure of depression. This project attempts to rectify this problem by exploring the concurrent and discriminant validity of the Brief Screen for Depression (BSD) using a sample of 244 students attending the University of the West Indies, Mona, Jamaica. Participants were administered the BSD along with the Beck Depression Inventory (BDI), the Center for Epidemiologic Studies Depression scale (CES-D) the University of California at Los Angeles (UCLA) Loneliness Scale - Revised, (UCLA-R) and the Responding Desirably on Attitudes and Opinions scale (RD16). Overall, the BSD was found to have an acceptable level of concurrent validity as evidenced by high correlations with scores on the BDI (0.64) and the CES-D (0.62), and an acceptable level of discriminant validity as demonstrated through moderate correlations with the UCLA Loneliness Scale (0.40). In addition, the BSD was found to possess a moderate degree of sensitivity in identifying individuals who may be experiencing clinically significant symptoms of depression. PMID- 17691240 TI - Hermaphroditism: cytogenetics, gonadal pathology and gender assignment: a case report. AB - True hermaphroditism is a rare intersex disorder in which individuals possess both testicular and ovarian gonadal tissue. A case of true unilateral hermaphroditism presenting with ambiguous external genitalia, right scrotal testis and left pelvic ovotestis is herein outlined Phallic, gonadal and genetic factors were considered before male gender was assigned. Gender assignment procedures have been questioned by intersex activists opposed to early genital surgery. Western societies have a binary perspective on gender and this leads to a stigma being placed on intersex cases. A multidisciplinary approach to this problem involving paediatric specialists in the field, of endocrinology, surgery and psychiatry is necessary, along with educational programmes that promote tolerance in society to variations in gender. PMID- 17691241 TI - A new radiological classification for ameloblastoma based on analysis of 19 cases. AB - OBJECTIVE: To describe ameloblastoma of the jawbone in young Jamaicans, with special emphasis on radiological findings, and to introduce a radiological classification which could assist in the categorization of these cases according to their biological behaviour and hence their subsequent surgical and medical management. SUBJECTS AND METHODS: The series comprised all the 18 cases of ameloblastoma of the jaw seen in patients under the age of 20 years in the two major hospitals in Jamaica with an oral and maxillofacial surgery department from 1980 to 1995. Radiological and histological diagnosis was confirmed in all. A case of maxillary ameloblastoma in a 13-year old girl seen in the year 2000 was also included in this study. This last case had special attributes. RESULTS: All 19 patients had primary lesions of ameloblastoma. The mean age was 16.1 years with a mode of 18 years and a range of 13 to 19 years. The male to female ratio was 1.1:1. Eighteen cases were seen in the mandible and one case in the maxilla. Of these, 42% were unilocular and 58% were multilocular radiologically. Thirty two per cent of cases had unerupted teeth associated with the lesions and 32% had root resorption. Based on our new radiological classification, the most predominant radiological type was IIb2 with root resorption (42%). There was no radiological type classically simulating dentigerous cyst (Ia2). CONCLUSION: Ameloblastoma in young Jamaicans presented more in the adolescent period and are predominantly unicystic and rare in the maxilla. A new classification for ameloblastoma based solely on radiological presentation is adopted. PMID- 17691243 TI - Non-syndromal, true congenital ankylosis of the temporomandibular joint: a case report. AB - A case of a six-week old boy with bilateral congenital fibrous intra-articular ankylosis of the temporomandibular joint is presented The literature is reviewed and limitations to management are highlighted. PMID- 17691242 TI - Urinary fluoride levels in children in a single school in Trinidad and Tobago: a preliminary investigation. AB - OBJECTIVE: To determine urinary fluoride levels in school children in a non fluoridated area in Trinidad and Tobago. METHOD: Morning urine samples were requested from 750 children aged 5 to 14 years, attending a primary school in the area of St Joseph, north west Trinidad. Urine was collected at home and brought to school in labelled plastic bottles. Urinary fluoride concentration (ppm) was measured using an ion-specific electrode. RESULTS: Urine samples were available for 500 children (67%). Mean age was 8.5 years. Overall mean fluoride concentration was 0.5 ppm +/- standard deviation (SD) 0.27; males (n = 263) were 0.58 ppm +/- 0.28 and females (n = 237) 0.55 ppm +/- 0.27. Children in the 5 to 7 year age group had the highest levels (0.64 ppm +/- 0.33). CONCLUSION: Mean urinary fluoride levels in this sample of school children were low indicating a fluoride intake below the optimum level for caries prevention. Fluoridation programmes may need to be implemented to increase fluoride intake among school children in the study area. PMID- 17691244 TI - Radiological assessment of type II Stafne idiopathic bone cyst in a patient undergoing implant therapy: a case report. AB - This paper is intended to describe the confirmative role of radiology in the diagnosis of Stafne Idiopathic bone Cyst (SIBC) without the need for histopathology especially when dental implants are considered so as to avoid unnecessary invasive surgical exploration of this benign pathology. Other pathologies may present not unlike SIBC and as such it is mandatory to rule out such possibilities especially prior to dental implant therapy. The use of orthopanthomogram and non-sialographic computed tomography (CT) scan in the reported case together with a review of CT scan confirmatory role in the diagnosis of SIBC from the literature was the basis for this clinical report. Based on the CTscan findings of the jaw in this case and review of the literature, the implant procedure was commenced without the need of histopathology and/or for invasive surgical exploration of this pathology. All pathologic lesions of the jawbone seen on the orthopanthomogram should be confirmed prior to commencement of implant procedure even when such pathologies are seen in areas remote from the proposed implant site. The pre-implant radiological assessment utilizing non-sialographic CT scan alone is confirmatory of SIBC. PMID- 17691245 TI - Screening for postpartum depression. AB - Postpartum depression, a potentially serious public health problem can be effectively treated. With the implementation of universal screening with a standardized, self-administered screening tool, in conjunction with appropriate education and training of health care providers to increase awareness of this problem and to impart greater diagnostic suspicion, identification of and early intervention for PPD can be facilitated. There is need for increased collaboration between Obstetric and Consultation Liaison Psychiatric Services, with particular emphasis on the prevention of psychiatric morbidity associated with pregnancy, thereby improving the quality of life for and interaction between mother and child. The establishment of a true Liaison Psychiatric Service dedicated to pregnancy and the postpartum period, with a Psychiatrist employed by the Obstetric Services, may be of great value. PMID- 17691246 TI - Salmonella enteritidis related prosthetic joint infection. PMID- 17691247 TI - Episode of major depression refractory to pharmacotherapy. PMID- 17691248 TI - Ethylene glycol poisoning highlighting the role of the Caribbean Poison Information Centre. PMID- 17691249 TI - Tropical spastic paraparesis and polymyositis--a still unfolding story. PMID- 17691250 TI - Get involved with your hospital's disaster planning initiatives. PMID- 17691251 TI - Simulated disaster helps hospital fine-tune its plan. PMID- 17691252 TI - Prepare for disaster with scenario-based planning. PMID- 17691253 TI - Quality measures gain importance as CMS moves to value-based purchasing. PMID- 17691254 TI - Social worker/CM handle babies for moms. PMID- 17691255 TI - Costly errors are common in same-day surgery arena. PMID- 17691256 TI - Putting nurses in access results in financial gains. PMID- 17691257 TI - [Toxic epidermal necrolysis and Stevens-Johnson syndrome]. AB - Epidermal necrolysis (Stevens-Johnson syndrome, toxic epidermal necrolysis) is an acute and severe skin disease, induced by "(drug allergy" and characterized by the destruction of the epithelium of the skin and mucous membranes. It is extremely rare: about 2 cases per million per year. It is a life-threatening emergency. Blisters and detachment may involve a high portion of the body surface area and several mucosal sites. Visceral complications are frequent. The clinical diagnosis should be confirmed by a skin biopsy showing full-thickness necrosis of the epidermis. A dozen "high risk" medications account for 50% of cases. Symptomatic management in specialized units is urgent. The mortality rate is high (20-25%) and about one half of survivors will have sequelae, especially on the eyes. PMID- 17691258 TI - [Juvenile idiopathic arthritis. (I) Clinical aspects]. AB - Juvenile idiopathic arthritis (JIA), formerly know as juvenile chronic arthritis, is a broad term encompassing several disorders starting before the age of 16. It is characterized by arthritis lasting more than 6 weeks, of unknown etiology, usually persisting for six month initially. Approximately 1 in 5 000 children are affected in France. Of the various distinguishable clinical forms, oligoarticular JIA is the most frequent one. It is characterized by an involvement of up to 4 joints during the first 6 months and is mostly observed in females. The prognosis may be further complicated by the presence of uveitis, associated with an insidious progression. In systemic JIA (also called Still's disease) as well as in some polyarticular forms, with or without rheumatoid factor, inflammation may continue in adulthood. Severe polyarticular involvement or hip involvement may be associated with a poor functional prognosis. PMID- 17691259 TI - [PET, extended fever and tuberculous lymphadenitis]. PMID- 17691260 TI - [What is research in general practice?]. PMID- 17691261 TI - [To detect teenagers' suicide behaviour (I). Elaboration of a test and its validation]. AB - CONTEXT: General practitioner is used to be consulted by teenagers who have already had suicide ideas or attempted suicide and who were not been taking care for. The most of the time the GP doesn't know their antecedents; but as they are at risk to do it again, it's important to detect them. OBJECTIVE: To elaborate and to validate a test to detect teenagers' suicide behaviour. METHOD: After participating to a survey (Lycoll) which included 3 872 teenagers, 17 GPs and 3 psychiatrists (ADOC) created a screening test to be used by GPs. It was a questionnaire, named TSTS, with 4 questions completed by 5 items to explore the troubles' severity. Then, this test has been experienced among 38 GPs who didn't know it before. This study has been done as a clinical audit. Each physician has been visited by a research clinical assistant who had been taught for it, to estimate the screening of suicide ideas or attempted suicide before and after taking knowledge of the test. RESULTS: Results indicate a very good acceptability of this screening tool which has been used for 60% of teenagers' office visits. It allowed to guide a large number of visits towards preoccupations which were different from the initial one and to detect suicide antecedents among 13% teenagers "tested" among whom 2/3 had already seen a GP. CONCLUSION: This test is recommended to GPs in usual practice to detect teenagers at suicide risk. PMID- 17691262 TI - [To detect teenagers' suicide behaviour (II). Clinical audit among 40 general practitioners]. AB - CONTEXT: [corrected] General practitioner is used to be consulted by teenagers who have already had suicide ideas or attempted suicide and who were not been taking care for. The most of the time the GP doesn't know their antecedents; but as they are at risk to do it again, it's important to detect them. OBJECTIVE: To elaborate and to validate a test to detect teenagers' suicide behaviour. METHOD: After participating to a survey (Lycoll) which included 3 872 teen-agers, 17 GPs and 3 psychiatrists (ADOC) created a screening test to be used by GPs. It was a questionnaire, named TSTS, with 4 questions completed by 5 items to explore the troubles' severity. Then, this test has been experienced among 38 GPs who didn't know it before. This study has been done as a clinical audit. Each physician has been visited by a research clinical assistant who had been taught for it, to estimate the screening of suicide ideas or attempted suicide before and after taking knowledge of the test. RESULTS: Results indicate a very good acceptability of this screening tool which has been used for 60% of teenagers' office visits. It allowed to guide a large number of visits towards preoccupations which were different from the initial one and to detect suicide antecedents among 13% teenagers "tested" among whom 2/3 had already seen a GP. CONCLUSION: This test is recommended to GPs in usual practice to detect teen-agers at suicide risk. PMID- 17691263 TI - [Research in general medicine in France: state of localities ]. PMID- 17691264 TI - [Evaluation of a screening programme for diabetic retinopathy (DODIA study)]. AB - CONTEXT: In France, 43% to 63% of diabetics have an annual fundoscopy. Do the new screening tools, coupled with teletransmission of the images, allow for satisfying ophthalmological screening? It is an important matter given the foreseeable reduction in the number of French ophthalmologists in the forthcoming years. OBJECTIVES: To measure the quality of screening for diabetic retinopathy (DR), in the framework of a network, by the provision of a retinograph by numeric camera (with teletransmission of the images and centralised interpretation), in a screening centre located in town. METHOD: The study evaluated the quality of screening obtained in two comparable groups of general practitioners, one using the retinograph and the other using the classical method of screening by ophthalmologist. The screening was targeted at diabetics who had not had a fundoscopy in the preceding year, nor had known DR or a treating ophthalmologist (for the retinography group only). RESULTS: 667 patients were sampled in the retinography group (456 included) and 707 in the control group (426 included) between 1/04/02 and 1/11/02; 417 patients were followed until the end of the study in the 2 groups. A screening examination was considered effective if it was performed within the six months following its request, and by the presence of a report in the file of the general practitioner. The percentage of patients thus screened was 74% in the retinography group and 71,5% in the other group (not significant). 16% of diabetics in the retinography group had DR compared with 10% of patients in the control group. The analysis of the level of satisfaction of patients tended to show a preference for the system of screening by fundal photography. CONCLUSION: In the framework of a healthcare network, the availability of a retinograph by numeric camera, with the interpretation of photos by teletransmission of the images, obtained a high level of quality of screening for diabetic retinopathy that was at least as good as that obtained by a healthcare network using the classical ophthalmological screening method. PMID- 17691265 TI - [Research in general medicine: states of localities. 2. French scientific production in general medicine]. PMID- 17691266 TI - [Impact of peer visits]. AB - OBJECTIVES: To measure the impact of an intervention on the general practitioners (GP) of Reunion in order to improve the management of patients with type 2 diabetes, in conforming with the recommendations of the Anaes. METHOD: Randomised intervention study on a random sample of 120 practitioners out of a total of 630 GP in Reunion, 60 in the intervention group (IG) and 60 in the control group (CG). Each doctor of the IG received 2 visits by a "visiting GP" which have had specific training. The period of observation included the 12 months before, and the 6 months after the date of the intervention. Data were collected retrospectively, at the end of 18 months of observation; in medical records of 25 diabetics seen consecutively in consultation, the GP collected the dates of performance of six procedures under surveillance: HbA1c, examination of the feet, fundoscopy, ECG, estimation of the creatinine clearance, level of micro albuminuria. Outcome measures were delays in performance of the procedures conforming to the recommendations. RESULTS: 42 GP out of 60 in the IG, and 40 out of 60 in the CG participated to the study. Patients included, 792 in the IG and 789 in the CG, were comparable for age, sex-ratio and profession. The distribution of delays in performance before the intervention was comparable in the two groups. The comparison between the groups after the intervention showed a significantly important improvement in the IG for 4 to 6 of the procedures: examination of the feet, fundoscopy, creatinine clearance and micro-albuminuria. CONCLUSION: In the short-term, a "outreach visit" or "academic detailing" improves the delay in performance of most of the surveillance procedures in type 2 diabetes. PMID- 17691267 TI - [Early screening and brief intervention among excessive alcohol users: mobilizing general practitioners in an efficient way]. AB - OBJECTIVE: The program "Boire moins, c'est mieux" (BMCM--"The less alcohol, the better") initiated by the ANPAA offered 550 general practitioners (GPs) in 2003 to follow training courses so as to perform "early screening and brief intervention" (ESBI) in general practice. Phone calls to the medical offices, a financial compensation offer and a media campaign in the immediate environment of general practitioners were used. The study aimed at assessing the respective efficiency of these three methods. METHOD: Mailing was the control mobilization method. Phone calls were used in addition to mailing for one GP out of two, according to a previous draw. Financial compensation (2 + for each questionnaire filled out, and 10 + for each BI delivered) was used when GPs were invited a second time to attend the training. Community-based mobilization only occurred in the site in Saint-Quentin-en-Yvelines (France). The primary endpoint was the actual participation to the training evenings. The secondary endpoints were the registration to trainings and the ESBI activity following the training. RESULTS: Phone calls enabled to multiple by 7 the number of participants attending training sessions, as compared to the impact of mailing only (p < 10-7); phone calls had no proper impact on ESBI activity following the training. Financial compensation had a powerful impact on the level of ESBI activities (p = 10-4); however, announcing it had no effect on registrations and barely modified the impact of phone calls. The proportion of the population benefiting from a screening action doubled in the site where a community-based action occurred (p < 10-7). CONCLUSION: A mere phone call was particularly efficient in increasing the number of trained GPs. Financial incentive led to an activity level very close to systematic screening. Community-based approach increased significantly the proportion of the screened population. PMID- 17691268 TI - [To develop research in general medicine]. PMID- 17691269 TI - [Medical workforce under construction for 2008 (1)]. PMID- 17691270 TI - [Bronchopulmonary infections in the enfant and the child]. PMID- 17691271 TI - [Screening of orthopaedic abnormalities of infant]. PMID- 17691272 TI - [Prevention of foetal risks]. PMID- 17691273 TI - [Prescription of the thermal spa]. PMID- 17691274 TI - [Robert Debre during German occupation of France]. PMID- 17691275 TI - Lipid-lowering drugs: use and expenditure in Portugal (1995-2004). AB - INTRODUCTION: Due to their morbidity and mortality, cardiovascular diseases are one of the most significant public health problems in industrialized countries, including Portugal. The appropriate use of lipid-lowering drugs to prevent and treat these diseases is therefore of major and increasing importance in therapy today, in terms of both public health and allocation of financial resources by the health system. OBJECTIVES: The present study aims to characterize use and expenditure for lipid-lowering drugs in Portugal, and the impact of current policies on their consumption and cost. METHODS: The analysis refers to lipid lowering drugs prescribed and dispensed to outpatients in mainland Portugal covered by the National Health Service (NHS) between January 1, 1995 and June 30, 2004. The Anatomical Therapeutic Chemical classification index recommended by the World Health Organization was used in order to calculate various utilization and expenditure indicators. RESULTS: The use of lipid-lowering drugs in Portugal showed a large increase in terms of defined daily doses per 1000 inhabitants per day (DID), from 10.21 DID in 1995 to 67.93 DID in 2004, mainly due to increased use of statins (an average annual growth of 34.5%). Expenditure on lipid-lowering drugs reached around 123 million euros in 2003, representing. 5% of total NHS expenditure on outpatient medicines. However, the daily treatment cost of these medicines has decreased, particularly in the case of statins and more markedly following increased availability of generic medicines. CONCLUSIONS: The study indicates a change in the pattern of lipid-lowering drug utilization and a more rational use of these medicines with the introduction of statins. The increased use of statins follows changes in clinical guidelines for the treatment of dyslipidemia and suggests a favorable evolution in the number of individuals taking statins, although this has had a significant impact on pharmaceutical expenditure, representing a major expense for patients and the NHS. In conclusion, the measures studied for expenditure containment have been successful in the case of statins, with significant development of the generics market (31% market share in 2004), reduction of costs (35% between 1995 and 2004) and hence increased access of patients to such therapy. PMID- 17691276 TI - The paradigm of stains: will the lower cost of generics translate into health gains? PMID- 17691277 TI - Dobutamine stress echocardiography as a predictor of coronary lesion severity on coronary angiography. AB - In order to evaluate the capacity of dobutamine stress echocardiography (stress echo) to predict the severity of atherosclerotic lesions observed on coronary angiography in patients with coronary artery disease, we performed a retrospective study at Instituto Nacional de Cardiologia and Universidade Federal Fluminense, Brazil. The health records of 40 patients who underwent both stress echo and coronary angiography within a period of less than 14 days were assessed. For the stress echo analysis, the heart was divided into 16 segments and the different types of response assessed: biphasic, ischemic, viable or unchanged. The main arteries - left anterior descending artery (LAD), left circumflex coronary artery (LCx) and right coronary artery (RCA) and their branches - were studied by coronary angiography to assess the degree of obstruction (in %), the type of lesion (A, B1, B2 or C), and the presence or absence of collateral circulation. The following results were obtained: patients showing an altered response on stress echo (ischemic) presented a higher degree of coronary obstruction as well as more complex lesions in the anterior descending artery on coronary angiography. A higher degree of obstruction was associated with more complex lesions (in LAD, LCx and RCA) and collateral circulation (in LAD and RCA). The presence of more complex lesions also correlated with collateral circulation in the LAD. Based on these results, we concluded that dobutamine stress echocardiography is a non-invasive test capable of predicting the severity of coronary lesions in patients with chronic ischemic cardiopathy. PMID- 17691278 TI - Nicorandil preserves the function of the mitochondrial phosphorylative and oxidative system in an animal model of global ischemia-reperfusion. AB - Ischemia followed by reperfusion (IR) negatively affects mitochondrial function. At the level of the oxidative-phosphorylative system, IR inhibits the respiratory complexes and ATP synthase, and increases the passive leak of protons through the inner mitochondrial membrane, uncoupling respiration from phosphorylation, decreasing mitochondrial potential and, consequently, ATP production. Drugs that minimize the mitochondrial damage induced by IR may prove to be clinically effective. In the present work, we analyzed the impact of nicorandil, a mitochondrial ATP-sensitive potassium channel agonist, on mitochondrial dysfunction at the level of the oxidative-phosphorylative system of rat hearts subjected to IR. The decrease in the respiratory control ratio (RCR) induced by IR leads to the conclusion that IR has a negative impact on the activity of the mitochondrial respiratory system, uncoupling oxidation from phosphorylation. This effect is reversed by nicorandil, which increases not only RCR, but also the ADP/O ratio. Regarding respiratory rate, state 3 rate was approximately the same for all the experimental groups, while state 4 rate was lower for the group where IR was induced in the presence of nicorandil. This result is in accordance with the data obtained for the RCR and ADP/O. State 4 rate is most affected by uncoupling, given that it is controlled by proton leak. Mitochondria subjected to IR in the presence of nicorandil have a lower state 4 rate, i.e. they are less uncoupled. From these results we conclude that nicorandil preserves the function of mitochondria subjected to IR in terms of both respiration and phosphorylative capacity. PMID- 17691279 TI - Prognosis of decompensated heart failure: role of NT-proBNP. AB - BACKGROUND: The prognostic value of natriuretic peptides in heart failure (HF) is well established. The objective of this study was to evaluate the role of NT proBNP in predicting outcome in decompensated HF. METHODS: Patients admitted with decompensated HF to our Internal Medicine Department between November 2002 and April 2004 with at least two measurements of NT-proBNP (within 24 hours of admission and on discharge) were analyzed. Patients discharged alive were followed for up to 6 months. The primary endpoint was death or readmission. RESULTS: We included 304 patients (72.7+/-11.6 years of age, 53.9% female, 49.3% ischemic etiology). Echocardiography was performed in 73.7%. Left ventricular systolic function (LVSF) was preserved in 20.7%, mildly to moderately depressed in 32.2% and severely depressed in 20.7%. There was a significant decrease in median NT-proBNP levels during hospitalization (from 7006 to 3796 pg/ml, p<0.001). The patients were classified in three groups according to NT-proBNP variation: 1 decreasing by at least 30% (n=162); 2 - no significant variation (n=95); and 3 - increasing by at least 30% (n=47). The primary endpoint was observed in 43% of the patients. In univariate analysis, variables predictive of outcome were: NT-proBNP at discharge (> median: HR=2.72; 95% CI=1.89-3.92): variation in NT-proBNP levels during hospitalization (group 2 vs. group 1 - HR=2.28; 95% CI=1.52-3.42; group 3 vs. group 1 - HR=4.82; 95% CI=3.11-7.49); renal failure (creatinine >2 mg/dL - HR=1.65; 95% CI=1.07-2.53); and treatment with ACE-Is (HR=0.59; 95% CI=0.39-0.89). After adjustment for NYHA class at discharge, pulse pressure, LVSF, renal function and hemoglobin, only NT-proBNP at discharge and NT-proBNP variation remained independent predictors of prognosis (NT-proBNP at discharge > median: HR=2.02; 95% CI=1.28-3.2; NT-proBNP variation: group 2 vs. group 1 - HR=2.24; 95% CI=1.37-3.66; group 3 vs. group 1 - HR=3.85; 95% CI=2.24-6.63). CONCLUSION: Our results extend previous reports on the value of NT-proBNP in predicting outcome after discharge in patients hospitalized due to decompensated HF, and demonstrate its potential usefulness and applicability in clinical practice. PMID- 17691280 TI - Transient left ventricular apical ballooning--characterization of an increasingly common new diagnostic entity. Another case report. AB - Transient left ventricular apical ballooning syndrome (ABS) is characterized by chest pain, electrocardiographic alterations mimicking acute myocardial infarction (MI), transient left ventricular apical dyskinesis and normal coronary angiogram. It usually has a favorable prognosis. We present the case of a 71-year old female patient, with a history of respiratory infection, who was admitted to the emergency department with chest discomfort, electrocardiographic alterations suggesting anterolateral MI, and shock. The admission echocardiogram revealed apical dyskinesis and dilatation, basal hypercontractility and a left intraventricular gradient of 75.27 mmHg. Elevation of cardiac biomarkers was disproportionately low. Coronary angiography was normal and the echocardiographic abnormalities disappeared after the tenth day of hospitalization. We describe the diagnostic criteria and characteristics of ABS. It is more prevalent in post menopausal women and has a recognized association with stress. Its incidence will probably rise with increasing awareness of this entity, aging populations, and wider access to echocardiography and cardiac catheterization. PMID- 17691281 TI - Ectopic origin of the right coronary artery--case report. AB - Coronary artery anomalies can occur in isolation or in association with other congenital heart defects. Clinical presentation ranges from asymptomatic forms to sudden cardiac death. The authors report a case of anomalous origin of the right coronary artery from the left sinus of Valsalva, diagnosed with multidetector computed tomography coronary angiography. PMID- 17691282 TI - Cardiac angiosarcoma--a review. AB - Based on a case of a patient with angiosarcoma (AS) of the right atrium with superior vena cava syndrome associated with urticaria and polyarthralgias, who died soon after surgery, the authors present a brief review of the subject of cardiac AS, an extremely rare pathology, usually diagnosed late due to its non specific symptomatology. Several topics are discussed, including mechanisms of clinical manifestations caused by blood flow obstruction and valve dysfunction, local invasion with arrhythmias and pericardial effusion, embolic phenomena and constitutional symptoms. Imaging and histopathologic methods of diagnosis are considered, as well as references to cytogenetic analysis. Surgery is the first treatment choice, but heart AS are frequently not completely resectable and concomitant metastases at the time of surgery are common, both usually leading to a dismal prognosis. Chemotherapy, radiotherapy and even heart transplantation do not substantially improve the survival of these patients. Urticaria is not generally assumed by most authors to be associated with malignancy, but there are rare reports of its association with some malignant tumors. PMID- 17691283 TI - Prenatal diagnosis of interrupted inferior vena cava. PMID- 17691284 TI - An introduction to neural networks surgery, a field of neuromodulation which is based on advances in neural networks science and digitised brain imaging. AB - Operative Neuromodulation is the field of altering electrically or chemically the signal transmission in the nervous system by implanted devices in order to excite, inhibit or tune the activities of neurons or neural networks and produce therapeutic effects. The present article reviews relevant literature on procedures or devices applied either in contact with the cerebral cortex or cranial nerves or in deep sites inside the brain in order to treat various refractory neurological conditions such as: a) chronic pain (facial, somatic, deafferentation, phantom limb), b) movement disorders (Parkinson's disease, dystonia, Tourette syndrome), c) epilepsy, d) psychiatric disease, e) hearing deficits, and f) visual loss. These data indicate that in operative neuromodulation, a new field emerges that is based on neural networks research and on advances in digitised stereometric brain imaging which allow precise localisation of cerebral neural networks and their relay stations; this field can be described as Neural networks surgery because it aims to act extrinsically or intrinsically on neural networks and to alter therapeutically the neural signal transmission with the use of implantable electrical or electronic devices. The authors also review neurotechnology literature relevant to neuroengineering, nanotechnologies, brain computer interfaces, hybrid cultured probes, neuromimetics, neuroinformatics, neurocomputation, and computational neuromodulation; the latter field is dedicated to the study of the biophysical and mathematical characteristics of electrochemical neuromodulation. The article also brings forward particularly interesting lines of research such as the carbon nanofibers electrode arrays for simultaneous electrochemical recording and stimulation, closed-loop systems for responsive neuromodulation, and the intracortical electrodes for restoring hearing or vision. The present review of cerebral neuromodulatory procedures highlights the transition from the conventional neurosurgery of resective or ablative techniques to a highly selective "surgery of networks". The dynamics of the convergence of the above biomedical and technological fields with biological restorative approaches have important implications for patients with severe neurological disorders. PMID- 17691285 TI - Management of chronic severe pain: cerebral neuromodulatory and neuroablative approaches. AB - Two approaches are utilized when targeting the brain to treat pain. The first, a non-destructive approach, uses either electrical stimulation of brain targets thought to modulate the process of pain perception, or pharmacological agents are introduced into ventricular spaces to target pain modulating receptors. Electrical stimulation targets include; the thalamic nuclei, the periventricular and periaqueductal grey (PVG and PAG) matter or the motor cortex. Currently, the pharmacological agent of choice for intracerebroventricular injection is morphine. In general, electrical stimulation is used for nonmalignant type pain, and pharmacological modulation for malignant type pain. The second, a destructive approach, is usually employed with the goal of interrupting the signals that lead to pain perception at various levels. Neuroablation is usually performed on cellular complexes such as "nuclei, or gyri" or on tracts with the aim of disrupting the sensory and limbic pathways involved in the emotional processes associated with pain. Specific cerebral neuroablation targets include; the thalamic medial group of nuclei, the cingulated gyrus, and the trigeminal nucleus and tract. There are fewer reports in the literature detailing the brain, when compared to the spine, as a target to treat pain, and further research is required. PMID- 17691286 TI - Extradural cortical stimulation for central pain. AB - Central pain results from a central nervous system injury and represents a challenge for the pain therapist. Human studies have shown that motor cortex stimulation (MCS), i.e. the placement of a stimulating plate on the dura overlying the motor cortex can relieve brain central pain. Studies suggest that MCS directly affects activity in the first and second order somatosensory areas, thalamic nuclei and also inhibits spinal primary afferents and spinothalamic tract neurons. The following factors have been found to predict analgesia by MCS: intact or almost intact corticospinal motor function, mild or negligible sensory loss, absence of thermal sensory threshold alteration within the painful area, positive response to the barbiturate and/or ketamine test, positive response to the propofol test, positive response to transcranial magnetic stimulation (TMS). The targeting of the cortical area is made by anatomical localization by computed tomography (CT), magnetic resonance imaging (MRI), neuronavigation, intraoperative neurophysiological recordings, functional MRI (fMRI), and intraoperative clinical assessment. We perform the procedure under local anaesthesia. We describe in detail our surgical technique and stimulation protocol. Furthermore, we review the most important studies with respect to their results, the observed side effects and complications. The future prospects and likely developments of MCS for central pain are also discussed. PMID- 17691287 TI - Motor cortex stimulation for neuropathic pain. AB - Since the initial publication of Tsubokawa in 1991, epidural motor cortex stimulation (MCS) is increasingly reported as an effective surgical option for the treatment of refractory neuropathic pain although its mechanism of action remains poorly understood. The authors review the extensive literature published over the last 15 years on central and neuropathic pain. Optimal patient selection remains difficult and the value of pharmacological tests or transcranial magnetic stimulation in predicting the efficacy of MCS has not been established. Pre operative functional magnetic resonance imaging (fMRI), 3-dimensional volume MRI, neuronavigation and intra-operative neurophysiological monitoring have contributed to improvements in the technique for identifying the precise location of the targeted motor cortical area and the correct placement of the electrode array. MCS should be considered as the treatment of choice in post-stroke pain, thalamic pain or facial anesthesia dolorosa. In brachial plexus avulsion pain, it is preferable to propose initially dorsal root entry zone (DREZ)-tomy; MCS may be offered after DREZotomy has failed to control the pain. In our experience, the results of MCS on phantom limb pain are promising. In general, the efficacy of MCS depends on: a) the accurate placement of the stimulation electrode over the appropriate area of the motor cortex, and b) on sophisticated programming of the stimulation parameters. A better understanding of the MCS mechanism of action will probably make it possible to adjust better the stimulation parameters. The conclusions of multicentered randomised studies, now in progress, will be very useful and are likely to promote further research and clinical applications in this field. PMID- 17691288 TI - Motor cortex stimulation for chronic non-malignant pain: current state and future prospects. AB - Motor cortex stimulation (MCS) was proposed by Tsubokawa in 1991 for the treatment of post-stroke thalamic pain. Since that time, the indications have been increased and included trigeminal neuropathic pain and later other types of central and peripheral deafferentation pain. The results reported in the literature are quite good; the mean long-term success rate is 80% in facial pain and 53% in non-facial pain. Our own results are less impressive: 4 of 14 patients (28%) experienced a greater than 40% pain relief, but in 2 of them the effect faded with time. Only few minor complications have been reported. The accurate placement of the epidural electrode over the motor cortex that somatotopically corresponds to the painful area is believed to be essential for pain relief. Predictive factors included the response to pharmacological tests, the relative sparing from the disease process of the cortico-spinal tract and the sensory system, and the analgesic response achieved during the test period of MCS. A possible predictive factor might be a test of repetitive transcranial magnetic stimulation (rTMS) of the motor cortex. MCS may act by rebalancing the control of non-nociceptive sensory inputs over nociceptive afferents at cortical, thalamic, brainstem and spinal level. In addition, it may interfere with the emotional component of nociceptive perception. Biochemical processes involving endorphins and GABA may also be implicated in the mechanism of MCS. It is time for a large multicenter prospective randomized double blind study evaluating not only the effect of MCS on pain (based on the available guidelines for assessment of neuropathic pain), but also the optimal electrode placement and stimulation parameters, and the possible relationship with the response to rTMS. New electrode design and a new generation of stimulators may help in improving the results. PMID- 17691289 TI - Stimulation of primary motor cortex for intractable deafferentation pain. AB - The stimulation of the primary motor cortex (M1) has proved to be an effective treatment for intractable deafferentation pain. This treatment started in 1990, and twenty-eight studies involving 271 patients have been reported so far. The patients who have been operated on were suffering from post-stroke pain (59%), trigeminal neuropathic pain, brachial plexus injury, spinal cord injury, peripheral nerve injury and phantom-limb pain. The method of stimulation was: a) epidural, b) subdural, and c) within the central sulcus. Overall, considering the difficulty in treating central neuropathic pain, trigeminal neuropathic pain and certain types of refractory peripheral pain, the electrical stimulation of M1 is a very promising technique; nearly 60% of the treated patients improved with a higher than 50% pain relief after several months of follow-up and sometimes of a few years in most reports. The mechanism of pain relief by the electrical stimulation of M1 has been under investigation. Recently, repetitive transcranial magnetic stimulation (rTMS) of M1 has been reported to be effective on deafferentation pain. In the future, rTMS may take over from electrical stimulation as a treatment for deafferentation pain. PMID- 17691290 TI - Cathodal, anodal or bifocal stimulation of the motor cortex in the management of chronic pain? AB - The conditions of motor cortex stimulation (MCS) applied with epidural electrodes, in particular monopolar (cathodal or anodal) and bipolar stimulation, are discussed. The results of theoretical studies, animal experiments and clinical studies lead to similar conclusions. Basically, cortical nerve fibres pointing at the epidural electrode and those normal to this direction are activated by anodal and cathodal stimulation, respectively. Because MCS for the relief of chronic pain is generally applied bipolarly with electrodes at a distance of at least 10 mm, stimulation may actually be bifocal. The polarity and magnitude of a stimulus needed to recruit cortical nerve fibres varies with the calibre and shape of the fibres, their distance from the electrode and their position in the folded cortex (gyri and sulci). A detailed analysis of intra operative stimulation data suggests that in bipolar MCS the anode of the bipole giving the largest motor response in the pain region is generally the best electrode for pain management as well, when connected as a cathode. These electrode positions are most likely confined to area 4. PMID- 17691291 TI - Somatosensory cortex stimulation for deafferentation pain. AB - Functional neuroimaging has demonstrated that a relationship exists between the intensity of deafferentation pain and the degree of deafferentation-related reorganization of the primary somatosensory cortex. It has also revealed that this cortical reorganization can be reversed after the attenuation of pain. Deafferentation pain is also associated with hyperactivity of the somatosensory thalamus and cortex. Therefore, in order to suppress pain, it seems logical to attempt to modify this deafferentation-related somatosensory cortex hyperactivity and reorganization. This can be achieved using neuronavigation-guided transcranial magnetic stimulation (TMS), a technique that is capable of modulating cortical activity. If TMS is capable of suppressing deafferentation pain, this benefit should be also obtained by the implantation of epidural stimulating electrodes over the area of electrophysiological signal abnormality in the primary somatosensory cortex. The first studies demonstrated a statistically significant pain suppression in all patients and a clinically significant pain suppression in 80% of them. This clinical experience suggests that somatosensory cortex stimulation may become a neurophysiology-based new approach for treating deafferentation pain in selected patients. In this chapter, we review the relevant recent reports and describe our studies in this field. PMID- 17691292 TI - Localization of precentral gyrus in image-guided surgery for motor cortex stimulation. AB - According to recent clinical data, motor cortex stimulation (MCS) is an alternative treatment for central pain syndromes. We present our minimal invasive technique of image guidance for the placement of motor cortex stimulating electrode and assess the clinical usefulness of both neuronavigation and vacuum headrest. Neuronavigation was used for identification of precentral gyrus and accurate planning of the single burr-hole. The exact location was reconfirmed by intraoperative phase reversal of somatosensory evoked potential (SSEP) and clinical response after electrical stimulation test. Implementation of navigation technique facilitated localization of the precentral gyrus with a high degree of accuracy. Determination of stimulating electrode placement was possible in every case. Postoperative clinical and neuroradiological evaluations were performed in each patient. All patients experienced postoperative relief from pain. Our preliminary series may confirm image guidance as a useful tool for surgery of MCS. Additionally, minimal and safe exposure can be performed using a single burr hole and vacuum head rest. PMID- 17691293 TI - Anatomical and physiological basis, clinical and surgical considerations, mechanisms underlying efficacy and future prospects of cortical stimulation for pain. AB - The analgesic efficacy of cortical stimulation on refractory neuropathic pain has been established. Although it offers pain relief to 45-75% of the patients, this technique remains under evaluation and the definitive protocol for its application has not been established yet. The mechanisms underlying the analgesic efficacy of cortical stimulation are still largely unknown. Successive technical adaptations have been proposed and tried in order to reduce the number of non responding patients. In this chapter, we summarize the limited amount of crucial information that has been acquired so far on pain processing in the central nervous system, on the functional pathophysiology of neuropathic pain and on the mechanisms underlying the efficacy of cortical stimulation. We also discuss key issues that could help to increase the success rate and enhance the future prospects of the technique. PMID- 17691294 TI - Chronic electrostimulation of the trigeminal ganglion in trigeminal neuropathy: current state and future prospects. AB - Over two decades ago, the electrostimulation of the trigeminal ganglion (TGES) was established as a treatment option for patients with trigeminopathic pain due to a (iatrogenic) lesion of the trigeminal nerve, on whom the other therapeutic methods, either neurosurgical or conservative have very limited efficacy and usually are associated with a poor outcome. The technique of TGES which uses the setup also used for the thermocoagulation lesion for trigeminal neuralgia was first published by Steude in 1984 and has not been altered substantially. After a percutaneous puncture with a 16 gage needle of the oval foramen, a monopolar electrode (diameter 0.9mm, custom-made) is placed in the postganglionic trigeminal nerve. After a successful test-stimulation phase, a permanent electrode pulse generator system is implanted. Our experience includes more than 300 patients with a minimum follow-up of one year. Of these patients, 52% showed a good to excellent analgesic effect. The TGES-induced analgesia was persistent in long term-follow-up in all patients. The impact of TGES on cerebral pain modulation was proven by electrophysiology and PET. TGES is an effective, minimally invasive and reversible treatment option in selected patients with trigeminopathic pain; it should, therefore, always be considered as the primary treatment-option. Electrodes with two leads and a diameter not exceeding the 0.9 mm, allowing bipolar stimulation might enhance the neuromodulatory efficacy and options of TGES. PMID- 17691295 TI - Neuromodulatory approaches to the treatment of trigeminal autonomic cephalalgias. AB - The trigeminal autonomic cephalalgias (TACs) are a group of primary headache syndromes characterised by intense pain and associated activation of cranial parasympathetic autonomic outflow pathways out of proportion to the pain. The TACs include cluster headache, paroxysmal hemicrania and SUNCT (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing). The pathophysiology of these syndromes involves activation of the trigeminal-autonomic reflex, whose afferent limb projects into the trigeminocervical complex in the caudal brainstem and upper cervical spinal cord. Functional brain imaging has shown activations in the posterior hypothalamic grey matter in TACs. This paper reviews the anatomy and physiology of these conditions and the brain imaging findings. Current treatments are summarised and the role of neuromodulation procedures, such as occipital nerve stimulation and deep brain stimulation in the posterior hypothalamus are reviewed. Neuromodulatory procedures are a promising avenue for these highly disabled patients with treatment refractory TACs. PMID- 17691296 TI - Deep brain stimulation for neuropathic pain. AB - Deep brain stimulation (DBS) for pain was one of the earliest indications for the therapy. This study reports the outcome of DBS of the sensory thalamus and the periventricular and peri-aqueductal grey area (PVG/PAG) complex for different intractable neuropathic pain syndromes. Forty-seven patients (30 males and 17 females) were selected for surgery; they were suffering from any of the following types of pain: post-stroke neuropathic pain, phantom limb pain, post-herpetic neuralgia, anaesthesia dolorosa, brachial plexus injury and neuropathic pain secondary to neural damage from a variety of causes. Of the 47 patients selected for trial stimulation, 38 patients proceeded to permanent implantation. Patients suffering from post-stroke pain were the most likely to fail trial stimulation (33%), in contrast to individuals with phantom limb/post-brachial plexus injury pain and anaesthesia dolorosa, all of whom underwent permanent implantation. PVG stimulation alone was optimal in 17 patients (53%), whilst a combination of PVG and thalamic stimulation produced the greatest degree of analgesia in 11 patients (34%). Thalamic stimulation alone was optimal in 4 patients (13%). DBS of the PVG alone was associated with the highest degree of pain alleviation, with a mean improvement of 59% (p <0.001) and a > or =50% improvement in 66% of patients. Post-stroke pain responds in 70% of patients. We conclude that the outcomes of surgery appear to vary according to aetiology, but it would appear that the effects are best for phantom limb syndromes, head pain and anaesthesia dolorosa. PMID- 17691297 TI - Surgical considerations in movement disorders: deep brain stimulation, ablation and transplantation. AB - Surgical therapy for movement disorders has been practiced since the early 20th century, mostly for Parkinson's disease. At its onset, large destructive procedures like open resection of cortex, parts of the basal ganglia or its fibre connections produced variable, ill-documented results. With the introduction of the stereotactic operating technique in the second half of the century, ablative surgery became more refined, and more selective interventions became possible to alleviate the suffering of those patients for whom no other treatment modalities were yet available. However, the introduction of levodopa-based pharmacological therapy pushed surgical therapy almost completely to the background. In the past two decades, there has been a resurgence of interest in surgery for movement disorders, due to both limitations of long-term pharmacological therapy and the advent of the treatment modality of deep brain stimulation. The subject has now grown into a large field of clinical and scientific interest. Parkinson's disease is the most widespread surgical indication, but in other movement disorders considerable improvement can be achieved by surgery as well, most notably in dystonia. A short review of the surgical therapy for these disorders is presented. PMID- 17691298 TI - Deep brain stimulation and chemical neuromodulation: current use and perspectives for the future. AB - During the last decade there has been a marked increase in the applications of deep brain stimulation for the treatment of neurological and psychiatric disorders. In addition, the last years were marked by the first studies using the intraparenchymal administration of drugs into the brain. There have been improvements in outcome and an increase in the number of surgical candidates and conditions to be treated. This will act as a driving force to improve the technology applied to design and manufacture new devices. PMID- 17691299 TI - GDNF delivery for Parkinson's disease. AB - The mainstays of Parkinson's disease (PD) treatment remain symptomatic, including initial dopamine replacement and subsequent deep brain stimulation, however, neither of these approaches is neuroprotective. Neurotrophic factors - proteins that activate cell signalling pathways regulating neuronal survival, differentiation, growth and regeneration - represent an alternative for treating dopaminergic neurons in PD but are difficult to administer clinically because they do not pass through the blood-brain barrier. Glial cell line-derived neurotrophic factor (GDNF) has potent neurotrophic effects particularly but not exclusively on dopaminergic neurons; in animal models of PD, it has consistently demonstrated both neuroprotective and neuroregenerative effects when provided continuously, either by means of a viral vector or through continuous infusion either into the cerebral ventricles (ICV) or directly into the denervated putamen. This led to a human PD study in which GDNF was administered by monthly bolus intracerebroventricular injections, however, no clinical benefit resulted, probably because of the limited penetration to the target brain areas, and instead significant side effects occurred. In an open-label study of continuous intraputamenal GDNF infusion in five patients (one unilaterally and four bilaterally), we reported excellent tolerance, few side effects and clinical benefit evident within three months of the commencement of treatment. The clinical improvement was sustained and progressive, and by 24-months patients demonstrated a 57 and 63% improvement in their off-medication motor and activities of daily living UPDRS subscores, respectively, with clear benefit in dyskinesias. The benefit was associated with a significant increase in putamenal 18F-dopa uptake on positron emission tomography (PET), and in one patient coming to autopsy after 43 months of unilateral infusion there was evident increased tyrosine hydroxylase immunopositive nerve fibres in the infused putamen. A second open trial in 10 patients using unilateral intraputamenal GDNF infusions has also demonstrated a greater than 30% bilateral benefit in both on- and off-medication scores at 24 weeks. Based on our 6-month results, a randomized controlled clinical trial was conducted to confirm the open-label results, however, GDNF infusion over 6-months did not confer the predetermined level of clinical benefit to patients with PD despite increased 18F-dopa uptake surrounding the catheter tip. It is possible that technical differences between this trial and the positive open label studies contributed to this negative outcome. PMID- 17691300 TI - Neuronal networks of the basal ganglia and the value of recording field potentials from them. AB - The basal ganglia constitute parts of highly sophisticated and complex neuronal networks, which represent essential elements of functional circuits, actively involved in the control of movement. The physiologic properties of these networks and their interchange with different brain areas could serve as a model for the pathophysiologic explanation of various movement disorders, particularly Parkinson's disease. Stimulation of these networks and subsequent recording of the evoked Local Field Potentials is currently used not only for understanding the pathophysiology of movement disorders but also for the physiologic localization of the anatomical target during deep brain stimulation procedures. An overview of the currently available research and clinical data from the recording of Local Field Potentials as well as the advantages, the disadvantages and the limitations of this methodology are presented in this chapter. PMID- 17691301 TI - Technical aspects and considerations of deep brain stimulation surgery for movement disorders. AB - Deep brain stimulation (DBS) represents one of the more recent advancements in Neurosurgery. Even though its most successful applications evolved in movement disorders (MDs), indications now include pain, psychiatric disorders, epilepsy, cluster headaches and Tourette syndrome. As this type of surgery gains popularity and the indications for DBS surgery increase, so it will certainly increase the number of neurosurgeons who will use this neuromodulatory technique. A detailed description of the technical aspects of the DBS procedure, as it is performed in our department, is presented. In our opinion, our method is a good combination of all the well-established necessary techniques in a cost-effective way. This technical article may be helpful to neurosurgeons considering to start performing this type of surgery. It could also prompt others who perform DBS regularly to express their views, and hence, lead to further refinement of this demanding procedure. PMID- 17691302 TI - Deep brain stimulation for Parkinson's disease. AB - Indications for the treatment of Parkinson's disease (PD) with deep brain stimulation (DBS) are severe, therapy refractory tremor and complications of long term levodopa uptake. Since its first application DBS has become a standard therapy for these patients. Theoretically, the ventrolateral part of the internal pallidum (GPI) or the subthalamic nucleus (STN) are suitable targets in order to treat all cardinal symptoms of patients in an advanced stage of PD stereotactically. Although clinical efficacy of both GPI or STN stimulation is obviously comparable, it has become widely accepted to prefer STN over GPI DBS. If PD-associated, medically intractable tremor is the most disabling symptom, stimulation of the ventrolateral motor thalamus can be an alternative. Anatomical targets for DBS are small and located in critical brain areas. Furthermore, this type of surgery is highly elective. As a consequence, high resolution multiplanar imaging and adequate treatment planning software are indispensable prerequisites for DBS surgery. Currently, commercially available impulse generators deliver a permanent high frequency periodic pulse train stimulation that interacts rather unspecifically with the firing pattern of both normal and pathological neurons. Prospectively, the development of more specific stimulation paradigms may help to improve the efficacy of this treatment modality. PMID- 17691303 TI - Neuromodulation of prelemniscal radiations in the treatment of Parkinson's disease. AB - In patients with Parkinson's disease (PD), tetrapolar electrodes were implanted in the prelemniscal radiations (RAPRL) to treat tremor, rigidity and bradykinesia. Fifteen patients were implanted unilaterally and five patients bilaterally and followed-up for one year. The selection criteria included the presence of unilateral pronounced tremor and rigidity in patients implanted unilaterally or bilateral symptoms including severe bradykinesia in patients implanted bilaterally. In the operating room, the tremor decreased significantly or was abolished following the insertion of the electrode in the RAPRL. This effect was temporary and subsided when the stimulation was off. However, when the stimulator was turned on, the severity of the symptoms and signs decreased significantly. The post-implantation MRI confirmed that the electrode contacts used for stimulation were inserted in RAPRL, a group of fibers located between the red nucleus and subthalamic nucleus, above the substantia nigra, medially to the zona incerta and below the thalamus. The patients were evaluated using the UPDRS part III, before implantation and every 3 months during the first year. Global scores decreased significantly. The pre- and postoperative median values (range in round brackets) were as follows: tremor improved from 3 (2-16) to 1 (2 3) (p<0.001); rigidity was either abolished or decreased markedly from 2 (1-16) to 0 (0-4) (p< 0.001); bradykinesia improved from 2 (0-4) to 1 (0-2) (p<0.001). We conclude that RAPRL, an area anatomically different from STN, is a good target for electrical stimulation in order to treat effectively all the main symptoms of PD. PMID- 17691304 TI - Deep brain stimulation for torsion dystonia. AB - Deep brain stimulation (DBS) at the globus pallidus pars internus (GPi) is an effective treatment for some patients with medically refractory torsion dystonia. In this chapter we review the classification and treatment of torsion dystonia including the current indications for DBS surgery. Details of the DBS procedure and programming of the DBS devices are discussed. Pallidal DBS is most effective in patients with primary generalized dystonia. Children and adolescents possessing the DYT1 gene mutation may respond best of all. Patients with cervical dystonia may also improve with pallidal DBS but definitive clinical evidence is lacking. As a group, patients with secondary dystonias respond less well to DBS than do patients with primary dystonia; however, patients with dystonia secondary to anoxic brain injury who have grossly intact basal ganglia anatomy, and patients with tardive dystonia may represent secondary dystonia subtypes for whom pallidal DBS is a viable option. PMID- 17691305 TI - Deep brain stimulation for treatment of cervical dystonia. AB - Pallidal deep brain stimulation is an efficient treatment option in those patients with cervical dystonia who do not benefit from conservative treatment including local botulinum toxin injections. Given the fact that other surgical treatment options such as selective peripheral denervation are available, it may be considered third-line treatment in most instances. Chronic bilateral pallidal stimulation improves dystonic posture and movements, pain caused by dystonia and disability related to dystonia. Preliminary data on longterm follow-up confirm its beneficial effect in the majority of patients. Given the frequency of cervical dystonia, pallidal deep brain stimulation will play a major role in the future. PMID- 17691306 TI - Subthalamic nucleus stimulation for primary dystonia and tardive dystonia. AB - With the renaissance of stereotactic pallidotomy for Parkinson's disease in 1990s, pallidotomy has become increasingly used as an effective treatment for various manifestations of medically refractory dystonia. More recently, deep brain stimulation of globus pallidus internus (GPi) has been replacing pallidotomy. Although GPi DBS has great promise for treating dystonia, there are some disadvantages. We introduce our experiences in subthalamic nucleus (STN) DBS for primary dystonia and tardive dystonia in this chapter. We propose that STN DBS has the following advantages over GPi DBS: (1) symptomatic improvement is seen immediately after stimulation, allowing us to quickly select the most suitable stimulation parameters; (2) the stimulation parameters for the STN are lower than those used for the GPi, resulting in longer battery life; and (3) STN DBS results in better symptomatic control than GPi DBS in dystonia patients when our STN data is compared to that obtained by others with using the GPi as the target. We suggest that STN DBS may be the most appropriate surgical technique for dystonia. PMID- 17691307 TI - DBS in tourette syndrome: rationale, current status and future prospects. AB - Tourette syndrome is a neuropsychiatric disorder with onset in early childhood and characterized by tics, often associated with behavioural abnormalities. Symptoms often disappear before or during adulthood. Treatment consists of psychotherapy or pharmacotherapy. A small percentage of patients is treatment refractory. After the introduction of deep brain stimulation (DBS) of the thalamus as a new therapeutical approach in 1999, several other brain nuclei have been targeted in a small number of patients, like the globus pallidus internus, anteromedial and ventroposterolateral part, and the nucleus accumbens. In the published reports, a tic reduction rate of at least 66% is described. The effects of DBS on associated behavioural disorders are more variable. The number of treated patients is small and it is unclear whether the effects of DBS are dependent on the target nucleus. The pathophysiology of Tourette syndrome is not well understood. On the basis of our current knowledge of cortico-basal ganglia thalamocortical circuits, an explanation for the beneficial effects of DBS on tics is proposed. It is concluded that a meticulous evaluation of the electrode position, and a blinded assessment of the clinical effects on tics and behavioural disorders, is absolutely mandatory in order to identify the best target of DBS for Tourette syndrome. PMID- 17691308 TI - Extradural cortical stimulation for movement disorders. AB - Extradural cortical stimulation is a recent addition to the armamentarium of operative neuromodulation. Motor cortex stimulation (MCS) is offered by positioning a stimulating plate extradurally on the primary motor cortex. It is a minimally invasive technique that was originally proposed for the control of central neuropathic pain. Currently, its use has been extended to patients with movement disorders. The need for minimally invasive therapies, with low morbidity mortality which can be applied to patients who are excluded from deep brain stimulation (DBS), led to the first attempt of MCS in Parkinson's disease (PD). Following the demonstration that transcranial magnetic stimulation (TMS) is beneficial in PD, we attempted direct extradural MCS on patients with advanced PD not meeting the criteria for DBS. The mechanisms of action may include "hyperdirect" motor cortex-subthalamic nucleus (MI-STN) input, inhibition, resynchronisation, plasticity changes, interhemispheric transfer of inhibition/excitation and modulation of other cortical areas. In this article, we review the mechanism of action of MCS in movement disorders, the predictive factors of MCS efficacy in PD, the indications, particularly in the elderly who are not suitable for DBS, the adverse effects, and the technique for localization of the central sulcus and for performing the procedure. The future prospects and developments are also discussed. PMID- 17691309 TI - Motor cortex stimulation for Parkinson's disease. AB - In 2000, Canavero and Paolotti reported the improvement of symptoms in a case of advanced Parkinson disease (PD), following chronic epidural motor cortex stimulation (MCS). In 2002, the same group reported the results obtained in 2 patients with PD. Unilateral MCS proved to be beneficial bilaterally. They concluded that MCS may represent a cost-effective alternative to deep brain stimulation. In 2003, Pagni promoted an Italian Multicenter Study and in June 2005 the results in the first 29 cases were reported. Any symptom of PD could be modulated by MCS, but improvement of different symptoms was variable and unpredictable, with some patients being unresponsive. L-Dopa induced dyskinesias, painful dystonia and motor fluctuations were satisfactorily controlled. In the author's series, 2 patients were unresponsive and 5 patients showed a clinical improvement, particularly evident in the off-medication state; UPDRS-III mean improvement was 30% at 3 months and 22% at 12 months. Quality of life (QOL) also improved. Assessment by the Parkinon's disease quality of life (PDQL) scale showed a mean decrease by 26% at 12 months. No complication or adverse events were observed. These preliminary data indicated the possibility to modulate PD symptoms by MCS. Several unsettled issues remain such as the optimal electrode position, the best stimulation parameters, the usefulness of unilateral versus bilateral stimulation, the prognostic factors for best selection of patients, and the optimal assessment of clinical effects. The mechanisms of MCS may be only the subject of hypothesis. PMID- 17691310 TI - Stereotactic stimulation of the anterior lobe of the cerebellum in cerebral palsy from a suboccipital approach. AB - The anatomical connections of the anterior lobe of the cerebellum with the reticular formation in the brainstem, upper motor neurons and the limbic system, as well as the results of experimental and clinical observations indicate that this region is a proper area for modulation of certain types of central motor disorders but also of limbic functions. Through a direct stereotacticaly suboccipital approach electrodes were introduced into the anterior lobe of the cerebellum in four patients (3 females and one male, 24, 29, 45 and 19 years old, respectively) suffering from cerebral palsy and being confined to a wheelchair with severe spastic choreoathetoid movements, with minimal hand function, but in good mental state. After a period of test stimulation (up to 10 days), the pulse generators were implanted and chronic high-frequency stimulation was applied (for 37, 58, 9 and 32 months, respectively). In agreement with our previous experience (transtentorial approach in 30 patients), noticeable improvements in spasticity were immediate and a gradual reduction in choreoatetoid movements was observed in the following days to weeks. Improvements in speech, swallowing, respiration, posture, ambulation, and mood states were combined with development of new motor skills. Caution with the proper positioning of the electrode in the target and the selection of optimal program for stimulation are of paramount importance. PMID- 17691311 TI - Electrical stimulation devices in the treatment of epilepsy. AB - Over the last ten years there has been a progressively increasing interest in the research and clinical application of implantable electrical brain stimulation devices in the treatment of drug-resistant epilepsy. The concept is not new, but the efforts were strengthened and accelerated after the efficacy of vagus nerve stimulation in controlling epilepsy was first demonstrated in the early 1990s and gained subsequently the approval of the USA Food and Drug Administration in 1997. This chapter reviews the progress made in this field. Special emphasis is given to the most important available evidence from animal and human studies, the neuroanatomical pathways and the role of the relevant neurotransmitters, the stimulation devices and the significance of correct programming of the stimulation parameters. The chapter also examines the antiepileptic efficacy of stimulation in all the known targets including vagus nerve, cerebellum, thalamus, subthalamic nucleus, locus ceruleus, and epileptogenic cortex. On the basis of the current evidence, the future directions of this exciting field are described. PMID- 17691312 TI - Brain stimulation for epilepsy. AB - Brain stimulation has been receiving increasing attention as an alternative therapy for epilepsy that cannot be treated by either antiepileptic medication or surgical resection of the epileptogenic focus. The stimulation methods include transcranial magnetic stimulation (TMS) or electrical stimulation by implanted devices of the vagus nerve (VNS), deep brain structures (DBS) (thalamic or hippocampal), cerebellar or cortical areas. TMS is the simplest and least invasive approach. However, the most common epileptogenic areas (mesial temporal structures) probably lie too deep beneath the surface of the skull for effective TMS. The efficacy of VNS in reducing the frequency or severity of seizures is quite variable and depends on many factors which are currently investigated. VNS is well-tolerated and approved in many countries. DBS is much more invasive than either TMS or VNS. Currently, a number of targets for DBS are investigated including caudate, centromedian or anterior thalamic nuclei, and subthalamic nucleus. Direct stimulation of the epileptic cortical focus is another approach to the neuromodulation in epilepsy. Finally, another line of research investigates the usefulness of implantable seizure detection devices. The current chapter presents the most important evidence on the above methods. Furthermore, other important issues are reviewed such as the selection criteria of patients for brain stimulation and the potential role of brain stimulation in the treatment of depression in epileptic patients. PMID- 17691313 TI - Clinical experience with vagus nerve stimulation and deep brain stimulation in epilepsy. AB - Patients with refractory epilepsy present a particular challenge to new therapies. Vagus nerve stimulation (VNS) for the control of intractable seizures has become available since 1989. VNS is a relatively noninvasive treatment. It reduces seizure frequency by > or =50% in 1/3 of patients; an additional 1/3 of patients experience a worthwhile reduction of seizure frequency between 30 and 50%. In the remaining 1/3 of the patients there is little or no effect. Efficacy has a tendency to improve with longer duration of treatment up to 18 months postoperatively. Deep brain stimulation (DBS) or direct electrical stimulation of brain areas is an alternative neurostimulation modality. The cerebellum, various thalamic nuclei, the pallidum, and, more recently, medial temporal lobe structures have been chosen as targets. DBS for epilepsy is beyond the stage of proof-of-concept but still needs thorough evaluation in confirmatory pilot studies before it can be offered to larger patient populations. Analysis of larger patient groups and insight in the mode of action may help to identify patients with epileptic seizures or syndromes that respond better either to VNS or to DBS. Randomized and controlled studies in larger patient series are mandatory to identify the potential treatment population and optimal stimulation paradigms. Further improvements of clinical efficacy may result from these studies. PMID- 17691314 TI - Vagus nerve stimulation: indications and limitations. AB - Vagus nerve stimulation (VNS) is an established treatment for selected patients with medically refractory seizures. Recent studies suggest that VNS could be potentially useful in the treatment of resistant depressive disorder. Although a surgical procedure is required in order to implant the VNS device, the possibility of a long-term benefit largely free of severe side effects could give VNS a privileged place in the management of resistant depression. In addition, VNS appears to affect pain perception in depressed adults; a possible role of VNS in the treatment of severe refractory headache, intractable chronic migraine and cluster headache has also been suggested. VNS is currently investigated in clinical studies, as a potential treatment for essential tremor, cognitive deficits in Alzheimer's disease, anxiety disorders, and bulimia. Finally, other studies explore the potential use of VNS in the treatment of resistant obesity, addictions, sleep disorders, narcolepsy, coma and memory and learning deficits. PMID- 17691315 TI - Vagus nerve stimulation for intractable epilepsy: outcome in two series combining 90 patients. AB - Vagus nerve stimulation (VNS) is the most widely used non-pharmacological treatment for medically intractable epilepsy and has been in clinical use for over a decade. It is indicated in patients who are refractory to medical treatment or who experience intolerable side effects, and who are not candidates for resective surgery. VNS used in the acute setting can both abort seizures and have an acute prophylactic effect. This effect increases over time in chronic treatment to a maximum at around 18 months. The evidence base supporting the efficacy of VNS is strong, but its exact mechanism of action remains unknown. A vagus nerve stimulator consists of two electrodes embedded in a silastic helix that is wrapped around the cervical vagus nerve. The stimulator is always implanted on the left vagus nerve in order to reduce the likelihood of adverse cardiac effects. The electrodes are connected to an implantable pulse generator (IPG) which is positioned subcutaneously either below the clavicle or in the axilla. The IPG is programmed by computer via a wand placed on the skin over it. In addition, extra pulses of stimulation triggered by a hand-held magnet may help to prevent or abort seizures. VNS is essentially a palliative treatment and the number of patients who become seizure free is very small. A significant reduction in the frequency and severity of seizures can be expected in about one third of patients and efficacy tends to improve with time. Vagus nerve stimulation is well tolerated and has few significant side effects. We describe our experience on the use of VNS on drug-resistant epilepsy in 90 patients treated in two departments (in Athens, Greece and Newcastle, England). PMID- 17691316 TI - Electrical stimulation and gene-based neuromodulation for control of medically refractory epilepsy. AB - The failure of available antiepileptic medications to adequately control seizures in a substantial number of patients underscores the need to develop novel epilepsy therapies. Recent advancements in technology and the success of neuromodulation in treating a variety of neurological disorders have spurred interest in exploring promising therapeutic alternatives, such as electrical stimulation and gene-based synaptic control. A variety of different stimulation approaches to seizure control targeting structures in the central or peripheral nervous system have been investigated. Most studies have been based on uncontrolled observations and empirical stimulation protocols. Today the vagus nerve stimulator is the only FDA approved adjunctive treatment for epilepsy that utilizes electrical stimulation. Other potential strategies including direct stimulation of the epileptogenic cortex and deep brain stimulation of various targets are currently under investigation. Chronically implanted devices for electrical stimulation have a variety of limitations. First, they are susceptible to malfunction and infection. Second, most systems require battery replacement. Finally, electrical stimulation is incapable of manipulating neuronal function in a transmitter specific fashion. Gene delivery to epileptogenic targets or targets implicated in regulating seizure threshold has been investigated as an alternative means of neuromodulation in animal models. In summary, positive preliminary results and the lack of alternative treatment options provide the impetus for further exploration of electrical stimulation and gene-based therapies in pharmacoresistant epilepsy. Various specific targets and approaches to modulating their activity have been investigated in human studies. PMID- 17691317 TI - Rationale, mechanisms of efficacy, anatomical targets and future prospects of electrical deep brain stimulation for epilepsy. AB - Electrical stimulation of deep brain structures is a promising new technology for the treatment of medically intractable seizures. Performed in vitro and on animal models of epilepsy, electrical stimulation has shown to reduce seizure frequency. Preliminary results on humans are encouraging. However, such improvements emerge despite a lack of understanding of the precise mechanisms underlying electrical stimulation either delivered directly on the epileptogenic zone (direct control) or through an anatomical relay of cortico-subcortical networks (remote control). Anatomical targets such as the thalamus (centromedian nucleus, anterior thalamus, mamillary body and mamillothalamic tracts), the subthalamic nucleus, the caudate nucleus and direct stimulation of the hippocampal formation have been successfully investigated. Although randomized controlled studies are still missing, deep brain stimulation is a promising treatment option for a subgroup of carefully selected patients with intractable epilepsy who are not candidates for resective surgery. The effectiveness, the optimal anatomic targets, the ideal stimulation parameters and devices, as well as patient selection criteria are still to be defined. PMID- 17691318 TI - Anatomical and physiological basis and mechanism of action of neurostimulation for epilepsy. AB - Neurostimulation is an emerging treatment for neurological diseases. Different types of neurostimulation exist mainly depending of the part of the nervous system that is being affected and the way this stimulation is being administered. Vagus nerve stimulation (VNS) is a neurophysiological treatment for patients with medically or surgically refractory epilepsy. Over 30,000 patients have been treated with VNS. No clear predictive factors for responders have been identified. To date, the precise mechanism of action remains to be elucidated. Better insight in the mechanism of action may identify seizure types or syndromes that respond better to VNS and may guide the search for optimal stimulation parameters and finally improve clinical efficacy. Deep brain stimulation (DBS) has been used extensively as a treatment for movement disorders. Several new indications such as obsessive compulsive behaviour and cluster headache are being investigated with promising results. The vast progress in biotechnology along with the experience in other neurological diseases in the past ten years has led to a renewed interest in intracerebral stimulation for epilepsy. Epilepsy centers around the world have recently reinitiated trials with deep brain stimulation in different intracerebral structures such as the thalamus, the hippocampus and the subthalamic nucleus. PMID- 17691319 TI - The role of neuromodulation of the hippocampus in the treatment of intractable complex partial seizures of the temporal lobe. AB - We present the results of chronic electrical stimulation of the hippocampus (ESH) in 9 patients with complex partial seizures and at least 18 months follow-up. The magnetic resonance imaging (MRI) scan was normal in 5 while in 4 patients it showed hippocampal sclerosis. The seizure frequency ranged from 10 to 50 seizures per month. All patients were submitted to implantation of diagnostic 8-contact bilateral hippocampal depth electrodes to determine the location of epileptic foci. Once the focus was located, the diagnostic electrodes were replaced by deep brain stimulation (DBS) electrodes. Following DBS, all patients improved. With respect to outcome, patients were divided in two groups, one seizure-free (5 patients) and the other with residual seizures (4 patients). Both groups shared similar clinical features. However, the patients who were seizure free had normal MRI scan while those who had residual seizures were being stimulated on a sclerotic hippocampus. We conclude that electrical stimulation of the epileptic hippocampal formation can control mesial temporal seizures. Best results are obtained if we stimulate a hippocampus which does not show sclerosis in the MRI. In these cases, seizures are stopped and the recent memory tests improve even in patients with bilateral foci. This result is of extreme importance to patients who have either intractable seizures and normal MRI or bilateral epileptogenic foci, are excluded as candidates for temporal lobectomy and are left with no other alternative. PMID- 17691320 TI - Neurosurgical aspects of temporal deep brain stimulation for epilepsy. AB - Deep brain stimulation (DBS), which mimics the effect of ablative surgery in movement disorders, is considered by analogy as potentially useful in the epileptic temporal lobe as an alternative to resection. It could be applied to patients in whom resective surgery is less beneficial, e.g. cases without memory impairment or with bilateral hippocampal involvement. In patients who undergo invasive presurgical analysis, the necessary intrahippocampal leads can serve for the application of DBS, provided that they are suited for chronic use. The hippocampus, in which the focus of epilepsy is detected, is stimulated continuously using high-frequency square-wave pulses. The reduction of interictal spike activity during a period of acute stimulation is the criterion for deciding whether the leads will be connected to an internal pulse generator. We are conducting a pilot study, with 16 patients enrolled so far, ten of whom have been followed up for more than one year. Some theoretical considerations are dedicated to hippocampal DBS. PMID- 17691321 TI - Deep brain stimulation for treatment of the epilepsies: the centromedian thalamic target. AB - Electrical stimulation (ES) of the thalamic centromedian nucleus (CMN) has been proposed as a minimally invasive alternative for the treatment of difficult-to control seizures of multifocal origin and seizures that are generalized from the onset. ES intends to interfere with seizure propagation in a non-specific manner through the thalamic system. By adopting a frontal parasagittal approach and based on anterior-posterior (AC-PC) commissure intersection, deep brain stimulation (DBS) electrodes are stereotactically inserted. Electrophysiologic confirmation of electrodes position is accomplished by eliciting cortical recruiting responses and direct current (DC) shifts by low- and high-frequency stimulation through the electrodes. Cycling mode of bipolar stimulation has been used at 60-130 Hz, 0.45 msec, 2.5-3.5 V, 1 min ON in one side 4 min OFF, 1 min ON in the other side and 4 min OFF forward and back for 24h. ES of CMN significantly decreases generalized seizures of cortical origin and focal motor seizures. Best results are obtained in non-focal generalized tonic clonic seizures and atypical absences of the Lennox-Gastaut syndrome. Experience has indicated that the most effective target for seizure control is the thalamic parvocellular centromedian subnucleus. PMID- 17691322 TI - Anterior thalamic nucleus stimulation for epilepsy. AB - One option for treatment of medically refractory debilitating epilepsy is stimulation of the anterior thalamic nucleus, which projects via the cingulate gyrus to limbic structures and neocortex. In this chapter we describe the technique for anterior thalamic deep brain stimulation and report outcomes of early series of patients. The prospective double-blind randomized Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) trial will evaluate the efficacy of this technique for epilepsy treatment. PMID- 17691323 TI - Cerebellar and thalamic stimulation treatment for epilepsy. AB - The present chapter describes the most important available experimental and clinical evidence on the role of electrical stimulation of the cerebellum or the thalamus in the control of epilepsy. Cerebellum serves as an integrator of sensory information and regulator of motor coordinating and training. The sole output of the cerebellum is inhibitory Purkinje cell projections to deep cerebellar nuclei in the brainstem. Cerebellar stimulation in animal models of epilepsy has given mixed results. Nevertheless, more than 130 epileptic patients have been subjected to cerebellar stimulation and the results from uncontrolled studies have been encouraging. The anterior thalamic nucleus (ATN) is part of the Papez circuit, a group of limbic structures with demonstrated role in epilepsy. The centromedian thalamic nucleus (CMN) is considered part of the thalamic reticular system. Stimulation of either of these nuclei in experimental animals has been associated with considerable antiepileptic effects. On the basis of the research evidence, numerous studies have been done on humans, which gave promising results. Currently, a multicenter trial on stimulation of the ATN, the SANTE trial is in progress in the USA. On the basis of the reported studies, the authors aim to provide insights into how the electrical stimulation of the above structures exerts an antiepileptic effect and also provide suggestions regarding the future progress in this field. PMID- 17691324 TI - A novel closed-loop stimulation system in the control of focal, medically refractory epilepsy. AB - The concept of seizure abortion after prompt detection by employing stimulation is a very appealing one. Several investigators in previous experimental and clinical studies have used stimulation of various anatomical targets with promising results. In this chapter, the authors present their experience with a novel, implantable, local closed-loop responsive neuro-stimulation system (RNS) (Neuropace, Inc., Mountain View, CA, USA). This system consists of a cranially implanted pulse generator, one or two quadripolar subdural strip or depth leads and an external programmer. The system components and technical characteristics are presented. The criteria for selecting candidates for implantation as well as the preliminary results of a clinical trial are also presented. Closed-loop stimulation system appears to be a safe treatment option with promising results for the management of patients with well-localized, focal medically-refractory epilepsy, who are not candidates for surgical resection. PMID- 17691325 TI - Neurosurgery for psychiatric disorders: from the excision of brain tissue to the chronic electrical stimulation of neural networks. AB - Neurosurgical treatment for psychiatric disorders has a long and controversial history dating back to antiquity. Both enthusiastic reports and social outcry have accompanied psychosurgical practice, particularly over the last century. Frontal lobotomy has probably been the only medical advance which was first awarded a Nobel prize in medicine and then irreparably stigmatized by scientific rejection and public criticism. In the present paper, the historical milestones of psychosurgery are briefly overviewed. The particular circumstances of the rise and fall of frontal lobotomy are also discussed. Furthermore, the clinical and surgical considerations of the four major psychosurgical procedures which are still in practice are presented. Over the last fifteen years, the advent of deep brain stimulation (DBS) methodology coupled with accurate stereotactic techniques and guided by elaborate neuroimaging methods have revolutionized neurosurgery, particularly for the alleviation of certain disabling movement disorders. Investigationally, chronic electrical stimulation of selected brain structures, clearly implicated in the pathophysiology of neuropsychiatric disorders, has already been applied with promising results. Given the tainted past of psychiatric neurosurgery, modern neuroscientists have to move forward cautiously, in a scientifically justified and ethically approved framework. The transition from the indiscriminate destruction of brain structures to the selected electrical modulation of neural networks lies ahead; contemporary neuroscientists would substantiate this aim but should remind the controversial history of the field. PMID- 17691326 TI - Behavioural and physiological effects of electrical stimulation in the nucleus accumbens: a review. AB - Electrical stimulation (ES) in the brain is becoming a new treatment option in patients with treatment-resistant obsessive-compulsive disorder (OCD). A possible brain target might be the nucleus accumbens (NACC). This review aims to summarise the behavioural and physiological effects of ES in the NACC in humans and in animals and to discuss these findings with regard to neuroanatomical, electrophysiological and behavioural insights. The results clearly demonstrate that ES in the NACC has an effect on reward, activity, fight-or-flight, exploratory behaviour and food intake, with evidence for only moderate physiological effects. Seizures were rarely observed. Finally, the results of ES studies in patients with treatment-resistant OCD and in animal models for OCD are promising. PMID- 17691327 TI - Neuromodulation of the inferior thalamic peduncle for major depression and obsessive compulsive disorder. AB - Neuromodulation of the inferior thalamic peduncle is a new surgical treatment for major depression and obsessive-compulsive disorder. The inferior thalamic peduncle is a bundle of fibers connecting the orbito-frontal cortex with the non specific thalamic system in a small area behind the fornix and anterior to the polar reticular thalamic nucleus. Electrical stimulation elicits characteristic frontal cortical responses (recruiting responses and direct current (DC)-shift) that confirm correct localization of this anatomical structure. A female with depression for 23 years and a male with obsessive-compulsive disorder for 9 years had stereotactic implantation of electrodes in the inferior thalamic peduncle and were evaluated over a long-term period. Initial OFF stimulation period (1 month) showed no consistent changes in the Hamilton Depression Scale (HAM-D), Yale Brown Obsessive Compulsive Scale (YBOCS), or Global Assessment of Functioning scale (GAF). The ON stimulation period (3-5 V, 130-Hz frequency, 450-msec pulse width in a continuous program) showed significant decrease in depression, obsession, and compulsion symptoms. GAF improved significantly in both cases. The neuropsychological tests battery showed no significant changes except from a reduction in the perseverative response of the obsessive-compulsive patient and better performance in manual praxias of the female depressive patient. Moderate increase in weight (5 kg on average) was observed in both cases. PMID- 17691328 TI - Chronic high frequency stimulation of the posteromedial hypothalamus in facial pain syndromes and behaviour disorders. AB - Chronic high frequency stimulation (HFS) of the posteromedial hypothalamus (PMH) has been the first direct therapeutic application of functional neuroimaging data in a restorative reversible procedure for the treatment of an otherwise refractory neurological condition; in fact, the target coordinates for the stereotactic implantation of the electrodes have been provided by positron emission tomography (PET) studies, which were performed during cluster headache attacks. HFS of PMH produced a significant and marked reduction of pain attacks in patients with chronic cluster headache (CCH) and in one patient with short lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). The episodes of violent behaviour and psychomotor agitation during the attacks of CCH supported the idea that the posteromedial hypothalamus could be also involved in the control of aggressiveness; this has been previously suggested, in the seventies, by the results obtained in Sano's hypothalamotomies for the treatment of abnormal aggression and disruptive behaviour. On the basis of these considerations, we have performed HFS of the PMH and controlled successfully violent and disruptive behaviour in patients refractory to the conventional sedative drugs. Finally, we also tested the same procedure in three patients with refractory atypical facial pain, but unfortunately, they did not respond to this treatment. PMID- 17691329 TI - Vagus nerve stimulation for depression: rationale, anatomical and physiological basis of efficacy and future prospects. AB - Treatment-resistant depression (TRD) is a major public health concern due to its high costs to society. One of the novel approaches for the treatment of depression is the vagus nerve stimulation (VNS). Therapeutic brain stimulation through delivery of pulsed electrical impulses to the left cervical vagus nerve now has established safety and efficacy as an adjunct treatment for medication resistant epilepsy and has recently been approved as an adjunct long-term treatment for chronic or recurrent depression. There is considerable evidence from both animal and human neurochemical and neuroimaging studies, that the vagus nerve and its stimulation influence limbic and higher cortical brain regions implicated in mood disorders, providing a rationale for its possible role in the treatment of psychiatric disorders. Clinical studies (open-label and comparator with treatment in naturalistic setting) in patients with TRD have produced promising results, especially when the response rates at longer-term (one- and two-year) follow-up time points are considered. Ongoing research efforts will help determine the place of VNS in the armament of therapeutic modalities available for major depression. PMID- 17691330 TI - Experimental and clinical aspects of the efferent auditory system. AB - The discovery of active mechanisms in the cochlea and the efferent auditory pathways from the brain to the cochlea demonstrated the existence of a modulation of the auditory input in the central nervous system (CNS). Otoacoustic emissions (OAEs) are weak signals that can be recorded in the ear canal and are considered a byproduct of an active process from the outer hair cells (OHCs) to the basilar membrane. The efferent auditory system plays an inhibitory role on the activity of OHCs; its stimulation reduces auditory nerve response, basilar membrane motility and OAEs amplitude. Indirect stimulation by contralateral sound is also inhibitory; a reduction of OAEs amplitude can be recorded and such an effect disappears after olivocochlear bundle section. The efferent system seems to play a role in detection of signals in noise, protection in noise-induced cochlear damage, development of hearing and processing of complex auditory signals. With respect to clinical application, OAEs suppression after contralateral auditory stimulation seems to be the only objective and non-invasive method for evaluation of the functional integrity of the medial efferent system, and, therefore, for evaluation of the structures lying along its course, at least up to the level of inferior colliculi. PMID- 17691331 TI - Functional outcome of auditory implants in hearing loss. AB - The auditory implant provides a new mechanism for hearing when a hearing aid is not enough. It is the only medical technology able to functionally restore a human sense i.e. hearing. The auditory implant is very different from a hearing aid. Hearing aids amplify sound. Auditory implants compensate for damaged or non working parts of the inner ear because they can directly stimulate the acoustic nerve. There are two principal types of auditory implant: the cochlear implant and the auditory brainstem implant. They have common basic characteristics, but different applications. A cochlear implant attempts to replace a function lost by the cochlea, usually due to an absence of functioning hair cells; the auditory brainstem implant (ABI) is a modification of the cochlear implant, in which the electrode array is placed directly into the brain when the acoustic nerve is not anymore able to carry the auditory signal. Different types of deaf or severely hearing-impaired patients choose auditory implants. Both children and adults can be candidates for implants. The best age for implantation is still being debated, but most children who receive implants are between 2 and 6 years old. Earlier implantation seems to perform better thanks to neural plasticity. The decision to receive an implant should involve a discussion with many medical specialists and an experienced surgeon. PMID- 17691332 TI - Auditory brainstem implants: current state and future directions with special reference to the subtonsillar approach for implantation. AB - In this article, the authors describe the current state of the auditory brainstem implant (ABI), comparing it to that of the cochlear implant (CI). The CI restores hearing by stimulating the cochlear nerve in the cochlea in patients whose deafness has been caused by inner ear disease; the ABI restores hearing by stimulating the cochlear nucleus of the brainstem in patients who are deaf because of bilateral cochlear nerve dysfunction. Up to now, about 500 patients worldwide have undergone ABI and had their hearing restored, most of whom suffer from neurofibromatosis type 2. Hearing performance, however, is not as good as that offered by the cochlear implant. To improve the quality of hearing, new techniques such as advanced coding strategies and penetrating electrodes, are now being introduced. PMID- 17691333 TI - Auditory brainstem implants: past, present and future prospects. AB - The purpose of the auditory brainstem implant (ABI) is to directly stimulate the cochlear nucleus complex and offer restoration of hearing in patients suffering from profound retrocochlear sensorineural hearing loss. Electrical stimulation of the auditory pathway via an ABI has been proven to be a safe and effective procedure. The function of current ABIs is similar to that of cochlear implants in terms of device hardware with the exception of the electrode array and the sound-signal processing mechanism. The main limitation of ABI is that electrical stimulation is performed on the surface of the cochlear nuclei, thereby making impractical the selective activation of deeper layers by corresponding optimal frequencies. In this article, we review the anatomical, and experimental basis of ABIs and the indications, and surgical technique for their implantation. To the best of our knowledge, we describe the first pathology images of the cochlear nucleus in a patient who had received an ABI. PMID- 17691334 TI - Twenty-five years of auditory brainstem implants: perspectives. AB - The auditory brainstem implant (ABI) provides auditory sensations, recognition of environmental sounds and aid in spoken communication in more than 300 patients worldwide. It is no more a device under investigation but it is widely accepted for the treatment of patients who have lost hearing due to bilateral tumors of the vestibulocochlear nerve. Most of these patients are completely deaf when the implant is switched off. In contrast to the cochlear implants (CI), only few of the implanted patients achieve open-set speech recognition without the help of visual cues. In the last few years, patients with lesions other than tumors have also been implanted. Auditory perceptual performance in patients who are deaf due to trauma, cochlea aplasia or other non-tumor lesions of the cochlea or the vestibulocochlear nerve turned out to be much better than in NF2 tumor patients. Until recently, the target region for ABI implantation has been the ventral cochlear nucleus (CN). The electrodes are implanted via the translabyrinthine or retrosigmoid approach. Currently, new targets along the central auditory pathways and new, minimally invasive techniques for implantation are under investigation. These techniques may further improve auditory perceptual performance in ABI patients and provide hearing to a variety of types of central deafness. PMID- 17691335 TI - Auditory cortex stimulation for tinnitus. AB - Functional imaging techniques have demonstrated a relationship between the intensity of tinnitus and the degree of reorganization of the primary auditory cortex. Studies in experimental animals and humans have revealed that tinnitus is associated with a synchronized hyperactivity in the auditory cortex and proposed that the underlying pathophysiological mechanism is thalamocortical dysrhythmia; hence, decreased auditory stimulation results in decreased firing rate, and decreased lateral inhibition. Consequently, the surrounding brain area becomes hyperactive, firing at gamma band rates; this is considered a necessary precondition of auditory consciousness, and also tinnitus. Synchronization of the gamma band activity could possibly induce a topographical reorganization based on Hebbian mechanisms. Therefore, it seems logical to try to suppress tinnitus by modifying the tinnitus-related auditory cortex reorganization and hyperactivity. This can be achieved using neuronavigation-guided transcranial magnetic stimulation (TMS), which is capable of modulating cortical activity. If TMS is capable of suppressing tinnitus, the effect should be maintained by implanting electrodes over the area of electrophysiological signal abnormality on the auditory cortex. The results in the first patients treated by auditory cortex stimulation demonstrate a statistically significant tinnitus suppression in cases of unilateral pure tone tinnitus without suppression of white or narrow band noise. Hence, auditory cortex stimulation could become a physiologically guided treatment for a selected category of patients with severe tinnitus. PMID- 17691336 TI - Implantable visual prostheses. AB - Visual impairment and blindness is primarily caused by optic neuropathies like injuries and glaucomas, as well as retinopathies like agerelated macular degeneration (MD), systemic diseases like diabetes, hypertonia and hereditary retinitis pigmentosa (RP). These pathological conditions may affect retinal photoreceptors, or retinal pigment epithelium, or particular subsets of retinal neurons, and in particular retinal ganglion cells (RGCs). The RGCs which connect the retina with the brain are unique cells with extremely long axons bridging the distance from the retina to visual relays within the thalamus and midbrain, being therefore vulnerable to heterogeneous pathological conditions along this pathway. When becoming mature, RGCs loose the ability to divide and to regenerate their accidentally or experimentally injured axons. Consequently, any loss of RGCs is irreversible and results to loss of visual function. The advent of micro- and nanotechnology, and the construction of artificial implants prompted to create visual prostheses which aimed at compensating for the loss of visual function in particular cases. The purpose of the present contribution is to review the considerable engineering expertise that is essential to fabricate current visual prostheses in connection with their functional features and applicability to the animal and human eye. In this chapter, 1) Retinal and cortical implants are introduced, with particular emphasis given to the requirements they have to fulfil in order to replace very complex functions like vision. 2) Advanced work on material research is presented both from the technological and from the biocompatibility aspect as prerequisites of any perspectives for implantation. 3) Ultimately, experimental studies are presented showing the shaping of implants, the procedures of testing their biocompatibility and essential modifications to improve the interfaces between technical devices and the biological environment. The review ends by pointing to future perspectives in the rapidly accelerating process of visual prosthetics and in the increasing hope that restoration of the visual system becomes reality. PMID- 17691337 TI - Restoring visual perception using microsystem technologies: engineering and manufacturing perspectives. AB - Microsystem technologies offer significant advantages in the development of neural prostheses. In the last two decades, it has become feasible to develop intelligent prostheses that are fully implantable into the human body with respect to functionality, complexity, size, weight, and compactness. Design and development enforce collaboration of various disciplines including physicians, engineers, and scientists. The retina implant system can be taken as one sophisticated example of a prosthesis which bypasses neural defects and enables direct electrical stimulation of nerve cells. This micro implantable visual prosthesis assists blind patients to return to the normal course of life. The retina implant is intended for patients suffering from retinitis pigmentosa or macular degeneration. In this contribution, we focus on the epiretinal prosthesis and discuss topics like system design, data and power transfer, fabrication, packaging and testing. In detail, the system is based upon an implantable micro electro stimulator which is powered and controlled via a wireless inductive link. Microelectronic circuits for data encoding and stimulation are assembled on flexible substrates with an integrated electrode array. The implant system is encapsulated using parylene C and silicone rubber. Results extracted from experiments in vivo demonstrate the retinotopic activation of the visual cortex. PMID- 17691338 TI - A neuroprosthesis for restoring sight. AB - Macular degeneration (MD) and retinitis pigmentosa (RP), two diseases that cause degeneration of retinal photoreceptor cells, are the leading causes of blindness in the United States. Anatomical studies have shown that other retinal neuronal cells (bipolar cells, ganglion cells) are preserved in these diseases and they are capable of eliciting visual percepts when electrically stimulated. We describe the design of a prototype 16-electrode retinal prosthesis, and the physiological and clinical results on six blind patients with RP who had the device implanted. The US Department of Energy artificial retina program is described. The goal of the program is construction of a 1000-electrode retinal neuroprosthesis with the potential of enabling blind patients to read large print and ambulate with ease. PMID- 17691339 TI - Towards the bionic eye--the retina implant: surgical, opthalmological and histopathological perspectives. AB - Degenerations of the outer retina such as retinitis pigmentosa (RP) lead to blindness due to photoreceptor loss. There is a secondary loss of inner retinal cells but significant numbers of bipolar and ganglion cells remain intact for many years. Currently, no therapeutic option to restore vision in these blind subjects is available. Short-term pattern electrical stimulation of the retina using implanted electrode arrays in subjects blind from RP showed that ambulatory vision and limited character recognition are possible. To produce artificial vision by electrical retinal stimulation, a wireless intraocular visual prosthesis was developed. Images of the environment, taken by a camera are pre processed by an external visual encoder. The stimulus patterns are transmitted to the implanted device wirelessly and electrical impulses are released by microcontact electrodes onto the retinal surface. Towards a human application, the biocompatibility of the utilised materials and the feasibility of the surgical implantation procedure were stated. In acute stimulation tests, thresholds were determined and proved to be within a safe range. The local and retinotopic activation of the visual cortex measured by optical imaging of intrinsic signals was demonstrated upon electrical retinal stimulation with a completely wireless and remotely controlled retinal implant. Potential obstacles are reviewed and further steps towards a successful prosthesis development are discussed. PMID- 17691340 TI - Motor cortex stimulation: role of computer modeling. AB - Motor cortex stimulation (MCS) is a promising clinical technique used to treat chronic, otherwise intractable pain. However, the mechanisms by which the neural elements that are stimulated during MCS induce pain relief are not understood. Neither is it known which of the main neural elements, i.e. cell bodies, dendrites or fibers are immediately excited by the electrical pulses in MCS. Moreover, it is not known what are the effects of MCS on fibers which are parallel or perpendicular to the cortical layers, below or away from the electrode. The therapy and its efficacy are less likely to be improved until it is better understood how it may work. In this chapter, we present our efforts to resolve this issue. Our computer model of MCS is introduced and some of its predictions are discussed. In particular, the influence of stimulus polarity and electrode position on the electrical field and excitation thresholds of different neural elements is addressed. Such predictions, supported with clinical evidence, should help to elucidate the immediate effects of an electrical stimulus applied over the motor cortex and may ultimately lead to optimizations of the therapy. PMID- 17691341 TI - Computational models simulating electrophysiological activity in the basal ganglia. AB - Modeling of the basal ganglia has played a substantial role in gaining insight into the mechanisms involved in the computational processes performed by this elusive group of nuclei. Models of the basal ganglia have undergone revolutionary changes over the last twenty years due to the rapid accumulation of neuroscientific data. In this chapter, we present distinct modeling approaches that can be used to enhance our understanding of the functional dynamics of information processing within the basal ganglia, and their interactions with the rest of the brain. Specific examples of recently developed models dealing with the analysis of computational processing issues at different structural levels of the basal ganglia are discussed. PMID- 17691342 TI - Computational perspectives on neuromodulation of aging. AB - Cognitive functions, such as memory, attention, and perception, decline with age. Besides other neuroanatomical changes, the level of dopamine also attenuates during aging. We review how computational modeling can provide insights in how these lifetime changes in dopamine levels are expressed at the behavioral level yielding a bridge across different levels. Results indicate that attenuation of dopamine lowers the signal to noise ratio providing a less distinctive neural representation, and detrimental cognitive performance. PMID- 17691343 TI - The periaqueductal grey area and the cardiovascular system. AB - In this chapter, we report that blood pressure can be increased or decreased depending on whether an electrode is in ventral or dorsal PAG. We also describe that it is theoretically possible to treat orthostatic hypotension. These are exciting developments not only because they provide an example of direct translational research from animal research to humans but also because they highlight a potential for future clinical therapies. The control of essential hypertension without drugs is attractive because of the side effects of medication such as precipitation of heart failure [10]. Similarly, drug treatment of orthostatic hypotension cannot differentiate between the supine and standing positions and can therefore lead to nocturnal hypertension [22, 29]. A stimulator could be turned off at night or contain a mercury switch that reacts to posture. PMID- 17691344 TI - Therapeutic potential of computer to cerebral cortex implantable devices. AB - In this article, an overview of some of the latest developments in the field of cerebral cortex to computer interfacing (CCCI) is given. This is posed in the more general context of Brain-Computer Interfaces in order to assess advantages and disadvantages. The emphasis is clearly placed on practical studies that have been undertaken and reported on, as opposed to those speculated, simulated or proposed as future projects. Related areas are discussed briefly only in the context of their contribution to the studies being undertaken. The area of focus is notably the use of invasive implant technology, where a connection is made directly with the cerebral cortex and/or nervous system. Tests and experimentation which do not involve human subjects are invariably carried out a priori to indicate the eventual possibilities before human subjects are themselves involved. Some of the more pertinent animal studies from this area are discussed. The paper goes on to describe human experimentation, in which neural implants have linked the human nervous system bidirectionally with technology and the internet. A view is taken as to the prospects for the future for CCCI, in terms of its broad therapeutic role. PMID- 17691346 TI - Neural networks on chemically patterned electrode arrays: towards a cultured probe. AB - One type of future, improved neural interfaces is the 'cultured probe'. It is a hybrid type of neural information transducer or prosthesis, for stimulation and/or recording of neural activity. It would consist of a micro-electrode array (MEA) on a planar substrate, each electrode being covered and surrounded by a local circularly confined network ('island') of cultured neurons. The main purpose of the local networks is that they act as bio-friendly intermediates for collateral sprouts from the in vivo system, thus allowing for an effective and selective neuron electrode interface. As a secondary purpose, one may envisage future information processing applications of these intermediary networks. In this chapter, first, progress is shown on how substrates can be chemically modified to confine developing networks, cultured from dissociated rat cortex cells, to 'islands' surrounding an electrode site. Additional coating of neurophobic, polyimide coated substrate by tri-block-copolymer coating enhances neurophilic-neurophobic adhesion contrast. Secondly, results are given on neuronal activity in patterned, unconnected and connected, circular 'island' networks. For connected islands, the larger the island diameter (50, 100 or 150 microm), the more spontaneous activity is seen. Also, activity may show a very high degree of synchronization between two islands. For unconnected islands, activity may start at 22 days in vitro (DIV), which is two weeks later than in unpatterned networks. PMID- 17691345 TI - Trimodal nanoelectrode array for precise deep brain stimulation: prospects of a new technology based on carbon nanofiber arrays. AB - Although deep brain stimulation (DBS) has recently been shown to be effective for neurological disorders such as Parkinson's disease, there are many limitations of the current technology: the large size of current microelectrodes (approximately 1 mm diameter); the lack of monitoring of local brain electrical activity and neurotransmitters (e.g. dopamine in Parkinson's disease); the open-loop nature of the stimulation (i.e. not guided by brain electrochemical activity). Reducing the size of the monitoring and stimulating electrodes by orders of magnitude (to the size of neural elements) allows remarkable improvements in both monitoring (spatial resolution, temporal resolution, and sensitivity) and stimulation. Carbon nanofiber nanoelectrode technology offers the possibility of trimodal arrays (monitoring electrical activity, monitoring neurotransmitter levels, precise stimulation). DBS can then be guided by changes in brain electrical activity and/or neurotransmitter levels (i.e. closed-loop DBS). Here, we describe the basic manufacture and electrical characteristics of a prototype nanoelectrode array for DBS, as well as preliminary studies with electroconductive polymers necessary to optimize DBS in vivo. An approach such as the nanoelectrode array described here may offer a generic electrical-neural interface for use in various neural prostheses. PMID- 17691347 TI - Brain-computer interface: a reciprocal self-regulated neuromodulation. AB - Brain-computer interface (BCI) is a system that records brain activity and process it through a computer, allowing the individual whose activity is recorded to monitor this activity at the same time. Applications of BCIs include assistive modules for severely paralyzed patients to help them control external devices or to communicate, as well as brain biofeedback to self regulate brain activity for treating epilepsy, attention-deficit hyperactivity disorder (ADHD), anxiety, and other psychiatric conditions, or to enhance cognitive performance in healthy individuals. The vast majority of BCIs utilizes non-invasive scalp recorded electroencephalographic (EEG) signals, but other techniques like invasive intracortical EEG, or near-infrared spectroscopy measuring brain blood oxygenation are tried experimentally. PMID- 17691348 TI - Cicerone: stereotactic neurophysiological recording and deep brain stimulation electrode placement software system. AB - Stereotactic neurosurgery and neurophysiological microelectrode recordings in both humans and monkeys are typically done with conventional 2D atlases and paper records of the stereotactic coordinates. This approach is prone to error because the brain size, shape, and location of subcortical structures can vary between subjects. Furthermore, paper record keeping is inefficient and limits opportunities for data visualization. To address these limitations, we developed a software tool (Cicerone) that enables interactive 3D visualization of co registered magnetic resonance images (MRI), computed tomography (CT) scans, 3D brain atlases, neurophysiological microelectrode recording (MER) data, and deep brain stimulation (DBS) electrode(s) with the volume of tissue activated (VTA) as a function of the stimulation parameters. The software can be used in pre operative planning to help select the optimal position on the skull for burr hole (in humans) or chamber (in monkeys) placement to maximize the likelihood of complete microelectrode and DBS coverage of the intended anatomical target. Intra operatively, Cicerone allows entry of the stereotactic microdrive coordinates and MER data, enabling real-time interactive visualization of the electrode location in 3D relative to the surrounding neuroanatomy and neurophysiology. In addition, the software enables prediction of the VTA generated by DBS for a range of electrode trajectories and tip locations. In turn, the neurosurgeon can use the combination of anatomical (MRI/CT/3D brain atlas), neurophysiological (MER), and electrical (DBS VTA) data to optimize the placement of the DBS electrode prior to permanent implantation. PMID- 17691349 TI - StimExplorer: deep brain stimulation parameter selection software system. AB - StimExplorer is a Windows-based software package intended to aid the clinical implementation of deep brain stimulation (DBS) technology. StimExplorer uses detailed computer models to provide a quantitative description of the 3D volume of tissue activated (VTA) by DBS as a function of the stimulation parameters and electrode location within the brain. The stimulation models are tailored to the individual patient by importing their magnetic resonance imaging (MRI) data and interactively scaling 3D anatomical nuclei to fit the patient anatomy. The user also inputs the DBS electrode orientation, location, and impedance data. The software then provides theoretically optimal stimulation parameter suggestions, intended to represent the start point for clinical programming of the DBS device. The software system is packaged into a clinician-friendly graphical user interface that allows for simultaneous interactive 3D visualization of the MRI, anatomical nuclei, DBS electrode, and VTAs for a wide range of stimulation parameter settings (contact, impedance, voltage, pulse width, and frequency). The goals of the StimExplorer system are to educate clinicians on the impact of stimulation parameter manipulation, and improve therapeutic outcomes by providing quantitative anatomical and electrical information useful for customizing DBS to individual patients. PMID- 17691350 TI - Connections of the basal ganglia with the limbic system: implications for neuromodulation therapies of anxiety and affective disorders. AB - The basal ganglia are best known for their role in motor planning and execution. However, it is currently widely accepted that they are also involved in cognitive and emotional behaviors. Parts of the basal ganglia play a key role in reward and reinforcement, addictive behaviors and habit formation. Pathophysiological processes underlying psychiatric disorders such as depression, obsessive compulsive disorder and even schizophrenia involve the basal ganglia and their connections to many other structures and particularly to the prefrontal cortex and the limbic system. In this article, we aim, on the basis of current research, to describe in a succinct manner the most important connections of the basal ganglia with the limbic system which are relevant to normal behaviors but also to psychiatric disorders. Currently, we possess sufficiently powerful tools that enable us to modulate brain networks such as cortex stimulation (CS) or deep brain stimulation (DBS). Notably, neuromodulation of basal ganglia function for the treatment of movement disorders has become a standard practice, which provides insights into the psychiatric problems that occur in patients with movement disorders. It is clear that a sound understanding of the currently available knowledge on the circuits connecting the basal ganglia with the limbic system will provide the theoretical platform that will allow precise, selective and beneficial neuromodulatory interventions for refractory psychiatric disorders. PMID- 17691351 TI - An introduction to operative neuromodulation and functional neuroprosthetics, the new frontiers of clinical neuroscience and biotechnology. AB - Operative neuromodulation is the field of altering electrically or chemically the signal transmission in the nervous system by implanted devices in order to excite, inhibit or tune the activities of neurons or neural networks and produce therapeutic effects. It is a rapidly evolving biomedical and high-technology field on the cutting-edge of developments across a wide range of scientific disciplines. The authors review relevant literature on the neuromodulation procedures that are performed in the spinal cord or peripheral nerves in order to treat a considerable number of conditions such as (a) chronic pain (craniofacial, somatic, pelvic, limb, or due to failed back surgery), (b) spasticity (due to spinal trauma, multiple sclerosis, upper motor neuron disease, dystonia, cerebral palsy, cerebrovascular disease or head trauma), (c) respiratory disorders, (d) cardiovascular ischemia, (e) neuropathic bladder, and (f) bowel dysfunction of neural cause. Functional neuroprosthetics, a field of operative neuromodulation, encompasses the design, construction and implantation of artificial devices capable of generating electrical stimuli, thereby, replacing the function of damaged parts of the nervous system. The present article also reviews important literature on functional neuroprostheses, functional electrical stimulation (FES), and various emerging applications based on microsystems devices, neural engineering, neuroaugmentation, neurostimulation, and assistive technologies. The authors highlight promising lines of research such as endoneural prostheses for peripheral nerve stimulation, closed-loop systems for responsive neurostimulation or implanted microwires for microstimulation of the spinal cord to enable movements of paralyzed limbs. The above growing scientific fields, in combination with biological regenerative methods, are certainly going to enhance the practice of neuromodulation. The range of neuromodulatory procedures in the spine and peripheral nerves and the dynamics of the biomedical and technological domains which are reviewed in this article indicate that new breakthroughs are likely to improve substantially the quality of life of patients who are severely disabled by neurological disorders. PMID- 17691352 TI - Electricity in the treatment of nervous system disease. AB - Electricity has been used in medicine for almost two millenniums beginning with electrical chocks from the torpedo fish and ending with the implantation of neuromodulators and neuroprostheses. These implantable stimulators aim to improve functional independence and quality of life in various groups of disabled people. New indications for neuromodulation are still evolving and the field is rapidly advancing. Thanks to modern science and computer technology, electrotherapy has reached a degree of sophistication where it can be applied relatively safely and effectively in a variety of nervous system diseases, including pain, movement disorders, epilepsy, Tourette syndrome, psychiatric disease, addiction, coma, urinary incontinence, impotence, infertility, respiratory paralysis, tinnitus and blindness. PMID- 17691353 TI - The current range of neuromodulatory devices and related technologies. AB - The pace of technology dictates changes in every aspect of human life. Medical profession is not an exception. The development of sophisticated electronic devices has radically influenced diagnosis and therapy. Today neurosurgical science is revolutionized with numerous implanted and non-implanted devices that modulate and stimulate the nervous system. Physicians, patients and non-technical experts involved in this field need to understand the core mechanisms and the main differences of this technology so that they can use it effectively. It will take years until clinicians reach a "consensus" about the use of these devices, but in the course of action objective information about the current status of the methods and equipment, and the technical, biological, and financial complications that arise in practice will speed up their public approval and acceptance. PMID- 17691354 TI - Management of chronic severe pain: spinal neuromodulatory and neuroablative approaches. AB - The spinal cord is the target of many neurosurgical procedures used to treat pain. Compactness and well-defined tract separation in addition to well understood dermatomal cord organization make the spinal cord an ideal target for pain procedures. Moreover, the presence of opioid and other receptors involved in pain modulation at the level of the dorsal horn increases the suitability of the spinal cord. Neuromodulative approaches of the spinal cord are either electrical or pharmacological. Electrical spinal cord modulation is used on a large scale for various pain syndromes including; failed back surgery syndrome (FBSS), complex regional pain syndrome (CRPS), neuropathic pain, angina, and ischemic limb pain. Intraspinal delivery of medications e.g. opioids is used to treat nociceptive and neuropathic pains due to malignant and cancer pain etiologies. Neuroablation of the spinal cord pain pathway is mainly used to treat cancer pain. Targets involved include; the spinothalamic tract, the midline dorsal column visceral pain pathway and the trigeminal tract in the upper spinal cord. Spinal neuroablation can also involve cellular elements such as with trigeminal nucleotomy and the dorsal root entry zone (DREZ) operation. The DREZ operation is indicated for phantom type pain and root avulsion injuries. Due to its reversible nature spinal neuromodulation prevails, and spinal neuroablation is performed in a few select cases. PMID- 17691355 TI - Intrathecal opioids for intractable pain syndromes. AB - For more than 20 years intrathecal opioid application with implantable pumps is an option for selected patients with malignant as well as non-malignant pain. In general, most types of pain should be treatable by opioid medication. However, the associated systemic side-effects such as nausea, vomiting, constipation or the risk of suppression of the central nervous system hinder the application of oral or intravenous opioid therapy as a sole, widely applicable treatment. Causes of non-malignant pain that may represent an indication for intrathecal drug delivery systems include: failed back syndrome, neuropathic pain, axial spinal pain, complex regional pain syndrome, diffuse pain, brachial plexitis, central pain, failed spinal cord stimulation (SCS) therapy, arachnoiditis, poststroke pain, spinal cord injury pain and peripheral neuropathy. Due to the proximity to the receptor sites, the therapeutic effect of intrathecal drug application lasts longer and the rate of systemic side effects is reduced. Before definitive pump implantation, the therapeutic effect of intrathecal opioid therapy is tested with an external pump. If there is no clear and satisfactory effect in this trial application, pump implantation is not indicated. In our patients, with a follow up exceeding 3 years, the reduction of non-malignant pain (assessed with the Visual Analogue Scale, VAS) was good or excellent (pain decrease >50%) in 71.3% of the patients, fair (VAS 5-6) in 19.8% and poor (VAS 7-10) in 8.9%. After 3 years of continuous treatment, we observed catheter-related technical problems (catheter dislocation, obstruction, kinking, disconnection or rupture) in 17 of 165 patients. Pump malfunctions were very rare (8 of 165 cases) and limited to older pump types. Reversible, specific drug-related side effects of long-term therapy with intrathecal pumps developed in 32 of the 165 patients. In our series, the mean serum/cerebrospinal fluid (CSF) concentration ratio for morphine was 1/3000, which explains the low rate of systemic side effects. Local diffusion difficulties in CSF cause an uneven distribution of morphine in CSF. Therefore the clinical effect is markedly influenced by the position of the catheter tip, a fact that should be kept in mind during catheter implantation. Intrathecal drug application is cost effective and can significantly improve the quality of life in selected patients. An intensive training in this method and awareness of its specific complications is necessary for everyone to participate in the consulting and implanting team. Pumps for chronic intrathecal opioid application should only be implanted in specialized centers. PMID- 17691356 TI - Management of chronic back and leg pain by intrathecal drug delivery. AB - Intrathecal delivery of analgesic drugs by implantable pump systems has been recognized as a treatment option for patients with chronic pain of benign or malignant origin that is resistant to oral or parenteral medication. Patients with chronic back and leg pain (CBLP), a benign but severely disabling condition of the lumbar spine with multifactorial genesis, have been demonstrated in a number of retrospective and in some prospective clinical studies to benefit from intrathecal delivery of opioid and/or non-opioid substances, either as single drugs or in combinations. In addition, intrathecal therapy for CBLP has been proven safe and less expensive that conventional medical therapy. This chapter summarizes the clinical and experimental evidence and the personal experience of the authors with long-term intrathecal infusion therapy for CBLP. It discusses important clinical issues such as drug selection, drug combinations, and side effects and complications of intrathecal infusion. It is concluded that further clinical research is needed in order to provide stronger evidence for the usefulness of a number of drugs currently used for intrathecal therapy on a mostly empirical basis. PMID- 17691357 TI - Drug-enhanced spinal stimulation for pain: a new strategy. AB - Neuropathic pain is notoriously difficult to manage and only a few classes of drugs may provide adequate benefits. Thus, in many cases spinal cord stimulation (SCS) is considered; however, in this group of patients, between 30-50% of the cases offered a percutaneous SCS trial may fail to obtain a satisfactory effect. Additionally, a certain number of patients with a good initial effect, report that after a period the benefits are reduced necessitating additional peroral drug therapy. Based on animal studies of transmitters and receptors involved in the effects of SCS in neuropathic pain, the GABA-B receptor seems to play a pivotal role for the effect and, moreover, the agonist baclofen injected intrathecally in rats potentiated the SCS effect in animals not responsive to SCS per se. Based on these and further studies, 48 patients with neuropathic pain and inadequate response to SCS were given intrathecal (i.t.) baclofen (ITB) in bolus doses as an adjuvant. In this group 7 patients enjoyed such a good effect that they were implanted with both SCS and drug delivery systems for ITB. Four additional cases received baclofen pumps alone. Some other patients were given intrathecal (i.t.) adenosine in combination with SCS and initially preferred this to baclofen. The chronic use of this drug in a pump however proved to be technically problematic and all the adenosine cases were eventually terminated. At follow-ups, in average 32 and 67 months after start of SCS + baclofen therapy, more than 50% still enjoy a very good effect. The daily dose of baclofen needed to maintain the effects was approximately doubled during the observation period. There were few and mild side-effects. However, in a group of three patients with peroral baclofen therapy and SCS, complaints of side-effects were common and this therapy was terminated. Informal reports from collegues support the negative experience with additional peroral baclofen. In conclusion, in patients with neuropathic pain demonstrating inadequate response to SCS (small VAS reduction; short duration) a trial of intrathecal baclofen in combination with SCS may be warranted. PMID- 17691358 TI - Neurosurgical pain therapy with epidural spinal cord stimulation (SCS). AB - Neurosurgical therapy for intractable pain with epidural implantable electrodes has become a widely used and efficient alternative when conservative or less invasive therapies are no longer effective. A complete interdisciplinary work-up is required before considering a patient as a candidate for a spinal cord stimulation (SCS) device. In more than 1300 patients we implanted an SCS device in our clinic; more than 52% reported a significant (>50%) long-term improvement for more than 3 years and a significant reduction in their analgesic drugs. Although placement of the electrode and implantation of the stimulator are technically easy to perform, they do carry a risk of potentially debilitating complications such as meningitis or component migration. Hence. SCS therapy should only be performed in specialized centers. In peripheral vascular disease (PVD) and angina, the initial results are very promising, but the long-term efficacy has to be proven by multicenter studies. PMID- 17691359 TI - Spinal cord stimulation for failed back surgery syndrome and other disorders. AB - Chronic pain is a complex condition that requires a multi-disciplinary approach to management. Spinal cord stimulation (SCS) has evolved into a relatively easily implemented, reversible technique with low morbidity for the management of chronic, intractable pain in selected patients. Percutaneous placement of electrode arrays, under local anaesthesia. supported by programmable, implanted electronics has been a major technical advance. Multicenter prospective studies were conducted and demonstrated that SCS. as a neuromodulation procedure, is indeed a superior method for treatment of chronic pain if the patients are selected with caution and a proper strategy. Future development of innovative electrodes and pulse generation systems will continue to improve this therapy. PMID- 17691360 TI - Spinal cord stimulation for the treatment of chronic non-malignant pain. AB - Over the past four decades, techniques and devices for spinal cord stimulation have undergone considerable refinement. Currently, percutaneous implantable electrodes are placed in the epidural space and a low-frequency electrical current is used to modify the transmission of chronic pain signals in the dorsal columns of the spinal cord. Before permanent implantation, the spinal cord stimulation will be examined during a test phase to determine its analgesic effect and tolerability. We have reviewed our experience in 88 patients with chronic nonmalignant pain. The follow-up of our study ranged from 15 to 75 months, with an average of 60 months. The indication for SCS in these 88 patients was mainly neuropathic pain syndromes. The patients were followed up by the Visual Analog Scale (VAS), level of activity and subjective assessment of the quality of life. On the basis of the patients' self-assessments using the VAS, the degree of pain relief was excellent/good in 72 of 88 patients (82%). At the end of the follow-up period, 50% of the patients were in a better psychological status and 86% of the patients reported an improvement in activities of their daily living and a reduction in the use of analgesic medication. Ninety percent of the patients stated that they would go through the procedure again for the same result. The findings of the present study indicate that spinal cord stimulation is an efficacious therapy for the treatment of chronic non-malignant pain. PMID- 17691361 TI - Dual electrode spinal cord stimulation in chronic leg and back pain. AB - Patients with chronic back and leg pain (CBLP) suffer from a disabling spinal condition of multifactorial origin and are often resistant to medical therapy. Spinal cord stimulation (SCS) is a minimally invasive option for treatment of chronic pain in these patients, which involves placement of epidural electrodes close to the midline of the spinal cord. SCS was originally introduced and used for decades with a single electrode. The development of fully implantable dual channel pulse generators connected to dual multicontact electrodes has given pain clinicians a more versatile tool to treat axial low back pain accompanied by radicular neuropathic pain with irregular and asymmetric distribution, a feature which is found in most CBLP patients. It has been hypothesized that using dual electrodes may improve long term outcome for CBLP patients compared with single electrodes. Current evidence however does not lend strong support to this assumption. Given the high cost of treatments for CBLP and of SCS itself, there is an urgent need for high-quality evidence for the effectiveness of dual electrode SCS in relieving pain and/or improving function in patients with CBLP. PMID- 17691362 TI - Factors affecting spinal cord stimulation outcome in chronic benign pain with suggestions to improve success rate. AB - For patient selection, psychological factors like fear avoidance, depression, secondary gain or refusal to be weaned off narcotics should be avoided. Trial Stimulation is an important tool to reduce the rate of failed permanent implants, and to improve cost-effectiveness. The etiology of pain has a strong influence on the success rate. The success rate is inversely proportional to the time interval from the initial onset of symptoms to the time of implantation. Multi-polar and multi-channel systems improve the long-term reliability and success rate and have proven to reduce the incidence of open surgery in case of electrode displacement. Third party coverage like the Worker's Compensation negatively affects the long term success. Reducing the complication rate directly benefits long term success rates. The electrode fracture rate can be reduced by using the paramedian approach, the use of three wing silicone anchor placed immediately at the point of exit of the lead from the deep fascia and avoiding a hard plastic twist lock anchor. The displacements can be reduced by fixing the anchor to the deep fascia firmly, supplemented by the use of silicone glue, and by placing the implantable pulse generator (IPG) in the abdominal wall, instead of the gluteal region. The use of prophylactic antibiotics tends to reduce the infection rate. PMID- 17691363 TI - Hardware failures in spinal cord stimulation (SCS) for chronic benign pain of spinal origin. AB - Spinal cord stimulation (SCS) has become an established clinical option for treatment of refractory chronic pain not related to cancer. Current hardware and implantation techniques for SCS are already highly developed and continuously improving, however equipment failures over the course of the long-term treatment are still encountered in a relatively high proportion of treated cases. Percutaneous SCS electrodes seem to be particularly prone to dislocation and insulation failures. This review summarizes the experience of the authors with management of hardware failures and their causes in patients treated with SCS for chronic pain of benign origin. The published literature is critically surveyed and discussed. PMID- 17691364 TI - Minimally invasive placement of epidural plate electrodes under local anaesthesia in spinal cord stimulation. AB - In the treatment of pain syndromes of different aetiologies a change has occurred from destructive interventions to stimulation procedures. Spinal cord stimulation is the best known example of this treatment strategy. It is used often in patients with persistent neuropathic pain syndromes in an extremity, for instance following low back surgery. This treatment is most frequently performed by a percutaneous placement of a single electrode, with the aid of a specially designed Tuohy needle to reach the epidural space. In cases where, for different reasons, a larger, plate electrode is needed, this has to be placed surgically by a small laminectomy. The general anaesthesia mostly needed for this procedure prevents trial stimulation necessary to check the correct electrode position. Besides this, the laminectomy procedure can subsequently result in new pain complaints due to the invasiveness of the procedure. To solve both problems we have modified the implantation technique. By using a tubular retractor system (METRx system, Medtronic Sofamor Danek, Memphis, TN), originally developed for minimally invasive degenerative disc surgery, it is possible to reach the epidural spinal space and introduce the plate electrode with a small approach under local anaesthesia both allowing trial stimulation and avoiding severe postoperative backache related to the approach in these patients. PMID- 17691365 TI - Implantation of surgical electrodes for spinal cord stimulation: classical midline laminotomy technique versus minimal invasive unilateral technique combined with spinal anaesthesia. AB - The implantation of surgical electrodes is still considered painful and invasive. Is there a possibility to diminish these disadvantages by applying a less invasive implantation procedure at the thoracic level and eventually combine this approach with a less stressful paresthesia coverage testing in the intraoperatively awake patient? In this paper, the postoperative outcome of two surgical techniques to insert surgical plate electrodes at the thoracic level is compared. In a prospective single blind study. the Classical Midline Laminotomy technique (CML) is opposed to a Minimal Invasive unilateral Technique (MIT). There were ten patients in each group, allocated at random. Postoperative pain was measured by an unbiased third party on the first and third day after electrode implantation using the Visual Analogue Scale (VAS) score. Length of hospital stay was compared in both groups. Patients were asked if they would. if necessary, undergo the same procedure again. In all comparisons, the MIT group scored significantly better. It can be concluded that a minimal invasive unilateral technique has some advantages over midline laminotomy. Refinements of the implantation procedure are discussed, i.e minimal invasive unilateral technique in combination with spinal (intrathecal) anaesthesia, surgical hints and the technique's use in revision surgery for migrated electrodes. PMID- 17691366 TI - Peripheral nerve stimulation for the treatment of neuropathic craniofacial pain. AB - Treatment of neuropathic pain in the region of head and face presents a challenging problem for pain specialists. In particular, those patients who do not respond to conventional treatment modalities usually continue to suffer from pain due to lack of reliable medical and surgical approaches. Peripheral nerve stimulation (PNS) has been used for treatment of neuropathic pain for many decades, but only recently it has been systematically applied to the craniofacial region. Here we summarize published experience with PNS in treatment of craniofacial pain and discuss some technical details of the craniofacial PNS procedure. PMID- 17691367 TI - Stimulation of the occipital nerve for the treatment of migraine: current state and future prospects. AB - Migraine is a common disabling malady. Despite the development of therapeutic agents such as the triptans, a significant number of patients continue to suffer. The evolution of peripheral nerve stimulation for headache management, may significantly improve the management of those who suffer from moderate to refractory migraine symptoms. PMID- 17691368 TI - Occipital neurostimulation for treatment of intractable headache syndromes. AB - Intractable migraine and other headache syndromes affect almost 40 million Americans and many more millions worldwide. Although many treatment protocols exist, mainly designed around medication regimens, there are estimated to be at least 3-5% of these headache sufferers that do not respond in a meaningful way to medications and whose lives can be severely restricted to darkened, quiet rooms, heavy doses of narcotics, failed personal relationships and an overwhelming sense of hopelessness. In this article, we describe current neuromodulation-based approach to the management of intractable headache. PMID- 17691369 TI - The phenomenon of spasticity: a pathophysiological and clinical introduction to neuromodulation therapies. AB - Spasticity is part of the complex clinical picture which results from the upper motor neuron impairment. The underlying mechanisms that produce the automatic overactivity of the muscle groups may manifest themselves as either passive movements dependent on the exerted velocity or persistent muscle overactivity in the form of spastic dystonia. The therapeutic management of spasticity is closely related to the aims of rehabilitation; these include avoidance of complications, restoration of movement, re-education of motion and gait, development of self dependency, and social integration, as well as modification and reorganization of the cortical brain map. The latter is achieved through long-term learning processes which are subserved by new neurophysiological dynamics. and the mechanisms of neuroplasticity which develop during neural regeneration. PMID- 17691370 TI - Intrathecal baclofen in current neuromodulatory practice: established indications and emerging applications. AB - Intrathecal baclofen (ITB) has evolved into a standard treatment for severe spasticity of both spinal and cerebral origin. The accumulated promising data from reported series of patients receiving ITB therapy together with the fact that spastic hypertonia commonly coexists with other neurological disorders have constituted a solid basis for offering this kind of treatment to patients suffering from other movement disorders. These include motor disorders such as dystonia, amyotrophic lateral sclerosis, status dystonicus, Hallervorden-Spatz disease, Freidreich's ataxia, "stiff-man" syndrome, but also vegetative states after revere brain trauma, anoxic encephalopathy or other pathology and more recently, various chronic pain syndromes. In this article, on the basis of the established applications of ITB therapy, we review the important emerging indications of this rewarding neuromodulation method and attempt to identify its future potential beneficial role in other chronic and otherwise refractory neurological disorders. PMID- 17691371 TI - Intrathecal baclofen therapy: indications, pharmacology, surgical implant, and efficacy. AB - Intrathecal baclofen (ITB) therapy is an option for those in whom predominantly lower extremity spasticity is severe, problematic, and intractable to oral doses of medications and/or focal treatment. When delivered to the lumbar area, ITB avoids high concentrations from reaching the brain (4:1 ratio lumbar to brain cisterns). A screening test dose is done prior to implanting the pump via a lumbar puncture with 50 microg baclofen, working up to 100 microg if necessary. There are two [2] types of pumps. The electronic programmable type has the advantage of flexibility of dosing and frequent change of doses for fine-tuning the patient's optimal dose. The mechanical constant flow type has the advantages of (1) being gas driven and not needing battery replacement, and (2) not needing a programmer to refill, thus allowing geographically removed patients to benefit from ITB. Catheter complications are reduced by using a shallow-angle paramedian oblique insertion to the spine, and meticulous anchoring of the catheter. Threading the catheter to T6/7 rather than the traditional T10/11 can allow upper limb relief also. Long term efficacy is excellent, although catheter complications are frequent. and if not recognized and treated, can lead to significant effects of withdrawal of baclofen. PMID- 17691372 TI - Intrathecal baclofen in the treatment of spasticity. AB - Spasticity is a disorder of the sensorimotor system resulting in velocity dependent increased muscle tone and tendon reflexes. Intrathecal baclofen is currently the most effective means of treating diffuse abnormal spasticity of both cerebral and spinal origin in the adult and pediatric patient. Careful patient assessment, selection and continued therapies are essential to a successful intrathecal baclofen management program. Once a patient receives a baclofen pump, close monitoring is needed for dose adjustment and pump problems. Baclofen overdose and withdrawal by either system failure or human error can cause significant side effects and be life threatening. Excellent understanding of the baclofen delivery system, programming and dose effects are needed to evaluate any patient complaints. Future uses of intrathecal pump therapy includes use of other intrathecal drugs besides baclofen (or in combination with baclofen) and the effects of placing the catheter tip at various spinal levels. At the University of Minnesota, Sister Kenny Institute and Gillette Children's Specialty Healthcare our experience has shown excellent results with this form of therapy over the last 12-16 years. PMID- 17691373 TI - Intrathecal baclofen therapy in patients with severe spasticity. AB - Spasticity has been described as "a motor disorder, characterized by a velocity dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, resulting from hyper-excitability of the stretch reflex as one component of the upper motor neuron syndrome". In patients with complete spinal cord lesions, severe untreatable spasticity can make movement, sitting and hygiene difficult or impossible while it may alter gait and personal care in patients with partial lesions. From a clinical point of view, it is useful to distinguish spinal cord spasticity from supraspinal spasticity. Traditionally, the Ashworth scale is the most widely used to quantify the tone of single muscles. In order to quantify hypereflexia, the Reflex Scale is also used. In the spinal spasticity which is characterized by spasms, the Spasm Frequency Scale is useful in order to monitor their frequency. Initially, management of spasticity is based on non-invasive treatments that later become more invasive. The first approach. the conservative treatment, usually includes elimination of the nociceptive stimuli, rehabilitative therapy (physical and occupational), orthopaedic prostheses and plaster corsets. These treatments, do not resolve spasticity in about 33% of cases. In these severe cases, more invasive procedures such as muscle infiltrations with botulin toxin and intrathecal baclofen infusion can be used. PMID- 17691374 TI - Intrathecal antispastic drug application with implantable pumps: results of a 10 year follow-up study. AB - Since 1986, more than 300 patients received an intrathecal baclofen (ITB) pump for the treatment of severe spasticity. Chronic ITB administration is a safe and effective method, which significantly decreases pathologically exaggerated muscle tone and improves the quality of life in most patients. This therapy is indicated in severe spasticity of cerebral or spinal origin that is unresponsive to oral antispastic medications. It is also useful in patients who may experience intolerable side effects when they receive orally effective baclofen doses. The therapeutic dose required to treat spasticity of cerebral origin is about three times higher than in spasticity of spinal origin. In carefully selected patients who suffer from spasticity, pump implantation is a cost-effective treatment which improves their quality of life. In our series with a follow-up period of 10 years, the ITB dose remained constant and no development of tolerance was observed in most patients. Destructive procedures such as myelotomy are no longer performed in our department in order to treat spasticity. PMID- 17691375 TI - Intrathecal baclofen for the treatment of spasticity. AB - Spasticity is a clinical condition characterized by a velocity-dependent increase of muscle tone due to "parapyramidal" disturbance of the inhibitory afferents to the second motor neuron. Intrathecal baclofen (ITB) is at present the most effective treatment tor generalized spasticity provided that an accurate assessment of patients to be candidates for ITB is made. The most important patient ,election criterion is lack of positive response to any oral antispastic drug or appearance of undesired side effects of such oral treatment. Spasticity should not be treated in patients in whom it may be helpful to maintain posture due to their very poor muscle strength. When assessing a spastic patient alternative treatments such as Botox and peripheral neurotomies must also be considered, particularly in cases of predominantly focal spasticity. According to our experience, it is advisable to divide spastic patients into two different groups: the first group including wheel-chaired and bed-ridden patients, the second group comprising spastic patients who are still able to move. In each of these two groups treatment goals vary and require different protocols for the patients' evaluation. Assessment of patients is completed with the functional index measurement (FIM) scale in order evaluate changes in patients' quality of life caused by variations in the motor performance. Currently, treatment of spasticity with ITB is the most effective way of reducing spasticity regardless of its cause. PMID- 17691376 TI - Management of spasticity in multiple sclerosis by intrathecal baclofen. AB - Since its introduction, chronic intrathecal baclofen (ITB) infusion has been proved to improve spasticity, spasms and related pain. In the literature, the reported clinical improvement is evident in more than 85% of the patients suffering from spasticity and in more than 66% of the patients suffering from spasms. Usually, the evaluation of spasticity is carried out by the Asworth Scale although there is not yet general accordance on the validity of this scale. It is possible that some of the scales used to assess the implanted patients are not sensitive enough to detect changes in the quality of life or functional outcome. After the pump's implantation, the overall care seems to be rather simple for a devoted team. The side effects are usually temporary but they can worry the patients. The most dangerous side effects are baclofen overdose and withdrawal syndrome. These complications are totally avoidable by adopting an approach attentive to the details regarding the patient, the device, and the procedure. PMID- 17691377 TI - Surgical management of spasticity of cerebral origin in children. AB - In children, spasticity is commonly seen in the context of cerebral palsy (CP), but also following head injury, cerebral infarct or other brain insults. CP is a wide term used to describe a constellation of symptoms that characterise the physical impairment of movement due to abnormal brain development. The management of spasticity is tailored according to the clinical picture of the child. Ambulatory mild spastic diplegics tend to reach the maximum of their disability in the first few years of life, and change little after the age of 5-7 years. Such patients who are between 3-5 years and who attempt to mobilise with walking frames are often good candidates for either dorsal rhizotomy or intrathecal baclofen (ITB) administration with the implantation of an indwelling pump. Non ambulatory mild spastic diplegics and spastic quadriplegics have more profound spasticity, painful spasms, orthopaedic deformities, and difficulties with daily care and posture. ITB has become established as the first line of surgical treatment for these patients. In the last decade, there has been a definite trend away from ablative treatments and towards reversible stimulation and infusion systems. Current pumps have practical limitations but, in the next decade, it is anticipated that technological improvements will render the pumps more patient friendly. PMID- 17691378 TI - Efficacy of intrathecal baclofen delivery in the management of severe spasticity in upper motor neuron syndrome. AB - In the treatment of patients with severe spasticity, intrathecal administration of baclofen (ITB) was introduced in order to exert its effect directly at the receptor sites in the spinal cord, and have better therapeutic efficacy with smaller drug doses compared to oral antispasmodic medications. Apart from our own research in Groningen, a review is performed to present and discuss the efficacy of ITB in patients with spasticity and hypertonia as symptoms of the upper motor neuron syndromes. The majority of the ITB studies describe proven efficacy in the reduction of spasticity and spasms in short-term and long-term follow-up. Functional improvements in daily care, hygiene, pain, etc are described but not often with reliable and validated instruments. A few studies reported significant improvement in walking performance in ambulant patients. The studies that have been done on the efficacy of ITB in relation to quality of life (QOL) showed some evidence of improvement. Future research is needed on fine tuning in the ITB therapy using functional assessment instruments. PMID- 17691379 TI - Intrathecal baclofen in the treatment of spasticity, dystonia and vegetative disorders. AB - Baclofen (beta-p-chlorophenyl-GABA) binds to a number of spinal and cerebral sites and depresses the excitability of motor neurons. Intrathecal administration induces much higher CSF concentrations compared to the limited passage through the blood-brain barrier after oral administration. The development of reliable implanted pumps allows long-term intrathecal baclofen treatment (ITB). Baclofen is mainly an antispastic drug and the main indication of ITB is generalized lower limb spasticity in spinal cord injury and multiple sclerosis. The side-effects are due to either drug over-dose or withdrawal and to malfunctions of the implanted device (disconnections of the catheter, infections, etc.). Large numbers of patients have been treated over the past twenty years. More recently, baclofen has been used in the treatment of spasticity of cerebral origin, and in the treatment of other motor disorders, mainly dystonia. The results in cerebral palsy are promising and ITB's role will probably grow in the management of the movement disorders of these children. Further studies are required on the exact site of action, on the possible association with other drugs, especially clonidine and on the development of sustained release formulations. PMID- 17691380 TI - Intrathecal baclofen in the management of post-stroke hypertonia: current applications and future directions. AB - This chapter will review the application of intrathecal baclofen (ITB) in the management of post-stroke hypertonia, a major complication that results in deformity and discomfort, and limits mobility and performance of activities of daily living (ADL). Initially, ITB was considered only in conditions characterized by severe multi-limb spastic hypertonia in non-ambulatory individuals. Lately, ITB is used in persons with stroke who can ambulate, with the intent of further improving walking ability. Early clinical experience and evidence suggest that when used in the appropriate patient, ITB is efficacious and safe in managing post-stroke hypertonia in individuals of various functional levels. This chapter will also review clinical situations that are common in the stroke population, which may influence treatment decision choices. There are still ample opportunities to conduct research on this treatment modality, especially in the areas of patient selection and outcomes in the stroke population. PMID- 17691381 TI - Intrathecal baclofen in the treatment of post-stroke central pain, dystonia, and persistent vegetative state. AB - Intrathecal baclofen (ITB) administration is a fully established treatment for severe spasticity. However, it is not widely known that baclofen, an agonist of the GABA-B receptor, has additional beneficial effects in other conditions such as chronic pain, coma, dystonia, tetanus, and hyypothalamic storm. Sporadic cases of dramatic recovery from persistent vegetative state after intrathecal administration of baclofen have been reported. There have been also reports on the use of baclofen for control of dystonia due to cerebral palsy, neuropathic central pain syndrome or reflex sympathetic dystrophy. On the other hand, epidural spinal cord stimulation (SCS) has been used in the management not only of pain but also of spasticity, dystonia, and in order to improve deteriorated consciousness, but the effects so far have been modest and variable. Similarities between ITB and SCS are interesting as both involve the spinal GABAergic system. Based on a 15-year personal experience of intrathecal baclofen, I would stress the importance of this treatment not only for spasticity but also for other difficult neurological disorders. PMID- 17691383 TI - The importance of neurorehabilitation to the outcome of neuromodulation in spasticity. AB - The neuromodulation specialist who is involved in the management of spasticity should not be interested only in the technical aspects of the implantation of a device. It is important that (s)he has a sound understanding of all aspects of this serious disability in order to determine appropriately whether an ablative or a neuromodulatory intervention (intrathecal baclofen administration, spinal cord stimulation, peripheral nerve stimulation) is best for the patient. It is also important that s(he) is able to collaborate effectively with the physiatrists, othopaedic surgeons, neurologists, physiotherapists, neuropsychologists, and care counselors. In this article, we review our approach to the neurorehabilitation of patients with spasticity due to multiple sclerosis, spinal cord injury, cerebrovascular disease or head injury and, on the basis of our experience, we highlight the importance of the integrated management that combines both rehabilitation and neuromodulation methods in order to ensure the maximum benefits for the patients. PMID- 17691382 TI - Neurophysiological basis and clinical applications of the H-reflex as an adjunct for evaluating response to intrathecal baclofen for spasticity. AB - Implanted programmable pumps that infuse intrathecal baclofen (ITB) markedly enhance the ability of clinicians to manage severe spasticity in appropriately selected patients. Studies addressing the efficacy of this treatment modality have primarily used clinical outcome measures of impairment, particularly reduction in stiffness as measured by the Ashworth scale. Several recent studies, however, highlight comparalively higher sensitivity of neurophysiologic techniques, especially the H-reflex, as an objective index of spinal cord response to ITB administration. We review the conceptual, physiological, and methodological hases for use of the H-reflex as an adjunct to clinical evaluation among patients receiving ITB infusion, including published reports and selected case studies that address the potential advantages and limitations of such techniques when applied to dose titration and system "troubleshooting" scenarios, We also address the implications of such findings in the context of reported complications such as "tolerance" to ITB administration and catheter "microfracture". The accumulated knowledge suggests that H-reflex is a sensitive method for documenting altered spinal cord responsiveness in the presence of ITB delivery. We therefore recommend using H-reflex as an adjunct to clinical evaluation when judging the overall effectiveness of ITB administration. PMID- 17691384 TI - Epidural spinal cord stimulation in lower limb ischemia. AB - Epidural spinal cord stimulation (SCS) has been used as a method to improve microcirculatory blood flow, relieve ischemic pain and reduce amputation rate in patients with severe peripheral arterial occlusive disease (PAOD). In this article, the theories attempting to explain the mechanisms of SCS vasoactive action are presented. Our method of patient screening and our surgical technique for SCS implantation are described. In addition, the various published series reporting on the efficacy of SCS in PAOD are critically reviewed. The contemporary reports demonstrate the efficacy of SCS in ischemic pain relief. In the light of these results and our own experience, we conclude with an appraisal of modern techniques for assessing critical limb ischemia. PMID- 17691385 TI - Spinal cord stimulation in the treatment of chronic critical limb ischemia. AB - This paper reviews the clinical experience and proposed working mechanisms of spinal cord stimulation (SCS) in the treatment of chronic critical limb ischemia (CCLI). SCS appears to provide a significant long-term relief of ischemic pain and to improve healing of small ulcers, most likely due to effects on the nutritional skin blood flow. Despite these observations, randomized trials were not able to show limb salvage. Assessment of the microcirculatory skin blood flow, by means of transcutaneous oxygen pressure measurements and videocapillaromicroscopy, is necessary to evaluate the remaining microcirculatory reserve capacity likely to be exploited by SCS and to help identify patients that will benefit most from this treatment and in whom stimulation could lead to limb salvage. PMID- 17691386 TI - Cervical spinal cord stimulation in cerebral ischemia. AB - Spinal cord stimulation (SCS) is a well established therapy in the treatment for chronic pain. SCS has also been shown to increase peripheral blood flow and is now an accepted treatment in the management of ischemic limb pain and angina. There is a growing body of evidence that cervical spinal cord stimulation also increases cerebral blood flow (CBF) in both animal and human models. SCS could potentially impact on the treatment of cerebral vasospasm and stroke by an increase in CBEF The utility of SCS is also being explored in novel applications such as adjunctive tumor therapy, where resistance to therapy conferred by tissue hypoxia may be ameliorated by CBF augmentation. PMID- 17691387 TI - Spinal cord stimulation in the treatment of post-stroke patients: current state and future directions. AB - A decrease in cerebral blood flow (CBF) and brain metabolic activity are well known complications of stroke. Spinal cord stimulation (SCS) is successfully being used for the treatment of several low-perfusion syndromes. The aim of this chapter is to describe the data that support the effect of SCS on CBF and the use of SCS in the treatment of stroke and cerebral low perfusion syndromes. In addition, we present our relevant studies. Since April 1995, we have assessed 49 non-stroke patients. The following parameters were measured pre- and post-stroke: (1) CBF in healthy contralateral tissue by single photon emission computed tomography (SPECT), (2) systolic and diastolic velocity in the middle cerebral artery (MCA) by transcranial Doppler, (3) blood flow quantification in the common carotid artery (CCA) by color Doppler, and (4) glucose metabolism in healthy contralateral tissue by positron emission tomography (PET). Our results showed that during cervical SCS there was a significant (p < 0.001) increase in systolic (> or =21%) and diastolic (>26%) velocity in the MCA, and CCA blood flow (> or =51%) as well as glucose metabolism (44%). We concluded that cervical SCS (cSCS) can modify CBF and brain metabolism. Its potential role in the management of stroke and low-perfusion syndromes is further investigated by experimental studies and reports describing clinical experience. Appropriate clinical trials are warranted. PMID- 17691388 TI - Neurostimulation for refractory angina pectoris. AB - Spinal cord stimulation (SCS) has been shown to be particularly useful, safe and effective treatment in the management of patients with refractory angina pectoris and those unsuitable for percutaneous or surgical revascularisation. Clinical and experimental research has shown that it decreases myocardial ischemia without masking the clinical symptoms of its imminent development. In addition to providing pain relief, neurostimulation has also been shown to improve microcirculatory blood flow and increase the myocardial threshold for ischaemia. The anti-ischaemic effects of SCS have been evaluated by: (a) exercise testing, (b) ambulatory electrocardiogram (ECG), and (c) invasive measurements of lactate from coronary sinus blood samples. Patients have reported not only significantly fewer angina attacks but also decreased consumption of glyceryl trinitrate and improved quality of life. A number of mechanisms have been proposed including placebo effects, primary anti-nociceptive effects, involvement of endogenous opiates, anti sympathetic nervous system effects, increases in coronary blood flow, and redistribution of myocardial blood flow. PMID- 17691389 TI - Diaphragm pacing with a spinal cord stimulator: current state and future directions. AB - Diaphragm pacing with electrical stimulation of the phrenic nerve is an established treatment for central hypoventilation syndrome. The device, however, is not readily available. We tested the same spinal cord stimulator we use for pain control in phrenic nerve stimulation. We implanted a spinal cord stimulator (Itrel 3 or X-trel, Medtronic, MN) in 6 patients with chronic hypoventilation because of brainstem or high cervical cord dysfunction. The stimulation electrode was placed along the right phrenic nerve in the neck, and the device was implanted in the anterior chest. We used the cyclic mode, and set the parameters at I second ramp up, 2 seconds on, 3 seconds off. The pulse width and the frequency were set at 150 microseconds and 21 Hz, respectively. The amplitude of the output was adjusted to obtain sufficient tidal volume and to maintain PaCO2 at around 40 mm Hg. During a follow-up period up to four years, stable and sufficient ventilation was observed in all patients without any complications. Although further long follow-up is necessary, diaphragm pacing with the spinal cord stimulator is feasible and effective for the treatment of the central hypoventilation syndrome. PMID- 17691390 TI - Neuroprostheses for management of dysphagia resulting from cerebrovascular disorders. AB - Swallowing is a complicated process that involves intricate timing between many different muscles in the mouth and neck. The primary purpose of swallowing is to move food through the mouth and pharynx and into the esophagus for transport to the stomach for digestion. Dysphagia is a general term that refers to a disruption in any part of the process. The consequences of dysphagia include social embarrassment; malnutrition; and aspiration. Of these, aspiration is the most significant as it is associated with a significantly greater risk of pneumonia and death. If patients fail to adequately protect the airways with standard exercise and therapy, they are often disallowed from taking food by mouth and receive nutrition by alternate means. If patients still experience frequent pneumonia, more drastic surgical measures that permanently separate the airway from foodway are required. As an alternative to these surgical procedures, neuroprostheses can dynamically restore airway protection. There are two primary protective mechanisms that neuroprostheses seek to restore. The first is laryngeal elevation and the second is vocal fold closure. The present article is an introductory overview of the swallowing process, the primary muscles and nerves related to swallowing, the effects of dysphagia, the standard treatment options, and the neuroprosthetic options. PMID- 17691391 TI - Management and rehabilitation of neuropathic bladder in patients with spinal cord lesion. AB - The patients with spinal cord lesion (SCL) develop problems of urination due to impaired neural control of the lower urinary tract, such as incontinence or retention; these conditions constitute risks for the upper urinary tract and should be treated appropriately over the various phases of the disease. The therapeutic approach in the acute and subacute post-traumatic phase is of particular importance for the early and late management of the subsequent urinary disturbances. When the rehabilitation program is completed, it is estimated that deficiencies in sphincter control have greater impact on personal and social life of individuals than the movement disability. Currently, as the number of sufferers from SCLs is constantly increasing, medical science faces two great challenges: (i) to develop and apply modern treatment modalities in the framework of advanced neurorehabilitation programs, and (ii) to provide well-organized follow-up management. All efforts should be directed towards the functional integrity of the upper urinary tract and the acquirement of the greatest possible independence for the patient. PMID- 17691392 TI - Sacral neuromodulation as a functional treatment of bladder overactivity. AB - Sacral neuromodulation, namely the electrical stimulation of the sacral nerves has become an alternative treatment for cases of idiopathic bladder overactivity. The mechanism of action in this type of spinal cord modulation is only partially understood but it seems to involve stimulation of inhibitory interneurons. Temporary sacral nerve stimulation is the first step. It consists of the temporary application of neurostimulation as a diagnostic test in order to check the integrity of the sacral root and determine the best location for the implant. If the test stimulation is successful, a permanent device is implanted. In experienced hands, this is a safe procedure. When the patients are selected on the basis of sound criteria, more than three-quarters of them show a clinically significant improvement with a reduction in the frequency of incontinence episodes by more than 50%; however, the results vary according to each author's method of evaluation. The application of this technique should be combined with careful follow-up and attentive adjustments of the stimulation parameters in order to optimize the coordination of activity between the neurological systems involved. PMID- 17691393 TI - Dorsal rhizotomy combined with anterior sacral root stimulation for neurogenic bladder. AB - A spinal cord lesion (traumatic or not) above the sacral micturition center may induce hyperreflexia of the detrusor, spasticity of the sphincter and vesico sphincter dyssynergia. Eventually, alterations in the upper urinary tract can be associated with increased mortality in this patient population. Sacral rhizotomies combined with implantation of an anterior sacral root stimulator appear to be an effective method not only for the treatment of voiding dysfunction but also for defecation and sexual disorders. The clinical and electrophysiological checks and the surgical technique are described. In most series, the results show a constant improvement in the patient's functional status. Ninety percent of patients gain satisfactory continence and no longer require an incontinence appliance. Bladder capacity and compliance increase dramatically. As a consequence, urinary infection rate decreases. The majority of patients remain dry, and more than 80% have a complete voiding or a post-void residue of less than 50ml and do not require any catheterization. Anterior sacral root stimulation combined with sacral posterior rhizotomy is a valuable method to restore bladder function in spinal cord-injured patients suffering from hyperactive bladder. PMID- 17691394 TI - Surgical therapy of neurogenic detrusor overactivity (hyperreflexia) in paraplegic patients by sacral deafferentation and implant driven micturition by sacral anterior root stimulation: methods, indications, results, complications, and future prospects. AB - Spinal cord injured patients with a suprasacral lesion usually develop a spastic bladder. The neurogenic detrusor overactivity (NDO) and the overactive external sphincter cause incontinence and threaten these patients with recurrent urinary tract infections (UTI), renal failure and autonomic dysreflexia. All of these severe disturbances may be well managed by sacral deafferentation (SDAF) and implantation of a sacral anterior root stimulator (SARS). Since September 1986 to December 2002, 464 paraplegic patients (220 females, 244 males) received a SDAF SARS. The SDAF was done intradurally in almost all cases, which means that we used a single operation field to do a two-stages procedure (SDAF and SARS). The results include data on 440 patients with a mean follow-up of 8.6 years (18 months to 18 years) until December 2004. The complete deafferentation was successful in 95.2%. Of these patients, 420 paraplegics use the SARS for voiding, (frequency 4.7 per day) and 401 for defecation (frequency 4.7 per week). Continence was achieved in 364 patients (83%). UTIs decreased from 6.3 per year preoperatively to 1.2 per year postoperatively. Kidney function remained stable. Early complications were 6 CSF leaks and 5 implant infections. Late compli cations included receiver or cable failures and required surgical repair in 44 patients. A step-by-step program for trouble-shooting distinguishes implant failure from myogenic or neurogenic failure. SDAF is able to restore the reservoir function of urinary bladder and makes the patient achieve continence. Autonomic dysreflexia disappeared in most cases. By accurate adjustment of stimulation parameters, it is possible for the patient to have a low resistance micturition. The microsurgical technique requires intensive education. In addition, the therapist should be able to manage late complications. PMID- 17691395 TI - Sacral neuromodulation in the treatment of defecation disorders. AB - A large number of patients present with fecal incontinence due to idiopathic pelvic neuropathy or lesions of pelvic nerves, iatrogenic or secondary to other pelvic diseases or dysfunctions, involving sacral nerves. On the other hand, in many patients, constipation could be related to a peripheral neuropathy impairing normal defecation. Sacral neuromodulation (SNM) has been demonstrated as an effective approach in neuropathic defecation disorders. Its application is usually safe and easy, with a limited rate of complications or adverse events. The surgical procedure is made under local anesthesia. SNM effectiveness can be reliably tested during a short term period (up to 30 days) before the decision for a permanent implant. Results in most series show significant clinical improvement, with reduction in the number of incontinence episodes, decrease of incontinence score and improvement in patients' quality of life. A few reports suggest a potential and interesting application of SNM in constipation. Findings from anorectal manometry and other physiology examinations are not conclusive in order to define SNM mechanisms of actions and suggest that a multifactorial effect "modulates" the deficient neuromuscular system causing the defecation disorders. PMID- 17691396 TI - Sacral nerve stimulation for fecal disorders: evolution, current status, and future directions. AB - Sacral nerve stimulation (SNS) aims to recruit residual function of the anorectal continence organ by electrostimulation of its peripheral nerve supply. Since its first application for the treatment of fecal incontinence in 1994, its acceptance has been broadened and it is today considered a valuable addition to the therapeutic armentarium. Initially, its use was based on conceptual considerations, but changed to a pragmatic trial and error approach. Thus, the patients selection evolved: patients suffering from fecal incontinence due to a wide variety of causes are today selected for permanent SNS after a phase of temporary test stimulation. This test is highly predictive. If it is of clinical benefit, a neurostimulation device is implanted for chronic stimulation. Permanent stimulation not only improves or restores continence, but also has a substantial impact on quality of life. This has been uniformaly proven in multiple single and multicentre trials in a wide variety of aetiologies causing fecal incontinence. Despite the growing experience with the clinical use of SNS and its therapeutic effectiveness, the knowledge of its mechanism of action remains limited. Current research aims to improve our understanding of its action, to expand the spectrum of clinical applications and to implement recent technical developments. PMID- 17691397 TI - Neurally augmented sexual function. AB - Neurally Augmented Sexual Function (NASF) is a technique utilizing epidural electrodes to restore and improve sexual function. Orgasmic dysfunction is common in adult women, affecting roughly one quarter of populations studied. Many male patients suffering from erectile dysfunction are not candidates for phosphdiesterase therapy due to concomitant nitrate therapy. Positioning the electrodes at roughly the level of the cauda equina allows for stimulation of somatic efferents and afferents as well as modifying sympathetic and parasympathetic activity. Our series of women treated by NASF is described. Our experience shows that the evaluation of potential candidates for both correctable causes and psychological screening are important considerations. PMID- 17691398 TI - Neuromodulatory approaches to chronic pelvic pain and coccygodynia. AB - Intractable chronic pelvic pain (CPP) despite a multidisciplinary approach is challenging to treat. Every structure in the abdomen and/or pelvis could have a role in the etiology of CPP. Management of chronic pelvic pain may require a combination of interventions, including pharmacological, physical and psychological therapy. Interventions suggested to date include nerve blocks (ilioinguinal, iliohypogastric, genitofemoral, hypogastric, presacral) and trigger point injections, radiofrequency treatments, spinal cord stimulation (SCS), sacral root stimulation, sacral magnetic stimulation and sacral stimulation via tibial nerve. Peripheral nerve stimulation (PNS) has been particularly successful in the treatment of mononeuropathies. Indications for targeted stimulation include localised pain in non dermatomal distribution. Herein, the epicenter of the site of pain (target) is stimulated either transcutaneously or percutaneously or via permanent neuromodulating implant. Targeted and PNS probably are underused treatment modalities given the simplicity of the technique. The introduction of a stimulating electrode directly to the center of peripherally affected, painful areas, thereby bypassing the spinal cord and peripheral nerves is a novel simple procedure with effectiveness in the control of intractable neuropathic pain. Development of newer devices and miniaturization of electrodes will play a role in refinement and further simplification of subcutaneous neuromodulation. PMID- 17691399 TI - Neuromodulation by functional electrical stimulation (FES) of limb paralysis after stroke. AB - Functional Electrical Stimulation (FES) in stroke patients has been demonstrated to provide clinical benefits such as improvement in movement, skills, function and decrease of spasticity. Imaging and neurophysiological studies have shown cortical excitability and reorganization. After injury, the parameters of timing, intensity, frequency, and duration of FES are still to be determined. Additional issues that should be determined are whether the changes induced by FES are long lasting, and which clinical and electrophysiological parameters are important and to what extent. PMID- 17691400 TI - Neuromodulation of effects of upper limb motor function and shoulder range of motion by functional electric stimulation (FES). AB - Upper extremity motor impairment is a major contributing factor to functional disability of stroke patients. Functional electric stimulation (FES) is one of the therapeutic regimens for the management of upper extremity dysfunction after stroke. This review shows that therapeutic FES intervention on supraspinatus and posterior deltoid muscles for 6 weeks is effective to speed up upper limb motor recovery in hemiplegia of short-duration after stroke or less severely affected symptoms. The positive effect of FES could be attributable to neural mechanisms including: an enhanced information flow from the joint and muscle afferents, a better visual perception of the movement produced, and a stronger muscle contraction due to direct stimulation of the motor neuron. However, FES was demonstrated as not being effective in reducing the shoulder range of motion of external rotation in patients with either short- or long-duration hemiplegia. In order to offer better management in maintaining or improving limited shoulder range of motion, other types of electrical stimulation should be considered. PMID- 17691401 TI - Neuromodulation of lower limb monoparesis: functional electrical therapy of walking. AB - After Cerebro-Vascular Accident (CVA), restoration of normal function, such as locomotion, depends on reorganization of existing central nervous system (CNS) circuitry. This capacity for reorganization, generally referred to as plasticity, is thought to underlie many instances of functional recovery after injury as well as learning and memory in the undamaged CNS. Both the reorganization of the supraspinal and spinal circuitry are highly important for the recovery of walking. The neural mechanisms responsible for learning and adapting processes are thought to involve changes both in the efficacy of synaptic function and the pattern of synaptic connections within neural circuits. In the uninjured CNS, these changes occur as a result of alterations in the amount of neural activity within circuits and are, therefore, termed activity-dependent. In this chapter, we will present several therapies of walking that provide effective input for the training of the existing CNS circuitry; thereby, contribute to long term recovery of sensory-motor functions. The focus of this chapter is Functional Electrical Therapy (FET) of walking, that is, the multi-channel electrical stimulation of sensory-motor systems that lead to more normal stance and swing of the paretic leg during the walking exercise. PMID- 17691402 TI - FES cycling. AB - Spinal cord injury (SCI) leads to a partial or complete disruption of motor, sensory, and autonomic nerve pathways below the level of the lesion. In paraplegic patients, functional electrical stimulation (FES) was originally widely considered as a means to restore walking function but this was proved technically very difficult because of the numerous degrees of freedom involved in walking. FES cycling was developed for people with SCI and has the advantages that cycling can be maintained for reasonably long periods in trained muscles and the risk of falls is low. In the article, we review research findings relevant to the successful application of FES cycling including the effects on muscle size, strength and function, and the cardiovascular and bone changes. We also describe important practical considerations in FES cycling regarding the application of surface electrodes, training and setting up the stimulator limitations, implanted stimulators and FES cycling including FES cycling in groups and other FES exercises such as FES rowing. PMID- 17691403 TI - Reconstruction of upper limb motor function using functional electrical stimulation (FES). AB - Functional electrical stimulation (FES) techniques progress by adopting the developments in computers and engineering, but complete functional reconstruction is not yet possible to be achieved. The attachment of the devices to the body can be complex, and training to handle FES is not easy. FES systems are expensive and their coverage by medical insurance is limited with the exception of a few systems. Hence, recognition of FES by the medical community is limited and as a result, it is not a common therapy. However, FES is the main method available for reconstruction of motor function, at present. The improvement in activities of daily living (ADL) of patients using FES may not only improve the patient's quality of life (QOL) but also reduce the burden to persons who look after them, and hence, secure a valuable work force. The medical insurance should support the use of FES and reduce the patients' financial burden. Studies and developments based on a close collaboration of users (patients and care-givers), persons involved in therapy (doctors and nurses), and manufactures (engineers and technicians) are necessary. In addition to FES, other methods such as therapeutic electrical stimulation (TES) for prevention of atrophy and spasms of paralytic limbs show the therapeutic potential of neuromodulation. PMID- 17691404 TI - Neural prostheses in clinical practice: biomedical microsystems in neurological rehabilitation. AB - Technical devices have supported physicians in diagnosis, therapy, and rehabilitation since ancient times. Neural prostheses interface parts of the nervous system with technical (micro-) systems to partially restore sensory and motor functions that have been lost due to trauma or diseases. Electrodes act as transducers to record neural signals or to excite neural cells by means of electrical stimulation. The field of neural prostheses has grown over the last decades. An overview of neural prostheses illustrates the opportunities and limitations of the implants and performance in their current size and complexity. The implementation of microsystem technology with integrated microelectronics in neural implants 20 years ago opened new fields of application, but also new design paradigms and approaches with respect to the biostability of passivation and housing concepts and electrode interfaces. Microsystem specific applications in the peripheral nervous system, vision prostheses and brain-machine interfaces show the variety of applications and the challenges in biomedical microsystems for chronic nerve interfaces in new and emerging research fields that bridge neuroscientific disciplines with material science and engineering. Different scenarios are discussed where system complexity strongly depends on the rehabilitation objective and the amount of information that is necessary for the chosen neuro-technical interface. PMID- 17691405 TI - Neuroprosthetics of the upper extremity--clinical application in spinal cord injury and challenges for the future. AB - The complete restoration of movements lost due to a spinal cord injury (SCI) is the greatest hope of physicians, therapists and certainly of the patients themselves. Particularly, in patients with lesions of the cervical spinal cord every little improvement of missing or weak grasp function will result in a large gain in quality of life. Despite the fact that novel drugs for axonal regeneration in the spinal cord are in the phase of imminent human application, up to now, the only possibility of restoration of basic movements in SCI persons consists in the use of functional electrical stimulation (FES). While FES systems in the lower extremities for standing or walking have not reached widespread clinical acceptance yet, devices are available for demonstrable improvement of the grasp function. This applies to tetraplegic patients with stable, active shoulder function, but missing control of hand and fingers. Particularly, with the use of implantable systems a long-term stable, user-friendly application is possible. Most recent work aims at the development of minimally invasive, subminiature systems for individual functional support. The possibility of direct brain control of FES systems will extend the application of grasp neuroprostheses to patients with injuries of the highest cervical spinal cord. PMID- 17691406 TI - Neural prostheses and biomedical microsystems in neurological rehabilitation. AB - Interfaces between electrodes and the neural system differ with respect to material and shape depending on their intended application and fabrication method. This chapter will review the different electrode designs regarding the technological implementation and fabrication process. Furthermore this book chapter will describe electrodes for interfacing the peripheral nerves like cuff, book or helix as well as electrodes for interfacing the cortex like needle arrays. The implantation method and mechanical interaction between the electrode and the nervous tissue were taken into consideration. To develop appropriate microtechnological assembling strategies that ensure proper interfacing between the tiny electrodes and microelectronics or connectors is one of the major challenges. The integration of electronics into the system helps to improve the reliability of detecting neural signals and reduces the size of the implants. Promising results with these novel electrodes will pave the road for future developments such as visual prosthetics or improved control of artificial limbs in paralyzed patients. PMID- 17691407 TI - Restoration of neurological functions by neuroprosthetic technologies: future prospects and trends towards micro-, nano-, and biohybrid systems. AB - Today applications of neural prostheses that successfully help patients to increase their activities of daily living and participate in social life again are quite simple implants that yield definite tissue response and are well recognized as foreign body. Latest developments in genetic engineering, nanotechnologies and materials sciences have paved the way to new scenarios towards highly complex systems to interface the human nervous system. Combinations of neural cells with microimplants promise stable biohybrid interfaces. Nanotechnology opens the door to macromolecular landscapes on implants that mimic the biologic topology and surface interaction of biologic cells. Computer sciences dream of technical cognitive systems that act and react due to knowledge-based conclusion mechanisms to a changing or adaptive environment. Different sciences start to interact and discuss the synergies when methods and paradigms from biology, computer sciences and engineering, neurosciences, psychology will be combined. They envision the era of "converging technologies" to completely change the understanding of science and postulate a new vision of humans. In this chapter, these research lines will be discussed on some examples as well as the societal implications and ethical questions that arise from these new opportunities. PMID- 17691408 TI - The role of spinal cord stimulation in the management of patients with brain tumors. AB - High grade gliomas (HGG) have decreased blood flow resulting in hypoxia, limited access by chemotherapeutic agents, and reduced radiation-sensitivity. Spinal cord stimulation (SCS) has been used successfully in the treatment of pain and ischemic syndromes. The present article summarizes our investigations into the effects of SCS in patients with HGG. Before their scheduled radio-chemotherapy, 23 patients with HGG were assessed pre- and post-SCS using several evaluation techniques: (1) transcranial Doppler (TCD) for middle cerebral artery blood flow; (2) color Doppler for common carotid artery blood flow; (3) single photon emission computed tomography (SPECT) for tumor blood flow; (4) polarographic probe technique for tumor pO2 measurement; (5) positron emission tomography (PET) for tumor glucose metabolism. Pre-SCS, the tumors were more ischemic and more hypoxic than healthy tissues. Post-SCS, there was significant: (1) increase in blood flow measured by TCD (> or =18%), color Doppler (> or =61%) and SPECT (15%), (2) increase in oxygenation and decrease (> or =45%) in percentage of hypoxic values <10 mmHg and <5 mmHg, and (3) increase (43%) in glucose metabolism. Our studies show that SCS can modify loco-regional blood flow and oxygen supply, as well as glucose-metabolism in HGG. This suggests that SCS could prove useful as an adjuvant treatment to radio-chemotherapy. These data merit further confirmatory studies. PMID- 17691409 TI - Dorsal column stimulation for persistent vegetative state. AB - Dorsal column stimulation (DCS) is described as a therapy for persistent deterioration of consciousness. The mechanism of its effect has not yet been elucidated. Various other methods, such as deep brain stimulation of the CM-p f complex, vagus nerve stimulation, and musical functional therapy, are being investigated as potential treatments of this problem. We present our series of DCS for persistent vegetative state and review the potential mechanisms of action and the relevant literature. PMID- 17691410 TI - Relationship between intrathecal baclofen and the central nervous system. AB - The GABA(B) receptor agonists display a number of pharmacological effects including central muscle relaxation, decreased self-administration of cocaine and narcotic drugs, antinociception, cognitive impairment as well as enhancement of synaptic plasticity. The main relationships between intrathecal or intracerebral baclofen and the Central Nervous System (CNS) are reviewed with particular attention to actions on pain, epilepsy and basal ganglia regulation. Since baclofen may be involved in synaptic plasticity and the development of neuronal pathways, the main issues of this field are reviewed with particular attention to the effects of baclofen on the developing brain. The role of baclofen in the regulation of movement has not been clearly understood, but recent findings support its important involvement in globus pallidus and subthalamic nucleus. The neuroprotective action of baclofen in cerebral ischemia is a matter of debate. The effects of baclofen in cognition and attention are another important issue because patients with chronic intrathecal baclofen (ITB) administration often present with impairment of cognitive functions. Drug craving and its improvement after baclofen administration is also reviewed. Finally, the clinically interesting results on the regulation of food intake and blood pressure are highlighted. The preliminary experience on the effects in cortical neuron viability at different concentrations of ITB is reported. PMID- 17691411 TI - Robot-aided rehabilitation of neural function in the upper extremities. AB - Repetitive movements can improve muscle strength and movement coordination in patients with neurological disorders and impairments. Robot-aided approaches can serve to enhance the rehabilitation process. They can not only improve the therapeutic outcome but also support clinical evaluation and increase the patient motivation. This chapter provides an overview of existing systems that can support the movement therapy of the upper extremities in subjects with neurological pathologies. The devices are compared with respect to technical function, clinical applicability, and clinical outcomes. PMID- 17691412 TI - Experimental therapies for chronic pain. AB - Chronic pain, an underestimated but complex medical and social phenomenon, is often resistant to currently used analgesic drugs. The effect of these substances is frequently self-limiting, with increasing level of unwanted side effects caused by increased doses. Moreover, most pharmacological therapies for pain are administered systemically, either via the enteral or the parenteral route, and exert their effects on a multitude of organs and structures in the body regardless of their involvement in chronic pain pathways. Unlike pharmacological agents, biological pain therapies provide a means to target single molecules or specific types of neural cells in spatially limited areas in the central nervous system. Biological therapies utilize externally administered natural or synthetic agents acting at specific receptors on the spinal or supraspinal level, or virus or cell vectors allowing the expression and secretion of such agents in small compartments. By targeting a particular receptor or other specific protein involved in signal transmission, biological approaches to the treatment of chronic pain may provide greater analgesic efficacy without the limitations associated with current pharmacological therapies. This review summarizes published data on the most important of the currently known targets for biological therapy of chronic pain, and focuses on therapeutic approaches for modulation of these targets and on results from preclinical and clinical trials. Biological therapies for chronic pain hold great promise and are rapidly developing, but currently still are in a very early stage and therefore deemed experimental and not suitable for routine clinical use. PMID- 17691413 TI - Science, policy and practice--lessons from America. AB - The experience in the United States regarding drug abuse prevention has involved three entities: scientific researchers, practitioners who work with youth, and policy makers. To the degree that each of these entities play complimentary roles, society benefits. In the past, these three entities have not collaborated or taken advantage of the strengths that each has to offer. Future goals should place an emphasis on scientific researchers contributing to the development and rigorous testing of programmatic approaches. Practitioners not only need to adopt effective programs and implement with fidelity, but also need to provide scientists opportunities to collaborate in order to make programs work for specific settings and populations. Finally, policy makers need to support prevention with funding and policy that is friendly to effective prevention and immune from political whims. Entities outside the United States can learn from the thirty years of experience of prevention experienced in North America. PMID- 17691414 TI - [Recreational nightlife in Spanish young people as a risk factor in comparison with more traditional ones]. AB - AIM: To estimate the predictive relevance for drug use of recreational nightlife related variables in comparison with other intrapersonal and interpersonal risk / protective factors. SAMPLE: 806 young people interviewed by Irefrea in recreational nightlife environments from 4 Spanish cities during year 2001. The sample was approximately balanced by drug use (users and non-users), gender and age group (adolescents and young adults). MEASUREMENTS: Participants were interviewed using a structured questionnaire comprising questions on demographics, drug use frequency and related attitudes, sensation seeking, risk and deviant behaviours, habits on recreational nightlife, peer and family characteristics and mediating variables. FINDINGS: Multivariate predictors for drug use were several intrapersonal and interpersonal risk / protective factors: ever used tobacco and alcohol, lower religiosity and risk perception for drug use, involvement in risk behaviours and in problem behaviours, more favourable attitudes for drug use, peer drug use and bonding with drug-using peers. Drug users are also distinguished from non-users by their recreational habits (greater involvement, specific significance and cultural and physical context in recreational nightlife). A global multivariate logistic regression analysis correctly classified 92% individuals using legal and illegal drugs. Among the factors studied, recreational styles were between the best predictors of drug use. CONCLUSIONS: It suggests the need to make an in depth study of weekend recreational habits and add them to the objectives of the prevention of drug use and misuse. PMID- 17691415 TI - [Venlafaxine extended release and alcohol dependence]. AB - OBJECTIVES: The aim is to determine the effect of the treatment with venlafaxine extended release in patients with alcohol or cocaine dependence disorder that initiate detoxification treatment. METHODS: Observational, open, prospective study carried out in Spain in 2005. 55 patients older than 18 years of age with diagnosis of alcohol and/or cocaine dependence disorder, hospitalized in Specialty Care Center to initiate detoxification treatment, were included. Daily doses of 75 to 225 mg of venlafaxine extended release were administered for 6 months. RESULTS: Treatment was associated with significant reductions in EuropASI scores in the following areas: 3, alcohol use, baseline and final score of 8.2 +/ 0.2 and 6.4 +/- 0.4, respectively (P < 0.01); 5, family/social relations, initial score of 6.9 +/- 0.2 and of 5.2 +/- 0.5 at endpoint (P < 0.001); 1, medical status, scores of 3.7 +/- 0.4 and 0.9 +/- 0.3 (baseline and final visits, respectively) (P < 0.001); and 6, psychiatric status, with a baseline score of 7.8 +/- 0.1 and final score of 5.4 +/- 0.4 (P < 0.001). The VAS alcohol craving scores at baseline were 26.7 +/- 4.6, decreasing to 4.1 +/- 1.5 at endpoint (P < 0.001). CONCLUSIONS: The results of this observational study suggest that venlafaxine extended release could be effective as a coadyuvant in the treatment of alcohol dependent patients in alcohol detoxification therapy. Nevertheless, this should be confirmed with bigger placebo-controlled samples. PMID- 17691416 TI - [Coping self-efficacy against alcohol and other drugs use as treatment outcome predictor and its relation with personality dimensions: evaluation of a sample of addicts using DTCQ, VIP and MCM-II]. AB - Perceived self-efficacy in being able to resist taking drugs when faced with situations of stress or social pressure was studied using the Drug Taking Confidence Questionnaire (DTCQ; Annis and Martin, 1985). In general, stronger self-efficacy is associated with the achievement of therapeutic objectives. We studied the predictive capacity of this questionnaire, administered at the beginning of treatment to a sample of substance-addicts in respect of compliance with objectives. We made a psychometric study of the instrument and its relationship with personality variables assessed with MCMI-II and VIP Data suggest that: (1) 50 DTCQ items can be reduced to 8 and even to 3 in order to achieve the same results, (2) self-efficacy at the beginning of treatment only predicts outcomes in the short-term, and (3) self-efficacy is a characteristic that is explained on the basis of personality structure. The best results are obtained from intermediate self-efficacy scores, whereas very low or very high scores predict poor outcome levels and display strong correlations with psychopathologic variables. PMID- 17691417 TI - [What do adolescents and young people think about recreational drug use and sexual risks?]. AB - The objective of this article is to analyse the opinions of adolescents and young people, from gypsy and non-gypsy populations, on the relationship between recreational drug use and sexual practices that increase the risk of HIV infection. A descriptive qualitative research was undertaken. 14 focus groups were conducted with 98 adolescents and young people, and 7 semi-structured interviews with young recreational drug users. Both sort of results were triangulated. Two major discursive lines emerge in the analysis. The first one defends the notion that moderate consumption of alcohol facilitates the sexual encounter, but it does not imply risky behaviours. However, polydrug use or an elevated use of recreational drugs is related to a lack of concern for sexual risks, and in men with the loss of sexual sensitivity that sometimes justifies not using a condom. The second line argues other reasons for the non-use of condoms, such as their lack of availability, confidence in one's sexual partner, a concept of desire as something uncontrollable, infatuation and the state of mind or self-esteem. Some recommendations to prevent sexual transmission of HIV are derived from the results, such as the distribution of condoms in places where alcohol and other drugs are consumed, publicising the use of condoms and other latex barriers for oral genital sexual practices, working with young males on the optimisation of pleasure, designing preventive interventions targeting stable partners, and training adolescent girls in the social skills needed to negotiate the use of condoms. PMID- 17691418 TI - [Gender and accessibility barriers to treatment in alcohol abuse patients in the Autonomous Region of Valencia]. AB - INTRODUCTION: This study aimed at identifying the factors that contribute to delaying the access of alcohol abuse patients to specific treatment centres in the Autonomous Region of Valencia (Spain). METHOD: 563 patients from Addictive Behaviours Units (UCA) and Alcohology Units (UA) were interviewed. A survey was conducted which included items on previous requested treatment in other centres and on barriers of accessibility to treatment in specific ambulatory centres. A descriptive analysis and t-student and ANOVA with Scheffe post-hoc tests were carried out. RESULTS: 59.7% of respondents said they had requested previous treatment in non-specific resources due to physical or psychical trouble that they now relate to their alcohol use although they did not do so at the time, in addition to being motivated by their own alcohol abuse (42.8%). The most attended resources were Primary Care and Specialist Unit Care. Women showed a higher demand for treatment in Mental Health Services (p < 0,05). The most important treatment barriers were included in the axis "unawareness of illness and related problems" (2.2; dt = 0,6). Women obtained higher scores in the axes "stigmatisation and environment response" and "treatment intrinsic factors". CONCLUSIONS: gender differences in barriers that delay access to treatment do exist. It is necessary to build gender-adapted intervention guidelines to be used in Primary Care and Mental Health services to reduce the accessibility barriers to treatment. PMID- 17691419 TI - [Substance use and risk perception: comparative study of adolescents in Bogota and Barcelona]. AB - The purpose of this article is to determine the differences and similarities between adolescents from Barcelona and Bogota in their psychoactive substance use habits, their perception of the activities that involve this use and how their risk perception can influence these habits. The sample consists of 865 school students from both cities, with ages between 15 and 18 years. Risk perception was assessed using the risk variables studied by Benthin, Slovic and Severson (1993). Substance use habits were assessed on the basis of the answers given by the youngsters to questions on the age when they first used any substance, frequency of use in the last week and use intentions in the next year. The findings suggest that the age they begin to use alcohol and marijuana and the first time they get drunk differ significantly between the adolescents in the two cities. The Barcelona youngsters have a higher tendency and actual use in respect of all the substances studied than the Bogota youngsters. Perceived pleasure or benefits predict an increase in both the intention and frequency of use for almost every substance in this study for all, with the exception of the older adolescents (17 to 18 year-olds) from Bogota. Fear of the consequences or the perception of a risk of illness or injury and conditions favouring use do not seem to have an obvious influence on the various use habits. PMID- 17691420 TI - [A review about cannabis use like as risk factor of schizophrenia]. AB - Cannabis use is extremely prevalent in young people and there is controversy over the psychosocial harm of this use. One risk stands out--that of the possibility of cannabis being a risk factor of an illness as serious and incapacitating as schizophrenia. An avalanche of information has emerged recently on this subject, which it is essential to review. There are a number of cohort studies that support the idea of cannabis use as inducing psychotic symptoms and a precipitating factor of schizophrenia. These studies haves some methodological limitations, which we subject to critical analysis, such as the different outcome evaluations, heterogeneity in the measurements of vulnerability to the psychosis, the difficulty in controlling the possible confusion factors and the inadequate interpretation of the results obtained. In conclusion, we consider that the use of cannabis is clearly associated with the inducement of psychotic symptoms and is, possibly, a risk factor of schizophrenia in people with a genetic or psychosocial vulnerability, preventive methods being necessary in high-risk groups. These are fundamentally those of users of large quantities of cannabis and those who initiate use in adolescence. PMID- 17691421 TI - [The use of Emdogain in periodontal and osseous regeneration]. AB - The goal of regenerative periodontal therapy is the reconstitution of the lost periodontal structures (i. e. the new formation of root cementum, periodontal ligament and alveolar bone). Results from basic research have pointed to the important role of an enamel matrix protein derivative (EMD) in periodontal wound healing. Histological results from experiments in animals and from human case reports have shown that treatment with EMD promotes periodontal regeneration. Moreover, clinical studies have indicated that treatment with EMD positively influences periodontal wound healing in humans. The goal of the current overview is to present the clinical indications for regenerative therapy with EMD based on the existing evidence. PMID- 17691422 TI - [The prosthetic rehabilitation of a patient after gunshot wound and initial maxillofacial surgical reconstruction. A case report]. AB - An improvement of prognosis after tumour therapy as well as a rather high number of multiple traumas in the craniofacial area imply a high treatment need for craniofacial tissue defects. For a successful rehabilitation of these individuals, reconstructive oral and maxillofacial surgery and prosthodontics must collaborate closely and synergistically. Besides medical and psychological findings, functional and esthetical aspects need to be taken into account. In this case report the prosthetic reconstruction of a patient with a tooth supported telescopic defect prosthesis in the maxilla and with a multiple-unit implant-supported fixed prosthesis plus two full ceramic crowns in the mandible is shown. The prosthetic solution was indicated after maxillofacial reconstruction due to the consequence of a suicide attempt. PMID- 17691423 TI - [Recommendations for dental care prior to intensity-modulated radiotherapy (IMRT). Adaptation of the University Hospital Zurich (USZ) guidelines]. AB - This article is aimed to inform about the recently performed adjustments of the established standard procedures for pre-radiotherapeutic dental care (GROTZ 2003; Shaw et al. 2000) on intensity modulated radiation therapy (IMRT) at the Department of Radiation Oncology, University Hospital Zurich (USZ). The adjustments described base on prospectively assessed results and clinical observations of more than 300 head and neck cancer patients treated with definitive or postoperative IMRT at the own institution. In order to explain the clinical differences between conventional radiation techniques and IMRT, a brief introduction section addresses characteristics of IMRT delivery, optimization of normal tissue sparing, and resulting improved normal tissue tolerance (Fig. 1a c). In conclusion, careful adjustments of pre-treatment dental care as proposed (Tab. I) are recommended for IMRT patients. This requires close case-related interdisciplinary cooperation between the referring radiation oncologist and the dentist or dental care centre, respectively. The depicted sketches (Fig. 2) are thought to get completed by the radiation oncologist, in order to inform the dentist about topographic risk areas/levels for radiation-induced late effects. PMID- 17691424 TI - [ASAQ, a breakthrough in the fight against malaria]. PMID- 17691425 TI - [Venomous and poisonous animals. IV. Envenomations by venomous aquatic vertebrates]. AB - Epidemiological information on marine envenomation is generally less extensive in Europe than in tropical regions where these injuries are more severe and the need for medical advice is more frequent. For these reasons use of regional Poison Control Centers in the area where the injury occurs must be encouraged. The purpose of this review is to describe envenomation by bony fish (lion fish, stone fish, and catfish), cartilaginous fish (stingrays and poisonous sharks), or other venomous aquatic vertebrates (moray-eels and marine snakes). Understanding of these envenomation syndromes is important not only in tropical areas but also in Europe where importation of dangerous species has increased in recent years. PMID- 17691426 TI - [Bubonic plague: the old scourge is alive and well. Inter-regional conference on prevention and control of bubonic plague, April 7-11, 2006, Antananarivo, Madagascar]. PMID- 17691427 TI - [Update on HIV infection in Mayotte]. AB - Mayotte is a small French island located in the Indian Ocean between Madagascar and Mozambique. It is one of the four Comorian Islands and has a population of about 200,000. The first cases of AIDS were diagnosed in 1989. Since then, the number of serological tests performed annually has stabilized at around 14000. However the number of new cases and treatment reports appears to be increasing slowly. Five of the 15 cases diagnosed in 2005 were at the AIDS stage. In 2006, 74 people were treated at the Mayotte hospital including 5 children. The mean age of the 69 adult patients was 38 years. Contamination was heterosexual for 71% of the adult cases, homosexual in 13% and transfusional in 3%. Women accounted for 59.5% of adult patients because of antenatal screening. All cases in Mayotte involved HIV type 1 infection. Forty-nine patients are undergoing treatment. Viremia is undetectable in 74% as compared to 85% in 2005. This decrease is due to a drop in attendance from 7.2 in 2005 to fold 4.5 in an island environment where HIV is still considered as a shameful disease. PMID- 17691428 TI - [Update on Kaposi's sarcoma]. AB - Kaposi's sarcoma (KS) is a mesenchymal tumor involving blood and lymphatic vessels and induced by viral growth factors (HHV8-IL6). This article reviews the epidemiology, pathogenesis, clinical spectrum (classic KS, iatrogenic immunosuppressive KS, endemic African KS, and AIDS-KS), histological features, staging criteria and treatment of KS. Unlike industrialized countries that have benefited from widespread use of highly active antiretroviral therapy (HAART), developing countries continue to have a high incidence of AIDS-KS. Future therapeutic targets for KS are enhancement of immune function and treatment with angiogenesis inhibitors PMID- 17691429 TI - [Human African trypanosomiasis: involvement of host genetics]. AB - Two genetic epidemiological studies were carried out in the Ivory Coast and Democratic Republic of Congo to assess the role of human genetic diversity in susceptibility to human African trypanosomiasis (HAT). Findings showed that four single DNA polymorphisms located on genes coding for cytokines were correlated with a variable risk for development of the disease. Whereas presence of the rare A and T alleles for IL10 592 C/A and IL6 4339 C/T polymorphisms appeared to protect against HAT, presence of the T allele and AA genotype for IL1 5417 C/T and TNFalpha-308 G/A polymorphisms were correlated with an increase in HAT risk. These results will improve understanding of the host-parasite interaction and, ultimately, assist the development of new therapeutic and prophylactic tools. PMID- 17691430 TI - [White tumor of the wrist: a rare site of tuberculosis involvement]. PMID- 17691431 TI - [Human leptospirosis in French Polynesia. Epidemiological, clinical and bacteriological features]. AB - Leptospirosis is a severe zoonotic disease that constitutes a major public health problem for the island populations of French Polynesia. Due to protean clinical manifestations and the risk of misdiagnosis with dengue fever, endemic viral disease, laboratory studies are necessary to confirm diagnosis of leptospirosis. At the request of the Pacific Public Health Surveillance Network, a prospective study was conducted in the population of Raieatea in the Windward Islands and the Marquis Islands to determine the epidemiological features of the disease and to define appropriate control measures. A total of 113 patients were enrolled in study between March 2004 and March 2005. Thirty-three cases were confirmed based on demonstration of serum DNA or seroconversion. The estimated annual incidence of leptospirosis was 1.7 per 1000 inhabitants. Cases involved mainly (75%) young men (mean age, 30.5 years) and occurred predominantly during the rainy season. Swimming in fresh water was the only factor showing significant correlation (p < 0.02) with positive diagnosis of leptospirosis. The most frequently identified serotype was Leptospira icterohemorrahgiae (43% of strains), thus suggesting that the rat was the most common human transmission vector. However other serotypes were found, underlining the presence of diverse reservoirs and casting doubt on the efficacy of immunization using a monovalent vaccine. These findings also indicate that enhancement of prevention and control measures for leptospirosis is needed. PMID- 17691432 TI - [Prevalence of opportunistic digestive parasitic infections in Kinshasa, Democratic Republic of Congo. Results of a preliminary study in 50 AIDS patients]. AB - In the Democratic Republic of Congo (DRC), as in many African countries, AIDS and its procession of opportunistic infections are a major cause of morbidity and mortality. In Kinshasa, the estimated prevalence rate of HIV-infected persons is between 4 and 5%, corresponding to more than 200,000 people. Due to the lack of trained laboratory personnel and appropriate diagnostic equipment, no local investigation has been carried out to determine the prevalence of the opportunistic digestive parasitic infection in HIV-infected persons. As a step to obtaining this information that is needed for implementation of an adequate care policy, a preliminary investigation was carried out in Paris, France on 50 stool samples from 50 AIDS-patients hospitalized in 3 reference hospitals in Kinshasa. Eleven patients (22%) had digestive symptoms with a diarrhea syndrome. Further study using specialized techniques demonstrated 2 cases of digestive infection related to opportunistic parasites (4%). The first involved a Cryptosporidium sp. The second represented the first case of Enterocytozoon bieneusi infection reported in the literature from the DRC. PMID- 17691433 TI - [Primary and acquired resistance to antituberculous drugs in strains of Mycobacterium tuberculosis isolated in Rwanda]. AB - This study was undertaken within the framework of a surveillance project on the resistance of Mycobacterium tuberculosis to first-line antituberculosis drugs in four provinces of Rwanda with a high prevalence of tuberculosis (TB). The purpose was to determine the prevalence of primary and acquired resistance of M. tuberculosis to major antituberculosis drugs. A cohort of patients (n=710) with pulmonary TB documented by positive microscopic examinations of exhaustive samples was recruited at 7 treatment centers. Sputum samples were cultured on Lowenstein-Jensen and Coletsos media. Sensitivity to antituberculosis drugs was tested using a BACTEC 460 radiometric system. M. tuberculosis was isolated in 644 of the 710 patients (90.7%). A total of 296 out of 573 tested for HIV infection (51.7%) were positive. Primary resistance to one, two, three or four antituberculosis drugs was observed in 3.5%, 2.9%, 1.4% and 5.7% respectively. The prevalence of acquired resistance to antituberculosis drugs was 11.2%. Primary monoresistance to streptomycin was the most prevalent (2.3%) followed by resistance to ethambutol (1%). The combined rate of multiresistance was 11.6% with 7% involving new cases and 25.5% involving retreatment. This study showed that the rates of primary and acquired resistance to first-line antituberculosis drugs were high and that TB was associated with HIV infection. The National TB Control Program must implement measures to coordinate diagnosis and management of TB and HIV infection. PMID- 17691434 TI - [Primary peritonitis in Sub-Saharian Africa: a 15 case series]. AB - Primary peritonitis (PP) is an infection of the peritoneal cavity occurring in the absence of a documented intraabdominal source of contamination. It is one of the main infectious complications of cirrhosis but is rare in healthy subjects. The purpose of this retrospective study is to describe a series of 15 cases of PP treated over a 3-year period at the Principal Hospital in Dakar, Senegal. The patient population was young (all but 2 under age of 13 years) and predominantly female (87%) with no predisposing factors. Clinical presentation always involved typical peritonitis. Surgical exploration was performed in all cases by laparotomy (n=13) or laparoscopy (n=2). Intra-operative bacteriologic sampling was performed systematically. Probabilistic antimicrobial therapy was administered in all cases using a triple-drug combination including a cephalosporin or betalactamine, an aminoside and metronidazole. This unconventional combination was designed to allow low-cost wide-spectrum coverage. As in patients with cirrhosis, the most common microbial agents were gram negative bacteria (47%). Streptococcus pneumoniae was identified in 40% of cases. Infectious ORL and pulmonary sites were suspected in some cases. Although no supporting bacteriologic evidence was obtained, the high frequency of pneumococcal involvement as well as the age and female predominance of the patient population is consistent with contamination via the female genital tract. The cases in this series present unusual epidemiological, clinical and bacteriologic features. In Europe surgical treatment can be avoided thanks to the availability of modern facilities to support further laboratory examinations. In Africa antimicrobial therapy and peritoneal lavage are the mainstay treatments. Use of laparoscopy should be expanded. PMID- 17691435 TI - [Knowledge and acceptance of obstetric peridural analgesia: survey of pregnant women in Togo]. AB - The purpose of this study was to evaluate knowledge and acceptance of obstetric peridural analgesia among pregnant women in Togo. A prospective, descriptive survey was carried out over a period of one month. A standardized survey form was used to collect data. A total of 303 pregnant women with a mean age of 27 +/- 6 years were interviewed. A proportion of primiparous and multiparous was the same, i.e., 50%. Among multiparous women, 83.5% described labor pain during previous deliveries as severe. Twelve percent of the pregnant women interviewed claimed knowledge of techniques to control labor pain. Three pregnant women reported a detailed understanding of peridural analgesia obtained from the Internet. A total of 253 women (83.5%) replied affirmatively when asked if they would opt for peridural analgesia if it was offered free of charge for delivery at the end of the current pregnancy. Acceptance was motivated by better delivery conditions for the newborn (112 women) and comfort achieved by pain relief (130 women). Refusal was motivated by a religious belief that painful delivery was in the natural order (31 women). Among the six Moslem women that refused painless delivery, two from the Djerma ethnic group stated that pain was the best expression of their femininity. The acceptance rate fell from 83.5% to 70% if peridural analgesia was offered at extra charge. Most pregnant women in Togo expressed interest in trying peridural analgesia. It is compulsory in medical indications. PMID- 17691436 TI - [First-trimester abortion at University Hospital Center in Dakar, Senegal: utility of manual vacuum aspiration]. AB - The purpose of this retrospective study was to evaluate the utility of the manual vacuum aspiration (MVA) for management of incomplete first-trimester abortions. All patients treated for incomplete first trimester abortion using MVA under local anesthesia at University Hospital Center in Dakar from January 1, 2002 to December 31, 2003 were included. A total of 2379 pregnancy losses were recorded among the 14476 patients admitted during the study period. First-trimester abortion was treated using the MVA method under local anesthesia in 1372 cases (57.7%). For 87% of patients, the duration of hospitalization was less than 12 hours. The epidemiological characteristics of these women were young age (mean, 29 years old), low parity (mean, 2 children) and low gestational age (mean, 10 weeks after amenorrhea). Spontaneous abortion accounted for 94.4% of cases and clandestine abortion for 5.6%. No complications occurred during MVA procedures and no morbidity was observed with a follow-up of one year. These findings show that MVA is a safe and effective method for completing incomplete first-trimester abortions. In our practice use of this simple technique led to a considerable improvement in post-abortion care. PMID- 17691437 TI - [Skin and mucosal manifestations of chikungunya virus infection in adults in Reunion Island]. AB - Numerous skin and mucosal manifestations were observed during the 2005-2006 chikungunya epidemic in Reunion Island. A prospective study was carried out in a consecutive series of 212 patients treated for chikungunya at the emergency unit of the Saint-Pierre Hospital in Reunion Island from March 8 to April 27, 2006. Diagnosis of chikungunya was suspected in patients with fever and joint pain and confirmed by RT-PCR and/or serology (IgM). Skin involvement was observed in 50% of patients. It consisted of exanthema with patches of healthy skin mainly on the trunk and limbs that sometimes displayed diffuse, congestive and even edematous features. Itching was reported in some cases (19.3%) and was sometimes isolated. Peeling of the skin was observed in a few cases but remained uncommon in adults. Outcome was rapidly favorable in most cases sometimes with scaling or persistence of dyschromic patches. These findings suggest that chikungunya should be suspected in subjects presenting a febrile rash while in an endemic areas or after returning from a tropical zone. PMID- 17691439 TI - [Case report of solitary breast cysticercosis in Madagascar]. AB - The purpose of this report is to describe a case of solitary breast cysticercosis presenting as a banal breast lump in a 15-year-old girl. Surgical excision was performed and histological examination demonstrated the presence of two Cysticercus cellulosae larvae. Characteristic features of this uncommon location are discussed based on a review of the literature. PMID- 17691438 TI - [Bilharziasis caused by Schistosoma mansoni in a traveler returning from Guinea: failure of serodiagnostic testing]. AB - The purpose of this report is to describe a case of febrile hypereosinophilic syndrome in a traveler three weeks after returning from a sightseeing trip to Guinea. Laboratory testing demonstrated an inflammatory response syndrome and hepatic cytolysis. Parasite serology led to suspicion of toxocariasis that was treated using albendazole. Follow-up tests at two months showed the presence of Schistosoma mansoni eggs in stools despite negative standard serodiagnostic testing (hemagglutination). Secondarily Western blot testing of serum samples at one, two and 14 months after returning from Guinea continued to show only protein bands specific to toxocariasis with no bands specific to bilhariziasis. These findings provide further evidence of the limitations of serological testing for detection of bilharziasis in travelers and the difficulty of diagnosis. Guinea is a high-risk tourist destination. Intestinal and urinary bilharziasis are endemic over three-fourths of country. Travelers planning even short stays in areas where bilharziasis is endemic should be advised on preventive measures. PMID- 17691440 TI - [Subcutaneous hydatid cyst. Case report of an exceptional location]. AB - Primary subcutaneous cyst hydatid disease is an exceptional entity. We report a new case involving a 70-year-old woman hospitalized for a subcutaneous mass in the hypogastric area with no local inflammatory signs. Radiological examination was consistent with a partially calcified subcutaneous cyst in the hypogastric area. Complete surgical resection of the mass was performed with uneventful postoperative recovery. Histopathological examination of the surgical specimen demonstrated multivesicular hydatid cyst. PMID- 17691441 TI - [Molecular markers for malaria drug resistance: necessary but not sufficient criteria to decide change in treatment policy]. AB - Molecular markers or gene mutations that are associated with resistance have been the recent focus for an attempt to promptly determine the establishment of resistance to known and currently used antimalaria drugs. For control managers, the effective management of malaria would involve strategies of interruption of the malaria transmission and/or improved therapeutic management of malaria. To place molecular markers within the context of control programs requires that one recognises the two data pools necessary for effective evidence-based policy change. These include data on socio-economic determinants on the one hand and biomedical data on the other. The markers for clinical efficacy of drugs have principally been genes either associated with transport or metabolism of the drug. In malaria those that have been the most characterised are the Pfcrt, Pfmdrl for the quinolines and the dhfr and dhps genes for the anti-folates. The PfATPase has been suggested to be involved in the recently developed artermisinine based combination therapies (ACT). To consider changes in drug policy, a control manager needs to address: efficacy, transmissibility, disease dynamics, safety, epidemics, tolerability and compliance. Except for safety and tolerability/compliance, molecular markers do provide useful information. However these markers still have to be validated alongside in vitro studies and in many different ecological settings and shown to be stable over time or associated with changing drug efficacy situations. Besides the evidence provided with these tools, the government will be required to ensure a mass education of the population and care providers, and fight against illicit street vendors. The governments will therefore still wary on the resources necessary to occasion an effective switch in drug policy especially at the district level and in the rural areas where meaningful, cost-effective programs are most needed. PMID- 17691442 TI - [Proteomic analysis and parasitosis: principles and applications]. AB - O'Farrel described a method allowing two-dimensional (2D) protein separation more than 30 years ago. Since then the original technique has made enormous progress. This progress has been accompanied by advances in mass spectrometry technology as well as various genome-sequencing programs. Today 2D electrophoresis has become the workhorse of proteomics, allowing resolution of complex structures containing thousands of proteins and providing a global view of the state of a proteome. This article presents the different steps and limitations of proteomic analysis: preparation of biological material, 2D electrophoresis, protein detection systems, and available tools for protein identification. Alternative proteomic approaches to 2D electrophoresis are also presented. A few applications are described as examples to illustrate the utility of proteomic analysis for studying the mechanisms underlying virulence, resistance to antimalarial therapies and immune response against pathologic agents. PMID- 17691443 TI - [Risk of nosocomial infection in intertropical Africa--part 2: patient infection]. AB - Patients admitted to hospitals in tropical Africa are at increased risk for nosocomial infection. However accurate description of this risk is difficult due to a lack of published data in the literature. The main promoting factors are poor health care facilities, high microbial levels in the hospital and community environment and generally uncertain health status. Most available information is about neonatal infection. The increasing number of reports involving multiresistant bacteria is evidence of poor hospital sanitation. Infections involving operative incision sites, tuberculosis and respiratory virus transmission are grossly underestimated. Infections transmitted by the parenteral route are probably decreasing due to more widespread use of disposal equipment and adequate transfusion safety measures. Epidemics involving viral hemorrhagic fever are rare but highly publicized events that attest to daily neglect of nosocomial risk factors in some health care facilities PMID- 17691444 TI - [Massive rectal bleeding leading to diagnosis of intestinal tuberculosis]. PMID- 17691446 TI - [Multiple myeloma]. PMID- 17691447 TI - [B-type natriuretic peptide (BNP) in the outpatient clinic--usefulness and pitfalls]. AB - B-type natriuretic peptide (BNP) is an established biomarker for the differentiation of acute dyspnoea in the emergency department. However, evidence for BNP testing in outpatients is less strong. BNP is not a global test to detect cardiac abnormalities and is only helpful in a few clearly defined clinical settings. Similarly to its use in emergency department patients, BNP is useful in outpatients presenting with dyspnoea to estimate the likelihood of heart failure as the cause of dyspnoea. However, BNP does not provide any reliable information on the underlying cardiac pathology, and in virtually all cases additional examinations are required (primarily echocardiography). In addition, BNP is helpful for risk stratification in patients with heart failure, coronary artery disease and pulmonary artery hypertension. PMID- 17691448 TI - [Abdominal pain in pregnancy--ultrasound as the diagnostic tool of choice for rapid decision making]. AB - Pregnant women with abdominal pain profit by using ultrasound as a first line diagnostic tool. Together with the clinical evaluation the ultrasound examination in the same room reduces time until a diagnostic decision can be made. By a systematic approach and the classification in pregnancy-related sources of pain and pregnancy-unrelated sources of pain the risks for mother and child can be quickly recognised and the necessary diagnostic and therapeutic steps can be taken. The sonographer must be experienced and a good ultrasound equipment must be available at the site. PMID- 17691449 TI - [Non-invasive central blood pressure measurement: how and why?]. AB - Until today, the usual way to measure arterial blood pressure has been cuff sphygmomanometry, at the level of the brachial artery. Yet, for some years, a non invasive tool has been available, that enables an estimation of the aortic pressure. This is done by using an aplanation tonometry technique to record the pulse wave within the radial artery, with subsequent convertion to a central pressure wave by means of a mathematical method (transfer function). This measurement informs us about the pressure near the target organs: this pressure is influenced by the reflected waves, which are responsible for an augmentation of systolic blood pressures when arterial compliance is abnormally low. Recent clinical trials have shown that for the same value of peripheral blood pressure, different antihypertensive treatments may not impact identically on central blood pressure. PMID- 17691450 TI - [61 years old woman with atypical angina and high global risk]. PMID- 17691451 TI - [Vitamin B12 therapy: oral or intramuscular]. PMID- 17691453 TI - [Molecular genetics and epigenetics in the morphogenesis mechanisms]. AB - The progress of molecular genetics principally changed the views on heredity and, in the long run, wrecked the synthetic theory of evolution, designed for the microevolutionary processes in populations only. Molecular genetics as a whole is sufficient for analyzing evolutionary processes in viruses and prokaryotes. But in multicellular organisms, with the advent of more complicated morphogenesis, epigenetic processes took effect. Appealing exclusively to the integrity of the organism in ontogeny is insufficient for the understanding of these processes; further studies of the molecular basis for this integrity are required. The discovery of homeobox genes was an important step on this path. The theory of evolution should include not only the molecular processes but also the laws of ecosystem and biosphere processes, which study requires handling many problems of ecology, parasitology, palaeontology, and geology. All these fields together comprise an enormous area of knowledge for which the development of a unified theory is scarcely possible. PMID- 17691454 TI - [Power-law species richness accumulation as manifestation of the fractal community structure]. AB - Applications of the fractal to describing the species structure of communities are discussed. Fundamental notions of fractal geometry are explained in the first part. The problem of applying the concept of fractal to describe the spatial allocation of particular species and of community as a whole is reviewed in the second part. In the final part, the usage of the selfsimirity principle for analyzing community organization is substantiated, and evidence of the fractal structure of biocenoses is presented according to Whittaker's concept of alpha diversity. It is shown that community is characterized, as a fractal object, by scale invariance, by power function relationship between the number of structural elements of the community (individuals, populations, species) and the scale (sampling effort), and, finally, by fractional value of the power (fractal dimension). Power function is the formula the takes into account the share of rare species, or species represented by a single individual. providing for no saturation of the function f(x). This formula also does not contradict the A.P. Levich's "rule of ecological non-additivity" and, lastly, allows the application of fractal formalism to characterize the species structure of a community. It is concluded that the mathematical image of species richness is a monofractal, i.e., a set characterised by only one parameter, fractal dimension. Thus, the species structure of a community (as well as the pattern of its spatial allocation) displays self-similarity and is a fractal. PMID- 17691455 TI - [Self-similar properties of the spatial structure of intertidal macro- and microbenthic communities]. AB - Spatial distribution (SD) of White Sea intertidal soft-bottom communities was studied at scales from decimetres to dozens of kilometres on the basis of an extensive dataset (464 samples of macrofauna, 349 samples of ciliates, and 333 samples of diatoms). We used the information index of structural heterogeneity D(I) (Azovsky et al., 2000 // Mar. Biol. 136 (3): 581-590) to characterize spatial variability in the species composition of the communities at different extent (total area surveyed) and grain (finest spatial resolution). The type of distribution was determined via the relation between D(I) and parameters of the spatial scale (extent and grain). At small scale (in terms of extent), all the communities were distributed randomly (mosaic SD). At larger scales, the estimated spatial variability depended neither on extent nor grain, exclusively on their ratio, i.e., was scale-invariant. This means that at some scale the spatial patterns of communities display self-similar properties (fractal SD). Such SD was found at a rather wide range of scales scales: 10(1)-10(4) m for the macrofauna, 10(0)-10(3) m for the ciliates, and 10(-1)-10(2) m for the diatoms. At still greater scales, patchy or gradient patters were observed. Thus, the ranges of fractal distribution were proportional to the average size of the organisms (approximately 10(4)-10(7) times the body size). We suppose that such spatial pattern reflects community self-organization in a relatively homogeneous environment and may be the most efficient way to realize the highest structural diversity on the basis of pre-formed complexes of predominant species. We also suppose that fractal-like patterns may be a general feature of the spatial organization of communities. PMID- 17691456 TI - [Community structure and competition between plankton algae of the White Sea using different nitrogen substrates]. AB - Phytoplankton was studied in the Kandalaksha Bay, White Sea, and exposed in situ for 18 days with the addition of 180 micromol of nitrogen in the form of nitrate, urea, ammonium, and glycine. Species composition, abundance, and biomass of algae were estimated every three days. After the enrichment, the abundance of phytoplankton increased, and its structure changed. On the 18th day of the experiment, the biomass of phytoplankton communities assimilating different nitrogen substrates was subequal. Because all the environmental factors except nitrogen substrates were identical and the level of grazing was insignificant, the similarity of the dynamics of phytoplankton assimilating organic and nitrogen demonstrates that the algae compete for organic nitrogen. Competitive parameters of algae were related to the form of nitrogen source. For instance, the competitive ability of Cylindrotheca closterium was the highest in communities that assimilated organic nitrogen, while the competitive ability of Licmophora oedipus was the highest in communities that assimilated nitrate. The competitive ability of species also depended on the type of organic substrate. For example, in L. oedipus the ability to compete for urea was higher than the ability to compete for glycine. On the contrary, in small pennate diatoms and in Nitzschia sp. the ability to compete for glycine was higher. PMID- 17691457 TI - [Population as a conservation and management unit in vertebrate animals]. AB - Under discussion are such population groups as management unit (stock) and evolutionarily significant unit, along with the problem of short-term ans long term goals of conservation activities and wildlife management. The short-term goals may differ from the long-term goals. Management units (stocks) are demographically independent populations, though genetically they may be interconnected to a high degree. It is at this level of population organization that the short-term nature management goals are reached: the preservation of stable reproduction of management units, and the exclusion of excessive pressure on small groups. The evolutionarily significant units have independent conservation status determined by significant reproductive isolation and unique adaptations. It is at this level that long-term management goals are reached: the conservation of the native population structure, the evolutionarily significant differences, the maximum genetic diversity, and, thus, the evolutionary potential. PMID- 17691458 TI - [Fluctuating asymmetry of craniometric characters in rodents (Mammalia: Rodentia): interspecific and interpopulational comparisons]. AB - Ontogenetic instability was studied in four rodent species (Ellobius talpinus, Microtus arvalis, M. rossiaemeridionalis, Mus musculus). It was measured by fluctuating asymmetry (FA) of 21 craniometric characters. Each species was represented by two populations differing in average level of chromosomic instability and in degree of anthropogenic influence. Relation between FA and individual age was observed in none of the studied species. The level of cranial structure FA in rodents is probably formed during embryogeny or early postnatal ontogeny and is not changing significantly during the further development. The studied species showed distinct differences in the degree of ontogenetic instability of the axial skull, but not of the mandible. No connection was found between craniometric character FA and technogenic stress. The differences of cranial FA level among the studied species of rodents agree with their systematic position and the sequence of their evolutionary divergence. PMID- 17691460 TI - Who determines culture? PMID- 17691459 TI - [The usage of individual-oriented model in studies on the role of the maternal effect in the reproductive switch in Cladocera]. AB - An individual-oriented model of the population of Daphnia longispina, an abundant zooplankton species in lakes and temporary water bodies of the Palaearctic temperate zone, is described. The concept of the model is based on the growth and reproduction potential of an individual and its ability to switch from parthenogenesis to gamogenesis, which is determined by the life conditions of three successive generations. The model was used for testing hypotheses on the role of maternal effect in the population dynamics of Daphnia. Several important conclusions are made, including the verification of the importance of this phenomenon for the seasonal adaptations in crustaceans. The possibility of maternal effect accumulation in a series of successive generations probably increases the tolerance of populations to annual oscillations of environmental factors. The model affirms the role of the maternal effect, along with the interpopulational polimorphism, as a mechanism providing for the stability of biological systems at the species (population) level. PMID- 17691461 TI - Generic substitution in allergic rhinitis. PMID- 17691462 TI - Mosvold hospital ARV programme. PMID- 17691463 TI - Health and social scientists need to weigh in. PMID- 17691464 TI - Eastern Cape spurred into action. PMID- 17691465 TI - 'Opi-phobia' among doctors leads to unnecessary suffering. PMID- 17691466 TI - Cape town reaches best TB cure rate. PMID- 17691467 TI - Doctors without borders set up office in SA. PMID- 17691468 TI - When should antiretroviral treatment be started in patients with HIV-associated tuberculosis in South Africa? PMID- 17691470 TI - HIV/AIDS impact on health services--lessons learnt. PMID- 17691469 TI - Routine testing for HIV--ethical and legal implications. PMID- 17691471 TI - From Mahlangeni to Gumede--the second generation of black doctors in South Africa (1913 - 1930). PMID- 17691472 TI - A clarion call for action based on refined DALY estimates for South Africa. PMID- 17691473 TI - Licensing of medical practitioners to use X-ray equipment. PMID- 17691474 TI - Teenage fertility rates falling in South Africa. PMID- 17691475 TI - Where have all the diabetics gone? PMID- 17691476 TI - Prescribed minimum benefits--quagmire or foundation for social health reform? PMID- 17691477 TI - Sentinel lymph node biopsy in breast cancer--a modified audit for surgeons in private practice. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) is a technique that is widely used in the management of early breast cancer. Surgeons are encouraged to validate their initial SLNB results by performing an audit in which both a SLNB and an axillary lymph node dissection (ALND) are performed. For surgeons in solo private practice this is not financially viable as the SLNB would not be paid for by the medical insurance companies. METHODS: Forty consenting patients were enrolled in the audit. The initial 5 patients (group A) were entered into a traditional audit - an ALND and a SLNB. The next 35 patients (group B) formed part of a modified audit - an axillary sample was performed if the sentinel node was negative (group B1) and an ALND if the node was positive (group B2). RESULTS: Ninety-two per cent of patients with an ipsilateral sentinel axillary node on preoperative scintigraphy had their node identified at the time of surgery. Eight patients had evidence of lymphatic spread. Two patients had parasternal sentinel nodes which were not removed. Group A had a mean of 10.8 nodes removed, group B1 5.8 nodes, and group B2 13.2 nodes. Twenty-three of 35 patients (66%) in group B were spared an axillary dissection. CONCLUSION: The modified audit of group B allowed patients to benefit from the procedure (and thus the medical aids charged) and yet permitted our team to ascertain the accuracy of the technique in our hands. We feel this is an approach that may be used by other surgeons working alone. PMID- 17691478 TI - Haematogenous pyogenic bone and joint sepsis--reducing avoidable morbidity. AB - BACKGROUND AND OBJECTIVES: Delayed presentation of haematogenous bone and joint sepsis is common in our childhood population and leads to a large burden of avoidable morbidity extending into adult life. We set out to determine causative factors in these delays. DESIGN: A prospective study was undertaken over a 1-year period. SETTING: Ngwelezane Hospital, a regional hospital in Kwa-Zulu-Natal serving 9 rural district hospitals. SUBJECTS: Children under 15 years with their first presentation of bone and joint sepsis, comprising 80 consecutive cases. Tuberculosis cases were excluded. OUTCOME MEASURES: Children were categorised at follow-up into two groups. The first group had uncomplicated recoveries, with complete return of function and no clinical or radiological signs of unresorbed sequestra. The second group had complications, with evidence of one or more of the following: chronicity of infection, pathological fracture, deformity, growth plate disturbance, avascular necrosis or joint stiffness. RESULTS: Delay in obtaining definitive treatment correlated strongly with initial misdiagnosis. Only 4/25 septic hips were correctly diagnosed and referred expediently; 19/50 osteomyelitis cases were initially misdiagnosed and treated as cellulitis, and a further 19/50 were misdiagnosed as trauma. Predictably, delayed treatment correlated strongly with a complicated outcome. No significant associations were found between delays and distance to nearest primary health care facility, relative levels of socio-economic deprivation within the study group, maternal educational attainment, or traditional healer consultation. CONCLUSION: Health care professionals at all levels should be alerted to the continued high incidence of this disease. We propose some 'red flags' to assist primary health care workers in the diagnosis of this condition. PMID- 17691479 TI - Knowledge and expectations of labour among primigravid women in the public health sector. AB - OBJECTIVES: We analysed knowledge and expectations of the process and pain of labour in primigravidas attending a local midwifery obstetric unit (MOU). It was anticipated that the results of this study could inform the development of interventions aimed at improving the analgesic care of women delivering at primary health care obstetric units. DESIGN: Qualitative analysis of data obtained from in-depth semi-structured interviews. SETTING: A Cape Town MOU. SUBJECTS: 30 black African, Xhosa-speaking primigravidas. OUTCOME MEASURES: An open-ended interview guide was developed. The themes explored included previous painful experiences, knowledge of labour, expectations of and attitudes towards labour pain, and knowledge of biomedical analgesia. RESULTS: Patients were poorly informed about the process and pain of labour. Most women appeared highly motivated concerning their ability to cope with labour. Most expected pain, but had no concept of the severity or duration of the pain, and knew very little concerning methods available for pain relief in labour. CONCLUSION: Women at this MOU were poorly prepared for the experience of delivery. Antenatal programmes should incorporate sensitive education concerning the process and pain of labour and the methods available to alleviate pain. PMID- 17691480 TI - [Primary and secondary malabsorption in the veterinary theory and praxis]. AB - Pathological conditions, which are the reason of indigestive and resorption in small intestine are linked with nutrition and are so-called malabsorptions. The reason of these conditions is on one hand decreasing of production abilities and on the other hand bad prosperity of farm husbandry eventually domestic animals. Malabsorptions are classified from pathological point of view to secondary and primary. To the first category belong the postsurgical state of digestive organs, malfunction of digestive organs from the various reasons such as decreasing of bile activity, decreasing of pancreas activity or for the reason of the malignant changes in the digestive organs or as the consequence of antibiotic treatment or cytostatics. The second category represents endogenous malfunction of intestine enzymes, which are linking with hypersensitivity to some kinds of feed. However the secondary malabsorptions are epiphenomenon several diseases, are in text also cure method mentioned, respectively mark of cure in some stadium diagnosed malabsorption. This present study is particulary oriented to pathogenesis and characterisation of the primary and secondary malabsorptions in the veterinary theory and praxis. PMID- 17691481 TI - [DNA repair--a new molecular target of anticancer therapy]. AB - DNA-damaging agents and radiation have a central role besides other cancer treatment modalities currently. The balance between DNA damage and capacity of DNA repair mechanisms determines the final therapeutic outcome. An elevated ability of cancer cells to recognize DNA damage and initiate DNA repair pathways is an important mechanism for therapeutic resistance and has a negative impact upon therapeutic efficacy. Pharmacological inhibition of recently detected targets of DNA repair with several small-molecule compounds, therefore, has the potential to enhance the cytotoxicity of anticancer agents. PMID- 17691482 TI - [Metabotropic glutamate receptors as a possible target of antiepileptic therapy]. AB - Antagonists of glutamate ionotropic receptors exhibit marked anticonvulsant action but also serious side effects, therefore attention is shifted to drugs influencing metabotropic glutamate receptors. These receptors are classified into three groups (I-III) and eight subtypes. Anticonvulsant action in experimental models was demonstrated for antagonists of group I receptors (mGluR1 and mGluR5) as well as for agonists of groups II (mGluR2 and mGluR3) and III (mGluR4, mGluR6, mGluR7 and mGluR8). Preclinical data are far from being complete but clear anticonvulsant action and absence of serious side effects speak in favor of further research. PMID- 17691483 TI - [From graphic charts to educational models]. AB - Thirty five years ago, A.C. Guyton at al. published a description of the large model of physiological relations in a form of a graphic chart. The authors brought this large-scale chart to life using a modern simulation tool- Matlab/Simulink. The original layout, connections and descriptions were saved in the implementation, but contrary to the old system analysis diagram, the new one is also a functional simulation model itself. Thus, the new implementation gives the user the possibility to see and study behaviour of all model's variables in time. Authors also describe the technology of development of multimedia learning simulators. PMID- 17691484 TI - [Morphological characteristic of renal injury in hypertensive rat strain transgenic for the mouse Ren-2 renin gene (TGR [mRen2] 27]. AB - The hypertensive rat strain transgenic for the mouse Ren-2 renin gene (TGR) strain name TGR [mRen 2] 27 is a valuable monogenic model of renin-dependent and thus angiotensin II dependent hypertension. It carries a salt -sensitive component. Homozygous animals exhibit clinically and morphologically typical sings of fulminant hypertension. Glomerular changes in accelerated (malignant) hypertension are acute or chronic. The acute changes have focal character; the most obvious change is segmental fibrinoid necrosis. Fibrinoid necrosis may extend from a similar lesion in the afferent arteriole and may be associated with crescent. Chronic changes are of two different types. The first is similar to that seen in benign hypertension, in that there is collapse of the capillary tuft with wrinkling of the glomerular basement membrane accompanied by collagenization of Bowmann's space. In the second type, glomeruli are also collapsed but seem almost acellular. Male heterozygous TGR are more suitable for experiments because their hypertension is lower and this model is much more similar to clinical situation. Morphologically prominent hyalinosis and segmental sclerotisation of capillary tuft of some glomeruli is present. These features correspond to secondary form of focal segmental glomerulosclerosis (FSGS). High salt diet in heterozygous animals induces a transition from benign to malignant phase of hypertension. In such case ischemic changes are superimposed on the pre-existing renal parenchymal disease (secondary FSGS). Selective blockade of endothelin receptors ET(A) is superior to non-selective ET(A)/ET(B) blockade in attenuating of hypertension and also morphology. ET receptor blockade in homozygous and heterozygous TGR has similar effect on morphological structure of renal parenchyma applied in rats with established hypertension as in young animals. Podocyte injury is crucial also in experimental hypertensive glomerulopathy. Podocytes showed degenerative changes and thickening of glomerular basement membrane was also present. Degree of morphological podocyte injury rather than hypertension correlated with mortality in homozygous TGR. PMID- 17691486 TI - [Arterial activity and antiflutter stabilization of blood stream]. AB - The passage of a pulse wave via an intact segment of a dog's thoracic aorta, its denerved autograft, and thoracic aortal allograft from a dog donor, was studied using equipment for arterial pressure measurement and tensometry of longitudinal and transversal blood vessel deformations at the point of pressure measurement. The frequency characteristics of the equipment were adjusted beforehand. The experiment demonstrated the impossibility of the formation and spread of a normal solitary pulse wave and preservation of laminar blood flow without an intact aortal innervation. Optimal blood flow hydrodynamics in the aorta is possible only in the presence of the system for neuroreflectory control of each wave passing; the system must determine the solitary character of the wave and provide antifluttery stabilization for blood flow. PMID- 17691485 TI - [The role of the serotoninergic system in the pathogenesis of experimental ulcerous colitis]. AB - Ulcerous colitis was modeled in a rat experiment by introducing picrylsulfonic acid. The role of serotoninergic structures in the pathogenesis of ulcerous colitis was studied by preliminary administration of serotonin or spiperone, a 5 HT2 serotonin blocker. Spiperone was shown to inhibit the damaging action of picrylsulfonic acid during the first ten days of the beginning of modeling, and to accelerate reparative processes. PMID- 17691487 TI - [On the topical aspects of the activity of the Federal Service for Legal and Organizational Providence of the Activity in the Sphere of Sanitary and Epidemiological Providence and Consumer Rights]. AB - The reorganization of the Federal Service on the Control Over the Sphere of Consumer Rights and Human Welfare has made it possible to significantly increase the number of specialists working in the sphere of consumer rights. In 2005, Federal Service on the Control Over the Sphere of Consumer Rights and its territorial organs carried out 155000 inspections of the legislation on consumer rights; more than 55% of them were off-schedule inspections of economic subjects. The inspections revealed almost 210000 facts of failure of the subjects to follow the rules of consumer legislation (140 reports on infringements). Of all the infringements, 40% were failures to satisfy consumer's rights for information. The Federal Service has opened a hotline on the actual problems of consumer rights. Similar hotlines have been opened by Magadan and Saint Petersburg etc. territory administrations. Among the main tasks directed to perfection of governmental control over consumer rights protection is development of a complex of measures aimed at prevention of infringements in this area, especially in dwelling sphere, medical aid, transportation, retail etc. Also needed are development and realization of interaction between territory organs of the Federal Service and local offices as well as public and remedial organizations working in the field of consumer rights and human welfare. Problems of hygiene and epidemiology in the Federal Service are nowadays being solved by 28 epidemiological, hygienic, and antiplague research institutes employing 3000 researchers including 290 doctors of science and 820 candidates of science. Territory administrations present the main regional structure of the Federal Service. This should be taken into account when building relations between territory administrations and regional offices of the Federal Service. The main directions of the activity of the Federal Service in 2006 are determined by 15 December 2005 order #794 and include a vast list. PMID- 17691488 TI - [Conseptual approaches to evaluation of the cost of quality of medical care: international practice]. AB - The article presents analysis of the basic approaches to evaluation of the cost of medical care quality that are used in the practice of a range of European countries and the USA. There are three processes considered in terms of the general management of the quality - value management from the point of view of a) business, the patient, c) healthcare personnel. Hence, benefits from the results depend on the quality of activity. The authors present a new point of view that connect constant improvement of quality with reengineering (re-design) of medical providence process so that their costs be lower than expenses caused by bad quality. PMID- 17691489 TI - [Philosophic and medical aspects of palliative care and the problems of euthanasia]. AB - The attitude of the society to the problem of euthanasia remains ambiguous from both moral and legal viewpoints. The authors review the attitudes of well-known philosophers, historians, and writers to the man's right for peaceful dying, and analyze various points of view on the problems of euthanasia. The article analyses ethical problems of palliative care as active care for a dying patient and his/her family. The philosophy of modern palliative medicine must favor the realization of the right for a peaceful death. The authors of the article consider palliative care for the dying to be an alternative to euthanasia. PMID- 17691491 TI - Some new math for philanthropy. PMID- 17691490 TI - [The translocation of macromolecules via the hematoencephalic barrier]. AB - The solution to the problem of transportation of high-molecular substances via the hematoencephalic barrier (HEB) is a necessary condition for the development of theoretical and applied aspects of selective transport of biologically active substances (neurotrops, medications) from blood into the brain. In the last decades, views on the possibility of macromolecular transport through intact HEB have changed substantially. Under physiological conditions, translocation of macromolecular substances via HEB is performed with the help of specific molecular transport systems and by endocytosis. The former mechanism prevails both in intensity and the nomenclature of the substances transported. The permeability of the intact (unchanged) HEB for macromolecules exists to an extent necessary for normal CNS functioning. Destruction of dense contacts in the HEB, local retraction and death of endotheliocytes, destruction of the basal membrane take place in pathological processes in the nervous tissue under the influence of inflammatory factors (cytokines, metalloproteinases etc) induced by activated endotheliocytes, T-lymphocytes, macrophages and glial cells; this in fact opens the paracell way for macromolecular components of blood. PMID- 17691492 TI - My passion. AB - There is a tension between the technical skills of dentistry that most practitioners are good at and enjoy and the business aspects of managing a successful practice. Inattention to the business side of practice can rob dentists of the success and satisfaction of their work. Fortunately, dentists can be trained to be effective leaders of their practices. The increase in commercialism will make that increasingly imperative. The CEO of Pride Institute explains her passion for teaching and coaching dentists to create and implement their visions. PMID- 17691493 TI - Practice management consulting: how to build a better practice throughout your career. AB - Practice management consulting focuses on placing a sound business system under the technical expertise of dentists. Dentists should spend almost all of their time at chairside where they can add greatest value to their patients. The good practices of business can be learned and implemented just like the good practices of dentistry can. Consulting may be necessary for any practice that is having issues; it is also recognized as an opportunity to raise any practice to higher levels. PMID- 17691494 TI - Who has the right to hold you back from your ideal practice? AB - Dentistry is growing in complexity, both technically and as a business. Dentists regularly and wisely seek help in developing their technical skills and should do the same in the area of business systems. Often the key to fulfilling practice is a team that shares the dentist's values and supports the functions that make the office efficient. The key to building such teams is communication. PMID- 17691495 TI - Passion, profitability, and positive attitude. AB - Many dentists work for their practices, experiencing frustration and lost enthusiasm. Their vision of the possibilities of their practices has been limited. They no longer see their practices as the result of choices they can make. Coaching can help overcome this narrow perspective. The commercial opportunities of Web marketing, new services such as implants and sedation dentistry, and large CE programs should be embraced by dentists to continue the recent trend of dentists earning more than physicians. PMID- 17691496 TI - Performance measurement approaches to more productive dental practices. AB - Although the trend is changing, most dentists work alone. This means a major impediment to improving practice productivity is lack of benchmarks against which to judge outcomes. The example of treating periodontal conditions based on population baseline parameters is used to illustrate how practices can become more successful with the help of organizations that provide performance measurement consulting. PMID- 17691497 TI - The evolving relationship between specialists and general dentists: practical and ethical challenges. AB - As dentistry evolves, so has the interrelationship between specialists and dentists, in many cases to maintain a full office schedule amidst changes in patient needs and practice philosophies. This essay will consider the ethical implications as well as the enablers and disablers of relationships between specialists working in a general dentist's office. Dentists need to consider all of the ethical implications before embarking on new relationships between dentists and specialists in order to best maintain patient trust and to provide enhanced patient care. PMID- 17691498 TI - Small ethics. AB - Traditionally, ethics in the professions has focused on big problems that could be found on other peoples' back porches. Small, habitual, frequent, and personal lapses get little attention. In this essay, the literature on opportunism is applied to dentistry with a view toward bringing matters of "near ethics" within reach. Examples of small lapses are discussed under the headings of shirking, free riding, shrinkage, pressing, adverse selection, moral hazard, and risk shifting. The conditions that support opportunism include relationships with small numbers of transactions and uneven access to information. Practical limits on understanding all the consequences of agreements and the costs of supervising others and enforcing corrections of breaches are inescapable aspects of opportunism. Opportunism may not be accepted by all as the subject matter of ethical, but curbing it is a worthy goal and understanding the causes and management of opportunism casts some light on the ethical enterprise. Four suggestions are offered for addressing issue of opportunism. PMID- 17691500 TI - Estate strategies and your family business. PMID- 17691499 TI - Housecall dentistry. PMID- 17691501 TI - Health care reform--it's all about accountability. PMID- 17691502 TI - A restoration revolution. PMID- 17691503 TI - How to make MassHealth work for you. PMID- 17691504 TI - Scleroderma and dentistry: every dentist is a scleroderma specialist. AB - Scleroderma is an autoimmune, rheumatoid factor-positive disease that may be localized or systemic, affecting the skin, lungs, kidneys, and cardiovascular system. Dental effects include xerostomia, microstomia, idiopathic resorption of tooth and bone, oral effects of medications, erosion and decay caused by gastroesophageal reflux disease (GERD), and poor oral hygiene due to physical and emotional effects of the disease. All dentists have the knowledge and ability to treat those suffering with scleroderma. PMID- 17691506 TI - J. Murray Gavel, DMD: bridging research and practice. AB - Few dentists have left as lasting a legacy as the late J. Murray Gavel, DMD. Today's practitioner can learn a great deal by emulating Dr. Gavel's approach to dentistry. An examination of his life also provides a snapshot of how the profession has changed and matured. As the 14th Annual Dr. J. Murray Gavel Lecture approaches, this article takes a look back at his life. PMID- 17691505 TI - Panoramic radiographs: a screening tool for calcified carotid atheromatous plaque. AB - Stroke is the third leading cause of death in the United States, according to a 2005 National Center for Health Statistics report. Atherosclerotic plaque in the cervical carotid artery accounts for a major proportion of strokes and also leads to billions of dollars in direct and indirect costs annually. The carotid bifurcation area, which is a likely site for atherosclerotic plaque accumulation, is well within the field of view of a diagnostic panoramic radiograph. Panoramic radiographs are the most frequently used extraoral images in private dental practices. It is only logical to use this widely available diagnostic tool to screen for calcifications in the cervical carotid arteries. If this oral and maxillofacial manifestation of a systemic disorder is identified during routine dental care and the patient is referred for appropriate follow-up and management, it would help reduce morbidity and bring significant savings in overall health care costs associated with atherosclerosis. PMID- 17691507 TI - Commonly encountered radiolucencies and radiopacities of the jaws. AB - Radiolucencies and radiopacities of the jaws are frequently encountered during the course of routine radiographic examination. Understanding when such radiographic features indicate a need for biopsy and histopathologic examination is important for appropriate patient management. PMID- 17691508 TI - A clinico-pathologic correlation. PMID- 17691509 TI - Exfoliative cheilitis. PMID- 17691510 TI - Class I malocclusion. PMID- 17691511 TI - An accurate portrayal. PMID- 17691512 TI - Unhappy pharmacists. PMID- 17691513 TI - Discharging the homeless. PMID- 17691514 TI - Staffing. Help wanted: demand is hot for IT professionals. PMID- 17691515 TI - Technology. EHRs hinder participation in pay for performance. PMID- 17691516 TI - Other voices. Mega influence. PMID- 17691517 TI - Competition. Regulators set sights on the expanding retail health clinic market. PMID- 17691518 TI - Design & construction. Finding funds for aging facilities is haphazard. PMID- 17691519 TI - Surgery with a guaranteed price. PMID- 17691520 TI - Quality. New Joint Commission measures in the works. PMID- 17691521 TI - Pharmacy. Medicare drug plan poses challenges for treating home patients. PMID- 17691522 TI - Seven tactics for hardwiring quality cost savings into hospital operations. PMID- 17691523 TI - Notes from the trail [Part 5]. PMID- 17691524 TI - The 2007 Most Wired results. Ten lessons from the top 100. AB - Information technology provides a wide range of tools to help hospitals improve quality. Here are 10 IT lessons from this year's 100 Most Wired Hospitals and Health Systems. Also inside, we reveal the 2007 award winners for Most Improved, Innovator, Small and Rural, Supply Chain and Most Wireless. And inaugural Most Wired International Certificates of Merit go to hospitals in Ireland, Spain and Japan. PMID- 17691525 TI - Will payment issues spoil the boom? Home care heats up. AB - Disease management and technology breakthroughs could relieve the health care staffing shortage and control costs by letting people with chronic conditions remain in their homes while caregivers monitor them from remote locations. But who pays? PMID- 17691526 TI - The 2007 NOVA Awards. AB - Though their initiatives vary in focus, the six winners of this year's NOVA awards have common commitment to partner with other community groups to spur transformational advances in their neighborhoods and the individuals who live there. PMID- 17691527 TI - States scorecard finds wide gaps in five key health care measures; no connection seen between high spending and high quality. PMID- 17691528 TI - Measuring what matters most. Current programs represent an excellent way to jump start performance reporting, but.... PMID- 17691529 TI - 2006 employment decisions under the ADA Title I--survey update. PMID- 17691530 TI - Evaluation of periodontal changes following intra-alveolar prosthesis for maxillary cheek tooth extraction in ponies. AB - This study investigated the placement of an intra-alveolar prosthesis of bone substitute on gingival/periodontal health in 5 ponies following repulsion of cheek teeth 108 and 208. In each pony, one randomly chosen alveolus was allowed to heal by second intention while the other was filled with a non-resorbable, biocompatible bone substitute. At 6, 12 and 24-months after surgery, both maxillary arches were evaluated for wear abnormalities and for gingival health using a periodontal scoring system. Recorded changes included development of overgrowths on mandibular cheek teeth, widening of maxillary interproximal spaces due to tooth drift with subsequent food accumulation, gingivitis, and subgingival pocket formation. Diastema formation initially occurred between the maxillary 06 and 07s but resolved after 24-months, whereas the diastemata that developed between the maxillary 09 and 10s remained. It was concluded that maxillary cheek teeth extraction induced progressive changes in the position of adjacent teeth that caused periodontitis. The use of a bone substitute prosthesis in the alveolus did not prevent the development of periodontal disease. PMID- 17691531 TI - Scanning electron microscopic study of the dentinal tubules in dog canine teeth. AB - Dentin adhesive restorative techniques are regularly used in veterinary dentistry. Knowledge of the microanatomic structure and properties of dentin is essential to ensure success in restorative procedures. The aim of this study was to describe the density and diameter of dentinal tubules in dog canine teeth using recently described standardized scanning electron microscopy techniques. The results showed dentin of dog canine teeth to be more oval-shaped with a higher tubular density and slightly larger tubular diameters compared with human teeth. These features suggest dog canine teeth have less intertubular dentin compared with human teeth, which may theoretically result in lower resin-dentin shear bond strengths. PMID- 17691532 TI - Reattachment of tooth fragment: an in vitro study. AB - Canine tooth fracture is common in dogs. Application of an esthetic and durable restoration may be challenging in veterinary dental practice. This study used traditional human dental laboratory methods to evaluate fracture strength of intact dog canine teeth and fractured teeth that had been restored by reattachment of the tooth fragment. The results showed that the teeth restored by reattachment of the tooth fragment supported a test load equal to 45.4 % of the load necessary to fracture intact canine teeth. PMID- 17691533 TI - Mandibular fracture repair in a harbor seal. AB - A 30-year-old captive female harbor seal (Phoca vitulina) bit down upon a metal ring within a hoop-net normally used to assist in securing the seal for routine physical examination. Radiographic examination performed under general anesthesia revealed a unilateral closed fracture of the rostral left mandible between the first and second premolar teeth. The rostral fragment was displaced ventrally and slight laxity of the mandibular symphysis was noted. The fracture was repaired surgically using an oral dental acrylic splint incorporating circumferential mandibular cerclage wire. The mandibular symphysis was stabilized using interdental wire between the right and left canine teeth. The fixation device was removed following evaluation of radiographs that showed signs of bony union 12 months postoperatively. PMID- 17691534 TI - Surgical management of compound odontoma in a dog. PMID- 17691535 TI - Oral soft tissue anatomy in the dog and cat. PMID- 17691536 TI - Composite restoration of enamel defects. PMID- 17691537 TI - Fifty years of United Kingdom national population projections: how accurate have they been? AB - This article considers the accuracy of the official national population projections made for the UK over the last fifty years The findings take account of the revision to population estimates following the 2001 Census and are largely similar to the findings of a previous review carried out after the 1991 Census. The total population has been projected reasonably accurately but this is largely a chance result of compensating errors in the assumptions of fertility, mortality and net migration. The largest differences between projected and actual populations are for the very young and the very old, while projections of the working age population have been comparatively accurate. Fertility and mortality errors have reduced in more recent projections, while migration errors have grown. However, this may simply reflect the volatility or stability of the respective time-series at the time the projections are made. Changes in estimates of the past and current size of the population (highlighted by the revisions made to population estimates following the 2001 Census) are also shown to play a part in explaining projection error. PMID- 17691538 TI - Understanding recent trends in marriage. AB - This article explores recent trends in marriage. Following consistent falls in marriage rates in the last quarter of the 20th century the early years of this century have seen some relatively large fluctuations in marriage numbers and rates. This article illustrates some of the recent trends in marriage. One innovation is that it presents marriage data by month, controlled for the effect of peak marriage days in the week. It also discusses a recent legislative change, affecting those subject to immigration control that wish to marry, which may be one of many factors affecting latest marriage trends. Readers should bear in mind that the 2005 data shown in the article are provisional. PMID- 17691539 TI - Using administrative data sources in the estimation of emigration. AB - It is important that migration is measured accurately, for example to inform population estimates and projections. However, current sources of information present challenges in producing robust estimates of emigration from Great Britain. This article reports on work carried out by the Office for National Statistics to investigate the potential for using administrative data sources to contribute to the measurement of emigration. PMID- 17691540 TI - Characterization of local chicken production systems and their potential under different levels of management practice in Jordan. AB - This study aimed to characterize the local chickens and their production systems and to investigate the opportunities for improvement. The study was carried out in 18 villages in northern Jordan with the participation of 120 households. Data were collected by individual interviews and surveys supported with structured questionnaires. A scoring system was developed to study the effect of different levels of management on chicken performance. The main reasons for keep local chickens were egg production and generation of income. The main features of the production systems were improper housing and inadequate hygiene. Newcastle disease, predators, and parasites were the main causes of flock losses. Purchasing rate was controlled by the chickens' phenotype, sex and age, and by season of year. The average flock size was 41.6 (+/-32.9) chickens per household, with a hen:cock ratio of 6.4:1. The average effective population size was 15.35, which indicated a high rate of inbreeding (5.52%). The main selection criterion adopted by farmers was egg production. There were positive significant correlations (p<0.001) between management level and chickens' performance. Hatchability, survivability, flock size, number of clutches, egg weight and egg mass were the major parameters that improved significantly with improvement in management level. Local chickens fulfil significant functions in the livelihood of rural smallholders; however, many constraints affected the efficiency of the production systems. Solutions should start with improving the management practices and establishing an effective breeding system. PMID- 17691541 TI - Village poultry consumption and marketing in relation to gender, religious festivals and market access. AB - This study aimed to examine village poultry consumption and marketing in Ethiopia in relation to gender, socio-cultural events and market access. The main objects of the research were producers, poultry markets, producer-sellers, and intermediary sellers in three locations representing different levels of market access in Tigray. About 3000 farm records were collected over a period of 12 months from 131 producers to obtain quantitative data on sales and consumption. Ninety-three semi-structured interviews with 58 producer-sellers and 35 intermediaries and 12 group discussions with these market actors were conducted to explore organization, price dynamics and socio-cultural aspects of poultry marketing. In total, 928 producer-sellers and 225 intermediaries were monitored monthly to examine participation by gender in poultry marketing. Better market access was associated with a shorter market chain and higher prices for the producers. Female-headed households had smaller poultry sales and consumption per household but sale and consumption per family member were 25% and 66% higher, respectively, than in male-headed households. While women dominated in the producer-sellers group, intermediaries were mainly men. Religious festivals periodically shifted local demand and prices of poultry. To improve the benefit of poultry keeping, poverty-stricken households may profit from better market access through better market information, infrastructure, market group formation and careful planning to match the dynamics in demand. PMID- 17691542 TI - Feeding strategies for small-scale dairy systems based on perennial (Lolium perenne) or annual (Lolium multiflorum) ryegrass in the central highlands of Mexico. AB - Small-scale dairying is an option for campesinos in Mexico. The costs of feeding are high and strategies based on quality forages are a priority. The performance, agronomic variables and feeding costs were evaluated for dairy cows continuously grazing perennial ryegrass-white clover for 9 h/day (PRG) or fed cut herbage from annual ryegrass for 8 weeks followed by 9 h/day for 6 weeks on a tethered rotational grazing pattern (ARG). All cows received 3 kg/day of an 18% crude protein (CP) concentrate. A 14-week split-plot on-farm experiment was designed with 10 cows from two participating farmers, and 1.5 ha per strategy. Milk yield was recorded weekly and milk composition, live weight and body condition score were recorded every 14 days. Net herbage accumulation was greater for ARG (8222 kg organic matter (OM)/ha) than for PRG (5915 kg OM/ha) (p<0.05), with higher CP in PRG (p<0.05). Milk yield was 19 kg/cow per day for PRG and 15.9 kg/ cow per day for ARG (p>0.05). Over 14 weeks, PRG produced 1422 kg more milk. There were no differences for live weight or condition score (p>0.05), but linear regression shows a live weight gain of 0.200 kg/cow per day for PRG. Protein and fat content showed no differences (p>0.05), but milk fat content in PRG was below standard. ARG had 60% higher costs, and margins were 38% higher in PRG. ARG has a place in rain-fed fields. The results provide viable options for improving these systems that may be suitable in their socio-economic context and their social and personal objectives. PMID- 17691543 TI - Village-based indigenous chicken production system in north-west Ethiopia. AB - Surveys using both purposive and random sampling methods was carried out in four zones of north-west Ethiopia to describe the village-based poultry production systems and constraints in order to design future improvement and conservation strategies. The majority of the respondents were female (74.16%). This indicated that most of the time the women, whether in male-headed or female-headed households, are responsible for chicken rearing while the men are responsible for crop cultivation and other off-farm activities. About 99% of the respondents gave supplementary feeds to their chickens. Almost all farmers provided night shelter for their chickens, in part of the kitchen (1.36%), in the main house (39.07%), in hand-woven baskets (7.29%), in bamboo cages (1.51%) or in a separate shed purpose-made for chickens (50.77%). The major causes of death of chickens during the study were seasonal outbreaks of Newcastle disease (locally known as fengele) and predation. It is important to collect and conserve local poultry breeds before they are fully replaced by the so-called improved breeds. As most of the poultry production is managed by women, focusing on training and education of women will enable not only the improvement of poultry production but also family planning and the overall living standards of the family and the community. PMID- 17691544 TI - Dairy production practices among smallholder dairy farmers in Butere/Mumias and Kakamega districts in Western Kenya. AB - A survey was conducted on 176 smallholder dairy farms in Butere/Mumias and Kakamega districts of Western Kenya to establish the dairy production practices and constraints in the industry. There was low milk production (16.6 kg of milk per capita), which was attributed to the low number of dairy animals. The average land size was 2.4 ha with only 30.3% being allocated to pasture or fodder crops. Farmers with large farms (>2 ha) set aside bigger pieces (1.2 vs 0.4 ha) for pasture/fodder crop cultivation (p<0.001), owned more (5.25 vs 3.18) dairy animals (p<0.01) and produced more (9.2 vs 7.5 kg/cow per day) milk (p<0.05) compared to those on smaller farms of less than 2 ha. The average herd size was 4.2 animals, of which only 45.0% were in milk, producing 8.0 kg/animal per day. Every kilogram of dairy meal fed increased milk production by 0.68 kg (p<0.001). Over 90% of milk produced was consumed locally. The public institutions provided 74% of total extension services to farmers. About 49.5% of total dairy animals were bought from other districts owing to scarcity. PMID- 17691545 TI - Supplementation with groundnut haulms for sheep fattening in the West African Sahel. AB - Groundnut haulms along with cowpea hay are major crop residues used for animal fattening in the West African Sahel. In traditional sheep fattening, feeds are always provided ad-hoc and in an unregulated fashion, which is rather wasteful. As a preliminary study to establish the optimal feeding levels of groundnut haulms for profitable sheep fattening, a feeding trial was conducted for 70 days with four levels of groundnut haulms (0, 150, 300 and 450 g/day) and a basal diet of bush hay. The effects of supplementation with groundnut haulms on feed intake, water consumption, live weight changes and economic return were determined. Twenty-four Peuhl Oudah rams with average initial weight of 28.6 kg (SD = 1.4) were randomly allocated to four treatments defined by the four levels of groundnut haulms in the diet. Faeces and urine were collected in weeks 5 and 9 of the trial. Digestible organic matter intake (g/(kg LW)0.75) and nitrogen intake (g/day) increased linearly with the level of groundnut haulms offered. Sheep that were fed only bush hay lost 18.4 g/day, while those that were offered 150, 300 and 450 g of groundnut haulms gained 1.4, 19.3 and 40.2 g/day, respectively. The gross return ranged from 1883 to 4946 FCFA per ram. Net benefit, after removing the feed and veterinary costs from the gross return, ranged from 368 to 1400 FCFA per ram. PMID- 17691546 TI - The place of Sanga cattle in dairy production in Uganda. AB - A survey was carried out on milk production and reproductive performance of dairy cattle: 24 farms, with a total of 900 animals and distributed in four agro ecological zones, were visited every 15 days over 18 months. Cows were fed on natural pastures as the only source of feed, and animal performance was dependent on the season and exhibited a dramatic drop in dry spells. Numeric productivity indices integrating productive performance for settler's, multipurpose, crop livestock integrated and modern farms were 0.56, 0.74, 0.69 and 0.63, respectively. Milk productivity was higher on modem farms (6.7 L/cow per day) than in the other systems, and higher with Holstein-Friesian cows (7.7 L/cow per day) than with indigenous cattle (1.8 L/cow per day) or crossbred animals (3.7 L/cow per day). This paper speculates on the opportunity to improve the genetic potential of indigenous cattle, concomitantly with the efforts to adapt exotic cattle to a mountainous equatorial environment. PMID- 17691547 TI - Sexual behaviour of yearling Awassi, Charollais x Awassi and Romanov x Awassi rams exposed to oestrous Awassi ewes. AB - This study was conducted to evaluate the sexual performance of 10-month-old, ram lambs of different breed groups. Eight ram lambs each of Awassi (A), F1 CharollaisxAwassi (CA) and F1 RomanovxAwassi (RA) breed types were subjected to sexual performance tests by being individually exposed to two oestrous Awassi ewe lambs for four 20-min periods. Bouts of leg kicking and anogenital sniffing were similar among breed groups. Mounting frequency was greater (p<0.05) in RA than in A and CA ram lambs. Tail-raising was greater (p<0.05) and mating rate tended to be greater (p<0.10) in A than in RA and CA ram lambs. The number of mounts per tail-raising (efficiency) was influenced by breed group and test day (p<0.05). Awassi ram lambs maintained the best efficiency throughout the experiment. Efficiency in RA and CA ram lambs improved with each test day. Results of the present study indicate that RA ram lambs have greater mounting frequency than A and CA, while Awassi are more capable of mating with fat-tailed females than the CA and RA ram lambs. PMID- 17691548 TI - The control motive and marital violence. AB - The role of the control motive in marital violence is examined using data on current and former marriages from the Survey of Violence and Threats of Violence Against Women and Men. The findings indicate no support for the position that husbands engage in more marital violence than wives because they are more controlling. In former marriages, we observe statistical interactions between gender and control: former husbands who were controlling or jealous were particularly likely to be verbally aggressive and to engage in violence. The controlling husbands (present and former), however, are not particularly likely to engage in violence that is frequent, injurious, or unprovoked. The evidence suggests that husband and wives may differ in their methods of control but not their motivation to control. PMID- 17691549 TI - Coping among victims of relationship abuse: a longitudinal examination. AB - This longitudinal study examined the associations between relationship abuse, coping variables, and mental health outcomes among a sample of battered women obtained from shelter and nonresidential community agencies (N = 61). Sexual aggression was a stronger predictor of poorer mental health than was physical assault. Engagement coping strategies were generally predictive of positive mental health, and disengagement coping strategies were generally predictive of poorer mental health. Results highlight the complexity of the associations between different forms of relationship abuse, coping strategies, and mental health among this population. PMID- 17691550 TI - Men's recognition of violence against women and spousal abuse: comparison of three groups of men. AB - Our goal was to assess whether men in the following three groups differ in their ability to recognize and judge the severity of diverse forms of aggressive behavior: (a) men who reported being physically aggressive toward their spouses and who were entering treatment for domestic violence; (b) men who, after participating in a treatment program, were no longer physically violent; and (c) men who reported never having been physically violent towards their spouses (NPV group-non-physically violent). All 81 men in the study reported being verbally aggressive toward their spouses. Men who had been in treatment for spousal abuse and who had not been physically violent toward their spouses since finishing the program were better able than the other two groups to recognize emotionally abusive behaviors. PMID- 17691551 TI - Prevalence and characteristics of sexual violence victimization among U.S. adults, 2001-2003. AB - This article provides the most recent U.S. prevalence estimates of forced sex and unwanted sexual activity. Results of a national telephone survey conducted in 2001-2003 indicate that 1 in 59 U.S. adults (2.7 million women and 978,000 men) experienced unwanted sexual activity in the 12 months preceding the survey and that 1 in 15 U.S. adults (11.7 million women and 2.1 million men) have been forced to have sex during their lifetime. There were 60.4% of females and 69.2% of males who were 17 years old or younger at the time the first forced sex occurred. This study provides an update to the National Violence Against Women Survey with more recent national data. Findings suggest that victimization rates have remained consistent since the 1990s. These findings suggest that a continued effort toward primary prevention of sexual violence, particularly rape of children and adolescents, is needed. PMID- 17691552 TI - A gender-based incidence study of workplace violence in psychiatric and forensic settings. AB - Limited data exist analyzing the role of gender in workplace violence in health care settings. This study examined whether different types of threatening incidents with patients (physical, verbal, sexual, or posturing) were salient to male versus female staff across psychiatric settings (inpatient forensic, inpatient acute/chronic psychiatric, and outpatient psychiatric). Results indicated that although women disproportionately experienced sexualized threats, they were not more likely to report such incidents as salient and threatening. The study also assessed the extent to which situational variables contributed to staff's feelings of threat. Results showed that rapport with the patient, quality of relationships with coworkers, and presence of coworkers in the area were not significantly related to how threatened staff felt in a recent threatening incident. Findings are discussed within the context of staff training and organizational benefits. PMID- 17691553 TI - Female victims of domestic violence: which victims do police refer to crisis intervention? AB - Factors associated with activation of a volunteer-based crisis intervention services program for victims of police-reported intimate partner violence (IPV) were examined to determine if those for whom services were activated were representative of the overall eligible population. The study population comprised 2,092 adult female victims of male-perpetrated police-reported IPV. Crisis intervention services were requested by responding patrol officers in 415 (19.8%) of these incidents. Activation of crisis intervention services was more likely for victims who were married to their abusive partner, pregnant, or of Latina or Asian race/ethnicity and among IPV incidents involving physical abuse, visible victim injuries, and arrest of the abusive partner. Additionally, one of the city's five police precincts was less likely than the remaining four to utilize these services. Activation of crisis intervention services was associated with factors related to need and feasibility of service delivery, but differential activation at the precinct level was also found to be influential. PMID- 17691554 TI - Maternal childhood parental abuse history and current intimate partner violence: data from the Pacific Islands Families Study. AB - Pacific peoples are a rapidly growing but socially disadvantaged segment of New Zealand society. Within this context, individuals may be particularly vulnerable to the experience of intimate partner violence (IPV). The aim of the study was to establish the association between the experience of maternal and/or paternal emotional or physical abuse and current severe physical partner violence perpetration or victimization among a cohort of Pacific women. Paternal physical abuse was the only statistically significant risk factor from childhood parenting history that was independently associated with severe physical perpetration and victimization within the mother's current intimate partner relationship (RR 2.6). These findings highlight the deleterious effect of paternal physical violence on subsequent IPV and contribute to the development of empirically based and considered ways to approach these complex phenomena. PMID- 17691555 TI - Gender differences in the relationship between intimate partner violence victimization and the perception of dating situations among college students. AB - Although the prevalence and severity of dating violence among college students is well known, the relationship between past victimization and perceptions of future dating situations has not been examined. Using both qualitative and quantitative research methods, this study investigated gender differences in the relationship between intimate partner violence victimization and the perceptions of dating situations. The study found that the more psychological, physical, or sexual violence that was experienced by females, the more likely they perceived dating situations as inappropriate. Males, on the other hand, were more likely to report aggressive behaviors in dating situations only if victimized by sexual violence. Implications for professionals working with college students or community prevention programs are discussed. PMID- 17691556 TI - The relationship between mothers' social networks and severe domestic violence: a test of the social isolation hypothesis. AB - To understand the relationship between characteristics of mothers' social networks and domestic violence, battered mothers who were severely assaulted were compared to battered mothers who were not severely assaulted and mothers who were not assaulted. The results showed that all three groups of mothers had several family members in their social networks with whom they had frequent contact during the past month. No differences were found between the groups on the number of family members who gave emotional support. However, the mothers who were severely assaulted had fewer friends, fewer contacts with their friends, fewer long-term friendships, and fewer friends who really listened to them than did the nonbattered mothers and the battered mothers who were not severely assaulted. Batterers may be more successful in disrupting friendship ties than family ties. PMID- 17691557 TI - A clinicians' guide to adverse drug reactions. PMID- 17691558 TI - Integrating approaches to paraquat poisoning. PMID- 17691559 TI - Maternal and cord blood levels of insulin-like growth factors--I and--II and insulin-like growth factor binding protein-1: correlation with birth weight and maternal anthropometric indices. AB - OBJECTIVES: To study the correlation of maternal and cord blood insulin like growth factor (IGF)-I and -II and IGF binding protein (IGFBP)-1 levels with birth weight and maternal anthropometric indices. DESIGN: Longitudinal prospective study. SETTING: Academic Institutions and a Tertiary Care Maternity Hospital. PARTICIPANTS: Women with uncomplicated singleton pregnancy (N = 35) and their newborns. MEASUREMENTS: Maternal weight, height, symphysiofundal height and serum levels of IGF-I, IGF-II, IGFBP-1 were measured thrice during the antenatal period, within 24 h of delivery and at 6 weeks and 6 months postpartum. Newborn anthropometric indices were recorded at birth, and at 6 weeks and 6 months of age. Cord blood levels of IGF-1, IGF-II, IGFBP-1, paternal height and weight, and placental weight measured. RESULTS: Maternal and cord blood IGF-I levels were lower than values reported for Caucasians. All newborns showed adequate growth at birth, and up to 6 months of age. Cord blood IGF-1 positively correlated with chest circumference (r = 0.4532, P = 0.0262), IGFBP-1, negatively with birth weight (r = -0.4024, P = 0.0461) and IGF-II had no effect. Cord blood IGF-I positively correlated with maternal levels at 28 +/- 2 (r = 0.4571, P = 0.0247) and 36 +/- 2 (r = 0.4291, P = 0.0364) weeks of amenorrhoea, whereas IGF-II and IGFBP-1 did not correlate with maternal values. Maternal IGF-I, IGF-II and IGFBP 1 did not correlate with newborn or maternal anthropometric indices. Placental weight correlated significantly with birth weight (r = 0.5299, P = 0.0348) and head circumference (r = 0.5031, P = 0.0470). CONCLUSIONS: Cord blood IGFBP-1 and placental weight appear to be determinants of birth weight variation even among appropriately grown for gestational age newborns. PMID- 17691560 TI - Adenocarcinoma of the stomach in a tertiary care hospital in Sri Lanka. AB - OBJECTIVES: Adenocarcinoma of the stomach carries a dismal prognosis when it presents late. Our objective was to describe the location of the tumour, stage at presentation, resectability and survival in a cohort of patients with adenocarcinoma of the stomach, presenting to a tertiary referral centre. DESIGN AND SETTING: Data were collected retrospectively from all patients with gastric neoplasms who presented to the University Surgical Unit, Colombo South Teaching Hospital from May 2000 to October 2006. RESULTS: Ninety three patients presented with malignant gastric neoplasms during this period. Majority (86/93) were adenocarcinomas. Mean age at presentation was 58.3 (range 33-83) years. Male to female ratio was 3.15:1. 52.6% of tumours were in the proximal stomach involving the cardia. Thirty per cent involved the body, and 17.5% the distal stomach. 93% had Stage III or IV disease at presentation. Twenty seven patients (32.5%) had resectable tumours with a mean survival of 25.3 months. Five year survival was less than 5%, in patients who were not offered surgical resection. There were no patients in our series with early gastric cancer. CONCLUSION: All our patients presented with advanced gastric cancer and the majority had unresectable disease. The high proportion of patients having proximal gastric carcinoma is similar to the recent changes seen in the west. PMID- 17691561 TI - A tribute to Dr Kumariah Balasubramaniam, MBBS (Ceylon), PhD and Diploma in Clinical Pharmacology (Manchester, UK). PMID- 17691562 TI - Management of persistent pancreatico-peritoneal fistulae by endoscopic transpapillary stenting. PMID- 17691563 TI - A middle-aged man with monoclonal gammopathy and osteopetrosis. PMID- 17691564 TI - Unusual manifestations in Miller-Fisher syndrome. PMID- 17691565 TI - Volatile substance misuse is often missed. PMID- 17691566 TI - Rabies vaccination of domesticated dogs in the Central Province of Sri Lanka. PMID- 17691567 TI - Knowledge and practice on use of anthelminthics by mothers in selected areas in the Colombo District. PMID- 17691568 TI - Gestational diabetes mellitus: the importance of adherence to diagnostic criteria in research. PMID- 17691569 TI - [Influence of mast cell function on the analgesic effect of acupuncture of "Zusanli" (ST 36) in rats]. AB - OBJECTIVE: To investigate the role of mast cells in acupuncture analgesia in rats. METHODS: A total of 48 Sprague Dawley (SD) rats were divided into normal control, acupoinc Effect [("Zusanli"(ST 36)-acupuncture (Acu), non-acupoint (3 mm left to ST36), disodium cromoglycate (DSC, 0.02 gmL, for acupoint injection), normal saline (NS, for acupoint injection), DSC + Acu, NS-b+ Acu and DSC+contralach Center ral Acu groups, with 6 cases in each group. The latency of tail flick response to heat irradiation was used as the pain threshold. "Zusanli" (ST 36) was punctured with filiform needle and stimulated by lifting and thrusting the needle for 30 min. After sacrifice under anesthesia (1% embutal) c, tissues of T36 area were sampled, sliced (4 microm), and stained with Toluidine Blue for skin and Neutral Red for muscles. RESULTS: Compared with normal control group, the ratios of pain threshold increased significantly in all the 7 experimental groups (P < 0.05), and those of DSC and NS groups were significantly lower than those of acupoint-Acu, non-acupoint, DSC+ Acu, NS+ Acu and DSC + contralateral Acu groups (P < 0.05) n. Comp + Acu group, the ratios of NS+Acu and DSC+ contralateral Acu groups were evidently higher (P < 0.05, 0.01). Compared with control group, the degranulation ratio of acupoint-Acu group was significantly higher (P < 0.05, 0.001 in muscle and skin separately), and the ratio of DSC+ Acu group was markedly lower than that of acupoint-Acu group (P < 0.01 in skin). CONCLUSION: Acupuncture of ST36 has a significant analgesia and enhances the degranulation of mast apparently cells, which is weakened by injection of DSC in the acupoint area, suggesting an important role of mast cells in acupuncture-induced analgesia. PMID- 17691570 TI - [Effect of acupuncture combined with intraperitoneal injection of paclitaxel on apoptosis in Lewis mice with lung carcinoma]. AB - OBJECTIVE: To observe the effect of acupuncture in combination with Paclitaxel on apoptosis in Lewis lung carcinoma mice so as to investigate their anti-cancer mechanism. METHODS: A total of 48 mice with inoculated Lewis lung carcinoma (LLC) were randomized into model, acupuncture, medication and acupuncture + medication groups, with 12 cases in each group. LLC model was established by subcutaneously incubating LLC cells into the left hindlimb of the C17 BL/6 mice. "Feishu" (BL13) was punctured and stimulated manually by manipulating the acupuncture needle with small amplitude for 1 main twice again, followed by intraperitoneal injection of Paclitaxel (10 mg/kg). The treatment was given once daily, continuously for 10 days. The tumor weight was recorded, the inhibitory rate of LLC calculated and the apoptosis of LLC cells displayed with TUNEL method. RESULTS: Compared with model group, the tumor weight values of acupuncture, medication and acupuncture + medication groups were significantly lower (P < 0.05), and the tumor inhibitory rates and the apoptotic index (Al) were markedly higher (P < 0.05). Comparison among acupuncture, medication and acupuncture + medication groups showed that the tumor weight values of the later 2 groups were obviously lower than that of acupuncture group, and that of acupuncture + medication group was apparently lower than the weight of medication group (P < 0.05); while the inhibitory rate of tumor and Al in acupuncture + medication group were significantly higher than those in acupuncture and medication groups (P < 0.05). The findings showed that acupuncture, medication and acupuncture + medication could significantly suppress the growth of tumor and promote apoptosis of LLC cells, and the effect of the combined treatment group was significantly superior to that of simple acupuncture and medication. CONCLUSION: Combination of acupuncture and Paclitaxel has a synergistic effect in inhibiting the growth of LLC and accelerating apoptosis of tumor cells. PMID- 17691571 TI - [Influence of intrathecal injection of fluorocitrate on the protective effect of electroacupuncture on gastric mucosa in high humid heat stress rats]. AB - OBJECTIVE: To study if the spinal glial cells involve in the protective effect of acupuncture on gastric mucosa in high humid heat stress rats. METHODS: Thirty-six male SD rats were randomized into 6 groups: control, stress model, electroacupuncture (EA), Fluorocitrate(FCA, intrathecal injection of FCA. 1 microL, 60 min before humid heat stress), EA+ normal saline (NS, intrathecal injection of NS) and EA+ FCA groups. Stress model was established by putting the rats in a container with higher temperature and higher humidity [(40.0 +/- 0.5) degrees C, relative humidity (60 +/- 5)%] for 60 min. EA (50 Hz, intermittent waves, 2-5 V) was applied to bilateral "Zusanli" (ST 36) for 60 min. Using immunofluorescent methods, we observed glial fibrillary acidic protein (GFAP) and microglia OX42 immunoreactivity (OD value) in the tissue of the lumbar enlargement segment of the spinal cord. We evaluated and recorded the damage index (DI) of gastric mucosa of rats according to Guth's method. RESULTS: There were clear dot-line-like hemorrhage foci with formation of ulcer in the gastric mucosa 60 minutes after high humid heat stimulation. Compared with model group, DI of gastric mucosa in EA and EA+ NS groups decreased significantly (P < 0.05, suggesting a protective effect of EA on the gastric mucosa under stress), OD values of EA and EA + NS groups increased considerably (P < 0.05). Comparison between EA and EA+ FCA groups showed that DI of EA + FCA group was higher than that of EA group, while the OD values of GFAP and OX42 in EA+ FCA group was markedly lower than those in EA group (P < 0.05), suggesting an inhibitory effect of FCA on the effects of EA in improving stress-induced damage of gastric mucosa and upregulation of GFAP and OX42 expression. CONCLUSION: EA at "Zusanli" (ST 36) can prevent the gastric mucosa from injury caused by high humid heat stimulation. The lumbar spinal glial cells may play a role in EA's protective function. PMID- 17691572 TI - [Protective effect of electroacupuncture of "xiusanzhen" on neuronal mitochondria in rats with acute cerebral ischemia-reperfusion injury]. AB - OBJECTIVE: To explore the protective effect of electroacupuncture (EA) of "Xiusanzhen"([Chinese characters: see text]) on mitochondria of cortical neurons in acute cerebral ischemia-reperfusion (CI/R) rats. METHODS: A total of 30 cases of SD rats were divided into control, model and EA groups. CI/R model was established by occlusion of the middle cerebral artery and reperfusion. EA (80 100 Hz, 1-3 mA) was applied to "Xiusanzhen" (the median line of the nose root, 2 mm to the lateral median line on the bilateral sides) for 60 min. Content of serum reduced glutathione (GSH) and glutathion peroxidase (GSH-Px) activity were detected by using Tietze's reducase assay and dithio-bis-nitrobenzoic acid (DTNB) direct method respectively. The surface density (Sv), numerical density (Nv) and perimeter/area (Pv) of the mitochondria of the cerebral neurons were detected using stereological technique and electronic microscope. RESULTS: Compared with control group, Sv and Pv of model group increased significantly (P < 0.05), while serum GSH content and GSH-Px activity of model group decreased considerably (P < 0.05). While in comparison with model group, Sv and Pv of EA group lowered obviously (P < 0.05), and GSH and GSH-Px both increased pronouncedly (P < 0.05). No significant difference was found among 3 groups in Nv (P > 0.05). CONCLUSION: EA of "Xiusanzhen" has a definite protective effect on mitochondria of cortical neurons in acute focal cerebral ischemia-reperfusion rats, which may be related with its antioxidation. PMID- 17691573 TI - [Effects of electric mildly-warmed needle of inner mongolian medicine on liver MDA and GSH content, GSH-Px and SOD activity in fatigue rats]. AB - OBJECTIVE: To investigate the effect of electric mildly-warmed needle of inner Mongolian medicine on changes of free radical metabolism in the liver tissue of rats with fatigue. METHODS: A total of 33 male SD rats were evenly randomized into control, model and electro-mildly-warmed needle (EMWN) groups. Fatigue model was established by forcing the rat to swim in a water pool till exhaustion, once daily, continuously for 21 days. "Dinghui" (central spot of the bregmatic bone) and "Xinxue" (the center of the depression beneath the 7th thoracic vertebra) were punctured with silver needle which was warmed electrically by using a MLY-I Electrical Needle-warming Apparatus, once every 3 days. 7 sessions altogether. After decapitation, the rat's liver was taken, homogenated and centrifuged for detecting malondialdehyde (MDA) content with thio-barbituric acid, reduced glutathione (GSH) contents, glutathione peroxidase (GSH-Px) activity with chromatometry and superoxide dismutase (SOD) activity with xanthine oxidase method respectively. RESULTS: Compared with control group, liver GSH content, GSH Px and SOD activity in model group lowered significantly (P < 0.05, 0.01), while in comparison with model group, these 3 indexes of EMWN group increased considerably (P < 0.05, 0.01). No significant differences were found among 3 groups in MDA levels (P > 0.05). The results showed that the effect of mildly warmed needle treatment could resist fatigue induced decline of activity of antioxidant enzymes. CONCLUSION: Electric mildly-warmed needle therapy of inner Mongolian medicine can raise the activity of antioxidant enzymes in liver tissue of fatigue rats, which may underlie the action of mildly-warmed needle in improving fatigue. PMID- 17691574 TI - [Effect of warmth-promotion needling on cerebral SOD, MDA and AChE in vascular dementia rats]. AB - OBJECTIVE: To observe the effect of warmth-promotion needling on cerebral malondialdehyde (MDA) content, superoxide dismutase (SOD) and acetylcholinesterase (AChE) activity so as to explore its underlying mechanism in improving vascular dementia (VD). METHODS: Forty Wistar rats were randomized into control, model, medication, needle-twirling and warmth-promotion groups with 8 cases in each. VD model was established by occlusion of the bilateral common carotid arteries and reperfusion in combination with intraperitoneal injection of sodium nitroprusside (2.5 mg/kg). Warmth-promotion needling was applied to "Dazhui" (GV 14), "Baihui" (GV 20) and "Shuigou" (GV 26). Rats of medication group were intragastric perfusion of Nimodipine suspension (0.0108 g/kg). The treatment was given once daily continuously for 15 days. SOD and AChE activity and MDA content of the brain (right side) tissue were detected with purine oxidase method, hydroxylamine chromatometry and thio-malonylurea method separately. RESULTS: In comparison with control group. SOD activity of model group decreased significantly (P < 0.01), AChE activity and MDA content increased considerably (P < 0.01); while compared with model group, SOD activity of warmth promotion, needle-twirling and medication groups raised evidently (P < 0.01), AChE activity and MDA content of the later 3 groups lowered significantly (P < 0.05, 0.01). The effects of warmth-promotion group were significantly superior to that of medication group in lowering MDA content and to those of needle-twirling group in raising SOD activity and lowering AChE activity and MDA content (P < 0.05). CONCLUSION: Warmth-promotion needling can function well in resisting lipid peroxidation injury and lowering AChE activity in VD rats, which may contribute to its effect in improving learning-memory ability. PMID- 17691575 TI - [Effect of acupoint application therapy on expression of IL-4 and IFN-gamma in lung tissue of asthma rats]. AB - OBJECTIVE: To observe the effect of acupoint application of Chinese herbal medicines on pathological changes of pulmonary tissue in asthma rats so as to explore its underlying mechanism. METHODS: A total of 33 Wistar rats were randomized into normal control (n=6), model (n=9), dexamethasone (DX, n=9) and acupoint-application (A-A, n=9) groups. Asthma model was established by intraperitoneal injection of 10% ovalbumin(OVA, 1 mL)and forced inhalation of atomized 2% OVA (25 mL) for 40 min, once daily for 2 weeks. "Dazhui" (GV 14). "Pishu" (BL 20), "Feishu" (BL 13) and "Shenshu" (BL 23) were selected for external application of Chinese medicinal herbs (pricklyash peel, white mustard seeds, asarum herb, etc.) for rats of A-A group, and that of control drugs (ang kak, black rice, ginger juice, etc) for rats of DX group. Infiltration degrees of eosinophils (Eos), lymphocytes (L) and macrophages (MO) in the pulmonary tissue were observed under microscope. IL-4 and IFN-gamma expression was displayed by using immunohistochemical method. RESULTS: In comparison with control group, the infiltration degrees of E(OS). L and Mphi increased significantly in model, DX and acupoint-application groups (P < 0.05, 0.01); while compared with model group, the infiltration of E(OS), L and Mphi in DX group, E(OS) in A-A group decreased significantly (P < 0.05, 0.01). No significant differences were found between DX and A-A groups in these 3 indexes (P > 0.05). Results of immunohisto chemical staining in the lung tissue indicated that compared with control group, IL-4 expression in model increased significantly (P < 0.01), IFN-gamma expression decreased considerably in model and DX group (P < 0.01); when compared with model group, IL-4 in both A-A group and DX group decreased significantly, and IFN-gamma expression in A-A group increased considerably (P < 0.05, 0.01). No significant differences were found between DX and A-A groups in IL-4 expression (P > 0.05). CONCLUSION: Acupoint application of Chinese herbal medicines can balance Thl/Th2 and effectively reduce the infiltration of eosinophils, which may contribute to its therapeutic effect in relieving asthma. PMID- 17691576 TI - [Observation on the effect of acupuncture of "Wuyi" (ST 15) and multiple acupoints on the size of lacteal gland in rats with cyclomastopathy]. AB - OBJECTIVE: To compare the therapeutic effects of acupuncture of "Wuyi" (ST 15) and multi-acupoints for hyperplasia of mammary glands so as to choose the key acupoints for cyclomastopathy. METHODS: A total of 48 FEMALE Wistar rats were randomized into normal control, model, "Wuyi" (ST 15) and multi-point groups with 12 cases in each group. Cyclomastopathy model was established by intraperitoneal injection of benzestrofol (0.5 mg/kg per day) for 25 days. followed by administration of flavolutan (4 mg/kg per day, i.p.) for 5 days. Bilateral ST15 were punctured and stimulated manually for ST15 group; while for multi-point group, bilateral ST15, "Hegu" (LI 4), "Zusanli" (ST 36) and "Shanzhong" (CV 17) were punctured, once daily, 27 sessions altogether. After decapitation, the rats' second pairs of mammary glands were removed to be fixed routinely, embedded in paraffin, sectioned (5 microm), and stained with H & E method for observing the structural changes under microscope and with norphometry. RESULTS: Compared with control group, the diameter and area of acinar lumina (AL) of mammary glands in model group increased significantly (P < 0.01), whereas those in both ST15 and multi-point groups were significantly lower than those 2 indexes in model group (P < 0.01). No significant differences were found between ST15 and multi-point groups in the diameter and area of AL. CONCLUSION: "Wuyi" (ST 15) can effectively suppress estrogenic hormones-induced hyperplasia of mammary glands and is thus a key acupoint for treatment of cyclomastopathy. PMID- 17691577 TI - [Comparison of the analgesic effect of acupuncture between otopoint-penetrative needling and otopoint-straight needling for cervical type and nerve-root type cervicospondylopathy]. AB - OBJECTIVE: To confirm the better analgesic effect of otopoint-penetrative needling for cervical type and nerve-root type cervicospondylopathy. METHODS: A total of 98 cervicospondylopathy outpatients (50 cases of cervical type and 48 cases of nerve-root type) were randomly divided into treatment group (otopoint penetrative needling) and control group (otopoint-straight needling) in the light of paring method of comprehensive factors of sexes, ages and the state of disease. The main oto-points used were bilateral Jingzhui Area (AH 13) in combination with Jian-Jianguanjie-Suogu (Shoulder-Shoulder-joint-Collarbone) Area, etc. The simplified McGill Pain Scaling was used to give the score of patient's pain before the treatment, 5 min and 30 min after the treatment. RESULTS: Results of sequential trial indicated that the analgesic effect of otopoint-penetrative needling was significantly superior to that of otopoint straight needling 30 min after the treatment (P < 0.05). Findings of matched-pair t test showed that no marked differences were found between two groups in the pain scores before the treatment, while after the treatment, the pain scores of otopoint-penetrative needling group were significantly lower than those of otopoint-straight needling group (P < 0.001, 0.01), meaning that the analgesic effect of otopoint-penetrative needling was significantly better than that of otopoint-straight needling 5 min and 30 min after the treatment in both men and women, in both cervical type and nerve-root type patients, and in both young and older patients. CONCLUSION: The analgesic effect of otopoint-penetrative needling is obviously superior to that of otopoint-straight needling. PMID- 17691578 TI - [Clinical treatment of apoplectic aphemia with multi-needle puncture of scalp points in combination with visual-listening-speech training]. AB - OBJECTIVE: To observe the therapeutic effect of cluster-needle stimulation of scalp-points combined with rehabilitation training for apoplectic aphemia. METHODS: A total of 56 outpatients were randomized into control (medication, manicol/ beronald, Ca2+ antagonist, citicoline, etc.) group. rehabilitation (Rehab, visual-listening, articulation and speech training) group and acupuncture [Dingqu: 1 cun and 2 cun parallel to the line joining Baihui (GV 20) and Qianding (GV 21) respectively on the bilateral sides. Dingqianqu: 1 cun and 2 cun parallel to the line joining GV21 and Xinghui (GV 22) separately on both sides. etc] combined with rehabilitation (Acup+ Rehab) group. Aphasia Battery of Chinese (ABC) was used to assess the patient's speech ability, i.e., aphasia quocient (AQ); The Chinese functional communication (CFCP) test was used to evaluate the patient's daily life speech communication ability, and Boston Diagnostic Aphasia Examination (BDAE) was also conducted to assess the severity of aphasia. RESULTS: After the treatment, the speech ability, oral presentation, listening comprehension, writing ability, AQ index and CFCP were all improved significantly in 3 groups (P < 0.005, 0.01); the total effective rate (85.00%) of Acup+ Rehab group was significantly higher than those of Rehab group (77.78%) and control group (64.71%, P < 0.05, 0.01). The scores of ABC, AQ index, CFCP and BDAE grade in Acup+ Rehab group were significantly higher than those of Rehab and control groups (P < 0.05, 0.01), and those scores of Rehab group were also significantly higher than those of control group (P < 0.05, 0.01). CONCLUSION: The cluster needle puncture of scalp-points combined with rehabilitation training is an effective therapy for improving apoplectic aphemia. PMID- 17691579 TI - [Analysis on the therapeutic effect of acupuncture of Jiaji (EX-B 2) for treatment of cervical hypertension]. AB - OBJECTIVE: To observe the therapeutic effect of acupuncture therapy for treatment of cervical hypertension. METHODS: Sixty cases of cervical hypertension patients were randomly divided into treatment group and control group by using random table method. For patients of treatment group bilateral cervical Jiaji (EX-B 2) were punctured, and for those of control group, Fengchi (GB 20), Taichong (LR 3), Quchi (LI 11), Zusanli (ST 36) and Sanyinjiao (SP 9) were punctured. Changes of blood pressure and clinical symptoms were recorded before and after the treatment. RESULTS: Of the two 30 cases in treatment and control groups, 18 (60.0%) and 13 (43.3%) had a remarkable hypotensive effect, 10 (33.3%) and 9 (30.0%) had a hypotensive effect, 2 (6.7%) and 8 (26.7%) had no apparent changes in blood pressure; 12 (40.0%) and 5 (16.7%) experienced marked improvement in clinical symptoms, 15 (50.0%) and 16 (53.3%) were effective, 3 (10.0%) and 9 (30.0%) failed in the treatment, with the effective rates being 90.0% and 70.0% respectively. The therapeutic effect of treatment group was apparently superior to that of control group in lowering blood pressure and the cumulative scores of clinical symptoms and in improving clinical symptoms (P < 0.05, 0.01). CONCLUSION: Acupuncture of Jiaji (EX-B 2) is an effective therapy in the treatment of cervical hypertension. PMID- 17691580 TI - [Effect of electroacupuncture on gastrointestinal dynamics in acute pancreatitis patients and its mechanism]. AB - OBJECTIVE: To investigate the therapeutic effect and mechanism of electroacupuncture (EA) in treating gastrointestinal disorder in acute pancreatitis (AP) patients. METHODS: A total of 94 cases of AP patients were divided into acupuncture group (n=56) and control group (n=38). The severity of AP was evaluated according to APACHE II and Balthazar CT scoring system. EA (4 Hz, 4-6 V) was applied to bilateral Zusanli (ST 36), Shangjuxu (ST 37), Xuanzhong (GB 39), Taichong (LR 3), and Gongsun (SP 4) for 60 min, twice a day, 5 days altogether. Total and segmental colonic transit time (CTT) were determined by using ingestion of radiopaque markers (SITZMARKS) according to the modified Metcalf's method, serum motilin (MTL), cholecystokinin (CCK), vasoactive intestinal peptide (VIP) contents were assayed using enzyme linked immunosorbent assay (ELISA). RESULTS: Compared with normal values, total and segmental CTT of AP patients (control group) increased apparently (P < 0.05), especially in right colon, serum MTL and CCK contents in both control and treatment groups on the 1st day decreased considerably (P < 0.05), while serum VIP levels of both control and treatment groups on the 1st day increased markedly (P < 0.05). In comparison with control group, total and segmental CTT of treatment group decreased significantly (P < 0.05). Auto-comparison of both control and treatment groups showed that serum MTL and CCK contents on day 9 were significantly higher than those on day 1 (P < 0.05), while serum VIP contents on day 9 in these two groups were both obviously lower than those on day 1 (P < 0.05). No significant differences were found between treatment group and control group in serum MTL, CCK and VIP levels on the 9th day after the treatment (P > 0.05). CONCLUSION: Acupuncture is able to enhance the gastrointestinal dynamics, improve its motor activity. PMID- 17691581 TI - [Effect of electroacununcture on sex hormone levels in patients with Sjogren's syndrome]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) on serum testosterone (T), estradiol (F2), luteotropic hormone (LH), follicle-stimulating hormone (FSH), progesterone (P), and prolactin (PRL) in patients with Sjogren's Syndrome (SS) in order to analyze the correlation between the adjustment effect of EA and changes of hormone levels. METHODS: Fifty-seven middle-aged and old women with SS were divided into medication group (n=27) and acupuncture group (n=30). Patients in acupuncture group were treated with EA (80 Hz, 2.5 mA) of Shenshu (BL 23), Taixi (KI 3), Hegu (LI 4), etc. for 30 min, once every other day, and those of medication group were treated with oral administration of hydroxyl-chloroquine (6 mg/kg per day), oral transfer agent liquid, Vit B1, Vit B2, Vit C, fish-liver oil, one tablet/time, t.i.d., and pilocarpine (20 mg/d), continuously for 2 months. Venous blood samples were collected before and after the treatment to examine contents of the abovementioned sex hormones by using electro chemiluminescent immunoassay (CLIA). RESULTS: (1) Before the treatment, no significant differences were found between two groups in the levels of serum T, E2, LH, FSH, P and PRL (P > 0.05). After the treatment, self-comparison of each group showed that serum EF and T contents in acupuncture group increased significantly (P < 0.01) and serum LH content decreased significantly (P < 0.01); while in medication group, only serum LH decreased markedly (P < 0.05) in comparison with its basic value of pretreatment. No significant changes were found in serum P, FSH and PRL levels in both groups after the treatment (P > 0.05). The results suggested that the therapeutic effect of acupuncture group was better than that of medication group in regulating multiple sex hormones. CONCLUSION: EA can effectively adjust E2, T and LH levels in Sjogren's Syndrome patients and improve most patients' clinical symptoms, and the therapeutic effect of EA is better than that of medication. PMID- 17691582 TI - [Summary of the research on Master Dou's Canon of Acupuncture]. AB - Doutaishi Zhenjing ("[Chinese characters: see text]" Master DOU's Canon of Acupuncture) is a monograph on acupoints, without spreading widely. Now, there exist two manuscript writings, namely, Yang's Jiachuan Zhenjing Tuxiang ("[Chinese characters: see text]") YANG's Patrimonial Acupuncture Canon and Pictures) and Yulong Ge ("[Chinese characters: see text]") Jade Dragon Verse), but both are not complete. The maneuvers of acupuncture needle and indications of acupoints recorded in Master DOU's Canon of Acupuncture still have an important clinical significance in guiding current acupuncture practice. In the present paper, the authors simply introduce their study results about this monograph from the title and published time, writer, origin and development of the handed copies, basic contents and the academic source for further study in the coming days. PMID- 17691583 TI - [Discussion on the essence of meridian-collateral system]. AB - The meridian-collateral system of traditional Chinese medicine refers to the regulating system composed of the known loose connective tissue, liquid-Qi of tissue, energy substances, nerves, blood vessels, lymph, etc. existing in the fascia space between the skin, muscles and bone and some associated unknown synthetic functions. This hypothesis of meridian-collateral, Qi-passage, and fascia space composed of multiple substances is probably able to unify different viewpoints about that the meridian-collateral system is in fact an integrated substance of nerves, body fluid and energy. In the present paper, the authors introduce their viewpoints about the essence of meridian-collaterals from nerves, humor and energy, and unknown function of the known anatomical structure. PMID- 17691584 TI - [Progress in the study on the relationship between effects of acu-moxibustion and mast cells in acupoints]. AB - The present paper reviews develonment of researches on the relationship between mast cells (MCs) and effects of acupuncture and moxibustion from (1) the formation, distribution, types, morphological characters of MCs and their biological effects, (2) the number and degranulation of MCs in acupoints, (3) the relavance of MCs and the phenomenon of sensation transmission along meridian, and 4) the correlation between the therapeutic effect of acupuncture for relieving allergic reaction and MCs. Researches show that (1) MCs act as one of the characteristic constituents in acupoints where the MCs are in close relation with the effects of acupuncture and moxibustion, (2) MCs participate in the regulatory process of the organism in physiology and pathology. The underlying mechanism of MCs-related neuro-humoral regulation and meridian needs to be studied further. PMID- 17691585 TI - Interactions between iron(III)-hydroxide polymaltose complex and commonly used drugs / simulations and in vitro studies. AB - Under physiological conditions, ferric ions are essentially insoluble because of the formation of polynuclear hydroxo-bridged complexes. Ferrous ions are more soluble but may produce hydroxyl radicals on reaction with hydrogen peroxide. Chelation of ferric and ferrous ions with organic ligands may prevent these undesirable reactions. Alternatively, iron(III)-hydroxide/oxide can be stabilized and solubilized by tight interactions with carbohydrates. The data presented in this work show that, because of its physicochemical properties, the iron(III) hydroxide polymaltose complex (IPC, Maltofer) does not interact with the active ingredients of commonly used drugs such as acetylsalicylic acid (CAS 50-78-2), tetracycline hydrochloride (CAS 64-75-5), calcium hydrogen-phosphate (CAS 7757-93 9), methyl-L-dopa sesquihydrate (CAS 41372-08-1), and magnesium-L-aspartate hydrochloride (CAS 28184-71-6). In contrast, as confirmed by calculations using thermodynamic parameters, FeCl3 x 6H2O (CAS 10025-77-1) can form different types of complexes with these substances. Moreover, the data show that under aerobic conditions high concentrations of ascorbic acid (CAS 50-81-7) can lead to mobilization of iron from IPC and, thus, support the observation that orange juice slightly increases the uptake of iron from IPC. PMID- 17691586 TI - Interactions between iron(III)-hydroxide polymaltose complex and commonly used medications / laboratory studies in rats. AB - Simple iron salts, such as iron sulphate, often interact with food and other medications reducing bioavailability and tolerability. Iron(III)-hydroxide polymaltose complex (IPC, Maltofer) provides a soluble form of non-ionic iron, making it an ideal form of oral iron supplementation. The physicochemical properties of IPC predict a low potential for interactions. The effects of co administration with aluminium hydroxide (CAS 21645-51-2), acetylsalicylic acid (CAS 50-78-2), bromazepam (CAS 1812-30-2), calcium acetate (CAS 62-54-4), calcium carbonate (CAS 471-34-1), auranofin (CAS 34031-32-8), magnesium-L-aspartate hydrochloride (CAS 28184-71-6), methyldopa sesquihydrate (CAS 41372-08-1), paracetamol (CAS 103-90-2), penicillamine (CAS 52-67-5), sulfasalazine (CAS 599 79-1), tetracycline hydrochloride (CAS 64-75-5), calcium phosphate (CAS 7757-93 9) in combination with vitamin D3 (CAS 67-97-0), and a multi-vitamin preparation were tested in rats fed an iron-deficient diet. Uptake of iron from radiolabelled IPC with and without concomitant medications was compared. None of the medicines tested had a significant effect on iron uptake. Iron-59 retrieval from blood and major storage organs was 64-76% for IPC alone compared with 59-85% following co administration with other medications. It is concluded that, under normal clinical conditions, IPC does not interact with these medications. PMID- 17691588 TI - Effect of an oral iron(III)-hydroxide polymaltose complex on tetracycline pharmacokinetics in patients with iron deficiency anemia. AB - The study was carried out as an open-label, but laboratory-blind, single-dose, single-centre, randomized, two-period crossover study. Twenty-two patients with iron deficiency anemia completed the study. The study consisted of two treatment phases of 36 h, separated by a washout period of between 6 and 14 days. The two treatments were given orally. The reference treatment was tetracycline (CAS 60-54 8) alone (2 x 250 mg capsules) and the test treatment was iron(III)-hydroxide polymaltose complex (IPC, Maltofer) together with tetracycline (2 x 250 mg capsules). IPC had no pharmacokinetic effect on the rate of absorption of tetracycline. With concomitant administration of tetracycline and IPC sufficiently high tetracycline concentrations, to ensure bacteriostasis, will be reached. An inhibitor effect of IPC to the tetracycline absorption, as it is known for ferrous salts, could not be observed. PMID- 17691587 TI - Effect of oral tetracycline on iron absorption from iron(III)-hydroxide polymaltose complex in patients with iron deficiency anemia / a single-centre randomized controlled isotope study. AB - The study was carried out as an open-label, laboratory-blind, single-dose, randomized, two-period crossover, isotope efficacy study. Twenty-two patients with iron-deficiency anemia were enrolled in the study. The study consisted of two treatment phases of 15 days each, including blood sample measurements for Fe 59 activity. The two treatments were given orally. Treatment A was Fe-59 labeled iron(III)-hydroxide polymaltose complex (IPC, Maltofer) equivalent to 100 mg elemental iron given orally. Treatment B consisted of Fe-59 labeled IPC complex equivalent to 100 mg elemental iron and 500 mg tetracycline HCl (CAS 64-75-5) given orally. No differences between the two treatment groups with regard to the erythrocyte iron uptake were found, and thus IPC can be used with tetracycline, if necessary. PMID- 17691589 TI - Effect of oral aluminium hydroxide on iron absorption from iron(III)-hydroxide polymaltose complex in patients with iron deficiency anemia / a single-centre randomized controlled isotope study. AB - The study was carried out as an open-label, laboratory-blind, single-dose, randomized, two-period crossover, isotope efficacy study. Twenty-two patients with iron-deficiency anemia were enrolled in the study. The study consisted of two treatment phases of 15 days each, including blood sample measurements for Fe 59 activity. The 2 treatments were given orally. Treatment A was Fe-59 labeled iron(III)-hydroxide polymaltose complex (IPC, Maltofer), equivalent to 100 mg elemental iron given orally, and Treatment B consisted of Treatment A combined with 600 mg aluminium hydroxide (CAS 21645-51-2) (10 ml). No differences between the two treatment groups with regard to the erythrocyte uptake were found, and thus IPC can be used with aluminium hydroxide, if necessary. PMID- 17691590 TI - Food interaction of oral uptake of iron / a clinical trial using 59Fe. AB - OBJECTIVES: A primary objective of the study was to evaluate how food as well as a specific enhancer or an inhibitor of iron uptake affect erythrocyte iron uptake after oral administration of iron(III)-hydroxide polymaltose complex (IPC, Maltofer) in subjects with or without iron deficiency. Secondary objectives of the study were 1. to compare the uptake of 59Fe in erythrocytes between subjects with or without iron deficiency, 2. to evaluate the 59Fe activity in plasma after oral administration of IPC and 3. to evaluate the safety of oral administration of IPC by adverse events (AEs), vital signs, and hematological and clinical chemistry parameters. DESIGN: Single-centre study with a crossover design. Each subject participated in two periods where single doses of 100 mg iron as IPC labeled with 59Fe were administered. In one period the subjects were fasting and in the other they were fed (Group A and Group B). Alternatively the study medication was administered in the fed state with an iron absorption enhancer (orange juice) or an iron absorption inhibitor (black tea, Group C and Group D). Eight subjects were included in each group, i.e. 32 subjects were included in total. All subjects completed the study and were included in the analyses of data. RESULTS: In terms of relative incorporation of iron in erythrocytes, both subjects with and without iron deficiency benefited from the concomitant administration of an enhancer with the IPC. In iron deficiency subjects the iron uptake was improved when administered with food whereas for the normal subjects the uptake was greater during fasting conditions. The uptake of 59Fe in erythrocytes was greater in subjects with iron deficiency compared to the normal subjects, except when IPC was administered during fasting conditions. The safety assessments performed in this study did not demonstrate any unexpected observations or safety concerns with IPC. CONCLUSION: In both subjects with and without iron deficiency treated with IPC the relative iron incorporation in erythrocytes increased in case of a concomitant administration of an enhancer. Furthermore, the 59Fe uptake in erythrocytes was higher in subjects with iron deficiency compared to normal subjects, except when IPC was administered during fasting conditions. PMID- 17691591 TI - Effect of oral supplementation with iron(III)-hydroxide polymaltose complex on the immunological profile of adolescents with varying iron status. AB - OBJECTIVE: To assess the effects of iron supplementation on immunological parameters of adolescents with varying iron status. METHOD: Adolescents of both sexes with varying iron status were allocated to four treatment groups by using inclusion criteria. Three of the four groups received iron(III)-hydroxide polymaltose complex (IPC, Maltofer) containing 100 mg of iron 6 days a week for 8 months. The fourth group was given a placebo. Immunological parameters were assessed at baseline and after 4 and 8 months of supplementation. RESULTS: Increases from baseline to 4 months and from 4 to 8 months of supplementation were observed for Bactericidal Capacity of Neutrophils (BCA), NitroBlue Tetrazolium Reduction Test (NBT), and phytohaemagglutinin (PHA) in all three supplemented groups. No increase was found in the control placebo group except for PHA. No side effects were noted in any participants. CONCLUSION: IPC supplementation for eight months led to significant improvements of immunological parameters in iron deficient adolescents with and without anemia. PMID- 17691592 TI - Effects of iron deficiency anemia on cognitive function in children. AB - OBJECTIVE: To examine the effects of iron deficiency anemia on cognitive function and intelligence in children. METHODS: Matched case-control study was carried out with 30 children (aged 6-12 years) with iron deficiency anemia (IDA) but without any chronic disease and with normal neuromotor development. The WISC-R intelligence test was performed before and after 4-6 months of iron/vitamin treatment (5 mg iron/kg/day as iron(III)-hydroxide polymaltose complex, IPC, and multivitamin preparation). Pre- and post-treatment IQ scores of the IDA group were evaluated and compared to the control group. RESULTS: Treatment and control groups were similar in terms of age and gender (mean age 9.1 +/- 1.9 years for IDA group, 8.8 +/- 1.5 years for controls, 37 % versus 40 % girls, respectively). Mean total IQ score of the IDA group was 12.9 points lower than that of the control group and this was statistically significant (p < 0.01). Although a highly significant increase of 4.8 points in total IQ was found after treatment with IPC in the IDA group (p < 0.01), post-treatment mean total IQ score of the IDA group was 8.2 points lower than that of the control group. However this difference of 8.2 points was not statistically significant (p > 0.05). There were significant differences in the subtests of WISC-R between the pre-treatment IDA group and the control group. A significant improvement was found especially in these subtests following treatment. CONCLUSION: Iron deficiency anemia in children can affect long-term cognitive function. The WISC-R intelligence test subsets and pre- and post-treatment IQ scores of the IDA group were significantly differing from control group. PMID- 17691593 TI - Iron(III)-hydroxide polymaltose complex in iron deficiency anemia / review and meta-analysis. AB - Iron(III)-hydroxide polymaltose complex (IPC) is an iron preparation with non ionic iron and polymaltose in a stable complex. The usefulness of IPC in the treatment of iron deficiency anemia (IDA) has recently been a topic of much debate. By reviewing the published literature an overview is provided of the existing comparative evidence vs. ferrous sulfate as reference. For this purpose the standard methods and criteria as described by the Cochrane group are employed. The aim was to establish whether there are differences concerning efficacy (primary end-point: hemoglobin after approx. 2 months of treatment) and concerning safety (number of patients with adverse drug reactions [ADRs]). From an initial group of 14 comparative trials identified, 6 comparative studies (1 double blind) conducted in adults could be retained for analysis. Four pediatric studies initially selected had to be rejected because of heterogeneity of data at baseline. In adults (319 IPC, 238 ferrous sulfate) at the end of the study period (8-13 weeks) the mean hemoglobin values were 12.13 +/- 1.19 g/dl with IPC vs. 11.94 +/- 1.84 g/dl with ferrous sulfate (weighted mean difference WMD = 0.01 [95% CI -0.23, 0.21] g/dl). Not all studies reported on ferremia (higher with IPC), transferrin saturation (no difference) or ferritin (lower with IPC). Adverse drug reactions were reported less frequently with IPC (14.9%) than with ferrous sulfate (34.1%; p < 0.001), particularly upper digestive troubles, stained teeth and diarrhea. The meta-analysis of studies conducted in adult patients with iron deficiency anemia, comparing IPC with ferrous sulfate in equivalent doses, showed that the two compounds attained similar hemoglobin levels, thus suggesting similar efficacy. The tolerance of IPC in adults was clearly better than that of ferrous sulfate; the differences were also significant for the individual adverse reactions. This probably reflects a better risk/benefit ratio of IPC in adults. Properly conducted randomized controlled trials, particularly in pediatrics, are needed. PMID- 17691594 TI - Safety and efficacy of iron(III)-hydroxide polymaltose complex / a review of over 25 years experience. AB - The following review of iron(III)-hydroxide polymaltose complex (IPC, Maltofer) shows that iron is significantly bioavailable after oral administration, especially in iron-deficient subjects. Numerous clinical trials in men, women, children and infants have shown that IPC is effective in treating iron deficiency anaemia (IDA). Due to its kinetic properties, IPC is best given with meals, and probably in an iron dose slightly higher than that of the classical iron salts. In terms of acceptance and patient compliance, IPC presents a clear advantage over ferrous salts. Many studies have shown a lower rate of treatment interruption with IPC than with ferrous salts. This is usually associated with a lower incidence of adverse events related to the upper gastro intestinal tract. PMID- 17691595 TI - Operating in the green. PMID- 17691596 TI - Smokeless tobacco. PMID- 17691597 TI - Diagnostic testing for inhalant allergies. AB - Allergic rhinitis is one of the most commonly treated disorders seen in otolaryngology office settings. It is often difficult to distinguish the symptoms associated with allergic rhinitis from other causes of rhinitis. Many times these nasal symptoms can be effectively treated using nonspecific pharmacotherapeutic agents in conjunction with general information on ways to reduce exposure to allergens or irritants in the environment. When allergic rhinitis is suspected and a targeted treatment approach is needed, allergy testing can confirm the diagnosis and guide effective treatment for the condition. This paper discusses various methods for diagnosing inhalant allergies with a special focus on a newer approach to skin testing, known as modified quantitative testing or MQT. This paper also presents an overview of the immune response as it occurs in allergic rhinitis, along with a discussion of common inhalant allergens. Finally, this paper offers a general approach to allergy testing and patient preparation. PMID- 17691598 TI - The Nurse Reinvestment Act revisited. AB - The United States is in the midst of a widely recognized critical nursing shortage. In 2002 the "Nurse Reinvestment Act" was passed with overwhelming bipartisan support in an effort to address this serious public health threat. The Act is due for reauthorization of funding in 2007. This paper provides a brief overview of the programs contained within the Act and describes practical ways in which members of the nursing community can take action to insure renewed support for the Act. PMID- 17691599 TI - The sounds of handheld audio players. AB - Hearing experts and public health organizations have longstanding hearing safety concerns about personal handheld audio devices, which are growing in both number and popularity. This paper reviews the maximum sound levels of handheld compact disc players, MP3 players, and an iPod. It further reviews device factors that influence the sound levels produced by these audio devices and ways to reduce the risk to hearing during their use. PMID- 17691600 TI - Search for Babesia bovis vaccine candidates. AB - Babesia bovis is a tick-borne apicomplexan pathogen that remains an important constrain for the development of cattle industries worldwide. Effective control can be achieved by vaccination with live attenuated forms of the parasite, but they have several drawbacks and thus the development of alternative subunit vaccines, either based in recombinant versions of full size proteins or in recombinant or synthetic peptides containing combinations of protective B-cell and T-cell epitopes is needed. Our current strategies for the identification of vaccine candidate antigens include the identification of functionally relevant antigens, bioinformatics, and comparative genomics using the recently sequenced B. bovis genome. These led us to the functional and immunological characterization of members of the VMSA gene family, a group of well conserved putative cysteine and serine proteases, and to the definition of a surface exposed B-cell epitope present in the Merozoite Surface Antigen-2c. Work in progress is focused in defining additional epitopes, and to determine whether they are neutralization-sensitive. These approaches might unravel useful vaccine candidates for B. bovis, and will increase our understanding of the pathogenicity mechanisms of these and related hemoparasites. PMID- 17691601 TI - Vaccination against large Babesia species from dogs. AB - The original observation of Sibinovic that soluble parasite antigens (SPA) of B. canis could be used to protect dogs against challenge infection formed the starting point for the development of an effective vaccine. With the advent of in vitro cultivation techniques for haemoprotozoan parasites an important tool became available for the commercial production of the vaccine antigens. A first generation vaccine was developed for dogs, but it appeared that the level of protection induced was not complete. In contrast to what was found with the SPA from serum/plasma of infected animals, protection induced with SPA from a single Babesia canis strain protected against a homologous challenge infection only. Further research led to the discovery that a combination of SPA of B. canis and SPA of B. rossi induced a broad spectrum of immunity. This improved vaccine, Nobivac Piro, not only induces protection against heterologous B. canis infection, but also against heterologous B. rossi infection. PMID- 17691602 TI - Advances in the development of molecular tools for the control of bovine babesiosis in Mexico. AB - The severe negative impact that bovine babesiosis has in the Mexican cattle industry has not been ameliorated basically due to the lack of safe and effective commercially available vaccines and sensitive and reliable diagnostic tests. In recent years, the Bovine Babesiosis Laboratory at the National Center for Disciplinary Research in Veterinary Parasitology-INIFAP in Morelos State, Mexico has been directing efforts towards three main research areas: (1) The development of in vitro culture-derived, improved and safer live vaccines. This has been done in two ways: using gamma-irradiated bovine serum and erythrocytes for the in vitro culture of vaccine strains, which reduces the risk of contaminating pathogens, and improving the immune response, by the addition of L. casei, a strong stimulant of the innate immune system. (2) The study of antigens considered as vaccine candidates with the goal of developing a recombinant vaccine that suits the country's needs. Knowing their degree of conservation or variation in Mexican isolates, their phylogenetic relationship and their protective, immuno-stimulatory properties, are first steps towards that goal. (3) The development of new tools for diagnosis, detection and discrimination of bovine babesiosis is the third area. Developing variants of ELISA, which are more reliable than the currently used IFAT, are a priority, and finally, taking advantage of the genomes of Babesia bigemina, and B. bovis, we are identifying genes than allow us to discriminate isolates using molecular tools. PMID- 17691603 TI - Babesiosis in Italy: an overview. AB - Babesiosis is a tick-transmitted disease caused by hematotropic parasites of the genus Babesia. Tick-borne diseases (TBD) have increasingly been recognized in the world as public health problems. The piroplasms are transmitted by ticks and are able to infect a wide variety of vertebrate hosts which are competent in maintaining the transmission cycle. Babesiosis occurrence is usually linked to seasonal variations that affect the vector, but climatic changes have not been common in the subtropical regions of Italy, especially during the last few years. This paper is aimed at compiling information about babesiosis in Italy both from the available literature and from the records of our Centre. Recent biotechnological approaches have aid to the detection of parasites and the monitoring of tick vectors. Moreover, our research has lately been focused on the investigation of the presence of Babesia parasites in wild animals, yielding very interesting results. PMID- 17691604 TI - Human babesiosis, an emerging zoonosis. AB - Data of human babesiosis are shortly reviewed with particular emphasis to Europe. In Europe, most cases of human babesiosis are caused by Babesia divergens. Although both phenotypic and genotypic features suggest that zoonotic B. microti may occur in Europe, convincing medical evidence is lacking. Recently a non Babesia divergens organism causing zoonotic infection has been found in Italy and Austria. Overall, the seroprevalence against both B. microti and B. divergens microrganisms in human ranges 1.5%-11.5% in Europe. PMID- 17691605 TI - Animal babesiosis: an emerging zoonosis also in Italy? AB - In Italy, babesiosis is widespread in several Central and Southern Regions, but few data are available on its presence in most Italian areas. In 2004 a project was financed by the MIUR to investigate on the babesiosis epidemiology in vertebrate and invertebrate hosts, and on the transmission risk for humans in Central and Northern Regions of the country. Microscopy and/or molecular tools were applied to blood samples of wild animals, livestock and pets, and to 1,677 ticks collected on animals or in the environment, with the aim of detect babesial parasites. Moreover, serological tests were used to evaluate the circulation of these protozoa among animals and people at risk. Microscopy identified as positive 5.0% of the animals, mostly living in Central Regions, but also in Northern areas considered Babesia-free. Serology evidenced the same general trend. PCR detected "piroplasm" DNA in 13.8% of the animals, and sequencing identified babesial parasites in 101/233 samples. The ticks were identified as belonging to 12 species, mostly represented by Ixodes ricinus, Rhipicephalus sanguineus and Dermacentor marginatus. Molecular analyses evidenced babesial parasites in 3.8% of them; in Rh. sanguineus was also demonstrated the vertical transmission of Babesia canis canis. To date 30 human sera have been analysed: 3 showed antibodies to B. microti. Animal babesiosis is largely present among pets, wild and farm animals, whereas goats seem refractory to the infection. In wild ungulates have been found the B. divergens-like, and the Babesia EU1 strains (reported in Italy in humans). Our findings evidenced the low reliability of microscopy in epidemiological studies, and the need of new/improved immunological tests to face diagnostic problems. The monitoring of infected areas and infection rates, joined to appropriate control programs, seems necessary to avoid the transmission of babesiosis to humans. PMID- 17691606 TI - A review of nucleic-acid-based diagnostic tests for Babesia and Theileria, with emphasis on bovine piroplasms. AB - Nucleic acid-based methods offer a variety of tools for the detection of parasites. This field of veterinary and medical sciences is rapidly evolving, leading to greater sensitivity and higher throughput. One of the reasons justifying such a fast development is the fact that tests targeting several taxa can be created. The present article deals with the applications of molecular diagnostics of tick-borne diseases in Parasitology. Special attention is given to Babesia and Theileria species infecting livestock. The commonly used molecular methods in diagnostic of tick-transmitted hematic protozoa are the following: (i) final time polymerase chain reaction; (ii) reverse line blotting (RLB); (iii) real time PCR, based on SYBR Green or probe fluorescence; (iv) isothermal amplification methods: loop-mediated amplification (LAMP) and self sustaining sequence replication (3SR, also named as "Nucleic Acid Sequence Based Amplification", NASBA, or Transcription Mediated Amplification, TMA). In general, none of these methods could be considered better than another. Their score in diagnostic applications greatly depends on the laboratory size. Small-scale laboratories handling few samples may find final time PCR a cheap alternative. On the contrary, large-scale laboratories prefer methods amenable to automation, like RLB, PCR-ELISA or qPCR. PMID- 17691607 TI - Identification, characterization and manipulation of Babesia-bovis-infected red blood cells using microfluidics technology. AB - Nowadays numerous microfluidic systems are being developed to address a variety of clinical problems. Latest advances in microfluidic technology are promising to revolutionize the detection of pathogens in vivo through the development of integrated lab-on-chip devices. Such microfabricated systems will undertake all steps in sample analysis from collection and preparation to molecular detection. Micro total analysis systems are suitable candidates for point of care diagnostics due to small size, low cost production and enabled portability. The work here presented aimed the use of microfluidic platforms to identify and manipulate bovine red blood cells infected by the protozoan parasite Babesia bovis. A microfabricated device based on impedance spectroscopy was used for single cell discrimination and its sensitivity and applicability as a diagnostic method for bovine babesiosis was studied. Furthermore, manipulation and sorting of normal and infected red blood cells was performed on a dielectrophoresis based microfabricated cell cytometer. Single cell analysis of normal and B. bovis infected red blood cells was performed by electrorotation and dielectric parameters such as permittivities and conductivities of the cellular membrane and cytoplasm were determined. PMID- 17691608 TI - Serological diagnostic tools for the major tick-borne protozoan diseases of livestock. AB - Tick-borne protozoan diseases, babesiosis and theileriosis, are among the most important diseases affecting the productivity of livestock worldwide and resulting in high economic losses. A prerequisite for the control of these diseases is to study their epidemiology by mapping their distribution and seasonality. As clinical diagnostic and surveillance tools, serological tests such as the complement fixation test (CFT), the indirect fluorescent antibody test (IFAT) and the enzyme linked immunosorbent assay (ELISA) have been successfully used over decades. With the development in molecular biology, recombinantly expressed parasite molecules have emerged and substituted crude parasite antigen used in serology. A popular format of these tests is the antibody binding competitive inhibition and the indirect antibody detection ELISA. Under the precondition that these tests are correctly designed and validated, they provide a powerful tool for epidemiology, with greater advantages of affordability and amenability to standardization. This paper reviews the pathogenic tick-borne protozoan diseases and the respective diagnostic ELISA based serological tests currently available for serosurveillance. PMID- 17691609 TI - Taking advantage of the polymorphism of the MSA-2 family for Babesia bovis strain characterization. AB - The Merozoite Surface Antigen-2 (MSA-2) family of Babesia bovis is a group of variable genes which share conserved 5' and 3' conserved ends. These genes encode membrane anchored glycoproteins, named MSA-2a1, a2, b and c, which are immunodominant antigens located on the surface of sporozoites and merozoites. In this work, we have analyzed the sequences of the msa-2a1, a2 and 2b genes in two geographically distant strains from Mexico and Argentina and detected a certain degree of genotypic diversity that can be exploited for the development of a new molecular tool for the discrimination of B. bovis field samples. Here, we describe a PCR restriction assay based on the msa2-a1, -a2 and -2b genes of B. bovis. When field strains from Argentina, Mexico and USA were analyzed, the results showed a strain-specific band pattern indicating the presence of differentially located BspMI restriction sites. This approach provides a simple method for the genotyping/strain differentiation of B. bovis field samples. PMID- 17691611 TI - Removing our loupes: encouraging surgeons to develop a broader perspective for the future. PMID- 17691610 TI - Optimization of Babesia bovis transfection methods. AB - The tick borne Babesia parasites remain an important limitation for development of cattle industries worldwide. A stable transfection of Babesia bovis will be useful for functional analysis of the recently sequenced B. bovis genome and to design improved methods to control Babesia infections. In this study, we describe a novel system for nucleofection of B. bovis infected erythrocytes and we optimize methods to introduce plasmids encoding the luciferase reporter gene into Babesia infected erythrocytes or free merozoites using either a BioRad GenePulser II electroporation system or nucleofection technology (Amaxa) A comparative study among four different transfection methods: transfection of infected erythrocytes and purified merozoites with 2 or 100 microg of plasmid, using electroporation (BioRad GenePulser II) or nucleofection (Amaxa) indicates that electroporation of infected erythrocytes with 100 microg of plasmid or nucleofection with 2 microg of plasmid are the most efficient ways to transfect B. bovis parasites. The data also indicate that nucleofection is more efficient than electroporation for transfecting small quantities of plasmids (2 microg range), whereas the inverse is true for transfection of larger quantities (100 microg range). This information will facilitate further development of efficient stable transfection systems. PMID- 17691612 TI - The future of the American College of Surgeons: uniting two perspectives. PMID- 17691613 TI - The road to innovation: emerging technologies in surgery. PMID- 17691614 TI - The globalization of surgery: surpassing the frontiers. PMID- 17691615 TI - International medical graduates in American surgery: past, present, future. PMID- 17691616 TI - New trends and developments in fellowship training. PMID- 17691617 TI - New ways of practicing surgery: alternatives and challenges. PMID- 17691618 TI - The necessity of physician involvement in the political process. Interview by Shawn Friesen. PMID- 17691619 TI - The rockets' red glare. PMID- 17691620 TI - Avoid medications with formaldehyde in patients with contact allergies. PMID- 17691621 TI - A 9-year-old girl who is unable to walk. PMID- 17691622 TI - Alternating acetaminophen with ibuprofen for fever: is this a problem? PMID- 17691623 TI - Tick-borne diseases. PMID- 17691624 TI - The epidemic of methicillin-resistant Staphylococcus aureus colonization and infection in children: effects on the community, health systems, and physician practices. PMID- 17691625 TI - West Nile Virus. PMID- 17691626 TI - Hot topics in pediatric HIV/AIDS. PMID- 17691627 TI - Magnetic resonance imaging features of oblique and straight distal sesamoidean desmitis in 27 horses. AB - Injury to the oblique and straight distal sesamoidean ligaments is becoming recognized as a more common cause of lameness in horses than was previously thought. The purpose of this study was to review the magnetic resonance (MR) imaging findings of 27 horses affected with desmitis of the oblique and/or straight distal sesamoidean ligament and determine long-term prognosis for horses with this diagnosis. Imaging was performed with horses in right lateral recumbency in a high-field 1 T magnet. All horses had lameness localized to the digit or metacarpophalangeal/metatarsophalangeal joint region with diagnostic local anesthetic blocks. Ten horses had forelimb lameness and 17 horses had hind limb lameness. MR imaging revealed abnormalities in the oblique distal sesamoidean ligaments in 18 horses, in the straight distal sesamoidean ligament in three horses, and in both the oblique and straight distal sesamoidean ligament in six horses. Treatment consisted of a 6-month rest and rehabilitation program in all horses. The digital flexor tendon sheath was injected with methylprednisolone acetate and hyaluronic acid in 22 horses to decrease inflammation in the injured ligaments before starting the rest and rehabilitation program. Two horses had ligament splitting performed, one in the oblique distal sesamoidean ligament and one in the straight distal sesamoidean ligament. MR imaging is an effective method for diagnosing injury to the oblique and straight distal sesamoidean ligaments in horses. Treatment, primarily a 6-month rest and rehabilitation program, allowed 76% of the horses to successfully resume performance. PMID- 17691628 TI - Magnetic resonance imaging of subarticular bone marrow lesions in dogs with stifle lameness. AB - A bone bruise is a magnetic resonance (MR) imaging sign thought to signify acute traumatic microfracture of trabecular bone with hemorrhage and edema in the marrow that may occur without grossly visible disruption of the adjacent cortices or overlying cartilage. In approximately 75% of people with acute anterior cruciate ligament tears, bone bruises are detected in characteristic locations within the femur and tibia and are best seen as high-signal lesions using fat suppression sequences. We questioned whether this is a component of naturally acquired stifle lameness in dogs and obtained short-tau inversion recovery (STIR) images of six dogs with stifle lameness. High-signal STIR lesions were detected in five of six (83%) dogs and eight of 12 (67%) limbs. We observed these lesions deep to the intercondylar fossa of the femur and intercondylar eminence of the tibia, which are atypical locations in people. High-signal STIR lesions were detected in dogs with only synovitis, partial tear of the cranial cruciate ligament (CCL) and complete tear of the CCL. One of these lesions was seen in the lateral tibial condyle, a typical location in humans with acute anterior cruciate ligament tear. As the MR imaging appearance of stress fractures and bone bruises are similar, and the high-signal STIR lesions are at attachment sites of the CCL, this finding may be due to stress disease or other unknown causes, rather than bone bruising. High-signal STIR lesions may be a common sign in naturally acquired canine stifle disease, but the pathogenesis, prognostic and diagnostic values need further investigation. PMID- 17691629 TI - Virtual endoscopy of dogs using multi-detector row CT. AB - Virtual endoscopy uses CT data to display hollow viscera such as the stomach, duodenum and colon as if by real endoscopic observation. The results are independent of the operator skill because virtual endoscopy does not require direct manipulation of endoscopic equipment. The purpose of this study was to evaluate the utility of virtual endoscopy in small animals. Ten beagles were examined by conventional endoscopy and virtual endoscopy using multidetector CT. Virtual images were image-processed at a workstation designed for depicting virtual endoscopy using CT data. Virtual images were visually comparable with conventional endoscopic images, especially in the area of the angular incisure and pylorus. The advantages of virtual endoscopy are observation from any viewing angle, a reduced learning curve for diagnostic interpretation, quantification of lesion size in three dimensions and a potential for reducing anesthesia time. The disadvantages of virtual endoscopy are a lack of color recognition information, an inability to retrieve biopsy samples, limited visualization of the duodenum, artifacts from respiration/peristalsis motion and an inability to observe function. Based on our results, we suggest that conventional endoscopy is still superior to virtual endoscopy in dogs. However, as technology improves, virtual endoscopy may emerge as a suitable alternative or adjunctive diagnostic tool for certain digestive disorders in small animals. PMID- 17691630 TI - Intracranial subarachnoid hemorrhage following lumbar myelography in two dogs. AB - Intracranial subarachnoid hemorrhage is a rare but serious complication of lumbar puncture in humans. Possible sequelae include increased intracranial pressure, cerebral vasospasm, or mass effect, which can result in dysfunction or brain herniation. We describe two dogs that developed intracranial subarachnoid hemorrhage following lumbar myelography. In both dogs, myelography was performed by lumbar injection of iohexol (Omnipaque). Both the dogs underwent uneventful ventral decompressive surgery for disk herniation; however, the dogs failed to recover consciousness or spontaneous respiration following anesthesia. Neurologic assessment in both dogs postoperatively suggested loss of brain stem function, and the dogs were euthanized. There was diffuse subarachnoid hemorrhage and leptomeningeal hemorrhage throughout the entire length of the spinal cord, brain stem, and ventrum of brain. No evidence of infectious or inflammatory etiology was identified. The diagnosis for cause of brain death was acute subarachnoid hemorrhage. Our findings suggest that fatal subarachnoid hemorrhage is a potential complication of lumbar myelography in dogs. The cause of subarachnoid hemorrhage is not known, but may be due to traumatic lumbar tap or idiosyncratic response to contrast medium. Subsequent brain death may be a result of mass effect and increased intracranial pressure, cerebral vasospasm, or interaction between subarachnoid hemorrhage and contrast medium. PMID- 17691631 TI - Dynamic computed tomography of the pancreas in normal dogs and in a dog with pancreatic insulinoma. AB - To establish optimal imaging conditions for enhanced computed tomography (CT) for canine pancreatic tumors, 10 healthy beagles were subjected to dynamic CT. This technique was then applied to a dog with suspected insulinoma. The changes in mean peak enhancement and the delay time of the aorta and pancreas were determined. In normal beagles, maximal arterial and pancreatic CT enhancement was observed at 15 +/- 2 s (795 +/- 52 Housfield unit [HU]) and 28 +/- 9 s (118 +/- 16HU) after contrast medium injection, respectively. Multiphase enhanced CT was performed in a pug with suspected insulinoma using the CT protocol defined for the normal beagles with some parameters modified; the images were acquired at the arterial (14 s after contrast medium injection), pancreatic (after 28 s), and equilibrium (after 90 s) phases; scanning was followed by exploratory laparotomy. CT images were characterized by an enhanced mass in the left pancreatic lobe at the arterial phase, during which the difference between the CT values of the mass and normal pancreas was the highest. Histopathologic diagnosis of the pancreatic mass was insulinoma. Thus, it appears that enhanced CT imaging can be used to delineate the pancreas from a pancreatic mass, and it may be helpful in deciding the need for surgery. PMID- 17691632 TI - Vertebral heart size in retired racing Greyhounds. AB - The vertebral heart size (VHS) is used to objectively assess cardiac dimensions on thoracic radiographs. A high VHS suggest the presence of cardiac pathology, such as dilated cardiomyopathy, degenerative atrioventricular valvular disease, pericardial effusion, pericardioperitoneal diaphragmatic hernia, tricuspid dysplasia, ventricular septal defect, or patent ductus arteriosus, among others. However, breed or body conformation can influence the VHS. Because Greyhounds have a high prevalence of physiologic systolic murmurs associated with high aortic velocity, and large cardiac dimensions when compared with dogs of similar size, they are frequently suspected of having heart disease. The purpose of this study was to compare the VHS in normal Greyhounds with those in Rottweilers, and a group of dogs from various other breeds using both analog and digital radiology. The VHS was significantly higher in Greyhounds (P< 0.0001), when compared with Rottweilers and to other dog breeds. The mean VHS on lateral radiographs for Greyhounds was 10.5 +/- 0.1, for Rottweilers it was 9.8 +/- 0.1, and for mixed breed dogs it was 10.1 +/- 0.2. This study confirms that the relative cardiomegaly reported in necropsy and echocardiographic studies in Greyhounds is easily detected using plain radiography and the VHS. PMID- 17691633 TI - Imaging diagnosis--discospondylitis and septic arthritis in a dog. AB - A 6-year-old German Shepherd dog was evaluated for hind limb lameness. When a diagnosis, could not be achieved using radiography and ultrasonography, bone scintigraphy was performed to look for occult lameness or the presence of multiostic disease. Bone scintigraphy was useful in identification of increased radiopharmaceutical uptake in the thoracic spine and right coxofemoral joint, which directed further testing leading to the diagnosis of discospondylitis, septic arthritis of the coxofemoral joint, and a urinary tract infection. PMID- 17691635 TI - Three-dimensional ultrasonographic in vitro imaging of lesions of the meniscus and femoral trochlea in the equine stifle. AB - The purpose of this in vitro study was to evaluate the value of three-dimensional (3D) ultrasonography for the diagnosis of equine meniscal and trochlear ridge lesions under in vitro conditions. Lesions were created in the isolated meniscus and femoral trochlea of 25 cadaver stifle joints. Cylindric, conic, and cuboid lesions were created on the trochlear ridge. Five different meniscal tear configurations were created. A total of 107 lesions of the trochlear ridge and 103 lesions of the meniscus were created. 3D ultrasonography was performed in a waterbath, using a 7.5 MHz 3D scanner. Trochlear ridge lesions were seen as either hypoechoic or anechoic breaks in continuity or as irregular notches. One hundred and one out of the 107 trochlear lesions were visible using 2D ultrasonography whereas 104 out of the 107 lesions could be seen using the 3D Cine mode. Three lesions could not be detected by either technique. Eighty-five out of the 103 meniscal lesions were seen with 2D ultrasonography and 90 with 3D Cine mode. Radial tears and horizontal tears were the least commonly visualized 3D. The 3D Cine mode led to a small improvement in lesion detection. 3D ultrasound could be considered as an extension and refinement of the ultrasound techniques already in use and can increase the diagnostic capabilities. However, technical improvements have to be achieved before 3D ultrasound can be used in the daily practice for diagnosis of equine stifle joint disorders. PMID- 17691634 TI - Endoscopic ultrasound of the canine abdomen. AB - The aim of this study was to develop a standardized procedure for examination of the canine abdomen using endoscopic ultrasound and to describe the organs and structures that could be identified transgastrically. The abdomen of four healthy dogs and two cadavers were examined with endoscopic ultrasound. Five anatomic landmarks were used for standardized imaging of the cranial abdomen. These were the portal vein, splenic head and body, duodenum, left kidney, and aorta. High resolution images of the following organs and structures could be made: distal esophagus, gastric wall from the cardia to the pylorus, liver, caudal vena cava, hepatic lymph nodes, liver hilus, and associated vessels, trifurcation of the celiac artery as well as the path of its branches and the left pancreatic limb and body. Structures that were more difficult to image were the distal duodenum and right pancreatic limb, the entire jejunum, ileum, and cecum as well as the tail of the spleen. Endoscopic ultrasound allowed excellent visualization of the gastric wall and regional structures without interference with gas artefacts. Centrally located organs such as the pancreas could be well examined transgastrically with endoscopic ultrasound without interference by overlying intestinal segments as is common with transabdominal ultrasound. PMID- 17691636 TI - Association between renal hypoechoic subcapsular thickening and lymphosarcoma in cats. AB - The purpose of this study was to investigate the association between renal hypoechoic subcapsular thickening observed ultrasonographically and the presence of renal lymphosarcoma in cats. The ultrasonography database was retrospectively searched for cats that underwent ultrasound examination and ultrasound guided needle renal aspirate, renal biopsy, or necropsy. One radiologist unaware of the final diagnosis evaluated the images for the presence of hypoechoic subcapsular thickening and other abnormal findings. Fifty-four cats met the inclusion criteria. Hypoechoic subcapsular thickening was found in 21 cats of which 17 had lymphosarcoma; the remaining four cats had a different diagnosis. Eleven out of 33 cats without hypoechoic subcapsular thickening were positive for lymphosarcoma, and the rest had a different diagnosis. There was a significant association between hypoechoic subcapsular thickening and renal lymphosarcoma (P = 0.001). The positive predictive value of hypoechoic subcapsular thickening for lymphosarcoma was 80.9% and the negative predictive value was 66.7%. The sensitivity and specificity of hypoechoic subcapsular thickening for the diagnosis of renal lymphosarcoma were 60.7% and 84.6%, respectively. The results of this study indicate that the presence of hypoechoic subcapsular thickening in feline kidneys is associated with renal lymphosarcoma. PMID- 17691637 TI - Ultrasound approach to the canine distal tibia and trochlear ridges of the talus. AB - The aim of the present study was to evaluate to what extent the distal tibia and the trochlear ridges of the talus can be examined with ultrasound (US) in the dog and to establish a protocol for an optimal US examination of these ridges. Six hind limbs of deceased adult mixed-breed dogs were used. In two limbs, needles were placed using US guidance on the trochlea of the talus, just dorsal to and plantar to the distal tibia: one with the tarsal joint in extension and one with the joint in flexion. Then mediolateral (ML) radiographs of both joints were made with the needle in place to determine the percentage of the trochlear ridge of the talus that can be seen using US imaging. An US examination of the tarsal joint was performed on the four other limbs using microconvex (8 MHz) and linear (12 MHz) transducers (Logiq 7) and compound imaging. A three-step protocol was performed including a dorsal approach with the limb extended and the linear transducer (step I), a plantar approach with the limb flexed and the linear transducer (step II), and a plantar approach with the limb flexed and the microconvex transducer (step III). After the US examination, the four limbs were frozen and sectioned, two in a transverse and two in a sagittal plane. Bony structures on the US images were matched with the corresponding anatomic sections. The distal tibia and both trochlear ridges of the talus were easily recognized on the US images using the proposed protocol. When combining the dorsal and plantar approaches, it was possible to visualize up to 75% of the trochlear ridges of the talus in the dog. PMID- 17691638 TI - Ultrasonographic assessment of fracture healing after plate osteosynthesis. AB - The goals of this study were to assess the ability of ultrasonography (US) to assess uncomplicated fracture healing and to establish normal images. Twenty-two dogs, ranging in age from 6 to 180 months were studied. Body weight ranged from 2.2 to 60 kg. All fractures were treated by plate osteosynthesis. US (B-mode and power Doppler) and radiography were performed until both were consistent with complete healing. B-mode US was performed in all dogs, and power Doppler US in 14. Fracture healing was judged to be complete based on US earlier than when based on radiography. The tissue immediately adjacent to the plate appeared vascularized on power Doppler images at a time when the tissue at the fracture site had a negative power Doppler exam. US appears useful for assessment of primary fracture healing and power Doppler was useful for detecting vascularization at the fracture site in nonhealed fractures. Power Doppler interrogation should be performed away from any metal implant, as a result from an interrogation adjacent to an implant will not reflect actual vascularization at the fracture site. PMID- 17691639 TI - Quantitative contrast ultrasound analysis of renal perfusion in normal dogs. AB - Eight normal dogs with no evidence of renal disease, weighing between 8 and 25 kg were imaged using contrast harmonic ultrasound after injection of a microbubble contrast medium. All dogs received three separate bolus injections of 0.05 ml of commercial contrast medium (Definity). Time/mean pixel value (MPV) curves were generated for selected regions in the cortex and medulla of the left kidney in each dog. Upslope, downslope, baseline, peak intensity, and time to peak were calculated for each zone. For a bolus injection, within the renal cortex (averaging all subjects) the upslope was 7.4 +/- 1.5 MPV/s, downslope was -0.4 +/ .2 MPV/s, baseline was 66.8 +/- 9.3 MPV, peak was 103.6 +/- 8.2 MPV, time to peak (from injection) was 12.8 +/- 5.3 s and from time of contrast medium reaching the kidney was 5.1 +/- 2.0 s. Within the renal medulla (averaging all subjects), upslope was 2.8 +/- 1.7 MPV/s, downslope was -0.3 +/- .2 MPV/s, baseline was 39.3 +/- 6.0 MPV, peak was 65.2 +/- 14.3 MPV, time to peak from injection was 20.9 +/- 6.4 s and from time of contrast reaching the kidney was 11.6 +/- 4.1 s. These baseline data may prove useful in the evaluation of dogs with diffuse disease or vascular compromise. PMID- 17691640 TI - Scintigraphic evaluation of the stifle in normal horses and horses with forelimb lameness. AB - We tested the hypotheses that mature horses without lameness have a repeatable radiopharmaceutical uptake pattern in the stifle, which is bilaterally symmetric; immature horses have a different radiopharmaceutical uptake pattern; and forelimb lameness alters the radiopharmaceutical uptake pattern in the stifle. The objectives of the study were to describe the normal radiopharmaceutical uptake patterns using region of interest (ROI) analysis; to compare uptake patterns between left and right stifles of the same horse and between mature and immature horses; to compare radiopharmaceutical uptake in mature normal horses with those with forelimb lameness. Lateral scintigraphic images of the stifle from 51 horses aged 2-16 years were evaluated using seven ROIs and a reference site (midfemur). After subtraction of a background count, ratios between the mean counts per pixel for each ROI to the reference site were calculated. There was a repeatable radiopharmaceutical uptake pattern in mature normal horses that was bilaterally symmetrical. The caudoproximal aspect of the tibia and the patella had the highest ratios. Radiopharmaceutical uptake patterns in horses with forelimb lameness were not significantly different. Immature normal horses had a different symmetric pattern, with greatest radiopharmaceutical uptake ratios in the caudoproximal aspect of the tibia and the tibial crest. It was concluded that there are symmetric, repeatable radiopharmaceutical uptake patterns in both immature and mature horses, which are not altered by forelimb lameness. PMID- 17691641 TI - Investigation of two methods for assessing thyroid-lobe asymmetry during pertechnetate scintigraphy in suspected hyperthyroid cats. AB - Our aim was to investigate thyroid:thyroid (T:T) ratio and visual inspection for assessing thyroid-lobe asymmetry in suspected hyperthyroid cats. Although thyroid salivary asymmetry is a preferred test, inherent thyroid symmetry may assist image interpretation. Association was determined using a scatter plot and Spearman's rank correlation. Agreement was assessed using the kappa (K) statistic. Accuracy was assessed by sensitivity and specificity. Hyperthyroidism was diagnosed in 33/48 (69%) cats based on elevated serum total thyroxine level. Using two Wilcoxan rank-sum tests, a significant difference (P < 0.0001) was detected between cats with and without hyperthyroidism for both methods of assessing thyroid symmetry. For the 18 cats with T:T ratios < or = 1.5, there was poor correlation between the two methods (r(s) = 0.39). Using a cut-point of 1.5 for the T:T ratio, the test accurately predicted hyperthyroidism in 28/33 cats (sensitivity, 85%; 95% confidence interval (CI), 71-99%) and correctly predicted that hyperthyroidism was absent in 14/15 cats (specificity, 93%; CI, 77-100%). For visual inspection, agreement for diagnosing hyperthyroidism was excellent between methods (kappa = 0.82), within the same examiner (weighted kappa = 0.85) and between examiners (weighted kappa = 0.89). Considering cats with only definitely asymmetric thyroid lobes as positive, visual inspection accurately predicted hyperthyroidism in 28/33 cats (sensitivity, 85%; CI, 71-99%) and correctly predicted that hyperthyroidism was absent in 11/15 cats (specificity, 73%; CI, 48-99%). Thyroid-lobe asymmetry occurs more frequently in hyperthyroid than in euthyroid cats but caution should be exercised because some euthyroid cats have asymmetric thyroid glands. PMID- 17691642 TI - Response of nineteen cats with nasal lymphoma to radiation therapy and chemotherapy. AB - The records of 19 cats treated for stage I nasal lymphoma with radiation therapy and chemotherapy were reviewed to determine response to therapy, treatment outcome and possible prognostic indicators. All cats were treated with megavoltage radiation therapy to a total dose ranging from 22 to 48 Gy (median dose = 42 Gy). All cats were prescribed at least 6 months of multiagent chemotherapy. The median progression-free interval for all cats was 945 days (31 months). Two cats did not achieve clinical remission. Of 17 cats evaluable for relapse, 10 (58.8%) were progression free during the entire follow-up period. Four cats (23.5%) suffered local recurrence, while three (17.6%) experienced distant relapse. The median survival time was 955 days (31.4 months). The only variable found to have a significant negative impact on survival was destruction of the cribriform plate before therapy (P= 0.002). The long progression free and survival times reported here indicate that cats with stage I nasal lymphoma treated with aggressive local and systemic therapy can have a favorable outcome when compared with other anatomic forms of lymphoma. Despite strong clinical responses to the multimodality therapy used, the fact that three (17.6%) cats relapsed distantly supports the recommendation that treatment with radiation therapy alone is insufficient until further prospective studies can be performed. PMID- 17691643 TI - Statistical briefing: likelihood ratios. PMID- 17691644 TI - In defense of ambiguity. PMID- 17691645 TI - Stretch, substitute, rotate. Be innovative in giving patients access to your services. PMID- 17691646 TI - Colleagues discuss charge posting, claims-submittal time. PMID- 17691647 TI - CMS launches voluntary Medicare pay-for-reporting program. PMID- 17691648 TI - Boom times are coming. PMID- 17691649 TI - Put that phone to work. An advanced communication management system can enhance service to your patients. PMID- 17691650 TI - Feel 25 at 115. 'Longevity medicine' promises enhanced health, longer life--if you can afford it. PMID- 17691651 TI - A costly affliction. Is your practice suffering from embezzlement? PMID- 17691652 TI - Hospital-owned medical practices. Some are integrated, others disconnected. PMID- 17691653 TI - Quality quandary. Are you on track to establish a medical practice quality program? AB - Medicare and private health insurance companies are establishing pilot pay-for performance programs in medical practices as a response to consumer-driven health care. Now is the time to initiate or improve your organization's quality program. This article describes five areas that you, as a professional practice administrator, should address and provides ideas and resources to assist with the process. PMID- 17691654 TI - It's no-show time! How leaders at one practice tackled the no-show problem--and how you can, too. AB - Patients who fail to keep appointments without notice--"no-shows"--adversely affect patient access and clinical revenue. The medical center at the University of California-San Francisco saw no-shows take an estimated $7 million annually out of its revenue. Although the reasons and rates for no-shows vary greatly among medical practices, the approaches the author describes for this academic medical center can be applied in any practice setting. PMID- 17691655 TI - The ties that bind. What you should know about the operational, ethical issues of restrictive covenants. AB - Restrictive covenants--also called noncompete clauses--in physician contracts can be a contentious issue, sometimes inspiring litigation. They pose many questions for medical practice administrators. Are restrictive covenants really necessary to protect a medical group? Are they ethical? Does their use deny medical care to patients? And how do they apply to medical practice administrators? This article reviews restrictive covenants from all these perspectives and provides a worksheet to figure your practice's protectable interests. PMID- 17691656 TI - Eyes as fenestrations to the ears: a novel mechanism for high-frequency and ultrasonic hearing. AB - Intense airborne ultrasound has been associated with hearing loss, tinnitus, and various nonauditory subjective effects, such as headaches, dizziness, and fullness in the ear. Yet, when people detect ultrasonic components in music, ultrasound adds to the pleasantness of the perception and evokes changes in the brain as measured in electroencephalograms, behavior, and imaging. How does the airborne ultrasound get into the ear to create such polar-opposite human effects? Surprisingly, ultrasound passes first through the eyes; thus, the eye becomes but another window into the inner ear. PMID- 17691657 TI - High-frequency hearing threshold in adult women with multiple sclerosis. AB - Our objective was to determine the high-frequency hearing thresholds of women with multiple sclerosis (MS) and to investigate the presence of side dominance for high-frequency perception. We submitted 19 affected and 106 nonaffected women (controls) to high-frequency audiometry and classified them in subgroups according to their age (30-40, 40-50, and 50-60 years). We analyzed data through selected statistical tests. We could detect no consistent effect of side dominance and observed a general increase in the hearing sensitivity for high frequencies in MS patients. We concluded that high-frequency sounds seemed to be detected more easily by MS patients than by controls. PMID- 17691658 TI - Vestibular and optokinetic nystagmus in ketamine-anesthetized rabbits. AB - The aim of this work has been to analyze the modification of vestibular and optokinetic nystagmus in animals after administration of therapeutic doses of ketamine. Three healthy rabbits (two reds and one white), weighing between 2.5 and 3 kg, were submitted to electronystagmography recording. The rabbits, head blocked, were placed on a Tonnies rotatory chair in the middle of a rotatory cylindrical chamber, the internal area of which was covered with 32 black vertical contrasts. All the rabbits underwent rotatory vestibular stimulation by stop test and optokinetic stimulation. After each test and a rest period for the animals, we administered 10 mg/kg of ketamine and performed the same ENG workup. In the first (red) rabbit, we collected eye-movement data at 3 minutes and 40 minutes after the intramuscular injection of a single dose of ketamine (10 mg/kg). In the second (white) rabbit, we performed ENG recording with the animal under anesthesia for the entire time of the test; in the third (red) rabbit, we analyzed the optokinetic response, from the administration of the drug until the end of its effects. Our data highlight the action of the drug on the structures that control the ocular movements and led to the conclusion of the presence of a second feedback integrator. PMID- 17691659 TI - Acoustic injury and TRPV1 expression in the cochlear spiral ganglion. AB - Acoustic trauma not only produces temporary and permanent hearing loss but is a common cause of chronic tinnitus. Recent work indicated a possible role for the transient receptor potential channel vanilloid subfamily type 1 (TRPV1) in modulating the effects of cochlear injury. In our research, we investigated the effects of acoustic damage on TRPV1 expression in spiral ganglion neurons of adult rats. After exposing them unilaterally to noise, we extracted cochleas and processed the spiral ganglion for TRPV1 expression at four posttrauma intervals (2 hours, 24 hours, 12 days, and 16.9 months). We measured TRPV1 immunodensity in the apical, middle, and basal turns of the cochlea. We found a significant interaction (p = .039) between posttrauma interval and regional cochlear receptor expression: For survival intervals between 24 hours and 2 weeks, TRPV1 density increased in all cochlear regions; at the longest survival interval (16.9 months), TRPV1 density was dramatically reduced in the basal region. We also psychophysically tested the long-survival subjects, which showed evidence of 20 kHz tonal tinnitus. These results suggest that TRPV1 may participate after cochlear injury in a signal cascade that is responsible for the neuroplastic events leading to tinnitus and hyperacusis. PMID- 17691660 TI - Clear Tinnitus, middle-ear pressure, and tinnitus relief: a prospective trial. AB - GOAL: Our goal was to establish the efficacy, in a 12-week period, of Clear Tinnitus for tinnitus relief in patients with tinnitus of the severe, disabling type. HYPOTHESIS: We hypothesized that tinnitus relief with Clear Tinnitus reflects improvement in the sensory component of the tinnitus complaint by controlling the factor of aeration of the middle ears and improving eustachian tube function. METHOD: In a prospective clinical trial of a homeopathic preparation--Clear Tinnitus--we attempted to identify in 15 tinnitus patients (14 male, 1 female; mean age, 47.6 years) its clinical efficacy for establishing tinnitus relief for a 3-month period. We employed a descriptive data analysis method across dimensions of risk to evaluate a base of multidimensional evidence and establish support for our hypothesis. A medical-audiological tinnitus patient protocol completed by each patient identified the clinical type of tinnitus as predominantly cochlear, with a central and middle-ear component bilaterally. We identified fluctuation in middle-ear pressure (MEP) via patients' clinical history, supported by physical examination and established with tympanometry, as a factor influencing the clinical course of the tinnitus in each patient. RESULTS: Eleven of 15 patients completed the study. Seven responders reported tinnitus relief; four did not respond. Descriptive data analysis failed to detect any trends in a change in response with audiometric tests across the hearing spectrum; thus, we could derive no coefficients of hearing change. Evaluation revealed high-frequency tinnitus in 11 patients. The Feldmann masking curve comparison at the start and end of the study showed no significant change in the 11 patients. There was no significant alteration in the minimum masking levels or loudness discomfort levels before and after the study. Tympanometry and MEP measurement indicated a significant difference in MEP with an improvement on average of -58.18 in the right ear and -40.90 in the left ear for the 11 patients. Quantitative electroencephalography analysis revealed a marked difference in the number of significant abnormal recordings between the different frequency bands, with the delta band significantly higher than the theta, alpha, and beta bands for both the overall cohort of patients (n = 11) and those reporting tinnitus relief (n = 7). The tinnitus outcome questionnaires--the tinnitus intensity index, the tinnitus annoyance index, and the tinnitus reaction questionnaire--revealed a significant difference for the patients (7 of 11) obtaining tinnitus relief. Results of the tinnitus stress test, the tinnitus handicap index, and the measurement of depression scale before and after the study were not statistically significant. CONCLUSIONS: Patients who completed the study demonstrated with tympanometry a statistical and clinical significance in MEP improvement or maintenance of MEP (or both). Patients with tinnitus of the severe disabling type selected for this study and responding to Clear Tinnitus reported tinnitus relief accompanied by improvement in or maintenance of MEP of the middle ears. The statistical and clinical significance of Clear Tinnitus for establishing tinnitus relief remains to be established with a larger cohort of tinnitus patients. PMID- 17691661 TI - Applications of the marchbanks transcranial-cerebral sonography technique in neurootology: preliminary report. AB - Transcranial-cerebral sonography (TCCS) is a noninvasive technique that allows clinicians to detect nanoliter (billionths of a liter) displacements of the tympanic membrane. This technique was developed to assess cerebrospinal fluid (CSF) pressure in cases of shunted hydrocephalus; it takes advantage of the CSF connection to the inner ear through the cochlear aqueduct. The movements of the tympanic membrane that are observed in TCCS are those evoked by the acoustic stapedius reflex and those spontaneous movements generated by intracranial arterial, venous, and respiratory pulses transmitted through the inner ear to the stapes and thence to the tympanic membrane. Analysis of the amplitude and direction of these displacements has enabled neurosurgeons and neurologists to estimate CSF pressures accurately in patients evaluated by TCCS. TCCS allows for applications in neurootology, particularly in those patients who present with symptoms of pulsating tinnitus, dizziness and imbalance, or hearing loss. This preliminary report describes the test and its application in a series of patients whose diagnoses included pulsating tinnitus, idiopathic intracranial hypertension, Meniere's disease, perilymphatic fistula, perilymphatic hypertension, arterial stenosis, and Arnold-Chiari syndrome. We conclude that TCCS is a valuable addition to the armamentarium of neurootologists. PMID- 17691662 TI - Cholesteatoma of the tympanic part of the temporal bone. AB - This article presents accounts of two patients with cholesteatoma of the tympanic part of the temporal bone, located immediately lateral to the tympanic annulus (and with an intact tympanic membrane). The lesions were located deep in the anterior and inferior walls of the canal, especially in the vaginal process of the tympanic part. These more severe cases required surgical correction (removal of the sac of cholesteatoma) with very good results. Pathogenesis and differential diagnosis are discussed. PMID- 17691663 TI - Effective maneuver of the positional test: turning head and body together. AB - We performed three maneuvers of the positional test in supine patients: (1) body maneuver, in which patients turned only the body to one side while keeping the head as still as possible; (2) head-only maneuver, in which patients turned only the head to one side while keeping the body still; and (3) head and body maneuver, in which patients turned the head and body together to one side. The nystagmus provocation rates of those three maneuvers among 86 vertiginous patients were 9% in the body maneuver, 16% in the head-only maneuver, and 33% in the head and body maneuver, respectively. We proved that performing the positional test by turning the head and body together is very effective in provoking positional nystagmus. PMID- 17691664 TI - Monocular electronystagmographic analysis of caloric nystagmus. AB - We compared the horizontal component of nystagmus of the right and left eyes using monocular recording of electronystagmography. We examined the eye movements of 135 patients during bithermal caloric testing and those of 50 patients during the rotation test. We measured the number of nystagmic beats, the slow-phase velocities, and the amplitudes during 10 seconds of the culmination phase of caloric response. We also measured the number of nystagmic beats during the first 30 seconds in postrotatory nystagmus. The eye on the cold-irrigated side moved significantly more strongly than did the eye on the nonirrigated side, whereas a warm irrigation did not induce a significant difference between the irrigated and nonirrigated eyes. The summated activities of each eye during the four different stimulations under bithermal caloric testing did not show any significant differences. The activities of postrotatory nystagmus were almost equal in both eyes in 50 patients. We concluded that the inhibitory effect of cold caloric stimulation is probably transmitted more intensively to the eye on the irrigated side. PMID- 17691666 TI - Tinnitus school: an educational approach to tinnitus management based on a stress reaction tinnitus model. AB - Stress is a significant factor influencing the clinical course of tinnitus. The auditory system is particularly sensitive to the effects of various stress factors (chemical, oxidative, emotional, etc.). Different stages of reaction (alarm, resistance, exhaustion) lead to different characteristics of tinnitus and to different therapeutic approaches. Individual characteristics of stress reaction may explain different aspects of tinnitus in various patients with different responses to treatment, despite similar audiological and etiological factors. A model based on individual reactions to stress factors (stress-reaction tinnitus model, or SRTM) could explain tinnitus as an alarm signal. In each patient, stressors have to be identified during the alarm phase to prevent an evolution toward the resistance and exhaustion phases. In the exhaustion phase, chronic tinnitus is due to the organization of a paradoxical auditory memory and a pathologically shifted attention to tinnitus. The aim of our study is to describe a therapeutic proposal based on the SRTM by taking an educational approach to management of chronic tinnitus. The educational aspect is emphasized; thus, we named our approach tinnitus school. Selection of appropriate patients and follow-up is based on psychometrics of tinnitus and stress questionnaires, including a tinnitus reaction questionnaire, a tinnitus cognitive questionnaire, and a 20-item perceived stress questionnaire. Tinnitus school is a three-phase program: counseling, training, and home training. Training is based on a tinnitus fitted physiotherapeutic protocol. PMID- 17691665 TI - Neurootological aspects of juvenile vertigo. AB - Pathologies from childhood to adolescence carry physical, cognitive, motor, linguistic, perceptual, social, emotional, and neurosensory characteristics. The ages between 8 and 14 or 15 especially carry very special traits of a rollover in data processing with respect to balance regulation. Data acquisition of neurootological function provides us with a network of information about the sensory status of our young patients. Major neurootological complaints leading to functional neurootological investigations are vertigo (including giddiness), dizziness, and nausea. These complaints may occur acutely but also are present in some patients at a young age as longer-lasting complaints. Physiological and clinical vertigo syndromes are commonly found as a combination of four principal phenomena: perceptual (vertigo), oculomotor (nystagmus), postural (dystaxia), and vegetative (nausea, vomiting). These four cardinal manifestations of vertigo are related to different levels of the vestibular analyzer and require different methods of investigation. The focus of our study is the phase of restructuring of equilibrium regulation in children between the ages of 8 and 15 years. PMID- 17691667 TI - Posttraumatic balance disorders. AB - Head trauma is being more frequently recognized as a causative agent in balance disorders. Most of the published literature examining traumatic brain injury (TBI) after head trauma has focused on short-term prognostic indicators and neurocognitive disorders. Few data are available to guide those individuals who see patients with balance disorders secondary to TBI. Our group has previously examined balance disorders after mild head trauma. In this study, we study all classes of head trauma. We provide a classification system that is useful in the diagnosis and management of balance disorders after head trauma and we examine treatment outcomes. As dizziness is one of the most common outcomes of TBI, it is essential that those who study and treat dizziness be familiar with this subject. PMID- 17691668 TI - How will the FDA impact the laboratory developed test? PMID- 17691669 TI - The doctorate in clinical laboratory science: A view of the strategy for continuity, growth, and realization of potential. PMID- 17691670 TI - Evaluation of effectiveness of a continuing education program on antimicrobial susceptibility testing. AB - OBJECTIVE: To evaluate the effectiveness of a course designed to increase use of the most recently published Clinical and Laboratory Standards Institute (CLSI) standards for antimicrobial susceptibility testing (AST) and reporting. DESIGN: A one-day continuing education course in AST was designed and delivered at multiple sites. Data collected from course evaluations, pre- and post-tests, and pre- and post-practices assessments were used to evaluate the effectiveness of the training. SETTING: The same course was held in 31 cities across the United States (US). PARTICIPANTS: Clinical laboratory scientists who attended the courses. MAIN OUTCOME MEASURES: Participant satisfaction; AST knowledge; number of labs using most recent CLSI standards; compliance with 28 specific CLSI AST recommendations. RESULTS: Data indicate a high level of participant satisfaction, a gain in AST knowledge, an increase in the number of laboratories acquiring the most recently published CLSI guidelines, and improvement in 4 of 28 specific AST practices. PMID- 17691671 TI - Comparison of two platelet count estimation methodologies for peripheral blood smears. AB - OBJECTIVE: To compare two manual methods for estimating platelet counts from Wright's stained peripheral blood smears regarding their correlation with each other and with automated platelet counts. This correlation was examined in relation to whether the platelet count was high, low, or normal and in relation to whether the hemoglobin value was low versus normal or high. DESIGN: Peripheral blood smears were Wright's stained and both platelet count estimation methodologies were performed on each slide. The traditional estimation method was the average number of platelets per oil immersion field (OIF) multiplied by 20,000 to yield a platelet count estimate per uL. The alternate estimation method was the average number of platelets per OIF multiplied by the patient's hemoglobin value in g/dL and then multiplied by 1,000 to yield a platelet count estimation per uL. The platelet count estimates were performed without the technologists having prior knowledge of the automated platelet counts which were produced on a Coulter LH750 analyzer. The agreement between the two manual methodologies with each other and each method with the automated count was assessed using the paired T-test and correlation coefficient analyses. These analyses were performed for the whole dataset as well as for subsets based on the automated platelet count and the hemoglobin value. SETTING: East Carolina University's Clinical Laboratory Science program in collaboration with the Clinical Pathology/Laboratory at Pitt County Memorial Hospital (PCMH) in Greenville NC. PARTICIPANTS: One hundred eighty-four blood samples in EDTA anticoagulant VacutainerI tubes were used to conduct this study. Each blood sample had two peripheral blood smears made and stained on an automatic slide stainer. The blood samples were obtained from the Clinical Pathology/Laboratory of Pitt County Memorial Hospital in October and November of 2004. Each sample was given a unique numeric identifier with no personal identifying information from any sample being recorded. MAIN OUTCOME MEASURE: Platelet counts by two slide estimation methods and by an automated reference method. RESULTS: The traditional platelet count estimation method had a mean for the sample of 269,000/uL, while the alternate estimation method had a mean of 155,000/uL. The mean for the automated platelet counts was 268,000/uL. The traditional estimation method showed no statistically significant difference in mean from the automated platelet counts based on the paired T-test (p = 0.87). The traditional estimation method counts and automated counts had a high Pearson Product Moment correlation coefficient of r = .90 and a minimally dispersed scatterplot, thus showing strong agreement. The alternate platelet count estimation method had a mean for the sample of 155,000/uL which, based on the paired T-test, was highly significantly different from the automated count mean (p < 0.0001) and the traditional estimation method mean (p < 0.0001). The alternate estimation method and automated counts had a lower r value of .81 and greater dispersion in the scatterplot. In comparing the estimation methods with each other and with the automated method, the differences and similarities in agreement observed for the whole dataset were also observed with each platelet count and hemoglobin subset of data. CONCLUSIONS: Though the alternate platelet count estimation method has been recommended for use particularly with patients with low hemoglobin values, this study found that the traditional estimation method provided more agreement with automated counts than did the alternate estimation method for all samples as well as for the subset of samples with low hemoglobin values. For the present, the traditional method of estimating platelet counts from blood smears to evaluate automated results appears to provide adequate quality assurance. PMID- 17691672 TI - Are new CLS practitioners prepared to stay? AB - OBJECTIVE: This study assessed the relationship between the educational preparation and career expectations of CLS students and their subsequent retention in the laboratory profession. DESIGN: Survey participants were given a list of 32 tasks that may be expected of early career professionals. Participants were asked to rate their educational preparation for and how frequently they performed each task in their current job using a four point Lickert scale. Additional questions addressed the participants' preparation for their current jobs, career satisfaction, plans for staying in the profession, and factors that influence retention. PARTICIPANTS: The survey sample consisted of 972 Clinical Laboratory Scientists who passed the National Credentialing Agency for Laboratory Personnel (NCA) CLS examination between June 2002 and June 2004. MAIN OUTCOME MEASURES: The mean rating for the level of preparation and the frequency of use for each of the 32 competencies was calculated. The mean ratings were used to assess the educational preparation in each competency and identify areas in which the level of preparation did not match the need for that skill in current practice. Using analysis of variance, respondents' answers to questions on their number of years of experience, their plans to stay in the profession, and their job satisfaction were compared based on their perceived level of preparation and the degree to which they felt their current jobs matched their career expectations at graduation. RESULTS: The response rate was 31%. Most of the respondents felt that they were well prepared for the responsibilities of their current laboratory position. There was a good match between the respondents' ratings of their preparation in each competency and the frequency with which they were required to perform that competency. Phlebotomy and flow cytometry appeared to have more preparation than respondents felt they needed. Troubleshooting, resolving problems, and performing multiple tasks were identified as areas in which more preparation was needed. The mean number of years that respondents planned to stay in the profession was 15.5 years and the factors that were most important in keeping them in the profession included interesting work, good salaries, and advancement opportunities. The respondents who rated the match between their career-entry expectations and their current job the highest were more satisfied and planned to stay in the profession the longest. CONCLUSION: Early career laboratory professionals felt well prepared for their jobs, though teaching of some tasks could be improved to better prepare graduates for the work environment. Most respondents indicated that they were prepared to stay in the profession for at least ten years; however they indicated that interesting work, good salaries, and opportunities to advance in the profession would be important in their decision to stay. A good match between laboratory employees' career expectations at the time of graduation and their work environment appears to improve their satisfaction with their careers and their desire to stay in the profession. PMID- 17691673 TI - Semen analysis. PMID- 17691674 TI - The history of ORL-Head and Neck Nursing. PMID- 17691675 TI - Evaluating and managing delirium, dementia, and depression in older adults hospitalized with otorhinolaryngic conditions. AB - Nurses caring for patients who have otorhinolaryngic conditions undergoing medical and surgical treatments find that their patient populations are becoming older and sicker. These patients are more likely to develop delirium, often superimposed on depression or dementia. Sorting out the medical, surgical, and psychosocial changes in geriatric patients presents unique challenges to otorhinolaryngology (ORL) nurses. This paper reviews the evaluation and management of delirium, dementia, and depression in hospitalized elders, focusing on a new resource, the evidence-based Mental Health Toolkit, developed by the National Conference of Gerontological Nurse Practitioners (NCGNP). The paper further provides material for a structured journal club activity, including a common ORL clinical scenario and learning objectives, as well as discussion questions and answers. PMID- 17691676 TI - Research evidence to update practice guidelines for domestic violence screening in military settings. PMID- 17691677 TI - Radiology corner. Case #7. PMID- 17691678 TI - Psychiatric medications for deployment: an update. AB - OBJECTIVE: This article discusses issues regarding the usage of psychotropic medications during military deployments, with emphasis on Operation Iraqi Freedom. METHOD: The role of psychotropic medications in the Army combat stress control doctrine is reviewed and compared with operational experiences of psychiatrists who have deployed to Iraq, Bosnia, and Egypt. RESULTS: Many issues regarding psychotropic medications experienced by deployed psychiatrists are not discussed in the Army combat stress control doctrine. CONCLUSION: The advent of new psychotropic medications, the changes in the types of conflicts fought, and the role of National Guard and Reserve forces in current conflicts have all had an impact on the role and usage of psychotropic medications during military deployments. PMID- 17691679 TI - The cost of preventing stigma by hospitalizing soldiers in a general hospital instead of a psychiatric hospital. AB - Hospitalization costs are lower in psychiatric hospitals than in psychiatric departments of general hospitals. However, soldiers hospitalized in psychiatric hospitals are subject to the stigma associated with mental illness. The goal of this study was to examine the financial costs of preventing such stigma by hospitalizing soldiers in psychiatric departments of general hospitals, rather than less expensive psychiatric hospitals. Another goal was to find ways to reduce hospitalization costs, taking into consideration the consequences of the stigma for patients and their families. Costs, medical data, and demographic data were gathered from records of soldiers hospitalized for psychiatric illness. The most expensive causes of hospitalization were determined (acute psychotic state and adjustment disorders), and the characteristics of a soldier most likely to encounter psychosis were described. Recommendations include rerouting patients from hospitalization to ambulatory day care, when possible, and from general to psychiatric hospitals. We also recommend adopting a psychiatric diagnosis-related group price list to standardize sums paid per diagnosis and creating a system for considering, on a case-by-case basis, early discharge of soldiers with psychotic disorders during the stressful first half-year of military service. PMID- 17691680 TI - Risk for increased utilization and adverse health outcomes among men served by the Veterans Health Administration. AB - Using data from a nationally representative survey, we evaluated the prevalence of multiple risk factors known to predict increased health care utilization and adverse health outcomes, comparing U.S. men who rely solely on the Veterans Affairs Health Administration (VA) for health care to men in the general population. Adjusting for age and race, men who only use the VA were significantly more likely to have multiple socioeconomic and lifestyle risk factors including current smoking. Their self-reported health status was more often fair or poor and they were more likely to report the presence of multiple chronic diseases ranging from arthritis to previous heart attack to poor mental health. Although the finding that VA-only users are at elevated health risk was anticipated, our study now provides nationally representative estimates of the magnitude of these differences and reinforces the importance of accounting for them when making VA to non-VA comparisons. PMID- 17691681 TI - Credibility of neuropsychological performances of Persian Gulf War veterans and military control subjects participating in clinical epidemiological research. AB - We investigated whether Persian Gulf War veterans (GWVs) were more likely than Persian Gulf War-era veterans deployed elsewhere (GEVs) to have noncredible neuropsychological examinations. A total of 301 GWVs and 99 GEVs underwent neuropsychological testing. The credibility of 173 examinations showing impairment was evaluated based on test performances, clinical background, psychometric measures, and other self-report data. All 11 examinations judged less than fully credible by one neuropsychologist, plus 19 examinations judged impaired but credible, were then evaluated independently by two more neuropsychologists. Noncredibility was judged with excellent reliability (93% agreement). Seven examinations were judged noncredible. Rates of noncredibility did not differ between GWVs (1%) and GEVs (4%). The pattern of associations of noncredible examinations with cognitive, psychological, and clinical variables generally indicated defective neuropsychological scores, with no coherent pattern, and personality disorder. Findings supported the validity of noncredibility judgments and suggested that noncredible examinations are not a significant problem in neuropsychological investigations of GWVs. PMID- 17691682 TI - Expeditionary medicine in Africa: the French experience. AB - The French army is often engaged in stability and support operations in Africa, and its military health service has gained much experience. The goal of this article is to present our military medical management strategies during the two main phases of military action. These situations most often begin with an initial combat phase, with combat casualty care. This consists of first aid, i.e., treatment of bleeding points, followed by battlefield forward medical care, damage control surgery, and resuscitation in forward surgical units. The quieter second phase of peacekeeping operations is dominated by the management of tropical diseases and their prevention, essential for the preservation of the military strength. PMID- 17691683 TI - Developing an effective medication soldier readiness process. AB - With the ever high operation tempo that our Armed Forces experience, it is imperative that military providers understand their soldiers' medication needs and how to ensure that those medications are properly processed by the supporting military pharmacy. Without a definitive plan, the surgeons responsible for soldiers' health will fail. This article outlines the experiences of the 4th Infantry Division and Darnall Army Community Hospital while preparing the 4th Infantry Division soldiers for deployment in support of Operation Iraqi Freedom 2005-2007. It details some important statistics that medical planners and unit surgeons can use when preparing their soldiers for deployment. Finally, we outline the lessons learned from this latest deployment and suggest components of an effective medication soldier readiness process. PMID- 17691684 TI - Functioning and psychiatric symptoms among military men and women exposed to sexual stressors. AB - OBJECTIVE: The goal was to describe military men's and women's functioning and psychiatric symptoms according to their military sexual stressor exposure. METHOD: A cross-sectional survey of 204 Army soldiers and 611 other active duty troops (487 men and 327 women) was performed. RESULTS: Forty-five percent of men and 80% of women reported at least one sexual stressor type (i.e., sexual identity challenges, sexual harassment, or sexual assault). After adjustment, subjects reporting more types of sexual stressors had poorer physical, work, role, and social functioning; more-severe post-traumatic stress disorder, depression, and anxiety symptoms; and more somatic concerns, compared with subjects reporting fewer or no sexual stressor types (all p < or = 0.004). Interactions by gender were insignificant (all p > 0.11). Within sexual stressor category, men and women reported similar mean adjusted functioning and psychiatric symptoms. CONCLUSIONS: For both men and women, impaired functioning and more severe psychiatric symptoms were more common among those reporting more types of sexual stressors. PMID- 17691685 TI - Blast injury of the ear: clinical update from the global war on terror. AB - The purpose of this study was to describe the effects of blast exposure on hearing status. This study retrospectively analyzed hearing thresholds and otologic complaints for >250 patients with blast-related injuries from the global war on terror. Of patients who received full diagnostic evaluations, 32% reported a history of tympanic membrane perforation, 49% experienced tinnitus, 26% reported otalgia (ear pain), and 15% reported dizziness. Expected hearing thresholds were computed by applying age-correction factors to hearing tests performed earlier in the service members' careers and before their most recent deployment. Expected hearing thresholds were significantly better than actual postdeployment thresholds, indicating that significant changes occurred in the patients' hearing that could not be accounted for by age. Results from this study underline the need for documentation of pre-and postdeployment hearing tests and prompt otologic evaluation for the blast-exposed population. PMID- 17691686 TI - Characterizing self-reported dizziness and otovestibular impairment among blast injured traumatic amputees: a pilot study. AB - The incidence of vestibular and audiologic injury related to blast injury remains underreported. The primary objective of this study was to document self-reported otovestibular impairment in blast-injured amputees. Secondary objectives include a description of the Walter Reed Army Medical Center Blast Injury Questionnaire and other aspects of the audiology service and amputee physical therapy section standards of care for blast injury management. A case study illustrates the application of these standards of care. Thirty-three patients were evaluated by audiologists and physical therapists using the Walter Reed Army Medical Center Blast Injury Questionnaire, followed by audiologic and vestibular screening; 24% of patients reported symptoms of vertigo or oscillopsia following blast trauma, and 51% reported subjective hearing loss. The case study subject reported an increase in function after vestibular rehabilitation therapy. Thorough screening by audiologists and physical therapists can facilitate appropriate diagnosis and management for blast-injured patients. PMID- 17691687 TI - Correction factors for body mass bias in military physical fitness tests. AB - Recent research findings combined with the theoretical laws of biological similarity make the compelling case that all physical fitness test items for the Army, Air Force, and Navy impose a 15 to 20% physiological bias against heavier, not fatter, men and women. Using the published findings that actual scores of muscle and aerobic endurance scale by body mass raised to the 1/3 power, correction factor tables were developed. This correction factor can be multiplied by one's actual score (e.g., push-ups, sit-ups, abdominal crunches, or curl-up repetitions or distance run time) to yield adjusted scores that are free of body mass bias. These adjusted scores eliminate this bias, become better overall indicators of physical fitness relevant to military tasks, are easily applied to the scoring tables used in the present physical fitness tests, and do not reward body fatness. Use of these correction factors should be explored by all military services to contribute to more relevant fitness tests. PMID- 17691688 TI - Effects of gender and body adiposity on physiological responses to physical work while wearing body armor. AB - The purpose of this study was to identify the effects of gender and body adiposity on physiological responses to the stress of wearing body armor. Using a within-subject, repeated-measures design, 37 military personnel volunteered to undergo two experimental conditions, with body armor and without body armor. Female and male subjects with body armor, compared to those without body armor, had no significant differences in percentage increases in aerobic capacity, heart rate, or respiratory rate while walking at slow or moderate pace. However, women, as compared to men, had a significantly increased difference in the rating of perceived physical exertion between wearing and not wearing body armor at a slow pace. Fourteen subjects were not able to complete treadmill testing while wearing body armor because of volitional fatigue and/or limiting dyspnea. Body fat was the best single predictor of treadmill test completion. PMID- 17691689 TI - Diagnosing cutaneous leishmaniasis: the advantage of forward deployed histology in avoiding a surgical pitfall. AB - Military surgeons are often consulted for excisional debridement of skin lesions that fail to respond to medical therapy among soldiers who have been operating in areas of Afghanistan where cutaneous leishmaniasis is endemic. Wide surgical excision without knowledge of the primary etiology can lead to a surgical pitfall. Failure to properly treat cutaneous leishmaniasis, however, can lead to medical pitfalls of permanent disfigurement, deformity, and disability. Forward deployed surgeons should be supported by a laboratory that can confirm the presence of atypical organisms in biopsies of these lesions. With a x 100 microscope and Wright-Giemsa stains, a medical treatment facility is able to confirm cutaneous leishmaniasis, which allows for rapid transfer of soldiers for definitive antimicrobial therapy. PMID- 17691690 TI - Avian influenza: potential impact on sub-Saharan military populations with high rates of human immunodeficiency virus/acquired immunodeficiency syndrome. AB - Several sub-Saharan militaries have large percentages of troops with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. With the arrival of avian influenza in Africa, the potential exists that some of those soldiers might also become infected with H5N1, the virus responsible for the disease. Two possible scenarios have been postulated regarding how such a coinfection of HIV and H5N1 might present. (1) Soldiers already weakened by HIV/acquired immunodeficiency syndrome rapidly succumb to H5N1. The cause of death is a "cytokine storm," essentially a runaway inflammatory response. (2) The weakened immune system prevents the cytokine storm from occurring; however, H5N1 is still present, replicating, and being shed, leading to the infection of others. A cytokine storm is particularly dangerous for individuals of military age, as evidenced by the large number of soldiers who died during the 1918 influenza epidemic. If large numbers of sub-Saharan soldiers suffer a similar fate from avian influenza, then military and political instability could develop. PMID- 17691691 TI - Seroepidemiological survey of rodents collected at a U.S. military installation, Yongsan Garrison, Seoul, Republic of Korea. AB - A seroepidemiological study of selected rodent-borne diseases (hantavirus [Seoul [SEO] virus], scrub typhus [Orientia tsutsugamushi], murine typhus [Rickettsia typhi], and leptospirosis [Leptospira interrogans]), as part of the U.S. military rodent surveillance and control program, was conducted from 2001 through 2005 at Yongsan Garrison, Seoul, Republic of Korea. Rodents were collected to determine the prevalence of rodent-borne diseases at a U.S. military installation in an urban environment. A total of 1,750 rodents representing three species was collected by using baited live traps (Tomahawk), glue boards, and poison baits (dead rodents observed but not assayed). The Norway rat, Rattus norvegicus (99.8%), accounted for nearly all of the rodents captured/observed. Only three roof rats, Rattus rattus (0.2%), and one house mouse, Mus musculus (<0.1%), were collected. R. norvegicus rats were the only rodents that were serologically positive for SEO virus (9.6%), scrub typhus (2.8%), murine typhus (3.8%), and leptospirosis (4.6%). One of six rodents that were positive for SEO virus by immunofluorescent antibody test was positive for SEO virus antigen by reverse transcriptase-polymerase chain reaction. Infection rates for SEO virus, scrub typhus, murine typhus, and leptospirosis varied annually. Rodents were captured from 228 (20.7%) of 1,104 total buildings in Yongsan Garrison. The Yongsan commissary had the highest annual infestation rate (22 rodents per year), followed by Commisky's Club (18 rodents per year). Annual infestation rates were high for food service facilities, which often store perishable food products outdoors for short periods of time, attracting rodent populations; refuse from these facilities provides harborage and food for rodents. The effect of rodent populations outside the boundary of Yongsan Garrison was not determined. PMID- 17691692 TI - African trypanosomiasis in a British soldier. AB - BACKGROUND: Sleeping sickness (human African trypanosomiasis) is a parasitic infection transmitted by day-biting tsetse flies. The diagnostic standard is microscopy of blood, lymph node aspirates, or cerebrospinal fluid. The disease is invariably fatal if not treated. There are >300,000 new cases of sleeping sickness each year and approximately 100,000 deaths. CASE PRESENTATION: We describe a British soldier who acquired sleeping sickness in Malawi. He gave no history of a painful insect bite but presented with classic early signs of sleeping sickness (a primary chancre, regional lymphadenopathy, circinate erythema, and a cyclical fever pattern). His condition worsened in the next week, and trypanosomes were observed in a blood sample. The patient was aeromedically evacuated to Johannesburg, where stage 1 Trypanosoma brucei rhodesiense infection was confirmed; he also had renal and liver failure, pancytopenia, and heart block. He was treated with intravenously administered suramin, and he recovered fully over the next 5 months. RECOMMENDATIONS: Medical officers deploying to eastern and southeastern Africa must be familiar with the common presenting signs and symptoms of T. b. rhodesiense sleeping sickness and should have 24-hour access to a reliable, local, clinical microscopy service. Confirmed sleeping sickness requires immediate transfer to a tertiary diagnostic and treatment center, where suramin (for T. b. rhodesiense infection), pentamidine (for Trypanosoma brucei gambiense infection), and melarsoprol (for stage 2 disease) must be immediately available. PMID- 17691693 TI - Comparison of the urine Leukocyte Esterase Test to a Nucleic Acid Amplification Test for screening non-health care-seeking male soldiers for Chlamydia trachomatis and Neisseria gonorrhoeae infections. AB - We evaluated the Leukocyte Esterase Test (LET) as a screening tool by testing urine from 1,438 non-health care-seeking male Army basic trainees with LET and a Nucleic Acid Amplification Test. Compared to Nucleic Acid Amplification Test results, LET sensitivity and specificity for detection of chlamydia and gonorrhea were 45.8% and 97.4%, and 60.0% and 96.2%, respectively. The prevalence of chlamydia and gonorrhea was 3.3% and 0.3%, respectively. In this population, the prevalence of gonorrhea was too low to produce reliable estimates of performance characteristics of the LET for gonorrhea. The LET is not warranted for use in screening non-health care-seeking male Army trainees. PMID- 17691694 TI - Comparison of real-time polymerase chain reaction and conventional polymerase chain reaction methods for the rapid identification of Bacillus anthracis. AB - Bacillus anthracis spores have been shown to be one of the most effective biological weapons. For the rapid detection of B. anthracis spores, several genetic markers, including chromosomal and plasmid-based sequences, were studied with polymerase chain reaction (PCR) methods. In the present study, a method using a primer/probe set based on the pXO1-encoded pag gene for the detection of B. anthracis was tested in addition to culture. Eight pathological samples (four blood-immersed cotton specimens, two spleen tissue specimens, and two blood smears) with confirmed positive results for anthrax were used. All samples were suspended in saline solution and fixed with Gram and Giemsa stains for examination of colony and capsule formation. Amplicons were analyzed on 2% agarose gels with the classic PCR method. For real-time PCR, a fluorescently labeled TaqMan probe was used with a Smartcycler. Positive smear and cotton samples were confirmed with the standard culture and real-time PCR methods, but the same samples were found to be negative with the classic PCR method. A spleen sample known to be positive for B. anthracis was found to be negative with the culture method because of possible contamination with Proteus-type bacteria. PMID- 17691695 TI - Application of the Mangled Extremity Severity Score in a combat setting. AB - OBJECTIVE: The aim of this study was to examine the Mangled Extremity Severity Score (MESS) in a combat setting. METHODS: Data on extremity injuries were collected from a forward surgical team. MESS and Revised Trauma Score values were retrospectively calculated for each patient. Student's t test was used to compare amputated and salvaged limbs. RESULTS: A total of 60 extremities was identified in 49 patients. There were 10 major vascular repairs (20%). MESS values differed significantly for the eight amputations performed (mean MESS, 7.87 +/- 1.91) and 50 salvaged extremities (mean MESS, 2.44 +/-_ 0.438; p = 0.001). CONCLUSIONS: A MESS of >7 correlated with amputation, thus validating the MESS in a combat setting. A young average patient age and high-energy injury mechanism on the battlefield leave ischemic time and shock as the most important factors in dictating whether a MESS is >7 or <7. PMID- 17691696 TI - Prevalence and epidemiology of pathological gambling at Naval Medical Center Portsmouth psychiatry clinic. AB - OBJECTIVE: Gambling has exploded in popularity, but pathological gambling (PG) is infrequently diagnosed. The objectives of this study were to calculate the prevalence of PG in a psychiatry clinic, to determine whether PG is underdiagnosed, and to analyze risk factors for PG. METHODS: A survey was completed by 584 outpatients presenting to the Naval Medical Center Portsmouth psychiatry clinic over 6 months. Epidemiological data, smoking status, and alcohol use were assessed, and the South Oaks Gambling Screen was administered. RESULTS: The prevalence of PG determined with the South Oaks Gambling Screen was 1.4%. The electronically documented prevalence of PG was 0.04%. Male subjects, smokers, and subjects with an alcohol problem were more likely to have a gambling problem. Active duty members did not have statistically significantly higher rates of PG. CONCLUSIONS: PG is markedly underdiagnosed. Military members are not at elevated risk for PG, relative to their dependents. Further research and greater awareness of PG are needed. PMID- 17691697 TI - Rising hepatitis A immunity in U.S. military recruits. AB - BACKGROUND: The U.S. military immunizes new recruits against hepatitis A. Since 2001, immunization with the hepatitis A vaccine has been recommended for civilian adolescents in higher risk areas. Recently, the Armed Forces Epidemiological Board recommended serologic screening where feasible to reduce redundant recruit immunizations. OBJECTIVES: The purpose of this study was to determine hepatitis A seroprevalence in recruit populations to inform screening policy. METHODS: Banked serum from a sample of military recruits (n = 2,592) in 2004 was tested for total antibody to hepatitis A (anti-hepatitis A virus (HAV)). RESULTS: The overall anti HAV seroprevalence was 12.0% (95% confidence interval, 10.8%-13.3%). Adjusted to the age distribution of the 18- to 34-year-old population, the seroprevalence was 11.9% (10.5%-13.4%). The lowest seroprevalence was noted in the 1984 birth cohort, with significantly higher seroprevalence among younger recruits. CONCLUSIONS: Rising hepatitis A immunity among successive birth cohorts suggests increasing compliance with immunization recommendations. In anticipation of rising population immunity, universal screening of military recruits for anti-HAV is recommended. PMID- 17691698 TI - Case for diagnosis. Brodie abscess. PMID- 17691699 TI - Bilateral quadriceps tendon ruptures in a healthy, active duty soldier. PMID- 17691700 TI - Automating anemia assay. PMID- 17691702 TI - The masks of allergy undone by IVT. PMID- 17691703 TI - Flow cytometry: an overview. PMID- 17691704 TI - HIPAA: where are we now? PMID- 17691705 TI - Hard evidence required to bring official charges. PMID- 17691706 TI - Extended platelet storage makes a welcome difference. PMID- 17691707 TI - A novel approach to public policy. PMID- 17691708 TI - Optimizing hemodialysis practices in Canada could improve patient survival. AB - Data from the Canadian Organ Replacement Registry (CORR) and the Dialysis Outcomes and Practice Patterns Study (DOPPS) were used to determine whether practice patterns have changed in Canada since the introduction of the Canadian Society of Nephrology (CSN) Guidelines in 1999. DOPPS data were then used to calculate the impact of not meeting the proposed guideline targets and to estimate the potential life years gained if all Canadian hemodialysis patients achieved guideline targets. For dialysis dose and hemoglobin targets, Canadian facility performance has significantly improved over time. The vascular access use patterns show trends toward a worse pattern with increased catheter use. A calculation of the percentage of attributable risk suggests that 49% of deaths could possibly be averted if all patients currently outside the guidelines achieved them over the next five years. This corresponds to a decrease in the annual death rate from 18 to 10.1 per hundred patient years. These data support the need for improved adherence to guidelines. If Canadian caregivers were to optimize practice patterns, patient outcomes could be improved. PMID- 17691709 TI - Nurses' perceptions of the impact of a renal nursing professional practice model on nursing outcomes, characteristics of practice environments and empowerment- Part II. AB - The purpose of this study was to examine the effect of a renal nursing professional practice model (PPM) on nurses'perceptions of empowerment, characteristics of practice environments and the impact on nursing care outcomes in a university-based teaching hospital in Canada. Quantitative and qualitative methodologies were used. This paper will focus on the qualitative results. Content analysis was the data analysis method used. The following themes emerged: 1) Attunement, familiarity/knowing the patient, going the distance, 2) Patient outcomes, consistency and continuity of care, autonomy/taking the initiative, 3) Nurse rewards: satisfaction and accountability, empowerment/input, and 4) Facilitating systems: communication, support and assignment. The quantitative results had a significant (p = .005) improvement post-PPM implementation in the nursing foundations for quality of care subscale of the Practice Environment Scale of the Nursing Work Index (NWI-PES) and organizational relationships (p =.016) measured by the Conditions of Work Effectiveness II (CWEQ-II) questionnaires. This study provides evidence for PPMs and primary nursing as effective frameworks to positively impact nursing and patient outcomes in a hemodialysis unit. PMID- 17691710 TI - The design of a hemodialysis nursing orientation program. AB - With the ever-increasing number of persons requiring treatment for kidney disease, the need for competent hemodialysis (HD) nurses continues. Professional organizations support the use of nursing orientation programs, which have been shown to decrease staff turnover. An instructor's manual, student's handbook and learner's manual for HD orientation were developed in response to this need. Morrison, Ross & Kemp's (2004) instructional design model guided the creation of this material, while Bandura's concept of self-efficacy (1997) and Knowles' Adult Learning Theory (1984) gave direction for implementing this program. The focus of this paper is to outline how the instructional development model, self-efficacy concept and adult learning theory supported the development of this HD orientation. The materials developed for the orientation program should enable new HD nurses to provide improved holistic care to their patients and families. PMID- 17691711 TI - Nurse practitioners in the Northern Alberta Renal Program. AB - The presence of nurse practitioners (NPs) in nephrology is not a new concept; literature out of the United States documents their existence quite well Since 1973, the collaboration of NPs and nephrologists has provided cost-effective care for dialysis patients and an alternative for health authorities anticipating a nephrologist shortage. Integration of NPs ensures high-quality, cost-effective, patient-focused care. In 1995, NPs began their integration into the Canadian nephrology field and, in 2004, the Northern Alberta Renal Program (NARP) hired its first nurse practitioner. Currently, there are five NPs who work collaboratively with nephrologists to manage and co-ordinate nephrology care. This article will review the history of NPs in Canada and the introduction of NPs in NARP. PMID- 17691712 TI - Challenges of providing PD to the remote northwest of Ontario. PMID- 17691713 TI - Pandemic influenza and renal disease. PMID- 17691715 TI - Fluorescence polarization spectroscopy at combined high-aperture excitation and detection: application to one-photon-excitation fluorescence microscopy. AB - A problem of the one-photon-excitation fluorescence polarization spectroscopy of macroscopically isotropic media, in the case of combined high-aperture excitation and detection, is considered and described in a spherical representation. The case of inhomogeneous intensity distribution in the cross-section of the parallel beam of exciting light, which is converted by an objective lens into inhomogeneous radial distribution of the intensity of the focused exciting light, is also taken into account. The obtained formalism is adapted to the description of confocal fluorescence polarization microscopy. It is shown that the total and magic-angle-detected fluorescence decays do not solely represent the kinetic evolution of the excited-state because of the contribution of the dynamic evolution of photoselected fluorophores. The time-evolution of emission anisotropy is nonexponential. The outlined theory predicts that the total and magic-angle-detected fluorescence decays solely represent the kinetic fluorescence decay, and thereby, the emission anisotropy becomes an (multi)exponential function of time for the excitation-detection cone half-angles not higher than about 15-20 degrees. The initial values of the emission anisotropy are not modified by the application of the excitation-detection apertures if the cone half-angles do not exceed 10-15 degrees. The histograms of unpolarized fluorescence, calculated from the parallel and the perpendicular components of polarized fluorescence, detected at the excitation-detection cones wider than about 65 degrees solely represent the kinetic fluorescence decay. At such conditions, the microscope objective operates like an "integrating sphere". The calibration method, which is based on a general (symmetry adapted) formula describing fluorescence polarization experiments on macroscopically isotropic samples, is discussed. This method enables the analysis of all fluorescence polarization experiments without the necessity of considering the expressions for polarized fluorescence decays relating to a particular experimental case of interest. With this method, any commercially available microscope objective can be calibrated, and its optical properties can be precisely verified. The application of the outlined theory to different fluorescence spectroscopy techniques is indicated. The expressions derived for confocal fluorescence polarization microscopy can be employed in the numerical analysis of the data recovered from the photochemical bioimaging. PMID- 17691716 TI - Photodissociation dynamics of phenol. AB - The photodissociation of phenol at 193 and 248 nm was studied using multimass ion imaging techniques and step-scan time-resolved Fourier-transform spectroscopy. The major dissociation channels at 193 nm include cleavage of the OH bond, elimination of CO, and elimination of H(2)O. Only the former two channels are observed at 248 nm. The translational energy distribution shows that H-atom elimination occurs in both the electronically excited and ground states, but elimination of CO or H(2)O occurs in the electronic ground state. Rotationally resolved emission spectra of CO (1 L direction and 1.66 +/- 0.09 in the L --> D direction. Secondary kinetic isotope effects were found for the external aldimine formation steps in both the L --> D (1.13 +/- 0.05, forward; 0.90 +/- 0.03, reverse) and D --> L (1.13 +/- 0.06, forward; 0.89 +/- 0.03, reverse) directions. The secondary equilibrium isotope effects calculated from these are 1.26 +/- 0.07 and 1.27 +/- 0.07 for the L --> D and D --> L directions, respectively. These equilibrium isotope effects imply substantial ground-state destabilization of the C-H bond via hyperconjugation with the conjugated Schiff base/pyridine ring pi system. The magnitudes of the intrinsic primary kinetic isotope effects, the lower boundary on the energy of the quinonoid intermediate, and the protonation states of the active site catalytic acids/bases (K39-epsilonNH2 and Y265-OH) suggest that the pKa of the substrate Calpha-H bond in the external aldimine lies between those of the two catalytic bases, such that the proton abstraction transition state is early in the D --> L direction and late in the L --> D direction. PMID- 17691730 TI - The twisted C11=C12 bond of the rhodopsin chromophore--a photochemical hot spot. PMID- 17691729 TI - De novo design of a single-chain diphenylporphyrin metalloprotein. AB - We describe the computational design of a single-chain four-helix bundle that noncovalently self-assembles with fully synthetic non-natural porphyrin cofactors. With this strategy, both the electronic structure of the cofactor as well as its protein environment may be varied to explore and modulate the functional and photophysical properties of the assembly. Solution characterization (NMR, UV-vis) of the protein showed that it bound with high specificity to the desired cofactors, suggesting that a uniquely structured protein and well-defined site had indeed been created. This provides a genetically expressed single-chain protein scaffold that will allow highly facile, flexible, and asymmetric variations to enable selective incorporation of different cofactors, surface-immobilization, and introduction of spectroscopic probes. PMID- 17691731 TI - Calculations of the effects of substituents on bond localization in annelated cyclopentadienyl radicals. AB - UB3LYP/6-31G(d) calculations have been performed in order to predict the ground states, 2A2 or 2B1, of cyclopentadienyl radicals that are mono- and bis-annelated with a wide variety of substituents. Unlike the case in the annelated cyclooctatetraenes, studied by Baldridge and Siegel, our calculations find that the sizes of the coefficients of the degenerate MOs at the annelated carbons are more important than the symmetries of the substituent's frontier orbitals in determining the mode of bond localization in the annelated cyclopentadienyl radicals. PMID- 17691732 TI - Sc3N@C78: encapsulated cluster regiocontrol of adduct docking on an ellipsoidal metallofullerene sphere. AB - The first N-tritylpyrrolidino derivatives of D(3h) (78:5) Sc(3)N@C(78) were successfully synthesized and isolated. The addition sites for the two nearly equivalent kinetic monoadducts 1a and 1b are across two different 6,6 junction sites on the Sc(3)N@C(78) cage that are offset from the horizontal plane defined by the Sc(3)N cluster. The adducts were characterized by NMR experiments, DFT calculations and X-ray crystallographic analysis of Sc(3)N@C(78) derivative 1a. A unique finding of this study is the regiocontrol of adduct docking by the internal Sc(3)N cluster. PMID- 17691733 TI - Enhanced stability of large molecules vacuum-sublimated onto Au(111) achieved by incorporation of coordinated Au-atoms. PMID- 17691734 TI - Cinchona alkaloids/TMAF combination-catalyzed nucleophilic enantioselective trifluoromethylation of aryl ketones. AB - The catalytic, nucleophilic enantioselective trifluoromethylation reaction of both acyclic and cyclic aryl ketones using the Ruppert-Prakash reagent is now at hand, with an operationally simple procedure, based on the combination of ammonium bromide of cinchona alkaloids with TMAF. The procedure is reliable and general. Trifluoromethyl-substituted tetrasubstituted aryl alcohols have been synthesized in up to 94% ee. PMID- 17691735 TI - Energy transfer in oligofluorene-C60 and C60-oligofluorene-C60 donor-acceptor conjugates. AB - Two complementary series of C(60)-(Fl)(n) and C(60)-(Fl)(n)-C60 (Fl = 9,9 dihexylfluorene-2,7-diyl; n = 1-5) derivatives with terminal N methylfulleropyrrolidine units have been synthesized from CHO-(Fl)(n) and CHO (Fl)(n)-CHO precursors via 1,3-dipolar cycloaddition reaction of in situ generated azomethine ylides with an excess of C60. In solution electrochemical experiments, these conjugates give rise to amphoteric redox behavior. Three consecutive quasireversible reduction waves have been observed at the expected potentials for the N-methylfulleropyrrolidine cores. For the C(60)-(Fl)(n)-C(60) series, each reduction wave is a two-electron process with no observable interaction between the C(60) units. Two or, in some cases, three oxidation waves -most of them irreversible--are ascribed to the oligofluorene system. These waves are cathodically shifted with an increasing number of fluorene units and anodically shifted by the conjugated terminal aldehyde units, compared to the N methylfulleropyrrolidine termini. Steady-state and time-resolved photolytic techniques show that an efficient transduction of singlet excited-state energy transfer prevails from the photoexcited oligofluorene to the energy accepting fullerene. PMID- 17691736 TI - Electrophilic cyclization of (Z)-selenoenynes: synthesis and reactivity of 3 iodoselenophenes. AB - We present here our results of the electrophilic cyclization reaction of (Z) selenoenynes with different electrophiles such as I(2), ICl, PhSeBr, and PhSeCl. The cyclization reaction proceeded cleanly under mild reaction conditions, and 3 substituted selenophenes were formed in moderate to excellent yields. We observed that the nature of solvent and structure of (Z)-selenoenyne were important to the cyclization reaction. In addition, the obtained 3-iodoselenophenes were readily transformed to more complex products using a metal-halogen exchange reaction with n-BuLi and trapping the intermediate formed with aldehydes, furnishing the desired secondary alcohols in good yields. Conversely, using the palladium or copper catalyzed cross-coupling reactions with terminal alkynes or alkyl alcohols, we were able to convert 3-iodoselenophene to Sonogashira or Ullmann type products, respectively, in good yields. PMID- 17691737 TI - Conformationally constrained aliphatic-aromatic amino-acid-conjugated hybrid foldamers with periodic beta-turn motifs. AB - In this note, we describe the design, synthesis, and structural studies of novel hybrid foldamers derived from Aib-Pro-Adb building blocks that display repeat beta-turn structure motif. The foldamer having a conformationally constrained aliphatic-aromatic amino acid conjugate adopts a well-defined, compact, three dimensional structure, governed by a combined conformational restriction imposed by the individual amino acids with which it is made of. Conformational investigations by single-crystal X-ray and solution-state NMR studies were undertaken to investigate the conformational preference of these foldamers with a hetero-backbone. Our findings suggest that constrained aliphatic-aromatic amino acid conjugates would offer new avenues for the de novo design of hybrid foldamers with distinctive structural architectures. PMID- 17691738 TI - Phenothiazine cruciforms: synthesis and metallochromic properties. AB - We report the synthesis and characterization of five novel phenothiazine containing cruciforms (5-9). The targets were prepared by a NaH-promoted Horner reaction of tetraethyl(2,5-diiodo-1,4-phenylene)bis(methylene)diphosphonate with 10-hexyl-10H-phenothiazine-3-carbaldehyde. The formed intermediary 3,3'-(1E,1'E) 2,2'-(2,5-diiodo-1,4-phenylene)bis(ethene-2,1-diyl)bis(10-hexyl-10H phenothiazine) was reacted with several different aromatic alkynes (1-tert-butyl 4-ethynylbenzene, N,N-dibutyl-4-ethynylaniline, 1-ethynyl-3 (trifluoromethyl)benzene, and 1-ethynyl-3,5-bis(trifluoromethyl)benzene) to give the corresponding cruciform fluororphores (XF). The XFs were fully characterized by NMR and IR spectroscopy and then exposed to trifluoroacetic acid as well as to several metal triflates. The XFs show dramatic shifts in emission and to a lesser extent in absorption when exposed to magnesium triflate or zinc triflate. In the case of magnesium triflate, a blue shift in emission was observed; in contrast, addition of zinc triflate results in either quenching or a red-shifted emission. Due to the electronic situation, these XFs display spatially separated frontier molecular orbitals, allowing the HOMO or the LUMO of the XFs to be addressed independently by addition of zinc or magnesium ions. Phenothiazine XFs may have potential in array-type sensory applications for metal cations. PMID- 17691739 TI - Conversion of 2-alkylcinnamaldehydes to 2-alkylindanones via a catalytic intramolecular Friedel-Crafts reaction. AB - The preparation of indanones by the intramolecular acylation of 3-arylpropanoic acids or halides requires the use of noncatalytic acid promoters. In the presence of 5-10 mol % FeCl(3), in situ generated dimethyl acetals of (E)-2 alkylcinnamaldehydes cyclize to 1-methoxy-2-alkyl-1H-indenes in good-to-high yields. The 1-methoxyindenes were converted in high yield into 2-alkylindanones by treatment with triethylamine, to effect isomerization to the isomeric enol ethers, followed by acid-catalyzed hydrolysis. Thus, a catalytic, intramolecular Friedel-Crafts reaction leading to 2-alkylindanones from 2-alkylcinnamaldehydes was developed. PMID- 17691740 TI - Diastereospecific photocyclization of a isopropylbenzophenone derivative in crystals and the morphological changes. AB - Reaction of crystals of 2,4,6-triisopropylbenzophenone derivative with the (S) phenylethylamide group caused diastereospecific Norrish type II photocyclization by UV irradiation to give (R,S)-cyclobutenol as a sole product. In contrast, the solution photolysis gave an almost 1:1 mixture of (R,S)- and (S,S)-cyclobutenol. The specific diastereodifferentiation in the crystalline state is attributed to the smooth transformation with minimum molecular motion due to the very similar molecular shapes as well as the 2-fold helical arrangements between the reactant crystal and the product (R,S)-cyclobutenol crystal. UV irradiation of the bulk crystals led to cracking and breaking into small fragments. In contrast, the microcrystals maintained the single-crystalline morphology in the course of photocyclization, suggesting the single-crystal-to-single-crystal transformation. PMID- 17691741 TI - Air-stable racemization catalysts for the dynamic kinetic resolution of secondary alcohols. AB - The substitution of a carbonyl ligand with PPh(3) in cyclopentadienylruthenium dicarbonyl complexes produces a new class of recyclable alcohol racemization catalysts. The catalysts are active at room temperature under aerobic conditions in the presence of silver oxide. Furthermore, the catalysts are compatible with the use of a lipase and isopropenyl acetate for the dynamic kinetic resolution (DKR) of secondary alcohols under ambient conditions. PMID- 17691742 TI - Synthesis of hexahydropyrrolo[2,3-b]indole alkaloids based on the aza-Pauson Khand-type reaction of alkynecarbodiimides. AB - Upon treatment with 30 mol % of Co2(CO)(8) and 30 mol % of TMTU in toluene at 70 degrees C, benzene-bridged alkynecarbodiimides efficiently underwent a ring closing reaction to give the pyrrolo[2,3-b]indol-2-ones in good yields. These conditions could nearly suppress the formation of the urea derivatives, which were consistently observed when 10 mol % of Co2(CO)(8) and 60 mol % of TMTU in benzene were used. The synthesis of the eight hexahydropyrrolo[2,3-b]indole alkaloids was accomplished from the resulting pyrrolo[2,3-b]indol-2-ones via the introduction of an angular substituent at the C(3a)-position by treatment with NaBH(4)/alkyl bromide as the crucial step. PMID- 17691743 TI - t-Bu-QuinoxP* ligand: applications in asymmetric Pd-catalyzed allylic substitution and Ru-catalyzed hydrogenation. AB - The potential of the t-Bu-QuinoxP* ligand (1) as a chiral ligand in asymmetric synthesis was examined. The ligand exhibited good to excellent asymmetric induction in Pd-catalyzed asymmetric allylic substitution of 1,3-diphenyl-2 propenyl acetate (up to 98.7% ee) and in Ru-catalyzed asymmetric hydrogenation of ketones (up to 99.9% ee). PMID- 17691744 TI - Side-chain truncation of apicularen A by olefin cross-metathesis with ethylene. AB - The three olefinic double bonds of natural apicularen A (1a) were cleaved by olefin cross-metathesis in the presence of ethylene and Hoveyda-Grubbs catalyst with concomitant E/Z isomerization of Delta(17,18). On extended conversion, 18,19 seco-apicularen A (3) was accumulated and isolated in pure state in 25% yield. In total synthesis, 3 is a valuable late-stage intermediate for side-chain-modified apicularens. PMID- 17691745 TI - Iridoids from the green leaves of Eucommia ulmoides. AB - The bark of Eucommia ulmoides is a well-known crude drug in oriental medicine, and its leaves have been consumed as a beverage. From the green leaves of this plant, three new iridoids (1-3) were isolated, together with 12 known compounds. Compound 1 is the first iridoid possessing a saturated bond between C-3 and C-4 and having an ether linkage between C-3 and C-2 of the glucose unit. Furthermore, 2 and 3 may be regarded as the first naturally occurring conjugates of an iridoid and an amino acid. PMID- 17691746 TI - Diversity-oriented synthesis of functionalized quinolin-2(1H)-ones via Pd catalyzed site-selective cross-coupling reactions. AB - Biologically active 3-amino-4-arylquinolin-2(1H)-ones and 3-alkenyl-4 arylquinolin-2(1H)-ones were synthesized in an efficient and concise manner, utilizing readily available 4-hydroxyquinolin-2(1H)-one as starting material. The key steps, which introduced selectivity and diversity in the synthesis, were the palladium-catalyzed site-selective Suzuki-Miyaura/Buchwald-Hartwig amination and Suzuki-Miyaura/Heck coupling reactions of 3-bromo-4-trifloxy-quinolin-2(1H)-one. PMID- 17691747 TI - From superhydrophilicity to superhydrophobicity: the wetting behavior of a methylsilicone/phenolic resin/silica composite surface. AB - A methylsilicone/phenolic resin/silica composite surface was prepared by a casting method. The wetting behavior of the surface was investigated. It was found that the as-prepared surface can be varied from superhydrophilicity to superhydrophobicity as the drying temperature increased. Methylsilicone/silica and phenolic resin/silica composite surfaces were also prepared as comparisons. Both of them cannot achieve superhydrophobicity. A mechanism was proposed to explain this phenomenon. PMID- 17691748 TI - Atomic layer deposition of conformal inorganic nanoscale coatings on three dimensional natural fiber systems: effect of surface topology on film growth characteristics. AB - Atomic-scale material deposition is utilized to achieve uniform coverage and modification of the surface properties of natural fiber and woven fabric materials, where irregular nanoscale features are embedded in a macroscale interpenetrating fiber network. The complex surface topology of the woven fabric results in significantly different film-growth thickness per ALD cycle as compared to planar surfaces coated using the same process conditions, likely due to reactant adsorption within the fiber starting material, as well as impeded reactant transport out of the fabric system during the purge cycle. Cotton textiles modified with conformal nanoscale Al2O3 are found to show extreme hydrophobic effects, distinctly different from planar surfaces that receive the same coatings. The results highlight key concerns for achieving controlled conformal coatings on complex surfaces and open the possibility for new textile finishing approaches to create novel fabric-based materials with specialized function and performance. PMID- 17691749 TI - From designer clusters to synthetic crystalline nanoassemblies. AB - Clusters have the potential to serve as building blocks of materials, enabling the tailoring of materials with novel electronic or magnetic properties. Historically, there has been a disconnect between magic clusters found in the gas phase and the synthetic assembly of cluster materials. We approach this challenge through a proposed protocol that combines gas-phase investigations to examine feasible units, theoretical investigations of energetic compositional diagrams and geometrical shapes to identify potential motifs, and synthetic chemical approaches to identify and characterize cluster assemblies in the solid state. Through this approach, we established As7(3-) as a potential stable species via gas-phase molecular beam experiments consistent with its known existence in molecular crystals with As to K ratios of 7:3. Our protocol also suggests another variant of this material. We report the synthesis of a cluster compound, As7K1.5(crypt222-K)1.5, composed of a lattice of As7 clusters stabilized by charge donation from cryptated K atoms and bound by sharing K atoms. The bond dimensions of this supercluster assembled material deduced by X-ray analysis are found to be in excellent agreement with the theoretical calculations. The new compound has a significantly larger band gap than the hitherto known solid. Thus, our approach allows the tuning of the electronic properties of solid cluster assemblies. PMID- 17691750 TI - Using unsymmetrical indirect covariance processing to calculate GHSQC-COSY spectra. AB - GHSQC-TOCSY experiments allow sorting of proton-proton connectivity information as a function of (13)C chemical shift. GHSQC-TOCSY is a relatively insensitive 2D NMR experiment. Given two coherence transfer experiments, A --> B and A --> C, it is possible to indirectly determine B <--> C. Unsymmetrical indirect covariance processing of a (1)H- (13)C GHSQC and a GCOSY spectrum afforded a GHSQC-COSY spectrum, with an information content analogous to a GHSQC-TOCSY experiment. However, GHSQC-TOCSY is of significantly lower sensitivity and the data require considerably more time to acquire than either of the component experiments. Investigators needing access to GHSQC-TOCSY type data can, in principle, access it from more readily acquired 2D NMR data. Strychnine ( 1) was used as a model compound to illustrate this capability. PMID- 17691751 TI - In situ analysis of living embryonic stem cells by coherent anti-stokes Raman microscopy. AB - Embryonic stem cells (ESC), derived from preimplantation embryos, are defined by their ability to both self-renew and differentiate into all of the cells and tissues of a mature animal. Efforts to develop methods for in vitro culture of ESC for research or eventual therapeutic applications are hampered by the lack of rapid, nondestructive assays for distinguishing ESC from other (differentiated) cells within a growing culture. Coherent anti-Stokes Raman scattering (CARS) microscopy is shown here to be a sensitive and nondestructive method for identifying mouse ESC based on selective observation of specific molecular vibrations believed to be spectroscopic markers indicating the differentiated vs undifferentiated states of such cells. The nonlinear nature of CARS also permits imaging with subcellular resolution, potentially offering a means by which chemical changes accompanying the early stages of differentiation may be associated with certain intracellular compartments (e.g., nucleus, cytoplasm, membranes). A novel exposure/collection configuration is described, which yields high collection efficiency and low interference from nonresonant background components. PMID- 17691752 TI - Synchrotron-based X-ray spectromicroscopy used for the study of an atypical micrometric pigment in 16th century paintings. AB - Grunewald is a famous German painter of the 16th century, whose celebrity is associated with his unique skill in handling colors. This article presents the analysis of materials used to render a metallic aspect in the Isenhein Altarpiece and the Basel's Crucifixion. Such samples are challenging objects for microanalysis due to both chemical and physical complexity. Their study by synchrotron-based X-ray microscopy techniques was made possible thanks to recent developments carried out at the ID21 beam line (European Synchrotron Radiation Facility, ESRF). A submicron X-ray fluorescence probe revealed the main presence of lead, sulfur, antimony, and calcium. The fluorescence-line interferences (in particular K-lines of sulfur with M-lines of lead, and K-lines of calcium with L lines of antimony) were resolved with the fitting program, PyMCA. 2D-mapping highlighted the presence of micrometer grains of sulfur and antimony into a lead matrix. XANES measurements were performed at both the sulfur K-edge and the antimony L-edge to refine information from an atomic to a molecular level. Beam stability was a key point in this study to selectively probe micrometer pigment grains, dispersed in the lead matrix. They confirm that the grains are made of stibnite (antimony sulfide), a very atypical pigment. Chemical mapping of sulfides is perfectly correlated with antimony mapping and provides a clear visualization of the stibnite pigments, in addition to their identification. Besides its artistic relevancy, this work aims at illustrating developments of synchrotron X-ray microprobe methods for the chemical characterization and observation of complex and micrometer-scale materials. PMID- 17691753 TI - Polymeric inverse micelles as selective peptide extraction agents for MALDI-MS analysis. AB - Analyses of peptides in complex mixtures are significant challenges in proteomics applications. Here, we report an amphiphilic polymer-based nanoassembly that is capable of selectively extracting peptides, on the basis of their isoelectric points, into an immiscible organic phase from an aqueous solution. The isoelectric point (pI) cutoff in these extractions depends on the pH of the aqueous solution, and thus, sequential fractionation of peptide mixtures based on pI can be accomplished by varying the pH of the aqueous solution. Additionally, we observe an unexpected enhancement in the MALDI-MS signal for extracted peptides ionized in the presence of the polymer, which allows us to obtain reproducible ion signals for some peptides at concentrations as low as 10 pM. PMID- 17691754 TI - Prediction of macroscopic properties of protic ionic liquids by ab initio calculations. AB - We have systematically investigated combinations of anions and cations in a number of protic ionic liquids based on alkylamines and used ab initio methods to gain insight into the parameters determining their liquid range and their conductivity. A simple, almost linear, relation of the experimentally determined melting temperature with the calculated volume of the anion forming the ionic liquid is found, whereas the dependence of the melting temperature with increasing cation volume goes through a minimum for relatively short side chain length. On the basis of the present results, we propose a strategy to predict the nature of protic ionic liquids in terms of low vapor pressure and conductivity. Comparisons with previously reported strategies for prediction of melting temperatures for aprotic ionic liquids are also made. PMID- 17691755 TI - Signature of the conformational preferences of small peptides: a theoretical investigation. AB - An extensive computational study of the conformational preferences of N acetylphenylalaninylamide (NAPA) is reported, including conformational and anharmonic frequency analyses, as well as calculations of excitation energies of the four NAPA conformers lowest in energy. Particular attention is paid to the influence of hydrogen-bonding interactions on the relative stability of the conformers, which was found to be very sensitive to both the level of quantum chemical computations and the anharmonic treatment of molecular vibrations. The assignments of the UV spectral peaks are well supported by the multireference CASSCF/MS-CASPT2 calculations. Upon consideration of the second-order Moller Plesset (MP2) and density functional theory (DFT) structures, overall energetics, and harmonic and anharmonic corrections, we found no conclusive theoretical evidence for the assumed conformational propensity of small model peptides toward extended beta-strand structures. PMID- 17691756 TI - A diabatic representation including both valence nonadiabatic interactions and spin-orbit effects for reaction dynamics. AB - A diabatic representation is convenient in the study of electronically nonadiabatic chemical reactions because the diabatic energies and couplings are smooth functions of the nuclear coordinates and the couplings are scalar quantities. A method called the fourfold way was devised in our group to generate diabatic representations for spin-free electronic states. One drawback of diabatic states computed from the spin-free Hamiltonian, called a valence diabatic representation, for systems in which spin-orbit coupling cannot be ignored is that the couplings between the states are not zero in asymptotic regions, leading to difficulties in the calculation of reaction probabilities and other properties by semiclassical dynamics methods. Here we report an extension of the fourfold way to construct diabatic representations suitable for spin coupled systems. In this article we formulate the method for the case of even electron systems that yield pairs of fragments with doublet spin multiplicity. For this type of system, we introduce the further simplification of calculating the triplet diabatic energies in terms of the singlet diabatic energies via Slater's rules and assuming constant ratios of Coulomb to exchange integrals. Furthermore, the valence diabatic couplings in the triplet manifold are taken equal to the singlet ones. An important feature of the method is the introduction of scaling functions, as they allow one to deal with multibond reactions without having to include high-energy diabatic states. The global transformation matrix to the new diabatic representation, called the spin-valence diabatic representation, is constructed as the product of channel-specific transformation matrices, each one taken as the product of an asymptotic transformation matrix and a scaling function that depends on ratios of the spin-orbit splitting and the valence splittings. Thus the underlying basis functions are recoupled into suitable diabatic basis functions in a manner that provides a multibond generalization of the switch between Hund's cases in diatomic spectroscopy. The spin-orbit matrix elements in this representation are taken equal to their atomic values times a scaling function that depends on the internuclear distances. The spin-valence diabatic potential energy matrix is suitable for semiclassical dynamics simulations. Diagonalization of this matrix produces the spin-coupled adiabatic energies. For the sake of illustration, diabatic potential energy matrices are constructed along bond-fission coordinates for the HBr and the BrCH(2)Cl molecules. Comparison of the spin-coupled adiabatic energies obtained from the spin-valence diabatics with those obtained by ab initio calculations with geometry-dependent spin-orbit matrix elements shows that the new method is sufficiently accurate for practical purposes. The method formulated here should be most useful for systems with a large number of atoms, especially heavy atoms, and/or a large number of spin-coupled electronic states. PMID- 17691757 TI - Energetics of cresols and of methylphenoxyl radicals. AB - Combustion calorimetry studies were used to determine the standard molar enthalpies of formation of o-, m-, and p-cresols, at 298.15 K, in the condensed state as Delta(f)H(m) degrees (o-CH(3)C(6)H(4)OH,cr) = -204.2 +/- 2.7 kJ.mol(-1), Delta(f)H(m) degrees (m-CH(3)C(6)H(4)OH,l) = -196.6 +/- 2.1 kJ.mol(-1), and Delta(f)H(m) degrees (p-CH(3)C(6)H(4)OH,cr) = -202.2 +/- 3.0 kJ.mol(-1). Calvet drop calorimetric measurements led to the following enthalpy of sublimation and vaporization values at 298.15 K: Delta(sub)H(m) degrees (o-CH(3)C(6)H(4)OH) = 73.74 +/- 0.46 kJ.mol(-1), Delta(vap)H(m) degrees (m-CH(3)C(6)H(4)OH) = 64.96 +/- 0.69 kJ.mol(-1), and Delta(sub)H(m) degrees (p-CH(3)C(6)H(4)OH) = 73.13 +/- 0.56 kJ.mol(-1). From the obtained Delta(f)H(m) degrees (l/cr) and Delta(vap)H(m) degrees /Delta(sub)H(m) degrees values, it was possible to derive Delta(f)H(m) degrees (o-CH(3)C(6)H(4)OH,g) = -130.5 +/- 2.7 kJ.mol(-1), Delta(f)H(m) degrees (m-CH(3)C(6)H(4)OH,g) = -131.6 +/- 2.2 kJ.mol(-1), and Delta(f)H(m) degrees (p CH(3)C(6)H(4)OH,g) = -129.1 +/- 3.1 kJ.mol(-1). These values, together with the enthalpies of isodesmic and isogyric gas-phase reactions predicted by the B3LYP/cc-pVDZ, B3LYP/cc-pVTZ, B3P86/cc-pVDZ, B3P86/cc-pVTZ, MPW1PW91/cc-pVTZ, CBS QB3, and CCSD/cc-pVDZ//B3LYP/cc-pVTZ methods, were used to obtain the differences between the enthalpy of formation of the phenoxyl radical and the enthalpies of formation of the three methylphenoxyl radicals: Delta(f)H(m) degrees (C(6)H(5)O*,g) - Delta(f)H(m) degrees (o-CH(3)C(6)H(4)O*,g) = 42.2 +/- 2.8 kJ.mol(-1), Delta(f)H(m) degrees (C(6)H(5)O*,g) - Delta(f)H(m) degrees (m CH(3)C(6)H(4)O*,g) = 36.1 +/- 2.4 kJ.mol(-1), and Delta(f)H(m) degrees (C(6)H(5)O*,g) - Delta(f)H(m) degrees (p-CH(3)C(6)H(4)O*,g) = 38.6 +/- 3.2 kJ.mol(-1). The corresponding differences in O-H bond dissociation enthalpies were also derived as DH degrees (C(6)H(5)O-H) - DH degrees (o-CH(3)C(6)H(4)O-H) = 8.1 +/- 4.0 kJ.mol(-1), DH degrees (C(6)H(5)O-H) - DH degrees (m-CH(3)C(6)H(4)O H) = 0.9 +/- 3.4 kJ.mol(-1), and DH degrees (C(6)H(5)O-H) - DH degrees (p CH(3)C(6)H(4)O-H) = 5.9 +/- 4.5 kJ.mol(-1). Based on the differences in Gibbs energies of formation obtained from the enthalpic data mentioned above and from published or calculated entropy values, it is concluded that the relative stability of the cresols varies according to p-cresol < m-cresol < o-cresol, and that of the radicals follows the trend m-methylphenoxyl < p-methylphenoxyl < o methylphenoxyl. It is also found that these tendencies are enthalpically controlled. PMID- 17691758 TI - Stochastic fluctuations and chiral symmetry breaking: exact solution of Lente model. AB - The stochastic description for the autocatalytic process has been proposed by Lente (J. Phys. Chem. A 2004, 108, 9475) to demonstrate chiral symmetry breaking. He assumed that the number of reacting molecules is macroscopic and that no products are present initially. The Lente model consisting of a finite number of molecules that may include the product molecules as chiral seeds is explored and the characteristics of stochastic distributions of the product are examined. It is shown that the presence of racemic product in the substrate reduces the possibility of chiral symmetry breaking while a few more molecules of a specific enantiomer added can yield chiral dominance for strong autocatalysis. Besides, small reactive volumes or dense reactant concentrations have a preference for chiral symmetric breaking. PMID- 17691759 TI - Nucleation of bulk phases in the HCl/H2O system. AB - We report experimental results on the low-temperature uptake of HCl on H(2)O ice (ice). HCl was deposited on the surface at greater than monolayer amounts at 85 K, and the ice substrate was heated. The temperature dependence of the HCl vapor pressure from this phase was measured from 110 to 150 K, with the nucleation of a bulk hydrate phase observed at 150 K. Measurements were conducted in a closed system by simultaneous application of gas phase mass spectrometry and surface spectroscopy to characterize vapor/solid equilibrium and the nucleation of bulk hydrate phases. Combining the nucleation data reported here with data we reported previously (180 to 200 K) and data from two other laboratories (165 and 170 K), the thermodynamic boundaries for the nucleation of both the metastable bulk solution and bulk hydrate phases subsequent to monolayer adsorption of HCl have been determined. The nucleation of the metastable bulk solution phase occurs promptly at monolayer coverage at the ice/liquid coexistence boundary on the binary bulk phase diagram. The nucleation of the bulk hexahydrate occurs from this metastable solution along a locus of points defining a state of constant solution free energy. This measured free energy is -51.2 +/- 0.9 kJ/mol. Finally, the temperature dependence of the HCl vapor pressure from the low-temperature phase is reported here for the first time and is consistent with that of the metastable solution predicted by this thermodynamic model of uptake, extending the range of validity of this model of adsorption followed by bulk solution and hydrate nucleation to a lower bound in temperature of 110 K. PMID- 17691760 TI - Isolation, characterization, and biological evaluation of syn and anti diastereomers of [(99m)Tc]technetium depreotide: a somatostatin receptor binding tumor imaging agent. AB - The early and later eluting [(99m)TcO]depreotide products on RP-HPLC were confirmed to be the anti and syn diastereomers, respectively, based on proton NMR and circular dichroism spectroscopy. NMR provided evidence of a folded, conformationally constrained structure for the syn diastereomer. The syn diastereomer is predominant (anti/syn approximately 10:90) in the [(99m)TcO]depreotide preparation and shows a slightly higher affinity (IC50 = 0.15 nM) for the somatostatin receptor than the anti diastereomer (IC50 = 0.89 nM). Both diastereomers showed higher binding affinities than the free peptide (IC(50) = 7.4 nM). Biodistribution studies in AR42J tumor xenograft nude mice also showed higher tumor uptake for syn [(99m)TcO]depreotide (6.58% ID/g) than for the anti [(99m)TcO]depreotide (3.38% ID/g). Despite the differences in biological efficacy, the favorable binding affinity, tumor uptake, and tumor-to background ratio results for both diastereomeric species predict that both are effective for imaging somatostatin receptor-positive tumors in vivo. PMID- 17691761 TI - Novel generation of pH indicators for proton magnetic resonance spectroscopic imaging. AB - We describe the synthesis of 1,omega-di-1H-imidazoles 2 and 3, derived from l threitol and d-mannitol, respectively, showing suitable magnetic and toxicological properties, as novel extracellular pH indicators for 1H spectroscopic imaging by magnetic resonance methods. PMID- 17691762 TI - Development of a peptidomimetic ligand for efficient isolation and purification of factor VIII via affinity chromatography. AB - Hemophilia A, one of the most severe bleeding disorders, results from an inherited deficiency of factor VIII (FVIII) function. Treatment by injection of FVIII has been a common procedure for decades. Nevertheless, the production and purification of FVIII remains a challenging task. Current procedures using immunoaffinity chromatography are expensive and suffer from the instability of the applied antibody ligands, which elute along with the product and contaminate it. Recently, FVIII was purified by use of octapeptide ligands, but their low protease-resistance limits their application. We here report the systematic rational and combinatorial optimization procedure that allowed us to transfer the octapeptide ligands into a small peptidomimetic. This compound is the smallest ligand known for separation of such a large protein (330 kDa). It not only binds and purifies FVIII with high efficiency but also is stable, protease-resistant, and cheap to produce in preparative scale. Hence it offers a valuable alternative to antibody-based purification procedures. PMID- 17691763 TI - 2-aroylindoles and 2-aroylbenzofurans with N-hydroxyacrylamide substructures as a novel series of rationally designed histone deacetylase inhibitors. AB - Histone deacetylase (HDAC) inhibitors are considered to be drugs for targeted cancer therapy and second-generation HDIs are currently being tested in clinical trials. Here, we report on the synthesis and biological evaluation of a novel HDAC inhibitor scaffold with the hydroxamate Zn(2+) complexing headgroup, selected from the 2-aroylindol motif. Inhibition of nuclear extract HDAC and recombinant HDAC 1 as well as induction of histone H3K(9+14) hyperacetylation mediated by E-N-hydroxy-(2-aroylindole)acrylamides or E-N-hydroxy-(2 aroylbenzofuran)acrylamides were studied. Moreover, the cytotoxic activity, the effects on the cell cycle, and histone H3S(10) phosphorylation of selected compounds were determined. By use of a panel of 24 different human tumor cell lines, mean IC(50) values of the most potent analogues 6c and 7b were 0.75 and 0.65 microM, respectively. The novel compounds were shown to be no substrates of the P-glycoprotein drug transporter. Comparable to N(1)-hydroxy-N(8) phenyloctanediamide "2 (SAHA)", cells in the S phase of the cell cycle are depleted, with partial arrest in G1 and G2/M and finally induction of massive apoptosis. PMID- 17691764 TI - CAESAR: a new conformer generation algorithm based on recursive buildup and local rotational symmetry consideration. AB - A highly efficient conformer search algorithm based on a divide-and-conquer and recursive conformer build-up approach is presented in this paper. This approach is combined with consideration of local rotational symmetry so that conformer duplicates due to topological symmetry in the systematic search can be efficiently eliminated. This new algorithm, termed CAESAR (Conformer Algorithm based on Energy Screening and Recursive Buildup), has been implemented in Discovery Studio 1.7 as part of the Catalyst Component Collection. CAESAR has been validated by comparing the conformer models generated by the new method and Catalyst/FAST. CAESAR is consistently 5-20 times faster than Catalyst/FAST for all data sets investigated. The speedup is even more dramatic for molecules with high topological symmetry or for molecules that require a large number of conformers to be sampled. The quality of the conformer models generated by CAESAR has been validated by assessing the ability to reproduce the receptor-bound X-ray conformation of ligands extracted for the Protein Data Bank (PDB) and assessing the ability to adequately cover the pharmacophore space. It is shown that CAESAR is able to reproduce the receptor-bound conformation slightly better than the Catalyst/FAST method for a data set of 918 ligands retrieved from the PDB. In addition, it is shown that CEASAR covers the pharmacophore space as well or better than Catalyst/FAST. PMID- 17691765 TI - Tetranuclear complexes of [Fe(CO)2(C5H5)]+ with TCNX ligands (TCNX=TCNE, TCNQ, TCNB): intramolecular electron transfer alternatives in compounds (mu4 TCNX)[MLn]4. AB - The complexes {(mu4-TCNX)[Fe(CO)2(C5H5)]4}(BF4)4 were prepared as light-sensitive materials from [Fe(CO)2(C5H5) (THF)](BF4) and the corresponding TCNX ligands (TCNE = tetracyanoethene, TCNQ=7,7,8,8-tetracyano-p-quinodimethane, TCNB=1,2,4,5 tetracyanobenzene). Whereas the TCNE and TCNQ complexes are extremely easily reduced species with reduction potentials>+0.3 V vs ferrocenium/ferrocene, the tetranuclear complex of TCNB exhibits a significantly more negative reduction potential at about -1.0 V. Even for the complexes with strongly pi-accepting TCNE and TCNQ, the very positive reduction potentials, the unusually high nitrile stretching frequencies>2235 cm(-1), and the high-energy charge-transfer transitions indicate negligible metal-to-ligand electron transfer in the ground state, corresponding to a largely unperturbed (TCNX degrees)(FeII)4 formulation of oxidation states as caused by orthogonality between the metal-centered HOMO and the pi* LUMO of TCNX. Mossbauer spectroscopy confirms the low-spin iron(II) state, and DFT calculations suggest coplanar TCNE and TCNQ bridging ligands in the complex tetracations. One-electron reduction to the 3+ forms of the TCNE and TCNQ complexes produces EPR spectra which confirm the predominant ligand character of the then singly occupied MO through isotropic g values slightly below 2, in addition to a negligible g anisotropy of frozen solutions at frequencies up to 285 GHz and also through an unusually well-resolved solution X band EPR spectrum of {(mu4-TCNE)[Fe(CO)2(C5H5)]4}3+ which shows the presence of four equivalent [Fe(CO)2(C5H5)]+ moieties through 57Fe and 13C(CO) hyperfine coupling in nonenriched material. DFT calculations reproduce the experimental EPR data. A survey of discrete TCNE and TCNQ complexes [(mu4-TCNX)(MLn)4] exhibits a dichotomy between the systems {(mu4-TCNX)[Fe(CO)2(C5H5)]4}4+ and {(mu4 TCNQ)[Re(CO)3(bpy)]4}4+ with their negligible metal-to-ligand electron transfer and several other compounds of TCNE or TCNQ with Mn, Ru, Os, or Cu complex fragments which display evidence for a strong such interaction, i.e., an appreciable value delta in the formulation {(mu4-TCNXdelta-)[Mx+delta/4Ln]4}. Irreversibility of the first reduction of {(mu4-TCNB)[Fe(CO)2(C5H5)]4}(BF4)4 precluded spectroelectrochemical studies; however, the high-energy CN stretching frequencies and charge transfer absorptions of that TCNB analogue also confirm the exceptional position of the complexes {(mu4-TCNX)[Fe(CO)2(C5H5)]4}(BF4)4. PMID- 17691767 TI - Systematic studies of early actinide complexes: uranium(IV) fluoroketimides. AB - The reaction of (C5Me5)2U(CH3)2 with 2 equiv of N[triple bond]C-ArF gives the fluorinated uranium(IV) bis(ketimide) complexes (C5Me5)2U[-N=C(CH3)(ArF)]2 [where ArF=2-F-C6H4 (4), 3-F-C6H4 (5), 4-F-C6H4 (6), 2,6-F2-C6H3 (7), 3,5-F2-C6H3 (8), 2,4,6-F3-C6H2 (9), 3,4,5-F3-C6H2 (10), and C6F5 (11)]. These have been characterized by single-crystal X-ray diffraction, 1H and 19F NMR, cyclic voltammetry, UV-visible-near-IR absorption spectroscopy, and variable-temperature magnetic susceptibility. Density functional theory (DFT) results are reported for complexes 6 and 11 for comparison with experimental data. The most significant structural perturbation imparted by the F substitution in these complexes is a rotation of the fluorinated aryl (ArF) group out of the plane defined by the N=C(CMe)(Cipso) fragment in complexes 7, 9, and 11 when the ArF group possesses two o-fluorine atoms. Excellent agreement is obtained between the DFT-calculated and experimental crystal structures for 11, which displays the distortion, as well as for 6, which does not. In 7, 9, and 11, the out-of-plane rotation results in large angles (phi=53.7-89.4 degrees) between the planes formed by ketimide atoms N=C(CMe)(Cipso) and the ketimide aryl groups. Complexes 6 and 10 do not contain o-fluorine atoms and display interplanar angles in the range of phi=7 26.8 degrees. Complex 4 with a single o-fluorine substituent has intermediate values of phi=20.4 and 49.5 degrees. The distortions in 7, 9, and 11 result from an unfavorable steric interaction between one of the two o-fluorine atoms and the methyl group [-N=C(CH3)] on the ketimide ligand. All complexes exhibit UV/UIV and UIV/UIII redox couples, although the distortion in 7, 9, and 11 appears to be a factor in rendering the UIV/UIII couple irreversible. The potential separation between these couples remains constant at 2.15+/-0.03 V. The electronic spectra are dominated by unusually intense f-f transitions in the near-IR that retain nearly identical band energies but vary in intensity as a function of the fluorinated ketimide ligand, and visible and near-UV bands assigned to metal (5f) to-ligand (pi*) charge-transfer and interconfiguration (5f2-->5f16d1) transitions, respectively. Variable-temperature magnetic susceptibility data for these complexes indicate a temperature-independent paramagnetism (TIP) below approximately 50 K that results from admixing of low-lying crystal-field excited states derived from the symmetry-split 3H4 5f2 manifold into the ground state. The magnitude of the TIP is smaller for the complexes possessing two o-fluorine atoms (7, 9, and 11), indicating that the energy separation between ground and TIP-admixed excited states is larger as a consequence of the greater basicity of these ligands. PMID- 17691766 TI - MO tripeptide diastereomers (M=99/99mTc, Re): models to identify the structure of 99mTc peptide targeted radiopharmaceuticals. AB - Biologically active molecules, such as many peptides, serve as targeting vectors for radiopharmaceuticals based on 99mTc. Tripeptides can be suitable chelates and are easily and conveniently synthesized and linked to peptide targeting vectors through solid-phase peptide synthesis and form stable TcVO complexes. Upon complexation with [TcO]3+, two products form; these are syn and anti diastereomers, and they often have different biological behavior. This is the case with the approved radiopharmaceutical [99mTcO]depreotide ([99mTcO]P829, NeoTect) that is used to image lung cancer. [99mTcO]depreotide indeed exhibits two product peaks in its HPLC profile, but assignment of the product peaks to the diastereomers has proven to be difficult because the metal peptide complex is difficult to crystallize for structural analysis. In this study, we isolated diastereomers of [99TcO] and [ReO] complexes of several tripeptide ligands that model the metal chelator region of [99mTcO]depreotide. Using X-ray crystallography, we observed that the early eluting peak (A) corresponds to the anti diastereomer, where the Tc=O group is on the opposite side of the plane formed by the ligand backbone relative to the pendant groups of the tripeptide ligand, and the later eluting peak (B) corresponds to the syn diastereomer, where the Tc=O group is on the same side of the plane as the residues of the tripeptide. 1H NMR and circular dichroism (CD) spectroscopy report on the metal environment and prove to be diagnostic for syn or anti diastereomers, and we identified characteristic features from these techniques that can be used to assign the diastereomer profile in 99mTc peptide radiopharmaceuticals like [99mTcO]depreotide and in 188Re peptide radiotherapeutic agents. Crystallography, potentiometric titration, and NMR results presented insights into the chemistry occurring under physiological conditions. The tripeptide complexes where lysine is the second amino acid crystallized in a deprotonated metallo-amide form, possessing a short N1-M bond. The pKa measurements of the N1 amine (pKa approximately 5.6) suggested that this amine is rendered more acidic by both metal complexation and the presence of the lysine residue. Furthermore, peptide chelators incorporating a lysine (like the chelator of [TcO]depreotide) likely exist in the deprotonated form in vivo, comprising a neutral metal center. Deprotonation possibly mediates the interconversion process between the syn and anti diastereomers. The N1 amine group on non-lysine-containing metallopeptides is not as acidic (pKa approximately 6.8) and does not deprotonate and crystallize as do the metallo-amide species. Three of the tripeptide ligands (FGC, FSC, and FKC) were radiolabeled with 99mTc, and the individual syn and anti isomers were isolated for biodistribution studies in normal female nude mice. The main organs of uptake were the liver, intestines, and kidneys, with the FGC compounds exhibiting the highest liver uptake. In comparing the diastereomers, the syn compounds had substantially higher organ uptake and slower blood clearance than the anti compounds. PMID- 17691768 TI - Unusual (mu-aqua)bis(mu-carboxylate) bridge in homometallic M(II) (M=Mn, Co and Ni) two-dimensional compounds based on the 1,2,3,4-butanetetracarboxylic acid: synthesis, structure, and magnetic properties. AB - The first coordination compounds of 1,2,3,4-butanetetracarboxylate anion (butca4 ) of the formula [M2(butca)(H2O)5]n.2nH2O [M=Mn(II) (1), Co(II) (2), and Ni(II) (3)] were prepared and their X-ray crystal structures and magnetic properties investigated. The three complexes have a very similar two-dimensional structure which consists of (4,4) networks, 1 and 2 being isostructural. The tetracarboxylate ligand acts as a 4-fold connector leading to two-dimensional (4,4) networks of metal atoms, this topology being possible because of its planar conformation. The nodes of these networks are formed by dinuclear motifs which exhibit the unusual (mu-aqua)bis(mu-carboxylate) bridging unit which is analogous to that observed in some molecules of biological interest. The variable temperature magnetic susceptibility measurements of 1-3 show that 1 and 2 are antiferromagnetically coupled systems whereas 3 exhibits a ferromagnetic behavior. The analysis of the magnetic data of 1-3 through a simple dinuclear model allowed the determination of the values of the magnetic coupling (J) -3.6 (1), -1.2 (2), and +1.47 cm(-1) (3) with the Hamiltonian being defined as H= JSA.SB. The countercomplementarity between the two bridges (aqua and syn-syn carboxylate) accounts for the trend exhibited by the values of the magnetic coupling in this family. PMID- 17691769 TI - Synthesis, molecular structure (X-ray and DFT), and solution behavior of titanium 4-Acyl-5-pyrazolonates. Correlations with related antitumor beta-diketonato derivatives. AB - Previously reported structure-activity relationships have shown two features for effective antitumor activity of titanium beta-diketone complexes: (a) ligand asymmetry and (b) the presence of planar substitutents on the ligand. Mono- and dinuclear derivatives, studied with diffraction and DFT methods show that (a) is consistent with different Ti-O(beta-diketonato) bond lengths, which are longer than Ti-O(oxo) and Ti-O(alkoxy) ones. pi-pi features observed in dinuclear derivatives correlate with strong reactivity of related complexes with DNA and support DNA intercalation by such planar groups, in agreement with (b). Large variation for Ti-O bond lengths and Ti-O-C bond angles in the ethoxy moiety is associated with the titanium withdrawing effect and oxygen bonding s character; it is confirmed through exploration of the Cambridge crystallographic database. This ethoxy geometrical flexibility also suggests versatile accommodation in protein pockets and/or other biological targets. Electrospray ionization mass spectrometry (ESI-MS) spectra show formation of di- and trinuclear Ti-4-acyl-5 pyrazolonato cationic oligomers. Hydrolysis/oligomerization is also described by NMR results. PMID- 17691770 TI - Heats of formation of boron hydride anions and dianions and their ammonium salts [BnHmy-][NH4+]y with y=1-2. AB - Thermochemical parameters of the closo boron hydride BnHn2- dianions, with n=5 12, the B3H8- and B11H14- anions, and the B5H9 and B10H14 neutral species were predicted by high-level ab initio electronic structure calculations. Total atomization energies obtained from coupled-cluster CCSD(T)/complete basis set (CBS) extrapolated energies, plus additional corrections were used to predict the heats of formation of the simplest BnHmy- species in the gas phase in kcal/mol at 298 K: DeltaHf(B3H8-)=-23.1+/-1.0; DeltaHf(B5H52-)=119.4+/-1.5; DeltaHf(B6H62 )=64.1+/-1.5; and DeltaHf(B5H9)=24.1+/-1.5. The heats of formation of the larger species were evaluated by the G3 method from hydrogenation reactions (values at 298 K, in kcal/mol with estimated error bars of+/-3 kcal/mol): DeltaHf(B7H72 )=51.8; DeltaHf(B8H82-)=46.1; DeltaHf(B9H92-)=24.4; DeltaHf(B10H102-)=-12.5; DeltaHf(B11H112-)=-11.8; DeltaHf(B12H122-)=-86.3; DeltaHf(B11H14-)=-57.3; and DeltaHf(B10H14)=18.7. A linear correlation between atomization energies of the dianions and energies of the BH units was found. The heats of formation of the ammonium salts of the anions and dianions were predicted using lattice energies (UL) calculated from an empirical expression based on ionic volumes. The UL values (0 K) of the BnHn2- dianions range from 319 to 372 kcal/mol. The values of UL for the B3H8- and B11H14- anions are 113 and 135 kcal/mol, respectively. The calculated lattice energies and gas-phase heats of formation of the constituent ions were used to predict the heats of formation of the ammonium crystal salts [BnHmy-][NH4+]y. These results were used to evaluate the thermodynamics of the H2 release reactions from the ammonium hydro-borate salts. PMID- 17691771 TI - Synthesis and structures of an unusual germanium(II) calix[4]arene complex and the first germanium(II) calix[8]arene complex and their reactivity with diiron nonacarbonyl. AB - The protonolysis reaction of the germanium(II) amide Ge[N(SiMe3)2]2 with calix[4]arene and calix[8]arene furnishes the two germanium(II) calixarene complexes {calix[4]}Ge2 and {calix[8]}Ge4, respectively, which have been crystallographically characterized. The calix[4]arene complex contains a Ge2O2 rhombus at the center of the molecule and is one of the only four germanium(II) calix[4]arenes that have been structurally characterized. The calix[8]arene species is the first reported germanium calix[8]arene complex, and it exhibits an overall bowl-shaped structure which contains two Ge2O2 fragments. The latter complex reacts with Fe2(CO)9 to yield an octairon compound, which has also been structurally characterized and contains four GeFe2 triangles arranged around the macrocyclic ring. The germanium(II) centers are oxidized to germanium(IV) in this process, with concomitant reduction of the neutral diiron species to Fe2(CO)(8)2- anions. PMID- 17691772 TI - Synthesis and molecular structures of phenylamides of magnesium, calcium, strontium, and barium--from molecular to polymeric structures. AB - Several preparative procedures for the synthesis of the THF complexes of the alkaline earth metal bis(phenylamides) of Mg (1), Ca (2), Sr (3), and Ba (4) are presented such as metalation of aniline with strontium and barium, metathesis reactions of MI2 with KN(H)Ph, and metalation of aniline with arylcalcium compounds or dialkylmagnesium. The THF content of these compounds is rather low and an increasing aggregation is observed with the size of the metal atom. Thus, tetrameric [(THF)2Ca{mu-N(H)Ph}2]4 (2) and polymeric [(THF)2Sr{mu N(H)Ph}2]infinity and {[(THF)2Ba{mu-N(H)Ph}2]2[(THF)Ba{mu-N(H)Ph}2]2}infinity show six-coordinate metal atoms with increasing interactions to the pi systems of the phenyl groups with increasing the radius of the alkaline earth metal atom. PMID- 17691774 TI - Protein-templated organic/inorganic hybrid materials prepared by liquid-phase deposition. AB - Organic/inorganic hybrid thin films for protein recognition have been prepared by the liquid-phase deposition (LPD) coupled with template synthesis, i.e., molecular imprinting, where pepsin (Pep) was used as a model protein and titanium oxide was deposited on gold substrates in the presence of Pep-poly-L-lysine (PL) complexes. The complexes remained in the templated film after the deposition, and the binding sites for Pep were constructured after Pep was removed from the film. Surface plasmon resonance signals on the deposited films were measured to examine the binding behaviors toward proteins. The binding of Pep on the templated film was reversible, and the binding isotherm of Pep depicted a saturation curve with a binding constant of 7.3 x 105 M(-1), which was 10 times higher than that of albumin. In contrast, titanium oxide films prepared without PL did not show any selectivity; therefore, the hybridization of PL as the organic binder with the inorganic material is necessary to obtain selective binding sites for Pep. It was also shown that the hybridization process should proceed without denaturing the template protein, in order to obtain selective binding sites for the template. The procedure for preparation of the films was simple to perform, and the process for hybridization of the thin films with nanometer-order thickness was easily controlled by changing the LPD reaction time period. Consequently, the proposed LPD coupled with template synthesis is among the most appropriate methods to prepare hybrid materials with protein recognition ability, which proceeds under mild conditions in aqueous solution. PMID- 17691775 TI - Mechanistic studies of UV assisted [4 + 2] cycloadditions in synthetic efforts toward vibsanin E. AB - Quantum chemical DFT calculations at the B3LYP/6-31G(d) level have been used to study the stereochemical course of the photochemical cycloaddition of enone 9 with dienes. The observed products of this photochemically induced cycloaddition showed a stereoselectivity, which is opposite to what would be expected by FMO considerations. The quantum chemical calculations revealed that the unusual stereoselectivity of the reaction can be rationalized by assuming a stereospecific photochemical cis-trans isomerization of enone 9 to trans isomer 9a followed by a thermal Diels-Alder reaction of the diene onto the highly reactive trans enone. The photochemical reaction step involves the selective formation of a twisted triplet intermediate, which accounts for the selectivity of the reaction. PMID- 17691773 TI - Prediction of the 3D structure and dynamics of human DP G-protein coupled receptor bound to an agonist and an antagonist. AB - Prostanoids play important physiological roles in the cardiovascular and immune systems and in pain sensation in peripheral systems through their interactions with eight G-protein coupled receptors. These receptors are important drug targets, but development of subtype specific agonists and antagonists has been hampered by the lack of 3D structures for these receptors. We report here the 3D structure for the human DP G-protein coupled receptor (GPCR) predicted by the MembStruk computational method. To validate this structure, we use the HierDock computational method to predict the binding mode for the endogenous agonist (PGD2) to DP. Based on our structure, we predicted the binding of different antagonists and optimized them. We find that PGD2 binds vertically to DP in the TM1237 region with the alpha chain toward the extracellular (EC) region and the omega chain toward the middle of the membrane. This structure explains the selectivity of the DP receptor and the residues involved in the predicted binding site correlate very well with available mutation experiments on DP, IP, TP, FP, and EP subtypes. We report molecular dynamics of DP in explicit lipid and water and find that the binding of the PGD2 agonist leads to correlated rotations of helices of TM3 and TM7, whereas binding of antagonist leads to no such rotations. Thus, these motions may be related to the mechanism of activation. PMID- 17691776 TI - Quantitative in vitro biopolymerization to chitin in native chitosomal membranes supported by silica microparticles. AB - To investigate the unknown physical mechanisms of chitin biosynthesis quantitatively, we designed a quantitative in vitro biopolymerization assay by deposition of native chitosomal membranes from Saccharomyces cerevisiae onto solid silica microparticles of a defined size (o = 3 microm). The homogeneous coating of particle surfaces with native chitosomal membranes observed by confocal microscopy agrees well with the surface coverage calculated by the phosphate analysis. The amount of the synthesized chitin polymers is determined by radioactive assays, which demonstrate that chitin synthase in particle supported membranes retains its specific enzymatic activity. In comparison to planar substrates, particle supports of defined size (and thus surface area) enable us to amplify the signals from immobilized proteins owing to the much larger surface area and to the capability of concentrating the sample to any given sample volume. Moreover, the large density of particle supports offers unique advantages over purified chitosomes in the quick separation of particle supported membranes and materials in bulk within 1 min. This allows for the termination of the polymerization reaction without the disruption of the whole membranes, and thus the chitin polymers released in bulk can quantitatively be extracted. The obtained results demonstrate that the native biological membranes on particle supports can be utilized as a new in vitro biopolymerization assay to study the function of transmembrane enzyme complexes. PMID- 17691777 TI - Tunable luminescent lanthanide coordination polymers based on reversible solid state ion-exchange monitored by ion-dependent photoinduced emission spectra. PMID- 17691778 TI - Polyelectrolyte diode: nonlinear current response of a junction between aqueous ionic gels. AB - We demonstrate that a fixed junction between two aqueous gels containing oppositely charged polyelectrolytes could rectify electric current. The agarose based gels were "doped" with sodium poly(styrene sulfonic acid) and poly(diallyl dimethylammonium chloride). The unidirectional current response of the interface between the cationic and anionic gels originates directly from anisotropy in the mobile ionic charges in the gels. The current depends on the concentration of polyelectrolyte, the background ionic concentration, and the distance traveled by the ions. The I-V curves from the devices demonstrated a combination of transient and stationary rectification effects. The current densities achieved were comparable to or higher than those obtained with previously reported organic semiconductor diodes. The diodes had good long-term stability in both DC and AC conduction modes. The materials and the process of preparation of these devices are simple, inexpensive, and scalable. They could be used in flexible and biocompatible electronic circuits. PMID- 17691779 TI - Magnetic exchange coupling in chloride-bridged 5f-3d heterometallic complexes generated via insertion into a uranium(IV) dimethylpyrazolate dimer. PMID- 17691780 TI - Antibiotic deactivation by a dizinc beta-lactamase: mechanistic insights from QM/MM and DFT studies. AB - Hybrid quantum mechanical/molecular mechanical (QM/MM) methods and density functional theory (DFT) were used to investigate the initial ring-opening step in the hydrolysis of moxalactam catalyzed by the dizinc L1 beta-lactamase from Stenotrophomonas maltophilia. Anchored at the enzyme active site via direct metal binding as suggested by a recent X-ray structure of an enzyme-product complex (Spencer, J.; et al. J. Am. Chem. Soc. 2005, 127, 14439), the substrate is well aligned with the nucleophilic hydroxide that bridges the two zinc ions. Both QM/MM and DFT results indicate that the addition of the hydroxide nucleophile to the carbonyl carbon in the substrate lactam ring leads to a metastable intermediate via a dominant nucleophilic addition barrier. The potential of mean force obtained by SCC-DFTB/MM simulations and corrected by DFT/MM calculations yields a reaction free energy barrier of 23.5 kcal/mol, in reasonable agreement with the experimental value of 18.5 kcal/mol derived from kcat of 0.15 s(-1). It is further shown that zinc-bound Asp120 plays an important role in aligning the nucleophile, but accepts the hydroxide proton only after the nucleophilic addition. The two zinc ions are found to participate intimately in the catalysis, consistent with the proposed mechanism. In particular, the Zn(1) ion is likely to serve as an "oxyanion hole" in stabilizing the carbonyl oxygen, while the Zn(2) ion acts as an electrophilic catalyst to stabilize the anionic nitrogen leaving group. PMID- 17691781 TI - Sequence-specific resonance assignment of soluble nonglobular proteins by 7D APSY NMR spectroscopy. AB - Based on sequence-specific resonance assignments, NMR is the method of choice for obtaining atomic-resolution experimental data on soluble nonglobular proteins. So far, however, NMR assignment of unfolded polypeptides in solution has been a time consuming task, mainly due to the small chemical shift dispersion, which has limited practical applications of the NMR approach. This paper presents an efficient, fully automated method for sequence-specific backbone and beta-carbon NMR assignment of soluble nonglobular proteins with sizes up to at least 150 residues. The procedure is based on new APSY (automated projection spectroscopy) experiments which benefit from the short effective rotational correlation times in soluble nonglobular polypeptides to record five- to seven-dimensional NMR data sets, which reliably resolves chemical shift degeneracies. Fully automated sequence-specific resonance assignments of the backbone nuclei and C(beta) are described for the uniformly (13)C,(15)N-labeled urea-denatured 148-residue outer membrane protein X (OmpX) from E. coli. The method is generally applicable to systems with similar spectroscopic properties as unfolded OmpX, and we anticipate that this paper may open the door for extensive atomic-resolution studies of chemical denaturant-unfolded proteins, as well as some classes of functional nonglobular polypeptides in solution. PMID- 17691782 TI - Synthesis and characterization of the homologous M-M bonded series Ar'MMAr' (M = Zn, Cd, or Hg; Ar' = C6H3-2,6-(C6H3-2,6-Pr(i)2)2) and related arylmetal halides and hydride species. AB - The synthesis and structural characterization of the first homologous, molecular M-M bonded series for the group 12 metals are reported. The compounds Ar'MMAr' (M = Zn, Cd, or Hg; Ar' = C(6)H(3)-2,6-(C(6)H(3)-2,6-Pr(i)(2))(2)) were synthesized by reduction of the corresponding arylmetal halides by alkali metal/graphite (Zn or Hg) or sodium hydride (Cd). These compounds possess almost linear C-M-M-C core structures with two-coordinate metals. The observed M-M bonds distances were 2.3591(9), 2.6257(5), and 2.5738(3) A for the zinc, cadmium, and mercury species, respectively. The shorter Hg-Hg bond in comparison to that of Cd-Cd is consistent with DFT calculations which show that the strength of the Hg-Hg bond is greater. The arylmetal halides precursors (Ar'MI)(1 or 2), and the highly reactive hydrides (Ar'MH)(1 or 2), were also synthesized and fully characterized by X-ray crystallography (Zn and Cd) and multinuclear NMR spectroscopy. The arylzinc and arylcadmium iodides have iodide-bridged dimeric structures, whereas the arylmercury iodide, Ar'HgI, is monomeric. The arylzinc and arylcadmium hydrides have symmetric (Zn) or unsymmetric (Cd) mu-H-bridged structures. The Ar'HgH species was synthesized and characterized by spectroscopy, but a satisfactory refinement of the structure was precluded by the contamination of monomeric Ar'HgH by Ar'H. It was also shown that the decomposition of Ar'Cd(mu-H)(2)CdAr' at room temperature leads to the M-M bonded Ar'CdCdAr', thereby supporting the view that the reduction of the iodide proceeds via the hydride intermediate. PMID- 17691783 TI - Systematic exploration of the structural features of yatakemycin impacting DNA alkylation and biological activity. AB - A systematic examination of the impact of the yatakemycin left and right subunits and their substituents is detailed along with a study of its unique three subunit arrangement (sandwiched vs extended and reversed analogues). The examination of the ca. 50 analogues prepared illustrate that within the yatakemycin three subunit structure, the subunit substituents are relatively unimportant and that it is the unique sandwiched arrangement that substantially increases the rate and optimizes the efficiency of its DNA alkylation reaction. This potentiates the cytotoxic activity of yatakemycin and its analogues overcoming limitations typically observed with more traditional compounds in the series (CC-1065, duocarmycins). Moreover, a study of the placement of the alkylation subunit within the three subunit arrangement (sandwiched vs extended and reversed analogues) indicates that it not only has a profound impact on the rate and efficiency of DNA alkylation but also controls and establishes the DNA alkylation selectivity as well, where both enantiomers of such sandwiched agents alkylate the same adenine sites exhibiting the same DNA alkylation selectivity independent of their absolute configuration. PMID- 17691784 TI - Palladium acetate-catalyzed cyclization reaction of 2,3-allenoic acids in the presence of simple allenes: an efficient synthesis of 4-(1'-bromoalk-2'(Z)-en-2' yl)furan-2(5H)-one derivatives and the synthetic application. AB - We have realized a cyclization reaction of 2,3-allenoic acids 1 in the presence of simple alkyl- or aryl-substituted allenes 3. In this reaction, the cyclic oxypalladation of 2,3-allenoic acid with Pd(II) would afford the furanonyl palladium intermediate 2, which could be trapped by the simple allene to afford a pi-allylic intermediate anti-9. This intermediate anti-9 could be nucleophilically attacked by Br- to yield 4-(1'-bromoalk-2'(Z)-en-2'-yl)furan 2(5H)-one derivatives Z-5 and Pd(0). The in-situ formed Pd(0) was efficiently converted to the catalytically active Pd(II) species by benzoquinone in HOAc. The functional groups, such as malonate, acetoxyl, and phthalic amide in allene 3, are tolerable under the current conditions. High efficiency of chirality transfer was observed when optically active 2,3-allenoic acids were used, which reveals that the formation of the intermediates 2 was a highly stereoselective anti oxypalladation process. The highly selective formation of Z-isomer may be explained by face-selective coordination of allene 3 with the palladium atom in intermediate 2: the palladium atom coordinates to the terminal C=C double bond of allene 3 from the face opposite to the substituent group to avoid the steric congestion. The products Z-5 could be further elaborated via the S(N)2 nucleophilic substitution with amine or sodium benzenesulfinate, the reduction of the C-Br bond by NaBH(4), and the CuBr.SMe(2)-catalyzed S(N)2'-substitution with CH(3)MgBr. PMID- 17691785 TI - Catalytic efficiency of iron(III) oxides in decomposition of hydrogen peroxide: competition between the surface area and crystallinity of nanoparticles. AB - Various iron(III) oxide catalysts were prepared by controlled decomposition of a narrow layer (ca. 1 mm) of iron(II) oxalate dihydrate, FeC(2)O(4).2H(2)O, in air at the minimum conversion temperature of 175 degrees C. This thermally induced solid-state process allows for simple synthesis of amorphous Fe(2)O(3) nanoparticles and their controlled one-step crystallization to hematite (alpha Fe(2)O(3)). Thus, nanopowders differing in surface area and particle crystallinity can be produced depending on the reaction time. The phase composition of iron(III) oxides was monitored by XRD and (57)Fe Mossbauer spectroscopy including in-field measurements, providing information on the relative contents of amorphous and crystalline phases. The gradual changes in particle size and surface area accompanying crystallization were evaluated by HRTEM and BET analysis, respectively. The catalytic efficiency of the synthesized nanoparticles was tested by tracking the decomposition of hydrogen peroxide. The obtained kinetic data gave an unconventional nonmonotone dependence of the rate constant on the surface area of the samples. The amorphous nanopowder with the largest surface area of 401 m(2) g(-1) revealed the lowest catalytic efficiency, while the highest efficiency was achieved with the sample having a significantly lower surface area, 337 m(2) g(-1), exhibiting a prevailing content of crystalline alpha-Fe(2)O(3) phase. The obtained rate constant, 26.4 x 10(-3) min( 1) (g/L)(-1), is currently the highest value published. The observed rare catalytic phenomenon, where the particle crystallinity prevails over the surface area effects, is discussed with respect to other processes of heterogeneous catalysis. PMID- 17691786 TI - Organocatalytic enantioselective cascade Michael-alkylation reactions: synthesis of chiral cyclopropanes and investigation of unexpected organocatalyzed stereoselective ring opening of cyclopropanes. AB - The development of efficient methods for the facile construction of important molecular architectures is a central goal in organic synthesis. An unprecedented organocatalytic asymmetric cascade Michael-alkylation reaction of alpha,beta unsaturated aldehydes with bromomalonates has been developed. The process, efficiently catalyzed by chiral diphenylprolinol TMS ether in the presence of base 2,6-lutidine, serves as a powerful approach to the preparation of synthetically and biologically important cyclopropanes in high levels of enantio- and diastereoselectivities. Remarkably, the power of the cascade process is fueled by its high efficiency of the production of two new C-C bonds, two new stereogenic centers, and one quaternary carbon center in one single operation, which otherwise is difficult to achieve by traditional strategies. Moreover, the beauty of the cascade process is further underscored by the nature of the product formation depending on the reaction conditions. With the alternation of base from 2,6-lutidine (1.1 equiv), which is effective for the cyclopropanations, to NaOAc (4.0 equiv), the spontaneous ring-opening of cyclopropanes takes place to lead to stereoselective (E) alpha-substituted malonate alpha,beta-unsaturated aldehydes. A possible reaction mechanism, which involves a Michael-alkylation-retro-Michael pathway, is proposed and verified by experimental studies. This investigation represents the first example of an organocatalyst-promoted ring opening of the cyclopropanes, whereas such reactions have been intensively explored by Lewis acid-based catalysis. PMID- 17691787 TI - Total synthesis of (+)-tedanolide. AB - A convergent, stereocontrolled total synthesis of (+)-tedanolide (1), an architecturally complex marine antitumor macrolide, has been achieved in 31 steps (longest linear sequence). Highlights of the synthesis comprise a highly efficient dithiane union, followed by an Evans-Tishchenko "oxidation" to enable formation of the seco-ester in the presence of an oxidatively labile dithiane, a highly refined protecting group strategy, and a chemo- and stereoselective epoxidation at C(18,19). PMID- 17691788 TI - Direct catalytic enantioselective Mannich reactions: synthesis of protected anti alpha,beta-diamino acids. PMID- 17691789 TI - Backbone assignments in solid-state proteins using J-based 3D heteronuclear correlation spectroscopy. PMID- 17691790 TI - Transcriptional up-regulation in cells mediated by a small molecule. PMID- 17691791 TI - Construction and DNA condensation of cyclodextrin-based polypseudorotaxanes with anthryl grafts. PMID- 17691793 TI - Thermal and photochemical cleavage of Si=Si double bond in tetrasila-1,3-diene. PMID- 17691792 TI - Synthesis and characterization of manganese-doped silicon nanoparticles: bifunctional paramagnetic-optical nanomaterial. PMID- 17691795 TI - Trivalent antigens for degranulation of mast cells. AB - Degranulation of basophils and mast cells plays a central role in allergic reactions. Degranulation is a response to cell surface receptor aggregation caused by association of receptors with antibodies bound to multivalent antigens. Tools used in studying this process have included small-molecule divalent antigens, but they suffer from weak signaling apparently due to small aggregate size. We have prepared trivalent antigens that allow formation of larger aggregates and potent responses from mast cells. PMID- 17691796 TI - A practical, enantioselective synthetic route to a key precursor to the tetracycline antibiotics. AB - A practical, enantioselective synthetic route to a key precursor to the tetracycline antibiotics is reported. The route proceeds in nine steps (21% yield) from the commercial substance methyl 3-hydroxy-5-isoxazolecarboxylate. Key steps in the route involve enantioselective addition of divinylzinc to 3 benzyloxy-5-isoxazolecarboxaldehyde and an endo-selective intramolecular furan Diels-Alder cycloaddition reaction. The route described has provided more than 40 g of chromatographically pure 1 with 93% ee. PMID- 17691797 TI - Solution and crystal conformations of myrionine, a new 8beta-alkyl-cis decahydroquinoline of Myrioneuron nutans. AB - Myrionine (1), a new 8beta-alkyl-cis-decahydroquinoline, was isolated from Myrioneuron nutans. Its structure was determined by spectral methods and then confirmed by X-ray analysis and total synthesis. In solution, 1 gives rise to an N-in/N-out equilibrium. The solvent has weak influence on the N-in/N-out ratio for myrionine (1), whereas together with the anions, it plays an important role for myrionine hydrochloride (9) and hydroiodide (10). The two N-in and N-out conformations obtained separately by crystallization of 9 and 10, respectively, were analyzed by X-ray diffraction. PMID- 17691798 TI - Stereo- and regioselective glycosylations to the bis-C-arylglycoside of kidamycin. AB - In explorations toward the total synthesis of the antitumor anthrapyran natural product kidamycin, the regioselective introduction of aminosugars angolosamine and vancosamine as C-arylglycosides has been accomplished onto hydroxylated anthrapyran aglycones. Specifically, the 9,11-dihydroxylated anthrapyran A undergoes sequential glycosylations with angolosamine synthon B and vancosamine synthon C to regio- and stereoselectively afford bis-C-glycoside D corresponding to the C-glycoside pattern of kidamycin. PMID- 17691799 TI - Asymmetric synthesis of 2-alkyl-3-phosphonopropanoic acids via P-C bond formation and hydrogenation. AB - Allylic acetates, formed by the acetylation of Baylis Hillman adducts, undergo addition of phosphorus nucleophiles to give stereoselectively the Z-unsaturated esters. TFA cleavage of the tert-butyl ester and asymmetric hydrogenation of the unsaturated acid yields the phosphono alkyl propanoic acid moiety, commonly found in phosphonate- and phosphinate-based enzyme inhibitors. PMID- 17691800 TI - Organocatalytic and highly enantioselective direct alpha-amination of aromatic ketones. AB - The first highly enantioselective direct alpha-amination of aryl ketones was reported to be catalyzed by organic primary amines derived from cinchona alkaloids. Excellent enantioselectivities (88-99% ee) have been achieved for a broad spectrum of aryl ketones. The presence of 4 A molecular sieves was of great assistance for the high conversions and enantiocontrol. PMID- 17691801 TI - First total synthesis and structural reassignment of (-)-aplysiallene. AB - The first total synthesis of (-)-aplysiallene has been completed in 16 steps and features a key sequential Mukaiyama aerobic oxidative cyclization to prepare the fused bis-THF core. The original stereochemical assignment has been revised as shown. PMID- 17691802 TI - Carotenoid biosynthetic pathway in the citrus genus: number of copies and phylogenetic diversity of seven genes. AB - The first objective of this paper was to analyze the potential role of allelic variability of carotenoid biosynthetic genes in the interspecific diversity in carotenoid composition of Citrus juices. The second objective was to determine the number of copies for each of these genes. Seven carotenoid biosynthetic genes were analyzed using restriction fragment length polymorphism (RFLP) and simple sequence repeats (SSR) markers. RFLP analyses were performed with the genomic DNA obtained from 25 Citrus genotypes using several restriction enzymes. cDNA fragments of Psy, Pds, Zds, Lcy-b, Lcy-e, Hy-b, and Zep genes labeled with [alpha (32)P]dCTP were used as probes. For SSR analyses, two primer pairs amplifying two SSR sequences identified from expressed sequence tags (ESTs) of Lcy-b and Hy-b genes were designed. The number of copies of the seven genes ranged from one for Lcy-b to three for Zds. The genetic diversity revealed by RFLP and SSR profiles was in agreement with the genetic diversity obtained from neutral molecular markers. Genetic interpretation of RFLP and SSR profiles of four genes (Psy1, Pds1, Lcy-b, and Lcy-e1) enabled us to make inferences on the phylogenetic origin of alleles for the major commercial citrus species. Moreover, the results of our analyses suggest that the allelic diversity observed at the locus of both of lycopene cyclase genes, Lcy-b and Lcy-e1, is associated with interspecific diversity in carotenoid accumulation in Citrus. The interspecific differences in carotenoid contents previously reported to be associated with other key steps catalyzed by PSY, HY-b, and ZEP were not linked to specific alleles at the corresponding loci. PMID- 17691803 TI - Volumetric properties of sunflower methyl ester oil at high pressure. AB - Biodiesel is an alternative to diesel oil (DO), because it is a fuel obtained from renewable resources that has lower emissions than DO. Biomass production should promote agricultural activity to obtain fuels for the transport sector. The study of the behavior of biodiesel at varying pressure and temperature is very interesting because diesel engines are mechanical systems that work with fuels submitted to high pressure. The specific volume, isothermal compressibility, and cubic expansion coefficients of refined sunflower methyl ester oil (SMEO) and unrefined sunflower methyl ester oil (URSMEO) were obtained and compared with those of DO from 0.1 to 350 MPa and 288.15 to 328.15 K. This work shows that oil refinement did not significantly modify any of the properties studied of the final biodiesel. Compared with DO, both SMEOs were about 6% denser, whereas isothermal compressibility and cubic expansion coefficients were bigger or smaller for DO depending on pressure and temperature. PMID- 17691804 TI - Identification of the razor clam species Ensis arcuatus, E. siliqua, E. directus, E. macha, and Solen marginatus using PCR-RFLP analysis of the 5S rDNA region. AB - Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis of the 5S ribosomal DNA region has been applied to the establishment of DNA-based molecular markers for the identification of five razor clam species: Ensis arcuatus, E. siliqua, E. directus, E. macha, and Solen marginatus. PCR amplifications were carried out using a pair of universal primers from the coding region of 5S rDNA. S. marginatus was simply distinguished by the different size of the amplicons obtained. Species-specific restriction endonuclease patterns were found with the enzymes Hae III for E. arcuatus, E. siliqua, and E. directus, and Acs I for E. macha, and when two enzymes were combined, the four species were also identified. Thus, this work provides a simple, reliable, and rapid protocol for the accurate identification of Ensis and Solen species in fresh and canned products, which is very useful for traceability and to enforce labeling regulations. PMID- 17691805 TI - Insect pest management agents: hormonogen esters (juvenogens). AB - The chemical part of this investigation focused on designing structures and synthesizing a series of six new esters (juvenogens), derived from biologically active insect juvenile hormone bioanalogues (juvenoids, JHAs) and unsaturated short-chain linear and branched fatty acids for possible application as biochemically targeted insect hormonogen agents. The structures of the new compounds were assigned on the basis of a detailed NMR analysis of their (1)H and (13)C NMR spectra. The biological part of this investigation focused on introductory biological screening tests with these compounds against the red firebug (Pyrrhocoris apterus), termites (Reticulitermes santonensis and Prorhinotermes simplex), and the blowfly (Neobellieria bullata). The biological activity of the juvenogens was studied in relation to the fatty acid functionality in the structures. Notable biological activity in topical tests and medium activity in peroral tests was found for the juvenogens 3 and 7 with P. apterus. The compounds 6 and 8 showed the lowest activity in both topical and oral assays with P. apterus. Considerable effect of all tested juvenogens was observed in P. simplex; however, the juvenogens 5 and 6 (derivatives of the only branched short-chain fatty acid) showed no activity against R. santonensis. The effect of the compounds 3-8 on larval hatching of N. bullata was only moderate (larval hatching 80-90%); however, the proliferation effect caused by 5, 6, and 8 is more pronounced than the effect caused by 3, 4, and 7. PMID- 17691806 TI - Chemical characterization of Cuban propolis by HPLC-PDA, HPLC-MS, and NMR: the brown, red, and yellow Cuban varieties of propolis. AB - Sixty-five samples of propolis were collected from eleven regions of Cuba; methanolic extracts of propolis were prepared from all samples, and a classification method was developed using a combination of NMR, HPLC-PDA, and HPLC-ESI/MS techniques. The analysis of (1)H and (13)C NMR spectra and chromatographic profiles of all propolis extracts allowed the definition of three main types of Cuban propolis directly related to their secondary metabolite classes: brown Cuban propolis (BCP), rich in polyisoprenylated benzophenones, red Cuban propolis (RCP), containing isoflavonoids as the main constituents, and yellow Cuban propolis (YCP), probably with aliphatic compounds. Subsequently, the principal compounds of the brown and red types were characterized by HPLC-ESI/MS analysis. Instrumental techniques used are complementary; NMR was shown to be a quick and informative tool for the rapid analysis of crude propolis polar extracts and allowed the identification of the main class of secondary metabolites, while LC-PDA and LC-MS techniques were useful tools for qualitative and quantitative analysis of marker compounds of Cuban propolis. PMID- 17691807 TI - Purification, cloning, and identification of two thaumatin-like protein isoforms in jelly fig (Ficus awkeotsang) Achenes. AB - Jelly curd used for a popular summer drink in Taiwan is prepared by extracting the pericarpial portion of jelly fig (Ficus awkeotsang Makino) achenes. The two most abundant proteins found in jelly curd have been identified as a pectin methylesterase and a chitinase. A method was developed to purify the next abundant protein by 40% ammonium sulfate precipitation and flowing through Mono Q chromatography. In sodium dodecyl sulfate-polyacrylamide gel electrophoresis analyses, the purified protein migrated as a polypeptide of 20 kDa in the absence of beta-mercaptoethanol but split into a minor polypeptide of 20 kDa and a major polypeptide of 27 kDa in the presence of this reducing agent. Two cDNA fragments encoding precursor polypeptides of two putative thaumatin-like protein isoforms were obtained by polymerase chain reaction cloning and subsequently overexpressed in Escherichia coli to generate recombinant proteins for antibody preparations. Immunological detection and mass spectrometric analyses indicated that the two split polypeptides were thaumatin-like protein isoforms encoded by the two cloned cDNA fragments. PMID- 17691808 TI - Quantification of vitamin E and gamma-oryzanol components in rice germ and bran. AB - Rice bran is a rich natural source of vitamin E and gamma-oryzanol, which have been extensively studied and reported to possess important health-promoting properties. However, commercial rice bran is a mixture of rice bran and germ, and profiles of vitamin E and gamma-oryzanol components in these two different materials are less well-studied. In the current study, vitamin E and gamma oryzanol components in rice bran and germ were analyzed by liquid chromatography/mass spectrometry/mass spectrometry. The components were identified by electrospray ionization mass spectrometry (ESI-MS) with both positive- and negative-ion modes. Both deprotonated molecular ion [M - H](-) and protonated molecular ion [M + H](+) found as the base peaks in spectra of vitamin E components made ESI-MS a valuable analytic method in detecting vitamin E compounds, especially when they were at very low levels in samples. Ultraviolet absorption was used for quantification of vitamin E and gamma-oryzanol components. While the level of vitamin E in rice germ was 5 times greater than in rice bran, the level of gamma-oryzanol in rice germ was 5 times lower than in rice bran. Also, the major vitamin E component was alpha-tocopherol in rice germ and gamma-tocotrienol in rice bran. These data suggest that rice bran and germ have significantly different profiles of vitamin E and gamma-oryzanol components. The method enables rapid and direct on-line identification and quantification of the vitamin E and gamma-oryzanol components in rice bran and germ. PMID- 17691809 TI - Enhanced hyaluronic acid production in Bacillus subtilis by coexpressing bacterial hemoglobin. AB - Bacillus subtilis strains that can produce hyaluronic acid (HA) were constructed by integrating the HA synthase gene (hasA) and the UDP-glucose dehydrogenase gene of group C Streptococcus (hasB) or of B. subtilis itself (tauD) into the amyE locus of the B. subtilis chromosome. All of the inserted genes were under the control of a strong constitutive vegII promoter of B. subtilis. Although HA production could be achieved by expressing hasA alone, coexpressing hasB or tauD with hasA could enhance HA production at least 2-fold. To replenish the energy consumed for HA biosynthesis, Vitreoscilla hemoglobin (VHb) was coexpressed with the HA-expressing genes. With the expression of VHb, not only the cell concentration was enhanced 25%, but also HA production was further increased by 100%. About 1.8 g/L of HA was obtained by the recombinant strain B. subtilis carrying VHb, hasA, and tauD genes in the expression cassette after 30 h cultivation. PMID- 17691810 TI - Cloning of the thaumatin I cDNA and characterization of recombinant thaumatin I secreted by Pichia pastoris. AB - Thaumatin is a sweet-tasting protein comprising a mixture of some variants. The major variants are thaumatins I and II. Although the amino acid sequence of thaumatin I was known and the nucleotide sequence of cDNA of thaumatin II was elucidated, the nucleotide sequence of thaumatin I has been controversial. We have cloned two thaumatin cDNAs from the fruit of Thaumatococcus daniellii Benth. One is the same nucleotide sequence as that of thaumatin II already reported, and the other is a novel nucleotide sequence. The amino acid sequence deduced from the novel cDNA was the same amino acid sequence as that of thaumatin I, the only exception being the residue at position 113 (Asp instead of Asn), indicating that the novel thaumatin cDNA is that for thaumatin I. This thaumatin I cDNA was transformed into Pichia pastoris X-33, and the recombinant thaumatin I expressed was purified and characterized. The threshold value of sweetness of the recombinant thaumatin I was the same as that of the plant thaumatin I, although several unexpected amino acid residues were attached to the N-terminal of the recombinant thaumatin I. These indicate that the N-terminal portion of thaumatin is not critical for the elicitation of sweetness. PMID- 17691811 TI - Mechanism exploration during lipase-mediated methanolysis of renewable oils for biodiesel production in a tert-butanol system. AB - tert-Butanol has been developed as a novel reaction medium for lipase-mediated methanolysis of renewable oils for biodiesel production, in which lipase could maintain high catalytic activity, although the log P value of tert-butanol was just about 0.35. The related mechanism exploration has been carried out, and it has been proposed first in this manuscript that in the biodiesel production system, log P(environment) (log P(environment) = x(methanol) log P(methanol) + x(oils) log P(oils) + x(solvent) log P(solvent)) including reactants and organic solvent should be taken into account to consider the effect of the whole environment on lipase activity instead of just considering the effect of the organic solvent itself. Further study showed that the operational stability of the lipase could be improved significantly in this system and there was no loss in lipase activity even after its being continuously used for 200 batches. The phase diagrams of the ternary-components tert-butanol/methanol/rapeseed oils were plotted further, and it was found that the methanol tolerance was the saturated methanol concentration in the system. It was demonstrated first here that the improved stability of the lipase was due to the elimination of negative effects caused by methanol and byproduct glycerol in the tert-butanol system. PMID- 17691812 TI - Application of a cell-once-through perfusion strategy for production of recombinant antibody from rCHO cells in a Centritech Lab II centrifuge system. AB - Based upon the results of scale-down intermittent perfusion processes, a cell once-through (COT) perfusion concept was applied to a dual bioreactor system coupled to a Centritech Lab II centrifuge for culture of recombinant Chinese hamster ovary (rCHO) cells for monoclonal antibody production. In this new culture mode, i.e., the COT perfusion process, total spent medium was transferred to the centrifuge and a fixed percentage was removed. Approximately 99% of the viable cells are transferred to another bioreactor filled with fresh medium by single operation of the Centritech Lab II centrifuge system for about 30 min. Accordingly, a significant reduction of the cell-passage frequency to the centrifuge led to minimization of cell damage caused by mechanical shear stress, oxygen limitation, nutrient limitation, and low temperature outside the bioreactor. The effects of culture temperature shift and fortified medium on cell growth and recombinant antibody production in the COT perfusion process were investigated. Although the suppressive effects of low culture temperature on cell growth led to a loss of stability in a long-term COT perfusion culture system, the average antibody concentration at 33 degrees C was 157.8 mg/L, approximately 2.4-fold higher than that at 37 degrees C. By the use of a fortified medium at 37 degrees C, rCHO cells were maintained at high density above 1.2 x 10(7) cells/mL, and antibody was produced continuously in a range of 260-280 mg/L in a stable long-term COT perfusion culture. The proposed new culture mode, the COT perfusion approach, guarantees the recovery of rCHO cells damaged by lowered temperature or high lactate and ammonium concentration. It will be an attractive choice for minimization of cell damage and stable long-term antibody production with high cell density. PMID- 17691813 TI - Characterization of alginate lyase activity on liquid, gelled, and complexed states of alginate. AB - A study of alginate lyase was carried out to determine if this enzyme could be used to remove alginate present in the core of alginate/poly-L-lysine (AG/PLL) microcapsules in order to maximize cell growth and colonization. A complete kinetic study was undertaken, which indicated an optimal activity of the enzyme at pH 7-8, 50 degrees C, in the presence of Ca2+. The buffer, not the ionic strength, influenced the alginate degradation rate. Alginate lyase was also shown to be active on gelled forms of alginate, as well as on the AG/PLL complex constituting the membrane of microcapsules. Batch cultures of CHO cells in the presence of alginate showed a decrease of the growth rate by a factor of 2, although the main metabolic flux rates were not modified. The addition of alginate lyase to cell culture medium increased the doubling time 5-7-fold and decreased the protein production rate, although cell viability was not affected. The addition of enzyme to medium containing alginate did not improve growth conditions. This suggests that alginate lyase is probably not suitable for hydrolysis of microcapsules in the presence of cells, in order to achieve high cell density and high productivity. However, the high activity may be useful for releasing cells from alginate beads or AG/PLL microcapsules. PMID- 17691814 TI - A population balance model describing the cell cycle dynamics of myeloma cell cultivation. AB - A multi-staged population balance model is proposed to describe the cell cycle dynamics of myeloma cell cultivation. In this model, the cell cycle is divided into three stages, i.e., G1, S, and G2M phases. Both DNA content and cell volume are used to differentiate each cell from other cells of the population. The probabilities of transition from G1 to S and division of G2M are assumed to be dependent on cell volume, and transition probability from S to G2M is determined by DNA content. The model can be used to simulate the dynamics of DNA content and cell volume distributions, phase fractions, and substrate and byproduct concentrations, as well as cell densities. Measurements from myeloma cell cultivations, especially the FACS data with respect to DNA distribution and cell fractions in different stages, are employed for model validation. PMID- 17691815 TI - Molecular dynamics simulations to investigate the effects of zinc ions on the structural stability of the c-Cbl RING domain. AB - In eukaryotic cells, ubiquitylation of proteins plays a critical role in regulating diverse cell processes by the ubiquitin activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin protein ligase (E3). E3 is the key component that confers specificity to ubiquitylation and directs the conjugation of ubiquitin to a specific target protein. RING domains are small structured protein domains that require the coordination of zinc ions for a stable tertiary fold and some of them are involved in the E3 family. In this study, we reported the detailed relationships between the two zinc ions and the structural stability of the c-Cbl RING domain by molecular dynamics simulations. Our results show that these two zinc ions play an important role in maintaining both the secondary and tertiary structural stabilities of the c-Cbl RING domain. Our results also reveal that the secondary structural stability of the c-Cbl RING domain is mainly determined by the hydrogen-bonding networks in or near the two zinc ion binding sites. Our results further demonstrate that zinc ion binding site 2 is more structurally stable than site 1. PMID- 17691816 TI - Role of silent gene mutations in the expression of caprine growth hormone in Escherchia coli. AB - This report describes the strategy for overexpression of caprine growth hormone (cGH) gene of beetal goat in E. coli through introducing silent mutations in the 5'-end of the coding sequence. The silent mutations introduced were aimed at minimizing translation-inhibiting secondary structures in the mRNA. Free energies of the resultant mRNAs were calculated from the ribosomal binding site of mRNA to +24 base using the Mfold web server. The construct with native sequence did not show any expression, whereas introduction of the silent mutations had strong influence on the expression levels. Some constructs (pETcGH2-7) showed 12-30% expression of total cell proteins while some others (pETcGH8-16) showed 30 to 53% of total cell protein. Any variation in the amount of mRNA transcript for the various constructs, as determined by quantitative PCR, was not enough to suggest that the variable level of the gene expression was due to variation in the transcription levels. It appears that the expression levels are not always correlated with free-energy values of the secondary structures in the 5'-end region of the mRNA; instead some key silent nucleotide alterations at certain sites of 5'-end of the sequence reorganize the secondary structure in such a way that it has positive impact on translation without considerably altering the free energy values. An empirical approach for determining the optimum 5'-end substitutions for hyperexpression of a recombinant protein thus seems necessary. PMID- 17691817 TI - Two-stage system for hydrogen production by immobilized cyanobacterium Gloeocapsa alpicola CALU 743. AB - Previous studies showed that cell suspensions of unicellular nondiazotrophic cyanobacterium G. alpicola grown under nitrate-limiting conditions intensively produces H2 via fermentation of endogenous glycogen with hydrogen yield more then 90% of theoretical maximum (3.8 mol H2 per mol glucose). H2 production is realized by a Hox hydrogenase on the stages of NAD(P)H generation. Exploiting this property, the two-stage cyclic system for sustained hydrogen production was developed using a photobioreactor (PhBR) with G. alpicola immobilized on glass fiber TR-0.3. Immobilization of the cells on the matrix occurred during growth directly in PhBR operated in continuous mode; the density of culture immobilized achieved 37 g Chl alpha cm(-2). The first stage of the cycle was the photosynthetic incubations of G. alpicola in the flow of the culture medium, which contained limiting concentrations of nitrate for efficient glycogen accumulation and activation of hydrogenase. The second stage was the fermentation of glycogen, with H2 production realized in darkness with continuous Ar sparging and without medium flow. Standardization of optimal parameters for both stages provided a stable cyclic regime of the system: photosynthesis (24 hours) fermentation (24 hours). The total amount of H2 evolved in one cycle was 957.6 mL L(-1)(matrix), and the overage rate of H2 production during the cycle (48 hours) was about 20 mL h(-1) L(-1)(matrix). Ten consequent cycles was carried out in this regime with reproducible H2 production, although PhBR with the same sample of immobilized culture was operated over a period of more then three months. PMID- 17691818 TI - Extensive sugar modification improves triple helix forming oligonucleotide activity in vitro but reduces activity in vivo. AB - We are developing triple helix forming oligonucleotides (TFOs) for gene targeting. Previously, we synthesized bioactive TFOs containing 2'-O-methylribose (2'-OMe) and 2'-O-aminoethylribose (2'-AE) residues. Active TFOs contained four contiguous 2'-AE residues and formed triplexes with high thermal stability and rapid association kinetics. In an effort to further improve bioactivity, we synthesized three series of TFOs containing the 2'-AE patch and additional ribose modifications distributed throughout the remainder of the oligonucleotide. These were either additional 2'-AE residues, the conformationally locked BNA/LNA ribose with a 2'-O,4'-C-methylene bridge, or the 2'-O,4'-C-ethylene analogue (ENA). The additionally modified TFOs formed triplexes with greater thermal stability than the reference TFO, and some had improved association kinetics. However, the most active TFOs in the biochemical and biophysical assays were the least active in the bioassay. We measured the thermal stability of triplexes formed by the TFOs in each series on duplex targets containing a change in sequence at a single position. The Tm value of the variant sequence triplexes increased as the number of all additional modifications increased. A simple explanation for the failure of the improved TFOs in the bioassay was that the increased affinity for nonspecific targets lowered the effective nuclear concentration. Enhancement of TFO bioactivity will require chemical modifications that improve interaction with the specific targets while retaining selectivity against mismatched sequences. PMID- 17691819 TI - Perturbations in factor XIII resulting from activation and inhibition examined by solution based methods and detected by MALDI-TOF MS. AB - Factor XIII can be activated proteolytically by thrombin cleavage of the activation peptide or non-proteolytically by exposure to 50 mM Ca2+. The resultant transglutaminase cross-links Q and K residues within the noncovalently associated fibrin clot. Hydrogen deuterium exchange coupled with MALDI-TOF MS demonstrated that FXIII activation protects regions within the beta sandwich (98 104) and the beta barrel 1 (526-546) from deuterium, while exposing the potential Q substrate recognition site (220-230) to deuteration (Turner, B. T., Jr., and Maurer, M. C. (2002) Biochemistry 41, 7947-7954). Chemical modification indicated the availability of several residues upon activation including K73, K221, C314, and C409 (Turner, B. T., Jr., Sabo, T. M., Wilding, D., and Maurer, M. C. (2004) Biochemistry 43, 9755-9765). In the current work, activations of FXIII by IIa and by Ca2+ as well as FXIIIa inhibition by the K9 DON peptide (with the Q isostere 6 diazo-5-oxo-norleucine) and iodoacetamide were further examined. New findings unique for FXIIIaIIa included alkylation of C238 and C327, acetylation of K68, and increased proteolysis of 207-214. By contrast, FXIIIaCa led to increased proteolysis of 73-85 and 104-125 and to a loss of K129 acetylation. The FXIIIa inhibitors K9 DON and iodoacetamide both promoted even greater protection from deuteration for the beta sandwich (98-104) and beta barrel 1 (526-546). Interestingly, only K9 DON was able to block modification of catalytic core C409 near the dimer interface. The solution based approaches reveal that activation and inhibition lead to local and long range effects to FXIII(a) and that many are influenced by Ca2+ binding. Important glimpses are being provided on FXIIIa allostery and the presence of putative FXIIIa exosites. PMID- 17691820 TI - Studies on the replication of the ring opened formamidopyrimidine, Fapy.dG in Escherichia coli. AB - Fapy.dG is produced in DNA as a result of oxidative stress from a precursor that also forms OxodG. Bypass of Fapy.dG in a shuttle vector in COS-7 cells produces G --> T transversions slightly more frequently than does OxodG (Kalam, M. A., et al. (2006) Nucleic Acids Res. 34, 2305). The effect of Fapy.dG on replication in Escherichia coli was studied by transfecting M13mp7(L2) bacteriophage DNA containing the lesion within the lacZ gene in 4 local sequence contexts. For comparison, experiments were carried out side-by-side on OxodG. The efficiency of lesion bypass was determined relative to that of a genome containing native nucleotides. Fapy.dG was bypassed less efficiently than OxodG. Bypass efficiency of Fapy.dG and OxodG increased modestly in SOS-induced cells. Mutation frequencies at the site of the lesions in the originally transfected genomes were determined using the REAP assay (Delaney, J. C., Essigmann, J. M. (2006) Methods Enzymol. 408, 1). G --> T transversions were the only mutations observed above background when either Fapy.dG or OxodG was bypassed. OxodG mutation frequencies ranged from 3.1% to 9.8%, whereas the G --> T transversion frequencies observed upon Fapy.dG bypass were T transversions. PMID- 17691821 TI - Subdomain switching reveals regions that harbor substrate specificity and regulatory properties of protein tyrosine kinases. AB - Csk and Src are two protein tyrosine kinases that share a similar overall multidomain structural organization and a high degree of sequence homology but have different substrate specificities and regulatory properties. In this study, we generated chimeric kinases of Csk and Src by switching the C-terminal lobes of their catalytic domains, and we characterized their substrate specificity and regulatory properties. First, both Csk and Src phosphorylate Src as a common substrate, but on different Tyr residues. The C-terminal lobes of the kinase catalytic domain determined the site of phosphorylation on Src. Furthermore, toward several physiological substrates of Src, the substrate specificity was also determined by the C-terminal lobe of the catalytic domain regardless of the regulatory domains and the N-terminal lobe of the catalytic domain. Second, Csk and Src represent two general regulatory strategies for protein tyrosine kinases. Csk catalytic domain is inactive and is positively regulated by the regulatory domains, while Src catalytic domain is active and suppressed by its interactions with the regulatory domains. The regulatory properties of the chimeric kinases were more complicated. The regulatory domains and the N-lobe did not fully determine the response to a regulatory ligand, suggesting that the C-lobe also contributes to such responses. On the other hand, the intrinsic kinase activity of the catalytic domain correlates with the identity of the N-lobe. These results demonstrate that the chimeric strategy is useful for detailed dissection of the mechanistic basis of substrate specificity and regulation of protein tyrosine kinases. PMID- 17691823 TI - Structural and functional characterization of CC chemokine CCL14. AB - CC chemokine ligand 14, CCL14, is a human CC chemokine that is of recent interest because of its natural ability, upon proteolytic processing of the first eight NH2-terminal residues, to bind to and signal through the human immunodeficiency virus type-1 (HIV-1) co-receptor, CC chemokine receptor 5 (CCR5). We report X-ray crystallographic structures of both full-length CCL14 and signaling-active, truncated CCL14 [9-74] determined at 2.23 and 1.8 A, respectively. Although CCL14 and CCL14 [9-74] differ in their ability to bind CCR5 for biological signaling, we find that the NH2-terminal eight amino acids (residues 1 through 8) are completely disordered in CCL14 and both show the identical mode of the dimeric assembly characteristic of the CC type chemokine structures. However, analytical ultracentrifugation studies reveal that the CCL14 is stable as a dimer at a concentration as low as 100 nM, whereas CCL14 [9-74] is fully monomeric at the same concentration. By the same method, the equilibrium between monomers of CCL14 [9-74] and higher order oligomers is estimated to be of EC1,4 = 4.98 microM for monomer-tetramer conversion. The relative instability of CCL14 [9-74] oligomers as compared to CCL14 is also reflected in the Kd's that are estimated by the surface plasmon resonance method to be approximately 9.84 and 667 nM for CCL14 and CCL14 [9-74], respectively. This approximately 60-fold difference in stability at a physiologically relevant concentration can potentially account for their different signaling ability. Functional data from the activity assays by intracellular calcium flux and inhibition of CCR5-mediated HIV-1 entry show that only CCL14 [9-74] is fully active at these near-physiological concentrations where CCL14 [9-74] is monomeric and CCL14 is dimeric. These results together suggest that the ability of CCL14 [9-74] to monomerize can play a role for cellular activation. PMID- 17691822 TI - Insights into the solution structure of human deoxyhemoglobin in the absence and presence of an allosteric effector. AB - We present a nuclear magnetic resonance (NMR) study in solution of the structures of human normal hemoglobin (Hb A) in the deoxy or unligated form in the absence and presence of an allosteric effector, inositol hexaphosphate (IHP), using 15N 1H residual dipolar coupling (RDC) measurements. There are several published crystal structures for deoxyhemoglobin A (deoxy-Hb A), and it has been reported that the functional properties of Hb A in single crystals are different from those in solution. Carbonmonoxyhemoglobin A (HbCO A) can also be crystallized in several structures. Our recent RDC studies of HbCO A in the absence and presence of IHP have shown that the solution structure of this Hb molecule is distinctly different from its classical crystal structures (R and R2). To have a better understanding of the structure-function relationship of Hb A under physiological conditions, we need to evaluate its structures in both ligated and unligated states in solution. Here, the intrinsic paramagnetic property of deoxy-Hb A has been exploited for the measurement of RDCs using the magnetic-field dependence of the apparent one-bond 1H-15N J couplings. Our RDC analysis suggests that the quaternary and tertiary structures of deoxy-Hb A in solution differ from its recently determined high-resolution crystal structures. Upon binding of IHP, structural changes in deoxy-Hb A are also observed, and these changes are largely within the alpha1beta1 (or alpha2beta2) dimer itself. These new structural findings allow us to gain a deeper insight into the structure-function relationship of this interesting allosteric protein. PMID- 17691824 TI - Functionality of the seventh and eighth transmembrane domains of acyl-coenzyme A:cholesterol acyltransferase 1. AB - Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1) is a resident enzyme in the endoplasmic reticulum. ACAT1 is a homotetrameric protein and contains nine transmembrane domains (TMDs). His460 is a key active residue and is located within TMD7. Human ACAT1 has seven free Cys, but the recombinant ACAT1 devoid of free Cys retains full enzyme activity. To further probe the functionality of TMD7 (amino acids 446-460) and TMD8 (amino acids 466-481), we used a parental ACAT1 devoid of free Cys as the template to perform Cys-scanning mutagenesis within these regions. Each of the single Cys mutants was expressed in Chinese hamster ovary (CHO) cell line AC29 lacking endogenous ACAT1. We measured the effect of single Cys substitution on enzyme activity and used the Cu(1,10 phenanthroline)2SO4-mediated disulfide cross-linking method to probe possible interactions of engineered Cys between the two identical subunits. The results show that several residues in one subunit closely interact with the same residues in the other subunit; mutating these residues to Cys does not lead to large loss in enzyme activity. Helical wheel analysis suggests that these residues are located at one side of the coil. In contrast, mutating residues F453, A457, or H460 to Cys causes large loss in enzyme activity; the latter residues are located at the opposite side of the coil. A similar arrangement is found for residues in TMD8. Thus, helical coils in TMD7 and TMD8 have two distinct functional sides: one side is involved in substrate-binding/catalysis, while the other side is involved in subunit interaction. PMID- 17691826 TI - Forced detachment of immersed elastic rubber beads. AB - We investigate the strength of adhesion and the dynamics of detachment of elastic beads (Young's modulus E approximately 1 MPa) adhering to a horizontal solid surface in a viscous liquid. The beads are initially compressed on the surface. Their unbinding is imposed by fast vertical stretching (above a certain threshold value). The decrease in the contact radius is monitored by interferential microscopy. We find that the dynamics of detachment involves three steps: (i) fast elastic decompression, (ii) slow adhesive detachment, and (iii) catastrophic rupture. They can be interpreted by a transfer of the Johnson Kendall Roberts (JKR) energy toward viscous losses in the liquid wedge, near the rubber/solid/liquid (R/S/L) contact line. PMID- 17691827 TI - Ultrathin silica films immobilized on gold supports: fabrication, characterization, and modification. AB - A novel method for covalent attachment of ultrathin silica films (thickness <10 nm) to gold substrates is reported. Silica layers were prepared using spin coating of sol-gel precursor solutions onto gold substrates that were cleaned and oxidized using UV photo-oxidation in an ozone atmosphere. The gold oxide layer resulting from this process acts as a wetting control and adhesive agent for the ultrathin silica layer. Control of silica layer thickness between approximately 6 and 60 nm through modification of precursor solution composition or by repetitive deposition is demonstrated. Films were characterized using infrared spectroscopy, ellipsometry, atomic force microscopy, and cyclic voltammetry. For the standard deposition parameters developed here, films were determined to be 5.5 +/- 0.75 nm thick, and were stable in aqueous solutions ranging in pH from 2 to 10 for at least 30 min. Films contained nanoscopic defects with radii of S1 singlet transition could be observed in the absorption spectrum centered at 320 nm. These observations were supported by theoretical density functional calculations (B3LYP) in which the geometries of nine isomers of warfarin were optimized and their respective eight lowest singlet and three lowest triplet excitation energy levels were predicted. Examination of the fluorescence excitation and emission spectra of the isomers in nonpolar and polar organic solvents showed the presence of the deprotonated open side chain form of warfarin in 2-propanol, ethanol, and acetonitrile. Time-resolved fluorescence experiments revealed a short decay time constant, tau1, in all solvents studied while in more polar environments a second longer one, tau2, was evident varying between 0.5 and 1.6 ns depending on solvent polarity. The variation of number and length of fluorescence lifetimes as a function of solvent environment has provided a tool for examining warfarin protein binding. Studies on the binding of warfarin to human serum albumin (HSA) have been undertaken, and different modes of binding were observed which are indicative of binding to the anion-selective Sudlow I and, second, a lower affinity mode of interaction. PMID- 17691836 TI - Coarse-grained representation of beta-helical protein building blocks. AB - A general strategy to develop coarse-grained models of beta-helical protein fragments is presented. The procedure has been applied to a building block formed by a two-turn repeat motif from E. coli galactoside acetyltransferase, which is able to provide a very stable self-assembled tubular nanoconstruct upon stacking of its replicas. For this purpose, first, we have developed a computational scheme to sample very efficiently the configurational space of the building block. This method, which is inspired by a strategy recently designed to study amorphous polymers and by an advanced Monte Carlo algorithm, provides a large ensemble of uncorrelated configurations at a very reasonable computational cost. The atomistic configurations provided by this method have been used to obtain a coarse-grained model that describes the amino acids with fewer particles than those required for full atomistic detail, i.e., two, three, or four depending on the chemical nature of the amino acid. Coarse-grained potentials have been developed considering the following types of interactions: (i) electrostatic and van der Waals interactions between residues i and i + n with n >/= 2; (ii) interactions between residues i and i + 1; and (c) intra-residue interactions. The reliability of the proposed model has been tested by comparing the atomistic and coarse-grained energies calculated for a large number of independent configurations of the beta-helical building block. PMID- 17691838 TI - Identification of proton-transfer pathways in human carbonic anhydrase II. AB - We investigate the probable proton-transfer pathways from the surface of human carbonic anhydrase II into the active site cavity through His-64 that has been widely implicated as a key residue along the proton-transfer path. A recursive analysis of hydrogen-bonded clusters in the static crystallographic structure shows that there is no complete path through His-64 in either of its experimentally detected conformations. Side chain conformational fluctuation of His-64 from its outward conformation toward the active site is found to provide a crucial dynamic connectivity needed to complete the path coupled to local reorganization of the protein structure and hydration. The energy and free energy barriers along the detected pathway have been estimated to derive the mechanism of His-64 rotation toward the active site. We also investigate a dynamical connectivity map that highlights networks of disordered water molecules that may promote a direct (and probably transient) access of the solvent to the active site. Our studies reveal how such solvent access channels may be related to the putative proton shuttle mediated by His-64. The paths thus identified can be potentially used as reaction coordinates for further studies on the molecular mechanism of enzyme action. PMID- 17691837 TI - First-principles calculation of pKa for cocaine, nicotine, neurotransmitters, and anilines in aqueous solution. AB - The absolute pKa values of 24 representative amine compounds, including cocaine, nicotine, 10 neurotransmitters, and 12 anilines, in aqueous solution were calculated by performing first-principles electronic structure calculations that account for the solvent effects using four different solvation models, i.e., the surface and volume polarization for electrostatic interaction (SVPE) model, the standard polarizable continuum model (PCM), the integral equation formalism for the polarizable continuum model (IEFPCM), and the conductor-like screening solvation model (COSMO). Within the examined computational methods, the calculations using the SVPE model lead to the absolute pKa values with the smallest root-mean-square-deviation (rmsd) value (1.18). When the SVPE model was replaced by the PCM, IEFPCM, and COSMO, the rmsd value of the calculated absolute pKa values became 3.21, 2.72, and 3.08, respectively. All types of calculated pKa values linearly correlate with the experimental pKa values very well. With the empirical corrections using the linear correlation relationships, the theoretical pKa values are much closer to the corresponding experimental data and the rmsd values become 0.51-0.83. The smallest rmsd value (0.51) is also associated with the SVPE model. All of the results suggest that the first-principles electronic structure calculations using the SVPE model are a reliable approach to the pKa prediction for the amine compounds. PMID- 17691839 TI - Preferential binding of fluorine to aluminum in high peralkaline aluminosilicate glasses. AB - For two series of fluoride-containing aluminosilicate glasses of high peralkaline type, we apply 27Al, 19F, 29Si, and 23Na NMR spectroscopy to understand the structural changes introduced by the addition of alkali fluorides. Adding fluoride in concentrations above the solubility limit causes crystallization of different phases in sodium and potassium glasses despite identical composition. However, the NMR spectra reveal that the structural evolution of the precrystallized states is similar in both series. In particular, fluorine coordinates exclusively to alkaline cations and aluminum. No indication of direct bonding with silicon was found from 19F --> 29Si cross-polarization experiments. In contrast to other glass systems, double resonance experiments in these peralkaline systems show that halide addition produces at most a minor fraction of tetrahedral aluminum containing fluorine in its coordination sphere. Instead, the fluorine addition prior to crystallization converts up to about 20% of the initial tetrahedral aluminum (1 mol % in absolute units) to 5- and 6-fold coordinated aluminum. A minor portion of five-coordinated aluminum groups is considered as the intermediate to the growing fraction of octahedral aluminum in the silicate matrix. The initialization of the crystallization process is correlated with the saturation of the silicate matrix by octahedral aluminum clusters segregating out under further doping by fluoride. It is suggested that the formation of the nonframework Al-F bonds is responsible for structural relaxation, reflected by the reduction of the glass transition temperature. PMID- 17691840 TI - Applications of ionic liquids in carbohydrate chemistry: a window of opportunities. AB - Ionic liquids (ILs) are composed only of ions. Of special interest to this review are those where at least one ion (the cation) is organic and whose melting points are below or not far above room temperature. ILs are designated as "green" solvents because they have extremely low vapor pressure, are non-inflammable, and thermally and chemically stable. Therefore, many of them can be, in principle, recycled into the process indefinitely. The objective of the present review is to discuss different aspects of the use of ILs in carbohydrate chemistry, in particular, dissolution and functionalization of simple sugars, cyclodextrins, cellulose, starch, and chitin/chitosan. The molecular structure and synthesis of ILs most frequently employed in carbohydrate chemistry are discussed with an emphasis on imidazolium and pyridinium cations with different counterions. The physicochemical properties of ILs that are relevant to the dissolution and functionalization of carbohydrates, in particular their polarities and hydrogen bonding abilities, are discussed. Dissolution of simple saccharides and biopolymers in ILs is presented with an emphasis on the mechanism of carbohydrate -IL interactions. Finally, the very interesting novel applications of the solutions obtained are addressed. These include, inter alia, spinning of the dissolved biopolymer into fibers, extrusion into slabs and rods, formation of matrixes for a myriad of substrates, including biomacromolecules, formation of nanocomposites, and functionalization to produce important derivatives. The use of ILs in many branches of science is expanding fast; it is hoped that this review will draw the attention of researchers to the "window of opportunities" that these green solvents open into carbohydrate chemistry. PMID- 17691841 TI - Sorption of water by bidisperse mixtures of carbohydrates in glassy and rubbery states. AB - Water sorption by bidisperse carbohydrate mixtures consisting of varying ratios of a narrow-molecular-weight distribution maltopolymer and the disaccharide maltose is investigated to establish a quantitative relation between the composition of the carbohydrate system and the water sorption isotherm. The sorption of water is approached from two limiting cases: the glassy state at low water content and the dilute aqueous carbohydrate solution. In the glassy state, the water content at a given water activity decreases with increasing maltose content of the matrix, whereas in the rubbery state it increases with increasing maltose content. The water sorption behavior in the glassy state is quantified using a variety of models, including the often-utilized but physically poorly founded Guggenheim-Anderson-de Boer model, several variants of the free-volume theory of sorption by glassy polymers, and a two-state sorption model introduced in the present paper. It is demonstrated that both the free-volume models and the two-state sorption model, which all encompass the Flory-Huggins theory for the rubbery-state sorption but which differ in their modeling of the glassy-state sorption, provide a physically consistent foundation for the analysis of water sorption by the carbohydrate matrixes. PMID- 17691842 TI - Degradation of high-molar-mass hyaluronan and characterization of fragments. AB - A sample of high-molar mass hyaluronan was oxidized by seven oxidative systems involving hydrogen peroxide, cupric chloride, ascorbic acid, and sodium hypochlorite in different concentrations and combinations. The process of the oxidative degradation of hyaluronan was monitored by rotational viscometry, while the fragments produced were investigated by size-exclusion chromatography, matrix assisted laser desorption ionization-time-of-flight mass spectrometry, and non isothermal chemiluminometry. The results obtained imply that the degradation of hyaluronan by these oxidative systems, some of which resemble the chemical combinations present in vivo in the inflamed joint, proceeds predominantly via hydroxyl radicals. The hyaluronan fragmentation occurred randomly and produced species with rather narrow and unimodal distribution of molar mass. Oxidative degradation not only reduces the molecular size of hyaluronan but also modifies its component monosaccharides, generating polymer fragments that may have properties substantially different from those of the original macromolecule. PMID- 17691843 TI - Synthesis and characterization of novel thiol-reactive poly(ethylene glycol) cross-linkers for extracellular-matrix-mimetic biomaterials. AB - Synthetic extracellular matrix hydrogels can be used for three-dimensional cell culture, wound repair, and tissue engineering. Using the bifunctional electrophile poly(ethylene glycol) diacrylate (PEGDA), thiol-modified glycosaminoglycans and polypeptides can be cross-linked into biocompatible materials in the presence of cells or tissues. However, the rate of in situ cross linking with PEGDA under physiological conditions may occur too slowly for clinical applications requiring a fast-curing preparation. To explore a wider range of cross-linking time courses, five homo-bifunctional PEG derivatives were synthesized and examined as cross-linking agents for thiol-modified derivatives of hyaluronan (HA). Thiol reaction rate constants were measured over a pH range of 7.4 to 8.6. The order of reactivity for the functional groups used was determined to be maleimide > iodoacetate > bromoacetate > iodoacetamide > acrylate > bromoacetamide, with rates increasing exponentially with increasing pH. The range of gelation times at physiological pH varied from less than 1 min to over 2 h. Addition of the cross-linkers to cell culture medium showed minimal cytotoxicity toward primary human dermal fibroblasts at concentrations anticipated during in situ cross-linking. Moreover, hydrogels prepared from thiol modified gelatin and thiol-modified HA were biocompatible and supported attachment and proliferation of fibroblasts and hepatocytes. PMID- 17691844 TI - Shell-cross-linked micelles containing cationic polymers synthesized via the RAFT process: toward a more biocompatible gene delivery system. AB - Block copolymers poly(2-(dimethylamino) ethyl methacrylate)-b-poly(polyethylene glycol methacrylate) (PDMAEMA-b-P(PEGMA)) were prepared via reversible addition fragmentation chain transfer polymerization (RAFT). The polymerization was found to proceed with the expected living behavior resulting in block copolymers with varying block sizes of low polydispersity (PDI <1.3). The resulting block copolymer was self-assembled in an aqueous environment, leading to the formation of pH-responsive micelles. Further stabilization of the micellar system was performed in water using ethylene glycol dimethacrylate and the RAFT process to cross-link the shell. The cross-linked micelle was found to have properties significantly different from those of the uncross-linked block copolymer micelle. While a distinct critical micelle concentration (CMC) was observed using block copolymers, the CMC was absent in the cross-linked system. In addition, a better stability against disintegration was observed when altering the ionic strength such as the absence of changes of the hydrodynamic diameter with increasing NaCl concentration. Both cross-linked and uncross-linked micelles displayed good binding ability for genes. However, the cross-linked system exhibited a slightly superior tendency to bind oligonucleotides. Cytotoxicity tests confirmed a significant improvement of the biocompatibility of the synthesized cross-linked micelle compared to that of the highly toxic PDMAEMA. The cross-linked micelles were taken up by cells without causing any signs of cell damage, while the PDMAEMA homopolymer clearly led to cell death. PMID- 17691845 TI - Gold-catalyzed synthesis of oxygen- and nitrogen-containing heterocycles from alkynyl ethers: application to the total synthesis of andrachcinidine. AB - In this paper we report that homopropargylic ethers containing pendent oxygen or nitrogen nucleophiles react with electrophilic gold catalysts in the presence of water to form saturated heterocyclic ketones. Mechanistic studies demonstrated that the reactions proceed through a sequence of alkyne hydration, alkoxy group elimination, and intramolecular conjugate addition. Diastereoselectivities for tetrahydropyran and piperidine formation are very good to excellent. This method has been applied to an efficient total synthesis of the natural product andrachcinidine. Utilizing propargylic ether substrates rather than homopropargylic ethers promotes regioselective hydration of internal alkynes, thereby expanding the scope of products that can be accessed through this protocol. PMID- 17691847 TI - Gibbs energies of transfer of anions from water to mixed aqueous organic solvents. PMID- 17691846 TI - Study on the reactivity of oxabicyclic alkenes in ruthenium-catalyzed [2+2] cycloadditions. AB - The ruthenium-catalyzed [2+2] cycloadditions of various bicyclic alkenes with an alkyne have been investigated. The presence of the oxygen in the bridgehead of the bicyclic alkene significantly enhanced the rate of the ruthenium-catalyzed [2+2] cycloadditions. The presence of a C1-substituent on the oxanorbornadiene decreased the rate of the cycloaddition and electron-withdrawing C1-substituents were found to be more reactive than electron-donating C1-substituents in the Ru catalyzed [2+2] cycloaddition. The nature of the substituent on the benzene ring of oxabenzonorbornadienes showed little effect on the rate of the cycloaddition. PMID- 17691848 TI - Scanned probe imaging of quantum dots inside InAs nanowires. AB - We show how a scanning probe microscope (SPM) can be used to image electron flow through InAs nanowires, elucidating the physics of nanowire devices on a local scale. A charged SPM tip is used as a movable gate. Images of nanowire conductance versus tip position spatially map the conductance of InAs nanowires at liquid-He temperatures. Plots of conductance versus backgate voltage without the tip present show complex patterns of Coulomb-blockade peaks. Images of nanowire conductance identify their source as multiple quantum dots formed by disorder along the nanowire--each dot is surrounded by a series of concentric rings corresponding to Coulomb blockade peaks. An SPM image locates the dots and provides information about their size. In this way, SPM images can be used to understand the features that control transport through nanowires. The nanowires were grown from metal catalyst particles and have diameters approximately 80 nm and lengths 2-3 microm. PMID- 17691849 TI - Surface charge sensitivity of silicon nanowires: size dependence. AB - Silicon nanowires of different widths were fabricated in silicon on insulator (SOI) material using conventional process technology combined with electron-beam lithography. The aim was to analyze the size dependence of the sensitivity of such nanowires for biomolecule detection and for other sensor applications. Results from electrical characterization of the nanowires show a threshold voltage increasing with decreasing width. When immersed in an acidic buffer solution, smaller nanowires exhibit large conductance changes while larger wires remain unaffected. This behavior is also reflected in detected threshold shifts between buffer solutions of different pH, and we find that nanowires of width >150 nm are virtually insensitive to the buffer pH. The increased sensitivity for smaller sizes is ascribed to the larger surface/volume ratio for smaller wires exposing the channel to a more effective control by the local environment, similar to a surrounded gate transistor structure. Computer simulations confirm this behavior and show that sensing can be extended even down to the single charge level. PMID- 17691850 TI - Synthesis and characterization of polymer-coated quantum dots with integrated acceptor dyes as FRET-based nanoprobes. AB - A fluorescence resonance energy transfer pair consisting of a colloidal quantum dot donor and multiple organic fluorophores as acceptors is reported and the photophysics of the system is characterized. Most nanoparticle-based biosensors reported so far use the detection of specific changes of the donor/acceptor distance under the influence of analyte binding. Our nanoparticle design on the other hand leads to sensors that detect spectral changes of the acceptor (under the influence of analyte binding) at fixed donor/acceptor distance by the introduction of the acceptor into the polymer coating. This approach allows for short acceptor-donor separation and thus for high-energy transfer efficiencies. Advantageously, the binding properties of the hydrophilic polymer coating further allows for addition of poly(ethylene glycol) shells for improved colloidal stability. PMID- 17691851 TI - Orientational order in block copolymer films zone annealed below the order- disorder transition temperature. AB - We report measurements of rapid ordering and preferential alignment in block copolymer films zone annealed below the order-disorder transition temperature. The orientational correlation lengths measured after approximately 5 h above the glass-transition temperature ( approximately 2 microm) were an order of magnitude greater than that obtained under equivalent static annealing. The ability to rapidly process polymers with inaccessible order-disorder transition temperatures suggests zone annealing as a route toward more robust nanomanufacturing methods based on block copolymer self-assembly. PMID- 17691852 TI - A biological porin engineered into a molecular, nanofluidic diode. AB - We changed the nonrectifying biological porin OmpF into a nanofluidic diode. To that end, we engineered a pore that possesses two spatially separated selectivity filters of opposite charge where either cations or anions accumulate. The observed current inhibition under applied reverse bias voltage reflects, we believe, the creation of a zone depleted of charge carriers, in a sense very similar to what happens at the np junction of a semiconductor device. PMID- 17691853 TI - Strong extinction of a far-field laser beam by a single quantum dot. AB - Through the utilization of index-matched GaAs immersion lens techniques, we demonstrate a record extinction (12%) of a far-field focused laser beam by a single InAs/GaAs quantum dot. This contrast level enables us to report for the first time resonant laser transmission spectroscopy on a single InAs/GaAs quantum dot without the need for phase-sensitive lock-in detection. PMID- 17691854 TI - Biomimetic glycoliposomes as nanocarriers for targeting P-selectin on activated platelets. AB - The cell glycocalyx is an attractive model for surface modification of liposomes with the objectives of tissue targeting and prolonged circulation time. Here, we reported on glycocalyx-mimicking liposomes, prepared by incorporating a glycolipid of 3'-sulfo-Lewis a (SuLe(a))-PEG-DSPE with a headgroup of SuLe(a) and a spacer of poly(ethylene glycol) (PEG) linked to two hydrophobic tails. This PEG spaced structure is used to mimic the extended structure of P-selectin glycoprotein ligand 1 (PSGL-1) on activated leukocytes, in order to facilitate the specific binding of liposomes to the receptor of P-selectin expressed on activated platelets. Our results indicate that SuLe(a)-PEG-DSPE can form stable, narrowly distributed liposomes with 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol, with a vesicle size of 113.3 nm. The resultant SuLe(a) PEG-liposomes can facilitate their binding to the receptor of P-selectin 22 times higher than SuLe(a)-liposomes without a PEG spacer. Further studies by fluorescence microscopy show that SuLe(a)-PEG-liposomes can bind to activated platelets in vitro effectively. It suggests that biomimetic SuLe(a)-PEG-liposomes may be used as nanocarriers to target activated platelets for drug delivery to the injury sites of cardiovascular diseases. PMID- 17691855 TI - Molecular characterization of specifically active recombinant fused enzymes consisting of CYP3A4, NADPH-cytochrome P450 oxidoreductase, and cytochrome b5. AB - Microsomal cytochrome P450 3A4 (CYP3A4) catalyzes monooxygenase reactions toward a diverse group of exogenous and endogenous substrates and requires cytochrome b5 (b5) in the oxidation of the typical substrate testosterone. To analyze the molecular interaction among CYP3A4, NADPH-cytochrome P450 oxidoreductase (P450 reductase), and b5, we constructed several fused enzyme genes and expressed them in Saccharomyces cerevisiae. The recombinant fused enzymes CYP3A4-truncated (t) P450 reductase-t-b5 (3RB) and CYP3A4-t-b5-t-P450 reductase (3BR) in yeast microsomes showed a higher specific activity in 6beta-hydroxylation of testosterone than did the reconstitution premixes of CYP3A4, P450 reductase, and b5. The purified fused enzymes exhibited lower Km values and substantially increased Vmax values in 6beta-hydroxylation of testosterone and oxidation of nifedipine. Moreover, the fused enzymes showed significantly higher activities in cytochrome c reduction than the reconstitution premixes. Although the affinity of 3RB toward cytochrome c was twice as high as that of 3BR, 3BR and 3RB showed nearly the same affinity toward NADPH/NADH. In addition, the heme of the CYP3A4 moiety of 3RB was reduced preferentially and more rapidly than that of 3BR, whereas the heme of the b5 moiety of 3BR was selectively reduced compared with that of 3RB. These results suggest that the conformation of the 3RB molecule was the most suitable for high activity because of appropriate ordering of the CYP3A4, P450 reductase, and b5 moieties for efficient electron flow. Thus, we believe that the b5 moiety plays an important role in the efficient transfer of the second electron in the vicinity of the CYP3A4 moiety. PMID- 17691856 TI - Midwives' competence: is it affected by working in a rural location? AB - INTRODUCTION: Rising health care costs and the need to consolidate expertise in tertiary services have led to the centralisation of services. In the UK, the result has been that many rural maternity units have become midwife-led. A key consideration is that midwives have the skills to competently and confidently provide maternity services in rural areas, which may be geographically isolated and where the midwife may only see a small number of pregnant women each year. Our objective was to compare the views of midwives in rural and urban settings, regarding their competence and confidence with respect to 'competencies' identified as being those which all professionals should have in order to provide effective and safe care for low-risk women. METHOD: This was a comparative questionnaire survey involving a stratified sample of remote and rural maternity units and an ad hoc comparison group of three urban maternity units in Scotland. Questionnaires were sent to 82 midwives working in remote and rural areas and 107 midwives working in urban hospitals with midwife-led units. RESULTS: The response rate from midwives in rural settings was considerably higher (85%) than from midwives in the urban areas (60%). Although the proportion of midwives who reported that they were competent was broadly similar in the two groups, there were some significant differences regarding specific competencies. Midwives in the rural group were more likely to report competence for breech delivery (p = 0.001), while more urban midwives reported competence in skills such as intravenous fluid replacement (p <0.001) and initial and discharge examination of the newborn (p <0.001). Both groups reported facing barriers to continuing professional development; however, more of the rural group had attended an educational event within the last month (p <0.001). Lack of time was a greater barrier for urban midwives (p = 0.02), whereas distance to training was greater for rural midwives (p = 0.009). Lack of motivation or interest was significantly higher in urban units (p = 0.006). CONCLUSION: It is often assumed that midwives in rural areas where there are fewer deliveries, will be less competent and confident in their practice. Our exploratory study suggests that the issue of competence is far more complex and deserves further attention. PMID- 17691857 TI - Core drivers of quality: a remote health example from Australia. AB - CONTEXT: In July 2005 the National Rural Health Alliance released a discussion paper on advanced nursing practice in rural and remote areas of Australia. The paper called for more debate and research about advanced nursing practice roles, especially on how the roles contribute to quality care and patient health outcomes. Monash University School of Rural Health, Victoria, Australia, completed two studies exploring the role and practice of remote area nurses working autonomously in bush nursing centres in East Gippsland, Victoria. The studies confirmed the nursing role as advanced and expanded, and the care effective and of high quality. The studies also revealed the contribution of the remote area nurse to quality care involved more than demonstrating effective healthcare delivery and evidence based clinical practice. The significance of context emerged as an important determinant. ISSUE: Articulating measures for quality care in Australian remote health practice is problematic. The concept 'quality' is multidimensional and time and context specific. Current Australian health service and professional competency standards fail to combine external structural and organisational factors, and the social and economic situation of a given remote community. Together, these factors create the context, and influence practice and remote health service delivery. It is accepted that context shapes remote nursing practice, however the term 'context' is commonly interpreted as an environmental, structural or geographical construct. These terms are valid; however, they do not describe other drivers that impact on remote area nursing and service delivery. In practice, therefore, to what extent does context influence the contribution of remote nursing roles to quality care? LESSONS LEARNED: Four core drivers that model the remote area nursing context were identified: the system, the organisation, the community and the individual. An integrated conceptual model consisting of the core drivers is presented, and this provides a broad framework to illustrate factors influencing the delivery of quality remote health care, in an attempt to crystallise the role of context. Central to the model is the remote area nurse. This article outlines the core drivers and discusses how these drivers impact on remote area nursing practice in Victoria and the provision of quality care. The model is transferable to other remote nursing contexts and provides an alternative approach to evaluate the contribution of a remote area nursing role. Enhancing our understanding of the influence of context may assist in identifying relevant indicators to measure the quality of remote health care delivered by nurses in advanced practice roles. PMID- 17691858 TI - Efficient and rapid osteoinduction in an immune-competent host. AB - Osteoinductive systems to induce targeted rapid bone formation hold clinical promise, but development of technologies for clinical use that must be tested in animal models is often a difficult challenge. We previously demonstrated that implantation of human cells transduced with Ad5F35BMP2 to express high levels of bone morphogenetic protein-2 (BMP2) resulted in rapid bone formation at targeted sites. Inclusion of human cells in this model precluded us from testing this system in an immune-competent animal model, thus limiting information about the efficacy of this approach. Here, for the first time we demonstrate the similarity between BMP2-induced endochondral bone formation in a system using human cells in an immune-incompetent mouse and a murine cell-based BMP2 gene therapy system in immune-competent animals. In both cases the delivery cells are rapidly cleared, within 5 days, and in neither case do they appear to contribute to any of the structures forming in the tissues. Endochondral bone formation progressed through a highly ordered series of stages that were both morphologically and temporally indistinguishable between the two models. Even longterm analysis of the heterotopic bone demonstrated similar bone volumes and the eventual remodeling to form similar structures. The results suggest that the ability of BMP2 to rapidly induce bone formation overrides contributions from either immune status or the nature of delivery cells. PMID- 17691859 TI - Objective assessment of the fusion frequency in functional electrical stimulation using the fast Fourier transform. AB - In functional electrical stimulation (FES) the dynamics of tetanic muscle contractions is often described by the fusion frequency (FF), as determined by palpation: contractions elicited by stimulation frequencies above the FF appear smooth. To contribute to a more objective assessment of this important FES parameter, we have developed a dedicated signal analysis method based on fast Fourier transformation (FFT). The ripple to peak ratio (R(rpFFT)) - the relation between ripple amplitude and peak force value of a recorded tetanic muscle force in relation to the applied stimulation frequency - was determined automatically by analysing a 0.2-s interval in the steady state of a stimulation burst. The method was tested on simulated data and on force recordings from isolated tibialis anterior muscles of six rabbits. The results were compared to manual estimates. The robustness of the method was tested by adding noise and hum. Simulated noise at 100% of the ripple force increased R(rpFFT) by 4%. Hum at 20 Hz away from the stimulation frequency caused changes of less than 0.5%. The results of the automated analysis of recorded signals matched the manual estimates sufficiently well, especially for stimulation frequencies near or above FF. R(rpFFT) therefore seems suitable for automated, objective and robust assessment of the ripple and the FF of electrically stimulated muscle. PMID- 17691860 TI - Ultrasonographic contrast-agent imaging of sub-millimeter vessel structures with spatial compounding: in vitro analyses. AB - In clinical diagnostics, ultrasonographic contrast-agent imaging gives access to medical parameters such as perfusion and vascularization. In addition to the artifacts that are typical for ultrasonic imaging, e.g., speckle noise and depth dependent sensitivity and resolution, contrast-agent imaging shows more pronounced depth dependence and may suffer from shadowing artifacts that arise from high attenuation of the ultrasound waves by the contrast agent at high concentrations. By imaging an object from different viewing angles in one 2D image plane and summing the images obtained (spatial compounding), image quality can be increased and artifacts can be suppressed. In the present study, we combined both techniques to overcome the limitations of contrast-agent imaging. We used a commercially available ultrasound scanner and a custom-made high precision mechanical system to rotate the ultrasound transducer fully around the object under investigation. Using this set-up, ultrasound data were acquired in reflection mode to generate a 360 degrees compound scan of a flow-mimicking phantom supplied with contrast agent. PMID- 17691861 TI - Modular optical topometric sensor for 3D acquisition of human body surfaces and long-term monitoring of variations. AB - Optical topometric 3D sensors such as laser scanners and fringe projection systems allow detailed digital acquisition of human body surfaces. For many medical applications, however, not only the current shape is important, but also its changes, e.g., in the course of surgical treatment. In such cases, time delays of several months between subsequent measurements frequently occur. A modular 3D coordinate measuring system based on the fringe projection technique is presented that allows 3D coordinate acquisition including calibrated color information, as well as the detection and visualization of deviations between subsequent measurements. In addition, parameters describing the symmetry of body structures are determined. The quantitative results of the analysis may be used as a basis for objective documentation of surgical therapy. The system is designed in a modular way, and thus, depending on the object of investigation, two or three cameras with different capabilities in terms of resolution and color reproduction can be utilized to optimize the set-up. PMID- 17691862 TI - Does a specific MR imaging protocol with a supine-lying subject replicate tarsal kinematics seen during upright standing? AB - Magnetic resonance (MR) imaging is becoming increasingly important in the study of foot biomechanics. Specific devices have been constructed to load and position the foot while the subject is lying supine in the scanner. The present study examines the efficacy of such a newly developed device in replicating tarsal kinematics seen during the more commonly studied standing loading conditions. The results showed that although knee flexion and the externally applied load were carefully controlled, subtalar and talo-navicular joint rotations while lying during MR imaging and when standing (measured opto-electrically with markers attached to intracortical pins) did not match, nor were they systematically shifted. Thus, the proposed MR protocol cannot replicate tarsal kinematics seen during upright standing. It is concluded that specific foot loading conditions have to be considered when tarsal kinematics are evaluated. Improved replication of tarsal kinematics in different postures should comprehensively consider muscle activity, a fixed hip position, and a well-defined point of load application. PMID- 17691863 TI - Measures for reducing ultra-high-molecular-weight polyethylene wear in total knee replacement: a simulator study. AB - Wear of ultra-high-molecular-weight polyethylene (UHM-WPE) inlays is associated with aseptic loosening in total knee replacement (TKR). The aim of this study was to investigate the in vitro performance of a TKR system that combines several measures to decrease UHMWPE wear. Tests were carried out on a BPK-S Integration system (R&D, P. Brehm Chirurgie-Mechanik, Weisendorf, Germany) according to ISO 14,243-1 in a knee joint simulator. Calf serum with a high protein concentration of 30 g/l was chosen as the test lubricant. PE wear was measured gravimetrically. Particle analysis was performed by scanning electron microscopy, with measurement of particle size and shape. Low mean wear rates of 1.20 mg per million cycles were found for the fixed bearing type and 2.47 mg per million cycles for the rotating-platform bearing design. Anteroposterior deflection was low. The contact areas for both types of bearings were large and showed a constant pattern throughout the test. Backside wear was obvious on rotating platforms. Particle analysis revealed equally sized and round-shaped particles in both types of bearings (fixed, 0.35 microm; mobile, 0.32 microm). In conclusion, the combination of design features and surface modifications of the BPK-S integration TKR system leads to low gravimetric UHMWPE wear. PMID- 17691864 TI - [Finite element analysis of a cemented ceramic femoral component for the assembly situation in total knee arthroplasty]. AB - The femoral components of the total knee replacements are generally made of metal. In contrast, ceramic femoral components promise improved tribological and allergological properties. However, ceramic components present a risk of failure as a result of stress peaks. Stress peaks can be minimised through adequate implant design, proper material composition and optimum force transmission between bone and implant. Thus, the quality of the implant fixation is a crucial factor. The objective of the present study was to analyse the influence of the cement layer thickness on stress states in the ceramic femoral component and in the femur. Two- and three- dimensional finite element analyses of an artificial knee joint with cement layers of different thickness and with an unbalanced cement layer thickness between the ceramic femoral component and the femur were performed. Higher stress regions occurred in the area of force transmission and in the median plane. The maximum calculated stresses were below the accepted tensile strength. Stresses were found to be lower for cement layer thickness of <2.0 mm. PMID- 17691865 TI - [Elbow dysplasia in the dog: finite element analysis]. AB - For young active dogs of large, fast-growing breeds, diseases of the elbow represent an increasing important disorder. Genetic predisposition, overweight and joint overload have been proposed as possible causes of elbow dysplasia. In this study, the influence of various biomechanical parameters on load transfer in healthy and pathological dog elbows has been analysed by means of a two dimensional finite element model. Pathological changes in the elbow structure, such as altered material properties or asynchronous bone growth, have a distinct influence on the contact pressure in the joint articulation, internal bone deformation and stresses in the bones. The results obtained support empirical observations made during years of experience and offer explanations for clinical findings that are not yet well understood. PMID- 17691866 TI - Association between a cell-seeded collagen matrix and cellular cardiomyoplasty for myocardial support and regeneration. AB - The objective of cellular cardiomyoplasty is to regenerate the myocardium using implantation of living cells. Because the extracellular myocardial matrix is deeply altered in ischemic cardiomyopathies, it could be important to create a procedure aiming at regenerating both myocardial cells and the extracellular matrix. We evaluated the potential of a collagen matrix seeded with cells and grafted onto infarcted ventricles. A myocardial infarction was created in 45 mice using coronary artery ligation. Animals were randomly assigned to 4 local myocardial treatment groups. Group I underwent sham treatment (injection of cell culture medium). Group II underwent injection of human umbilical cord blood mononuclear cells (HUCBCs). Group III underwent injection of HUCBCs and fixation onto the epicardium of a collagen matrix seeded with HUCBCs. Group IV underwent fixation of collagen matrix (without cells) onto the infarct. Echocardiography was performed on postoperative days 7 and 45, followed by histological studies. Echocardiography showed that the association between the cell-loaded matrix and the intrainfarct cell implants was the most efficient approach to limiting postischemic ventricular dilation and remodeling. Ejection fraction improved in both cell-treated groups. The collagen matrix alone did not improve left ventricular (LV) function and remodeling. Histology in Group III showed fragments of the collagen matrix thickening and protecting the infarct scars. Segments of the matrix were consistently aligned along the LV wall, and cells were assembled within the collagen fibers in large populations. Intramyocardial injection of HUCBCs preserves LV function following infarction. The use of a cell-seeded matrix combined with cell injections prevents ventricular wall thinning and limits postischemic remodeling. This tissue engineering approach seems to improve the efficiency of cellular cardiomyoplasty and could emerge as a new therapeutic tool for the prevention of adverse remodeling and progressive heart failure. PMID- 17691867 TI - Differences in the expression of cathepsin B in B16 melanoma metastatic variants depend on transcription factor Sp1. AB - Cathepsin B contributes to the invasiveness of B16 melanoma cells in mice, with the highly metastatic B16a melanoma producing six- to eightfold more cathepsin B mRNA and protein than the less metastatic B16F1 variant. The proximal promoter region of the cathepsin B (Ctsb) gene (-149 to +94) was previously found to be capable of reproducing this pattern of differential gene activation in B16 melanoma variants. The binding of B16 melanoma nuclear proteins to this promoter region has now been mapped to three GC-boxes (Sp1 transcription factor binding sites) and a potential X-box [tax response element (TRE)/c-AMP responsive element (CRE) site]. Mutation of the GC-boxes at -55 and -37 independently decreased the expression of a luciferase reporter gene in B16a cells to the level observed in B16F1 cells. Promoter activity was also attenuated by mutations within the GC rich segment between +6 and +16, but not by mutation of the putative X-box. Both Sp1 and Sp3 bound the GC-boxes in the Ctsb promoter, and western blotting showed the level of Sp1 to be greater in B16a compared to B16F1 cells. B16F1 cells that were made to express Sp1 at levels observed in B16a cells produced corresponding increased amounts of endogenous cathepsin B mRNA and enzyme activity. Thus, the difference in cathepsin B expression between high and low metastatic B16 melanoma variants is largely due to different levels of Sp1. PMID- 17691868 TI - Chondrogenic differentiation of human articular chondrocytes differs in biodegradable PGA/PLA scaffolds. AB - Cartilage tissue engineering is applied clinically to cover and regenerate articular cartilage defects. Two bioresorbable nonwoven scaffolds, polyglycolic acid (PGA) and poly(lactic-co-glycolic acid) (PLGA) (90/10 copolymer of L-lactide and glycolide), were seeded with human chondrocytes after initial progeny in a monolayer with a serum-free medium. Two subgroups of nontreated and plasma treated (using low-pressure plasma technique) scaffolds were investigated. The constructs were cultivated after seeding in six-well plates with serum-free medium for 7 days and implanted subcutaneously into nude mice for 6 and 12 weeks. Chondrogenic differentiations were investigated using immunhistology and reverse transcriptase-polymerase chain reaction. Cell adhesion only differed from 50% to 65% without a significant difference between the groups. During further cultivation for 7 days, the aggrecan synthesis of the seeded constructs was always higher in the PGA groups (p < 0.05). The mRNA gene expression for collagen type II was significantly higher in the PGA groups after 6 and 12 weeks (p < 0.05). A decrease in the expression of collagen type I was investigated in all groups. The expression for collagen type X and cartilage oligomeric matrix protein (COMP) increased in all groups over time. After cell proliferation in serum-free medium, the long-term chondrogenic differentiation in PGA scaffolds in vitro is cartilage specific and may be utilized in cartilage tissue engineering applications. PMID- 17691869 TI - Religious fatalism and its association with health behaviors and outcomes. AB - OBJECTIVE: To examine the association between religious fatalism and health care utilization, health behaviors, and chronic illness. METHODS: As part of Nashville's REACH 2010 project, residents (n=1273) participated in a random telephone survey that included health variables and the helpless inevitability subscale of the Religious Health Fatalism Questionnaire. RESULTS: Religious health fatalism was higher among African Americans and older participants. Some hypotheses about the association between fatalism and health outcomes were confirmed. CONCLUSION: Religious fatalism is only partially predictive of health behaviors and outcomes and may be a response to chronic illness rather than a contributor to unhealthy behaviors. PMID- 17691870 TI - Infant sleep position: discerning knowledge from practice. AB - OBJECTIVE: To determine decision-making factors for infant sleep position among low-income parents and other relatives. METHODS: Data were collected from 18 focus groups conducted with low-income parents and relatives of infants across the state of Missouri. RESULTS: That the decision-making process regarding infant sleep practices was complex. CONCLUSION: Although most participants are familiar with the "Back to Sleep" campaign, there was a lack of understanding over why nonprone sleep is necessary, and the change in this message over time added to the parents' uncertainty. PMID- 17691871 TI - Changes in smoking behavior between first and second pregnancies. AB - OBJECTIVE: To assess changes in maternal smoking behavior at the second pregnancy. METHODS: First and second birth certificates were matched for 5241 white and black mothers in Kansas City, Mo, who had singleton births between 1994 and 2003. RESULTS: The pregnancy-smoking quit rate was 24.9%, and the pregnancy smoking initiation rate was 4.8%. CONCLUSION: Twenty-five percent of women who smoked and 5% of women who did not smoke during their first pregnancy changed their behavior during their second pregnancy. These findings reflect a minimal net shift in pregnancy-smoking between pregnancies and support the importance of persistent antismoking socialization that is independent of a pregnant woman's previous pregnancy-smoking status. PMID- 17691872 TI - Discriminators of Complementary and Alternative Medicine provider use among men with HIV/AIDS. AB - OBJECTIVE: To examine comprehensively the potential correlates of Complementary and Alternative Medicine (CAM) practitioner use among men with HIV/AIDS. METHODS: Men (n=122) recruited from HIV/AIDS service organizations completed extensive written surveys. Questions comprised several domains that have been thought or demonstrated to influence individuals to use CAM, and also addressed respondents' social networks. RESULTS: Discriminant analyses revealed 2 social network variables and 2 attitudinal variables proved statistically significant when controlling for relationships among variables. CONCLUSION: The significant contribution of social influence/social networks in choosing CAM modalities demonstrated has not heretofore been examined in CAM user studies; implications for future research are discussed. PMID- 17691873 TI - Assessing medical expenditures on 4 smoking-related diseases, 1996-2001. AB - OBJECTIVE: To examine the current-period cost of treating 4 major smoking-related diseases: lung cancer, chronic obstructive pulmonary disease, ischemic heart disease, and cerebrovascular disease. METHODS: Analyses are based on the MarketScan database, a medical claims database from large employers. RESULTS: We found that total expenditures to treat ischemic heart disease were highest, followed by those to treat chronic obstructive pulmonary disease (COPD). When median expenditures per claim and disease severity were considered, lung cancer was the most expensive condition to treat and ischemic heart disease the least expensive. Median treatment expenditures increased as the severity of disease increased. CONCLUSION: Treating smoking-related diseases is costly in the current period and over a lifetime. PMID- 17691874 TI - Developing a questionnaire to measure perceived attributes of eHealth innovations. AB - OBJECTIVE: To design a valid and reliable questionnaire to assess perceived attributes of technology-based health education innovations. METHODS: College students in 12 personal health courses reviewed a prototype eHealth intervention using a 30-item instrument based upon diffusion theory's perceived attributes of an innovation. RESULTS: Principal components analysis found 5 factors accounted for 44.4% of the variance: 29.0% (relative advantage), 9.6% (simplicity), 6.5% (trialability), 5.0% (observability), and 4.4% (translatability). Internal consistency reliability ranged from .66 to .91 for the 5 factors. CONCLUSION: The instrument can help eHealth developers determine and improve the adoption potential of their applications throughout the development cycle. PMID- 17691875 TI - Promoting physical activity for low-income minority women in primary care. AB - OBJECTIVE: To examine the effects of a primary-care weight management intervention on physical activity (PA) among overweight/obese women. METHODS: This randomized controlled trial included 139 women (92% African American). The effects of a physician-delivered tailored intervention were compared with standard care. Repeated measures analyses of variance (ANOVA) were used to examine changes in PA (measured by a 7-day physical activity recall) and physical fitness (measured by heart rate recovery following exercise). RESULTS: Although the intervention group demonstrated an increase in PA, this did not differ significantly from standard care. A significantly greater proportion of intervention participants (90%) achieved current PA recommendations compared with standard care (77%), P<.03. CONCLUSION: These results provide novel information suggesting that a physician-delivered intervention may have limited effectiveness for increasing PA among this at-risk population. PMID- 17691876 TI - The Diabetes Detection Initiative: a pilot program of selective screening. AB - OBJECTIVE: To identify adults who might have undiagnosed type 2 diabetes. METHODS: Using social marketing methods, we identified the characteristics and preferences of the pilot communities. Risk assessment tests were developed to reflect these preferences. Clinics with registries provided quantitative evaluation data and all clinics shared qualitative data. RESULTS: Baseline and intervention period data showed that the number of newly detected cases of diabetes increased by 11.5 per month for the 8 registry clinics. CONCLUSION: Findings have advanced our understanding of screening by identifying ways of improving the identification of undiagnosed diabetes. PMID- 17691877 TI - Intrinsic and extrinsic motivations for healthful dietary change in African Americans. AB - OBJECTIVE: To describe associations of intrinsic and extrinsic motivations for dietary change with participant characteristics and current diet among African Americans. METHODS: Cross-sectional survey of 658 African American adults in North Carolina provided information on intrinsic (self-image and health concerns) and extrinsic (social influence) motivation scales, participant characteristics, and diet. RESULTS: Most respondents considered it important to change their diet for health reasons; fewer were motivated by self-image or social influence. Motivation scales were significantly associated with demographic, behavioral, and psychosocial characteristics and fat, but not fruit/vegetable consumption, after adjustment for covariates (P<0.05). CONCLUSION: Tailoring on intrinsic and extrinsic motives may improve the effectiveness of dietary interventions in African Americans. PMID- 17691881 TI - Social influences on adolescent substance use. AB - OBJECTIVES: To assess the overtime relationships between adolescent and peer substance use and parenting practices. METHODS: Five times from sixth to ninth grade, students (n=2453) in 7 middle schools reported smoking, drinking, and marijuana use; the number of substance-using friends; and parent practices. Relationships were assessed using latent growth curve modeling. RESULTS: Adolescent substance use predicted the growth in substance-using friends, and substance-using friends predicted adolescent use, except for smoking. The negative over-time relationship between parenting practices and adolescent substance use was mediated by the growth in the number of substance-using friends. CONCLUSIONS: The results are consistent with both selection and socialization effects and provide evidence of the protective effects of positive parenting practices. PMID- 17691878 TI - Low-income rural women and depression: factors associated with self-reporting. AB - OBJECTIVE: To examine factors associated with self-reporting depression for low income rural women experiencing depressive symptoms. METHODS: Data were from 219 Rural Families Speak participants with CES-D scores >15. Chi-square and multiple logistic regression were utilized. RESULTS: Just over one half (52.5%) of respondents who were experiencing depressive symptoms self-reported depression, whereas 47.5% of respondents self-reported no depression. Women reporting depression were significantly likelier to report physical health problems, injury/illness, and more frequent physician visits. Women reporting no depression were significantly likelier to have been pregnant in the previous 3 years. CONCLUSIONS: Women reporting depression had more health care system exposure and perhaps depressive symptomotology knowledge. Public health campaigns should educate about depressive symptoms, including postpartum depression, to reduce stigma and increase treatment-seeking. PMID- 17691882 TI - Presentation of the second annual Judy K. Black Early Career Research Award. PMID- 17691883 TI - Body mass index and percentage body fat as health indicators for young adults. AB - OBJECTIVES: To investigate the validity of an axiom that body mass index (BMI) and percentage body fat (%BF), above an ideal, are health risk factors. METHODS: Participants were 2615 volunteers who participated in a health-screening program conducted in college residence halls over a consecutive 8-year period. RESULTS: Nearly half of all participants were misclassified when BMI and/or %BF were used to define better versus poorer health whether analyzing all variables together, by individual factor, or by type of variable. CONCLUSIONS: Results of this study indicate that BMI and %BF are poor indicators of health status among young adults. PMID- 17691886 TI - Hollywood quits--behind the scenes of a Hollywood-based smoking cessation program. AB - OBJECTIVES: To develop, implement, and assess the efficacy of a comprehensive, evidence-based smoking cessation program for entertainment industry workers and their families. METHODS: Study participants were recruited from 5 outpatient medical clinics and a worksite setting. Tobacco use data were collected during the initial counseling visit and at 6-month follow-up. Univariate and multivariate regressions were used in analysis. RESULTS: More than 50% of participants (n=470) self-reported 7-day abstinence at follow-up. The majority of participants used combination cessation medications, with more than 50% still using at least 1 medication at 6 months. CONCLUSIONS: This evidence-based smoking cessation program using behavioral counseling and combination pharmacotherapy was successful with entertainment industry workers. PMID- 17691887 TI - Microarrays for rapid identification of plant viruses. AB - Many factors affect the development and application of diagnostic techniques. Plant viruses are an inherently diverse group that, unlike cellular pathogens, possess no nucleotide sequence type (e.g., ribosomal RNA sequences) in common. Detection of plant viruses is becoming more challenging as globalization of trade, particularly in ornamentals, and the potential effects of climate change enhance the movement of viruses and their vectors, transforming the diagnostic landscape. Techniques for assessing seed, other propagation materials and field samples for the presence of specific viruses include biological indexing, electron microscopy, antibody-based detection, including enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), and microarray detection. Of these, microarray detection provides the greatest capability for parallel yet specific testing, and can be used to detect individual, or combinations of viruses and, using current approaches, to do so with a sensitivity comparable to ELISA. Methods based on PCR provide the greatest sensitivity among the listed techniques but are limited in parallel detection capability even in "multiplexed" applications. Various aspects of microarray technology, including probe development, array fabrication, assay target preparation, hybridization, washing, scanning, and interpretation are presented and discussed, for both current and developing technology. PMID- 17691889 TI - Efficient enumeration of phylogenetically informative substrings. AB - We study the problem of enumerating substrings that are common amongst genomes that share evolutionary descent. For example, one might want to enumerate all identical (therefore conserved) substrings that are shared between all mammals and not found in non-mammals. Such collection of substrings may be used to identify conserved subsequences or to construct sets of identifying substrings for branches of a phylogenetic tree. For two disjoint sets of genomes on a phylogenetic tree, a substring is called a tag if it is found in all of the genomes of one set and none of the genomes of the other set. We present a near linear time algorithm that finds all tags in a given phylogeny; and a sublinear space algorithm (at the expense of running time) that is more suited for very large data sets. Under a stochastic model of evolution, we show that a simple process of tag-generation essentially captures all possible ways of generating tags. We use this insight to develop a faster tag discovery algorithm with a small chance of error. However, since tags are not guaranteed to exist in a given data set, we generalize the notion of a tag from a single substring to a set of substrings. We present a linear programming-based approach for finding approximate generalized tag sets. Finally, we use our tag enumeration algorithm to analyze a phylogeny containing 57 whole microbial genomes. We find tags for all nodes in the phylogeny except the root for which we find generalized tag sets. PMID- 17691890 TI - Efficiently computing the Robinson-Foulds metric. AB - The Robinson-Foulds (RF) metric is the measure most widely used in comparing phylogenetic trees; it can be computed in linear time using Day's algorithm. When faced with the need to compare large numbers of large trees, however, even linear time becomes prohibitive. We present a randomized approximation scheme that provides, in sublinear time and with high probability, a (1 + epsilon) approximation of the true RF metric. Our approach is to use a sublinear-space embedding of the trees, combined with an application of the Johnson-Lindenstrauss lemma to approximate vector norms very rapidly. We complement our algorithm by presenting an efficient embedding procedure, thereby resolving an open issue from the preliminary version of this paper. We have also improved the performance of Day's (exact) algorithm in practice by using techniques discovered while implementing our approximation scheme. Indeed, we give a unified framework for edge-based tree algorithms in which implementation tradeoffs are clear. Finally, we present detailed experimental results illustrating the precision and running time tradeoffs as well as demonstrating the speed of our approach. Our new implementation, FastRF, is available as an open-source tool for phylogenetic analysis. PMID- 17691891 TI - Leveraging information across HLA alleles/supertypes improves epitope prediction. AB - We present a model for predicting HLA class I restricted CTL epitopes. In contrast to almost all other work in this area, we train a single model on epitopes from all HLA alleles and supertypes, yet retain the ability to make epitope predictions for specific HLA alleles. We are therefore able to leverage data across all HLA alleles and/or their supertypes, automatically learning what information should be shared and also how to combine allele-specific, supertype specific, and global information in a principled way. We show that this leveraging can improve prediction of epitopes having HLA alleles with known supertypes, and dramatically increases our ability to predict epitopes having alleles which do not fall into any of the known supertypes. Our model, which is based on logistic regression, is simple to implement and understand, is solved by finding a single global maximum, and is more accurate (to our knowledge) than any other model. PMID- 17691892 TI - Assessing significance of connectivity and conservation in protein interaction networks. AB - Comparative analyses of cellular interaction networks enable understanding of the cell's modular organization through identification of functional modules and complexes. These techniques often rely on topological features such as connectedness and density, based on the premise that functionally related proteins are likely to interact densely and that these interactions follow similar evolutionary trajectories. Significant recent work has focused on efficient algorithms for identification of such functional modules and their conservation. In spite of algorithmic advances, development of a comprehensive infrastructure for interaction databases is in relative infancy compared to corresponding sequence analysis tools. One critical, and as yet unresolved aspect of this infrastructure is a measure of the statistical significance of a match, or a dense subcomponent. In the absence of analytical measures, conventional methods rely on computationally expensive simulations based on ad-hoc models for quantifying significance. In this paper, we present techniques for analytically quantifying statistical significance of dense components in reference model graphs. We consider two reference models--a G(n, p) model in which each pair of nodes in a graph has an identical likelihood, p, of sharing an edge, and a two level G(n, p) model, which accounts for high-degree hub nodes generally observed in interaction networks. Experiments performed on a rich collection of protein interaction (PPI) networks show that the proposed model provides a reliable means of evaluating statistical significance of dense patterns in these networks. We also adapt existing state-of-the-art network clustering algorithms by using our statistical significance measure as an optimization criterion. Comparison of the resulting module identification algorithm, SIDES, with existing methods shows that SIDES outperforms existing algorithms in terms of sensitivity and specificity of identified clusters with respect to available GO annotations. PMID- 17691893 TI - Markov methods for hierarchical coarse-graining of large protein dynamics. AB - Elastic network models (ENMs) and, in particular, the Gaussian Network Model (GNM) have been widely used in recent years to gain insights into the machinery of proteins. The extension of ENMs to supramolecular assemblies presents computational challenges, because of the difficulty in retaining atomic details in mode decomposition of large protein dynamics. Here, we present a novel approach to address this problem. We rely on the premise that, all the residues of the protein machinery (network) must communicate with each other and operate in a coordinated manner to perform their function successfully. To gain insight into the mechanism of information transfer between residues, we study a Markov model of network communication. Using the Markov chain perspective, we map the full-atom network representation into a hierarchy of ENMs of decreasing resolution, perform analysis of dominant communication (or dynamic) patterns in reduced space(s) and reconstruct the detailed models with minimal loss of information. The communication properties at different levels of the hierarchy are intrinsically defined by the network topology. This new representation has several features, including: soft clustering of the protein structure into stochastically coherent regions thus providing a useful assessment of elements serving as hubs and/or transmitters in propagating information/interaction; automatic computation of the contact matrices for ENMs at each level of the hierarchy to facilitate computation of both Gaussian and anisotropic fluctuation dynamics. We illustrate the utility of the hierarchical decomposition in providing an insightful description of the supramolecular machinery by applying the methodology to the chaperonin GroEL-GroES. PMID- 17691894 TI - Hypergraph model of multi-residue interactions in proteins: sequentially constrained partitioning algorithms for optimization of site-directed protein recombination. AB - Relationships among amino acids determine stability and function and are also constrained by evolutionary history. We develop a probabilistic hypergraph model of residue relationships that generalizes traditional pairwise contact potentials to account for the statistics of multi-residue interactions. Using this model, we detected non-random associations in protein families and in the protein database. We also use this model in optimizing site-directed recombination experiments to preserve significant interactions and thereby increase the frequency of generating useful recombinants. We formulate the optimization as a sequentially constrained hypergraph partitioning problem; the quality of recombinant libraries with respect to a set of breakpoints is characterized by the total perturbation to edge weights. We prove this problem to be NP-hard in general, but develop exact and heuristic polynomial-time algorithms for a number of important cases. Application to the beta-lactamase family demonstrates the utility of our algorithms in planning site-directed recombination. PMID- 17691895 TI - The MASH pipeline for protein function prediction and an algorithm for the geometric refinement of 3D motifs. AB - The development of new and effective drugs is strongly affected by the need to identify drug targets and to reduce side effects. Resolving these issues depends partially on a thorough understanding of the biological function of proteins. Unfortunately, the experimental determination of protein function is expensive and time consuming. To support and accelerate the determination of protein functions, algorithms for function prediction are designed to gather evidence indicating functional similarity with well studied proteins. One such approach is the MASH pipeline, described in the first half of this paper. MASH identifies matches of geometric and chemical similarity between motifs, representing known functional sites, and substructures of functionally uncharacterized proteins (targets). Observations from several research groups concur that statistically significant matches can indicate functionally related active sites. One major subproblem is the design of effective motifs, which have many matches to functionally related targets (sensitive motifs), and few matches to functionally unrelated targets (specific motifs). Current techniques select and combine structural, physical, and evolutionary properties to generate motifs that mirror functional characteristics in active sites. This approach ignores incidental similarities that may occur with functionally unrelated proteins. To address this problem, we have developed Geometric Sieving (GS), a parallel distributed algorithm that efficiently refines motifs, designed by existing methods, into optimized motifs with maximal geometric and chemical dissimilarity from all known protein structures. In exhaustive comparison of all possible motifs based on the active sites of 10 well-studied proteins, we observed that optimized motifs were among the most sensitive and specific. PMID- 17691896 TI - Biological networks: comparison, conservation, and evolution via relative description length. AB - We describe a new approach for comparing cellular-biological networks and finding conserved regions in two or more such networks. Our distance measure is based on the description length of one network, given the description of the other one, and it is efficiently computable. We employ these distances as inputs for generating phylogenetic trees. Using KEGG's metabolic networks as our starting point, we obtained trees that are not perfect, but are very good (considering the characteristics of the inputs). Our approach enables us to identify conserved regions among more than a dozen metabolic networks, and among two protein interaction networks. These conserved regions appear to be biologically relevant, proving the viability of our approach. PMID- 17691897 TI - Simulating protein motions with rigidity analysis. AB - Protein motions, ranging from molecular flexibility to large-scale conformational change, play an essential role in many biochemical processes. Despite the explosion in our knowledge of structural and functional data, our understanding of protein movement is still very limited. In previous work, we developed and validated a motion planning based method for mapping protein folding pathways from unstructured conformations to the native state. In this paper, we propose a novel method based on rigidity theory to sample conformation space more effectively, and we describe extensions of our framework to automate the process and to map transitions between specified conformations. Our results show that these additions both improve the accuracy of our maps and enable us to study a broader range of motions for larger proteins. For example, we show that rigidity based sampling results in maps that capture subtle folding differences between protein G and its mutants, NuG1 and NuG2, and we illustrate how our technique can be used to study large-scale conformational changes in calmodulin, a 148 residue signaling protein known to undergo conformational changes when binding to Ca(2+). Finally, we announce our web-based protein folding server which includes a publicly available archive of protein motions: (http://parasol.tamu.edu/foldingserver/). PMID- 17691899 TI - Molecular targets for nutritional preemption of cancer. AB - Malignant cells are characterized by alterations in multiple signaling pathways that promote proliferation, inhibit apoptosis, promote angiogenesis in the case of solid tumors, and enable cancer cells to invade and migrate through tissues. A variety of foods and their bioactive dietary constituents appear to have merit in reducing cancer risk and modifying tumor behavior. All of the major signaling pathways, which are deregulated in cancer, and which serve as potential targets for cancer prevention, have been reported to respond to one or more dietary components. Herein, we provide a brief overview of the importance of diet as a modifier of carcinogen metabolism, DNA repair, cell proliferation, apoptosis, inflammation, immunity, differentiation, angiogenesis, hormonal regulation and cellular energetics. This special issue of Current Cancer Drug Targets provides a collection of articles from researchers who are actively involved in examining the role of dietary components in cancer prevention and therapy. The remaining articles in this series provide more details about the specifics about the importance of these processes during carcinogenesis and proof-of-principal about the modifying capabilities of food patterns, specific foods and individual bioactive food components. PMID- 17691898 TI - A study of accessible motifs and RNA folding complexity. AB - mRNA molecules are folded in the cells and therefore many of their substrings may actually be inaccessible to protein and microRNA binding. The need to apply an accessibility criterion to the task of genome-wide mRNA motif discovery raises the challenge of overcoming the core O(n(3)) factor imposed by the time complexity of the currently best known algorithms for RNA secondary structure prediction. We speed up the dynamic programming algorithms that are standard for RNA folding prediction. Our new approach significantly reduces the computations without sacrificing the optimality of the results, yielding an expected time complexity of O(n(2) psi(n)), where psi(n) is shown to be constant on average under standard polymer folding models. A benchmark analysis confirms that in practice the runtime ratio between the previous approach and the new algorithm indeed grows linearly with increasing sequence size. The fast new RNA folding algorithm is utilized for genome-wide discovery of accessible cis-regulatory motifs in data sets of ribosomal densities and decay rates of S. cerevisiae genes and to the mining of exposed binding sites of tissue-specific microRNAs in A. thaliana. PMID- 17691900 TI - Targeting carcinogen metabolism by dietary cancer preventive compounds. AB - Prevention is one of the most important and promising strategies to control cancer. Many dietary bioactive compounds, mostly phytochemicals, have been found to decrease the risk of carcinogenesis. Modulating the metabolism and disposition pathways of carcinogens represents one of the major mechanisms by which dietary compounds prevent carcinogenesis. In the present review, the specific molecular targets of dietary compounds within carcinogen metabolism, including various enzymes and transporters and their regulatory signaling pathways, are briefly reviewed. The expression of phase I enzymes, which presumably mostly activate carcinogens, is mainly regulated by xenobiotics sensing nuclear receptors such as AhR, CAR, PXR, and RXR. On the other hand, phase II enzymes catalyze the conjugations of carcinogens and generally are transcriptionally controlled by the Nrf2/ARE signaling pathways. The Nrf2/ARE signaling pathway, which regulates the expression of many detoxifying enzymes, is a major target of dietary compounds. The final excretion of carcinogens and their metabolites is mediated by phase III transporters, which share many regulatory mechanisms with phase I/II enzymes. Indeed, the expression of metabolizing enzymes and transporters is often coordinately regulated. Besides transcriptional regulation, the activities of phase I/II enzymes and phase III transporters could be directly activated or inhibited by dietary compounds. Furthermore, genetic polymorphisms have profound effects on the individual response to dietary compounds. Finally, the effects of cancer prevention and the risk of carcinogenesis are determined by the network composed of known/unknown molecular targets and signaling pathways and its interaction with various xenobiotics, including carcinogens, drugs, and diet. With the rapid advances in the post genomic sciences, it could be possible to decipher this network and better predict the clinical outcomes of cancer prevention by dietary bioactive compounds. PMID- 17691901 TI - Nutrition and DNA repair--potential molecular mechanisms of action. AB - At its most fundamental, cancer is a genetic disease in the sense that the primary events in tumorigenesis involve damage to the genome. The genome is subject to damage continuously from both exogenous agents and endogenous processes but this becomes functionally important only if the damage is not detected and resolved in a timely and effective manner. In mammals there are 5 DNA repair pathways, encoded by approximately 150 genes, which appear to have arisen early in evolution and which are highly conserved. Given the substantial epidemiological and experimental evidence that variation in dietary intake accounts for a significant proportion of the variance in cancer prevalence, an a priori case can be made that dietary factors may influence the effectiveness of DNA repair. A review of the literature has identified 4 observational and 8 intervention studies in human subjects where DNA repair (or a component thereof) has been measured in relation to nutrition. This rather limited evidence base precludes drawing definitive conclusions, but the fact that there were significant effects of dietary supplements in 5 out of the 8 intervention studies suggests that food components and/or nutritional status may influence DNA repair. This review considers possible molecular mechanisms through which such factors could modulate repair. PMID- 17691902 TI - Nutrient regulation of tumor and vascular endothelial cell proliferation. AB - Specific bioactive dietary components, such as the steroid receptor superfamily ligands vitamins A and D, have been studied extensively as potential cancer preventive and therapeutic agents due to their ability to regulate key processes in a variety of cell types which are dysregulated in neoplastic transformation namely, proliferation and differentiation. Alteration of one or more factors that regulate cell cycle control has been described as a predisposing event for early tumor development. In addition to tumor cell proliferation, the viability, growth and metastasis of solid tumors are also dependent on the vascularization of the tumor and establishment of blood flow. Both vitamins A and D exhibit anti angiogenic properties which further strengthen their role as potential targets for the prevention and treatment of cancer. This review focuses on the role of vitamins A and D in preventing early tumor initiation and progression via control of the cell cycle in both tumor and vascular endothelial cells. PMID- 17691903 TI - Using nutrigenomics to evaluate apoptosis as a preemptive target in cancer prevention. AB - Apoptosis, a form of programmed cell death, is a pivotal defense against cancer and is essential in maintaining tissue homeostasis. Many diseases including cancer have been associated with aberrantly regulated apoptotic cell death, thus elucidation of events associated with both apoptosis and carcinogenesis provides the opportunity for dietary intervention with the plethora of bioactive components in the diet. Apoptosis occurs primarily through two well-recognized pathways in cells including the intrinsic, mitochondrial-mediated pathway and the extrinsic, death receptor-mediated pathway. Dietary components can modulate apoptosis through effects on protein expression and function, mRNA expression, and on the human genome, either directly or indirectly, to modulate gene expression. Thus, apoptosis is an emerging target of dietary bioactive agents. However, apoptosis is a complex process, with numerous specific targets within each pathway that may or may not overlap. Furthermore, biological systems are also extremely complex and exhibit properties that extend far beyond observations associated with each independent cellular process. This is further complicated by the temporal nature of many of these effects. As a result, it is critical to evaluate the entire biological system from the nutrigenomics perspective to include critical evaluation of DNA polymorphisms or SNPs of a gene, expression of that specific gene, expression of specific processed mRNA (alternative splicing), protein production from that mRNA, post-translational modification of the resultant protein, and formation of respective metabolites. Evolution of the fields of nutrigenetics, epigenomics, transcriptomics, proteomics, and metabolomics has begun to permit this approach so that a comprehensive picture emerges from not only a single cell but tissues and whole organisms. Studies such as these can ultimately be used to study tumors to understand the molecular events that accompany carcinogenesis and perturbations that occur during cell death processes and how an individual's response to diet can impact these processes. PMID- 17691904 TI - Cancer preventive phytochemicals as speed breakers in inflammatory signaling involved in aberrant COX-2 expression. AB - A causal association between inflammation and cancer has long been suspected. Multiple lines of compelling evidence from clinical, epidemiologic and laboratory studies support that inflammation plays a critical role in the promotion and progression stages of carcinogenesis. Recent progress in our understanding of the molecular biology of cancer highlights the intracellular signal transduction network, including that involved in mediating the inflammatory response, which often functions abnormally during carcinogenesis. One of the key players in inflammatory signaling is cyclooxygenase-2 (COX-2). Aberrant upregulation of COX 2 is frequently observed in various precancerous and malignant tissues. Pro inflammatory stimuli trigger the activation of an intracellular signal transduction network comprising proline-directed serine/threonine kinases, and their downstream transcription factors, resulting in an inappropriate induction of COX-2. Therefore, the normalization of inappropriately overamplified signaling cascades implicated in chronic inflammation-associated carcinogenesis by use of COX-2 specific inhibitors has been recognized as a rational and pragmatic strategy in molecular target-based cancer prevention. This review highlights the cancer preventive effects of some anti-inflammatory phytochemicals derived from edible plants, and their underlying molecular mechanisms with a focus on representative transcription factors and upstream kinases responsible for COX-2 induction. PMID- 17691905 TI - Cancer prevention by dietary bioactive components that target the immune response. AB - Dietary bioactive food components that interact with the immune response have considerable potential to reduce the risk of cancer. Reduction of chronic inflammation or its downstream consequences may represent a key mechanism that can be reduced through targeting signal transduction or through antioxidant effects. Major classes of macronutrients provide numerous examples, including amino acids such as glutamine or arginine, lipids such as the omega-3 polyunsaturated fatty acids, DHA or EPA, or novel carbohydrates such as various sources of beta-glucans. Vitamins such as C and E are commonly used as antioxidants, while zinc and selenium are minerals with a wide spectrum of impacts on the immune system. Some of the most potent immunomodulators are phytochemicals such as the polyphenols, EGCG or curcumin, or isothiocyanates such as PEITC. There is accumulating evidence for cancer prevention by probiotics and prebiotics, and these may also affect the immune response. Genomic approaches are becoming increasingly important in characterising potential mechanisms of cancer prevention, optimising the rational selection of dietary bioactive food components, or identifying humans with differing nutrient requirements for cancer protection. PMID- 17691906 TI - Nutritional modulation of terminal end buds: its relevance to breast cancer prevention. AB - Findings with experimental rodent models reveal that exposures to dietary factors during the in utero and pubertal periods when the mammary gland is undergoing extensive modeling and re-modeling, alter susceptibility to develop mammary tumors. Similar observations have been made in humans: childhood exposure to genistein in soy or to some other bioactive food components reduces later breast cancer risk, although they may have no effect if consumed during adulthood. Thus, food components may be more effective in affecting cancer risk in some periods of life than others. Many of these dietary exposures modify fetal and postnatal hormonal environment, including changing the concentrations of estrogens and leptin. The hormonal alterations then may induce persistent epigenetic changes by affecting gene promoter regions or by inducing histone modifications that affect chromatin transcription. The targets of epigenetic changes are likely to be the terminal end buds (TEBs), the structures where carcinogen-induced mammary tumors in rats and mice are initiated. More specifically, the site of these changes in TEBs may be the stem cells and their niche; this might explain how an exposure early in life affects the risk of breast cancer decades later. Similar structures in women, called terminal ductal lobular units, are the sites where most human breast cancers rise. According to this hypothetical model, cancer is initiated only when the epigenetically altered cells are exposed to carcinogens/radiation, etc. during adult life. In a "normal" stem cell or its niche, cancer initiating exposures do not necessarily cause cancer, because the cells can either repair the damage or undergo apoptosis. Thus, the most likely molecular targets of early life dietary exposures are genes that regulate DNA adduct formation, repair DNA damage or induce apoptosis, such as genes affecting cellular metabolism, tumor suppressor genes or genes promoting cell survival. It is possible that some of these epigenetic changes also explain why the number of TEBs generally, but not always, correlates with breast cancer risk. This hypothesis may imply that adult intake of some bioactive dietary components reduces cancer risk increased by early life dietary exposures or inhibits tumor growth by reversing epigenetic changes in various molecular targets. PMID- 17691907 TI - Inducible nitric oxide synthase-vascular endothelial growth factor axis: a potential target to inhibit tumor angiogenesis by dietary agents. AB - Human solid tumors remain latent in the absence of angiogenesis since it is a critical process for their further growth and progression. Experimental evidence suggests that targeting tumor angiogenesis may be a novel strategy to check tumor growth and metastases. Recent studies suggest that several bioactive food components can suppress tumor growth by inhibiting angiogenesis. This suppression occurs because of a direct effect on the tumor, as well as a direct effect on vascular endothelial cells. These food components can target epigenetic processes and thereby suppress the pro-angiogenic tumor microenvironment. One likely epigenetic target is inducible nitric oxide synthase (iNOS). iNOS is known to regulate vascular endothelial growth factor (VEGF) expression, and thereby tumor angiogenesis. The ability of food components to influence the inducible form of cyclooxygenase, COX-2 may also contribute to their impact on tumor growth and angiogenesis. This review focuses on recent developments related to the angiogenic role of the iNOS-VEGF axis and how dietary components may target this axis. Overall, studies suggest that the anti-angiogenic potential of physiologically concentrations of relevant food components could be used as a practical approach for cancer prevention and intervention. PMID- 17691908 TI - Energy balance and carcinogenesis: underlying pathways and targets for intervention. AB - The prevalence of obesity, an established epidemiologic risk factor for many cancers, has risen steadily for the past several decades in the U.S. Particularly alarming are the increasing rates of obesity among children, portending continuing increases in the rates of obesity and obesity-related cancers for many years to come. Unfortunately, the mechanisms underlying the association between obesity and cancer are not well understood. In particular, the effects and mechanistic targets of interventions that modulate energy balance, such as reduced calorie diets and physical activity, on the carcinogenesis process have not been well characterized. The purpose of this review is to provide a strong foundation for future mechanistic-based research in this area by describing key animal and human studies of energy balance modulations involving diet, exercise, or pharmaceutical agents and by focusing on the interrelated pathways affected by alterations in energy balance. Particular attention in this review is placed on the components of the insulin/IGF-1/Akt pathway, which has emerged as a predominant target for disrupting the obesity-cancer link. Also discussed is the promise of global approaches, including genomics, proteomics, and metabolomics, for the elucidation of energy balance-responsive pathways. The ultimate goal of this work is to provide the missing mechanistic information necessary to identify targets for the prevention and control of cancers related to or caused by excess body weight. PMID- 17691909 TI - Kit: molecule of interest for the diagnosis and treatment of mastocytosis and other neoplastic disorders. AB - Kit a type III receptor tyrosine kinase, along with its ligand the stem cell factor, play a critical role in normal cell growth, differentiation, development and survival. Ligand independent activation of kit (dysregulated kit function) has been found to be an important component of oncogenesis in a large number of neoplastic disorders such as systemic mastocytosis, gastro intestinal stromal tumors, germ cell tumors, acute myelogenous leukemia with the disruption of the core binding factor, amongst others. The identification of small molecule inhibitors with activity against Kit, has offered a wider and more effective range of therapeutic options in the treatment of these neoplastic processes. Novel tyrosine kinase inhibitors such as imatinib, nilotinib and dasatinib, have been found to be effective in the management of various subtypes of systemic mastocytosis and gastrointestinal stromal tumors. Non-tyrosine kinase inhibitors like rapamycin, 17-AAG and IMD- 0354 have been added to the therapeutic armamentarium, with the hope that combination therapy might have a synergistic effect, or prevent/delay the development of drug resistance. PMID- 17691910 TI - Cyclopentenyl cytosine (CPEC): an overview of its in vitro and in vivo activity. AB - The experimental cytotoxic drug cyclopentenyl cytosine (CPEC) is an analogue of cytidine. Besides its antiviral effect, its potential use in the treatment of cancer has become an important area of research. CPEC is activated by intracellular phosphorylation ultimately forming its metabolite CPEC-TP. CPEC-TP is a non competitive inhibitor of cytidine-5'-triphosphate synthetase (CTP synthetase), an important enzyme in the formation of CTP. Studies have shown that cancer cells have a high CTP synthetase activity, thus making them interesting targets for chemotherapy. CPEC has been preclinically studied in different malignancy models. In vitro results on leukemia show activity in the nanomolar range on several cell lines. However in vivo results are conflicting and the findings vary from increase in life span over 100% to only limited effectiveness. Interesting results have been obtained in colorectal and neuroblastoma cells. In several neuroblastoma cell lines incubation with CPEC in combination with cytarabine or gemcitabine has resulted in increased cell death compared to incubation with with only one of the agents. CPEC has been studied in a phase I trial in patients with solid tumors. In five of 26 patients unexplained cardiotoxicity (extreme hypotension) occurred. The cardiotoxic effects could not be reproduced in animal models. However, precautions should be taken when using this drug in future clinical trials. Low dosage of CPEC seems necessary and intensive cardiac monitoring is advisable. In this manuscript, it is demonstrated that CPEC has an anti-cancer effect in several tumor models: CPEC might be a potentially useful drug in anticancer treatment. PMID- 17691911 TI - A novel candidate compound with urethane structure for anticancer drug development. AB - Diethyl-4,4'-methylenebis(N-phenylcarbamate) (MDU) is a urethane compound that we originally synthesized, along with three other compounds, to investigate how polyurethane is hydrolysed. We tested the four compounds for cytotoxicity in two Chinese hamster cell lines (CHL and V79) and a human cancer cell line (HeLa S3). MDU showed the strongest cytotoxicity in all the cell lines with an IC50 of around 0.1 microg/ml. We further investigated MDU for its ability to induce chromosome aberrations (CAs) and micronuclei (MN) in CHL cells. MDU induced around 100% polyploid cells at 0.5 microg/ml after 24- and 48-h treatment in the CA test and a significantly increased frequency of micronuclei, polynuclear cells, and mitotic cells in the MN test, suggesting that it may induce numerical CAs. MDU's ability to cause mitotic arrest in CHL cells was greater than that of taxol and colchicine. Based on a COMPARE analysis using JFCR39, a panel of cancer cell lines, we predicted MDU to be a tubulin inhibitor. We confirmed this possibility in nerve growth factor-stimulated PC12 cells as well as in HT1080 cells, in which MDU exhibited the activity to inhibit tubulin polymerization. MDU is simpler in structure than existing anticancer drugs taxol and vincristine and can be synthesized relatively easily. Here we offer MDU as a potential new type of anticancer drug, stable even at room temperature, and inexpensive. PMID- 17691912 TI - SMILES in QSPR/QSAR Modeling: results and perspectives. AB - The technique of constructing optimal descriptors calculated with the Simplified molecular input line entry system (SMILES) is described. SMILES based optimal descriptors and descriptors calculated with molecular graphs (hydrogen filled graphs and graph of atomic orbitals) are compared in modeling done by means of quantitative structure - property/activity relationships (QSPR/QSAR). QSPR/QSAR models for normal boiling points of organic compounds, mutagenicity of heteroaromatic amines, toxicity, and anti-HIV-1 potentials of TIBO and HEPT derivatives are described in details. Possible ways to improve the SMILES based concept of QSPR/QSAR analyses are discussed. PMID- 17691913 TI - Prediction of MHC binding peptides and epitopes from alfalfa mosaic virus. AB - Peptide fragments from alfalfa mosaic virus involved multiple antigenic components directing and empowering the immune system to protect the host from infection. MHC molecules are cell surface proteins, which take active part in host immune reactions and involvement of MHC class-I & II in response to almost all antigens. Coat protein of alfalfa mosaic virus contains 221 aa residues. Analysis found five MHC ligands in coat protein as 64-LSSFNGLGV-72; 86- RILEEDLIY 94; 96-MVFSITPSY-104; 100- ITPSYAGTF-108; 110- LTDDVTTED-118; having rescaled binding affinity and c-terminal cleavage affinity more than 0.5. The predicted binding affinity is normalized by the 1% fractil. The MHC peptide binding is predicted using neural networks trained on c-terminals of known epitopes. In analysis predicted MHC/peptide binding is a log transformed value related to the IC50 values in nM units. Total numbers of peptides found are 213. Predicted MHC binding regions act like red flags for antigen specific and generate immune response against the parent antigen. So a small fragment of antigen can induce immune response against whole antigen. This theme is implemented in designing subunit and synthetic peptide vaccines. The sequence analysis method allows potential drug targets to identify active sites against plant diseases. The method integrates prediction of peptide MHC class I binding; proteosomal c terminal cleavage and TAP transport efficiency. PMID- 17691914 TI - In vivo 19F MR studies of fluorine labeled photosensitizers in a murine tumor model. AB - The main focus of this report is the MR spectroscopy of the changes in the concentration of fluorine labeled photosensitizer that occur following the IP administration. This process is studied by (19)F in vivo MR methodology in a murine tumor model. The animal model used in these studies was mice bearing radiation induced fibrosarcoma (RIF) tumor on the foot dorsum. The mice were injected with a solution of approximately 100 micro-moles of the fluorinated photosensitizer and the (19)F MR examination of the photosensitizer in the tumor or the muscle was performed. The pharmacokinetic (PK) profile for each labeled compound was generated using the (19)F MR data at various time points post photosensitizer administration. The pharmacokinetic parameters were analyzed and the relationship of these results to photodynamic therapy is discussed. The (19)F MR methods clearly demonstrate utility in measuring the pharmacokinetic profiles and provide a new approach in the evaluation of appropriate photosensitizers for use in preclinical mammalian systems. PMID- 17691915 TI - Current treatment strategies for non-alcoholic fatty liver disease (NAFLD). AB - Nonalcoholic fatty liver disease (NAFLD) is recognized as the most common cause of chronic liver disease worldwide. NAFLD is a clinicopathologic syndrome ranging from simple steatosis, which is relatively benign, to the more severe form known as nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis, liver failure, and hepatocellular carcinoma. NAFLD is associated with significant liver related morbidity and mortality, and its underlying pathophysiology is thought to result from a multiple hit process. The initial insult is the accumulation of hepatic fat secondary to insulin resistance. In the setting of hepatic steatosis, the second hit can be caused by reactive oxygen species, inflammatory cytokines, and adipokines. Several therapeutic modalities that target these mechanisms are under investigation, but no proven treatment has yet emerged. Insulin sensitizers such as thiazolidinediones and metformin show promise, and several studies have explored the role of lipid lowering agents, antioxidants, and cytoprotective agents. Novel agents such as anti-obesity drugs, selective cannabinoid-1 receptor blockers, and dual PPAR alpha and gamma agonists are also under investigation. Unfortunately, data on the long-term safety and efficacy of these agents and their impact on liver related histologic outcomes are currently lacking. NAFLD treatment currently focuses on reducing metabolic risk factors, with the mainstay of therapy focusing on life-style modifications such as gradual weight loss through diet and regular exercise. PMID- 17691916 TI - Metabolic activation of herbal and dietary constituents and its clinical and toxicological implications: an update. AB - In recent years, there has been a globally increasing application of herbal medicines and dietary supplements to treat various chronic diseases and to promote health. However, there are increasing clinical reports on the organ toxicities associated with consumption of herbal medicines. This review updates the knowledge on metabolic activation of herbal components and its clinical and toxicological implications. Like many synthetic drugs undergoing metabolic activation to form reactive metabolites which are often associated with drug toxicity, it is recognized that some herbal components may also be converted to toxic, or even mutagenetic and carcinogenic metabolites by cytochrome P450s (CYPs) and less frequently by Phase II conjugating enzymes. This is exemplified by aristolochic acids (AAs) in Aristolochia spp, which undergo reduction of the nitro group by hepatic CYP1A1/2 or peroxidases in extrahepatic tissues to generate highly reactive cyclic nitrenium ions. The latter can react with macromolecules (DNA and protein), resulting in activation of H-ras oncogene and gene mutation in renal cells and finally carcinogenesis of the kidneys. Some naturally occurring flavonoids (e.g. quercetin) and alkenylbenzenes (e.g. safrole, methyleugenol and estragole) can undergo metabolic activation by sequential 1-hydroxylation and sulfation, resulting in reactive intermediates capable of forming DNA adducts and finally genotoxicity. Additional examples are pulegone present in essential oils from many mint species; and teucrin A, a diterpenoid found in germander (Teuchrium chamaedrys) used as an adjuvant to slimming dietary supplements but caused severe hepatotoxicity. Extensive pulegone metabolism generated p-cresol that was a glutathione depletory, whereas the furan ring of the diterpenoids in germander was oxidized by CYP3A4 to reactive epoxide which can inactivate hepatic CYP3A and epoxide hydrolase through covalent binding. The hepatotoxic and carcinogenic species of plant pyrrolizidine alkaloids (e.g. echimidine and jacobine), namely pyrrole-type metabolites, are generated by hepatic CYP2B6 and CYP3A4. Potential mechanisms underlying the hepatotoxicity of kava have been related to intracellular glutathione depletion and/or quinone formation. Some herbal constituents (e.g. capsaicin from chili peppers, glabridin from licorice root, oleuropein in olive oil, dially sulfone in garlic, and resveratrol found in red wine) behave as mechanism-based inhibitors of various CYPs. This may provide an explanation for some reported herb-drug interactions. In addition, the inhibition of CYPs by herbal constituents may decrease the formation of toxic metabolites and thus inhibit carcinogenesis, as CYPs play an important role in procarcinogen activation. Due to the wide use and easy availability of herbal medicines, further research should be conducted to ensure the safety and quality of herbal medicine. PMID- 17691917 TI - Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy. AB - Cancer chemotherapy is characterized by a broad range of efficacy and toxicity among patients. Most anticancer drugs show wide interindividual variability in pharmacokinetics and have narrow therapeutic windows. Since drug metabolism is often an essential determinant of interindividual variability in pharmacokinetics, pharmacogenomic studies of drug-metabolizing enzymes are expected to rationalize cancer chemotherapy in terms of patient, treatment, and dosage selection. Candidate gene approaches to pharmacogenomics are based on existing knowledge in clinical pharmacology, used to select the target(s) to be analyzed. So far, the candidate gene approach has provided important clues for pharmacogenomic-based personalized chemotherapy with 6-mercaptopurine (6-MP), solely metabolized by thiopurine S-methyltransferase (TPMT), and irinotecan, mainly detoxified by UDP-glucuronosyltransferase 1A1 (UGT1A1). Reduced activity of TPMT caused by polymorphisms in the TPMT gene and decreased activity of UGT1A1 caused by UGT1A1*28 are related to severe toxic effects of 6-MP and irinotecan, respectively. In response to these findings, the Food and Drug Administration in the United States has supported clinical pharmacogenetic testing by revising the package inserts for these anticancer drugs. The genome wide approach to pharmacogenomics has gradually evolved with continued progress in genome sciences and technologies. This approach can disclose previously unknown relations of factors, as well as identify potential multigenetic associations. The genome wide approach can also identify genes underlying the phenotypic effects of anticancer drugs. This approach may play a complemental role to the candidate gene approach in the future of cancer pharmacogenomics. This review describes recent progress in pharmacogenomics in the field of cancer chemotherapy. PMID- 17691918 TI - Overlapping ligand specificity of P-glycoprotein and serum alpha(1)-acid glycoprotein: evidences and potential implications. AB - Plasma alpha(1)-acid glycoprotein (AGP) is an important modulator of drug disposition, since it binds and transports of a vast array of pharmaceutical agents. The ABC transporter efflux pump, P-glycoprotein (P-gp), also recognizes and binds a broad range of weakly basic and uncharged xenobiotics. Its efflux activity plays a key role in pharmacokinetics of drugs, and overexpression of P gp in malignant cells confers multidrug resistance (MDR) to anticancer agents. Comparison of ligand specificities of AGP and P-gp revealed high similarity showing that both proteins interact with the same therapeutic classes of drugs (alpha/beta-blockers, anticancer agents, Ca(2+) antagonists, antipsychotics/neuroleptics, HIV protease inhibitors etc.) as well as with additional endo- and exogenous compounds (steroids, dyes, natural substances). A wealth of examples are presented to show the potential use of drug-AGP binding data to predict drug-P-gp interactions and vice versa. In addition, structural and functional similarities between AGP and P-gp have been highlighted. Based on these data, several proposals have been made: 1) AGP and P-gp might act synergistically in protecting cells from harmful xenobiotics; 2) An extensive shared list of their ligands allows prediction of mutual binding interactions; 3) Interaction of drugs and drug candidates, both with AGP and P-gp, should be considered to optimize pharmacotherapy and to delineate the causes of drug-drug interactions; 4) Structures of known AGP binders could be exploited in searching for novel scaffolds of P-gp modulators to overcome cancer MDR and efflux-mediated resistance in microorganisms and parasites; 5) Novel fluorescent probes for studying P-gp structure and function can be pre-selected among AGP binder agents. PMID- 17691919 TI - Control by substrate of the cytochrome p450-dependent redox machinery: mechanistic insights. AB - Based on initial studies with bacterial CYP101A1, a popular concept emerged predicting that substrate-induced low-to-high spin conversion of P450s is universally associated with shifts of the midpoint potential to a more positive value to maximize rates of electron transfer and metabolic turnover. However, evaluation of the plethora of observations with pro- and eukaryotic hemoproteins suggests a caveat as to generalization of this principle. Thus, some P450s are inherently high-spin, so that there is no need for a supportive substrate triggered impulse to electron flow. With other enzymes, high-spin content is not consonant with reductive activity, and spin transition as such is not essential to sustaining substrate oxidation. Also, with certain proteins the low-spin conformer is reduced as swift as the high-spin entity. Moreover, there is not regularly a linear relationship between high-spin level and anodic shift of the reduction potential. Similarly, in given cases turnover may proceed despite insignificant or even lacking substrate-provoked alterations in the redox behaviour. Thus, folding of the disparate and sometimes conflicting data into a harmonized overall picture is a lingering problem. Apart from direct perturbation of the electrochemical properties, substrate docking may entail changes in enzyme conformation such as to favour productive complexation with redox partners or modulate electron transfer conduits within preformed donor/acceptor adducts, resulting in elevated ease of flow of reducing equivalents. Substrate-steered ordering of the oligomeric aggregation state of P450s is likely to impose steric constraints on heterodimers, causing one component to more readily align with electron carriers. Careful uncovering of electrochemical mechanisms in these systems will be fruitful to tailoring of novel bioenergetic machines and redox chains via redox-inspired protein engineering or molecular Lego, capable of generating products of interest or degrading toxic pollutants. Finally, availability of P450 nanobiochips for high-throughput screening of substrate libraries might expedite drug development. PMID- 17691920 TI - N-dealkylation of arylpiperazine derivatives: disposition and metabolism of the 1 aryl-piperazines formed. AB - In recent years several arylpiperazine derivatives have reached the stage of clinical application, mainly for the treatment of depression, psychosis or anxiety. Examples are the pyrimidinylpiperazine buspirone, the chlorophenylpiperazine derivatives nefazodone and trazodone, the dichlorophenylpiperazine aripiprazole and the benzisothiazolyl derivatives perospirone and ziprasidone. Most of them undergo extensive pre-systemic and systemic metabolism including CYP3A4-dependent N-dealkylation to 1-aryl piperazines. These metabolites are best known for the variety of serotonin receptor-related effects they cause in man and animals, although some have affinity for other neurotransmitter receptors; others, however, are still largely unexplored despite uncontrolled use as amphetamine-like designer drugs. Once formed they distribute extensively in tissues, including brain which is the target site of most arylpiperazine derivatives, and are then primarily biotransformed by CYP2D6-dependent oxidation to hydroxylates which are excreted as conjugates; only 1-(2-benzisothiazolyl)-piperazine is more susceptible to sulfur oxidation than to aromatic hydroxylation. In studies analysing animal brain and human blood, 1-aryl-piperazine concentrations were either higher or lower than the parent compound(s), although information is available only for some derivatives. At steady state, the metabolite-to-parent drug ratios varied widely among individuals taking the same dosage of the same arylpiperazine derivative. This is consistent with the known individual variability in the expression and activity of CYP3A4 and CYP2D6. This review also surveys current published information on physiological and pathological factors affecting the 1 aryl-piperazine-to-parent drug ratios and examines the potential role of 1-aryl piperazine formation in the pharmacological actions of the arylpiperazine derivatives that are already or will shortly be available in major markets. PMID- 17691921 TI - Different roles of pummelo furanocoumarin and cytochrome P450 3A5*3 polymorphism in the fate and action of felodipine. AB - OBJECTIVE: Herein we aim to test if pummelo furanocoumarins can inhibit cytochrome P450 (CYP) 3A both in vitro and in vivo, and to explore the influence of CYP3A5*3 (GenBank AC005020: A22893-->G) polymorphism in the pharmacokinetics and pharmacological response to felodipine. METHOD: Fruit juices of pummelo grapefruit (Citrus paradisi Macf., G), 'Guanximiyou' (C. grandis Osbeck vs. Guanxi, P) and 'Changshanhuyou' (C. changshanhuyou Y.B. Chang, H) were selected by screening Citrus fruit juices for their furanocoumarin contents and their inhibition of testosterone 6beta-hydroxylation in human liver microsomes. Twelve healthy male Chinese were administered 250 mL G, P, H or water (W) alternatively with 26-mumol (10-mg) plain tablet felodipine, and were observed for 12 h. RESULTS: G had more furanocoumarins and at higher levels than P while H had none, and their potencies for in vitro CYP3A inhibition were in the order as G > P > H. The geometric mean and 90% confidence intervals of pharmacokinetic parameters for human oral felodipine with G, P, H and W were respectively as follows: peak plasma concentration (nmol.L(-1)), 37 (32-44), 25 (21-29), 19 (16-22) and 18 (15 21); area under the plasma concentration-time curve (nmol.h.L(-1)), 118 (103 136), 84 (73-97), 64 (56-74) and 59 (51-68). Subjects showed higher heart rates with G than with H or W. CYP3A5*3 polymorphism showed no significant effect on felodipine pharmacokinetics and related hemodynamic changes. CONCLUSIONS: This work supports the hypothesis that CYP3A inhibition by furanocoumarins caused pummelo fruit juice-drug interaction; while the role of CYP3A5 in the population pharmacokinetics of felodipine and blood pressure response appear to be limited. PMID- 17691922 TI - The regulation of liver cytochrome p450 by the brain dopaminergic system. AB - Genes encoding different cytochrome P450 (CYP) isoforms are regulated by endogenous hormones (e.g. pituitary hormones, thyroid hormones, glucocorticoids) which are all under control of the central nervous system. The aim of the present study was to investigate the influence of lesions of brain dopaminergic pathways on the level and the activity of CYP isoforms (1A, 2A, 2B, 2C6, 2C11, 2D, 3A) in rat liver. At 48 h after lesion of the tuberoinfundibular pathway, only the activity and the protein level of CYP2B were significantly decreased. Seven days after lesion of the above-mentioned pathway, significant inhibition of CYP2B, CYP2C11 and CYP3A activities and a decrease in CYP protein levels were observed. At the same time, the activity and the protein level of CYP1A considerably increased. Fourteen days after damage of the mesolimbic pathway, the activity and the protein level of CYP3A were significantly reduced, while those of CYP1A were substantially elevated. In contrast, lesion of the nigrostriatal pathway did not affect any CYP isoforms studied. The obtained results provide the first direct evidence for the influence of brain dopaminergic system on the level and the activity of CYP in the liver, which is pathway- and isoform-dependent. Hence stimulation or inhibition of the brain dopaminergic system (e.g. by dopamine receptor-blocking neuroleptics) may cause changes in CYP activity of physiological, pharmacological and toxicological significance, since CYP isoforms that are regulated by the dopaminergic system catalyze the metabolism of endogenous substances (e.g. steroids), clinically important drugs (e.g. psychotropics, calcium channel antagonists, antibiotics) and toxins. PMID- 17691923 TI - Different inflammatory biomarker patterns in the cerebro-spinal fluid following heart surgery and major non-cardiac operations. AB - Cognitive decline occurs frequently after cardiac surgery and it may lead to patient morbidity. The purpose of this study is to focus on the static incidence of neuro-psychiatric impairment associated with altered inflammatory biomarkers in the cerebro-spinal fluid (CSF) that may provide an insight into the mechanisms of acute peri-operative cognitive disturbances related to heart surgery. Immuno assays were used to evaluate concentrations of several cytokines in CSF of patients undergoing either off-pump coronary artery bypass grafting (OP-CABG) or major non-cardiac surgeries. Inter-group analysis showed no differences in baseline cytokine abundance. Levels of IL-8 have markedly increased both after OP CABG and major non-cardiac surgeries (34.59+/-7.15 vs. 99.45+/-6.35, and 27.44+/ 7.17 vs. 66.63+/-15.18). Rantes showed significantly greater quantity in CSF of the non-cardiac group after surgery (8.71+/-3.37 vs. 114.56+/-65.42), whereas it became somewhat less abundant in the post-operative period but statistically unchanged in the OP-CABG cohort (19.87+/-15.71 vs. 9.37+/-3.65). IP-10 and MCP-1 did not show significant changes in their concentrations in either patient population (OP-CABG: 254.41+/-160.01 vs. 224.55+/-214.39, and 140.37+/-40.98 vs. 147.16+/-37.98; non-cardiac: 274.99+/-219.44 vs. 395.09+/-468.30, and 126.56+/ 31.24 vs. 124.41+/-49.89, respectively). These findings suggest that cardiac surgery provokes alterations in the levels of various cytokines in the CSF, and the OP-CABG induced changes in biomarker profile differs from that seen after major non-cardiac surgeries. This, along with other biomarkers, may offer an explanation for relationships between the pronounced incidence of cognitive impairment after heart operations. PMID- 17691924 TI - Impact of periconceptional undernutrition on the development of the hypothalamo pituitary-adrenal axis: does the timing of parturition start at conception? AB - There are a number of critical windows during prenatal and postnatal life and a range of potential agents including exposure to maternal and fetal stressors, nutrition, and antenatal administration of synthetic glucocorticoids and postnatal maternal care and behaviour that are important in programming the subsequent reactivity of the HPA axis. Recently, it has become clear that the periconceptional period is also an important critical period during which changes in the level of maternal nutrition result in altered development of the fetal HPA axis. These findings have potential implications for the ability of the fetus to respond to acute and chronic stressors, for the timing of parturition and have potential implications for adult cardiovascular and metabolic health outcomes. In this review we focus on the different models which have been used to investigate the impact of maternal undernutrition during the periconceptional period on the prepartum activation of the fetal HPA axis. We propose that the term "periconceptional" should be used to refer to the developmental stages which include some or all of the following early events: oocyte maturation, follicular development, conception, and embryo/blastocyst growth up until implantation. When maternal undernutrition extends beyond implantation, up until early placentation, then it is appropriate to describe maternal undernutrition as occurring during 'early gestation'. Further work is required to define the relative contributions of nutritional factors operating in the periconceptional and early gestational periods on the programming of the subsequent development of the HPA axis and is of importance for fetal, postnatal and subsequent adult cardiovascular and metabolic health. PMID- 17691925 TI - Maternal nutrient restriction is not equivalent to maternal biological stress. AB - An increase in fetal glucocorticoid exposure has long been considered to be a primary mechanism by which maternal nutritional manipulation may result in long term adaptations in the fetus such that it is at increased risk of a range of adult diseases including hypertension, diabetes and obesity. Animal studies in which high doses of synthetic glucocorticoids have been administered to the mother shown some long term programming effects, but these are nearly always accompanied by a reduction in maternal food intake. In this review, we will, therefore, consider the extent to which maternal food restriction and elevated maternal glucocorticoid concentrations can result in the same or different adaptations within the fetus such that they exhibit developmental changes in blood pressure control and/or metabolic homeostasis. One factor that appears to be critical in determining the mother's response is the stage of gestation at which her nutrient intake is manipulated. This may be explained in part by the placenta's ability to inactivate glucocorticoids. Irrespective of the mechanisms involved, it is clear that long term tissue specific adaptations within a range of organs, including adipose tissue and the kidney, can be greatly altered following changes in maternal glucocorticoid secretion. PMID- 17691926 TI - Fetal mechanisms that lead to later hypertension. AB - Extensive epidemiological and experimental evidence suggests the nutritional environment in which a developing conceptus is exposed is a major factor determining later cardiovascular disease. In this review a consideration of the extent to which altered maternal/fetal nutritional environments may predispose toward later anomalies in blood pressure control and hypertension will be undertaken. In particular, a focus will be on potentially novel mechanistic pathways through which early-mid gestational undernutrition may impact upon fetal/adult adipocyte, renal and brain function, that act to increase the risk of later hypertension developing. Within the review we shall also present an opinion on the differing animal models that are currently employed to address developmental programming and introduce a conceptual framework that synthesises current available evidence. PMID- 17691927 TI - Maternal nutrition and predisposition to later kidney disease. AB - Although it is well-accepted that size at birth is inversely related to adult blood pressure and cardiovascular risk in humans, the majority of information available with regard to maternal nutrition, prenatal growth, and subsequent renal disease comes from animal models. Restriction of food or protein during specific windows of pregnancy leads to hypertension in adult offspring. Depending on the degree of maternal restriction, nephron number and renal function in the offspring may be reduced, and proteinuria and histological signs of renal disease are present. All of these abnormalities appear to worsen with age. Female gender is relatively protective against these prenatal insults, but with more severe maternal dietary restriction female offspring are also affected. In addition to macronutrients, roles for several micronutrients have been identified in fetal programming for hypertension and renal disease. Ongoing investigations into the roles of sex hormones, the renin-angiotensin system, and vitamin A in these developmental processes may lead to strategies for prevention of dietary programming for hypertension and renal disease in humans. PMID- 17691928 TI - Influences of maternal nutritional status on vascular function in the offspring. AB - Fetal growth restriction leading to low birthweight is associated with increased risk of ischaemic heart disease and hypertension in later life. Increasingly, it is recognised that cardiovascular risk may also be initiated in early life when the fetus and neonate are exposed to maternal nutritional excess. This review summarises the studies in man and animals that have investigated the potential role of vascular disorders in the aetiology of atherosclerosis and hypertension arising from early life nutritional deprivation or excess. Malfunction of the arterial endothelial cell layer in the offspring has been frequently described in association with both maternal under and overnutritional states and may play a permissive role in the origin of these disorders. Also prevalent is evidence for increased stiffness of the large arteries which may contribute to systolic hypertension. Further investigation is required into the intriguing suggestion that early life nutritional imbalance may adversely influence vascular angiogenesis leading to rarefaction and increased peripheral vascular resistance. PMID- 17691929 TI - Is later obesity programmed in utero? AB - The global prevalence of obesity has increased markedly over the last two decades with over 50% of all adults in the UK and USA classified as overweight or obese. Furthermore, the prevalence of obesity in children has risen by over 40% in the last 16 years. Obesity results from the interaction of many factors, including genetic, metabolic, behavioral, and environmental influences. However, the rate at which obesity is increasing suggests that environmental and behavioral influences, rather than genetic changes, have fueled the epidemic. In this context, it is of particular relevance that epidemiological and experimental studies have highlighted a relationship between the periconceptual, fetal and early infant phases of life and the subsequent development of adult adiposity. This relationship; the "developmental origins of health and disease" (DOHaD) model, speculates that the fetus adapts to adverse environmental cues in utero with permanent readjustments in homeostatic systems to aid survival. However, these adaptations, known as predictive adaptive responses, may ultimately be disadvantageous in postnatal life and may lead to an increased risk of chronic non-communicable disease in adulthood. This review summarises recent work in animal models and observations in the clinical and epidemiological settings on the in-utero origins of obesity and related metabolic disorders. PMID- 17691930 TI - Fetal determinants of type 2 diabetes. AB - Type 2 diabetes, which has dramatically increased during the last decade normally results from a combination of pancreatic beta cell dysfunction and insulin resistance. One of the most recent risk factors identified for type 2 diabetes is a sub-optimal fetal and neonatal environment. Numerous human epidemiological studies worldwide have highlighted that a disturbed nutritional environment of the fetus, either poor or too abundant will compromise the health of the offspring by increasing the susceptibility to insulin resistance, to glucose intolerance and to diabetes in later life. In addition to adverse intrauterine events, the detrimental role of catch-up growth and of the mismatch between the prenatal and the postnatal metabolic environment in such pathology is now clear. To understand the mechanisms that are responsible for such programming and to be able to design prevention strategies, a number of animal models have been created. This manuscript reviews the data from several rodent models in which maternal or neonatal diet has been altered. These include models of maternal under-nutrition and over-nutrition as well as gestational diabetes. In general, abnormal beta cell mass and beta cell dysfunction are present at birth and insulin resistance, glucose intolerance and diabetes appear in adult offspring. Obesity, pregnancy and ageing exaggerate the phenotype and there is some evidence to suggest that the phenotype can be transmitted to a second generation independently of any further environmental modification. Possible underlying mechanisms are discussed and evidence for potential early intervention strategies are reported. PMID- 17691931 TI - Statins exert multiple beneficial effects on patients undergoing percutaneous revascularization procedures. AB - BACKGROUND AND AIMS: Statins are an essential component of the therapeutic approach of patients with atherosclerotic disease. Statin use is also associated with improved peri-operative and long-term outcomes in these patients. We aimed to define the role of statin treatment in patients undergoing percutaneous revascularization procedures. LITERATURE SEARCH METHOD: We searched Medline for studies assessing the effect of statin treatment on percutaneous interventions. LITERATURE SEARCH RESULTS: Early statin treatment is associated with improved outcomes in patients undergoing percutaneous coronary intervention procedures. Current evidence implies that statin treatment may also play a beneficial role in the management of patients undergoing percutaneous renal artery revascularization and endovascular abdominal aortic aneurysm repair, carotid angioplasty/stenting and endovascular peripheral arterial interventions. CONCLUSIONS: Preliminary data suggest that statins exert multiple beneficial actions in patients undergoing percutaneous interventions. Future randomized trials are expected to further evaluate the beneficial effects of statins in these procedures. PMID- 17691932 TI - Molecular mechanisms of diabetic nephropathy and its therapeutic intervention. AB - Diabetic nephropathy is a leading cause of end-stage renal failure, which could account for disabilities and high mortality rates in patients with diabetes. Diabetic nephropathy seems to occur as a result of an interaction between metabolic and hemodynamic factors, which activate common pathways that lead to renal damage. Recent large landmark clinical studies have shown that intensive glucose control reduces the risk of the development and progression of diabetic nephropathy, and the blockade renin-angiotensin system (RAS) is also an important target for both metabolic and hemodynamic derangements in diabetic nephropathy. However, diabetic nephropathy remains the leading cause of end-stage renal failure in developed countries. Therefore, to develop novel therapeutic strategies that specifically target diabetic nephropathy may be helpful for most patients with diabetes. High glucose, via various mechanisms such as increased production of oxidative stress and advanced glycation end products (AGEs), and activation of the RAS and protein kinase C (PKC), elicits vascular inflammation and alters gene expression of growth factors and cytokines, thereby it might be involved in the development and progression of diabetic nephropathy. This article summarizes the molecular mechanisms of diabetic nephropathy and the potential therapeutic interventions that may prevent this devastating disorder even in the presence of hyperglycemia, control of which is often difficult with current therapeutic options. PMID- 17691933 TI - Nanochemistry-based immunotherapy for HIV-1. AB - Highly active antiretroviral treatment (HAART), i.e. the combination of three or more drugs against human immunodeficiency virus type 1 (HIV-1), has greatly improved the clinical outcome of HIV-1-infected individuals. However, HAART is unable to reconstitute HIV-specific immunity and eradicate the virus. Several observations in primate models and in humans support the notion that cell mediated immunity can control viral replication and slow disease progression. Thus, besides drugs, an immunotherapy that induces long-lasting HIV-specific T cell responses could play a role in the treatment of HIV/AIDS. To induce such immune responses, DermaVir Patch has been developed. DermaVir consists of an HIV 1 antigen-encoding plasmid DNA that is chemically formulated in a nanoparticle. DermaVir is administered under a patch after a skin preparation that supports the delivery of the nanoparticle to Langerhans cells (LC). Epidermal LC trap and transport the nanomedicine to draining lymph nodes. While in transit, LC mature into dendritic cells (DC), which can efficiently present the DNA-encoded antigens to naive T-cells for the induction of cellular immunity. Pre-clinical studies and Phase I clinical testing of DermaVir in HIV-1-infected individuals have demonstrated the safety and tolerability of DermaVir Patch. To further modulate cellular immunity, molecular adjuvants might be added into the nanoparticle. DermaVir Patch represents a new nanomedicine platform for immunotherapy of HIV/AIDS. In this review, the antiviral activity of DermaVir-induced cellular immunity is discussed. Furthermore, the action of some cytokines currently being tested as adjuvants are highlighted and the adjuvant effect of cytokine plasmid DNA included in the DermaVir nanoparticle is reviewed. PMID- 17691934 TI - New insights on the perturbations of T cell cycle during HIV infection. AB - The role of the Human Immunodeficiency Virus (HIV) in the pathogenesis of the Acquired Immune-Deficiency Syndrome (AIDS) is changed. Direct HIV-mediated killing of CD4(+) T cells is not the only mechanism leading to lymphocyte depletion. There is increasing evidence that, during the chronic phases of infection, T cell activation, accelerated cell turnover, and cytokines imbalance induce the so-called cell cycle dysregulation (CCD). CCD is a recently discovered immune-pathogenic mechanism that mainly induces the depletion of both CD4(+) and CD8(+) uninfected T cells. It is due to a significant perturbation of protein metabolism as ubiquitin pathway defects of protein degradation are associated with an increased and unscheduled expression of cyclin B and p34 cdc kinase. Moreover, significant changes in the nucleolar structure and post-translational regulation of nucleolin have also been described. As modulation of CCD by anti retroviral and immune-therapies has been suggested to predict a good immunological response in HIV-infected patients, a better understanding of such a mechanism is needed in order to further clarify its role in the pathogenesis and progression of HIV infection. PMID- 17691935 TI - Eosinophilopoiesis at the cross-roads of research on development, immunity and drug discovery. AB - Eosinophils are a minority subpopulation of leukocytes whose roles in host defense against infection remain controversial, but which have been implicated in the pathogenesis of both acute allergic inflammation and the chronic bronchopulmonary remodelling in asthma. Eosinophilia, a hallmark of both helminth infections and atopic diseases, is maintained through upregulation of eosinophilopoiesis by means of increased production and effectiveness of Interleukin-5 (IL-5), a major Th2 cytokine. These mechanisms are further modulated by a wide variety of agents, including glucocorticoids, nonsteroidal anti-inflammatory drugs and mediators of inflammation. We review recent progress made by different groups in the study of eosinophilopoiesis that led to the identification of the heterogeneous targets for developmental regulation by IL-5 and other agents, and to the ongoing characterization of the molecular mechanisms that ensure their commitment to the eosinophil lineage. We argue that the study of eosinophilopoiesis provides insight into basic developmental processes, and especially into how modulators influence the constitutive rate of eosinophil production by controlling the rates of apoptosis and terminal differentiation. The mechanisms underlying the apparently paradoxical effects of dexamethasone, a drug widely employed to control inflammation, as well as the role of specific molecular targets (including inducible NO synthase and CD95/Fas) in developmental regulation, are discussed in detail. We further argue that eosinophilopoiesis offers unique insights of how immune and endocrine effector loops interact to control both the steady-state responses to IL-5 and the susceptibility to modulation of these responses by drugs and cytokines. We also review the existing evidence on the recruitment of circulating stem cells and progenitors into inflammatory sites, and on a critical role for IL-5 in the accumulation of eosinophil lineage-committed progenitors in lungs of allergic mice. Finally, we review recent progress in the study of the regulatory T cell populations present in bone-marrow, and discuss alternative mechanisms through which cellular immunity may influence eosinophilopoiesis. PMID- 17691936 TI - Cross-talk between NO and arachidonic acid in inflammation. AB - Inducible nitric oxide synthase (iNOS) is expressed in a variety of cell types, in particular in inflammatory cells, in response to diverse pro-inflammatory stimuli. This process requires critical levels of arachidonic acid (AA), generated by constitutive phospholipase A(2) (PLA(2)), promoting tyrosine kinase dependent phosphorylation, and inhibition, of constitutive NOS. Lowering basal NO levels is indeed critical for the activation of nuclear factor-kappaB (NF kappaB), and thus for the expression of genes (e.g. iNOS) regulated by this transcription factor. It is interesting to note that NO and AA, two small lipid soluble molecules, rapidly cross the plasma membrane thereby allowing the triggering of the above responses in distal cells. That is, constitutive NO might inhibit NF-kappaB activity in the same cells (e.g. astrocytes) in which it is generated, as well as in other cells that do not express constitutive NOS (e.g. microglia). NO from cells unable to respond to pro-inflammatory stimuli (e.g. neurons) will also contribute to these effects. Along the same line, AA released by pro-inflammatory molecules in specific cell types (e.g. astrocytes) might suppress constitutive NOS activity in the same cells as well as in other cells (e.g. neurons). Thus, AA produced at the very early stages of the inflammatory response is a likely critical signal switching the regulation of the "NO tone" from physiological (i.e. mediated by constitutive NOS) to pathological (i.e. mediated by iNOS). This second phase of the inflammatory response is often accompanied by the onset of deleterious effects in the tissue in which a critical role is played by iNOS-derived NO (directly or indirectly, i.e. via formation of peroxynitrite) as well as by products of the AA cascade. In summary, we suggest that the relative amounts of NO and AA, released by their constitutive enzymes, produce autocrine and paracrine effects regulating the onset of an inflammatory response in which, in addition to other factors, NO and AA are extensively released by their inducible enzymes. PMID- 17691937 TI - The involvement of the nitric oxide in the effects and expression of opioid receptors during peripheral inflammation. AB - Peripheral inflammation enhances the antinociceptive effects of opioid receptor agonists through the activation of peripheral opioid receptors whose expression also increases during inflammatory pain. Similarly, intestinal inflammation also increases the antitransit and antiexudative effects of opioids as well as the expression of neuronal and extra-neuronal opioid receptors located in the gut. Nitric oxide has been described either as pro- or antiinflammatory and could produce both pro- and antinociceptive effects. In addition, numerous studies have shown that the L-arginine-nitric oxide-cGMP system participates in the antinociceptive and in the intestinal effects produced by opioids during peripheral inflammation by enhancing their effects. Thus, substances capable of inhibiting cyclic guanosine-3',5'-monophosphate (cGMP) degradation or nitric oxide donors increase the analgesic effects of opioid receptor agonists during peripheral inflammation. At the same time, the administration of nitric oxide synthase (NOS) or guanylate cyclase inhibitors decreases those effects. In accordance with these results, different clinical trials have also demonstrated that the co-administration of nitric oxide donors with opioids is highly beneficial in the treatment of pain in patients. In the gut, nitric oxide has a further pro- and antiinflammatory action. It is also involved in the enhanced antitransit and antiexudative effects produced by opioids and in the up regulation of the mu-opioid receptor gene transcription observed in the inflamed intestine. To sum up, a better knowledge of the involvement of the L-arginine nitric oxide-cGMP pathway in the opioid mechanisms of action and a better understanding of the pathways that regulate the expression of opioid receptors during peripheral inflammation are essential to developing improved analgesic/antiinflammatory therapies. PMID- 17691938 TI - Biological markers for multiple sclerosis. AB - Multiple sclerosis (MS) is the most common disabling neurological disease in young adults and is thought to result from an autoimmune attack against autoantigens within the myelin sheath. A characteristic feature of MS is the broad heterogeneity of clinical, histopathological and immunological phenotypes, which urges a more differentiated defining of patients by biological markers that reflect the underlying disease process and allow the prediction of disease courses and treatment responses. Here we review the current research on the identification of biomarkers for MS in cerebrospinal fluid and/or blood. We will focus on antibodies to myelin and non-myelin antigens, cells and soluble molecules of the immune system and the brain as biomarkers for 1) the diagnosis and prediction of clinical courses, 2) disease activity and 3) treatment response in MS. PMID- 17691939 TI - Antileukotriene drugs: clinical application, effectiveness and safety. AB - Cysteinyl leukotrienes (Cys-LTs) are potent proinflammatory mediators derived from arachidonic acid through the 5-lypoxigenase (5-LO) pathway. They exert important pharmacological effects by interaction with at least two different receptors: Cys-LT(1) and Cys-LT(2). By competitive binding to the Cys-LT(1) receptor, leukotriene receptor antagonist drugs such as montelukast, zafirlukast, and pranlukast, block the effects of Cys-LTs and alleviate the symptoms of many chronic diseases, especially bronchial asthma and allergic rhinitis. Evidence obtained by randomized clinical trials as also by direct experience derived from patients suffering from asthma and allergic rhinitis justifies a broader role for leukotrienes receptor antagonists (LTRAs). Recently published studies and case reports have demonstrated beneficial effects of LTRAs on other diseases commonly associated with asthma (exercise induced asthma, rhinitis, chronic obstructive pulmonary disease, interstitial lung disease, chronic urticaria, atopic dermatitis, allergic fungal disease, nasal polyposis, and paranasal sinus disease) as well as other diseases not connected to asthma (migraine, respiratory syncytial virus postbronchiolitis, systemic mastocytosis, cystic fibrosis, pancreatitis, vulvovaginal candidiasis, cancer, atherosclerosis, eosinophils cystitis, otitis media, capsular contracture, and eosinophilic gastrointestinal disorders). The aim of this review is to show the most recent applications and effectiveness in clinical practice of the LTRAs. PMID- 17691940 TI - Monoclonal antibody "gold rush". AB - The market, sales and regulatory approval of new human medicines, during the past few years, indicates increasing number and share of new biologics and emergence of new multibillion dollar molecules. The global sale of monoclonal antibodies in 2006 were $20.6 billion. Remicade had annual sales gain of $1 billion during the past 3 years and five brands had similar increase in 2006. Rituxan with 2006 sales of $4.7 billion was the best selling monoclonal antibody and biological product and the 6th among the top selling medicinal brand. It may be the first biologic and monoclonal antibody to reach $10 billion annual sales in the near future. The strong demand from cancer and arthritis patients has surpassed almost all commercial market research reports and sales forecast. Seven monoclonal antibody brands in 2006 had sales exceeding $1 billion. Humanized or fully human monoclonal antibodies with low immunogenicity, enhanced antigen binding and reduced cellular toxicity provide better clinical efficacy. The higher technical and clinical success rate, overcoming of technical hurdles in large scale manufacturing, low cost of market entry and IND filing, use of fully human and humanized monoclonal antibodies has attracted funds and resources towards R&D. Review of industry research pipeline and sales data during the past 3 years indicate a real paradigm shift in industrial R&D from pharmaceutical to biologics and monoclonal antibodies. The antibody bandwagon has been joined by 200 companies with hundreds of new projects and targets and has attracted billions of dollars in R&D investment, acquisitions and licensing deals leading to the current Monoclonal Antibody Gold Rush. PMID- 17691941 TI - Hepatobiliary diseases and insulin resistance. AB - In recent years, there has been an increasing prevalence of obesity and related diseases. This epidemiological change has increased the interest of researchers in the molecular and biochemical pathways involved in the pathogenesis of hepatic and biliary diseases. Insulin resistance is considered the major mechanism involved in the hepatic and biliary manifestations of obesity. Epidemiological, clinical, and basic research demonstrates that insulin resistance is associated with gallstone disease, nonalcoholic fatty liver disease, and poor outcomes in viral hepatitis C treatments. Fascinating experimental evidence demonstrates that fat-induced hepatic insulin resistance may result from the activation of kinases leading to impaired insulin signaling. The insulin-resistant state is characterized by a failure to suppress hepatic glucose production and glycogenolysis, with enhanced fat accumulation in hepatocytes because of increased lipolysis, increased free fatty acid uptake by hepatocytes, and increased hepatic synthesis of triglycerides. This molecular signaling induces a low-grade chronic inflammatory state, characterized by increased levels of proinflammatory molecules and acute-phase proteins. This review summarizes the most important molecular and biochemical issues in the hepatic and biliary diseases associated with insulin resistance. PMID- 17691942 TI - Novel agents in the management of Mycobacterium tuberculosis disease. AB - The goals of tuberculosis control are to cure active disease, prevent relapse, reduce transmission and avert the emergence of drug resistance. However, since the 1960s, there have been few developments in available therapies. Currently available agents are complicated by numerous side-effects, drug interactions and the need for a long duration of therapy. Rifampicin-containing regimes lead to hepatic enzyme induction which can complicate or preclude the use of protease inhibitors and non-nucleoside reverse transcriptase inhibitors in patients infected with the human immunodeficiency virus. Furthermore, emerging drug resistance has complicated management for many patients and clinicians. Therefore, new chemotherapeutic agents are urgently needed. Existing antimicrobials are emerging as potent antituberculous agents. Recent studies have demonstrated the antituberculous activity of newer fluoroquinolones including levofloxacin, moxifloxacin, and gatifloxacin. Their use as first line antituberculous agents is currently under investigation. Furthermore, the oxazolidinones linezolid and PNU-100480 have been shown to have antituberculous activity in addition to their antibacterial effects. Several other agents are currently being developed for the treatment of tuberculosis. These agents include diarylquinolones (R207910), nitroimidazopyrans (PA-824, OPC-67683), ethambutol analogues (SQ109), cerulenin, trans-cinnamic acid, macrolides, pyrroles (LL3858), long-acting rifamycins and inhaled interferon-gamma. Furthermore, vaccines are being explored for pre-exposure and post-exposure use. This review will describe therapeutic developments in the management of tuberculosis, highlighting mechanisms of action of new pharmacological agents and their potential for clinical use. PMID- 17691943 TI - Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin module for acute myelogenous leukemia therapy: from bench to bedside. AB - The phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B, PKB)/mammalian Target Of Rapamycin (mTOR) signaling pathway plays a critical role in many cellular functions which are elicited by extracellular stimuli. However, constitutively active PI3K/Akt/mTOR signaling has also been firmly established as a major determinant for cell growth, proliferation, and survival in an wide array of human cancers. Thus, blocking the PI3K/AKT/mTOR signal transduction network could be an effective new strategy for targeted anticancer therapy. Pharmacological inhibitors of this signaling cascade are powerful antineoplastic agents in vitro and in xenografted models of tumors, and some of them are now being tested in clinical trials. Recent studies showed that PI3K/Akt/mTOR axis is frequently activated in acute myelogenous leukemia (AML) patient blasts and strongly contributes to proliferation, survival, and drug-resistance of these cells. Both the disease-free survival and overall survival are significantly shorter in AML cases with PI3K/Akt/mTOR upregulation. Therefore, this signal transduction cascade may represent a target for innovative therapeutic treatments of AML patients. In this review, we discuss the possible mechanisms of activation of this pathway in AML cells and the downstream molecular targets of the PI3K/Akt/mTOR signaling network which are important for blocking apoptosis, enhancing proliferation, and promoting drug-resistance of leukemic cells. We also highlight several pharmacological inhibitors which have been used to block this pathway for targeted therapy of AML. These small molecules induce apoptosis or sensitize AML cells to existing drugs, and might be used in the future for improving the outcome of this hematological disorder. PMID- 17691944 TI - Molecular target-guided tumor therapy with natural products derived from traditional Chinese medicine. AB - A tremendous interest exists in the Western world in Traditional Chinese Medicine (TCM) with rapidly increasing export rates of TCM products from China to Europe and USA. This led to a national decision of the Chinese government to implement a "Plan for the Modernization of Chinese Medicine". Concerning the use of Chinese medicinal herbs, two major directions can be distinguished. One field is phytochemistry and pharmacognosy. Secondary metabolites isolated from Chinese plants can be easily subjected to pharmacological, molecular biological, and pharmacogenomic analyses using methods of modern cell and molecular biology as exemplified for camptothecin from Camptotheca acuminata in the present review. The second field of interest is phytomedicine. Standardized international quality guidelines help to improve quality, safety and efficacy of Chinese medicinal herbs. Sustainability of natural products from TCM can be reached by breeding high-yield varieties or by biotechnological approaches. In the long term, natural products from TCM can contribute to the development of molecular target-guided therapies and individualized treatment strategies. PMID- 17691945 TI - Discovery and development of ATPase inhibitors of DNA gyrase as antibacterial agents. AB - DNA gyrase is an attractive and well established target for the development of antibacterial agents. This bacterial enzyme, whose biological function is to control the topological state of DNA molecules, consists of two catalytic subunits; GyrA is responsible for DNA breakage and reunion, while the subunit GyrB contains the ATP-binding site. Coumarins and cyclothialidines are natural products that inhibit the ATPase activity of DNA gyrase by blocking the binding of ATP to subunit GyrB. The mechanism of action of these compounds was exhaustively characterized by biochemical methods and supported by protein crystallography. The abundance of crystallographic data on the N-terminal domain of GyrB in its complexes with various ligands has enabled the structure-based design of novel efficient chemotypes as inhibitors of the ATPase domain. This review summarizes the discovery of ATPase inhibitors of DNA gyrase B in the last decade and their development as potential antibacterial agents. PMID- 17691946 TI - Viral infection--a cure for type 1 diabetes? AB - Autoimmune diseases are thought to arise as a detrimental combination of genetic predisposition and environmental factors. Because of their potential for direct cellular damage and causing extensive inflammation, viruses are one of the major candidates for triggering autoimmunity. Although there is epidemiological evidence, direct proof for viruses as causative agents for autoimmune disease is hard to get since most viruses have been eliminated from the system by the time of diagnosis. However, evidence from various animal models suggests that viruses can indeed initiate or accelerate autoimmune diseases, such as type 1 diabetes or experimental allergic encephalomyelitis. In contrast, viruses have been also demonstrated to abrogate autoimmune disease in animal models. These observations might offer one explanation why increased frequencies of allergies and autoimmune diseases parallel with higher hygienic standards. This review reflects on the epidemiological evidence for the association of viruses with autoimmune diseases, the experimental evidence for viruses to abrogate an ongoing autoimmune destruction and evaluates the possibility for a therapeutic application. PMID- 17691947 TI - HTR2A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies. AB - Variants at the gene encoding for the 5-hydrosytryptamine (serotonin) receptor 2A (HTR2A) have been associated with many psychiatric disorders such as schizophrenia, mood disorders, attention deficit hyperactivity disorder, suicide, anxiety disorders, obsessive-compulsive disorder, eating disorders, and Alzheimer's disease. The studied SNPs differ across studies, in the present review we focused on available evidence with the aim of identifying the overall phenotypic profile of HTR2A variant carriers. We then extensively analyzed all SNPs of the HTR2A gene with criteria of frequency, haplotype blocks, previous evidence, functionality in order to obtain a list of suitable SNPs for future studies that properly cover all possible genetic control of the HTR2A gene. Genetic association studies report conflicting and generally negative results. Most replicated data suggest C allele of the 102 T/C and Tyr452 variants as risk factor for psychosis and antipsychotic response, but the number of not replicating studies does not allow to draw any definite conclusion. Moreover their impact as risk factors is very small. In the other investigated psychiatric fields, evidence shows no involvement or at least a small and not replicated role for HTR2A gene variants. Conflicting and negative results could be due to a real marginal role of this receptor gene variants, or it could be caused by a lack of gene coverage of investigated SNPs. We suggest a wider investigation of the HTR2A gene to better understand its role in psychiatric disorders, preferably complemented with the use of proteomic or metabolomic approaches. PMID- 17691948 TI - Anti-arrhythmic properties of N-3 poly-unsaturated fatty acids (n-3 PUFA). AB - Omega-3 fatty acids (Poly-Unsaturated Fatty Acids or PUFA n-3) have been initially found to reduce plasma levels of triglycerides and to increase levels of high-density lipoprotein in patients with marked hypertriglyceridemia. However, in both bench research studies and clinical trials, omega-3 fatty acid intake has recently been associated with an anti-arrhythmic efficacy. At experimental level, n-3 PUFA administration produces several actions on ionic channels regulating transmembrane action potential. At clinical level, the most significant finding was the reduction in the incidence of sudden death in survivors of MI in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevention trial and the subsequent recommendation for administration of fish oil as part of the post-infarction regimen in European guidelines. More recently, Omega-3 fatty acids administration has been associated with a lower incidence of atrial fibrillation in patients who underwent cardiac surgery. Contrasting results have been instead reported in patients with implantable cardioverter defibrillators. This article reviews in detail the basic and clinical research studies of fish oil as an anti-arrhythmic entity, the types of arrhythmias that have been beneficially affected by fish oil administration, and the presumed and known mechanisms by which the beneficial actions are exerted. PMID- 17691949 TI - Current treatments of primary sclerosing cholangitis. AB - Primary Sclerosing Cholangitis (PSC) is a chronic cholestatic disease characterized by hepatic inflammation and obliterative fibrosis, resulting in both intra- and extra-hepatic bile duct strictures. End-stage liver disease and bile duct carcinoma represent frequent complications. Incidence and prevalence of PSC in USA have been recently estimated as 0.9 per 100,000 person-years, and 1-6 per 100,000 person-years, respectively. Major diagnostic criteria include the presence of multifocal strictures, beadings of bile ducts, and compatible biochemical profile, once excluded secondary causes of cholangitis. Since the aetiology of PSC remains poorly defined, medical therapy is currently limited to symptom improvement and prolonged survival. Ursodeoxycholic acid (UDCA), corticosteroids and immunosuppressants have been proposed alone or in combination to improve the clinical outcome. In selected cases, surgical or endoscopic procedures need to be considered. Orthotopic liver transplantation (OLT) is at the moment the only definitive approach although disease relapse has been reported. In this article the state of the art in PSC treatment and future promises in this field are reviewed. PMID- 17691950 TI - Estrogen(s) and analogs as a non-immunogenic endogenous ligand in targeted drug/DNA delivery. AB - The maximum therapeutic potentials of pharmacologically active molecules are generally not attained due to their non specific delivery. Ligands associated with drug or delivery system through which it is delivered provide navigation and direction to the carrier system(s) so as to reach and release bioactive(s) at the desired site of action in a optimum therapeutic concentration vis a vis minimizing the undesired side effects associated with non specific delivery. Many ligands employed and implicated in targeted drug delivery have been reportedly found to be mild to strong immunogenic. Hence, their potential utility is considered to be compromised in achieving concept of magic bullet. Therefore endogenous ligand (bio self molecules) based drug/DNA delivery may be a better alternative they being biocomponents so are non-immunogenic and biocompatible per se. Estrogens and their receptors are over expressed in the several pathophysiological conditions including cardiovascular, osteoarthritis and cancer of prostate and ovaries etc. The selective high density of such portal may be utilized for targeting such estrogen receptor rich sites. The several scientific communities from various fields of specialization of science have explored estrogen(s) and their analogs for the purpose of targeting of bioactive(s) either by preparing estrogen-drug conjugates of using estrogens as site-directing ligands attached with various carrier system(s). This review presents an exhaustive account of how hormones especially estrogens and their derivatives could be used for site-specific delivery of bioactive(s), as diagnostic agents and also the future prospects of these bioligands in controlled and targeted clinical pharmacology. Estrogen-drug conjugates and various carrier systems that utilized estrogens as ligands for site-specific delivery have been reviewed and are discussed in detail. PMID- 17691951 TI - Killer beacons for combined cancer imaging and therapy. AB - Precisely localizing therapeutic agents in neoplastic areas would greatly improve their efficacy for killing tumor cells and reduce their toxicity to normal cells. Photodynamic therapy (PDT) is a promising cancer treatment modality, and near infrared fluorescence imaging (NIRF-I) is a sensitive and noninvasive approach for in vivo cancer detection. This review focuses on the current efforts to engineer single molecule constructs that allow these two modalities to be combined to achieve a high level of selectivity for cancer treatment. The primary component of these so called killer beacons is a fluorescent photosensitizer responsible for both imaging and therapy. By attaching other components, e.g. various DNA- or peptide-based linkers, quenchers or cancer cell-specific delivery vehicles, their primary diagnostic and therapeutic functions as well as their target specificity and pharmacological properties can be modulated. This modular design makes these agents customizable, offering the ability to assemble a few simple and often interchangeable functional modules into beacons with totally different functions. This review will summarize following three types of killer beacons: photodynamic molecular beacons, traceable beacons and beacons with built in apoptosis sensor. Despite the rapid progress in killer beacon development, numerous challenges remain before these beacons can be translated into clinics, such as photobleaching, delivery efficiency and cancer-specificity. In this review we outline the basic principles of killer beacons, the current achievements and future directions, including possible cancer targets and different therapeutic applications. PMID- 17691952 TI - Zoledronic acid - a multiplicity of anti-cancer action. AB - Bisphosphonates (BPs) are inhibitors of bone-resorption and have become the current standard of care for preventing skeletal complications associated with bone metastases. Among BPs, zoledronic acid (ZOL) has the strongest activity of anti-bone resorption and shows diverse direct anti-cancer effects in vitro. Some chemical and biological characteristics of ZOL indicate the potential for in vivo growth inhibition and the mechanisms responsible for the observed anti-cancer effects are beginning to be elucidated. ZOL inhibits farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway. Consequently, it inhibits the prenylation of small G-proteins such as Ras, Rap1, Rho and Rab, reduces the signals they mediate, and thereby prevents the growth, adhesion/spreading, and invasion of cancer cells. ZOL, which has a high affinity for mineralized bone, rapidly localizes to bone, resulting in therapeutically effective local concentrations for the cancer cells in bone. ZOL also blocks osteolysis and osteoclastgenesis, thus preventing the release of various growth factors which are abundantly stored in bone. Moreover, ZOL stimulates gammadelta T cells, which play important roles in innate immunity against cancer. In addition, ZOL is also a potent inhibitor of angiogenesis, probably due to the modification of various angiogenic properties of endothelial cells. Furthermore, ZOL synergizes with a variety of anticancer agents including chemotherapeutic drugs, molecular targeted agents, and other biological agents. Based on these potential anti-cancer properties, several clinical trials have been initiated to test the combination of ZOL and other agents. The accumulated encouraging evidence to date indicate that ZOL is an attractive anti-cancer agent which promises to be the next exciting therapy for patients with various cancers. PMID- 17691953 TI - DNA minor groove binders: an overview on molecular modeling and QSAR approaches. AB - Molecular recognition of DNA by small molecules and proteins is a fundamental problem in structural biology and drug design. Understanding of recognition in both sequence-selective and sequence neutral ways at the level of successful prediction of binding modes and site selectivity will be instrumental for improvements in the design and synthesis of new molecules as potent and selective gene-regulatory drugs. Minor groove is the target of a large number of non covalent binding agents. DNA binding with specific sequences, mostly AT, takes place by means of a combination of directed hydrogen bonding to base pair edges, van der Waals interactions with the minor groove walls and generalized electrostatic interactions. These factors are also responsible for protein-DNA recognition, and a number of unifying rules governing the interactions have been elucidated although it has been realized that the earlier goal of a simple recognition code between amino acids and bases is not attainable. At present relatively little is understood about the mode of action at the molecular level of the majority of minor groove-interacting drugs, although there is increasing evidence that they may act by directly blocking or inhibiting protein-DNA recognition. The present review has the aim to focus on interactions between minor groove binders and DNA through a variety of techniques that are commonly used to analyze the DNA binding properties of small molecules. In fact in the last years several articles dealing with in silico techniques on DNA minor groove binders (molecular modeling, molecular dynamics, QSAR) have been published. All these studies can be considered a support in defining valid predictive models. For this reason a compendium of all matter could be an useful support for future developments. PMID- 17691954 TI - Prostacyclin, atherothrombosis, and cardiovascular disease. AB - Prostacyclin (PGI(2)) is a major product of COX-2 catalyzed metabolism of arachidonic acid in the endothelium. Recent studies have demonstrated that PGI(2) protects against atherothrombosis. The prostacyclin receptor knockout mice exhibit increased atherosclerosis, enhanced thrombosis, and enhanced proliferative response to carotid vascular injury with increased intima to media ratios [1-3]. Moreover, the recent withdrawal of rofecoxib (Vioxx) due to increased cardiovascular events further supports the critical role of prostacyclin in inhibiting atherothrombosis in humans. Such studies have paralleled intense chemical biology studies to develop more stable prostacyclin analogues. Indeed a number of these analogues are currently being successfully used for the treatment of pulmonary hypertension. In this review we will summarize the current literature on some principles of prostacyclin analogue development, our current understanding of the receptor, and recent developments which implicate prostacyclin in atherothrombotic protection. More than 68 million Americans suffer from cardiovascular disease, which causes more deaths, disability and economic loss than any other group of diseases. Further clinical investigations of orally stable prostacyclin analogues for treatment of cardiovascular diseases other than pulmonary hypertension may now be warranted. PMID- 17691955 TI - Contribution of platelet-derived CD40 ligand to inflammation, thrombosis and neoangiogenesis. AB - CD40-CD40L interactions have been involved in inflammation and thrombosis. Several diseases are characterized by inflammation, hypercoagulability and increased prevalence of thromboembolic events. In the past decade, a series of preclinical and clinical studies has provided more insight into the pathogenetic mechanisms linking inflammatory mediators to the activation and regulation of the haemostatic system. In particular, the study of CD40-CD40L interactions has greatly contributed to understanding the role of platelets in a variety of pathophysiological conditions, including atherothrombosis, immuno-inflammatory diseases and, possibly, cancer. A wide variety of preclinical and clinical studies have generated clinical interest in the use of CD40L as a prognostic marker of thrombotic risk. However, the use of sCD40L in clinical studies requires reliable methods. For the correct interpretation of results, clinical and research laboratories and physicians must be aware of the limitations of immunoassays for this cytokine, which underlines the need for standardization of preanalytic conditions. This review will focus on biochemical evidence of CD40L involvement in platelet activation, contribution of platelet-derived CD40L to inflammation, thrombosis and neoangiogenesis, and possible methodological pitfalls regarding the appropriate specimen and preparation for laboratory evaluation of blood soluble CD40L as a biomarker in various human diseases characterized by underlying inflammation, such as atherothrombosis, cancer and immuno-inflammatory diseases. PMID- 17691956 TI - The role of PDE5-inhibitors in cardiopulmonary disorders: from basic evidence to clinical development. AB - Phosphodiesterases (PDE) are a class of proteins whose most relevant biological activity concerns the modulation of intracellular levels of cyclic nucleotides, e.g., cGMP and cAMP. PDE isoenzyme 5 (PDE5) is specifically involved in cGMP inactivation in the smooth muscle cell. Chemical inhibition of PDE5 by sildenafil, tadalafil or vardenafil recently became a valid therapeutic option aimed at overexpressing the molecular pathway originated from nitric oxide and expressed via increased cell cGMP availability. Based on the optimal tolerability and proven efficacy in various human disorders, EMEA and FDA have approved PDE5 inhibition as an efficient therapy in some cardiovascular, pulmonary and vascular diseases. More specifically, PDE5 inhibition appears successful for the treatment of idiopathic arterial pulmonary hypertension. Furthermore, PDE5 inhibition resulted in important protective effects in the myocardium, i.e., antyhypertrophic and antiapoptic, as well as vascular functions, i.e., increased tolerance to ischemia/reperfusion injury and improved endothelial function, thereby implying a potential usefulness in the treatment of patients with heart failure and coronary artery disease. Evidence currently available for considering PDE5-inhibition an additional opportunity in the treatment of common cardiopulmonary disorders is here provided. PMID- 17691957 TI - Diabetic cardiomyopathy and its prevention by metallothionein: experimental evidence, possible mechanisms and clinical implications. AB - Cardiac failure is a leading cause for the mortality of diabetic patients, in part due to a specific cardiomyopathy, referred to as diabetic cardiomyopathy, which occurs with or without co-existence of vascular diseases. Although several mechanisms responsible for diabetic cardiomyopathy have been proposed, oxidative stress is widely considered as one of the major causes for the pathogenesis of the disease. Thus, a few laboratories are trying to develop antioxidants used to prevent diabetic cardiomyopathy. Metallothioneins (MTs) are cysteine-rich metal binding proteins with several biological roles including antioxidant property. We and others have indicated the significant cardiac protection of MT against diabetes using cardiac-specific MT-overexpressing transgenic mice and OVE26MT mice (cross-bred of cardiac MT transgenic mice with genetically engineered diabetic OVE26 mice). Several possible mechanisms responsible for MT's cardiac protection from diabetes were revealed. These include MT's important roles in calcium regulation, zinc homeostasis, insulin sensitization, and antioxidant action. Since MT is ubiquitously expressed in mammalian tissues and is highly inducible by a variety of reagents such as zinc, the clinical potential for inducing cardiac MT as an antioxidant by zinc supplementation to prevent various diabetic complications, including cardiomyopathy, has been explored in diabetic animal models and patients. Since zinc has been therapeutically used for several other non-diabetic diseases in clinics, it provides further potential use of zinc for diabetic patients. Therefore, this review will briefly introduce the biochemical features of MT along with its critical roles in redox homeostasis and antioxidant function in the heart, and then discuss the current research on the prevention of diabetic cardiomyopathy by MT with an emphasis on experimental evidence, possible mechanisms, and clinical implications. PMID- 17691958 TI - Mouse models of asthma: can they give us mechanistic insights into the role of nitric oxide? AB - New clinical practice guidelines for patients with asthma include the recommendation to monitor exhaled breath nitric oxide (NO) levels. NO concentrations in exhaled breath are increased in asthmatics and increased NO levels correlate with worsening airway inflammation and asthma symptoms. The multiple roles of NO in the lung have not been delineated clearly. Clinical trials are being performed presently that test the apparently conflicting hypotheses that either donors or inhibitors of NO in the lung are effective strategies for treating asthma. These strategies evolved, in part, from results of pre-clinical studies performed in mice and other animal models. This review evaluates the existing literature with regard to mouse models of asthma and explores the often conflicting data on the role of NO, the nitric oxide synthase (NOS) enzymes, and the arginase enzymes in allergic airway inflammation. While we will emphasize the ovalbumin exposure mouse model, we will also examine other models. Where inconsistencies are identified among the studies, we attempt to determine whether such inconsistencies arise from methodological differences or alternative mechanisms. Ultimately, we address whether the allergen-exposed mouse is a suitable model for identifying promising new drugs for the treatment of human asthma. While a consensus is building that NO is beneficial or protective in subsets of asthmatics, results from studies using mouse models to investigate the individual roles of NO and the NOS enzymes in airway inflammation are often contradictory. Further research efforts with this model will allow us to distinguish which asthma patients may benefit best from NO donors and which may benefit from NO inhibitors. PMID- 17691959 TI - Escape mutations in HIV infection and its impact on CD8+ T cell responses. AB - Cellular immune responses play an important role in the control of HIV replication. Although clear evidence exists on its influence during acute HIV infection, its role during the chronic phase of the disease remains controversial. This review describes the cellular immune responses elicited against HIV mediated by CD8(+) T lymphocytes, and the mechanisms by which these cells are inefficient to completely control HIV replication and halt disease progression. The role of escape mutations as one of the most relevant mechanisms HIV has developed to evade host cellular immune responses is highlighted. PMID- 17691960 TI - Gene profiles within the adult subventricular zone niche: proliferation, differentiation and migration of neural progenitor cells in the ischemic brain. AB - Focal cerebral ischemia induces neurogenesis in the subventricular zone (SVZ) of the adult human brain. Neurogenesis is controlled by proliferation, differentiation, and migration of neural progenitor cells. This article reviews emerging data that changes of cell cycle kinetics of neural progenitor cells induced by stroke contribute to increased neural progenitor cell proliferation and that gene profiles control proliferation, differentiation, and migration of neural progenitor cells within the SVZ niche. A better understanding of gene profiles that control the biological function of adult SVZ neural progenitor cells could lead to more selective and effective treatments to enhance neurogenesis during stroke recovery. PMID- 17691961 TI - Potential utility of telmisartan, an angiotensin II type 1 receptor blocker with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity for the treatment of cardiometabolic disorders. AB - The metabolic syndrome is strongly associated with insulin resistance and consists of a constellation of factors such as hypertension and hyperlipidemia that raise the risk for cardiovascular diseases and diabetes mellitus. There is widespread agreement that the renin-angiotensin system (RAS) plays a pivotal role in the pathogenesis of insulin resistance and cardiovascular disease in diabetes. Indeed, large clinical trials have demonstrated substantial benefit of the blockade of this system for cardiovascular end-organ protection. Thus the blockade of the RAS may be a promising strategy for the treatment of the patients with the metabolic syndrome. Although several types of angiotensin II type 1 (AT(1)) receptor blockers (ARBs) are commercially available for the treatment of patients with hypertension, we have recently found that telmisartan (Micardis) could have the strongest binding affinity to AT(1) receptor. Further, telmisartan is reported to act as a partial agonist of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). These observations suggest that, due to its unique PPAR-gamma-modulating activity, telmisartan may be one of the most promising sartans for the treatment of cardiometabolic disorders. In this paper, we reviewed the potential utility of telmisartan in insulin resistance and vascular complications in diabetes. PMID- 17691962 TI - Dissecting cause and effect in the pathogenesis of psychiatric disorders: genes, environment and behaviour. AB - It has long been established that the development of psychiatric illness results from a complex interplay between genetic and environmental factors. Postmortem and genetic linkage studies have identified a number of promising candidate genes which have been reinforced by replication and functional studies. However, the fact that concordance rates for monozygotic twins rarely approach 100% highlights the involvement of environmental factors. Whilst epidemiological studies of psychiatric cohorts have demonstrated potential risk factors, such studies are clearly limited and in many cases the potential mechanism linking a given risk factor with pathogenesis remains unclear. A very powerful method of elucidating the mechanisms underlying gene-environment interactions is the use of appropriate animal models of psychiatric pathology. Whilst animals cannot be used to map the entire complexity of diseases such as schizophrenia, dissecting the symptom profile into more simply encapsulated traits or endophenotypes has proved to be a successful approach. Such endophenotypes provide a measurable link between aetiological factors and phenotypic outcome. Given the potential for the careful control and modification of an experimental animal's environment, the combination of studies of candidate genes with investigations of environmental factors is an effective heuristic tool, allowing examination of behavioural endophenotypes in conjunction with cellular and molecular outcomes. This review will consider the extant genetic, molecular, pharmacological and lesion-based models of psychiatric disorders, and the relevant methods of environmental manipulation appearing in the literature. We will discuss studies where such models have been combined, and the potential for future experimentation in this area. PMID- 17691963 TI - The Wnt/beta-catenin pathway in Wilms tumors and prostate cancers. AB - Wnt/beta-catenin signaling is constitutively increased in several major classes of tumors arising from the urogenital tract. In this review we focus on this pathway mainly in Wilms tumors and prostate carcinomas, followed by a brief discussion of its potential role in other types of urological tumors. Molecular studies in these types of cancers have highlighted novel components upstream and downstream of this central oncogenic pathway. Beta-catenin gain-of-function mutations are strongly linked to WT1 loss-of-function mutations in syndromic Wilms tumors, and Wnt/beta-catenin signaling increases androgen receptor mRNA expression and blocks apoptosis in prostate cancers. Novel downstream target genes activated by Wnt/beta-catenin signaling are emerging from expression profiling in genetically defined classes of Wilms tumors, and similar analyses are expected to reveal additional downstream genes of this pathway specific to prostate cancers. The identities of these genes will likely suggest new targeted therapies for urological malignancies. PMID- 17691964 TI - Opportunities to improve the prevention and treatment of cervical cancer. AB - Human papillomavirus (HPV) is a causal agent for approximately 5.3% of cancers worldwide, including cervical cancer, and subsets of genital and head and neck cancer. Persistent HPV infection is a necessary, but not sufficient, cause of cervical cancer. Of the >100 HPV genotypes, only about a dozen, termed "high risk", are associated with cancer. HPV-16 is present in approximately 50% of all cervical cancers and HPV-16, HPV-18, HPV-31 and HPV-45 together account for approximately 80%. Most high-risk HPV infections are subclinical, and are cleared by the host's immune system. The remainder produces low or high-grade squamous intraepithelial lesions (SILs), also called cervical intraepithelial neoplasia (CIN), which also may regress spontaneously. However persistent high grade SIL represents the precursor lesion of cervical cancer and carcinogenic progression is associated with integration of the viral DNA, loss of E2 and upregulation of viral oncogene expression, and chromosomal rearrangements like 3q gain. Cytologic screening of the cervix for SIL and intervention has reduced the incidence of cervical cancer in the US by an estimated 80% and HPV viral DNA and other molecular tests may improve screening further. The licensure of a preventive HPV vaccine ushers in a new era, but issues remain, including: protection restricted to a few oncogenic HPV types, access in low resource settings and impact on current cytologic screening protocols. Importantly, preventive HPV vaccination does not help with current HPV infection or disease. Here we examine the potential of second-generation preventive HPV vaccines and therapeutic HPV vaccination to address these outstanding issues. PMID- 17691965 TI - Molecular pathogenesis of pancreatic cancer: advances and challenges. AB - Pancreatic ductal adenocarcinoma (PDAC) is still a devastating and incurable disease with a median survival of 3-6 months and a 5-year survival rate of 1-4% when all stages are considered. Although crucial advances in our understanding of the molecular pathogenesis of the disease have been made, the exceptional aggressiveness of PDAC remains largely unexplained. Some key results will probably direct future PDAC research activities. For example, recent identification of pancreatic tumor stem cells has stimulated the debate over the cell of origin. Further, powerful new genetically engineered mouse models support the concept that stepwise progression of epithelial precursor lesions leads to invasive PDAC as a result of accumulating mutations in K-ras, INK4A/ARF, TP53 and DPC4; these models accentuate the initiating function of the K-ras mutation. Established PDAC exhibits all the classic hallmarks of cancer, including self sufficiency in growth signals, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion, and metastasis. This review provides an overview of the molecular machinery that PDAC utilizes to acquire these tumorigenic capacities. Moreover, recent advances have identified essential elements of key pathways partly recapitulating developmental signals, and of the tumor microenvironment that promotes tumor growth through the complex interplay of its different cellular components. In spite of progress in molecular research, there is still a dichotomy between the encouraging results obtained with targeted interference of numerous oncogenic pathways in vitro and a lack of significant improvement in clinical detection and survival. Thus our primary challenge remains to translate the solid knowledge of genetic and epigenetic alterations in PDAC into clinical tools which can be used for early diagnosis and effective therapy. PMID- 17691966 TI - Toll-like receptors, new horizons in sepsis. AB - Sepsis and septic shock, its more severe form, have shown alarming increases in incidence and a persistently high mortality rate, despite technological advancement allowing adequate support of vital functions in intensive care units. Progress in understanding of physiopathology has directed the therapeutic approach, until recently limited to sustaining failing organ systems and combating infectious agents, towards the alterations provoked by an unbalanced systemic inflammatory response and its deleterious effects on cellular function. Less than 10 years ago, the discovery of Toll-Like Receptor proteins, which allow the detection of pathogen molecular patterns, initiate and modulate the immune response, opened up new and exciting possibilities in approaches to sepsis. The elucidation of the transduction pathways triggered by Toll-Like Receptors activation signals exposes promising therapeutic targets. Currently, mechanisms associated within the context of Toll-Like Receptor signalization are identified in the tolerance phenomena described in the past. The description of genetic polymorphisms associated with Toll-Like Receptors, and the different patterns of response to infectious insults have defined high-risk subgroups of imbalanced immune response with greater specificity. A better understanding of the molecular structures involved in the process and the negative-regulation of some of them have opened up possibilities in antagonizing and modulating the response to the inflammatory activation mediated by Toll-Like Receptors. Having understood how the immune system recognizes pathogens and organizes the inflammatory response upon the discovery of Toll-Like Receptors and their signaling pathways, we gained an insight into the possibilities of specific treatment instead of supportive measures for sepsis. PMID- 17691967 TI - Exciting news from the messenger. PMID- 17691968 TI - Safety analysis and improved cardiac function following local autologous transplantation of CD133(+) enriched bone marrow cells after myocardial infarction. AB - The CD133(+) bone marrow cell (BMC) population includes primitive multipotent stem cells which induce neoangiogenesis. Studies suggested transplantation of these cells to infarcted myocardium can have a favorable impact on tissue perfusion and contractile performance. We assessed the feasibility, safety and functional outcomes of autologus CD133(+) BMC transplantation during coronary artery bypass grafting (CABG) in patients with recent myocardial infarction. In a prospective, nonrandomized, open-label study, 27 patients with recent myocardial infarction underwent CABG and intramyocardial injection of autologous bone marrow derived CD133(+) cells (18 patients, BMC group) or CABG alone (9 patients, control group). At 6 months after CABG, the Wall Motion Score Index (WMSI) was significantly reduced for akinetic/dyskinetic segments treated with CD133(+) cells compared with the control group (P<0.006). Likewise, comparison between baseline and follow up results of dobutamine stress echocardiography and myocardial perfusion scintigraphy showed improvement of myocardial viability and local perfusion of the infarcted zone of the BMC group compared with the control group. No complications related to CD133(+) cell transplantation were noted, either procedurally or during postoperative at a mean of 14 months follow up. In patients with recent myocardial infarction, transplantation of CD133(+) cells to the peri-infarct zone during CABG surgery is feasible and safe, with no evidence of early or late adverse events. Moreover, these cells might restore tissue viability and improve perfusion of the infarcted myocardium, suggesting that they may induce myogenesis as well as angiogenesis. PMID- 17691969 TI - Cerebral aneurysm formation in nitric oxide synthase-3 knockout mice. AB - We sought to evaluate the influence of specific vasoactive gene knockouts on the process of intracranial aneurysm formation in mice. Thirty wild type, 7 nitric oxide synthase (NOS)-2 knockout, 6 NOS-3 knockout, and 8 plasminogen activator inhibitor (PAI)-1 knockout female mice underwent left common carotid artery ligation at 2 to 6 months of age. After a survival period (average 20.4 months +/ 1.5 months), the brains were perfusion fixed with 10% buffered formalin for 10 minutes and then perfused with India ink. Brain and intact cerebral circulation were surgically removed and further fixed in 10% buffered formalin for 4 additional days. The basal cerebral circulation of each brain was examined for the presence of intracranial aneurysms under a surgical microscope (3x-21x). Suspected aneurysms were further dissected for histological analysis. Specimens were embedded in epoxy resin, cut into 0.5 and 1.0 micron sections, and stained with Toluidine blue. A neuropathologist blinded to genotype and surgical microscopy results examined the slides for evidence of aneurysmal pathology. Two intracranial aneurysms in 2 NOS-3 knockout mice were confirmed by histology. No intracranial aneurysms were confirmed in any wild type, NOS-2 knockout, or PAI-1 knockout mice. Histological analysis of aneurysms revealed loss of elastica, subendothelial collagen deposition, and perivascular lymphocytic infiltration. Our results suggest that NOS-3 knockout, but not PAI-1 or NOS-2 knockout, predisposes to the formation of intracranial aneurysms in mice subjected to unilateral carotid artery ligation. Due to small sample sizes however, selection bias cannot be excluded and further investigation is necessary to confirm our results. PMID- 17691970 TI - Neurohormonal activation in ischemic stroke: effects of acute phase disturbances on long-term mortality. AB - A stress response consisting of elevated levels of cortisol and catecholamines is common after acute stroke. The plasma levels of natriuretic peptides are known to be elevated after ischemic stroke, but the relations of these neurohormonal systems in the acute phase of stroke and their impact on long-term prognosis have not been studied previously. A series of 51 consecutive patients (mean age 68+/ 11 years) with an ischemic first-ever stroke underwent a comprehensive clinical investigation, scoring of their neurologic deficit by Scandinavian Stroke Scale (SSS), Barthel Index (BI) and Modified Ranking Scale (MRS) as well as measurements of plasma cortisol, norepinephrine, epinephrine, ACTH and atrial (N ANP) and brain (N-BNP) natriuretic peptides on the 2nd and 7th days after ischemic stroke. The patients were followed up for 44+/-21 months. Higher levels of cortisol, ACTH and natriuretic peptides were observed in the stroke patients who died (n=22) during the follow-up than in the stroke survivors. Cortisol levels associated significantly with the 2nd and 7th day N-ANP and N-BNP levels, catecholamine levels (r= 0.55 - 0.94, p<0.01 for all) and measures of neurologic deficit (r= 0.36 - -0.44, p<0.05). High acute phase cortisol levels assessed either in the morning (RR=5.4, p<0.05) or in the evening (RR=5.8, p<0.05) predicted long-term mortality after stroke in multivariate analysis. Activation of the hypothalamus-pituitary-adrenal axis in ischemic stroke is associated with elevated levels of natriuretic peptides. High cortisol and natriuretic peptide values predict long-term mortality after ischemic stroke, suggesting that this profound neurohumoral disturbance is prognostically unfavourable. PMID- 17691971 TI - A non-steroidal anti-inflammatory agent provides significant protection during focal ischemic stroke with decreased expression of matrix metalloproteinases. AB - The present study was designed to investigate whether the neuroprotective effect of nimesulide was mediated by inhibiting expression of matrix metalloproteinase-9 (MMP-9) and/or matrix metalloproteinase-2 (MMP-2) in a rat model of thrombolytic reperfusion after the embolic focal cerebral ischemia (FCI). It was found that nimesulide at therapeutically relevant doses (3, 6 and 12 mg/kg) decreased neurological deficits, infarct volume, brain index and brain water content in a dose-dependent manner. Hemorrhagic transformation was reduced by 64% with treatment of 12 mg/kg nimesulide. Quantitative analysis of immunohistochemical staining of brain slices showed that the neuron number expressing MMP-9 and MMP-2 increased in the model animals treated with vehicle (p<0.01 vs sham group), and significantly decreased in nimesulide-treated animals (p<0.05 or p<0.01 vs vehicle group). Our results demonstrate that nimesulide significantly reduces the degree of neuronal injury and hemorrhage transformation caused by thrombolytic reperfusion after the embolic FCI, and that inhibition of MMP-9 and MMP-2 expression contributes at least in part to the neuroprotection. PMID- 17691972 TI - Effects of thyroid hormones on memory and on Na(+), K(+)-ATPase activity in rat brain. AB - Thyroid hormones (THs), including triiodothyronine (T3) and tetraiodothyronine (T4), are recognized as key metabolic hormones of the body. THs are essential for normal maturation and function of the mammalian central nervous system (CNS) and its deficiency, during a critical period of development, profoundly affects cognitive function. Sodium-potassium adenosine 5'-triphosphatase (Na(+), K(+) ATPase) is a crucial enzyme responsible for the active transport of sodium and potassium ions in the CNS necessary to maintain the ionic gradient for neuronal excitability. Studies suggest that Na(+), K(+)-ATPase might play a role on memory formation. Moreover, THs were proposed to stimulate Na(+), K(+)-ATPase activity in the heart of some species. In this work we investigated the effect of a chronic administration of L-thyroxine (L-T4) or propylthiouracil (PTU), an antithyroid drug, on some behavioral paradigms: inhibitory avoidance task, open field task, plus maze and Y-maze, and on the activity of Na(+), K(+)-ATPase in the rat parietal cortex and hippocampus. By using treatments which have shown to induce alterations in THs levels similar to those found in hyperthyroid and hypothyroid patients, we aimed to understand the effect of an altered hyperthyroid and hypothyroid state on learning and memory and on the activity of Na(+), K(+)-ATPase. Our results showed that a hyper and hypothyroid state can alter animal behavior and they also might indicate an effect of THs on learning and memory. PMID- 17691974 TI - Physiology and pathophysiology of Na(+)/H(+) exchange isoform 1 in the central nervous system. AB - Na(+)/H(+) exchangers (NHEs) conduct the electroneutral exchange of proton (H(+)) and sodium (Na(+)) ions across cellular membranes down their concentration gradients. To date, nine NHE family members have been cloned from mammals and share a common secondary structure. The ubiquitous exclusive plasma membrane NHE isoform 1 (NHE1) is a major membrane transport mechanism in regulation of intracellular pH (pH(i)) and volume. In addition to its role in regulation of ionic homeostasis, NHE1 can directly interact with other regulatory cellular signaling pathways, including modulation of the activity of mitogen-activated protein kinases (MAPKs) and Akt/protein kinase B (PKB). Thus, NHE1 is a multifaceted regulator of cell migration, proliferation, and cell death. NHE1 also plays pivotal roles under a number of pathophysiological conditions such as osmotic stress, acidosis, and mechanical stress. NHE1 is the most abundant NHE isoform in the rat central nervous system (CNS). This review discusses distribution and regulation of NHE1, and its physiological roles in the CNS. Moreover, it includes an extensive presentation of studies on activation of NHE1 under ischemic conditions in the CNS and its impact on Na(+) and Ca(2+) ionic homeostasis as well as on cell survival and damage. PMID- 17691973 TI - Vascular injury during elevated glucose can be mitigated by erythropoietin and Wnt signaling. AB - Impacting a significant portion of the world's population with increasing incidence in minorities, the young, and the physically active, diabetes mellitus (DM) and its complications affect approximately 20 million individuals in the United States and over 100 million individuals worldwide. In particular, vascular disease from DM may lead to some of the most serious complications that can extend into both the cardiac and nervous systems. Unique strategies that can prevent endothelial cell (EC) demise and elucidate novel cellular mechanisms for vascular cytoprotection become vital for the prevention and treatment of vascular DM complications. Here, we demonstrate that erythropoietin (EPO), an agent that has recently been shown to extend cell viability in a number of systems extending beyond hematopoietic cells, prevents EC injury and apoptotic nuclear DNA degradation during elevated glucose exposure. More importantly, EPO employs Wnt1, a cysteine-rich glycosylated protein involved in gene expression, cell differentiation, and cell apoptosis, to confer EC cytoprotection and maintains the integrity of Wnt1 expression during elevated glucose exposure. In addition, application of anti-Wnt1 neutralizing antibody abrogates the protective capacity of both EPO and Wnt1, illustrating that Wnt1 is an important component in the cytoprotection of ECs during elevated glucose exposure. Intimately linked to this cytoprotection is the downstream Wnt1 pathway of glycogen synthase kinase (GSK 3beta) that requires phosphorylation of GSK-3beta and inhibition of its activity by EPO. Interestingly, inhibition of GSK-3beta activity during elevated glucose leads to enhanced EC survival, but does not synergistically improve protection by EPO or Wnt1, suggesting that EPO and Wnt1 are closely tied to the blockade of GSK 3beta activity. Our work exemplifies an exciting potential application for EPO in regards to the treatment of DM vascular disease complications and highlights a previously unrecognized role for Wnt1 and the modulation of the downstream pathway of GSK-3beta to promote vascular cell viability during DM. PMID- 17691975 TI - The response of the aged brain to stroke: too much, too soon? AB - Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain injury, but the cellular processes underlying these phenomena are only recently coming to light. Potential mechanisms include changes in brain plasticity-promoting factors, unregulated expression of neurotoxic factors, or differences in the generation of scar tissue that impedes the formation of new axons and blood vessels in the infarcted region. Behaviorally, aged rats are more severely impaired by stroke than are young rats, and they also show diminished functional recovery. Infarct volume does not differ significantly in young and aged animals, but critical differences are apparent in the cytological response to stroke, most notably an age-related acceleration of the establishment of the glial scar. The early infarct in older rats is associated with a premature accumulation of BrdU-positive microglia and astrocytes, persistence of activated oligodendrocytes, a high incidence of neuronal degeneration, and accelerated apoptosis. Regeneration-associated mechanisms in the rat brain are active throughout life, albeit at lower levels in the aged animals. However; after stroke in aged rats, neuroepithelial marker-positive cells emanating largely from capillaries did not make a significant contribution to neurogenesis in the infarcted cortex of aged animals. Furthermore, the expression of plasticity associated proteins, such as MAP1B, was delayed in aged rats. Tissue recovery was further delayed by the upregulation of Nogo, ephrin-A5 and MAG, which exert a powerful negative effect on axonal sprouting in the aged peri-infarct cortex, and by an age-related increase in the amount of the neurotoxic C-terminal fragment of the beta-amyloid precursor protein (betaAPP) at 2 wks post-stroke. Our findings indicate that the aged brain has the capability to mount a cytoproliferative response to injury, but the timing of the cellular and genetic response to cerebral insult is dysregulated in aged animals, thereby further compromising functional recovery. Elucidating the molecular basis of this phenomenon in the aging brain could yield novel approaches to neurorestoration following stroke or head injury in the elderly. PMID- 17691977 TI - 5HT1F- and 5HT7-receptor agonists for the treatment of migraines. AB - Serotonin was the first neurotransmitter believed to be involved in cephalic pain transfer forward to the cortex, but the precise mechanism was confirmed only after sumatriptan, a 5-HT(1B/1D0) high affinity agonist, was introduced in the acute treatment of migraine. Although very efficient for migraine relief, activation of 5-HT(1B) receptor may also cause vasoconstriction outside brain, within the heart arteries for example. Unlike 5-HT(1B), the 5-HT(1D) receptor is not located in vascular tissues but exclusively within neuronal, but high affinity agonists for 5-HT(1D) failed to prove clinical significance in randomized trials. The recent clone of 5-HT(1F) receptor together with data showing that sumatriptan exerts high affinity for this receptor subtype generated high expectations. Potent agonists for 5-HT(1F) receptors were effective in animal models for migraine and later clinical trials showed efficacy even in humans, introducing the first line future anti-migraine drugs. Apart from 5 HT(1F), another new cloned 5-HT subtype receptor, the 5-HT(7) also attracts attention. Recently developed and clinically tested selective 5HT(7) antagonists SB-269970-A and SB-656104-A suggest that the receptor may play a role in other CNS disorders including anxiety and cognitive disturbances, suggesting a potential role for the migraine prophylaxis. These data and speculations are discussed in details in this paper with special references. PMID- 17691978 TI - Pathophysiology of tension-type headache: potential drug targets. AB - The pathophysiology of tension-type headache is still far from clear, although recent advances in basic and clinical research have increased our knowledge about mechanisms underlying this disorder. Experimental studies suggest that increased excitability of the CNS generated by repetitive and sustained pericranial myofascial input may be responsible for transformation of episodic tension-type headache into chronic form. Future studies should focus on the identification of the source of peripheral nociception in patients with tension-type headache and the development of more effective and specific treatment modalities. PMID- 17691979 TI - CGRP-receptor antagonism in migraine treatment. AB - Primary headaches are among the most prevalent neurological disorders, afflicting up to 16% of the adult population. Associated pain originates from intracranial blood vessels that are innervated by sensory nerves storing several neurotransmitters. In primary headaches, there is a clear association between the headache and the release of calcitonin gene-related peptide (CGRP) but not with other neuronal messengers. The specific purpose of this review is to describe CGRP in the human cranial circulation and to elucidate a possible role for a specific antagonist in the treatment of primary headaches. Acute treatment by administration of a triptan (5-HT(1B/1D) agonist) results in alleviation of the headache and normalization of the elevated CGRP level. The mechanism of action of triptans involves vasoconstriction of intracranial vessels and a presynaptic inhibitory effect of the trigeminal sensory nerves. The central role of CGRP in migraine and cluster headache pathophysiology has led to the search for small molecule CGRP antagonists, which would predictably have less cardiovascular side effects as compared to the triptans. The initial pharmacological profile of such a group of compounds has recently been disclosed. These compounds have high selectivity for human CGRP receptors and are reported to be efficacious in the relief of acute attacks of migraine. PMID- 17691980 TI - GABAergic drugs for the treatment of migraine. AB - Within the last decades significant progress has been made in the understanding of the underlying pathophysiological mechanisms of migraine. There is a general agreement now that migraine is not only a vascular phenomenon but also a genetically determined heterogenic ion-channelopathy resulting in cortical spreading-depression-like events, the temporary impairment of antinociceptive structures of the brainstem and the activation of the trigeminal-vascular system. The development and use of drugs targeting ion-channels and subsequently reducing cortical excitability appears as a promising avenue for both the acute treatment of migraine and migraine prevention. This review summarizes the current knowledge and evidence for GABAergic drugs in the treatment of migraine. PMID- 17691981 TI - The role of glutamate and its receptors in migraine. AB - Glutamate (Glu) is the principal excitatory neurotransmitter in the central nervous system. Its receptors are classified into ionotropic receptors, which are ion channels and include NMDA, AMPA and kainate receptors, named after the agonists that selectively bind to them, and metabotropic receptors, which are G protein coupled receptors. The trigeminal system is considered to play a key role in migraine pathophysiology, trafficking pain signals from the head and face to the trigeminal nucleus caudalis. The role of glutamate in the pathophysiology of migraine is implicated by data from animal and human studies. Animal studies include experiments of cortical spreading depression, studies of c-fos protein expression in trigeminal nucleus caudalis, studies of plasma protein extravasation and electrophysiological studies. Human studies investigating the role of Glu in migraine pathogenesis measured the levels of Glu in plasma, platelets and cerebrospinal fluid, studied its effect on migraine symptoms and examined the effect of Glu in modulating sensitization. Findings from both the animal and the human studies suggest a link between glutamate and migraine and further suggest that glutamate plays a key role in migraine mechanisms. In the future, efforts should be made to further investigate the role of glutamate in migraine pathogenesis and, subsequently, in migraine treatment. PMID- 17691982 TI - Nitric oxide in migraine. AB - The potent vasodilatator and messenger molecule nitric oxide (NO) is believed to play a key role in migraine pathogenesis. NO donors such as glyceryl trinitrate (GTN) can cause headache. Infusion of GTN leads to a migraine attack in migraineurs with a latency of 4 to 6 hours. In this review we focus in the role of nitric oxide and the transcription factor nuclear factor-kappaB (NF-kappaB) in migraine pathophysiology in humans and animal models. NO is involved in pain transmission, hyperalgesia, chronic pain, inflammation and central sensitization mostly in a cyclic guanosinemono-phosphate (cGMP) dependent way. We aim to illustrate how NO is implicated in the induction of a migraine attack in migraineurs and how experimental animal models may help to elucidate the mechanisms of the human GTN response. Because of the role of NO in migraine we try to assess if and how the action of preventative migraine drugs involves the NO pathways. More knowledge about the involvement of NO in the genesis of migraine headache may also provide possible future therapeutic targets for acute migraine therapy. PMID- 17691983 TI - Novel targets for drugs in schizophrenia. AB - Since the discovery of the first antipsychotic drug, chlorpromazine, in the early 1950s, all effective antipsychotic drugs have been found to share the common property of dopamine D2 receptor antagonism. There has been some suggestion that simple D2 receptor antagonism may not confer optimal antipsychotic efficacy. Currently available antipsychotic drugs leave many symptoms of the illness untreated and cause unacceptable side effects. Recent research in schizophrenia suggests a number of potential new non-D2 targets for pharmacotherapy including glutamate, acetylcholine and serotonin neurotransmitter systems. This review summarises the main neurochemical theories of schizophrenia, and, in the light of these, examines possible therapeutic targets for new antipsychotic drugs. PMID- 17691984 TI - Chinese herbs and herbal extracts for neuroprotection of dopaminergic neurons and potential therapeutic treatment of Parkinson's disease. AB - Parkinson's disease (PD) is a common and debilitating degenerative disease resulting from massive degenerative loss of dopamine neurons, particularly in the substantia nigra. The most classic therapy for PD is levodopa administration, but the efficacy of levodopa treatment declines as the disease progresses. The neuroprotective strategies to rescue nigral dopamine neurons from progressive death are currently being explored, and among them, the Chinese herbs and herbal extracts have shown potential clinical benefit in attenuating the progression of PD in human beings. Growing studies have indicated that a range of Chinese herbs or herbal extracts such as green tea polyphenols or catechins, panax ginseng and ginsenoside, ginkgo biloba and EGb 761, polygonum, triptolide from tripterygium wilfordii hook, polysaccharides from the flowers of nerium indicum, oil from ganoderma lucidum spores, huperzine and stepholidine are able to attenuate degeneration of dopamine neurons and sympotoms caused by the neurotoxins 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) in vitro and in vivo conditions. In addition, accumulating data have suggested that Chinese herbs or herbal extracts may promote neuronal survival and neurite growth, and facilitate functional recovery of brain injures by invoking distinct mechanisms that are related to their neuroprotective roles as the antioxidants, dopamine transporter inhibitor, monoamine oxidase inhibitor, free radical scavengers, chelators of harmful metal ions, modulating cell survival genes and signaling, anti-apoptosis activity, and even improving brain blood circulation. New pharmaceutical strategies against PD will hopefully be discovered by understanding the various active entities and valuable combinations that contribute to the biological effects of Chinese herbs and herbal extracts. PMID- 17691985 TI - Therapeutic potential of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors for the treatment of retinal and eye diseases. AB - 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, generically termed statins, are widely prescribed for their cholesterol-lowering properties. In addition to lipid-lowering properties, statins have pleiotropic effects including anti-inflammatory, anti-apoptotic, and antiproliferative effects. Recently, data from experimental and observational studies have indicated that statins could also become a treatment option for diseases of the central nervous system (CNS). Many neurodegenerative diseases particularly affect the retina and other ocular structures and are the cause for blindness. This review, focused on recent clinical and experimental data, discusses known and putative mechanisms of statin actions underlying neuroprotective effects in relevant retinal and eye diseases. In addition, it presents evidence for the role of heat shock proteins (Hsps) as target of statin-mediated neuroprotective effects in ocular diseases. PMID- 17691986 TI - Extrasynaptic GABA and glutamate receptors in epilepsy. AB - Epilepsy is a neurological disorder in which normal brain function is disrupted as a consequence of intensive and synchronous burst activity from neuron assemblies. Epilepsies result from long-lasting plastic changes in the brain affecting neurotransmitter release, the properties of receptors and channels, synaptic reorganization and astrocyte activity. There is considerable evidence for alterations in glutamatergic and GABAergic synaptic transmission in the origin of the paroxysmal depolarization shifts that initiate epileptic activity. However, recent studies on non-synaptic transmission, receptor mobility and glia neuron signaling pathways suggest that extrasynaptic GABA and glutamate receptors may play an important role in seizure initiation, maintenance and arrest. Extracellular aminoacids such as glutamate, aspartate, glycine and GABA seem to communicate neurons and glial cells acting primarily on extrasynaptic receptors. Synaptic and extrasynaptic glutamate and GABA receptors have been show to play different roles in neuronal excitability. NMDA and GABAA receptors expressed in a single neuron can be differentially regulated based on subcellular localization, and it has been proposed that distinct regulation of synaptic versus extrasynaptic receptors provides a mechanism for receptor adaptation in response to a variety of stimuli. Furthermore, glutamate and GABA receptors are highly mobile, and the number and composition of extrasynaptic receptors can be modulated by several factors. This review addresses recent advances in our understanding of the role of extrasynaptic receptors in epilepsy, suggesting that extrasynaptic receptors and their mechanisms of regulation are expected to be important pharmacological targets. PMID- 17691988 TI - Camptothecin: therapeutic potential and biotechnology. AB - Camptothecin (CPT) and its derivatives have been received considerable attention recently. Two semi-synthetic derivatives, topotecan and irinotecan, are currently prescribed as anticancer drugs. Several more are now in clinical trial. CPT is produced in many plants belonging to unrelated orders of angiosperms. At present, CPT supplied for pharmaceutical use is extracted from the plants, Camptotheca acuminata and Nothapodytes foetida. Several efforts have been made to sustain a stable production of CPT by in vitro cell cultures of C. acuminata, N. foetida and Ophiorrhiza pumila. Recent report showed that plants are not the only sources that produce CPT. CPT was reported to be produced from the endophytic fungus isolated from the inner bark of N. foetida. The hairy root cultures of C. acuminata and O. pumila produce and secrete CPT into the medium in large quantities. These reports suggest the possibility to develop large-scale production of CPT. In addition, recent advance in the cloning and characterization of biosynthetic enzymes involved in CPT biosynthetic pathway provides valuable information for developing genetically engineered CPT-producing plants. PMID- 17691989 TI - Tropane and nicotine alkaloid biosynthesis-novel approaches towards biotechnological production of plant-derived pharmaceuticals. AB - Many plants belonging to the Solanaceae family have been used as a source of pharmaceuticals for centuries because of their active principles, tropane and nicotine alkaloids. Tropane alkaloids, atropine, hyoscyamine and scopolamine, are among the oldest drugs in medicine. On the other hand nicotine, the addictive agent in tobacco, has only recently gained attention as a backbone for novel potential alkaloids to be used for certain neurological diseases. The biotechnological production of alkaloids utilizing plant cells as hosts would be an attractive option. However, to date very little success in this field has been gained because of the lack of understanding how these compounds are synthesized in a plant cell. Metabolic engineering attempts have already shown that when the rate-limiting steps of the biosynthetic pathway are completely known and the respective genes cloned, the exact regulation towards desired medicinal products will be possible in the near future. The new functional genomics tools, which combine transcriptome and metabolome data, will create a platform to better understand a whole system and to engineer the complex plant biosynthetic pathways. With the help of this technology, it is not only possible to produce known plant metabolites more effectively but also to make arrays of new compounds in plants and cell cultures. PMID- 17691990 TI - Metabolic engineering in isoquinoline alkaloid biosynthesis. AB - Higher plants produce diverse classes of metabolites. Metabolic engineering offers tremendous potential to improve the production and quality of these chemicals. This report summarizes the possibility of using metabolic engineering in benzylisoquinoline alkaloid biosynthesis. Benzylisoquinoline alkaloids, such as morphine, sanguinarine, and berberine, are synthesized from tyrosine via reticuline in Magnoliaceae, Ranunculaceae, Berberidaceae, Papaveraceae, and many other species. The early pathway from tyrosine to reticuline is common among many plant species, whereas there is more diversity in late pathways. This review describes several strategies to improve the yield and quality of benzylisoquinoline alkaloids. First, the overexpression of a rate-limiting enzyme in an early pathway to increase the overall alkaloid yield is discussed. Second, the introduction of a new branch into the pathway has been shown to produce novel metabolites. Finally, the possibility of accumulating a pathway intermediate by the knock-down of a key step is examined. Further metabolic modification is also discussed, since the latter two modifications may lead to the production of novel compound(s) from an accumulated intermediate through metabolic activation. These metabolic changes could be further modified to increase chemical diversity through somatic variation in cell culture. Besides this direct metabolic engineering with isolated biosynthetic genes, the regulation of biosynthetic activity with transcription factors and/or with reconstruction of the entire biosynthesis will also be discussed for the next generation of metabolite production. PMID- 17691991 TI - Advancements in the understanding of Paclitaxel metabolism in tissue culture. AB - Paclitaxel is a potent chemotherapeutic agent approved in the treatment of a variety of cancers, and under evaluation for the treatment of Alzheimer's and heart disease. Originally isolated from Taxus brevifolia, this highly substituted ring diterpenoid belongs to a family of plant secondary metabolites known as taxoids. Paclitaxel is currently supplied through both a semi-synthetic process and plant cell culture. Taxus spp. cell culture offers the potential to produce large amounts of paclitaxel and related taxoids, although variability in accumulation and low yields represent key limitations. Thus, intense efforts have been put forth towards understanding Taxus spp. metabolism to increase paclitaxel accumulation in cell culture. While elicitation and environmental optimization have provided some success in increasing paclitaxel accumulation in vitro, understanding metabolism of paclitaxel on the molecular level is essential for process optimization. Utilizing direct and indirect molecular techniques, a further understanding of paclitaxel biosynthesis has been gained, though knowledge into other aspects of paclitaxel global metabolism, such as regulation, transport, and degradation is lacking. Taxus spp. cell cultures are highly heterogeneous, displaying significant cell-cell variability in growth and paclitaxel accumulation. Information gathered on culture subpopulations as well as putative transcriptional bottlenecks in paclitaxel biosynthesis, coupled with successful transformation of Taxus spp. will allow for the targeted metabolic engineering of Taxus spp. or other model organisms for paclitaxel accumulation to ensure future supply of this important pharmaceutical. PMID- 17691992 TI - Recent advances in Cannabis sativa research: biosynthetic studies and its potential in biotechnology. AB - Cannabinoids, consisting of alkylresorcinol and monoterpene groups, are the unique secondary metabolites that are found only in Cannabis sativa. Tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabichromene (CBC) are well known cannabinoids and their pharmacological properties have been extensively studied. Recently, biosynthetic pathways of these cannabinoids have been successfully established. Several biosynthetic enzymes including geranylpyrophosphate:olivetolate geranyltransferase, tetrahydrocannabinolic acid (THCA) synthase, cannabidiolic acid (CBDA) synthase and cannabichromenic acid (CBCA) synthase have been purified from young rapidly expanding leaves of C. sativa. In addition, molecular cloning, characterization and localization of THCA synthase have been recently reported. THCA and cannabigerolic acid (CBGA), its substrate, were shown to be apoptosis-inducing agents that might play a role in plant defense. Transgenic tobacco hairy roots expressing THCA synthase can produce THCA upon feeding of CBGA. These results open the way for biotechnological production of cannabinoids in the future. PMID- 17691993 TI - Accumulation and membrane transport of plant alkaloids. AB - Among a large number of plant secondary metabolites, alkaloids comprise one of the most important groups due to their strong and divergent biological activities, and some are applied for clinical use. Alkaloids are often highly accumulated in particular organs of medicinal plants, which are called the 'medicinal part', whereas it is known that some alkaloids are translocated from source organs to such sink organs. The movement of biosynthetic intermediates from specific cells to other types of cells in tissue, and further detailed movement within the organelles in a cell is also suggested. However, little is known how alkaloids are transported across membranes and finally accumulated in specific organelles such as vacuole of the sink organ. To increase the productivity of valuable alkaloids in planta, not only biosynthetic genes of alkaloids but also genes involved in their transport will be important. Recently, the involvement of ABC transporters in the translocation of berberine alkaloid from root to rhizome was reported, while H(+) antiporters were also suggested as the responsible transporters for vacuolar accumulation of the alkaloid. In this review, we describe intra-organ, intra-tissue and intra-cellular transport of the alkaloid via membrane transports. Furthermore, we discuss the possibility of increasing alkaloid production in transgenic plants by using alkaloid transporter genes. PMID- 17691994 TI - Mechanisms underlying the cardiovascular effects of COX-inhibition: benefits and risks. AB - Selective inhibitors of cyclooxygenase-2 (COX-2) were designed to minimize gastrointestinal complications of traditional non-steroidal anti-inflammatory drugs (NSAIDs) attributed to the suppression of COX-1-derived prostanoids. Selective COX-2 inhibitors (coxibs) are effective anti-inflammatory and analgesic drugs. However, recently it has become apparent that some coxibs increase the risk of serious cardiovascular events, including myocardial infarction and stroke. This has led to the withdrawal of rofecoxib from markets and has raised the concern about an inherent atherothrombotic risk of this class of drugs. This question should be carefully analyzed in the light of the current knowledge on COX-2 functions in the cardiovascular system. COX-2 is regarded as an inducible enzyme involved in the pathophysiology of inflammation and pain. In the cardiovascular system, COX-2 has also been associated with pro-inflammatory/pro atherogenic stages, due to its up-regulation in monocyte-derived macrophages present in atherosclerotic lesions. However, experimental and clinical studies suggest that COX-2 is "constitutively" expressed in some tissues, among them in the vascular endothelium, where COX-2-derived prostanoids, especially prostacyclin (PGI(2)), contribute in the maintenance of vascular homeostasis and integrity. This review provides an updated overview on the functions of COX-2 in the cardiovascular system addressing key issues that could help to understand why chronic COX-2 inhibition may have undesirable effects in patients at cardiovascular risk. PMID- 17691996 TI - Efficacy of the newest COX-2 selective inhibitors in rheumatic disease. AB - Non-steroidal antiinflammatory drugs (NSAIDs) are standard treatment for the pain and inflammation associated with arthritis. Traditional NSAIDs and cyclooxygenase 2 (COX-2) selective inhibitors exhibit comparable efficacy, with different safety profiles. Traditional NSAIDs are associated with an increased risk of serious gastrointestinal (GI) adverse events versus COX-2 selective inhibitors, and chronic use frequently necessitates adjunctive therapy with gastroprotective agents. COX-2 selective inhibitors are often used in preference to avoid these GI adverse events. Recent studies have raised the concern that COX-2 selective inhibitors and traditional NSAIDs appear to be associated with a higher incidence of thrombotic cardiovascular events versus placebo. The key in prescribing these agents is for the physician to take a proactive approach to patient management and evaluation of GI and cardiovascular risk factors. This review examines the role of the newest COX-2 selective inhibitors, etoricoxib and lumiracoxib, in treating rheumatic disease. PMID- 17691997 TI - Global gastrointestinal safety profile of etoricoxib and lumiracoxib. AB - Cyclo-oxygenase (COX)-2 selective inhibitors (coxibs) were designed to reduce the incidence of gastrointestinal (GI) adverse events (AEs) which occur with non selective NSAIDs (ns-NSAIDs). Etoricoxib and lumiracoxib are regarded as second generation coxibs because of their higher COX-2 selectivity. There are three published pooled analyses relating to the GI tolerability of etoricoxib (60-120 mg/day) and lumiracoxib (200-400 mg/day) which used individual patient's data from studies sponsored by the manufacturers. We also reviewed new clinical trials published after the pooled analyses, to determine the global GI safety profiles of etoricoxib and lumiracoxib. We included discontinuations due to GI events, endoscopic ulcers, symptomatic ulcers, and ulcer complications. Current evidence suggests that etoricoxib and lumiracoxib have significantly more favorable GI profiles than ns-NSAIDs, and are similar to first generation coxibs with respect to GI safety. The most clinically important benefit of the coxibs is seen in the reduced rate of symptomatic ulcer and ulcer complications, which are still common in chronic NSAIDs users especially in high risk patients. In the largest GI outcome study of any coxib, TARGET, involving more than 18,000 patients, lumiracoxib was associated with a 79% reduction in ulcer complications in patients not taking aspirin. The differences between etoricoxib or lumiracoxib and ns-NSAIDs in relation to ulcer complications are apparent early during treatment and remain constant over time during the course of treatment; therefore, benefit of etoricoxib and lumiracoxib can be seen in patients with high GI ulcer complication risk who require NSAIDs from the beginning of use to throughout the prescription duration. PMID- 17691998 TI - How to advise aspirin use in patients who need NSAIDs. AB - NSAIDs are widely used all over the world. NSAID use is rising due to increasing availability without a prescription, use of aspirin for prevention of thrombotic disorders and the ageing population. Aspirin is used as an analgesic drug in many countries, but the main current indication is low-dose aspirin for the prevention of cardiovascular events. However, NSAIDs and aspirin use account for approximately 20-25% of all reported drug adverse events. Most of those are gastrointestinal including dyspepsia, hemorrhage, perforation and even death. The COX-2- selective inhibitors (coxibs) have demonstrated equivalent efficacy to nonspecific NSAIDs in the management of arthritis and pain but have less gastrointestinal adverse events, although coxibs and probably all NSAIDs, significantly increase risk of serious thromboembolic events. Concomitant use of low-dose aspirin is present in more than 20% of all patients taking either NSAIDs or coxibs, thus increasing the risk of gastrointestinal side effects. Furthermore, at present, it is not known whether aspirin decreases the cardiovascular risks of COX-2 inhibitors or NSAIDs. Appropriate strategies for gastrointestinal risk reduction with NSAIDs and aspirin must consider the overall health status of our patients including the presence of cardiovascular and gastrointestinal risk factors. Use of the lowest possible dose of these drugs, gastroprotectants, especially proton pump inhibitors and Helicobacter pylori eradication will reduce the risk of gastrointestinal side effects in patients taking low-dose aspirin and NSAIDs or coxibs. PMID- 17691999 TI - Prevention of cancer in the upper gastrointestinal tract with COX-inhibition. Still an option? AB - Epidemiological studies have shown that the regular use of nonsteroidal anti inflammatory drugs (NSAIDs) is associated with a reduction of gastrointestinal cancer risk. Since up-regulation of COX-2 has been reported in different stages of the esophageal and gastric carcinogenic sequence, the cyclooxygenase-2 selective inhibitors (COXIBs) were considered a good alternative to traditional NSAIDs since they cause less injury to the gastrointestinal mucosa. However, recent chemoprevention trial data reporting an increased risk of cardiovascular events have raised serious concerns on the safety of COXIBs in chemoprevention strategies. Moreover, low expression of COX-2 has been reported in a subset of gastrointestinal cancers due to COX-2 methylation, indicating that these patients could be less responsive to treatment by specific COX-2 inhibitors. Furthermore, the COX-1 isoform may have a potential role in the angiogenic process associated with esophageal adenocarcinoma, which suggests that inhibition of COX-1 may be another effective therapeutic target in upper gastrointestinal cancer. Finally, lipoxygenase-derived products may be increased following COX-inhibition due to shunting of the arachidonic acid metabolism. Specifically, the 5-LOX pathway seems to be relevant in gastrointestinal cancer development. Taken together, these data indicate that a re-evaluation of potential chemoprevention strategies for cancers of the upper gastrointestinal tract needs to be considered. PMID- 17692000 TI - Current and future clinical strategies in colon cancer prevention and the emerging role of chemoprevention. AB - In the third millennium preventive medicine is becoming a corner stone in our concept of health. Colorectal cancer (CRC) fits the criteria of a disease suitable for prevention interventions. It is a prevalent disease that is associated with considerable mortality and morbidity rates, with more than 1,000,000 new cases and 500,000 deaths annually. CRC has a natural history of transition from precursor to malignant lesion that spans, on average, 10-15 years, providing a window of opportunity for effective interventions and prevention. Indeed, CRC is preventable in up to 90% of the cases. Simple life style modifications (balanced diet avoidance of smoking and alcohol, and moderate physical activity) can prevent up to 50% of the cases of colorectal cancer. Compliance with current screening methods is a major barrier to the achievement of optimal results, a large part of the average risk population has not been screened by any method. Several newly developed screening modalities, such as the virtual colonoscopy and stool genetic testing may improve compliance. In addition, chemoprevention, a new science that has emerged during the last decade, presents an alternative approach to reducing mortality from colorectal cancer as well as other cancers. Chemoprevention involves the long-term use of a variety of oral agents that can delay, prevent or even reverse the development of adenomas in the large bowel. In light of the recent evidence of the efficacy of chemoprevention in persons at high risk for CRC cancer, it seems only appropriate to consider similar strategies for the general population. PMID- 17692001 TI - Development of novel inhibitors targeting intracellular steps of peptidoglycan biosynthesis. AB - The widespread emergence of pathogenic bacterial strains with resistance to antibiotics is becoming a serious threat to public health. Continuous development of novel antibacterials therefore remains one of the biggest challenges to science and unmet needs in the clinics. The biosynthetic pathway of bacterial peptidoglycan, an essential building block of cell walls, has been well studied and appears to be a rich source of attractive enzyme targets for new antibacterials. We have therefore reviewed the intracellular part of peptidoglycan biosynthesis, including the enzymes GlmS, GlmM, GlmU for formation of UDP-GlcNAc, subsequent pentapeptide synthesis by MurA-MurF, and its connection to lipid carrier by MraY and MurG. Naturally occurring inhibitors and the development of low-molecular weight inhibitors of the intracellular part of peptidoglycan synthesis are presented. PMID- 17692002 TI - Cooling the injured brain: how does moderate hypothermia influence the pathophysiology of traumatic brain injury. AB - Neither any neuroprotective drug has been shown to be beneficial in improving the outcome of severe traumatic brain injury (TBI) nor has any prophylactically induced moderate hypothermia shown any beneficial effect on outcome in severe TBI, despite the optimism generated by preclinical studies. This contrasts with the paradox that hypothermia still is the most powerful neuroprotective method in experimental models because of its ability to influence the multiple biochemical cascades that are set in motion after TBI. The aim of this short review is to highlight the most recent developments concerning the pathophysiology of severe TBI, to review new data on thermoregulation and induced hypothermia, the regulation of core and brain temperature in mammals and the multiplicity of effects of hypothermia in the pathophysiology of TBI. Many experimental studies in the last decade have again confirmed that moderate hypothermia confers protection against ischemic and non-ischemic brain hypoxia, traumatic brain injury, anoxic injury following resuscitation after cardiac arrest and other neurological insults. Many posttraumatic adverse events that occur in the injured brain at a cellular and molecular level are highly temperature-sensitive and are thus a good target for induced hypothermia. The basic mechanisms through which hypothermia protects the brain are clearly multifactorial and include at least the following: reduction in brain metabolic rate, effects on cerebral blood flow, reduction of the critical threshold for oxygen delivery, blockade of excitotoxic mechanisms, calcium antagonism, preservation of protein synthesis, reduction of brain thermopooling, a decrease in edema formation, modulation of the inflammatory response, neuroprotection of the white matter and modulation of apoptotic cell death. The new developments discussed in this review indicate that, by targeting many of the abnormal neurochemical cascades initiated after TBI, induced hypothermia may modulate neurotoxicity and, consequently, may play a unique role in opening up new therapeutic avenues for treating severe TBI and improving its devastating effects. Furthermore, greater understanding of the pathophysiology of TBI, new data from both basic and clinical research, the good clinical results obtained in randomized clinical trials in cardiac arrest and better and more reliable cooling methods have given hypothermia a second chance in treating TBI patients. A critical evaluation of hypothermia is therefore mandatory to elucidate the reasons for previous failures and to design further multicenter randomized clinical trials that would definitively confirm or refute the potential of this therapeutic modality in the management of severe traumatic brain injuries. PMID- 17692003 TI - Membrane Channels as Therapeutic Targets - Part IV. PMID- 17692004 TI - Automated electrophysiology in drug discovery. AB - Ion channels play essential roles in nervous system signaling, electrolyte transport, and muscle contraction. As such, ion channels are important therapeutic targets, and the search for compounds that modulate ion channels is accelerating. In order to identify and optimize ion channel modulators, assays are needed that are reliable and provide sufficient throughput for all stages of the drug discovery process. Electrophysiological assays offer the most direct and accurate characterization of channel activity and, by controlling membrane potential, can provide information about drug interactions with different conformational states. However, these assays are technically challenging and notoriously low-throughput. The recent development of several automated electrophysiology platforms has greatly increased the throughput of whole cell electrophysiological recordings, allowing them to play a more central role in ion channel drug discovery. While challenges remain, this new technology will facilitate the pharmaceutical development of ion channel modulators. PMID- 17692005 TI - Molecular regulation and pharmacology of pacemaker channels. AB - The spontaneous activity of cardiac tissue originates in specialized pacemaker cells in the sino-atrial node that generate autonomous rhythmic electrical impulses. A number of regions in the brain are also able to generate spontaneous rhythmic activity to control and regulate important physiological functions. The generation of pacemaker potentials relies on a complex interplay between different types of currents carried by cation channels. Among these currents, the hyperpolarization-activated current (termed I(f), cardiac pacemaker "funny" current, and I(h) in neurons) is the major component contributing to the initiation of cardiac and neuronal excitability and to the modulation of this excitability by neurotransmitters and hormones. I(f) is an inward current activated by hyperpolarization of the membrane potential and by intracellular cyclic nucleotides such as cAMP. The identification at the end of the 1990s of a family of mammalian genes that encode for four Hyperpolarization-activated Cyclic Nucleotide-gated channels, HCN1-4, has made analysis of the location of these channels and the study of their biophysical properties an obtainable goal. As a result, specific agents have been developed for their ability to selectively reduce heart rate by lowering cardiac pacemaker activity where f-channels are their main natural target. These drugs include alinidine, zatebradine, cilobradine, ZD-7288 and ivabradine. Recent data indicate that pharmacological tools such as W7 and genistein, which have been used to identify some intracellular pathways involved in ionic channel modulation, also have the ability to inhibit I(f) directly. This opens new perspectives for the future development of other specific rhythm-lowering agents. PMID- 17692006 TI - Molecular pharmacology of the glycine receptor chloride channel. AB - The glycine receptor (GlyR) Cl(-) channel belongs to the cysteine-loop family of ligand-gated ion channel receptors. It is best known for mediating inhibitory neurotransmission in motor and sensory reflex circuits of the spinal cord, although glycinergic synapses are also present in the brain stem, cerebellum and retina. Extrasynaptic GlyRs are widely distributed throughout the central nervous system and they are also found in sperm and macrophages. A total of 5 GlyR subunits (alpha1-4 and beta) have been identified. Embryonic receptors comprise alpha2 homomers whereas adult receptors comprise predominantly alpha beta heteromers in a 2:3 stoichiometry. Notably, the alpha3 subunit is present in synaptic GlyRs that mediate inhibitory neurotransmission onto spinal nociceptive neurons. These receptors are specifically inhibited by inflammatory mediators, implying a role for alpha3-containing GlyRs in inflammatory pain sensitisation. Because molecules that increase GlyR current may have clinical potential as muscle relaxant and peripheral analgesic drugs, this review focuses on the molecular pharmacology of GlyR potentiating substances. Of all GlyR potentiating substances identified to date, we conclude that 5HT(3)R antagonists such as tropisetron offer the most promise as therapeutic lead compounds. However, one problem is that that virtually all known GlyR potentiating compounds, including tropisetron analogues, lack specificity for the GlyR. Another is that almost nothing is known about the pharmacological properties of alpha3-containing GlyRs, which is the subtype of choice for targeting by novel antinociceptive agents. These issues need to be addressed before GlyR-specific therapeutics can be developed. PMID- 17692007 TI - Purine ionotropic (P2X) receptors. AB - Purinergic signaling is involved in the proper functioning of virtually all organs of the body. Although in some cases purines have a major influence on physiological functions (e.g. thrombocyte aggregation), more often they are just background modulators contributing to fine tuning of biological events. However, under pathological conditions, when a huge amount of adenosine 5'-triphosphate (ATP) can reach the extracellular space, their significance is increasing. ATP and its various degradation products activate membrane receptors divided into two main classes: the metabotropic P2Y and the ionotropic P2X family. This latter group, the purine ionotropic receptor, is the object of this review. After providing a description about the distribution and functional properties of P2X receptors in the body, their pharmacology will be summarized. In the second part of this review, the role of purines in those organ systems and body functions will be highlighted, where the (patho)physiological role of P2X receptors has been suggested or is even well established. Besides the regulation of organ systems, for instance in the cardiovascular, respiratory, genitourinary or gastrointestinal system, some special issues will also be discussed, such as the role of P2X receptors in pain, tumors, central nervous system (CNS) injury and embryonic development. Several examples will indicate that purine ionotropic receptors might serve as attractive targets for pharmacological interventions in various diseases, and that selective ligands for these receptors will probably constitute important future therapeutic tools in humans. PMID- 17692008 TI - Channel-like functions of the 18-kDa translocator protein (TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response. AB - Due to its channel-like properties, the peripheral-type benzodiazepine receptor (PBR) has been renamed the translocator protein (TSPO). In eukaryotes, the TSPO is primarily located in the outer mitochondrial membrane. In prokaryotes, it is found in the cell membrane. A broad spectrum of functions has been attributed to the TSPO, including various host defense responses, developmental processes, and mitochondrial functions. In the present review, we focus on the role of TSPO in immunological responses, apoptosis, and steroidogenesis, to determine whether these functions may be governed by a common denominator including TSPO. At physiological concentrations (nM range), the TSPO specific ligands, PK 11195 and Ro5-4864, appear to be anti-apoptotic. Knockdown of TSPO by genetic manipulation, resulting a reduction by more than 50% in [(3)H]PK 11195 binding, was reported to show anti-apoptotic effects, suggesting a potential pro-apoptotic function of TSPO. However, a reduction of more than 70% of TSPO abundance was found to cause cell death, possibly due to impairment of other essential cell functions. The pro apoptotic function of TSPO may involve the modulation of the channel formed by the mitochondrial voltage-dependent anion channel (VDAC) and the adenine nucleotide transporter (ANT) [i.e., the mitochondrial permeability transition pore (MPTP)]. The frequently reported pro-apoptotic effects of PK 11195 and Ro5 4864 may be due to sites with low-affinity binding for these specific TSPO ligands, and not directly related to VDAC and ANT. Also at concentrations in the nM range, PK 11195 and Ro5-4864 appear to stimulate steroidogenesis. For this function TSPO by itself appears to suffice i.e. no involvement of VDAC and ANT. TSPO appears to operate as a translocator/channel to transfer cholesterol into mitochondria where it is converted to pregnenolone, a precursor of further steroidogenesis. Apoptosis and steroids play important roles in various aspects of the host defense response. Thus, our review suggests that the involvement of TSPO and its ligands in such seemingly disparate biological functions as immunological responses, apoptosis, and steroidogenesis may have a common denominator in the multi-dimensional role of TSPO in the host-defense response to disease and injury. PMID- 17692009 TI - Pharmacology of voltage-gated proton channels. AB - Voltage-gated proton channels are highly proton selective ion channels that are present in many cells. Although their unitary conductance is 1000 times smaller than that of most ion channels, detection of single-channel currents supports their identification as channels rather than carriers. Proton channels are gated by membrane depolarization, but their absolute voltage dependence is also strongly regulated by the pH gradient, DeltapH (pHo-pHi). A model of this behavior postulates regulatory protonation sites that are alternately accessible to external or internal solutions. Consequently, proton channels open only when the electrochemical gradient is outward, and serve to extrude acid from cells. No "classical" blockers of proton channels that bind to and physically occlude the channel have been identified. A number of weak bases that inhibit proton currents probably act indirectly, perhaps by changing local pH. The best known and most potent inhibitors are polyvalent cations, especially Zn(2+) and Cd(2+). These cations are coordinated at two or more external protonation sites, most likely His residues where they compete with protons and interfere with gating. In phagocytes, proton channels are required to compensate for the electrogenic action of NADPH oxidase. During the "respiratory burst," i.e., when NADPH oxidase is active, proton channels in these cells adopt an "activated" gating mode. Recently, two labs identified a gene that codes for either the proton channel itself or a protein that is essential for proton channel activity. Expression of this protein results in currents with many similarities to the native channel. PMID- 17692010 TI - Aquaporins as targets for drug discovery. AB - The intracellular hydric balance is an essential process of mammalian cells. The water movement across cell membranes is driven by osmotic and hydrostatic forces and the speed of this process is dependent on the presence of specific aquaporin water channels. Since the molecular identification of the first water channel, AQP1, by Peter Agre's group, 13 homologous members have been found in mammals with varying degree of homology. The fundamental importance of these proteins in all living cells is suggested by their genetic conservation in eukaryotic organisms through plants to mammals. A number of recent studies have revealed the importance of mammalian AQPs in both physiology and pathophysiology and have suggested that pharmacological modulation of aquaporins expression and activity may provide new tools for the treatment of variety of human disorders, such as brain edema, glaucoma, tumour growth, congestive heart failure and obesity in which water and small solute transport may be involved. This review will highlight the physiological role and the pathological involvement of AQPs in mammals and the potential use of some recent therapeutic approaches, such as RNAi and immunotherapy, for AQP-related diseases. Furthermore, strategies that can be developed for the discovery of selective AQP-drugs will be introduced and discussed. PMID- 17692011 TI - Pharmacological regulators of intracellular calcium release channels. AB - Intracellular Ca(2+) release channels, such as inositol 1,4,5-trisphosphate receptors (IP(3)Rs) and ryanodine receptors (RyRs), facilitate the release of Ca(2+) from intracellular storage organelles in response to extracellular and intracellular stimuli. Consequently, these large, tetrameric proteins play a central role in Ca(2+) signalling and Ca(2+) homeostasis in virtually all cells. Recent data suggests that intracellular Ca(2+) release channels may also have an important pathophysiological function in certain disease states, including cardiac arrhythmias and heart failure. As a result, there has been much interest in the identification and characterization of novel, selective regulators of these channels. In this article, we review the wide array of pharmacological agents that interact directly with intracellular Ca(2+) release channels and describe the mechanisms underlying their ability to modify channel function. PMID- 17692012 TI - Modulation of ion channels in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a disease characterized by a progressive increase in pulmonary arterial pressure leading to right ventricular hypertrophy, right heart failure and ultimately to death. PAH is a disease of small pulmonary arteries inducing vascular narrowing leading to a progressive increase in pulmonary vascular resistance. The therapeutic means that improve PAH are still very limited and are too often restricted to heart/lungs transplantation. Numerous forms of pulmonary hypertension exist. Although it is still unclear as to all types of PAH share a common pathogenesis, it is generally admitted that pulmonary vasoconstriction and remodelling of the arterial wall are key events. In this review, we discuss pulmonary artery smooth muscle cells (PASMC) ion channels implication in both phenomena and we examine whether variations in expression and/or the activity of these channels can contribute to the development of PAH with special attention to K(+), Cl(-) and voltage- and non voltage-activated Ca(2+) channels. For each family of ion channels, we describe their implication in the control of both membrane potential and resting cytosolic calcium concentration which are key parameters of PASMC in PAH. We also provide evidence for an implication of these channels in not only vasoconstriction but also proliferation and/or decreased apoptosis of PASMC, phenomena which contribute to remodelling of pulmonary arterial wall. In this respect, PAH may be considered as form of vascular "channelopathy". Finally, we present examples of some substances acting on ion channels and thus potentially constituting innovative therapeutic approaches of PAH. PMID- 17692013 TI - Involvement of membrane channels in autoimmune disorders. AB - Ion channels are ubiquitous transmembrane proteins that are involved in a wide variety of cellular functions by selectively controlling the passage of ions across the plasma membrane. Among these functions many immune processes, including those in autoimmune reactions, also rely on the operation of ion channels, but the roles of ion channels can be very diverse. Here the participation of ion channels in three different roles in autoimmune processes is discussed: 1. ion channels in effector immune cells attacking other tissues causing autoimmune diseases, such as multiple sclerosis; 2. ion channels as direct targets of the immune system whereby loss of channel function leads to disease, as in myasthenia gravis; 3. ion channels whose function is modulated in the target cells by an apoptotic signal transduction cascade, such as the Fas/Fas ligand pathway. The numerous tasks that ion channels perform in autoimmune disorders and the wealth of information that has been gathered about them in recent years together provide a good basis for the design and production of drugs that may be effectively used in the therapy of these diseases. PMID- 17692015 TI - Targeting the Nogo-A signalling pathway to promote recovery following acute CNS injury. AB - Functional recovery following acute CNS injury in humans, such as spinal cord injury and stroke, is exceptionally limited, leaving the affected individual with life-long neurological deficits such as loss of limb movement and sensation leading to a compromised quality of life. As yet, there is no effective treatment on the market for such injuries. This lack of functional recovery can at least in part be attributed to the restriction of axonal regeneration and neuroplasticity by several CNS myelin proteins that have been shown to be potent inhibitors of neurite outgrowth in vitro, namely myelin-associated glycoprotein (MAG), Nogo-A and oligodendrocyte myelin glycoprotein (OMgp). Nogo-A contains multiple neurite outgrowth inhibitory domains exposed on the surface of myelinating oligodendrocytes located within its amino-terminal region (amino-Nogo-A) and C terminal region (Nogo-66). Although structurally dissimilar; Nogo-66, MAG and OMgp exert their inhibitory effects by binding the GPI-linked neuronal Nogo-66 receptor (NgR) that transduces the inhibitory signal to the cell interior via transmembrane co-receptors LINGO-1 and p75(NTR)or TROY. Although the receptor(s) for amino-Nogo-A are unknown, amino-Nogo-A and NgR ligands mutually activate the small GTPase RhoA. Consistent with their neurite outgrowth inhibitory function, approaches counter-acting Nogo-A using function-blocking antibodies, NgR using peptide antagonists and receptor bodies or RhoA using deactivating enzymes have been shown to significantly enhance axonal regeneration and neuroplasticity leading to improved functional recovery in animal models of acute CNS injury. These in vivo findings thus provide a sound basis for the development of an effective treatment for acute CNS injuries in humans. PMID- 17692016 TI - Overcoming chondroitin sulphate proteoglycan inhibition of axon growth in the injured brain: lessons from chondroitinase ABC. AB - The presence of numerous axon-inhibitory molecules limits the capacity of injured neurons in the adult mammalian central nervous system (CNS) to regenerate damaged axons. Among others, chondroitin sulphate proteoglycans (CSPGs) enriched in glycosaminoglycan (GAG) chains, acting intracellularly via Rho GTPase activation and cytoskeletal modification, prevent axon re-growth after injury. However, axon regeneration can be induced by modulating the extrinsic environment or the intrinsic neural response to axon extension. Among other strategies, the use of chondroitinase ABC (ChABC) to degrade GAGs and decrease CSPG-associated inhibition has been analyzed. Recent reports have extended the use of this enzyme, in combination with cell transplantation or pharmacological treatment. The steady advances made in these combinations offer promising perspectives for the development of new therapies to repair the injured nervous system. PMID- 17692017 TI - Rho-ROCK inhibitors as emerging strategies to promote nerve regeneration. AB - Several myelin-associated proteins in the central nervous system (CNS) have been identified as inhibitors of axonal regeneration following the injury of the adult vertebrate CNS. Among these inhibitors, myelin-associated glycoprotein (MAG), Nogo, and oligodendrocyte-myelin glycoprotein (OMgp) are well characterized. Recently, the repulsive guidance molecule (RGM) was included as a potent myelin derived neurite outgrowth inhibitor in vitro and in vivo. The discovery of the receptors and downstream signals of these inhibitors enabled further understanding of the mechanism underlying the failure of axonal regeneration. The activation of RhoA and its effector Rho kinases (ROCK) after the ligation of these inhibitors to the corresponding receptors has been shown to be a key element for axonal growth inhibition. Blockade of the Rho-ROCK pathway reverses the inhibitory effects of these inhibitors in vitro and promotes axonal regeneration in vivo. Therefore, the Rho-ROCK inhibitors have a therapeutic potential against injuries to the human CNS, such as spinal cord injuries. PMID- 17692018 TI - DNA vaccine and the CNS axonal regeneration. AB - Vaccines have been considered in treating many CNS degenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), epilepsy, multiple sclerosis (MS), spinal cord injury (SCI), and stroke. DNA vaccines have emerged as novel therapeutic agents because of the simplicity of their generation and application. Myelin components such as NOGO, MAG and OMGP are known to trigger demyelinating autoimmunity and to prevent axonal regeneration. For these reasons DNA vaccines encoding NOGO, MAG and OMGP, and fragments thereof, make them suitable vehicles for treatment of SCIs and MS. We need to obtain a deeper understanding of the immunologic mechanisms underlying the neuroprotective immunity to optimize the design of DNA vaccines for their use in clinical setting. In this review, we discuss recent findings suggesting that DNA vaccines hold a promising future for the treatment of axonal degeneration and demyelination. PMID- 17692019 TI - Eph/ephrin signaling as a potential therapeutic target after central nervous system injury. AB - Recent work indicates that the expression of Eph and ephrin proteins is upregulated after injury in the central nervous system (CNS). Although to date, much of the interest in these protein families in the nervous system has been on their roles during development, their presence in the adult CNS at multiple time points after injury suggest that they play significant roles in key aspects of the nervous system's response to damage. Several fundamental features of Eph and ephrin biology, such as bidirectional signaling, promiscuity of ligand-receptor binding, and potential cis regulation of function, present challenges for the formulation of rational and effective Eph/ephrin based strategies for CNS axon regeneration. However, recent work that have identified specific functions for individual Ephs and ephrins in injury-induced phenomena such as axon sprouting, cellular remodeling, and scar formation has begun to tease apart their contributions and may provide a number of potential entry points for beneficial therapeutic intervention. PMID- 17692020 TI - Using nanotechnology to design potential therapies for CNS regeneration. AB - The nanodelivery of therapeutics into the brain will require a step-change in thinking; overcoming the blood brain barrier is one of the major challenges to any neural therapy. The promise of nanotechnology is that the selective delivery of therapeutics can be delivered through to the brain without causing secondary damage. There are several formidable barriers that must be overcome in order to achieve axonal regeneration after injury in the CNS. The development of new biological materials, in particular biologically compatible scaffolds that can serve as permissive substrates for cell growth, differentiation and biological function is a key area for advancing medical technology. This review focuses on four areas: First, the barriers of delivering therapies to the central nervous system and how nanotechnology can potentially solve them; second, current research in neuro nanomedicine featuring brain repair, brain imaging, nanomachines, protein misfolding diseases, nanosurgery, implanted devices and nanotechnologies for crossing the blood brain barrier; third, health and safety issues and fourth, the future of neuro nanomedicine as it relates to the pharmaceutical industry. PMID- 17692021 TI - Physiological roles of neurite outgrowth inhibitors in myelinated axons of the central nervous system--implications for the therapeutic neutralization of neurite outgrowth inhibitors. AB - It has long been recognized that the central nervous system (CNS) exhibits only limited capacity for axonal regeneration following injury. It has been proposed that myelin-associated inhibitory molecules are responsible for the nonpermissive nature of the CNS environment to axonal regeneration. Experimental strategies to enhance regeneration by neutralizing these inhibitory molecules are rapidly advancing toward clinical application. It is therefore important that the physiological distribution and functions of these supposed inhibitory molecules should be understood. In this review, we examine the distribution of these inhibitors of neurite outgrowth in relation to the longitudinal polarization of the myelinated axon into the node of Ranvier and associated domains and explore their potential domain specific physiological functions. Potential implications for the therapeutic strategy of neutralizing these inhibitory molecules to promote neural repair are discussed. PMID- 17692023 TI - Molecular targeting of protein kinases to optimize selectivity and resistance profiles of kinase inhibitors. AB - This article reviews several important observations in the field of protein kinase drug discovery, exemplified mainly by targeting c-Abl for the treatment of CML. Structure-based strategy and insight are provided for the optimization of the selectivity and resistant mutation profiles of protein kinase inhibitors. PMID- 17692024 TI - The role of halogen bonding in inhibitor recognition and binding by protein kinases. AB - Halogen bonds are short-range molecular interactions that are analogous to classical hydrogen bonds, except that a polarized halogen replaces the hydrogen as the acid in the Lewis acid/base pair. Such interactions occur regularly in the structures of many ligand-protein complexes, but have only recently been recognized in biological systems as a distinct class with well-defined physical characteristics. In this review, we survey twelve single crystal structures of protein kinase complexes with halogenated ligands in order to characterize the role of halogen bonds in conferring specificity and affinity for halogenated inhibitors in this important class of enzymes. From this survey, we attempt to identify the properties of halogen bonds that can be generally applied to bottom up strategies for designing inhibitors for this and other enzyme targets. PMID- 17692025 TI - Recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors. AB - This article describes recent advances in the development and biological evaluation of small molecule inhibitors for the serine/threonine kinase Akt (PKB). Akt plays a pivotal role in cell survival and proliferation through a number of downstream effectors. Recent studies indicate that unregulated activation of the PI3K/Akt pathway is a prominent feature of many human cancers and Akt is over-expressed or activated in all major cancers. Akt is considered an attractive target for cancer therapy and inhibition of Akt alone or in combination with standard cancer chemotherapeutics has been postulated to reduce the apoptotic threshold and preferentially kill cancer cells. The development of specific and potent inhibitors will allow this hypothesis to be tested in animals. Recently, several series of small molecule, ATP-competitive inhibitors have been reported with a range of Akt potencies and selectivities. Phosphatidylinositol (PI) analogs have been reported to inhibit Akt, but these inhibitors may also have specificity problems with respect to other pleckstrin homology (PH) domain containing proteins and may have poor bioavailability. In addition, novel allosteric inhibitors have been reported which are PH domain dependent, exhibit selectivity for the individual Akt isozymes and inhibit the activity and the activation of Akt. Compounds within these classes Akt inhibitors have sufficient potency and specificity to test for tumor efficacy in animal models and recently reported preliminary experiments are reviewed. PMID- 17692026 TI - Recent advances of MEK inhibitors and their clinical progress. AB - The RAS/RAF/MEK/ERK signaling pathway has been a major clinical focus in oncology research in recent years. A clearer association of B-RAF mutations to cancers such as melanoma, papillary thyroid cancer and others has brought an increasing interest in chemotherapeutics that target this cellular signaling pathway. In this review, the authors summarize the current understanding of science and therapeutic use of the MEK inhibitors targeting the RAS/RAF/ MEK/ERK pathway. Clinical progresses of PD0325901 and AZD6244 are highlighted in addition to developments of new MEK inhibitors. Recently disclosed MEK inhibitors in two sub divided classes, ATP noncompetitive and ATP competitive inhibitors are discussed. PMID- 17692027 TI - Molecular design and clinical development of VEGFR kinase inhibitors. AB - Vascular angiogenesis has been shown to play a key role in many solid tumors. The vascular endothelial growth factor (VEGF) isoforms and their tyrosine kinase receptors (VEGFRs) have been under intense research for effective anticancer drug candidates. Epidermal growth factor (EGF) and its receptor (EGFR) provide another pathway critical in monitoring angiogenesis. VEGF exerts its effect through binding to tyrosine kinase receptors, mainly VEGFR-1 (Flt-1, the fms-like tyrosine kinase-1) and VEGFR-2 (Flk-1/KDR, fetal liver kinase-1). This paper reviews the progress, mechanism, and binding modes of recently approved kinase inhibitors, such as sunitinib (Sutent), sorafenib (Nexavar) and dasatinib (Sprycel), as well as other inhibitors that are still under clinical development. Recent clinical treatments suggest that most inhibitors of VEGFR (and/or EGFR) exert their therapeutic effect through not only targeting the VEGFR (and/or EGFR) pathway, but also inhibiting other pathways, such as RAF/MEK/ERK pathway. A new pharmacophore model for second generation of type II tyrosine kinase inhibitors and recent advances in the combination of VEGFR tyrosine kinase inhibitors and other chemotherapeutics are also covered. PMID- 17692028 TI - Targeting protein multiple conformations: a structure-based strategy for kinase drug design. AB - Multiple conformations of a protein kinase target offer an opportunity to design small-molecule inhibitors with distinct but clinically useful profiles. This article analyzes and classifies the binding pockets in the kinase catalytic cleft in different conformational states. Targeting kinase multiple conformations as an emerging strategy in the field is exemplified with important small-molecule agents in the clinic. The structure-based analysis in the paper provides a rationale for thwarting the development of drug-resistant mutations in antikinase therapy. PMID- 17692029 TI - A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. AB - This manuscript describes a comparison of the physicochemical properties of marketed oral drugs with those of 45 structurally confirmed orally bioavailable anti-cancer protein kinase inhibitors currently in different phases of clinical development. It is evident from the data presented that these kinase inhibitors are on average larger (over 110 Da), more lipophilic (over 1.5 log units) and more complex (approximately two more rotatable bonds) than those of marketed oral drugs. In contrast, hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) counts are not significantly different. PMID- 17692030 TI - CC-chemokine receptors in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality and disability in the world, with a prevalence that is expected to increase in the next decades. The disease is characterized by a chronic inflammatory response of the airways and lungs to noxious particles and gases, mostly cigarette smoke. The molecular and cellular mechanisms that lead to this exaggerated influx of cells belonging to both the innate and adaptive immune system are not yet completely unravelled. However, there is now growing evidence that the recruitment of these inflammatory cells in response to cigarette smoke is largely regulated by chemokines acting as ligands for chemokine receptors. Several of these receptors, which fall mainly in the CC- or CXC-category, have been implicated in the pathogenesis of COPD. In this review we will focus mainly on the CC-family, as the involvement of CXC-receptors in COPD has already been extensively reviewed. In patients with COPD, several CC-chemokines like MIP 1alpha, MIP-3alpha, RANTES and MCP-1 are upregulated, suggesting the contribution of their respective receptor in the pathogenesis of the disease. Using knock out mice, this contribution has been further confirmed for CCR5 and CCR6, evidenced by an attenuated accumulation of inflammatory cells like macrophages, dendritic cells, neutrophils and CD8(+) T-lymphocytes upon cigarette smoke-exposure. Moreover, mice deficient for CCR5 or CCR6 are partially protected from the development of pulmonary emphysema, another hallmark of COPD. These data suggest that chemokine receptors are potential therapeutic targets to reduce the chronic inflammation and parenchymal destruction in COPD. PMID- 17692031 TI - Measuring T cell cytokines in allergic upper and lower airway inflammation: can we move to the clinic? AB - Recent insights regarding the development of allergic diseases such as allergic rhinitis, asthma and atopic eczema are based on the functional diversity of T helper (Th)1 and Th2 lymphocytes. Th2 cells (secreting Interleukin (IL)-4, IL-5, IL-9 and IL-13) are considered to be responsible for the induction and for many of the manifestations of atopic diseases. Local overproduction of Th2 cytokines at the site of allergic inflammation, and an intrinsic defect in the production of IFN-gamma by Th1 cells in atopic individuals, have now been reported by several authors. Both IFN-gamma and IL-10 have been suggested to play a modulatory role in the induction and maintenance of allergen-specific tolerance in healthy individuals. However, recent studies indicate that Th1 cells, secreting IFN-gamma might cause severe airway inflammation. On the other hand, 'inflammatory T cells' or Th17 cells, producing IL-17, could represent a link between T cell inflammation and granulocytic influx as observed in allergic airway inflammation. We focus in this review on local (at the side of inflammation) T cell cytokine production and cytokine production by circulating T cells (after in vitro restimulation) from individuals with allergic airway disease, rhinitis and/or asthma. We furthermore review the changes in local T cell cytokine production and/or cytokine production by circulating T cells (after restimulation in vitro) from allergic/asthmatic individuals after treatment with anti-inflammatory agents or immunotherapy. Finally, we discuss whether measuring these T cell cytokines in the airways might be of diagnostic importance or could help to follow-up patients with allergy/asthma. PMID- 17692032 TI - Heat shock paradox and a new role of heat shock proteins and their receptors as anti-inflammation targets. AB - This article discusses the role of heat shock proteins (Hsps) and their receptors as anti-inflammation targets. Hsps are highly conserved proteins that protect cells against noxious or deleterious stimulus. Intracellular Hsps function as molecular chaperones governing protein assembly, folding, or transport and as anti-apoptotic regulators of cell signalling pathways leading to cell death. In addition, intracellular Hsps have recently been shown to have an anti inflammatory role in various inflammatory conditions such as infection, ischemia/reperfusion injury, and cardiovascular diseases. However, the heat shock response and the induction of Hsps have paradoxical effects against cell injury. Hsp induction before a pro-inflammatory stimulus is clearly beneficial but Hsp induction after a pro-inflammatory stimulus is cytotoxic. These paradoxical and contradictory effects may result from the different functions of intracellular versus extracellular Hsps. Extracellular Hsps released from cells with compromised integrity may function as danger signals activating innate immunity by interacting with their receptors. Therefore, modulating the levels of intracellular Hsps or the activities of Hsp receptors will be potential drug targets in inflammation. PMID- 17692033 TI - MCP-1/CCL2 as a therapeutic target in myocardial infarction and ischemic cardiomyopathy. AB - The CC chemokine Monocyte Chemoattractant Protein (MCP)-1/CCL2 mediates recruitment of mononuclear cells, modulates monocyte and lymphocyte phenotype and regulates fibrous tissue deposition and angiogenesis. MCP-1 is markedly induced in the infarcted myocardium and plays an important role in infarct healing and post-infarction remodeling. MCP-1 null mice exhibit decreased macrophage recruitment in the infarcted heart, delayed phagocytosis of dead cardiomyocytes, diminished fibroblast infiltration and attenuated left ventricular remodeling. Targeted deletion of CCR2, the primary MCP-1 receptor also protects from the development of adverse remodeling following myocardial infarction. In addition to its role in infarct healing, MCP-1 signaling plays an important role in the development of interstitial fibrosis in a mouse model of brief repetitive myocardial ischemia and reperfusion. Our review manuscript discusses the mechanisms responsible for MCP-1-mediated effects in the ischemic myocardium and explores MCP-1 targeting as a novel therapeutic approach in patients with myocardial infarction and ischemic non-infarctive cardiomyopathy. PMID- 17692034 TI - Genetics and genomics of hepatic acute phase reactants: a mini-review. AB - Systemic acute phase response is a component of innate immunity and a consequence of local or systemic inflammation. A prominent feature of acute phase reaction is the alteration of gene expression in hepatocytes. The classical acute phase reactants are released into the blood and may be exuded into other body fluids. Generally, they exert anti-inflammatory action and are important players of the homeostasis maintenance. The genetic background influences a person's response to disturbances of homeostasis, including infections, stress and tissue injury. The most frequent and physiologically relevant genetic polymorphisms of the representatives of classical acute phase proteins are discussed herein. The genetic variations of acute phase proteins or their regulators are associated with several pathological conditions. The high-throughput genomic and proteomic technologies combined with bioinformatics give the most recent approaches to the study and analysis of acute phase proteins, thereby widening the scope of the term 'acute phase reactants' or discovering novel ones. Simultaneous testing of numerous analytes, including acute phase proteins from the same, small volume sample may give diagnostic tools for diseases. Accumulating knowledge about acute phase reaction may lead to the development of novel therapies and other prevention alternatives. PMID- 17692035 TI - Sublingual specific immunotherapy: state of the art. AB - Sublingual immunotherapy (SLIT) was first attempted more than a century ago. After a long parenthesis probably related to the lack of impressive clinical results, the advances on allergen quantification and characterization, together with the improvements in the recombination techniques have renewed the interest in this therapy during the past decade. There are currently enough high quality clinical trials on its efficacy in the management of respiratory allergies (asthma and rhinoconjunctivitis) to conclude that SLIT could be an effective tool for the management of those diseases. This effectiveness has been shown both in children and in adults. However, while there are some clues related to the mechanism of action of SLIT, there is still much to know about it. In addition, more studies comparing the effectiveness of SLIT vs the standard subcutaneous immunotherapy (SCIT) are needed to definitely establish the role of SLIT in the treatment of allergic diseases. SLIT has proven a very safe therapy as compared to SCIT, a fact which adds a very important advantage to the sublingual route. PMID- 17692036 TI - Neurogenic inflammation and asthma. AB - Over the past number of decades there has been considerable interest in the role of neurogenic inflammation in asthma with the identification of many biologically active neuropeptides in the lung. Whilst there is convincing evidence of neurogenic inflammation in various animal models of asthma, the evidence in humans is less clear and replicating the experimental approaches in humans has proven difficult with different studies producing conflicting results. In terms of human studies, research has focused on whether pro-inflammatory neuropeptides are elevated in the asthmatic airway, and if so, what their functional effects are. There have also been studies to assess the efficacy of tachykinin receptor antagonists in improving indices of asthma control. Information to date would suggest that neuropeptides are present in human airways and are possibly upregulated in asthma, but this effect does not appear to be specific and may occur in other inflammatory airways conditions (chronic obstructive pulmonary disease (COPD) and smoking). At present there is insufficient evidence to suggest that tachykinin receptor antagonists confer any additional benefit over inhaled corticosteroid regimes for asthmatic patients. PMID- 17692037 TI - Microvascular theory of exercise-induced bronchoconstriction in asthma: potential implication of vascular endothelial growth factor. AB - Exercise-induced bronchoconstriction (EIB) is used to describe the increase in airway resistance that follows exercise in asthmatic patients. To date, two major hypotheses, water- and heat-loss theory, have been put forward to explain the mechanism of EIB. However, there is increasing evidence that airway microcirculation has the potential to contribute to the pathophysiological mechanisms of EIB. Bronchial asthma is a chronic airway inflammatory disease associated with airway remodeling, including the growth and proliferation of new blood vessels. Airway microvascular remodeling is likely to be induced by several growth factors, such as vascular endothelial growth factor (VEGF). VEGF has powerful effects on vascular function and also increases microvascular permeability. In this respect, high expression of VEGF in asthmatic airways contributes to the pathogenesis of EIB via increased airway microvascular permeability. Moreover, endothelial cells in airway microcirculation stimulated by high levels of VEGF is sensitive to exercise challenge and therefore, the change in circulating thrombomodulin levels with exercise can be an index of functional properties in endothelial cells. In this review, we will demonstrate the possible roles of VEGF on EIB in asthmatic patients in details. I will then propose a molecular mechanism explaining the microvascular theory of EIB based on functional abnormalities of endothelial cells in newly generated microvessels in asthmatic airways. These findings suggest that the intervention against VEGF offers a possible new strategy for the treatment of EIB in asthmatic patients. PMID- 17692038 TI - Systemic inflammatory response, bacterial translocation and nitric oxide donors. AB - Abdominal aortic surgery is relatively common and is associated with considerable post-operative morbidity and death. The aortic cross-clamping (supra or infrarenal) necessary for the insertion of a vascular graft, often in circumstances of haemorrhagic shock (e.e. a ruptured aneurysm) elicits a Systemic Inflammatory Response Syndrome (SIRS) and an Ischaemia-Reperfusion syndrome (I R), with affectation of many organs including the kidneys and the intestine. Experimentally, the exogenous use of nitric oxide donors has proved to be able to control the SIRS, minimising the damage due to I-R and protecting from renal dysfunction and BT. However, clinical experience in these situations is still limited. Here we review the current status and experience of the authors in the use of nitric oxide donors in the control of the SIRS induced by infrarenal, suprarenal aortic cross-clamping, with or without haemorrhagic shock; and the Bacterial Translocation phenomenon (BT) induced by aortic cross-clamping below the mesenteric artery with or without associated hemorrhaging. PMID- 17692040 TI - Medical chemistry to spy cancer stem cells from outside the body. AB - Accumulating evidence indicates that cancer is maintained by cancer stem cells (CSC). The goal of molecular imaging is to detect pathologic biomarkers, which can lead to early recognition of cancer, better therapeutic management, and improved monitoring for recurrence. The main focus of this review is to describe the different classes of tracers, contrast agents and dyers, and their putative application to improve cancer stem cells detection and follow-up. Although the in vivo cancer diagnosis has not significantly changed for the past three decades, however, in the future it might be possible to trace all cancer cells, including the cancer stem cells. PMID- 17692041 TI - Current scenario of 1,4-diazepines as potent biomolecules--a mini review. AB - The aim of this review is precisely to give a comprehensive account of the large volume of work carried out on 1,4-diazepines regardless of the degree of unsaturation in the diazepine system. This review mainly emphasizes recent work on the diazepines also including earlier work. PMID- 17692042 TI - Alpha-methylated polyamines as potential drugs and experimental tools in enzymology. AB - We describe synthesis of alpha-methylated analogues of the natural polyamines and their use as tools in unraveling polyamine functions. Experiments with alpha methylated spermidine and spermine revealed that the polyamines are exchangeable in supporting cellular growth. Degradation of the analogues by polyamine oxidase disclosed hidden, aldehyde-guided stereospecificity of the enzyme. PMID- 17692039 TI - The endocannabinoid signaling system: a potential target for next-generation therapeutics for alcoholism. AB - Research into the endocannabinoid signaling system has grown exponentially in recent years following the discovery of cannabinoid receptors (CB) and their endogenous ligands, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Important advances have been made in our understanding of the endocannabinoid signaling system in various aspects of alcoholism, including alcohol-seeking behavior. Alcohol increases the synthesis or impairs the degradation of endocannabinoids, leading to a locally elevated endocannabinoid tone within the brain. Elevated endocannabinoid tone might be expected to result in compensatory down-regulation of CB1 receptors or dampened signal transduction. Following release, endocannabinoids diffuse back to the presynaptic neuron where they act as short-range modulators of synaptic activity by altering neurotransmitter release and synaptic plasticity. Mice treated with the CB1 receptor antagonist SR141716A (rimonabant) or homozygous for a deletion of the CB1 receptor gene exhibit reduced voluntary alcohol intake. CB1 knockout mice also show increased alcohol sensitivity, withdrawal, and reduced conditioned place preference. Conversely, activation of CB1 receptor promotes alcohol intake. Recent studies also suggest that elevated endocannabinoid tone due to impaired degradation contributes to high alcohol preference and self-administration. These effects are reversed by local administration of rimonabant, suggesting the participation of the endocannabinoid signaling system in high alcohol preference and self administration. These recent advances will be reviewed with an emphasis on the endocannabinoid signaling system for possible therapeutic interventions of alcoholism. PMID- 17692043 TI - Neuronal histamine and histamine receptors in food intake and obesity. AB - Histamine is a neurotransmitter and neuromodulator within the central nervous system that affects the regulation of food intake and obesity. This review focuses on the roles of neuronal histamine and its receptors in regulating food intake and obesity. PMID- 17692044 TI - Organosulfur compounds in cancer chemoprevention. AB - There has been a renewed interest to the application of natural products derived from cruciferous plants and members of Allium genus in chemoprevention of cancer. The potential chemopreventive properties of these vegetables have been attributed to the presence of high level of organosulfur compounds in these plants. Organosulfur compounds have been shown to exert diverse biological effects such as: (a) induction of carcinogen detoxification, (b) inhibition of tumor cell proliferation, (c) antimicrobial effect, (d) free radical scavenging, (e) inhibition of DNA adduct formation, (f) induction of cell cycle arrest and induction of apoptosis etc. It has been suggested that these compounds act as chemopreventive agents through a combination of above mechanisms. Epidemiological and experimental carcinogenesis provides overwhelming evidence to support the claim that individuals consuming diet rich in organosulfur are less susceptible to different types of cancers. The protective effects of OSCs against carcinogenesis have been shown in stomach, esophagus, mammary glands, breast, skin and lungs of experimental animals. Cumulatively all these studies show a strong correlation between cancer prevention and intake of organosulfur compounds in one form or the other. Since the protective effects of all these phytochemicals are as a result of additives and synergistic combination further studies are warranted for complete understanding of chemopreventive action of organosulfur compounds and define the effective dose that has no toxicity in humans. In this review an attempt has been made to summarize the different aspects of organosulfur compounds with relation to their source, chemopreventive mechanistic action, epidemiologic and experimental carcinogenesis. PMID- 17692045 TI - PEG-interferon alpha-2b for acute hepatitis C: a review. AB - Acute infection due to hepatitis C virus results in a chronic progression in 50 84% of cases. In the light of the risk of developing chronic disease and the response rate to treatment once the disease is established, it is very important to consider early treatment of acute hepatitis C before it progresses to the chronic form. The aim of this review is to evaluate the real efficacy and tolerance of Peg-interferon alpha-2b in monotherapy and in association with ribavirin in the treatment of patients affected by acute C hepatitis, to delineate the viral factors correlated with the sustained virological response and to consider when treatment should be started in relation to onset and what is the optimal duration of therapy. Also the pharmacodynamic and pharmacokinetic characteristics of PEG-IFN alpha-2b and ribavirin are reassessed. The analysis of literature demonstrates that Peg-interferon alpha-2b treatment is efficacious in terms of attaining sustained virological response (71-94% of cases). Treatment must be started within three months of onset and must be prolonged for three months. Only two studies have provided evidence the needed of a prolonged treatment for six months for genotype 1 infections. In all studies therapy has been generally well tolerated. Sustained virological response is independent of baseline viral load and of HCV genotypes in patients treated for six months, while in subjects treated for three months it seems to be dependent on HCV genotype, with genotype 1 characterized by a less favourable outcome. Combination therapy with ribavirin does not seem to increase the response rate but could be proposed as a second choice to patients not responding to IFN monotherapy. PMID- 17692046 TI - FTY720: a most promising immunosuppressant modulating immune cell functions. AB - FTY720, the pharmacological analog of S1P, acts as an agonist of sphingosine-1 phosphate receptors, resulting in the inhibition of lymphocyte egress from secondary lymphoid tissues and thymocytes from the thymus, peripheral lymphopenia and interfering with normal functions of several other cell types. FTY720 has been clinically tried for transplantation and multiple sclerosis, showing promising protective effects. This review will summarize potential applications and effects of FTY720. PMID- 17692047 TI - Large compound databases for structure-activity relationships studies in drug discovery. AB - Large libraries of chemical compounds reflect the exponentially growing data enrichment in drug discovery that trends towards fully automated informatics solutions to study structure - activity relationships by screening docked ligand candidates to biological target structures. We review otherwise disseminated user descriptions of mainly public databases with free access and also our integrated data mining tool GPDBnet for phyto-pharmacology. PMID- 17692048 TI - Structural aspects of peptides with immunomodulating activity. AB - The main function of the innate immune system from insects to mammals is to detect the presence of and act against invading microorganisms by recognizing their unique molecular signatures, most importantly, components of bacterial cell walls. A large number of peptides and derivatives, both synthetic and of natural origin, are known to influence immune responses in mammals by interacting with the conserved microbial structures, making the former attractive targets for drug development. This review focuses on structural aspects of the immunomodulating peptides and their receptors, including primary constitution, stereochemistry, conformation, binding and hydrophobic properties. PMID- 17692049 TI - Raloxifene: cardiovascular considerations. AB - Ovarian hormone deficiency status is associated with increased cardiovascular morbidity and mortality, suggesting that estrogen might exhibit a favorable cardiovascular effect. Estrogen has a multitude of beneficial biological effects on surrogate markers of cardiovascular disease that may account for this hypothesis. However, none of the randomized trials already conducted with hormone replacement therapy showed overall benefit by means of reducing clinical ischemic cardiovascular events and/or suppressing atherogenesis. Moreover, the Women's Health Initiative study (WHI) has suggested a possible detrimental effect for hormone replacement therapy including increased cardiovascular morbidity, ovarian and breast cancer. Hence, any beneficial effect of estrogen must be carefully weighed against its carcinogenic properties together with its side effects. The need for a more efficient and specific molecule led to the development of the selective estrogen receptor modulators (SERMs). This new generation of drugs mimic the effect of estrogen in some tissues while antagonize several estrogen effects in other tissues. These unique properties offer the possibility to attain the beneficial effects of estrogen while avoiding its carcinogenic effect and the accompanying adverse reactions. Here we review the different effects of raloxifene- a protype second generation SERM on the cardiovascular system. We discuss raloxifene's role at different levels of the atherothrombotic cascade addressing each level separately; trying to clarify the net effect of raloxifene in modulating thrombosis in the arterial tree. PMID- 17692050 TI - Targeting of FAK Ser910 by ERK5 and PP1delta in non-stimulated and phorbol ester stimulated cells. AB - Ser910 of FAK (focal adhesion kinase) was phosphorylated in fibroblasts treated with the phorbol ester PMA and dephosphorylated by PP1d (protein phosphatase 1d), as indicated by shRNA (small-hairpin RNA) gene silencing. Ser910 of FAK was reported previously to be an ERK (extracellular-signal-regulated kinase) 1/2 target in cells treated with phorbol esters. In contrast, various approaches, including the use of the MEK (mitogen-activated protein kinase/ERK kinase) inhibitors UO126 and CI-1040 to inhibit ERK1/2 pointed to the involvement of ERK5. This hypothesis was confirmed by: (i) shRNA ERK5 gene silencing, which resulted in complete pSer910 loss in non-stimulated and PMA-stimulated cells; (ii) direct phosphorylation of recombinant FAK by ERK5; and (iii) ERK5 activation by PMA. PMA stimulation and ERK5 silencing in MDA-MB 231 and MDA-MB 361 breast cancer cells indicated Ser910 targeting by ERK5 also in these cells. Given the proximity of Ser910 to the FAT (focal adhesion targeting) regulatory domain of FAK, cell proliferation and morphology were investigated in FAK-/- cells expressing S910A mutant FAK. The cell growth rate decreased and exposure to PMA induced peculiar morphological changes in cells expressing S910A, with respect to wild-type FAK, suggesting a role for Ser910 in these processes. The present study indicates, for the first time, the phosphorylation of Ser910 of FAK by ERK5 and its dephosphorylation by PP1d, and suggested a role for Ser910 in the control of cell shape and proliferation. PMID- 17692051 TI - The utility of tuberless models of tuberous sclerosis. PMID- 17692052 TI - mTOR in tuberous sclerosis and other neurological disorders. PMID- 17692053 TI - Can preventative antiepileptic therapy alter outcome in infants with tuberous sclerosis complex? PMID- 17692054 TI - Treatment before seizures: new indications for antiepileptic therapy in children with tuberous sclerosis complex. PMID- 17692055 TI - Lamotrigine effect on GABA transmission in Angelman syndrome? PMID- 17692057 TI - Laugier-Hunziker syndrome and hypocellular marrow: a fortuitous association? PMID- 17692056 TI - Malignant atrophic papulosis. AB - Malignant atrophic papulosis (MAP; also known as Degos' disease) has a purely cutaneous variant and a systemic variant with cutaneous manifestations. Both have similar cutaneous eruptions. MAP manifests as erythematous, pink or red papules (2-15 mm), which evolve into scars with central, porcelain-white atrophic centres. Purely cutaneous MAP is a benign condition that can be life-long. Systemic MAP has a grim prognosis, but is not uniformly fatal. The cause of death is usually intestinal perforation. Death usually occurs within 2-3 years from the onset of systemic involvement. Systemic MAP can involve the nervous, opthalmological, gastrointestinal, cardiothoracic and hepatorenal systems. No specific laboratory test can be used to aid in diagnosing MAP. Histopathologically, a wedge-shaped degeneration of collagen is present with a prominent interface reaction with squamatization of the dermoepidermal junction, melanin incontinence and epidermal atrophy. No treatment has been shown to be effective in the treatment of MAP. PMID- 17692058 TI - The use of the pulsed dye laser in a case of an occupationally acquired arteriovenous malformation. PMID- 17692059 TI - Focal craniofacial hyperhidrosis associated with selective serotonin reuptake inhibitors. PMID- 17692060 TI - Acquired hyperplasia of the tunica dartos mimicking smooth muscle hamartoma. PMID- 17692061 TI - Statin-induced Ro/SSa-positive subacute cutaneous lupus erythematosus. PMID- 17692062 TI - Disseminated molluscum contagiosum in a patient with chronic plaque psoriasis taking methotrexate. PMID- 17692063 TI - Adalimumab-induced cutaneous lupus. PMID- 17692064 TI - Adalimumab vs. etanercept in psoriasis. PMID- 17692065 TI - Squamous cell carcinoma on the scalp following treatment with 5% imiquimod cream. PMID- 17692066 TI - The value of randomized clinical trials for daily clinical practice. PMID- 17692067 TI - Meningococcal disease in a kidney transplant recipient with mannose-binding lectin deficiency. AB - We describe the case of a kidney transplant recipient who developed meningococcemia, without meningeal signs, 2 months after transplantation. Plasma levels of complement components C3, C4, and CH 50 were within the normal range. However, using a method to screen for the functional activity of all 3 pathways of complement, no activation via the mannose-binding lectin (MBL) pathway could be detected (0%). A subsequent quantification of MBL pathway components revealed normal levels of MASP 2 but undetectable amounts of MBL. To our knowledge, this is the first report of meningococcal disease after organ transplantation in a patient with MBL deficiency. PMID- 17692068 TI - Paradoxical worsening of tuberculosis in a heart-lung transplant recipient. AB - We report on a heart-lung transplant recipient who presented with pulmonary tuberculosis (TB) 2.5 months after transplantation and then developed a paradoxical reaction after 4 months of adequate anti-TB treatment. She eventually recovered with anti-TB and high-dose steroid treatments. METHODS: Using sequential bronchoalveolar lavages, we assessed the inflammatory response in the lung and investigated the alveolar immune response against a Mycobacterium tuberculosis antigen. RESULTS: The paradoxical reaction was characterized by a massive infiltration of the alveolar space by M. tuberculosis antigen-specific CD4(+) T cells and by the presence of a CD4(-)CD8(-) T lymphocyte subpopulation bearing phenotypic markers (CD16(+)/56(+)) classically associated with NK cells. CONCLUSION: This case report illustrates that even solid organ transplant recipients receiving intense triple-drug immune suppression may be able to develop a paradoxical reaction during TB treatment. Transplant physicians should be aware of this phenomenon in order to differentiate it from treatment failure. PMID- 17692069 TI - Acute hantavirus infection or renal transplant rejection. AB - Hantaviruses belong to the so-called emerging pathogens that are transmitted to humans by infected rodents and their excreta. In Central Europe, hantavirus infections usually occur in a mild to moderate form of hemorrhagic fever with renal syndrome. In contrast to the mostly benign or even asymptomatic course of hantavirus infections in previously healthy individuals, the acute hantavirus infection in kidney transplant recipients represents an exceptional situation regarding diagnosis and therapy. We describe the case of a 44-year-old kidney transplant recipient with acute renal transplant failure associated with acute hantavirus infection. PMID- 17692070 TI - Treatment of Candida albicans pericarditis in a heart transplant patient. AB - Pericarditis due to Candida species is a rare clinical entity, associated with thoracic surgery and immunosuppression. We report here the second case of pericarditis due to Candida albicans in a heart transplant patient, which presented as tamponade approximately 3 weeks post transplant, in the absence of evidence of sternal osteomyelitis. The patient was treated with pericardiocentesis and a combination of caspofungin and fluconazole, but the patient ultimately required the explantation of retained epicardial leads and the creation of a pericardial window. This case illustrates that Candida species must be considered in the differential diagnosis in post-transplant pericarditis, and that foreign body removal is, as always, key in helping to resolve such infections. This case also demonstrates the first use of caspofungin with fluconazole to treat Candida pericarditis. We discuss the conflicting data regarding the use of caspofungin, alone or in combination therapy, in treating infections involving biofilms, such as the infected pericardium. PMID- 17692071 TI - Pasteurella multocida septic shock following liver transplantation treated with drotrecogin alpha (activated). AB - Severe sepsis and progression to septic shock in solid organ transplant recipients is associated with a high mortality. We describe a fulminant case of septic shock in a liver transplant recipient caused by Pasteurella multocida, a gram-negative coccobacillus most commonly associated with domestic cats and dogs. P. multocida is a rare cause of bacteremia and has not been reported as a cause of septic shock following liver transplantation. In addition to standard therapy, the patient was managed with drotrecogin alpha (activated) recombinant activated protein C (APC), an evidence-based agent that has been shown to significantly improve outcome in severe sepsis in the non-transplant population. The known risk factors, clinical course, and outcomes of severe infection associated with P. multocida are also briefly reviewed. This case illustrates the need for transplant recipients and their healthcare providers to carefully consider the risk of severe infection associated with domestic animal exposure. PMID- 17692072 TI - Unusual presentation of central nervous system manifestations of Varicella zoster virus vasculopathy in renal transplant recipients. AB - We describe 2 renal transplant recipients with severe but reversible neurological manifestations related to Varicella zoster virus (VZV) cerebral vasculopathy. To the best of our knowledge, this is the first description of cerebral VZV vasculopathy in solid organ transplant recipients. We review the published literature on the clinical presentation, diagnosis and treatment. In solid organ transplant recipients presenting with neurological signs and symptoms, a diagnosis of VZV-associated vasculopathy should be considered. PMID- 17692073 TI - Genetically stable expression of functional miraculin, a new type of alternative sweetener, in transgenic tomato plants. AB - Miraculin is a taste-modifying protein isolated from the red berries of Richadella dulcifica, a shrub native to West Africa. Miraculin by itself is not sweet, but it is able to turn a sour taste into a sweet taste. This unique property has led to increasing interest in this protein. In this article, we report the high-yield production of miraculin in transgenic tomato plants. High and genetically stable expression of miraculin was confirmed by Western blot analysis and enzyme-linked immunosorbent assay. Recombinant miraculin accumulated to high levels in leaves and fruits, up to 102.5 and 90.7 microg/g fresh weight, respectively. Purified recombinant miraculin expressed in transgenic tomato plants showed strong sweetness-inducing activity, similar to that of native miraculin. These results demonstrate that recombinant miraculin was correctly processed in transgenic tomato plants, and that this production system could be a good alternative to production from the native plant. PMID- 17692074 TI - Rapid reduction of arsenate in the medium mediated by plant roots. AB - Microbes detoxify arsenate by reduction and efflux of arsenite. Plants have a high capacity to reduce arsenate, but arsenic efflux has not been reported. Tomato (Lycopersicon esculentum) and rice (Oryza sativa) were grown hydroponically and supplied with 10 microm arsenate or arsenite, with or without phosphate, for 1-3 d. The chemical species of As in nutrient solutions, roots and xylem sap were monitored, roles of microbes and root exudates in As transformation were investigated and efflux of As species from tomato roots was determined. Arsenite remained stable in the nutrient solution, whereas arsenate was rapidly reduced to arsenite. Microbes and root exudates contributed little to the reduction of external arsenate. Arsenite was the predominant species in roots and xylem sap. Phosphate inhibited arsenate uptake and the appearance of arsenite in the nutrient solution, but the reduction was near complete in 24 h in both -P- and +P-treated tomato. Phosphate had a greater effect in rice than tomato. Efflux of both arsenite and arsenate was observed; the former was inhibited and the latter enhanced by the metabolic inhibitor carbonylcyanide m chlorophenylhydrazone. Tomato and rice roots rapidly reduce arsenate to arsenite, some of which is actively effluxed to the medium. The study reveals a new aspect of As metabolism in plants. PMID- 17692075 TI - Intraspecific variation in temperature dependence of gas exchange characteristics among Plantago asiatica ecotypes from different temperature regimes. AB - There are large inter- and intraspecific differences in the temperature dependence of photosynthesis, but the physiological cause of the variation is poorly understood. Here, the temperature dependence of photosynthesis was examined in three ecotypes of Plantago asiatica transplanted from different latitudes, where the mean annual temperature varies between 7.5 and 16.8 degrees C. Plants were raised at 15 or 30 degrees C, and the CO(2) response of photosynthetic rates was determined at various temperatures. When plants were grown at 30 degrees C, no difference was found in the temperature dependence of photosynthesis among ecotypes. When plants were grown at 15 degrees C, ecotypes from a higher latitude maintained a relatively higher photosynthetic rate at low measurement temperatures. This difference was caused by a difference in the balance between the capacities of two processes, ribulose-1,5-bisphosphate regeneration (J(max)) and carboxylation (V(cmax)), which altered the limiting step of photosynthesis at low temperatures. The organization of photosynthetic proteins also varied among ecotypes. The ecotype from the highest latitude increased the J(max) : V(cmax) ratio with decreasing growth temperature, while that from the lowest latitude did not. It is concluded that nitrogen partitioning in the photosynthetic apparatus and its response to growth temperature were different among ecotypes, which caused an intraspecific variation in temperature dependence of photosynthesis. PMID- 17692076 TI - Waving and skewing: how gravity and the surface of growth media affect root development in Arabidopsis. AB - Arabidopsis seedlings growing on inclined agar surfaces exhibit characteristic root behaviours called 'waving' and 'skewing': the former consists of a series of undulations, whereas the latter is a deviation from the direction of gravity. Even though the precise basis of these growth patterns is not well understood, both gravity and the contact between the medium and the root are considered to be the major players that result in these processes. The influence of these forces on root surface-dependent behaviours can be verified by growing seedlings at different gel pitches: plants growing on vertical plates present roots with slight waving and skewing when compared with seedlings grown on plates held at minor angles of < 90 degrees . However, other factors are thought to modulate root growth on agar; for instance, it has been demonstrated that the presence and concentration of certain compounds in the medium (such as sucrose) and of drugs able to modify the plant cell cytoskeleton also affect skewing and waving. The recent discovery of an active role of ethylene on surface-dependent root behaviour, and the finding of new mutants showing anomalous growth, pave the way for a more detailed description of these phenomena. PMID- 17692077 TI - Acclimation of photosynthesis and respiration is asynchronous in response to changes in temperature regardless of plant functional group. AB - Gas exchange, fluorescence, western blot and chemical composition analyses were combined to assess if three functional groups (forbs, grasses and evergreen trees/shrubs) differed in acclimation of leaf respiration (R) and photosynthesis (A) to a range of growth temperatures (7, 14, 21 and 28 degrees C). When measured at a common temperature, acclimation was greater for R than for A and differed between leaves experiencing a 10-d change in growth temperature (PE) and leaves newly developed at each temperature (ND). As a result, the R : A ratio was temperature dependent, increasing in cold-acclimated plants. The balance was largely restored in ND leaves. Acclimation responses were similar among functional groups. Across the functional groups, cold acclimation was associated with increases in nonstructural carbohydrates and nitrogen. Cold acclimation of R was associated with an increase in abundance of alternative and/or cytochrome oxidases in a species-dependent manner. Cold acclimation of A was consistent with an initial decrease and subsequent recovery of thylakoid membrane proteins and increased abundance of proteins involved in the Calvin cycle. Overall, the results point to striking similarities in the extent and the biochemical underpinning of acclimation of R and A among contrasting functional groups differing in overall rates of metabolism, chemical composition and leaf structure. PMID- 17692078 TI - Transcriptome analysis of root-knot nematode functions induced in the early stages of parasitism. AB - Root-knot nematodes of the genus Meloidogyne are obligate biotrophic parasites able to infest > 2000 plant species. The nematode effectors responsible for disease development are involved in the adaptation of the parasite to its host environment and host response modulation. Here, the differences between the transcriptomes of preparasitic exophytic second-stage juveniles (J2) and parasitic endophytic third-stage juveniles (J3) of Meloidogyne incognita were investigated. Genes up-regulated at the endophytic stage were isolated by suppression subtractive hybridization and validated by dot blots and real-time quantitative polymerase chain reaction (PCR). Up-regulation was demonstrated for genes involved in detoxification and protein degradation, for a gene encoding a putative secreted protein and for genes of unknown function. Transcripts of the glutathione S-transferase gene Mi-gsts-1 were 27 times more abundant in J3 than in J2. The observed Mi-gsts-1 expression in the oesophageal secretory glands and the results of functional analyses based on RNA interference suggest that glutathione S-transferases are secreted during parasitism and are required for completion of the nematode life cycle in its host. Secreted glutathione S transferases may protect the parasite against reactive oxygen species or modulate the plant responses triggered by pathogen attack. PMID- 17692079 TI - Ectopic expression of phosphoenolpyruvate carboxylase in Vicia narbonensis seeds: effects of improved nutrient status on seed maturation and transcriptional regulatory networks. AB - Seed maturation responds to endogenous and exogenous signals like nutrient status, energy and hormones. We recently showed that phosphoenolpyruvate carboxylase (PEPC) overexpression in Vicia narbonensis seeds alters seed metabolism and channels carbon into organic acids, resulting in greater seed storage capacity and increased protein content. Thus, these lines represent models with altered sink strength and improved nutrient status. Here we analyse seed developmental and metabolic parameters, and C/N partitioning in these seeds. Transgenic embryos take up more carbon and nitrogen. Changes in dry to FW ratio, seed fill duration and major seed components indicate altered seed development. Array-based gene expression analysis of embryos reveals upregulation of seed metabolism, especially during the transition phase and at late maturation, in terms of protein storage and processing, amino acid metabolism, primary metabolism and transport, energy and mitochondrial activity, transcriptional and translational activity, stress tolerance, photosynthesis, cell proliferation and elongation, signalling and hormone action and regulated protein degradation. Stimulated cell elongation is in accordance with upregulated signalling pathways related to gibberellic acid/brassinosteroids. We discuss that activated organic and amino acid production leads to a wide-range activation of nitrogen metabolism, including the machinery of storage protein synthesis, amino acid synthesis, protein processing and deposition, translational activity and the methylation cycle. We suggest that alpha-ketoglutarate (alpha-KG) and/or oxalacetate provide signals for coordinate upregulation of amino acid biosynthesis. Activation of stress tolerance genes indicates partial overlap between nutrient, stress and abscisic acid (ABA) signals, indicating a common interacting or regulatory mechanism between nutrients, stress and ABA. In conclusion, analysis of PEPC overexpressing seeds identified pathways responsive to metabolic and nutrient control on the transcriptional level and its underlying signalling mechanisms. PMID- 17692080 TI - Cleome, a genus closely related to Arabidopsis, contains species spanning a developmental progression from C(3) to C(4) photosynthesis. AB - C(4) photosynthesis involves alterations to leaf development, cell biology and biochemistry. Different lineages of C(4) plants use varying mechanisms to generate the C(4) pathway. Although the biochemistry of C(4) photosynthesis was described around 20 years ago, the phylogenetic distance between Arabidopsis and the traditional C(4) models has not facilitated the transfer of knowledge from Arabidopsis research to understanding C(4) systems. We show that Cleome, a genus closely related to Arabidopsis, contains species spanning a developmental progression from C(3) to C(4) photosynthesis. The majority of species we assessed are C(3) plants but have increased venation in leaves. Three C(3) species have both increased venation and enlarged bundle sheath cells, and there is also a tendency to accumulate proteins and transcripts needed for C(4) photosynthesis. Cleome gynandra shows all the characteristics needed for efficient C(4) photosynthesis, including alterations to leaf biochemistry, cell biology and development, and belongs to the NAD-dependent malic enzyme subtype. Combined with its phylogenetic proximity to Arabidopsis, the developmental progression from C(3) to C(4) photosynthesis within the genus provides a potentially excellent new model to increase our understanding of C(4) photosynthesis, and provide insights into its evolution. PMID- 17692081 TI - Plant dispersal, neighbourhood size and isolation by distance. AB - A theoretical relationship between isolation by distance or spatial genetic structure (SGS) and seed and pollen dispersal is tested using extensive spatial temporal simulations. Although for animals Wright's neighbourhood size N(e) = 4pisigma(2)(t) has been ascertained also, where sigma(2)(t) is the axial variance of distances between parents and offspring, and it was recently confirmed that N(e) = 4pi(sigma(2)(f) + sigma(2)(m))/2 when dispersal of females and males differ, the situation for plants had not been established. This article shows that for a very wide range of conditions, neighbourhood size defined by Crawford's formula N(e) = 4pi(sigma(2)(s) + sigma(2)(p)/2) fully determines SGS, even when dispersal variances of seed (sigma(2)(s)) and pollen sigma(2)(p)) differ strongly. Further, self-fertilization with rate s acts as zero-distance pollen dispersal, and N(e) = 4pi[sigma(2)(s) + sigma(2)(p)(1 - s)/2] fully determines SGS, for most cases where there are both likely parameter values and substantial SGS. Moreover, for most cases, there is a loglinear relationship, I(1) = 0.587 - 0.117 ln(N(e)), between SGS, as measured by I(1), Moran's coefficient for adjacent individuals, and N(e). However, there are several biologically significant exceptions, namely for very low or large N(e), SGS exceeds the loglinear values. There are also important exceptions to Crawford's formula. First, plants with low seed dispersal, high outcross pollen dispersal and high selfing rate show larger SGS than predicted. Second, in plants with very low (near zero) seed dispersal, selfing decreases SGS, opposite expectations. Finally, in some cases seed dispersal is more critical than pollen dispersal, in a manner inconsistent with Crawford's formula. PMID- 17692082 TI - Heterogeneity of fiber characteristics in the rat masseter and digastric muscles. AB - The functional requirements in muscle use are related to the fiber type composition of the muscles and the cross-sectional area of the individual fibers. We investigated the heterogeneity in the fiber type composition and fiber cross sectional area in two muscles with an opposing function, namely the digastric and masseter muscles (n = 5 for each muscle) of adult male rats, by means of immunohistochemical staining according to their myosin heavy chain (MyHC) content. The digastric and masseter muscles were taken from Wistar strain male rats 10 weeks old. In the masseter six predefined sample locations were examined; in the digastric four. Most regions showed dominant proportions of type IIA and IIX fibers. However, both muscles also revealed a regional heterogeneity in their fiber type distribution. In the digastric, type I fibers were detected only at the central and deep areas of the anterior and posterior belly, respectively. Meanwhile, the peripheral area of the anterior belly contained a higher proportion of type IIB fibers. In the masseter, the type I fibers were absent. In the superficial masseter the distribution of IIA and IIB fibers was significantly different between the superior and inferior regions. In the deep masseter, regional differences were observed among all four examined areas, of which the posterolateral region contained the highest proportion of type IIB fibers. The cross-sectional areas of type IIB fibers were always the largest, followed by the type IIX and IIA fibers. Only a few differences in cross-sectional area of corresponding fiber types were detected between the various sites. In conclusion, the masseter and digastric muscles showed an obvious heterogeneity of fiber type composition and fiber cross-sectional area. Their heterogeneity reflects the complex role of the both muscles during function. This detailed description of the fiber type composition can serve as a reference for future studies examining the muscular adaptations after the onset of various diseases in the masticatory system. PMID- 17692083 TI - Vaginal blood flow after radical hysterectomy with and without nerve sparing. A preliminary report. AB - Radical hysterectomy with pelvic lymphadenectomy (RHL) for cervical cancer causes damage to the autonomic nerves, which are responsible for increased vaginal blood flow during sexual arousal. The aim of the study of which we now report preliminary data was to determine whether a nerve-sparing technique leads to an objectively less disturbed vaginal blood flow response during sexual stimulation. Photoplethysmographic assessment of vaginal pulse amplitude (VPA) during sexual stimulation by erotic films was performed. Subjective sexual arousal was assessed after each stimulus. Thirteen women after conventional RHL, 10 women after nerve sparing RHL, and 14 healthy premenopausal women participated. Data were collected between January and August 2006. The main outcome measure was the logarithmically transformed mean VPA. To detect statistically significant differences in mean VPA levels between the three groups, a univariate analysis of variance was used. Mean VPA differed between the three groups (P= 0.014). The conventional group had a lower vaginal blood flow response than the control group (P= 0.016), which tended also to be lower than that of the nerve-sparing group (P= 0.097). These differences were critically dependent on baseline vaginal blood flow differences between the groups. The conventional group follows a vaginal blood flow pattern similar to postmenopausal women. Conventional RHL is associated with an overall disturbed vaginal blood flow response compared with healthy controls. Because it is not observed to the same extent after nerve-sparing RHL, it seems that the nerve-sparing technique leads to a better overall vaginal blood flow caused by less denervation of the vagina. PMID- 17692084 TI - Laparoscopy versus laparotomy for benign ovarian tumor: a systematic review and meta-analysis. AB - To determine the efficacy, safety, and cost of laparoscopic surgery compared with laparotomy in women with ovarian tumors assumed to be benign. This study is a systematic review. We searched (MEDLINE, EMBASE, LILACS, and COCHRANE LIBRARY) trials registers and reference lists of published trial reports. Six randomized controlled trials were identified involving 324 patients. Duration of surgery, adverse effects of surgery, pain, length of hospital stay, and economic outcomes were compared. The mean duration of surgery was longer in the laparoscopy group overall (weighted mean difference 11.39, 95% CI 0.57-22.22). The pooled estimate for febrile morbidity decreased for laparoscopy (Peto OR 0.34, 95% CI 0.13-0.88). The odds of any adverse effect were decreased after laparoscopic procedures (Peto OR 0.26, 95% CI 0.12-0.55). The odds of being pain free were significantly greater for the laparoscopy group (Peto OR 7.35, 95% CI 4.3-12.56). Mean length of hospital stay was shorter in the laparoscopy group with reduction of 2.79 days (95% CI -2.95 to -2.62). In economic outcomes, there was a significant reduction of US$1045 (95% CI -1361 to -726.97) in the laparoscopy group. Laparoscopy is associated with a reduction in the following: febrile morbidity, urinary tract infection, postoperative complications, postoperative pain, days in hospital, and total cost. These findings should be interpreted with caution as only a small number of studies were identified including a total of only 324 women. PMID- 17692085 TI - Significance of E2F-1 overexpression in epithelial ovarian cancer. AB - E2F-1 is a downstream regulator of the Rb pathway and is a transcription factor that plays a key role in the control of cell cycle progression. Deregulation of E2F-1 expression and Rb pathway is involved in carcinogenesis. The aim of this study was to evaluate E2F-1 expression and Rb pathway alteration and to elucidate their correlation with clinical and pathologic parameters in epithelial ovarian cancer (EOC). We investigated overexpression of E2F-1 and alterations of p16(INK4a), cyclin D1, CDK4, and pRb using immunohistochemistry and tissue microarray methods in 72 EOC patients. Overexpression of E2F-1 was detected in 45.8% of samples. The overall abnormal expression frequencies of p16(INK4a), cyclin D1, CDK4, and pRb were 33.3%, 11.1%, 12.5%, and 38.9%, respectively. E2F-1 overexpression was not associated with alteration of the Rb pathway. E2F-1 overexpression was correlated with FIGO stage, histologic grade, and mitotic index; it was a valuable prognostic variable along with FIGO stage in the multivariated analysis. The results suggest that E2F-1 has a growth-promoting effect in EOC and that E2F-1 overexpression may provide a useful prognostic indicator for EOC. PMID- 17692086 TI - The use and understanding of CA125 as a tumor marker for ovarian cancer: a questionnaire-based survey. AB - The aim of this study was to assess the level of understanding of the role of the tumor marker CA125 in ovarian cancer among doctors of different grades specializing in obstetrics and gynecology (O&G), medicine, surgery, and primary care (general practitioners [GPs]). The study involves a questionnaire-based survey. Two hundred and fifty-nine questionnaires were distributed. An overall response rate of 47.1% was achieved. All grades of doctors and all major specialties were represented. There was a significant difference in the level of self-reported CA125 ordering between the medical specialties, O&G being the most frequent users and primary care the least (P < 0.001), and between the grade of doctors, senior house officers/preregistration house officers and GPs less than consultants and middle grade doctors (P < 0.001). Electronic literature was the first source of advice for the majority of respondents (38.5%). The knowledge of false-positive causes for a raised CA125 was low in medicine, surgery, and primary care specialties, as was the awareness of the sensitivity and specificity of CA125 in epithelial and nonepithelial ovarian cancers. The role of CA125 in ovarian cancer is poorly understood, especially among doctors working outside O&G. Guidelines should be developed to aid clinicians from all specialties in the most appropriate application of CA125 in their practice. Substantial cost savings could be made by the introduction of clear protocol-driven ordering in an attempt to reduce the number of inappropriate tests performed. PMID- 17692087 TI - An individual prediction of the future (disease-free) survival of patients with a history of early-stage cervical cancer, multistate model. AB - To evaluate the possibility to give a prediction of the future (disease-free) survival, given the fact that a patient with a history of early-stage cervical cancer has been disease free for a specific period after treatment. Between January 1984 and April 2005, 615 patients with cervical cancer stages I-IIA underwent radical hysterectomy with or without adjuvant radiotherapy. The Kaplan Meier method was used to detect statistical significance and multistate risk models to estimate the influence of covariates and to generate predicted survival curves by simulation. Simulations were done for patients with positive lymph nodes (n= 123), patients with negative lymph nodes (n= 492), and 4 hypothetical patients. The 5-year cancer-specific survival and disease-free survival of the entire group was 84% and 76%, respectively. The probability of death of the two lymph node groups and the four hypothetical patients was demonstrated in predicted cumulative probability plots. It is possible with multistate risk models to give a detailed prediction of the future (disease-free) survival, given the fact that a patient has been disease free for a specific period after treatment. This possibility is an important step forward to improve the quality of cancer care. PMID- 17692088 TI - Prospective evaluation of weekly topotecan in recurrent platinum-resistant epithelial ovarian cancer. AB - Topotecan administered on a weekly basis has been reported to possess antineoplastic activities with lower toxicities than the standard 5-day regimen every 3 weeks. We studied the activity of weekly topotecan regimen in recurrent platinum-resistant epithelial ovarian cancer patients. Ovarian cancer patients with documented platinum-resistant recurrences were treated with weekly intravenous topotecan (4 mg/m(2)) on days 1, 8, and 15 on a 28-day cycle. Prospective data collection included patients' demographics together with disease and treatment-related toxicities. Responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) and CA125 criteria. Progression-free survival and overall survival time from commencement of weekly treatment were estimated using the Kaplan-Meier method. All P values less than 0.05 were considered to be statistically significant. Twenty-two patients were treated. Weekly topotecan was used most commonly as third-line chemotherapy (range 1-5). A total of 244 weekly treatments were administered, with a median of 12 weekly treatments per patient. Two patients (9%) reported grade 3/4 gastrointestinal and two had grade 3/4 hematologic toxicities respectively. No dose reduction or treatment delay was required. Partial response was observed in two patients (9.1%) and another seven patients (31.8%) showed stable disease. No significant association was observed between best clinical response and patients' initial platinum sensitivity status. The estimated median progression-free survival was 20.9 weeks (95% CI 11.2-30.5) from the start of the weekly regimen. Weekly topotecan is well tolerated in patients with recurrent platinum-resistant ovarian cancer with modest activity. PMID- 17692089 TI - Radiotherapy in congenital vulvar lymphangioma circumscriptum. AB - Congenital lymphangioma circumscriptum (LC) of the vulva is a rare disorder with unknown etiology. Treatment options include ablative approaches such as laser therapy, sclerotherapy, and surgery. Radiotherapy has been shown to be effective in the management of congenital lymphangioma especially in the thoracic and abdominal lesions. In this report, we describe a patient with persistent vulvar LC despite sclerosing therapy and several surgical excisions. She was treated with a course of external radiotherapy and showed a dramatic objective response with relief of all symptoms. PMID- 17692091 TI - Modified uterine manipulator and vaginal rings for total laparoscopic radical hysterectomy. AB - At present, there is no standard technique that allows surgeons performing total laparoscopic radical hysterectomy to complete the colpotomy and remove an adequate (2-cm) margin of upper vaginal tissue while maintaining adequate pneumoperitoneum. We evaluated the feasibility and safety of using a modified uterine manipulator for total laparoscopic radical hysterectomy in patients with cervical or endometrial cancer. A retrospective review was performed in all patients who underwent total laparoscopic radical hysterectomy using a modified uterine manipulator at our institution during the period April 2004 to December 2006. This analysis included 30 patients who underwent surgery with the modified uterine manipulator. There were no reports of difficulty with placement of the instrument, multiple attempts at placement, difficulty with uterine manipulation, or uterine perforation. In no patient was a vaginal incision or episiotomy required to fit the instrument through the introitus. In no case was there loss of pneumoperitoneum during colpotomy. Additional upper vaginal tissue had to be removed after intraoperative assessment of the adequacy of the surgical specimen in five (16.7%) of 30 patients. Use of the modified uterine manipulator according to our technique is safe and feasible, allowing for adequate vaginal resection and maintenance of pneumoperitoneum. PMID- 17692090 TI - Assessment of TP53 mutation using purified tissue samples of ovarian serous carcinomas reveals a higher mutation rate than previously reported and does not correlate with drug resistance. AB - The TP53 mutation frequency in ovarian serous carcinomas has been reported to range between 50% and 80%, but a stringent analysis of TP53 using purified epithelial samples has not yet been performed to accurately assess the mutation frequency and to correlate it with the histologic grade. The purpose of this study was to assess the TP53 mutational profile in a relatively large series of high-grade (53 primary and 18 recurrent) and 13 low-grade ovarian serous tumors using DNA isolated from affinity-purified tumor cells and to correlate it with in vitro drug resistance. All samples were affinity purified, and the tumor DNA was analyzed for TP53 mutations in exons 4-9. In vitro drug resistance assays to carboplatin, cisplatin, paclitaxel, and taxotere were performed on the same tumor samples and correlated with the TP53 mutation status. TP53 mutations were detected in 57 (80.3%) of 71 high-grade carcinomas and in one (7.8%) of 13 low grade serous tumors (an invasive low-grade serous carcinoma). The mutations were predominantly missense mutations (59.6%). TP53 mutations were associated with high-grade serous carcinomas and recurrent disease (P < 0.0001). There was no statistically significant correlation between TP53 mutation status and drug resistance assays or clinical stage (P > 0.25). The frequency of TP53 mutations using purified tumor DNA from ovarian serous carcinomas was 80.3%, which is much higher than previously reported. Furthermore, we found that TP53 is not directly involved in the development of drug resistance in high-grade ovarian serous carcinomas. PMID- 17692092 TI - A combination of chemoirradiation and chemotherapy for treatment of advanced clear cell adenocarcinoma of the cervix. AB - Clear cell adenocarcinoma of the cervix (CCAC) is an uncommon tumor. No good treatment option has been reported for advanced disease, and the prognosis is generally poor. We report a case of a 14-year-old girl with stage III CCAC. She was given whole-pelvic external irradiation (40 Gy in 20 daily fractions) and high-dose rate brachytherapy with concurrent weekly cisplatin (40 mg/m(2)), followed by further external irradiation to the parametria with central shield (14 Gy in seven daily fractions). She then received one cycle of carboplatin (area under the curve [AUC] 6) with paclitaxel (175 mg/m(2)) and two cycles of carboplatin (AUC 4) with gemcitabine (1000 mg/m(2) on days 1 and 8) because she developed anaphylactic shock to paclitaxel. Chemotherapy was stopped after the third cycle due to initial poor general condition. However, she gradually improved while on palliative care. Reassessment 6 months later showed no evidence of residual disease, and she remained disease free during a follow-up of 1 year. The complete response in this case suggests that chemoirradiation followed by combination chemotherapy may be a treatment option for advanced CCAC. PMID- 17692093 TI - Comorbidity and ovarian cancer survival in Denmark, 1995-2005: a population-based cohort study. AB - The impact of comorbid diseases on ovarian cancer survival is largely unknown. We therefore examined (i) the prevalence of comorbidity among ovarian cancer patients and (ii) the impact of comorbidity on ovarian cancer survival and mortality. Using hospital discharge data, we identified Danish women diagnosed with ovarian cancer between 1995 and 2005 (n= 1995 within a population of 1.6 million) and then computed Charlson comorbidity index scores (0, 1-2, and 3+). We estimated the prevalence of comorbidity and computed absolute survival and relative mortality rate ratios (MRRs) according to comorbidity level, using patients with Charlson score 0 as the reference group. During the study period, the proportion of patients without comorbidity fell from 81% to 75%, while the proportion of patients with comorbidity score 1-2 and 3+ rose from 16% to 21% and from 4% to 5%, respectively. Overall 1-year survival increased from 68% in 1995 1997 to 70% in 1998-2000 and to 73% in 2001-2004. For patients with Charlson score 1-2, 1-year adjusted MRRs were 1.1 (95% CI, 0.8-1.6) in 1995-1997, 1.3 (95% CI, 1.0-1.8) in 1998-2000, and 1.7 (95% CI, 1.3-2.4) in 2001-2004. For patients with Charlson score 3+, 1-year adjusted MRRs were 2.4 (95% CI, 1.4-4.3) in 1995 1997, 1.6 (95% CI, 1.0-2.7) in 1998-2000, and 2.2 (95% CI, 1.3-3.8) in 2001-2004. The 5-year MRRs were similar to the 1-year MRRs. One quarter of Danish women with ovarian cancer were found to have comorbid conditions, and 5% had severe comorbidity. Severe comorbidity was a predictor of poorer survival. PMID- 17692094 TI - Clinical application of Clostridium botulinum type A neurotoxin purified by a simple procedure for patients with urinary incontinence caused by refractory destrusor overactivity. AB - Type A neurotoxin of Clostridium botulinum was purified by a simple procedure using a lactose gel column. This procedure was previously reported for type B neurotoxin. Hemagglutinin-positive toxins (19S and 16S) were bound to the column under acid conditions, and the neurotoxin alone was dissociated from these hemagglutinin-positive toxins by changing the pH of the column to an alkaline condition. The toxicity of this purified toxin preparation was retained for at least 1 year at -30 degrees C by supplementing it with either 0.1% albumin or 0.05% albumin plus 1% trehalose. This preparation was used to treat 18 patients with urinary incontinence caused by refractory idiopathic and neurogenic detrusor overactivity; 16 of the patients showed excellent improvement. Improvements started within 1 week after injection in most cases and lasted 3-12 months [corrected] PMID- 17692095 TI - Distribution of candidate division JS1 and other Bacteria in tidal sediments of the German Wadden Sea using targeted 16S rRNA gene PCR-DGGE. AB - The bacterial candidate division JS1 dominates a number of 16S rRNA gene libraries from deep subseafloor sediments, yet its distribution in shallow, subsurface sediments has still to be fully documented. Sediment cores (down to 5.5 m) from Wadden Sea tidal flats (Neuharlingersieler Nacken and Groninger Plate) were screened for JS1 16S rRNA genes using targeted PCR-denaturing gradient gel electrophoresis (DGGE), which also detects some other important Bacteria. Bacterial subpopulations at both sites were dominated by Gammaproteobacteria in the upper sediment layers (down to 2 m) and in deeper layers by members of the Chloroflexi. The deeper layers of Neuharlingersieler Nacken consisted of grey mud with low sulphate (0.1-10 mM), elevated total organic carbon (TOC) ( approximately 1-2%) and JS1 sequences were abundant. In contrast, the deeper sandy layers of Groninger Plate, despite also having reduced sulphate concentrations, had lower TOC (<0.6%) with few detectable JS1 sequences. Results indicated that JS1 prefers muddy, shallow, subsurface sediments with reduced sulphate, whereas Chloroflexi may out-compete JS1 in shallow, sandy, subsurface sediments. Bacterial population changes at both sites ( approximately 2 m) were confirmed by cluster analysis of DGGE profiles, which correlated with increased recalcitrance of the organic matter. This study extends the biogeographical range of JS1. The presence of JS1 and Chloroflexi in Wadden Sea sediments demonstrates that subsurface tidal flats contain similar prokaryotic populations to those found in the deeper subseafloor biosphere. PMID- 17692096 TI - Characterization of the bacterial community associated with the surface and mucus layer of whiting (Merlangius merlangus). AB - The bacterial community inhabiting the mucus layer and surface of whiting was examined to determine whether the bacteria present are a reflection of the surrounding water or an indigenous bacterial flora is present. The outer mucus, mouth mucus and gut of four whiting harvested from a site in the Irish Sea and the surrounding water were examined by terminal restriction fragment length polymorphism (tRFLP) analysis of the 16S rRNA gene and clone library construction. The water community was the most diverse, with only a small number of shared water-mucus phylotypes present. The bacterial flora associated with the outer mucus layer were more diverse than that of the mouth mucus and gut. All three mucus layers were characterized by the presence of a dominant phylotype, identified as clone wom-1, highly similar to Photobacterium iliopiscarium. In addition to other Photobacterium phylotypes, members of the CFB and Clostridia groups were also detected. Subsequently, whiting from 11 different sites along the east and south coast of Ireland were compared by tRFLP analysis. Strikingly, the mucus layer of whiting at all sites was characterized by the presence and dominance of a TRF corresponding to the clone wom-1 which was virtually absent from the water column. PMID- 17692098 TI - Spatially correlated recruitment of a marine predator and its prey shapes the large-scale pattern of density-dependent prey mortality. AB - Patterns of predator dispersal can be critical to the dynamics of prey metapopulations. In marine systems, oceanic currents may shape the dispersal of planktonic larvae of both predators and prey, producing spatial correlations in the recruitment of both species and distinctive geographic patterns of prey mortality. I examined the potential for this phenomenon in two fishes, a wrasse and its grouper predator, at a Caribbean island where the near-shore oceanographic regime produces a temporally consistent spatial pattern of fish recruitment. I found that recruitment and adult abundance of groupers were spatially correlated with recruitment of wrasse prey. Furthermore, the local abundance of predators strongly affected the nature of density-dependent prey mortality. At sites with few predators, wrasse mortality was inversely density dependent, while mortality was positively density-dependent at sites with higher predator densities. This phenomenon could be important to the dynamics of any metacommunity in which physical forces produce correlated dispersal. PMID- 17692097 TI - Multiple-locus variable-number tandem repeat analysis of Salmonella Enteritidis isolates from human and non-human sources using a single multiplex PCR. AB - Simplified multiple-locus variable-number tandem repeat analysis (MLVA) was developed using one-shot multiplex PCR for seven variable-number tandem repeats (VNTR) markers with high diversity capacity. MLVA, phage typing, and PFGE methods were applied on 34 diverse Salmonella Enteritidis isolates from human and non human sources. MLVA detected allelic variations that helped to classify the S. Enteritidis isolates into more evenly distributed subtypes than other methods. MLVA-based S. Enteritidis clonal groups were largely associated with sources of the isolates. Nei's diversity indices for polymorphism ranged from 0.25 to 0.70 for seven VNTR loci markers. Based on Simpson's and Shannon's diversity indices, MLVA had a higher discriminatory power than pulsed field gel electrophoresis (PFGE), phage typing, or multilocus enzyme electrophoresis. Therefore, MLVA may be used along with PFGE to enhance the effectiveness of the molecular epidemiologic investigation of S. Enteritidis infections. PMID- 17692099 TI - The maximum entropy formalism and the idiosyncratic theory of biodiversity. AB - Why does the neutral theory, which is based on unrealistic assumptions, predict diversity patterns so accurately? Answering questions like this requires a radical change in the way we tackle them. The large number of degrees of freedom of ecosystems pose a fundamental obstacle to mechanistic modelling. However, there are tools of statistical physics, such as the maximum entropy formalism (MaxEnt), that allow transcending particular models to simultaneously work with immense families of models with different rules and parameters, sharing only well established features. We applied MaxEnt allowing species to be ecologically idiosyncratic, instead of constraining them to be equivalent as the neutral theory does. The answer we found is that neutral models are just a subset of the majority of plausible models that lead to the same patterns. Small variations in these patterns naturally lead to the main classical species abundance distributions, which are thus unified in a single framework. PMID- 17692100 TI - Circulating dendritic cells subsets and CD4+Foxp3+ regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasome. AB - Immune thrombocytopenic purpura (ITP) is an autoimmune disorder, and high-dose dexamethasome (HD-DXM) has been used as a first-line therapy for patients with ITP. However, little is known about the role of dendritic cells (DCs) and CD4(+)Foxp3(+) regulatory T (Treg) cells in the pathogenesis of chronic ITP and the effects of HD-DXM on DCs and Treg cells. In this study, we investigated the amounts of circulating myeloid DCs (mDCs), plasmacytoid DCs (pDCs), and CD4(+)Foxp3(+) Treg cells in 26 untreated adult patients with chronic ITP. All patients had thrombocytopenia (platelet count <50 x 10(9)/L) for more than 6 months. We also observed short-time changes of DCs and Treg cells after treatment with HD-DXM in these patients. Both mDCs and pDCs numbers in patients were comparable with that of healthy controls. In contrast, the percentage of Treg cells was significantly reduced in patients when compared with healthy controls (P < 0.0001). After 4-days treatment with HD-DXM, Treg cells and mDCs were increased (P < 0.0001 and P < 0.05), while pDCs decreased (P < 0.0001), and CD11c expression level in mDCs was downregulated (P < 0.0001). These results suggest that Treg cells are deficient in ITP and the immunosuppressive therapy of glucocorticoids could cause the short-time changes of these cells. PMID- 17692101 TI - Intestinal marginal zone B-cell lymphoma of MALT type: clinical manifestation and outcome of a rare disease. AB - Intestinal marginal zone B-cell lymphoma of the MALT type (I-MZL) is a relatively uncommon form of lymphoma. Twenty-seven patients with histologically-confirmed I MZL were analyzed. The patients initially presented with abdominal pain (62.9%), and diarrhea (22.2%). The most common involved site was the ileo-caecal area (40.7%). Musshoff's stage I(E), II(E)1, II(E)2, III(E) and IV were present in 44%, 15%, 11%, 7.4% and 22% respectively. Sixty-three percent were in the low risk group according to the Follicular Lymphoma International Prognostic Index. Complete response and partial response were achieved in 82% and 4% patients. The estimated 5-year overall survival (OS) and progression-free survival (PFS) rates were 86% and 54%. Stage > or = II(E)2 was determined to be a poor prognostic factor for PFS and OS. I-MZL commonly manifests in an early-stage, low-risk state and tends to respond well to local and systemic treatment with favorable prognosis. I-MZL tends to be an indolent disease - characterized by prolonged survival with frequent relapses, similarly to other site MZLs. PMID- 17692102 TI - Molecular analysis in a patient with severe factor VII deficiency and an inhibitor: report of a novel mutation (S103G). AB - Congenital factor VII (FVII) deficiency is an autosomal recessive bleeding disorder with variable phenotypic correlation between FVII activity and bleeding risk. We report a novel mutation of the FVII gene that creates the amino acid change Ser 103 to Gly, which resulted in severe FVII deficiency with reduced FVII antigen. This mutation in the heterozygous form was also present in a mildly affected, unrelated patient. We also report on the natural history of an FVII inhibitor in the patient with severe FVII deficiency. PMID- 17692103 TI - Plasma cell growth fraction using Ki-67 antigen expression identifies a subgroup of multiple myeloma patients displaying short survival within the ISS stage I. AB - The current most powerful prognostic model in Multiple Myeloma (MM) combines beta 2 microglobulin (b2m) with albumin, corresponding to the International Staging System (ISS). However, the prognosis of patients within the ISS stage I (high albumin and low b2m) may vary. Ki-67 is a nuclear protein associated with cell proliferation. We retrospectively evaluated the percentage of bone marrow plasma cells expressing Ki-67 antigen (Ki-67 index) in a series of 174 untreated MM patients at diagnosis. Median survival was 51, 41 and 20 months respectively, and median Ki-67 index was 3.0%, 6.1% and 6.5% in ISS stages I, II, and III respectively. Independently of ISS, Ki-67 index > or =4% was highly predictive of adverse prognosis. Ki-67 index correlated with markers of intrinsic malignancy and with markers of tumour burden. Within ISS stage I, median survival was of 31 months (RR of death 2.65) in patients with Ki-67 index > or =4%. Eventually, the combination of Ki-67 with b2m produced an efficient prognostic model, which appeared most effective in our series when compared with b2m and KI-67 with chromosome 13 deletion models. In this series, we demonstrated that a proliferation marker provides clear-cut additional survival prognostic information to b2m into the ISS model. PMID- 17692104 TI - Migraine secondary to superior oblique myokymia. PMID- 17692105 TI - Low-dose gabapentin in treatment of high-altitude headache. AB - Headache is the most prevalent symptom of acute mountain sickness. We conducted a pilot clinical trial at an altitude of 3500 m to evaluate the efficacy of gabapentin in treatment of high-altitude headache (HAH). Twenty-four adult HAH patients (10 female, 14 male; age 18-50 years) were randomly assigned to receive either 300 mg of gabapentin capsule or identical placebo. After 1 h the presence of HAH and need to receive supplementary analgesic were assessed. The duration of the HAH-free phase after taking additional analgesic was also registered. Four patients in the gabapentin group asked for additional analgesics, whereas nine placebo recipients did not find primary medication satisfactory after the first hour of treatment (P = 0.04). The mean HAH-free period was 17.10 h in the gabapentin group, which was significantly higher than in the placebo group with a mean of 10.08 h (P = 0.02). This preliminary observation indicates that gabapentin is effective in treatment and alleviation of HAH. PMID- 17692106 TI - Serotonin, 5-HT 1B/1D receptor, agonists are effective in acute benign lymphocytic meningitis--a case report. PMID- 17692107 TI - Thyroid function and anti-thyroid autoantibodies in untreated children with vertically acquired chronic hepatitis C virus infection. AB - OBJECTIVE: The reported data on thyroid function and anti-thyroid autoantibodies in adults with untreated hepatitis C virus (HCV) infection are controversial. Data are scarce for HCV-infected children, and only in those treated with interferon-alpha (IFN-alpha). We investigated thyroid function and anti-thyroid autoantibodies in a cohort of untreated children with vertically acquired, chronic, HCV infection. DESIGN AND PATIENTS: FT4 and TSH serum levels (measured by immunometric assays) and anti-thyroglobulin (TgA) and anti-thyroperoxidase (TPOA) antibodies (evaluated by fluorescence enzymatic immunoassays) were studied in 36 consecutive HCV-infected children and 150 age- and sex-matched controls. The prevalence of thyroid involvement was also related to family history of autoimmune disease, distribution of HCV genotypes, and duration and activity of HCV infection. RESULTS: Four out of 36 (11.1%) HCV-infected children and 4/150 controls (2.7%) showed subclinical hypothyroidism [P = 0.04; relative risk (RR) 4.56, 95% confidence interval (CI) 1.08-19.21]. None of these had anti-thyroid autoantibodies. Two out of 36 (5.6%) HCV-infected children and 1/150 (0.7%) controls had increased TgA values with normal levels of TSH (P > 0.05). Subclinical hypothyroidism and anti-thyroid autoantibodies were not related to family history of autoimmune disease, duration of infection, HCV viral load, liver function or different HCV genotype distribution, but seemed to be related to the presence of active HCV infection. CONCLUSIONS: Our data suggest a role for HCV infection in the development of nonautoimmune thyroid disease in untreated HCV-infected children, confirming previous studies in adults. Clinicians should be aware of thyroid dysfunction even in untreated children. PMID- 17692108 TI - Anti-androgens increase N-terminal pro-BNP levels in men with prostate cancer. AB - OBJECTIVE: The aim of this study was to determine the effects of anti-androgens on left ventricular (LV) function and levels of N-terminal proB-type natriuretic peptide (NT-proBNP), a sensitive cardiac risk marker, in men with prostate cancer as these are widely used drugs in this condition, and evidence suggests that endogenous androgens are cardioprotective in men. DESIGN AND PATIENTS: Forty three men (mean age 70.7 +/- 6.2 years) with prostate cancer were randomized to goserelin (an LH-releasing hormone analogue) or bicalutamide (an androgen receptor blocker) for 6 months; 20 men with a history of prostate cancer on no treatment were studied in parallel. RESULTS: Mean changes in testosterone and oestradiol, respectively, from baseline to 6 months were -88% and -46% with goserelin, +50% and +44% with bicalutamide, and -1% and -9% for the 'no treatment' group. Bicalutamide significantly increased NT-proBNP from baseline to 3 and 6 months (median value at baseline, 3 and 6 months: 55, 101 and 118 ng/l, respectively). Goserelin caused a significant increase from baseline to 3 months but not to 6 months (median value at baseline, 3 and 6 months: 66, 87 and 72 ng/l, respectively). No significant changes occurred in the 'no-treatment' cohort (median value at baseline 3 and 6 months: 60, 53 and 60 ng/l, respectively). No significant changes in LV function, blood pressure (BP), body mass index or waist hip ratio occurred to account for the changes in NT-proBNP. CONCLUSION: Androgen receptor blockade and, to a lesser extent, androgen suppression cause an increase in NT-pro-BNP in men with prostate cancer. The significance is not clear but could imply an adverse effect on cardiovascular risk following hormonal manipulation. PMID- 17692109 TI - What is the natural history of nonoperated nonfunctioning pituitary adenomas? AB - BACKGROUND: Series of patients systematically investigating the outcome of clinically nonfunctioning pituitary adenomas (NFAs) not treated by surgery or radiotherapy during long follow-up periods are limited. Most reports involve the follow-up of selected cases of incidentally found lesions, rendering their results unreliable on the assessment of the pros and cons of a 'watch and wait' policy. OBJECTIVE: To investigate the outcome of a series of consecutive patients with presumed NFA (microadenoma or macroadenoma), who were not offered treatment at presentation (for a number of reasons) and were regularly followed up, and to identify possible factors predicting subsequent increase in tumour size. PATIENTS AND METHODS: All patients presenting to the Department of Endocrinology in Oxford between 1989 and 2005 with presumed NFA were studied retrospectively. Inclusion criteria were: (i) imaging features suggestive of a pituitary adenoma, (ii) no clinical and/or biochemical evidence of hormonal hypersecretion by the tumour, (iii) monitoring being the initial choice of management, and (iv) at least one repeat scan during the follow-up period. Subjects presenting with acute apoplexy were excluded. Follow-up management included clinical evaluation, assessment of the visual acuity and fields and imaging at regular intervals. The duration of observation was estimated from the dates of first and last scan. RESULTS: Forty subjects were included in the study [18 males/22 females, median age 52 years (range 18-89), 16 with microadenoma/24 with macroadenoma]. The mean follow-up period was 42 months (range 8-128). During the observation interval, 12.5% of the microadenomas and 50% of the macroadenomas increased in size. The 48-month probability for enlargement was 19% for the microadenomas and 44% for the macroadenomas. Among the subjects with tumour enlargement, 57% showed new or worse visual field defects (all had macroadenomas) and 21% showed chiasmatic involvement on imaging without visual deterioration (all had macroadenomas). New or worse visual field defects were found in 67% of the macroadenomas showing increase in size. No microadenoma enlarged to cause visual deterioration. In microadenomas, sex and age at presentation were not predictors of enlargement. In macroadenomas, sex, age, visual field defects or cavernous sinus invasion at presentation were not predictors of enlargement. CONCLUSIONS: The 'watch and wait' policy seems reasonable for microadenomas but is probably not a safe approach for macroadenomas, which appear to have a significant growth potential; in these cases, given the lack of established medical treatment, the decision for surgical intervention should balance the presence of significant comorbidities and the anaesthetic/peri-operative risks at presentation against the probability of tumour enlargement and its consequences, as well as the possible loss of advantages associated with early operation. PMID- 17692110 TI - Recombinant human luteinizing hormone, lutropin alfa, for the induction of follicular development and pregnancy in profoundly gonadotrophin-deficient women. AB - OBJECTIVE: To provide evidence of efficacy and safety for use of lutropin alfa in inducing follicular development and pregnancy in hypogonadotrophic hypogonadal women with profound gonadotrophin deficiency. DESIGN: An open-label, noncomparative extension of a randomized, double-blind, placebo-controlled study PATIENTS: A total of 31 hypogonadotrophic hypogonadal women with profound gonadotrophin deficiency in 23 medical centres in four countries were studied. INTERVENTIONS: Lutropin alfa 75 IU and follitropin alfa (75-225 IU), individually based on each patient's response as is consistent with usual medical practice. MEASUREMENTS: Follicular development as defined by (i) at least one follicle >or= 17 mm; (ii) preovulatory serum oestradiol level >or= 109 pg/ml on the day of hCG administration; and (iii) midluteal phase P(4) level >or= 7.9 ng/ml. Pregnancy and over-response leading to cycle cancellation were considered treatment successes. Pregnancy rates were assessed. RESULTS: In a total of 54 cycles, 27 of 31 (87.1%) profoundly gonadotrophin-deficient patients achieved follicular development within three cycles. Twenty of 27 patients (74.1%) who achieved follicular development and received hCG became pregnant; 16 (59.3%) continued to clinical pregnancy. One patient was hospitalized for severe ovarian hyperstimulation syndrome. Lutropin alfa was well tolerated. CONCLUSIONS: Coadministration of lutropin alfa 75 IU and follitropin alfa is safe and effective in inducing follicular development and pregnancy in hypogonadotrophic hypogonadal women with profound gonadotrophin deficiency in a setting consistent with established medical practice. PMID- 17692111 TI - Evaluating environmental tobacco smoke exposure in a group of Turkish primary school students and developing intervention methods for prevention. AB - BACKGROUND: In countries like Turkey where smoking is highly prevalent, children's exposure to tobacco smoke is an important public health problem. The goals of this study were to determine the self-reported environmental tobacco smoke exposure status of primary school students in grades 3 to 5, to verify self reported exposure levels with data provided from a biomarker of exposure, and to develop methods for preventing school children from passive smoking. METHODS: The study was conducted on 347 primary school students by using a standard questionnaire and urinary cotinine tests. Children with verified ETS exposure were randomly assigned to 2 intervention groups. Two phone interviews were conducted with the parents of the first group regarding their children's passive smoking status and its possible consequences. On the other hand, a brief note concerning urinary cotinine test result was sent to parents of the second group. Nine months after the initial urinary cotinine tests, measurements were repeated in both groups. RESULTS: According to questionnaire data, 59.9% of the study group (208 of 347) were exposed to ETS. Urinary cotinine measurements of children were highly consistent with the self-reported exposure levels (P < 0.001). Two different intervention methods were applied to parents of the exposed children. Control tests suggested a remarkable reduction in the proportion of those children demonstrating a recent exposure to ETS in both groups. Proportions of children with urinary cotinine concentrations 10 ng/ml or lower were 79.5% in Group I and 74.2% in Group II (P > 0.05). CONCLUSION: Self-reported ETS exposure was found to be pretty accurate in the 9-11 age group when checked with urinary cotinine tests. Only informing parents that their children' ETS exposure were confirmed by a laboratory test seems to be very promising in preventing children from ETS. PMID- 17692112 TI - Implementing hospital guidelines improves warfarin use in non-valvular atrial fibrillation: a before-after study. AB - BACKGROUND: The use of oral anticoagulant therapy (OAT) to prevent non-valvular atrial fibrillation (NVAF) related-strokes is often sub-optimal. We aimed to evaluate whether implementing guidelines on antithrombotic therapy (AT) by a multifaceted strategy may improve appropriateness of its prescription in NVAF patients discharged from a large tertiary-care hospital. METHODS: A survey was conducted on all consecutive NVAF patients discharged before (1st January-30th June 2000, n = 313) and after (1st January-30th June 2004, n = 388) guideline development and implementation. RESULTS: When strongly recommended, OAT use increased from 56.6% (60/106 in 2000) to 81.9% (86/105 in 2004), with an absolute difference of +25.3% (95%CI: 15% 35%). In patients for whom the choice OAT/acetylsalicylic acid should be individualised, those discharged without any AT were 33.7% (34/101) in 2000 and 16.9% (21/124) in 2004 (-16.7%;95%CI: -26.2% 7.2%). In a logistic regression model, OAT prescription in 2004 was increased by 2.11 times (95%CI: 1.47 3.04), after accounting for stroke risk, presence of contraindications (OR = 0.18; 0.13 0.27), older age (OR = 0.30; 0.21 0.45), prophylaxis at admission (OR = 3.03; 2.08 4.43). OAT was positively associated with the stroke risk in the 2004 sample only. CONCLUSION: The guideline implementation has substantially improved the appropriateness of OAT at discharge, through a better evaluation at patient's individual level of the benefit-to-risk ratio. PMID- 17692113 TI - GnRH and LHR gene variants predict adverse outcome in premenopausal breast cancer patients. AB - BACKGROUND: Breast cancer development and progression are dependent on estrogen activity. In premenopausal women, estrogen production is mainly regulated through the hypothalamic-pituitary-gonadal (HPG) axis. METHODS: We have investigated the prognostic significance of two variants of genes involved in the HPG-axis, the GnRH (encoding gonadotropin-releasing hormone) 16Trp/Ser genotype and the LHR (encoding the luteinizing hormone receptor) insLQ variant, in retrospectively collected premenopausal breast cancer patients with a long follow-up (median follow-up of 11 years for living patients). RESULTS: Carriership was not related with breast cancer risk (the case control study encompassed 278 premenopausal cases and 1,758 premenopausal controls). A significant adverse relationship of the LHR insLQ and GnRH 16Ser genotype with disease free survival (DFS) was observed in premenopausal (hormone receptor positive) breast cancer patients. In particular, those patients carrying both the GnRH 16Ser and LHR insLQ allele (approximately 25%) showed a significant increased risk of relapse, which was independent of traditional prognostic factors (hazard ratio 2.14; 95% confidence interval 1.32 to 3.45; P = 0.002). CONCLUSION: We conclude that the LHR insLQ and GnRH 16Ser alleles are independently associated with shorter DFS in premenopausal patients. When validated, these findings may provide a lead in the development of tailored treatment for breast cancer patients carrying both polymorphisms. PMID- 17692114 TI - Geobacillus zalihae sp. nov., a thermophilic lipolytic bacterium isolated from palm oil mill effluent in Malaysia. AB - BACKGROUND: Thermophilic Bacillus strains of phylogenetic Bacillus rRNA group 5 were described as a new genus Geobacillus. Their geographical distribution included oilfields, hay compost, hydrothermal vent or soils. The members from the genus Geobacillus have a growth temperatures ranging from 35 to 78 degrees C and contained iso-branched saturated fatty acids (iso-15:0, iso-16:0 and iso-17:0) as the major fatty acids. The members of Geobacillus have similarity in their 16S rRNA gene sequences (96.5-99.2%). Thermophiles harboring intrinsically stable enzymes are suitable for industrial applications. The quest for intrinsically thermostable lipases from thermophiles is a prominent task due to the laborious processes via genetic modification. RESULTS: Twenty-nine putative lipase producers were screened and isolated from palm oil mill effluent in Malaysia. Of these, isolate T1T was chosen for further study as relatively higher lipase activity was detected quantitatively. The crude T1 lipase showed high optimum temperature of 70 degrees C and was also stable up to 60 degrees C without significant loss of crude enzyme activity. Strain T1T was a Gram-positive, rod shaped, endospore forming bacterium. On the basic of 16S rDNA analysis, strain T1T was shown to belong to the Bacillus rRNA group 5 related to Geobacillus thermoleovorans (DSM 5366T) and Geobacillus kaustophilus (DSM 7263T). Chemotaxonomic data of cellular fatty acids supported the affiliation of strain T1T to the genus Geobacillus. The results of physiological and biochemical tests, DNA/DNA hybridization, RiboPrint analysis, the length of lipase gene and protein pattern allowed genotypic and phenotypic differentiation of strain T1T from its validly published closest phylogenetic neighbors. Strain T1T therefore represents a novel species, for which the name Geobacillus zalihae sp. nov. is proposed, with the type strain T1T (=DSM 18318T; NBRC 101842T). CONCLUSION: Strain T1T was able to secrete extracellular thermostable lipase into culture medium. The strain T1T was identified as Geobacillus zalihae T1T as it differs from its type strains Geobacillus kaustophilus (DSM 7263T) and Geobacillus thermoleovorans (DSM 5366T) on some physiological studies, cellular fatty acids composition, RiboPrint analysis, length of lipase gene and protein profile. PMID- 17692115 TI - A continuum mathematical model of endothelial layer maintenance and senescence. AB - BACKGROUND: The monolayer of endothelial cells (ECs) lining the inner wall of blood vessels deteriorates as a person ages due to a complex interplay of a variety of causes including cell death arising from shear stress of blood flow and cellular oxidative stress, cellular senescence, and decreased rate of replacement of dead ECs by progenitor stem cells. RESULTS: A continuum mathematical model is developed to describe the dynamics of large EC populations of the endothelium using a system of differential equations for the number densities of cells of different generations starting from endothelial progenitors to senescent cells, as well as the densities of dead cells and the holes created upon clearing dead cells. Aging of cells is manifested in three ways, namely, losing the ability to divide when the Hayflick limit of 50 generations is reached, decreasing replication rate parameters and increasing death rate parameters as cells divide; due to the dependence of these rate parameters on cell generation, the model predicts a narrow distribution of cell densities peaking at a particular cell generation. As the chronological age of a person advances, the peak of the distribution - corresponding to the age of the endothelium - moves towards senescence correspondingly. However, computer simulations also demonstrate that sustained and enhanced stem cell homing can halt the aging process of the endothelium by maintaining a stationary cell density distribution that peaks well before the Hayflick limit. The healing rates of damaged endothelia for young, middle-aged, and old persons are compared and are found to be particularly sensitive to the stem cell homing parameter. CONCLUSION: The proposed model describes the aging of the endothelium as being driven by cellular senescence, with a rate that does not necessarily correspond to the chronological aging of a person. It is shown that the age of the endothelium depends sensitively on the homing rates of EC progenitor cells. PMID- 17692116 TI - The value of routine histopathological examination of appendicectomy specimens. AB - BACKGROUND: Appendicectomy specimens removed from patients with suspected acute appendicitis often appear macroscopically normal but histopathological analysis of these cases may reveal a more sinister underlying pathology. We evaluated histopathological reports of 1225 appendicectomy specimens at the Norfolk and Norwich University Hospital (NNUH) over the past three years. METHODS: Histopathology reports for all appendices analysed at the NNUH between March 2003 and March 2006 were reviewed by examination of the case notes. The analysis focussed on the confirmation of acute appendicitis, incidental unexpected incidental findings other than inflammation, whether these abnormalities were suspected on gross examination at the time of surgery, and the effect on patient management and prognosis. RESULTS: The histopathology reports disclosed a variety of abnormal incidental lesions. Of the 1225 specimens, 46 (3.75%) revealed abnormal diagnoses other than inflammatory changes. Twenty-four (1.96%) of these were clinically significant and affected further patient management. Only two of these (0.16%) were suspected on macroscopic examination intra-operatively. CONCLUSION: Twenty-four of the 1225 specimens (1.96%) had an impact on patient management or outcome and were not suspected on macroscopic examination at the time of surgery. These would have been missed had the specimens not been examined microscopically. The intra-operative diagnosis of the surgeon is therefore unreliable in detecting abnormalities of the appendix. This study supports the sending of all appendicectomy specimens for routine histopathological examination. PMID- 17692117 TI - A randomised controlled trial of early insulin therapy in very low birth weight infants, "NIRTURE" (neonatal insulin replacement therapy in Europe). AB - BACKGROUND: Studies in adult intensive care have highlighted the importance of insulin and improved glucose control on survival, with 32% reduction in mortality, 22% reduction in intensive care stay and halving of the incidence of bacteraemia. Very low birth weight infants requiring intensive care also have relative insulin deficiency often leading to hyperglycaemia during the first week of life. The physiological influences on insulin secretion and sensitivity, and the potential importance of glucose control at this time are not well established. However there is increasing evidence that the early postnatal period is critical for pancreatic development. At this time a complex set of signals appears to influence pancreatic development and beta cell survival. This has implications both in terms of acute glucose control but also relative insulin deficiency is likely to play a role in poor postnatal growth, which has been associated with later motor and cognitive impairment, and fewer beta cells are linked to risk of type 2 diabetes later in life. METHODS: A multi-centre, randomised controlled trial of early insulin replacement in very low birth weight babies (VLBW, birth weight < 1500 g). 500 infants will be recruited from 10 centres in the UK and Europe. Babies will be randomised to receive a continuous insulin infusion (0.05 units/kg/h) or to receive standard neonatal care from the first day of life and for the next 7 days. If blood glucose (BG) levels fall infants will receive 20% dextrose titrated to maintain normoglycaemia (4-8 mmol/l). If BG is consistently above 10 mmol/l babies will receive standard treatment with additional insulin infusion. The primary end point will be mortality on or before expected date of delivery, secondary end points will be markers of morbidity and include episodes of sepsis, severity of retinopathy, chronic lung disease and growth. PMID- 17692118 TI - Covert observation in practice: lessons from the evaluation of the prohibition of smoking in public places in Scotland. AB - BACKGROUND: A ban on smoking in wholly or substantially enclosed public places has been in place in Scotland since 26th March 2006. The impact of this legislation is currently being evaluated in seven studies, three of which involve direct observation of smoking in bars and other enclosed public places. While the ethical issues around covert observation have been widely discussed there is little practical guidance on the conduct of such research. A workshop was therefore convened to identify practical lessons learned so far from the Scottish evaluation. METHODS: We convened a workshop involving researchers from the three studies which used direct observation. In addition, one of the fieldwork managers collected written feedback on the fieldwork, identifying problems that arose in the field and some solutions. RESULTS: There were four main themes identified: (i) the difficulty of achieving and maintaining concealment; (ii) the experience of being an observer; (iii) the risk of bias in the observations and (iv) issues around training and recruitment. These are discussed. CONCLUSION: Collecting covert observational data poses unique practical challenges, in particular in relation to the health and safety of the researcher. The findings and solutions presented in this paper will be of value to researchers designing similar studies. PMID- 17692119 TI - ABO blood group system and placental malaria in an area of unstable malaria transmission in eastern Sudan. AB - BACKGROUND: Understanding the pathogenesis of malaria in pregnancy and its consequences for both the mother and the baby is fundamental for improving malaria control in pregnant women. AIM: The study aimed to investigate the role of ABO blood groups on pregnancy outcomes in an area of unstable malaria transmission in eastern Sudan. METHODS: A total of 293 women delivering in New Half teaching hospital, eastern Sudan during the period October 2006-March 2007 have been analyzed. ABO blood groups were determined and placental histopathology examinations for malaria were performed. Birth and placental weight were recorded and maternal haemoglobin was measured. RESULTS: 114 (39.7%), 61 (22.1%) and 118 (38.2%) women were primiparae, secundiparae and multiparae, respectively. The ABO blood group distribution was 82(A), 59 (B), 24 (AB) and 128 (O). Placental histopathology showed acute placental malaria infections in 6 (2%), chronic infections in 6 (2%), 82 (28.0%) of the placentae showed past infection and 199 (68.0%) showed no infection. There was no association between the age (OR = 1.02, 95% CI = 0.45-2.2; P = 0.9), parity (OR = 0.6, 95% CI = 0.3-1.2; P = 0.1) and placental malaria infections. In all parity blood group O was associated with a higher risk of past (OR = 1.9, 95% CI = 1.1-3.2; P = 0.01) placental malaria infection. This was also true when primiparae were considered separately (OR = 2.6, 95% CI = 1.05-6.5, P = 0.03). Among women with all placental infections/past placental infection, the mean haemoglobin was higher in women with the blood group O, but the mean birth weight, foeto-placental weight ratio was not different between these groups and the non-O group. CONCLUSION: These results indicate that women of eastern Sudan are at risk for placental malaria infection irrespective to their age or parity. Those women with blood group O were at higher risk of past placental malaria infection. PMID- 17692120 TI - TGF-beta receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF beta1 expression in colon carcinoma: a retrospective study. AB - BACKGROUND: Histological phenotype and clinical behaviour of malignant tumours are not only dependent on alterations in the epithelial cell compartment, but are affected by their interaction with inflammatory cells and tumour-associated stroma. Studies in animal models have shown influence of tumour-associated macrophages (TAM) on histological grade of differentiation in colon carcinoma. Disruption of transforming growth factor beta (TGF-beta) signalling in tumour cells is related to more aggressive clinical behaviour. Expression data of components of this pathway in tumour-associated stroma is limited. METHODS: Tissue micro arrays of 310 colon carcinomas from curatively resected patients in UICC stage II and III were established. In a first step we quantified amount of CD68 positive TAMs and expression of components of TGF-beta signalling (TGF beta1, TGF-beta receptors type 1 and 2, Smad 3 and 4) in tumour and associated stroma. Further we analyzed correlation to histological and clinical parameters (histological grade of differentiation (low-grade (i.e. grade 1 and 2) vs. high grade (i.e. grade 3 and 4)), lymph node metastasis, distant metastasis, 5 year cancer related survival) using Chi-square or Fisher's exact test, when appropriate, to compare frequencies, Kaplan-Meier method to calculate 5-year rates of distant metastases and cancer-related survival and log rank test to compare the rates of distant metastases and survival. To identify independent prognostic factors Cox regression analysis including lymph node status and grading was performed. RESULTS: High-grade tumours and those with lymph node metastases showed higher rates of TAMs and lower expression of TGF-beta1. Loss of nuclear Smad4 expression in tumor was associated with presence of lymph node metastasis, but no influence on prognosis could be demonstrated. Decrease of both TGF-beta receptors in tumour-associated stroma was associated with increased lymph node metastasis and shorter survival. Stromal TGF-beta receptor 2 expression was an independent prognostic factor for cancer related survival. CONCLUSION: Histological phenotype and clinical behaviour of colon cancer is not only influenced by mutational incidents in tumour cells but also affected by interaction of tumour tissue with inflammatory cells like macrophages and associated stroma and TGF-beta signalling is one important part of this crosstalk. Further studies are needed to elucidate the exact mechanisms. PMID- 17692121 TI - Prostaglandin E2 potentiation of P2X3 receptor mediated currents in dorsal root ganglion neurons. AB - Prostaglandin E2 (PGE2) is a well-known inflammatory mediator that enhances the excitability of DRG neurons. Homomeric P2X3 and heteromeric P2X2/3 receptors are abundantly expressed in dorsal root ganglia (DRG) neurons and participate in the transmission of nociceptive signals. The interaction between PGE2 and P2X3 receptors has not been well delineated. We studied the actions of PGE2 on ATP activated currents in dissociated DRG neurons under voltage-clamp conditions. PGE2 had no effects on P2X2/3 receptor-mediated responses, but significantly potentiated fast-inactivating ATP currents mediated by homomeric P2X3 receptors. PGE2 exerted its action by activating EP3 receptors. To study the mechanism underlying the action of PGE2, we found that the adenylyl cyclase activator, forskolin and the membrane-permeable cAMP analogue, 8-Br-cAMP increased ATP currents, mimicking the effect of PGE2. In addition, forskolin occluded the enhancement produced by PGE2. The protein kinase A (PKA) inhibitors, H89 and PKA I blocked the PGE2 effect. In contrast, the PKC inhibitor, bisindolymaleimide (Bis) did not change the potentiating action of PGE2. We further showed that PGE2 enhanced alpha,beta-meATP-induced allodynia and hyperalgesia and the enhancement was blocked by H89. These observations suggest that PGE2 binds to EP3 receptors, resulting in the activation of cAMP/PKA signaling pathway and leading to an enhancement of P2X3 homomeric receptor-mediated ATP responses in DRG neurons. PMID- 17692122 TI - Inactivation of nucleolin leads to nucleolar disruption, cell cycle arrest and defects in centrosome duplication. AB - BACKGROUND: Nucleolin is a major component of the nucleolus, but is also found in other cell compartments. This protein is involved in various aspects of ribosome biogenesis from transcription regulation to the assembly of pre-ribosomal particles; however, many reports suggest that it could also play an important role in non nucleolar functions. To explore nucleolin function in cell proliferation and cell cycle regulation we used siRNA to down regulate the expression of nucleolin. RESULTS: We found that, in addition to the expected effects on pre-ribosomal RNA accumulation and nucleolar structure, the absence of nucleolin results in a cell growth arrest, accumulation in G2, and an increase of apoptosis. Numerous nuclear alterations, including the presence of micronuclei, multiple nuclei or large nuclei are also observed. In addition, a large number of mitotic cells showed a defect in the control of centrosome duplication, as indicated by the presence of more than 2 centrosomes per cell associated with a multipolar spindle structure in the absence of nucleolin. This phenotype is very similar to that obtained with the inactivation of another nucleolar protein, B23. CONCLUSION: Our findings uncovered a new role for nucleolin in cell division, and highlight the importance of nucleolar proteins for centrosome duplication. PMID- 17692123 TI - Analgesic and anti-inflammatory drug use and risk of bladder cancer: a population based case control study. AB - BACKGROUND: Use of phenacetin and other analgesic and non-steroidal anti inflammatory drugs (NSAIDs) potentially influences bladder cancer incidence, but epidemiologic evidence is limited. METHODS: We analyzed data from 376 incident bladder cancer cases and 463 controls from a population-based case-control study in New Hampshire on whom regular use of analgesic drugs and NSAIDs was obtained. Odds ratios and 95% confidence intervals were computed using logistic regression with adjustment for potentially confounding factors. Separate models by tumor stage, grade and TP53 status were conducted. RESULTS: We found an elevated odds ratio (OR) associated with reported use of phenacetin-containing medications, especially with longer duration of use (OR >8 years = 3.00, 95% confidence interval (CI) = 1.4-6.5). In contrast, use of paracetamol did not relate overall to risk of bladder cancer. We also found that regular use of any NSAID was associated with a statistically significant decrease in bladder cancer risk (OR = 0.6, 95% CI = 0.4-0.9), and specifically use of aspirin. Further, the association with NSAID use was largely among invasive, high grade and TP53 positive tumors. CONCLUSION: While these agents have been investigated in several studies, a number of questions remain regarding the effects of analgesic and NSAID use on risk of bladder cancer. PMID- 17692124 TI - Proteomic analysis of plasma membrane and secretory vesicles from human neutrophils. AB - BACKGROUND: Polymorphonuclear neutrophils (PMN) constitute an essential cellular component of innate host defense against microbial invasion and exhibit a wide array of responses both to particulate and soluble stimuli. As the cells recruited earliest during acute inflammation, PMN respond rapidly and release a variety of potent cytotoxic agents within minutes of exposure to microbes or their products. PMN rely on the redistribution of functionally important proteins, from intracellular compartments to the plasma membrane and phagosome, as the means by which to respond quickly. To determine the range of membrane proteins available for rapid recruitment during PMN activation, we analyzed the proteins in subcellular fractions enriched for plasma membrane and secretory vesicles recovered from the light membrane fraction of resting PMN after Percoll gradient centrifugation and free-flow electrophoresis purification using mass spectrometry-based proteomics methods. RESULTS: To identify the proteins light membrane fractions enriched for plasma membrane vesicles and secretory vesicles, we employed a proteomic approach, first using MALDI-TOF (peptide mass fingerprinting) and then by HPLC-MS/MS using a 3D ion trap mass spectrometer to analyze the two vesicle populations from resting PMN. We identified several proteins that are functionally important but had not previously been recovered in PMN secretory vesicles. Two such proteins, 5-lipoxygenase-activating protein (FLAP) and dysferlin were further validated by immunoblot analysis. CONCLUSION: Our data demonstrate the broad array of proteins present in secretory vesicles that provides the PMN with the capacity for remarkable and rapid reorganization of its plasma membrane after exposure to proinflammatory agents or stimuli. PMID- 17692126 TI - Effects of steroidal and nonsteroidal aromatase inhibitors on markers of bone turnover in healthy postmenopausal women. AB - INTRODUCTION: In contrast to nonsteroidal aromatase inhibitors, the steroidal aromatase inactivator exemestane does not have detrimental effects on bone in animal models. This study was designed to compare the effects of exemestane with the nonsteroidal aromatase inhibitors anastrozole and letrozole on serum and urine levels of biomarkers of bone turnover in healthy postmenopausal women. METHODS: Changes in the concentrations of bone-turnover markers, estrogens, and lipids were assessed after daily administration of exemestane (25 mg), letrozole (2.5 mg), anastrozole (1 mg), or placebo for 24 weeks in healthy postmenopausal women. The primary end point was the percentage change from baseline in bone turnover-marker levels at week 24. The baseline-adjusted area under the curve (AUC) for weeks 0-12 and 0-24 was calculated to evaluate changes in bone turnover over time, rather than at discrete time points. RESULTS: Seventy-four (88%) of 84 randomized subjects were evaluable for bone-marker assays. Reductions in plasma estrogen levels and increases in bone-resorption markers were comparable for each aromatase inhibitor. Uniquely, exemestane consistently increased the percentage change from baseline in the level of serum procollagen type I N-terminal propeptide (PINP), a marker of bone formation, at week 24. In the active treatment groups, the baseline-adjusted AUC at weeks 0-12 and 0-24 for PINP was significantly greater for exemestane than the other aromatase inhibitors. CONCLUSION: Exemestane increased serum levels of the bone-formation marker PINP after 24 weeks, suggesting a specific bone-formation effect related to its androgenic structure. Potential effects on cortical bone and reduced fracture risk must be verified in a comparative clinical trial. PMID- 17692127 TI - Expressed sequences tags of the anther smut fungus, Microbotryum violaceum, identify mating and pathogenicity genes. AB - BACKGROUND: The basidiomycete fungus Microbotryum violaceum is responsible for the anther-smut disease in many plants of the Caryophyllaceae family and is a model in genetics and evolutionary biology. Infection is initiated by dikaryotic hyphae produced after the conjugation of two haploid sporidia of opposite mating type. This study describes M. violaceum ESTs corresponding to nuclear genes expressed during conjugation and early hyphal production. RESULTS: A normalized cDNA library generated 24,128 sequences, which were assembled into 7,765 unique genes; 25.2% of them displayed significant similarity to annotated proteins from other organisms, 74.3% a weak similarity to the same set of known proteins, and 0.5% were orphans. We identified putative pheromone receptors and genes that in other fungi are involved in the mating process. We also identified many sequences similar to genes known to be involved in pathogenicity in other fungi. The M. violaceum EST database, MICROBASE, is available on the Web and provides access to the sequences, assembled contigs, annotations and programs to compare similarities against MICROBASE. CONCLUSION: This study provides a basis for cloning the mating type locus, for further investigation of pathogenicity genes in the anther smut fungi, and for comparative genomics. PMID- 17692125 TI - Hitting bacteria at the heart of the central dogma: sequence-specific inhibition. AB - An important objective in developing new drugs is the achievement of high specificity to maximize curing effect and minimize side-effects, and high specificity is an integral part of the antisense approach. The antisense techniques have been extensively developed from the application of simple long, regular antisense RNA (asRNA) molecules to highly modified versions conferring resistance to nucleases, stability of hybrid formation and other beneficial characteristics, though still preserving the specificity of the original nucleic acids. These new and improved second- and third-generation antisense molecules have shown promising results. The first antisense drug has been approved and more are in clinical trials. However, these antisense drugs are mainly designed for the treatment of different human cancers and other human diseases. Applying antisense gene silencing and exploiting RNA interference (RNAi) are highly developed approaches in many eukaryotic systems. But in bacteria RNAi is absent, and gene silencing by antisense compounds is not nearly as well developed, despite its great potential and the intriguing possibility of applying antisense molecules in the fight against multiresistant bacteria. Recent breakthrough and current status on the development of antisense gene silencing in bacteria including especially phosphorothioate oligonucleotides (PS-ODNs), peptide nucleic acids (PNAs) and phosphorodiamidate morpholino oligomers (PMOs) will be presented in this review. PMID- 17692128 TI - Phylogenetic review of tonal sound production in whales in relation to sociality. AB - BACKGROUND: It is widely held that in toothed whales, high frequency tonal sounds called 'whistles' evolved in association with 'sociality' because in delphinids they are used in a social context. Recently, whistles were hypothesized to be an evolutionary innovation of social dolphins (the 'dolphin hypothesis'). However, both 'whistles' and 'sociality' are broad concepts each representing a conglomerate of characters. Many non-delphinids, whether solitary or social, produce tonal sounds that share most of the acoustic characteristics of delphinid whistles. Furthermore, hypotheses of character correlation are best tested in a phylogenetic context, which has hitherto not been done. Here we summarize data from over 300 studies on cetacean tonal sounds and social structure and phylogenetically test existing hypotheses on their co-evolution. RESULTS: Whistles are 'complex' tonal sounds of toothed whales that demark a more inclusive clade than the social dolphins. Whistles are also used by some riverine species that live in simple societies, and have been lost twice within the social delphinoids, all observations that are inconsistent with the dolphin hypothesis as stated. However, cetacean tonal sounds and sociality are intertwined: (1) increased tonal sound modulation significantly correlates with group size and social structure; (2) changes in tonal sound complexity are significantly concentrated on social branches. Also, duration and minimum frequency correlate as do group size and mean minimum frequency. CONCLUSION: Studying the evolutionary correlation of broad concepts, rather than that of their component characters, is fraught with difficulty, while limits of available data restrict the detail in which component character correlations can be analyzed in this case. Our results support the hypothesis that sociality influences the evolution of tonal sound complexity. The level of social and whistle complexity are correlated, suggesting that complex tonal sounds play an important role in social communication. Minimum frequency is higher in species with large groups, and correlates negatively with duration, which may reflect the increased distances over which non-social species communicate. Our findings are generally stable across a range of alternative phylogenies. Our study points to key species where future studies would be particularly valuable for enriching our understanding of the interplay of acoustic communication and sociality. PMID- 17692129 TI - Perigraft air is not always pathological: a case report. AB - BACKGROUND: The presence of perigraft air is a common finding in the immediate post-operative phase following abdominal aortic aneurysm repair whilst the later appearance of air, in association with elevated inflammatory markers, is regarded as being indicative of the serious complication of graft infection. What is not known is at what timepoint following surgery does the perigraft air become a significant finding. CASE PRESENTATION: We report the case of a 71 year old man who underwent a computed tomography scan 15 days following repair of an abdominal aortic aneurysm because of the presence of unexplained pyrexia. The scan showed the presence of perigraft air and a small haematoma. The patient was managed conservatively and after 6 weeks the air and haematoma had resolved completely. CONCLUSION: The presence of perigraft air in the early postoperative phase is probably a normal finding, is not associated with graft infection and can be managed non-operatively. PMID- 17692130 TI - Acute pancreatitis related to therapeutic dosing with colchicine: a case report. AB - BACKGROUND: Colchicine is used in the treatment and prophylaxis of gout. It possesses a narrow therapeutic window, frequently resulting in dose-limiting gastrointestinal side-effects such as diarrhoea and emesis. As colchicine is a cellular anti-mitotic agent, the most serious effects include myelosuppression, myoneuropathy and multiple organ failure. This occurs with intentional overdose or with therapeutic dosing in patients with reduced clearance of colchicine due to pre-existing renal or hepatic impairment. Acute pancreatitis has rarely been reported, and only in association with severe colchicine overdose accompanied by multi-organ failure. CASE PRESENTATION: We report a case of acute pancreatitis without other organ toxicity related to recent commencement of colchicine for acute gout, occurring in an elderly male with pre-existing renal impairment. CONCLUSION: 1) Colchicine should be used with care in elderly patients or patients with impaired renal function.2) Aside from myelosuppression, myoneuropathy and multiple organ failure, colchicine may now be associated with acute pancreatitis even with therapeutic dosing; this has not previously being reported. PMID- 17692131 TI - Redox stress proteins are involved in adaptation response of the hyperthermoacidophilic archaeon Sulfolobus solfataricus to nickel challenge. AB - BACKGROUND: Exposure to nickel (Ni) and its chemical derivatives has been associated with severe health effects in human. On the contrary, poor knowledge has been acquired on target physiological processes or molecular mechanisms of this metal in model organisms, including Bacteria and Archaea. In this study, we describe an analysis focused at identifying proteins involved in the recovery of the archaeon Sulfolobus solfataricus strain MT4 from Ni-induced stress. RESULTS: To this purpose, Sulfolobus solfataricus was grown in the presence of the highest nickel sulphate concentration still allowing cells to survive; crude extracts from treated and untreated cells were compared at the proteome level by using a bi-dimensional chromatography approach. We identified several proteins specifically repressed or induced as result of Ni treatment. Observed up regulated proteins were largely endowed with the ability to trigger recovery from oxidative and osmotic stress in other biological systems. It is noteworthy that most of the proteins induced following Ni treatment perform similar functions and a few have eukaryal homologue counterparts. CONCLUSION: These findings suggest a series of preferential gene expression pathways activated in adaptation response to metal challenge. PMID- 17692132 TI - Mapping of oxidative stress responses of human tumor cells following photodynamic therapy using hexaminolevulinate. AB - BACKGROUND: Photodynamic therapy (PDT) involves systemic or topical administration of a lesion-localizing photosensitizer or its precursor, followed by irradiation of visible light to cause singlet oxygen-induced damage to the affected tissue. A number of mechanisms seem to be involved in the protective responses to PDT, including activation of transcription factors, heat shock proteins, antioxidant enzymes and apoptotic pathways. RESULTS: In this study, we address the effects of a destructive/lethal hexaminolevulinate (HAL) mediated PDT dose on the transcriptome by using transcriptional exon evidence oligo microarrays. Here, we confirm deviations in the steady state expression levels of previously identified early defence response genes and extend this to include unreported PDT inducible gene groups, most notably the metallothioneins and histones. HAL-PDT mediated stress also altered expression of genes encoded by mitochondrial DNA (mtDNA). Further, we report PDT stress induced alternative splicing. Specifically, the ATF3 alternative isoform (deltaZip2) was up regulated, while the full-length variant was not changed by the treatment. Results were independently verified by two different technological microarray platforms. Good microarray, RT-PCR and Western immunoblotting correlation for selected genes support these findings. CONCLUSION: Here, we report new insights into how destructive/lethal PDT alters the transcriptome not only at the transcriptional level but also at post-transcriptional level via alternative splicing. PMID- 17692133 TI - No relationship between circulating levels of sex steroids and mammographic breast density: the Prospect-EPIC cohort. AB - BACKGROUND: High breast density is associated with increased breast cancer risk. Epidemiologic studies have shown an increase in breast cancer risk in postmenopausal women with high levels of sex steroids. Hence, sex steroids may increase postmenopausal breast cancer risk via an increase of breast density. The objective of the present study was to study the relation between circulating oestrogens and androgens as well as sex hormone binding globulin (SHBG) in relation to breast density. METHODS: We conducted a cross-sectional study among 775 postmenopausal women, using baseline data of a random sample of the Prospect EPIC study. Prospect-EPIC is one of two Dutch cohorts participating in the European Prospective Investigation into Cancer and Nutrition, and women were recruited via a breast cancer screening programme. At enrolment a nonfasting blood sample was taken and a mammogram was made. Oestrone, oestradiol, dehydroepiandrosterone sulfate, androstenedione, testosterone and SHBG levels were measured, using double-antibody radioimmunoassays. Concentrations of free oestradiol and free testosterone were calculated from the measured oestradiol, testosterone and SHBG levels Mammographic dense and nondense areas were measured using a semiquantitative computerized method and the percentage breast density was calculated. Mean breast measures for quintiles of hormone or SHBG levels were estimated using linear regression analyses. RESULTS: Both oestrogens and testosterone were inversely related with percent breast density, but these relationships disappeared after adjustment for BMI. None of the sex steroids or SHBG was associated with the absolute measure of breast density, the dense area. CONCLUSION: The results of our study do not support the hypothesis that sex steroids increase postmenopausal breast cancer risk via an increase in breast density. PMID- 17692134 TI - Impacts of yeast metabolic network structure on enzyme evolution. PMID- 17692135 TI - Staffing level: a determinant of late-onset ventilator-associated pneumonia. AB - A body of knowledge exists to suggest an association between nurse staffing and adverse patient outcomes. Hugonnet and colleagues add further evidence by linking nurse staffing to late-onset ventilator-associated pneumonia. Discussed are a number of concerns surrounding the analytic component of this study, including the construction of variables and the statistical models. The authors' estimation that hospitals maintaining a nurse-to-patient ratio above 2.2 could decrease the risk of health care associated infections is based on findings that are potentially biased and unrealistic. PMID- 17692136 TI - Selenium supplementation in critically ill patients: can too much of a good thing be a bad thing? AB - A recent study by Forceville and colleagues evaluated the effect of high-dose selenium administration as a treatment for septic shock. The study was negative and conflicts with existing clinical data regarding selenium administration in critically ill patients. Perhaps the key to understanding the differences between these discrepant observations lies in considering the dose and timing of selenium administration. PMID- 17692137 TI - The effect of probiotic fermented milk and inulin on the functions and microecology of the intestine. AB - We investigated the effects of a probiotic fermented milk and inulin on gastrointestinal function and microecology. The study was double-blinded and comprised 66 healthy adults (22 male, 44 female), mean age 40 years (range, 22-60 years). After a 12-d baseline period the subjects were randomized to consume, for 3 weeks, 3x200 ml daily of either (1) a fermented milk with probiotics (Bifidobacterium longum BB536, Bifidobacterium spp. 420 and Lactobacillus acidophilus 145), (2) a fermented milk with the same probiotics plus 4 g inulin, or (3) a control fermented milk. During the last 7 d of the baseline and the intervention periods, the subjects kept a record of their defaecation frequency and gastrointestinal symptoms, and collected all their faeces. Intestinal transit time, stool weight and faecal enzyme activities were measured. Thirty-nine subjects were randomized to give faecal samples for analysis of pH and microbes, including lactobacilli, bifidobacteria, coliforms, Escherichia coli, Bacteroides and Clostridium perfringens. Consumption of fermented milk with probiotics or with probiotics and inulin increased the faecal number of lactobacilli (P=0.009, P=0.003) and bifidobacteria (P=0.046, P=0.038) compared with the baseline. Compared with the control fermented milk, both active products increased lactobacilli (P=0.005, ANCOVA). Subjects consuming fermented milk with probiotics and inulin suffered from gastrointestinal symptoms, especially flatulence, more than the others (P<0.001). In conclusion, the probiotic fermented milk product had a positive effect by increasing the number of lactobacilli and bifidobacteria in the colon. Inulin did not alter this effect but it increased gastrointestinal symptoms. PMID- 17692138 TI - Differential expression and secretion of alpha1-acid glycoprotein in bovine milk. AB - alpha1-Acid glycoprotein (AGP) is a lipocalin that is produced mainly by the liver and secreted into plasma in response to infections and injuries. In this study, we evaluated AGP isoforms that can be detected in bovine milk. We found that milk-AGP content is made up of at least two isoform groups, a low MW group (44 kDa) that is produced in the mammary gland (MG-AGP), and a higher MW group (55-70 kDa), that is produced by somatic cells (SC-AGP). Identical SC-AGP isoforms can be found both in milk and blood PMN cells. Analysis of the mammary tissue cDNA showed that the sequence of the MG-AGP isoform is identical to that of plasma AGP. Each group contains several proteins with different MWs and different isoelectric points, as shown by 2D-electrophoresis. The glycosylation patterns of these isoforms were analysed by means of specific lectin binding, to evaluate the degree of sialylation, fucosylation and branching. The MG-AGP glycan pattern was identical to plasma AGP produced by the liver. Several differences were detected, however, between plasma and SC-AGP isoforms, the most evident being the strong degree of fucosylation and the elevated number of di-antennary glycans in SC-AGP. Immunohistochemistry showed that AGP is found in all tissues that make up the mammary gland, but that it is most likely produced for the main part by the alveoli. PMID- 17692139 TI - Up to new tricks - a review of cross-species transmission of influenza A viruses. AB - Influenza is a highly contagious disease that has burdened both humans and animals since ancient times. In humans, the most dramatic consequences of influenza are associated with periodically occurring pandemics. Pandemics require the emergence of an antigenically novel virus to which the majority of the population lacks protective immunity. Historically, influenza A viruses from animals have contributed to the generation of human pandemic viruses and they may do so again in the future. It is, therefore, critical to understand the epidemiological and molecular mechanisms that allow influenza A viruses to cross species barriers. This review summarizes the current knowledge of influenza ecology, and the viral factors that are thought to determine influenza A virus species specificity. PMID- 17692140 TI - A ten-year review of commercial vaccine performance for control of tick infestations on cattle. AB - Ticks are important ectoparasites of domestic and wild animals, and tick infestations economically impact cattle production worldwide. Control of cattle tick infestations has been primarily by application of acaricides which has resulted in selection of resistant ticks and environmental pollution. Herein we discuss data from tick vaccine application in Australia, Cuba, Mexico and other Latin American countries. Commercial tick vaccines for cattle based on the Boophilus microplus Bm86 gut antigen have proven to be a feasible tick control method that offers a cost-effective, environmentally friendly alternative to the use of acaricides. Commercial tick vaccines reduced tick infestations on cattle and the intensity of acaricide usage, as well as increasing animal production and reducing transmission of some tick-borne pathogens. Although commercialization of tick vaccines has been difficult owing to previous constraints of antigen discovery, the expense of testing vaccines in cattle, and company restructuring, the success of these vaccines over the past decade has clearly demonstrated their potential as an improved method of tick control for cattle. Development of improved vaccines in the future will be greatly enhanced by new and efficient molecular technologies for antigen discovery and the urgent need for a tick control method to reduce or replace the use of acaricides, especially in regions where extensive tick resistance has occurred. PMID- 17692141 TI - Streptococcus suis infections in humans: the Chinese experience and the situation in North America. AB - Infections caused by Streptococcus suis are considered a global problem in the swine industry. In this animal species, S. suis is associated with septicemia, meningitis, endocarditis, arthritis and, occasionally, other infections. Moreover, it is an agent of zoonosis that afflicts people in close contact with infected pigs or pork-derived products. Although sporadic cases of S. suis infection in humans have been reported, a large outbreak due to S. suis serotype 2 emerged in the summer of 2005 in Sichuan, China. A similar outbreak was observed in another Chinese province in 1998. Symptoms reported in these two outbreaks include high fever, malaise, nausea and vomiting, followed by nervous symptoms, subcutaneous hemorrhage, septic shock and coma in severe cases. The increased severity of S. suis infections in humans, such as a shorter incubation time, more rapid disease progression and higher rate of mortality, underscores the critical need to better understand the factors associated with pathogenesis of S. suis infection. From the 35 capsular serotypes currently known, serotype 2 is considered the most virulent and frequently isolated in both swine and humans. Here, we review the epidemiological, clinical and immunopathological features of S. suis infection in humans. PMID- 17692143 TI - Transmission of the microsporidian gill parasite, Loma salmonae. AB - Since it was first reported in 1987 at a hatchery in British Columbia, Loma salmonae has become increasingly important as an emerging parasite affecting the Canadian salmonid aquaculture industry. L. salmonae causes Microsporidial Gill Disease of Salmon (MGDS) in farmed Pacific salmonids, Oncorhynchus spp., resulting in respiratory distress, secondary infections and high mortality rates. In the last decade, laboratory studies have identified key transmission factors for this disease and described the pathogenesis of MGDS. L. salmonae enters the host via the gut, where it injects sporoplasm into a host cell, which then migrates to the heart for a two-week merogony-like phase, followed by a macrophage-mediated transport of the parasite to the gill, with a final development stage of a spore-laden xenoma within the endothelial and pillar cells. Xenoma rupture triggers a cascade of inflammatory events leading to severe, persistent, and extensive proliferative branchitis. The development of robust and reliable experimental challenge models using several exposure methods in marine and freshwater environments with several fish hosts, is a primary reason for the success of scientific research surrounding L. salmonae. To date, demonstrated factors affecting MGDS transmission include host species, strain and size, the length of contact time between naive and infected fish, water temperature and flow rates. PMID- 17692142 TI - Endothelial cells as active participants in veterinary infections and inflammatory disorders. AB - Endothelial cells were once viewed as relatively inert cells lining the vasculature. They are now recognized as active and responsive regulators of coagulation, platelet adhesion, fluid homeostasis, wound healing, leukocyte extravasation and vascular tone. Endothelial cells play a key role in the host response to infectious agents by regulating leukocyte trafficking, producing inflammatory cytokines and presenting antigen in association with major histocompatibility class II (MHC II) molecules. A number of infectious agents have a tropism for endothelial cells. Infection of endothelial cells can promote thrombosis, vascular leakage, and increased adherence and emigration of leukocytes. Furthermore, activation of a systemic inflammatory response, in the absence of direct endothelial cell infection, can also lead to endothelial cell dysfunction. The purpose of this review is to highlight the interactions between endothelial cells and infectious or inflammatory agents that contribute to coagulation disturbances, vasculitis and edema. A select group of viral and bacterial pathogens will be used as examples to demonstrate how endothelial cell dysfunction contributes to the pathogenesis of infectious and inflammatory disorders. PMID- 17692144 TI - Explaining unexplained diarrhea and associating risks and infections. AB - Gastrointestinal illnesses are common afflictions. However, knowledge of their etiology is often lacking. Moreover, most cases of infections with reportable enteric pathogens (Campylobacter jejuni, Escherichia coli O157:H7, Salmonella, Shigella, Yersinia, Cryptosporidia and Giardia) have sporadic modes of acquisition, yet control measures are often biased towards mitigation of risks discerned by outbreak analysis. To determine the etiology of unexplained diarrhea it is important to study populations that can be matched to appropriate controls and to couple thorough classic microbiologic evaluation on receipt of specimens with archiving and outgrowth capabilities. Research evaluations should address the potential roles of a broad panel of candidate bacterial pathogens including diarrheagenic E. coli, Listeria monocytogenes, Helicobacters and jejuni Campylobacters, and also apply novel massively parallel sequencing and nucleic acid detection technologies that allow the detection of viral pathogens. To fill voids in our knowledge regarding sources of known enteric pathogens it will be critical to extend case-control studies to assess risk factors and exposures to patients with non-epidemic illnesses and to appropriate controls. By filling these gaps in our knowledge it should be possible to formulate rational prevention mechanisms for human gastrointestinal illnesses. PMID- 17692145 TI - Comparative genomics and proteomics to study tissue-specific response and function in natural Mycobacterium bovis infections. AB - Bovine tuberculosis (bTB) is an established zoonotic disease which affects cattle and wildlife worldwide and new strategies are required to control and eradicate the disease. The European wild boar (Sus scrofa) is a major reservoir of bTB in Spain. The objective of this paper was to review tissue-specific response and function of mandibular lymph nodes (MLN) and oropharyngeal tonsils (OT) in European wild boar naturally infected with Mycobacterium bovis. Genomics and proteomics data were used to compare differential gene expression and global protein patterns in OT and MLN of M. bovis-infected and uninfected European wild boar and the results were analyzed considering previous reports of experimental infections in laboratory and domestic animals. The results showed tissue-specific differences in OT and MLN in response to M. bovis infection. Tissue-specific differences in gene expression and protein profiles suggested different functions for OT and MLN during mycobacterial infection and provided information to characterize the pathobiology of M. bovis infection in European wild boar with important implications for the control of bTB in Spain. The characterization of molecular events in tissues that play different roles during mycobacterial infection in naturally infected individuals may be relevant to understand the pathobiology of M. bovis infection and to design effective strategies for the control of bTB in wildlife reservoirs. PMID- 17692146 TI - Agrosecurity for concentrated animal feeding operations (CAFOs): commentary on recent planning activities. AB - Agrosecurity has become a major concern for livestock operations. This paper reviews post 11 September 2001, American planning activities and offers commentary on issues related to these plans. A critical issue is the need for as many people as possible to be aware of plans and preparations already completed and actions still necessary. There is a sizeable disparity within the animal agriculture sector about information known and understood at different levels. Several readiness exercises have highlighted the need for better broad-spectrum communication: communication within disciplines, within agencies, across disciplines, across agencies, and most importantly everyone involved must talk with industry at all levels. The best preparation involves close coordination between law enforcement, industry, governmental agencies at all levels, academia, risk managers and communicators, veterinarians, engineers, economists, game theorists, and others. This paper features issues related to concentrated animal feeding operations (CAFOs), highlights some of the lessons learned through these exercises, and discusses a plan of action patterned after the activities of a regional agricultural jurisdictional working group. PMID- 17692147 TI - Buffalopox: an emerging and re-emerging zoonosis. AB - Outbreaks of buffalopox or pox-like infections affecting buffaloes, cows and humans have been recorded in many parts of the world. Since the first outbreak in India, a large number of epidemics have occurred. Unlike in the previous years, generalized forms of the disease are now rare; however, there are severe local forms of the disease affecting the udder and teats, leading to mastitis thereby undermining the productivity of milk animals. The causative agent buffalopox virus (BPXV) is a member of the Orthopoxvirus, and is closely related to Vaccinia virus (VACV), the type-species of the genus. Earlier studies with restriction fragment length polymorphism and recent investigations involving sequencing of the genes that are essential in viral pathogenesis have shown that BPXV is phylogenetically very closely related to VACV and may be considered as a clade of the latter. The review discusses the epidemiology, novel diagnostic methods for the disease, and molecular biology of the virus, and infers genetic relationships of BPXV with other members of the genus. PMID- 17692148 TI - High-calcium diet with whey protein attenuates body-weight gain in high-fat-fed C57Bl/6J mice. AB - An inverse relationship between Ca intake and BMI has been found in several studies. It has been suggested that Ca affects adipocyte metabolism via suppressing 1,25-dihydroxycholecalciferol (1,25(OH)2-D3) and decreases fat absorption. We studied the effect of Ca and milk proteins (whey and casein) on body weight in C57Bl/6J mice. Male mice, age 9 weeks, were divided into three groups (ten mice per group) receiving modified high-fat (60% of energy) diets. Two groups received a high-Ca diet (1.8% calcium carbonate (CaCO3)), with casein or whey protein (18% of energy), and one group received a low-Ca diet (0.4% CaCO3) with casein for 21 weeks. Food intake was measured daily and body weight twice per week. Body fat content (by dual-energy X-ray absorptiometry) of all mice and faecal Ca and fat excretion of seven mice/group were measured twice during the study. Final body weight (44.1 (SEM 1.1) g) and body fat content (41.6 (SEM 0.6) %) were significantly lower (P < 0.05) in the high-Ca whey group than in the low-Ca casein group (48.1 (SEM 0.8) g and 44.9 (SEM 0.8) %). Body weight and body fat content of the high-Ca casein group did not differ significantly from the low-Ca casein group even though serum 1,25(OH)2-D3 levels were significantly lower (P < 0.001) in both high-Ca groups than in the low-Ca casein group. Thus changes in serum 1,25(OH)2-D3 do not seem to affect body weight in this animal model. There was a significant difference in fat excretion between the high-Ca whey and low-Ca casein groups (3.9 (SEM 0.9) % in the high-Ca whey v. 1.4 (SEM 0.2) % in the low-Ca casein group; P < 0.05), which may partly explain the effect on body weight. PMID- 17692149 TI - Genetics and diet--gene interactions: involvement, confidence and knowledge of dietitians. AB - Diet-gene interactions have become the focus of much research in recent years. However, little is known about UK dietitians' involvement, confidence and knowledge in genetics and diet-gene interactions. A validated postal questionnaire sent to a randomly selected sample of 600 dietitians in the UK resulted in 390 responses (65 %). Most dietitians had no involvement in eleven activities relating to genetics and diet-gene interactions and lacked confidence in undertaking such activities. However, a significant positive association was found between involvement and confidence for all activities tested (P < 0.0001). A mean knowledge score of 41 % (sd 19) indicated generally low levels of knowledge in genetics and diet-gene interactions. Knowledge scores were higher for those who reported discussing the genetic basis of disease or discussing how diet-gene interactions affected risk (P < 0.05). For the majority of activities, dietitians who reported higher confidence had higher knowledge scores. Given the importance of interactions between genetics and nutrition in preventing and managing disease, this study identifies a need to increase the involvement, confidence and knowledge in genetics and diet-gene interactions of dietitians in the UK. PMID- 17692150 TI - Association between zinc pool sizes and iron stores in premenopausal women without anaemia. AB - The simultaneous occurrence of Zn and Fe deficiencies in man has been known since the discovery of human Zn deficiency. However, it is not established that low Fe stores per se or Fe-deficiency anaemia infer low Zn status. Therefore our objective was to identify relationships between Zn and Fe status in premenopausal women without anaemia. We also examined the contribution of food frequencies and blood loss to Zn and Fe status. The subjects were thirty-three apparently healthy premenopausal women without anaemia, who were not taking dietary supplements containing Zn or Fe or oral contraceptives. Main outcomes were Zn kinetic parameters based on the three-compartment mammillary model and serum ferritin (SF) concentration; contributing factors were the frequency of consumption of specific foods and menorrhagia. Lower SF was significantly associated with smaller sizes of Zn pools. The breakpoint in the relationship between SF and the lesser peripheral Zn pool was found to be 21.0 microg SF/l. SF also correlated positively with frequency of beef consumption and negatively with bleeding through menstrual pads (BTMP). Similar to SF, the Zn pool sizes correlated positively with frequency of beef consumption, and negatively with BTMP. In summary, Zn pool sizes and Fe stores were highly correlated in premenopausal women. SF concentrations < 20 microg/l suggest an increased likelihood of low Zn status. PMID- 17692151 TI - Convenience food in the diet of children and adolescents: consumption and composition. AB - Despite an increasing trend towards the use of convenience food, there is to date little debate on it in the nutritional sciences. In the present study, we present and evaluate data on consumption frequencies and composition of savoury convenience food in German families using data from the Dortmund Nutritional and Anthropometric Longitudinally Designed (DONALD) Study. The DONALD Study is an ongoing, longitudinal (open cohort) study (started 1985), collecting detailed data on diet, development, and metabolism in infants, children and adolescents. Dietary intake was measured by yearly repeated 3 d weighed dietary records (n 1558) in 554 subjects (278 boys; 276 girls), 3-18 years old, between 2003 and 2006. A total of 1345 (86%) 3 d dietary records mentioned consumption of at least one convenience food. Convenience food consumption (percentage of total food intake, g/d) increased with age from approximately 3% in the 3-8 year olds to 7% in 14-18-year-old boys and 5% in 14-18-year-old girls (P < 0.0001) but remained constant during the study period. Convenience foods contributed more to total fat (g/d) (P < 0.001) and less to total carbohydrate (P < 0.0001) than to total energy (kJ/d) intake. The 700 convenience-food products recorded by our sample had on average fourteen ingredients; 4% were flavourings and 16% were food additives. In conclusion, convenience foods were widely consumed by our sample of German children and adolescents and their consumption increased with age. The composition of convenience food was characterised by a high fat content and a high number of flavourings and food additives. PMID- 17692152 TI - Clinical and economic impact of using macrogol 3350 plus electrolytes in an outpatient setting compared to enemas and suppositories and manual evacuation to treat paediatric faecal impaction based on actual clinical practice in England and Wales. AB - OBJECTIVE: To estimate the clinical and economic impact of using macrogol 3350 plus electrolytes (macrogol 3350; Movicol; Movicol Paediatric Plain) in an outpatient setting compared to enemas and suppositories and manual evacuation to treat paediatric faecal impaction. METHODS: A chart review was undertaken to extract clinical outcomes and resource use from the case notes of a cohort of children aged 2-11 years with faecal impaction who initially received either macrogol 3350 (in an outpatient setting) or enemas and suppositories or manual evacuation for initial disimpaction. Five centres across England and Wales participated in the study. These data were used to inform a decision model which depicted the management of children during the disimpaction phase and for a period of 12 weeks following initial disimpaction. Unit resource costs at 2005/2006 prices were applied to the resource utilisation estimates within the model, enabling the incremental costs and consequences of using macrogol 3350 in an outpatient setting, compared to the other treatments, to be estimated. RESULTS: 112 patients treated with macrogol 3350, 101 who received enemas and suppositories and 11 who underwent a manual evacuation were eligible for analysis. Ninety-seven per cent of children treated with macrogol 3350 were successfully disimpacted within 5 days, compared to 73% of those who received enemas and suppositories and 89% of those who underwent a manual evacuation (p < 0.001). There were no significant differences in reported adverse events between the different treatments for disimpaction, with the exception of vomiting which was significantly higher among those who underwent a manual evacuation (18% versus 2% with the other treatments; p < 0.01). There were no significant differences in the number of clinician outpatient visits between treatments. However, macrogol 3350-treated patients had significantly fewer hospital admissions than those who received the other interventions (0.1 versus 1.4 and 1.0 for enemas and suppositories and manual evacuation respectively; p < 0.05) and occupied fewer bed days. The total NHS cost of disimpaction and subsequent maintenance of children initially treated with macrogol 3350 was estimated to be 694 pounds sterling (95% CI: 496 pounds sterling; 892 pounds sterling). This compared with 2759 pounds sterling (95% CI: 1266 pounds sterling; 4252 pounds sterling) and 2333 pounds sterling (95% CI: 1609 pounds sterling; 3058 pounds sterling) for those who initially received enemas and suppositories or underwent a manual evacuation, respectively. Hence, using macrogol 3350 instead of enemas and suppositories and manual evacuation to disimpact the whole annual cohort of faecally impacted children aged 2-11 years in England could potentially reduce annual NHS expenditure on this condition by 59% (5 million pounds sterling) and reduce the annual number of paediatric hospital admissions for this condition by 92% (4330). CONCLUSION: Within the limitations of our model, macrogol 3350 affords the NHS a clinically effective and cost-effective treatment for the disimpaction of children suffering from faecal impaction compared to enemas and suppositories or a manual evacuation, and has the potential to release healthcare resources for alternative use within the system. PMID- 17692153 TI - Effect of rosuvastatin versus atorvastatin treatment on paraoxonase-1 activity in men with established cardiovascular disease and a low HDL-cholesterol. AB - OBJECTIVE: Paraoxonase-1 (PON-1) is a high-density lipoprotein (HDL) associated enzyme involved in the protective mechanisms of HDL. Our aim was to compare the effect of treatment with rosuvastatin and atorvastatin on serum PON-1 activity. METHODS: We performed a prespecified prospective study in 68 patients, part of a larger, multicentre randomized study--RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport). Patients aged 40-80 years, all men, with established cardiovascular disease and high-density lipoprotein cholesterol (HDL-C) < 1.0 mmol/L (< 40 mg/dL) entered a 6-week dietary run-in period before receiving treatment with rosuvastatin 10 mg or atorvastatin 20 mg daily for 6-weeks. Doses were increased after 6 weeks to rosuvastatin 20 mg or atorvastatin 40 mg and after 12 weeks to rosuvastatin 40 mg or atorvastatin 80 mg daily. Serum PON-1 activity and lipid profile were determined at baseline, 6 and 18 weeks. RESULTS: After 18 weeks, the rosuvastatin arm showed a significant increase of PON-1 activity (6.39 U/L, p = 0.02) whereas this was not observed in the atorvastatin arm (1.84 U/L, p = 0.77). The difference between groups did not reach significance (p = 0.11). Both rosuvastatin and atorvastatin resulted in significant (p = 0.0001) and similar increases in HDL-C after 6 weeks [0.06 mmol/L (2.32 mg/dL) vs. 0.05 mmol/L (1.93 mg/dL)] and after 18 weeks [0.10 mmol/L (3.87 mg/dL) vs. 0.10 mmol/L (3.87 mg/dL)]. CONCLUSIONS: Rosuvastatin treatment resulted in a significant increment of serum PON-1 activity with increasing dose while this was not observed with atorvastatin. PMID- 17692154 TI - Effect of ezetimibe in patients who cannot tolerate statins or cannot get to the low density lipoprotein cholesterol target despite taking a statin. AB - BACKGROUND: Recent guidelines underline the need for high-risk patients to reach strict low density lipoprotein cholesterol (LDL-C) targets (1.8-2.6 mmol/L; 70 100 mg/dL), and specifically mention the possible use of combination therapy (e.g.statin + ezetimibe) to achieve these goals. METHODS: A retrospective case note audit was carried out to assess the response to administering ezetimibe in patients unable to tolerate statins (Group 1), or high dose of statins (Group 2) and patients who cannot achieve the LDL-C target (2.6 mmol/L; 100 mg/dL) despite taking a statin (Group 3). RESULTS: Ezetimibe lowered LDL-C levels by 20-29% across the 3 patient groups after 2-3 months of treatment. High density lipoprotein cholesterol (HDL-C) levels tended to remain unchanged, although there was a consistent trend for a fall if baseline values were 'high'. However, the LDL-C/HDL-C ratio changed significantly and favourably in all groups. The fall in fasting triglyceride levels in all groups was greater (reaching 19-25%) when baseline levels were > or = 1.5 or 1.7 mmol/L (136-150 mg/dL). There were no marked abnormalities in liver function tests or creatine kinase activity. In Group 3 there was a significant trend for a fall in serum creatinine levels across the tertiles of baseline creatinine values. Limitations of the present study include the small sample size (especially in Groups 1 and 2), its short term duration and the absence of event-based end-points. Therefore, the results are hypothesis-generating rather than conclusive. CONCLUSIONS: When used alone or added to a statin, ezetimibe favourably altered the LDL-C/HDL-C ratio and lowered triglyceride levels. Ezetimibe was well tolerated in patients with statin intolerance and was associated with a 26% fall in LDL-C. An additional action may be some degree of improved renal function. Further studies are needed to confirm these findings. PMID- 17692156 TI - [Influence of bioethics in clinical ethics]. PMID- 17692155 TI - Efficacy and safety of hydroxychloroquine sulphate in rheumatoid arthritis: a randomized, double-blind, placebo controlled clinical trial--an Indian experience. AB - OBJECTIVE: Hydroxychloroquine (HCQ) has been used for a long time worldwide as a therapy for rheumatoid arthritis (RA). This trial was designed to determine whether HCQ was efficacious and safe in Indian patients with RA. RESEARCH DESIGN AND METHODS: The trial was a multicentre, placebo controlled, randomized and double-blind study. One hundred and twenty-two patients with RA were enrolled in 3 different centres for the trial (26 males and 96 females in the age group of 18 60 years). Patients were randomized to receive either hydroxychloroquine tablets (n = 61) two tablets of 200 mg daily or placebo (n = 61) two tablets daily. After 8 weeks all patients received one tablet of hydroxychloroquine 200 mg daily for 4 weeks. Every patient also received one tablet of Nimesulide 100 mg twice daily. MAIN OUTCOME MEASURES: Assessment of response at 12 weeks using modified ACR 20 (American College of Rheumatology 20) criteria where Health Assessment Questionnaire (HAQ) was replaced by ARA (American Rheumatology Association) functional class. RESULTS: 40.4% of patients on hydroxychloroquine showed improvement by modified ACR response criteria whereas only 20.7% (p = 0.02) showed improvement in the placebo group. No significant side effects were observed in any of the patients. There were no ocular toxicities. CONCLUSIONS: Hydroxychloroquine was found to be an effective and well-tolerated drug in rheumatoid arthritis in Indian patients. PMID- 17692157 TI - [Causes for failure of the medical appointment program in a family medicine clinic]. AB - The objective of this study was to identify, for both patients and health services, the probable causes for non-attendance at medical appointments in a family medicine clinic located in Mexico City. The three top reasons of visit, type 2 diabetes, hypertension and antenatal care were analyzed. Four hundred and thirty-nine patients who missed their appointment during May 2004 answered an interview. Patient's variables were age, gender, schooling, employment status, workday, employer support to attend to the appointment, physical conditions, family support, affordability of the travel expenses to attend to the clinic, place of residence, forgetting the appointment and hospitalization. Health services variables were conflict between the dates of the appointment with the family doctor and with the laboratory, mistakes in the agenda, re-scheduling or cancellation of the appointment, entitlement to receive medical care, absence of the family doctor, and patient's decision to leave the clinic before the appointment. Data were analyzed by using descriptive statistics. 45.8% of patients forgot their appointment and 44% had administrative problems that impaired their receive medical care; 76.4% of pregnant women had administrative problems as well. Addressing these two possible causes is essential to the success of the medical appointment program. PMID- 17692158 TI - [Usefulness of Doppler ultrasonography to detect fetal anemia in rh alloimmunized pregnancies]. AB - BACKGROUND: pregnant women with Rh alloimmunization (RhA) are submitted to invasive procedures to assess fetal anemia (FA). Recently a non-invasive approach to FA diagnosis has been proposed using Doppler ultrasound (DU) to identify increased peak velocity of systolic blood flow (Vm) in the middle cerebral artery (MCA). METHODOLOGY: eleven Rh alloimmunized pregnant women with serum red-cell antibody titers > 1:16 were included. Twenty-four procedures were done measuring the VmMCA followed by cordocentesis and fetal hemoglobin (FH) analysis. Pearson's linear correlation was calculated between the multiples of the median (MoM) of the VmMCA and the MoM of the FH, as well as the sensitivity, specificity and positive predictive value (PPV) for FA prediction. RESULTS: we found FA (FH mean = 6 g/dL) in 12 of 24 evaluations with a VmMCA mean of 1.5 MoM and a range from 1.22 to 1.68 MoM; in the remaining 12 cases the FH was normal (FH mean = 13.1 g/dL) with a VmMCA mean of 0.97 MoM and a range from 0.35-1.17 MoM (p < 0.001). Eleven fetuses with anemia had a MoM of the VmMCA above 1.29, except one with 1.22 MoM. The linear correlation between the MoM of the VmMCA and the MoM of FH was 0.83. The sensitivity of the MoM of the VmMCA to detect FA was 91%, specificity of 100% and PPV of 100%. CONCLUSIONS: DU measurement of the VmMCA was a useful non-invasive technique to evaluate FA. The sensitivity and PPV for FA diagnosis in RhA was above 90%. PMID- 17692159 TI - [Depression in adolescents and family functioning]. AB - OBJECTIVE: to determine the frequency of depression and family function in adolescents. METHODOLOGY: 252 students participated in the study, 134 males and 118 females; the average age was 16 years. The Birleson depression self-rating scale and the Family Adaptability and Cohesion Scale III (FACES III) served to assess depression and family functionality. RESULTS: the overall depression was 29.8%, although in young males was 18.7% and in young females was 42.4% (p < 0.05, OR = 3.2). The rigidly dispersed family was more frequently found in the group of adolescents with depression (p < 0.05, OR = 6.3). While in the group of adolescents without depression the most frequent were, the flexible agglutinated (p < 0.05; OR = 0.215), structurally agglutinated (p < 0.05, OR = 0.215) and rigidly agglutinated families (p < 0.05, OR = 0.106). CONCLUSIONS: this study showed that a significant percentage of adolescents suffer depression. This finding should prompt to further actions to detect adolescents' depression in primary care settings to provide timely care and to avert its severe consequences such as suicide, drug and alcohol use. PMID- 17692160 TI - [The burnout syndrome in medical residents working long periods]. AB - OBJECTIVE: to evaluate the burnout syndrome in medical residents with working periods longer than 80 hours per week. METHODOLOGY: an analytical cross-sectional study was conducted with medical residents working at Instituto Mexicano del Seguro Social hospital in Veracruz, Mexico. The residents were classified in two groups. One group working for > or = 80 h per week (study group, SG) and another group working < 80 h per week (comparison group, CG) were studied. Participants were selected by simple random sampling. The clinical evaluation instrument was the scale of Maslach burnout inventory. RESULTS: 143 medical residents were included in the sample (SG n = 72, CG n = 71); the average age was 29.6 +/- 2.5 years, 65 % were males and 51 % were unmarried. Their length of service was 2.2 +/- 0.7 years. The mean working time was 100.5 +/- 7.2 hours per week for the SG and 64.4 +/- 9.3 hours for the CG. Burnout syndrome was present in 46 (63.8 %) medical residents with long workdays (p = 0.002); it was observed more frequently in those residents that were on call 3 times per week (p = 0.002) and among surgery residents (p = 0.035). CONCLUSION: working periods longer than 80 h per week are related to the appearance of burnout syndrome. PMID- 17692161 TI - [Epidemiologic profile of very low birth weight infants treated with red blood cell transfusions]. AB - INTRODUCTION: during the neonatal period seventy to ninety percent of very low birth weight (VLBW) infants (birth weight < 1500 g), are transfused with red blood cells (RBC) at least once; that represents infectious, biochemical, immunologic and oxidative risks. The objective of this paper is to describe the epidemiological profile of the VLBW infants that are transfused with RBC. METHODOLOGY: a retrospective review of 61 VLBW newborns admitted to the Neonatology Unit of a tertiary care hospital in Monterrey, Mexico was conducted. The sample was collected consecutively. The information included the newborns epidemiological profile and the characteristics of transfusion events. RESULTS: the prevalence of transfused newborns was 70.5%, 82 transfusions were in the early postnatal period (<28 days) and 32 in the late postnatal period (> or = 28 days); 43.9% of newborns had mechanical ventilation and their fraction of inspired oxygen was > or = 0.3. Mean birth weight and standard deviation of VLBW newborns were 1206 +/- 198 g; the hematocrit before transfusion was 33.63 +/- 4.17 mg/dL, and the RBC volume per transfusion was 16.85 +/- 4.85 mL. On average, the newborns had two donors and two transfusions. CONCLUSIONS: the epidemiological profile of the newborns included in this analysis was similar to published international reports. The transfusion characteristics suggest the possibility to apply restrictive guidelines and to evaluate a single-donor blood program for these newborns. PMID- 17692162 TI - [Diagnostic criteria for cervicovaginitis and its congruency with the Mexican official norm to prevent and control vaginal infections]. AB - OBJECTIVE: to analyze currently used criteria to diagnose and treat cervicovaginitis in primary care and its congruency with the Mexican Official Norm (MON). METHODOLOGY: a cross sectional study was conducted to analyze 227 cases with cervicovaginitis. The information was obtained from the clinical charts and the variables were related to the criteria for diagnosis and treatment stated by MON. RESULTS: the mean age of patients was 31.5 years (SD 7.7). The cervicovaginitis cases were more frequent in the group of 31-35 years of age (21.4%). The etiology was ascertained in 20.7%; 48.5% of clinical charts had registered the clinical information (symptoms and signs); 25.1% were given specific treatment; in 20.7% of cases treatment was given to the sexual partner, regardless of the etiology. 24.7% had registered preventive actions; 10.6% had gynecological examination; 26.9% had laboratory exams and 27.3% of cases were followed up. CONCLUSIONS: little correspondence exists between the MON criteria and the clinical information registered in the clinical charts. This was found in less than thirty percent of cases. The gynecological examination and use of laboratory exams were infrequent, and there were a low percentage of cases in which the etiology was reported and related to the drug treatment. PMID- 17692163 TI - [Reliability and validity of a generic job exposure matrix applied on a small business]. AB - OBJECTIVE: to evaluate the reliability and validity of a generic job exposure matrix (JEM) applied in a small business. METHODOLOGY: procedures to evaluate a JEM integrated by six sections: the number of exposed workers per area, frequency of exposure, time of exposure time, level of exposure, safety controls, and proximity to source of exposure, was evaluated. The JEM also obtains information about possible health effects from exposure to occupational/environment agents. Two observers estimated the risk of exposure to epoxy resins on 31 workers of an epoxy resin facility in Mexico City. The rater agreements between the two observers were assessed through percent agreement (PA), weighted kappa (kappa(w)) and the intraclass correlation coefficient (ICC). RESULTS: disagreements were greater for the number of exposed workers (PA = 61.3, kappa(w) = 0.24, ICC = 0.33), level of exposure (PA= 66.7, kappa(w) = 0.25, ICC= 0.56), and safety controls (PA = 54.8, kappa(w) = 0.23, ICC = 0.69) sections. Percent agreement and kappa(w) were 64% and 0.58, respectively. In accordance with Landis and Koch, Altman, Fleiss, and Byrt classifications for the interpretation of kappa value, the weighted kappa (0.58) ranged from moderate to a fair good level. CONCLUSIONS: despite the discordance in some sections, the JEM proved to be useful to identify the risk of exposure in this type of small business. PMID- 17692164 TI - [Clinical ethics committees in Mexico: their development in the Mexican Institute of Social Security]. AB - The Mexican Institute of Social Security (IMSS) considers the relevance of ethics in a similar context than other countries have developed. According to these considerations, IMSS implemented formally of system of local committees on clinical ethics (CLEC), not only to provide support when ethical dilemmas emerge, but to facilitate the development of an ethics culture among health professionals. The implementation of the CLEC network started in 2004, and since then, its number has increased across the country. Currently IMSS has 78 CLECs. Their number continues to grow due to the level of awareness about the importance of ethics for making medical decisions. In November 2006 the first CLEC national meeting was held and the need to redefine strategies to improve performance of CLECS emerged. This article reports the current situation of the CLECs in Mexico. PMID- 17692165 TI - [Noise conditions inside waiting rooms of primary care clinics]. AB - OBJECTIVES: to explore the acoustic noise conditions of the waiting rooms in primary care facilities and to evaluate whether the ambient noise level was within the recommended levels for these facilities. METHODOLOGY: the waiting rooms of four primary care clinics located in the south of Mexico City were tested. Several recording points homogeneously distributed and close to the seats of the users were chosen. In each recording point, four recordings of the ambient noise were carried out in intervals of 20 to 40 minutes; this was done during the provision of care. The day in which the recordings were made was randomly selected. The values of the specifications used in the analysis of the ambient noise levels were determined in the laboratory. RESULTS: the ambient noise level of the waiting rooms in each of the four clinics was above 55 dB-A. This level is considered as the threshold of annoyance. In one of the clinics, the level exceeded 65 dB-A. The chief contributors to the noise were the conversations of the people that were at the waiting room or in adjacent rooms, and in some cases the sound from the TV sets. CONCLUSIONS: the study showed that the ambient noise level passed the upper limits indicated by The American National Standard Institute. It is appropriate to define criteria to guarantee suitable noise conditions inside health care facilities and to revise current Mexican standards. PMID- 17692166 TI - [Double lip treated with "midmoon" incision. Report of a case]. AB - A double-lip is an anomaly which may be either congenital or acquired and may occur either isolated or as a component of Ascher's syndrome. The upper lip is involved more often than the lower, although on occasion both may be involved. Apart from a deformity that interferes with mastication and speech, surgical treatment may be indicated for cosmetic reasons. Various surgical techniques to correct the double lip have been described: elliptical incision, w-plasty, triangle incision and elliptical incision on each side, combined with a vertical midline z-plasty to release the lip's central constriction. In the case presented a long midmoon incision was used, preserving the maxillary labial frenum. Satisfactory function and aesthetic results were achieved in this patient. PMID- 17692167 TI - [Nesiritide, a novel treatment for heart failure]. AB - Nesiritide, is a recombinant form of human-B-type natriuretic peptide (hBNP) used for the therapy of acute decompensated heart failure. hBNP produces natriuresis, diuresis, hypotension, and smooth muscle relaxation preventing myocardial fibrosis and vascular smooth muscle cell proliferation. Nesiritide treatment of patients with heart failure causes balanced arterial and venous dilatation with reduction in the pulmonary capillary wedge pressure (PCWP) and increases the cardiac index. It is administered intravenously with a recommended dosage as intravenous bolus of 2 microg/kg/min followed by a continuous infusion of 0.01 microg/kg/min for less than 48 hours. Clinical experience has shown that in patients with heart failure, this drug reduces PCWP, increases cardiac index without changes in heart rate, with the subsequent improvement in clinical symptoms of dyspnea after 3 hours of treatment. Also, there is evidence of less ventricular tachyarrhytmia when compared with dobutamine and better tolerance with less secondary effects when compared with nitroglycerin. It has been suggested that there is an increase in the mortality hazard ratio at 30 days with this treatment, however clinical trials using Nesiritide did not analyze mortality at short or long term as primary end-point. Recently published meta analysis reported that there is no-increase in mortality at 30 days or 6 months with this treatment. Nesiritide is a novel and effective option for the medical treatment of acute decompensated heart failure. PMID- 17692168 TI - [Usefulness of GH and IGF-1 to establish the dose and frequency of application of octreotide to treat acromegaly]. AB - OBJECTIVE: to determine the dose and frequency of application of octreotide LAR to treat acromegaly by monitoring the levels of circulating growth hormone (GH) and insulin-like growth factor (IGF-1). MATERIAL AND METHODS: twelve patients (five men and seven women) with acromegaly, whose age was on average 48.9 years (range 35-67) participated. Eight had been surgically treated, yet non cured and 4 patients were treated de novo. The study lasted between 12-18 months. The initial octreotide dose was 20 mg/4 weeks intramuscular. Before administering the fourth dose, the levels of IGF-1 and GH were measured; then, the dose was adjusted and three more injections were applied. If the levels of GH and IGF-1 continued safe, the dose and frequency of application of octreotide LAR were individualized thus applying the minimum number of injections. RESULTS: the interval of octreotide LAR application to maintain the levels of GH and IGF-1 within safe range was prolonged to more than four weeks in nine patients (75%); in six patients (50%), the interval changed to eight weeks and to twelve weeks in three patients (25%). Three patients (25%) continued receiving injections in four week intervals. The levels of GH and IGF-1 were lower during the treatment period when compared with the baseline measurements (p < 0.01). CONCLUSION: the adjustment of the dose of octreotide LAR keeps the levels of GH within safe range and reduces in 75% the frequency of injections to treat acromegaly. PMID- 17692169 TI - [Economic studies and decision analysis as tools for decision making]. AB - Management implies decision-making and economics deals with efficiency which means to obtain the best possible results with the available resources, and to compare such results with those that were foreseen. The economic evaluation comprises a set of techniques aimed at comparing resource allocation on alternate courses of action and its consequences. In health care, these results are the overall well-being of the society. This paper summarizes the techniques that are customarily used in economic evaluation, and intends to serve as an introductory text to increasing the ability of the readers to grasp original articles in the field of health economics. PMID- 17692170 TI - Prostate cancer. Clinical practice guidelines in oncology. PMID- 17692171 TI - Point: open radical prostatectomy should not be abandoned. AB - Robotic-assisted laparoscopic radical prostatectomy is now one of the most common ways to treat prostate cancer. Although it is undoubtedly an outstanding procedure, in many contexts the advantages of the laparoscopic approach are overstated. The authors believe that open radical prostatectomy will continue to have an important role. For example, an extensive lymphadenectomy is more easily accomplished with the open technique and may be important in staging and possibly curing patients at high risk for prostate cancer. Also, tactile sensation is a valuable asset in assessing the extent of local tumor, and this cannot yet be replicated with a robotic approach. Furthermore, obese patients, those with a history of extensive prior surgical procedures, and men with extremely large prostates may experience advantages with the open technique. Finally, the open approach has a significant advantage in terms of hospital costs. PMID- 17692172 TI - Counterpoint: robot-assisted laparoscopic prostatectomy: perhaps the surgical gold standard for prostate cancer care. AB - Robot-assisted laparoscopic prostatectomy (RALP) has gained immense popularity. This article examines the most critical outcome measures in prostate cancer surgery and shows the reasons why this technique is gaining in popularity. Operative time, length of stay, blood loss, transfusions, postoperative pain, continence, potency, and cancer control all favor or tend toward improvement and benefit in RALP compared with traditional radical retropubic prostatectomy. In addition, as even greater experience and technological improvements are incorporated, further outcome improvements will be appreciated. RALP is now an accepted treatment option for prostate cancer and may soon be the most desirable treatment of prostate cancer patients. PMID- 17692173 TI - Point: active surveillance for favorable risk prostate cancer. AB - Active surveillance for favorable risk prostate cancer has become increasingly popular in populations where prostate cancer screening is widespread, because of evidence that prostate cancer screening results in the detection of disease that is not clinically significant in many patients (i.e., untreated, would not pose a threat to health). This approach is supported by data showing that patients who fall into the category of clinically insignificant disease can be identified with reasonable accuracy, and that patients who are initially classified as low-risk who reclassified over time as higher-risk and are treated radically are still cured in most cases. Active surveillance means 1) identifying patients who have a low likelihood of disease progression during their lifetime, based on clinical and pathologic features of the disease, and patient age and comorbidity; 2) close monitoring over time; 3) developing reasonable criteria for intervention, which will identify more aggressive disease in a timely fashion and not result in excessive treatment; and 4) meeting the communication challenge to reduce the psychological burden of living with untreated cancer. This article reviews the results of active surveillance, the criteria for patient selection, and the appropriate triggers for intervention. PMID- 17692174 TI - Counterpoint: the case for immediate active treatment. AB - Active monitoring strategies recently have received attention as possible treatment options for men with low-risk prostate cancer who have a life expectancy of more than 10 years. However, no current criteria sufficiently predict outcomes for individuals with clinically localized disease and an otherwise long life expectancy who undergo either immediate or delayed treatment, or no treatment. This article describes the available evidence regarding treatment outcomes in men with low-risk prostate cancer and presents the case for immediate active treatment. PMID- 17692175 TI - Point: the value of predicting life expectancy in men with clinically localized prostate cancer. AB - The prediction of life expectancy in prostate cancer screening and treatment is a controversial topic that evokes various opinions regarding its validity. The authors believe incorporating life expectancy prediction into the treatment algorithms for prostate cancer is important. Using a combination of clinical judgment and specific predictive tools, physicians can estimate the life expectancy of patients with prostate cancer. These estimates can then be used to help guide treatment discussion. Estimating life expectancy benefits older men in whom decisions regarding the best form of treatment may be difficult. PMID- 17692176 TI - Counterpoint: prostate cancer life expectancy can not be accurately predicted from currently available tools. AB - A large and growing percentage of prostate cancers are diagnosed among men of advanced age. Current guidelines stratify treatment recommendations based on life expectancy; therefore, accurate determination of life expectancy is essential. Evidence shows that patient-related factors, including age, comorbidities, and functional status, are critical determinants of life expectancy. Equally strong evidence supports tumor-related factors, including Gleason score, tumor stage, and prostate-specific antigen, and efficacy of treatment. Currently, no available tools comprehensively consider all pertinent factors in determining life expectancy. PMID- 17692177 TI - Prostate cancer early detection. Clinical practice guidelines in oncology. PMID- 17692178 TI - Update on PSA testing. AB - The use of prostate-specific antigen (PSA) testing for prostate cancer screening has increased dramatically over the past decade. Determining the most efficient way to use PSA testing and how to interpret total PSA levels and changes in PSA values over time remain challenging. Guidelines for early detection of prostate cancer have a direct impact on the number of unnecessary tests performed and are critical for developing a successful screening approach for prostate cancer. The age at which PSA screening should begin, PSA testing intervals, and the importance of understanding fluctuations in PSA values over time are discussed in the framework of recent discoveries in the field. Results from ongoing randomized trials will confirm whether prostate cancer screening is an effective method for reducing deaths from prostate cancer and what approaches will provide the most cost-effective screening strategies. PMID- 17692179 TI - New and old directions. AB - Improved social and educational opportunities and access to informed healthcare are helping today's generations of people with Down syndrome to achieve more and live longer. This progress is bringing new challenges. Scientific research is steadily improving our understanding of the condition. Future improvements in the lives of people with Down syndrome will require multidisciplinary efforts and more applied or translational research with practical outcomes. In this context, this journal has reviewed the roles it plays in communicating research to specialists and non-specialists, families, practitioners and researchers alike. PMID- 17692180 TI - Ten years of achievement in Russia. AB - The Moscow charity Downside Up is celebrating its 10th Anniversary this year. In Russia, on average only 15% of children with Down syndrome live with their families. In Moscow, thanks to the work of Downside Up, some 45% of new babies are now being taken home. Downside Up is working to ensure children with Down syndrome receive high quality services from birth to 7 years. PMID- 17692181 TI - Teaching numeracy. AB - Understanding number concepts and basic mathematical skills is important for many everyday activities in modern societies. Little is understood about the numeracy abilities of people with Down syndrome. At present, it appears that numeracy is an area of relative difficulty and that progress with more complex mathematical understanding is slow. However, some teaching approaches that seek to utilise certain relative strengths to communicate number concepts seem to be useful in practice. Further research is needed to define the precise difficulties experienced by children with Down syndrome and to evaluate teaching strategies. PMID- 17692182 TI - Shaping speech. AB - Clear speech can often be challenging for people with Down syndrome. The shape of the hard palate in the top of the mouth influences speech production. A new paper reports detailed measures of the shape and size of the hard palate among children with Down syndrome. PMID- 17692183 TI - Teeth grinding. AB - Teeth grinding turns out to be no more common in children with Down syndrome than it is in other children and it reduces with age. These are reassuring findings as teeth grinding can be quite an annoying problem at home and at school. PMID- 17692184 TI - Oral health problems and quality of life. AB - There is a higher incidence of oral health problems among individuals with Down syndrome, particularly after 10 years of age, indicating a need for better teaching of teeth brushing and more regular visits to the dentist. Do these oral health problems affect their quality of life? PMID- 17692185 TI - Increasing opportunities for physical activity. AB - Being physically active can have a number of benefits - having fun, meeting with friends, keeping healthy and experiencing success. For children with Down syndrome the foundations need to be laid early if they are to keep active in school, teenage and adult years and parents ask for more help in this area from professionals. PMID- 17692186 TI - Drug treatment improves memory in mice. AB - Mice that carry additional copies of genes comparable to those present on human chromosome 21 have been shown to perform better on memory tests when treated with drugs that target brain function. Could this be an important break-through in the search for pharmacological therapies to assist people with Down syndrome? PMID- 17692187 TI - Prevalence of bruxism among Mexican children with Down syndrome. AB - This study sought to determine the prevalence of bruxism in a Mexican community of children with Down syndrome, and to evaluate bruxism's relationship with age, sex, intellectual disability level, and type of chromosomal abnormality of trisomy 21. Using a cross-sectional design, 57 boys and girls (3 to 14 years old) were examined. Three approaches to establish presence or absence of bruxism were employed: parental questionnaire, clinical examination, and dental study casts. Data were analysed using bivariate analyses and conditional logistic regression. We found that the overall prevalence of bruxism was 42%. No statistically significant associations between bruxism and age, sex, or intellectual disability level were found. There was, however, a significant association between bruxism and type of chromosomal abnormality, with mosaicism being more frequently associated with bruxism. PMID- 17692188 TI - The impact of periodontal disease on the quality of life of individuals with Down syndrome. AB - OBJECTIVE: This study aimed to determine the prevalence of periodontal disease among children and adolescents with Down syndrome and the possible repercussions of such pathology in the quality of life of the group in question. METHOD: The sample consists of 93 individuals with Down syndrome 6 - 20 years old, living in Brazil (Minas Gerais). Periodontal probing was carried out on every site of each tooth. The Plaque Index and periodontal clinical parameters were recorded. A broad interview was carried out with the mothers, consisted of an adaptation of the Oral Health Impact File OHIP-14 that was used to measure the negative repercussions of periodontal disease in the daily lives of these individuals. RESULTS: The prevalence of gingivitis was 91%, whereas periodontitis was found in 33% of the individuals. When the impact of periodontal disease on the quality of life was correlated with the clinical periodontal parameters, it was observed that there are significant statistical differences among them: bleeding on probing, probing depth and attachment loss. These same results, correlated with all the different groups that are categorised according to the diagnosis of periodontal disease, also show significant differences. CONCLUSIONS: Periodontal disease can be considered as a condition with high prevalence within the group in question, which has negative effects on the quality of life of the subjects. These effects are aggravated by the seriousness of the disease. PMID- 17692189 TI - Metric analysis of the hard palate in children with Down syndrome: a comparative study. AB - The hard palate is viewed as playing an important role in the passive articulation of speech. Its probable role in the defective articulation of speech in individuals with Down syndrome has been examined in the present study. In individuals with Down syndrome, the hard palate is highly arched, constricted, and narrow and stair type with malformed misaligned teeth and a large and fissured tongue. As a result good palato-lingual contact is not achieved, with resulting defective articulation. Using orthodontic and prosthodontic principles could modify this situation, i.e. the anatomy of the hard palate. The altered palatal contour may give better placing to the tongue, leading to improved palato lingual contact and articulation. The dimensional parameters measured were: average linear width (AVL), average curvilinear width (AVCL), average height (AVH) at different planes; average antero-posterior length (AAP), average volume (V), palatal arch length (PAL), and palatal index (PI). The findings were compared with those of controls of the same age and sex. The AVL, AVCL, AAP, PAL, V and PI values of patients with Down syndrome were found to be less than the corresponding values of controls and the average height values of patients with Down syndrome were greater than the corresponding values of controls. Statistical significance was observed in all measurements between the controls and the patients with Down syndrome, especially in those concerning the height and the volume of the oral cavity. Observations from this study have suggested that prostheses might be designed to modify the palatal anatomy and produce better articulation in people with Down syndrome. PMID- 17692190 TI - Parents' perceptions of health and physical activity needs of children with Down syndrome. AB - Individuals with Down syndrome typically have low fitness levels and obesity despite data that indicate physiological gains from physical activity and exercise interventions. Low fitness levels and obesity in individuals with Down syndrome may be related to sedentary lifestyles, social and recreational opportunities, or low motivation to be physically active. These causal influences on the overall health of individuals with Down syndrome may be related to parental or caregiver support. Through this study, parents of children with Down syndrome from preschool to adolescent ages were interviewed about their perceptions of the health and physical activity needs of their children. Data from four focus groups indicated the following most salient themes: (1) all parents believed participation in physical activity has immediate and long-term positive health impacts on their child with Down syndrome, and most of the parents thought their child would benefit from being more physically active, (2) most parents observed that their child participated in physical activities primarily for social reasons, most notably to be with their peers with or without Down syndrome or to be with their sibling(s), and that without such motivation their child would choose sedentary activities, (3) parents of teenagers identified a need for their child to learn an individual sport to have sporting opportunities that do not require ability-matched teammates and opponents, and (4) parents recognised their need for help from physical activity specialists through either parent education regarding home-based physical activity programmes or an increase in appropriate community-based physical activity programmes for their child with Down syndrome. The interview data suggest future research should evaluate the outcomes of long-term individualised home-based physical activity interventions for children with Down syndrome. Additionally, educators, recreation specialists, and therapists should assist children and youth with their acquisition of skills used in individual and dual sports. PMID- 17692191 TI - Down syndrome in the neurology clinic: Too much? Too little? Too late? AB - This paper presents a review of all patients with Down syndrome seen over a 5 year period by one consultant neurologist in general outpatient and specialist cognitive function clinics. It revealed only 7 cases in > 4500 general referrals (= 0.2%), all referred with suspected seizure disorders. The diagnosis of epilepsy was confirmed in 6 patients. Only one new, comorbid, diagnosis was made. Neurologists have little exposure to, and hence little chance to develop expertise in, the neurological complications of Down syndrome. It is suggested that closer liaison between neurologists and psychiatrists with an interest in learning disability might improve the management of neurological problems in patients with Down syndrome. PMID- 17692192 TI - Oral health condition and treatment needs of a group of Nigerian individuals with Down syndrome. AB - OBJECTIVE: This study was carried out to determine the oral health condition and treatment needs of a group of individuals with Down syndrome in Nigeria. METHOD: Participants were examined for oral hygiene status, dental caries, malocclusion, hypoplasia, missing teeth, crowding and treatment needs. Findings were compared with controls across age group, sex and educational background of parents. RESULT: Participants with Down syndrome had poorer oral hygiene than controls, with no significant sex difference. Oral hygiene was similar in the lower age groups but deteriorated with age in the Down syndrome group. CONCLUSION: Individuals with Down syndrome in Nigeria have poorer oral health and more treatment needs than controls. They would benefit from frequent oral health assessment. PMID- 17692193 TI - Computed tomography colonography compared with conventional colonoscopy for the detection of colorectal polyps. AB - OBJECTIVE: To determine the diagnostic accuracy of computed tomography colonography (CTC) compared with conventional colonoscopy (CC). METHODS: Patients with an indication of CC were included. Fifty patients underwent CTC using multidetector CT before diagnostic colonoscopy was performed by an expert colonoscopist. Diagnostic accuracy was assessed individually both for each polyp and for each patient. RESULTS: Fifty patients were included and 40 polyps were analyzed. The by-polyp sensitivity of CTC was 15% for polyps 5 mm or less, 75% for polyps 5- 10 mm and 75% for polyps 10 mm or larger. By-patient specificity was 6% for polyps 5 mm or less, 75% for polyps 5-10 mm and 80% for polyps 10 mm or larger. The specificity of CTC was 94%. CTC was preferred over CC by 90% of the patients. The mean colonoscopy examination time was 30 minutes for CC and 35 minutes for CTC (p < 0.05). CONCLUSIONS: The sensitivity of CTC is moderate in detecting polyps larger than 10 mm, low in detecting 5-10 mm polyps and very low in detecting those less than 5 mm. The overall specificity of the procedure was 94%. Procedure time was lower with CC than with CTC but the latter was better tolerated by most patients. PMID- 17692194 TI - [Value of contrast-enhanced ultrasound in the diagnosis of hepatocarcinoma in focal lesions detected in patients with liver disease]. AB - OBJECTIVE: To assess the value of contrast-enhanced ultrasound in the detection of arterial hypervascularity as a diagnostic criterion of hepatocellular carcinoma (HCC) in patients with focal lesions and liver disease. PATIENTS AND METHODS: This prospective study included patients with chronic liver disease and focal liver lesions on ultrasound (US) examination. SonoVue was used as contrast agent. We employed a US imaging technique with contrast-specific software operating at a low mechanical index (< 0.14) (Hitachi EUB 6500). The contrast enhancement pattern was analyzed during the arterial phase and classified as diffuse (homogeneous or heterogeneous), peripheral, adjacent parenchyma-like enhancement, and absent. The diagnostic procedure was completed by combined study with computed tomography, magnetic resonance imaging, histologic data and clinical features. RESULTS: A total of 23 nodules in 22 patients were included in the study (one patient had two different US lesions). The final diagnosis was hepatocellular carcinoma (HCC) in 12 patients, benign lesions in nine, metastases in one and cholangiocarcinoma in one. In the 10 patients with diffuse contrast enhancement, the lesion was malignant and in the eight patients with diffuse homogeneous enhancement, the lesion was a HCC. Seventy-five percent of the patients with HCC had a diffuse enhancement pattern during the arterial phase. This pattern involved malignancy with 71.4% sensitivity, 100% specificity, 100% positive predictive value, 69.2% negative predictive value, and 82.6% accuracy. The diffuse homogeneous pattern involved HCC with 66.7% sensitivity, 100% specificity, 100% positive predictive value, 73.3% negative predictive value and 82.6% accuracy. CONCLUSIONS: Contrast-enhanced US with SonoVue allows the vascularity of focal liver lesions to be assessed. In our study, 75% of patients with HCC showed arterial hypervascularity. A diffuse homogeneous enhancement pattern during the arterial phase was highly specific to HCC. In cirrhotic patients, this arterial pattern could avoid the need for further investigations, although clinical staging should be completed with another diagnostic test. PMID- 17692195 TI - [Management of spontaneous hepatic hemorrhage due to focal nodular hyperplasia]. AB - Focal nodular hyperplasia is a benign liver tumor that usually follows an asymptomatic course. Hemorrhage of hepatic focal nodular hyperplasia is exceptional and occurs in tumors such as hepatocellular carcinoma and hepatic adenoma. We report the case of a woman with spontaneous rupture and hemorrhage of focal nodular hyperplasia. Hemodynamic stabilization was achieved by selective hepatic arterial embolization. Elective hepatic resection was subsequently performed. This clinical course is extremely rare. We describe the therapeutic management of these complications using hepatic transarterial embolization, which could avoid potentially harmful aggressive treatments. PMID- 17692196 TI - [Microcytic and hypochromic anemia due to a high-grade undifferentiated, embryonal, pleomorphic sarcoma]. AB - Undifferentiated (embryonal) sarcoma (UES) of the liver is a primary malignant tumor, rarely diagnosed in adults. Because of the absence of specific symptoms, rapid tumor growth, and normality of the common tumor markers, this neoplasm has a poor prognosis. Histologically, UES of the liver is characterized by anaplastic cells within myxoid matrix. Histological, immunohistochemical and chromosomic alterations are similar in UES and in mesenchymal hamartoma, suggesting a relation between these entities. The mainstay of treatment is surgery, while adjuvant treatment could increase survival. PMID- 17692197 TI - [Tonsillar hypertrophy and mesenteric adenopathies as the main manifestations in a patient with Whipple's disease]. AB - Whipple's disease is an infrequent chronic infection caused by Tropheryma whipplei, identified in 1992. Intestinal, articular, central nervous system and cardiac involvement is common. The presence of abdominal adenopathies, especially mesenteric adenopathies, without peripheral adenopathies or gastrointestinal, articular, neurological or cardiac symptoms is rare. We present the case of a male patient with tonsillar hypertrophy, mesenteric adenopathies, fever and constitutional syndrome, leading to suspicion of lymphoma. Biopsy findings of the lingual tonsil and mesenteric adenopathies were compatible with Whipple's disease. The diagnosis was confirmed by blood polymerase chain reaction. PMID- 17692198 TI - [Amebic liver abscess: medical treatment or percutaneous aspiration?]. AB - Amebic liver abscess is an emergent disease in Spain due to immigration and travel to endemic countries. Although mainly pharmacological, treatment can sometimes require drainage, especially when there is a high risk of rupture due to location or size. We report a case of amebic liver abscess that, due to its large size and lack of response to metronidazole therapy, required percutaneous drainage. This technique, with ultrasound-guided percutaneous aspiration, would be indicated in lesions with a diameter of > 5 cm, abscesses of the left lobe, and those unresponsive to medical treatment. PMID- 17692199 TI - [Role of liver biopsy in the diagnosis and management of chronic hepatitis C]. AB - For several years, liver biopsy has been the established gold standard for evaluating the status of liver disease in patients with chronic hepatitis C. Although this procedure continues to be recommended, current practice is changing for 2 main reasons: firstly, treatment is more effective and, secondly, biochemical and serological tests provide a great deal of information on disease progression. Pathologists can increase the importance and utility of liver biopsy in chronic hepatitis C, providing information not only on the stage of fibrosis and necroinflammatory activity but also on the grade of steatosis and iron accumulation, which are implicated in disease progression. Moreover, these specialists can identify other diseases, such as steatohepatitis and hereditary hemochromatosis. Nevertheless, the use of serological tests will reduce the indications for liver biopsy. PMID- 17692200 TI - [Hepatitis E virus: zoonotic implications]. AB - The Hepatitis E virus (HEV) is transmitted primarily by the feco-oral route throughout contaminated water and/or food, and is one of the main causes of acute hepatitis worldwide. Hepatitis E shows a high mobility but a low mortality rate, except in pregnant women, where it can be as high as 30%. HEV causes sporadic cases and epidemic outbreaks, mainly in Africa, Asia and Central America. In Europe, there is an increase in the number of reported autochthonous cases no related with travel to endemic areas. In addition, HEV also infects animals, including pigs, and its zoonotic potential has been recently demonstrated. In fact, porcine and human strains of the same area are genetically more closely related to each other than to strains of the same species but a different geographical region, and there are data suggesting that people in close contact with pigs presents a higher prevalence of specific anti-HEV antibodies. All together, these data have drove to an increase interest in determining the incidence of the disease in animals, its possible zoonotic risk, and its implications for human health. In the present article we revised the current knowledge about HEV, with special emphasis in the possible consequences of its zoonotic potential. PMID- 17692201 TI - [Probiotics and prebiotics in inflammatory bowel disease]. AB - Multiple studies of the immune system in patients with inflammatory bowel disease (IBD) have demonstrated the presence of altered intestinal mucosal immunity, probably genetically determined, giving rise to increased immunoreactivity against elements of the commensal flora. The basic strategy in the treatment of IBD is aimed at suppressing inflammatory responses. With the exception of studies of antibiotic therapy, little attention has been paid to modifying intestinal flora. Modification of intestinal flora through probiotics provides the possibility of acting microbiologically as well as immunologically. From the physiopathological point of view, the use of probiotics in IBD is a good therapeutic alternative. However, at present, studies with probiotics have only yielded positive results in highly specific situations. Secondary physiopathological data from clinical trials suggest a beneficial effect. However, this effect should be confirmed either in studies with a larger number of patients or by applying strategies that more effectively modify the composition of intestinal flora. PMID- 17692202 TI - [Autoimmune pancreatitis. Retrospective diagnosis and the need for subspecialization in gastroenterology]. PMID- 17692203 TI - [Accidental rupture of a Sengstaken-Blakemore balloon]. PMID- 17692204 TI - [Hypertransaminasemia in adult celiac disease]. PMID- 17692205 TI - [Peritoneal serous papillary carcinoma. Report of a case]. PMID- 17692206 TI - [Acute pancreatitis as the form of presentation of inflammatory bowel disease]. PMID- 17692207 TI - Acute hepatitis associated to leflunomide in a patient with rheumatoid arthritis. PMID- 17692208 TI - [Clinical significance of the antimicrobial resistance of biofilms]. PMID- 17692209 TI - [Activity and penetration of linezolid and vancomycin against Staphylococcus epidermidis biofilms]. AB - INTRODUCTION: The activity and capacity for penetration of linezolid and vancomycin were comparatively evaluated against Staphylococcus epidermidis biofilms. METHODS: The activity of linezolid versus vancomycin was assessed against 24-hour S. epidermidis biofilms developed on silicon catheters. Penetration of the two antimicrobial agents was measured in biofilms developed on polycarbonate membrane filters. Penetration and activity were comparatively tested using S. epidermidis, slime-producing and non-slime-producing strains. RESULTS: The activity of linezolid against S. epidermidis biofilms was significantly greater than that of vancomycin for both strains. Neither antimicrobial completely eradicated bacterial survival in 24-hour biofilms. Linezolid penetration in biofilms was greater than that of vancomycin for both S. epidermidis strains. CONCLUSIONS: Linezolid showed higher in vitro activity than vancomycin against S. epidermidis biofilms on silicone catheters. This effect may be due to the capability of linezolid to cross the bacterial biofilm. PMID- 17692210 TI - [Specialized home care for infectious disease. Experience from 1995 to 2002]. AB - OBJECTIVE: In 1995 a specialized home care service for infectious diseases was created in our institution. The aim was to improve the quality of life of patients with prolonged parenteral antimicrobial therapy requirements, reduce the length of hospital stay, and improve the care received after discharge by clinical and analytical surveillance. This study reviews the experience of this service from 1995 to 2002 using prospectively recorded data. METHODS: An analysis was performed of the number of patients included in the home care program per year, number of patients with HIV infection, infectious disease diagnosed, department referring the patient, antimicrobial treatment administered, destination at discharge, and reason for hospital re-admission. RESULTS: The number of patients included each year from 1995 to 2002 was 52, 55, 77, 232, 213, 321, 280 and 219, respectively. The percentage of HIV-infected patients decreased from 90% in 1995 to 23% in 2002. The main reason for referral to the program changed from substitution of day-care hospital treatment to early discharge from hospitalization. Whereas CMV infection was the most frequent infection treated during the 1995-1998 period, bacterial infections predominated in the following years. In 148 episodes, self-administration or a portable infusion pump was used for drug administration. Self-administration was associated with a greater risk of complications (24% vs. 12%, OR 2.3, 95% CI 1.5-3.6, P < 0.001) and catheter related sepsis (4% vs. 0%, OR 12.9, 95% CI 10.9-15.3, P < 0.001). HIV-infected patients were re-hospitalized due to complications unrelated to the home care service more frequently than HIV-uninfected patients. CONCLUSIONS: The percentage of HIV-infected patients included in the infectious disease home care service has progressively decreased since 1996, a fact likely to be related to the introduction of highly active antiretroviral therapy and better control of opportunistic infections. Currently, bacterial infections are the most frequent infections treated in the service. Early hospital discharge is now the main reason for referral to the home program. PMID- 17692211 TI - [Primary antiretroviral drug resistance among patients diagnosed with HIV infection in Gran Canaria (Spain) between 2002 and 2005]. AB - BACKGROUND: This study examines the prevalence of primary resistance to antiretroviral drugs in patients diagnosed with HIV infection during 2002 to 2005 and determines the clinical and epidemiological characteristics of this population. METHODS: A prospective analysis of genotypic resistance was carried out in 125 patients by gene sequencing (88.0% diagnosed in 2002, 28.9% in 2003 2004, and 87.9% in 2005). Thirteen patients had a diagnosis of recent primary infection. RESULTS: Sixteen patients (12.8%) carried viruses with at least one drug-resistance mutation; among them, 4 had recent infection (30.8%) and 12 chronic infection or infection of unknown duration (10.7%). Six patients (4.8%) presented at least one resistance mutation to nucleoside/tide reverse transcriptase inhibitors, 9 patients (7.2%) to non-nucleoside/ tide reverse transcriptase inhibitors inhibitors and 2 patients (1.6%) to protease inhibitors. One patient (0.8%) harbored a multidrug-resistant variant. The frequency of primary resistance was higher in patients with HIV subtype B (15.5%), in the homosexual/bisexual population (17.9%), and in patients diagnosed in 2005 (17.9%). Prevalence increased from 9.3% in 2002 to 16.3% in 2005 in chronically infected patients or those with unknown duration of the infection. CONCLUSIONS: Primary resistance to antiretroviral drugs is high in both recent and chronic HIV infection and has increased in recent years. Genotype resistance testing in patients with a diagnosis of HIV infection is recommended before beginning antiretroviral therapy. PMID- 17692212 TI - [HIV infection in immigrants: clinical and epidemiological differences as compared to the native population in a Health Area in Madrid (2002-2004)]. AB - OBJECTIVE: To describe the incidence and characteristics of immigrant patients attended in a dedicated HIV Unit in Madrid (Spain). METHODS: Cross-sectional study including all patients whose first visit to our HIV Unit took place between January 2001 and December 2004. RESULTS: Among a total of 516 new patients seen during the study period, 101 (19.6%) were immigrants (59% from Latin America, 27% from sub-Saharan Africa). Considering only patients who had not received previous clinical care in other centers (n = 298), 25.5% were immigrants. As compared to Spanish patients, there was a higher proportion of women among the immigrant population (40% vs. 26%: P = 0.008), age was lower (35 vs. 38 years; P = 0.003), and educational level was higher (39% vs. 13% secondary or higher education; P < 0.0001), with no statistical differences regarding employment (37% vs. 27% were unemployed; P = 0.07). Sexual transmission was more frequent among immigrants (85% vs. 37%; P < 0.0001), but the main sexual route of infection in both groups was heterosexual contact (71% and 66%). There were no differences in the baseline clinical, immunological, or virological status. CONCLUSION: A large number of new patients attended for the first time in a dedicated HIV Clinic in Madrid were immigrants. Although these patients showed some differences in demographic characteristics and the mechanism of HIV transmission, no significant differences were found in their clinical or immunological characteristics as compared to Spanish patients. PMID- 17692213 TI - [GEIPC-SEIMC (Study Group for Infections in the Critically Ill Patient of the Spanish Society for Infectious Diseases and Clinical Microbiology) and GTEI SEMICYUC ( Working Group on Infectious Diseases of the Spanish Society of Intensive Medicine, Critical Care, and Coronary Units) recommendations for antibiotic treatment of gram-positive cocci infections in the critical patient]. AB - In recent years, an increment of infections caused by gram-positive cocci has been documented in nosocomial and hospital-acquired-infections. In diverse countries, a rapid development of resistance to common antibiotics against gram positive cocci has been observed. This situation is exceptional in Spain but our country might be affected in the near future. New antimicrobials active against these multi-drug resistant pathogens are nowadays available. It is essential to improve our current knowledge about pharmacokinetic properties of traditional and new antimicrobials to maximize its effectiveness and to minimize toxicity. These issues are even more important in critically ill patients because inadequate empirical therapy is associated with therapeutic failure and a poor outcome. Experts representing two scientific societies (Grupo de estudio de Infecciones en el Paciente Critico de la SEIMC and Grupo de trabajo de Enfermedades Infecciosas de la SEMICYUC) have elaborated a consensus document based on the current scientific evidence to summarize recommendations for the treatment of serious infections caused by gram-positive cocci in critically ill patients. PMID- 17692214 TI - [Spectrum and risk factors of invasive fungal infection]. AB - In recent years, invasive fungal infection has become a growing problem in immunosuppressed patients. Simultaneously, changes in medical practice, such as the use of anti-Candida prophylaxis with azoles, has led to a shift in the epidemiology of these infections from Candida spp. to Aspergillus and other filamentous molds. Moreover, new risk factors for invasive fungal infection have been identified and the time of onset is different from that seen a decade ago. Recognition of these trends in patients receiving novel immunosuppressive regimens has important implications for the clinical management of fungal infection in this population. PMID- 17692216 TI - [Hemoptysis in a young immunocompetent woman]. PMID- 17692215 TI - [Infections in stem cell transplantation]. AB - The morbidity and mortality associated with infections in stem cell transplantation (SCT) has decreased considerably in recent years because of increasing knowledge of related risk factors, immune recovery, and the pattern of infection according to the phase of evolution of SCT, and the introduction of new and more effective antimicrobial agents. These advances, together with the use of peripheral blood stem cells, T-lymphoid cell depletion, stimulating factors, and more potent immunosuppressors has reduced SCT mortality and broadened the indications for this treatment. Nevertheless, infection continues to a prominent complication in these patients. PMID- 17692217 TI - [Skin lesions in a female patient with non-Hodgkin lymphoma]. PMID- 17692218 TI - [Possible Epstein Barr virus encephalitis in a patient with HIV infection]. PMID- 17692219 TI - [Ekiri syndrome complicating shigellosis]. PMID- 17692220 TI - [Knee prosthesis infection due to Pasteurella multocida]. PMID- 17692221 TI - [Autochthonous amebic liver abscess: microbiological diagnosis by PCR]. PMID- 17692222 TI - [Some discrepancias on biodefense matters]. PMID- 17692223 TI - [To your meeting. XXVII semFYC Congress in Valladolid and Salamanca]. PMID- 17692224 TI - [Present and future of family medicine MIR]. PMID- 17692225 TI - [An instrument to evaluate primary health care from the population perspective]. AB - OBJECTIVE: To reduce, translate, and adapt transculturally, the short version of the PCAT questionnaire for users (PCAT Customer client version), in order to achieve an abbreviated version of the original instrument in Catalan and Castilian that is conceptually similar to the English original, culturally adequate and viable for use among the Spanish population, and useful for inclusion in the health surveys. DESIGN: Translation and adaptation of one questionnaire. Three steps were followed: a) question selection; b) transcultural adaptation of the selected questions, by means of direct translations to Castilian and Catalan with subsequent re-translation to English; c) clarity, acceptability, and familiarity with content of the 2 pretest questionnaire versions were evaluated through cognitive interviews of persons with different profiles in the targeted population. RESULTS: Fifteen questions were selected for the adult version and 24 for the <15 year-old version. These facilitated the identification of a primary health care provider and the collection of information on the dimensions of first contact, continuity of care, comprehensiveness of care and coordination. CONCLUSIONS: It is hoped that these instruments will be useful when included in the questionnaires of health surveys throughout Spain. The items selected facilitate evaluation of the degree to which primary health care succeeds as the first user contact with health services, maintains continuity of attention, coordinates and provides services, making them available when necessary. Furthermore, cultural competence will be evaluated. PMID- 17692226 TI - [Evaluation needs the population perspective]. PMID- 17692227 TI - [Self-perception of the care and teaching work of family medicine mentors]. AB - OBJECTIVE: To determine the characteristics of Family Medicine mentors' care and teaching work. DESIGN: Transversal, observational study. SETTING: Teaching Health Centres in Valencia province, Spain. PARTICIPANTS: Ninety-one accredited mentors with third-year residents. MAIN MEASUREMENTS: Self-administered questionnaire collecting general data of mentors, characteristics of their care work, organisation of consultations between mentor and residents, teaching dedication, satisfaction and motivation, and proposals for improvement. RESULTS: Sixty-six per cent of the questionnaires sent out were analysed. Mentors had an average 7.1 years experience and 43.2 consultations/day. They devoted 4.4 hours a week solely to teaching, which 68.8% judged insufficient. 24% of mentors did a consultation at the same time as the resident. The satisfaction and motivation levels were high, with more advantages than disadvantages cited. CONCLUSIONS: On the whole, organisational strategies ensuring residents' autonomy were used. Mentors were satisfied and motivated, even though they thought the time devoted was insufficient. PMID- 17692228 TI - [Primary care and the power of the health system to solve problems: a study from the professionals' view-point]. AB - OBJECTIVE: To identify professionals' view of the problem-solving capacity of primary care in the health system. DESIGN: Interpretative study, based on the Grounded Theory method and the focus-group technique. SETTING: Eight primary care centres. PARTICIPANTS: In all, 198 professionals: 86 physicians, 69 nurse and 43 who were not health professionals. INTERVENTIONS: Data were obtained by: open questions in the focus groups, recording and transcription of the contributions; division of the text into autonomous sense units; sense units grouped by their common characteristics; inductive definition of each category; relationship between categories and triangulation of inter-team data. RESULTS: The problem solving capacity of professionals should be characterized by: care for the bio psycho-social demands and needs of the population; the integration of the following dimensions of professional competence: communication and teamwork; the promotion of prevention and public education. However, health-care daily practice prioritised quantitative parameters linked to reactive actions that were distant from the singularity of patients' pathologies. CONCLUSIONS: The desired problem solving capacity of primary health care is threatened by excessive quantitative measurement, by shortcomings in human resources and facilities, and by the well known lack of time in health-care delivery. PMID- 17692229 TI - [Compliance with hypertension therapy in Spain, according to the views of family doctors. Complex project]. AB - OBJECTIVES: To evaluate physicians' knowledge of therapy compliance, their attitudes towards it and their training needs in this field. DESIGN: Transversal, descriptive study using a questionnaire. SETTING: Primary care centres in Spain. PARTICIPANTS: Three thousand and thirty-four general practitioners. MAIN MEASUREMENTS: Definition of non-compliance, non-compliance in their own consultations and in the rest of Spain, methods of measurement, causes, association with therapy failure, efficacy and use of compliance-enhancing strategies, and need for training. RESULTS: Most participants (92%; 95% CI, 91.1 92.9) defined non-compliance as patients' failure to take 5%-20% of their pills. A total of 32.4% (95% CI, 30.9%-33.9%) of the physicians estimated that less than 10% of their patients were non-compliers, whereas 6.8% (95% CI, 6.0-7.6) thought this was also the rate in the rest of Spain. The preferred methods of measurement were patient response (77.0%; 75.7-78.4) and their own clinical experience (76.0%; 74.6-77.4). About half (50.7%) believed that lack of compliance was associated with therapy failure in more than 50% of cases. The presence of adverse side-effects was considered a very important cause of poor compliance by 81.9%. The most common and effective strategies were: use of single-dose drugs (84.3%; 83.1-85.5) and nursing support (84.9%; 83.8-86.0). Moreover, 65.2% (63.7 66.7) of the surveyed physicians had not received any education about compliance as medical students and 42% (40.4-43.6) said further training in compliance was needed. CONCLUSIONS: A high percentage of physicians define compliance incorrectly and believe that other doctors have more non-complying patients than they do. They tend to favour non-validated measuring methods and they lack training. PMID- 17692230 TI - [Job stress and quality of life of primary care health-workers: evidence of validity of the PECVEC questionnaire]. AB - OBJECTIVES: To evaluate the relationship between Health-Related Quality of Life (HRQL) and stress at work among Primary Care workers, as evidence of the construct validity of the Spanish version (PECVEC) of the profile of quality of life in the chronically ill (PLC) questionnaire. In addition, to check its other psychometric properties. DESIGN: Cross-sectional study. SETTING: Eighteen primary care centres in Health Area IV, Asturias (Oviedo), Spain, sharing similar socio demographic conditions. PARTICIPANTS: Two hundred and thirty-three primary care nurses and physicians. MAIN MEASUREMENTS: HRQL was evaluated by the 6 general dimensions of the Spanish version of the PLC. Stress at work was evaluated by the three scales of the Effort-Reward Imbalance (ERI) questionnaire. RESULTS: The construct validity of the PECVEC was assessed by testing the inverse associations of QoL dimensions and job stress ones, when the most important confuser variables were monitored. The non-response rate was low (<3%), and no floor effects and only small ceiling effects were observed. Internal consistency analysis and exploratory and confirmatory factor analysis demonstrated high reliability, factorial validity and convergent/divergent validity of the PECVEC. CONCLUSIONS: The PECVEC demonstrates adequate psychometric properties for evaluating HRQL in healthy subjects. PMID- 17692231 TI - [The illnesses of artisans]. PMID- 17692232 TI - [The seminar 'Learn to look again to transform: direct observation'. Contributions to family doctor training]. PMID- 17692233 TI - [Family medicine in Uruguay: towards a new model of care]. PMID- 17692234 TI - [General practitioners as a "risk factor" for Fournier's gangrene]. PMID- 17692235 TI - [Predictors of alcohol consumption in adolescents and young people with type-1 diabetes]. PMID- 17692236 TI - [Review of pharmacological treatment of the menopause]. PMID- 17692237 TI - [Eye screening service in primary care at Osona (Barcelona). Results (2002-05)]. PMID- 17692239 TI - [The bio-psychosocial model, from theory to practice]. PMID- 17692240 TI - [Oral anti-coagulation as a primary care service. A necessity that cannot be postponed]. PMID- 17692241 TI - [Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) annual campaign for 2007: the year for smoking prevention and control]. PMID- 17692242 TI - [Changes in the prevalence of asthma in the Spanish cohort of the European Community Respiratory Health Survey (ECRHS-II)]. AB - OBJECTIVE: The rise in the prevalence of asthma in the second half of the 20th century has not been evenly distributed according to recent surveys. We assessed changes in the prevalence of asthma after a period of 9 to 10 years in a cohort of young adults in the Spanish arm of the European Community Respiratory Health Survey (ECRHS). MATERIAL AND METHODS: The ECRHS-II is a multicenter cohort study taking place in 27 centers around Europe, with Spanish centers located in Albacete, Barcelona, Galdakao, Huelva, and Oviedo. The ECRHS questionnaire was administered to individuals who had participated in the first phase of the survey; spirometry and methacholine challenge tests were also performed according to the published protocol. RESULTS: Among new smokers, the prevalence of wheezing in the last 12 months increased from 10% to 33%, while the frequency of phlegm production rose from 8% to 22% (P< .05). In ex-smokers, the prevalences of wheezing and phlegm production decreased from 21% to 12% and from 15% to 8%, respectively (P< .05). Symptom prevalences remained similar for never smokers, although the frequency of diagnosed asthma rose from 4% to 7% (P< .05). After adjusting for smoking, age, sex, and center, we found no significant differences in the frequency of symptoms or asthma, even when the phrase bronchial hyperreactivity was included in the definition. However, the rate of reported asthma rose annually by 0.34% (95% confidence interval [CI], 0.20%-0.48%), while diagnosed asthma rose by 0.26% (95% CI, 0.13%-0.39%) and treated asthma by 0.16% (95% CI, 0.07%-0.25%). CONCLUSIONS: Increased prevalence rates of asthma diagnosis and treatment have been detected, but the rates of reported symptoms have remained similar, consistent with the assumption that more persons are being classified as asthmatics. PMID- 17692243 TI - [Comparison of 2 methods for inspiratory muscle training in patients with chronic obstructive pulmonary disease]. AB - OBJECTIVE: The aim of this study was to compare the use of threshold and resistive load devices for inspiratory muscle training in patients with chronic obstructive pulmonary disease (COPD). A randomized prospective trial was designed to compare use of the 2 devices under training or control conditions. PATIENTS AND METHODS: Thirty-three patients with moderate or severe COPD were randomly assigned to home treatment with a threshold device, a resistive load device, or a control situation in which either of those devices was maintained at a minimum load throughout the study. Training was performed daily in 2 sessions of 15 minutes each for 6 weeks. In the patients who underwent training with threshold (n=12) and resistive load (n=11) devices, the loads used were adjusted weekly until the maximum tolerated load was reached to ensure that the interventions were as equivalent as possible. Respiratory function, respiratory muscle function, and quality of life were assessed before and after training and the different inspiratory pressure profiles were compared between training groups. RESULTS: Both peak inspiratory pressure and scores on the Chronic Respiratory Questionnaire (CRQ) improved in the groups that received inspiratory muscle training compared with control subjects: maximal static inspiratory pressure increased from 86 cmH2O to 104.25 cmH2O (P< .01) in the threshold device group and from 91.36 cm H2O to 105.7 cmH2O (P< .01) in the resistive load device group. The resistive load group showed the largest increase in CRQ quality-of-life scores. Differences between the dyspnea score on the CRQ at the beginning and end of the training period were as follows: 3 points in the resistive load group, 2.58 in the threshold group, and 2.5 in the control group. Significant differences in duty cycle measured during training sessions were observed between groups at the end of training (0.31 in the threshold group and 0.557 in the resistive load group), but the mean pressure-time index was similar (0.11) in both groups because of the greater peak and mean inspiratory pressures in the threshold device group. CONCLUSIONS: Load readjustment allowed equivalent training intensities to be achieved with different inspiratory pressure profiles. Our study demonstrated the effectiveness of inspiratory muscle training without control of breathing pattern but showed no superiority of one training method over another. PMID- 17692244 TI - [Appropriateness of hospital stays in a pulmonology department]. AB - OBJECTIVE: To analyze the number of inappropriate stays generated by patients admitted through a pulmonology department over a 1-year period and to identify the causes and predictors of those stays. PATIENTS AND METHODS: A representative sample of hospital stays corresponding to patients admitted by the pulmonology department at Hospital de Valme, Seville, Spain, in 2004 was analyzed retrospectively using the Appropriateness Evaluation Protocol. The review was conducted by 2 physicians who did not belong to the pulmonology department. Multiple linear regression analysis was performed to identify predictors of inappropriate stay. RESULTS: Of the 1166 stays analyzed, 1038 (89%) were judged to be appropriate and 128 (11%) inappropriate. The most common reason for inappropriate stay was the delay in performing diagnostic tests and receiving results (64%). The main justification for appropriate stay was the need for respiratory treatment (59.6%) and parenteral treatment (46.1%). The predictive model generated by multiple linear regression analysis identified the following predictors of inappropriate stay: stay on a ward other than the pulmonology ward, diagnosis on admission, and season of the year. CONCLUSIONS: The rate of inappropriate stay was low in comparison with other studies. The majority of inappropriate stays were attributed to delays in performing diagnostic tests and receiving results. Diagnosis on admission, season of the year, and stay on a ward other than the pulmonology ward were the strongest predictors of inappropriate stay. PMID- 17692245 TI - [Risk factors for mortality in chronic obstructive pulmonary disease]. AB - OBJECTIVE: Although the factors predictive of survival in patients with chronic obstructive pulmonary disease (COPD) have been widely studied, full consensus has yet to be reached. The objective of this study was to further clarify how lung function parameters, exercise tolerance, and quality of life influence survival in patients with COPD. PATIENTS AND METHODS: This prospective study included 60 patients diagnosed with COPD. At the start of the study, patients underwent respiratory function tests, exercise testing, and 6-minute walk test. They also answered a chronic respiratory disease questionnaire to measure health-related quality of life. Follow-up lasted 7 years. RESULTS: Five of the 60 patients withdrew from the study. Twenty-six of the remaining 55 patients (47%) died during the study. Univariate Cox regression analysis showed a correlation between survival and age, degree of obstruction, inspiratory capacity, carbon monoxide diffusing capacity, and peak exercise tolerance. No correlation was found between survival and body mass index, PaO2, PaCO2, total lung capacity, residual volume, maximal respiratory pressures, 6-minute walk distance, or health-related quality of life. Age, degree of obstruction (measured as the ratio of forced expiratory volume in 1 second to forced vital capacity after administration of bronchodilator), and maximum minute ventilation in the exercise test were introduced initially in the multivariate Cox stepwise regression analysis, but only maximum minute ventilation remained in the final model (relative risk, 0.926; P< .001). CONCLUSIONS: Our findings show that peak exercise tolerance is the best predictor of survival in patients with COPD. PMID- 17692246 TI - [Will we still have antibiotics tomorrow?]. AB - Since the discovery of antibiotics, it has been generally believed that these antimicrobials are capable of curing almost all bacterial infections. More recently, the appearance of increasing resistance to antibiotics and the emergence of multiresistant microorganisms have given rise to growing concern among physicians, and that concern has now started to filter through to society in general. The problem is further aggravated by a situation that not many people are currently aware of, that is, the limited prospects for future development of new antibiotics in the short to medium term. Appropriate use of available antibiotics based on a thorough understanding of their in vivo activity and the emergence of new forms of administration, such as inhalers, may help to alleviate the problem. PMID- 17692247 TI - [Preliminary experience with the use of electromagnetic navigation for the diagnosis of peripheral pulmonary nodules and enlarged mediastinal lymph nodes]. AB - Electromagnetic navigation is a new technique that can be used with bronchoscopy to obtain samples of small peripheral nodular lesions and enlarged mediastinal lymph nodes. It is very versatile in that it enables both transbronchial biopsies and fine-needle aspiration to be performed. We describe 2 cases in which navigation with the superDimension/Bronchus system combined with traditional diagnostic techniques facilitated a definitive diagnosis by bronchoscopy. Electromagnetic navigation can obviate the need for more invasive diagnostic procedures such as surgery, thus saving time and money and avoiding complications. PMID- 17692248 TI - [Idiopathic bronchiolocentric interstitial pneumonia: a new idiopathic interstitial pneumonia]. AB - Idiopathic interstitial pneumonias represent a diverse group of lung diseases with diffuse effects on the lung parenchyma. In 2002, the American Thoracic Society/European Respiratory Society consensus classification unified the descriptions of the different entities encompassed by idiopathic interstitial pneumonias. Despite this broad consensus there are still some entities without a clear definition and others, such as idiopathic bronchiolocentric interstitial pneumonia, that were only later described. We present the case and outcome of a woman diagnosed with idiopathic bronchiolocentric interstitial pneumonia by lung biopsy. PMID- 17692249 TI - [Treatment of central sleep apnea syndrome of multifactorial origin by home ventilatory support]. AB - We report the case of a patient with chronic renal failure and primary hyperparathyroidism who developed nonhypercapnic central sleep apnea syndrome (CSAS), which was multifactorial in origin and attributed to metabolic factors. Given an inadequate response to oxygen therapy and continuous positive airway pressure (CPAP) revealed by several polygraph studies, the patient was treated with bilevel positive airway pressure ventilatory support. Three months after treatment commenced, a parathyroidectomy was performed and hemodialysis was initiated. At this point it was observed that the patient no longer experienced somnolence; moreover, polysomnography revealed partial improvement in the CSAS and normalization of ventilatory patterns on application of nasal CPAP at 7 cm H2O. We discuss the pathogenesis of CSAS associated with chronic kidney failure along with the treatment options and conclude that treatment should be customized due to the lack of predictability of patient response. PMID- 17692250 TI - [Primary lung carcinoma with intestinal metastases: 3 cases in a series of 420 patients]. PMID- 17692251 TI - [Good wine needs no bush: quality spirometry in a primary care setting is possible]. PMID- 17692252 TI - [Airway calcium deposition and broncholithiasis in disorders of mucociliary clearance]. PMID- 17692253 TI - [Exposure to environmental tobacco smoke in childhood]. PMID- 17692254 TI - [Prevalence of resistance to antiretroviral drugs in Spain]. AB - INTRODUCTION: The development of resistance to antiretroviral therapy (ART) reduces the effectiveness of these drugs in HIV-infected children. METHODS: We performed a cross-sectional study in 86 vertically HIV-infected children, divided into four groups according to prior treatment: group 1: nucleoside reverse transcriptase inhibitor (NRTI), group 2: NRTI and non-nucleoside reverse transcriptase inhibitor (NNRTI), group 3: NRTI and protease inhibitor (PI), group 4: NRTI, NNRTI and PI. RESULTS: In group 1 (11 children), the median treatment duration was 35 months (26 to 108). Nucleoside-associated mutations (NAMs) were found in 10 of these patients and the Q151M multiresistance mutation was found in two. The three children in group 2 were treated for 9, 32 and 42 months with NRTI and NNRTI. One child showed three NAMs and another showed Q151M. Two children had the K103N mutation. Group 3 (36 children) received treatment with NRTI and PI for 48.0 +/- 27.6 and 23.0 +/- 14.6 months, respectively. NAMs were observed in 94 % of the patients in this group, and one child showed the Q151M mutation. In group 4 (36 children) total treatment duration was 70.0 +/- 36.1 months (13.0 +/- 12.1 months with NNRTI, and 39.0 +/- 14.3 months with PI). NAMs were observed in all patients in this group, and Q151M was found in three children. K103N and Y181C were detected in 24 (67%) and 10 (28%) of the children respectively, while 32 (90%) showed primary mutations to PI. CONCLUSIONS: A high prevalence of resistance mutations to NRTI and early appearance of resistance to NNRTI were observed in treated children. PMID- 17692255 TI - [Why are HIV-infected infants still being born in Spain?]. AB - INTRODUCTION: Despite the success of preventive measures against mother-to-child transmission (MTCT) of human immunodeficiency virus-1 and -2 (HIV-1 and -2) in developed countries, HIV-infected infants continue to be born. The aim of this study was to evaluate failures in the prevention of MTCT and the clinical characteristics of infected infants. METHODS: The Foundation for the Investigation and Prevention of AIDS in Spain (FIPSE) Cohort in Madrid prospectively follows up children at risk of MTCT HIV born in eight public hospitals in Madrid. From May 2000 to December 2005, 632 children born to HIV infected mothers were evaluated. Data from pregnancy follow-up, antiretroviral therapy (ART), and symptoms at diagnosis in infected infants were analyzed. RESULTS: Nine infants were infected. The rate of vertical transmission was 1.42 (95% CI 0.7-2.68). Of the nine mothers, seven had not received ART during pregnancy (and five had not received ART at delivery). Of the mothers who received ART, one had only done so for the last month of pregnancy. Two infants were given three drugs as prevention of MTCT, one received bitherapy and six received monotherapy. The median age at diagnosis was 2.4 months (range 7 days-2 years). The mean plasma viral load at diagnosis was 276,000 copies/ml (range: 11,900-1,000,000). Five of the infants were symptomatic at diagnosis (P. jirovaci pneumonia in two, sepsis in one, recurrent bacterial infections in one, hepatosplenomegaly in one). Four of the nine infants had been admitted to hospital prior to HIV diagnosis. DISCUSSION: Missed opportunities for the prevention of MTCT were identified in eight of the nine HIV-infected infants (89%). Administration of AZT during labor in HIV-infected mothers and triple therapy for the prevention of MTCT in high risk infants is not universal. Hospital admission in young infants at risk might lead to suspicion of infection in infants born to HIV-infected mothers. Improved implementation of all the preventive measures for MTCT should be encouraged. PMID- 17692256 TI - [Severe bronchiolitis. Epidemiology and clinical course of 284 patients]. AB - INTRODUCTION: Bronchiolitis is the leading cause of hospital admission and a frequent cause of pediatric intensive care unit (PICU) admission among infants during the winter months. The objective of this study was to analyze the characteristics and clinical course of patients admitted to the PICU for bronchiolitis. PATIENTS AND METHOD: We performed a descriptive, observational study by clinical chart review of all patients admitted to the PICU for severe bronchiolitis from November 1994 to March 2006. RESULTS: A total of 284 patients were included. Most were admitted during December and January and 74% had respiratory syncytial virus (RSV) infection. At least one risk factor for severe disease was present in 68% of the patients: the most frequent risk factor was age < 6 weeks (45%), followed by prematurity (30%). Mechanical ventilation was required in 64 of the 284 patients (24%). Mortality was 1.8% and was associated with chronic pre-existing illness (p < 0.001). The factors associated with a greater risk of mechanical ventilation and a longer PICU stay were the association of two or more risk factors (42/284; 15%), the presence of apnea (73/284; 25.7%), and images of pulmonary consolidation or atelectasis on admission chest X-ray (157/284; 55%). CONCLUSIONS: Most patients admitted for severe bronchiolitis to the PICU are healthy infants whose principal risk factor is young age. The main predictors of severe clinical course during PICU stay are the association of two or more risk factors, the presence of apnea, and pulmonary consolidation on admission chest X-ray. Bronchiolitis-associated mortality is low and is associated with pre-existing chronic illness. PMID- 17692257 TI - [Prenatal detection of primary non-refluxing megaureter. Review of our casuistics]. AB - BACKGROUND: Most primary non-refluxing megaureters resolve spontaneously and the indications for surgery are not sufficiently well established. OBJECTIVES: To analyze the clinical features, treatment and outcome of asymptomatic primary non refluxing megaureter. PATIENTS AND METHODS: We retrospectively studied 58 infants with primary non-refluxing megaureter. The diagnostic methods used were renal ultrasound, renal isotopic renogram, DMSA scan, and evaluation of renal function. RESULTS: The mean age at postnatal diagnosis was 24 days. The mean follow-up was 4 years. Sixty-nine percent of the patients were male. Fifty-seven percent were left megaureters and 22% were bilateral (71 affected renal units). Eleven percent of megaureters were grade I, 48% were grade II, and 41% were grade III. Only nine patients (15%) received surgical treatment. The indications for surgical treatment were severe megaureter (3/9 patients; 33%), prolonged T1/2 (3/9 patients; 33%), reduced function (1/9 patients; 11%), prolonged T1/2 plus reduced function (1/9 patients; 11%) and increased dilation (1/9 patients; 11%). The mean age at surgery was 7 months. Outcomes in the non-surgical group (85% of the patients; 60 renal units) were as follows: 90% of megaureters were corrected or improved on ultrasound scan and 10% showed no change. In the first renogram, function was low in 4/60 kidneys (7%) and T1/2 was prolonged in 3/60 (5%). Finally, all kidneys in the non-surgical group had normal function, except one, which was injured from the beginning. T1/2 was normal in all kidneys. Outcomes in the surgical group (10 megaureters) were as follows: 80% of megaureters were corrected or improved after surgical intervention and 20% showed no change. At diagnosis, 4/10 kidneys (40%) had reduced function. In the post-surgical renogram 2/10 kidneys (20%) continued to show reduced function, 1/10 kidney (10%) showed restored renal function, and 1/10 kidney (10%) was nephrectomized. Initial T1/2 was prolonged in 4/10 patients (40%), and after surgery T1/2 was normal in all patients. The final DMSA scan showed 5/71 kidneys (7%) with irreversible damage (one slightly injured, two moderately injured, and three severely injured). The remaining 66 kidneys were normal. Overall renal function and blood pressure were normal in all patients. CONCLUSIONS: Primary non-refluxing megaureter is usually a functional and benign congenital malformation that resolves during the first months of life. Although the malformation can persist, only a few patients require surgical treatment. Most authors agree that initial treatment should not be surgical and that surgery should be reserved for patients who develop ureteral dilation, a decrease in differential renal function, and/or severe symptoms during follow-up. In a few patients (7% of our series), the renal unit belonging to the megaureter shows irreversible congenital injury. In these patients, surgery is not useful. PMID- 17692258 TI - [Supraventricular tachycardia in infants and children]. AB - INTRODUCTION: Supraventricular tachycardia (SVT) is the second most frequent form of arrhythmia in pediatrics after extrasystole. OBJECTIVES: 1. To determine the clinical characteristics and treatment of SVT in infants and children. 2. To determine treatment response and the drugs used. METHOD: A retrospective review of 61 cases of SVT requiring PICU admission (1999-2004) was performed. PICU admission was due to persistent SVT after vagal maneuvers. RESULTS: There were 61 patients and 39 were boys (63.9%). The mean age was 2.1 years (SD +/- 3.1). Twelve patients had congenital heart disease (19.7%); three (4.9%) were admitted after heart surgery, and the remaining patients had no antecedents (60.7%). The mean cardiac frequency was 238 beats/min (SD +/- 42.86). Heart failure (HF) was observed in 14 patients (23%). Statistically significant differences were found between the presence of HF and time since onset (p < 0.01) and younger age (p < 0.01). The most frequent diagnosis was SVT due to re-entry in 28 patients (45.9%). Medical treatment was required in 46 patients (75.4%) and response was achieved in 35 (57.4%). At crisis the first drug used was adenosine triphosphate (ATP) in 35 patients (61.4%) with good response in 21 (36.8%). As maintenance therapy digoxin was used in 29 patients (50.9%) without relapses in 22 (78.6%). Radiofrequency ablation was required in 17 patients (27.9%), and there were three relapses (17.6%). The ages of patients who underwent ablation ranged from 3.5 days to 13 years. CONCLUSIONS: 1. HF was observed mainly in infants. 2. Most of the patients had good response to ATP therapy. 3. Radiofrequency ablation was mainly required in patients aged more than 1 year. PMID- 17692259 TI - [Variability in antibiotic prescription in the pediatric population of Castile and Leon (Spain) from 2001 to 2005 in relation to urban or rural setting]. AB - OBJECTIVES: To compare systemic antibiotic prescribing in the pediatric population of Castile and Leon in relation to urban or rural setting. MATERIAL AND METHODS: Data on non-hospital antibiotic consumption in the pediatric population were gathered from the database that processes the antibiotics billed in the Health Service of Castile and Leon. These data were analyzed according to the Anatomical Therapeutic Chemical Classification System (ATC) and the results were expressed as defined daily doses per 1000 inhabitants per day (DID). RESULTS: Overall antibiotic consumption in the pediatric population was markedly higher in the rural setting (24.37 DID in rural areas vs. 19.54 DID in urban areas). Interannual variability was similar in both settings, with prescriptions reaching a peak in 2003. In the qualitative analysis, prescription of amoxicillin and, to a lesser extent, of cefixime and azithromycin was higher in rural areas. Differences in prescription in the urban and rural areas of the distinct health areas varied, the greatest differences being found in Segovia. CONCLUSIONS: Wide quantitative and qualitative variability in antibiotic use was found between the various urban and rural zones of basic health areas. Although we suspected that the results for the urban setting would be underestimated due to the excessive use of emergency services, more detailed studies are required to better understand the determinants of antibiotic use in children. PMID- 17692260 TI - [Residents in pediatrics in primary care centers: 5 years of compulsory rotation in Health Area 11 of Madrid]. AB - INTRODUCTION: Currently, primary care center rotation is not compulsory for residents in pediatrics. The aim of this study was to describe the experience of tutors and residents during primary care rotation, which has been compulsory for residents in the Hospital 12 Octubre in Madrid for the last 5 years. METHODS: We performed an observational, descriptive, cross-sectional study through a survey carried out in June 2005 of 12 accredited tutors and 38 residents. RESULTS: Sixty eight percent of the residents did not know how primary care centers worked. Eighty-four percent of the residents considered that the first year of residence was the best year for rotation in primary care, 64% would choose the center according to the tutor, and 97% highlighted the teaching of the tutors. Tutors and residents believed that the length of the rotation (1.5 months) was short. All tutors and residents thought that the main objectives were achieved and recognized the importance of the rotation. Tutors found teaching gratifying and all agreed that their work should be compensated by professional recognition or greater access to training. Coordination with the hospital's pediatric teaching board should be improved. CONCLUSIONS: Compulsory rotation in primary care is feasible and is a positive component of pediatrics training. Residents and tutors considered this experience to be satisfactory and well adapted to the established objectives. The position of teaching coordinator should be created in primary care, the length of rotations prolonged and tutors' work should be compensated. PMID- 17692261 TI - [11beta-hydroxylase deficiency: improvement of final height with growth hormone and gonadotropin-releasing hormone analog]. AB - Steroid 11beta-hydroxylase deficiency is the second most common cause of congenital adrenal hyperplasia. 11beta-hydroxylase intervenes in cortisol synthesis and its deficiency leads to accumulation of adrenal androgens- producing prenatal virilization and, subsequently, hyperandrogenism--as well as 11-deoxycorticosterone, leading to the development of hypertension. We describe a 7-year-old girl who was referred for pubarche and accelerated skeletal maturation due to 11beta-hydroxylase deficiency. Because the patient's predicted height was below her target height, the combination of gonadotropin-releasing hormone analog and growth hormone was added to oral glucocorticoid therapy. With this therapeutic strategy, the patient's predicted height improved significantly and the girl reached a final height in agreement with her target height at the age of 13 years and 6 months. PMID- 17692262 TI - [Hepatomegaly due to glycogen storage disease and type 1 diabetes mellitus]. AB - Patients with type 1 diabetes and poor metabolic control can develop hepatomegaly due to intrahepatic glycogen deposition. If these patients also have elevated liver enzymes, dyslipidemia, cushingoid features and delayed growth or sexual maturation, Mauriac syndrome can be diagnosed. This disorder is common and reversible with optimization of insulin therapy. We report three adolescents with type 1 diabetes and a long-standing history of poor glycemic control, who developed hepatomegaly, elevated liver enzymes and dyslipidemia with preserved liver function. One of these patients also had delayed growth and another had hypogonadotropic hypogonadism. Liver ultrasound showed changes suggestive of glycogenosis. In all three patients, optimization of insulin therapy achieved good glycemic control and reversed the manifestations within 2 weeks. The etiology of Mauriac syndrome is controversial since both prolonged hyperglycemia and hyperinsulinization produce glycogen accumulation in the liver. Hypercortisolism (due to ketosis or hypoglycemia) contributes to glycogen storage and also causes growth and sexual maturation delay. PMID- 17692263 TI - [Association between asthma and viral infections]. AB - Viral respiratory infections are the factor most frequently associated with asthma (independently of phenotype, age, and phase of the natural history of asthma during which the infection occurs) and there is a strong temporal association between viral respiratory infections and acute obstructive/asthmatic episodes. Nevertheless, the role of viral infections in the pathogenesis of asthma remains poorly characterized. The factors that could explain this association are heterogeneous and sometimes contradictory. The four main causative mechanisms implicated in the association between viral respiratory infections and the subsequent development of asthma or wheezing in children are alterations in airway function and size, dysregulation (congenital and acquired) of airway tone, alterations in the immune response to infections, and the genetic variants involved in immune response. These mechanisms should be taken into account in future preventive and therapeutic strategies. PMID- 17692264 TI - [Management of pediatric multiple trauma patients. Perspective of the pediatric intensive care unit]. AB - OBJECTIVE: To study the epidemiology and management of pediatric trauma patients as well as the organizational, human and technical resources dedicated to these children from the perspective of the pediatric intensive care unit (PICU). MATERIAL AND METHODS: A standardized data collection form was sent to 43 PICUs in Spain. Items inquired about the existence of training courses, trauma clinical practice guidelines and trauma registers, and which physician was in charge of trauma patients. Data on casuistics, the age of trauma patients, and the availability of human and technical resources, were also recorded. RESULTS: Twenty-four PICUs completed the questionnaire. The PICU physician was responsible for trauma patient care in 66% of the hospitals. No training courses were available in 59% of the hospitals. No trauma register was available in 62% of the hospitals. Trauma patients represented 11% of PICU admissions, and most patients were aged up to 14 years old. An anesthetist was always at the hospital in 100% of the hospitals. A radiologist and traumatologist were always at the hospital in 91%, a neurosurgeon in 66% and a pediatric surgeon in 50%. The remaining surgical and medical specialties were on call. Continuous intracranial pressure monitoring was available in 87% of the PICUs, jugular venous saturation monitoring in 54% and continuous electroencephalogram and transcranial Doppler ultrasound in 50%. Computed tomography and ultrasound were available at all times in all hospitals. Magnetic nuclear resonance and echocardiography were available at all times in 44% of the hospitals, and arteriography in 42%. CONCLUSION: In Spain, the organization of pediatric trauma management is based on pediatric teams under the supervision of a PICU physician. Some hospitals show a lack of technical and human resources. Therefore, the minimum criteria required to consider a hospital as a pediatric trauma center should be established. Trauma training courses are required. PMID- 17692265 TI - [Cerebral vasculitis associated with ulcerative colitis]. PMID- 17692267 TI - [Recommendations for administration of the influenza vaccine in patients with egg allergy]. PMID- 17692266 TI - [Intrafamilial outbreak of Shigella flexneri gastroenteritis in Madrid]. PMID- 17692268 TI - [Tumor with abscess formation in the left inguinal area]. PMID- 17692269 TI - [Vesicular lesions localized to eyelids]. PMID- 17692270 TI - I still think it was a banana: memorable 'lies' and forgettable 'truths'. AB - Interpersonal influences on cognition can distort memory judgements. Two experiments examined the nature of these 'social' influences, and whether their persistence is independent of their accuracy. Experiment 1 found that a confederate's social proximity, as well as the content and the confidence of their utterances, interactively modulates participants' immediate conformity. Notably, errant confederate statements that 'lied' about encoded material had a particularly strong immediate distorting influence on memory judgements. Experiment 2 revealed that these 'lies' were also memorable, continuing a day later to impair memory accuracy, while accurate confederate statements failed to produce a corresponding and lasting beneficial effect on memory. These findings suggest that an individual's 'informational' social influence can be selectively heightened when they express misinformation to someone who suspects no deceptive intent. The methods newly introduced here thus allow multiple social and cognitive factors impinging on memory accuracy to be manipulated and examined during realistic, precisely controlled dyadic social interactions. PMID- 17692271 TI - Efficacy of valacyclovir vs acyclovir for the prevention of recurrent herpes simplex virus eye disease: a pilot study. AB - PURPOSE: To compare the efficacy of one-year treatment with valacyclovir vs acyclovir in preventing recurrence of the herpes simplex virus (HSV) eye disease. DESIGN: Prospective, randomized, clinical trial pilot study. METHODS: Fifty-two immunocompetent patients with a history of recurrent ocular HSV disease were treated at the Ocular Immunology Service, San Raffaele Hospital, Milan, Italy. Twenty-six patients were randomized to the valacyclovir group (one 500 mg tablet daily), and 26 patients were randomized to the acyclovir group (one 400 mg tablet twice daily). The recurrence rate of ocular HSV disease during 12 months of treatment and drug-related side effects were monitored. RESULTS: Recurrence of any type of ocular HSV disease during the 12-month treatment period was 23.1% in the valacyclovir group, compared with 23.1% in the acyclovir group. No difference between the two groups was observed regarding the nature, frequency, or severity of adverse events. The most frequent adverse events were nausea and headache. CONCLUSIONS: One-year suppression therapy with oral valacyclovir (500 mg tablet daily) was shown to be as effective and as well tolerated as acyclovir (400 mg tablet twice daily) in reducing the rate of recurrent ocular HSV disease. PMID- 17692272 TI - LOC387715/HTRA1 variants in polypoidal choroidal vasculopathy and age-related macular degeneration in a Japanese population. AB - PURPOSE: To investigate whether variants in the LOC387715 locus and the HtrA serine peptidase 1 (HTRA1) gene within the 10q26 locus are associated with polypoidal choroidal vasculopathy (PCV) and wet age-related macular degeneration (AMD) in a Japanese population, and whether genetic diversity exists between PCV and wet AMD in this locus. DESIGN: Cross-sectional study. METHODS: We genotyped 243 Japanese individuals, including 76 PCV cases, 73 wet AMD cases, and 94 controls using two single nucleotide polymorphisms (SNPs) that are located in the LOC387715 locus (rs10490924) or the HTRA1 gene (rs11200638). Genotyping was performed using TaqMan assays (Applied Biosystems, Foster City, California, USA). RESULTS: Two SNPs generated highly significant allelic associations with PCV (rs10490924, P = 5.7 x 10(-6); rs11200638, P = 5.2 x 10(-6)) and AMD (rs10490924, P = 1.4 x 10(-6); rs11200638, P = 3.4 x 10(-7)). The odds ratios and population attributable risks were higher for the AMD cases than for the PCV cases. Homozygotes for the risk allele at rs11200638 had a 6.33-fold increased risk of PCV and a 13.77-fold increased risk of wet AMD when compared with homozygotes for the wild-type allele. There were no significant differences in either allelic or genotypic frequencies between PCV and AMD cases. CONCLUSIONS: The LOC387715/HTRA1 variants are associated with PCV and wet AMD in the Japanese population. The associations are stronger in AMD than in PCV. PCV and AMD share common genetic factors, which suggests that PCV and wet AMD are similar in some pathophysiologic aspects. PMID- 17692273 TI - A gap analysis approach to assess patient persistence with glaucoma medication. AB - PURPOSE: To develop an alternative method for analysis of patient persistence with prescribed medications using the prostaglandin class of intraocular pressure (IOP)-lowering drugs as a model. DESIGN: A retrospective study of prescription refill patterns. METHODS: Patients with a pharmacy claim for a 2.5 ml bottle of latanoprost, travoprost, or bimatoprost between September 1, 2002 and December 31, 2002 were identified from a retail pharmacy database and were followed up for 12 months. Three separate analyses defined gaps in therapy as spans in excess of 45, 60, or 120 days without a refill for the same medication. Patients were categorized by the number of gaps in therapy and the cumulative length of gaps. A Kaplan-Meier analysis was conducted using a 120-day allowable refill period. RESULTS: For refill periods of 45, 60, and 120 days, 10.6%, 28.6%, and 77.5% of patients, respectively, had no gaps in therapy, and 32.6%, 53.4%, and 86.5%, respectively, had 30 days or fewer off therapy annually. According to the 45-day threshold analysis, 50.7% of patients had three or more gaps vs 18.5% in the 60 day analysis and none in the 120-day analysis. The Kaplan-Meier curve shows 88.6% and 76.1% of patients were persistent for 120 days and one year, respectively. CONCLUSIONS: Compared with Kaplan-Meier survival curves, the gap analysis approach may better parallel clinical experience with patient persistence, in which patients stop and restart medications for a variety of reasons over time. This method also may help to identify avenues for investigation of lack of persistency among many patients. PMID- 17692274 TI - Posterior iris fixation of the iris-claw intraocular lens implantation through a scleral tunnel incision. AB - PURPOSE: To evaluate the technique, efficacy, and safety of posterior iris fixation of iris-claw intraocular lens (IOLs) implantation through a scleral tunnel incision for aphakia correction. DESIGN: Noncomparative, interventional case series. METHODS: A secondary posterior iris fixation of the Artisan iris claw IOL (Ophthec BV, Groningen, The Netherlands) was implanted for aphakia correction in the authors' clinical practice. Uncorrected visual acuity, best spectacle-corrected visual acuity (BSCVA), astigmatism, manifest refraction, lens position, pigment dispersion, and intraocular pressure (IOP) were evaluated in 32 consecutive eyes of 32 patients. RESULTS: BSCVA was 20/40 or better in 28 eyes (87.50%) during the mean follow-up time (nine months). Mean postoperative spherical equivalent was -0.70 diopters (D; standard deviation [SD], 0.47 D) at six months after surgery. Mean prediction error was -0.13 D (SD, 0.28 D), and mean absolute prediction error was 0.26 D (SD, 0.15 D). Preoperative mean astigmatism was -1.08 D (SD, 0.55 D; range, 0.0 to -2.0 D). At six months after surgery, mean astigmatism was -2.1 D (SD, 0.81 D; range, -0.75 to -3.75 D). There was no significant postoperative IOP increase. Lens position, evaluated by Oculus Pentacam (Pentacam 70700: Oculus, Wetzlar, Germany) and ultrasound biomicroscopy [UBM] (Ophthalmic Technologies Inc, Toronto, Ontario, Canada), was parallel to the iris plane. CONCLUSIONS: Posterior iris fixation of the iris-claw IOL implantation through a scleral tunnel incision is a safe procedure and an effective option for aphakic eyes without capsule support. PMID- 17692275 TI - Conjunctival epithelial changes induced by cilia in patients with epiblepharon or entropion. AB - PURPOSE: To evaluate the effect of mechanical trauma induced by cilia on the conjunctival epithelium in patients with epiblepharon or entropion and to evaluate changes in epithelium after surgical correction in patients with entropion. DESIGN: Case-control study. METHODS: One hundred and seven eyes of 61 patients were enrolled in this study and were divided into three groups: the epiblepharon group (n = 59), the entropion group (n = 17), and the age-matched control group for the epiblepharon group (n = 31). Impression cytologic specimens were obtained from nasal and temporal bulbar conjunctiva of the epiblepharon and control groups immediately after the induction of general anesthesia. In the entropion group, these were obtained before and one month after surgical correction. Conjunctival changes were graded using the Tseng method and goblet cell densities were compared. RESULTS: Cytologic scores were significantly higher in the epiblepharon group than in the control group (P < .001), and goblet cell densities of nasal and temporal conjunctiva were significantly lower in the epiblepharon group than in the control group (P = .044 and P = .018, respectively). In the entropion group, postoperative scores were significantly lower than preoperative scores in both conjunctival areas (P = .033 and P = .003, respectively). No statistically significant difference was found between nasal and temporal conjunctiva in the three groups. CONCLUSIONS: The persistent mechanical trauma by cilia in patients with epiblepharon or entropion can induce squamous metaplasia of the conjunctival epithelium. However, these conjunctival changes can be reversed by surgical correction. PMID- 17692276 TI - Ocular involvement associated with an epidemic outbreak of chikungunya virus infection. AB - PURPOSE: To study the range of ocular symptoms in a cohort of patients with chikungunya infection. DESIGN: Retrospective, observational case series. METHODS: Patients attending a tertiary eye care hospital in South India were included in the study. We included adult patients with serologically confirmed chikungunya virus infection who received clinical care at the Aravind Eye Hospital, Madurai, South India. They were assessed for demographic characteristics, ocular symptoms, laboratory parameters, and chikungunya virus infection severity. Patients underwent a complete ophthalmologic examination that included visual acuity, slit lamp examination, and indirect funduscopic examination. Visual outcome at the end of three months was the main outcome measure. RESULTS: The charts of 37 patients were analyzed based on the clinical picture and the serologic results. Forty patients were included as controls and tested negative. There were 21 males and 16 females with a mean age of 44.17 years. The main ocular symptoms included granulomatous and nongranulomatous anterior uveitis, optic neuritis retrobulbar neuritis, and dendritic lesions. Of the 26 patients who were followed up for three months, the visual acuity improved in 11 patients (42.3%), remained the same in 12 patients (46.15%), and worsened in three patients (11.5%). CONCLUSIONS: The main ocular manifestation associated with the recent epidemic outbreak of chikungunya virus infection in South India included granulomatous and nongranulomatous anterior uveitis, optic neuritis, retrobulbar neuritis, and dendritic lesions. The visual prognosis generally was good, with most patients recovering good vision. Further studies are needed to understand the pathogenesis of this disease. PMID- 17692277 TI - A multiple reaction monitoring method for absolute quantification of the human liver alcohol dehydrogenase ADH1C1 isoenzyme. AB - Although significant progress has been made in protein quantification using mass spectrometry during recent years, absolute protein quantification in complex biological systems remains a challenging task in proteomics. The use of stable isotope-labeled standard peptide is the most commonly used strategy for absolute quantification, but it might not be suitable in all instances. Here we report an alternative strategy that employs a stable isotope-labeled intact protein as an internal standard to absolutely quantify the alcohol dehydrogenase (ADH) expression level in a human liver sample. In combination with a new targeted proteomics approach employing the method of multiple reaction monitoring (MRM), we precisely and quantitatively measured the absolute protein expression level of an ADH isoenzyme, ADH1C1, in human liver. Isotope-labeled protein standards are predicted to be particularly useful for measurement of highly homologous isoenzymes such as ADHs where multiple signature peptides can be examined by MRM in a single experiment. PMID- 17692278 TI - Metal-enhanced biosensor for genetic mismatch detection. AB - DNA biosensors are increasingly used in hybridization reactions, mutation detection, genomic sequencing, and identification of pathogens. However, the inability to monitor the recognition signals without resorting to the use of labels or electroactive mediators has led to DNA devices with inadequate sensitivity. Moreover, some electroactive species require high redox potentials that often destroy the DNA complementarity. This article presents the concept of metal-enhanced detection (MED) for the determination of DNA-DNA reactions and presents the application of this concept for mismatch detection. The MED concept relies on the idea that metallic films deposited as a continuous layer or monolayer onto a solid electrode, or even electrostatically held, could greatly enhance the rate of electron transfer by reducing the distance between the donor and acceptor species and could lead to label-free assays during DNA hybridization reactions. The MED concept has been tested for voltammetric detection of gene sequence of Microcystis spp. The resulting biosensor involved the immobilization of a 17-mer DNA probe that is complementary to a specific gene sequence of Microcystis spp. on a gold electrode via avidin-biotin chemistry. Electrochemical reduction and oxidation of DNA-captured Ag(+) ions provided the detection signals for the target gene sequence in solution. A linear response of silver cathodic peak current with concentration of the target oligonucleotide sequence was observed with a detection limit of 7 x 10(-9)M. This label-free approach was successfully applied to detecting two-base-pair mismatches in the gene sequence of Microcystis spp. PMID- 17692279 TI - [Willebrand factor deficiency and septorhinoplasty]. AB - INTRODUCTION: Willebrand disease can be diagnosed late, sometimes only when hemorrhage complicates surgery. French guidelines do not recommend investigation before surgery when no personal or familial hemorrhagic diathesis is reported. OBJECTIVE: To consider the advantages of Willebrand factor dosage before septorhinoplasty. METHOD: Three cases of septorhinoplasty and Willebrand factor deficiency complicated with hemorrhage compromising the functional result are reported. The routine tests (platelet count, bleeding time, and activated partial thromboplastin time) and Willebrand factor dosage were done before or after surgery. RESULTS: In the three cases, no personal or familiar hemorrhagic diathesis was found. For two cases, a hemorrhage occurred during surgery. One of them had prolonged and repeated nose bleedings after surgery. In this case, iterative packings damaged the result of surgery and a new rhinoplasty had to be done. In one case, a prolonged activated partial thromboplastin time before surgery revealed a Willebrand factor deficiency, leading to prophylactic treatment (desmopressin) of bleeding. CONCLUSION: The cases described suggest that systematic dosage of Willebrand factor before septorhinoplasty could be advantageous and that functional prognosis can be impaired by uncontrolled epistaxis. PMID- 17692280 TI - Selectivity in ISG15 and ubiquitin recognition by the SARS coronavirus papain like protease. AB - The severe acute respiratory syndrome coronavirus papain-like protease (SARS-CoV PLpro) carries out N-terminal processing of the viral replicase polyprotein, and also exhibits Lys48-linked polyubiquitin chain debranching and ISG15 precursor processing activities in vitro. Here, we used SDS-PAGE and fluorescence-based assays to demonstrate that ISG15 derivatives are the preferred substrates for the deubiquitinating activity of the PLpro. With k(cat)/K(M) of 602,000 M(-1)s(-1), PLpro hydrolyzes ISG15-AMC 30- and 60-fold more efficiently than Ub-AMC and Nedd8 AMC, respectively. Data obtained with truncated ISG15 and hybrid Ub/ISG15 substrates indicate that both the N- and C-terminal Ub-like domains of ISG15 contribute to this preference. The enzyme also displays a preference for debranching Lys48- over Lys63-linked polyubiquitin chains. Our results demonstrate that SARS-CoV PLpro can differentiate between ubiquitin-like modifiers sharing a common C-terminal sequence, and that the debranching activity of the PLpro is linkage type selective. The potential structural basis for the demonstrated specificity of SARS-CoV PLpro is discussed. PMID- 17692281 TI - Differential mitotic activation of endogenous c-Src, c-Yes, and Lyn in HeLa cells. AB - Src-family tyrosine kinases (SFKs) play an important role in mitosis. Despite overlapping expression of multiple SFK members, little is known about how individual SFK members are activated in M phase. Here, we examined mitotic activation of endogenous c-Src, c-Yes, and Lyn, which are co-expressed in HeLa cells. c-Src, c-Yes, and Lyn were activated at different levels in M phase, and the activation was inhibited by Cdc2 inactivation. Mitotic c-Src and c-Yes exhibited normal- and retarded-electrophoretic-mobility forms on SDS polyacrylamide gels, whereas Lyn did not show mobility retardation. Like c-Src, the retardation of electrophoretic mobility of c-Yes was caused by Cdc2-mediated phosphorylation. The normal- and retarded-mobility forms of c-Src were comparably activated, but activation of the retarded-mobility form of c-Yes was higher than that of the normal-mobility form of c-Yes. Thus, these results suggest that endogenous c-Src, c-Yes, and Lyn are differentially activated through Cdc2 activation during M phase. PMID- 17692282 TI - Energy diagrams and mechanism for proton pumping in cytochrome c oxidase. AB - The powerful technique of energy diagrams has been used to analyze the mechanism for proton pumping in cytochrome c oxidase. Energy levels and barriers are derived starting out from recent kinetic experiments for the O to E transition, and are then refined using general criteria and a few additional experimental facts. Both allowed and non-allowed pathways are obtained in this way. A useful requirement is that the forward and backward rate should approach each other for the full membrane gradient. A key finding is that an electron on heme a (or the binuclear center) must have a significant lowering effect on the barrier for proton uptake, in order to prevent backflow from the pump-site to the N-side. While there is no structural gating in the present mechanism, there is thus an electronic gating provided by the electron on heme a. A quantitative analysis of the energy levels in the diagrams, leads to Prop-A of heme a(3) as the most likely position for the pump-site, and the Glu278 region as the place for the transition state for proton uptake. Variations of key redox potentials and pK(a) values during the pumping process are derived for comparison to experiments. PMID- 17692283 TI - Cellular uptake and subcellular distribution of chlorin e6 as functions of pH and interactions with membranes and lipoproteins. AB - The uptake and more importantly the subcellular distribution of photosensitizers are major determinants of their efficacy. In this paper, the cellular internalization of chlorin e6 (Ce6), a photosensitizer bearing three carboxylic chains, is considered with emphasize on pH effects. Small unilamellar vesicles are used as models to investigate the dynamics of interactions of Ce6 with membranes. The entrance and exit steps from the outer lipid hemileaflet are very fast (~ms). A slow transfer of Ce6 through the membrane was observed only for thin bilayers made of dimyristoleoyl-phosphatidylcholine. Ce6 did not permeate through bilayers consisting of longer phospholipids more representative of biological membranes. These results along with previous data on the interactions of Ce6 with low-density lipoproteins (LDL) are correlated with cellular studies. After 15 min incubation of HS68 human fibroblasts with Ce6, fluorescence microscopy revealed labeling of the plasma membrane and cytosolic vesicles different from lysosomes. When vectorized by LDL, Ce6 was mainly localized in lysosomes but absent from the plasma membrane. Internalization of LDL bound photosensitizer via ApoB/E receptor mediated pathway was demonstrated by overexpression experiments. A pH decrease from 7.4 to 6.9 did not affect the intracellular distribution of Ce6, but significantly increased its overall cellular uptake. PMID- 17692284 TI - Responsibility and impulsivity and their interaction in relation to obsessive compulsive symptoms. AB - In the present study, the role of responsibility and impulsivity and their interaction in obsessive-compulsive symptoms was investigated. The obsessive compulsive inventory-revised (OCI-R), an attention deficit and hyperactivity/impulsivity self-report scale (AD/HD-SR), the responsibility attitudes scale (RAS), Eysenck's impulsiveness/venturesomeness/empathy questionnaire (IVE), the community epidemiological survey-depression (CES-D) and the Penn State worry questionnaire (PSWQ) were administered to a sample of 405 Icelandic university students. Responsibility attitudes (RAS) and impulsivity measures were significantly related to scores on the OCI-R total scale, even when depression had been taken into consideration. The interaction between responsibility and hyperactivity/impulsivity added to the prediction of OCI-R scores over and above simple effects. PMID- 17692285 TI - Investigation of the indulgence cycles hypothesis of suppression on experimentally induced visual intrusions in dysphoria. AB - Within the thought control literature, Wegner [(1989). White bears and other unwanted thoughts: Suppression, obsession, and the psychology of mental control. New York, NY, USA: Penguin Press.] referred to the combined initial suppression and expression phases of thought control as an indulgence cycle which results in the rebound effect typically observed in suppression studies. According to Ironic Process Theory [Wegner, (1994). Ironic processes of mental control. Psychological Review, 101, 34-52.], this rebound leads to further attempts to suppress that are difficult due to the target thought's hyperaccessibility, resulting in a secondary rebound effect owing to a positive feedback system of indulgence cycles. The current study investigated (i) the effects of repeated suppression and opportunities for expression by using a method to index the frequency, duration, and associated levels of distress of an experimentally induced visual intrusion, and (ii) whether any observed effects were differentially linked to depressive symptomatology in an analogue sample of low and high dysphoric participants. Results supported a secondary rebound effect in those participants most successful at suppressing target intrusions. The findings offer an important extension to the emerging literature on the management of intrusive memories in depression. PMID- 17692286 TI - Identification and characterization of an Ipomoea nil glucosyltransferase which metabolizes some phytohormones. AB - A glucosyltransferase gene InGTase1 was identified from the immature seeds of morning glory (Ipomoea nil), whose product shows a broad substrate-preference, including that of some phytohormones. When 2-trans-abscisic acid, indole-3-acetic acid, salicylic acid (SA) or (+/-)-jasmonic acid was reacted with InGTase1 and UDP-[(14)C]-glucose, each (14)C-labeled compound with high polarity was detected after thin layer chromatography. SA metabolites were identified as SA glucosyl ester by using (1)H NMR and GC/MS. Detailed substrate-preferences of InGTase1 were examined with some analogous compounds, which elucidated that the arm length and/or orientation of a carboxyl group of the compounds or its surrounding electron density severely affected the enzymatic activity. The broad substrate preference will greatly contribute to the synthesis of various glucoconjugates. PMID- 17692287 TI - Embryonic stem cells ameliorate piroxicam-induced colitis in IL10-/- KO mice. AB - The primary objective of this work is to determine the repairing potential of murine embryonic stem cells (ES) in murine model of Crohn's disease (CD). Colitis, induced in IL10-/- KO mice using piroxicam, was associated with the increased levels of IL-12. Enhanced yellow fluorescent protein (EYFP) marked murine ES cells (R1/129) and control non-fluorescent ES cells were subjected to in vitro differentiation into intestinal epithelial cells. IL 10-/- KO mice were injected with pre-differentiated ES-YFP cells and sacrificed after 2 and 3 months. Histopathological analysis of intestines demonstrated a progressive improvement in colitis (from grade-4 to grade-1 and -0) and decreased levels of IL-12 cytokine following transplantation. Fluorescent and confocal microscopy demonstrated presence of ES-EYFP cells in the colon, small intestine, liver, and thymus tissues but none in the spleen and bone marrow. The EYFP signal was not detected in sham (non-transplanted mice with induced colitis) and control IL10-/- KO mice. Engraftment, detected at 3 months post-transplant, correlated with markedly improved grading in colon histology (grade-1 or -0) and weight gain, as well as with decreased rectal prolapses. In vitro pre-differentiated ES cells migrated and homed exclusively into the colon, small intestine, and the liver, engrafted for long term, reduced inflammation and tissue damage, and restored immune balance. These findings suggest that pre-differentiated ES cells may become alternative source of stem cell therapy for CD with dual functions i.e. regenerating damaged epithelium and restoring immune imbalance occurring in this disease. PMID- 17692288 TI - Inhibition of corneal neovascularization by recombinant adenovirus-mediated sFlk 1 expression. AB - The interaction of vascular endothelial growth factor (VEGF) and its receptors (Flt-1, Flk-1/KDR) is correlated with neovascularization in the eyes. Therefore, blocking the binding of VEGF and the corresponding receptor has become critical for inhibiting corneal neovascularization. In this study, we have expressed the cDNA for sFlk-1 under the control of cytomegalovirus immediate-early promoter (CMV) from an E1/partial E3 deleted replication defective recombinant adenovirus, and Ad.sflk-1 expression was determined by Western blotting. We have shown that conditioned media from Ad.sflk-1-infected ARPE-19 cells significantly reduced VEGF-induced human umbilical vein endothelial cells (HUVEC) and murine endothelial cells (SVEC) proliferation in vitro compared with the control vector. In vivo, adenoviral vectors expressing green fluorescent protein alone (Ad.GFP) were utilized to monitor gene transfer to the cornea. Moreover, in the models of corneal neovascularization, the injection of Ad.sflk-1 (10(8)PFU) into the anterior chamber could significantly inhibit angiogenic changes compared with Ad.null-injected and vehicle-injected models. Immunohistochemical analysis showed that corneal endothelial cells and corneal stroma of cauterized rat eyes were efficiently transduced and expressed sFlk-1. These results not only support that adenoviral vectors are capable of high-level transgene expression but also demonstrate that Ad.sflk-1 gene therapy might be a feasible approach for inhibiting the development of corneal neovascularization. PMID- 17692289 TI - Oligomerization of BH4-truncated Bcl-x(L) in solution. AB - BH4 domain is critical for the anti-apoptotic functions of Bcl-2 and Bcl-x(L) and their binding abilities with other members of the Bcl-2 family. The cleavage of the BH4 domain in Bcl-x(L) and Bcl-2 by caspase 1 or 3 converts the anti apoptotic Bcl-x(L) and Bcl-2 into pro-apoptotic proteins that potently induce apoptosis. Herein, we report that recombinant Bcl-x(L) proteins without N terminal 61 residues, His(6)-NDelta61-Bcl-x(L)-CDelta21 and NDelta61-Bcl-x(L) CDelta21, form oligomers in solution, whereas Bcl-x(L)-CDelta21 exists as a monomer. The oligomerization of the truncated proteins is independent of protein lipid interaction, protein concentration or the ion strength of the solution. Circular dichroism spectrum shows a significant decrease in the content of alpha helices upon deletion of N-terminal residues. NDelta61-Bcl-x(L)-CDelta21 also loses its heterodimerization capability with the BH3 peptide derived from Bak. This newly acquired property might be linked to its ability to induce apoptosis in cells. PMID- 17692290 TI - Autophagic cell death, polyploidy and senescence induced in breast tumor cells by the substituted pyrrole JG-03-14, a novel microtubule poison. AB - JG-03-14, a substituted pyrrole that inhibits microtubule polymerization, was screened against MCF-7 (p53 wild type), MDA-MB231 (p53 mutant), MCF-7/caspase 3 and MCF-7/ADR (multidrug resistant) breast tumor cell lines. Cell viability and growth inhibition were assessed by the crystal violet dye assay. Apoptosis was evaluated by the TUNEL assay, cell cycle distribution by flow cytometry, autophagy by acridine orange staining of vesicle formation, and senescence based on beta-galactosidase staining and cell morphology. Our studies indicate that exposure to JG-03-14, at a concentration of 500 nM, induces time-dependent cell death in the MCF-7 and MDA-MB231 cell lines. In MCF-7 cells, a residual surviving cell population was found to be senescent; in contrast, there was no surviving senescent population in treated MDA-MB231 cells. No proliferative recovery was detected over a period of 15 days post-treatment in either cell line. Both the TUNEL assay and FLOW cytometry indicated a relatively limited degree of apoptosis (<10%) in response to drug treatment in MCF-7 cells with more extensive apoptosis (but <20%) in MDA-MB231 cells; acidic vacuole formation indicative of autophagic cell death was relatively extensive in both MCF-7 and MDA-MB231 cells. In addition, JG-03-14 induced the formation of a large hyperdiploid cell population in MDA-MB231 cells. JG-03-14 also demonstrated pronounced anti-proliferative activity in MCF-7/caspase 3 cells and in the MCF-7/ADR cell line. The observation that JG-03-14 promotes autophagic cell death and also retains activity in tumor cells expressing the multidrug resistance pump indicates that novel microtubule poisons of the substituted pyrroles class may hold promise in the treatment of breast cancer. PMID- 17692291 TI - The non-steroidal anti-inflammatory drug piroxicam blocks ligand binding to the formyl peptide receptor but not the formyl peptide receptor like 1. AB - The anti-inflammatory drug piroxicam has been reported to affect the production of reactive oxygen species in phagocytes. This anti-inflammatory effect is thought to be mediated through inhibition of cyclooxygenase (COX), an enzyme important for prostaglandin synthesis. We have compared the effects of piroxicam on superoxide production mediated by two closely related G-protein coupled receptors expressed on neutrophils, the formyl peptide receptor (FPR) and the formyl peptide receptor like 1 (FPRL1). Neutrophils were stimulated with agonists that bind specifically to FPR (the peptide ligand N-formyl-Met-Leu-Phe, fMLF) or FPRL1 (the peptide ligand Trp-Lys-Tyr-Met-Val-L-Met-NH(2), WKYMVM) or both of these receptors (the peptide ligand Trp-Lys-Tyr-Met-Val-D-Met-NH(2), WKYMVm). Piroxicam reduced the neutrophil superoxide production induced by the FPR agonist but had no significant effect on the FPRL1 induced response. Neutrophil intracellular calcium changes induced by the agonist WKYMVm (that triggers both FPR and FPRL1) were only inhibited by piroxicam when the drug was combined with the FPRL1 specific antagonist, Trp-Arg-Trp-Trp-Trp-Trp (WRW(4)), and this was true also for the inhibition of superoxide anion release. Receptor-binding analysis showed that the fluorescently labelled FPR specific ligand N-formyl-Nle Leu-Phe-Nle-Tyr-Lys (fNLFNYK), was competed for in a dose-dependent manner, by the FPR ligand fMLF and as well as by piroxicam. We show that piroxicam inhibits the neutrophil responses triggered through FPR, but not through FPRL1 and this inhibition is due to a reduced binding of the activating ligand to its cell surface receptor. PMID- 17692292 TI - A longitudinal typology of symptoms of depression and anxiety over the life course. AB - BACKGROUND: Little is known about long-term profiles of depressive and anxious symptomatology over the life course and about the developmental determinants of different trajectories. The objective of this study was to identify a novel typology of symptoms of depression and anxiety over the life course and examine its neurodevelopmental antecedents in an epidemiological sample. METHODS: A longitudinal latent variable analysis was conducted on measures of anxious and depressive symptoms at ages 13, 15, 36, 43, and 53 years among 4627 members of the Medical Research Council National Survey of Health & Development (the British 1946 birth cohort). Early life predictors of class membership were studied with ordinal logistic regression. RESULTS: We identified six distinct profiles up to age 53: absence of symptoms (44.8% of sample); repeated moderate symptoms (33.6%); adult-onset moderate symptoms (11.3%); adolescent symptoms with good adult outcome (5.8%); adult-onset severe symptoms (2.9%); and repeated severe symptoms over the life course (1.7%). Heavier babies had lower likelihood of depressive and anxious symptoms (odds ratio [OR] = .92; 95% confidence interval [CI] .85-.99), whereas delay in first standing (OR = 1.19; 95% CI 1.11-1.28) and walking (OR = 1.22; 95% CI 1.14-1.31) was associated with subsequent higher likelihood of symptoms, controlling for social circumstances and stressful life events during childhood. CONCLUSIONS: There was evidence of distinct profiles of depressive and anxious symptomatology over the life course and associations with markers of neurodevelopment. This suggests very early factors are associated with long-term experience of symptoms of depression and anxiety. PMID- 17692293 TI - A promoter polymorphism in the monoamine oxidase A gene is associated with the pineal MAOA activity in Alzheimer's disease patients. AB - BACKGROUND: Monoamine oxidase A (MAOA) is involved in the pathogenesis of mood disorders and Alzheimer's disease (AD). MAOA activity and gene expression have been found to be up-regulated in different brain areas of AD patients, including the pineal gland. Increased pineal MAOA activity might contribute to the reduced pineal melatonin production in AD. A promoter polymorphism of a variable number tandem repeats (VNTR) in the MAOA gene shows to affect MAOA transcriptional activity in vitro. METHODS: Here we examined in 63 aged controls and 44 AD patients the effects of the MAOA-VNTR on MAOA gene expression and activity in the pineal gland as endophenotypes, and on melatonin production. RESULTS: AD patients carrying long MAOA-VNTR genotype (consisting of 3.5- or 4-repeat alleles) showed higher MAOA gene expression and activity than the short-genotyped (i.e., 3-repeat allele) AD patients. Moreover, the AD-related up-regulation of MAOA showed up only among long-genotype bearing subjects. There was no significant effect of the MAOA-VNTR on MAOA activity or gene expression in controls, or on melatonin production in both controls and AD patients. CONCLUSION: Our data suggest that the MAOA-VNTR affects the activity and gene expression of MAOA in the brain of AD patients, and is involved in the changes of monoamine metabolism. PMID- 17692294 TI - Administration of pigment epithelium-derived factor (PEDF) inhibits cold injury induced brain edema in mice. AB - Brain edema is the most life-threatening complication that occurs as a result of a number of insults to the brain. However, its therapeutic options are insufficiently effective. We have recently found that administration of pigment epithelium-derived factor (PEDF) inhibits retinal hyperpermeability in rats by counteracting biological effects of vascular endothelial growth factor (VEGF). In this study, we investigated whether PEDF could inhibit cold injury-induced brain edema in mice. Cold injury was induced by applying a pre-cooled metal probe on the parietal skull. VEGF and its receptor Flk-1 gene and/or protein expressions were up-regulated in the cold-injured brain. Cold injury induced brain edema, which was reduced by intraperitoneal injection of VEGF antibodies (Abs) or apocynin, an inhibitor of NADPH oxidase. PEDF mRNA and protein levels were up regulated in response to cold injury. PEDF dose-dependently inhibited the brain edema, whose effect was neutralized by simultaneous treatments with anti-PEDF Abs. Although VEGF and Flk-1 gene and/or protein expressions were not suppressed by PEDF, PEDF or anti-VEGF Abs inhibited the cold injury-induced NADPH oxidase activity in the brain. Further, PEDF treatment inhibited activation of Rac-1, an essential component of NADPH oxidase in the cold-injured brain, while it did not affect mRNA levels of gp91phox, p22phox, or Rac-1. These results demonstrate that PEDF could inhibit the cold injury-induced brain edema by blocking the VEGF signaling to hyperpermeability through the suppression of NADPH oxidase via inhibition of Rac-1 activation. Our present study suggests that PEDF may be a novel therapeutic agent for the treatment of brain edema. PMID- 17692295 TI - Locomotory patterns, spatiotemporal organization of exploration and spatial memory in serotonin transporter knockout mice. AB - Serotonin transporter knockout (SERT-/-) mice are extensively used as a genetic model of several neuropsychiatric disorders, and consistently display anxiety like behaviors and inactivity in different tests. To better understand how these mice organize their behavior, we assessed the open field and elevated plus maze spatiotemporal patterning of activity in adult male SERT wild type (+/+), heterozygous (+/-) and -/- mice on C57BL/6J genetic background using new videotracking and analytic procedures. In addition, we analyzed their spatial memory, assessing within- and between-trial habituation, and examined specific motor characteristics of their movement in these two tests. In the open field test, SERT-/- mice showed reduced vertical exploration throughout the arena, reduced central (but not peripheral) horizontal exploration, unaltered within trial habituation, and slightly poorer between-trial habituation for horizontal activity. In the elevated plus maze, SERT-/- mice demonstrated anxiety-like avoidance of open arms, hypoactivity, as well as unaltered within-trial and between-trial habituation (except for poorer between-trial habituation of total horizontal activity). In both tests, SERT-/- mice showed greater prevalence of horizontal over vertical dimension of their exploration in the areas protected by the walls (open field periphery, plus maze closed arms), but not in open aversive areas, such as the center of the open field or center or open arms of the maze. In both arenas, SERT-/- mice consistently displayed increased turning behavior, potentially representing a perseverance-like phenotype or aberrant spatial strategies in novel environments. Overall, using a fine-graded behavioral analysis in two different novelty tests, this study revealed alterations in motor and spatiotemporal patterning of activity in SERT-/- mice. Given the relevance of exploratory strategies to human personality traits and brain disorders, our data may be useful for developing further neurobehavioral models using these mice. PMID- 17692296 TI - Naloxone rapidly evokes endogenous kappa opioid receptor-mediated hyperalgesia in naive mice pretreated briefly with GM1 ganglioside or in chronic morphine dependent mice. AB - Low-dose naloxone-precipitated withdrawal hyperalgesia is a reliable indicator of physical dependence after chronic morphine treatment. A remarkably similar long lasting (>3-4 h) hyperalgesia is evoked by injection of a low dose of naloxone (10 microg/kg, s.c.) in naive mice after acute pretreatment with the glycolipid, GM1 ganglioside (1 mg/kg) (measured by warm-water-immersion tail-flick assays). GM1 treatment markedly increases the efficacy of excitatory Gs-coupled opioid receptor signaling in nociceptive neurons. Co-treatment with an ultra-low-dose (0.1 ng/kg, s.c.) of the broad-spectrum opioid receptor antagonist, naltrexone or the selective kappa opioid receptor antagonist, nor-binaltorphimine, blocks naloxone-evoked hyperalgesia in GM1-pretreated naive mice and unmasks prominent, long-lasting (>4 h) inhibitory opioid receptor-mediated analgesia. This unmasked analgesia can be rapidly blocked by injection after 1-2 h of a high dose of naltrexone (10 mg/kg) or nor-binaltorphimine (0.1 mg/kg). Because no exogenous opioid is administered to GM1-treated mice, we suggest that naloxone may evoke hyperalgesia by inducing release of endogenous bimodally acting opioid agonists from neurons in nociceptive networks by antagonizing putative presynaptic inhibitory opioid autoreceptors that "gate" the release of endogenous opioids. In the absence of exogenous opioids, the specific pharmacological manipulations utilized in our tail-flick assays on GM1-treated mice provide a novel bioassay to detect the release of endogenous bimodally acting (excitatory/inhibitory) opioid agonists. Because mu excitatory opioid receptor signaling is blocked by ultra-low doses of naloxone, the higher doses of naloxone that evoke hyperalgesia in GM1 treated mice cannot be mediated by activation of mu opioid receptors. Co treatment with ultra-low-dose naltrexone or nor-binaltorphimine may selectively block signaling by endogenous GM1-sensitized excitatory kappa opioid receptors, unmasking inhibitory kappa opioid receptor signaling, and converting endogenous opioid receptor-mediated hyperalgesia to analgesia. Co-treatment with kelatorphan stabilizes putative endogenous opioid peptide agonists released by naloxone in GM1-treated mice, so that analgesia is evoked rather than hyperalgesia. Acute treatment of chronic morphine-dependent mice with ultra-low-dose naltrexone (0.1 ng/kg) results in remarkably similar rapid blocking of naloxone (10 microg/kg) precipitated withdrawal hyperalgesia and unmasking of prominent opioid analgesia. These studies may clarify complex mechanisms underlying opioid physical dependence and opioid addiction. PMID- 17692297 TI - Aspartyl, arginyl and alanyl aminopeptidase activities in the hippocampus and hypothalamus of streptozotocin-induced diabetic rats. AB - Acid (aspartyl), basic (arginyl) and neutral (alanyl) aminopeptidases degrade angiotensins, vasopressin, oxytocin, bradykinin and enkephalins. These peptides regulate memory, energy homeostasis, water-salt balance and blood pressure, functions that are mainly exerted in the hippocampus and hypothalamus, and that can be affected by diabetes mellitus. To evaluate the relationship between the diabetes mellitus and processing and inactivation roles of these representative aminopeptidases, we measured their activities in both brain structures of control and streptozotocin-diabetic rats. Hypothalamic soluble aspartyl and arginyl aminopeptidases presented significant decreased activity levels in diabetic rats, which were mitigated by insulin therapy. In addition to membrane-bound puromycin sensitive and insensitive alanyl aminopeptidases, its soluble puromycin sensitive form did not differ between diabetic and control rats in both brain structures. Glucose and/or insulin did not seem to alter in vitro the hypothalamic activities of soluble aspartyl and arginyl aminopeptidases. The implied hypothalamic control of regulatory peptide activity by aspartyl and arginyl aminopeptidases supports the hypothesis that the hydrolytic ability of these enzyme types could be a common link for the disruptions of water-salt balance, blood pressure and energy homeostasis in diabetes mellitus. PMID- 17692298 TI - The developing and evolving retina: using time to organize form. AB - Evolutionary and other functional accounts of the retina and its normal development highlight different aspects of control of its growth and form than genomic and mechanistic accounts. Discussing examples from opsin expression, developmental regulation of the eye's size and optical quality, regulation of eye size with respect to brain and body size, and the development of the fovea, these different aspects of control are contrasted. Contributions of mouse models, particularly with regard to relative timing of events in different species are reviewed, introducing a Web-based utility for exploration of timing issues (www.translatingtime.net). Variation at the individual level, in early experience, and also across species is an essential source of information to understand normal development and its pathologies. PMID- 17692299 TI - Convenient conversion of wheat hemicelluloses pentoses (D-xylose and L-arabinose) into a common intermediate. AB - The transformation of D-xylose and L-arabinose, the two major components of wheat straw and bran, into a unique multifunctional, optically pure, five-carbon synthon has been achieved. The synthetic sequence requires three steps: suitable protection of the hydroxyl groups of the pentoses, introduction of an iodide at the C-5 position and zinc-mediated opening of the furanose ring leading to the formation of a common substituted pent-4-enal. PMID- 17692300 TI - Preparation of 2-C- and 3-C-cyano-2-enopyranoside derivatives and their epoxidation. AB - Methyl 4,6-O-benzylidene-2-C- and 3-C-cyano-2,3-dideoxy-D-erythro-hex-2 enopyranosides and -2-enitols were prepared and their epoxidation was performed. PMID- 17692301 TI - S100A1B and S100BB urine levels in preterm and term healthy newborns. PMID- 17692302 TI - Differential influence of open surgery and sepsis on the circulating insulin-like growth factors and their binding proteins as representative metabolic markers. AB - OBJECTIVES: In critical illnesses and stress conditions many endocrine systems are disturbed. In the current study we determined the influence of open surgery, post-operative sepsis and its early therapy on the components of the insulin-like growth factor (IGF) system in patients with malignant gastric or pancreatic tumors. DESIGN AND METHODS: Twenty-one patients and eighty-one age- and sex matched healthy subjects were included in this study. IGF-I, IGF-II, IGF binding proteins (IGFBPs), cortisol, insulin and protein concentrations (total, albumin and IgG) were determined pre-operatively, post-operatively, when sepsis was diagnosed and 48 h after initiating therapy. RESULTS: The concentrations of circulating IGF-I, IGF-II and IGFBP-3 were significantly lower in pre-operative patients compared to healthy subjects. Sepsis caused a further decrease in IGF-I and IGFBP-3 but an increase in IGFBP-1, IGFBP-2 and IGFBP-4 resulting in a redistribution of IGF molecules from ternary to binary complexes. CONCLUSIONS: The presence of malignant gastric or pancreatic tumors followed by post-operative sepsis caused a serious misbalance in components of the IGF system which failed to recover during the time of our longitudinal study. PMID- 17692303 TI - Increased urinary level of oxidized nucleosides in patients with mild-to-moderate Alzheimer's disease. AB - OBJECTIVE: Oxidative stress may play an important role in the pathogenesis of Alzheimer's disease (AD). DESIGN AND METHODS: To investigate the possible role of oxidative DNA damage in the pathogenesis of AD, we measured the metabolite concentrations of oxidized nucleosides (pseudouridine, 1-methyladenosine, 5 methylcytidine, 5-methyl-2'-deoxycytidine, 3-methyluridine, N(2), N(2) dimethylguanosine, 8-hydroxy-2'-deoxyguanosine, 5-deoxyadenosine and 2 deoxyguanosine) in urine between AD (n=36) and control subjects (n=34) using liquid chromatography-mass spectrometry (LC-MS) without urine preparation. RESULTS: In AD, the 3-methyluridine, 1-methyladenosine, 8-hydroxy-2' deoxyguanosine (p<0.05, respectively), 2-deoxyguanosine (p<0.01) and pseudouridine, N(2), N(2)-dimethylguanosine (p<0.001, respectively) were significantly increased when compared with the control subjects. CONCLUSION: The results indicate that oxidized urinary nucleosides may be useful as biomarkers for AD in early stages. PMID- 17692304 TI - Which children benefit from letter names in learning letter sounds? AB - Typical U.S. children use their knowledge of letters' names to help learn the letters' sounds. They perform better on letter sound tests with letters that have their sounds at the beginnings of their names, such as v, than with letters that have their sounds at the ends of their names, such as m, and letters that do not have their sounds in their names, such as h. We found this same pattern among children with speech sound disorders, children with language impairments as well as speech sound disorders, and children who later developed serious reading problems. Even children who scored at chance on rhyming and sound matching tasks performed better on the letter sound task with letters such as v than with letters such as m and h. Our results suggest that a wide range of children use the names of letters to help learn the sounds and that phonological awareness, as conventionally measured, is not required in order to do so. PMID- 17692305 TI - Infants rapidly learn word-referent mappings via cross-situational statistics. AB - First word learning should be difficult because any pairing of a word and scene presents the learner with an infinite number of possible referents. Accordingly, theorists of children's rapid word learning have sought constraints on word referent mappings. These constraints are thought to work by enabling learners to resolve the ambiguity inherent in any labeled scene to determine the speaker's intended referent at that moment. The present study shows that 12- and 14-month old infants can resolve the uncertainty problem in another way, not by unambiguously deciding the referent in a single word-scene pairing, but by rapidly evaluating the statistical evidence across many individually ambiguous words and scenes. PMID- 17692306 TI - The psychology of meta-ethics: exploring objectivism. AB - How do lay individuals think about the objectivity of their ethical beliefs? Do they regard them as factual and objective, or as more subjective and opinion based, and what might predict such differences? In three experiments, we set out a methodology for assessing the perceived objectivity of ethical beliefs, and use it to document several novel findings. Experiment 1 showed that individuals tend to regard ethical statements as clearly more objective than social conventions and tastes, and almost as objective as scientific facts. Yet, there was considerable variation in objectivism, both across different ethical statements, and across individuals. The extent to which individuals treat ethical beliefs as objective was predicted by the way they grounded their ethical systems. Groundings which emphasize the religious, pragmatic, and self-identity underpinnings of ethical belief each independently predicted greater ethical objectivity. Experiment 2 replicated and extended these findings with a refined measure of ethical objectivism. Experiment 3 demonstrated the robustness of the religious grounding of ethics, and differentiates it from mere religious belief and from political orientation. The results shed light on the nature of ethical belief, and have implications for the resolution of ethical disputes. PMID- 17692307 TI - Complexin I is required for mammalian sperm acrosomal exocytosis. AB - Regulated exocytosis in many cells is controlled by the SNARE complex, whose core includes three proteins that promote membrane fusion. Complexins I and II are highly related cytosolic proteins that bind tightly to the assembled SNARE complex and regulate neuronal exocytosis. Like somatic cells, sperm undergo regulated exocytosis; however, sperm release a single large vesicle, the acrosome, whose release has different characteristics than neuronal exocytosis. Acrosomal release is triggered upon sperm adhesion to the mammalian egg extracellular matrix (zona pellucida) to allow penetration of the egg coat. Membrane fusion occurs at multiple points within the acrosome but how fusion is activated and the formation and progression of fusion points is synchronized is unclear. We show that complexins I and II are found in acrosome-intact mature sperm, bind to SNARE complex proteins, and are not detected in sperm after acrosomal exocytosis (acrosome reaction). Although complexin-I-deficient sperm acrosome-react in response to calcium ionophore, they do not acrosome-react in response to egg zona pellucida proteins and have reduced fertilizing ability, in vitro. Complexin II is present in the complexin-I-deficient sperm and its expression is increased in complexin-I-deficient testes. Therefore, complexin I functions in exocytosis in two related but morphologically distinct secretory processes. Sperm are unusual because they express both complexins I and II but have a unique and specific requirement for complexin I. PMID- 17692308 TI - The role of maternal Activin-like signals in zebrafish embryos. AB - Maternal Activin-like proteins, a subgroup of the TGF-beta superfamily, play a key role in establishing the body axes in many vertebrates, but their role in teleosts is unclear. At least two maternal Activin-like proteins are expressed in zebrafish, including the Vg1 orthologue, zDVR-1, and the nodal-related gene, Squint. Our analysis of embryos lacking both maternal and zygotic squint function revealed that maternal squint is required in some genetic backgrounds for the formation of dorsal and anterior tissues. Conditional inactivation of the ALK4, 5 and 7 receptors by SB-505124 treatment during the cleavage stages ruled out a role for maternal Squint, zDVR-1, or other Activin-like ligands before the mid blastula transition, when the dorsal axis is established. Furthermore, we show that maternal Squint and zDVR-1 are not required during the cleavage stages to induce zygotic nodal-related gene expression. nodal-related gene expression decreases when receptor inhibition continues past the mid-blastula transition, resulting in a progressive loss of mesoderm and endoderm. We conclude that maternally expressed Activin-like signals do not act before the mid-blastula transition in zebrafish, but do have a variably penetrant role in the later stages of axis formation. This contrasts with the early role for these signals during Xenopus development. PMID- 17692309 TI - The multitude and diversity of environmental carcinogens. AB - We have recently proposed that lifestyle-related factors, screening and aging cannot fully account for the present overall growing incidence of cancer. In order to propose the concept that in addition to lifestyle related factors, exogenous environmental factors may play a more important role in carcinogenesis than it is expected, and may therefore account for the growing incidence of cancer, we overview herein environmental factors, rated as certainly or potentially carcinogenic by the International Agency for Research on Cancer (IARC). We thus analyze the carcinogenic effect of microorganisms (including viruses), radiations (including radioactivity, UV and pulsed electromagnetic fields) and xenochemicals. Chemicals related to environmental pollution appear to be of critical importance, since they can induce occupational cancers as well as other cancers. Of major concerns are: outdoor air pollution by carbon particles associated with polycyclic aromatic hydrocarbons; indoor air pollution by environmental tobacco smoke, formaldehyde and volatile organic compounds such as benzene and 1,3 butadiene, which may particularly affect children, and food pollution by food additives and by carcinogenic contaminants such as nitrates, pesticides, dioxins and other organochlorines. In addition, carcinogenic metals and metalloids, pharmaceutical medicines and cosmetics may be involved. Although the risk fraction attributable to environmental factors is still unknown, this long list of carcinogenic and especially mutagenic factors supports our working hypothesis according to which numerous cancers may in fact be caused by the recent modification of our environment. PMID- 17692310 TI - Sources, transport, fate, and toxicity of pollutants in the San Francisco Bay estuary. PMID- 17692311 TI - Opening the calcium-activated potassium channel participates in the cardioprotective effect of puerarin. AB - The aim of the present study was to determine whether the effective cardioprotection conferred by puerarin against ischemia and reperfusion is mediated by the calcium-activated potassium channel. Hearts isolated from male Sprague-Dawley rats were perfused on a Langendorff apparatus and subjected to 30 min of global ischemia followed by 120 min of reperfusion. The production of formazan, which provides an index of myocardial viability, was measured by absorbance at 550 nm, and the level of lactate dehydrogenase (LDH) in the coronary effluent was determined. Pretreatment with puerarin at 0.24 mmol/l for 5 min before ischemia increased myocardial formazan content and reduced LDH release during reperfusion. Administration of paxilline (1 micromol/l), an antagonist of the calcium-activated potassium channel, attenuated the protective effects of puerarin. In isolated ventricular myocytes, pretreatment with puerarin prevented simulated ischemia and reperfusion injury, hydrogen peroxide-induced cell death and the release of reactive oxygen species. Paxilline and chelerythrine (a protein kinase C inhibitor) both attenuated the effects of puerarin. These findings indicate that puerarin protects the myocardium against ischemia and reperfusion injury via opening the calcium-activated potassium channel and activating protein kinase C. PMID- 17692312 TI - Anticonvulsant effect of wogonin isolated from Scutellaria baicalensis. AB - In previous studies, we identified sedative effects of Scutellaria baicalensis extracts and found that these extracts or their constituents may also have anticonvulsive effects. Wogonin is a natural product isolated from S. baicalensis, which possesses central nervous system effects such as anxiolytic and neuroprotective activities. In this study, we investigated the effects of wogonin on convulsion related behaviors, such as myorelaxation, motor coordination, and anticonvulsant effects of wogonin on chemical induced seizure and electroshock seizure in mice or rats. The effect of wogonin on membrane potential was also observed. Wogonin was intraperitoneally injected into mice or rats 30 min prior to testing. Animals treated with wogonin did not change locomotor activities as well as endurance times on the rota-rod, which indicates that wogonin did not cause a sedative and myorelaxation effect. Wogonin significantly blocked convulsion induced by pentylenetetrazole and electroshock but not convulsion induced by strychnine. Wogonin also significantly reduced the electrogenic response score, but flumazenil treatment reversed this decrease to the level of the control group. The wogonin treatment increased Cl(-)influx into the intracellular area as dose increased. Flumazenil and bicuculline treatment, however, inhibited the Cl(-) influx induced by wogonin. These results indicate that the anticonvulsive effects produced by wogonin were mediated by the GABAergic neuron. PMID- 17692314 TI - Kinetics of strain-dependent differential gene expression in oxygen-induced retinopathy in the rat. AB - Recent evidence suggests that retinopathy of prematurity, a potentially blinding condition of premature human neonates, has a genetically-determined component. Different inbred strains of rat exhibit differential susceptibility to oxygen induced retinopathy (OIR), a well-established experimental model of retinopathy of prematurity. To explore the basis for this differential susceptibility, we quantified the retinal expression of 8 angiogenesis-related genes during early post-natal retinal development in rats with OIR. Inbred Fischer 344 (F344), Dark Agouti (DA) and Sprague Dawley (SPD) rat neonates were exposed to alternating cycles of 80% oxygen in air and normoxia for up to 14 days. After 14 days of cyclic hyperoxic exposure, some rats were exposed to normoxia for a further 4 days. Retinal mRNA for vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), pigment epithelium-derived factor (PEDF), angiopoietin-2 (Ang2), Tie2, cyclooxygenase-2 (COX2), insulin-like growth factor-1 (IGF1) and erythropoietin (EPO) were quantified by real-time reverse-transcriptase polymerase chain reaction at different time-points. Time-course analysis showed that expression of mRNA for VEGF, VEGFR2 and Ang2 was significantly greater in OIR-resistant (F344) retinae than in OIR-susceptible (DA) retinae during the first 9 days of cyclic hyperoxia. However, at post-natal days 14 and 18, retinal mRNAs for VEGF, EPO, VEGFR2, Ang2, IGF1, COX2 and PEDF were expressed to a significantly greater extent in OIR-susceptible (DA, SPD) than OIR-resistant (F344) retinae. The VEGF/PEDF ratio was greater in the F344 compared with the DA strain up to day 9, but was higher in the DA than the F344 strain at days 14 and 18. Thus, we found that retinal expression of angiogenesis-related genes was significantly higher in OIR-resistant rats than in OIR-susceptible rats during early retinal development, but the pattern reversed during the proliferative phase of OIR. We conclude that susceptibility to OIR correlates with differential gene expression very early in retinal microvascular development, during periods of cyclic hyperoxic exposure rather than during subsequent sustained hypoxia. PMID- 17692313 TI - The stimulus-dependent co-localization of serum- and glucocorticoid-regulated protein kinase (Sgk) and Erk/MAPK in mammary tumor cells involves the mutual interaction with the importin-alpha nuclear import protein. AB - In Con8 rat mammary epithelial tumor cells, indirect immunofluorescence revealed that Sgk (serum- and glucocorticoid-regulated kinase) and Erk/MAPK (extracellular signal-regulated protein kinase/mitogen activated protein kinase) co-localized to the nucleus in serum-treated cells and to the cytoplasmic compartment in cells treated with the synthetic glucocorticoid dexamethasone. Moreover, the subcellular distribution of the importin-alpha nuclear transport protein was similarly regulated in a signal-dependent manner. In vitro GST-pull down assays revealed the direct interaction of importin-alpha with either Sgk or Erk/MAPK, while RNA interference knockdown of importin-alpha expression disrupted the localization of both Sgk and Erk into the nucleus of serum-treated cells. Wild type or kinase dead forms of Sgk co-immunoprecipitated with Erk/MAPK from either serum- or dexamethasone-treated mammary tumor cells, suggesting the existence of a protein complex containing both kinases. In serum-treated cells, nucleus residing Sgk and Erk/MAPK were both hyperphosphorylated, indicative of their active states, whereas, in dexamethasone-treated cells Erk/MAPK, but not Sgk, was in its inactive hypophosphorylated state. Treatment with a MEK inhibitor, which inactivates Erk/MAPK, caused the relocalization of both Sgk and ERK to the cytoplasm. We therefore propose that the signal-dependent co-localization of Sgk and Erk/MAPK mediated by importin-alpha represents a new pathway of signal integration between steroid and serum/growth factor-regulated pathways. PMID- 17692315 TI - Axial hypertonicity in Parkinson's disease: direct measurements of trunk and hip torque. AB - A cardinal feature of Parkinson's disease (PD) is muscle hypertonicity, i.e. rigidity. Little is known about the axial tone in PD or the relation of hypertonia to functional impairment. We quantified axial rigidity to assess its relation to motor symptoms as measured by UPDRS and determine whether rigidity is affected by levodopa treatment. Axial rigidity was measured in 12 PD and 14 age matched controls by directly measuring torsional resistance of the longitudinal axis to twisting (+/-10 degrees ). Feet were rotated relative to fixed hips (Hip Tone) or feet and hips were rotated relative to fixed shoulders (Trunk Tone). To assess tonic activity only, low constant velocity rotation (1 degrees /s) and low acceleration (<12 degrees /s(2)) were used to avoid eliciting phasic sensorimotor responses. Subjects stood during testing without changing body orientation relative to gravity. Body parts fixed against rotation could translate laterally within the boundaries of normal postural sway, but could not rotate. PD OFF medication had higher axial rigidity (p<0.05) in hips (5.07 N m) and trunk (5.30 N m) than controls (3.51 N m and 4.46 N m, respectively), which did not change with levodopa (p>0.10). Hip-to-trunk torque ratio was greater in PD than controls (p<0.05) and unchanged by levodopa (p=0.28). UPDRS scores were significantly correlated with hip rigidity for PD OFF-medication (r values=0.73, p<0.05). Torsional resistance to clockwise versus counter-clockwise axial rotation was more asymmetrical in PD than controls (p<0.05), however, there was no correspondence between direction of axial asymmetry and side of disease onset. In conclusion, these findings concerning hypertonicity may underlie functional impairments of posture and locomotion in PD. The absence of a levodopa effect on axial tone suggests that axial and appendicular tones are controlled by separate neural circuits. PMID- 17692316 TI - High glucose enhances MMP-2 production in adventitial fibroblasts via Akt1 dependent NF-kappaB pathway. AB - To understand the role of adventitial fibroblasts (AF) in diabetic vascular diseases, the importance of high glucose (HG, 25mM) on matrix metalloproteinase-2 (MMP-2) production in AF was determined. HG enhanced mRNA, protein and gelatinolytic activity of MMP-2. The enhanced MMP-2 activity was significantly attenuated not only by a PI3K inhibitor but also by an Akt inhibitor. These HG induced MMP-2 responses were markedly reduced in Akt1-deficient (1KO) cells. The diminished HG-induced MMP-2 responses were completely restored by re-expression of Akt1. Both the reporter activity and electrophoretic mobility shift assay for activator protein-1 and nuclear factor-kappa B (NF-kappaB) were enhanced by HG, but NF-kappaB were not increased in 1KO cells. Furthermore, HG-induced MMP-2 responses were markedly suppressed by NF-kappaB decoy oligodeoxynucleotides. Based on these results, it is suggested that HG augments MMP-2 production via PI3K/Akt1/NF-kappaB pathway. PMID- 17692317 TI - Early life stress effects on adult stress-induced corticosterone secretion and anxiety-like behavior in the C57BL/6 mouse are not as robust as initially thought. AB - Understanding environmental effects on mouse brain development would allow us to take advantage of powerful genetic tools to determine the interaction between genetic and epigenetic factors governing brain development in C57BL/6 mice. Experiment 1 examined whether time of day for neonatal manipulations affects adult stress-induced hormone secretion. Three rearing groups were examined: early handled (EH; dam removed 10 min/day); maternal separated (MS; dam removed 180 min/day); and an animal facility raised (AFR) control. Separations occurred during either the first or last 3 h of the light phase. Corticosterone (CORT) secretion in response to 100 dB white noise was assessed in adulthood. Both EH and MS males separated during the last 3 h of the light phase exhibited blunted stress-induced CORT compared to all other groups. Experiment 2 varied time of behavior testing. A fourth group was also added: maternal isolated (MI; separated from dam and littermates 180 min/day). Adult male behavior was assessed in three different tests. EH males tested in the elevated zero maze (EZM) during the light phase and MS males tested in the EZM during the dark phase exhibited diminished anxiety-like behavior compared to the other groups. We conclude that the EH protocol is marginally effective in blunting stress-induced CORT secretion and anxiety-like behavior in C57BL/6 mice, and these early handling effects are influenced by time of day. We also conclude that the 3 h MS or MI protocol is not effective in exacerbating future adult stress-induced CORT secretion or anxiety like behavior in C57BL/6 mice. PMID- 17692318 TI - Region-specific patterns of vascular remodelling occur early in atherosclerosis and without loss of smooth muscle cell markers. AB - BACKGROUND: Vascular remodelling is characterized by increased smooth muscle cell (SMC) proliferation and migration. Coincident with these events, SMC markers of differentiation are known to down-regulate in advanced stages of atherosclerosis, a process known as phenotypic modulation. However, it is not known when this first begins. Here we sought to determine if regions of the mouse aorta with varying susceptibilities for atherosclerosis display differential vascular remodelling and SMC gene expression at the earliest stages of disease. METHODS AND RESULTS: LDLrKO mice were fed normal or high cholesterol diet for 0-98 days. In the latter, ORO and H&E staining of arch, thoracic and abdominal aortic sections revealed infrequent occurrences of lipid deposition at d28, but significant region-specific vascular remodelling. Immunostaining for PCNA revealed increased cellular proliferation in the intima and inner media at d28 in all three regions. qRT-PCR of SMC revealed increased expression of SM22alpha and SM-MHC in the arch by d28, which subsequently decreased by d98. By contrast, eNOS gene expression was consistently decreased in the arch over these times. A temporal increase in macrophage-specific CD68 expression was observed in the arch but not thoracic or abdominal regions. CONCLUSION: Remodelling of the vascular myocyte compartment due to cellular proliferation is an early event in atherosclerosis and is associated with increases in SMC-specific gene expression. These events precede subsequent lesion formation and SMC phenotypic modulation. PMID- 17692319 TI - Angiotensin II AT1 receptor blockade normalizes CD11b+ monocyte production in bone marrow of hypercholesterolemic monkeys. AB - The enhanced production of monocytes expressing pro-inflammatory markers such as the integrin CD11b in patients with hypercholesterolemia may promote vascular inflammation and exacerbate atherogenesis. The objective of the present study was to determine whether hypercholesterolemia stimulates the production of CD11b(+) monocytes in bone marrow, and whether the renin-angiotensin system participates in this process and thus provides a target for therapeutic intervention. The dietary induction of hypercholesterolemia in adult male cynomolgus monkeys was accompanied by increased bone marrow cellularity and elevated peripheral blood and bone marrow monocyte CD11b expression. Isolated bone marrow CD34(+) hematopoietic stem cells (HSCs) evaluated by in vitro functional assays exhibited enhanced myeloproliferative capacity and differentiation into CD11b(+) monocytes. Treatment of hypercholesterolemic monkeys with the angiotensin II AT(1) receptor blocker losartan for 15 weeks reduced bone marrow cellularity, suppressed peripheral blood and bone marrow monocyte CD11b expression, and normalized CD34(+) cell function assays. All variables returned to pretreatment levels 6 weeks after discontinuation of losartan treatment. Hypercholesterolemia was associated with increased CD34(+) cell AT(1) receptor expression and an exaggerated in vitro myeloproliferative response to angiotensin II stimulation that positively correlated to plasma LDL concentrations. In vitro exposure to native low-density lipoproteins (LDL) also increased CD34(+) cell AT(1) receptor expression and the myeloproliferative response to angiotensin II stimulation in a dose-dependent and receptor-mediated manner. Our data provide support for a positive regulatory role of plasma LDL on AT(1) receptor-mediated HSC differentiation and the production of pro-atherogenic monocytes. LDL-regulated HSC function may explain in part hypercholesterolemia-induced inflammation as well as the anti-inflammatory and anti-atherosclerotic effects of AT(1) receptor blockers. PMID- 17692320 TI - The HMG-CoA reductase inhibitor rosuvastatin inhibits plasminogen activator inhibitor-1 expression and secretion in human adipocytes. AB - Human preadipocytes and adipocytes are known to produce the proatherogenic factor PAI-1 and proinflammatory cytokines, and obesity was found to be state of increased adipose production of these factors. In the present study, we investigated the effect of rosuvastatin on the regulation of PAI-1 gene expression in human adipocytes. Human preadipocytes, adipocytes in primary culture and the SGBS cell line were used as cell models. Cells were transfected using various constructs and promoter activity was measured as luciferase activity. PAI-1 expression was measured by quantitative RT-PCR and ELISA. Rosuvastatin inhibited PAI-1 mRNA expression and secretion of the protein in a concentration-dependent manner. This effect was reversed by isoprenoids. Addition of MEK-inhibitors and NFkappaB inhibitors also reduced PAI-1 expression and PAI-1 promoter luciferase activity. Further experiments revealed that rosuvastatin down regulated the MEKK-1 mediated activation of the PAI-1 promoter. In conclusion our data suggest that rosuvastatin inhibits PAI-1 expression and release from human adipocytes via a MEKK-1-dependent but not a NFkappaB-dependent mechanism. PMID- 17692321 TI - Non-consecutive versus consecutive footstrikes as an equivalent method of assessing gait asymmetry. AB - Asymmetry of gait is often studied to characterize populations and assess the efficacy of treatment protocols. However, despite the continuous nature of gait, many studies have made comparisons between data from non-consecutive footstrikes. This is typically considered a limitation of these studies. However, if gait characteristics are sufficiently repeatable within a side, consecutive footstrikes may not be necessary to properly describe the asymmetry between sides. Therefore, one purpose of this study was to compare asymmetry values calculated from consecutive and non-consecutive footstrikes. Additionally, the variability of gait within and between sides was compared to assess the repeatability and distinctiveness of the characteristics on each side. The results suggest that kinetic and kinematic asymmetry can be assessed from either consecutive or non-consecutive footstrikes. Further, the patterns of movement tend to be sufficiently consistent within a side, such that the variability within a side is much lower than the variability between sides. However, there may be some variables, or populations, that exhibit high within-side variability. Several trials of consecutive footstrikes may be a better way to characterize asymmetry of those variables. PMID- 17692323 TI - Comparison of two derivatizing agents for the simultaneous determination of selenite and organoselenium species by gas chromatography and atomic emission detection after preconcentration using solid-phase microextraction. AB - Two methods for the simultaneous determination of selenite and two organoselenium compounds, dimethylselenide (DMSe) and dimethyldiselenide (DMDSe), are proposed. Both methods involve sample preconcentration by solid-phase microextraction (SPME) and capillary gas chromatography coupled to atomic emission detection (GC AED). The main difference between the methods is the derivatizing agent used to complex the inorganic species: sodium tetraethylborate and 4,5-dichloro-1,2 phenylenediamine. The parameters affecting the derivatization and preconcentration steps, chromatographic separation as well as detection of the compounds were optimized. Direct immersion (DI) mode and a relatively long extraction time were selected for the method involving the formation of the piazselenol complex, better sensitivity being achieved for the three analytes under study. In this case, detection limits ranged between 3 and 25 ng L(-1), depending on the compound. Headspace mode (HS) and extraction times of 20 min were selected for the method involving tetraalkylborate, and detection limits of between 7.3 and 55 ng L(-1) were obtained. DMSe and Se(IV) were found in several of the water samples analyzed at concentrations of 0.07-1.0 ng mL(-1). PMID- 17692322 TI - Determination of banned 10 azo-dyes in hot chili products by gel permeation chromatography-liquid chromatography-electrospray ionization-tandem mass spectrometry. AB - An accurate method based on the use of gel permeation chromatography (GPC)-liquid chromatography-tandem mass spectrometry interfaced with electrospray ionization (GPC-LC-ESI-MS/MS) was devised for the simultaneous determination of Sudan (I IV), Sudan Orange G, Sudan Red B, Sudan Red G, Sudan Red 7B, Butter Yellow and Para Red in hot chili products. A GPC clean-up procedure was developed for simultaneous quantification of 10 dyes in hot chili and hot chili products avoiding some interference and permitting multiple injections without damaging the column. A HPLC was performed on an Inertsil C18 column using a multistep gradient elution with 0.1% formic acid and methanol as the mobile phase. Mass spectral acquisition was done in positive ion mode. Linearity of around three orders in the magnitude of concentration was generally obtained with the correlation coefficients (r2) of 0.9984-0.9997. Limit of detection (LOD) and limit of quantification (LOQ) for the investigated dyes were in the ranges of 0.1 1.8 and 0.4-5.0 microg/kg depending on matrices, respectively. The recoveries of the 10 synthetic dyes in five matrices ranged from 81.7 to 92.9%. The intra- and inter-day precision (RSDs) was between 2.9-7.8 and 3.9-8.1%, respectively. This method has been applied successfully for the determination of the studied 10 banned dyes in hot chili products. PMID- 17692324 TI - The effect of electrolyte on the encapsulation efficiency of vesicles formed by the nonionic surfactant, 2C18E12. AB - Encapsulation efficiencies of vesicles formed by the nonionic surfactant 1,2 dioctadecyl-rac-glycerol-3-omega-methoxydodecylethylene glycol (abbreviated as 2C18E12) and its phospholipid counterpart, distearoylphosphatidylcholine (DSPC) at 298 K, were determined by the entrapment of the water-soluble dye, carboxyfluorescein (CF) to be 0.045+/-0.001 and 0.03+/-0.04 L mol(-1) for 2C18E12 vesicles prepared using low osmolarity (270 m Osm) Krebs-Henseleit (K-H) buffer and a modified 'high salt' (1600 m Osm) variant of K-H buffer, respectively, and 0.64+/-0.01 and 0.31+/-0.04 Lmol(-1) for DSPC vesicles prepared under the same conditions and in the same buffers. Freeze fracture electron microscopy studies confirmed the presence of vesicles when 2C18E12 and DSPC were dispersed in water and both buffer solutions. Small angle neutron scattering (SANS) studies, using D2O in place of H2O, showed that when 2C18E12 vesicles were prepared in the 'high salt' variant of K-H buffer as opposed to K-H buffer or water, a higher proportion of multilamellar vesicles (MLV) were formed. Furthermore when prepared in the 'high salt' variant of K-H buffer, the 2C18E12 bilayers were thinner, and when present in the form of MLV exhibited a smaller layer of water separating the bilayers. However, even in the absence of electrolyte, 2C18E12 formed surprisingly thin bilayers due to the penetration of the polyoxyethylene chains into the hydrophobic chain region of the bilayer. Due to the dehydrating effect of the high concentration of electrolyte present in the 'high salt' variant of K H, the polyoxyethylene head groups penetrated further into the hydrophobic region of the bilayer making the bilayer even thinner. In the case of the DSPC vesicles, although the SANS study showed an increase in the relative proportion of multilamellar to unilamellar vesicles when samples were prepared in the 'high salt' variant of K-H buffer, no differences were observed in the thickness and the d-spacing of the vesicle bilayers. Variable temperature turbidity measurements of 2C18E12, and DSPC vesicles prepared in water indicated phase changes at 320+/-0.5 and 327+/-0.5 K, respectively, and were unchanged when the 'high salt' variant of K-H buffer was used as hydrating medium. Taken together, these results suggest that a low phase transition temperature was not the reason for the poor entrapment efficiency of 2C18E12 vesicles but rather the very 'thin' hydrophobic barrier formed by the penetration of the polyoxyethylene chains into the hydrophobic region of the bilayer. PMID- 17692325 TI - Dynamic Monte Carlo simulation of aggregation of nanoparticles in the presence of diblock copolymer. AB - The aggregation of hydrophobic nanoparticles in the presence of diblock copolymers is investigated using dynamic Monte Carlo simulation on a simple cubic lattice. One nanoparticle occupies one lattice site, one block copolymer (A(m)B(m)) occupies 2m sequentially linked sites with m segments of A and m segments of B, and solvents are represented by any unoccupied sites. All of them are self-avoiding and nearest-neighbor interactions are considered. A compact big aggregate, dispersed aggregates wrapped by polymer chains, and an ordered lamellar structure are obtained by varying the concentration of copolymer. The structures are seen to be controlled by competing forces between the interaction of copolymer with nanoparticles and the self-assembly of copolymer in solution. The critical concentration of copolymer needed to form the lamellar structure, C(p,L), decreases with the chain length. It is also found that C(p,L) decreases roughly linearly with the concentration of nanoparticles C(n), which can be approximately expressed as C(p,L)=0.764-0.857C(n) when m=2. The simulation demonstrates that addition of diblock copolymer can effectively control the aggregation of nanoparticles and lead to the formation of a variety of nanostructures. PMID- 17692326 TI - Dynamics of liquid penetration into capillary tubes. AB - The dynamics of penetration is considered in the case where inertia effects are small. The effect of the contact line speed on the dynamic contact angle is taken into consideration. Analytical solutions are obtained for short and large times, and are found to cover together most of the time domain. The results obtained numerically show good agreement with the asymptotic solutions. The large-time solutions are valid in the case of penetration into horizontal capillaries. The large-time asymptotic solution shows a correction term compared to the Lucas Washburn equation, which is found to be a limiting case valid for very large times (horizontal capillaries case). The analysis shows how to include gravity effects in the case of penetration into vertical tubes. Excellent agreement is found with available published experimental data. PMID- 17692327 TI - Is trace metal release in wetland soils controlled by organic matter mobility or Fe-oxyhydroxides reduction? AB - Aerobic and anaerobic incubation experiments on a wetland soil samples were used to assess the respective roles of organic matter (OM) release, Fe-oxyhydroxides reduction and redox/speciation changes on trace metal mobility during soil reduction. Significant amounts of Cu, Cr, Co, Ni, Pb, U, Th and Rare Earth Elements (REE) were released during anaerobic incubation, and were accompanied by strong Fe(II) and dissolved organic matter (DOM) release. Aerobic incubation at pH 7 also resulted in significant trace metal and DOM release, suggesting that Fe oxyhydroxide reduction is not the sole mechanism controlling trace metal mobility during soil reduction. Using these results and redox/speciation modeling, four types of trace metal behavior were identified: (i) metals bound to organic matter (OM) and released by DOM release (REE); (ii) metals bound to both OM and Fe oxyhydroxides, and released by the combined effect of DOM release and Fe(III) reduction (Pb and Ni); (iii) metals bound solely to soil Fe-oxyhydroxides and released by its reductive dissolution (Co); and (iv) metals for which release mechanisms are unclear because their behavior upon reduction is affected by changes in redox state and/or solution speciation (Cu, Cr, U and Th). Even though the process of soil Fe-oxyhydroxide reduction is important in controlling metal mobility in wetland soils, the present study showed that the dominant mechanism for this process is OM release. Thus, OM should be systematically monitored in experimental studies dedicated to understand trace metal mobility in wetland soils. Due to the fact that the process of OM release is mainly controlled by pH variations, the pH is a more crucial parameter than Eh for metal mobility in wetland soils. PMID- 17692328 TI - Orthophosphate and metaphosphate ion removal from aqueous solution using alum and aluminum hydroxide. AB - The removal of orthophosphates (10(-2) kg P m(-3)), condensed phosphates (10(-2) kg P m(-3)), and mixtures of both (5 x 10(-3) kg P m(-3) as orthophosphate and 5 x 10(-3) kg P m(-3) as metaphosphate) in aqueous solution is studied using alum and aluminum hydroxide. The effects of coagulant dose, pH, temperature, aging of aluminum hydroxide, and presence of different ions are investigated. On the basis of the experimental results, alum is much more efficient in phosphorus removal than aluminum hydroxide even if, in both cases, at the conditions studied, the active coagulant form is Al(OH)(3). The differences then could be due to the higher activity of the in situ formed hydroxide. Orthophosphates and metaphosphates seem to have similar behavior vs pH variation: maximum removal is achieved at pH values 5-6 in all cases. On the other hand, in the simultaneous presence of both P forms, orthophosphate and metaphosphate ions have different affinities for the surface sites of aluminum hydroxide, since for both alum and aluminum hydroxide, orthophosphates are preferentially removed compared to metaphosphates, due probably to orientation effects and the charge per P atom. The presence of sodium, potassium, magnesium, sulfate, chloride, and magnesium, at the concentrations studied and for a pH value of 6, does not influence P removal. Temperature variation, between 25 and 60 degrees C, does not affect alum efficiency but both P forms are increasingly removed with increasing temperature, probably due to polymer Al(OH)(3) breaking, producing new surfaces for adsorption. Aging decreases sorption capacity of Al(OH)(3), while crystallites of increasing size are formed. Finally adsorption of both P forms is best described by the Freundlich isotherm [[K(F)=(49.1-69.1) x 10(-3) (m(3)kg(-1))(1/N), 1/N: 0.14-0.19 for T=25-60 degrees C] and [ K(F)=(1.58-2.79) x 10(-3) (m(3)kg( 1))(1/N), 1/N: 2.17-2.47 for T=25-60 degrees C] for orthophosphate and metaphosphate, respectively. PMID- 17692329 TI - Supramolecular interactions between beta-cyclodextrin and hydrophobically end capped poly(ethylene glycol)s: a quartz crystal microbalance study. AB - In this study, the supramolecular interactions occurring between beta cyclodextrin-based surfaces and macromolecular chains modified at one end with naphthyl, adamantyl, or phenyladamantyl hydrophobic groups were investigated by means of a quartz crystal microbalance. beta-Cyclodextrin-functionalized gold electrodes were obtained through the amide-coupling reaction between mono-6-deoxy 6-amino-beta-cyclodextrin and 11-mercaptoundecanoic acid self-assembled monolayer allowing the reproducible preparation of densely grafted surfaces with host properties. The interaction data obtained for the three different modified poly(ethylene glycol)s are in good agreement with our previous studies performed by high performance liquid chromatography and surface plasmon resonance. This evidences that the driving force for the supramolecular interaction is based on the inclusion of the hydrophobic terminal group of the chains within the cyclodextrin cavities. The reversibility of the inclusion process was proven through the regeneration of the original host properties of the sensing surfaces using sodium dodecylsulfate as a competitor for the desorption of the poly(ethylene glycol) chains. PMID- 17692330 TI - Unusual behavior of CMC for binary mixtures of alkyltrimethylammonium bromides: dependence on chain length difference. AB - The critical micelle concentrations (CMC) of binary mixtures of alkyltrimethylammonium bromides (CnTAB) were measured by a conductivity method. The CMCs of C12TAB-C14TAB and C14TAB-C16TAB systems exhibit the usual behavior, namely a monotonic decrease of the CMC with the mole fraction of the longer chain surfactant. However, the CMC behaviors of C10TAB-C16TAB, C11TAB-C16TAB, C12TAB C16TAB, and C11TAB-C14TAB are unusual. The behaviors of the CMCs with mole fraction for these systems consist of three regions, of which the first is characterized by a very small decrease of the CMC in the range of low mole fraction, followed by a second where there is an abrupt decrease of the CMC, and a third where the CMCs exhibit their usual behavior. The molecular interaction parameter omega is almost equal to zero for mixtures that have the usual CMC behavior, but is small and positive for those systems with unusual CMCs. We infer that for very low mole fractions of C16TAB, the C16TA ion in the C12TAB-C16TAB system penetrates imperfectly into the micelle and its two methylene groups exist outside the micelle. PMID- 17692331 TI - Phonological awareness and the use of phonological similarity in letter-sound learning. AB - The effects of the phonological similarity between a letter sound and the sound in a spoken word, and phonological awareness on letter-sound learning were examined. Two groups of 41 kindergartners were taught four letter sounds. First, both groups had to learn the associations between four symbols and four familiar words. Next, both groups were taught the letter sounds that were paired to these same symbols. Each letter sound corresponded to the first sound of the word that was previously associated with that symbol in the phonological similarity group, whereas such a relation was absent in the other group. In addition, measures of vocabulary, letter knowledge, and phonological awareness were administered. Phonological similarity facilitated letter-sound learning. Individual differences in phonological awareness had a strong effect on letter-sound learning even after current letter knowledge was controlled. Unexpectedly, the effects of phonological awareness and the ability to use phonological similarity on letter sound learning were found to be independent. PMID- 17692332 TI - Clonidine, octopaminergic receptor agonist, reduces protein feeding in the blow fly, Phormia regina (Meigen). AB - Results in this study are consistent with those of Murdock and his colleagues who clearly demonstrated that clonidine, an agonist of octopaminergic receptors in some insects, significantly increases sucrose feeding. Their studies, however, did not examine the effect of clonidine on protein feeding. Injection of a 20 microg/microl/fly dose of clonidine significantly reduces protein feeding in both sexes of Phormia regina, instead of stimulating feeding as is observed with carbohydrate feeding. The manner in which the flies are fed prior to starvation and the method of testing influences the amounts of diet consumed. It is proposed that the biogenic amines influence the state of hunger (i.e., protein versus carbohydrates) while other chemicals and neural mechanisms (i.e., such as sulfakinins and stretch receptors, respectively) affect satiety. PMID- 17692333 TI - Senescence in the worker honey bee Apis Mellifera. AB - Honey bees are social insects that exhibit striking caste-specific differences in longevity. Queen honey bees live on average 1-2 years, whereas workers live 2-6 weeks in the summer and about 20 weeks in the winter. It is not clear whether queen-worker differences in longevity are due to intrinsic physiological differences in the rate of senescence, to differential exposure to extrinsic factors such as predation and adverse environmental conditions, or both. To determine if the relatively short lifespan of worker bees involves senescence, we measured age-specific resistance to three different physiological stressors (starvation, thermal, and oxidative stress) while eliminating age-related differences in foraging activity and minimizing age-related differences in energy expenditure. Despite these manipulations, older worker bees were still significantly less resistant to all three stressors than were younger bees. These results indicate that the regulation of worker bee lifespan involves senescence, in addition to extrinsic factors. PMID- 17692334 TI - Crystallographic evidence for water-assisted photo-induced peptide cleavage in the stony coral fluorescent protein Kaede. AB - A coral fluorescent protein from Trachyphyllia geoffroyi, Kaede, possesses a tripeptide of His62-Tyr63-Gly64, which forms a chromophore with green fluorescence. This chromophore's fluorescence turns red following UV light irradiation. We have previously shown that such photoconversion is achieved by a formal beta-elimination reaction, which results in a cleavage of the peptide bond found between the amide nitrogen and the alpha-carbon at His62. However, the stereochemical arrangement of the chromophore and the precise structural basis for this reaction mechanism previously remained unknown. Here, we report the crystal structures of the green and red form of Kaede at 1.4 A and 1.6 A resolutions, respectively. Our structures depict the cleaved peptide bond in the red form. The chromophore conformations both in the green and red forms are similar, except a well-defined water molecule in the proximity of the His62 imidazole ring in the green form. We propose a molecular mechanism for green-to red photoconversion, which is assisted by the water molecule. PMID- 17692335 TI - The variability in type I collagen helical pitch is reflected in the D periodic fibrillar structure. AB - The variability in amino acid axial rise per residue of the collagen helix is a potentially important parameter that is missing in many structural models of fibrillar collagen to date. The significance of this variability has been supported by evidence from collagen axial structures determined by electron microscopy and X-ray diffraction, as well as studies of the local sequence dependent conformation of the collagen helix. Here, sequence-dependent variation of the axial rise per residue was used to improve the fit between simulated diffraction patterns derived from model structures of the axially projected microfibrillar structure and the observed X-ray diffraction pattern from hydrated rat tail tendon. Structural models were adjusted using a genetic algorithm that allowed a wide range of structures to be tested efficiently. The results show that variation of the axial rise per residue could reduce the difference metric between model and observed data by up to 50%, indicating that such a variable is a necessary part of fibril model structure building. The variation in amino acid translation was also found to be influenced by the number of proline and hydroxyproline residues in the triple helix structure. PMID- 17692337 TI - Metabolism in adipose tissue in response to citalopram and trimipramine treatment -an in situ microdialysis study. AB - The intake of antidepressants is often accompanied by weight gain. Antidepressants may influence lipid and carbohydrate metabolism that can result in metabolic changes and obesity. We investigated the effect of citalopram and trimipramine on interstitial glycerol, glucose and lactate concentration and blood flow in subcutaneous adipose tissue of obese subjects by means of the microdialysis technique. In addition, the effect of stimulation with norepinephrine on metabolic response was investigated. Each subject was compared to a control subject matched for BMI and age. Each group comprised 10 subjects. Circulating plasma triglyceride concentrations were higher in drug-treated groups. In subcutaneous adipose tissue, microdialysis experiments revealed a higher and prolonged glycerol release in the presence of norepinephrine, but not under basal conditions. In citalopram treated subjects, basal glucose and lactate concentrations were higher compared with controls or with the trimipramine treated group. Local administration of norepinephrine induced a decrease in glucose levels and an increase in lactate levels, but without significant differences between groups. Local adipose tissue blood flow decreased in control groups following norepinephrine application, but remained constant in the antidepressant groups. In conclusion, citalopram and trimipramine affected glucose and lipid metabolism in adipose tissue and resulted in enhanced release of glycerol and free fatty acids into the circulation. PMID- 17692336 TI - Carboxyl pK(a) values, ion pairs, hydrogen bonding, and the pH-dependence of folding the hyperthermophile proteins Sac7d and Sso7d. AB - Sac7d and Sso7d are homologous, hyperthermophile proteins with a high density of charged surface residues and potential ion pairs. To determine the relative importance of specific amino acid side-chains in defining the stability and function of these Archaeal chromatin proteins, pK(a) values were measured for the acidic residues in both proteins using (13)C NMR chemical shifts. The stability of Sso7d enabled titrations to pH 1 under low-salt conditions. Two aspartate residues in Sso7d (D16 and D35) and a single glutamate residue (G54) showed significantly perturbed pK(a) values in low salt, indicating that the observed pH dependence of stability was primarily due to these three residues. The pH dependence of backbone amide NMR resonances demonstrated that perturbation of all three pK(a) values was primarily the result of side-chain to backbone amide hydrogen bonds. Few of the significantly perturbed acidic pK(a) values in Sac7d and Sso7d could be attributed to primarily ion pair or electrostatic interactions. A smaller perturbation of E48 (E47 in Sac7d) was ascribed to an ion pair interaction that may be important in defining the DNA binding surface. The small number (three) of significantly altered pK(a) values was in good agreement with a linkage analysis of the temperature, pH, and salt-dependence of folding. The linkage of the ionization of two or more side-chains to protein folding led to apparent cooperativity in the pH-dependence of folding, although each group titrated independently with a Hill coefficient near unity. These results demonstrate that the acid pH-dependence of protein stability in these hyperthermophile proteins is due to independent titration of acidic residues with pK(a) values perturbed primarily by hydrogen bonding of the side-chain to the backbone. This work demonstrates the need for caution in using structural data alone to argue the importance of ion pairs in stabilizing hyperthermophile proteins. PMID- 17692338 TI - An update on non-peptide angiotensin receptor antagonists and related RAAS modulators. AB - The renin-angiotensin-aldosterone-system (RAAS) is an important regulator of blood pressure and fluid-electrolyte homeostasis. RAAS has been implicated in pathogenesis of hypertension, congestive heart failure, and chronic renal failure. Aliskiren is the first non-peptide orally active renin inhibitor approved by FDA. Angiotensin Converting Enzyme (ACE) Inhibitors are associated with frequent side effects such as cough and angio-oedema. Recently, the role of ACE2 and neutral endopeptidase (NEP) in the formation of an important active metabolite/mediator of RAAS, ang 1-7, has initiated attempts towards development of ACE2 inhibitors and combined ACE/NEP inhibitors. Furukawa and colleagues developed a series of low molecular weight nonpeptide imidazole analogues that possess weak but selective, competitive AT1 receptor blocking property. Till date, many compounds have exhibited promising AT1 blocking activity which cause a more complete RAAS blockade than ACE inhibitors. Many have reached the market for alternative treatment of hypertension, heart failure and diabetic nephropathy in ACE inhibitor intolerant patients and still more are waiting in the queue. But, the hallmark of this area of drug research is marked by a progress in understanding molecular interaction of these blockers at the AT1 receptor and unraveling the enigmatic influence of AT2 receptors on growth/anti-growth, differentiation and the regeneration of neuronal tissue. Different modeling strategies are underway to develop tailor made molecules with the best of properties like Dual Action (Angiotensin And Endothelin) Receptor Antagonists (DARA), ACE/NEP inhibitors, triple inhibitors, AT2 agonists, AT1/TxA2 antagonists, balanced AT1/AT2 antagonists, and nonpeptide renin inhibitors. This abstract gives an overview of these various angiotensin receptor antagonists. PMID- 17692339 TI - Effects of ulvoid (Ulva spp.) accumulation on the structure and function of eelgrass (Zostera marina L.) bed. AB - The objective of this study is to clarify the effect of ulvoid (Ulva spp.) accumulation on the structure and function of an eelgrass bed by the coast of Iwakuni, Seto Inland Sea, Japan. We monitored eelgrass shoot density and volume of ulvoid accumulation in the study site and evaluated effects of the accumulated ulvoid canopy on the percent survival, seedling density, growth rates, photosynthetic photon flux density (PPFD) and carbon contents of eelgrass. Eelgrass shoot density decreased by the accumulation of ulvoid. Also, seedling density decreased by the increase in the ulvoid volumes. Shoot density, seedling density and leaf elongation were negatively correlated with ulvoid volume. Carbon contents in eelgrass decreased by the accumulation of ulvoid (canopy height: 25cm). These results suggest that accumulation of ulvoid bloom has significant negative impacts on the structure and function of eelgrass bed, i.e. decreases in vegetative shoot density, seedling density, shoot height and growth rate. PMID- 17692340 TI - A multibiomarker approach in barramundi (Lates calcarifer) to measure exposure to contaminants in estuaries of tropical North Queensland. AB - A suite of biomarkers were measured in barramundi (Lates calcarifer) from five North Queensland estuaries along a perceived pollution gradient. The biomarkers selected were 7-ethoxyresorufin-O-deethylase (EROD), cytochrome P450, fluorescent aromatic compounds (FACs), DNA integrity, RNA:DNA ratio, cholinesterase activity (ChE), condition factor and hepatosomatic index. The resulting database was subjected to uni- and multi-variate analyses in order to assess the most suitable biomarkers to assess pollution in North Queensland estuaries and to classify the environmental quality of the sites. Principal components analysis (PCA) on the biochemical markers revealed that EROD, EROD/P450, DNA damage and to a lesser extent ChE and FACs were found to be responsive to contaminants in the environment while cytochrome P450, condition factor and the hepatosomatic index were found to be less responsive biomarkers. This study has demonstrated the utility of applying a multibiomarker approach in conjunction with traditional analysis of contaminants in providing valuable information in environmental risk assessment. PMID- 17692342 TI - [Intradiploic epidermoid cyst of the occipital bone]. AB - BACKGROUND: A rare case of intradiploic epidermoid cyst of the occipital bone is described and recent literature, which emphasizes the radiological evaluation and surgical treatment of this lesion is reviewed. CASE DESCRIPTION: A 56-year-old female patient complained of headache and occasional episodes of vertigo for one year. Computed tomographic scan and magnetic resonance imaging were performed. The patient underwent occipital right craniotomy followed by total removal of the cyst and its capsule. RESULT: The postoperative course was uneventful and the patient was discharged 4 days later. CONCLUSION: A review of the literature shows that intradiploic epidermoid cyst of the occipital bone is rare. Correct radiological assessment and complete excision of this lesion and its capsule provides complete recovery. PMID- 17692341 TI - Regulation of multiple angiogenic pathways by Dll4 and Notch in human umbilical vein endothelial cells. AB - The Notch ligand, Dll4, is essential for angiogenesis during embryonic vascular development and is involved in tumour angiogenesis. Several recent publications demonstrated that blockade of Dll4 signalling inhibits tumour growth, suggesting that it may constitute a good candidate for anti-cancer therapy. In order to understand the role of Dll4 at the cellular level, we performed an analysis of Dll4-regulated genes in HUVECs. The genes identified included several angiogenic signalling pathways, such as VEGF, FGF and HGF. In particular we identified downregulation (VEGFR2, placenta growth factor PlGF) of VEGF pathway components resulting in the overall effect of limiting the response of HUVEC to VEGF. However extensive upregulation of VEGFR1 was observed allowing continued response to its ligand PlGF but the soluble form of the VEGFR1, sVEGFR1 was also upregulated. PlGF enhanced tubulogenesis of HUVEC suggesting that downregulation of PlGF and upregulation of VEGFR1 including sVEGFR1 are important mechanisms by which Dll4 attenuates PlGF and VEGF signalling. Dll4-stimulated HUVECs had impaired ERK activation in response to VEGF and HGF indicating that Dll4 signalling negatively regulates these pathways. Dll4 expression reduced vessel sprout length in a 3D tubulogenesis assay confirming that Dll4 signalling inhibits angiogenesis. Altogether, our data suggest that Dll4 expression acts as a switch from the proliferative phase of angiogenesis to the maturation and stabilisation phase by blocking endothelial cell proliferation and allowing induction of a more mature, differentiated phenotype. The regulation of sVEGFR1 provides a novel mechanism for Dll4 signalling to regulate cells at distance, not just in adjacent cells. PMID- 17692343 TI - VRX-03011, a novel 5-HT4 agonist, enhances memory and hippocampal acetylcholine efflux. AB - Recent evidence suggests that 5-hydroxytryptamine (5-HT)(4) receptor activity enhances cognition and provides neuroprotection. Here we report the effects of VRX-03011, a novel partial 5-HT(4) agonist, that is both potent (K(i) approximately 30 nM) and highly selective (K(i) > 5 microM for all other 5-HT receptors tested). In separate experiments, rats received VRX-03011 (0.1-10 mg/kg i.p.) 30 min prior to spontaneous alternation testing in a no-delay or a 30-s delay condition. VRX-03011 (1, 5 and 10 mg/kg, but not 0.1 mg/kg) significantly enhanced delayed spontaneous alternation performance while none of the doses enhanced performance in the no-delay test. VRX-03011 (1 and 5 mg/kg) concomitantly enhanced hippocampal acetylcholine output and delayed spontaneous alternation scores compared to that of vehicle controls, but had no effect on hippocampal acetylcholine release under a resting condition. Moreover, suboptimal doses of VRX-03011 and the acetylcholinesterase inhibitor galanthamine combined to enhance memory. VRX-03011 also regulated amyloid precursor protein (APP) metabolism by inducing a concentration-dependent increase in the non amyloidogenic soluble form of APP (sAPPalpha) with an EC(50) approximately 1--10 nM. VRX-03011 had no effect on contractile properties in guinea pig ileum or colon preparations with an EC(50) > 10 microM and did not alter rat intestinal transit at doses up to 10 mg/kg. These findings suggest that VRX-03011 may represent a novel treatment for Alzheimer's disease that reduces cognitive impairments and provides neuroprotection without gastrointestinal side effects. PMID- 17692344 TI - CB1 receptor stimulation in specific brain areas differently modulate anxiety related behaviour. AB - There is a general consensus that the effects of cannabinoid agonists on anxiety seem to be biphasic, with low doses being anxiolytic and high doses ineffective or possibly anxiogenic. Besides the behavioural effects of cannabinoids on anxiety, very few papers have dealt with the neuroanatomical sites of these effects. We investigated the effect on rat anxiety behavior of local administration of THC in the prefrontal cortex, basolateral amygdala and ventral hippocampus, brain regions belonging to the emotional circuit and containing high levels of CB1 receptors. THC microinjected at low doses in the prefrontal cortex (10 microg) and ventral hippocampus (5 microg) induced in rats an anxiolytic-like response tested in the elevated plus-maze, whilst higher doses lost the anxiolytic effect and even seemed to switch into an anxiogenic profile. Low THC doses (1 microg) in the basolateral amygdala produced an anxiogenic-like response whereas higher doses were ineffective. All these effects were CB1-dependent and closely linked to modulation of CREB activation. Specifically, THC anxiolytic activity in the prefrontal cortex and ventral hippocampus was paralleled by an increase in CREB activation, whilst THC anxiogenic response in the basolateral amygdala was paralleled by a decrease in CREB activation. Our results suggest that while a mild activation of CB1 receptors in the prefrontal cortex and ventral hippocampus attenuates anxiety, a slight CB1 receptor stimulation in the amygdala results in an anxiogenic-like response. The molecular underpinnings of these effects involve a direct stimulation of CB1 receptors ending in pCREB modulation and/or a possible alteration in the fine tuning of local neuromodulator release. PMID- 17692345 TI - Hydrogen sulfide induced neuronal death occurs via glutamate receptor and is associated with calpain activation and lysosomal rupture in mouse primary cortical neurons. AB - Hydrogen sulfide (H(2)S) is a cytotoxic gas recently proposed as a novel neuromodulator. Endogenous levels of H(2)S in the brain range between 50 and 160 microM and perturbed H(2)S synthesis has been reported in the brains from stroke, Alzheimer's disease and Down syndrome patients. Recently, in immature non glutamate receptor expressing mouse cortical neurons H(2)S was shown to inhibit cell death exhibited by high concentrations of glutamate whereas H(2)S was not cytotoxic. Due to the reported role of H(2)S in facilitating LTP through NMDA receptors we examined the effects of H(2)S on glutamate receptor functioning using mature cortical neurons expressing functional glutamate receptor subtypes. Addition of 100 microM glutamate exhibited extensive cell death which was exacerbated by co-incubation with < or = 200 microM of the H(2)S donor sodium hydrosulfide (NaHS). At <200 microM NaHS induced apoptosis whereas >200 microM NaHS induced necrosis. Cell death was inhibited by pharmacological glutamate receptor antagonists MK801 and APV (NMDA receptor antagonists), and CNQX (kainate and AMPA receptor antagonist) but not kynurenate (broad spectrum glutamate receptor antagonist), GYKI52466 (more selective AMPA receptor antagonist) and CYZ (AMPA receptor potentiator). Although markers of apoptosis were observed, we did not detect caspase activation either by Western blotting or fluorescence assays and caspase inhibitors did not prevent cell death. Rather, H(2)S induced calpain activation and lysosomal membrane destabilization; processes inhibited by preferential antagonists of NMDA and kainate receptors. These data suggest that H(2)S induced neuronal death through ionotropic glutamate receptors, which recruits apoptosis to ensure cellular demise and employs calpains and lysosomal rupture. This study provides novel insights into cell death observed in neurodegenerative diseases involving glutamate receptor activation and perturbed H(2)S synthesis. PMID- 17692346 TI - Altered figure-ground perception in monkeys with an extra-striate lesion. AB - The visual system binds and segments the elements of an image into coherent objects and their surroundings. Recent findings demonstrate that primary visual cortex is involved in this process of figure-ground organization. In the primary visual cortex the late part of a neural response to a stimulus correlates with figure-ground segregation and perception. Such a late onset indicates an involvement of feedback projections from higher visual areas. To investigate the possible role of feedback in figure-ground perception we removed dorsal extra striate areas of the monkey visual cortex. The findings show that figure-ground perception is reduced when the figure is presented in the lesioned hemifield and perception is normal when the figure appeared in the intact hemifield. In conclusion, our observations show the importance for recurrent processing in visual perception. PMID- 17692347 TI - Functional compensation or pathology in cortico-subcortical interactions in preclinical Huntington's disease? AB - Huntington's disease (HD) is an autosomal dominant neurological disorder, with degeneration amongst others affecting the basal ganglia dopaminergic system. Recent findings suggest compensatory as well as pathogenetic mechanisms mediated via the adenosine receptor system in the presymptomatic stage (pHD) of HD. The adenosine receptor system is functionally related to the dopaminergic system. In this study, we assessed error processing, a dopamine-dependent cognitive function, using an event-related potential the error negativity (Ne/ERN) in pHD and controls. This was done by means of a flanker task. The Ne consists of a cognitive and a motor component, expressed via different frequency bands. Time frequency decomposition of the Ne into delta and theta sub-components was applied to assess if degeneration or compensation predominantly involve cognitive or motor processes. No parameter of the behavioral data (reaction times, error frequency, corrections, post-error slowing) differed between the groups. A selective increase in the power of the cognitive delta-Ne component was found in pHD relative to controls inversely related to the estimated age of onset (eAO). Thus, the increase in the power of the cognitive delta-Ne component was stronger in pHD with an earlier eAO. An earlier eAO implies stronger pathogenetic mechanisms. Due to the behavioral data our results speak for a solely cognitive compensating-mechanism controlling performance monitoring in pHD. In contrast, correlations with eAO suggest that the increase in delta-Ne activity is also related to pathogenesis. It is proposed that compensation is a transient effect of the whole pathogenetic dynamics of HD, with these two processes not foreclosing each other. PMID- 17692348 TI - Behavioural, histological and cytokine responses during hyperalgesia induced by carrageenan injection in the rat tail. AB - We produced experimental inflammatory hyperalgesia by injecting carrageenan into the tail of Sprague-Dawley rats. We compared the rats' voluntary running wheel activity following carrageenan injection into the tail to that after carrageenan injection into the hind paw, the conventional site of inflammation, to identify whether the site of inflammatory-induced hyperalgesia altered voluntary activity. We also measured voluntary running before and after injection of carrageenan or saline into the tail or hind paw, and in separate groups of rats we measured the nociceptive response and the associated pro-inflammatory cytokine profiles following a carrageenan injection into the tail. Female rats were injected intradermally with either 2 mg carrageenan or saline into the dorsal surface of the tail. Withdrawal responses to noxious heat (49 degrees C water), and punctate mechanical (electronic anaesthesiometer) challenges were recorded in 12 rats for 3 days before and 1 h to 48 h after injection. In a separate group of rats, interleukin (IL)-1beta, IL-6, tumour necrosis factor-alpha (TNF-alpha) and cytokine-induced neutrophil chemoattractant (CINC-1) concentrations were measured in plasma and tail tissue samples taken at the site of injection, 3 h, 6 h and 24 h after injections. Voluntary wheel running was reduced significantly following carrageenan injection into the hind paw compared to that after saline injection into the hind paw. Carrageenan injection into the tail did not result in significant reduction in wheel running compared to that after saline injection into the tail. Both thermal and mechanical hyperalgesia were present after carrageenan injection into the tail (P<0.01, ANOVA). The hyperalgesia at the site coincided with significant increases in TNF-alpha, IL-1beta, IL-6 and CINC-1 tissue concentrations, peaking 6 h after carrageenan injection (P<0.01, ANOVA). We conclude that carrageenan injection into the tail produces inflammatory hyperalgesia with underlying pro-inflammatory cytokine release, but does not affect voluntary running wheel activity in rats. PMID- 17692349 TI - [Otologic sequels in velopalatine clefts. Analysis and management]. AB - As early as in 1878, medical teams managing children born with a velopalatine cleft had noted the prevalence of middle-ear pathologies largely related to anatomic and inflammatory Eustachian tube dysfunction. The aim of this study was to describe otologic sequels related to a velopalatine cleft and to suggest an adapted management. These sequels are evolving presentations of chronic serous otitis; they worsen the functional prognosis (hypoacousia) and more rarely the vital prognosis (cerebral or infectious complications of cholesteatoma). We must stress the importance of prevention: during the initial management, by Eustachian tube rehabilitation, and by ENT (Ear, Noseand Throat) follow-up allowing to prevent these sequels and to bring hearing to normal as soon as possible, so as to support cognitive development, language skills, and sociofamilial integration of the children. PMID- 17692350 TI - 6E-hydroximinosteroid homodimerization by cross-metathesis processes. AB - A rapid and efficient synthesis of 6E-hydroximinosteroid homodimers is described. The two new compounds were linked at position 3 of the steroid nucleus via a ruthenium catalyzed cross-metathesis reaction. The cytotoxic activity of these compounds was evaluated in vitro on human lung carcinoma A549 (ATCC CCL-185), colon adenocarcinoma HCT-116 (ATCC CCL-247), human caucasian glioblastoma multiforme T98G (ECACC 92090213) and human pancreatic adenocarcinoma PSN1 (ECACC 94060601) tumour cells. Homodimer 10b presented selective activity against HCT 116, although they are not highly toxic when compared with the monomer counterparts. PMID- 17692351 TI - Preparation and characterization of some keto-bile acid azines. AB - New acyclic dimers of ketocholanic acids with hydrazine were obtained. Crystal structure was determined for the 3,7-dihydroxy-12-ketocholanic acid azine. Some distinctive (1)H NMR signals are assigned for the entire set of azines. PMID- 17692352 TI - A role for transforming growth factor-beta apoptotic signaling pathway in liver injury induced by ingestion of water contaminated with high levels of Cr(VI). AB - Hexavalent chromium [Cr(VI)] exposure is commonly associated with lung cancer. Although other adverse health effects have been reported, some authors, on assuming that orally ingested Cr(VI) is efficiently detoxified upon reduction by body fluids, believe that Cr(VI) do not target cells other than respiratory tract cells. In rodents, ingested Cr(VI)-contaminated water was reported to induce, in the liver, increases in TGF-beta transcripts. As TGF-beta dependent signaling pathways are closely associated with hepatic injury, the present study was undertaken addressing two specific issues: the effects of ingestion of water contaminated with high levels of Cr(VI) in rat liver structure and function; and the role of the TGF-beta pathway in Cr(VI)-induced liver injury. Examination of Wistar rats exposed to 20 ppm Cr(VI)-contaminated water for 10 weeks showed increased serum glucose and alanine aminotransferase (ALT) levels. Liver histological examination revealed hepatocellular apoptosis, further confirmed by immunohystochemical study of Caspase 3 expression. Liver gene expression analysis revealed increased expression of Smad2/Smad4 and Dapk, suggesting the involvement of the TGF-beta pathway in the apoptotic process. Since no changes in Smad3 expression were observed it appears apoptosis is using a Smad3-independent pathway. Increased expression of both Caspase 8 and Daxx genes suggests also the involvement of the Fas pathway. Gene expression analysis also revealed that a p160(ROCK)-Rho-independent pathway operates, leading to cell contraction and membrane blebbing, characteristic apoptotic features. These findings suggest that either the amount of Cr(VI) ingested overwhelmed the body fluids reductive capacity or some Cr(VI) escapes the reductive protection barrier, thus targeting the liver and inducing apoptosis. PMID- 17692354 TI - Polychlorinated biphenyl (PCB) induction of CYP3A4 enzyme activity in healthy Faroese adults. AB - The CYP3A4 enzyme is, along with other cytochrome P450 enzymes, involved in the metabolism of environmental pollutants and is highly inducible by these substances. A commercial polychlorinated biphenyl (PCB) mixture, 1,1,1,-trichloro 2-(o-chlorophenyl), 2-(p'-chlorophenyl)ethane (o,p'-DDT) and 1,1,-dichloro-2,2 bis (p-chlorophenyl)ethene (p,p'-DDE) are known to induce CYP3A4 activity through activation of nuclear receptors, such as the pregnane X receptor. However, this induction of CYP3A4 has not yet been investigated in humans. Thus, the aim of the study was to determine the variability of the CYP3A4 phenotype in regard to increased concentrations of PCBs and other persistent organohalogen pollutants (POPs) in healthy Faroese adults. In 310 randomly selected Faroese residents aged 18-60 years, the CYP3A4 activity was determined based on the urinary 6beta hydroxycortisol/cortisol (6beta-OHC/FC) ratio. POP exposures were assessed by measuring their concentrations in serum lipid. The results showed a unimodal distribution of the 6beta-OHC/FC ratio with values ranging from 0.58 to 27.38. Women had a slightly higher 6beta-OHC/FC ratio than men (p=0.07). Confounder adjusted multiple regression analysis showed significant associations between 6beta-OHC/FC ratios and summation PCB, PCB-TEQ and p,p'-DDE, o,p'-DDT and HCB, respectively, but the associations were statistically significant for men only. PMID- 17692353 TI - Oral carcinogenicity study with nickel sulfate hexahydrate in Fischer 344 rats. AB - Until now, existing data on the oral carcinogenicity of nickel substances have been inconclusive. Yet, the assessment of oral carcinogenicity of nickel has serious scientific and regulatory implications. In the present study, nickel sulfate hexahydrate was administered daily to Fischer 344 rats by oral gavage for 2 years (104 weeks) at exposure levels of 10, 30 and 50 mg NiSO(4).6H(2)O/kg. This treatment produced a statistically significant reduction in body weight of male and female rats, compared to controls, in an exposure-related fashion at 30 and 50 mg/kg/day. An exposure-dependent increase in mortality was observed in female rats. However, the overall study survival rate (males and females) was at least 25 animals per group (compliant with OECD guidelines) in the treated animals. Daily oral administration of nickel sulfate hexahydrate did not produce an exposure-related increase in any common tumor type or an increase in any rare tumors. One tumor type was statistically increased in a nickel sulfate-treated group compared to the study controls (keratoacanthoma in the 10 mg NiSO(4).6H(2)O/kg/day males), but there was no exposure-response relationship for this common tumor type. This study achieved sufficient toxicity to reach the Maximum Tolerated Dose (MTD) while maintaining a sufficiently high survival rate to allow evaluation for carcinogenicity. The present study indicated that nickel sulfate hexahydrate does not have the potential to cause carcinogenicity by the oral route of exposure in the Fischer 344 rat. Data from this and other studies demonstrate that inhalation is the only route of exposure that might cause concern for cancer in association with nickel exposures. PMID- 17692355 TI - Heparan sulfate is a binding molecule but not a receptor for CEACAM1-independent infection of murine coronavirus. AB - A highly neurovirulent mouse hepatitis virus (MHV) JHMV strain (wt) with receptor (MHVR)-independent infection activity and its low-virulent mutant srr7 without such activity were found to attach to MHVR-negative, non-permissive BHK cells. To identify the molecule that interacts with JHMV, we focused on heparan sulfate (HS) since it works as a receptor of a mutant MHV-rec1 that infects in an MHVR independent fashion. The present study indicates that HS interacts with both wt JHMV and srr7 but it does not function as an entry receptor as it apparently does for MHV-rec1. Furthermore, HS failed to serve as an entry receptor in the MHVR independent infection of wt JHMV, indicating that HS is not a host factor that wt JHMV utilizes in an MHVR-independent infection. PMID- 17692356 TI - Improvement of remote monitoring on water quality in a subtropical reservoir by incorporating grammatical evolution with parallel genetic algorithms into satellite imagery. AB - Parallel GEGA was constructed by incorporating grammatical evolution (GE) into the parallel genetic algorithm (GA) to improve reservoir water quality monitoring based on remote sensing images. A cruise was conducted to ground-truth chlorophyll-a (Chl-a) concentration longitudinally along the Feitsui Reservoir, the primary water supply for Taipei City in Taiwan. Empirical functions with multiple spectral parameters from the Landsat 7 Enhanced Thematic Mapper (ETM+) data were constructed. The GE, an evolutionary automatic programming type system, automatically discovers complex nonlinear mathematical relationships among observed Chl-a concentrations and remote-sensed imageries. A GA was used afterward with GE to optimize the appropriate function type. Various parallel subpopulations were processed to enhance search efficiency during the optimization procedure with GA. Compared with a traditional linear multiple regression (LMR), the performance of parallel GEGA was found to be better than that of the traditional LMR model with lower estimating errors. PMID- 17692357 TI - The control of mercury vapor using biotrickling filters. AB - The feasibility of using biotrickling filters for the removal of mercury vapor from simulated flue gases was evaluated. The experiments were carried out in laboratory-scale biotrickling filters with various mixed cultures naturally attached on a polyurethane foam packing. Sulfur oxidizing bacteria, toluene degraders and denitrifiers were used and compared for their ability to remove Hg 0 vapor. In particular, the biotrickling filters with sulfur oxidizing bacteria were able to remove 100% of mercury vapor, with an inlet concentration of 300-650 microg m(-3), at a gas contact time as low as six seconds. 87-92% of the removed mercury was fixed in or onto the microbial cells while the remaining left the system with the trickling liquid. The removal of mercury vapors in a biotrickling filter with dead cells was almost equivalent to this in biotrickling filters with live cells, indicating that significant abiotic removal mechanisms existed. Sulfur oxidizing bacteria biotrickling filters were the most effective in controlling mercury vapors, suggesting that sulfur played a key role. Identification of the location of metal deposition and of the form of metal was conducted using TEM, energy dispersive X-ray analysis (EDAX) and mercury elution analyses. The results suggested that mercury removal was through a series of complex mechanisms, probably both biotic and abiotic, including sorption in and onto cellular material and possible biotransformations. Overall, the study demonstrates that biotrickling filters appear to be a promising alternative for mercury vapor removal from flue gases. PMID- 17692358 TI - Degradation of the drug diclofenac in water by sonolysis in presence of catalysts. AB - Diclofenac, as one of the most popular antiphlogistics, is produced in great quantities. Nowadays this drug is ubiquitously present in the aquatic environment due to its resistance to biodegradation. Degradation by ultrasonic irradiation is a possibility to eliminate diclofenac from water without the addition of chemicals. The sonolysis of diclofenac in water was investigated at ultrasound frequencies of 24 kHz, 216 kHz, 617 kHz, and 850 kHz and in the presence of various catalysts (TiO2, SiO2, SnO2, and titanosilicate). The degradation of diclofenac by sonolysis of an aqueous solution at 617 kHz followed first-order kinetics. Catalysts, especially TiO2 increased the rate of degradation. Within 30 min of irradiation, the relative concentration of diclofenac decreased from 100% to 16%. By HPLC and GC-MS methods, chlorinated anilines, phenols and carboxylic acid derivatives were detected as a result of the sonolysis. About 35% of organic chlorine was transformed into inorganic chloride. Most of the identified degradation products in the sonolysis of diclofenac were the same compounds that were detected during photo-oxidation experiments with this anti-inflammatory drug. PMID- 17692359 TI - High variation of PCDDs, PCDFs, and dioxin-like PCBs ratio in cooked food from the first total diet survey in Taiwan. AB - This study determined the levels of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs), and dioxin-like polychlorinated biphenyls (dl-PCBs) in 240 individual food samples, belonging to 37 different foodstuffs in first total diet study (TDS) in Taiwan. The foods were collected from markets located in eight cities or counties around Taiwan. The food was cooked in a laboratory according to recipes typically used in Taiwan. In this study, PCDD/Fs were lower than the limits proposed by the European Union (EU) regulation for commercialized food, except for a notable PCDD/Fs level in ducks (3.660 pg WHO-TEQ/g, fat) obtained from central Taiwan. We hypothesize the duck meat might be probably polluted via emission of a fly ash recycling plant located near the duck farms. In addition to fish, most foods had high PCDD/Fs to dl-PCBs ratio. Needle fish and sea perch had relatively lower PCDD/Fs and dl-PCBs levels compared with those in other fish. Data from this study can be utilized for further consideration about dietary intake. PMID- 17692360 TI - Comment on "Persistent organic pollutants in 9/11 world trade center rescue workers: reduction following detoxification" by James Dahlgren, Marie Cecchini, Harpreet Takhar, and Olaf Paepke [Chemosphere 69/8 (2007) 1320-1325]. PMID- 17692361 TI - Bio-syngas production with low concentrations of CO2 and CH4 from microwave induced pyrolysis of wet and dried sewage sludge. AB - This paper assesses the feasibility of producing syngas from sewage sludge via two pyrolysis processes: microwave-induced pyrolysis (MWP) and conventional pyrolysis (CP). The changes in the composition of the produced gas as a function of the pyrolysis treatment and the initial moisture content of the sludge were evaluated. It was found that MWP produced a gas with a higher concentration of syngas than CP, reaching values of up to 94vol%. Moreover, this gas showed a CO2 and CH4 concentration around 50% and 70%, respectively, lower than that obtained in the gas from CP. With respect to the effect of moisture on gas composition, this was more pronounced in CP than in MWP. Thus, the presence of moisture increases the concentration of H2 and CO2 and decreases that of CO, especially when CP was used. In order to elucidate the behaviour of CO2 during the pyrolysis, the CO2 gasification kinetics of the char obtained from the pyrolysis were investigated. It was established that in microwave heating the gasification reaction is much more favoured than in conventional heating. Therefore, the low concentration of CO2 and the high concentration of CO in the microwave pyrolysis gas could be due to the self-gasification of the residue by the CO2 produced during the devolatilization of the sewage sludge in the pyrolysis process. PMID- 17692362 TI - Sources of polycyclic aromatic hydrocarbons (PAHs) in street dust in a tropical Asian mega-city, Bangkok, Thailand. AB - We collected samples of roadside air, automobile exhaust soot, tires, asphalt, and used engine oil in a tropical Asian mega-city, Bangkok, Thailand, and analyzed them for polycyclic aromatic hydrocarbons (PAHs) and hopanes. The concentrations and compositions of PAHs and hopanes were utilized to identify the sources of PAHs in street dust, in which high concentrations of PAHs were reported in our previous study. Weight-based concentrations of total PAHs had the following order: gasoline-powered vehicle soot (2600+/-2900 microg/g; n=4)>diesel powered vehicle soot (115+/-245 microg/g; n=7) approximately roadside aerosols (101+/-35 microg/g; n=5) approximately used engine oil (97+/-65 microg/g; n=4) approximately tire wear particles (82+/-41 microg/g; n=5)>asphalt (2.3+/-1.6 microg/g; n=3)>street dust (1.1+/-0.8 microg/g; n=10). In cluster analysis, all the source materials fell into different clusters from that in which street dust fell, indicating that multiple source materials contribute to PAHs in the street dust. Multiple regression analysis of PAH profiles and diagnostics of hopane compositions identified tire debris as the major contributor of PAHs to street dust, followed by diesel vehicle exhaust. PMID- 17692363 TI - Osmium in environmental samples from Northeast Sweden. Part I. Evaluation of background status. AB - Osmium (Os) concentrations and (187)Os/(188)Os isotope abundance ratios are presented for sedimentary materials, soils, humus, plants, mushrooms, mosses and lichens collected in the vicinity of the town of Lulea, Northeast Sweden, the data for biological specimens being the first reported. Contributions from sampling and varying exposure time to the observed environmental variability were evaluated. Sedimentary materials (from both fresh and brackish water) are most elevated in radiogenic (187)Os, followed by inorganic soil horizons, mushrooms and humus. The Os isotopic compositions of plants, mosses and lichens are much less radiogenic, with mean (187)Os/(188)Os lying within a relatively narrow 0.3 0.6 range. Significant temporal variations in Os concentrations and isotopic compositions of plant samples are attributed to integrative uptake of airborne Os with non-radiogenic composition. Measured Os concentrations in biological matrices increase in the order: small shrub leaves (blueberry and lingonberry)< or =spruce needles< or =mushrooms< or =tree leaves< or =pine needles or =18 min was applied to mice with bilateral regional cerebral blood flow (rCBF)> or =10% of baseline at 2.5 min of ischemia. However, only groups with ischemic duration< or =18 min were used for statistical analysis because of the high mortality in the other groups. After 7 days, patency of PcomA and hippocampal neuronal loss in the CA1 subfield were evaluated. Outcome variability was reduced when hemispheres containing PcomA were excluded from analysis; ischemic outcome was not affected by the presence of a contralateral PcomA. Extending ischemic duration based on rCBF did not reduce outcome variability because the initial rCBF could not reliably predict PcomA. Therefore, after an optimal ischemic duration, evaluating hippocampal injury in each hemisphere independently according to the existence of PcomA is an effective and reliable method to obtain consistent results in this pre-clinical mouse model. PMID- 17692390 TI - Maternal plasma cytokines in early- and mid-gestation of normal human pregnancy and their association with maternal factors. AB - Few studies have assessed longitudinal changes in circulating cytokine levels during normal pregnancy. We have examined the natural history of maternal plasma cytokines from early- to mid-pregnancy in a large, longitudinal cohort. Multiplex flow cytometry was used to measure interleukin (IL)-2, IL-6, IL-12, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF) in early- (median [IQR]: 8.5 weeks [7.1, 10.0]) and mid-pregnancy (25.0 [24.1, 26.1]) from 1274 Danish women delivering singleton term infants. GM-CSF decreased from early- to mid-pregnancy (median percent change [95% CI]: -51.3% [-59.1%, -41.8%]), while increases were observed in IL-6 (24.3% [4.6%, 43.9%]), IL-12 (21.3% [8.9%, 35.7%]) and IFN-gamma (131.7% [100.2%, 171.6%]); IL-2 (-2.8% [-11.5%, 0.0%]) and TNF-alpha (0% [-5.9%, 25.6%]) remained stable. Positive correlations were found between all cytokines, both in early- and mid-pregnancy (all p<0.001). Early- and mid-pregnancy levels were rank correlated for IL-2, IL-12, TNF-alpha and GM-CSF, but not IL-6 and IFN-gamma; these correlations were generally weaker than correlations between different cytokines at a single time point in pregnancy. Women with a pre-pregnancy BMI <18.5 had reduced levels of IFN-gamma and GM-CSF compared to women in other BMI categories, while women aged >or=35 years had elevated IL-2, IL-6, TNF-alpha and IFN-gamma. Early-pregnancy levels of TNF-alpha were higher in women with a prior preterm delivery. Cytokine levels were not associated with gravidity. In conclusion, cytokines were detected in plasma during early- and mid-pregnancy, with IL-6, IL-12, IFN-gamma and GM-CSF concentrations varying over pregnancy. Concentrations may depend on BMI, maternal age and prior preterm delivery. PMID- 17692391 TI - Facial asymmetry in maxillary sinus hypoplasia. AB - Maxillary sinus hypoplasia is a rare finding for pediatric patients. We describe two children with maxillary sinus hypoplasia associated with facial asymmetry. One patient underwent endoscopic maxillary antrostomy. For the other, treatment was deferred at the patient's request. The management options of facial asymmetry for patients with maxillary sinus hypoplasia are discussed. PMID- 17692392 TI - Rottlerin: an inappropriate and ineffective inhibitor of PKCdelta. AB - Rottlerin has been used as a protein kinase Cdelta (PKCdelta)-selective inhibitor in hundreds of studies, on the basis of initial substrate phosphorylation studies in vitro. However, in more recent studies, rottlerin did not block PKCdelta activity but did block other kinase and non-kinase proteins in vitro and activated multiple Ca(2+)-sensitive K(+) channels with high potency. Rottlerin uncouples mitochondria, and this uncoupling depolarizes the mitochondrial membrane potential, reduces cellular ATP levels, activates 5'-AMP-activated protein kinase (AMPK) and affects mitochondrial production of reactive oxygen species (ROS). Classical mitochondrial uncouplers also produce these secondary changes, and reductions in ATP can block PKCdelta tyrosine phosphorylation and activation and generate effects resembling those produced by direct inhibition of kinase. Rottlerin also has effects in cells in which PKCdelta is downregulated or genetically deleted. These findings indicate that there have been gross misinterpretations in studies using rottlerin as a pharmacological tool to identify PKCdelta-dependent cellular events and indicate that rottlerin should not be used to determine the involvement of PKCdelta in biological processes. PMID- 17692393 TI - Programmed death as a therapeutic target to reduce myocardial infarction. AB - In the United States, angioplasty or bypass surgery to remove coronary occlusions is performed on approximately two million patients each year. Although reperfusion is essential for salvaging ischemic myocardium, it also promotes infarction by activating programmed cell death in the formerly ischemic tissue. Reperfusion injury begins when oxidative stress and calcium accumulation by the mitochondria cause activation of the so-called mitochondrial death channels. These channels have become the focus of evolving strategies to protect the heart from infarction. Preclinical and preliminary clinical studies indicate that agents with diverse modes of action can reduce infarct size by 50% or more and significantly preserve myocardial functions. This article reviews the most advanced pharmacological approaches for their ability to reduce infarct size by inhibiting the mitochondrial death pathways. PMID- 17692394 TI - Treatment of inflammatory diseases by selective eicosanoid inhibition: a double edged sword? AB - Eicosanoids are generally considered to be potent pro-inflammatory mediators, and their suppression has, therefore, been a desirable therapeutic goal. However, analysis of the literature reveals that inhibition of specific eicosanoids per se is a simplistic approach because it overlooks the fact that net pathophysiological effects of these lipid mediators arise from a complex balance between eicosanoids derived from different pathways, which might exhibit both pro and anti-inflammatory activities (depending on organs and disease stage), or which might have essential physiological roles. An alternative strategy, discussed in this review, might be to control inflammatory lipid mediators in such a way as to avoid disrupting this intricate inter-eicosanoid balance and its physiological sequelae. PMID- 17692395 TI - Liaisons dangereuses: P2X(7) and the inflammasome. AB - Inflammation is initiated by specific pathogen constituents, in addition to intrinsic host molecules that are released by injured or dying cells. Among such host endogenous pro-inflammatory factors, nucleotides (mainly ATP) are attracting increasing interest for their potential as natural adjuvants. Extracellular ATP stimulates a family of receptors, named P2, one of which, P2X(7), is a potent mediator of interleukin (IL)-1beta and IL-18 processing and release. The mechanism and physiological significance of this unusual pro-inflammatory activity have long remained elusive. Recent data unveiling the structure and function of a novel caspase-activating platform, the inflammasome, shed light on P2X(7) receptor coupling to IL-1beta release, and suggest a fascinating scenario for the initiation and amplification of the innate immune response. Here, I outline the intriguing links between the P2X(7) receptor and the NALP3 inflammasome, review recent evidence showing that this receptor is a potent activator of this multimolecular platform and discuss implications for pathogen immune cell interaction and for anti-inflammatory drug development. PMID- 17692396 TI - Functional relevance of neurotransmitter receptor heteromers in the central nervous system. AB - The existence of neurotransmitter receptor heteromers is becoming broadly accepted and their functional significance is being revealed. Heteromerization of neurotransmitter receptors produces functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. Neurotransmitter receptor heteromers can function as processors of computations that modulate cell signaling. Thus, the quantitative or qualitative aspects of the signaling generated by stimulation of any of the individual receptor units in the heteromer are different from those obtained during coactivation. Furthermore, recent studies demonstrate that some neurotransmitter receptor heteromers can exert an effect as processors of computations that directly modulate both pre- and postsynaptic neurotransmission. This is illustrated by the analysis of striatal receptor heteromers that control striatal glutamatergic neurotransmission. PMID- 17692397 TI - Phosphodiesterase type 5 inhibition coupled to strong reinforcement results in two periods of transient retention loss in the young chick. AB - Previous behavioural studies which have administered phosphodiesterase type-5 (PDE5) inhibitors have consistently demonstrated improved retention. However, when young chicks were trained on a strongly reinforced passive avoidance task 100microM zaprinast caused two periods of transient retention loss. This is opposed to past findings and may suggest an effect on retrieval. It is hypothesised that the level of reinforcement is central to this phenomenon. The molecular corollary of this may be the need to maintain cGMP homeostasis such that strong reinforcement+zaprinast may impair retention through the production of excessive levels of cGMP. This was demonstrated by two challenge studies whereby increasing concentrations of 8-Br-cGMP were administered in the presence of the guanylate cyclase inhibitor ODQ (100microM; ic) resulting in an inverted "U-shaped" retention curve. These findings suggest a more complex role for PDE5 and cGMP in memory processing than previously described and question the role of PDE5 inhibitors as nootropes under all circumstances. PMID- 17692398 TI - Transcription and alternative splicing in the yir multigene family of the malaria parasite Plasmodium y. yoelii: identification of motifs suggesting epigenetic and post-transcriptional control of RNA expression. AB - The Plasmodium interspersed repeat (pir) genes represent the largest multigene family in Plasmodium genomes, and the only one shared between the human pathogen, P. vivax, the simian malaria species P. knowlesi and the rodent malaria species P.y. yoelii, P. berghei and P.c. chabaudi. PIR have been shown to be expressed on the surface of red blood cells and are thought to play a role in antigenic variation. Here we have used a range of bioinformatic and experimental approaches to investigate the existence of gene subsets within P.y. yoelii pir. We have identified five groups of yir genes which could be further distinguished by chromosomal location and different alternative splicing events. Two of the groups were not highly represented among the transcribed pirs in blood stage parasites. Together these data suggest that different pir genes may be active at different stages of the life cycle of P. yoelii and may have different functions. Analysis of the 5' UTR identified a unique highly conserved yir/bir/cir specific promoter motif, which could serve as a general recognition element for yir transcription. However, its presence in front of all yirs makes it unlikely to play a role in regulating differential expression. PMID- 17692399 TI - Characterization of human malaria parasite Plasmodium falciparum eIF4E homologue and mRNA 5' cap status. AB - The mRNA 5' cap is an essential structural feature for translation of eukaryotic mRNA. Translation is initiated by recognition of the cap by the translation initiation factor eIF4E. To further our understanding of mRNA translation in the human malaria parasite Plasmodium falciparum, we have investigated the parasite eIF4E and its interaction with capped mRNA. We have purified P. falciparum eIF4E as a recombinant protein and demonstrated that it has canonical mRNA cap binding activity. We used this protein to purify P. falciparum capped mRNAs from total parasite RNA. Microarray analysis comparing total and eIF4E-purified capped mRNAs shows that 34 features were more than twofold under-represented in the purified RNA sample, including 19 features representative of nuclear transcripts. The putatively uncapped nuclear transcripts may represent a class of mRNAs targeted for storage and cap removal. PMID- 17692400 TI - Differential regulated expression of keratinocyte growth factor and its receptor in experimental and human liver fibrosis. AB - BACKGROUND AND AIM: Immunomodulatory and protective properties have been identified for the keratinocyte growth factor (KGF). For hepatocytes, pro proliferative and anti-apoptotic effects of this growth factor have been reported in vitro. This study was designed to characterize a putative role of KGF in observed histomorphological changes in both, human and experimental liver fibrosis. METHODS: Liver fibrosis and cirrhosis was induced in rats by repetitive exposure to phenobarbitone and increasing doses of carbon tetrachloride. Human samples were obtained from patients undergoing surgery for partial hepatectomy or transplantation. Organ samples were scored for inflammation and morphological changes. Expression of KGF and its receptor (KGFR) mRNA was quantified by real time RT-PCR. Protein expression and receptor phosphorylation was determined by Western blot analysis. In-situ hybridization and immunohistochemistry were utilized to determine distribution of KGF and KGFR in the liver. RESULTS: Expression of KGF was significantly increased in damaged liver tissue in correlation to the degree of fibrosis, whereas expression of the receptor was up regulated in early stages of liver fibrosis and down-regulated in cirrhotic organs. Protein expression of this growth factor and its receptor correlated with the alterations in mRNA. KGF expression was restricted to mesenchymal cells, whereas expression of KGFR was detected on hepatocytes only. CONCLUSION: The expression of KGF and KGFR is differentially and significantly regulated in damaged liver tissue. This growth factor might therefore not only contribute to morphological alterations but also regeneration of liver parenchyma most likely mediated by indirect mechanisms of action. PMID- 17692401 TI - Cystinyl aminopeptidase activity is decreased in renal cell carcinomas. AB - The involvement of peptidases in carcinogenetic processes of several tumor types has been researched in recent years. Although kidney is one of the major tissues known to express cystinyl-aminopeptidase (CAP), little is known about its role in renal neoplasia. This study analyzes fluorimetrically membrane-bound and soluble CAP activity in the three main renal cancers: clear cell (CCRCC), papillary (PRCC), and chromophobe (ChRCC) renal cell carcinomas. Overall, a marked decrease of membrane-bound CAP activity in all the three renal cell carcinomas was detected when compared with their respective surrounding non-tumor tissues. So, the tumor vs. non-tumor CAP ratios (units of peptidase per mg of protein) was as follows: 926+/-111 vs. 3778+/-276 for CCRCCs, 737+/-181 vs. 4351+/-950 for PRCCs, and 592+/-118 vs. 4905+/-935 for ChRCCs. In contrast, the soluble fraction of this enzyme displayed minor and non-significant changes when comparing tumor and non-tumor CAP activities in the whole series. After stratification by stage and grade, CCRCCs displayed significant differences: pT3 category had significantly higher levels of membrane-bound activity than pT1, and high grade cases (G3-4) had higher soluble CAP activity than low grade ones (G1-2). These data may open additional possibilities in the study of renal cell carcinoma with regard to the prognosis of patients. PMID- 17692403 TI - The panacea for cardiovascular diseases: the role of statins in the management of heart failure. PMID- 17692402 TI - Early prediction of the need for non-routine discharge planning for the elderly. AB - Successful home return from hospital admission is a key issue to provide quality healthcare in a society with numerous older subjects. Therefore, a screening method for early identification of patients who require intensive, non-routine discharge planning needs to be established. We have developed a 7-item screening sheet (the screening sheet at admission: SSA) and conducted a prospective cohort study to examine its usefulness in predicting the need for non-routine discharge planning. The SSA score yielded an area under receiver operating characteristic curve of 0.82. Moreover, a cutoff score of 2 or higher gave sensitivity, specificity and positive and negative predictive values of 0.82, 0.72, 0.13 and 0.99, respectively. A stepwise logistic regression model demonstrated that age of 75 years or more and impairment in basic activities of daily living (ADL) were significantly associated with requirement for non-routine discharge planning in surgical patients, while living alone or with a spouse aged 75 or older and readmission within 1 month were also significant predictors in medical patients. The SSA score may be useful in identifying patients who need further assessment and planning. While the four items were particularly important predictors, differences between medical and surgical patients should also be considered. PMID- 17692404 TI - Common origin of both right and left coronary arteries from the right sinus of Valsalva. AB - Anomalous origin of the left main coronary artery (LMCA) from the right sinus of Valsalva (RSOV) represents in about 2 per 10,000 patients undergoing diagnostic cardiac catheterization. This rare anomaly correlates with sudden cardiac death after exercise and angina. We describe the case of a middle-aged woman, suffering from typical angina pectoris, with an anomalous common origin of all coronary arteries from the RSOV. We also provide the variations of the anomaly and discuss briefly on pathophysiology and treatment. PMID- 17692405 TI - Management of the ascending aortic pseudo-aneurysms--a single centre experience. AB - Pseudo-aneurysms of the ascending aorta are rare complications of aortic root and/or valve surgery and generally, surgical intervention has been advised. In the present case series we follow the natural progression of this condition in eight patients. We conclude that the most obvious predisposing factors for pseudo aneurysm formation are: 1) Multiple aortic valve/root surgery for infective endocarditis and 2) A spectrum of diseases involving the ascending aortic wall. PMID- 17692406 TI - Systolic eccentricity index identifies right ventricular dysfunction in pulmonary hypertension. PMID- 17692407 TI - G-CSF after myocardial infarction accelerates angiogenesis and reduces fibrosis in swine. AB - OBJECTIVE: Recent studies have suggested that granulocyte colony-stimulating factor (G-CSF) may improve cardiac function after acute myocardial infarction (AMI) by accelerating angiogenesis or cardiomyogenesis, but negative results and side effect of G-CSF have also been reported. However, no previous studies have used large animal models of ischemia/reperfusion to investigate the effect and side effect of G-CSF after AMI. METHODS: The diagonal branch of the left anterior descending coronary artery of swine was balloon-occluded for 1 h and then reperfused. The animals of the G-CSF group were injected with G-CSF subcutaneously (5.0 microg/kg/day) for 6 days after MI and then sacrificed after 4 weeks. The control group received the same volume of saline. RESULTS: There were no differences between the groups in the rate of thrombotic obstruction or progression of stenosis lesion in coronary angiography. The ejection fraction and end-diastolic volume in the G-CSF group were not significantly improved over the control values. The fibrotic area was significantly smaller in the G-CSF group than in the controls (P<0.05), and the numbers of vessels counted in anti-von Willebrand factor and anti-alpha-smooth muscle actin-stained sections were significantly larger (P<0.005 and P<0.05, respectively). The expression of collagen III mRNA was significantly lower in the G-CSF group than in the control in the infarct (P<0.0005) and border areas (P<0.005), and TGF-beta mRNA was significantly lower in the G-CSF group in the border area (P<0.05). CONCLUSIONS: G-CSF could modify the healing process after AMI by accelerating angiogenesis in a swine ischemia/reperfusion model. At the dose administered, however, G-CSF did not seem to improve the global cardiac function. PMID- 17692408 TI - Angiotensin receptor blockers in the prevention of atrial fibrillation recurrence: need for a definitive trial. PMID- 17692409 TI - Obesity does not influence the correlation between exercise capacity and serum NT proBNP levels in chronic heart failure. AB - Recent studies have shown that obesity is an independent predictor of lower N terminal pro-BNP (NT-proBNP) levels and raised concerns about the validity of this biomarker in obese subjects. We evaluated the influence of obesity (body mass index>or=30 kg/m(2)) on the correlation between exercise capacity and serum NT-proBNP levels in 100 chronic heart failure (CHF) patients referred for cardiopulmonary exercise testing. Circulating NT-proBNP levels correlated well with lean body mass-adjusted peak oxygen consumption (VO(2)) in the entire cohort (R=-0.72, p<0.001) and in the obese (R=-0.71, p<0.001) and non-obese (R=-0.72, p<0.001) subgroups. There was no significant difference between the correlation coefficients of the two subgroups (p=0.934). In conclusion NT-proBNP levels predict exercise capacity in CHF patients irrespective of the presence of obesity. PMID- 17692410 TI - Estimation of global and regional cardiac function using 64-slice computed tomography: a comparison study with echocardiography, gated-SPECT and cardiovascular magnetic resonance. AB - BACKGROUND: Sixty-four-slice multidetector spiral computed tomography (CT) has improved temporal resolution and reduced acquisition time. We aimed to evaluate the functional analysis using 64-slice CT comparing with echocardiography, electrocardiographically gated single-photon emission tomography (SPECT) and cardiovascular magnetic resonance (CMR). METHODS: Six-three patients (77.4+/-18.6 bpm) underwent 64-slice CT and CMR (echocardiography in 55; SPECT in 33) within 2 weeks were retrospectively reviewed. The left ventricular volumetric data from different methods were compared with CMR. Regional wall motion was compared between CT and CMR in a 17-segment and 4-point system (1=normal to 4=akinesis/dyskinesis). RESULTS: Ejection fraction (EF), end-diastolic volume (EDV) and end-systolic volume (ESV) by CT agreed well with CMR (bias+/-SD, 0.22%+/-4.18, r=0.97;-0.59 mL+/-15.21, r=0.98; 1.09 mL+/-10.61, r=0.99) over a wide range of left ventricular (LV) function (EF 18-76% by CMR). Our results also showed good correlation of EF measured by CT and echocardiography (r=0.87) or SPECT (r=0.91, all P<0.0001); however, standard deviation of EF difference between CT and CMR was significantly less than echocardiography or SPECT (P<0.005). For regional wall motion, an exact agreement of 97% (kappa=0.91) was found between CT and CMR. CONCLUSION: Sixty-four-slice CT agreed well with CMR in LV function assessment, and had a superior accuracy than echocardiography and SPECT on EF estimation. Sixty-four-slice CT is considered a clinically acceptable and robust method to evaluate LV function. PMID- 17692411 TI - Clopidogrel resistance: a diagnostic challenge. AB - No clear and generally accepted definition of clopidogrel resistance has been achieved up to now. We believe that the new point-of-care assays of platelet function may help the clinicians to overcome to define clopidogrel resistance especially in patients undergoing percutaneous coronary intervention in whom the level of inhibition of platelets is clinically essential. PMID- 17692412 TI - Cardiac rupture or pericardial effusion? AB - After cardiogenic shock, myocardial rupture is the leading cause of in-hospital death from acute myocardial infarction (AMI). When possible, rapid diagnosis must lead to an emergency surgical repair to prevent sudden death. However, in some cases, despite new imaging techniques, the diagnosis may be difficult to obtain and the decision whether or not to operate, difficult. In the present report we describe the challenging case of a patient presenting a sub-acute cardiac rupture three days after anterior AMI. PMID- 17692413 TI - The Stress-Recovery Index for the risk stratification of women with typical chest pain. AB - AIM: To prospectively assess the prognostic value of the Stress-Recovery Index (SRI) in women with typical chest pain. METHODS: 165 women without known coronary artery disease, who complained of typical chest pain, were exercise tested and prospectively followed-up for the occurrence of cardiac death and nonfatal myocardial infarction. SRI, defined as the difference in absolute values between the area of heart rate-adjusted ST-segment depression during exercise and recovery, was derived in all. Clinical data, resting ejection fraction, and exercise testing data were entered into a sequential Cox's model; SRI was entered last. Model validation was performed by bootstrap adjusted by the degree of optimism in estimates. Survival curves were set up using Kaplan-Meier method and compared by the log-rank test. RESULTS: During a median follow-up time of 42 months, 19 events (14 cardiac deaths and 5 nonfatal myocardial infarction) were observed. Age (hazard ratio 3.58, 95% CI 0.87-15) and SRI (hazard ratio 0.62, 95% CI 0.42-0.92) were multivariate predictors of outcome. However, the addition of SRI increased the prognostic power of the model on top of clinical and exercise testing variables, as demonstrated by the significant (p=0.003) increase of the area under the ROC curve of the risk function. Survival analysis showed ascending SRI quartiles to identify a significant (p=0.005) increase in event-free survival. CONCLUSIONS: SRI is of value in predicting outcome of women with typical chest pain and provides additional prognostic information on the top of clinical and standard exercise testing data. PMID- 17692414 TI - Modeling the effect of sterilization rate on owned dog population size in central Italy. AB - A spreadsheet population dynamics model was constructed to evaluate the impact of female dog sterilization on the domestic dog population for the province of Teramo, Italy. Baseline owned dog population structure as well as the annual number of births, adoptions, abandonments, and purchases were estimated based on regional managed kennel data in addition to a telephone questionnaire administered to members of the local population. Age- and gender-dependent death rates were based on domestic dog life tables. The model predicts that at the current female dog sterilization rate of 30%, the owned dog population will most probably continue to increase. After 20 years, a mean annual increase of 2.6% (median: 2.5%, 95% CI: -3.2% to 8.8%) is projected assuming that the average age at sterilization is 3 years. A sterilization rate of at least 55% is estimated to be needed to halt population growth if the current age structure for female dog sterilization is maintained. However, if the province of Teramo were to focus on sterilizing female dogs less than 1 year of age, the required sterilization rate to arrest population growth could be reduced to as low as 26%. PMID- 17692415 TI - Stem cells in veterinary medicine--attempts at regenerating equine tendon after injury. AB - Stem cells have evoked considerable excitement in the animal-owning public because of the promise that stem cell technology could deliver tissue regeneration for injuries for which natural repair mechanisms do not deliver functional recovery and for which current therapeutic strategies have minimal effectiveness. This review focuses on the current use of stem cells within veterinary medicine, whose practitioners have used mesenchymal stem cells (MSCs), recovered from either bone marrow or adipose tissue, in clinical cases primarily to treat strain-induced tendon injury in the horse. The background on why this treatment has been advocated, the data supporting its use and the current encouraging outcome from clinical use in horses treated with bone-marrow-derived cells are presented together with the future challenges of stem-cell therapy for the veterinary community. PMID- 17692416 TI - Analysis of toxicity in patients with high risk prostate cancer treated with intensity-modulated pelvic radiation therapy and simultaneous integrated dose escalation to prostate area. AB - BACKGROUND AND PURPOSE: To report the treatment-related morbidity in patients with prostate cancer treated with an optimized pelvic intensity-modulated radiation therapy (IMRT) and simultaneous integrated dose escalation to prostate/prostate bed. MATERIALS AND METHODS: Between November 2003 and May 2006, 55 patients with localized prostate cancer and >15% risk of lymph node involvement were treated with pelvic IMRT and simultaneous dose escalation to prostate area. Twenty-four patients received a radical radiation therapy program, and the remaining thirty-one patients received a postoperative irradiation as adjuvant treatment or after biochemical or macroscopic local/regional relapse. After a customized immobilization all patients underwent contrast-enhanced CT. On the CT slices CTV1 and CTV2 were delineated. CTV(1) included the prostate and seminal vesicles or prostate bed. CTV(2) consisted of CTV(1) plus pelvic nodes. CTV(1) and CTV(2) were then expanded by 0.5 and 1cm, respectively, to generate the planning target volumes. IMRT treatment plans were generated using commercial inverse planning software. Total doses of 66-80 Gy and 50-59 Gy in 33-40 fractions were prescribed to the prostate area and pelvis, respectively. The worst acute and late rectal, intestinal and GU toxicities during and after treatment were scored according to the EORTC/RTOG scales. RESULTS: The IMRT dose distribution provided excellent PTV coverage and satisfying sparing of all the organs at risk, with no patient experiencing >grade 2 acute or late toxicities. Patients without acute grade 2 intestinal, rectal, and GU toxicity were 91%, 71%, and 63%, respectively. After a median follow-up of 19 months (interquartile range of 9 to 28 months), late grade 2 toxicity was detected only for rectum, with an actuarial 2-year rate of freedom from G2 rectal bleeding of 92%. (CI 95% 0.83 0.99.) CONCLUSIONS: Pelvic IMRT and simultaneous dose escalation to prostate area is a well-tolerated technique in patients with prostate cancer requiring treatment of pelvic lymph nodes, and seems to be associated with a lower frequency and severity of side effects when compared with conventional techniques reported in other series. PMID- 17692417 TI - Image-guided radiotherapy of bladder cancer: bladder volume variation and its relation to margins. AB - BACKGROUND AND PURPOSE: To control and account for bladder motion is a major challenge in radiotherapy (RT) of bladder cancer. This study investigates the relation between bladder volume variation and margins in conformal and image guided RT (IGRT) for this disease. MATERIALS AND METHODS: The correlation between the relative bladder volume (RBV, defined as repeat scan volume/planning scan volume) and the margins required to account for internal motion was first studied using a series of 20 bladder cancer patients with weekly repeat CT scanning during treatment. Both conformal RT (CRT) and IGRT were simulated; in the latter translational movement of the bladder was accounted for by isocentre shifting. Further analysis of bladder volumes and margins was performed using a second series of eight patients with twice-weekly repeat CT scanning. In an attempt to control bladder volume variation these patients were given fluid intake restrictions on alternating weeks during treatment. RESULTS: IGRT gave the strongest correlation between the RBV and margin size (R(2)=0.75; p<0.001). Using IGRT, isotropic margins >10mm were required in only 1% of the situations when the RBV1, whereas isotropic margins >10mm were required in 55% of the situations when the RBV>1. Less marked correlation was found using CRT (R(2) in the range 0.43 0.53, p<0.001) for four different methods used to assess the margins required in the six directions, although a strong correlation was found for the superior margin (R(2)=0.63; p<0.001). Fluid intake restriction gave a small reduction in both bladder volume (average absolute volume reduced from 126 to 121cm(3); RBV from 0.83 to 0.80) and bladder volume variation, but not sufficient to translate into margin reduction. CONCLUSIONS: The study showed the potential for a large margin reduction in bladder RT if the bladder volume is controlled and this potential was even greater for IGRT. An attempt to control the bladder volume by restricting fluid intake prior to the treatment session failed to give any reduction in the margins required. PMID- 17692418 TI - Time-varying spectral entropy differentiates between positive and negative feed back-related EEG activity in a hypothesis testing paradigm. AB - Positive and negative performance feedbacks have been shown to differentially modulate amplitudes of the associated electroencephalographic (EEG) brain activity. In the present study, we tested whether feedback also modulates the organization of neuronal oscillations. Ten college students serially tested hypotheses concerning a hidden rule by judging its presence or absence in triplets of digits and revised them on the basis of an exogenous performance feedback. The EEG signal time-locked to feedback was convolved with a family of complex wavelets. The time-varying spectral entropy of the resulting time frequency representation was then computed. The results showed that feedback differentially modulated spectral organization at frontal and posterior scalp regions around 200 ms and in the 300-500 ms range. Spatio-temporal principal component analysis (PCA) indicated that feedback-specific modulations essentially resulted from the interplay between fronto-polar, fronto-central, and parieto occipital components. Functional and methodological implications were discussed. PMID- 17692419 TI - Exposure to chronic constant light impairs spatial memory and influences long term depression in rats. AB - Exposure to chronic constant light (CCL) influences circadian rhythms and evokes stress. Since hippocampus is sensitive to stress, which facilitates long-term depression (LTD) in the hippocampal CA1 area, we examined whether CCL exposure influenced hippocampus-dependent spatial memory and synaptic plasticity in Wistar rats. Here we report that CCL exposure (3 weeks) disrupted 24-h cycle of locomotion activity in open field test. These rats showed shorter escape latency during initial phase of spatial learning but impaired hippocampus-dependent spatial memory without affecting the visual platform learning task in Morris water maze (MWM) compared with control rats. This effect may be due to stress adaptation as reflected by reduced thigmotaxis and anxiety-like behaviors in CCL rats. Moreover, in CA1 area of the hippocampal slices, CCL rats failed to show LTD by low frequency stimulation (LFS, 900 pulses, 1 Hz), while showed decreased short-term depression compared with control rats indicating the induction of LTD was influenced by CCL exposure. Furthermore, additional acute stress enabled LFS to induce LTD in control rats but not in CCL rats. Thus, these results suggested that CCL exposure impaired spatial memory and influenced hippocampal LTD, which may be due to stress adaptation. PMID- 17692420 TI - The influence of the cationic of quaternized chitosan on antifungal activity. AB - Quaternized chitosan: N-(2-hydroxyl-phenyl)-N,N-dimethyl chitosan (NHPDCS), N-(5 chloro-2-hydroxyl-phenyl)-N,N-dimethyl chitosan (NCHPDCS), N-(2-hydroxyl-5-nitro phenyl)-N,N-dimethyl chitosan (NHNPDCS) and N-(5-bromic-2-hydroxyl-phenyl)-N,N dimethyl chitosan (NBHPDCS) were synthesized and their antifungal activities against Botrytis cinerea Pers. (B. cinerea Pers.) and Colletotrichum lagenarium (Pass) Ell.et halst (C. lagenarium (Pass) Ell.et halst) were investigated. The results indicated that the quaternized chitosan derivatives had better inhibitory effects than chitosan, and the antifungal activities should be affected by the cation in these compounds. PMID- 17692422 TI - Electrophoretic purification of tumor-targeted polyethylenimine-based polyplexes reduces toxic side effects in vivo. AB - Non-viral vectors based on polyethylenimine (PEI) are usually generated with an excess of PEI. However, the amount of unbound polymer correlates with toxicity limiting the in vivo use of these gene carriers. Purification based on size exclusion chromatography of PEI/DNA polyplexes smaller than 200 nm has been shown to efficiently remove unbound PEI polymer. A novel purification method based on electrophoresis can purify PEI polyplexes independent of their size resulting in polyplexes with final PEI nitrogen/DNA phosphate ratios between 2.6 and 3.1. Also unbound PEI conjugates like PEGylated PEI and transferrin-conjugated PEI can be separated from the polyplexes, providing formulations with clearly defined compositions. Purified polyplexes can mediate in vitro gene transfer with high transfection efficiencies while demonstrating lower cellular toxicity. Purified polyplexes were well-tolerated when systemically delivered into tumor-bearing mice at 100 microg/20 g body weight, with tumor gene expression levels up to 5 fold higher than the non-purified polyplexes. Mice receiving non-purified gene carriers exhibited severe toxicity leading to high mortality and unfavourable gene expression patterns. PMID- 17692421 TI - Development of bionanocapsules targeting brain tumors. AB - Bionanocapsules (BNCs) are hollow nanoparticles that are composed of L protein (the hepatitis B virus surface antigen) and show specific affinity for human hepatocytes. The pre-S1 peptide displayed on the surface of BNCs is the specific ligand for binding to the receptor on human hepatocytes. Therefore, BNCs are not delivered to other tissues, such as the brain. The aim of the present study was to develop a novel drug delivery system (DDS) targeting brain tumors using BNCs that selectively targeted brain tumors. Epidermal growth factor receptor (EGFR), especially a constitutively active genomic sequence deletion variant of EGFR (EGFRvIII), is overexpressed in human glioblastoma. In the present study, we replaced the pre-S1 peptide with the antibody affinity motif of protein A and made hybrid BNCs conjugated with anti-human EGFR antibody recognizing EGFRvIII. The hybrid BNCs were efficiently delivered to glioma cells but not normal glial cells. Moreover, we confirmed the specific delivery of the hybrid BNCs to brain tumors in an in vivo brain tumor model. These results suggest that this new approach using BNCs is a promising system for brain tumor-targeted drug delivery. PMID- 17692423 TI - Depression and diabetes in a rural community in Pakistan. AB - AIMS: To determine the prevalence of depression amongst subjects with diabetes and associated risk factors in a rural area of Pakistan. METHODS: One thousand two hundred and ninety rural individuals aged 20 years and above were randomly included in the study. Fasting plasma glucose (FPG), BMI, WHR were recorded. Depression was assessed by Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: The prevalence of depression was 5.4% (95% CI: 4.2-6.6), slightly higher amongst women compared to men. Depression prevalence was 14.7% (6.6-22.8) amongst those with diabetes as opposed to 4.9 (3.7-6.1) amongst those without diabetes. Age, gender, and diabetes were independent risk factors for depression, while obesity had a protective effect. CONCLUSIONS: A relatively low prevalence of depression were recorded amongst the rural inhabitants, while a high prevalence was observed amongst diabetic subjects in Pakistan. This may suggest that psychiatric intervention may be required both for improved care and for primary prevention of diabetes. PMID- 17692424 TI - Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity. AB - BACKGROUND/AIMS: Nutritional supplements are frequently considered to be harmless but indiscriminate use of unlabelled ingredients may lead to significant adverse reactions. METHODS: In 2004, identification of four index cases of acute hepatitis associated with Herbalife intake led to a ministry of health investigation in all Israeli hospitals. Twelve patients with acute idiopathic liver injury in association with consumption of Herbalife products were investigated. RESULTS: Eleven of the patients were females, aged 49.5+/-13.4 y. One patient had stage I primary biliary cirrhosis and another had hepatitis B. Acute liver injury was diagnosed after 11.9+/-11.1 months of initiation of Herbalife consumption. Liver biopsies demonstrated active hepatitis, portal inflammation rich with eosinophils, ductular reaction and parenchymal inflammation with peri-central accentuation. One patient developed sub-fulminant and two fulminant episodes of hepatic failure. Hepatitis resolved in eleven patients, while one patient succumbed to complications following liver transplantation. Three patients resumed consumption of Herbalife products following normalization of liver enzymes, resulting in a second bout of hepatitis. CONCLUSIONS: An association between intake of Herbalife products and acute hepatitis was identified in Israel. We call for prospective evaluation of Herbalife products for possible hepatotoxicity. Until then, caution should be exercised by consumers, especially among individuals suffering from underlying liver disease. PMID- 17692425 TI - Pooled analysis of amino acid changes in the HBV polymerase in patients from four major adefovir dipivoxil clinical trials. AB - BACKGROUND/AIMS: The rtA181V and rtN236T mutations have been associated with resistance to adefovir dipivoxil (ADV). Recent reports have proposed other ADV resistance (ADV-R) mutations. The aims of this study were to confirm the role of rtA181V and rtN236T in clinical resistance to ADV and to screen for other potential ADV-R mutations. METHODS: Patients from ADV studies (n=998) were screened for viral breakthrough and/or insufficient HBV DNA suppression after at least 48 weeks of ADV therapy [virologic failure, VF]. McNemar's exact test was used to test for differences in the proportion of patients with switches from consensus amino acid (AA) at baseline to non-consensus AA at VF and vice versa. RESULTS: Data obtained from 172 paired HBV polymerase sequences demonstrated that only positions rt181 and rt236 had significantly more changes among patients with VF after adjusting for multiple comparisons (p<0.0005). When tested separately, the mutations rtA181V and rtN236T were statistically significant (p<0.0005); no other AA position was associated with VF. Patients who had HBV DNA breakthrough were more likely to develop ADV-R mutations than patients with insufficient HBV DNA suppression (36% vs. 5%). CONCLUSIONS: rtA181V and rtN236T were the only HBV polymerase mutations significantly associated with virologic failure to adefovir dipivoxil. PMID- 17692426 TI - Hepatocellular carcinoma in human immunodeficiency virus (HIV)-infected patients: is it really different, and if so, why? PMID- 17692428 TI - The prevalence of atopic triad in children with physician-confirmed atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is often associated with comorbidities such as allergic rhinitis and asthma. OBJECTIVE: We sought to describe the frequency of these comorbidities in children with AD. METHODS: We conducted a cross-sectional study of the first 2270 children with physician-confirmed AD enrolled in a large postmarketing cohort. All were queried for information on comorbidities using a questionnaire from the International Study of Asthma and Allergies in Childhood. RESULTS: In all, 71.3% reported at least one additional form of atopy (symptoms of asthma or allergic rhinitis). A total of 33.3% reported only symptoms of asthma or allergic rhinitis whereas 38.0% reported symptoms of asthma and allergic rhinitis. By age 3 years, nearly 66% reported at least one additional form of atopy. A statistically significant trend toward poorer disease control was observed for those with additional atopic illnesses (P < .001). LIMITATIONS: This is a cross-sectional study. CONCLUSION: Individuals with AD exhibit a predisposition to additional atopic illnesses by age 3 years and in turn the presence of these illnesses correlates with poor disease control. PMID- 17692427 TI - Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. AB - The circadian timing system controls drug metabolism and cellular proliferation over the 24 h through molecular clocks in each cell, circadian physiology, and the suprachiasmatic nuclei--a hypothalamic pacemaker clock that coordinates circadian rhythms. As a result, both the toxicity and efficacy of over 30 anticancer agents vary by more than 50% as a function of dosing time in experimental models. The circadian timing system also down-regulates malignant growth in experimental models and possibly in cancer patients. Programmable-in time infusion pumps and rhythmic physiology monitoring devices have made possible the application of chronotherapeutics to more than 2000 cancer patients without hospitalization. This strategy first revealed the antitumor efficacy of oxaliplatin against colorectal cancer. In this disease, international clinical trials have shown a five-fold improvement in patient tolerability and near doubling of antitumor activity through the chronomodulated, in comparison to constant-rate, delivery of oxaliplatin and 5-fluorouracil-leucovorin. Here, the relevance of the peak time, with reference to circadian rhythms, of the chemotherapeutic delivery of these cancer medications for achieving best tolerability was investigated in 114 patients with metastatic colorectal cancer and in 45 patients with non-small cell lung cancer. The incidence of severe adverse events varied up to five-fold as a function of the choice of when during the 24 h the peak dose of the medications was timed. The optimal chronomodulated schedules corresponded to peak delivery rates at 1 a.m. or 4 a.m. for 5 fluorouracil-leucovorin, at 1 p.m. or 4 p.m. for oxaliplatin, and at 4 p.m. for carboplatin. Sex of patient was an important determinant of drug schedule tolerability. This finding is consistent with recent results from a chronotherapy trial involving 554 patients with metastatic colorectal cancer, where sex also predicted survival outcome from chronotherapy, but not conventional drug delivery. Ongoing translational studies, mathematical modeling, and technology developments are further paving the way for tailoring cancer chronotherapeutics to the main rhythmic characteristics of the individual patient. Targeting therapeutic delivery to the dynamics of the cross-talk between the circadian clock, the cell division cycle, and pharmacology pathways represents a new challenge to concurrently improve the quality of life and survival of cancer patients through personalized cancer chronotherapeutics. PMID- 17692429 TI - Subtle presentation of isolated brainstem injury in a child with minor head injury. AB - Fallen television sets can cause significant injuries in toddlers. We report the case of a child with a focal brainstem injury who presented with subtle physical examination findings, which eventually led to aspiration and airway compromise. This case illustrates the importance of maintaining a high index of suspicion and performing a careful physical examination in traumatized, preverbal children who sustain an apparently minor head injury. The limitation of computed tomography studies in detecting brainstem injury is also discussed. PMID- 17692430 TI - First isolation of an antifungal lipid transfer peptide from seeds of a Brassica species. AB - An antifungal peptide with a molecular mass of 9412 and an N-terminal sequence exhibiting notable homology to those of lipid transfer proteins was isolated from seeds of the vegetable Brassica campestris. The purification protocol entailed ion exchange chromatography on Q-Sepharose, affinity chromatography on Affi-gel blue gel, ion exchange chromatography by fast protein liquid chromatography (FPLC) on Mono S, and gel filtration by FPLC on a Superdex peptide column. The antifungal peptide was adsorbed on Affi-gel blue gel and Mono S. It inhibited mycelial growth in Fusarium oxysporum and Mycosphaerella arachidicola with an IC(50) value of 8.3 microM and 4.5 microM, respectively. It exhibited dose dependent binding to lyso-alpha-lauroyl phosphatidylcholine. The present findings constitute the first report on a non-specific lipid transfer protein from the seeds of a Brassica species. PMID- 17692431 TI - Structure-activity relationships of Bak derived peptides: affinity and specificity modulations by amino acid replacement. AB - To study the structure-activity relationships (SAR) and the binding activity of pro-apoptotic Bak BH3 domain, we synthesised several 16mer peptide analogues corresponding to the region (72)-GQVGRQLAIIGDDINR-(87). Using different amino acids varying in length, steric and electronic properties, we investigated the role and the nature of physicochemical parameters of residues Val74, Leu78, Ile81 and Ile85, previously identified to be crucial for interactions. With this aim, we measured the affinity of these peptides on two anti-apoptotic proteins Bcl x(L) and Bcl-2 by a polarization fluorescence competitive assay. We defined that the most potent peptide on Bcl-x(L), which presents a 4.6-fold increase as compared to the parent peptide affinity, was obtained when Ile85 was mutated with a 4-chlorophenylalanine. Finally, assays of eight Bak peptide analogues on Bcl-2 allowed us to postulate that modulations at position 78 could afford peptides with a binding selectivity enhanced for Bcl-x(L). These pharmacological and physicochemical parameter data should prove useful for the rational design of non peptide ligands as potential antagonists of Bcl-2 protein interactions. PMID- 17692432 TI - Synthesis of N-aryl-5-amino-4-cyanopyrazole derivatives as potent xanthine oxidase inhibitors. AB - Some pyrazolo[3,4-d]pyrimidines, structurally related with allopurinol, a well known xanthine oxidase inhibitor, clinically used in the therapy of gout, have also been reported as potent inhibitors of xanthine oxidase and the growth of several human tumour cell lines. Considering the potential interest of this family of compounds, the aim of the present study was to synthesise and provide a full chemical characterization of new N-aryl-5-amino-4-cyanopyrazole derivatives and their corresponding pyrazolo[3,4-d]pyrimidines. Their biological activity pertaining to the xanthine oxidase inhibition and effect on the growth of three tumour cell lines (MCF-7, NCI-H460, and SF-268) are also provided. With only one exception, the synthesised compounds showed no effect on the growth of the three tumour cell lines. However, a strong xanthine oxidase inhibitory activity was observed for almost all pyrazolo[3,4-d]pyrimidines tested, revealing some of them IC(50) values below 1 microM. The results of the molecular docking studies of these compounds, against xanthine oxidoreductase are also described, providing an atomistic explanation of the differences in the inhibitory efficiency. MEP calculations were used to explain different inhibitory efficiency of similar inhibitors. PMID- 17692433 TI - Synthesis and antimicrobial activity of novel sulfone-linked bis heterocycles. AB - Novel sulfone-linked bis heterocycles pyrazolines in combination with thiadiazoles, oxadiazoles and triazoles were prepared from E-styrylsulfonylacetic acid methyl ester and tested for their antimicrobial activity. The compound 8 showed pronounced activity than the compounds 6 and 7. PMID- 17692434 TI - Synthesis of 6-amino-1,4-dihydropyridines that prevent calcium overload and neuronal death. AB - The synthesis and pharmacology of 6-amino-1,4-dihydropyridines, such as ethyl 6 amino-4-aryl-5-cyano-1,4-dihydro-2-methyl-3-pyridinecarboxylic acids (3-16) and 2 amino-4-aryl-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydro-3-quinolinenitriles (17-21) are described. Compounds 18 and 21, at the concentration of 0.3 microM, proved to be the best blockers of the [Ca(2+)] overload induced by depolarization with high [K(+)] of SH-SY5Y neuroblastoma cells, with values of 63.8% and 50.4%, respectively. Most of the compounds induced a remarkable neuroprotective effect against toxicity caused by high [K(+)]-elicited [Ca(2+)] overload, and against H(2)O(2)-generated free radicals, in SH-SY5Y cells. PMID- 17692435 TI - Aldehyde dehydrogenase inhibitors: alpha,beta-acetylenic N-substituted aminothiolesters are reversible growth inhibitors of normal epithelial but irreversible apoptogens for cancer epithelial cells from human prostate in culture. AB - The pharmacomodulation of the N atom of alpha,beta-acetylenic aminothiolesters or the replacement of the thiolester moiety by more electrophilic groups did not permit any clear rationale to be established for improving the selective growth inhibitory activity of this family of compounds over that of the previously synthesized alpha,beta-acetylenic aminothiolesters DIMATE and MATE [G. Quash, G. Fournet, J. Chantepie, J. Gore, C. Ardiet, D. Ardail, Y. Michal, U. Reichert, Biochem Pharmacol 64 (2002) 1279-92]. Hence DIMATE and MATE were investigated more thoroughly for selectivity and growth-inhibitory activity using human prostate epithelial normal cells (HPENC) on the one hand and human prostate epithelial cancer cells (DU145) on the other. Unequivocal evidence was obtained showing that both compounds were reversible growth inhibitors of HPENC but irreversible growth inhibitors of DU145. Growth-inhibition of DU145 was due to the induction of early apoptosis as revealed by the flow cytometric analytical profile of inhibitor-treated cells, of the decrease in the redox potential and increase in superoxide anion content of their mitochondria. Of the two intracellular enzymes: aldehyde dehydrogenases 1 and 3 (ALDH1 and ALDH3) targeted by DIMATE and MATE, ALDH3 was inhibited to the same extent by both compounds whereas ALDH1 was less susceptible to inhibition by MATE. As the induction of ALDH3 by xenobiotics is hormone-dependent, MATE, the more selective of the two inhibitors, is a useful tool not only for examining the role of the ALDH3 isoform in hormone-sensitive and resistant prostate cancer cells in culture but also for investigating if it can inhibit the growth of xenografts of prostate cancer in immunodeficient mice. PMID- 17692436 TI - [Human papillomavirus vaccination: differing views and issues at stake]. PMID- 17692437 TI - A palmitoyl-tailed sequential oligopeptide carrier for engineering immunogenic conjugates. AB - The main guideline in designing effective immunogens as vaccine candidates capable of eliciting potent and specific immune responses is to combine B/T cell epitopes and adjuvants as immunostimulators on the same carrier that links the major histocompatibility complex with T cell receptors. Aiming at contributing to the development of carriers for human usage a helicoid type sequential oligopeptide carrier, SOC(n)-II, formed by the repeating tetrapeptide unit (Aib Lys-Aib-Gly)(n), n=2-7, elongated from the amino-terminus by the palmitoyl group, known for its adjuvanticity, is now presented. The main B cell epitope, PPGMRPP, of the Sm autoantigen against which the majority of antibodies in patients with systemic lupus erythematosus is directed, was coupled to the Lys-N(epsilon)H(2) groups of the carrier in four copies and the resulting conjugate Palm-SOC(4)-II Sm(4) was subjected to animal immunizations without utilizing any adjuvant. The induced immune response was comparable with that produced when Ac-SOC(4)-II-Sm(4) was administered in animals following the conventional immunization protocol of complete/incomplete Freund's adjuvant. High titers of anti-Palm-SOC(4)-II-Sm(4) antibodies were generated, which recognize the priming immunogenic conjugate, as well as reconstituted Sm mimics but not the carrier alone. It is concluded that Palm-SOC(n)-II carrier is a valuable tool for engineering immunogens eliciting enhanced and specific humoral immune responses. PMID- 17692438 TI - Comparative immunogenicity of trivalent influenza vaccine administered by intradermal or intramuscular route in healthy adults. AB - The present study was undertaken with controls using equal doses ID and IM plus the standard full dose IM to assess the role of route of vaccine in immunogenicity of inactivated influenza vaccine. The study was a prospective, randomized, active-controlled, open label clinical trial conducted in healthy young adult outpatients to compare the effect of route (IM versus ID) on antibody responses to influenza vaccine. Volunteers received 3, 6 or 9 microg of vaccine by ID or IM route; 15 microg IM was also studied. Low doses of vaccine given by either route were almost as immunogenic as the standard 15 microg IM dose of influenza vaccine. ID route was not superior to IM vaccine at inducing antibodies. ID vaccine induced significantly more local inflammatory response than IM vaccine. PMID- 17692439 TI - Long-term persistence of antibodies after one or two doses of MMR-vaccine. AB - Outbreaks of measles, mumps and rubella have occurred recently despite long standing mass immunization with MMR. Antibody titres for measles, mumps and rubella of 160 students (17-23 years) with proof of at least one MMR-vaccine were studied according to the number of MMR-vaccines received. The proportion of subjects with positive antibody titres was significantly higher in those who received two vaccines against measles (77.1% versus 58.7%, p=0.05), mumps (67.5% versus 55.6%, p=0.009) and rubella (99.2% versus 71.4%, p=0.008). Comparable significant trends were seen for GMTs for measles and mumps. A similar non significant trend was noted for rubella. PMID- 17692440 TI - Diphtheria toxoid-containing microparticulate powder formulations for pulmonary vaccination: preparation, characterization and evaluation in guinea pigs. AB - In this study, the potential of N-Trimethyl chitosan (TMC, degree of quaternization 50%) and dextran microparticles for pulmonary delivery of diphtheria toxoid (DT) was investigated. The antigen-containing microparticles were prepared by drying of an aqueous solution of polymer and DT through a supercritical fluid (SCF) spraying process. The median volume diameter of the dry particles, as determined by laser diffraction analysis, was between 2 and 3 microm and the fine particle mass fractions smaller than 5 microm, as determined by cascade impactor analysis, were 35 and 56% for the dextran and TMC formulations, respectively. The water content of the particles as measured by Karl-Fischer titration was 2-3% (w/w). Pulmonary immunization with DT-TMC microparticles containing 2 or 10 Lf of DT resulted in a strong immunological response as reflected by the induction of IgM, IgG, IgG subclasses (IgG1 and IgG2) antibodies as well as neutralizing antibody titers comparable to or significantly higher than those achieved after subcutaneous (SC) administration of alum-adsorbed DT (2 Lf). Moreover, the IgG2/IgG1 ratio after pulmonary immunization with DT-TMC microparticles was substantially higher as compared to SC administered alum-adsorbed DT. In contrast, pulmonarily administered DT dextran particles were poorly immunogenic. Among the tested formulations only pulmonarily administered DT-containing TMC microparticles induced detectable pulmonary secretory IgA levels. In conclusion, in this paper it is demonstrated that TMC microparticles are a potent new delivery system for pulmonary administered DT antigen. PMID- 17692441 TI - Kinetic extractions to assess mobilization of Zn, Pb, Cu, and Cd in a metal contaminated soil: EDTA vs. citrate. AB - Kinetic EDTA and citrate extractions were used to mimic metal mobilization in a soil contaminated by metallurgical fallout. Modeling of metal removal rates vs. time distinguished two metal pools: readily labile (QM1) and less labile (QM2). In citrate extractions, total extractability (QM1+QM2) of Zn and Cd was proportionally higher than for Pb and Cu. Proportions of Pb and Cu extracted with EDTA were three times higher than when using citrate. We observed similar QM1/QM2 ratios for Zn and Cu regardless of the extractant, suggesting comparable binding energies to soil constituents. However, for Pb and Cd, more heterogeneous binding energies were hypothesized to explain different kinetic extraction behaviors. Proportions of citrate-labile metals were found consistent with their short-term, in-situ mobility assessed in the studied soil, i.e., metal amount released in the soil solution or extracted by cultivated plants. Kinetic EDTA extractions were hypothesized to be more predictive for long-term metal migration with depth. PMID- 17692442 TI - Long-term effects of aided phytostabilisation of trace elements on microbial biomass and activity, enzyme activities, and composition of microbial community in the Jales contaminated mine spoils. AB - We studied the effectiveness of remediation on microbial endpoints, namely microbial biomass and activity, microbial and plant species richness, of an As contaminated mine spoil, amended with compost (C) alone and in combination with beringite (B) or zerovalent iron grit (Z), to increase organic matter content and reduce trace elements mobility, and to allow Holcus lanatus and Pinus pinaster growth. Untreated spoil showed the lowest microbial biomass and activity and hydrolase activities, and H. lanatus as sole plant species, whereas the presented aided phytostabilisation option, especially CBZ treatment, significantly increased microbial biomass and activity and allowed colonisation by several plant species, comparable to those of an uncontaminated sandy soil. Microbial species richness was only increased in spoils amended with C alone. No clear correlation occurred between trace element mobility and microbial parameters and plant species richness. Our results indicate that the choice of indicators of soil remediation practices is a bottleneck. PMID- 17692443 TI - The nitrate leached below maize root zone is available for deep-rooted wheat in winter wheat-summer maize rotation in the North China Plain. AB - In winter wheat (Triticum aestivum L.)-summer maize (Zea mays L.) rotation system in the North China Plain, maize roots do not extend beyond 1.2 m in the vertical soil profile, but wheat roots can reach up to 2.0 m. Increases in soil nitrate content at maize harvest and significant reductions after winter wheat harvest were observed in the 1.4-2.0 m depth under field conditions. The recovery of 15N isotope (calcium nitrate) from various (1.0, 1.2, 1.4, 1.6, 1.8 and 2.0 m) soil depths showed that deep-rooting winter wheat could use soil nitrate up to the 2.0 m depth. This accounted partially, for the reduced nitrate in the 1.4-2.0 m depth of the soil after harvest of wheat in the rotation system. PMID- 17692445 TI - Evaluation of short-term and subchronic toxicity of magnolia bark extract in rats. AB - Magnolia bark has been traditionally used in Chinese and Japanese medicines, and its extract is a constituent of currently marketed dietary supplements and cosmetic products. The safety of magnolia bark extract (MBE) was assessed in short-term and subchronic studies. In a 21-day pilot study, rats were administered MBE at levels of 0, 60, 120, 240 or 480 mg/kg body weight (bw)/day in the diet. There were no treatment-related effects in clinical observations, macroscopic or microscopic findings, hematological, clinical chemistry, urinalysis, or organ weight measurements, and there were no deaths or significant differences in body weight and weight gain. In the 90-day study, rats were administered 0, 60, 120 or 240 mg MBE/kg bw/day in the diet. No mortality, ophthalmic abnormalities or treatment-related findings in clinical observations, hematology, coagulation or organ weight measurements were observed. There were no treatment-related macroscopic or microscopic findings. Differences between treated and control groups in body weight, weight gain, food consumption and utilization, clinical chemistry and urinalysis parameters were not considered toxicologically significant as they were not dose-related and/or because values remained within historical control ranges. These results support the safety of MBE for oral consumption. PMID- 17692444 TI - Evaluation of the in vitro and in vivo genotoxicity of magnolia bark extract. AB - Magnolia bark extract (MBE) is an extract of the dried stem, root, or branch bark of magnolia trees that has been used historically in traditional Chinese and Japanese medicines, and more recently as a component of dietary supplements and cosmetic products. To study the genotoxic potential of MBE, a bacterial reverse mutation assay and an in vivo micronucleus test were conducted. Compositional analysis of the test substance revealed that MBE contains 94% magnolol and 1.5% honokiol. MBE exerted no mutagenic activity in various bacterial strains of Salmonella typhimurium and in Escherichia coli WP2 uvrA, either in the absence or presence of metabolic activation at all doses tested. In the micronucleus test, various doses of MBE did not affect the proportions of immature to total erythrocytes, nor did it increase the number of micronuclei in the immature erythrocytes of Swiss albino mice. The results of these studies demonstrate that MBE is not genotoxic under the conditions of the in vitro bacterial reverse mutation assay and the in vivo micronucleus test, and support the safety of MBE for dietary consumption. PMID- 17692446 TI - The emotional costs of caring incurred by men and women in the British labour market. AB - This study investigates whether men and women in caring occupations experience more negative job-related feelings at the end of the day compared to the rest of the working population. The data are from Wave Nine of the British Household Panel Survey (1999) where respondents were asked whether, at the end of the working day, they tended to keep worrying or have trouble unwinding, and the extent to which work left them feeling exhausted or "used up." Their responses to these questions were used to develop ordinal dependent variables. Control variables in the models include: number of children, age, hours worked per week, managerial responsibilities and job satisfaction, all of which have been shown in previous research to be significantly related to "job burnout." The results are that those in caring occupations are more likely to feel worried, tense, drained and exhausted at the end of the working day. Women in particular appear to pay a high emotional cost for working in caring occupations. Men do not emerge unscathed, but report significantly lower levels of worry and exhaustion at the end of the day than do women. PMID- 17692447 TI - Successful augmentation with aripiprazole in clomipramine-refractory obsessive compulsive disorder. PMID- 17692448 TI - Amisulpride versus risperidone in the treatment of depression in patients with schizophrenia: a randomized, open-label, controlled trial. AB - OBJECTIVE: To determine the effectiveness of amisulpride on depression in patients with schizophrenia, in comparison to risperidone. METHOD: In this open label, 12-week study, patients with stable schizophrenia and a comorbid major or minor depressive episode (DSM-IV) taking risperidone were randomized into a risperidone-continuation group (N = 45) or an amisulpride-switch group (N = 42). The main outcome measures were changes from baseline on the Calgary Depression Scale for Schizophrenia (CDSS) and the Beck Depression Inventory (BDI). Secondary efficacy measures included the Positive and Negative Syndrome Scale (PANSS), and the Global Assessment of Functioning. Safety measures included treatment-emergent adverse events and extrapyramidal symptoms. RESULTS: The mean dose at endpoint was 4.2 mg/day for risperidone and 458.3 mg/day for amisulpride. Improvements in the CDSS and BDI scores were significantly greater in the amisulpride-switch group than in the risperidone-continuation group at weeks 8 and 12, and at the endpoint. The amisulpride-switch group also showed a significantly greater reduction in the score for the PANSS depression/anxiety factor, and the total score from baseline to endpoint. No significant difference was observed between the two groups for treatment-emergent adverse events or change from baseline for extrapyramidal symptoms. CONCLUSION: Switching from risperidone to amisulpride in patients with stable schizophrenia with comorbid depression improved depressive symptoms significantly compared to continuing with risperidone. PMID- 17692449 TI - Gender-specific association between iron status and the history of attempted suicide: implications for gender paradox of suicide behaviors. AB - PURPOSE: Iron deficiency (ID) has been linked with high impulsivity, and an increased risk of ID was reported among suicide attempters. We hypothesized that poor iron status might be prevalent among suicide attempters, who have high impulsivity. METHODS: As a part of the third National Health and Nutrition Examination Survey (1988-1994), a set of iron indices were measured in 2598 men and 2975 women aged 17-39 years, who completed a mental disorder diagnostic interview. RESULTS: Using non-attempters as reference within each gender, we observed a gender-dependent association between poor iron status and the history of attempted suicide. For male attempters (n=74), the prevalence ratios (PR) of abnormal serum ferritin, serum iron and protoporphyrin were 18.3 (95%CI=3.3 101.7), 3.2 (1.1-9.4) and 5.4(1.8-15.6). In contrast, the PR of abnormal serum ferritin for female attempters (n=217) was 0.3 (0.1-0.6). The hematological indices did not differ significantly between attempters and non-attempters among either men or women. Compared with non-attempters, male attempters were prone to a higher odds [17.5 (4.2-72.4)] while female attempters to a lower odds [0.6 (0.3 1.1)] of ID. CONCLUSION: These data suggest new opportunities for exploring biological bases of gender paradox of suicidal behaviors and a novel way to enhance therapeutic and preventive interventions against suicide. PMID- 17692450 TI - History of safe use as applied to the safety assessment of novel foods and foods derived from genetically modified organisms. AB - Very few traditional foods that are consumed have been subjected to systematic toxicological and nutritional assessment, yet because of their long history and customary preparation and use and absence of evidence of harm, they are generally regarded as safe to eat. This 'history of safe use' of traditional foods forms the benchmark for the comparative safety assessment of novel foods, and of foods derived from genetically modified organisms. However, the concept is hard to define, since it relates to an existing body of information which describes the safety profile of a food, rather than a precise checklist of criteria. The term should be regarded as a working concept used to assist the safety assessment of a food product. Important factors in establishing a history of safe use include: the period over which the traditional food has been consumed; the way in which it has been prepared and used and at what intake levels; its composition and the results of animal studies and observations from human exposure. This paper is aimed to assist food safety professionals in the safety evaluation and regulation of novel foods and foods derived from genetically modified organisms, by describing the practical application and use of the concept of 'history of safe use'. PMID- 17692451 TI - Effect of chronic nicotine administration on the rat lung and liver: beneficial role of melatonin. AB - Cigarette smoking is common in societies worldwide and has been identified as injurious to human health. The current study was designed to investigate the protective effect of melatonin, a radical scavenger and antioxidant, on nicotine induced oxidative stress and morphological changes in the lung and liver of the rats. Three groups of male rats (controls, nicotine-treated [0.5 mg/kg], and nicotine plus melatonin [10 mg/kg] were used in this study. Levels of lipid peroxidation (LPO) products, superoxide dismutase (SOD) and glutathione (GSH) activity were measured in the tissue homogenates. Immunohistochemical and histological changes were also examined. The results revealed an increase in LPO and decrease in both SOD and GSH activity in the lung and liver homogenates on nicotine-treated rats. Melatonin administration to nicotine-treated rats attenuated the increase in LPO products and restored the SOD activity and GSH levels. The immunohistochemical and histological examination demonstrated marked increase in the immunoreactivity of nitrotyrosine, a specific "footprint" of peroxynitrite, and tissue damage in the lung and liver of nicotine-administered animals. Again, melatonin treatment reduced both nitrotyrosine reactivity and tissue damage associated with nicotine administration. These results, along with previous observations, suggest that melatonin may be useful in combating free radical-induced oxidative stress and tissue injury that is a result of nicotine toxicity. PMID- 17692452 TI - Role of the amino acid invariants in the active site of MurG as evaluated by site directed mutagenesis. AB - To evaluate their role in the active site of the MurG enzyme from Escherichia coli, 13 residues conserved in the sequences of 73 MurG orthologues were submitted to site-directed mutagenesis. All these residues lay within, or close to, the active site of MurG as defined by its tridimensional structure [Ha et al., Prot. Sci. 9 (2000) 1045-1052, and Hu et al., Proc. Natl. Acad. Sci. USA 100 (2003) 845-849]. Thirteen mutants proteins, in which residues T15, H18, Y105, H124, E125, N127, N134, S191, N198, R260, E268, Q288 or N291 have been replaced by alanine, were obtained as the C-terminal His-tagged forms. The effects of the mutations on the activity were checked: (i) by functional complementation of an E. coli murG mutant strain by the mutated genes; and (ii) by the determination of the steady-state kinetic parameters of the purified proteins. Most mutations resulted in an important loss of activity and, in the case of N134A, in the production of a highly unstable protein. The results correlated with the assigned or putative functions of the residues based on the tridimensional structure. PMID- 17692453 TI - Emotion regulation and potentiated startle across affective picture and threat-of shock paradigms. AB - Past studies beginning with Jackson et al. [Jackson, D.C., Malmstadt, J.R., Larson, C.L., Davidson, R.J., 2000. Suppression and enhancement of emotional responses to unpleasant pictures. Psychophysiology 37 (4), 515-522.] document increases and decreases in emotionally-potentiated startle by way of instructing participants to enhance or suppress their emotional responses to symbolic sources of threat (unpleasant pictures). The present study extends this line of work to a threat-of-shock paradigm to assess whether startle potentiation elicited by threat of actual danger or pain is subject to emotion regulation. Results point to successful volitional modulation for both Affective-Picture and Threat-of Shock experiments with startle magnitudes from largest to smallest occurring in the enhance, maintain, and suppress conditions. Successful regulation of startle potentiation to the threat of shock found by the current study supports the external validity of the Jackson paradigm for assessment of regulation processes akin to those occurring in the day-to-day context in response to real elicitors of emotion. PMID- 17692454 TI - Non-classical actions of the mineralocorticoid receptor: misuse of EGF receptors? AB - The mineralocorticoid receptor (MR) plays a key role in cardiovascular and renal injury. The underlying mechanisms seem to involve the epidermal growth factor receptor (EGFR) for the development of fibrosis and vascular dysfunction. Both enhanced EGFR transactivation by activated MR as well as upregulation of EGFR expression by aldosterone-bound MR have been described. While the former seems to be mediated by the tyrosine kinase cSrc, reporter gene assays and chromatin immunoprecipitation data indicate that the latter is caused by an interaction between MR and the EGFR promoter. Pharmacological inhibition of EGFR function prevents some of MR's pathological actions in cell culture systems, like vascular smooth muscle cells. Thus, transactivation as well as enhanced expression of EGFR may be an important switch for the pathophysiological actions in the reno cardiovascular continuum. Furthermore, EGFR signaling may serve as a negative feedback loop to limit sodium retention. Overall, MR's "misuse" of the EGFR is one possible explanation for the pathophysiological effects of aldosterone, making the EGFR a potential target for therapeutical interventions against reno cardiovascular remodelling. PMID- 17692455 TI - N-acetyl cysteine and caffeic acid phenethyl ester sensitize astrocytoma cells to Fas-mediated cell death in a redox-dependent manner. AB - In this study, we investigated the role of reactive oxygen species (ROS) in Fas induced cell death in human astrocytoma cells. Fas activation increased intracellular ROS levels in a NADPH oxidase- and caspase-dependent manner. ROS inhibitors such as N-acetyl cysteine (NAC) and caffeic acid phenethyl ester (CAPE) dramatically sensitized astocytoma cells to Fas-induced loss of mitochondrial transmembrane potential and subsequent cell death, which were abrogated by pretreatment with z-VAD-fmk, a broad-spectrum caspase inhibitor. These results collectively indicate that NAC and CAPE sensitize astrocytoma cells to Fas-induced apoptosis in a redox-dependent manner, suggesting a potential use in the treatment of malignant brain tumors. PMID- 17692456 TI - High level of MUC1 in serum of ovarian and breast cancer patients inhibits huHMFG 1 dependent cell-mediated cytotoxicity (ADCC). AB - The huHMFG-1 (AS1402) antibody is a humanised IgG1 directed against MUC1 and is currently in clinical trials for the treatment of breast carcinoma. Adenocarcinomas over-express and shed MUC1, and high MUC1 serum levels are associated with progressive disease. Here, we have investigated the effects of MUC1 present in sera from breast and ovarian cancer patients and that of NK cells on in vitro huHMFG-1-mediated ADCC, performed with and without the addition of various cytokines. Screening for patients with high levels of NK cells bearing the FcgammaRIIIa-158V polymorphism, adjusting the dosage to circulating levels of MUC1 and co-administration of NK cell activating cytokines may increase the efficacy of huHMFG-1 treatment. PMID- 17692457 TI - Guava (Psidium guajava) leaf powder: novel adsorbent for removal of methylene blue from aqueous solutions. AB - Batch sorption experiments were carried out using a novel adsorbent, guava leaf powder (GLP), for the removal of methylene blue (MB) from aqueous solutions. Potential of GLP for adsorption of MB from aqueous solution was found to be excellent. Effects of process parameters pH, adsorbent dosage, concentration, particle size and temperature were studied. Temperature-concentration interaction effect on dye uptake was studied and a quadratic model was proposed to predict dye uptake in terms of concentration, time and temperature. The model conforms closely to the experimental data. The model was used to find optimum temperature and concentration that result in maximum dye uptake. Langmuir model represent the experimental data well. Maximum dye uptake was found to be 295mg/g, indicating that GLP can be used as an excellent low-cost adsorbent. Pseudo-first-order, pseudo-second order and intraparticle diffusion models were tested. From experimental data it was found that adsorption of MB onto GLP follow pseudo second order kinetics. External diffusion and intraparticle diffusion play roles in adsorption process. Free energy of adsorption (DeltaG degrees ), enthalpy change (DeltaH degrees ) and entropy change (DeltaS degrees ) were calculated to predict the nature of adsorption. Adsorption in packed bed was also evaluated. PMID- 17692458 TI - Boron removal from aqueous solutions by activated carbon impregnated with salicylic acid. AB - In this study, the removal of boric acid from aqueous solution by activated carbon impregnated with salicylic acid was studied in batch system. pH, adsorbent amount, initial boron concentration, temperature, shaking rate and salicylic acid film thickness were chosen as parameters. Boron removal efficiencies increased with increasing adsorbent amount, temperature and pH, decreasing initial boron concentration. As thickness of salicylic acid film on activated carbon becomes thin up to 0.088nm, the efficiency increased, and then, the efficiency decreased with becoming thinner than 0.088nm of salicylic acid film. Shaking rate was no effect on removal efficiency. In result, it was determined that the use of salicylic acid as an impregnant for activated carbon led to the increase of the amount of boron adsorbed. A lactone ring, being the most appropriate conformation, forms between boric acid and -COOH and -OH groups of salicylic acid. PMID- 17692459 TI - Stabilization of heavy metals in ceramsite made with sewage sludge. AB - In order to investigate stabilization of heavy metals in ceramsite made with sewage sludge as an additive, the configuration of heavy metals in ceramsite was analysed by XRD and while leaching tests were conducted to find out the effect of sintering temperature (850 degrees C, 900 degrees C, 950 degrees C, 1000 degrees C, 1100 degrees C, and 1200 degrees C), pH (1, 3, 5, 7, 9, and 12), and H2O2 concentration (0.5molL(-1), 1molL(-1), 1.5molL(-1), 3molL(-1), and 5molL(-1)) on stabilization of heavy metals (Cd, Cr, Cu, and Pb) in ceramsite. The results indicate that leaching contents of heavy metals do not change above 1000 degrees C and sintering temperature has a significant effect on stabilization of heavy metals in ceramsite; leaching contents of heavy metals decrease as pH increases and increase as H2O2 concentration increases. XRD analysis reveals that the heavy metals exist in steady forms, mainly Pb2O(CrO(4)), CdSiO3, and CuO at 1100 degrees C. It is therefore concluded that heavy metals are properly stabilized in ceramsite and cannot be easily released into the environment again to cause secondary pollution. PMID- 17692460 TI - Comments on "The effect of substituent groups on the reductive degradation of azo dyes by zerovalent iron" by M. Hou, et al. [J. Hazard. Mater. 145 (2007) 305]. AB - This letter discusses possible improvements in experimental conditions to enable a purposeful discussion on the effect of substituent groups on the reductive degradation of azo dyes by elemental iron (Fe(0)) in a recent article by Hou and his co-workers. Also recalled is the pH dependence of the iron corrosion mechanism which is usually overlooked in the iron technology literature. PMID- 17692461 TI - Vasoactive intestinal peptide induction by ciliary neurotrophic factor in donor human corneal endothelium in situ. AB - After peripheral nerve axotomy, vasoactive intestinal peptide (VIP) gene expression is upregulated in neurons, whereas ciliary neurotrophic factor (CNTF) accumulates extracellularly at the lesion site. Although CNTF-induced VIP gene expression has been reported in cultured sympathetic neurons and neuroblastoma cells, it still remains to be determined if CNTF and VIP play interrelated roles in nerve injury. The corneal endothelium, like sympathetic neurons, derives from the neural crest. Previously, we demonstrated that a sublethal-level of oxidative stress induces CNTF release from corneal endothelial (CE) cells in situ. Here, we show that human CE cells express the 53 kDa ligand-binding alpha subunit of the CNTF receptor (CNTFRalpha). We further demonstrate that CNTF induces VIP immunoreactivity in human donor corneas. To determine if the increase in VIP immunoreactivity was reflected by an increase in gene expression, donor human corneas were bisected and treated with CNTF or vehicle, and analyzed by real-time RT-qPCR. Two experiments using different sets of bisected corneas indicated that CNTF induced increases in VIP mRNA levels of 6.5+/-2.2-fold (N=7 corneas) and 2.3+/-0.6-fold (N=10 corneas) (mean+/-S.E.M.), respectively. Whereas VIP is produced as a CE autocrine factor against oxidative stress, the present study suggested that oxidative stress-released CNTF plays a role in protecting CE cells against oxidative stress injury by upregulating VIP expression. PMID- 17692463 TI - Coulomb interactions in Ga LMIS. AB - For low emission currents from around 1 microA Ga liquid-metal ion sources (LMIS) produce fine optically bright ion beams that are strongly limited by the Coulomb particle-particle interactions. We present computations of the energy spread, the beam virtual crossover size, and beam brightness based on direct numerical integration of the equation of motion in a numerically calculated field for a number of dimensions of the emission tip. The Coulomb particle-particle interactions are included into the calculation of ion beam evolution. A comparison with experimental data allows to estimate the tip size. PMID- 17692462 TI - Individual differences in pain sensitivity: genetic and environmental contributions. AB - Large individual differences in pain sensitivity present a challenge for medical diagnosis and may be of importance for the development of chronic pain. Variance in pain sensitivity is partially mediated by genetic factors, but the extent of this contribution is uncertain. We examined cold-pressor pain and contact heat pain in 53 identical (MZ) and 39 fraternal (DZ) twin pairs, and 4 single twins to determine the heritability of the two phenotypes, and the extent to which the same genetic and environmental factors affect both pain modalities. An estimated 60% of the variance in cold-pressor pain and 26% of the variance in heat pain was genetically mediated. Genetic and environmental factors were only moderately correlated across pain modalities. Genetic factors common to both modalities explained 7% of the variance in cold-pressor and 3% of the variance in heat pain. Environmental factors common to both modalities explained 5% of variance in cold pressor and 8% of the variance in heat pain. The remaining variance was due to factors that were specific to each pain modality. These findings demonstrate that cold-pressor pain and contact heat pain are mainly distinct phenomena from both a genetic and an environmental standpoint. This may partly explain disparate results in genetic association studies and argues for caution in generalizing genetic findings from one pain modality to another. It also indicates that differences in pain scale usage account for a minor portion of the variance, providing strong support for the validity of subjective pain ratings as measures of experienced pain. PMID- 17692464 TI - Effects of supplemental feeding on gastrointestinal parasite infection in elk (Cervus elaphus): preliminary observations. AB - The effects of management practices on the spread and impact of parasites and infectious diseases in wildlife and domestic animals are of increasing concern worldwide, particularly in cases where management of wild species can influence disease spill-over into domestic animals. In the Greater Yellowstone Ecosystem, USA, winter supplemental feeding of Rocky Mountain elk (Cervus elaphus) may enhance parasite and disease transmission by aggregating elk on feedgrounds. In this study, we tested the effect of supplemental feeding on gastrointestinal parasite infection in elk by comparing fecal egg/oocyst counts of fed and unfed elk. We collected fecal samples from fed and unfed elk at feedground and control sites from January to April 2006, and screened all samples for parasites. Six different parasite types were identified, and 48.7% of samples were infected with at least one parasite. Gastrointestinal (GI) nematodes (Nematoda: Strongylida), Trichuris spp., and coccidia were the most common parasites observed. For all three of these parasites, fecal egg/oocyst counts increased from January to April. Supplementally fed elk had significantly higher GI nematode egg counts than unfed elk in January and February, but significantly lower counts in April. These patterns suggest that supplemental feeding may both increase exposure and decrease susceptibility of elk to GI nematodes, resulting in differences in temporal patterns of egg shedding between fed and unfed elk. PMID- 17692465 TI - Biomineralization: functions of calmodulin-like protein in the shell formation of pearl oyster. AB - Calmodulin-like protein (CaLP) was believed to be involved in the shell formation of pearl oyster. However, no further study of this protein was ever performed. In this study, the in vitro crystallization experiment showed that CaLP can modify the morphology of calcite. In addition, aragonite crystals can be induced in the mixture of CaLP and a nacre protein (at 16 kDa), which was detected and purified from the EDTA-soluble matrix of nacre. These results agreed with that of immunohistological staining in which CaLP was detected not only in the organic layer sandwiched between nacre (aragonite) and the prismatic layer (calcite), but also around the prisms of the prismatic layer. Take together, we concluded that (1) CaLP, as a component of the organic layer, can induce the nucleation of aragonite through binding with the 16-kDa protein, and (2) CaLP may regulate the growth of calcite in the prismatic layer. PMID- 17692466 TI - Induction of histone acetylation on the CRBPII gene in perinatal rat small intestine. AB - The expression of genes associated with lipid and vitamin A metabolism is elevated when the small intestinal mucosa is maturing rapidly during the perinatal period. We have previously reported that cellular retinol-binding protein type II (CRBPII) mRNA levels rise abruptly in the rat small intestine during this period. In this study, we examined whether the acetylation of histones H3 and H4 is involved in the intestinal expression of CRBPII during the perinatal stage. The expression of cyclin D1 and cyclin B1 genes, which are markers of cell proliferation, decreased markedly during the perinatal period, whereas expression of CRBPII as well as villin, a marker of intestinal maturation, increased rapidly. Using a ChIP assay, we showed rapid induction of acetylation of the histones H3 and H4 which interacted with the promoter/enhancer region of the CRBPII gene at this time. The binding of CBP and p300, which have histone acetyltransferase activity, as well as binding of retinoid X receptor alpha (RXRalpha) increased on the CRBPII promoter/enhancer region during the perinatal period. These results suggest that CRBPII gene expression during the perinatal period is associated with abrupt acetylation of histones H3 and H4 followed by the binding of CBP/p300 and RXRalpha. PMID- 17692467 TI - Distinct N-glycan glycosylation of P-glycoprotein isolated from the human uterine sarcoma cell line MES-SA/Dx5. AB - The uterine sarcoma human cell line MES-SA/Dx5 overexpresses the MDR1 gene product, P-glycoprotein (Pgp). Pgp is a heavily glycosylated, ATP-dependent drug efflux pump expressed in many human cancers. There are more than 150 known isoforms of Pgp, which complicates the characterization of Pgp glycans because each isoform could present a different glycome. The contribution of these oligosaccharides to the structure and function of Pgp remains unclear. We identified distinct Pgp glycans recognized by the lectins in the digoxigenin (DIG) glycan differentiation kit from Roche Allied Science, all of which were N glycans. Pgp was isolated using both slab and preparative gel elution. The monoclonal antibody C219 was used to identify the presence of Pgp and Pgp treated with PNGase F on our blots. Pgp isolated from MES-SA/Dx5 cells contains at least two different complex N-glycans--one high mannose tree, detected by GNA, and one branched hybrid oligosaccharide-capped with terminal sialic acids, detected by SNA and MAA. DSA, specific for biantennary oligosaccharides possessing beta(1-4) N-acetyl-D-glucosamine residues, also recognized the blotted Pgp and is probably detecting the core Galbeta(1-4)-GlcNAc(x) component found in other Pgps. PMID- 17692469 TI - Estimation of blood volume in burns patients using radioisotope chromium-51: a pilot study. PMID- 17692470 TI - Expression of pannexin2 protein in healthy and ischemized brain of adult rats. AB - The expression pattern of the pannexin2 protein (Px2) in healthy and ischemized brains of adult rats was investigated. A polyclonal antibody for rat Px2 was generated in chicken and purified for affinity. This antibody was used to study by Western blot, Enzyme-Linked Immunosorbent Assay, and immunohistochemistry, the expression pattern of Px2 in healthy brain of adult rats and in the hippocampus of rats submitted to bilateral clamping of carotid arteries for 20 min, followed by different times of reperfusion (I/R) (8 h, 24 h, 48 h, 72 h, 14 days and 30 days). Immunohistochemical studies visualized the wide and complex expression pattern of Px2 in the healthy brain. All Px2(+) positive cells were neurons which also showed no puncta on their cellular membranes. Both pyramidal cells and interneurons, the majority of which were positive to parvalbumin, were stained in healthy hippocampus. The number of Px2 interneurons in the hippocampus showed a progressive reduction at successive time intervals after I/R, with a negative peak of about -40% after 72 h from I/R. Interneurons which were positive for both Px2 and parvalbumin, represented about the 85% of all parvalbumin cells stained in the hippocampus. This percentage rested grossly unmodified at different time intervals after I/R in spite of the progressive neuronal depletion. Concomitantly, an intense astrogliosis occurred in the hippocampus. Most of the astroglial cells expressed de novo and for a transient time (from 24 h to 14 days from I/R), Px2. Primary co-cultures of hippocampal neurons and astrocytes were submitted to transient ischemia-like injury. This set of experiments further confirmed the in vivo results by showing that Px2 is de novo and transiently expressed in astroglial cells following a transient ischemia-like injury. These results suggested the expression of Px2 in the astrocytes may be induced either from injured neurons or by biochemical pathways internal to the astrocyte itself. In conclusion, our results showed the transient expression of Px2 in astrocytes of reactive gliosis occurring in the hippocampus following I/R injury. We hypothesize that Px2 expression in astrocytes following an ischemic insult is principally involved in the formation of hemichannels for the release of signaling molecules devoted to influence the cellular metabolism and the redox status of the surrounding environment. PMID- 17692468 TI - The Ras-association domain family (RASSF) members and their role in human tumourigenesis. AB - Ras proteins play a direct causal role in human cancer with activating mutations in Ras occurring in approximately 30% of tumours. Ras effectors also contribute to cancer, as mutations occur in Ras effectors, notably B-Raf and PI3-K, and drugs blocking elements of these pathways are in clinical development. In 2000, a new Ras effector was identified, RAS-association domain family 1 (RASSF1), and expression of the RASSF1A isoform of this gene is silenced in tumours by methylation of its promoter. Since methylation is reversible and demethylating agents are currently being used in clinical trials, detection of RASSF1A silencing by promoter hypermethylation has potential clinical uses in cancer diagnosis, prognosis and treatment. RASSF1A belongs to a new family of RAS effectors, of which there are currently 8 members (RASSF1-8). RASSF1-6 each contain a variable N-terminal segment followed by a Ras-association (RA) domain of the Ral-GDS/AF6 type, and a specialised coiled-coil structure known as a SARAH domain extending to the C-terminus. RASSF7-8 contain an N-terminal RA domain and a variable C-terminus. Members of the RASSF family are thought to function as tumour suppressors by regulating the cell cycle and apoptosis. This review will summarise our current knowledge of each member of the RASSF family and in particular what role they play in tumourigenesis, with a special focus on RASSF1A, whose promoter methylation is one of the most frequent alterations found in human tumours. PMID- 17692472 TI - Liver derived endogenous opioids may interfere with the therapeutic effect of interferon in chronic hepatitis C. AB - A substantial number of patients with chronic hepatitis C does not respond to treatment with interferon and ribavirin, the approved drugs to treat this viral infection. In vitro studies have shown that morphine, which exerts its effects by binding to opioid receptors, enhances the expression of hepatitis C RNA in hepatitis C-replicon containing liver cells, and that it interferes with the antiviral effect of interferon on the hepatitis C virus. Met-enkephalin, one of the endogenous opioid peptides, can bind to the same receptors to which morphine binds, triggering similar receptor-mediated effects. The liver in cholestasis can express Met-enkephalin immunoreactivity (MEIR). MEIR can also be detected in the liver of some patients with chronic hepatitis C. This finding suggests that Met enkephalin is produced by or that it accumulates in the liver of patients with this viral hepatitis. Analogous to the effect of morphine on the hepatitis C replicon containing liver cells, we hypothesize that Met-enkephalin enhances the replication of the hepatitis C virus in liver cells, and that it interferes with the antiviral effect of interferon, contributing to the lack of efficacy of this medication in the treatment of this viral infection in some patients. If this hypothesis is correct, the study of opiate antagonists in combination with antiviral therapy in patients with hepatitis C expressing MEIR in their livers merits consideration. PMID- 17692471 TI - The immediate early gene early growth response gene 3 mediates adaptation to stress and novelty. AB - Stress and exploration of novel environments induce neural expression of immediate early gene transcription factors (IEG-TFs). However, as yet no IEG-TF has been shown to be required for the normal biological or behavioral responses to these stimuli. Here we show that mice deficient for the IEG-TF early growth response gene (Egr) 3, display accentuated behavioral responses to the mild stress of handling paralleled by increased release of the stress hormone corticosterone. Egr3-/- mice also display abnormal responses to novelty, including heightened reactivity to novel environments and failure to habituate to social cues or startling acoustic stimuli. In a Y-maze spontaneous alternation task, they perform fewer sequential arm entries than controls, suggesting defects in immediate memory. Because stress and novelty stimulate hippocampal long-term depression (LTD), and because abnormalities in habituation to novelty and Y-maze performance have been associated with LTD deficits, we examined this form of synaptic plasticity in Egr3-/- mice. We found that Egr3-/- mice fail to establish hippocampal LTD in response to low frequency stimulation and exhibit dysfunction of an ifenprodil-sensitive (NR1/NR2B) N-methyl-d-aspartate receptor subclass. Long term potentiation induction was not altered. The NR2B-dependent dysfunction does not result from transcriptional regulation of this subunit by Egr3, because NR2B mRNA levels did not differ in the hippocampi of Egr3-/- and control mice. These findings are the first demonstration of the requirement for an IEG-TF in mediating the response to stress and novelty, and in the establishment of LTD. PMID- 17692473 TI - Intra-arterial rhenium-188 lipiodol in the treatment of inoperable hepatocellular carcinoma: results of an IAEA-sponsored multination study. AB - PURPOSE: Intra-arterial injections (IAI) of 131I-lipiodol is effective in treating hepatocellular carcinoma patients, but is expensive and requires a 7-day hospitalization in a radioprotection room. 188Re is inexpensive, requires no patient isolation, and can be used with lipiodol. METHODS AND MATERIALS: This International Atomic Energy Agency-sponsored phase II trial aimed to assess the safety and the efficacy of a radioconjugate 188Re + lipiodol (188Re-Lip) in a large cohort of hepatocellular carcinoma patients from developing countries. A scout dose is used to determine the maximal tolerated dose (lungs <12 Gy, normal liver <30 Gy, bone marrow <1.5 Gy) and then the delivery of the calculated activity. Efficacy was assessed using response evaluation criteria in solid tumor (RECIST) and alpha-feto-protein (alpha FP) levels and severe adverse events were graded using the Common Toxicity Criteria of the National Cancer Institute scale v2.0. RESULTS: The trial included 185 patients from eight countries. The procedure was feasible in all participating centers. One treatment was given to 134 patients; 42, 8, and 1 received two, three, and four injections, respectively. The injected activity during the first treatment was 100 mCi. Tolerance was excellent. We observed three complete responses and 19 partial responses (22% of evaluable patients, 95% confidence interval 16-35%); 1- and 2 year survivals were 46% and 23%. Some factors affected survival: country of origin, existence of a cirrhosis, Cancer of the Liver Italian Program score, tumor dose, absence of progression, and posttreatment decrease in alpha FP level. CONCLUSIONS: IAI of 188Re-Lip in developing countries is feasible, safe, cost effective, and deserves a phase III trial. PMID- 17692474 TI - Renal toxicity of adjuvant chemoradiotherapy with cisplatin in gastric cancer. AB - PURPOSE: Adjuvant, 5-fluorouracil (5-FU)-based chemoradiotherapy for completely resected high-risk gastric adenocarcinoma has been shown to improve survival in a randomized Intergroup trial. However, the results still showed an unsatisfactory outcome. On the basis of previously reported results of a Phase II trial using a more aggressive, cisplatin-containing chemoradiotherapy schedule, we investigated the effects of this approach on long-term renal function. PATIENTS AND METHODS: Between December 2000 and September 2003, 27 patients were treated at Tubingen University in a Phase II multicenter trial investigating adjuvant chemoradiotherapy. The adjuvant chemoradiotherapy consisted of two cycles of adjuvant 5-FU, folinic acid, cisplatin (200 mg/m2), and paclitaxel before and after radiotherapy (45 Gy in 1.8-Gy fractions) with daily concomitant 5-FU (225 mg/m2/24 h). A dose constraint of 5% reactive. RESULTS: Positive staining was found in 43 cases (58.9%). The immunoreactivity did not correlate with age, International Federation of Gynecology and Obstetrics stage, lymph node metastasis, or tumor size. For patients who were CD24 negative, the total failure and distant metastasis rates were decreased about 20% compared with the rates for patients who were CD24 positive. On univariate analysis, the 5-year distant metastasis-free survival rate of CD24-negative patients was significantly greater than that of the CD24-positive patients (84.7% vs. 66.7%, respectively, p = 0.0497). The International Federation of Gynecology and Obstetrics stage and CD24 expression were significantly associated with distant metastasis-free survival on multivariate analysis. CONCLUSIONS: CD24 expression was a significant independent prognostic factor for distant metastasis-free survival in patients with uterine cervical squamous cell carcinoma. In the future, prospective determination of CD24 expression might aid clinical practice in the selection of the appropriate therapy for individual patients. PMID- 17692476 TI - Historical perspectives and a focus on fitness. PMID- 17692477 TI - Distal control of the pig whey acidic protein (WAP) locus in transgenic mice. AB - Distal control of the whey acidic protein (WAP) locus was studied using a transgenic approach. A series of pig genomic fragments encompassing increasing DNA lengths upstream of the mammary specific whey acidic protein (WAP) gene transcription start point (tsp) and 5 kb downstream were used for microinjection in mouse fertilized eggs. Our data pointed out three regions as potent regulators for WAP but not for RAMP3 gene expression (a non mammary-specific gene located 30 kb upstream of the WAP gene). WAP gene activating elements were present in the 80 kb to -30 kb and -145 kb to -130 kb regions whereas inhibitors were present in the -130 kb to -80 kb region. The stimulatory regions were characterized by peaks of histone H4 acetylation and a poor nucleosome occupancy in lactating sow mammary glands but not in liver. These data reveal for the first time the existence of several remote potent regulatory regions of the pig WAP gene. PMID- 17692478 TI - Effects of ultrashort gamete co-incubation time on porcine in vitro fertilization. AB - A reduction in co-incubation time has been suggested as an alternative method to reduce polyspermic fertilization. The aim of this study was to evaluate the effect of short periods of gamete co-incubation during pig in vitro fertilization. A total of 2,833 in vitro matured oocytes were inseminated with thawed spermatozoa and coincubated for 0.25, 1, 2, 3, 7, 10 min and 6h. The oocytes from the 0.25-10 min groups were washed three times in modified Tris buffered medium (mTBM) medium to remove spermatozoa not bound to the zona and transferred to the same medium (containing no spermatozoa) until 6h of co incubation time were completed. After 6h, presumptive zygotes from each group were cultured in NCSU-23 medium for 12-15 h to assess fertilization parameters. After each period of co-incubation, 45-50 oocytes from each group were stained with Hoechst-33342 and the number of spermatozoa bound to the zona was counted. Although the number of zona bound spermatozoa increased (p<0.05) with the co incubation time, no increase was observed in penetration rates among groups from 2 min to 6h of co-incubation time (ranging from 53.5+/-2.8 to 61.3+/-2.6%). Similarly, the efficiency of fertilization reached a maximum for the 2 min of co incubation group with values ranging between 32.3+/-2.4 and 41.9+/-2.5%. The reduction of co-incubation time did not affect the monospermy rate (range: 71.3+/ 3.4-80.2+/-3.8%) and the mean number of spermatozoa/oocyte (range: 1.2+/-0.4 1.4+/-0.5). These results show that, under our in vitro conditions, high penetration rate can be obtained with co-incubation times as short as 2 min, although monospermy could not be improved using this strategy. PMID- 17692479 TI - Prematuration of bovine oocytes with butyrolactone I: effects on meiosis progression, cytoskeleton, organelle distribution and embryo development. AB - The effects of prematuration (PM) of bovine oocytes with butyrolactone I (BLI) for 24h on meiosis progression, cell structures and embryo development were assessed. Germinal vesicle (GV) rates decreased (97.4-65.1%, P<0.05) with decreasing BLI concentrations (100-25microM). Without BSA in PM medium, GV rates were similar (98.7-97.2, P>0.05) with low BLI (10-25microM). After in vitro maturation (IVM) for 24h, metaphase II (MII) rates for controls (IVM only) were similar (91.1%, P>0.05) to PM with 10microM BLI in BSA-free medium (B10=91.5%) and 100microM BLI in medium with BSA (B100=92.4%). Meiosis resumption occurred earlier in treated oocytes (71.4-74.3% in GV for B10 and B100, respectively, after 6h IVM compared with 97.3% in controls, P<0.05). By 18h of IVM, most oocytes reached MII (72.0-78.9%, P>0.05). Microtubules and microfilaments were unaffected by BLI. Cortical granules (CG) migration was reversibly blocked by BLI. Mitochondria translocation was partially blocked by PM culture and after IVM more oocytes in B10 and B100 (95.2 and 98.2%, respectively) had mitochondria translocated to a mature pattern (all cytoplasm) than controls (81.5%, P<0.05). Cleavage rates were similar (81-87%, P>0.05), but blastocysts (day 7) decreased in B100 (33.0%, P<0.05) compared with controls and B10 (38.3 and 41.6%, respectively). Day 8 hatching rates (11.0-19.2%) and mean total cell numbers (136 150) were similar (P>0.05). PM did not improve oocyte competence but also did not cause major structural alterations, suggesting that PM may be improved and used to study the mechanisms involved in oocyte differentiation. PMID- 17692481 TI - Biodistribution of intravenously administered amphiphilic beta-cyclodextrin nanospheres. AB - Amphiphilic beta-cyclodextrin (betaCDa) nanospheres (mean diameter 90-110 nm) prepared by the solvent displacement method were developed as a colloidal drug delivery system. In order to survey the fate of these nanoparticles, the amphiphilic beta-cyclodextrin was first iodinated by a two-step procedure involving iodination of the primary face followed by an acylation of the secondary face. After radiolabeling of this derivative with (125)I, nanospheres made of betaCDa/betaCDa (125)I were formulated. After a single intravenous injection of labeled nanoparticles in mice, the organ distribution was analyzed from 10 min to 6 days. A rapid clearance of (125)I-labeled betaCDa nanospheres from the blood circulation to the mononuclear phagocyte system was visualized by non-invasive planar imaging study. Radioactivity measurements in organs showed that the nanospheres mainly concentrated in the liver and the spleen where 28 and 24% of the radioactivity per gram of organ was, respectively, found 10 min after injection. At the opposite, the blood activity was low at that time and become negligible thereafter. Finally, the fact that no particular sign of toxicity is observed in injected animals should be emphasized since it is the first report on intravenous administration of betaCDa nanoparticles. PMID- 17692480 TI - Dual effects of Tween 80 on protein stability. AB - In this paper, we used IL-2 mutein as a model protein and evaluated the effect of Tween 80, a non-ionic surfactant. In summary, we found that the dual effects of Tween 80 on the stability of IL-2SA, such as that shaking-induced aggregation of IL-2 mutein was significantly inhibited in the presence of Tween 80. However, this surfactant adversely affected the stability of IL-2 mutein in solution during storage in terms of both oxidation and aggregation. These adverse effects are strongly temperature and formulation-dependent. Data particularly showed that IL-2 mutein in solution forms soluble aggregates to a different degree in different formulations during storage at 40 degrees C for 2 months. Aggregation was barely detectable during storage at 5 degrees C for 22 months. Addition of 0.1% Tween 80 significantly increased the rate of IL-2 mutein aggregation during storage. The IL-2 mutein aggregates are linked by both disulfide and non disulfide bonds and their relative contribution is temperature-dependent. IL-2 mutein can be oxidized also to a different degree in different formulations during storage and the oxidation rate is strongly temperature-dependent with an activation energy between 21 and 25 kcal/mol. Addition of 0.1% Tween 80 not only increased the rate of oxidation in general but also altered the temperature dependency of IL-2 mutein oxidation. PMID- 17692482 TI - Purified and surfactant-free coenzyme Q10-loaded biodegradable nanoparticles. AB - The intent of this work was to synthesize and comprehensively characterize ubiquinone-loaded, surfactant-free biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles in vitro. Surfactant-free, empty and ubiquinone (CoQ10) loaded biodegradable nanoparticles were synthesized by nanoprecipitation, and the physicochemical properties of these nanoparticles were analyzed with a variety of techniques. Nanoprecipitation consistently yielded individual, sub-200nm, surfactant-free empty and CoQ10-loaded nanoparticles, where the physical and drug encapsulation characteristics were controlled by varying the formulation parameters. CoQ10 release was sustained for 2 weeks but then plateaued before 100% CoQ10 release. A novel, nondestructive purification protocol involving transient sodium dodecyl sulfate (SDS) adsorption to nanoparticles followed by centrifugation and dialysis was developed to yield purified, surfactant-free, CoQ10-loaded nanoparticles. This protocol permitted removal of unencapsulated CoQ10, prevented centrifugation-induced nanoparticle aggregation and preserved the surfactant-free and drug encapsulation properties of the nanoparticles. These CoQ10-loaded nanoparticles are promising as sustained drug delivery devices due to their extended CoQ10 release. Importantly, a surfactant-free nanoprecipitation procedure is presented that in combination with a novel purification step enables the synthesis of individual and purified CoQ10-loaded nanoparticles. PMID- 17692483 TI - Preparation and characterization of extruded magnetoliposomes. AB - Phospholipid vesicles encapsulating magnetic nanoparticles (here after called magnetoliposomes) have been prepared for targeting a drug to a specific organ using a magnetic force, as well as for local hyperthermia therapy. Magnetoliposomes are also an ideal platform for use as contrast agents. We describe the preparation and characterization of liposomes containing magnetite, a ferrimagnetic material. These liposomes were obtained by extrusion. To prevent the aggregation of particles, the magnetite was treated--prior to encapsulation- with a surfactant, resulting in a stable ferrofluid suspension. Once the ferrofluid had been obtained, it was used to hydrate the phospholipid layers. Magnetoliposomes had a diameter of around 200 nm, the same pore size as the membranes used for the extrusion. The encapsulation efficiency was dependent on the initial amount of ferrofluid present at the encapsulation stage, and in the worst case was 19%. This value corresponded to 82.06 mmol of magnetite per mole of phospholipid. Although we have used a determined membrane pore to obtain the magnetoliposomes, the method described here allows to prepare magnetoliposomes of different sizes as well as of different magnetite content. PMID- 17692484 TI - Antinociceptive effect from Davilla elliptica hydroalcoholic extract. AB - Davilla elliptica St Hill (Dilleniaceae) is widely used for multiple purposes in Brazil. The aim of this study was to verify the pharmacological support of this folk use and evaluate its use as antinociceptive. The hydroalcoholic extract of the stems (100-1000 mg/kg, p.o.) induced reduction of response in the formalin test inflammatory phase in mice. This antinociceptive effect does not involve the opioidergic pathway since it was not reverted by pre-treatment with naloxone nor due to myorelaxant activity since it did not affect rota-rod and tail-flick performance. Our results indicate a participation of the nitrergic pathway and may be of particular potential importance in clinical medicine, in view of the current interest in the assessment of new medicines originated from plants. PMID- 17692485 TI - Buyang Huanwu Decoction promotes growth and differentiation of neural progenitor cells: using a serum pharmacological method. AB - Buyang Huanwu Decoction (BYHWD), a traditional Chinese medicine, has been developed as a drug to be used for treatment of stroke for hundreds of years. However, the underlying mechanisms remain unknown. In this study, a serum pharmacological method was employed to investigate the effects of BYHWD on growth and differentiation of cultured neural progenitor cells derived from embryonic hippocampus. In culture medium containing BYHWD, the average neurite length of neural progenitor cells grew significantly longer than in control serum without BYHWD. Moreover, more neurofilament (NF) positive cells and glial fibrillary acidic protein (GFAP) positive cells were detected in the presence of BYHWD. The concentration of intracellular Ca(2+) in progenitor cells cultured with BYHWD was significantly lower than that cultured without BYHWD. These results suggest that BYHWD may promote growth and differentiation of neural progenitor cells. PMID- 17692486 TI - Buyang Huanwu Decoction can improve recovery of neurological function, reduce infarction volume, stimulate neural proliferation and modulate VEGF and Flk1 expressions in transient focal cerebral ischaemic rat brains. AB - Buyang Huanwu Decoction is a classic formula for treating stroke-induced disability in traditional Chinese medicine (TCM). To explore its pharmacological basis, we investigated the effects of the whole formula and its herbal components on the neurological behavior performance and infarction volume in focal cerebral ischaemia rats. The neurological deficit scores and infarction volume were measured at days 3, 7 and 14 after 30 min of occlusion of middle cerebral artery. The results showed that Buyang Huanwu Decoction and its herbal components significantly improved the neurological behavior performances and reduced the infarction volume in the ischaemic brains. To elucidate the potential therapeutic mechanisms, we investigated the proliferation of progenitors by detecting the immunohistochemical staining of thymidine analog 5-bromo-2'-deoxyuridine (BrdU) and found that the formula stimulated the proliferation of the progenitors at hippocampus and subventricular zone (SVZ) in the ischaemic brains. As vascular endothelial growth factor (VEGF) and its receptor fetal liver kinase (Flk1) are important neurotrophic, neuroprotective and neuroproliferative factors, we studied the expressions of VEGF and Flk1 in the hippocampus, SVZ and cortex in the ischaemic brains and found that the formula led to increase the numbers of VEGF-positive and Flk1-positive cells in the SVZ and cortex in the ischaemic brains. The results indicate that the therapeutic effects of Buyang Huanwu Decoction for recovery of neurological deficits are associated with the stimulation of the proliferation of progenitors and the enhancement of the expressions of VEGF and Flk in ischaemic brains. PMID- 17692487 TI - Human longevity within an evolutionary perspective: the peculiar paradigm of a post-reproductive genetics. AB - The data we collected on the genetics of human longevity, mostly resulting from studies on centenarians, indicate that: (1) centenarians and long-living sib pairs are a good choice for the study of human longevity, because they represent an extreme phenotype, i.e., the survival tail of the population who escaped neonatal mortality, pre-antibiotic era illnesses, and fatal outcomes of age related complex diseases. (2) The model of centenarians is not simply an additional model with respect to well-studied organisms, and the study of humans has revealed characteristics of ageing and longevity (geographical and sex differences, role of antigenic load and inflammation, role of mtDNA variants) which did not emerge from studies in laboratory model systems and organisms. (3) All the phenotypic characteristics of nonagenarians and centenarians fit the hypothesis that ageing is a remodelling process where the body of survivors progressively adapts to internal and external damaging agents they are exposed to during several decades, largely unpredicted by evolution. (4) Such a remodelling process, which can be considered a Darwinian process occurring at the somatic level within the framework of the evolutionary constraints, established by evolution for Homo sapiens as a species, may explain why the same gene polymorphism can have different (beneficial or detrimental) effects at different ages. (5) Geographic and demographic evidence suggest that longevity can be achieved by different combinations of genes, environment, and chance quantitatively and qualitatively different in many geographic areas, and that population-specific genetic factors, play a role on the longevity trait. (6) The concomitant and integrated use of new in silico and high throughput strategies will greatly accelerate the identification of new longevity genes in humans. PMID- 17692488 TI - Intrauterine devices and uterine peristalsis: evaluation with MRI. AB - Intrauterine devices (IUDs) have been viewed as an effective form of contraception. However, the mechanism by which IUDs disturb fertility remains controversial. This study aimed to evaluate the effects of IUDs on uterine contractility using cine MR. Eleven healthy female volunteers of reproductive age bearing IUDs and 12 women not bearing IUDs were evaluated during the periovulatory phase. MR images were obtained with a 1.5-T magnet, acquiring 60 serial images every 3 s via half-Fourier acquisition single-shot turbo spin echo to be displayed on cine mode. Assessments were based on (a) the presence of peristaltic waves, (b) the frequency and direction of peristaltic waves and (c) the extent of peristaltic waves. Static images were evaluated for thickness of the junctional zone (JZ) and myometrium. A fundo-cervical (FC)-directed peristaltic wave was identified in 4 of 11 IUD-bearing subjects and in only 1 of 12 subjects from the control group. FC waves extended through more than half of the thickness of the myometrium. Peristaltic frequency in IUD users (5.0/3 min) was less than that of the control group (6.5/3 min). The JZ and myometrium were significantly thicker in IUD users. FC-directed waves were more often observed in IUD-bearing subjects, which might explain the inhibition of active sperm transport. PMID- 17692489 TI - Development and initial evaluation of 7-T q-ball imaging of the human brain. AB - Diffusion tensor imaging (DTI) noninvasively depicts white matter connectivity in regions where the Gaussian model of diffusion is valid but yields inaccurate results in those where diffusion has a more complex distribution, such as fiber crossings. q-ball imaging (QBI) overcomes this limitation of DTI by more fully characterizing the angular dependence of intravoxel diffusion with larger numbers of diffusion-encoding directional measurements at higher diffusion-weighting factors (b values). However, the former technique results in longer acquisition times and the latter technique results in a lower signal-to-noise ratio (SNR). In this project, we developed specialized 7-T acquisition methods utilizing novel radiofrequency pulses, eight-channel parallel imaging EPI and high-order shimming with a phase-sensitive multichannel B0 field map reconstruction. These methods were applied in initial healthy adult volunteer studies, which demonstrated the feasibility of performing 7-T QBI. Preliminary comparisons of 3 T with 7 T within supratentorial crossing white matter tracts documented a 79.5% SNR increase for b=3000 s/mm2 (P=.0001) and a 38.6% SNR increase for b=6000 s/mm2 (P=.015). With spherical harmonic reconstruction of the q-ball orientation distribution function at b=3000 s/mm2, 7-T QBI allowed for accurate visualization of crossing fiber tracts with fewer diffusion-encoding acquisitions as compared with 3-T QBI. The improvement of 7-T QBI at b factors as high as 6000 s/mm2 resulted in better angular resolution as compared with 3-T QBI for depicting fibers crossing at shallow angles. Although the increased susceptibility effects at 7 T caused problematic distortions near brain-air interfaces at the skull base and posterior fossa, these initial 7-T QBI studies demonstrated excellent quality in much of the supratentorial brain, with significant improvements as compared with 3-T acquisitions in the same individuals. PMID- 17692490 TI - Assessment of extravascular extracellular space fraction in human melanoma xenografts by DCE-MRI and kinetic modeling. AB - Tumor aggressiveness and response to therapy are influenced by the extravascular extracellular space fraction (EESF) of the malignant tissue. The EESF may, therefore, be an important prognostic parameter for cancer patients. The aim of this study was to investigate whether gadopentetate dimeglumine (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to assess the EESF of tumors. Amelanotic human melanoma xenografts (A-07, R-18) were used as preclinical models of human cancer. Images of E.F (E is the initial extraction fraction of Gd-DTPA and F is perfusion) and lambda (the partition coefficient of Gd-DTPA) were obtained by Kety analysis of DCE-MRI data. Our study was based on the hypothesis that lambda is governed by the EESF and is not influenced significantly by microvascular density (MVD) or blood perfusion. To test this hypothesis, we searched for correlations between lambda and E.F, MVD or EESF by comparing lambda images with E.F images, histological preparations from the imaged tissue and the radial heterogeneity in EESF obtained by invasive imaging. Positive correlations were found between lambda and EESF. Thus, median lambda was larger in A-07 tumors than in R-18 tumors by a factor of 4.2 (P<.00001), consistent with the histological observation that EESF is approximately fourfold larger in A-07 tumors than in R-18 tumors. The radial heterogeneity in lambda in A-07 and R-18 tumors was almost identical to the radial heterogeneity in EESF. Moreover, lambda was larger in tissue regions with high EESF than in tissue regions with low EESF in A-07 tumors (P=.048). On the other hand, significant correlations between lambda and MVD or E.F could not be detected. Consequently, Kety analysis of Gd-DTPA-based DCE-MRI series of xenografted tumors provides lambda images that primarily reflect the EESF of the tissue. PMID- 17692491 TI - Regional variations and the effects of age and gender on glutamate concentrations in the human brain. AB - Proton magnetic resonance spectroscopy was performed at 3 T using the echo time averaged point-resolved spectroscopy method to determine the effects of age, gender and brain region on glutamate (Glu) concentrations in the healthy human brain. Thirty healthy men and 20 healthy women aged between 21 and 71 years were studied. Significant regional variations of Glu concentrations were observed. Glu concentration in the gray matter (GM) was approximately 25% higher than that in the white matter. Significant age-dependent decreases in Glu concentrations were observed in the basal ganglia (r=-0.75, P<.001) and parietal GM (r=-0.66, P<.001) of men but not those of women. Our findings demonstrate regional variations of Glu concentrations and suggest that the male brain may be more vulnerable to aging than the female brain. Our results also highlight the importance of brain region, age and gender matching in clinical studies. PMID- 17692492 TI - Analysis of silibinin in rat plasma and bile for hepatobiliary excretion and oral bioavailability application. AB - Silibinin is an herbal ingredient isolated from milk thistle. The aim of this study was to develop a simple liquid chromatographic system to assay silibinin in plasma and bile for pharmacokinetic study. Silibinin was given oral and intravenously. The plasma sample (25 microL) was vortex-mixed with 50 microL of internal standard solution (naringenin 10 microg/mL in acetonitrile) to achieve protein precipitation. Silibinin in the rat plasma and bile was separated using a reversed-phase C18 column (250 mm x 4.6 mm, 5 microm) with a mobile phase of acetonitrile -10 mM monosodium phosphate (pH 5.45 adjusted with orthophosphoric acid) (50:50, v/v) and the flow-rate of 1 mL/min. The UV detection wavelength was 288 nm. The concentration-response relationship from the present method indicated linearity over a concentration range of 0.5-100 microg/mL. Intra- and inter-assay precision and accuracy of silibinin fell well within the predefined limits of acceptability (<15%). An ultrafiltration method was used in this experiment and the protein binding of silibinin was 70.3+/-4.6%. After silibinin administration in rats, the disposition of silibinin in the plasma and bile fluid was due to rapid distribution and equilibration between the blood and hepatobiliary system, and the bile levels of unconjugated silibinin and total silibinin were greater than those in the plasma. The oral bioavailability of silibinin in rats was estimated to be 0.73%. PMID- 17692493 TI - Validation of a high-performance liquid chromatographic assay for the quantification of Reovirus particles type 3. AB - An anion exchange high-performance liquid chromatography (HPLC) method for the quantification of human Reovirus type 3 particles was validated according to the performance criteria of precision, specificity, linearity of calibration and working range, limits of detection and quantification, accuracy and recovery. Samples taken at various stages of Reovirus purification were used for the validation of the method. The method was specific for Reovirus which eluted around 9.8min without interference from any other component in the sample. Reovirus can be detected between 0.32E+12 and 2.10E12VP/mL by the proposed method that has the correlation coefficient of linearity equal to 0.9974 and the slope of linearity equal to 5.74E-07 area units/(VPmL). PMID- 17692494 TI - Influence of Pharmaceutical Care intervention and communication skills on the improvement of pharmacotherapeutic outcomes with elderly Brazilian outpatients. AB - OBJECTIVE: The goal of this study was to evaluate the influence of Pharmaceutical Care intervention on the results obtained with a group of elderly outpatients and to analyze the communication skills used by healthcare professionals (research pharmacists, dispensing pharmacists, and physicians) during counseling about healthcare and drug therapy. METHODS: The instruments were applied to 30 elderly outpatients assisted at the pharmacy of a primary healthcare unit in Ribeirao Preto (SP), Brazil. The group of patients received follow-up for a period of 12 months. RESULTS: It was observed that Pharmaceutical Care intervention and humanized communication, of an educational nature, optimized the use of medication, reduced symptoms caused by drug therapy, and improved the health conditions of the patients. CONCLUSION: Pharmaceutical Care intervention was essential for the establishment of therapeutic relationships and influenced the care given to elderly people as well as the achievement of positive health outcomes. PRACTICE IMPLICATIONS: After this study, Pharmaceutical Care programs were implemented in different PHCU's of Ribeirao Preto and pharmacists are following-up 300 elderly patients. PMID- 17692495 TI - [Transfer of emergency neurosurgical patients: when and how?]. AB - The annual incidence of severe head injury lies between 9 and 25/100000 inhabitants, depending on the criteria used for its definition. In most countries, the shortage in neurosurgical ICU beds makes it impossible to take in charge all patients with a severe brain injury. But the beneficial effect of a specialized neurosurgical ICU on outcome after brain injury has been demonstrated in several retrospective studies. Ideally, the best strategy is to admit the patients with a severe head injury directly in a neurosurgical centre. When this is not possible, the appropriate decision of a secondary transfer relies on the quality of the relationships between physicians in the community and the neurosurgical hospitals. Teleradiology is the best method to avoid unnecessary transportation or deleterious delays before transfer. In an era of decreasing medical budgets, technical improvements to enhance medical cooperation should be encouraged. PMID- 17692496 TI - [Kyphoscoliosis and ascending aortic aneurysm: a new case of intermittent right to-left shunting through a patent foramen oval]. AB - Platypnaea-orthodeoxia syndrome is usually due to an atrial right-to-left shunt through a patent foramen ovale. We report a case of foramen ovale reopened an unusual circumstance. A 83-year-old patient presenting back pains since a few days was admitted in emergency for dyspnaea and refractory hypoxia. The only way to control her back pains was to stay seated in a kyphoscoliosis position. The imagery explorations pointed out an ascending aortic aneurysm, which compressed the right atrium and distorted the position of the atrial septum relative to caval inflow, when the patient was in her painless position, explaining this gravity-related refractory hypoxia. PMID- 17692497 TI - [Coronary stents and anaesthesia]. AB - The coronary stents are widely used to prevent coronary restenosis after percutaneous coronary intervention. Dual antiplatelet therapy (acetyl salicylic acid and a thienopyridine-clopidogrel or ticlopidine) are prescribed at least during six weeks after conventional stent and six months after drug eluting stent insertion to prevent stent thrombosis. When an invasive procedure is required, a risk of stent thrombosis arises after stopping antiplatelet therapy and a risk of bleeding when continuing this treatment. Therefore, cardiologists should choose carefully the type of coronary stent before insertion and concerned physicians (anaesthesiologists, surgeons, cardiologists) should decide a perioperative strategy in these high-risk patients. PMID- 17692498 TI - A review of high throughput technology for the screening of natural products. AB - High throughput screening is commonly defined as automatic testing of potential drug candidates at a rate in excess of 10,000 compounds per week. The aim of high throughput drug discovery is to test large compound collections for potentially active compounds ('hits') in order to allow further development of compounds for pre-clinical testing ('leads'). High throughput technology has emerged over the last few years as an important tool for drug discovery and lead optimisation. In this approach, the molecular diversity and range of biological properties displayed by secondary metabolites constitutes a challenge to combinatorial strategies for natural products synthesis and derivatization. This article reviews the approach of High throughput technique for the screening of natural products for drug discovery. PMID- 17692499 TI - Pioglitazone ameliorates endothelial dysfunction and restores ischemia-induced angiogenesis in diabetic mice. AB - Angiogenesis, the formation of new blood vessels, is a physiological response to tissue ischemia. Clinical evidence suggests that diabetic patients have endothelial dysfunction and impaired angiogenesis in response to ischemia. Here, we investigated the impact of diabetes on ischemia-induced collateral growth, and tested the hypothesis that peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist augments collateral flow to ischemic tissue. We conducted unilateral hindlimb ischemia surgery in KKAy mice. Blood flow recovery was markedly impaired in diabetic mice compared with that in wild-type mice as determined by laser Doppler imaging. Treatment of KKAy mice with pioglitazone partially restored the blood flow recovery. Anti-CD31 immunostaining revealed that pioglitazone also significantly improved the capillary density in ischemic limb muscle. Endothelial NO synthase (eNOS) activity was ameliorated in diabetic mice treated with pioglitazone as determined by vasorelaxation in response to acetylcholine. Pioglitazone normalized vascular endothelial growth factor (VEGF) protein levels, which was decreased in ischemic muscle of KKAy mice, and up regulated eNOS phosphorylation at Ser-1177 and Akt phosphorylation at Ser-473 in ischemic muscle. Pioglitazone had no beneficial effects on blood flow recovery in diabetic mice treated with N(G)-nitro-l-arginine methyl ester (L-NAME). Our findings demonstrate that pioglitazone significantly ameliorates endothelial dysfunction and enhances blood flow recovery after tissue ischemia in diabetic mice. Activation of eNOS appears to be essential for pioglitazone to promote angiogenesis in ischemic tissue. PMID- 17692500 TI - Genotoxicity of acrylamide in human hepatoma G2 (HepG2) cells. AB - The recent finding that acrylamide (AA), a carcinogen in animal experiments and a probable human carcinogen, is formed in foods during cooking raises human health concerns. The relevance of dietary exposure for humans is still under debate. The purpose of the study was to evaluate the possible genotoxicity of acrylamide in human hepatoma G2 (HepG2) cells, a cell line of great relevance to detect genotoxic/antigenotoxic substances, using single cell gel electrophoresis (SCGE) assay and micronucleus test (MNT). In order to clarify the underlying mechanism(s) we evaluated the intracellular generation of reactive oxygen species (ROS) and the level of oxidative DNA damage by immunocytochemical analysis of 8 hydroxydeoxyguanosine (8-OHdG). The involvement of glutathione (GSH) in the AA induced oxidative stress was examined through treatment with buthionine sulfoximine (BSO) to deplete GSH. The results indicate that AA caused DNA strand breaks and increase in frequency of MN in HepG2 cells in a dose-dependent manner. The possible mechanism underlies the increased levels of ROS, depletion of GSH and increase of 8-OHdG formation in HepG2 cells treated with AA. We conclude that AA exerts genotoxic effects in HepG2 cells, probably through oxidative DNA damage induced by intracellular ROS and depletion of GSH. PMID- 17692501 TI - The alpha- and beta-expansin and xyloglucan endotransglucosylase/hydrolase gene families of wheat: molecular cloning, gene expression, and EST data mining. AB - Expansins and xyloglucan endotransglucosylase/hydrolases (XTHs) are families of extracellular proteins with members that have been shown to play an important role in cell wall growth. In this study, three, six, and five members of the wheat alpha-expansin (TaEXPA1 to TaEXPA3), beta-expansin (TaEXPB1 to TaEXPB6), and XTH (TaXTH1 to TaXTH5) gene families, respectively, were isolated from a dwarf wheat line. The mRNA expression analysis by real-time RT-PCR indicates that these genes display different transcription levels in different stages/organs/treatments, possibly suggesting their functional roles in the cell wall expansion process. Moreover, the comparison of the expression levels reveals that most of the expansins show lower expression than the XTHs. Finally, we present the analysis of wheat alpha- and beta-expansins and XTH families by expressed sequence tag data mining. PMID- 17692502 TI - Expressed transcripts associated with high rates of egg production in chicken ovarian follicles. AB - The purpose of this study was to characterize differentially expressed transcripts associated with varying rates of egg production in Taiwan country chickens. Ovarian follicles were isolated from two strains of chicken which showed low (B) or high (L2) rates of egg production, then processed for RNA extraction and cDNA library construction. Three thousand and eight forty clones were randomly selected from the cDNA library and amplified by PCR, then used in microarray analysis. Differentially expressed transcripts (P<0.05, log(2)> or = 1.75) were sequenced, and aligned using GenBank. This analysis revealed 20 non redundant sequences which corresponded to known transcripts. Eight transcripts were expressed at a higher level in ovarian tissue prepared from chicken strain B, and 12 transcripts were expressed at a higher level in L2 birds. These differential patterns of expression were confirmed by semi-quantitative RT-PCR. We show that transcripts of cyclin B2 (cycB2), ferritin heavy polypeptide 1 (FTH1), Gag-Pol polyprotein, thymosin beta4 (TB4) and elongation factor 1 alpha1 (EEF1A1) were enriched in B strain ovarian follicles. In contrast, thioredoxin (TXN), acetyl-CoA dehydrogenase long chain (ACADL), inhibitor of growth family member 4 (ING4) and annexin II (ANXA2) were expressed in at higher levels in the L2 strain. We suggest that our approach may lead to the isolation of effective molecular markers that can be used in selection programs in Taiwan country chickens. PMID- 17692503 TI - Application of multiplex bead array assay for Yq microdeletion analysis in infertile males. AB - The purpose of this study was to apply the multiplex bead array as a diagnostic tool for male infertility. The multiplex bead array offers a new platform in high throughput nucleic acid detection. Six loci, including sex-determining regions on the Y (SRY) chromosome as a control and five sequence-tagged sites (STS) in azoospermia-factor regions, were used in this system. Extracted genomic DNA from infertile male blood was used for multiplex polymerase chain reaction (PCR). After multiplex PCR using specific Cy3-labeled primer sets, the PCR product was hybridized with capture probes. A multiplexed PCR-liquid bead was arrayed for simultaneous detection using the Luminex system. This assay system correctly identified the presence or deletion of the Y chromosome. Therefore, this method provides a sensitive and high-throughput method for probing the deletion of the Y chromosome, and offers a completely new approach to male infertility screening. PMID- 17692504 TI - Influence of interleukin-2 deficiency on the generation of autoimmune B cells. AB - The production of auto-antibodies is one of the predominant characteristics of autoimmune disorders. Because IL-2 deficient mice develop autoimmunity, we asked how IL-2 deficiency might impair endogenous mechanisms of B cell tolerance. To this end, we mated BALB/c anti-dsDNA H chain knock-in mice, in which B cells producing anti-dsDNA antibodies are properly regulated, with IL-2 deficient mice and assessed the phenotype of their offspring. IL-2 deficient mice expressing the anti-dsDNA H chain knock-in allele developed anti-dsDNA antibodies of both IgM and IgG isotypes. Production of these antibodies occurred through the disruption of several mechanisms of endogenous tolerance, including deletion, maturational arrest, and follicular exclusion. In summary, our results suggest that IL-2 plays an important role in regulating B cell tolerance. PMID- 17692505 TI - Ultrasound induces cyclooxygenase-2 expression through integrin, integrin-linked kinase, Akt, NF-kappaB and p300 pathway in human chondrocytes. AB - It has been shown that ultrasound (US) stimulation accelerates fracture healing in the animal models and in clinical studies. However, the precise molecular events generated by US in chondrocytes have not been clarified well. Here we found that US stimulation transiently increased the surface expression of alpha2, alpha5, beta1 or beta3 but not alpha3 or alpha4 integrins in human chondrocytes, as shown by flow cytometric analysis. US stimulation increased prostaglandin E(2) formation as well as the protein and mRNA levels of cyclooxygenase-2 (COX-2). At the mechanistic level, anti-integrin beta1 and beta3 antibodies or beta1 and beta3 integrin small interference RNA attenuated the US-induced COX-2 expression. Integrin-linked kinase (ILK) inhibitor (KP-392), Akt inhibitor, NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) also inhibited the potentiating action of US. US stimulation promotes kinase activity of ILK, phosphorylation of Akt. In addition, US stimulation also induces IKKalpha/beta phosphorylation, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation at Ser(276), p65 and p50 translocation from the cytosol to the nucleus, and kappaB-luciferase activity. The binding of p65 to the NF-kappaB element, as well as the recruitment of p300 and the enhancement of p50 acetylation on the COX-2 promoter was enhanced by US. Taken together, our results provide evidence that US stimulation increases COX-2 expression in chondrocytes via the integrin/ILK/Akt/NF-kappaB and p300 signaling pathway. PMID- 17692506 TI - Mastoparan inhibits beta-adrenoceptor-G(s) signaling by changing the localization of Galpha(s) in lipid rafts. AB - Mastoparan, a wasp venom toxin, has various pharmacological activities, the mechanisms of which are still unknown. To clarify the action of mastoparan on G protein-coupled receptor-mediated signaling, we previously examined the effect of mastoparan on G(q)-mediated signaling and demonstrated that mastoparan binds to gangliosides causing a decrease in Galpha(q/11) content in lipid rafts, and resulting in the inhibition of G(q)-mediated phosphoinositide hydrolysis (Sugama et al., Mol. Pharmacol., 68, 1466, 2005). In the present study, we examined the effect of mastoparan on beta-adrenoceptor-G(s) signaling in 1321N1 human astrocytoma cells. Mastoparan inhibited isoproterenol-induced elevation of cyclic AMP in a concentration-dependent manner. Although mastoparan is known to be an activator of G(i), pertussis toxin only slightly attenuated mastoparan-induced inhibition of cyclic AMP elevation, suggesting that a major part of the inhibition of cyclic AMP elevation induced by mastoparan is not mediated by Galpha(i). By contrast, mastoparan-induced inhibition of cyclic AMP elevation was clearly attenuated by preincubation of the cells with ganglioside mixtures. Moreover, mastoparan changed the localization of Galpha(s) in lipid rafts without disrupting the structure of lipid rafts. Fluorescent staining analysis showed that mastoparan released GFP-Galpha(s) from plasma membranes into the cytosol. These results suggest that the mastoparan-induced suppression of cyclic AMP elevation is mainly caused by changing the localization of Galpha(s) in lipid rafts into a compartment in the cellular interior where it is not available to activate adenylyl cyclase. PMID- 17692507 TI - Rapid changes in substance P signaling and neutral endopeptidase induced by skin scratching stimulation in mice. AB - BACKGROUND: Skin-scratching is a commonly seen behavior in patients with pruritus which sometimes exacerbates original lesions. Substance P (SP) signaling may play a predominant role in the pathophysiology induced by skin-scratching, however, it has not been well-elucidated. OBJECTIVES: To clarify changes in SP, its receptor NK-1R and a degradating enzyme neutral endopeptidase (NEP) induced by skin scratching stimulation in mice. METHODS: After skin-scratching stimulation was given to mice, changes in SP signaling were investigated as follows. Mast cell degranulation was examined with toluidine blue staining. SP-immunoreactive nerve fibers and the expressions of NK-1R and NEP were examined with immunofluorescence. Protein contents of SP and the enzymatic activity of NEP were examined with an ELISA and a colorimetric assay, respectively. RESULTS: After skin-scratching stimulation, mast cells significantly degranulated within several minutes. SP-immunoreactive nerve fibers disappeared immediately from sensory nerve fibers, indicating the quick secretion and the depletion of SP. Both protein contents of SP and NEP activity in skin decreased dramatically soon after skin-scratching stimulation and thereafter they returned to the basal level within a week. The expression of NK-1R was significantly upregulated in epidermal basal keratinocytes after several days, in which NEP and NK-1R were well coexpressed. Blocking NK-1R by an NK-1R antagonist suppressed scratching-induced decreases in SP-immunoreactive nerve fibers and in NEP activity. CONCLUSIONS: The present study clarified changing patterns of factors involved in SP signaling and NEP induced by skin-scratching stimulation. These findings provide basic and useful information to understand the pathophysiology of scratching-associated pruritic skin diseases. PMID- 17692508 TI - Glycerol facilitates the disaggregation of recombinant adeno-associated virus serotype 2 on mica surface. AB - Preparation of distributed virus on a solid substrate is a prerequisite for investigation of the properties and individualism of virus, while many previous studies showed that virus has a tendency to aggregate on solid substrates. In this communication, we report a novel approach by which well-separated recombinant adeno-associated virus serotype 2 (rAAV2) could be prepared on bare mica surface. The key technique in this approach is the addition of less than 3% (v/v) glycerol into the virus solution and subsequently deposition onto mica surface for the sample preparation. The possible mechanisms are also briefly discussed. PMID- 17692509 TI - The effect of smoking cessation and steroid treatment on emphysema in guinea pigs. AB - BACKGROUND: Emphysema induced by cigarette smoking is characterized by an inflammatory process, which is resistant to steroid and remains active in lung tissue long after smoking has stopped. Latent adenoviral infection (Ad5) increases emphysema development and the inflammatory response to cigarette smoke and, in allergic lung inflammation, suppresses anti-inflammatory effects of steroids. OBJECTIVES: The present study was designed to examine the effect of smoking cessation and steroid treatment on lung emphysema and inflammation in a guinea pig model of emphysema and to determine if latent adenoviral infection induces resistance to the inflammatory effects of steroid. METHODS: Latent adenovirus or sham infected animals exposed to room air or cigarette smoke for 16 weeks were either sacrificed immediately or treated with dexamethasone or diluent for an additional 5 weeks without smoke exposure. Lung morphometry, inflammatory cells and mediators were studied. RESULTS: Smoking cessation was associated with an increase in lung surface area and surface area to volume ratio. Smoking cessation was also associated with decreases in lung neutrophils, CD4 cells, and IL-8, RANTES and IFN-gamma mRNAs to control levels. Steroid treatment significantly lowered neutrophils, eosinophils and IFN-gamma mRNA and, while adenoviral infection did not alter these steroid-induced changes, it independently increased airway wall neutrophils and CD8 cells. CONCLUSION: Smoking cessation decreases lung inflammation and latent adenoviral infection does not induce steroid resistance in this animal model. PMID- 17692510 TI - State of municipal solid waste management in Delhi, the capital of India. AB - Delhi is the most densely populated and urbanized city of India. The annual growth rate in population during the last decade (1991-2001) was 3.85%, almost double the national average. Delhi is also a commercial hub, providing employment opportunities and accelerating the pace of urbanization, resulting in a corresponding increase in municipal solid waste (MSW) generation. Presently the inhabitants of Delhi generate about 7000tonnes/day of MSW, which is projected to rise to 17,000-25,000tonnes/day by the year 2021. MSW management has remained one of the most neglected areas of the municipal system in Delhi. About 70-80% of generated MSW is collected and the rest remains unattended on streets or in small open dumps. Only 9% of the collected MSW is treated through composting, the only treatment option, and rest is disposed in uncontrolled open landfills at the outskirts of the city. The existing composting plants are unable to operate to their intended treatment capacity due to several operational problems. Therefore, along with residue from the composting process, the majority of MSW is disposed in landfills. In absence of leachate and landfill gas collection systems, these landfills are a major source of groundwater contamination and air pollution (including generation of greenhouse gases). This study describes and evaluates the present state of municipal solid waste management in Delhi. The paper also summarizes the proposed policies and initiatives of the Government of Delhi and the Municipal Corporation of Delhi to improve the existing MSW management system. PMID- 17692512 TI - Common cues regulate neural and vascular patterning. AB - Nerves and blood vessels often follow parallel trajectories as they course through the body to their distal targets. Proteins that regulate the process of axon guidance have likewise been shown to play a crucial role in blood vessel migration. With the recent description of the endothelial tip cell as an analog of the axonal growth cone, the nerve-vessel analogy seems complete. Notwithstanding these considerable similarities, one crucial difference remains between neural and vascular guidance. While a navigating axon is but a single cell, a sprouting vessel is composed of multiple cells that must be co-ordinately regulated. Recent studies of the Dll4-Notch1 signaling pathway have provided valuable insight into how the vasculature accomplishes this crucial task. PMID- 17692514 TI - Activation of estrogen receptor-beta by a special extract of Rheum rhaponticum (ERr 731), its aglycones and structurally related compounds. AB - The special extract ERr 731 from the roots of Rheum rhaponticum is the major constituent of Phytoestrol N which is used for the treatment of climacteric symptoms in menopausal women. However, the molecular mode of action of ERr 731 was unknown. For the first time, ERr 731 and its aglycones trans-rhapontigenin and desoxyrhapontigenin were investigated with regard to the activation of the estrogen receptor-alpha or estrogen receptor-beta (ERalpha, ERbeta). The related hydroxystilbenes cis-rhapontigenin, resveratrol and piceatannol were studied as comparators. As controls, 17beta-estradiol or the selective ERalpha (propylpyrazoltriol) or ERbeta-agonists (diarylpropionitril) were used. Neither in ERalpha-expressing yeast cells, in the ERalpha-responsive Ishikawa cells, nor in human endometrial HEC-1B cells transiently transfected with the ERalpha an activation of ERalpha by ERr 731 or the other single compounds was detected. Furthermore, an antiestrogenic effect was not observed. In contrast in human endometrial HEC-1B cells transiently transfected with the ERbeta, 100 ng/ml ERr 731 and the single compounds significantly induced the ERbeta-coupled luciferase activity in a range comparable to 10(-8)M 17beta-estradiol. All effects were abolished with the pure ER antagonist ICI 182780, indicating an ER-specific effect. The ERbeta agonistic activity by ERr 731 could be of importance for its clinical use, as central functions relevant to climacteric complaints are proposed to be mediated via ERbeta activation. PMID- 17692515 TI - Effects of progesterone in the spinal cord of a mouse model of multiple sclerosis. AB - The spinal cord is a target of progesterone (PROG), as demonstrated by the expression of intracellular and membrane PROG receptors and by its myelinating and neuroprotective effects in trauma and neurodegeneration. Here we studied PROG effects in mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis characterized by demyelination and immune cell infiltration in the spinal cord. Female C57BL/6 mice were immunized with a myelin oligodendrocyte glycoprotein peptide (MOG(40-54)). One week before EAE induction, mice received single pellets of PROG weighing either 20 or 100 mg or remained free of steroid treatment. On average, mice developed clinical signs of EAE 9-10 days following MOG administration. The spinal cord white matter of EAE mice showed inflammatory cell infiltration and circumscribed demyelinating areas, demonstrated by reductions of luxol fast blue (LFB) staining, myelin basic protein (MBP) and proteolipid protein (PLP) immunoreactivity (IR) and PLP mRNA expression. In motoneurons, EAE reduced the expression of the alpha 3 subunit of Na,K-ATPase mRNA. In contrast, EAE mice receiving PROG showed less inflammatory cell infiltration, recovery of myelin proteins and normal grain density of neuronal Na,K-ATPase mRNA. Clinically, PROG produced a moderate delay of disease onset and reduced the clinical scores. Thus, PROG attenuated disease severity, and reduced the inflammatory response and the occurrence of demyelination in the spinal cord during the acute phase of EAE. PMID- 17692516 TI - Removal of methylene blue dye from aqueous solutions by adsorption using yellow passion fruit peel as adsorbent. AB - The removal of color from aquatic systems caused by presence of synthetic dyes is extremely important from the environmental viewpoint because most of these dyes are toxic, mutagenic and carcinogenic. In this present study, the yellow passion fruit (Passiflora edulis Sims. f. flavicarpa Degener) peel a powdered solid waste, was tested as an alternative low-cost adsorbent for the removal of a basic dye, methylene blue (MB), from aqueous solutions. Adsorption of MB onto this natural adsorbent was studied by batch adsorption isotherms at room temperature. The effects of shaking time and pH on adsorption capacity were studied. An alkaline pH was favorable for the adsorption of MB. The contact time required to obtain the maximum adsorption was 56 h at 25 degrees C. Yellow passion fruit peel may be used as an alternative adsorbent to remove MB from aqueous solutions. PMID- 17692517 TI - Synthesis and antibacterial activity of C11, C12-cyclic urea analogues of ketolides. AB - C11, C12-cyclic urea analogues of ketolides were designed and synthesized by use of a novel ketene acetal intermediate. This intermediate enabled introduction of an amino group at C12 stereospecifically and in high yield. The resulting cyclic urea ketolides appear to have in vitro activity similar to that of telithromycin which contains a C11, C12 cyclic carbamate moiety. Some of the C2 fluorinated compounds have improved potency against erm-containing Streptococcus pyogenes. PMID- 17692518 TI - Synthesis of novel HIV protease inhibitors (PI) with activity against PI resistant virus. AB - A series of HIV protease inhibitors with modifications on the P3 position have been designed and synthesized. These compounds exhibit excellent antiviral activity against both the wild type enzyme and PI-resistant clinical viral isolates. The synthesis and biological activity of the compounds are described. PMID- 17692519 TI - Identification of dissociated non-steroidal glucocorticoid receptor agonists. AB - A new series of ligands for the glucocorticoid receptor (GR) is described. SAR development was guided by docking 3 into the GR active site and optimizing an unsubstituted phenyl ring for key interactions found in the steroid A-ring binding pocket. To identify compounds with an improved side effect profile over marketed steroids the functional activity of compounds was evaluated in cell based assays for transactivation (aromatase) and transrepression (IL-6). Through this effort, 36 has been identified as a partial agonist with a dissociated profile in these cell based assays. PMID- 17692520 TI - Anti-tubercular agents. Part IV: Synthesis and antimycobacterial evaluation of nitroheterocyclic-based 1,2,4-benzothiadiazines. AB - In continuation of our earlier work on benzothiadiazines, we have prepared a series of nitrofuran, nitrothiophene and arylfuran coupled benzothiadiazines and evaluated them for antimycobacterial and antibacterial activities. One of the compounds 2f has shown good in vitro antimycobacterial activity. All the synthesized compounds have shown moderate to good antibacterial activity. PMID- 17692521 TI - Association between subjective descriptors of coronary pain and disease characteristics: a pilot study in a Hellenic rural population. AB - PURPOSE: We explored whether the way Hellenic patients describe their cardiac chest pain (verbal descriptions of the nature, intensity, temporal quality, location and radiation) associates with the diagnosis [acute myocardial infarction (AMI) versus unstable angina (UA)] as well as with the location of the coronary lesions. METHODS: A cross-sectional correlational design was employed to study 80 consecutive coronary care patients (44 with AMI, 36 with UA) from northwestern Hellas. RESULTS: Pain intensity did not differ significantly between AMI and UA, in contrast to treatment-seeking behaviour and accompanying symptoms (p< or =0.03). Of AMI patients, women used more often the word "pain" (p=0.011), and indicated pain at the left shoulder (p=0.004). AMI patients used fewer words (p=0.03), and experienced pain at the back of the neck (p=0.03) and of the left arm (p=0.02) less often. The descriptions "knob", "constriction" and "drill" were more prevalent in UA patients (p<0.01). The description "drill" discriminated between diagnostic groups in a multivariate model (p=0.03). Associations between the infarct and pain location (p< or =0.03), and the use of some sensory descriptors (p< or =0.02) were detected. Pain locations associated with ECG findings (p< or =0.005). CONCLUSIONS: Subjective acute coronary pain descriptions and pain characteristics may associate with the pathophysiological processes in coronary syndromes. PMID- 17692522 TI - Influence of bright light therapy on postoperative patients: a pilot study. AB - Bright light therapy is a method of maintaining or restoring the natural circadian rhythm by assisting daytime awakening using bright lights. Postoperative delirium is one of the potential complications encountered by patients receiving postoperative care in the intensive care unit (ICU), but there have been no studies on the use of light for the prevention of postoperative delirium. The objective of this study was to examine whether the circadian rhythms of patients after surgery for oesophageal cancer can be adjusted and whether the postoperative delirium crisis rate can be reduced by bright light therapy. The subjects were 11 patients operated on for oesophageal cancer in Osaka University Hospital. After informed consent was obtained, they were divided into a study group and a control group by a random sampling method. After removal of the endotracheal tube, the study group was exposed to light. The light intensity was about 5000lx immediately before the eyes, and the distance from the light source was about 100 cm. The control group was placed in a natural lighting environment after extubation. In both groups, the rhythms of physical activities and autonomic activities were monitored after surgery, and delirium was evaluated. A significant difference was observed in the delirium score between the study group and control group on the morning of day 3 of bright light therapy by the Mann-Whitney U-test (P=0.014). The study group could begin ambulation about 2 days earlier than the control group. Bright light therapy may reduce the rate of postoperative delirium and make early ambulation possible. However, our study involved a very small sample size. We want to increase the sample in the future after having reviewed clinical application methods. PMID- 17692523 TI - Analysis of pressure distribution below the metatarsals with different insoles in combat boots of the German Army for prevention of march fractures. AB - AIM: The aim of the present study was the assessment of metatarsal head loading in combat boots of the German armed forces. With respect to the prevention of metatarsal stress fractures, we evaluated how cushioning insoles (made of EVA foam or neoprene) achieved a load reduction in comparison with conventional insoles. MATERIAL AND METHODS: Local pressure, force and impulse values were determined with the pedar-m expert in-shoe pressure measurement system applied in 26 volunteers during walking with four different insoles made of synthetic mesh, EVA foam and neoprene. Data analysis was performed with SAS and tested for statistical differences with non-parametric tests (with p<0.05 as a significance level). RESULTS: For the peak pressures under the metatarsal heads (MT) the following order was found: MT-II>MT-III>MT-I>MT-IV>MT-V. A comparison of the insoles indicated that the neoprene insole resulted in the lowest peak pressures with significant load reductions under MT-III to MT-V (p<0.00001). Furthermore, the impulse values under MT-II to MT-V were significantly lower with neoprene insoles (p<0.0002). However, the subjects rated the conventional insoles as more comfortable and better fitting than the newly developed insoles. DISCUSSION/CONCLUSION: The cushioning insoles were superior to the conventional insoles with respect to the plantar pressure distribution. With respect to the load reduction we can conclude that the modified insoles might be able to reduce the incidence of march fractures. The biomechanical advantage does not appear to be related to personal preferences. PMID- 17692524 TI - Shoulder motion description: the ISB and Globe methods are identical. AB - BACKGROUND: Three-dimensional shoulder position may be described by rotation sequences such as the proposed ISB standard. Alternative techniques to describe position (the Globe method) seek to simplify this description by eliminating rotation sequences and substituting unambiguous measurements. METHODS: Both methods (ISB and Globe) were applied to an analysis of shoulder positions, and an overall comparison was performed. FINDINGS: The ISB and Globe methods are numerically identical and interchangeable. INTERPRETATION: While all analytic methods are mathematically equivalent, investigators have sought simpler and more easily-applied ways of describing shoulder position that would be accurate, easily understood by clinicians, and unambiguous. This study demonstrates that the ISB rotation sequence and Globe descriptive method are numerically the same. PMID- 17692525 TI - Mono- and disalicylic acid derivatives: PTP1B inhibitors as potential anti obesity drugs. AB - A series of compounds containing one or two salicylic acid moieties were synthesized, and their efficacy to inhibit the phosphohydrolase activity of PTP1B examined. Some of the methylenedisalicylic acid derivatives were potent inhibitors of PTP1B. Of those derivatives, 3c exhibited about a 14-fold selectivity against TC-PTP, and this compound was tested in a mouse model for its efficacy to prevent diet-induced obesity. It effectively suppressed the increases in body weight and adipose mass, without any noticeable toxic effect. The compound also prevented increases in the plasma triglyceride, cholesterol, and nonesterified fatty acid concentrations; thus, expanding its therapeutic potential to other related metabolic diseases, such as hyperlipidemia and hypercholesterolemia. PMID- 17692526 TI - Scanning transmitted and reflected light microscopy: a novel microscopy for visualizing biomaterials at interfaces. AB - Two new types of light microscopy, scanning transmitted light and scanning reflected light microscopy (STLM and SRLM, respectively) were developed. STLM and SRLM are based on optical density recognition (ODR) of the scanned transmitted or reflected light, respectively, from the object to be visualized. The obtained image is a result of enhanced interference between the scanning and transmitted/reflected beams from the object. The new microscopy, in its initial phase, is ideally suited for monitoring macroscopic and sub-millimeter size self assembly and for elucidating the connection between the macroscopic and nanoscopic worlds if combined with atomic force microscopy (AFM) or electron microscopy (EM). The method is demonstrated by monitoring the growth of 3D crystals from their original liquid phase. Some preliminary measurements carried out using the prototype of the new microscopy are presented and its current and future possible applications are described. PMID- 17692527 TI - Effects of atrazine on female Wistar rats: morphological alterations in ovarian follicles and immunocytochemical labeling of 90 kDa heat shock protein. AB - Fertility in female mammals may be affected by a variety of endocrine disrupters present in the environment. Herbicide atrazine is an example of endocrine disrupter employed in agriculture, which disrupts estrous cyclicity in rats. Aiming to characterize morphologically the effect of low and sublethal doses of atrazine on the ovaries of Wistar rats, in an effort to determine the possible intrafollicular target site through which this herbicide acts adult females were submitted to both subacute and subchronic treatments. Additionally, immunocytochemical labeling of 90 kDa heat shock protein (HSP90) was performed in order to evaluate the role played by this protein in the ovary, under stressed conditions induced by herbicide exposure. The results indicated that atrazine induced impaired folliculogenesis, increased follicular atresia and HSP90 depletion in female rats submitted to subacute treatment, while the subchronic treatment with low dose of atrazine could compromise the reproductive capacity reflected by the presence of multioocytic follicle and stress-inducible HSP90. PMID- 17692528 TI - Factors affecting the morphology of benzoyl peroxide microsponges. AB - Benzoyl peroxide (BPO) is primarily used in the treatment of mild to moderate acne. However, its application is associated with skin irritation. It has been shown that encapsulation and controlled release of BPO could reduce the side effect while also reducing percutaneous absorption when administered to the skin. The aim of the present investigation was to design and formulate an appropriate encapsulated form of BPO, using microsponge technology, and explore the parameters affecting the morphology and other characteristics of the resultant products employing scanning electron microscopy (SEM). Benzoyl peroxide particles were prepared using an emulsion solvent diffusion method by adding an organic internal phase containing benzoyl peroxide, ethyl cellulose and dichloromethane into a stirred aqueous phase containing polyvinyl alcohol (PVA). Different concentrations of BPO microsponges were incorporated in lotion formulations and the drug release from these formulations were studied. The SEM micrographs of the BPO microsponges enabled measurement of their size and showed that they were spherical and porous. Results showed that the morphology and particle size of microsponges were affected by drug:polymer ratio, stirring rate and the amount of emulsifier used. The results obtained also showed that an increase in the ratio of drug:polymer resulted in a reduction in the release rate of BPO from the microsponges. The release data showed that the highest and the lowest release rates were obtained from lotions containing plain BPO particles and BPO microsponges with the drug:polymer ratio of 13:1, respectively. The kinetics of release study showed that the release data followed Peppas model and the main mechanism of drug release from BPO microsponges was diffusion. PMID- 17692529 TI - Primary and redo valve replacement before and after liver transplantation. AB - We report the case of a 39-year-old man who underwent life-saving aortic valve replacement with a bioprosthesis for acute endocarditis while on the liver transplant waiting list, followed by successful transplantation and late valve re replacement with a mechanical prosthesis, 10.8 years after primary valve surgery. PMID- 17692530 TI - Pathophysiology and types of dyslipidemia in PCOS. AB - Polycystic ovary syndrome (PCOS) is an endocrinopathy that affects women of reproductive age. PCOS shares components with the metabolic syndrome and has broad health implications. Lipid abnormalities, including elevated low-density lipoprotein (LDL), triglyceride levels and decreased high-density lipoprotein (HDL), are often found in women with PCOS. It is clear that obesity, insulin resistance and hyperandrogenism coexist in PCOS, and have independent and interactive effects on dyslipidemia, although the mechanisms of these interactions remain elusive. Here, we review the types and pathophysiology of dyslipidemia associated with PCOS and its related conditions. PMID- 17692531 TI - mu-crystallin, a NADPH-dependent T(3)-binding protein in cytosol. AB - Thyroid hormone action is initiated through nuclear thyroid hormone receptors (TRs). Before the discovery of these nuclear receptors, possible major binding sites for thyroid hormones were thought to be cytosolic owing to high thyroid hormone-binding activity in crude cytosolic fractions. Several cytosolic thyroid hormone-binding proteins have been identified, including reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent 3,5,3'-triiodo-L-thyronine (T(3))-binding protein, also known as mu-crystallin, which was initially cloned as the ortholog of bacterial ornithine cyclodeaminase. The expression of mu crystallin is developmentally regulated and cell-type specific. Recently, patients with nonsyndromic deafness were reported to have point mutations in the mu-crystallin gene. Cytosolic thyroid hormone-binding proteins, especially mu crystallin, have roles in adaptation to environmental alterations by thyroid hormone, which might have a role in hearing function. PMID- 17692532 TI - Expression of a Beauveria bassiana chitinase (Bbchit1) in Escherichia coli and Pichia pastoris. AB - Beauveria bassiana chitinase (Bbchit1) is an important cuticle degrading enzyme involved in pathogenesis of fungi against insect. To obtain enough active chitinase for performing in vitro functional analysis, Bbchit1 gene was expressed in Escherichia coli and Pichia pastoris, respectively. The high-level production of recombinant Bbchit1 was detected in E. coli expression system, however mainly located in inclusion bodies. Refolding of solubilized inclusion body proteins was achieved by dialysis. In P. pastoris expression system, Bbchit1 was secreted into the culture medium under the induction of methanol. Active Bbchit1 was purified to near 90% purity from culture medium by desalting chromatography and anion exchange chromatography. The yield of Bbchit1 produced by P. pastoris was estimated at 153 mg/L, significantly higher than that of the refolded Bbchit1 from E. coli inclusion bodies (50 mg/L). Additionally, the specific activity of Bbchit1 from P. pastoris was also higher than that from E. coli (3.9 U/mg versus 2.8 U/mg). These results indicated P. pastoris was a convenient expression system for the efficient production of Bbchit1. PMID- 17692533 TI - Concatenated metallothionein as a clonable gold label for electron microscopy. AB - Localization of proteins in cells or complexes using electron microscopy has mainly relied upon the use of heavy metal clusters, which can be difficult to direct to sites of interest. For this reason, we would like to develop a clonable tag analogous to the clonable fluorescent tags common to light microscopy. Instead of fluorescing, such a tag would initiate formation of a heavy metal cluster. To test the feasibility of such a tag, we exploited the metal-binding protein, metallothionein (MT). We created a chimeric protein by fusing one or two copies of the MT gene to the gene for maltose binding protein. These chimeric proteins bound many gold atoms, with a conservative value of 16 gold atoms per copy of metallothionein. Visualization of gold-labeled fusion proteins by scanning electron microscopy required one copy of metallothionein while transmission electron microscopy required two copies. Images of frozen-hydrated samples of simple complexes made with anti-MBP antibodies hint at the usefulness of this method. PMID- 17692534 TI - Structural basis of specificity of a peptidyl urokinase inhibitor, upain-1. AB - Urokinase-type plasminogen activator (uPA) plays a crucial role in the regulation of plasminogen activation, tumor cell adhesion and migration. The inhibition of uPA activity is a promising mechanism for anti-cancer therapy. A cyclic peptidyl inhibitor, upain-1, CSWRGLENHRMC, was identified recently as a competitive and highly specific uPA inhibitor. We determined the crystal structure of uPA in complex with upain-1 at 2.15 A. The structure reveals that the cyclic peptide adopts a rigid conformation stabilized by a disulfide bond (residues 1-12) and three tight beta turns (residues 3-6, 6-9, 9-12). The Glu7 residue of upain-1 forms hydrogen bonds with the main chain nitrogen atoms of residues 4, 5, and 6 of upain-1, and is also critical for maintaining the active conformation of upain 1. The Arg4 of upain-1 is inserted into the uPA's specific S1 pocket. The Ser2 residue of upain-1 locates close to the S1beta pocket of uPA. The Gly5 and Glu7 residues of upain-1 occupy the S2 pocket and the oxyanion hole of uPA, respectively. Furthermore, the Asn8 residue of upain-1 binds to the 37- and 60 loops of uPA and renders the specificity of upain-1 for uPA. Based on this structure, a new pharmacophore for the design of highly specific uPA inhibitors was proposed. PMID- 17692535 TI - Case studies of power and control related to tobacco use during pregnancy. AB - OBJECTIVE: The objective was to identify and describe elements of power and control evident in couple tobacco-related interaction patterns during pregnancy. METHODS: Using a case study approach, elements of the Duluth Abuse Intervention Project Power and Control Wheel were used to examine women's experiences of tobacco reduction during pregnancy and post partum. Three cases were selected from a larger qualitative sample, using a maximum variation sampling approach. RESULTS: Although no direct evidence of partner abuse or violence accompanying partner efforts to influence women's smoking was described, most of the elements of power and control were present in the case study, and appeared to cause an emotional toll and a negative impact on women's ability to freely express their views about their own tobacco use. CONCLUSIONS: Elements of power and control, however subtle, are potentially important and unrecognized dimensions of women's tobacco reduction experiences. Additional care and attention should be taken in designing tobacco reduction interventions and policies directed at pregnant and post partum women and their partners to reduce the possibility that these interventions may contribute to the use of power and control. PMID- 17692536 TI - Aging, grey matter, and blood flow in the anterior cingulate cortex. AB - The anterior cingulate cortex (ACC) is thought to be the neuroanatomical interface between emotion and cognition. Because effective emotion-cognition interactions are essential to optimal decision making, clarifying how the functionality of the ACC changes in older age using functional imaging holds great promise for ultimately understanding what contributes to the psychological changes occurring in late life. However, the interpretation of functional imaging studies is complicated by the fact that aging is associated with changes in grey matter volume and in the cerebral vasculature. In the present study, we obtained high-resolution structural magnetic resonance (MR) imaging data and quantitative blood flow images to examine the association between aging, blood flow, and grey matter volume in the ACC. Twenty-six healthy individuals between 25 and 79 years of age underwent quantitative [15O]water positron emission tomography (PET) imaging. The ACC was traced onto tissue-classified images derived from T1- and T2 weighted MRIs using previously defined methods. The ACC was divided into dorsal, rostral, and subgenual regions. Age was negatively correlated with blood flow in dorsal and rostral ACC regions. Effects were weaker but in a similar direction for the subgenual ACC. While older age and lower blood flow were both associated with smaller rostral ACC grey matter volumes, mediation analysis revealed that grey matter volume only partially mediated the effect of age on blood flow in the rostral ACC. Neural alterations not detectable on MR images may lead to reduced blood flow due to fewer and/or less metabolically active neurons. Alternatively, lower blood flow may be a cause, rather than a consequence, of smaller grey matter volume in the ACC. PMID- 17692537 TI - Levetiracetam monotherapy in juvenile myoclonic epilepsy. AB - PURPOSE: To describe our experience with levetiracetam (LEV) as initial or conversion monotherapy treatment for juvenile myoclonic epilepsy (JME). Valproate, the usual first line agent for JME, has chronic adverse effects, particularly for women of childbearing potential. Since JME requires lifetime treatment, chronic adverse effects of therapy are important consideration. METHODS: We reviewed the medical records of patients with JME treated with LEV in the first 4 years after marketing. We recorded demographic data, results of EEG and imaging studies, antiepileptic drug (AED) history, LEV initial dose and final dose, side effects related to LEV, and therapeutic response to treatment. We classified JME into definite and probable based on clinical and EEG criteria. The minimum duration of follow up was 1 year. RESULTS: LEV was the first therapy in 12 patients and the initial appropriate agent in 16. Fourteen patients had been treated with another appropriate AED. Eighty percent (24/30) of patients became seizure free with LEV monotherapy and two additional patients showed improved seizure control. Final therapeutic doses of LEV ranged from 12 to 50mg/(kgday). Complete seizure control using LEV was not predicted by previous AED use. Treatment failure with valproate also did not predict failure of LEV. Patients with definite JME responded best within the study group (11 of 11 seizure free, p<0.05). CONCLUSIONS: This study supports consideration of LEV for first line treatment of JME and suggests the need for a large prospective trial. PMID- 17692538 TI - D-Lactate inhibition of memory in a single trial discrimination avoidance task in the young chick. AB - L-Lactate is a metabolite possibly able to meet some neuronal energy demands. However, a clear role for L-lactate in behaviour remains elusive. Administration of the inactive isomer D-lactate (1.75 mM; ic), immediately post-training, resulted in a persistent retention loss from 40 min post-training when used in conjuction with a single trial discrimination avoidance task designed for the young chick. Furthermore, 1mM noradrenaline (ic) administered 20 min post training overcame the retention loss induced by D-lactate. Although not directly demonstrated in the current study, it is plausible that D-lactate inhibited memory processing by competing with L-lactate for uptake into neurons. The time of onset of the retention loss induced by D-lactate is in accord with findings where the action of noradrenaline is inhibited. The successful challenge of D lactate inhibition by a high concentration of noradrenaline may suggest a relationship by some unidentified mechanism. PMID- 17692539 TI - Crosstalk between keratinocytes and adaptive immune cells in an IkappaBalpha protein-mediated inflammatory disease of the skin. AB - Inflammatory diseases at epithelial borders develop from aberrant interactions between resident cells of the tissue and invading immunocytes. Here, we unraveled basic functions of epithelial cells and immune cells and the sequence of their interactions in an inflammatory skin disease. Ubiquitous deficiency of the IkappaBalpha protein (Ikba(Delta)(/Delta)) as well as concomitant deletion of Ikba specifically in keratinocytes and T cells (Ikba(K5Delta/K5Delta lckDelta/lckDelta)) resulted in an inflammatory skin phenotype that involved the epithelial compartment and depended on the presence of lymphocytes as well as tumor necrosis factor and lymphotoxin signaling. In contrast, mice with selective ablation of Ikba in keratinocytes or lymphocytes showed inflammation limited to the dermal compartment or a normal skin phenotype, respectively. Targeted deletion of RelA from epidermal keratinocytes completely rescued the inflammatory skin phenotype of Ikba(Delta)(/Delta) mice. This finding emphasizes the important role of aberrant NF-kappaB activation in both keratinocytes and lymphocytes in the development of the observed inflammatory skin changes. PMID- 17692541 TI - Inability of RUNX1/AML1 to breach AML1-ETO block of embryonic stem cell definitive hematopoiesis. AB - The t(8;21)(q22:q22) translocation associated with acute myeloid leukemia fuses the AML1/RUNX1 N-terminal portion located on chromosome 21 to most of the ETO/MTG8 gene on chromosome 8. Various investigators have shown that the fusion product AML1-ETO on its own is unable to promote leukemia. Early studies using transgenic mouse models demonstrated that the direct knock-in of the fusion protein expression is embryonic lethal, similar to the AML1 knockout, suggesting that AML1-ETO has a dominant negative role over AML1. Using the embryonic stem cells generated for such studies, we show here that the presence of the fusion product AML1-ETO blocks definitive hematopoiesis in vitro as well, in both one and two step methylcellulose methods of embryonic stem cell hematopoietic differentiation. However, there is a very low occurrence of macrophage colonies, similar to the knock-in mice that display macrophages in cell cultures of yolk sac derived cells. In addition, we show that exogenous expression of AML1 is unable to bypass this AML1-ETO induced definitive hematopoietic block in these cells. This inability is not linked to an inability to reverse gene expression inhibition by AML1-ETO of the PU.1 gene associated with stem cell maintenance and myeloid differentiation. Our results suggest that AML1-ETO functions in a complex competitive manner with AML1 involving transcriptional regulation, protein protein interactions and post-transcriptional mechanism(s) affecting early embryonic hematopoiesis and possibly leukemogenesis. PMID- 17692540 TI - The proapoptotic factors Bax and Bak regulate T Cell proliferation through control of endoplasmic reticulum Ca(2+) homeostasis. AB - The Bcl-2-associated X protein (Bax) and Bcl-2-antagonist/killer (Bak) are essential regulators of lymphocyte apoptosis, but whether they play a role in viable T cell function remains unclear. Here, we report that T cells lacking both Bax and Bak display defects in antigen-specific proliferation because of Ca(2+) signaling defects. Bax(-/-), Bak(-/-) T cells displayed defective T cell receptor (TCR)- and inositol-1,4,5-trisphosphate (IP(3))-dependent Ca(2+) mobilization because of altered endoplasmic reticulum (ER) Ca(2+) regulation that was reversed by Bax's reintroduction. The ability of TCR-dependent Ca(2+) signals to stimulate mitochondrial NADH production in excess of that utilized for ATP synthesis was dependent on Bax and Bak. Blunting of Ca(2+)-induced mitochondrial NADH elevation in the absence of Bax and Bak resulted in decreased reactive-oxygen-species production, which was required for T cell proliferation. Together, the data establish that Bax and Bak play an essential role in the control of T cell proliferation by modulating ER Ca(2+) release. PMID- 17692542 TI - The interplay between clathrin-coated vesicles and cell signalling. AB - Internalization of cargo proteins and lipids at the cell surface occurs in both a constitutive and signal-regulated manner through clathrin-mediated and other endocytic pathways. Clathrin-coated vesicle formation is a principal uptake route in response to signalling events. Protein-lipid and protein-protein interactions control both the targeting of signalling molecules and their binding partners to membrane compartments and the assembly of clathrin coats. An emerging aspect of membrane trafficking research is now addressing how signalling cascades and vesicle coat assembly and subsequently disassembly are integrated. PMID- 17692543 TI - Reduction and S-nitrosation of the neuropeptide oxytocin: implications for its biological function. AB - Oxytocin (OT; Cys-Tyr-Ile-Gln-Asn-Cys-Pro-leu-Gly), a posterior pituitary peptide hormone, is characterized by a Cys1-Cys6 disulfide bond in its stable, isolated state. This paper describes a simple, one-step method for the production of OT in its reduced, dithiol form (OT dithiol), free of reducing agent. The effects of temperature, pH, and metal-ion chelators on the autoxidation of OT dithiol were examined to establish if this form is likely to persist under biological conditions. It was found that OT dithiol has a half-life of 1.8h with respect to reformation of OT disulfide at 37 degrees C and pH 6.9 in the presence of the copper chelators, DTPA and neocuproine. S-Nitrosation of OT dithiol by acidified nitrite at pH 3.0 was examined by absorption spectroscopy and HPLC-UV-MS, which revealed that both singly and doubly S-nitrosated OT are formed. These results suggest novel chemical aspects to OT signaling, the biological implications of which are discussed here. PMID- 17692544 TI - Stress response in the central nervous system of a transgenic mouse model of bovine spongiform encephalopathy. AB - An immunohistochemical study was performed to evaluate the stress-related proteins heat shock protein 25 (HSP25) and metallothionein 1+2 (MT1+2) in the brains of a murine model of bovine spongiform encephalopathy (BSE). Transgenic mice (BoTg110) expressing the bovine cellular prion protein were intracerebrally inoculated with brainstem homogenate from BSE infected cattle. PrP(BSE) deposits were found in the brain as early as 150 days post-inoculation (dpi) and in mice sacrificed terminally at 290-320dpi. Glial proliferation and spongiform change were associated with an increase in glial immunostaining of MT1+2 and HSP25, respectively. These proteins are associated with oxidative stress and heavy metal metabolism, which may have a role in the pathogenesis of BSE. PMID- 17692545 TI - Effect of subluteal concentrations of progesterone on luteinizing hormone and ovulation in lactating dairy cows. AB - Two experiments were conducted to determine if administration of progesterone within a low, subluteal range (0.1-1.0 ng/mL) blocks the luteinizing hormone (LH) surge (experiments 1 and 2) and ovulation (experiment 2) in lactating dairy cows. In experiment 1, progesterone was administered to cycling, lactating dairy cows during the luteal phase of the estrous cycle using a controlled internal drug release (CIDR) device. CIDRs were pre-incubated in other cows for either 0 (CIDR 0), 14 (CIDR-14) or 28 days (CIDR-28). One group of cows received no CIDRs and served as controls. One day after CIDR insertion, luteolysis was induced by two injections of prostaglandin (PG) F(2alpha) (25 mg) at 12 h intervals. Two days after the first injection, estradiol cypionate (ECP; 3 mg) was injected to induce a LH surge. Concentrations of progesterone after luteolysis were 0.11, 0.45, 0.78 and 1.20 ng/mL for cows treated with no CIDR, CIDR-28, CIDR-14, and CIDR-0, respectively. LH surges were detected in 4/4 controls, 4/5 CIDR-28, 2/5 CIDR-14 and 0/5 CIDR-0 cows following ECP. In experiment 2, progesterone was administered to cycling, lactating, Holstein cows during the luteal phase of the estrous cycle as in experiment 1. Luteolysis was induced as in experiment 1. The occurrence of an endogenous LH surge and ovulation were monitored for 7 days. Concentrations of progesterone after luteolysis were 0.13, 0.30, 0.70 and 1.20 ng/mL for cows treated with no CIDR, CIDR-28, CIDR-14 and CIDR-0, respectively. LH surges and ovulation were detected in 5/5 controls, 3/7 CIDR-28, 0/5 CIDR-14 and 0/5 CIDR-0 cows. It was concluded that low concentrations of progesterone can reduce the ability of either endogenous or exogenous estradiol to induce a preovulatory surge of LH and ovulation. PMID- 17692546 TI - Prediction of protein-ligand complex structure by docking software guided by other complex structures. AB - We developed a new scoring method that selects a protein-ligand complex structure with higher geometrical accuracy than the top-scoring complex structure, using the structural information of known protein-ligand complexes. To apply this method, one or more protein-ligand complex structures must be known for the target protein. A number of predicted structures were generated by the protein compound docking program for a new ligand, and one of these structures, which showed the maximum overlap with the ligand coordinates of the known protein ligand complex, was selected as the most probable complex structure. PMID- 17692547 TI - Fluticasone, but not salmeterol, reduces cigarette smoke-induced production of interleukin-8 in human airway smooth muscle. AB - Cigarette smoke is the leading risk factor for the development of chronic obstructive pulmonary disease. We have recently shown that cigarette smoke extract synergises with tumour necrosis factor alpha (TNFalpha) in the induction of interleukin-8 (IL-8) from human airway smooth muscle cells. We have investigated the effect of fluticasone propionate, a corticosteroid, and salmeterol, a beta 2-adrenergic receptor agonist, on cigarette smoke extract induced IL-8 production by human airway smooth muscle cells. Human airway smooth muscle cells in primary culture were exposed to cigarette smoke extract and/or TNFalpha (1 ng ml(-1)) with and without pretreatment with fluticasone (10(-13) 10(-8)M) and/or salmeterol (10(-11)-10(-6)M). IL-8 was analysed by ELISA. Fluticasone dose-dependently inhibited IL-8 release induced by cigarette smoke extract, TNFalpha or combined cigarette smoke extract and TNFalpha. However, while IL-8 release in the presence of cigarette smoke extract alone was completely inhibited by fluticasone, IL-8 production induced by cigarette smoke extract and TNFalpha was only partially reduced. Salmeterol alone had no effect on cigarette smoke extract and/or TNFalpha-induced IL-8 production from human airway smooth muscle cells. Combined fluticasone and salmeterol did not cause further inhibitory effects compared to fluticasone alone. Fluticasone but not salmeterol is effective in reducing cigarette smoke extract-induced IL-8 production in human airway smooth muscle cells. The reduced inhibition of cigarette smoke extract- and TNFalpha-induced IL-8 release by fluticasone may explain why corticosteroids are less effective in chronic obstructive pulmonary disease where increased amounts of TNFalpha are present. PMID- 17692548 TI - In Silico characterization of phosphorylase kinase: evidence for an alternate intronic polyadenylation site in PHKG1. AB - Phosphorylase kinase (PhK), the key enzyme that regulates glycogenolysis, has traditionally been thought to be expressed predominantly in muscle and liver. In this study, we show by two different database searches (Expressed Sequence Tag and UniGene) that PhK gene expression occurs in at least 28-36 different tissues, and that the genes encoding the alpha, beta, and gamma subunits of PhK undergo extensive transcriptional processing. In particular, we have identified exon 6 of PHKG1 as a 3' composite terminal exon due to the presence of a weak polyadenylation and cleavage site in intron 6. We have verified biochemically that transcriptional processing of PHKG1 does occur in vivo; mRNA corresponding to the alternate variant is expressed in skeletal muscle, brain, heart, and tongue. In silico translation of this mRNA yields a PhK gamma subunit that contains the first 181 residues of the protein, followed by an additional 21 amino acids. The implication of this alternate processing is discussed within the context of gamma catalysis and regulation. PMID- 17692549 TI - Lowering methylation demand by creatine supplementation paradoxically decreases DNA methylation. PMID- 17692550 TI - Molecular genetics of HMG-CoA lyase deficiency. AB - 3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is a rare autosomal recessive genetic disorder that affects ketogenesis and l-leucine catabolism, which generally appears during the first year of life. Patients with HL deficiency have a reduced capacity to synthesize ketone bodies. The disease is caused by lethal mutations in the HL gene (HMGCL). To date, up to 30 variant alleles (28 mutations and 2 SNPs) in 93 patients have been reported, with a recognizable population-specific mutational spectrum. This disorder is frequent in Saudi Arabia and the Iberian Peninsula (Portugal and Spain), where two mutations (122G>A and 109G>A) have been identified in 87% and 94% of the cases, respectively. In most countries a few patients have a high level of allelic heterogeneity. The mutations are distributed along the gene sequences, although some clustering was observed in exon 2, conforming a possible hot spot. Recently, the crystal structures of the human and two bacterial HL have been published. These experimentally obtained structures confirmed the overall architecture, previously predicted by our group and others using bioinformatic approaches, which shows the (betaalpha)8-barrel structure of the enzyme. In addition, the crystals confirmed the presence of an additional COOH domain containing important structures and residues for enzyme functionality and oligomerization processes. Here, we review all HMGCL mis-sense mutations identified to date, and their implication in enzyme structure and function is discussed. We found that genotype phenotype correlations are difficult to establish because the evolution of the disease seems more related to the causes of hypoglycaemia (fasting or acute illness) than to a particular genotype. PMID- 17692551 TI - The relative importance of CD4+ and CD8+T cells in immunity to pulmonary paracoccidioidomycosis. AB - Protective immunity in paracoccidioidomycosis (PCM) is believed to be mediated by cellular immunity, but the role of T cell subsets has never been investigated. The aim of this study was to characterize the function of CD4+ and CD8+ T cells in the immunity developed by susceptible, intermediate and resistant mice after P. brasiliensis infection. In susceptible mice, depletion of CD4+ T cells did not alter disease severity and anergy of cellular immunity but diminished antibody production. Anti-CD8 treatment led to increased fungal loads, but restored DTH reactivity. In resistant mice, both CD4+ and CD8+ T cells control fungal burdens and cytokines although only the former regulate DTH reactions and antibody production. In the intermediate strain, deficiency of whole T and CD8+ T cells but not of CD4+ T or B cells led to increased mortality rates. Thus, in pulmonary PCM: (a) irrespective of the host susceptibility pattern, fungal loads are mainly controlled by CD8+ T cells, whereas antibody production and DTH reactions are regulated by CD4+ T cells; (c) CD4+ T cells play a protective role in the resistant and intermediate mouse strains, whereas in susceptible mice they are deleted or anergic; (d) genetic resistance to PCM is associated with concomitant CD4+ and CD8+ T cell immunity secreting type 1 and type 2 cytokines. PMID- 17692552 TI - Potentiation of fluindione or warfarin by dexamethasone in multiple myeloma and AL amyloidosis. AB - OBJECTIVES: Patients with primary systemic (AL) amyloidosis or multiple myeloma are frequently treated with cyclic dexamethasone (DXM) courses and often require oral anticoagulants. We previously reported a strong potentiation of oral anticoagulants with intravenous methylprednisolone and observed a similar potentiation with DXM in 3 patients, which led us to prospectively investigate the interaction between DXM and oral anticoagulants. METHODS: Nine patients with multiple myeloma (n=6) or AL amyloidosis (n=3), including 6 prospective patients, taking fluindione (n=8) or warfarin (n=1), were studied for a total of 10 cycles. DXM (40 mg/day for 4 days every 28 days) was administered alone (n=4) or with melphalan (n=5). One patient was studied for 2 consecutive cycles after a moderate increase in the international normalized ratio (INR) during the first course of DXM. International normalized ratio (INR) was measured serially during DXM administration. Plasma oral anticoagulant concentrations were measured for 5 cycles. RESULTS: The mean INR increased from 2.75 (range: 1.80-3.6) at baseline to 5.22 (3.09-7.07) after DXM. Oral anticoagulants were transiently stopped during 8 cycles and 1 mg oral vitamin K was given during 2. No serious bleeding was observed. Plasma oral anticoagulant concentrations increased after DXM administration. In controls receiving DXM without oral anticoagulants, DXM alone did not increase prothrombin time. CONCLUSION: High dose DXM can potentiate oral anticoagulants and elevate INR substantially. INR should therefore be monitored repeatedly during concomitant administration of these 2 drugs to allow individual adaptation of oral anticoagulant doses. PMID- 17692553 TI - Hydrocarbon oxidation catalyzed by vanadium polyoxometalate supported on mesoporous MCM-41 under ultrasonic irradiation. AB - Vanadium polyoxometalate (PVMo) supported on mesoporous MCM-41, MCM-41-NH(2), as efficient and heterogeneous catalysts, with large surface area, for hydrocarbon oxidation with hydrogen peroxide is reported. Oxidation of the alkenes and alkanes gave product selectivities, which are similar to those observed for corresponding homogeneous catalyst. PVMo-MCM was prepared by introduction of PVMo into the mesoporous molecule sieves of MCM-41 by impregnation and adsorption techniques. The samples were characterized by X-ray diffraction (XRD), thermal gravimetric-differential thermal analysis (TG-DTA), FT-IR, scanning electron microscopy (SEM), UV-Vis and cyclic voltametry (CV). Ultrasonic irradiation has a particular effect on MCM-41 structural uniformity and reduced the reaction times and improved the product yields. In addition, the solid catalysts could be recovered and reused several times without loss of its activity. PMID- 17692554 TI - Real-time morphologic changes of the iliotibial band during therapeutic stretching; an ultrasonographic study. AB - The purpose of this study was to evaluate the utility of ultrasonography (US) in determining the morphological changes of the iliotibial band (ITB) with the modified Ober maneuver. Forty-four subjects (23 men and 21 women, mean age (+/- SD), 24.7+/-4.7 years) who had no previous history of lower back, gluteus, hip or knee pain and satisfied additional inclusion criteria were recruited. Twenty out of the 44 subjects were initially examined by both MRI and US for measurement confirmation. Band width of the left ITB (the measures of which were highly correlated between techniques) was then assessed for these 44 subjects by US with the modified Ober maneuver in three gradually increased hip adduction positions; neutral, adducted and adducted with weight in these 44 subjects. In addition, examiner reliability was assessed by conducting duplicate measurements in 20 randomly chosen subjects. Results demonstrated that measures of band width, but not thickness, were highly correlated between MRI and US (p<0.001, r=0.850). Significant reductions in band width were observed between the three positions with the modified Ober maneuver (p<0.001). Intratester reliability was high (intraclass correlation coefficient (ICC)=0.86-0.94). Band width changes indicated that the ITB was subjected to a significant stretching force during hip adduction. We conclude that US is a reliable means to directly assess the real time effects of stretching exercises. PMID- 17692555 TI - The intracellular form of human MAGP1 elicits a complex and specific transcriptional response. AB - Microfibril-associated glycoprotein-1 (MAGP1) is found associated with microfibrils in the extracellular matrix (ECM). In humans, MAGP1 is expressed as two alternatively spliced isoforms: MAGP1A, the extracellular microfibril associated form; and MAGP1B, an exclusively intracellular isoform derived from the skipping of exon 3. The biological function of MAGP1B is unknown. We performed gene expression profiling to study the cellular response to MAGP1B using whole-genome genechips. We found that MAGP1B specifically induces the expression of genes linked to cell adhesion, motility, metabolism, gene expression, development and signal transduction. Versican, a gene product involved in the structure and functional regulation of the ECM, showed the highest up-regulation in response to MAGP1B. These studies suggest a dual role for MAGP1, with extracellular MAGP1A involved in ECM function, and intracellular MAGP1B modulating the expression of genes that function in cell adhesion, migration and control of ECM deposition. PMID- 17692556 TI - Enhancement of intravesical delivery with Syn3 potentiates interferon-alpha2b gene therapy for superficial bladder cancer. AB - Intravesical administration of interferon alpha-2b protein (IFN) has been successfully used in the treatment of patients with superficial bladder tumors. Local dosing of IFN minimizes well-known systemic side effects of the drug, but exposure to bladder tumors is limited by the duration of instillation and transient concentrations achieved in the urothelium. Intravesical delivery of the gene encoding interferon results in an alternative strategy for IFN-based therapy of the disease, enabling sustained exposure of IFN protein that results from production by tumor and non-tumor cells in the urothelium. Efficient gene delivery and expression of IFN has been achieved using a recombinant adenovirus gene delivery system (rAd-IFN) in conjunction with the novel small molecule excipient Syn3. Studies with rAd-IFN/Syn3 in animal models result in urine concentrations of IFN that persisted for weeks and correlated with potent anti tumor effects. The objective of this review is to communicate the rationale and preclinical findings that support ongoing clinical investigation of intravesical rAd-IFN/Syn3 in superficial bladder cancer. PMID- 17692557 TI - The intragenic approach as a new extension to traditional plant breeding. AB - The novel intragenic approach to genetic engineering improves existing varieties by eliminating undesirable features and activating dormant traits. It transforms plants with native expression cassettes to fine-tune the activity and/or tissue specificity of target genes. Any intragenic modification of traits could, at least in theory, also be accomplished by traditional breeding and transgenic modification. However, the new approach is unique in avoiding the transfer of unknown or foreign DNA. By consequently eliminating various potential risk factors, this method represents a relatively safe approach to crop improvement. Therefore, we argue that intragenic crops should be cleared through the regulatory process in a timely and cost-effective manner. PMID- 17692558 TI - Development of serum-free culture systems for human embryonic stem cells. AB - Human embryonic stem cells, because of their unique combination of long-term self renewal properties and pluripotency, are providing new avenues of investigation of stem cell biology and human development and show promise in providing a new source of human cells for transplantation therapies and pharmaceutical testing. Current methods of propagating these cells using combinations of mouse fibroblast feeder cultures and bovine serum components are inexpensive and, in general, useful. However, the systematic investigation of the regulation of self-renewal and the production of safer sources of cells for transplantation depends on the elimination of animal products and the use of defined culture conditions. Both goals are served by the development of serum-free culture methods for human embryonic stem cells. PMID- 17692559 TI - Nuclear fractal dimension as a prognostic factor in oral squamous cell carcinoma. AB - Strong theoretical reasons exist for using fractal geometry in measurements of natural objects, including most objects studied in pathology. Indeed, fractal dimension provides a more precise and theoretically more appropriate approximation of their structure properties and especially their shape complexity. The aim of our study was to evaluate the nuclear fractal dimension (FD) in tissue specimens from patients with oral cavity carcinomas in order to assess its potential value as prognostic factor. Relationships between FD and other factors including clinicopathologic characteristics were also investigated. Histological sections from 48 oral squamous cell carcinomas as well as from 17 non-malignant mucosa specimens were stained with Hematoxylin-Eosin for pathological examination and with Feulgen for nuclear complexity evaluation. The sections were evaluated by image analysis using fractal analysis software to quantify nuclear FD by the box-counting method. Carcinomas presented higher mean values of FD compared to normal mucosa. Well differentiated neoplasms had lower FD values than poorly differentiated ones. FD was significantly correlated with the nuclear size. Patients with FD lower than the median value of the sample had statistically significant higher survival rates. Within the sample of patients studied, FD was proved to be an independent prognostic factor of survival in oral cancer patients. In addition this study provides evidence that there are several statistically significant correlations between FD and other morphometric characteristics or clinicopathologic factors in oral squamous cell carcinomas. PMID- 17692560 TI - The dynamic plant stem cell niches. AB - Stem cells exist in specific locations called niches, where extracellular signals maintain stem cell division and prevent differentiation. In plants, the best characterised niches are within the shoot and root meristems. Networks of regulatory genes and intercellular signals maintain meristem structure in spite of constant cell displacement by division. Recent works have improved our understanding of how these networks function at the cellular and molecular levels, particularly in the control of the stem cell population in the shoot meristem. The meristem regulatory genes have been found to function partly through localised control of widely used signals such as cytokinin and auxin. The retinoblastoma protein has also emerged as a key regulator of cell differentiation in the meristems. PMID- 17692561 TI - Role of histone and DNA methylation in gene regulation. AB - Transcription is known to be regulated by given chromatin states, distinguished as transcriptionally active euchromatin and silent heterochromatin. In plants, silencing in heterochromatin is associated with hypermethylation of DNA and specific covalent modifications of histone H3. Several lines of evidence have suggested that maintenance of DNA methylation patterns at CG sequences is responsible for the formation of stable and thus heritable activity states termed epialleles. By contrast, histone modification and DNA methylation outside CGs confer the flexibility of transcriptional regulation necessary for plant development and adaptive responses to the environment. Recent studies have refined our understanding of the biological significance of and the molecular mechanisms involved in the interplay between DNA and histone H3 methylation. PMID- 17692563 TI - Proctophantastes brayi, n. sp. (Digenea: Zoogonidae) parasite of the deep-sea fish Polymixia Lowe, 1838 from Vanuatu. AB - Proctophantastes brayi n. sp. (Digenea: Zoogonidae; Lepidophyllinae) has been found in the intestine of two species of deep-sea fish Polymixia (silver eye fish) near the island of Erromango in Vanuatu at a depth ranging from 720 to 830 m. Specimen whole mounts, histological and scanning electron microscopy preparations showed that P. brayi differs from the five known species of the genus Proctophantastes (P. abyssorum, P. gillissi, P. glandulosum, P. infundibulum and P. nettastomatis) by the following morphological characters: (i) a slit in the anterior part of the oral sucker, (ii) Laurer's canal is absent, (iii) a more extended periatrial gland than the ones in the other species of Proctophantastes, consisting of divided masses of cells and that form a conspicuous multilobated structure which does not have a membrane-bounded sac, (iv) the distal part of the metraterm has vesicle-like processes which we refer to as metratermal sacs, in addition to atrial sacs, (v) a long extension of the glandular cells surrounding the saccular bladder which extends posteriorly to the excretory pore. PMID- 17692564 TI - Sympatric species of Deretrema Linton, 1910: D. combesae n. sp. and D. combesorum n. sp. (Digenea: Zoogonidae) from the manybar goatfish Parupeneus multifasciatus (Quoy & Gaimard, 1824) (Perciformes: Mullidae) from New Caledonia. AB - Two sympatric species of Deretrema, D. combesae n. sp. and D. combesorum n. sp. are described from the manybar goatfish Parupeneus multifasciatus from off New Caledonia, South Pacific. D. combesae n. sp. does not fit any of the described Deretrema subgenera. The combination of the characters, tegumental spines, caeca reaching past the testes, the vitellarium reaching into the hindbody, much of the uterus at the level of and anterior to the gonads, a long oesophagus, testes in the hindbody and the pre-testicular ovary are not found in any of the described subgenera. D. combesorum n. sp. fits into the subgenus Deretrema (Deretrema), but differs from the described species in the sucker-ratio, eggs size, elongate shape and contiguous testes. The sympatry of these dissimilar species of Deretrema casts doubt on the value of the subgenera in Deretrema. PMID- 17692565 TI - Distinct metabolic handling of 3beta-hydroxy-17a-oxa-D-homo-5alpha-androstan-17 one by the filamentous fungus Aspergillus tamarii KITA: Evidence in support of steroid/hydroxylase binding hypothesis. AB - Aspergillus tamarii KITA transforms progesterone in to testololactone in high yield through a sequential four-step enzymatic pathway which also has the flexibility to transform a range of steroidal substrates. This study has investigated the further metabolism of testololactone and a range of fully saturated steroidal lactone analogues. In contrast to testololactone, which even after 120 h incubation did not undergo further metabolism, the lactone analogues entered the minor hydroxylation pathway. Uniquely, after forming 3beta-hydroxy 17a-oxa-D-homo-5alpha-androstan-17-one (48 h) 4 distinct positions on the steroid skeleton were monohydroxylated (11beta, 6beta, 7beta, 11alpha) which geometrically relate to the four binding positions (normal, reverse, inverted normal and inverted reverse) possible within the steroidal hydroxylase(s). This is the first evidence demonstrating the four possible steroid/hydroxylase(s) binding interactions with a single molecule that has previously been hypothesized with a single organism. In addition a rare 1beta-monohydroxylation was observed, this may be indicative of dehydration generating 1-ene functionality in A. tamarii rather than dehydrogenation as reported in man and microorganisms. The importance of these findings in relation to steroid/hydroxylase binding interactions is discussed. PMID- 17692566 TI - Evidence for cost reduction based on pre-admission MRSA screening in general surgery. AB - Colonization with methicillin-resistant Staphylococcus aureus (MRSA) is a risk factor for MRSA infection causing increased costs in patient's care and treatment. To evaluate cost efficiency, pre-admission MRSA screening and subsequent MRSA decolonization of patients admitted to the Department of General Surgery at the University Hospital of Munster were determined. In 2004, 2054 (89.3%) out of the total of 2299 hospital-admitted patients were screened for MRSA (1769 elective and 530 direct admissions); 1536 patients underwent pre admission MRSA screening (86.8% of the 1769 elective admissions), of whom seven patients (0.5%) were MRSA-positive and five of these were successfully decolonized before admission. In case of direct admissions, i.e., emergency cases or transferral from other hospitals, 2.4% and 8.6% were MRSA-positive, respectively. There were 25 patients MRSA positive during their hospital stay, two of these were nosocomially acquired, which represent 0.1 nosocomial MRSA cases in 1000 in-patients. The average MRSA carrier was (65+/-15 years) older than the other patients (55+/-17 years), had a significantly higher rate of pulmonary disease, coronary heart disease and certain infections; and had a longer hospital stay (27 versus 10 days, p<0.05). The total costs of the MRSA screening were approximately 20,000 euro. Since the estimated costs for handling MRSA treatment and isolation during a hospital stay are 6000-10,000 euro for each affected patient, we estimated that approximately 20,000 euro could be saved by detecting and successfully decolonizing a total of five patients through pre admission screening. In this calculation, additional costs due to the increased morbidity and mortality of MRSA carriers and the possible spread of MRSA through unrecognized colonization were not included. In conclusion, pre-admission screening for MRSA is an effective method to reduce the hospital burden of MRSA colonized patients and the savings due to consistent decolonization before elective admission outweigh the costs of screening. PMID- 17692567 TI - Effects of low-level radio-frequency (3kHz to 300GHz) energy on human cardiovascular, reproductive, immune, and other systems: a review of the recent literature. AB - OBJECTIVES: Occupational or residential exposures to radio-frequency energy (RFE), including microwaves, have been alleged to result in health problems. A review of recent epidemiological studies and studies of humans as subjects in laboratory investigations would be useful. METHODS: This paper is a narrative review of the recent medical and scientific literature (from mid-1998 through early 2006) dealing with possible effects of RFE on humans, relating to topics other than cancer, tumors, and central nervous system effects (areas covered in a previous review). Subject areas in this review include effects on cardiovascular, reproductive, and immune systems. RESULTS: A large number of studies were related to exposures from cellular telephones. Although both positive and negative findings were reported in some studies, in a majority of instances no significant health effects were found. Most studies had some methodological limitations. Although some cardiovascular effects due to RFE were reported in epidemiological studies (e.g., lower 24-h heart rate, blunted circadian rhythm of heart rate), there were no major effects on a large number of cardiovascular parameters in laboratory studies of volunteers during exposure to cell-phone RFE. In population based studies of a wide range of RFE frequencies, findings were equivocal for effects on birth defects, fertility, neuroblastoma in offspring, and reproductive hormones. Some changes in immunoglobulin levels and in peripheral blood lymphocytes were reported in different studies of radar and radio/television transmission workers. Due to variations in results and difficulties in comparing presumably exposed subjects with controls, however, it is difficult to propose a unifying hypothesis of immune-system effects. Although subjective symptoms may be produced in some sensitive individuals exposed to RFE, there were no straightforward differences in such symptoms between exposed and control subjects in most epidemiological and laboratory studies. Consistent, strong associations were not found for RFE exposure and adverse health effects. The majority of changes relating to each of the diseases or conditions were small and not significant. CONCLUSIONS: On the basis of previous reviews of older literature and the current review of recent literature, there is only weak evidence for a relationship between RFE and any endpoint studied (related to the topics above), thus providing at present no sufficient foundation for establishing RFE as a health hazard. PMID- 17692568 TI - Human papillomavirus vaccine-recent results and future developments. AB - A subset of human papillomaviruses that infect the anogenital tract and the upper aero-digestive tract is the cause of a number of benign and malignant tumors in these locations, including cervical cancer. Since the past year, a vaccine directed at human papillomaviruses types 6 and 11, the main cause of genital warts, and types 16 and 18, the main cause of cervical cancer, has been on the international market. Another vaccine directed at types 16 and 18 alone is soon expected to be widely available. This review presents the updated, currently available clinical information that has demonstrated the efficacy and safety of these vaccines. It examines the questions remaining on their safety, true efficacy, spectrum of activity, and protection duration. The future directions of the current clinical research and its possible impact on prevention are discussed. PMID- 17692569 TI - Dendritic cell-endothelial cell cross-talk in angiogenesis. AB - Dendritic cells (DCs) are professional antigen-presenting cells that have a pivotal role in the onset and regulation of adaptive immune responses. DCs have the ability to regulate inflammation through their capacity to release cytokines and chemokines and kill pathogens, which they share with other phagocytes. Recent observations have shown that different DC subsets produce and release various pro and anti-angiogenic mediators depending on their activation status and cytokine milieu. In particular, alternatively activated DCs exert a potent pro-angiogenic activity that is mediated by the prototypic angiogenic growth factor vascular endothelial growth factor-A (VEGF-A). In turn, pro- and anti-angiogenic mediators can affect the biology of DCs, modulating their differentiation and maturation. Finally, DCs can trans-differentiate into endothelial-like cells, possibly contributing to vasculogenesis in the adult. Thus, DCs might exert an important impact on the neovascularization process in different physiopathological conditions. PMID- 17692570 TI - Proximal signaling control of human effector CD4 T cell function. AB - The functional coupling of T cell receptor (TCR)-mediated signaling events in primary human T cells remains undefined. We demonstrate here that alterations in the expression of proximal TCR-coupled signaling subunits are associated with distinct effector capacities in differentiated human CD4 T cells. Analysis of proximal signaling profiles using biochemical and single cell approaches reveals decreased CD3zeta and ZAP-70 expression correlating with functional anergy, with increased CD3zeta/ ZAP-70 expression and phosphorylation connoting acquisition of effector capacity. By contrast, the FcRgamma signaling subunit known to be expressed in human effector cells and in T cells from the autoimmune disease SLE is up-regulated upon activation, yet does not correlate with functional capacity in effector cells, and does not alter signaling or function in primary FcRgamma transfectants. Our results have implications for targeting signaling molecules in immunotherapy and evaluating the functional consequence of signaling alterations associated with autoimmunity and chronic diseases. PMID- 17692571 TI - Low CD4 T-cell counts despite low levels of circulating HIV: insights from the comparison of HIV-1 infected patients with a discordant response to antiretroviral therapy to patients with untreated advanced HIV-2 disease. AB - A significant proportion of HIV-1+ patients with suppression of viremia under antiretroviral therapy fail to recover CD4(+) T-cell counts (ART-Discordants). Similarly, untreated HIV-2+ patients can also exhibit major CD4 depletion in spite of undetectable viremia. We characterize here the immunological disturbances associated with major CD4-lymphopenia in these two scenarios as compared to untreated viremic HIV-1+ patients with similar CD4-lymphopenia and HIV-1+ patients with successful immunological and virological responses under ART. Low CD4 counts were associated with major naive CD4 and CD8 depletion, irrespective of type of infection or ART-exposure. However, ART-Discordants exhibited lower levels of T-cell activation as compared to both untreated HIV-2 and HIV-1 cohorts, and a less marked increase in circulating IL-7 despite similar CD4 depletion. Nevertheless, ART-Discordants showed a preserved Bcl-2 expression, suggesting increased IL-7 consumption, which in conjunction with the relatively lower T-cell activation may contribute to their CD4 count stability and low rate of opportunistic infections. PMID- 17692573 TI - Accidental overdosage of levetiracetam in two children caused no side effects. PMID- 17692572 TI - Efficacy of low-dose rituximab for mixed cryoglobulinemia. AB - Rituximab at 375 mg/m(2) x 4 is effective for refractory HCV-related mixed cryoglobulinemia. We conducted a pilot study to assess the efficacy of a lower dosage, 250 mg/m(2) x 2. Six consecutive patients with mixed cryoglobulinemia were treated. All patients had severe or life-threatening disease manifestations, including necrotizing skin ulcers, renal disease, hyperviscosity or intestinal vasculitis. Four of five evaluable patients (excluding one early death) had >80% decrease of cryocrit and remission of vasculitis at the end of a 22- to 55-week (median 40) follow-up. The non-responder failed to respond to additional rituximab treatment, suggesting intrinsic resistance rather than insufficient dosage as the cause of treatment failure. No sustained increase of HCV viremia after rituximab was observed. Rituximab at 250 mg/m(2) x 2 may be as effective as at 375 mg/m(2) x 4 for treating mixed cryoglobulinemia. Larger studies are required to assess the efficacy of low-dose rituximab. PMID- 17692574 TI - Irreversible brain injury following status epilepticus. AB - Described here is a patient with medically intractable generalized epilepsy who developed status epilepticus (SE) affecting his right cerebral hemisphere for about 48 hours, which led to irreversible injury to that hemisphere. His partial SE did not respond to the first-line therapies, repeated doses of midazolam, or continuous intravenous infusion of propofol. Extensive investigations failed to find a cause of his SE except for a low serum valproic acid. A minor trauma that he suffered 1 week prior to his SE was of questionable significance. Neurological examination, neuropsychological testing, electroencephalography, and magnetic resonance imaging all demonstrated striking abnormalities limited to the affected cerebral hemisphere that did not resolve with repeated testing. This case illustrates permanent focal brain injury following prolonged partial SE in a patient with previously known generalized seizure disorder. PMID- 17692575 TI - Chitosan-coated PLGA nanoparticles for DNA/RNA delivery: effect of the formulation parameters on complexation and transfection of antisense oligonucleotides. AB - Cationically modified poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles have recently been introduced as novel carriers for DNA/RNA delivery. The colloidal characteristics of the nanoparticles--particle size and surface charge--are considered the most significant determinants in the cellular uptake and trafficking of the nanoparticles. Therefore, our aim was to introduce chitosan coated PLGA nanoparticles, whose size and charge are tunable to adapt for a specific task. The results showed that biodegradable nanoparticles as small as 130 nm and adjustable surface charge can be tailored controlling the process parameters. As a proof of concept, the overall potential of these particulate carriers to bind the antisense oligonucleotides, 2'-O-methyl-RNA, and improve their cellular uptake was demonstrated. The study proved the efficacy of chitosan coated PLGA nanoparticles as a flexible and efficient delivery system for antisense oligonucleotides to lung cancer cells. PMID- 17692576 TI - Protein seeding of gold nanoparticles and mechanism of glycation sensing. AB - The plasmon resonance of gold nanoparticles (GNPs) synthesized on a protein template senses formation of advanced glycosylated end products (AGEs). A graded alteration of plasmon resonance (both the peak and intensity are affected) is observed as the glycation progresses. Transmission electron microscopy shows significant shift of the size distribution of GNPs in presence of glycation. The higher plasmon resonance is thus caused by increased formation of GNPs, which in turn is attributed to a larger number of smaller particles. To study the binding of the protein with the GNP, infrared (IR) spectroscopy and circular dichroism (CD) studies were undertaken. Whereas the CD studies confirmed the emergence of beta-structure and loss of alpha-helix, the IR data indicated glycation-induced alterations in the amide I region. The proposed sensor for formation of AGEs thus apparently operates by direct or indirect conjugation with amino groups. Incidentally, glycation and AGE formation are responsible for a number of diabetes-related clinical conditions, and the present approach could be adopted for use for a simple colorimetric assay for the AGEs. PMID- 17692577 TI - Glargine versus NPH insulin in cystic fibrosis related diabetes. AB - BACKGROUND: Cystic fibrosis related diabetes (CFRD) with fasting hyperglycemia is found in 15% of adult and 11% of adolescent CF patients. Because of concerns about hypoglycemia, it is not common practice to treat CFRD with 24-hour basal insulin therapy, despite evidence that insulin deficiency may contribute to protein catabolism and have an adverse effect on weight, muscle mass, pulmonary function, and, ultimately, survival. We hypothesized that insulin glargine would improve blood glucose control and weight in patients with CFRD without causing hypoglycemia. METHODS: A randomized cross-over study compared 12 weeks each of bedtime NPH or glargine in 19 CFRD patients. RESULTS: There was significantly greater reduction in fasting plasma glucose with glargine (P=0.03), and participants showed a non-significant trend towards weight gain with this insulin (P=0.07). No serious hypoglycemia occurred. At study end, all patients chose to continue glargine. CONCLUSIONS: A study of longer duration is needed to determine whether insulin glargine impacts protein catabolism and overall clinical status in CF patients, but these initial data suggest that this is a promising therapy in CFRD. PMID- 17692579 TI - Method to determine stability and recovery of carboprost and misoprostol in infusion preparations. AB - The two synthetic prostaglandin analogues, carboprost and misoprostol, are used extensively in obstetric and gynaecological practice. Our recent research of these compounds' use for intra-umbilical injection to treat adherent placenta necessitated their storage in solution for 3-4 days. This raised concerns over the stability and applied dosage in the in-house infusion preparations. It requires various pharmacological preparations before administration in clinical practice. We used LCMS to develop a simultaneous, valid, fast and simple method to assess the stability and recovery of their in-house preparations in different conditions. The linearity between 0-40 microg/ml was above 0.995. The reproducibility (CV) was within 5.2%. The limit of quantitation of the method for both compounds is about 2 microg/ml. The accuracy of both compounds from 0.4-40 microg/ml is 96.4-104.3% while the precision is 0.4-7.4%. The recoveries of carboprost in the infusion were from 100.3+/-4.0 to 102.4+/-1.6% and that of misoprostol in Cytotec tablet was from 44.9+/-3.5 to 50.0+/-5.0% in water and saline at 4 degrees C and room temperature. No interference was found from the matrix and between the tested compounds. The compounds were basically stable for 6 days in water and in saline, whether they were stored at 4 degrees C or at room temperature. However, only half of the dosage of misoprostol was recovered in the solution. Therefore, misoprostol dosage should be adjusted before clinical application. PMID- 17692578 TI - Liquid movement across the surface epithelium of large airways. AB - The cystic fibrosis transmembrane conductance regulator CFTR gene is found on chromosome 7 [Kerem, B., Rommens, J.M., Buchanan, J.A., Markiewicz, D., Cox, T.K., Chakravarti, A., Buchwald, M., Tsui, L.C., 1989. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073-1080; Riordan, J.R., Rommens, J.M., Kerem, B., Alon, N., Rozmahel, R., Grzelczak, Z., Zielenski, J., Lok, S., Plavsic, N., Chou, J.L., et al., 1989. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245, 1066-1073] and encodes for a 1480 amino acid protein which is present in the plasma membrane of epithelial cells [Anderson, M.P., Sheppard, D.N., Berger, H.A., Welsh, M.J., 1992. Chloride channels in the apical membrane of normal and cystic fibrosis airway and intestinal epithelia. Am. J. Physiol. 263, L1-L14]. This protein appears to have many functions, but a unifying theme is that it acts as a protein kinase C- and cyclic AMP-regulated Cl(-) channel [Winpenny, J.P., McAlroy, H.L., Gray, M.A., Argent, B.E., 1995. Protein kinase C regulates the magnitude and stability of CFTR currents in pancreatic duct cells. Am. J. Physiol. 268, C823-C828; Jia, Y., Mathews, C.J., Hanrahan, J.W., 1997. Phosphorylation by protein kinase C is required for acute activation of cystic fibrosis transmembrane conductance regulator by protein kinase A. J. Biol. Chem. 272, 4978-4984]. In the superficial epithelium of the conducting airways, CFTR is involved in Cl(-) secretion [Boucher, R.C., 2003. Regulation of airway surface liquid volume by human airway epithelia. Pflugers Arch. 445, 495-498] and also acts as a regulator of the epithelial Na(+) channel (ENaC) and hence Na(+) absorption [Boucher, R.C., Stutts, M.J., Knowles, M.R., Cantley, L., Gatzy, J.T., 1986. Na(+) transport in cystic fibrosis respiratory epithelia. Abnormal basal rate and response to adenylate cyclase activation. J. Clin. Invest. 78, 1245 1252; Stutts, M.J., Canessa, C.M., Olsen, J.C., Hamrick, M., Cohn, J.A., Rossier, B.C., Boucher, R.C., 1995. CFTR as a cAMP-dependent regulator of sodium channels. Science 269, 847-850]. In this chapter, we will discuss the regulation of these two ion channels, and how they can influence liquid movement across the superficial airway epithelium. PMID- 17692580 TI - cis-3,4-Methylene-heptanoylcarnitine: characterization and verification of the C8:1 acylcarnitine in human urine. AB - Acylcarnitine profiles have been used to diagnose specific inherited metabolic diseases. For some acylcarnitines, however, the detailed structure of their acyl group remains a question. One such incompletely characterized acylcarnitine is cis-3,4-methylene-heptanoylcarnitine. To investigate this problem, we isolated the "C8:1" acylcarnitine from human urine, transesterified it to form its acyl picolinyl ester, and characterized it by GC/EI-MS. These results were compared to GC/EI-MS results from authentic standards we synthesized (cis-3,4-methylene heptanoylcarnitine, trans-2-octenoylcarnitine, 3-octenoylcarnitine, cis-4 octenoylcarnitine, and trans-4-octenoylcarnitine). Only cis-3,4-methylene heptanoylcarnitine matched the urinary "C8:1" acylcarnitine. The standards were then spiked in human urine, converted to pentafluorophenacyl esters, and detected by HPLC/MS. cis-3,4-Methylene-heptanoylcarnitine exactly matched the "C8:1" acylcarnitine in urine, whereas none of the other C8:1 acylcarnitine standards matched. Based on the data from GC/EI-MS and HPLC/MS, the "C8:1" acylcarnitine in human urine is shown to be cis-3,4-methylene-heptanoylcarnitine. PMID- 17692581 TI - Effects of granulocyte colony stimulating-factor in a rat model of acute liver injury. AB - BACKGROUND/AIM: Controversial experimental observations suggest that granulocyte colony stimulating-factor may promote hepatic regeneration after hepatectomy and chemical injury either by directly stimulating adult liver cells or facilitating the mobilization of bone marrow cells and their homing to the liver. We investigated whether different schedules of granulocyte colony stimulating-factor administration protect against experimental acute liver injury. METHODS: Acute liver injury was induced in Sprague-Dawley fed rats by injecting a single intraperitoneal dose of carbon tetrachloride. Recombinant human granulocyte colony stimulating-factor or vehicle was given daily after intoxication (4 days) or before (7 days) and after carbon tetrachloride administration. Liver injury and regeneration were assessed 2 and 4 days after damage. Bone marrow cells mobilization was evaluated by the white blood cell count and the assessment of circulating clonogenic haematopoietic progenitors (colony forming unit-cells). RESULTS: In this experimental model, although granulocyte colony stimulating factor induced the significant mobilization of colony forming unit-cells, the study cytokine had no effect on liver injury (serum alanine amino transaminase level and necrotic index) and liver regeneration (mitotic index and bromodeoxyuridine incorporation), regardless of the administration schedule. CONCLUSIONS: This study does not support the conclusion that: (1) granulocyte colony stimulating-factor exerts a protective effect against toxic-induced, non lethal acute liver injury and (2) promotes hepatocyte regeneration. PMID- 17692582 TI - Assessment of the quality of life in chronic pancreatitis using Sf-12 and EORTC Qlq-C30 questionnaires. AB - BACKGROUND: SF-12 Health Survey, and European Organisation for Research and Treatment of Cancer Quality of life Questionnaire-C30 are the two main questionnaires proposed and validated for assessing the quality of life in chronic pancreatitis. AIMS: To evaluate the role of the information furnished by both the SF-12 Health Survey and European Organisation for Research and Treatment of Cancer Quality of life Questionnaire-C30 questionnaires, and to determine which of these two questionnaires may be considered more efficacious, in clinical practice, in describing the quality of life of patients with chronic pancreatitis. PATIENTS: We studied 163 consecutive patients with proven chronic pancreatitis. METHODS: The Italian version of the SF-12 Health Survey and the Italian neutral version of the European Organisation for Research and Treatment of Cancer Quality of life Questionnaire-C30 Version 3.0 questionnaires were administered. RESULTS: Pancreatic pain was the only clinical variable able to significantly impair the SF-12 Health Survey component summaries as well as all domains of the European Organisation for Research and Treatment of Cancer Quality of life Questionnaire-C30, while body mass index was positively related to the physical component summary-12 and to the domains of the European Organisation for Research and Treatment of Cancer Quality of life Questionnaire-C30. A high level of reliability of the domains/scores of the two questionnaires in evaluating the quality of life in patients with chronic pancreatitis was found and two main factors were identified. These two factors were mainly related to the two SF-12 Health Survey summary components. CONCLUSIONS: From a practical point of view, the SF-12 Health Survey is more reliable and easier to use in routine clinical practice than the European Organisation for Research and Treatment of Cancer Quality of life Questionnaire-C30. PMID- 17692583 TI - Self-reinforced composites of bioabsorbable polymer and bioactive glass with different bioactive glass contents. Part II: In vitro degradation. AB - The in vitro degradation behavior of self-reinforced bioactive glass-containing composites was investigated comparatively with plain self-reinforced matrix polymer. The materials used were spherical bioactive glass 13-93 particles, with a particle size distribution of 50-125 microm, as a filler material and bioabsorbable poly-L,DL-lactide 70/30 as a matrix material. The composites containing 0, 20, 30, 40 and 50 wt.% of bioactive glass were manufactured using twin-screw extruder followed by self-reinforcing. The samples studied were characterized determining the changes in mechanical properties, thermal properties, molecular weight, mass loss and water absorption in phosphate buffered saline at 37 degrees C for up to 104 weeks. The results showed that the bioactive glass addition modified the degradation kinetics and material morphology of the matrix material. It was concluded that the optimal bioactive glass content depends on the applications of the composites. The results of this study could be used as a guideline when estimating the best filler content of other self-reinforced osteoconductive filler containing composites which are manufactured in a similar way. PMID- 17692584 TI - Skin-reducing mastectomy with breast reconstruction and sub-pectoral implants. AB - One of the difficulties of an immediate breast reconstruction with a sub-pectoral tissue expander is fashioning the lower, medial end of the pouch because of the insertion of the fibres of the pectoral muscle into the ribs. This often requires delayed corrections to provide a good cosmetic result with fullness of the lower medial quadrant of the reconstructed breast. Skin-reducing mastectomy (SRM) is a technique that potentially resolves this cosmetic problem by creating a dermomuscular pouch with adequate volume in the lower-medial quadrant and, at the same time, provides satisfactory coverage of the silicone implant. Much of the surgical scarring lies in relatively concealed areas of the breast. The risk of complications is reduced by use of permanent expanders and achieving compatibility between the length of the skin flaps and that of the dermomuscular pouch. The indications for this technique are the same as those of a skin-sparing mastectomy. The procedure is particularly useful for women with large breasts and in cases of bilateral prophylactic mastectomy for women at increased risk of breast cancer. We report our experience with 18 skin-reducing mastectomies carried out in 10 women. One had a complication (5%) (haematoma and infection) and one had poor long-term cosmetic result (5%) (fibrosis of the lower pole of the reconstructed breast). SRM is, from an oncological perspective, a skin sparing mastectomy (type IV) that provides a good cosmetic result by creating a dermomuscular pouch. PMID- 17692585 TI - Breast reduction surgery without drains. PMID- 17692586 TI - Bone voyage: an expedition into the molecular and cellular parameters affecting bone graft fate. AB - The demand for bone grafts in orthopaedic and craniofacial surgery is steadily increasing. Estimations suggest that about 500,000 are performed annually in the United States that include bone grafting as a component of the surgery, and the majority of these surgeries employ autografts. This perspective focuses on the biological events that occur during osseointegration of such bone grafts. Here, three key factors of graft osseointegration--the embryonic origin, the inclusion of skeletal progenitor cells, and the integrity of the recipient site--are discussed. Altogether, they form the foundation for survival of the bone graft and eventually for a positive clinical outcome of the procedure. PMID- 17692587 TI - Effects of estradiol, calcitriol and both treatments combined on bone histomorphometry in rats with chronic kidney disease and ovariectomy. AB - BACKGROUND: The aim of this experimental study was to analyze the histomorphometric changes observed when using different doses of estradiol, calcitriol and both treatments combined, in rats with both chronic kidney disease (CKD) and ovariectomy (OVX). METHODS: Six groups of rats with CKD+OVX were treated for 8 weeks with placebo, with different doses of 17beta-estradiol (E2), with calcitriol or with both treatments combined (E2+calcitriol). Histomorphometric studies were carried out at the proximal tibia segment. RESULTS: All groups that received active treatments showed a trabecular bone volume similar to those of rats with normal ovarian function. Treatment with E2 was effective, E2-10 diminished osteoid and eroded surfaces, and E2-30 was able to achieve a bone remodeling similar to that of the normal group. Calcitriol proved to have a positive effect on bone microarchitecture, achieving normal trabecular connectivity. The combined treatment with E2-30+calcitriol was the most effective treatment as it was not only capable of achieving normal trabecular remodeling and connectivity, but also normal trabecular bone volume. CONCLUSIONS: E2 and calcitriol seem to have independent effects on cancellous bone turnover in rats with CKD+OVX. In rats with chronic kidney disease and ovariectomy, these two agents are able to produce additive effects on bone and offer additional advantages as opposed to the use of both drugs independently. PMID- 17692588 TI - An alternative treatment approach to gingival recession: gingiva-colored partial porcelain veneers: a clinical report. AB - This clinical report describes the treatment of excessive gingival recession involving maxillary right and left central incisors in a 30-year-old woman. The loss of the gingival soft tissue caused an increase in crown length. Gingiva colored partial porcelain laminate veneers were applied to imitate the lost gingiva and to provide a natural anatomical tooth length. This method may be a minimally invasive alternative treatment method for gingival soft tissue loss, providing esthetic results and patient satisfaction. PMID- 17692589 TI - Rehabilitation of a patient with amelogenesis imperfecta using all-ceramic crowns: a clinical report. AB - This article presents a patient with amelogenesis imperfecta rehabilitated with all-ceramic crowns following surgical and orthodontic intervention. The 6-year evaluation of the esthetics and function of the restorations showed evidence of isolated pulp exposure and crown fractures in the posterior areas. PMID- 17692590 TI - Strength estimation of different designs of ceramic inlays and onlays in molars based on the Tsai-Wu failure criterion. AB - STATEMENT OF PROBLEM: Successful restoration of large molar defects is a serious clinical problem. Studies on the strength of teeth restored with ceramic restorations of various designs have provided conflicting results. PURPOSE: The purpose of this study was to determine the shapes of large MOD ceramic restorations in molars most likely to prevent failure and to produce a favorable distribution of contact stresses between the cement and teeth during mastication. MATERIAL AND METHODS: The study was performed using a finite element analysis with contact elements. Eight 2-dimensional models of mandibular first molars with the following designs of MOD ceramic restorations were created: an inlay with a butt joint margin, an inlay with a beveled margin, an onlay with a butt joint margin, and an onlay with a rounded shoulder margin. The restorations had 3-mm or 5-mm isthmus widths. Models of opposing maxillary crowns were also developed. Computational simulation of mastication of boluses in the frontal plane was conducted, during which the stresses occurring in the ceramic restorations, cement, and tooth structure were calculated. The Tsai-Wu failure criterion was used to evaluate the strength of the materials. Contact stresses at the adhesive interface between the tooth structure and resin cement around these restorations were analyzed. RESULTS: According to the Tsai-Wu failure criterion, the margin of the beveled inlay and the surrounding tissue could be damaged during masticatory simulation. At the junction of the butt joint margin inlay and enamel, contact tensile stresses appeared. The lowest inverse of the Tsai-Wu strength ratio index appeared in the onlay with a rounded shoulder margin. At the adhesive interfaces around margins of large onlays, compressive contact stresses occurred. CONCLUSIONS: For the large molar MOD ceramic restorations tested, the lowest values of the inverse of the Tsai-Wu strength ratio index and a favorable distribution of contact stresses between restoration and tissues appeared in the onlay with a rounded shoulder margin. PMID- 17692591 TI - Use of a porcelain color discrimination test to evaluate color difference formulas. AB - STATEMENT OF PROBLEM: Limited studies have indicated that an alternative small color difference formula would be more appropriate for use in dentistry. PURPOSE: The purposes of this study were to determine which color difference formula provides a superior degree of fit for judgments of perceptibility and acceptability and to determine if different groups of evaluators have different levels of perceptibility and acceptability for each color difference formula. MATERIAL AND METHODS: Each observer from 4 groups (4 dentists, 4 dental assistants, 4 technicians, and 4 patients)made independent observations of perceptibility and acceptability judgments on pairs of opaque porcelain (VitaOmega 900) disks (14 mm in diameter by 3 mm thick). Color differences of the pairs were calculated using DeltaE*(ab), DeltaE(CMC)(l:c), and DeltaE(2000) color difference formulas, and the observer judgments were regressed to each color difference in dependently for perceptibility and acceptability. The area under the receiver operator curves was calculated and ranked, and the optimal factor for the CMC (Colour Measurement Committee, Society of Dyers and Colourists, Great Britain) color difference formula was chosen. A repeated measures maximum likelihood ANOVA (alpha=.05) was applied to determine statistical significance of fit among the observer groups, and the various color difference formulas for both perceptibility and acceptability. Tukey-Kramer Adjustment (alpha=.05) was used as a post hoc test. RESULTS: A difference in the degree of fit of the judgments of color differences was found for the 3 formulas (P=.001)and the 2 judgment types (P<.001) studied, with no significant interaction (P=.979). The Tukey-Kramer test identified a lower degree of fit for the DeltaE*(ab) formula compared to DeltaE(CMC)(2:3) and DeltaE(2000) formulas. No significant difference was found in the mean judgment levels among the observer groups (P=.474) studied, nor within any interaction (P>.404). CONCLUSIONS: DeltaE(2000) and DeltaE(CMC)(2:3) color difference formulas provide a better fit to the calculated color differences,therefore providing better indicators of human perceptibility and acceptability of color differences between tooth colors. PMID- 17692592 TI - Defining a natural tooth color space based on a 3-dimensional shade system. AB - STATEMENT OF PROBLEM: The natural tooth color space reported by a manufacturer may not represent the comprehensive spectrum of natural teeth for all population groups. PURPOSE: The purpose of this study was to define a natural tooth color space within the Greater Buffalo, New York population and to compare that to the color space determined by a manufacturer. MATERIAL AND METHODS: Nine hundred and thirty-three maxillary central incisors (501 patients) were measured with a shade taking device (Vita Easyshade). For each tooth, L*, a*, b* values, chroma, hue, and the closest shade (Vita 3D-Master) were recorded. A linear regression analysis was performed to determine how well the manufacturer's values predict actual values for L*, a*, and b*. Color differences (DeltaE*) between the Buffalo population and the closest shade were also calculated. A 1-sample t test was used to determine whether the color differences seen in the sample were statistically different from the perceptibility threshold, DeltaE*=3.7 (alpha=.05). RESULTS: All 3 attributes of the Buffalo population displayed a broader range than those from the shade guide. However, the regression analysis revealed a significantly positive relationship between the L*, a*, and b* values of the 2 methods (P<.001). The 1-sample t test revealed a significant DeltaE* (mean DeltaE*=6.15) difference from the perceptibility threshold of DeltaE*=3.7 (P<.001). CONCLUSIONS: Color differences between the Buffalo population and the shade guide were frequently above published perceptibility thresholds, but within the range of acceptability. The Buffalo population tooth color space encompassed the manufacturer's color space. PMID- 17692593 TI - Flexural strength and fracture toughness of dental core ceramics. AB - STATEMENT OF PROBLEM: Many different strengthened all-ceramic core materials are available. In vitro study of their mechanical properties, such as flexural strength and fracture toughness, is necessary before they are used clinically. PURPOSE: The purpose of this study was to evaluate and compare the mechanical properties of 6 commonly used all-ceramic core materials using biaxial flexural strength and indentation fracture toughness tests. MATERIAL AND METHODS: Specimens of 6 ceramic core materials (Finesse, Cergo, IPS Empress, In-Ceram Alumina, In-Ceram Zirconia, and Cercon Zirconia) were fabricated (n=25) with a diameter of 15 mm and width of 1.2 +/- 0.2 mm. For each group, the specimens were tested to compare their biaxial flexural strength (piston on 3 balls) (n=15), Weibull modulus, and indentation fracture toughness (n=10) (IF method). The data were analyzed with 1-way ANOVA test (a=.05). The Tamhane multiple comparison test was used for post hoc analysis. RESULTS: Mean (SD) of biaxial flexural strength values (MPa) and Weibull modulus (m) results were: Finesse (F): 88.04 (31.61), m=3.17; Cergo (C): 94.97 (13.62), m=7.94; IPS Empress (E): 101.18 (13.49), m=10.13; In-Ceram Alumina (ICA): 341.80 (61.13), m=6.96; In-Ceram Zirconia (ICZ): 541.80 (61.10), m=10.17; and Cercon Zirconia (CZ): 1140.89 (121.33), m=13.26. The indentation fracture toughness results showed that there were significant differences between the tested ceramics. The highest fracture toughness values (MPa x m(0.5)) were obtained with the zirconia-based ceramic core materials. CONCLUSIONS: Significant differences were found in strength and toughness values of the materials evaluated. Cercon Zirconia core material showed high values of biaxial flexural strength and indentation fracture toughness when compared to the other ceramics studied. PMID- 17692594 TI - Hardness comparison of bulk-filled/transtooth and incremental-filled/occlusally irradiated composite resins. AB - STATEMENT OF PROBLEM: Use of a bulk-fill/transtooth composite resin insertion/irradiation technique may not provide as well polymerized a restoration as when using a conventional incremental placement/irradiation technique. Little information exists as to how the hardness of restorations produced by the 2 techniques compare. PURPOSE: The purpose of this study was to determine the effect of composite resin placement and an irradiation technique on the axial hardness at various depths in a Class I composite resin to include the influence of composite resin filler classification and shade. MATERIAL AND METHODS: Cylindrical Class I preparations were made in 70 recently extracted human molars and restored with either a light (A1) or dark shade (A4) of a microfill, microhybrid, or nanohybrid composite resin, or with a single shade of a translucent material. Half were placed using a conventional 2-mm-thick incremental-fill/occlusal irradiation technique, and half using a bulk fill/transtooth irradiation method (n=5). Specimens were sectioned occluso apically and axial Knoop hardness values were obtained at depths of 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0 mm. Hardness at 0.5 mm was used as a control to compare to deeper readings. Statistical analyses consisted of multiple ANOVAs and Dunnett's post-hoc tests performed at appropriately determined significance levels. RESULTS: For 3 multishaded materials tested, axial hardness values were relatively unaffected by composite resin shade or filler classification for the incremental technique, but were significantly affected by these factors when using the bulk-fill/transtooth irradiation method. A single shade translucent material was not affected in either the bulk or incremental condition. CONCLUSIONS: Use of a bulk-fill/transtooth irradiation technique for composite resin placement does not result in axial hardness values equivalent to that of an incremental-fill/occlusal irradiation technique. PMID- 17692595 TI - Compositional characteristics and hardness of acrylic and composite resin artificial teeth. AB - STATEMENT OF PROBLEM: New types of artificial teeth are commercially available; however, evidence-based information regarding composition and properties is lacking. PURPOSE: The purpose of this study was to qualify the compositional characteristics and hardness of new commercially available types of acrylic resin and composite resin artificial teeth. MATERIAL AND METHODS: Twelve brands of 3 types (2 conventional acrylic resins, 3 cross-linked acrylic resins, and 7 composite resins) of artificial teeth were examined. The filler geometry and composition were observed using scanning electron microscopy and energy disperse x-ray analysis, respectively. Vickers hardness was determined for each layer of the polished cross-sectioned teeth. The inorganic content of the enamel layer was determined by thermogravimetric analysis with an ash method. The swelling behavior of the artificial teeth after 12 hours of methyl methacrylate immersion was observed to determine the cross-linking structure. The data were statistically analyzed using 1-way analysis of variance and Tukey's multiple comparison (alpha=.05). RESULTS: Examined teeth were composed of 2, 3, or 4 layers of resin. Different sizes and shapes of filler were found but were composed only of silicon oxide. Vickers hardness ranged from 17.4 to 47.0 kgf/mm(2). The inorganic content ranged from 0 to 42.8 mass%. The enamel layer of all teeth, except for 3 products, produced negligible swelling, and the base layer of all the teeth, except for 2 products, produced obvious swelling. A significant linear correlation was observed between hardness and inorganic content. CONCLUSIONS: Within the limitations of this study, differences in size, shape, distribution, and content of the silica filler and the cross-linking nature of the resin matrix were found among the commercial brands of artificial teeth evaluated. PMID- 17692596 TI - In vivo evaluation of noncarious cervical lesions in sleep bruxism subjects. AB - STATEMENT OF PROBLEM: Occlusal load has frequently been suggested to be involved in the development of a noncarious cervical lesion (NCL). However, there is a lack of clinical studies evaluating NCLs and occlusal parameters in sleep bruxism (SB) subjects. PURPOSE: The purpose of this clinical study was to assess the frequency of NCLs and determine potential occlusal differences between SB subjects and healthy control subjects. MATERIAL AND METHODS: A total of 91 volunteers, 58 women and 33 men, with a mean (SD) age of 28.37 (4.89) years (range of 20 to 39 years), participated in this investigation. The clinical assessment of SB was based on the criteria of the American Academy of Sleep Medicine. The participants were divided into 2 groups; 58 subjects were assigned to the SB group and 33 subjects to the control group, following a thorough dental examination that was performed by a single trained dentist. Additionally, the following parameters were recorded: mean number of teeth present, existence/absence of NCLs, frequency of NCLs relating to the type of tooth, type of occlusal guidance scheme, existence of a slide from centric occlusion (CO) to maximum intercuspation (MI), length of the slide, and report of tooth hypersensitivity. Group differences were statistically analyzed using chi-square tests for the qualitative variables and Mann-Whitney U tests for the quantitative variables (alpha=.05). RESULTS: NCLs were significantly more prevalent in SB subjects (39.7%) than in the control subjects (12.1%) (P=.006). In SB subjects, the first premolars were the teeth most affected, and in control subjects, the first molars were most affected. Tooth hypersensitivity was reported in 62.1% of the SB subjects and in 36.4% of the control subjects (P=.018). The evaluation of occlusal guidance schemes revealed no significant difference between the groups. In SB subjects (70.7%), a slide from CO to MI was significantly more prevalent than in control subjects (42.4%) (P=.008). Moreover, SB subjects demonstrated a significantly longer mean (SD) slide of 0.77 (0.69) mm compared to that of control subjects of 0.4 (0.57) mm (P=.008). CONCLUSIONS: Within the limitations of this study, SB subjects demonstrated significantly more NCLs than the control group; whereas, the type of occlusal guidance scheme seems to be of minor importance in the development of NCLs. PMID- 17692597 TI - Indication of root orientation on a cast for implant surgical guide fabrication. PMID- 17692598 TI - Fabrication of a custom-made ceramic post and core using CAD-CAM technology. PMID- 17692600 TI - Exchange of organs and patients with foreign nations during the first 15 months of activity of the Italian gate to Europe. AB - The Italian Gate to Europe (IGE) was established in April 2005 to supply a single national coordinating center for the exchange of organs and patients with the rest of Europe. When an organ is offered from Italy, the IGE ascribes it to the first foreign organization that accepts it on a first-come, first-served basis. In the case of offers from abroad, the IGE allocates the organ to one of the three Italian Interregional Centres in rotation. On the basis of international agreements, the IGE also manages the transfer of foreign patients to Italian transplant centers. The first 15 months of activity have been compared with the previous period of the same length. The IGE managed 353 contacts. 53 organs were transplanted in Italy versus 19 in the previous period. Seven foreign patients received liver transplantations in Italy. The increase in imported organs could be a function of IGE creation, since it allowed a reduced response time to offers and guaranteed the participation of all Italian centers in the program of international exchanges with a subsequent increase in the pool of recipients and equitable distribution of transplanted organs. The drop in the number of exported organs was a probable a consequence of increased acceptance criteria of Italian centers. The mentioned international agreements have allowed us to better meet the health care needs of foreign citizens who live in countries with low per million-population donation rates with no detriment to the probability of Italian citizens being transplanted. PMID- 17692601 TI - Is legalizing the organ market possible? AB - INTRODUCTION: Two opposing views of the human body have existed since time began. Can it be traded or does its value go beyond a monetary one? Today it is illegal to sell organs but the success of organ transplantation has give rise to an enormous controversy. The continued increase in the need for organs has lead to a major use of live donors. Consequently, clandestine selling of organs is becoming more widespread for two main reasons: scientific progress and market demand. Our aim was to consider the protection of ethical principles through legislation. MATERIALS AND METHODS: Based on the principle that it is morally unacceptable for people to die on a waiting list, we analysed various ways in which the National Health Service could give incentives to live donors, including reimbursement of health expenses, tax relief, pension or early retirement benefits, or education grants for the children. Possible incentives for cadaveric organ donation included reimbursal of health and funeral costs, or increase in widow/er's pension. CONCLUSION: The tendency may be toward reimbursement of costs rather than actual payments. A legal, ethical organ market could save thousands of human lives, but it must be correctly regulated. PMID- 17692602 TI - Incidence of neoplastic donors in Organizzazione Centro Sud Trapianti area during the 2003-2005 period. AB - The aim of this study is to evaluate the incidence of malignant tumors in cadaver donors and the possibility of neoplastic disease transmission to the recipients in the Organizzazione Centro Sud Trapianti (OCST) area. Among 1744 potential donors identified from 2003 to 2005, 125 (7.1%) showed an elevated malignant neoplastic risk. In 2003 a malignant tumor was diagnosed in 60 donors of mean age 59.6 +/- 19.9 years (median 62.5, M:36 F:24); in 2004, 33 donors of mean age, 61.4 +/- 15.9 years (median 63, M:19 F:14); in 2005, 32 donors of mean age of 62.8 +/- 15.5 years (median 65.5, M:20 F:12). Prostatic cancer was the most common tumor (23.2%). In 101 of 125 cases (80.8%) the tumor was diagnosed before organ retrieval, in 23 (18.4%) cases, during the donor operation but before the transplant, and in one case (0.8%) after transplantation. Each tumor was evaluated according to the histologic types and grades. From 12 of those donors with neoplasia, 24 organs were retrieved (10 livers, 11 kidneys, 3 hearts) transplanted in 23 recipients (one liver-kidney combined transplant). Three recipients died during the perisurgical period due to causes unrelated to the tumor and therefore were not considered in the follow-up evaluation. Among the remaining nine recipients who had a mean follow-up of 38.83 months (range 9-42), no donor-transmitted disease has become apparent by imaging control. A careful donor evaluation including histologic grading and strict application of Centro Nazionale Trapianti guidelines allowed us to use donors with malignant tumors in selected cases with an apparently reduced risk of transmitted neoplastic disease. PMID- 17692603 TI - The registry of brain deaths in quality control program: evaluation of potentiality of each hospital in Abruzzo and Molise regions. AB - Quality control procedures in donation and transplantation of organ and tissue, which were started in 2001, are aspects of the activity of Regional Centre for Transplantation. Over the years there has been a significant increase in the number of diagnosed brain deaths that is close to the figure reported in the international literature of 50/60 per million inhabitants (p.m.i). Misidentification of brain death is still the most important cause of loss of organs for transplantation; in fact in Italy, there are some regions that overcome this value, but there are other regions in which the number of brain death identified is still low. Abruzzo and Molise in 2003 achieved the highest registered brain deaths (61 p.m.i.); in 2004, 51; in 2005, 43; and the projection for 2006 is about around 50. For this study we collected data from five hospitals with a neurosurgical unit, which were representative of procurement activity in two regions, because they had identified the most brain deaths, 53/65 in 2005. The data were compared among hospitals and with the Spanish country data (1999 2003), which was avant-garde for the processing of organ donation and transplantation in Europe. Some useful indices to define the theoretical capacity of donation for each hospital (ability to identify brain death, the cause of donor loss) were evaluated for determining the efficacy of the procedure in organ procurement. PMID- 17692604 TI - Redox proteomics and immunohistology to study molecular events during ischemia reperfusion in human liver. AB - Oxidative stress is a condition occurring in liver disorders and causing liver damage due to ischemia-reperfusion (I/R) during liver transplantation. Several markers of chronic oxidative stress are well known; however, early protein targets of oxidative injury are not well defined. To identify them, we used a differential proteomics approach to HepG2 human liver cells that has been treated for 10 minutes with 500 micromol/L H(2)O(2). By differential proteomic analysis, using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry, we identified four proteins sensitive to H(2)O(2) treatment that underwent posttranslational modification of native polypeptides. Three of the proteins belong to the Peroxiredoxin family of hydroperoxide scavengers, PrxI, PrxII, and Prx VI, that showed changes in their pI as result of hyperoxidation. Mass mapping experiments demonstrated specific modification of the peroxiredoxins active site thiol into sulphinic and/or sulphonic acid, thus explaining an increased negative charge. The oxidation kinetics of all peroxiredoxins were extremely rapid and sensitive, occurring at H(2)O(2) doses unable to affect common markers of cellular oxidative stress. A differential proteomics approach was also applied to liver needle biopsies after cold (T(1)) and warm (T(2)) ischemia. Proteomic analysis of this material was related to histological changes and immunophenotypic expression of APE1/Ref-1. Hyperoxidation of PrxI occurring during I/R upon liver transplantation is dependent on the time of warm ischemia. Histological changes and APE1/Ref-1 expression parallel Peroxiredoxin changes. Our present data may be relevant to better graft preservation and evaluation for transplantation. PMID- 17692605 TI - Inhibition of tumor necrosis factor alpha gene transcription by pentoxifylline reduces normothermic liver ischemia-reperfusion injury in rats. AB - Pentoxifylline (PTX) has been shown to protect the liver against normothermic ischemia-reperfusion (I-R) injury. The aims of this study were to investigate the action of PTX on tumor necrosis factor alpha (TNFalpha) gene transcription following normothermic liver I-R as well as to evaluate the resulting effects on liver function and survival. A segmental normothermic liver ischemia was induced for 90 minutes. Rats were divided into three groups: group 1, control, Ringer lactate administration; group 2, PTX treatment; group 3, sham-operated control rats. PTX (50 mg/kg) was injected intravenously 30 minutes before induction of ischemia and 30 minutes before reperfusion. The nonischemic liver lobes were resected at the end of ischemia. Survival rates were compared and serum activities of TNFalpha, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase were measured. Liver histology was assessed 6 hours after reperfusion. Liver TNFalpha mRNA was assessed by polymerase chain reaction amplification at different times after reperfusion. PTX treatment significantly decreased serum activities of TNFalpha and inhibited liver expression of TNFalpha mRNA. The extent of liver necrosis and serum levels of liver enzymes were significantly decreased by PTX treatment, resulting in a significant increase in 7-day survival compared with nontreated control rats. In conclusion, PTX inhibits liver TNFalpha gene transcription, decreases serum TNFalpha levels, and reduces liver injury following normothermic I-R. PMID- 17692606 TI - Subnormothermic machine perfusion protects against rat liver preservation injury: a comparative evaluation with conventional cold storage. AB - Hypothermic machine perfusion (MP) of the liver has been reported to improve graft function reclaiming marginal livers, such as those from non-heart-beating donors. Livers from obese donors often have fatty infiltrates and are more susceptible to hypothermic conditions. No data exist about MP at temperatures >4 degrees C. This study evaluated liver function after organ preservation by comparing MP at 20 degrees C with conventional cold storage. METHODS: For MP, rat livers were perfused for 6 hours using an oxygenated Krebs-Henseleit (KH) solution at 20 degrees C (pH 7.4). For cold storage, livers were perfused in situ and preserved with Celsior solution at 4 degrees C for 6 hours. The reperfusion period with KH (2 hours at 37 degrees C) was performed under the same conditions both among livers preserved by MP or cold storage. Hepatic enzyme release (aspartate aminotransferase [AST], alanine aminotransferase [ALT], lactate dehydrogenase [LDH], and gamma-glutamyl transferase [GGT]), bile production, and ATP levels were measured during MP and reperfusion. RESULTS: At the end of reperfusion, livers preserved by MP showed significantly decreased liver damage compared with cold storage: AST, 18 +/- 4 vs. 45 +/- 6 mU/mL (P < .01); ALT, 1.5 +/- .07 vs. 6 +/- 0.5 mU/mL (P < .01); and LDH, 82 +/- 2 vs. 135 +/- 29 mU/mL (P < .05). No difference was observed between bile production between MP and cold storage. High levels of biliary GGT and LDH were found in cold preserved livers. ATP levels were higher in livers preserved with MP compared with those preserved by cold storage. CONCLUSIONS: MP at 20 degrees C resulted in a better quality of liver preservation, improving hepatocyte survival, compared with conventional cold storage. This may provide a new method for successful utilization of marginal livers, in particular fatty livers. PMID- 17692607 TI - Liver damage during ischemia/reperfusion and glutathione: implications for potential organ donors. AB - Free radicals play a central role in the development of liver ischemia/reperfusion (I/R) injury. Reduced glutathione (GSH) is the main hepatic free radical scavenger. Brain-dead patients exhibit abnormalities of endocrine status. Many clinicians administer thyroid hormones to improve the transplantation outcomes. We previously reported that thyroxine (T(4)) pretreatment decreased rat liver tissue GSH, which was associated with increased liver I/R-induced damage. In this study, we investigated whether the reduction in GSH by T(4) pretreatment affected cell viability during anoxia or oxidative stress in suspensions of isolated hepatocytes. Furthermore, we evaluated the levels of GSH in isolated livers from hypothyroid rats preserved at 0-1 degrees C and reperfused. Thyroid hormone modulation was obtained by T(4) or 6 propylthiouracil (PTU) treatment. Isolated hepatocytes from T(4)-pretreated rats that underwent anoxia and oxidative stress, which was induced by tert butylhydroperoxide, displayed progressive, time-dependent loss of cell viability, which was greater than that in hepatocytes in non-T(4)-pretreated rats. A significant decrease in GSH levels was observed in isolated hepatocytes obtained from hyperthyroid rats compared with those from euthyroid rats. In contrast, administration of the antithyroid drug PTU increased liver concentrations of GSH at the end of reperfusion thereby improving liver function after cold storage. These results may yield new protective strategies in the management of brain-dead organ donors. PMID- 17692608 TI - Protective effect of an inhibitor of interleukin-8 (meraxin) from ischemia and reperfusion injury in a rat model of kidney transplantation. AB - INTRODUCTION: Since the ischemia and reperfusion injury is one of the main causes of delayed graft function after transplantation, research efforts have focused on studying the molecules involved in this inflammatory process. The chemokine interleukin-8 (IL-8) seems to be the main one responsible through a chemoattractive action toward neutropils. Therefore, one of the strategies adopted to prevent this process is blocking the binding between IL-8 and its receptors. The aim of our study was to test the effect of meraxin, a new derivative from repertaxin, to protect the renal graft from ischemia and reperfusion injury. MATERIALS AND METHODS: Eighty male syngenic rats were divided into four groups. The control group underwent only kidney transplantation, while the other groups were treated with meraxin at various dosages 2 hours before graft reperfusion. Blood and histological samples were taken at sacrifice 24 hours after transplantation. RESULTS: Creatinine was significantly lower in the group treated with the high dosage of meraxin. Histological observation of the grafted tissue showed instead only a mild and not significant neutrophilic infiltration, equal in each group. CONCLUSIONS: Graft function was improved by the administration of meraxin at high dosage, but this effect did not seem to be connected to a reduction in inflammatory infiltration in the parechymal tissue. Maybe the cause is in the mechanisms of clotting activation, due to alteration of adhesion molecules and endothelial cells. PMID- 17692609 TI - Use of monitoring intraoperative parathyroid hormone during parathyroidectomy in patients on waiting list for renal transplantation. AB - This report describes the use of intraoperative parathyroid hormone (ioPTH) assay during parathyroidectomy for patients with secondary hyperparathyroidism on the waiting list for renal transplantation. The levels of ioPTH were determined among waiting list patients undergoing subtotal parathyroidectomy and tertiary hyperparathyroidism patients undergoing procedures. The levels of ioPTH were significantly reduced at 10 minutes by 59.7,3% among with secondary hyperparathyroidism and 68.9% among tertiary hyperparathyroidism. A 15 minutes it was 85% in secondary hyperparathyroidism and 89.7% in tertiary hyperparathyroidism. A decrement of 50% in basal values at 10 minutes and 85% decrement or more at 15 minutes was predictive for the success of abnormal parathyroid gland removal. The application of this technique during subtotal parathyroidectomy results was useful to predict a correct excision of abnormal parathyroid glands among patients with secondary hyperparathyroidism on the waiting list and for tertiary hyperparathyroidism patients. PMID- 17692610 TI - Kidney dimensions at sonography are correlated with glomerular filtration rate in renal transplant recipients and in kidney donors. AB - The gold standard to assess renal function is the measurement of glomerular filtration rate (GFR). For practical reasons, renal function is often evaluated from serum creatinine (S Cr) or cystatin C (S Cys), and GFR is predicted from SCr. Ultrasound scanning of the kidneys is used only to evaluate renal morphology. The aim of this study was to evaluate the relationship between sonographic renal dimensions and GFR in renal transplant recipients and in kidney donors. GFR (urinary clearance of (99m)Tc-DTPA), S Cr, and S Cys were measured in 33 donors (28 females [F], 5 males [M]; SCr, 0.81-1.90 mg/dL) and 30 recipients (8 F, 22 M; SCr, 0.96-2.42 mg/dL). GFR was also predicted using the Cockcroft and Gault (CG) formula and with the simplified Modification of Diet in Renal Disease (MDRD) formula. Length, width, and depth of kidneys and renal sinus were measured using renal sonography. Among sonographic measurements, kidney length showed the best correlation with GFR. A closer correlation with GFR was found in donors (r = 0.639; P < .00007) than in recipients (r = 0.511; P < .005). In either case, the correlation of kidney length with GFR was greater than that of S Cr or S Cys, and similar to that of CG or MDRD GFR. Accuracy of kidney length as an indicator of GFR impairment was not statistically different from laboratory tests. Only in donors did CG show better accuracy. In conclusion, renal dimensions at sonography closely correlated with GFR. Thus, renal sonography can give information also on the function of the renal graft and of the remaining kidney of living donors. PMID- 17692611 TI - Renal embolization as an alternative to surgical nephrectomy in children. AB - PURPOSE: Complete renal embolization may be an alternative to surgical nephrectomy. The indications for renal embolization do not differ from those for surgical nephrectomy, but the less invasive nature of the technique is a major advantage. Few case reports are available in the pediatric age group. Our experience showed that complete renal embolization was feasible in pediatric patients with results comparable to those obtained in adults. MATERIALS AND METHODS: Twelve pediatric patients underwent 14 renal embolizations. The indications for embolization were as follows: (1) severe hypertension in 7 patients with end-stage renal failure; in these cases, a unilateral native nephrectomy was recommended prior to renal transplantation; (2) end-stage hydronephrosis in 3 patients with moderate hypertension or recurrent urinary infection; (3) nephrotic syndrome in 1 patient; or (4) ablation of an irreversibly rejected renal allograft in 1 patient. The embolization was performed under epidural anesthesia in 10 patients and under general anesthesia in 2 patients, by means of a polyvinyl alcohol injection with hemostatic gelatin powder and placement of coils. Postembolization course was followed. RESULTS: The embolization was successful in all 12 patients. In 1 patient, the procedure had to be repeated as a small accessory artery had revascularized the upper pole. In another patient, the procedure was bilateral in 2 separate sessions. In 10 patients, severe flank pain required narcotic analgesia. Two patients had fever. None had hypertension peaks. Median hospital stay was 4 days. At mean follow-up of 16 months, the results were stable. CONCLUSION: Renal embolization can avoid surgical nephrectomy also in pediatric patients. The advantages are less morbidity and shorter hospital stay. Our results in the short and medium term were equal to those of surgical removal. The procedure appeared to be safe and minimally invasive. PMID- 17692612 TI - Ethical aspects of renal transplantation from living donors. AB - Kidney transplantation from living donors is widely performed all over the world. Living nephrectomy for transplantation has no direct advantages for the donor other than increased self-esteem, but it at least remains an extremely safe procedure, with a worldwide overall mortality of 0.03%. This theoretical risk for the donor seems to be justified by the socioeconomic advantages and increased quality of life of the recipient, especially in selected cases, such as pediatric patients, when living donor kidney transplantation can be performed in a preuremic phase, avoiding the psychological and physical stress of dialysis, which in children is not well tolerated and cannot prevent retarded growth. According to the Ethical Council of the Transplantation Society, commercialism must be effectively prevented, not only for ethical but also medical reasons. The risks are too high, not only for the donors, but also for the recipients, as a consequence of poor donor screening and evaluation with consequent transmission of human immunodeficiency virus (HIV) or other infective agents, as well as of inappropriate medical and surgical management of donors and also recipients, who are often discharged too early. Most public or private insurance companies consider kidney donation a safe procedure without long-term impairment and therefore do not increase the premium, whereas recipient insurance of course should cover hospital fees for the donors. "Rewarded gifting" or other financial incentives to compensate for the inconvenience and loss of income related to the donation are not advisable, at least in our opinion. Our Center does not perform anonymous living organ donation or "cross-over" transplantation. PMID- 17692613 TI - Laparoscopic live donor nephrectomy: single center experience. AB - AIMS: The aim of this study was a retrospective assessment of the safety of laparoscopic live donor nephrectomy (LLDN) and the outcome of these renal transplantations. METHODS: From November 2001 to October 2006, we performed 30 LLDN (all left nephrectomies) after excluding any renal vascular anomalies in the donor. All laparoscopic procedures were performed by a team consisting of an expert laparoscopic surgeon and a transplant surgeon. The donor mean age was 48.9 +/- 7.6 years (range 22 to 69), 33% of the donors were men and their mean Body Mass Index was 24.7 +/- 3.8 kg/m(2). The recipients were a 32 +/- 14 years old (range 6 to 64), with 66% of them men, and their mean time on dialysis, 33 +/- 49 months (range 0 to 120). RESULTS: After a mean follow-up of 39 +/- 14 months, all donors and recipients are alive. The mean operative time was 272 +/- 41 min (range 225-360) and the mean warm ischemia time, 161 +/- 35 seconds (range 107 to 240). Surgical complications in the donors were one incisional hernia and two cases of pneumonia. The donor's mean hospital stay was 5.3 +/- 1.7 days (range 3 to 12) and their mean serum creatinine at discharge was 111 +/- 21 micromol/L. There was one surgical complication-a hematoma-among the recipients, and all transplants functioned immediately except for one case. CONCLUSIONS: LLDN was confirmed to be safe and effective, with no negative impact on transplants success. Expertise in laparoscopic surgery is needed to minimize the side effects for the transplant donor and for the recipient. PMID- 17692614 TI - Depression and quality of life in living related renal transplantation. AB - BACKGROUND: More than other operations on the body, organ transplantation has a psychological resonance relating to the self and body image representation, both in donors and in recipients. In the medical literature there are many psychopathological patterns related to ESRD and to the changes in psychologic assessment and lifestyle after transplantation. Similar changes have been found in living donors. METHODS: Forty-eight donor-recipient couples were evaluated before and 4 months after transplantation, using clinical interview, according to the DSM IV TR criteria; The structured Interview for renal transplantation, both for recipients and for donors; psychodiagnostic tests: mini-mental state; Hamilton Rating Scale for Depression; Hamilton Anxiety Scale; Self-Rating Anxiety Scale; Short-Form 36 Health Survey Questionnaire. RESULTS: Comparisons by paired Students t tests showed a significant Hamilton depression variation among recipients, with improvement in the gained score and reduction of depressive symptom (Hamilton score >7) frequency from 45.8% to 32%, and a decreased proportion of patients with a score >18 from 16.4% to 0%. There was no significant Hamilton Depression variation among donors, but there was somehow a reduction in depressive symptom frequency (Hamilton score >7) from 37.5% to 33.3% and a decrease among >18 scores from 12.6% to 0% patients. CONCLUSIONS: Living donor kidney transplantation did not adversely affect the lives of donors and significantly improved many aspects of the lives of recipients. However, physical and psychological aspects may be impaired by living donation. Careful donor selection, with appropriate pretransplantation psychiatric consulting, allows those with a normal life quality to donate without consequence to their physical or psychological status. PMID- 17692615 TI - Fenoldopam vs dopamine as a nephroprotective strategy during living donor kidney transplantation: preliminary data. AB - Fenoldopam is a selective DA1 agonist with potential nephroprotective capabilities. The aim of this study was to compare the nephroprotective effect of fenoldopam and dopamine during general anesthesia for living donor kidney transplantation. METHODS: Forty donors enrolled in the study received a similar anesthetic and fluid protocol. The patients were randomly divided into group F (receiving 0.1 mg*kg-1*min-1 fenoldopam) versus group D (receiving "renal dose" 3 mg*kg-1*min-1 dopamine). The mean volume of infused fluids, diuresis, and urinary electrolytes (Na, K, Cl) at infusion start and 120 minutes later were studied. RESULTS: Anthropometric parameters, administered anesthetics, mean infused volume, and urine outputs, did not show significant differences between the groups. Statistically significant differences were observed for urinary excretion of sodium, potassium, and chloride after 120 minutes of continuous fenoldopam infusion, with significant variations within groups for sodium only. CONCLUSIONS: Fenoldopam compared with dopamine resulted in better nephroprotective effects. No adverse events were recorded, and side effects were minimal. Further studies are necessary to evaluate these data. PMID- 17692616 TI - The finding of vascular and urinary anomalies in the harvested kidney for transplantation. AB - INTRODUCTION: In kidney transplantation, anatomical vascular and excretory anomalies may represent causes of failure. Today's surgical techniques have made the most of the organs with anatomic anomalies and iatrogenic injury successfully used for transplantation. MATERIALS AND METHODS: From January 2000 to June 2006, we harvested 230 kidneys, of including 88 kidneys (20%) with vascular, urinary, or vascular-urinary anomalies; 64 kidneys were implanted and 15 were sent to other transplantation centers. Only 9 kidneys were not appropriate for transplantation. RESULTS: All patients who received kidneys with the above mentioned anomalies were carefully examined after the transplantation and short term and long-term complications were evaluated with respect to controls without anomalies. DISCUSSION: Renal anatomic anomalies are frequently observed during kidney transplantation and may produce postsurgical complications. However, the presence of these anomalies does not necessarily imply the impossibility of using the kidney for a transplant, especially because of improved surgical techniques. Our experience in transplantation procedures showed that even if kidneys present the above-mentioned anomalies they can still be considered appropriate for transplantation when we perform a correct harvesting/back-table transplant surgery. So vascular and urinary anomalies have to be considered always an incentive to research new surgical solutions and to perform a careful surgical technique. PMID- 17692617 TI - Monolateral dual kidney transplantation from marginal donors. AB - BACKGROUND: Dual kidney transplantation (DKT) offers a safe way to face the organ shortage with good short-term and medium-term renal function. However, its application is limited by the longer operating time and the risk of surgical complication. This study reviews our results with DKT performed with an ipsilateral technique in terms of graft loss, graft and patient survival rates, and surgical complications. PATIENTS AND METHODS: From January 2002 to March 2006, 23 patients underwent DKT through a monolateral Gibson incision with placement of both kidneys. RESULTS: One primary nonfunction occurred (4%). Delayed graft function was observed in 3 DKT (13.3%). Acute rejection rate was 4.3% (1 patient). All patients are alive at a mean follow-up of 28 months. One year and 2-year graft survival rates were 100% and 96%, respectively. Mean serum creatinine level at 1-year posttransplantation was 1.3 mg/dL (range, 0.8-2.1 mg/dL). One DKG recipient lost 1 graft, retaining the second normal functioning graft due to ureteral necrosis. The mean hospital stay after transplantation was 15 days (range, 12-34 days). CONCLUSIONS: Monolateral placement in DKT offers the advantage of a single incision, minimizing the surgical risk. Tailored immunosuppression and careful selection of potential recipients, by excluding those with severe cardiopulmonary pathologies, could significantly improve both patient and graft survival in this group of patients. PMID- 17692618 TI - Efficacy of early biopsy in kidney allograft recipients with delayed graft function. AB - It is accepted that kidney transplants that display delayed graft function (DGF) show poorer survival and function, particularly when an acute rejection episode (ARE) occurs. A diagnostic biopsy to establish the reason for DGF, or acknowledge an ARE, even if borderline, can improve short- and long-term graft survivals. From January 2002 to September 2006 we retrospectively evaluated 358 kidney transplant recipients. We performed a biopsy to evaluate the cause of DGF in all patients who required dialysis, or had serum creatinine levels that increased, remained unchanged, or decreased less than 10% per day on three consecutive days during the first week after transplantation. An ARE was found in 18.8% (n = 19) of the biopsies. Early biopsy for patients with DGF is a safe method that allows uncovering of an ARE that would otherwise be undetected. The immediate recognition and treatment of rejection episodes can certainly increase long-term survival and function of renal transplants. PMID- 17692619 TI - Renal allograft immune response is influenced by patient and donor cytokine genotypes. AB - This study investigated the impact of specific cytokine genotypes on the incidence of acute rejection episodes (ARE), chronic graft dysfunction (CGD), and anti-HLA donor-specific antibody (DS-Ab) production in 86 renal transplant recipients and 70 cadaveric donors. A PCR-SSP method was performed for the analysis of polymorphisms in TNF-alpha, IL-6, TGF-beta, IL-10, and IFN-gamma cytokines. DS-Ab monitoring of sera was performed using a FCXM analysis. Observed cytokine frequencies for patients and donors were not significantly different from the expected frequencies under Hardy-Weinberg equilibrium conditions. The evaluation in recipients revealed a higher frequency of DS-Ab-positive patients among the TNF-alpha high (50.0% vs 25.7%), and for the IL-10 cytokine a greater incidence of ARE-positive patients (35.8% vs 18.2%) with the high + intermediate, compared with the low genotype. The combined effect of these 2 genotypes predisposed to DS-Abs (71.4% vs 25.3%; P = 0.02; odds ratio [OR] = 7.37). As for the TGF-beta1 cytokine, we observed a higher number of CGD-positive patients among high compared with intermediate producers (14.3% vs 0%; P = .050). The analysis of donors revealed a significantly lower incidence of ARE-positive patients among recipients whose donors were carriers of the high IL-6 G/G genotype compared with the G/C+C/C-genotypes (16.7% vs 41.2%; P = .03), suggesting a protective effect of the G/G genotype on ARE and a predisposing role of donor (-174)allele C. In addition, we noted an association between the IFN gamma low A/A-genotype and a higher incidence of ARE (42.1% vs 0%; P = .002) and DS-Ab production (47.4% vs 12.5%; P = .02) compared with high producers. PMID- 17692620 TI - Application of an artificial neural network model to predict delayed decrease of serum creatinine in pediatric patients after kidney transplantation. AB - Artificial neural network, a computer-based technology that uses nonlinear statistics to recognize the relationship between input variables and an output variable, has been previously applied to outcome prediction in adult kidney recipients. In this study, we evaluated the effectiveness of a neural network model to predict a delayed decrease of serum creatinine in pediatric kidney recipients. The neural network was constructed with a training set of pediatric kidney recipients (n = 107) by using 20 input variables and assuming for the output variable, the time after 3 days to reach a serum creatinine level 50% below that before kidney transplantation. In the final model, the following input variables showing higher predictive values were retained: serum creatinine on day 1 post transplant, urine volume in the first 24 hours, diagnostic category, pretransplant dialysis mode, patient sex, donor sex, body weight on day 1 posttransplant, and patient age. The model was validated in a second set of patients (n = 41) by blinding the network for the output variable. The overall accuracies of the neural network for the training set, the validation set, and the whole patient cohort were 89.1%, 76.92%, and 87.14%, respectively. A comparative logistic regression analysis revealed only serum creatinine on day 1 posttransplant to be an independent predictor for the output variable (overall accuracy: 79.05%). The neural network showed sensitivity and specificity for the whole patient cohort to be 0.875 and 0.87, respectively, whereas using logistic regression sensitivity and specificity yields 0.37 and 0.94, respectively. This study proposes a neural network model that seemed to predict a delayed decrease in serum creatinine among pediatric kidney recipients. The availability of the source code may allow development of stand-alone neural networks to validate our model in prospective studies. PMID- 17692621 TI - Renal grafts from elderly donors: histological studies and long-term results. AB - To satisfy the increasing requests for renal grafts, elderly donors are increasingly accepted for kidney transplant at many centers. The main unresolved question is the long-term effect on graft survival of potential histological lesions due to donor age. We present a prospective histological study performed from January 1997 to December 2001 on 184 consecutively transplanted renal grafts in which the only criterion for graft acceptance was a normal value of serum creatinine upon admission to the intensive care unit independent of donor age. At the end of the study, 57 recipients (31%) of mean age 55 years (range 39 to 67 years) received a renal graft from donors aged more than 60 years (mean age 66 years; range 60 to 75 years), this cohort denoted as older donor kidney transplant group (ODKTG) and 127 recipients (69%) with a mean age of 49 years (range 21 to 63 years) received a renal graft from donors whose age was lower than 60 years (mean age 49 years; range 16 to 59 years), a cohort denoted as the younger donor kidney transplant group (YDKTG). The two groups were comparable for time of dialysis, cold ischemia time, immunosuppression therapy, grading of histological damage. At the end of the study with a mean follow-up of 5.6 years (range 3.5 to 7.5 years), primary graft nonfunction and delayed graft function were significantly more represented in the ODKTG than the YDKTG. Cumulative patient and graft survival was 84.3% and 79.4% in the ODKTG, respectively, and 93.8% and 85.9% in the YDKTG, respectively (P = NS). Cumulative serum creatinine values were 1.98 mg/100 mL in ODKTG and 1.65 mg/100 mL in YDKTG (P = NS). In conclusion, renal grafts from older donors presented histological damage comparable to that seen among renal grafts from younger donors. PMID- 17692622 TI - Higher incidence of acute rejection in renal transplant recipients with low everolimus exposure. AB - Everolimus (EVL) has shown a potential to reduce nephrotoxicity associated with cyclosporine (CsA) while providing similar protection against rejection. We analyzed the incidence of acute rejection episodes (ARE) among 20 cadaveric renal transplant recipients treated with the combination of EVL + CsA. Immunosuppression consisted of basiliximab induction given pretransplant and on day 4 posttransplant; EVL at a starting dose of 1.5 mg/day followed by concentration control to trough levels of 3 to 8 ng/mL by day 7; CsA at a starting dose of 4 mg/kg per day and then concentration controlled with C2 monitoring (C2 500-700 ng/mL); and steroids in a tapering regimen to reach 5 mg by day 30. The overall incidence of ARE was 25%. On postoperative day 7, patients with ARE showed significantly lower mean EVL trough concentrations compared with those not experiencing ARE (NO ARE: 2.2 +/- 2.1 ng/mL vs 4.8 +/- 2.4 ng/mL) (P = .05). The CsA C2 values were close to the lower end of the target range on day 3 (583 +/- 334 ng/mL). All rejecting grafts were functioning at 3 months posttransplantations, but mean serum creatinine was higher in the ARE group (ARE 2.2 +/- 0.7 mg/dL vs 1.1 +/- 0.2 NO ARE; P = .04). In conclusion, whenever EVL is used in combination with CsA to protect kidney transplant patients against the risk of acute rejection, a threshold of 3 ng/mL must be reached in the first week posttransplantation. We suggest careful monitoring of EVL exposure and increased EVL starting doses. PMID- 17692623 TI - Histological markers of humoral rejection in renal transplant patients. AB - Diagnosis of "suspicious humoral rejection" can be formulated in the presence of peritubular capillary (PTC) C4d deposition and one of the following tissue changes: (1) acute tubular necrosis, (2) glomerulitis or presence of polymophonuclear leukocytes or monocytes in PTC, or (3) arteritis. From January 2004 to October 2006, we performed immunohistochemical staining with anti-C4d antibody on 54 renal biopsies from 39 renal transplant patients. In 25 biopsies we observed diffuse (n = 13) or focal (n = 12) C4d deposition. Based on C4d positivity, patients were divided into three groups: group 1 included 19 C4d negative patients; group 2, 10 patients with diffuse C4d-positivity; and group 3, 10 patients with focal C4d-positivity. Panel-reaction antibody-positive tests were associated with diffuse C4d-positivity: 50% of group 2 patients showed a positive test, while no group 1 or 3 patients had a positive test (P < .001). Glomerulitis was observed in six biopsies and associated with diffuse C4d staining. Graft loss occurred in 3/10 group 2 patients (30%); 2/19 group 1 patients (10.5%), and 1/10 group 3 patients (10%). Viral infections were experienced in the year of the biopsy by 50% of group 1 patients 80% of group 2 patients, and 100% of group 3 patients (P < .025), indicating a significantly greater number of infections among patients with C4d-positive biopsies. In eight cases, anti-thymocyte globulin was administered less than 21 days before the biopsy: four had diffuse and four had focal C4d positivity. PMID- 17692624 TI - Impact of recipient and donor ages on patient and graft survival after kidney transplantation. AB - BACKGROUND: The purpose of the study was to evaluate the impact of donor and recipient ages on patient and graft survival after kidney transplant. METHODS: Patients in a hospital database undergoing kidney transplant for end-stage renal disease (ESRD) during the period 1985 to May 2006 (n = 410; mean age 42 +/- 10 years; 61% men and 39% women) were divided into two groups: group A, patients of 60 years or older (6%, n = 24), and group B, those younger than 60 years (94, n = 386). In 204 patients (49.8%) the pancreas was transplanted simultaneously with the kidney. RESULTS: Overall 1-, 3-, 5-year patient survivals were 92%, 90%, 88% in group A and 95%, 90%, 87% in group B (P = .6, NS). Overall 1-, 3-, 5-year kidney graft was 92%, 75%, 65% in group A and 92%, 84%, 79% in group B (P = .7, NS). Donors were divided into two groups: group 1, 55 years or older (15%, n = 62), versus group 2, those younger than 55 years (85%, n = 348). Overall 1-, 3-, 5-year patient survivals were 91%, 86%, 76% in group 1 and 97%, 94%, 90% in group 2 (P = .0009). Overall 1-, 3-, 5-year kidney graft survivals were 87%, 82%, 76% in group 1 and 94%, 86%, 82% in group 2 (P = .02). CONCLUSIONS: Renal transplantation is an effective option for the treatment of ESRD in elderly patients. The overall rates of patient and kidney graft survival are comparable to those of younger patients. Donor age > or =55 years had a negative effect on patient and kidney graft survival. PMID- 17692625 TI - Bologna transplant center results in double kidney transplantation: update. AB - INTRODUCTION: Double-kidney transplantation is performed using organs from marginal donors with a histological score not suitable for single kidney transplantation. The aim of this study was to verify the results obtained with double-kidney transplantation in terms of graft/patient survivals and complications. PATIENTS AND METHODS: Between September 2001 and September 2006. 26 double-kidney transplantations were performed in our center. Indications for surgery were: chronic glomerulonephritis (n = 17), polycystic disease (n = 4), reflux nephropathy (n = 1), hypertensive nephroangiosclerosis (n = 4). The kidneys were all perfused with Celsior solution and mean cold ischemia time was 16.7 +/- 2.5 hours. In all cases, a pretransplant kidney biopsy was performed to evaluate the damage (mean score: 4.3). Immunosuppression was tacrolimus-based for all patients. RESULTS: Eighteen patients had good renal postoperative function, while the other eight displayed acute tubular necrosis. Two of the patients who had severe acute tubular necrosis never recovered renal function. There was only one episode of acute rejection, while the incidence of urinary complications was 31%. There were two surgical reoperations for intestinal perforation. Graft and recipient survivals were 82.7% and 100%, and 78.9% and 94% at 3 and 36 months, respectively. CONCLUSIONS: Double-kidney transplantation is a safe strategy to face the organ shortage. The score used in this study is useful to determine whether a kidney should be refused or suitable for single- or dual-kidney transplantation. The results of our experience are encouraging, but the series is too small to allow a conclusion. PMID- 17692626 TI - Older kidneys donor transplantation: five years' experience without biopsy and using clinical laboratory and macroscopic anatomy evaluation. AB - INTRODUCTION: The exponential increase in organ demand is not associated with a similar increase of available kidneys. This emergency led to expanded criteria to consider a kidney transplantable. The aim of this retrospective study was to explain our use of older donor kidneys without biopsy. MATERIALS AND METHODS: Between 2000 and 2005, 58 older kidneys were harvested: 27 were transplanted in our center; 13 were discarded; and 18 were transplanted in other centers. We considered 3 factors to define kidney quality: macroscopic anatomy, multiple factors linked to the donor, and clinical-laboratory data. After transplantation, we observed the patients for at least 1 year and up to 6 years. DISCUSSION: At 1 year, 24/27 (89%) patients had a functional kidney, 2 patients showed an initial renal failure and 1 patient lost the kidney. At maximum follow-up, 19 patients (70%) had functional kidneys, 4 with initial renal failure. These results compared with the kidneys harvested using Standard Donor Kidney Criteria are acceptable. Obviously we need long-term follow-up to increase, the amount of data and obtain a definitive outcome. CONCLUSION: Biopsy is the gold standard for the definition of an older kidney's quality. When a biopsy is not feasible, the study of the macroscopic anatomy the kidney's donor and of some donor's parameters represent an acceptable biopsy alternative, being able to rescue some organs that would be otherwise lost. PMID- 17692627 TI - Voriconazole in the treatment of invasive aspergillosis in kidney transplant recipients. AB - BACKGROUND: Aspergillosis and other invasive mold infections are severe complications in immunosuppressed patients, and in renal transplant patients it is the most common cause of systemic fungal disease with an incidence ranging from 0.4% to 2.4% with a high mortality of 56% to 100%. We present our experience with voriconazole in a population of kidney transplant recipients with invasive aspergillosis. PATIENTS AND METHODS: From January 2002 to December 2005, 245 kidney transplantations were performed. RESULTS: Four patients (1.6%) presented with clinical and laboratory findings of invasive aspergillosis. Three patients presented with pulmonary aspergillosis, while one patient presented with pulmonary and ocular aspergillosis. All patients underwent a therapy with voriconazole 200 mg twice a day, in combination with caspofungin in one patient. All patients are alive, with no clinical recurrence of aspergillosis at a median follow-up of 13 months. One patient lost her graft due to discontinuation of immunosuppression. CONCLUSIONS: Voriconazole is a potent and well-tolerated antifungal drug that is extremely efficacious in the treatment of invasive aspergillosis in kidney transplant recipients. A careful monitoring of immunosuppressive drugs should be considered to avoid nephrotoxicity. PMID- 17692628 TI - Cyst infection in renal allograft recipients with adult polycystic kidney disease: the diagnostic value of labeled leukocyte scanning: case reports. AB - Occult infection following renal transplantation is a common diagnostic problem facing nephrologists and transplant surgeons. Patients with adult polycystic kidney disease (APKD) are prone to recurrent infections in their native kidneys and this can present with little if any localizing signs. Conventional radiological imaging with computed tomography or ultrasonography has a low sensitivity and specificity in such patients due to anatomic distortion and poor native renal function, and therefore identifying the source of sepsis can be difficult. Two cases are presented where patients with APKD who had received kidney transplants were investigated unsuccessfully for occult sepsis. White cell labeled scanning identified the location of the infection in the patients' native polycystic kidney in both cases, allowing targeted treatment in the form of native nephrectomy. White cell-labeled scanning has an important role in the investigation of occult infection in renal allograft recipients with APKD. PMID- 17692629 TI - Metabolic syndrome after kidney transplantation. AB - BACKGROUND: Metabolic syndrome (MS) includes some risk factors for development of diabetes and cardiovascular disease, obesity (BMI > 30), high triglycerides, low HDL cholesterol, hypertension and impaired glucose tolerance. Following the definition of the Adult Treatment Panel III criteria, a diagnosis of MS was established when 3 or more factors were present. In renal transplant patients MS has been reported to negatively influence both patient and graft survivals. The present study sought to verify the effect of MS among our cases. METHODS: 298 cadaveric renal transplant recipients operated between January 1, 1996 and December 31, 2001 with absence of diabetes before transplantation, stable renal function 1 year posttransplantation and at least 4 years follow up were retrospectively evaluated from the end of the first post-operative year. RESULTS: 50 patients out of 298 (16,7%) had MS at the beginning of the study, including 37 of them with 3 and 13 with 4 risk factors. Only one patient with MS died of cardiovascular disease. Graft failure was observed in 23.5% MS patients versus 9,7% patients without the Syndrome (p:n.s.) Only Creatinine and the incidence of Cardiovascular Diseases at 4 years were statistically higher in MS patients (P < .001). CONCLUSIONS: These results suggested that MS is a risk factor for increasing CVD morbidity and decreased graft function, but early treatment of risk factors as soon as they become apparent can limit the adverse effects on patient and graft survival. PMID- 17692630 TI - Topical photodynamic therapy of actinic keratosis in renal transplant recipients. AB - Organ transplant recipients (OTRs) show an increased risk of precancerous (mostly actinic keratosis [AK]) and cancerous (mostly squamous cell carcinomas [SCC] and basal cell carcinomas [BCC]) cutaneous lesions. Their frequency increases with time after transplantation. AKs seem to progress more often and faster to invasive SCC in OTRs compared with the general population. The steady increase of risk of cutaneous premalignancies and malignancies with time after transplantation is an alarming figure because the number of organ allograft recipients who live for many years after transplantion is rapidly growing. This points out the need to devote more resources to skin cancer prevention, detection, and management. Various therapies, including cryotherapy, topical 5 fluorouracil, imiquimod, topical diclofenac, curettage, electrosurgery, carbon dioxide laser, and surgical excision, are available for AKs. However, most of these are limited by frequent relapses and the presence of multiple lesions over a wide area. Topical photodynamic therapy (PDT) represents an innovative therapeutic approach for nonsurgical treatment of cutaneous precancerous lesions and skin cancers. In this study we confirmed the usefulness of PDT in the treatment of AKs in OTRs, even in lesions relapsing or unresponsive to conventional treatment. We showed a complete response rate of 71%, after 2 treatments sessions that were 2 weeks apart. The response rate of scalp/facial lesions (72%) was higher compared with acral lesions (40%). Topical PDT could represent a useful therapeutic alternative for AKs in OTRs because large lesions can be treated with excellent cosmetic outcome. PMID- 17692631 TI - Intraperitoneal Tenckhoff catheter for the treatment of recurrent lymphoceles after kidney transplantation: our early experience. AB - Lymphoceles may occur as frequently as 16% of the time after kidney transplantation, becoming clinically evident between 18 and 180 days after surgery. The management of lymphoceles is unclear. Percutaneous needle aspiration and external drainage are associated with high recurrence and complications. Surgical intraperitoneal marsupialization of lymphocele is considered the treatment of choice, but requires hospital admission, general anesthesia, and sometimes extensive surgical dissection. We discuss our experience in the treatment of recurrent symptomatic lymphocele intraperitoneally drained using a Tenckhoff catheter in 7 consecutive patients. Clinical manifestations became evident between 26 and 90 days after transplantation. The diagnosis was obtained with abdominal ultrasound in all cases; mean lymphocele diameter was 14 +/- 6 cm. After percutaneous drainage, performed to differentiate urinoma/lymphocele and to rule out infections, the lymphocele recurred within 1 month. Thereafter, we decided to treat recurrent lymphatic collection using a Tenckhoff catheter. The lymphocele was located during the operative procedure using a sterile 3.5-MHz ultrasound probe. With the patient under local anesthesia, we performed 2 vertical 1-cm incisions to the lymphocele and peritoneum, respectively. The Tenckoff catheter was first positioned into the lymphocele and the tunneled inside the peritoneal cavity. One cuff of the Tenckhoff was fixed to the fascia to avoid possible delocalization. The patients were discharged the same day. The catheter was removed 6 months later with no evidence of lymphocele recurrence. PMID- 17692632 TI - Algorithm for prioritization of patients on the waiting list for liver transplantation. AB - Prioritization of patients on the waiting list (WL) for OLT is still a critical issue. Numerous models have been developed to predict mortality before and after OLT. AIM: The aim of the study was to prospectively evaluate cirrhotics with and without hepatocellular carcinoma (HCC) undergoing orthotopic liver transplantation (OLT) severity of liver disease on the WL and at transplant, mortality on the WL and after OLT, and their correlations. MATERIALS AND METHODS: An algorithm based on seven patient variables (MELD, CTP, UNOS, HCC, BMI, waiting time, age) was created by software dedicated to prioritize patients on the waiting list. RESULTS: We evaluated 118 patients including 75 men and 43 women of age range 19 to 66 years, who underwent OLT from July 2004 to June 2006. Mean CTP and MELD at listing were 8.44 (range 6-12) and 13 (range 2-24), respectively. Overall mortality on the WL at 24 months was 13%, which was significantly higher among patients with MELD > 25 compared to patients with MELD 0 to 15 (P < .0001) or MELD 16 to 25 (P = .0007) at listing. Mean MELD at OLT was 15 (range 7-36), which was significantly lower in patients with than without HCC (MELD 12 vs 16; P = .0003). Six hundred-day patient survival was significantly lower among patients with MELD > 25 compared to patients with MELD < 25 at OLT (P = .017), whereas no difference in survival was observed between patients with and without HCC. CONCLUSIONS: The sickest patients are characterized by high mortality both on the waiting list and after liver transplantation. Patients with HCC are transplanted in better condition compared to patients without HCC with the same survival. PMID- 17692633 TI - First-line liver resection and salvage liver transplantation are increasing therapeutic strategies for patients with hepatocellular carcinoma and child a cirrhosis. AB - AIM: The present study focused on nine patients with hepatocellular carcinoma (HCC) associated with Child A liver cirrhosis undergoing first-line liver resection and salvage liver transplantation (SLT) for liver tumor recurrence. PATIENTS AND METHODS: Forty-six patients with HCC underwent liver transplantation (OLT); 37 (80.5%) were primary liver transplantations (PLTs) and 9 (19.5%) were SLTs. All patients who underwent SLT received minor transabdominal liver resections. RESULTS: The posttransplant 1-, 3-, and 5-year overall survival rates for SLT (88.9%, 88.9%, and 88.9%) were similar to those for PLT (78%, 62.7%, and 62.7%). Four (10.8%) patients in the PLT group had HCC recurrence, while there was zero recurrence in the SLT group. The 1-, 3-, 5-year disease-free survival rates for PLT (89%, 74%, and 74%) were similar to those for SLT (100%, 100%, and 100%). The 1-, 3-, 5-year disease-free survival rates after PLT were 89%, 74%, and 74%, and after SLT were 100%, 100%, and 100%, respectively. The operative mortality, intraperioperative bleeding, operative time, intensive care unit stay, in-hospital stay, and overall incidence of postoperative complications were similar in the two groups. CONCLUSIONS: In our experience, SLT for HCC is a feasible procedure with similar results in terms of overall survival, disease free survival, and postoperative complications to those reported for patients who underwent PLT at our institute. An important role exists for SLT as shown by the fact that such a strategy has been used in the 20% of the patients undergoing OLT for HCC. PMID- 17692634 TI - Alcohol- and substance-dependent subjects: the correlated factors in qualifying for liver transplantation. AB - OBJECTIVES: To identify the most significant variables in determining if candidates with past or current addictions can be considered for liver transplantation. METHODS: Data relating to 58 cases from January 2001 to December 2003 were collected and analyzed. RESULTS: The decisional algorithm identified by discriminant analysis is based on the following variables: the duration of remission, treatment adherence, and the presence of a valid help relationship. Candidates undergoing initial remission (up to 12 months) must demonstrate both adherence and affective support; those with over 5 years of remission, however, are considered sufficiently reliable. A positive judgment is significantly correlated to overall survival and clinical improvement even without transplantation. CONCLUSIONS: In toxicological evaluation, treatment adherence and the presence of a valid help relationship for patients in remission from addictions can improve the selection criteria for liver transplantation, making it more dependable. PMID- 17692635 TI - Molecular adsorbents recirculating system treatment in acute-on-chronic hepatitis patients on the transplant waiting list improves model for end-stage liver disease scores. AB - BACKGROUND: The aim of our study was to show an improvement in Model for End Stage Liver Disease (MELD) score after treatment with Molecular adsorbents recirculating system (MARS) in acute-on-chronic hepatitis (AoCHF) patients. MELD was adopted to determine the prognosis of patients with liver chronic desease. We evaluated the possibility to improve the MELD score of patients awaiting liver transplantation using a liver support device, namely, MARS. PATIENTS AND METHODS: From September 1999 to April 2006, we treated 80 patients whose diagnoses were hepatitis C, 41.25%; hepatitis B, 27.5%; alcholic, 17.5%; intoxication, 8.75%; primary biliary cirrhosis, 5%. The overall mean age was 45 years (23 to 62), the cohort included 56 men and 24 women. Inclusion criteria were bilirubin >15 mg/dL; MELD >20; encephalopathy >II; and International Normalized Ratio, >2.1. Other parameters evaluated included ammonia, creatinine, lactate, glutamic oxalic transminase, and guanosine 5'-triphosphate. All patients were treated with a mean of 6-hour cycles of MARS (range, 5 to 8 hours) for a minimum of three treatments and a maximum of 20 treatments over 3 months. Clinical conditions were evaluated by improved hemodynamic parameters, kidney function, liver function, coagulation, neurologic status using the SOFA score, Glasgow Coma Scale (GCS), and Acute Physiology and Chronic Health Evaluation II Criteria. RESULTS: The MELD score for all categories of living patients showed significant improvements at the end of treatment and at 3-months follow-up, but the small number of patients was a limitation to determine prediction of mortality. CONCLUSION: Our study shows that MARS treatment improved multiple organ functions-liver, renal, neurologic, and hemodynamic. The improved MELD score gave patients on the transplant waiting list longer survival, allowing them a greater opportunity for liver transplantation. PMID- 17692637 TI - Hemodynamics during liver transplantation. AB - Assessing the optimal volemia in the perioperative course of liver transplantation is a challenge for the anesthesiologist. Traditional estimates of intravascular volume status, such as pulmonary artery occlusion pressure (PAOP), have been widely shown to poorly correlate with changes in cardiac output among critically ill patients. Hence, there has been recent interest in alternative, catheter-related, bedside device volume estimates using thermodilution. Continuous end diastolic volume (CEDVI) showed better correlations with cardiac performance than cardiac filling pressures in studies performed in critically ill patients. When compared with conventional pressure-derived data, preload monitoring estimated as intrathoracic blood volume index (ITBVI) with the PiCCO system based on an integrated transpulmonary thermodilution technique better reflected left ventricular filling both in critically ill patients and those who underwent liver transplantation. Moreover, in liver transplantation, the use of transoesophageal echocardiography (TEE) has been increasing for it provides rapid visualization of the dimension and function of heart chambers as well as the left ventricular end diastolic area index (EDAI) that seem to correlate with graded acute hypovolemia, although its validity as on preload index is still under discussion. PMID- 17692636 TI - Relationship between laboratory parameters and intensive care unit stay post liver transplantation: proposal of a model. AB - The aim of this study was to create a model that forecasted the stay in the intensive care unit in post-liver transplantation. METHODS: Twenty-three consecutive patients who underwent liver transplantation provided samples for serum sodium, serum creatinine, total bilirubin, cholesterol, aspartate and alanine aminotransferase, alkaline phosphatase (ALP), albumin, and platelet count for correlation together with age at transplantation in a Pearson correlation model with intensive care unit stay. Multivariate analysis used a regression model to evaluate the relationship between the dependent variable "intensive care unit stay" and the predictor variables that were correlated by a Pearson correlation test. To test the acceptability and strength of the model, analyses of variance was performed and a multiple correlation coefficient R was calculated for the model. RESULTS: Pearson correlation test showed a strong correlation between intensive care unit stay and creatinine (correlation coefficient = 0.34, P = .03), serum sodium (correlation coefficient = -0.42, P < .01), and total bilirubin (correlation coefficient = -0.29, P = .06). Other variables showed no significant correlation, namely correlation coefficients < 0.24 (P > .1). The final model to evaluate the relationship between the dependent variable "intensive care unit stay" and laboratory parameters included ALP, serum creatinine, serum sodium, and total bilirubin as well as a correction for age. CONCLUSIONS: The most significant parameters were total bilirubin, serum creatinine, and serum sodium. The proposal model significantly correlated with the variable "intensive care unit stay." Such data are particularly important since increased intensive care unit stay correlates with a significant reduction in 1-year survival rate. PMID- 17692638 TI - Adult-to-adult living donor liver transplantation using left lobes: the importance of surgical modulations on portal graft inflow. AB - BACKGROUND: Due to the shortage of available cadaveric organs, living donor liver transplantation (LDLT) has been recently applied extensively in adults. The use of the left lobe should be encouraged because of donor safety, but frequently the metabolic requirements of severely cirrhotic patients are great and subsequent graft dysfunction is encountered after transplantation. The importance of increased portal inflow to the graft in previously severely cirrhotic patients and other hemodynamic changes in LDLT using left lobes are still under debate, as are the surgical modulations to correct them. In this study, we have reported an initial series of adult-to-adult LDLT using left lobes, underlining the hemodynamic changes encountered during the transplant and the surgical modulations we applied to correct them. METHODS: Eight adult recipients underwent left lobe liver transplantation from living donors. Portal vein pressure and central venous pressure were measured before and after surgical modulation. RESULTS: We encountered four cases of small-for-size syndrome. Two patients were retransplanted; the other two died. Seventy-five percent of our recipients survived and 50% did not require further surgery. CONCLUSION: Surgical portal inflow modulation should be considered in cases of left lobe liver transplantation between adults. PMID- 17692639 TI - Portal vein arterialization in hepatobiliary surgery and liver transplantation. AB - We reviewed the literature reports and our personal experience on partial portal vein arterialization (PPVA) to prevent and treat acute liver failure (ALF) following major hepatobiliary surgery or another etiology. Experimental studies in rats have assessed the efficacy of PPVA in treatment of ALF induced by extended resections in normal or fatty livers or in toxic carbon-tetrachloride damage. The treated groups showed greater survival and faster recovery of liver function. Among 11 clinical cases reported in the literature, PPVA was performed in four cases to prevent and in seven cases to treat ALF. Eight patients survived, showing rapid recovery of liver function and resolution of the clinical condition. This relatively simple procedure has shown itself able to promote liver regeneration. The PPVA procedure has shown itself to be safe and simple as well as to offer a promising approach to the failing liver. PMID- 17692640 TI - Comparison of two techniques of arterial anastomosis during adult cadaveric liver transplantation. AB - Arterial complications are a major source of morbidity and mortality after orthotopic liver transplantation (OLT). The incidence of hepatic artery thrombosis (HAT) ranges from 1.6% to 8%, with a mortality rate that ranges from 11% to 35%. We have described herein a technique of arterial anastomosis aiming to perform the anastomosis as straight as possible to avoid any kinking, redundancy, or malposition of the artery when the liver is released in its final position. We compared this technique with the traditional technique of arterial anastomosis using an aortic Carrel patch, namely, 198 OLT (group A) with the traditional technique and 117 OLT (group B) with the modified technique. An aorto hepatic bypass was necessary in 25% of the cases in group A and in 21% of the cases in group B (P = .33). Vascular anomalies were present in 20% of cases in group A and in 27.5% in group B (P = .14). Fourteen cases (7%) of HAT developed in group A versus 0 cases in group B (P = .003). In group B, we experienced 2 (1.7%) late arterial stenoses that were successfully treated using percutaneous transluminal angioplasty. The 14 cases of HAT occurring in group A were successfully managed using immediate surgical revascularization with graft salvage in 6 cases (43%), whereas the remaining 8 cases needed urgent retransplantation. We suggest that a technique of arterial anastomosis aimed at avoiding kinking, redundancy, or malposition of the artery may be a viable option to reduce the risk of HAT after OLT. PMID- 17692641 TI - Modified liver hanging maneuver during orthotopic liver transplantation with inferior vena cava preservation: results after 120 consecutive applications. AB - The outflow venovenous anastomosis represent a crucial aspect during orthotopic liver transplantation (OLT) with inferior vena cava (IVC) preservation. The modified Belghiti liver hanging maneuver applied to the last phase of hepatectomy, lifting the liver, provides a better exposure of the suprahepatic region and allows easier orthogonal clamping of the three suprahepatic veins with a minimal portion of IVC occlusion. The outflow anastomosis constructed with a common cloacae of the three native suprahepatic veins is associated with a lower incidence of graft related venous outflow complications. The procedure planned in 120 consecutive OLT was achieved in 118 (99%). The outflow anastomosis was constructed on the common cloaca of the three hepatic veins in 111/120 cases (92.5%). No major complications were observed (bleeding during tunnel creation, graft outflow dysfunction, etc) except in one patient with acute Budd-Chiari, who successfully underwent retransplantation. PMID- 17692642 TI - Activated recombinant factor VII in orthotopic liver transplantation. AB - Orthotopic liver transplantation (OLT) is affected by important alterations of hemostasis. The aim of this study was to evaluate the efficacy of recombinant factor VII activated (rFVIIa) to reduce intraoperative bleeding during OLT. METHODS: Twenty OLT patients were assigned in double-blind way to a rFVIIa group or a control group. Inclusion criteria were hemoglobin > 8 g/dL: INR > 1,5 and fibrinogen > 100 mg/dL. We administered a single bouls of rFVIIa (40 microg/kg) or placebo. We determined INR, partial thromboplastin time, fibrinogen, ATIII, and blood cell counts. Blood products were administered as follows: 4 units of fresh frozen plasma when INR > 1.5, and 1 unit of RBC for Hb < 10 g/dL. The study ended 6 hours after the bolus. RESULTS: No thromboembolic events occurred. The INR was different between rFVIIa group and the controls at T0 (1.9 vs 1.6 P < .021) and during T1 (1.2 vs 1.6 P < .004). The total transfused red blood cells was 300 mL +/- 133 in rFVIIa group and 570 mL +/- 111 in control group (P < .017). The total fresh frozen plasma was 600 mL +/- 154 in rFVIIa group and 1400 mL +/- 187 in control group (P < .001). Total blood loss was greater in the control group than the rFVIIa group: 1140 mL +/- 112 vs 740 mL +/- 131 (P < .049). DISCUSSION: The use of rFVIIa during OLT can reduce the risk of bleeding during surgery. The literature has described cases who did not benefit from the treatment. An adequate cut-off of INR, allowed us to treat only patients at greater bleeding risk. PMID- 17692643 TI - Fenoldopam and gastric tonometry during orthotopic liver transplantation. AB - The aim of this study was to evaluate the effects of continuous infusion of fenoldopam on splanchnic perfusion in orthotopic liver transplant (OLT) recipients. PATIENTS AND METHODS: We enrolled 40 patients of mean age 57+/-16 years who underwent (OLT). They were randomly divided into two double blinded groups; continuous fenoldopam (0.06 mcg/kg per minute) or placebo infusion. Hemodynamics, gastric tonometry, urine output, renal function parameters, and diuretics use were collected during selected phases of the surgery and postoperatively every 12 hours for 72 hours in the intensive care unit. RESULTS: No significant differences were observed between the two groups concerning hemodynamics, though in the fenoldopam group we observed increased splanchnic perfusion during the whole study period but particularly after arterial unclamping (pHi 7,31+/-0.04 vs 7.28+/-0.05; P < .05) and at 48 hours after surgery (pHi 7.49+/-0.15 vs 7.39+/-0.15; P < .05). Creatinine and blood urea nitrogen values were slightly higher in the placebo group, but this data did not reach statistical significance, while higher doses of furosemide were administered to the placebo group to maintain a urinary output over 200 mL/hour during the whole study. DISCUSSION: In this study we observed that continuous fenoldopam infusion (0.06 mg/kg per minute) improved splanchnic perfusion without affecting systemic pressure. CONCLUSION: Patients undergoing OLT have altered splanchnic perfusion related to cirrhosis, surgical manipulation, and fluid shifts during and after surgery. The use of a splanchnic vasodilator drug improved outcomes in these patients. PMID- 17692644 TI - Microbiologic contamination of intraoperative blood salvaged during liver transplantation. AB - Bacterial contamination is one of the potential risks of blood salvage and reinfusion during orthotopic liver transplantation (OLT) because cell-saver machines lack antibacterial protection devices. This study was designed to analyze the potential bacterial contamination of blood salvaged during OLT; a secondary end point was to evaluate whether reinfusion of potentially contaminated blood may have been responsible for clinically manifested infective complications in the same patient. After induction of anesthesia, a blood sample was drawn from the central venous catheter (CVC) immediately after its positioning, to exclude potential coexisting hematic contamination of the recipient. During the procedure, 2 other samples of salvaged blood were collected for bacteriological analysis. Twenty-six of 38 samples of salvaged blood were positive for microorganisms, whereas 12 did not reveal the presence of infectious agents. In 19 of 26 positive samples, Staphylococcus species (73%) were isolated with only 2 of 38 samples drawn from CVC being contaminated. Candida Albicans was cultured in 2 samples. The high percentage (73%) of coagulase-negative Staphylococci indicates that blood contamination could have been caused by microorganisms from the air or suctioned from contact surfaces and the surgical field. Although almost 70% of processed and reinfused units tested positive for microbes, none of the postoperative blood cultures (at day 1 and day 3) revealed growth of the same species, not even in the 2 patients who had positive CVC cultures after induction of anesthesia. PMID- 17692645 TI - Long-term results of liver transplantation for hepatocellular carcinoma: an update of the University of Padova experience. AB - BACKGROUND: Hepatocellular carcinoma (HCC) competes with benign liver disease as indication for liver transplantation (OLT). The aim of this study was to determine long-term results of OLT for HCC. METHODS: We retrospectively analyzed the prognostic role of HCC diagnosis at pathological exam in adult OLT. In the HCC group, we evaluated the prognostic role of the time of diagnosis (incidental versus nonincidental) and of pathological tumor TNM staging. The primary endpoint was 1-, 3-, and 10-year patient survivals. RESULTS: From 1991 to 2006, among 550 adults who underwent first OLT, HCC was found in 120 patients at pathological exam. In 26 cases (22%), the diagnosis of HCC was incidental. There were 59 cases (49%) of pathological T1 to T2 tumor (one nodule < 5 cm, or two to three nodules < 3 cm, without metastases and/or vascular invasion), and 61 cases (51%) of pathologic T3-T4a tumor. HCC diagnosis did not show a significant prognostic impact by Cox survival analysis. After a median follow-up of 31 months, 1-, 5-, and 10-year survivals were 91%, 81%, and 73% in the HCC group, and 84%, 76%, and 67% in the non-HCC group. Time of HCC diagnosis (incidental versus nonincidental) and pathological TNM staging (T1 to T2 vs T3 to T4a) did not result significant survival predictors upon Cox analysis. CONCLUSION: In our experience, the long term results of OLT for HCC overlapped those of OLT for benign disease, although 51% of tumors were T3 to T4a at pathological exam. PMID- 17692646 TI - Outcome after liver transplantation in patients with cirrhosis and hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is considered an optimal indication for liver transplantation (LT) because it may eliminate both the tumor and the underlying liver disease. The present study sought to compare cumulative survival, rate of HCC recurrence, and causes of death among patients with cirrhosis and HCC before and after the adoption of more restrictive criteria (Milan selection criteria) at the time of patient listing. Among 226 adult patients who received an elective liver transplantation between 1999 and 2005, 58 (27%) had a diagnosis of HCC at the time. The 38 patients who underwent transplantation for HCC in the period 1989 to 1998 were considered the "historical group." After LT (mean follow-up, 34 + 28 months), the cumulative survival rate was better among HCC versus non-HCC recipients (93% vs 71% at 1 year and 81% vs 67% at 3 years, respectively; P < .046), although the difference tended to attenuate after 5 years (66% vs 67%, respectively). Tumor recurrence (evaluated in patients surviving at least 3 months after LT) was observed in 10/31 in the historical group versus 4/53 among those who underwent transplantation after 1999. Among the causes of death, recurrence represented 50% in the old series and 23% in patients who underwent transplantation after 1999. Cumulative survival significantly improved among HCC patients who underwent transplantation after 1999 (93% vs 66% at 1 year and 81% vs 50% at 3 years; P < .00001). The 58 patients who underwent transplantation with a diagnosis of cirrhosis and concomitant HCC after 1999 showed even better survival than patients who underwent transplantation for end-stage liver disease without malignancy. PMID- 17692647 TI - Superiority of transplantation versus resection for the treatment of small hepatocellular carcinoma. AB - The best therapy for hepatocellular carcinoma (HCC) is still debated. Hepatic resection (HR) is the treatment of choice for single HCC in Child A patients, whereas liver transplantation (OLT) is usually reserved for Child B and C patients with multiple nodules. The aim of this study was to compare HR and OLT for HCC within the Milan criteria on an intention-to-treat basis. Forty-eight patients were treated by OLT and 38 by HR. Three- and 5-year patient survival rates were significantly higher (P = .0057) in the OLT group (79% and 74%) than after HR (61% and 26%). The 3- and 5-year disease-free survival rate was better (P = .0005) for OLT (74% and 74%) versus HR (41% and 11%). The probability of HCC recurrences after resection was greater (P = .0002) than after transplantation, achieving 31% and 76% for HR and 2% and 2% for OLT at 3 and 5 years after surgery. The median waiting list time was 118 days; two patients dropped out for HCC progression. We concluded that OLT is superior to HR for small HCC in cirrhotic patients assuming that OLT can be performed within 6 to 10 months after listing to reduce dropouts due to tumor progression. PMID- 17692648 TI - Hepatitis C virus-related cirrhosis as a significant mortality factor in intention-to-treat analysis in liver transplantation. AB - INTRODUCTION: Liver transplantation represents the gold standard for the treatment of chronic liver disease. The whole transplantation process was assessed using an intention-to-treat analysis and considering patients from the time of their inclusion on the list and throughout lengthy follow-up. MATERIALS AND METHODS: From January 1, 1999 to June 1, 2004, 373 adults joined the waiting list for liver transplantation at our institution. The main variables analyzed were: age, gender, etiology, Model for End-stage Liver Disease score, Child-Pugh class, United Network for Organ Sharing (UNOS) status. Global survival was evaluated using intention-to-treat analysis from the time of patient inclusion in the list to the end of their late follow-up. RESULTS: The median waiting time was 20 months (range 0.1 to 70.2). By univariate analysis, the variables significantly influencing survival when patients joined the waiting list were: encephalopathy; ascites, poor nutritional status, Child-Pugh class C, UNOS 2, hepatitis C virus (HCV) and bilirubin > 2 mg/dL. By multivariate analysis, only HCV-related cirrhosis emerged as having an independent prognostic value. By intention-to-treat analysis, the 5-year survival rate was 67% and 79% for HCV positive and HCV-negative patients, respectively (P = .0003). CONCLUSIONS: HCV related cirrhosis is an independent prognostic factor for survival according to an intention-to-treat analysis. Different inclusion criteria or treatments while on the waiting list and after transplantation need to be considered in the future for HCV-positive patients. PMID- 17692649 TI - Selective bilirubin removal by plasma treatment with Plasorba BR-350 for early cholestatic graft dysfunction. AB - Early cholestatic graft dysfunction is a frequent cause of morbidity after orthotopic liver transplantation (OLT). We analyze the role of selective bilirubin plasma absorption (PAP) using Plasorba BR-350 in 4 OLT patients who had experienced early severe cholestatic graft dysfunction within 15 days after transplantation. Patients were treated with 3 consecutive cycles of PAP with Plasorba BR-350. The median amount of plasma treated was 7500 mL. Median treatment duration was 231 minutes. The average plasma bilirubin level was 37 +/- 1 mg/dL before PAP and decreased to 15 +/- 0.2 mg/dL at the end of the third cycle of PAP; 3 of 4 cases had progressive bilirubin normalization after PAP. The average amount of bilirubin removed from the plasma of the patients during each PAP treatment was 143 +/- 24 mg. At the beginning of each cycle of PAP, the Plasorba BR-350 was able to remove >90% of the total plasma bilirubin, a percentage that decreased to 60%, 50%, and 40% after 2 L, 4 L, and 7 L of plasma were treated, respectively. Liver biopsies performed after the third treatment showed reduced cholestasis when compared with the pretreatment biopsy specimen. The preliminary data suggested that PAP selective for bilirubin removal may not only reduce the bilirubin level, but may also improve the histological pattern of the graft in terms of reduced cholestatic signs. PMID- 17692650 TI - Prognostic impact of model for end-stage liver disease score in patients undergoing liver transplantation with suboptimal livers. AB - BACKGROUND/AIMS: The aim of this retrospective study is to analyze the prognostic impact of Model for End-Stage Liver Disease (MELD) score in patients undergoing liver transplantation (OLT) with suboptimal livers. METHODS: Between January 2002 and January 2006, 160 adult patients with liver cirrhosis received a whole liver for primary OLT at our institution including 81 with a suboptimal liver (SOL group) versus 79 with an optimal liver (group OL). The definition of suboptimal liver was: one major criterion (age >60 years, steatosis >20%) or at least two minor criteria: sodium >155 mEq/L, Intensive Care Unit stay >7 days, dopamine >10 microg/kg/min, abnormal liver tests, and relevant hemodynamic instability. RESULTS: Baseline recipients characteristics were comparable in the two study groups. The SOL group had a significantly greater number of early graft deaths (<30 days) than the OL group, while the 3-year Kaplan-Meier patient survivals were similar. Using logistic regression, MELD score was significantly related to patient death only in the SOL group (P = .01), and the receiver operator characteristics curve method identified 17 as the best MELD cutoff with the 3 year survival of 93% versus 85% for MELD < or =7 versus >17, respectively (P > 05). In comparison, it was 94% and 72% in the SOL group (P < .05). Similarly, MELD >17 was significantly associated with early graft death rates only in the SOL group. CONCLUSION: This study advised surgeons to not use suboptimal livers for patients with advanced MELD scores, thus supporting a donor-recipient matching policy. PMID- 17692651 TI - Medical report type in liver transplantation as a quality system document: new prospects for computerization. AB - The usage of a computerized system to organize data and ease the activity procedures of liver transplantation is useful in clinical transplantation. Preliminary cognitive research on systems of clinical transplantation database concerning medical reports was performed to verify their development level. The survey highlighted that, so far, there has been no experimentation that can be applied to a medical report type devoted to liver transplantation. Regulations in force substantially point out that the medical report ought to contain all items that have to be taken into account in handling the patient from pretransplantation to follow-up. The Department of Transplantation of Genoa chose its medical report model for liver transplantation. The medical report model included the following items: personal data; case history; diagnosis; initial examination for prelisting; fitness for transplantation; assistance context; clinical data including subjective, objective, and instrumental parameters; pharmacological therapies; informed consent, evaluation of fitness; nursing data; counseling and clinical evaluations according to protocols and guidelines of the national transplantation centers. If the computing is well trained, it is supposed to help maintain a whole data view provided it is supplied information in an adequate way. Immediate clinical procedural advantages and useful scientific observations may be obtained from a high-quality database. In fact, all functions have to be applied to specific clinical, administrative needs to be remotely shared and conveniently integrated with each other to make the liver transplantation medical report an easy and handy instrument for inputting and handling data. It must be a precise, complete instrument that may be accessible in real time from any site connected with the intranet network, be unchangeable, and be protected to ensure certification and forensic medicine value. PMID- 17692652 TI - Application of a Bayesian simulation model to a database for split liver transplantation on two adult recipients in the environment of WinBUGS (Bayesian Inference Using Gibbs Sampling). AB - A Bayesian simulation model has been applied to a database developed for split liver transplantation on two adult recipients (SLT A/A) in the context of a macroregional project funded by the Italian Ministry of Health. The model was entered within Bayesian inference Using Gibbs Sampling (WinBUGS), a free software for Bayesian analysis of complex statistical models using Markov chain Monte Carlo techniques developed by the MRC Biostatistics Unit Cambridge jointly with the Imperial College School of Medicine at St Mary's, London. The model was built by using data entry performed from January 1, 2005 to August 5, 2005. In that period, 20 potential donors suitable for the SLT A/A procedure were entered into the database. We only selected the continuous and dichotomous donor-related variables (DRV, n = 62) for which almost one data entry procedure. The model assumed that a database user learned during data entry procedures for each donor, and that the probability of a successful input may depend on the number of previous errors and corrections. After binary transformation of the DRV (value 0 for each input record, value 1 for each no input record), we calculated an overall value of 0.28 +/- 0.27 (median: 0.3; 95% confidence interval: from 0.18 to 0.629). The transformed DRV were entered within the WinBUGS environment after model specification, assuming as success (y = 1) each procedure of input record, and as failure (y = 0) each procedure of no input record. A unequivocal convergence was obtained after 10,000 iterations, and a simulation run was launched for a further 10,000 updates. We obtained a negligible Monte Carlo error and a fine profile in the kernel density plot. This study supported the application of simulation models to databases concerning liver transplantation as a useful strategy to identify a critical state in the data entry process. PMID- 17692653 TI - A preliminary data entry analysis on a multicentric informative system for split liver transplantation in two adult recipients. AB - In the context of the national research program "Innovative Strategies to Expand Cadaveric Donor Pool for Liver Transplantation" (SITF project), funded by the Italian Ministry of Health, an experimental and multicentric Web-based information system was developed to automate theoretical matching between a potential donor and two adult recipients for in situ split liver transplantation (SLT A/A). Data entry in the SITF database was performed in addition to activities formally required for patient and donor management by national legislation and guidelines. Data entry carried out within the SITF database from January 1, 2005 to August 8, 2005 was processed by stratifying original variables as donor- and patient-related. Only records required for donor-recipients matching had a mandatory data entry. The donor subset showed data entry procedures in 62 variables for 20 potential donors, whereas in the patient subset, we found 28 variables for 100 potential liver recipients. In the donor subset, 1004 records were filled, for a raw completeness of 77.08%. After adjustment for appropriateness, there were 935 remaining records with an adjusted completeness of 76.64% (P = .823). In the patient subset, 2653 records were filled, for a raw completeness of 98.69%. No difference in patient subset records was found after rechecking for appropriateness. A significant difference occurred for adjusted completeness between the donor versus the patient subsets (P < .0001). The results of this study suggested that only the presence of mandatory donor records may produce a consistent database suitable for SLT A/A. PMID- 17692654 TI - Split liver network: a collaborative internet-based scenario to expand the organ pool. AB - BACKGROUND: Split liver transplantation (SLT) has become a crucial option to maximize the liver pool, while organ procurement organizations (OPOs) usually allocate whole livers to single centers. In 2003, Italian Ministry of Health funded the Innovative Strategies to Expand Cadaveric Donor Pool for Liver Transplantation project with the goal to establish sharing criteria for SLT for two adults (SLT A/A), involving Italian transplantation centers, the North Italy Transplant OPO, and the Italian National Transplant Center. METHODS: SITF group defined donor/recipient inclusion criteria, setting minimum graft/recipient weight ratio (GRWR) at 1.2%. Donors and recipients on waiting list were shared on an Internet secured Web-based application (Split Liver Network [SLN]). SLN performs real-time matches between the registered donor and all patients on the bases of GRWR, displaying a size-based list of matched donor/patients, figuring hemiliver allocation once the whole organ is referred to a specific center. RESULTS: In the 2005 period, 47 donors and 124 patients were entered by nine centers, and six hemiliver allocations for three SLT A/A procedures were performed. By retrospective simulation of 32 donors and 613 recipients in the Nord Italia Transplant area, matchable recipients were available for all donors, while blood group frequency seemed a determining factor, more than donor body weight. COMMENTS: SLN hemiliver allocation might increase matching possibilities, offering a timely transplant for recipients of rare group, small-size, or in need of short wait. Our experience suggests that such an environment may be helpful to share a macroregional pool of liver recipients and to optimize SLT. PMID- 17692655 TI - Application of the RAND/UCLA appropriateness method to evaluate an informative system for liver transplantation in adult and pediatric recipients. AB - The Delphi Method (DM) is the most frequently used technique to acquire structured expert-opinion elicitation (EOE). It has been increasingly applied to construct guidelines in medicine and to evaluate the appropriateness of clinical procedures. In this study, the RAND/UCLA appropriateness method was used as a structured EOE process to evaluate the appropriateness of a dataset concerning liver transplantation in adult and pediatric recipients for an information system funded by the Italian Ministry of Health. The original dataset was obtained using an interdisciplinary pool of regional experts (n = 60). This dataset held 280 items stratified into three groups: I. pretransplant items (n = 123); II. transplant items (n = 65); III. early posttransplant and follow-up items (n = 92). In the second DM round, the dataset was subjected to an extraregional panel of independent experts (n = 9) to assess a score ranging from 1 to 9 on each item based on increasing appropriateness, according to the RAND/UCLA Appropriateness Method. Overall agreement, uncertainty, and disagreement between experts was 95.89%, 3.12%, and 0.99%, respectively. For each group, agreement-uncertainty disagreement were 99.35%/0.65%/0% (group I), 91.53%/5.30%/3.17% (group II), and 96.87%/3.13%/0% (group III), respectively. This study supported the use of a structured EOE process to evaluate the appropriateness of a large dataset for liver transplantation activity. PMID- 17692656 TI - Sirolimus monotherapy in liver transplantation. AB - INTRODUCTION: Since 1999, a new immunosuppressive drug was administered to renal transplant patients. The SRL molecule acts by blocking post-receptor signal transduction of interleukin-2 (IL-2) interacting with a family of intracellular binding proteins termed immunophilins FKBPs. Among these FKBPs, FK506 12-kd binding protein is the most relevant. SRL is an immunosuppressive drug. Therefore it can inhibit the immune system; at the same time the drug is not nephrotoxic, neurotoxic, and without diabetogenic effects. METHODS: Among 285 patients who underwent liver transplantation, 27 took Sirolimus as monotherapy. Immunosuppressive treatment upto cyclosporine (CsA) or tacrolimus (FK) associated with steroids (methylprednisolone) and mycophenolate Mofetil (MMF) was initiated among subjects with pre-transplant renal failure. SRL was administered as monotherapy for patients who developed nephrotoxicity, or neurotoxicity, or diabetes. Moreover, patients affected by multifocal HCC who did not meet the Milan criteria or patients who developed Kaposi's Sarcoma were prescribed SRL monotherapy. RESULTS: Nephrotoxicity occurred in 14 patients with mean serum creatinine level 2.2 mg/dl. Eleven patients with real failure showed significant improvements after a mean period of 28 days of SRL monotherapy (range: 6-45 days). The mean creatinine serum level after treatment with SRL monotherapy was 1.0 mg/dl (range: 0.7-1.2 mg/dl). Neurotoxicity occurred in 4 patients with tremor, confusion, and agitation. Each patient had complete improvement of symptoms after a few days of Sirolimus monotherapy. Among Three patients who developed Kaposi's Sarcoma, two underwent remission. One patient had diabetes due to calcineurin inhibitors, and one showed arterial hypertension not treatable with drugs. After the switch, we treated these patients with medications. Another important indication was HCC not meeting the Milan criteria. CONCLUSION: SRL monotherapy may be used to manage complication of calcineurin inhibitors or Kaposi's Sarcoma. PMID- 17692657 TI - Combined liver and kidney transplantation: analysis of Padova experience. AB - BACKGROUND/AIM: The main indications for combined liver and kidney transplantation (CLKT) are as follows: (1) cirrhosis with renal damage dependent or not upon liver disease, (2) renal failure with dialysis and concomitant liver end-stage disease, (3) congenital diseases, and (4) enzymatic liver deficiency with concomitant renal failure. The aim of this study was to evaluate our results with CLKT both in adult and pediatric patients. METHODS: From September 1995 to September 2006, 15 CLKT (2.8%) among 541 liver transplantations included 4 pediatric patients (27%). The main indications for CLKT were hepatitis C virus (HCV) and polycystic diseases in adult patients, and primary hyperoxaluria in pediatric patients. RESULTS: The double transplantation was performed from the same donor in all cases. All adult patients received whole liver grafts, whereas 3 split transplants and 1 whole liver graft were transplanted in the pediatric patients. Median liver and kidney cold ischemia times were 468 and 675 minutes, respectively. After a median follow-up of 36 months (range, 1-125), the overall survival rate was 80%. Five-year patient and graft survival rates were 100% for adult CLKT, whereas they were 50% for pediatric patients. We observed only 2 cases (18%) of delayed renal function, requiring temporary hemodialysis with progressive graft improvement. There was only 1 case of kidney retransplantation due to early graft nonfunction in a pediatric patient. CONCLUSION: Although CLKT is related to major surgical risks, results after transplantation are satisfactory with an evident immunological advantage. PMID- 17692658 TI - Liver transplantation in HIV-positive patients. AB - AIMS: The aim of this study was to evaluate the feasibility of liver transplantation (OLT) in human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfected patients in Italy. METHODS: Between September 2002 and April 2006, 12 HIV(+) coinfected patients (11 men, mean age 42 years) underwent OLT at our Institute. Eleven (91%) patients were HCV-positive and one was hepatitis B virus-positive. Pre-OLT plasma HIV 1-RNA level was undetectable and CD4(+) T-cell count >200 cells/microL for 3 months in all patients. Six patients had to stop highly active antiretroviral therapy (HAART) before OLT because of liver disease severity (n = 2) and for hepato cellular carcinoma (n = 4). RESULTS: The actuarial 1-, 2-, and 3-year survival rates were 83.3%, 58.3%, and 58.3%, respectively, which were significantly lower than those observed among HIV negative patients transplanted in our center. Six patients are alive with a mean follow-up of 26 months (range: 5 to 46 months). We recorded a low rate of opportunistic infections and rejection. All alive patients have low levels of HIV RNA, and the CD4(+) T-cell counts increased after OLT. Nine patients developed early recurrence of hepatitis C requiring combination therapy with peg-interferon plus ribavirin. Significant improvement in the quality of life was observed in 7/11 patients. CONCLUSIONS: OLT in HIV-positive patients was feasible with good results in the short and medium term. Early severe HCV recurrence may be observed. Key challenges for the management of HIV(+) patients after transplantation included treatment of severe HCV recurrence and attention to the pharmacological interactions of HAART with immunosuppressive drugs. PMID- 17692660 TI - Endoscopic treatment of bile duct complications after orthotopic liver transplantation. AB - AIM: To assess the indications and results of endoscopic retrograde cholangio pancreatography (ERCP) in patients who have undergone ortotopic liver transplantation (OLT). METHODS: We reviewed data from 42 consecutive patients who underwent ERCP for biliary complications after OLT over an 8-year period, in particular recording indications and success of the treatment after a mean of 17 months follow-up. RESULTS: Cholangiograms performed in 33/42 patients (79%) displayed anastomotic strictures in 17 patients (52%), bile duct stones in 8 (24%), both bile duct stones and an anastomotic stricture in 2 (6%), papillary stenosis in 1 (3%), and anastomotic biliary leakage in 1 (3%). In contrast, the contrastogram was normal in four patients (12%). Stone extraction was completed in 9/10 patients (90%) with a mean of 1.2 sessions, while stricture dilation was achieved in 12/19 patients (63%) after a mean of 1.7 sessions, by stent positioning (n = 7), balloon dilation (n = 4), or Soehendra dilator (n = 1). Both biliary leakage and papillary stenosis were cured by ERCP. Only one procedure related complication -- severe pancreatitis (2.4%) -- was observed and no mortality. CONCLUSION: ERCP is a safe and effective mode of management of bile duct complications after OLT. It should be attempted before a surgical approach. Better results are obtained for treatment of biliary stones than of anastomotic strictures. PMID- 17692659 TI - Pediatric liver transplantation: the University of Padua experience. AB - OBJECTIVE: The objective of this study was to analyze experience on pediatric liver transplantation (LT) between June 1993 and September 2006, including split liver transplantation (SLT), living donor liver transplantation (LDLT), and auxiliary partial orthotopic liver transplantation (APOLT). Furthermore, hepatocyte transplantation (HT) had a role in one patient with metabolic disease. METHODS: From November 1990 to September 2006, 657 LTs were performed including 63 pediatric LTs (9.6%) in 57 patients (32 boys and 25 girls). Six were retransplantations (9.5%). Thirty-two patients (57%) were younger than 5 years. The types of graft included the following: 26 whole organs (41%), 32 in situ split organs (51%), 4 reduced-size organs (6%), and 1 graft from a living donor (2%). Two patients received an APOLT, 4 patients received a combined kidney-liver transplantation (CKLT), and 1 patient received HT. Of the 63 pediatric LTs, 16 were behaved to be highly urgent (25%). RESULTS: Overall 1-, 3-, 5-, and 10-year patient survival rates were 82%, 82%, 78%, and 78%, respectively. Overall 1-, 3-, 5-, and 10-year graft survival rates were 76%, 76%, 72%, and 72%, respectively. In patients younger than 1 year, the 5-year survival rate was 100%. Perioperative mortality was 8.8%. Vascular complications occurred in 4 patients (6.3%). Six children required retransplantation due to primary nonfunction (PNF) in 4 cases (7%) and vascular thrombosis in 2 cases (3.5%). CONCLUSIONS: Cholestatic liver disease and age younger than 1 year were the best prognostic factors for excellent survival. PMID- 17692661 TI - Acute renal failure after liver transplantation in MELD era. AB - Model for End-Stage Liver Disease (MELD) score was used in our center from 2003 to assess the position of orthotopic liver transplantation (OLT) candidates on a waiting list. A key component of MELD score in the assessment of the degree of the illness is renal function. In this study, we measured the effects of this new scoring system on renal function and therapeutic strategies. We evaluated the incidence of acute renal function (ARF) after OLT requiring renal replacement therapy (hemofiltration or hemodialysis) in two patient groups: 240 transplanted before MELD era and 224 after the introduction of this parameter to select candidates. ARF occurred in 8.3% of patients in the pre-MELD group versus 13% in the MELD group, while the mortality rates were 40% and 27%, respectively. The creatinine level before OLT seemed to be a good predictor of ARF (P < .001), and blood transfusion rates (P < .05) as well as intraoperative diuresis (P < .05). In our analysis we did not observe a correlation between MELD score and postoperative ARF. PMID- 17692662 TI - Gram-positive bloodstream infections in liver transplant recipients: incidence, risk factors, and impact on survival. AB - The objective of the study was to assess the incidence, risk factors, and survival of gram-positive bloodstream infections (GP-BSI(s)) among liver transplant recipients during the first year after transplantation. Between October 2000 and September 2006, 42 episodes of GP-BSI(s) occurred in 205 patients with an overall incidence of 0.20 episodes/patient. Coagulase-negative staphylococci were detected in 45.2% of cases, Enterococcus species in 42.9% (E faecalis, eight; E faecium, seven; E avium, two; E gallinarum, one) and Staphylococcus aureus in 11.9%. Retransplantation was the only independent risk factor for GP-BSI (odds ratio [OR], 0.253; 95% confidence interval (CI), 0.089 to 0.715; P = .009). Thirty-day mortality rate was 28.5% and S aureus infections were related to a poorer outcome. It is noteworthy that all the isolates of S aureus were methicillin-resistant. Ampicillin was inactive against all the strains of E faecium and 50% of E avium isolates, but active against all E faecalis and E gallinarum strains. All the isolates were glycopeptide susceptible. No significant differences in mortality rate were observed in relation to sex, etiologies of end-stage liver disease, cytomegalovirus infection/reinfection, type of donor, rejection, or retransplantation. GP-BSI, the only independent risk factor for death (OR, 0.262; 95% CI, 0.106 to 0.643; P = .003), reduced the survival rate by 26% in the first year posttransplant. In conclusion, GP-BSI(s) impact significantly on morbidity and mortality posttransplant, particularly among retransplantations. Control measures are required to reduce the incidence of GP-BSI(s) in liver transplant recipients. These findings must be considered when empirical antimicrobial therapy is indicated while awaiting blood-culture results. PMID- 17692663 TI - Incidence and timing of infections after liver transplant in Italy. AB - BACKGROUND: Infections are one of the main complications that cause high morbidity and mortality in transplant recipients. This study sought to estimate the incidence of infections and their main determinants in liver transplant recipients in the first year after transplantation. PATIENTS AND METHODS: A prospective study was conducted on 103 consecutive patients (72% men) who underwent transplantation in three centers in Northern (Bologna) and Central (Rome) Italy in 2005. Person-years (PY) at risk, incidence rates (IR), IR ratios and 95% confidence intervals were computed for viral, fungal, and bacterial infections. RESULTS: The 103 patients (median age 55 years) contributed a total of 78.2 PYs, with a median follow-up of 286 days (interquartile range: 194 to 365 days). Fifty-eight patients (56.3%) experienced one or more infections, namely, 151 events (IR = 193.2 infections/100 PYs). IR for bacterial, fungal, and viral infections were 110.0, 56.3, and 26.9 infections/100 Pys, respectively. Within the first 30 days after transplantation, 37.9% patients (39/103) developed one or more events. Bacterial infections represented the most frequent event (86/151, 57.0%). Risk factors significantly associated with increased IR were gender (female), age (>50 years), prolonged intensive care stay volume of blood transfused during surgery and posttransplant, and need for retransplantation. CONCLUSIONS: These preliminary results showed the relevance of infectious events after liver transplantation especially those of bacterial etiology, and identified factors mainly associated with their occurrence. PMID- 17692664 TI - Clinical effects of use polymyxin B fixed on fibers in liver transplant patients with severe sepsis or septic shock. AB - Polymyxin B (PMX-B) is a polycationic antibiotic, known to bind the lipid A portion of endotoxin, a cell wall component exclusively found in gram-negative bacteria (GNB). An extracorporeal hemoperfusion device (TORAYMYXIN) has been developed: PMX is covalently bound to the surface of an insoluble carrier material to inactivate endotoxin in blood without exerting toxicity on the brain or the kidney. The aim of this study was to evaluate the efficacy, safety, and clinical effects of direct hemoperfusion with an immobilized polymyxin B fiber column (DHP-PMX) among liver transplant patients with severe sepsis or septic shock. METHODS: From June 2004 to May 2005, 10 patients (6 men and 4 women) of overall mean age of 55 years (46-65 range) underwent orthotopic liver transplantation (OLT) and developed severe sepsis or septic shock according to The Consensus Conference of American College Physicians/Society of Critical Care Medicine (ACCP/SCCM) criteria. GNB were detected in all treated patients who received conventional antibiotic therapy, vasopressor or inotropic agents, and ventilatory support. The DHP-PMX treatment was performed three times in each patient. Hemodynamic and respiratory parameters and dosages of vasopressor or inotropic drugs were assessed at baseline and after each treatment. RESULTS: No adverse events occurred. From baseline to the third treatment the mean arterial pressure increased from 64 +/- 5 mm Hg to 89 +/- 4 mm Hg); while the dosages of dobutamine and norepinephrine were reduced: 6.4 to 1 mcg/kg/min and 1.3 to 0.001 mcg/kg per min, respectively. The PaO(2)/FiO(2) ratio increased: 214 to 291 mm Hg. CONCLUSION: The use of DHP-PMX may be an important aid in patients with sepsis in association with conventional therapy. PMID- 17692666 TI - Heart transplantation in older candidates. AB - Over the last few years significant changes have occurred in both donor and recipient profiles for heart transplantation (HTX). New therapeutic approaches to chronic heart failure have created a novel class of patients aged between 61 and 70 years. Although they are older than the conventional upper limit, they may undergo HTX using marginal donors. We retrospectively reviewed the outcomes of suboptimal donor implants in older recipients to examine negative prognostic factor. METHODS: Among 272 patients who underwent HTX at our institution from May 1994 to December 2005, 75 (26.5%) were 61 to 72 years (group 1). The remaining 197 (73.5%) denoted as group 2 ranged in age from 18 to 60 years. The Sex distribution, cause of end-stage heart failure, preoperative pulmonary hypertension, pre-HTX clinical status and mean follow-up did not show any significant difference between the two groups. However, group 1 patients had their organs retrieved from marginal donors (89%) vs group 2 (29%; P < .005). They were deceased mainly due to cerebrovascular events, (namely, 82% vs 27%, respectively, P < .005). RESULTS: All analyzed variables-actuarial survival, perioperative mortality, 12-month acute rejection freedom, 100-month chronic rejection freedom, infection freedom, neoplasia freedom, chronic renal failure freedom-did not show any significant difference. CONCLUSION: Advances in chronic heart failure medical therapy have generated a new class of HTX candidates aged between 61 and 70 years who benefitted from transplantation of organs retrieved from suboptimal donors. PMID- 17692665 TI - Posttransplant lymphoproliferative disorders after liver transplantation: analysis of early and late cases in a 255 patient series. AB - We reviewed the incidence and the impact of posttransplant lymphoproliferative disorders (PTLDs) on patient survival among a consecutive series of 255 patients. Five cases of PTLD were observed in adults: two cases were early (less than 1 year) and three cases, late lymphomas. The EBV positivity and the degree of immunosuppression were the main risk factors. We labeled cases as early or late according to whether the time elapsed from the transplant to the first clinical evidence of PTLD was less than 12 months. The median time from transplant to diagnosis of PTLD was 8 (early) and 108 (late) months. All cases were treated by reduction in immunosuppressive therapy with conventional chemotherapy and rituximab. The early cases with lymphoma located at the hepatic hilum died due to local complications (biliary sepsis and hemobilia), after an initial partial response to chemotherapy. The three patients with late cases are in remission after a mean follow-up of 23 months. PMID- 17692667 TI - Possible role of everolimus in improving renal function in long-term heart transplantation. AB - Patient survival after heart transplantation has improved dramatically since the availability of calcineurine inhibitor (CNIs); the number of long-term patients is progressively increasing. However, in these patients, nephrotoxicity of CNIs has been largely responsible for the progressive development of renal dysfunction. Since impaired renal function is an important issue that reduces long-term patient survival, it is important to develop strategies to improve renal function while maintaining immunologic safety to preserve graft function. Everolimus is an mTOR inhibitor sirolimus analogue, that has proved, to be highly efficacious to prevent acute myocardial rejection and reduce the severity of cardiac allograft vasculopathy in de novo HTx patients. There is reasonable evidence that, in long term heart transplanted patients, renal function may improve when everolimus is administered associated with a progressive reduction of CNIs. So far there is no evidence to identify which patient may benefit from this therapeutic approach. Indeed everolimus alone may be equally effective to prevent rejection and improve renal function when CNIs are completely discontinued, but data are still lacking on the risks, dosages and side effects of this type of immunosuppression. Ongoing clinical studies will provide further guidance about the possibility to halt or reduce the progression of renal impairment in long term heart transplant patients. PMID- 17692668 TI - Prevalence of substance-related disorders in heart transplantation candidates. AB - Substance abuse cessation is one of the leading factors in determining the eligibility for the heart transplantation waiting list, as noncompliance with this issue may seriously endanger posttransplantation outcomes. Yet, the prevalence of substance-related disorders among candidates for heart transplantation has not been evaluated enough. Eighty three heart transplantation candidates were assessed for prior or current substance-related disorders through the Structured Clinical Interview for mental disorders according to DSM-IV. A prior history of at least one substance-related disorder was found in 64% of patients, with nicotine dependence as the most prevalent diagnosis (61.4% of the sample). Ten subjects were currently smokers, despite heart failure. A prior history of alcohol abuse and caffeine intoxication was found in 9.6% and 2.4% of patients, respectively. Substance abuse or dependence behaviors should be monitored during all the phases of heart transplantation program. Early identification of current substance-related disorders may allow better allocation of organ resources and proper lifestyle modification programs provision. A prior history of substance-related disorders should alert physicians to assess patients for possible relapse, especially after transplantation. The inclusion of a specialist in the assessment and treatment of substance-related disorders in the heart transplantation unit may reduce the risk of unsuccessful outcomes due to noncompliance with an adequate lifestyle. PMID- 17692669 TI - Surgical treatment of posttransplant bronchial stenoses: case reports. AB - BACKGROUND: Bronchial stenoses are still a frequent complication after lung transplantation. The stenosis usually involves the anastomotic site, but rarely a distal site. The first choice treatment is an endoscopic balloon dilatation, laser ablation, and stenting. Unrelenting strictures may require an open surgical approach. MATERIALS AND METHODS: Between 1995 and 2006, 154 patients underwent lung transplantation, including 134 who survived the perioperative period and were followed to evaluate the incidence of bronchial stenosis. Among 219 anastomoses at risk, 13 (5.9%) stenoses occurred in 11 patients. Conservative endoscopic management was effective for eight patients, but a surgical approach was necessary for three patients with segmental distal stenosis. RESULTS: One patient received a lower sleeve bilobectomy; one patient, wedge bronchoplasty of the bronchus intermedius; and another patient, an isolated sleeve resection of the bronchus intermedius. All patients had good outcomes with resolution of stenosis. CONCLUSIONS: Although rare, the surgical approach for bronchial strictures after lung transplantation is a good option. Parenchyma-sparing techniques are feasible and effective. PMID- 17692670 TI - Anesthetic concerns in lung transplantation for severe pulmonary hypertension. AB - Lung transplantation has become a consolidated treatment for patients with severe pulmonary hypertension (PH). Several difficulties are encountered during the procedure in such candidates, who are still recognized as more severely affected by perioperative morbility and mortality than those undergoing lung transplantation for other diseases. Right ventricular (RV) enlargement with tricuspid regurgitation, small left ventricle (LV) with an asymmetric hypetrophic wall, interventricular septal shift toward the left, with ventricular stiffness and diastolic incompetence, are typical preoperative echocardiographic findings of end-stage PH. A smooth induction and tracheal intubation will help prevent hypertensive crisis in highly susceptible candidates. Uncompensated vasodilatation or myocardial depression caused by anesthetics and mechanical ventilation may be responsible for acute RV dysfunction associated with low systemic blood pressure. Resuscitation and emergency adoption of cardiopulmonary by-pass (CPB) has been described for near-fatal anesthesia induction. Cardiovascular instability can develop after institution of one-lung ventilation and pulmonary artery clamping. An acute increase in pulmonary pressure results in a decrease in RV ejection fraction and then in acute RV failure. Interdependence of the right and left ventricles occurs such that RV function can alter LV function. Early detection of impending circulatory and/or respiratory deterioration is warranted to prevent an irreversible decline in cardiac output, resulting in hazardous cardiac arrest. Inhaled nitric oxide represents the first choice for treatment of PH and RV failure associated with systemic hypotension during lung transplantation. Intraoperative situations requiring CPB must be identified before development of systemic shock, which represents a late ominous sign of RV failure. PMID- 17692671 TI - Transesophageal echocardiography during lung transplantation. AB - Transesophageal echocardiography (TEE) is a semi-invasive monitoring technique increasingly used in cardiac surgery and in major noncardiac surgery for patients with known or supposed cardiac or coronary problems. During lung transplantation (LTx), the close interrelation between heart and lung function makes TEE an invaluable tool for instantly monitoring the physiopathological situation in the subsequent steps of the intervention. In patients scheduled for LTx, induction of anesthesia could be a dangerous moment with the possibility of cardiogenic shock if pulmonary hypertension (PH) exists; pneumatic tamponade is also possible in patients with emphysema caused by alpha(1)-antitrypsin deficiency, with subsequent cardiac insufficiency. One-lung ventilation is a critical phase during LTx; hypoxemia resulting from ventilation of a diseased dependent lung could impair heart oxygenation, particularly if tachycardia is present. Clamping of the pulmonary artery before pneumonectomy could exacerbate cardiac afterload, especially in patients with previous PH. High transmural pressure, linked with low systemic pressure, makes right ventricle (RV) perfusion pressure inadequate. Hypoxemia and PH are the most frequent causes of intraoperative RV decompensation. In this special setting, TEE is irreplaceable in informing the anesthesiologist about the correct time for extracorporeal oxygenation. Lung reperfusion brings with it the possibility of coronary gaseous embolism, easily detected with TEE. After LTx, TEE can be used to detect strictures, thrombi, or permeability of pulmonary venous anastomoses. To summarize, intraoperative TEE during LTx contributes to the immediate recognition of critical events and allows for rapid therapeutic interventions. PMID- 17692672 TI - Malignancies following lung transplantation. AB - During the last 2 decades, long-term survival after lung transplantation has significantly improved. However, among the complications related to the continuous administration of immunosuppressive drugs, malignancy plays an important role. We retrospectively revisited our series of patients to report our experience. From January 1991 we performed 134 lung transplantations in 128 recipients (mean age, 33.4 +/- 13.5 years). In all patients the first-line immunosuppressive regimen was based on a calcineurin inhibitor (cyclosporine or tacrolimus), an antimetabolic agent (azathioprine), and steroids. Five patients (4.2%) developed malignancy and the mean time of occurrence after the transplantation was 46.4+/-23 months. The mean age was 41 +/- 16 years (P = not significant [ns]). The tumors were as follows: laryngeal cancer (radiotherapy), colon cancer (surgery plus adjuvant chemotherapy), gastric cancer (surgery plus adjuvant chemotherapy), endobronchial non-Hodgkin lymphoma (NHL) (endoscopic resection plus chemoradiotherapy), and cutaneous and visceral Kaposi's sarcoma (KS) (chemotherapy). All patients have reduced the dose of immunosuppressive drugs; in 1 of them, tacrolimus was changed to rapamycin. Two patients died because of neoplastic dissemination, another 1 due to obliterans bronchiolitis. The 2 patients with NHL and KS are alive at 6 and 9 months, respectively, without signs of recurrence. Malignancies after lung transplantation represent an important problem. A multidisciplinary approach is mandatory to obtain satisfactory results in terms of improved quality of life and long-term survival. PMID- 17692674 TI - Coping strategies in intestinal transplantation. AB - The psychological construct of coping has been studied extensively in other medical populations and has more recently been applied in the field of transplant psychology. Coping can be defined as all abilities used by people to face problematical and stressful situations, as the data in literature describe the experience of transplantation. The purpose of this study was to describe the coping styles used by 25 intestinal transplant recipients. To assess the coping strategies, we used the Italian version of Coping Orientation to Problems Experienced (COPE) by Sica, Novara, Dorz, and Sanavio (1997). The authors divided these strategies into three classes: problem-focused, emotion-focused, and potentially disadaptive strategies. This questionnaire is usually used in a medical setting. Even if the long process of psychological-clinical adaptation required by intestinal transplantation put patients in a passive acceptance of their situation and their incapacity to face it, our patients showed high levels of problem-focused strategies, indicators of positive outcomes for this intervention. Anyway, this is a slow and gradual path that goes with the psychological distress and the need for a peculiar psychological support of problem-focused strategies. The result suggested that assessment of coping strategies should be explored in intestinal transplant to encourage the use of action-oriented methods and discourage those with possible negative effects. PMID- 17692673 TI - Italian experience in adult clinical intestinal and multivisceral transplantation: 6 years later. AB - PATIENTS AND METHODS: Between December 2000 and November 2006, 28 isolated intestinal transplants and nine multivisceral transplants (five with liver) from cadaveric donors have been performed for short gut syndrome (n = 15), chronic intestinal pseudo-obstruction (n = 10), Gardner's syndrome (n = 9), radiation enteritis (n = 1), intestinal atresia (n = 1), and massive intestinal angiomatosis (n = 1). Indications for transplantations were: loss of venous access, recurrent sepsis due to central line infection, and/or major electrolyte and fluid imbalance. Liver dysfunction was present in 19 cases. All patients were adults of median age at transplant of 34.7 years and mean weight 59.6 kg. All recipients were on total parenteral nutrition for a mean time of 38.8 months. Mean donor/recipient body weight ratio was 1.1. RESULTS: The mean follow-up was 892 +/- 699 days. Twenty-five patients were alive (67.5%) with 3-year patient survivals of 70% for isolated intestinal transplantations and 41% for the multivisceral transplantations (P = .01). The mortality rate was 32.5% with losses due to sepsis (63%) or rejection. Our 3-year graft survival rates were 70% for isolated intestinal transplantations and 41% for multivisceral transplantations (P = .02); graftectomy rate was 16%. These were 88% of grafts working properly with patients on regular diet with no need for parenteral nutrition. DISCUSSION AND CONCLUSIONS: Induction therapy has reduced the doses of postoperative immunosuppressive agents, especially in the first period, lowering the risk of renal failure and sepsis, mucosal surveillance protocol for early detection of rejection dramatically reduced the number of severe acute chronic rejections. PMID- 17692675 TI - Regenerative medicine: an insight. AB - Regenerative Medicine is a rapidly evolving field of therapy integrating different scientific and technological areas, including cell biology, biomedical and computer engineering, and clinical medicine, thus creating an interdisciplinary exchange network of skill, ideas, materials and efforts between basic and clinical research. Even if significant achievements have been obtained particularly in Plastic Surgery, Ophthalmology and Orthopedics, the field is still experimental and so far has failed to meet the expectations. The present article reviews the major hurdles that are still hampering the translational "bench to bedside" process and limiting the availability of these innovative therapeutic tools. PMID- 17692676 TI - Fertility following solid organ transplantation. AB - Fertility is usually restored in women after solid organ transplantation, and successful pregnancies have been reported in female recipients of kidney, liver, heart, pancreas-liver, and lung transplants. However, women with solid organ allografts have higher incidence of pregnancy complications like hypertension, preeclampsia, preterm delivery. Hypertension appears to be dependent on the type of immunosuppressive agents. The influence of pregnancy on the risk of rejection is poorly known on the basis of available data. Rejection rate appears to be at least similar to the nonpregnant population. In some cases, such as in liver transplant pregnant women, even higher as compared to the nonpregnant population. Maintaining appropriate blood levels of immunosuppressive drugs is currently recommended. Malformation rate in the offsprings of transplanted women appears to not be increased; long-term follow- up of children born to allograft recipients is necessary to investigate possible developmental, immunological, or oncological disorders. We followed 70 pregnancies after kidney transplantation and nine after liver transplantation. All recipients were maintained on immunosuppressive therapy during pregnancy, except one mother who refused immunosuppression and experienced transplant rejection. Hypertension was the most frequent complication during pregnancy: in 23% of kidney transplantated mothers and in one out of nine liver transplant recipients. The only malformation observed in the newborns was the dislocation of the hip in the child of a kidney transplant recipient. PMID- 17692677 TI - Incidence of fungal infections in a solid organ recipients dedicated intensive care unit. AB - Invasive fungal infections are a significant cause of morbidity and mortality for patients undergoing solid organ transplantation. Our aim was to evaluate the incidence of invasive fungal infections in solid organ recipients within a dedicated intensive care unit (ICU). MATERIALS AND METHODS: From May 2002 to May 2005, 278 patients undergoing solid organ transplantation (105 liver, 142 kidney, 20 lung, 2 combined liver-kidney, 9 combined pancreas-kidney) were admitted to our posttransplant intensive care unit. We retrospectively analyzed data obtained from the ICU stay. Fungal infection was defined by positivity of normally sterile biological samples and by elevated positivity of normally non sterile biological samples. We did not consider superficial fungal infections and asymptomatic colonizations. RESULTS: Forty-six patients (16.5%) developed a fungal infection; at least one mycotic agent was isolated from each patient. Candida albicans was the most common pathogen, isolated from 71 % of infected patients (33 of 46). Infected patients showed a mortality rate of 35%, while that for non infected recipients was 3.5%. Total length of ICU stay was the most significant risk factor among infected patients (30.26 days vs 5.04 days P < .0001). Mean time between transplantation and first positive samples was 6.17 days (SD 8.88). CONCLUSION: Fungal infections in solid organ transplant patients are a major issue because of their associated morbidity and mortality. Candida albicans was the most common pathogen and total length of ICU stay was the most important risk factor. PMID- 17692678 TI - Preliminary evaluation of the new TACR flex method versus MEIA method in the therapeutic monitoring of tacrolimus in organ transplantation. AB - Tacrolimus (FK506) is an effective macrolide immunosuppressant widely used to prevent organ rejection following transplantation. Monitoring blood levels of tacrolimus is essential to assess organ rejection versus toxicity, because of the narrow therapeutic range and pharmacokinetic variability. The increased request for therapeutic drug monitoring is an interesting challenge for clinical laboratories. The automated immunoassay methods provide correct results and a turnaround time considerably reduced compared to HPLC and HPLC-MS which remain the gold standard for accuracy and economical advantages. A new immunoassay method, TACR Flex Dimension, is a commercially available, automated pretreatment test. The purpose of this study was to compare two analytical methods: the MEIA II tacrolimus immunoassay using the IMx analyzer and the new TACR Flex tacrolimus immunoassay on the Dimension system. Tacrolimus results obtained using the two methods were compared using European control and 93 whole blood samples from kidney and liver transplant patients. The tacrolimus concentrations measured by Flex Dimension for all samples were higher (0.7 to 16.1 ng/mL) than results obtained with MEIA (0.2 to 13.4 ng/mL), a mean difference expressed in percentage of 31.7%, and a correlation coefficient of 0.85. The data obtained by both methods using three European controls showed similar concentrations. The TACR Flex Dimension method provided a higher automation level and therefore a lower incidence of preanalytical errors and a lower turnaround time. PMID- 17692679 TI - Specific alloantigen self-control by regulatory T cells in organ transplantation: a review. AB - Multidrug immunosuppressive protocols have increased short-term patient and graft survival rates from 50% to 90% in the past two decades. Unfortunately, chronic graft rejection still remains the main cause of long-term failure and patients must undergo lifelong immunosuppression. The severe side effects such as life threatening infections, secondary malignancies, and cardiovascular dysfunction all together include roughly 50% of deaths among kidney transplant patients with functioning grafts. Therefore, it should be of crucial importance to reduce immunosuppression and seek induction of specific tolerance to donor alloantigens. Several investigations have suggested that the acquisition of tolerance to self and/or foreign antigens is dependent on the number and function of naturally occurring and acquired regulatory T cells, which can control all aggressive T cells. The regulatory T cells together with their receptors, costimulatory molecules, cytokines, chemokines, and growth factors all contribute to maintain an equilibrium between aggressive and suppressive effector immune responses. As a consequence of increased knowledge, new immunosuppressive approaches based on either alloantigen-specific regulatory T-cell expansion in vivo or in vitro have been proposed to achieve donor-specific transplantation tolerance in kidney allograft recipients. This contribution attempted to summarize knowledge about regulatory T cells and developing methods to induce specific tolerance in kidney transplantation. PMID- 17692680 TI - Rat pancreatic islet size standardization by the "hanging drop" technique. AB - INTRODUCTION: Rejection and hypoxia are the main factors that limit islet engraftment in the recipient liver in the immediate posttransplant period. Recently authors have reported a negative relationship of graft function and islet size, concluding that small islets are superior to large islets. Islets can be dissociated into single cells and reaggregated into so called "pseudoislets," which are functionally equivalent to intact islets but exhibit reduced immunogenicity. The aim of our study was develop a technique that enabled one to obtain pseudoislets of defined, preferably small, dimensions. MATERIALS AND METHODS: Islets were harvested from Lewis rats by the collagenase digestion procedure. After purification, the isolated islets were dissociated into single cells by trypsin digestion. Fractions with different cell numbers were seeded into single drops onto cell culture dishes, which were inverted and incubated for 5 to 8 days under cell culture conditions. Newly formed pseudoislets were analyzed for dimension, morphology, and cellular composition. RESULTS: The volume of reaggregated pseudoislets strongly correlated with the cell number (r(2) = .995). The average diameter of a 250-cell aggregate was 95 +/- 8 microm (mean +/- SD) compared with 122 +/- 46 microm of freshly isolated islets. Islet cell loss may be minimized by performing reaggregation in the presence of medium glucose (11 mmol/L) and the GLP-1 analogue Exendin-4. Morphology, cellular composition, and architecture of reaggregated islets were comparable to intact islets. CONCLUSION: The "hanging drop" culture method allowed us to obtain pseudoislets of standardized size and regular shape, which did not differ from intact islets in terms of cellular composition or architecture. Further investigations are required to minimize cell loss and test in vivo function of transplanted pseudoislets. PMID- 17692681 TI - Prolonged survival with FK778 (malononitrilamide) monotherapy after small bowel transplantation: a large animal study. AB - Malononitrilamide 715 (FK778) is a new class of immunosuppressant, derived from the active metabolite of leflunomide A77 1726. We investigated the efficacy of two different immunosuppressive induction protocols with tacrolimus plus FK778 followed by FK778 monotherapy. In a swine model of small bowel transplantation, we observed three groups, divided by different therapy regimens: group 1 (n = 5): no immunosuppressant (control group); group 2 (n = 10): oral tacrolimus (from postoperative day [POD] 0 to 30) and FK778 (from POD 0 to 60); group 3 (n = 8): oral tacrolimus, as group 2, and FK778 (from POD 7 to POD 60). Median survival was 11, 60, and 21 days in groups 1, 2, and 3, respectively. In group 1 all animals died of acute rejection; in group 2 the causes of death were technical complication (n = 1) and sepsis (n = 1); in group 3, one animal died from obstruction, two from pneumonia, one from peritonitis, one from sepsis. Group 2 accounted for 0.5 infection episode/animal versus 0.62 in group 3 (P < .05). Acute rejection was absent or mild in 66% and 75% of group 3 and 2 biopsies, respectively (P < .05). The D-xylose absorption curves from groups 2 and 3 were similar to those of the nontransplanted healthy animals. In conclusion, FK778 monotherapy after a consistent induction period with tacrolimus combined immunosuppression is able to extend survival and preserve optimal absorptive capacity of the small bowel allograft in our pig model. The association of tacrolimus and FK778 from day 1, compared to the delayed administration of FK778 from day 7, results in a significant reduction of infections and postoperative complications. PMID- 17692682 TI - Elemental enteral nutrition preserves the mucosal barrier and improves the trophism of the villi after small bowel transplantation in piglets. AB - The main goals for a successful small bowel transplantation (SBTx) are the control of acute rejection and maintenance of the mucosal barrier, which plays a key role in preventing bacterial translocation and preserving absorptive capacity. According to recent evidence that sustaining enteral nutrition (EN) as rehabilitative therapy improves the integrity of the mucosal barrier after SBTx, we studied the trophic effect of a new elemental enteral solution whose proteinic supply is represented by oligomeric-aminoacidic chains. In a swine SBTx model we studied three groups, divided by the different postoperative feeding: group 1 (n = 5): standard swine chow, group 2 (n = 5): polymeric enteral solution, group 3 (n = 5): elemental enteral solution (Peptamen, Nestle Corp). All animals were immunosuppressed with a tacrolimus/FK778 combined oral therapy. The nutritional indices evaluated were: body weight, episodes of diarrhea, D-xylose absorption test, and histopatological and villi morphometric analysis. Three pigs died before the end of the study, two in group 1 (pneumonia and sepsis), one in group 2 (pneumonia). Mean days of diarrhea were 15, 10, and 3 in groups 1, 2, and 3, respectively (P < .05). The final/starting weight ratio was 1.08 for group 3 and 0.92 for group 2 (P < .05); the D-xylose curves showed a statistically significant difference for group 3 versus the groups 2 and 1 (P < .05), as well as for the villi height (P < .01) and width (P < .05). In conclusion, elemental enteral solution, with its basic protein supply, does not require a very complex enzymatic system to be metabolized. Thus, it may contribute to a faster recovery of the mucosal barrier and to limit the hypercatabolic state. PMID- 17692683 TI - A new experimental model of isolated perfused pig liver to support acute hepatic failure. AB - Liver transplantation still represents the only effective treatment for patients with liver failure, but many patients die while awaiting transplantation, even though many attempts have been made to increase the organ procurement rates and to partially support hepatic function in recent years. Our aim was to design an "open" ex vivo perfused liver model to simplify liver support using an isolated porcine liver perfused with arterial and portal blood from the recipient pig, while monitoring the metabolic capacity of the supporting graft. It was possible to perfuse the isolated liver for 6 hours as a bridging procedure with satisfactory hemodynamic homeostasis controlled by software biofeedbacks. PMID- 17692684 TI - Disseminated Scedosporium apiospermum infection in renal transplant recipient: long-term successful treatment with voriconazole: a case report. AB - Scedosporium apiospermum, the asexual form of Pseudallescheria boydii, is a ubiquitous fungus that represents an unfrequent complication of immune suppression. It accounts for 20% of all non-Aspergillus mold infections in organ transplant recipients. The infection can be localized or disseminated in multiple organs, including lungs, brain, joints, tendons, and skin, and is difficult to treat, due to resistance of S apiospermum to amphotericin B and other antifungal agents. The mortality rate is about 50%. To our knowledge, there are no prospective studies or registries of transplant recipients to guide diagnosis and there are no evidence-based recommendations for the optimal management of this infection. We report a case of S apiospermum infection in a woman with renal transplantation. The first occurrence of infection was a solitary nodule on the forearm, which was surgically excised. Two following relapses were disseminated to the knee, the Achilles tendon, and the skin of the left leg. The infection was successfully treated with voriconazole, but due to the severe iatrogenic immune suppression, a strong reduction in immunosuppressant drugs was needed. PMID- 17692685 TI - Conversion to rapamycin immunosuppression for malignancy after kidney transplantation: case reports. AB - INTRODUCTION: Malignancies are a well-known complication of immunosuppressive therapy among renal transplant recipients, representing an important cause of long-term morbidity and mortality. Rapamycin has been shown to limit the proliferation of a number of malignant cell lines in vivo and in vitro. METHODS: Eight patients developed the following malignancies after kidney transplantation (mean 102.6 months; range 12 to 252): metastatic gastric cancer (n = 1), metastatic colon cancer (n = 1), bilateral nephrourothelioma (n = 1), skin cancer (n = 1), Kaposi's sarcoma (n = 2), posttransplant lymphoproliferative disorder (PTLD) (n = 2). After the diagnosis of malignancy, the patients were switched from calcineurin inhibitor-based immunosuppression to rapamycin (monotherapy, n = 2), associated with steroids (n = 4) or mycophenolate mofetil (n = 2). RESULTS: Both patients with metastatic cancer underwent chemotherapy and then succummbed after 6 and 13 months. After a mean follow-up of 20.3 months (range 2 to 47), the remaining six patients are free from cancer disease. Renal graft function was unchanged from diagnosis throughout the follow-up. CONCLUSION: Our observations suggested that rapamycin-based immunosuppression offered the possibility of regression of nonmetastatic tumors. Nevertheless, it is difficult to assess whether tumor regression was attributed to Rapamycin treatment or to the reduced immunosuppression. PMID- 17692686 TI - Peritoneal leiomyosarcoma in a kidney transplant patient: a case report. AB - Sarcomas are rare neoplasms, accounting for a 1.7% incidence among all transplanted patients presenting with de novo malignancies. Our present report focused on a 46-year-old woman who received immunosuppressive therapy based on cyclosporine and steroids for renal transplantation. Eight years after transplantations, she suffered lower abdominal pain and a mass involving peritoneal soft tissues was located near the right iliac vessels. Upon radical tumor excision, the histological examination revealed a high-grade leiomyosarcoma. Immunosuppression was reduced and cyclosporine switched to rapamycin. After 30 days, a computed tomography scan revealed two small pulmonary metastases, so the patient received adriamycin. Six months after the diagnosis, there was no intra-abdominal relapse and the pulmonary metastasis remain stable. The function of the transplanted kidney was normal and the patient was listed for laparoscopic pulmonary resection. Sarcomas in solid organ transplant patients appear to have aggressive features with 62% being high grade and 40% metastatic at the time of primary diagnosis with a recurrence rate of 30% and a 5-year survival rate of 25%. Patients diagnosed with sarcoma should be treated with multimodality therapy. After aggressive surgery whenever possible, a combination of a traditional cytotoxic drug and a "signal" blocking agent like rapamycin may increase selectivity toward tumor cells. PMID- 17692687 TI - Interferon-alpha therapy and anti-human leukocyte antigen antibodies in hepatitis C virus-positive patient: case report. AB - Interferon-alpha (IFN-alpha) is currently the only treatment for patients with chronic hepatitis C. Yet it can induce acute renal transplantation rejection possibly by stimulating humoral responses. We tested patient sera for detection of donor-specific anti-human leukocyte antigen (HLA) antibodies observing an increased panel-reactive antibodies value after IFN-alpha therapy. Then, we also investigated whether antiviral treatment with IFN-alpha was related to an increased and/or different production of class I and class II anti-HLA antibodies. Patient sera analysis performed by a cytofluorimetric method using flow PRA tests showed the appearance of new HLA-antibody specificities. This study underlined that INF-alpha therapy modifies a patient's immune profile; hence, it is recommended to confirm HLA-antibody specificities after treatment in order to protect recipients from enhanced rejection risk owing to a false negative donor-specific cross-match. PMID- 17692688 TI - Modifications of intracranial pressure after molecular adsorbent recirculating system treatment in patients with acute liver failure: case reports. AB - Cerebral dysfunction may be fatal in patients with acute liver failure (ALF); intracranial pressure (ICP) monitoring may be mandatory to direct measures to prevent further cerebral edema. Recently the introduction of dialysis with the molecular adsorbent recirculating system (MARS) has improved the outcomes among patients with ALF. The aim of this study was to evaluate ICP changes after MARS treatment among patients with ALF. METHODS: Three patients -- 14, 18 and 16 years old -- were admitted to the ICU for acute liver failure induced by HBV in two cases and by acetaminophen in the other one. Because of Glasgow Coma Score (GCS) <8, they were intubated and ventilated to protect the airway and maintain moderate hypocapnia. Invasive monitoring of intracranial pressure MARS treatments were performed in all patients. RESULTS: The patients received MARS treatments every day after their admission to liver transplantation. After MARS therapy the ICP decreased on average from 21 to 7 mm Hg. Significant hemodynamic modifications were not observed and their neurological conditions improved. CONCLUSION: MARS treatment improved the clinical pictures of these patients increasing the available time to obtain an urgent liver graft. PMID- 17692689 TI - The role of liver transplantation in the treatment of hereditary hemorrhagic telangiectasia: a short literature review. AB - The liver is involved in up to 73% of patients suffering from hereditary hemorrhagic telangiectasia (HHT), but only some of them become symptomatic. Although management is often conservative, sometimes a more aggressive approach is required. The role of surgery is still undefined. Open ligation, banding, or closure of the arteriovenous malformation feeding artery have been proposed but rejected, as they are followed by an unacceptably high incidence of complications, derived from ischemia of the biliary tree. Orthotopic liver transplantation (OLT) has been successfully attempted in 28 patients with cardiac, biliary, or portal hypertension as well as mixed clinical presentations. Twenty-four were alive at time of data collection. Cardiovascular and pulmonary functions have improved after the operation in most cases. Intrahepatic relapse of the hallmark lesion of the disease (telangiectasia and arterovenous malformation) has been recently described in two cases. OLT represents a valuable therapeutic option for hepatic-based HHT, provided early diagnosis and referral to a specialized unit. PMID- 17692690 TI - Functional assessment of the stomatognathic system. AB - Clinically objective assessment of the occlusal function remains largely, even today, in the research laboratory instead of in the clinical setting, as part of the routine assessment along with the morphologic documentation. Functional outcomes of the stomatognathic system can be measured in terms of occlusal contact area, maximal voluntary bite force, maximal voluntary excursions, masticatory force, masticatory cycle pattern and masticatory performance. It should be emphasized, however, that many of these measures remain to be standardized and validated as tools relevant for assessment of patients who have dentofacial skeletal deformities. This remains a promising area of active research. PMID- 17692691 TI - Psychological considerations in orthognathic surgery. AB - More adolescents and young adults are requiring facial skeletal surgical procedures. They are vulnerable in emotional development, and the stress of surgery adds to this. Interaction between adolescent patients and caregivers must be assessed in treatment planning for a successful outcome. Focus is on correcting the morphologic deformity, but assessment and planning should also include psychosocial aspects of the patient. Adolescents and young adults who need psychological support should be followed closely from the beginning, until at least 1 year postsurgery. Success of surgical intervention should be measured both in terms of the occlusal function and morphological improvement, and changes in psychosocial interaction and an improved quality of life for the patient. PMID- 17692692 TI - Pitfalls in orthognathic surgery: avoidance and management of complications. AB - Complications in orthognathic surgery may arise at any point in the patient's treatment: during preoperative planning, during perioperative orthodontic care, or during the surgery itself. This article addresses the complications that arise as a result of the intraoperative technique. In this article, complications are grouped by procedure. The initial discussion focuses on complications occurring during maxillary surgery, namely the LeFort I type osteotomy. The second section discusses complications occurring during mandibular procedures, the bilateral sagittal split osteotomy and genioplasty. PMID- 17692693 TI - Aesthetic facial osteotomies in Latin Americans. AB - There are considerable differences in the facial appearance of different races resulting from the shape and proportions of the skeletal support, the muscle insertions, and the color and quality of the skin. The surgeon's challenge is to understand the ethnic concepts of beauty and the unique anatomic characteristics of the individual face. This article discusses surgical procedures on the skeleton of the zygoma-malar region and the correction of the anterior projection of the dental arches that are relevant to this patient population. PMID- 17692694 TI - The surgical management of post-traumatic malocclusion. AB - Facial skeleton fractures should be reduced as early as possible to restore optimal function and minimize skeletal and soft-tissue deformity. With unsatisfactory outcome from delayed treatment because of comorbidity, or despite optimal management, late reconstruction can succeed with conventional orthognathic surgical procedures. Management follows well-established principles of correcting dentofacial deformities, coordinated with orthodontic and prosthodontic support. Planning should include dental records when available, and clinical photographs. The late deformity of midfacial fractures can be corrected by following initial fracture lines; condylar fracture patients can be treated by remote osteotomies. Before surgical intervention, diminished temporomandibular joint (TMJ) mobility should be managed with aggressive physiotherapy to maximize stomal opening. Additionally, successful outcome will depend on a stable TMJ relation without ongoing remodeling. PMID- 17692696 TI - Orthognathic surgery and a tale of how three procedures came to be: a letter to the next generations of surgeons. AB - Although the transoral sagittal splitting of the ramus, the osseous genioplasty, and the LeFort osteotomy today are common procedures used by many specialties to solve a broad range of problems, this was not always so. This article describes Hugo Obwegeser's firsthand experience of how these procedures came to be. PMID- 17692697 TI - Facial skeletal growth and timing of surgical intervention. AB - Various forces and factors influence the development and maturation of the craniofacial skeleton. These encompass genetic and micro- and macro-environmental factors whose intricacies and interplay must be understood, recognized, and respected in the surgical planning and treatment of maxillofacial deformities. The theories of and experimentation with such factors, which dictate the timing of surgical intervention, are the focus of this article. The common procedures that make up the surgical armamentarium of the maxillofacial surgeon are catalogued in the setting of this developmental timeline. PMID- 17692698 TI - The aesthetic dentofacial analysis. AB - Surgical-orthodontic treatment planning for facial skeletal surgery begins with analysis of the morphologic form of the face, the soft-tissue envelope, and the underlying facial skeleton integrated with the dentition. This article demonstrates how systematic analysis of all the facial components, both anatomically static and functionally dynamic, leads to a greater appreciation of the subtleties of the interaction of each of the facial elements and how each can be managed appropriately through a unified orthodontic-surgical approach. PMID- 17692699 TI - The effects of maxillofacial surgery on speech and velopharyngeal function. AB - Individuals undergoing conventional maxillary advancement surgery or maxillary distraction should have perceptual and instrumental assessment of speech and velopharyngeal function, pre- and postsurgically. They should be counseled on the risk of deterioration in velopharyngeal function, particularly for those who have repaired cleft palate presenting with characteristics of borderline velopharyngeal function. These individuals should also be counseled that there may be a positive change in speech articulation, with normalization of the maxillary-mandibular relationship, especially for the highly sibilant /s/ and /z/ sounds. This article highlights speech errors often seen in individuals who have dentofacial skeletal deformities, and discusses the impact of conventional orthognathic surgery and distraction osteogenesis on speech production. Methods of assessing speech production, including perceptual assessment and instrumentation are also reviewed. PMID- 17692700 TI - Orthodontic management of dentofacial skeletal deformities. AB - The treatment of complex malocclusions with overriding skeletal discrepancies requires an exceptional amount of pretreatment planning. The roles of the orthodontist and the surgeon are equally important. Sufficient input from each member of the orthognathic surgical team is necessary before any patient care is delivered. Because the goals of presurgical orthodontic treatment are more often than not opposite to the routine orthodontic regimen, detailed planning, using diagnostic orthodontic set-ups and predictive visual imaging, is often needed to confirm the procedures necessary to create an aesthetic and functional result. Without this integrated team approach, successful outcomes of treatment can be problematic. PMID- 17692701 TI - Two-dimensional cephalometry and computerized orthognathic surgical treatment planning. AB - Cephalometric radiographs provide for standardized skull/facial views that allow for comparison over time to assess growth in an individual, and to compare that individual against standardized population norms. Cephalometric analysis and surgical prediction are done by robust cephalometric imaging software that can rapidly analyze the radiograph, and retrace and recalculate the analysis for a variety of possible surgical outcomes; however, the validity of the prediction depends on the accuracy of the records, the algorithm specific to the software, and the specifics of the patient population. Three-dimensional digital imaging to replace conventional two-dimensional photographic images and CT scans, with corresponding cephalometric analysis to replace two-dimensional cephalometric films, is already on the horizon. PMID- 17692702 TI - Three-dimensional computerized orthognathic surgical treatment planning. AB - Three-dimensional volumetric imaging allows better visualization of the morphologic deformity, planning the surgical approach, and evaluating the response not visualized previously with two-dimensional dentofacial records. This in time will replace conventional two-dimensional cephalometric planning and plaster cast model surgery. Three-dimensional craniofacial imaging requires application of various techniques from applied mathematics, computer sciences, and bioengineering. Although it is today in its infancy, it has the potential to accurately simulate the operative experience for surgical planning, with improved morphologic outcomes, patient-specific biomechanical modeling to allow functional assessment of the various outcomes, and accurate simulation for surgical resident training. PMID- 17692703 TI - Aesthetics of facial skeletal surgery. AB - Orthognathic surgical planning should derive primarily from aesthetic considerations, and these should be based not on rigid cephalometric and anthropometric norms but on the surgeon's aesthetic sense. The historic goals of orthognathic surgery have addressed both stability and aesthetics. Stability relates to establishing a healthy, functional occlusion; aesthetic goals have focused on normalizing facial balance and proportions. With the advent of rigid fixation and bone graft substitutes, sacrificing facial aesthetics to attain stability and achieve a normal occlusion is no longer necessary. Orthognathic surgery now can be envisioned truly as aesthetic surgery. PMID- 17692704 TI - The surgical tools: the LeFort I, bilateral sagittal split osteotomy of the mandible, and the osseous genioplasty. AB - Orthognathic surgery involves the surgical manipulation of the elements of the facial skeleton to restore normal anatomic and functional relationships in patients who have dentofacial skeletal anomalies. The elements of the facial skeleton can be repositioned, redefining the face through a variety of well established osteotomies. Most maxillofacial deformities can be managed with the three basic osteotomies discussed in this article: the LeFort I type osteotomy, the bilateral sagittal split osteotomy of the mandibular ramus, and the horizontal osteotomy of the symphysis of the chin (osseous genioplasty). PMID- 17692705 TI - The approach to dentofacial skeletal deformities using a multisegmentation technique. AB - This article describes the authors' approach to correcting dentofacial skeletal deformities requiring multisegmentation of the maxilla. Achieving optimal results requires a close collaboration within the orthodontic-surgical team. The importance of attention to detail in the course of the surgical procedure cannot be overemphasized, because complications of avascular necrosis cannot be corrected easily. The multisegmental maxilla is a valuable technique and adds to the versatility of the LeFort I in the treatment of open bite and transverse discrepancies in dentoalveolar deformities. PMID- 17692706 TI - The osseous genioplasty. AB - Despite its existence for nearly half a century and its versatility in solving a complex range of chin deformities, osseous genioplasty through an intraoral approach remains a rusty tool in many surgeons' armamentarium. The osseous genioplasty is not solely within the domain of the maxillofacial or craniofacial surgeon; it is well within the reach of any surgeon whose practice involves facial aesthetics. The surgeon who masters this relatively simple procedure can solve a broad range of chin deformities that an implant cannot solve: a chin that is too long, too short, or asymmetric. PMID- 17692707 TI - Basic guidelines for the surgical correction of mandibular anteroposterior deficiency and excess. AB - During the past decades, knowledge and understanding of all aspects of orthognathic surgery have increased greatly. Diagnostic skills and treatment planning have become more sophisticated and, through experience, surgical techniques have attained a level enabling the treatment of the most complex jaw deformities with confidence. In this article, guidelines for the treatment of mandibular anteroposterior dentofacial deformities are discussed. It should, however, always be kept in mind that the face and mouth are complex, three dimensional structures and multifunctional in character. An artistic flair and the ability to think originally have become essential for the orthognathic surgeon, because no two dentofacial deformities are the same. PMID- 17692708 TI - Maxillary and midface deformities: characteristics and treatment strategies. AB - The embryologic and postnatal development of the craniofacial region is an extremely complex process. Historically, patients who presented with complex craniomaxillofacial deformities were managed by focusing solely on the mandible with correction of the occlusion, without regard for the midface. Mandibular procedures long preceded the surgeon's ability to address the midface and cranio orbital regions adequately. H. Obwegeser's LeFort I technique, followed by the transcranial approaches of P. Tessier, now allow the surgeon to address fully a complex range of craniomaxillofacial deformities. The surgeon today has the ability to disassemble the midface, either as a single unit or multiple units, in various planes, to address each patient's unique deformity specifically. PMID- 17692709 TI - Surgical approach to the patient with bimaxillary protrusion. AB - The patient who has bimaxillary protrusion often is treated using a combination of orthodontics and orthognathic surgery, and the general approach is dental extraction with retraction of the incisors. In certain cases, maxillary excess may be corrected solely with LeFort I osteotomy and setback and without dental extraction or anterior segmental osteotomies. This article discusses (1) treatment evaluation and planning and (2) the specific surgical techniques, primarily anterior segmental osteotomies and the technical details for setback of the LeFort I osteotomized segment (more than 5 mm), as they relate to the surgical approach of the patient who has bimaxillary protrusion. PMID- 17692710 TI - Aesthetic facial skeletal contouring in the Asian patient. AB - In response to facial skeletal differences across race, and cultural differences in what patients feel to be aesthetically desirable, surgical procedures continue to evolve. Mandibular angle reduction and zygoma reduction are powerful procedures for affecting facial skeletal change to achieve a softer, less angular, facial contour. Achieving a safe and satisfying result relies equally on success in preoperative evaluation and in intraoperative execution. The following considerations are particularly important during initial evaluation: patient age, skeletal relative to soft tissue contribution to facial prominences, asymmetries, and a clear understanding of the patient's perception of the deformity. Intraoperatively, complications are avoided through the careful planning of osteotomies to avoid adjacent structures. PMID- 17692711 TI - Transgender feminization of the facial skeleton. AB - In transsexualism, there is a strong and ongoing cross-gender identification, and a desire to live and be accepted as a member of the opposite gender; thus there is a wish for somatic treatment to make one's body as congruent as possible with gender identity. Makeup and change in hairstyle and accessories further feminize the face, and in time, most persons became more adapted to their life as a member of the opposite gender. There is a need for more objective standardization of the differences in the facial features of the two sexes, to facilitate surgical treatment planning and more objectively assess the outcome of the facial surgery on psychosocial functioning and appearance. PMID- 17692712 TI - Facial skeletal surgery in the management of adult obstructive sleep apnea syndrome. AB - Obstructive sleep apnea (OSA) remains a significant public health problem because of its neurocognitive sequelae. Additionally, with persistent obstruction, it has an impact on the cardiovascular system, leading to hypertension and cardiac failure as one of its causative or comorbid factors. For the surgeon managing OSA, there is a stepwise sequence of surgical procedures, from improving nasal airflow to facial skeletal maxillary-mandibular advancement, with the cumulative goal of volumetrically increasing the retropharyngeal airway space. Familiarity with conventional orthognathic principles is essential in achieving this goal. PMID- 17692713 TI - The LeFort I transmaxillary approach to skull base tumors. AB - This article discusses the surgical approach using the LeFort I and its variations to the extracranial skull base for removal of craniocervical lesions from the sphenoid to the fourth cervical vertebra between the carotids. Clival lesions with superior and inferior extension and nasopharyngeal lesions can be accessed by this approach. The outcome of surgical, radiation, and chemotherapeutic treatment is beyond the scope of this brief article, which focuses on the technical aspects of cranial base tumor exposure. PMID- 17692714 TI - Principles in treatment planning of facial skeletal anomalies. AB - This article succinctly presents principles gleaned from the author's extensive experience, and the experience of his mentors, in treating facial skeletal anomalies. PMID- 17692715 TI - The vocabulary of dentofacial deformities. AB - Planning the reconstruction of patients with skeletal and dental anomalies requires medical, surgical, and dental specialties working together. Language frequently is a common barrier and this article provides a glossary of terms that can be used as a guide. PMID- 17692716 TI - Dosing of insulin glargine in the treatment of type 2 diabetes. AB - BACKGROUND: Type 2 diabetes is a progressive disease characterized by insulin resistance and declining beta-cell function, often leading to a requirement for insulin therapy to maintain good glycemic control and prevent diabetes-associated complications. Adequate insulin dosing is crucial to the achievement of good glycemic control with minimal hypoglycemia, and dose titration immediately following insulin initiation is needed to ensure its success. Insulin may be initiated as an add-on therapy to oral treatment using a single evening basal insulin dose and titrating according to fasting blood glucose (FBG) levels (with an ideal target of <5.5 mmol/L [<100 mg/dL] to achieve glycosylated hemoglobin [HbA1c] <7%). OBJECTIVE: This review investigated options for, and clinical efficacy of, titration algorithms of insulin glargine in type 2 diabetes. METHODS: Articles from peer-reviewed journals were identified through searches of MEDLINE (years: 2000-2006). Search terms included insulin glargine, titration, algorithm, and type 2 diabetes. Studies were assessed and included in this review if they provided information regarding the method of dose titration of insulin glargine used. RESULTS: A total of 12 studies were identified and included in this review. In the 24-week Treat-to-Target study, in which 756 patients were randomized to receive either insulin glargine or neutral protamine Hagedorn (NPH) insulin, once-daily using a simple titration regimen (titration of daily insulin dose by 0-2, 2, 4, or 6-8 IU if mean fasting plasma glucose over the 3 previous days was >or=5.6-<6.7, >or=6.7-<7.8, >or=7.8-<10.0 or >or=10 mmol/L [>or=100 <120, >or=120-<140, >or=140-<180, or >or=180 mg/dL], respectively, in the absence of plasma glucose <4.0 mmol/L [<72 mg/dL]) more patients reached HbA1c or=18 years undergoing abdominal surgery that required a >or=3-cm incision. Patients who discontinued short-acting parenteral opioids and developed moderate or severe pain (4-point categorical scale [none, mild, moderate, or severe] and pain intensity >or=50 mm on a 100-mm visual analog scale [from 0 = no pain to 100 = worst pain imaginable]) within 30 hours after abdominal surgery were randomized to receive oxymorphone IR 10 or 20 mg, oxycodone IR 15 mg, or placebo every 4 to 6 hours after the previous dose. The study included 2 efficacy assessments: a single-dose evaluation for up to 6 hours after the dose, and a multipledose evaluation for up to 48 hours after the first dose. Pain was assessed at 15 minute intervals during the hour after the first dose, hourly thereafter for the next 5 hours, and before each subsequent dose. The primary efficacy end point was the median time to study discontinuation for all causes. Assessment of tolerability was based on the proportion of study discontinuations due to treatment-emergent adverse events (AEs). RESULTS: Three hundred thirty-one patients were included in the study. Demographic characteristics were similar across all groups: 98.8% (327) of patients were women, and 80.1% (265) of the abdominal surgeries were hysterectomies. The mean (SD) age of the study population was 42.6 (9.3) years. The median time to study discontinuation for all causes was significantly longer for all active treatments compared with placebo (oxymorphone IR 10 mg, 17.9 hours; oxymorphone IR 20 mg, 20.3 hours; oxycodone IR 15 mg, 24.1 hours; placebo, 4.8 hours; P < 0.006). Oxymorphone IR 20 mg was significantly more effective than placebo over the 6-hour single-dose evaluation (P < 0.05). With multiple dosing, all active-treatment groups had significantly lower least squares mean current and average pain intensities compared with placebo (P < 0.004 and P < 0.005, respectively). The least squares means of the average pain intensity were significantly lower among patients treated with oxymorphone IR 10 mg, oxymorphone IR 20 mg, or oxycodone IR 15 mg compared with those who received placebo (39.7, 35.2, 39.8, and 50.1, respectively; P < 0.005). Discontinuations due to treatment-emergent AEs did not differ significantly between groups: 8.5% (7/82), 17.3% (14/81), 13.3% (11/83), and 12.9% (11/85) in the oxymorphone IR 10-mg, oxymorphone IR 20-mg, oxycodone IR 15-mg, and placebo groups, respectively. The proportions of patients reporting at least 1 treatment emergent AE were 46.3% (38/82), 51.9% (42/81), and 54.2% (45/83) in the oxymorphone IR 10-mg, oxymorphone IR 20-mg, and oxycodone IR 15-mg groups, respectively, compared with 34.1% (29/85) in the placebo group (P = NS). The fixed-dose design was a study limitation, as it did not allow titration to effect and thus did not mirror clinical practice. CONCLUSION: In this predominantly female population undergoing abdominal surgery, oxymorphone IR given every 4 to 6 hours for up to 48 hours provided efficacious and tolerable analgesia for moderate to severe pain. PMID- 17692718 TI - A 12-week, multicenter, randomized, partially blinded, active-controlled, parallel-group study of budesonide inhalation suspension in adolescents and adults with moderate to severe persistent asthma previously receiving inhaled corticosteroids with a metered-dose or dry powder inhaler. AB - BACKGROUND: Nebulized budesonide inhalation suspension (BIS) is approved in the United States for children with asthma aged 1 to 8 years. OBJECTIVE: The primary objective of this study was to compare the efficacy of BIS 0.5 mg QD and 2.0 mg BID in terms of the mean change from baseline to end of treatment in predose forced expiratory volume in 1 second (FEV1). METHODS: In this 12-week, partially blinded, randomized study, subjects aged >or=12 years with moderate to severe persistent asthma previously receiving inhaled corticosteroids (ICSs) by dry powder inhaler (DPI) or metered-dose inhaler (MDI) continued therapy during a 2- to 3-week run-in period and then switched to BIS 0.5 mg QD, 1.0 mg QD, 1.0 mg BID, or 2.0 mg BID, or budesonide DPI 400 microg BID (active reference arm). Besides FEV1 (the primary variable), other outcome variables included changes in forced vital capacity (FVC) from baseline to weeks 4, 8, and 12 and to the average over the treatment period; as well as changes from baseline to the end of treatment in diary-collected daytime and nighttime asthma symptom scores, rescue medication use, nighttime awakenings due to asthma, morning and evening peak expiratory flow (PEF), percentages of symptom-free and medication-free periods, and the incidence of predefined asthma events. Adverse events were recorded by subjects. Steady-state pharmacokinetics of budesonide were assessed in all treatment arms. Efficacy analyses included data in a modified intent-to-treat approach. Differences in the change from baseline to end of treatment in FEV1 were assessed using analysis of covariance (ANCOVA). For secondary variables, changes from baseline to each visit or to the treatmentperiod average were compared among groups using an ANCOVA model. P or=65 years. There was no significant difference in mean change in predose FEV1 between BIS 0.5 mg QD and BIS 2.0 mg BID (0.02 vs 0.01 L). On average, mean values for the BIS dosage groups did not indicate any deterioration from baseline to the treatment period for variables associated with asthma control such as FEV1, FVC, daytime and nighttime asthma symptom scores, rescue medication use, nighttime awakenings, morning and evening PEF, percentages of symptom-free and rescue medication-free periods, and predefined asthma events. The BIS 1.0-mg BID treatment appeared to be closest to budesonide DPI in plasma budesonide concentrations and improvement in predose FEV1 (0.08 vs 0.12 L). All treatments were well tolerated. CONCLUSIONS: In this study, no difference in efficacy between BIS 2.0 mg BID and 0.5 mg QD was found in adolescents and adults with persistent asthma when transitioned from ICSs delivered with a DPI or MDI. Subjects taking all BIS dosages experienced similar responses for variables associated with asthma control. PMID- 17692719 TI - A randomized, placebo-controlled trial of varenicline, a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist, as a new therapy for smoking cessation in Asian smokers. AB - BACKGROUND: Rates of smoking in East Asian men range from >35% to >60%, and are increasing in women and the young. OBJECTIVE: This study evaluated the efficacy and tolerability of 1 mg BID varenicline, a novel alpha4beta2 nicotinic acetylcholine receptor partial agonist, for smoking cessation in smokers in Taiwan and Korea. METHODS: A randomized, double-blind, placebo-controlled, 12 week treatment, 12-week follow-up trial was conducted at 5 sites each in Korea and Taiwan. Eligible subjects, smoking >or=10 cigarettes/d, received brief smoking-cessation counseling and were randomly assigned in a 1:1 ratio to varenicline 1 mg BID (titrated during the first week) or placebo. Smoking status was established by self-report and confirmed at clinic visits by end-expiratory carbon monoxide or= 5% for varenicline were nausea (43.7% for varenicline vs 11.3% placebo), insomnia (15.1% vs 13.7%), increased appetite (7.9% vs 6.5%), constipation (7.1% vs 2.4%), anxiety (5.6% vs 2.4%), and abnormal dreams (5.6% vs 0.8%). Adverse events resulted in <10% treatment discontinuations overall. CONCLUSION: Varenicline was an efficacious and well-tolerated pharmacotherapy for smoking cessation in this group of Asian smokers over a 12-week treatment period, and its effects persisted for a further 12-week follow-up period. PMID- 17692720 TI - Efficacy and tolerability of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, in a 12-week, randomized, placebo-controlled, dose response study with 40-week follow-up for smoking cessation in Japanese smokers. AB - BACKGROUND: Varenicline, a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist, has been developed specifically for smoking cessation. In Japan, 39.3% of men smoke and this is a major public health concern. OBJECTIVE: The primary objective of this study was to evaluate the efficacy and dose-response relationship of varenicline in Japanese smokers. METHODS: In this double-blind, placebo-controlled, randomized, parallel-group study, subjects were randomized to receive varenicline at 0.25 mg BID, 0.5 mg BID, 1 mg BID, or placebo for 12 weeks followed by a 40-week, nontreatment follow-up phase. The primary efficacy variable was the continuous abstinence rate (CAR), defined as no reported smoking (not even a puff) or other nicotine use and confirmed by end-expiratory carbon monoxide level or=5 on the Tobacco Dependence Screener), and constituted the primary analysis group. Of these, 385 (74.8%) subjects were male, and the mean age was within the range of 39.0 to 40.2 years. Across treatment groups, subjects claimed to have smoked a mean of 23.1 to 24.9 cigarettes per day in the preceding 30 days, and the mean score on the Fagerstrom Test for Nicotine Dependence was within the range from 5.4 to 5.7. The CAR for weeks 9-12 was significantly higher for all doses of varenicline compared with placebo (39.5% [51/129]). The highest CAR of 65.4% (85/130) was achieved with varenicline 1 mg BID (odds ratio [OR] [95% CI] = 2.98 [1.78-4.99]; P < 0.001). The CAR for weeks 9 52 was significantly greater for varenicline 1 mg BID than placebo (34.6% [45/130] vs 23.3% [30/129]; OR [95% CI] = 1.81 [1.04-3.17]; P = 0.036). The CARs for weeks 9-24 at 0.25, 0.5, and 1 mg BID were 33.6% (43/128), 35.2% (45/128), 37.7% (49/130), and for weeks 9-52 at 0.25 and 0.5 mg BID were 27.3% (35/128) and 28.9% (37/128) but failed to reach significance versus the placebo (29.5% [38/129] for weeks 9-24 and 23.3% [30/129] for weeks 9-52). Treatment-emergent adverse events (AEs) were more prevalent among varenicline-treated subjects (79.1% [121/153] at 0.25 mg BID, 80.6% [125/155] at 0.5 mg BID, and 80.1% [125/156] at 1 mg BID) than placebo subjects (71.4% [110/154]). The 3 most prevalent AEs at varenicline 1 mg BID were nasopharyngitis (35.9% [56/156]), nausea (24.4% [38/156]), and headache (10.3% [16/156]), all of which were of mild or moderate intensity. Nausea was the only AE that appeared dose related (7.2% [11/153] at 0.25 mg BID, 9.7% [15/155] at 0.5 mg BID, and 24.4% [38/156] at 1 mg BID) versus placebo (7.8% [12/154]). CONCLUSIONS: Varenicline was associated with dose-dependent improvement in smoking abstinence rates during the last 4 weeks of treatment and in the longer term over 40 weeks of nontreatment follow-up. The dose associated with the highest efficacy was varenicline 1 mg BID. PMID- 17692721 TI - Meta-analysis of the efficacy of a single dose of phenylephrine 10 mg compared with placebo in adults with acute nasal congestion due to the common cold. AB - BACKGROUND: Although nonprescription oral phenylephrine 10 mg has been judged "generally recognized as safe and effective" by the US Food and Drug Administration (FDA), its efficacy as a nasal decongestant has been questioned. OBJECTIVE: This study assessed available data on the efficacy of oral phenylephrine 10 mg as a nasal decongestant. METHODS: Three sources were used to identify potentially relevant publications--the bibliography of the phenylephrine section of the 1976 FDA monograph on over-the-counter cold, cough, allergy, bronchodilator, and antiasthmatic products; a 2004 Cochrane Review of nasal decongestants for the common cold; and a search of MEDLINE from 1966 through January 2007 using the term phenylephrine nasal. To be included in the analyses, studies had to have a single-dose, randomized, placebo-controlled design; involve an orally administered product in which phenylephrine 10 mg was the sole active ingredient; enroll patients with acute nasal congestion due to the common cold; evaluate nasal airway resistance (NAR) as the efficacy end point; and have sufficient data in the study report to allow reanalysis and/or meta-analysis of phenylephrine 10 mg versus placebo. Reanalysis of individual studies and fixed effects and random-effects meta-analyses were performed. Statistical significance at 30 and 60 minutes after dosing (the primary time points) and a >or=20% reduction in NAR from baseline were considered indicative of a clinically meaningful difference. RESULTS: Fifteen potentially relevant studies were identified, of which 8 met the inclusion criteria. Data from 7 crossover studies involving a total of 113 subjects were reanalyzed and then pooled for meta analysis; results from the initial phase of the eighth study, a parallel-group trial involving 50 subjects, were included in the reanalysis of individual studies but not in the meta-analyses. Significant differences in favor of phenylephrine were seen in 4 of the 8 studies (P or=20% with phenylephrine. CONCLUSION: These meta-analyses of 7 crossover studies and the reanalysis of a parallel-group study support the effectiveness of a single oral dose of phenylephrine 10 mg as a decongestant in adults with acute nasal congestion associated with the common cold. PMID- 17692722 TI - Efficacy and tolerability of valdecoxib in treating the signs and symptoms of severe rheumatoid arthritis: a 12-week, multicenter, randomized, double-blind, placebo-controlled study. AB - OBJECTIVE: This study compared the efficacy and tolerability of the cyclooxygenase-2-selective inhibitor valdecoxib with the nonselective NSAID naproxen and with placebo in treating severe rheumatoid arthritis (RA). METHODS: This 12-week, multicenter, randomized, double-blind, placebo-controlled study compared the efficacy and tolerability of valdecoxib 10 mg QD (n = 170) or naproxen 500 mg BID (n = 167) with placebo (n = 171) in treating the signs and symptoms of severe RA. Study patients were aged >or=18 years and were diagnosed as having RA for >or=6 months that was stable due to a treatment regimen. Severe RA was defined as a physician's and patient's global assessment of disease activity of fair, poor, or very poor at baseline; >or=6 tender or painful joints; >or=3 swollen joints; >or=45 minutes of morning stiffness; a visual analog scale pain rating of >or=40 mm; or increases since baseline in these measures. Efficacy outcome measures included the percentage of patients achieving an American College of Rheumatology Responder Index 20% (ACR-20) at weeks 1, 6 and 12. Adverse events (AEs) were graded by the investigator as mild, moderate, or severe at weeks 1, 6, and 12. RESULTS: Of the 508 patients randomized, 340 completed the study. The study groups were comparable for age, ethnic origin, weight, height, and concomitant medications, but the naproxen group had significantly more men (29% [49/167]) than the valdecoxib (18% [31/170]) and placebo (16% [27/171]) groups. The percentage of patients achieving an ACR-20 response was significantly greater in the valdecoxib and naproxen treatment groups (58.8% [100/170] and 60.8% [101/166], respectively) than in the placebo group (39.6% [67/169]) at week 12 (both, P < 0.001). The percentage of patients achieving an ACR-20 response was significantly greater in the naproxen group than in the placebo group at both week 1 (53.6% [89/166] vs 37.9% [64/169]; P = 0.003) and week 6 (64.5% [107/166] vs 46.7% [79/169]; P = 0.001), and in the valdecoxib group compared with placebo at week 1 (52.9% [90/170]; P = 0.008) but not at week 6. Patients in the valdecoxib and naproxen groups had significantly improved efficacy compared with placebo in most of the other secondary assessments of inflammation, pain, and function. The incidence of AEs was similar in all groups (valdecoxib, 54.1% [92/170]; naproxen, 55.4% [92/166]; and placebo, 52.9% [90/170]). CONCLUSION: Valdecoxib 10 mg QD administered over 12 weeks was significantly better than placebo and similar to naproxen 500 mg BID in treating the signs and symptoms of severe RA in these patients. PMID- 17692723 TI - Tretinoin gel microspheres 0.04% versus 0.1% in adolescents and adults with mild to moderate acne vulgaris: a 12-week, multicenter, randomized, double-blind, parallel-group, phase IV trial. AB - BACKGROUND: Topical retinoids are considered first-line therapy in the treatment of acne vulgaris, yet can be associated with cutaneous irritation, including erythema, peeling, dryness, burning, and itching. Tretinoin gel microsphere (TGM) formulations were developed to minimize these effects. A lower-strength TGM formulation may be desirable to further reduce exposure to tretinoin. OBJECTIVE: This study was conducted to assess the efficacy and safety profile of a lower dose TGM (0.04%) formulation compared with TGM 0.1% for the treatment of mild to moderate acne vulgaris. METHODS: In this multicenter, double-blind, parallel group, Phase IV dose-ranging study, patients with facial acne were randomized to apply either TGM 0.04% or TGM 0.1% to the face each night for 12 weeks. Patients must have discontinued systemic retinoid treatment for at least 1 year before the study and were not to have used any topical retinoids, systemic antibiotics, nicotinamide, or systemic steroids for at least 1 month. All other topical medications applied to the face (including corticosteroids, antimicrobials, salicylic acid, and benzoyl peroxide) were to be discontinued at least 2 weeks before the study. End points were the acne lesion count (total, inflammatory, and noninflammatory lesions) and the investigators' and patients' assessments of improvement. Adverse events (including severity and relationship to treatment) and signs and symptoms of cutaneous irritation at the treatment site were monitored at each study visit. RESULTS: One hundred fifty-six patients (78 TGM 0.04%, 78 TGM 0.1%) were randomized and received treatment. Patients ranged in age from 12 to 41 years (mean, 18.4 years) and were predominantly white (n = 89 [57.1%]) and male (n = 80 [51.3%]). Both TGM 0.04% and TGM 0.1% were associated with a reduction from baseline in total, inflammatory, and noninflammatory lesions. The differences between groups in the change in lesion counts from baseline to weeks 2, 4, 8, and 12 were not statistically significant. However, there was a greater reduction in inflammatory lesions at week 2 for TGM 0.1% compared with TGM 0.04% (14.8% vs 6.0%, respectively; P < 0.047). Both treatment groups had similar improvements in the investigators' global evaluation and the patients' assessment of the response to treatment. Both TGM 0.04% and TGM 0.1% were well tolerated. The most common adverse events were skin-associated burning sensation (2.6% in the TGM 0.04% group and 7.7% in the TGM 0.1% group) and irritation (6.4% and 3.8%, respectively). In the TGM 0.04% group, significantly fewer patients experienced dryness of the treatment area during the early phase of treatment (P < 0.027). However, for other measures of cutaneous irritation (peeling, burning/stinging, and itching), either there were no statistically significant differences between treatment groups or, in the case of erythema, there was a significant difference in favor of TGM 0.1% (P = 0.035). CONCLUSIONS: Both TGM 0.04% and TGM 0.1% were associated with reductions in lesion counts in these patients with mild to moderate facial acne. Both concentrations were generally well tolerated. The results suggested an early (week 2) incremental benefit for the use of TGM 0.1% in the treatment of inflammatory lesions. PMID- 17692724 TI - Retrospective analysis of electrocardiographic changes after administration of oral or intravenous garenoxacin in five phase I, placebo-controlled studies in healthy volunteers. AB - BACKGROUND: Certain fluoroquinolones and macrolide antibiotics have been associated with prolongation of the corrected QT (QTc) interval or QT dispersion, leading to cardiac arrhythmias. Garenoxacin is a des-F(6)-quinolone with broad spectrum antimicrobial activity and a favorable pharmacokinetic/pharmacodynamic profile. Its effects on electrocardiographic (ECG) parameters in healthy volunteers have not been reported. OBJECTIVE: The cardiac safety profile of garenoxacin was further examined using data from healthy volunteers enrolled in 5 dose-ranging and comparative Phase I clinical studies. METHODS: This was a retrospective analysis of 5 randomized, double-blind, placebo-controlled studies in which 224 healthy volunteers received oral or intravenous garenoxacin (50-1200 mg/d) for 1 to 28 days' dosing duration (450 milliseconds for men, >470 milliseconds for women) or the PR interval (>250 milliseconds). One subject had a change in QTcB of 67 milliseconds 4 hours after administration of garenoxacin 400 mg PO on day 7, but the actual value was 418 milliseconds (baseline, 351 milliseconds); the corresponding change in QTcF was 49 milliseconds (actual, 408 milliseconds; baseline, 359 milliseconds). The means for other derived ECG parameters were generally similar between garenoxacin-treated volunteers and placebo controls. CONCLUSION: In this retrospective analysis of data from healthy volunteers, garenoxacin had no clinically relevant dose-, route-of-administration , or concentration-dependent effects on the QTc or PR interval across a dose range from 50 to 1200 mg/d. PMID- 17692725 TI - A retrospective analysis of possible renal toxicity associated with vancomycin in patients with health care-associated methicillin-resistant Staphylococcus aureus pneumonia. AB - OBJECTIVE: The goal of this investigation was to determine whether more aggressive vancomycin dosing is associated with greater risk for renal toxicity in patients with health care-associated pneumonia (HCAP) attributed to methicillin-resistant Staphylococcus aureus (MRSA). METHODS: This was a retrospective, single-center, observational cohort study. The following information was obtained for all study patients from automated hospital, microbiology, and pharmacy databases: age, sex, weight, serial serum creatinine (SCr), age- and sex-adjusted creatinine clearance (CrCl) during receipt of vancomycin, vancomycin serum trough concentrations, duration of vancomycin therapy, and Acute Physiology and Chronic Health Evaluation II scores. Renal toxicity was defined as either a 0.5-mg/dL increase from baseline in SCr or a >or=50% increase in SCr based on serial SCr measurements. Data for patients who met the definition of renal toxicity were compared with data for those who did not. RESULTS: Ninety-four patients (mean [SD]age, 59.0 [15.6] years; 59 [62.8%] men; 73 (77.7%) white; mean baseline CrCl, 70.3 [23.0] mL/min) were identified as having MRSA HCAP. Forty (42.6%) patients developed renal toxicity. Patients who developed renal toxicity were significantly more likely than patients who did not develop renal toxicity to have greater mean vancomycin serum trough concentrations (20.8 [9.9] g/mL vs 14.3 [6.7] g/mL, respectively; P < 0.001), vancomycin serum trough concentrations >or=15 g/mL (67.5% vs 40.7%; P = 0.01), and a prolonged duration (>or=14 days) of vancomycin treatment (45.0% vs 20.4%; P = 0.011). Logistic regression analysis identified a maximum vancomycin serum trough concentration of >or=15 g/mL as being independently associated with renal toxicity (adjusted odds ratio = 2.82; 95% CI, 1.02-7.74; P = 0.045). The overall mean change in CrCl for the study population was -13.5 (-16.0) mL/min (range, 0.0 to -62.6 mL/min). Patients with maximum measured vancomycin serum trough concentrations >or=15 g/mL (n = 49) had significantly greater absolute changes in CrCl compared with patients with maximum measured vancomycin serum trough concentrations <15 g/mL (n = 45) (-18.9 [-17.0] vs -7.6 [-12.5] mL/min, respectively; P < 0.001). CONCLUSIONS: The results suggest that aggressive vancomycin dosing and prolonged vancomycin administration may be associated with greater risk for renal toxicity in patients with MRSA HCAP. However, this retrospective study cannot establish causation, and a prospective, randomized, double-blind trial is needed. PMID- 17692726 TI - Clinical evaluation of novel bisphosphonate dosing regimens in osteoporosis: the role of comparative studies and implications for future studies. AB - BACKGROUND: Daily nitrogen-containing bisphosphonates have shown antifracture efficacy in many studies of postmenopausal osteoporosis. However, current dosing schedules are often inconvenient or impractical for patients. Efforts to reduce dosing frequency to improve adherence (ie, compliance and persistence), and therefore treatment outcomes, are ongoing. Although a number of trial designs can be used to consider the efficacy of therapy, comparing the efficacy of different regimens should only be undertaken in purposefully designed head-to-head studies. OBJECTIVE: This article summarizes the design and conduct of clinical studies that have investigated alternative bisphosphonate regimens and those that have directly compared different approved bisphosphonates. It also explores the implications for future studies of postmenopausal osteoporosis treatment. METHODS: Using the terms bisphosphonate, daily, weekly, and monthly, a search (completed in 2006) of the PubMed database was conducted to identify primary English-language publications of pertinent studies comparing either novel with established regimens of the same bisphosphonates or different established bisphosphonates. RESULTS: The first option is the equivalence or noninferiority bridging study for comparison of new treatment regimens versus the established regimen of the same bisphosphonate, known as the active comparator. Four such studies have led to the registration of novel bisphosphonate dosing regimens designed to provide easier dosing alternatives for patients. The second option is the active comparator study, which compares one bisphosphonate with the most prescribed weekly bisphosphonate. Weekly dosed oral alendronate has previously been shown to be superior (for bone mineral density gains) to daily and weekly dosed oral risedronate. An ongoing noninferiority study, Monthly Oral Therapy with Ibandronate for Osteoporosis Intervention, is comparing weekly alendronate with ibandronate, a monthly oral bisphosphonate. CONCLUSIONS: The exploration of new dosing schedules and formulations aims to identify the optimal bisphosphonate regimen for postmenopausal osteoporosis. To achieve this, careful consideration must be given to the choice of a scientifically valid study design that effectively, and ethically, meets the study objectives. Given the concerns regarding placebo-controlled antifracture studies, 2 alternative study designs should be considered, both using validated surrogate end points (bone mineral density and biochemical markers of bone turnover) as the principal mode of assessment. PMID- 17692727 TI - Immunogenicity and tolerability of an investigational formulation of interferon beta1a: 24- and 48-week interim analyses of a 2-year, single-arm, historically controlled, phase IIIb study in adults with multiple sclerosis. AB - BACKGROUND: RNF (Rebif New Formulation, Merck Serono International S.A., Geneva, Switzerland), a formulation of interferon-beta1a (IFN-beta1a) without human- or animal-derived components, is currently under investigation. It was developed with the aim of maximizing the treatment benefit for patients with multiple sclerosis (MS) by improving injection tolerability and reducing the development of neutralizing antibodies (NAbs). OBJECTIVE: This paper reports the results of planned 24- and 48-week interim analyses comparing immunogenicity and tolerability data from an ongoing study of RNF with historical-control data for the currently approved formulation of IFN-beta1a from the EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) study. METHODS: Patients in the 96-week, multicenter, singlearm, Phase IIIb RNF study received 44 microg/0.5 mL SC tiw; patients in the EVIDENCE study received an identical regimen of the currently approved formulation of IFN-beta1a. Criteria for inclusion in the RNF study were age between 18 and 60 years, an Expanded Disability Status Scale (EDSS) score <6.0, and a diagnosis of relapsing MS (McDonald criteria). Criteria for inclusion in the EVIDENCE study were age between 18 and 55 years, an EDSS score of 0 to 5.5, and a diagnosis of clinically definite relapsing-remitting MS (Poser criteria). Patients in both studies were treatment naive. Both studies used the same cytopathic-effect assay for NAbs to assess immunogenicity; patients who had NAb titers >or=20 neutralizing units (NU)/mL were considered NAb+. The primary end point was to compare the proportions of NAb+ patients in the RNF study and the historical data. Comparisons were descriptive and used exact 95% CIs. Safety analyses included 8 prespecified adverse events (AEs) of interest. RESULTS: Baseline demographic characteristics were well balanced between the RNF (N = 260) and EVIDENCE (N = 339) studies, except that patients in the RNF study were slightly younger (median age, 34.0 vs 39.0 years, respectively), and a few had secondary progressive MS (n = 6) or progressive relapsing MS (n = 1). At week 48, 87.3% of patients in the RNF study remained on treatment. The incidence of the prespecified AEs of interest in the RNF and EVIDENCE studies was as follows: flu-like symptoms (70.8% and 48.1%, respectively), injection-site reactions (29.6% and 83.8%), hepatic disorders (13.1% and 16.8%), cytopenia (9.6% and 11.8%), depression and suicidal ideation (5.8% and 19.8%), skin rashes (5.4% and 12.1%), hypersensitivity reactions (5.4% and 3.2%), and thyroid disorders (2.3% and 5.0%). Overall, the majority (96.9%) of AEs in the RNF study were mild (69.5%) or moderate (27.5%) in severity. The proportions of patients in the RNF and EVIDENCE studies with NAbs at both 24 and 48 weeks were 2.5% (95% CI, 0.9-5.5) and 14.3% (95% CI, 10.7 18.6), respectively; the proportions with NAbs at week 48 only were 13.9% (95% CI, 9.9-18.7) and 24.4% (95% CI, 19.9-29.4). The proportions of NAb+ patients with high NAb titers (>1000 NU/mL) at week 48 were 11.1% in the RNF study and 19.5% in the EVIDENCE study. CONCLUSIONS: The results of these interim analyses suggest that RNF had an improved overall tolerability and safety profile and a lower immunogenic potential compared with the approved IFN-beta1a formulation assessed in the EVIDENCE study. Two-year results from the RNF study are anticipated before the end of 2007. PMID- 17692728 TI - Bioavailability of two oral suspension and two oral tablet formulations of acyclovir 400 mg: two single-dose, open-label, randomized, two-period crossover comparisons in healthy Mexican adult subjects. AB - BACKGROUND: Acyclovir is an important antiviral drug, used extensively for treatment of herpes simplex and varicella zoster. Six oral generic formulations of acyclovir are available in Mexico; however, a literature search failed to identify data information concerning the bioavailability of these formulations in the Mexican population. OBJECTIVE: The aim of these 2 studies was to compare the bioavailability of 4 oral formulations of acyclovir 400 mg--2 tablet formulations and 2 suspension formulations--with their corresponding listed drug references in Mexico (a list issued by Mexican Health Authorities). METHODS: Two separate, single-dose, open-label, randomized, 2-period crossover studies were conducted at the Centro de Estudios Cientificos y Clinicos Pharma, S.A. de C.V. (clinical unit), Mexico City, Mexico. For each study, a different set of eligible subjects were selected. They included healthy Mexican volunteers of either sex. For each study, subjects were randomly assigned to receive 1 test formulation of acyclovir 400 mg followed by the reference formulation, or vice versa, with a 1-week washout period between doses. After a 12-hour (overnight) fast, subjects received a single 400-mg dose (tablet or 10-mL suspension) of the corresponding formulation. For the analysis of pharmacokinetic properties, including C(max), AUC from time 0 (baseline) to time t (AUC(0-t)), and AUC from baseline to infinity (AUC(0-infinity)), blood samples were drawn at baseline, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, and 24 hours after dosing. The formulations were considered bioequivalent if the natural logarithm (ln) transformed ratios of Cmax and AUC were within the predetermined equivalence range of 80% to 125% and if P or=52-week follow-up, the rate of remissions was 81.5% to 100% (P < 0.003). CONCLUSION: Based on the results from the present 1-year extension study, treatment with this probiotic-prebiotic complex may be an option for short-term (2-4 weeks) and long-term ( approximately 60-week) reductions in IBS symptoms. PMID- 17692730 TI - Hemorrhagic cystitis in a patient receiving conventional doses of dacarbazine for metastatic malignant melanoma: case report and review of the literature. AB - INTRODUCTION: Hemorrhagic cystitis is a potentially life-threatening complication in patients receiving cancer therapy. This urologic emergency is commonly associated with the chemotherapeutic use of oxazaphosphorine alkylating agents. This report describes a case of hemorrhagic cystitis associated with dacarbazine treatment. CASE SUMMARY: A 63-year-old man with asymptomatic metastatic malignant melanoma received 3 cycles of dacarbazine (600-850 mg/m2) monochemotherapy, each 3 weeks apart. Two weeks after the third cycle, he presented with gross hematuria and mild dysuria. Physical examination revealed no significant finding. Hematuria was confirmed by urinalysis, and urinary infection was excluded by repeated urine cultures. Ultrasonography revealed diffuse bladder wall thickening with no discrete mass or ulceration. Cystoscopy findings revealed generalized inflammation and edema of the mucosa of the bladder, confirming the diagnosis of hemorrhagic cystitis. The patient's gross hematuria continued for 2 weeks and then completely resolved with supportive care. Two weeks after complete resolution, the patient experienced 2 transient episodes of gross hematuria that lasted a few hours and subsided spontaneously. DISCUSSION: Dacarbazine is currently considered the standard first-line treatment in patients with advanced malignant melanoma. At standard prescribed doses (a single dose of 850-1000 mg/m2 or 250 mg/m2 for 5 days per cycle), dacarbazine is a reasonably well tolerated chemotherapeutic drug; nausea, vomiting, and myelosuppression are the most common adverse effects. Association of dacarbazine with hemorrhagic cystitis has not been reported previously (in a PubMed literature search from 1950-2006), and only 1 case report associates temozolomide (an analog of dacarbazine) with hemorrhagic cystitis. Based on the Naranjo adverse drug reactions probability scale, an objective assessment revealed dacarbazine to be a probable cause of hemorrhagic cystitis in this case. CONCLUSIONS: This case report suggests that dacarbazine at conventional doses was a probable cause of hemorrhagic cystitis. Regular urinalysis and early intervention are recommended, as a means of detecting early hematuria and subsequently reducing or discontinuing dacarbazine treatment. Adequate hydration before, during, and after dacarbazine administration may be useful in preventing this complication. PMID- 17692731 TI - Transition from methylphenidate or amphetamine to atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder--a preliminary tolerability and efficacy study. AB - BACKGROUND: The primary treatment for attention-deficit/hyperactivity disorder (ADHD) has been psychostimulants. Recently developed nonpsychostimulant treatments have allowed certain patients to switch from a psychostimulant to a nonpsychostimulant. However, the outcomes of such switches have not been systematically studied. OBJECTIVE: The purpose of this pilot study was to assess treatment tolerance and efficacy during a cross-taper transition from methylphenidate or amphetamine to atomoxetine among children and adolescents with ADHD. METHODS: This pilot study was conducted in patients (aged 6-17 years) with incomplete responses (failure to obtain full reduction/elimination of symptoms) or intolerance of adverse events (AEs) during psychostimulant treatment. Patients continued ongoing psychostimulant treatment during the first week of the study. Transition to atomoxetine began by administering atomoxetine 0.5 mg/kg . d plus full-dose psychostimulant for 1 week, followed in the second week by 1.2 mg/kg . d atomoxetine plus half-dose psychostimulant. Patients remained on 1.2 mg/kg . d atomoxetine monotherapy for the remaining 5 weeks. This stepwise transition was enacted due to the difference in pharmacodynamics between the psychostimulants and atomoxetine. Applying a stepwise cross-titration allowed for better control of ADHD symptoms during the intervening period. Change in ADHD symptoms, as measured by the mean change in the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-administered and -scored (ADHDRS-IV Parent:Inv), was assessed from baseline to end point. RESULTS: Of the 62 subjects enrolled in the study, 39 (62.9%) were diagnosed as ADHD-combined type. Similar proportions were receiving methylphenidate (51.6%) and amphetamine (48.4%). Slightly more wished to switch due to inadequate response (53.2%) than intolerability (46.8%). Nine subjects discontinued at various times during the course of the study (patient or parent/caregiver decision [4], AE [2], protocol violation [2], and lack of efficacy [1]). Mean (SD) ADHDRS-IV-Parent:Inv total scores (n = 59, last-observation-carried-forward) improved significantly from baseline (visit 2) to an end point (32.1 [10.5] vs 22.6 [14.0]; P < 0.001). Of the 58 subjects answering in the atomoxetine monotherapy phase, 38 (65.5%) reported a preference for atomoxetine treatment over their previous psychostimulant. Tolerability results were as follows: 26 (44.1%) of 59 patients reported >or=1 AE, the most common being somnolence (4 [6.8%]), fatigue (3 [5.1%]), decreased appetite (3 [5.1%]), cough (3 [5.1%]), headache (3 [5.1%]), and contact dermatitis (2 [3.4%]). No clinically severe AEs were reported. Both mean (SD) diastolic (2.4 [7.8] mm Hg; P = 0.031) and systolic (2.4 [7.9] mm Hg; P = 0.029) blood pressures increased significantly from baseline to end point. Electrocardiography revealed a significant increase in mean (SD) heart rate (9.2 [11.6] bpm; P < 0.001) and a corresponding decrease in mean (SD) RR interval ( 77.8 [98.2] ms; P < 0.001). Statistically significant, but mild, increases in diastolic pressure and heart rate were observed. CONCLUSION: These children and adolescent patients were successfully switched from methylphenidate or amphetamine to atomoxetine treatment, with resulting improvement in ADHD symptom severity from baseline in this pilot study. PMID- 17692732 TI - Medication adherence research in populations: measurement issues and other challenges. PMID- 17692733 TI - Cost-effectiveness of clopidogrel in myocardial infarction with ST-segment elevation: a European model based on the CLARITY and COMMIT trials. AB - BACKGROUND: Several health economic studies have shown that the use of clopidogrel is cost-effective to prevent ischemic events in non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina. OBJECTIVE: This study was designed to assess the cost-effectiveness of clopidogrel in short- and long-term treatment of ST-segment elevation myocardial infarction (STEMI) with the use of data from 2 trials in Sweden, Germany, and France: CLARITY (Clopidogrel as Adjunctive Reperfusion Therapy) and COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial). METHODS: A combined decision tree and Markov model was constructed. Because existing evidence indicates similar long term outcomes after STEMI and NSTEMI, data from the long-term NSTEMI CURE trial (Clopidogrel in Unstable Angina to Prevent Recurrent Events) were combined with 1 month data from CLARITY and COMMIT to model the effect of treatment up to 1 year. The risks of death, myocardial infarction, and stroke in an untreated population and long-term survival after all events were derived from the Swedish Hospital Discharge and Cause of Death register. The model was run separately for the 2 STEMI trials. A payer perspective was chosen for the comparative analysis, focusing on direct medical costs. Costs were derived from published sources and were converted to 2005 euros. Effectiveness was measured as the number of life years gained (LYG) from clopidogrel treatment. RESULTS: In a patient cohort with the same characteristics and event rates as in the CLARITY population, treatment with clopidogrel for up to 1 year resulted in 0.144 LYG. In Sweden and France, this strategy was dominant with estimated cost savings of euro 111 and euro 367, respectively. In Germany, clopidogrel treatment had an incremental cost effectiveness ratio (ICER) of euro 92/LYG. Data from the COMMIT study showed that clopidogrel treatment resulted in 0.194 LYG at an incremental cost of euro 538 in Sweden, euro 798 in Germany, and euro 545 in France. The corresponding ICERs were euro 2772/LYG, euro 4144/LYG, and euro 2786/LYG, respectively. CONCLUSIONS: Treatment of these STEMI patients with clopidogrel appeared to be cost-effective in all 3 European countries studied. Predicted ICERs were below generally accepted threshold values. PMID- 17692734 TI - Comparison of hospitalizations, emergency department visits, and costs in a historical cohort of Texas Medicaid patients with chronic obstructive pulmonary disease, by initial medication regimen. AB - BACKGROUND: Limited information is available on the relative outcomes and treatment costs of various pharmacotherapies for chronic obstructive pulmonary disease (COPD) in a Medicaid population. OBJECTIVE: This study compared the effects of initial medication regimens for COPD on COPD-related and all-cause events (hospitalizations and/or emergency department [ED] visits) and COPD related and all-cause costs. METHODS: The study population was a historical cohort of Texas Medicaid beneficiaries aged 40 to 64 years with COPD-related medical costs (International Classification of Diseases, Ninth Revision, Clinical Modification codes 491.xx, 492.xx, 496.xx), 24 months of continuous Medicaid enrollment (12 months before and after the index prescription), and at least 1 prescription claim (index) for a combination product containing fluticasone propionate + salmeterol, an inhaled corticosteroid, salmeterol, or ipratropium between April 1, 2001, and March 31, 2003. The analyses of events employed Cox proportional hazards regression, controlling for baseline factors and preindex events. The analyses of costs used a 2-part model with logistic regression and generalized linear model to adjust for baseline characteristics and preindex utilization and costs. RESULTS: The study population included 6793 patients (1211 combination therapy, 968 inhaled corticosteroid, 401 salmeterol, and 4213 ipratropium). Only combination therapy was associated with a significantly lower risk for any COPD-related event (hazard ratio [HR] = 0.733; 95% CI, 0.650-0.826) and any all-cause event (HR = 0.906; 95% CI, 0.844-0.972) compared with ipratropium. COPD-related prescription costs were higher in all cohorts compared with the ipratropium cohort, but COPD-related medical costs were lower, offsetting the increase in prescription costs. For all-cause costs, prescription costs were higher in the combination-therapy cohort (+$415; P < 0.05) and the salmeterol cohort (+$247; P < 0.05) compared with the ipratropium cohort, but significant reductions in all-cause medical costs in the combination-therapy cohort (-$1735; P < 0.05) and salmeterol cohort (-$1547; P < 0.05) more than offset the increase in prescription costs. CONCLUSIONS: In this historical population of Texas Medicaid beneficiaries, the combination-therapy cohort was 27% less likely to have a COPD-related event than the ipratropium cohort, 10% less likely to have any all-cause event, had similar COPD-related costs, and had reduced all-cause costs. Thus, compared with the ipratropium cohort, the combination-therapy cohort had an improvement in outcomes (based on the decreased time to a hospitalization or ED visit), with similar or decreased direct medical costs. Future research is needed in other patient groups. PMID- 17692735 TI - Factors related to antipsychotic oversupply among Central Texas Veterans. AB - BACKGROUND: There have been many studies of underadherence to antipsychotics, but antipsychotic overadherence, or medication oversupply, in which patients receive more prescription medications than are needed, has been overlooked. Both underadherence and oversupply can have an important impact on clinical outcomes. OBJECTIVES: This study examined adherence (based on the medication possession ratio [MPR]) among patients treated with antipsychotics in the Central Texas Veterans Health Care System (CTVHCS) and investigated factors associated with their adherence status. METHODS: Data from September 1995 to October 2002 were extracted from the computerized patient record system of the CTVHCS for continuously enrolled adult outpatients receiving antipsychotic monotherapy and filling at least 2 prescriptions within a year of the index date. Patients' prescription records were tracked for up to 12 months. Underadherence was defined as an MPR <0.8, good adherence as an MPR from 0.8 to 1.2, and oversupply as an MPR >1.2. RESULTS: Of 3268 eligible patients, 49.9% had good adherence, 42.6% were underadherent, and 7.6% had medication oversupply. The overall mean (SD) MPR was 0.83 (0.33). Multinomial logistic regression analysis revealed that compared with patients with good adherence, underadherent patients were significantly more likely to be nonwhite (P < 0.001), younger (P < 0.01), and receiving chlorpromazine therapy (P < 0.05), and were less likely to be receiving fluphenazine (P < 0.01), olanzapine (P < 0.05), or risperidone (P < 0.05). Patients with medication oversupply were significantly more likely to be receiving olanzapine (P < 0.001), quetiapine (P < 0.01), or risperidone (P < 0.05) than those with good adherence. CONCLUSIONS: Although half of adult outpatients receiving antipsychotic monotherapy in the CTVHCS were adherent to their treatment regimens, a large proportion were underadherent, and a small proportion had medication oversupply. Patients receiving second-generation antipsychotics were more likely to be adherent and were more likely to have medication oversupply than patients receiving first-generation antipsychotics. PMID- 17692736 TI - Publish, don't perish. PMID- 17692737 TI - Writing a paper. PMID- 17692738 TI - ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. PMID- 17692739 TI - Cardiovascular protection using beta-blockers: a critical review of the evidence. AB - For more than 3 decades, beta-blockers have been widely used in the treatment of hypertension and are still recommended as first-line agents by national and international guidelines. Recent meta-analyses indicate that, in patients with uncomplicated hypertension, compared with other antihypertensive agents, first line therapy with beta-blockers was associated with an increased risk of stroke, especially in the elderly cohort with no benefit for the end points of all-cause mortality, cardiovascular morbidity, and mortality. In this review, we critically analyze the evidence supporting the use of beta-blockers in patients with hypertension and evaluate evidence for its role in other indications. The review of the currently available literature shows that in patients with uncomplicated hypertension, there is a paucity of data or absence of evidence to support use of beta-blockers as monotherapy or as first-line agents. Given the increased risk of stroke, their "pseudo-antihypertensive" efficacy (failure to lower central aortic pressure), lack of effect on regression of target end organ effects like left ventricular hypertrophy and endothelial dysfunction, and numerous adverse effects, the risk benefit ratio for beta-blockers is not acceptable for this indication. However, beta-blockers remain very efficacious agents for the treatment of heart failure, certain types of arrhythmia, hypertropic obstructive cardiomyopathy, and in patients with prior myocardial infarction. PMID- 17692740 TI - Angiographic stent thrombosis after routine use of drug-eluting stents in ST segment elevation myocardial infarction: the importance of thrombus burden. AB - OBJECTIVES: This study sought to investigate the impact of thrombus burden on the clinical outcome and angiographic infarct-related artery stent thrombosis (IRA ST) in patients routinely treated with drug-eluting stent (DES) implantation for ST-segment elevation myocardial infarction (STEMI). BACKGROUND: There are limited data for the safety and effectiveness of DES in STEMI. METHODS: We retrospectively analyzed 812 consecutive patients treated with DES implantation for STEMI. Intracoronary thrombus burden was angiographically estimated and categorized as large thrombus burden (LTB), defined as thrombus burden > or =2 vessel diameters, and small thrombus burden (STB) to predict clinical outcomes. Major adverse cardiac events (MACE) were defined as death, repeat myocardial infarction, and IRA reintervention. RESULTS: Mean duration of follow-up was 18.2 +/- 7.8 months. Large thrombus burden was an independent predictor of mortality (hazard ratio [HR] 1.76, p = 0.023) and MACE (HR 1.88, p = 0.001). The cumulative angiographic IRA-ST was 1.1% at 30 days and 3.2% at 2 years, and continued to augment beyond 2 years. It was significantly higher in the LTB compared with the STB group (8.2% vs. 1.3% at 2 years, respectively, p < 0.001). Significant independent predictors for IRA-ST were LTB (HR 8.73, p < 0.001), stent thrombosis at presentation (HR 6.24, p = 0.001), bifurcation stenting (HR 4.06, p = 0.002), age (HR 0.55, p = 0.003), and rheolytic thrombectomy (HR 0.11, p = 0.03). CONCLUSIONS: Large thrombus burden is an independent predictor of MACE and IRA-ST in patients treated with DES for STEMI. PMID- 17692741 TI - Volume-to-creatinine clearance ratio: a pharmacokinetically based risk factor for prediction of early creatinine increase after percutaneous coronary intervention. AB - OBJECTIVES: This study sought to validate a pharmacokinetically derived measure of the risk of an early increase in serum creatinine after percutaneous coronary intervention (PCI). BACKGROUND: The ratio of the volume of contrast media to the creatinine clearance (V/CrCl) has been shown to correlate with the area under the curve of contrast media concentration over time. METHODS: We calculated V/CrCl in 3,179 consecutive patients undergoing PCI. An increase in serum creatinine of >0.5 mg/dl by 24 to 48 h was considered abnormal. Receiver-operator characteristic methods were used to identify the optimal sensitivity and specificity for the observed range of V/CrCl. The predictive value of V/CrCl for the risk of an early increase in creatinine was assessed using multivariable logistic regression. RESULTS: The overall incidence of an abnormal, early increase in creatinine was 1.5%. The mean and median values of V/CrCl for patients with (mean 5.2 +/- 4.4, median 4.3, interquartile range 2.7 to 6.0) and without (mean 3.0 +/- 2.0, median 2.5, interquartile range 1.7 to 3.8) an early creatinine increase were each significantly (p < 0.001) different between groups. Furthermore, there was a significant association between V/CrCl and an early increase in creatinine (overall and trend, p < 0.001). The receiver-operator characteristic curve analysis indicated that a V/CrCl ratio of 3.7 was a fair discriminator for the early creatinine increase (C-statistic 0.69). After adjusting for other known predictors of post-PCI creatinine increase, V/CrCl > or =3.7 remained significantly associated with an early abnormal increase in serum creatinine (odds ratio 3.84; 95% confidence interval 2.0 to 7.3, p < 0.001). CONCLUSIONS: A V/CrCl ratio >3.7 was a significant and independent predictor of an early abnormal increase in serum creatinine after PCI in this unselected patient population. PMID- 17692742 TI - Aldosterone receptor antagonism induces reverse remodeling when added to angiotensin receptor blockade in chronic heart failure. AB - OBJECTIVES: The objective of this study was to determine if adding spironolactone to an angiotensin II receptor blocker improves left ventricular (LV) function, mass, and volumes in chronic heart failure. BACKGROUND: Add-on spironolactone therapy substantially improves clinical outcomes among patients with severe heart failure (HF) on standard therapy. However, the value of combining spironolactone with an angiotensin II receptor blocker on LV reverse remodeling in mild-to moderate systolic HF is unclear. METHODS: Fifty-one systolic HF patients with left ventricular ejection fraction (LVEF) <40% were randomly assigned to receive 1-year treatment of candesartan and spironolactone (combination group) or candesartan and placebo (control group). Reverse remodeling was assessed by serial cardiac magnetic resonance imaging and echocardiographic tissue Doppler imaging (TDI). RESULTS: There were significant improvements in LVEF (35 +/- 3% vs. 26 +/- 2%, p < 0.01) and reduction of LV end-diastolic volume index (121 +/- 16 ml/m2 vs. 155 +/- 14 ml/m2, p = 0.001), end-systolic volume index (88 +/- 17 ml/m2 vs. 120 +/- 15 ml/m2, p < 0.0005), and LV mass index (81 +/- 6 g/m2 vs. 93 +/- 6 g/m2, p = 0.002) in the combination group at 1 year. In addition, there was significant increase in peak basal systolic velocity and strain by TDI, decrease in index of filling pressure, and increase in cyclic variation integrated backscatter. In the control group, there were no significant changes in all these parameters after 1 year. CONCLUSIONS: The addition of spironolactone to candesartan has significant beneficial effects on LV reverse remodeling in patients with mild-to-moderate chronic systolic HF. PMID- 17692743 TI - Myocardial structural effects of aldosterone receptor antagonism in heart failure. PMID- 17692744 TI - Effects of multiple oral doses of an A1 adenosine antagonist, BG9928, in patients with heart failure: results of a placebo-controlled, dose-escalation study. AB - OBJECTIVES: This study sought to assess the pharmacokinetics and clinical effects of oral BG9928 in heart failure (HF) patients. BACKGROUND: Declining renal function during HF treatment is associated with poor outcomes. BG9928, a selective inhibitor of the A1 adenosine receptor, is proposed to cause natriuresis without causing a decline in renal function. METHODS: A randomized, double-blind, placebo-controlled study was conducted in patients with HF and systolic dysfunction who were receiving standard therapy. Patients were randomized to receive BG9928 (3, 15, 75, or 225 mg) or placebo orally for 10 days. The primary end point was change in sodium excretion. Changes in potassium excretion, creatinine clearance, and body weight also were evaluated. RESULTS: A total of 50 patients were studied. BG9928 increased sodium excretion compared with placebo, and natriuresis was maintained over 10 days with little kaliuresis. A linear trend in dose response was observed on day 1 (p = 0.04) but not on days 6 or 10. Adjusted creatinine clearance was unchanged over the 10 days. Patients who received 15, 75, or 225 mg of BG9928 had a reduction in body weight compared with placebo (-0.6, -0.7, -0.5, vs. +0.3 kg, respectively) at the end of study. BG9928 was well tolerated. The pharmacokinetic profile of BG9928 was consistent with once-daily dosing. CONCLUSIONS: Oral BG9928 over the dose range of 3 to 225 mg/day produced significant increases in sodium excretion in patients with stable HF without causing kaliuresis or reducing renal function. PMID- 17692745 TI - Measurement of the interleukin family member ST2 in patients with acute dyspnea: results from the PRIDE (Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study. AB - OBJECTIVES: The aim of this study was to examine the value of measurement of the interleukin-1 receptor family member ST2 in patients with dyspnea. BACKGROUND: Concentrations of ST2 have been reported to be elevated in patients with heart failure (HF). METHODS: Five hundred ninety-three dyspneic patients with and without acute destabilized HF presenting to an urban emergency department were evaluated with measurements of ST2 concentrations. Independent predictors of death at 1 year were identified. RESULTS: Concentrations of ST2 were higher among those with acute HF compared with those without (0.50 vs. 0.15 ng/ml; p < 0.001), although amino-terminal pro-brain natriuretic peptide (NT-proBNP) was superior to ST2 for diagnosis of acute HF. Median concentrations of ST2 at presentation to the emergency department were higher among decedents than survivors at 1 year (1.08 vs. 0.18 ng/ml; p < 0.001), and in multivariable analyses, an ST2 concentration > or =0.20 ng/ml strongly predicted death at 1 year in dyspneic patients as a whole (HR = 5.6, 95% confidence interval [CI] 2.2 to 14.2; p < 0.001) as well as those with acute HF (hazard ratio [HR] = 9.3, 95% CI 1.3 to 17.8; p = 0.03). This risk associated with an elevated ST2 in dyspneic patients with and without HF appeared early and was sustained at 1 year after presentation (log-rank p value <0.001). A multi-marker approach with both ST2 and NT-proBNP levels identified subjects with the highest risk for death. CONCLUSIONS: Among dyspneic patients with and without acute HF, ST2 concentrations are strongly predictive of mortality at 1 year and might be useful for prognostication when used alone or together with NT-proBNP. PMID- 17692746 TI - Bradycardia pacing-induced short-long-short sequences at the onset of ventricular tachyarrhythmias: a possible mechanism of proarrhythmia? AB - OBJECTIVES: The purpose of this study was to characterize interactions between normal pacing system operation and the initiating sequence of ventricular tachycardia (VT)/ventricular fibrillation (VF). BACKGROUND: Abrupt changes in ventricular cycle lengths (short-long-short, S-L-S) might initiate VT/VF. The S-L S sequences might be passively permitted or actively facilitated by bradycardia pacing. METHODS: Initiating sequences of 1,356 VT/VF episodes in the PainFree Rx II (n = 634) and EnTrust Trial (n = 421) were analyzed with stored electrograms and by pacing mode (DDD/R, VVI/R, and Managed Ventricular Pacing [MVP]). Interactions between pacing and VT/VF initiation were classified as: non-pacing associated, pacing associated, pacing permitted, and pacing facilitated. RESULTS: Non-pacing associated (no pacing, no S-L-S) and pacing associated (ventricular pacing without S-L-S) onset accounted for 44.0% and 29.8% of all VT/VF, respectively. Pacing permitted (S-L-S sequences without ventricular pacing) episodes accounted for 6.4% (DDD/R), 20.0% (MVP), and 25.6% (VVI/R) of 1,356 VT/VF episodes. Pacing facilitated onset (S-L-S sequences actively facilitated by ventricular pacing including the terminal beat after a pause) accounted for 8.2% (MVP), 9.4% (VVI/R), and 14.8% (DDD/R) of 1,356 VT/VF episodes. Pacing facilitated S-L-S VT/VF occurred in 2.6% (MVP), 3.3% (VVI/R), and 5.2% (DDD/R) of patients with episodes and was the sole initiating sequence in approximately 1% of patients. Pause durations during pacing facilitated S-L-S differed between modes (DDD/R 793 +/- 172 ms vs. MVP 865 +/- 278 ms vs. VVI/R 1180 +/- 414 ms, p = 0.002). The majority of these episodes were monomorphic VT. CONCLUSIONS: Ventricular tachycardia/VF in some implantable cardioverter-defibrillator patients might be initiated by S-L-S sequences that are actively facilitated by bradycardia pacing operation and might constitute an important mechanism of ventricular proarrhythmia. PMID- 17692747 TI - Pacemaker pro-arrhythmia: beyond spike-on-T and endless loop tachycardia. PMID- 17692748 TI - Central sympatholysis as a novel countermeasure for cocaine-induced sympathetic activation and vasoconstriction in humans. AB - OBJECTIVES: The aim of this study was to determine whether cocaine's sympathomimetic actions can be reversed by a potent centrally acting alpha2 adrenergic receptor (AR) agonist (dexmedetomidine). BACKGROUND: We recently showed that cocaine stimulates the human cardiovascular system primarily by acting in the brain to increase sympathetic nerve activity (SNA), the neural stimulus to norepinephrine release. Thus, SNA constitutes a putative new drug target to block cocaine's adverse cardiovascular effects at their origin. METHODS: In 22 healthy cocaine-naive humans, we measured skin SNA (microneurography) and skin blood flow (laser Doppler velocimetry) as well as heart rate and blood pressure before and after intranasal cocaine (2 mg/kg) alone and in combination with dexmedetomidine or saline. RESULTS: During intranasal cocaine alone, SNA increased by 2-fold and skin vascular resistance increased from 13.2 +/- 2.3 to 20.1 +/- 2.2 resistance units while mean arterial pressure increased by 14 +/- 3 mm Hg and heart rate by 18 +/- 3 beats/min (p < 0.01). Dexmedetomidine abolished these increases, whereas intravenous saline was without effect. Dexmedetomidine was effective in blocking these sympathomimetic actions of cocaine even in all 7 subjects who were homozygous for the Del322-325 polymorphism in the alpha2C AR, a loss-of-function mutation that is highly enriched in blacks. CONCLUSIONS: The data advance the novel hypothesis that central sympatholysis with dexmedetomidine constitutes a highly effective countermeasure for cocaine's sympathomimetic actions on the human cardiovascular system, even in individuals carrying the alpha2CDel322-325 polymorphism. (Study to Improve Scientific Understanding of the Cardiovascular Actions of Cocaine; http://clinicaltrials.gov/ct/show/NCT00338546?order=1; NCT00338546). PMID- 17692751 TI - Left ventricular apical ballooning syndrome as a novel cause of acute mitral regurgitation. PMID- 17692749 TI - Pulmonary arterial thrombosis in eisenmenger syndrome is associated with biventricular dysfunction and decreased pulmonary flow velocity. AB - OBJECTIVES: This study sought to determine what factors are associated with pulmonary artery thrombi in Eisenmenger patients. BACKGROUND: Pulmonary artery thrombosis is common in Eisenmenger syndrome, although its underlying pathophysiology is poorly understood. METHODS: Adult patients with Eisenmenger syndrome underwent computed tomography pulmonary angiography, cardiac magnetic resonance imaging, and echocardiography. Measurement of ventricular function, pulmonary artery size, and pulmonary artery blood flow were obtained. Hypercoagulability screening and platelet function assays were performed. RESULTS: Of 55 consecutive patients, 11 (20%) had a detectable thrombus. These patients were older (p = 0.032), but did not differ in oxygen saturation, hemoglobin, or hematocrit from those without thrombus. Right ventricular ejection fraction by magnetic resonance imaging was lower in those with thrombus (0.41 +/- 0.15 vs. 0.53 +/- 0.13, p = 0.017), as was left ventricular ejection fraction (0.48 +/- 0.12 vs. 0.60 +/- 0.09, p = 0.002), a finding corroborated by tissue Doppler and increased brain natriuretic peptide. Those with thrombus also had a larger main pulmonary artery diameter (48 +/- 14 mm vs. 38 +/- 9 mm, p = 0.007) and a lower peak systolic velocity in the pulmonary artery (p = 0.003). There were no differences in clotting factors, platelet function, or bronchial arteries between groups. Logistic regression showed pulmonary artery velocity to be independently associated with thrombosis. CONCLUSIONS: Pulmonary arterial thrombosis among adults with Eisenmenger syndrome is common and relates to older age, biventricular dysfunction, and slow pulmonary artery blood flow rather than degree of cyanosis or coagulation abnormalities. Further work to define treatment efficacy is needed. PMID- 17692752 TI - On the mechanisms of transmural dispersion of myocardial mechanics. PMID- 17692754 TI - Immediate coronary imaging for acute chest pain: are we there yet? PMID- 17692757 TI - Non-invasive determination of hemoglobin by digital photography of palpebral conjunctiva. AB - The objective of this study was to determine whether digital photography could be used to calculate hemoglobin. This prospective blinded study was conducted in a tertiary care Emergency Department (ED). A convenience sample of 65 patients provided consent; 44 patients were enrolled for formula derivation and 19 for prospective analysis. Hemoglobin concentration in blood was determined by a cell counter. Software was developed to predict the hemoglobin value based on a formula derived using the images and known hemoglobin values from a derivation set of patients. Pearson's rank order correlation between the calculated and measured hemoglobin was r(77) = 0.634, p < 0.01 for the derivation group and r(36) = 0.522, p < 0.01 for the evaluation group. It is possible to derive an objective method that correlates conjunctiva color with measured hemoglobin and, when applied prospectively, is able to predict hemoglobin concentration in ED patients. This technology has broad applications in regions with limited resources. PMID- 17692758 TI - Cardiac monitoring of human subjects exposed to the taser. AB - The Taser (TASER International, Scottsdale, AZ) is a high-voltage, low-amperage device used by many law enforcement agencies. Our objective in this study was to evaluate for rhythm changes utilizing cardiac monitoring during deployment of the Taser on volunteers. A prospective, observational study evaluated law enforcement personnel who had continuous electrocardiographic monitoring immediately before, during, and after having a voluntary exposure to the Taser X-26. Changes in cardiac rate, rhythm, ectopy, morphology, and conduction intervals were measured. A total of 105 subjects were evaluated. The mean shock duration was 3.0 s (range 0.9-5 s). Mean heart rate increased 15 beats/min (95% CI 12.6-18.3), from 122 beats/min before shock to 137 beats/min immediately after shock. One subject had a single premature ventricular contraction both before and after the shock, but no other subject developed ectopy or dysrhythmia. Poor inter-rater agreement prevented determination of the overall effect of shock on conduction intervals. However, several interpretable tracings demonstrated change in QT duration-either shortening or prolongation after shock. Human subjects exposed to a brief shock from the Taser developed significant increases in heart rate, but there were no cardiac dysrhythmias or morphologic changes. Alterations in the QT interval were observed in some subjects but their true incidence and clinical significance are unknown. PMID- 17692759 TI - Can urine dipstick be used as a surrogate for serum creatinine in emergency department patients who undergo contrast studies? AB - Contrast-induced nephropathy (CIN) is a complication associated with contrasted computed tomography (CT). Elevated creatinine (Cr) is often used to screen for CIN. This study evaluates dipstick urinalysis (Udip) detection of Cr > 1.5 mg/dL. If sufficiently sensitive, Udip results could then be incorporated into future rapid screening protocols for patients undergoing contrast studies. This retrospective record review evaluated all Emergency Department patients over 2 years with documented Udip and serum creatinine results. Patient demographics and pertinent past medical history were also collected. Data were collected on 2421 patient visits, with 241 having Cr > 1.5 mg/dL (9.9%). There were 923 patient visits with a negative Udip (38.1%). Sensitivity and negative predictive value for abnormal Udip in detecting elevated creatinine were 85.5% and 96.2% (p < 0.01), respectively. Thirty-five patient visits (among 26 patients) had negative urine dip and Cr > 1.5 mg/dL, but each reported at least one of the following at triage: prior renal disease, hypertension, diabetes, congestive heart failure, or age > 60 years. Udip is a sensitive screening test, but alone is not accurate enough to predict patients at potential risk for CIN (Cr > 1.5 mg/dL). However, combining Udip results with risk factor screening may allow a rapid method for predicting which patients may safely undergo contrast CT scanning in the ED, but this needs prospective evaluation. PMID- 17692760 TI - 'Silent' Prinzmetal's ST elevation related to atenolol overdose. AB - Prinzmetal's angina is a condition characterized by chest pain, transient ST elevation, and negative biochemical markers of myocardial cell necrosis. We describe a case of chemically-induced "silent" ST segment elevation related to Atenolol overdose in a patient without coronary artery stenosis. We conclude that the cause for the transient myocardial ischemia is coronary vasospasm, precipitated by beta-blocker overdose. PMID- 17692761 TI - Spontaneous rupture of the renal pelvis caused by calculus: a case report. AB - Rupture of the urinary collecting system associated with peripelvic extravasation of the urine is an unusual condition and commonly associated with obstructing calculus. We report a patient, recently given chemotherapy due to lymphoma, with acute abdomen symptoms. He had a renal pelvis rupture with perirenal extravasation of urine, an uncommon condition due to a stone in the ureter. Diagnosis was suspected on serial ultrasonography, and confirmed by computed tomograhy. Diagnosis, follow-up, and therapeutic approach are discussed. PMID- 17692762 TI - Mind the gap. AB - The "oxygen saturation gap" is the difference between the calculated oxygen saturation from a standard blood gas machine and the reading from a pulse oximeter. If it is greater than 5%, the patient's hemoglobin may be abnormal, representing carbon monoxide poisoning, methemoglobinemia, or sulfhemoglobinemia. We report a case where awareness of the saturation gap led to the diagnosis of carbon monoxide poisoning. PMID- 17692763 TI - A case of strangulated small bowel obstruction caused by Meckel's diverticulum in an adult. AB - Meckel's diverticulum results from incomplete closure of the omphalomesenteric duct, and is the most common congenital anomaly of the small intestine. We present a case report of a 42-year-old patient who developed a strangulated intestinal obstruction as a complication of Meckel's diverticulum. The strangulated bowel obstruction was suggested by contrast-enhanced computed tomography. He recovered after a diverticulectomy and had no need for a small bowel resection. PMID- 17692764 TI - Effective treatment of hereditary angioedema with fresh frozen plasma in an emergency department. AB - Hereditary angioedema (HAE) is a rarely seen disorder of C1 inhibitor (C1-INH) deficiency usually manifested by non-pruritic swelling of the skin. Acute exacerbations are not sensitive to conventional medications, and C1-esterase inhibitor concentrates are recommended as the first-line therapy. However, fresh frozen plasma is the main treatment alternative in many centers due to the lack of C1-esterase inhibitor concentrates. In this report, we present 3 patients with acute exacerbations of hereditary angioedema who were effectively and safely treated with fresh frozen plasma. PMID- 17692766 TI - Are one or two dangerous? Calcium channel blocker exposure in toddlers. AB - Unintentional pediatric ingestions of calcium channel blockers are increasing in frequency due to increased use of this antihypertensive class. Potential toxic effects include severe refractory hypotension and death; however, the true toxicity of unintentional pediatric ingestions of 1-2 pills is poorly defined. A literature review was conducted to more closely determine toxic and lethal dosages of calcium channel blockers in the pediatric population under 6 years of age. Results indicate that, although most accidental pediatric ingestions are asymptomatic, a small number do result in cardiovascular instability or even death. The dihydropyridines, particularly nifedipine, and the phenylalkylamine verapamil are most often implicated in symptomatic ingestions. There are no adequate data to identify which children are predisposed to illness, or to determine cutoffs for toxic dosages. However, ingestions of only one pill have been documented to cause severe symptoms, including death. Thus, emergency evaluation to assess potential toxicity is necessary, and gastrointestinal decontamination and in-hospital observation of at least 6 h after toxic ingestion for regular release medications, and 12-24 h after toxic ingestion for sustained release medications is recommended for all cases of unintentional calcium channel blocker ingestion in children younger than 6 years of age. PMID- 17692765 TI - Impact of activated charcoal after acute acetaminophen overdoses treated with N acetylcysteine. AB - Previous studies have suggested that patients receiving both activated charcoal (AC) and N-acetylcysteine (NAC) after acute acetaminophen (APAP) overdoses may have improved outcomes. We evaluated all acute acetaminophen overdoses that received NAC therapy reported to US poison centers for the years 1993 through 2004. Groups were separated based on therapy received: 1) both AC and NAC and 2) NAC alone. There were 97,960 acetaminophen overdoses reported, with 49,427 patients (50%) receiving NAC and AC. Reports of AST/ALT > 1000, a major effect, and death were 1301 (2.9%), 2957 (6.6%), and 232 (0.5%), respectively, for patients receiving NAC plus AC, vs. 5273 (12%), 4534 (10.3%), and 369 (0.8%), respectively, for patients receiving NAC alone (p < 0.01). Use of Toxic Exposure Surveillance System data in the present study has a number of limitations, including its retrospective nature and no documentation of when NAC therapy was initiated. It is possible that those patients who did not receive AC presented to the Emergency Department later in their overdose and had NAC therapy initiated later, and therefore they were predisposed to a greater risk of hepatic injury. Evaluation of 12 years of acute APAP overdoses suggests that the use of AC, in addition to NAC therapy, may provide improved patient outcomes. PMID- 17692767 TI - The effects of minimizing ambulance diversion hours on emergency departments. AB - This study explores the effects of minimizing Emergency Department (ED) bypass on individual hospital's ED census, ambulance transports, and admissions. Five hospitals in a geographic area collected data over 3 weeks. The first and third week represented controls, whereas the second week hospitals minimized their usage of bypass. Data collected included hours on bypass, ED census, ambulance runs, hospital admissions, and inter-facility transfers. The total number of hours on bypass for all hospitals for pre-trial, trial, and post-trial weeks were 112.2, 0.3, and 47, respectively. There were several statistical shifts in the proportion of ambulance runs and admissions seen by individual hospitals. Clinically, these shifts in patients were minor and within ED capacity. Hospitals in a given geographic area may successfully reduce the number of hours on bypass with possible minor shifting in the number of ambulance runs and admissions that are within ED capacity. PMID- 17692768 TI - Cumulative CT exposures in emergency department patients evaluated for suspected renal colic. AB - Computed tomography (CT) is the diagnostic standard in Emergency Department evaluation of suspected renal colic but delivers substantial radiation. We determined the frequency of CT scan in suspected renal colic, diagnosis and outcome, and cumulative CT scans per patient. A retrospective chart review with waiver of informed consent was conducted. A total of 356 patient encounters were reviewed from January to October 2003. Mean age was 39 years. Seventy-four percent included a CT scan, with 38% normal, 58% showing urolithiasis, and 1% showing emergent etiologies. Six percent of patients undergoing CT were admitted for urolithiasis, and 6% had a urologic procedure within 7 days. Sixteen percent of patients did not have a CT scan, and 79% underwent two or more CT scans. Emergency Department patients presenting with symptoms suggesting renal colic are likely to undergo CT on multiple occasions. Radiation exposures from repeated CT scans are substantial, and a clinical decision rule for this scenario is needed. PMID- 17692769 TI - The role of post-reduction radiographs after shoulder dislocation. AB - We sought to determine whether post-reduction radiographs add clinically important information to what is seen on pre-reduction X-rays in Emergency Department (ED) patients with anterior shoulder dislocations. In this prospective, observational study, clinicians recorded preliminary pre-reduction and post-reduction X-ray readings on patients with shoulder dislocations. The films were subsequently reviewed by a blinded attending radiologist. Seventy three patients presented to the ED with shoulder dislocations over an 18-month period; 55 of these patients had pre- and post-reduction X-rays and were included in the study. Eight of these patients had fractures seen on preliminary reading of post-reduction X-rays; one (1.8%, 95% confidence interval [CI] 0-9.7%) of these fractures was not seen on preliminary reading of pre-reduction films. On preliminary reading, all patients' shoulders were relocated on post-reduction X rays (100%; 95% CI 93.5-100%). Forty of these patients had their X-rays read by a blinded attending radiologist. Sixteen fractures were seen on post-reduction X rays, of which 6 (15.0%; 95% CI 5.7-29.8%) were not seen on pre-reduction X-rays. All patients (100%; 95% CI 91.2-100%) whose post-reduction films were read by blinded attending radiologists had shoulder relocation confirmed. In conclusion, although the majority (62.5%) of fractures associated with shoulder dislocations are seen on pre-reduction radiographs, more than one-third (37.5%) of fractures may be visible only on post-reduction X-rays. None of the fractures missed on pre reduction X-rays changed patient management in the ED. There were no persistent shoulder dislocations found on post-reduction films. PMID- 17692770 TI - Operator confidence correlates with more accurate abdominal ultrasounds by emergency medicine residents. AB - The purpose of this study was to assess whether greater operator confidence correlates with more accurate focused abdominal ultrasounds (FAUS) by residents. This was a prospective study of novice residents performing FAUS in patients with abdominal pain. FAUS included focused assessment with sonography for trauma, gall bladder, renal, and aortic examinations. Residents answered the question, "How confident are you of your findings?" using a visual scale from 1 (doubtful) to 5 (certain). The results of the resident-performed FAUS were compared to subsequent criterion evaluations. Thirty-eight residents with an average experience of 27 (95% confidence interval [CI] 18-36) prior US examinations evaluated 504 patients. Greater operator confidence correlated with improved accuracy of FAUS (R(2) = 0.858, p = 0.0369). Sensitivity and specificity were 14% (95% CI 4-37 %) and 71% (95% CI 48-88 %) with a confidence level of 2/5 but 85% (95% CI 73-93 %) and 100% (95% CI 97-100 %) with a confidence level of 5/5. Greater operator confidence correlates with improved accuracy in FAUS. This should be considered in the development of training guidelines. PMID- 17692771 TI - Complicated soft tissue infection. PMID- 17692772 TI - Lupus pernio. PMID- 17692773 TI - Ovarian hyperstimulation syndrome. PMID- 17692774 TI - Tracheobronchial rupture. PMID- 17692775 TI - Anticonvulsant hypersensitivity syndrome. PMID- 17692777 TI - Approaches to treatment of community-acquired pneumonia in the emergency department and the appropriate role of fluoroquinolones. PMID- 17692778 TI - Update on the National Vaccine Injury Compensation Program. AB - The National Childhood Vaccine Injury Act of 1986, as amended, established the Vaccine Injury Compensation Program (VICP). The VICP went into effect on October 1, 1988 and is a Federal "no-fault" system designed to compensate individuals, or families of individuals, who have been injured by covered vaccines. From 1988 until July 2006, a total of 2531 non-autism/thimerosal and 5030 autism/thimerosal claims were made to the VICP. The compensation paid for the non-autism/thimerosal claims from 1988 until 2006 was $902,519,103.37 for 2542 awards. There was no compensation for any of the autism/thimerosal claims. On the basis of the deaths and extensive suffering to patients and families from the adverse reactions to vaccines, all physicians must provide detailed information in the Vaccine Information Statement to the patient or the parent or legal guardian of the child about the potential dangers of vaccines as well as the VICP. PMID- 17692779 TI - A survey of the use of foreign-purchased medications in a border community emergency department patient population. AB - Many reports suggest that the use of imported medications in the United States continues to grow, fueled mostly by the rising price of prescription drugs. This trend may be problematic for several reasons, including the potential for counterfeit or impure products, a lack of pharmacist support outside of the United States, and the ability to purchase agents without a prescription from some countries. We performed a survey of Emergency Department (ED) patients in a border community to observe the magnitude of imported medication use, and to begin to determine the rationale behind the practice. A survey was conducted of 1008 ED patient encounters of individuals reporting at triage to be on any prescription or over-the-counter medication. Participants were queried on their use of imported medications and implications of such use through a questionnaire. A total of 966 patient encounter surveys were included in the analysis. Of this number, 7% reported the use of medications purchased outside of the United States. Most of these were purchased in person and in Mexico. The most commonly cited reason for importing medications was decreased cost, and almost a quarter of those importing medications stated that their physician had recommended it. The most common medications imported were antibiotics, and nearly a third of all of those buying foreign medications had done so without a prescription. Our study suggests that many patients in our community purchase medications outside of the United States. PMID- 17692780 TI - Registry of the International Society for Heart and Lung Transplantation: introduction to the 2007 annual reports--100,000 transplants and going strong. PMID- 17692781 TI - Registry of the International Society for Heart and Lung Transplantation: twenty fourth official adult heart transplant report--2007. PMID- 17692782 TI - Registry of the International Society for Heart and Lung Transplantation: twenty fourth official adult lung and heart-lung transplantation report-2007. PMID- 17692783 TI - Registry of the International Society for Heart and Lung Transplantation: tenth official pediatric heart transplantation report--2007. PMID- 17692784 TI - Molecular testing for long-term rejection surveillance in heart transplant recipients: design of the Invasive Monitoring Attenuation Through Gene Expression (IMAGE) trial. AB - BACKGROUND: Acute rejection continues to occur beyond the first year after cardiac transplantation, but the optimal strategy for detecting rejection during this late period is still controversial. Gene expression profiling (GEP), with its high negative predictive value for acute cellular rejection (ACR), appears to be well suited to identify low-risk patients who can be safely managed without routine invasive endomyocardial biopsy (EMB). METHODS: The Invasive Monitoring Attenuation Through Gene Expression (IMAGE) study is a prospective, multicenter, non-blinded, randomized clinical trial designed to test the hypothesis that a primarily non-invasive rejection surveillance strategy utilizing GEP testing is not inferior to an invasive EMB-based strategy with respect to cardiac allograft dysfunction, rejection with hemodynamic compromise (HDC) and all-cause mortality. RESULTS: A total of 199 heart transplant recipients in their second through fifth post-transplant years have been enrolled in the IMAGE study since January 13, 2005. The study is expected to continue through 2008. CONCLUSIONS: The IMAGE study is the first randomized, controlled comparison of two rejection surveillance strategies measuring outcomes in heart transplant recipients who are beyond their first year post-transplant. The move away from routine histologic evaluation for allograft rejection represents an important paradigm shift in cardiac transplantation, and the results of this study have important implications for the future management of heart transplant patients. PMID- 17692785 TI - End-organ function in patients on long-term circulatory support with continuous- or pulsatile-flow assist devices. AB - BACKGROUND: Limited data exist about the long-term effects of continuous-flow vs pulsatile-flow left ventricular assist devices (LVADs) on end-organ function. METHODS: We reviewed the data of patients who underwent LVAD implantation at our institution between 1989 and 2004 and who were supported for >6 months. The continuous-flow (C-LVAD) group included 12 patients bridged to transplant with either a Jarvik 2000 or a Thoratec HeartMate II LVAD. The pulsatile (P-LVAD) group included 58 patients supported by a Thoratec HeartMate I LVAD. Follow-up was up to 15 months after LVAD implantation. Average duration of LVAD support was 370 +/- 182 days (range 180 to 754) for the C-LVAD group and 315 +/- 111 days (range 180 to 1,334) for the P-LVAD group. RESULTS: Patients from both groups were comparable for age, gender, body weight, cardiac index, ejection fraction, creatinine, blood urea nitrogen, creatinine clearance, albumin, total bilirubin, and transaminase levels before implantation. C-LVAD patients had a lower pre operative hemoglobin than did P-LVAD patients (10.5 +/- 1.7 g/dl vs 12.2 +/- 1.9 g/dl; p = 0.01). In both groups, albumin, blood urea nitrogen, creatinine, creatinine clearance, total bilirubin, and transminase levels either improved or stayed within the normal range at 6, 9, 12, and 15 months after LVAD implantation. Four of the 12 C-LVAD patients and 28 of the 58 P-LVAD patients underwent cardiac transplantation. Actuarial survival, censored for transplant, at 9, 12, and 15 months was 90% for the C-LVAD group and 88%, 78%, and 74% for the P-LVAD group (p = not statistically significant). CONCLUSIONS: On the basis of these data, it appears that continuous- and pulsatile-type LVADs provide adequate blood flow to maintain proper end-organ function during prolonged circulatory support. PMID- 17692786 TI - Suction events during left ventricular support and ventricular arrhythmias. AB - BACKGROUND: Axial blood pumps have very successfully entered the arena of prolonged clinical support. However, they offer only limited inherent load responsive mechanisms for adjusting pumping performance to venous return and changes in the physiologic requirements of the patient. Therefore, excessive ventricular unloading can be observed in various situations of temporarily reduced venous return. In this study we report severe ventricular arrhythmias closely related to suction events in rotary blood pumps, a phenomenon that has not been described previously. METHODS: Data from a clinical trial intended to prove the feasibility of an automatic speed control system for pump recipients were analyzed with regard to electrocardiographic changes during ventricular collapse. The occurrence of excessive unloading was detected by an automatic suction detection system. Electrocardiograms (ECGs) were classified semi manually, aided by a graphical use interface. For statistical data analysis, Wilcoxon's signed-rank test was utilized. RESULTS: After automatic suction detection a significant increase in monomorphic ventricular tachycardia was observed, from 0.015 to 0.099 event per second (p < 0.05). Furthermore, it was found that arrhythmic activity in terms of morphologic ventricular tachycardia increased after suction from 0.009 to 0.014 event per second. CONCLUSIONS: Excessive ventricular unloading of the left ventricle during continuous left ventricular support can induce ventricular arrhythmias. We detected evidence supporting an increase in arrhythmic activity after suction. This turned out to be a transient effect, which vanished within 5 minutes after suction. ECG events related to suction have a sudden onset and are severe ventricular arrhythmias, which can consist of even just one extrasystolic beat, and they usually cease after clearance of suction. PMID- 17692787 TI - Systemic inflammation and metabolic syndrome in cardiac allograft vasculopathy. AB - BACKGROUND: Metabolic syndrome and elevation of inflammatory markers is common in transplant recipients. We investigated the role of insulin resistance and C reactive protein (CRP) in predicting development of angiographic cardiac allograft vasculopathy (CAV). METHODS: CRP and lipid profile were measured in 114 cardiac transplant recipients at 4.7 +/- 3.1 years post-transplant. A triglyceride/high-density lipoprotein cholesterol (TG/HDL) ratio of >or=3 was considered a marker of insulin resistance. Ninety-seven patients (mean age +/- SD: 48.2 +/- 16.7 years) subsequently underwent routine coronary angiography at 8.6 +/- 3.2 years post-transplantation. Diagnosis of CAV required the presence of stenosis of >or=40% in any major branch, and/or distal pruning of secondary side branches. Coronary artery stenosis >or=70% was defined as severe. RESULTS: Eighty one percent of patients were treated with statins. Low-density lipoprotein (LDL) cholesterol level was 98 +/- 26 mg/dl at study entry. CRP and TG/HDL were found to be predictors of development of CAV. CAV severity correlated with TG/HDL (p < 0.005), but not with CRP level. Freedom from CAV 5 years after study entry was 9% in patients with TG/HDL >3, CRP >3 mg/liter, as compared with 65% in patients with TG/HDL <3, CRP <3 mg/liter (p = 0.003). The combination of CRP >3 mg/liter and TG/HDL >3 identified a sub-group of patients having a 2.8-fold increased odds ratio for a combined end-point of cardiovascular (CV) events (percutaneous coronary intervention, coronary artery bypass graft, left ventricular ejection fraction <45%) and death (95% confidence interval 0.90 to 8.45, p = 0.07) compared to patients with CRP <3 mg/liter and TG/HDL <3. CONCLUSIONS: CRP >3 mg/liter and TG/HDL >3 are cumulative risk factors for angiographic CAV and the combined end-point of CV events and death in transplant patients and these patients should be targeted for intervention. PMID- 17692788 TI - Survival of lung transplant patients with cystic fibrosis harboring panresistant bacteria other than Burkholderia cepacia, compared with patients harboring sensitive bacteria. AB - BACKGROUND: The impact of panresistant bacteria, other than Burkholderia cepacia, on the survival after lung transplantation in patients with cystic fibrosis (CF) remains controversial. METHODS: To determine the impact of panresistant bacteria in CF patients on survival after lung transplantation a retrospective multicenter study was performed. All lung transplant recipients with a pre-transplant diagnosis of CF, at the University of Toronto (n = 53) and Duke University (n = 50), were included. Patients were included in the panresistant group if at least one specimen isolated from their respiratory secretions grew bacteria resistant or intermediate to all classes of antibiotics tested. Patients with sensitive or resistant B cepacia were excluded because of its adverse impact upon post transplant survival. RESULTS: Forty-five of 103 (43.7%) patients harbored panresistant bacteria (43 had Pseudomonas aeruginosa, 1 had Stenotrophomonas maltophilia, and 1 had Achromobacter xylosoxidans). According to log-rank test, there was decreased survival in patients with panresistant bacteria compared to patients with sensitive bacteria (survival: 91.1 +/- 4.2% vs 98.3 +/- 1.7% at 3 months; 88.6 +/- 4.8% vs 96.6 +/- 2.4% at 1 year; 63.2 +/- 8.6% vs 90.7 +/- 4.0% at 3 years; 58.3 +/- 9.2% vs 85.6 +/- 5.2% at 5 years; p = 0.016). The results did not differ significantly between the two centers. Both groups had similar or better survival than CF patients as reported by the United Network of Organ Sharing (UNOS) registry (1-year, 86.0%; 3 years, 65.4%; 5 years, 49.6%). CONCLUSIONS: Patients with CF harboring panresistant bacteria have slightly decreased survival, but their survival is comparable to the results published by the UNOS registry. PMID- 17692789 TI - Association between elevated whole blood Epstein-Barr virus (EBV)-encoded RNA EBV polymerase chain reaction and reduced incidence of acute lung allograft rejection. AB - BACKGROUND: Accurate functional assessment of patient immunosuppression after solid-organ transplantation remains elusive. Despite therapeutic serum immunosuppressive drug levels many lung transplant recipients still develop allograft rejection. We investigated the hypothesis that detection of latent Epstein-Barr virus (EBV) in peripheral blood may be a functional marker for the net effects of administered immunosuppression. METHODS: A retrospective analysis was performed on data obtained from a prospective trial investigating the ability of a novel EBV polymerase chain reaction (PCR) panel for LMP (latent membrane protein 1), EBNA (EBV nuclear antigen) and EBER (EBV-encoded RNA) to predict future development of post-transplant lymphoproliferative disorder (PTLD). Thirty one lung transplant patients were followed for up to 2 years after transplantation with EBV PCR panels performed on plasma and whole blood. Patients were assessed for occurrences of Grade 2 or higher acute rejection and episodes of infection. RESULTS: Patients with whole blood EBER-positive PCR had a statistically significant lower incidence (45% vs 83%) of Grade 2 or higher acute allograft rejection than patients with no positive assays (odds ratio [OR] = 0.17, 95% confidence interval [CI] 0.021 to 1.2, p = 0.048). Positive whole blood EBER PCR did not correlate with increased risk for infectious complications (OR = 1.6, 95% CI 0.22 to 11, p = 0.69). CONCLUSIONS: These results suggest that whole blood EBER EBV PCR load may represent an important functional measure of immunosuppression in solid-organ transplant patients. PMID- 17692790 TI - Incidence of malignancies in heart and/or lung transplant recipients: a single institution experience. AB - BACKGROUND: The purpose of this study was to determine the incidence and type of malignancies in heart and/or lung transplant recipients at a single institution in Victoria, Australia, and to compare these findings with the non-transplant general Victorian population. METHODS: Recipients of heart and/or lung transplants at the Alfred Hospital between February 1989 and January 2004 were cross-referenced with the Victorian Cancer Registry. The medical records of all patients with a cancer diagnosis by January 1, 2005 were reviewed. Data were collected on baseline demographics, including cancer type, stage, treatment and survival. Cancer incidence was then compared with rates found in the Victorian population. RESULTS: There were 907 transplants (Tx) conducted between February 1989 and January 1, 2004 on 905 patients, which included 424 heart (HTx), 56 heart-lung (HLTx), 200 single-lung (SLTx), and 227 double-lung (DLTx) procedures. Of these patients, 606 (67%) were male and 299 (33%) were female. Mean age at transplantation was 46.4 years (range 12.6 to 70.4 years). Four hundred twenty four (47%) deaths have occurred. Median survival for all patients after transplantation was 8.6 years. One hundred two cancers were confirmed, translating to a 7.1-fold increased incidence compared with the non-transplant population. The most common cancer diagnoses were lymphoproliferative disorders (692 per 100,000 person-years), head and neck cancer (336 per 100,000 person years) and lung cancer (251 per 100,000 person-years). Compared with the non transplant population this translates into a 26.2-, 21.0- and 9.3-fold increased risk for developing these cancers, respectively, after cardio-pulmonary transplantation. CONCLUSIONS: Certain malignancies are more common after heart and/or lung transplantation. The most predominant in our cohort were lymphoproliferative disorders, head and neck cancer and lung cancer. PMID- 17692791 TI - Resolution of severe ischemia-reperfusion injury post-lung transplantation after administration of endobronchial surfactant. AB - BACKGROUND: Ischemia-reperfusion injury (IRI) is a prominent cause of primary graft failure after lung transplantation and is associated with an altered surfactant profile. Experimental animal studies have found that replacement with exogenous surfactant administered via fiber-optic bronchoscopy (FOB) enhanced recovery from IRI with improved pulmonary compliance and gas exchange after lung transplantation. We report our clinical experience with FOB instillation of surfactant in severe IRI after human lung transplantation. METHODS: This study is a retrospective review of 106 consecutive lung or heart-lung transplants performed at a single institution. Severe IRI was defined as diffuse roentgenographic alveolar infiltrates, worsening hypoxemia and decreased lung compliance within 72 hours of lung transplantation. One vial of surfactant (20 mg/ml phospholipid) was instilled into each segmental bronchus upon diagnosis of IRI. RESULTS: Six patients (5 bilateral sequential and 1 re-do heart-lung transplant), mean age 46 years, were diagnosed with IRI and surfactant was administered at a mean of 37 hours (range 2.3 to 98) post-transplant. Mean graft ischemia time was 376 minutes (range 187 to 625) and cardiopulmonary bypass time 174 minutes (range 0 to 210). Mean Pao(2) [mm Hg]/Fio(2) ratio before and 48 hours after surfactant instillation was 70 and 223, respectively. Significant resolution of radiologic infiltrates was evident in all cases within 24 hours. Successful extubation occurred at a mean of 13.5 days and survival is presently 100% at 19 months (range 3 to 54). CONCLUSIONS: Bronchoscopic instillation of surfactant improves oxygenation and prognosis after severe IRI in lung transplant recipients. It represents a cost-effective, relatively non-invasive therapeutic alternative to extracorporeal membrane oxygenation. PMID- 17692792 TI - Mucormycosis of the bronchial anastomosis: a case of successful medical treatment and historic review. AB - Rhizomucor is a genus of zygomycetes that can cause pulmonary mucormycosis. In the immunocompromised host, mucormycosis was fatal until advances in anti-fungal therapy were combined with surgery. Although uncommon, fungal infection at the bronchial anastomosis is associated with a significant risk of morbidity and mortality after lung transplantation. Our patient is a middle-aged woman with end stage chronic obstructive pulmonary disease who received a bilateral lung transplant. After discharge, she developed increasing dyspnea. Bronchoscopy revealed stenosis and Rhizomucor at the right anastomosis. Repeated endobronchial debridement, systemic lipid-soluble amphotericin, and inhaled amphotericin successfully resolved the infection. The residual stenosis was treated with a self-expandable metal stent. At 3 months, the patient continues on inhaled amphotericin suppression therapy without sequelae. Anastomosis mucormycosis is a grave complication after lung transplantation. Without combination therapy of surgery and anti-fungal drugs, mortality has been exceedingly high. We present a case wherein endobronchial debridement and anti-fungal therapy were successful without surgery. PMID- 17692793 TI - Successful outcome of human metapneumovirus (hMPV) pneumonia in a lung transplant recipient treated with intravenous ribavirin. AB - Human metapneumovirus (hMPV) has recently been shown to be a prominent cause of respiratory infections in immunocompromised hosts, and is associated with high morbidity and mortality. We report a case of hMPV pneumonia in a lung transplant recipient presenting with respiratory failure and sepsis syndrome. hMPV was diagnosed by polymerase chain reaction, and treated with intravenous ribavirin with a successful outcome. PMID- 17692794 TI - Myxoma of donor origin in a transplanted heart. AB - Myxomas are the most common primary cardiac tumors but their presence in the transplanted heart is extremely rare. We report a case of left atrial myxoma in a patient after heart transplantation. DNA analysis confirmed a donor origin. To our knowledge, this is the first report of myxoma of donor origin in a transplanted heart. PMID- 17692795 TI - Does tricuspid annular plane systolic excursion or systolic velocity allow a precise determination of right ventricular function after heart transplantation? PMID- 17692796 TI - Altered cytoskeletal protein localization in cardiomyocytes of idiopathic cardiomyopathy patients. PMID- 17692797 TI - Successful lung transplantation for post-BMT bronchiolitis obliterans and lipoid pneumonia associated with atypical mycobacterium and aspergillosis infection. PMID- 17692798 TI - Multiple myeloma: lusting for NF-kappaB. AB - Multiple myeloma (MM) is a late-stage B cell malignancy that has received much attention recently because of its therapeutic susceptibility to proteasome inhibitors. Two papers in this issue of Cancer Cell show that primary MM samples and MM cell lines frequently have mutations in genes encoding regulators and effectors of NF-kappaB signaling, and that these mutations lead to chronic NF kappaB target gene expression, which is required for the viability of these MM tumor cells. These results reveal the molecular basis for constitutive NF-kappaB activity in many MMs and further validate the NF-kappaB signaling pathway as an appropriate target for MM therapy. PMID- 17692799 TI - Life, death, BH3 profiles, and the salmon mousse. AB - New drugs that neutralize the antiapoptotic members of the Bcl-2 family hold promise for rational cancer therapies, both alone and in combination with other agents. An understanding of how and why such agents may trigger apoptosis on their own, and how resistance to these drugs can occur, depends on the complexity of the Bcl-2 family interactions that control mitochondrial outer membrane permeabilization (MOMP). By extracting mitochondria from tumor cells and exposing them to peptides corresponding to the regulatory BH3-only proteins, MOMP predicts not only which cells will undergo apoptosis in response to Bcl-2 antagonists, but also why other cells may be resistant. PMID- 17692800 TI - Tissue culture as a hostile environment: identifying conditions for breast cancer progression studies. AB - The cell culture environment (substrate, atmosphere, and medium) can have a significant influence on the characteristics of cells that propagate from clinical samples. In this issue of Cancer Cell, Ince and colleagues report improved conditions for the culture of primary human breast epithelial cells. They demonstrate that, when cells cultured using the new conditions are experimentally transformed, they are more tumorigenic, form tumor xenografts that closely resemble human breast ductal adenocarcinoma, and are more metastatic compared to cells cultured under standard conditions similarly transformed. This suggests that pre-existing differences in cell culture can modulate the tumor phenotype. PMID- 17692801 TI - New Myc-anisms for DNA replication and tumorigenesis? AB - The c-Myc proto-oncogene is an essential activator of cell proliferation and one of the genes most commonly deregulated in cancer. Although these activities of c Myc are thought to result from its function as a transcription factor, the scientific literature contains hints that this is not the whole story. A new paper in Nature by Dominguez-Sola et al. reports the surprising observation that c-Myc promotes DNA replication via a nontranscriptional mechanism, and that c-Myc deregulation causes DNA damage predominately during S phase. These results identify c-Myc as a new DNA replication factor and suggest an alternative model for its role in cell growth and tumorigenesis. PMID- 17692802 TI - A new mutational AKTivation in the PI3K pathway. AB - Although multiple members of the phosphatidylinositol-3-kinase pathway (PI3K) are targeted by germline or somatic mutations, functional mutations in the three akt isoforms have proven elusive. This is somewhat surprising, as AKT represents a key node in the PI3K pathway, exhibiting transforming activity when incorporated into the AKT8 retrovirus. A recent report in Nature identifies a transforming E17K PH domain mutation in akt1 in breast (8%), colorectal (6%), and ovarian (2%) cancers. E17K-akt1 transforming activity appears due to PtdIns(3,4)P2- and PtdIns(3,4,5)P3-independent recruitment of AKT1 to the membrane. This novel observation raises important theoretical and clinical questions. PMID- 17692803 TI - HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. AB - O(2) deprivation (hypoxia) and cellular proliferation engage opposite cellular pathways, yet often coexist during tumor growth. The ability of cells to grow during hypoxia results in part from crosstalk between hypoxia-inducible factors (HIFs) and the proto-oncogene c-Myc. Acting alone, HIF and c-Myc partially regulate complex adaptations undertaken by tumor cells growing in low O(2). However, acting in concert these transcription factors reprogram metabolism, protein synthesis, and cell cycle progression, to "fine tune" adaptive responses to hypoxic environments. PMID- 17692804 TI - Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. AB - Mechanisms of constitutive NF-kappaB signaling in multiple myeloma are unknown. An inhibitor of IkappaB kinase beta (IKKbeta) targeting the classical NF-kappaB pathway was lethal to many myeloma cell lines. Several cell lines had elevated expression of NIK due to genomic alterations or protein stabilization, while others had inactivating mutations of TRAF3; both kinds of abnormality triggered the classical and alternative NF-kappaB pathways. A majority of primary myeloma patient samples and cell lines had elevated NF-kappaB target gene expression, often associated with genetic or epigenetic alteration of NIK, TRAF3, CYLD, BIRC2/BIRC3, CD40, NFKB1, or NFKB2. These data demonstrate that addiction to the NF-kappaB pathway is frequent in myeloma and suggest that IKKbeta inhibitors hold promise for the treatment of this disease. PMID- 17692805 TI - Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. AB - Activation of NF-kappaB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-kappaB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2 and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the noncanonical NF-kappaB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-kappaB pathway in the pathogenesis of multiple myeloma. PMID- 17692806 TI - Disruption of tumor cell adhesion promotes angiogenic switch and progression to micrometastasis in RAF-driven murine lung cancer. AB - Progression of non-small-cell lung cancer (NSCLC) to metastasis is poorly understood. Two genetic approaches were used to evaluate the role of adherens junctions in a C-RAF driven mouse model for NSCLC: conditional ablation of the cdh1 gene and expression of dominant-negative (dn) E-cadherin. Disruption of E cadherin caused massive formation of intratumoral vessels that was reversible in the early phase of induction. Vascularized tumors grew more rapidly, developed invasive fronts, and gave rise to micrometastasis. beta-catenin was identified as a critical effector of E-cadherin disruption leading to upregulation of VEGF-A and VEGF-C. In vivo, lung tumor cells with disrupted E-cadherin expressed beta catenin target genes normally found in other endodermal lineages suggesting that reprogramming may be involved in metastatic progression. PMID- 17692807 TI - Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes. AB - We investigated the influence of normal cell phenotype on the neoplastic phenotype by comparing tumors derived from two different normal human mammary epithelial cell populations, one of which was isolated using a new culture medium. Transformation of these two cell populations with the same set of genetic elements yielded cells that formed tumor xenografts exhibiting major differences in histopathology, tumorigenicity, and metastatic behavior. While one cell type (HMECs) yielded squamous cell carcinomas, the other cell type (BPECs) yielded tumors closely resembling human breast adenocarcinomas. Transformed BPECs gave rise to lung metastases and were up to 10(4)-fold more tumorigenic than transformed HMECs, which are nonmetastatic. Hence, the pre-existing differences between BPECs and HMECs strongly influence the phenotypes of their transformed derivatives. PMID- 17692809 TI - Abstracts of the 30th European Cystic Fibrosis Conference, 13-16 June 2007, Belek, Turkey. PMID- 17692808 TI - BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. AB - Cancer cells exhibit many abnormal phenotypes that induce apoptotic signaling via the intrinsic, or mitochondrial, pathway. That cancer cells nonetheless survive implies that they select for blocks in apoptosis. Identifying cancer-specific apoptotic blocks is necessary to rationally target them. Using a panel of 18 lymphoma cell lines, we show that a strategy we have developed, BH3 profiling, can identify apoptotic defects in cancer cells and separate them into three main classes based on position in the apoptotic pathway. BH3 profiling identifies cells that require BCL-2 for survival and predicts sensitivity to the BCL-2 antagonist ABT-737. BCL-2 dependence correlates with high levels of proapoptotic BIM sequestered by BCL-2. Strikingly, BH3 profiling can also predict sensitivity to conventional chemotherapeutic agents like etoposide, vincristine, and adriamycin. PMID- 17692810 TI - [Ketosis-prone atypical diabetes mellitus: report of two cases]. AB - An atypical presentation of diabetes mellitus was described in black subjects, initially in adolescents by Winter et al. then, in adult populations. The principal characteristics of "African" diabetes are an acute onset with severe hyperglycemia and ketosis, and a clinical course of type 2 diabetes mellitus. In the subsequent clinical course after initiation of insulin therapy, prolonged remission is often possible with cessation of insulin therapy and maintenance of appropriate metabolic control. In the subsequent clinical course after initiation of insulin therapy, prolonged remission is often possible with cessation of insulin therapy and maintenance of appropriate metabolic control. The molecular mechanisms underlining the insulin secretory dysfunction are still to be understood and may involve glucolipotoxicity processes. The HLA alleles associated with susceptibility to type 1 diabetes were reported of high frequency in some populations with this form of diabetes, in the absence of makers of pancreatic beta cell autoimmunity. The aim of the present review is to discuss two cases of African diabetes and review the specific diagnostic, metabolic, pathogenic and management features of this atypical diabetes. PMID- 17692811 TI - [How to examine and pack a patient with epistaxis?]. PMID- 17692812 TI - [Late and sudden recovery of sudden deafness or vestibular neuronitis]. AB - INTRODUCTION: Vestibular neuronitis (VN) and sudden deafness (SD) are well defined entities. The abrupt appearance of symptoms in both disorders represents an important element for the diagnosis. In cases of VN, symptoms regress gradually over time as the peripheral function recovers, or the central nervous system compensates for the balance deficit. In cases of SD, the recovery occurs in about half the cases and is generally progressive. The chances to recover normal levels of hearing are better if the recovery occurs early after the onset of the deficit. The goal of the paper is to present new insights of these disorders based on four unusual cases and on an evaluation of the delay for the function's recovery. MATERIAL AND METHODS: 1) We report two cases of VN and two of SD whose the recovery was late and sudden; 2) The recovery time after a SD was retrospectively analysed using the chart of 36 patients seen100 mV. Addition of penetrating lipophilic anion TPB, which increases the BLM conductance for lipophilic cations, yielded the Nernstian Delta Psi, i.e. 30 mV per ten-fold dication gradient. In the State 4 mitochondria, dications stimulated respiration and lowered Delta Psi. Moreover, they inhibited the State 3 respiration with succinate or glutamate and malate (but not with TMPD and ascorbate) in an uncoupler-sensitive fashion. Effect on the in State 4 mitochondria, similarly to that on BLM, was accounted for by a time-dependent membrane damage. On the other hand, the State 3 effect was most probably due to inhibition of the respiratory chain Complex I and/or Complex III. The damaging and inhibitory activities of lipophilic dications should be taken into account when one considers a possibility to use them as a vehicle to target antioxidants or other compounds to mitochondria. PMID- 17692815 TI - Infrared spectroscopy of proteins. AB - This review discusses the application of infrared spectroscopy to the study of proteins. The focus is on the mid-infrared spectral region and the study of protein reactions by reaction-induced infrared difference spectroscopy. PMID- 17692816 TI - Thermodynamic and kinetic characterisation of individual haems in multicentre cytochromes c3. AB - The characterisation of individual centres in multihaem proteins is difficult due to the similarities in the redox and spectroscopic properties of the centres. NMR has been used successfully to distinguish redox centres and allow the determination of the microscopic thermodynamic parameters in several multihaem cytochromes c(3) isolated from different sulphate-reducing bacteria. In this article we show that it is also possible to discriminate the kinetic properties of individual centres in multihaem proteins, if the complete microscopic thermodynamic characterisation is available and the system displays fast intramolecular equilibration in the time scale of the kinetic experiment. The deconvolution of the kinetic traces using a model of thermodynamic control provides a reference rate constant for each haem that does not depend on driving force and can be related to structural factors. The thermodynamic characterisation of three tetrahaem cytochromes and their kinetics of reduction by sodium dithionite are reported in this paper. Thermodynamic and kinetic data were fitted simultaneously to a model to obtain microscopic reduction potentials, haem-haem and haem-proton interacting potentials, and reference rate constants for the haems. The kinetic information obtained for these cytochromes and recently published data for other multihaem cytochromes is discussed with respect to the structural factors that determine the reference rates. The accessibility for the reducing agent seems to play an important role in controlling the kinetic rates, although is clearly not the only factor. PMID- 17692817 TI - PPAR alpha-activation results in enhanced carnitine biosynthesis and OCTN2 mediated hepatic carnitine accumulation. AB - In fasted rodents hepatic carnitine concentration increases considerably which is not observed in PPAR alpha-/- mice, indicating that PPAR alpha is involved in carnitine homeostasis. To investigate the mechanisms underlying the PPAR alpha dependent hepatic carnitine accumulation we measured carnitine biosynthesis enzyme activities, levels of carnitine biosynthesis intermediates, acyl carnitines and OCTN2 mRNA levels in tissues of untreated, fasted or Wy-14643 treated wild type and PPAR alpha-/- mice. Here we show that both enhancement of carnitine biosynthesis (due to increased gamma-butyrobetaine dioxygenase activity), extra-hepatic gamma-butyrobetaine synthesis and increased hepatic carnitine import (OCTN2 expression) contributes to the increased hepatic carnitine levels after fasting and that these processes are PPAR alpha-dependent. PMID- 17692818 TI - Cloning and functional characterization of human SMCT2 (SLC5A12) and expression pattern of the transporter in kidney. AB - Recently, we cloned two Na(+)-coupled lactate transporters from mouse kidney, a high-affinity transporter (SMCT1 or slc5a8) and a low-affinity transporter (SMCT2 or slc5a12). Here we report on the cloning and functional characterization of human SMCT2 (SLC5A12) and compare the immunolocalization patterns of slc5a12 and slc5a8 in mouse kidney. The human SMCT2 cDNA codes for a protein consisting of 618 amino acids. When expressed in mammalian cells or Xenopus oocytes, human SMCT2 mediates Na(+) -coupled transport of lactate, pyruvate and nicotinate. The affinities of the transporter for these substrates are lower than those reported for human SMCT1. Several non-steroidal anti-inflammatory drugs inhibit human SMCT2-mediated nicotinate transport, suggesting that NSAIDs interact with the transporter as they do with human SMCT1. Immunofluorescence microscopy of mouse kidney sections with an antibody specific for SMCT2 shows that the transporter is expressed predominantly in the cortex. Similar studies with an anti-SMCT1 antibody demonstrate that SMCT1 is also expressed mostly in the cortex. Dual labeling of SMCT1 and SMCT2 with 4F2hc (CD98), a marker for basolateral membrane of proximal tubular cells in the S1 and S2 segments of the nephron, shows that both SMCT1 and SMCT2 are expressed in the apical membrane of the tubular cells. These studies also show that while SMCT2 is broadly expressed along the entire length of the proximal tubule (S1/S2/S3 segments), the expression of SMCT1 is mostly limited to the S3 segment. These studies suggest that the low-affinity transporter SMCT2 initiates lactate absorption in the early parts of the proximal tubule followed by the participation of the high-affinity transporter SMCT1 in the latter parts of the proximal tubule. PMID- 17692819 TI - Rumination and attention in major depression. AB - Up until recently, it had been assumed that attentional biases for negative information do not exist in depression. However studies using post-conscious exposure durations have produced contradictory results. The limitations of common attentional tasks, suitability of stimulus materials and differences in stimulus duration times may have contributed to these inconsistencies. We aimed to address many of these issues and examine attentional responses in major depression at two post-conscious exposure times. We also investigated possible roles for rumination and distraction in increasing and lessening attentional biases for negative information. We used a fully controlled experimental design to test the effects of both induced and trait rumination and distraction on attention in patients with major depression and healthy controls. Attention was assessed using the dot probe task. The findings revealed an attentional bias for negative information in depressed patients only at the longer post-conscious exposure duration. Furthermore although this bias was not influenced by either induced or trait distraction, it was related to trait rumination. Overall, the results showed that depression is associated with a strategic attentional bias towards negative information and that this bias is stronger in individuals who habitually ruminate. PMID- 17692820 TI - The impact of CREB and its phosphorylation at Ser142 on inflammatory nociception. AB - Peripheral noxious stimulation leads to phosphorylation and thereby activation of the transcription factor CREB in the spinal cord. CREB phosphorylation occurs mainly at serine 133, but the phosphorylation site at serine 142 may also be important. We investigated the impact of spinal CREB protein levels and phosphorylation at Ser142 on the nociceptive behaviour in rat and mouse models of inflammatory nociception. Downregulation of total CREB protein in the rat spinal cord by antisense-oligonucleotides resulted in antinociceptive effects. After peripheral noxious stimulation CREB was phosphorylated in the spinal cord at serine 133 and 142 indicating a potential role of both residues in nociceptive processing. However, Ser142 mutant mice developed equal behavioural correlates of hyperalgesia as wild-type mice in different inflammatory models. Thus, our data confirm that CREB is essential for spinal nociceptive processing. However, prevention of phosphorylation only at serine 142 is not sufficient to modulate the nociceptive response. PMID- 17692821 TI - Snail1 is involved in the renal epithelial-mesenchymal transition. AB - The pathological significance of the tubular epithelial-mesenchymal transition (EMT) in kidney diseases is becoming increasingly recognized, and the transcription factor Snail1 plays a critical role in EMT. The results of this study show that Snail1 mRNA and protein were upregulated in the tubular epithelial cells of the obstructed kidneys in a rat model of unilateral ureteral obstruction and in human proximal tubule HKC-8 cells treated with TGF-beta1. Glycogen synthase kinase-3beta (GSK-3beta) regulates the Snail1 level by degrading Snail1 protein. The level of the phosphorylated inactive form of GSK 3beta was increased in the tubular epithelial cells of the obstructed kidney. TGF beta1 increased the phosphorylated form of GSK-3beta in HKC-8 cells, and inhibition of GSK-3beta by the selective inhibitors lithium and TDZD-8 caused Snail1 protein to accumulate. This study demonstrated that Snail1 is involved in renal tubular EMT and that TGF-beta1 regulates Snail1 at the transcription and protein degradation levels. PMID- 17692822 TI - Interactions of 2'-fluoro-substituted dUMP analogues with thymidylate synthase. AB - A series of 2'-fluoro-substituted dUMP/FdUMP analogues were synthesized, their interaction with human recombinant thymidylate synthase investigated, and structural (1)H and (19)F NMR study of the corresponding nucleosides performed. While 2'-F-dUMP (fluorine in the "down" configuration), in striking contrast to 2'-F-ara-UMP (fluorine in the "up" configuration) and 2',2''-diF-dUMP, showed substrate activity, 2'-F-ara-UMP and 2',2''-diF-dUMP were classic inhibitors, and 2',5-diF-ara-UMP behaved as a strong slow-binding inhibitor, suggesting the 2'-F substituent in the "up" position to interfere with the active center cysteine thiol addition to the pyrimidine C(6) and the pyrimidine C(5)-F to prevent this interference. In support, the direct through space heteronuclear coupling J(HF) was observed for the fluorine "up" derivatives, 2'-F-ara-U and 2',5-diF-ara-U, causing the splitting of the H(6) resonance lines. The absence of such splitting in 2',2''-diF-dUrd, indicating an unusual orientation of the base in relation to the furanose, was associated with an exceptionally weak interaction with the enzyme. PMID- 17692823 TI - Osteo-maturation of adipose-derived stem cells required the combined action of vitamin D3, beta-glycerophosphate, and ascorbic acid. AB - This study investigated the effects of various components [vitamin D3 (VD3), beta glycerophosphate (BGP), and ascorbic acid (AA)] on the potential of human adipose derived progenitor cells (ADPCs) to transdifferentiate into osteoblast-like cells. ADPCs were induced under four different supplement groups: (1) VD3+BGP+AA, (2) VD3 alone, (3) BGP+AA, and (4) no VD3, BGP or AA. Mineralization studies and presence of bone matrix-related proteins by immunostaining showed that the Group 1 ADPCs showed their ability to undergo osteoblastic differentiation. Further evaluation was made by estimation of levels of RUNX-2 and TAZ genes. Group 1 ADPCs showed the consistent expression of RUNX-2 and TAZ levels over the study period of 28days. The study showed good correlation among various parameters evaluated to conclude that ADPCs could be an alternative source for generating osteoblast-like cells. PMID- 17692824 TI - A mastoparan analog without lytic effects and its stimulatory mechanisms in mast cells. AB - Mastoparan, a tetradecapeptide isolated from wasp venom, is known to not only induce the secretion of histamine but also cause cell lysis in rat peritoneal mast cells. This lytic effect makes investigations concerning MP-induced signaling mechanisms difficult. Here, we report that a mastoparan derivative peptide, [Lys(10), Leu(13)]mastoparan, also designated "mas 11'', induces exocytosis with greater activity than mastoparan without the undesired lytic effect. The signaling mechanisms triggered by mas 11 were also investigated, and it was clearly demonstrated that mas 11 induced not only the non-lytic release of beta-hexosaminidase but also an increase in the concentration of cytosolic free Ca(2+) in the cells and these effects were mostly prevented by pertussis toxin, suggesting the involvement of G(i)-type G protein in the signaling. Mas 11 is a promising stimulatory molecule with which to investigate the exocytotic mechanisms induced by not only mastoparan but also various amphiphilic peptides in the cells. PMID- 17692825 TI - Tryptophan orientation in model lipid membranes. AB - Tryptophans in membrane proteins display strong preference for the lipid membrane interface and are important for anchoring proteins at the proper longitudinal level. Linear dichroism spectroscopy on indoles in shear-deformed liposomes has been used to show that this positioning is accompanied by an intrinsically adopted orientation, also observed for tryptophans in membrane-bound peptides. Similarities in orientation of different indoles suggest that tryptophan will adopt this orientation independent of the protein it is part of. From the orientation of indole electronic transition moments L(a), L(b) and B(b), a binding model is proposed where the indole long axis is approximately 60-65 degrees from the membrane normal and the indole plane is at an oblique angle. We propose that dipole-dipole interactions and steric constraints in the membrane hydrocarbon region determine positioning and orientation of tryptophans whereas hydrogen bonding and cation-pi interactions with lipid head-groups, though contributing to the membrane affinity of indoles, are less important. PMID- 17692826 TI - Evidence that genetic deletion of the TNF receptor p60 or p80 inhibits Fas mediated apoptosis in macrophages. AB - Almost 19 members of the tumor necrosis factor (TNF) superfamily have been identified that interact with 29 different receptors. Whether these receptors communicate with each other is not understood. Recently, we have shown that receptor activator of NF-kappaB ligand signaling is modulated by genetic deletion of the TNF receptor. In the current report, we investigated the possibility of a cross-talk between Fas and TNF-alpha signaling pathway in macrophage cell lines derived from wild-type (WT) mice and from mice with genetic deletion of the type 1 TNF receptor (p60(-/-)), the type 2 TNF receptor (p80(-/-)), or both receptors (p60(-/-)p80(-/-)). We found that the macrophages expressing TNF receptors were highly sensitive to apoptosis induced by anti-Fas. The genetic deletion of TNF receptors, however, made the cells resistance to anti-Fas-induced apoptosis. Anti Fas induced activation of caspase-3 and PARP cleavage in WT cells but not in TNF receptor-deleted cells. This difference was found to be independent of the expression of Fas, Fas-associated protein with death domain (FADD) or TNF receptor-associated death domain (TRADD). We found that anti-Fas induced recruitment of TNFR1 into Fas-complex. We also found that TRADD, which mediates TNF signaling, was constitutively bound to Fas receptor in TNF receptor-deleted cells but not in wild-type cells. Transient transfection of TNFR1 in TNFR1 deleted cells sensitized them to anti-Fas-induced apoptosis. Overall our results demonstrate that Fas signaling is modulated by the TNF receptors and thus provide the evidence of cross-talk between the receptors of two cytokines. PMID- 17692827 TI - Cytotoxicity of beta-carbolines in dopamine transporter expressing cells: structure-activity relationships. AB - Some beta-carbolines (BC) are natural constituents in the human brain deriving from tryptophan, tryptamine, and serotonin. In vitro and animal experiments suggest that BC-cations may cause neurodegeneration with a higher vulnerability of dopaminergic than of other neurons. Despite the possible implication of the BC cations in the pathogenesis of Parkinson's disease (PD), the underlying mechanisms are poorly understood. The present study further explores the structural requirements for the cytotoxic effects of BCs and searches for additional compounds involved in the pathogenesis of PD. Previous studies were now extended to serotonin-derived BCs, tetrahydro-BCs, a BC-dimer, and a BC enantiomer to reveal possible stereoselectivity. Neutral, rather lipophilic BCs may pass the plasma membrane and the outer and inner mitochondrial membranes by diffusion whereas the cationic, more polar compounds, can be transported by the dopamine transporter (DAT). In the present study, 4 out of 17 BC-cations caused DAT-independent toxicity. This number is unexpected in view of previous findings that all BC-cations are transported by DAT. 3-Carboxylated and 6-methoxylated BCs were poor substrates. The size alone does not seem to be a limiting factor. A dimeric BC-cation was readily transported by the DAT despite its much larger structure compared to dopamine. Furthermore, (R)-enantiomers were preferentially transported. The neutral BCs were approximately one order of magnitude less toxic than the cationic BCs. There are considerable differences of the transport efficiency between the BCs. Potent cytotoxic tetrahydro-BCs were detected. Because precursor tetrahydro-BCs are present in the brain, the search for the occurrence of these compounds in human brain is warranted. PMID- 17692828 TI - Ursolic acid ameliorates cognition deficits and attenuates oxidative damage in the brain of senescent mice induced by D-galactose. AB - Ursolic acid (UA), a pentracyclic triterpene, is reported to have an antioxidant activity. Here we assessed the protective effect of UA against the d-galactose (D gal)-induced neurotoxicity. We found that UA markedly reversed the D-gal induced learning and memory impairment by behavioral tests. The following antioxidant defense enzymes were measured: superoxide dismutases (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR). The content of the lipid peroxidation product malondialdehyde (MDA) was also analyzed. Our results indicated that the neuroprotective effect of UA against D-gal induced neurotoxicity might be caused, at least in part, by the increase in the activity of antioxidant enzymes with a reduction in lipid peroxidation. And UA also inhibited the activation of caspase-3 induced by D-gal. Furthermore, we found that UA significantly increased the level of growth-associated protein GAP43 in the brain of D-gal-treated mice. These results suggest that the pharmacological action of UA may offer a novel therapeutic strategy for the treatment of age related conditions. PMID- 17692829 TI - Acute stress potentiates anxiety in humans. AB - BACKGROUND: Stress is an important factor in the development and maintenance of anxiety disorders. Stress also potentiates anxiety-like response in animals, but empirical evidence for a similar effect in humans is still lacking. METHODS: To test whether stress increases anxiety in humans, we examined the ability of a social stressor (speech and a counting task) to potentiate the facilitation of startle in the dark. Measures of subjective distress and of hypothalamic pituitary-adrenal axis and autonomic nervous system activity (e.g., salivary cortisol, alpha-amylase, blood pressure, and heart rate) were also taken to confirm the effectiveness of the stress manipulation. RESULTS: Startle was significantly facilitated in the dark. This effect was potentiated by prior exposure to the social stressor. The social stressor induced increases in salivary cortisol and alpha amylase as well as increases in blood pressure, heart rate, and subjective distress. CONCLUSION: The findings indicate that stress potentiates anxiety. Animal studies suggest that such an effect might be mediated by glucocorticoid effects on corticotropin-releasing hormone in limbic structures. PMID- 17692830 TI - Localization of L-DOPA uptake and decarboxylating neuronal structures in the cat brain using dopamine immunohistochemistry. AB - The present study examined dopamine-immunoreactive neuronal structures using immunohistochemistry in conjunction with an anti-dopamine antiserum, following injection of l-3,4-dihydroxyphenylalanine (L-DOPA) with or without an inhibitor of monoamine oxidase (Pargyline) in the cat brain. L-DOPA injection made it possible to detect dopamine immunoreactivity in presumptive serotonergic and noradrenergic cell bodies and axons. Weak to moderate dopamine immunoreactivity was observed in non-aminergic cells (possibly so-called "D" cells containing aromatic L-amino acid decarboxylase (AADC)) in several hypothalamic, midbrain, pontine and medullary nuclei. Intense dopamine immunoreactivity became visible in a large number of cells and axons (possibly containing AADC) with wide distribution in the brain following administration of L-DOPA with Pargyline. AADC is most likely active in cells and axons that take up L-DOPA, where it decarboxylates the L-DOPA to dopamine. However, newly synthesized dopamine in such cells is rapidly oxidized by monoamine oxidase. PMID- 17692831 TI - Plastic changes induced by neonatal handling in the hypothalamus of female rats. AB - Early-life events can exert profound long-lasting effects on several behaviors such as fear/anxiety, sexual activity, stress responses and reproductive functions. Present study aimed to examine the effects of neonatal handling on the volume and number of cells in the hypothalamic paraventricular nucleus (pPVN, parvocellular and mPVN, magnocellular regions) and the supraoptic nucleus (SON) in female rats at 11 and 90 days of age. Moreover, in the same areas, immunohistochemistry for oxytocin (OT) and glial fibrillary acidic protein (GFAP) were analyzed in the adult animals. Daily handling during the first 10 postnatal days reduced the number of cells in the pPVN and SON at both the 11 and 90 days. Handling decreased the number of OT-positive parvocellular cells in the PVN in adult females. No significant differences were detected on the optical density (OD) of GFAP-positive cells between the handled and nonhandled adult females. The effect of handling on cell loss was observed 24 h after the 10-day handling period and persisted into adulthood, indicating a stable morphological trace. Results suggest that neonatal handling can induce plastic changes in the central nervous system. PMID- 17692832 TI - An investigation into the lipid-binding properties of alpha-, beta- and gamma synucleins in human brain and cerebrospinal fluid. AB - Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are both characterized by the formation and intraneuronal accumulation of fibrillar aggregates of alpha-synuclein (alpha-syn) protein in affected brain regions. alpha-Syn has biochemical properties and a structural motif characteristic of fatty acid binding proteins. Using the fatty acid binding resin Lipidex-1000, we investigated the capture of alpha-, beta-, and gamma-syn proteins as lipid associated proteins from normal and DLB brain lysates, and from normal human cerebrospinal fluid (CSF). These were eluted from Lipidex-1000 and analyzed by SDS-NuPAGE followed by Western blotting. Using this methodology, we have been able to extract full-length and truncated forms of alpha-syn from brain lysates. We also extracted low levels of beta-syn from DLB brains, but failed to extract any gamma-syn. We were able to capture only full-length monomeric alpha-syn from normal human CSF. Our data confirm the fatty acid binding properties of alpha syn, and to a lesser extent beta-syn, but suggest that gamma-syn does not share this same characteristic. PMID- 17692833 TI - Postnatal development and kinetics of [3H]gaboxadol binding in rat brain: in vitro homogenate binding and quantitative autoradiography. AB - The postnatal development of the binding of the GABA(A) receptor agonist [(3)H]gaboxadol in rat brain was investigated. Using brain tissue from rats obtained at postnatal days 1, 10, 25, and >25 (adult), the binding of [(3)H]gaboxadol and the benzodiazepine [(3)H]flunitrazepam to GABA(A) receptors was compared in homogenate binding assays and quantitative receptor autoradiography. Kinetic and equilibrium data obtained in homogenate binding studies revealed two different [(3)H]gaboxadol affinities. A kinetically derived K(D) of 3.7 nM in adult cerebellum, calculated from the association and dissociation rate constants k(on) (1.45 x 10(8) M(-1) min(-1)) and k(off) (0.54 min(-1)) was contrasted by an equilibrium K(D) of 38.6 nM, obtained by homologous competition experiments. Quantitative analysis of autoradiographic data revealed an increase in specific [(3)H]gaboxadol binding sites during brain development, which resembles the anatomical and temporal pattern of the postnatal expression of the extrasynaptic delta subunit of GABA(A) receptors. In conclusion, by the radioligand binding data obtained on native tissue, binding of gaboxadol to GABA(A) receptors located outside the synaptic junctions could be postulated. PMID- 17692834 TI - Evidence for the auditory P3a reflecting an automatic process: elicitation during highly-focused continuous visual attention. AB - The P3a is an event-related potential (ERP) component believed to reflect an attention-switch to task-irrelevant stimuli or stimulus information. The present study concerns the automaticity of the processes underlying the auditory P3a. More specifically, we investigated whether the auditory P3a is an attention independent component, that is, whether it can still be elicited under highly focused selective attention to a different (visual) channel. Furthermore, we examined whether the auditory P3a can be modulated by the demands of the visual diversion task. Subjects performed a continuous visual tracking task that varied in difficulty, based on the number of objects to-be-tracked. Task-irrelevant auditory stimuli were presented at very rapid and random rates concurrently to the visual task. The auditory sequence included rare increments (+10 dB) and decrements (-20 dB) in intensity relative to the frequently-presented standard stimulus. Importantly, the auditory deviant stimuli elicited a significant P3a during the most difficult visual task, when conditions were optimised to prevent attentional slippage to the auditory channel. This finding suggests that the elicitation of the auditory P3a does not require available central capacity, and confirms the automatic nature of the processes underlying this ERP component. Moreover, the difficulty of the visual task did not modulate either the mismatch negativity (MMN) or the P3a but did have an effect on a late (350-400 ms) negativity, an ERP deflection perhaps related to a subsequent evaluation of the auditory change. Together, these results imply that the auditory P3a could reflect a strongly-automatic process, one that does not require and is not modulated by attention. PMID- 17692835 TI - Secretory phospholipase A2-alpha from Arabidopsis thaliana: functional parameters and substrate preference. AB - The secretory phospholipase A2-alpha from Arabidopsis thaliana (AtsPLA2-alpha), being one of the first plant sPLA2s obtained in purified state, has been characterised with respect to substrate preference and optimum conditions of catalysis. The optima of pH, temperature, and calcium concentration were similar to the parameters of secretory PLA2s from animals. However, substrate preferences markedly differed. In contrast to pancreatic PLA2s, AtsPLA2-alpha preferred zwitterionic phospholipids, and showed lower activity toward anionic phospholipids. In substrates with two identical fatty acid chains, AtsPLA2-alpha showed optimum activity toward phospholipids with decanoyl groups. In substrates with palmitoyl groups in sn-1 position, acyl chains with higher degree of unsaturation in sn-2 position were preferred, excluding arachidonic acid, showing the evolutionary adaptation of the enzyme to substrate composition in plants. Km values for short chain phospholipids were comparable to sPLA2s from animals, whereas k cat values were much smaller and interfacial activation was less important. PMID- 17692836 TI - Possible origins of undetectable EPO in urine samples. AB - BACKGROUND: In order to determine the possible origins of undetectable EPO profiles in athletes' urine, we analyzed the data obtained from a large number of official anti-doping urine tests aimed at detecting recombinant erythropoietin. The following variables were considered as potential causes for lack of EPO detection: athlete's gender, competition effect, urine specific gravity as well as possible usage of proteasic adulterants to evade doping detection. RESULTS: Statistical analyses indicated that undetectable EPO profiles were clearly related to urine properties such as low EPO concentrations or extreme specific gravities. The addition of very small quantities of protease was shown to remove all traces of EPOs in urine. This finding led to the development of a simple, specific and sensitive test that reveals proteasic activity based on albumin digestion. CONCLUSIONS: Urine characteristics clearly affect the detectability of an EPO profile. At the same time, addition of anti-proteases prevents the adulteration of urine. These two findings have clear practical implications with regards to the timing of urine collection as well as the entire anti-doping control procedure. PMID- 17692837 TI - A zebrafish LMO4 ortholog limits the size of the forebrain and eyes through negative regulation of six3b and rx3. AB - The Six3 and Rx3 homeodomain proteins are essential for the specification and proliferation of forebrain and retinal precursor cells of the vertebrate brain, and the regulatory networks that control their expression are beginning to be elucidated. We identify the zebrafish lmo4b gene as a negative regulator of forebrain growth that acts via restriction of six3 and rx3 expression during early segmentation stages. Loss of lmo4b by morpholino knockdown results in enlargement of the presumptive telencephalon and optic vesicles and an expansion of the post-gastrula expression domains of six3 and rx3. Overexpression of lmo4b by mRNA injection causes complementary phenotypes, including a reduction in the amount of anterior neural tissue, especially in the telencephalic, optic and hypothalamic primordia, and a dosage-sensitive reduction in six3 and rx3 expression. We suggest that lmo4b activity is required at the neural boundary to restrict six3b expression, and later within the neural plate to for attenuation of rx3 expression independently of its effect on six3 transcription. We propose that lmo4b has an essential role in forebrain development as a modulator of six3 and rx3 expression, and thus indirectly influences neural cell fate commitment, cell proliferation and tissue growth in the anterior CNS. PMID- 17692838 TI - Laboratory measurements of the volatilization of PCBs from amended dredged material. AB - Since 1997, over 6 million cubic meters of material dredged from the navigation channels of NY/NJ Harbor has been amended with Portland cement and then used as fill and capping material at landfill and brownfield sites in New Jersey, New York, and Pennsylvania. Previous studies have determined that polychlorinated biphenyls (PCBs) will volatilize from this material as it dries. In the present study, time constants for the decay of the volatilization rate were determined taking into account the degree of stabilization. The experiments were conducted in a laminar flow flux chamber in which air was drawn past the dredged material and then through a polyurethane foam (PUF), sample matrix. The concentration of PCBs on the PUF found at various time increments at the downstream end of the chamber was compared to that found for the same time increments in a PUF installed in an air sampler at the upstream end of the chamber in order to calculate the flux. The time constant determined for raw dredged material was about 4 times greater than material stabilized with 8% Portland cement. The average time constants for the decay of flux rates from raw dredged material were 56, 67, and 60h for the di-, tri-, and tetra-chlorinated homologues, respectively. These times decreased with increasing proportion of Portland cement in the mixture. When stabilized with 8% Portland cement, the average time constants were 14, 13, and 19h, respectively. The effects of temperature on PCB flux rate were also investigated. The results suggest that a 3 degrees C temperature increase will more than double the flux rate. PMID- 17692839 TI - A gender-independent proarrhythmic action of 17beta-estradiol in anaesthetized rabbits. AB - Women are at increased risk of having drug-induced arrhythmias such as torsade de pointes but less susceptible to arrhythmias associated with myocardial ischaemia. We have shown previously that 17beta-estradiol had greater antiarrhythmic activity in female rats than in male rats subject to myocardial ischaemia. The aim of this work was to investigate the effects of acute administration of 17beta estradiol in both sexes in an established in vivo model of drug-induced arrhythmias. In alpha(1)-adrenoceptor-stimulated, pentobarbital-anaesthetized rabbits, 17beta-estradiol (100, 300 or 1000 ng/kg bolus followed by 10, 30 or 100 ng/kg/min infusion) tended to increase the incidence of torsade de pointes, induced by clofilium, in both sexes: from 50% in controls to 80%, 70% and 80% in females; from 40% in controls to 60%, 70% and 80% in males with increasing doses of 17beta-estradiol (n=10 per group). The total duration of all episodes of torsade de pointes was increased significantly by the highest dose of 17beta estradiol compared to vehicle in both female and male rabbits: from 9+/-4 s to 93+/-26 s in females; from 26+/-14 s to 96+/-20 s in males. There were no baseline differences between the sexes in heart rate, QTc interval or epicardial monophasic action potential duration. The proarrhythmic effect of acute administration of 17beta-estradiol in the alpha(1)-adrenoceptor-stimulated anaesthetized rabbit model was independent of gender. This indicates that the underlying mechanism differs from that involved in the gender-selective reduction of ischaemia-induced arrhythmias by 17beta-estradiol. PMID- 17692840 TI - Angiotensin II type 1 receptor blockade prevents decrease in adult stem-like cells in kidney after ureteral obstruction. AB - Infusion of renal side population (SP) cells, enriched with adult stem-like cells, can ameliorate acute renal failure. We investigated the effects of an angiotensin II type 1 (AT(1)) receptor antagonist, valsartan on SP cell changes in renal injury by ureteral obstruction. Renal SP fraction was reduced by 38%, and the number of cells expressing CD45, a marker of hematopoietic system, in renal SP cells was increased in obstructed kidneys. Valsartan attenuated renal injury and the associated SP profile changes. Angiotensin AT(1) receptor blockade may exert regenerative effect by preserving adult stem-like cells such as SP cells in the kidney. PMID- 17692841 TI - Differences in agonist/antagonist properties at human dopamine D(2) receptors between aripiprazole, bifeprunox and SDZ 208-912. AB - Aripiprazole is the first dopamine D(2) receptor partial agonist approved for use in schizophrenia and bipolar disorder. Other partial agonists have failed in various stages of development, either for reasons of poor tolerability or lack of efficacy. We conducted an in vitro comparative analysis between aripiprazole, bifeprunox, SDZ 208-912, OPC-4392 and ACR16 in attempt to correlate specific pharmacological properties with clinical outcome. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of this inhibition produced by dopamine in clonal CHO cell lines expressing high and low densities of human dopamine D(2L) and D(2S) receptors. In cells expressing high receptor densities, all drugs except ACR16 predominantly behaved as agonists. However, in cells expressing low receptor densities, all drugs showed significantly lower maximal effects than dopamine. Aripiprazole's intrinsic activity was lower than that observed with bifeprunox and OPC-4392, and higher than that of SDZ 208-912. Aripiprazole's antagonist activity was greater than that of bifeprunox and OPC-4392, and less than that of SDZ 208-912. In conclusion, our data suggests that aripiprazole's unique intrinsic activity profile may account for its demonstrated clinical efficacy in the treatment of both positive and negative symptoms of schizophrenia, as well as its demonstrated low liability for parkinsonism and hyperprolactinemia. A higher degree of intrinsic activity, and lower relative antagonist activity, such as that observed with bifeprunox and OPC-4392 may translate into a clinically suboptimal improvement of positive symptoms. SDZ 208-912's intrinsic activity may be lower than the optimal level needed to minimize extrapyramidal symptoms. PMID- 17692842 TI - RhoB affects macrophage adhesion, integrin expression and migration. AB - Rho GTPases regulate multiple cellular responses, including cell motility and cell cycle progression. The Rho isoform RhoB represses transformation and affects endosomal trafficking, but its effects on cell adhesion and migration have not been investigated in detail. Here we show that RhoB-null macrophages are more rounded than wild-type macrophages on fibronectin and uncoated glass, and have reduced adhesion to ICAM-1 and glass but not fibronectin. This correlated with lower cell surface expression of beta2 and beta3 integrins but not beta1 integrin. RhoB-null cells migrated faster than Wt cells on fibronectin, consistent with their smaller spread area, but slower than Wt cells on glass, reflecting their reduced adhesion. C3 transferase, which inhibits RhoA, RhoB and RhoC, induced cell spreading but this effect was reduced in RhoB-null cells. However, RhoB is not required for assembly of podosomes, which are integrin-based adhesion sites, whereas C3 transferase induced a decrease in podosomes and defects in tail retraction. Since macrophages do not express RhoC, these effects of C3 transferase are due to inhibition of RhoA rather than RhoB. Our results suggest that RhoB affects cell shape and migration by regulating surface integrin levels. PMID- 17692843 TI - CagA-independent disruption of adherence junction complexes involves E-cadherin shedding and implies multiple steps in Helicobacter pylori pathogenicity. AB - Infection with Helicobacter pylori (H. pylori) leads to depolarization and migration of polarized epithelial cells, both strongly enhanced by injection of the pathogenic factor CagA (cytotoxin-associated gene A) into the host cytoplasm. Depolarization and migration of epithelial cells imply the disruption of cell adhesion junctions (AJs) comprising a protein complex of E-cadherin, beta catenin, p120(ctn), and alpha-catenin. Here, we analyzed the disintegration of E cadherin-mediated AJs and demonstrated that loss of E-cadherin-dependent cell cell contacts is entirely independent of CagA. Upon infection with H. pylori, either wild-type (wt) or a cagA mutant (DeltacagA), interaction between E cadherin and alpha-catenin dissociated rapidly, while binding of E-cadherin to beta-catenin and p120(ctn) was hardly affected. Simultaneously, loss of cell adhesion involved E-cadherin cleavage induced by a bacterial factor secreted by H. pylori. Finally, beta-catenin-mediated transcription, a hallmark of many carcinomas, was not activated in H. pylori-infected epithelial cells at this stage of infection. Altogether, our data indicate that H. pylori-induced pathogenesis is a multi-step process initiated by CagA-independent mechanisms. These include proteolytical cleavage of E-cadherin and dissociation of the E cadherin/beta-catenin/p120(ctn) complex from the actin cytoskeleton by disrupting binding to alpha-catenin. PMID- 17692844 TI - Cortical and subcortical plasticity in the brains of humans, primates, and rats after damage to sensory afferents in the dorsal columns of the spinal cord. AB - The failure of injured axons to regenerate following spinal cord injury deprives brain neurons of their normal sources of activation. These injuries also result in the reorganization of affected areas of the central nervous system that is thought to drive both the ensuing recovery of function and the formation of maladaptive neuronal circuitry. Better understanding of the physiological consequences of novel synaptic connections produced by injury and the mechanisms that control their formation are important to the development of new successful strategies for the treatment of patients with spinal cord injuries. Here we discuss the anatomical, physiological and behavioral changes that take place in response to injury-induced plasticity after damage to the dorsal column pathway in rats and monkeys. Complete section of the dorsal columns of the spinal cord at a high cervical level in monkeys and rats interrupts the ascending axon branches of low threshold mechanoreceptor afferents subserving the forelimb and the rest of the lower body. Such lesions render the corresponding part of the somatotopic representation of primary somatosensory cortex totally unresponsive to tactile stimuli. There are also behavioral consequences of the sensory loss, including an impaired use of the hand/forelimb in manipulating small objects. In monkeys, if some of the afferents from the hand remain intact after dorsal column lesions, these remaining afferents extensively reactivate portions of somatosensory cortex formerly representing the hand. This functional reorganization develops over a postoperative period of 1 month, during which hand use rapidly improves. These recoveries appear to be mediated, at least in part, by the sprouting of preserved afferents within the cuneate nucleus of the dorsal column-trigeminal complex. In rats, such functional collateral sprouting has been promoted by the post-lesion digestion of the perineuronal net in the cuneate nucleus. Thus, this and other therapeutic strategies have the potential of enhancing sensorimotor recoveries after spinal cord injuries in humans. PMID- 17692845 TI - Heregulin-induced epigenetic regulation of the utrophin-A promoter. AB - Utrophin is the autosomal homolog of dystrophin, the product of the Duchenne's muscular dystrophy (DMD) locus. Utrophin is of therapeutic interest since its over-expression can compensate dystrophin's absence. Utrophin is enriched at neuromuscular junctions due to heregulin-mediated utrophin-A promoter activation. We demonstrate that heregulin activated MSK1/2 and phosphorylated histone H3 at serine 10 in cultured C2C12 muscle cells, in an ERK-dependent manner. MSK1/2 inhibition suppressed heregulin-mediated utrophin-A activation. MSK1 over expression potentiated heregulin-mediated utrophin-A activation and chromatin remodeling at the utrophin-A promoter. These results identify MSK1/2 as key effectors modulating utrophin-A expression as well as identify novel targets for DMD therapy. PMID- 17692846 TI - Response of zonal chondrocytes to extracellular matrix-hydrogels. AB - We investigated the biological response of chondrocytes isolated from different zones of articular cartilage and their cellular behaviors in poly (ethylene glycol)-based (PEG) hydrogels containing exogenous type I collagen, hyaluronic acid (HA), or chondroitin sulfate (CS). The cellular morphology was strongly dependent on the extracellular matrix component of hydrogels. Additionally, the exogenous extracellular microenvironment affected matrix production and cartilage specific gene expression of chondrocytes from different zones. CS-based hydrogels showed the strongest response in terms of gene expression and matrix accumulation for both superficial and deep zone chondrocytes, but HA and type I collagen-based hydrogels demonstrated zonal-dependent cellular responses. PMID- 17692847 TI - Bioinformatic analysis of post-transcriptional regulation by uORF in human and mouse. AB - RNA decay is thought to exert an important influence on gene expression by maintaining a steady-state level of transcripts and/or by eliminating aberrant transcripts. However, the sequence elements which control such processes have not been determined. Upstream open reading frames (uORFs) in the transcripts of several genes are reported to control translational initiation by stalling ribosomes and thereby promote RNA decay. We therefore performed bioinformatic analysis of the tissue-wide expression profiles and mRNA half-life of transcripts containing uORFs in humans and mice to assess the relationship between RNA decay and the presence of uORFs in transcripts. The expression levels of transcripts containing uORF were markedly lower than those not containing uORF. Moreover, the half-life of the uORF-containing transcripts was also shorter. These results suggest that uORFs are sequence elements that down-regulate RNA transcripts via RNA decay mechanisms. PMID- 17692848 TI - Main antimicrobial components of Tinospora capillipes, and their mode of action against Staphylococcus aureus. AB - In this investigation, the antibacterial modes of action of Radix Tinosporae, its major single components, and nine antibiotics with different targets or modes-of action on Staphylococcus aureus were studied. Metabolic profiles of cultures treated with different medicines were acquired by HPLC/ESI-MS. After HPLC-MS data pretreatment, those profiles acquired were reduced into several MS vectors. Then statistical processing by principal components analysis was carried out upon those vectors, two conclusions could be drawn: (1) the antibacterial mode of action of Radix Tinosporae is similar to that of rifampicin and norfloxacin, which act on nucleic acid; (2) its active components playing main antimicrobial roles on Staphylococcus aureus might be alkaloids, such as palmatine and jatrorrhizine. PMID- 17692849 TI - Complex formation between recombinant ATP sulfurylase and APS reductase of Allium cepa (L.). AB - Recombinant ATP sulfurylase (AcATPS1) and adenosine-5'-phosphosulfate reductase (AcAPR1) from Allium cepa have been used to determine if these enzymes form protein-protein complexes in vitro. Using a solid phase binding assay, AcAPR1 was shown to interact with AcATPS1. The AcAPR1 enzyme was also expressed in E. coli as the N-terminal reductase domain (AcAPR1-N) and the C-terminal glutaredoxin domain (AcAPR1-C), but neither of these truncated proteins interacted with AcATPS1. The solid-phase interactions were confirmed by immune-precipitation, where anti-AcATPS1 IgG precipitated the full-length AcAPR1 protein, but not AcAPR1-N and AcAPR1-C. Finally, using the ligand binding assay, full-length AcATPS1 has been shown to bind to membrane-localised full-length AcAPR1. The significance of an interaction between chloroplastidic ATPS and APR in A. cepa is evaluated with respect to the control of the reductive assimilation of sulfate. PMID- 17692850 TI - A role for phospholipase A in auxin-regulated gene expression. AB - Auxin increases phospholipase A(2) activity within 2min (Paul, R., Holk, A. and Scherer, G.F.E. (1998) Fatty acids and lysophospholipids as potential second messengers in auxin action. Rapid activation of phospholipase A(2) activity by auxin in suspension-cultured parsley and soybean cells. Plant J. 16, 601-611) and the phospholipase A inhibitors, ETYA and HELSS, inhibit elongation growth of etiolated Arabidopsis hypoctyls (Holk, A., Rietz, S., Zahn, M., Quader, H. and Scherer, G.F.E. (2002) Molecular identification of cytosolic, patatin-related phospholipases A from Arabidopsis with potential functions in plant signal transduction. Plant Physiol. 130, 90-101). To identify the mode of action, rapid auxin-regulated gene expression was tested for sensitivity to these PLA(2) inhibitors using seedlings expressing beta-glucuronidase (GUS) under the control of the synthetic auxin-responsive promoter DR5. ETYA and HELSS inhibited the auxin-induced increases in GUS activity, the steady-state level of the corresponding GUS mRNA and the mRNAs encoded by four other auxin-induced genes, IAA1, IAA5, IAA19 and ARF19. Factors that bind to the auxin response elements of the DR5 promoter and thereby regulate gene expression are regulated by a set of proteins such as Aux/IAA1 whose abundances are, in part, under control of E3 ubiquitin ligase SCF complexes. To investigate this mechanism further, the effect of ETYA on Aux/IAA1 degradation rate was examined using seedlings expressing Aux/IAA1:luciferase fusion proteins. In the presence of cycloheximide and excluding synthesis of IAA1:luciferase, ETYA had no apparent effect on degradation rates of IAA1, either with or without exogenous auxin. Therefore, the E3 ubiquitin ligase SCF(TIR1) complex is an unlikely direct target of the PLA inhibitor. When cycloheximide was omitted, however, the inhibitors ETYA and HELSS blocked a sustained auxin-induced decrease in its steady-state level, indicating an unknown target capable to regulate Aux/IAA protein levels and, hence, transcription. PMID- 17692851 TI - Nestling testosterone controls begging behaviour in the pied flycatcher, Ficedula hypoleuca. AB - Begging signals and endogenous testosterone (T) levels of young birds have been shown to be positively correlated. If T is causally involved in controlling the level of begging effort, an endocrine control mechanism could explain the evolution of begging as a costly signal reflecting need. We tested experimentally whether elevated circulating T levels enhanced begging behaviour in nestling pied flycatchers, Ficedula hypoleuca. A pilot study confirmed that nestling T levels could be elevated within a natural physiological range using an oral dose of T. After T-dosing, nestling begging behaviour was measured as: i) the duration of begging displays and ii) the maximum height of begging stretches. Our results show that nestling T levels were elevated at 90 min post dosing and that at this time point both measures of begging behaviour were performed more intensely by T dosed nestlings than controls. Nestling begging displays in response to dosing varied between individuals, which in part was explained either by the date in the breeding season or nestling mass. The results of this study confirm the causal nature of T in controlling nestling begging signals and suggest that it may be part of the mechanism that controls begging behaviour in nestling birds. PMID- 17692852 TI - Expansive remodeling in venous bypass grafts: novel implications for vein graft disease. AB - OBJECTIVE: To date, intimal hyperplasia has been regarded as the principle mechanism responsible for subsequent vein graft disease. Lumen remodeling has not been previously considered as an additional mechanism. The objectives of this study were to determine changes in lumen remodeling in arterialized vein grafts, the accompanying cellular and extracellular matrix events contributing to remodeling, and the effects of a high cholesterol diet. METHODS AND RESULTS: Reversed jugular vein-to-common carotid artery interposition grafts were constructed in 70 normocholesterolemic and 11 hypercholesterolemic male New Zealand white rabbits. The lumen area initially remained unchanged between 1 and 4 weeks but significantly increased by 40% at 12 weeks. This phase of expansive positive remodeling was accompanied by significantly increased cell apoptosis, collagen synthesis (1.7-fold), collagen content (3.7-fold), gelatinase (MMP-2 and MMP-9) levels and decreased tissue inhibitor of metalloproteinase (TIMP) levels. Expansive remodeling temporally corresponded to high macrophage infiltration and increased low density lipoprotein (LDL) retention (fourfold) in the vein grafts. A high cholesterol diet stimulated early macrophage infiltration and increased MMP-12 (metalloelastase) levels, which was associated with earlier onset of expansive remodeling. CONCLUSION: Expansive lumenal remodeling is a novel mechanism of vein graft response to the arterial circulation, which is accelerated by a high cholesterol diet. PMID- 17692853 TI - Pressure during compaction of morsellised bone gives an increase in stiffness: an in vitro study. AB - Morsellised bone impaction is used in joint prosthesis revision surgery to repair structural damage to the periarticular bone stock. The initial stiffness of the impacted bone is crucial for the survival of the revised hip joint. Impaction of morsellised bone in a femoral canal can cause fractures that may induce implant loosening in both femur and acetabulum. Alternative techniques to increase stiffness can therefore be of major interest. In this study we analyse whether applying a constant pressure during impaction can increase the stiffness of the morsellised bone. We constructed bone pellets by impaction with and without applying a constant pressure. The constrained stiffness and coefficient of secondary strain were determined by unidirectional load testing after construction of the pellets. A significant increase in constrained stiffness (P < 0.001) from 3.9 to 5.5 MPa and a decrease in the coefficient of secondary strain (P < 0.001) from 1.1 to 0.5 were found. PMID- 17692854 TI - Role of biomechanics and muscle activation strategy in the production of endpoint force patterns in the cat hindlimb. AB - We used a musculoskeletal model of the cat hindlimb to compare the patterns of endpoint forces generated by all possible combination of 12 hindlimb muscles under three different muscle activation rules: homogeneous activation of muscles based on uniform activation levels, homogeneous activation of muscles based on uniform (normalized) force production, and activation based on the topography of spinal motoneuron pools. Force patterns were compared with the patterns obtained experimentally by microstimulation of the lumbar spinal cord in spinal intact cats. Magnitude and orientation of the force patterns were compared, as well as the proportion of the types found, and the proportions of patterns exhibiting points of zero force (equilibrium points). The force patterns obtained with the homogenous activation and motoneuron topography models were quite similar to those measured experimentally, with the differences being larger for the patterns from the normalized endpoint forces model. Differences in the proportions of types of force patterns between the three models and the experimental results were significant for each model. Both homogeneous activation and normalized endpoint force models produced similar proportions of equilibrium points as found experimentally. The results suggest that muscle biomechanics play an important role in limiting the number of endpoint force pattern types, and that muscle combinations activated at similar levels reproduced best the experimental results obtained with intraspinal microstimulation. PMID- 17692855 TI - Purification of an Fc-fusion biologic: clearance of multiple product related impurities by hydrophobic interaction chromatography. AB - An hydrophobic interaction chromatography step was developed for the large-scale production of an Fc-fusion biologic. Two abundant product-related impurities were separated from the active monomer using a Butyl resin and a simple step-wash and step-elution strategy. Capacity and resolution of the HIC step was optimal when sodium sulfate was employed as the lyotropic salt and pore size of the Butyl resin was 750A. Factorial analysis identified critical parameters for the Butyl chromatography and an operating window capable of delivering high product quality and yield over a broad column loading range. PMID- 17692856 TI - Simultaneous determination of triclocarban and triclosan in municipal biosolids by liquid chromatography tandem mass spectrometry. AB - A sensitive and accurate method was developed for the simultaneous determination of triclosan and triclocarban in sludge and treated biosolids from municipal wastewater treatment plants (WWTPs). The methods involved extraction by pressurized liquid extraction (PLE), followed by sample clean-up on a Oasis HLB solid phase extraction (SPE) cartridge and analysis by liquid chromatography with electrospray ionization and tandem mass spectrometry (LC-ESI-MS/MS). Accurate quantification was achieved by isotope dilution using stable isotopes of triclosan and triclocarban as internal standards. Matrix effects (ME) in samples of spiked biosolids (n=5) were evaluated by a standard addition method, and these analyses indicated mean ME values of 79.7+/-6.7 and 100.5+/-8.4% for triclosan and triclocarban, respectively; indicating that the sample clean-up method effectively removed interferences. The mean recoveries from the spiked biosolids sample were 97.7+/-6.2 and 98.3+/-5 for triclosan and triclocarban, respectively, and the limits of detection (LOD) were 1.5 and 0.2 ng/g (d.w.) for triclosan and triclocarban, respectively. The method was applied to the analysis of triclosan and triclocarban in samples of activated sludge and treated biosolids collected from three WWTPs in Ontario, Canada. These preliminary results indicate that triclosan and triclocarban co-occur in municipal sludge and treated biosolids at concentrations ranging from 0.62 to 11.55 microg/g dry weight for triclosan, and from 2.17 to 5.97 microg/g dry weight for triclocarban. PMID- 17692857 TI - Utility of 5A molecular sieves to measure carbon isotope ratios in lipid biomarkers. AB - A procedure using 5A zeolite sorption to separate cyclic/branched organic compounds from the linear ones was developed and carbon isotopic fractionation effects were investigated in different families of compounds, e.g. within the hydrocarbon and alcohol compounds. The 5A sieve has a pore size such that only linear components can be incorporated into the pores whereas the cyclic/branched compounds are remaining free in the organic solution. The sorbed compounds were released from the molecular sieve with HF and solvent extracted with hexane. The method enables the isolation of linear saturated classes, such as n-alkanes and n fatty alcohols from branched/cyclic compounds without isotopic fractionation for compound-specific isotope analysis (CSIA) of delta(13)C. However, alkene hydrocarbons, sterols and some aromatics were completely or partly degraded with the molecular sieve. PMID- 17692858 TI - Displacement chromatography of proteins on hydrophobic charge induction adsorbent column. AB - Displacement chromatography of protein mixtures is proposed on hydrophobic charge induction chromatography (HCIC). We have used an HCIC medium, MEP-Hypercel as the stationary phase and a quaternary ammonium salt, benzethonium chloride, as the displacer. It was found that the multiple interactions between proteins/displacer and the HCIC sorbent, i.e. hydrophobic interaction and charge repulsion, enabled a greater flexibility for the design of displacement processes and ease of column regeneration by adjustment of pH. The capacity factors of proteins and displacers were used to predict their performances in column displacement, and the experimental results agreed well with the prediction. An isotachic displacement train of lysozyme and alpha-chymotrypsinogen A was formed with benzethonium chloride as the displacer at pH 5.0 with good yields and purities of the two proteins. Column regeneration was efficiently achieved by charge repulsion between the displacer and the adsorbent at lower pH values (pH 3 and 4). The results indicate that the displacement chromatography on HCIC is a good alternative to traditional hydrophobic displacement chromatography. PMID- 17692859 TI - Direct separation of regioisomers and enantiomers of monoacylglycerols by tandem column high-performance liquid chromatography. AB - An HPLC-based method for direct separation of the regioisomers and enantiomers of monoacylglycerols (MAGs), i.e. sn-1-MAG, sn-2-MAG and sn-3-MAG, has been established. The method employs a tandem column system, in which two different columns (a conventional silica gel column and an enantioselective column) are connected in series. Three isomers of monooleoylglycerols (MOGs) and monolinoleoylglycerols (MLGs) were resolved on the system with resolution factor (R(s)) of more than 1.1 between adjacent peaks. In addition, all types of oleoylglycerols, i.e. trioleoylglycerol (TOG), sn-1,2-dioleoylglycerol (DOG), sn 2,3-DOG, sn-1,3-DOG, sn-1-MOG, sn-3-MOG and sn-2-MOG, were successfully separated on the tandem column system, although baseline separation of the enantiomers was not achieved. By means of the established analytical method, the reaction course of Candida antarctica lipase B (CALB)-mediated esterification of glycerol with oleic acid was monitored. It was found that sn-1-MOG and sn-2,3-DOG were preferably generated over sn-3-MOG and sn-1,2-DOG, respectively, in the early stage of the reaction, and the maximal enantiomer excess (%ee) of sn-1-MOG and sn 2,3-DOG were 32 and 53%, respectively, at 2 h. The enantiomeric purities of these chiral acylglycerols decreased after prolonged reaction. The mechanisms for the formation of these chiral acylglycerols are discussed. PMID- 17692860 TI - Poly(methyl methacrylate) microchip device integrated with gold nanoelectrode ensemble for in-column biochemical reaction and electrochemical detection. AB - This paper proposes a poly(methyl methacrylate) (PMMA) based microchip with an integrated gold nanoelectrode ensemble (GNEE) and a quartet-T loading channel for in-column urea/urease reactions and electrochemical detections. The on-chip GNEE electrode is fabricated using an electrodeless deposition process on a thin polycarbonate (PC) film and bonded directly onto a PMMA substrate to carry out high-performance electrochemical detections. The in-column bio-catalytic reaction of urea/urease is successfully demonstrated utilizing a novel approach based on the different electrokinetic mobilities of urea and urease in capillary electrophoresis (CE) channel. The experimental results significantly show that the GNEE electrode provides a better detection response for the reaction product of ammonia (NH(4)(+)) than a conventional planar gold electrode. The detection results demonstrate a satisfactory determination coefficient (R(2) value) and high reproducibility with a detection limit of 14.8 and 62.8 microM while detecting standard ammonia solution and the urea/urease reaction product of NH(4)(+), respectively. These results confirm the capability of the proposed device for the high-resolution CE-electrochemical detection (CE-ED) of bioanalytical reactions. PMID- 17692861 TI - Determination of three major triterpenoids in epicuticular wax of cabbage (Brassica oleracea L.) by high-performance liquid chromatography with UV and mass spectrometric detection. AB - Lupeol, together with alpha- and beta-amyrins in smaller quantities, has been found for the first time in the epicuticular wax of white cabbage (Brassica oleracea L. convar. capitata (L.) Alef. var. alba DC) leaf surface extract. The three triterpenoids were identified by a new high-performance liquid chromatographic (HPLC) method with UV and mass spectrometric (MS) detection using atmospheric pressure chemical ionization (APCI). All three isomeric compounds gave a parent ion peak at m/z 409 [M+H-18](+) and the relative intensities of some characteristic fragment ion peaks in tandem mass spectrometric (MS-MS) spectra of this parent ion enabled differentiation between the isomers. An additional peak at m/z 439 [M+H](+), which could be oleanonic or ursonic aldehyde, was detected by HPLC-APCI-MS. Saponification of cabbage leaf surface extract with 20% NaOH in methanol at 65 degrees C for 2h had no influence on lupeol, or alpha- or beta-amyrins, but lead to the formation of three additional compounds, which were not identified. PMID- 17692862 TI - Effect of magnesium/calcium ratio in solutions subjected to electrodialysis: characterization of cation-exchange membrane fouling. AB - Electrodialysis is based on the migration of charged species through perm selective membranes under an electric field. Fouling, which is the accumulation of undesired solid materials at the interfaces of these membranes, is one of the major problems of this process. The aim of the present work was to investigate the nature and the morphology of fouling observed at different Mg/Ca ratios (R=0, 1/20, 1/10, 1/5, 2/5) on cation-exchange membranes (CEM) during conventional electrodialysis treatments. It appeared that for R=0, the fouling observed on the surface in contact with the basified concentrate was formed of only Ca(OH)2. As soon as magnesium was introduced into the solution treated, CaCO3 was observed. Furthermore, the X-ray diffraction results also identified the CaCO3 observed as calcite. To our knowledge, this is the first time that the presence of magnesium has been demonstrated to induce a CaCO3 fouling on CEM during electrodialysis. PMID- 17692863 TI - Interfacial properties of cetyltrimethylammonium-coated SiO(2) nanoparticles in aqueous media as studied by using different indicator dyes. AB - In this paper, we compare the properties of SiO(2)/water interface modified by cetyltrimethylammonium bromide (CTAB) with those of CTAB spherical micelles. The suspension of uniform silica nanoparticles coated with CTAB adlayer was investigated by using a set of acid-base indicators. The study of the colloidal system has been provided using electron microscopy and dynamic light scattering methods; the diameter of the initial SiO(2) particles in dried state was ca. 40 nm. The increase in the zeta-potential value of nanoparticles from -34 to +(37 54) mV on going from pure silica suspension to the CTAB-containing system points on the silica surface recharging and formation of surfactant bilayer (or multilayer) on the silica/water interface. To obtain further information about the interfacial surfactant adlayer, the behavior of different indicator dyes has been studied in CTAB-modified SiO(2) suspension. Comparison of the indices of apparent ionization constants, i.e., pK(a)(a) values of phenol red, bromothymol blue, and fluorescein with those determined in CTAB micellar solutions have confirmed the supposition about certain similarity between CTAB-covered silica nanoparticles and common spherical surfactant micelles. However, the experiments on kinetics of bromophenol blue fading, as well as the spectral properties of methyl orange and solvatochromic Reichardt's indicator and some other data revealed the specificity of surfactant-coated silica nanoparticles, presumably, originating from their surface morphology. PMID- 17692864 TI - Electron transfer studies on cholesterol LB films assembled on thiophenol and 2 naphthalenethiol self-assembled monolayers. AB - We have formed the cholesterol monolayer and multilayer LB films on the self assembled monolayers of 2-naphthalenethiol (2-NT) and thiophenol (TP) and studied the electrochemical barrier properties of these composite films using cyclic voltammetry and electrochemical impedance spectroscopy. We have also characterized the cholesterol monolayer film using grazing angle FTIR, scanning tunneling microscopy (STM) and atomic force microscopy (AFM). Cholesterol has a long hydrophobic steroid chain, which makes it a suitable candidate to assemble on the hydrophobic surfaces. We find that the highly hydrophobic surface formed by the self-assembled monolayers (SAM) of 2-NT and TP act as effective platforms for the fabrication of cholesterol monolayer and multilayer films. The STM studies show that the cholesterol monolayer films on 2-NT form striped patterns with a separation of 1.0 nm between them. The area per cholesterol molecule is observed to be 0.64 nm2 with a tilt angle of about 28.96 degrees from the surface normal. The electrochemical studies show a large increase in charge transfer resistance and lowering of interfacial capacitance due to the formation of the LB film of cholesterol. We have compared the behavior of this system with that of cholesterol monolayer and multilayers formed on the self-assembled monolayer of thiophenol. PMID- 17692865 TI - Influence of the Hofmeister series of anions on the molecular organization of positively ionized monolayers of a viologen derivative. AB - The effects of the Hofmeister series of ions are ubiquitous in chemistry and biology. In this paper specific ion effects on the surface behavior of a viologen dication, namely 1,1(')-dioctadecyl-4,4(')-bipyridilium, are shown. Surface pressure and surface potential vs area isotherms were obtained on aqueous subphases containing potassium salts with several representative counterions in the Hofmeister series (C6H5O3-7, SO2 -4, HPO2-4, Cl-, Br-, NO-3, I-, and ClO-4). The parameters obtained from the compression isotherms (area per molecule, phase transitions, Young modulus, initial surface potential, and variation of the surface potential upon compression) are dependent on the nature of the counterion, indicating ion specificity. Aqueous subphases containing C6H5O3-7, SO2-4, and HPO2-4 anions yield more expanded viologen monolayers and these anions do not effectively penetrate into the monolayer. Brewster angle microscopy was used to map the different phases of the viologen monolayers at the air-water interface. The Langmuir films were also characterized by UV-vis spectroscopy, with quantitative analysis of the reflection spectra supporting an organizational model in which the viologen chromophore undergoes a gradual transition to a more vertical position with respect to the water surface upon compression. A comparison of the tilt angles of the viologen on the different subphases indicates that anions that can more easily penetrate in the monolayer permit the viologen moieties to adopt a slightly more vertical position with respect to the water surface. PMID- 17692866 TI - Calorimetric study on interaction of water-soluble copolymers with ionic surfactant. AB - Using isothermal titration microcalorimetry (ITC), we examined the aggregation behavior of water-soluble copolymers, poly(methoxypolyethylene glycol methacrylate-co-ethyl acrylate)s (PME-EA)s, with ionic surfactant, sodium dodecyl sulfate (SDS). From ITC measurements the values of critical aggregation concentration (cac) and saturation concentration (C(2)), the concentration at which the aggregation of the copolymers starts to form and reaches saturation, respectively, were determined. Thermodynamic parameters such as DeltaG(0)(agg), DeltaH(agg), and TDeltaS(0)(agg) of the aggregation were deduced. Results indicate that cac of the PME-EA remained constant with increase in the concentration of the copolymers, while C(2) increased linearly. On the other hand, the effect of the weight ratio of the EA unit in the copolymer was such that cac of the PME400-EA decreased, while C(2) increased with increase in the weight ratio. The results suggested that the EA units are the main binding sites of the copolymer with SDS. PMID- 17692867 TI - Protozoal meningoencephalitis in sea otters (Enhydra lutris): a histopathological and immunohistochemical study of naturally occurring cases. AB - Protozoal meningoencephalitis is considered to be an important cause of mortality in the California sea otter (Enhydra lutris). Thirty nine of 344 (11.3%) California (CA) and Washington state (WA) sea otters examined from 1985 to 2004 had histopathological evidence of significant protozoal meningoencephalitis. The aetiological agents and histopathological changes associated with these protozoal infections are described. The morphology of the actively multiplicative life stages of the organisms (tachyzoites for Toxoplasma gondii and merozoites for Sarcocystis neurona) and immunohistochemical labelling were used to identify infection with S. neurona (n=22, 56.4%), T. gondii (n=5, 12.8%) or dual infection with both organisms (n=12, 30.8%). Active S. neurona was present in all dual infections, while most had only the latent form of T. gondii. In S. neurona meningoencephalitis, multifocal to diffuse gliosis was widespread in grey matter and consistently present in the molecular layer of the cerebellum. In T. gondii meningoencephalitis, discrete foci of gliosis and malacia were more widely separated, sometimes incorporated pigment-laden macrophages and mineral, and were found predominantly in the cerebral cortex. Quiescent tissue cysts of T. gondii were considered to be incidental and not a cause of clinical disease and mortality. Protozoal meningoencephalitis was diagnosed more frequently in the expanding population of WA sea otters (10 of 31, 32.3%) than in the declining CA population (29 of 313, 9.3%). Among sea otters with protozoal meningoencephalitis, those that had displayed neurological signs prior to death had active S. neurona encephalitis, supporting the conclusion that S. neurona is the most significant protozoal pathogen in the central nervous system of sea otters. PMID- 17692868 TI - A new approach to isolation and culture of human Kupffer cells. AB - Macrophages are a diverse population of cells that are able to adapt to specific tissue environments. Kupffer cells are liver resident macrophages and form the largest population of fixed tissue macrophages. Their isolation offers an exciting opportunity to study this subpopulation of uniquely adapted cells. However existing Kupffer cell isolation techniques are tedious and are still largely based on enzymatic digestion to liberate tissue macrophages from the closely associated surrounding tissue. Isolation techniques have continually evolved over the last 3 decades but are neither easily applicable nor user friendly. This is highlighted by a review of current literature which will show that there is a scarcity of published studies employing human Kupffer cells. The other difficulty with Kupffer cells and some other populations of macrophages in culture is the strong tenacity with which they adhere to solid substrate and their resistance to conventional sub-culture dissociation agents. The difficulty with cell dissociation has previously required cells to be grown in suspension culture. This has been achieved by culturing macrophages in Teflon bags but unfortunately this deprives cells of the maturation signals generated by adherence. In this article we have upped the ante by describing a 'user friendly' method for Kupffer cell isolation and new culture techniques that allow Kupffer cells to be grown in adherency whilst at the same time circumventing the difficulties posed by the adherence of these unique cells. PMID- 17692869 TI - The structure of RseB: a sensor in periplasmic stress response of E. coli. AB - An elegant network of signal transduction has evolved in the bacterial cell envelope to respond to environmental stress. It is initiated by sensing unfavourable and harmful changes in the periplasm. The stress signal is then transmitted by a controlled degradation of the transmembrane anti-sigma-factor RseA that leads to the activation of the alternative sigma factor sigma(E). The periplasmic protein RseB exerts a crucial role in modulating the stability of RseA. RseB from Escherichia coli has been crystallized and crystal structures were determined at 2.4 A and at 2.8 A resolution. The protein forms a homodimer, with the monomer composed of two domains. The large domain resembles an unclosed beta-barrel that is structurally remarkably similar to a protein family capable of binding the lipid anchor of lipoproteins. The small C-terminal domain, connected to the large domain by a partially unstructured loop, is responsible for interaction with RseA. On the basis of the structure of RseB, we suggest that it acts as a sensor of periplasmic stress with a dual functionality: it detects mislocalized lipoproteins and propagates the signal to induce the sigma(E) response. PMID- 17692870 TI - Interaction of the family-B DNA polymerase from the archaeon Pyrococcus furiosus with deaminated bases. AB - The interaction of archaeal family B DNA polymerases with deaminated bases has been examined. As determined previously by our group, the polymerase binds tightly to uracil (the deamination product of cytosine), in single-stranded DNA, and stalls replication on encountering this base. DNA polymerisation was also inhibited by the presence of hypoxanthine, the deamination product of adenine. Quantitative binding assays showed that the polymerase bound DNA containing uracil 1.5-4.5-fold more strongly than hypoxanthine and site-directed mutagenesis suggested that the same pocket was used for interaction with both deaminated bases. In contrast the polymerase was insensitive to xanthine, the deamination product of guanine. Traces of uracil and hypoxanthine in DNA can lead to inhibition of the PCR by archaeal DNA polymerases, an important consideration for biotechnology applications. Dual recognition of uracil and hypoxanthine may be facilitated by binding the bases with the glycosidic bond in the anti and syn conformation, respectively. PMID- 17692871 TI - Isotopomer subspaces as indicators of metabolic-pathway structure. AB - The relative abundances and rates of formation of particular isotopic isomers (isotopomers) of metabolic intermediates from (13)C-labelled substrates in living cells provide information on the routes taken by the initial (13)C-atoms. When a primary substrate such as [U,(13)C] d-glucose is added to human erythrocytes, the pattern of labels in terminal metabolites is determined by a set of carbon-group exchange reactions in both glycolysis and the pentose phosphate pathway (PPP). Of a given terminal metabolite, not all possible isotopomers will be produced from each possible primary substrate isotopomer. There are only 8 different (13)C isotopomers of lactate but not all of these are produced when one of the 64 possible (13)C-isotopomers of glucose is used as the input substrate; thus a subset of all 63 glucose isotopomers x 8 lactate isotopomers+1 unlabelled glucose x 1 unlabelled lactate=505 pattern associations, would be produced if a complete experimental analysis were performed with all the glucose variants. The pattern of labelling in this isotopomer subspace reflects the nature of the re-ordering reactions that 'direct' the metabolism. Predicting the combinatorial rearrangements for particular sets of reactions and comparing these with real data should enable conclusions to be drawn about which enzymes are involved in the real metabolic system. An example of the glycolysis-PPP system is discussed in the context of a debate that occurred around the F- and L-type PPPs and which one actually operates in the human RBC. As part of this discussion we introduce the term 'combinatorial deficit' of all possible isotopomers and we show that this deficit is less for the F- than the L-type pathway. PMID- 17692872 TI - Modeling of body mass index by Newton's second law. AB - Since laws of physics exists in nature, their possible relationship to terrestrial growth is introduced. By considering the human body as a dynamic system of variable mass (and volume), growing under a gravity field, it is shown how natural laws may influence the vertical growth of humans. This approach makes sense because the non-linear percentile curves of different aspects of human physical growth from childhood to adolescence can be described in relation to physics laws independently of gender and nationality. Analytical relations for the dependence of stature, measured mass (weight), growth velocity (and their mix as the body mass index) on age are deduced with a set of common statistical parameters which could relate environmental, genetics and metabolism and different aspects of physical growth on earth. A relationship to the monotone smoothing using functional data analysis to estimate growth curves and its derivatives is established. A preliminary discussion is also presented on horizontal growth in an essentially weightless environment (i.e., aquatic) with a connection to the Laird-Gompertz formula for growth. PMID- 17692873 TI - Percolation on fitness landscapes: effects of correlation, phenotype, and incompatibilities. AB - We study how correlations in the random fitness assignment may affect the structure of fitness landscapes, in three classes of fitness models. The first is a phenotype space in which individuals are characterized by a large number n of continuously varying traits. In a simple model of random fitness assignment, viable phenotypes are likely to form a giant connected cluster percolating throughout the phenotype space provided the viability probability is larger than 1/2(n). The second model explicitly describes genotype-to-phenotype and phenotype to-fitness maps, allows for neutrality at both phenotype and fitness levels, and results in a fitness landscape with tunable correlation length. Here, phenotypic neutrality and correlation between fitnesses can reduce the percolation threshold, and correlations at the point of phase transition between local and global are most conducive to the formation of the giant cluster. In the third class of models, particular combinations of alleles or values of phenotypic characters are "incompatible" in the sense that the resulting genotypes or phenotypes have zero fitness. This setting can be viewed as a generalization of the canonical Bateson-Dobzhansky-Muller model of speciation and is related to K SAT problems, prominent in computer science. We analyze the conditions for the existence of viable genotypes, their number, as well as the structure and the number of connected clusters of viable genotypes. We show that analysis based on expected values can easily lead to wrong conclusions, especially when fitness correlations are strong. We focus on pairwise incompatibilities between diallelic loci, but we also address multiple alleles, complex incompatibilities, and continuous phenotype spaces. In the case of diallelic loci, the number of clusters is stochastically bounded and each cluster contains a very large sub cube. Finally, we demonstrate that the discrete NK model shares some signature properties of models with high correlations. PMID- 17692874 TI - Comparative study of the transcriptional regulatory networks of E. coli and yeast: structural characteristics leading to marginal dynamic stability. AB - Dynamical properties of the transcriptional regulatory network of Escherichia coli and Saccharomyces cerevisiae are studied within the framework of random Boolean functions. The dynamical response of these networks to a single point mutation is characterized by the number of mutated elements as a function of time and the distribution of the relaxation time to a new stationary state, which turn out to be different in both networks. Comparison with the behavior of randomized networks reveals relevant structural characteristics other than the mean connectivity, namely the organization of circuits and the functional form of the in-degree distribution. The abundance of single-element circuits in E. coli and the broad in-degree distribution of S. cerevisiae shift their dynamics towards marginal stability overcoming the restrictions imposed by their mean connectivities, which is argued to be related to the simultaneous presence of robustness and adaptivity in living organisms. PMID- 17692875 TI - Diabetic pregnancy in rats leads to impaired glucose metabolism in offspring involving tissue-specific dysregulation of 11beta-hydroxysteroid dehydrogenase type 1 expression. AB - Population-based studies have shown that the offspring of diabetic mothers have an increased risk of developing obesity, insulin resistance, type 2 diabetes and hypertension in later life. To investigate mechanism for the high incidence of metabolic diseases in the offspring of diabetic mothers, we focused on the tissue specific glucocorticoid regulation by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) and studied offspring born to streptozotocin-induced diabetic rats. The body weights of newborn rats from diabetic mothers were heavier than those from control mothers. Offspring born to diabetic mothers demonstrated insulin resistance and mild glucose intolerance after glucose loading at 10 weeks and showed significantly increased 11beta-HSD1 mRNA and enzyme activity in adipose tissue at 12 weeks of age without obvious obesity. Hepatic 11beta-HSD1 mRNA was also elevated. We propose that the 11beta-HSD1 in adipose tissue and liver may play a key role in the development of metabolic syndrome in the offspring of diabetic mothers. Tissue-specific glucocorticoid dysregulation provides a candidate mechanism for the high incidence of metabolic diseases in the offspring of diabetic mothers. Therefore early analyses before apparent obesity are needed to elucidate the molecular mechanisms that may be programmed during the fetal period. PMID- 17692876 TI - Antihyperalgesic effects induced by the IL-1 receptor antagonist anakinra and increased IL-1beta levels in inflamed and osteosarcoma-bearing mice. AB - Based on the well established involvement of IL-1beta in inflammatory hyperalgesia, we have assessed the possible role played by IL-1beta in a murine model of bone cancer-induced pain. With this aim, we measured IL-1beta levels at the region of the tibia and the spinal cord in mice bearing a tibial osteosarcoma induced by the inoculation of NCTC 2472 cells, and we tested whether the IL-1 receptor antagonist, anakinra, inhibits some hypernociceptive reactions evoked by the neoplastic injury. Parallel experiments were performed in mice with a chronic inflammatory process (intraplantar injection of complete Freund's adjuvant, CFA). IL-1beta levels were increased in the tibial region of osteosarcoma-bearing mice and in the paws of inflamed mice. To a lesser extent, the content of IL-1beta in the spinal cord was also augmented in both situations. Osteosarcoma-induced thermal hyperalgesia was inhibited by 30 and 100 mg/kg of systemic anakinra, but only 300 mg/kg prevented inflammatory thermal hyperalgesia. Mechanical hyperalgesia induced by the osteosarcoma was blocked by 100 and 300 mg/kg of anakinra, whereas a partial reversion of inflammatory mechanical hyperalgesia was induced by 300 mg/kg. Anakinra, intrathecally administered (1 and 10 microg) did not modify hyperalgesia of either origin. Besides, both tumoral and inflammatory mechanical allodynia remained unaltered after the administration of anakinra. In conclusion, some hyperalgesic symptoms observed in this model of bone cancer are mediated by the peripheral release of IL-1beta and may be inhibited by antagonists of type I IL-1 receptors with a similar or greater potency than symptoms produced by inflammation. PMID- 17692877 TI - Avian influenza virus infection induces differential expression of genes in chicken kidney. AB - The pathogenic process of highly pathogenic avian influenza virus (HPAIV) infection is poorly understood. To explore the differential expression of kidney genes as a result of HPAIV infection, two cDNA libraries were constructed from uninfected and infected kidneys by suppression subtractive hybridization (SSH). Fifteen genes including IFN-stimulated genes (ISG12), lymphocyte antigen 6 complex locus E gene (LY6E), matrix Gla protein gene (MGP), lysozyme gene, haemopoiesis related membrane protein 1 gene, KIAA1259, MGC68696, G6pc-prov protein gene (G6PC), MGC4504, alcohol dehydrogenase gene (ADH), glutathione S transferase gene (GST), sodium-dependent high-affinity dicarboxylate transporter gene (SDCT), Synaptotagmin XV (SytXV) and two novel genes were found significantly up-regulated or dramatically suppressed. Differential expression of these genes was further identified by Northern blot. Functional analysis indicated that the regulation of their expression might contribute to the pathogenic process of HPAIV infection. In contrast, the increased expression of three IFN-stimulated genes named ISG12, LY6E, and haemopoiesis related membrane protein 1 gene might reflect host defense responses. Further study showed that ISG12 protein failed to directly interact with NS1 protein of HPAIV which expressed simultaneously in the organs where HPAIV replication occurred, by use of BacterioMatch two-hybrid system. Therefore, our findings may provide new insights into understanding the molecular mechanism underlying the pathophysiological process of HPAIV infection in chicken. PMID- 17692878 TI - Pharmacokinetics of diclofenac and its interaction with enrofloxacin in sheep. AB - The pharmacokinetics of diclofenac was investigated in sheep given diclofenac alone (1mgkg(-1), i.v. or i.m.) and in combination with enrofloxacin (5mgkg(-1), i.v.). The plasma concentration-time data following i.v. administration of diclofenac was best described by a two compartment open pharmacokinetic model. The elimination half-life (t(1/2beta)), area under concentration-time-curve (AUC), volume of distribution (Vd(area)), mean residence time (MRT) and total body clearance (Cl(B)) were 1.03+/-0.18h, 12.17+/-1.98microg h ml(-1), 0.14+/ 0.02Lkg(-1), 1.36+/-0.16h and 0.10+/-0.02Lkg(-1)h(-1), respectively. Following i.m. administration of diclofenac alone and in conjunction with enrofloxacin, the plasma concentration-time data best fitted to a one compartment open model. The t(1/2beta), AUC, Vd(area), MRT and Cl(B) were 1.33+/-0.10h, 7.32+/-1.01microg h mL(-1), 0.13+/-0.01Lkg(-1) and 0.07+/-0.01Lkg(-1)h(-1), respectively. Co administration of enrofloxacin did not affect Vd(area) and MRT but absorption rate constant (K(a)), beta, t1/2Ka, t1/2beta, AUC, AUMC, Cl(B) and bioavailability (F) were significantly increased. This may be due to direct inhibition of cytochrome P(450) isozymes by enrofloxacin. A dose of 1.4mgkg(-1) of diclofenac administered every 6h may be appropriate for use in sheep. PMID- 17692879 TI - A crystalline compound (BM-ANF1) from the Indian toad (Bufo melanostictus, Schneider) skin extract, induced antiproliferation and apoptosis in leukemic and hepatoma cell line involving cell cycle proteins. AB - In our earlier communication, it was reported that Indian toad (Bufo melanostictus) skin extract (TSE) possesses antiproliferative and apoptogenic activity in U937 and K562 cells [Giri et al., 2006. Antiproliferative, cytotoxic and apoptogenic activity of Indian toad (Bufo melanostictus, Schneider) skin extract in U937 and K562 cells. Toxicon 48 (4), 388-400]. In the present study, a compound (BM-ANF1) has been isolated from the TSE by alumina gel column chromatography, crystallized and evaluated for its antiproliferative and apoptogenic activity in U937, K562 and HepG2 cells. BM-ANF1 produced dose dependent inhibition of U937, K562 and HepG2 cell growth. The antiproliferative activity was reflected by the MTT assay and demonstrated by the reduced expression of proliferative cell nuclear antigen (PCNA). Flow-cytometric analysis showed that BM-ANF1 arrested the cell cycle at G1 phase and enhanced annexin-V binding in U937 and K562 cells. Scanning electron microscopic and fluorescent microscopic analysis of U937 and K562 cells revealed the apoptogenic nature of the compound. Alkaline comet assay showed that BM-ANF1 produced DNA fragmentation. The dose-dependent expression of caspase 3 indicated that the apoptogenic properties of BM-ANF1 were mediated through the activation of downstream effector nucleases in the cancer cells. The increased expression of p53 and moderate expression of p21(Cip1)/p27(Kip1) due to BM-ANF1 treatment in HepG2 cells supported that the apoptogenic activity of BM-ANF1 was mediated through p53 tumor-suppressor gene expression followed by the expression of p21(Cip1) and p27(Kip1) and it was likely to be linked with cell cycle arrest at G1 phase in cancer cells. From the present study, it may be suggested that the crystalline compound, BM-ANF1, was antiproliferative and apoptogenic in human leukemic and hepatoma cells. PMID- 17692880 TI - Design and dynamic evaluation for a linear ultrasonic stage using the thin-disc structure actuator. AB - The design of a novel, single-axis ultrasonic actuating stage has been proposed. It consists of a movable plate, an edge-driving ultrasonic actuator as an actuating device, and a magnetic Magi encoder as a position sensor. The stage is impelled using a friction-contact mechanism by the ultrasonic actuator with long distance movement. Very high actuating and braking abilities are obtained. The stable and precise positioning control of the stage was achieved by using a neural-fuzzy controller. This simple and inexpensive structure of the single-axis stage demonstrates that the mechanical design of ultrasonic actuating concept could be done flexibly according to the requirements for various applications. PMID- 17692881 TI - Human CD4(+) memory T-lymphocyte responses to SARS coronavirus infection. AB - Little is known about CD4(+) T-cell immunity to the severe acute respiratory syndrome (SARS) coronavirus. In two SARS patients, we examined the memory CD4(+) T-cell responses to peptides derived from SARS coronavirus structural proteins. We generated CD4(+) T-cell lines to 3 peptides from the spike (S) protein and defined their HLA restriction. In one patient, the predominant memory CD4(+) T cell response was directed against an epitope outside the S protein receptor binding domain. In both patients, the frequency of CD4(+) memory T-cells to virus structural proteins and anti-SARS coronavirus IgG levels were low by 12 months after infection. This report expands our understanding of the specificity and duration of anti-SARS coronavirus CD4(+) T-cell immune responses. PMID- 17692882 TI - Inhibition of interleukin-6 expression by the V protein of parainfluenza virus 5. AB - The V protein of parainfluenza virus 5 (PIV5) plays an important role in the evasion of host immune responses. The V protein blocks interferon (IFN) signaling in human cells by causing degradation of the STAT1 protein, a key component of IFN signaling, and blocks IFN-beta production by preventing nuclear translocation of IRF3, a key transcription factor for activating IFN-beta promoter. Interleukin 6 (IL-6), along with tumor necrosis factor (TNF)-alpha and IL-1beta, is a major proinflammatory cytokine that plays important roles in clearing virus infection through inflammatory responses. Many viruses have developed strategies to block IL-6 expression. Wild-type PIV5 infection induces little, if any, expression of cytokines such as IL-6 or TNF-alpha, whereas infection by a mutant PIV5 lacking the conserved C-terminal cysteine rich domain (rPIV5VDeltaC) induced high levels of IL-6 expression. Examination of mRNA levels of IL-6 indicated that the transcription activation of IL-6 played an important role in the increased IL-6 expression. Co-infection with wild-type PIV5 prevented the activation of IL-6 transcription by rPIV5VDeltaC, and a plasmid encoding the full-length PIV5 V protein prevented the activation of IL-6 promoter-driven reporter gene expression by rPIV5VDeltaC, indicating that the V protein played a role in inhibiting IL-6 transcription. The activation of IL-6 was independent of IFN-beta even though rPIV5VDeltaC-infected cells produced IFN-beta. Using reporter gene assays and chromatin immunoprecipitation (ChIP), it was found that NF-kappaB played an important role in activating expression of IL-6. We have proposed a model of activating and inhibiting IL-6 transcription by PIV5. PMID- 17692883 TI - Absence of E protein arrests transmissible gastroenteritis coronavirus maturation in the secretory pathway. AB - A recombinant transmissible gastroenteritis coronavirus (rTGEV) in which E gene was deleted (rTGEV-DeltaE) has been engineered. This deletion mutant only grows in cells expressing E protein (E(+) cells) indicating that E was an essential gene for TGEV replication. Electron microscopy studies of rTGEV-DeltaE infected BHK-pAPN-E(-) cells showed that only immature intracellular virions were assembled. These virions were non-infectious and not secreted to the extracellular medium in BHK-pAPN-E(-) cells. RNA and protein composition analysis by RNase-gold and immunoelectron microscopy showed that rTGEV-DeltaE virions contained RNA and also all the structural TGEV proteins, except the deleted E protein. Nevertheless, full virion maturation was blocked. Studies of the rTGEV DeltaE subcellular localization by confocal and immunoelectron microscopy in infected E(-) cells showed that in the absence of E protein virus trafficking was arrested in the intermediate compartment. Therefore, the absence of E protein in TGEV resulted in two actions, a blockade of virus trafficking in the membranes of the secretory pathway, and prevention of full virus maturation. PMID- 17692884 TI - Losing sight of the bigger picture: peripheral field loss compresses representations of space. AB - Three experiments examine how the peripheral visual field (PVF) mediates the development of spatial representations. In Experiment 1 participants learned and were tested on statue locations in a virtual environment while their field-of view (FOV) was restricted to 40 degrees , 20 degrees , 10 degrees , or 0 degrees (diam). As FOV decreased, overall placement errors, estimated distances, and angular offsets increased. Experiment 2 showed large compressions but no effect of FOV for perceptual estimates of statue locations. Experiment 3 showed an association between FOV size and proprioception influence. These results suggest the PVF provides important global spatial information used in the development of spatial representations. PMID- 17692885 TI - Perceiving colour at a glimpse: the relevance of where one fixates. AB - We used classification images to examine whether certain parts of a surface are particularly important when judging its colour, such as its centre, its edges, or where one is looking. The scene consisted of a regular pattern of square tiles with random colours from along a short line in colour space. Targets defined by a square array of brighter tiles were presented for 200ms. The colours of the tiles within the target were biased by an amount that led to about 70% of the responses being correct. Subjects fixated a point that fell within the target's lower left quadrant and reported each target's colour. They tended to report the colour of the tiles near the fixation point. The influence of the tiles' colour reversed at the target's border and was weaker outside the target. The colour at the border itself was not particularly important. When coloured tiles were also presented before (and after) target presentation they had an opposite (but weaker) effect, indicating that the change in colour is important. Comparing the influence of tiles outside the target with that of tiles at the position at which the target would soon appear suggests that when judging surface colours during the short "glimpses" between saccades, temporal comparisons can be at least as important as spatial ones. We conclude that eye movements are important for colour vision, both because they determine which part of the surface of interest will be given most weight and because the perceived colour of such a surface also depends on what one looked at last. PMID- 17692886 TI - Oxidation of suspected N-nitrosodimethylamine (NDMA) precursors by ferrate (VI): kinetics and effect on the NDMA formation potential of natural waters. AB - The potential of ferrate (Fe(VI)) oxidation to remove N-nitrosodimethylamine (NDMA) precursors during water treatment was assessed. Apparent second-order rate constants (k(app)) for the reactions of NDMA and its suspected precursors (dimethylamine (DMA) and 7 tertiary amines with DMA functional group) with Fe(VI) were determined in the range of pH 6-12. Four model NDMA precursors (dimethyldithiocarbamate, dimethylaminobenzene, 3-(dimethylaminomethyl)indole and 4-dimethylaminoantipyrine) showed high reactivity toward Fe(VI) with k(app) values at pH 7 between 2.6 x 10(2) and 3.2 x 10(5)M(-1)s(-1). The other NDMA precursors (DMA, trimethylamine, dimethylethanolamine, dimethylformamide) and NDMA had k(app) values ranging from 0.55 to 9.1M(-1)s(-1) at pH 7. In the second part of the study, the NDMA formation potentials (NDMA-FP) of the model NDMA precursors and natural waters were measured with and without pre-oxidation by Fe(VI). For most of the NDMA precursors with the exception of DMA, a significant reduction of the NDMA-FP (>95%) was observed after complete transformation of the NDMA precursor. This result was supported by low yields of DMA from the Fe(VI) oxidation of tertiary amine NDMA precursors. Pre-oxidation of several natural waters (rivers Rhine, Neckar and Pfinz) with a high dose of Fe(VI) (0.38 mM = 21 mg L(-1) as Fe) led to removals of the NDMA-FP of 46-84%. This indicates that the NDMA precursors in these waters have a low reactivity toward Fe(VI) because it has been shown that for fast-reacting NDMA precursors Fe(VI) doses of 20 microM (1.1 mg L(-1) as Fe) are sufficient to completely oxidize the precursors. PMID- 17692887 TI - Photocatalytic degradation and drug activity reduction of Chloramphenicol. AB - The photocatalytic degradation of Chloramphenicol, an antibiotic drug, has been investigated in aqueous heterogeneous solutions containing n-type oxide semiconductors as photocatalysts. The disappearance of the organic molecule follows approximately a pseudo-first-order kinetics according to the Langmuir Hinshelwood model. It was observed that, with TiO(2) P-25 as photocatalyst, quantitative degradation of the organic molecule occurs after 4h of illumination. During this time, the dechlorination of the substrate is complete, while the organic nitrogen was recovered in the form of nitrate and ammonium ions. The effect of temperature on the degradation rate of Chloramphenicol shows similar apparent activation energies for both TiO(2) P-25 and ZnO photocatalysts. The initial apparent photonic efficiency (zeta(0)) of the photo-oxidation and the mineralization under various experimental conditions have been calculated, while the Kirby-Bauer disc diffusion method showed a 100% reduction of the drug activity after 90 min of photocatalytic treatment. PMID- 17692888 TI - Biofiltration for removal of BOM and residual ammonia following control of bromate formation. AB - Nitrification was developed within a biological filter to simultaneously remove biodegradable organic matter (BOM) and residual ammonia added to control bromate formation during the ozonation of drinking water. Testing was performed at pilot scale using three filters containing sand and anthracite filter media. BOM formed during ozonation (e.g., assimilable organic carbon (396-572 microg/L), formaldehyde (11-20 microg/L), and oxalate (83-145 microg/L)) was up to 70% removed through biofiltration. Dechlorinated backwash water was required to develop the nitrifying bacteria needed to convert the residual ammonia (0.1-0.5 mg/L NH(3)-N) to nitrite and then to nitrate. Chlorinated backwash water resulted in biofiltration without nitrification. Deep-bed filtration (empty-bed contact time (EBCT) = 8.3 min) did not enhance the development of nitrification when compared with shallow-bed filtration (EBCT = 3.2 min). Variable filtration rates between 4.8 and 14.6 m/h (2 and 6 gpm/sf) had minimal impact on BOM removal. However, conversion of ammonia to nitrite was reduced by 60% when increasing the filtration rate from 4.8 to 14.6 m/h. The results provide drinking water utilities practicing ozonation with a cost-effective alternative to remove the residual ammonia added for bromate control. PMID- 17692889 TI - Chemical and biological technologies for hydrogen sulfide emission control in sewer systems: a review. AB - Biogenic corrosion of sewers represents a cost of about 10% of total sewage treatment cost in Flanders (Belgium) and is further increasing. In the past, research has resulted in a number of prevention methods, such as injection of air, oxygen, H(2)O(2), NaClO, FeCl(3) and FeSO(4). The possibility of biological oxidation of sulfide using nitrate as the electron acceptor has also been explored in sewer systems. However, all of these methods have a problem with the high cost (euro 1.9-7.2 kg(-1)S removal). In this review, new approaches for hydrogen sulfide emission control in sewer systems are discussed. The control of hydrogen sulfide emission by using a microbial fuel cell (MFC) can be cost effective while the BOD is removed partially. The use of phages that target sulfate-reducing bacteria (SRB) can possibly inhibit sulfide formation. Novel inhibitors, such as slow release solid-phase oxygen (MgO(2)/CaO(2)) and formaldehyde, warrant further study to control hydrogen sulfide emission in sewer systems. PMID- 17692890 TI - Enhanced inactivation of E. coli and MS-2 phage by silver ions combined with UV-A and visible light irradiation. AB - Silver ions have been widely used as an effective water disinfectant or antimicrobial material for many decades. In addition, the application of silver ions in combination with other biocides, especially UV(254) (UV-C) irradiation, was reported to be effective in enhancing its germicidal activity. However, it is not yet known how UV-A (300-400 nm) or visible light irradiation, which have little or no antimicrobial activities, affect microorganism inactivation by silver ions. This study newly reports that the inactivation efficiencies of Escherichia coli and MS-2 phage by silver ions were significantly enhanced by UV A or visible light irradiation. UV-A irradiation enhanced the inactivation of E. coli and MS-2 phage by 3.0 and 2.5 log/30 min, respectively, as compared with the simple summated value of individual applications of silver ions and UV-A. A similar trend was observed with visible light irradiation (>400 nm) although the level of enhancement was lessened. The photochemical reaction of silver-cysteine complex was suggested as a possible mechanism for this enhancement. Spectrophotometric and MALDI-TOF mass analyses support the fact that silver ions coupled with light irradiation causes critical cell damage through the complexation of silver ions with thiol (-SH) groups in structural or enzymatic proteins of the microorganisms and their subsequent photochemical destruction. PMID- 17692891 TI - Mineralization of salicylic acid in acidic aqueous medium by electrochemical advanced oxidation processes using platinum and boron-doped diamond as anode and cathodically generated hydrogen peroxide. AB - Solutions containing 164 mg L(-1) salicylic acid of pH 3.0 have been degraded by electrochemical advanced oxidation processes such as anodic oxidation, anodic oxidation with electrogenerated H(2)O(2), electro-Fenton, photoelectro-Fenton and solar photoelectro-Fenton at constant current density. Their oxidation power has been comparatively studied in a one-compartment cell with a Pt or boron-doped diamond (BDD) anode and a graphite or O(2)-diffusion cathode. In the three latter procedures, 0.5mM Fe(2+) is added to the solution to form hydroxyl radical (()OH) from Fenton's reaction between Fe(2+) and H(2)O(2) generated at the O(2) diffusion cathode. Total mineralization is attained for all methods with BDD and for photoelectro-Fenton and solar photoelectro-Fenton with Pt. The poor decontamination achieved in anodic oxidation and electro-Fenton with Pt is explained by the slow removal of most pollutants by ()OH formed from water oxidation at the Pt anode in comparison to their quick destruction with ()OH produced at BDD. ()OH generated from Fenton's reaction oxidizes rapidly all aromatic pollutants, but it cannot destroy final Fe(III)-oxalate complexes. Solar photoelectro-Fenton treatments always yield quicker degradation rate due to the very fast photodecarboxylation of these complexes by UVA irradiation supplied by solar light. The effect of current density on the degradation rate, efficiency and energy cost of all methods is examined. The salicylic acid decay always follows a pseudo-first-order kinetics. 2,3-Dihydroxybenzoic, 2,5 dihydroxybenzoic, 2,6-dihydroxybenzoic, alpha-ketoglutaric, glycolic, glyoxylic, maleic, fumaric, malic, tartronic and oxalic acids are detected as oxidation products. A general reaction sequence for salicylic acid mineralization considering all these intermediates is proposed. PMID- 17692892 TI - Persulfate oxidation of trichloroethylene with and without iron activation in porous media. AB - In situ chemical oxidation with persulfate anion (S2O82*) is a viable technique for remediation of groundwater contaminants such as trichloroethylene (TCE). An accelerated reaction using S2O82* to destroy TCE can be achieved via chemical activation with ferrous ion to generate sulfate radicals (SO4*)(E degrees =2.6 V). The column study presented here simulates persulfate oxidation of TCE in porous media (glass beads and a sandy soil). Initial experiments were conducted to investigate persulfate transport in the absence of TCE in the column. The persulfate flushing exhibited a longer residence time and revealed a moderate persulfate interaction with soils. In TCE treatment experiments, the results indicate that the water or persulfate solution would push dissolved TCE from the column. Therefore, the effluent TCE concentration gradually increased to a maximum when about one pore volume was replaced with the flushing solution in the column. The presence of Fe2+ concentration within the column caused a quick drop in effluent TCE concentration and more TCE degradation was observed. When a TCE solution was flushing through the soil column, breakthrough of TCE concentration in the effluent was relatively slow. In contrast, when the soil column was flushed with a mixed solution of persulfate and TCE, persulfate appeared to preferentially oxidize soil oxidizable matter rather than TCE during transport. Hence, persulfate oxidation of soil organics may possibly reduce the interaction between TCE and soil (e.g., adsorption) and facilitate the transport of TCE through soil columns resulting in faster breakthrough. PMID- 17692893 TI - Possible effects of persistent organochlorinated pollutants cocktail on thyroid hormone levels and pituitary-thyroid interrelations. AB - In polluted district of Michalovce in East Slovakia (POLL) and two districts with background pollution (BCGR) 2046 adults (834 males and 1212 females aged 20-75 years) were examined. Serum levels of thyrotropin (TSH), free thyroxine (FT4), total triiodothyronine (TT3) and antithyroperoxidase antibodies (TPOab) were estimated by electrochemiluminiscent assay and also these of 15 polychlorinated biphenyl congeners (PCBs), p,p'-DDE, p,p'-DDT, hexachlorobenzene (HCB) and hexachlorocyclohexane were measured by high resolution gas chromatography/mass spectrometry. In addition, also dioxins, furans, coplanar- and mono-ortho-PCBs as well as selected hydroxylated and methylsulphonated PCBs and DDE metabolites were measured by appropriate methods based on gas chromatography/mass spectrometry principle. In POLL significantly higher levels of all organochlorines were found than these in BCGR. When pooled values from both areas were stratified in terms of PCBs level and treated as continuous variables, positive association of PCBs with FT4 and TT3 was found, the latter two being also mutually associated. However, within the category of PCBs level <530 ng/glipid (n=232) the association between PCBs and both the FT4 (p<0.09) and TT3 (p<0.03) was negative and any association of these was not found within the category of PCBs level of 531-1000 ng/g (n=691). In contrast, in the category of 531-2000 ng/g (n=1307) positive association appeared between PCBs and FT4 (p<0.001) as well as TT3 (p<0.05). Highly significant association of PCBs with FT4 (p<0.001) was further found in the categories with PCBs level of 1001-101414 ng/g (n=1307) and 2001-101414 (n=1123), while significant association with TT3 was observed only in the category of 531-2000 ng/g. Such findings suggest possible threshold level in positive effect of PCBs on FT4 and TT3 level which seems to be individual and located somewhere around the PCBs level of 1000 ng/g. However, highly significant negative association of both FT4 and TT3 with TSH was found in each of above indicated PCBs categories. Considerable difference in FT4 and TT3 level between large groups of subjects with the same range of PCBs level was also found suggesting different individual susceptibility to the effects of organochlorines. Among a total of 26 cases from POLL with very low TSH level (<0.5 mU l(-1)) 13 cases showed very high level of PCBs, FT4 and TT3, thus supporting a hypothesis on a novel sporadic form of high PCBs related peripheral subclinical hyperthyroidism possibly resulting from the long-term disruption of equilibrium between bound and free thyroxine in plasma by high PCBs level followed by a striking inhibition of TSH release from the pituitary. PMID- 17692894 TI - Homo floresiensis and the evolution of the hominin shoulder. AB - The holotype of Homo floresiensis, diminutive hominins with tiny brains living until 12,000 years ago on the island of Flores, is a partial skeleton (LB1) that includes a partial clavicle (LB1/5) and a nearly complete right humerus (LB1/50). Although the humerus appears fairly modern in most regards, it is remarkable in displaying only 110 degrees of humeral torsion, well below modern human average values. Assuming a modern human shoulder configuration, such a low degree of humeral torsion would result in a lateral set to the elbow. Such an elbow joint would function more nearly in a frontal than in a sagittal plane, and this is certainly not what anyone would have predicted for a tool-making Pleistocene hominin. We argue that Homo floresiensis probably did not have a modern human shoulder configuration: the clavicle was relatively short, and we suggest that the scapula was more protracted, resulting in a glenoid fossa that faced anteriorly rather than laterally. A posteriorly directed humeral head was therefore appropriate for maintaining a normally functioning elbow joint. Similar morphology in the Homo erectus Nariokotome boy (KNM-WT 15000) suggests that this shoulder configuration may represent a transitional stage in pectoral girdle evolution in the human lineage. PMID- 17692895 TI - The oxidatively induced DNA lesions 8,5'-cyclo-2'-deoxyadenosine and 8-hydroxy-2' deoxyadenosine are strongly resistant to acid-induced hydrolysis of the glycosidic bond. AB - The 8,5'-cyclopurine-2'-deoxynucleosides (cPu) are unique oxidatively induced DNA lesions in that they are specifically repaired by NER. In the absence of NER, a possible mechanism for cPu removal is spontaneous glycosidic bond hydrolysis followed by enzymic processing. Such a mechanism could be significant if the glycosidic bond in cPu were substantially destabilized, as shown for other DNA lesions. Therefore, we investigated the stability of the glycosidic bond in a cPu, (5'S)-8,5'-cyclo-2'-deoxyadenosine (S-cdA) against acid hydrolysis. For comparison, we also studied 8-hydroxy-2'-deoxyadenosine (8-OH-dA). We found that the glycosidic bond in S-cdA is approximately 40-fold more resistant to glycosidic bond hydrolysis compared to dA. Interestingly, under the same conditions, the glycosidic bond in 8-OH-dA was even more stable than in S-cdA. These studies effectively rule out any mechanism for the removal of S-cdA or 8-OH dA from DNA that requires spontaneous glycosidic bond hydrolysis, and further support the proposed role of cPu in the neurodegeneration observed in xeroderma pigmentosum patients who lack NER. Of broader significance, since NER does not function in non-transcribed DNA sequences of terminally differentiated cells, including neurons, cPu are expected to accumulate in such sequences even in individuals with normal NER, which could be important in the ageing process. PMID- 17692896 TI - Removal of toxic metals from aqueous solutions by fungal biomass of Agaricus macrosporus. AB - Fungi such as Agaricus macrosporus show potential for the removal of heavy metals from aqueous solutions contaminated by zinc, copper, mercury, cadmium or lead. This study investigated biosorption of these metals by living or non-living biomass of A. macrosporus from an acid solution, an acid solution supplemented with potassium and phosphorus, and an alkaline solution. Uptake showed a pH dependent profile. Maximum percentage uptake of all metals was found to occur at alkaline pH (Cu 96%, Pb 89%). With living biomass, metal biosorption was greater and faster in K/P-supplemented acid medium than in non-supplemented acid medium, with equilibrium reached within 15 min for all metals, and the highest percentage uptake being of cadmium (96%). In general, the greatest differences in biosorption capacity were seen for living biomass, between supplemented and non supplemented acid medium; the smallest differences were between living and dead biomass in alkaline medium. These results support the potential utility of A. macrosporus for heavy metal removal. PMID- 17692897 TI - The adverse effects of fine particle air pollution on respiratory function in the elderly. AB - There is increasing concern that airborne particles are critical risk factors for adverse health conditions in susceptible populations. The objective of this panel study is to investigate an association between particulate matter and the peak expiratory flow rate (PEFR) in the elderly and to compare estimated risks using PM10 or PM2.5 levels as a measure of exposure. During a 2-year longitudinal follow-up study, we contacted subjects living in an asylum for the elderly, provided them with a mini-Wright peak flow meter, and instructed to record all the flow readings, any respiratory symptoms, passive smoking activity, and hours spent outdoors for that given day. Daily levels of particulate matter were measured by two separate mini-volume air samplers (for PM10 and PM2.5) placed on the rooftop of the two-story residence asylum building. In our statistical models, we assumed that the expected response varied linearly for each participant with a slope and intercept that depended on fixed or time-varying covariates using a mixed linear model. The daily mean levels of PM10 and PM2.5 were 78 microg/m3 and 56 microg/m3, respectively. For every 10 microg/m3 increase in PM10 and PM2.5 levels, there was an estimated PEFR change of -0.39 l/min (95% CI, -0.63, -0.14) and -0.54 l/min (95% CI, -0.89, -0.19), respectively. These data also suggest that fine particles have a more adverse respiratory health impact for sensitive individuals such as the elderly and that more research and control strategies should focus on the smaller particles associated with air pollution. PMID- 17692898 TI - Validity of building characteristics and dorm dampness obtained in a self administrated questionnaire. AB - A self-administrated questionnaire used in a cross-sectional study on associations between environmental factors and allergies was validated by building inspections and physical measurements. The agreement was good between the reports from occupants and inspectors regarding technical characteristics, such as type of surface materials etc., but a poor to slight agreement (kappa<0.2) regarding on assessments of moisture damages, such as mould or damp spots, and a mouldy smell, between occupants and inspectors. Dampness problems reported by occupants were associated with health effects (case status), while such problems observed by inspectors were not. The air relative humidity was slightly higher, during winter time, in rooms with condensation on windowpanes. The results indicate that questionnaire surveys give valid data regarding most technical characteristics. With regard to moisture damages, occupants reports seem more relevant than inspector reports, in a study of health. PMID- 17692899 TI - Relationships between personal, indoor, and outdoor exposures to trace elements in PM(2.5). AB - Twenty-four hour average fine particle concentrations of 23 trace elements (TEs) were measured concurrently in (a) ambient air in three urban neighborhoods (Battle Creek-BCK; East St. Paul-ESP; and Phillips-PHI), (b) air inside residences of participants, and (c) personal air near the breathing zone of healthy, non-smoking adults. The outdoor (O), indoor (I), and personal (P) samples were collected in the Minneapolis/St. Paul metropolitan area over three seasons (Spring, Summer, Fall) using either the federal reference (O) or inertial impactor (I,P) inlets to collect PM(2.5). In addition to descriptive statistics, a hierarchical, mixed-effects statistical model was used to estimate the mutually adjusted effects of monitor location, community, and season on mean differences between monitoring locations while accounting for within-subject and within monitoring period correlation. The relationships among P, I, and O concentrations varied across TEs. The O concentrations were usually higher than P or I for elements like Ca and Al that originate mainly from entrained crustal material, while P concentrations were often highest for other elements with non-crustal sources. Unadjusted mixed model results demonstrated that O monitors more frequently underestimated than overestimated P TE exposures for elements associated with non-crustal sources. This finding was true even though the O TE measurements were taken in the same neighborhoods as the P and I measurements. Further adjustment for community or season effects in the mixed models reduced the number of significant O-P and O-I differences compared to unadjusted models, but still indicated a tendency for underestimation of personal and indoor TE exposures by central site monitors, particularly in the PHI community. These results indicate that community and season are important covariates for developing long term TE exposure estimates, and that personal exposure to trace elements in PM(2.5) is likely to be underestimated by outdoor central site monitors. PMID- 17692900 TI - Sources and characteristics of lead pollution in the urban environment of Guangzhou. AB - Guangzhou, the capital of the southeastern province of Guangdong, is one of the largest and most rapidly developing industrial cities in China. In recent years its rapid economic development has brought great prosperity to the Pearl River Delta (PRD) region, but has also given rise to a wide variety of environmental problems. The current level of lead (Pb) contamination (75-926 mg/kg) in the surface environment of Guangzhou remains a major concern, even though the use of leaded petrol in the city was banned in 1997. The Pb isotope ratios (206Pb/207Pb(min-max) : 1.1612-1.1961 and 208Pb/207Pb(min-max) : 2.4495-2.4838) of the urban dusts from unconfined (road dusts and gully sediments) and relatively confined (vehicular tunnel) settings in Guangzhou remains in a relatively narrow range, comparable with those of the regional natural and anthropogenic sources. This study highlights the inherent shortcomings of the Pb isotope fingerprinting technique for provenancing Pb sources, as both the target media (urban dusts) and potential sources have similar and highly radiogenic Pb isotope values. This could not only lead to an overestimation of the effectiveness of phasing-out of leaded petrol, but also an underestimation of the ever-increasing relative contributions from other potential sources of pollution, including coal combustion, industrial emissions of local Pb-ores and non-additive Pb contents of crude oils. Re-suspended Pb-bearing particulates deposited from early vehicular exhaust emission of leaded petrol with distinctly low Pb isotope compositions are still an important source of Pb pollution in the region. PMID- 17692901 TI - The MASTER registry on venous thromboembolism: description of the study cohort. AB - INTRODUCTION: Information on the epidemiology and long-term clinical outcome of venous thromboembolism (VTE) is mainly based on data from clinical trials and thus may be not representative of the full spectrum of VTE patients. The aim of this multicenter registry (MASTER) was to prospectively collect data on the epidemiology and long-term clinical outcome of VTE in an unselected cohort of patients. MATERIALS AND METHODS: In symptomatic patients with objectively confirmed acute VTE, information about clinical presentation, diagnostic methods, temporary and permanent risk factors, pre-event prophylaxis and treatment were captured by an electronic data network at the time of the index event. A 24-month follow-up is currently ongoing. RESULTS: From January 2002 to October 2004, 2119 patients were included in the MASTER registry in 25 Italian centers. At entry, the mean patient age was 59.3+/-18.1 years (range 18-99 years). 1541 patients (72.7%) were affected by deep vein thrombosis, 206 patients (9.7%) by pulmonary embolism and 372 patients (17.5%) by both deep vein thrombosis and pulmonary embolism. 676 patients (31.9%) received home-treatment. 899 patients (42.4%) had one or more temporary risk factors. 381 patients (18.0%) had a known cancer at the time of the index event and in 50 patients (2.4%) a new cancer was discovered at the time of the index event. 311 patients (14.7%) had a previous VTE. CONCLUSIONS: Following a real world approach, our registry describes the clinical presentation, risk factors, diagnosis and treatment procedures in a large cohort of unselected patients with VTE. PMID- 17692902 TI - Recurrent femoral deep vein thrombosis: rare complication of a pelvic mass induced by polyethylene wear debris following total hip arthroplasty. A case report. PMID- 17692903 TI - Influence of polymorphonuclear leukocytes on the plasma clot formation as evaluated by thromboelastometry (ROTEM). AB - OBJECTIVE: It has been emphasized that polymorphonuclear leukocytes (PMN) participate in the regulation of coagulation. However, the mechanisms of action are not clear. Besides a procoagulant activity, anticoagulant or fibrinolytic properties are attributed to these cells. To explore their global effect, we have studied their involvement in the clot formation with thromboelastometry, which gives global view over the clotting process, in particular on the structure of the clot and on the kinetic of its formation. METHODS: PMN were isolated from healthy blood donors and resuspended into autologous platelet-free plasma. The ROTEM device was used. Coagulation was triggered only by adding calcium chloride. Thromboelastometric profiles of PMN-rich plasma (PMN-RP) were compared with autologous platelet-rich (PRP) and platelet-poor plasma (PPP). The inhibition of both tissue factor and intrinsic pathways was also studied. RESULTS AND CONCLUSIONS: The procoagulant activity of resting PMN was demonstrated as the initiation of fibrin formation with PMN-RP was significantly faster compared with both PRP and PPP. The kinetic of plasma clotting was remarkably improved with PMN RP compared with PPP. However, the clot with PMN-RP had the same poor viscoelastical properties as PPP. Thromboelastometry gives a new point of view in the involvement of PMN in coagulation, in the absence of any PMN pre-activation. Their impact was centred on the kinetic and the facilitation of the clot formation. PMID- 17692904 TI - Effect of oral anticoagulant therapy on thrombospondin-1 and von Willebrand factor in patients with stable heart failure. AB - INTRODUCTION: Heart failure (HF) is associated with coagulation activation, abnormal inflammation and endothelial dysfunction. High levels of von Willebrand factor (VWF) may manifest endothelial dysfunction and hypercoagulable state. The haemostatic activity of VWF is a function of multimers size; only large multimers of VWF are haemostatically active. Thrombospondin-1 (TSP-1) reduces the average multimer size of VWF. Patients with HF are in risk of thromboembolic events and oral anticoagulation therapy (OAT) has been shown to prevent it. This study was designed to evaluate whether VWF and TSP-1 levels are modified by OAT in stable HF patients. The effect of OAT on markers of inflammation and coagulation was also investigated. MATERIALS AND METHODS: Fifty-nine patients with stable HF were studied and 33 of them received OAT. VWF, TSP-1, fibrinogen, prothrombin fragment 1+2 (F1+2), tissue factor (TF), D-dimer, endogenous thrombin generation (ETG), C reactive protein (CRP), tumour necrosis factor alpha (TNFalpha) and interleukin 6 (IL-6) were measured. RESULTS: Stable HF patients receiving OAT had higher VWF (p=0.02) and lower TSP-1 (p=0.02), ETG and F1+2 (p=0.003) than patients without OAT. However, there were no significant differences in the levels of fibrinogen, TF, D-dimer, CRP, IL6 and TNFalpha. The TSP-1/VWF ratio in patients receiving AOT was significantly lower than in patients without OAT (p=0.005). CONCLUSION: OAT may have a dual effect on the haemostatic profile in stable HF by reducing thrombin generation and increasing the VWF. The decrease of TSP-1 induced by OAT may be clinically effective in neoangiogenesis. The increase of VWF in patients receiving anticoagulant treatment may also reflect an effect of OAT on endothelial dysfunction. PMID- 17692905 TI - Endothelial capillary tube formation and cell proliferation induced by tumor cells are affected by low molecular weight heparins and unfractionated heparin. AB - BACKGROUND: Clinical studies suggest a survival advantage in cancer patients receiving low molecular weight heparin (LMWH). A suggested mechanism for this beneficial effect may reside in the antiangiogenic activity of heparins. OBJECTIVES: In this study we investigated whether two different LMWHs, i.e. enoxaparin and dalteparin, and unfractionated heparin (UFH), affect the angiogenic potential of human microvascular endothelial cells (HMEC-1) promoted by tumor cells. METHODS: HMEC-1 cells were incubated with tumor cell conditioned media (TCM) derived from human breast cancer and leukemic cells (i.e. MCF-7, MDA.MB.231, and NB4 cell lines) or recombinant cytokines (i.e. VEGF, FGF-2, TNF alpha) +/-heparins. Capillary-like tube formation in Matrigel and cell proliferation were evaluated. RESULTS: All three TCM induced a significant (p<0.05) increase in total length of tubes formed by HMEC-1 in Matrigel. These increases were significantly counteracted (62 to 100% mean inhibition) by enoxaparin and dalteparin, but were significantly less affected by UFH. Similarly, the tube formation induced by standard VEGF, FGF-2, or TNF-alpha was 100% inhibited by enoxaparin, and 70-90% by dalteparin, whereas minor or no inhibition was observed with UFH. VEGF was the most active cytokine in TCM of both breast cancer and leukemic cells. EC proliferation was significantly increased by standard angiogenic factors, and slightly affected by breast cancer TCM (p=ns). The addition of heparins significantly counteracted the proliferative stimuli. CONCLUSIONS: These results support a major role for LMWH compared to UFH in inhibiting the proangiogenic effect exerted by tumor cells or purified angiogenic factors on microvascular endothelium. PMID- 17692906 TI - Urologic function and urodynamic evaluation of urinary diversion (Rome pouch) over time in gynecologic cancers patients. AB - OBJECTIVE: To describe the urologic late complications and urodynamics outcome adopting teniamyotomies technique to create a low-pressure reservoir using the cecum, ascending colon and proximal part of the transverse colon without detubularization (Rome pouch). METHODS: Twenty-eight consecutive patients affected by gynecological cancer and submitted urinary diversion with "Rome pouch" technique were included. After 3 and 12 months from the surgical procedure patients were submitted to urodynamic evaluation of the neobladders. Excretory urography was performed in all patient. Abdominal X-ray, serum electrolytes, creatinine and cultures of the reservoir are obtained during every visit. Long term urologic complications were recorded. Patient quality of life was assessed using a 10 cm grade visual analog scale (VAS). RESULTS: Urodynamics performed 12 months postoperatively showed that the mean maximum reservoir capacity was 439.9+/-58.9 cm H(2)O. The mean reservoir pressure at maximum capacity was 19.2+/ 8.4 cm H(2)O (no contractive wave during the filling in any patient). The mean maximum closure pressure in the efferent tube, at maximum capacity, was 88.8+/ 32.3 cm H(2)O. Continence was excellent for 26 (93%) and 23 (92%) patients at 3 and 12 months respectively. A total of 9 (32%) and 6 (24%) patients suffered late complications at 3 and 12 months follow-up respectively. However only one patient with pouch leakage underwent surgical pouch revision. CONCLUSION: Our experience demonstrated that Rome pouch creation with multiple teniamyotomies has good capacity with low internal pressure and good continence with a low rate of late urologic complications. Thus, comparing results to those of other continent pouch models, the Rome pouch technique represents a valid alternative. PMID- 17692907 TI - Epigenetic considerations for endometrial cancer prevention, diagnosis and treatment. AB - Aberrant DNA methylation is an important molecular alteration commonly detected in various malignancies. Hypermethylation and expression silencing have been frequently found in multiple genes including those for steroid receptors, tumor suppressors, and DNA repair factors. Differential DNA methylation patterns are detected in type I and type II endometrial cancers, suggesting divergent epigenetic backgrounds and unique tumorigenic pathways. In this review, the implications of new findings in the field of epigenetics are discussed for endometrial cancer prevention, diagnosis, and treatment. DNA methylation-based assays may be explored as a useful adjunct diagnostic tool. Epigenetic modification reagents, including DNA methyltransferase and histone deacetylase inhibitors, when used alone or in combination with conventional chemotherapy, may be beneficial for endometrial cancer patients. Recent studies on epigenetic reactivation of the progesterone receptor provide a novel approach for re sensitization of advanced, PR-negative endometrial cancers to progestational therapy. PMID- 17692908 TI - Smoke load/cancer death rate associations in Korea females, 1985-2004. AB - BACKGROUND: Korea female death rates from many cancers have risen rapidly since 1985. The sources of those cancer death epidemics are unclear but may be related to rising cumulative tobacco smoke damage (smoke load). We assessed Korea female smoke load/cancer death rate associations from 1985 to 2004. METHODS: Lung cancer rates were used as a smoke load bio-index. Subtracting lung, stomach, and uterine corpus cancer death World age standard rates (rates) from all-sites rates gave us non-lung-stomach-uterine corpus (NLSUc) rates. Lung/NLSUc linear regressions were run, adjusted for autocorrelation. Estimated, lower, and upper bound smoking attributable fractions (SAFs) were calculated using the formula SAF=1 {(unexposeds' cancer death rate)/(observed rate)}, based on the linear regression and respective best, upper, and lower bound estimated lung, stomach, and uterine cancer death rates in the unexposed. RESULTS: Lung cancer death rates (smoke load) can explain 88% of the variance in NLSUc rates from 1985 to 2004 after adjusting for autocorrelation. The estimated Korea female all-sites cancer death rate SAF in 2004 was 43% (sensitivity range 29-56%). CONCLUSIONS: Smoke load, probably from tobacco given the epidemic time course, may cause a large cancer death burden in Korea females despite their very low self-reported prevalence of smoking. PMID- 17692909 TI - Mercury speciation in sediments at a municipal sewage sludge marine disposal site. AB - Mercury speciation was performed in excess activated sewage sludge (ASS) and in marine sediments collected at the AAS disposal site off the Mediterranean coast of Israel in order to characterize the spatial and vertical distribution of different mercury species and assess their environmental impact. Total Hg (HgT) concentrations ranged between 0.19 and 1003ng/g at the polluted stations and 5.7 and 72.8ng/g at the background station, while the average concentration in ASS was 1181+/-273ng/g. Only at the polluted stations did HgT concentrations decrease exponentially with sediment depth, reaching background values at 16-20cm, the vertical distribution resulting from mixing of natural sediment with ASS solids and bioturbation by large populations of polycheates. Average Methyl Hg (MeHg) concentration in ASS was 39.7+/-7.1ng/g, ca. 3% of the HgT concentration, while the background concentrations ranged between 0.1 and 0.61ng/g. MeHg concentrations in surficial polluted sediments were 0.7-5.9ng/g (ca. 0.5% of the HgT) and decreased vertically, similar to HgT. A positive correlation between MeHg and Hg only at the polluted stations, higher MeHg concentrations at the surface of the sediment and not below the redoxline, and no seasonality in the concentrations suggest that the MeHg originated from the ASS and not from in situ methylation. By doing selective extractions, we found that ca. 80% of the total Hg in ASS and polluted sediments was strongly bound to amorphous organo-sulfur and to inorganic sulfide species that are not bioavailable. The fractions with potential bioaccessible Hg had maximal concentrations in the range in which biotic effects should be expected. Therefore, although no bioaccumulation was found in the biota in the area, the concentration in the polluted sediments are not negligible and should be carefully monitored. PMID- 17692910 TI - Poly(aspartate-g-PEI800), a polyethylenimine analogue of low toxicity and high transfection efficiency for gene delivery. AB - High-molecular-weight polyethylenimine (25 kDa, PEI25k) is one of the most common cationic polymers utilized in non-viral gene therapy. However, its methylene backbone (-CH(2)CH(2)N(x)-) and high charge density can result in poor biodegradability and high toxicity to cells. We hypothesize that optimizing the polymer length and charge density of PEI analogues may result in decreased toxicity and higher transfection efficiency, and improved biocompatibility in vivo. A series of PEI analogues with controlled molecular weight and charge density were synthesized by grafting low-molecular-weight PEI800 (800 Da) to a polyaspartate peptide backbone of varying degrees of polymerization. The optimum polymer had a degree of polymerization of 65 with an average of 16 PEI800 groups conjugated to it. All of the polycations investigated in the study caused inflammation and apoptosis/necrosis in the liver and spleen of rodents 24h post injection; however, by day 5, the optimized poly(aspartate-g-PEI800) polymer and PEI800 did not show tissue damage or apoptosis, whereas PEI25k exhibited evidence of apoptosis/necrosis in the kidneys and spleen. Our study points to the need to optimize gene carriers to minimize toxicity, especially important for the safe delivery of therapeutic genes to explicit organs. PMID- 17692911 TI - Imatinib mesylate therapy in chronic myeloid leukemia patients in stable complete cytogenic response after interferon-alpha results in a very high complete molecular response rate. AB - To determine the impact on minimal residual disease by switching to imatinib chronic phase chronic myeloid leukaemia (CP-CML) patients responsive to interferon-alpha (IFNalpha), in stable complete cytogenetic response (CCR) but with persistent PCR positivity. Twenty-six Philadelphia positive (Ph+) CML patients in stable CCR after IFNalpha but persistently positive at PCR analysis during this treatment, were given imatinib mesylate at standard dose. At enrolment into the study, median IFN treatment and CCR duration were 88 months (range 15-202) and 73 months (range 10-148), respectively. Imatinib treatment resulted in a progressive and consistent decline of the residual disease as measured by quantitative PCR (RQ-PCR) in all but one of the 26 patients; at the end of follow-up, after a median of 32 months (range 21-49) of treatment, a major molecular response (BCR/ABL levels <0.1) was reached in 20 patients (77%), and BCR/ABL transcripts were undetectable in 13 (50%). The achievement of molecular response was significantly correlated with post-IFN baseline transcript level (mean 1.194 for patients achieving complete molecular response versus 18.97 for those who did not; p<0.001), but not with other clinical/biological disease characteristics. These results indicate that patients induced into CCR by IFN treatment represent a subset with very favourable prognosis, which can significantly improve molecular response with imatinib and further support investigative treatment schedules combining these two drugs. PMID- 17692912 TI - A new look at apoptosis in MDS; an uneasy neighbor. PMID- 17692913 TI - Cytokines and chemokines in postovulatory follicle regression of domestic chicken (Gallus gallus domesticus). AB - The mechanism of postovulatory follicle (POF) regression in birds is still poorly understood. In the current study, expression of IL-1beta, IL-6, GM-CSF, IFN gamma, IL-2, IL-4, IL-13, chCXCLi2, chCCLi2, chCCLi4, chCCLi7, IL-10 and TGF beta2 mRNAs was estimated in regressing POF by semi-quantitative RT-PCR. In addition, the changes in immune cell population, histological and apoptotic changes were also studied in regressing POF. The expression of cytokines (IL 1beta, IL-6, IL-10 and TGF-beta2) and chemokines (chCXCLi2, chCCLi2, chCCLi4 and chCCLi7) was upregulated in POFs, suggesting a role for these molecules in tissue regression. The histological findings suggested a significant infiltration of immune cells, especially heterophils, lymphocytes and macrophages, into the regressing POF. The flow cytometry analysis of lymphocyte subpopulations revealed that CD3(+), CD4(+), CD8(+) and Bu-1(+) lymphocytes were significantly increased during this regression. The significant up-regulation of chemokines might have attracted the immune cells during POF regression. The percentage of apoptotic cells was significantly increased during the regression of POF. The up-regulation of IL-1beta, IL-6, IL-10 and TGF-beta2 and down-regulation of GM-CSF might have induced apoptosis during the POF regression. However, expression of IFN-gamma, IL 2, IL-4 and IL-13 was not significantly altered during POF regression. In conclusion, cytokines appear to play an important role in the regression of POF in chicken. Furthermore, the regression of chicken POF seems to be an inflammatory event similar to luteolysis of the mammalian corpus luteum. PMID- 17692914 TI - The ecotoxicity of ionic liquids and traditional organic solvents on microalga Selenastrum capricornutum. AB - In this study, the effects of several ionic liquids and traditional organic solvents on the growth of the green microalga, Selenastrum capricornutum, were investigated. The toxicities were strongly related to the incubation time and chemical structures of the ionic liquids. The toxicities of tetrabutylphosphonium and tetrabutylammonium containing bromide anion were observed to decrease when the incubation time was raised from 48 to 96 h. Conversely, the toxicities of 1 butyl-3-methylimidazolium and 1-butyl-3-methylpyridinium containing bromide anion were found to increase with increasing incubation time. Of the ionic liquids tested, 1-butyl-1-methylpyrrolidinium bromide was found to be the least toxic, which is similar in toxicity level of dimethylformamide. In general, the toxicities of the ionic liquids were estimated to be two and four orders of magnitude greater than those of the organic solvents examined, although ionic liquids are being considered as green solvents. PMID- 17692915 TI - Potential of some monoterpenoids and their new N-methyl carbamate derivatives against Schistosomiasis snail vector, Biomphalaria alexandrina. AB - Some monoterpenoids and their corresponding new N-methyl carbamate derivatives were used to study their molluscicidal effect on Biomphalaria alexandrina, the snail-vector of Schistosoma mansoni in Egypt. Improving the efficacy of the tested monoterpenoids and/or their corresponding carbamates by either piperonyl butoxide (PBO) or triton X-100 (TX) was also performed. Thymol, beta-citronellol, carvacrol, and geraniol exhibited high molluscicidal activity against the snails. Geraniol, beta-citronellol, and carvacrol were strongly synergized by PBO but, an opposite trend was found with TX. The molluscicidal activity of geraniol or beta citronellol when mixed with PBO was as potent as copper sulfate. Another attempt to improve the bioactivity of monoterpenoids was through their structure modifications. Thus, conversion of the tested monoterpenoids into their corresponding carbamates led to enhancement in the activity of aliphatic monoterpenoids and reduction in the aromatics. PMID- 17692916 TI - Recent progress in molecular biology of Crimean-Congo hemorrhagic fever. AB - Crimean-Congo hemorrhagic fever (CCHF) is a severe hemorrhagic fever in humans with a case fatality rate of up to 50%. A causative agent of CCHF is CCHF virus, which is a tick-borne virus in the family Bunyaviridae, genus Nairovirus. The virus is transmitted to humans through infected tick bites, squashed ticks or from direct contact with viremic animals or humans. Outbreaks of CCHF have been documented in Africa, the Middle East, Eastern Europe and Western Asia where the vector and/or reservoir ticks of Hyalomma spp. are distributed. Recent advances in molecular and biochemical analyses of CCHF virus revealed that the virus encodes larger proteins compared to other genus of Bunyavirus and the processing of viral proteins are complicated. Recent studies also showed that the CCHF viruses are relatively divergent in its genome sequence and the viruses are grouped in seven different clades. In general, these phylogenetic analyses based on sequences of S-RNA and L-RNA segment of CCHF viruses indicate that the seven clades correlate with their geographical location. The phylogenetic topology based on M-RNA segment sequences of CCHF viruses is different from those based on S-RNA and L-RNA segments. These analyses indicate that M-RNA segment reassortment events occur more frequently than those in S- and L-RNA segments. PMID- 17692917 TI - Workers describe the effect of the workers' compensation process on their health: a Quebec study. AB - This article reports on a Canadian qualitative study designed to examine the workers' experience of the workers' compensation process and to look at the effects of the process on the physical and mental health of claimants. Eighty five in depth individual interviews of injured workers in Quebec and six group interviews with workers and worker advocates from Quebec, Ontario and British Columbia were analysed to determine the positive and negative impact on claimant health of various steps of the workers' compensation process and of behaviours of significant actors in that process. While superior access to health care and access to economic support both contributed to claimant well-being, various facets of the process undermined the mental health of workers, and in some cases, also had a negative impact on physical health. Primary characteristics of the process that influenced outcomes included stigmatization of injured workers and the significant power imbalance between the claimants and the other actors in the system; the effect of both these mechanisms was tempered by social support. The article describes how caseworkers, physicians, appeal tribunals, employers and compensation boards contribute to the positive or negative impacts on worker health and concludes with recommendations designed to promote the therapeutic aspects of workers' compensation and to curtail those facets that are harmful to worker health. It also has implications for researchers who wish to consider the role of lawyers or compensation in the development or prevention of disability. PMID- 17692918 TI - Rat salivary gland reveals a more restricted IgA repertoire than ileum. AB - Secretory IgA is the most abundantly produced Ig in different mucosal tissues, such as the gastrointestinal tract and the salivary glands. These mucosal tissues are considered to be part of the common mucosal immune system. The specificity and immunoglobulin (Ig) VH gene repertoire of the IgA producing cells of both tissues is still largely unknown. To investigate the diversity of the antibody repertoire of IgA producing cells at different mucosal effector sites, we analysed used Ig VH genes by H-CDR3 spectrotyping and VH gene sequencing of both ileum and salivary gland IgA producing cells of PVG rats. Both types of tissues showed a limited diversity for the two major VH gene families, J558 and PC7183. The salivary gland showed even less diversity than the ileum of the same rat. Cloning and sequencing of used IgA VH genes confirmed the very restricted usage of VH genes since multiple sets of clonally related sequences in both types of tissues were found. More clones were found in salivary gland than in ileum and both tissues did not have shared VDJ joining regions. IgA derived from salivary gland used germline or near germline VH genes, whereas the ileal VH genes contained more mutations. Furthermore, clonal evolution patterns from all analyzed VH gene sequences of the salivary gland IgA producing cells show mainly randomly acquired somatic mutations, in contrast to the clonal evolution patterns often observed as a consequence of affinity maturation in germinal center reactions in peripheral lymphoid organs and Peyer's patches. Our results imply that IgA producing cells in the salivary gland are neither induced at the same place nor selected in the same way as the IgA producing cells in the ileum. The function of the IgA secreted by salivary gland is very likely a first line of defense with (near) germline encoded IgA, whereas in the intestine the majority of utilized IgA VH genes show evidence of somatic hypermutation. PMID- 17692919 TI - Enhancement of anti-tumor activity in vitro and in vivo by CD150 and SAP. AB - Signaling lymphocyte activation molecule (SLAM, CD150) is a co-stimulatory receptor involved in T cell activation. The activity of CD150 is dependent on the intracellular signaling molecule SAP. Here, we investigated anti-CD3 activated human lymphocytes, transfected either with CD150-plasmid or with CD150- or SAP siRNA in cytotoxicity assays against human colon cancer cells in vitro and in a xenograft model (CB/Scid/CrL mice) in vivo. Up-regulation or silencing of CD150 was accompanied by increased or decreased cytotoxic activity, respectively. Similar effects could also be shown in an IFN-gamma ELISpot assay. Furthermore, CD150 co-localized after activation with lipid rafts in specific membrane compartments on CD8 T cells. Treatment of xenografted mice with CD150 over expressing lymphocytes decelerated tumor growth significantly. Lymphocytes were detectable in spleen 18 days after injection and expressed mainly CD8, CD45RO and CD150 above average. In conclusion, over-expression of CD150 in lymphocytes is accompanied with enhanced cytotoxic activity and IFN-gamma secretion in vitro and anti-tumor activity in vivo, whereas silencing of CD150 down-regulates effector functions. Adoptive cell transfer of CD150 over-expressing lymphocytes results in an accumulation of CD8, CD45RO and CD150 cells in tumor and spleen indicating together with the observed CD150 co-localization with lipid rafts that CD150 mediates a Th1 response. PMID- 17692920 TI - Repeated intermittent MDMA binges reduce DAT density in mice and SERT density in rats in reward regions of the adolescent brain. AB - The popular recreational drug, 3,4-methylenedioxymethamphetamine (MDMA) is often taken as intermittent binges by adolescents at dance clubs. The neurobiological mechanisms that underlie MDMA-induced psychiatric conditions are still poorly understood. In the present study, mimicking adolescent patterns of administration, repeated intermittent MDMA binges (3x5 mg/(kg day) given 3h apart, every 7th day for 4 weeks) were given to adolescent mice and rats. Behavioral responses in the open-field and autoradiographic ligand-binding to dopamine (DAT) and serotonin (SERT) transporters in reward regions of the brain were measured. In the open-field, total horizontal activity (HA) was significantly increased in both mice and rats following the first and third weekly administered MDMA binge. However, rats, but not mice, exhibited an enhanced activity in the centre of the open-field arena, indicating on reduced anxiety or enhanced impulsivity, which is known to be associated with altered serotonin activity. Specific binding of DAT, but not SERT, was significantly reduced in the mouse AcbSh and CPU using in vitro autoradiography. On the contrary, SERT, but not DAT density was significantly reduced in the AcbSh of rats. Taken together, our data provide evidence for differential regulation of DAT and SERT densities in reward-related brain regions of rats and mice after long-term intermittent administration of MDMA. PMID- 17692921 TI - Synthesis, structure and antimicrobial activity of manganese(II) and cobalt(II) complexes of the polyether ionophore antibiotic Sodium Monensin A. AB - Mononuclear neutral manganese(II) and cobalt(II) complexes with the antibiotic Sodium Monensin A (Mon-Na, 1b) were synthesized and characterized. The crystal structures of M(Mon-Na)2Cl2.H2O (M=Mn, 2; M=Co, 3) were determined by X-ray crystallography. The complexes crystallize in monoclinic space group C2 with a tetrahedrally coordinated transition metal attached to oxygen atoms of deprotonated carboxyl groups of two Sodium Monensin molecules and two chloride ions. The sodium ion remains in the cavity of the ligand and cannot be replaced by Mn(II) or Co(II). The complexes were additionally characterized by different spectroscopic techniques (UV-Visible, EPR, FAB-MS). A preferable octahedral environment around the transition metal centers is observed in polar solvents while the complexes retain their tetrahedral structure in non-polar media. The antimicrobial activity of 1b, 2 and 3 was tested against Gram(+) and Gram(-) bacteria. PMID- 17692923 TI - Prediction rules for bacterial meningitis. PMID- 17692922 TI - Prolonged (3-month) mycological cure rate after boric acid suppositories in diabetic women with vulvovaginal candidiasis. AB - OBJECTIVE: Patients with diabetes mellitus (DM) are at increased risk of vulvovaginal candidiasis (VVC) due to C. glabrata. In our previous study we had shown that patients with diabetes mellitus and VVC show an overall superior mycological cure rate (74% versus 51%) with boric acid therapy at 15th day as compared to fluconazole. Present study was carried out to assess long term response to boric acid in diabetic women with VVC. MATERIAL AND METHODS: Subjects included 40 consecutive diabetic women (type 2 DM=26 and type 1 DM=14) who had achieved mycological cure (high vaginal swab culture negativity) on day 15 of therapy following single-dose oral-150 mg fluconazole (n=21) or 600 mg of boric acid suppositories given daily for 14 days (n=19). At third month of follow up, patients were assessed for signs and symptoms of VVC and a repeat HVS was collected for fungal culture. HbA1c was measured to assess glycaemic control. RESULTS: The mean age, BMI, HBA1c and frequency of various Candida species isolated at initial diagnosis were comparable in the fluconazole and boric acid treatment groups. Fifteen of 21 (71.4%) and 12 of 19 (63.1%) women who achieved mycological cure at 15 day remain cured at three months in the fluconazole and boric acid treated groups, respectively (P=0.83). With 74% mycological cure at 15th day, this would indicate that on an average only 46.6% of diabetic women with VVC would remain cured at 3 months after a course of 14 days boric acid therapy. Most of the patients relapsed with no change in Candida species. The demographic profile and mean HbA1c (8.6+/-2.2 versus 8.8+/-2.4%, P=0.83) were comparable in patients with (n=27) and without mycological cure (n=13). CONCLUSION: The results of the current study indicating comparable mycological cure rate at 3 months between fluconazole and boric acid treated patients would support use of boric acid in the acute management of VVC in view of its superior short term response in diabetic women with C. glabrata infections. However, there is need to explore other therapeutic regimens which are effective in achieving long term mycological cure in diabetic women with VVC. PMID- 17692924 TI - Hypernatremia in bacterial meningitis. PMID- 17692926 TI - Corticosteroid receptors and neuroplasticity. AB - The balance in actions mediated by mineralocorticoid (MR) and glucocorticoid (GR) receptors in certain regions of the brain, predominantly in the limbic system, appears critical for neuronal activity, stress responsiveness, and behavioral programming and adaptation. Alterations in the MR/GR balance appear to make nervous tissue vulnerable to damage; such damage can have adverse effects on the regulation of the stress response and may increase the risk for psychopathology. Besides the hippocampal formation, other subpopulations of neurons in extra hippocampal brain areas have been also shown recently to be sensitive to changes in the corticosteroid milieu. From a critical analysis of the available data, the picture that emerges is that the balance (or imbalance) between MR/GR activation influences not only cell birth and death, but also other forms of neuroplasticity. MR occupation appears to promote pro-survival actions, while exclusive GR activation favors neurodegeneration. Interestingly, the sustained co activation of both receptors, for example in chronic stress conditions, usually results in less drastic effects, restricted to dendritic atrophy and impaired synaptic plasticity. As our knowledge of the plastic changes underpinning the wide spectrum of behavior effects triggered by corticosteroids/stress growths, researchers should be able to better define new targets for therapeutic intervention in stress-related disorders. PMID- 17692927 TI - The influence of static correlations on multivariate correlation analysis of the EEG. AB - The choice of the EEG reference strongly influences the results derived from different correlation measures. Such a dependence may easily mislead the interpretation of the correlation structure of the brain activity. We provide a systematic study of the influence of the choice of reference on linear multivariate EEG correlation patterns as determined by sensitive correlation measures derived from the equal-time correlation matrix. In addition, an effective algorithm to extract the effect of static correlations is developed. The eigenvalues of the correlation matrix and their spacing statistics are studied for artificial time series with known correlation structure and for an epileptic EEG in various montages. The correction method proposed in this paper works with varying quality for different choices of the EEG reference. Furthermore, the optimal choice of the reference depends also on the correlation structure of the underlying system. PMID- 17692928 TI - The tryptophan hydroxylase (TPH) 2 gene unlike TPH-1 exhibits no association with stress-induced depression. AB - BACKGROUND: Serotonin (5-HT) has been implicated in the pathophysiology of several psychiatric disorders including major depression (MD). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin (5 HT), and might be related to the pathogenesis of MD. Two isoforms are known, TPH 1 and TPH-2. Their association with MD is still debated. METHODS: A case-control design was used for candidate gene-disease association in 194 patients with stress-induced MD, and 246 healthy controls, all North European Caucasians. Five TPH-2 polymorphisms were analyzed in terms of genotype, allele, and haplotype based associations. RESULTS: Neither single marker nor haplotype-based analyses showed significant associations between TPH-2 and MD. LIMITATIONS: The interpretations are limited by the restricted population size. CONCLUSIONS: There was no association between TPH-2 gene variants and MD in the same population that had shown a strong association with TPH-1. Hence, the results suggest that in this particular group of stress-induced depression patients TPH-1 appears to be more relevant to MD pathogenesis than TPH-2. PMID- 17692925 TI - Neural networks a century after Cajal. AB - At the time of Golgi and Cajal's reception of the Nobel Prize in 1906 most scientists had accepted the notion that neurons are independent units. Although neuroscientists today still believe that neurons are independent anatomical units, functionally, it is thought that some sort of population coding occurs. Throughout this essay, we provide evidence that suggests that populations of neurons can code information through the synchronization of their responses. This synchronization occurs at several levels in the brain. Whereas spike synchrony refers to the correlation between spikes of different neurons' spike trains, oscillatory synchrony refers to the synchronization of oscillatory responses, generally among large groups of neurons. In the first section of this essay we describe the dependence of the brain's developmental processes on synchronous firing and how these processes form a brain that supports and is sensitive to synchronous spikes. Data are then presented that suggest that spike and oscillatory synchrony may serve as useful neural codes. Examples from sensory (auditory, olfactory and somatosensory), motor and higher cognitive (attention, memory) systems are then presented to illustrate potential roles for these synchronous codes in normal brain function. Results from these studies collectively suggest that spike synchrony in sensory and motor systems may provide detail information not available from changes in firing rate. Oscillatory synchrony, on the other hand, may be globally involved in the coordination of long-distance neuronal communication during higher cognitive processes. These concepts represent a dramatic shift in direction since the times of Golgi and Cajal. PMID- 17692929 TI - Molecular cloning and expression analysis of pig CD81. AB - CD81, also known as TAPA-1 (target of antiproliferative antibody 1), is a member of the tetraspanin family of proteins and a component of the B cell co-receptor complex. Several studies have shown that CD81 plays significant roles in a variety of immune responses, including activation of B cells and T cells. In this study, we cloned pig Cd81 cDNA using RT-PCR coupled with rapid amplification of cDNA ends (RACE)-PCR and determined the complete cDNA sequence of pig Cd81. Pig Cd81 cDNA contains an open reading frame (711 bp) encoding 236 amino acids. The identity of pig CD81 with those of human, cattle, rat, and mouse are 90.30%, 92.26%, 86.22%, and 86.22%, respectively. Alignment of the CD81 amino acid sequence with those of mammalian species showed that the large extracellular loop (LEL) is the most divergent, whereas other domains are largely conserved. Pig Cd81 mRNA was detected by RT-PCR in a broad range of tissues, including lymphoid tissues as well as nonlymphoid tissues, indicated variety of cellular functions of CD81 in most pig tissues. Flow cytometry analyses demonstrated that human CD81 antibody recognizes a pig CD81 on the cell surface. Further, immunohistochemistry analysis using human CD81 antibody on pig spleen was revealed that CD81 expression is widely diffused in spleen tissue. Future study will be focused on defining the functional role of CD81 during the course of pig infectious diseases. PMID- 17692930 TI - Non-HLDA8 animal homologue section anti-leukocyte mAbs tested for reactivity with equine leukocytes. AB - In addition to the 379 monoclonal antibodies (mAbs) tested in the animal homologues section of HLDA8, another 155 mAbs were screened at the Institute for Zoo and Wildlife Research, Berlin for cross-reactivity with equine leukocytes. For this purpose, one colour flow-cytometric analysis was performed as screening test. This additional screening indicated further 16 mAbs as positive with staining homologous to human pattern, 1 mAb with weak (positive) reactivity, 11 mAbs with positive, but likely not valuable staining, 12 mAbs with alternate expression pattern from that expected from human immunology, 2 mAbs with questionable variable staining, 13 mAbs with weak-positive expression and alternate pattern, and 78 negative mAbs. In 23 cases, more appropriate target cells, such as thymocytes or stem cells, were not available for screening. The results support and add to the value of the "cross-reactivity" approach for equine immunology. PMID- 17692931 TI - Deaf children with cochlear implants before the age of 1 year: comparison of preverbal communication with normally hearing children. AB - OBJECTIVES: To compare preverbal behaviors of deaf children implanted under 1 year of age with age-matched hearing children. METHODS: The study assessed 20 children; 10 deaf children implanted under 1 year of age and 10 normally hearing children of the same age. Preverbal skills were measured before, 6 months, and 1 year after implantation, using Tait Video Analysis that is able to predict later speech outcomes in young implanted children. RESULTS: Regarding vocal turns, the normally hearing group outperformed the implanted group although the latter children became quite vocal, nearly 60% of their turns being taken in this way. The mean vocal autonomy in implanted children, 1 year after implantation, was very close to the respective of hearing children (38.5 versus 43.5). Regarding the non-looking vocal turns, by the 12-month interval, hearing children had somewhat higher scores than implanted children, but the difference was not significant and the increase in implanted children was much higher (40-fold increase versus 4-fold increase). However, implanted children were more likely to use silent communication than hearing children, although gestural turns were decreasing with time. CONCLUSIONS: The small numbers in this study, although two of the largest European cochlear implant centers were combined to recruit such young implantees, led us to be cautious in interpreting the results. However, it seems that in deaf implanted children under 1 year of age, some preverbal communication behaviors are developing to an extent (although at a somewhat lower level) not significantly different from those of age-matched normally hearing children. PMID- 17692932 TI - Detection of infectious canine parvovirus type 2 by mRNA real-time RT-PCR. AB - A TaqMan real-time RT-PCR assay was developed for detection of RNA transcripts produced by replicating CPV-2. A pair of primers and a TaqMan probe targeting the spliced NS2 mRNA were designed. A synthetic DNA fragment was constructed to mimic the spliced NS2 mRNA by PCR-based gene assembly and was used for generation of standard RNAs. The detection limit of the assay was 1x10(2) RNA copies and standard curve displayed a linear range from 1x10(2) to 1x10(9) copies and a good reproducibility. The assay was then applied to determine the mRNA loads in the tissues of dogs naturally infected by CPV-2. mRNA was detected in a variety of tissues, including the central nervous system. PMID- 17692933 TI - Anxiety responses, plasma corticosterone and central monoamine variations elicited by stressors in reactive and nonreactive mice and their reciprocal F1 hybrids. AB - Stressor-provoked anxiety, plasma corticosterone, and variations of brain monoamine turnover are influenced by genetic factors, but may also be moderated by early life experiences. To evaluate the contribution of maternal influences, behavioral and neurochemical stress responses were assessed in strains of mice that were either stressor-reactive or -resilient (BALB/cByJ and C57BL/6ByJ, respectively) as well as in their reciprocal F(1) hybrids. BALB/cByJ mice demonstrated poorer maternal behaviors than did C57BL/6ByJ dams, irrespective of the pups being raised (inbred or F(1) hybrids). The BALB/cByJ mice appeared more anxious than C57BL/6ByJ mice, exhibiting greater reluctance to step-down from a platform and a greater startle response. Although the F(1) behavior generally resembled that of the C57BL/6ByJ parent strain, in the step-down test the influence of maternal factors were initially evident among the F(1) mice (particularly males) with a BALB/cByJ dam. However, over trials the C57BL/6ByJ like behavior came to predominate. BALB/cByJ mice also exhibited greater plasma corticosterone elevations, 5-HT utilization in the central amygdala (CeA), and greater NE turnover in the paraventricular nucleus of the hypothalamus (PVN). Interestingly, among the F(1)'s corticosterone and 5-HIAA in the CeA resembled that of the BALB/cByJ parent strain, whereas MHPG accumulation in the PVN was more like that of C57BL/6ByJ mice. It seems that, to some extent, maternal factors influenced anxiety responses in the hybrids, but did not influence the corticosterone or the monoamine variations. The inheritance profiles suggest that anxiety was unrelated to either the corticosterone or monoamine changes. PMID- 17692934 TI - Do discrimination tasks discourage multi-dimensional stimulus processing? Evidence from a cross-modal object discrimination in rats. AB - Neurobiologists are becoming increasingly interested in how complex cognitive representations are formed by the integration of sensory stimuli. To this end, discrimination tasks are frequently used to assess perceptual and cognitive processes in animals, because they are easy to administer and score, and the ability of an animal to make a particular discrimination establishes beyond doubt that the necessary perceptual/cognitive processes are present. It does not, however, follow that absence of discrimination means the animal cannot make a particular perceptual judgement; it may simply mean that the animal did not manage to discover the relevant discriminative stimulus when trying to learn the task. Here, it is shown that rats did not learn a cross-modal object discrimination (requiring association of each object's visual appearance with its odour) when trained on the complete task from the beginning. However, they could eventually make the discrimination when trained on the component parts step by step, showing that they were able to do the necessary cross-modal integration in the right circumstances. This finding adds to growing evidence that discrimination tasks tend to encourage feature-based discrimination, perhaps by engaging automatic, habit-based brain systems. Thus, they may not be the best way to assess the formation of multi-dimensional stimulus representations of the kind needed in more complex cognitive processes such as declarative memory. Instead, more natural tasks such as spontaneous exploration may be preferable. PMID- 17692935 TI - Stimulation of 5-HT1A, 5-HT1B, 5-HT2A/2C, 5-HT3 and 5-HT4 receptors or 5-HT uptake inhibition: short- and long-term memory. AB - In order to determine whether short- (STM) and long-term memory (LTM) function in serial or parallel manner, serotonin (5-hydroxtryptamine, 5-HT) receptor agonists were tested in autoshaping task. Results show that control-vehicle animals were modestly but significantly mastering the autoshaping task as illustrated by memory scores between STM and LTM. Thus, post-training administration of 8-OHDPAT (agonist for 5-HT(1A/7) receptors) only at 0.250 and 0.500 mg/kg impaired both STM and LTM. CGS12066 (agonist for 5-HT(1B)) produced biphasic affects, at 5.0 mg/kg impaired STM but at 1.0 and 10.0 mg/kg, respectively, improved or impaired LTM. DOI (agonist for 5-HT(2A/2C) receptors) dose-dependently impaired STM and, at 10.0 mg/kg only impaired LTM. Both, STM and LTM were impaired by either mCPP (mainly agonist for 5-HT(2C) receptors) or mesulergine (mainly antagonist for 5 HT(2C) receptors) lower dose. The 5-HT(3) agonist mCPBG at 1.0 impaired STM and its higher dose impaired both STM and LTM. RS67333 (partial agonist for 5-HT(4) receptors), at 5.0 and 10.0 mg/kg facilitated both STM and LTM. The higher dose of fluoxetine (a 5-HT uptake inhibitor) improved both STM and LTM. Using as head pokes during CS as an indirect measure of food-intake showed that of 30 memory changes, 21 of these were unrelated to the former. While some STM or LTM impairments can be attributed to decrements in food-intake, but not memory changes (either increase or decreases) produced by 8-OHDPAT, CGS12066, RS67333 or fluoxetine. Except for animals treated with DOI, mCPBG or fluoxetine, other groups treated with 5-HT agonists 6 h following autoshaping training showed similar LTM and unmodified CS-head-pokes scores. PMID- 17692936 TI - The novel peptide apelin regulates intrarenal artery tone in diabetic mice. AB - Apelin, a newly identified angiotensin (Ang) II homologue, has been implicated in diabetes. We previously reported that apelin exerts an opposing influence on the Ang II signaling. Our aim was to further implore whether apelin could regulate intrarenal artery tone in response to Ang II and Ang IV in diabetes. A Multi Myograph system was used to determine the isometric renal artery tone in diabetic db/db and control db/m+ mice. The phosphorylation, and protein levels of endothelial nitric oxide (NO) synthase (eNOS), and apelin receptor APJ were analyzed by Western blotting. Diminished expression of APJ protein and enhanced contractile responses to Ang II and Ang IV were exhibited in renal arteries from db/db mice. Apelin supplement reversed the abnormal renal vascular responsiveness to Ang II and acetylcholine, but not to Ang IV in db/db mice. Finally, in db/db mice, significant increases in phosphorylation of eNOS on serine 1177 and in NO generation were found in renal arteries pretreated with apelin. Our findings provide novel evidence for the regulatory roles of renal apelin system in vascular functions in diabetes. Apelin treatment may regulate the balance between Ang II and NO and thereby exert beneficial effects on the diabetic vascular pathophysiology. PMID- 17692937 TI - The insulinotropic effect of GIP is impaired in patients with chronic pancreatitis and secondary diabetes mellitus as compared to patients with chronic pancreatitis and normal glucose tolerance. AB - BACKGROUND: The incretin effect is reduced and the insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is abolished in patients with type 2 diabetes mellitus (T2DM). OBJECTIVE AND DESIGN: To evaluate the causality of this deficiency we investigated 8 patients with chronic pancreatitis (CP) and normal glucose tolerance (NGT) (fasting plasma glucose (FPG): 5.5 (4.5-6.0) mM (mean (range); HbA(1c): 5.8 (5.4-6.3) %) and 8 patients with CP and secondary diabetes not requiring insulin (FPG: 7.1 (6.0-8.8) mM; HbA(1c): 7.0 (5.8-10.0) %) during three 15-mM hyperglycaemic clamps with continuous iv infusion of saline, glucagon-like peptide-1 (GLP-1) or GIP. RESULTS: The initial (0-20 min) insulin and C-peptide responses were enhanced significantly in both groups by GLP-1 and GIP, respectively, compared to saline (P<0.05). In both groups GLP-1 infusion resulted in significantly greater insulin and C-peptide responses from 20-120 min compared with saline infusion. During GIP infusion the late-phase insulin response (20-120 min) was 3.1+/-1.0 fold greater than during saline infusion in the group of patients with CP and NGT (P<0.05), whereas there was no significant differences in patients with CP and DM. CONCLUSIONS: The lack of GIP amplification of the late insulin response to iv glucose develops alongside the deterioration of glucose tolerance in patients with CP, suggesting that the same may be true for the loss of the GIP effect in patients with T2DM. PMID- 17692938 TI - Risk factors and type of dementia: vascular or Alzheimer? AB - The most efficient strategy for combating Alzheimer's disease (AD) is to prevent the onset of clinically significant symptoms. Determining the clinical characteristics, risk factors, and indices of cognitive reserve would help in achieving this goal. The aim of this study was to determine the risk factors for AD and vascular dementia (VD) in the elderly and to highlight the importance of risk factor modification in the early diagnosis. Consecutive 1436 patients (mean age=72.7+/-6.9 years, 34.2% male) were enrolled in the study. After a comprehensive geriatric and cognitive assessment, patients were grouped as AD group (n=203), VD group (n=73) and normal cognitive status (NCS) group (n=1160). Thirty-three possibly related factors including demographic characteristics, co existing diseases and laboratory parameters were examined. The results revealed that female sex, advanced age, depression, and intake of vitamin supplements were independent related factors for AD; whereas depression and low-density lipoprotein-cholesterol (LDL-C) were independent related factors for VD. For every geriatric patient admitted for any reason, cognitive assessment should be performed, risk factors should be determined and the patients at high risk should be followed up carefully. PMID- 17692939 TI - Double superior vena cava: right connected to left atrium and left to coronary sinus. AB - Left persistent superior vena cava connected to coronary sinus may coexist with right superior vena cava connected to left atrium. Surgical correction is not mandatory if there is no cyanosis due to a big interjugular bridging vein. PMID- 17692940 TI - Coronary ischemia induced Wolf Parkinson White syndrome. AB - A 60-year-old woman was admitted to cardiology clinic because of typical chest pain. The presenting electrocardiography (ECG) revealed sinus rhythm and T wave inversion on inferolateral wall. Her chest pain relapsed at second day of admission and electrocardiogram recorded during chest pain had ECG changes consistent with Wolf Parkinson White (WPW) syndrome. She underwent cardiac catheterization and borderline lesion was detected in proximal of left anterior descending artery and direct stent implantation was performed. This is the first case report in which acute ischemia may induce typical ECG changes of WPW in a patient with concealed WPW syndrome. We concluded that acute coronary ischemia may manifest concealed WPW syndrome. PMID- 17692941 TI - Coronary aneurysm in Lyme Disease: treatment by covered stent. PMID- 17692942 TI - Ventricular outflow tract obstruction, systolic anterior motion and acute mitral regurgitation in Tako-Tsubo syndrome. AB - Tako-Tsubo syndrome is characterized by ECG changes mimicking acute myocardial infarction, left ventricular wall motion abnormalities in the apical region with preserved function of base, and normal coronary arteries. We report the cases of two old women, presenting apical akinesis, basal hyperkinesis, severe systolic dysfunction and severe mitral regurgitation (MR). Doppler echocardiography showed a left ventricular outflow tract obstruction (LVOTO), systolic anterior motion (SAM) of the mitral valve anterior leaflet. The patients recovered and, early later, left ventricular ejection fraction was documented as normal at echocardiography. The contemporary presence of LVOTO, SAM and MR might explain worsening of heart failure or incidence of cardiogenic shock in some patients with Tako-Tsubo syndrome. PMID- 17692943 TI - Amiodarone-induced epididymitis: a case report and review of the literature. AB - Epididymitis, as an unusual side-effect of amiodarone use, in a patient with dilated cardiomyopathy is reported along with a pertinent literature review. The diagnosis was one of exclusion after the patient received several regimens of antimicrobials and was only established after a dose reduction of the amiodarone regimen. Cardiologists should be aware of this rare but existing side effect of amiodarone, in order promptly intervene with dose adjustment or discontinuation of amiodarone and to avoid prolonged use of unnecessary antimicrobial regimens. PMID- 17692944 TI - Ventricular late potential duration correlates to the time of onset of electrical transients during ventricular activation in subjects post-acute myocardial infarction. AB - Ventricular late potentials (VLP) are electrical signals detected at the terminal region of the ventricular activation on surface ECG and often correlated to regions of fragmented electrical conduction in subjacent damaged myocardium. Intraventricular electrical transients (IVET) arisen from myocardial infarction scars may influence VLP identification depending on transient time of onset and duration. Seventy-six subjects after first ST elevation acute myocardial infarction (STEAMI) VLP were stratified according to initial myocardial wall insulted, whether anterior or inferior wall and electrical transient tracked throughout ventricular activation using spectral turbulence analysis technique. VLP were more prevalent in inferior than anterior STEAMI. No differences regarding IVET duration was observed between anterior and inferior STEAMI. Time of onset but not duration of IVET correlated to VLP duration. Scar location after STEAMI influences detection ventricular late potentials in SAECG. PMID- 17692945 TI - When does an infarcted heart rupture? A pathological study of 148 out-of-hospital sudden death cases. PMID- 17692946 TI - Left and right atrial size and the occurrence predictors in patients with paroxysmal atrial fibrillation. AB - The purpose of the present study is to evaluate left and right atrial volume in patients with paroxysmal atrial fibrillation (PAF) and to select the best clinical variables to predict the occurrence of PAF. 157 patients and 106 normal subjects were enrolled. In patients with PAF, right atrial volume and dimension were all significantly greater (P<0.001 approximately 0.05). Left atrial (LA) volume were obviously higher (P<0.01) before correction for age. Atrial dilation and right atrial shape remoding are evident compared to normal controls. Patients are more prone to PAF occurrence if they have increased LA anterior-posterior diameter, greater P maximum and advancing age. PMID- 17692948 TI - Long term outcome of elective day case percutaneous coronary intervention in patients with stable angina. AB - Patients undergoing elective PCI are traditionally admitted overnight, however day case PCI cuts costs and has been proposed as a safe method for selected patients. We evaluated the success and long term clinical outcomes of day case percutaneous coronary intervention (PCI) for outpatients with stable angina. In total, 484 consecutive patients treated over a five year period with planned day case PCI were studied and followed up for 12 months. Successful PCI with same day discharge was performed in 463 patients (95.7%). There were 21 patients (4.3%) who required hospital admission. Reasons for failed discharge were hematoma formation (n=7, 1.4%), coronary dissection (n=4, 0.8%), post-procedural chest pain (n=3, 0.6%), prolonged procedure (n=2, 0.4%), and 1 each of acute stent thrombosis, coronary perforation, anaphylaxis, minor drug reaction and a functional study for untreated disease. One year follow up was complete for 439/484 (90.7%). At 12 months there were 6 hospitalizations for angina (1.2%, 95% CI 0.6-3.0%), 20 repeat revascularisations (4.1%, 95% CI 2.7-6.3%), 3 myocardial infarctions (0.6%, 95% CI 0.2-2.1%) and 2 deaths (0.4%, 95% CI 0.1-1.6%). Event free survival at 1 year follow up was 93.6% (95% CI 90.7-95.6%). Selecting patients for day case PCI is safe, and can achieve a high rate of success with excellent long term outcomes. PMID- 17692947 TI - Optimal revascularization strategy for diabetic patients with multivessel coronary artery disease: the duel between old hero and young warrior. AB - Given the results of the BARI and ARTS I trials and a meta-analysis, coronary artery bypass surgery has been preferred to percutaneous coronary intervention in diabetics with multivessel coronary artery disease requiring hypoglycemic treatment and in whom internal mammary artery grafts can be used. This approach was strongly recommended in a 2002 ACC/AHA Task Force on the management of patients with acute coronary syndrome. But, these recommendations were made before the availability of drug-eluting stents. We strongly believe that the ongoing, multi-centre FREEDOM, CARDia and SYNTAX trials will elucidate the optimal revascularization strategy for diabetic patients with multivessel disease in the near future. PMID- 17692949 TI - Antioxidant status of South Indian patients undergoing coronary artery bypass graft surgery: a role of intra operative magnesium supplementation. AB - The aim of the study is to evaluate the effect of magnesium on the level and progression of oxidative stress in the erythrocytes and erythrocyte membrane, during heart surgery involving cardiopulmonary bypass. A clinical trial (n=52) was conducted and we took five blood samples at different times during the cardiac surgery. The level of lipid per-oxidation and activity of antioxidant enzymes were analyzed. The results revealed an increase in oxidative stress after CPB in erythrocytes and erythrocyte membrane. However, the extensive treatment of the patients with magnesium influences the cellular response to ischemia and thus induces cardio-protection against oxidative stress. PMID- 17692950 TI - Coronary stent strut fracture after drug-eluting stent implantation: a newly recognized complication. AB - Stent strut fracture (SSF) after drug-eluting stent (DES) implantation may be an important complication after DES implantation particularly in patients undergoing sirolimus eluting stent implantation. Since SSF is a highly relevant adverse event which can result in in-stent restenosis and thrombosis, we believe that DES with flexible stent platform or biodegradable DES may be needed to prevent this potential catastrophic complication. PMID- 17692951 TI - Effect of renin-angiotensin aldosteron system blockers on postoperative atrial fibrillation. AB - BACKGROUND: No randomized studies have been conducted to evaluate the effects of renin-angiotensin aldosteron system blockers on postoperative atrial fibrillation (AF). The aim of this study was to evaluate the effect of angiotensin converting enzyme inhibitors (ACEIs) and ACEI plus candesartan, an angiotensin receptor blocker on postoperative AF. METHODS: A group of consecutive patients undergoing coronary artery bypass and/or valve surgery was studied (n=128). The patients were randomized to ACEI group (n=49) and ACEI plus candesartan group (n=49). Thirty patients not on ACEI or angiotensin receptor blocker constituted the control group. RESULTS: The rate of postoperative AF was higher in the control group (33.3%) compared to the ACEI group (12.2%, p=0.02) or ACEI plus candesartan group (10.2%, p=0.01). With the Cox proportional model, univariable negative predictors of postoperative AF, were the use of ACEI (RR 0.34, 95% CI 0.12 to 0.93, p=0.03) and the use of ACEI plus candesartan (RR 0.28, 95% CI 0.09 to 0.83, p=0.02); the positive predictor of postoperative AF was age>or=65 (RR 3.10, 95% CI 1.30 to 7.37, p=0.01). With the multivariable Cox proportional model, the only predictor of postoperative AF was age>or=65 (RR 9.70, 95% CI 2.04 to 46.1, p=0.004). CONCLUSION: ACEI alone and ACEI plus candesartan decrease the incidence of postoperative AF compared to the control group. Candesartan has no additional effect on the rates of postoperative AF when added to ACEI. PMID- 17692952 TI - A rare case of left superior vena cava draining into left atrium demonstrated by MDCT. AB - We describe a rare case of persistent left superior vena cava draining directly into the left atrium with no associated anomaly of the coronary sinus or the atrial septum, discovered by multidetector computed tomography. PMID- 17692953 TI - Out-of-hospital cardiac arrest caused by transient left ventricular apical ballooning syndrome. AB - We describe a case of out-of-hospital cardiac arrest due to ventricular fibrillation in a patient with transient left ventricular apical ballooning syndrome. Our report confirms that left ventricular apical ballooning may have the same complications of myocardial infarction, adding the early ventricular fibrillation to the previous findings of left ventricular wall rupture, ventricular arrhythmias during hospitalization and complete atrio-ventricular block. Moreover, left ventricular apical ballooning may have different and unusual clinical onsets, including sudden cardiac death due to ventricular tachyarrhythmias in the absence of associated symptoms. Therefore, in our opinion left ventricular apical ballooning may be considered as a possible cause of sudden death in otherwise healthy women. PMID- 17692955 TI - Rupture of guide wire during percutaneous transluminal coronary angioplasty, a case report. AB - The rupture of the guide wire is a very uncommon complication that may produce important consequences as occlusion of the artery of systemic embolism. The management of this event may be interventional or conservative, depending on the clinical situation of the patient and the position of the guide wire inside vessel. Here we present a case that we decided to leave the fragment in the artery. The retained filament and the coronary stenotic lesion was stented successfully. PMID- 17692954 TI - Smoking and its effects on mortality in adults with congenital heart disease. AB - AIMS: To describe smoking habits in adults with congenital heart disease (ACHD) and to assess the relationship between smoking exposure and cardiovascular mortality. METHODS: Data on smoking history and cardiovascular mortality were extracted from the Euro Heart Survey on adult congenital heart disease - a retrospective cohort study, that included patients diagnosed with 1 of 8 subgroups of ACHD (Atrial Septal Defects, Ventricular Septal Defects, Marfan Syndrome, Aortic Coarctation, Tetralogy of Fallot (ToF), Transposition of the Great Arteries (TGA), Fontan circulation, and Cyanotic disease). RESULTS: Complete data of 3375 ACHD patients (median age 28 years) were available for analysis. At inclusion, 9.3% (n=314) were current smokers and 4.2% (n=142) of the patients had smoked in the past. During a median follow-up of 5.1 years, 101 patients (3%) died. In the majority of cases the cause of death was cardiovascular (n=81; 80%). Kaplan-Meier and Cox survival analysis for each of the defects separately showed a significantly increased age and sex-adjusted cardiovascular mortality associated with smoking exposure in TGA patients (Hazard ratio 4.2 (95% CI 1.0-16.8); P=0.044). Also in ToF mortality was higher amongst smokers, though not significantly (HR 3.4 (95% CI 0.6-18.5); P=0.15). In the remaining defects no relationship between smoking and cardiovascular mortality was observed. CONCLUSION: The prevalence of smoking amongst ACHD patients is relatively low. Smoking exposure is associated with increased cardiovascular mortality in patients with TGA. Prospective long-term follow-up studies are necessary. PMID- 17692956 TI - Electrical storm and termination with propofol therapy: a case report. PMID- 17692957 TI - Adam Christian Thebesius, a historical perspective. AB - The Silesian physician Adam Christian Thebesius (1686-1732) was one of the most renowned scientists studying the coronary circulation and its pathologies in the eighteenth century. His groundbreaking work opened the field of coronary microcirculation for generations of scientists to come. In 1708, Thebesius published his anatomical thesis, "Disputatio medica inauguralis de circulo sanguinis in corde", describing the cardiac veins that emptied into chambers of the heart, the vasa cordis minima. He documented the small veins with their valves connecting the chambers of the heart with the coronary vessels. Thebesius is also known for his studies of the coronary sinus, namely, the valve of the coronary sinus, the Thebesian valve. PMID- 17692958 TI - Infective endocarditis in the setting of infundibular-valvular pulmonary stenosis with incomplete cor triatriatum dextrum and patent foramen ovale. AB - Cor triatriatum dextrum is a rare congenital malformation, usually associated with complex right heart abnormalities, characterized by a membrane that divides the right atrium into two chambers. It is considered the result of the incomplete and abnormal regression of the embryonic right valve of the sinus venosus. With an incomplete regression, a fenestrated or an unfenestrated membrane may persist in the right atrium. Cor triatriatum dextrum may be seen with congenital cardiac defects associated with the right heart. We have diagnosed infective endocarditis in a 19 year old male patient with asymptomatic incomplete cor triatriatum dextrum, PFO and valvular-infundibular severe pulmonary stenosis based on the Duck criteria, with a positive blood culture and 3 minor criteria. Echocardiography did not reveal any vegetations. Antibiotherapy was given and then regions responsible of the stenosis were resected surgically. After surgery a small outlet type VSD development was observed. PMID- 17692959 TI - Myocardial injury in thrombotic thrombocytopenic purpura: a frequent, perplexing complication. AB - BACKGROUND: Although thrombotic thrombocytopenic purpura (TTP) typically involves the heart, angina and myocardial injury are uncommonly reported; fatal cardiogenic shock is exceptional. METHODS: We analyzed 26 patients with TTP who had objective evidence of myocardial injury. RESULTS: Myocardial injury was evident in 6 patients. None had coronary disease. Mean age was 43.6 years; four patients (66%) were female. Mean troponin, creatinine and hemoglobin levels were 7.82 ng/dL (or=18 months for this analysis. Late RILIT consisted of 8 different symptoms, comprising the 5 symptoms from the RTOG toxicity score supplemented with urgency, fecal incontinence and anal pain. Late RILIT and late RTOG toxicity were scored prospectively and correlated with: 1. Different rectum, sigmoid colon and small bowel volume parameters. 2. Patient-related morbidity. We calculated the median, quartile and percentiles for the different volume parameters and correlated them with grade 1-3 late RILIT. RESULTS: Median follow-up was 42 months. Three patients developed grade 3 red blood loss. We registered grade 2 RILIT and RTOG toxicity in 13% and 10%, respectively, the most frequent grade 1 symptom being fecal urgency. The intermediate rectal volume parameters were significantly correlated with late RILIT. We were able to calculate cut-off dose-volume histograms (DVHs) that predict for grade 0-2 RILIT. CONCLUSIONS: After IMRT for prostate cancer, the overall incidence of grade >or=2 RILIT is low. Cut-off DVHs can be used for patient counseling. PMID- 17692977 TI - Quality of life, anorectal and sexual functions after preoperative radiotherapy for rectal cancer: report of a randomised trial. AB - BACKGROUND AND PURPOSE: Patients (N=316) with resectable cT3-4 low-lying and mid rectal cancer were randomised to receive either preoperative 5x5Gy irradiation with subsequent surgery performed within 7 days or chemoradiation (50.4, 1.8Gy per fraction plus boluses of 5-fluorouracil and leucovorin) followed by surgery after 4-6 weeks. No differences were found in sphincter preservation, survival, local control and late complications. Early complications were less frequent in the short-course group. The aim of this report is to find out whether large doses per fraction of short-course schedule result in more severe anorectal and sexual dysfunction and quality of life (QoL) impairment. MATERIALS AND METHOD: Patients who were free of disease were asked to answer the QLQ-C30 and those without stoma were, additionally, asked to fill in a questionnaire of anorectal (19 items) and sexual function (1 item). RESULTS: Two hundred and twenty-two patients (86% response rate) completed the QLQ-C30 and 118 (86% response rate) the anorectal sexual function questionnaire. The median time from surgery to filling in the QLQ C30 questionnaire was 12 months, and to filling in the anorectal-sexual function questionnaire - 13 months. We did not find significant differences between the randomised groups regarding QoL and the anorectal and sexual functions. Approximately two-thirds of patients had anorectal function impairment. Approximately 20% of patients stated that this considerably influenced their QoL. CONCLUSIONS: QoL and the anorectal and sexual functioning did not differ in patients receiving short-course radiotherapy, as compared to those receiving chemoradiation. PMID- 17692978 TI - Intraoperative real-time planned conformal prostate brachytherapy: post implantation dosimetric outcome and clinical implications. AB - PURPOSE: To report the dosimetric outcome of patients with clinically localized prostate cancer treated with I-125 permanent implantation using an intraoperative real-time conformal planning technique. METHODS AND MATERIALS: Five hundred and sixty-two patients with prostate cancer were treated with I-125 permanent interstitial implantation using a transrectal ultrasound-guided approach. Real time intraoperative treatment planning software that incorporates inverse planning optimization was used. Dose-volume constraints for this inverse-planning system included: prostate V100 >or=95%, maximal urethral dose or=140 Gy was achieved. In these patients, the V100 and D90 values did not have a significant influence on PSA relapse-free survival outcomes. The median maximum rectal dose and urethral doses were 104 Gy (72% of the prescription dose) and 187 Gy (130% of the prescription dose). The average and maximum rectal doses exceeding 100% of the prescription dose were less than 1% and 10% of patients, respectively. Average and maximum urethral doses exceeding 150% of the prescription dose were noted in 3% and 24% of patients, respectively. Average and maximum urethral doses exceeded 120% of the prescription dose in 21% and 58% of patients, respectively. Among patients where >or=2.5 cm(3) of the rectum was exposed to the prescription dose, the incidence of late grade 2 toxicity rectal toxicity was 9% compared to 4% for smaller volumes of the rectum exposed to similar doses (p=0.003). No dosimetric parameter in these patients with tight dose confines for the urethra influenced acute or late urinary toxicity. CONCLUSION: Real-time intraoperative planning was associated with a 90% consistency of achieving the planned intraoperative dose constraints for target coverage and maintaining planned urethral and rectal constraints in a high percentage of implants. Rectal volumes of >or=2.5 cm(3) exposed to the prescription doses were associated with an increased incidence of grade 2 rectal bleeding. Further enhancements in imaging guidance for optimal seed deposition are needed to guarantee optimal dose distribution for all patients. Whether such improvements lead to further reduction in acute and late morbidities associated with therapy requires further study. PMID- 17692979 TI - Evaluation of thoracic spinal cord motion using dynamic MRI. AB - The aim of study was to assess the thoracic spinal cord motion during normal breathing using dynamic magnetic resonance imaging (dMRI). We found that the mean motion range at different thoracic levels is typically within 0.5mm. The good stability makes this an excellent position for stereotactic radiotherapy (SBRT). PMID- 17692980 TI - Comparison of three accelerated partial breast irradiation techniques: treatment effectiveness based upon biological models. AB - BACKGROUND AND PURPOSE: Accelerated partial breast irradiation (APBI) is being studied in a phase III randomized trial as an alternative to whole breast irradiation (WBI) for early stage breast cancer patients. There are three methods for APBI: multi-catheter brachytherapy (MCT), MammoSite brachytherapy (MST), or 3D conformal (3DCRT). There is a paucity of data comparing among methods. Using a linear-quadratic (LQ) model, we evaluated the anticipated efficacy among the APBI methods for equivalent uniform dose (EUD), Tumor Control Probability (TCP), and Normal Tissue Complication Probability (NTCP). MATERIALS AND METHODS: Treatment plans from five patients treated by each APBI modality were retrospectively selected. Dose-volume-histograms (DVH) for planning target volume (PTV), breast, and lung were generated. The LQ parameters alpha=0.3Gy(-1) and alpha/beta=10Gy were used for calculations. The values of EUD, TCP, and NTCP were calculated based on DVHs. RESULTS: The average EUD (normalized to 3.4Gy BID) for the MCT, MST, and 3DCRT APBI was 35, 37.2, and 37.6Gy. When normalized to 2Gy fractionation these become, 42.2, 46.4, and 46.9Gy. Average TCP for MCT, MST, and 3DCRT PBI was 94.8%, 99.1%, and 99.2%. The NTCP values for breast and lung were low for all three methods. CONCLUSIONS: The EUD for PTV and TCP were most similar in MST and 3DCRT APBI and were lower in MCT APBI. This questions the equivalence of the three APBI modalities that are currently being evaluated in the NSABP B39/RTOG 0413 protocol. PMID- 17692981 TI - Decomposition of working memory-related scalp ERPs: crossvalidation of fMRI constrained source analysis and ICA. AB - Both functional magnetic resonance imaging (fMRI)-constrained source analysis and independent component analysis (ICA) claim to estimate the neuronal sources of electroencephalographic (EEG) scalp signals. In fMRI-constrained source analysis, event-related potential (ERP) generator locations are defined by fMRI activation patterns, and their contribution to the scalp ERP signal is probed. In contrast, ICA assumes that networks of cortical generators can be separated on the basis of their statistical independence. While good arguments can be put forward to justify both approaches, it is unclear how results from both methods compare. A clarification of these issues is of utmost importance to reconcile findings made using identical paradigms but these two complementary analysis methods. As both methods share the concept of spatially static sources a natural space to compare both methods and to crossvalidate the respective findings is at the level of source activity in the form of dipole source waves and independent component time courses and their corresponding maps. We used fMRI-constrained source analysis and ICA followed by clustering using the Kuhn-Munkres algorithm to analyze data from a working memory experiment. We demonstrate that crossvalidation is indeed possible using an appropriate statistical test. However, the sensitivity of this crossvalidation approach is ultimately limited by the low number of dimensions that contribute significant variance to the grand average scalp ERP. We conclude that testing at the single-subject level is preferable for crossvalidation purposes if the signal-to-noise ratio of the data allows for this approach. PMID- 17692982 TI - Prepulse inhibition of acoustic startle in Japanese patients with chronic schizophrenia. AB - Prepulse inhibition (PPI) of acoustic startle reflex has been suggested as a neurophysiologic measure of information processing abnormalities in schizophrenia. However, there has been little information on PPI and related measures in Asian patients with schizophrenia. We examined startle response to acoustic stimuli, its habituation, and PPI in 20 Japanese patients with chronic schizophrenia under antipsychotic medication and 16 healthy controls matched for age and sex. We measured PPI with 115 dB of pulse (40 ms), 82, 86, or 90 dB of prepulse (20 ms) and 30, 60, or 120 ms of lead interval (LI). The startle response to pulse alone trials was significantly smaller in schizophrenics than in controls, which may be due, at least in part, to medication. There was no significant difference in habituation of startle response during the test session between the two groups. PPI differed significantly between the two groups when LI was 120 ms. No significant relationship was found on startle response or PPI with age of onset, number of previous admission, medication dosages, or symptom scores assessed with the Positive and Negative Syndrome Scale (PANSS). Our results confirm impaired PPI in chronic schizophrenia patients compared with controls in Japanese. PMID- 17692983 TI - A sucrose-inducible promoter system for the intra- and extracellular protein production in Bacillus megaterium. AB - A sucrose-inducible promoter system (P(sacB)) from Bacillus megaterium was identified using a secretome approach. It was successfully employed for the extracellular production of the homologous levansucrase SacB (4252.4 U l(-1)) and the heterologous green fluorescent protein GFP (7.9 mg g(CDW)(-1)). Mutational analysis of B. megaterium P(sacB) allowed the identification of important promoter elements. The sucrose-inducible promoter provides a useful alternative to the established xylose-inducible promoter system (P(xylA)) for recombinant gene expression in B. megaterium. PMID- 17692984 TI - Grading and staging systems for inflammation and fibrosis in chronic liver diseases. AB - Liver biopsy is an important part of the evaluation of patients with a variety of liver diseases. Besides establishing the diagnosis, the biopsy is often used to assess the severity of the disease in terms of both grade and stage. The stage in most chronic liver diseases relates to the degree of scarring with the end stage being cirrhosis with its clinical complications. The grade relates to the severity of the underlying disease process, with features that vary with the pathogenetic mechanisms. Chronic viral hepatitis has been the object of the most extensive efforts at grading and staging, stimulated by the advent of new forms of therapy. Systems have also been developed for fatty liver disease, allograft rejection and chronic cholestatic diseases, but these have not been as widely used. Simple grading and staging systems for chronic hepatitis, including the IASL, Batts-Ludwig, and Metavir systems, are most appropriate for management of individual patients, while more complex systems such as the Histology Activity Index (HAI) are appropriate for evaluation of large cohorts of patients when statistical analysis is required. PMID- 17692985 TI - Peg-interferon alone or combined with ribavirin in HCV cirrhosis with portal hypertension: a randomized controlled trial. AB - BACKGROUND/AIMS: Risks and benefits of antiviral therapy in HCV cirrhosis with portal hypertension are poorly known. METHODS: We performed a randomized controlled trial in 102 HCV patients with compensated cirrhosis and portal hypertension: 51 received 1 microg/kg/week of Pegylated-interferon alpha-2b and 51 Pegylated-interferon plus 800 mg/day of ribavirin up to 52 weeks. RESULTS: By intention-to-treat analysis, five patients on monotherapy and eleven on combination therapy achieved a sustained virological response (9.8% vs. 21.6%, p=0.06). The response was more frequent for genotypes 2 or 3 than genotype 1 (66.6% vs. 11.3%, p=0.001). Genotype 1, who had low viral load at start of therapy, were HCV-RNA negative at 4 weeks, and were adherent to the scheduled therapy had a higher probability of sustained virological response. Patients with sustained virological response had less disease events compared to nonresponders (6.2% vs. 38.3%, p=0.03 by log rank test) during follow-up. CONCLUSIONS: In HCV cirrhosis with portal hypertension Peg-interferon plus ribavirin is a feasible treatment. Although the rate of viral eradication is modest, tailoring by genotype and early viral response allows to keep patients on treatment who are more likely to have viral eradication. Patients with viral eradication have fewer disease complications during follow-up. PMID- 17692986 TI - Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: a U.S.-Canadian multicenter study. AB - BACKGROUND/AIMS: HIV-infected patients now live longer and often have complications of liver disease, especially with hepatitis B or C virus coinfection. Limited data are available on those with hepatocellular carcinoma (HCC). METHODS: A retrospective analysis from 1992 to 2005 in 6 centers identified 63 HIV-infected HCC patients. Controls were 226 consecutive HIV negative HCC patients from four sites. RESULTS: HIV-positive patients were younger than controls (52 vs. 64 years, p<0.001), more commonly had chronic hepatitis B or C (97% vs. 73%, p<0.001), were more frequently symptomatic (51% vs. 38%, p=0.048), had a higher median alfa-fetoprotein level (227 vs. 51 ng/ml, p=0.005), but a similar mean Child-Turcotte-Pugh score (7.0 vs. 7.5, p=0.05) and HCC staging score (Barcelona-Clinic-Liver-Cancer stages C+D in 50% vs. 58%, p=0.24). HCC developed faster in HIV/HCV-coinfected than in HCV-monoinfected patients (mean, 26 vs. 34 years after HCV infection, p=0.002). HIV-positive patients received proven therapy more often (48% vs. 31%, p=0.017), but median survival was similar (6.9 vs. 7.5 months, p=0.44). Independent factors predicting survival were symptomatic presentation (hazard ratio [HR], 0.437; p<0.001), any proven therapy (HR, 2.19; p<0.001), diagnosis after 01-Jan-2002 (HR, 1.52; p=0.010), Barcelona-Clinic-Liver-Cancer stages C+D (HR, 0.491; p<0.001), AST/ALT >or= 2.00 (HR, 0.597; p=0.001), AFP >or= 400 ng/mL (HR, 0.55, p=0.003), and platelets >or= 100,000/mm3 (HR, 0.651; p=0.012), but not HIV-serostatus (p=0.19). In HIV-infected patients without HCC therapy (n=33), median survival was longer with undetectable HIV RNA (<400 copies/mL) than with HIV viremia (6.5 vs. 2.6 months, p=0.013). CONCLUSIONS: HIV-positive HCC patients are younger and more frequently symptomatic and infected with HCV or HBV than HIV-negative patients. Tumor staging and survival are similar. In untreated patients, undetectable HIV RNA independently predicts better survival. PMID- 17692987 TI - Treatment of chronic HCV in advanced liver disease: unmet challenges, reason for optimism. PMID- 17692988 TI - Slimming at all costs: Herbalife-induced liver injury. PMID- 17692989 TI - Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife products. AB - BACKGROUND/AIMS: Herbal agents are popular and perceived as safe because they are supposedly 'natural'. We report 10 cases of toxic hepatitis implicating Herbalife products. METHODS: To determine the prevalence and outcome of hepatotoxicity due to Herbalife products. A questionnaire was sent to all public Swiss hospitals. Reported cases were subjected to causality assessment using the CIOMS criteria. RESULTS: Twelve cases of toxic hepatitis implicating Herbalife preparations (1998 2004) were retrieved, 10 sufficiently documented to permit causality analysis. Median age of patients was 51 years (range 30-69) and latency to onset was 5 months (0.5-144). Liver biopsy (7/10) showed hepatic necrosis, marked lymphocytic/eosinophilic infiltration and cholestasis in five patients. One patient with fulminant liver failure was successfully transplanted; the explant showed giant cell hepatitis. Sinusoidal obstruction syndrome was observed in one case. Three patients without liver biopsy presented with hepatocellular (2) or mixed (1) liver injury. Causality assessment of adverse drug reaction was classified as certain in two, probable in seven and possible in one case(s), respectively. CONCLUSIONS: We present a case series of toxic hepatitis implicating Herbalife products. Liver toxicity may be severe. A more detailed declaration of components and pro-active role of regulatory agencies would be desirable. PMID- 17692990 TI - NASH and thiazolidinediones: not to be taken lightly. PMID- 17692991 TI - Which patients with genotype 1 chronic hepatitis C can benefit from prolonged treatment with the 'accordion' regimen? AB - The on-treatment virological response to pegylated interferon plus ribavirin therapy is a useful tool in the management of patients with chronic hepatitis C. The time at which hepatitis C virus RNA becomes undetectable by a sensitive PCR assay has a huge impact on the probability of achieving a sustained virological response, particularly in genotype 1 patients, and may be useful in selecting patients for prolonged therapy. Indiscriminate extension of treatment in patients with hepatitis C virus genotype 1 is not beneficial. However, there is a subgroup of patients - the so-called 'slow responders' - who benefit from extending treatment from 48 to 72 weeks and can be readily identified after 4-12 weeks of combination therapy. Thus, it is important to distinguish slow responders from null responders. In the TeraVIC-4 study virological relapse rates were significantly lower, and sustained virological response rates were significantly higher, in those treated for 72 weeks with peginterferon alfa-2a (40 kDa) plus ribavirin (45% vs. 32% with 48 weeks, P=0.014). Patients are best served by quantitative determination of the hepatitis C virus RNA level at weeks 4, 12 and 24. The results of these determinations can then be used to tailor the length of therapy. PMID- 17692992 TI - Large changes in regulome size herald the main prokaryotic lineages. AB - Using a large-scale reconstruction of ancestral gene content, we show that radical changes in regulome size occur at the origins of major prokaryotic lineages. Subsequently, the duplication and deletion of regulators slows down in most lineages, except proteobacteria, significantly reducing the scaling of regulators and keeping their average proportion lineage-specific. Our results also suggest that major transitions in prokaryote evolution are related to changes in regulatory capacity rather than proteome innovations. PMID- 17692993 TI - A cell cycle automaton model for probing circadian patterns of anticancer drug delivery. AB - To optimize the temporal patterning of drug delivery used in cancer chronotherapy, we resort to an automaton model describing the transitions through the successive phases of the cell cycle. The model accounts for the progressive desynchronization of cells due to the variability of the durations of the cell cycle phases, and for the entrainment of the cell cycle by the circadian clock. Focusing on the cytotoxic effect of the anticancer drug 5-fluorouracil (5-FU), which kills cells in the S phase, we compare the effect of continuous infusion of 5-FU with various circadian patterns of 5-FU administration that peak either at 4 a.m., 10 a.m., 4 p.m., or 10 p.m. The model indicates that the cytotoxic effect of 5-FU is minimum for the circadian delivery peaking at 4 a.m., and maximum for the continuous infusion or the circadian pattern peaking at 4 p.m. These results fit well with experimental observations and illustrate how the modeling approach based on the cell cycle automaton may help to predict the cytotoxic effect of anticancer drugs affecting various phases of the cell cycle. PMID- 17692994 TI - Dizygotic twins with congenital malalignment of the great toenails: reappraisal of the pathogenesis. AB - Congenital malalignment of the great toenails (CMGTN) is a heritable disorder, in which the longitudinal axis of the nail plate is not parallel to the corresponding axis of the distal phalanx of the hallux, but laterally deviated. We describe a pair of 1(1/2)-month-old dizygotic twins with laterally deviated nail plates of the great toenails since birth. By the time the infants were 10 months of age, significant realignment was observed. Adult pedigree members also showed slight similar deviations of the nail plates. We suggest that desynchronization of growth between the nail and the adherent end-phalanx of the hallux may result in temporarily larger nail plates, which are gliding outwards, in order to fit into the underlying bony space. During postnatal life, spontaneous realignment is usually observed, probably as a result of a faster growing end-phalanx. PMID- 17692995 TI - Lysophosphatidic acid stimulates astrocyte proliferation through LPA1. AB - Lysophosphatidic acid (LPA) is an extracellular lipid mediator that regulates nervous system development and functions through multiple types of LPA receptors. Here we explore the role of LPA receptor subtypes in cortical astrocyte functions. Astrocytes cultured under serum-free conditions were found to express the genes of five LPA receptor subtypes, lpa1 to lpa5. When astrocytes were treated with dibutyryl cyclic adenosine monophosphate, a reagent inducing astrocyte differentiation or activation, lpa1 expression levels remained unchanged, but those of other LPA receptor subtypes were relatively reduced. LPA stimulated DNA synthesis in both undifferentiated and differentiated astrocytes, but failed to do so in astrocytes prepared from mice lacking lpa1 gene. LPA also inhibited [3H]-glutamate uptake in both undifferentiated and differentiated astrocytes; and LPA-induced inhibition of glutamate uptake was still observed in lpa1-deficient astrocytes. Taken together, these observations demonstrate that LPA1 mediates LPA-induced stimulation of cell proliferation but not inhibition of glutamate uptake in astrocytes. PMID- 17692996 TI - NMDA and non-NMDA receptor-mediated differential Ca2+ load and greater vulnerability of motor neurons in spinal cord cultures. AB - Glutamate receptor activated neuronal cell death has been implicated in the pathogenesis of motor neuron disease but the molecular mechanism responsible for neuronal dysfunction needs to be elucidated. In the present study, we examined the contribution of NMDA and non-NMDA sub-types of glutamate receptors in selective vulnerability of motor neurons. Glutamate receptor activated Ca2+ signaling, mitochondrial functions and neurotoxicity in motor neurons and other spinal neurons were studied in mixed spinal cord primary cultures. Exposure of cells to glutamate receptor agonists glutamate, NMDA and AMPA elevated the intracellular Ca2+, mitochondrial Ca2+ and caused mitochondrial depolarization and cytotoxicity in both motor neurons and other spinal neurons but a striking difference was observed in the magnitude and temporal patterns of the [Ca2+]i responses between the two neuronal cell types. The motor neurons elicited higher Ca2+ load than the other spinal neurons and the [Ca2+]i levels were elevated for a longer duration in motor neurons. AMPA receptor stimulation was more effective than NMDA. Both the NMDA and non-NMDA receptor antagonists APV and NBQX inhibited the Ca2+ entry and decreased the cell death significantly; however, NBQX was more potent than APV. Our results demonstrate that both NMDA and non-NMDA sub-types of glutamate receptors contribute to glutamate-mediated motor neuron damage but AMPA receptors play the major role. AMPA receptor-mediated excessive Ca2+ load and differential handling/regulation of Ca2+ buffering by mitochondria in motor neurons could be central in their selective vulnerability to excitotoxicity. PMID- 17692997 TI - Insulin rescues amyloid beta-induced impairment of hippocampal long-term potentiation. AB - Cerebral accumulation of amyloid beta-protein (Abeta) is generally believed to play a critical role in the pathogenesis of Alzheimer's disease (AD). Recent evidence suggests that Abeta-induced synaptic dysfunction is one of earliest pathogenic events observed in AD. Here we report that synthetic Abeta(1-42) strongly inhibited the induction of long-term potentiation (LTP) in the CA1 region of rat hippocampal slices. To ascertain which Abeta(1-42) sequences contribute to the impairment of LTP, we compared actions of several Abeta fragments and found that the sequence within 25-35 region of Abeta mainly contributes to the expression of LTP impairment. Importantly, we show that insulin and insulin-like growth factor-1 significantly inhibit Abeta oligomer formation, particularly dimers and trimers, and ameliorate the synthetic Abeta induced suppression of LTP. Furthermore, dithiothreitol was found to be capable of significantly preventing the inhibitory effect of insulin on Abeta oligomer formation. In contrast, hemoglobin promotes Abeta oligomer formation and enhances Abeta-mediated inhibition of LTP induction. These results suggest that insulin may have utility in treating the earliest stages of Abeta-induced synaptic dysfunction in AD patients. PMID- 17692998 TI - Design, synthesis and antiproliferative activity of some 3-benzylidene-2,3 dihydro-1-benzopyran-4-ones which display selective toxicity for malignant cells. AB - A series of 3-benzylidene-4-chromanones 1a-l were prepared and their cytotoxicity towards human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 lymphoid leukemia cells were compared to the previously generated biodata in these three assays for the isosteric 2-benzylidene-1-tetralones 2a-l. Over 40% of the compounds in series 1 were more potent than their counterparts in series 2, while equipotency was noted in one-third of the comparisons made. In general the IC(50) values of 1a-l towards the human T-lymphocytes were in the low micromolar range. Molecular modelling revealed differences in shapes of representative molecules in series 1 and 2 which may contribute to the variation in cytotoxic potencies. Most of the compounds in series 1 displayed greater potencies towards HSC-2, HSC-3, HSC-4 and HL-60 neoplasms than HGF, HPC, and HPLF normal cells and were well tolerated in mice. PMID- 17692999 TI - New amido derivatives as potential BKCa potassium channel activators. XI. AB - The vasorelaxing effects of exogenous activators of large-conductance calcium activated potassium channels (BK channels) can furnish the pharmacological rational basis for the treatment of hypertension and/or other diseases related with an impaired contractility of vessels. Since in previous works some benzanilide derivatives showed BK channel-induced vasorelaxing activity, in this paper we have taken into consideration the introduction of methylene spacer(s) between the amide linker and one or both the aromatic substituents, to evaluate the pharmacological effect caused by these lengthenings and to obtain possible useful information about structure-activity relationships. Overall, the main findings of this work suggest that the introduction of one or two methylene group(s) in the amide linker exerts a negative influence on the BK-opening properties, which can be due to an excessive lengthening of the spacer between the two aromatic rings and/or to further degrees of conformational freedom. PMID- 17693000 TI - Construction and biological characterization of artificial recombinants between a wild type flavivirus (Kunjin) and a live chimeric flavivirus vaccine (ChimeriVax JE). AB - Although the theoretical concern of genetic recombination has been raised related to the use of live attenuated flavivirus vaccines [Seligman, Gould, Lancet 2004;363:2073-5], it has little foundation [e.g., Monath TP, Kanesa-Thasan N, Guirakhoo F, Pugachev K, Almond J, Lang J, et al. Vaccine 2005;23:2956-8]. To investigate biological effects of recombination between a chimeric yellow fever (YF) 17D/Japanese encephalitis (JE) vaccine virus (ChimeriVax-JE) and a wild-type flavivirus Kunjin (KUN-cDNA), the prM-E envelope protein genes were swapped between the two viruses, resulting in new YF 17D/KUN(prM-E) and KUN/JE(prM-E) chimeras. The prM-E genes are easily exchangeable between flavivirues, and thus the exchange was expected to yield the most replication-competent chimeras, while other rationally designed recombinants would be more likely to be crippled or non viable. The new chimeras proved highly attenuated in comparison with the KUN-cDNA parent, as judged by plaque size and growth kinetics in cell culture, low viremia in hamsters, and reduced neurovirulence/neuroinvasiveness in mice. These data provide strong experimental evidence that the potential of recombinants, should they ever emerge, to cause disease or spread (compete in nature with wild-type flaviviruses) would be indeed extremely low. PMID- 17693001 TI - Transposition of the mental nerve by piezosurgery followed by postoperative neurosensory control: a case report. AB - Transposition of the mental nerve is a preprosthetic procedure that is effective for patients with hyperaesthesia caused by the effect of a dental prosthesis on the alveolar ridge. We present the case of a 74-year-old woman with pain and hyperaesthesia of the right inferior alveolar nerve caused by a dental prosthesis. Caudal transposition of the right mental nerve by piezosurgery resulted in postoperative neurosensory controls of the lower lip showing normal nerve function 2 months later. PMID- 17693002 TI - Kinetic and dynamic aspects of soil-plant-snail transfer of cadmium in the field. AB - The proper use of bioaccumulation in the assessment of environmental quality involves accounting for chemical fluxes in organisms. Cadmium (Cd) accumulation kinetics in a soil-plant-snail food chain were therefore investigated in the field under different soil contamination (from 0 to 40 mg kg(-1)), soil pH (6 and 7) and season. Allowing for an accurate and sensitive assessment of Cd transfer to snails, toxicokinetics appears an interesting tool in the improvement of risk assessment procedures and a way to quantify metal bioavailability for a defined target. On the basis of uptake fluxes, snails proved to be sensitive enough to distinguish moderate soil contaminations. The soil pH did not appear, in the range studied, as a modulating parameter of the Cd transfer from soil to snail whereas the season, by influencing the snail mass, may modify the internal concentrations. The present data specifying a time integrated assessment of environmental factors on metal bioavailability and transfer to terrestrial snails should ensure their rational use in environmental biomonitoring. PMID- 17693003 TI - Translating science into policy: using ecosystem thresholds to protect resources in Rocky Mountain National Park. AB - Concern over impacts of atmospheric nitrogen deposition to ecosystems in Rocky Mountain National Park, Colorado, has prompted the National Park Service, the State of Colorado Department of Public Health and Environment, the Environmental Protection Agency, and interested stakeholders to collaborate in the Rocky Mountain National Park Initiative, a process to address these impacts. The development of a nitrogen critical load for park aquatic resources has provided the basis for a deposition goal to achieve resource protection, and parties to the Initiative are now discussing strategies to meet that goal by reducing air pollutant emissions that contribute to nitrogen deposition in the Park. Issues being considered include the types and locations of emissions to be reduced, the timeline for emission reductions, and the impact of emission reductions from programs already in place. These strategies may serve as templates for addressing ecosystem impacts from deposition in other national parks. PMID- 17693004 TI - Attention to low- and high-spatial frequencies in categorizing facial identities, emotions and gender in children with autism. AB - This study was aimed at investigating face categorization strategies in children with autistic spectrum disorders (ASD). Performance of 17 children with ASD was compared to that of 17 control children in a face-matching task, including hybrid faces (composed of two overlapping faces of different spatial bandwidths) and either low- or high-pass filtered faces. Participants were asked to match faces on the basis of identity, emotion or gender. Results revealed that children with ASD used the same strategies as controls when matching faces by gender. By contrast, in the identity and the emotion conditions, children with ASD showed a high-pass bias (i.e., preference for local information), contrary to controls. Consistent with previous studies on autism, these findings suggest that children with ASD do use atypical (local-oriented) strategies to process faces. PMID- 17693005 TI - Estrogen abolishes latent inhibition in ovariectomized female rats. AB - Estrogen is frequently prescribed as a method of birth control and as hormone replacement therapy for post-menopausal women with varied effects on cognition. Here the effects of estrogen on attention were examined using the latent inhibition (LI) behavioral paradigm. Ovariectomized (OVX) female rats were given either estrogen benzoate (EB, 10 or 100 microg/ml/kg; SC) or sesame oil vehicle. Males and OVX females receiving vehicle displayed normal LI. In contrast, LI was abolished in OVX females receiving EB. The lack of LI in OVX females receiving EB was a result of low suppression ratios, reflecting strong conditioning between the tone and the shock in these subjects even if they were pre-exposed to the tone. Thus, estrogen impaired the ability of OVX females to ignore irrelevant stimuli. Since different cognitive tasks vary in their required ability to ignore irrelevant stimuli, these results may account for some of the variations in the current literature on estrogen and cognition. PMID- 17693006 TI - Association study of polymorphisms in the mitochondrial aspartate/glutamate carrier SLC25A12 (aralar) gene with schizophrenia. AB - Aralar is a mitochondrial calcium-regulated aspartate-glutamate carrier mainly distributed in brain and skeletal muscle, and involved in the transport of aspartate from mitochondria to the cytosol of a cell. Studies have shown that the brain N-acetyl aspartate (NAA) levels are greatly decreased in aralar-deficient mice, suggesting that aralar plays an important role in the synthesis of NAA in neuronal cells. Since magnetic resonance spectroscopy studies have revealed consistently reduced NAA levels in various brain regions of schizophrenic patients and their unaffected relatives, genes that affect aralar levels or NAA metabolism in the brain may be implicated in the pathogenesis of schizophrenia. Aralar is encoded by the SLC25A12 gene. In the past this gene has been found to be associated with susceptibility to autism; in this study we tested the hypothesis that SLC25A12 genetic variants confer susceptibility to schizophrenia. Six SLC25A12 polymorphisms were studied in a sample population of 253 people with schizophrenia and 216 normal controls. Significant linkage disequilibrium was obtained among the six polymorphisms. However, neither single marker nor haplotype analysis revealed an association between variants at the SLC25A12 locus and schizophrenia, suggesting that it is unlikely that the SLC25A12 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia in the Chinese population. Further studies with SLC25A12 variants relating to brain NAA levels in patients with schizophrenia are suggested. PMID- 17693007 TI - Re: Analysis of genotoxic potentiality of stevioside by comet assay. PMID- 17693008 TI - Genome health nutrigenomics and nutrigenetics--diagnosis and nutritional treatment of genome damage on an individual basis. AB - The term nutrigenomics refers to the effect of diet on gene expression. The term nutrigenetics refers to the impact of inherited traits on the response to a specific dietary pattern, functional food or supplement on a specific health outcome. The specific fields of genome health nutrigenomics and genome health nutrigenetics are emerging as important new research areas because it is becoming increasingly evident that (a) risk for developmental and degenerative disease increases with DNA damage which in turn is dependent on nutritional status and (b) optimal concentration of micronutrients for prevention of genome damage is also dependent on genetic polymorphisms that alter function of genes involved directly or indirectly in uptake and metabolism of micronutrients required for DNA repair and DNA replication. Development of dietary patterns, functional foods and supplements that are designed to improve genome health maintenance in humans with specific genetic backgrounds may provide an important contribution to a new optimum health strategy based on the diagnosis and individualised nutritional treatment of genome instability i.e. Genome Health Clinics. PMID- 17693010 TI - Yolk sac size and embryonic heart rate as prognostic factors of first trimester pregnancy outcome. AB - OBJECTIVES: To investigate embryonic heart rate (EHR) and yolk sac diameter (YSD) during the first trimester and their role as prognostic markers of first trimester pregnancy outcome. STUDY DESIGN: Prospective cohort study involving 219 women conducted in the 4th Academic Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Greece. Gestational age (GA) was determined ultrasonographically based on gestational sac diameter and crown-rump length. EHR and YSD were evaluated during the first 12 weeks and subsequently compared between the pregnancies that continued beyond the first trimester and those that resulted in spontaneous abortion. Receiver-operating characteristic (ROC) curves were used for the evaluation of the prognostic value of the combination of gestational age with embryonic heart rate and yolk sac diameter. RESULTS: The EHR and YSD were significantly correlated to advancing gestational age (p<0.001) in pregnancies continuing beyond 12 weeks. Pregnancies that resulted in spontaneous abortion exhibited a statistically significant lower EHR (p<0.001), smaller YSD (p=0.001) or absent yolk sac. ROC curve analysis demonstrated the predictive value of the combination of GA with EHR (area under the ROC curve: 0.971, p<0.001) and GA with YSD (area under the ROC curve: 0.858, p<0.001) for first trimester pregnancy outcome. CONCLUSIONS: EHR and YSD progressively increase in healthy pregnancies during the first trimester. Embryonic bradycardia and absence of yolk sac or even a smaller yolk sac diameter than expected for any gestational age are predictors of poor pregnancy outcome during the first 12 weeks. PMID- 17693011 TI - Validation of the prolapse quality of life questionnaire (P-QOL) in a Turkish population. AB - OBJECTIVE: To validate the Turkish translated version of the prolapse quality of life questionnaire (P-QOL). STUDY DESIGN: After establishing the test-retest reliability and internal consistency in a pilot study, 310 patients were enrolled in the study and general and subscale scores of the questionnaires were calculated. All participants underwent the International Continence Society (ICS) prolapse score (POP-Q). RESULTS: One hundred and forty-five (49.7%) women were symptomatic and 147 (50.3%) were asymptomatic. The level of missing data ranged from 0 to 2.2%. For the test-retest reliability, Spearman's rho was from 0.91 to 1.00 for all domains (p<0.001). The severity of P-QOL was strongly correlated with the vaginal examination findings among the symptomatic group (p<0.001). Items correlated with the objective vaginal examination findings. The total and domain scores for P-QOL of symptomatic and asymptomatic women were found to be statistically significant (p<0.001). CONCLUSION: The Turkish translated version of the P-QOL is reliable, consistent and valid instrument for assessing symptom severity, impact on quality of life in women with uterovaginal prolapse. It is easy to understand may be easily administered and self-completed by the women. PMID- 17693012 TI - Ultrasound speed in articular cartilage under mechanical compression. AB - Ultrasound elastography is a method that can be used to determine the elastic properties of soft tissues and it has been recently applied to study of articular cartilage. While ultrasound elastography techniques assume a constant ultrasound speed in tissue under mechanical compression, ultrasound speed in articular cartilage has been found to vary depending on the loading conditions. This may limit the quantitative use of the technique for determination of the elastic properties of articular cartilage along the axis of ultrasound propagation. The aim of the present study was to investigate the origin of the load-related variation in ultrasound speed. Samples of human and bovine articular cartilage (n = 82) were mechanically and acoustically tested during unconfined compression. A statistically significant (p < 0.05) variation of ultrasound speed was found in cartilage during a stress-relaxation test. A finite element model was constructed by exploiting microscopically determined collagen and proteoglycan contents, collagen orientation and biochemical analyses of water content. From the finite element simulations, collagen orientation and the void ratio (fluid-to-solid ratio) as a function of time were assessed and, together with the experimentally determined ultrasound speed, a linear model predicting variation of the ultrasound speed in human articular cartilage under mechanical compression was established. The model predicted compression-related ultrasound speed with an error of <0.3% at each time point. The effect of strain rate on variation of ultrasound speed was tested in bovine cartilage samples. The decrease in ultrasound speed was found to be proportional to the strain rate. The results suggest that ultrasound speed in articular cartilage is controlled mainly by collagen orientation and the void ratio and depends on the imposed strain rate. A numerical simulation revealed that the compression-related decrease in ultrasound speed induces notable errors in mechano-acoustically determined strain. A method to eliminate the compression-related errors in measured strain and elastic properties may be needed in mechano-acoustic measurements of articular cartilage. PMID- 17693013 TI - A tribute to peter N. T. Wells, emeritus editor of ultrasound in medicine and biology. PMID- 17693014 TI - Re: Josef Beatrice, raeto T. Strebel, Thomas Pfammatter, Jaime H. Rohweder and Tullio Sulser. Life-threatening complication after right renal extracorporeal shock wave lithotripsy: large hepatic haematoma requiring embolisation of the right hepatic artery. Eur Urol 2007;52:909-11. PMID- 17693015 TI - Lipid management in ischemic stroke patients. AB - OBJECTIVES: In-hospital initiation and maintaining of lipid-lowering therapy (LLT) after discharge is recommended for dyslipidemic stroke patients. However, little is known about actual adherence to treatment in Taiwan. This study aims to describe the current practice of lipid testing and LLT and to identify predictors for patient to receive LLT. METHODS: Between February 2001 and December 2002, a total of 1105 consecutive ischemic stroke patients were prospectively registered. Dyslipidemic ischemic stroke patients were recruited and followed over a 6 months period. RESULTS: In-hospital lipid testing was performed in 91% of all patients and LLT was initiated in 74% (350/476) of dyslipidemic patients. During the 6 months follow-up period, lipid testing was performed in 77% (266/345) and LLT was maintained in 45% (154/345) of patients. However, the target LDL cholesterol level (<100mg/dL) was achieved in only 30% (78/255) of patients. Older patients had a lower chance to receive LLT. CONCLUSIONS: The in-hospital initiation of LLT and lipid testing was considered adequate as compared to other studies. However, after discharge from the hospital, many patients, especially older patients remained untreated. Efforts to close treatment gaps in lipid management require sustained quality improvement efforts. More awareness in this area is needed. PMID- 17693016 TI - Differential apoptotic induction of gambogic acid, a novel anticancer natural product, on hepatoma cells and normal hepatocytes. AB - Gambogic acid (GA) is the major active ingredient of gamboge, a brownish resin exuded from Garcinia hanburryi tree in Southeast Asia. In this study, we compared the different apoptotic induction of GA on human normal embryonic hepatic L02 cells and human hepatoma SMMC-7721 cells by detecting growth inhibition, observing morphological changes, and the expressions of the relative apoptotic proteins (Bax, Bcl-2 and caspase-3). The results indicated that GA could selectively induce apoptosis of SMMC-7721 cells, while had relatively less effect on L02 cells. To illustrate the distinct selective antitumor mechanism of GA, we further study its distribution in cultured cells and in tumor-bearing mice. The results indicated that SMMC-7721 cells have higher GA binding activity than L02 cells. The retention time of GA in grafted tumor was longer than in liver, renal and other organs. Collectively, the selective anticancer activity of GA could be due to its significant apoptotic inducing effects as well as its higher distribution and longer retention time in tumor cells compared to the normal cells. So GA might be a kind of highly effective anticancer drug candidate with low toxicity to normal tissue. PMID- 17693018 TI - Ozone and membrane filtration based strategies for the treatment of cork processing wastewaters. AB - The degradation of the pollutant organic matter present in the cork processing wastewater was studied by combining chemical treatments, which used ozone and some Advanced Oxidation Processes, and membrane filtration procedures. Two schemes were conducted: firstly, a single ozonation stage followed by an UF stage; and secondly, a membrane filtration stage, using different MF and UF membranes, followed by a chemical oxidation stage, where ozone, UV radiation, and the AOPs constituted by ozone plus UV radiation and ozone plus hydrogen peroxide, were used. The membrane filtration stages were carried out in tangential filtration laboratory equipment, and the membranes used were two MF membranes with pores sizes of 0.65 and 0.1microm, and three UF membranes with molecular weights cut-off of 300, 10, and 5kDa. The effectiveness of the different stages (conversions in the chemical procedures and rejection coefficients in the membrane processes) were evaluated in terms of several parameters which measure the global pollutant content of the wastewater: COD, absorbance at 254nm, tannins content, color, and ellagic acid. In the ozonation/UF combined process the following removals were achieved: 100% for ellagic acid and color, 90% for absorbance at 254nm, more than 80% for tannins, and 42-57% for COD reduction. In the filtration/chemical oxidation combined process, 100% elimination of ellagic acid, more than 90% elimination in color, absorbance at 254nm and tannins, and removal higher than 80% in COD were reached, which indicates a greater purification power of this combination. PMID- 17693019 TI - Evaluation of small-scale constructed wetland for water quality and Hg transformation. AB - Elevated concentrations of nutrients and mercury (Hg) make Steamboat Creek (SBC) the most polluted tributary of the Truckee River. Since wetlands are considered cost-effective, reliable, and potential sites for methylmercury (MeHg) production, a small-scale wetland system was constructed and monitored for several years in order to quantify both nutrient removal and transformation of mercury. Results indicated seasonal variations in nutrient removal with 40-75% of total nitrogen and 30-60% of total phosphorus being removed with highest removals during summer and lowest removals during winter. The wetland system behaved as a sink for MeHg during the winter months and as a source for MeHg during summer months. PMID- 17693020 TI - Influence of brown coal on limit of phytotoxicity of soils contaminated with heavy metals. AB - The paper gives knowledge and application values in efficiency of applying brown coal to limit uptake of heavy metals from contaminated soils by different plant species. The paper determines possibility and principles of using brown coal in reclamation of soils contaminated with heavy metals and rebuilding soils on devastated terrains like terrain in the influence zone of Copper-Smelter "Legnica". On the basis of pot experiment it was stated that increasing doses of brown coal limited phytotoxicity of soils. Results of the paper show that tested fertilizer could be applied on soils strongly contaminated with heavy metals giving long-lasting improvement of reclaimed soils. PMID- 17693021 TI - Treatment of wastewater containing toxic chromium using new activated carbon developed from date palm seed. AB - The use of a new activated carbon developed from date palm seed wastes, generated in the jam industry, for removing toxic chromium from aqueous solution has been investigated. The activated carbon has been achieved from date palm seed by dehydrating methods using concentrated sulfuric acid. The batch experiments were conducted to determine the adsorption capacity of the biomass. The effect of initial metal concentration (25-125mgl(-1)), pH, contact time, and concentration of date palm seed carbon have been studied at room temperature. A strong dependence of the adsorption capacity on pH was observed, the capacity increase as pH value decrease and the optimum pH value is pH 1.0. Kinetics and adsorption equilibrium were studied at different sorbent doses. The adsorption process was fast and the equilibrium was reached within 180min. The maximum removal was 100% for 75mgl(-1) of Cr(+ concentration on 4gl(-1) carbon concentration and the maximum adsorption capacity was 120.48mgg(-1). The kinetic data were analyzed using various kinetic models - pseudo-first order equation, pseudo-second order equation, Elovich equation and intraparticle diffusion equation - and the equilibrium data were tested using several isotherm models, Langmuir, Freundlich, Koble-Corrigan, Redlich-Peterson, Tempkin, Dubinin-Radushkevich and Generalized isotherm equations. The Elovich equation and pseudo-second order equation provide the greatest accuracy for the kinetic data and Koble-Corrigan and Langmuir models the closest fit for the equilibrium data. Activation energy of sorption has also been evaluated as 0.115 and 0.229kJmol(-1). PMID- 17693022 TI - Central administration of insulin suppresses food intake in chicks. AB - Although the orexigenic action of peptide hormones such as ghrelin and growth hormone releasing peptide is different between chickens and mammals, the anorexigenic action of peptide hormones is similar in both species. For example, central administration of peptide hormones such as leptin, cholecystokinin or glucagon has been shown to suppress food intake behavior in chickens and mammals. Central administration of insulin suppresses food intake in mammals. However, the anorexigenic action of insulin in chickens has not yet been identified. In the present study, we investigated the effects of central administration of insulin on food intake in chicks. Intracerebroventricular administration of insulin in chicks significantly suppressed food intake. Central administration of insulin significantly upregulated mRNA levels of proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART) and corticotropin-releasing factor (CRF), but did not influence mRNA levels of neuropeptide Y and agouti-related protein in the hypothalamus. These results suggest that alpha-melanocyte stimulating hormone (alpha-MSH, an anorexigenic peptide from the post-translational cleavage of POMC), CART and CRF are involved in the anorexigenic action of insulin in chicks. Furthermore, central administration of alpha-MSH or CART significantly suppressed food intake. In addition, alpha-MSH significantly upregulated CRF mRNA expression, suggesting that the anorexigenic action of alpha-MSH is mediated by CRF. Our findings demonstrate that insulin functions in chicks as an appetite suppressive peptide in the central nervous system and suggest that this anorexigenic action is mediated by CART, alpha-MSH and CRF. PMID- 17693023 TI - Nerve growth factor sequestering therapy attenuates non-malignant skeletal pain following fracture. AB - Current therapies to treat skeletal fracture pain are extremely limited. Some non steroidal anti-inflammatory drugs have been shown to inhibit bone healing and opiates induce cognitive dysfunction and respiratory depression which are especially problematic in the elderly suffering from osteoporotic fractures. In the present report, we developed a closed femur fracture pain model in the mouse where skeletal pain behaviors such as flinching and guarding of the fractured limb are reversed by 10mg/kg morphine. Using this model we showed that the administration of a monoclonal antibody against nerve growth factor (anti-NGF) reduced fracture-induced pain-related behaviors by over 50%. Treatment with anti NGF reduced c-Fos and dynorphin up-regulation in the spinal cord at day 2 post fracture. However, anti-NGF treatment did not reduce p-ERK and c-Fos expression at 20 and 90 min, respectively, following fracture. This suggests NGF is involved in maintenance but not the acute generation of fracture pain. Anti-NGF therapy did not inhibit bone healing as measured by callus formation, bridging of the fracture site or mechanical strength of the bone. As the anti-NGF antibody does not appreciably cross the blood-brain barrier, the present data suggest that the anti-hyperalgesic action of anti-NGF therapy results from blockade of activation and/or sensitization of the CGRP/trkA positive fibers that normally constitute the majority of sensory fibers that innervate the bone. These results demonstrate that NGF plays a significant role in driving fracture pain and that NGF sequestering therapies may be efficacious in attenuating this pain. PMID- 17693024 TI - Characterization of anti-coagulant properties of prenylated coumarin ferulenol. AB - We investigated the mechanisms underlying severe bleeding occurring upon consumption of Ferula communis. The prenylated coumarin ferulenol extracted from this plant did not directly affect blood coagulation but showed hepatocyte cytotoxicity and, at non-cytotoxic concentrations (<100 nM), impaired factor X biosynthesis (40% reduction). Studies with ferulenol derivatives indicated the prenyl residue as major determinant of ferulenol activity. PMID- 17693025 TI - Molecular effectors of multiple cell death pathways initiated by photodynamic therapy. AB - Photodynamic therapy (PDT) is a recently developed anticancer modality utilizing the generation of singlet oxygen and other reactive oxygen species, through visible light irradiation of a photosensitive dye accumulated in the cancerous tissue. Multiple signaling cascades are concomitantly activated in cancer cells exposed to the photodynamic stress and depending on the subcellular localization of the damaging ROS, these signals are transduced into adaptive or cell death responses. Recent evidence indicates that PDT can kill cancer cells directly by the efficient induction of apoptotic as well as non-apoptotic cell death pathways. The identification of the molecular effectors regulating the cross-talk between apoptosis and other major cell death subroutines (e.g. necrosis, autophagic cell death) is an area of intense research in cancer therapy. Signaling molecules modulating the induction of different cell death pathways can become useful targets to induce or increase photokilling in cancer cells harboring defects in apoptotic pathways, which is a crucial step in carcinogenesis and therapy resistance. This review highlights recent developments aimed at deciphering the molecular interplay between cell death pathways as well as their possible therapeutic exploitation in photosensitized cells. PMID- 17693026 TI - Inhibition of p38 MAP kinase improves survival of cardiac myocytes with hypoxia and burn serum challenge. AB - This study was aimed to investigate the effects of SB203580, the specific p38 mitogen-activated protein (MAP) kinase inhibitor, on cardiac myocyte survival and secretion of cytokines in an in vitro model of hypoxia and burn serum challenge. Results demonstrated that hypoxia and burn serum induced a persistent activation of p38 MAP kinase in primary cultured neonatal rat cardiomyocytes during the 12h period of stimulation, concomitant with a time-dependent increased expression of tumor necrosis factor (TNF)-alpha and inducible nitric oxide (iNOS), a progressively developed oxidative stress reflected by malondialdehyde (MDA) production, and myocytes injury evidenced by the increased levels of released lactate dehydrogenase (LDH) and the decreased myocyte viability. Furthermore, hypoxia and burn serum resulted in a significant increase in myocyte apoptosis, which may account for the impairment of myocyte viability as observed. SB203580 abolished p38 MAP kinase activation, blunted the upregulation of TNF-alpha, iNOS and the subsequent nitric oxide (NO) production, reduced oxidative stress, and alleviated hypoxia and burn serum-induced myocytes injury or apoptosis. These results demonstrated for the first time that inhibition of p38 MAP kinase improves survival of cardiac myocytes with hypoxia and burn serum challenge possibly via reducing the production of cytokines, such as TNF-alpha and NO, and the subsequent oxidative stress, providing strong evidence that the excessive inflammatory cytokines produced by cardiomyocytes themselves may be sufficient to cause myocardial injury after burn. PMID- 17693027 TI - Synergistic activation of astrocytes by ATP and norepinephrine in the rat supraoptic nucleus. AB - Supraoptic nucleus (SON) neurons receive a dense innervation from noradrenergic fibers, the activity of which stimulates vasopressin (VP) and oxytocin (OT) release, notably during homeostatic regulation of blood pressure and volume. This regulation is known to involve the co-release of norepinephrine (NE) and ATP, which act in synergy to stimulate Ca(2+) increase in SON neurons and to enhance release of VP and OT from hypothalamo-neurohypophysial explants. We here demonstrate that both ATP and NE also trigger transient intracellular Ca(2+) rise in rat SON astrocytes, the two agonists showing a synergistic action similarly to what has been reported in SON neurons. The responses to both agonists are not or are only moderately affected after blockade of neuronal activity by tetrodotoxin, or of neurotransmitter release by removal of extracellular Ca(2+), suggesting that the receptors involved are located on the astrocytes themselves. ATP acts via P2Y(1) receptors, as indicated by the pharmacological profile of Ca(2+) responses and the strong immunolabeling for this receptor in SON astrocytes. Responses to NE involve both alpha and beta adrenergic receptors, the latter showing a permissive role on the former. These results point to further implication of SON astrocytes in the regulation of VP and OT secretion, and suggest that they are potentially important elements participating in all regulatory processes of hypothalamo-neurohypophysial function that involve activation of noradrenergic pathways. PMID- 17693028 TI - Transcranial near-infrared light therapy improves motor function following embolic strokes in rabbits: an extended therapeutic window study using continuous and pulse frequency delivery modes. AB - Photon or near-infrared light therapy (NILT) may be an effective neuroprotective method to reduce behavioral dysfunction following an acute ischemic stroke. We evaluated the effects of continuous wave (CW) or pulse wave (P) NILT administered transcranially either 6 or 12 h following embolization, on behavioral outcome. For the studies, we used the rabbit small clot embolic stroke model (RSCEM) using three different treatment regimens: 1) CW power density of 7.5 mW/cm(2); 2) P1 using a frequency of 300 mus pulse at 1 kHz or 3) P2 using a frequency of 2 ms pulse at 100 Hz. Behavioral analysis was conducted 48 h after embolization, allowing for the determination of the effective stroke dose (P(50)) or clot amount (mg) that produces neurological deficits in 50% of the rabbits. Using the RSCEM, a treatment is considered beneficial if it significantly increases the P(50) compared with the control group. Quantal dose-response analysis showed that the control group P(50) value was 1.01+/-0.25 mg (n=31). NILT initiated 6 h following embolization resulted in the following P(50) values: (CW) 2.06+/-0.59 mg (n=29, P=0.099); (P1) 1.89+/-0.29 mg (n=25, P=0.0248) and (P2) 1.92+/-0.15 mg (n=33, P=0.0024). NILT started 12 h following embolization resulted in the following P(50) values: (CW) 2.89+/-1.76 mg (n=29, P=0.279); (P1) 2.40+/-0.99 mg (n=24, P=0.134). At the 6-h post-embolization treatment time, there was a statistically significant increase in P(50) values compared with control for both pulse P1 and P2 modes, but not the CW mode. At the 12-h post-embolization treatment time, neither the CW nor the P1 regimens resulted in statistically significant effect, although there was a trend for an improvement. The results show that P mode NILT can result in significant clinical improvement when administered 6 h following embolic strokes in rabbits and should be considered for clinical development. PMID- 17693029 TI - Neuronal activation by stimuli that predict sexual reward in female rats. AB - Conditioned stimuli (CSs) associated with paced copulation induce a conditioned partner preference for males bearing the CS. Here we examined the activation of Fos immunoreactivity (Fos-IR) following exposure to a CS previously paired with either paced or nonpaced copulation. Ovariectomized, hormone-primed rats received 10 sequential conditioning trials at 4-day intervals. In experiment 1, females in the odor-paired group learned to associate an almond odor on a male with paced copulation and an unscented male with nonpaced copulation. In the odor-unpaired group, females received the opposite association. In experiment 2, females associated two different strains of male, Long-Evans or Wistar, with paced or nonpaced copulation, respectively. A preference test indicated that females in both experiments developed a conditioned preference for the pacing-related males, as indicated by significantly more solicitations toward the male and a preference to copulate with the pacing-related male. Subsequently, females were exposed to the CS (odor or strain) alone for 1 h prior to kill and preparation of their brains for immunocytochemistry. In both experiments, the CS associated with paced copulation produced significantly more Fos-IR in the piriform cortex, medial preoptic area, and ventral tegmental area, relative to the same odor or strain cues associated with nonpaced copulation. These findings provide evidence that the state associated with paced copulation can be conditioned to environmental stimuli such as neutral odors or strain cues, which earn an incentive value via classical conditioning. The significance of the brain areas activated is discussed with regard to their role in sexual and other motivated behaviors. PMID- 17693030 TI - Sex-dependent differences in the activity and modulation of N-methyl-d-aspartic acid receptors in rat dorsal root ganglia neurons. AB - Women have greater temporal summation of experimental pain stimuli and also have a higher propensity for developing chronic visceral pain conditions. Sex hormone mediated regulation of N-methyl-d-aspartic acid receptors (NMDARs) in nociceptive pathways is a plausible mechanism that may underlie these phenomena. The aim of this study was to compare the effect of 17-beta-estradiol (E2) in modulation of NMDAR activity in adult male and female rat dorsal root ganglia (DRG) neurons. DRG neurons were collected from adult male or female rats and grown in short-term culture in steroid-free media. NMDAR currents were recorded on small to medium size neurons by whole cell patch clamp using rapid perfusion with saturating concentrations of N-methyl-d-aspartic acid and glycine in the absence of extracellular Mg(2+). We found that the average density of NMDAR currents was 2.8 fold larger in DRG neurons from female rats compared with male rats (P<0.0001). Addition of 100 nM E2 increased NMDAR currents 55+/-15% in female neurons, but only 19+/-7% in male neurons. Potentiation was maximal after 20-40 min and dose dependent with an apparent 50% excitatory concentration of 17-23 nM. This effect was mimicked by E2 conjugated to BSA and attenuated by pretreatment with the protein tyrosine kinase inhibitor lavendustin A (1 microM) or the estrogen receptor (ER) antagonist, ICI 182,780 (1 microM), strongly suggesting activation of a cell surface ER acting through a non-genomic mechanism involving protein tyrosine kinases to increase NMDAR currents. These results identify sex-based differences in both the basal expression and the regulation of the NMDARs in DRG neurons. PMID- 17693031 TI - Gastric electrical stimulation modulates hypothalamic corticotropin-releasing factor-producing neurons during post-operative ileus in rat. AB - High-frequency/low-energy gastric electrical stimulation (GES) is an efficient therapy to treat gastric emptying-related disorders but its mechanism of action remains poorly understood. We aimed to assess the effects of high-frequency/low energy GES on corticotropin-releasing factor (CRF)-producing neurons in the paraventricular nucleus of the hypothalamus (PVN), which are involved in gastric ileus induced by laparotomy. Two electrodes were implanted in the rat gastric antrum during laparotomy, then stimulation (amplitude: 2 mA; pulse duration 330 micros; frequency: 2 Hz; 1 min ON/2 min OFF) or sham stimulation (control group) were applied. Using immunohistochemistry, the number of c-Fos protein-expressing neurons (c-Fos protein-immunoreactive cells, Fos-IR) was quantified in the PVN after 1 h of stimulation. The number of neurons expressing simultaneously c-Fos protein and CRF mRNA was measured by means of immunocytochemistry combined with in situ hybridization. Finally, c-Fos and CRF mRNA levels in the hypothalamus were determined by in situ hybridization or quantitative reverse transcriptase polymerase chain reaction. Fos-IR in the PVN was significantly decreased 1 h after GES (P<0.05) but was not affected by sub-diaphragmatic vagotomy. The number of neurons containing c-Fos protein and CRF mRNA was lower in the GES group compared with the control group (P<0.05). In addition, c-Fos and CRF mRNA levels in the PVN were significantly decreased by GES (P50% in panic symptoms, clinically significant decreases in asthma symptoms, improvement in asthma quality of life, and maintenance of clinical stability in asthma. Albuterol use decreased significantly in the 14-session protocol and at a borderline level I the 8-session protocol, while pulmonary function was maintained. A controlled evaluation of this procedure is warranted. PMID- 17693055 TI - Use of real-time RT-PCR as a rapid molecular approach for differentiation of field and vaccine strains of bluetongue virus serotypes 2 and 9. AB - Since 2000 severe, long-lasting epidemics of bluetongue virus (BTV) have been described in Italy, caused by BTV serotypes 2, 4, 9 and 16. Vaccination programs have been applied extensively to control the infection, in spite of concerns about the potential dissemination of attenuated vaccine strains of BTV in susceptible animals. Accordingly, rapid and reliable differentiation between vaccine and field strains is paramount in routine diagnosis of BTV to evaluate the extent of this phenomenon. In the present study, we report the development of two real-time RT-PCR assays able to recognise BTV serotypes 2 and 9, respectively, and we evaluated the use of the assays for discrimination between field and vaccine strains. A total of 65 samples collected in Italy from 2000 to 2006 and diagnosed as positive for either BTV-2 or -9 were analysed by the TaqMan assays. Both the assays were found to be highly sensitive and reproducible, ensuring correct serotype characterisation and prediction of the origin of the strains, as confirmed by characterisation using virus neutralisation and sequencing. PMID- 17693056 TI - Differential galanin upregulation in dorsal root ganglia and spinal cord after graded single ligature nerve constriction of the rat sciatic nerve. AB - Single ligature nerve constriction (SLNC) is a newly developed animal model for the study of neuropathic pain. SLNC of the rat sciatic nerve induces pain-related behaviors, as well as changes in the expression of neuropeptide tyrosine and the Y(1) receptor in lumbar dorsal root ganglia (DRGs) and spinal cord. In the present study, we have analyzed the expression of another neuropeptide, galanin, in lumbar DRGs and spinal cord after different degrees of constriction of the rat sciatic nerve. The nerve was ligated and reduced to 10-30, 40-80 or 90% of its original diameter (light, medium or strong SLNCs). At different times after injury (7, 14, 30, 60 days), lumbar 4 and 5 DRGs and the corresponding levels of the spinal cord were dissected out and processed for galanin immunohistochemistry. In DRGs, SLNC induced a gradual increase in the number of galanin-immunoreactive (IR) neurons, in direct correlation with the degree of constriction. Thus, after light SLNC, a modest upregulation of galanin was observed, mainly in small-sized neurons. However, following medium or strong SLNCs, there was a more drastic increase in the number of galanin-IR neurons, involving also medium and large-sized cells. The highest numbers of galanin-IR neurons were detected 14 days after injury. In the dorsal horn of the spinal cord, medium and strong SLNCs induced a marked ipsilateral increase in galanin like immunoreactivity in laminae I-II. These results show that galanin expression in DRGs and spinal cord is differentially regulated by different degrees of nerve constriction and further support its modulatory role on neuropathic pain. PMID- 17693057 TI - Autophagy: highlighting a novel player in the autoimmunity scenario. AB - Autophagy is a physiological cellular mechanism that degrades and recycles proteins and other molecules to maintain an adequate amino acid level during nutritional starvation of the cell. Autophagy is involved in cellular homeostasis and differentiation, as well as in tissue remodeling, aging, cancer, and other diseases. Under particular environmental conditions, autophagy can also be a contributor to programmed cell death, or can act as a defense mechanism for the elimination of intracellular bacteria and viruses. According to recent experimental data, autophagy may be implicated in autoimmunity by promotion of major histocompatibility complex (MHC) class II presentation of cytosolic antigens and control of T lymphocyte homeostasis, and its induction by Th1 cytokines and perhaps by specific serum autoantibodies. We review herein the role of autophagy in immune function and its possible contribution to breakdown of tolerance and development of autoimmunity. PMID- 17693058 TI - Inhibition of RIP and c-FLIP enhances TRAIL-induced apoptosis in pancreatic cancer cells. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has recently emerged as a cancer therapeutic agent because it is capable of preferentially inducing apoptosis in human cancer over normal cells. The majority of human pancreatic cancers, unfortunately, are resistant to TRAIL treatment. Here, we show that the inhibition of caspase-8 cleavage is the most upstream event in TRAIL resistance in pancreatic cancers. TRAIL treatment led to the cleavage of caspase-8 and downstream caspase-9, caspase-3, and DNA fragmentation factor 45 (DFF45) in TRAIL-sensitive pancreatic cancer cell lines (BXPC-3, PACA-2). This caspase-8-initiated caspase cascade, however, was inhibited in TRAIL-resistant pancreatic cancer cell lines (PANC-1, ASPC-1, CAPAN-1, CAPAN-2). The long and short forms of cellular Fas-associated death domain-like interleukin-1beta converting enzyme-inhibitory protein (c-FLIP(L), c-FLIP(S)) were highly expressed in the TRAIL-resistant as compared to the sensitive cells; knockdown of c-FLIP(L) and c-FLIP(S) by a short hairpin RNA (shRNA) rendered the resistant cells sensitive to TRAIL-induced apoptosis through the cleavage of caspase-8 and activation of the mitochondrial pathway. Receptor-interacting protein (RIP) has been reported in TRAIL-induced activation of NF-kappaB and we show here that knockdown of RIP sensitized the resistant cells to TRAIL-induced apoptosis. These results indicate the role of c-FLIP and RIP in caspase-8 inhibition and thus TRAIL resistance. Treatment of the resistant cells with camptothecin, celecoxib and cisplatin resulted in the downregulation of c-FLIP and caused a synergistic apoptotic effect with TRAIL. These studies therefore suggest that combination treatment with chemotherapy can overcome TRAIL resistance and enhance TRAIL therapeutic efficacy in treating pancreatic cancers. PMID- 17693059 TI - Validation of the English and French versions of the Community Assessment of Psychic Experiences (CAPE) with a Montreal community sample. AB - OBJECTIVE: The aim of this study was to examine the reliability, validity and factor structure of the Community Assessment of Psychic Experiences (CAPE), a 42 item self-report questionnaire. We analyzed the internal consistency of the CAPE to determine whether the 3-factor structure (positive, negative and depressive symptoms) found by the CAPE authors would also be found in our sample. METHOD: A sample of 2275 individuals from the general community in the Montreal area completed the questionnaire in either French or English. RESULTS: The internal consistencies of the original three subscales were good and the confirmatory factor models had a good fit. The exploratory factor analysis suggested a 3-5 factor solution, without improving the alternative factor structures. The 4 factor solution separated positive symptoms into factors we called 'bizarre positive symptoms' and 'social delusions', and the 5-factor solution separated positive symptoms further and included a 'popular psychic beliefs' factor. Results suggest that the scalability might be improved by shortening the original questionnaire to 23 items with the same 3 original scales. CONCLUSION: We support the internal consistency of the CAPE. Although alternative scaling (4 and 5 factors) did not improve the model fit, researchers interested in distinguishing 3 factors of positive symptoms could find utility in these two new scales. Finally, reducing the number of CAPE items could be useful for shorter surveys. Future studies should test the implications of these suggestions. PMID- 17693060 TI - How to find the way out from four rooms? The learning of "chaining" associations may shed light on the neuropsychology of the deficit syndrome of schizophrenia. AB - Recent meta-analytic evidence suggests that clinical neuropsychological methods are not likely to uncover circumscribed cognitive impairments in the deficit syndrome of schizophrenia. To overcome this issue, we adapted a cognitive neuroscience perspective and used a new "chaining" habit learning task. Participants were requested to navigate a cartoon character through a sequence of 4 rooms by learning to choose the open door from 3 colored doors in each room. The aim of the game was to learn the full sequence of rooms until the character reached the outside. In the training phase, each stimulus leading to reward (open door in each room) was trained via feedback until the complete sequence was learned. In the probe phase, the context of rewarded stimuli was manipulated: in a given room, in addition to the correct door of that room, there also appeared a door which was open in another room. Whereas the training phase is dominantly related to basal ganglia circuits, the context-dependent probe phase requires intact medial-temporal lobe functioning. Results revealed that deficit and non deficit patients were similarly impaired on the probe phase compared with controls. However, the training phase was only compromised in deficit patients. More severe negative symptoms were associated with more errors on the training phase. Executive functions were unrelated to performance on the "chaining" task. These results indicate that the deficit syndrome is associated with prominently impaired stimulus-response reinforcement learning, which may indicate abnormal functioning of basal ganglia circuits. PMID- 17693061 TI - Effects of Wolbachia on sperm maturation and architecture in Drosophila simulans Riverside. AB - Wolbachia is an intracellular obligate symbiont, that is relatively common in insects and also found in some nematodes. Cytoplasmic incompatibility (CI) is the most commonly expressed form, of several sex altering phenotypes caused by this rickettsial-like bacterium. CI is induced when infected males mate with uninfected females, and is likely the result of bacterial-induced modification of sperm grown in a Wolbachia-infected environment. Several studies have explored the dynamics of Wolbachia bacteria during sperm development in Drosophila. This study confirms and extends these earlier investigations of Wolbachia's distribution and proliferation in male germ cell lines. We examined Wolbachia population dynamics during testis development of Drosophila simulans (Riverside) by studying their distribution during the early mitotic divisions of secondary spermatogonial and subsequent meiotic cyst cells. Wolbachia are found in lower concentration in spermatogonial than in spermatocyte cells. Cytoplasmically incompatible crosses result in low levels of viable embryos despite the occurrence of fairly high levels of uninfected cysts. During meiotic divisions Wolbachia organize themselves at the poles during prophase and telophase but arrange themselves in equatorial bands during metaphase and anaphase. Moreover, during meiosis Wolbachia are asymmetrically divided between some daughter cells. There is no strong relationship between the fusome and Wolbachia and we have not found evidence that bacteria cross the ring canals. Wolbachia were observed at the distal and proximal sides of individualization complexes. Multiple altered sperm structures were observed during the process of individualization of infected sperm. PMID- 17693062 TI - Concerted action of Msx1 and Msx2 in regulating cranial neural crest cell differentiation during frontal bone development. AB - The homeobox genes Msx1 and Msx2 function as transcriptional regulators that control cellular proliferation and differentiation during embryonic development. Mutations in the Msx1 and Msx2 genes in mice disrupt tissue-tissue interactions and cause multiple craniofacial malformations. Although Msx1 and Msx2 are both expressed throughout the entire development of the frontal bone, the frontal bone defect in Msx1 or Msx2 null mutants is rather mild, suggesting the possibility of functional compensation between Msx1 and Msx2 during early frontal bone development. To investigate this hypothesis, we generated Msx1(-/-);Msx2(-/-) mice. These double mutant embryos died at E17 to E18 with no formation of the frontal bone. There was no apparent defect in CNC migration into the presumptive frontal bone primordium, but differentiation of the frontal mesenchyme and establishment of the frontal primordium was defective, indicating that Msx1 and Msx2 genes are specifically required for osteogenesis in the cranial neural crest lineage within the frontal bone primordium. Mechanistically, our data suggest that Msx genes are critical for the expression of Runx2 in the frontonasal subpopulation of cranial neural crest cells and for differentiation of the osteogenic lineage. This early function of the Msx genes is likely independent of the Bmp signaling pathway. PMID- 17693063 TI - A dosage-dependent role for Spry2 in growth and patterning during palate development. AB - The formation of the palate involves the coordinated outgrowth, elevation and midline fusion of bilateral shelves leading to the separation of the oral and nasal cavities. Reciprocal signaling between adjacent fields of epithelial and mesenchymal cells directs palatal shelf growth and morphogenesis. Loss of function mutations in genes encoding FGF ligands and receptors have demonstrated a critical role for FGF signaling in mediating these epithelial-mesenchymal interactions. The Sprouty family of genes encode modulators of FGF signaling. We have established that mice carrying a deletion that removes the FGF signaling antagonist Spry2 have cleft palate. We show that excessive cell proliferation in the Spry2-deficient palate is accompanied by the abnormal progression of shape changes and movements required for medially directed shelf outgrowth and midline contact. Expression of the FGF responsive transcription factors Etv5, Msx1, and Barx1, as well as the morphogen Shh, is restricted to specific regions of the developing palate. We detected elevated and ectopic expression of these transcription factors and disorganized Shh expression in the Spry2-deficient palate. Mice carrying a targeted disruption of Spry2 fail to complement the craniofacial phenotype characterized in Spry2 deletion mice. Furthermore, a Spry2 BAC transgene rescues the palate defect. However, the BAC transgenic mouse lines express reduced levels of Spry2. The resulting hypomorphic phenotype demonstrates that palate development is Spry2 dosage sensitive. Our results demonstrate the importance of proper FGF signaling thresholds in regulation of epithelial mesenchymal interactions and cellular responses necessary for coordinated morphogenesis of the face and palate. PMID- 17693064 TI - Cloning and characterization of a novel MyoD enhancer-binding factor. AB - Glucocorticoid-induced gene-1 (Gig1) was identified in a yeast one-hybrid screen for factors that interact with the MyoD core enhancer. The Gig1 gene encodes a novel C2H2 zinc finger protein that shares a high degree of sequence similarity with two known DNA binding proteins in humans, Glut4 enhancer factor and papillomavirus binding factor (PBF). The mouse ortholog of PBF was also isolated in the screen. The DNA binding domain of Gig1, which contains TCF-E-tail CR1 and CR2 motifs shown to mediate promoter specificity of TCF-E-tail isoforms, was mapped to a C-terminal domain that is highly conserved in Glut4 enhancer factor and PBF. In mouse embryos, in situ hybridization revealed a restricted pattern of expression of Gig1 that overlaps with MyoD expression. A nuclear-localized lacZ knockin null allele of Gig1 was produced to study Gig1 expression with greater resolution and to assess Gig1 functions. X-gal staining of Gig1(nlacZ) heterozygous embryos revealed Gig1 expression in myotomal myocytes, skeletal muscle precursors in the limb, and in nascent muscle fibers of the body wall, head and neck, and limbs through E14.5 (latest stage examined). Gig1 was also expressed in a subset of Scleraxis-positive tendon precursors/rudiments of the limbs, but not in the earliest tendon precursors of the somite (syndetome) defined by Scleraxis expression. Additional regions of Gig1 expression included the apical ectodermal ridge, neural tube roof plate and floor plate, apparent motor neurons in the ventral neural tube, otic vesicles, notochord, and several other tissues representing all three germ layers. Gig1 expression was particularly well represented in epithelial tissues and in a number of cells/tissues of neural crest origin. Expression of both the endogenous MyoD gene and a reporter gene driven by MyoD regulatory elements was similar in wild-type and homozygous null Gig1(nlacZ) embryos, and mutant mice were viable and fertile, indicating that the functions of Gig1 are redundant with other factors. PMID- 17693065 TI - [Laryngospasm with convulsion in an infant. Caution: danger of confusion with the bottles unidoses of chlorhexidine]. PMID- 17693066 TI - [What are the neonatal risks in low-risk pregnancies: implications for the organization of birth centers]. AB - AIM: This study was designed to identify pregnant women at low risk for severe neonatal morbidity. This population should apply for delivery in birth centers. POPULATION AND METHODS: This study was retrospective and included all livebirths in Burgundy over a 4-year period. Fifteen obstetric criteria recorded in the regional perinatal database were used to select pregnant women at low risk for severe neonatal morbidity. Incidence of severe neonatal morbidity in the low and high risk groups was assessed from the following markers: postnatal death; severe neurological conditions (ischemic encephalopathy, seizures, meningitis, intraventricular hemorrhage stage 3-4 and cystic periventricular leukomalacia in preterm infants); tracheal intubation; hospitalization in neonatal intensive care unit. RESULTS: The incidence of severe neonatal morbidity was significantly different (P<0.0001) in the low risk group (0.34% [IC 95%: 0.29-0.40]; N=46345) as compared with the high risk group (5.6% [IC 95%: 5.3-5.9]; N=24961). The main neonatal diseases in the low risk group were: respiratory diseases (29.8%); congenital heart diseases (17.9%) and perinatal asphyxia (15.3%). CONCLUSION: Even though the low risk criteria were associated with a low incidence of severe neonatal morbidity, residual morbidity should be considered in organization of birth centers in France. PMID- 17693067 TI - [Polycythemia vera and JAK-2 mutation in childhood: a case report]. AB - Erythrocytosis is a rare disorder in childhood and is mainly secondary to causes such as long-term chronic cardiopulmonary diseases or haemoglobin dysfunction. In some cases, polycythaemia is found when renal, hepatic or cerebellar tumours are diagnosed. Polycythemia vera (PV) is uncommon in paediatrics and usually clinical and biological features are used to diagnose and classify PV. The V617F mutation of JAK-2 has been described recently and is found in almost 90% of adult patients with PV. This mutation allows now a reliable and early diagnosis. Therapeutic management is based on phlebotomy and cytoreductive therapy. In young adults and children, interferon alpha is theoretically superior as it is effective and there is no risk of inducing leukemia. We report here a case of PV in a 10-year-old girl with the V617F JAK-2 mutation. PMID- 17693068 TI - Malignant tumours of the heart: a review of tumour type, diagnosis and therapy. AB - Primary cardiac neoplasms are rare and occur less commonly than metastatic disease of the heart. In this overview, current published studies concerning malignant neoplasms of the heart are reviewed, together with some insights into their aetiology, diagnosis and management. We searched medline using the subject 'cardiac neoplasms'. We selected about 110 articles from between 1973 and 2006, of which 76 sources were used to complete the review. Sarcomas are the most common cardiac tumours and include myxosarcoma, liposarcoma, angiosarcoma, fibrosarcoma, leiomyosarcoma, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, neurofibrosarcoma, malignant fibrous histiocytoma and undifferentiated sarcoma. The classic symptoms of cardiac tumours are intracardiac obstruction, signs of systemic embolisation, and systemic or constitutional symptoms. However, serious complications including stroke, myocardial infarction and even sudden death from arrhythmia may be the first signs of a tumour. Echocardiography and angiography are essential diagnostic tools for evaluating cardiac neoplasms. Computed tomography and magnetic resonance imaging studies have improved the diagnostic approach in recent decades. Successful treatment for benign cardiac tumours is usually achieved by surgical resection. Unfortunately, resection of the tumour is not always feasible. The prognosis after surgery is usually excellent in the case of benign tumours, but the prognosis of malignant tumours remains dismal. In conclusion, there are limited published data concerning cardiac neoplasms. Therefore, a high level of suspicion is required for early diagnosis. Surgery is the cornerstone of therapy. However, a multi-treatment approach, including chemotherapy, radiation as well as evolving approaches such as gene therapy, might provide a better palliative and curative result. PMID- 17693069 TI - The effect of altering the 20:5n-3 and 22:6n-3 content of a meal on the postprandial incorporation of n-3 polyunsaturated fatty acids into plasma triacylglycerol and non-esterified fatty acids in humans. AB - Previous studies suggest that consuming meals containing large amounts of fish oil is associated with selective postprandial incorporation of 20:5n-3 and 22:6n 3 into plasma non-esterified fatty acids (NEFA). We investigated the effect of consuming meals containing different amounts of 20:5n-3 and 22:6n-3 comparable to dietary habits of western populations on the postprandial incorporation of 18:3n 3, 20:5n-3 and 22:6n-3 into plasma triacylglycerol (TAG) and NEFA over 6h in middle aged subjects. 20:5n-3 incorporation into plasma TAG was greater than 22:6n-3 irrespective of the test meal. Conversely, 22:6n-3 incorporation into plasma NEFA was greater than 20:5n-3, irrespective of the test meal. There was no effect of the amount of 20:5n-3+22:6n-3 in the test meal on the 18:3n-3 incorporation into plasma TAG or NEFA. These findings suggest differential metabolism of 20:5n-3 and 22:6n-3 in the postprandial period when consumed in amounts typical of western dietary habits. PMID- 17693070 TI - Lipid composition of spermatozoa in normozoospermic and asthenozoospermic males. AB - INTRODUCTION: Lipids play an important role in the structural and functional activity of spermatozoa. We investigated the phospholipids composition and fatty acid-bound phospholipid of spermatozoa from asthenozoospermic and normozoospermic men. PATIENTS AND METHODS: Semen samples were analyzed in 15 asthenozoospermic and eight normozoospermic subjects and the sperm phospholipids and fatty acids were determined using high performance thin layer chromatography and gas chromatography, respectively. RESULTS: The most abundant (mean+/-SE) phospholipids in normozoospermic and asthenozoospermic samples were phosphatidylethanolamine (70.9+/-11.5 and 44.2+/-8.5 nmol/10(8) spermatozoa, respectively) and phosphatidylcholine (58.6+/-9.5 and 34.6+/-3.2 nmol/10(8) spermatozoa, respectively). Compared to normozoospermic samples, asthenozoospermic samples showed lower levels of polyunsaturated fatty acids (PUFA; p<0.01) and higher levels of saturated fatty acids (SFA; p<0.05). DISCUSSION: Changes in content of phospholipids and its fatty acid composition of spermatozoa may be related to infertility in asthenozoospermic males. PMID- 17693071 TI - Breath condensate nitrite correlates with hyperinflation in chronic obstructive pulmonary disease. AB - Estimating the degree of pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) is not always straight forward. Standard pulmonary function tests provide only a crude estimate of this important aspect of COPD. In addition, good patient cooperation cannot always be achieved and therefore adds to the uncertainties with regard to the extent of hyperinflation of the lung. The aim of this investigation was to characterize exhaled breath condensate nitrite in volunteers, healthy smokers, and stable COPD (GOLD-stages 0-4) and to compare this parameter with inflammatory markers in exhaled breath condensate and with lung function in order to test the hypothesis that elevated exhaled breath condensate nitrite reflects hyperinflation in COPD. We found a logarithmic correlation of exhaled breath condensate nitrite to residual volume (r=0.75, p<0.0001), total lung capacity (r=0.51, p<0.0001), and thoracic gas volume (r=0.71, p<0.0001) but no correlation of exhaled breath condensate nitrite concentrations with levels of inflammatory cytokines in exhaled breath condensate (interleukin (IL)-8, IL-1beta, IL-6, IL-10, IL-12, and tumor necrosis factor alpha). Analysis of COPD subgroups revealed a logarithmic correlation of EBC nitrite to residual volume, total lung capacity, and intrathoracic gas volume exclusively for patients characterized by GOLD classes 2, and higher. Our results confirm a relation of exhaled breath condensate nitrite levels and hyperinflation measured by conventional pulmonary function tests. Investigations using isolated lung models and cells stretched in culture also provide insight into this relation. Exhaled breath condensate nitrite may be a biochemical indicator of pulmonary overdistension. PMID- 17693072 TI - The prevalence of alpha(1)-antitrypsin deficiency in a representative population sample from Poland. AB - AIM: Severe alpha(1)-antitrypsin (AAT) deficiency is one of the most common genetic disorders in Caucasians. The aim of the present study was to assess an unbiased frequencies of PI*S and PI*Z alleles using genotyping of a representative sample from the general population of Poland. METHODS: A random sample of age- and gender-stratified residents, aged 20 years or older, was drawn from the municipal directory of Krakow, Poland. The two most common deficiency alleles: PI*S and PI*Z were genotyped with qualitative real-time PCR using degenerative dual-labeled allele-specific fluorescent probes. RESULTS: In the total population of 859 adult subjects (mean age: 49.5 years; range: 20-90), 28 heterozygotes MS, 18 heterozygotes MZ and one homozygote S were diagnosed. The frequency of PI*S allele was 17.5 (95% CI: 11.6-23.9) per 1000; and that of PI*Z was 10.5 (95% CI: 5.8-15.7) per 1000. Therefore, the estimated prevalence of inherited severe AAT deficiency (homozygotes Z) in Poland is 1/9110 (95% CI: 1/4057-1/29,727). CONCLUSIONS: In the whole population of Poland comprising 38 millions, one may expect of about 4189 (95% CI: 1284-9406) subjects with severe AAT deficiency. These numbers are high enough to consider genetic testing being introduced into a common clinical practice. PMID- 17693073 TI - Comparative biology: beyond sequence analysis. AB - Comparative analysis is a fundamental tool in biology. Conservation among species greatly assists the detection and characterization of functional elements, whereas inter-species differences are probably the best indicators of biological adaptation. Traditionally, comparative approaches were applied to the analysis of genomic sequences. With the growing availability of functional genomic data, comparative paradigms are now being extended also to the study of other functional attributes, most notably the gene expression. Here we review recent works applying comparative analysis to large-scale gene expression datasets and discuss the central principles and challenges of such approaches. PMID- 17693074 TI - Anesthetic management of thoracotomy for spontaneous pneumothorax in a pregnant woman. PMID- 17693075 TI - Ultra-low dose combined spinal-epidural anaesthesia. PMID- 17693076 TI - Internal carotid artery dissection: an unusual cause of postpartum headache. AB - We report a case of postpartum headache caused by internal carotid artery dissection in a 36-year-old woman following uneventful epidural analgesia for spontaneous labor and vaginal delivery. Cervicocerebral arterial dissection requires rapid diagnosis and anticoagulation to prevent thrombus formation and to avoid secondary cerebral thromboembolism. Fortunately, our patient suffered ischemic symptoms, but no permanent neurologic deficit. Anesthesiologists should consider carotid artery dissection in the differential diagnosis of postpartum headache. PMID- 17693077 TI - Anesthetic management of labor in a patient with congenitally corrected transposition of the great arteries. AB - Laboring patients with congenitally corrected transposition of the great arteries present an interesting challenge to anesthesiologists because of the physiological changes that take place during pregnancy and the stress induced by labor. This paper describes the detailed management of a symptomatic parturient with congenitally corrected transposition of the great arteries. The patient was managed with epidural analgesia instituted early in labor with a continuous low concentration infusion of local anesthetic and opioid but without an initial bolus. She underwent uneventful forceps-assisted vaginal delivery. PMID- 17693078 TI - An observational study of the relationship between lumbar epidural space depth and body mass index in Michigan parturients. AB - BACKGROUND: Studies of urban parturient populations demonstrate increasing prevalence of obesity, which contributes to difficult epidural catheter placement. The aim of this study was to characterize the relationship between lumbar epidural space depth and body mass index in United States parturients from Michigan. METHODS: We studied the records of 2009 parturients at or beyond 36 weeks' gestation. In addition to lumbar epidural space depth and body mass index, we recorded maternal age, gestational age and vertebral interspace of epidural placement. A multi-linear regression model was created with centimeter depth from skin to lumbar epidural space as the dependent variable and body mass index as the independent variable, adjusted for maternal age, gestational age and vertebral interspace. RESULTS: Lumbar epidural space depth was (mean +/- SD) 5.3 cm+/-1.21, with more than 96% of catheters placed at L2-3 or L3-4. Mean body mass index was 31.5+/-6.2 kg/m(2). Mean maternal age was 29.3+/-5.7 years while mean gestational age was 39.3+/-1.3 weeks. In a multi-linear regression model, body mass index and maternal age were significant predictors of centimeter depth. When adjusted for maternal age, gestational age and vertebral interspace of catheter placement, body mass index was associated with an increase in depth (P<0.0001, R(2)=0.3646). Maternal age, when adjusted for body mass index and vertebral interspace, was associated with a decreased depth (P=0.0014). CONCLUSION: When maternal age, gestational age and vertebral interspace are controlled for, increasing body mass index is associated with increasing depth, while increasing maternal age is associated with decreasing depth. PMID- 17693079 TI - Undiagnosed myasthenia gravis masquerading as eclampsia. AB - This case describes an apparently healthy 21-year-old parturient who presented at term with a prolapsed cord requiring immediate cesarean section. She experienced postoperative seizures. After a presumptive diagnosis of eclampsia, magnesium sulfate was given. During a complicated postoperative course, ventilatory failure necessitating multiple intubations eventually led to a new diagnosis of myasthenia gravis. This report describes how the signs and symptoms of myasthenia gravis may mimic post-partum eclampsia as well as worsen the side effects of magnesium therapy. PMID- 17693080 TI - Spinal anaesthesia: are two pairs of hands better than one? PMID- 17693081 TI - Technical difficulties and complication rates associated with the use of combined spinal-epidural anaesthesia for caesarean section. PMID- 17693082 TI - Epidural volume extension and low-dose sequential combined spinal-epidural blockade: two ways to reduce spinal dose requirement for caesarean section. PMID- 17693083 TI - Successful spinal blockade in a parturient with myotonia congenita. PMID- 17693084 TI - Differential expression of cyclin-dependent kinase inhibitors and apoptosis related proteins in endocervical lesions. AB - The development of neoplasia is associated with abnormalities of cell cycle control and apoptosis. In this study, a panel of cyclin-dependent kinase inhibitors (CDKIs) and apoptosis-related proteins (p16, p21, p53, Bcl2 and hsp27) was analysed by immunohistochemistry in 91 glandular cervical lesions. A significant increase in p21 and p53 expression occurred from normal cervix (n=11) through endometriosis/tubo-endometrioid metaplasia (TEM) (n=19) and cervical glandular intraepithelial neoplasia (CGIN)/adenocarcinoma in situ (AIS) (n=33) to invasive adenocarcinoma (n=28). p16 showed diffuse strong expression in CGIN/AIS and invasive adenocarcinoma compared with focal expression in some TEM/endometriosis lesions and no expression in normal cervix. Bcl2 was highly expressed in TEM/endometriosis compared with CGIN/AIS and adenocarcinoma. p16 immunostaining discriminated accurately between neoplastic and non-neoplastic cervical lesions, provided that diffuse strong positivity was present. Similarly, diffuse expression of Bcl2 distinguished endometriosis/TEM from CGIN/AIS. These data demonstrate that analysis of CDKIs and apoptosis-related proteins provides useful information in the diagnostic assessment of glandular lesions of the cervix. PMID- 17693085 TI - New distributed activation energy model: numerical solution and application to pyrolysis kinetics of some types of biomass. AB - In the present paper, a new distributed activation energy model has been developed, considering the reaction order and the dependence of frequency factor on temperature. The proposed DAEM cannot be solved directly in a closed from, thus a method was used to obtain the numerical solution of the new DAEM equation. Two numerical examples to illustrate the proposed method were presented. The traditional DAEM and new DAEM have been used to simulate the pyrolytic process of some types of biomass. The new DAEM fitted the experimental data much better than the traditional DAEM as the dependence of the frequency factor on temperature was taken into account. PMID- 17693086 TI - Synthetic tyrosyl gallate derivatives as potent melanin formation inhibitors. AB - Three tyrosyl gallate derivatives (1-3) with variable hydroxyl substituent at the aromatic ring of tyrosol were synthesized and evaluated as potent inhibitors on tyrosinase activity and melanin formation in melan-a cells. Among three tyrosyl gallate derivatives, 4-hydroxyphenethyl 3,4,5-trihydroxybenote (1) (IC(50)=4.93 microM), 3-hydroxyphenethyl 3,4,5-trihydroxybenote (2) (IC(50)=15.21 microM), and 2-hydroxyphenethyl 3,4,5-trihydroxybenote (3) (IC(50)=14.50 microM) exhibited significant inhibitory effect on tyrosinase activity. Compound 1 was the most active compound, though it did not show the inhibitory effect on melanin formation in melan-a cells. However, compounds 2 (IC(50)=8.94 microM) and 3 (IC(50)=13.67 microM) significantly suppressed the cellular melanin formation without cytotoxicity. This study shows that the position of hydroxyl substituent at the aromatic ring of tyrosol plays an important role in the intracellular regulation of melanin formation in cell-based assay system. PMID- 17693087 TI - Between-day reliability of repeated plantar pressure distribution measurements in a normal population. AB - The objective of this study was to determine the reliability of repeated plantar pressure distribution measurements during normal gait across multiple testing sessions. Testing sessions were conducted on 5 separate days at approximately the same time of day. Nine subjects (five males, four females, age 26+/-8.4 years) who were free of any musculoskeletal injury were recruited. A capacitive pressure distribution platform (EMED AT, Novel GmbH, Munich, Germany), sampling at 50Hz was used to collect plantar pressure patterns during barefoot walking at a self selected speed. Four parameters were investigated: peak pressure, maximum force, impulse, and contact time, and these were investigated in 10 areas of the foot after using the PRC mask method of subdividing the foot into ten anatomical areas of interest. Individual means of all the five repeated trials for each foot were calculated, and these values were used to calculate intraclass correlation coefficients (ICC) and coefficients of variation (CoV) for all parameters. The results of this investigation show a generally good level of reliability, the quality of which is dependent on the region of the foot and the parameter investigated. Areas with typically high loading characteristics, such as the central forefoot showed a higher level of reliability in the ICC's (>0.9) than less loaded areas such as the medial midfoot (<0.8). The conclusion of this study is that plantar pressure distribution measurements can be used in comparative evaluations since the measures of repeatability are satisfactory for the parameters and foot regions usually used in the investigation of clinical populations such as neuropathic diabetics. PMID- 17693088 TI - Code and context: Prochlorococcus as a model for cross-scale biology. AB - Prochlorococcus is a simple cyanobacterium that is abundant throughout large regions of the oceans, and has become a useful model for studying the nature and regulation of biological diversity across all scales of complexity. Recent work has revealed that environmental factors such as light, nutrients and predation influence diversity in different ways, changing our image of the structure and dynamics of the global Prochlorococcus population. Advances in metagenomics, transcription profiling and global ecosystem modeling promise to deliver an even greater understanding of this system and further demonstrate the power of cross scale systems biology. PMID- 17693089 TI - Are promyelocytic leukaemia protein nuclear bodies a scaffold for caspase-2 programmed cell death? AB - Promyelocytic leukaemia protein nuclear bodies (PML-NBs) are nuclear structures whose function is still poorly understood. They are implicated in various biological functions, such as viral infection, cellular transformation, innate immunity and growth control, and they might be dynamic hubs sensing stress and DNA damage. Data from PML(-/-) mice suggest that PML-NBs are involved in apoptosis via caspase-independent mechanisms, probably involving p53-dependent and independent pathways. However, the recently demonstrated co-localization of caspase-2 within the PML-NB nuclear structures presents a new paradigm for nuclear cell death. Here, we show that these nuclear structures have a protein known as SP100 that could contain a caspase recruitment domain (CARD). If verified experimentally, this discovery will suggest a mechanism by which caspase 2 could be recruited into the complex and ultimately lead to apoptosis. PMID- 17693090 TI - Metallocene-based antimalarials: an exploration into the influence of the ferrocenyl moiety on in vitro antimalarial activity in chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. AB - To establish the role of the ferrocenyl moiety in the antiplasmodial activity of ferroquine, compounds in which this moiety is replaced by the corresponding ruthenium-based moieties were synthesized and evaluated. In both the sensitive (D10) and resistant (K1) strains of Plasmodium falciparum, ruthenoquine analogues showed comparable potency to ferroquine. This suggests that a probable role of the ferrocenyl fragment is to serve simply as a hydrophobic spacer group. In addition, ferroquine analogues with different aromatic substituents were synthesized and evaluated. Unexpectedly high activity for quinoline compounds lacking the 7-chloro substituent suggests the ferrocenyl moiety may have an additive and/or synergistic effect. PMID- 17693091 TI - Atomic force microscopy observation of peroxynitrite-induced erythrocyte cytoskeleton reorganization. AB - Atomic force microscopy (AFM) was used to study surface layers of fixed intact erythrocytes. Advantages of simultaneous analysis of surface topography and lateral force maps in the investigation of cytoskeleton structure were shown. Fractal analysis was applied to the lateral force maps of erythrocyte surfaces to evaluate the complexity of the cytoskeleton. Peroxynitrite was used as an oxidant to induce changes in the cytoskeleton structure of intact erythrocytes. Peroxynitrite action on whole blood leads to local abnormalities in the erythrocyte cytoskeleton structure, as well as cytoskeleton reorganization in protruded regions of crenated erythrocytes. PMID- 17693092 TI - Scanning electron microscopy study on nanoemulsions and solid lipid nanoparticles containing high amounts of ceramides. AB - Ceramides are the most important intercellular lipids of the stratum corneum, regulating the barrier function of the skin and participating as second signal messenger in stress-induced apoptosis. The high lipophilicity of ceramides presents a pharmacological problem. In order to overcome this problem two lipophilic delivery systems were used for the incorporation of the ceramides: (1) nanoemulsions (NE) and (2) solid lipid nanoparticles (SLN). The influence of the incorporation of ceramides on the particle shape, size and Polydispersity Index was investigated by photon correlation spectroscopy (PCS) and scanning electron microscopy (SEM). The results showed that NE can incorporate larger amounts of ceramides than SLN (up to 23.2% and 5% of lipid matrix, respectively) without any significant alteration on the morphology of the dispersed particles. The incorporation of higher amounts of ceramides into SLN, leads to anisometric platelet-like formations that are known to be caused by the transition of triglycerides from alpha- to beta-mesomorph. The results of this study can be useful for the design of appropriate delivery systems and for further pharmacological evaluations. PMID- 17693093 TI - Evaluation of the ethanol intake on the Calomys callosus seminal vesicle structure. AB - The effects of chronic alcohol ingestion on the structure of the glandular epithelium of the seminal vesicle of the rodent Calomys callosus were analyzed in 24 adult animals aged 3 months divided into three experimental groups. The control group received a solid diet and tap water, the alcoholic group received the same solid diet and ethanol P.A. diluted 20% in water (v/v) for 4 months. The abstinent group received the same liquid diet of the alcoholic one for the same period and after that the alcoholic diet was changed by water for a period of 3 months. After treatment, all animals were anesthetized, weighed and sacrificed. At the end of treatment, mean body weight did not differ between animal groups. The glandular epithelial cells of the alcoholic and abstinent groups showed atrophy and ultrastructural alterations such as the presence of altered nuclei, intense dilatation of the cisterns of the granular endoplasmic reticulum, intense digestive vacuoles and lipid droplets. Ethanol ingestion provokes marked lesions on the epithelium of the seminal vesicle probably interfering on the glandular secretion. PMID- 17693094 TI - Commonalities in fly embryogenesis and mammalian pituitary patterning. AB - During embryonic development, morphogenetic gradients can specify the formation of gene expression territories. Here, we explore possible commonalities between pattern formation in the Drosophila blastoderm and murine pituitary. Shared principles include the need for positive feedback involving fate-determining genes to maintain a differentiated state, and the existence of intra- or extracellular inhibitory signals that improve spatial resolution of neighboring territories. The precision of spatial segregation is, however, limited by stochastic gene expression. Variability in gene expression at territory boundaries might give rise to a poorly differentiated pool of cells, which could harbor stem-like properties. The ideas outlined here deserve further theoretical and experimental exploration. PMID- 17693095 TI - Abdominal adiposity and the polycystic ovary syndrome. AB - Abdominal adiposity, overweightness and obesity are frequently present in patients with polycystic ovary syndrome (PCOS). A large body of evidence suggests that abdominal adiposity and the resulting insulin resistance contribute to ovarian and, possibly, adrenal hyperandrogenism. However, androgen excess itself might also contribute to abdominal fat deposition in hyperandrogenic women. Recent genomic and proteomic analyses of visceral fat from PCOS patients have detected differences in gene expression and protein content compared with those of non-hyperandrogenic women. Here we review the existing evidence for a vicious circle whereby androgen excess favoring the abdominal deposition of fat further facilitates androgen secretion by the ovaries and adrenals in PCOS patients. PMID- 17693096 TI - Fragmentation of multiply-charged intact protein ions using MALDI TOF-TOF mass spectrometry. AB - Top down proteomics in a TOF-TOF instrument was further explored by examining the fragmentation of multiply charged precursors ions generated by matrix-assisted laser desorption ionization. Evaluation of sample preparation conditions allowed selection of solvent/matrix conditions and sample deposition methods to produce sufficiently abundant doubly and triply charged precursor ions for subsequent CID experiments. As previously reported, preferential cleavage was observed at sites C-terminal to acidic residues and N-terminal to proline residues for all ions examined. An increase in nonpreferential fragmentation as well as additional low mass product ions was observed in the spectra from multiply charged precursor ions providing increased sequence coverage. This enhanced fragmentation from multiply charged precursor ions became increasingly important with increasing protein molecular weight and facilitates protein identification using database searching algorithms. The useable mass range for MALDI TOF-TOF analysis of intact proteins has been expanded to 18.2 kDa using this approach. PMID- 17693097 TI - Three-dimensional elemental mapping of phosphorus by quantitative electron spectroscopic tomography (QuEST). AB - We describe the development of quantitative electron spectroscopic tomography (QuEST), which provides 3-D distributions of elements on a nanometer scale. Specifically, it is shown that QuEST can be applied to map the distribution of phosphorus in unstained sections of embedded cells. A series of 2-D elemental maps is derived from images recorded in the energy filtering transmission electron microscope for a range of specimen tilt angles. A quantitative 3-D elemental distribution is then reconstructed from the elemental tilt series. To obtain accurate quantitative elemental distributions it is necessary to correct for plural inelastic scattering at the phosphorus L(2,3) edge, which is achieved by acquiring unfiltered and zero-loss images at each tilt angle. The data are acquired automatically using a cross correlation technique to correct for specimen drift and focus change between successive tilt angles. An algorithm based on the simultaneous iterative reconstruction technique (SIRT) is implemented to obtain quantitative information about the number of phosphorus atoms associated with each voxel in the reconstructed volume. We assess the accuracy of QuEST by determining the phosphorus content of ribosomes in a eukaryotic cell, and then apply it to estimate the density of nucleic acid in chromatin of the cell's nucleus. From our experimental data, we estimate that the sensitivity for detecting phosphorus is 20 atoms in a 2.7 nm-sized voxel. PMID- 17693098 TI - Nuclear gene sequences resolve species phylogeny and mitochondrial introgression in Leptocarabus beetles showing trans-species polymorphisms. AB - We studied the phylogenetic relationships among Japanese Leptocarabus ground beetles, which show extensive trans-species polymorphisms in mitochondrial gene genealogies. Simultaneous analysis of combined nuclear data with partial sequences from the long-wavelength rhodopsin, wingless, phosphoenolpyruvate carboxykinase, and 28S rRNA genes resolved the relationships among the five species, although separate analyses of these genes provided topologies with low resolution. For both the nuclear gene tree resulting from the combined data from four genes and a mitochondrial cytochrome oxidase subunit I (COI) gene tree, we applied a Bayesian divergence time estimation using a common calibration method to identify mitochondrial introgression events that occurred after speciation. Three mitochondrial lineages shared by two or three species were likely subject to introgression due to interspecific hybridization because the coalescent times for these lineages were much shorter than the corresponding speciation times estimated from nuclear gene sequences. We demonstrated that when species phylogeny is fully resolved with nuclear gene sequence data, comparative analysis of nuclear and mitochondrial gene trees can be used to infer introgressive hybridization events that might cause trans-species polymorphisms in mitochondrial gene trees. PMID- 17693099 TI - Knee Images Digital Analysis (KIDA): a novel method to quantify individual radiographic features of knee osteoarthritis in detail. AB - OBJECTIVE: Radiography is still the golden standard for imaging features of osteoarthritis (OA), such as joint space narrowing, subchondral sclerosis, and osteophyte formation. Objective assessment, however, remains difficult. The goal of the present study was to evaluate a novel digital method to analyse standard knee radiographs. METHODS: Standardized radiographs of 20 healthy and 55 OA knees were taken in general practise according to the semi-flexed method by Buckland Wright. Joint Space Width (JSW), osteophyte area, subchondral bone density, joint angle, and tibial eminence height were measured as continuous variables using newly developed Knee Images Digital Analysis (KIDA) software on a standard PC. Two observers evaluated the radiographs twice, each on two different occasions. The observers were blinded to the source of the radiographs and to their previous measurements. Statistical analysis to compare measurements within and between observers was performed according to Bland and Altman. Correlations between KIDA data and Kellgren & Lawrence (K&L) grade were calculated and data of healthy knees were compared to those of OA knees. RESULTS: Intra- and inter-observer variations for measurement of JSW, subchondral bone density, osteophytes, tibial eminence, and joint angle were small. Significant correlations were found between KIDA parameters and K&L grade. Furthermore, significant differences were found between healthy and OA knees. CONCLUSION: In addition to JSW measurement, objective evaluation of osteophyte formation and subchondral bone density is possible on standard radiographs. The measured differences between OA and healthy individuals suggest that KIDA allows detection of changes in time, although sensitivity to change has to be demonstrated in long-term follow-up studies. PMID- 17693100 TI - Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) is closely associated with the chondrocyte nucleus in human articular cartilage. AB - OBJECTIVE: Insulin-like growth factor-I (IGF-I) is critically involved in the control of cartilage matrix metabolism. It is well known that IGF-binding protein 3 (IGFBP-3) is increased during osteoarthritis (OA), but its function(s) is not known. In other cells, IGFBP-3 can regulate IGF-I action in the extracellular environment and can also act independently inside the cell; this includes transcriptional gene control in the nucleus. These studies were undertaken to localize IGFBP-3 in human articular cartilage, particularly within cells. DESIGN: Cartilage was dissected from human femoral heads derived from arthroplasty for OA, and OA grade assessed by histology. Tissue slices were further characterized by extraction and assay of IGFBPs by IGF ligand blot (LB) and by enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry (IHC) for IGF-I and IGFBP-3 was performed on cartilage from donors with mild, moderate and severe OA. Indirect fluorescence and immunogold-labeling IHC studies were included. RESULTS: LBs of chondrocyte lysates showed a strong signal for IGFBP-3. IHC of femoral cartilage sections at all OA stages showed IGF-I and IGFBP-3 matrix stain particularly in the top zones, and closely associated with most cells. A prominent perinuclear/nuclear IGFBP-3 signal was seen. Controls using non-immune sera or antigen-blocked antibody showed negative or strongly reduced stain. In frozen sections of human ankle cartilage, immunofluorescent IGFBP-3 stain co-localized with the nuclear 4',6-diamidino-2-phenyl indole (DAPI) stain in greater than 90% of the cells. Immunogold IHC of thin sections and transmission electron immunogold microscopy of ultra-thin sections showed distinct intra-nuclear staining. CONCLUSIONS: IGFBP-3 in human cartilage is located in the matrix and within chondrocytes in the cytoplasm and nuclei. This new finding indicates that the range of IGFBP-3 actions in articular cartilage is likely to include IGF independent roles and opens the door to studies of its nuclear actions, including the possible regulation of hormone receptors or transcriptional complexes to control gene action. PMID- 17693101 TI - Influence of concomitant heeled footwear when wearing a lateral wedged insole for medial compartment osteoarthritis of the knee. AB - OBJECTIVE: To compare the influence of concomitant heeled footwear when wearing a lateral wedged insole for medial compartment of osteoarthritis (OA) of the knee, between everyday walking shoes for outdoor use and socks or flat footwear without a heel for indoor use. DESIGN: A total of 227 outpatients were prospectively randomized and treated with a neutral wedged insole inserted into shoes (placebo with shoes; n=45), a wedged insole inserted into shoes (inserted insole with shoes; n=45), a sock-type ankle supporter with a wedged insole when wearing socks or flat footwear (inserted insole without shoes; n=46), a subtalar strapped insole when wearing shoes (strapped insole with shoes; n=45), and the strapped insole with socks or flat footwear (strapped insole without shoes; n=46). The Lequesne index of knee OA at week 12 was compared with the baseline in each treatment group. RESULTS: Twenty patients withdrew from the study, and the 207 patients who completed the 12-week study were evaluated. At the final assessment, participants wearing the inserted insole without shoes (P=0.003), the strapped insole with shoes (P<0.0001), and the strapped insole without shoes (P<0.0001) demonstrated significantly improved Lequesne index scores in comparison with their baseline assessments. No significant differences were found in the placebo (P=0.16) or the inserted insole with shoes (P=0.2) groups. CONCLUSION: Concomitant heeled footwear may decrease the efficacy of an inserted lateral wedged insole. The optimal usage of a lateral wedged insole for knee OA would be the combination with socks or flat footwear without heels. PMID- 17693102 TI - Human chitotriosidase polymorphisms G354R and A442V associated with reduced enzyme activity. AB - A common polymorphism in the chitotriosidase gene (CHIT1) exists in which a 24 bp duplication in exon 10 results in aberrant splicing and deletion of 87 nucleotides. In this study, the gene frequency was found to be 0.56 (n=2054) in subjects of Asian ancestry, 0.17 (n=984) in subjects of European ancestry and 0.07 (n=536) in subjects of African ancestry. Notably, the median enzyme activity in wild-type subjects (TT) was much higher in subjects of European ancestry (2.69 mU/ml, n=202 subjects), than subjects of African (2.57 mU/ml, n=230 subjects) (P<0.0001) and Asian ancestry (0.86 mU/ml, n=114 subjects) (P<0.0001). The question of why chitotriosidase deficiency exists at such a high frequency is a challenging one. We postulated that if there was a selective advantage for chitotriosidase deficiency then there would be polymorphisms that would be associated with reduced enzyme activity independent of the 24 bp duplication. We found that the G102S and the A442G polymorphisms found occurring in subjects of all ancestries were not significantly associated with a reduction of enzyme activity. In contrast, the G354R (P<0.0001) and the A442V (P=0.0013) polymorphisms occurring predominantly in subjects of African ancestry were significantly associated with reduced chitotriosidase activity. We also investigated the possibility that chitotriosidase deficiency was associated with tuberculosis or with atopy, including allergic rhinitis, contact dermatitis, food or drug allergies and asthma. PMID- 17693103 TI - COPII under the microscope. AB - Transport through the secretory pathway begins with COPII regulation of ER export. Driven by the Sar1 GTPase cycle, cytosolic COPII proteins exchange on and off the membrane at specific sites on the ER to regulate cargo exit. Here recent developments in COPII research are discussed, particularly the use of live-cell imaging, which has revealed surprising insights into the coat's role. The seemingly static ER exit sites are in fact highly dynamic, and the ability to visualise trafficking processes in intact living cells has highlighted the adaptable nature of COPII in cargo transport and the emerging roles of auxiliary factors. PMID- 17693105 TI - Coated vesicles in plant cells. AB - Coated vesicles represent vital transport intermediates in all eukaryotic cells. While the basic mechanisms of membrane exchange are conserved through the kingdoms, the unique topology of the plant endomembrane system is mirrored by several differences in the genesis, function and regulation of coated vesicles. Efforts to unravel the complex network of proteins underlying the behaviour of these vesicles have recently benefited from the application in planta of several molecular tools used in mammalian systems, as well as from advances in imaging technology and the ongoing analysis of the Arabidopsis genome. In this review, we provide an overview of the roles of coated vesicles in plant cells and highlight salient new developments in the field. PMID- 17693104 TI - MMPs as therapeutic targets--still a viable option? AB - Matrix metalloproteinases (MMPs) appear to be ideal drug targets--they are disease-associated, extracellular enzymes with a dependence on zinc for activity. This apparently straightforward target, however, is much more complex than initially realized. Although disease associated, the roles for particular enzymes may be healing rather than harmful making broad-spectrum inhibition unwise; targeting the catalytic zinc with specificity is difficult, since other related proteases as well as non-related proteins can be affected by some chelating groups. While the failure of early-generation MMP inhibitors dampened enthusiasm for this type of drug, there has recently been a wealth of studies examining the basic biology of MMPs which will greatly inform new drug trials in this field. PMID- 17693107 TI - Tiotropium improves FEV1 in patients with COPD irrespective of smoking status. AB - This study evaluated whether the effect of tiotropium on the change in trough forced expiratory volume in 1s (FEV1), vs. placebo, is affected by smoking status. In a 3-month, double-blind study in 31 centres in Portugal, 311 (289 completed) patients were randomised to tiotropium 18 microg once daily or placebo. Baseline mean (standard deviation (SD)) FEV1 was 1.11 (0.39) l in the tiotropium group and 1.13 (0.39) l in the placebo group. Patients had an average smoking history of 55 (25.7) pack-years; 80 (26%) were smokers and 224 (74%) were ex-smokers. The primary end-point was change in morning pre-dose (i.e. trough) FEV1 after 12 weeks. Trough FEV1 at 12 weeks was significantly improved with tiotropium vs. placebo: the difference in means was 102 ml, P=0.0011, 95% confidence interval (CI) (41, 164). The difference in means in smokers was 138 ml, P=0.0105, CI (32, 244); in ex-smokers it was 66 ml, P=0.0375, CI (3, 129). The difference between smokers and ex-smokers was not statistically significant (P=0.6982) and may be due to greater variability and differences in disease severity. The significant improvement in lung function in patients treated with tiotropium vs. placebo in both smokers and ex-smokers suggests that tiotropium is an effective and well-tolerated therapy in chronic obstructive pulmonary disease (COPD), regardless of smoking status. PMID- 17693106 TI - Maternal influence in the transmission of asthma susceptibility. AB - Asthma is one of the most common chronic diseases in children, with increasing morbidity and mortality. A genetic predisposition and exposure to allergens have been implicated as major risk factors for the development of asthma. However, increasing evidence indicates that the mother plays a crucial role in mediating the development of fetal-infant immune responses to inhaled allergens. The exact nature and mechanism of this maternal influence and how it might be associated with the development of allergic sensitization and asthma are not clear. Under normal conditions, the maternal environment during pregnancy promotes an initial Th2 skewed immune response in the offspring which transitions to a nonallergic Th1 type response after birth. However, the allergic mother's influence may delay the normal transition to a nonallergic immune response to inhaled allergens in her children, thus increasing the risk for the development of allergic sensitization and/or asthma. Understanding the underlying mechanisms by which the maternal immune environment can influence the development of the fetal-infant immune response to inhaled allergens may lead to identifying new targets for the prevention of allergic sensitization and asthma. PMID- 17693108 TI - Effect of capsaicin on plasma and tissue levels of insulin-like growth factor-I in spontaneously hypertensive rats. AB - OBJECTIVE: Plasma levels of insulin-like growth factor-I (IGF-I), an important substance for maintaining cardiovascular homeostasis, are lower in spontaneously hypertensive rats (SHR) than in normotensive Wistar Kyoto rats (WKY). Calcitonin gene-related peptide (CGRP) increases IGF-I production in vitro and in vivo, suggesting that stimulation of sensory neurons might increase the production of IGF-I in SHR. DESIGN: Levels of CGRP and IGF-I in plasma, kidneys and heart in WKY and SHR and cellular cyclic AMP levels in dorsal root ganglion neurons (DRGs) isolated from WKY and SHR were measured by an ELISA-based method. RESULTS: Levels of CGRP and IGF-I in plasma, kidneys and heart of SHR were about half of those of WKY. Administration of capsaicin significantly increased levels of CGRP and IGF-I in plasma and tissues of SHR to the levels in WKY and these increases were completely reversed by pretreatment with capsazepine, an inhibitor of vanilloid receptor-1 activation. CGRP release and cellular levels of cAMP in DRGs isolated from SHR were significantly lower than those in DRGs isolated from WKY. Capsaicin increased both CGRP release and cellular cAMP levels in DRGs isolated from SHR to the levels in DRGs isolated from WKY. CONCLUSIONS: Sensory neuron activation might be lower in SHR than in WKY probably due to decreased production of cAMP in sensory neurons, explaining why IGF-I levels in plasma and tissues are lower in SHR than in WKY. PMID- 17693109 TI - Analysis of the liver soluble proteome from bull terriers affected with inherited lethal acrodermatitis. AB - Lethal acrodermatitis (LAD) is a genetic disease affecting bull terrier dogs. The phenotype is similar to that for acrodermatitis enteropathica in humans, but is currently without treatment. The purpose of the research presented here is to determine the biochemical defects associated with LAD using proteomic methodologies. Two affected (male and female) and one unaffected (male) bull terrier pups were euthanized at 14 weeks of age, their livers dissected and prepared for two-dimensional gel electrophoresis (2DE) and densitometry. Approximately 200 protein spots were observed. The density of the spots within each gel was normalized to the total spot volume of the gel; only those soluble liver protein spots that were consistently different in both of the livers of the affected pups compared to the unaffected pup were excised manually and submitted for MALDI mass spectrometry. Thirteen proteins were identified as differentially expressed in the affected, compared to the unaffected, pups. The proteins were involved in numerous cellular physiological functions, including chaperones, calcium binding, and energy metabolism, as well as being associated with the inflammatory response. Of note were haptoglobin, glutamine synthetase, prohibitin and keratin 10 which exhibited at least a fourfold level of differential expression. These data represent the first proteomic analysis of this mutation. The differentially expressed proteins that were identified may be key in understanding the etiology of LAD, and may lead to diagnostic tools for its identification within the bull terrier population. PMID- 17693110 TI - Bacteriuria in cats with feline lower urinary tract disease: a clinical study of 134 cases in Norway. AB - Feline lower urinary tract disease (FLUTD) is considered to be one of the most common diagnoses in feline patients. Several authors have concluded that feline idiopathic cystitis is the most common cause of FLUTD, whereas infectious cystitis is diagnosed in only 2% of the cases. In the period from January 2003 to February 2005, 134 cats that presented with signs of lower urinary tract disorders were included in a study at the Norwegian School of Veterinary Science. Ninety-seven percent were first opinion cases. All the cats went through a physical examination, and blood samples were collected for haematology and clinical chemistry. The urine analysis included urine stix, specific gravity, microscopic examination of the sediment and microbiological culturing. The urine samples were collected as voided mid-stream urine samples, by catheter or by cystocentesis and the method used was registered. Of the 134 cats included in the study, 37% were diagnosed as having obstructive and 63% as having non-obstructive FLUTD. In total 44 cats (33%) were diagnosed with bacteriuria, exceeding 10(3) colony forming units per millilitre (cfu/ml) and 33 (25%) of these cats had bacterial growth exceeding 10(4) cfu/ml, either alone or in combination with crystals and/or uroliths. Six cats (18%) with bacterial growth exceeding 10(4) cfu/ml were older than 8 years. No significant difference was found between the sampling methods performed with regard to bacteriuria. This study indicates that bacteriuria may have been underdiagnosed in Norwegian cats with clinical signs of FLUTD. It also confirms the importance of microbiological culturing in first opinion cases with FLUTD and that a skilled operator can get representative samples regardless the choice of method. PMID- 17693111 TI - Co-infection with Mycoplasma haemofelis and 'Candidatus Mycoplasma haemominutum' in three cats from Brazil. AB - The two most common haemotropic Mycoplasma of cats, Mycoplasma haemofelis and 'Candidatus Mycoplasma haemominutum' have been identified using molecular techniques in all continents, except Antarctica. We report the first molecular characterization in South America of a dual infection with M haemofelis and 'Candidatus Mycoplasma haemominutum' in three domestic cats. The 16S ribosomal RNA gene was amplified in three anaemic cats in which haemoplasma organisms were seen attached to the erythrocytes in the peripheral blood smear. Bands of the expected size for M haemofelis and 'Candidatus Mycoplasma haemominutum' were observed in all three cats. The 393 bp segment of one of the amplicons had a similarity value of 100% to M haemofelis, whereas the other amplicon, a 192 bp segment, was 100% similar to 'Candidatus Mycoplasma haemominutum'. After diagnosis, two cats received blood transfusion and they were all treated with doxycycline. All three cats recovered uneventfully. PMID- 17693112 TI - Tracheostomy in cats: 23 cases (1998-2006). AB - Tracheostomies can be used to provide a patent airway in animals with upper airway obstruction but have been reported to be more difficult to manage in cats than in other animals. The purpose of this study is to retrospectively describe the indications, complications and outcome of cats undergoing tracheostomy. Twenty-three cats underwent tracheostomy for laryngeal mass (n=13), trauma (n=5) and upper airway swelling (n=5). Major and minor complications were recorded in 10 and 17 cats, respectively. Seventeen cats were discharged to home, four cats were euthanased and two cats died in hospital. Complications with stoma healing were reported in one cat. Of seven cats discharged with a permanent tracheostomy, one cat is alive and six cats survived at home for between 2 and 281 days. Although complications are common, temporary tracheostomies can be beneficial for conditions in which the underlying cause can be treated. Despite risk of occlusion, permanent tracheostomies can be effective palliative procedures for cats with severe upper airway disease. PMID- 17693113 TI - Chronic osteomyelitis of the metatarsal sesamoid due to Corynebacterium jeikeium in a patient with rheumatoid arthritis. PMID- 17693114 TI - Proprioceptive feedback enhancement induced by vibratory stimulation in complex regional pain syndrome type I: an open comparative pilot study in 11 patients. AB - OBJECTIVE: Complex regional pain syndrome type I (CRPS-I) is now considered as a central nervous system disease with peripheral manifestations. CRPS-I may result from a mismatch between sensory input and motor output leading to a disorganization of motor programming in cortical structures. According to previous studies in the field of motor control, one efficient way to correct this mismatch could be a proprioceptive feedback enhancement. The goal of the present study was to determine whether vibratory stimulation by improving proprioceptive feedback may increase range of motion and minimize pain in patients with CRPS-I. METHODS: An open non-randomized study was conducted in 11 patients with CRPS-I of the hand and wrist. Conventional rehabilitation sessions were given for 10 weeks. During each session, patients in the intervention group (n=7) received vibratory stimulation of the affected region; the remaining 4 patients served as the controls. RESULTS: After 10 weeks, range-of-motion gains were about 30% larger and pain severity was about 50% lower in the intervention group than in the control group. A significant decrease in analgesic use occurred in the intervention group. DISCUSSION: Vibratory stimulation may significantly improve range of motion and pain in patients with CRPS-I, probably by reestablishing consonance between sensory input and motor output at cortical level. Prospective randomized studies in larger numbers of patients are needed. Cross-over designs or simulated vibratory stimulation should be used to minimize bias. PMID- 17693115 TI - Perceptions in 7700 patients with rheumatoid arthritis compared to their families and physicians. AB - OBJECTIVE: To compare perceptions of patients with rheumatoid arthritis (RA) to those of their families and usual physicians regarding pain and subjective experience of the disease. METHODS: Questionnaires were mailed to patients listed in the files of a non-profit patient organization (Association Francaise des Polyarthritiques). Each patient, one family member (or close friend), and the usual physician were each asked to complete a questionnaire. Concordance among replies made by patients, family/friends, and physicians was evaluated using the kappa coefficient. RESULTS: Questionnaires were sent to 20,468 patients, among whom 7702 (38%) mailed back adequate data. The family member was usually the spouse (70%) and the usual physician a rheumatologist (68%). Joint pain was described by patients as variable (80%) and unpredictable (68%). Patients reported a need to push themselves (86%), frustration (86%), anxiety about possible disease progression (89%), and being prevented from making plans for the future (6%). A negative impact was reported on recreational activities (84%), work (56%), and family life and sexuality (51%). Concordance was excellent for pain severity (kappa>0.90) and good for the main joint-pain characteristics and experience of the disease (kappa>0.70), although family members tended to overestimate, and physicians to underestimate, the intensity of the pain. CONCLUSION: We found good overall agreement between perceptions of patients, their families, and their physicians, despite differences between these last two groups. Our qualitative analysis showed not only a major physical impact of the disease, but also marked negative psychosocial effects. PMID- 17693116 TI - [Laparoscopic ovarian transposition and cryopreservation of ovarian tissue before chemo-radiotherapy for rectal cancer]. AB - We report a case of laparoscopic ovarian transposition and ovarian cryopreservation in a nulliparous 25-year-old woman with rectal cancer. The authors focus on the surgical technique and the importance of preserving ovarian function. PMID- 17693117 TI - WITHDRAWN: In vivo bioluminescent source estimation using computational optical biopsy. PMID- 17693118 TI - ECG compression using uniform scalar dead-zone quantization and conditional entropy coding. AB - A new wavelet-based method for the compression of electrocardiogram (ECG) data is presented. A discrete wavelet transform (DWT) is applied to the digitized ECG signal. The DWT coefficients are first quantized with a uniform scalar dead-zone quantizer, and then the quantized coefficients are decomposed into four symbol streams, representing a binary significance stream, the signs, the positions of the most significant bits, and the residual bits. An adaptive arithmetic coder with several different context models is employed for the entropy coding of these symbol streams. Simulation results on several records from the MIT-BIH arrhythmia database show that the proposed coding algorithm outperforms some recently developed ECG compression algorithms. PMID- 17693119 TI - Corrosive places, inhuman spaces: mental health in Australian immigration detention. AB - Since their establishment in 1992, Australian Immigration Detention Centres have been the focus of increasing concern due to allegations of their serious impact on the mental health of asylum seekers. Informed by Foucault's treatise on surveillance and the phenomenological work of Casey, this paper extends the current clinical data by examining the architecture and location of detention centres, and the complex relationships between space, place and mental health. In spatialising these relationships, we argue that Immigration Detention Centres operate not only as Panopticons, but are embodied by asylum seekers as 'anti places': as places that mediate and constitute thinned out and liminal experiences. In particular, it is the embodied effects of surveillance and suspended liminality that impact on mental health. An approach which locates the embodiment of place and space as central to the poor mental health of asylum seekers adds an important dimension to our understandings of (dis)placement and mental health in the lives of the exiled. PMID- 17693120 TI - CD147 depletion down-regulates matrix metalloproteinase-11, vascular endothelial growth factor-A expression and the lymphatic metastasis potential of murine hepatocarcinoma Hca-F cells. AB - Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147), which is a plasma membrane glycoprotein enriched on the surface of many malignant tumors promotes adhesion, invasion and metastasis of tumor cells. In addition, tumor associated CD147 also induces vascular endothelial growth factors (VEGFs) expression. To investigate the possible role of CD147 in the mouse hepatocarcinoma cell line Hca-F with highly metastatic potential in the lymph nodes, we used an RNA interference (RNAi) approach to silence CD147 expression. The results showed that CD147 depletion in Hca-F cells resulted in the significantly decreased expression of matrix metalloproteinase-11 (MMP-11), VEGF A at both mRNA and protein levels. The reduced CD147 expression also attenuated the invasive, adhesive, metastatic ability of Hca-F cells to lymph nodes both in vitro and in vivo. Our current findings reveal that the tumor biological marker CD147 functionally mediates MMP-11, VEGF-A expression and tumor lymphatic metastasis. PMID- 17693121 TI - Isolation, culture and immortalisation of hepatic oval cells from adult mice fed a choline-deficient, ethionine-supplemented diet. AB - Oval cells have great potential for use in cell therapy to treat liver disease, however this cannot be achieved until the factors which govern their proliferation and differentiation are better understood. We describe a method to establish primary cultures of murine oval cells, and the derivation of two novel lines from these. Primary cultures from the livers of wildtype or TAT-GRE lacZ transgenic mice subjected to a choline-deficient, ethionine-supplemented diet comprised up to 80% oval cells at day 7 based on A6 or CK19 staining. Cell lines were clonally derived, which underwent spontaneous immortalisation following prolonged maintenance in culture. Immunostaining and RT-PCR demonstrated they express hepatocytic and biliary markers and they were therefore termed "bipotential murine oval liver" (BMOL) cells. Under proliferating culture conditions, BMOL or BMOL-TAT cells abundantly expressed oval cell and biliary markers, whereas mature hepatocytic markers were upregulated when the growth conditions were changed to facilitate differentiation. Hepatic differentiation of BMOL-TAT cells could be traced by measuring the expression of their lacZ transgene, which is driven by a promoter element from tyrosine aminotransferase (TAT), a marker of adult hepatocytes. Interestingly, haematopoietic markers were upregulated in superconfluent cultures, indicating a possible multipotentiality. None of the cell lines grew in semi-solid agar, nor did they form tumours in nude mice, suggesting they are non-tumourigenic. These novel murine oval cell lines, together with a reliable method for isolation and culture of primary oval cells, will provide a useful tool for investigating the contribution of oval cells to liver regeneration. PMID- 17693122 TI - The cyclic cystine knot miniprotein MCoTI-II is internalized into cells by macropinocytosis. AB - The cyclotides are macrocyclic knotted proteins characterized by a compact topology and exceptional stability. Accordingly it has been hypothesized that they may be useful as protein engineering frameworks for the stabilization and delivery of bioactive peptide sequences. This study examined the internalization of cyclotides into mammalian cells, a vital step for the delivery of bioactive peptide sequences to intracellular targets. Although the entry of various linear peptides into cells has been reported previously, this is the first report of internalization of a macrocyclic peptide. Cell uptake was examined for representatives of two cyclotide subfamilies; the first was MCoTI-II, a member of the trypsin inhibitor subfamily, which was internalized by a macrophage and breast cancer cell line and the second, the prototypic cyclotide kalata B1 from the Mobius subfamily, which remained extracellular. Biotin labeled MCoTI-II entered macrophages by macropinocytosis, resulting in vesicular encapsulation without trafficking to lysosomes for degradation. The ready uptake, coupled with low cytotoxicity, indicates that MCoTI-II has the potential to transport grafted bioactivities to intracellular targets, making it a potentially valuable framework in drug design applications. PMID- 17693123 TI - Nuclear factor-kappaB1: regulation and function. AB - The transcription factor NF-kappaB is a critical regulator of many cellular processes including cell survival and inflammation. NF-kappaB functions as a hetero- or homo-dimer which can be formed from five NF-kappaB subunits, NF kappaB1 (p50 and its precursor p105), NF-kappaB2 (p52 and its precursor p100), RelA (p65), RelB and c-Rel. The most studied dimer is p50:p65, which is activated by the classical pathway and usually promotes gene expression. Activation of p50:p65 is linked with cell survival and promoting inflammation. This review provides a detailed overview of the structure, synthesis and function of the lesser characterised NF-kappaB subunit; NF-kappaB1 (p105 and p50). The diverse interactions of NF-kappaB1 with co-activators, co-repressors and other signaling networks that influence NF-kappaB1 gene expression are discussed. Finally the anti-inflammatory actions of NF-kappaB1 signaling will be assessed and the crucial need to design novel therapeutic drugs which exploit and amplify the anti inflammatory actions of p50 will be explored. PMID- 17693124 TI - Historical developments in the research of interferon receptors. AB - Interferons (IFNs) were discovered 50 years ago independently by Isaacs and Lindemann and by Nagata and Kojima. When it was later realized that IFNs are active at very low concentrations, research began to determine how their powerful effects were generated from such a small initial signal. It has since been established that interferons, as well as all other cytokines, employ cell surface receptors to translate their presence in the serum to a potent cellular response to a viral infection. These receptor complexes are composed of multiple distinct glycosylated transmembrane polypeptides, a number of protein tyrosine kinases, and interact transiently with a large variety of other proteins including transcription factors, phosphatases, signaling repressors, and adaptor proteins coupling the receptor to alternative signaling pathways. Three major receptor complexes exist that are exclusive to each of three major classes of interferon. Even though the effects of each major class of interferon vary physiologically, each receptor complex interacts with its ligand in similar ways and activates similar signaling cascades. In this mini-review, we take a historical perspective at the major events in the characterization of interferon receptors, discussing interesting results that still need to be explained. PMID- 17693125 TI - Present role and future potential of type I interferons in adjuvant therapy of high-risk operable melanoma. AB - Few molecular therapeutic approaches have been so rigorously investigated in relation to the pathophysiology and outcome of human diseases as type I interferons. Historically, IFNs were discovered after the phenomenon of 'interference' was first described by Isaacs and Lindenmann in 1957, and for years IFNs (IFNalpha) were considered as potential "antiviral penicillins" until the broader spectrum of effects upon normal cell physiology, the natural and adaptive immune systems, and tumor growth and proliferation were described. Interferon beta (IFNbeta) was the second human gene after insulin to be cloned, and it codes for the first cytokine used to treat human malignancies. Despite the progress in understanding and treating cancer over the last 25 years, IFN alpha (IFNalpha) remains the most commonly used biologically active cytokine in the treatment of solid tumors, and for some like melanoma, the only successful agent. In this review we discuss the role of type I interferons in the pathophysiology and treatment of melanoma, with emphasis on the 22 years of work conducted at the University of Pittsburgh. We discuss potential mechanisms that partially explain the clinical benefit, and set the groundwork for building upon, the design of more effective treatments for this disease. PMID- 17693126 TI - Refining the plant steroid hormone biosynthesis pathway. AB - Many of the biochemical conversions in plant steroid hormone biosynthesis are catalysed by cytochrome P450 enzymes (CYPs or P450s). A recent paper by Toshiyuki Ohnishi et al. (2006) indicates the role of CYP90C1 and CYP90D1 in the synthesis of the most bioactive plant steroid hormone, brassinolide. These results highlight the need for refining the brassinolide biosynthesis pathway. PMID- 17693127 TI - Goldmann applanation tonometry over daily disposable contact lens: accuracy and safety of procedure. AB - PURPOSE: To study accuracy and safety, related to sensation (discomfort) and trauma, when using Goldmann applanation tonometry (GAT) on eyes wearing daily disposable soft contact lenses. METHODS: The intra-ocular pressure (IOP) of 136 normal eyes of 68 subjects was measured by Goldmann tonometer. Measurements were made in one eye with a contact lens (hilafilcon A) without anaesthetic drops and then without the contact lens using one drop of 0.4% oxybuprocaine hydrochloride. Each contact lens used was identical as to back optic zone, back vertex power. Standard Goldmann procedure only was used for the fellow eye of each subject. Subjective sensation (discomfort) responses to both procedures were studied in a subgroup (66 eyes) using a scale of discomfort, from 1 (no sensation) to 5 (highest sensation). Epithelial staining after tonometry was evaluated for this subgroup. RESULTS: No significant differences were found for the IOP with and without contact lens (t<1; p=0.63) for the IOP range studied. There was a good correlation between the two procedures (r=0.81; p<0.05). Lowest sensation was found with tonometry on the anaesthetized cornea; this condition was significantly different from other conditions (p<0.005). No difference was found among the other conditions (contact lens insertion, tonometry on contact lens and application of topical anaesthetic). Corneal epithelial staining following the standard tonometry procedure was significantly higher than following the procedure with a contact lens (p<0.00005). CONCLUSIONS: Measurement of IOP by GAT over a daily disposable soft contact lens is accurate, compared to the standard procedure and within the IOP's normal range studied here. Also using a contact lens results in less trauma whilst discomfort is similar. PMID- 17693128 TI - Effect of metformin on clastogenic and biochemical changes induced by adriamycin in Swiss albino mice. AB - Diabetes mellitus (DM) is a chronic disease that is characterized by deteriorating glycemic control. The disease is known to be caused by imbalance between reactive oxygen species (ROS) and antioxidant defense systems. Hyperglycemia is commonly observed in a wide variety of diseases, including cancer. Although, therapy against glycemic control, is used in all these diseases, the diabetic cancer patients are on additional therapy with anticancer drugs. The objective of present study was to study if Glucophage (metformin), a very popular antidiabetic agent can avert the mutagenicity and lipid peroxidation caused by adriamycin (ADR), which is a commonly used cytotoxic drug. The experimental protocol included oral treatment of mice with different doses (62.5, 125 and 250 mg/kg day) of metformin for 7 days. Some mice in each group were injected i.p. with ADR (15 mg/kg). In each case animals were killed, 30 or 24, 48 and 72 h after the last treatment and femurs were excised for cytological studies by micronucleus test. Additional experiments on estimation of glutathione (GSH) and malondialdehyde (MDA) were undertaken in blood and serum, respectively. Twenty-four hour after the treatment, blood from each mouse was collected from heart and preserved for analysis. The results obtained revealed that pretreatment with metformin: (i) reduced the ADR-induced frequency of micronuclei without any alteration in its cytotoxicity and (ii) protected against the ADR-induced increase and decrease of MDA and GSH, respectively. The exact mechanism of action is not known, however, the inhibition of ADR-induced clastogenicity and lipid peroxidation by metformin may be attributed to the antioxidant action of the latter. Our results demonstrate that metformin might be useful to avert secondary tumor risk by decreasing the accumulation of free radicals and inhibition of mutagenicity. PMID- 17693129 TI - First case of canine peritoneal larval cestodosis caused by Mesocestoides lineatus in Germany. AB - A 13-year-old Dalmatian dog was presented with a history of abdominal enlargement and reduced appetite for several months. Acute clinical signs were anorexia, vomiting and diarrhoea. During exploratory laparotomy, acute intestinal perforation due to a foreign body and peritonitis was diagnosed. In addition, the abdominal cavity was filled with multiple small (0.5 cm), white, cyst-like structures. Histopathology revealed typical cestode structures of the cyst walls but no protoscolices were found. PCR was performed with cestode specific primers of the mitochondrial 12S rDNA. The sequence showed a 99.75% identity with a Mesocestoides lineatus isolate published in the NCBI GenBank. This is the first case of canine peritoneal larval cestodosis (CPLC) in Germany and the first evidence of M. lineatus as causal agent for CPLC. PMID- 17693130 TI - Spectroscopic investigation of Ginkgo biloba terpene trilactones and their interaction with amyloid peptide Abeta(25-35). AB - The beneficial effects of Ginkgo biloba extract in the "treatment" of dementia are attributed to its terpene trilactone (TTL) constituents. The interactions between TTLs and amyloid peptide are believed to be responsible in preventing the aggregation of peptide. These interactions have been investigated using infrared vibrational absorption (VA) and circular dichroism (VCD) spectra. Four TTLs, namely ginkgolide A (GA), ginkgolide B (GB), ginkgolide C (GC) and bilobalide (BB) and amyloid Abeta(25-35) peptide, as a model for the full length peptide, are used in this study. GA-monoether and GA-diether have also been synthesized and investigated to help understand the role of individual carbonyl groups in these interactions. The precipitation and solubility issues encountered with the mixture of ginkgolide+Abeta peptide for VA and VCD studies were overcome using binary ethanol-D(2)O solvent mixture. The experimental VA and VCD spectra of GA, GB, GC and BB, GA-monoether and GA-diether have been analyzed using the corresponding spectra predicted with density functional theory. The time dependent experimental VA and VCD spectra of Abeta(25-35) peptide and the corresponding experimental spectra in the presence of TTLs indicated that the effect of the TTLs in modulating the aggregation of Abeta(25-35) peptide is relatively small. Such small effects might indicate the absence of a specific interaction between the TTLs and Abeta(25-35) peptide as a major force leading to the reduced aggregation of amyloid peptides. It is possible that the therapeutic effect of G. biloba extract does not originate from direct interactions between TTLs and the Abeta(25-35) peptide and is more complex. PMID- 17693131 TI - Quantitative analysis of X-ray absorption spectra using a 2D map representation. AB - A promising possibility for the quantitative analysis of X-ray absorption near edge structure (XANES) spectra of nanosized electrode materials is demonstrated. We used a 2D map representation technique, which utilizes the values of the first derivatives of the absorbance with respect to the inserted Li(+) content plotted over the two-dimensional space defined by the inserted Li(+) content (mole) versus photon energy (eV) as a single map. The technique was applied to XANES spectra of the Li(y)CoO system in the first Li(+) insertion reaction for determining the structural and electronic variations associated with the change in Li(+) content. The obtained show that the intensities of two peaks at 7725 and 7711 eV increased with the Li(+) content and the difference of intensity change of these two peaks carried out for successive couples of spectra yielded the largest changes at 1.05 and 1.98 mol of Li content. This approach for quantitative analysis of XANES without using conventional simulation techniques enable us to interpret X-ray absorption spectroscopy (XAS) as a quantitative analytical technique with greater confidence. PMID- 17693132 TI - Auditing description-logic-based medical terminological systems by detecting equivalent concept definitions. AB - OBJECTIVE: To specify and evaluate a method for auditing medical terminological systems (TSs) based on detecting concepts with equivalent definitions. This method addresses two important problems: redundancy, where the same concept is represented more than once (described by different terms), and underspecification, where different concepts have the same representation and hence appear indistinguishable from each other. DESIGN: The auditing method is applicable for TSs that are or can be represented in a description logic (DL). The method relies on the assumption that concept definitions are non-primitive (i.e. they are regarded as providing necessary and sufficient conditions). Whereas this assumption may not hold for many definitions, it does serve the purpose of detecting sets of logically equivalent concepts by a DL reasoner. Such a set may include the same concept which is defined more than once and/or different concepts that are underspecified as they appear indistinguishable from each other by their represented properties. Analysis of these sets provides insight into the representation quality of concepts and provides hints at improving the TS. MEASUREMENTS: In our case study the method is applied to the DICE TS, a comprehensive TS in intensive care. It comprises about 2500 concepts and 40 properties and relations. RESULTS: In DICE we found four concepts that were defined twice. Furthermore, 100 sets were found containing more than 300 underspecified concepts. The sizes of these sets ranged from 2 to 13. Analysis revealed that many concepts can be more completely defined, either by adding existing relations, or by the introduction of new relations into the terminological system. CONCLUSION: The method proved both usable and valuable for auditing TSs. DL reasoning is fully automated and all equivalent concept definitions are systematically found. The resulting sets of equivalent concepts clearly point out which concept definitions are to be reviewed, as they contain duplicate definitions of a concept, and (inherently or unnecessarily) underspecified concepts. PMID- 17693133 TI - Apoptosis in tissues from fatal dengue shock syndrome. AB - BACKGROUND: Apoptosis, or programmed cell death, has been implicated in dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) pathogenesis. OBJECTIVES: To determine the in vivo apoptosis contribution to the pathogenesis of fatal DHF/DSS during a Cuban dengue epidemic. STUDY DESIGN: We detected apoptosis by the TdT mediated dUTP Nick-End Labeling (TUNEL) technique and dengue virus (DENV) antigens by an immunohistochemical assay in different tissues from six individuals who died of DHF/DSS during the Santiago de Cuba DENV-2 epidemic in 1997. RESULTS: DENV antigens were immunolocalized mainly in hepatocytes. Apoptotic cells were found in five of the six cases studied. Apoptosis was demonstrated in liver, brain, intestinal and lung tissues. Severe brain hypoxia and ischemia in the studied subjects during DHF/DSS probably might induce apoptosis in cerebral cells. Apoptotic microvascular endothelial cells (ECs) in pulmonary and intestinal tissues, a finding only previously reported in vitro, are likely related to vascular plasma leakage manifested by the individuals. CONCLUSIONS: Apoptosis was demonstrated in cerebral cells, white blood cells, intestinal and pulmonary microvascular ECs from Cuban fatal cases of DHF/DSS. As far as we know, these findings have not been previously reported in DHF/DSS. Our results indicate there is very likely an in vivo contribution of apoptosis to the pathophysiological mechanisms of DHF/DSS. PMID- 17693134 TI - PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial. AB - BACKGROUND: In patients with locally advanced adenocarcinoma of the oesophagogastric junction (AEG), early metabolic response defined by 18 fluorodeoxyglucose-PET ([(18)F]FDG-PET) during neoadjuvant chemotherapy is predictive of histopathological response and survival. We aimed to assess the feasibility of a PET-response-guided treatment algorithm and its potential effect on prognosis. METHODS: Between May 27, 2002, and Aug 4, 2005, 119 patients with locally advanced adenocarcinoma of AEG type 1 (distal oesophageal adenocarcinoma) or type 2 (gastric cardia adenocarcinoma) were recruited into this prospective, single-centre study. All patients were assigned to 2 weeks of platinum and fluorouracil-based induction chemotherapy (evaluation period). Those with decreases in tumour glucose standard uptake values (SUVs), predefined as decreases of 35% or more at the end of the evaluation period and measured by PET, were defined as metabolic responders. Responders continued to receive neoadjuvant chemotherapy of folinic acid and fluorouracil plus cisplatin, or folinic acid and fluorouracil plus cisplatin and paclitaxel, or folinic acid and fluorouracil plus oxaliplatin for 12 weeks and then proceeded to surgery. Metabolic non-responders discontinued chemotherapy after the 2-week evaluation period and proceeded to surgery. The primary endpoint was median overall survival of metabolic responders and non-responders. Secondary endpoints were median event-free survival, postoperative complications and mortality, number of residual tumour-free (R0) resections, and histopathological responses. This study has been registered in the European Clinical Trials Database (EudraCT) as trial 2007-003356-11. FINDINGS: 110 patients were evaluable for metabolic responses. 54 of these patients had metabolic responses (ie, decrease of 35% or more in tumour glucose SUV) after 2 weeks of induction chemotherapy, corresponding to a response of 49% (95% CI 39-59). 104 patients had tumour resection (50 in the responder group and 54 in the non-responder group). After a median follow-up of 2.3 years (IQR 1.7 3.0), median overall survival was not reached in metabolic responders, whereas median overall survival was 25.8 months (19.4-32.2) in non-responders (HR 2.13 [1.14-3.99, p=0.015). Median event-free survival was 29.7 months (95% CI 23.6 35.7) in metabolic responders and 14.1 months (7.5-20.6) in non-responders (hazard ratio [HR] 2.18 [1.32-3.62], p=0.002). Major histological remissions (<10% residual tumour) were noted in 29 of 50 metabolic responders (58% [95% CI 48-67]), but no histological response was noted in metabolic non-responders. INTERPRETATION: This study confirmed prospectively the usefulness of early metabolic response evaluation, and shows the feasibility of a PET-guided treatment algorithm. These findings might enable tailoring of multimodal treatment in accordance with individual tumour biology in future randomised trials. PMID- 17693135 TI - Determinants of depressive symptoms in hospitalised men and women with heart failure. AB - BACKGROUND: Depressive symptoms are prominent and related to an increased risk on cardiovascular disease outcomes and all cause mortality in HF patients. AIM: To intervene effectively, factors related to depressive symptoms in men and women should be identified. METHODS: Depressive symptoms of 921 hospitalised HF patients (61% male; age 71+/-11; LVEF 33%+/-14, NYHA II-IV) were assessed by the Center for Epidemiological Studies-Depression scale (CES-D). RESULTS: Overall 40% of the patients had depressive symptoms (CES-D >or=16), which were more common in women than in men (47% versus 36%, p<0.001). Multivariable analysis in men revealed that depressive symptoms were related to age (OR 0.84, 95% CI 0.71-0.98, p=0.03, per 10 years), physical health (OR 0.76, 95% CI 0.71-0.83, p<0.001, per 10 units) and HF symptoms. In women depressive symptoms were also related to NYHA II-III versus IV (OR 0.60, 95% CI 0.37-0.95, p<0.03) and COPD (OR 2.33, 95% CI 1.20-4.53, p<0.012). CONCLUSION: Depressive symptoms are more common in women than in men. In both men and women depressive symptoms are related to age and physical health. For clinical factors: In men only HF symptoms, but in women also NYHA and COPD were related to depressive symptoms. PMID- 17693136 TI - Syk deficiency in human non-releaser lung mast cells. PMID- 17693137 TI - An intensive interactive course for 3D echocardiography: is 'crop till you drop' an effective learning strategy? AB - BACKGROUND: Three-dimensional echocardiography (3DE) appears to show incremental benefit over two-dimensional echocardiography (2DE), but it's uptake has been slow. We tested attendees before and after an intensive interactive training course to identify its efficacy. METHODS: Attendees (n = 35, 23 cardiologists, 12 sonographers) were shown how to use 3DE review software and asked to identify the pathology of five patients (wall motion abnormality, peri-prosthetic mitral regurgitation, subaortic membrane, small ventricular septal defect, submitral stenosis) on 2D and 3D images. In the following one and a half-day interactive teaching course, brief presentations on application of 3DE for assessment of wall motion, valve and congenital abnormalities were followed by review of 3D datasets, during which the attendees made their own interpretations before being shown the optimal viewing strategy. Test cases were not discussed and the test was repeated at the end of the course. RESULTS: Most attendees (57%) had access but with little or no use of a 3DE system. Three-dimensional echocardiography had no incremental value before training. After training, overall correct responses significantly improved compared with baseline interpretation, although improvement was not the same for all diagnoses. All groups (cardiologists vs. sonographers, inexperienced vs. moderately experienced reviewers) improved similarly. CONCLUSIONS: Incorporation of 3DE into standard practice may be limited by inexperience. An interactive teaching course with rehearsal and direct mentoring appears to overcome this limitation and may improve the uptake of this technique. PMID- 17693138 TI - Lumbar sympathectomy attenuates cold allodynia but not mechanical allodynia and hyperalgesia in rats with spared nerve injury. AB - In certain patients with neuropathic pain, the pain is dependent on activity in the sympathetic nervous system. To investigate whether the spared nerve injury model (SNI) produced by injury to the tibial and common peroneal nerves and leaving the sural nerve intact is a model for sympathetically maintained pain, we measured the effects of surgical sympathectomy on the resulting mechanical allodynia, mechanical hyperalgesia, and cold allodynia. Decreases of paw withdrawal thresholds to von Frey filament stimuli and increases in duration of paw withdrawal to pinprick or acetone stimuli were observed in the ipsilateral paw after SNI, compared with their pre-SNI baselines. Compared with sham surgery, surgical lumbar sympathectomy had no effect on the mechanical allodynia and mechanical hyperalgesia induced by SNI. However, the sympathectomy significantly attenuated the cold allodynia induced by SNI. These results suggest that the allodynia and hyperalgesia to mechanical stimuli in the SNI model is not sympathetically maintained. However, the sympathetic nervous system may be involved, in part, in the mechanisms of cold allodynia in the SNI model. PERSPECTIVE: The results of our study suggest that the SNI model is not an appropriate model of sympathetically maintained mechanical allodynia and hyperalgesia but may be useful to study the mechanisms of cold allodynia associated with sympathetically maintained pain states. PMID- 17693139 TI - Association between the DQA MHC class II gene and Puumala virus infection in Myodes glareolus, the bank vole. AB - Puumala virus (PUUV) is a hantavirus specifically harboured by the bank vole, Myodes (earlier Clethrionomys) glareolus. It causes a mild form of hemorrhagic fever with renal syndrome (HFRS) in humans, called Nephropathia epidemica (NE). The clinical severity of NE is variable among patients and depends on their major histocompatibility complex (MHC) genetic background. In this study we investigated the potential role of class II MHC gene polymorphism in the susceptibility/resistance to PUUV in the wild reservoir M. glareolus. We performed an association study between the exon 2 of the DQA gene and PUUV antibodies considering a natural population of bank voles. Because immune gene polymorphism is likely to be driven by multiple parasites in the wild, we also screened bank voles for other potential viral and parasitic infections. We used multivariate analyses to explore DQA polymorphism/PUUV associations while considering the potential antagonist and/or synergistic effects of the whole parasite community. Our study suggests links between class II MHC characteristics and viral infections including PUUV and Cowpox virus. Several alleles are likely to be involved in the susceptibility or in the resistance of bank voles to these infections. Alternatively, heterozygosity does not seem to be associated with PUUV or any other parasite infections. This result thus provides no evidence in favour of the hypothesis of selection through overdominance. Finally this multivariate approach reveals a strong antagonism between ectoparasitic mites and PUUV, suggesting direct or indirect immunogenetic links between infections by these parasites. Other datasets are now required to confirm these results and to test whether the associations vary in space and/or time. PMID- 17693140 TI - Prevalence and antimicrobial susceptibility of microorganisms isolated from sputa of patients with cystic fibrosis. AB - BACKGROUND: New emerging pathogens and associated antimicrobial resistance mechanisms have been observed in the respiratory tract of patients suffering from cystic fibrosis (CF) in the last years. Amongst others, the rate of metallo-beta lactamase (MBL)-producing Pseudomonas aeruginosa strains is growing. However, there are no published data on the prevalence of MBL-producing P. aeruginosa in CF patients to our knowledge. METHODS: In this study, 271 sputum samples of 60 CF patients were collected during a 12-months period. Microbiological cultures and antimicrobial susceptibility tests of the most frequently isolated bacteria were performed. RESULTS: 464 bacterial and 414 fungal strains were isolated and characterized. 63.3% of the patients harbored Staphylococcus aureus, 50% P. aeruginosa, 16.6% Haemophilus influenzae, 15% Stenotrophomonas maltophilia and 13.3% non tuberculous Mycobacteria (NTM). Methicillin resistant S. aureus (MRSA) and MBL-producing P. aeruginosa were detected in 3 (5%) and 5 (8.3%) patients respectively. Among the fungi, Aspergillus fumigatus and Candida albicans showed the highest prevalence. CONCLUSIONS: The detection of MBL-producing P. aeruginosa and MRSA in CF patients confirms that antimicrobial resistance patterns should be always kept under surveillance. Moreover hygiene regulations in CF clinics should prevent a further spread of resistant bacterial strains. PMID- 17693141 TI - Ventilatory response to acute hypoxia in transgenic mice over-expressing erythropoietin: effect of acclimation to 3-week hypobaric hypoxia. AB - We used transgenic mice constitutively over-expressing erythropoietin ("tg6" mice) and wild-type (wt) mice to investigate whether the high hematocrit (hct), consequence of Epo over-expression affected: (1) the normoxic ventilation (V (E)) and the acute hypoxic ventilatory response (HVR) and decline (HVD), (2) the increase in ventilation observed after chronic exposure to hypobaric hypoxia (430mmHg for 21 days), (3) the respiratory "blunting", and (4) the erythrocythemic response induced by chronic hypoxia exposure. V (E) was found to be similar in tg6 and wt mice in normoxia (FIO2=0.21). Post-acclimation V (E) was significantly elevated in every time point in wt mice at FIO2=0.10 when compared to pre-acclimation values. In contrast, tg6 mice exhibited a non-significant increase in V (E) throughout acute hypoxia exposure. Changes in V (E) are associated with adjustments in tidal volume (V(T)). HVR and HVD were independent of EE in tg6 and wt mice before chornic hypoxia exposure. HVR was significantly greater in wt than in tg6 mice after chronic hypoxia. After acclimation, HVD decreased in tg6 mice. Chronic hypoxia exposure caused hct to increase significantly in wt mice, while only a marginal increase occurred in the tg6 group. Although pre-existent EE does not appear to have an effect on HVR, the observation of alterations on V(T) suggests that it may contribute to time dependent changes in ventilation and in the acute HVR during exposure to chronic hypoxia. In addition, our results suggest that EE may lead to an early "blunting" of the ventilatory response. PMID- 17693142 TI - A simple HPLC method for the determination of bifendate: application to a pharmacokinetic study of bifendate liposome. AB - A rapid, sensitive and simple high-performance liquid chromatographic (HPLC) method with ultraviolet detector (UV) has been developed for the determination of bifendate in 100 microl plasma of rats. Sample preparation was carried out by deproteinization with 100 microl of acetonitrile. A 20 microl of supernatant was directly injected into the HPLC system with methanol-double distilled water (65/35, v/v) as the mobile phase at a flow rate of 1.0 ml/min. Separation was performed with a microBondapak C(18) column at 30 degrees C. The peak was detected at 278 nm. The calibration curve was linear (r(2)=0.9989) in the concentration range of 0.028-2.80 microg/ml in plasma. The intra- and inter-day variation coefficients were not more than 6.55% and 6.07%, respectively. The limit of detection was 5 ng/ml. The mean recoveries of bifendate were ranged from 94.53% to 99.36% in plasma. The present method has been successfully applied to the pharmacokinetic study of bifendate liposome in rats. PMID- 17693143 TI - Identification of a novel glyoxylate reductase supports phylogeny-based enzymatic substrate specificity prediction. AB - Phylogenetic analysis of the superfamily of D-2-hydroxyacid dehydrogenases identified the previously unrecognized cluster of glyoxylate/hydroxypyruvate reductases (GHPR). Based on the genome sequence of Rhizobium etli, the nodulating endosymbiont of the common bean plant, we predicted a putative 3-phosphoglycerate dehydrogenase to exhibit GHPR activity instead. The protein was overexpressed and purified. The enzyme is homodimeric under native conditions and is indeed capable of reducing both glyoxylate and hydroxypyruvate. Other substrates are phenylpyruvate and ketobutyrate. The highest activity was observed with glyoxylate and phenylpyruvate, both having approximately the same kcat/Km ratio. This kind of substrate specificity has not been reported previously for a GHPR. The optimal pH for the reduction of phenylpyruvate to phenyllactate is pH 7. These data lend support to the idea of predicting enzymatic substrate specificity based on phylogenetic clustering. PMID- 17693144 TI - PinA from Aspergillus nidulans binds to pS/pT-P motifs using the same Loop I and XP groove as mammalian Pin1. AB - Binding of the Cdc25c-T48 ligand to PinA from Aspergillus nidulans has been characterised by the identification of 15N and 1H resonances from 1H-15N HSQC NMR titration experiments using previous backbone assignments. It is shown that the binding site for the Cdc25c-T48 ligand with PinA is the same as in the mammalian protein Pin1, although with a reduced binding affinity. It had previously been proposed that the arginine residue (R17) in the loop I region of the Pin1 WW domain is essential for binding to the pSer/pThr-Pro motifs of phosphorylated ligands such as Cdc25c. In PinA, a fungal homologue of Pin1, the arginine residue (R17) is replaced with an asparagine residue (N17). The effect of substitution of R17 by N17 in Pin1 has been investigated via a computational study, which predicted that changing R17 to N17 in Pin1 lowers the ligand binding affinity as a result of reduced hydrogen bonding between the protein and the phosphate group of the ligand. PMID- 17693145 TI - L-Carnitine in the treatment of fatigue in adult celiac disease patients: a pilot study. AB - BACKGROUND: Fatigue is common in celiac disease. L-Carnitine blood levels are low in untreated celiac disease. L-Carnitine therapy was shown to improve muscular fatigue in several diseases. AIM: To evaluate the effect of L-carnitine treatment in fatigue in adult celiac patients. METHODS: Randomised double-blind versus placebo parallel study. Thirty celiac disease patients received 2 g daily, 180 days (L-carnitine group) and 30 were assigned to the placebo group (P group). The patients underwent clinical investigation and questionnaires (Scott-Huskisson Visual Analogue Scale for Asthenia, Verbal Scale for Asthenia, Zung Depression Scale, SF-36 Health Status Survey, EuroQoL). OCTN2 levels, the specific carnitine transporter, were detected in intestinal tissue. RESULTS: Fatigue measured by Scott-Huskisson Visual Analogue Scale for Asthenia was significantly reduced in the L-carnitine group compared with the placebo group (p=0.0021). OCTN2 was decreased in celiac patients when compared to normal subjects (-134.67% in jejunum), and increased after diet in both celiac disease treatments. The other scales used did not show any significant difference between the two celiac disease treatment groups. CONCLUSION: L-Carnitine therapy is safe and effective in ameliorating fatigue in celiac disease. Since L-carnitine is involved in muscle energy production its decreased absorption due to OCTN2 reduction might explain muscular symptoms in celiac disease patients. The diet-induced OCTN2 increase, improving carnitine absorption, might explain the L-carnitine treatment efficacy. PMID- 17693146 TI - Cadaveric comparison of two facial flap-harvesting techniques for alloplastic facial transplantation. AB - BACKGROUND: Functional and aesthetic reconstruction of severe facial deformities presents a major challenge, and the results are rarely satisfactory. Recent clinical success of composite tissue allograft transplantation and improvements in autoimmune regulation have initiated efforts to reconstruct severe facial deformities with alloplastic tissue. Few reports address the full facial flap dissection approach, where lengthy procedural times remain a limiting factor in achieving optimal graft survival. Extensive vascular anastomoses within facial tissues provide a unique opportunity to explore alternative graft harvesting strategies to optimise operative ischaemia. OBJECTIVE: The aim of the study was to shorten donor-graft harvesting time and reduce warm ischaemia. We evaluated alternative facial harvesting strategies through mock cadaveric facial transplantations. METHODS: Cadaveric dissections were performed to explore facial scalp reconstruction alternatives. Six paired sub-superficial muscloaponeurotic system (SMAS) plane composite facial-scalp flaps were harvested using either a superficial temporal artery (STA) or a facial artery (FA) pedicle technique (Group I) or an external carotid artery (ECA) pedicle technique. Total harvesting times and lengths of vascular pedicles were measured. RESULTS: Harvesting time for a STA and FA pedicle total facial flap (mean=113min, range = 105-120 min, SD = 6 min) was shorter than that for an ECA pedicle flap (mean = 232 min, range = 225-240 min, SD = 6 min) (P<0.01). Mean pedicle lengths for the STA, the FA, the ECA, the external jugular vein, and the facial vein were 37 +/- 2.1, 35 +/- 1.8, 26 +/- 1.4, 52 +/- 3.0 and 42 +/- 2.6mm, respectively. Mean pedicle lengths for the supraorbital, supratrochlear, infraorbital, mental, and facial nerve were 15 +/- 1.5, 14 +/- 1.4, 24 +/- 1.2, 30 +/- 1.6 and 32 +/- 1.8mm, respectively. CONCLUSION: Compared with previously reported ECA pedicle total facial allograft harvesting techniques, an STA and FA pedicle flap provides a shorter harvesting time and potentially safer dissection method for facial transplantation by avoiding interference with the complicated anatomy of the carotid and submental triangle. Early graft ischaemic damage can be minimised by this harvesting technique, which significantly shortens harvesting time compared with previously described approaches, while maintaining adequate full facial perfusion. PMID- 17693147 TI - Automatic segmentation of cortical and trabecular compartments based on a dual threshold technique for in vivo micro-CT bone analysis. AB - The use of high resolution peripheral quantitative computed tomography (HR-pQCT) and in vivo micro-CT for studies of bone disease and treatment has become increasingly common, and with these methods comes large quantities of data requiring analysis. A simple, robust, and fully-automated segmentation algorithm is presented that efficiently segments bone regions. The dual threshold technique refers to two required threshold inputs that are used to extract the periosteal and endosteal surfaces of the cortex. The proposed method was tested against the gold standard, semi-automated hand contouring, using 45 datasets: mouse, rat, human, and cadaver data from the tibia or radius with nominal isotropic resolutions of 10-82 microm. The performance of the proposed method to segment cortical and trabecular compartments was evaluated qualitatively from visualizations and quantitatively based on morphological measurements. Visual inspection confirmed successful segmentation of all datasets using the new method, with qualitatively better results when applied to the human and cadaver data compared to the gold standard. The dual threshold algorithm was able to extract thin and porous cortices, whereas some clipping and perforations occurred for the gold standard. Morphological parameters measured for segmentation by the proposed method versus the gold standard agreed (95% confidence) for Tb.Th, Tb.Sp, and Tb.N, but not Ct.Th and BV/TV for the human and cadaver datasets. Nonetheless, correlations ranged from 0.95 to 1.00 for all morphological parameters except the cadaver Ct.Th because systematic errors were present. Poor agreement for Ct.Th and BV/TV was due to qualitatively incorrect segmentation by the gold standard when the cortex was thin compared to trabeculae, or operator bias during hand contouring. Since Tb.Th, Tb.Sp, and Tb.N were insensitive to segmentation method, despite operator bias, they are robust parameters for inter site comparisons. The dual threshold method offers a robust and fully-automated alternative to the gold standard that can efficiently segment bone regions with accurate and repeatable results. The algorithm can be easily implemented since it uses simple image analysis tools. Two input thresholds allow adjustment of the masked output, and are easily determined by trial and error. Using the same input thresholds for similar datasets assures maximal consistency while alleviating time consuming semi-automated contouring. PMID- 17693148 TI - VEGF producing bone marrow stromal cells (BMSC) enhance vascularization and resorption of a natural coral bone substitute. AB - Bone graft substitutes often exhibit poor bone regeneration in large defects because of inadequate vascularization. Studies have shown that if blood supply is compromised, application of osteogenic factors alone could not induce successful healing. This study was to evaluate the effects of vascular endothelial growth factor, which combined with a coralline scaffold, on vascularization, scaffold resorption and osteogenesis in a rabbit radius critical size defect model. The scaffold was either coated with a control-plasmid DNA (group 1), coated with VEGF plasmid DNA (group 2), loaded with mesenchymal stem cells (BMSC) transfected with control plasmid (group 3) or with both stem cells and the VEGF plasmid (group 4). X-rays were taken every 4 weeks up to week 16, when animals were euthanized. The volume of new bone was measured by mu-CT scans and blood vessels were counted after anti-CD31 staining of endothelial cells. The results from the solitary VEGF and VEGF-transfected cells (groups 2 and 4) demonstrated significantly enhanced vascularization, osteogenesis and resorption of the carrier when compared to the control group. The highest degree of osteogenesis was found when the carrier was loaded with BMSC (group 3), whereas VEGF-transfected cells led to the highest vascularization and fastest resorption of the bone substitute. Additionally, VEGF transfected BMSC led to a more homogenous vascularization of the defect. The results indicate that VEGF can be a helpful factor to improve healing in large bone defects, in which bone substitutes will otherwise not be vascularized and replaced by fresh bone. PMID- 17693150 TI - Isokinetic training increases ulnar bending stiffness and bone mineral in young women. AB - Numerous studies have investigated the effects of physical activity on bone health; however, little is known about the effects of isokinetic strength training on bone. While bone mineral density (BMD) is widely used to assess bone health and fracture risk, there are several limitations of this measure that warrant new technology development to measure bone strength. The mechanical response tissue analyzer (MRTA) assesses bone strength by measuring maximal bending stiffness (EI). We hypothesized that isokinetic strength training of the elbow flexors and extensors would increase ulnar EI, BMD, and bone mineral content (BMC) in young women. Fifty-four women trained the nondominant arm 3 times per week for 20 weeks; 32 trained concentrically (CON) and 22 trained eccentrically (ECC). Subjects were assessed for the following variables pre- and post-training: CON and ECC peak torque of the elbow flexors and extensors with isokinetic dynamometry, ulnar mineral content and density using dual-energy X-ray absorptiometry, and ulnar EI using MRTA. Isokinetic training increased CON (17%) and ECC (17%) peak torque, even when controlling for changes in the untrained arm. Eccentric training increased CON and ECC peak torque while CON training improved CON peak torque only. Isokinetic training increased ulnar EI 28%, which was statistically greater than the untrained arm. Ulnar EI increased 25% with CON training and 32% with ECC training. Both training modes resulted in greater EI gains compared to the untrained limb. Isokinetic training increased ulnar BMC (2.7%) and BMD (2.3%), even when controlling for untrained ulna changes. Both training modalities resulted in BMC and BMD increases; however, only CON training yielded gains when controlling for changes in the untrained limb. In conclusion, isokinetic strength training increases ulnar EI, BMC, and BMD in young women; no statistical differences were noted between CON and ECC training modes. PMID- 17693151 TI - Highlight issue: enzymology of drug metabolism and toxicology. PMID- 17693154 TI - Medical students as champions for social justice. PMID- 17693149 TI - Type XXVII collagen at the transition of cartilage to bone during skeletogenesis. AB - COL27A1 is a member of the collagen fibrillar gene family and is expressed in cartilaginous tissues including the anlage of endochondral bone. To begin to understand its role in skeletogenesis, the temporospatial distributions of its RNA message and protein product, type XXVII collagen, were determined in developing human skeletal tissues. Laser capture microdissection and quantitative reverse-transcription polymerase chain reaction demonstrated that gene expression occurred throughout the growth plate and that it was higher in the resting and proliferative zones than in hypertrophic cartilage. Immunohistochemical analyses showed that type XXVII collagen was most evident in hypertrophic cartilage at the primary ossification center and at the growth plate and that it accumulated in the pericellular matrix. Synthesis of type XXVII collagen overlapped partly with that of type X collagen, a marker of chondrocyte hypertrophy, preceded the transition of cartilage to bone, and was associated with cartilage calcification. Immunogold electron microscopy of extracted ECM components from mouse growth plate showed that type XXVII collagen was a component of long non-banded fibrous structures, filamentous networks, and thin banded fibrils. The timing and location of synthesis suggest that type XXVII collagen plays a role during the calcification of cartilage and the transition of cartilage to bone. PMID- 17693155 TI - Looking for a volunteer to help fight dengue fever. PMID- 17693156 TI - Peace-keeping efforts in Darfur. PMID- 17693157 TI - Ductal carcinoma in situ and breast MRI. PMID- 17693158 TI - Stroke prevention in elderly patients with atrial fibrillation. PMID- 17693159 TI - Tetrahydrobiopterin for patients with phenylketonuria. PMID- 17693160 TI - Protecting the rights of those in conflict. PMID- 17693161 TI - When rumours derail a mass deworming exercise. PMID- 17693162 TI - Health care for refused asylum seekers in the UK. PMID- 17693163 TI - Clinical update: sporadic primary hyperparathyroidism. PMID- 17693164 TI - Joseph Graziano: tackling arsenic poisoning in Bangladesh. PMID- 17693165 TI - Health workers and vaccination coverage in developing countries. PMID- 17693166 TI - Health workers and vaccination coverage in developing countries. PMID- 17693167 TI - Health workers and vaccination coverage in developing countries. PMID- 17693168 TI - Health workers and vaccination coverage in developing countries. PMID- 17693170 TI - Long-term risks of increased use of intravenous iron. PMID- 17693171 TI - Long-term risks of increased use of intravenous iron. PMID- 17693173 TI - Measurement of health and disability. PMID- 17693174 TI - Risk-minimisation strategies for peanut allergy. PMID- 17693175 TI - Healing the wounds of Tiananmen: Beijing Olympics and beyond. PMID- 17693177 TI - MRI for diagnosis of pure ductal carcinoma in situ: a prospective observational study. AB - BACKGROUND: Diagnosing breast cancer in its intraductal stage might be helpful to prevent the development of invasive cancer. Our aim was to investigate the sensitivity with which ductal carcinoma in situ (DCIS) is diagnosed by mammography and by breast MRI. METHODS: During a 5-year period, 7319 women who were referred to an academic national breast centre received MRI in addition to mammography for diagnostic assessment and screening. Mammograms and breast MRI studies were assessed independently by different radiologists. We investigated the sensitivity of each method of detection and compared the biological profiles of mammography-diagnosed DCIS versus DCIS detected by MRI alone. We also compared the risk profiles of women with mammography-detected DCIS with those of MRI detected DCIS. FINDINGS: 193 women received a final surgical pathology diagnosis of pure DCIS. Of those, 167 had undergone both imaging tests preoperatively. 93 (56%) of these cases were diagnosed by mammography and 153 (92%) by MRI (p<0.0001). Of the 89 high-grade DCIS, 43 (48%) were missed by mammography, but diagnosed by MRI alone; all 43 cases missed by mammography were detected by MRI. By contrast, MRI detected 87 (98%) of these lesions; the two cases missed by MRI were detected by mammography. Age, menopausal status, personal or family history of breast cancer or of benign breast disease, and breast density of women with MRI-only diagnosed DCIS did not differ significantly from those of women with mammography-diagnosed DCIS. INTERPRETATION: MRI could help improve the ability to diagnose DCIS, especially DCIS with high nuclear grade. PMID- 17693178 TI - Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. AB - BACKGROUND: Anticoagulants are more effective than antiplatelet agents at reducing stroke risk in patients with atrial fibrillation, but whether this benefit outweighs the increased risk of bleeding in elderly patients is unknown. We assessed whether warfarin reduced risk of major stroke, arterial embolism, or other intracranial haemorrhage compared with aspirin in elderly patients. METHODS: 973 patients aged 75 years or over (mean age 81.5 years, SD 4.2) with atrial fibrillation were recruited from primary care and randomly assigned to warfarin (target international normalised ratio 2-3) or aspirin (75 mg per day). Follow-up was for a mean of 2.7 years (SD 1.2). The primary endpoint was fatal or disabling stroke (ischaemic or haemorrhagic), intracranial haemorrhage, or clinically significant arterial embolism. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN89345269. FINDINGS: There were 24 primary events (21 strokes, two other intracranial haemorrhages, and one systemic embolus) in people assigned to warfarin and 48 primary events (44 strokes, one other intracranial haemorrhage, and three systemic emboli) in people assigned to aspirin (yearly risk 1.8%vs 3.8%, relative risk 0.48, 95% CI 0.28-0.80, p=0.003; absolute yearly risk reduction 2%, 95% CI 0.7-3.2). Yearly risk of extracranial haemorrhage was 1.4% (warfarin) versus 1.6% (aspirin) (relative risk 0.87, 0.43-1.73; absolute risk reduction 0.2%, -0.7 to 1.2). INTERPRETATION: These data support the use of anticoagulation therapy for people aged over 75 who have atrial fibrillation, unless there are contraindications or the patient decides that the benefits are not worth the inconvenience. PMID- 17693179 TI - Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. AB - BACKGROUND: Early and strict dietary management of phenylketonuria is the only option to prevent mental retardation. We aimed to test the efficacy of sapropterin, a synthetic form of tetrahydrobiopterin (BH4), for reduction of blood phenylalanine concentration. METHODS: We enrolled 89 patients with phenylketonuria in a Phase III, multicentre, randomised, double-blind, placebo controlled trial. We randomly assigned 42 patients to receive oral doses of sapropterin (10 mg/kg) and 47 patients to receive placebo, once daily for 6 weeks. The primary endpoint was mean change from baseline in concentration of phenylalanine in blood after 6 weeks. Analysis was on an intention-to-treat basis. The study is registered with ClinicalTrials.gov, number NCT00104247. FINDINGS: 88 of 89 enrolled patients received at least one dose of study drug, and 87 attended the week 6 visit. Mean age was 20 (SD 9.7) years. At baseline, mean concentration of phenylalanine in blood was 843 (300) micromol/L in patients assigned to receive sapropterin, and 888 (323) micromol/L in controls. After 6 weeks of treatment, patients given sapropterin had a decrease in mean blood phenylalanine of 236 (257) micromol/L, compared with a 3 (240) micromol/L increase in the placebo group (p<0.0001). After 6 weeks, 18/41 (44%) patients (95% CI 28-60) in the sapropterin group and 4/47 (9%) controls (95% CI 2-20) had a reduction in blood phenylalanine concentration of 30% or greater from baseline. Blood phenylalanine concentrations fell by about 200 micromol/L after 1 week in the sapropterin group and this reduction persisted for the remaining 5 weeks of the study (p<0.0001). 11/47 (23%) patients in the sapropterin group and 8/41 (20%) in the placebo group experienced adverse events that might have been drug related (p=0.80). Upper respiratory tract infections were the most common disorder. INTERPRETATION: In some patients with phenylketonuria who are responsive to BH4, sapropterin treatment to reduce blood phenylalanine could be used as an adjunct to a restrictive low-phenylalanine diet, and might even replace the diet in some instances. PMID- 17693180 TI - Nutritional iron deficiency. AB - Iron deficiency is one of the leading risk factors for disability and death worldwide, affecting an estimated 2 billion people. Nutritional iron deficiency arises when physiological requirements cannot be met by iron absorption from diet. Dietary iron bioavailability is low in populations consuming monotonous plant-based diets. The high prevalence of iron deficiency in the developing world has substantial health and economic costs, including poor pregnancy outcome, impaired school performance, and decreased productivity. Recent studies have reported how the body regulates iron absorption and metabolism in response to changing iron status by upregulation or downregulation of key intestinal and hepatic proteins. Targeted iron supplementation, iron fortification of foods, or both, can control iron deficiency in populations. Although technical challenges limit the amount of bioavailable iron compounds that can be used in food fortification, studies show that iron fortification can be an effective strategy against nutritional iron deficiency. Specific laboratory measures of iron status should be used to assess the need for fortification and to monitor these interventions. Selective plant breeding and genetic engineering are promising new approaches to improve dietary iron nutritional quality. PMID- 17693181 TI - Do human rights matter to health? AB - Legal instruments and litigation as a way to enforce the rights to life and to health is a relatively new strategy that is increasingly common. We show how legal measures have been used to attain health and human rights with case examples from India and South Africa that resulted in large public-health benefits. PMID- 17693182 TI - Photoprotection. AB - Sun exposure is the main cause of photocarcinogenesis, photoageing, and photosensitivity; thus, photoprotection is an important issue. In a skin cancer prevention strategy, behavioural measures--eg, wearing sun protective clothes and a hat and reducing sun exposure to a minimum--should be preferred to sunscreens. Often this solution is deemed to be unacceptable in our global, outdoor society, and sunscreens could become the predominant mode of sun protection for various societal reasons (eg, healthiness of a tan, relaxation in the sun). The application of a liberal quantity of sunscreen has been shown to be by far the most important factor for effectiveness of the sunscreen, followed by the uniformity of application and the specific absorption spectrum of the agent used. The sunscreen market--crowded by numerous products--shows various differences worldwide. Nevertheless, sunscreens should not be abused in an attempt to increase time in the sun to a maximum. Controversies about safety of sunscreens and clinical recommendations are discussed. PMID- 17693183 TI - Hearing dysphasic voices. PMID- 17693184 TI - Heterogeneity of PLAG1 gene rearrangements in pleomorphic adenoma. AB - Pleomorphic adenoma (PA), a benign mixed salivary gland tumor, has been associated with abnormal karyotypes in up to 70% of cases, with nonrandom involvement of 8q12, the locus of the pleomorphic adenoma (PLAG1) gene. In this study, cytogenetics and fluorescence in situ hybridization (FISH) were used to investigate PLAG1 involvement in PA from seven patients. There were two males and five females ranging in age from 25 to 65 years. Samples of parotid gland tissue from the tumor sites, set up as solid tumor cultures, showed a normal karyotype in two cases [46,XY;46,XX] and cytogenetic abnormalities in five cases (71%). The abnormalities comprised one variant translocation [t(1;4;8)(p32;q35;q12)], two classic translocations [t(5;8)(p13;q12)], one novel deletion [del(12)(p11.2p12.1)], and a novel insertion [ins(9;8)(p22;q12q21.1)]. FISH was performed in all cases by using two probes from the RP11 library, flanking PLAG1; a sequence 1.48 megabases (Mb) upstream and another 2.27 Mb downstream, covering a total area of 3.8 Mb. The PLAG1 gene was intact and normally situated in four cases - the 46,XY, 46,XX, del(12p), and one t(5;8). PLAG1 was disrupted in three cases - one t(5;8), ins(9;8), and t(1;4;8). In addition, genomic instability was seen in two cases, one with PLAG1 amplification in the form of a homogeneously staining region, and the other in der(8) ring formation. The data provide further unique cases showing the complexity of PLAG1 gene rearrangements in PA. PMID- 17693185 TI - The interferon-alpha responsive gene TMEM7 suppresses cell proliferation and is downregulated in human hepatocellular carcinoma. AB - Multiple regions on the chromosome arm 3p are frequently affected by loss of heterozygosity in human cancers. A candidate tumor suppressor gene is TMEM7, at 3p21.3, which encodes a transmembrane protein. TMEM7 is expressed specifically in the liver, and the encoded protein shares substantial sequence homology with human and mouse 28-kDa interferon-alpha (IFN-alpha) responsive protein. In investigation of the possible role of TMEM7 in development of hepatocellular carcinoma (HCC), we examined TMEM7 expression in 20 primary HCC and 18 HCC cell lines and found recurrent functional alterations. Although TMEM7 mRNA was expressed in normal hepatic cells, downregulation or inactivation of the gene was detected in 85% of primary HCC and 33% of HCC cell lines. To identify the mechanisms responsible, we examined genomic deletion and mutation, and also the effect of inhibitors of DNA methyltransferase and histone deacetylase on cells with low or no endogenous TMEM7 expression. Homozygous deletion of TMEM7 was not detected in 17 pairs of human HCC and corresponding noncancerous liver tissues, nor in any of the 18 HCC cell lines. TMEM7 mutation was not detected in the 18 HCC cell lines (low or normal TMEM7 expression). Treatment of two of six cell lines exhibiting downregulation or loss of TMEM7 with 5-aza-2'-deoxycytidine and trichostatin A yielded additive increase in TMEM7 expression, implicating aberrant DNA methylation and histone deacetylation in transcriptional silencing of this gene. Ectopic expression of TMEM7 in two TMEM7-deficient HCC lines suppressed cell proliferation, colony formation, and cell migration in vitro and reduced tumor formation in nude mice. Treatment of two highly invasive HCC cell lines with IFN-alpha for 7 days significantly increased TMEM7 expression and inhibited cell migration. These findings implicate loss of TMEM7 expression in hepatocarcinogenesis and suggest that modification of TMEM7 expression by IFN alpha may have therapeutic relevance in a subset of HCC. PMID- 17693186 TI - Genomic imbalances in Schistosoma-associated and non-Schistosoma-associated bladder carcinoma. An array comparative genomic hybridization analysis. AB - Carcinoma of the urinary bladder is the most common malignancy in many tropical and subtropical countries due to endemic infection by Schistosoma hematobium (bilharzia). In the current study, we performed a high-resolution analysis of gene copy number amplifications using array comparative genomic hybridization to compare DNA copy number changes in pools of Schistosoma-associated (SA) and non Schistosoma-associated (NSA) bladder cancer (BC). Many DNA copy number changes were detected in all studies, with multiple gains and losses of genetic material. The most frequent alterations were gains on 5p15.2 approximately p15.33, 8q13.1, and 11q13, and losses on 8p21.3 approximately p22 and 22q13. Even when SA pools showed no Schistosoma-specific gene copy number profiling as compared to NSA pools, some genes seemed to be gained (ELN on 7q11.23) and some lost (PRKAG3 on 2q35 and PRDM6 on 5q23.2) in SA-SCC. The following genes were gained in all histopathologic categories: SRC (20q11.23), CEBPB (20q13.13), and GPR9 (Xq13.1). Our study did not provide clear evidence of differences in carcinogenesis of SA BC and NSA-BC. PMID- 17693187 TI - Identification and characterization of DNA imbalances in neuroblastoma by high resolution oligonucleotide array comparative genomic hybridization. AB - Neuroblastoma (NB) is a pediatric tumor characterized by high genetic heterogeneity. Although the prognostic significance of some genomic abnormalities (i.e., MYCN amplification, 1p loss, and 17q gain) is recognized, genes that are involved in chromosome rearrangements remain largely unknown. Considerable progress has been made over the last years in characterizing DNA abnormalities by metaphase comparative genomic hybridization (mCGH) and array CGH (aCGH). Here we report a pilot study of 5 localized and 12 disseminated NB by 44,000 and of 4 out of 17 cases by 244,000 oligonucleotide aCGH. Localized tumors were predominantly characterized by losses of whole chromosomes 3, 4, 10, and 16, and gains of 6, 7, 8, 13, 17, 18, and 20, whereas disseminated tumors showed several structural aberrations including 17q gain and 3p and 11q losses. Characterization of chromosome 2p in MYCN-amplified NB revealed several structural rearrangements with regions of gain interspersed among sites of amplification, indicating that the MYCN amplicon may encompass several genes. The high-resolution zooming in chromosomal aberrant regions detected several micro-deletions and micro amplifications in the NB genome. Our results indicate that the increased sensitivity of the aCGH also allows the identification of DNA aberrations in challenging samples (i.e., NB showing tissue and genetic heterogeneity). PMID- 17693188 TI - Polymorphisms of the DNA gene XPD and risk of bladder cancer in a Southeastern Chinese population. AB - The incidence rate for bladder cancer has been increasing in many countries, and bladder cancer is the most common urinary cancer in China. We explored the association of single-nucleotide polymorphisms in DNA repair genes with bladder cancer. The hypothesis is that the xeroderma pigmentosum complementary group D (XPD) 156-22541C-->A and 751-35931A-->C polymorphisms are associated with the risk of bladder cancer. In a population-based case-control study, 215 patients with newly diagnosed bladder transitional cell carcinoma and 245 cancer-free controls/healthy subjects (frequency-matched by the age and sex) were genotyped. These two polymorphisms were studied using the polymerase chain reaction restriction fragment length polymorphism method. We found that the A allele of XPD Arg156Arg (C22541A) and the C allele of XPD Lys751Gln (A35931C) is associated with increased risk of bladder cancer (adjusted odds ratio = 1.54 and 95% confidence interval = 1.19-2.01, 1.65, and 1.12-2.73, respectively). Smoking is also a risk factor in the etiology of bladder cancer, but alcohol intake is a protective factor during the development of bladder cancer. These two XPD polymorphisms may play an important role in the etiology of bladder cancer in the southeastern Chinese population. PMID- 17693189 TI - Aberrant EVI1 expression in acute myeloid leukemias associated with the t(3;8)(q26;q24). AB - EVI is a proto-oncogene that is activated in acute myeloid leukemia with chromosomal rearrangements that map to chromosome 3q26. We previously reported the clinicopathologic features of five cases of acute myeloid leukemia carrying t(3;8)(q26;q24). Using fluorescence in situ hybridization analysis, we demonstrate in the current study that the breakpoint on chromosome 3 is at EVI1/MDS1, and the breakpoint on chromosome 8 is just distal to the PVT1 oncogene homolog, a C-MYC activator in mice. The breakpoint on chromosome 8 was detected between the components of the LSI MYC dual-color break-apart rearrangement probe. Reverse-transcriptase polymerase chain reaction assay showed expression of EVI1 in all four cases analyzed, and DNA sequence analysis confirmed the findings. Reverse transcriptase polymerase chain reaction assay also demonstrated the expression of PVT1 and C-MYC in all four cases assessed. Western blot analysis detected EVI1 in one case analyzed. We conclude that the t(3;8)(q26;q24) results in deregulated EVI1 expression, similar to other balanced or unbalanced chromosomal translocations involving chromosome 3q26. PMID- 17693190 TI - Altered transforming growth factor-beta pathway expression pattern in rat endometrial cancer. AB - Endometrial cancer is the most abundant female gynecologic malignancy, ranking fourth in incidence among invasive tumors in women. Females of the BDII inbred rat strain are extremely prone to endometrial adenocarcinoma (EAC), and approximately 90% of virgin females spontaneously develop EAC during their lifetime. Thus, these rats serve as a useful model for the genetic analysis of this malignancy. In the present work, gene expression profiling, by means of cDNA microarrays, was performed on cDNA from endometrial tumor cell lines and from cell lines derived from nonmalignant lesions/normal tissues of the endometrium. We identified several genes associated with the transforming growth factor-beta (TGF-beta) pathway to be differentially expressed between endometrial tumor cell lines and nonmalignant lesions by using clustering and statistical inference analyses. The expression levels of the genes involved in the TGF-beta pathway were independently verified using semiquantitative reverse-transcription polymerase chain reaction. Repressed TGF-beta signaling has been reported previously in EAC carcinogenesis, but this is the first report demonstrating aberrations in the expression of TGF-beta downstream target genes. We propose that the irregularities present in TGF-beta pathway among the majority of the EAC tumor cell lines may affect EAC carcinogenesis. PMID- 17693192 TI - Malignant solitary fibrous tumor of the soft tissue: a cytogenetic study. AB - We report on a case of a solitary fibrous tumor that developed in the thigh of an 82-year-old woman. The tumor was composed of areas of high-grade sarcoma and typical solitary fibrous tumor. Its karyotype was: 70,XXX,+X[4],+1[2],add(1)(p36)[4],add(1)[2],+2[4], 3[4],+6[4],add(6)(p11)x2[4],+7[4],+9[3],-11[4],-12[4],-13[4],add(13)(p11)x2[4], 14[4],+15[4],-16[3],-17[4],-19[4],+20,[4],+21[4],+22[2],+mar1x2[4][cp4]. PMID- 17693191 TI - PRAME expression is not associated with down-regulation of retinoic acid signaling in primary acute myeloid leukemia. AB - The tumor antigen preferentially expressed antigen of melanoma (PRAME) is frequently overexpressed in a wide variety of malignant diseases, including acute myeloid leukemia (AML). It was recently shown that PRAME can function as a repressor of retinoic acid signaling, as indicated by down-regulation of retinoic acid receptor-beta (RARB) and cyclin-dependent kinase inhibitor 1A (CDKN1A). Another study suggested that PRAME can induce caspase-independent apoptosis via down-regulation of heat shock 27-kDa protein 1 (HSPB1) and S100 calcium-binding protein A4 (S100A4). The transcriptional repression of PRAME depends on the formation of a complex with the enhancer of zeste homolog 2 (EZH2). To test whether these mechanisms play an important roll in AML, we analyzed the expression of PRAME, EZH2, RARB, HSPB1, S100A4, and CDKN1A by real-time polymerase chain reaction in primary leukemic cells from 52 children with AML. All genes were expressed in many patients, but the level of expression of the last four genes was not associated with either PRAME expression or PRAME and EZH2 co-expression. In conclusion, the above mechanisms do not seem to play a major role in the pathogenesis of AML; they could be neutralized by other pathways that affect the same targets. PMID- 17693193 TI - Unstable translocation (8;22) in a case of giant cell reparative granuloma. AB - Giant cell reparative granuloma (GCRG) is an uncommon lesion most often affecting the jaw but also the small bones of the hands and feet. GCRG overlaps clinically and radiographically with other giant cell-rich tumors such as giant cell tumor of bone (GCTB) and aneurysmal bone cyst (ABC). In the only case of a cytogenetically investigated GCRG reported previously, a balanced translocation involving chromosomes 4 and X was found. In the present study, chromosome banding and fluorescence in situ hybridization (FISH) analyses were used to characterize the primary lesion and local recurrence of a GCRG in the thumb and skin biopsy of a 45-year-old woman. The skin showed a normal karyotype. Various forms of a dic(8;22) containing 8q, 22q, and smaller or larger parts of 8p were found in both GCRG samples. In addition, ring chromosomes, most often composed of chromosome 11 material, and telomeric associations were found. The latter aberrations were more frequent in the primary lesion. Normal FISH signals were seen when using probes capable of detecting USP6 rearrangements. The variant 8;22 aberrations were interpreted to originate from an unstable dic(8;22)(p23;p11) that gradually evolved into a functionally monocentric chromosome in the dominating subset of cell populations. We conclude that our case of GCRG shared several cytogenetic characteristics with GCTB but none with ABC. PMID- 17693194 TI - Feasibility of using the combined MDS-EVI1/EVI1 gene expression as an alternative molecular marker in acute myeloid leukemia: a report of four cases. AB - To establish an additional marker for polymerase chain reaction (PCR)-based measurement of minimal residual disease (MRD) detection in acute myeloid leukemia (AML), the expression level of the combined MDS1-EVI1 and EVI1 gene was quantified by real-time reverse transcription PCR (RT-PCR) in four AML cases at initial presentation and as a follow-up marker during anti-leukemic therapy. Quantification of the MDS1-EVI1/EVI1 gene expression correlated closely to the clinical course of the disease in all four cases. A hematologic complete remission was accompanied by a reduction of MDS1-EVI1/ EVI1 expression levels of at least 2 log while persistent leukemia was reflected by an MDS1-EVI1/ EVI1 expression in the range of the primary diagnostic sample. After achieving a complete cytomorphologic remission, three patients relapsed after 154, 210, and 280 days, respectively. Molecular relapse was detected on the basis of increasing expression levels of MDS1-EVI/EVI 29, 36, and 93 days before hematologic manifestation. In conclusion, the combined MDS-EVI1/EVI1 gene may serve as an alternative MRD marker in AML, especially in samples where other specific markers are lacking. PMID- 17693195 TI - Monosomy 7 mosaicism in metastatic choroidal melanoma. AB - Uveal melanoma is the most common primary intraocular malignancy in adults. Several cytogenetic studies on uveal melanoma cells have revealed that the majority of these cells harbor alterations in chromosomes 3, 6, and 8. This report describes the results of cytogenetic analysis performed on a fresh choroidal melanoma tissue sample from a patient with cerebellar metastasis. Monosomy 7 mosaicism was observed. To our knowledge, monosomy 7 has not been reported in patients with uveal melanoma. We suggest that observation of monosomy 7 may be related to an aggressive clinical behavior and unusual cerebellar metastasis in uveal melanoma. Further data are necessary to define the exact role of monosomy 7 in the pathogenesis and evolution of uveal melanoma. PMID- 17693196 TI - Chronic myeloid leukemia in an XX male. PMID- 17693197 TI - Robertsonian translocations in stem cell recipients as a possible indication for cytogenetic analysis of family donors. PMID- 17693198 TI - Adult T-cell leukemia/lymphoma with a complex karyotype and central nervous system involvement. PMID- 17693199 TI - Concomitant t(4;11) and t(1;19) in a patient with biphenotypic acute leukemia. PMID- 17693201 TI - Airway physiology and clinical function testing. AB - The advent of pulmonary function testing in small animals has opened the door to new interpretations of old diseases. This article reviews the salient features of airway pathophysiology in dogs and cats that relate to the interpretation of newly developed airway function tests. PMID- 17693202 TI - Respiratory defenses in health and disease. AB - Every breath holds the potential to introduce infectious organisms and irritating particulates into the respiratory tract. Despite this continuous exposure, the lungs usually remain sterile. Further, potential pathogens are distinguished from innocuous particulates, thus sparing the respiratory tract from damaging inflammation. The article reviews the complex defenses used to protect the respiratory tract and also discusses the implications of failed defense systems. PMID- 17693203 TI - Approach to the respiratory patient. AB - Several challenges arise when evaluating a dog or cat with respiratory disease. The history can span a long period, and some owners may have a difficult time in recognizing or describing respiratory abnormalities. A good history and thorough physical examination are essential when evaluating the respiratory patient. There are some noninvasive diagnostics that can aid in the diagnosis of respiratory disease; however, other more invasive tests often require anesthesia, which can be a potential hazard with a respiratory patient. This article focuses on reviewing the function of the respiratory system and how best to identify and diagnose cats and dogs with respiratory disease by implementing a thorough history and physical examination as well as appropriate diagnostic testing. PMID- 17693204 TI - Advances in respiratory imaging. AB - Although conventional radiography is still the first diagnostic imaging approach to respiratory disease, CT is proving to be invaluable as an adjunctive procedure in characterizing nasal and thoracic pathologic findings. CT eliminates superimposition of overlying structures and offers superior contrast resolution as compared with conventional radiography. These advantages allow for more precise characterization and localization of lesions and are invaluable for guiding rhinoscopic, bronchoscopic, and surgical procedures. PMID- 17693205 TI - Update on canine sinonasal aspergillosis. AB - Sinonasal aspergillosis is a frequent cause of nasal discharge that occurs in otherwise healthy, young to middle-aged dogs. A local immune dysfunction is suspected in affected animals, and the role of increased interleukin-10 mRNA expression in the nasal mucosa of affected dogs is currently under investigation. Despite recent advances in imaging techniques, the "gold standard" for diagnosing the disease is direct visualization of fungal plaques during endoscopy or observation of fungal elements on cytology or histopathologic examination. Treatment can be challenging; however, the use of topical enilconazole or clotrimazole through noninvasive techniques has increased the success of treatment and decreased the morbidity and duration of hospitalization. PMID- 17693206 TI - Canine eosinophilic bronchopneumopathy. AB - Eosinophilic bronchopneumopathy (EBP) is a disease characterized by eosinophilic infiltration of the lung and bronchial mucosa, as demonstrated by examination of bronchoalveolar lavage fluid cytologic preparations or histologic examination of the bronchial mucosa. Although the precise cause of EBP is unknown, a hypersensitivity to aeroallergens is suspected. The diagnosis relies on typical history and clinical signs, demonstration of bronchopulmonary eosinophilia by cytology or histopathologic examination, and exclusion of known causes of lower airway eosinophilia. Most dogs display an excellent response to oral corticosteroid therapy; however, side effects of this treatment can be limiting. New therapeutic approaches are being studied, including the use of aerosol therapy, cyclosporine, or drugs interfering with T helper 2 immune response. PMID- 17693207 TI - Interstitial lung diseases. AB - Several noninfectious nonneoplastic interstitial lung diseases (ILDs) have been recognized in dogs and cats. Overall, these ILDs are poorly characterized in dogs and cats, although awareness of the conditions based on descriptions of clinical case series may be increasing. Lung biopsy remains crucial to the diagnosis, characterization, and classification of ILDs. Histopathologic findings can help to guide clinicians in selecting appropriate therapy and providing an accurate prognosis to pet owners. Only with definitive recognition of these pulmonary conditions can our knowledge of the clinical course and response to therapy be improved. PMID- 17693208 TI - Cardiac effects of pulmonary disease. AB - Pulmonary hypertension (PHT) is the primary cardiac consequence of pulmonary disease. It develops as alveolar hypoxia of pulmonary disease, coupled with vasoactive and mitogenic substances released from pulmonary endothelial and vascular smooth muscle cells damaged by the primary disease process, mediates arterial vasoconstriction and vascular remodeling to raise pulmonary vascular resistance. Independent of the underlying pulmonary disease, PHT produces clinical signs of respiratory distress, exercise intolerance, syncope, and right heart failure. Diagnosis of PHT is made by estimation of pulmonary artery pressures by means of continuous-wave Doppler echocardiographic assessment of tricuspid or pulmonic regurgitant flow velocity. Treatment of PHT is directed at the underlying pulmonary disease but may also aim to attenuate pulmonary artery pressure and limit the clinical sequelae of PHT. No treatments are of proven benefit in veterinary patients; irrespective of the nature of the inciting pulmonary disease, the prognosis is often grave. PMID- 17693209 TI - Advances in respiratory therapy. AB - Effective respiratory therapy depends on obtaining a definitive diagnosis and following established recommendations for treatment. Unfortunately, many respiratory conditions are idiopathic in origin or are attributable to nonspecific inflammation. In some situations, disorders are controlled rather than cured. Recent advances in pulmonary therapeutics include the use of new agents to treat common diseases and application of local delivery of drugs to enhance drug effect and minimize side effects. PMID- 17693210 TI - Medical and surgical management of pyothorax. AB - Pyothorax is the accumulation of septic suppurative inflammation within the pleural cavity. The cause and source of infection in dogs and cats often are unknown. Management of these cases can be challenging, because controversy exists over the best method for treatment. Reported outcomes and recurrence rates vary widely. PMID- 17693211 TI - Nutritional considerations for animals with pulmonary disease. AB - Recent publications in the human and veterinary literature have indicated that patients with pulmonary disease require specific nutritional consideration to ensure that optimal benefit is derived with nutrition support. Although additional research is needed in this area, preliminary recommendations can be made using information from the scant studies performed thus far in veterinary medicine and from information extrapolated from the human literature. These recommendations are likely to provide significant clinical benefit to patients with pulmonary disease. This article aims to provide the reader with a summary of the available information and links to other relevant sources. PMID- 17693213 TI - Health beliefs and high-risk sexual behaviors among HIV-infected African American men. AB - The purpose of this study was to describe whether the health beliefs of HIV infected African American heterosexual men and men who have sex with men predict condom use during anal, vaginal, and oral sex. The sample consisted of 130 HIV infected African American men with a mean age of 46 years. Multiple logistic regression analysis showed that the odds of noncondom use during anal sex was highest among heterosexual men and those with perceived barriers to condoms. Furthermore, participants without a relationship and those not discussing safe sex with their partners were more likely not to use condoms during vaginal sex. PMID- 17693214 TI - Reliability and validity of the self-efficacy expectations and outcome expectations after implantable cardioverter defibrillator implantation scales. AB - The purpose of this study was to assess the reliability and validity characteristics of two new scales that measure self-efficacy expectations (Self Efficacy Expectations After Implantable Cardioverter Defibrillator Implantation Scale [SE-ICD]) and outcome expectations (Outcome Expectations After ICD Implantation Scale [OE-ICD]) in survivors (N = 168) of sudden cardiac arrest, all of whom received an ICD. Cronbach's alpha reliability demonstrated good internal consistency (SE-ICD alpha = .93 and OE-ICD alpha = .81). Correlations with other self-efficacy instruments (general self-efficacy and social self-efficacy) were consistently high. The instruments were responsive to change across time with effect sizes of .46 for SE-ICD and .26 for OE-ICD. These reliable, valid, and responsive instruments for measurement of self-efficacy expectations and outcome expectations after an ICD can be used in research and clinical settings. PMID- 17693215 TI - Effects of a theory-driven music and movement program for stroke survivors in a community setting. AB - Many countries lack effective community-based rehabilitation programs despite the increasing numbers of stroke survivors. Therefore, we have conducted a pilot investigation in South Korea of a newly constructed community-based intervention program combining rhythmic music and specialized rehabilitation movement. The 8 week program was based on rhythmic auditory stimulation (RAS) theory, which uses rhythm to enhance stroke survivors' movements. Thirty-three stroke survivors were randomized into one of two groups: The experimental group (n = 16) carried out an 8-week RAS music-movement exercise intervention; the control group (n = 17) received referral information about available usual care services. Participants in the experimental group gained a wider range of motion and flexibility, had more positive moods, and reported increased frequency and quality of interpersonal relationships. PMID- 17693216 TI - Emergency nurses' knowledge, attitudes, and experiential survey on advance directives. AB - The purpose of this study was to determine emergency nurses' knowledge of, attitudes toward, and experiences with advance directives (ADs). This was a descriptive, correlation, mailed survey study sent to a random sample of members of the Emergency Nurses Association. The results, based on the responses of 579 emergency nurses, found that the nurses were not very knowledgeable about ADs in general (68% correct) and even less knowledgeable about the Patient Self Determination Act (PSDA) (51% correct) and their state laws (56% correct). The nurses were experienced with ADs but they were less confident in their ability to assist patients with completing ADs. Forty-seven percent of the nurses agreed that actively assisting some terminally ill patients to die should be made legal. Nurses need information pertaining to ADs in general, the PSDA, and their individual state laws. This could increase their level of confidence in being able to effectively assist patients to understand and complete ADs. PMID- 17693217 TI - Nursing of malnourished children with emphasis on polyunsaturated fatty acids. AB - Omega-3 (Omega-3) and omega-6 (Omega-6) fatty acids (FAs) are essential FAs needed for brain and retina development and maintenance of red blood cell (RBC) membranes. This study investigated the association between the profile of FAs in the membranes of RBCs and malnutrition in children. Demographic, anthropometric, and breast-feeding data and blood samples for analysis of FAs were obtained from malnourished and well-nourished children. The results indicate significant between-group differences in the profile of FAs. These findings support the need for adequate intake of Omega-3 FAs in promoting optimal growth and development processes and emphasize the role of nurses as providers of nutritional and anticipatory guidance for parents and caretakers. PMID- 17693218 TI - "Getting into the skin": empathy and role taking in certified nursing assistants' care of dying residents. AB - Twenty-four percent of Americans die in nursing homes, and 80% to 95% of nursing home care is delivered by certified nursing assistants (CNAs). Interview data were collected from 27 CNAs at three facilities. Data were coded and analyzed for recurrent themes using the concepts of empathy and role taking. The results revealed that CNAs used role taking to guide their caregiving actions and to understand the emotional experience of residents. Compassionate detachment, a hallmark of empathy, was evident in effective care, but problems with the ability to detach were also revealed. Organizational factors that supported empathy and those that undermined empathy were also examined. Recommendations for improving care are discussed in this article. PMID- 17693219 TI - Sample size considerations when groups are the appropriate unit of analysis. AB - This article discusses issues to be considered by nurse researchers when groups should be used as the unit of randomization. Advantages and disadvantages are presented, with statistical calculations needed to determine the effective sample size. Examples of these concepts are presented using data from the Black Cosmetologists Promoting Health Program. Different hypothetical scenarios and their impact on sample size are also presented. Given the complexity of calculating the sample size when using groups as the unit of randomization, it is advantageous for researchers to work closely with statisticians when designing and implementing studies that anticipate the use of groups as the unit of randomization. PMID- 17693220 TI - A profile of Irish and U.S. nursing homes: evidence for change. PMID- 17693222 TI - Editorial developments at the journal. PMID- 17693223 TI - References to tuberculosis in Greek popular music (Rebetico). PMID- 17693224 TI - Co-morbidity does not reflect complexity in internal medicine patients. AB - Internal medicine patients are mostly elderly; they have multiple co-morbidities, which are usually chronic, rather than self-limiting or acute diseases. Neither administrative indicators nor co-morbidity indexes, though validated in elderly patients, are able to completely define these "complex" patients or to allow physicians to correctly "cope" with them. For the complex patients found in internal medicine wards, internists need not only to find the best diagnosis and treatment, but also to apply a complex intervention (i.e., a comprehensive assessment and both continuous and multi-disciplinary care) in order to maintain their health and ability to function and to prevent or delay disability, frailty, and displacement from home and community. The aim of this review is to underscore the differences between the concepts of co-morbidity and complexity, to discuss instruments for their measurement, and to highlight related implications, areas of uncertainty, and the responsibilities of internists in the assessment and management of inpatients of their wards. The conclusion we come to is that it is mandatory to shift from a finance/administrative-based management system to a clinical process model (clinical governance) driven by the quality of the medical outcome and the cost of achieving that outcome. From a "complexity theory" standpoint, patient-centered care and collaboration can be seen as simple rules that guide desirable behaviors in a complex system. By exploring the real complexity of our patients, we exercise the holistic, anthropologic medicine of the person that is internal medicine. PMID- 17693225 TI - Stress-induced cardiomyopathy: A review. AB - In clinical practice it is essential to bear stress-induced cardiomyopathy (SICMP) in mind as it is an insufficiently known cardiac pathology that mimics acute coronary syndromes (ACS), often with signs of cardiac failure. In the chronic phase, it poses differential diagnostic problems with regard to coronary artery pathology. Taxonomic confusion, due to the pathology also being called "takotsubo" or "ampulla cardiomyopathy", has resulted in inappropriate diagnoses and therapy. Available evidence strongly suggests that, in the presence of several cardiac risk factors, excessive sympathetic stimulation may induce this cardiomyopathy. The predilection of this cardiomyopathy for Mediterranean and Indo-Asian women, who represent 85% of cases, is probably explained by the fact that there is a significant correlation between female gender, a short (<158 cm) stature, a small (<1.9 m(2)) body surface area, and hypoplastic coronary arteries. Furthermore, 40% of SICMP patients have a hypoplastic branching of the coronary arteries in the apical region of the heart. This anomaly strongly favors the apical localization of the dyskinesia. The prognosis of SICMP is good as far as life expectancy is concerned. However, in most cases, the symptoms become chronic, medical treatment rarely improves dyspnea and chest pain, and the quality of life is, therefore, reduced. In this paper, we address diagnostic misunderstandings and we review the clinical and pathophysiological features of SICMP. PMID- 17693226 TI - Thyrotoxic hypokalemic periodic paralysis: An overlooked pathology in western countries. AB - Thyrotoxic hypokalemic periodic paralysis (THPP) is a complication of hyperthyroidism that is mostly diagnosed in Asian populations; consequently, it can be difficult to recognize in western populations. THPP represents an endocrine emergency that can result in respiratory insufficiency, cardiac arrhythmias, and death. Its differential diagnosis from the other more common forms of hypokalemic paralysis is important to avoid inappropriate therapy. Here, we discuss the main pathogenetic hypotheses, clinical features, and therapies of this disease. We also report an example of THPP management in our primary care unit. PMID- 17693227 TI - The diseases we cause: Iatrogenic illness in a department of internal medicine. AB - BACKGROUND: The aim of this study was to estimate the incidence, main causes, and risk factors of iatrogenic disease occurring in a department of internal medicine. METHODS: Over a 1-year period, physicians systematically filled out a 2 page questionnaire for all patients admitted to the ward. A database was created and the data were statistically analyzed. Patients undergoing immunosuppressive, chemo-, or radiation therapy were excluded. Missing data were completed by reviewing the patients' charts. The patients were then divided into two groups: those with and those without iatrogenic disease. The groups were compared using several parameters including gender, age, social features, days of hospitalization, associated illness, functional status, medical impression, prognosis, associated renal or liver function impairment, drugs taken daily, and outcome. In the group with iatrogenic disease, the type, severity, and predictability were also analyzed. RESULTS: Of the 879 patients admitted to the ward, 445 completed questionnaires and were included in the study. A total of 102 patients (22.9%) developed 121 iatrogenic events. Forty-four patients (43.1%) were admitted for iatrogenic illness, 10 (9.8%) developed life-threatening events, and in 3 (6.8%) it was the cause of death. Fifty-eight patients (56.8%) registered 77 episodes of iatrogenic disease during their hospital stay, 20 (19.6%) developed life-threatening events, and 9 (11.7%) died, 4 (5.2%) of an iatrogenic cause (nosocomial infections). Significant differences were found in 20 out of 26 parameters studied (p<0.005 for all cases; 95% confidence interval). Eighteen percent of all iatrogenic disease was severe, 61.9% predictable, 54.5% avoidable, and 59% drug-related, 80% of which was due to side effects or adverse reactions. Infection and metabolic and electrolyte disorders were the most frequent effects. CONCLUSIONS: It is possible to identify risk factors for iatrogenic events. Chronically ill elderly inpatients are the main target of iatrogenic events. PMID- 17693228 TI - Economic evaluation of assistance to HIV patients in a Spanish hospital. AB - BACKGROUND: Little is known about the global effects of HAART on the use of medical resources after the complete implementation of this therapy in Spain. This study was designed to determine the use of medical resources and the costs of health care for HIV-infected patients. METHODS: All patients with HIV infection who came to our institution during the year 2002 were included in the study. We analyzed the global assistance data and pharmaceutical costs during the year. Costs were calculated based on a unitary cost for DRG and an officially assigned standard cost for outpatient clinic, visits to the day care unit and to the emergency room (ER), outpatient surgery, and total costs of pharmacy. RESULTS: The total cost for HIV-related health care assistance was euro739,048. The cost related to admissions was euro150,766.60; euro8631 per first visit and euro49,199.40 per successive visit; euro5085.10 per day care unit; euro14,920 per outpatient surgery; euro7655.70 per ER visit; and euro491,342.40 per antiretroviral treatment. A significant proportion of the total outpatient assistance was given by physicians other than HIV specialists, namely, 63% of the costs attributed to the first visit and 41% per successive visit. CONCLUSION: More than 50% of the costs of caring for HIV-infected patients are still attributed to antiretroviral therapy. Specialists other than infectious disease specialists provide a significant proportion of outpatient assistance. A method to control HIV costs is greatly needed. PMID- 17693229 TI - Biopsy-negative giant cell arteritis: Does anti-CD83 immunohistochemistry advance the diagnosis? AB - BACKGROUND: In situ maturation of adventitial dendritic cells (DC) with expression of CD83 has been proposed as an early event in the pathogenesis of giant cell arteritis (GCA), preceding the appearance of an inflammatory infiltrate. The aim of this study was to evaluate the added value of anti-CD83 staining of temporal artery biopsy (TAB) specimens in patients with biopsy negative temporal arteritis. METHODS: Fourteen patients with TAB performed in our medical center since 2001 and considered negative for GCA due to the absence of any inflammatory infiltrate were identified by a computerized search of patient records. Their paraffin-embedded TAB specimens were retrieved, reprocessed, and stained with anti-CD83 monoclonal antibody (Serotec, 1:40). Three TAB specimens of patients with biopsy-proven GCA served as positive controls and three specimens of popliteal and/or tibial arteries of patients with atherosclerotic peripheral vascular disease were used as negative controls. Follow-up of the patients was confirmed by personal contact with their rheumatologists and analysis of their hospital charts. RESULTS: Follow-up was available for 12 of 14 patients. Five of these patients were considered to have biopsy-negative GCA: they satisfied the ACR classification criteria, were successfully treated with glucocorticosteroids, and had a follow-up of at least 10 months with no alternative diagnosis established. Anti-CD83 staining was negative in all but one patient who demonstrated a single CD83-positive cell adjacent to the internal elastic membrane. Positive anti-CD83 staining of the inflammatory infiltrate throughout the arterial wall was observed in all patients with biopsy-proven GCA (positive controls). Negative controls did not show any CD83-positive cells. CONCLUSIONS: In this pilot study, anti-CD83 immunohistochemical staining of paraffin-embedded specimens did not improve the yield of TAB in patients with suspected GCA. PMID- 17693231 TI - Osteonecrosis of the jaw. A newly emerging site-specific osseous pathology in patients with cancer treated with bisphosphonates. Report of five cases and review of the literature. AB - BACKGROUND: Bisphosphonates are commonly used as standard care in the management of patients with advanced-stage cancer involving bone. There has recently been growing concern that the use of bisphosphonates is associated with osteonecrosis of the jaw (ONJ). METHODS: Between 2001 and 2005, five patients with ONJ associated with pamidronate and zoledronate therapy were diagnosed at our department. The patients had breast cancer, renal carcinoma, mesothelioma, and multiple myeloma, all involving bone. The literature was reviewed. RESULTS: The duration of bisphosphonate therapy before presentation of ONJ ranged from 21 to 36 months. The lesions were localized to the mandible (n=3) and maxilla (n=2). All of the patients presented with pain and exposed bone; in two of them, symptoms began after tooth extraction. A review of the literature through March 2006 identified more than 250 reported cases of ONJ. CONCLUSIONS: The findings in our patients, combined with the literature review, suggest that: (1) the most common clinical presentation of ONJ is pain and exposed bone of the mandible or maxilla; (2) for patients who develop ONJ, conservative, non-surgical treatment is strongly recommended; (3) clinical dental examination and a panoramic jaw radiograph should be performed before patients begin bisphosphonate therapy; (4) dental treatment and other oral procedures should be completed before initiating bisphosphonate therapy; (5) patients should be informed and instructed on the importance of maintaining good oral hygiene and having regular dental assessment; and (6) the medical community needs to be aware of the association between bisphosphonate usage and ONJ so that unnecessary and harmful surgical procedures can be avoided. PMID- 17693230 TI - Prognostic differences between routine invasive and conservative strategies for the management of high-risk, non-ST segment acute coronary syndromes: Experience from two consecutive periods in a single center. AB - BACKGROUND: The optimal revascularization strategy for non-ST elevation acute coronary syndromes (NSTE-ACS) remains controversial, especially in a real world context. The objective of this work was to assess differences at 1 year in all cause mortality and the composite endpoint of mortality or acute myocardial infarction (MI) between two management strategies for NSTE-ACS: a conservative strategy (CS) versus a routine invasive strategy (RIS). METHODS: Of 799 consecutive patients admitted to our institution, 369 were treated with CS (from January 2001 to October 2002); 430 patients admitted with the same diagnosis were treated with RIS (from November 2002 to November 2004). A propensity score (PS) matched sample was created and included 694 patients (87% of the original population). The event rate was compared between each paired member of the PS matched sample, one receiving RIS and the other CS, and their differences were tested by Cox proportional analysis. RESULTS: No significant differences in baseline characteristics were noted between the two management cohorts. By design, the rate of in-hospital catheterization and revascularization procedures increased in RIS compared with CS. The mortality rate was lower, but not significant, in RIS (HR: 0.76, 95% CI=0.51-1.11; p=0.155). For the composite of death or MI, RIS showed a relative risk reduction of 29% (HR: 0.71, 95% CI=0.53 0.94); p=0.018) compared with CS, differences that become non-significant (p=0.680) if we adjust for differences in rate of revascularization procedures and changes in medication prescription. CONCLUSIONS: RIS was associated with a 1 year lower risk of the combined endpoint of all-cause death and MI in patients with NSTE-ACS, attributable to changes in frequency of revascularization procedures and in medical treatment. PMID- 17693232 TI - Endogenous subclinical hyperthyroidism: Metabolic and cardiac parameters. AB - BACKGROUND: Subclinical hyperthyroidism (SH) is defined by suppressed TSH and normal levels of thyroid hormones. Endogenous subclinical hyperthyroidism (ESH) is probably less common than exogenous SH. Adverse effects of SH due to exogenous administration of thyroxine have been well studied, while the impact of ESH on the cardiovascular system and metabolic parameters remains controversial. METHODS: In a cross-sectional study, we examined patients with endogenous clinical hyperthyroidism (ECH; n=20), ESH (TSH<0.1 muU/mL, n=25), and mild ESH (TSH=0.1-0.3 muU/mL, n=32), as well as healthy controls (n=50). Biochemical and metabolic parameters influenced by thyroid hormones were assessed and cardiac parameters were studied using echocardiography and 24-hour ECG-blood pressure monitoring. RESULTS: Biochemical and metabolic parameters did not differ significantly between ESH and healthy subjects. The ECH group had significantly higher sex hormone-binding globulin, osteocalcin, and carboxy-terminal telopeptide levels than healthy subjects. No significant differences were noted in echocardiographic parameters between ESH patients and healthy subjects. The ECH group had a significantly higher heart rate, cardiac output, and cardiac index than the control group, as well as end-diastolic and end-systolic diameters of the left ventricle, and end-diastolic and end-systolic volumes of the left ventricle. The 24-hour ECG-blood pressure monitoring parameters did not differ significantly either between SH and healthy subjects while, in the ECH group, mean heart rate, maximum heart rate, and mean tachycardia episodes were significantly increased. CONCLUSION: Only subjects with ECH showed differences in metabolic and cardiac parameters from controls, while no significant effects were noted in the endogenous subclinical forms. PMID- 17693233 TI - A case of Aeromonas hydrophila enteritis in the course of ulcerative colitis. AB - A 24-year-old man with a previous diagnosis of ulcerative pancolitis presented with severe malabsorption with watery diarrhea, malaise, and weight loss. Physical examination revealed paleness, hypotension, tachycardia, edema, ascites, and left-sided pleural effusion. Laboratory analysis revealed hypoalbuminemia and hypocalcemia. Further examination revealed that malabsorption was related to Aeromanas hydrophila infection. Clinical improvement was observed upon oral ciprofloxacin treatment. No clinical or laboratory activation of ulcerative colitis was detected during this infection. PMID- 17693234 TI - Angiotropic lymphoma: Associated chromosomal abnormalities. AB - Intravascular angiotropic lymphoma (IVL) is a rare variant of non-Hodgkin's lymphoma. Diagnosis in most cases is only achieved at post-mortem. We present a patient with pyrexia of unknown origin diagnosed with angiotropic lymphoma by bone marrow biopsy. We also review the limited published literature on associated chromosomal abnormalities. We provide further support for previously proposed non random changes in IVL, namely, structural aberrations of chromosomes 1, 6 and 10, as well as identify further aberrations that may be non-random in chromosomes 4, 5 and 8, and postulate that the 6q21-24 region may be the site of a tumour suppressor gene. B-cell angiotropic lymphoma is a rare, but important, cause of pyrexia of unknown origin and we advocate that prolonged fever that has resisted diagnosis should prompt histological and immunocytochemical examination of bone marrow to facilitate rapid diagnosis and early institution of treatment. PMID- 17693235 TI - Parvovirus B19 infection as a cause of cytopenia with a lupus-like presentation in the elderly: A case report. AB - Most cases of parvovirus B19 infection are asymptomatic and occur in childhood; half of all 15-year-old adolescents have specific anti-parvovirus B19 antibodies. Here, we report a rare case of parvovirus B19 primary infection, rare due to (1) its occurrence in a geriatric patient (an 82-year-old woman), (2) its lupus-like presentation, and (3) its potential role in precipitating congestive heart failure. PMID- 17693236 TI - Massive pericardial effusion secondary to Hashimoto's disease. AB - Although relatively rare, hypothyroidism remains a significant cause of moderate to severe pericardial effusion. Pericardial effusion secondary to hypothyroidism does not usually cause symptoms since it tends to regress slowly and ultimately disappear several months after the patient has reverted to the euthyroid state. Thus, hypothyroidism must be ruled out in patients with an unexplained pericardial effusion, both to improve prognosis and to avoid unnecessary pericardiocentesis. Even when they have a massive pericardial effusion, patients should receive the standard treatment for hypothyroidism. We herein describe a 79 year-old woman with a massive pericardial effusion associated with hypothyroidism who showed a good response to standard levothyroxine replacement therapy after 5months. PMID- 17693237 TI - A case of empyema necessitatis. AB - We present a case of empyema necessitatis presenting with an inflammatory cellulitis of the chest wall. Most of the cases previously reported were due to tuberculosis, pneumococcus or actinomycosis, with only a few cases being due to Staphylococcus aureus, as in this case. Early treatment with antibiotics and surgical drainage can prevent further complications. PMID- 17693238 TI - Large-bore thoracentesis - A case report of a fatal consequence. AB - Thoracentesis is a widely employed diagnostic and, at times, therapeutic procedure in many patients with diseases involving the pleural space. It has been associated with a wide range of complications. Ultrasound-guided thoracentesis is suggested if the volume of the effusion is small or if the fluid is loculated. Large-bore needle thoracentesis has also been advised. We report here a case of sonography-guided, large-bore needle thoracentesis with a fatal complication due to cardiocentesis in a woman with a dilated left ventricle. PMID- 17693239 TI - A case of scabies masquerading as drug eruption. PMID- 17693240 TI - Lymphocytic colitis. PMID- 17693241 TI - Lipid-lowering therapy and primary prevention of cardiovascular disease. PMID- 17693242 TI - Alcaligenes xylosoxidans osteomyelitis without trauma in a patient with Good's syndrome. PMID- 17693243 TI - Detrimental action of thiazolidinediones on bone. PMID- 17693244 TI - Spontaneous bacterial peritonitis must be considered in ascites patients with abdominal tenderness. PMID- 17693245 TI - Abdominal tenderness in ascites patients does not indicate spontaneous bacterial peritonitis. PMID- 17693246 TI - Detrimental action of thiazolidinediones on bone (rebuttal). PMID- 17693247 TI - Is proteomics the new genomics? AB - Mass spectrometry (MS)-based proteomics has become a formidable tool for the investigation of posttranslational modifications to proteins, protein interactions, and organelles. Is it now ready to tackle comprehensive protein expression analysis? PMID- 17693248 TI - A "reductionist" view of cardiomyopathy. AB - Oxidative stress due to the generation of reactive oxygen species has been implicated in many diseases. Rajasekaran et al. (2007) now make the surprising discovery that its counterpart "reductive stress," caused by an increase in reduced glutathione, contributes to cardiomyopathy triggered by protein aggregation. PMID- 17693249 TI - Fetal to adult stem cell transition: knocking Sox17 off. AB - What controls the inherent differences between fetal and adult hematopoietic stem cells (HSCs)? In this issue of Cell, Kim et al. (2007) demonstrate in mice that the endodermal transcription factor Sox17 is required for the maintenance of fetal and neonatal but not adult HSCs. PMID- 17693250 TI - The nuclear pore complex: oily spaghetti or gummy bear? AB - In this issue, Frey and Gorlich (2007) provide new insight into the selective barrier that controls protein traffic through the nuclear pore complex. They show that a single protein domain of the nuclear pore protein Nsp1 can form a hydrogel that allows highly selective access of nuclear transport receptors and their cargos, but rejects other proteins of similar size. PMID- 17693251 TI - GRASPing unconventional secretion. AB - GRASP proteins associate with the Golgi apparatus and have been implicated in the stacking of Golgi cisternae, vesicle tethering, and mitotic progression, but their specific functions are unclear. In this issue, Kinseth et al. (2007) show unexpectedly that a GRASP homolog is required for an unconventional secretory pathway that bypasses the usual route for Golgi-dependent membrane traffic. PMID- 17693252 TI - Bone weighs in on obesity. AB - Obesity, insulin resistance, and diabetes are related disorders of energy metabolism for which therapies are suboptimal. In this issue of Cell, Lee et al. (2007) demonstrate in mice that bone regulates the insulin/glucose axis and energy metabolism, providing a new framework for approaching common disorders of bioenergetics. PMID- 17693253 TI - Antiviral immunity directed by small RNAs. AB - Plants and invertebrates can protect themselves from viral infection through RNA silencing. This antiviral immunity involves production of virus-derived small interfering RNAs (viRNAs) and results in specific silencing of viruses by viRNA guided effector complexes. The proteins required for viRNA production as well as several key downstream components of the antiviral immunity pathway have been identified in plants, flies, and worms. Meanwhile, viral mechanisms to suppress this small RNA-directed immunity by viruses are being elucidated, thereby illuminating an ongoing molecular arms race that likely impacts the evolution of both viral and host genomes. PMID- 17693254 TI - Human alpha B-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice. AB - The autosomal dominant mutation in the human alphaB-crystallin gene inducing a R120G amino acid exchange causes a multisystem, protein aggregation disease including cardiomyopathy. The pathogenesis of cardiomyopathy in this mutant (hR120GCryAB) is poorly understood. Here, we show that transgenic mice overexpressing cardiac-specific hR120GCryAB recapitulate the cardiomyopathy in humans and find that the mice are under reductive stress. The myopathic hearts show an increased recycling of oxidized glutathione (GSSG) to reduced glutathione (GSH), which is due to the augmented expression and enzymatic activities of glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase, and glutathione peroxidase. The intercross of hR120GCryAB cardiomyopathic animals with mice with reduced G6PD levels rescues the progeny from cardiac hypertrophy and protein aggregation. These findings demonstrate that dysregulation of G6PD activity is necessary and sufficient for maladaptive reductive stress and suggest a novel therapeutic target for abrogating R120GCryAB cardiomyopathy and heart failure in humans. PMID- 17693255 TI - IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. AB - TNFalpha has recently emerged as a regulator linking inflammation to cancer pathogenesis, but the detailed cellular and molecular mechanisms underlying this link remain to be elucidated. The tuberous sclerosis 1 (TSC1)/TSC2 tumor suppressor complex serves as a repressor of the mTOR pathway, and disruption of TSC1/TSC2 complex function may contribute to tumorigenesis. Here we show that IKKbeta, a major downstream kinase in the TNFalpha signaling pathway, physically interacts with and phosphorylates TSC1 at Ser487 and Ser511, resulting in suppression of TSC1. The IKKbeta-mediated TSC1 suppression activates the mTOR pathway, enhances angiogenesis, and results in tumor development. We further find that expression of activated IKKbeta is associated with TSC1 Ser511 phosphorylation and VEGF production in multiple tumor types and correlates with poor clinical outcome of breast cancer patients. Our findings identify a pathway that is critical for inflammation-mediated tumor angiogenesis and may provide a target for clinical intervention in human cancer. PMID- 17693257 TI - Self-organization of MTOCs replaces centrosome function during acentrosomal spindle assembly in live mouse oocytes. AB - Chromosome segregation in mammalian oocytes is driven by a microtubule spindle lacking centrosomes. Here, we analyze centrosome-independent spindle assembly by quantitative high-resolution confocal imaging in live maturing mouse oocytes. We show that spindle assembly proceeds by the self-organization of over 80 microtubule organizing centers (MTOCs) that form de novo from a cytoplasmic microtubule network in prophase and that functionally replace centrosomes. Initially distributed throughout the ooplasm, MTOCs congress at the center of the oocyte, where they contribute to a massive, Ran-dependent increase of the number of microtubules after nuclear envelope breakdown and to the individualization of clustered chromosomes. Through progressive MTOC clustering and activation of kinesin-5, the multipolar MTOC aggregate self-organizes into a bipolar intermediate, which then elongates and thereby establishes chromosome biorientation. Finally, a stable barrel-shaped acentrosomal metaphase spindle with oscillating chromosomes and astral-like microtubules forms that surprisingly exhibits key properties of a centrosomal spindle. PMID- 17693256 TI - Endocrine regulation of energy metabolism by the skeleton. AB - The regulation of bone remodeling by an adipocyte-derived hormone implies that bone may exert a feedback control of energy homeostasis. To test this hypothesis we looked for genes expressed in osteoblasts, encoding signaling molecules and affecting energy metabolism. We show here that mice lacking the protein tyrosine phosphatase OST-PTP are hypoglycemic and are protected from obesity and glucose intolerance because of an increase in beta-cell proliferation, insulin secretion, and insulin sensitivity. In contrast, mice lacking the osteoblast-secreted molecule osteocalcin display decreased beta-cell proliferation, glucose intolerance, and insulin resistance. Removing one Osteocalcin allele from OST-PTP deficient mice corrects their metabolic phenotype. Ex vivo, osteocalcin can stimulate CyclinD1 and Insulin expression in beta-cells and Adiponectin, an insulin-sensitizing adipokine, in adipocytes; in vivo osteocalcin can improve glucose tolerance. By revealing that the skeleton exerts an endocrine regulation of sugar homeostasis this study expands the biological importance of this organ and our understanding of energy metabolism. PMID- 17693258 TI - Mec1/Tel1 phosphorylation of the INO80 chromatin remodeling complex influences DNA damage checkpoint responses. AB - The yeast Mec1/Tel1 kinases, ATM/ATR in mammals, coordinate the DNA damage response by phosphorylating proteins involved in DNA repair and checkpoint pathways. Recently, ATP-dependent chromatin remodeling complexes, such as the INO80 complex, have also been implicated in DNA damage responses, although regulatory mechanisms that direct their function remain unknown. Here, we show that the Ies4 subunit of the INO80 complex is phosphorylated by the Mec1/Tel1 kinases during exposure to DNA-damaging agents. Mutation of Ies4's phosphorylation sites does not significantly affect DNA repair processes, but does influence DNA damage checkpoint responses. Additionally, ies4 phosphorylation mutants are linked to the function of checkpoint regulators, such as the replication checkpoint factors Tof1 and Rad53. These findings establish a chromatin remodeling complex as a functional component in the Mec1/Tel1 DNA damage signaling pathway that modulates checkpoint responses and suggest that posttranslational modification of chromatin remodeling complexes regulates their involvement in distinct processes. PMID- 17693259 TI - A saturated FG-repeat hydrogel can reproduce the permeability properties of nuclear pore complexes. AB - The permeability barrier of nuclear pore complexes (NPCs) controls the exchange between nucleus and cytoplasm. It suppresses the flux of inert macromolecules > or = 30 kDa but allows rapid passage of even very large cargoes, provided these are bound to appropriate nuclear transport receptors. We show here that a saturated hydrogel formed by a single nucleoporin FG-repeat domain is sufficient to reproduce the permeability properties of NPCs. Importin beta and related nuclear transport receptors entered such hydrogel >1000x faster than a similarly sized inert macromolecule. The FG-hydrogel even reproduced import signal dependent and importin-mediated cargo influx, allowing importin beta to accelerate the gel entry of a large cognate cargo more than 20,000-fold. Intragel diffusion of the importin beta-cargo complex occurred rapidly enough to traverse an NPC within approximately 12 ms. We extend the "selective phase model" to explain these effects. PMID- 17693260 TI - SARA-regulated vesicular targeting underlies formation of the light-sensing organelle in mammalian rods. AB - The light-sensing organelle of the vertebrate rod photoreceptor, the outer segment (OS), is a modified cilium containing approximately 1,000 stacked disc membranes that are densely packed with visual pigment rhodopsin. The mammalian OS is renewed every ten days; new discs are assembled at the base of the OS by a poorly understood mechanism. Our results suggest that discs are formed and matured in a process that involves specific phospholipid-directed vesicular membrane targeting. Rhodopsin-laden vesicles in the OS axonemal cytoplasm fuse with nascent discs that are highly specialized with abundant phosphatidylinositol 3-phosphate (PI3P). This membrane coupling is regulated by the FYVE domain containing protein, SARA, through its direct interaction with PI3P, rhodopsin, and SNARE protein syntaxin 3. Our model, in contrast to the previously proposed evagination model, suggests that the vesicular delivery of rhodopsin in the OS concentrates rhodopsin into discs, and this process directly participates in disc biogenesis. PMID- 17693261 TI - Mitochondrial fusion protects against neurodegeneration in the cerebellum. AB - Mutations in the mitochondrial fusion gene Mfn2 cause the human neurodegenerative disease Charcot-Marie-Tooth type 2A. However, the cellular basis underlying this relationship is poorly understood. By removing Mfn2 from the cerebellum, we established a model for neurodegeneration caused by loss of mitochondrial fusion. During development and after maturity, Purkinje cells require Mfn2 but not Mfn1 for dendritic outgrowth, spine formation, and cell survival. In vivo, cell culture, and electron microscopy studies indicate that mutant Purkinje cells have aberrant mitochondrial distribution, ultrastructure, and electron transport chain activity. In fibroblasts lacking mitochondrial fusion, the majority of mitochondria lack mitochondrial DNA nucleoids. This deficiency provides a molecular mechanism for the dependence of respiratory activity on mitochondrial fusion. Our results show that exchange of mitochondrial contents is important for mitochondrial function as well as organelle distribution in neurons and have important implications for understanding the mechanisms of neurodegeneration due to perturbations in mitochondrial fusion. PMID- 17693262 TI - Does sumoylation control K2P1/TWIK1 background K+ channels? AB - A novel model for the regulation of cell excitability has recently been proposed. It originates from the observation that the background K(+) channel K2P1 (TWIK1) may be silenced by sumoylation in Xenopus oocytes and that inactivation of the putative sumoylation site (mutation K274E) gives rise to robust current expression in transfected COS-7 cells. Here, we show that only the mutation K274E, and not K274R, is associated with an increase of K2P1 current density, suggesting a charge effect of K274E. Furthermore, we failed to observe any band shift by western blot analysis that would confirm an eventual sumoylation of K2P1 in COS-7 cells and oocytes. PMID- 17693263 TI - Posttranscriptional gene silencing. PMID- 17693264 TI - Who should perform image-guided breast biopsy and treatment? PMID- 17693265 TI - What's best for the patient? PMID- 17693266 TI - The safety of the same-day discharge for selected patients after laparoscopic fundoplication: a prospective cohort study. AB - BACKGROUND: We conducted a prospective cohort study to assess the acceptability, feasibility and safety of day-case laparoscopic fundoplication for gastroesophageal reflux disease in an university-based tertiary care center. METHODS: The procedure was proposed as routine for patients with proven symptomatic uncomplicated gastroesophageal reflux disease fulfilling predetermined inclusion criteria from September 2003 to December 2005. Standard anesthetic, surgical, analgesic, and antiemetic protocols were used. Acceptability, admission, complication, and reoperation rates and patient satisfaction were evaluated. Postoperative pain and nausea were assessed using an 11-point numeric rating scale (NRS). The Gastrointestinal Quality of Life Index (GIQLI) was administered before and after surgery. RESULTS: Among 100 patients screened, 40 (40%) were included. Seven patients were admitted because of inadequate pain control (n = 3), nausea or vomiting (n = 3), or anxiety (n = 1); 33 were discharged as planned 6 to 8 hours after operation. Only 1 patient was readmitted and reoperated because of fundoplicature migration following uncontrolled vomiting. At follow-up, 92.5% of patients were satisfied with the day-case treatment. If offered a similar operation in the future, 82.5% of patients would have accepted day-case treatment. The Gastrointestinal Quality of Life Index was 90.7 (+/-21.2) preoperatively compared with 105.8 (+/-21.8) postoperatively (P < .001). CONCLUSIONS: Day-case laparoscopic fundoplication is feasible in selected patients. However, (1) strict control of postoperative nausea and pain is essential, and (2) preoperative standardized education program for ambulatory surgery might be useful in order to enhance patient acceptability and satisfaction rates. PMID- 17693267 TI - Reappraisal of duct-to-duct biliary reconstruction in hepatic resection for liver tumors. AB - BACKGROUND: Duct-to-duct reconstruction is theoretically suitable for short segmental defects of the bile duct. This technique would also be useful, without jeopardizing the curability, in selected cases with hepatic malignancies requiring concomitant liver and bile duct resection. METHODS: For biliary reconstruction after hepatectomy, duct-to-duct reconstruction was performed in 4 patients at our institution between 1994 and 2004. The surgical techniques used are presented, along with the results of evaluation of the outcome, including postoperative and long-term morbidity and survival. RESULTS: Duct-to-duct reconstruction was safely performed in the 4 patients with the defects ranging in size from 10 to 19 mm. None of the cases developed local recurrence at the anastomotic site. None of the cases developed stenosis of the anastomotic site either, but cholangitis occurred in 1 patient. CONCLUSIONS: Duct-to-duct reconstruction for short segmental defects after the removal of hepatic malignant tumors is feasible with less operative and long-term morbidity. It is essential to select patients carefully when thinking of performing duct-to-duct anastomosis without complication and cancer infiltration. PMID- 17693268 TI - Validation of clinical prediction rules for a low probability of nonsentinel and extensive lymph node involvement in breast cancer patients. AB - BACKGROUND: Two recently developed clinical prediction rules aim to anticipate the lack of nonsentinel lymph node metastases and the involvement of less than 4 lymph nodes in breast cancer patients with positive sentinel lymph nodes (SLNs). METHODS: The University of Louisville Breast SLN Study clinical prediction rules were validated on an independent set of SLN-positive patients with tumors < or = 15 mm. RESULTS: The data on 475 and 473 patients, respectively, were used for the validation. The areas under the receiver operating characteristic curves were similar to the originals for both predictive tools (.70 and .76). The lowest score of 1 identified 5 of 7 patients with disease limited to the SLNs and 161 of 165 as having less than 4 involved lymph nodes. CONCLUSIONS: A subset of patients with SLN-only involvement and less than 4 metastatic lymph nodes can probably be identified by means of the Louisville clinical prediction rules, but prediction of the lack of non-SLN metastasis seems less reliable. PMID- 17693269 TI - Treatment outcomes in patients with signet ring cell carcinoma of the colorectum. AB - BACKGROUND: The aim of this study was to evaluate the clinicopathologic features and prognosis of signet ring cell (SRC) carcinoma and compare them with those of mucinous and poorly differentiated adenocarcinomas of the colorectum. METHODS: The clinicopathologic data of 35 patients with primary SRC carcinoma were reviewed and compared with the data from 294 patients with mucinous and 252 patients with poorly differentiated adenocarcinoma. RESULTS: Eighty percent of the SRC patients presented with more advanced disease (stages III and IV), whereas 55.1% and 64.7% of the patients in the mucinous and poorly differentiated groups had advanced disease at diagnosis, respectively (80% vs 55.1%, P = .04 and 80.0% vs 64.7%, P = .437). Median survival time for patients with SRC was 18.4 months (95% confidence interval 10.4 to 19.6). Three- and 5-year survival rates in the SRC group were 33.7% and 25.3%, respectively. The overall survival rate of patients with SRC was significantly poorer than that of patients with mucinous or poorly differentiated adenocarcinoma (P < .001). CONCLUSIONS: SRC of the colorectum is characterized by advanced stage at diagnosis with lower rates of curative resection. It tends to affect younger patients with more propensity for lymphovascular invasion. PMID- 17693270 TI - Recovery of sexual function after scrotal hernia repair. AB - BACKGROUND: Most of the patients with scrotal hernia have sexual dysfunction to some extent. Therefore, we investigated the recovery of sexual function after scrotal hernia repair by using an internationally approved, patient-administered questionnaire. METHODS: In a prospective follow-up study, 34 patients with scrotal hernia were investigated to assess sexual function before and 3 months after hernia repair by using the International Index of Erectile Function (IIEF) questionnaire. The mean scores obtained on pre- and postoperative visits for all domains of sexual function were analyzed and compared with the Wilcoxon test. Hernia repair was performed by using a standardized Lichtenstein technique. RESULTS: The total mean score of the IIEF-15 was 52.08 before surgery and 56.20 after the procedure, with this difference considered statistically significant (P < .001). Eighty-five percent of the patients improved their scores versus 9% and 6% who showed worsening or no change at all in IIEF scores after surgery, respectively. All of the 5 sexual function domains except the orgasm domain presented statistically significant improvement. CONCLUSIONS: This study showed that scrotal hernia repair caused a positive impact on sexual function after surgery. There was no case of surgery-related erectile dysfunction. Therefore, one of the major indications to repair large scrotal hernias may be to improve the quality of sexual life. PMID- 17693271 TI - Proposed new score predicting malignancy of intraductal papillary mucinous neoplasms of the pancreas. AB - BACKGROUND: Our objective was to predict malignancy for intraductal papillary mucinous neoplasms of the pancreas (IPMN) before operation. METHODS: Sixty-four resected patients with IPMN were examined and 17 parameters were investigated for their relation to malignancy by univariate and multivariate analysis. RESULTS: Multivariate logistic regression analysis showed that IPMN type, the size of main pancreatic duct, and serum carbohydrate antigen 19-9 were significant for malignancy. Size of the main pancreatic duct > or = 6.5 mm and serum carbohydrate antigen 19-9 > or = 35 U/mL scored 3 points, main duct type scored 2 points, and patulous papilla, jaundice, diabetes mellitus, and tumor size > or = 42 mm scored 1 point. When IPMNs with 3 and more than 3 points using the new score were diagnosed as malignant, accuracy was 90.6%. CONCLUSION: This scoring system for IPMN is feasible to detect malignancy and useful for selecting an appropriate treatment. PMID- 17693272 TI - Local pancreatic resection with preoperative endoscopic transpapillary stenting. AB - BACKGROUND: Pancreatic fistula, although not common, can cause serious complications after pancreatectomy. During local pancreatectomy, injury to the main pancreatic duct (in addition to the accessory and side branch ducts) increases the risk of pancreatic fistula formation. Nonetheless, local pancreatic resection maintains the advantage of preserving pancreatic parenchyma. METHODS: In this study, we reviewed the cases of 5 patients who underwent preoperative endoscopic transpapillary pancreatic stenting to help prevent refractory fistula development after local pancreatic resection. RESULTS: Stenting was successful in all 5 patients, and none developed a refractory grade C postoperative pancreatic fistula. CONCLUSIONS: These results suggest that in selected patients, preoperative endoscopic pancreatic stenting may be an effective prophylactic measure to lower the risk of refractory grade C fistula formation after local pancreatic resection. PMID- 17693274 TI - Posttraumatic free intraperitoneal rupture of liver cystic echinococcosis: a case series and review of literature. AB - BACKGROUND: A serious complication of cystic echinococcus (CE) is the rupture of the cysts. Free intra-abdominal rupture occurs in approximately 3.2% of all cases. Posttraumatic rupture of liver CE is very rare. METHODS: The objective of the current study was to evaluate the clinical and radiographic findings and surgical treatment of this complication. RESULTS: Twenty patients with posttraumatic ruptured liver CE were treated. The incidence rate of hydatid rupture was 3.06%. The common presenting symptom was abdominal pain. All patients were operated on under emergency conditions. There were 26 cysts in 20 patients, and all of the cysts were treated surgically. CONCLUSION: Hydatid cyst rupture must be kept in mind in the management of trauma patients with cystic mass in the liver in particular and free intra-abdominal fluid, especially in the endemic area. We preferred conservative (unroofing associated with various procedures for the management of the residual cavity) rather than radical procedures such as hepatic resection or pericystectomy for the surgical treatment. PMID- 17693275 TI - The evaluation of the causes of subjective voice disturbances after thyroid surgery. AB - BACKGROUND: Voice changes following thyroidectomy is a rare form of morbidity not infrequently encountered. Injury to the recurrent laryngeal nerve or external branch of the superior laryngeal nerve is the most well-known cause of post thyroidectomy voice disturbances. However, voice dysfunction is a more complex entity. The aim of the current study was to assess the possible factors that influence voice changes after thyroidectomy. METHODS: Forty-eight consecutive patients who had undergone thyroidectomy were studied. The acoustic voice analysis (mean vocal fundamental frequency [Fo], mean percentage vocal jitter and shimmer, and noise-to-harmonic ratio) and videolaryngostroboscopic examination of these patients were performed preoperatively, on the second postoperative day, and 3 months after the operation. The presence of subjective voice changes was recorded prospectively based on a symptom scale. RESULTS: No major complications occurred perioperatively or in the postoperative period. Videolaryngostroboscopic examinations were normal in all patients before and after thyroidectomy. Eighteen (37.5%) patients complained of subjective voice changes in the early postoperative period and 7 (14.6%) of these were still uncomfortable after 3 months. Although the difference was significant by means of all acoustic voice parameters measured in the early postoperative period, Fo is the only parameter that continues to be significant after 3 months. CONCLUSIONS: Irrespective from recurrent laryngeal nerve and/or injuries to the external branch of the superior laryngeal nerve, voice may temporarily be affected by thyroidectomy. Most of the subjective complaints and acoustic voice parameters return to normal in a few months after surgery. PMID- 17693276 TI - Hyperparathyroidism after radioactive iodine therapy. AB - BACKGROUND: Radioactive iodine (RAI) treatment has been suggested to cause primary hyperparathyroidism (HPT). We describe a series of patients with HPT and a history of RAI exposure. METHODS: Patient demographic and clinical information was evaluated, including the latency time to the development of HPT after RAI exposure. RESULTS: We treated 11 patients with HPT and a history of RAI exposure. RAI treatment was administered for benign thyroid disease in 9 (82%) cases. Thirty-six cases of HPT after RAI exposure in the English literature were compiled for further analysis. In this collective experience, the average latency time to the development of HPT after RAI treatment was 13.5 +/- 9.1 years and was found to be inversely correlated with age at RAI exposure. CONCLUSIONS: Patients who undergo RAI treatment are at risk of developing HPT, and this risk appears to increase in elderly patients. Serum calcium surveillance is recommended for patients who have undergone RAI treatment. PMID- 17693277 TI - Classification of adverse events occurring in a surgical intensive care unit. AB - INTRODUCTION: We aimed to describe the preventability and provider specificity of surgical intensive care unit (SICU) deaths and complications compared with those in a cohort of trauma patients. METHODS: Data were collected on all trauma and SICU admissions from July 1, 2001, to June 30, 2004, from administrative (Trauma Base and Project Impact) and morbidity databases. Services were protocol driven and staffed by in-house attendings. Performance improvement assessments were made by consensus. Deaths and complications were classified as preventable, potentially preventable, or nonpreventable, and provider-specific or not. Statistical significance was established at the P < .05 level. RESULTS: One hundred sixty-eight deaths (5.6% rate), 464 procedure-related, and 694 non procedure-related complications were noted in 2969 SICU patients compared with 166 deaths (3.6% rate), 178 procedure-related, and 261 non-procedure-related complications in 4,655 trauma patients. Thirty-one percent of SICU deaths were preventable/potentially preventable compared with 14% of trauma deaths, but only 1.9% was attributable to the SICU provider. SICU complications were less frequently preventable/potentially preventable than in trauma patients (52% versus 61%) and less often provider-specific (5% versus 19%). CONCLUSIONS: SICU complications are deemed preventable less often than in trauma patients and, if so, infrequently incriminate the SICU provider. Preventable and potentially preventable SICU deaths are rarely attributed to SICU care. These data suggest that SICU performance improvement should focus on systems solutions and pre-SICU care. PMID- 17693278 TI - Treating morbid obesity with laparoscopic adjustable gastric banding. AB - BACKGROUND: Morbid obesity results in multiple comorbidities and an increased mortality rate. The National Institutes of Health has stated that surgery is the most effective long-term therapy; therefore, we evaluated a laparoscopically implantable adjustable gastric band. METHODS: We reviewed 2 multicenter prospective, open-label, single-arm surgical trials--trial A (3 years) and trial B (1 year)--with ongoing safety follow-up. These trials were conducted in United States community and university hospitals (trial A = 8 sites and trial B = 12 sites). Trial A comprised 292 subjects (mean +/- SD preoperative weight: 133 kg +/- 24.4), and trial B comprised 193 subjects (129 kg +/- 20.8). Intervention included placement of a constrictive, adjustable band around the upper stomach to limit food intake and induce weight loss. Main outcome measures were the primary efficacy end point of weight loss. Secondary end-points were change in quality-of life, safety parameters, and complications, including band slippage, reoperation, and device explantation. RESULTS: In the 2 trials, 485 devices were implanted (92% laparoscopically), and no deaths occurred. Of the patients in trial A, 206 (70.5%) completed the 3-year follow-up, and 142 (73.6%) of patients in trial B completed the 1-year follow-up. Weight-loss results, using the last value carried forward, for all 292 patients in trial A and all 193 patients in trial B demonstrated a change in mean body mass index (kg/m2) +/- SD from 47.4 +/- 7.0 to 39.0 +/- 7.3 in trial A and from 46.7 +/- 7.8 to 38.4 +/- 7.6 in trial B subjects at 1 year (P < .001 for both trials A and B), with minimal further change at 3 years (39.0 +/- 8.5) in trial A subjects. The percentage of initial body weight lost at 1 year was 17.7% +/- 9.4% for trial A subjects and 18.2% +/- 8.9% for trial B subjects, whereas the 3-year total for trial A subjects was 18.3% +/- 13.1%. At 1 year, 76% of patients in trial A and 66% of patients in trial B had complications, mostly related to upper gastrointestinal symptoms. By 9 years after surgery, 33% (96 of 292) of trial A subjects had their devices explanted because of complications or inadequate weight loss. CONCLUSIONS: These first generation implantable adjustable gastric band results suggest that this is a viable bariatric surgery therapeutic option for the treatment of obesity. PMID- 17693281 TI - The relationship of lymph node dissection and colon cancer survival in the Veterans Affairs Central Cancer Registry. AB - BACKGROUND: The extent of lymphadenectomy in colon cancer may impact potential to cure and accuracy of staging. METHODS: The Veterans Affairs Central Cancer Registry database was queried for TNM stage I-III colon adenocarcinoma patients and yielded 5,823 individuals. The number of lymph nodes examined, number positive, and the positive:examined lymph node ratio were studied with respect to overall survival by using log-rank and Kaplan-Meier analysis. RESULTS: The overall survival (OS) in stage II patients was greater with the higher number of lymph node (LN) examined. For stage II patients, the 5-year OS was 34%, 43%, 47%, and 55% for the lowest to highest quartiles (P = .007). For stage III patients, the 5-year OS was 31%, 27%, 38%, and 53% for the lowest to highest quartiles (not significant overall). OS is greater with an increased number of positive lymph nodes (P < .001). The lymph node ratio was more powerful prognostically with a 5 year OS of 27% for the highest quartile versus 44% for the lowest. CONCLUSIONS: More extensive lymphadenectomy is associated with improved OS in stage II colon cancer patients. The positive:examined LN ratio is more powerful prognostically than the number of nodes examined or LN positivity. PMID- 17693282 TI - Extended hepatic resection for gallbladder cancer. AB - BACKGROUND: Although radical cholecystectomy is the standard of care for gallbladder cancers that invade perimuscular connective tissue or perforate visceral peritoneum, the role of extended right hepatectomy in achieving negative resection margins is not clear. METHODS: Clinicopathologic, perioperative, and long-term outcome data were reviewed from patients who underwent hepatic resection for gallbladder cancer. RESULTS: From 1995 to 2005, 22 consecutive patients underwent hepatic resection for gallbladder cancer, and 11 underwent extended hepatectomy. Negative resection margins were achieved in all patients. There were no significant differences in postoperative morbidity, mortality, and long-term survival after extended and minor hepatectomy. T3 tumors negatively predicted overall and recurrence-free survival. COMMENTS: Extended hepatectomy achieves negative resection margins for patients with gallbladder cancer and is associated with acceptable morbidity and long-term survival. PMID- 17693283 TI - Predictors of early mortality in veteran patients with pancreatic cancer. AB - BACKGROUND: Identification of predictors of outcome may assist in guiding treatment options for patients with pancreatic cancer. The aim of the current study was to determine clinical factors and laboratory values that predicted mortality of less than 6 months in a male population of the same age and body mass index at the time of diagnosis of pancreatic cancer who died as a result of their disease. METHODS: Only patients with proven diagnosis of pancreatic cancer (n = 69) were included in the study. Patients were grouped into early (< or = 6 months; n = 31) and late (> 6 months; n = 38) survivors. Forty-four clinical factors were assessed by univariate analysis. Significant factors (P <.05) were included in a multivariate regression model to determine independent predictors of early mortality. RESULTS: All patients in the cohort were men. Both the early and late death cohorts were of similar age and body mass index. Twenty-five patients (36%) underwent surgical intervention (palliative 17%, exploratory laparotomy without resection 6%, pancreaticoduodenectomy 13%). Thirty-six patients (52%) underwent placement of a biliary stent. Eight patients received exclusively palliative care. The mean overall length of survival was 7.8 +/- .6 months. Univariate analysis demonstrated that patients who died within 6 months had a significantly increased blood level of carbohydrate antigen 19-9, alkaline phosphatase, and white blood cell (WBC) count. Early mortalities also had a decreased blood albumin level. Multivariate analysis of these factors revealed that low serum albumin and an increased WBC count independently predicted survival of less than 6 months. CONCLUSION: Serum albumin and WBC count may be used in conjunction with other diagnostic modalities and overall patient status in determining treatment options for patients with pancreatic cancer. PMID- 17693284 TI - Ertapenem or ticarcillin/clavulanate for the treatment of intra-abdominal infections or acute pelvic infections in pediatric patients. AB - BACKGROUND: Ertapenem, a group I carbapenem antibiotic, has been shown to be safe and effective in treating adults with complicated intra-abdominal (cIAI) or acute pelvic infection (API). This study evaluated ertapenem for treating these infections in children. METHODS: In an open-label study, children aged 2 to 17 years with cIAI or API were randomized 3:1 to receive ertapenem or ticarcillin/clavulanate. Children 13 to 17 years of age received 1 g parenterally daily, and those 2 to 12 years of age received 15 mg/kg twice daily. Patients < 60 kg received ticarcillin/clavulanate 50 mg/kg 4 to 6 times daily and 3.1 g 4 to 6 times daily for those > or = 60 kg. Patients were assessed for safety and tolerability throughout the study and for efficacy after the completion of therapy. RESULTS: One hundred five patients, 72 (69%) with cIAI, received > or = 1 dose of study drug and were included in the safety analysis. Eighty-one patients were treated with ertapenem. Infusion site pain was the most common drug related adverse event in both groups. In the modified intent-to-treat analysis, the age-adjusted posttreatment clinical response rates were 87% (43/50 patients) and 100% (25/25 patients) in the cIAI and API patients, respectively, for ertapenem and 73% (11/15 evaluable patients) and 100% (8/8 evaluable patients), respectively, for ticarcillin/clavulanate. Overall age-adjusted response rates were 91% (68/75 evaluable patients) for ertapenem and 83% (19/23 evaluable patients) for the comparator. CONCLUSIONS: This study suggests that ertapenem is generally safe and efficacious for treating cIAI or API in pediatric patients. PMID- 17693285 TI - Effects of resterilization on mechanical properties of polypropylene meshes. AB - BACKGROUND: The re-use of sterile packaged polypropylene meshes in hernia surgery is not recommended by the manufacturers. However, especially in developing and underdeveloped countries, many surgeons are obliged to re-use the mesh pieces after resterilization because of economic problems. The purpose of this study was to determine the effects of ethylene oxide and autoclave resterilization on the mechanical properties of polypropylene meshes. METHODS: Repetitive ethylene oxide gas and autoclave sterilizations were applied to polypropylene meshes (Herniamesh S.r.l., San Mauro, Italy) up to 3 times and the effects on the mechanical properties were examined. Gas resterilizations were applied for 4.5 hours at 55 degrees C, whereas for autoclave resterilizations the specimens were kept at 134 degrees C and 3 atm pressure for 64 minutes. Ethylene oxide gas-sterilized samples were labeled as G(n) and autoclave-sterilized samples were labeled as A(n). Effects of the resterilizations on maximum load (Fmax), elongation at maximum load (deltaL), and energy required for complete failure of the specimen (E) were measured. RESULTS: Fmax in the groups showed no significant differences. DeltaL values of groups A2, A3, and G3 were found to be significantly lower in comparison with the control group, whereas differences between the control group and other groups were not statistically significant. E values of A2 and A3 groups were significantly lower than that in the control group (P < .05), whereas the differences between the control group and other groups were not found to be statistically significant. No significant variations were determined between samples sterilized 1, 2, or 3 times in scanning electron microscopy micrographs, however, small irregularities were observed on autoclaved samples. CONCLUSIONS: Single use of polypropylene meshes is always recommended because of biocompatibility and infection risks. However, if re-use of the open packages is needed, ethylene oxide sterilization is preferred over autoclave sterilization. If ethylene oxide sterilization is not available then 1 cycle of resterilization with an autoclave can be used. PMID- 17693287 TI - Laparoscopic versus open-component separation: a comparative analysis in a porcine model. AB - BACKGROUND: The ideal surgical treatment for complicated ventral hernias remains elusive. Traditional component separation provides local advancement of native tissue for tension-free closure without prosthetic materials. This technique requires an extensive subcutaneous dissection with division of perforating vessels predisposing to skin-flap necrosis and complicated wound infections. A minimally invasive component separation may decrease wound complication rates; however, the adequacy of the myofascial advancement has not been studied. METHODS: Five 25-kg pigs underwent bilateral laparoscopic component separation. A 10-mm incision was made lateral to the rectus abdominus muscle. The external oblique fascia was incised, and a dissecting balloon was inflated between the internal and external oblique muscles. Two additional ports were placed in the intermuscular space. The external oblique was incised from the costal margin to the inguinal ligament. The maximal abdominal wall advancement was recorded. A formal open-component separation was performed and maximal advancement 5 cm superior and 5 cm inferior to the umbilicus was recorded for comparison. Groups were compared using standard statistical analysis. RESULTS: The laparoscopic component separation was completed successfully in all animals, with a mean of 22 min/side. Laparoscopic component separation yielded 3.9 cm (SD 1.1) of fascial advancement above the umbilicus, whereas 4.4 cm (1.2) was obtained after open release (P = .24). Below the umbilicus, laparoscopic release achieved 5.0 cm (1.0) of advancement, whereas 5.8 cm (1.2) was gained after open release (P = .13). COMMENTS: The minimally invasive component separation achieved an average of 86% of the myofascial advancement compared with a formal open release. The laparoscopic approach does not require extensive subcutaneous dissection and might theoretically result in a decreased incidence or decreased complexity of postoperative wound infections or skin-flap necrosis. Based on our preliminary data in this porcine model, further comparative studies of laparoscopic versus open component separation in complex ventral hernia repair is warranted to evaluate postoperative morbidity and long-term hernia recurrence rates. PMID- 17693286 TI - Short tandem repeat polymorphism in exon 4 of esophageal cancer-related gene 2 detected in genomic DNA is a prognostic marker for esophageal cancer. AB - BACKGROUND: Short tandem repeat (STR) polymorphisms in exon 4 of the esophageal cancer-related gene 2 (ECRG2) are a risk marker for esophageal carcinoma. The aim of the present study was to correlate these STRs with clinical outcome. METHODS: Genomic DNA of 86 patients who underwent complete surgical resection was analyzed for STRs TCA3/TCA3, TCA3/TCA4, and TCA4/TCA4 in exon 4 of ECRG2 by polymerase chain reaction and DNA sequencing. RESULTS: ECRG2 STR TCA3/TCA3 and TCA3/TCA4 were found in 40 (47%) patients, respectively, and TCA4/TCA4 in 6 (7%) cases. TCA3/TCA3 genotype was significantly associated with reduced survival (P < .05, log-rank test). TCA3/TCA3 STR was the strongest prognostic factor determined by multivariate Cox regression analysis. CONCLUSIONS: Genetically fixed STR polymorphism TCA3/TCA3 in exon 4 of ECRG2 is associated with poor clinical outcome in surgically treated esophageal cancer patients and might be a potential prognostic marker. The usefulness of these genetic markers to predict responsiveness toward neoadjuvant treatment of esophageal cancer patients would be of high clinical interest and should be examined in future studies. PMID- 17693288 TI - Right-sided Bochdalek's hernia in an adult. AB - Bochdalek hernia is a type of congenital diaphragmatic hernia that typically presents in childhood, but may rarely be detected in adults. The treatment of choice is operative repair due to the risk of visceral herniation and strangulation. PMID- 17693289 TI - Giant mucinous cystadenoma of the appendix. AB - Mucocele of the appendix is a rare entity, characterized by distension of the lumen caused by an accumulation of mucoid substance. We report herein the case of a 73-year-old man with a 3-week history of abdominal pain caused by a large mucinous cystadenoma. The lesion was removed intact, which is the optimal treatment. PMID- 17693290 TI - Chronic pain after mesh repair of inguinal hernia: a systematic review. AB - BACKGROUND: Chronic pain is a severe complication of mesh-based inguinal hernia repair. Its perceived risk varies widely in the literature. The current objectives are to review the incidence, severity, and consequences of chronic pain and its etiologies. DATA SOURCES: A multi-database systematic search was conducted for prospective trials on mesh-based inguinal hernia repair reporting the measurement and outcome of pain at least 3 months postoperatively with a minimum follow-up of 80%. CONCLUSIONS: After mesh-based inguinal hernia repair, 11% of patients suffer chronic pain. More than a quarter of these patients have moderate to severe pain, mostly with a neuropathic origin. As a consequence of chronic pain, almost one third of patients have limitations in daily leisure activities. Chronic pain is less frequent after endoscopic repair and with the use of a light-weighted mesh. PMID- 17693291 TI - Assessment of communication skills of surgical residents using the Social Skills Inventory. AB - BACKGROUND: Interpersonal and communication skills are 1 of the 6 core competencies articulated as essential to resident education by the Accreditation Council for Graduate Medical Education. The current study assessed verbal and nonverbal communication skills among surgical residents. METHODS: The communication skills of surgical residents (n = 64) were assessed using the Social Skills Inventory. RESULTS: The majority of surgical residents demonstrated strong verbal and nonverbal skills, although the equilibrium index scores demonstrated an imbalance in the social skill profile for a minority (17.2%) of residents. Post graduate year was positively related to social expressivity (r = .31, P < .01) and social control (r = .27, P < .01) skills. In some cases, being proficient in one social skill was actually negatively related to another. CONCLUSIONS: The Social Skills Inventory was found to be a useful instrument for the multidimensional assessment of resident communication skills. Areas of strengths and weaknesses were identified and could be used for targeting areas for future educational interventions. PMID- 17693292 TI - Modified thoracentesis technique using a triple-lumen catheter. AB - Therapeutic thoracentesis may be preferable over tube thoracostomy in select clinical scenarios in which a symptomatic pleural effusion develops after an isolated and limited physiologic insult. Notable risks in patients undergoing bedside thoracentesis include parenchymal lung injury, abdominal organ injury, and incomplete pleural drainage. These risks are driven in part by inexperienced house officers performing the technique, coupled with technical limitations imparted by hospital-provided thoracentesis kits. To address these concerns, we present a modification to the technique of bedside thoracentesis whereby a triple lumen catheter is placed into the pleural space over a guidewire. This approach overcomes shortcomings of the packaged thoracentesis kits, improves patient comfort, minimizes the risk of lung injury, and provides more complete drainage of the pleural cavity in patients requiring therapeutic thoracentesis. This approach carries a small risk of air entry into the pleural space, which can be minimized with meticulous technique. Furthermore, by using a Seldinger approach, our technique can improve resident comfort with thoracentesis by drawing on a more robust skill set that likely already has developed during their training in central line placement. PMID- 17693293 TI - Percutaneous tracheostomy placement with external laser light transillumination identifies proper tracheal orientation and improves surgeon insertion confidence. AB - Complications of percutaneous tracheostomy include bleeding, loss of airway control, inadvertent injury to surrounding structures, and equipment damage, all of which can be attributed to poor visualization and inaccurate orientation. Initially, we performed percutaneous tracheostomy in the intensive care unit setting using the single-dilator technique with video bronchoscopy without external transillumination. During our first 30 procedures, the video bronchoscope was damaged in four instances, requiring costly repairs each time. To decrease the potential for uncertainty, loss of airway control, and equipment damage, the investigators developed a technique incorporating an external laser light source to transilluminate the trachea to accurately identify the correct and appropriate orientation. Since integration of the external transillumination technique, no additional video bronchoscopes have been damaged in 100 subsequent procedures. We conclude transillumination using an external laser light source is useful in identifying the tracheostomy insertion site. This tool decreases instrument damage and improves surgeon confidence during percutaneous tracheostomy placement. PMID- 17693294 TI - A new technique of polypropylene mesh-reinforced pancreaticojejunostomy. AB - Anastomotic leakage of pancreaticojejunostomy is a common problem and a significant cause of morbidity and mortality after pancreatic resection. An appropriate technique to minimize pancreatic leakage is very important. Recently we have performed a safe and simple mesh-reinforced pancreaticojejunostomy, by which a strip of polypropylene mesh is wrapped around the pancreatic stump in order to secure the end-to-end pancreaticojejunal anastomosis. No leakage developed in all 10 patients who received this procedure. PMID- 17693295 TI - Laparoscopic modified Devine exclusion gastrojejunostomy as a palliative surgery to relieve malignant pyloroduodenal obstruction by unresectable cancer. AB - BACKGROUND: Malignant pyloroduodenal obstruction by an unresectable cancer makes ingesting food or liquids impossible for patients. The patient's quality of life deteriorates rapidly, leading to a dismal prognosis. The modified Devine exclusion (MDE) method of open laparotomy has been reported to be effective in such cases. METHODS: We performed laparoscopic MDE gastrojejunostomy in 8 cases. The patient data collected included surgical time, morbidity and mortality, length of stay, the state and duration of adequate oral ingestion, and outcome. RESULTS: The median surgical time was 191 minutes. There were no complications postoperatively. The median postoperative stay was 7 days. In that time, feeding conditions were restored to pre-illness levels. All patients were palliated successfully using this procedure. CONCLUSIONS: Laparoscopic MDE gastrojejunostomy allows patients to regain their ability to eat, significantly improving their quality of life. This alternative laparoscopic procedure is effective for patients whose prognosis is poor as a result of unresectable cancer. PMID- 17693296 TI - Re: Carotid artery fibromuscular dysplasia. PMID- 17693297 TI - Laparoscopic program for novice laparoscopic surgeons. PMID- 17693298 TI - Initial treatment of anorectal melanoma. PMID- 17693299 TI - The Easyknot: to unravel a cinch. PMID- 17693300 TI - A novel efficient way to estimate the chemical rank of high-way data arrays. AB - A novel method, a subspace projection of pseudo high-way data array (SPPH), was developed for estimating the chemical rank of high-way data arrays. The proposed method determines the chemical rank through performing singular value decomposition (SVD) on the slice matrices of original high-way data array to produce a pseudo high-way data array and employing the idea of the difference of the original truncated data set and the pseudo one. Compared with traditional methods, it uses the information from eigenvectors combined with the projection residual to estimate the rank of the three-way data arrays instead of using the eigenvalue. In order to demonstrate the excellent performance of the new method, simulated and real three-way data arrays were carried out by the proposed method. The results showed that the proposed method could accurately and quickly determine the chemical rank to fit the trilinear model. Moreover, the newly proposed method was compared with the other four factor-determining methods, i.e. factor indicator function (IND), ADD-ONE-UP, core consistency diagnostic (CORCONDIA) and two-mode subspace comparison (TMSC) approaches. It was found that the proposed method can deal with more complex situations with existence of severe collinearity and trace concentration than many other methods can and performs well in practical applications. PMID- 17693301 TI - Quantitative structure-retention relationships for organic pollutants in biopartitioning micellar chromatography. AB - Quantitative structure-retention relationship (QSRR) models have been successfully developed for the prediction of the retention factor (log k) in the biopartitioning micellar chromatography (BMC) of 66 organic pollutants. Heuristic method (HM) and radial basis function neural networks (RBFNN) were utilized to construct the linear and non-linear QSRR models, respectively. The optimal QSRR model was developed based on a 6-17-1 radial basis function neural network architecture using molecular descriptors calculated from molecular structure alone. The RBFNN model gave a correlation coefficient (R2) of 0.8464 and root mean-square error (RMSE) of 0.1925 for the test set. This paper provided a useful model for the predicting the log k of other organic compounds when experiment data are unknown. PMID- 17693302 TI - Removing uncertain variables based on ensemble partial least squares. AB - A strategy, named as removing uncertain variables based on ensemble partial least squares (RUV-EPLS), was proposed. In this strategy, the uncertainty in PLS regression coefficients is evaluated by the criterion of stability, and the variables whose regression coefficients carry a relatively large uncertainty are eliminated. Then, a new EPLS model with the remaining variables is constructed. To reasonably control the quality of the PLS member models in the RUV-EPLS, an objective criterion based on the F-test is used, which makes the RUV-EPLS convenient to perform in practice. To validate the effectiveness and universality of the strategy, it was applied to two different sets of near-infrared (NIR) spectra. It is of great interest to be found that the RUV-EPLS is not so sensitive to the outliers as many other calibration methods, and the selected variables are indeed known to be informative for corresponding compounds, which results in a reliable and high-quality calibration model. The study reveals that the RUV-EPLS method is of value to improve stability and predictive ability of multivariate calibration involving complex matrices that may contain a small number of outliers. PMID- 17693303 TI - Application of probabilistic neural networks in qualitative analysis of near infrared spectra: determination of producing area and variety of loquats. AB - Near infrared (NIR) spectra of a sample can be treated as a signature, allowing samples to be grouped on basis of their spectral similarities. Near infrared spectroscopy (NIRS) combined with probabilistic neural networks (PNN) have been used to discriminate producing area and variety of loquats. Two varieties of loquats ('Dahongpao' and 'Jiajiaozhong') picked from two producing areas of 'Tangxi' and 'Cunan' in Zhejiang province were analyzed in this study. Principal component analysis (PCA) was applied before PNN modeling and the results indicated that the dimension of the vast spectral data can be effectively reduced. For each model, half samples were used to train the network and the remaining half were used to test the network. The results of the PCA-PNN models for discriminating the variety of samples from the same producing area or for discriminating the producing area of the same variety samples were much better than those of the PCA-PNN models for discriminating variety or producing area of all loquat samples. The results of this study show that NIRS combined with PCA PNN is a feasible way for qualitative analysis of discriminating fruit producing areas and varieties. PMID- 17693304 TI - Urinary nucleosides based potential biomarker selection by support vector machine for bladder cancer recognition. AB - BACKGROUND: Urinary nucleosides are potential biomarkers for many kinds of cancers. But up to now, it has been little focused in bladder cancer recognition. The aim of present study is try to validate the potential of urinary nucleoside as biomarker for bladder cancer diagnosis by finding out some urinary nucleosides with good discriminative performance for bladder cancer recognition in urinary nucleoside profile. METHODS: 20 urinary samples for cancer and the same number for control are collected and treated by capillary electrophoresis-mass spectrometry experiments to achieve urinary nucleoside profile, in which 44 peaks were integrated and the ratios of the relative peak area to the concentration of urinary creatinine were used as features to describe all samples. Support vector machine based recursive feature elimination (SVM-RFE) and a new feature selection method called support vector machine based partial exhaustive search algorithm (SVM-PESA) were used for biomarker identification and seeking optimal feature subsets for bladder cancer recognition. RESULTS: Based on the urinary nucleoside profile, 22 optimal feature subsets consist of 3-4 features were found with 95% 5 fold cross validation accuracy, 100% sensitivity and 90% specificity by SVM-PESA, whose performance were much better than that of optimal feature subset selected by SVM-RFE. By analyzing the statistical histogram of features' appearance frequency in several best feature subsets, urinary nucleosides with m/z 317, 290 and 304 were thought as potential biomarkers for bladder cancer recognition. CONCLUSIONS: These results indicated urinary nucleosides may be useful as tumor biomarkers for bladder cancer, and the new method for biomarker selection is effective. PMID- 17693305 TI - Retention prediction of adrenoreceptor agonists and antagonists on a diol column in hydrophilic interaction chromatography. AB - Retention prediction models using multiple linear regression (MLR) and artificial neural networks (ANN) were developed for adrenoreceptor agonists and antagonists chromatographed on a diol column under hydrophilic interaction chromatographic (HILIC) mode at three pH conditions (3.0, 4.0 and 5.0). Using stepwise MLR, the retention behavior of the analytes was satisfactorily described by a five predictor model; the predictors being the percentage of acetonitrile in the mobile phase (% ACN), the logarithm of partition coefficient (log D), the number of hydrogen bond donor (HBD), the number of hydrogen bond acceptor (HBA), and the total absolute atomic charge of the molecule (TAAC). Among the five descriptors, % ACN had the strongest effect on the retention as indicated by its relatively higher standardized coefficient compared to the other four predictors. The inclusion of the four predictors which are related to the properties of the compounds (log D, HBD, HBA and TAAC), suggested hydrophilic interaction, hydrogen bonding and ionic interaction as possible mechanisms of retention of the analytes on the studied system. The models derived from MLR also showed adequate fit as proven by the high correlation (R2 as high as 0.9667) between observed and predicted log k values for the training set and good predictive power on the test set (R2 greater than 0.97). ANN analyses of the data were also conducted using the five predictors derived from MLR as inputs and log k as output. The trained ANNs showed better predictive abilities as compared to MLR models as indicated by relative higher R2 and lower root mean square error of predictions (RMSEP) for both training and test sets. The derived models can be used as references for method development and optimization of chromatographic conditions for the separation of adrenoreceptor agonists and antagonists. PMID- 17693307 TI - Derivatized humic acids modified gold electrode: electrochemical characterization and analytical applications. AB - The preparation and application of a humic acids modified gold electrode (HA-CME) have been described. Derivatization of HAs as beta-thioesters caused their partial fragmentation and, thus, a consequent separation by size exclusion chromatography (SEC) was necessary. The CME prepared with functionalized HAs having an average MW of 52000 demonstrated to be effective for trace As(III) determination (LOQ = 0.3 microg L(-1)). This CME has been characterized both by electrochemical techniques and atomic force microscopy (AFM). The HA-CME provided reliable measurements in natural waters at different salinity with no need of desalting the sample. Total inorganic arsenic could be determined after reduction of As(V) with SO2. Under these conditions, organic arsenic species were not mineralized and did not interfere. PMID- 17693306 TI - Determination of gadolinium(III) ions in soil and sediment samples by a novel gadolinium membrane sensor based on 6-methyl-4-{[1-(2-thienyl)methylidene]amino}3 thioxo-3,4-dihydro-1,2,4-triazin-5-(2H)-one. AB - Highly selective and sensitive poly(vinyl chloride) (PVC) membrane electrodes based on 6-methyl-4-{[1-(2-thienyl)methylidene]amino}3-thioxo-3,4-dihydro-1,2,4 triazin-5-(2H)-one (MATDTO) as new carriers for gadolinium ion-selective electrode was reported. The membrane solutions containing PVC, o-nitrophenyl octyl ether (NPOE) as plasticizer, sodium tetraphenyl borate (NaTPB) as lipophilic ionic additive, and MATDTO, displays a calibration response for Gd3+ ions over a wide concentration range of 1.0x10(-6)-1.0x10(-1) M with Nernstian slopes of 19.8+/-0.2 mV per decade and a detection limit as 5.8x10(-7) M. The sensor has a relatively fast response time of <10 s and can be used in the pH range 3.2-8.7 for at least 2 months without any significant divergence in potentials. The selectivity coefficients for mono-, di-, and trivalent cations indicate good selectivity for Gd(III) ions over a large number of interfering cations. The membrane sensor was used as an indicator electrode in the potentiometric titration of Gd(III) ions with EDTA. The proposed electrode was also applied to the determination of concentration of Gd(III) ions in soil and sediment samples and validation with CRMs. PMID- 17693308 TI - Utilising gallium for enhanced electrochemical copper analysis at the bismuth film electrode. AB - A sensitive anodic stripping voltammetric procedure at the bismuth film electrode (BFE) for trace analysis of copper (II) in the presence of gallium is presented. The new protocol circumvents the problems of overlapping stripping signals between copper and bismuth that previously hampered the analysis of copper at the BFE. The results illustrate that the addition of gallium not only improves the reproducibility of the bismuth stripping signal but also facilitates much improved resolution between the stripping signals of bismuth and copper. Investigations into the effect of gallium on the stripping response of copper and bismuth were studied showing a 4:1 gallium:copper mole ratio produces optimum signals from bismuth and copper indicating a possible stoichiometric relationship. Optimisation of other key variables including electrolyte composition, accumulation parameters and appropriate waveform settings were studied and optimised. The optimised procedures show a range of linear calibration plots (R2>0.994) ranging from 2 to 500 microg L(-1) and the relative standard deviation for a solution containing 100 microg L(-1) copper was 3.7% (n=10). Utilising an accumulation time of 300 s the limit of detection was 1.4 microg L(-1) (S/N=3). This technique was successfully applied to the analysis of copper in tap water representing the first successful copper determination in real samples using the BFE. PMID- 17693309 TI - Cell-sorption of paramagnetic metal ions on a cell-immobilized micro-column in the presence of an external magnetic field. AB - The cell-sorption of paramagnetic ions of Mn2+ and Cr3+ onto a Chlorella vulgaris (C. vulgaris) cell-immobilized micro-column was significantly improved in the presence of an external magnetic field generated in a finite solenoid, by placing the micro-column in the center of the solenoid in a sequential injection system. Magnetic field creates an opposite drift velocity on the hydrated paramagnetic ions against the flow of the sample zone, retards the moving velocity of the metal ions and provides extra contacting time with the cells on the micro-column and offers more chances for the paramagnetic ions to interact with the various functional groups or binding sites on the cell surface, which significantly facilitates cell-sorption of the paramagnetic ions. The sorption efficiencies of Mn2+ and Cr3+ at the 20 microg L(-1) level were improved from 45 to 80% and 60 to 90%, respectively, in a magnetic field of 240 mT. The system was applied for the separation/preconcentration of ultra-trace level of manganese. The presence of an external magnetic field significantly alleviated the interfering effects from coexisting metal ions. Within a liner range of 0.025-0.5 microg L(-1) and a sampling volume of 500 microL, an enrichment factor of 21.2, a limit of detection of 0.008 microg L(-1), along with a sampling frequency of 20 h(-1) was attained, achieving a precision of 2.1% R.S.D. (0.2 microg L(-1)). Manganese contents in a certified reference material of riverine water and a snow water were analyzed. PMID- 17693310 TI - In situ derivatization and hollow fiber membrane microextraction for gas chromatographic determination of haloacetic acids in water. AB - An alternative method for gas chromatographic determination of haloacetic acids (HAAs) in water using direct derivatization followed by hollow fiber membrane liquid-phase microextraction (HF-LPME) has been developed. The method has improved the sample preparation step according to the conventional US EPA Method 552.2 by combining the derivatization and the extraction into one step prior to determination by gas chromatography electron captured detector (GC-ECD). The HAAs were derivatized with acidic methanol into their methyl esters and simultaneously extracted with supported liquid hollow fiber membrane in headspace mode. The derivatization was attempted directly in water sample without sample evaporation. The HF-LPME was performed using 1-octanol as the extracting solvent at 55 degrees C for 60 min with 20% Na2SO4. The linear calibration curves were observed for the concentrations ranging from 1 to 300 microg L(-1) with the correlation coefficients (R2) being greater than 0.99. The method detection limits of most analytes were below 1 microg L(-1) except DCAA and MCAA that were 2 and 18 microg L(-1), respectively. The recoveries from spiked concentration ranged from 97 to 109% with %R.S.D. less than 12%. The method was applied for determination of HAAs in drinking water and tap water samples. The method offers an easy one step high sample throughput sample preparation for gas chromatographic determination of haloacetic acids as well as other contaminants in water. PMID- 17693311 TI - Quantification of human pharmaceuticals in water samples by high performance liquid chromatography-tandem mass spectrometry. AB - An improved analytical method for determination of human pharmaceuticals in natural and wastewaters with ng L(-1) sensitivity is presented. The method is applicable to pharmaceuticals from a wide range of therapeutic classes including antibiotics, analgesics, anti-inflammatories and anti-cancer compounds. Pharmaceuticals were extracted from waters using solid-phase extraction, and after concentration, analysed by high performance liquid chromatography with tandem mass spectrometric detection (HPLC-MS/MS). Identification of each compound was secured using retention time and by the selected reaction monitoring of two transitions, one of which was additionally used for quantification. Limits of detection ranged from 0.03 to 0.96 ng L(-1) and were up to two orders of magnitude lower than those of previously published methods. The method was validated using spiked samples prepared from tap, river and sea water as well as wastewater effluents, collected from the North of Scotland. Analysis of wastewater effluents revealed the presence of mefenamic acid, ibuprofen, erythromycin, diclofenac and trimethoprim. None of the selected pharmaceuticals were detected in river, tap or sea water samples. PMID- 17693312 TI - Development of a new sample pre-treatment procedure based on pressurized liquid extraction for the determination of metals in edible seaweed. AB - A new, simple, fast and automated method based on acetic acid-pressurized liquid extraction (PLE) has been developed for the simultaneous extraction of major and trace elements (As, Ca, Cd, Co, Cr, K, Mg, Mn, Na, Pb, Sr and Zn) from edible seaweeds. The target elements have been simultaneously determined by inductively coupled plasma-optical emission spectrometry (ICP-OES). The influence of several extraction parameters (e.g. acetic acid concentration, extraction temperature, extraction time, pressure, number of cycles, particle size and diatomaceous earth (DE) mass/sample mass ratio) on the efficiency of metal leaching has been evaluated. The results showed that metal extraction efficiency depends on the mass ratio of the dispersing agent mass and the sample. The optimized procedure consisted of the following conditions: acetic acid (0.75 M) as an extracting solution, 5 min of extraction time, one extraction cycle at room temperature at a pressure of 10.3 MPa and addition of a dispersing agent (at a ratio of 5:1 over the sample mass). The leaching procedure was completed after 7 min (5 min extraction time plus 1 min purge time plus 1 min end relief time). Limits of detection and quantification and repeatability of the over all procedure have been assessed. Method validation was performed analysing two seaweed reference materials (NIES-03 Chlorella Kessleri and NIES-09 Sargasso). The developed extraction method has been applied to red (Dulse and Nori), green (Sea Lettuce) and brown (Kombu, Wakame and Sea Spaghetti) edible seaweeds. PMID- 17693313 TI - Determination of delta9-tetrahydrocannabinol in indoor air as an indicator of marijuana cigarette smoking using adsorbent sampling and in-injector thermal desorption gas chromatography-mass spectrometry. AB - The marijuana leaves are usually mixed with tobaccos and smoked at amusement places in Taiwan. Recently, for investigation-legal purposes, the police asked if we can identify the marijuana smoke in a KTV stateroom (a private room at the entertainment spot for singing, smoking, alcohol drinking, etc.) without marijuana residues. A personal air-sampler pump fitted with the GC liner-tube packed with Tenax-TA adsorbent was used for air sampling. The GC-adsorbent tube was placed in the GC injector port and desorbed directly, followed by GC-MS analysis for the determination of delta9-tetrahydrocannabinol (delta9-THC) in indoor air. The average desorption efficiency and limit of detection for delta9 THC were 89% and 0.1 microg m(-3), respectively, approximately needing 1.09 mg of marijuana leaves smoked in an unventilated closed room (3.0 m x 2.4 m x 2.7 m) to reach this level. The mean delta9-THC contained in the 15 marijuana plants seized from diverse locations was measured to be 0.32%. The delta9-THC in room air can be successfully identified from mock marijuana cigarettes, mixtures of marijuana and tobacco, and an actual case. The characteristic delta9-THC peak in chromatogram can serve as the indicator of marijuana. Positive result suggests marijuana smoking at the specific scene in the recent past, facilitating the formulation of further investigation. PMID- 17693314 TI - Characterization and identification of isomeric flavonoid O-diglycosides from genus Citrus in negative electrospray ionization by ion trap mass spectrometry and time-of-flight mass spectrometry. AB - Flavonoid O-diglycosides are important bioactive compounds from genus Citrus. They often occur as isomers, which makes the structural elucidation difficult. In the present study, the fragmentation behavior of six flavonoid O-diglycosides from genus Citrus was investigated using ion trap mass spectrometry in negative electrospray ionization (ESI) with loop injection. For the flavonoid O rutinosides, [M-H-308]- ion was typically observed in the MS2 spectrum, suggesting the loss of a rutinose. The fragmentation patterns of flavonoid O neohesperidosides were more complicated in comparison with their rutinoside analogues. A major difference was found in the [M-H-120]- ion in the MS2 spectrum, which was a common feature of all the flavonoid O-neohesperidosides. The previous literature for naringin located the loss of 120Da to the glycan part, whereas the present study for naringin had shown that the [M-H-120]- ion was produced by a retro-Diels-Alder reaction in ring C, and this fragmentation pattern was confirmed by the accurate mass measurement using an orthogonal time of-flight mass spectrometer. Combined with high performance liquid chromatography (HPLC) and diode array detection (DAD), the established approach to the structural identification of flavonoid O-diglycosides by ion trap mass spectrometry was applied to the analysis of extracts of two Chinese medicines derived from genus Citrus, namely Fructus aurantii and F. aurantii immaturus. According to the HPLC retention behavior, the diagnostic UV spectra and the molecular structural information provided by multistage mass spectrometry (MS(n)) spectra, 13 flavonoid O-glycosides in F. aurantii and 12 flavonoid O-glycosides in F. a. immaturus were identified rapidly. PMID- 17693315 TI - Fourier transform infrared spectroscopy as a suitable technique in the study of the materials used in waterproofing of archaeological amphorae. AB - The resinous materials from the interior surfaces of two Roman and one Iberian amphora were studied with Fourier transform infrared (FTIR) spectroscopy. The results were then compared with those obtained by synchrotron radiation-FTIR, scanning electron microscopy (SEM), and gas chromatography-mass spectrometry (GC MS). The FTIR spectra obtained by the technique of KBr micropellets, prepared directly with the materials scraped from the amphora without any further sample preparation, provided enough information to establish their diterpenoic nature, and even to differentiate between the two main materials employed for waterproofing purposes, pitch and wood tar. Methyl dehydroabietic acid (DHAM) is the main chemical marker that allows a distinction to be made between these two materials. Pitch and wood tar were prepared in the laboratory heating pine resin and resinous pine wood, respectively. These resinous waterproofing materials were compared with the coatings extracted from the amphorae. The samples whose direct FTIR spectra showed a signal at approximately 1740 cm(-1), attributed to a carbonyl group of methyl ester, presented as well a peak of DHAM in the GC-MS chromatogram of the neutral fraction of their extract. Samples without this signal in their spectra did not present DHAM in their chromatogram. This work studies, for the first time, waterproofing of an amphora attributed to the Iberian culture. PMID- 17693316 TI - Preliminary study on application of mid infrared spectroscopy for the evaluation of the virgin olive oil "freshness". AB - The freshness of virgin olive oils (VOO) from typical cultivars of Garda regions was evaluated by attenuated total reflectance (ATR) and Fourier transform infrared (FTIR) spectroscopy, in combination with multivariate analysis. The olive oil freshness decreased during storage mainly because of oxidation processes. In this research, 91 virgin olive oils were packaged in glass bottles and stored either in the light or in the dark at room temperature for different periods. The oils were analysed, before and after storage, using both chemical methods and spectroscopic technique. Classification strategies investigated were partial least square discriminant analysis (PLS-DA), linear discriminant analysis (LDA), and soft independent modelling of class analogy (SIMCA). The results show that ATR-MIR spectroscopy is an interesting technique compared with traditional chemical index in classifying olive oil samples stored in different conditions. In fact, the FTIR PCA results allowed a better discrimination among fresh and oxidized oils, than samples separation obtained by PCA applied to chemical data. Moreover, the results obtained by the different classification techniques (PLS DA, LDA, SIMCA) evidenced the ability of FTIR spectra to evaluate the olive oil freshness. FTIR spectroscopy results are in agreement with classical methods. The spectroscopic technique could be applied for the prediction of VOOs freshness giving information related to chemical modifications. The great advantages of this technique, compared to chemical analysis, are related to rapidity, non destructive characteristics and low cost per sample. In conclusion, ATR-MIR represents a reliable, cheap and fast classification tool able to assess the freshness of virgin olive oils. PMID- 17693317 TI - Investigation of photobleaching and saturation of single molecules by fluorophore recrossing events. AB - A method for investigation of photobleaching and saturation of single molecules by fluorophore recrossing events in a laser beam is described. The diffraction limited probe volumes encountered in single-molecule detection (SMD) produce high excitation irradiance, which can decrease available signal. The single molecules of several dyes were detected and the data was used to extract interpeak times above a defined threshold value. The interpeak times revealed the number of fluorophore recrossing events. The number of molecules detected that were within 2 ms of each other represented a molecular recrossing for this work. Calcein, fluorescein and R-phycoerythrin were analyzed and the saturation irradiance and photobleaching effects were determined as a function of irradiance. This approach is simple and it serves as a method of optimizing experimental conditions for single-molecule detection. PMID- 17693318 TI - Alpha-glucosidase based bismuth film electrode for inhibitor detection. AB - A biosensing system based on alpha-glucosidase (AG) activity was developed by using bismuth film modified glassy carbon electrode (BiFE). AG enzyme was immobilized on the BiFE by means of gelatin membrane and the activity was measured by the following of liberated 4-nitrophenol from the 4-nitrophenyl-alpha D-glucopyranoside (PNPGP) which is the synthetic substrate of the enzyme at the working potential of -950 mV. The proposed system was used as an AG based biosensing system. Experimental data showed that the response current of 4 nitrophenol obtained at the BiFE was linear in concentration range between 0.033 and 0.33 mM of PNPGP. Before examining the analytical characteristics, pH optimization of the AG-biosensor was also performed. Furthermore, the proposed method was applied to analyze two different AG inhibitors (Amaryl and Acorbose) which are important in Noninsulin-dependent diabetes mellitus (NIDDM). PMID- 17693319 TI - A dual detector capillary waveguide biosensor for detection and quantification of hybridized target. AB - We describe a novel technique for improving the sensitivity of analytical instruments based on the measurement of fluorescent intensity. Independent measurement of the Rayleigh scattered intensity component by means of a second photodetector leads to normalized data, which are independent of various experimental parameters. Incorporation of this technique into a fully automated capillary waveguide biosensor improved the instrument sensitivity by a factor of three. The technique enables quantification, as well as detection, of the hybridized target molecules. PMID- 17693320 TI - The development of a multi-nitroimidazole residue analysis assay by optical biosensor via a proof of concept project to develop and assess a prototype test kit. AB - An assay based on optical biosensor technology has been developed to detect a broad range of nitroimidazole drug residues and their metabolites (dimetridazole (DMZ), metronidazole (MNZ), ronidazole (RNZ), hydroxymetronidazole (HO-MNZ) and hydroxydimetridazole (HO-DMZ)) in chicken muscle. The detection limit for the procedure was determined as 0.5 ppb for DMZ and detection capabilities (CCbetas) ranged from <1 ppb for DMZ, MNZ and RNZ to <2 ppb for HO-MNZ and HO-DMZ. Intra assay variation (n=6) was calculated as 11.6% at a concentration of 1 ppb DMZ and 4.7% at a concentration of 2 ppb DMZ. Inter-assay variation (n=3) was determined to be 14.2% at a concentration of 1 ppb DMZ and 3.5% at a concentration of 2 ppb DMZ. A prototype kit based on this assay was produced and a multinational study was undertaken to independently evaluate its performance. The resulting data showed that the kit can be implemented with little difficulty in laboratories of varying expertise and is sensitive enough to meet the standards required by international law. Feedback from this study led to the incorporation of some minor improvements to the kit. The commercial partner in the project, XenoSense Ltd., was consulted with regards to producing a commercial test kit based on the prototype assay. As feedback from the collaborative study had been positive with respect to speed, ease of use and performance of the kit, the decision to commercialise the kit was taken. In conclusion, the prototype nitroimidazole kit was shown to offer numerous advantages over existing analytical techniques. PMID- 17693321 TI - Use of diffusive gradients in thin films and tangential flow ultrafiltration for fractionation of Al(III) and Cu(II) in organic-rich river waters. AB - Diffusive gradients in thin films (DGT) and tangential-flow ultrafiltration (TF UF) were combined for fractionation of Al and Cu in river water containing high content of dissolved organic carbon. A procedure based on ultrafiltration data is proposed to determine diffusion coefficients of the analytes in water samples and model solutions containing both free metal (M) and complex (metal-humic substance). Aiming to evaluate the accuracy of the proposed approach, the DGT results were compared with those from a protocol for determination of labile Al and Cu based on solid phase extraction (SPE). Good agreement between data from DGT and SPE were attained for model solutions. For analysis of real organic-rich water samples, differences between DGT and SPE measurements were consistent with the time-scales of the techniques. The concentration of labile Al determined by DGT were lower than the total dissolved concentrations (determined by inductively coupled plasma mass spectrometry) and exceeded the ultrafiltered concentration, indicating that inorganic Al species (species small enough to pass through 1 kDa membrane) were minor species as compared with Al organic complexes. For both Al and Cu, there were species not measured by DGT as they are not sufficiently labile. PMID- 17693322 TI - Analysis of post-Byzantine icons from the Church of the Assumption in Cephalonia, Ionian Islands, Greece: a multi-method approach. AB - A multi-method approach has been developed for the characterisation of the proteinaceous binding media, drying oils and pigments present in samples from the panel paintings of the Church of the Assumption in Cephalonia (Ionian Islands, Greece). The analytical protocol involved the use of scanning electron microscopy/energy dispersive X-ray analysis (SEM/EDX), Raman spectroscopy and gas chromatography. The identification of the pigments was achieved by SEM/EDX and Raman spectroscopy. The latter technique was also used for the detection of the binding media, while their characterisation was achieved by gas chromatographic analysis of ethyl chloroformate derivatives. The aim of this multi-method protocol was to obtain as much information as possible from the panel paintings of the Church of the Assumption, through non-destructive methods, before proceeding to gas chromatography. Little scientific information is available for the understanding of the construction technique and the materials used by the post-Byzantine artists and whatever is available comes mainly from artists' manuals. One of the aims of this paper is to provide a scientific background to the technology of the Ionian post-Byzantine icons. PMID- 17693325 TI - Cancer of the gallbladder and extrahepatic bile ducts. PMID- 17693326 TI - Continuous quality improvement and assisted reproductive technology multiple gestations: some progress, some answers, more questions. AB - The past decade has seen a fall in the number of embryos transferred accompanied by a reduction in the rate of higher order multiple pregnancies occurring from U.S. assisted reproductive technology (ART) cycles, which is temporally related to voluntary adherence to embryo transfer guidelines. The twin rate has remained relatively constant. The ability to continue the reduction in multiple pregnancies while maintaining advocacy positions for both patient couples and offspring will best occur with attention to scientific, sociologic, economic, and provider issues. PMID- 17693327 TI - Combination of 17beta-estradiol with the environmental pollutant TCDD is involved in pathogenesis of endometriosis via up-regulating the chemokine I-309-CCR8. AB - OBJECTIVE: To explore the effects of the combined E(2) with the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on CCR8-I-309 expression by the endometriotic lesion-associated cells in the pathogenesis of endometriosis. DESIGN: Prospective laboratory study. SETTING: University hospital. PATIENT(S): Chinese women with endometriosis. INTERVENTION(S): The endometriotic tissue and matched eutopic endometrium were collected. Endometrial stromal cells (ESCs), HPMC, and U937 cells were treated with 17beta-E(2) or TCDD. The ESCs were stimulated with I-309. MAIN OUTCOME MEASURE(S): The expression of CCR8 in tissues was analyzed by reverse transcription-polymerase chain reaction and immunohistochemistry. The effect of I-309 on integrin beta1 and alphavbeta3 expression intensity was analyzed by flow cytometry, and the chemotactic activity of I-309 on the ESC was explored by chemotactic assay. Concentration of I-309 in the culture supernatant was quantified by enzyme-linked immunosorbent assay. RESULT(S): CCR8 was overexpressed in the endometriotic tissue. I-309 promoted the expression of integrin beta1. Estradiol and TCDD up-regulated CCR8 expression by ESCs. Estradiol magnified the stimulatory effect of TCDD on I-309 secretion by U937. The interaction of HPMC and U937 cells promoted I-309 secretion. CONCLUSION(S): These findings imply that the combination of 17beta-E(2) with the environmental pollutant TCDD is involved in the pathogenesis of endometriosis via up-regulating the chemokine CCR8-I-309. PMID- 17693328 TI - Comparison of FSH flare with and without pretreatment with oral contraceptive pills in poor responders undergoing in vitro fertilization. AB - OBJECTIVE: To compare FSH, LH, estrogen, and P flare response following 1 mg lupron injection in poor responders with or without pretreatment with oral contraceptive pills (OCPs). DESIGN: Prospective study. SETTING: University hospital. PATIENT(S): Poor responders undergoing IVF flare protocol from October 2002 to November 2003. INTERVENTION(S): Patients were divided into group A, who received OCPs before IVF cycle (n = 12), and group B, who did not (n = 7). One milligram Lupron was injected SC after measuring day 2 serum FSH, LH, estrogen, and P. After 24 hours, serum hormones were measured before lupron administration. MAIN OUTCOME MEASURE(S): Serum FSH, LH, estrogen, and P before and after 1 mg lupron RESULT(S): Basal FSH was similar in both groups (8.6 +/- 4.5 vs. 9.6 +/- 2.9 mIU/mL). Group A patients had significantly lower day 2 FSH (3.6 +/- 3.6 vs. 10.1 +/- 4.2 mIU/mL; P<.05). After lupron, although both groups had a significant rise in FSH and LH, mean LH rise in group B was 39.5 +/- 31 mIU/mL versus 11.3 +/ 4.6 mIU/mL in group A (P<.05). CONCLUSION(S): Pretreatment with OCPs in GnRH agonist flare protocol suppresses pre-Lupron FSH but does not blunt FSH flare. It blunts LH flare, which may be beneficial. PMID- 17693329 TI - Re: Gel instillation sonohysterography: first experience with a new technique. PMID- 17693330 TI - Chiropractic and the changing US health care marketplace: where we are going and what needs to be done. AB - This editorial reviews the current health care marketplace in the United States as it relates to chiropractic and the complementary and alternative medicine community. A 4-part strategy of research, education, alliance-building, and politics, is offered to address current obstacles. PMID- 17693331 TI - The benefits outweigh the risks for patients undergoing chiropractic care for neck pain: a prospective, multicenter, cohort study. AB - OBJECTIVE: This study describes both positive clinical outcomes and adverse events in patients treated for neck pain by a chiropractor. METHODS: This study was a prospective, multicenter, observational cohort study. Patients with neck pain of any duration who fulfilled the inclusion criteria were recruited in a practice-based study. Data were collected on the patients and from the chiropractors at baseline, the first 3 visits, and at 3 and 12 months. Clinical outcome measures included (1) neck pain in the 24 hours preceding the visit, (2) neck disability, (3) treatment satisfaction, (4) global assessment, and (5) adverse events. Recovery was defined as "completely improved" or "much better" using the global assessment scale. An adverse event was defined as either a new related complaint or a worsening of the presenting or existing complaint by >30% based upon an 11-point numerical rating scale. RESULTS: In all, 79 chiropractors participated, recruiting 529 subjects, representing 4891 treatment consultations. Follow-up was possible for 90% and 92%, respectively, at 3 and 12 months. Most patients had chronic, recurrent complaints; mild to moderate disability of the neck; and a mild amount of pain at baseline; and two thirds had sought previous care for the presenting complaint in the preceding 6 months. Adverse events after any of the first 3 treatments were reported by 56%, and 13% of the study population reported these events to be severe in intensity. The most common adverse events affected the musculoskeletal system or were pain related, whereas symptoms such as tiredness, dizziness, nausea, or ringing in the ears were uncommon (<8%). Only 5 subjects (1%) reported to be much worse at 12 months. No serious adverse events were recorded during the study period. Of the patients who returned for a fourth visit, approximately half reported to be recovered, whereas approximately two thirds of the cohort were recovered at 3 and 12 months. CONCLUSION: Adverse events may be common, but are rarely severe in intensity. Most of the patients report recovery, particularly in the long term. Therefore, the benefits of chiropractic care for neck pain seem to outweigh the potential risks. PMID- 17693332 TI - Consent: its practices and implications in United kingdom and United States chiropractic practice. AB - OBJECTIVE: This study explores the implementation of consent procedures in a sample of chiropractors in the United Kingdom (UK) and the United States (US) and how well they satisfy the core ethical principles of autonomy, veracity, justice, nonmaleficence, and beneficence. METHODS: A precoded questionnaire was sent to 500 geographically stratified, randomly selected chiropractors in the UK and 500 similarly selected chiropractors within 10 states (50 from each) across the US. Questionnaires were dispatched 100 per month over a 5-month period. Nonresponders were followed up twice. Quantitative data were analyzed descriptively. Qualitative data were charted and examined for emergent themes. RESULTS: The overall response rate was 35% (346 of 1000), equating to 23% (n = 117) of the US and 46% (n = 231) of the UK cohort. Results suggest chiropractors view consent as an event rather than a process and revealed important omissions in key areas. Reasons specified for the nondisclosure of risk have important negative implications on the principles of autonomy, veracity, and justice, whereas paternalistic tendencies are indicative of tension between beneficence and paternalism. CONCLUSION: Results from this survey suggest a patient's autonomy and right to self-determination may be compromised when seeking chiropractic care. Difficulties and omissions in the implementation of valid consent processes appear common, particularly in relation to risk. Practitioners felt that a serious adverse event occurred so infrequently that this, coupled with a lack of convincing evidence regarding the risk associated with certain treatment, rendered the routine discussion of major risk unnecessary. PMID- 17693333 TI - Effectiveness of traditional bone setting in chronic neck pain: randomized clinical trial. AB - OBJECTIVE: This study evaluates the effectiveness of traditional bone setting (TBS) in chronic neck pain (cNP) compared with conventional physiotherapy (PT) and massage (M). METHODS: This was a randomized clinical trial. Working-aged employed subjects with cNP (n = 105; 37 men and 68 women; mean age, 41.5 years) were randomized into TBS, PT, and M groups. Follow-up times were 1, 6, and 12 months after the treatments. Neck pain intensity (visual analog scale), perceived disability (Neck Disability Index [NDI]), and neck spine mobility measurements were used as outcomes. Global assessment was evaluated by the subjects (scale from -1 to +10). Data were analyzed using time (pre and post) by group (TBS, PT and M), 2- way analysis of variance for repeated measures. RESULTS: Neck pain decreased and NDI scores improved in all groups 1 month after the treatment (P < .001). The improvement of NDI and persons' satisfaction were significantly better after TBS. Neck spine mobility in rotation movements tended to improve significantly better and the frons-knee distance improved more after TBS. One year later, both NDI and neck pain were significantly better after TBS than in reference groups. A significant improvement was reported by 40% to 45.5% of subjects in the PT and M groups and by 68.6% in the TBS group. Bone setters' ability to communicate and to interact with patients was evaluated significantly higher. In the TBS group, the number of sick days was minimal as was the use of painkillers during 1-year follow-up compared to that in the reference groups. CONCLUSIONS: Traditional bone setting, which is a soft manual mobilization technique focusing on the muscles, joints, and ligaments, appears to be effective in cNP. Two thirds of subjects experienced it as beneficial, and it seems to be able to improve disability and pain in patients with cNP. Subjective and partially objective benefits of TBS were found in those patients more than after other interventions, and the effects lasted at least for 1 year. PMID- 17693334 TI - Three-dimensional manual contact force evaluation of graded perpendicular push force delivery by second-year physiotherapy students during simple feedback training. AB - OBJECTIVE: The purpose of this study was to investigate a quantitative biomechanical evaluation method for contact forces exerted during a manual examination and treatment technique used in a learning environment. The evaluation was based on three-dimensional (3D) force component data. METHODS: A hand-/palm-held computerized 3D force component measuring system was used during a simple feedback experiment involving 20 second-year university students of physiotherapy who delivered 5 sets of graded perpendicular manual push forces on the sensor part of the system, which was placed on the padded surface of an examination/treatment table. In an effect study with a multiple time-series design, a randomly chosen subgroup of subjects received concurrent visual 3D kinetic/dynamic force-time feedback. RESULTS: The students delivered graded perpendicular forces with good intrasubject consistency (intraclass correlation coefficient [3, 1]: mean, 0.80; range, 0.76-0.88) but with poor intersubject consistency (intraclass correlation coefficient [2, 1]: mean, 0.38; range, 0.15 0.74). A temporary performance improvement in forward-backward force direction deviations from the perpendicular in the subgroup given feedback indicates that students are sensitive to feedback training. CONCLUSION: An evaluation tool using 3D contact force component measurement enables the assessment of the overall magnitude of the manual contact force as well as its directional aspect. Compared with existing evaluations based on 1-dimensional force components, this 3D system allows for a more complete and, at the same time, more specific quantitative evaluation of the manual contact forces. Three-dimensional dynamic/kinetic augmented feedback has the additional potential of helping students and practitioners to improve their palpation and force delivery skills. PMID- 17693335 TI - Reliability and normative database of the Zebris cervical range-of-motion system in healthy controls with preliminary validation in a group of patients with neck pain. AB - OBJECTIVE: The first aim of this study was to determine the reliability of the Zebris (Achen, Germany) ultrasound-based testing of cervical range of motion (ROM). The second aim was to develop a normative database in a healthy sample of 96 volunteers. The third aim was to evaluate, with the Zebris system, the ROM in a sample of patients with chronic neck pain compared to healthy controls to determine if cervical ROM could discriminate between these groups and between subgroups of pain patients (with or without whiplash injury). METHODS: The study participants were 96 healthy volunteers, 14 patients with idiopathic neck pain, and 16 patients with chronic whiplash. Cervical ROM was measured in the 3 planes with the Zebris CMS 70P ultrasound-based motion analysis system. The intra- and interrater reliability of the protocol was tested in 12 volunteers. RESULTS: Full cycle measurements showed high reliability (intraclass correlation coefficient, 0.80-0.94) with the SE of measurement ranging from 4.25 degrees to 7.88 degrees. The distribution of ROM measures showed a great individual variation, with a significant age-related decrease in ROM in all directions. Range of motion was reduced in patients with chronic whiplash in all primary movements, compared to healthy subjects, whereas in patients with idiopathic neck pain, only rotation showed reduced ROM. CONCLUSION: Results demonstrate a high degree of test-retest reliability in measuring cervical ROM. The use of normative data for ROM when evaluating patients with neck disorders needs to take age into account. The current study has demonstrated that patients with chronic neck pain demonstrate reduced ROM, which differs between patients with idiopathic neck pain and those with chronic whiplash. PMID- 17693336 TI - Responsiveness of the short-form 36 and oswestry disability questionnaire in chronic nonspecific low back and lower limb pain treated with customized foot orthotics. AB - PURPOSE: This study reports the responsiveness of the Short-Form 36 (SF-36) and Oswestry Disability Questionnaire (ODQ) to treatment with customized foot orthotics. METHODS: Thirty consecutive patients presenting to a primary care clinic with chronic (>3 months), nonspecific, low back pain and/or soft tissue lower limb disorders completed the SF-36 and ODQ before and 6 weeks after prescription of customized foot orthotics. Locations of any pain in the lower half of the body (including the low back), age, sex, and duration of the most chronic pain were recorded. Responsiveness statistics of the ODQ and SF-36 physical and mental summary scores were calculated, as was correlation among these scores and the self-reported pain improvement scores. RESULTS: All subjects completed the baseline and 6-week questionnaires. The mean age of the sample was 53.9 +/- 12.9 years, with 57% men and 43% women. The mean duration of the most chronic pain symptom was 14 +/- 14 months (range, 3-60 months). The mean ODQ score at baseline was 42.8% +/- 14. 8% and at 6 weeks was 16.6% +/- 5.0%. The physical component score of the SF-36 was 39.8 +/- 5.0 at baseline and at 6 weeks was 47.3 +/- 3.8. The mental component score of the SF-36 at baseline was 45.7 +/ 6.1 and at 6 weeks was 47.9 +/- 5.0. The responsiveness of the ODQ was calculated to be 9.40, the responsiveness being 1.77 for the physical component score of the SF-36 and 0.24 for the mental component score of the SF-36. CONCLUSIONS: In this cohort, the ODQ and the physical component of the SF-36 appear to be responsive to treatment effects, with the ODQ having the highest responsiveness. The ODQ may be a useful outcome measure in trials of the effectiveness of customized foot orthotics in patients with nonspecific, chronic low back and/or soft tissue lower limb pain. PMID- 17693337 TI - A case report of an uncommon cause of cauda equina symptoms. AB - OBJECTIVE: This case report discusses a patient who presented with right-sided buttock pain of apparently uncomplicated mechanical origin that was eventually diagnosed as a primary Ewing sarcoma/primitive neuroectodermal tumor of the sacrum. CLINICAL FEATURES: A 32-year-old male full-time student presented for care with right-sided buttock pain. INTERVENTION AND OUTCOME: After examination, the patient was referred to his general practitioner for urgent magnetic resonance imaging, the report revealed no explanation for the presenting symptoms. After further imaging and biopsy, an eventual diagnosis of Ewing sarcoma/primitive neuroectodermal tumor was reached. The patient died 12 months later. CONCLUSION: This case highlights a nondiscal cause for cauda equina symptoms. It emphasizes potential diagnostic complexities that may present due to preconceptions based upon the probability of symptoms being related to a specific disease process. PMID- 17693338 TI - A case of vertebral metastasis with pathologic c2 fracture. AB - OBJECTIVE: This report discusses a patient with a pathologic fracture of the C2 vertebra secondary to osteolytic metastasis from squamous cell carcinoma of the lung. CLINICAL FEATURES: The patient was a 68-year-old man with a chief complaint of neck pain who was referred by his physician to a chiropractic office. The initial onset of neck pain began after a forceful sneeze that resulted in a sensation of "a twig snapping" in the neck. Radiographs revealed osteolytic destruction and pathologic fracture of the C2 spinous process. INTERVENTION AND OUTCOME: The patient was referred back to his primary care physician, who then referred him to an oncologist, who immediately initiated a course of radiation therapy and pain medication. Palliative care by the chiropractor consisted of soft tissue massage of the cervical spine musculature to treat associated muscle spasms and pain. The patient responded well to gentle myofascial therapy. However, the osteolytic destruction of the C2 posterior elements progressed, resulting in an unstable subluxation of C2 and associated cord compression. The spine was stabilized with a rigid collar, but the metastatic destruction progressed, eventually resulting in quadriplegia and subsequent death from respiratory distress. CONCLUSION: Patients with a history of cancer complaining of new onset of back or neck pain should be assumed to have vertebral metastasis until proven otherwise. Trivial trauma should be taken seriously in these cases and investigated with appropriate clinical, laboratory, and imaging examinations. Vertebral malignancies may be a contraindication to spinal manipulation; however, the chiropractic physician plays a significant role in early detection and diagnosis. PMID- 17693340 TI - Health services research related to chiropractic: review and recommendations for research prioritization by the chiropractic profession. PMID- 17693341 TI - The electromyographic activity of thoracic paraspinal muscles identified as abnormal with palpation. PMID- 17693343 TI - Peripheral neuropathy related to chemotherapy. AB - OBJECTIVES: To review the evidence base for prevention and intervention of chemotherapy-induced peripheral neuropathy (PN). DATA SOURCES: Medical and nursing literature. CONCLUSION: Many small studies that reported positive findings have either not been validated in large prospective, randomized controlled trials (RCT), or have not been further studied. Prevention strategies based on RCTs include the use of xaliproden to reduce the incidence of grade 3 PN in patients receiving oxaliplatin-based regimens, and dose reduction or interruption until recovery. There are gaps in the literature of nurse-sensitive outcome studies for nursing assessment and intervention IMPLICATIONS FOR NURSING PRACTICE: Nurses need to be knowledgeable about the evidence, or lack of it, on strategies to prevent and manage chemotherapy-induced PN. Nurses also need to measure the effectiveness of interventions for PN, such as exercise, patient teaching about self-care strategies, and develop and/or participate in well designed intervention studies regarding the prevention and management of PN. PMID- 17693344 TI - Prevention of infection in patients with cancer. AB - OBJECTIVES: To provide clinicians with the most reliable, updated evidence to support clinical decision-making and improve outcomes for patients with cancer who are at increased risk for infection. DATA SOURCES: Review of two evidence based summaries of prevention of infection interventions published by the Oncology Nursing Society; MEDLINE and guidelines.gov literature review. CONCLUSION: Handwashing is the most important intervention to prevent infection in patients with cancer. Guidelines-based intravascular catheter care and preventive activities can reduce infection incidence in this vulnerable patient population. Understanding risk factors for aggressive pathogens can help identify patients for rapid surveillance and isolation procedures. Additional multi-site research is required in oncology settings to recommend recent interventions for practice. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses should assess their adherence to evidence-based guidelines on infection prevention. Outcomes are optimized when clinicians identify high-risk patients and provide scientifically supported interventions. PMID- 17693345 TI - Extravasation management. AB - OBJECTIVES: To describe the mechanisms of injury associated with DNA binding and DNA non-binding vesicants. To review various procedures used in clinical practice to manage vesicant extravasations. DATA SOURCES: Journal articles, published case reports, personal experience. CONCLUSION: There is a lack of evidenced-based information and consensus about vesicant extravasation management. The antidotes sodium thiosulfate for mechlorethamine extravasations and hyaluronidase for plant alkaloid extravasations are recommended by the manufacturers of these vesicants. Data suggest that administration of IV dexrazoxane is effective in preventing tissue necrosis following anthracycline extravasation. Dimethyl sulfoxide also may have a role in treating anthracycline extravasations, but further research is needed. IMPLICATIONS FOR NURSING PRACTICE: Nurses who administer vesicant chemotherapy agents must be aware of the most current (or lack of) evidence for extravasation treatment. Well-informed nurses can serve as patient advocates and may be instrumental in detecting, managing, and documenting these injuries. Most importantly, nurses play a key role in preventing vesicant extravasation injuries. PMID- 17693346 TI - Hypersensitivity reactions to biological drugs. AB - OBJECTIVES: To review the current evidence regarding hypersensitivity reactions related to the administration of biological drugs in the management of cancer, and to provide the nurse with appropriate interventions related to the management of hypersensitivity reactions. DATA SOURCES: Review articles and research studies from the medical and nursing literature. CONCLUSION: Current evidence is available regarding the types of reactions that are associated with the administration of biological drugs in the management of cancer. Medical and nursing studies that review the most effective management of hypersensitivity reactions related to the administration of biological drugs. A review of "best practice" is offered in this article regarding the management of hypersensitivity reactions related to the administration of biological drugs. IMPLICATIONS FOR NURSING PRACTICE: Nurses play a key role in the early identification of hypersensitivity reactions. Management of hypersensitivity reactions must be rapid for optimal patient outcomes. PMID- 17693347 TI - Prevention and management of oral mucositis in patients with cancer. AB - OBJECTIVES: To review current evidence that applies to the development of a nursing plan of care for the prevention and treatment of oral mucositis related to cytotoxic therapy. DATA SOURCES: Research studies, review articles, evidence based guidelines, web-based material, and clinical experience. CONCLUSION: Although high-level research evidence regarding mucositis is limited, use of multiple types of evidence in developing a structured plan of care facilitates improved patient outcomes and the advancement of the current body of knowledge. IMPLICATIONS FOR NURSING PRACTICE: Nurses play a key role in the identification and use of evidence to guide the care of patients at risk for cytotoxic therapy related oral mucositis. PMID- 17693348 TI - Cytoprotective agents used in the treatment of patients with cancer. AB - OBJECTIVE: To provide a review of the literature of commonly prescribed cytoprotective agents used in the treatment of patients with cancer. DATA SOURCES: Journal articles, research reports, review articles, and web sites. CONCLUSION: Multiple agents have been theorized to have cytoprotective properties. Significant evidence exists supporting the use of some cytoprotective agents approved by the US Food and Drug Administration (FDA). More research is needed to determine the efficacy of new cytoprotective agents and expanded indications for those agents currently used. IMPLICATIONS FOR NURSING PRACTICE: Knowledge of the indications for and side effect profiles of cytoprotective agents is a necessary component of oncology nursing care. Familiarity with evidence-based research that supports or refutes the use of FDA-approved cytoprotective agents or alternative agents is helpful when suggesting, prescribing, or administering such agents. PMID- 17693349 TI - Clinical dilemma: dyspnea. AB - OBJECTIVES: To review the current state of evidence for the nursing treatment of cancer-related dyspnea. DATA SOURCES: Nursing and medical literature, published guidelines, and Cochrane Systematic reviews. CONCLUSION: Limited evidence exists for the current strategies used to treat dyspnea among persons with cancer. IMPLICATIONS FOR NURSING PRACTICE: Nurses must be cognizant of the level of evidence or the lack of scientific evidence supporting treatment strategies used. Keeping abreast of the developments in the area of dyspnea management is imperative as research adds to the current body of evidence. Nurses are uniquely positioned to add to the body of evidence through collaboration with nurse researchers. PMID- 17693350 TI - Clinical dilemmas: vascular access devices. AB - OBJECTIVES: To present an overview of clinical dilemmas regarding maintenance care and managing complications of vascular access devices (VADs). DATA SOURCES: Current research and published literature. CONCLUSION: The use of VADs has increased over the past three decades because they have proven to be an effective and convenient method of accessing the venous system. The difficulty of maintaining VADs during the course of treatment however, continues to be a challenge resulting in practice dilemmas. IMPLICATIONS FOR NURSING PRACTICE: Although VADs have been in use for more than 30 years, no universal standard of maintenance care exists. Research is still needed to establish evidence-based practice regarding the care and maintenance of VADs. PMID- 17693353 TI - The time is right for a 3-year orthodontic curriculum. PMID- 17693354 TI - The role of the orthodontic residency in the ABO certification process. PMID- 17693355 TI - Postgraduate education in orthodontics-an idea whose time has come ... and gone? PMID- 17693356 TI - Letter to the editor. "Orthodontic treatment changes of chin position in Class II Division 1 patients". PMID- 17693357 TI - Complete orthodontic load systems on teeth in a continuous full archwire: the role of triangular loop position. AB - INTRODUCTION: A novel approach to characterizing orthodontic spring-generated force and moment systems has been developed. This method allows simultaneous measurement of all 6 force and moment components acting on a tooth. METHODS: A continuous full archwire space-closure technique was simulated, and the complete force and moment systems acting on the teeth adjacent to the extraction space were measured. RESULTS AND CONCLUSIONS: The data showed that, in addition to the intended forces and moments, there are nontrivial activation-dependent interactions with the other load components, and these complex relationships are affected by the position of the triangular loop. PMID- 17693358 TI - Evaluation of root resorption after open bite treatment with and without extractions. AB - INTRODUCTION: In this study, we evaluated the root resorption degree in open bite and normal overbite patients, treated with and without premolar extractions. METHODS: A sample of 120 patients was selected and divided into 4 groups. Group 1 comprised 32 patients treated with premolar extractions with an initial mean age of 14.01 +/- 2.58 years and an initial mean overbite of -3.45 +/- 0.23 mm. Group 2 included 28 open bite patients treated without extractions, with an initial mean age of 13.27 +/- 2.75 years and an initial mean overbite of -3.10 +/- 0.24 mm. Group 3 comprised 30 patients with normal overbite, treated with premolar extractions, having a mean age of 13.28 +/- 1.79 years and a mean overbite of 1.09 +/- 0.24 mm at the beginning of treatment. Group 4 consisted of 30 patients with normal overbite, treated without extractions, at a mean age of 12.87 +/- 1.43 years and a mean overbite of 1.67 +/- 0.24 mm at the beginning of treatment. The groups were matched by initial age, treatment time, and malocclusion type. Pretreatment and posttreatment periapical radiographs were used to evaluate the amount of root resorption. The groups were compared by using the Kruskal-Wallis and Dunn nonparametric tests. Correlations between the degree of root resorption and amount of tooth movement, usage time of anterior vertical elastics, and treatment time were investigated with the Spearman correlation coefficient. RESULTS: No statistically significant difference was found between the root resorption degrees of open bite vs normal overbite groups, but the extraction groups had statistically significant greater root resorption than the nonextraction groups. Significant correlations were observed in the extraction groups between root resorption degree and amount of overjet correction and retraction of maxillary incisor apex. CONCLUSIONS: Root resorption was similar between open bite and normal overbite treatment protocols, but extraction treatment showed greater root resorption than nonextraction treatment. There was a statistically significant correlation of overjet correction and retraction of maxillary central incisor apices with the degree of root resorption. PMID- 17693359 TI - Gingival response to mandibular incisor intrusion. AB - INTRODUCTION: The aims of the study were to evaluate the rate of accompanying gingival movement and the changes in attached and keratinized gingivae after orthodontic intrusion of mandibular incisors. METHODS: The study was carried out with 16 subjects whose mandibular incisors were orthodontically intruded for the correction of overbite. The orthodontic intrusion was performed with the segmented utility arch technique. Periodontal indexes and the widths of attached and keratinized gingivae were recorded before and after treatment. The gingival movement in relation to orthodontic intrusion was determined by means of radioopacity with a specially designed metal device indicating the position of the gingival margin and the mucogingival junction on the cephalograms taken before treatment and after intrusion. RESULTS: There were no statistically significant changes in the width of attached and keratinized gingivae after treatment (P >.05). The gingival margin and the mucogingival junction moved in the same direction as the teeth by 79% and 62%, respectively. A statistically significant decrease of the clinical crown length was also observed (P <.05). CONCLUSIONS: These results suggest that orthodontic intrusion does not lead to significant changes in the width of attached and keratinized gingivae when adequate plaque control is maintained. The gingiva moves in the same direction with the tooth, yet considerably less. This might indicate the need for follow-up or gingival correction after intrusion therapy. PMID- 17693360 TI - A comparative evaluation of bracket bonding with 1-, 2-, and 3-component adhesive systems. AB - INTRODUCTION: Today, 1- and 2-component adhesives are available for bracket bonding that could diminish the possibility of contamination during the bonding procedure and save the clinician chair-side time. Our aim in this study was to compare the shear bond strengths and the adhesive remnant index (ARI) scores of 1 , 2-, and 3-component adhesives after thermocycling. METHODS: Fifty stainless steel brackets (10 per adhesive group) were bonded to extracted third molars with 5 adhesives. Group 1 was a 1-component adhesive, RelyX Unicem (3M Espe, Seefeld, Germany). Group 2 was a 1-component adhesive, Maxcem (Kerr, Orange, Calif). Group 3 was a self-conditioning 2-component adhesive system, Multilink (Ivoclar Vivadent, Schaan, Liechtenstein). Group 4 was a 2-component adhesive system, Transbond Plus primer (self-etching) and Transbond XT adhesive (3M Unitek, Monrovia, Calif). Group 5 (control group) was a conventional 3-component adhesive system consisting of an etchant, Transbond XT primer, and XT adhesive (3M Unitek). All samples were thermocycled (6000 x 5 degrees C/55 degrees C) in a mastication device before shear bond strength testing and evaluation with the ARI. RESULTS: No significant differences of shear bond strength between the 2- and 3-component adhesive systems were found. Significant decreases of shear bond strength were observed with 1-component adhesives, RelyX Unicem and Maxcem, compared with 2- and 3-component systems. The ARI scores indicated no significant differences between the groups. CONCLUSIONS: With enhanced shear bond strength, 1 component adhesives have the potential to compete successfully with 2- or 3 component adhesives. PMID- 17693362 TI - Orthodontic bonding to several ceramic surfaces: are there acceptable alternatives to conventional methods? AB - INTRODUCTION: The objectives of this study were to determine the effects of various surface conditioning methods on 3 types of ceramic materials (feldsphatic, leucite-based, and lithia disilicate-based) in orthodontic bonding. METHODS: A total of 210 ceramic disk samples were fabricated and divided into 3 groups. In each group, 5 subgroups were prepared by sandblasting; sandblasting and hydrofluoric (HF) acid; sandblasting and silane; sandblasting, HF acid, and silane; and tribochemical silica coating and silane. Mandibular incisor brackets were bonded with light-cured adhesive. The samples were stored in water for 24 hours at 37 degrees C and then thermocycled. Shear bond tests were performed, and the failure types were classified with adhesive remnant index scores. RESULTS: In all 3 ceramic groups, the lowest shear bond strength values were found in the sandblasted-only samples. For the feldspathic and lithia disilicate-based ceramic, the highest bond strength values were obtained with silica coating (15.2 and 13.2 MPa, respectively). For the leucite-based ceramic, HF without silane produced the highest bond strength value (14.7 MPa), but comparable values were obtained with silicatization also (13.4 MPa). CONCLUSIONS: The silica-coating technique could replace the other conditioning techniques in bonding brackets to ceramic. However, debonding must be done carefully because of the risk of porcelain fracture. PMID- 17693361 TI - The North Carolina Medicaid program: participation and perceptions among practicing orthodontists. AB - INTRODUCTION: Limited provider participation in the Medicaid program is a barrier to access to orthodontic care for Medicaid-eligible patients. The goals of this study were to determine the participation level of North Carolina (NC) orthodontists in the Medicaid program, to examine NC orthodontists' perceptions of the Medicaid program and its beneficiaries, and to determine whether there are differences between practitioners who do and do not accept Medicaid patients. METHODS: Questionnaires were mailed to all active orthodontists (n = 203) as reported in the NC State Dental Board of Licensing Section of the NC Health Professions Data System. Respondents were categorized as current Medicaid providers, past Medicaid providers, or orthodontists who have never accepted Medicaid. RESULTS: Forty of 166 respondents were current Medicaid providers, 33 were past providers, and 93 never accepted Medicaid patients. All 3 groups thought that low fee reimbursement is a major problem. Those who have never participated in the Medicaid program were more likely to perceive each barrier as a major problem. Past Medicaid providers saw broken appointments and tardiness to appointments as greater problems than current providers. CONCLUSIONS: Perceptions of Medicaid patients and lack of knowledge appear to be major barriers to provider participation. PMID- 17693363 TI - A 20-year cohort study of health gain from orthodontic treatment: psychological outcome. AB - INTRODUCTION: Despite the widespread expectation that orthodontic treatment improves psychological well-being and self-esteem, there is little objective evidence to support this. The aim of this study was to compare the dental and psychosocial status of people who received, or did not receive, orthodontic treatment as teenagers. METHODS: A prospective longitudinal cohort design was adopted. A multidisciplinary research team evaluated 1018 participants, aged 11 to 12 years, in 1981. Extensive assessments of dental health and psychosocial well-being were conducted; facial and dental photographs and plaster casts of dentition were obtained and rated for attractiveness and pretreatment need. No recommendations about orthodontic treatment were made, and an observational approach was adopted. At the third follow-up, 337 subjects (30-31 years old) were reexamined in 2001. One-way ANOVA was used to explore differences between the 4 groups (need/no need; treatment/no treatment). RESULTS: The percentage changes in index of complexity, outcome and need scores for the 4 groups were need/no treatment (12.7%), no need/no treatment (-17.1%), need/treatment (31%), and no need/treatment (-11.4%). Participants with a prior need for orthodontic treatment as children who obtained treatment had better tooth alignment and satisfaction. However, when self-esteem at baseline was controlled for, orthodontic treatment had little positive impact on psychological health and quality of life in adulthood. CONCLUSIONS: Lack of orthodontic treatment when there was need did not lead to psychological difficulties in later life. PMID- 17693364 TI - Surgical-orthodontic treatment and patients' functional and psychosocial well being. AB - INTRODUCTION: Surgical-orthodontic treatment is a common treatment approach for adult patients with skeletal maxillomandibular discrepancy. Some patients report improvement in signs and symptoms of temporomandibular disorder (TMD) after surgery. Whether the correction of malocclusion is responsible for the improvement of TMD symptoms after orthognathic surgery is still controversial. The objectives of this prospective study were to evaluate subjective treatment outcomes in patients with bilateral sagittal split osteotomy (BSSO) and to find out whether signs and symptoms of TMD and changes in occlusion are related to patient satisfaction. METHODS: Eighty-two patients (53 female, 29 male) with a mean age of 32 years (range, 16-53 years) treated with BSSO in the Oral and Maxillofacial Department at Kuopio University Hospital in Finland were examined; 64 had mandibular advancement, and 18 had mandibular setback. Occlusion and signs and symptoms of TMD were registered pre- and postoperatively. At the postoperative examination (mean, 1.8 years after BSSO), the patients were asked to fill out a questionnaire about the influence of treatment on their masticatory function and symptoms of TMD, as well as their satisfaction with the treatment outcome. RESULTS: TMD symptoms were significantly reduced after treatment. Improvements were also reported in facial appearance (82%) and chewing ability (61%); also, facial (56%) and temporomandibular joint (40%) pain disappeared. However, in 12% of the patients, temporomandibular joint problems were worse after treatment. Most patients (73%) were very satisfied with the outcomes; no one expressed dissatisfaction. Multiple logistic regression analysis showed that subjects with improved mastication and self-confidence, and those without long term neurosensory deficits, expressed high satisfaction with the treatment outcome. Patients with mandibular setback were more pleased with the outcome than those with mandibular advancement. CONCLUSIONS: Orthognathic patients generally experience functional and psychosocial benefits after surgical-orthodontic treatment. In addition to functional and morphological reasons, the psychosocial factors should be more emphasized when making the treatment decision and comparing the alternative treatment approaches. PMID- 17693365 TI - Caries preventive measures used in orthodontic practices: an evidence-based decision? AB - INTRODUCTION: Although it is well known that treatment with fixed appliances increases the risk of enamel demineralization, little information is available about preventive measures that orthodontists actually use. This study was executed to survey measures used in orthodontic practices to prevent decalcifications during fixed appliance treatment, and to compare these measures with the available evidence-based information. METHODS: A questionnaire was sent to all privately practicing orthodontists in the Netherlands who were affiliated with the Dutch Dental Association. RESULTS: Of 229 orthodontists, 178 (78%) returned the questionnaires. Most of the orthodontists had a basic practice protocol for preventing demineralizations at the start of treatment. This protocol nearly always included oral hygiene instructions. If demineralizations occurred, 99% of the orthodontists took extra measures. Comparing the measures applied in the orthodontic practices with the evidence from a systematic review, a number of differences became apparent. The additional use of chlorhexidine or toothpaste with a high fluoride concentration (which has been demonstrated to have an inhibitive effect) is rarely prescribed. Fluoride rinse is prescribed most often, although there is not any high-quality, long-term study that demonstrates a caries preventive effect in orthodontic patients. Sixty-eight percent of the orthodontists considered it necessary to develop a practice guideline for preventing demineralizations. CONCLUSIONS: Orthodontists do not implement the available evidence in order to prevent enamel demineralizations during fixed-appliance treatment. A practice guideline incorporating this information should be developed. PMID- 17693366 TI - Craniofacial changes in Class III malocclusion as related to skeletal and dental maturation. AB - INTRODUCTION: In this large cross-sectional study, we aimed to analyze growth trends in white subjects with Class III malocclusion using both skeletal and dental maturation staging. METHODS: The sample consisted of 1091 pretreatment lateral cephalometric records of Class III patients (560 female, 531 male). Cephalometric dentoskeletal measurements were compared at subsequent stages in cervical vertebral maturation and Hellman's categorization of dental development by means of ANOVA with Bonferroni post-hoc tests in both sexes separately. RESULTS: The findings indicated that, in Class III malocclusion, the pubertal peak in mandibular growth occurs between stages 3 and 4 of cervical vertebral maturation, with average increases in total mandibular length of about 8 and 5.5 mm in Class III boys and girls, respectively. CONCLUSIONS: Significant changes in total mandibular length occur until young adulthood (18 years on average), with increases between late maturation stages (4 through 6) that were twice as large as in subjects with normal occlusion for the Class III females, and 3 times as large as in subjects with normal occlusion for the Class III males. Growth trends toward accentuated Class III profile and increased vertical dimension of the face also become apparent at late developmental stages (corresponding with complete eruption of the second and third molars). PMID- 17693367 TI - A longitudinal study of normal asymmetric mandibular growth and its relationship to skeletal maturation. AB - INTRODUCTION: Our aims in this investigation were to assess asymmetric mandibular growth relative to skeletal maturation and to determine whether asymmetric growth occurs during a period of high growth velocity. METHODS: We evaluated lateral oblique and hand-wrist radiographs of 30 male and 30 female Class I participants in the Burlington Growth Study who were assessed at 3 time periods with the skeletal maturation index (SMI). The body, the ramus, the effective length, and the gonial angle on each side of the mandible were measured. Asymmetry between the right and left sides was analyzed with the SMI and for sex dependency. RESULTS: The left ramus was consistently longer than the right in all evaluation periods (P <.05). The right body was consistently longer than the left in all evaluation periods (P <.05). The effective length showed no asymmetry until the last maturation group, when the right side was longer (P <.05). The gonial angle had no significant differences. Tests to determine differences between the sexes showed no significance in asymmetry, but the body, the ramus, and the effective length were longer in males than in females (P <.05). CONCLUSIONS: Asymmetry does not occur or increase during any specific growth period. PMID- 17693368 TI - Childhood obesity and skeletal maturation assessed with Fishman's hand-wrist analysis. AB - INTRODUCTION: The purpose of this study was to determine whether increased body mass index is associated with accelerated skeletal maturation. METHODS: The skeletal ages of 107 children, aged 9 to 16 years, were determined by using Fishman's hand-wrist analysis. The difference between chronologic age and dental age was analyzed against body mass index, sex, and age. RESULTS: The mean differences between chronologic and skeletal ages for normal weight, overweight, and obese subjects were 0.51 years, 0.44 years, and 1.00 years, respectively. Although there was a trend for obese subjects to have accelerated skeletal maturation compared with overweight and normal-weight subjects, the difference was not statistically significant. Skeletal age differences significantly decreased with increasing age. The mean skeletal age differences were 0.90 year for 9- to 13-year-olds and 0.26 year for 13- to 16-year-olds. Mean skeletal age did not differ significantly by sex. CONCLUSIONS: Overweight or obese children did not have significantly accelerated skeletal maturation after adjusting for age and sex. PMID- 17693369 TI - Treatment effects of headgear biteplane and bionator appliances. AB - INTRODUCTION: The purpose of this investigation was to evaluate the dentoalveolar and skeletal cephalometric changes produced by headgear (HG) biteplane and bionator appliances in subjects with Class II Division 1 malocclusion. METHODS: The sample comprised 60 patients with Class II Division 1 malocclusion; 30 (15 boys, 15 girls; mean age, 10.02 years) were treated with the HG biteplane for a mean period of 1.78 years, and 30 (15 boys, 15 girls; mean age, 10.35 years) were treated with a bionator for a mean period of 1.52 years. For comparison, a control group of 30 untreated Class II children (15 boys, 15 girls) with an initial mean age of 10.02 years, followed for 1.48 years, was established. Lateral cephalometric headfilms were obtained at the beginning and at the end of the treatment or observation period. RESULTS: The results showed that forward growth of the maxilla was restricted in the HG biteplane group. Bionator treatment, however, produced a statistically significant increase in mandibular protrusion. Both appliances provided increases in total mandibular and ramus lengths. There were no statistically significant differences in craniofacial growth direction. The mandibular incisors were tipped labially with bionator treatment and lingually in the HG biteplane group. The maxillary incisors were retruded with both appliances; there also were a significant increase in mandibular posterior dentoalveolar height and a restriction in the vertical development of the maxillary molars. CONCLUSIONS: Class II treatment with HG biteplane and bionator appliances is efficient over the short term, with pronounced dentoalveolar movements and smaller but still significant skeletal effects. The stability of these results should be examined in a long-term study. PMID- 17693370 TI - Morphologic and hemodynamic analysis of dental pulp in dogs after molar intrusion with the skeletal anchorage system. AB - INTRODUCTION: We have successfully treated skeletal open bite by intruding posterior teeth with the skeletal anchorage system. Our aim in this study was to morphologically and hemodynamically evaluate the changes in pulp tissues when molars are radically intruded. METHODS: The mandibular fourth premolars of 9 adult beagle dogs were divided into 3 groups: a sham operated group (n = 6, 3 dogs), 4-month intrusion group (n = 6, 3 dogs), and a further 4-month retention group (n = 6, 3 dogs). We evaluated the morphological changes of the pulp and dentin-the amount of vacuolar degeneration in the odontoblast layer, the predentin width and nervous continuity in the pulp tissue, and the pulpal blood flow response evoked by electrical stimulation in the dental pulp. RESULTS: Extreme molar intrusion with the skeletal anchorage system caused slight degenerative changes in the pulp tissue, followed by recovery after the orthodontic force was released. Circulatory system and nervous functions were basically maintained during the intrusion, although a certain level of downregulation was observed. These morphologic and functional regressive changes in the pulp tissue after molar intrusion improved during the retention period. CONCLUSIONS: Histologic changes and changes in pulpal blood flow and function are reversible, even during radical intrusion of molars. PMID- 17693371 TI - Self-ligating vs conventional brackets in the treatment of mandibular crowding: a prospective clinical trial of treatment duration and dental effects. AB - INTRODUCTION: The aim of this study was to investigate the duration of mandibular crowding alleviation with self-ligating brackets compared with conventional appliances and the accompanying dental effects. METHODS: Fifty-four subjects were selected from a pool of patients satisfying the following inclusion criteria: nonextraction treatment in the mandibular or maxillary arches; eruption of all mandibular teeth; no spaces in the mandibular arch; irregularity index greater than 2 in the mandibular arch; and no therapeutic intervention planned with any extraoral or intraoral appliance. The patients were randomly assigned to 2 groups: 1 group received treatment with a self-ligating bracket (Damon 2, Ormco, Glendora, Calif) and the other with a conventional edgewise appliance (Microarch, GAC, Central Islip, NY), both with 0.022-in slots. The irregularity index of the mandibular arch was normalized between the groups, and the time to alignment was estimated in days. Treatment duration was assessed by data modeling with the Cox proportional hazard regression. Lateral cephalometric radiographs were used to assess the alteration of mandibular incisor position before and after alignment. Measurements of intercanine and intermolar widths were also made on dental casts to determine changes associated with correction. RESULTS AND CONCLUSIONS: Overall, no difference in the time required to correct mandibular crowding with Damon 2 and conventional brackets was observed. For moderate crowding (irregularity index <5), however, the self-ligating group had 2.7 times faster correction. This difference was marginally insignificant for subjects with irregularity index scores greater than 5. Greater crowding prolonged treatment by an additional 20% for each irregularity index unit. Increases in intercanine and intermolar widths associated with crowding correction regardless of bracket group were noted. The self-ligating group showed a statistically greater intermolar width increase than the conventional group. Also, an alignment-induced increase in the proclination of the mandibular incisors was observed for both bracket groups, but no difference was found between Damon 2 and conventional brackets for this parameter. PMID- 17693372 TI - Self-ligating brackets: present and future. AB - Recently, there has been a resurgence in the use of self-ligating (SL) brackets, which were introduced in the early 20th century. From a synthesis of both in vitro and in-vivo evidence-based literature, we present general concepts, principles, and axioms. The references to "active" and "passive" SL brackets are explained and juxtaposed in relation to their perceived advantages and disadvantages. We also present new concepts in regard to the future of SL brackets: combination bracket system, hybrid system, and selective use of SL brackets. PMID- 17693373 TI - Self-ligating vs conventional twin brackets during en-masse space closure with sliding mechanics. AB - INTRODUCTION: The aim of this study was to compare the rate of en-masse space closure with sliding mechanics between passive self-ligating SmartClip brackets (3M Unitek, Monrovia, Calif) and conventional twin brackets ligated with stainless steel ligatures. METHODS: Nineteen patients including 20 arches participated in this prospective trial with 0.018-in slot brackets. All patients had first premolar extractions in at least 1 arch, with the second premolar and the first molar distal to the extraction site bonded with SmartClip brackets on 1 side and conventional twin brackets on the other. The sides were alternated with each consecutive patient. Space closure was achieved on 0.016 x 0.022-in stainless steel wires with nickel-titanium coil springs activated 6 to 9 mm. The patients were recalled every 5 weeks until 1 side had closed. The distances from the mesial aspect of the canine bracket to the distal aspect of the first molar bracket were recorded before and after space closure, and an average rate of space closure per month was calculated. RESULTS: Thirteen patients completed the trial (14 arches); the median rates of tooth movement for the SmartClip bracket side (1.1 mm per month) and the conventional twin bracket side (1.2 mm per month) were not significantly different (P = .86). CONCLUSIONS: There was no significant difference in the rate of en-masse space closure between passive SmartClip brackets and conventional twin brackets tied with stainless steel ligatures. PMID- 17693374 TI - Transverse features of subjects with sucking habits and facial hyperdivergency in the mixed dentition. AB - INTRODUCTION: The aim of this study was to analyze the transverse characteristics of subjects with sucking habits and hyperdivergency in the mixed dentition. METHODS: The test group consisted of 80 subjects with sucking habits and hyperdivergency in the intermediate mixed dentition, and it was compared with a control group of 185 subjects. The prevalence rate of posterior crossbite was recorded. Maxillary and mandibular intercanine and intermolar widths, and anterior and posterior transverse interarch discrepancies were measured on the dental casts. The statistical comparisons between the test and control groups were performed with independent sample t tests and chi-square tests (P <.05). RESULTS: The prevalence rate of posterior crossbite in the test group was significantly greater (52%) than in the control group (14%) (P <.001). The test group had significantly smaller maxillary intermolar and intercanine widths and significantly greater posterior transverse discrepancy (P <.01). No significant differences were found for mandibular intermolar and intercanine widths or anterior transverse discrepancy. CONCLUSIONS: Prolonged sucking habits and hyperdivergency in the mixed dentition were associated with narrow maxillary intermolar and intercanine widths, increased posterior transverse discrepancies, and increased prevalence of posterior crossbites. PMID- 17693375 TI - Root resorption repair in mandibular first premolars after rotation. A transmission electron microscopy analysis combined with immunolabeling of osteopontin. AB - INTRODUCTION: A previous study with scanning electron microscopy showed that orthodontic root resorption occurs at the lateral surfaces of premolar roots for 2 to 6 weeks after orthodontic rotation. The purpose of this investigation was to observe how resorbed cementum repairs during rotation movement. METHODS: Twenty one mandibular first premolars from 12 patients, orthodontically indicated for extraction, were used. They were intra-individually divided into 2 groups: 8 teeth were not moved (control group), and 13 were rotated (experimental group). In the experimental group, a rotational force (25 g both buccally and lingually) with a precise biomechanical model, individually calibrated, was applied for 2, 3, 4, or 6 weeks. After extraction, the teeth were fixed and decalcified, and 8 were conventionally processed for transmission electron microscopy, and 13 teeth were processed for high-resolution immunocytochemistry by using an antibody against osteopontin. The samples were analyzed in a transmission electron microscope. RESULTS: This examination showed areas of repair in previously resorbed lacunae in the experimental group. Both the clastic cells and the root surface showed immunolabeling for osteopontin. In addition to areas of cementum resorption and various degrees of cell and extracellular matrix degeneration, active cementoblasts and fibroblasts in several stages of differentiation and activity appeared adjacent to newly synthesized collagen fibers, thus reestablishing the function of the periodontal ligament. CONCLUSIONS: We concluded that cementum repair occurs after resorption during rotation movement and that noncollagenous matrix protein osteopontin plays a role in both resorbing and repairing. PMID- 17693376 TI - Titanium screw anchorage for correction of canted occlusal plane in patients with facial asymmetry. AB - INTRODUCTION: Facial asymmetry is a major complaint of orthodontic patients. In those with severe facial asymmetry, combination treatment of LeFort I osteotomy and mandibular surgery was commonly used. This article demonstrates the usefulness of titanium screws for orthodontic anchorage to intrude the molars in 2 patients with facial asymmetry and canted occlusal plane. METHODS AND RESULTS: The first patient was a woman, aged 29 years 6 months, with mandibular protrusion and canted occlusal plane; she was treated with molar intrusion and intraoral vertical ramus osteotomy. During presurgical orthodontic treatment, a titanium screw was implanted in the zygomatic process, and the molars were intruded for 6 months by using an elastic chain of 200 g. After intrusion, the molars were intruded 3.0 mm, and the canted maxillary occlusal plane was improved. The second patient was a young man, aged 16 years 5 months, with mandibular deviation and canted occlusal plane; he was treated with a combination of titanium screw anchorage and intraoral vertical ramus osteotomy. A miniscrew was implanted in the alveolar bone, and the orthodontic load began immediately after placement surgery by using an elastic chain. After 5 months of intrusion, the molars had been intruded by 3.0 mm. CONCLUSIONS: Compared with 2-jaw surgery, this method of molar intrusion is less invasive, involves less psychological stress, is less expensive, and results in less postoperative discomfort. Therefore, treatment with titanium screws for molar intrusion to correct a canted occlusal plane could become a new treatment strategy for patients with facial asymmetry. PMID- 17693377 TI - Nonsurgical treatment of an adult with a Class III malocclusion. AB - This case report describes the orthodontic treatment of a 43-year-old man with Class III malocclusion and crossbite of the maxillary anterior teeth. Treatment options included orthognathic surgery, nonextraction treatment, premolar extractions, and mandibular incisor extraction. The patient opted for nonsurgical treatment that included the extraction of a mandibular central incisor. PMID- 17693378 TI - Category 4: Class II Division 2 malocclusion with deep overbite. AB - This case report was part of the resident display of cases sponsored by the College of Diplomates of the American Board of Orthodontics at the annual session of the American Association of Orthodontists, May 20-24, 2005, in San Francisco, Calif. PMID- 17693379 TI - Remote access of electronic patient data with cellular wireless broadband technology. AB - Wireless cellular broadband technology currently transmits data at speeds that only wired broadband connections were capable of until now. By using high-speed data access protocols such as evolution data optimized (EV-DO) or enhanced data rate for global system for mobile communications evolution (EDGE), gaining access to patient data in an orthodontic office remotely has become a relatively simple task. Affordable and convenient cellular broadband networks allow the orthodontist to remotely access schedules, and update, review, add, or modify data virtually from anywhere. Newer generation wireless broadband technologies have made the virtual office a reality. This article discusses the various broadband technologies that are available for the orthodontist as a techno-savvy consumer and the availability of wide area networks that include third-generation cellular technologies that can be used for remote access of patient data. The new enterprise-level gadgets that use third-generation technologies are also introduced. PMID- 17693380 TI - Prognostic importance of plasma NT-pro BNP in chronic heart failure in patients treated with a beta-blocker: results from the Carvedilol Or Metoprolol European Trial (COMET) trial. AB - BACKGROUND: Plasma levels of N-terminal pro-brain natriuretic peptide (NT-pro BNP) are increased in patients with chronic heart failure (CHF). Beta-blockers (BB) may influence these levels but it is unclear whether changes in NT-pro BNP reflect concomitant changes in prognosis. OBJECTIVES: To assess the prognostic importance of NT-pro BNP at baseline and during follow-up, in patients in whom beta-blocker therapy is initiated. METHODS: In COMET, 3029 patients with CHF in NYHA class II-IV and EF<35% were randomised to carvedilol or metoprolol tartrate and were followed for an average of 58 months. Blood samples were collected for the measurement of NT-pro BNP at baseline (n=1559) and during follow-up (n=309). RESULTS: Baseline plasma concentrations of NT-pro BNP above the median (1242 pg/ml) were associated with higher all-cause mortality (RR 2.77; 95% CI 2.33-3.3, p<0.001). Patients who achieved NT-pro BNP levels<400 pg/ml during follow-up had a lower subsequent mortality (RR 0.32; 95% CI 0.15-0.69, p=0.004). CONCLUSIONS: The plasma concentration of NT-pro BNP is a powerful predictor of mortality in patients with CHF. Patients who achieve an NT-pro BNP of <400 pg/ml subsequent to treatment with a beta-blocker have a favourable prognosis. PMID- 17693381 TI - Development and testing of the quality of life in children with vernal keratoconjunctivitis questionnaire. AB - PURPOSE: To develop and validate a questionnaire that measures health-related quality of life (HRQoL) in children with vernal keratoconjunctivitis (VKC). DESIGN: Prospective, observational case series. METHODS: An initial list of 42 items was developed and administered to 30 children with active VKC (six girls and 24 boys; mean age, nine +/- two years). The 30 most significant items were selected and converted into questions on a three-step scale for validation in 41 children with active VKC (eight girls and 33 boys; mean age, 9.5 +/- 2.1 years). Twenty-two children also completed the generic KINDL questionnaire. Clinical signs were evaluated and scored and total sign scores (TSSs) were calculated. Validation was performed by factorial analysis and Pearson correlation. Internal consistency was computed by the Chronbach alpha on the extracted factors. RESULTS: Factorial analysis extracted two factors with good internal consistency: symptoms (12 items; alpha = 0.89) and daily activities (four items; alpha = 0.77). Correlations of Quality of Life in Children with Vernal Keratoconjunctivitis (QUICK) scores to KINDL scores were in the expected direction. Most patients reported itching (93%), burning (90%), redness (90%), the need to use eye drops (90%), tearing (83%), and photophobia (80%). The children's greatest concerns were limitations on going to the pool (71%), playing sports (58%), and meeting friends (58%). QUICK symptom scores were correlated significantly to conjunctival hyperemia (P < .001), secretion (P = .042), chemosis (P = .012), superficial punctate keratopathy (P < .001), and TSS (P = .010). CONCLUSIONS: The QUICK questionnaire is a new, simple instrument to measure HRQoL in children with severe allergic conjunctivitis. This test is effective for the global evaluation of the impact of VKC on children's daily lives. PMID- 17693382 TI - Comparison of diagnostic accuracy of Heidelberg Retina Tomograph II and Heidelberg Retina Tomograph 3 to discriminate glaucomatous and nonglaucomatous eyes. AB - PURPOSE: To compare the diagnostic accuracy of the Moorfields regression analysis (MRA), parameters, and glaucoma probability score (GPS) from Heidelberg Retinal Tomograph (HRT) 3 (Heidelberg Engineering, Heidelberg, Germany) with MRA and parameters from HRT II in discriminating glaucomatous and healthy eyes in subjects of African and European ancestry. DESIGN: Case-control institutional setting. METHODS: Seventy-eight glaucoma patients (44 of African ancestry, 34 of European ancestry) and 89 age-matched controls (46 of African ancestry, 33 European ancestry), defined by visual fields and self-reported race were included. Imaging was obtained with HRT II, and data were exported to a computer with the HRT 3 software using the same contour line. Area under the receiver operating characteristic (ROC) curves (AUCs), sensitivity, and specificity were evaluated for the entire group, the African ancestry group, and the European ancestry group separately. Mean disk area was compared between correctly and incorrectly diagnosed eyes by each technique. RESULTS: Disk, cup, and rim areas from HRT 3 were lower than HRT II (P < .0001). AUC (sensitivity at 95% specificity) was 0.85 (54%) for vertical cup-to-disk ratio (VCDR) HRT 3, 0.84 (45%) for VCDR HRT II, and 0.81 (44%) for GPS at the temporal sector. MRA HRT 3 showed greater sensitivity but lower specificity than HRT II for the entire group, the African ancestry group, and the European ancestry group. GPS classification had the lowest specificity. Glaucomatous eyes incorrectly classified by GPS had smaller mean disk area (P = .0002); control eyes incorrectly classified had greater mean disk area (P = .015). CONCLUSIONS: VCDR from HRT 3 showed higher sensitivity than HRT II and GPS for the entire group and for those of African ancestry and of European ancestry separately. Sensitivity of MRA improved in HRT 3 with some trade-off in specificity compared with MRA of HRT II. GPS yielded erroneous classification associated to optic disk size. PMID- 17693383 TI - Effects of organic solvents on the enzyme activity of Trypanosoma cruzi glyceraldehyde-3-phosphate dehydrogenase in calorimetric assays. AB - In drug discovery programs, dimethyl sulfoxide (DMSO) is a standard solvent widely used in biochemical assays. Despite the extensive use and study of enzymes in the presence of organic solvents, for some enzymes the effect of organic solvent is unknown. Macromolecular targets may be affected by the presence of different solvents in such a way that conformational changes perturb their active site structure accompanied by dramatic variations in activity when performing biochemical screenings. To address this issue, in this work we studied the effects of two organic solvents, DMSO and methanol (MeOH), in the isothermal titration calorimetry (ITC) kinetic assays for the catalyzed reaction of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from Trypanosoma cruzi. The solvent effects on T. cruzi GAPDH had not yet been studied. This enzyme was shown here to be affected by the organic solvents content up to 5.0% for MeOH and up to 7.5% for DMSO. The results show that when GAPDH is assayed in the presence of DMSO (5%, v/v) using the ITC experiment, the enzyme exhibits approximately twofold higher activity than that of GAPDH with no cosolvent added. When MeOH (5%, v/v) is the cosolvent, the GAPDH activity is sixfold higher. The favorable effects of the organic solvents on the Michaelis-Menten enzyme-substrate complex formation ensure the consistency of the biological assays, structural integrity of the protein, and reproducibility over the measurement time. The reaction was also kinetically monitored by standard spectrophotometric assays to establish a behavioral performance of T. cruzi GAPDH when used for screening of potential inhibitors. PMID- 17693384 TI - Unveiling heme proteins conformational stability through a UV absorbance ratio method. PMID- 17693385 TI - [Hormonal treatment in transsexual patients. Metabolic consequences]. AB - Transsexualism is a sexual identity disorder distinguished by the extreme conviction of belonging to the opposite sex with a total disharmony in the original sex. Diagnosis is established when patients respond to three criteria (DSM-IV): 1) Desire to live and to be accepted as members of opposite sex; 2) Presence of sexual identity disorder for minimal two years; 3) Lack of mental disease or chromosomal anomalies. When diagnosis is confirmed, hormonal treatment can be started and so, improve the secondary sexual characters of selected sex. For patients F-M, treatment is composed of testosterone, most commonly esters of testosterone. For patients M-F, treatment consists of estrogens. These estrogens are frequently associated to an anti-androgen (cyproterone acetate) in the pre reassignment phase. Avoiding the hepatic way, transdermal form is recommended. Hormonal treatments are not devoid of secondary effects: the most frequent one is venous thromboembolism. Considering contraindications and potential complications, each patient must be selected carefully. The endocrinological follow-up is essential and necessary. PMID- 17693386 TI - Rat hepatic stellate cells acquire retinoid responsiveness after activation in vitro by post-transcriptional regulation of retinoic acid receptor alpha gene expression. AB - Activation of hepatic stellate cells (HSCs) is a key process in liver fibrogenesis and retinoid loss is a remarkable feature of activated HSCs. However, roles of retinoids in liver fibrogenesis are obscure. We show that mRNA levels of RARalpha, beta and gamma were decreased during rat HSC activation in vitro. However, protein levels of RARalpha and beta were increased during HSC activation. A retinoic acid response element-containing luciferase assay indicated that HSCs became responsive to retinoids only after activation in vitro and that this response was mediated by, at least in part, RARalpha subtype. Immunocytochemical analysis showed that RARalpha proteins were mainly distributed in cytosol as many spots. All-trans retinoic acid treatment strongly lowered the cytosolic RARalpha protein levels. These results indicate that rat HSCs become retinoid responsive after activation in vitro, through post-transcriptional up regulation of RARalpha gene expression. PMID- 17693387 TI - Pioneer round of translation occurs during serum starvation. AB - The pioneer round of translation plays a role in translation initiation of newly spliced and exon junction complex (EJC)-bound mRNAs. Nuclear cap-binding protein complex CBP80/20 binds to those mRNAs at the 5'-end, recruiting translation initiation complex. As a consequence of the pioneer round of translation, the bound EJCs are dissociated from mRNAs and CBP80/20 is replaced by the cytoplasmic cap-binding protein eIF4E. Steady-state translation directed by eIF4E allows for an immediate and rapid response to changes in physiological conditions. Here, we show that nonsense-mediated mRNA decay (NMD), which restricts only to the pioneer round of translation but not to steady-state translation, efficiently occurs even during serum starvation, in which steady-state translation is drastically abolished. Accordingly, CBP80 remains in the nucleus and processing bodies are unaffected in their abundance and number in serum-starved conditions. These results suggest that mRNAs enter the pioneer round of translation during serum starvation and are targeted for NMD if they contain premature termination codons. PMID- 17693388 TI - Functional analysis of rod monochromacy-associated missense mutations in the CNGA3 subunit of the cone photoreceptor cGMP-gated channel. AB - Thirty-nine missense mutations, which had been identified in rod monochromacy or related disorders, in the CNGA3 subunit of cone photoreceptor cGMP-gated channels were analyzed. HEK293 cells were transfected with cDNA of the human CNGA3 subunit harboring each of these mutations in an expression vector. Patch-clamp recordings demonstrated that 32 of the 39 mutants did not show cGMP-activated current, suggesting that these 32 mutations cause a loss of function of the channels. From the remaining 7 mutants that showed cGMP-activated current, two mutations in the cyclic nucleotide-binding domain, T565M or E593K, were further studied. The half maximal activating concentration (K(1/2)) for cGMP in the homomeric CNGA3-T565M channels (160microM) was 17.8-fold higher than that of the homomeric wild-type CNGA3 channels (9.0microM). Conversely, the K(1/2) for cGMP in the homomeric CNGA3-E593K channels (3.0microM) was 3-fold lower than that of the homomeric wild type CNGA3 channels. These results suggest that the T565M and E593K mutations alter the apparent affinity for cGMP of the channels to cause cone dysfunction, resulting in rod monochromacy. PMID- 17693389 TI - Attenuation of insulin secretion by insulin-like growth factor binding protein-1 in pancreatic beta-cells. AB - IGFBP-1 is involved in glucohomeostasis, but the direct action of IGFBP-1 on the beta-cell remains unclear. Incubation of dispersed mouse beta-cells with IGFBP-1 for 30min inhibited insulin secretion stimulated by glucose, glucagon-like peptide 1 (GLP-1) or tolbutamide without changes in basal release of insulin and in cytosolic free Ca(2+) concentration ([Ca(2+)](i)) and NAD(P)H evoked by glucose. In contrast, IGFBP-1 augmented glucose-stimulated insulin secretion in intact islets, associated with a reduced somatostatin secretion. These results suggest a suppressive action of IGFBP-1 on insulin secretion in isolated beta cells through a mechanism distal to energy generating steps and not involving regulation of [Ca(2+)](i). In contrast, IGFBP-1 amplifies glucose-stimulated insulin secretion in intact islets, possibly by suppressing somatostatin secretion. These direct modulatory influences of IGFBP-1 on insulin secretion may imply an important regulatory role of IGFBP-1 in vivo and in the pathogenesis of type 2 diabetes, in which loss of insulin release is an early pathogenetic event. PMID- 17693390 TI - Non-selective effects of selective serotonin reuptake inhibitors. PMID- 17693391 TI - Delta-opioid receptors are critical for tricyclic antidepressant treatment of neuropathic allodynia. AB - BACKGROUND: The therapeutic effect of antidepressant drugs against depression usually necessitates a chronic treatment. A large body of clinical evidence indicates that antidepressant drugs can also be highly effective against chronic neuropathic pain. However, the mechanism by which these drugs alleviate pain is still unclear. METHODS: We used a murine model of neuropathic pain induced by sciatic nerve constriction to study the antiallodynic properties of a chronic treatment with the tricyclic antidepressants nortriptyline and amitriptyline. Using knockout and pharmacological approaches in mice, we determined the influence of delta-opioid receptors in the therapeutic action of chronic antidepressant treatment. RESULTS: In our model, a chronic treatment by tricyclic antidepressant drugs totally suppresses the mechanical allodynia in neuropathic C57Bl/6J mice. This therapeutic effect can be acutely reversed by an injection of the delta-opioid receptor antagonist naltrindole. Moreover, the antiallodynic property of antidepressant treatment is absent in mice deficient for the delta opioid receptor gene. CONCLUSIONS: The antiallodynic effect of chronic antidepressant treatment is mediated by a recruitment of the endogenous opioid system acting through delta-opioid receptors. PMID- 17693393 TI - Risk factors for invasive pneumococcal disease among Navajo adults. AB - Invasive pneumococcal disease (IPD) is 3-5 times more common among Navajo adults than in the general US population. The authors conducted a case-control study to identify risk factors for IPD among Navajo adults. Navajos aged > or =18 years with IPD were identified through prospective, population-based active laboratory surveillance (December 1999-February 2002). Controls matched to cases on age, gender, and neighborhood were selected. Risk factors were identified through structured interviews and medical record reviews. The authors conducted a matched analysis based on 118 cases and 353 controls. Risk factors included in the final multivariable analysis were chronic renal failure (odds ratio (OR) = 2.6, 95% confidence interval (CI): 0.9, 7.7), congestive heart failure (OR = 5.6, 95% CI: 2.2, 14.5), self-reported alcohol use or alcoholism (OR = 2.9, 95% CI: 1.5, 5.4), body mass index (weight (kg)/height (m)(2)) <5th (OR = 3.2, 95% CI: 1.0, 10.6) or >95th (OR = 2.8, 95% CI: 1.0, 8.0) percentile, and unemployment (OR = 2.6, 95% CI: 1.2, 5.5). The population attributable fractions were 10% for chronic renal failure, 18% for congestive heart failure, 30% for self-reported alcohol use or alcoholism, 6% for body mass index, and 20% for unemployment. Several modifiable risk factors for IPD in Navajos were identified. The high prevalence of renal failure, alcoholism, and unemployment among Navajo adults compared with the general US population may explain some of their increased risk of IPD. PMID- 17693394 TI - Asymmetric synaptic depression in cortical networks. AB - Synaptic depression is essential for controlling the balance between excitation and inhibition in cortical networks. Several studies have shown that the depression of intracortical synapses is asymmetric, that is, inhibitory synapses depress less than excitatory ones. Whether this asymmetry has any impact on cortical function is unknown. Here we show that the differential depression of intracortical synapses provides a mechanism through which the gain and sensitivity of cortical circuits shifts over time to improve stimulus coding. We examined the functional consequences of asymmetric synaptic depression by modeling recurrent interactions between orientation-selective neurons in primary visual cortex (V1) that adapt to feedforward inputs. We demonstrate analytically that despite the fact that excitatory synapses depress more than inhibitory synapses, excitatory responses are reduced less than inhibitory ones to increase the overall response gain. These changes play an active role in generating selective gain control in visual cortical circuits. Specifically, asymmetric synaptic depression regulates network selectivity by amplifying responses and sensitivity of V1 neurons to infrequent stimuli and attenuating responses and sensitivity to frequent stimuli, as is indeed observed experimentally. PMID- 17693392 TI - Brain metabolite abnormalities in the white matter of elderly schizophrenic subjects: implication for glial dysfunction. AB - BACKGROUND: Abnormalities in the white matter of the brain may occur in individuals with schizophrenia as well as with normal aging. Therefore, elderly schizophrenic patients may suffer further cognitive decline as they age. This study determined whether elderly schizophrenia participants, especially those with declined cognitive function (Clinical Dementia Rating score > 1), show white matter metabolite abnormalities on proton magnetic resonance spectroscopy and whether there are group differences in age-dependent changes in these brain metabolites. METHOD: Twenty-three elderly schizophrenia and twenty-two comparison participants fulfilling study criteria were enrolled. Localized, short echo-time (1)H MRS at 4 Tesla was used to assess neurometabolite concentrations in several white matter regions. RESULTS: Compared with healthy subjects, schizophrenia participants had lower N-acetyl compounds (-12.6%, p = .0008), lower myo-inositol (-16.4%, p = .026), and higher glutamate + glutamine (+28.7%, p = .0016) concentrations across brain regions. Schizophrenia participants with Clinical Dementia Rating >/= 1 showed the lowest NA in the frontal and temporal regions compared with control subjects. Interactions between age and schizophrenia status on total creatine and choline-containing compounds were observed; only schizophrenia participants showed age-related decreases of these metabolites in the right frontal region. CONCLUSIONS: Decreased NA in these white matter brain regions likely reflects reduced neuronal content associated with decreased synapses and neuronal cell volumes. The elevated glutamate + glutamine, if reflecting elevated glutamate, could result from excess neuronal glutamate release or glial dysfunction in glutamate reuptake. The decreased myo-inositol in participants with schizophrenia suggests decreased glial content or dysfunctional glia, which might result from glutamate-mediated toxicity. PMID- 17693395 TI - Critical spatial frequencies for illusory contour processing in early visual cortex. AB - Single neurons in primate V2 and cat A18 exhibit identical orientation tuning for sinewave grating and illusory contour stimuli. This cue invariance is also manifested in similar orientation maps to these stimuli, but in V1/A17 the illusory contour maps appear reversed. We hypothesized that this map reversal depends upon the spatial frequencies of the inducers in the illusory contours, relative to the spatial selectivities of these brain areas. We employed intrinsic signal optical imaging to measure orientation maps in cat A17/18 to illusory contours with inducers at spatial frequencies from 0.15 to 1.6 cpd. A17 illusory contour maps were indeed reversed compared with grating-driven maps for inducer spatial frequencies <1.3 cpd, whereas A18 maps were invariant. Simulations based on known neurophysiology demonstrated that map reversal can arise from linear filtering, and map invariance can be explained by a nonlinear (filter-rectify filter) mechanism. The simulation also correctly predicted that A17 could show invariant maps when the inducer spatial frequency is sufficiently high (1.6 cpd), and that A18 maps could reverse at lower inducer frequencies (0.18 cpd). Thus, the map reversal or invariance to illusory contours depends critically on the relationship of the inducer spatial frequencies to the spatial filtering properties of neurons in each brain area. PMID- 17693396 TI - Dopamine modulation of prefrontal cortex interneurons occurs independently of DARPP-32. AB - Dopamine (DA) exerts a strong influence on inhibition in prefrontal cortex. The main cortical interneuron subtype targeted by DA are fast-spiking gamma aminobutyric acidergic (GABAergic) cells that express the calcium-binding protein parvalbumin. D1 stimulation depolarizes these interneurons and increases excitability evoked by current injection. The present study examined whether this direct DA-dependent modulation of fast-spiking interneurons involves DARPP-32. Whole-cell patch-clamp recordings were made from fast-spiking interneurons in brain slices from DARPP-32 knockout (KO) mice, wild-type mice, and rats. Low concentrations of DA (100 nM) increased interneuron excitability via D1 receptors, protein kinase A, and cyclic adenosine 3',5'-monophosphate in slices from both normal and DARPP-32 KO mice. Immunohistochemical staining of slices from normal animals revealed a lack of colocalization of DARPP-32 with calcium binding proteins selective for fast-spiking interneurons, indicating that these interneurons do not express DARPP-32. Therefore, although DARPP-32 impacts cortical inhibition through a previously demonstrated D2-dependent regulation of GABAergic currents in pyramidal cells, it is not involved in the direct D1 mediated regulation of fast-spiking interneurons. PMID- 17693397 TI - Parallel evolution of Pitx1 underlies pelvic reduction in Scottish threespine stickleback (Gasterosteus aculeatus). AB - Little is known about the genetic and molecular mechanisms that underlie adaptive phenotypic variation in natural populations or whether similar genetic and molecular mechanisms are utilized when similar adaptive phenotypes arise in independent populations. The threespine stickleback (Gasterosteus aculeatus) is a good model system to investigate these questions because these fish display a large amount of adaptive phenotypic variation, and similar adaptive phenotypes have arisen in multiple, independent stickleback populations. A particularly striking pattern of parallel evolution in sticklebacks is reduction of skeletal armor, which has occurred in numerous freshwater locations around the world. New genetic and genomic tools for the threespine stickleback have made it possible to identify genes that underlie loss of different elements of the skeletal armor. Previous work has shown that regulatory mutations at the Pitx1 locus are likely responsible for loss of the pelvic structures in independent stickleback populations from North America and Iceland. Here we show that the Pitx1 locus is also likely to underlie pelvic reduction in a Scottish population of threespine stickleback, which has apparently evolved pelvic reduction under a different selection regime than the North American populations. PMID- 17693398 TI - Binding and activation of DNA topoisomerase III by the Rmi1 subunit. AB - Rmi1 is a conserved oligonucleotide and oligosaccharide binding-fold protein that is associated with RecQ DNA helicase complexes from humans (BLM-TOP3 alpha) and yeast (Sgs1-Top3). Although human RMI1 stimulates the dissolution activity of BLM TOP3 alpha, its biochemical function is unknown. Here we examined the role of Rmi1 in the yeast complex. Consistent with the similarity of top3Delta and rmi1Delta phenotypes, we find that a stable Top3.Rmi1 complex can be isolated from yeast cells overexpressing these two subunits. Compared with Top3 alone, this complex displays increased superhelical relaxation activity. The isolated Rmi1 subunit also stimulates Top3 activity in reconstitution experiments. In both cases elevated temperatures are required for optimal relaxation unless the substrate contains a single-strand DNA (ssDNA) bubble. Interestingly, Rmi1 binds only weakly to ssDNA on its own, but it stimulates the ssDNA binding activity of Top3 5-fold. Top3 and Rmi1 also cooperate to bind the Sgs1 N terminus and promote its interaction with ssDNA. These results demonstrate that Top3-Rmi1 functions as a complex and suggest that Rmi1 stimulates Top3 by promoting its interaction with ssDNA. PMID- 17693399 TI - Crystal structure of bacteriophage T4 5' nuclease in complex with a branched DNA reveals how flap endonuclease-1 family nucleases bind their substrates. AB - Bacteriophage T4 RNase H, a flap endonuclease-1 family nuclease, removes RNA primers from lagging strand fragments. It has both 5' nuclease and flap endonuclease activities. Our previous structure of native T4 RNase H (PDB code 1TFR) revealed an active site composed of highly conserved Asp residues and two bound hydrated magnesium ions. Here, we report the crystal structure of T4 RNase H in complex with a fork DNA substrate bound in its active site. This is the first structure of a flap endonuclease-1 family protein with its complete branched substrate. The fork duplex interacts with an extended loop of the helix hairpin-helix motif class 2. The 5' arm crosses over the active site, extending below the bridge (helical arch) region. Cleavage assays of this DNA substrate identify a primary cut site 7-bases in from the 5' arm. The scissile phosphate, the first bond in the duplex DNA adjacent to the 5' arm, lies above a magnesium binding site. The less ordered 3' arm reaches toward the C and N termini of the enzyme, which are binding sites for T4 32 protein and T4 45 clamp, respectively. In the crystal structure, the scissile bond is located within the double-stranded DNA, between the first two duplex nucleotides next to the 5' arm, and lies above a magnesium binding site. This complex provides important insight into substrate recognition and specificity of the flap endonuclease-1 enzymes. PMID- 17693400 TI - Site-specific effects of peptide lipidation on beta-amyloid aggregation and cytotoxicity. AB - Beta-amyloid (Abeta) aggregates at low concentrations in vivo, and this may involve covalently modified forms of these peptides. Modification of Abeta by 4 hydroxynonenal (4-HNE) initially increases the hydrophobicity of these peptides and subsequently leads to additional reactions, such as peptide cross-linking. To model these initial events, without confounding effects of subsequent reactions, we modified Abeta at each of its amino groups using a chemically simpler, close analogue of 4-HNE, the octanoyl group: K16-octanoic acid (OA)-Abeta, K28-OA Abeta, and Nalpha-OA-Abeta. Octanoylation of these sites on Abeta-(1-40) had strikingly different effects on fibril formation. K16-OA-Abeta and K28-OA-Abeta, but not Nalpha-OA-Abeta, had increased propensity to aggregate. The type of aggregate (electron microscopic appearance) differed with the site of modification. The ability of octanoyl-Abeta peptides to cross-seed solutions of Abeta was the inverse of their ability to form fibrils on their own (i.e. Abeta approximately Nalpha-OA-Abeta>>K16-OA-Abeta>>K28-OA-Abeta). By CD spectroscopy, K16-OA-Abeta and K28-OA-Abeta had increased beta-sheet propensity compared with Abeta-(1-40) or Nalpha-OA-Abeta. K16-OA-Abeta and K28-OA-Abeta were more amphiphilic than Abeta-(1-40) or Nalpha-OA-Abeta, as shown by lower "critical micelle concentrations" and higher monolayer collapse pressures. Finally, K16-OA Abeta and K28-OA-Abeta are much more cytotoxic to N2A cells than Abeta-(1-40) or Nalpha-OA-Abeta. The greater cytotoxicity of K16-OA-Abeta and K28-OA-Abeta may reflect their greater amphiphilicity. We conclude that lipidation can make Abeta more prone to aggregation and more cytotoxic, but these effects are highly site specific. PMID- 17693401 TI - Disruption of telomere maintenance by depletion of the MRE11/RAD50/NBS1 complex in cells that use alternative lengthening of telomeres. AB - Immortalized human cells are able to maintain their telomeres by telomerase or by a recombination-mediated DNA replication mechanism known as alternative lengthening of telomeres (ALT). We showed previously that overexpression of Sp100 protein can suppress ALT and that this was associated with sequestration of the MRE11/RAD50/NBS1 (MRN) recombination protein complex by Sp100. In the present study, we determined whether MRN proteins are required for ALT activity. ALT cells were depleted of MRN proteins by small hairpin RNA-mediated knockdown, which was maintained for up to 100 population doublings. Knockdown of NBS1 had no effect on the level of RAD50 or MRE11, but knockdown of RAD50 also depleted cells of NBS1, and knockdown of MRE11 depleted cells of all three MRN proteins. Depletion of NBS1, with or without depletion of other members of the complex, resulted in inhibition of ALT-mediated telomere maintenance, as evidenced by decreased numbers of ALT-associated promyelocytic leukemia bodies and decreased telomere length. In some clones there was an initial period of rapid shortening followed by stabilization of telomere length, whereas in others there was continuous shortening at a rate within the reported range for normal human somatic cells lacking a telomere maintenance mechanism. In contrast, depletion of NBS1 in telomerase-positive cells did not result in telomere shortening. A recent study showed that NBS1 was required for the formation of extrachromosomal telomeric circles (Compton, S. A., Choi, J. H., Cesare, A. J., Ozgur, S., and Griffith, J. D. (2007) Cancer Res. 67, 1513-1519), also a marker for ALT. We conclude that the MRN complex, and especially NBS1, is required for the ALT mechanism. PMID- 17693402 TI - Direct protein kinase C-dependent phosphorylation regulates the cell surface stability and activity of the potassium chloride cotransporter KCC2. AB - The potassium chloride cotransporter KCC2 plays a major role in the maintenance of transmembrane chloride potential in mature neurons; thus KCC2 activity is critical for hyperpolarizing membrane currents generated upon the activation of gamma-aminobutyric acid type A and glycine (Gly) receptors that underlie fast synaptic inhibition in the adult central nervous system. However, to date an understanding of the cellular mechanism that neurons use to modulate the functional expression of KCC2 remains rudimentary. Using Escherichia coli expression coupled with in vitro kinase assays, we first established that protein kinase C (PKC) can directly phosphorylate serine 940 (Ser(940)) within the C terminal cytoplasmic domain of KCC2. We further demonstrated that Ser(940) is the major site for PKC-dependent phosphorylation for full-length KCC2 molecules when expressed in HEK-293 cells. Phosphorylation of Ser(940) increased the cell surface stability of KCC2 in this system by decreasing its rate of internalization from the plasma membrane. Coincident phosphorylation of Ser(940) increased the rate of ion transport by KCC2. It was further evident that phosphorylation of endogenous KCC2 in cultured hippocampal neurons is regulated by PKC-dependent activity. Moreover, in keeping with our recombinant studies, enhancing PKC-dependent phosphorylation increased the targeting of KCC2 to the neuronal cell surface. Our studies thus suggest that PKC-dependent phosphorylation of KCC2 may play a central role in modulating both the functional expression of this critical transporter in the brain and the strength of synaptic inhibition. PMID- 17693403 TI - Alternatively spliced T-cell receptor transcripts are up-regulated in response to disruption of either splicing elements or reading frame. AB - Nonsense mutations create premature termination codons (PTCs), leading to the generation of truncated proteins, some of which have deleterious gain-of-function or dominant-negative activity. Protecting cells from such aberrant proteins is non-sense-mediated decay (NMD), an RNA surveillance pathway that degrades transcripts harboring PTCs. A second response to nonsense mutations is the up regulation of alternatively spliced transcripts that skip the PTC. This nonsense associated altered splicing (NAS) response has the potential to rescue protein function, but the mechanism by which it is triggered has been controversial. Some studies suggest that, like NMD, NAS is triggered as a result of nonsense mutations disrupting reading frame, whereas other studies suggest that NAS is triggered when nonsense mutations disrupt exonic splicing enhancers (ESEs). Using T-cell receptor-beta (TCRbeta), which naturally acquires PTCs at high frequency, we provide evidence that both mechanisms act on a single type of mRNA. Mutations that disrupt consensus ESE sites up-regulated an alternatively spliced TCRbeta transcript that skipped the mutations independently of reading frame disruption and the NMD factor UPF1. In contrast, reading frame-disrupting mutations that did not disrupt consensus ESE sites elicited UPF1-dependent up-regulation of the alternatively spliced TCRbeta transcript. Restoration of reading frame prevented this up-regulation. Our results suggest that the response of an mRNA to a nonsense mutation depends on its context. PMID- 17693404 TI - Mechanism of stabilization of a bacterial collagen triple helix in the absence of hydroxyproline. AB - The Streptococcus pyogenes cell-surface protein Scl2 contains a globular N terminal domain and a collagen-like domain, (Gly-Xaa-X'aa)(79), which forms a triple helix with a thermal stability close to that seen for mammalian collagens. Hyp is a major contributor to triple-helix stability in animal collagens, but is not present in bacteria, which lack prolyl hydroxylase. To explore the basis of bacterial collagen triple-helix stability in the absence of Hyp, biophysical studies were carried out on recombinant Scl2 protein, the isolated collagen-like domain from Scl2, and a set of peptides modeling the Scl2 highly charged repetitive (Gly-Xaa-X'aa)(n) sequences. At pH 7, CD spectroscopy, dynamic light scattering, and differential scanning calorimetry of the Scl2 protein all showed a very sharp thermal transition near 36 degrees C, indicating a highly cooperative unfolding of both the globular and triple-helix domains. The collagen like domain isolated by trypsin digestion showed a sharp transition at the same temperature, with an enthalpy of 12.5 kJ/mol of tripeptide. At low pH, Scl2 and its isolated collagen-like domain showed substantial destabilization from the neutral pH value, with two thermal transitions at 24 and 27 degrees C. A similar destabilization at low pH was seen for Scl2 charged model peptides, and the degree of destabilization was consistent with the strong pH dependence arising from the GKD tripeptide unit. The Scl2 protein contained twice as much charge as human fibril-forming collagens, and the degree of electrostatic stabilization observed for Scl2 was similar to the contribution Hyp makes to the stability of mammalian collagens. The high enthalpic contribution to the stability of the Scl2 collagenous domain supports the presence of a hydration network in the absence of Hyp. PMID- 17693405 TI - TAp73 is a downstream target of p53 in controlling the cellular defense against stress. AB - TAp73 is a p53 tumor suppressor gene homologue that is known to be mainly involved in apoptosis. We report here that TAp73 is necessary for the cellular response to oxidative stress and that TAp73 functions as a downstream target of p53 in this process. We show that p53 physically interacts with the TAp73 promoter under stress conditions that lead to cell death. Particularly, p53 binds to a palindromic site in the TAp73 promoter, activates the promoter of TAp73, and selectively induces TAp73 transcription. TAp73 expression is highly increased under oxidative stress in a p53-dependent manner. Furthermore, knock-down of TAp73 expression inhibits the cellular apoptotic response to oxidative damage. In contrast, the ectopic expression of TAp73 in p53(-/-) mouse embryonic fibroblasts induces oxidative cell death. Our findings demonstrate that p53 is a direct transcriptional regulator of TAp73. Our data reveal a new pathway for cellular protection against oxidative damage and provide evidence that TAp73 is a stress response gene and a downstream effector in the p53 pathway. PMID- 17693406 TI - Characterization of the C-terminal domain of a potassium channel from Streptomyces lividans (KcsA). AB - KcsA, a potassium channel from Streptomyces lividans, is a good model for probing the general working mechanism of potassium channels. To date, the physiological activator of KcsA is still unknown, but in vitro studies showed that it could be opened by lowering the pH of the cytoplasmic compartment to 4. The C-terminal domain (CTD, residues 112-160) was proposed to be the modulator for this pH responsive event. Here, we support this proposal by examining the pH profiles of: (a) thermal stability of KcsA with and without its CTD and (b) aggregation properties of a recombinant fragment of CTD. We found that the presence of the CTD weakened and enhanced the stability of KcsA at acidic and basic pH values, respectively. In addition, the CTD fragment oligomerized at basic pH values with a transition profile close to that of channel opening. Our results are consistent with the CTD being a pH modulator. We propose herein a mechanism on how this domain may contribute to the pH-dependent opening of KcsA. PMID- 17693407 TI - The PP2A-associated protein alpha4 plays a critical role in the regulation of cell spreading and migration. AB - Compared with kinases, the role of protein phosphatases in regulating biological functions is less well understood. Here we show that alpha4, a non-catalytic subunit of the protein phosphatase 2A, plays a major role in the control of cell spreading, migration, and cytoskeletal architecture. Fibroblasts lacking alpha4 were impaired in their ability to spread and migrate compared with wild-type cells, whereas enforced expression of alpha4 promoted cell spreading and migration. These effects were not restricted to fibroblasts. Using a T cell specific alpha4 transgenic mouse model, increased alpha4 expression was found to increase lymphocyte motility and chemotaxis. Elevated alpha4 expression results in an increase in the GTP-bound state of Rac1, and GTP-bound Rac1 was dramatically reduced in alpha4-deficient cells. A constitutively active mutant of Rac1 rescued the defects of cell spreading and migration caused by alpha4 deletion, while inhibition of Rac1 blocked the ability of alpha4 to promote cell migration. Together, these data define a novel role for the protein phosphatase 2A regulatory subunit alpha4 in the regulation of cell spreading and migration. PMID- 17693408 TI - Ing1 mediates p53 accumulation and chromatin modification in response to oncogenic stress. AB - ING proteins are putative tumor suppressor proteins linked to the p53 pathway and to the chromatin modification machinery. Here we have analyzed the role of the products of the murine Ing1 locus in cellular tumor-protective responses, using mouse primary fibroblasts where the Ing1 locus has been inactivated by the integration of a betageo cassette. We show that Ing1-deficient mouse embryonic fibroblasts display a defective senescence-like antiproliferative response against oncogenic Ras, affecting several senescence-specific markers. This phenotype is accompanied by a reduced accumulation of p53, which can be explained by the reduced basal p53 protein stability in the Ing1-deficient background. Ing1 deficiency also results in defects in the appearance of heterochromatic marks upon expression of oncogenic Ras, suggestive of impaired heterochromatin formation during oncogene-induced senescence. Our results support an important role for the Ing1 locus in protection against oncogenic stress in vivo, both as a mediator of p53 activation and as a regulator of chromatin remodeling processes. PMID- 17693410 TI - p24A, a type I transmembrane protein, controls ARF1-dependent resensitization of protease-activated receptor-2 by influence on receptor trafficking. AB - Protease-activated receptor-2 (PAR-2), the second member of the G protein-coupled PAR family, is irreversibly activated by trypsin or tryptase and then targeted to lysosomes for degradation. Intracellular presynthesized receptors stored at the Golgi apparatus repopulate the cell surface after trypsin stimulation, thereby leading to rapid resensitization to trypsin signaling. However, the molecular mechanisms of the exocytic trafficking of PAR-2 from the Golgi apparatus to the plasma membrane remain largely unclear. Here we show that p24A, a type I transmembrane protein, which is a crucial constituent of the Golgi apparatus, associates with PAR-2 at the Golgi apparatus. The protein interaction occurs between the N-terminal region of p24A (residues 1-105; p24A-GL (GOLD domain with a small linker)) and the second extracellular loop of PAR-2. After receptor activation, PAR-2 dissociates from p24A. Importantly, we found that ADP ribosylation factor 1 regulated the dissociation process and initiated PAR-2 trafficking to the plasma membrane. Conversely, overexpression of the fragment p24A-GL, but not other mutants containing the functional coiled-coil domain of p24A, arrested PAR-2 at the Golgi apparatus and inhibited receptor trafficking to the plasma membrane, which consequently prevented resensitization of PAR-2. These findings identify a new function of p24A as a regulator of signal-dependent trafficking that regulates the life cycle of PAR-2, Thus, we reveal a new molecular mechanism underlying resensitization of PAR-2. PMID- 17693409 TI - Down syndrome critical region-1 is a transcriptional target of nuclear factor of activated T cells-c1 within the endocardium during heart development. AB - Patients with Down syndrome have characteristic heart valve lesions resulting from endocardial cushion defects. The Down syndrome critical region 1 (DSCR1) gene, identified at the conserved trisomic 21 region in those patients, encodes a calcineurin inhibitor that inactivates nuclear factor of activated T cells (NFATc) activity. Here, we identify a regulatory sequence in the promoter region of human DSCR1 that dictates specific expression of a reporter gene in the endocardium, defined by the temporal and spatial expression of Nfatc1 during heart valve development. Activation of this evolutionally conserved DSCR1 regulatory sequence requires calcineurin and NFATc1 signaling in the endocardium. NFATc1 proteins bind to the regulatory sequence and trigger its enhancer activity. NFATc1 is sufficient to induce the expression of Dscr1 in cells that normally have undetectable or minimal NFATc1 or DSCR1. Pharmacologic inhibition of calcineurin or genetic Nfatc1 null mutation in mice abolishes the endocardial activity of this DSCR1 enhancer. Furthermore, in mice lacking endocardial NFATc1, the endogenous Dscr1 expression is specifically inhibited in the endocardium but not in the myocardium. Thus, our studies indicate that the DSCR1 gene is a direct transcriptional target of NFATc1 proteins within the endocardium during a critical window of heart valve formation. PMID- 17693411 TI - Connexin levels regulate keratinocyte differentiation in the epidermis. AB - To understand the role of connexin43 (Cx43) in epidermal differentiation, we reduced Cx43 levels by RNA-mediated interference knockdown and impaired its functional status by overexpressing loss-of-function Cx43 mutants associated with the human disease oculodentodigital dysplasia (ODDD) in rat epidermal keratinocytes. When Cx43 expression was knocked down by 50-75%, there was a coordinate 55-65% reduction in Cx26 level, gap junction-based dye coupling was reduced by 60%, and transepithelial resistance decreased. Importantly, the overall growth and differentiation of Cx43 knockdown organotypic epidermis was severely impaired as revealed by alterations in the levels of the differentiation markers loricrin and involucrin and by reductions in vital and cornified layer thicknesses. Conversely, although the expression of Cx43 mutants reduced the coupling status of rat epidermal keratinocytes by approximately 80% without altering the levels of endogenous Cx43 or Cx26, their ability to differentiate was not altered. In addition, we used a mouse model of ODDD and found that newborn mice harboring the loss-of-function Cx43(G60S) mutant had slightly reduced Cx43 levels, whereas Cx26 levels, epidermis differentiation, and barrier function remained unaltered. This properly differentiated epidermis was maintained even when Cx43 and Cx26 levels decreased by more than 70% in 3-week old mutant mice. Our studies indicate that Cx43 and Cx26 collectively co-regulate epidermal differentiation from basal keratinocytes but play a more minimal role in the maintenance of established epidermis. Altogether, these studies provide an explanation as to why the vast majority of ODDD patients, where Cx43 function is highly compromised, do not suffer from skin disease. PMID- 17693412 TI - Functional consequence of protein kinase A-dependent phosphorylation of the cardiac ryanodine receptor: sensitization of store overload-induced Ca2+ release. AB - The phosphorylation of the cardiac Ca(2+)-release channel (ryanodine receptor, RyR2) by protein kinase A (PKA) has been extensively characterized, but its functional consequence remains poorly defined and controversial. We have previously shown that RyR2 is phosphorylated by PKA at two major sites, serine 2,030 and serine 2,808, of which Ser-2,030 is the major PKA site responding to beta-adrenergic stimulation. Here we investigated the effect of the phosphorylation of RyR2 by PKA on the properties of single channels and on spontaneous Ca(2+) release during sarcoplasmic reticulum Ca(2+) overload, a process we have referred to as store overload-induced Ca(2+) release (SOICR). We found that PKA activated single RyR2 channels in the presence, but not in the absence, of luminal Ca(2+). On the other hand, PKA had no marked effect on the sensitivity of the RyR2 channel to activation by cytosolic Ca(2+). Importantly, the S2030A mutation, but not mutations of Ser-2,808, diminished the effect of PKA on RyR2. Furthermore, a phosphomimetic mutation, S2030D, potentiated the response of RyR2 to luminal Ca(2+) and enhanced the propensity for SOICR in HEK293 cells. In intact rat ventricular myocytes, the activation of PKA by isoproterenol reduced the amplitude and increased the frequency of SOICR. Confocal line scanning fluorescence microscopy further revealed that the activation of PKA by isoproterenol increased the rate of Ca(2+) release and the propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). Collectively, our data indicate that PKA-dependent phosphorylation enhances the response of RyR2 to luminal Ca(2+) and reduces the threshold for SOICR and that this effect of PKA is largely mediated by phosphorylation at Ser 2,030. PMID- 17693413 TI - Inhibition of skeletal muscle ClC-1 chloride channels by low intracellular pH and ATP. AB - Skeletal muscle acidosis during exercise has long been thought to be a cause of fatigue, but recent studies have shown that acidosis maintains muscle excitability and opposes fatigue by decreasing the sarcolemmal chloride conductance. ClC-1 is the primary sarcolemmal chloride channel and has a clear role in controlling muscle excitability, but recombinant ClC-1 has been reported to be activated by acidosis. Following our recent finding that intracellular ATP inhibits ClC-1, we investigated here the interaction between pH and ATP regulation of ClC-1. We found that, in the absence of ATP, intracellular acidosis from pH 7.2 to 6.2 inhibited ClC-1 slightly by shifting the voltage dependence of common gating to more positive potentials, similar to the effect of ATP. Importantly, the effects of ATP and acidosis were cooperative, such that ATP greatly potentiated the effect of acidosis. Adenosine had a similar effect to ATP at pH 7.2, but acidosis did not potentiate this effect, indicating that the phosphates of ATP are important for this cooperativity, possibly due to electrostatic interactions with protonatable residues of ClC-1. A protonatable residue identified by molecular modeling, His-847, was found to be critical for both pH and ATP modulation and may be involved in such electrostatic interactions. These findings are now consistent with, and provide a molecular explanation for, acidosis opposing fatigue by decreasing the chloride conductance of skeletal muscle via inhibition of ClC-1. The modulation of ClC-1 by ATP is a key component of this molecular mechanism. PMID- 17693414 TI - Adaptation of flowering-time by natural and artificial selection in Arabidopsis and rice. AB - The adaptation of plants to natural environments depends on the adaptation of flowering-time control at the appropriate season to set seeds. Possible molecular mechanisms underlying this adaptation have recently been revealed. In Arabidopsis thaliana, a model long-day plant, control of floral transition by vernalization and long-day floral promotion pathways is a key regulator in adaptation to different regions. A floral repressor termed FLC and a floral promoter termed CONSTANS (CO), which control FT, a florigen gene, are key transcriptional regulators of these pathways. Recent analyses of haplotypes in accessions of A. thaliana revealed that FLC regulation by an activator termed FRIGIDA (FRI) had been a target for natural selection. By contrast, in rice (Oryza sativa), a model short-day plant, two independent floral pathways-Heading date 1 (Hd1, a CO orthologue)-dependent and Early heading date 1 (Ehd1)-dependent pathways-control Hd3a (an FT orthologue) and flowering time. Interestingly, there is an antagonistic action between Hd1 and Ehd1 in the control of flowering time under long-day conditions, because Hd1 represses floral transition whereas Ehd1 promotes it. A wild rice species, Oryza rufipogon, has common ancestry with cultivated rice and grows wild in the tropics, yet cultivated rice is grown even in the cold regions of northern latitudes. During domestication, the adaptation of O. sativa to northern regions by artificial selection may have become possible through interactions of the two pathways. These suggest that the domestication process of rice will provide novel insights into the adaptation of plants in evolution. PMID- 17693416 TI - Monosodium glutamate but not linoleic acid differentially activates gustatory neurons in the rat geniculate ganglion. AB - To date, only one study has examined responses to monosodium glutamate (MSG) from gustatory neurons in the rat geniculate ganglion and none to free fatty acids. Accordingly, we recorded single-cell responses from geniculate ganglion gustatory neurons in anesthetized male rats to MSG and linoleic acid (LA), as well as to sucrose, NaCl, citric acid, and quinine hydrochloride. None of the 52 neurons responded to any LA concentration. In contrast, both narrowly tuned groups of gustatory neurons (sucrose specialists and NaCl specialists) responded to MSG, as did 2 of the broadly tuned groups (NaCl generalist(I) and acid generalists). NaCl generalist(II) neurons responded only to the highest MSG concentration and only at low rates. No neuron type responded best to MSG; rather, responses to 0.1 M MSG were significantly less than those to NaCl for Na(+) -sensitive neurons and to sucrose for sucrose specialists. Interestingly, most Na(+) -sensitive neurons responded to 0.3 M MSG at levels comparable with those to 0.1 M NaCl, whereas sucrose specialists responded to 0.1 M MSG despite being unresponsive to NaCl. These results suggest that the stimulatory effect of MSG involves activation of sweet- or salt-sensitive receptors. We propose that glutamate underlies the MSG response of sucrose specialists, whereas Na(+) -sensitive neurons respond to the sodium cation. For the latter neuron groups, the large glutamate anion may reduce the driving force for sodium through epithelial channels on taste cell membranes. The observed concentration-dependent responses are consistent with this idea, as are cross-adaptation studies using 0.1 M concentrations of MSG and NaCl in subsets of these Na(+) -sensitive neurons. PMID- 17693415 TI - The relationship between PROP and ethanol preferences: an evaluation of 4 inbred mouse strains. AB - Ethanol's taste attributes undoubtedly contribute to the development of drug preference. Ethanol's taste is both sweet and bitter. Taster status for bitter 6 n-propylthiouracil (PROP) has been proposed as a genetic marker for alcoholism; however, human results are conflicting. We collected preference scores for both tastants in 4 mouse strains selected on the basis of previously reported taste preference, with the generally accepted idea that inbred mice show minimal within strain variation. Eighty-eight male mice (22 per strain) participated. The strains were as follows: C57BL/6J, ethanol preferring; BALB/cJ, ethanol avoiding; SWR/J, PROP avoiding; and C3HeB/FeJ, PROP neutral. Using a brief-access (1-min trials) 2-bottle preference test, we assessed the taste response of each strain to PROP and ethanol on separate days. Although PROP avoiding versus neutral mice could be segregated into significantly different populations, this was not the case for ethanol avoiding versus preferring mice, and all strains showed high variability. On average, only BALB/cJ, SWR/J, and C3HeB/FeJ mice conformed to their literature-reported preferences; nonetheless, there were a substantial number of discordant animals. C57BL/6J did not conform to previous results, indicating that they are ethanol preferring. Finally, we did not observe a significant relationship between PROP and ethanol preferences across strains. The high variability per strain and the number of animals in disagreement with their respective literature-reported preference raise concerns regarding their utility for investigations underlying mechanisms of taste-mediated ingestive responses. Absent postingestive consequences, the brief-access results suggest a possible degree of previously masked polymorphisms in taste preferences or a more recent drift in underlying genetic factors. The absence of a relationship between PROP and ethanol indicates that the bitter quality in ethanol may be more highly related to other bitter compounds that are mediated by different genetic influences. PMID- 17693417 TI - Dopamine beta-hydroxylase like immunoreactive cells in the frog taste disc. AB - We immunohistochemically examined the existence of dopamine beta-hydroxylase (DBH), a noradrenalin (NA)-synthesizing enzyme from dopamine, in the taste disc of frog, Rana catesbeiana. DBH-like immunoreactive cells were located in the intermediate layer in the taste disc; the cells showed an apical process reaching the surface of the disc and one or several basal processes. Cells with a thick apical process and those with a thin apical process were both immunoreactive: these cells corresponded to type II and III receptor cells of the frog taste disc. Immunoreactive granules were observed in the cytoplasm of those cells. In the frog taste disc, only type III cells are reported to have afferent synapses with the nerve via basal processes but those basal processes have not been reported in type II cells. In the present study, we found that type II-like cells possessed a long basal process extending toward the basal lamina. Mucous (type Ia) cells, wing (type Ib) cells, and glia-like sustentacular (type Ic) cells were all immunohistochemically unreactive. The present observations support the argument that NA (or adrenalin) may work as a chemical transmitter in the frog taste organ. PMID- 17693418 TI - Hip fractures after stroke and their prevention. AB - Increased fracture risk is a recognized complication following stroke. Bone loss following a hemiplegic stroke has been proposed as a major risk factor for post stroke hip fracture, with a recent focus on the development of novel therapeutic measures to prevent bone loss and fractures after stroke. We briefly review the literature on the epidemiology and pathophysiology of bone loss and hip fracture after stroke, and then critically review recent studies on preventive strategies. PMID- 17693419 TI - Diabetes, but not the metabolic syndrome, predicts the severity and extent of coronary artery disease in women. AB - BACKGROUND: Previous studies have suggested that diabetes and metabolic syndrome are significant risk factors for coronary artery disease (CAD). However, in women, their relative importance remains controversial. AIM: To evaluate risk factors for CAD in women and their association with the severity and extent of coronary angiographic findings. METHODS: We clinically evaluated 243 consecutive female patients with chest pain who underwent coronary angiography. The location and extent of coronary artery occlusions were assessed using the modified Gensini index. RESULTS: Compared with women with normal coronary arteries (n = 90), those with CAD (n = 153) reported less physical activity (p = 0.001), and had higher prevalences of diabetes (p = 0.046), hypertension (p = 0.002), and the metabolic syndrome (p = 0.001). They also had lower HDL cholesterol levels (p = 0.017), higher levels of triglycerides (p = 0.005), and higher fasting plasma glucose (FPG) (p < 0.001). Physical activity, FPG, serum triglycerides and HDL cholesterol, but not the metabolic syndrome, were independent predictors of CAD. A score combining the extent and severity of angiographic findings was significantly higher in women with diabetes (p = 0.007), hypertension (p = 0.010) and FPG >or=100 mg/dl (p = 0.031), but showed no association with the metabolic syndrome. In a multivariate linear regression analysis, diabetes was an independent predictor of the extent and severity of angiographic score (p = 0.013). DISCUSSION: Diabetes, fasting plasma glucose and hypertension, but not the metabolic syndrome, were associated with severity of coronary angiographic findings in these women. PMID- 17693420 TI - The breast cancer continuum in hormone-receptor-positive breast cancer in postmenopausal women: evolving management options focusing on aromatase inhibitors. AB - There are now a number of highly effective options for the treatment of hormone receptor-positive breast cancer. Although tamoxifen was the standard hormonal treatment for many years, we now have another option for postmenopausal women: the third-generation aromatase inhibitors (AIs) anastrozole, exemestane and letrozole. A number of trials have investigated the use of third-generation AIs compared with tamoxifen throughout the continuum of treatment settings for postmenopausal women with breast cancer. In the neoadjuvant setting, letrozole, given for 4 months, resulted in better overall clinical response and breast conserving surgery rates than tamoxifen. The Immediate Preoperative Anastrozole Tamoxifen or Combined with Tamoxifen trial gave anastrozole for 3 months with no difference in clinical response but significantly improved breast-conserving surgery rates. Compared with tamoxifen, anastrozole and letrozole significantly improved disease-free survival as early adjuvant treatment for hormone-receptor positive disease. Switching to anastrozole or exemestane after 2 to 3 years of adjuvant tamoxifen for a total of 5 years of therapy was also more effective than continued tamoxifen. All three agents are approved in the early adjuvant or switching setting in the USA. Letrozole following 5 years of tamoxifen as extended adjuvant treatment improved disease-free survival and, in the node positive subgroup, overall survival when compared with placebo. Anastrozole and letrozole are both approved for the first-line treatment of hormone-sensitive advanced breast cancer in postmenopausal women; letrozole showed an improved response rate compared with tamoxifen. Anastrozole, letrozole and exemestane are all indicated for the second-line treatment of advanced breast cancer. In summary, third-generation AIs have been shown to have superior efficacy over tamoxifen in the metastatic, neoadjuvant and adjuvant settings and to improve outcome as extended adjuvant therapy following 5 years of tamoxifen. Ongoing studies will further define the role of sequential adjuvant treatment. Appropriate duration of treatment is another important area of investigation. This review will cover hormonal therapy for postmenopausal women with breast cancer and will not address the treatment of premenopausal women. PMID- 17693421 TI - Pharmacokinetic and safety study of subcutaneously administered weekly ING-1, a human engineere monoclonal antibody targeting human EpCAM, in patients with advanced solid tumors. AB - BACKGROUND: ING-1 is a high-affinity, human engineeredtrade mark monoclonal antibody that recognizes a 40 kilodalton epithelial cell adhesion molecule (EpCAM) glycoprotein that is expressed in high levels on most adenocarcinomas and is an attractive target for immunotherapy. METHODS: ING-1 was administered subcutaneously weekly at doses between 0.1 and 2 mg/kg/week. Pharmacokinetic samples were drawn during weeks 1 and 6. RESULTS: Fourteen patients with advanced refractory cancer received a median of 6 (range 1-9) doses of ING-1. At 1 mg/kg, a 62-year-old man with colon cancer developed reversible grade 3 pancreatitis after the third dose. His plasma ING-1 levels were similar to the other two patients dosed at 1 mg/kg. Two patients dosed at 0.6 mg/kg experienced stable disease at 6 weeks. Peak drug levels increased with dose and time, suggesting drug accumulation with repeated dosing. Low human anti-human antibody response was noted in three of the 13 patients assessed and was directed towards the variable region of ING-1. CONCLUSIONS: Weekly ING-1 administered subcutaneously was well tolerated at 0.6 mg/kg/week and further experience at this dose is warranted to demonstrate safety. The risk of pancreatitis and the marginal anti tumor effect may preclude further monotherapy studies; however, combination studies with chemotherapy are warranted. PMID- 17693422 TI - Modelling and simulation techniques for membrane biology. AB - One of the most important aspects of Computational Cell Biology is the understanding of the complicated dynamical processes that take place on plasma membranes. These processes are often so complicated that purely temporal models cannot always adequately capture the dynamics. On the other hand, spatial models can have large computational overheads. In this article, we review some of these issues with respect to chemistry, membrane microdomains and anomalous diffusion and discuss how to select appropriate modelling and simulation paradigms based on some or all the following aspects: discrete, continuous, stochastic, delayed and complex spatial processes. PMID- 17693423 TI - Muscarinic receptor dysfunction induced by exposure to low levels of soman vapor. AB - In the eye, it has been previously reported that exposure to a cholinesterase inhibitor results in a reduced miotic response following prolonged exposure and a decreased miotic response to the cholinergic agonists. However, no studies exist that characterize the effect of a single low-level vapor exposure to a nerve agent on parasympathetic function in the eye or determine the threshold dose for such an effect. The present study investigated the hypotheses that a single low level exposure to soman vapor would result in dysfunction of the parasympathetic pathway mediating the pupillary light reflex resulting from a loss of muscarinic receptor function on the pupillary sphincter muscle. Adult male rats were exposed to soman vapor in a whole-body dynamic airflow exposure chamber. Rats exposed to low levels of soman vapor dose-dependently developed miosis (threshold dose between 4.1 and 6.1 mg-min/m3). Pupil size returned to preexposure levels within 48 h due to desensitization of pupillary muscarinic receptors, as assessed by the pupillary response to the muscarinic agonist oxotremorine. An attenuated pupillary light reflex was also present in miotic animals (threshold dose near 6.1 mg-min/m3). While pupil size recovers within 48 h, other measures of pupillary function, including the light reflex, acetylcholinesterase activity, and muscarinic receptor responsiveness, did not return to normal for up to 10 days postexposure. Recovery of the light reflex coincided with the recovery of pupillary muscarinic receptor function, suggesting that the attenuation of the light reflex was due to receptor desensitization. PMID- 17693424 TI - Glutathione-dependent reduction of arsenate by glycogen phosphorylase responsiveness to endogenous and xenobiotic inhibitors. AB - Rabbit muscle glycogen phosphorylase-a (GPa) reduces arsenate (As(V)) to the more toxic arsenite (As(III)) in a glutathione (GSH)-dependent fashion. To determine whether reduction of As(V) by GPa is countered by compounds known to inhibit GP catalyzed glycogenolysis, the effects of thiol reagents, endogenous compounds (glucose, ATP, ADP) as well as nonspecific glycogen phosphorylase inhibitors (GPIs; caffeine, quercetin, flavopiridol [FP]), and specific GPIs (1,4-dideoxy 1,4-imino-D-arabinitol [DAB], BAY U6751, CP320626) were tested on reduction of As(V) by rabbit muscle GPa in the presence of glycogen (substrate), AMP (activator), and GSH, and the As(III) formed from As(V) was quantified by high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry. The As(V)-reducing activity of GPa was moderately sensitive to thiol reagents. Glucose above 5mM and ADP or ATP at physiological levels diminished GPa-catalyzed As(V) reduction. All GPIs inhibited As(V) reduction by GPa in a concentration-dependent fashion; however, their effects were differentially affected by glucose (10mM) or AMP (200microM instead of 25microM), known modulators of the action of some GPIs on the GP-catalyzed glycogenolysis. Inhibition of As(V) reduction by DAB and quercetin was not influenced by glucose or AMP. Glucose that potentiates the inhibitory effects of caffeine, BAY U6751, and CP320626 on the glycogenolytic activity of GPa also enhanced the inhibitory effects of these GPIs on GPa-catalyzed As(V) reduction. AMP at high concentration alleviated the inhibition by BAY U6751 and CP320626 (whose antagonistic effect on GP-catalyzed glycogen breakdown is also AMP sensitive), whereas the inhibition in As(V) reduction by FP or caffeine was little affected by AMP. Thus, GPIs inhibit both the glycogenolytic and As(V)-reducing activities of GP, supporting that the latter is coupled to glycogenolysis. It was also shown that a GPa-rich extract of rat liver contained GSH-dependent As(V)-reducing activity that was inhibited by specific GPIs, suggesting that the liver-type GPa can also catalyze reduction of As(V). PMID- 17693425 TI - Glutathione-dependent reduction of arsenate by glycogen phosphorylase a reaction coupled to glycogenolysis. AB - Arsenate (As(V)) is reduced in the body to the more toxic arsenite (As(III)). We have shown that two enzymes catalyzing phosphorolytic cleavage of their substrates, namely purine nucleoside phosphorylase and glyceraldehyde-3-phosphate dehydrogenase, can reduce As(V) in presence of an appropriate thiol and their substrates. Another phosphorolytic enzyme that may also reduce As(V) is glycogen phosphorylase (GP). With inorganic phosphate (P(i)), GP catalyzes the breakdown of glycogen to glucose-1-phosphate; however, it also accepts As(V). Testing the hypothesis that GP can reduce As(V), we incubated As(V) with the phosphorylated GPa or the dephosphorylated GPb purified from rabbit muscle and quantified the As(III) formed from As(V) by high-performance liquid chromatography-hydride generation-atomic fluorescence spectrometry. In the presence of adenosine monophosphate (AMP), glycogen, and glutathione (GSH), both GP forms reduced As(V) at rates increasing with enzyme and As(V) concentrations. The As(V) reductase activity of GPa was 10-fold higher than that of GPb. However, incubating GPb with GP kinase and ATP (that converts GPb to GPa) increased As(V) reduction by phosphorylase up to the rate produced by GPa incubated under the same conditions. High concentration of inorganic sulfate, which activates GPb like phosphorylation, also promoted reduction of As(V) by GPb. As(V) reduction by GPa (like As(V) reduction in rats) required GSH. It also required glycogen (substrate for GP) and was stimulated by AMP (allosteric activator of GP) even at low micromolar concentrations. P(i), substrate for GP competing with As(V), inhibited As(III) formation moderately at physiological concentrations. Glucose-1 phosphate, the product of GP-catalyzed glycogenolysis, also decreased As(V) reduction. Summarizing, GP is the third phosphorolytic enzyme identified capable of reducing As(V) in vitro. For reducing As(V) by GP, GSH and glycogen are indispensable, suggesting that the reduction is linked to glycogenolysis. While its in vivo significance remains to be tested, further characterization of the GP catalyzed As(V) reduction is presented in the adjoining paper. PMID- 17693426 TI - Th2 Cytokines in Skin Draining Lymph Nodes and Serum IgE Do Not Predict Airway Hypersensitivity to Intranasal Isocyanate Exposure in Mice. AB - Isocyanate exposure in the workplace has been linked to asthma and allergic rhinitis. Recently, investigators have proposed that Th2 cytokine responses in lymph nodes draining the site of dermal application of chemicals including isocyanates may be used to identify sensitizers that cause asthma-like responses. The purpose of this study was to determine if the cytokine profile induced after dermal sensitization with isocyanates and serum IgE predict immediate (IHS) and methacholine-induced late (LHS) respiratory hypersensitivity responses after intranasal challenge. Dermal application of hexylmethane diisocyanate (HMDI), toluene diisocyanate (TDI), or methylene diisocyanate (MDI) significantly increased interleukin-4 (IL-4), IL-5, and IL-13 secretion in parotid lymph node cells. Isophorone diisocyanate (IPDI) increased IL-4 and IL-13, but not IL-5. Tolyl(mono)isocyanate (TMI), tetramethylene xylene diisocyanate (TMXDI), or the contact sensitizer dinitrochlorobenzene (DNCB), only induced minor increases in some of the Th2 cytokines. HMDI, TDI, MDI, and IPDI elicited greater increases in total serum IgE than DNCB, TMI, and TMXDI. All chemicals except TMXDI caused IHS after intranasal challenge of sensitized female BALB/c mice. Only HMDI-, TMI-, or TMXDI-sensitized and challenged mice had increases in LHS. All chemicals elicited epithelial cytotoxicity indicative of nasal airway irritation. The discordance between dermal cytokine profiles and respiratory responses suggests that dermal responses do not necessarily predict respiratory responses. Serum IgE also was not predictive of the respiratory responses to the isocyanates, suggesting that other unknown mechanisms may be involved. PMID- 17693427 TI - Analysis of exposure biomarker relationships with the Johnson SBB distribution. AB - Application of the Johnson bivariate S(B) distribution, or alternatively the S(BB) distribution, is presented here as a tool for the analysis of concentration data and in particular for characterizing the relationship between exposures and biomarkers. Methods for fitting the marginal S(B) distributions are enhanced by maximizing the Shapiro-Wilk W statistic. The subsequent goodness of fit for the S(BB) distribution is evaluated with a multivariate Z statistic. Median regression results are extended here with methods for calculating the mean and standard deviation of the conditional array distributions. Application of these methods to the evaluation of the relationship between exposure to airborne bromopropane and the biomarker of serum bromide concentration suggests that the S(BB) distribution may be useful in stratifying workers by exposure based on using a biomarker. A comparison with the usual two-parameter log-normal approach shows that in some cases the S(BB) distribution may offer advantages. PMID- 17693428 TI - Periodontal conditions in subjects following orthodontic therapy. A preliminary study. AB - The present study evaluated the periodontal conditions in dental students after appliance removal (mean period 7.16 +/- 3.5 years) compared with an untreated control group. Twenty-five subjects in the treated group (16 females and 9 males: 23.0 +/- 2.04 years) and 29 in a control group (15 females and 14 males: 23.99 +/ 2.46 years) underwent a periodontal examination: visible plaque index (VPI), gingival bleeding index (GBI), bleeding on probing (BOP), periodontal probing depth (PPD), and clinical attachment loss (CAL) of canines, premolars, and banded first molars and unbanded second molars. Statistical analysis was performed using a Mann-Whitney test, a Student's t-test, and Tukey's analysis of variance. The level of significance was set at 5 per cent. The median percentage of positive sites for the treated and control groups for VPI (1.25 +/- 2.37 and 1.25 +/- 5.45), GBI (0.95 +/- 1.81 and 1.23 +/- 2.14), and BOP (0.83 +/- 6.45 and 0.83 +/- 3.43) did not differ between groups. Mean PPD values were 1.33 +/- 0.19 and 1.34 +/- 0.14 for the treated and 1.40 +/- 0.24 and 1.39 +/- 0.25 for the control group. No intra- or intergroup differences were observed. For the control group, the smallest PPD was at the canines followed by premolars and molars. PPD was less for premolars than molars but similar to the canines in the treated group. No differences in CAL were observed between the examined teeth in the control group. For the treated group, the canines showed lower CAL values than the first molars. The results indicate that the use of orthodontic appliances is not necessarily related to a worsening of periodontal conditions. PMID- 17693429 TI - The shape and size of the sella turcica in skeletal Class I, Class II, and Class III Saudi subjects. AB - The purpose of this study was to describe the shape and measure the size of the sella turcica in Saudi subjects with different skeletal types. Lateral cephalometric radiographs of 180 individuals (90 males and 90 females) with an age range of 11-26 years were taken and distributed according to skeletal classification; 60 Class I, 60 Class II, and 60 Class III. The sella turcica on each radiograph was analysed and measured to determine the shape of the sella, in addition to the linear dimensions of length, depth, and diameter. A Student's t test was used to calculate differences in linear dimensions, while a one-way analysis of variance was performed to study the relationship between skeletal type and sella size. The results show that the sella turcica presented with a normal morphology in the majority of subjects (67 per cent). No significant differences in linear dimensions between genders could be found. When age was evaluated, significant differences were found between the older (15 years or more) and the younger (11-14 years) age groups at the 0.01 and 0.001 levels for length, depth, and diameter. Sella size of the older age group was larger than in the younger age group. When skeletal type was compared with sella size, a significant difference was found in the diameter of sella between the Class II and Class III subjects (P < 0.01). Larger diameter values were present in the skeletal Class III subjects, while smaller diameter sizes were apparent in Class II subjects (multiple comparison tests). When gender, age, and skeletal type were all compared with the size of the sella (regression analyses), age was significantly related to a change of length (P < 0.01) and diameter (P < 0.001). Sella shape and dimensions reported in the current study can be used as reference standards for further investigations involving the sella turcica area in Saudi subjects. PMID- 17693430 TI - Cervical vertebral body fusions in patients with skeletal deep bite. AB - Cervical column morphology was examined in 41 adult patients with a skeletal deep bite, 23 females aged 22-42 years (mean 27.9) and 18 males aged 21-44 years (mean 30.8) and compared with the cervical column morphology in an adult control group consisting of 21 subjects, 15 females, aged 23-40 years (mean 29.2 years) and six males aged 25-44 years (mean 32.8 years) with neutral occlusion and normal craniofacial morphology. None of the patients or control subjects had received orthodontic treatment. For each individual, a visual assessment of the cervical column and measurements of the cranial base angle, vertical craniofacial dimensions, and morphology of the mandible were performed on a profile radiograph. In the deep bite group, 41.5 per cent had fusion of the cervical vertebrae and 9.8 per cent posterior arch deficiency. The fusion always occurred between C2 and C3. No statistically significant gender differences were found in the occurrence of morphological characteristics of the cervical column (females 43.5 per cent, males 38.9 per cent). Morphological deviations of the cervical column occurred significantly more often in the deep bite group compared with the control group (P < 0.05). Logistic regression analysis showed that the vertical jaw relationship (P < 0.05), overbite (P < 0.001), and upper incisor inclination (P < 0.01) were significantly correlated with fusion of the cervical vertebrae (R(2) = 0.40). PMID- 17693431 TI - A persistent RNA.DNA hybrid formed by transcription of the Friedreich ataxia triplet repeat in live bacteria, and by T7 RNAP in vitro. AB - Expansion of an unstable GAA.TTC repeat in the first intron of the FXN gene causes Friedreich ataxia by reducing frataxin expression. Deficiency of frataxin, an essential mitochondrial protein, leads to progressive neurodegeneration and cardiomyopathy. The degree of frataxin reduction correlates with GAA.TTC tract length, but the mechanism of reduction remains controversial. Here we show that transcription causes extensive RNA.DNA hybrid formation on GAA.TTC templates in bacteria as well as in defined transcription reactions using T7 RNA polymerase in vitro. RNA.DNA hybrids can also form to a lesser extent on smaller, so-called 'pre-mutation' size GAA.TTC repeats, that do not cause disease, but are prone to expansion. During in vitro transcription of longer repeats, T7 RNA polymerase arrests in the promoter distal end of the GAA.TTC tract and an extensive RNA.DNA hybrid is tightly linked to this arrest. RNA.DNA hybrid formation appears to be an intrinsic property of transcription through long GAA.TTC tracts. RNA.DNA hybrids have a potential role in GAA.TTC tract instability and in the mechanism underlying reduced frataxin mRNA levels in Friedreich Ataxia. PMID- 17693432 TI - Interactions of the G quartet forming semaphorin 3F RNA with the RGG box domain of the fragile X protein family. AB - Fragile X syndrome, the most common cause of inherited mental retardation, is caused by the transcriptional silencing of the fmr1 gene due to an unstable expansion of a CGG trinucleotide repeat and its subsequent hypermethylation in its 5' UTR. This gene encodes for the fragile X mental retardation protein (FMRP), an RNA-binding protein that has been shown to use its RGG box domain to bind to G quartet-forming RNA. In this study, we performed a detailed analysis of the interactions between the FMRP RGG box domain and one of its proposed RNA targets, human semaphorin 3F (S3F) RNA by using biophysical methods such as fluorescence, UV and circular dichroism spectroscopy. We show that this RNA forms a G quartet-containing structure, which is recognized with high affinity and specificity by the FMRP RGG box. In addition, we analyzed the interactions of human S3F RNA with the RGG box and RG cluster of the two FMRP autosomal paralogs, the FXR1P and FXR2P. We found that this RNA is bound with high affinity and specificity only by the FXR1P RGG box, but not by the FXR2P RG cluster. Both FMRP and FXR1P RGG box are able to unwind the G quartet structure of S3F RNA, however, the peptide concentrations required in this process are very different: a ratio of 1:6 RNA:FMRP RGG box versus 1:2 RNA:FXR1P RGG box. PMID- 17693433 TI - Ligand-induced folding of the thiM TPP riboswitch investigated by a structure based fluorescence spectroscopic approach. AB - Riboswitches are genetic control elements within non-coding regions of mRNA. They consist of a metabolite-sensitive aptamer and an adjoining expression platform. Here, we describe ligand-induced folding of a thiamine pyrophosphate (TPP) responsive riboswitch from Escherichia coli thiM mRNA, using chemically labeled variants. Referring to a recent structure determination of the TPP/aptamer complex, each variant was synthesized with a single 2-aminopurine (AP) nucleobase replacement that was selected to monitor formation of tertiary interactions of a particular region during ligand binding in real time by fluorescence experiments. We have determined the rate constants for conformational adjustment of the individual AP sensors. From the 7-fold differentiation of these constants, it can be deduced that tertiary contacts between the two parallel helical domains (P2/J3 2/P3/L3 and P4/P5/L5) that grip the ligand's ends in two separate pockets, form significantly faster than the function-critical three-way junction with stem P1 fully developed. Based on these data, we characterize the process of ligand binding by an induced fit of the RNA and propose a folding model of the TPP riboswitch aptamer. For the full-length riboswitch domain and for shorter constructs that represent transcriptional intermediates, we have additionally evaluated ligand-induced folding via AP-modified variants and provide insights into the sequential folding pathway that involves a finely balanced equilibrium of secondary structures. PMID- 17693434 TI - Thermodynamically modulated partially double-stranded linear DNA probe design for homogeneous real-time PCR. AB - Real-time PCR assays have recently been developed for diagnostic and research purposes. Signal generation in real-time PCR is achieved with probe designs that usually depend on exonuclease activity of DNA polymerase (e.g. TaqMan probe) or oligonucleotide hybridization (e.g. molecular beacon). Probe design often needs to be specifically tailored either to tolerate or to differentiate between sequence variations. The conventional probe technologies offer limited flexibility to meet these diverse requirements. Here, we introduce a novel partially double-stranded linear DNA probe design. It consists of a hybridization probe 5'-labeled with a fluorophore and a shorter quencher oligo of complementary sequence 3'-labeled with a quencher. Fluorescent signal is generated when the hybridization probe preferentially binds to amplified targets during PCR. This novel class of probe can be thermodynamically modulated by adjusting (i) the length of hybridization probe, (ii) the length of quencher oligo, (iii) the molar ratio between the two strands and (iv) signal detection temperature. As a result, pre-amplification signal, signal gain and the extent of mismatch discrimination can be reliably controlled and optimized. The applicability of this design strategy was demonstrated in the Abbott RealTime HIV-1 assay. PMID- 17693435 TI - Ubiquitylation-independent degradation of Xeroderma pigmentosum group C protein is required for efficient nucleotide excision repair. AB - The Xeroderma Pigmentosum group C (XPC) protein is indispensable to global genomic repair (GGR), a subpathway of nucleotide excision repair (NER), and plays an important role in the initial damage recognition. XPC can be modified by both ubiquitin and SUMO in response to UV irradiation of cells. Here, we show that XPC undergoes degradation upon UV irradiation, and this is independent of protein ubiquitylation. The subunits of DDB-Cul4A E3 ligase differentially regulate UV induced XPC degradation, e.g DDB2 is required and promotes, whereas DDB1 and Cul4A protect the protein degradation. Mutation of XPC K655 to alanine abolishes both UV-induced XPC modification and degradation. XPC degradation is necessary for recruiting XPG and efficient NER. The overall results provide crucial insights regarding the fate and role of XPC protein in the initiation of excision repair. PMID- 17693437 TI - What cardioversion protocol for ventricular fibrillation should be followed for patients who arrest shortly post-cardiac surgery? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was how many cardioversion attempts should be performed for patients who have gone into ventricular fibrillation post-cardiac surgery prior to performing chest reopening. Using the reported search, 1183 papers were identified. Fifteen papers represented the best evidence on the subject. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study comments and weaknesses were tabulated. The quality and level of evidence was assessed using the International Liaison Committee of Resuscitation guideline recommendations. The most recent European Resuscitation Council guidelines suggest single attempts at cardioversion, spaced at 2-min intervals, for all patients going into ventricular fibrillation or pulseless ventricular tachycardia. Cardiac surgery presents a unique challenge for these guidelines in that emergency re-sternotomy may provide additional lifesaving interventions once it is deemed that external cardioversion is unlikely to succeed. The 15 papers identified demonstrated that the success of the first attempt at cardioversion for VF/VT was around 78%. The chance of the second shock succeeding was around 35%. The chance of a third shock succeeding was 14%. Very little data were found on the chance of further shocks succeeding. Of note none of these papers were in patients on the intensive care after cardiac surgery. We conclude that, due to the importance of minimising the delay to chest reopening, three shocks should be quickly delivered. If these do not succeed the chance of a 4th shock succeeding is likely to be <10% and, thus, immediate chest reopening should be performed. (This is a Class-IIa recommendation using ILCOR guideline recommendations.). PMID- 17693436 TI - Fluorescent probing for RNA molecules by an unnatural base-pair system. AB - Fluorescent labeling of nucleic acids is widely used in basic research and medical applications. We describe the efficient site-specific incorporation of a fluorescent base analog, 2-amino-6-(2-thienyl)purine (s), into RNA by transcription mediated by an unnatural base pair between s and pyrrole-2 carbaldehyde (Pa). The ribonucleoside 5'-triphosphate of s was site-specifically incorporated into RNA, by T7 RNA polymerase, opposite Pa in DNA templates. The fluorescent intensity of s in RNA molecules changes according to the structural environment. The site-specific s labeling of RNA hairpins and tRNA molecules provided characteristic fluorescent profiles, depending on the labeling sites, temperature and Mg2+ concentration. The Pa-containing DNA templates can be amplified by PCR using 7-(2-thienyl)imidazo[4,5-b]pyridine (Ds), another pairing partner of Pa. This site-specific fluorescent probing by the unnatural pair system including the s-Pa and Ds-Pa pairs provides a powerful tool for studying the dynamics of the local structural features of 3D RNA molecules and their intra and intermolecular interactions. PMID- 17693438 TI - What is the patency of the short saphenous vein when used for coronary artery bypass grafting? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was what the patency of the short saphenous vein is, when used for coronary artery bypass grafting. Altogether 347 papers were found using the reported search, of which nine represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that small reports give a two-year patency of 77% and a six-year patency of 65% and duplex studies show that the short saphenous vein may be from 2.8 mm to 4.2 mm in diameter. However, caution should be applied when considering these patency rates as they are derived from individual studies of <40 patients. The lesser saphenous vein may be considered as an alternative to brachial or cephalic vein in patients with unsuitable long saphenous vein, and unsuitable mammary, radial or gastroepiploic arteries. PMID- 17693439 TI - Recurrent endocarditis of a bicuspid aortic valve due to Q fever. AB - A 46-year-old man was referred to our institution for a recurrent endocarditis with negative blood culture. Clinical examination and complementary investigations confirmed the diagnosis of aortic valve endocarditis with left ventricular fistula. Blood culture was negative but serological tests were positive for Coxiella burnetti. Aortic valve replacement and fistula repair were done. A combination of Doxycycline and Chloroquine antibiotics was given postoperatively with a clinical improvement. Coxiella burnetti should be systemically searched for in all cases of endocarditis even with negative blood cultures. This case is interesting because of its rarity, diagnosis, therapeutic problems and its severe complication. PMID- 17693440 TI - New oligosaccharyltransferase assay method. AB - We developed a new in vitro assay for oligosaccharyltransferase (OST), which catalyzes the transfer of preassembled oligosaccharides on lipid carriers onto asparagine residues in polypeptide chains. The asparagine residues reside in the sequon, Asn-X-Thr/Ser, where X can be any amino acid residue except Pro. We demonstrate the potency of our assay using the OST from yeast. In our method, polyacrylamide gel electrophoresis is used to separate the glycopeptide products from the peptide substrates. The substrate peptide is fluorescently labeled and the formation of glycopeptides is analyzed by fluorescence gel imaging. Two in vitro OST assay methods are now widely used, but both the methods depend on previous knowledge of the oligosaccharide moiety: One method uses lectin binding as the separation mechanism and the other method uses biosynthetically or chemoenzymatically synthesized lipid-linked oligosaccharides as donors. N-linked protein glycosylation is found in all three domains of life, but little is known about the N-glycosylation in Archaea. Thus, our new assay, which does not require a priori knowledge of the oligosaccharides, will be useful in such cases. Indeed, we have detected the OST activity in the membrane fraction from a hyperthermophilic archaeon, Pyrococcus furiosus. PMID- 17693441 TI - A novel strategy for mammalian cell surface glycome profiling using lectin microarray. AB - The glycome represents the total set of glycans expressed in a cell. The glycome has been assumed to vary between cell types, stages of development and differentiation, and during malignant transformation. Analysis of the glycome provides a basis for understanding the functions of glycans in these cellular processes. Recently, a technique called lectin microarray was developed for rapid profiling of glycosylation, although its use was mainly restricted to glycoproteins of cell lysates, and thus unable to profile the intact cell surface glycans. Here we report a simple and sensitive procedure based on this technology for direct analysis of the live mammalian cell-surface glycome. Fluorescent labeled live cells were applied in situ to the established lectin microarray consisting of 43 immobilized lectins with distinctive binding specificities. After washing, bound cells were directly detected by an evanescent-field fluorescence scanner in a liquid phase without fixing and permeabilization. The results obtained by differential profiling of CHO and its glycosylation-defective mutant cells, and splenocytes of wild-type and beta1-3-N acetylglucosaminyltransferase II knockout mice performed as model experiments agreed well with their glycosylation phenotypes. We also compared cell surface glycans of K562 cells before and after differentiation and found a significant increase in the expression of O-glycans on differentiated cells. These results demonstrate that the technique provides a novel strategy for profiling global changes of the mammalian cell surface glycome. PMID- 17693442 TI - Vascular pathology and osteoarthritis. AB - There is mounting evidence that vascular pathology plays a role in the initiation and/or progression of the major disease of joints: osteoarthritis (OA). Potential mechanisms are: episodically reduced blood flow through the small vessels in the subchondral bone at the ends of long bones, and related to this, reduced interstitial fluid flow in subchondral bone. Blood flow may be reduced by venous occlusion and stasis or by the development of microemboli in the subchondral vessels. There are several likely effects of subchondral ischaemia: the first of these is compromised nutrient and gas exchange into the articular cartilage, a potential initiator of degradative changes in the cartilage. The second is apoptosis of osteocytes in regions of the subchondral bone, which would initiate osteoclastic resorption of that bone and at least temporarily reduce the bony support for the overlying cartilage. It may be important to recognize these potential aetiological factors in order to develop more effective treatments to inhibit the progression of OA. PMID- 17693443 TI - Scleroderma patients nailfold videocapillaroscopic patterns are associated with disease subset and disease severity. AB - OBJECTIVE: To evaluate in a large group of scleroderma patients, the association of nailfold videocapillaroscopic patterns with both demographic and clinical features. METHODS: One hundred and three Italian patients (91 women and 12 men, mean age 54.3 years, median disease duration 7 yrs, 68 with limited and 35 with diffuse subset of disease), consecutively enrolled for the study, underwent nailfold videocapillaroscopy; the microvascular alterations were classified into three different patterns, early, active and late. The nailfold videocapillaroscopic patterns were correlated with such numerous clinical features as sex, age, disease duration, disease subset, disease activity, haematochemical data, involvement of skin, heart, lung and peripheral vessels. RESULTS: Nailfold videocapillaroscopic patterns were significantly associated with disease subsets (P = 0.018). Severity of skin, lung, heart and peripheral vascular involvement progressively increased across nailfold videocapillaroscopic patterns, from early to late pattern (P < 0.001 for cutaneous and peripheral vascular involvement; P = 0.003 and 0.002 for lung and heart involvement, respectively) as well as homocysteine plasma levels (P = 0.02). Patients with late pattern showed an increased risk to have an active disease [OR (odds ratio) 3.50; 95% CI (confidence interval) 1.31-9.39], to present digital ulcers (OR 5.74; 95% CI 2.08-15.89) and moderate to severe skin (OR 5.28; 95% CI 1.93 14.19), heart (OR 5.75; 95% CI 2.04-16.21) and lung involvement (OR 4.41; 95% CI 1.63-11.92). CONCLUSIONS: Our study showed that scleroderma microangiopathy correlates with disease subset and severity of peripheral vascular, skin, heart and lung involvement; patients with late pattern showed an increased risk to have an active disease and to show a moderate/severe skin or visceral involvement compared to patients with early and active patterns. Therefore nailfold videocapillaroscopy, a simple, non-invasive and non-expensive investigation, is useful in staging scleroderma patients and also provides prognostic information. PMID- 17693444 TI - Atorvastatin therapy improves endothelial-dependent vasodilation in patients with systemic lupus erythematosus: an 8 weeks controlled trial. AB - INTRODUCTION: Patients with systemic lupus erythematosus (SLE) have recognized reduction in endothelium-dependent vasodilation. Evidence demonstrates that statins are able to improve endothelial function independently on their hypolipemic action. OBJECTIVES: To evaluate the efficacy of atorvastatin in improving vasodilation in SLE patients with and without conventional risk factors for coronary heart disease (CHD). PATIENTS AND METHODS: Sixty-four SLE women, mean age 31 +/- 8 yrs, received atorvastatin 20 mg/day during 8 weeks. Thirty-one patients in this intervention group did not have conventional risk factors for CHD, while 33 others had hypertension, dyslipidaemia and/or obesity. Twenty-four SLE control patients, mean age 34 +/- 7.5 yrs, not receiving atorvastatin were followed during the same time period. High-resolution ultrasound was used to measure brachial artery diameter in resting conditions, during reactive hyperaemia and after sub-lingual glyceryl trinitrate (GTN). Measurements were performed at baseline and at the end of the study (8 weeks). RESULTS: Atorvastatin was associated with a significant increase in flow-mediated dilation (FMD) [3.8 (2.8-7.9%) vs 6.9 (4.2-10.7%), P < 0.001] while GTN-mediated dilation (GTND) was unaffected [20.9 (16.6-26.1%) vs 20.1(16.6-25.4%), P = 0.514]. FMD increase was observed in patients with conventional risk factors [4.1 (3.1-8.7%) vs 6.5 (4-10%), P = 0.046] and also for those without conventional risk factors for CHD [3.6 (2.6-7.3%) vs 7.1 (4.5-10.9%), P = 0.001]. Resting brachial artery diameter also increased significantly in patients receiving atorvastatin (2.79 +/ 0.30 mm vs 2.92 +/- 0.40 mm, P < 0.001). No significant difference in artery diameter and FMD was seen in control patients at the end of the study. When compared to the control patients, atorvastatin treatment was associated with significant increase in resting diameter (+0.13 +/- 0.1 mm vs -0.02 +/- 0.07 mm, P < 0.001) and FMD (+1.9 +/- 3.9% vs -0.3 +/- 1.8%, P = 0.009). CONCLUSION: Our results demonstrate that an 8-week 20 mg/day atorvastatin series improved endothelium-dependent vasodilation in SLE patients independently on the presence of conventional risk factors for atherosclerotic disease. PMID- 17693445 TI - Outreach visits to improve dementia care in general practice: a qualitative study. AB - BACKGROUND: Outreach visits reflect newer developments in adult learning theory, where the learner is actively involved in the session. Previous studies have indicated a positive effect of outreach visits on GPs' behaviour. However, the empirical role of the facilitator in the visits is poorly described. OBJECTIVE: To explore general practitioners' perception of the outcome of a facilitator programme about dementia, in relation to central aspects of the facilitator's communicative role during the visits. METHOD: Observational studies, and focus group discussions with participating general practitioners (3 groups, 19 participants) as well as with facilitators (4 participants) in Vejle County, Denmark. RESULTS: Facilitators drew both on a 'factual' knowledge of dementia and a more 'experience-based' knowledge when conveying programme messages. They described themselves as 'carriers of experience'. All general practitioners described an outcome of the programme, and all wished to receive a future visit by a facilitator on new topics. The outcome was described not as ground-breaking medical news, but as practical effects in terms of knowledge of dementia, motivation for working with dementia, structured assessment and management of dementia and critical reflection of established practices regarding dementia. Some general practitioners remained critical as to whether this outcome justified the resources used in the programme. The experience-based dialogue was described as central to the outcome as it linked factual knowledge to clinical practice. CONCLUSION: This study confirms that outreach visits contribute to the integration of factual knowledge in clinical practice, but it also underscores the importance of addressing tacit communicative practices during facilitator visits and their implications for the outcome of the programme. PMID- 17693446 TI - Dietary, physical activity and sedentary behaviour among Australian secondary students in 2005. AB - The aim of this study was to provide a current assessment of Australian secondary students' self-reported dietary, physical activity and sedentary behaviour. This study also examined the relationship between television viewing and students' dietary behaviour. Data are from a cross-sectional survey of 18 486 secondary students in 2005 from all Australian states except Western Australia. Participants reported their usual daily consumption (number of serves) of vegetables and fruit; their weekly consumption of unhealthy/non-core foods including fast food meals, snack foods and high-energy drinks; their engagement in moderate-vigorous physical activity over the previous week; and hours spent using electronic media for entertainment and doing homework on school days. The study found that 20% of students were meeting the daily requirement of four serves of vegetables, whereas 39% were eating the recommended three daily serves of fruit. Consumption of unhealthy/non-core foods was high, with 46% of students having fast food meals at least twice a week, 51% eating snack foods four or more times per week and 44% having high-energy drinks four or more times per week. Fourteen per cent of students engaged in recommended levels of physical activity and 29% engaged in recommended levels of sedentary behaviour. Age and gender differences occurred for most measures, and there were some socio-economic status differences. Heavier television use was associated with lower consumption of fruit and higher consumption of unhealthy/non-core foods. On the basis of the results of this study, it appears that a significant proportion of Australian secondary students fall short of current, national dietary and physical activity recommendations for teenagers. Continual monitoring of these behaviours is essential to help inform research and policy and identify where future efforts should be directed. PMID- 17693447 TI - Antenatal screening for syphilis. PMID- 17693448 TI - Journal impact factors for 2006. PMID- 17693449 TI - Syphilis screening and intervention in 500,000 pregnant women in Shenzhen, the People's Republic of China. AB - OBJECTIVES: To understand the disease epidemiology of syphilis in pregnant women, and to evaluate the effectiveness of the screening and intervention programme, for the purpose of controlling mother-to-child syphilis transmission in Shenzhen, in the People's Republic of China (PRC). METHODS: At the Shenzhen Center for Disease Control and Prevention (SZCDC), we used the toluidine red unheated serum test (TRUST) for the primary screening of pregnant women, and confirmed positive results with the Treponema pallidum particle agglutination (TPPA) test. We informed and treated those with positive results. For the women who chose to proceed with the pregnancy, we clinically screened their babies for congenital syphilis using the 19S-IgM FTA-Abs test. RESULTS: Between 1 July 2002 and 31 December 2005, we screened 477,656 pregnant women for syphilis, of whom 2208 (0.5%) tested positive. From 2003 to 2005, we collected epidemiological and treatment data from 2019 positive syphilis cases. Of these, 1855 (91.9%) of the pregnant women received treatment. Among the 1020 infants born to these women, 92 (9.0%) were confirmed to have congenital syphilis. If we exclude the mothers who had syphilis positive babies without undergoing prenatal screening, the project's success rate for mother-to-child transmission intervention was 99.1%. CONCLUSIONS: After four years of implementation, we proved the programme to be successful in preventing mother-to-child syphilis transmission. Further work should be done to ensure the earlier screening and treatment of pregnant women. PMID- 17693450 TI - Prevention of sexually transmitted infections and under 18 conceptions. PMID- 17693451 TI - Selection of quinolone resistance in Streptococcus pneumoniae exposed in vitro to subinhibitory drug concentrations. AB - OBJECTIVES: Does exposure to subinhibitory concentrations of quinolones favour overexpression of efflux pumps or selection of target site mutations? METHODS: ATCC 49,619 (fully susceptible) and SP32 (clinical isolate with PmrA-mediated efflux and mutation in ParE) were exposed for 24 h in broth to ciprofloxacin, levofloxacin, moxifloxacin or garenoxacin at concentrations of 0.5x the MIC, with daily re-adjustments for up to 13 days. Efflux was detected phenotypically (decrease in MIC in the presence of reserpine), and expression of pmrA and patA/patB was measured by real-time PCR and comparative RT-PCR, respectively. Target site mutations were detected by sequencing of the quinolone resistance determining regions in parC, parE and gyrA. The clonal identity of isolates was checked by PFGE of genomic DNA. RESULTS: Ciprofloxacin selected for stable mutants with 2.5-5-fold MIC increases for ciprofloxacin, 2-3-fold for levofloxacin and 1.3-2-fold for garenoxacin and moxifloxacin [partial reversion with reserpine for ciprofloxacin, gemifloxacin and levofloxacin (SP32 strain only), but not for garenoxacin and moxifloxacin]. Increased MICs were associated with overexpression of patA/B but not pmrA. In contrast, exposure to levofloxacin, moxifloxacin or garenoxacin selected target site mutations (gyrA, parC, parE) in both strains. Increases in MIC caused by efflux were similar to those caused by target site mutations. CONCLUSIONS: Exposure of Streptococcus pneumoniae to subinhibitory MICs of ciprofloxacin, a substrate for efflux pumps, results in patA/B-mediated efflux whatever the initial level of expression of pmrA of the strain. Quinolones that are poorly (levofloxacin) or not affected (moxifloxacin, garenoxacin) in their activity by efflux transporters preferentially select for target site mutants. PMID- 17693452 TI - ABA regulates apoplastic sugar transport and is a potential signal for cold induced pollen sterility in rice. AB - Cold temperatures cause pollen sterility and large reductions in grain yield in temperate rice growing regions of the world. Induction of pollen sterility by cold involves a disruption of sugar transport in anthers, caused by the cold induced repression of the apoplastic sugar transport pathway in the tapetum. Here we demonstrate that the phytohormone ABA is a potential signal for cold-induced pollen sterility (CIPS). Cold treatment of the cold-sensitive cultivar Doongara resulted in increased anther ABA levels. Exogenous ABA treatment at the young microspore stage induced pollen sterility and affected cell wall invertase and monosaccharide transporter gene expression in a way similar to cold treatment. In the cold-tolerant cultivar R31, ABA levels were significantly lower under normal circumstances and remained low after cold treatment. The differences in endogenous ABA levels in Doongara and R31 correlated with differences in expression of the ABA biosynthetic genes encoding zeaxanthin epoxidase (OSZEP1) and 9-cis-epoxycarotenoid dioxygenase (OSNCED2, OSNCED3) in anthers. The expression of three ABA-8-hydroxylase genes (ABA8OX1, 2 and 3) in R31 anthers was higher under control conditions and was regulated differently by cold compared with Doongara. Our results indicate that the cold tolerance phenotype of R31 is correlated with lower endogenous ABA levels and a different regulation of ABA metabolism. PMID- 17693453 TI - CSR1, the sole target of imidazolinone herbicide in Arabidopsis thaliana. AB - The imidazolinone-tolerant mutant of Arabidopsis thaliana, csr1-2(D), carries a mutation equivalent to that found in commercially available Clearfield crops. Despite their widespread usage, the mechanism by which Clearfield crops gain imidazolinone herbicide tolerance has not yet been fully characterized. Transcription profiling of imazapyr (an imidazolinone herbicide)-treated wild type and csr1-2(D) mutant plants using Affymetrix ATH1 GeneChip microarrays was performed to elucidate further the biochemical and genetic mechanisms of imidazolinone resistance. In wild-type shoots, the genes which responded earliest to imazapyr treatment were detoxification-related genes which have also been shown to be induced by other abiotic stresses. Early-response genes included steroid sulfotransferase (ST) and 1-aminocyclopropane-1-carboxylic acid oxidase (ACO), as well as members of the glycosyltransferase, glutathione transferase (GST), cytochrome P450, ATP-binding cassette (ABC) transporter, multidrug and toxin extrusion (MATE) and alternative oxidase (AOX) protein families. Later stages of the imazapyr response involved regulation of genes participating in biosynthesis of amino acids, secondary metabolites and tRNA. In contrast to the dynamic changes in the transcriptome profile observed in imazapyr-treated wild type plants, the transcriptome of csr1-2(D) did not exhibit significant changes following imazapyr treatment, compared with mock-treated csr1-2(D). Further, no substantial difference was observed between wild-type and csr1-2(D) transcriptomes in the absence of imazapyr treatment. These results indicate that CSR1 is the sole target of imidazolinone and that the csr1-2(D) mutation has little or no detrimental effect on whole-plant fitness. PMID- 17693454 TI - A dynamical model of environmental effects on allocation to carbon-based secondary compounds in juvenile trees. AB - BACKGROUND AND AIMS: Patterns and variations in concentration of carbon-based secondary compounds in plant tissues have been explained by means of different complementary and, in some cases, contradictory plant defence hypotheses for more than 20 years. These hypotheses are conceptual models which consider environmental impacts on plant internal demands. In the present study, a mathematical model is presented, which converts and integrates the concepts of the 'Growth-Differentiation Balance' hypothesis and the 'Protein Competition' model into a dynamic plant growth model, that was tested with concentration data of polyphenols in leaves of juvenile apple, beech and spruce trees. The modelling approach is part of the plant growth model PLATHO that considers simultaneously different environmental impacts on the most important physiological processes of plants. METHODS: The modelling approach for plant internal resource allocation is based on a priority scheme assuming that growth processes have priority over allocation to secondary compounds and that growth-related metabolism is more strongly affected by nitrogen deficiency than defence-related secondary metabolism. KEY RESULTS: It is shown that the model can reproduce the effect of nitrogen fertilization on allocation patterns in apple trees and the effects of elevated CO(2) and competition in juvenile beech and spruce trees. The analysis of model behaviour reveals that large fluctuations in plant internal availability of carbon and nitrogen are possible within a single vegetation period. Furthermore, the model displays a non-linear allocation behaviour to carbon-based secondary compounds. CONCLUSIONS: The simulation results corroborate the underlying assumptions of the presented modelling approach for resource partitioning between growth-related primary metabolism and defence-related secondary metabolism. Thus, the dynamical modelling approach, which considers variable source and sink strengths of plant internal resources within different phenological growth stages, presents a successful translation of existing concepts into a dynamic mathematical model. PMID- 17693455 TI - A fold-back single-chain diabody format enhances the bioactivity of an anti monkey CD3 recombinant diphtheria toxin-based immunotoxin. AB - T-cell depleting anti-CD3 immunotoxins have utility in non-human primate models of transplantation tolerance and autoimmune disease therapy. We recently reported that an affinity matured single-chain (scFv) anti-monkey CD3 antibody, C207, had increased binding to T-cells and increased bioactivity in a diphtheria toxin (DT) based biscFv immunotoxin compared with the parental antibody, FN18. However, FN18 scFvs and their mutant derivatives such as C207 did not exhibit robust bivalent character in the biscFv format. We now report that C207 in a diabody format exhibits a 7-fold increase in binding to T-cells over scFv (C207) indicating considerable divalent character for the diabody. This construct was formed by reducing the V(L)/V(H) linker to five residues and was secreted from Pichia pastoris as the non-covalent dimer. An immunotoxin based on this diabody format was secreted as a non-covalent dimer but was devoid of bioactivity and failed to bind T-cells, suggesting steric hindrance from the two large closely positioned truncated DT moieties. We constructed a single-chain diabody immunotoxin by fusing to the truncated DT C-terminus L1-VL-L1-VH-L2-VL-L1-VH where L1 is a five residue linker and L2 is the longer (G4S)3 linker permitting interactions between the distal and proximal VL/VH domains. This 'fold-back' immunotoxin was secreted predominantly as the monomer and exhibited a 5- to 7-fold increase in bioactivity over DT390biscFv(C207) and depleted monkey T-cells in vivo. PMID- 17693456 TI - Influence of different carboxy-terminal mutations on the substrate-, reaction- and enantiospecificity of the arylacetonitrilase from Pseudomonas fluorescens EBC191. AB - Different members of the nitrilase superfamily (D-carbamoylases, Nit-Fhit proteins, amidases, cyanide dihydratases and nitrilases) were compared by multiple sequence alignments and a long carboxy-terminal extension (about 50 amino acids) identified in all nitrilases and cyanide dihydratases which was not present in other members of the nitrilase superfamily. The function of this C terminal part was experimentally analysed in the arylacetonitrilase of Pseudomonas fluorescens EBC191 by the construction of various deletion mutants, chimeric enzymes with other bacterial nitrilases and site-specific mutagenesis. The enzyme variants were tested with the substrates 2-phenylpropionitrile and mandelonitrile and compared regarding specific activities, degree of amide formation and enantioselectivity. The enzyme variants containing deletions up to 32 amino acids did not show significant differences in comparison with the wild type enzyme. Deletion mutants with 47-67 amino acids missing generally demonstrated reduced enzyme activities, increased amounts of amide formation and increased proportions of the (R)-enantiomers of the amides and acids formed. Also certain exchanges of H296 in the C-terminal motif DpvGHY led to enzyme variants with a similar phenotype. Chimeric enzymes which contained up to 59 amino acids deriving from the nitrilases of Rhodococcus rhodochrous NCIMB11216 or Alcaligenes faecalis ATCC8750 were active and resembled, with respect to the enantioselectivity and degree of amide formation, the wild-type enzyme of P.fluorescens. PMID- 17693457 TI - Outcome of single-chamber, ventricular pacemakers with transvenous leads implanted in children. AB - AIMS: In children with bradyarrhythmias, ventricular demand, rate-responsive pacemakers (VVI/R PM) are often indicated, but no study is entirely dedicated to their outcome. METHODS AND RESULTS: We evaluated the outcomes of children with VVI/R PM implanted at our centre, with a retrospective analysis. Between 1990 and 2005, 117 children (63 with congenital heart defects), received VVI/R PM with endocardial lead at 5.3 +/- 3.9 years of age for atrioventricular block (n = 105) and sinus node dysfunction. The majority of the leads were unipolar (n = 78), tined (n = 110), and steroid eluting (n = 89). The leads were fixed to subcutaneous tissues by absorbable suture in all patients; in 17 patients, also an atrial loop was created. Follow-up (FU) was 7.8 +/- 4.1 years. There were 22 system failures (19%), due to lead malfunction (n = 20) and system erosion/infection. The log-rank test for equality of survivor functions showed no significant risk factor. However, lead malfunction occurred only in the group without loop, but FU duration was longer in these patients. Complications at implantation were haemothorax (2.5%) and lead dislodgement (5%). Clinically silent occlusion of the subclavian vein was documented at FU by Echo-Doppler in 5%. CONCLUSION: In this particular group of patients, VVI/R pacing has good results, but after long-term FU shows 19% of failures, mainly lead-related. PMID- 17693458 TI - Cohort Profile: the Swiss Hepatitis C Cohort Study (SCCS). PMID- 17693459 TI - The impact of gender on outcomes of patients with ST elevation myocardial infarction transported for percutaneous coronary intervention: analysis of the PRAGUE-1 and 2 studies. AB - BACKGROUND: Data comparing survival outcomes for women versus men transported for pPCI were absent. OBJECTIVES: To assess the impact of gender on 30-day mortality of patients with STEMI transported for pPCI. METHODS: The data from the PRAGUE-1 and PRAGUE-2 trials were analysed. Studies compared thrombolysis in the community hospital and pPCI after transportation to cardiocentre. A group of 520 patients treated with thrombolysis, and 530 transported for pPCI, were analysed. RESULTS: Women were older, with a higher risk profile. They had longer ischaemia time. Mortality of patients treated with TL was significantly higher in women than in men (15% vs 9%, p = 0.043). There was no significant gender difference in mortality in the PCI group (8.2% of women vs 6.2% of men, p = 0.409). Mortality of women treated with on-site TL was nearly twice as high as mortality of women transported for pPCI (p = 0.043). After adjustment in a multivariate model the odds ratio for mortality in women was 0.74 (95% CI 0.26 to 2.05; p = 0.556). CONCLUSION: Long-distance transportation of women with STEMI from a community hospital to a tertiary PCI centre is a significantly more effective treatment strategy than on-site TL. Gender did not determine survival in patients transported for pPCI. PMID- 17693460 TI - The impact of private-sector provision on equitable utilisation of coronary revascularisation in London. AB - OBJECTIVE: To investigate the impact of including private-sector data on assessments of equity of coronary revascularisation provision using NHS data only. DESIGN: Analyses of hospital episodes statistics and private-sector data by age, sex and primary care trust (PCT) of residence. For each PCT, the share of London's total population and revascularisations (all admissions, NHS-funded, and privately-funded admissions) were calculated. Gini coefficients were derived to provide an index of inequality across subpopulations, with parametric bootstrapping to estimate confidence intervals. SETTING: London. PARTICIPANTS: London residents undergoing coronary revascularisation April 2001-December 2003. INTERVENTION: Coronary artery bypass graft or angioplasty. MAIN OUTCOME MEASURES: Directly standardised revascularisation rates, Gini coefficients. RESULTS: NHS funded age-standardised revascularisation rates varied from 95.2 to 193.9 per 100,000 and privately funded procedures from 7.6 to 57.6. Although the age distribution did not vary by funding, the proportion of revascularisations among women that were privately funded (11.0%) was lower than among men (17.0%). Privately funded rates were highest in PCTs with the lowest death rates (p = 0.053). NHS-funded admission rates were not related to deprivation nor age standardised deaths rates from coronary heart disease. Privately funded admission rates were lower in more deprived PCTs. NHS provision was significantly more egalitarian (Gini coefficient 0.12) than the private sector (0.35). Including all procedures was significantly less equal (0.13) than NHS-funded care alone. CONCLUSION: Private provision exacerbates geographical inequalities. Those responsible for commissioning care for defined populations must have access to consistent data on provision of treatment wherever it takes place. PMID- 17693461 TI - Mechanics of single cells: rheology, time dependence, and fluctuations. AB - The results of mechanical measurements on single cultured epithelial cells using both magnetic twisting cytometry (MTC) and laser tracking microrheology (LTM) are described. Our unique approach uses laser deflection for high-performance tracking of cell-adhered magnetic beads either in response to an oscillatory magnetic torque (MTC) or due to random Brownian or ATP-dependent forces (LTM). This approach is well suited for accurately determining the rheology of single cells, the study of temporal and cell-to-cell variations in the MTC signal amplitude, and assessing the statistical character of the tracers' random motion in detail. The temporal variation of the MTC rocking amplitude is surprisingly large and manifests as a frequency-independent multiplicative factor having a 1/f spectrum in living cells, which disappears upon ATP depletion. In the epithelial cells we study, random bead position fluctuations are Gaussian to the limits of detection both in the Brownian and ATP-dependent cases, unlike earlier studies on other cell types. PMID- 17693462 TI - Structural determinants of the packing and electrostatic behavior of unsaturated phosphoglycerides. AB - Docosahexaenoic acid-containing phosphoglycerides accumulate preferentially in membranes of the retina, brain, and spermatozoa, but the functional significance of this largely remains to be determined. Previously we compared the physical properties of homogeneous monolayers of these and other phosphoglyceride species to obtain insights into their physiological roles. Particularly noteworthy were the unusually low dipole moments of species having sn-2-docosahexaenoyl chains. In this study, we have investigated the electrostatic and lateral packing properties of related phosphoglycerides and found that: 1), The dipole moment lowering effect of the docosahexaenoyl group arises from its having a Z double bond at chain position n-3. 2), The large dipole moment-lowering effects at sn-1 of an ether bond to an alkyl or a 1Z alkenyl chain and that of a sn-2-esterified n-3 fatty acid are additive. 3), The 1Z double bond in an alkenyl chain lowers the molecular area of a phosphoglyceride and, concomitantly, makes it less compressible. 4), Ethanolamine-containing phosphoglycerides are generally less compressible than their corresponding choline analogs. Our data showing that relatively small lipid structural changes markedly alter lipid physical properties in fluid phases underscores the need to study the function of peripheral and integral membrane proteins in the presence of appropriate lipid species. PMID- 17693463 TI - Modeling hypertrophic IP3 transients in the cardiac myocyte. AB - Cardiac hypertrophy is a known risk factor for heart disease, and at the cellular level is caused by a complex interaction of signal transduction pathways. The IP3 calcineurin pathway plays an important role in stimulating the transcription factor NFAT which binds to DNA cooperatively with other hypertrophic transcription factors. Using available kinetic data, we construct a mathematical model of the IP3 signal production system after stimulation by a hypertrophic alpha-adrenergic agonist (endothelin-1) in the mouse atrial cardiac myocyte. We use a global sensitivity analysis to identify key controlling parameters with respect to the resultant IP3 transient, including the phosphorylation of cell membrane receptors, the ligand strength and binding kinetics to precoupled (with G(alpha)GDP) receptor, and the kinetics associated with precoupling the receptors. We show that the kinetics associated with the receptor system contribute to the behavior of the system to a great extent, with precoupled receptors driving the response to extracellular ligand. Finally, by reparameterizing for a second hypertrophic alpha-adrenergic agonist, angiotensin II, we show that differences in key receptor kinetic and membrane density parameters are sufficient to explain different observed IP3 transients in essentially the same pathway. PMID- 17693464 TI - Rheological behavior of living cells is timescale-dependent. AB - The dynamic mechanical behavior of living cells has been proposed to result from timescale-invariant processes governed by the soft glass rheology theory derived from soft matter physics. But this theory is based on experimental measurements over timescales that are shorter than those most relevant for cell growth and function. Here we report results measured over a wider range of timescales which demonstrate that rheological behaviors of living cells are not timescale invariant. These findings demonstrate that although soft glass rheology appears to accurately predict certain cell mechanical behaviors, it is not a unified model of cell rheology under biologically relevant conditions and thus, alternative mechanisms need to be considered. PMID- 17693465 TI - Confinement and manipulation of actin filaments by electric fields. AB - When an AC electric field was applied across a small gap between two metal electrodes elevated above a surface, rhodamine-phalloidin-labeled actin filaments were attracted to the gap and became suspended between the two electrodes. The variance of each filament's horizontal, lateral displacement was measured as a function of electric field intensity and position along the filament. markedly decreased as the electric field intensity increased. Hypothesizing that the electric field induces tension in the filament, we estimated the tension using a linear, Brownian dynamic model. Our experimental method provides a novel means for trapping and manipulating biological filaments and for probing the surface conductance and mechanical properties of single polymers. PMID- 17693466 TI - Molecular basis of the apparent near ideality of urea solutions. AB - Activity coefficients of urea solutions are calculated to explore the mechanism of its solution properties, which form the basis for its well-known use as a strong protein denaturant. We perform free energy simulations of urea solutions in different urea concentrations using two urea models (OPLS and KBFF models) to calculate and decompose the activity coefficients. For the case of urea, we clarify the concept of the ideal solution in different concentration scales and standard states and its effect on our subsequent analysis. The analytical form of activity coefficients depends on the concentration units and standard states. For both models studied, urea displays a weak concentration dependence for excess chemical potential. However, for the OPLS force-field model, this results from contributions that are independent of concentration to the van der Waals and electrostatic components whereas for the KBFF model those components are nontrivial but oppose each other. The strong ideality of urea solutions in some concentration scales (incidentally implying a lack of water perturbation) is discussed in terms of recent data and ideas on the mechanism of urea denaturation of proteins. PMID- 17693467 TI - Cytoplasmic domain of zebrafish myelin protein zero: adhesive role depends on beta-conformation. AB - Solution spectroscopy studies on the cytoplasmic domain of human myelin protein zero (P0) (hP0-cyt) suggest that H-bonding between beta-strands from apposed molecules is likely responsible for the tight cytoplasmic apposition in compact myelin. As a follow-up to these findings, in the current study we used circular dichroism and x-ray diffraction to analyze the same type of model membranes previously used for hP0-cyt to investigate the molecular mechanism underlying the zebrafish cytoplasmic apposition. This space is significantly narrower in teleosts compared with that in higher vertebrates, and can be accounted for in part by the much shorter cytoplasmic domain in the zebrafish protein (zP0-cyt). Circular dichroism measurements on zP0-cyt showed similar structural characteristics to those of hP0-cyt, i.e., the protein underwent a beta-->alpha structural transition at lipid/protein (L/P) molar ratios >50, and adopted a beta conformation at lower L/P molar ratios. X-ray diffraction was carried out on lipid vesicle solutions with zP0-cyt before and after dehydration to study the effect of protein on membrane lipid packing. Solution diffraction revealed the electron-density profile of a single membrane bilayer. Diffraction patterns of dried samples suggested a multilamellar structure with the beta-folded P0-cyt located at the intermembrane space. Our findings support the idea that the adhesive role of P0 at the cytoplasmic apposition in compact myelin depends on the cytoplasmic domain of P0 being in the beta-conformation. PMID- 17693468 TI - Optimization of electrostatic interactions in protein-protein complexes. AB - In this article, we present a statistical analysis of the electrostatic properties of 298 protein-protein complexes and 356 domain-domain structures extracted from the previously developed database of protein complexes (ProtCom, http://www.ces.clemson.edu/compbio/protcom). For each structure in the dataset we calculated the total electrostatic energy of the binding and its two components, Coulombic and reaction field energy. It was found that in a vast majority of the cases (>90%), the total electrostatic component of the binding energy was unfavorable. At the same time, the Coulombic component of the binding energy was found to favor the complex formation while the reaction field component of the binding energy opposed the binding. It was also demonstrated that the components in a wild-type (WT) structure are optimized/anti-optimized with respect to the corresponding distributions, arising from random shuffling of the charged side chains. The degree of this optimization was assessed through the Z-score of WT energy in respect to the random distribution. It was found that the Z-scores of Coulombic interactions peak at a considerably negative value for all 654 cases considered while the Z-score of the reaction field energy varied among different types of complexes. All these findings indicate that the Coulombic interactions within WT protein-protein complexes are optimized to favor the complex formation while the total electrostatic energy predominantly opposes the binding. This observation was used to discriminate WT structures among sets of structural decoys and showed that the electrostatic component of the binding energy is not a good discriminator of the WT; while, Coulombic or reaction field energies perform better depending upon the decoy set used. PMID- 17693469 TI - Coarse-grained biomolecular simulation with REACH: realistic extension algorithm via covariance Hessian. AB - Coarse-graining of protein interactions provides a means of simulating large biological systems. Here, a coarse-graining method, REACH, is introduced, in which the force constants of a residue-scale elastic network model are calculated from the variance-covariance matrix obtained from atomistic molecular dynamics (MD) simulation. In test calculations, the C(alpha)-atoms variance-covariance matrices are calculated from the ensembles of 1-ns atomistic MD trajectories in monomeric and dimeric myoglobin, and used to derive coarse-grained force constants for the local and nonbonded interactions. Construction of analytical model functions of the distance-dependence of the interresidue force constants allows rapid calculation of the REACH normal modes. The model force constants from monomeric and dimeric myoglobin are found to be similar in magnitude to each other. The MD intra- and intermolecular mean-square fluctuations and the vibrational density of states are well reproduced by the residue-scale REACH normal modes without requiring rescaling of the force constant parameters. The temperature-dependence of the myoglobin REACH force constants reveals that the dynamical transition in protein internal fluctuations arises principally from softening of the elasticity in the nonlocal interactions. The REACH method is found to be a reliable way of determining spatiotemporal protein motion without the need for expensive computations of long atomistic MD simulations. PMID- 17693470 TI - Molecular and supramolecular structural studies on human tropoelastin sequences. AB - One of the unusual properties of elastin is its ability to coacervate, which has been proposed to play an important role in the alignment of monomeric elastin for cross-linking into the polymeric elastin matrix. The temperature at which this transition takes place depends on several factors including protein concentration, ionic strength, and pH. Previously, polypeptide sequences encoded by different exons of the human tropoelastin gene have been analyzed for their ability to coacervate and to self-assemble. Few of them were indeed able to coacervate and only one, that encoded by exon 30 (EX30), gave amyloid fibers. In this article, we report on two chemically synthesized peptides-a decapeptide and an octadecapeptide-whose sequences are contained in the longer EX30 peptide and on a polypeptide (EX1-7) of 125 amino-acid residues corresponding to the sequence coded by the exons 1-7 and on a polypeptide (EX2-7) of 99 amino-acid residues encoded by exons 2-7 of human tropoelastin obtained by recombinant DNA techniques. Molecular and supramolecular structural characterization of these peptides showed that a minimum sequence of approximately 20 amino acids is needed to form amyloid fibers in the exon 30-derived peptides. The N-terminal region of mature tropoelastin (EX2-7) gives rise to a coacervate and forms elastinlike fibers, whereas the polypeptide sequence containing the signal peptide (EX1-7) forms mainly amyloid fibers. Circular dichroism spectra show that beta-structure is ubiquitous in all the sequences studied, suggesting that the presence of a beta-structure is a necessary, although not sufficient, requirement for the appearance of amyloid fibers. PMID- 17693471 TI - Structure and phase diagram of nucleosome core particles aggregated by multivalent cations. AB - The degree of compaction of the eukaryotic chromatin in vivo and in vitro is highly sensitive to the ionic environment. We address the question of the effect of multivalent ions on the interactions and mutual organization of the chromatin structural units, the nucleosome core particles (NCPs). Conditions of precipitation of NCPs in the presence of 10 mM Tris buffer and various amounts of either magnesium (Mg(2+)) or spermidine (Spd(3+)) are explored, compared, and discussed in relation to theoretical models. In addition, the structure of the aggregates is analyzed by complementary techniques: freeze-fracture electron microscopy, cryoelectron microscopy, and x-ray diffraction. In Mg(2+)-NCP aggregates, NCPs tend to stack on top of one another to form columns that are not long-range organized. In the presence of Spd(3+), NCPs precipitate to form a dense isotropic phase, a disordered phase of columns, a two-dimensional columnar hexagonal phase, or a three-dimensional crystal. The more ordered phases (two dimensional or three-dimensional hexagonal) are found close to the precipitation line, where the number of positive charges carried by cations is slightly larger than the number of available negative charges of the NCPs. All ordered phases coexist with the dense isotropic phases. Formation of hexagonal and columnar phases is prevented by an excess of polycations. PMID- 17693472 TI - Hoogsteen-paired homopurine [RP-PS]-DNA and homopyrimidine RNA strands form a thermally stable parallel duplex. AB - Homopurine deoxyribonucleoside phosphorothioates possessing all internucleotide linkages of R(P) configuration form a duplex with an RNA or 2'-OMe-RNA strand with Hoogsteen complementarity. The duplexes formed with RNA templates are thermally stable at pH 5.3, while those formed with a 2'-OMe-RNA are stable at neutrality. Melting temperature and fluorescence quenching experiments indicate that the strands are parallel. Remarkably, these duplexes are thermally more stable than parallel Hoogsteen duplexes and antiparallel Watson-Crick duplexes formed by unmodified homopurine DNA molecules of the same sequence with corresponding RNA templates. PMID- 17693474 TI - Structure and aggregation mechanism of beta(2)-microglobulin (83-99) peptides studied by molecular dynamics simulations. AB - Many human neurodegenerative diseases are associated with amyloid fibril formation. The human 99-residue beta(2)-microglobulin (beta2m) is one of the most intensively studied amyloid-forming proteins. Recent studies show that the C terminal fragments 72-99, 83-89, and 91-96 form by themselves amyloid fibrils in vitro and play a significant role in fibrillization of the full-length beta2m protein under acidic pH conditions. In this work, we have studied the equilibrium structures of the 17-residue fragment 83-99 in solution, and investigated its dimerization process by multiple molecular dynamics simulations. We find that an intertwined dimer, with the positions of the beta-strands consistent with the results for the monomer, is a possible structure for two beta2m(83-89) peptides. Based on our molecular-dynamics-generated dimeric structure, a protofibril model is proposed for the full-length beta2m protein. PMID- 17693473 TI - Proton transport behavior through the influenza A M2 channel: insights from molecular simulation. AB - The structural properties of the influenza A virus M2 transmembrane channel in dimyristoylphosphatidylcholine bilayer for each of the four protonation states of the proton-gating His-37 tetrad and their effects on proton transport for this low-pH activated, highly proton-selective channel are studied by classical molecular dynamics with the multistate empirical valence-bond (MS-EVB) methodology. The excess proton permeation free energy profile and maximum ion conductance calculated from the MS-EVB simulation data combined with the Poisson Nernst-Planck theory indicates that the triply protonated His-37 state is the most likely open state via a significant side-chain conformational change of the His-37 tetrad. This proposed open state of M2 has a calculated proton permeation free energy barrier of 7 kcal/mol and a maximum conductance of 53 pS compared to the experimental value of 6 pS. By contrast, the maximum conductance for Na(+) is calculated to be four orders of magnitude lower, in reasonable agreement with the experimentally observed proton selectivity. The pH value to activate the channel opening is estimated to be 5.5 from dielectric continuum theory, which is also consistent with experimental results. This study further reveals that the Ala-29 residue region is the primary binding site for the antiflu drug amantadine (AMT), probably because that domain is relatively spacious and hydrophobic. The presence of AMT is calculated to reduce the proton conductance by 99.8% due to a significant dehydration penalty of the excess proton in the vicinity of the channel-bound AMT. PMID- 17693475 TI - Unfolding kinetics of beta-lactoglobulin induced by surfactant and denaturant: a stopped-flow/fluorescence study. AB - The beta-->alpha transition of beta-lactoglobulin, a globular protein abundant in the milk of several mammals, is investigated in this work. This transition, induced by the cationic surfactant dodecyltrimethylammonium chloride (DTAC), is accompanied by partial unfolding of the protein. In this work, unfolding of bovine beta-lactoglobulin in DTAC is compared with its unfolding induced by the chemical denaturant guanidine hydrochloride (GnHCl). The final protein states attained in the two media have quite different secondary structure: in DTAC the alpha-helical content increases, leading to the so-called alpha-state; in GnHCl the amount of ordered secondary-structure decreases, resulting in a random coil rich final state (denatured, or D, state). To obtain information on both mechanistic routes, in DTAC and GnHCl, and to characterize intermediates, the kinetics of unfolding were investigated in the two media. Equilibrium and kinetic data show the partial accumulation of an on-pathway intermediate in each unfolding route: in DTAC, an intermediate (I(1)) with mostly native secondary structure but loose tertiary structure appears between the native (beta) and alpha-states; in GnHCl, another intermediate (I(2)) appears between states beta and D. Kinetic rate constants follow a linear Chevron-plot representation in GnHCl, but show a more complex mechanism in DTAC, which acts like a stronger binding species. PMID- 17693476 TI - Fluctuations of transfer RNAs between classical and hybrid states. AB - Adjacent transfer RNAs (tRNAs) in the A- and P-sites of the ribosome are in dynamic equilibrium between two different conformations called classical and hybrid states before translocation. Here, we have used single-molecule fluorescence resonance energy transfer to study the effect of Mg(2+) on tRNA dynamics with and without an acetyl group on the A-site tRNA. When the A-site tRNA is not acetylated, tRNA dynamics do not depend on [Mg(2+)], indicating that the relative positions of the substrates for peptide-bond formation are not affected by Mg(2+). In sharp contrast, when the A-site tRNA is acetylated, Mg(2+) lengthens the lifetime of the classical state but does not change the lifetime of the hybrid state. Based on these findings, the classical state resembles a state with direct stabilization of tertiary structure by Mg(2+) ions whereas the hybrid state resembles a state with little Mg(2+)-assisted stabilization. The antibiotic viomycin, a translocation inhibitor, suppresses tRNA dynamics, suggesting that the enhanced fluctuations of tRNAs after peptide-bond formation drive spontaneous attempts at translocation by the ribosome. PMID- 17693477 TI - Surfactant protein A forms extensive lattice-like structures on 1,2 dipalmitoylphosphatidylcholine/rough-lipopolysaccharide-mixed monolayers. AB - Due to the inhalation of airborne particles containing bacterial lipopolysaccharide (LPS), these molecules might incorporate into the 1,2 dipalmitoylphosphatidylcholine (DPPC)-rich monolayer and interact with surfactant protein A (SP-A), the major surfactant protein component involved in host defense. In this study, epifluorescence microscopy combined with a surface balance was used to examine the interaction of SP-A with mixed monolayers of DPPC/rough LPS (Re-LPS). Binary monolayers of Re-LPS plus DPPC showed negative deviations from ideal behavior of the mean areas in the films consistent with partial miscibility and attractive interaction between the lipids. This interaction resulted in rearrangement and reduction of the size of DPPC-rich solid domains in DPPC/Re-LPS monolayers. The adsorption of SP-A to these monolayers caused expansion in the lipid molecular areas. SP-A interacted strongly with Re-LPS and promoted the formation of DPPC-rich solid domains. Fluorescently labeled Texas red-SP-A accumulated at the fluid-solid boundary regions and formed networks of interconnected filaments in the fluid phase of DPPC/Re-LPS monolayers in a Ca(2+)-independent manner. These lattice-like structures were also observed when TR-SP-A interacted with lipid A monolayers. These novel results deepen our understanding of the specific interaction of SP-A with the lipid A moiety of bacterial LPS. PMID- 17693478 TI - O2 migration pathways are not conserved across proteins of a similar fold. AB - Recent advances in computational biology have made it possible to map the complete network and energy profile of gas migration pathways inside proteins. Although networks of O(2) pathways have already been characterized for a small number of proteins, the general properties and locations of these pathways have not been previously compared between proteins. In this study, maps of the O(2) pathways inside 12 monomeric globins were computed. It is found that, despite the conserved tertiary structure fold of the studied globins, the shape and topology of O(2) pathway networks exhibit a large variability between different globins, except when two globins are nearly identical. The locations of the O(2) pathways are, however, found to be correlated with the location of large hydrophobic residues, and a similar correlation is observed in two unrelated protein families: monomeric globins and copper-containing amine oxidases. The results have implications for the evolution of gas pathways in proteins and for protein engineering applications involving modifications of these pathways. PMID- 17693479 TI - Hybrid quantum mechanical/molecular mechanical molecular dynamics simulations of HIV-1 integrase/inhibitor complexes. AB - Human immunodeficiency virus (HIV)-1 integrase (IN) is an attractive target for development of acquired immunodeficiency syndrome chemotherapy. In this study, conventional and coupled quantum mechanical and molecular mechanical (QM/MM) molecular dynamics (MD) simulations of HIV-1 IN complexed with 5CITEP (IN-5CITEP) were carried out. In addition to differences in the bound position of 5CITEP, significant differences at the two levels of theory were observed in the metal coordination geometry and the areas involving residues 116-119 and 140-166. In the conventional MD simulation, the coordination of Mg(2+) was found to be a near perfect octahedral geometry whereas a distorted octahedral complex was observed in QM/MM. All of the above reasons lead to a different pattern of protein-ligand salt link formation that was not observed in the classical MD simulation. Furthermore to provide a theoretical understanding of inhibition mechanisms of 5CITEP and its derivative (DKA), hybrid QM/MM MD simulations of the two complexes (IN-5CITEP and IN-DKA) have been performed. The results reveal that areas involving residues 60-68, 116-119, and 140-149 were substantially different among the two systems. The two systems show similar pattern of metal coordination geometry, i.e., a distorted octahedron. In IN-DKA, both OD1 and OD2 of Asp-64 coordinate the Mg(2+) in a monodentate fashion whereas only OD1 is chelated to the metal as observed in IN-5CITEP. The high potency of DKA as compared to 5CITEP is supported by a strong salt link formed between its carboxylate moiety and the ammonium group of Lys-159. Detailed comparisons between HIV-1 IN complexed with DKA and with 5CITEP provide information about ligand structure effects on protein ligand interactions in particular with the Lys-159. This is useful for the design of new selective HIV-1 IN inhibitors. PMID- 17693481 TI - Angiogenesis is induced by airway smooth muscle strain. AB - Angiogenesis is an important feature of airway remodeling in both chronic asthma and chronic obstructive pulmonary disease (COPD). Airways in those conditions are exposed to excessive mechanical strain during periods of acute exacerbations. We recently reported that mechanical strain of human airway smooth muscle (HASM) led to an increase in their proliferation and migration. Sustained growth in airway smooth muscle in vivo requires an increase in the nutritional supply to these muscles, hence angiogenesis. In this study, we examined the hypothesis that cyclic mechanical strain of HASM produces factors promoting angiogenic events in the surrounding vascular endothelial cells. Our results show: 1) a significant increase in human lung microvascular endothelial cell (HMVEC-L) proliferation, migration, and tube formation following incubation in conditioned media (CM) from HASM cells exposed to mechanical strain; 2) mechanical strain of HASM cells induced VEGF expression and release; 3) VEGF neutralizing antibodies inhibited the proliferation, migration, and tube formations of HMVEC-L induced by the strained airway smooth muscle CM; 4) mechanical strain of HASM induced a significant increase in hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA and protein, a transcription factor required for VEGF gene transcription; and 5) mechanical strain of HASM induced HIF-1alpha/VEGF through dual phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and ERK pathways. In conclusion, exposing HASM cells to mechanical strain induces signal transduction pathway through PI3K/Akt/mTOR and ERK pathways that lead to an increase in HIF-1alpha, a transcription factor required for VEGF expression. VEGF release by mechanical strain of HASM may contribute to the angiogenesis seen with repeated exacerbation of asthma and COPD. PMID- 17693482 TI - Reduced store-operated Ca2+ entry in pulmonary endothelial cells from chronically hypoxic rats. AB - Chronic hypoxia (CH)-induced pulmonary hypertension may influence basal endothelial cell (EC) intracellular Ca(2+) concentration ([Ca(2+)](i)). We hypothesized that CH decreases EC [Ca(2+)](i) associated with membrane depolarization and reduced Ca(2+) entry. To test this hypothesis, we assessed 1) basal endothelial Ca(2+) in pressurized pulmonary arteries and freshly isolated ECs, 2) EC membrane potential (E(m)), 3) store-operated Ca(2+) current (I(SOC)), and 4) store-operated Ca(2+) (SOC) entry in arteries from control and CH rats. We found that basal EC Ca(2+) was significantly lower in pressurized pulmonary arteries and freshly isolated ECs from CH rats compared with controls. Similarly, ECs in intact arteries from CH rats were depolarized compared with controls, although no differences were observed between groups in isolated cells. I(SOC) activation by 1 muM thapsigargin displayed diminished inward current and a reversal potential closer to 0 mV in cells from CH rats compared with controls. In addition, SOC entry determined by fura 2 fluorescence and Mn(2+) quenching revealed a parallel reduction in Ca(2+) entry following CH. We conclude that differences in the magnitude of SOC entry exist between freshly dispersed ECs from CH and control rats and correlates with the decrease in basal EC [Ca(2+)](i). In contrast, basal EC Ca(2+) influx is unaffected and membrane depolarization is limited to intact arteries, suggesting that E(m) may not play a major role in determining basal EC [Ca(2+)](i) following CH. PMID- 17693483 TI - Modulation of alveolar fluid clearance by reactive oxygen-nitrogen intermediates. PMID- 17693484 TI - Hypoxia divergently regulates production of reactive oxygen species in human pulmonary and coronary artery smooth muscle cells. AB - Acute hypoxia causes pulmonary vasoconstriction and coronary vasodilation. The divergent effects of hypoxia on pulmonary and coronary vascular smooth muscle cells suggest that the mechanisms involved in oxygen sensing and downstream effectors are different in these two types of cells. Since production of reactive oxygen species (ROS) is regulated by oxygen tension, ROS have been hypothesized to be a signaling mechanism in hypoxia-induced pulmonary vasoconstriction and vascular remodeling. Furthermore, an increased ROS production is also implicated in arteriosclerosis. In this study, we determined and compared the effects of hypoxia on ROS levels in human pulmonary arterial smooth muscle cells (PASMC) and coronary arterial smooth muscle cells (CASMC). Our results indicated that acute exposure to hypoxia (Po(2) = 25-30 mmHg for 5-10 min) significantly and rapidly decreased ROS levels in both PASMC and CASMC. However, chronic exposure to hypoxia (Po(2) = 30 mmHg for 48 h) markedly increased ROS levels in PASMC, but decreased ROS production in CASMC. Furthermore, chronic treatment with endothelin 1, a potent vasoconstrictor and mitogen, caused a significant increase in ROS production in both PASMC and CASMC. The inhibitory effect of acute hypoxia on ROS production in PASMC was also accelerated in cells chronically treated with endothelin-1. While the decreased ROS in PASMC and CASMC after acute exposure to hypoxia may reflect the lower level of oxygen substrate available for ROS production, the increased ROS production in PASMC during chronic hypoxia may reflect a pathophysiological response unique to the pulmonary vasculature that contributes to the development of pulmonary vascular remodeling in patients with hypoxia-associated pulmonary hypertension. PMID- 17693485 TI - Involvement of {alpha}ENaC and Nedd4-2 in the conversion from lung fluid secretion to fluid absorption at birth in the rat as assayed by RNA interference analysis. AB - To explore interactions between the epithelial Na channel (ENaC) and neural precursor expressed, developmentally downregulated protein 4-2 (Nedd4-2) at the conversion of the rat lung from fluid secretion to absorption at birth, we used small-interfering RNA (siRNA) against alphaENaC and Nedd4-2. siRNA-generating plasmid DNA (pDNA) was administered via trans-thoracic intrapulmonary (ttip) injection 24 h before ENaC and Nedd4-2 expression, extravascular lung water, and mortality were measured. alphaENaC mRNA and protein were specifically reduced by approximately 65% after pSi-4 injection. Nedd4-2 mRNA and protein were reduced by approximately 60% after pSi-N1 injection. Interestingly, alphaENaC and betaENaC mRNA and protein expression were increased after Nedd4-2 silencing. Extravascular lung water was significantly increased after alphaENaC silencing and reduced after Nedd4-2 silencing. alphaENaC silencing resulted in a fourfold increase in newborn mortality, whereas silencing Nedd4-2 did not affect mortality. We also isolated distal lung epithelial (DLE) cells after in vivo alphaENaC or Nedd4-2 silencing and measured alphaENaC or Nedd4-2 expression in freshly isolated DLE cells. In these DLE cells, there were attenuated alphaENaC or Nedd4-2 mRNA and protein, thus demonstrating that alphaENaC and Nedd4-2 silencing occurred in alveolar epithelial cells after ttip injection. We also looked for pDNA by PCR to determine pDNA presence in the lungs and found strong evidence for pDNA presence in both lungs. Thus we provide evidence that ENaC and Nedd4-2 are involved in the transition from lung fluid secretion to fluid absorption near term and at birth. PMID- 17693486 TI - Regulation of vascular endothelial cell barrier function and cytoskeleton structure by protein phosphatases of the PPP family. AB - Reversible phosphorylation of cytoskeletal and cytoskeleton-associated proteins is a significant element of endothelial barrier function regulation. Therefore, understanding the mechanisms of phosphorylation/dephosphorylation of endothelial cell cytoskeletal proteins is vital to the treatment of severe lung disorders such as high permeability pulmonary edema. In vivo, there is a controlled balance between the activities of protein kinases and phosphatases. Due to various external or internal signals, this balance may be shifted. The actual balances at a given time alter the phosphorylation level of certain proteins with appropriate physiological consequences. The latest information about the structure and regulation of different types of Ser/Thr protein phosphatases participating in the regulation of endothelial cytoskeletal organization and barrier function will be reviewed here. PMID- 17693488 TI - Paving the road for lung stem cell biology: bronchioalveolar stem cells and other putative distal lung stem cells. AB - New discoveries in stem cell biology are making the biology of solid tissues increasingly complex. Important seminal studies demonstrating the presence of damage-resistant cell populations together with new isolation and characterization techniques suggest that stem cells exist in the adult lung. More detailed in vivo molecular and cellular characterization of bronchioalveolar stem cells (BASCs), other putative lung stem and progenitor cells, and differentiated cells is needed to determine the lineage relationships in adult lung. Lung diseases such as cystic fibrosis or chronic obstructive pulmonary disease, as well as the most common form of lung cancer in the United States, all involve apparent bronchiolar and alveolar cell defects. It is likely that the delicate balance of stem, progenitor, and differentiated cell functions in the lung is critically affected in patients with these devastating diseases. Thus the discovery of BASCs and other putative lung stem cells will lay the foundation for new inroads to understanding lung biology related to lung disease. PMID- 17693487 TI - Neonatal lung side population cells demonstrate endothelial potential and are altered in response to hyperoxia-induced lung simplification. AB - Lung side population (SP) cells are resident lung precursor cells with both epithelial and mesenchymal potential that are believed to play a role in normal lung development and repair. Neonatal hyperoxic exposure impairs lung development leading to a long-term decrease in gas exchange surfaces. The hypothesis that lung SP cells are altered during impaired lung development has not been studied. To address this issue, we characterized the endothelial potential of neonatal lung SP and subsets of lung SP from neonatal mice following hyperoxic exposure during room air recovery. Lung SP cells were isolated and sorted on the basis of their capacity to efflux Hoechst 33342. The lung SP was further sorted based on expression of Flk-1 and CD45. In vitro, both CD45(pos)/Flk-1(pos) and CD45(neg)/Flk-1(pos) bind isolectin B4 and incorporate LDL and form networks in matrigel, indicating that these populations have endothelial cell characteristics. Hyperoxic exposure of neonatal mice resulted in subtle changes in vascular and alveolar density on P13, which persisted with room air recovery to P41. During room air recovery, a decrease in lung SP cells was detected in the hyperoxic-exposed group on postnatal day 13 followed by an increase on day 41. Within this group, the lung SP subpopulation of cells expressing CD45 increased on day 21, 41, and 55. Here, we show that lung SP cells demonstrate endothelial potential and that the population distribution changes in number as well as composition following hyperoxic exposure. The hyperoxia-induced changes in lung SP cells may limit their ability to effectively contribute to tissue morphogenesis during room air recovery. PMID- 17693489 TI - Transducing particles of Staphylococcus aureus pathogenicity island SaPI1 are comprised of helper phage-encoded proteins. AB - The relationship between the composition of SaPI1 transducing particles and those of helper phage 80alpha was investigated by direct comparison of virion proteins. Twelve virion proteins were identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and mass spectrometry; all were present in both 80alpha and SaPI1 virions, and all were encoded by 80alpha. No SaPI1-encoded proteins were detected. This confirms the prediction that SaPI1 is encapsidated in a virion assembled from helper phage-encoded proteins. PMID- 17693490 TI - Biochemical and genetic investigation of initial reactions in aerobic degradation of the bile acid cholate in Pseudomonas sp. strain Chol1. AB - Bile acids are surface-active steroid compounds with toxic effects for bacteria. Recently, the isolation and characterization of a bacterium, Pseudomonas sp. strain Chol1, growing with bile acids as the carbon and energy source was reported. In this study, initial reactions of the aerobic degradation pathway for the bile acid cholate were investigated on the biochemical and genetic level in strain Chol1. These reactions comprised A-ring oxidation, activation with coenzyme A (CoA), and beta-oxidation of the acyl side chain with the C(19) steroid dihydroxyandrostadienedione as the end product. A-ring oxidizing enzyme activities leading to Delta(1,4)-3-ketocholyl-CoA were detected in cell extracts and confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Cholate activation with CoA was demonstrated in cell extracts and confirmed with a chemically synthesized standard by LC-MS/MS. A transposon mutant with a block in oxidation of the acyl side chain accumulated a steroid compound in culture supernatants which was identified as 7alpha,12alpha-dihydroxy-3-oxopregna-1,4 diene-20-carboxylate (DHOPDC) by nuclear magnetic resonance spectroscopy. The interrupted gene was identified as encoding a putative acyl-CoA-dehydrogenase (ACAD). DHOPDC activation with CoA in cell extracts of strain Chol1 was detected by LC-MS/MS. The growth defect of the transposon mutant could be complemented by the wild-type ACAD gene located on the plasmid pBBR1MCS-5. Based on these results, the initiating reactions of the cholate degradation pathway leading from cholate to dihydroxyandrostadienedione could be reconstructed. In addition, the first bacterial gene encoding an enzyme for a specific reaction step in side chain degradation of steroid compounds was identified, and it showed a high degree of similarity to genes in other steroid-degrading bacteria. PMID- 17693491 TI - Characterization of riboflavin (vitamin B2) transport proteins from Bacillus subtilis and Corynebacterium glutamicum. AB - Riboflavin (vitamin B(2)) is the direct precursor of the flavin cofactors flavin mononucleotide and flavin adenine dinucleotide, essential components of cellular biochemistry. In this work we investigated the unrelated proteins YpaA from Bacillus subtilis and PnuX from Corynebacterium glutamicum for a role in riboflavin uptake. Based on the regulation of the corresponding genes by a riboswitch mechanism, both proteins have been predicted to be involved in flavin metabolism. Moreover, their primary structures suggested that these proteins integrate into the cytoplasmic membrane. We provide experimental evidence that YpaA is a plasma membrane protein with five transmembrane domains and a cytoplasmic C terminus. In B. subtilis, riboflavin uptake was increased when ypaA was overexpressed and abolished when ypaA was deleted. Riboflavin uptake activity and the abundance of the YpaA protein were also increased when riboflavin auxotrophic mutants were grown in limiting amounts of riboflavin. YpaA-mediated riboflavin uptake was sensitive to protonophors and reduced in the absence of glucose, demonstrating that the protein requires metabolic energy for substrate translocation. In addition, we demonstrate that PnuX from C. glutamicum also is a riboflavin transporter. Transport by PnuX was not energy dependent and had high apparent affinity for riboflavin (K(m) 11 microM). Roseoflavin, a toxic riboflavin analog, appears to be a substrate of PnuX and YpaA. We propose to designate the gene names ribU for ypaA and ribM for pnuX to reflect that the encoded proteins function in riboflavin uptake and that the genes have different phylogenetic origins. PMID- 17693493 TI - The thiamine kinase (YcfN) enzyme plays a minor but significant role in cobinamide salvaging in Salmonella enterica. AB - Cobinamide (Cbi) salvaging is impaired, but not abolished, in a Salmonella enterica strain lacking a functional cobU gene. CobU is a bifunctional enzyme (NTP:adenosylcobinamide [NTP:AdoCbi] kinase, GTP:adenosylcobinamide-phosphate [GTP:AdoCbi-P] guanylyltransferase) whose AdoCbi kinase activity is necessary for Cbi salvaging in this bacterium. Inactivation of the ycfN gene in a DeltacobU strain abrogated Cbi salvaging. Introduction of a plasmid carrying the ycfN(+) allele into a DeltacobU DeltaycfN strain substantially restored Cbi salvaging. Mass spectrometry data indicate that when YcfN-enriched cell extracts were incubated with AdoCbi and ATP, the product of the reaction was AdoCbi-P. Results from bioassays confirmed that YcfN converted AdoCbi to AdoCbi-P in an ATP dependent manner. YcfN is a good example of enzymes that are used by the cell in multiple pathways to ensure the salvaging of valuable precursors. PMID- 17693492 TI - Characterization of an acid-dependent arginine decarboxylase enzyme from Chlamydophila pneumoniae. AB - Genome sequences from members of the Chlamydiales encode diverged homologs of a pyruvoyl-dependent arginine decarboxylase enzyme that nonpathogenic euryarchaea use in polyamine biosynthesis. The Chlamydiales lack subsequent genes required for polyamine biosynthesis and probably obtain polyamines from their host cells. To identify the function of this protein, the CPn1032 homolog from the respiratory pathogen Chlamydophila pneumoniae was heterologously expressed and purified. This protein self-cleaved to form a reactive pyruvoyl group, and the subunits assembled into a thermostable (alphabeta)(3) complex. The mature enzyme specifically catalyzed the decarboxylation of L-arginine, with an unusually low pH optimum of 3.4. The CPn1032 gene complemented a mutation in the Escherichia coli adiA gene, which encodes a pyridoxal 5'-phosphate-dependent arginine decarboxylase, restoring arginine-dependent acid resistance. Acting together with a putative arginine-agmatine antiporter, the CPn1032 homologs may have evolved convergently to form an arginine-dependent acid resistance system. These genes are the first evidence that obligately intracellular chlamydiae may encounter acidic conditions. Alternatively, this system could reduce the host cell arginine concentration and produce inhibitors of nitric oxide synthase. PMID- 17693494 TI - Synergistic interaction of Clostridium cellulovorans cellulosomal cellulases and HbpA. AB - Clostridium cellulovorans, an anaerobic bacterium, produces a small nonenzymatic protein called HbpA, which has a surface layer homology domain and a type I cohesin domain similar to those found in the cellulosomal scaffolding protein CbpA. In this study, we demonstrated that HbpA could bind to cell wall fragments from C. cellulovorans and insoluble polysaccharides and form a complex with cellulosomal cellulases endoglucanase B (EngB) and endoglucanase L (EngL). Synergistic degradative action of the cellulosomal cellulase and HbpA complexes was demonstrated on acid-swollen cellulose, Avicel, and corn fiber. We propose that HbpA functions to bind dockerin-containing cellulosomal enzymes to the cell surface and complements the activity of cellulosomes. PMID- 17693495 TI - Cell surface filaments of the gliding bacterium Flavobacterium johnsoniae revealed by cryo-electron tomography. AB - Flavobacterium johnsoniae cells glide rapidly over surfaces by an as-yet-unknown mechanism. Using cryo-electron tomography, we show that wild-type cells display tufts of approximately 5-nm-wide cell surface filaments that appear to be anchored to the inner surface of the outer membrane. These filaments are absent in cells of a nonmotile gldF mutant but are restored upon expression of plasmid encoded GldF, a component of a putative ATP-binding cassette transporter. PMID- 17693496 TI - Genome analysis of phage JS98 defines a fourth major subgroup of T4-like phages in Escherichia coli. AB - Numerous T4-like Escherichia coli phages were isolated from human stool and environmental wastewater samples in Bangladesh and Switzerland. The sequences of the major head gene (g23) revealed that these coliphages could be placed into four subgroups, represented by the phages T4, RB69, RB49, and JS98. Thus, JS98 defines a new major subgroup of E. coli T4-like phages. We conducted an analysis of the 169-kb JS98 genome sequence. Overall, 198 of the 266 JS98 open reading frames (ORFs) shared amino acid sequence identity with the reference T4 phage, 41 shared identity with other T4-like phages, and 27 ORFs lacked any database matches. Genes on the plus strand encoded virion proteins, which showed moderate to high sequence identity with T4 proteins. The right genome half of JS98 showed a higher degree of sequence conservation with T4 and RB69, even for the nonstructural genes, than did the left genome half, containing exclusively nonstructural genes. Most of the JS98-specific genes were found in the left genome half. Two came as a hypervariability cluster, but most represented isolated genes, suggesting that they were acquired separately in multiple acquisition events. No evidence for DNA exchange between JS98 phage and the E. coli host genome or coliphages other than T4 was observed. No undesired genes which could compromise its medical use were detected in the JS98 genome sequence. PMID- 17693497 TI - Complex formation by the mrpABCDEFG gene products, which constitute a principal Na+/H+ antiporter in Bacillus subtilis. AB - The Bacillus subtilis Mrp (also referred to as Sha) is a particularly unusual Na(+)/H(+) antiporter encoded by mrpABCDEFG. Using His tagging of Mrp proteins, we showed complex formation by the mrpABCDEFG gene products by pull-down and blue native polyacrylamide gel electrophoresis analyses. This is the first molecular evidence that the Mrp is a multicomponent antiporter in the cation-proton antiporter 3 family. PMID- 17693498 TI - Quorum-sensing regulation of the production of Blp bacteriocins in Streptococcus thermophilus. AB - The blp gene cluster identified in the genome sequences of Streptococcus thermophilus (blp(St)) LMG18311, CNRZ1066, and LMD-9 displays all the characteristics of a class II bacteriocin locus. In the present study, we showed that the blp(St) locus is only fully functional in strain LMD-9 and regulates the production of antimicrobial peptides that inhibit strains LMG18311 and CNRZ1066. The blp(St) cluster of LMD-9 contains 23 genes that are transcriptionally organized in six operons: blpABC(St) (peptide transporter genes and pheromone gene); blpRH(St) (two-component regulatory system genes); blpD(St)-orf1, blpU(St) orf3, and blpE-F(St) (bacteriocin precursors and immunity genes); and blpG-X(St) (unknown function). All the operons, except the regulatory unit blpRH(St), were shown to be coregulated at the transcriptional level by a quorum-sensing mechanism involving the mature S. thermophilus pheromone BlpC* (BlpC*(St)), which was extracellularly detected as two active forms (30 and 19 amino acids). These operons are differentially transcribed depending on growth phase and pheromone concentration. They all contain a motif with two imperfect direct repeats in their mapped promoter regions that could serve as binding sites of the response regulator BlpR(St). Through the construction of deletion mutants, the blp(St) locus of strain LMD-9 was shown to encode all the essential functions associated with bacteriocin production, quorum-sensing regulation, and immunity. PMID- 17693499 TI - Maintaining the transcription factor SpoIIID level late during sporulation causes spore defects in Bacillus subtilis. AB - During sporulation of Bacillus subtilis, four regulatory proteins act in the order sigma(E), SpoIIID, sigma(K), and GerE to temporally control gene expression in the mother cell. sigma(E) and sigma(K) work sequentially with core RNA polymerase to transcribe different sets of genes. SpoIIID and GerE are small, sequence-specific DNA-binding proteins that activate or repress transcription of many genes. Previous studies showed that transcriptionally active sigma(K) RNA polymerase inhibits early mother cell gene expression, reducing accumulation of SpoIIID late in sporulation. Here, the effects of perturbing the mother cell gene regulatory network by maintaining the SpoIIID level late during sporulation are reported. Persistent expression was obtained by fusing spoIIID to the sigma(K) controlled gerE promoter on a multicopy plasmid. Fewer heat- and lysozyme resistant spores were produced by the strain with persistent spoIIID expression, but the number of spores resistant to organic solvents was unchanged, as was their germination ability. Transmission electron microscopy showed structural defects in the spore coat. Reporter fusions to sigma(K)-dependent promoters showed lower expression of gerE and cotC and higher expression of cotD. Altered expression of cot genes, which encode spore coat proteins, may account for the spore structural defects. These results suggest that one role of negative feedback by sigma(K) RNA polymerase on early mother cell gene expression is to lower the level of SpoIIID late during sporulation in order to allow normal expression of genes in the sigma(K) regulon. PMID- 17693500 TI - Identification of the origin of transfer (oriT) and DNA relaxase required for conjugation of the integrative and conjugative element ICEBs1 of Bacillus subtilis. AB - Integrative and conjugative elements (ICEs), also known as conjugative transposons, are mobile genetic elements that can transfer from one bacterial cell to another by conjugation. ICEBs1 is integrated into the trnS-leu2 gene of Bacillus subtilis and is regulated by the SOS response and the RapI-PhrI cell cell peptide signaling system. When B. subtilis senses DNA damage or high concentrations of potential mating partners that lack the element, ICEBs1 excises from the chromosome and can transfer to recipients. Bacterial conjugation usually requires a DNA relaxase that nicks an origin of transfer (oriT) on the conjugative element and initiates the 5'-to-3' transfer of one strand of the element into recipient cells. The ICEBs1 ydcR (nicK) gene product is homologous to the pT181 family of plasmid DNA relaxases. We found that transfer of ICEBs1 requires nicK and identified a cis-acting oriT that is also required for transfer. Expression of nicK leads to nicking of ICEBs1 between a GC-rich inverted repeat in oriT, and NicK was the only ICEBs1 gene product needed for nicking. NicK likely mediates conjugation of ICEBs1 by nicking at oriT and facilitating the translocation of a single strand of ICEBs1 DNA through a transmembrane conjugation pore. PMID- 17693501 TI - Site-directed mutagenesis studies of tn5 transposase residues involved in synaptic complex formation. AB - Transposition (the movement of discrete segments of DNA, resulting in rearrangement of genomic DNA) initiates when transposase forms a dimeric DNA protein synaptic complex with transposon DNA end sequences. The synaptic complex is a prerequisite for catalytic reactions that occur during the transposition process. The transposase-DNA interactions involved in the synaptic complex have been of great interest. Here we undertook a study to verify the protein-DNA interactions that lead to synapsis in the Tn5 system. Specifically, we studied (i) Arg342, Glu344, and Asn348 and (ii) Ser438, Lys439, and Ser445, which, based on the previously published cocrystal structure of Tn5 transposase bound to a precleaved transposon end sequence, make cis and trans contacts with transposon end sequence DNA, respectively. By using genetic and biochemical assays, we showed that in all cases except one, each of these residues plays an important role in synaptic complex formation, as predicted by the cocrystal structure. PMID- 17693502 TI - Proteins P24 and P41 function in the regulation of terminal-organelle development and gliding motility in Mycoplasma pneumoniae. AB - Mycoplasma pneumoniae is a major cause of bronchitis and atypical pneumonia in humans. This cell wall-less bacterium has a complex terminal organelle that functions in cytadherence and gliding motility. The gliding mechanism is unknown but is coordinated with terminal-organelle development during cell division. Disruption of M. pneumoniae open reading frame MPN311 results in loss of protein P41 and downstream gene product P24. P41 localizes to the base of the terminal organelle and is required to anchor the terminal organelle to the cell body, but during cell division, MPN311 insertion mutants also fail to properly regulate nascent terminal-organelle development spatially or gliding activity temporally. We measured gliding velocity and frequency and used fluorescent protein fusions and time-lapse imaging to assess the roles of P41 and P24 individually in terminal-organelle development and gliding function. P41 was necessary for normal gliding velocity and proper spatial positioning of new terminal organelles, while P24 was required for gliding frequency and new terminal-organelle formation at wild-type rates. However, P41 was essential for P24 function, and in the absence of P41, P24 exhibited a dynamic localization pattern. Finally, protein P28 requires P41 for stability, but analysis of a P28(-) mutant established that the MPN311 mutant phenotype was not a function of loss of P28. PMID- 17693503 TI - Sequence analysis of the Staphylococcus aureus srrAB loci reveals that truncation of srrA affects growth and virulence factor expression. AB - The SrrAB system regulates metabolism and virulence factors in Staphylococcus aureus. We sequenced the srrAB loci of 21 isolates and performed a phylogenetic analysis. Vaginal and bovine isolates clustered together, while skin isolates were genetically diverse. Few nucleotide polymorphisms were observed, and most were synonymous. Two strains (N2 and N19) with N-terminal truncations in SrrA displayed defects in growth and abnormally upregulated virulence factor expression under low-oxygen conditions. PMID- 17693504 TI - Osmolality, temperature, and membrane lipid composition modulate the activity of betaine transporter BetP in Corynebacterium glutamicum. AB - The gram-positive soil bacterium Corynebacterium glutamicum, a major amino acid producing microorganism in biotechnology, is equipped with several osmoregulated uptake systems for compatible solutes, which is relevant for the physiological response to osmotic stress. The most significant carrier, BetP, is instantly activated in response to an increasing cytoplasmic K(+) concentration. Importantly, it is also activated by chill stress independent of osmotic stress. We show that the activation of BetP by both osmotic stress and chill stress is altered in C. glutamicum cells grown at and adapted to low temperatures. BetP from cold-adapted cells is less sensitive to osmotic stress. In order to become susceptible for chill activation, cold-adapted cells in addition needed a certain amount of osmotic stimulation, indicating that there is cross talk of these two types of stimuli at the level of BetP activity. We further correlated the change in BetP regulation properties in cells grown at different temperatures to changes in the lipid composition of the plasma membrane. For this purpose, the glycerophospholipidome of C. glutamicum grown at different temperatures was analyzed by mass spectrometry using quantitative multiple precursor ion scanning. The molecular composition of glycerophospholipids was strongly affected by the growth temperature. The modulating influence of membrane lipid composition on BetP function was further corroborated by studying the influence of artificial modulation of membrane dynamics by local anesthetics and the lack of a possible influence of internally accumulated betaine on BetP activity. PMID- 17693505 TI - Essential internal promoter in the spoIIIA locus of Bacillus subtilis. AB - The Bacillus subtilis spoIIIA locus encodes eight proteins, SpoIIIAA to SpoIIIAH, which are expressed in the mother cell during endospore formation and which are essential for the activation of sigma(G) in the forespore. Complementation studies indicated that this locus may be transcribed from two promoters, one promoter upstream from the first gene and possibly a second unidentified promoter within the locus. Fragments of the spoIIIA locus were expressed at an ectopic site to complement the sporulation-defective phenotype of a spoIIIAH deletion, and we determined that complementation required a fragment of DNA that extended into spoIIIAF. To confirm that there was a promoter located in spoIIIAF, we constructed transcriptional fusions to lacZ and found strong sporulation-induced promoter activity. Primer extension assays were used to determine the transcription start site, and point mutations introduced into the -10 and -35 regions of the promoter reduced its activity. This promoter is transcribed by sigma(E)-RNA polymerase and is repressed by SpoIIID. Therefore, we concluded that the spoIIIA locus is transcribed from two promoters, one at the start of the locus (P1(spoIIIA)) and the other within the locus (P2(spoIIIA)). Based on Campbell integrations and reverse transcription-PCR analysis of the P2(spoIIIA) region, we determined that P2(spoIIIA) is sufficient for transcription of spoIIIAG and spoIIIAH. Inactivation of P2(spoIIIA) blocked spore formation, indicating that P2(spoIIIA) is essential for expression of spoIIIAG and spoIIIAH. The P2(spoIIIA) activity is twice the P1(spoIIIA) activity; therefore, larger amounts of SpoIIIAG and SpoIIIAH than of proteins encoded at the upstream end of the locus may be required. PMID- 17693506 TI - PhoPQ-mediated regulation produces a more robust permeability barrier in the outer membrane of Salmonella enterica serovar typhimurium. AB - The PhoPQ two-component system of Salmonella enterica serovar Typhimurium produces a remodeling of the lipid A domain of the lipopolysaccharide, including the PagP-catalyzed addition of palmitoyl residue, the PmrAB-regulated addition of the cationic sugar 4-aminoarabinose and phosphoethanolamine, and the LpxO catalyzed addition of a 2-OH group onto one of the fatty acids. By using the diffusion rates of the dyes ethidium, Nile red, and eosin Y across the outer membrane, as well as the susceptibility of cells to large, lipophilic agents, we evaluated the function of this membrane as a permeability barrier. We found that the remodeling process in PhoP-constitutive strains produces an outer membrane that serves as a very effective permeability barrier in an environment that is poor in divalent cations or that contains cationic peptides, whereas its absence in phoP null mutants produces an outer membrane severely compromised in its barrier function under these conditions. Removing combinations of the lipid A remodeling functions from a PhoP-constitutive strain showed that the known modification reactions explain a major part of the PhoPQ-regulated changes in permeability. We believe that the increased barrier property of the remodeled bilayer is important in making the pathogen more resistant to the stresses that it encounters in the host, including attack by the cationic antimicrobial peptides. On the other hand, drug-induced killing assays suggest that the outer membrane containing unmodified lipid A may serve as a better barrier in the presence of high concentrations (e.g., 5 mM) of Mg(2+). PMID- 17693507 TI - Transcriptional regulation of stress response and motility functions in Helicobacter pylori is mediated by HspR and HrcA. AB - The hrcA and hspR genes of Helicobacter pylori encode two transcriptional repressor proteins that negatively regulate expression of the groES-groEL and hrcA-grpE-dnaK operons. While HspR was previously shown to bind far upstream of the promoters transcribing these operons, the binding sites of HrcA were not identified. Here, we demonstrate by footprinting analysis that HrcA binds to operator elements similar to the so-called CIRCE sequences overlapping both promoters. Binding of HspR and HrcA to their respective operators occurs in an independent manner, but the DNA binding activity of HrcA is increased in the presence of GroESL, suggesting that the GroE chaperonin system corepresses transcription together with HrcA. Comparative transcriptome analysis of the wild type strain and hspR and hrcA singly and doubly deficient strains revealed that a set of 14 genes is negatively regulated by the action of one or both regulators, while a set of 29 genes is positively regulated. While both positive and negative regulation of transcription by HspR and/or HrcA could be confirmed by RNA primer extension analyses for two representative genes, binding of either regulator to the promoters could not be detected, indicating that transcriptional regulation at these promoters involves indirect mechanisms. Strikingly, 14 of the 29 genes which were found to be positively regulated by HspR or HrcA code for proteins involved in flagellar biosynthesis. Accordingly, loss of motility functions was observed for HspR and HrcA single or double mutants. The possible regulatory intersections of the heat shock response and flagellar assembly are discussed. PMID- 17693508 TI - Cwp84, a surface-associated protein of Clostridium difficile, is a cysteine protease with degrading activity on extracellular matrix proteins. AB - Clostridium difficile pathogenicity is mediated mainly by its A and B toxins, but the colonization process is thought to be a necessary preliminary step in the course of infection. The aim of this study was to characterize the Cwp84 protease of C. difficile, which is highly immunogenic in patients with C. difficile associated disease and is potentially involved in the pathogenic process. Cwp84 was purified as a recombinant His-tagged protein, and specific antibodies were generated in rabbits. Treatment of multiple-band-containing eluted fractions with a reducing agent or with trypsin led to accumulation of a unique protein species with an estimated molecular mass of 61 kDa, corresponding most likely to mature autoprocessed Cwp84 (mCwp84). mCwp84 showed concentration-dependent caseinolytic activity, with maximum activity at pH 7.5. The Cwp84 activity was inhibited by various cysteine protease inhibitors, such as the specific inhibitor E64, and the anti-Cwp84-specific antibodies. Using fractionation experiments followed by immunoblot detection, the protease was found to be associated with the S-layer proteins, mostly as a nonmature species. Proteolytic assays were performed with extracellular matrix proteins to assess the putative role of Cwp84 in the pathogenicity of C. difficile. No degrading activity was detected with type IV collagen. In contrast, Cwp84 exhibited degrading activity with fibronectin, laminin, and vitronectin, which was neutralized by the E64 inhibitor and specific antibodies. In vivo, this proteolytic activity could contribute to the degradation of the host tissue integrity and to the dissemination of the infection. PMID- 17693509 TI - Structure of the Haemophilus influenzae HMW1B translocator protein: evidence for a twin pore. AB - Secretion of the Haemophilus influenzae HMW1 adhesin occurs via the two-partner secretion pathway and requires the HMW1B outer membrane translocator. HMW1B has been subjected to extensive biochemical studies to date. However, direct examination of the structure of HMW1B has been lacking, leaving fundamental questions about the oligomeric state, the membrane-embedded beta-barrel domain, the approximate size of the beta-barrel pore, and the mechanism of translocator activity. In the current study, examination of purified HMW1B by size exclusion chromatography and negative staining electron microscopy revealed that the predominant species was a dimer. In the presence of lipid, purified HMW1B formed two-dimensional crystalline sheets. Examination of these crystals by cryo electron microscopy allowed determination of a projection structure of HMW1B to 10 A resolution. The native HMW1B structure is a dimer of beta-barrels, with each beta-barrel measuring 40 A by 50 A in the two orthogonal directions and appearing largely occluded, leaving only a narrow pore. These observations suggest that HMW1B undergoes a large conformational change during translocation of the 125-kDa HMW1 adhesin. PMID- 17693510 TI - Mutations in type I and type IV pilus biosynthetic genes affect twitching motility rates in Xylella fastidiosa. AB - Xylella fastidiosa possesses both type I and type IV pili at the same cell pole. By use of a microfluidic device, the speed of twitching movement by wild-type cells on a glass surface against the flow direction of media was measured as 0.86 (standard error [SE], 0.04) microm min(-1). A type I pilus mutant (fimA) moved six times faster (4.85 [SE, 0.27] microm min(-1)) and a pilY1 mutant moved three times slower (0.28 [SE, 0.03] microm min(-1)) than wild-type cells. Type I pili slow the rate of movement, while the putative type IV pilus protein PilY1 is likely important for attachment to surfaces. PMID- 17693511 TI - The T4 RI antiholin has an N-terminal signal anchor release domain that targets it for degradation by DegP. AB - Lysis inhibition (LIN) of T4-infected cells was one of the foundational experimental systems for modern molecular genetics. In LIN, secondary infection of T4-infected cells results in a dramatically protracted infection cycle in which intracellular phage and endolysin accumulation can continue for hours. At the molecular level, this is due to the inhibition of the holin, T, by the antiholin, RI. RI is only 97 residues and contains an N-terminal hydrophobic domain and a C-terminal hydrophilic domain; expression of the latter domain fused to a secretory signal sequence is sufficient to impose LIN, due to its specific interaction with the periplasmic domain of the T holin. Here we show that the N terminal sequence comprises a signal anchor release (SAR) domain, which causes the secretion of RI in a membrane-tethered form and then its subsequent release into the periplasm, without proteolytic processing. Moreover, the SAR domain confers both functional lability and DegP-mediated proteolytic instability on the released form of RI, although LIN is not affected in a degP host. These results are discussed in terms of a model for the activation of RI in the establishment of the LIN state. PMID- 17693512 TI - Recombining population structure of Plesiomonas shigelloides (Enterobacteriaceae) revealed by multilocus sequence typing. AB - Plesiomonas shigelloides is an emerging pathogen that is widespread in the aquatic environment and is responsible for intestinal diseases and extraintestinal infections in humans and other animals. Virtually nothing is known about its genetic diversity, population structure, and evolution, which severely limits epidemiological control. We addressed these questions by developing a multilocus sequence typing (MLST) system based on five genes (fusA, leuS, pyrG, recG, and rpoB) and analyzing 77 epidemiologically unrelated strains from several countries and several ecological sources. The phylogenetic position of P. shigelloides within family Enterobacteriaceae was precisely defined by phylogenetic analysis of the same gene portions in other family members. Within P. shigelloides, high levels of nucleotide diversity (average percentage of nucleotide differences between strains, 1.49%) and genotypic diversity (64 distinct sequence types; Simpson's index, 99.7%) were found, with no salient internal phylogenetic structure. We estimated that homologous recombination in housekeeping genes affects P. shigelloides alleles and nucleotides 7 and 77 times more frequently than mutation, respectively. These ratios are similar to those observed in the naturally transformable species Streptococcus pneumoniae with a high rate of recombination. In contrast, recombination within Salmonella enterica, Escherichia coli, and Yersinia enterocolitica was much less frequent. P. shigelloides thus stands out among members of the Enterobacteriaceae. Its high rate of recombination results in a lack of association between genomic background and O and H antigenic factors, as observed for the 51 serotypes found in our sample. Given its robustness and discriminatory power, we recommend MLST as a reference method for population biology studies and epidemiological tracking of P. shigelloides strains. PMID- 17693513 TI - Organization of the aerotaxis receptor aer in the membrane of Escherichia coli. AB - The Aer receptor guides Escherichia coli to specific oxygen and energy-generating niches. The input sensor in Aer is a flavin adenine dinucleotide-binding PAS domain, which is separated from a HAMP/signaling output domain by two membrane spanning segments that flank a short (four-amino-acid) periplasmic loop. In this study, we determined the overall membrane organization of Aer by introducing combinations of residues that allowed us to differentiate intradimeric collisions from interdimeric collisions. Collisions between proximal residues in the membrane anchor were exclusively intra- or interdimeric but, with one exception, not both. Cross-linking profiles were consistent, with a rigid rather than flexible periplasmic loop and a tilted TM2 helix that crossed TM2' at residue V197C, near the center of the lipid bilayer. The periplasmic loop formed a stable neighborhood that (i) included a maximum of three Aer dimers, (ii) did not swap neighbors over time, and (iii) appeared to be constrained by interactions in the cytosolic signaling domain. PMID- 17693514 TI - Defining the stressome of Mycobacterium avium subsp. paratuberculosis in vitro and in naturally infected cows. AB - Mycobacterium avium subsp. paratuberculosis causes an enteric infection in cattle, with a great impact on the dairy industry in the United States and worldwide. Characterizing the gene expression profile of M. avium subsp. paratuberculosis exposed to different stress conditions, or shed in cow feces, could improve our understanding of the pathogenesis of M. avium subsp. paratuberculosis. In this report, the stress response of M. avium subsp. paratuberculosis on a genome-wide level (stressome) was defined for the first time using DNA microarrays. Expression data analysis revealed unique gene groups of M. avium subsp. paratuberculosis that were regulated under in vitro stressors while additional groups were regulated in the cow samples. Interestingly, acidic pH induced the regulation of a large number of genes (n=597), suggesting the high sensitivity of M. avium subsp. paratuberculosis to acidic environments. Generally, responses to heat shock, acidity, and oxidative stress were similar in M. avium subsp. paratuberculosis and Mycobacterium tuberculosis, suggesting common pathways for mycobacterial defense against stressors. Several sigma factors (e.g., sigH and sigE) were differentially coregulated with a large number of genes depending on the type of each stressor. Subsequently, we analyzed the virulence of six M. avium subsp. paratuberculosis mutants with inactivation of differentially regulated genes using a murine model of paratuberculosis. Both bacterial and histopathological examinations indicated the attenuation of all gene mutants, especially those selected based on their expression in the cow samples (e.g., lipN). Overall, the employed approach profiled mycobacterial genetic networks triggered by variable stressors and identified a novel set of putative virulence genes. A similar approach could be applied to analyze other intracellular pathogens. PMID- 17693515 TI - Short-tailed stx phages exploit the conserved YaeT protein to disseminate Shiga toxin genes among enterobacteria. AB - Infection of Escherichia coli by Shiga toxin-encoding bacteriophages (Stx phages) was the pivotal event in the evolution of the deadly Shiga toxin-encoding E. coli (STEC), of which serotype O157:H7 is the most notorious. The number of different bacterial species and strains reported to produce Shiga toxin is now more than 500, since the first reported STEC infection outbreak in 1982. Clearly, Stx phages are spreading rapidly, but the underlying mechanism for this dissemination has not been explained. Here we show that an essential and highly conserved gene product, YaeT, which has an essential role in the insertion of proteins in the gram-negative bacterial outer membrane, is the surface molecule recognized by the majority (ca. 70%) of Stx phages via conserved tail spike proteins associated with a short-tailed morphology. The yaeT gene was initially identified through complementation, and its role was confirmed in phage binding assays with and without anti-YaeT antiserum. Heterologous cloning of E. coli yaeT to enable Stx phage adsorption to Erwinia carotovora and the phage adsorption patterns of bacterial species possessing natural yaeT variants further supported this conclusion. The use of an essential and highly conserved protein by the majority of Stx phages is a strategy that has enabled and promoted the rapid spread of shigatoxigenic potential throughout multiple E. coli serogroups and related bacterial species. Infection of commensal bacteria in the mammalian gut has been shown to amplify Shiga toxin production in vivo, and the data from this study provide a platform for the development of a therapeutic strategy to limit this YaeT-mediated infection of the commensal flora. PMID- 17693516 TI - Host protein binding and adhesive properties of H6 and H7 flagella of attaching and effacing Escherichia coli. AB - It had been suggested that the flagella of enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) might contribute to host colonization. In this study, we set out to investigate the adhesive properties of H7 and H6 flagella. We studied the abilities of EHEC EDL933 (O157:H7) and EPEC E2348/69 (O127:H6) flagella to bind to bovine mucus, host proteins such as mucins, and extracellular matrix proteins. Through several approaches, we found that H6 and H7 flagella and their flagellin monomers bind to mucins I and II and to freshly isolated bovine mucus. A genetic approach showed that EHEC and EPEC fliC deletion mutants were significantly less adherent to bovine intestinal tissue than the parental wild-type strains. In addition, we found that EPEC bacteria and H6 flagella, but not EHEC, bound largely, in a dose-dependent manner, to collagen and to a lesser extent to laminin and fibronectin. We also report that EHEC O157:H7 strains agglutinate rabbit red blood cells via their flagella, a heretofore unknown phenotype in this pathogroup. Collectively, our data demonstrate that the H6 and H7 flagella possess adhesive properties, particularly the ability to bind mucins, that may contribute to colonization of mucosal surfaces. PMID- 17693517 TI - Binary toxin production in Clostridium difficile is regulated by CdtR, a LytTR family response regulator. AB - Clostridium difficile binary toxin (CDT) is an actin-specific ADP ribosyltransferase that is produced by various C. difficile isolates, including the "hypervirulent" NAP1/027 epidemic strains. In contrast to the two major toxins from C. difficile, toxin A and toxin B, little is known about the role of CDT in virulence or how C. difficile regulates its production. In this study we have shown that in addition to the cdtA and cdtB toxin structural genes, a functional cdt locus contains a third gene, here designated cdtR, which is predicted to encode a response regulator. By introducing functional binary toxin genes into cdtR(+) and cdtR-negative strains of C. difficile, it was established that the CdtR protein was required for optimal expression of binary toxin. Significantly increased expression of functional binary toxin was observed in the presence of a functional cdtR gene; an internal deletion within cdtR resulted in a reduction in binary toxin production to basal levels. Strains that did not carry intact cdtAB genes or cdtAB pseudogenes also did not have cdtR, with the entire cdt locus, or CdtLoc, being replaced by a conserved 68-bp sequence. These studies have shown for the first time that binary toxin production is subject to strict regulatory control by the response regulator CdtR, which is a member of the LytTR family of response regulators and is related to the AgrA protein from Staphylococcus aureus. PMID- 17693519 TI - Nanoscale visualization of a fibrillar array in the cell wall of filamentous cyanobacteria and its implications for gliding motility. AB - Many filamentous cyanobacteria are motile by gliding, which requires attachment to a surface. There are two main theories to explain the mechanism of gliding. According to the first, the filament is pushed forward by small waves that pass along the cell surface. In the second, gliding is powered by the extrusion of slime through pores surrounding each cell septum. We have previously shown that the cell walls of several motile cyanobacteria possess an array of parallel fibrils between the peptidoglycan and the outer membrane and have speculated that the function of this array may be to generate surface waves to power gliding. Here, we report on a study of the cell surface topography of two morphologically different filamentous cyanobacteria, using field emission gun scanning electron microscopy (FEGSEM) and atomic force microscopy (AFM). FEGSEM and AFM images of Oscillatoria sp. strain A2 confirmed the presence of an array of fibrils, visible as parallel corrugations on the cell surface. These corrugations were also visualized by AFM scanning of fully hydrated filaments under liquid; this has not been achieved before for filamentous bacteria. FEGSEM images of Nostoc punctiforme revealed a highly convoluted, not parallel, fibrillar array. We conclude that an array of parallel fibrils, beneath the outer membrane of Oscillatoria, may function in the generation of thrust in gliding motility. The array of convoluted fibrils in N. punctiforme may have an alternative function, perhaps connected with the increase in outer membrane surface area resulting from the presence of the fibrils. PMID- 17693518 TI - The alcohol dehydrogenase gene adhA in Corynebacterium glutamicum is subject to carbon catabolite repression. AB - Corynebacterium glutamicum has recently been shown to grow on ethanol as a carbon and energy source and to possess high alcohol dehydrogenase (ADH) activity when growing on this substrate and low ADH activity when growing on ethanol plus glucose or glucose alone. Here we identify the C. glutamicum ADH gene (adhA), analyze its transcriptional organization, and investigate the relevance of the transcriptional regulators of acetate metabolism RamA and RamB for adhA expression. Sequence analysis of adhA predicts a polypeptide of 345 amino acids showing up to 57% identity with zinc-dependent ADH enzymes of group I. Inactivation of the chromosomal adhA gene led to the inability to grow on ethanol and to the absence of ADH activity, indicating that only a single ethanol oxidizing ADH enzyme is present in C. glutamicum. Transcriptional analysis revealed that the C. glutamicum adhA gene is monocistronic and that its expression is repressed in the presence of glucose and of acetate in the growth medium, i.e., that adhA expression is subject to catabolite repression. Further analyses revealed that RamA and RamB directly bind to the adhA promoter region, that RamA is essential for the expression of adhA, and that RamB exerts a negative control on adhA expression in the presence of glucose or acetate in the growth medium. However, since the glucose- and acetate-dependent down-regulation of adhA expression was only partially released in a RamB-deficient mutant, there might be an additional regulator involved in the catabolite repression of adhA. PMID- 17693520 TI - Contribution of the FtsQ transmembrane segment to localization to the cell division site. AB - The Escherichia coli cell division protein FtsQ is a central component of the divisome. FtsQ is a bitopic membrane protein with a large C-terminal periplasmic domain. In this work we investigated the role of the transmembrane segment (TMS) that anchors FtsQ in the cytoplasmic membrane. A set of TMS mutants was made and analyzed for the ability to complement an ftsQ mutant. Study of the various steps involved in FtsQ biogenesis revealed that one mutant (L29/32R;V38P) failed to functionally insert into the membrane, whereas another mutant (L29/32R) was correctly assembled and interacted with FtsB and FtsL but failed to localize efficiently to the cell division site. Our results indicate that the FtsQ TMS plays a role in FtsQ localization to the division site. PMID- 17693521 TI - Cj0011c, a periplasmic single- and double-stranded DNA-binding protein, contributes to natural transformation in Campylobacter jejuni. AB - Campylobacter jejuni is an important bacterial pathogen causing gastroenteritis in humans. C. jejuni is capable of natural transformation, which is considered a major mechanism mediating horizontal gene transfer and generating genetic diversity. Despite recent efforts to elucidate the transformation mechanisms of C. jejuni, the process of DNA binding and uptake in this organism is still not well understood. In this study, we report a previously unrecognized DNA-binding protein (Cj0011c) in C. jejuni that contributes to natural transformation. Cj0011c is a small protein (79 amino acids) with a partial sequence homology to the C-terminal region of ComEA in Bacillus subtilis. Cj0011c bound to both single and double-stranded DNA. The DNA-binding activity of Cj0011c was demonstrated with a variety of DNAs prepared from C. jejuni or Escherichia coli, suggesting that the DNA binding of Cj0011c is not sequence dependent. Deletion of the cj0011c gene from C. jejuni resulted in 10- to 50-fold reductions in the natural transformation frequency. Different from the B. subtilis ComEA, which is an integral membrane protein, Cj0011c is localized in the periplasmic space of C. jejuni. These results indicate that Cj0011c functions as a periplasmic DNA receptor contributing to the natural transformation of C. jejuni. PMID- 17693523 TI - Celiac disease: are endomysial antibody test results being used appropriately? AB - BACKGROUND: The aim of this study was to retrospectively examine how positive IgA endomysial antibody (EMA) test results for celiac disease were being interpreted and acted on by physicians in the Calgary Health Region. METHODS: We reviewed consecutive EMA test results, with or without a serum IgA, obtained during a 17 month period. Seropositive tests were cross-referenced to the surgical database to determine the number of patients who underwent intestinal biopsy and the results of the biopsy. We sent questionnaires to the ordering physicians of positive tests with no record of intestinal biopsy. RESULTS: Among 11,716 EMA tests in 9533 patients, 349 results were positive in 313 patients (3%). Intestinal biopsies were performed in 218 (70%) of the seropositive patients; 194 of them were diagnostic of celiac disease. Celiac disease was also found in 10 EMA-negative patients. Of the 109 positive tests performed in 95 patients with no subsequent biopsy, 28 had appropriate indications to not perform a biopsy; the most common reason being that the test had been ordered to follow up on a previous biopsy-proven diagnosis of celiac disease (n = 21). For 33 other positive test results without a subsequent biopsy, management appeared to be inappropriate, most commonly (n = 21) because of a recommendation to follow a gluten-free diet despite lack of a tissue diagnosis of celiac disease. For the remaining 48 positive EMA results, administrative issues prevented evaluation (n = 19), the patients refused further evaluation (n = 11), or physician surveys were not returned (n = 18). CONCLUSIONS: Celiac disease affected 2% of patients, with a similar prevalence in male and female patients. Most positive EMA tests (77%) were appropriately managed by physicians. Beginning a gluten-free diet without biopsy or failing to follow up on a positive EMA test remain common errors of management. PMID- 17693522 TI - Characterization and biological role of the O-polysaccharide gene cluster of Yersinia enterocolitica serotype O:9. AB - Yersinia enterocolitica serotype O:9 is a gram-negative enteropathogen that infects animals and humans. The role of lipopolysaccharide (LPS) in Y. enterocolitica O:9 pathogenesis, however, remains unclear. The O:9 LPS consists of lipid A to which is linked the inner core oligosaccharide, serving as an attachment site for both the outer core (OC) hexasaccharide and the O polysaccharide (OPS; a homopolymer of N-formylperosamine). In this work, we cloned the OPS gene cluster of O:9 and identified 12 genes organized into four operons upstream of the gnd gene. Ten genes were predicted to encode glycosyltransferases, the ATP-binding cassette polysaccharide translocators, or enzymes required for the biosynthesis of GDP-N-formylperosamine. The two remaining genes within the OPS gene cluster, galF and galU, were not ascribed a clear function in OPS biosynthesis; however, the latter gene appeared to be essential for O:9. The biological functions of O:9 OPS and OC were studied using isogenic mutants lacking one or both of these LPS parts. We showed that OPS and OC confer resistance to human complement and polymyxin B; the OPS effect on polymyxin B resistance could be observed only in the absence of OC. PMID- 17693524 TI - Integrated strategy for fast and automated molecular characterization of genes involved in craniosynostosis. AB - BACKGROUND: Craniosynostosis, the premature fusion of 1 or more sutures of the skull, is a common congenital defect, with a prevalence of 1 in 2500 live births. Untreated progressive craniosynostosis leads to inhibition of brain growth and increased intracranial and intraorbital pressure. The heterogeneity of clinical phenotypes and the overlap of the various associated syndromes render the correct diagnosis of the different craniosynostoses particularly difficult. METHODS: To identify 10 common mutations in the genes for fibroblast growth factor receptors 2 and 3 (FGFR2 and FGFR3), we developed a microelectronic microchip assay that exploited the PCR multiplexing format and coupled it with serial addressing and probe hybridization on the same pad. For the molecular characterization of patients who tested negative in the microchip screening, we also developed conditions for denaturing HPLC (DHPLC) analysis of the most mutated regions of FGFR2 and FGFR3 and the entire coding region of the TWIST1 gene. RESULTS: In our cohort of 159 patients with various craniosynostosis syndromes, mutations were found in 100% of patients with Apert syndrome, 83.3% with Pfeiffer syndrome, 72.7% with Crouzon syndrome, 50.0% with Saethre-Chotzen syndrome, 27.7% with plagiocephaly, 31.8% with brachicephaly, 20% of complex cases, and 6.9% of mixed cases. No mutations were found in syndromic cases. CONCLUSIONS: The combined microchip-DHPLC strategy allows rapid and specific molecular diagnosis of craniosynostosis and is an effective tool for the medical and surgical management of these common congenital anomalies in a newborn or an infant with a developmental defect of the cranial vault. PMID- 17693525 TI - Pseudoxanthoma elasticum: genetic variations in antioxidant genes are risk factors for early disease onset. AB - BACKGROUND: Pseudoxanthoma elasticum (PXE) is a rare hereditary disorder characterized by progressive calcification and fragmentation of elastic fibers in connective tissues. PXE is caused by mutations in the ABCC6 gene, which encodes the membrane transporter multidrug resistance-associated protein 6. Chronic oxidative stress was recently suggested to play a crucial role in the pathogenesis of the disease. Our aim was to investigate the association of PXE with genetic variation in genes coding for antioxidant enzymes. METHODS: We used restriction fragment length polymorphism and allele-specific PCR analyses to evaluate the distribution of single-nucleotide polymorphisms in the genes encoding catalase (CAT), superoxide dismutase 2 (SOD2), and glutathione peroxidase 1 (GPX1) in DNA samples from 117 German PXE patients and 117 healthy age- and sex-matched control individuals. RESULTS: The investigated genetic variants had previously been shown to affect the activities of these antioxidant enzymes. We found a correlation between genotype and age of disease onset for polymorphisms in CAT (c.-262C>T), SOD2 (c.47C>T), and GPX1 (c.593C>T). Furthermore, the age of disease onset was inversely correlated with the number of mutated alleles, indicating a cumulative effect on the time of disease onset [mean (SD) age of 40.9 (13.6) years, 32.4 (16.3) years, and 25.7 (15.9) years for carriers of 0, 1-2, and >2 mutated alleles, respectively; P = 0.03]. CONCLUSION: Our findings demonstrate that increased oxidative stress due to activity affecting polymorphisms in genes encoding antioxidant enzymes leads to earlier PXE onset. PMID- 17693526 TI - Identification of 8 foodborne pathogens by multicolor combinational probe coding technology in a single real-time PCR. AB - BACKGROUND: Real-time PCR assays have been widely used for detecting foodborne pathogens but have been much less frequently applied in species identification, mainly because of the low number of species they can distinguish in 1 reaction. The present study used a new probe coding/labeling strategy, termed multicolor combinational probe coding (MCPC), to increase the number of targets that can be distinguished in a single real-time PCR for rapid and reliable species identification. METHODS: With MCPC, 8 pairs of species-specific tagged primers, 1 pair of universal primers, and 8 unilabeled or mix-labeled molecular beacon probes were included in a single reaction tube. Real-time PCR was performed, and the identity of each of the 8 pathogens was determined by amplification profile comparison. The method was validated via blind assessment of 118 bacterial strains, including clinical isolates and isolates from food products. RESULTS: The blind test with 118 samples gave no false-positive or -negative results for the target genes. The template DNA suitable for MCPC analysis was simply prepared by heating lysis, and the total PCR analysis was finished within 2.5 h, excluding template preparation. CONCLUSIONS: MCPC is suitable for rapid and reliable identification of foodborne pathogens at the species level. PMID- 17693527 TI - A ribonuclease III domain protein functions in group II intron splicing in maize chloroplasts. AB - Chloroplast genomes in land plants harbor approximately 20 group II introns. Genetic approaches have identified proteins involved in the splicing of many of these introns, but the proteins identified to date cannot account for the large size of intron ribonucleoprotein complexes and are not sufficient to reconstitute splicing in vitro. Here, we describe an additional protein that promotes chloroplast group II intron splicing in vivo. This protein, RNC1, was identified by mass spectrometry analysis of maize (Zea mays) proteins that coimmunoprecipitate with two previously identified chloroplast splicing factors, CAF1 and CAF2. RNC1 is a plant-specific protein that contains two ribonuclease III (RNase III) domains, the domain that harbors the active site of RNase III and Dicer enzymes. However, several amino acids that are essential for catalysis by RNase III and Dicer are missing from the RNase III domains in RNC1. RNC1 is found in complexes with a subset of chloroplast group II introns that includes but is not limited to CAF1- and CAF2-dependent introns. The splicing of many of the introns with which it associates is disrupted in maize rnc1 insertion mutants, indicating that RNC1 facilitates splicing in vivo. Recombinant RNC1 binds both single-stranded and double-stranded RNA with no discernible sequence specificity and lacks endonuclease activity. These results suggest that RNC1 is recruited to specific introns via protein-protein interactions and that its role in splicing involves RNA binding but not RNA cleavage activity. PMID- 17693528 TI - Engineered plant minichromosomes: a resurrection of B chromosomes? PMID- 17693529 TI - The maize floury1 gene encodes a novel endoplasmic reticulum protein involved in zein protein body formation. AB - The maize (Zea mays) floury1 (fl1) mutant was first reported almost 100 years ago, but its molecular identity has remained unknown. We report the cloning of Fl1, which encodes a novel zein protein body membrane protein with three predicted transmembrane domains and a C-terminal plant-specific domain of unknown function (DUF593). In wild-type endosperm, the FL1 protein accumulates at a high level during the period of zein synthesis and protein body development and declines to a low level at kernel maturity. Immunogold labeling showed that FL1 resides in the endoplasmic reticulum surrounding the protein body. Zein protein bodies in fl1 mutants are of normal size, shape, and abundance. However, mutant protein bodies ectopically accumulate 22-kD alpha-zeins in the gamma-zein-rich periphery and center of the core, rather than their normal discrete location in a ring at outer edge of the core. The 19-kD alpha-zein is uniformly distributed throughout the core in wild-type protein bodies, and this distribution is unaffected in fl1 mutants. Pairwise yeast two-hybrid experiments showed that FL1 DUF593 interacts with the 22-kD alpha-zein. Results of these studies suggest that FL1 participates in protein body formation by facilitating the localization of 22 kD alpha-zein and that this is essential for the formation of vitreous endosperm. PMID- 17693530 TI - Targeted degradation of PSEUDO-RESPONSE REGULATOR5 by an SCFZTL complex regulates clock function and photomorphogenesis in Arabidopsis thaliana. AB - Circadian clocks comprise several regulatory feedback loops that control gene transcription. However, recent evidence has shown that posttranslational mechanisms are also required for clock function. In Arabidopsis thaliana, members of the PSEUDO-RESPONSE REGULATOR (PRR) family were proposed to be components of the central oscillator. Using a PRR5-specific antibody, we characterized changes in PRR5 protein levels in relation to its mRNA levels under various circadian conditions. Under long-day conditions, PRR5 mRNA levels are undetectable at dusk but PRR5 protein levels remain maximal. Upon dark transition, however, PRR5 levels decrease rapidly, indicating dark-induced, posttranslational regulation. We demonstrated that the Pseudo-Receiver (PR) domain of PRR5 interacts directly with the F box protein ZEITLUPE (ZTL) in vitro and in vivo. Analyses of mutants and transgenic plants revealed an inverse correlation between PRR5 and ZTL levels, which depends on the PR domain. These results indicate that PRR5 is negatively regulated by ZTL, which likely mediates its ubiquitination and degradation. Phenotypic analyses of prr5 ztl double mutants showed that PRR5 is required for ZTL functions. ZTL contains a Light-Oxygen-Voltage domain, and its activity may be directly regulated by blue light. Consistent with this notion, we found that blue light stabilizes PRR5, although it does not alter ZTL levels. Together, our results show that ZTL targets PRR5 for degradation by 26S proteasomes in the circadian clock and in early photomorphogenesis. PMID- 17693531 TI - A molecular timetable for apical bud formation and dormancy induction in poplar. AB - The growth of perennial plants in the temperate zone alternates with periods of dormancy that are typically initiated during bud development in autumn. In a systems biology approach to unravel the underlying molecular program of apical bud development in poplar (Populus tremula x Populus alba), combined transcript and metabolite profiling were applied to a high-resolution time course from short day induction to complete dormancy. Metabolite and gene expression dynamics were used to reconstruct the temporal sequence of events during bud development. Importantly, bud development could be dissected into bud formation, acclimation to dehydration and cold, and dormancy. To each of these processes, specific sets of regulatory and marker genes and metabolites are associated and provide a reference frame for future functional studies. Light, ethylene, and abscisic acid signal transduction pathways consecutively control bud development by setting, modifying, or terminating these processes. Ethylene signal transduction is positioned temporally between light and abscisic acid signals and is putatively activated by transiently low hexose pools. The timing and place of cell proliferation arrest (related to dormancy) and of the accumulation of storage compounds (related to acclimation processes) were established within the bud by electron microscopy. Finally, the identification of a large set of genes commonly expressed during the growth-to-dormancy transitions in poplar apical buds, cambium, or Arabidopsis thaliana seeds suggests parallels in the underlying molecular mechanisms in different plant organs. PMID- 17693532 TI - Allele-specific expression patterns reveal biases and embryo-specific parent-of origin effects in hybrid maize. AB - We employed allele-specific expression (ASE) analyses to document biased allelic expression in maize (Zea mays). A set of 316 quantitative ASE assays were used to profile the relative allelic expression in seedling tissue derived from five maize hybrids. The different hybrids included in this study exhibit a range of heterosis levels; however, we did not observe differences in the frequencies of allelic bias. Allelic biases in gene expression were consistently observed for approximately 50% of the genes assayed in hybrid seedlings. The relative proportion of genes that exhibit cis- or trans-acting regulatory variation was very similar among the different genotypes. The cis-acting regulatory variation was more prevalent and resulted in greater expression differences than trans acting regulatory variation for these genes. The ASE assays were further used to compare the relative expression of the B73 and Mo17 alleles in three tissue types (seedling, immature ear, and embryo) derived from reciprocal hybrids. These comparisons provided evidence for tissue-specific cis-acting variation and for a slight maternal expression bias in approximately 20% of genes in embryo tissue. Collectively, these data provide evidence for prevalent cis-acting regulatory variation that contributes to biased allelic expression between genotypes and between tissues. PMID- 17693533 TI - The organization of high-affinity ammonium uptake in Arabidopsis roots depends on the spatial arrangement and biochemical properties of AMT1-type transporters. AB - The AMMONIUM TRANSPORTER (AMT) family comprises six isoforms in Arabidopsis thaliana. Here, we describe the complete functional organization of root expressed AMTs for high-affinity ammonium uptake. High-affinity influx of (15)N labeled ammonium in two transposon-tagged amt1;2 lines was reduced by 18 to 26% compared with wild-type plants. Enrichment of the AMT1;2 protein in the plasma membrane and localization of AMT1;2 promoter activity in the endodermis and root cortex indicated that AMT1;2 mediates the uptake of ammonium entering the root via the apoplasmic transport route. An amt1;1 amt1;2 amt1;3 amt2;1 quadruple mutant (qko) showed severe growth depression under ammonium supply and maintained only 5 to 10% of wild-type high-affinity ammonium uptake capacity. Transcriptional upregulation of AMT1;5 in nitrogen-deficient rhizodermal and root hair cells and the ability of AMT1;5 to transport ammonium in yeast suggested that AMT1;5 accounts for the remaining uptake capacity in qko. Triple and quadruple amt insertion lines revealed in vivo ammonium substrate affinities of 50, 234, 61, and 4.5 muM for AMT1;1, AMT1;2, AMT1;3, and AMT1;5, respectively, but no ammonium influx activity for AMT2;1. These data suggest that two principle means of achieving effective ammonium uptake in Arabidopsis roots are the spatial arrangement of AMT1-type ammonium transporters and the distribution of their transport capacities at different substrate affinities. PMID- 17693534 TI - MYB98 positively regulates a battery of synergid-expressed genes encoding filiform apparatus localized proteins. AB - The synergid cells within the female gametophyte are essential for reproduction in angiosperms. MYB98 encodes an R2R3-MYB protein required for pollen tube guidance and filiform apparatus formation by the synergid cells. To test the predicted function of MYB98 as a transcriptional regulator, we determined its subcellular localization and examined its DNA binding properties. We show that MYB98 binds to a specific DNA sequence (TAAC) and that a MYB98-green fluorescent protein fusion protein localizes to the nucleus, consistent with a role in transcriptional regulation. To identify genes regulated by MYB98, we tested previously identified synergid-expressed genes for reduced expression in myb98 female gametophytes and identified 16 such genes. We dissected the promoter of one of the downstream genes, DD11, and show that it contains a MYB98 binding site required for synergid expression, suggesting that DD11 is regulated directly by MYB98. To gain insight into the functions of the downstream genes, we chose five genes and determined the subcellular localization of the encoded proteins. We show that these five proteins are secreted into the filiform apparatus, suggesting that they play a role in either the formation or the function of this unique structure. Together, these data suggest that MYB98 functions as a transcriptional regulator in the synergid cells and activates the expression of genes required for pollen tube guidance and filiform apparatus formation. PMID- 17693535 TI - Genetic and molecular interactions between BELL1 and MADS box factors support ovule development in Arabidopsis. AB - In Arabidopsis thaliana and many other plant species, ovules arise from carpel tissue as new meristematic formations. Cell fate in proliferating ovule primordia is specified by particular ovule identity factors, such as the homeodomain factor BELL1 (BEL1) and MADS box family members SEEDSTICK (STK), SHATTERPROOF1 (SHP1), SHP2, and AGAMOUS. Both in the bel1 mutant and the stk shp1 shp2 triple mutant, integuments are transformed into carpelloid structures. Combining these mutants in a bel1 stk shp1 shp2 quadruple mutant, we showed that the bel1 phenotype is significantly enhanced. We also demonstrate that ovule differentiation requires the regulation of the stem cell maintenance gene WUSCHEL, repression of which is predominantly maintained by BEL1 during ovule development. Based on yeast three hybrid assays and genetic data, we show that BEL1 interacts with the ovule identity MADS box factors when they dimerize with SEPALLATA proteins. We propose a model for ovule development that explains how the balance between carpel identity activity and ovule identity activity is established by a MADS box homeodomain protein complex. PMID- 17693536 TI - Signaling from an altered cell wall to the nucleus mediates sugar-responsive growth and development in Arabidopsis thaliana. AB - Sugars such as glucose function as signal molecules that regulate gene expression, growth, and development in plants, animals, and yeast. To understand the molecular mechanisms of sugar responses, we isolated and characterized an Arabidopsis thaliana mutant, high sugar response8 (hsr8), which enhances sugar responsive growth and gene expression. Light-grown hsr8 plants exhibited increased starch and anthocyanin and reduced chlorophyll content in response to glucose treatment. Dark-grown hsr8 seedlings showed glucose-hypersensitive hypocotyl elongation and development. The HSR8 gene, isolated using map-based cloning, was allelic to the MURUS4 (MUR4) gene involved in arabinose synthesis. Dark-grown mur1 and mur3 seedlings also exhibited similar sugar responses to hsr8/mur4. The sugar-hypersensitive phenotypes of hsr8/mur4, mur1, and mur3 were rescued by boric acid, suggesting that alterations in the cell wall cause hypersensitive sugar-responsive phenotypes. Genetic analysis showed that sugar hypersensitive responses in hsr8 mutants were suppressed by pleiotropic regulatory locus1 (prl1), indicating that nucleus-localized PRL1 is required for enhanced sugar responses in hsr8 mutant plants. Microarray analysis revealed that the expression of many cell wall-related and sugar-responsive genes was altered in mur4-1, and the expression of a significant proportion of these genes was restored to wild-type levels in the mur4-1 prl1 double mutant. These findings reveal a pathway that signals changes in the cell wall through PRL1 to altered gene expression and sugar-responsive metabolic, growth, and developmental changes. PMID- 17693537 TI - Generation of single-copy T-DNA transformants in Arabidopsis by the CRE/loxP recombination-mediated resolution system. AB - We investigated whether complex T-DNA loci, often resulting in low transgene expression, can be resolved efficiently into single copies by CRE/loxP-mediated recombination. An SB-loxP T-DNA, containing two invertedly oriented loxP sequences located inside and immediately adjacent to the T-DNA border ends, was constructed. Regardless of the orientation and number of SB-loxP-derived T-DNAs integrated at one locus, recombination between the outermost loxP sequences in direct orientation should resolve multiple copies into a single T-DNA copy. Seven transformants with a complex SB-loxP locus were crossed with a CRE-expressing plant. In three hybrids, the complex T-DNA locus was reduced efficiently to a single-copy locus. Upon segregation of the CRE recombinase gene, only the simplified T-DNA locus was found in the progeny, demonstrating DNA had been excised efficiently in the progenitor cells of the gametes. In the two transformants with an inverted T-DNA repeat, the T-DNA resolution was accompanied by at least a 10-fold enhanced transgene expression. Therefore, the resolution of complex loci to a single-copy T-DNA insert by the CRE/loxP recombination system can become a valuable method for the production of elite transgenic Arabidopsis thaliana plants that are less prone to gene silencing. PMID- 17693538 TI - In vivo hexamerization and characterization of the Arabidopsis AAA ATPase CDC48A complex using forster resonance energy transfer-fluorescence lifetime imaging microscopy and fluorescence correlation spectroscopy. AB - The Arabidopsis (Arabidopsis thaliana) AAA ATPase CDC48A was fused to cerulean fluorescent protein and yellow fluorescent protein. AAA ATPases like CDC48 are only active in hexameric form. Forster resonance energy transfer-based fluorescence lifetime imaging microscopy using CDC48A-cerulean fluorescent protein and CDC48A-yellow fluorescent protein showed interaction between two adjacent protomers, demonstrating homo-oligomerization occurs in living plant cells. Interaction between CDC48A and the SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE1 (SERK1) transmembrane receptor occurs in very restricted domains at the plasma membrane. In these domains the predominant form of the fluorescently tagged CDC48A protein is a hexamer, suggesting that SERK1 is associated with the active form of CDC48A in vivo. SERK1 trans-phosphorylates CDC48A on Ser-41. Forster resonance energy transfer-fluorescence lifetime imaging microscopy was used to show that in vivo the C-terminal domains of CDC48A stay in close proximity. Employing fluorescence correlation spectroscopy, it was shown that CDC48A hexamers are part of larger complexes. PMID- 17693539 TI - Medicago truncatula as a model for nonhost resistance in legume-parasitic plant interactions. AB - Crenate broomrape (Orobanche crenata) is a root parasitic weed that represents a major constraint for grain legume production in Mediterranean and West Asian countries. Medicago truncatula has emerged as an important model plant species for structural and functional genomics. The close phylogenic relationship of M. truncatula with crop legumes increases its value as a resource for understanding resistance against Orobanche spp. Different cytological methods were used to study the mechanisms of resistance against crenate broomrape of two accessions of M. truncatula, showing early and late acting resistance. In the early resistance accession (SA27774) we found that the parasite died before a tubercle had formed. In the late resistance accession (SA4327) the parasite became attached without apparent problems to the host roots but most of the established tubercles turned dark and died before emergence. The results suggest that there are defensive mechanisms acting in both accessions but with a time gap that is crucial for a higher success avoiding parasite infection. PMID- 17693540 TI - Selective impairment of central mediation of baroreflex in anesthetized young adult Fischer 344 rats after chronic intermittent hypoxia. AB - Baroreflex control of heart rate (HR) is impaired after chronic intermittent hypoxia (CIH). However, the location and nature of this response remain unclear. We examined baroreceptor afferent, vagal efferent, and central components of the baroreflex circuitry. Fischer 344 (F344) rats were exposed to room air (RA) or CIH for 35-50 days and were then anesthetized with isoflurane, ventilated, and catheterized for measurement of mean arterial blood pressure (MAP) and HR. Baroreceptor function was characterized by measuring percent changes of integrated aortic depressor nerve (ADN) activity (Int ADNA) relative to the baseline value in response to sodium nitroprusside- and phenylephrine-induced changes in MAP. Data were fitted to a sigmoid logistic function curve. HR responses to electrical stimulation of the left ADN and the right vagus nerve were assessed under ketamine-acepromazine anesthesia. Compared with RA controls, CIH significantly increased maximum baroreceptor gain or maximum slope, maximum Int ADNA, and Int ADNA range (maximum - minimum Int ADNA), whereas other parameters of the logistic function were unchanged. In addition, CIH increased the maximum amplitude of bradycardic response to vagal efferent stimulation and decreased the time from stimulus onset to peak response. In contrast, CIH significantly reduced the maximum amplitude of bradycardic response to left ADN stimulation and increased the time from stimulus onset to peak response. Therefore, CIH decreased central mediation of the baroreflex but augmented baroreceptor afferent function and vagal efferent control of HR. PMID- 17693541 TI - Obesity augments vasoconstrictor reactivity to angiotensin II in the renal circulation of the Zucker rat. AB - Obesity is an emerging risk factor for renal dysfunction, but the mechanisms are poorly understood. Obese patients show heightened renal vasodilation to blockade of the renin-angiotensin system, suggesting deficits in vascular responses to angiotensin II (ANG II). This study tested the hypothesis that obesity augments renal vasoconstriction to ANG II. Lean (LZR), prediabetic obese (OZR), and nonobese fructose-fed Zucker rats (FF-LZR) were studied to determine the effects of obesity and insulin resistance on reactivity of blood pressure and renal blood flow to vasoconstrictors. OZR showed enlargement of the kidneys, elevated urine output, increased sodium intake, and decreased plasma renin activity (PRA) vs. LZR, and renal vasoconstriction to ANG II was augmented in OZR. Renal reactivity to norepinephrine and mesenteric vascular reactivity to ANG II were similar between LZR and OZR. Insulin-resistant FF-LZR had normal reactivity to ANG II, indicating the insulin resistance was an unlikely explanation for the changes observed in OZR. Four weeks on a low-sodium diet (0.08%) to raise PRA reduced reactivity to ANG II in OZR back to normal levels without effect on LZR. From these data, we conclude that in the prediabetic stages of obesity, a decrease in PRA is observed in Zucker rats that may lead to increased renal vascular reactivity to ANG II. This increased reactivity to ANG II may explain the elevated renal vasodilator effects observed in obese humans and provide insight into early changes in renal function that predispose to nephropathy in later stages of the disease. PMID- 17693543 TI - The history of the capillary wall: doctors, discoveries, and debates. AB - In 1628, William Harvey provided definitive evidence that blood circulates. The notion that blood travels around the body in a circle raised the important question of how nutrients pass between blood and underlying tissue. Perhaps, Harvey posited, arterial blood pours into the flesh as into a sponge, only then to find its way into the veins. Far from solving this problem, Marcello Malpighi's discovery of the capillaries in 1661 only added to the dilemma: surely, some argued, these entities are little more than channels drilled into tissues around them. As we discuss in this review, it would take over 200 years to arrive at a consensus on the basic structure and function of the capillary wall. A consideration of the history of this period provides interesting insights into not only the central importance of the capillary as a focus of investigation, but also the enormous challenges associated with studying these elusive structures. PMID- 17693542 TI - Endothelin-1-mediated vasoconstriction at rest and during dynamic exercise in healthy humans. AB - It is now generally accepted that alpha-adrenoreceptor-mediated vasoconstriction is attenuated during exercise, but the efficacy of nonadrenergic vasoconstrictor pathways during exercise remains unclear. Thus, in eight young (23 +/- 1 yr), healthy volunteers, we contrasted changes in leg blood flow (ultrasound Doppler) before and during intra-arterial infusion of the alpha(1)-adrenoreceptor agonist phenylephrine (PE) with that of the nonadrenergic endothelin A (ET(A))/ET(B) receptor agonist ET-1. Heart rate, arterial blood pressure, common femoral artery diameter, and mean blood velocity were measured at rest and during knee-extensor exercise at 20%, 40%, and 60% of maximal work rate (WR(max)). Drug infusion rates were adjusted for blood flow to maintain comparable doses across all subjects and conditions. At rest, PE infusion (8 ng x ml(-1) x min(-1)) provoked a rapid and significant decrease in leg blood flow (-51 +/- 3%) within 2.5 min. Resting ET-1 infusion (40 pg x ml(-1) x min(-1)) significantly decreased leg blood flow within 5 min, reaching a maximal vasoconstriction (-34 +/- 3%) after 25-30 min of continuous infusion. Compared with rest, an exercise intensity-dependent attenuation to PE-mediated vasoconstriction was observed (-18 +/- 5%, -7 +/- 2%, and -1 +/- 3% change in leg blood flow at 20%, 40%, and 60% of WR(max), respectively). Vasoconstriction in response to ET-1 was also blunted in an exercise intensity-dependent manner (-13 +/- 3%, -7 +/- 4%, and 2 +/- 3% change in leg blood flow at 20%, 40%, and 60% of WR(max), respectively). These findings support a significant contribution of ET-1 and alpha-adrenergic receptors in the regulation of skeletal muscle blood flow in the human leg at rest and suggest a similar, intensity-dependent "lysis" of peripheral ET and alpha-adrenergic vasoconstriction during dynamic exercise. PMID- 17693544 TI - Revisiting methods for assessing and comparing left ventricular diastolic stiffness: impact of relaxation, external forces, hypertrophy, and comparators. AB - Understanding diastolic function mandates feasible and accurate methods to construct and compare the diastolic pressure (P)-volume (V) relationship (PVR). This study compared the relaxation-corrected single beat (RC-SB) to the multiple beat (MB) (vena cava occlusion) method for constructing the diastolic PVR in 26 young normal or old hypertensive dogs before and after increases in afterload (phenylephrine) or acute volume expansion in the presence (n = 14) or absence (n = 12) of the pericardium. The PVR data were fit to P = alphae(beta x V). Derived stiffness indexes compared included the stiffness coefficient (beta), curve fitting constant (alpha), and the end-diastolic volume (EDV) at 10, 20, or 30 mmHg [EDV(x) = ln(P(x)/alpha)/beta] to account for covariance in alpha and beta. In pericardium-intact young normal and old hypertensive dogs studied over varying afterloads, the MB and RC-SB PVR appeared identical. The beta (r = 0.62) and alpha (r = 0.69) derived from the RC-SB vs. MB PVR showed moderate correlation but poor agreement. In contrast, the EDV(10-30) derived from RC-SB vs. MB PVR showed excellent correlation (r = 0.97) and agreement. The uncorrected SB method underestimated stiffness. As expected, after acute volume expansion, the RC-SB PVR was shifted upward from the MB PVR (decreased EDV(10-30); P < 0.05) in the pericardium-intact but not pericardium-absent dogs. The RC-SB method can substitute for the MB technique in construction of PVR in the absence of acute volume expansion. The concordance between these two methods was poorly reflected by comparing the derived alpha and beta but apparent when using EDV(10-30), which provides information regarding the position of the PVR in a single number. PMID- 17693545 TI - Efferent vagal nerve stimulation induces tissue inhibitor of metalloproteinase-1 in myocardial ischemia-reperfusion injury in rabbit. AB - Vagal nerve stimulation has been suggested to ameliorate left ventricular (LV) remodeling in heart failure. However, it is not known whether and to what degree vagal nerve stimulation affects matrix metalloproteinase (MMP) and tissue inhibitor of MMP (TIMP) in myocardium, which are known to play crucial roles in LV remodeling. We therefore investigated the effects of electrical stimulation of efferent vagal nerve on myocardial expression and activation of MMPs and TIMPs in a rabbit model of myocardial ischemia-reperfusion (I/R) injury. Anesthetized rabbits were subjected to 60 min of left coronary artery occlusion and 180 min of reperfusion with (I/R-VS, n = 8) or without vagal nerve stimulation (I/R, n = 7). Rabbits not subjected to coronary occlusion with (VS, n = 7) or without vagal stimulation (sham, n = 7) were used as controls. Total MMP-9 protein increased significantly after left coronary artery occlusion in I/R-VS and I/R to a similar degree compared with VS and sham values. Endogenous active MMP-9 protein level was significantly lower in I/R-VS compared with I/R. TIMP-1 mRNA expression was significantly increased in I/R-VS compared with the I/R, VS, and sham groups. TIMP-1 protein was significantly increased in I/R-VS and VS compared with the I/R and sham groups. Cardiac microdialysis technique demonstrated that topical perfusion of acetylcholine increased dialysate TIMP-1 protein level, which was suppressed by coperfusion of atropine. Immunohistochemistry demonstrated a strong expression of TIMP-1 protein in cardiomyocytes around the dialysis probe used to perfuse acetylcholine. In conclusion, in a rabbit model of myocardial I/R injury, vagal nerve stimulation induced TIMP-1 expression in cardiomyocytes and reduced active MMP-9. PMID- 17693546 TI - Salt-sensing mechanisms in blood pressure regulation and hypertension. AB - High salt consumption contributes to the development of hypertension and is considered an independent risk factor for vascular remodeling, cardiac hypertrophy, and stroke incidence. In this review, we discuss the molecular origins of primary sensors involved in the phenomenon of salt sensitivity. Based on the analysis of literature data, we conclude that the kidneys and central nervous system (CNS) are two major sites for salt sensing via several distinct mechanisms: 1) [Cl(-)] sensing in renal tubular fluids, primarily by Na(+)-K(+) Cl(-) cotransporter (NKCC) isoforms NKCC2B and NKCC2A, whose expression is mainly limited to macula densa cells; 2) [Na(+)] sensing in cerebrospinal fluid (CSF) by a novel isoform of Na(+) channels, Na(x), expressed in subfornical organs; 3) sensing of CSF osmolality by mechanosensitive, nonselective cation channels (transient receptor potential vanilloid type 1 channels), expressed in neuronal cells of supraoptic and paraventricular nuclei; and 4) osmolarity sensing by volume-regulated anion channels in glial cells of supraoptic and paraventricular nuclei. Such multiplicity of salt-sensing mechanisms likely explains the differential effects of Na(+) and Cl(-) loading on the long-term maintenance of elevated blood pressure that is documented in experimental models of salt sensitive hypertension. PMID- 17693547 TI - Modulation of the rate of cardiac muscle contraction by troponin C constructs with various calcium binding affinities. AB - We investigated whether changing thin filament Ca(2+) sensitivity alters the rate of contraction, either during normal cross-bridge cycling or when cross-bridge cycling is increased by inorganic phosphate (P(i)). We increased or decreased Ca(2+) sensitivity of force production by incorporating into rat skinned cardiac trabeculae the troponin C (TnC) mutants V44QTnC(F27W) and F20QTnC(F27W). The rate of isometric contraction was assessed as the rate of force redevelopment (k(tr)) after a rapid release and restretch to the original length of the muscle. Both in the absence of added P(i) and in the presence of 2.5 mM added P(i) 1) Ca(2+) sensitivity of k(tr) was increased by V44QTnC(F27W) and decreased by F20QTnC(F27W) compared with control TnC(F27W); 2) k(tr) at submaximal Ca(2+) activation was significantly faster for V44QTnC(F27W) and slower for F20QTnC(F27W) compared with control TnC(F27W); 3) at maximum Ca(2+) activation, k(tr) values were similar for control TnC(F27W), V44QTnC(F27W), and F20QTnC(F27W); and 4) k(tr) exhibited a linear dependence on force that was indistinguishable for all TnCs. In the presence of 2.5 mM P(i), k(tr) was faster at all pCa values compared with the values for no added P(i) for TnC(F27W), V44QTnC(F27W), and F20QTnC(F27W). This study suggests that TnC Ca(2+) binding properties modulate the rate of cardiac muscle contraction at submaximal levels of Ca(2+) activation. This result has physiological relevance considering that, on a beat-to-beat basis, the heart contracts at submaximal Ca(2+) activation. PMID- 17693548 TI - Integrative genomic and functional analyses reveal neuronal subtype differentiation bias in human embryonic stem cell lines. AB - The self-renewal and differentiation potential of human embryonic stem cells (hESCs) suggests that hESCs could be used for regenerative medicine, especially for restoring neuronal functions in brain diseases. However, the functional properties of neurons derived from hESC are largely unknown. Moreover, because hESCs were derived under diverse conditions, the possibility arises that neurons derived from different hESC lines exhibit distinct properties, but this possibility remains unexplored. To address these issues, we developed a protocol that allows stepwise generation from hESCs of cultures composed of approximately 70-80% human neurons that exhibit spontaneous synaptic network activity. Comparison of neurons derived from the well characterized HSF1 and HSF6 hESC lines revealed that HSF1- but not HSF6-derived neurons exhibit forebrain properties. Accordingly, HSF1-derived neurons initially form primarily GABAergic synaptic networks, whereas HSF6-derived neurons initially form glutamatergic networks. microRNA profiling revealed significant expression differences between the two hESC lines, suggesting that microRNAs may influence their distinct differentiation properties. These observations indicate that although both HSF1 and HSF6 hESCs differentiate into functional neurons, the two hESC lines exhibit distinct differentiation potentials, suggesting that they are preprogrammed. Information on hESC line-specific differentiation biases is crucial for neural stem cell therapy and establishment of novel disease models using hESCs. PMID- 17693549 TI - A pathogenicity island replicon in Staphylococcus aureus replicates as an unstable plasmid. AB - The SaPIs are 14- to 17-kb mobile pathogenicity islands in staphylococci that carry genes for superantigen toxins and other virulence factors and are responsible for the toxic shock syndrome and other superantigen-related diseases. They reside at specific chromosomal sites and are induced by certain bacteriophages to initiate an excision-replication-packaging program, resulting in their incorporation into small infective phage-like particles. These are responsible for very high transfer frequencies that often equal and sometimes exceed the plaque-forming titer of the inducing phage. The ability of the SaPIs to replicate autonomously defines them as individual replicons and, like other prokaryotic replicons, they possess replicon-specific initiation functions. In this paper, we report identification of the SaPI replication origin (ori) and replication initiation protein (Rep), which has helicase as well as initiation activity. The SaPI oris are binding sites for the respective Rep proteins and consist of multiple oligonucleotide repeats in two sets, flanking an AT-rich region that may be the site of initial melting. Plasmids containing the rep-ori complex plus an additional gene, pri, can replicate autonomously in Staphylococcus aureus but are very unstable, probably because of defective segregation. PMID- 17693550 TI - Estrogen receptor beta is essential for sprouting of nociceptive primary afferents and for morphogenesis and maintenance of the dorsal horn interneurons. AB - Estrogen is known to influence pain, but the specific roles of the two estrogen receptors (ERs) in the spinal cord are unknown. In the present study, we have examined the expression of ERalpha and ERbeta in the spinal cord and have looked for defects in pain pathways in ERbeta knockout (ERbeta(-/-)) mice. In the spinal cords of 10-month-old WT mice, ERbeta-positive cells were localized in lamina II, whereas ERalpha-positive cells were mainly localized in lamina I. In ERbeta(-/-) mice, there were higher levels of calcitonin gene-regulated peptide and substance P in spinal cord dorsal horn and isolectin B4 in the dorsal root ganglion. In the superficial layers of the spinal cord, there was a decrease in the number of calretinin (CR)-positive neurons, and in the outer layer II, there was a loss of calbindin-positive interneurons. During embryogenesis, ERbeta was first detectable in the spinal cord at embryonic day 13.5 (E13.5), and ERalpha was first detectable at E15.5. During middle and later embryonic stages, ERbeta was abundantly expressed in the superficial layers of the dorsal horn. ERalpha was also expressed in the dorsal horn but was limited to fewer neurons. Double staining for ERbeta and CR showed that, in the superficial dorsal horn of WT neonates [postnatal day 0 (P0)], most CR neurons also expressed ERbeta. At this stage, few CR-positive cells were detected in the dorsal horn of ERbeta(-/-) mice. Taken together, these findings suggest that, early in embryogenesis, ERbeta is involved in dorsal horn morphogenesis and in sensory afferent fiber projections to the dorsal horn and that ERbeta is essential for survival of dorsal horn interneurons throughout life. PMID- 17693551 TI - Structural basis of action for a human ether-a-go-go-related gene 1 potassium channel activator. AB - Activation of human ether-a-go-go-related gene 1 (hERG1) K(+) channels mediates cardiac action potential repolarization. Drugs that activate hERG1 channels represent a mechanism-based approach for the treatment of long QT syndrome, a disorder of cardiac repolarization associated with ventricular arrhythmia and sudden death. Here, we characterize the mechanisms of action and the molecular determinants for binding of RPR260243 [(3R,4R)-4-[3-(6-methoxy-quinolin-4-yl)-3 oxo-propyl]-1-[3-(2,3,5-trifluoro-phenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid] (RPR), a recently discovered hERG1 channel activator. Channels were heterologously expressed in Xenopus laevis oocytes, and currents were measured by using the two-microelectrode voltage-clamp technique. RPR induced a concentration dependent slowing in the rate of channel deactivation and enhanced current magnitude by shifting the voltage dependence of inactivation to more positive potentials. This mechanism was confirmed by demonstrating that RPR slowed the rate of deactivation, but did not increase current magnitude of inactivation deficient mutant channels. The effects of RPR on hERG1 kinetics and magnitude could be simulated by reducing three rate constants in a Markov model of channel gating. Point mutations of specific residues located in the S4-S5 linker or cytoplasmic ends of the S5 and S6 domains greatly attenuated or ablated the effects of 3 microM RPR on deactivation (five residues), inactivation (one residue), or both gating mechanisms (four residues). These findings define a putative binding site for RPR and confirm the importance of an interaction between the S4-S5 linker and the S6 domain in electromechanical coupling of voltage-gated K(+) channels. PMID- 17693552 TI - Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. AB - The innate immune system senses the invasion of pathogenic microorganisms and tissue injury through Toll-like receptors (TLR), a mechanism thought to be limited to immune cells. We now report that neurons express several TLRs, and that the levels of TLR2 and -4 are increased in neurons in response to IFN-gamma stimulation and energy deprivation. Neurons from both TLR2 knockout and -4 mutant mice were protected against energy deprivation-induced cell death, which was associated with decreased activation of a proapoptotic signaling cascade involving jun N-terminal kinase and the transcription factor AP-1. TLR2 and -4 expression was increased in cerebral cortical neurons in response to ischemia/reperfusion injury, and the amount of brain damage and neurological deficits caused by a stroke were significantly less in mice deficient in TLR2 or 4 compared with WT control mice. Our findings establish a proapoptotic signaling pathway for TLR2 and -4 in neurons that may render them vulnerable to ischemic death. PMID- 17693553 TI - Population genetics of the frog-killing fungus Batrachochytrium dendrobatidis. AB - Global amphibian decline by chytridiomycosis is a major environmental disaster that has been attributed to either recent fungal spread or environmental change that promotes disease. Here, we present a population genetic comparison of Batrachochytrium dendrobatidis isolates from an intensively studied region of frog decline, the Sierra Nevada of California. In support of a novel pathogen, we find low diversity, no amphibian-host specificity, little correlation between fungal genotype and geography, local frog extirpation by a single fungal genotype, and evidence of human-assisted fungus migration. In support of endemism, at a local scale, we find some diverse, recombining populations. Therefore neither epidemic spread nor endemism alone explains this particular amphibian decline. Recombination raises the possibility of resistant sporangia and a mechanism for rapid spread as well as persistence that could greatly complicate global control of the pathogen. PMID- 17693554 TI - Bacterial sensor kinase TodS interacts with agonistic and antagonistic signals. AB - The TodS/TodT two-component system controls expression of the toluene dioxygenase (TOD) pathway for the metabolism of toluene in Pseudomonas putida DOT-T1E. TodS is a sensor kinase that ultimately controls tod gene expression through its cognate response regulator, TodT. We used isothermal titration calorimetry to study the binding of different compounds to TodS and related these findings to their capacity to induce gene expression in vivo. Agonistic compounds bound to TodS and induced gene expression in vivo. Toluene was a powerful agonist, but ortho-substitutions of toluene reduced or abolished in vivo responses, although TodS recognized o-xylene with high affinity. These compounds were called antagonists. We show that agonists and antagonists compete for binding to TodS both in vitro and in vivo. The failure of antagonists to induce gene expression in vivo correlated with their inability to stimulate TodS autophosphorylation in vitro. We propose intramolecular TodS signal transmission, not molecular recognition of compounds by TodS, to be the phenomenon that determines whether a given compound will lead to activation of expression of the tod genes. Molecular modeling identified residues F46, I74, F79, and I114 as being potentially involved in the binding of effector molecules. Alanine substitution mutants of these residues reduced affinities (2- to 345-fold) for both agonistic and antagonistic compounds. Our data indicate that determining the inhibitory activity of antagonists is a potentially fruitful alternative to design specific two-component system inhibitors for the development of new drugs to inhibit processes regulated by two-component systems. PMID- 17693555 TI - Variations in behavior and condition of a Southern Ocean top predator in relation to in situ oceanographic conditions. AB - Responses by marine top predators to environmental variability have previously been almost impossible to observe directly. By using animal-mounted instruments simultaneously recording movements, diving behavior, and in situ oceanographic properties, we studied the behavioral and physiological responses of southern elephant seals to spatial environmental variability throughout their circumpolar range. Improved body condition of seals in the Atlantic sector was associated with Circumpolar Deep Water upwelling regions within the Antarctic Circumpolar Current, whereas High-Salinity Shelf Waters or temperature/salinity gradients under winter pack ice were important in the Indian and Pacific sectors. Energetic consequences of these variations could help explain recently observed population trends, showing the usefulness of this approach in examining the sensitivity of top predators to global and regional-scale climate variability. PMID- 17693556 TI - Tick-borne zoonotic bacteria in wild and domestic small mammals in northern Spain. AB - The prevalence and diversity of tick-borne zoonotic bacteria (Borrelia spp., Anaplasma phagocytophilum, Coxiella burnetii, and spotted fever group rickettsiae) infecting 253 small mammals captured in the Basque Country (Spain) were assessed using PCR and reverse line blot hybridization. Trapping sites were selected around sheep farms (study 1, 2000 to 2002) and recreational parks (study 2, 2003 to 2005). The majority of the studied mammals (162) were wood mice (Apodemus sylvaticus), but six other different species were also analyzed: yellow necked mice (Apodemus flavicollis), shrews (Crocidura russula and Sorex coronatus), bank voles (Clethrionomys glareolus), domestic mice (Mus domesticus), and moles (Talpa europaea). The results showed an infection rate ranging from 10.7% to 68.8%, depending on the small mammal species. One C. russula shrew and one A. sylvaticus mouse gave positive reactions for A. phagocytophilum, and C. burnetii was detected in two domestic mice and one A. sylvaticus mouse in a farm. The DNA of Borrelia spp. was detected in 67 animals (26.5%), most of them presenting positive hybridization with the probe for Borrelia sp. strain R57, the new Borrelia species previously detected in small mammals in our region. Furthermore, a second PCR and reverse line blot hybridization specific for B. burgdorferi sensu lato revealed the presence of Borrelia afzelii in 6.3% of C. glareolus voles and 14.3% of S. coronatus shrews. All small mammals were negative for spotted fever group rickettsiae. These results highlight the relevance of small mammals as reservoirs of some zoonotic bacteria. PMID- 17693557 TI - Changes in bacterial populations and in biphenyl dioxygenase gene diversity in a polychlorinated biphenyl-polluted soil after introduction of willow trees for rhizoremediation. AB - The aim of this study was to analyze the structural and functional changes occurring in a polychlorinated-biphenyl (PCB)-contaminated soil ecosystem after the introduction of a suitable host plant for rhizoremediation (Salix viminalis). We have studied the populations and phylogenetic distribution of key bacterial groups (Alpha- and Betaproteobacteria, Acidobacteria, and Actinobacteria) and the genes encoding iron-sulfur protein alpha (ISPalpha) subunits of the toluene/biphenyl dioxygenases in soil and rhizosphere by screening gene libraries using temperature gradient gel electrophoresis. The results, based on the analysis of 415 clones grouped into 133 operational taxonomic units that were sequence analyzed (>128 kbp), show that the rhizospheric bacterial community which evolved from the native soil community during the development of the root system was distinct from the soil community for all groups studied except for the Actinobacteria. Proteobacteria were enriched in the rhizosphere and dominated both in rhizosphere and soil. There was a higher than expected abundance of Betaproteobacteria in the native and in the planted PCB-polluted soil. The ISPalpha sequences retrieved indicate a high degree of catabolic and phylogenetic diversity. Many sequences clustered with biphenyl dioxygenase sequences from gram negative bacteria. A distinct cluster that was composed of sequences from this study, some previously described environmental sequences, and a putative ISPalpha from Sphingomonas wittichii RW1 seems to contain greater diversity than the presently recognized toluene/biphenyl dioxygenase subfamily. Moreover, the rhizosphere selected for two ISPalpha sequences that accounted for almost 60% of the gene library and were very similar to sequences harbored by Pseudomonas species. PMID- 17693559 TI - Phototrophic Fe(II) oxidation promotes organic carbon acquisition by Rhodobacter capsulatus SB1003. AB - Anoxygenic phototrophic Fe(II) oxidation is usually considered to be a lithoautotrophic metabolism that contributes to primary production in Fe-based ecosystems. In this study, we employed Rhodobacter capsulatus SB1003 as a model organism to test the hypothesis that phototrophic Fe(II) oxidation can be coupled to organic carbon acquisition. R. capsulatus SB1003 oxidized Fe(II) under anoxic conditions in a light-dependent manner, but it failed to grow lithoautotrophically on soluble Fe(II). When the strain was provided with Fe(II) citrate, however, growth was observed that was dependent upon microbially catalyzed Fe(II) oxidation, resulting in the formation of Fe(III)-citrate. Subsequent photochemical breakdown of Fe(III)-citrate yielded acetoacetic acid that supported growth in the light but not the dark. The deletion of genes (RRC00247 and RRC00248) that encode homologs of atoA and atoD, required for acetoacetic acid utilization, severely impaired the ability of R. capsulatus SB1003 to grow on Fe(II)-citrate. The growth yield achieved by R. capsulatus SB1003 in the presence of citrate cannot be explained by lithoautotrophic growth on Fe(II) enabled by indirect effects of the ligand [such as altering the thermodynamics of Fe(II) oxidation or preventing cell encrustation]. Together, these results demonstrate that R. capsulatus SB1003 grows photoheterotrophically on Fe(II)-citrate. Nitrilotriacetic acid also supported light-dependent growth on Fe(II), suggesting that Fe(II) oxidation may be a general mechanism whereby some Fe(II)-oxidizing bacteria mine otherwise inaccessible organic carbon sources. PMID- 17693560 TI - Use of the tna operon as a new molecular target for Escherichia coli detection. AB - A quantitative real-time PCR targeting the tnaA gene was studied to detect Escherichia coli and distinguish E. coli from Shigella spp. These microorganisms revealed high similarity in the molecular organization of the tna operon. PMID- 17693558 TI - Mixed infections, cryptic diversity, and vector-borne pathogens: evidence from Polygenis fleas and Bartonella species. AB - Coinfections within hosts present opportunities for horizontal gene transfer between strains and competitive interactions between genotypes and thus can be a critical element of the lifestyles of pathogens. Bartonella spp. are Alphaproteobacteria that parasitize mammalian erythrocytes and endothelial cells. Their vectors are thought to be various biting arthropods, such as fleas, ticks, mites, and lice, and they are commonly cited as agents of various emerging diseases. Coinfections by different Bartonella strains and species can be common in mammals, but little is known about specificity and coinfections in arthropod vectors. We surveyed the rate of mixed infections of Bartonella in flea vectors (Polygenis gwyni) parasitizing cotton rats (Sigmodon hispidus) in which previous surveys indicated high rates of infection. We found that nearly all fleas (20 of 21) harbored one or more strains of Bartonella, with rates of coinfection approaching 90%. A strain previously identified as common in cotton rats was also common in their fleas. However, another common strain in cotton rats was absent from P. gwyni, while a rare cotton rat strain was quite common in P. gwyni. Surprisingly, some samples were also coinfected with a strain phylogenetically related to Bartonella clarridgeiae, which is typically associated with felids and ruminants. Finally, a locus (pap31) that is characteristically borne on phage in Bartonella was successfully sequenced from most samples. However, sequence diversity in pap31 was novel in the P. gwyni samples, relative to other Bartonella previously typed with pap31, emphasizing the likelihood of large reservoirs of cryptic diversity in natural populations of the pathogen. PMID- 17693561 TI - Identification of indole derivatives as self-growth inhibitors of Symbiobacterium thermophilum, a unique bacterium whose growth depends on coculture with a Bacillus sp. AB - Symbiobacterium thermophilum is a syntrophic bacterium whose growth depends on coculture with a Bacillus sp. Recently, we discovered that CO(2) generated by Bacillus is the major inducer for the growth of S. thermophilum; however, the evidence suggested that an additional element is required for its full growth. Here, we studied the self-growth-inhibitory substances produced by S. thermophilum. We succeeded in purifying two substances from an ether extract of the culture supernatant of S. thermophilum by multiple steps of reverse-phase chromatography. Electron ionization mass spectrometry and nuclear magnetic resonance analyses of the purified preparation identified the substances as 2,2 bis(3'-indolyl)indoxyl (BII) and 1,1-bis(3'-indolyl)ethane (BIE). The pure growth of S. thermophilum was inhibited by authentic BII and BIE with MICs of 12 and 7 microg/ml, respectively; however, its growth in coculture with Bacillus was not inhibited by BII at the saturation concentration and was inhibited by BIE with an MIC of 14 microg/ml. Both BII and BIE inhibited the growth of other microorganisms. Unexpectedly, the accumulation levels of both BII and BIE in the pure culture of S. thermophilum were far lower than the MICs (<0.1 microg/ml) while a marked amount of BIE (6 to 7 microg/ml) equivalent to the MIC had accumulated in the coculture. An exogenous supply of surfactin alleviated the sensitivities of several BIE-sensitive bacteria against BIE. The results suggest that Bacillus benefits S. thermophilum by detoxifying BII and BIE in the coculture. A similar mechanism may underlie mutualistic relationships between different microorganisms. PMID- 17693562 TI - Multiplex PCR for simultaneous detection of bacteria of the genus Listeria, Listeria monocytogenes, and major serotypes and epidemic clones of L. monocytogenes. AB - A multiplex PCR assay which combines detection of bacteria of the genus Listeria, Listeria monocytogenes serotypes 1/2a and 4b, and epidemic clones I, II, and III of L. monocytogenes was developed. The assay provides a rapid, reliable, and inexpensive method for screening and subgrouping this important food-borne pathogen. PMID- 17693563 TI - Shuffling of promoters for multiple genes to optimize xylose fermentation in an engineered Saccharomyces cerevisiae strain. AB - We describe here a useful metabolic engineering tool, multiple-gene-promoter shuffling (MGPS), to optimize expression levels for multiple genes. This method approaches an optimized gene overexpression level by fusing promoters of various strengths to genes of interest for a particular pathway. Selection of these promoters is based on the expression levels of the native genes under the same physiological conditions intended for the application. MGPS was implemented in a yeast xylose fermentation mixture by shuffling the promoters for GND2 and HXK2 with the genes for transaldolase (TAL1), transketolase (TKL1), and pyruvate kinase (PYK1) in the Saccharomyces cerevisiae strain FPL-YSX3. This host strain has integrated xylose-metabolizing genes, including xylose reductase, xylitol dehydrogenase, and xylulose kinase. The optimal expression levels for TAL1, TKL1, and PYK1 were identified by analysis of volumetric ethanol production by transformed cells. We found the optimal combination for ethanol production to be GND2-TAL1-HXK2-TKL1-HXK2-PYK1. The MGPS method could easily be adapted for other eukaryotic and prokaryotic organisms to optimize expression of genes for industrial fermentation. PMID- 17693564 TI - Identification of isopentenol biosynthetic genes from Bacillus subtilis by a screening method based on isoprenoid precursor toxicity. AB - We have developed a novel method to clone terpene synthase genes. This method relies on the inherent toxicity of the prenyl diphosphate precursors to terpenes, which resulted in a reduced-growth phenotype. When these precursors were consumed by a terpene synthase, normal growth was restored. We have demonstrated that this method is capable of enriching a population of engineered Escherichia coli for those clones that express the sesquiterpene-producing amorphadiene synthase. In addition, we enriched a library of genomic DNA from the isoprene-producing bacterium Bacillus subtilis strain 6,051 in E. coli engineered to produce elevated levels of isopentenyl diphosphate and dimethylallyl diphosphate. The selection resulted in the discovery of two genes (yhfR and nudF) whose protein products acted directly on the prenyl diphosphate precursors and produced isopentenol. Expression of nudF in E. coli engineered with the mevalonate-based isopentenyl pyrophosphate biosynthetic pathway resulted in the production of isopentenol. PMID- 17693565 TI - Biosynthesis of Staphylococcus aureus autoinducing peptides by using the synechocystis DnaB mini-intein. AB - The Agr quorum-sensing system of Staphylococcus aureus modulates the expression of virulence factors in response to autoinducing peptides (AIPs). The peptides are seven to nine residues in length and have the C-terminal five residues constrained in a thiolactone ring. We have developed a new method to generate AIP structures using an engineered DnaB mini-intein from Synechocystis sp. strain PCC6803. In the method, an oligonucleotide encoding the AIP is ligated to the intein and the fusion protein is expressed and purified by affinity chromatography. To produce the correct AIP structure, intein splicing is interrupted, allowing the cysteine side chain to catalyze thiolactone ring formation and release AIP from the resin. The technique is simple and robust, and we have successfully produced the three main classes of AIPs using the intein system. The intein-generated AIPs possessed the correct thiolactone ring modification based on biochemical analysis, and, importantly, all the samples were bioactive against S. aureus. The AIP activity was confirmed through Agr interference and activation profiling with developed S. aureus reporter strains. The simplicity of the method, benefits of DNA encoding, and scalable nature enable the production of S. aureus AIPs for many biological applications. PMID- 17693566 TI - Archaeal and bacterial glycerol dialkyl glycerol tetraether lipids in hot springs of yellowstone national park. AB - Glycerol dialkyl glycerol tetraethers (GDGTs) are core membrane lipids originally thought to be produced mainly by (hyper)thermophilic archaea. Environmental screening of low-temperature environments showed, however, the abundant presence of structurally diverse GDGTs from both bacterial and archaeal sources. In this study, we examined the occurrences and distribution of GDGTs in hot spring environments in Yellowstone National Park with high temperatures (47 to 83 degrees C) and mostly neutral to alkaline pHs. GDGTs with 0 to 4 cyclopentane moieties were dominant in all samples and are likely derived from both (hyper)thermophilic Crenarchaeota and Euryarchaeota. GDGTs with 4 to 8 cyclopentane moieties, likely derived from the crenarchaeotal order Sulfolobales and the euryarchaeotal order Thermoplasmatales, are usually present in much lower abundance, consistent with the relatively high pH values of the hot springs. The relative abundances of cyclopentane-containing GDGTs did not correlate with in situ temperature and pH, suggesting that other environmental and possibly genetic factors play a role as well. Crenarchaeol, a biomarker thought to be specific for nonthermophilic group I Crenarchaeota, was also found in most hot springs, though in relatively low concentrations, i.e., <5% of total GDGTs. Its abundance did not correlate with temperature, as has been reported previously. Instead, the cooccurrence of relatively abundant nonisoprenoid GDGTs thought to be derived from soil bacteria suggests a predominantly allochthonous source for crenarchaeol in these hot spring environments. Finally, the distribution of bacterial branched GDGTs suggests that they may be derived from the geothermally heated soils surrounding the hot springs. PMID- 17693567 TI - Microbial community biofabrics in a geothermal mine adit. AB - Speleothems such as stalactites and stalagmites are usually considered to be mineralogical in composition and origin; however, microorganisms have been implicated in the development of some speleothems. We have identified and characterized the biological and mineralogical composition of mat-like biofabrics in two novel kinds of speleothems from a 50 degrees C geothermal mine adit near Glenwood Springs, CO. One type of structure consists of 2- to 3-cm-long, 3- to 4 mm-wide, leather-like, hollow, soda straw stalactites. Light and electron microscopy indicated that the stalactites are composed of a mineralized biofabric with several cell morphotypes in a laminated form, with gypsum and sulfur as the dominant mineral components. A small-subunit rRNA gene phylogenetic community analysis along the stalactite length yielded a diverse gradient of organisms, with a relatively simple suite of main constituents: Thermus spp., crenarchaeotes, Chloroflexi, and Gammaproteobacteria. PCR analysis also detected putative crenarchaeal ammonia monooxygenase subunit A (amoA) genes in this community, the majority related to sequences from other geothermal systems. The second type of speleothem, dumpling-like rafts floating on a 50 degrees C pool on the floor of the adit, showed a mat-like fabric of evidently living organisms on the outside of the dumpling, with a multimineral, amorphous, gypsum-based internal composition. These two novel types of biofabrics are examples of the complex roles that microbes can play in mineralization, weathering, and deposition processes in karst environments. PMID- 17693568 TI - Effect of insect larval midgut proteases on the activity of Bacillus thuringiensis Cry toxins. AB - To test the possibility that proteolytic cleavage by midgut juice enzymes could enhance or inhibit the activity of Bacillus thuringiensis insecticidal toxins, once activated, the effects of different toxins on the membrane potential of the epithelial cells of isolated Manduca sexta midguts in the presence and absence of midgut juice were measured. While midgut juice had little effect on the activity of Cry1Aa, Cry1Ac, Cry1Ca, Cry1Ea, and R233A, a mutant of Cry1Aa from which one of the four salt bridges linking domains I and II of the toxin was eliminated, it greatly increased the activity of Cry1Ab. In addition, when tested in the presence of a cocktail of protease inhibitors or when boiled, midgut juice retained almost completely its capacity to enhance Cry1Ab activity, suggesting that proteases were not responsible for the stimulation. On the other hand, in the absence of midgut juice, the cocktail of protease inhibitors also enhanced the activity of Cry1Ab, suggesting that proteolytic cleavage by membrane proteases could render the toxin less effective. The lower toxicity of R233A, despite a similar in vitro pore-forming ability, compared with Cry1Aa, cannot be accounted for by an increased susceptibility to midgut proteases. Although these assays were performed under conditions approaching those found in the larval midgut, the depolarizing activities of the toxins correlated only partially with their toxicities. PMID- 17693569 TI - Characterization of the polyurethanolytic activity of two Alicycliphilus sp. strains able to degrade polyurethane and N-methylpyrrolidone. AB - Two bacterial strains (BQ1 and BQ8) were isolated from decomposed soft foam. These were selected for their capacity to grow in a minimal medium (MM) supplemented with a commercial surface-coating polyurethane (PU) (Hydroform) as the carbon source (MM-PUh). Both bacterial strains were identified as Alicycliphilus sp. by comparative 16S rRNA gene sequence analysis. Growth in MM PUh showed hyperbolic behavior, with BQ1 producing higher maximum growth (17.8 +/ 0.6 mg.ml(-1)) than BQ8 (14.0 +/- 0.6 mg.ml(-1)) after 100 h of culture. Nuclear magnetic resonance, Fourier transform infrared (IR) spectroscopy, and gas chromatography-mass spectrometry analyses of Hydroform showed that it was a polyester PU type which also contained N-methylpyrrolidone (NMP) as an additive. Alicycliphilus sp. utilizes NMP during the first stage of growth and was able to use it as the sole carbon and nitrogen source, with calculated K(s) values of about 8 mg.ml(-1). Enzymatic activities related to PU degradation (esterase, protease, and urease activities) were tested by using differential media and activity assays in cell-free supernatants of bacterial cultures in MM-PUh. Induction of esterase activity in inoculated MM-PUh, but not that of protease or urease activities, was observed at 12 h of culture. Esterase activity reached its maximum at 18 h and was maintained at 50% of its maximal activity until the end of the analysis (120 h). The capacity of Alicycliphilus sp. to degrade PU was demonstrated by changes in the PU IR spectrum and by the numerous holes produced in solid PU observed by scanning electron microscopy after bacterial culture. Changes in the PU IR spectra indicate that an esterase activity is involved in PU degradation. PMID- 17693570 TI - Gender-stratified analysis of DLG5 R30Q in 4707 patients with Crohn disease and 4973 controls from 12 Caucasian cohorts. AB - BACKGROUND: DLG5 p.R30Q has been reported to be associated with Crohn disease (CD), but this association has not been replicated in most studies. A recent analysis of gender-stratified data from two case-control studies and two population cohorts found an association of DLG5 30Q with increased risk of CD in men but not in women and found differences between 30Q population frequencies for males and females. Male-female differences in population allele frequencies and male-specific risk could explain the difficulty in replicating the association with CD. METHODS: DLG5 R30Q genotype data were collected for patients with CD and controls from 11 studies that did not include gender-stratified allele counts in their published reports and tested for male-female frequency differences in controls and for case-control frequency differences in men and in women. RESULTS: The data showed no male-female allele frequency differences in controls. An exact conditional test gave marginal evidence that 30Q is associated with decreased risk of CD in women (p = 0.049, OR = 0.87, 95% CI 0.77 to 1.00). There was also a trend towards reduced 30Q frequencies in male patients with CD compared with male controls, but this was not significant at the 0.05 level (p = 0.058, OR = 0.87, 95% CI 0.74 to 1.01). When data from this study were combined with previously published, gender-stratified data, the 30Q allele was found to be associated with decreased risk of CD in women (p = 0.010, OR = 0.86, 95% CI 0.76 to 0.97), but not in men. CONCLUSION: DLG5 30Q is associated with a small reduction in risk of CD in women. PMID- 17693571 TI - Direct linkage of mitochondrial genome variation to risk factors for type 2 diabetes in conplastic strains. AB - Recently, the relationship of mitochondrial DNA (mtDNA) variants to metabolic risk factors for diabetes and other common diseases has begun to attract increasing attention. However, progress in this area has been limited because (1) the phenotypic effects of variation in the mitochondrial genome are difficult to isolate owing to confounding variation in the nuclear genome, imprinting phenomena, and environmental factors; and (2) few animal models have been available for directly investigating the effects of mtDNA variants on complex metabolic phenotypes in vivo. Substitution of different mitochondrial genomes on the same nuclear genetic background in conplastic strains provides a way to unambiguously isolate effects of the mitochondrial genome on complex traits. Here we show that conplastic strains of rats with identical nuclear genomes but divergent mitochondrial genomes that encode amino acid differences in proteins of oxidative phosphorylation exhibit differences in major metabolic risk factors for type 2 diabetes. These results (1) provide the first direct evidence linking naturally occurring variation in the mitochondrial genome, independent of variation in the nuclear genome and other confounding factors, to inherited variation in known risk factors for type 2 diabetes; and (2) establish that spontaneous variation in the mitochondrial genome per se can promote systemic metabolic disturbances relevant to the pathogenesis of common diseases. PMID- 17693572 TI - A multidimensional analysis of genes mutated in breast and colorectal cancers. AB - A recent study of a large number of genes in a panel of breast and colorectal cancers identified somatic mutations in 1149 genes. To identify potential biological processes affected by these genes, we examined their putative roles based on sequence similarity, membership in known functional groups and pathways, and predicted interactions with other proteins. These analyses identified functional groups and pathways that were enriched for mutated genes in both tumor types. Additionally, the results pointed to differences in molecular mechanisms that underlie breast and colorectal cancers, including various intracellular signaling and metabolic pathways. These studies provide a multidimensional framework to guide further research and help identify cellular processes critical for malignant progression and therapeutic intervention. PMID- 17693573 TI - Domain-wide regulation of gene expression in the human genome. AB - Transcription factor complexes bind to regulatory sequences of genes, providing a system of individual expression regulation. Targets of distinct transcription factors usually map throughout the genome, without clustering. Nevertheless, highly and weakly expressed genes do cluster in separate chromosomal domains with an average size of 80-90 genes. We therefore asked whether, besides transcription factors, an additional level of gene expression regulation exists that acts on chromosomal domains. Here we show that identical green fluorescent protein (GFP) reporter constructs integrated at 90 different chromosomal positions obtain expression levels that correspond to the activity of the domains of integration. These domains are up to 80 genes long and can exert an eightfold effect on the expression levels of integrated genes. 3D-FISH shows that active domains of integration have a more open chromatin structure than integration domains with weak activity. These results reveal a novel domain-wide regulatory mechanism that, together with transcription factors, exerts a dual control over gene transcription. PMID- 17693574 TI - A public-domain image processing tool for automated quantification of fluorescence in situ hybridisation signals. AB - AIMS: To develop and evaluate an automated method for quantification of HER2 fluorescence in situ hybridisation (FISH) signals. METHODS: Using a popular, open source image manipulation tool, ImageJ, a macro for FISH signal assessment was created. A comparison against traditional manual counting was performed in breast cancer specimens from 42 patients. The tumour specimens were hybridised with probes for HER2 and chromosome 17 centromere (CEP17) and selected areas were digitised for image processing. Hybridisation signals were calculated both manually and automatically with the ImageJ custom macro. RESULTS: The correlation coefficient between the automatic and manual HER2/CEP17 ratios was 0.98. The corresponding percentage agreement was 90% and the kappa value was 0.82. CONCLUSIONS: This study shows that it is possible to automate the determination of HER2 amplification by the use of open-source software, with results comparable to manual counting. The automated counting decreases the time needed for sample analysis and provides possibilities to enhance inter- and intralaboratory reproducibility of results. The FISH quantification tool (FishJ) is available for download as an ImageJ macro or alternatively it can be utilised through a web interface with an option of uploading FISH images for hybridisation signal counting. Combined with digitisation of FISH samples, the FishJ macro enables gene copy number to be assessed and re-evaluated on any area of a digitised specimen. PMID- 17693575 TI - Small bowel gastric metaplasia: a report of three cases in children. AB - AIMS: To report three children displaying gastric metaplasia antral pyloric type of the small bowel mucosa. METHODS: Analysis of clinical, histopathological and immunohistochemical data. RESULTS: The first patient was a 14-year-old girl with history of chronic intestinal pseudo-obstruction and chronic jejunitis; the second patient was a 6-year-old girl with a long-lasting jejunostomy; and the third patient was a 5-year-old girl with ileal-rectal anastomosis. The foci of gastric metaplasia were obvious with H&E-stained sections. The cells at the gastric metaplasia mucosa proved to be MUC-1 and sialyl-Tn positive by immunohistochemistry and they were in a pattern that was different from that of the adjacent mucosa; the cells were autofluorescent in H&E-stained sections. CONCLUSIONS: Gastric metaplasia of the small bowel mucosa in these cases seems to have resulted from chronic inflammation and persistent regenerative activity. This has rarely been reported outside Crohn disease, and if ever in children. PMID- 17693576 TI - Quantification of intrahepatic total hepatitis B virus DNA in chronic hepatitis B patients and its relationship with liver histology. AB - AIMS: This study was conducted to evaluate the relationship between total intrahepatic hepatitis B virus (HBV) DNA levels and liver histology in terms of the degree of histological activity index (HAI) that yields necroinflammation (HAI-NI) and fibrosis (HAI-F) of the liver. METHODS: Prospectively, Tru-cut needle biopsy samples were obtained from the livers of 42 patients with chronic hepatitis B. Levels of serum and liver HBV DNA were determined by quantitative real-time PCR. Demographic data of patients, together with hepatitis B serology, alanine aminotransferase levels, and HAI-NI and HAI-F scores, were recorded. RESULTS: Twenty of the patients were hepatitis B e antigen (HBeAg) positive, while 22 patients were positive for antibody to HBeAg (anti-HBe). Serum and liver total HBV DNA levels were found to correlate directly with each other in the two groups (r = 0.669, p = 0.001; and r = 0.880, p<0.001; respectively) and the correlation was more marked in anti-HBe-positive patients. Although serum HBV DNA levels correlated positively with HAI-NI and HAI-F scores in HBeAg-positive and HBeAg-negative patients, total liver HBV DNA levels correlated with HAI-NI and HAI-F scores in anti-HBe-positive patients only. CONCLUSIONS: Quantitative measurement of intrahepatic HBV DNA is a valuable marker of the histological status of the liver in anti-HBe-positive patients with chronic hepatitis B, and it may give an insight into the prognosis and the ideal time for the cessation of antiviral treatment. PMID- 17693577 TI - Value of multicolour fluorescence in situ hybridisation (UroVysion) in the differential diagnosis of flat urothelial lesions. AB - AIMS: During the past 10 years, multitarget fluorescence in situ hybridisation has been established as a valuable adjunct in the cytological diagnosis of precancerous and malignant lesions of the urinary tract. The aim of the present study was to define its value in detecting chromosomal imbalances in patients with various flat urothelial lesions in routine paraffin-embedded bladder biopsy samples. In addition, the HER2 gene amplification and HER2 expression pattern were examined, since alterations of the HER2 expression patterns have been demonstrated in invasive bladder cancer. METHODS: 29 samples of normal urothelium and 86 flat urothelial lesions (hyperplasia, reactive atypia, dysplasia and carcinoma in situ (CIS)) from 73 patients were analysed patients using tissue microarrays and centromeric probes for chromosomes 3, 7 and 17, and gene-specific probes for 9p21/P16 and HER2 (UroVysion, PathVysion). The expression of HER2 was studied by immunohistochemistry. RESULTS: Polysomy of at least one of the chromosomes was found in about half of the dysplastic cells, and in more than 90% of cells in CIS or cells in invasive bladder tumours. Polysomic cells were found in only 17% of urothelial hyperplasia, reactive atypia and normal urothelium of healthy patients, whereas about 30% of non-neoplastic lesions in patients with concomitant urothelial carcinoma showed polysomy of at least one chromosome. These alterations indicate a field effect and are associated with synchronous development of dysplastic lesions of a higher grade. Deletion of the P16 locus was most frequently observed in aneuploid lesions, whereas overexpression of HER2 was found in 10-20% of invasive urothelial carcinomas, and only occasionally in CIS (5%). An altered HER2 expression pattern was present in non-neoplastic lesions (25%). CONCLUSIONS: UroVysion fluorescence in situ hybridisation is a valuable tool for the detection of genetically unstable flat urothelial lesions, and can help to resolve difficult cases, particularly the differential diagnosis of reactive atypia and dysplasia. PMID- 17693578 TI - Frequent nuclear expression of beta-catenin protein but rare beta-catenin mutation in pulmonary sclerosing haemangioma. AB - BACKGROUND: Pulmonary sclerosing haemangioma (PSH) is an uncommon tumour that is composed of glandular/papillary lining cells and polygonal cells. The biological behaviour of this tumour has been investigated; however, the molecular pathogenesis of PSH remains unknown. AIMS: To characterise the role of the Wnt/beta-catenin pathway in the genesis of PSH. METHODS: 37 PSH samples were investigated immunohistochemically for detection of the beta-catenin protein and direct sequencing of exon 3 of the beta-catenin gene. RESULTS: Nuclear expression of beta-catenin was found in the lining component of 23 tumours (62%) and in the polygonal component of 11 tumours (30%). The expression of beta-catenin was stronger in the lining component, but weaker in the polygonal component. Interestingly, all the tumours with expression of beta-catenin in the polygonal component also expressed beta-catenin in the lining component. However, mutation of exon 3 of the beta-catenin gene was detected in only one tumour that expressed nuclear beta-catenin in lining and polygonal components. CONCLUSIONS: The Wnt/beta-catenin pathway is involved in the genesis of PSH, but mutation of exon 3 of the beta-catenin gene rarely contributes to the activation of the Wnt/beta catenin pathway in PSH. PMID- 17693579 TI - CysLT2 receptors interact with CysLT1 receptors and down-modulate cysteinyl leukotriene dependent mitogenic responses of mast cells. AB - Cysteinyl leukotrienes (cys-LTs) induce inflammation through 2 G protein-coupled receptors (GPCRs), CysLT(1) and CysLT(2), which are coexpressed by most myeloid cells. Cys-LTs induce proliferation of mast cells (MCs), transactivate c-Kit, and phosphorylate extracellular signal-regulated kinase (ERK). Although MCs express CysLT(2), their responses to cys-LTs are blocked by antagonists of CysLT(1). We demonstrate that CysLT(2) interacts with CysLT(1), and that knockdown of CysLT(2) increases CysLT(1) surface expression and CysLT(1)-dependent proliferation of cord blood-derived human MCs (hMCs). Cys-LT-mediated responses were absent in MCs from mice lacking CysLT(1) receptors, but enhanced by the absence of CysLT(2) receptors. CysLT(1) and CysLT(2) receptors colocalized to the plasma membranes and nuclei of a human MC line, LAD2. Antibody-based fluorescent lifetime imaging microscopy confirmed complexes containing both receptors based on fluorescence energy transfer. Negative regulation of CysLT(1)-induced mitogenic signaling responses of MCs by CysLT(2) demonstrates physiologically relevant functions for GPCR heterodimers on primary cells central to inflammation. PMID- 17693580 TI - Src-family kinase dependent disruption of endothelial barrier function by Plasmodium falciparum merozoite proteins. AB - Pulmonary complication in severe Plasmodium falciparum malaria is manifested as a prolonged impairment of gas transfer or the more severe acute respiratory distress syndrome (ARDS). In either clinical presentation, vascular permeability is a major component of the pathologic process. In this report, we examined the effect of clinical P falciparum isolates on barrier function of primary dermal and lung microvascular endothelium in vitro. We showed that parasite sonicates but not intact infected erythrocytes disrupted endothelial barrier function in a Src-family kinase-dependent manner. The abnormalities were manifested both as discontinuous immunofluorescence staining of the junctional proteins ZO-1, claudin 5, and VE-cadherin and the formation of interendothelial gaps in monolayers. These changes were associated with a loss in total protein content of claudin 5 and redistribution of ZO-1 from the cytoskeleton to the membrane and the cytosolic and nuclear fractions. There was minimal evidence of a proinflammatory response or direct cellular cytotoxicity or cell death. The active component in sonicates appeared to be a merozoite-associated protein. Increased permeability was also induced by P falciparum glycophosphatidylinositols (GPIs) and food vacuoles. These results demonstrate that parasite components can alter endothelial barrier function and thus contribute to the pathogenesis of severe falciparum malaria. PMID- 17693581 TI - Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease. AB - Graft-versus-host disease (GVHD) remains the major complication after allogeneic bone marrow transplantation (BMT). The process whereby acute GVHD mediated by alloreactive donor T cells transitions into chronic GVHD, which is characterized by prominent features of auto-immunity, has long been unresolved. In this study, we demonstrate that GVHD-associated autoimmunity and, by extension, chronic GVHD is attributable to the progressive loss of CD4(+)CD25(+)Foxp3(+) regulatory T cells during the course of acute GVHD. This leads to the expansion of donor derived CD4(+) T cells with T(H)1 and T(H)17 cytokine phenotypes that release proinflammatory cytokines and cause autoimmune-mediated pathological damage. These T cells are present early after transplantation, indicating that the pathophysiological events that lead to chronic GVHD are set in motion during the acute phase of GVHD. We conclude that the absence of CD4(+)CD25(+) regulatory T cells coupled with unregulated T(H)1 and T(H)17 cells leads to the development of autoimmunity and that donor-derived T(H)1 and T(H)17 cells serve as the nexus between acute and chronic GVHD. PMID- 17693582 TI - Adaptor protein Lnk negatively regulates the mutant MPL, MPLW515L associated with myeloproliferative disorders. AB - Recently, activating myeloproliferative leukemia virus oncogene (MPL) mutations, MPLW515L/K, were described in myeloproliferative disorder (MPD) patients. MPLW515L leads to activation of downstream signaling pathways and cytokine independent proliferation in hematopoietic cells. The adaptor protein Lnk is a negative regulator of several cytokine receptors, including MPL. We show that overexpression of Lnk in Ba/F3-MPLW515L cells inhibits cytokine-independent growth, while suppression of Lnk in UT7-MPLW515L cells enhances proliferation. Lnk blocks the activation of Jak2, Stat3, Erk, and Akt in these cells. Furthermore, MPLW515L-expressing cells are more susceptible to Lnk inhibitory functions than their MPL wild-type (MPLWT)-expressing counterparts. Lnk associates with activated MPLWT and MPLW515L and colocalizes with the receptors at the plasma membrane. The SH2 domain of Lnk is essential for its binding and for its down-regulation of MPLWT and MPLW515L. Lnk itself is tyrosine phosphorylated following thrombopoietin stimulation. Further elucidating the cellular pathways that attenuate MPLW515L will provide insight into the pathogenesis of MPD and could help develop specific therapeutic approaches. PMID- 17693583 TI - Infection of hematopoietic progenitor cells by HIV-1 subtype C, and its association with anemia in southern Africa. AB - Reports from southern Africa, an area in which human immunodeficiency virus type 1 (HIV-1) infection is caused almost exclusively by subtype C (HIV-1C), have shown increased rates of anemia in HIV-infected populations compared with similar acquired immunodeficiency syndrome (AIDS) patients in the United States, an area predominantly infected with subtype B (HIV-1B). Recent findings by our group demonstrated a direct association between HIV-1 infection and hematopoietic progenitor cell health in Botswana. Therefore, using a single-colony infection assay and quantitative proviral analysis, we examined whether HIV-1C could infect hematopoietic progenitor cells (HPCs) and whether this phenotype was associated with the higher rates of anemia found in southern Africa. The results show that a significant number of HIV-1C, but not HIV-1B, isolates can infect HPCs in vitro (P < .05). In addition, a portion of HIV-1C-positive Africans had infected progenitor cell populations in vivo, which was associated with higher rates of anemia in these patients (P < .05). This represents a difference in cell tropism between 2 geographically separate and distinct HIV-1 subtypes. The association of this hematotropic phenotype with higher rates of anemia should be considered when examining anti-HIV drug treatment regimens in HIV-1C-predominant areas, such as southern Africa. PMID- 17693584 TI - Regulator of G-protein signaling 4 interacts with metabotropic glutamate receptor subtype 5 in rat striatum: relevance to amphetamine behavioral sensitization. AB - Regulator of G-protein signaling (RGS) 4 negatively modulates signaling of several Galpha(q)-coupled receptors, including metabotropic glutamate receptor (mGluR) subtype 5 in neuronal and non-neuronal cell lines. In the brain, both RGS4 and mGluR5 receptors are enriched in the striatum, and their functions have been linked to psychostimulant-induced behavior and synaptic plasticity. However, it is not known whether RGS4 and mGluR5 interactions occur in rat striatum and whether chronic amphetamine (AMPH) treatment produces changes in RGS4 levels that are correlated with mGluR5 receptor activity. Using coimmunoprecipitation, the present study demonstrated that endogenous RGS4 binds mGluR5 receptors as well as key mGluR5-associated proteins, Galpha(q/11), and phospholipase C-beta1 (PLCbeta1) in preparations from rat striatum. In the next experiment, rats were treated with AMPH (5 mg/kg i.p. daily) for 5 days followed by 3 weeks of abstinence. At this time point, animals pretreated with AMPH displayed sensitized behavioral responses to AMPH challenge and decreased RGS4 protein in dorsal striatum and nucleus accumbens. Behavioral sensitization to AMPH was also accompanied by an increase in Galpha(q/11) and PLCbeta1 in dorsal striatum. In contrast, total levels of mGluR5 receptors in the striatum were not altered by any AMPH treatment. In conclusion, the present study demonstrates that RGS4 protein is an integral part of the mGluR5 protein complex in the striatum. This study further suggests that AMPH-induced changes in mGluR5-associated protein levels (RGS4, Galpha(q/11), and PLCbeta1) may be related to altered coupling of striatal mGluR5 receptors in animals sensitized to AMPH. PMID- 17693585 TI - Methylphenidate administration alters vesicular monoamine transporter-2 function in cytoplasmic and membrane-associated vesicles. AB - In vivo methylphenidate (MPD) administration increases vesicular monoamine transporter-2 (VMAT-2) immunoreactivity, VMAT-2-mediated dopamine (DA) transport, and DA content in a nonmembrane-associated (referred to herein as cytoplasmic) vesicular subcellular fraction purified from rat striatum: a phenomenon attributed to a redistribution of VMAT-2-associated vesicles within nerve terminals. In contrast, the present study elucidated the nature of, and the impact of MPD on, VMAT-2-associated vesicles that cofractionate with synaptosomal membranes after osmotic lysis (referred to herein as membrane-associated vesicles). Results revealed that, in striking contrast to the cytoplasmic vesicles, DA transport velocity versus substrate concentration curves in the membrane-associated vesicles were sigmoidal, suggesting positive cooperativity with respect to DA transport. Additionally, DA transport into membrane-associated vesicles was greater in total capacity in the presence of high DA concentrations than transport into cytoplasmic vesicles. Of potential therapeutic relevance, MPD increased DA transport into the membrane-associated vesicles despite rapidly decreasing (presumably by redistributing) VMAT-2 immunoreactivity in this fraction. Functional relevance was suggested by findings that MPD treatment increased both the DA content of the membrane-associated vesicle fraction and K(+)-stimulated DA release from striatal suspensions. In summary, the present data demonstrate the existence of a previously uncharacterized pool of membrane associated VMAT-2-containing vesicles that displays novel transport kinetics, has a large sequestration capacity, and responds to in vivo pharmacological manipulation. These findings provide insight into both the regulation of vesicular DA sequestration and the mechanism of action of MPD, and they may have implications regarding treatment of disorders involving abnormal DA disposition, including Parkinson's disease and substance abuse. PMID- 17693586 TI - N-Benzyladriamycin-14-valerate (AD 198): a non-cardiotoxic anthracycline that is cardioprotective through PKC-epsilon activation. AB - N-Benzyladriamycin-14-valerate (AD 198) is one of several novel anthracycline protein kinase C (PKC)-activating agents developed in our laboratories that demonstrates cytotoxic superiority over doxorubicin (Adriamycin; DOX) through its circumvention of multiple mechanisms of drug resistance. This characteristic is attributed at least partly to the principal cellular action of AD 198: PKC activation through binding to the C1b (diacylglycerol binding) regulatory domain. A significant dose-limiting effect of DOX is chronic, dose-dependent, and often irreversible cardiotoxicity ascribed to the generation of reactive oxygen species (ROS) from the semiquinone ring structure of DOX. Despite the incorporation of the same ring structure in AD 198, we hypothesized that AD 198 might also be cardioprotective through its ability to activate PKC-epsilon, a key component of protective ischemic preconditioning in cardiomyocytes. Chronic administration of fractional LD(50) doses of DOX and AD 198 to mice results in histological evidence of dose-dependent ventricular damage by DOX but is largely absent from AD 198-treated mice. The absence of significant cardiotoxicity with AD 198 occurs despite the equal ability of DOX and AD 198 to generate ROS in primary mouse cardiomyocytes. Excised rodent hearts perfused with AD 198 prior to hypoxia induced by vascular occlusion are protected from functional impairment to an extent comparable to preconditioning ischemia. AD 198-mediated cardioprotection correlates with increased PKC-epsilon activation and is inhibited in hearts from PKC-epsilon knockout mice. These results suggest that, despite ROS production, the net cardiac effect of AD 198 is protection through activation of PKC-epsilon. PMID- 17693587 TI - Differential down-regulation of aquaporin-2 in rat kidney zones by peripheral nociceptin/orphanin FQ receptor agonism and vasopressin type-2 receptor antagonism. AB - We previously showed that aquaresis induced by the peripherally acting nociceptin/orphanin FQ receptor agonist ZP120 is associated with a decreased protein level of aquaporin-2 (AQP2) in whole-kidney homogenates. We now examined the effects of Ac-RYYRWKKKKKKK-NH(2) (ZP120) (1 nmol/kg/min i.v. for 4 h) on renal regional expression (cortex/outer stripe of outer medulla, inner stripe of outer medulla, and inner medulla) and subcellular localization of aquaporin-2. Responses to ZP120 were compared to the effects of an equi-aquaretic dose ( approximately 40% inhibition of distal water reabsorption) of the vasopressin type-2 receptor antagonist 5-dimethylamine-1-[4-(2-methylbenzoylamino)benzoyl] 2,3,4,5-tetrahydro-1H-benzapine (OPC31260) (32 nmol/kg/min). ZP120 decreased the aquaporin-2 protein level in the rat cortex/outer stripe of outer medulla and decreased apical plasma membrane localization of aquaporin-2 in the cortex (P = 0.002) and in the inner medulla (P = 0.06). These effects were not accompanied by a decrease in the aquaporin-2 mRNA level. OPC31260-induced aquaresis was associated with a decreased aquaporin-2 protein level in both the cortex/outer stripe of outer medulla and in the inner stripe of outer medulla. Apical localization of aquaporin-2 was decreased throughout all kidney zones, and OPC31260 decreased the AQP2 mRNA level in the inner medulla. We conclude that equi-aquaretic doses of ZP120 and OPC31260 produce different patterns of aquaporin-2 down-regulation, suggesting different signaling pathways. PMID- 17693588 TI - Development and evaluation of a real-time PCR assay for detection of Pneumocystis jirovecii DNA in bronchoalveolar lavage fluid of HIV-infected patients. AB - BACKGROUND: Pneumocystis pneumonia (PCP) is conventionally diagnosed by identifying Pneumocystis jirovecii in lower respiratory tract samples using cytochemical stains. Molecular diagnosis of PCP is potentially more sensitive. METHODS: A study was undertaken to use an extensively optimised real-time polymerase chain reaction (PCR) using primers designed to hybridise with the P. jirovecii heat shock protein 70 (HSP70) gene to quantify P. jirovecii DNA in bronchoalveolar lavage (BAL) fluid from HIV-infected patients with and without PCP, and to compare this assay with conventional PCR targeting the P. jirovecii mitochondrial large subunit rRNA gene sequence (mt LSU rRNA). RESULTS: Sixty-one patients had 62 episodes of PCP (defined by detection of P. jirovecii in BAL fluid by cytochemical stains and typical clinical presentation). Quantifiable HSP70 DNA was detected in 61/62 (range approximately 13-18,608 copies/reaction; median approximately 332) and was detectable but below the limit of quantification (approximately 5 copies/reaction) in 1/62. Seventy-one other patients had 74 episodes with alternative diagnoses. Quantifiable HSP70 DNA was detectable in 6/74 (8%) episodes (range approximately 6-590 copies/reaction; median approximately 14) and detectable but below the limit of quantification in 34/74 (46%). Receiver-operator curve analysis (cut-off >10 copies/reaction) showed a clinical sensitivity of 98% (95% 91% to 100%) and specificity of 96% (95% CI 87% to 99%) for diagnosis of PCP. By contrast, clinical sensitivity of mt LSU rRNA PCR was 97% (95% CI 89% to 99%) and specificity was 68% (95% CI 56% to 78%). CONCLUSION: The HSP70 real-time PCR assay detects P. jirovecii DNA in BAL fluid and may have a diagnostic application. Quantification of P. jirovecii DNA by real-time PCR may also discriminate between colonisation with P. jirovecii and infection. PMID- 17693589 TI - Web sites and pediatric residency training programs in the United States. AB - The purpose of this study was to describe the use of Web sites by pediatric residency programs in the United States, the information provided on those Web sites, and the degree of user-friendliness in navigating the Web sites. Most residency programs (137/197) listed a Web address; 96% (131) of these sites were accessible and were analyzed. Most programs (98/131) provided information for 11 to 20 content items, 11 programs described less than 10 content items, and the remaining 22 programs listed 21 to 42 content items on their Web sites. Most Web sites (87%) were categorized into the user-friendly level. Extremely user friendly Web sites also provided information on significantly more content items. Although 95% and 96% of positions were filled through match in programs with user friendly Web sites and programs with extremely user-friendly Web sites, respectively, these were not statistically different from the programs with less user-friendly Web sites, where only 88% of positions were filled through the match. The majority of pediatric residency training programs have Web sites. Most of these Web sites were user-friendly and provided a variety of information sought by applicants. PMID- 17693590 TI - Toxic remedy: a case of a 3-year-old child with lead colic treated with lead monoxide (greta). AB - This article reports the case of a 3-year-old male with an elevated blood lead level. The child had a history of consuming imported lead-contaminated candies resulting in abdominal pains for which he was given a Hispanic folk remedy, called greta, by his mother. The home remedy aggravated the child's symptoms which prompted medical consultation. Analysis of the powdered folk remedy revealed a lead concentration of 140 000 ppm. This case highlights the complexities associated with identifying unfamiliar sources of lead poisoning, and their potential relationships to cultural practices. PMID- 17693591 TI - Hematometrocolpos presenting as sciatica, constipation, and urinary retention. PMID- 17693592 TI - Improving pediatric practice immunization rates through distance-based quality improvement: a feasibility trial from PROS. AB - The feasibility and effectiveness of a distance-based quality improvement model were examined in a cohort of Pediatric Research in Office Settings (PROS) practices, with the goal of improving immunization rates and practitioner behaviors and attitudes. Of an initially assessed 82 practices, 29 with baseline rates of < or =88% for children 8 to 15 months of age were randomized into year long paper-based education or distance-based quality improvement intervention groups. Outcomes were utility/helpfulness of quality improvement modalities, immunization rate change, and behavior/attitude change. Quality improvement participants attended approximately 75% of monthly conference calls but used the quality improvement Listserv and Web site infrequently (mean 1.09 and 0.92 uses, respectively). Helpfulness ratings of quality improvement modalities mirrored usage. Analyses revealed a 4.9% increase in quality improvement group immunization rates (P = .061), a 0.8% education group increase (P = .752), and a 4.1% difference between groups (P = .261). More quality improvement practices adopted systems identifying children behind in immunizations. A distance-based quality improvement model is feasible and may improve immunization rates. PMID- 17693593 TI - Ku heterodimer-independent end joining in Trypanosoma brucei cell extracts relies upon sequence microhomology. AB - DNA double-strand breaks (DSBs) are repaired primarily by two distinct pathways: homologous recombination and nonhomologous end joining (NHEJ). NHEJ has been found in all eukaryotes examined to date and has been described recently for some bacterial species, illustrating its ancestry. Trypanosoma brucei is a divergent eukaryotic protist that evades host immunity by antigenic variation, a process in which homologous recombination plays a crucial function. While homologous recombination has been examined in some detail in T. brucei, little work has been done to examine what other DSB repair pathways the parasite utilizes. Here we show that T. brucei cell extracts support the end joining of linear DNA molecules. These reactions are independent of the Ku heterodimer, indicating that they are distinct from NHEJ, and are guided by sequence microhomology. We also demonstrate bioinformatically that T. brucei, in common with other kinetoplastids, does not encode recognizable homologues of DNA ligase IV or XRCC4, suggesting that NHEJ is either absent or mechanistically diverged in these pathogens. PMID- 17693594 TI - Internal and surface-localized major surface proteases of Leishmania spp. and their differential release from promastigotes. AB - Major surface protease (MSP), also called GP63, is a virulence factor of Leishmania spp. protozoa. There are three pools of MSP, located either internally within the parasite, anchored to the surface membrane, or released into the extracellular environment. The regulation and biological functions of these MSP pools are unknown. We investigated here the trafficking and extrusion of surface versus internal MSPs. Virulent Leishmania chagasi undergo a growth-associated lengthening in the t(1/2) of surface-localized MSP, but this did not occur in the attenuated L5 strain. The release of surface-localized MSP was enhanced in a dose dependent manner by MbetaCD, which chelates membrane cholesterol-ergosterol. Furthermore, incubation of promastigotes at 37 degrees C with Matrigel matrix, a soluble basement membrane extract of Engelbreth-Holm-Swarm tumor cells, stimulated the release of internal MSP but not of surface-located MSP. Taken together, these data indicate that MSP subpopulations in distinct cellular locations are released from the parasite under different environmental conditions. We hypothesize that the internal MSP with its lengthy t(1/2) does not serve as a pool for promastigote surface MSP in the sand fly vector but that it instead functions as an MSP pool ready for quick release upon inoculation of metacyclic promastigotes into mammals. We present a model in which these different MSP pools are released under distinct life cycle-specific conditions. PMID- 17693595 TI - WdStuAp, an APSES transcription factor, is a regulator of yeast-hyphal transitions in Wangiella (Exophiala) dermatitidis. AB - APSES transcription factors are well-known regulators of fungal cellular development and differentiation. To study the function of an APSES protein in the fungus Wangiella dermatitidis, a conidiogenous and polymorphic agent of human phaeohyphomycosis with yeast predominance, the APSES transcription factor gene WdSTUA was cloned, sequenced, disrupted, and overexpressed. Analysis showed that its derived protein was most similar to the APSES proteins of other conidiogenous molds and had its APSES DNA-binding domain located in the amino-terminal half. Deletion of WdSTUA in W. dermatitidis induced convoluted instead of normal smooth colony surface growth on the rich yeast maintenance agar medium yeast extract peptone-dextrose agar (YPDA) at 37 degrees C. Additionally, deletion of WdSTUA repressed aerial hyphal growth, conidiation, and invasive hyphal growth on the nitrogen-poor, hypha-inducing agar medium potato dextrose agar (PDA) at 25 degrees C. Ectopic overexpression of WdSTUA repressed the convoluted colony surface growth on YPDA at 37 degrees C, and also strongly repressed hyphal growth on PDA at 25 degrees C and 37 degrees C. These new results provide additional insights into the diverse roles played by APSES factors in fungi. They also suggest that the transcription factor encoded by WdSTUA is both a positive and negative morphotype regulator in W. dermatitidis and possibly other of the numerous human pathogenic, conidiogenous fungi capable of yeast growth. PMID- 17693596 TI - Genotypic evolution of azole resistance mechanisms in sequential Candida albicans isolates. AB - TAC1 (for transcriptional activator of CDR genes) is critical for the upregulation of the ABC transporters CDR1 and CDR2, which mediate azole resistance in Candida albicans. While a wild-type TAC1 allele drives high expression of CDR1/2 in response to inducers, we showed previously that TAC1 can be hyperactive by a gain-of-function (GOF) point mutation responsible for constitutive high expression of CDR1/2. High azole resistance levels are achieved when C. albicans carries hyperactive alleles only as a consequence of loss of heterozygosity (LOH) at the TAC1 locus on chromosome 5 (Chr 5), which is linked to the mating-type-like (MTL) locus. Both are located on the Chr 5 left arm along with ERG11 (target of azoles). In this work, five groups of related isolates containing azole-susceptible and -resistant strains were analyzed for the TAC1 and ERG11 alleles and for Chr 5 alterations. While recovered ERG11 alleles contained known mutations, 17 new TAC1 alleles were isolated, including 7 hyperactive alleles with five separate new GOF mutations. Single-nucleotide polymorphism analysis of Chr 5 revealed that azole-resistant strains acquired TAC1 hyperactive alleles and, in most cases, ERG11 mutant alleles by LOH events not systematically including the MTL locus. TAC1 LOH resulted from mitotic recombination of the left arm of Chr 5, gene conversion within the TAC1 locus, or the loss and reduplication of the entire Chr 5. In one case, two independent TAC1 hyperactive alleles were acquired. Comparative genome hybridization and karyotype analysis revealed the presence of isochromosome 5L [i(5L)] in two azole-resistant strains. i(5L) leads to increased copy numbers of azole resistance genes present on the left arm of Chr 5, among them TAC1 and ERG11. Our work shows that azole resistance was due not only to the presence of specific mutations in azole resistance genes (at least ERG11 and TAC1) but also to their increase in copy number by LOH and to the addition of extra Chr 5 copies. With the combination of these different modifications, sophisticated genotypes were obtained. The development of azole resistance in C. albicans is therefore a powerful instrument for generating genetic diversity. PMID- 17693597 TI - Biosynthesis and immunogenicity of glucosylceramide in Cryptococcus neoformans and other human pathogens. PMID- 17693598 TI - Differential regulation and substrate preferences in two peptide transporters of Saccharomyces cerevisiae. AB - Dal5p has been shown previously to act as an allantoate/ureidosuccinate permease and to play a role in the utilization of certain dipeptides as a nitrogen source in Saccharomyces cerevisiae. Here, we provide direct evidence that dipeptides are transported by Dal5p, although the affinity of Dal5p for allantoate and ureidosuccinate is higher than that for dipeptides. Allantoate, ureidosuccinate, and to a lesser extent allantoin competed with dipeptide transport by reducing the toxicity of the peptide Ala-Eth and decreasing the accumulation of [(14)C]Gly Leu. In contrast to the well-studied di/tripeptide transporter Ptr2p, whose substrate specificity is very broad, Dal5p preferred to transport non-N-end rule dipeptides. S. cerevisiae W303 was sensitive to the toxic peptide Ala-Eth (non-N end rule peptide) but not Leu-Eth (N-end rule peptide). Non-N-end rule dipeptides showed better competition with the uptake of [(14)C]Gly-Leu than N-end rule dipeptides. Similar to the regulation of PTR2, DAL5 expression was influenced by the addition of Leu and by the CUP9 gene. However, DAL5 expression was downregulated in the presence of leucine and the absence of CUP9, whereas PTR2 was upregulated. Toxic dipeptide and uptake assays indicated that either Ptr2p or Dal5p was predominantly used for dipeptide transport in the common laboratory strains S288c and W303, respectively. These studies highlight the complementary activities of two dipeptide transport systems under different regulatory controls in common laboratory yeast strains, suggesting that dipeptide transport pathways evolved to respond to different environmental conditions. PMID- 17693601 TI - beta-catenin/TCF/Lef controls a differentiation-associated transcriptional program in renal epithelial progenitors. AB - In the embryonic kidney, progenitors in the metanephric mesenchyme differentiate into specialized renal epithelia in a defined sequence characterized by the formation of cellular aggregates, conversion into polarized epithelia and segmentation along a proximal-distal axis. This sequence is reiterated throughout renal development to generate nephrons. Here, we identify global transcriptional programs associated with epithelial differentiation utilizing an organ culture model of rat metanephric mesenchymal differentiation, which recapitulates the hallmarks of epithelialization in vivo in a synchronized rather than reiterative fashion. We observe activation of multiple putative targets of beta catenin/TCF/Lef-dependent transcription coinciding with epithelial differentiation. We show in cultured explants that isolated activation of beta catenin signaling in epithelial progenitors induces, in a TCF/Lef-dependent manner, a subset of the transcripts associated with epithelialization, including Pax8, cyclin D1 (Ccnd1) and Emx2. This is associated with anti-apoptotic and proliferative effects in epithelial progenitors, whereas cells with impaired TCF/Lef-dependent transcription are progressively depleted from the epithelial lineage. In vivo, TCF/Lef-responsive genes comprise a conserved transcriptional program in differentiating renal epithelial progenitors and beta-catenin containing transcriptional complexes directly bind to their promoter regions. Thus, beta-catenin/TCF/Lef-mediated transcriptional events control a subset of the differentiation-associated transcriptional program and thereby participate in maintenance, expansion and stage progression of the epithelial lineage. PMID- 17693602 TI - Neural plate morphogenesis during mouse neurulation is regulated by antagonism of Bmp signalling. AB - Dorsolateral bending of the neural plate, an undifferentiated pseudostratified epithelium, is essential for neural tube closure in the mouse spinal region. If dorsolateral bending fails, spina bifida results. In the present study, we investigated the molecular signals that regulate the formation of dorsolateral hinge points (DLHPs). We show that Bmp2 expression correlates with upper spinal neurulation (in which DLHPs are absent); that Bmp2-null embryos exhibit premature, exaggerated DLHPs; and that the local release of Bmp2 inhibits neural fold bending. Therefore, Bmp signalling is necessary and sufficient to inhibit DLHPs. By contrast, the Bmp antagonist noggin is expressed dorsally in neural folds containing DLHPs, noggin-null embryos show markedly reduced dorsolateral bending and local release of noggin stimulates bending. Hence, Bmp antagonism is both necessary and sufficient to induce dorsolateral bending. The local release of Shh suppresses dorsal noggin expression, explaining the absence of DLHPs at high spinal levels, where notochordal expression of Shh is strong. DLHPs ;break through' at low spinal levels, where Shh expression is weaker. Zic2 mutant embryos fail to express Bmp antagonists dorsally and lack DLHPs, developing severe spina bifida. Our findings reveal a molecular mechanism based on antagonism of Bmp signalling that underlies the regulation of DLHP formation during mouse spinal neural tube closure. PMID- 17693603 TI - What does the clinician need to improve patient care in systemic sclerosis? PMID- 17693604 TI - Protective effect of A at position - 168 in the type III promoter of the MHCIITA gene in systemic lupus erythematosus. PMID- 17693605 TI - Crico-thyroid perichondritis leading to sore throat in patients with active adult onset Still's disease. PMID- 17693606 TI - The low-penetrance R92Q mutation of the tumour necrosis factor superfamily 1A gene is neither a major risk factor for Wegener's granulomatosis nor multiple sclerosis. PMID- 17693607 TI - Serum serotonin levels are not useful in diagnosing fibromyalgia. PMID- 17693608 TI - Co-chaperone potentiation of vitamin D receptor-mediated transactivation: a role for Bcl2-associated athanogene-1 as an intracellular-binding protein for 1,25 dihydroxyvitamin D3. AB - The constitutively expressed member of the heat shock protein-70 family (hsc70) is a chaperone with multiple functions in cellular homeostasis. Previously, we demonstrated the ability of hsc70 to bind 25-hydroxyvitamin D3 (25-OHD3) and 1,25 dihydroxyvitamin D3 (1,25(OH)2D3). Hsc70 also recruits and interacts with the co chaperone Bcl2-associated athanogene (BAG)-1 via the ATP-binding domain that resides on hsc70. Competitive ligand-binding assays showed that, like hsc70, recombinant BAG-1 is able to bind 25-OHD3 (Kd=0.71+/-0.25 nM, Bmax 69.9+/-16.1 fmoles/microg protein) and 1,25(OH)2D3 (Kd=0.16+/-0.07 nM, Bmax = 38.1+/-3.5 fmoles/microg protein; both n=3 separate binding assays, P<0.001 for Kd and Bmax). To investigate the functional significance of this, we transiently overexpressed the S, M, and L variants of BAG-1 into human kidney HKC-8 cells stably transfected with a 1,25(OH)2D3-responsive 24-hydroxylase (CYP24) promoter reporter construct. As HKC-8 cells also express the enzyme 1alpha-hydroxylase, both 25-OHD3 (200 nM) and 1,25(OH)2D3 (5 nM) were able to induce CYP24 promoter activity. This was further enhanced following overexpression of all the three BAG 1 isoforms. By contrast, BAG-1 isoforms had no effect on metabolism of 25-OHD3 by HKC-8 cells (either via 1alpha- or 24-hydroxylase activities). Further studies showed that a mutant form of BAG-1S exhibited decreased binding of 1,25(OH)2D3 and this resulted in a concomitant loss of potentiation of CYP24 promoter transactivation. Similar effects were not observed for 25-OHD3. These data highlight a novel role for BAG-1 as an intracellular-binding protein for 1,25(OH)2D3 and further suggest that BAG-1 is able to potentiate vitamin D receptor-mediated transactivation by acting as a nuclear chaperone for 1,25(OH)2D3. PMID- 17693609 TI - Gene structure and promoter functional analysis of the marmoset type II GnRH receptor. AB - The marmoset type II GnRH receptor (GnRH-R) gene has the same structure and genomic organisation as the human and other type II GnRH-R genes. The gene consists of three exons and two introns and overlaps in the antisense orientation on its 5' end with peroxisomal membrane protein 11beta and on its 3' end with the RNA-binding motif protein 8A. However, these genes occur only at one locus in the marmoset genome, while in the human at two loci. Employing 5' rapid amplification of cDNA ends demonstrated that the marmoset type II GnRH-R gene has two transcriptional start sites at -341 and -567 nucleotides relative to the translational start codon and both start sites lack TATA and CAAT consensus sequences. A luciferase reporter construct with a 2.3 kb 5' flanking region of the type II GnRH-R gene was active in a wide variety of cell lines tested, consistent with the wide tissue expression of the receptor. Progressive 5' and 3' deletions were employed to identify sequences required for basal expression of the type II GnRH-R gene. This analysis identified negative regulatory elements in the regions -2342/-1995, -1679/-1084 and -458/-1 and positive regulatory elements in the regions -1995/-1679, -1084/-458 and -458/-1 relative to the translational start site. The strongest of the positive regions located between -766/-665 has enhancer activity when cloned in front of a heterologous minimal promoter and is critical for basal expression of the type II GnRH-R. PMID- 17693610 TI - Effect of nuclear export inhibition on estrogen receptor regulation in breast cancer cells. AB - We used the Crm1 inhibitor leptomycin B (LMB) to examine a possible involvement of nuclear export in estrogen receptor alpha (ER) level and function in MCF-7 breast carcinoma cells. As revealed by immunofluorescence microscopy and western blotting with anti-ER antibodies, LMB produced an accumulation of ER in cell nuclei. LMB also partly abrogated ER elimination resulting from Hsp90 disruption and 17beta-estradiol (E(2))-induced ER downregulation. By contrast, it was ineffective on ER downregulation caused by the pure anti-estrogen fulvestrant. Finally, LMB inhibited E(2)-induced progesterone receptor expression and the expression of an estrogen response element-driven luciferase reporter gene in unstimulated and E(2)-stimulated cells. Altogether, the data reported here suggest that: i) ER undergoes nuclear export directly or indirectly involving exportin Crm1; ii) degradation of unliganded and of agonist-bound ER probably occurs in an extranuclear compartment, while it is not the case for ER bound to a pure anti-estrogen; and iii) optimal ER-mediated gene transactivation seems to require nucleocytoplasmic shuttle of the receptor. PMID- 17693611 TI - Gender difference of androgen actions on skeletal muscle transcriptome. AB - Sarcopenia is related to metabolic syndrome in postmenopausal women. Hormone replacement therapies with androgens improve muscle functions by molecular mechanisms that are still unknown, at least partly because the skeletal muscle transcriptome has been less characterized in females. We performed the serial analysis of gene expression method in six experimental groups, intact (male and female), ovariectomy (OVX), OVX+dihydrotestosterone (DHT) injection 1, 3, or 24 h before kill in mice. The 438 transcript species differentially expressed between gender showed that females had higher expression levels of mRNA related to cytoskeleton/contractile apparatus and mitochondrial processes as well as protein, lipid, and amino acid metabolisms. In females, OVX and DHT modulated 109 and 128 transcript species respectively. OVX repressed transcripts of fast/glycolytic fiber, glycolysis, and glucose transport, whereas all these effects were reversed 3 h after the DHT injection. Moreover, DHT treatment induced transcripts which reduce intracellular Ca(2+) level at early time points. These results may suggest that DHT treatment in OVX mice increases muscle contractility by affecting fiber distribution and intracellular Ca(2+) concentration as well as improving glucose metabolism. On the other hand, transcripts of fast/oxidative fiber, oxidative phosphorylation, and ATP production were repressed 24 h after DHT administration. In our previous study using male mice, transcripts in oxidative phosphorylation and ATP production were induced 24 h after DHT injection (Yoshioka M, Boivin A, Ye P, Labrie F & St-Amand J 2006 Effects of dihydrotestosterone on skeletal muscle transcriptome in mice measured by serial analysis of gene expression. Journal of Molecular Endocrinology 36 247-259 ). These results demonstrate gender differences in DHT actions on skeletal muscle, and contribute to a precise understanding of the molecular mechanisms of androgen actions in the female skeletal muscle. PMID- 17693612 TI - Global expression profiling of glucose-regulated genes in pancreatic islets of spontaneously diabetic Goto-Kakizaki rats. AB - The spontaneously diabetic Goto-Kakizaki (GK) rat is frequently used as a model for human type 2 diabetes. Selective loss of glucose-sensitive insulin secretion is an early pathogenetic event in human type 2 diabetes, and such a defect also typifies islets from the GK rat. We investigated whether expression of specific glucose-regulated genes is disturbed in islets from GK rats when compared with Wistar rats. Large-scale gene expression analysis using Affymetrix microarrays and qRT-PCR measurements of mRNA species from normal and diabetic islets were performed after 48 h of culture at 3 or 20 mM glucose. Of the 2020 transcripts differentially regulated in diabetic GK islets when compared with controls, 1033 were up-regulated and 987 were down-regulated. We identified significant changes in islet mRNAs involved in glucose sensing, phosphorylation, incretin action, glucocorticoid handling, ion transport, mitogenesis, and apoptosis that clearly distinguish diabetic animals from controls. Such markers may provide clues to the pathogenesis of human type 2 diabetes and may be of predictive and therapeutical value in clinical settings in efforts aiming at conferring beta-cell protection against apoptosis, impaired regenerative capacity and functional suppression occurring in diabetes. PMID- 17693613 TI - Crosstalk between androgen receptor and epidermal growth factor receptor signalling pathways: a molecular switch for epithelial cell differentiation. AB - In the male, androgens promote growth and differentiation of sex reproductive organs through ligand activation of the androgen receptor (AR). Here, we show that androgens are not major actors of the cell cycle arrest associated with the differentiation process, and that the epidermal growth factor (EGF)-mediated signalling interferes with AR activities to regulate androgen response when epithelial cells are differentiated. Higher AR expression and enhanced androgen responsiveness correlate with reduction of phosphorylated ERK1/2 over differentiation. These modifications are associated with recruitment of cells in phase G(0)/G(1), up-regulation of p27(kip1), down-regulation of p21(Cip1) and p53 proteins, and accumulation of hypo-phosphorylated Rb. Exposure to EGF reduces AR expression levels and blocks androgen-dependent transcription in differentiated cells. It also restores p53 and p21(Cip1) levels, Rb hyper-phosphorylation, ERK1/2 activation and promotes cell cycle re-entry as p27(kip1) protein levels are decreased. Treatment with a MEK inhibitor reverses the EGF-mediated AR down regulation in differentiated cells, thus suggesting the existence of an inverse correlation between EGF and androgen signalling in non-tumoural epithelia. Interestingly, when androgen signalling is set in differentiated cells, dihydrotestosterone exerts an inhibitory effect on ERK activity but paradoxically does not modify EGFR (ErbB1) phosphorylation, indicating that androgens are able to disrupt the EGFR-ERK cascade. Overall, our data demonstrate the existence of a balance between AR and mitogen-activated protein kinase activities that favours either the maintenance of differentiated conditions or the enhancement of cell proliferation capacities. PMID- 17693614 TI - In vitro analysis of hGH secretion in the presence of mutations of amino acids involved in zinc binding. AB - Zinc (Zn(2+)) binding by human GH through amino acid residues His18, His21, and Glu174 has been described as a prerequisite for GH dimerization and storage in secretory granules. Our aim was to investigate in vitro whether disturbed Zn(2+) binding of mutant GH inhibits wild-type GH (wtGH) secretion and contributes to the pathogenetic mechanisms involved in dominantly transmitted isolated GH deficiency type II. Seven expression vectors harboring mutated human GH cDNAs were constructed in which nucleotide triplets encoding histidine or glutamine at positions 18, 21, and 174 were mutated to triplets encoding alanine: H18A, H21A, G174A, H18A-G174A, H21A-G174A, H18A-H21A, and H18A-H21A-G174A. These vectors were transiently cotransfected with a vector encoding wtGH or were singly transfected into rat pituitary GH(4)C(1) cells. Plasmids encoding beta -galactosidase were cotransfected. 48h after transfection, GH in media and cell extracts was measured using a GH-specific RIA, and results were normalized for transfection efficiency by means of beta -galactosidase activity. In comparison with the control transfection (wtGH/wtGH set at 100%), GH secretion remained unaffected when coexpressing wtGH and any of the GH mutants in which Zn(2+) binding was partially or completely prevented. When these mutants were singly expressed, the amount of GH in both media and cell extracts was decreased by about 50% when compared with cells expressing only wtGH. Our in vitro data do not support the hypothesis of disturbed Zn(2+) binding as a major pathogenetic mechanism in dominantly transmitted GH deficiency. PMID- 17693615 TI - Three promoters PII, PI.f, and PI.tr direct the expression of aromatase (cyp19) gene in male rat germ cells. AB - Aromatase is the key enzyme responsible for the irreversible transformation of androgens into estrogens. It is encoded by the cyp19 gene and is expressed in the mammalian testis under the control of the proximal promoter PII. Since both somatic and germ cells contain a biologically active aromatase, we looked for the existence of other promoters that may direct the expression of aromatase in adult rat germ cells. Besides the promoter II, we have shown the presence of transcripts derived from the brain promoter PI.f in spermatogonia-preleptotene spermatocytes (G-PL), pachytene spermatocytes (PS), and round spermatids (RS). A new aromatase cDNA has been isolated by 5'-rapid amplification of cDNA ends that we named I.tr (testis rat). The I.tr transcripts are found in all the testicular cell populations studied with a greater expression in PS. Because of the utilization of these three promoters in the adult rat testis, we studied their putative involvement according to the age. At 10 days, aromatase expression was very low and then strongly increased between 10 and 20 days, with a preferential activation of PII and PI.tr. Transcripts coming from PI.f were found starting from 20 days onwards. The new promoter PI.tr, localized between promoters PI.f and PII, is devoid of a TATA box but contains a transcriptional initiator (Inr) and putative regulatory sequences. Therefore, the identification of the specific trans-activating factors should bring some enlightenments to understand the regulation of these three promoters in germ cells especially according to their stage of development. PMID- 17693616 TI - Designing multidisciplinary longitudinal studies of human development: analyzing past research to inform methodology. AB - This review identifies key issues associated with the design of future longitudinal studies of human development. Sixteen international studies were compared for initial response and retention rate, sample size, type of data collected, and sampling frames. The studies had little information about the influences of fathers, extended family members, childcare, and educational institutions; the effects of peers; children's use of time; the needs of disabled children; urban versus rural environments; or the influence of genetic factors. A contemporary longitudinal study should include measures of physical and mental health, cognitive capacity, educational attainment, social adjustment, conduct and behavior, resiliency, and risk-taking behaviors. It needs to address genetic and intergenerational factors, cultural identity, and the influences of neighborhood, community, and wider social and political environments and to encompass outcomes at all life stages to systematically determine the role each factor plays in individuals' lives, including interactions within and across variables. PMID- 17693617 TI - Guidance for evaluating mass communication health initiatives: summary of an expert panel discussion sponsored by the Centers for Disease Control and Prevention. AB - In May 2004, 12 experts in evaluating large-scale health communication programs came to the Centers for Disease Control and Prevention to participate in an electronic focus group discussion. They offered advice on topics ranging from the role of logic models to the best strategies for controlling for self-selection bias in surveys regarding outcomes of exposure to mass media health messages. The experts also highlighted health communication evaluation topics that have received too little scientific attention. Finally, they made strategic policy recommendations. Use of the state-of-the-art evaluation methods that they recommended could improve the communication of factual and persuasive health messages and help to guard the public health of the nation. Their advice may also advance evaluation practice in other substantive areas, especially where it is difficult or impossible to implement randomized designs. PMID- 17693618 TI - The regression effect as a neglected source of bias in nonrandomized intervention trials and systematic reviews of observational studies. AB - Health care providers depend on the findings of observational intervention studies and systematic reviews of those studies to make evidence-based decisions about their clients' care. The nonrandom methods of group formation in observational studies necessitate carefully assessing threats to the validity of conclusions. Regression to the mean is a source of change in clinical outcome measures that has escaped widespread notice as a potential threat to the accuracy of conclusions from observational studies and systematic reviews thereof. Failure to assess the degree to which regression confounds study results elevates the risk of making clinical decisions using biased estimates of intervention effectiveness. Because the change in average outcome scores due to regression can be quantified, it is a type of bias whose direct influence can be known. Yet determining and reporting change due to regression is uncommon in observational studies or systematic reviews thereof. The means to quantify change due to regression in average outcome scores is illustrated by example in this article. PMID- 17693619 TI - Rater errors in a clinical skills assessment of medical students. AB - The authors used a many-faceted Rasch measurement model to analyze rating data from a clinical skills assessment of 173 fourth-year medical students to investigate four types of rater errors: leniency, inconsistency, the halo effect, and restriction of range. Students performed six clinical tasks with 6 standardized patients (SPs) selected from a pool of 17 SPs. SPs rated the performance of each student in six skills: history taking, physical examination, interpersonal skills, communication technique, counseling skills, and physical examination etiquette. SPs showed statistically significant differences in their rating severity, indicating rater leniency error. Four SPs exhibited rating inconsistency. Four SPs restricted their ratings in high categories. Only 1 SP exhibited a halo effect. Administrators of objective structured clinical examinations should be vigilant for various types of rater errors and attempt to reduce or eliminate those errors to improve the validity of inferences based on objective structured clinical examination scores. PMID- 17693620 TI - When to stop treatment arms in a clinical trial assessing time to event with more than two arms against a common control. AB - Two-arm time-to-event (or survival) trials are powered to continue until a required number of events is reached. The authors discuss how the required number of events should be defined for a study with three or more arms with various pairwise comparisons and a common control arm. They advocate stopping one active arm when the required number of events is observed in the applicable pairwise comparison but continuing with the other active arm and the control arm until the required number of events is observed in that pairwise comparison, thereby ensuring that the study continues until enough events are observed in each pairwise comparison. This article is the result of considerations during the design of a three-arm microbicide trial. PMID- 17693621 TI - Intracellular PAF catabolism by PAF acetylhydrolase counteracts continual PAF synthesis. AB - Stimulated inflammatory cells synthesize platelet-activating factor (PAF), but lysates of these cells show little enhancement in PAF synthase activity. We show that human neutrophils contain intracellular plasma PAF acetylhydrolase (PLA2G7), an enzyme normally secreted by monocytes. The esterase inhibitors methyl arachidonoylfluorophosphonate (MAFP), its linoleoyl homolog, and Pefabloc inhibit plasma PAF acetylhydrolase. All of these inhibitors induced PAF accumulation by quiescent neutrophils and monocytes that was equivalent to agonist stimulation. Agonist stimulation after esterase inhibition did not further increase PAF accumulation. PAF acetylhydrolase activity in intact neutrophils was reduced, but not abolished, by agonist stimulation. Erythrocytes, which do not participate in the acute inflammatory response, inexplicably express the type I PAF acetylhydrolase, whose only known substrate is PAF. Inhibition of this enzyme by MAFP caused PAF accumulation by erythrocytes, which was hemolytic in the absence of PAF acetylhydrolase activity. We propose that PAF is continuously synthesized by a nonselective acyltransferase activity(ies) found even in noninflammatory cells as a component of membrane remodeling, which is then selectively and continually degraded by intracellular PAF acetylhydrolase activity to modulate PAF production. PMID- 17693622 TI - Increased concentrations of circulating vitamin E in carriers of the apolipoprotein A5 gene - 1131T>C variant and associations with plasma lipids and lipid peroxidation. AB - The aim of this study was to investigate the effects of the apolipoprotein A5 (APOA5) 1131T>C gene variant on vitamin E status and lipid profile. The gene variant was determined in 297 healthy nonsmoking men aged 20-75 years and recruited in the VITAGE Project. Effects of the genotype on vitamin E in plasma, LDL, and buccal mucosa cells (BMC) as well as on cholesterol and triglyceride (TG) concentrations in plasma and apolipoprotein A-I (apoA-I), apoB, apoE, apoC III, and plasma fatty acids were determined. Plasma malondialdehyde concentrations as a marker of in vivo lipid peroxidation were determined. C allele carriers showed significantly higher TG, VLDL, and LDL in plasma, higher cholesterol in VLDL and intermediate density lipoprotein, and higher plasma fatty acids. Plasma alpha-tocopherol (but not gamma-tocopherol, LDL alpha- and gamma tocopherol, or BMC total vitamin E) was increased significantly in C allele carriers compared with homozygote T allele carriers (P = 0.02), but not after adjustment for cholesterol or TG. Plasma malondialdehyde concentrations did not differ between genotypes. In conclusion, higher plasma lipids in the TC+CC genotype are efficiently protected against lipid peroxidation by higher alpha tocopherol concentrations. Lipid-standardized vitamin E should be used to reliably assess vitamin E status in genetic association studies. PMID- 17693624 TI - Liver X receptors inhibit human monocyte-derived macrophage foam cell formation by inhibiting fluid-phase pinocytosis of LDL. AB - Liver X receptors (LXRs) are ligand-activated transcription factors involved in the control of lipid metabolism and inflammation. Several studies have recently shown that LXRs promote reverse cholesterol transport and inhibit atherosclerosis. Our study investigated whether LXRs affect macrophage uptake of LDL by human monocyte-derived macrophages. We have previously shown that human monocytes differentiated into macrophages with macrophage-colony-stimulating factor (M-CSF) constitutively take up large amounts of native LDL by receptor independent, fluid-phase pinocytosis. In the research reported here, human monocytes were differentiated to macrophages in the presence of M-CSF with or without the LXR agonists T0901317 or 22(R)-hydroxycholesterol. Then, macrophages were incubated with native (125)I-LDL to determine LDL uptake. T0901317 and 22(R) hydroxycholesterol inhibited (125)I-LDL uptake by 68 +/- 1% and 69 +/- 2%, respectively, and decreased pinocytotic vacuoles in the macrophages. (125)I-BSA uptake, a measure of fluid-phase pinocytosis, and (125)I-LDL uptake were the same, and T0901317 treatment inhibited uptake of both to the same degree. T0901317 did not affect receptor-mediated uptake of acetylated LDL, showing that the LXR effect is specific for fluid-phase pinocytosis of lipoproteins. Our results show that LXRs downregulate macrophage pinocytosis of LDL. The findings reveal an additional new mechanism by which LXR agonists may inhibit macrophage cholesterol accumulation and atherosclerosis, namely, by inhibiting macrophage uptake of LDL. PMID- 17693623 TI - Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammation. AB - Oxidative stress and inflammation are fundamental for the onset of aging and appear to be causatively linked. Previously, we reported that hepatocytes from aged rats, compared with young rats, are hyperresponsive to interleukin-1beta (IL 1beta) stimulation and exhibit more potent c-Jun N-terminal kinase (JNK) activation and attenuated interleukin-1 receptor-associated kinase-1 (IRAK-1) degradation. An age-related increase in the activity of neutral sphingomyelinase 2 (NSMase-2), a plasma membrane enzyme, was found to be responsible for the IL 1beta hyperresponsiveness. The results reported here show that increased NSMase activity during aging is caused by a 60-70% decrease in hepatocyte GSH levels. GSH, at concentrations typically found in hepatocytes from young animals, inhibits NSMase activity in a biphasic dose-dependent manner. Inhibition of GSH synthesis in young hepatocytes activates NSMase, causing increased JNK activation and IRAK-1 stabilization in response to IL-1beta, mimicking the hyperresponsiveness typical for aged hepatocytes. Vice versa, increased GSH content in hepatocytes from aged animals by treatment with N-acetylcysteine inhibits NSMase activity and restores normal IL-1beta response. Importantly, the GSH decline, NSMase activation, and IL-1beta hyperresponsiveness are not observed in aged, calorie-restricted rats. In summary, this report demonstrates that depletion of cellular GSH during aging plays an important role in regulating the hepatic response to IL-1beta by inducing NSMase-2 activity. PMID- 17693625 TI - ApoA-I cleaved by transthyretin has reduced ability to promote cholesterol efflux and increased amyloidogenicity. AB - A fraction of plasma transthyretin (TTR) circulates in HDL through binding to apolipoprotein A-I (apoA-I). Moreover, TTR is able to cleave the C terminus of lipid-free apoA-I. In this study, we addressed the relevance of apoA-I cleavage by TTR in lipoprotein metabolism and in the formation of apoA-I amyloid fibrils. We determined that TTR may also cleave lipidated apoA-I, with cleavage being more effective in the lipid-poor prebeta-HDL subpopulation. Upon TTR cleavage, discoidal HDL particles displayed a reduced capacity to promote cholesterol efflux from cholesterol-loaded THP-1 macrophages. In similar assays, TTR containing HDL from mice expressing human TTR in a TTR knockout background had a decreased ability to perform reverse cholesterol transport compared with similar particles from TTR knockout mice, reinforcing the notion that cleavage by TTR reduces the ability of apoA-I to promote cholesterol efflux. As amyloid deposits composed of N-terminal apoA-I fragments are common in the atherosclerotic intima, we assessed the impact of TTR cleavage on apoA-I aggregation and fibrillar growth. We determined that TTR-cleaved apoA-I has a high propensity to form aggregated particles and that it formed fibrils faster than full-length apoA-I, as assessed by electron microscopy. Our results show that apoA-I cleavage by TTR may affect HDL biology and the development of atherosclerosis by reducing cholesterol efflux and increasing the apoA-I amyloidogenic potential. PMID- 17693626 TI - Lipoprotein inflammatory properties and serum amyloid A levels but not cholesterol levels predict lesion area in cholesterol-fed rabbits. AB - Rabbits on a 1% cholesterol diet received injections of vehicle with or without D 4F or L-4F. After 1 month, the percent of aorta with atherosclerotic lesions was 24 +/- 15% (vehicle), 10 +/- 6% (D-4F) (P < 0.01 vs. vehicle), and 13 +/- 9% (L 4F) (P < 0.05 vs. vehicle). Inflammatory indexes for HDL and LDL were determined by measuring monocyte chemotactic activity after adding rabbit lipoproteins to human endothelial cells. HDL-inflammatory index (HII) and LDL-inflammatory index (LII), respectively, were 1.39 +/- 0.24; 1.35 +/- 0.29 (vehicle), 0.67 +/- 0.26; 0.63 +/- 0.38 (D-4F) (P < 0.001 vs. vehicle), and 0.67 +/- 0.2; 0.68 +/- 0.32 (L 4F) (P < 0.01 vs. vehicle). Serum amyloid A (SAA) levels were 95 +/- 39, 8 +/- 22, and 7 +/- 19 mug/ml, respectively, for vehicle, D-4F, and L-4F (P < 0.001 vs. vehicle). There was no correlation between lesion area and total plasma or HDL cholesterol levels. In contrast, there was a positive correlation with HII, LII, and SAA (P = 0.002, P = 0.0026, P = 0.0079, respectively). HII correlated closely with SAA levels (r = 0.6616; r(2) = 0.4377, P < 0.0001). Thus, HII, LII, and SAA are better predictors of lesion area than are total plasma or HDL-cholesterol levels in cholesterol-fed rabbits. PMID- 17693627 TI - Treatment in the field of 27 horses with epiglottic entrapment. AB - Twenty-seven horses were treated for epiglottic entrapment by using an oral, hand assisted bistoury knife technique, under general anaesthesia; 26 of them returned successfully to racing, but one developed a permanently displaced soft palate. After the surgery 13 of the horses had an increased handicap rating and 13 had a decreased rating. PMID- 17693628 TI - Prevalence of 'Candidatus Helicobacter suis' in pigs of different ages. AB - Samples from the antrum and fundus of the stomachs of 457 pigs from 22 different herds were screened for the presence of 'Candidatus Helicobacter suis' by pcr, and samples from the antrum and/or fundus of 222 of the stomachs were tested for urease activity. The prevalence of the infection was very low before weaning, increased rapidly after weaning and reached 90 per cent in the adult boars and sows. The agreement between the results obtained with the pcr test and the urease test was very good for some age groups and sampling sites, but poor for other age groups and sampling sites. PMID- 17693629 TI - Management of fractures near the carpal joint of two calves by transarticular fixation with a circular external fixator. AB - A four-ring circular external skeletal fixation device was evaluated for transcarpal fixation of compound fractures in two calves. Case 1 was an eight month-old female Holstein-Friesian x indigenous breed calf weighing 72 kg, which had a Salter-Harris type II fracture at the distal metaphysis of the right radius/ulna with an open contaminated wound on the medial aspect of the carpus. Case 2 was an 18-month-old crossbred Haryana heifer weighing 105 kg, which had a comminuted fracture at the proximal end of its left metacarpus with severe soft tissue trauma and an open wound on the medial aspect. In both cases, the fractures were repaired with four-ring circular fixators by fixing the proximal two rings in the distal radius/ulna and the distal two rings in the metacarpus. Postoperatively, both calves were treated with analgesic and anti-inflammatory drugs and antibiotic, and the pin-bone interfaces and the open wound were cleaned regularly with povidone-iodine solution. In both animals weight bearing was good to excellent in the immediate postoperative period. The fixator was well maintained and tolerated by the animals until the fractures healed after 45 to 60 days. The movement of the carpal joint was slightly affected when the fixator was removed on day 60, but a follow-up examination after one year showed that both calves had normal functional usage of the limbs. PMID- 17693630 TI - Correlation between perioperative factors and successful outcome in fibrosarcoma resection in cats. PMID- 17693631 TI - Ultrasonographic appearance of intestinal roundworms in a dog and a cat. PMID- 17693632 TI - Non-specific haemolytic alloantibody causing equine neonatal isoerythrolysis. PMID- 17693633 TI - Clinical signs and response to primaquine in falcons with Haemoproteus tinnunculi infection. PMID- 17693634 TI - Chastek paralysis in two wild foxes (Vulpes vulpes japonica). PMID- 17693635 TI - Does reactive badger culling lead to an increase in tuberculosis in cattle? AB - The conclusion from the randomised badger culling trial was that localised badger culling not only fails to control but can actually increase the incidence of bovine tuberculosis in cattle. Professor Simon More and colleagues from University College Dublin question that conclusion, arguing that the data do not provide sufficient evidence to rule out alternative hypotheses. PMID- 17693636 TI - Detection of Border disease virus in cattle. PMID- 17693637 TI - Emergency contingency plans for animals in Florida. PMID- 17693638 TI - Serosurvey of West Nile virus in equids and bovids in Spain. PMID- 17693639 TI - Cellular turnover of the polyglutamine disease protein ataxin-3 is regulated by its catalytic activity. AB - Ataxin-3, a deubiquitinating enzyme, is the disease protein in spinocerebellar ataxia type 3, one of many neurodegenerative disorders caused by polyglutamine expansion. Little is known about the cellular regulation of ataxin-3. This is an important issue, since growing evidence links disease protein context to pathogenesis in polyglutamine disorders. Expanded ataxin-3, for example, is more neurotoxic in fruit fly models when its active site cysteine is mutated (1). We therefore sought to determine the influence of ataxin-3 enzymatic activity on various cellular properties. Here we present evidence that the catalytic activity of ataxin-3 regulates its cellular turnover, ubiquitination, and subcellular distribution. Cellular protein levels of catalytically inactive ataxin-3 were much higher than those of active ataxin-3, in part reflecting slower degradation. In vitro studies revealed that inactive ataxin-3 was more slowly degraded by the proteasome and that this degradation occurred independent of ubiquitination. Slower degradation of inactive ataxin-3 correlated with reduced interaction with the proteasome shuttle protein, VCP/p97. Enzymatically active ataxin-3 also showed a greater tendency to concentrate in the nucleus, where it colocalized with the proteasome in subnuclear foci. Taken together, these and other findings suggest that the catalytic activity of this disease-linked deubiquitinating enzyme regulates several of its cellular properties, which in turn may influence disease pathogenesis. PMID- 17693640 TI - Cytochrome b5 increases the rate of product formation by cytochrome P450 2B4 and competes with cytochrome P450 reductase for a binding site on cytochrome P450 2B4. AB - The kinetics of product formation by cytochrome P450 2B4 were compared in the presence of cytochrome b(5) (cyt b(5)) and NADPH-cyt P450 reductase (CPR) under conditions in which cytochrome P450 (cyt P450) underwent a single catalytic cycle with two substrates, benzphetamine and cyclohexane. At a cyt P450:cyt b(5) molar ratio of 1:1 under single turnover conditions, cyt P450 2B4 catalyzes the oxidation of the substrates, benzphetamine and cyclohexane, with rate constants of 18 +/- 2 and 29 +/- 4.5 s(-1), respectively. Approximately 500 pmol of norbenzphetamine and 58 pmol of cyclohexanol were formed per nmol of cyt P450. In marked contrast, at a cyt P450:CPR molar ratio of 1:1, cyt P450 2B4 catalyzes the oxidation of benzphetamine congruent with100-fold (k = 0.15 +/- 0.05 s(-1)) and cyclohexane congruent with10-fold (k = 2.5 +/- 0.35 s(-1)) more slowly. Four hundred picomoles of norbenzphetamine and 21 pmol of cyclohexanol were formed per nmol of cyt P450. In the presence of equimolar concentrations of cyt P450, cyt b(5), and CPR, product formation is biphasic and occurs with fast and slow rate constants characteristic of catalysis by cyt b(5) and CPR. Increasing the concentration of cyt b(5) enhanced the amount of product formed by cyt b(5) while decreasing the amount of product generated by CPR. Under steady-state conditions at all cyt b(5):cyt P450 molar ratios examined, cyt b(5) inhibits the rate of NADPH consumption. Nevertheless, at low cyt b(5):cyt P450 molar ratios or =4 positive nodes, respectively). At the multivariate analysis, positive lymph nodes and endocrine non-responsive tumours were found to shorten LRR disease-free survival. In patients with positive hormone receptors, 5-year cumulative incidence of LRR disease-free survival were 2.3%, 7.6% and 7.6% for node negative, 1-3 and > or =4 positive lymph nodes, respectively. The same figures were 5.9%, 10.3% and 20.0% in patients with endocrine non-responsive tumours. CONCLUSIONS: patients with endocrine-responsive tumours treated by mastectomy and complete (level III) axillary dissection have a low risk of LRR even if four or more positive lymph nodes are involved, thus giving rise to doubts on the use of PMRT in this subset of patients. On the other hand, PMRT might play a role for patients with negative hormone receptors and four or more positive nodes. PMID- 17693649 TI - Gemcitabine and oxaliplatin combination: a multicenter phase II trial in unfit patients with locally advanced or metastatic urothelial cancer. AB - BACKGROUND: Up to 50% of patients with bladder cancer cannot be treated with cisplatin because they are considered unfit due to poor renal function. Gemcitabine and oxaliplatin are active, nonnephrotoxic therapies with nonoverlapping toxicity profiles that provide an alternative therapy for this group of patients. PATIENTS AND METHODS: In a multicenter study, patients received gemcitabine 1200 mg/m(2) on days 1 and 8 and oxaliplatin 100 mg/m(2) on day 8 every 21 days. Eligible criteria were creatinine clearance >30 ml/min and/or Eastern Cooperative Oncology Group (ECOG) performance status of two or less. RESULTS: Forty-six patients were assessable for response and toxicity. Median age was 69 years (range 52-85), median ECOG two (range 0-2). Median number of metastatic sites was 2 (range 1-6). Median creatinine clearance was 50.73 ml/min (range 30-87). A total of 187 cycles were given with a median of 5 (range 1-6). Hematological toxicity was mild with grade 3-4 peripherical neuropathy occurring in 4% of patients. Overall response rate was 48% (three complete response, 19 partial response, seven stable disease and 17 progressive disease). Median time to disease progression was 5 months. CONCLUSION: Gemcitabine oxaliplatin is an active and tolerable combination with response rate that merits further study in patients with impaired renal function but good performance status. PMID- 17693650 TI - VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek Myeloma Study Group. AB - BACKGROUND: We have previously demonstrated that vincristine, liposomal doxorubicin and dexamethasone (VAD-doxil) is equally effective with VAD-bolus yielding objective response rates of 61% as first-line treatment in multiple myeloma (MM). In a phase II study, the addition of thalidomide to VAD-doxil (TVAD doxil) proved feasible and increased response rate to 74%. The aim of the present multicenter prospective randomized clinical trial was to compare the efficacy and toxicity of VAD-doxil and TVAD-doxil in previously untreated MM patients. PATIENTS AND METHODS: We enrolled 232 newly diagnosed MM patients aged <75 years, 115 randomized to VAD-doxil (arm A) and 117 to TVAD-doxil (arm B). Patients in arm A received vincristine 2 mg i.v. and liposomal doxorubicin 40 mg/m(2) i.v., on day 1 and dexamethasone 40 mg p.o. daily on days 1-4, 9-12 and 17-20 for the first cycle and on days 1-4 for the next three cycles. Patients in arm B received additionally thalidomide 200 mg p.o. daily, at bedtime. Treatment was administered every 28 days. RESULTS: On an intention-to-treat basis, at least partial response was observed, in 62.6% and in 81.2% of patients randomized to arms A and B, respectively (P = 0.003). Progression-free survival (PFS) at 2 years was 44.8% in arm A and 58.9% in arm B (P = 0.013). Overall survival (OS) at 2 years was 64.6% and 77%, in arms A and B, respectively (P = 0.037). Considering overall toxicity, constipation, peripheral neuropathy, dizziness/somnolence, skin rash and edema were significantly higher in arm B compared with arm A (P < 0.01), but grade 3-4 toxicities were low and similar in both arms. CONCLUSIONS: The addition of thalidomide to VAD-doxil increases response and PFS rates and probably OS in previously untreated myeloma patients. The superiority of efficacy counterbalances the higher overall toxicity of TVAD-doxil. PMID- 17693651 TI - Ki-67 expression is predictive of prognosis in patients with stage I/II extranodal NK/T-cell lymphoma, nasal type. AB - BACKGROUND: Localized extranodal natural killer (NK)/T-cell lymphoma, nasal type, commonly has a low or low-intermediate risk of the international prognostic index (IPI), so the IPI has shown inconsistency in predicting prognosis. Thus, we analyzed Ki-67 expression and proposed a new prognostic model including Ki-67 expression for stage I/II extranodal NK/T-cell lymphoma. PATIENTS AND METHODS: We studied Ki-67 expression and its relationship with prognosis in 50 patients with extranodal NK/T-cell lymphoma. RESULTS: The patients were dichotomized by the median value: low (<65%) versus high Ki-67 (> or =65%). High Ki-67 was associated with a worse overall survival (OS; P = 0.021) and disease-free survival (DFS; P = 0.044). In multivariate analysis, Ki-67 expression and primary site of involvement were found to be an independent prognostic factor for OS and DFS (P < 0.05). Based on these results, we proposed a new clinico-pathological prognostic model with Ki-67 expression and the primary site of involvement. It showed a high degree of correlation with worse OS and DFS (P < 0.001). CONCLUSIONS: Ki-67 expression is predictive of prognosis, and our prognostic model may become a useful tool for predicting prognosis in patients with stage I/II extranodal NK/T cell lymphoma, nasal type. PMID- 17693652 TI - An open, randomized, controlled, phase II, single centre, two-period cross-over study to compare the quality of life and toxicity experienced on PEG interferon with interferon-alpha2b in patients with multiple myeloma maintained on a steady dose of interferon-alpha2b. AB - PURPOSE: To compare the effects of pegylated interferon-alpha2b (P-IFN) and interferon-alpha2b (IFN) on quality of life (QoL) and toxicity in patients with multiple myeloma maintained on a steady dose of IFN. PATIENTS AND METHODS: Consenting, eligible myeloma patients on IFN maintenance therapy for at least 6 weeks were randomly (1:1) allocated to receive P-IFN for 3 months followed by IFN for 3 months, or to continue with IFN for 3 months followed by P-IFN for 3 months (cross-over design). Patients were assessed for toxicity and QoL. Dose of P-IFN was equivalent to IFN. RESULTS: The study enrolled 60 patients. At enrollment, 35 patients were in complete remission, 20 in partial remission and 5 were minimal responders. P-IFN was associated with significantly better global QoL score (mean difference 8.4; P = 0.0002). There was a significant improvement in functional scales--physical (P = 0.03), emotional (P = 0.04), social (P = 0.0008) with P IFN. Fatigue (P = 0.0003), pain (P = 0.02) and appetite loss (P = 0.003) symptom scales were less in patients while on P-IFN. There were no statistically significant differences between treatment arms in QoL as measured by QLQ-MY24. CONCLUSION: These data suggest that patients on P-IFN have a better QoL. Dose escalation studies are warranted to investigate potential impact on survival. PMID- 17693653 TI - Assessment of the biological and pharmacological effects of the alpha nu beta3 and alpha nu beta5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors. AB - BACKGROUND: Cilengitide, an antiangiogenic agent that inhibits the binding of integrins alpha(nu)beta(3) and alpha(nu)beta(5) to the extracellular matrix, was studied at two dose levels in cancer patients to determine the optimal biological dose. PATIENTS AND METHODS: The doses of cilengitide were 600 or 1200 mg/m(2) as a 1-h infusion twice weekly every 28 days. A novel dose escalation scheme was utilized that relied upon the biological activity rate. RESULTS: Twenty patients received 50 courses of cilengitide with no dose-limiting toxic effects. The pharmacokinetic (PK) profile revealed a short elimination half-life of 4 h, supporting twice weekly dosing. Of the six soluble angiogenic molecules assessed, only E-selectin increased significantly from baseline. Analysis of tumor microvessel density and gene expression was not informative due to intrapatient tumor heterogeneity. Although several patients with evaluable tumor biopsy pairs did reveal posttreatment increases in tumor and endothelial cell apoptosis, these results did not reach statistical significance due to the aforementioned heterogeneity. CONCLUSIONS: Cilengitide is a well-tolerated antiangiogenic agent. The biomarkers chosen in this study underscore the difficulty in assessing the biological activity of antiangiogenic agents in the absence of validated biological assays. PMID- 17693654 TI - Prognosis for long-term survivors of cancer. AB - BACKGROUND: Many cancer patients who have already survived some time want to know about their prognosis, given the pre-condition that they are still alive. We described and interpreted population-based conditional 5-year relative survival rates. PATIENTS AND METHODS: The long-standing Eindhoven Cancer Registry collects data on all patients diagnosed with cancer in the southern part of the Netherlands. Patients aged 25-74 years, diagnosed between 1960 and 2004, were included. Conditional 5-year relative survival was computed for every additional year survived (follow-up period 1980-2004). RESULTS: For patients with colorectal cancer, cutaneous melanoma or stage I breast cancer, conditional 5-year relative survival was >95% after having survived 3-15 years. However, for stomach, lung, stage II or III breast, prostate cancer or Hodgkin lymphoma, conditional 5-year relative survival did not exceed 75-94%. Initial differences in survival at diagnosis between age, gender and stage groups largely disappeared after having survived for 5-10 years. CONCLUSION: Prognosis for patients with cancer generally improved with each year survived. Patients with colorectal cancer, cutaneous melanoma or stage I breast cancer hardly exhibit any excess mortality after 3-15 years, whereas for patients with other tumours survival remained poorer than for the general population. Insight into conditional survival is especially useful for (ex)patients, who may use this information to plan their remaining life. PMID- 17693655 TI - Association between glycosylated hemoglobin and cancer risk: a New Zealand linkage study. AB - BACKGROUND: The purpose of this study was to examine the relationship between glycosylated hemoglobin (HbA(1c)) level and subsequent cancer risk. MATERIAL AND METHODS: HbA(1c) measurements were made on blood samples of participants in a hepatitis B (HB) screening program (1999-2001). Cancer incidence was determined by linkage to cancer registrations and hospitalization records to the end of 2004. Participants previously diagnosed with diabetes or cancer were excluded. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated using Cox regression. RESULTS: Among the 46 575 participants (70% Maori, 12% Pacific, 5% Asian and 12% Other), 634 cancer cases were observed. For all cancers combined, a significant increased risk was found in persons with moderately elevated HbA(1c) levels (6%-6.9%) (HR 1.40, 95% CI: 1.11-1.76), with a smaller increased risk in persons with highly elevated levels (> or =7%) (HR 1.09, 95% CI: 0.80-1.48) as compared with persons having low HbA(1c) levels (<6%). The HRs for respiratory cancers were 2.27 (95% CI: 1.34-3.86) for the moderate HbA(1c) category and 1.58 (95% CI: 0.77-3.26) for the upper HbA(1c) category. For endometrial cancers, the HRs were 4.05 (95% CI: 1.10-14.88) and 5.07 (95% CI: 1.20-21.31), respectively. For other cancer sites, no significantly increased risks were found. CONCLUSIONS: These findings are consistent with other evidence that abnormal glucose metabolism may be associated with an increased risk of some cancers. PMID- 17693656 TI - Vascular disrupting therapy-induced mobilization of circulating endothelial progenitor cells. PMID- 17693657 TI - Lymphoma and human immunodeficiency virus (HIV) infection: another favourable setting? PMID- 17693658 TI - Burden of cervical cancer in the 27 member states of the European Union: estimates for 2004. PMID- 17693659 TI - The other side of p53. PMID- 17693660 TI - Interactions among GSTM1, GSTT1 and GSTP1 polymorphisms, cruciferous vegetable intake and breast cancer risk. AB - Isothiocyanates are anticarcinogenic phytochemicals found in cruciferous vegetables that both induce and are substrates for the gluthatione S-transferases (GSTs). The GSTs are phase II metabolizing enzymes involved in metabolism of various bioactive compounds. Functional polymorphisms in GST genes have been identified and may interact with cruciferous vegetable intake to affect cancer risk. We examined this hypothesis using data from the Long Island Breast Cancer Study Project, a population-based case-control study conducted in Long Island, NY, from 1996 to 1997. Cruciferous vegetable intake in the previous year was assessed via modified Block food frequency questionnaire. DNA was extracted from blood samples (n = 1052 cases and n = 1098 controls) and genotyped for GSTM1 deletion, GSTT1 deletion and GSTP1 Ile105Val using multiplex polymerase chain reaction and Taqman assays. Unconditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CI). We found an 86% increase in the OR for breast cancer among carriers of the GSTM1 null, GSTT1 null and GSTP 105Ile/Ile genotypes (OR = 1.86, 95% CI = 1.12, 3.08) and a 36% decrease in the OR among carriers of GSTM1 present, GSTT1 null and GSTP1 105Ile/Val + Val/Val genotypes (OR = 0.64, 95% CI = 0.42, 0.97) compared with GSTM1 present, GSTT1 present and GSTP1 105Ile/Ile carriers. We found no joint effects among GST polymorphisms and cruciferous vegetable intake and breast cancer risk. In conclusion, we found associations between specific combinations of three GST gene polymorphisms and breast cancer risk but these did not modify the association between cruciferous vegetable intake and breast cancer. Additional studies are needed to confirm the associations observed. PMID- 17693661 TI - Myricetin is a novel natural inhibitor of neoplastic cell transformation and MEK1. AB - Evidence suggests that mitogen-activated protein kinase kinase (MEK) plays a role in cell transformation and tumor development and might be a significant target for chemoprevention. 3,5,4'-Trihydroxy-trans-stilbene (resveratrol), a non flavonoid polyphenol found in various foods and beverages, including red wines, is reported to be a natural chemopreventive agent. However, the concentrations required to exert these effects might be difficult to achieve by drinking only one or two glasses of red wine a day. On the other hand, the flavonol content of red wine is approximately 30 times higher than that of resveratrol. Here we demonstrated that 3,3',4',5,5',7-hexahydroxyflavone (myricetin), one of the major flavonols in red wine, is a novel inhibitor of MEK1 activity and transformation of JB6 P+ mouse epidermal cells. Myricetin (10 microM) inhibited 12-O tetradecanoylphorbol-13-acetate (TPA) or epidermal growth factor (EGF)-induced cell transformation by 76 or 72%, respectively, compared with respective reductions of 26 or 19% by resveratrol (20 microM). A combination of myricetin and resveratrol exerted additive but not synergistic effects on either TPA- or EGF-induced transformation. Myricetin, but not resveratrol, attenuated tumor promoter-induced activation of c-fos or activator protein-1. Myricetin strongly inhibited MEK1 kinase activity and suppressed TPA- or EGF-induced phosphorylation of extracellular signal-regulated kinase (ERK) or p90 ribosomal S6 kinase, downstream targets of MEK. Moreover, myricetin inhibited H-Ras-induced cell transformation more effectively than either PD098059, a MEK inhibitor, or resveratrol. Myricetin directly bound with glutathione S-transferase-MEK1 but did not compete with ATP. Overall, these results indicated that myricetin has potent anticancer-promoting activity and mainly targets MEK signaling, which may contribute to the chemopreventive potential of several foods including red wines. PMID- 17693662 TI - Genetic polymorphisms in the Rb-binding zinc finger gene RIZ and the risk of lung cancer. AB - Histone methyltransferase (HMT) enzymes that methylate the lysine of histones are involved in chromatin-mediated gene expression. Previously, we reported that a novel polymorphism of SUV39H2, the HMT that is required for the methylation of H3 K9, was associated with an increased risk of lung cancer in Koreans. The retinoblastoma protein-interacting zinc finger gene RIZ (PRDM2) is also a member of a histone/protein-methyltransferase superfamily, and the inactivation of RIZ in many cancers was detected as frameshift mutations, hypermethylation and missense mutations. In this study, we show the association of RIZ polymorphisms with the risk of lung cancer. In a hospital-based study of 335 lung cancer patients and 335 age- and gender-matched healthy controls, 120 polymorphisms of RIZ were screened. Of the 120 genotyped single nucleotide polymorphisms (SNPs), 42 SNPs were selected for the statistical analysis based on their frequency (>5%) and linkage disequilibrium [LD; only a representative SNP was analyzed if there were absolute LDs (r2 = 1)]; this resulted in three LD blocks. The +92337G>A and +95701C>A polymorphisms showed a statistically significant association with the reduced risk of lung adenocarcinomas after correcting the P values for multiple testing [for carrying one variant allele versus none, adjusted odds ratio (aOR) = 0.55 (95% CI = 0.38-0.78), corrected P = 0.04; aOR = 0.54 (95% CI = 0.38-0.77), corrected P = 0.02, respectively]. One haplotype (Ht5) in LD block 3 of RIZ was significantly associated with the reduced risk of lung adenocarcinomas (aOR = 0.28, 95% CI = 0.13-0.58) as well as overall lung cancer (aOR = 0.50, 95% CI = 0.30-0.82). This study suggested that RIZ polymorphisms may be important predictive markers for lung cancer susceptibility. PMID- 17693663 TI - Heterozygous disruption of the PTEN promotes intestinal neoplasia in APCmin/+ mouse: roles of osteopontin. AB - The persistent activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is oncogenic and involved in colorectal neoplasia. Mutations of both regulatory subunit and catalytic subunit of PI3K have been demonstrated in colon cancers. In the present study, we show that heterozygous disruption of the phosphatase and tensin homolog (PTEN) tumor suppressor gene promoted tumor progression in APC(min/+) mice. Number and size of intestinal tumors were significantly increased in mice bearing both adenomatous polyposis coli (APC) and PTEN mutations. While APC(min/+)PTEN(+/+) mice developed adenomas, invasive carcinomas developed in APC(min/+)PTEN(+/-) mice. Large tumors often resulted in intestinal intussusception and early death of APC(min/+)PTEN(+/-) mice. Targeted array revealed that osteopontin (OPN) was the leading gene whose expression was strongly induced by deficiency of PTEN. In colon cancer cells, gain-of-function mutation of PI3K robustly increased levels of OPN and treatment with OPN reduced growth factor deprivation-induced programmed cell death. Moreover, OPN expression was strongly increased in Ras-induced transformation of intestinal epithelial cells in a PI3K-dependent manner. Inhibition of OPN expression by specific small interfering RNA reduced uncontrolled growth and invasiveness of Ras-transformed intestinal epithelial cells. Thus, our results suggest that the PI3K pathway promotes the transformation of intestinal adenoma to adenocarcinoma. OPN, a downstream effector of PI3K, protects transformed intestinal epithelial cells from programmed cell death and stimulates their anchorage-independent growth. PMID- 17693664 TI - Peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) ligands do not potentiate growth of human cancer cell lines. AB - Ligands for peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) increase skeletal muscle fatty acid catabolism, improve insulin sensitivity, increase serum high-density lipoprotein cholesterol, elicit anti inflammatory activity and induce terminal differentiation. Contradictory findings are also reported suggesting that PPARbeta/delta ligands potentiate tumorigenesis by increasing cell proliferation, by inhibiting apoptosis through phosphorylation of Akt and by increasing cyclooxygenase-2 (COX2) and vascular endothelial growth factor (VEGF) expression. The contradictory findings could be due to differences in the model system (cancer cell line versus in vivo), differences in cell culture conditions (with and without serum) or differences in ligands. The present study examined the effect of two different PPARbeta/delta ligands (GW0742 and GW501516) in human cancer cell lines (HT29, HCT116, LS-174T, HepG2 and HuH7) cultured in the presence or absence of serum and compared in vitro analysis with in vivo analysis. Neither PPARbeta/delta ligand increased cell growth or phosphorylation of Akt and no increase in the expression of VEGF or COX2 were detected in any cancer cell line in the presence or absence of serum. Similarly, liver, colon and colon polyps from mice administered these PPARbeta/delta ligands in vivo did not exhibit changes in these markers. Results from these studies demonstrate that serum withdrawal and/or differences in ligands do not underlie the disparity in responses reported in the literature. The quantitative nature of the present findings are inconsistent with the hypothesis that cancer cell lines respond differentially as compared with normal cells, and provide further evidence that PPARbeta/delta ligands do not potentiate tumorigenesis. PMID- 17693665 TI - Genetic pathways and mutation profiles of human cancers: site- and exposure specific patterns. AB - Cancer is a complex disease that involves the accumulation of both genetic and epigenetic alterations of numerous genes. Data in the Genetic Alterations in Cancer database for gene mutations and allelic loss [loss of heterozygosity (LOH)] in human tumors (e.g. lung, oral, esophagus, stomach and colon/rectum) were reviewed. Results for the genes and pathways implicated in tumor development at these sites are presented. Mutation incidence, spectra and codon specificity are described for lung, larynx and oral tumors. LOH occurred more frequently than gene mutations in tumors from all sites examined. The cell cycle gene, TP53 (all sites), and cell signaling gene, APC (colorectal and gastric cancers), were the only genes with similar incidences of LOH and mutation. Alterations of one or more cell cycle and cell signaling genes were reported for tumors from each site. Site-specific activation was apparent in the cell signaling mitogen-activated protein kinase oncogenes (KRAS in lung, HRAS in oral cancers and BRAF in esophageal and colorectal cancers). Analysis of genetic changes in lung tumors showed that the incidence of mutations in the TP53 and KRAS genes and the incidence of LOH in the FHIT gene were significantly greater in smokers versus non-smokers (P < 0.01). In lung and oral cancers, the TP53 GC --> TA transversion frequency increased with tobacco smoke exposure (P < 0.05). Furthermore, the TP53 mutational hot spots for lung and laryngeal cancers from smokers included codons 157, 245 and 273, whereas for oral tumors included codons 280 and 281. PMID- 17693666 TI - Single-nucleotide polymorphisms at the TP53-binding or responsive promoter regions of BAX and BCL2 genes and risk of squamous cell carcinoma of the head and neck. AB - Tumor protein 53 (TP53), a transcriptional factor, induces expression of the B cell lymphoma 2-associated X protein (BAX) gene by directly binding to the TP53 binding element in the BAX promoter but inhibits B-cell lymphoma 2 (BCL2) promoter-driven transcription through a responsive region in the BCL2 promoter. Therefore, we hypothesized that single-nucleotide polymorphisms (SNPs) of BAX and BCL2 promoters and the TP53 codon 72 SNP may jointly contribute to cancer risk. We tested this hypothesis in a hospital-based case-control study of 814 patients with squamous cell carcinoma of the head and neck (SCCHN) and 934 cancer-free controls in a US non-Hispanic white population. While there was no evidence of associations between BAX (-248 G>A), BCL2 (-938 C>A) or TP53 codon 72 SNPs and SCCHN risk in single-locus analyses, further analyses showed that, among TP53 heterozygotes after adjustment for age, sex and smoking and alcohol status, the BAX AA genotype was associated with an elevated risk of SCCHN [odds ratio (OR) = 6.60, 95% confidence interval (CI) = 1.38-31.50 compared with the BAX GG genotype or OR = 6.58, 95% CI = 1.38-31.49 compared with the combined genotypes (GG + AG)], whereas BCL2 A variant genotypes were associated with a decreased risk of SCCHN (adjusted OR = 0.68, 95% CI = 0.47-0.98 for CA vs CC and OR = 0.67, 95% CI = 0.48-0.95 for AA vs CA+CC). These altered risks appeared to be consistent with the roles of the anti-apoptotic BCL2 and the pro-apoptotic BAX. Our data suggest that the risk of SCCHN may be associated with these two SNPs of BAX and BCL2 promoter regions, particularly among TP53 heterozygotes. Larger studies are needed to validate these findings. PMID- 17693667 TI - If you haven't published your work, it's time to start. PMID- 17693668 TI - Effect of crew resource management on diabetes care and patient outcomes in an inner-city primary care clinic. AB - BACKGROUND: Diabetes care in our inner-city primary care clinic was suboptimal, despite provider education and performance feedback targeting improved adherence to evidence-based clinical guidelines. A crew resource management (CRM) intervention (communication and teamwork, process and workflow organisation, and standardised information debriefings) was implemented to improve diabetes care and patient outcomes. OBJECTIVE: To assess the effect of the CRM intervention on adherence to evidence-based diabetes care standards, work processes, standardised clinical communication and patient outcomes. METHODS: Time-series analysis was used to assess the effect on the delivery of standard diabetes services and patient outcomes among medically indigent adults (n = 619). RESULTS: The CRM principles were translated into useful process redesign and standardised care approaches. Significant improvements in microalbumin testing and associated patient outcome measures were attributed to the intervention. CONCLUSIONS: The CRM approach provided tools for management that, in the short term, enabled reorganisation and prevention of service omissions and, in the long term, can produce change in the organisational culture for continuous improvement. PMID- 17693669 TI - Estimating costs of quality improvement for outpatient healthcare organisations: a practical methodology. AB - BACKGROUND: Outpatient healthcare organisations worldwide participate in quality improvement (QI) programmes. Despite the importance of understanding the financial impact of such programmes, there are no established standard methods for empirically assessing QI programme costs and their consequences for small outpatient healthcare organisations. OBJECTIVE AND METHODS: The costs and cost consequences were evaluated for a diabetes QI programme implemented throughout the USA in federally qualified community health centres. For five case study centres, survey instruments and methods for data analysis were developed. RESULTS: Two types of cost/revenue were evaluated. Direct costs/revenues, such as personnel time, items purchased and grants received, were evaluated using self administered surveys. Cost/revenue consequences, which were cost/revenue changes that may have occurred due to changes in patient utilisation or physician behaviour, were evaluated using electronic billing data. Other methods for evaluating cost/revenue consequences if electronic billing data are not available are also discussed. CONCLUSION: This paper describes a practical taxonomy and method for assessing the costs and revenues of QI programmes for outpatient organisations. Results of such analyses will be useful for healthcare organisations implementing QI programmes and also for policy makers designing incentives for QI participation. PMID- 17693670 TI - Pneumothorax after insertion of central venous catheters in the intensive care unit: association with month of year and week of month. AB - RATIONALE: One of the complications associated with insertion of central venous catheters (CVCs) is pneumothorax (PTX). Because of housestaff inexperience, it was hypothesised that rates of PTX after insertion of CVCs in teaching hospitals would be highest in July and August and in the first week of the month (beginning of intensive care unit (ICU) rotation). METHODS: In a retrospective analysis of data from patients admitted to the ICU in two tertiary care teaching hospitals in British Columbia from 1999 to 2005, rates of PTX occurring after insertion of CVCs were calculated, and it was evaluated whether rates were increased during certain times of the year/month. RESULTS: During this period, 3548 patients were admitted to these ICUs and had at least one CVC placed. 5816 CVCs were inserted; 113 PTX occurred within 2 days after insertions (1.9% per CVC). The rate during the last week of the month was greater (2.7%) than during the first, second or third weeks (1.7%, 1.8% and 1.4%, respectively). This effect persisted after controlling for the Acute Physiology and Chronic Health Evaluation II score, the number of catheters placed per patient, gender, age and hospital. Rates of PTX after catheter placement did not vary by the month of the year. CONCLUSIONS: The rate of PTX after insertion of CVCs is greatest in the last week of the month. If this effect can be verified in other centres, increased supervision of residents at the end of ICU rotations when placing CVCs should be considered. Whether this effect applies to other patient safety outcomes in the ICU also needs further study. PMID- 17693671 TI - Patient safety: helping medical students understand error in healthcare. AB - OBJECTIVE: To change the culture of healthcare organisations and improve patient safety, new professionals need to be taught about adverse events and how to trap and mitigate against errors. A literature review did not reveal any patient safety courses in the core undergraduate medical curriculum. Therefore a new module was designed and piloted. DESIGN: A 5-h evidence-based module on understanding error in healthcare was designed with a preliminary evaluation using self-report questionnaires. SETTING: A UK medical school. PARTICIPANTS: 110 final year students. MEASUREMENTS AND MAIN RESULTS: Participants completed two questionnaires: the first questionnaire was designed to measure students' self ratings of knowledge, attitudes and behaviour in relation to patient safety and medical error, and was administered before and approximately 1 year after the module; the second formative questionnaire on the teaching process and how it could be improved was administered after completion of the module. CONCLUSIONS: Before attending the module, the students reported they had little understanding of patient safety matters. One year later, only knowledge and the perceived personal control over safety had improved. The students rated the teaching process highly and found the module valuable. Longitudinal follow-up is required to provide more information on the lasting impact of the module. PMID- 17693672 TI - Mature rapid response system and potentially avoidable cardiopulmonary arrests in hospital. AB - OBJECTIVE: To study the incidence, outcome and potentially avoidable causes of inpatient cardiopulmonary arrests in a hospital with a "mature" rapid response system (RRS). DESIGN: Retrospective observational study of all cardiopulmonary arrest events in 2005. SETTING: University of Pittsburgh Medical Center Presbyterian Hospital, a 730-bed academic, urban, tertiary care adult hospital in the USA. INTERVENTIONS: None. RESULTS: During the calendar year 2005, the 16th year since the establishment of a medical emergency team (MET)/RRS, the MET was activated 1942 times; 111 of these events were cardiopulmonary arrest events (3.26 arrest events/1000 patient admissions), and 1831 were non-arrest patient crisis events (53.8 crisis events/1000 patient admissions). A review of the 104 index cardiopulmonary arrest events revealed that 26 (25%) patients survived to discharge. Event survival decreased as the intensity of patient monitoring decreased (83% in intensive care units, 69% in monitored, and 36% in unmonitored units; p = 0.002), but the rate of subsequent in-hospital death was higher in the more intensely monitored settings (60%, 38%, 23%, respectively; p = 0.022). Nineteen (18%) arrests were deemed to be "potentially avoidable". Avoidable arrests were classified as: failure to adhere to established hospital patient care guideline or policy; inadequate monitoring or surveillance; or delays in dealing with patient needs including delay in MET/RRS activation. CONCLUSIONS: In spite of the high crisis event rate and a low rate of cardiac arrests, potentially avoidable cardiopulmonary arrests still occurred. According to the present study more cardiopulmonary arrest events might be avoided by better adherence to hospital patient care policies, by closer monitoring on floors and by preventing delays in addressing deterioration in patient condition. PMID- 17693673 TI - General practitioners and pharmaceutical sales representatives: quality improvement research. AB - BACKGROUND AND OBJECTIVE: Interaction between pharmaceutical sales representatives (PSRs) and general practitioners (GPs) may have an adverse impact on GP prescribing and therefore may be ethically questionable. This study aimed to evaluate the interactions between PSRs and GPs in an Australian general practice, and develop and evaluate a policy to guide the interaction. METHODS: Doctors' prescribing, diaries, practice promotional material and samples were audited and a staff survey undertaken. After receiving feedback, the staff voted on practice policy options. The resulting policy was evaluated 3 and 9 months. RESULTS: Prior to the intervention, GPs spent on average 40 min/doctor/month with PSRs. There were 239 items of promotional material in the practice and 4660 tablets in the sample cupboard. These were reduced by 32% and 59%, respectively, at 3 months after policy adoption and the reduction was sustained at 9 months. Vioxx was the most common drug name in promotional material. Staff adopted a policy of reduced access to PSRs including: reception staff not to make appointments for PSRs or accept promotional material; PSRs cannot access sample cupboards; GPs wishing to see PSRs may do so outside consulting hours. At 3 and 9 months, most staff were satisfied with the changes. Promotional items/room were not significantly reduced at 3 months (-4.0 items/room ; 95% CI -6.61 to -1.39; p = 0.066) or 9 months (-2.63 items/room; 95% CI -5.86 to 0.60; p = 0.24). Generic prescribing significantly increased at 3 months (OR 2.28, 95% CI 1.31 to 3.86; p = 0.0027) and 9 months (OR 2.07, 95% CI 1.13 to 3.82; p = 0.016). CONCLUSION: There was a marked reduction in interactions with PSRs with majority staff satisfaction and improved prescribing practices. The new policy will form part of the practice's orientation package. Reception staff give PSRs a letter explaining the policy. It is hoped that the extra 40 min/doctor of consulting time translates into more time with patients and time to evaluate more independent sources of drug information. PMID- 17693675 TI - Qualitative evaluation of an electronic prescribing and administration system. AB - OBJECTIVE: To provide a formative socio-technical evaluation of a pilot implementation of an integrated electronic prescribing, automated dispensing, barcode patient identification and electronic medication administration record (EMAR) system on one ward. DESIGN: A qualitative observational approach using discourse analysis within a socio-technical evaluation framework addressing systems functions, human perspectives and organisational context. SETTING: Surgical ward in a teaching hospital. PARTICIPANTS: Staff on study ward and in pharmacy. INTERVENTION: Implementation over time of an integrated electronic prescribing, automated dispensing, barcode patient identification and EMAR system. MAIN OUTCOME MEASURES: Assessment of technical performance, developed attitudes to the new system, changes to delivery of care and work practices. RESULTS: The system was successfully implemented on the ward, and remained in operation for over 2 years. Many of the technical components of the system initially showed problems, but the system evolved, with increased functionality and improved performance. Attitudes to the system in the early stages were mixed. Over time, and with experience of making the system work for them, staff attitudes changed to become more balanced and the potential benefits of the system became clearer to most. The system structured the work of staff, sometimes unexpectedly. CONCLUSIONS: Electronic prescribing systems need to be seen as occasions for change and learning rather than as black-boxed technical solutions to identified problems. The evaluation framework allows understanding as well as hypothesis testing, and is recommended for future evaluations of electronic prescribing systems. PMID- 17693676 TI - The impact of a closed-loop electronic prescribing and administration system on prescribing errors, administration errors and staff time: a before-and-after study. AB - OBJECTIVES: To assess the impact of a closed-loop electronic prescribing, automated dispensing, barcode patient identification and electronic medication administration record (EMAR) system on prescribing and administration errors, confirmation of patient identity before administration, and staff time. DESIGN, SETTING AND PARTICIPANTS: Before-and-after study in a surgical ward of a teaching hospital, involving patients and staff of that ward. INTERVENTION: Closed-loop electronic prescribing, automated dispensing, barcode patient identification and EMAR system. MAIN OUTCOME MEASURES: Percentage of new medication orders with a prescribing error, percentage of doses with medication administration errors (MAEs) and percentage given without checking patient identity. Time spent prescribing and providing a ward pharmacy service. Nursing time on medication tasks. RESULTS: Prescribing errors were identified in 3.8% of 2450 medication orders pre-intervention and 2.0% of 2353 orders afterwards (p<0.001; chi(2) test). MAEs occurred in 7.0% of 1473 non-intravenous doses pre-intervention and 4.3% of 1139 afterwards (p = 0.005; chi(2) test). Patient identity was not checked for 82.6% of 1344 doses pre-intervention and 18.9% of 1291 afterwards (p<0.001; chi(2) test). Medical staff required 15 s to prescribe a regular inpatient drug pre-intervention and 39 s afterwards (p = 0.03; t test). Time spent providing a ward pharmacy service increased from 68 min to 98 min each weekday (p = 0.001; t test); 22% of drug charts were unavailable pre intervention. Time per drug administration round decreased from 50 min to 40 min (p = 0.006; t test); nursing time on medication tasks outside of drug rounds increased from 21.1% to 28.7% (p = 0.006; chi(2) test). CONCLUSIONS: A closed loop electronic prescribing, dispensing and barcode patient identification system reduced prescribing errors and MAEs, and increased confirmation of patient identity before administration. Time spent on medication-related tasks increased. PMID- 17693677 TI - Preventing medication errors in community pharmacy: root-cause analysis of transcription errors. AB - BACKGROUND: Medication errors can have serious consequences for patients, and medication safety is essential to pharmaceutical care. Insight is needed into the vulnerability of the working process at community pharmacies to identify what causes error incidents, so that the system can be improved to enhance patient safety. METHODS: 40 randomly selected Danish community pharmacies collected data on medication errors. Cases that reached patients were analysed, and the most serious cases were selected for root-cause analyses by an interdisciplinary analysis team. RESULTS: 401 cases had reached patients and a substantial number of them had possible clinical significance. Most of these errors were made in the transcription stage, and the most serious were errors in strength and dosage. The analysis team identified four root causes: handwritten prescriptions; "traps" such as similarities in packaging or names, or strength and dosage stated in misleading ways; lack of effective control of prescription label and medicine; and lack of concentration caused by interruptions. CONCLUSION: A substantial number of the medication errors identified at pharmacies that reach patients have possible clinical significance. Root-cause analysis shows potential for identifying the underlying causes of the incidents and for providing a basis for action to improve patient safety. PMID- 17693678 TI - Preventing medication errors in community pharmacy: frequency and seriousness of medication errors. AB - BACKGROUND: Medication errors are a widespread problem which can, in the worst case, cause harm to patients. Errors can be corrected if documented and evaluated as a part of quality improvement. The Danish community pharmacies are committed to recording prescription corrections, dispensing errors and dispensing near misses. This study investigated the frequency and seriousness of these errors. METHODS: 40 randomly selected Danish community pharmacies collected data for a defined period. The data included four types of written report of incidents, three of which already existed at the pharmacies: prescription correction, dispensing near misses and dispensing errors. Data for the fourth type of report, on adverse drug events, were collected through a web-based reporting system piloted for the project. RESULTS: There were 976 cases of prescription corrections, 229 cases of near misses, 203 cases of dispensing errors and 198 cases of adverse drug events. The error rate was 23/10,000 prescriptions for prescription corrections, 1/10,000 for dispensing errors and 2/10,000 for near misses. The errors that reached the patients were pooled for separate analysis. Most of these errors, and the potentially most serious ones, occurred in the transcription stage of the dispensing process. CONCLUSION: Prescribing errors were the most frequent type of error reported. Errors that reached the patients were not frequent, but most of them were potentially harmful, and the absolute number of medication errors was high, as provision of medicine is a frequent event in primary care in Denmark. Patient safety could be further improved by optimising the opportunity to learn from the incidents described. PMID- 17693679 TI - Preventing medication errors in long-term care: results and evaluation of a large scale web-based error reporting system. AB - OBJECTIVE: To describe the implementation and evaluation of a web-based medication error reporting system. DESIGN: Evaluation study. SETTING: Long-term care. PARTICIPANTS: 25 nursing homes in the US state of North Carolina. INTERVENTION: Detailed information about all medication errors occurring in a facility during a 1 year period was entered into a web-based reporting system. An evaluation survey was conducted to assess usability and the potential for the system to prevent errors. MAIN OUTCOME MEASURES: Number and specific characteristics of medication errors reported. A survey evaluating ease of use of the system and whether the participants thought it would help improve medication safety. RESULTS: 23 (92%) sites entered 631 error reports for 2731 discrete error instances when weighted by the number of times the errors were repeated. 51 (8%) errors were classified as having a serious patient impact requiring monitoring/intervention or worse. The most common errors were dose omission (203, 32%), overdose (91, 14%), underdose (43, 7%), wrong patient (38, 6%), wrong product (38, 6%), and wrong strength (38, 6%). Errors most commonly occurred during medication administration (296, 47%) and were attributed to basic human error (402, 48%). Seven drugs were implicated in a third (175, 28%) of all errors: lorazepam, oxycodone, warfarin, furosemide, hydrocodone, insulin and fentanyl. 20 sites (86% of respondents) completed the evaluation survey and participants found the system easy to use and thought it would increase accuracy of reporting and improve patient safety. CONCLUSIONS: The web-based medication error reporting system was easy to use, with strong indications that it would be a valuable tool for preventing future errors. PMID- 17693680 TI - Chlamydia testing in community pharmacies: evaluation of a feasibility pilot in south east London. AB - BACKGROUND AND OBJECTIVE: Chlamydia trachomatis infection is a common sexually transmitted infection with serious sequelae. Excellent access to testing, treatment and contact tracing are an essential part of strategies to control it. With traditional sexual health services over-stretched, community pharmacies are well placed to provide this service. They have the potential to improve access by offering chlamydia testing and treatment from high street venues with long opening hours. This study evaluated the feasibility and acceptability to users and pharmacists of this service in independent community pharmacies. METHOD: A chlamydia testing and treatment service was offered in three community pharmacies in two inner London boroughs for a 3-month pilot. Data on the feasibility and acceptability of the new service were collected via a survey of client experience, in-depth semistructured interviews with clients and pharmacists, and structured evaluation reports completed by professional patients paid to visit the pharmacies. RESULTS: 83 tests were taken with eight (9.5%) of these positive for C trachomatis. Of those tested, 94% (n = 73) were women and 71% (n = 56) were from ethnic minorities. 80 clients completed the questionnaires and 24 clients were interviewed. Most clients heard about the service from the pharmacist when requesting emergency contraception and 16% (n = 13) would not otherwise have been tested. Clients valued the speed and convenience of the service and the friendly, non-judgmental approach of the pharmacist. Confidentiality when asking for the service at the counter was suboptimal, and the pharmacist trained to deliver the service was not always available to provide it. CONCLUSIONS: Chlamydia testing and treatment in community pharmacies is feasible and acceptable to users. The service increases access among young women at high risk of sexually transmitted infection but not among young men. PMID- 17693681 TI - Guidelines in context of evidence. AB - OBJECTIVE: In clinical practice guidelines, the quality of the available evidence is graded according to its reliability and quality. This study aimed to evaluate the quality of the available research evidence, using the levels of evidence, in the evidence summaries of 64 Finnish national evidence-based Current Care guidelines. DESIGN: Descriptive assessment. SETTING: Electronic web-based guidelines in Finland. MAIN OUTCOME MEASURES: The proportions of evidence summaries with different levels of evidence (A-D). RESULTS: The 64 guidelines had a total of 2419 evidence summaries. Of these, 532 (22.0%) were evidence level A, 891 (36.8%) were evidence level B, 808 (33.4%) were evidence level C, and 188 (7.8%) were evidence level D. Most--that is, 81% of the level C and D evidence summaries dealt with diagnosis and treatment. Most of the evidence summaries pertained to treatment (58.2%) and diagnosis (22.4%). The sections on diagnosis and treatment represented 80% of all the level A and level B evidence, and 81% of all the level C and level D evidence. CONCLUSIONS: There is adequate high-quality evidence (level A) to support only a fifth of the main statements of the 64 guidelines. This is most likely an optimistic estimate, since level D evidence often does not have an evidence summary. The guideline development groups find it easier to agree on recommendations based on level A and level B evidence. PMID- 17693682 TI - Patient safety culture in primary care: developing a theoretical framework for practical use. AB - OBJECTIVE: Great importance has been attached to a culture of safe practice in healthcare organisations, but it has proved difficult to engage frontline staff with this complex concept. The present study aimed to develop and test a framework for making the concept of safety culture meaningful and accessible to managers and frontline staff, and facilitating discussion of ways to improve team/organisational safety culture. SETTING: Eight primary care trusts and a sample of their associated general practices in north west England. METHODS: In phase 1 a comprehensive review of the literature and a postal survey of experts helped identify the key dimensions of safety culture in primary care. Semistructured interviews with 30 clinicians and managers explored the application of these dimensions to an established theory of organisational maturity. In phase 2 the face validity and utility of the framework was assessed in 33 interviews and 14 focus groups. RESULTS: Nine dimensions were identified through which safety culture is expressed in primary care organisations. Organisational descriptions were developed for how these dimensions might be characterised at five levels of organisational maturity. The resulting framework conceptualises patient safety culture as multidimensional and dynamic, and seems to have a high level of face validity and utility within primary care. It aids clinicians' and managers' understanding of the concept of safety culture and promotes discussion within teams about their safety culture maturity. CONCLUSIONS: The framework moves the agenda on from rhetoric about the importance of safety culture to a way of understanding why and how the shared values of staff working within a healthcare organisation may be operationalised to create a safe environment for patient care. PMID- 17693683 TI - Quantitative phosphoproteome profiling of Wnt3a-mediated signaling network: indicating the involvement of ribonucleoside-diphosphate reductase M2 subunit phosphorylation at residue serine 20 in canonical Wnt signal transduction. AB - The complexity of canonical Wnt signaling comes not only from the numerous components but also from multiple post-translational modifications. Protein phosphorylation is one of the most common modifications that propagates signals from extracellular stimuli to downstream effectors. To investigate the global phosphorylation regulation and uncover novel phosphoproteins at the early stages of canonical Wnt signaling, HEK293 cells were metabolically labeled with two stable isotopic forms of lysine and were stimulated for 0, 1, or 30 min with purified Wnt3a. After phosphoprotein enrichment and LC-MS/MS analysis, 1057 proteins were identified in all three time points. In total 287 proteins showed a 1.5-fold or greater change in at least one time point. In addition to many known Wnt signaling transducers, other phosphoproteins were identified and quantitated, implicating their involvement in canonical Wnt signaling. k-Means clustering analysis showed dynamic patterns for the differential phosphoproteins. Profile pattern and interaction network analysis of the differential phosphoproteins implicated the possible roles for those unreported components in Wnt signaling. Moreover 100 unique phosphorylation sites were identified, and 54 of them were quantitated in the three time points. Site-specific phosphopeptide quantitation revealed that Ser-20 phosphorylation on RRM2 increased upon 30-min Wnt3a stimulation. Further studies with mutagenesis, the Wnt reporter gene assay, and RNA interference indicated that RRM2 functioned downstream of beta-catenin as an inhibitor of Wnt signaling and that Ser-20 phosphorylation of RRM2 counteracted its inhibition effect. Our systematic profiling of dynamic phosphorylation changes responding to Wnt3a stimulation not only presented a comprehensive phosphorylation network regulated by canonical Wnt signaling but also found novel molecules and phosphorylation involved in Wnt signaling. PMID- 17693684 TI - Effect of iron injections on aerobic-exercise performance of iron-depleted female athletes. AB - This investigation examined the effect of intramuscular iron injections on aerobic-exercise performance in iron-deficient women. Sixteen athletes performed a 10-min steady-state submaximal economy test, a VO2max test, and a timed test to exhaustion at VO2max workload. Subjects were randomly assigned to an iron supplemented group (IG) receiving intramuscular iron injections or to a placebo group (PG). Twenty days after the first injection, exercise and blood testing were repeated. A final blood test occurred on Day 28. Post supplementation, no differences were found between the groups' submaximal or maximal VO2, heart rate, or blood lactate (P > 0.05). Time to exhaustion was increased in the IG (P < 0.05) but was not greater than that of the PG (P > 0.05). The IG's serum ferritin (SF) was significantly increased on Days 20 and 28 (mean +/- standard error: 19 +/- 3 to 65 +/- 11 to 57 +/- 12 microg/L; P < 0.01), with a percentage change from baseline significantly greater than in the PG (P < 0.01). It was concluded that intramuscular iron injections can effectively increase SF without enhancing submaximal or maximal aerobic-exercise performance in iron-depleted female athletes. PMID- 17693685 TI - Effect of preexercise ingestion of modified cornstarch on substrate oxidation during endurance exercise. AB - The purpose of this study was to investigate differences in substrate oxidation between dextrose (DEX) and unmodified (UAMS) and acid/alcohol-modified (MAMS) cornstarches. Seven endurance-trained men (VO2peak = 59.1 +/- 5.4 mL.kg-1.min-1) participated in 2 h of exercise (66.4% +/- 3.3% VO2peak) 30 min after ingesting 1 g/kg body weight of the experimental carbohydrate or placebo (PLA). Plasma glucose and insulin were elevated after DEX (P < 0.05) compared with UAMS, MAMS, and PLA. Although MAMS and DEX raised carbohydrate oxidation rate through 90 min of exercise, only MAMS persisted throughout 120 min (P < 0.05 compared with all trials). Exogenous-carbohydrate oxidation rate was higher in DEX than in MAMS and UAMS until 90 min of exercise. Acid/alcohol modification resulted in augmented carbohydrate oxidation with a small, sustained increase in exogenous-carbohydrate oxidation rate. MAMS appears to be metabolizable and available for oxidation during exercise. PMID- 17693686 TI - Rehydration after exercise in the heat: a comparison of 4 commonly used drinks. AB - To determine the effectiveness of 3 commonly used beverages in restoring fluid and electrolyte balance, 8 volunteers dehydrated by 1.94% +/- 0.17% of body mass by intermittent exercise in the heat, then ingested a carbohydrate-electrolyte solution (Gatorade), carbonated water/apple-juice mixture (Apfelschorle), and San Benedetto mineral water in a volume equal to 150% body-mass loss. These drinks are all are perceived to be effective rehydration solutions, and their effectiveness was compared with the rehydration effectiveness of Evian mineral water, which is not perceived in this way by athletes. Four hours after rehydration, the subjects were in a significantly lower hydration status than the pretrial situation on trials with Apfelschorle (-365 +/- 319 mL, P = 0.030), Evian (-529 +/- 319 mL, P < 0.0005), and San Benedetto (-401 +/- 353 mL, P = 0.016) but were in the same hydration status as before the dehydrating exercise on Gatorade (-201 +/- 388 mL, P = 0.549). Sodium balance was negative on all trials throughout the study; only with Apfelschorle did subjects remain in positive potassium balance. In this scenario, recovery of fluid balance can only be achieved when significant, albeit insufficient, quantities of sodium are ingested after exercise. There is a limited range of commercially available products that have a composition sufficient to achieve this, even though the public thinks that some of the traditional drinks are effective for this purpose. PMID- 17693687 TI - Positive and negative placebo effects resulting from the deceptive administration of an ergogenic aid. AB - The article describes a study examining placebo effects associated with the administration of a hypothetical ergogenic aid in sport. Forty-two team-sport athletes were randomly assigned to 2 groups. All subjects completed 3 x 30-m baseline sprint trials after which they were administered what was described to them as an ergogenic aid but was in fact 200 mg of cornstarch in a gelatin capsule. Group 1 was provided with positive information about the likely effects on performance of the substance, whereas Group 2 was provided with negative information about the same substance. The sprint protocol was repeated 20 min later. Although for Group 1 mean speed did not differ significantly between baseline and experimental trials, a significant linear trend of greater speed with successive experimental trials suggested that positive belief exerted a positive effect on performance (P < 0.01). Group 2 ran 1.57% slower than at baseline (P < 0.01, 95% confidence intervals 0.32-2.82%), suggesting that negative belief exerted a negative effect on performance. Collectively, data suggest that subjects' belief in the efficacy or otherwise of a placebo treatment might significantly influence findings in experimental research. PMID- 17693688 TI - Gastric emptying of fluids during variable-intensity running in the heat. AB - This study examined gastric emptying, core temperature, and sprint performance during prolonged intermittent shuttle running in 30 degrees C when ingesting a carbohydrate-electrolyte solution (CES) or flavored water (FW). Nine male soccer players performed 60 min of shuttle running, ingesting fluid before exercise and every 15 min during exercise. Gastric emptying was measured using a double sampling aspiration technique, and intestinal temperature was monitored via ingested capsules. There were no differences between trials in the total fluid volume emptied from the stomach during each exercise period (P = 0.054). The volume emptied every 15 min was 244 +/- 67 mL in the CES trial and 273 +/- 66 mL in the FW trial. Intestinal temperature was higher during exercise in the CES trial (P = 0.004), and cumulative sprint time was shorter (P = 0.037). Sprint performance was enhanced by the ingestion of a CES, which resulted in elevated core temperatures, and the rate of gastric emptying remained similar between solutions. PMID- 17693689 TI - Voluntary dehydration in runners despite favorable conditions for fluid intake. AB - This study investigated the relationship between runners' perceptions of fluid needs and drinking behavior under conditions of compensable heat stress (ambient temperature = 20.5 +/- 0.7 degrees C, 68.9 degrees F; relative humidity = 76.6%). Eighteen experienced runners (15 men, 40.5 +/- 2.5 y, and 3 women, 42 +/- 2.3 y) were given ad libitum access to a sports drink (6% carbohydrate-electrolyte solution) at Miles 2, 4, 6, and 8. After the run (75.5 +/- 8.0 min), subjects completed questionnaires that required them to estimate their individual fluid intake and sweat loss. Dehydration averaged 1.9% +/- 0.8% of initial body weight (a mean sweat loss of 21.6 +/- 5.1 mL.kg-1.h-1). Subjects replaced only 30.5% +/- 18.1% of sweat loss and underestimated their sweat loss by 42.5% +/- 36.6% (P 20 micromol/l) and as a factor for deciding between parenteral and enteral nutrition (as long as the pathology is considered). Citrullinemia should be used with care as a marker either of the intestinal absorption or following small bowel transplantation. SUMMARY: Citrulline is easily taken up by the gut, with a broad set of transporters that can remove it from the lumen in the enterocytes. This is confirmed by pharmacokinetic studies and the efficacy is so great that oral complementation with citrulline seems more efficient than complementation with arginine to provide arginine. PMID- 17693748 TI - Severe mucositis: how can nutrition help? AB - PURPOSE OF REVIEW: To review the recent evidence on the effect of nutrition on the incidence and severity of mucositis following anticancer treatment. RECENT FINDINGS: There have been many recent publications on mucositis and on nutrition in cancer, but very few on nutrition and mucositis in cancer. It is difficult to establish a definite link between nutritional status, nutritional interventions and mucositis. Malnutrition is probably a risk factor for mucositis, however, and some of the interventions that improve nutrition in cancer patients and reduce the risk of cancer in the general population work via mechanisms that might positively affect the development and course of mucositis. Whilst it can be tempting to extrapolate these findings to suggest that nutritional support can reduce the incidence and severity of mucositis, this would be premature. SUMMARY: There may well be a link between nutritional status, nutritional supplementation, anticancer treatment and mucositis, but it is not yet proven; and mechanism based, prospective, randomized studies are required to answer the question. This is likely to be an area of increased study in the future. PMID- 17693749 TI - The significance of bowel permeability. AB - PURPOSE OF REVIEW: In clinical research, increased permeability has been scrutinized as a potential indicator of the severity of gastrointestinal disease and as a potential cause of the perpetuation of severe inflammatory activity in infectious states. This review discusses old and recent epidemiological and clinical evidence to establish whether increased permeability in sepsis is a sequel or a cause of multiple organ failure. In addition, old and new evidence linking inflammation and permeability in abnormal gastrointestinal anatomy and function to liver abnormalities in susceptible patients will be reviewed. RECENT FINDINGS: Intestinal permeability has been found to be increased in several gastrointestinal diseases but not to be a very good marker of the severity of disease. Evidence is put forward supporting the claim that increased intestinal permeability is part of generalized leakiness of tight junctions in multiple organ failure and to play a less strong role as a primary event in its pathogenesis. Endemic malnutrition has been shown to be caused by interplay between malnutrition and intestinal inflammation. Recently experimental evidence has been put forward suggesting that enteral fat has anti-inflammatory effects on the intestine via the autonomic nervous system. Old clinical and new epidemiological evidence links intestinal inflammation, disruption of the enterohepatic cycle of bile acids, and liver disease. SUMMARY: The implications of the described findings are that inflammatory activity, locally induced by abnormal intestinal anatomy and disruption of the bile acid pool, or systemically by severe and uncontrolled inflammation/infection, should be the focus of treatment or research. In addition, the connection between intestinal inflammation and liver disease should be investigated. PMID- 17693750 TI - Bibliography. Current world literature. Assessment of nutritional status and analytical methods. PMID- 17693751 TI - Bibliography. Current world literature. Molecular cell biology and physiology of solute transport. PMID- 17693752 TI - Protein kinase C beta inhibition: the promise for treatment of diabetic nephropathy. AB - PURPOSE OF REVIEW: The prevalence of diabetes mellitus is increasing rapidly worldwide. The number of patients with diabetic nephropathy is also expected to increase considerably in the future despite currently available treatments that may prevent or slow kidney disease progression. Additional therapeutic agents are therefore urgently needed. RECENT FINDINGS: Ruboxistaurin mesylate is a bisindolylmaleimide that specifically inhibits the beta-isoform of protein kinase C. In animal models of diabetic nephropathy, ruboxistaurin normalized glomerular hyperfiltration, decreased urinary albumin excretion, preserved renal function and reduced mesangial expansion, glomerulosclerosis, and tubulointerstitial fibrosis. In humans with type 2 diabetes and nephropathy already treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, treatment with ruboxistaurin for 1 year reduced albuminuria and urinary transforming growth factor-beta, and maintained estimated glomerular filtration rate. Ruboxistaurin has so far been shown to be well tolerated at the doses tested. SUMMARY: Inhibition of protein kinase C beta may represent a novel strategy to improve kidney outcomes in patients with diabetes mellitus. Large scale, prospective trials are needed to confirm the safety and potential benefits of ruboxistaurin in patients with diabetic nephropathy. PMID- 17693753 TI - Baroreflex stimulation in the treatment of hypertension. AB - PURPOSE OF REVIEW: It is not uncommon for hypertension to be resistant to the effects of medical therapy, and this poses a significant risk of adverse cardiovascular events. Electrical stimulation of the carotid sinus is a novel treatment for hypertension, and has been shown to reduce blood pressure by activating the baroreflex and reducing sympathetic tone. RECENT FINDINGS: Evidence suggests that the baroreceptors play a more important role in long-term blood pressure regulation than was once believed. It appears that the baroreflex attenuates chronic hypertension in large part by inhibiting renal sympathetic tone. Animal and human studies have demonstrated a safe and effective lowering of blood pressure with chronic electrical stimulation of the carotid sinus, and have generated enthusiasm for implantable carotid sinus stimulators in the treatment of hypertension. SUMMARY: Electrical baroreflex stimulation appears safe and effective, and may represent a useful adjunct to medical therapy in patients with resistant hypertension. PMID- 17693754 TI - Antihypertensive agents and arterial stiffness: relevance to reducing cardiovascular risk in the chronic kidney disease patient. AB - PURPOSE OF REVIEW: Arterial stiffness is a sign of diffuse adventitial macrovascular disease. The purpose of the present review is to discuss, in patients with chronic kidney disease, the pathophysiology of increased arterial stiffness, the role of antihypertensive therapy on reduction of arterial stiffness, and the clinical ways by which the prognostication of cardiovascular disease in patients with chronic kidney disease can be refined using arterial stiffness monitoring. RECENT FINDINGS: Arterial stiffness is increased with increasing prevalence of traditional cardiovascular risk factors. In patients with chronic kidney disease some unique factors further increase the risk of arterial stiffness, and include volume overload, activation of the renin angiotensin system, anemia, and dysregulated mineral metabolism. Arterial stiffness is increased even in patients with early-stage chronic kidney disease. Blood pressure reduction when accompanied by a reduction in arterial stiffness is associated with improved prognosis. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers can preferentially improve arterial stiffness, which may be an additional mechanism of cardiovascular protection with these agents. SUMMARY: The impact of improvement in arterial stiffness with antihypertensive agents on cardiovascular outcomes needs well designed clinical trials. PMID- 17693755 TI - Renin inhibitors: novel agents for renoprotection or a better angiotensin receptor blocker for blood pressure lowering? AB - PURPOSE OF REVIEW: Direct renin inhibitors are the newest antihypertensive therapeutic class. The review describes their antihypertensive and antiproteinuric effects and possible renoprotective capabilities. RECENT FINDINGS: Clinical trials demonstrate direct renin inhibitors reduce systolic and diastolic blood pressure comparable with other commonly used antihypertensive drugs, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. They also reduce proteinuria and are renoprotective in experimental models of kidney disease. Direct renin inhibitors, when used with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, offer incremental blood pressure reduction far greater than that observed when an angiotensin-converting enzyme inhibitor and angiotensin receptor blocker are used together. This suggests that renin inhibitors possess a unique and distinct mechanism of action compared with the other two therapeutic classes. SUMMARY: Direct renin inhibitors, due to their antihypertensive and antiproteinuric effects, and the unique mechanism of action resulting in reduction in plasma renin activity and suppression of angiotensin II levels, may offer a unique opportunity to facilitate blood pressure reduction with both angiotensin converting enzyme inhibitors and angiotensin receptor blockers as well as other commonly used therapeutic classes. More effective blood pressure and proteinuria reduction coupled with a unique means of suppressing the renin angiotensin system may offer improved opportunity for renoprotection. PMID- 17693756 TI - Are differences in calcium antagonists relevant across all stages of nephropathy or only proteinuric nephropathy? AB - PURPOSE OF REVIEW: The main effects of classic calcium antagonists are mediated by the inhibition of L-type calcium channels broadly distributed within the renal vascular bed. Calcium antagonists act predominantly on the afferent arterioles, and dihydropyridines can favour the increase in glomerular hypertension and progression of kidney diseases, in particular when systemic blood pressure remains uncontrolled. RECENT FINDINGS: Calcium antagonists have been widely used in clinical practice because of their antihypertensive capacity. The prevention of renal damage is a very important aim of antihypertensive therapy. This is particularly so taking into account the high prevalence of chronic kidney disease in the general population. Non-dihydropyridines such as verapamil have been shown to possess an antiproteinuric effect that could be particularly relevant. SUMMARY: Recent data from clinical trials have confirmed that, in hypertensive patients with preserved renal function or with chronic kidney disease, calcium antagonists are effective antihypertensive drugs to be considered alone or in combination with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. In those patients presenting with proteinuric kidney disease, non-dihydropyridines could reduce proteinuria to a greater degree than dihydropyridines. PMID- 17693757 TI - Collectrin and the kidney. PMID- 17693758 TI - BK channels in the kidney. AB - PURPOSE OF REVIEW: Large, BK (calcium-activated potassium) channels are now regarded as relevant players in many aspects of renal physiology, including potassium secretion. This review will highlight recent discoveries regarding the function and localization of BK in the kidney. RECENT FINDINGS: Patch clamp electrophysiology has revealed BK in cultured podocytes, glomerular mesangial cells, and in several tubule segments including principal cells (connecting tubules/principal cells), and intercalated cells of connecting tubules and cortical collecting ducts. Flow-induced potassium secretion is mediated by BK in the distal nephron and may be partly the result of shear stress-induced increases in cell calcium concentrations. ROMK-/- and wild-type mice on a high potassium diet exhibit BK-mediated potassium secretion, and studies of BK-alpha-/- and BK beta1-/- mice suggest that flow-induced potassium secretion is mediated by BK alpha/beta1, which is specifically localized in the apical membrane of the connecting tubule of the mouse and connecting tubule plus initial cortical collecting duct of the rabbit. SUMMARY: BK channels, located in glomerular cells and in many nephron segments, especially mediate potassium secretion in the combined condition of potassium adaptation and high flow. Understanding the molecular makeup of BK in specific renal cells and the dietary and physiological conditions for their expression can yield improved potassium-sparing compounds. PMID- 17693759 TI - Regulation of renal ion transport by the calcium-sensing receptor: an update. AB - PURPOSE OF REVIEW: Extracellular calcium has profound effects on renal tubular transport, presumably via the calcium-sensing receptor, which is expressed in all nephron segments, but its effects in specific segments and the mechanism of regulation of transport are not fully understood. RECENT FINDINGS: Recognition that activating calcium-sensing receptor mutations result in a Bartter-like syndrome demonstrate that the transport effects of extracellular calcium are mediated by the calcium-sensing receptor. Its presence in the gills and solute and water-transporting organs of fish coupled with appropriate calcium-sensing receptor kinetics indicate that the calcium-sensing receptor was originally involved in the regulation of sodium chloride, calcium and magnesium transport. Based on its physiological effects on tubular transport and biochemical and genetic data, the calcium-sensing receptor appears to act by mechanisms that distinguish it from other G protein-coupled receptors. SUMMARY: The calcium sensing receptor mediates the effects of extracellular calcium on the kidney, is an essential control point in the regulation of calcium balance and possibly the physiological regulation of sodium chloride balance. The thick ascending limb of Henle and distal convoluted tubule appear to be the nephron segments most responsible for the effects of the calcium-sensing receptor, although its mechanisms of action are not fully established. PMID- 17693760 TI - Role of proteolysis in the activation of epithelial sodium channels. AB - PURPOSE OF REVIEW: Epithelial sodium channels mediate Na+ transport across high resistance, Na+-transporting epithelia. This review describes recent findings that indicate that epithelial sodium channels are activated by the proteolytic release of inhibitory peptides from the alpha and gamma subunits. RECENT FINDINGS: Non-cleaved channels have a low intrinsic open probability that may reflect enhanced channel inhibition by external Na+--a process referred to as Na+ self-inhibition. Cleavage at a minimum of two sites within the alpha or gamma subunits is required to activate the channel, presumably by releasing inhibitory fragments. The extent of epithelial sodium channel proteolysis is dependent on channel residency time at the plasma membrane, as well as on the balance between levels of expression of proteases that activate epithelial sodium channels and inhibitors of these proteases. Regulated epithelial sodium channel proteolysis has been observed in rat kidney and in human airway epithelia. SUMMARY: Proteolysis of epithelial sodium channel subunits plays a key role in modulating epithelial sodium channel activity through changes in channel open probability. PMID- 17693761 TI - The transient receptor potential vanilloid-responsive 1 and 4 cation channels: role in neuronal osmosensing and renal physiology. AB - PURPOSE OF REVIEW: To provide an overview of recent developments in the field of systemic osmoregulation, with attention to the brain and kidney. RECENT FINDINGS: A number of pivotal observations underscore the primary importance of transient receptor potential channels in systemic osmoregulation and their involvement constitutes the focus of this review. Recent data suggest that transient receptor potential vanilloid-responsive 4 is a central sensor or effector of systemic hypotonicity, whereas an unidentified variant of transient receptor potential vanilloid-responsive 1 potentially serves an analogous role in systemic hypertonicity. SUMMARY: Members of the transient receptor potential vanilloid responsive subfamily of transient receptor potential channels are likely to serve as central sensors of systemic anisotonicity. PMID- 17693762 TI - Claudins and paracellular transport: an update. AB - PURPOSE OF REVIEW: Claudins are tight junction proteins that form paracellular barriers and pores. The purpose of this timely review is to provide an update on the exciting new advances in our understanding of claudin biology and their relevance to renal physiology and pathophysiology. RECENT FINDINGS: Accumulating evidence from numerous studies indicates that the primary role of claudins is to determine the permeability and charge selectivity of the paracellular pathway to small ions. Studies in which claudins are overexpressed in cell lines have potential limitations and need to be interpreted cautiously. Ribonucleic acid interference is a novel approach to functional characterization. Claudins are believed to assemble into multimers by homophilic and heterophilic side-by-side and head-to-head interaction; however, there is still limited evidence for this. The roles of a few claudins in the renal tubule, including claudins 2, 8, 10, 16 and 19, have now been elucidated. SUMMARY: These findings reveal tantalizing clues to claudin biology and function. Much remains unknown, however, and these findings will hopefully encourage further research in this important area. PMID- 17693763 TI - Regulation of ion transport and blood pressure by cytochrome p450 monooxygenases. AB - PURPOSE OF REVIEW: Past and recent studies of the cytochrome P450 monooxygenase branch of the arachidonate cascade establish a role for this metabolic pathway in the regulation of vascular tone and tubular ion transport. Functional and electrophysiology studies indicate that the P450 eicosanoids participate in the regulation of vascular potassium and renal sodium channels, and of systemic blood pressures. RECENT FINDINGS: Associations between genetically controlled alterations in blood pressure and the activity or transcriptional regulation of renal Cyp2c arachidonic acid epoxygenases and Cyp4a omega-hydroxylases document a role for these enzymes in the pathophysiology of hypertension--a leading cause of cardiovascular, cerebral, and renal morbidity and mortality. Associations between a functional variant of the human CYP4A11 gene and hypertension suggest a potential role for this gene as a determinant of polygenic blood pressure control in humans. SUMMARY: These results provide new understandings of the role of P450s in renal physiology, as well as conceptually novel approaches for studies of the molecular basis of human hypertension that could lead to new strategies for the early diagnosis and clinical management of this devastating disease. PMID- 17693764 TI - Metabolic acidosis: new insights from mouse models. AB - PURPOSE OF REVIEW: Metabolic acidosis is a severe disturbance of extracellular pH homeostasis that can be caused both by inborn or acquired defects in renal acid excretion or metabolic acid production. Chronic metabolic acidosis causes osteomalacia with nephrocalcinosis and urolithiasis. In the setting of end-stage renal disease, metabolic acidosis is often associated with increased peripheral insulin resistance, and represents an additional independent morbidity risk factor. This review summarizes recent insight, gained primarily from mouse models, into the mechanisms whereby the kidney regulates and adapts acid excretion. RECENT FINDINGS: Human genetics and various mouse models have shed new light on mechanisms that contribute to the kidney's ability to excrete acid and adapt appropriately to metabolism. Progress in four specific areas will be highlighted: mechanisms contributing to the synthesis and excretion of ammonia; insights into adaptive processes during acidosis; mechanisms by which the kidney may sense acidosis; and the pathophysiology of acquired and inborn errors of renal acid handling. SUMMARY: Genetic mouse models and various messenger RNA and proteome profiling and screening technologies demonstrate the importance of various acid-base transporting proteins and a metabolic and regulatory network that contributes to the kidney's ability to maintain the systemic acid-base balance. PMID- 17693765 TI - Na+ and K+ transport by the renal connecting tubule. AB - PURPOSE OF REVIEW: The connecting tubule is emerging as a nephron segment critical to the regulation of Na+ and K+ excretion and the maintenance of homeostasis for these ions. The segment is difficult to study, however, and much of the available information we have concerning its functions is indirect. Here, we review the major transport mechanisms and transporters found in this segment and outline several unsolved problems in the field. RECENT FINDINGS: Recent electrophysiological and immunohistochemical measurements together with theoretical studies provide a more comprehensive view of ion transport in the connecting tubule. New signaling pathways governing Na+ and K+ transport have also been described. SUMMARY: Key questions about how Na+ and K+ transport are regulated remain unanswered. Is the connecting tubule the site of final regulation of both Na+ and K+ excretion? If so, how are the transport rates of these two ions independently controlled? PMID- 17693767 TI - Bibliography. Current world literature. Pharmacology and therapeutics. PMID- 17693766 TI - Renal physiology of SLC26 anion exchangers. AB - PURPOSE OF REVIEW: The multifunctional anion exchanger family (Slc26) encompasses 11 identified genes, but only 10 encode real proteins (Slc26a10 is a pseudogene). Most of the Slc26 proteins function primarily as anion exchangers, exchanging sulfate, iodide, formate, oxalate, hydroxyl ion, and bicarbonate anions, whereas other Slc26 proteins function as chloride ion channels or anion-gated molecular motors. The aim of this review is to present recent studies on the molecular function of the Slc26 family and its role in renal physiology and pathophysiology. RECENT FINDINGS: In proximal tubules, Slc26a1 (Sat-1) mediates sulfate and oxalate transport across the basolateral membrane, while Slc26a6 (CFEX, Pat-1) mediates a variety of anion exchange at the apical membrane to facilitate transcellular sodium chloride absorption. Targeted deletion of murine Slc26a6 leads to intestinal hyperabsorption of oxalate, hyperoxaluria, and kidney stones. Slc26a4 (pendrin) and Slc26a7 are expressed in intercalated cells, and are involved in acid-base homeostasis and blood pressure regulation. Messenger RNA for Slc26a2, Slc26a9, and Slc26a11 is also present in the kidney, yet the roles of these family members in renal physiology or pathophysiology are not clear. SUMMARY: Members of this multifunctional anion transporter family play evolving roles in the etiology of nephrolithiasis (Slc26a6) and hypertension (Slc26a4 and Slc26a6). Other Slc26 family members (Slc26a2, Slc26a9, Slc26a11) express mRNA in the kidney but their roles in renal physiology are not yet known. PMID- 17693769 TI - The department of energy's Russian health studies program. PMID- 17693770 TI - Mayak worker dosimetry study: an overview. AB - The Mayak Production Association (MPA) was the first plutonium production plant in the former Soviet Union. Workers at the MPA were exposed to relatively large internal radiation intakes and external radiation exposures, particularly in the early years of plant operations. This paper describes the updated dosimetry database, "Doses-2005." Doses-2005 represents a significant improvement in the determination of absorbed organ dose from external radiation and plutonium intake for the original cohort of 18,831 Mayak workers. The methods of dose reconstruction of absorbed organ doses from external radiation uses: 1) archive records of measured dose and worker exposure history, 2) measured energy and directional response characteristics of historical Mayak film dosimeters, and 3) calculated dose conversion factors for Mayak Study-defined exposure scenarios using Monte Carlo techniques. The methods of dose reconstruction for plutonium intake uses two revised models developed from empirical data derived from bioassay and autopsy cases and/or updates from prevailing or emerging International Commission on Radiological Protection models. Other sources of potential significant exposure to workers such as medical diagnostic x-rays, ambient onsite external radiation, neutron radiation, intake of airborne effluent, and intake of nuclides other than plutonium were evaluated to determine their impact on the dose estimates. PMID- 17693771 TI - Uncertainties analysis for the plutonium dosimetry model, doses-2005, using Mayak bioassay data. AB - The Doses-2005 model is a combination of the International Commission on Radiological Protection (ICRP) models modified using data from the Mayak Production Association cohort. Surrogate doses from inhaled plutonium can be assigned to approximately 29% of the Mayak workers using their urine bioassay measurements and other history records. The purpose of this study was to quantify and qualify the uncertainties in the estimates for radiation doses calculated with the Doses-2005 model by using Monte Carlo methods and perturbation theory. The average uncertainty in the yearly dose estimates for most organs was approximately 100% regardless of the transportability classification. The relative source of the uncertainties comes from three main sources: 45% from the urine bioassay measurements, 29% from the Doses-2005 model parameters, and 26% from the reference masses for the organs. The most significant reduction in the overall dose uncertainties would result from improved methods in bioassay measurement with additional improvements generated through further model refinement. Additional uncertainties were determined for dose estimates resulting from changes in the transportability classification and the smoking toggle. A comparison was performed to determine the effect of using the model with data from either urine bioassay or autopsy data; no direct correlation could be established. Analysis of the model using autopsy data and incorporation of results from other research efforts that have utilized plutonium ICRP models could improve the Doses-2005 model and reduce the overall uncertainty in the dose estimates. PMID- 17693772 TI - Mayak film dosimeter response studies, part I: measurements. AB - The Mayak Worker Dosimetry study is a joint Russian/U.S. project to evaluate doses received by workers at the Mayak Production Association facilities from 1948-1972. A key investigation in this project is the characterization of responses of the three types of film dosimeters used to monitor workers during this time period. Experimental irradiations of the dosimeters were performed in the radiation calibration laboratories at the National Research Center for Environment and Health (GSF) in Munich, Germany. The irradiations used photon sources from x-ray beams with ten different energy distributions and with Co and Cs isotopic gamma sources. Irradiations were performed with the dosimeters on phantoms and free-in-air. The dosimeters and phantoms were also positioned at varying angles to the radiation beam. The result of the experiments was a thorough characterization of the dosimeter response as a function of photon energy and as a function of angle for energy and angular ranges that cover the conditions encountered in the Mayak workplaces. The characterization data were then available for use in developing correction factors, which could be applied to worker dosimeter readings to provide a more accurate assessment of worker dose and estimates of doses to organs. PMID- 17693773 TI - Mayak film dosimeter response studies, part II: response models. AB - A study was performed of energy and angular responses of the film dosimeters that were used for worker monitoring at the Mayak Production Association (Mayak PA) in 1948-1992. The study used experimental data from tests with three types of individual film dosimeters, and the data were used to determine the dosimeters' energy and angular response characteristics in the range from 9 keV to Co energies, with the dosimeters exposed both free-in-air and on-phantom at horizontal and vertical rotation. Mathematical models of the dosimeters were developed to calculate the response characteristics of the dosimeters. The models of the film dosimeters were validated by comparing calculations to measurements. The models were then used as the basis for individual dose reconstruction in realistic photon spectra and worker exposure geometries at the Mayak PA workplaces. Reconstructed individual doses have been included in the Mayak worker database "Doses-2005" that is used for epidemiological studies of the Mayak workers' radiation exposures and subsequent health effects. PMID- 17693774 TI - Mayak film dosimeter response studies, part iii: application to worker dose assessment. AB - This paper describes the methods used to correct individual dosimeter readings for workers to obtain estimates of worker doses received at the Mayak Production Association (Mayak PA). Film dosimeters were used at Mayak PA for worker monitoring from 1948 until 1992. The method requires a determination of the relationship between the absorbed dose in film emulsion and the dose in air under calibration conditions, which is then extended to exposures in the actual radiation fields of the workplace. Corrections needed to account for actual workplace exposure conditions were determined by modeling with the Monte Carlo radiation transport computer code MCNP. Correction factors were developed to convert from dosimeter reading to a realistic worker dose. The method was applied as a basis for individual dose reconstruction using film dosimeters in realistic photon spectra and geometries at Mayak PA work areas. PMID- 17693778 TI - Effectiveness of an internet-based worksite smoking cessation intervention at 12 months. AB - OBJECTIVE: To evaluate effectiveness of an Internet-based smoking cessation program as part of a comprehensive health risk reduction initiative in a large, geographically dispersed employee population. METHODS: A financial incentive for participation was offered during 2003 health benefits enrollment. The primary cessation outcome was 7-day point prevalence abstinence at 12 months. RESULTS: A total of 1776 employees used the Internet program. Among those surveyed, the response rate was 32%. Quit rates ranged from 13% using intention to treat analysis (nonresponders counted as smokers) to 43% among survey responders. Higher Web site utilization was associated with better cessation outcomes, even after controlling for baseline motivation. CONCLUSIONS: The Internet program was successful at reaching a large number of geographically dispersed employees. The range of quit rates suggests that Internet cessation programs can be effective in promoting cessation and preventing relapse in a worksite setting. PMID- 17693780 TI - Roles of serum clara cell protein 16 and surfactant protein-D in the early diagnosis and progression of silicosis. AB - OBJECTIVE: To study roles of Clara cell protein 16 (CC16) and surfactant protein D (SP-D) as serum biomarkers in the early diagnosis and the pathogenesis of silicosis. METHODS: Thirty healthy volunteers, 30 silica-exposed workers, and 30 workers with suspected silicosis and phase I silicosis were included. Serum CC16 and SP-D concentrations were determined using enzyme-linked immunosorbent assay. RESULTS: Serum CC16 concentrations decreased in silica-exposed workers when compared with in controls, but serum SP-D levels increased, and this trend was obvious in phase 0 and I groups. Discriminant analysis showed that the accuracies of classifying group membership into control, phase 0, phase 0, and phase I were 86.7%, 46.7%, 66.7%, and 70%, respectively, and the total classification accuracy rate was 67.5%. CONCLUSION: Serum CC16 and SP-D may be useful biomarkers for early diagnosis, and serum SP-D concentration may associate with the pathogenesis of silicosis. PMID- 17693779 TI - Development of an Environmental Relative Moldiness index for US homes. AB - OBJECTIVE: The objective of this study was to establish a national relative moldiness index for homes in the United States. METHODS: As part of the Housing and Urban Development's American Healthy Homes Survey, dust samples were collected by vacuuming 2 m in the bedrooms plus 2 m in the living rooms from a nationally representative 1096 homes in the United States using the Mitest sampler. Five milligrams of sieved (300 mum pore, nylon mesh) dust was analyzed by mold-specific quantitative polymerase chain reaction for the 36 indicator species in 1096 samples. RESULTS: On the basis of this standardized national sampling and analysis, an "Environmental Relative Moldiness Index" was created with values ranging from about -10 to 20 or above (lowest to highest). CONCLUSIONS: The Environmental Relative Moldiness Index scale may be useful for home mold-burden estimates in epidemiological studies. PMID- 17693781 TI - Air trapping detected on end-expiratory high-resolution computed tomography in symptomatic World Trade Center rescue and recovery workers. AB - OBJECTIVES: We utilized end-expiratory chest computed tomography (CT) to investigate air trapping (AT) in symptomatic former World Trade Center (WTC) workers, and correlated the findings with clinical, physiological, and exposure related characteristics. METHODS: Twenty-nine WTC workers with lower respiratory symptoms were evaluated. Clinical data included symptom inventories, quantitative respiratory symptom scores, WTC dust exposure duration, pulmonary function tests, and inspiratory and end-expiratory high-resolution chest CT scans. The latter were scored quantitatively for AT (by two methods) and interstitial changes, and those scores were correlated with the clinical data. RESULTS: The two AT scoring methods yielded highly correlated results. AT was demonstrated in 25 of 29 patients, with scores ranging from 0 to 24 (mean, 10.6). There was a statistically significant correlation between AT and the duration of dust exposure. AT scores were significantly higher in patients with restrictive lung function data, and in lifetime nonsmokers. CONCLUSIONS: Our data suggest that AT from small airways disease may account for some of the reported clinical and pulmonary functional abnormalities in WTC dust-exposed workers, and support the use of high-resolution CT scans in the investigation and characterization of the pulmonary ailments of selected workers. PMID- 17693782 TI - Non-cancer mortality in supermarket meat workers. AB - OBJECTIVE: To report a non-cancer mortality update in supermarket meat workers. METHODS: Mortality of 10,383 supermarket meat workers was compared with that of a control group of non-meat workers and the US population from 1949 to 1989. RESULTS: Compared with both controls, male supermarket meat workers had an elevated relative risk for diabetes. There is also a suggestion of an increase in deaths from ischemic heart disease, other diseases of the kidney and ureter, alcoholism, and subarachnoid hemorrhage. Women had elevated relative risks for chronic bronchitis and ischemic heart disease, and possibly alcoholism. Numbers were too small to interpret the apparent increase in deaths from intracranial and intraspinal abcesses and acute nephritis in men and peritonitis in women. CONCLUSIONS: The role of occupational exposure to transmissible agents and exposure to fumes from the wrapping machine warrants further investigation. PMID- 17693783 TI - Natural history and risk factors of early respiratory responses to exposure to cotton dust in newly exposed workers. AB - OBJECTIVE: A prospective study of newly exposed cotton workers was performed to investigate the natural history of respiratory symptoms and lung function changes. METHODS: A total of 157 workers naive to cotton dust exposure were investigated by questionnaire, spirometry, and skin tests. They were examined before employment (baseline) and at the end of the first week, and the first, third, sixth, and 12th month after starting work. Acute airway response was defined as either a cross-first-shift or a cross-week fall in forced expiratory volume in one second (FEV1). The longitudinal change of lung function over the year was also calculated. Five hundred seventy-two personal dust sampling and 191 endotoxin measurements were performed to assess the exposure. RESULTS: Forty percent of workers reported work-related symptoms in the first week of the study. Smoking, endotoxin, and dust concentrations were risk factors for all work related symptoms. Acute airway responses were witnessed after immediate exposure. Female status was the only factor found to be predictive of acute airway response. The mean longitudinal fall in FEV1 at 1 year was 65.5 mL (standard error = 37.2). Age, early respiratory symptoms, and early fall in cross-week FEV1 were found to predict the 12-month fall in FEV1. Cross-first-shift and cross-week falls in FEV1 reduced in magnitude during the course of the study. CONCLUSIONS: This study of workers naive to cotton dust exposure has demonstrated that respiratory symptoms and acute airway responses develop early following first exposure, and a tolerance effect develops in those workers with the continued exposure. Current smoking and increasing exposure predicts the development of work-related lower respiratory tract symptoms, while early symptoms and acute airway changes across the working week predict the longitudinal loss of lung function at 1 year. PMID- 17693784 TI - An investigation of the role of non-work-time behavior in buffering the effects of work strain. AB - OBJECTIVE: In this exploratory study, we investigated the extent to which common leisure time behaviors, which generate positive feelings of fulfillment and personal reward, are significant in alleviating work-induced stress between successive work periods. We tested the hypotheses that such activities increase recovery from stress directly, and also by improving sleep quality, thereby alleviating maladaptive outcomes from work strain. METHOD: An on-line survey study was completed by a heterogeneous sample of 314 workers in diverse occupations, in good health. RESULTS: Non-work-time behaviors play a significant role in mediating maladaptive outcomes from work strain. Multivariate analysis of these relationships indicates both direct and indirect effects, the latter being associated with mediating sleep quality. Respondents reporting higher levels of active leisure activities, exercise, and creative (hobby) and social activity, reported significantly better sleep, recovery between work periods, and lower chronic maladaptive fatigue symptomology. CONCLUSION: Active and fulfilling non work-time behaviors are more significant in maximizing recovery from work strain than is commonly recognized. This effect is arguably due to the downregulation of stress-induced brain arousal, and stimulation of the pleasure-reward brain neurophysiology. Consistent recovery from work strain between work periods may represent a crucial factor in avoiding work-related "loss spirals" leading to maladaptive health outcomes, which can be particularly relevant to workers in inherently stressful occupations. PMID- 17693785 TI - Longitudinal study of serum lipids and liver enzymes in workers with occupational exposure to ammonium perfluorooctanoate. AB - OBJECTIVE: To examine the relationship between serum perfluorooctanoate (PFOA), a biomarker of ammonium perfluorooctanoate exposure, and lipids and liver enzymes. METHODS: We conducted a longitudinal study on 454 workers and used mixed models to examine the relationship between serum PFOA and lipids and liver enzymes. RESULTS: One part per million (ppm) increase in serum PFOA was associated with a 1.06 mg/dL increase in total cholesterol, but was not associated with changes in triglycerides or other lipoproteins, after adjusting for potential confounders. Serum PFOA was also associated with total bilirubin (0.008 mg/dL decline/ppm) and serum aspartate aminotransferase (0.35 units increase/ppm) but not with the other liver enzymes. CONCLUSIONS: These medical surveillance data collected on workers for up to 25 years contributes useful information on the effects of ammonium perfluorooctanoate exposure on human liver and lipid chemistry. PMID- 17693786 TI - Acute effects of some volatile organic compounds emitted from water-based paints. AB - OBJECTIVE: Acute effects during controlled exposure to some of the volatile organic compounds emitted from water-based paints were evaluated. METHODS: Healthy volunteers (10 atopics, 10 nonatopics, and 10 painters) were exposed to a mixture of propyleneglycol, texanol, diethyleneglycol monoethylether, diethyleneglycol monobutyl ether, and dipropyleneglycol monomethyl ether at a total concentration of 35 mg/m3 (G), a mixture of G and ammonia (15 mg/m3) (GA), and clean air (C). RESULTS: Subjective ratings of irritation in eyes, nose, throat, and dyspnea were significantly higher during the G and GA conditions, when compared with during the C condition. Nasal mucosal swelling was observed after G but not after GA exposure. No effects of the exposure on the pulmonary function, markers of inflammation in nasal lavages, and renal function in urine were seen. CONCLUSION: Exposure to G and GA caused mild irritation in eyes, nose, and airways. PMID- 17693787 TI - Mental health effects of changes in psychosocial work characteristics: a prospective cohort study. AB - OBJECTIVE: To explore a possible causal relationship between psychosocial work characteristics and mental health. METHODS: Using longitudinal data from the Maastricht Cohort Study on "Fatigue at Work" (n = 2332), the effects of changes in job demands and decision latitude on subsequent changes in need for recovery and prolonged fatigue were studied. RESULTS: Increasing job demands are a significant predictor of a subsequent increase in need for recovery (beta = 0.063) and prolonged fatigue (beta = 0.057). An increase in decision latitude predicted a subsequent decrease in need for recovery (beta = -0.078) and prolonged fatigue (beta = -0.063). After adjusting for changes in other work characteristics, the effects on changes in prolonged fatigue were no longer significant. CONCLUSION: These findings support a possible causal relationship between work characteristics and mental health and can be used for designing effective prevention and intervention strategies. PMID- 17693788 TI - Nurse practitioners as attending providers for workers with uncomplicated back injuries: using administrative data to evaluate quality and process of care. AB - OBJECTIVE: The objectives of this study were 1) to identify quality and process of care indicators available in administrative workers' compensation data and to document their association with work disability outcomes, and 2) to use these indicators to assess whether nurse practitioners (NPs), recently authorized to serve as attending providers for injured workers in Washington State, performed differently than did primary care physicians (PCPs). METHODS: Quality and process of care indicators for NP and PCP back injury claims from Washington State were compared using direct standardization and logistic regression. RESULTS: This study found little evidence of differences between NP and PCP claims in case mix or quality of care. CONCLUSIONS: The process of care indicators that we identified were highly associated with the duration of work disability and have potential for further development to assess and promote quality improvement. PMID- 17693789 TI - Five annual observations of respiratory findings in gun factory workers exposed to solvents. AB - OBJECTIVE: We investigated whether long-term, low-level exposures to solvents had adverse longitudinal effects on pulmonary functions. METHODS: The study was performed on 1091 workers 5 years ago and then on 697 workers 5 years later. Chronic respiratory symptoms were recorded using a questionnaire on respiratory symptoms. RESULTS: The annual decrease in forced expiratory volume in 1 second in the workers exposed to solvents was not significantly different from that of the unexposed workers (69.7 +/- 89.9 vs 75.8 +/- 87.6 mL/yr, P = 0.5, respectively). In 453 workers who were exposed to solvents 5 years ago, the prevalence rate of asthma was 1.1%. Five years later, it was 3.6% in 193 workers from the same group. The difference was statistically significant (P = 0.03). CONCLUSIONS: Longitudinally, the chronic exposure to low doses of solvents does not adversely affect the pulmonary functions, whereas it increases the asthma prevalence. PMID- 17693790 TI - Body mass index and premature mortality in physically heavily working men--a ten year follow-up of 20,000 construction workers. AB - OBJECTIVE: Although obesity is clearly associated with diabetes and cardiovascular disease, health consequences of being mildly or moderately overweight are less clear in physically heavily working men. METHODS: The association between body mass index (BMI) and mortality was assessed over a 10 year period in a cohort of 19,513 male construction workers, who underwent routine occupational health examination during 1986 to 1992. RESULTS: Among never smokers normal and overweight men experienced similar mortality. Among smokers, we observed a strong U-shaped association between BMI and all-cause mortality, which was lowest for BMI levels between 25 and 35 kg/m after control for potential covariates. CONCLUSIONS: BMI levels commonly considered to reflect overweight may not necessarily be associated with increased mortality in physically heavily working men. PMID- 17693791 TI - Surveillance of workers responding under the National Response Plan. AB - The National Response Plan (NRP) establishes the framework for the nation's response to major disasters. We offer seven recommendations related to surveillance of workers who respond to events under the NRP. These recommendations address the rationale for and principles of medical surveillance in the context of large-scale disasters and the NRP; means of identifying and registering the populations that should be included in surveillance activities; the role of exposure assessment in medical surveillance; behavioral health issues; and principles regarding the communication and use of surveillance data. PMID- 17693815 TI - Successful treatment of severe sepsis with recombinant human activated protein C in a patient with traumatic intracranial hemorrhage. PMID- 17693816 TI - Fracture of the proximal humerus with intrathoracic dislocation of the humeral head. PMID- 17693817 TI - Ruptured pseudoaneurysm after minor head trauma: a case report. PMID- 17693818 TI - Mediastinal widening after blunt chest trauma in a child: a very rare case of thymic bleeding in a child and possible differential diagnosis. PMID- 17693819 TI - Comment on article by Springborg et al. PMID- 17693820 TI - Alternate site surge capacity in times of public health disaster maintains trauma center and emergency department integrity: Hurricane Katrina. AB - BACKGROUND: Hospital surge capacity has been advocated to accommodate large increases in demand for healthcare; however, existing urban trauma centers and emergency departments (TC/EDs) face barriers to providing timely care even at baseline patient volumes. The purpose of this study is to describe how alternate site medical surge capacity absorbed large patient volumes while minimizing impact on routine TC/ED operations immediately after Hurricane Katrina. METHODS: From September 1 to 16, 2005, an alternate site for medical care was established. Using an off-site space, the Dallas Convention Center Medical Unit (DCCMU) was established to meet the increased demand for care. Data were collected and compared with TC/ED patient volumes to assess impact on existing facilities. RESULTS: During the study period, 23,231 persons displaced by Hurricane Katrina were registered to receive evacuee services in the City of Dallas, Texas. From those displaced, 10,367 visits for emergent or urgent healthcare were seen at the DCCMU. The mean number of daily visits (mean +/- SD) to the DCCMU was 619 +/- 301 visits with a peak on day 3 (n = 1,125). No patients died, 3.2% (n = 257) were observed in the DCCMU, and only 2.9% (n = 236) required transport to a TC/ED. During the same period, the mean number of TC/ED visits at the region's primary provider of indigent care (Hospital 1) was 346 +/- 36 visits. Using historical data from Hospital 1 during the same period of time (341 +/- 41), there was no significant difference in the mean number of TC/ED visits from the previous year (p = 0.26). CONCLUSIONS: Alternate-site medical surge capacity provides for safe and effective delivery of care to a large influx of patients seeking urgent and emergent care. This protects the integrity of existing public hospital TC/ED infrastructure and ongoing operations. PMID- 17693821 TI - Helicopter emergency medical services (HEMS): impact on on-scene times. AB - BACKGROUND: This study compared prehospital on-scene times (OSTs) for patients treated by nurse-staffed emergency medical services (EMS) with OST for patients treated by a combination of EMS and physician-staffed helicopter emergency medical services (HEMS). A secondary aim was to investigate the relationship between length of OST and mortality. METHODS: All trauma patients treated in the priority 1 emergency room of a Level I trauma center between January 2002 and 2004 were included in the study. To determine OST and outcome, hospital and prehospital data were entered into the trauma registry. OSTs for EMS and combined EMS/HEMS-treated patients were compared using linear regression analysis. Logistic regression analysis was used to compare mortality rates. RESULTS: The number of trauma patients included for analysis was 1,457. Of these, 1,197 received EMS assistance only, whereas 260 patients received additional care by an HEMS physician. HEMS patients had longer mean OSTs (35.4 vs. 24.6 minutes; p < 0.001) and higher Injury Severity Scores (24 vs. 9; p < 0.001). After correction for patient and trauma characteristics, like the Revised Trauma Score, age, Injury Severity Scores, daytime/night-time, and mechanism of trauma, the difference in OSTs between the groups was 9 minutes (p < 0.001). Logistic regression analyses showed a higher uncorrected chance of dying with increasing OST by 10 minutes (OR, 1.2; p < 0.001). This apparent effect of OST on mortality was explained by patient and trauma characteristics (adjusted OR, 1.0; p = 0.89). CONCLUSIONS: Combined EMS/HEMS assistance at an injury scene is associated with longer OST. When corrected for severity of injury and patient characteristics, no influence of longer OST on mortality could be demonstrated. PMID- 17693822 TI - FTY720 improves survival after transient ischemia and reperfusion of the hind limbs. AB - BACKGROUND: Ischemia and reperfusion (I/R) damage involves adhesion and transmigration of lymphocytes and neutrophils. FTY720 is an immunosuppressive agent that reduces the number of neutrophils and monocytes in peripheral blood as well as tissue lymphocyte infiltration. This study investigated the effect of FTY720 during hind limb I/R. METHODS: Male C57/BL6 mice underwent temporary ligation of the infrarenal aorta for 4 hours. After 48 hours of reperfusion, animals were killed by exsanguination. Tissue myeloperoxidase content reflecting neutrophil infiltration and reverse transcription polymerase chain reaction analysis of local cytokine transcription in lung, liver, and kidney were performed. RESULTS: After I/R, treatment with FTY720 improved survival and prevented upregulation of pro- and anti-inflammatory cytokines in evaluated organs, whereas no changes were detected in myeloperoxidase content after treatment with FTY720. CONCLUSIONS: Whereas neutrophil infiltration was not affected by treatment with FTY720, other immunocompetent or intrinsic cells appear to be involved in changes of cytokine production in different organs. PMID- 17693823 TI - Acute lower extremity compartment syndrome (ALECS) screening protocol in critically ill trauma patients. AB - BACKGROUND: Acute lower extremity compartment syndrome (ALECS) is a devastating complication that often presents silently in critically injured patients; therefore, we developed a protocol to screen high-risk patients. METHODS: This prospective observational study included all Shock Trauma intensive care unit patients who met specific high-risk criteria including pulmonary artery catheter directed shock resuscitation, open or closed tibial shaft fracture, major vascular injury below the aortic bifurcation, abdominal compartment syndrome, or pelvic or lower extremity crush injury. Patients were screened at admission and every 4 hours thereafter for the first 48 hours of admission. Screening included physical examination (PE) and anterior or deep posterior calf compartment pressure measurements when PE was suspicious or unreliable. A positive screening, defined as a DeltaP <30 mm Hg (where DeltaP is the difference between the diastolic blood pressure and the compartment pressure), mandated a four compartment fasciotomy. RESULTS: During a 6-month period, the incidence of ALECS in screened patients was surprisingly high at 20% (9 patients). With diligent screening, it was diagnosed early in the patient's Shock Trauma intensive care unit course. These were patients with severe injuries with an Injury Severity Score of 32.0 +/- 12.5 who exhibited significant volume depletion, with a base deficit of 12.9 +/- 5.9 mEq/L and a lactate level of 13.0 +/- 5.2 mmol/L, requiring large volume resuscitation. Although aggressive fasciotomy resulted in no limb loss, ALECS was associated with an exceedingly high mortality rate at 67%. CONCLUSIONS: ALECS is an important clinical entity in critically injured patients with trauma associated with significant mortality. Aggressive screening may provide some diagnostic insight to those at risk. PMID- 17693824 TI - Comparison of a new hemostatic agent to current combat hemostatic agents in a Swine model of lethal extremity arterial hemorrhage. AB - BACKGROUND: Gaining hemostatic control of lethal vascular injuries sustained in combat using topical agents remains a challenge. Recent animal testing using a lethal arterial injury model has demonstrated that QuikClot zeolite granules (QCG) and the HemCon chitosan bandage (HC) are not capable of providing hemostasis and improving survival over the Army gauze field bandage (AFB). We have developed a new hemostatic agent consisting of a granular combination of a smectite mineral and a polymer (WoundStat) capable of producing hemostasis in the face of high-pressure arterial bleeding. We compared the performance of WoundStat (WS) to QCG, HC, AFB, and the new QuikClot zeolite Advance Clotting Sponge (ACS) in a lethal vascular injury model. METHODS: Hemostatic agents were tested using a lethal femoral artery vascular injury model. Twenty-five (5 per group) male swine (42 kg +/- 3 kg) were anesthetized, instrumented, and splenectomized. A lethal femoral artery injury was produced by creating a 6-mm arteriotomy in the vessel. After 45 seconds of hemorrhage, animals were randomized to be treated with AFB (control group), HC, QCG, ACS, or WS. Pressure (200 mm Hg) was applied over the product in the wound for 3 minutes. A second application and 3 additional minutes of pressure was provided if hemostasis was not achieved. Fluid resuscitation was begun at the time of application with 500 mL of Hextend, followed by lactated Ringer's solution at 100 mL/min to achieve and maintain a postapplication mean arterial blood pressure of 65 mm Hg. Animals were observed for 180 minutes or until death. Primary endpoints were survival, survival time, post-treatment blood loss, and amount of resuscitation fluid. RESULTS: All animals treated with WS survived to 180 minutes and required only a single application. No animal in the AFB, QCG, or ACS group survived. One animal in the HC group survived. Survival (p < 0.05) and survival times (p < 0.0001) for WS animals were significantly greater than for all other groups. No significant difference in survival or survival time existed between the AFB, QCG, ACS, or HC groups. Post-treatment blood loss (p = 0.0099) and postresuscitation fluid volume (p = 0.006) was significantly less for animals treated with WS than for all other groups. No significant difference in these parameters existed between the AFB, QCG, ACS, and HC groups. CONCLUSION: WS was superior to the other hemostatic agents tested in this study of lethal arterial vascular injury. Additional study is warranted on this agent to determine its potential for use in combat and civilian trauma. PMID- 17693825 TI - Abdominal insufflation for control of bleeding after severe splenic injury. AB - BACKGROUND: To date, there is no rapid method to control intracavitary bleeding without an operation. Over 70% of trauma deaths from uncontrollable internal bleeding occur early after injury before an operation is feasible. Abdominal insufflation (AI) by carbon dioxide has been shown to reduce the rate of bleeding after intra-abdominal injury in pigs. The concept was proven in highly lethal models of severe vascular and liver injuries. Similar injuries in humans would result in immediate exsanguination and low likelihood for any intervention. We hypothesized that AI would similarly reduce bleeding in a model of moderate but persistent bleeding from a splenic injury. This model represents a clinically relevant scenario of continuous bleeding, which does not kill the patient immediately but may ultimately result in death if not managed early. METHODS: A new model of splenic injury was applied on 19 pigs, randomized to standard resuscitation (SR, N = 10) or standard resuscitation with AI to 20 cm H2O (SRAI, N = 9). For 30 minutes, the pigs were bled and the hemodynamics recorded. At 30 minutes, the abdomen was opened and free blood was collected and measured. Outcomes were blood loss, mean arterial pressure, hemoglobin, lactate levels, and arterial blood gases at the end of the experiment. RESULTS: All pigs survived to the end of the experiment. Blood loss was lower (1,114 +/- 486 mL vs. 666 +/- 323 mL, p = 0.03) and final mean arterial pressure higher (64 +/- 12 mm Hg vs. 54 +/- 8 mm Hg, p = 0.04) in SRAI when compared with those in SR animals. Heart rate, arterial blood gases, oxygen saturation, hemoglobin, and lactate levels were similar in the two groups, except there was a more acidotic pH among SRAI animals (7.27 +/- 0.06 vs. 7.47 +/- 0.21, p = 0.02). CONCLUSIONS: AI is a novel method to control intra-abdominal bleeding temporarily. With proper portable instruments and first-responder training, this is a technique that can potentially be used in the field to save lives from intra-abdominal exsanguination. PMID- 17693826 TI - Hypotension begins at 110 mm Hg: redefining "hypotension" with data. AB - BACKGROUND: Clinicians routinely refer to hypotension as a systolic blood pressure (SBP) < or =90 mm Hg. However, few data exist to support the rigid adherence to this arbitrary cutoff. We hypothesized that the physiologic hypoperfusion and mortality outcomes classically associated with hypotension were manifest at higher SBPs. METHODS: A total of 870,634 patient records from the National Trauma Data Bank with emergency department SBP and mortality data were analyzed. Patients (140,898) with severe head injuries, a Glasgow Coma Score < or =8, and base deficit (BD) <5, or missing data items were excluded from analysis. Admission BD, as a measure of metabolic hypoperfusion, was evaluated in 81,134 patients and mortality was plotted against SBP. RESULTS: Baseline mortality was <2.5%. However, at 110 mm Hg, the slope of the mortality curve increased such that mortality was 4.8% greater for every 10-mm Hg decrement in SBP. This effect was consistent to a maximum of 26% mortality at a SBP of 60 mm Hg. Hypoperfusion (change in the slope of BD curve) began to increase above baseline of 4.5 at a SBP 118 mm Hg. CONCLUSION: Taking the BD and mortality measurements together, this analysis shows that a SBP < or =110 mm Hg is a more clinically relevant definition of hypotension and hypoperfusion than is 90 mm Hg. This analysis will also be useful for developing appropriately powered studies of hemorrhagic shock. PMID- 17693827 TI - The impact of safety belt use on liver injuries in motor vehicle crashes: the importance of motor vehicle safety systems. AB - BACKGROUND: Liver injuries (LIs) are one of the most serious and common consequences of motor vehicle crashes (MVCs). In the unstable patient, early detection of LI based on clinical suspicion will improve acute trauma care and outcomes. The specific objectives of this analysis are to identify crash scene and occupant risk factors for LI from MVC. METHODS: Crash Injury Research and Engineering Network data were used to identify risk factors for LI; age, sex, safety belt use, air bag deployment, DeltaV (change in velocity), principal direction of force, vehicle crush, and intrusion. Occupants with LI were compared with four control groups without LI; (1) no abdominal (ABD) injury (NO_ABD), (2) any ABD (ANY_ABD), (3) ABD Abbreviated Injury Scale score of 1 to 2 (ABD_1-2), and (4) ABD Abbreviated Injury Scale score of 3 or more (ABD_3+). LI occupants were compared with each control group and odds ratios (OR) for risk of LI were computed. RESULTS: There were 311 Crash Injury Research and Engineering Network subjects aged 5 or more years with LI. The total mean Injury Severity Score was 37.6. LI was strongly and significantly associated with safety belt restraint use without air bag deployment, compared with each control group: Liver injury - restrained + air bag not deployed versus (1) NO_ABD, N = 1,519; OR = 4.4, (2) ANY_ABD, N = 317; OR = 2.6, (3) ABD_1 to 2, N = 155; OR = 3.1, (4) ABD_3+, N = 217; OR = 2.4 (p < 0.001). This association was independent of driver or passenger status and principal direction of force. LIs were also strongly and significantly associated with greater vehicle interior intrusion. CONCLUSIONS: LIs were strongly associated with a safety belt restraint in use in the absence of air bag deployment during MVC. This data may have profound importance to the trauma surgeon as an early indicator for LI during resuscitation. These findings also have important implications for future research efforts to improve safety systems in motor vehicles and reduce morbidity and mortality from MVCs in the United States. PMID- 17693828 TI - Implementation of antibiotic rotation protocol improves antibiotic susceptibility profile in a surgical intensive care unit. AB - BACKGROUND: Antibiotic rotation has been proposed as a way to potentially reduce the development of antimicrobial resistant bacteria in intensive care units. We assessed the effect of an antibiotic rotation protocol on the antibiotic susceptibility profiles of three clinically relevant gram-negative microorganisms within our surgical intensive care unit (SICU). METHODS: Our SICU implemented an antibiotic rotation protocol in 2003. Four antibiotics (piperacillin/tazobactam, imipenem/cilastin, ceftazidime, and ciprofloxacin) were rotated as the primary antibiotic used to treat suspected gram-negative infections every month, with the four-drug cycle being repeated every 4 months. Antibiotic susceptibility data for three microorganisms (Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae) were collected for the year before (2002) and the year after (2004) the implementation of the rotation protocol. Changes in antimicrobial susceptibility rates were analyzed for the three microorganisms. As a comparison, a similar analysis was conducted for microorganisms isolated from our medical intensive care unit, where no antibiotic rotation protocol was implemented. RESULTS: Implementation of an antibiotic rotation protocol in our SICU resulted in a significant increase in the percentage of P. aeruginosa isolates sensitive to ceftazidime (67% in 2002 vs. 92% in 2004, p = 0.002) and piperacillin/tazobactam (78% in 2002 vs. 92% in 2004, p = 0.043). Isolates from the medical intensive care unit did not demonstrate an increase in antimicrobial susceptibility. In fact, the susceptibility of E. coli to piperacillin/tazobactam decreased during this time period (p = 0.047). CONCLUSIONS: Implementation of an antibiotic rotation protocol in our SICU resulted in overall improvement in the antibiotic susceptibility profile of gram-negative microorganisms relative to our medical intensive care unit, where such a protocol was not used. PMID- 17693829 TI - Hemoglobin drops within minutes of injuries and predicts need for an intervention to stop hemorrhage. AB - BACKGROUND: Hemoglobin (Hgb) levels obtained shortly after injury may not detect occult bleeding in trauma patients because of the time needed for plasma levels to equilibrate, or may be confounded by crystalloid-related hemodilution. We hypothesized that Hgb levels measured within minutes of arrival can identify trauma patients who are actively bleeding. METHODS: A retrospective study of 404 consecutive patients was undertaken at an urban Level I trauma center, which included 39 patients who required emergent surgical or radiologic intervention to control bleeding. All 404 patients underwent point-of-care Hgb measurements within 30 minutes of emergency department (ED) arrival. Hgb levels were correlated with physiologic signs of hemorrhage(blood pressure, heart rate, base deficit, pH, and resuscitation volume), and the need for emergent interventions to stop hemorrhage. RESULTS: Early Hgb levels were significantly lower in patients who required emergent interventions to stop hemorrhage (mean +/- SD: 12 +/- 2 gm/dL vs. 13 +/- 2 gm/dL, p < 0.001). Lower Hgb levels were associated with increasing heart rate, decreasing blood pressure, decreasing pH, worsening base deficit, and increasing transfusion requirements. Hgb < or =10 gm/dL was associated with a greater than three-fold increase in the need for emergent interventions to stop bleeding (odds ratio 3.14, 95% confidence interval 1.18 8.35, p < 0.03), and correctly identified the need for intervention in 87% of patients. CONCLUSION: Hemorrhage in trauma patients is associated with an early decrease in Hgb level. Hgb < or =10 gm/dL in the first 30 minutes of patient arrival will correctly identify presence or absence of significant bleeding in almost 9 of 10 trauma patients. PMID- 17693830 TI - A new resource-constrained triage method applied to victims of penetrating injury. AB - BACKGROUND: Resource-constrained triage occurs when the number of trauma patients exceeds the capacity for simultaneous transport and treatment. The objective of this article is to apply a new resource-constrained triage method (denoted Sacco triage method [STM]) to victims of penetrating trauma and compare it with existing methods. METHODS: STM is a mathematical model of resource-constrained triage. Its objective is to maximize expected survivors given constraints on the timing and availability of resources. The model incorporates estimates of time dependent victim survival probabilities based on initial assessments and expected deteriorations. For application to penetrating trauma, an "RPM" score based on respiratory rate, pulse rate, and best motor response was used to predict survivability. Logistic function-generated survival probability estimates for scene values of RPM were determined from 7,274 penetrating injury patients from the Pennsylvania Trauma Outcome Study. The Delphi Method provided expert consensus on victim deterioration rates, and the model was solved using linear programming. The accuracy of predicting survivability was assessed using calibration and discrimination statistics. STM was compared with START (Simple Triage and Rapid Treatment)-like triage methods with respect to process and outcomes (assessed by expected number of survivors in simulated resource constrained casualty incidents). RESULTS: RPM was shown to be an accurate predictor of survival probability for penetrating trauma, equivalent to the Revised Trauma Score and exceeding that of the Injury Severity Score, as measured by calibration and discrimination statistics. In the simulations, STM had substantially more expected survivors than did current triage methods. CONCLUSIONS: Resource-constrained triage is modeled as an evidence-based, outcome driven method (STM) that maximizes expected survivors in consideration of resources. STM offers lifesaving and operational advantages over current methods. PMID- 17693831 TI - Trauma team activation and the impact on mortality. AB - BACKGROUND: Trauma centers use injury mechanism, physiology, and anatomic criteria to determine the extent of trauma team activation (TTA). We examined whether physiologic variables in our three-tier TTA system stratified patients appropriately by injury severity and mortality. METHODS: The trauma registry at our Level I trauma center was retrospectively reviewed for full (level 1 or L1), partial (level 2 or L2), and limited (level 3) adult TTA. Data were collected on age, injury severity score (ISS), hospital length of stay, systolic blood pressure (SBP), heart rate, respiratory rate (RR), Glasgow coma score (GCS), and intubation status. Penetrating injuries, traumatic arrests, and interfacility transfers were excluded. Data are median (25%75%). Statistical analysis included hazard ratios (HzR), Kruskal-Wallis, chi, and survival analyses. The p value overall was <0.05, and pair wise was <0.05 versus L1. RESULTS: There were 494 adult TTAs for blunt injury from the scene out of 1,969 admissions. Variables associated with mortality (HzR; 95% confidence interval) by univariate analysis include SBP <90 (9.4; 4.2, 21.2), RR >29 or <10 (17.8; 4.8, 66.0), intubation status (4.5; 2.3, 8.9), and GCS <8 (9.7; 4.8, 19.9). When combined in a multivariate model to evaluate multiple predictors simultaneously, SBP <90 and GCS <8 appear to be the strongest predictors of mortality (RR and intubation were not significant in the presence of SBP and GCS). The three-tier system identified patients with increased ISS and early (< or =4 weeks) mortality risk. There was a statistically significant difference in survival between L1 and L2 at 38 days, but not for >38 days (p = 0.739). CONCLUSIONS: TTA criteria selected patients with greater ISS and early mortality, but impact on long-term survival may not be appreciated. Full TTA criteria for blunt injury may be limited to GCS <8, SBP <90, RR >29 or <10, and intubation status. PMID- 17693832 TI - Management deficiencies and death preventability of road traffic fatalities before and after a new trauma care system in Victoria, Australia. AB - BACKGROUND: The Consultative Committee's findings that preventable or potentially preventable (P/PP) death rates (survival prospects > or =25%) of road crash fatalities who received treatment were unaltered between 1992 and 1998 led to a Ministerial Taskforce on Trauma and the gradual introduction of a new Victorian trauma care system. The present study compares outcomes before (1997-1998) and after (2002-2004) the new system. METHODS: The emergency and clinical management and death preventability of 245 consecutive fatalities in the 'before' period and 193 in the 'after' period was assessed by the committee's multidisciplinary panels using the complete hospital, ambulance, and autopsy findings. RESULTS: Emergency department admissions to expanded Major Trauma Services (MTS) increased from 34% to 62% (p < 0.05). More patients were attended by Advanced Trauma Life Support paramedics (p < 0.05) and scene times increased (p < 0.05). Patients admitted within 1 hour decreased from 70% to 45% (p < 0.05). The mean number of deficiencies per patient including those contributing to death was decreased (p < 0.05). The combined P/PP death rates decreased from 36% to 28% (22% relative risk reduction). The P/PP death rates for MTS, Metropolitan Trauma Services, Rural Trauma Services, and Urgent Care Centers for 2002 to 2004 were 25%, 33%, 50%, and 83%, respectively, and did not differ significantly from those of 1997 to 1998 (23%, 49%, 36%, 75%, respectively). The P/PP death rates in MTS were less than those of the other hospital groups. CONCLUSIONS: The new Victorian trauma care system has resulted in a significant decrease in deficiencies including those contributing to death and a decrease in P/PP deaths rates. The improvement has been largely consequent to a marked increase in admissions to MTS. PMID- 17693834 TI - Outcomes of acute respiratory distress syndrome (ARDS) in elderly patients. AB - BACKGROUND: Elderly patients have become an increasingly prevalent proportion of the intensive care unit population. Outcomes of patients with acute respiratory distress syndrome (ARDS) have been improving in recent years, but studies of ARDS rarely include substantial numbers of elderly patients. Historically, the mortality rate for ARDS has been 69% to 80% among elderly patients. We reviewed our experience with ARDS to determine whether outcomes were improving over time, and in particular whether outcomes were equally favorable among our elderly patients aged 65 years or older. METHODS: Patients who developed ARDS in a university surgical intensive care unit from 1993 to 2003 were identified and their data were collected prospectively. Data collected included age, gender, cause of ARDS, Acute Physiology and Chronic Health Evaluation (APACHE) III score (AIII), initial Pao2:FIO2, lung injury score (LIS), maximum positive end expiratory pressure, multiple organ dysfunction pulmonary and nonpulmonary organ dysfunction scores (MODnp), vasopressor dependence, and development of ventilator associated pneumonia. Outcomes of patients >65 years old with ARDS were compared with those of patients <65 years old. RESULTS: In the study period, 343 patients developed ARDS, 210 of whom were >65 years old. Overall, age was 65.2 +/- 0.2 years, with a mean APACHE III score of 83.4 +/- 2.0 points. Sixty-six percent were men. The initial Pao2:FIO2 for the entire group was 104.3 +/- 4.1, and was less in younger patients. Maximum positive end-expiratory pressure was 15.6 +/- 0.5 cm H2O, and mean LIS was 3.3 +/- 0.6 points; these values did not differ between cohorts. Elderly patients had a mortality of 51.9% when compared with 41.7% for younger patients (p = not significant). By logistic regression analysis, factors predicting mortality included APACHE III score (each point, odds ratio [OR], 1.022; 95% confidence interval [CI], 1.008-1.035; p < 0.01) and nonpulmonary multiple organ dysfunction score (each point, OR, 1.366; 95% CI, 1.223-1.526; p < 0.0001), but neither age (p = 0.37), LIS (p = 0.49), multiple organ dysfunction pulmonary (p = 0.90), nor year of treatment (p = 0.74) had any effect on mortality. CONCLUSIONS: The mortality rate for elderly patients with ARDS is lower in our experience when compared with historical series, even though illness severity may be higher, and comparable to that of other patients. Careful hemodynamic monitoring and resuscitation combined with other strategies to ameliorate nonpulmonary organ dysfunction achieved good outcomes in high-risk patients and could contribute in the future to further improved outcomes of elderly patients with ARDS. PMID- 17693833 TI - Discharge rounds in the 80-hour workweek: importance of the trauma nurse practitioner. AB - BACKGROUND: Daily multidisciplinary discharge rounds have been shown to decrease length of stay (LOS), increase patient volumes, and virtually eliminates "bypass" (inability to accept admissions). Originally, these were attended by senior house staff from each trauma team. Implementation of the 80-hour workweek precluded house staff participation, raising concerns that these rounds would loss their benefits. Certified nurse practitioners (CRNPs) were added to the trauma teams to assist in patient care and represent the team on discharge rounds, replacing the fellows. We hypothesized that this would offset any potential negative effects. METHODS: A senior trauma physician leads discharge rounds, focusing on each patient's plan of care. Rounds cover 90 inpatient beds and last approximately 60 minutes. CRNPs from each trauma team, orthopedics, and neurosurgery as well as the teams' discharge planner, hospital bed manager, unit nursing staff, and physical, occupational, and speech therapists participate in discharge rounds. RESULTS: The results are stratified by time period: June 1998 to May 1999 is before discharge rounds, June 1999 to May 2001 is during the house staff period, and June 2001 to May 2004 is when CRNPs replaced fellows and residents. During the 5-year period, 1999 to 2004, daily discharge rounds maintained their efficacy. We have increased admissions, whereas LOS has remained the same. Admissions of greater than 24 hours have increased, whereas average injury severity score has statistically remained the same. Bypass has virtually been eliminated. CONCLUSIONS: Adding CRNPs to discharge rounds has allowed us to have the continued benefits of decreased LOS and increased patient volume. Bypass remains rare. CRNPs can effectively replace some house staff functions. PMID- 17693835 TI - Modulation of the glycemic response using insulin attenuates the pulmonary response in an animal trauma model. AB - BACKGROUND: Hyperglycemia has been shown to be an independent prognostic indicator of poor outcome in the traumatized patient. The role of insulin and the prevention of hyperglycemia in the trauma patient have as yet not been fully explored. We hypothesized that the systemic inflammatory response to trauma could be modified by modulating the glycemic response to trauma using insulin. METHODS: A rodent model of end- organ (lung) injury in trauma was chosen. Two groups underwent bilateral femur fracture and 15% blood loss. The third group was anesthetized only. The treatment group immediately received subcutaneous insulin according to a sliding scale. The control groups received normal saline subcutaneously. The animals were maintained under anesthesia for 4 hours from injury. Blood samples were then taken. Bronchoalveolar lavage was performed for neutrophil content and total protein estimation. The left lower lobe was harvested for wet:dry lung weight ratios as a measure of end-organ tissue edema. RESULTS: Measures of end-organ injury, wet:dry lung weight ratios, and bronchoalveolar lavage neutrophil content were significantly reduced in the insulin-treated animals compared with in the controls (p < 0.05). Neutrophil respiratory burst activity was increased in insulin-treated animals compared with in controls (p < 0.05). CONCLUSIONS: Insulin reduces leukocyte lung sequestration and end-organ (lung) edema, indicating an endothelial protective effect in this injured-animal model without attenuating neutrophil function. This work confirms that modifying the glycemic response to trauma using insulin may have a role in reducing adult respiratory distress syndrome rates in injured patients and thereby lead to improved outcomes. PMID- 17693836 TI - Increased insulin requirements are associated with pneumonia after severe injury. AB - BACKGROUND: Hyperglycemia after severe injury has been associated with an increased risk of infection and death. Strict glycemic control has been found to be valuable in select surgical populations. Varying amounts of insulin by infusion are required to maintain blood glucose levels within normal limits. Little is known about how insulin requirements are affected by the presence of infection, and therefore, the purpose of this study was to characterize this relationship. METHODS: Medical records of all intubated, injured patients admitted to the intensive care unit during a 16-month period were reviewed. Patients were included if they were managed with an insulin infusion, and they had a single bronchoalveolar lavage (BAL) culture performed for presumed pneumonia between 48 hours and 8 days. Mean hourly and 24-hour insulin requirements were analyzed before BAL was performed and then compared with values after cultures were obtained. This difference was then compared between patients with and without pneumonia. RESULTS: Eighty-two patients met inclusion criteria during the 16-month study period. The hourly and 24-hour insulin requirements significantly increased from before to after BAL was performed in patients with pneumonia (n = 54) and not in those without (n = 28) (p = 0.008). The 24-hour insulin requirement increased by 26.2 units from before to after BAL in the pneumonia group versus 7.6 units in the nonpneumonia group (p = 0.029). A mean hourly insulin requirement increase of 1.2 units more than the pre-BAL level demonstrated an 86% positive predictive value and 89% specificity for pneumonia. CONCLUSIONS: An increase in insulin requirements at the time of obtaining pulmonary cultures is associated with the presence of pneumonia and may represent a valuable tool for earlier recognition. PMID- 17693838 TI - Nonoperative management of epidural hematomas and subdural hematomas: is it safe in lesions measuring one centimeter or less? AB - BACKGROUND: Management of a patient with a closed head injury is based on neurologic status and computerized tomography scan results. We hypothesized that those patients with an epidural hematoma (EDH) or subdural hematoma (SDH) <1 cm in thickness could safely be treated nonoperatively. METHODS: We retrospectively reviewed charts of 204 consecutive patients with either an EDH or SDH. RESULTS: There were 122 lesions < or =1 cm and 82 lesions >1 cm. In the first group, 115 were managed nonoperatively, with 111 good outcomes (minimal deficit with a Rancho Los Amigos score [RLAS] > or =3), two poor outcomes (severely disabled with RLAS <3), and two deaths. Twenty-eight patients with lesions greater than 1 cm had concomitant cerebral edema (CE) with an 89% mortality rate. The mortality rate in this group without CE was 20%, demonstrating the presence of CE in this group may have adversely affected the mortality rate, regardless of intervention. CONCLUSIONS: This data suggests that EDH or SDH <1 cm thick can be safely managed nonoperatively unless there is concomitant CE. PMID- 17693837 TI - Traumatic brain injury in intoxicated patients. AB - BACKGROUND: We sought to evaluate the effect alcohol intoxication may have had in nonsurgically treated patients with severe traumatic brain injury. METHODS: The Montreal General Hospital Traumatic Brain Injury Registry was used to identify all adult patients with a Glasgow Coma Scale score < or =8 at admission, within a 15-month period. All charts were retrospectively reviewed. RESULTS: Twenty-three patients had toxic blood alcohol levels (BAL > or =21.7 mmol/L), 24 were alcohol negative (BAL <3 mmol/L), and 10 were alcohol-influenced or had unknown BAL. Patients were more likely to have intracranial pressure monitoring if they had multiple intracranial hemorrhages, sustained multiple injuries, or had a post resuscitative Glasgow Coma Scale score < or =8. Intoxicated patients had a mean delay of 151 minutes more in the insertion time of an intracranial pressure monitoring device, compared with alcohol-negative patients. CONCLUSIONS: Alcohol was a confounding factor in the treatment of some of our patients. PMID- 17693840 TI - Use of nuclear magnetic resonance spectroscopy to assess renal dysfunction after hypertonic-hyperoncotic resuscitation in rats. AB - BACKGROUND: The aim of this study was to evaluate the renal tolerance of a hypertonic-hyperoncotic solution (HHS) administration during uncontrolled hemorrhagic shock (UHS). METHODS: UHS was produced in rats by a preliminary bleed followed by tail amputation. Hydroxyethylstarch (HHS) 200/0.5 6% in NaCl 7.2% was administered to the HHS groups (n = 20) and normal saline (NS) to the NS group (n = 20). Infusion rates were adjusted to prevent mean arterial pressure (MAP) from falling either below 40 mm Hg in the HHS40 (n = 10) and NS40 groups (n = 10), or below 80 mm Hg in the HHS80 (n = 10) and NS80 groups (n = 10). Data obtained were compared with a sham group and a no resuscitation (NR) group. Nephrotoxicity was evaluated by nuclear magnetic resonance analysis in urine samples. RESULTS: Survival was 60% in the NS40 group and 40% in the NS80 group, 70% in the HHS40 group, and 60% in the HHS80 group (p = not significant). Within and between target groups of 40 mm Hg MAP and 80 mm Hg MAP, there was no significant difference in survival. The mean values of renal metabolites to creatinine (ct) ratios were not significantly different among the six groups. Principal component analysis showed that the HHS80 group was characterized by an increase in allantoin/ct and urea/ct ratios demonstrating acute renal dysfunction and failure of nitrogen metabolism. CONCLUSION: In prolonged UHS, an infusion of HHS may not increase the rate of survival. HHS infusion in normotensive resuscitation appears to be associated with renal toxicity. PMID- 17693839 TI - The effect of aprotinin on brain ischemic-reperfusion injury after hemorrhagic shock in rats: an experimental study. AB - BACKGROUND: We aimed to demonstrate the positive effects of the serine protease inhibitor aprotinin on neural ischemia-reperfusion injury and apoptosis in a rat model. METHODS: There were 18 rats divided into 3 groups: group A (sham, n = 6), group B (ischemia-reperfusion, n = 6), and group C (ischemia-reperfusion + aprotinin, n = 6). The systolic blood pressure of the group B and C rats was decreased to 40% to 50% of the normal level by taking blood from the femoral vein to develop hemorrhagic shock. The blood was retained and given to the remaining group B and C rats for reperfusion 20 minutes after the procedure. In group B, isotonic solution and, in group C, aprotinin was administered to the rats 5 minutes before reperfusion. After the rats were killed, the brain tissue samples were fixed for histopathologic examination. Brain tissue superoxide dismutase, malondialdehyde, and tissue myeloperoxidase level and apoptotic cell analyses were performed in all groups. RESULTS: Superoxide dismutase level decreased from group A to group B and increased from group B to group C (p < 0.05). Malondialdehyde and myeloperoxidase levels and apoptotic cells increased from group A to group B and decreased from group B to group C (p < 0.05). CONCLUSION: The results suggest that the systemic use of aprotinin in ischemic neural tissue prevents reperfusion injury and also protects the morphologic, functional, and biochemical integrity of the neural tissue. PMID- 17693841 TI - Perioperative creatine phosphokinase (CPK) and troponin I trends after elective hip surgery. AB - BACKGROUND: Perioperative myocardial infarction (MI) is an important risk factor for cardiac morbidity and mortality after hip surgery. On the basis of the limitations of creatine kinase cardiac muscle isoenzyme (CK-MB) in the perioperative setting, and the high specificity of troponin I, we hypothesized that troponin I would be effective at detecting perioperative MI more frequently than CK-MB would be, after hip surgery. METHODS: A prospective study of the serum levels of creatine phosphokinase (CPK), its isoenzyme CK-MB, and troponin I, in 90 patients with risk factors for coronary artery disease, undergoing hip surgery is reported. We measured these cardiac markers in the postoperative period for 5 days, after hemiarthroplasty, total hip arthroplasty, and hip intramedullary nailing. RESULTS: We found increased levels of creatine phosphokinase and CK-MB, after all the types of operation, with maximum levels reached on the first postoperative day and the levels were more pronounced after total hip arthroplasty. False-elevated CK-MB index >6% without MI was evidenced in 43.3% of patients. Troponin I levels were elevated >3.1 ng/mL only in the patients who suffered MI postoperatively. All the patients who suffered MI had both CK-MB index and troponin I levels elevated. Also, we found high correlation between maximum CK-MB levels and size of implants, which means that reaming and its heating effect may be responsible for false-elevated CK-MB levels, except direct muscle damage caused by surgical incision. CONCLUSION: CK-MB index and troponin I have the same sensitivity, but troponin I is more specific than CK-MB index in detecting MI after hip surgery. PMID- 17693842 TI - Male sexual dysfunction after pelvic fracture. AB - BACKGROUND: The assessment of multiple aspects of male sexual function after pelvic fracture. METHODS: A cross-sectional retrospective study of male sexual function was conducted. Patients admitted with traumatic pelvic fracture between January 1995 and June 2001 were included. One hundred and two patients were invited by mail. After performing a standardized clinical examination including an interview, the patients were asked to answer a questionnaire at home. Sexual dysfunction was classified as erectile dysfunction (ED), ejaculatory dysfunction, sensory loss in genital region, and pain during sexual activity. ED was assessed by the International Index of Erectile Function (IIEF). The pelvic injury was classified using Tile's classification. RESULTS: Complete data of 77 men were available (age 35 +/- 13). A total of 47 patients (61%) reported limitations in sexual function. Persistent ED was found in 15 patients (19%). The patient's report of ED could be verified by a low IIEF score in 14 cases. Injury patterns, which may increase the incidence of sexual dysfunction, could be identified. A ruptured symphysis appeared to bear a risk of temporary ED. Comparing compression and distraction in type B injuries, patients with distraction injury showed more severe sexual function. Posterior ring disruptions seemed to increase the risk of persistent problems, possibly caused by nerve damage. CONCLUSIONS: This study emphasizes that major pelvic trauma may impair sexual function in men. The results demonstrate an objective measurement of ED by the IIEF as well as an extended spectrum of complaints. The IIEF questionnaire might be considered to identify patients that need further medical evaluation. PMID- 17693843 TI - Coverage of skin defects in spaghetti wrist trauma: application of the reverse posterior interosseous flap and its anatomy. AB - BACKGROUND: To introduce the application of reverse posterior interosseous flap in spaghetti wrist trauma. METHODS: From 2003 to July 2005, 12 cases of skin defects over the volar wrist in spaghetti wrist trauma were covered by the reverse posterior interosseous flap. The size of the skin defects ranged from 5 cm x 4 cm to approximately 10 cm x 6 cm when the wrist was in the neutral position. The skin defects over donors were covered by split skin graft. RESULTS: All flaps and skin grafts survived uneventfully. The follow-up period was at least 3 months. The texture, color, and thickness of the skin paddle matched the surrounding skin. The sensation of the flap recovered to S0 to S1 on a five-point scale. The functional recovery of the hand and fingers was dependent on the original injuries to the tendons and nerves. CONCLUSION: The reverse posterior interosseous flap is a suitable alternative to cover skin defects in spaghetti wrist. The pedicle should include 2 cm of fascia and septum between the extensor carpi ulnaris and extensor digiti quinti proprius, and the subcutaneous tunnel should be wide enough to avoid venous congestion. Temporarily blocking the proximal end of the posterior interosseous artery to observe the blood supply of the flap is helpful to avoid its failure before completing the flap. PMID- 17693844 TI - Electroencephalogram, circulation, and lung function after high-velocity behind armor blunt trauma. AB - BACKGROUND: Behind armor blunt trauma (BABT) is defined as the nonpenetrating injury resulting from a ballistic impact on personal body armor. The protective vest may impede the projectile, but some of the kinetic energy is transferred to the body, causing internal injuries and occasionally death. The aim in this study was to investigate changes in electroencephalogram (EEG) and physiologic parameters after high-velocity BABT. METHODS: Eight anesthetized pigs, wearing body armor (including a ceramic plate) on the right side of their thorax, were shot with a 7.62-mm assault rifle (velocity approximately 800 m/s). The shots did not penetrate the armor and these animals were compared with control animals (n = 4), shot with blank ammunition. EEG and several physiologic parameters were thereafter monitored during a 2-hour period after the shot. RESULTS: All animals survived during the experimental period. Five of the exposed animals showed a temporary effect on EEG. Furthermore, exposed animals displayed decreased cardiac capacity and an impaired oxygenation of the blood. Postmortem examination revealed subcutaneous hematomas and crush injuries to the right lung. CONCLUSION: The results in our animal model indicate that high-velocity BABT induce circulatory and respiratory dysfunction, and in some cases even transient cerebral functional disturbances. PMID- 17693845 TI - Left ventricle injury with a normal pericardial window: case report and review of the literature. PMID- 17693846 TI - Repair of right renal vein avulsion after auto-pedestrian crash. PMID- 17693847 TI - A simple technique to remove a bent femoral intramedullary nail and broken interlocking screw. PMID- 17693848 TI - Nitrotyrosine as an oxidative stress marker: evidence for involvement in neurologic outcome in human traumatic brain injury. AB - BACKGROUND: Oxidative stress has been indicated as a mechanism of secondary neuronal injury in traumatic brain injury (TBI). Nitrotyrosine in the cerebrospinal fluid (CSF) may be an in vivo marker of oxidative nitric oxide damage. We tested the hypothesis that increased levels of nitrotyrosine correlate with poor neurologic outcomes in patients with TBI and attempted to identify the source of increased CSF nitrotyrosine. METHODS: This institutional-review-board approved study included 10 adults with severe closed TBI (Glasgow Coma Scale score <8) and no documented hypoxic brain injury. These patients underwent routine evaluation and, when indicated, placement of an intraventricular catheter. CSF samples (n = 27) were collected 2 to 72 hours after TBI and were also obtained from four healthy individuals. Nitrotyrosine levels were measured, and immunohistochemistry was performed. Neurologic follow-up extended to 1 month after injury. RESULTS: Nitrotyrosine was not detected in the control samples but was detected in 13 CSF samples from 7 TBI patients (range, 22.4-97.6 nM/mL). Seven patients had poor outcomes, and, in each, nitrotyrosine was detected. Nitrotyrosine immunoreactivity was detected in neurons and glia and confirmed in brain homogenate. CONCLUSION: Oxidative stress contributes to secondary brain injury in patients with TBI. Poor neurologic outcome is associated with increased levels of nitrotyrosine in the CSF. Identifying patients or the stage at which oxidative stress is more active using CSF markers of oxidative injury may help in the development of more targeted treatments. PMID- 17693849 TI - Too much of a good thing? Tracing the history of the propofol infusion syndrome. PMID- 17693850 TI - Grade V renal laceration: an unusual complication of transfemoral carotid angiography. PMID- 17693851 TI - Rapid evolutionary papules in a uremic patient. PMID- 17693852 TI - Comment on the article "Predictive model for estimating risk of crush syndrome: a data mining approach". PMID- 17693853 TI - Comment on article by Seamon et al. PMID- 17693854 TI - Injury due to Heelys shoes. PMID- 17693855 TI - Should pyloric exclusion for duodenal and pancreatico-duodenal injuries be abandoned? PMID- 17693856 TI - Comment on the article "The practice of venous thromboembolism prophylaxis in the major trauma patient". PMID- 17693858 TI - Comment on article by Cothren et al. PMID- 17693860 TI - Comment on the article "Damage control surgery before organ harvesting". PMID- 17693861 TI - Comment on article by Ahmed and Cheng-Robles. PMID- 17693875 TI - The 2007 John Charnley Award. Factors leading to low prevalence of DVT and pulmonary embolism after THA: analysis of genetic and prothrombotic factors. AB - We evaluated 136 hips (104 patients) to determine the prevalence of and contributing factors in deep vein thrombosis (DVT) and pulmonary embolism (PE) in those who were not given thromboprophylaxis when undergoing primary cementless total hip arthroplasty (THA). We performed coagulation assays, a full blood count, blood typing, and serum chemical profile tests for all patients on three separate occasions. Molecular genetic testing was performed preoperatively to detect the genetic traits involving DVT. DVT was diagnosed by roentgenographic venography, and PE was diagnosed by perfusion lung scanning. Our patients had a low prevalence of DVT and no patient had PE. Patients with bilateral THA had similar rates (p = 0.158; CI, -0.134-0.125) of venographic DVT as patients with unilateral THA (16 of 65 or 25% versus 12 of 72 or 17% respectively). We observed a relationship between DVT and factor V Leiden mutation, antithrombin-III level, and prothrombin promoter G20210A mutation. We saw no relationship between DVT and coagulation or thrombophilic data. We conclude combinations of absent thrombophilic polymorphisms with low clinical prothrombotic risk factors led to low prevalence of DVT and virtually absent PE after THA in the current series of patients, who had not received any form of prophylactic or therapeutic treatment for DVT. PMID- 17693876 TI - Resurfacing for Perthes disease: an alternative to standard hip arthroplasty. AB - Metal-on-metal total hip resurfacing is an alternative to conventional total hip arthroplasty with several reports describing the benefits of this procedure in young patients. We retrospectively compared the clinical (including range-of motion and leg length restoration) and radiographic outcome of resurfacing in young patients with Legg-Calve-Perthes to those of patients of a similar age treated with a standard total hip arthroplasty. Eighteen patients (19 hip resurfacings) who had a mean age of 33 years (range, 18-34 years) were followed for a minimum of 26 months (mean, 51 months; range, 26-72 months). We used an anterolateral approach in four hips and a posterior approach with a trochanteric advancement in 15 hips. Eighteen of the 19 hips had Harris hip scores greater than 80 points at final followup. All patients improved range of motion while avoiding any clinically apparent impingement. Leg length was gained in 16 hips where preoperative measurements were available. The short-term results of hip resurfacing for the treatment of Perthes disease compare similarly to those found in the literature for standard total hip arthroplasty in young patients. The trochanteric advancement technique described may aid in treating the deformed femoral anatomy. PMID- 17693877 TI - Precision and bias of imageless computer navigation and surgeon estimates for acetabular component position. AB - Computer navigation has the potential to permit accurate placement of components. We first hypothesized acetabular inclination and anteversion using navigation would be within 5 degrees of postoperative computed tomography scans, then secondly, computer precision would be better than that of surgeons. In the first phase, we obtained postoperative CT scans in 30 hips to ascertain the computer navigation values for inclination and anteversion of the cup. In the second phase, in 99 patients with 101 hips, we determined the surgeon's precision by comparing surgeons' blind estimates for trial cup position with computer navigation values. The navigation precision for inclination was 4.4 degrees with a bias of 0.03 degrees and for anteversion was 4.1 degrees with a bias of 0.73 degrees. The experienced surgeons' precision was 11.5 degrees for inclination and 12.3 degrees for anteversion, whereas the less experienced surgeons' precision was 13.1 degrees for inclination and 13.9 degrees for anteversion. The data supported the first hypothesis as computer navigation had a bias for inclination and anteversion of less than 1 degrees with precision less than 5 degrees. The precision of computer navigation was better than that of surgeons. This imageless computer navigation system allows more accurate acetabular component placement. PMID- 17693881 TI - Management of periacetabular bone loss in revision hip arthroplasty. AB - The goals of acetabular revision surgery are to restore the anatomy and achieve stable fixation for the new acetabular component. The existing bone stock and the type of defect are determining factors in the surgical decision making. When necessary, and especially in younger patients, attempts should be made to restore the bone stock by grafting. The advent of modern reconstruction options, like the trabecular metal revision system and the cup-cage construct, provide more options in addressing the management of severe defects. Trabecular metal has a porosity similar to bone and provides an environment more favorable to bone graft remodeling than conventional metals. We present an overview of our experience and current approach to acetabular revision. In addition, we report our preliminary results with trabecular metal cups and trabecular metal cup-cage constructs used in conjunction with bone graft for addressing major bone defects. PMID- 17693883 TI - Predictors of long-term viral failure among ugandan children and adults treated with antiretroviral therapy. AB - BACKGROUND: HIV RNA viral load testing is costly and is generally unavailable in resource-limited settings. We identified predictors of viral failure and documented genotypic mutations in a subset of patients with viral failure after 12 months on antiretroviral therapy (ART). METHODS: From April 2004 to June 2005, consecutive treatment-naive patients beginning ART at a university clinic in Uganda were enrolled. Clinical information, CD4 cell count, and HIV RNA level were collected at baseline and every 3 to 6 months. Independent predictors of viral failure were identified using multivariate logistic regression. Genotypic drug resistance for 8 patients with viral failure at 12 months was measured at baseline and at 6 and 12 months. RESULTS: Five hundred twenty-six adults and 250 children (0 to 18 years of age) were started on first-line ART regimens and followed for 12 months. Outcomes could not be assessed in 13% of patients (79 died and 21 were withdrawn). Children were almost twice as likely to have viral failure compared with adults (26% vs. 14%; P = 0.0001). In adults, the sole independent predictor of viral failure was treatment with stavudine (d4T)/lamivudine (3TC)/nevirapine (NVP) versus zidovudine (ZDV)/3TC/efavirenz (EFV) (odds ratio [OR] = 2.59, 95% confidence interval [CI]: 1.20 to 5.59). In children, independent predictors of viral failure included male gender (OR = 2.44, 95% CI: 1.20 to 4.93), baseline CD4% <5 (OR = 2.69, 95% CI: 1.28 to 5.63), and treatment with d4T/3TC/NVP versus ZDV/3TC/EFV (OR = 2.46, 95% CI: 1.23 to 4.90). All 8 patients with viral breakthrough and genotypic drug resistance results had nonnucleoside reverse transcriptase inhibitor (NNRTI)- and 3TC associated mutations. CONCLUSIONS: These data demonstrate the effectiveness of ART in a low-resource setting. Children and patients of all ages taking the d4T/3TC/NVP regimen were more likely to have viral failure. Our data suggest that viral failure occurring 6 months or more after the start of ART regimens commonly used in Uganda is likely to be associated with NNRTI- and 3TC-resistant virus. PMID- 17693887 TI - Elevated syringe borrowing among men who have sex with men: a prospective study. AB - OBJECTIVE: Despite efforts to scale up HIV prevention services for drug users, high rates of HIV risk behavior persist among some subpopulations. Given that few prospective studies have considered the relationship between sexual activity and syringe sharing, we sought to evaluate syringe sharing among male injection drug users (IDUs) who have sex with men (MSM) in Vancouver. METHODS: We performed a longitudinal analysis of factors associated with syringe borrowing among male participants enrolled in the Vancouver Injection Drug Users Study during the years 1996 to 2005 using generalized estimating equations (GEE). RESULTS: Among the 1019 male participants included in this analysis, 553 (54.3%) reported borrowing syringes during the study period. In multivariate GEE analysis, MSM were at an elevated risk for syringe borrowing (adjusted odds ratio [AOR] = 1.50, 95% confidence interval [CI]: 1.10 to 2.04) after extensive adjustment for other known risk factors. CONCLUSIONS: Among male participants, having sex with men was found to be strongly and independently associated with syringe borrowing. Our findings may aid policy makers in their efforts to identify IDUs who should be targeted with education and prevention efforts, and indicate the need for ongoing development of prevention interventions that address sexual orientation. PMID- 17693888 TI - Lessons from a multisite international trial in the Caribbean and South America of an HIV-1 Canarypox vaccine (ALVAC-HIV vCP1452) with or without boosting with MN rgp120. AB - BACKGROUND: The first multicenter, international National Institutes of Allergy and Infectious Diseases (NIAID)-sponsored HIV vaccine trial took place in Brazil, Haiti, Peru and Trinidad. This randomized, double-blind, placebo-controlled, phase 2 trial evaluated the safety and immunogenicity of a clade B-derived, live canarypox HIV vaccine, vCP1452. vCP1452 was administered alone or with a heterologous boost of MN rgp120 glycoprotein. The trial was pivotal in deciding whether these vaccines advanced to phase 3 efficacy trials. METHODS: Forty seronegative volunteers per site were randomized to ALVAC alone, ALVAC plus MN rgp120, or placebo in a 0, 1, 3, and 6 month schedule. Immunogenicity was assayed by chromium-release cytotoxic T lymphocyte (CTL) responses; interferon-gamma (IFN gamma) enzyme-linked immunosorbent spot assays (ELISpot); lymphocyte proliferation assays (LPA); neutralization; and enzyme-linked immunosorbent assays (ELISA). RESULTS: Enrollment and follow-up were excellent. Both vaccines were well tolerated. Neutralizing antibody to the laboratory-adapted MN strain was detected. Cellular immune responses, as measured by CTL, ELISpot, and LPA, did not differ between vaccines and placebos. CONCLUSIONS: The observation of disappointing immunogenicity in this and a parallel domestic study has informed future vaccine development. Equally important, challenges to doing an integrated trial across countries, cultures, languages, and differing at-risk populations were overcome. The identification of specific safety, ethical, logistic, and immunological issues in this trial established the foundation for current larger international studies. PMID- 17693890 TI - Randomized control trial of peer-delivered, modified directly observed therapy for HAART in Mozambique. AB - OBJECTIVE: To assess the efficacy of a peer-delivered intervention to promote short-term (6-month) and long-term (12-month) adherence to HAART in a Mozambican clinic population. DESIGN: A 2-arm randomized controlled trial was conducted between October 2004 and June 2006. PARTICIPANTS: Of 350 men and women (> or = 18 years) initiating HAART, 53.7% were female, and 97% were on 1 fixed-dose combination pill twice a day. INTERVENTION: Participants were randomly assigned to receive 6 weeks (Monday through Friday; 30 daily visits) of peer-delivered, modified directly observed therapy (mDOT) or standard care. Peers provided education about treatment and adherence and sought to identify and mitigate adherence barriers. OUTCOME: Participants' self-reported medication adherence was assessed 6 months and 12 months after starting HAART. Adherence was defined as the proportion of prescribed doses taken over the previous 7 days. Statistical analyses were performed using intention-to-treat (missing = failure). RESULTS: Intervention participants, compared to those in standard care, showed significantly higher mean medication adherence at 6 months (92.7% vs. 84.9%, difference 7.8, 95% confidence interval [CI]: 0.0.02, 13.0) and 12 months (94.4% vs. 87.7%, difference 6.8, 95% CI: 0.9, 12.9). There were no between-arm differences in chart-abstracted CD4 counts. CONCLUSIONS: A peer-delivered mDOT program may be an effective strategy to promote long-term adherence among persons initiating HAART in resource-poor settings. PMID- 17693892 TI - Pharmacokinetics of coadministered ritonavir-boosted elvitegravir and zidovudine, didanosine, stavudine, or abacavir. AB - OBJECTIVE: To evaluate the potential for clinically relevant drug interactions between ritonavir-boosted elvitegravir (EVG/r) and the nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine (ZDV), didanosine (ddI), stavudine (d4T), or abacavir (ABC) upon coadministration. METHODS: In 3 studies, healthy subjects were administered a single dose of ddI, d4T, or ABC, or multiple doses of ZDV, followed by multiple doses of EVG/r alone and together with an NRTI; pharmacokinetics (PK) of EVG and NRTIs were evaluated after individual administration and coadministration. Lack of PK alteration bounds (90% confidence intervals [CI]) for the NRTIs were based on the lack of PK-based dose adjustments per prescribing information. RESULTS: Twenty-four of 28, 32/32, and 24/26 subjects completed the ZDV-EVG/r, ddI/d4T-EVG/r, and ABC-EVG/r studies, respectively. All study drugs were well tolerated and no serious adverse events were noted. The PK of ZDV, its glucuronide (G-ZDV), d4T, ABC, and EVG were within the lack of PK alteration 90% CI bounds upon coadministration. Exposures of ddI were modestly (approximately 15%) lower, but these changes are unlikely to be clinically meaningful. CONCLUSIONS: There are no clinically relevant drug interactions between EVG/r and the NRTIs zidovudine, didanosine, stavudine, or abacavir. These agents can be coadministered without dose adjustment. PMID- 17693895 TI - Associations between recent gender-based violence and pregnancy, sexually transmitted infections, condom use practices, and negotiation of sexual practices among HIV-positive women. AB - BACKGROUND: This study sought to document the prevalence of recent gender-based violence (rGBV) among seropositive women and to determine the association between rGBV and pregnancy, sexually transmitted infections (STIs), condom use, and negotiation of sexual practices. METHODS: A total of 304 seropositive women recruited from HIV clinics in the southeastern United States who reported being sexually active in the previous 6 months with 1 partner were included in analyses. Gender-based violence during the previous 3 months, condom use, and negotiation of sexual practices were assessed. Biologic samples for pregnancy and STI testing were collected. RESULTS: A total of 10.2% of women reported a history of rGBV. rGBV was related to inconsistent condom use practices, pregnancy, and abuse stemming from requests for condom use. No associations were found between rGBV and negotiation of sexual practices and STIs. CONCLUSIONS: The prevalence of rGBV among HIV-positive women emphasizes the need for screening of abuse and highlights the need for the design and implementation of integrated intervention approaches necessary in addressing the needs of this population. PMID- 17693896 TI - Nanoparticle-Based biobarcode amplification assay (BCA) for sensitive and early detection of human immunodeficiency type 1 capsid (p24) antigen. AB - Nanotechnology-based techniques are being widely evaluated in medical testing and could provide a new generation of diagnostic assays due to their high degrees of sensitivity, high specificity, multiplexing capabilities, and ability to operate without enzymes. In this article, we have modified a nanoparticle-based biobarcode amplification (BCA) assay for early and sensitive detection of HIV-1 capsid (p24) antigen by using antip24 antibody-coated microplates to capture viral antigen (p24) and streptavidin-coated nanoparticle-based biobarcode DNAs for signal amplification, followed by detection using a chip-based scanometric method. The modified BCA assay exhibited a linear dose-dependent pattern within the detection range of 0.1 to 500 pg/ml and was approximately 150-fold more sensitive than conventional enzyme-linked immunosorbent assay (ELISA). No false positive results were observed in 30 HIV-1-negative samples, while all 45 HIV-1 RNA positive samples were found HIV-1 p24 antigen positive by the BCA assay. In addition, the BCA assay detected HIV-1 infection 3 days earlier than ELISA in seroconversion samples. Preliminary evaluation based on testing a small number of samples indicates that the HIV-1 p24 antigen BCA may provide a new tool for sensitive and early detection of HIV-1 p24 antigen in settings where HIV-1 RNA testing is currently not routinely performed. PMID- 17693897 TI - An imaging algorithm for evaluation of abnormal uterine bleeding: does sonohysterography play a role? PMID- 17693898 TI - Effects of dietary equol administration on the mammary gland in ovariectomized Sprague-Dawley rats. AB - OBJECTIVE: To evaluate the effects of dietary equol, a metabolite of soy-derived daidzein or formononetin present in red clover, on the mammary gland of ovariectomized Sprague-Dawley rats. DESIGN: Sixty ovariectomized rats were divided into five groups (n = 12) and fed soy-free chow with the addition of equol (50 mg/kg chow and 400 mg/kg chow) or estradiol-3 benzoate (E2B) (4.3 mg/kg chow and 17.3 mg/kg chow). The control group received soy-free chow only. After 3 months animals were killed, blood was collected, and the mammary glands were removed for histological and immunohistochemical evaluation. RESULTS: Equol and E2B treatment significantly increased serum equol and 17beta-estradiol concentrations, respectively. Serum prolactin in animals treated with high-dose equol was also significantly higher than in the controls. Animals treated with high-dose equol had a significantly higher number of terminal ducts and type II lobules compared with controls. This was also apparent in animals treated with low- and high-dose E2B, but a higher number of type I lobules also was seen. Compared with controls, animals treated with high-dose equol had a significantly higher percentage of proliferating cell nuclear antigen-positive cells in terminal ducts and type II lobules. The percentage of progesterone receptor positive cells in animals treated with high-dose equol was significantly higher only in type II lobules. In animals treated with low- and high-dose E2B, the percentage of proliferating cell nuclear antigen- and progesterone receptor positive cells was significantly higher in all the mammary structures. Low-dose equol did not have any effects on the parameters listed above. CONCLUSIONS: High dose dietary equol administration to ovariectomized rats exerts clear mammotropic effects. PMID- 17693902 TI - Hemostatic markers in healthy postmenopausal women during intranasal and oral hormone therapy: a randomized trial. AB - OBJECTIVE: To study changes in the hemostatic balance during intranasal compared with oral administration of 17beta-estradiol (E2) and norethisterone (NET) or NET acetate in postmenopausal women. A wide range of markers of coagulation and fibrinolysis associated with coronary artery disease was tested. DESIGN: In a two center, randomized, double-blind, comparative trial, 90 healthy postmenopausal women (aged 56.6 +/- 4.7 y) received daily continuous combined hormone therapy, either E2/NET 175 microg/275 mug intranasally as a spray (n = 47) or E2/NET acetate 1 mg/0.5 mg orally as a capsule (n = 43) for 1 year. Hemostatic markers were measured in blood samples taken at baseline and after 12, 24, and 52 weeks of treatment. RESULTS: After 52 weeks of treatment, changes in the intranasal group in markers of coagulation-fibrinogen (-1.3%), factor VII activity (-14.0%), and prothrombin fragment 1 + 2 (+5.8%)-were significantly less (P < 0.05) than the changes in the oral group for these parameters (-6.5%, -20.3%, and +19.0%, respectively). Changes in activated factor VII did not differ between the groups. Neither group showed significant changes in thrombin-antithrombin complex. In the intranasal group, decreases in markers of fibrinolysis-tissue-type plasminogen activator (-10.4%) and plasminogen activator inhibitor-1 antigen (-13.8%)-were significantly less (P < 0.05) than the decreases in the oral group (-17.8% and 38.0%, respectively). A decrease in plasminogen activator inhibitor-1 activity and increases in D-dimer and plasmin-alpha2-antiplasmin complex did not differ between the groups. No differences were found between the groups in homocysteine, which overall was unaltered in both groups. CONCLUSIONS: During intranasal E2/NET therapy, changes in the coagulatory and fibrinolytic markers were to some extent less than those observed during oral therapy. PMID- 17693903 TI - Adipocytokines and the postmenopausal metabolic syndrome: cause and effect, association, or neither? PMID- 17693904 TI - Use of recombinant activated factor VII in intractable bleeding during pediatric neurosurgical procedures. AB - OBJECTIVE:: To report the use of recombinant activated factor VII (NovoSeven; Novo Nordisk A/S, Bagsvaerd, Denmark) in children undergoing major neurosurgical procedures and experiencing massive uncontrolled hemorrhagic shock. DESIGN:: Retrospective review of patients and analysis of clinical and biological effects of an intravenous administration of recombinant activated factor VII. SETTING:: Neurosurgical anesthesia and critical care unit of a pediatric university hospital. PATIENTS/SUBJECTS:: Four children, <12-kg body weight, experiencing life-threatening perioperative hemorrhage required conventional treatment (massive red blood cells, fresh frozen plasma, platelet transfusion, and surgical hemostatic maneuvers) that failed to obtain definite hemostasis. INTERVENTIONS:: Intravenous administration of recombinant activated factor VII (100 mug/kg). RESULTS:: Intravenous administration resulted in a significant decrease in blood loss within minutes (preventing further need of transfusion), normalization of biological hemostasis markers, and improved surgical hemostasis. No side effects of recombinant activated factor VII were noted, and all patients, except one, had a good recovery. CONCLUSIONS:: These four patients support the use of recombinant activated factor VII as a useful adjunct to control massive life-threatening bleeding during pediatric neurosurgical procedures when other means failed. However, the data are still limited in children, and more extensive research is needed to define the indications of recombinant activated factor VII in massive surgical hemorrhage in low-weight children. PMID- 17693905 TI - Effect of inhaled corticosteroid on pulmonary injury and inflammatory mediator production after cardiopulmonary bypass in children. AB - OBJECTIVE: To determine whether inhaled steroid administration after cardiopulmonary bypass will attenuate pulmonary inflammation and improve lung compliance and oxygenation. DESIGN: Randomized, prospective, double-blind, placebo-controlled clinical trial. SETTING: Children's Hospital of Michigan, intensive care unit. PATIENTS: Thirty-two children <2 yrs of age with congenital heart disease requiring cardiopulmonary bypass. INTERVENTIONS: Participants were randomly assigned to one of two groups. Group 1 (n = 16) received an inhaled steroid, Budesonide (0.25 mg/2 mL), and group 2 (n = 16) received an inhaled placebo (2 mL of inhaled 0.9% saline). The nebulizations were given at the end of cardiopulmonary bypass, 6 hrs after cardiopulmonary bypass, and 12 hrs after cardiopulmonary bypass. Two hours after each nebulization, bronchoalveolar lavage for interleukin-6 and interleukin-8 was collected. MEASUREMENTS AND MAIN RESULTS: The concentrations of interleukin-6 and interleukin-8 in the bronchoalveolar lavage increased in both groups after cardiopulmonary bypass. Interleukin-6 peaked 2 hrs after cardiopulmonary bypass and was decreasing by 14 hrs after cardiopulmonary bypass. However, administration of corticosteroid did not affect the production of interleukin-6 when compared with the placebo group (378 +/- 728 vs. 287 +/- 583 pg/mL pre-cardiopulmonary bypass, 1662 +/- 1410 vs. 1584 +/- 1645 pg/mL at the end of cardiopulmonary bypass, 2601 +/- 3132 vs. 3677 +/- 4935 pg/mL 2 hrs after cardiopulmonary bypass, and 1792 +/- 3100 vs. 1283 +/- 1344 pg/mL 14 hrs after cardiopulmonary bypass; p > .05). Likewise, interleukin-8 in the lavage fluid was similar in both the placebo and steroid groups at all time points (570 +/- 764 vs. 990 +/- 1147 pg/mL pre-cardiopulmonary bypass, 1647 +/- 1232 vs. 1394 +/- 1079 pg/mL at the end of cardiopulmonary bypass, 1581 +/- 802 vs. 1523 +/- 852 pg/mL 2 hrs after cardiopulmonary bypass, and 1652 +/- 1069 pg/mL vs. 1808 +/ 281 pg/mL 14 hrs after cardiopulmonary bypass; p > .05). Lung compliance and oxygenation were similar in both groups. CONCLUSIONS: Cardiopulmonary bypass is associated with a pulmonary inflammatory response. Inhaled corticosteroid did not affect the pulmonary inflammatory response as measured by interleukin-6 and interleukin-8 concentrations in the lung lavage after cardiopulmonary bypass. Pulmonary mechanics and oxygenation were not improved by the use of inhaled corticosteroid. PMID- 17693906 TI - The experiences of pediatric nurses caring for children in a persistent vegetative state. AB - OBJECTIVE: The number of children surviving in a persistent vegetative state is increasing with advances in medical technology. Caring for a neurologically devastated child presents unique challenges not previously described. Our objective was to gain an understanding of the pediatric nurse's experience of caring for children in a persistent vegetative state. DESIGN: Qualitative phenomenologic study using in-depth interviews. SETTING: Monitored step-down care unit of an academic children's hospital. PARTICIPANTS: Eight registered nurses employed at a step-down care unit. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Nurses in this study described caring for children in a persistent vegetative state as a dynamic process with negative and positive aspects. Six themes emerged from this study: focusing on the parents, delivering sensorially offensive physical care, enduring conflicting emotions, suffering moral distress, finding relief and comfort, and gaining perspective. CONCLUSIONS: Our qualitative study suggests that caring for a child in a persistent vegetative state is difficult. Pediatric nurses described the experience as emotionally stressful and ethically challenging. To cope with the demands of caring for the child in a persistent vegetative state, the nurses in this study modified the traditional concept of the pediatric nurse-patient relationship. PMID- 17693907 TI - Extubation after cardiothoracic surgery in neonates, children, and young adults: One year of institutional experience. AB - OBJECTIVE:: Describe risk factors associated with successful and early extubation in the pediatric cardiac intensive care unit. DESIGN:: Retrospective chart review. SETTING:: University hospital, cardiac intensive care unit. MEASUREMENTS AND MAIN RESULTS:: Review of 212 consecutive surgical admissions from January 2003 to January 2004, excluding deaths. Preoperative, intraoperative, and postoperative variables were studied. Successful extubation was defined as no reintubation at any time during the cardiac intensive care unit course and early extubation was defined as mechanical ventilation 24 hrs after surgery. A history of prematurity (odds ratio [OR], 5.84, 2.29-14.9; p < .001), base excess (OR, 1.47, 1.27-1.70; p < .001), cardiopulmonary bypass time (OR, 1.01, 1.01 to -1.2; p < .05), and the need for surgical reintervention (OR, 18.29, 2.78 to -120.07; p < .05) were associated with intubation for >24 hrs. CONCLUSION:: Extubation without the need for reintubation can be achieved in nearly all children following cardiothoracic surgery. The majority of successful extubations can be achieved within 24 hrs of surgery. PMID- 17693909 TI - Pharmacokinetics of dexmedetomidine in postsurgical pediatric intensive care unit patients: preliminary study. AB - OBJECTIVE: To characterize the pharmacokinetics of dexmedetomidine and monitor any dexmedetomidine-related adverse events in postoperative pediatric patients requiring short-term mechanical ventilation, analgesia, and sedation in the pediatric intensive care unit (PICU). DESIGN: Prospective, case series. SETTING: Operating room and PICU in a large, urban children's hospital. Enrollment from February 14 to November 25, 2002. PATIENTS: Ten children (4 months to 7.9 yrs of age) who received postoperative infusions of dexmedetomidine. INTERVENTIONS: Toward the end of the operation, patients received dexmedetomidine at 1 microg/kg per hr for 10 mins. The anesthesiologist then titrated the infusion, as clinically indicated, to a rate of 0.2-0.7 microg/kg per hr. In the PICU, the infusion was titrated by the nursing staff based on assessment with a modified Ramsey Sedation Scale, while maintaining heart rate and blood pressure within normal limits for age. Dexmedetomidine was continued until the intensivist felt the patient no longer benefited, but for no longer than 24 hrs. MEASUREMENTS AND MAIN RESULTS: At specified times during the infusion and after discontinuation, dexmedetomidine plasma concentrations were determined. Pharmacokinetic parameters were calculated using a two-compartment model. Vital signs, sedation scores, adjunct sedative or analgesic medications, and adverse events were recorded. Average duration of infusion was 18.8 hrs (range, 8-24 hrs). Means (+/-sd) were calculated for the following: clearance, 0.57 (+/-0.14) L/hr per kg; volume of distribution at steady state, 1.53 (+/-0.37) L/kg; and terminal elimination half life, 2.65 (+/-0.88 hrs)-all similar to published values in adults. There were no serious adverse events related to dexmedetomidine. CONCLUSIONS: Dexmedetomidine, administered as a continuous infusion, produces consistent, predictable concentrations in children and infants. Further evaluations of the safety, efficacy, and pharmacodynamics of dexmedetomidine are warranted. PMID- 17693910 TI - Using pediatric advanced life support in pediatric residency training: does the curriculum need resuscitation? AB - OBJECTIVE: The Pediatric Advanced Life Support (PALS) course is used throughout North American pediatric residency programs to provide a core pediatric resuscitation curriculum. Despite this widespread use, its effectiveness has not been formally assessed in pediatric residents. This study aimed to evaluate the PALS curriculum's effectiveness in providing pediatric residents with knowledge, skill and confidence in pediatric resuscitation. DESIGN: Course evaluation. SETTING: Tertiary care pediatric hospital. SUBJECTS: Pediatric residents. INTERVENTIONS: Subjects were followed prospectively for 1 yr following completion of an annual PALS course. Multiple choice and short answer questionnaires were used to evaluate residents' knowledge immediately before and after completion of the course and throughout the following year. Confidence in ten aspects of pediatric resuscitation was assessed. Scores were compared before and after the PALS course to evaluate acquisition of knowledge and confidence. Scores at 12 months were compared with the immediate post-PALS course scores to evaluate maintenance of knowledge and confidence over time. Technical skills were evaluated by staff anesthetists using a 3-point scale. MEASUREMENTS AND MAIN RESULTS: Knowledge questionnaire scores were significantly higher post-PALS compared with pre-PALS, but knowledge of the details of PALS algorithms decreased significantly over the following 12 months. Confidence ratings improved post-PALS on only two of ten measures and remained very low overall. Residents could complete the four core technical skills but required assistance or multiple attempts. CONCLUSIONS: PALS is successful in providing basic resuscitation knowledge to pediatric residents, but knowledge of critical algorithm details is not sustained. The course does not provide for the expected level of competency in relevant technical skills. Residents do not achieve the confidence to feel well prepared to provide comprehensive care to pediatric patients in cardiopulmonary arrest. These findings support the hypothesis that the PALS course alone is insufficient to provide pediatric residents with competency in cardiopulmonary resuscitation. PMID- 17693911 TI - Diagnosis of catheter-related bloodstream infection in neonates: a study on the value of differential time to positivity of paired blood cultures. AB - OBJECTIVE: Diagnosis of neonatal catheter-related bloodstream infection (CRBSI) is currently based on isolation of identical bacterial species from bloodstream and catheter tip cultures. This requires removal of the catheter followed by the insertion of a new catheter. The objective of this study was to investigate whether differential time to positivity (DTP) of blood cultures drawn from paired peripheral vein and central vascular catheter is useful for diagnosing neonatal CRBSI, avoiding removal of the catheter. DESIGN: Retrospective observational study. SETTING: Neonatal intensive care unit, University Hospital of Antwerp, Belgium. PATIENTS: Neonates with probable and definite nosocomial bloodstream infection. INTERVENTIONS: All episodes of nosocomial bloodstream infection (NBSI) in an approximately 7.5-yr period were identified retrospectively. Definite NBSI episodes in which paired blood cultures were obtained were retained to calculate DTP, to determine the optimal DTP cutoff for the diagnosis of CRBSI, and to assess the validity of DTP for the diagnosis of CRBSI. MEASUREMENTS AND MAIN RESULTS: Of 32 NBSI episodes included in the study, 16 were CRBSI, seven were non CRBSI, and nine were classified as "diagnosis uncertain." In CRBSI, blood cultures drawn from a central vascular catheter were positive earlier than those drawn from a peripheral vein (median 9.67 hrs vs. 21.58 hrs, p < .01). Median DTP was 10.42 hrs in CRBSI and -0.33 hrs in non-CRBSI (p = .01). The optimal DTP cutoff for the diagnosis of CRBSI was > or =1 hr (area under the receiver operating characteristic curve = 0.84 +/- 0.11), with a sensitivity of 94%, a specificity of 71%, a positive predictive value of 88%, and a negative predictive value of 83%. CONCLUSIONS: Differential time to positivity of paired blood cultures may have some potential in the diagnosis of catheter-related infections in neonatal intensive care unit patients and should be subjected to a prospective study. PMID- 17693912 TI - Extracorporeal membrane oxygenation for refractory septic shock in children: one institution's experience. AB - OBJECTIVE: To report our institutional experience of venoarterial extracorporeal membrane oxygenation (ECMO) in children with septic shock and circulatory collapse. DESIGN: Retrospective case series. SETTING: Intensive care unit of a tertiary pediatric referral center. PATIENTS: Forty-five children with refractory septic shock who received venoarterial ECMO for hemodynamic support. INTERVENTIONS: Venoarterial ECMO. MEASUREMENTS AND MAIN RESULTS: We measured mean arterial pressure and inotropes before cannulation, ventilator settings, oxygenation, site and cause of infection, time on ECMO, complications of ECMO relating to the circuit or anticoagulation, survival to hospital discharge, and functional outcome assessment. Between July 1988 and October 2006, 441 children at our institution received extracorporeal life support for a variety of indications. Forty-five (10%) with septic shock received venoarterial ECMO specifically for hemodynamic support. Eighteen (40%) of these had suffered cardiac arrest and were receiving chest compressions immediately before cannulation. The median time spent on ECMO was 84 hrs (range, 32-135). There were mechanical problems with the ECMO circuit requiring intervention in 17 (38%) patients, such as oxygenator or pump head failure, clots in the circuit, or cannulae malposition. This caused no long-term harm in any but one of the patients, who died during a circuit change. Eleven patients (24%) had clinically apparent episodes of bleeding that required surgical intervention or blood transfusion. Twenty-one (47%) patients survived to hospital discharge. Atrioaortic cannulation through a sternotomy incision was associated with an improvement in survival to hospital discharge (73% of those with central cannulation survived vs. 44% without, p = .05). No survivors had severe disability at long-term follow-up. CONCLUSIONS: Extracorporeal membrane oxygenation can be safely used to resuscitate and support children with sepsis and refractory shock. Sepsis and multiorgan failure should not be considered a contraindication to ECMO. This study adds support to existing guidelines. PMID- 17693913 TI - Weaning children from mechanical ventilation with a computer-driven system (closed-loop protocol): a pilot study. AB - OBJECTIVE: To evaluate the applicability, tolerance, and efficacy of a closed loop protocol to wean children from mechanical ventilation. DESIGN: Prospective single-center pilot study. SETTING: Tertiary care university hospital. PATIENTS: Twenty mechanically ventilated children aged between 1 and 17 yrs, with a body weight > or =10 kg, no inotropes, and no heavy sedation. INTERVENTIONS: Patients were weaned in pressure support mode by a closed-loop computerized protocol (closed-loop protocol) that interprets clinical data in real time and controls pressure support levels. MEASUREMENTS AND MAIN RESULTS: The closed-loop protocol applicability and tolerance were evaluated. The efficacy of this protocol was evaluated by comparing the duration of mechanical ventilation with a historical group of 20 patients weaned with a clinician-decision protocol. The closed-loop protocol successfully decreased pressure support ventilation in 16 children, recommended separation from the ventilator in 14 children, and did not cause any serious adverse events. Mechanical ventilation duration was 5.1 +/- 4.2 days in the closed-loop group and 6.7 +/- 11.5 days (mean +/- sd) in the clinician decision group (p = .33) with no difference in the need for reintubation or noninvasive mechanical ventilation (one of 20 and four of 20, respectively; p = .20). CONCLUSIONS: A closed-loop protocol was successfully used to wean children from mechanical ventilation. Further studies are required to assess the impact of this novel therapeutic strategy on the length of mechanical ventilation. PMID- 17693914 TI - Selective medicated (normal saline and exogenous surfactant) bronchoalveolar lavage in severe aspiration syndrome in children. AB - OBJECTIVE: To study the ability of volume-controlled ventilation and medicated (normal saline plus surfactant) bronchoalveolar lavage in aspiration to reduce the duration of intubation and improve gas exchange. DESIGN: : Randomized controlled clinical trial. SETTING: Pediatric intensive care unit. PATIENTS: Twenty children, 1 month to 16 yrs old, who were intubated and mechanically ventilated, were randomized within 6 hrs of aspiration to receive volume controlled ventilation plus medicated bronchoalveolar lavage (treatment group) or the same ventilation and bronchosuction (control group). INTERVENTIONS: Volume controlled ventilation and positive end-expiratory pressure (10-12 cm H2O) were applied. Medicated bronchoalveolar lavage was performed using five aliquots of 5 mL of saline plus 10 mg/mL Curosurf (porcine surfactant, Chiesi Pharmaceutical SpA, Parma, Italy) in infants, five boluses of 10 mL of saline plus 5 mg/mL Curosurf in children, and four boluses of 25 mL of saline with 2.4 mg/mL Curosurf in adolescents for each affected lobe. One hour after bronchoalveolar lavage, 240 mg of Curosurf was administered locally. MEASUREMENTS AND MAIN RESULTS: All patients survived. In the treatment group, days of intubation were 4.6 (+/-1.07), oxygenation index and Pao2/Fio2 improved significantly at 24 hrs, and statistical reduction in tidal volume mL/kg was observed from 36 hrs. In the control group, days of intubation were 11.8 (+/-3.22) (p < .0001), no improvement in oxygenation was noted, and pneumonia was observed in seven children (70%). CONCLUSIONS: Even though this was an unblinded small clinical trial and low tidal volume strategy was not employed at an early stage after lung injury, there is some evidence that bronchoalveolar lavage with normal saline and surfactant may have clinical value in treating severe aspiration syndrome in children. More clinical studies are warranted to overcome study limitations and potential bias. PMID- 17693915 TI - Internal mammary artery injury after central venous catheterization. AB - OBJECTIVE: We describe an infrequent but potentially lethal complication: an iatrogenic injury of the internal mammary artery after central venous catheterization. DESIGN: Report of cases. SETTING: Pediatric intensive care unit. PATIENTS: The first patient we report on is a 3-yr-old girl who was severely neurologically damaged and was admitted to the pediatric intensive care unit for aspiration pneumonia and septic shock. Immediately after vein cannulation on the left internal jugular vein, the patient suffered hypotension and cardiac arrest, secondary to an adequately drained massive hemothorax. Restoration of spontaneous circulation was initially achieved, and the patient was transferred to the angiographic suite. Selective angiography during cardiopulmonary resuscitation for a second cardiac arrest revealed a laceration of the internal mammary artery. Resuscitation was not successful, and the patient died. The second case reported is a 7-yr-old girl admitted for bone marrow transplantation. She was electively taken to the angiographic suite for central venous insertion. An infraclavicular approach of the right subclavian vein was attempted, but radioscopy showed the guidewire inside the pleural space. Soon thereafter, the patient became hypotensive and was in shock. Radioscopy showed a large pleural effusion and a massive hemothorax was drained. Selective angiography demonstrated an injured internal mammary artery was embolized. Hemodynamics improved, and the patient was transferred to the pediatric intensive care unit, where she was extubated 12 hrs later. INTERVENTIONS: None. CONCLUSIONS: Central venous catheter placement in the intrathoracic vein may cause potentially lethal complications in the form of an injury to the internal mammary artery. Hypotension during or immediately after the procedure should be a warning of a serious adverse event, such as massive hemothorax, that may compromise life. Adequate drainage of the pleural cavity may not completely relieve vascular compression if some of the bleeding from an injured internal mammary artery is extrapleural. Early diagnosis and treatment by selective embolization of the injured vessel in interventional radiology is the first therapeutic choice and may be life saving. PMID- 17693916 TI - Is hyperglycemia really harmful? A critical appraisal of "Persistent hyperglycemia in critically ill children" by Faustino and Apkon (J Pediatr 2005; 146:30-34). AB - OBJECTIVE: To review the findings and to discuss the implications of hyperglycemia in critically ill children. DESIGN: A critical appraisal of an article with literature review. FINDINGS: In this single-center, retrospective cohort study, the authors report that the prevalence of hyperglycemia ranged from 16.7% to 75%, depending on the cutoff values (120 mg/dL, 150 mg/dL, and 200 mg/dL), among nondiabetic children admitted to a pediatric intensive care unit. Hyperglycemia correlated with an increased in-hospital mortality rate (relative risk, 2.5; 95% confidence interval, 1.26-4.93 for maximum glucose within 24 hrs, >150 mg/dL; and relative risk, 5.68; 95% confidence interval, 1.38-23.47 for highest glucose within 10 days, >120 mg/dL), as well as a longer length of stay in the pediatric intensive care unit. This finding is in concordance with other adult and pediatric studies. However, without adjustment for severity of illness, the study does not distinguish cause and effect, nor does it address the role of strict glucose control in this group of patients. CONCLUSIONS: This study adds to the growing body of knowledge that associates the timing, intensity, duration, and variability of glycemia with outcomes in critically ill children. However, its limitations restrict drawing causal relationships and prevents insights regarding therapy. PMID- 17693917 TI - Bronchioalveolar lavage with perfluorochemical liquid during conventional ventilation. AB - OBJECTIVE: Therapeutic approaches with bronchioalveolar lavage are currently used in infants with severe alveolar space-occupying material. In many circumstances, bronchioalveolar lavage has been performed in conjunction with extracorporeal membrane oxygenation. CASE REPORT: A 2-month-old boy with severe respiratory failure requiring assisted ventilation did not respond to any conventional treatments, including surfactant. An open-lung biopsy showed intra-alveolar accumulation of proteinaceous material and foamy macrophages but was not diagnostically conclusive. Therapeutic trials with bronchioalveolar lavage using normal saline were unsuccessful, causing episodes of severe hypoxemia. Then, bronchioalveolar lavage during conventional mechanical ventilation was performed with the use of a medical-grade perfluorochemical liquid (perfluordecalin). After instillation of liquid (10 mL/kg), the lungs were refilled three times during the first 24 hrs and repeated 48 hrs later. During perfluorochemical liquid treatment, the infant's condition remained stable, with small improvements in pulmonary mechanics. Suction from the endotracheal cannula yielded only small amounts of gelatinous material. Considering the progression of the disease and just minimal pulmonary improvements by this intervention, further treatment was considered futile. Support was, thus, minimized, and the infant died a few days later. An autopsy revealed the diagnosis to be consistent with Niemann-Pick C2 disease. CONCLUSION: This study demonstrated that bronchioalveolar lavage with perfluorochemical liquid could be performed safely during conventional mechanical ventilation without the additional support of extracorporeal membrane oxygenation in infants with severe alveolar space-occupying material. PMID- 17693918 TI - Probiotic administration and the incidence of nosocomial infection in pediatric intensive care: a randomized placebo-controlled trial. AB - OBJECTIVE: To evaluate the efficacy of probiotics in reducing the rates of nosocomial infection in pediatric intensive care. DESIGN: Randomized, double blind, placebo-controlled trial. SETTING: A 16-bed pediatric intensive care unit in a university-affiliated children's hospital. PATIENTS: Sixty-one pediatric patients were enrolled from April 2004 until December 2004. Screening of all patients admitted occurred on a daily basis. Patients were excluded if they had the following: evidence/suspicion of intestinal perforation, evidence/suspicion of mechanical gastrointestinal obstruction, absolute neutrophil count 16 pg/mL), the endotoxin group had a low IM osmolality (mean +/- SEM, 412+/-0.04 mOsm/kg H2O) in comparison with the control group (mean +/- SEM, 1,094+/-0.17 mOsm/kg H2O) and was not able to either decrease urine volume or raise urine osmolality. Desmopressin treatment in endotoxin-treated rats maintained mean arterial pressure, increased sodium reabsorption, IM osmolality, and urine osmolality, and decreased urine flow. The AQP2 intensity decreased in the endotoxin group, and the apical localization disappeared; both were not affected by desmopressin. Our results indicate that endotoxemia in rats acutely diminishes renal urinary concentration capacity and is associated with a decreased IM osmolality and diminished apical AQP2 localization. These findings may help to explain nonoliguric acute renal failure in human septic shock. PMID- 17693924 TI - Exportin 1 inhibition attenuates nuclear factor-kappaB-dependent gene expression. AB - Activation of nuclear factor (NF)-kappaB is mediated by signal-induced phosphorylation of IkappaBalpha, subsequent IkappaBalpha degradation, and then translocation of unbound NF-kappaB to the nucleus. Termination of gene expression occurs when IkappaBalpha binds NF-kappaB subunits (Rel A) in the nucleus. Leptomycin B specifically inhibits export of IkappaBalpha and the inactive IkappaBalpha/Rel A complex via the nuclear export protein exportin 1. We hypothesized that inhibition of IkappaBalpha nuclear export would increase nuclear IkappaBalpha and attenuate NF-kappaB inflammatory gene expression in pulmonary microvascular endothelial cells. We found that inhibition of exportin 1 causes nuclear accumulation of both endogenous NF-kappaB (Rel A) and IkappaBalpha. IL-1beta causes nuclear accumulation of NF-kappaB (Rel A) but does not increase nuclear IkappaBalpha. Inhibition of exportin 1 before IL-1beta prevented an increase in the nuclear ratio of NF-kappaB (Rel A) to IkappaBalpha and decreases NF-kappaB DNA binding. Furthermore, inhibition of exportin 1 attenuates IL-1beta-induced phosphorylation of IkappaBalpha without affecting IkappaB kinase phosphorylation. Lastly, inhibition of exportin 1 attenuates monocyte chemoattractant protein, IL-8, and intercellular adhesion molecule expression in response to IL-1beta stimulation. We suggest that the decrease in cell activation due to exportin 1 inhibition is a result of termination of NF kappaB DNA binding due to increased concentration of IkappaBalpha in the nucleus. PMID- 17693925 TI - L-arginine causes amelioration of cerebrovascular dysfunction and brain inflammation during experimental heatstroke. AB - Cerebrovascular dysfunction ensuing from severe heatstroke includes intracranial hypertension, cerebral hypoperfusion, and brain inflammation. We attempted to assess whether L-arginine improves survival during experimental heatstroke by attenuating these reactions. Anesthetized rats, 70 min after the start of heat stress (43 degrees C), were divided into two major groups and given the following: vehicle solution (1 mL/kg body weight) or L-arginine (50-250 mg/kg body weight) intravenously. Another group of rats was exposed to room temperature (24 degrees C) and used as normothermic controls. Their physiological and biochemical parameters were continuously monitored. When the vehicle-treated rats underwent heat stress, their survival time values were found to be 20 to 26 min. Treatment with i.v. doses of L-arginine significantly improved the survival rate during heatstroke (54-245 min). As compared with those of normothermic controls, all vehicle-treated heatstroke animals displayed higher levels of core temperature, intracranial pressure, and NO metabolite, glutamate, glycerol, lactate-pyruvate ratio, and dihydroxybenzoic acid in hypothalamus. In addition, hypothalamic levels of IL-1beta and TNF-alpha were elevated after heatstroke onset. In contrast, all vehicle-treated heatstroke animals had lower levels of MAP, cerebral perfusion pressure, cerebral blood flow, and brain partial pressure of oxygen. Administration of L-arginine immediately after the onset of heatstroke significantly reduced the intracranial hypertension and the increased levels of NO metabolite, glutamate, glycerol, lactate-pyruvate ratio, and dihydroxybenzoic acid in the hypothalamus that occurred during heatstroke. The heatstroke-induced increased levels of IL-1beta and TNF-alpha in the hypothalamus were suppressed by L-arginine treatment. In contrast, the hypothalamic levels of IL-10 were significantly elevated by L-arginine during heatstroke. The results suggest that L-arginine may cause attenuation of heatstroke by reducing cerebrovascular dysfunction and brain inflammation. PMID- 17693926 TI - CD4+ T-cell depletion is not associated with alterations in survival, bacterial clearance, and inflammation after cecal ligation and puncture. AB - Our recent studies indicate that mice depleted of T cells that bear the alphabeta T-cell receptor (alphabeta T cells) show less inflammation, less physiological dysfunction, and improved survival after cecal ligation and puncture (CLP) compared with control mice. Classic CD4(+) and CD8(+) T cells comprise most of the alphabeta T-cell population. We previously showed that CD8(+) T cells, in conjunction with natural killer (NK) cells, participate in CLP-induced inflammation. However, the contribution of CD4(+) T cells to the early inflammatory response caused by CLP is largely undefined. In the present study, we evaluated CLP-induced mortality, bacterial clearance, and inflammation in mice that were depleted of CD4(+) T cells. Compared with control mice, CD4 knockout mice and wild-type mice treated with anti-CD4 did not show significant differences in survival, cytokine production, and systemic bacterial counts. The combined depletion of CD4(+) T and NK cells resulted in improved survival and decreased cytokine production compared with mice possessing a full lymphocyte complement, especially when CD4(+) T and NK cell-deficient mice were treated with imipenem. These improvements were nearly identical to those observed in mice depleted only of NK cells. These studies show that CD4(+) T cells do not seem to play a critical role in facilitating the early inflammatory response caused by CLP. PMID- 17693927 TI - PP2A regulates upstream members of the c-jun N-terminal kinase mitogen-activated protein kinase signaling pathway. AB - We have previously demonstrated that inhibition of the serine-threonine phosphatase PP2A resulted in increased c-jun N-terminal kinase (JNK) activity, and that the regulatory subunit, A/alpha of PP2A, was physically associated with the JNK. Because there exists additional examples of phosphatases serving as negative regulators of multiple members of mitogen-activated protein kinase (MAPK) pathways in Drosophila and yeast, we hypothesized that PP2A may serve a homologous function in mammalian cells affording the regulation of additional upstream kinases in the JNK pathway. In human monocytes, activation of JNK by LPS proceeds through the MAPK kinase kinase MEKK-1 and, subsequently, the MAPK kinases MKK4 and/or MKK7. Using the human monocyte cell line THP-1, we show that pharmacological manipulation of the activity of PP2A seemed to regulate not only JNK but also the upstream kinases MKK4 and MEKK-1. Using coimmunoprecipitation, overexpression of tagged recombinant JNK, and bacterial two-hybrid strategies, evidence for physical interactions between the structural subunit, PP2A-A/alpha and MEKK-1, MKK4, and JNK was observed. These studies suggest that the target of regulation by PP2A includes upstream kinases in the JNK MAPK pathway. Furthermore, PP2A-A/alpha seems to serve as a structural protein to foster protein-protein interactions affording specificity of the regulation among members of this MAP kinase pathway. PMID- 17693928 TI - Alteration of right ventricular-pulmonary vascular coupling in a porcine model of progressive pressure overloading. AB - In acute pulmonary embolism, right ventricular (RV) failure may result from exceeding myocardial contractile resources with respect to the state of vascular afterload. We investigated the adaptation of RV performance in a porcine model of progressive pulmonary embolism. Twelve anesthetized pigs were randomly divided into two groups: gradual pulmonary arterial pressure increases by three injections of autologous blood clot (n=6) or sham-operated controls (n=6). Right ventricular pressure-volume (PV) loops were recorded using a conductance catheter. Right ventricular contractility was estimated by the slope of the end systolic PV relationship (Ees). After load was referred to as pulmonary arterial elastance (Ea) and assessed using a four-element Windkessel model. Right ventricular-arterial coupling (Ees/Ea) and efficiency of energy transfer (from PV area to external mechanical work [stroke work]) were assessed at baseline and every 30 min for 4 h. Ea increased progressively after embolization, from 0.26+/ 0.04 to 2.2+/-0.7 mmHg mL(-1) (P<0.05). Ees increased from 1.01+/-0.07 to 2.35+/ 0.27 mmHg mL(-1) (P<0.05) after the first two injections but failed to increase any further. As a result, Ees/Ea initially decreased to values associated with optimal SW, but the last injection was responsible for Ees/Ea values less than 1, decreased stroke volume, and RV dilation. Stroke work/PV area consistently decreased with each injection from 79%+/-3% to 39%+/-11% (P<0.05). In response to gradual increases in afterload, RV contractility reserve was recruited to a point of optimal coupling but submaximal efficiency. Further afterload increases led to RV-vascular uncoupling and failure. PMID- 17693930 TI - Calreticulin downregulation is associated with FGF-2-induced angiogenesis through calcineurin pathway in ischemic myocardium. AB - Fibroblast growth factor 2 (FGF-2) plays an integral role in therapeutic angiogenesis associated with myocardial infarct healing. Calcium (Ca(2+)) is one of the most universal important signaling molecules that affect cell proliferation and angiogenesis. Calreticulin (CRT), a 46-kd (Ca(2+)) -binding chaperone found mainly in the endoplasmic reticulum, plays an important role in regulating calcium homeostasis. The role of CRT in FGF-2-induced angiogenesis and its signaling pathways in ischemic myocardium are not clear. For this study, two dimensional gel electrophoresis and matrix-assisted laser desorption ionization mass spectrometry were used to analyze CRT's differential expression in myocardial microvascular endothelial cells treated with or without FGF-2. Western blotting analysis was used to detect the expression of CRT and calcineurin (CaN) in sham-operated, FGF-2-, or saline intramyocardially injected myocardium. It is found that FGF-2 induced angiogenesis after sustained ischemia with downregulation of CRT expression and upregulation of CaN expression in myocardium. The CRT expression was negatively correlated to angiogenesis. Furthermore, overexpression of CRT or inhibition of CaN with cyclosporine A abolishes FGF-2-induced microvascular endothelial cells proliferation and CaN expression. The results indicate that intramyocardial administration of FGF-2 decreases myocardial CRT expression in parallel with myocardial angiogenesis in ischemic myocardium. The study further indicates that Ca(2+)/CaN signaling pathway may be involved in CRT-related angiogenesis. PMID- 17693932 TI - Insulin regulates macrophage activation through activin A. AB - Strict control of serum glucose with insulin has been associated with a reduction in the development of multiple organ dysfunction syndrome potentially through alterations in macrophage activation. Although the mechanism responsible for this effect remains poorly elucidated, recent work has suggested that this may occur through the PI3K/AKT pathway. As a result, we set out to investigate the role and means of activation of this pathway by insulin on endotoxin-mediated activation of tissue-fixed macrophages. METHODS: THP-1 cells were stimulated with endotoxin with or without 24 h of insulin pretreatment. Cellular protein was extracted and analyzed by immunoblot for factors essential to Toll-like receptor 4 signaling. Supernatants were analyzed by enzyme-linked immunosorbent assay for TNF-alpha and IL-8 production. In addition, potential effect of the transforming growth factor superfamily was analyzed through selective inhibition of either the transforming growth factor beta or activin A receptors. RESULTS: Endotoxin exposure resulted in the activation of extracellular signal-regulated kinase 1/2, p38 and Jun kinase, the degradation of IkappaB, the activation of nuclear factor kappaB, and the production of TNF-alpha and IL-8. Insulin pretreatment delayed endotoxin mediated extracellular signal-regulated kinase 1/2, p38 and Jun kinase, the degradation of IkappaB, the activation of nuclear factor kappaB, and the production of TNF-alpha and IL-8. Insulin alone was associated with an increase in cytoplasmic SH2-containing inositol 5'-phosphatase (SHIP) but a decrease in lipid raft bound SHIP. The changes induced by insulin on SHIP and endotoxin mediated signaling were reversed by activin A blockade. CONCLUSIONS: Insulin results in regulation of macrophage activity in response to endotoxin through the release of activin A and subsequent production of SHIP. This increase in cytoplasmic SHIP results in attenuated endotoxin-mediated intracellular signaling and inflammatory mediator production. PMID- 17693933 TI - Stimulation of adenosine A2A receptor inhibits LPS-induced expression of intercellular adhesion molecule 1 and production of TNF-alpha in human peripheral blood mononuclear cells. AB - LPS stimulates CD14/Toll-like receptor (TLR) 4, leading to induce TNF-alpha production. Cell-to-cell interaction through the engagement between intercellular adhesion molecule (ICAM) 1 on monocytes and its ligand on T cells has been suggested to play a role in the TNF-alpha production by LPS-treated human peripheral blood mononuclear cells (PBMCs). Adenosine is reported to inhibit LPS induced TNF-alpha production. However, little is known about the mechanism of the inhibitory effects induced by adenosine on the LPS-induced immune responses. We found that adenosine inhibited the expression of ICAM-1 and the production of TNF alpha by human PBMC via adenosine A2A receptor in the presence of LPS. However, the stimulation of A1R or A3R enhanced the actions of adenosine. Adenosine had no effect on the expression of CD14 and TLR-4, suggesting that the inhibitory effects of adenosine on the LPS actions might be independent of the expression of CD14 and TLR-4. Thus, adenosine differentially regulates the expression of ICAM-1 and the production of TNF-alpha through plural subtypes of receptors. PMID- 17693934 TI - Prevention of injury-induced suppression of T-cell immunity by the CD1d/NKT cell specific ligand alpha-galactosylceramide. AB - Infection, sepsis, and multiple organ failure continue to be significant factors leading to morbidity and mortality after severe injury. Studies by our laboratory and others have identified injury-induced defects in both innate and adaptive components of host defense. We previously reported that CD1d-restricted natural killer T (NKT) cells actively suppress effector T-cell immunity after burn injury via production of excess IL-4 and failure to produce IFN-gamma. alpha Galactosylceramide (alpha-GalCer) is a synthetic NKT cell-specific ligand presented exclusively to invariant NKT cells and is known to improve immunity against tumors and infection by promoting IFN-gamma production. Here, we confirmed the role of Valpha14-Jalpha281 invariant NKT cells in mouse model of burn injury-induced suppression of T-cell immunity and further asked whether alpha-GalCer can improve immunity after injury via similar mechanisms. We observed that systemic treatment with alpha-GalCer prevented the injury-induced suppression of Ag-specific T-cell responsiveness both in vitro and in vivo and restored the ability of splenic lymphocytes to produce both IL-2 and IFN-gamma. Moreover, burn injury was associated with diminished expression of major histocompatibility complex II and CD40 on antigen presenting cells that were both restored by alpha-GalCer treatment to levels seen in sham-treated mice. Collectively, these data suggest that, via manipulation of the NKT cell population, we may be able to maintain T-cell function and improve host defense after burn injury. PMID- 17693935 TI - Recombinant bactericidal/permeability-increasing protein inhibits endotoxin induced high-mobility group box 1 protein gene expression in sepsis. AB - We investigated in vivo the effect of recombinant bactericidal/permeability increasing protein (rBPI21) on high-mobility group box 1 protein (HMGB1) expression in sepsis and its potential mechanism. Using a sepsis model induced by cecal ligation and puncture (CLP), rats were randomly divided into four groups as follows: normal control group, sham-operated group, CLP group, and BPI treatment group. Animals were killed at designated time points, and blood and tissue samples from liver, lungs, kidneys, and small intestine were harvested to determine related variables. In addition, we observed the effect of treatment with rBPI21 on survival rate in septic rats. The results showed that endotoxin content and expression levels of HMGB1 and LPS binding protein/CD14 mRNA in various organs were significantly increased at 12 and 24 h after CLP, which can be attenuated by treatment with rBPI21 (P<0.05-0.01). Meanwhile, treatment with rBPI21 in septic rats can markedly reduce serum alanine aminotransferase, creatinine levels, and pulmonary myeloperoxidase activity at 12 and 24 h after CLP, increase diamine oxidase activity at both time points (P<0.05-0.01), and improve the 1- to 10-day survival rates in animals subjected to CLP (P=0.012). These findings suggest that treatment with rBPI21 can significantly reduce endotoxin contents and expression levels of HMGB1 and LPS binding protein/CD14 mRNA in various organs in sepsis induced by CLP, and can protect against multiple organ damage resulting from sepsis. The effect of rBPI21 inhibiting HMGB1 gene expression in sepsis might be associated with endotoxin-dependent mechanisms. PMID- 17693937 TI - Protective role of heme oxygenase 1 in the intestinal tissue injury in hemorrhagic shock in rats. AB - Heme oxygenase (HO) 1 is inducible by a variety of oxidative stress and is thought to play an important role in the protection of tissues from oxidative injuries. Because hemorrhagic shock (HS) is an oxidative stress that results in tissue injury, we examined in this study the role of HO-1 induction in intestinal tissue injuries in a rat model of HS. The levels of HO-1 were significantly increased after HS both at transcriptional and protein levels in mucosal epithelial cells in the duodenum, jejunum, and colon, whereas their expression in the ileum was hardly detectable and not increased at all by the treatment. In contrast, HS-induced mucosal inflammation and apoptotic cell death in the duodenum, jejunum, and colon were far less than those observed in ileum as judged by the levels of expression of TNF-alpha, iNOS, activated caspase 3, and Bcl-2. Of note, inhibition of HO activity by tin-mesoporphyrin resulted in an aggravation of HS-induced tissue inflammation and apoptotic cell death. These findings indicate that HO-1 expression in the intestine is regulated in a highly site-specific manner after HS, and that HO-1 induction plays a fundamental role in protecting mucosal cells of the intestine from oxidative damages induced by HS. PMID- 17693938 TI - Gut luminal lactate measured by microdialysis mirrors permeability of the intestinal mucosa after ischemia. AB - The aim of the present study was to investigate the influence of a prolonged initial intestinal ischemic insult on transmucosal permeability after a subsequent ischemic event and whether microdialysis of biomarkers released to the gut lumen is able to reflect changes in intestinal permeability. The superior mesenteric artery was cross-clamped for 60 min followed by 4 h of reperfusion in 16 pigs. Nine pigs had a second cross-clamp of 60 min and 3 h of reperfusion, whereas seven pigs were observed for a further 4 h of reperfusion. Intestinal mucosal integrity was assessed by permeability of C-polyethylene glycol (PEG 4000) over the gut mucosa, luminal microdialysis of lactate, glucose and glycerol, and tonometry. During reperfusion, the PEG-4000 amount in venous blood was two times higher after the first than after the second ischemia (area under the curve, 44,780 [13,441-82,723] vs. 22,298 (12,213-49,698] counts min mL(-1), P=0.026 [mean {range}]). There was less lactate detected in the gut lumen after the second ischemia compared with the first (area under the curve, 797 [412 1,700] vs. 1,151 [880-1,969] mmol min L(-1), P=0.02) and a lower maximum concentration (4.8 [2.7-9.4] vs. 8.5 [5.0-14.9] mM, P=0.01). The same pattern was also seen for luminal glycerol and glucose. During the second ischemia, the intestinal mucosal/arterial CO2 gap was identical to the level during the first ischemic episode. A prolonged ischemic insult of the intestine confers protection, for reduced hyperpermeability against further ischemia. Microdialysis of biomarkers mirrors permeability changes associated with this type of protection. Lactate reflects permeability across the intestinal mucosa more precisely than glycerol. PMID- 17693939 TI - Hypovolemia does not affect speed of isovolumic left ventricular contraction and relaxation in excised canine heart. AB - Hypovolemia results in hypotension due to a decrease in left ventricular (LV) stroke volume. We have showed a logistic relaxation time constant (tauL) that is a superior lusitropic index during the LV pressure (LVP) falling phase independent of LV preload compared with the conventional monoexponential relaxation time constant (tauE). In the present study, we investigated the effect of decreasing LV preload on tauL and tauE during the LV contraction and other relaxation phases. The isovolumic LVP curve was analyzed at LV Volumes (LVVs) of 18, 14, and 10 mL during 2-Hz pacing in seven excised, cross-circulated canine hearts. TauL and tauE were evaluated using logistic and monoexponential analyses of the four phases of the cardiac cycle: the period from the onset to the maximum time derivative of LVP (LV dP/dtmax), from LV dP/dtmax to peak LVP, from peak LVP to the minimum time derivative of LVP (LV dP/dtmin), and from LV dP/dtmin to LV end-diastolic pressure. TauL and tauE during the four phases did not change significantly with the decrease in LVV. During the change in LVV, the logistic function always fit significantly better compared with the monoexponential function. In conclusion, hypovolemia does not affect the speed of isovolumic LV contraction and relaxation. Each phase of the LVP curve is of a logistic nature. TauL is as a useful index for estimation of the speed of alteration during each phase of cardiac systole and diastole. PMID- 17693940 TI - Activated protein C attenuates microvascular injury during systemic hypoxia. AB - In response to hypoxia, an inflammatory cascade is initiated and microvascular injury ensues. Specifically, within 10 min, leukocyte adherence to the endothelium begins, and leukocyte emigration and vascular leak soon follow. Activated protein C (APC) has been reported to have both anticoagulant and anti inflammatory properties. Activated protein C is best described in its role as a treatment for sepsis. However, it has been used, with some success, in experimental models of hypoxic injury. We hypothesized that APC would be protective against microvascular injury during systemic hypoxia. Randomized prospective animal study. Adult male Sprague-Dawley rats. To characterize the microvascular response to APC exposure during hypoxia, four rat groups were used: saline control, APC infusion alone (100 mg/kg bolus), hypoxia alone (10% O2), and simultaneous hypoxia + APC infusion. Measurements of leukocyte adherence (no. per 100-microm venule), leukocyte emigration (no. per 4,000 microm(2)), and venular leak by fluorescein isothiacyanate-labeled albumin (Fo/Fi) were performed during intravital microscopy of the intact venular bed. Leukocyte adherence decreased from 14.5 (+/-1.2) cells/100-microm venule in hypoxic rats to 4.4 (+/-1.5) cells/100-microm venule in those treated with both hypoxic gas and APC infusion (P < 0.001). Similarly, leukocyte emigration in hypoxic rats reached 12.3 (+/- 2.2) cells/4,000-microm(2) venule, but was reduced to 3.5 (+/-0.3) cells/4,000 microm(2) venule (P <.001). Venular permeability to protein was also significantly decreased in the APC-treated group from 0.82 (+/-0.14) to 0.25 (+/ 0.14) (P < 0.001). The infusion of APC attenuates the inflammatory response during systemic hypoxia at the microvascular level, as evidenced by measurements of leukocyte adherence, emigration, and venular permeability. Further investigation is needed to examine the potential role of APC in the treatment of hypoxic injury. PMID- 17693941 TI - Anesthetic preconditioning confers acute cardioprotection via up-regulation of manganese superoxide dismutase and preservation of mitochondrial respiratory enzyme activity. AB - The cellular and molecular mechanisms that underlie cardioprotection against I/R by anesthetic-induced preconditioning (APC) require further elucidation. Using isoflurane as a representative anesthetic, we evaluated the hypothesis that APC induces myocardial protection against I/R by attenuation of excessive reactive oxygen species and restoration of mitochondrial bioenergetics through postischemic up-regulation of manganese superoxide dismutase (MnSOD) expression and preservation of respiratory enzyme activity. Pentobarbital anesthetized open chest Sprague-Dawley rats were subject to 30-min left coronary artery occlusion, followed by 120-min reperfusion. Before ischemia, rats were randomly assigned to receive 0.9% saline, two cycles of brief coronary artery occlusion and reperfusion, or a 30-min exposure to 1.0 minimum alveolar concentration isoflurane in the absence or presence of a specific mitochondrial adenosine triphosphate-sensitive potassium (KATP) channel blocker, 5-hydroxydecanoate; a membrane-permeable superoxide scavenger, 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl; or a NOS inhibitor, N(G)-nitro-L-arginine methyl ester. Isoflurane exposure induced an initial increase in myocardial superoxide (O2-), but not NO level. It also significantly decreased infarct size and restored mitochondrial respiratory enzyme activity or ATP production in I/R rat hearts, along with suppression of the O2- surge at reperfusion and increase in MnSOD expression or enzyme activity. These protective effects were abrogated by 5-hydroxydecanoate or 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl, but not by N(G)-nitro-L-arginine methyl ester pretreatment. These results suggest that opening of mitochondrial KATP channel, followed by O2- signaling, induces postischemic augmentation of MnSOD and preservation of mitochondrial respiratory enzyme activities, leading to attenuated cardiac O2- surge and restored ATP production during reperfusion, and underlie APC-induced cardioprotection. PMID- 17693942 TI - Upper airway mucus deposition in lung tissue of burn trauma victims. AB - Previous study in an ovine model of smoke inhalation and burn (S + B) injury has shown distal migration of upper airway mucus. This study examines the localization of an upper airway gland specific mucus, mucin 5B (MUC5B) in lung autopsy tissues of burn-only injury and in victims of S + B injury. We hypothesize that victims with S + B injury would exhibit increased distal migration of MUC5B than that seen in victims of burn-only injury. Autopsy lung tissue from victims of burn injury alone (n = 38) and combined S + B injury (n = 22) were immunostained for MUC5B. No normal lung tissues were included in the study. Semiquantitative analysis of the extent of MUC5B in bronchioles and parenchyma was performed on masked slides. Irrespective of injury conditions, all victims showed MUC5B in bronchioles. Mucin 5B was seen in the parenchyma except in two burn victims. No statistically significant difference was seen in the mean bronchiolar and parenchyma MUC5B scores between S + B and burn-only victims (P > 0.05). No strong statistical correlation of MUC5B scores with days postinjury or to the number of ventilatory days was evident. The percentage of pneumonia, identified histologically, was also similar between study groups. This study did not confirm our results in an ovine model of S + B injury. In contrast, virtually all pediatric burn victims, regardless of concomitant inhalation injury, showed MUC5B in their bronchioles and parenchyma. Increased mucus synthesis and/or impaired mucociliary function may contribute to the pulmonary pathophysiology associated with burn injury. PMID- 17693943 TI - Endothelin B receptors preserve renal blood flow in a normotensive model of endotoxin-induced acute kidney dysfunction. AB - The aim was to investigate the role of endothelin 1 receptor subtypes in the early renal response to lipopolysaccharide (LPS) during normotensive endotoxemia with acute kidney dysfunction. Endotoxemia was induced in thiobutabarbital anesthetized rats (n = 9 per group) by infusion of LPS (dosage, 1 mg/kg per hour i.v.). The study groups (1) sham-saline, (2) LPS-saline, (3) LPS-BQ123, (4) LPS BQ788 and (5) LPS-BQ123 + BQ788 received isotonic saline, the ETA receptor antagonist BQ-123 (dosage, 30 nmol/kg per minute i.v.), and/or the ETB receptor antagonist BQ-788 (dosage, 30 nmol/kg per minute i.v.) before and during 2 h of LPS infusion. Renal clearance measurements, renal blood flow (RBF), and cortical and outer medullary perfusion (laser-Doppler flowmetry) and oxygen tension (Clark type microelectrodes) were analyzed throughout. Before LPS administration, there were no significant differences between groups in glomerular filtration rate (GFR), RBF, or in cortical (CLDF) and outer medullary perfusion. However, mean arterial pressure (MAP) was elevated in LPS-BQ788 group compared with LPS-BQ123 + BQ788 group (P < 0.05). In saline-treated rats, endotoxin induced an approximate 35% reduction in GFR (P < 0.05), without significant effects on MAP, RBF, or on CLDF and cortical PO2. In addition, LPS increased outer medullary perfusion and PO2 (P < 0.05). The fractional urinary excretion rates of sodium, potassium, and water were not significantly different in LPS-saline group compared with sham saline group. Neither selective nor combined ETA and ETB receptor blockade improved GFR. In BQ-788-infused rats, endotoxin produced marked reductions in RBF (-18% +/- 4% [P < 0.05]) and CLDF (-18% +/- 2% [P < 0.05]). Similarly, endotoxin decreased RBF (-14% +/- 3% [P < 0.05]) and CLDF (-10% +/- 2% [P < 0.05]) in LPS BQ123 + BQ788 group. Endotoxin reduced MAP (-22% +/- 4% [P < 0.05]) in BQ-123 treated rats but did not significantly influence MAP in other groups. We conclude that in early normotensive endotoxemia, ETB receptors exert a renal vasodilator influence and contribute to maintain normal RBF. PMID- 17693944 TI - Hydrophobicity of mucosal surface and its relationship to gut barrier function. AB - Loss of the gut barrier has been implicated in the pathogenesis of the multiple organ dysfunction syndrome, and, thus, understanding the intestinal barrier is of potential clinical importance. An important, but relatively neglected, component of the gut barrier is the unstirred mucus layer, which through its hydrophobic and other properties serves as an important barrier to bacterial and other factors within the gut lumen. Thus, the goal of this study was to establish a reproducible method of measuring mucosal hydrophobicity and test the hypothesis that conditions that decrease mucosal hydrophobicity are associated with increased gut permeability. Hydrophobicity was measured in various segments of normal gut by measuring the contact angle of an aqueous droplet placed on the mucosal surface using a commercial goniometer. Second, the effect of the mucolytic agent N-acetyl cysteine on mucosal hydrophobicity and gut permeability was measured, as was the effects of increasing periods of in vivo gut ischemia on these parameters. Gut ischemia was induced by superior mesenteric artery occlusion, and gut permeability was measured by the mucosal-to-serosal passage of fluoresceine isothiocyanate-dextran (4.3 kDa) (FD4) across the everted sacs of ileum. Intestinal mucosal hydrophobicity showed a gradual increase from the duodenum to the end of the ileum and remained at high level in the cecum, colon, and rectum. Both N-acetyl cysteine treatment and ischemia caused a dose-dependent decrease in mucosal hydrophobicity, which significantly correlated increased gut permeability. Mucosal hydrophobicity of the intestine can be reproducibly measured, and decreases in mucosal hydrophobicity closely correlate with increased gut permeability. These results suggest that mucosal hydrophobicity can be a reliable method of measuring the barrier function of the unstirred mucus layer and a useful parameter in evaluating the pathogenesis of gut barrier dysfunction. PMID- 17693945 TI - Muramyl dipeptide enhances the response to endotoxin to cause multiple organ injury in the anesthetized rat. AB - Nucleotide oligomerization domain (NOD) proteins recognize peptidoglycan fragments, resulting in up-regulation of transcription factors, and may enhance the inflammatory response to infection. Specifically, NOD2 has been shown to sense muramyl dipeptide (MDP), which is released during bacterial cell growth and replication. Activation of NOD2 by MDP enhances the inflammatory response caused by LPS (endotoxin). Here, we investigated the effects of MDP on the organ injury/dysfunction caused by systemic administration of a low dose of LPS. Male Wistar rats were coadministered with either MDP (1 - 10 mg kg(-1), i.v.) or vehicle (0.5 mL kg(-1) saline, i.v.), and a low dose of LPS (1 mg kg(-1), i.v.) or vehicle (1 mL kg(-1), saline, i.v.). MAP and heart rate were continuously monitored for 6 h. Markers of organ dysfunction/injury, plasma cytokine levels, and lung myeloperoxidase activity were measured 6 h after MDP and LPS coadministration. In a separate study, MDP (3 or 10 mg kg(-1), i.v.) or vehicle (0.5 mL kg(-1) saline, i.v.) was administered 24 h before LPS infusion. When compared with animals receiving low-dose LPS alone, coadministration of MDP (10 mg kg(-1), i.v.) and LPS, or administration of MDP (10 mg kg(-1), i.v.) 24 h before LPS resulted in a significant increase in the degree of organ injury, cytokine release, and lung injury caused by LPS alone. Thus, our results demonstrate that the two bacterial wall components MDP and LPS work in concert to cause multiple organ injury and systemic inflammation. We hope that our results stimulate other studies designed to evaluate the effects of NOD ligands in animal models of inflammation. PMID- 17693947 TI - The absence of circadian cues during recovery from sepsis modifies pituitary adrenocortical function and impairs survival. AB - Lighting and other environmental cues in the intensive care unit rarely adhere to a consistent daily pattern. To determine the influence of the daily light/dark (LD) cycle on recovery from sepsis, male Sprague Dawley rats were acclimated to lights-on condition at 6 AM and lights-off condition at 6 PM for 6 to 14 days. Catheter placement and cecal ligation and puncture (CLP) were performed under ketamine and xylazine. Rats were returned to the established LD cycle, to constant light (LL), or to constant dark (DD) at 6 PM. One-week survival was 83.33% during LD (n = 24), 62.5% during LL (n = 16), and 31.25% during DD (n = 16; P < 0.01 for difference from the LD group). Both plasma adrenocorticotropin (ACTH) and corticosterone levels in the morning of the first day after CLP were greater during DD than during LD (P < 0.05 in each case). The early elevation in ACTH was independent of survival. However, the greater frequency of nonsurviving DD rats accounted for the elevation of corticosterone in the DD group. Overall, most nonsurvivors had a unique response pattern composed of an early elevation of corticosterone in relation to plasma ACTH that then declined to a value above the normal circadian peak despite a late increase in endogenous ACTH when death was imminent. We conclude that the circadian cues provided by the LD cycle improve survival after CLP. Removal of these cues by DD increases the early appearance and incidence of a hormonal response pattern that is associated with a lethal outcome. PMID- 17693949 TI - Salicylanilide acetates: synthesis and antibacterial evaluation. AB - A new series of salicylanilide acetates was synthesized and evaluated for their in vitro antifungal and antituberculotic activity. Some of the evaluated compounds possessed comparable or better antifungal activity than a fluconazole standard. All these compounds exhibited very good potential and their in vitro activity against drug resistant and sensitive clinical isolates of Mycobacteria were found to be equivalent or better than a standard of isoniazide, a well-known first-line drug for tuberculosis treatment. PMID- 17693950 TI - Synthesis, characterization, and saccharide binding studies of bile acid porphyrin conjugates. AB - Synthesis and characterization of bile acid-porphyrin conjugates (BAPs) are reported. Binding of saccharides with BAPs in aqueous methanol was studied by monitoring changes in the visible absorption spectral of the porphyrin-moieties. Although these studies clearly showed absorbance changes, suggesting quite high if non-selective binding, the mass spectral studies do not unambiguously support these results. PMID- 17693951 TI - An efficient synthesis and reactions of novel indolylpyridazinone derivatives with expected biological activity. AB - Reaction of 4-anthracen-9-yl-4-oxo-but-2-enoic acid (1) with indole gave the corresponding butanoic acid 2. Cyclocondensation of 2 with hydrazine hydrate, phenyl hydrazine, semicarbazide and thiosemicarbazide gave the pyridazinone derivatives 3a-d. Reaction of 3a with POCl(3) for 30 min gave the chloropyridazine derivative 4a, which was used to prepare the corresponding carbohydrate hydrazone derivatives 5a-d. Reaction of chloropyridazine 4a with some aliphatic or aromatic amines and anthranilic acid gave 6a-f and 7, respectively. When the reaction of the pyridazinone derivative 3a with POCl(3) was carried out for 3 hr an unexpected product 4b was obtained. The structure of 4b was confirmed by its reaction with hydrazine hydrate to give hydrazopyridazine derivative 9, which reacted in turn with acetyl acetone to afford 10. Reaction of 4b with methylamine gave 11, which reacted with methyl iodide to give the trimethylammonium iodide derivative 12. The pyridazinone 3a also reacted with benzene- or 4-toluenesulphonyl chloride to give 13a-b and with aliphatic or aromatic aldehydes to give 14a-g. All proposed structures were supported by IR, (1)H-NMR, (13)C-NMR, and MS spectroscopic data. Some of the new products showed antibacterial activity. PMID- 17693952 TI - Microwave-assisted synthesis of substituted hexahydro-pyrrolo[3,2-c]quinolines. AB - New compounds with the ethyl hexahydro-1H-pyrrolo[3,2-c]quinoline-2-carboxylate skeleton were prepared by microwave-assisted intramolecular 1,3-dipolar cycloaddition reactions. The reactions were carried out under solvent-free conditions and compared with the same reaction in the presence of a solvent and a catalyst. Steric effects on the selectivity of the reaction were noted and evaluated. PMID- 17693953 TI - A convenient approach to heterocyclic building blocks: synthesis of novel ring systems containing a [5,6]Pyrano[2,3-c]pyrazol-4(1H)-one moiety. AB - Starting from commercially available educts, a straightforward synthetic route to new heterocyclic building blocks is exemplified with the one- or two-step synthesis of tri-, tetra-, or pentacyclic ring systems. Representatives of the following novel ring systems are prepared from 3-methyl-1-phenyl-2-pyrazolin-5 one and the corresponding o-halo-arenecarbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane: pyrimidino[4',5':5,6]pyrano[2,3-c]pyrazol-4(1H)-one, thieno[3',2':5,6]pyrano[2,3c]pyrazol- 4-(1H)-one, thieno[3',4':5,6]pyrano[2,3 c]pyrazol-4(1H)-one, thieno[3'',2'':4',5']thieno[2',3':5,6]-pyrano[2,3-c]pyrazol 4(1H)-one, [1,3]dioxolo[5',6'][1]benzothieno[2',3':5,6]pyrano-[2,3-c]- pyrazol 4(1H)-one, pyridazino[4',3':5,6]pyrano[2,3-c]pyrazol-4(1H)-one and pyrazolo [4'',3'':5',6']pyrido[3',4':5,6]pyrano[2,3-c]pyrazol-4(1H)-one. While the latter two ring systems are directly obtained due to a spontaneous intramolecular substitution reaction, in the other reactions uncyclised 4-aroylpyrazol-5-ols are produced, which are cyclised into the target heterocycles in a subsequent synthetic step (i.e. treatment with NaH in DMF). Detailed NMR spectroscopic investigations ((1)H-, (13)C-, (15)N-) with the obtained compounds were undertaken to unambiguously prove the new structures. PMID- 17693954 TI - Simple and regioselective bromination of 5,6-disubstituted-indan-1-ones with Br2 under acidic and basic conditions. AB - Bromination of 5,6-dimethoxyindan-1-one with Br(2) in acetic acid at room temperature produced exclusively the corresponding 2,4-dibromo compound in 95% yield. Reaction of 5,6-dimethoxyindan-1-one with Br(2) in the presence of KOH, K(2)CO(3) or Cs(2)CO(3 )at ~0 degrees C( )gave the monobrominated product 4-bromo 5,6-dimethoxyindan-3-one in 79%, 81% and 67% yield, respectively. 5,6 Dihydroxyindan-1-one was dibrominated on the aromatic ring affording 4,7-dibromo 5,6-dihydroxyindan-1-one both in acetic acid at room temperature and in the presence of KOH at ~0 degrees C. 5,6-Difluoroindan-1-one and 1-indanone were alpha-monobrominated in acetic acid and alpha,alpha-dibrominated under KOH conditions at room temperature. PMID- 17693955 TI - Inhibitory effects of 5,6,7-trihydroxyflavones on tyrosinase. AB - Baicalein (1), 6-hydroxyapigenin (6), 6-hydroxygalangin (13) and 6-hydroxy kaempferol (14), which are naturally occurring flavonoids from a set of 14 hydroxy-flavones tested, exhibited high inhibitory effects on tyrosinase with respect to L-DOPA, while each of the 5,6,7-trihydroxyflavones 1, 6, 13 or 14 acted as a cofactor to monophenolase. Moreover, 6-hydroxykaempferol (14) showed the highest activity and was a competitive inhibitor of tyrosinase compared to L DOPA. 5,6,7-Trihydroxyflavones 1, 6, 13 or 14 showed also high antioxidant activities. Hence, we conclude that the 5,6,7-trihydroxy-flavones are useful as good depigmentation agents with inhibitory effects in addition to their antioxidant properties. PMID- 17693956 TI - Antioxidant activity and total phenols in different extracts of four Staphylea L. Species. AB - Staphylea L. is a deciduous ornamental shrub that possesses significant cytotoxic and antibacterial activity, although the chemical composition of its extracts and the identity of the structures responsible for these biological activities are not yet known. In this study we have determined the total phenolic content in chloroform and ethyl acetate extracts of four Staphylea species: Staphylea colchica Stev., S. elegans Zab., S. holocarpa Hemsl. and S. pinnata L.. The antioxidant potential (DPPH radical and peroxynitrite scavenging activity) of these extracts was also determined and a correlation between the phenolic content and antioxidant activities of the ethyl acetate extracts has been found. Ethyl acetate extracts were more active and one of them, obtained from S. colchica Stev., possessed the highest activity. PMID- 17693957 TI - Synthesis and antimicrobial activity of some new 1,3,4-thiadiazole and 1,2,4 triazole compounds having a D,L-methionine moiety. AB - New 1,3,4-thiadiazole, 5a-e, and 1,2,4-triazolecompounds 6a-c, containing a D,L methionine moiety were synthesized by intramolecular cyclization of 1,4 disubstituted thiosemicarbazides 4a-e in acid and alkaline media, respectively. The potential antimicrobial effects of the synthesized compounds were investigated using the Staphylococcus aureus ATCC 25923, Bacillus antracis ATCC 8705, Bacillus cereus ATCC 10987, Sarcina lutea ATCC 9341 and Escherichia coli ATCC 25922 strains. The newly synthesized compounds exhibited promising activities against Bacillus antracis and Bacillus cereus. PMID- 17693958 TI - Synthesis of functionalised nucleosides for incorporation into nucleic acid-based serine protease mimics. AB - The synthesis of nucleosides modified with an extra imidazole, carboxyl and hydroxyl group is described. These nucleosides can be incorporated into an oligonucleotide duplex, thus generating a novel type of serine protease mimic. PMID- 17693959 TI - A new poly-substituted benzaldehyde from the leaves of Lysimachia fordiana Oliv. AB - A new poly-substituted benzaldehyde, 1, and a known compound quercetin (2) were isolated from the leaves of Lysimachia fordiana Oliv. The structure of compound 1, named fordianol, was determined as 2-heptyl-3,6-dihydroxy-4- methoxybenzaldehyde on the basis of spectroscopic methods. Fordianol did not inhibit the growth of SWO-38 (human brain neuroglioma), MCF-7 (human breast cancer) or HeLa (human cervical carcinoma) cell lines. PMID- 17693960 TI - Chrononutrition applied to formula milks to consolidate infants' sleep/wake cycle. AB - Some 30% of pre-weaning infants present problems of sleep during the night, especially those who are bottle-fed. The solution is for them to be breast-fed for as long as possible, or, if this is not possible, for the formula milk to reproduce breast-milk's natural circadian variations in the concentrations of tryptophan and those nucleotides which have a beneficial effect in consolidating the circadian sleep-wake cycle. OBJECTIVE: To study in pre-weaning infants the effect on nocturnal sleep of the administration of formula milk dissociated into its day/night components. MATERIALS AND METHODS: A prospective study was carried out on 30 pre-weaning infants of 4-20 weeks in age who preferentially showed sleep problems. The day dissociated formula, administered from 06:00-18:00, had lower levels of tryptophan and carbohydrates, and higher levels of proteins together with cytosine-5P, guanosine-5P, and inosine-5P. The night dissociated formula, administered from 18:00-06:00, had lower levels of proteins and medium chain triglycerides, higher levels of tryptophan and carbohydrates, together with adenosine-5P and uridine-5P. In a random, double-blind, design, three one-week diets were administered: Diet A (Control): normal initiation milk; Diet B: 06:00 18:00 normal initiation milk, 18:00-06:00 dissociated night formula; and Diet C: day/night formulas with the schedule given above. The sleep patterns were analyzed by means of actimeters (Actiwatch). Statistical analysis consisted of an ANOVA with a Scheffe F-test, taking a value of p<0.05 to be statistically significant. RESULTS: The children receiving the week of Diet C (with the day/night formulas in synchrony with the environment) showed increased hours of actual sleep (7.68 +/- 0.54 h vs. 6.77 +/- 0.12 h for the Diet A control) and improved sleep latency (0.44 +/- 0.04 h vs. 0.60 +/- 0.08 h for the Diet A control). The same children receiving the Diet B in another different week showed an improvement in sleep efficiency (76.43 +/- 3.4% vs. the Diet A control 69.86 +/- 0.94%) and sleep latency (0.45 +/- 0.04 h vs. the Diet A control 0.60 +/- 0.08h) The parents also reported, in response to follow-up questions, an improvement in the sleep of their infants during the Diet C week. CONCLUSION: Day/night infant formula milks designed according to the principles of chrononutrition help to consolidate the sleep/wake rhythm in bottle-fed infants. PMID- 17693961 TI - Altered circadian rhythms of corticosterone, melatonin, and phagocytic activity in response to stress in rats. AB - Corticosterone is thought to be the main glucocorticoid secreted in response to stressful exercise, while melatonin buffers the adverse immunological effects of stress. The present work was aimed to evaluate whether swimming-exercise-induced stress leads to changes in the chronobiology parameters of the circadian rhythms of melatonin and corticosterone, and in the number and phagocytosis of peritoneal macrophages in 3-month-old male Wistar rats. The animals were subjected to a physical activity trial consisting of 2 h of free swimming. Radioimmunoassay was used to determine the plasma levels of melatonin and corticosterone. Phagocytosis was measured by the latex-bead phagocytosis index (PI), i.e., the number of latex beads ingested by 100 macrophages, the phagocytosis percentage (PP), i.e., the percentage of cells that had phagocytosed at least one latex bead, and the phagocytosis efficiency (PE), i.e., the ratio PI: PP which indicates how effectively the phagocytes ingested the particles. Stress significantly decreased the MESOR and amplitude of the melatonin rhythm, and significantly increased the MESOR of the corticosterone rhythm. The control animals' peritoneal macrophage number and PI showed a circadian rhythm with maxima at 02:00 and 03:00, respectively. The stressed group displayed higher values of PI than the controls at most hours of the night, but the number of cells in the peritoneal cavity was practically the same at all hours studied. These data confirm that melatonin and corticosterone act as modulators of the innate immune response, and that the circadian rhythm of the two hormones are altered in situations of stress. PMID- 17693962 TI - Effect of carbimazole induced hypothyroidism and thyroxine replacement on the growth of the long bones in albino rats of different age groups. AB - To evaluate the effect of carbimazole induced hypothyroidism and thyroxine replacement, on the growth of long bones of albino rats of different age groups. Experimental albino rats were developed with carbimazole and carbimazole plus thyroxine for a period of six weeks. At the end of the experiment the animals were sacrificed, fixed and processed to demonstrate the bony and cartilaginous parts. The ulna and tibia of both sides were measured for intact bone length & diameter and the data compared. The reduction in length and circumference observed, at the end of experiment, in ulna was 10.89%, & 11.94% and in tibia it was 12.52%, 14.81% in carbimazole treated group respectively, while in carbimazole plus thyroxin treated group the reduction in length & circumference of ulna was 1.37% & 1.88% and in tibia it was 1.86% & 3.08% respectively. They were compared to their age matched controls. The reduction in length and circumference in ulna was 5.58% & 6.25% and 6.42% and 5.88% in tibia respectively among the carbimazole treated animals while in the carbimazole plus thyroxine treated animals the reduction was only 0.63% and 3.12% in ulna and 0.91% and 1.06% in tibia respectively. The results show that hypothyroidism and its replacement therapy affects the endochondral as well as periosteal bone growth and results in reduction in length as well as circumference of long bones. PMID- 17693963 TI - Homocysteine, folic acid and vitamin B12 concentration in patients with recurrent miscarriages. AB - OBJECTIVES: The aim of the project was the assessment of clinical usefulness of the determination of blood serum homocysteine concentration, folic acid and vitamin B12 in recurrent miscarriages. METHODS: 30 non-pregnant women with recurrent miscarriages (examined group-I) and for 20 non-pregnant women without obstetric failures in medical history (control group-II) were examined. RESULTS: In the examined group (group I), the average concentration of homocysteine (9,45 micromol/l) was not statistically higher in comparison to the control group (group II) (8,47 micromol/l) (p>0,05). In group I the average vitamin B12 concentration in blood serum was 178,3 pg/ml and it was statistically lower (p<0,001) in comparison with the control group (II) (268,6 pg/ml). Such a relation was not observed for the vitamin B12, where the average concentration of this parameter was not dependent on the miscarriage number. A high negative correlation (R= -0,5397, p<0,01) was observed between the level of folic acid and homocysteine concentration in the group of women with recurrent miscarriages and a very high negative correlation (r = -0,9586 p<0,001) in the control group. No relation (R=0,0992 p>0,05) between the average concentration of vitamin B12 in blood serum and the average homocysteine in the nullipara group with recurrent miscarriages CONCLUSIONS: Together with the increasing number of abortions, the average homocysteine concentrations grew and the average folic acid concentrations lowered. PMID- 17693964 TI - Prolactin as a factor for increased platelet aggregation. AB - Administration of antipsychotics appears to be related to increased risk of venous thromboembolism and cerebrovascular side effects. The biological mechanism responsible for this possible adverse drug reaction is unknown, but there is a growing number of elucidating hypotheses. Treatment with antipsychotics is associated with elevation of prolactin level. Prolactin has recently been recognized as potent platelet aggregation co-activator, and have therefore been postulated as an additional risk factor for both arterial and venous thrombosis. We briefly review the arguments for the role of hyperprolactinemia in pathogenesis of platelet aggregation. PMID- 17693965 TI - Single base substitution in growth hormone receptor gene influences the receptor density in bovine liver. AB - OBJECTIVES: Nucleotide sequence polymorphisms in the coding gene regions may influence the biological properties of proteins encoded by a gene. The A/T substitution in exon 8 of the growth hormone receptor (GHR) gene results in changed amino acid sequence 279 (Phe/Tyr) in the transmembrane domain of the receptor protein and therefore could influence its functional parameters. We searched for the relationship between the A/T nucleotide polymorphism in the GHR gene the receptor binding capacity and dissociation constant. METHODS: Nucleotide sequence variations in the exon 8 (coding for the transmembrane domain of the receptor) of the bovine GHR gene and in fragments of adjacent introns were analysed using PCR-SSCP and sequencing techniques. GH receptor binding capacity (Bmax) and dissociation constant (Kd) for GHR were determined by the Scatchard analysis in livers of ten bulls carrying the AA or AT GHR genotypes. RESULTS: Two single nucleotide polymorphisms (SNPs) were identified--the C/T transition in intron 8 at position 863+32 and the A/T transversion in exon 8 at position 836, the latter resulting in Phe/Tyr amino acid substitution in the receptor protein. The results showed significant differences in the GHR binding capacity between these genotypes. Bmax was significantly greater (p< or =0.01) in bulls carrying TT genotype of GHR in comparison to those with the AT genotype. No significant differences in the dissociation constants (Kd) were found. CONCLUSION: Our results demonstrated that single base substitution in the transmembrane domain encoding region of GH receptor gene may influence the physiological properties of the receptor. PMID- 17693966 TI - Circulating leptin levels are not influenced by thyroid status in hypothyroid and euthyroid women. AB - OBJECTIVES: Leptin regulates body weight by suppressing food intake and increasing energy expenditure. Alterations in thyroid hormone levels are also associated with changes in body weight but the effect of thyroid hormone deficiency on serum leptin in humans is unclear. DESIGN AND METHODS: The aim of this study was to measure leptin levels and to investigate their associations with thyroid hormones in 22 women with severe hypothyroidism after total thyroidectomy, and in a group of 22 healthy euthyroid control female subjects matched for age and body mass index (BMI). Their plasma leptin, free thyroxine, triiodothyronine and TSH were measured. RESULTS: Leptin levels in subjects and controls were (pg/mL) 18761.64+/-16973.96 and 18729.19+/-18014.05, respectively, p=0.9; leptin did not correlate with free thyroxine, triiodothyroinine and TSH: r=0.1039 and p=0.6453, r=0.0113 and p=0.9602, and r=-0.0525 and p=0.8165 for leptin and FT4, leptin and FT3, and leptin and TSH, respectively in subjects; r= 0.00056 and p=0.9980, r=0.248727 and p=0.2643, and r=-0.046919 and p=0.8357 for leptin and FT4, leptin and FT3, and leptin and TSH, respectively in controls. Leptin levels did not differ between subjects and controls and they did not correlate with thyroid hormones. CONCLUSIONS: Leptin levels are not influenced by hypothyroidism and do not correlate with thyroid hormones in euthyroid and hypothyroid women. PMID- 17693967 TI - Homocysteine serum concentration and uterine artery color Doppler examination in cases of recurrent miscarriages with unexplained etiology. AB - OBJECTIVES: To study the assessment of diagnostic value and clinical usefulness of the determination of homocysteine concentration in blood serum in cases of recurrent miscarriages and the relation between the concentration of homocysteine in blood serum and parameter values determining the Doppler blood flow in the uterine arteries. METHODS: Homocysteine concentration in blood serum was determined in a group of 30 women with at least two subsequent miscarriages with no clear reason and in the control group consisted of 20 non-pregnant women without a medical history of obstetric failures, having at least one healthy child. In all cases Color Doppler sonography was performed to determine flow velocity waveforms of the uterine arteries in luteal phase of the menstrual cycle. RESULTS: Both pulsatility (PI) and resistance indices (RI) were considerably higher (p<0.01, p<0.05) for the group of women with recurrent abortions. In the group of women with obstetrical failures high positive correlation (R=0.6903, p<0.001) and in the control group very high positive correlation (r=0.8163, p<0.001) was found, between average values of PI and average HC concentration. High positive correlation (R=0.6260, p<0.001) in the examined group and very high positive correlation (r=0.9201, p<0.001) in the control group was obtained between average values of RI, and average HC concentrations in blood serum . CONCLUSIONS: The recurring miscarriages occur in connection with the elevated homocysteine concentration, in consequence they can point out the pathology within the uterine-fetal blood vessels. PMID- 17693968 TI - Selected auxological aspects of anorexia nervosa--relations of body weight to body height and menstrual cycle. AB - Specific aspects of therapy of eating disorders in pubescent and adolescent girls are related to unfinished biological development in time of severe malnutrition. Namely the issues of 1) exact determination of recommended body weight (target weight, weight for discharge etc.) on the basis of the exact analysis of the weight history, 2) relation between body weight and menstrual cycle (menarche, amenorrhoea and remenorrhoea) and 3) risk of non-realization of the genetic growth potential (status of linear growth and skeletal maturity) are discussed in this article. The article brings the results of the data analysis of 90 inpatients with anorexia nervosa and the tables of the recommended target weight for adolescents with finished linear growth. The authors emphasize the importance of an exact analysis of growth and weight history and of reflection of biological age in girls with eating disorders for successful and reasonable realimentation therapy. PMID- 17693969 TI - Detection of genomic imbalances by comparative genomic hybridization in Chinese fetuses with malformations. AB - AIM: The purpose of the study was to evaluate the feasibility and reliability of comparative genomic hybridization (CGH) in the detection of genomic imbalances in Chinese malformed fetuses. METHODS: Genomic DNA was extracted from umbilical cord blood or fresh amniotic fluid of 9 malformed fetuses and labeled with SpectrumGreen dUTP or SpectrumRed dUTP. A pair of CGH analyses in which the fluorochromes were exchanged was carried out for each sample. RESULTS: Samples from 9 malformed fetuses were analyzed successfully by CGH. Numerical chromosome aberrations were detected in samples from cases 4, 8 and 9, and were verified by fluorochrome-exchanged CGH. Trisomy 21q was detected in case 4, del 2p24-pter and dup 12p13 was detected in case 8, and del 1p33-pter and del 22q11-12 were detected in case 9. CONCLUSION: CGH is a reliable technique for the detection of genomic imbalances. Fluorochrome-exchanged CGH can reduce inconsistencies in the results caused by deviations in the process of DNA labeling and hybridization, and increase the accuracy and reliability in cases when conventional cytogenetic analysis is unavailable. PMID- 17693970 TI - Circadian rhythm of salivary serotonin in patients with major depressive disorder. AB - OBJECTIVES: The present study aimed to explore the circadian rhythm of salivary serotonin in patients with major depressive disorder before and after treatment with fluoxetine and its relationship with clinical therapeutic effect. METHODS: This study investigated salivary serotonin in 13 outpatients with major depressive disorder and age- and sex-matched healthy controls. Depressed patients received six weeks fluoxetine treatment (20 mg/day), saliva was collected before and four weeks after treatment. A total of 8 time-point salivary serotonin was measured across the whole day. Multi-oscillator cosinor model was used to fit the rhythms. RESULTS: Serotonin concentration in saliva ranged from 0.32 ng/ml to 9.62 ng/ml. Salivary serotonin showed prominent circadian rhythm in 91% depressed patients and 92% healthy subjects. Circadian amplitude tend to be higher after fluoxetine treatment in depressed patients, so as the ultradian cycle amplitude. The serotonin circadian amplitude (After minus Before) was positively correlated with the decrease of Zung Self-Rating Depression Scale(SDS) scores at day 42 whereas there was no such correlation at day 28. There was no significant difference in the parameters of mesor, acrophase, harmonic and area under curve among three groups. CONCLUSIONS: Salivary serotonin in patients with major depressive disorder showed clear circadian rhythm. The relationship between the increase of salivary serotonin amplitude and clinical response deserve further study. PMID- 17693971 TI - Sex differences in the relationship between cortisol levels and the Empathy and Systemizing Quotients in humans. AB - OBJECTIVE: Little is known regarding the relationship between cortisol (a stress hormone) levels and psychological cognitive styles. Baron-Cohen proposed two fundamental cognitive styles, which are measured by the Empathy Quotient (EQ) and the Systemizng Quotient (SQ). Previous studies have examined the influences of prenatal testosterone exposure on EQ and SQ scores. This study aimed to examine the relationships between morning cortisol levels and EQ and SQ scores, and the 'brain types' which were determined by two quotients in both sexes. These relationships are potentially important in the developmental psychopathology of autism and neuroeconomics of empathy. METHODS: We assessed morning cortisol levels with LC/MS (liquid chromatography-mass spectrometry) and ESQ in healthy male and female university students. CONCLUSIONS: Results indicate clear sex differences between brain types: i.e. E-type males and S-type females (participants with atypical cognitive styles) have significantly higher cortisol levels than S-type males and E-type females (participants with typical cognitive styles). Implications for the role of sex in social adaptation of autistic patients are discussed. PMID- 17693972 TI - Endoscopic transsphenoidal treatment of hormonally active pituitary adenomas. AB - AIM OF THE STUDY: The paper presents endoscopic surgical technique used in the treatment of hormonally active pituitary adenomas and assessment of the method in terms of its effectiveness and safety. MATERIAL AND METHODS: In 217 cases the surgery was performed due to pituitary adenomas applying the technique developed by Jho and Carrau, with our own modifications. 70 patients were treated for hormonally active adenomas. The group consisted of 36 somatotrophic adenomas, 21 prolactinomas and 13 corticotrophic adenomas. There were 51 females and 19 males with mean age of 42.6 years (range 11-77 years). The follow-up period was between 7 and 56 months (mean - 34 months). The effectiveness and occurrence of complications were confirmed on the basis of neurosurgical, laryngological, endocrinological, ophthalmological examinations and neuroimaging. RESULTS: Biochemical and neurosurgical criteria for complete resection were obtained in 21 (58.3%) of 36 patients with all somatotrophic adenomas. In the group of prolactinomas complete resection was achieved in 17 (80.9%) of 21 patients. Of the 13 patients with Cushing's disease 11 (84.6%) were cured. In the studied group there were no deaths. In the postoperative course only 2 (2.8%) patients suffered liquorrhoeas and new anterior lobe pituitary insufficiency was noted in 8 (11.4%) cases. Meningitis was noted in 1 (1.4%) case and another 1 (1.4%) patient had epistaxis which required repeated endoscopic surgery. CONCLUSIONS: Endoscopic technique is an effective method of treatment of hormonally active pituitary adenomas. It is characterised as being minimal invasive and has a low severe complication rate. PMID- 17693973 TI - Relation of C-reactive protein to obesity, adipose tissue hormones and cardiovascular risk factors in men treated with early percutaneous intervention in course of acute myocardial infarction. AB - Adipose tissue appears to be a key regulator of CRP levels. C-reactive protein (CRP), a marker of systemic inflammation, predicts the occurrence of diabetes, the metabolic syndrome and atherosclerotic diseases. Adipokines, the proteins produced by adipocytes are additional factors thought to be involved in the chronic, subclinical inflammatory state of adiposity. AIM: The aim of the study was to assess the impact of obesity on the blood CRP levels and the relation of CRP to coronary risk factors and adipokines in men with acute myocardial infarction (AMI). METHODS: The study was performed in 37 obese (BMI> or =30) and 33 lean patients (BMI<25) with first AMI treated with percutaneous coronary intervention within the initial 6 hours of AMI. Clinical data, anthropometric measurements, biochemical parameters and blood adipokines concentration were analyzed. RESULTS: Values of the following parameters were significantly higher in obese than in lean patients: CRP, fasting glucose, glucose at admission, leptin and resistin, whereas HDL-cholesterol and adiponectin levels were lower. In univariate regression analysis CRP was related to obesity, HDL-cholesterol, fasting glucose, glucose at admission and adipokines but only glucose at admission and resistin were the independent positive factors and adiponectin an independent negative factor associated with CRP levels (R2= 51.1%). CONCLUSIONS: In the early stage of AMI inflammation is more pronounced in obese than in lean patients. The pleiotropic association between CRP and obesity, adipokines and cardiovascular risk factors might prove it to be an important link between inflammatory reaction and atherogenesis in which adipose tissue hormones are involved. PMID- 17693974 TI - Impact of anorexia nervosa on activation characteristics of lymphocytes. AB - OBJECTIVES: Anorexia nervosa (AN), a disease of chronic human starvation has a deep impact on the function of several organ systems. We hypothesized that disturbed cellular activation may contribute to complications in AN. We tested our assumption on short-term activation kinetics of lymphocytes. PATIENTS AND METHODS: Blood was taken from 11 AN and 10 healthy adolescents. Peripheral blood mononuclear cells were isolated and CD4+ lymphocytes were then activated with phythohemagglutinin for the determination of calcium-influx and membrane potential. Moreover, cells were also activated by anti-CD3/anti-CD28 coated beads and three days after the prevalence of interleukin-2 positive CD4+ cells were determined. RESULTS: After activation, more time was required to reach maximal calcium content in CD4+ cells of AN patients than in those of controls (control vs. AN (median, range): 86 [45-232] vs. 215 [59-235] second, p<0.05), but the rate of membrane potential alteration was similar. The number of interleukin 2 positive CD4+ cells was lower in AN (11.50 [7.60-15.30] vs. 13.50 [12.00-22.00] %, p<0.05). No association was detected between cell activation and any of clinical or anthropometric data of AN patients. CONCLUSIONS: These results suggest that AN may have an impact on calcium handling of the cells and, hence, cell activation characteristics. We assume that altered calcium flux kinetics may contribute to complications present in AN. PMID- 17693975 TI - A comparative study of plasma renin activity, aldosterone and atrial natriuretic hormone between normotensive and hypertensive people living at below sea level altitude (Jordan Valley) and those residing at moderate altitude above. AB - A cross-sectional study was designed to investigate the association of the levels of plasma renin activity (PRA) and aldosterone (ALDO) and atrial natriuretic hormone (ANH) with the rates of hypertension prevalence in people living at 340 meters below sea level, the Jordan Valley (JV) and those residing at 620 meters above sea level, Irbid City. 1072 natives from the JV and 1402 natives from Irbid City were covered by a questionnaire to estimate hypertension prevalence in the JV and Irbid city (population age: 35-65 years). Male subjects were selected from the JV (24 hypertensives, 46+/-15 years old, and 93 normotensives, 33+/-13 years old) and from Irbid City (31 hypertensives, 47+/-12 years old, and 89 normotensives, 40+/-13 years old) to evaluate the levels of PRA, ALDO and ANH. Hypertension was less common in the JV than in Irbid City (9.9% vs. 13.6%). The levels of PRA in the hypertensive subjects compared to the normotensive subjects were lower in the JV (1.7+/-1.0 vs. 2.6+/-1.4 ng/ml/hr) but were similar in Irbid City (2.9+/-2.7 vs. 3.2+/-2.7). The levels of ALDO in the hypertensive subjects compared to the normotensive subjects were similar in the JV (119+/-58 vs. 139+/ 66 pg/ml) but were higher in Irbid City (199+/-112 vs. 146+/-84). The levels of ANH in the hypertensive subjects compared to the normotensive subjects were lower in the JV (13.9+/-9.3 vs. 28.0+/-12.7 ng/ml) and were also lower in Irbid City (21.0+/-12.2 vs. 26.7+/-11.6). PMID- 17693976 TI - Effect of early estrogen replacement therapy on microvascular reactivity in patients after bilateral ovarectomy. AB - OBJECTIVES: The aim of the study was to evaluate skin microvascular reactivity (MVR) measured by laser Doppler flowmetry in women early after bilateral ovarectomy treated with oral and transdermal estrogen replacement therapy (ERT). DESIGN: Interventional, randomized study with a cross-over design. PATIENTS AND METHODS: 41 patients (49+/-6 years, 6-12 weeks after surgical castration) were treated with 17-beta-estradiol transdermally (0.05 mg/day) or orally (2 mg/day) for three months and 20 healthy female subjects (47+/-5 years) served as controls. RESULTS: Records of laser Doppler flowmetry were blinded prior to the evaluation. Maximal perfusion and velocity of perfusion increase during post occlusive reactive hyperemia (PORH) were lower before ERT comparing to controls at baseline (36+/-16 vs. 48+/-18 PU, p<0.05, and 2.8+/-1.9 vs. 4.2+/-2.3 PU, p<0.05, respectively). Velocity of perfusion increase in PORH decreased after oral ERT compared to baseline and also to transdermal ERT (2.1+/-1.2 vs. 2.8+/ 1.9 PU.s-1, p<0.05, and vs. 3.5+/-3.2 PU.s-1, p<0.01, respectively), nonsignificant increase of this parameter after transdermal ERT led to normalization when comparing to control group (3.6+/-3.2 vs. 4.2+/-2.3 PU.s-1, NS). Increase of HDL-cholesterol and decrease of LDL-cholesterol (2.1+/-0.4 vs. 1.8+/-0.4 mmol.l-1, p<0.01, and 2.5+/-0.7 vs. 3.1+/-1.0 mmol.l-1, p<0.01) was observed after oral ERT while HDL-cholesterol increase after transdermal ERT was less pronounced (1.96+/-0.42 mmol.l-1, p<0.05). LDL-cholesterol levels did not change. A correlation between HDL-cholesterol and maximal post-occlusive flow expressed in % of basal perfusion was observed in patients before treatment (r=0.47, p=0.002). CONCLUSIONS: Microvascular reactivity is impaired in women early after bilateral ovarectomy. No statistically significant improvement of MVR was observed after oral estrogen replacement therapy, normalization of MVR after transdermal ERT was only partial. Changes of MVR and lipid profile differed between oral and transdermal routes of estrogen replacement therapy. PMID- 17693977 TI - Decreased expression of CD69 in chronic fatigue syndrome in relation to inflammatory markers: evidence for a severe disorder in the early activation of T lymphocytes and natural killer cells. AB - There is some evidence that patients with chronic fatigue syndrome (CFS) suffer from immune abnormalities, such as immune activation and decreased immune cell responsivity upon polyclonal stimili. This study was designed to evaluate lymphocyte activation in CFS by using a CD69 expression assay. CD69 acts as a costimulatory molecule for T- and natural killer (NK) cell activation. We collected whole blood from CFS patients, who met CDC criteria, and healthy volunteers. The blood samples were stimulated with mitogens during 18 h and the levels of activated T and NK cells expressing CD69 were measured on a Coulter Epics flow cytometer using a three color immunofluorescence staining protocol. The expression of the CD69 activation marker on T cells (CD3+, CD3+CD4+, and CD3+CD8+) and on NK cells (CD45+CD56+) was significantly lower in CFS patients than in healthy subjects. These differences were significant to the extent that a significant diagnostic performance was obtained, i.e. the area under the ROC curve was around 89%. No differences either in the number of leukocytes or in the number or percentage of lymphocytes, i.e. CD3, CD4, CD8 and CD19, could be found between CFS patients and the controls. Patients with CFS show defects in T- and NK cell activation. Since induction of CD69 surface expression is dependent on the activation of the protein kinase C (PKC) activation pathway, it is suggested that in CFS there is a disorder in the early activation of the immune system involving PKC. PMID- 17693978 TI - Not in the mind but in the cell: increased production of cyclo-oxygenase-2 and inducible NO synthase in chronic fatigue syndrome. AB - Chronic fatigue syndrome (CFS) is a medically unexplained disorder, characterized by profound fatigue, infectious, rheumatological and neuropsychiatric symptoms. There is, however, some evidence that CFS is accompanied by signs of increased oxidative stress and inflammation in the peripheral blood. This paper examines the role of the inducible enzymes cyclo-oxygenase (COX-2) and inducible NO synthase (iNOS) in the pathophysiology of CFS. Toward this end we examined the production of COX-2 and iNOS by peripheral blood lymphocytes (PBMC) in 18 CFS patients and 18 normal volunteers and examined the relationships between those inflammatory markers and the severity of illness as measured by means of the FibroFatigue scale and the production of the transcription factor nuclear factor kappa beta (NFkappabeta). We found that the production of COX-2 and iNOS was significantly higher in CFS patients than in normal controls. There were significant and positive intercorrelations between COX-2, iNOS and NFkappabeta and between COX-2 and iNOS, on the one hand, and the severity of illness, on the other. The production of COX-2 and iNOS by PBMCs was significantly related to aches and pain, muscular tension, fatigue, concentration difficulties, failing memory, sadness and a subjective experience of infection. The results suggest that a) an intracellular inflammatory response in the white blood cells plays an important role in the pathophysiology of CFS; b) the inflammatory response in CFS is driven by the transcription factor NFkappabeta; c) symptoms, such as fatigue, pain, cognitive defects and the subjective feeling of infection, indicates the presence of a genuine inflammatory response in CFS patients; and d) CFS patients may be treated with substances that inhibit the production of COX-2 and iNOS. PMID- 17693979 TI - Not in the mind of neurasthenic lazybones but in the cell nucleus: patients with chronic fatigue syndrome have increased production of nuclear factor kappa beta. AB - There is now some evidence that chronic fatigue syndrome is accompanied by an activation of the inflammatory response system and by increased oxidative and nitrosative stress. Nuclear factor kappa beta (NFkappabeta) is the major upstream, intracellular mechanism which regulates inflammatory and oxidative stress mediators. In order to examine the role of NFkappabeta in the pathophysiology of CFS, this study examines the production of NFkappabeta p50 in unstimulated, 10 ng/mL TNF-alpha (tumor necrosis factor alpha) and 50 ng/mL PMA (phorbolmyristate acetate) stimulated peripheral blood lymphocytes of 18 unmedicated patients with CFS and 18 age-sex matched controls. The unstimulated (F=19.4, df=1/34, p=0.0002), TNF-alpha-(F=14.0, df=1/34, p=0.0009) and PMA (F=7.9, df=1/34, p=0.008) stimulated production of NFkappabeta were significantly higher in CFS patients than in controls. There were significant and positive correlations between the production of NFkappabeta and the severity of illness as measured with the FibroFatigue scale and with symptoms, such as aches and pain, muscular tension, fatigue, irritability, sadness, and the subjective feeling of infection. The results show that an intracellular inflammatory response in the white blood cells plays an important role in the pathophysiology of CFS and that previous findings on increased oxidative stress and inflammation in CFS may be attributed to an increased production of NFkappabeta. The results suggest that the symptoms of CFS, such as fatigue, muscular tension, depressive symptoms and the feeling of infection reflect a genuine inflammatory response in those patients. It is suggested that CFS patients should be treated with antioxidants, which inhibit the production of NFkappabeta, such as curcumin, N-Acetyl-Cysteine, quercitin, silimarin, lipoic acid and omega-3 fatty acids. PMID- 17693980 TI - Significance of increased lipid peroxidation in critically ill patients. AB - OBJECTIVES: Increased oxidative stress and low-T3 syndrome may develop in critically ill patients. The study aimed at evaluating the level of lipid peroxidation (LPO) in critically ill patients and at estimating the relationships among LPO level, the death rate, the rate of low-T3 syndrome and patient's clinical status. METHODS: Lipid peroxidation (LPO) level was studied in seventy (70) adult, critically ill patients and 48 healthy volunteers. Critically ill patients were classified into survivors and non-survivors, or those with and without the low-T3 syndrome (normal-T3). RESULTS: LPO level was four times higher in critically ill patients than in healthy volunteers. Among non-survivors, LPO level was higher in patients with the low-T3 syndrome than in patients without this syndrome, and among survivors, the tendency was opposite. Additionally, the extent, to which LPO level increased, depended on the kind of the disease. The degree of LPO variability was higher in survivors than in non-survivors. LPO level was lower in patients with higher number of therapeutic interventions. CONCLUSION: A tremendous increase in oxidative damage to lipids in critically ill patients strongly depends on the kind of pathological process and, under certain conditions, higher LPO levels could be due to more favourable outcome. PMID- 17693981 TI - The effects of odor on cortisol and testosterone in healthy adults. AB - OBJECTIVES: This study aimed to verify the influence of odor on the endocrine system (Cortisol, Testosterone). MATERIAL AND METHODS: Three odors (Musk, Rose and Floral) and air were given to 16 healthy volunteers (8 males, 8 females), and cortisol (C) and testosterone (T) levels were measured before and after stimulation. RESULTS: Each odor decreased levels of C, indicating that odor can attenuate stress. In males, T decreased with Musk, but increased with Floral. In females, T significantly increased with Musk, but decreased with Rose and Floral. CONCLUSIONS: These results indicate that influences on hormone levels depend on the type of odor, and sex differences exist in response to odors. PMID- 17693982 TI - Occurrence of lead in placenta--important information for prenatal and postnatal development of child. AB - This work points out consequences of lead on prenatal and postnatal development of child that have not been elaborated in such extent before. Our new method for proof of lead in placenta enabled us to show how lead is from mother's blood erythrocytes in the intervillous space released and received by the villous syncytiotrophoblast. This finding enriches relation between mother's erythrocytes, lead, calcium that is a lead carrier, and syncytiotrophoblast. Our finding of abundant thin terminal villi, that in some places form bunches observed in scanning electron microscope, points out deficiency of O2 and CO2 transport in placenta. This phenomenon is indirect evidence that periphery "starves" for oxygen that participates in maintaining conditions for intact development of child. Behaviour of fibrin deposit layer before the childbirth is also discussed. Attention is paid to possible rise of hyperkinetic syndrome of children as a consequence of mother's dwelling in environment polluted with lead. Presence of lead is verified by infrared spectroscopy. PMID- 17693983 TI - Central serotonergic hypofunction in autism: results of the 5-hydroxy-tryptophan challenge test. AB - Some studies have suggested that disorders in the central serotonergic function may play a role in the pathophysiology of autistic disorder. In order to assess the central serotonergic turnover in autism, this study examines the cortisol and prolactin responses to administration of L-5-hydroxy-tryptophan (5-HTP), the direct precursor of 5-HT in 18 male, post-pubertal, Caucasian autistic patients (age 13-19 y.; I.Q.>55) and 22 matched healthy volunteers. Serum cortisol and prolactin were determined 45 and 30 minutes before administration of 5-HTP (4 mg/kg in non enteric-coated tablets) or an identical placebo in a single blind order and, thereafter, every 30 minutes over a 3-hour period. The 5-HTP-induced increases in serum cortisol were significantly lower in autistic patients than in controls, whereas there were no significant differences in 5-HTP-induced prolactin responses between both study groups. In baseline conditions, no significant differences were found in serum cortisol and prolactin between autistic and normal children. The results suggest that autism is accompanied by a central serotonergic hypoactivity and that the latter could play a role in the pathophysiology of autism. PMID- 17693984 TI - Investigation of V600E BRAF mutation in papillary thyroid carcinoma in the Polish population. AB - Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid gland. The high incidence of RET/PTC and Trk rearrangements or point mutations in RAS and c-MET oncogenes are the genetic hallmarks of PTC. Recently, oncogene BRAF has become a subject of great interest. The mutation of BRAF gene is characteristic for PTC and poorly differentiated and/or undifferentiated cancers derived from PTC. The predominant mutation of this gene, reported in PTC, is a single transversion in exon 15 (T1799A), which results in substitution of valine to glutamate at residue 600 (BRAF V600E, formerly position 1796 and residue V599E). It has been proved that the frequency of this mutation in PTC varies within the range of 29% to 69% in different populations. OBJECTIVES: The aim of this study was to estimate the frequency of BRAF (V600E) mutation in PTC in the Polish population, and to evaluate the possible relationships between the presence of BRAF mutation and such parameters, as patient's age, gender, histopathological variant and the clinical staging of PTC. METHODS: Analysis of BRAF (V600E) mutation was performed by single strand conformation polymorphism (SSCP) analysis and real-time allele-specific polymerase chain reaction (ASPCR) in tumour tissues from 25 patients with PTC. We compared the sensitivity of real time AS-PCR, SSCP method and direct DNA sequencing of PCR products. We used 25 PTC tissues (including the follicular variant of PTC - 8 cases, the classic variant of PTC - 14 cases and the tall-cell variant of PTC - 3 cases). RESULTS: V600E mutation in BRAF gene was detected in 12/25 (48%) cases of PTC. Mutation screening of exon 15 gene BRAF revealed three types of mutations, i.e. V600E, V600M, and overlapping mutations V600E/V600K. No correlation was found between BRAF mutation and patient's age and sex and particular stage in clinical staging systems (TNM Staging, the University of Chicago clinical class, and Ohio State University Staging). Regarding the histopathological variants of PTC, mutation in BRAF gene was more frequent in classic variant of PTC as compared with follicular variant of PTC. CONCLUSION: The real-time AS-PCR method proved to be more sensitive than SSCP and sequencing of PCR products. Our study is the first one in which the frequency of BRAF (V600E) mutation in PTC was reported for the Polish population. Similarly to the results obtained by others, there was no coexistence of BRAF (V600E) mutation and RET/PTC and/or Trk rearrangements or RAS mutation in PTC tissue. Our results do not confirm the relationship between the BRAF (V600E) mutation and the clinical outcome of PTC. PMID- 17693985 TI - Assessment of cyclin D1 gene expression as a prognostic factor in benign and malignant thyroid lesions. AB - OBJECTIVE: Cyclin D1, encoded by CCND1 (cyclin D1) gene with locus in chromosome 11q13, is a protein that plays the key role in the passage through the restriction point in G1 phase of cell cycle. The aim of the study were: 1) an assessment of CCND1 gene expression level in benign and malignant thyroid lesions and 2) the evaluation of possible correlations between gene expression and the histopathological variants of papillary thyroid carcinoma (PTC), or tumour size, classified according to TNM definition of primary tumours (in case of PTC only) or patient's sex or age. DESIGN: Thirty five (35) tissue samples were analysed: 24 cases of PTC, 4 cases of medullary thyroid carcinoma (MTC), 4 cases of follicular adenoma (FA) and 3 cases of nodular goitre (NG). In real-time polymerase chain reaction (real-time PCR), two-step RT-PCR (reverse transcriptase polymerase chain reaction) in an ABI PRISM 7500 Sequence Detection System was employed. Cyclin D1 gene expression level was assessed, calculating the mean relative quantification rate (RQ rate) increase for each sample. RESULTS: The level of cyclin D1 gene expression was significantly higher in malignant thyroid tumours (PTC, MTC), as compared with that in macroscopically unchanged thyroid tissue, FA and/or NG groups. However, the differences of RQ rate value between different PTC variants were statistically insignificant. No correlation was found between RQ values and patients' sex or age. On the other hand, the correlation was observed between RQ values and tumour size. CONCLUSIONS: Cyclin D1 gene expression in various thyroid lesions may be helpful in diagnostically doubtful cases. However, our results--mostly due to the small numbers of cases in the groups other than PTC--do not yet allow considering cyclin D1 gene as a molecular prognostic marker. PMID- 17693986 TI - A method for evaluation of activity of growth hormone-releasing hormone analogues. AB - OBJECTIVE: It has been found that hGH-RH analogues with increased resistance to enzymatic degradation have a much higher potency than the native hGH-RH (1-29) NH2 and have an ability to partially reverse growth hormone deficiencies. THE AIM: The aim of these studies was to elaborate a method which can be used for preliminary evaluation of new GH-RH analogues both from the point of view of their potency to release GH and enzymatic stability. METHOD: Two highly active GH RH analogues with increased resistance to trypsin-like enzymes, and hGH-RH(1-29) NH2 used as a standard, in doses 1 nM, 10 nM, and 100 nM were added to pituitary rat cell culture, and medium was collected after 30, 60, 120 and 240 min. GH concentration was measured by RIA kit. RESULTS: It was observed that the potency of these two GH-RH analogues was several times higher than that of native compound. Moreover, the stimulation was much longer. This suggests that high activity of these analogues in vivo could be the result of increased enzymatic stability. CONCLUSION: This method can be used for selecting more potent and more stable releasing peptides before in vivo evaluation. PMID- 17693987 TI - The influence of dinoprostone on uterine cervix ripening and the course of labor. AB - OBJECTIVES: The aim of the study was to estimate the influence of dinoprostone in two different forms on the ripening of uterine cervix and the course of labor. MATERIAL AND METHODS: 128 pregnant women with indications for labor induction and uterine cervix Bishop's scores <6, divided into 2 groups: I--62 patients who had dinoprostone in the form of a gel applied for labor preinduction; II--66 women who were administered dinoprostone in the form of vaginal inserts. The effectiveness of both forms of dinoprostone were estimated and compared. RESULTS: No differences in Bishop's score changes were noticeable between the groups after 6-8 hours from application, however they were significant at the beginning of induction: I - 7.8+/-1.3 vs. II - 6.9+/-1.6 (p=0.0007). Almost half of the patients from group II had spontaneous contractions and required no labor induction at all. The average time from dinoprostone application till delivery was shorter in group II. CONCLUSIONS: Dinoprostone vaginal inserts seem to influence both uterine cervix and muscle, while gel-prepare uterine cervix for delivery more effectively. PMID- 17693988 TI - Effects of neuroendocrine changes on results of ambulatory blood pressure monitoring (ABPM) in adolescent girls with anorexia nervosa. AB - OBJECTIVES: Anorexia nervosa (AN) is characterized by marked neuroendocrine and autonomic dysfunctions. In the recent studies using automatic blood pressure monitoring (ABPM), lower BP values and lack of circardian variation of BP in anorectic patients were demonstrated. Unfortunately effects of hormonal changes, that may explain BP abnormalities were not analysed together. DESIGN: The aim of our study was the assessment of ABPM and hormonal status in anorectic girls. SETTINGS: The study was performed on hospitalized 25 female anorectic adolescents aged 12-18 years. Control group was 17 age and height matched girls with normal weight and negative history for hypertension. ABPM was performed between 5 and 7 day of hospitalization, every 30 minutes during active period and every 60 minutes during sleep. Hormones (FSH, LH, estradiol, cortisol and fT4) serum concentrations were also evaluated. RESULTS: Mean systolic BP values were significantly lower in patients with AN in comparison to controls. Maximal diastolic and mean arterial pressure values for the whole day and active period but not for sleep were lower in AN than in controls. Anorectic girls showed tendency to night-time bradycardia. Moreover, there were no physiological circadian variations of BP in AN. CONCLUSIONS: We conclude that hormonal regulation of blood pressure and heart rate in anorectic patients is at least partially preserved. Lower blood pressure values, bradycardia and lack of physiological night fall of BP in anorectic patients may result from altered autonomic system function resulting from hormonal disturbances and other centrally mediated mechanisms. PMID- 17693989 TI - Can prefrontal theta cordance differentiate between depression recovery and dissimulation? AB - We present a case report of a 37-year old woman diagnosed with depressive disorder, first episode, who was admitted into a psychiatric hospital after a failed suicidal attempt. She responded to antidepressant therapy, as evidenced by a >50% reduction in MADRS total score. She was discharged after 4 weeks of treatment, denying any suicidal ideations. The following day the patient committed suicide; she burned herself to death. It is very likely that the patient dissimulated her symptoms and ideations. Subsequently, her quantitative EEG records were retrospectively analyzed. An increase of prefrontal theta cordance value after the first week of mirtazapine therapy was found. Recently three small studies have revealed that decrease of prefrontal theta cordance after 1 week of antidepressant administration can predict clinical response in patients with unipolar depression. In our previous study the absence of a decreased theta prefrontal cordance was associated with lack of treatment response with NPV 1.0 (Bares et al., 2007). Thus, we hypothesize that prefrontal theta cordance could become an objective marker of change of depressive symptoms, independent of patients' compliance and symptom dissimulation, more precise than objective and self-rated depression rating scales. PMID- 17693990 TI - Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells. AB - Most advanced solid tumors metastasize to different organs. However, no gene therapy effective for multiple tumors has yet been developed. Since a unique characteristic of bone marrow-derived mesenchymal stem cells (MSCs) is that they migrate to tumor tissues, we wanted to determine whether MSCs could serve as a vehicle of gene therapy for targeting multiple tumors. First, we confirmed that mouse MSCs preferentially migrate to multiple tumors of the lung in the Colon-26 (C-26) lung metastasis model. Next, MSCs were efficiently transduced with NK4, an antagonist of hepatocyte growth factor (HGF), by an adenoviral vector with an RGD motif. MSCs expressing NK4 (NK4-MSCs) strongly inhibited development of lung metastases in the C-26 lung metastasis model after systemic administration via a tail vein. Treatment with NK4-MSCs significantly prolonged survival of the C-26 tumor-bearing mice by inhibiting tumor-associated angiogenesis and lymphangiogenesis and inducing apoptosis of the tumor cells. MSC-based gene therapy did not induce the severe adverse effects induced by conventional adenoviral vectors. These results indicate that MSCs can serve as a vehicle of gene therapy for targeting multiple lung metastatic tumors. PMID- 17693992 TI - Oncolytic virotherapy with an HSV amplicon vector expressing granulocyte macrophage colony-stimulating factor using the replication-competent HSV type 1 mutant HF10 as a helper virus. AB - Direct viral infection of solid tumors can cause tumor cell death, but these techniques offer the opportunity to express exogenous factors to enhance the antitumor response. We investigated the antitumor effects of a herpes simplex virus (HSV) amplicon expressing mouse granulocyte-macrophage colony-stimulating factor (mGM-CSF) using the replication-competent HSV type 1 mutant HF10 as a helper virus. HF10-packaged mGM-CSF-expressing amplicon (mGM-CSF amplicon) was used to infect subcutaneously inoculated murine colorectal tumor cells (CT26 cells) and the antitumor effects were compared to tumors treated with only HF10. The mGM-CSF amplicon efficiently replicated in CT26 cells with similar oncolytic activity to HF10 in vitro. However, when mice subcutaneously inoculated with CT26 cells were intratumorally injected with HF10 or mGM-CSF amplicon, greater tumor regression was seen in mGM-CSF amplicon-treated animals. Furthermore, mGM-CSF amplicon treatment prolonged mouse survival. Immunohistochemical analysis revealed increased inflammatory cell infiltration in the solid tumor in the mGM CSF amplicon-treated animals. These results suggest that expression of GM-CSF enhances the antitumor effects of HF10, and HF10-packaged GM-CSF-expressing amplicon is a promising agent for the treatment of subcutaneous tumors. PMID- 17693991 TI - Adenoviral-mediated gene transfer of ectodysplasin-A2 results in induction of apoptosis and cell-cycle arrest in osteosarcoma cell lines. AB - The extremely poor prognosis of patients with metastatic osteosarcoma indicates the need for novel therapeutic approaches. Ectodysplasin-A2 (EDA-A2) is a recently isolated member of the tumor necrosis factor superfamily that binds to X linked ectodermal dysplasia receptor (XEDAR). In this report, we have analyzed the biological activity of EDA-A2 against osteosarcoma-derived cell lines. We report that XEDAR is expressed in cell lines derived from osteosarcoma and adenoviral-mediated expression of EDA-A2 in these cells results in the induction of apoptosis via caspase activation and cell-cycle arrest in the G(0)/G(1) phase. Treatment with EDA-A2 also upregulates the expression of alkaline phosphatase, a marker of osteogenic differentiation, in a caspase-dependent fashion. Collectively, our results suggest that EDA-A2 may be a promising agent for the gene therapy of osteosarcoma. PMID- 17693994 TI - Tobacco amblyopia: does it really exist? PMID- 17693995 TI - Paraneoplastic vitelliform retinopathy associated with metastatic choroidal melanoma. PMID- 17693996 TI - Successful biologic treatment of ocular mucous membrane pemphigoid with anti-TNF alpha. PMID- 17693997 TI - Intravitreal bevacizumab (Avastin) for the treatment of bilateral acquired juxtafoveal retinal telangiectasis associated with choroidal neovascular membrane. PMID- 17693998 TI - Performance of colour Doppler imaging discriminating normal tension glaucoma from healthy eyes. AB - PURPOSE: Previous studies have shown decreased retrobulbar blood flow in normal tension glaucoma (NTG) compared to healthy controls. This study evaluates the ability of colour Doppler imaging (CDI) to identify patients with NTG. METHODS: Sixty-two patients with untreated NTG (mean age 57+/-14 years) and 40 age-matched controls (mean age 58+/-9 years) were included in a prospective cross-sectional institutional study. Peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive indices (RI=(PSV-EDV)/PSV) of the ophthalmic artery (OA), central retinal artery (CRA), and short posterior ciliary arteries (PCAs) were measured by means of CDI. Using receiver operating characteristic (ROC) curves, sensitivity was determined at 90% specificity. RESULTS: Patients with NTG showed significantly decreased PSV (P<0.0001) and EDV (P<0.0001) of the CRA, significantly decreased EDV of the nasal (P=0.004) and temporal (P=0.002) PCA, and significantly increased RI of the temporal (P=0.003) PCAs compared to healthy controls. Sensitivity values at 90% specificity were calculated: PSV of the CRA, 30.6%; EDV of the CRA, 48.4%; EDV of the nasal PCA, 43.9%; EDV of the temporal PCA, 45.9%; and RI of the temporal PCA, 39.3%. CONCLUSIONS: The power to identify NTG using CDI reaches 48% sensitivity at 90% specificity. Further longitudinal studies are needed to determine the prognostic value of CDI in glaucoma. PMID- 17693999 TI - Immediate intraocular pressure changes following intravitreal injections of triamcinolone, pegaptanib, and bevacizumab. AB - PURPOSE: To assess the intraocular pressure (IOP) changes, within the first 30 min after intravitreal injection of 0.1 ml (4 mg) triamcinolone, 0.09 ml (0.3 mg) pegaptanib, and 0.05 ml (1.25 mg) bevacizumab. METHODS: Records of patients who received intravitreal triamcinolone, pegaptanib, and bevacizumab and who had their IOP measured post-injection were reviewed. RESULTS: A total of 212 injections were performed (76 bevacizumab in 63 patients, 42 triamcinolone in 41 patients, 94 pegaptanib in 74 patients). At 10 min, over 87% of eyes receiving each drug had an IOP of less than 35 mmHg. Three of the 42 eyes receiving intravitreal triamcinolone were treated with IOP-lowering drops for pressures of 44, 46, and 60 mmHg. No patients treated with intravitreal bevacizumab or pegaptanib received IOP-lowering drops. The number of eyes in each injection group that had an IOP rise >10 mmHg within 30 min after injection was 27.6% of eyes receiving bevacizumab, 33.3% of eyes receiving triamcinolone, and 36.2% of eyes receiving pegaptanib. At 10 min, eyes with glaucoma were less likely to have an IOP<35 mmHg, but this difference became less marked with time. CONCLUSION: In our series, most patients receiving intravitreal injections did not require IOP lowering drops after injection, and none required a paracentesis. PMID- 17694000 TI - Research governance. PMID- 17694001 TI - Broadening horizons. PMID- 17694002 TI - Dumbing down. PMID- 17694003 TI - Poor CPD delivery. PMID- 17694004 TI - Out of date. PMID- 17694005 TI - Gemination or fusion? PMID- 17694006 TI - No overt connection. PMID- 17694020 TI - The use of outreach clinics for teaching undergraduate restorative dentistry. AB - AIM: To examine the experience of being an outreach teacher of undergraduate restorative dentistry; to describe the desirable characteristics of such teachers; and to consider the management of outreach teaching. DESIGN: A three year pilot of an outreach course in fourth year restorative dentistry began in 2001. Students spent one day per week treating adults in NHS community dental clinics, run by Primary Care Trusts (PCTs). Action research involved monitoring meetings with students, clinic staff (dental teachers and nurses), and PCT clinical service managers. These data are supplemented by an independent evaluation involving interviews with dental school academic staff, and an account by an outreach teacher. RESULTS: Outreach is a different and more demanding context for teaching restorative dentistry than the dental hospital, characterised by isolation, management responsibility, pressure, a steep learning curve, and stress. The desirable characteristics of outreach teachers are those which enable them to cope in this environment, together with a student-centred teaching style, and the appropriate knowledge. Management of teaching passed to the PCTs and this created an additional workload for them in relation to staffing, risk, and service-based issues. Four teaching surgeries were the maximum for a satisfactory level of patient care and student supervision. A key issue for the dental school is quality. The changes to teaching and the teaching environment introduced during and after the pilot to address problems identified are described. CONCLUSION: In developing facilities to enable students to benefit from the advantages of outreach, dental schools should recognise that the characteristics of the outreach environment need to be taken into account during planning, that staff selection is a critical success factor, and that an ongoing proactive approach to organisational arrangements and to the support of teaching staff is necessary. PMID- 17694021 TI - A practical guide to endodontic access cavity preparation in molar teeth. AB - The main objective of access cavity preparation is to identify the root canal entrances for subsequent preparation and obturation of the root canal system. Access cavity preparation can be one of the most challenging and frustrating aspects of endodontic treatment, but it is the key to successful treatment. Inadequate access cavity preparation may result in difficulty locating or negotiating the root canals. This may result in inadequate cleaning, shaping and filling of the root canal system. It may also contribute to instrument separation and aberrations of canal shape. These factors may ultimately lead to failure of treatment. Good access cavity design and preparation is therefore imperative for quality endodontic treatment, prevention of iatrogenic problems, and prevention of endodontic failure. PMID- 17694022 TI - Intraoral hair removal on skin graft using Nd:YAG laser. AB - This case report is a demonstration of the efficacy of laser hair removal on a graft site intraorally. A Polaris Long Pulse Nd:YAG laser was used for the procedures. PMID- 17694029 TI - Is manual dexterity essential in the selection of dental students? AB - OBJECTIVE: The purpose of this study was to determine whether basic manual dexterity (BMD) could be an important parameter in selecting students for the Degree in Dentistry (CLOPD) and to assess whether initial manual dexterity in students admitted to the CLOPD can improve with training in pre-clinical and clinical practice. DESIGN: Observational study. SETTING: The study was carried out at the Catholic University of Rome, in five consecutive academic years. SUBJECTS AND METHODS: Four hundred and thirty-three subjects (262 males and 171 females) were tested (10 different exercises) in five consecutive years. Two retests were performed after three and five years respectively from the beginning of the experimentation. MAIN OUTCOME MEASURES: The scores of individual exercises were averaged for each candidate, assessing the mean value of basic manual dexterity score (BMDS). RESULTS: It was possible to observe some differences among candidates coming from different types of high schools, since those having a prior university degree or a scientific high school degree proved better than those with classical or vocational high school qualifications (p < 0.05). A statistically significant improvement of BMDS has been observed in students who attended the CLOPD for at least 32 months. CONCLUSIONS: Data obtained revealed that basic manual dexterity is not essential in the selection of dental students. Students who could follow training significantly improved in their manual ability. PMID- 17694042 TI - Periodontal disease as a risk factor for acute myocardial infarction. A case control study in Goans highlighting a review of the literature. AB - OBJECTIVES: The aim of the present study was to investigate the possible association between periodontal health and acute myocardial infarction (AMI) in a case-control design. MATERIALS AND METHODS: A total of 500 patients, 250 with AMI and 250 with coronary heart disease (CHD) were included in this study. The patients in the AMI group were admitted in the department of Medicine, Goa Medical College and Hospital, Bambolim-Goa because of AMI. The patients in the CHD group had no documented history of recent acute coronary events. Medical history was taken and data on serum lipid values, decayed teeth, missing teeth, filled teeth, probing depth (PD), simplified oral hygiene index (OHI-S) and bleeding on probing (BOP) were recorded. Sample proportions were compared by Pearson's chi-square test and quantitative variables with Student's t-test. The relation of clinical parameters and conventional risk factors with AMI was assessed with multivariate logistic regression analysis. RESULTS: All the serum lipids and dental parameters were statistically different between AMI and CHD groups (p <0.05). Logistic regression analysis showed that serum lipids, number of decayed teeth, mean PD, percentage of sites with BOP, and oral hygiene were significantly associated with AMI (p <0.05). CONCLUSION: The results of this study indicate that periodontal disease may be associated with AMI. We propose that prospective randomised studies are needed to determine whether periodontal disease is a risk factor in the occurrence of AMI. PMID- 17694045 TI - Evaluation of dental extractions, suturing and INR on postoperative bleeding of patients maintained on oral anticoagulant therapy. AB - OBJECTIVES: To examine the consequences of temporary withdrawal of warfarin and/or suturing on bleeding and healing pattern following dental extractions. METHODS: Two hundred and fourteen patients on long-term oral anticoagulation (warfarin) therapy scheduled for dental extraction were randomly divided into four groups: no suturing and discontinued (group 1) or continued warfarin (group 2), and suturing and discontinued (group 3) or continued warfarin (group 4). International normalised ratio (INR) was determined at different time points (baseline, days 1, 3 and 7). RESULTS: Discontinuing warfarin reduced INR level significantly at day 1, which subsequently reached <1.5 in 96 out of 104 patients (group 1 and 3). Statistical comparisons among the different treatment groups did not reveal any significant difference regarding bleeding status or healing pattern. Interestingly, patients who received sutures showed higher but insignificant incidence of bleeding postoperatively compared to their respective controls. CONCLUSION: Dental extractions may be safely performed for patients on anticoagulation therapy provided the INR level is kept <3.0 and effective measures of local haemostasis are administered. The decision to suture should be made on case-by-case basis, as the trauma associated with soft tissue handling might outweigh its advantages in certain situations like simple extractions. PMID- 17694046 TI - Perioperative local anaesthetic in young paediatric patients undergoing extractions under outpatient 'short-case' general anaesthesia. A double-blind randomised controlled trial. AB - OBJECTIVE: To investigate if postoperative pain/discomfort and anxiety experienced by young children who had extractions under general anaesthesia (GA) were affected by perioperative injection techniques of local anaesthetic (LA). DESIGN: A single-centre, double-blind, randomised controlled trial. SETTING: Conducted in 2002/2003 at the Unit of Paediatric Dentistry, Eastman Dental Hospital, London. METHODS: Children, aged 2-6 years scheduled for extractions under GA, were randomly assigned to receive either no LA (NLA), infiltration injection (IFL) or intraligamental injection (ITR) perioperatively. All children received analgesic suppositories after induction. OUTCOME MEASURES: Anxiety was scored using the Venham Picture Scale. Postoperative pain was scored using the Simplified Toddler-Preschooler Postoperative Pain Scale and supplemented with the Modified Pain/Discomfort Scale. RESULTS: Eighteen children received NLA, 17 received IFL and 19 received ITR. Postoperative pain/discomfort and anxiety scores were not significantly different during the period of recovery. On the first night, the intraligamental group had significantly lower pain scores (p = 0.012). CONCLUSION: Postoperative pain/discomfort and anxiety during the period of recovery experienced by young children who had extractions under GA appear not to be affected by perioperative injection techniques of LA. Upon discharge, intraligamental injection appears beneficial, as it is probably well tolerated by causing less soft tissue numbness initially and thus, reduces perceived pain/discomfort. PMID- 17694048 TI - The structural basis for activation of plant immunity by bacterial effector protein AvrPto. AB - Pathogenic microbes use effectors to enhance susceptibility in host plants. However, plants have evolved a sophisticated immune system to detect these effectors using cognate disease resistance proteins, a recognition that is highly specific, often elicits rapid and localized cell death, known as a hypersensitive response, and thus potentially limits pathogen growth. Despite numerous genetic and biochemical studies on the interactions between pathogen effector proteins and plant resistance proteins, the structural bases for such interactions remain elusive. The direct interaction between the tomato protein kinase Pto and the Pseudomonas syringae effector protein AvrPto is known to trigger disease resistance and programmed cell death through the nucleotide-binding site/leucine rich repeat (NBS-LRR) class of disease resistance protein Prf. Here we present the crystal structure of an AvrPto-Pto complex. Contrary to the widely held hypothesis that AvrPto activates Pto kinase activity, our structural and biochemical analyses demonstrated that AvrPto is an inhibitor of Pto kinase in vitro. The AvrPto-Pto interaction is mediated by the phosphorylation-stabilized P+1 loop and a second loop in Pto, both of which negatively regulate the Prf mediated defences in the absence of AvrPto in tomato plants. Together, our results show that AvrPto derepresses host defences by interacting with the two defence-inhibition loops of Pto. PMID- 17694047 TI - Loss of integrin alpha(v)beta8 on dendritic cells causes autoimmunity and colitis in mice. AB - The cytokine transforming growth factor-beta (TGF-beta) is an important negative regulator of adaptive immunity. TGF-beta is secreted by cells as an inactive precursor that must be activated to exert biological effects, but the mechanisms that regulate TGF-beta activation and function in the immune system are poorly understood. Here we show that conditional loss of the TGF-beta-activating integrin alpha(v)beta8 on leukocytes causes severe inflammatory bowel disease and age-related autoimmunity in mice. This autoimmune phenotype is largely due to lack of alpha(v)beta8 on dendritic cells, as mice lacking alpha(v)beta8 principally on dendritic cells develop identical immunological abnormalities as mice lacking alpha(v)beta8 on all leukocytes, whereas mice lacking alpha(v)beta8 on T cells alone are phenotypically normal. We further show that dendritic cells lacking alpha(v)beta8 fail to induce regulatory T cells (T(R) cells) in vitro, an effect that depends on TGF-beta activity. Furthermore, mice lacking alpha(v)beta8 on dendritic cells have reduced proportions of T(R) cells in colonic tissue. These results suggest that alpha(v)beta8-mediated TGF-beta activation by dendritic cells is essential for preventing immune dysfunction that results in inflammatory bowel disease and autoimmunity, effects that are due, at least in part, to the ability of alpha(v)beta8 on dendritic cells to induce and/or maintain tissue T(R) cells. PMID- 17694049 TI - A concentration-dependent switch in the bacterial response to temperature. AB - We observed that bacteria grown below a critical concentration, in batch-mode cultures, swim towards warm regions when subjected to a temperature gradient. Above that concentration, they swim towards colder regions. Our findings indicate that the secreted intercellular signal, glycine, mediates this switch through methylation of Tsr receptors. At high bacterial concentration, the switch is reinforced by an inversion of the Tar/Tsr expression ratio. PMID- 17694050 TI - Experience-dependent recovery of vision following chronic deprivation amblyopia. AB - The shift in ocular dominance induced by brief monocular deprivation is greatest during a postnatal critical period and is thought to decline irreversibly thereafter. However, here we demonstrate that complete visual deprivation through dark exposure restores rapid ocular dominance plasticity in adult rats. In addition, the loss of visual acuity resulting from chronic monocular deprivation is reversed if dark exposure precedes removal of the occlusion in adulthood, suggesting a potential use for dark exposure in the treatment of adult amblyopia. PMID- 17694051 TI - Daytime sleep condenses the time course of motor memory consolidation. AB - Two behavioral phenomena characterize human motor memory consolidation: diminishing susceptibility to interference by a subsequent experience and the emergence of delayed, offline gains in performance. A recent model proposes that the sleep-independent reduction in interference is followed by the sleep dependent expression of offline gains. Here, using the finger-opposition sequence learning task, we show that an interference experienced at 2 h, but not 8 h, following the initial training prevented the expression of delayed gains at 24 h post-training. However, a 90-min nap, immediately post-training, markedly reduced the susceptibility to interference, with robust delayed gains expressed overnight, despite interference at 2 h post-training. With no interference, a nap resulted in much earlier expression of delayed gains, within 8 h post-training. These results suggest that the evolution of robustness to interference and the evolution of delayed gains can coincide immediately post-training and that both effects reflect sleep-sensitive processes. PMID- 17694052 TI - Activation of EGFR and ERK by rhomboid signaling regulates the consolidation and maintenance of sleep in Drosophila. AB - Epidermal growth factor receptor (EGFR) signaling in the mammalian hypothalamus is important in the circadian regulation of activity. We have examined the role of this pathway in the regulation of sleep in Drosophila melanogaster. Our results demonstrate that rhomboid (Rho)- and Star-mediated activation of EGFR and ERK signaling increases sleep in a dose-dependent manner, and that blockade of rhomboid (rho) expression in the nervous system decreases sleep. The requirement of rho for sleep localized to the pars intercerebralis, a part of the fly brain that is developmentally and functionally analogous to the hypothalamus in vertebrates. These results suggest that sleep and its regulation by EGFR signaling may be ancestral to insects and mammals. PMID- 17694053 TI - A stream of cells migrating from the caudal telencephalon reveals a link between the amygdala and neocortex. AB - The amygdaloid complex consists of diverse nuclei that belong to distinct functional systems, yet many issues about its development are poorly understood. Here, we identify a stream of migrating cells that form specific amygdaloid nuclei in mice. In utero electroporation showed that this caudal amygdaloid stream (CAS) originated in a unique domain at the caudal telencephalic pole that is contiguous with the dorsal pallium, which was previously thought to generate only neocortical cells. The CAS and the neocortex share mechanisms for specification (transcription factors Tbr1, Lhx2 and Emx1/2) and migration (reelin and Cdk5). Reelin, a critical cue for migration in the neocortex, and Cdk5, which is specifically required for migration along radial glia in the neocortex, were both selectively required for the normal migration of the CAS, but not for that of other amygdaloid nuclei. This is first evidence of a dorsal pallial contribution to the amygdala, demonstrating a developmental and mechanistic link between the amygdala and the neocortex. PMID- 17694054 TI - Unusual selection on the KIR3DL1/S1 natural killer cell receptor in Africans. AB - Interactions of killer cell immunoglobulin-like receptors (KIRs) with major histocompatibility complex (MHC) class I ligands diversify natural killer cell responses to infection. By analyzing sequence variation in diverse human populations, we show that the KIR3DL1/S1 locus encodes two lineages of polymorphic inhibitory KIR3DL1 allotypes that recognize Bw4 epitopes of protein">HLA-A and HLA-B and one lineage of conserved activating KIR3DS1 allotypes, also implicated in Bw4 recognition. Balancing selection has maintained these three lineages for over 3 million years. Variation was selected at D1 and D2 domain residues that contact HLA class I and at two sites on D0, the domain that enhances the binding of KIR3D to HLA class I. HLA-B variants that gained Bw4 through interallelic microconversion are also products of selection. A worldwide comparison uncovers unusual KIR3DL1/S1 evolution in modern sub-Saharan Africans. Balancing selection is weak and confined to D0, KIR3DS1 is rare and KIR3DL1 allotypes with similar binding sites predominate. Natural killer cells express the dominant KIR3DL1 at a high frequency and with high surface density, providing strong responses to cells perturbed in Bw4 expression. PMID- 17694055 TI - Promoter regions of many neural- and nutrition-related genes have experienced positive selection during human evolution. AB - Surveys of protein-coding sequences for evidence of positive selection in humans or chimpanzees have flagged only a few genes known to function in neural or nutritional processes, despite pronounced differences between humans and chimpanzees in behavior, cognition and diet. It may be that most such differences are due to changes in gene regulation rather than protein structure. Here, we present the first survey of promoter (5'-flanking) regions, which are rich in cis regulatory sequences, for evidence of positive selection in humans. Our results indicate that positive selection has targeted the regulation of many genes known to be involved in neural development and function, both in the brain and elsewhere in the nervous system, and in nutrition, particularly in glucose metabolism. PMID- 17694056 TI - A single positively selected West Nile viral mutation confers increased virogenesis in American crows. AB - West Nile virus (WNV), first recognized in North America in 1999, has been responsible for the largest arboviral epiornitic and epidemic of human encephalitis in recorded history. Despite the well-described epidemiological patterns of WNV in North America, the basis for the emergence of WNV-associated avian pathology, particularly in the American crow (AMCR) sentinel species, and the large scale of the North American epidemic and epiornitic is uncertain. We report here that the introduction of a T249P amino acid substitution in the NS3 helicase (found in North American WNV) in a low-virulence strain was sufficient to generate a phenotype highly virulent to AMCRs. Furthermore, comparative sequence analyses of full-length WNV genomes demonstrated that the same site (NS3 249) was subject to adaptive evolution. These phenotypic and evolutionary results provide compelling evidence for the positive selection of a mutation encoding increased viremia potential and virulence in the AMCR sentinel bird species. PMID- 17694057 TI - RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis. AB - Premature fusion of one or more of the cranial sutures (craniosynostosis) in humans causes over 100 skeletal diseases, which occur in 1 of approximately 2,500 live births. Among them is Apert syndrome, one of the most severe forms of craniosynostosis, primarily caused by missense mutations leading to amino acid changes S252W or P253R in fibroblast growth factor receptor 2 (FGFR2). Here we show that a small hairpin RNA targeting the dominant mutant form of Fgfr2 (Fgfr2(S252W)) completely prevents Apert-like syndrome in mice. Restoration of normal FGFR2 signaling is manifested by an alteration of the activity of extracellular signal-regulated kinases 1 and 2 (ERK1/2), implicating the gene encoding ERK and the genes downstream of it in disease expressivity. Furthermore, treatment of the mutant mice with U0126, an inhibitor of mitogen-activated protein (MAP) kinase kinase 1 and 2 (MEK1/2) that blocks phosphorylation and activation of ERK1/2, significantly inhibits craniosynostosis. These results illustrate a pathogenic role for ERK activation in craniosynostosis resulting from FGFR2 with the S252W substitution and introduce a new concept of small molecule inhibitor-mediated prevention and therapy for diseases caused by gain-of function mutations in the human genome. PMID- 17694058 TI - Global diversity and evidence for coevolution of KIR and HLA. AB - The killer immunoglobulin-like receptor (KIR) gene cluster shows extensive genetic diversity, as do the HLA class I loci, which encode ligands for KIR molecules. We genotyped 1,642 individuals from 30 geographically distinct populations to examine population-level evidence for coevolution of these two functionally related but unlinked gene clusters. We observed strong negative correlations between the presence of activating KIR genes and their corresponding HLA ligand groups across populations, especially KIR3DS1 and its putative HLA-B Bw4-80I ligands (r = -0.66, P = 0.038). In contrast, we observed weak positive relationships between the various inhibitory KIR genes and their ligands. We observed a negative correlation between distance from East Africa and frequency of activating KIR genes and their corresponding ligands, suggesting a balance between selection on HLA and KIR loci. Most KIR-HLA genetic association studies indicate a primary influence of activating KIR-HLA genotypes in disease risk; concomitantly, activating receptor-ligand pairs in this study show the strongest signature of coevolution of these two complex genetic systems as compared with inhibitory receptor-ligand pairs. PMID- 17694059 TI - Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3- precursor cells in the absence of interleukin 10. AB - CD4(+) regulatory T cells (T(reg) cells) that produce interleukin 10 (IL-10) are important contributors to immune homeostasis. We generated mice with a 'dual reporter' system of the genes encoding IL-10 and the transcription factor Foxp3 to track T(reg) subsets based on coordinate or differential expression of these genes. Secondary lymphoid tissues, lung and liver had enrichment of Foxp3(+)IL 10(-) T(reg) cells, whereas the large and small intestine had enrichment of Foxp3(+)IL-10(+) and Foxp3(-)IL-10(+) T(reg) cells, respectively. Although negative for Il10 expression, both Foxp3(+) and Foxp3(-) CD4(+) thymic precursor cells gave rise to peripheral IL-10(+) T(reg) cells, with only Foxp3(-) precursor cells giving rise to all T(reg) subsets. Each T(reg) subset developed in IL-10 deficient mice, but this was blocked by treatment with antibody to transforming growth factor-beta. Thus, Foxp3(+) and Foxp3(-) precursor cells give rise to peripheral IL-10-expressing T(reg) cells by a mechanism dependent on transforming growth factor-beta and independent of IL-10. PMID- 17694060 TI - Structural evidence for a germline-encoded T cell receptor-major histocompatibility complex interaction 'codon'. AB - All complexes of T cell receptors (TCRs) bound to peptide-major histocompatibility complex (pMHC) molecules assume a stereotyped binding 'polarity', despite wide variations in TCR-pMHC docking angles. However, existing TCR-pMHC crystal structures have failed to show broadly conserved pairwise interaction motifs. Here we determined the crystal structures of two TCRs encoded by the variable beta-chain 8.2 (V(beta)8.2), each bound to the MHC class II molecule I-A(u), and did energetic mapping of V(alpha) and V(beta) contacts with I-A(u). Together with two previously solved structures of V(beta)8.2-containing TCR-MHC complexes, we found four TCR-I-A complexes with structurally superimposable interactions between the V(beta) loops and the I-A alpha-helix. This examination of a narrow 'slice' of the TCR-MHC repertoire demonstrates what is probably one of many germline-derived TCR-MHC interaction 'codons'. PMID- 17694061 TI - Phason dynamics in nonlinear photonic quasicrystals. AB - We study the dynamics of phasons in a nonlinear photonic quasicrystal. The photonic quasicrystal is formed by optical induction, and its dynamics is initiated by allowing the light waves inducing the quasicrystal to nonlinearly interact with one another. We show quantitatively that, when phason strain is introduced in a controlled manner, it relaxes through the nonlinear interactions within the photonic quasicrystal. We establish experimentally that the relaxation rate of phason strain in the quasicrystal is substantially lower than the relaxation rate of phonon strain, as predicted for atomic quasicrystals. Finally, we monitor and identify individual 'atomic-scale' phason flips occurring in the photonic quasicrystal as its phason strain relaxes, as well as noise-induced phason fluctuations. PMID- 17694062 TI - Coherent orbital waves in the photo-induced insulator-metal dynamics of a magnetoresistive manganite. AB - Photo-excitation can drive strongly correlated electron insulators into competing conducting phases, resulting in giant and ultrafast changes of their electronic and magnetic properties. The underlying non-equilibrium dynamics involve many degrees of freedom at once, whereby sufficiently short optical pulses can trigger the corresponding collective modes of the solid along temporally coherent pathways. The characteristic frequencies of these modes range between the few GHz of acoustic vibrations to the tens or even hundreds of THz for purely electronic excitations. Virtually all experiments so far have used 100 fs or longer pulses, detecting only comparatively slow lattice dynamics. Here, we use sub-10-fs optical pulses to study the photo-induced insulator-metal transition in the magnetoresistive manganite Pr(0.7)Ca(0.3)MnO(3). At room temperature, we find that the time-dependent pathway towards the metallic phase is accompanied by coherent 31 THz oscillations of the optical reflectivity, significantly faster than all lattice vibrations. These high-frequency oscillations are suggestive of coherent orbital waves, crystal-field excitations triggered here by impulsive stimulated Raman scattering. Orbital waves are likely to be initially localized to the small polarons of this room-temperature manganite, coupling to other degrees of freedom at longer times, as photo-domains coalesce into a metallic phase. PMID- 17694063 TI - Imbibition by polygonal spreading on microdecorated surfaces. AB - Micropatterned surfaces have been studied extensively as model systems to understand influences of topographic or chemical heterogeneities on wetting phenomena. Such surfaces yield specific wetting or hydrodynamic effects, for example, ultrahydrophobic surfaces, 'fakir' droplets, tunable electrowetting, slip in the presence of surface heterogeneities and so on. In addition, chemical patterns allow control of the locus, size and shape of droplets by pinning the contact lines at predetermined locations. Applications include the design of 'self-cleaning' surfaces and hydrophilic spots to automate the deposition of probes on DNA chips. Here, we discuss wetting on topographically patterned but chemically homogeneous surfaces and demonstrate mechanisms of shape selection during imbibition of the texture. We obtain different deterministic final shapes of the spreading droplets, including octagons, squares, hexagons and circles. The shape selection depends on the topographic features and the liquid through its equilibrium contact angle. Considerations of the dynamics provide a 'shape' diagram that summarizes our observations and suggest rules for a designer's tool box. PMID- 17694064 TI - MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. AB - MicroRNAs are predicted to regulate thousands of mammalian genes, but relatively few targets have been experimentally validated and few microRNA loss-of-function phenotypes have been assigned. As an alternative to chemically modified antisense oligonucleotides, we developed microRNA inhibitors that can be expressed in cells, as RNAs produced from transgenes. Termed 'microRNA sponges', these competitive inhibitors are transcripts expressed from strong promoters, containing multiple, tandem binding sites to a microRNA of interest. When vectors encoding these sponges are transiently transfected into cultured cells, sponges derepress microRNA targets at least as strongly as chemically modified antisense oligonucleotides. They specifically inhibit microRNAs with a complementary heptameric seed, such that a single sponge can be used to block an entire microRNA seed family. RNA polymerase II promoter (Pol II)-driven sponges contain a fluorescence reporter gene for identification and sorting of sponge-treated cells. We envision the use of stably expressed sponges in animal models of disease and development. PMID- 17694065 TI - Tomographic phase microscopy. AB - We report a technique for quantitative three-dimensional (3D) mapping of refractive index in live cells and tissues using a phase-shifting laser interferometric microscope with variable illumination angle. We demonstrate tomographic imaging of cells and multicellular organisms, and time-dependent changes in cell structure. Our results will permit quantitative characterization of specimen-induced aberrations in high-resolution microscopy and have multiple applications in tissue light scattering. PMID- 17694066 TI - Clearance of amyloid-beta by circulating lipoprotein receptors. AB - Low-density lipoprotein receptor-related protein-1 (LRP) on brain capillaries clears amyloid beta-peptide (Abeta) from brain. Here, we show that soluble circulating LRP (sLRP) provides key endogenous peripheral 'sink' activity for Abeta in humans. Recombinant LRP cluster IV (LRP-IV) bound Abeta in plasma in mice and Alzheimer's disease-affected humans with compromised sLRP-mediated Abeta binding, and reduced Abeta-related pathology and dysfunction in a mouse model of Alzheimer disease, suggesting that LRP-IV can effectively replace native sLRP and clear Abeta. PMID- 17694067 TI - The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers. AB - Transformation and cancer growth are regulated by the coordinate actions of oncogenes and tumor suppressors. Here, we show that the novel E3 ubiquitin ligase HACE1 is frequently downregulated in human tumors and maps to a region of chromosome 6q21 implicated in multiple human cancers. Genetic inactivation of HACE1 in mice results in the development of spontaneous, late-onset cancer. A second hit from either environmental triggers or genetic heterozygosity of another tumor suppressor, p53, markedly increased tumor incidence in a Hace1 deficient background. Re-expression of HACE1 in human tumor cells directly abrogates in vitro and in vivo tumor growth, whereas downregulation of HACE1 via siRNA allows non-tumorigenic human cells to form tumors in vivo. Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1. Thus, HACE1 is a candidate chromosome 6q21 tumor-suppressor gene involved in multiple cancers. PMID- 17694068 TI - Molecular imaging of Akt kinase activity. AB - The serine/threonine kinase Akt mediates mitogenic and anti-apoptotic responses that result from activation of multiple signaling cascades. It is considered a key determinant of tumor aggressiveness and is a major target for anticancer drug development. Here, we describe a new reporter molecule whose bioluminescence activity within live cells and in mice can be used to measure Akt activity. Akt activity in cultured cells and tumor xenografts was monitored quantitatively and dynamically in response to activation or inhibition of receptor tyrosine kinase, inhibition of phosphoinositide 3-kinase, or direct inhibition of Akt. The results provide unique insights into the pharmacokinetics and pharmacodynamics of agents that modulate Akt activity, revealing the usefulness of this reporter for rapid dose and schedule optimization in the drug development process. PMID- 17694069 TI - Lsm proteins bind and stabilize RNAs containing 5' poly(A) tracts. AB - Many orthopoxvirus messenger RNAs have an unusual nontemplated poly(A) tract of 5 to 40 residues at the 5' end. The precise function of this feature is unknown. Here we show that 5' poly(A) tracts are able to repress RNA decay by inhibiting 3'-to-5' exonucleases as well as decapping of RNA substrates. UV cross-linking analysis demonstrated that the Lsm complex associates with the 5' poly(A) tract. Furthermore, recombinant Lsm1-7 complex specifically binds 5' poly(A) tracts 10 to 21 nucleotides in length, consistent with the length of 5' poly(A) required for stabilization. Knockdown of Lsm1 abrogates RNA stabilization by the 5' poly(A) tract. We propose that the Lsm complex simultaneously binds the 3' and 5' ends of these unusual messenger RNAs and thereby prevents 3'-to-5' decay. The implications of this phenomenon for cellular mRNA decay are discussed. PMID- 17694070 TI - MRE11-RAD50-NBS1 and ATM function as co-mediators of TRF1 in telomere length control. AB - Human telomeres are associated with ATM and the protein complex consisting of MRE11, RAD50 and NBS1 (MRN), which are central to maintaining genomic stability. Here we show that when targeted to telomeres, wild-type RAD50 downregulates telomeric association of TRF1, a negative regulator of telomere maintenance. TRF1 binding to telomeres is upregulated in cells deficient in NBS1 or under ATM inhibition. The TRF1 association with telomeres induced by ATM inhibition is abrogated in cells lacking MRE11 or NBS1, suggesting that MRN and ATM function in the same pathway controlling TRF1 binding to telomeres. The ability of TRF1 to interact with telomeric DNA in vitro is impaired by ATM-mediated phosphorylation. We propose that MRN is required for TRF1 phosphorylation by ATM and that such phosphorylation results in the release of TRF1 from telomeres, promoting telomerase access to the ends of telomeres. PMID- 17694071 TI - Structural dynamics in the gating ring of cyclic nucleotide-gated ion channels. AB - For ligand-gated ion channels, the binding of a ligand to an intracellular or extracellular domain generates changes in transmembrane pore-forming helices, which alters ion flow. The molecular mechanism for this allostery, however, remains unknown. Here we explore the structure and conformational rearrangements of the C-terminal gating ring of the cyclic nucleotide-gated channel CNGA1 during activation by cyclic nucleotides with patch-clamp fluorometry. By monitoring fluorescent resonance energy transfer (FRET) between membrane-resident quenchers and fluorophores attached to the channel, we detected no movement orthogonal to the membrane during channel activation. By monitoring FRET between fluorophores within the C-terminal region, we determined that the C-terminal end of the C linker and the end of the C-helix move apart when channels open. We conclude that during channel activation, a portion of the gating ring moves parallel to the plasma membrane, hinging toward the central axis of the channel. PMID- 17694072 TI - The biological role of death and lysis in biofilm development. AB - Recent studies have revealed that the regulated death of bacterial cells is important for biofilm development. Following cell death, a sub-population of the dead bacteria lyse and release genomic DNA, which then has an essential role in intercellular adhesion and biofilm stability. This Opinion focuses on the role of regulated cell death and lysis in biofilm development and provides a functional comparison between bacterial programmed cell death and apoptosis. The hypothesis that the differential regulation of these processes during biofilm development contributes to the antibiotic tolerance of biofilm cells is also explored. PMID- 17694074 TI - HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. AB - Acetylation of the epsilon-amino group of a lysine residue was first discovered with histones in 1968, but the responsible enzymes, histone acetyltransferases and deacetylases, were not identified until the mid-1990s. In the past decade, knowledge about this modification has exploded, with targets rapidly expanding from histones to transcription factors and other nuclear proteins, and then to cytoskeleton, metabolic enzymes, and signaling regulators in the cytoplasm. Thus, protein lysine acetylation has emerged as a major post-translational modification to rival phosphorylation. In this issue of Oncogene, 19 articles review various aspects of the enzymes governing lysine acetylation, especially about their intimate links to cancer. To introduce the articles, we highlight here four central themes: (i) multisubunit enzymatic complexes; (ii) non-histone substrates in diverse cellular processes; (iii) interplay of lysine acetylation with other regulatory mechanisms, such as noncoding RNA-mediated gene silencing and activation; and (iv) novel therapeutic strategies and preventive measures to combat cancer and other human diseases. PMID- 17694075 TI - Hat1: the emerging cellular roles of a type B histone acetyltransferase. AB - Hat1 is the sole known example of a type B histone acetyltransferase. While it has long been presumed that type B histone acetyltransferases participate in the acetylation of newly synthesized histones during the process of chromatin assembly, definitive evidence linking these enzymes to this process has been scarce. This review will discuss recent results that have begun to shed light on the roles of Hat1 and also address several outstanding questions relating to the cellular function of this enzyme. PMID- 17694077 TI - Distinct GCN5/PCAF-containing complexes function as co-activators and are involved in transcription factor and global histone acetylation. AB - Transcription in eukaryotes is a tightly regulated, multistep process. Gene specific transcriptional activators, several different co-activators and general transcription factors are necessary to access specific loci to allow precise initiation of RNA polymerase II transcription. As the dense chromatin folding of the genome does not allow the access of these sites by the huge multiprotein transcription machinery, remodelling is required to loosen up the chromatin structure for successful transcription initiation. In the present review, we summarize the recent evolution of our understanding of the function of two histone acetyl transferases (ATs) from metazoan organisms: GCN5 and PCAF. Their overall structure and the multiprotein complexes in which they are carrying out their activities are discussed. Metazoan GCN5 and PCAF are subunits of at least two types of multiprotein complexes, one having a molecular weight of 2 MDa (SPT3 TAF9-GCN5 acetyl transferase/TATA binding protein (TBP)-free-TAF complex/PCAF complexes) and a second type with about a size of 700 kDa (ATAC complex). These complexes possess global histone acetylation activity and locus-specific co activator functions together with AT activity on non-histone substrates. Thus, their biological functions cover a wide range of tasks and render them indispensable for the normal function of cells. That deregulation of the global and/or specific AT activities of these complexes leads to the cancerous transformation of the cells highlights their importance in cellular processes. The possible effects of GCN5 and PCAF in tumorigenesis are also discussed. PMID- 17694076 TI - The SAGA continues: expanding the cellular role of a transcriptional co-activator complex. AB - Throughout the last decade, great advances have been made in our understanding of how DNA-templated cellular processes occur in the native chromatin environment. Proteins that regulate transcription, replication, DNA repair, mitosis and other processes must be targeted to specific regions of the genome and granted access to DNA, which is normally tightly packaged in the higher-order chromatin structure of eukaryotic nuclei. Massive multiprotein complexes have been discovered, which facilitate access to DNA and recruitment of downstream effectors through three distinct mechanisms: chemical modification of histone amino-acid residues, ATP-dependent chromatin remodeling and histone exchange. The yeast Spt-Ada-Gcn5-Acetyl transferase (SAGA) transcriptional co-activator complex regulates numerous cellular processes through coordination of multiple histone post-translational modifications. SAGA is known to generate and interact with a number of histone modifications, including acetylation, methylation, ubiquitylation and phosphorylation. Although best characterized for its role in regulating transcriptional activation, SAGA is also required for optimal transcription elongation, mRNA export and perhaps nucleotide excision repair. Here, we discuss findings from recent years that have elucidated the function of this 1.8-MDa complex in multiple cellular processes, and how misregulation of the homologous complexes in humans may ultimately play a role in development of disease. PMID- 17694078 TI - Orchestration of chromatin-based processes: mind the TRRAP. AB - Chromatin modifications at core histones including acetylation, methylation, phosphorylation and ubiquitination play an important role in diverse biological processes. Acetylation of specific lysine residues within the N terminus tails of core histones is arguably the most studied histone modification; however, its precise roles in different cellular processes and how it is disrupted in human diseases remain poorly understood. In the last decade, a number of histone acetyltransferases (HATs) enzymes responsible for histone acetylation, has been identified and functional studies have begun to unravel their biological functions. The activity of many HATs is dependent on HAT complexes, the multiprotein assemblies that contain one HAT catalytic subunit, adapter proteins, several other molecules of unknown function and a large protein called TRansformation/tRanscription domain-Associated Protein (TRRAP). As a common component of many HAT complexes, TRRAP appears to be responsible for the recruitment of these complexes to chromatin during transcription, replication and DNA repair. Recent studies have shed new light on the role of TRRAP in HAT complexes as well as mechanisms by which it mediates diverse cellular processes. Thus, TRRAP appears to be responsible for a concerted and context-dependent recruitment of HATs and coordination of distinct chromatin-based processes, suggesting that its deregulation may contribute to diseases. In this review, we summarize recent developments in our understanding of the function of TRRAP and TRRAP-containing HAT complexes in normal cellular processes and speculate on the mechanism underlying abnormal events that may lead to human diseases such as cancer. PMID- 17694079 TI - MYST opportunities for growth control: yeast genes illuminate human cancer gene functions. AB - The MYST family of histone acetyltransferases (HATs) was initially defined by human genes with disease connections and by yeast genes identified for their role in epigenetic transcriptional silencing. Since then, many new MYST genes have been discovered through genetic and genomic approaches. Characterization of the complexes through which MYST proteins act, regions of the genome to which they are targeted and biological consequences when they are disrupted, all deepen the connections of MYST proteins to development, growth control and human cancers. Many of the insights into MYST family function have come from studies in model organisms. Herein, we review functions of two of the founding MYST genes, yeast SAS2 and SAS3, and the essential yeast MYST ESA1. Analysis of these genes in yeast has defined roles for MYST proteins in transcriptional activation and silencing, and chromatin-mediated boundary formation. They have further roles in DNA damage repair and nuclear integrity. The observation that MYST protein complexes share subunits with other HATs, histone deacetylases and other key nuclear proteins, many with connections to human cancers, strengthens the idea that coordinating distinct chromatin modifications is critical for regulation. PMID- 17694080 TI - Males absent on the first (MOF): from flies to humans. AB - Histone modifications such as acetylation, methylation and phosphorylation have been implicated in fundamental cellular processes such as epigenetic regulation of gene expression, organization of chromatin structure, chromosome segregation, DNA replication and DNA repair. Males absent on the first (MOF) is responsible for acetylating histone H4 at lysine 16 (H4K16) and is a key component of the MSL complex required for dosage compensation in Drosophila. The human ortholog of MOF (hMOF) has the same substrate specificity and recent purification of the human and Drosophila MOF complexes showed that these complexes were also highly conserved through evolution. Several studies have shown that loss of hMOF in mammalian cells leads to a number of different phenotypes; a G2/M cell cycle arrest, nuclear morphological defects, spontaneous chromosomal aberrations, reduced transcription of certain genes and an impaired DNA repair response upon ionizing irradiation. Moreover, hMOF is involved in ATM activation in response to DNA damage and acetylation of p53 by hMOF influences the cell's decision to undergo apoptosis instead of a cell cycle arrest. These data, highlighting hMOF as an important component of many cellular processes, as well as links between hMOF and cancer will be discussed. PMID- 17694081 TI - The MYST family of histone acetyltransferases and their intimate links to cancer. AB - The histone acetyltransferases (HATs) of the MYST family are highly conserved in eukaryotes and carry out a significant proportion of all nuclear acetylation. These enzymes function exclusively in multisubunit protein complexes whose composition is also evolutionarily conserved. MYST HATs are involved in a number of key nuclear processes and play critical roles in gene-specific transcription regulation, DNA damage response and repair, as well as DNA replication. This suggests that anomalous activity of these HATs or their associated complexes can easily lead to severe cellular malfunction, resulting in cell death or uncontrolled growth and malignancy. Indeed, the MYST family HATs have been implicated in several forms of human cancer. This review summarizes the current understanding of these enzymes and their normal function, as well as their established and putative links to oncogenesis. PMID- 17694082 TI - MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells. AB - Genes of the human monocytic leukemia zinc-finger protein MOZ (HUGO symbol, MYST3) and its paralog MORF (MYST4) are rearranged in chromosome translocations associated with acute myeloid leukemia and/or benign uterine leiomyomata. Both proteins have intrinsic histone acetyltransferase activity and are components of quartet complexes with noncatalytic subunits containing the bromodomain, plant homeodomain-linked (PHD) finger and proline-tryptophan-tryptophan-proline (PWWP) containing domain, three types of structural modules characteristic of chromatin regulators. Although leukemia-derived fusion proteins such as MOZ-TIF2 promote self-renewal of leukemic stem cells, recent studies indicate that murine MOZ and MORF are important for proper development of hematopoietic and neurogenic progenitors, respectively, thereby highlighting the importance of epigenetic integrity in safeguarding stem cell identity. PMID- 17694083 TI - Histone deacetylases and cancer. AB - Histone deacetylases (HDACs) regulate the expression and activity of numerous proteins involved in both cancer initiation and cancer progression. By removal of acetyl groups from histones, HDACs create a non-permissive chromatin conformation that prevents the transcription of genes that encode proteins involved in tumorigenesis. In addition to histones, HDACs bind to and deacetylate a variety of other protein targets including transcription factors and other abundant cellular proteins implicated in control of cell growth, differentiation and apoptosis. This review provides a comprehensive examination of the transcriptional and post-translational mechanisms by which HDACs alter the expression and function of cancer-associated proteins and examines the general impact of HDAC activity in cancer. PMID- 17694084 TI - The human Mi-2/NuRD complex and gene regulation. AB - The Mi-2/nucleosome remodeling and deacetylase (NuRD) complex is an abundant deacetylase complex with a broad cellular and tissue distribution. It is unique in that it couples histone deacetylation and chromatin remodeling ATPase activities in the same complex. A decade of research has uncovered a number of interesting connections between Mi-2/NuRD and gene regulation. The subunit composition of the enzyme appears to vary with cell type and in response to physiologic signals within a tissue. Here, we review the known subunits of the complex, their connections to signaling networks, and their association with cancer. In addition, we propose a working model that integrates the known biochemical properties of the enzyme with emerging models on how chromatin structure and modification relate to gene activity. PMID- 17694085 TI - HDAC3: taking the SMRT-N-CoRrect road to repression. AB - Known histone deacetylases (HDACs) are divided into different classes, and HDAC3 belongs to Class I. Through forming multiprotein complexes with the corepressors SMRT and N-CoR, HDAC3 regulates the transcription of a plethora of genes. A growing list of nonhistone substrates extends the role of HDAC3 beyond transcriptional repression. Here, we review data on the composition, regulation and mechanism of action of the SMRT/N-CoR-HDAC3 complexes and provide several examples of nontranscriptional functions, to illustrate the wide variety of physiological processes affected by this deacetylase. Furthermore, we discuss the implication of HDAC3 in cancer, focusing on leukemia. We conclude with some thoughts about the potential therapeutic efficacies of HDAC3 activity modulation. PMID- 17694086 TI - Class IIa histone deacetylases: regulating the regulators. AB - In the last decade, the identification of enzymes that regulate acetylation of histones and nonhistone proteins has revealed the key role of dynamic acetylation and deacetylation in various cellular processes. Mammalian histone deacetylases (HDACs), which catalyse the removal of acetyl groups from lysine residues, are grouped into three classes, on the basis of similarity to yeast counterparts. An abundance of experimental evidence has established class IIa HDACs as crucial transcriptional regulators of various developmental and differentiation processes. In the past 5 years, a tremendous effort has been dedicated to characterizing the regulation of these enzymes. In this review, we summarize the latest discoveries in the field and discuss the molecular and structural determinants of class IIa HDACs regulation. Finally, we emphasize that comprehension of the mechanisms underlying class IIa HDAC functions is essential for potential therapeutic applications. PMID- 17694087 TI - HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination. AB - Histone deacetylase 6 (HDAC6) is a unique enzyme with specific structural and functional features. It is actively or stably maintained in the cytoplasm and is the only member, within the histone deacetylase family, that harbors a full duplication of its deacetylase homology region followed by a specific ubiquitin binding domain at the C-terminus end. Accordingly, this deacetylase functions at the heart of a cellular regulatory mechanism capable of coordinating various cellular functions largely relying on the microtubule network. Moreover, HDAC6 action as a regulator of the HSP90 chaperone activity adds to the multifunctionality of the protein, and allows us to propose a critical role for HDAC6 in mediating and coordinating various cellular events in response to different stressful stimuli. PMID- 17694088 TI - Arabidopsis histone deacetylase 6: a green link to RNA silencing. AB - Epigenetic reprogramming is at the base of cancer initiation and progression. Generally, genome-wide reduction in cytosine methylation contrasts with the hypermethylation of control regions of functionally well-established tumor suppressor genes and many other genes whose role in cancer biology is not yet clear. While insight into mechanisms that induce aberrant cytosine methylation in cancer cells is just beginning to emerge, the initiating signals for analogous promoter methylation in plants are well documented. In Arabidopsis, the silencing of promoters requires components of the RNA interference machinery and promoter double-stranded RNA (dsRNA) to induce a repressive chromatin state that is characterized by cytosine methylation and histone deacetylation catalysed by the RPD3-type histone deacetylase AtHDA6. Similar mechanisms have been shown to occur in fission yeast and mammals. This review focuses on the connections between cytosine methylation, dsRNA and AtHDA6-controlled histone deacetylation during promoter silencing in Arabidopsis and discusses potential mechanistic similarities of these silencing events in cancer and plant cells. PMID- 17694089 TI - Sirtuins: critical regulators at the crossroads between cancer and aging. AB - Sirtuins (SIRTs 1-7), or class III histone deacetylases (HDACs), are protein deacetylases/ADP ribosyltransferases that target a wide range of cellular proteins in the nucleus, cytoplasm, and mitochondria for post-translational modification by acetylation (SIRT1, -2, -3 and -5) or ADP ribosylation (SIRT4 and -6). The orthologs of sirtuins in lower organisms play a critical role in regulating lifespan. As cancer is a disease of aging, we discuss the growing implications of the sirtuins in protecting against cancer development. Sirtuins regulate the cellular responses to stress and ensure that damaged DNA is not propagated and that mutations do not accumulate. SIRT1 also promotes replicative senescence under conditions of chronic stress. By participating in the stress response to genomic insults, sirtuins are thought to protect against cancer, but they are also emerging as direct participants in the growth of some cancers. Here, we review the growing implications of sirtuins both in cancer prevention and as specific and novel cancer therapeutic targets. PMID- 17694090 TI - NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs. AB - Histone deacetylases (HDACs) catalyse the removal of acetyl groups from the N terminal tails of histones. All known HDACs can be categorized into one of four classes (I-IV). The class III HDAC or silencing information regulator 2 (Sir2) family exhibits characteristics consistent with a distinctive role in regulation of chromatin structure. Accumulating data suggest that these deacetylases acquired new roles as genomic complexity increased, including deacetylation of non-histone proteins and functional diversification in mammals. However, the intrinsic regulation of chromatin structure in species as diverse as yeast and humans, underscores the pressure to conserve core functions of class III HDACs, which are also known as Sirtuins. One of the key factors that might have contributed to this preservation is the intimate relationship between some members of this group of proteins (SirT1, SirT2 and SirT3) and deacetylation of a specific residue in histone H4, lysine 16 (H4K16). Evidence accumulated over the years has uncovered a unique role for H4K16 in chromatin structure throughout eukaryotes. Here, we review the recent findings about the functional relationship between H4K16 and the Sir2 class of deacetylases and how that relationship might impact aging and diseases including cancer and diabetes. PMID- 17694091 TI - Structure and acetyl-lysine recognition of the bromodomain. AB - Histone lysine acetylation is central to epigenetic control of gene transcription. The bromodomain, found in chromatin-associated proteins and histone acetyltranferases, functions as the sole protein module known to bind acetyl-lysine motifs. Recent structural and functional analyses of bromodomains' recognition of lysine-acetylated peptides derived from major acetylation sites in histones and cellular proteins provide new insights into differences in ligand binding selectivity as well as unifying features of histone recognition by the bromodomains. These new findings highlight the functional importance of bromodomain/acetyl-lysine binding as a pivotal mechanism for regulating protein protein interactions in histone-directed chromatin remodeling and gene transcription. These new studies also support the notion that functional diversity of a conserved bromodomain structural fold is achieved by evolutionary changes of structurally flexible amino-acid sequences in the ligand binding site such as the ZA and BC loops. PMID- 17694092 TI - Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design. AB - The post-translational modification of histones plays an important role in chromatin regulation, a process that insures the fidelity of gene expression and other DNA transactions. Of the enzymes that mediate post-translation modification, the histone acetyltransferase (HAT) and histone deacetylase (HDAC) proteins that add and remove acetyl groups to and from target lysine residues within histones, respectively, have been the most extensively studied at both the functional and structural levels. Not surprisingly, the aberrant activity of several of these enzymes have been implicated in human diseases such as cancer and metabolic disorders, thus making them important drug targets. Significant mechanistic insights into the function of HATs and HDACs have come from the X-ray crystal structures of these enzymes both alone and in liganded complexes, along with associated enzymatic and biochemical studies. In this review, we will discuss what we have learned from the structures and related biochemistry of HATs and HDACs and the implications of these findings for the design of protein effectors to regulate gene expression and treat disease. PMID- 17694093 TI - Histone deacetylase inhibitors: molecular mechanisms of action. AB - This review focuses on the mechanisms of action of histone deacetylase (HDAC) inhibitors (HDACi), a group of recently discovered 'targeted' anticancer agents. There are 18 HDACs, which are generally divided into four classes, based on sequence homology to yeast counterparts. Classical HDACi such as the hydroxamic acid-based vorinostat (also known as SAHA and Zolinza) inhibits classes I, II and IV, but not the NAD+-dependent class III enzymes. In clinical trials, vorinostat has activity against hematologic and solid cancers at doses well tolerated by patients. In addition to histones, HDACs have many other protein substrates involved in regulation of gene expression, cell proliferation and cell death. Inhibition of HDACs causes accumulation of acetylated forms of these proteins, altering their function. Thus, HDACs are more properly called 'lysine deacetylases.' HDACi induces different phenotypes in various transformed cells, including growth arrest, activation of the extrinsic and/or intrinsic apoptotic pathways, autophagic cell death, reactive oxygen species (ROS)-induced cell death, mitotic cell death and senescence. In comparison, normal cells are relatively more resistant to HDACi-induced cell death. The plurality of mechanisms of HDACi-induced cell death reflects both the multiple substrates of HDACs and the heterogeneous patterns of molecular alterations present in different cancer cells. PMID- 17694094 TI - Beginning to understand microRNA function. PMID- 17694095 TI - Centromere cohesion: regulating the guardian. PMID- 17694096 TI - Delta N-p73: the enemy within. PMID- 17694098 TI - Numerical study of evaluating the optical quality of supersonic flow fields. AB - A numerical method based on the uniform and hexahedral grids generated from computational fluid dynamics is presented for the analysis of aero-optical performance. A single grid is taken as a cell with isotropy and homogeneity inside, and it is assumed that the light rays transmit grid by grid. Ray tracing is employed to track the transmission through the flow of supersonic fluids, and a recursive algorithm is derived. The line-of-sight errors and optical path differences produced by the mean density fields were calculated, the phase variances brought from the density fluctuations were computed, and the Strehl ratios were figured out. This method potentially provides a solution for the prediction of aero-optical effects. PMID- 17694099 TI - Determination of optical probe interrogation field of near-infrared reflectance: phantom and Monte Carlo study. AB - An optical probe used to localize human brain tissues in vivo has been reported previously. It was able to sense the underlying tissue structure with an optical interrogation field, termed as "look ahead distance" (LAD). A new side-firing probe has been designed with its optical window along its side. We have defined the optical interrogation field of the new side probe as "look aside distance" (LASD). The purpose of this study is to understand the dependence of the LAD and LASD on the optical properties of tissue, the light source intensity, and the integration time of the detector, using experimental and computational methods. The results show that a decrease in light intensity does decrease the LAD and LASD and that an increase in integration time of detection may not necessarily improve the depths of LAD and LASD. Furthermore, Monte Carlo simulation results suggest that the LAD/LASD decreases with an increase in reduced scattering coefficient to a point, after which the LAD/LASD remains constant. We expect that an optical interrogation field of a tip or side probe is approximately 1-2 mm in white matter and 2-3.5 mm in gray matter. These conclusions will help us optimally manipulate the parameter settings during surgery and determine the spatial resolution of the probe. PMID- 17694100 TI - Quantifying a similarity of classes of texture images. AB - To quantify the concept of similarity between classes of images three measures and algorithms of calculation are proposed. The first measure is calculated through the frequency of misclassification of subimages sampled randomly from images. The second one is calculated through the cross membership of the mass center of a class in a feature space. The third measure is defined through the membership of subimages, using the distance between each subimage and the mass center of a class in a feature space. We study these measures, classifying images in the coordinated clusters representation (CCR) feature space with the minimum distance classifier. A database of images of Rosa Porrino granite tiles, previously classified by three human experts, is used in the experiments. The calculated similarity between classes is in excellent accordance with the qualitative evaluation by the human experts. PMID- 17694101 TI - Images of strips on and trenches in substrates. AB - The computation of images of lines or strips on a substrate and trenches in a substrate or a layer above a substrate, all made of dielectric or conducting materials, is presented. The method is based on integral equations, of the single integral-equation kind, equivalent to Maxwell's equations and on Fourier optics. Examples of computed images illustrating some of the features found in the images are provided. Approximations involved in the model of the actual scatterer and microscope as well as in the theoretical and numerical representations are discussed. PMID- 17694102 TI - All-optical switch based on two-pump four-wave mixing in fibers without a frequency shift. AB - We report an all-optical switch based on two-pump four-wave mixing in fibers. The switched signal is not shifted in frequency in this scheme. For different signal wavelengths, the pump wavelengths and powers can be optimized to achieve the best performance. The principle of how to design the switch is discussed in detail. A high extinction ratio of -60 dB is obtained when the pump parameters are optimized by a genetic algorithm that exhibits good convergence property and high computing efficiency. The effect of zero-dispersion wavelength fluctuations along the fiber on the switch is analyzed. PMID- 17694103 TI - Guiding radar signals by arrays of laser-induced filaments: finite-difference analysis. AB - Circular arrays of plasma filaments induced by femtosecond laser pulses in atmospheric air are shown to support guided modes of electromagnetic radiation in the centimeter and millimeter wavelength range. With the refractive index of laser-induced filaments being lower than the refractive index of nonionized air, arrays of such filaments can serve as a structured waveguide cladding, providing an index guiding of radar signals in a nonionized gas region. In spite of attenuation of radar radiation induced by plasma absorption, filament-array waveguides are shown to enhance radar signal transmission relative to freely propagating radar beams. PMID- 17694104 TI - Scalar diffraction modeling in optical disk recording using wave function assembling. AB - A new scalar diffraction modeling method for simulating the readout signal of optical disks is described. The information layer is discretized into pixels that are grouped in specific ways to form written and unwritten areas. A set of 2D wave functions resulting from these pixels at the detection aperture is established. A readout signal is obtained via the assembly of wave functions from this set according to the content under the scanning spot. The method allows efficient simulation of jitter noise due to edge deformation of recorded marks, which is important at high densities. It is also capable of simulating a physically irregular mark, thereby helping to understand and optimize the recording process. PMID- 17694105 TI - Wavelength demultiplexing with layered multiple Bragg gratings in LiNbO3:Fe crystal. AB - Dense wavelength division multiplexing (DWDM) is an important technology for expanding the capacity of optical network. The optical component based on the superimposed Bragg gratings shows that it can be used as one of advantageous multichannel components because of its excellent angle and wavelength selectivities. An optimized method for recording multiple Bragg gratings for wavelength demultiplexing in optical telecommunication band is proposed to achieve gratings with equal diffraction efficiency. A structure of three layers with twenty four gratings is demonstrated in a LiNbO(3):Fe crystal by employing the optimized recording method. Then an initial wavelength demultiplexing experiment based on the formed gratings is carried out in optical telecommunication C-band. The results obtained by measuring and analyzing the transmitted spectra of the fabricated gratings show that the diffraction efficiencies of the gratings are uniform. It is suggested that this kind of multiple gratings can be used for increasing the number of the demultiplexed wavelengths in recording medium with unit volume for WDM. PMID- 17694106 TI - Moment-matching method for extracting beam jitter and boresight in experiments with satellites of small physical cross section. AB - The boresight and atmospheric jitter errors in a satellite tracking experiment are currently estimated by matching the probability density function (PDF) of the received signal counts with a set of PDFs of the signal for several combinations of jitter and boresight errors and then the best choice of jitter and boresight error is accepted via the chi-square test. Here a technique that can estimate atmospheric beam jitter and boresight error directly in a satellite active tracking experiment using the moments of the returns off the satellites is proposed. That is, we use the theoretical PDF for the signal return from a small target and compute the corresponding theoretical PDF moments. We can then form a few equations from these moments with only two unknowns, namely, the jitter and boresight. Solving for the unknowns is then unambiguous and very rapid. The method is valid for small physical cross-section targets and has been verified by using simulation and experimental data. Extending the case to asymmetric jitter and asymmetric boresight is possible. PMID- 17694107 TI - Multifrequency erbium-doped fiber laser operating at room temperature. AB - A method to realize room-temperature operation of a multifrequency Er-doped fiber laser with low-frequency shift feedback placed within a linear laser cavity is theoretically proposed and experimentally demonstrated. Simultaneous multiwavelength lasing with 0.5 nm wavelength spacing is experimentally demonstrated by applying a sinusoidal signal of 10 kHz to a fiber phase modulator inserted within the linear cavity to prevent single wavelength steady-state oscillation. In the linear cavity, an all-polarization-maintaining fiber Sagnac loop is used as a periodic filter, and a single-mode fiber loop with a polarization controller is used as a partial reflector and also as an output port. PMID- 17694108 TI - Calibration of spatially phase-shifted DSPI for measurement of large structures. AB - We present a method for the calibration of a spatially phase-shifted digital speckle pattern interferometer (SPS-DSPI), which was designed and built for the purpose of testing the James Webb space telescope (JWST) optical structures and related technology development structures. The need to measure dynamic deformations of large, diffuse structures to nanometer accuracy at cryogenic temperature is paramount in the characterization of a large diameter space and terrestrial based telescopes. The techniques described herein apply to any situation, in which high accuracy measurement of diffuse structures are required. The calibration of the instrument is done using a single-crystal silicon gauge. The gauge has four islands of different heights that change in a predictable manner as a function of temperature. The SPS-DSPI is used to measure the relative piston between the islands as the temperature of the gauge is changed. The measurement results are then compared with the theoretical changes in the height of the gauge islands. The maximum deviation of the measured rate of change of the relative piston in nm/K from the expected value is 3.3%. PMID- 17694109 TI - Heterodyne wavelength meter for continuous-wave lasers. AB - A wavelength meter based on a heterodyne interferometer is presented. A single wavelength test laser beam is modulated to two orthogonal linearly polarized components with different frequencies by a pair of acousto-optic modulators. Then the modulated laser beam and a two-wavelength laser beam are sent to a heterodyne interferometer in a common path. The ratio of two laser interference phase shifts in the heterodyne interferometer is equal to the ratio of their wavelengths. The heterodyne technique measures the heterodyne interference phase but not the interference intensity, which means that it could measure a light source whose intensity is not stable. The heterodyne interference signal is an alternating signal that can easily magnify and process the circuit that makes up the heterodyne wavelength meter and could be used to measure the low-intensity light source even when there are environmental disturbances. A tunable diode laser wavelength range of 630-637 nm has been measured to an accuracy of 5 parts in 10(7). PMID- 17694110 TI - Accurate determination of the optical performances of antireflective coatings by low coherence reflectometry. AB - We propose to use optical low coherence reflectometry to measure the reflectance of both faces of a plane substrate with one side coated in antireflective layers. We identify, through a detailed theoretical analysis, the optimum configuration and evaluate the expected sensitivity and accuracy of some realistic examples. Finally, we experimentally demonstrate the ability of this method to quantify reflection coefficients as low as 5x10(-7). That way, an accurate characterization of the performances, at 1550 nm, of antireflective coatings deposited on various plane substrates is achieved. PMID- 17694111 TI - Fabrication of highly rotational symmetric quasi-periodic structures by multiexposure of a three-beam interference technique. AB - A simple and efficient interference method for fabricating highly symmetric two dimensional (2-D) quasi-periodic structures (QPSs) is theoretically and experimentally demonstrated. With a three-beam interference technique, one can fabricate a periodic 2-D structure having sixfold symmetry. When this structure is multiduplicated into other specific orientations its combination results in a QPS with multifold symmetry. By use of n exposures with a rotation angle of 60 degrees /n, one can create a 2-D QPS with six n-fold symmetry. The QPS with a super high symmetry level, as high as 60-fold, is demonstrated for the first time to the best of our knowledge. The diffraction pattern of a QPS is consistent with the Fourier transform calculation. The fabricated structures should be useful for many applications, such as isotropic bandgap materials and extraction enhancement of light-emitting diodes. PMID- 17694112 TI - On-orbit vicarious calibration of ocean color sensors using an ocean surface reflectance model. AB - Recent advances in global biogeochemical research demonstrate a critical need for long-term ocean color satellite data records of consistent high quality. To achieve that quality, spaceborne instruments require on-orbit vicarious calibration, where the integrated instrument and atmospheric correction system is adjusted using in situ normalized water-leaving radiances, such as those collected by the marine optical buoy (MOBY). Unfortunately, well-characterized time-series of in situ data are scarce for many historical satellite missions, in particular, the NASA coastal zone color scanner (CZCS) and the ocean color and temperature scanner (OCTS). Ocean surface reflectance models (ORMs) accurately reproduce spectra observed in clear marine waters, using only chlorophyll a (C(a)) as input, a measurement for which long-term in situ time series exist. Before recalibrating CZCS and OCTS using modeled radiances, however, we evaluate the approach with the Sea-viewing Wide-Field-of-view Sensor (SeaWiFS). Using annual C(a) climatologies as input into an ORM, we derive SeaWiFS vicarious gains that differ from the operational MOBY gains by less than +/-0.9% spectrally. In the context of generating decadal C(a) climate data records, we quantify the downstream effects of using these modeled gains by generating satellite-to-in situ data product validation statistics for comparison with the operational SeaWiFS results. Finally, we apply these methods to the CZCS and OCTS ocean color time series. PMID- 17694113 TI - Multipoint phase calibration for improved compensation of inherent wavefront distortion in parallel aligned liquid crystal on silicon displays. AB - The inherent distortion of a reflective parallel aligned spatial light modulator (SLM) may need compensation not only for the backplane curvature but also for other possible nonuniformities caused by thickness variations of the liquid crystal layer across the aperture. First, we build a global look-up table (LUT) of phase modulation versus the addressed gray level for the whole device aperture. Second, when a lack of spatial uniformity is observed, we define a grid of cells onto the SLM aperture and develop a multipoint calibration. The relative phase variations between neighboring cells for a uniform gray level lead us to build a multi-LUT for improved compensation. Multipoint calibration can be done using either phase-shift interferometry or Fourier diffraction pattern analysis of binary phase gratings. Experimental results show the compensation progress in diffractive optical elements displayed on two SLMs. PMID- 17694114 TI - Simultaneous measurement of out-of-plane displacement and slope using a multiaperture DSPI system and fast Fourier transform. AB - The simultaneous quantitative measurement of out-of-plane displacement and slope using the fast Fourier transform method with a single three-aperture digital speckle pattern interferometry (DSPI) arrangement is demonstrated. The method coherently combines two sheared object waves with a smooth reference wave at the CCD placed at the image plane of an imaging lens with a three-aperture mask placed in front of it. The apertures also introduce multiple spatial carrier fringes within the speckle. A fast Fourier transform of the image generates seven distinct diffraction halos in the spectrum. By selecting the appropriate halos, one can directly obtain two independent out-of-plane displacement phase maps and a slope phase map from the two speckle images, one before and the second after loading the object. It is also demonstrated that by subtracting the out-of-plane displacement phase maps one can generate the same slope phase map. Experimental results are presented for a circular diaphragm clamped along the edges and loaded at the center. PMID- 17694115 TI - Three-dimensional computer model for simulating realistic solid-state lasers. AB - We developed an accurate and fast three-dimensional computer model for simulating realistic solid-state laser systems. An iteration of the beam propagation calculation was developed to account for the counterpropagation of the laser beams in the saturated gain medium and eventually obtain the converged solution for the output beam. An analytic method was devised to account for the curved cavity mirror and the surface deformation of the gain medium induced by the temperature gradient due to pump absorption. The temperature gradient induced thermal lensing and stress birefringence is also properly included in the model calculation. This model has been validated and shown to be very accurate and efficient for modeling three-dimensional laser systems in a personal computer. PMID- 17694116 TI - Frequency conversion of femtosecond laser pulses in an engineered aperiodic poled optical superlattice. AB - We theoretically propose a procedure based on a cascading genetic algorithm for the design of aperiodically quasi-phase-matched gratings for frequency conversion of optical ultrafast pulses during difference-frequency generation. By designing the sequence of a domain inversion grating, different wavelengths at the output idler pulse almost have the same phase response, so femtosecond laser pulses at wavelength 800 nm can be shifted to other wavelengths without group-velocity mismatch. PMID- 17694117 TI - Grating-coupled transmission-type surface plasmon resonance sensors based on dielectric and metallic gratings. AB - We investigated grating-coupled transmission-type surface plasmon resonance (SPR) for sensing applications. In the transmission-type SPR structure, propagating surface plasmons are outcoupled to radiation modes by dielectric and metallic gratings on a metal film. The results calculated in air and water suggest that the proposed structures present extremely linear sensing characteristics. In terms of a figure of merit, a metallic grating-based structure performs 5.4 and 3.7 times better than that of a dielectric grating in air and water, respectively. PMID- 17694118 TI - Optical and electrical properties between 0.4 and 12 microm for Sn-doped In2O3 films by pulsed laser deposition and cathode sputtering. AB - Optical properties of Sn-doped In(2)O(3) (ITO) have been studied in the optical range of 0.4-12 microm. A deposition has been made on BK7 glass, magnesium fluoride, sapphire, and zinc sulfide substrates. The layers have been characterized by their optical properties, DC electrical sheet resistivity, and Hall mobility. Sheet resistivity lies in the range of 6.8-318 Omega/sq for thicknesses between 16 and 280 nm. The best carrier mobility is obtained on BK7 and sapphire substrates, up to approximately 50 cm(2)/V s. The material shows good infrared transparency in the 3-5 microm range on magnesium fluoride and 0.4 4 microm on sapphire, and it is usable for practical applications up to 12 microm on zinc sulfide. Simulations have been carried out for optical indices and spectra calculations. The Drude model has been used to exploit the results in either direction: from electrical measured data to the simulation of optical spectra and indices, and from measured optical spectra to simulated optical indices and electrical parameters (mobility, carrier density). Hall mobility is considered a worthy and convenient material quality criteria for materials aimed at optics. PMID- 17694119 TI - Vibration measurement by temporal Fourier analyses of a digital hologram sequence. AB - A method for whole-field noncontact measurement of displacement, velocity, and acceleration of a vibrating object based on image-plane digital holography is presented. A series of digital holograms of a vibrating object are captured by use of a high-speed CCD camera. The result of the reconstruction is a three dimensional complex-valued matrix with noise. We apply Fourier analysis and windowed Fourier analysis in both the spatial and the temporal domains to extract the displacement, the velocity, and the acceleration. The instantaneous displacement is obtained by temporal unwrapping of the filtered phase map, whereas the velocity and acceleration are evaluated by Fourier analysis and by windowed Fourier analysis along the time axis. The combination of digital holography and temporal Fourier analyses allows for evaluation of the vibration, without a phase ambiguity problem, and smooth spatial distribution of instantaneous displacement, velocity, and acceleration of each instant are obtained. The comparison of Fourier analysis and windowed Fourier analysis in velocity and acceleration measurements is also presented. PMID- 17694120 TI - Phase-matching properties for AgGaGeS4. AB - The phase-matching conditions of AgGaGeS(4) have been measured for second harmonic generation at 0.8 and 5.3 microm, and difference-frequency generation at 2.2, 3.6-5.1, and 4.8-11.8 microm. The improved Sellmeier equations that reproduce well the various phase-matching conditions are presented. PMID- 17694121 TI - Passive Q-switching of diode pumped Nd:KGd(WO4)2 lasers by V3+:Y3Al5O12 crystal with anisotropy of nonlinear absorption. AB - Use of a V(3+):Y(3)Al(5)O(12) crystal as a saturable absorber Q-switch for 1.07 and 1.35 microm Nd:KGd(WO(4))(2) diode pumped lasers shows a considerable dependence of output characteristics on the orientation of the intracavity field polarization vector regarding V(3+):Y(3)Al(5)O(12) crystallographic axes. Anisotropy of nonlinear absorption of V(3+) ions in a Y(3)Al(5)O(12) single crystal at wavelengths of 1.08 and 1.35 microm has been experimentally studied. The experimental data are analyzed within the framework of a phenomenological model when the V(3+) ions are described as three sets of linear dipoles oriented along the crystallographic axes. Ground-state and excited-state absorption cross sections at 1.08 and 1.35 mum are evaluated to be sigma(gsa)=3.4x10(-18) cm(2), sigma(esa)=3.0x10(-19) cm(2) and sigma(gsa)=5.4x10(-18) cm(2), sigma(esa)=4.8x10( 19) cm(2), respectively. Saturation fluence and intensity at 1.08 and 1.35 microm are estimated as 55 mJ/cm(2) and 1.1 MW/cm(2), respectively. PMID- 17694122 TI - Interaction of a laser beam with the rotational lines of nitrogen in the wavelength region of 5700 A. AB - Propagation of a dye laser beam of wavelength 5700 A through nitrogen is considered. Values of transmittance, averaged over intervals of 0.5 cm(-1), are obtained for absorber thicknesses of 0.1, 1, and 10 atm-cm, using the quasi random model of molecular band absorption. From these values, intensities of the absorption lines in the first positive system of N(2) are simulated in the frequency interval of 17,540-17,548 cm(-1). PMID- 17694123 TI - Two-point time-series measurementsof hydroxyl concentration in a turbulent nonpremixed flame. AB - Quantitative two-point hydroxyl time-series measurements have been performed in a turbulent nonpremixed flame by using two-point picosecond time-resolved laser induced fluorescence. The current diagnostic system has been improved from its preliminary version to address optical aberrations and fluorescence lifetime fluctuations. In particular, with a newly designed collection system, the aberration-limited blur spot is reduced from 6 mm to 180 microm. Additional photon-counting channels enable the recovery of absolute OH concentrations through a triple-bin integration method. The present research represents what we believe to be the first application of this two-point technique to turbulent flames. Two independent schemes have been applied to remove uncorrelated noise in the derived two-point statistics. We show that optical aberrations can have a significant effect on space-time correlations. However, the sampling rate and fluctuations in the fluorescence lifetime barely affect the spatial autocorrelation function and thus the integral length scale. Such length scales for hydroxyl are found to rise linearly with increasing axial distance at peak [OH] locations. Along the jet centerline, the integral length scale varies slightly below the flame tip but increases rapidly above the flame tip. In addition, the OH length scale demonstrates the same trend as the OH time scale along the jet centerline, but the opposite trend at peak [OH] locations. PMID- 17694124 TI - Design and optimization of space-variant photonic crystal filters. AB - A space-variant photonic crystal filter is designed and optimized that may be placed over a detector array to perform filtering functions tuned for each pixel. The photonic crystal is formed by etching arrays of holes through a multilayer stack of alternating high and low refractive index materials. Position of a narrow transmission notch within a wide reflection band is varied across the device aperture by adjusting the diameter of the holes. Numerical simulations are used to design and optimize the geometry of the photonic crystal. As a result of physics inherent in the etching process, the diameter of the holes reduces with depth, producing a taper. Optical performance was found to be sensitive to the taper, but a method for compensation was developed where film thickness is varied through the device. PMID- 17694125 TI - Scattering properties of microalgae: the effect of cell size and cell wall. AB - The main objective of this work was to investigate how the cell size and the presence of a cell wall influence the scattering properties of the green microalgae Chlamydomonas reinhardtii. The growth cycle of two strains, one with a cell wall and one without, was synchronized to be in the same growth phase. Measurements were conducted at two different phases of the growth cycle on both strains of the algae. It was found that the shape of the scattering phase function was very similar for both strains at both growth phases, but the regular strain with a cell wall scatters more strongly than the wall-less mutant. It was also found that the mutant strain has a stronger increase in scattering than the regular strain, as the algae grow, and that the scattering from the regular strain is more wavelength dependent than from the mutant strain. PMID- 17694126 TI - Simultaneous defocusing of the aperture and medium on a spectroholographic storage system. AB - In a spectroholographic storage system the defocusing method is often used to obtain spectrum uniformity and improve the quality of the recorded information. However, defocusing introduces vignette and stronger interpixel cross talk in the marginal field of view. We report a method that defocuses the aperture and medium together. Based on the pixel spread function, two inequalities are introduced to estimate the upper and lower bounds of the energy received at the CCD. We balance the spectrum uniformity with interpixel cross talk and vignette and then allow the designer to select optimal structure values of the defocusing spectroholographic storage system, i.e., the defocusing value, aperture size, and fill factors for the spatial light modulator and CCD. PMID- 17694127 TI - Extended algorithm for the design of diffractive optical elements around the focal plane. AB - We present a multiplane algorithm for three-dimensional uniform illumination. The large-diameter diffractive optical element simulated by this algorithm homogeneously concentrates more than 86.5% of the incident energy into a 200 microm length of columnar space around the focal plane. The intensity profile in the whole space is nearly flattop, and the beam's quality measured by the root mean square is less than 20.6%. The algorithm is very useful if a great deal of tolerance is required for the installation error of the optical system or if it is used for some particular application, such as uniform illumination on an incline plane. PMID- 17694128 TI - 1.54-microm TM-mode waveguide optical isolator based on the nonreciprocal-loss phenomenon: device design to reduce insertion loss. AB - We developed a 1.5-microm band TM-mode waveguide optical isolator that makes use of the nonreciprocal-loss phenomenon. The device was designed to operate in a single mode and consists of an InGaAlAs/InP ridge-waveguide optical amplifier covered with a ferromagnetic MnAs layer. The combination of the optical waveguide and the magnetized ferromagnetic metal layer produces a magneto-optic effect called the nonreciprocal-loss phenomenon--a phenomenon in which the propagation loss of light is larger in backward propagation than it is in forward propagation. We propose the guiding design principle for the structure of the device and determine the optimized structure with the aid of electromagnetic simulation using the finite-difference method. On the basis of the results, we fabricated a prototype device and evaluated its operation. The device showed an isolation ratio of 7.2 dB/mm at a wavelength from 1.53 to 1.55 microm. Our waveguide isolator can be monolithically integrated with other waveguide-based optical devices on an InP substrate. PMID- 17694129 TI - Extension of distance measurement range in a sinusoidal wavelength-scanning interferometer using a liquid-crystal wavelength filter with double feedback control. AB - The optical path difference (OPD) and amplitude of a sinusoidal wavelength scanning (SWS) are controlled with a double feedback control system in an interferometer, so that a ruler marking every wavelength and a ruler with scales smaller than a wavelength are generated. These two rulers enable us to measure an OPD longer than a wavelength. A liquid-crystal Fabry-Perot interferometer (LC FPI) is adopted as a wavelength-scanning device, and double sinusoidal phase modulation is incorporated in the SWS interferometer. Because of a high resolution of the LC-FPI, the upper limit of the measurement range can be extended to 280 microm by the use of the phase lock where the amplitude of the SWS is doubled in the feedback control. The ruler marking every wavelength is generated between 80 microm and 280 microm, and distances are measured with a high accuracy of the order of a nanometer in real time. PMID- 17694130 TI - Statistical detection and imaging of objects hidden in turbid media using ballistic photons. AB - We exploit recent advances in active high-resolution imaging through scattering media with ballistic photons. We derive the fundamental limits on the accuracy of the estimated parameters of a mathematical model that describes such an imaging scenario and compare the performance of ballistic and conventional imaging systems. This model is later used to derive optimal single-pixel statistical tests for detecting objects hidden in turbid media. To improve the detection rate of the aforementioned single-pixel detectors, we develop a multiscale algorithm based on the generalized likelihood ratio test framework. Moreover, considering the effect of diffraction, we derive a lower bound on the achievable spatial resolution of the proposed imaging systems. Furthermore, we present the first experimental ballistic scanner that directly takes advantage of novel adaptive sampling and reconstruction techniques. PMID- 17694131 TI - Corrections to facilitate planar imaging of particle concentration in particle laden flows using Mie scattering, part 1: collimated laser sheets. AB - Planar nephelometry is a laser-based technique of imaging the light scattered from particles to provide information about the local number density of these particles. In many seeded flows of practical interest, such as pulverized coal flames, particle loadings are sufficiently high for the incident laser beam to be severely attenuated. Measurements in these flows are therefore difficult, and limited data are available under these conditions. Laser attenuation experiments were conducted in suspensions of spherical particles in water at various concentrations. This is used to formulate a calibration for the effects of diffuse scattering and laser sheet extinction. A model for the distribution of light through a heavily seeded, light-scattering medium is also developed and is compared with experimental results. It is demonstrated that the scattered signal may be considered proportional to the local particle concentration multiplied by the incident laser power. The incident laser power varies as a function of the attenuation by obscurement. This correction for planar nephelometry images thus extends the technique to provide pseudoquantitative data for instantaneous particle concentration measurements. PMID- 17694132 TI - Improved inverted bubble method for measuring small contact angles at crystal solution-vapor interfaces. AB - We propose and evaluate an improvement of the inverted bubble method, originally proposed by McLachlan and Cox [Rev. Sci. Instrum. 46, 80 (1975)], a technique for measuring small contact angles at crystal-solution-vapor interfaces on a gas bubble under a solid immersed in a test solution. A simple experimental setup is used to evaluate the proposed method. We conclude that the method is suitable for measuring small contact angles with a minimum detectable angle of about 3 degrees . Improvements in instrument design are proposed to lower the detection limit to 0.5 degrees or below. PMID- 17694133 TI - Long-term frequency stabilization of a continuous-wave tunable laser with the help of a precision wavelengthmeter. AB - For the first time to our knowledge we experimentally demonstrate an efficient method for the reduction of long-term radiation line drift in single-frequency cw Ti:sapphire and dye lasers that relies on a fast and precise wavelengthmeter together with a digital-analog feedback system. Generation line drift of lasers is reduced approximately by an order of magnitude down to 40 MHz/h, which corresponds to the residual drift in readings of the wavelengthmeter itself. The implemented automatic frequency control system allows us to lock the laser generation frequency to a specified absolute value. This approach may be used in single-frequency lasers of different types (solid-state, fiber, diode, dye lasers, etc.) and allows reduction by an order of magnitude or more of the long term generation line drift in lasers that are not equipped with other systems for long-term stabilization of output radiation frequency. PMID- 17694134 TI - Detection of trace Al in model biological tissue with laser-induced breakdown spectroscopy. AB - Laser-induced breakdown spectroscopy (LIBS), which is an excellent tool for trace elemental analysis, was studied as a method of detecting sub-part-per-10(6) (ppm) concentrations of aluminum in surrogates of human tissue. Tissue was modeled using a 2% agarose gelatin doped with an Al(2)O(3) nanoparticle suspension. A calibration curve created with standard reference samples of known Al concentrations was used to determine the limit of detection, which was less than 1 ppm. Rates of false negative and false positive detection results for a much more realistic sampling methodology were also studied, suggesting that LIBS could be a candidate for the real-time in vivo detection of metal contamination in human soft tissue. PMID- 17694135 TI - White-light interferometry using a channeled spectrum. I. General models and fringe estimation algorithms. AB - Astrometric measurements using stellar interferometry rely on the precise measurement of the central white-light fringe to accurately obtain the optical path-length difference of incoming starlight to the two arms of the interferometer. Because of dispersion in the optical system the optical path length difference is a function of the wavelength of the light and extracting the proper astrometric signatures requires accommodating these effects. One standard approach to stellar interferometry uses a channeled spectrum to determine phases at a number of different wavelengths that are then converted to the path-length delay. Because of throughput considerations these channels are made sufficiently broad so that monochromatic models are inadequate for retrieving the phase/delay information. The presence of dispersion makes the polychromatic modeling problem for phase estimation even more difficult because of its effect on the complex visibility function. We introduce a class of models that rely on just a few spectral and dispersion parameters. A phase-shifting interferometry algorithm is derived that exploits the model structure. Numerical examples are given to illustrate the robustness and precision of the approach. PMID- 17694136 TI - C-band external-cavity wavelength-tunable laser based on a liquid-crystal deflector. AB - A novel C-band external-cavity wavelength-tunable laser is proposed. The laser consists of a semiconductor gain chip, a collimating lens, a fixed etalon, a liquid-crystal deflector and a diffraction grating in a Littrow configuration. The lasing wavelength of this tunable external-cavity laser can be tuned to 19 wavelength channels of 100 GHz spacing. All channels are within 2.5 GHz of the ITU grids with a side-mode suppression ratio of approximately 35 dB over the whole range. PMID- 17694137 TI - Acousto-optic interaction of a Gaussian laser beam with an ultrasonic wave of cylindrical symmetry. AB - We present experimental studies of the interaction between a narrow Gaussian laser beam and a standing cylindrical ultrasonic wave. As a theoretical approach, a Fourier-optics-based successive diffraction model is used. Depending on the ratio of the Gaussian laser beam diameter to the first nodal diameter of the cylindrical ultrasound, light refraction or diffraction is observed. We experimentally investigate the time-averaged light intensity as well as the modulation of light in the far field of light refraction-diffraction by a cylindrical ultrasound. It is revealed that significant focusing appears if the phase front of the incident light is curved. The focusing effects of the acousto optic system depend on the width of the laser beam and curvature of the phase front. Finally, possible applications are discussed. PMID- 17694138 TI - Characterization and calibration of ultraviolet broadband radiometers measuring erythemally weighted irradiance. AB - An ultraviolet calibration center has been established in Davos, Switzerland. It provides a laboratory for characterizing the spectral and angular response of broadband radiometers. The absolute calibration of these instruments is performed through the comparison to the reference spectroradiometer QASUME. We present what we believe to be a novel calibration methodology that explicitly includes the information of the angular and spectral response functions. From the results of the latest broadband intercomparison campaign, the typical uncertainties of these instruments could be obtained. Most radiometers have an expanded uncertainty of approximately 7%. The angular response introduces an uncertainty of 0.9%-7.2%, depending on the cosine error of the radiometer. PMID- 17694139 TI - Graded-index fiber lens proposed for ultrasmall probes used in biomedical imaging. AB - The quality and parameters of probing optical beams are extremely important in biomedical imaging systems both for image quality and light coupling efficiency considerations. For example, the shape, size, focal position, and focal range of such beams could have a great impact on the lateral resolution, penetration depth, and signal-to-noise ratio of the image in optical coherence tomography. We present a beam profile characterization of different variations of graded-index (GRIN) fiber lenses, which were recently proposed for biomedical imaging probes. Those GRIN lens modules are made of a single mode fiber and a GRIN fiber lens with or without a fiber spacer between them. We discuss theoretical analysis methods, fabrication techniques, and measured performance compared with theory. PMID- 17694140 TI - Multiaccess interference in a non-line-of-sight ultraviolet optical wireless sensor network. AB - The concept of exploiting both the scattering properties and the absence of solar radiation in the "solar blind ultraviolet" spectral range for achieving a non line-of-sight (NLOS) communication link for wireless sensor networks has been discussed in scientific literature. We address the issue of the multiaccess interference (MAI) that would be encountered in a simple and low-cost sensor network operating on the above NLOS principle, for different sensor node densities and traffic levels, and use a Poisson model for the sensor node distribution. A metric for evaluation and comparison of sensor node distribution scenarios is derived and used to discuss the performance limitations of NLOS wireless sensor networks operating in the solar blind ultraviolet spectrum. Guidelines for NLOS wireless sensor network design are outlined taking into consideration the cumulative effect of interference from distant sensor nodes, the expected number of hops, and the trade-off between node redundancy and node isolation. The significant contribution of network traffic control to system operability is demonstrated. PMID- 17694141 TI - Recording schedule for partially coherent hologram multiplexing in a photorefractive medium. AB - The exposure schedule for partially coherent hologram multiplexing, in which data pages are multiplexed by multiple signal beams and a single reference beam, is investigated in detail for the case of a pi/2 phase-shifted photorefractive medium. We found that the optimum recording schedule for partially coherent multiplexing cannot be determined by the classical recording schedule theory because of time-constant errors induced by partially coherent interaction between a reference beam and self-diffraction signal beams. To overcome the issue, we derive a modified recursion equation that accounts for the time-constant errors, and we also propose a novel iterative recording-schedule correction algorism for finding the optimum solution. In the calculation with hologram multiplicity of 30 and photorefractive coupling strength of 3.0, we could successfully obtain a flat diffraction-efficiency profile after the second recursion. PMID- 17694142 TI - Study of birefringence of elliptical core photonic crystal fiber using Mathieu function. AB - The birefringence of the elliptical core photonic crystal fiber with circular pores in the cladding has been studied by using higher order Mathieu functions. It is observed that the birefringence decreases with decreasing wavelength. Calculated results also indicate the sensitivity to the radius of the pores in the cladding. High birefringence up to 0.0079 is obtained. The efficacy of this proposed method is proved by comparing the results. PMID- 17694143 TI - Holographic femtosecond laser processing using optimal-rotation-angle method with compensation of spatial frequency response of liquid crystal spatial light modulator. AB - Holographic femtosecond laser processing performs high-speed parallel processing using a computer-generated hologram (CGH) displayed on a liquid crystal spatial light modulator. A critical issue is to precisely control the intensities of the diffraction peaks of the CGH. We propose a method of compensating for the spatial frequency response in the design of CGH using the optimal-rotation-angle method. By applying the proposed method, the uniformity of the diffraction peaks was improved. We demonstrate holographic femtosecond laser processing with two dimensional and three-dimensional parallelism. PMID- 17694144 TI - Single-longitudinal-mode scan of a pulsed double-grating Ti:sapphire oscillator. AB - The method of the single-longitudinal-mode (SLM) scan of a pulsed double-grating Ti:sapphire laser oscillator with the grazing incidence cavity configuration was proposed based on the analysis of the optical path length. The SLM scan was experimentally confirmed for this cavity configuration, where the second grating was rotated around an arbitrary point with the translational scan of a back mirror. PMID- 17694145 TI - Distributed fiber temperature and strain sensor using coherent radio-frequency detection of spontaneous Brillouin scattering. AB - A novel technique that enables coherent detection of spontaneous Brillouin scattering in the radio-frequency (<500 MHz) region with excellent long-term stability has been demonstrated for distributed measurements of temperature and strain in long fiber. An actively stabilized single-frequency Brillouin fiber laser with extremely low phase noise and intensity noise is used as a well defined, frequency-shifted local oscillator for the heterodyne detection, yielding measurements of spontaneous Brillouin scattering with high frequency stability. Based on this approach, a highly stable real-time fiber sensor for distributed measurements of both temperature and strain over long fiber has been developed utilizing advanced digital signal processing techniques. PMID- 17694146 TI - Optical sparse aperture imaging. AB - The resolution of a conventional diffraction-limited imaging system is proportional to its pupil diameter. A primary goal of sparse aperture imaging is to enhance resolution while minimizing the total light collection area; the latter being desirable, in part, because of the cost of large, monolithic apertures. Performance metrics are defined and used to evaluate several sparse aperture arrays constructed from multiple, identical, circular subapertures. Subaperture piston and/or tilt effects on image quality are also considered. We selected arrays with compact nonredundant autocorrelations first described by Golay. We vary both the number of subapertures and their relative spacings to arrive at an optimized array. We report the results of an experiment in which we synthesized an image from multiple subaperture pupil fields by masking a large lens with a Golay array. For this experiment we imaged a slant edge feature of an ISO12233 resolution target in order to measure the modulation transfer function. We note the contrast reduction inherent in images formed through sparse aperture arrays and demonstrate the use of a Wiener-Helstrom filter to restore contrast in our experimental images. Finally, we describe a method to synthesize images from multiple subaperture focal plane intensity images using a phase retrieval algorithm to obtain estimates of subaperture pupil fields. Experimental results from synthesizing an image of a point object from multiple subaperture images are presented, and weaknesses of the phase retrieval method for this application are discussed. PMID- 17694147 TI - Determination of retardation parameters of multiple-order wave plate using a phase-sensitive heterodyne ellipsometer. AB - To characterize the linear birefringence of a multiple-order wave plate (MWP), an oblique incidence is one of the methods available. Multiple reflections in the MWP are produced, and oscillations in the phase retardation measurement versus the oblique incident angle are then measured. Therefore, an antireflection coated MWP is required to avoid oscillation of the phase retardation measurement. In this study, we set up a phase-sensitive heterodyne ellipsometer to measure the phase retardations of an uncoated MWP versus the oblique incident angle, which was scanned in the x-z plane and y-z plane independently. Thus, the effect on multiple reflections by the MWP is reduced by means of subtracting the two measured phase retardations from each other. As a result, a highly sensitive and accurate measurement of retardation parameters (RPs), which includes the refractive indices of the extraordinary ray n(e) and ordinary ray n(o), is obtained by this method. On measurement, a sensitivity (n(e),n(o)) of 10(-6) was achieved by this experiment setup. At the same time, the spatial shifting of the P and S waves emerging from the MWP introduced a deviation between experimental results and the theoretical calculation. PMID- 17694148 TI - Miniature eye-safe laser system for high-resolution three-dimensional lidar. AB - A microchip-laser-pumped optical parametric amplifier produces 35-microJ, 1.537 microm pulses of 190-ps duration at 8 kHz, in a near-diffraction-limited output beam with a Fourier-transform-limited spectrum. The flight-ready laser head is pumped by 20 W of optical power from two fiber-coupled laser-diode arrays, occupies a volume of 0.14 liters, and has a mass of 0.34 kg. PMID- 17694149 TI - Simultaneous determination of bubble diameter and relative refractive index using glare circles. AB - In the shadow image of a spherical gas bubble, high intensity rings are visible, i.e., glare circles. These can be used to obtain a more precise estimate of the bubble diameter than can be obtained from the shadow contour. The glare circle diameter can also be used to determine the relative refractive index by comparing it with the shadow diameter. The precision of this refractive index measurement reaches the third decimal, which is demonstrated experimentally. Thus, one can simultaneously determine the bubble diameter (from the shadow contour) and the relative refractive index (from the glare circle). PMID- 17694150 TI - Fabrication of x-ray zone plates by surface-plasma chemical vapor deposition. AB - A new cost-efficient sputter-slice technology for hard x-ray (10-30 keV) Fresnel zone plates fabrication, imposing no limitation to aspect ratio, is proposed. By means of a plasma chemical process, SiO(2)/Si(1-x)Ge(x)O(2) glassy film multilayer structures are deposited on a lateral surface of a silica rod, outermost layers being as thin as 100 nm. It has been shown by numerical simulation that for x=0.2 germanium fraction, 100-300 microm zone plate thickness and the number of zones of about 1000, first order diffraction efficiency as high as 20%-30% at the energy of approximately 20 keV can be achieved. PMID- 17694151 TI - Dispersion balancing of variable-delay monolithic pulse splitters. AB - We propose the use of birefringent materials to attain pulse separations suitable for pump-probe spectroscopy and spectral interferometry. By choice of material thickness and cut angle, it is possible to balance second-order dispersion while allowing for variable delays. The generated pulse pair is used to calibrate the phase response of an ultrafast liquid-crystal pulse shaper, and in the measurement of a rotational wave packet in impulsively aligned CO(2) molecules. PMID- 17694152 TI - Direct evaluation of reflector effects on radiant flux from InGaN-based light emitting diodes. AB - A metal layer formed on the backside of InGaN/sapphire-based light-emitting diodes deteriorates the inherent optical power output. An experimental approach of a suspended die is employed to study the effects of such metal layers via a direct comparison in radiant flux from a discrete die with and without a reflector. A sphere package that employs no reflector is proposed and fabricated. Light extraction of the sphere design is discussed; a light source in the sphere package would not have to be either an ideal point or placed at the center of the sphere, due to a finite critical angle at the sphere/air interface. PMID- 17694153 TI - Pupil plane imager for estimation of turbulence over long horizontal paths. AB - A pupil plane imaging system, consisting of a camera and optics that image the entrance pupil of a telescope, measures scintillation induced by atmospheric turbulence. Algorithms are developed to estimate the distribution of turbulence from scintillation assuming the well known relationship between scintillation scale size and the range of turbulence layer. The algorithms were exercised using a 75 cm pupil within a 1 meter telescope located at North Oscura Peak in New Mexico, based on light from a source 52.6 km away. Estimates of the C(n)(2) profile over the path are derived using coarse range bins. From the C(n)(2) profile, an estimate of Fried's transverse coherence length was computed and compared with that from other sensors. The algorithm is tested in several ways. Error sources are discussed, including the intrinsic insensitivity of the technique to turbulence near the pupil. PMID- 17694154 TI - Interferometric generation of parametrically shaped polarization pulses. AB - We demonstrate the capabilities of the recently introduced interferometric parallel pulse shaper setup and present a method for fully tailoring the three dimensional electrical field of femtosecond laser pulses. The possibility of producing parametric polarization pulses with arbitrary orientations and ellipticities in time is demonstrated with a selection of example pulses. PMID- 17694155 TI - In vivo 783-channel diffuse reflectance imaging system and its application. AB - A fiber-based reflectance imaging system was constructed to produce in vivo absorption spectroscopic images of biological tissues with diffuse light in the cw domain. The principal part of this system is the 783-channel fiber probe, composed of 253 illumination fibers and 530 detection fibers distributed in a 20x20 mm square region. During illumination with the 253 illumination fibers, diffuse reflected lights are collected by the 530 detection fibers and recorded simultaneously as an image with an electron multiplying CCD camera for fast data acquisition. After signal acquisition, a diffuse reflectance image was reconstructed by applying the spectral normalization method we devised. To test the applicability of the spectral normalization, we conducted two phantom experiments with chicken breast tissue and white Delrin resin by using animal blood as an optical inhomogeneity. In the Delrin phantom experiment, we present images produced by two methods, spectral normalization and reference signal normalization, along with a comparison of the two. To show the feasibility of our system for biomedical applications, we took images of a human vein in vivo with the spectral normalization method. PMID- 17694156 TI - Multiple-source optical diffusion approximation for a multilayer scattering medium. AB - A method for improving the accuracy of the optical diffusion theory for a multilayer scattering medium is presented. An infinitesimally narrow incident light beam is replaced by multiple isotropic point sources of different strengths that are placed in the scattering medium along the incident beam. The multiple sources are then used to develop a multilayer diffusion theory. Diffuse reflectance is then computed using the multilayer diffusion theory and compared with accurate data computed by the Monte Carlo method. This multisource method is found to be significantly more accurate than the previous single-source method. PMID- 17694157 TI - Estimation of laser beam pointing parameters in the presence of atmospheric turbulence. AB - The problem of estimating mechanical boresight and jitter performance of a laser pointing system in the presence of atmospheric turbulence is considered. A novel estimator based on maximizing an average probability density function (pdf) of the received signal is presented. The proposed estimator uses a Gaussian far field mean irradiance profile, and the irradiance pdf is assumed to be lognormal. The estimates are obtained using a sequence of return signal values from the intended target. Alternatively, one can think of the estimates being made by a cooperative target using the received signal samples directly. The estimator does not require sample-to-sample atmospheric turbulence parameter information. The approach is evaluated using wave optics simulation for both weak and strong turbulence conditions. Our results show that very good boresight and jitter estimation performance can be obtained under the weak turbulence regime. We also propose a novel technique to include the effect of very low received intensity values that cannot be measured well by the receiving device. The proposed technique provides significant improvement over a conventional approach where such samples are simply ignored. Since our method is derived from the lognormal irradiance pdf, the performance under strong turbulence is degraded. However, the ideas can be extended with appropriate pdf models to obtain more accurate results under strong turbulence conditions. PMID- 17694158 TI - Imaging polarimetry of forest canopies: how the azimuth direction of the sun, occluded by vegetation, can be assessed from the polarization pattern of the sunlit foliage. AB - Radiance, color, and polarization of the light in forests combine to create complex optical patterns. Earlier sporadic polarimetric studies in forests were limited by the narrow fields of view of the polarimeters used in such studies. Since polarization patterns in the entire upper hemisphere of the visual environment of forests could be important for forest-inhabiting animals that make use of linearly polarized light for orientation, we measured 180 degrees field-of view polarization distributions in Finnish forests. From a hot air balloon we also measured the polarization patterns of Hungarian grasslands lit by the rising sun. We found that the pattern of the angle of polarization alpha of sunlit grasslands and sunlit tree canopies was qualitatively the same as that of the sky. We show here that contrary to an earlier assumption, the alpha-pattern characteristic of the sky always remains visible underneath overhead vegetation, independently of the solar elevation and the sky conditions (clear or partly cloudy with visible sun's disc), provided the foliage is sunlit and not only when large patches of the clear sky are visible through the vegetation. Since the mirror symmetry axis of the alpha-pattern of the sunlit foliage is the solar antisolar meridian, the azimuth direction of the sun, occluded by vegetation, can be assessed in forests from this polarization pattern. Possible consequences of this robust polarization feature of the optical environment in forests are briefly discussed with regard to polarization-based animal navigation. PMID- 17694159 TI - Longitudinal temperature distribution in an end-pumped solid-state amplifier medium: application to a high average power diode pumped Yb:YAG thin disk amplifier. AB - We propose a simple analytical derivation making it possible to compute a one dimensional temperature variation in an end-pumped solid-state laser. This derivation takes into account the pump intensity variation along the crystal, the doping concentration, and temperature dependence of the thermal conductivity. We then compare this simulation with the one usually used, which does not take into account any of these dependences. The results show that, at room temperature, the two methods are in good agreement, but at a cryogenic temperature where the thermal conductivity varies fast with temperature, a large discrepancy is found, and the conventional computations underestimate both the average temperature and the longitudinal gradient. PMID- 17694160 TI - Background subtraction in pulsed photoacoustics through neural-network processing. AB - We report on the application of neural-network processing to pulsed photoacoustics for improving the detection limit by subtracting the window heating-associated background. This technique was applied to the measurement of ethylene traces excited by a TEA (transverse electrical discharge in gas at atmospheric pressure) CO(2) laser. The signal contains a term that shows absorption saturation, characteristic of the absorbing gas, and another, generated by window heating, linearly dependent on laser energy. At low concentrations, normalization to laser energy is not possible owing to the different absorption mechanisms. To overcome this problem we relied on a neural network filter, trained with experimentally obtained patterns, that subtracts the background and returns the sample concentration. This way, we reduced the detection limit to 20% of the previous limit obtained by reading the main resonance peak amplitude. PMID- 17694161 TI - Differences in Fourth-Graders' Participation Rates Across Four School-Based Nutrition Studies. AB - Federal policy has encouraged researchers to include children in research studies; thus, it is important to report experiences recruiting children to participate in studies. This article compares fourth-graders' participation rates across four school-based nutrition studies conducted in one school district in a southeastern state. For each study, children were observed eating school meals (breakfast and lunch); interviewed regarding dietary intake; and weighed and measured. For Study 1, children from 11 schools received $10 per interview for up to two interviews conducted in the morning at school. For Study 2, children from 10 schools received $25 if interviewed once in the evening, either by telephone or in a van parked outside the child's home. For Study 3, children from three schools received $10 per interview for up to three interviews held in the evening by telephone. For Study 4, children from six schools received $15 per interview for up to two interviews conducted either in the morning or afternoon at school, or in the evening by telephone. Recruitment procedures were similar for all studies.Participation rates were 73% (n=635) for Study 1, 57% (n=432) for Study 2, 66% (n=158) for Study 3, and 71% (n=296) for Study 4. Logistic regression was used to determine whether study (1, 2, 3, 4), race (black, white), or gender (male, female) were significant predictors of participation (agreed, denied). The results indicated that study (p<0.0001), race (p=0.0198), and gender (p=0.0188) were significant predictors, however, no two-factor interactions among these effects were significant. Post hoc pairwise comparisons with Bonferroni adjustment indicated that agreement to participate for Study 2 was lower (p<0.0001) than that for Studies 1, 3, and 4, which did not differ. Agreement to participate across all four studies was higher for black (69%) than white (63%; p=0.0054) children and for females (69%) than males (64%; p=0.0209). Schools provide a natural environment for nutrition research because school foodservice programs feed millions of children one or two meals (breakfast and/or lunch) each school day. Observations of children eating school meals provide a convenient and relatively unobtrusive means of validating children's dietary recalls. Thus, at some point, most child nutrition professionals are likely to be involved in research either directly (i.e. by conducting studies themselves) or indirectly (i.e. by allowing others access to their school cafeterias to collect data).This paper references the following data:Table 1. Similarities and Differences in the Designs for Each of the Four Studies.Table 2. Number and Percent of Fourth-Grade Children Who Agreed or Denied to Participate by Race and Gender Across all Four Studies Combined.Table 3. Number and Percent of Fourth-Grade Children Who Agreed or Denied to Participate by Gender and Race for Each of the Four Studies Separately. PMID- 17694162 TI - Neurovascular coupling and epilepsy: hemodynamic markers for localizing and predicting seizure onset. AB - Hemodynamic surrogates of epileptic activity are being used to map epileptic foci with PET, SPECT, and fMRI. However, there are few studies of neurovascular coupling in epilepsy. Recent data indicate that cerebral blood flow, although focally increased at the onset of a seizure, may be temporarily inadequate to meet the metabolic demands of both interictal and ictal epileptic events. Transient focal tissue hypoxia and hyperperfusion may be excellent markers for the epileptic focus and may even precede the onset of the ictal event. PMID- 17694163 TI - Is behavior in temporal lobe epilepsy different than in other epilepsies? The jury is out. PMID- 17694164 TI - The status of intravenous valproate for status. PMID- 17694165 TI - Epilepsy surgery in the frontal lobe: terra incognita or new frontier? PMID- 17694166 TI - The genetics of temporal lobe epilepsy and implications for treatment. PMID- 17694167 TI - Helpful data, but less certainty. PMID- 17694168 TI - Seizures beget seizures: a lack of experimental evidence and clinical relevance fails to dampen enthusiasm. PMID- 17694169 TI - Does leakage of the blood-brain barrier mediate epileptogenesis? PMID- 17694170 TI - Valproate enhances neuropeptide y expression: modulating the modulators. PMID- 17694171 TI - Glutamate receptors: finally fingered in inherited epilepsy? PMID- 17694172 TI - The best model for a cat is the same cat...or is it? PMID- 17694173 TI - Is too much inhibition to blame in autosomal dominant nocturnal frontal lobe epilepsy? PMID- 17694174 TI - The epileptic hippocampus revisited: back to the future. PMID- 17694175 TI - A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia. AB - Targeted disruption of a highly conserved distal enhancer reduces expression of the PU.1 transcription factor by 80% and leads to acute myeloid leukemia (AML) with frequent cytogenetic aberrations in mice. Here we identify a SNP within this element in humans that is more frequent in AML with a complex karyotype, leads to decreased enhancer activity, and reduces PU.1 expression in myeloid progenitors in a development-dependent manner. This SNP inhibits binding of the chromatin remodeling transcriptional regulator special AT-rich sequence binding protein 1 (SATB1). Overexpression of SATB1 increased PU.1 expression, and siRNA inhibition of SATB1 downregulated PU.1 expression. Targeted disruption of the distal enhancer led to a loss of regulation of PU.1 by SATB1. Interestingly, disruption of SATB1 in mice led to a selective decrease of PU.1 RNA in specific progenitor types (granulocyte-macrophage and megakaryocyte-erythrocyte progenitors) and a similar effect was observed in AML samples harboring this SNP. Thus we have identified a SNP within a distal enhancer that is associated with a subtype of leukemia and exerts a deleterious effect through remote transcriptional dysregulation in specific progenitor subtypes. PMID- 17694176 TI - Thyrocyte-specific Gq/G11 deficiency impairs thyroid function and prevents goiter development. AB - The function of the adult thyroid is regulated by thyroid-stimulating hormone (TSH), which acts through a G protein-coupled receptor. Overactivation of the TSH receptor results in hyperthyroidism and goiter. The Gs-mediated stimulation of adenylyl cyclase-dependent cAMP formation has been regarded as the principal intracellular signaling mechanism mediating the action of TSH. Here we show that the Gq/G11-mediated signaling pathway plays an unexpected and essential role in the regulation of thyroid function. Mice lacking the alpha subunits of Gq and G11 specifically in thyroid epithelial cells showed severely reduced iodine organification and thyroid hormone secretion in response to TSH, and many developed hypothyroidism within months after birth. In addition, thyrocyte specific Galphaq/Galpha11-deficient mice lacked the normal proliferative thyroid response to TSH or goitrogenic diet, indicating an essential role of this pathway in the adaptive growth of the thyroid gland. Our data suggest that Gq/G11 and their downstream effectors are promising targets to interfere with increased thyroid function and growth. PMID- 17694177 TI - TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways. AB - Transgenic mice with cardiac-restricted overexpression of secretable TNF (MHCsTNF) develop progressive LV wall thinning and dilation accompanied by an increase in cardiomyocyte apoptosis and a progressive loss of cytoprotective Bcl 2. To test whether cardiac-restricted overexpression of Bcl-2 would prevent adverse cardiac remodeling, we crossed MHCsTNF mice with transgenic mice harboring cardiac-restricted overexpression of Bcl-2. Sustained TNF signaling resulted in activation of the intrinsic cell death pathway, leading to increased cytosolic levels of cytochrome c, Smac/Diablo and Omi/HtrA2, and activation of caspases -3 and -9. Cardiac-restricted overexpression of Bcl-2 blunted activation of the intrinsic pathway and prevented LV wall thinning; however, Bcl-2 only partially attenuated cardiomyocyte apoptosis. Subsequent studies showed that c FLIP was degraded, that caspase-8 was activated, and that Bid was cleaved to t Bid, suggesting that the extrinsic pathway was activated concurrently in MHCsTNF hearts. As expected, cardiac Bcl-2 overexpression had no effect on extrinsic signaling. Thus, our results suggest that sustained inflammation leads to activation of multiple cell death pathways that contribute to progressive cardiomyocyte apoptosis; hence the extent of such programmed myocyte cell death is a critical determinant of adverse cardiac remodeling. PMID- 17694180 TI - The AOFAS visitation program to Walter Reed. PMID- 17694179 TI - Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. AB - Loss of cardiac myocytes in heart failure is thought to occur largely through an apoptotic process. Here we show that heart failure can also be precipitated through myocyte necrosis associated with Ca2+ overload. Inducible transgenic mice with enhanced sarcolemmal L-type Ca2+ channel (LTCC) activity showed progressive myocyte necrosis that led to pump dysfunction and premature death, effects that were dramatically enhanced by acute stimulation of beta-adrenergic receptors. Enhanced Ca2+ influx-induced cellular necrosis and cardiomyopathy was prevented with either LTCC blockers or beta-adrenergic receptor antagonists, demonstrating a proximal relationship among beta-adrenergic receptor function, Ca2+ handling, and heart failure progression through necrotic cell loss. Mechanistically, loss of cyclophilin D, a regulator of the mitochondrial permeability transition pore that underpins necrosis, blocked Ca2+ influx-induced necrosis of myocytes, heart failure, and isoproterenol-induced premature death. In contrast, overexpression of the antiapoptotic factor Bcl-2 was ineffective in mitigating heart failure and death associated with excess Ca2+ influx and acute beta-adrenergic receptor stimulation. This paradigm of mitochondrial- and necrosis-dependent heart failure was also observed in other mouse models of disease, which supports the concept that heart failure is a pleiotropic disorder that involves not only apoptosis, but also necrotic loss of myocytes in association with dysregulated Ca2+ handling and beta-adrenergic receptor signaling. PMID- 17694181 TI - Orthopedic surgery considerations in post-polio syndrome. PMID- 17694182 TI - Implantable direct-current bone stimulators in high-risk and revision foot and ankle surgery: a retrospective analysis with outcome assessment. AB - Efficacy and morbidity of a surgically implanted direct-current bone stimulator were evaluated in 38 patients (40 feet) with fracture nonunion or at high risk for nonunion; 14 of these patients had Charcot (diabetic) neuroarthropathy. Union occurred in 26 (65%) of the 40 feet; complications other than nonunion occurred in 16 feet (40%). Two amputations (5%) were performed in cases of intractable neuritis and deep infection. Of the 6 cases of deep infection (15%), 5 resolved with device removal, and the sixth case required below-knee amputation. Use of a bone stimulator in patients with diabetes may be problematic, but the device did not have any adverse effects in other high-risk patients. PMID- 17694178 TI - Brain fatty acid synthase activates PPARalpha to maintain energy homeostasis. AB - Central nervous system control of energy balance affects susceptibility to obesity and diabetes, but how fatty acids, malonyl-CoA, and other metabolites act at this site to alter metabolism is poorly understood. Pharmacological inhibition of fatty acid synthase (FAS), rate limiting for de novo lipogenesis, decreases appetite independently of leptin but also promotes weight loss through activities unrelated to FAS inhibition. Here we report that the conditional genetic inactivation of FAS in pancreatic beta cells and hypothalamus produced lean, hypophagic mice with increased physical activity and impaired hypothalamic PPARalpha signaling. Administration of a PPARalpha agonist into the hypothalamus increased PPARalpha target genes and normalized food intake. Inactivation of beta cell FAS enzyme activity had no effect on islet function in culture or in vivo. These results suggest a critical role for brain FAS in the regulation of not only feeding, but also physical activity, effects that appear to be mediated through the provision of ligands generated by FAS to PPARalpha. Thus, 2 diametrically opposed proteins, FAS (induced by feeding) and PPARalpha (induced by starvation), unexpectedly form an integrative sensory module in the central nervous system to orchestrate energy balance. PMID- 17694183 TI - Surgical stabilization of nonplantigrade Charcot arthropathy of the midfoot. AB - Fifty-one adults (28 men, 23 women) with Charcot arthropathy of the midfoot underwent surgical correction. Mean patient age was 58 years (SD, 9.9 years). All affected feet were nonplantigrade and at high risk for ulcers. Before surgery, mean lateral talar-first metatarsal angle was 27.6 degrees (SD, 12.8 degrees). Corrective osteotomy was performed to achieve plantigrade alignment. At minimum 1 year follow-up, 44 of 51 patients had the desired outcome. Mean lateral talar first metatarsal angle had decreased to 6.4 degrees (SD, 7.7 degrees). Despite its associated high complication rate, corrective osteotomy can help patients become ulcer- and infection-free and maintain their ability to walk with commercially available therapeutic footwear. A treatment algorithm is presented. PMID- 17694184 TI - Reduction of high-grade isthmic and dysplastic spondylolisthesis in 5 adolescents. AB - Treatment of high-grade isthmic and dysplastic spondylolisthesis in children and adolescents remains a challenge. Surgical treatment of spondylolisthesis has been recommended in adolescents with pain refractory to nonoperative modalities, slippage progression, or > 50% slippage on presentation. Controversy exists as to the optimal surgical approach for high-grade spondylolisthesis. In this report, we describe 5 cases of high-grade isthmic and dysplastic spondylolisthesis in adolescents and review the literature on surgical treatment for this entity. Operative records, charts, x-rays, and Scoliosis Research Society outcome questionnaires (SRS-22) were retrospectively evaluated for 5 consecutive patients diagnosed with and treated for high-grade spondylolisthesis. Each patient received treatment consisting of decompression, reduction, and circumferential fusion with transpedicular and segmental fixation from a posterior approach. Two patients had transient L5 nerve root deficit, which resolved within 3 months. Reduction benefits include a decrease in shear stresses (and resulting decreased rates of postoperative pseudarthrosis and slip progression), restoration of sagittal alignment and lumbosacral spine balance, and improvement in clinical deformity. PMID- 17694185 TI - A woman with unilateral knee pain in the absence of arthritis or trauma. PMID- 17694186 TI - A unique case of ulnar tunnel syndrome in a bicyclist requiring operative release. AB - The continued growth of recreational and competitive sports is accompanied by the need for health care providers to recognize and treat conditions in athletes that have been traditionally associated with other occupational injury. This is particularly important when early diagnosis and prompt intervention for prevention and treatment may alter the outcome. We present an interesting case of ulnar tunnel syndrome in a high-performance bicyclist with compressive ulnar neuropathy refractory to nonoperative management but successfully treated with surgical release. We review evaluation, diagnosis, and historical and current treatment algorithms. PMID- 17694187 TI - Angled posteroanterior fluoroscopy for L5-S1 discography: a technical note. AB - Lumbar discography, a useful modality for evaluating patients with lower back pain, is performed under fluoroscopy with posteroanterior and lateral fluoroscopic imaging. Despite use of fluoroscopy, needle placement into the L5-S1 disc may be difficult, especially in the presence of degenerative changes. We describe use of angled posteroanterior fluoroscopy with the fluoroscopy beam directed 30 degrees to 40 degrees caudally in a prone patient for clear visualization of the L5-S1 disc space. Use of this radiographic view aids in accurate needle placement and might decrease both procedure duration and fluoroscopic exposition. PMID- 17694188 TI - The new era in the treatment of rheumatoid arthritis. PMID- 17694189 TI - Early intervention in rheumatoid arthritis. PMID- 17694190 TI - New and promising treatments for rheumatoid arthritis. PMID- 17694191 TI - The pathogenesis of rheumatoid arthritis. PMID- 17694192 TI - The merits of regional anesthesia for patients undergoing total hip replacement. PMID- 17694193 TI - Comparison of outcomes of using spinal versus general anesthesia in total hip arthroplasty. AB - Blood loss, operative time, and rate of complications were compared in 606 patients undergoing primary unilateral total hip arthroplasty with either spinal anesthesia (SA) or general anesthesia (GA). Patients were followed for 2 years after surgery. Compared with GA, SA resulted in mean reductions of 12% in operative time, 25% in estimated intraoperative blood loss, 38% in rate of operative blood loss, and 50% in intraoperative transfusion requirements. Compared with patients receiving GA, patients receiving SA had higher hemoglobin levels on postoperative days 1 and 2 and a 20% lower total transfusion requirement. SA appears superior to GA for this procedure. PMID- 17694194 TI - Utility of judet oblique x-rays in preoperative assessment of acetabular periprosthetic osteolysis: a preliminary study. AB - Anteroposterior (AP) x-rays provide limited information about size and location of acetabular osteolytic lesions after total hip arthroplasty (THA). In the study reported here, we sought to determine the utility of oblique (Judet) x-rays in preoperative assessment of acetabular lesions. AP, anterior (obturator), and posterior (iliac oblique) x-rays of 10 patients (10 hips) who underwent revision THA were evaluated retrospectively. Mean osteolytic area was 790 mm2 (SD, 520 mm2) on anterior oblique x-rays and 384 mm2 (SD, 396 mm2) on AP x-rays (P = .005). Mean osteolytic area on posterior oblique x-rays was 512 mm2 (SD, 430 mm2) (P = .34). Judet x-rays were useful in determining size and location of acetabular osteolysis. PMID- 17694195 TI - Tibial fracture after total knee arthroplasty treated with retrograde intramedullary fixation. PMID- 17694196 TI - Total knee arthroplasty for degenerative arthritis in a patient with femoral trochlear dysplasia: a case report. PMID- 17694197 TI - Effect of endodontic access type on the resistance to fracture of maxillary incisors. AB - OBJECTIVE: To compare the effect of endodontic access cavity location--labial versus palatal--on the resistance to fracture of maxillary incisors. METHOD AND MATERIALS: Sixty intact human maxillary incisors were selected: 20 pairs of central incisors and 10 pairs of lateral incisors. From each pair, 1 tooth was randomly selected to receive a palatal access cavity; the other tooth of the same pair received a labial access cavity. The teeth were divided into 4 test groups: group 1, central incisors with labial access; group 2, central incisors with palatal access; group 3, lateral incisors with labial access; and group 4, lateral incisors with palatal access. A lateral condensation technique was used to fill the canals with gutta-percha cones and AH-26 (Dentsply DeTrey). The access cavities were restored with hybrid resin composite. Specimens were mounted in a jig that allowed loading at the center of the palatal surface of the tooth, over the cingulum, at an angle of 130 degrees to the long axis of the tooth. Continuous compressive force at a crosshead speed of 2 mm/min was applied by an Instron universal testing machine. Load at fracture and mode of failure were recorded. Multiple analysis of variance (MANOVA) with repeated measures was used to statistically compare differences between groups at a significance of 5%. RESULTS: Mean failure loads for the 4 test groups were as follows: 894 N (group 1), 821 N (group 2), 774 N (group 3), and 705 N (group 4). No significant difference in failure load values was found among all tested groups (F = 0.5; P >.05). The mode of failure in all groups was an oblique radicular fracture, either at the level of the cementoenamel junction in 40% to 45% or at the root level in 55% to 60% of the teeth. CONCLUSION: Different endodontic accesses labial or palatal-did not affect the failure resistance of maxillary incisors under simulated occlusal load. PMID- 17694198 TI - Chromatic behavior of porcelain fired on titanium. AB - OBJECTIVE: To investigate the chromatic changes of 3 porcelains after firing on titanium. METHOD AND MATERIALS: Thirty-six veneer crowns were obtained by firing 3 different porcelains to titanium: Ti22 (Noritake), Triceram (Esprident), and Vitatitankeramik (Vita). A single shade was used for each porcelain. Besides the titanium-porcelain specimens, 3 titanium-free controls (one for each porcelain) were obtained. A spectrophotometer was used to measure the color of porcelain facings of the veneer crowns and the porcelain controls. Once the chromatic digital values were recorded, the color differences between the titanium porcelain samples and the corresponding porcelain controls were computed. The results were statistically analyzed. RESULTS: The least chromatic difference was observed for Ti22 porcelain, and the greatest difference for Triceram porcelain. Regarding the direction of the chromatic alteration after firing on titanium, very significant differences were found between the porcelains. CONCLUSION: Perceivable differences were found between the shade of the porcelain fired to titanium and that of the same porcelain fired alone. No significant differences were found between the 3 porcelains regarding the total chromatic modification. PMID- 17694199 TI - Failure probability of implant-supported restorations using highly filled all composite crowns. AB - OBJECTIVES: To evaluate the effect of the surface preparation of a gold cylinder on the failure probability of highly filled all-composite restorations used as implant-supported prostheses, and to determine the effect of the location of load application. METHOD AND MATERIALS: Gold cylinders (Nobel Biocare) were prepared with 1 of 4 different surface preparations (n = 20 per surface treatment), and then an indirect resin composite (Targis, Ivoclar Vivadent) was applied. The 4 surface treatment conditions were (1) untreated (prep 1); (2) airborne-particle abraded with 50-Microm alumina (prep 2); (3) airborne-particle abraded with 50 Microm alumina followed by application of a metal conditioner (Alloy Primer, J. Morita) (prep 3); and (4) airborne-particle abraded with 50-Mum alumina followed by application of the bonding primer for the indirect resin system (Targis Link) (prep 4). A compressive load was applied vertically at 1 mm and 2 mm from the access cavity on the occlusal surface until the restorations failed. RESULTS: The prep 4 specimens had the highest fracture resistance. The fracture resistance at the 1-mm location was significantly higher than that at the 2-mm location. The failure load of the all-composite restorations with any of the surface preparations was lower than that of the resin-veneered restorations used as controls. CONCLUSION: The prep 4 conditions decreased the probability of fracture of the highly filled all-indirect resin composite restorations. Eccentric loading of the all-composite restorations should be minimized in light of the higher probability of failure associated with such a loading condition. PMID- 17694200 TI - Dental visits and personality traits among young adults. AB - OBJECTIVE: To evaluate the relationship between dental behavior, dental anxiety, and personality attachment traits among a healthy young adult population. METHOD AND MATERIALS: The study population consisted of 450 young adults (18 to 19 years old) who arrived for dental screening before military service. The survey was based on a questionnaire about dental behavior (ie, dental treatments and follow up frequency, last dental visit, etc) as well as the Corah Dental Anxiety Scale (DAS) questionnaire, and the Self-Report Measurement of Adult Attachment (SRAA) questionnaire used to rate 3 adult attachment styles (secure, anxious, and avoidant). RESULTS: The questionnaire was completed by 429 participants (95.3% response rate), in which 131 (30.5%) reported regular visits to their dental clinician and 61 (14.2%) did not visit a dental clinic at all. A total of 287 participants (66.9%) reported their last dental visit to be during the previous 2 years before the study, and 49 (11.4%) reported no visit to a dental office during the previous 5 years. DAS score ranged from 4 to 20 (mean 8.5 +/- 3.3). High levels of dental anxiety, as indicated by DAS scores, correlated with less frequent dental visits, as well as with no visit to a dental clinic over the past few years. Participants who scored high on avoidant attachment were more likely to report occasional or no dental visits (P = .03). High DAS scores were more frequent among anxiously attached persons (P <.001) and among participants who scored high on attachment avoidance (P = .0013). CONCLUSIONS: Physiologic factors could have an impact on the patient's response. Patients, particularly anxious and avoidant attached ones, tend to visit the dental clinic less frequently. PMID- 17694201 TI - Measurement of sealant surface area by clinical/computerized analysis: 11-year results. AB - OBJECTIVE: To analyze the clinical behavior of 2 pit and fissure sealants through clinical/computerized evaluation. METHOD AND MATERIALS: Occlusal sealants were placed on maxillary and mandibular first and second premolars according to a split-mouth design. All premolars were sealed with either Concise (3M Espe) or Prisma Shield (Caulk/Dentsply) sealant agents. A hematoxylin-based staining solution was applied on the occlusal surface 7 days, 18 months, 36 months, and 11 years after occlusal sealing to allow checking of the sealant material on the surface. At each analysis time all occlusal surfaces were photographed, and the photographs corresponding to each time period were analyzed with SigmaScan 4.0 Software. The alterations of the sealed area of each sealant were analyzed with the software and recorded. Next, the measurements of the areas were tabulated and analyzed according to each period. Analysis of variance (ANOVA), with parts subdivided into time, and the t test, with a significance level of 5%, were used. RESULTS: The greatest sealed area was maintained by the sealant Concise. However, over the course of 11 years, all sealants began to show the same level of alteration in sealed area. CONCLUSION: The sealing materials showed alteration in sealed area over time, but they were efficient in controlling caries lesion formation on premolar pits and fissures. PMID- 17694202 TI - Self-injurious behavior in a patient with mental retardation: review of the literature and a case report. AB - Self-injurious behavior is deliberate harm to the body that may lead to factitious oral injuries. Management of patients with self-inflicted injury continues to be a challenge for the dental profession. The purpose of this article is to review clinical findings in a patient who presented with severe, painful gingival recession in the primary dentition. A case report of an 8-year old girl with mental retardation is presented. The periodontal examination showed bilateral gingival recession of the mandibular canines and the mandibular first and second molars so severe that it was possible to clinically observe the exposed roots. The diagnosis of self-inflicted gingival lesions and self injurious behavior was established. Although the lesions are no longer present, the self-injurious behavior persists. Psychologic support was suggested, and an oral removable appliance was fitted. PMID- 17694203 TI - Panoramic radiographic examination of edentulous mouths. AB - OBJECTIVE: Panoramic radiographs often are the first method used to screen edentulous patients before complete denture therapy. However, routine radiographic examination of edentulous patients is being questioned because of the cumulative effects and cost of radiation exposure. The purpose of this study was to determine the frequency and location of significant radiographic findings in edentulous jaws. METHOD AND MATERIALS: Panoramic radiographs from 338 patients were included in the survey (183 men, 155 women; 676 edentulous arches). The radiographs were evaluated by 1 oral radiology specialist for the following clinically significant radiographic findings: retained root fragments, impacted teeth, radiolucencies associated with cysts, radiopacities associated with localized sclerotic bone formation, location of the mental foramen on the crest, and location of the maxillary sinus close to the crest of the ridge. The data were analyzed using descriptive statistics. RESULTS: Radiographic findings were found in 47.6% (56.5% women, 43.5% men) of the edentulous patients. Fifty-two subjects (29 women, 23 men) had 67 submucosal or intrabony root remains, 50 of which were located in the maxilla. The most frequent finding was retained root fragment, followed by radiopacities. Impacted teeth were found in 11 women and 10 men. In 15 patients the mental foramen was situated at the top of the residual ridge. Of these patients, 13 were women and 2 were men. In 29 patients (14 women, 15 men) the maxillary sinus was close to the crest of the ridge. Six patients (3 women, 3 men) had a bilateral maxillary sinus close to the crest of the ridge. The other 23 patients had a unilateral maxillary sinus close to the crest of the ridge, and except for in 2 men, all were in the left side of the maxilla. CONCLUSION: Routine panoramic examination of the jaws is necessary to detect impacted teeth, retained root fragments, and other radiographic findings that may require treatment before construction of complete dentures. PMID- 17694204 TI - Susceptibility to carieslike lesions after dental bleaching with different techniques. AB - OBJECTIVE: To assess the influence of dental bleaching on the susceptibility of developing carieslike lesions. METHOD AND MATERIALS: Enamel slabs obtained from recently extracted human third molars were submitted to different bleaching techniques: at-home, with 10% and 16% carbamide peroxide (G1 and G2, respectively; Whiteness Perfect); and in-office, with 37% carbamide peroxide (G3; Whiteness Super) and 35% hydrogen peroxide (G4; Whiteness HP), activated by light emitting diode and laser. The control groups G5 and G6 were not bleached. Afterward, all specimens, with the exception of G6, were exposed to a highly cariogenic challenge by means of pH cycling. G6 served as the control for the artificial caries development methodology. Assessment of the enamel carieslike lesions was made visually by 3 independent examiners, who attributed scores representing the severity of white spot lesions (0 to 3). Statistical analysis was performed with the Kruskal-Wallis (P .001) and multiple paired comparison tests. RESULTS: Interrater reliability was expressed in a range of 0.70 to 0.82 kappa values. The median scores per group were as follows: G1 and G2 = 1; G3, G4, and G5 = 2; and G6 = 0. CONCLUSION: Home bleaching reduced the susceptibility to dental caries, while in-office bleaching did not influence the development of caries lesions. PMID- 17694205 TI - Fluid filtration evaluation of 3 obturation techniques. AB - OBJECTIVE: To evaluate coronal leakage and apical material extrusion of 3 obturation techniques. METHOD AND MATERIALS: The coronal part of 60 freshly extracted human maxillary central incisors was removed, leaving roots 10 mm in length. After instrumentation by hand K-files and smear layer removal, the 60 roots were divided randomly into 3 groups. The roots of each group were obturated using different obturation techniques. The obturation techniques tested were cold lateral condensation, System B, and Thermafil. Leakage measurements were accomplished using fluid filtration methodology. Filling material extrusion was recorded using a yes or no statement. Results were subjected to statistical analysis using chi-square tests. RESULTS: Fluid filtration results revealed no significant differences among the 3 techniques tested 48 hours after obturation (P >.05). Thermafil tended to extrude significantly more material beyond the apex (P <.05). CONCLUSIONS: The 3 obturation techniques are equally effective at sealing the root canals. Thermafil's tendency for slight material extrusion should be considered when obturating canals with insufficient apical constriction. PMID- 17694206 TI - Comparative electrochemical investigation of the effect of aging on corrosion of dental amalgam. AB - OBJECTIVE: To investigate corrosion in dental amalgam and evaluate the effects of composition and long-term aging on the alloy's corrosion behavior. METHOD AND MATERIALS: A sample of high-copper and low-copper formulations was employed. Corrosion tests were performed using a 3-electrode polarization cell. Anodic polarization curves were drawn, and the potential and the current density corresponding to the first anodic peak were registered. Scanning electron microscopy was performed, and the different metallurgical phases of the alloy's microstructure were examined and analyzed chemically using an energy-dispersive x ray technique. The amalgams' corrosion behavior was evaluated at 1 week and after aging in a simulated oral environment for 6 months, 1 year, and 2 years. Data were analyzed using analysis of variance (ANOVA)Scheffe post hoc test at a .05 significance level. RESULTS: The potential values recorded by the high-copper amalgam were higher (P <.05) than those scored by the low-copper alloy. This was attributed to the presence of a tin-mercury, g2, phase in larger quantities in the low-copper amalgam than in the high-copper alloy. For both formulations the potentials increased significantly (P <.05) by about 70 mV after 2 years. This was ascribed to the gradual elimination of the corrosion-susceptible g2 phase and formation of a tin-copper, h, phase, particularly in the high-copper amalgam. CONCLUSION: High-copper amalgam exhibited better resistance to corrosion than the low-copper alloy. Aging in a simulated oral environment improved corrosion behavior for both high- and low-copper amalgams. PMID- 17694207 TI - The influence of cervical finish line, internal relief, and cement type on the cervical adaptation of metal crowns. AB - OBJECTIVE: The aim of this investigation was to evaluate the cervical adaptation of metal crowns under several conditions, namely (1) variations in the cervical finish line of the preparation, (2) application of internal relief inside the crowns, and (3) cementation using different luting materials. METHOD AND MATERIALS: One hundred eighty stainless-steel master dies were prepared simulating full crown preparations: 60 in chamfer (CH), 60 in 135-degree shoulder (OB), and 60 in rounded shoulder (OR). The finish lines were machined at approximate dimensions of a molar tooth preparation (height: 5.5 mm; cervical diameter: 8 mm; occlusal diameter: 6.4 mm; taper degree: 6; and cervical finish line width: 0.8 mm). One hundred eighty corresponding copings with the same finish lines were fabricated. A 30-Microm internal relief was machined 0.5 mm above the cervical finish line in 90 of these copings. The fit of the die and the coping was measured from all specimens (L0) prior to cementation using an optical microscope. After manipulation of the 3 types of cements (zinc phosphate, glass ionomer, and resin cement), the coping was luted on the corresponding standard master die under 5-kgf loading for 4 minutes. Vertical discrepancy was again measured (L1), and the difference between L1 and L0 indicated the cervical adaptation. RESULTS: Significant influence of the finish line, cement type, and internal relief was observed on the cervical adaptation (P <.001). The CH type of cervical finish line resulted in the best cervical adaptation of the metal crowns regardless of the cement type either with or without internal relief (36.6 +/- 3 to 100.8 +/- 4 Microm) (3-way analysis of variance and Tukey's test, a = .05). The use of glass-ionomer cement resulted in the least cervical discrepancy (36.6 +/- 3 to 115 +/- 4 Microm) than those of other cements (45.2 +/- 4 to 130.3 +/- 2 Microm) in all conditions. CONCLUSION: The best cervical adaptation was achieved with the chamfer type of finish line. The internal relief improved the marginal adaptation significantly, and the glass-ionomer cement led to the best cervical adaptation, followed by zinc phosphate and resin cement. PMID- 17694208 TI - Effect of thermocycling on microleakage of resin composites polymerized with LED curing techniques. AB - OBJECTIVE: To evaluate the effect of thermocycling on microleakage of cervical cavities restored with hybrid and flowable resin composites polymerized with 3 different light-emitting diode (LED) curing techniques. METHOD AND MATERIALS: A total of 120 wedge-shaped cervical cavities were prepared on the buccal surfaces of human molars, restored with hybrid resin composite (Z250, 3M Espe) or with flowable resin composite (Filtek Flow, 3M Espe), and cured with either an LED standard light, an LED high-intensity light, or an LED exponential mode, which is a kind of soft-start curing method. The teeth in each group were divided randomly into 2 subgroups: (1) thermocycling for 1,000 cycles at 5 degrees C and 55 degrees C with a dwell time of 60 seconds, and (2) no thermocycling treatment. All teeth were immersed in 0.5% basic fuchsin dye solution for 24 hours. The teeth then were longitudinally sectioned and scored on a 0 to 3 scale at the enamel and dentin margins. RESULTS: Nonparametric statistical analysis of the results showed a significant difference in microleakage between the nonthermocycled and thermocycled specimens, except for specimens cured with soft start polymerization. CONCLUSION: The soft-start polymerization technique with LED light was not affected by thermocycling regimens. PMID- 17694209 TI - The ubiquitious case report. PMID- 17694210 TI - Bonded indirect restorations for posterior teeth: the luting appointment. AB - Classic bonded indirect restorations are laboratory fabricated and require 2 appointments: one for provisionalization and one for luting. This article describes the adhesive luting procedure, from try-in of the workpiece to finishing and polishing after the adhesive cementation, and it represents the second part of an updated technique for bonded inlays and onlays. The clinical sequence is described step by step with 2 cases. Particular attention is given to the adhesive treatment of the restoration and the cavity as well as the choice of the resin cement. Following the adhesive philosophy and due to improvements in materials and techniques, the simplified approach described may provide predictable luting restoration of the posterior dentition. PMID- 17694211 TI - Variables associated with longitudinally registered plaque accumulation in a cohort of Flemish schoolchildren. AB - OBJECTIVES: To analyze the change in pattern of plaque accumulation on buccal and occlusal surfaces of permanent teeth and associated variables in a cohort of 4,468 children examined on a yearly basis between the ages of 7 and 12 years. METHOD AND MATERIALS: Oral hygiene level on buccal surfaces was assessed using the Plaque Index of Silness and Loe; for occlusal surfaces, a simplified version of the index as described by Carvalho et al was used. Data on oral health habits were collected using questionnaires completed by the parents and by the school health care center. Multiple ordinal logistic regression models using first-order generalized estimating equations were fitted to estimate population average effects taking into account the correlated structure of the data. RESULTS: Girls brushed significantly more frequently than boys (as reported by the parents) and presented with significantly less dental plaque. In all survey years, starting to brush at a young age, no daily consumption of sugar-containing drinks, and brushing at least twice a day were significantly associated with lower plaque accumulation scores. Parental help did not seem to influence the accumulation of occlusal plaque, but it did influence the amount of buccal plaque on incisors and premolars at older ages. The presence of sealants was significantly associated with less dental plaque. CONCLUSION: Regarding future policies for preventive strategies in schoolchildren, help with brushing at older ages can be recommended. Application of sealants can be encouraged, but further research is needed to confirm whether the presence of sealants improves oral cleanliness. PMID- 17694212 TI - Comparison of dentin caries excavation with polymer and conventional tungsten carbide burs. AB - OBJECTIVE: To compare the effectiveness of polymer burs (SmartPrep, SS White) and conventional carbide burs in removing dentin caries. METHOD AND MATERIALS: Thirty extracted permanent teeth were assigned to 2 groups according to the caries removal technique. One experienced clinician performed all excavation procedures, monitoring the caries removal by checking the hardness of the dentin with a dental explorer. The excavation working time was documented and stopped in each group when a leather-hard texture was reached. After the teeth were embedded and sectioned (400 Microm), the caries in the remaining dentin was assessed using a caries detector. On microscope images of the samples, the mean stain depth of the remaining carious tissue per tooth was measured by AnalySIS computer software. RESULTS: Mean carious surface areas differed minimally but not statistically significantly after use of polymer burs (31.5 mm2 +/- 0.18) and carbide burs (38.1 mm2 +/- 0.15). Mean carious surface staining depth was slightly smaller with carbide burs (0.26 mm +/- 1.38) than with polymer burs (0.40 mm +/- 1.15). The mean-quartile test for the total carious surface (P = .363) and the carious margin (P = .681) showed no statistically significant differences. Of the carbide bur-treated samples, 84.5% were caries free as opposed to 93.0% in the polymer bur group. The results also showed no significant difference between the mean working time of the polymer burs (5.11 minutes) and the carbide burs (4.99 minutes). CONCLUSION: Under these experimental conditions, polymer burs and tungsten carbide burs were similarly effective for caries removal. PMID- 17694213 TI - Diplopia and acute rectus muscle palsy as symptoms of an infected follicular cyst of a maxillary right third molar: a case report. AB - Severely impacted third molars have a high risk of developing a dentigerous cyst. Dental cysts in the maxilla can cause acute infection of the maxillary sinus that can involve the orbital cavity. Possible complications of infections of the orbital cavity are eyesight reduction, including blindness, and disseminated infections, including brain abscesses. This article reports on a 53-year-old male patient with diplopia caused by acute rectus inferior muscle palsy as symptoms of an empyema of the maxillary right sinus. An infected follicular cyst due to the impacted and displaced maxillary right third molar caused the empyema. An emergency trepanation with drainage of the right maxillary sinus was performed. Additionally, intravenous antibiotic therapy with penicillin G and metronidazole resulted in improvement. In a secondary surgical process 2 weeks later, the cyst and the third molar were removed. Complete recovery was noted. It is important to be familiar with clinical diagnostics in cases of undefined pain of the teeth and jaws. Radiographic imaging is indicated in such cases. Disseminated odontogenic infections must be considered as the primary origin of pain and diplopia. PMID- 17694214 TI - Two-year clinical evaluation of Cerec 3D ceramic inlays inserted by undergraduate dental students. AB - OBJECTIVE: To evaluate the clinical results of final-year dental students' clinical performance after a practical computer-based course and training in the new Cerec 3 method. METHOD AND MATERIALS: Cerec 3D restorations (Sirona) were made and inserted in patients by 50 dental students. The students were in their final semester in the Department of Operative Dentistry. Before treatment of the patients began, the students had undergone computer-based Cerec 3D training. The training included lessons comprising the whole Cerec procedure from planning to insertion of the restoration. Vital permanent premolars or molars requiring a 2- or 3-surface restoration were selected for the study. The evaluation started 1 week after luting. The inlays were examined in accordance with the US Public Health Service (USPHS) criteria at baseline and after 6, 12, and 24 months. RESULTS: The 2-year survival rate of the restorations was estimated to be 93.3% according to Kaplan-Meier. No statistically significant changes were observed in color match, surface texture, and anatomic form. The decrease of pulpal hypersensitivity during the observation period was statistically significant (P <.05). CONCLUSION: Dental students are capable of delivering demanding clinical tasks after appropriate training. The introduction of CAD/CAM restorations to the dental curriculum resulted in high short-term success rates. Further investigations are required to evaluate the long-term success of those restorations. To achieve a clinically adequate performance, it is necessary to consider the basic rules and technology associated with ceramic restorations. PMID- 17694215 TI - Methamphetamine abuse and dentistry: a review of the literature and presentation of a clinical case. AB - Methamphetamine is not a new drug. It has a long and storied history of legitimate clinical use and recreational abuse. Unfortunately, abuse of methamphetamine is increasing with alarming frequency in the United States and leads to appalling destruction of dentition. The pathognomonic effects of methamphetamine abuse on teeth have led to the term "meth mouth." This term, while descriptive of the clinical appearance of patients, is a misnomer. A review of available information on methamphetamine abuse is presented and discussed. A clinical case is documented to help clinicians recognize and manage patients who may be abusing methamphetamines. PMID- 17694216 TI - Effect of liquid-polish coating on in vivo biofilm accumulation on provisional restorations: part 1. AB - OBJECTIVE: Biofilm accumulation on provisional restorations may affect the surrounding tissues' integrity. The purpose of this study was to test in vivo biofilm formation on polymethyl methacrylate (PMMA) self-cured acrylic resin provisional crowns. METHOD AND MATERIALS: Three types of PMMA surfaces were tested: (1) polished, (2) polished and coated with bonding agent, and (3) polished and coated with light-cured liquid polish. After 12 hours in the oral cavity, the crown was removed and examined by confocal laser scanning microscope (CLSM) and scanning electron microscope (SEM). RESULTS: Biofilm, 250 Mum thick, was observed with CLSM on the polished acrylic surface. Significantly less bacterial accumulation was observed on the crowns coated with bonding agent, whereas no biofilm was observed on the crowns coated with liquid polish (P <.001). SEM examination confirmed these findings. CONCLUSIONS: Bonding resin or liquid polish coatings significantly reduce early biofilm formation, which in turn might affect the overall plaque accumulation on provisional restorations. PMID- 17694217 TI - Ectopic molar near the coronoid process: case report. AB - This article reports a case of retrieval of an ectopic molar medial to the coronoid process of the mandible that caused chronic discharging of a sinus into the mouth and recurrent facial swelling. Possible origin of the tooth and surgical approaches are discussed. PMID- 17694219 TI - Displacement of a maxillary third molar into the infratemporal fossa: case report. AB - The case of a maxillary third molar displaced into the infratemporal fossa, with difficulty in localization due to the synchronous creation of oroantral communication, is described in this article. The patient was referred to the oral and maxillofacial department and underwent successful surgical treatment through an intraoral access. The causes of tooth displacement into the infratemporal fossa, the aid of a computerized tomography (CT) scan in tooth localization, and the difficulty in treating this complication, particularly when the tooth migrates toward the base of the skull, are emphasized. Prevention of maxillary third molar displacement into the infratemporal fossa predominates over removal and is achieved by adequate flap design, correct extraction technique, and a distal retractor during surgical extraction. In the case of displacement, no effort to retrieve the tooth is recommended because of the risk of hemorrhage, neurologic injury, and further displacement of the tooth. The patient should be treated with antibiotics and referred to an oral and maxillofacial department. PMID- 17694218 TI - Efficacy of 1% ropivacaine gel for topical anesthesia of human oral mucosa. AB - OBJECTIVE: To evaluate the efficacy of 1% ropivacaine for topical anesthesia in dentistry. METHOD AND MATERIALS: Thirty healthy volunteers randomly (blind crossover) received the following treatments: 20 mg of 1% ropivacaine gel (ropivacaine-20), 60 mg of 1% ropivacaine gel (ropivacaine-60), 20 mg of the eutectic mixture of local anesthetics 2.5% lidocaine and 2.5% prilocaine (EMLA cream, AstraZeneca; EMLA-20), 60 mg of EMLA (EMLA-60), 20 mg of 20% benzocaine gel (Benzotop, DFL; benzocaine-20), and 60 mg of 20% benzocaine gel (benzocaine 60), applied on the maxillary buccal fold of the right canine at different sessions. Pain was assessed by visual analog scale (VAS) and 11-point box scale (BS-11) after the insertion of 30-gauge needles. Soft tissue anesthesia was measured by pinprick test. Data were analyzed by Friedman and Pearson correlation tests. RESULTS: All the topical anesthetics evaluated showed similar performance in relation to the pain perceived after needle insertion (P >.05), and there were no significant differences among groups considering VAS or BS-11 (P = .177 and P = .179, respectively). The duration of soft tissue anesthesia was not statistically significantly different for ropivacaine-20, EMLA-20, benzocaine-20, ropivacaine-60, EMLA-60, and benzocaine-60, but EMLA-60 showed significantly longer duration than the other agents (P <.05). CONCLUSION: All topical anesthetics were similar in reducing pain to needle insertion. EMLA-60 promoted longer duration of soft tissue anesthesia. PMID- 17694220 TI - Multiple anomalies involving testicular and suprarenal arteries: embryological basis and clinical significance. AB - Variations in the origin of arteries in the abdomen are very common but with the invention of new operative techniques within the abdominal cavity, the anatomy of abdominal vessels has assumed much more clinical importance. During routine dissection of the abdominal cavity, we came across multiple arterial anomalies involving testicular and suprarenal arteries. On the right side, there was double testicular artery (medial and lateral) and the right inferior suprarenal artery aroused from the medial testicular artery. The right inferior phrenic artery (IPA) and middle suprarenal artery took origin from a common trunk just above the origin of right renal artery (RRA). On the left side, the left testicular artery was arching over the lower tributary of the left renal vein proper (LRVP). Apart from the developmental and morphological interest in arching gonadal arteries, they are of practical importance from a clinical and surgical viewpoint. The embryological and clinical significance of above variations has been described. PMID- 17694222 TI - [Control of aspirin effect in chronic cardiovascular patients using two whole blood platelet function assays. PFA-100 and Multiplate]. AB - In this study two aspirin sensitive platelet function tests which are based on the analysis of whole blood were evaluated and correlated with each other. In vitro bleeding time was determined using the PFA-100 analyzer (Dade Behring, Marburg, Germany) using the collagen/epinephrine cartridge and citrated blood. Whole blood aggregometry was performed using the Multiplate analyzer (Dynabyte medical, Munich, Germany) using hirudin blood (25 mug/ml). Aggregatin was triggered using arachidonic acid (ASPItest), collagen (COLtest) or TRAP-6 (thrombin receptor activating peptide, TRAPtest). Following informed consent citrated blood and hirudin blood was drawn from 76 cardiovascular patients which were on long-term aspirin therapy (aspirin patients). In addition hirudin blood was drawn from 57 healthy blood donors for assessment of whole blood aggregometry. PFA-100 closure times of the aspirin patients were 273 +/- 49 s. Based on the cut-off of 170 s a non response to the aspirin therapy was detected in 5 of 76 patients. Whole blood aggregation was comparable in the aspirin patients vs the blood donors AUC values in the TRAP test, whereas in COLtest and ASPItest significantly reduced aggregations were detected (p < 0.05). Of the five patients that had a normal PFA-100 closure time only one had normal aggregation in ASPItest, and also only one had a normal aggregation in COLtest. The high rate of response to the aspirin therapy which was found in PFA-100 and ASPItest can be explained by the assumed high level of compliance of the cohort. In the applied tests different patients were stratified as aspirin-non-responders. This highlights the importance of the assay conditions for the diagnosis of an aspirin non-response. PMID- 17694223 TI - [Modified platelet aggregation test in patients on ASA and/or clopidogrel]. AB - Therapy with acetylsalicylic acid (ASA) and/or clopidogrel is used to achieve prophylactic inhibition of platelet aggregation in patients with arterial thrombosis. We examined if aggregometry can be used to see the effect of antiplatelet drugs (ASA 30, 50, 100, 300 mg/d, clopidogrel 75 mg/d or ASA 100 + clopidogrel 75 mg/d). A modified platelet aggregation test was used to investigate maximum aggregation in response to ADP, collagen, adrenalin and arachidonic acid. Reference values were established based on healthy individuals. We devised a simple scoring system for detection of inadequate platelet inhibition. Compared with the control group, we detected a significant delay of maximum aggregation in response to all agonists in patients on ASA and combination therapy ASA + clopidogrel. Patients on clopidogrel alone were found to have prolonged aggregation when induced with ADP, collagen and arachidonic acid. The failure rate to achieve adequate platelet inhibition on 100 mg/d ASA, 75 mg/d clopidogrel or combination therapy was 27%, 26% and 7%, respectively. Our results demonstrate that platelet inhibition in aggregometry is inadequate in many patients with arterial thrombosis. PMID- 17694224 TI - [Preoperative identification of patients with impaired (primary) haemostasis. A practical concept]. AB - The findings of a large prospective study designed to identify primary and/or secondary haemostatic disorders before surgical interventions are presented. A total of 5649 unselected adult patients were enrolled to identify impaired haemostasis before surgical interventions. Each patient was asked to answer a standardized questionnaire concerning bleeding history. Activated partial thromboplastin time (aPTT), prothrombin time (PT), and platelet counts (PC) including PFA-100 (platelet function analyzer): collagen-epinephrine (C/E), and collagen-ADP (C/ADP) were routinely done in all patients. Additional tests, bleeding time (BT), von Willebrand factor (VWF:Ag, VWF:Rcof) and a further haemostaseological diagnostic was performed only in patients with a positive bleeding history and/or evidence of impaired haemostasis; e.g., drug ingestion. The bleeding history was negative in 5021 patients (88.8%) but positive in the remaining 628 (11.2%). Impaired haemostasis could be verified only in 256 (40.8%) of these patients. The vast majority was identified with PFA-100: C/E (n = 250; 97.7%). The sensitivity of the PFA-100: collagen-epinephrine was the highest (90.8%) in comparison to the other screening tests (BT, aPTT, PT, VWF : Ag). The positive predictive value (to detection of impaired haemostasis) of the PFA-100: collagen-epinephrine with the standardized questionnaire was high (82%), but the negative predictive value was higher (93%). The use of a standardized questionnaire and, if indicated, the PFA-100: C/E and/or other specific tests not only ensure the detection of impaired haemostasis in almost every case but also a significant reduction of the costs. Based on these data, national regards are formulated or under construction. PMID- 17694225 TI - [Coagulation analysis in transplantation patients]. AB - In patients post organ transplantation, the underlying disorder necessitating the transplantation, as well as the transplantation itself, can both mask pre existing haemostatic abnormalities or lead to them. Since the liver is the main production site for coagulation factors, orthotopic liver transplantation predestinates for acquiring or losing a genetically determined coagulation defect. In coagulation diagnostics, this may lead to a discrepancy between functional plasma tests and molecular biologic findings if these are gathered from nucleated cells of the peripheral blood, as is the standard. Due to the rareness of most defects and the lack of consequences in case of diagnosis of a more common coagulation disorder, no general screening before or after transplantation is required. Underlying diseases leading to liver transplantation as well as the actual transplantation must be considered when interpreting the findings. PMID- 17694226 TI - [Hereditary factor V deficiency and factor V inhibitor without bleeding. Rare causes of pathological screening tests of coagulation]. AB - Isolated reduction in factor V activity either occur in form of a hereditary deficiency of factor V as an acquired inhibitor against factor V. Diagnosis can not be made by bleeding alone because in both cases it can occur or not occur. Two patients were investigated showing pathological screening tests of coagulation without bleeding. A hereditary and an acquired deficiency of factor V were proved. PMID- 17694227 TI - Unusual bleeds, unusual clots. AB - Nine unusual bleeding and clotting disorders (or mimickers of such) are described in the format of case presentations, with focus on clinical history, images and diagnostic tests, followed by a discussion of the disease itself and a summarizing clinical teaching point. The disease entities discussed are acquired factor VIII inhibitor, acquired von Willebrand factor inhibitor, haemophilic pseudotumour, Gardner-Diamond syndrome, coumarin-induced skin necrosis, purple toe syndrome, brachiocephalic vein thrombosis with breast enlargement, and leg swelling due to nephrogenic fibrosing dermopathy and lymphoedema. The publication is meant to demonstrate the fascination of clinical coagulation. PMID- 17694228 TI - [Plasma blood coagulation in mammals (domestic and zoo animals). Experience with screening tests and determinations of individual factor activities]. AB - Plasma coagulation in mammals shows an essentially uniform structure. Differences are in species specific composition and quantity of coagulation factors. Many of the coagulation disorders occurring in humans have been observed in other mammals. Almost all the coagulation studies performed to date have been in domestic animals. For the majority of mammalian species, e.g. zoo animals, therefore, we have either no data at all or only isolated results. The methods used for coagulation testing in veterinary medicine have not yet been standardized. The significance and informative value of the screening tests are limited in animals compared with humans. The activities of individual factors in animals are determined by coagulometric tests. The results can be determined in relation to the activity in humans with the help of a human normal plasma or in relation to the activity of the respective animal with the help of a normal plasma from the same species. The problem is the parallelity of the dilution curves used as reference curves. The coagulation factor activities given for mammals usually differ more or less markedly from those in humans. PMID- 17694230 TI - An informatics benchmarking statement. AB - OBJECTIVES: Benchmarking statements provide a mechanism for making academic standards explicit within a subject area. They allow comparisons between courses to be based on learning outcomes rather than by defining a curriculum. No such statement has been produced for informatics. In the absence of any established benchmarking statements for informatics a new biomedical informatics course at St. George's has developed a first benchmarking statement - which defines the skills knowledge and understanding a biomedical informatics student should acquire by the time they complete the course. METHODS: Review of national biomedical science and computing subject benchmarking statements and academic educational objectives and national occupational competencies in informatics. RESULTS: We have developed a twenty-item benchmarking statement and this is available on-line at: http://www.gpinformatics.org/benchmark2006/. This benchmarking statement includes a definition and justification for all twenty statements. We found international educational objectives and national informatics competencies useful and these are mapped to each one. National subject benchmarks for computing and biomedical science were less useful and have not been systematically mapped. CONCLUSIONS: Benchmarking the skills, knowledge and understanding that a student should acquire during their course of study may be more useful than setting a standard curriculum. This benchmarking statement is a first step towards defining the learning outcomes and competencies a student of this discipline should acquire. The international informatics community should consider moving from a standard curriculum to an agreed subject benchmarking statement for medical, health and biomedical informatics. PMID- 17694231 TI - An objective method for bed capacity planning in a hospital department - a comparison with target ratio methods. AB - OBJECTIVES: To propose an objective approach in order to determine the number of beds required for a hospital department by considering how recruitment fluctuates over time. To compare this approach with classical bed capacity planning techniques. METHODS: A simulated data-based evaluation of the impact that the variability in hospital department activity produces upon the performance of methods used for determining the number of beds required. The evaluation criteria included productive efficiency measured by the bed occupancy rate, accessibility measured by the transfer rate of patients due to lack of available beds and a proxy of clinical effectiveness, by the proportion of days during which there is no possibility for unscheduled admission. RESULTS: When the variability of the number of daily patients increases, the Target Occupancy Rate favors productive efficiency at the expense of accessibility and proxy clinical effectiveness. On the contrary, when the variability of the department activity is marginal, the Target Activity Rate penalizes the proxy of clinical effectiveness, and the Target Occupancy Rate underoptimizes productive efficiency. The method we propose led to a superior performance in terms of accessibility and proxy of clinical effectiveness at the expense of productive efficiency. Such a situation is suitable for intensive care units. In the case of other departments, a weighting procedure should be used to improve productive efficiency. CONCLUSIONS: This approach could be considered as the first step of a family of methods for quantitative healthcare planning. PMID- 17694232 TI - The effect of interactive multimedia on preoperative knowledge and postoperative recovery of patients undergoing laparoscopic cholecystectomy. AB - OBJECTIVES: Aim of this study is the evaluation of the impact of a multimedia CD (MCD) on preoperative anxiety and postoperative recovery of patients undergoing elective laparoscopic cholecystectomy (LC). METHODS: Sixty consecutive candidates for elective LC were randomly assigned to four groups. Group A included 15 patients preoperatively informed regarding LC through the MCD presented by Registered Nurse (RN). Patients in group B (n = 15) were informed through a leaflet. Patients in group C (n = 15) were informed verbally from a RN. Finally, the control Group D included 15 patients informed conventionally by the attending surgeon and anesthesiologist, as every other patient included in groups A, B, and C. Preoperative assessment of knowledge about LC was performed after each informative session through a questionnaire. Evaluation of preoperative anxiety was conducted using APAIS scale. Postoperative pain and nausea scores were measured using an NRS scale, 16 hours after the patient had returned to the ward. RESULTS: Statistical processing of the results (single linear regression) showed that patients in groups A, B, and C achieved a higher knowledge score, less preoperative anxiety score and less postoperative pain and nausea, compared to Group D. In multiple regression analysis, group A had a higher knowledge score compared to the four groups (p < 0.001 r(2) = 0.41). CONCLUSION: Informative sessions using MCD is an effective means of improving patient's preoperative knowledge, especially in day-surgery cases, like LC. PMID- 17694233 TI - Impact of different sampling strategies on score results of the Nine Equivalents of Nursing Manpower Use Score (NEMS). AB - OBJECTIVE: Prospective observational study to assess the impact of two different sampling strategies on the score results of the NEMS, used widely to estimate the amount of nursing workload in an ICU. METHODS: NEMS scores of all patients admitted to the surgical ICU over a one-year period were automatically calculated twice a day with a patient data management system for each patient day on ICU using two different sampling strategies (NEMS(individual): 24-hour intervals starting from the time of admission; NEMS(8 a.m.): 24-hour intervals starting at 8 a.m.). RESULTS: NEMS(individual) and NEMS(8 a.m.) were collected on 3236 patient days; 687 patients were involved. Significantly lower scores were found for the NEMS(8 a.m.) (25.0 +/- 8.7) compared to the NEMS(individual) (26.1 +/- 8.9, p < 0.01); the interclass correlation coefficient (ICC) was good but not excellent: 0.78. The inter-rater correlation between the two NEMS scores was high or very high (kappa = 0.6-1.0) for six out of nine variables of the NEMS. CONCLUSIONS: Different sampling strategies produce different score values, especially due to the end of stay. This has to be taken into account when using the NEMS in quality assurance projects and multi-center studies. PMID- 17694234 TI - Nursing information systems - applying usability testing to assess the training needs for nursing students. AB - OBJECTIVE: In order to ensure the successful implementation of a nursing information system (NIS), nurses and nursing students must be adequately trained. In order to do this effectively, it is essential to understand their training needs. This study focuses on the training needs of nursing students in particular through the identification of the usage problems they encounter. Usability testing, which involves observing users' interaction with an NIS, overcomes the deficiencies of traditional approaches of training needs analysis such as interview and survey. The study applied usability test to assess training needs of nursing students to learn to use a specific NIS, the "Care Planning Assessment Tool" (CPAT). METHODS: An experiment in which novice CPAT users were expected to learn to use the software through task-based exploration was conducted. Eight nursing undergraduate students who had never used the software were recruited. Participants' interactions with the system were captured by screen capture software. Meanwhile, participants' "think aloud" verbal expression of their usage problems was audio-taped. RESULTS: A coding scheme was used in analysing the captured audio and video data. Ten common usage problems were identified. From these problems, three areas of knowledge gap that this cohort of novice users experienced were identified. CONCLUSION: The training needs of nursing students learning to use an NIS was conceptualised in a model consisting of three types of knowledge, i.e. computer skills, knowledge about the NIS and knowledge about procedure of nursing documentation. The knowledge gap must be filled in order to ensure effective training. PMID- 17694235 TI - Errors in survival rates caused by routinely used deterministic record linkage methods. AB - OBJECTIVE: It was the objective of this study to assess the impact of applying various record linkage methods to one of the most important outcome measures in oncological epidemiology, namely survival rates. METHODS: To assess the life status of patients, incidence data published by the Cancer Registry of Tyrol were analyzed with three routinely used methods of record linkage for incidence and mortality data. Of these methods, two were deterministic and the third a probabilistic method developed by the Cancer Registry of Tyrol. We studied the impact of record linkage methods on a simple measure (mortality rate) and a more complex measure (relative survival rate). The analysis was based on the published incidence data for Tyrol for the years 1992 to 1996. Results of deterministic record linkage methods were simulated. RESULTS: The error rates for simple mortality rate and relative survival rate are considerable. For the first deterministic record linkage method, relative differences in mortality rate range from 11.9% to 14.8% (men) and 24.5% to 28.2% (women) and relative differences in relative five-year survival from 11.4% to 16.3% (men) and from 19.3% to 26.4% (women). For the second deterministic record linkage method, relative differences in mortality rate range from 4.8% to 5.9% (men) and from 4.9% to 7.4% (women), while relative differences in relative five-year survival range from 5.1% to 7.0% (men) and from 4.4% to 6.1% (women). CONCLUSIONS: Our study shows that in order to calculate valid mortality and survival rates a probabilistic method of record linkage must be applied. PMID- 17694236 TI - Split bundle detection in polarimetric images of the human retinal nerve fiber layer. AB - OBJECTIVES: One method for assessing pathological retinal nerve fiber layer (NFL) appearance is by comparing the NFL to normative values, derived from healthy subjects. These normative values will be more specific when normal physiological differences are taken into account. One common variation is a split bundle. This paper describes a method to automatically detect these split bundles. METHODS: The thickness profile along the NFL bundle is described by a non-split and a split bundle model. Based on these two fits, statistics are derived and used as features for two non-parametric classifiers (Parzen density based and k nearest neighbor). Features were selected by forward feature selection. Three hundred and nine superior and 324 inferior bundles were used to train and test this method. RESULTS: The prevalence of split superior bundles was 68% and the split inferior bundles' prevalence was 13%. The resulting estimated error of the Parzen density- based classifier was 12.5% for the superior bundle and 10.2% for the inferior bundle. The k nearest neighbor classifier errors were 11.7% and 9.2%. CONCLUSIONS: The classification error of automated detection of split inferior bundles is not much smaller than its prevalence, thereby limiting the usefulness of separate cut-off values for split and non-split inferior bundles. For superior bundles, however, the classification error was low compared to the prevalence. Application of specific cut-off values, selected by the proposed classification system, may therefore increase the specificity and sensitivity of pathological NFL detection. PMID- 17694237 TI - Discovery of factors influencing the growth of geographic atrophy in patients with age-related macular degeneration. AB - OBJECTIVES: Identifying factors influencing the growth of geographic atrophy (GA) in patients with age-related macular degeneration (AMD). METHODS: Data on the natural course and suspected modifying factors were collected as part of the multicenter, longitudinal, observational FAM-study in 178 eyes of 114 patients with atrophic AMD. The endpoint of interest - the size of GA - was measured in fundus autofluorescence images. The influence of different putative risk factors on progression of GA is investigated with a forward selection procedure based on the likelihood ratio test. In order to interpret non-significant results of the forward selection procedure, the power of the tests used was quantified by a parametric post-hoc bootstrap approach. RESULTS: A mean increase in GA of 1.75 mm(2) per year was estimated for the given population (95% CI: [1.46; 2.02]). Patient and eye-specific random effects could be assessed. Neither patient specific risk factors nor ocular-specific risk factors show any significant influence on GA growth. The post-hoc bootstrap procedure shows that only very strong effects can be detected on the basis of the given data. For example, the hypercholesteremia which would result in an additional increase of GA by near 4 mm(2) per year can be detected with a power of 80%. CONCLUSIONS: The use of linear mixed effects regression models offers a convenient way to explore sources of variation in the natural course of GA. Data from further follow-up examinations and data about other putative risk factors than those investigated will be needed to further investigate of the GA growth process. The procedure described in this article is easily applicable to other putative risk factors as well as to other fields of application. PMID- 17694238 TI - A new proposal for setting parameter values in restricted randomization methods. AB - OBJECTIVES: Complete randomization could result in an undesirable imbalance in the number of patients assigned to each treatment, especially in small trials. Therefore, a variety of restricted randomization procedures has been developed. By varying parameters it is possible to appropriately modify the balancing characteristics of these designs. However, there is little information on what are sensible choices for the parameters. Therefore, we suggest a new method for suitable determination of parameter values of restricted randomization rules. METHODS: For restriction to be effective, it need not yield exact equality. As the reliability of a test is not very sensitive to slight deviations from equal sample sizes we define that a given maximum tolerable imbalance d can be achieved or exceeded with a given probability p(*). By using this condition, parameter values of restricted procedures are determinable. RESULTS: For permuted-block, biased-coin, urn, and big-stick randomization we investigated the impact of parameters on balancing properties. For different extents of restriction and by using the submitted condition, the values of parameters to be chosen are determined. CONCLUSIONS: Up to now choice of parameter values has often occurred at random. Now it is possible to determine values of parameters by specifying the tolerable degree of imbalance and the risk to be worse. As a consequence restriction will, as much as possible, not be imposed and not imposed more than necessary in order to preserve the intrinsic quality of randomization. PMID- 17694239 TI - From Health Information Systems to eHealth - A special topic issue on the IMIA HIS Working Conference in Oeiras, Portugal. PMID- 17694240 TI - The Rhone-Alpes health platform. AB - OBJECTIVES: The purpose of this work is to develop a health information platform connecting most health facilities in the Rhone-Alpes region. The health platform called SIS-RA is used through a Web interface. An iconic interface is dedicated to the platform and presents information in a unique way for all users. METHODS: New techniques have been used to develop this platform which will be used by a great number of Rhone-Alpes doctors in the future. We chose a usercentered design which takes into account doctors' requirements (hospital and GP). We also consider that no system has to be rebuilt, but a direct connection to the legacy systems should be provided. RESULTS: The platform permits fast and more appropriate medical decisions than those made without this information system. The iconic interface presents all medical documents in a uniform way. Currently, 11 healthcare facilities and 15 community health networks are connected to SIS-RA sharing more than 60,000 records with 1.2 million indexed items. 3200 doctors use the system. CONCLUSION: The platform is approved by French supervision authorities (regional hospitals association (ARH)), regional practitioners union (URML) and Rhones-Alpes region administration and is known as the official shared health record. PMID- 17694241 TI - Dutch virtual integration of healthcare information. AB - OBJECTIVES: As information technology creates opportunities for cooperation which crosses the boundaries between healthcare institutions, it will become an integral part of the Dutch healthcare system. Along with many involved organizations in healthcare the National IT Institute for Healthcare in the Netherlands (NICTIZ) is working on the realization of a national IT infrastructure for healthcare and a national electronic patient record (EPR). METHODS: An underlying national architecture is designed to enable the Dutch EPR virtually, not in a national database, nor on a patient's smartcard. The required secure infrastructure provides generic functions for healthcare applications: patient identification, authentication and authorization of healthcare professionals. RESULTS: The first national applications in the EPR program using a national index of where patient data is stored, are the electronic medication record and the electronic record for after hours GP services. The rollout of the electronic medication record and electronic record for after hours GP services has been started in 2007. CONCLUSIONS: To guarantee progress of electronic data exchange in healthcare in the Netherlands we have primarily opted for two healthcare applications: the electronic medication record and the electronic record for after hours GP services. The use of a national switch-point containing the registry of where to find what information, guarantees that the professional receives the most recent information and omits large databases to contain downloaded data. Proper authorization, authentication as well as tracing by the national switchpoint also ensures a secure environment for the communication of delicate information. PMID- 17694242 TI - National health IT services in Finland. AB - OBJECTIVES: In 2002 a decision was reached to set up a nation-wide electronic health record system in Finland. The legal framework of actors with the necessary mandate was approved in the parliament in December 2006. A set of standards and norms have been selected that all health care actors need to follow. Functional specifications of the services were completed in 2006. Setting up the centralized health IT services begins in 2007. Centralization of patient record data allows the reorganization of health service providers to take place at local and regional levels according to need. The services allow users to access patient records securely from anywhere with the provision that they have the right to access private patient data. METHODS: The functionality of the services and the necessary infrastructure has been agreed to in projects and working groups involving users, experts, key stakeholders and vendors. RESULTS: The legal framework was approved in the parliament in December 2006. The functional specifications of the centralized health IT services were finalized in 2006. CONCLUSIONS: The implementation of the services will start in 2007. PMID- 17694243 TI - Local, regional and national interoperability in hospital-level systems architecture. AB - OBJECTIVES: Interoperability of applications in health care is faced with various needs by patients, health professionals, organizations and policy makers. A combination of existing and new applications is a necessity. Hospitals are in a position to drive many integration solutions, but need approaches which combine local, regional and national requirements and initiatives with open standards to support flexible processes and applications on a local hospital level. METHODS: We discuss systems architecture of hospitals in relation to various processes and applications, and highlight current challenges and prospects using a service oriented architecture approach. We also illustrate these aspects with examples from Finnish hospitals. RESULTS: A set of main services and elements of service oriented architectures for health care facilities are identified, with medium term focus which acknowledges existing systems as a core part of service-oriented solutions. The services and elements are grouped according to functional and interoperability cohesion. CONCLUSIONS: A transition towards service-oriented architecture in health care must acknowledge existing health information systems and promote the specification of central processes and software services locally and across organizations. Software industry best practices such as SOA must be combined with health care knowledge to respond to central challenges such as continuous change in health care. A service-oriented approach cannot entirely rely on common standards and frameworks but it must be locally adapted and complemented. PMID- 17694244 TI - Towards new scopes: sensor-enhanced regional health information systems - part 1: architectural challenges. AB - OBJECTIVES: To analyze utilization of sensor technology in telemonitoring and home care and to discuss concepts and challenges of sensor-enhanced regional health information systems (rHIS). METHODS: The study is based upon experience in sensor-based telemedicine and rHIS projects, and on an analysis of HIS-related journal publications from 2003 to 2005 conducted in the context of publishing the IMIA Yearbook of Medical Informatics. RESULTS: Health-related parameters that are subject to sensor-based measurement in home care and telemonitoring are identified. Publications related to telemonitoring, home care and smart houses are analyzed concerning scope and utilization of sensor technology. Current approaches for integrating sensor technology in rHIS based on a corresponding eHealth infrastructure are identified. Based on a coarse architecture of home care and telemonitoring systems ten challenges for sensor-enhanced rHIS are identified and discussed: integration of home and health telematic platforms towards a sensor-enhanced telematic platform, transmission rate guarantees, ad hoc connectivity, cascading data analysis, remote configuration, message and alert logistic, sophisticated user interfaces, unobtrusiveness, data safety and security, and electronic health record integration. CONCLUSIONS: Utilization of sensor technology in health care is an active field of research. Currently few research projects and standardization initiatives focus on general architectural considerations towards suitable telematic platforms for establishing sensor enhanced rHIS. Further research finalized by corresponding standardization is needed. Part 2 of this paper will present experiences with a research prototype for a sensor-enhanced rHIS telematic platform. PMID- 17694245 TI - Using web services for linking genomic data to medical information systems. AB - OBJECTIVES: To develop a new perspective for biomedical information systems, regarding the introduction of ideas, methods and tools related to the new scenario of genomic medicine. METHODS: Technological aspects related to the analysis and integration of heterogeneous clinical and genomic data include mapping clinical and genetic concepts, potential future standards or the development of integrated biomedical ontologies. In this clinicomics scenario, we describe the use of Web services technologies to improve access to and integrate different information sources. We give a concrete example of the use of Web services technologies: the OntoFusion project. RESULTS: Web services provide new biomedical informatics (BMI) approaches related to genomic medicine. Customized workflows will aid research tasks by linking heterogeneous Web services. Two significant examples of these European Commission-funded efforts are the INFOBIOMED Network of Excellence and the Advancing Clinico-Genomic Trials on Cancer (ACGT) integrated project. CONCLUSIONS: Supplying medical researchers and practitioners with omics data and biologists with clinical datasets can help to develop genomic medicine. BMI is contributing by providing the informatics methods and technological infrastructure needed for these collaborative efforts. PMID- 17694246 TI - Survey on the status of the hospital information systems in Portugal. AB - OBJECTIVES: To diagnose the hospital information systems' situation in Portugal. METHODS: Developing a survey on HIS department heads. RESULTS: Several weaknesses were identified in most HIS departments, such as substantial lack of people and of qualifications to deal with HIS challenges. The Nolan and McFarlan Matrix helped assess the SNS IS maturity at stage 3, characterized by the generalized lack of IS integration. CONCLUSIONS: The results are very relevant to explain the many delays (and conflicts) in implementing HIS and therefore the actual status of HIS in Portugal. The most successful cases of HIS implementation were recognized as related to the existence of an active CIO. Complexity theory can further define guidelines for the development of HIS that help keep the navigation towards "smart healthcare". PMID- 17694247 TI - Expanding the scope of health information systems - from hospitals to regional networks, to national infrastructures, and beyond. AB - OBJECTIVES: To identify current developments, obstacles, and opportunities for health information systems. METHODS: International reports were discussed during an IMIA HIS Working Conference with a focus on architectural design, project goals and drivers, obstacles, and opportunities. RESULTS: Technology and standards are available to build regional and national health IT networks, and successful implementations are currently being realized. There is, however, little consensus and communication concerning goals, benefits and risks of large scale health IT initiatives. Complexity tends to be under-estimated, and the public needs to be more involved in the decision-making process. CONCLUSION: On all levels and across borders, a climate of exchange of ideas, experiences - both successes and failures-, policies, standards, systems, and information should be created. PMID- 17694249 TI - ABO blood group. Related investigations and their association with defined pathologies. AB - The ABO blood group system was discovered by Karl Landsteiner in 1901. Since then, scientists have speculated on an association between different pathologies and the ABO blood group system. The aim of this pilot study was to determine the significance between different blood types of the ABO blood group system and certain pathologies. We included 237 patients with known diagnosis, blood group, sex, and age in the study. As a statistical method, the Chi-square test was chosen. In some cases, a significant association between the blood groups and defined diseases could be determined. Carriers of blood group O suffered from ulcus ventriculi and gastritis (X(2)1 = 78.629, p < 0.001), colitis ulcerosa and duodenitis (X(2)1 = 5.846, p < 0.016), whereas male patients carrying blood group A tended to contract different types of tumours. In patients with intestinal tumours, females with blood group A were more likely to develop the pathology, whereas in males, the blood group O dominated. The development of cholelithiasis was found, above all, in patients with blood group O, which differed from other research where a correlation between this pathology and blood group A was found. PMID- 17694250 TI - Role of polymorphonuclear leukocytes in the pathophysiology of typical hemolytic uremic syndrome. AB - Thrombotic microangiopathy and acute renal failure are cardinal features of post diarrheal hemolytic uremic syndrome (HUS). These conditions are related to endothelial and epithelial cell damage induced by Shiga toxin (Stx), through an interaction with its globotriaosylceramide (Gb3) receptor. Although, Stx is the main pathogenic factor and necessary for HUS development, clinical and experimental evidence suggest that the inflammatory response is able to potentiate Stx toxicity. Lipopolysaccharides (LPS) and neutrophils (PMN) represent two central components of inflammation during a Gram-negative infection. In this regard, patients with high peripheral PMN counts at presentation have a poor prognosis. In the present review, we discuss the contribution of experimental models and patient's studies in an attempt to elucidate the pathogenic mechanisms of HUS. PMID- 17694251 TI - Swallow syncope associated with complete atrioventricular block in an adolescent. AB - We describe a 16-year-old female with a history of swallowing-induced syncope. The physical examination, ECG, echocardiography, barium swallow test, and thyroid function tests were within normal limits. The ambulatory ECG revealed intermittent complete atrioventricular block only associated with swallowing. There was also intermittent first-degree atrioventricular block not related to eating. An electrophysiologic study was performed during the implantation of a single-chamber transvenous ventricular pacemaker. There was mild atrioventricular nodal conduction disturbance with a His-ventricular interval of 70 msec and Wenckebach cycle length of 420 msec. During 1 year follow-up, the patient remained asymptomatic. PMID- 17694252 TI - Static treatment of paralytic lagophthalmos with autogenous tissues. AB - BACKGROUND: Long-standing facial paralysis is frequently seen in patients who have undergone surgical procedures with sacrifice of the facial nerve and have never been counseled about limiting its consequences. Lagophthalmos must always be treated in these patients to protect vision. The authors describe their techniques of static treatment for lagophthalmos using autologous tissues and their classification system for standardizing patients. METHODS: From July 2001 to September 2005, 12 patients (9 men and 2 women) ranging in age from 37 to 77 years (mean, 58.5 years) were treated. Their paralysis was attributable to acoustic neuroma resection in seven cases, to resection of a cerebral vascular anomaly in two cases, and to total parotidectomy with facial nerve sacrifice in three cases. The patients were treated with elongation of the levator palpebrae superioris muscle using a fascia lata graft, bolstering of the lower eyelid with a conchal cartilage graft, or both, combined with a Kuhnt type resection when needed. RESULTS: Complete closure was achieved for nine patients (75%). For all the patients, resolution of symptoms and keratitis was achieved. No complications were observed. The follow-up period ranged from 14 to 51 months (mean, 39.5 months). The cosmetic outcome also was satisfactory. CONCLUSIONS: For candidates eligible to undergo static treatment of lagphthalmos, the techniques described may be considered valuable options for the correction of lagophthalmos using autologous tissues, thus avoiding the complications related to alloplastic material implantation. PMID- 17694253 TI - Anatomically shaped breast prosthesis in vivo: a change of dimension? AB - BACKGROUND: In addition to the already existing round cohesive gel-filled breast prostheses, anatomically shaped breast prostheses were introduced in 1990 to provide a more natural shape to the augmented or reconstructed breast. To date, however, it is unclear whether the anatomic configuration of the prostheses is maintained after subpectoral implantation. Recently, a three-dimensional (3D) magnetic resonance imaging (MRI) technique became available, offering a precise visualization of the prosthesis in vivo. Using this 3D MRI technique, this study aimed to compare the shape of commercially available round and anatomically shaped silicone gel-filled breast prostheses before and after implantation. METHODS: Using 3D MRI, 6 conventionally round and 12 symmetrically shaped silicone gel-filled prostheses were scanned in vitro. Scans were made in vivo 6 weeks after subpectoral implantation of these prostheses in nine patients. The in vivo 3D images were compared with the in vitro 3D images. RESULTS: Overall, a 3.5% decrease in projection was found on the in vivo images, as compared with the in vitro images. On the craniocaudally oriented images, a slight lateral shift of the cohesive gel was observed in the majority of the prostheses. Inamed Style 510 prostheses showed the best in vivo preservation of their configuration. CONCLUSIONS: The results show that both the round and the anatomically shaped silicone prostheses in vivo largely maintain their original in vitro configuration after subpectoral implantation. PMID- 17694254 TI - Apelin-13 and apelin-36 exhibit direct cardioprotective activity against ischemia reperfusion injury. AB - Protection against myocardial ischemia-reperfusion (I/R) injury involves activation of phosphatidylinositol-3-OH kinase (PI3K)- Akt/protein kinase B and p44/42 mitogen-activated protein kinase (MAPK), components of the reperfusion injury salvage kinase (RISK) pathway. The adipocytokine, apelin, activates PI3K Akt and p44/42 in various tissues and we, therefore, hypothesised that it might demonstrate cardioprotective activity. Employing both in vivo (open-chest) and in vitro (Langendorff and cardiomyocytes) rodent (mouse and rat) models ofmyocardial I/R injury we investigated if apelin administered at reperfusion at concentrations akin to pharmacological doses possesses cardioprotective activity. Apelin-13 and the physiologically less potent peptide, apelin-36, decreased infarct size in vitro by 39.6% (p<0.01) and 26.1% (p<0.05) respectively. In vivo apelin-13 and apelin-36 reduced infarct size by 43.1% (p<0.01) and 32.7% (p<0.05). LY294002 and UO126, inhibitors of PI3K-Akt and p44/42 phosphorylation respectively, abolished the protective effects of apelin-13 in vitro.Western blot analysis provided further evidence for the involvement of PI3K-Akt and p44/42 in the cardioprotective actions of apelin. In addition,mitochondrial permeability transition pore (MPTP) opening was delayed by both apelin- 13 (127%, p<0.01) and apelin-36 (93%, p<0.01) which, in the case of apelin-13, was inhibited by LY294002 and mitogen-activated protein kinase kinase (MEK) inhibitor 1. This is the first study to yield evidence that the adipocytokine, apelin, produces direct cardioprotective actions involving the RISK pathway and the MPTP. PMID- 17694255 TI - An elastic, plastic, viscous model for slow shear of a liquid foam. AB - We suggest a scalar model for deformation and flow of an amorphous material such as a foam or an emulsion. To describe elastic, plastic and viscous behaviours, we use three scalar variables: elastic deformation, plastic deformation rate and total deformation rate; and three material-specific parameters: shear modulus, yield deformation and viscosity. We obtain equations valid for different types of deformations and flows slower than the relaxation rate towards mechanical equilibrium. In particular, they are valid both in transient or steady flow regimes, even at large elastic deformation. We discuss why viscosity can be relevant even in this slow shear (often called "quasi-static") limit. Predictions of the storage and loss moduli agree with the experimental literature, and explain with simple arguments the non-linear large amplitude trends. PMID- 17694256 TI - Spatial distribution patterns of trees at different life stages in a warm temperate forest. AB - We have investigated tree distributions in relation to topography between different tree life history stages, from the seed-dispersal stage to the adult stage in a warm temperate evergreen broadleaved forest on Yakushima Island, Japan, to clarify the critical stages in determining adult tree distributions. We conducted a census of all living trees > or =30 cm tall and collected seed falls over three years using 25 seed traps in a 50 m x 50 m quadrat. Four life stages were defined: stage 1, dispersed seed; stage 2, individuals taller than 30 cm and diameter at breast height (DBH) < 1 cm; stage 3, trunks 1 cm < or = DBH < 10 cm; stage 4, trunks with DBH > or = 10 cm. We classified 17 common tree species into three groups; group A was distributed mainly on the upper slope, group B on the lower slope, and group C on both. Most of group A and B trees at stages 2-4 showed an aggregated distribution along the topographical gradient. The densities at stage 1 showed weaker aggregations according to slope. Topography-specific tree distribution was probably determined at the regeneration stage, and later survival was less effective as a mechanism of vegetation differentiation. PMID- 17694257 TI - Power Doppler and spectral Doppler measurements of knee-joint synovitis in rheumatoid arthritis patients with superficial pattern signals and in those with deep pattern signals. AB - Power Doppler and spectral Doppler ultrasonography were used to scan 127 knee joints of 72 patients with rheumatoid arthritis (RA). Synovial effusion thickness and synovial proliferation (pannus) thickness, as well as the flow signal diameter, were measured on ultrasonogram prints of the power Doppler using digital calipers. In addition, color-flow signal grades on power Doppler and the resistance index (RI) values on spectral Doppler were evaluated. The values of these five variables were compared among 58 joints with superficial pattern flow signals and 69 joints with deep pattern flow signals. Compared with the joints with deep pattern signals, the joints with superficial pattern signals had significantly higher mean values of effusion thickness (P < 0.0001) and flow signal grades (P < 0.0001), and significantly lower mean RI (P < 0.0001). On the other hand, the joints with deep pattern signals had a significantly higher value of signal diameter (P = 0.0125) and had a trend to higher value of pannus thickness (P = 0.079) as well. Significant correlations were observed between effusion thickness and signal grades (P < 0.0001); effusion thickness and RI (P < 0.0001); signal diameter and pannus thickness (P = 0.0102); signal diameter and RI (P < 0.0001); and signal grades and RI (P < 0.0001). The ultrasonographic measurements of synovitis in RA patients provide valuable information on synovial inflammation. PMID- 17694258 TI - Comparison of in-office magnetic resonance imaging versus conventional radiography in detecting changes in erosions after one year of infliximab therapy in patients with rheumatoid arthritis. AB - The objective of this study was to compare standard hand radiographs with in office 0.2 T magnetic resonance imaging (MRI) in monitoring response to therapy in patients with rheumatoid arthritis (RA) who were receiving infliximab, to evaluate the frequency and location of erosions, and to determine if there were differences in outcome based on disease duration at baseline. Patients who satisfied the American College of Rheumatology criteria for RA and were receiving infliximab therapy were evaluated with a baseline and 1-year follow-up MRI. Magnetic resonance images were interpreted by two blinded, board-certified radiologists. Bone erosions were identified as well-defined defects extending through the cortical margin. The mean age of the 48 patients was 58.5 years. The median infliximab dosage was 4 mg/kg. Baseline data showed that 41 patients had abnormal MRIs. The mean time between the baseline and follow-up MRI examinations was 10.5 months. Follow-up MRI revealed regression in 11 patients. Thirty-one patients had both MRIs and radiographs. Magnetic resonance imaging was approximately twice as sensitive as radiography in detecting erosions at baseline. In-office MRI was useful in monitoring disease response after the initiation of infliximab treatment. Magnetic resonance imaging is potentially a very valuable diagnostic tool and prognostic indicator for use in patients with RA. PMID- 17694259 TI - Diagnosis of distal radioulnar joint subluxation in patients with rheumatoid wrist by computed tomography. AB - Subluxation of the distal radioulnar joint (DRUJ) is associated with extensor tendon rupture in patients with rheumatoid arthritis (RA). However, it remains difficult to quantitatively evaluate DRUJ subluxation in RA wrist. We devised a new method for assessing DRUJ subluxation. This study investigated whether the new method, known as the RA subluxation ratio (RASR), or a conventional method was superior for detecting extensor tendon rupture in the RA wrist. Thirty-five RA wrists and 10 wrists of healthy volunteers were scanned using computed tomography. The RA wrists were divided into a tendon rupture group and a nonrupture group. The dorsal surface of the distal radius from Lister's tubercle to the ulnar aspect of the distal radius maintains a planar surface in the RA wrist. Therefore, we defined the RASR as the extent of dorsal subluxation of the ulna relative to this plane. We quantified subluxation of the DRUJ by using the RASR or the modified radioulnar line method, and compared the two methods. The RASR was 0.440 in the rupture group, 0.333 in the nonrupture group, and 0.106 in the healthy volunteers. The RASR was significantly higher than the modified radioulnar line method in the sensitivity of diagnosing tendon rupture. PMID- 17694260 TI - Improvement of disease activity of rheumatoid arthritis patients from 2000 to 2006 in a large observational cohort study IORRA in Japan. AB - The objective of this study was to show whether the disease activity of rheumatoid arthritis (RA) patients had improved in Japan, and whether the improvement of disease activity had resulted in a better outcome of patients. In a single-institute-based prospective observational cohort of RA patients (Institute of Rheumatology, Rheumatoid Arthritis, IORRA), a total of 7512 patients were enrolled, and their information was collected biannually. A cross sectional data set A that included all patients in each phase was analyzed. From October 2000 to April 2006, disease activity score DAS28 significantly improved from 4.15 to 3.63, and the frequency of patients in remission (DAS28 < 2.6) increased from 8.5% to 21.5%. During this period, the frequency of methotrexate users increased from 33.9% to 58.7% and the average dosage of methotrexate also increased from 5.59 mg/week to 6.94 mg/week; on the other hand, there was no increase in any adverse reaction among the methotrexate users. To investigate the relationship between longitudinal disease control and progression of disability, a longitudinal data set B that included 712 patients who completed all phases of the study from 2000 to 2006 was selected and was analyzed. The disability index JHAQ of a poorly controlled group (average DAS > 5.1) increased (+34.8%), that of a moderately controlled group (average DAS 3.2-5.1) also increased (+14.0%), but that of a well-controlled group (average DAS < 3.2) decreased (-13.0%). In conclusion, by using a prospective observational cohort IORRA in Japan, we demonstrate that RA disease activity improved from 2000 to 2006, which correlates with an increased use of methotrexate. The suppression of disease activity resulted in a better outcome for patients. PMID- 17694261 TI - Impact of rheumatoid arthritis on quality of life. AB - Quality of life (QOL) of patients affected by various diseases is now recognized as an important outcome variable. Consenting patients with rheumatoid arthritis (American College of Rheumatology criteria) were included in the study. Quality of life was assessed using the World Health Organization Quality of Life assessment, short form (WHOQOL-BREF). Disease activity was assessed by the Disease Activity Score (DAS28) for 3 variables and functional disability by the Health Assessment Questionnaire (HAQ). Extra-articular manifestations (ExRA) were diagnosed clinically. Seventy-five age-matched normal controls and 136 patients (19 males) were included. The mean duration of rheumatoid arthritis (RA) was 9 +/ 5.8 years. The mean DAS28 and HAQ were 4.43 +/- 1.4 and 0.97 +/- 1.6, respectively. At least one ExRA was present in 30 (22.1%) patients. The WHOQOL scores were significantly lower in patients with RA compared to normal controls. Patients and normal controls scored highest in the social relationship domain. There was significant inverse correlation of HAQ with all four domains of WHOQOL. There was significant inverse correlation of DAS28 with the physical health and psychological domains. Patients with ExRA scored significantly lower in the physical health domain of WHOQOL. Multiple regression analysis showed only HAQ to independently affect QOL. Quality of life is compromised in patients with RA. Patients and normal controls scored higher in the social relationship domain. Functional disability is the most important factor affecting QOL in RA. PMID- 17694262 TI - Decreased numbers of signal-joint T cell receptor excision circle-containing CD4+ and CD8+ cells in systemic lupus erythematosus patients. AB - Systemic lupus erythematosus (SLE) patients have a decreased number of peripheral blood T cells containing signal-joint T cell receptor excision circles (Sj TRECs), which are considered an indicator of thymic output. The objective of this study was to investigate the mechanism of the decrease in such T cells. Peripheral blood T cells from SLE patients were classified into CD4+ and CD8+ cells. Sj TREC levels were measured by real-time PCR. Telomerase activity was determined by the telomeric repeat amplification protocol assay. The numbers of Sj TREC containing CD4+ and CD8+ cells were lower in the peripheral blood of SLE patients than in the controls. A correlation was found between the numbers of Sj TREC-positive CD4+ and CD8+ cells. The level of TRECs is influenced by an increase in cell division. To examine this increase, telomerase activity as an indicator of cell division was measured simultaneously; however, there was no correlation between the Sj TREC level and telomerase activity. These results suggest that decreased thymic output occurs in SLE patients. PMID- 17694263 TI - Dermatan sulfate in the synovial fluid of patients with knee osteoarthritis. AB - Biochemical factors play an important role in osteoarthritis (OA) pathogenesis. The purpose of this study is to clarify whether the dermatan sulfate (DS) levels in the synovial fluid of patients with knee OA are related to residual cartilage. Synovial fluid was obtained from 51 OA patients. Knee radiographs were evaluated with the Kellgren-Lawrence (K/L) grading scale. The levels of the following disaccharides were measured by high-performance liquid chromatography (HPLC): DS (DSDeltaDi4S), chondroitin 6-sulfate (CSDeltaDi6S), and chondroitin 4-sulfate (CSDeltaDi4S). The concentration of cartilage oligomeric matrix protein (COMP) was measured by a sandwich ELISA. The levels of DSDeltaDi4S in Grades 0 and I OA were significantly higher than levels in Grade II (P = 0.0458), Grade III (P < 0.0001) and Grade IV (P < 0.0001), and we found strong relationships between the levels of DSDeltaDi4S and those of CSDeltaDi6S (P < 0.0001, r = 0.705), CSDeltaDi4S (P < 0.0001, r = 0.750), and COMP (P < 0.0001, r = 0.699). We conclude that the presence of DSDeltaDi4S reflects proteoglycan metabolism in the residual articular cartilage of OA patients. This suggests that metabolism of the small leucine-rich repeat proteoglycans decorin and biglycan, which contain chains of DSDeltaDi4S, is similar to that of aggrecan. PMID- 17694264 TI - Imatinib mesylate both prevents and treats the arthritis induced by type II collagen antibody in mice. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease that is associated with joint destruction. Imatinib mesylate (imatinib) is an inhibitor that specifically targets a set of protein tyrosine kinase, such as abl, c-kit, and platelet-derived growth factor receptor (PDGFR) and it is widely used to treat chronic myeloid leukemia (CML). The purpose of the present study is to determine whether imatinib can provide benefit in the arthritis induced by anti-collagen type II antibody (CAIA) in mice, a model that provides an opportunity to study the effector inflammatory phase of arthritis without involving the priming phase of the immune responses. Mice treated with intraperitoneal administration of imatinib (1 or 10 mg/kg) prior to the development of CAIA displayed significant reductions in the severity of CAIA as assessed by arthritis score, histology, and synovial PDGF and vascular endothelial growth factor expression. In addition, treatment of the mice that had developed CAIA with intraperitoneal administration of imatinib (1 or 10 mg/kg) inhibited the progression of arthritis as assessed by those parameters. These results suggest that imatinib prevents and treats CAIA. Imatinib may thus have both a preventive and therapeutic potential for the joint inflammation at the effector stage of RA. PMID- 17694265 TI - Higher maximal serum concentration of methotrexate predicts the incidence of adverse reactions in Japanese rheumatoid arthritis patients. AB - Weekly pulsed low-dose methotrexate (MTX) is a standard regimen for rheumatoid arthritis (RA). Severe adverse reactions to MTX, such as pneumonia and cytopenia, sometimes occur; however, it is difficult to predict the development of these adverse reactions. In this article, we examine the serum concentrations of orally administered MTX of 69 Japanese patients with RA in the clinical setting. The maximum serum concentration (C (max)) after the first dose of the weekly administration and the time at which C (max) was obtained (T (max)) were analyzed. C (max) correlated with the administered dose before measurement. The average T (max) was 2.0 +/- 0.8 h, and none of the patients showed a T (max) of more than 4 h. In addition, we demonstrated that the weekly MTX dosage and the mean dosage of steroids were significantly higher in patients with adverse reactions than in those without them, and the C (max) after the first dose of the weekly administration particularly correlated with the incidence of adverse reactions (P < 0.001). In fact, the cut-off point of C (max) (0.16 micromol/l) was a sensitive predictor of the adverse reactions (sensitivity 81% and specificity 67%). We concluded that C (max) after the first dose of weekly administration is a useful parameter for predicting the development of adverse reactions to MTX. PMID- 17694266 TI - Proximal femoral fracture in patients with rheumatoid arthritis. AB - Hip fracture occurrence was examined cross-sectionally in Japanese patients with rheumatoid arthritis (RA). Between January 2005 and June 2006 we studied RA outpatients with a past history of hip fractures. Patients included 1 man and 25 women. As 3 women had bilateral hip fractures, the total number was 29. Age at the time of fracture was 72.1 +/- 4.5 years. Of the 29 fractures, 22 were cervical and 7 were trochanteric. Four fractures were spontaneous while the others occurred in falls. 24 fractures were associated with oral steroid administration. All 5 fractures unassociated with prednisolone were cervical. Of the 26 patients, 8 were taking bisphosphonate when fracture occurred. Cervical fracture was treated with total hip arthroplasty in 1 patient whose hip showed RA changes. In others whose hip joint lacked RA change, procedures included osteosynthesis in 2 patients with good function over 6 years; and hemiarthroplasty with a bipolar system in 19 displaced fractures, with good function over 4.1 years. Osteosynthesis was performed for all 7 trochanteric fractures. Trabeculae were thin, and fewer transverse trabeculae could be found in specimens from cervical fracture. Hip fracture in RA patients occurred 10 years earlier than in the general population, and many fractures were cervical. PMID- 17694267 TI - Motion analysis of the wrist joints in patients with rheumatoid arthritis. AB - We investigated the characteristics of the wrist joint motion in patients with rheumatoid arthritis (RA), using a biaxial flexible goniometer. Wrist joint range of motion and velocity were measured on the dominant hand in RA patients (n = 22) and normal individuals (n = 5). We investigated flexion-extension (FE) task, radial-ulnar deviation (RUD) task, and functional motion tasks, such as writing letters or unscrewing the lid of a jar. In normal individuals, there was cooperative coupling of FE and RUD during wrist movement, and this coupling motion was essential for normal wrist movements. On the other hand, in RA patients, wrist joint range of motion was restricted at various degrees, with reduced joint motion velocity that was severe on RUD. Functional wrist motion tasks indicated circumductive movement with both FE and RUD in normal individuals, whereas the direction of movement was limited in RA patients, and results revealed failure of cooperative coupling of FE and RUD. Our results indicate that disturbed coupling of FE and RUD results in difficulties in the cooperative movements and have great influence on the daily activities in RA wrist joint. PMID- 17694268 TI - Posterior interosseous nerve palsy related to rheumatoid synovitis of the elbow. AB - Posterior interosseous nerve palsy (PINP) is a rare complication of rheumatoid arthritis of the elbow. A 58-year-old woman with rheumatoid arthritis, who complained of an inability to extend her left fingers, was referred to our hospital. After a series of studies, extensor tendon ruptures were excluded, and PINP was diagnosed. By means of the Henry anterolateral approach, the radial nerve was exposed, which was compressed by swollen synovial membrane at the Frohse arcade. Elbow synovectomy was performed, and the arcade was opened to release the nerve. The PINP has been recovered completely within 2 weeks after surgery. Various examinations other than magnetic resonance imaging have been reported for the adjunctive diagnosis of PINP, but MR imaging was most useful as an adjunctive examination in this case. PMID- 17694269 TI - A case of pachydermoperiostosis treated by oral administration of a bisphosphonate and arthroscopic synovectomy. AB - Pachydermoperiostosis (PDP) is a rare hereditary disorder characterized by pachydermia, digital clubbing, and periosteal hypertrophy. Here, we report a case of PDP showing symptoms consistent with arthritis, which was treated by oral administration of risedronate sodium and arthroscopic synovectomy. PMID- 17694270 TI - A case of pure red cell aplasia complicated by Evans syndrome. AB - A 33-year-old woman complaining of severe anemia was admitted to our hospital for polyclonal hyperglobulinemia. She was diagnosed with pure red cell aplasia (PRCA) associated with Evans syndrome. Initially, the presence of human parvovirus B19 (HPV B19) IgM appeared to indicate that the cause of PRCA was HPV B19 infection. Evans syndrome improved with steroid therapy, but PRCA was refractory. Cyclosporine was administered; consequently, the patient markedly recovered from PRCA and was discharged. PRCA complicated by Evans syndrome occurred during the course of polyclonal hyperglobulinemia. The most direct etiology for the onset of PRCA was unclear; however, immunological disorders such as polyclonal hyperglobulinemia, in addition to HPV B19 infection, may have been partly responsible for the etiology of PRCA. PMID- 17694271 TI - Septic arthritis of the right ankle caused by Staphylococcus aureus infection in a rheumatoid arthritis patient treated with etanercept. AB - We report on a 65-year-old man with rheumatoid arthritis who developed septic arthritis of the right ankle and was treated with etanercept, low-dosage prednisolone, and salazosulfapyridine for 18 weeks. Staphylococcus aureus was cultured from ankle synovial fluid; hence, etanercept was stopped and cefazolin was administered. The patient responded well to arthroscopic synovectomy and irrigation of the ankle. Etanercept treatment should cease if it leads to septic arthritis and patients should be prescribed systemic antibiotics, with surgical debridement considered. PMID- 17694272 TI - A painful large ganglion cyst of the ankle treated by the injection of OK-432. AB - Despite its benign nature, a ganglion can be problematic. We successfully treated a patient with large painful ganglion in his ankle by OK-432 (lyophilized incubation mixture of group A Streptococcus pyogenes of human origin) injection. OK-432 injection seems to be a safe, convenient, and effective alternative to surgical treatment for either symptomatic or recurrent ganglia. PMID- 17694273 TI - Disturbances of the symphysis pubis in rheumatoid arthritis: report of two cases. AB - We present two rheumatoid arthritis (RA) patients suffering from disturbances of the symphysis pubis. Radiography revealed one with pelvic ring disruption with symphysis pubis diastasis, and the other with osteolysis at both pubic rami and disruption of the superior aspect of the symphysis pubis. Both cases had received long-term corticosteroid therapy, including pulse therapy. We recommend reducing the corticosteroid dose to prevent disturbances of the symphysis pubis especially in RA patients on long-term steroid therapy. PMID- 17694274 TI - Subcutaneous tendon rupture of extensor tendons on bilateral wrists associated with calcium pyrophosphate dihydrate crystal deposition disease. AB - Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is a well recognized inflammatory joint disorder. Extensor tendon rupture associated with CPPD deposition has rarely been described. We report herein the case of a 58-year old woman who underwent reconstruction for subcutaneous extensor tendon ruptures of the extensor tendons for the ring and little fingers on both wrists associated with CPPD deposition. The significance of this case is the occurrence at an earlier age compared to previous papers and the appearance on bilateral wrists. PMID- 17694275 TI - Spatial and temporal regulation of the forisome gene for1 in the phloem during plant development. AB - Forisomes are protein aggregates found uniquely in the sieve elements of Fabaceaen plants. Upon wounding they undergo a reversible, calcium-dependent conformational switch which enables them to act as cellular stopcocks. Forisomes begin to form in young sieve elements at an early stage of metaphloem differentiation. Genes encoding forisome components could therefore be useful as markers of early sieve element development. Here we present a comprehensive analysis of the developmental expression profile of for1, which encodes such a forisome component. The for1 gene is highly conserved among Fabaceaen species and appears to be unique to this phylogenetic lineage since no orthologous genes have been found in other plants, including Arabidopsis and rice. Even so, transgenic tobacco plants expressing reporter genes under the control of the for1 promoter display reporter activity exclusively in immature sieve elements. This suggests that the regulation of sieve element development is highly conserved even in plants where mature forisomes have not been detected. The promoter system could therefore provide a powerful tool for the detailed analysis of differentiation in metaphloem sieve elements in an unexpectedly broad range of plant species. PMID- 17694276 TI - The in vivo assessment of a novel scaffold containing heparan sulfate for tissue engineering with human mesenchymal stem cells. AB - Human mesenchymal stem cells (hMSCs) are an attractive tissue engineering avenue for the repair and regeneration of bone. In this study we detail the in vivo performance of a novel electrospun polycaprolactone scaffold incorporating the glycosaminoglycan heparan sulfate (HS) as a carrier for hMSC. HS is a multifunctional regulator of many key growth factors expressed endogenously during bone wound repair, and we have found it to be a potent stimulator of proliferation in hMSCs. To assess the potential of the scaffolds to support hMSC function in vivo, hMSCs pre-committed to the osteogenic lineage (human osteoprogenitor cells) were seeded onto the scaffolds and implanted subcutaneously into the dorsum of nude rats. After 6 weeks the scaffolds were retrieved and examined by histological methods. Implanted human cells were identified using a human nuclei-specific antibody. The host response to the implants was characterized by ED1 and ED2 antibody staining for monocytes/macrophages and mature tissue macrophages, respectively. It was found that the survival of the implanted human cells was affected by the host response to the implant regardless of the presence of HS, highlighting the importance of controlling the host response to tissue engineering devices. PMID- 17694277 TI - Selection using the alpha-1 integrin (CD49a) enhances the multipotentiality of the mesenchymal stem cell population from heterogeneous bone marrow stromal cells. AB - Bone marrow-derived mesenchymal stem cells consist of a developmentally heterogeneous population of cells obtained from colony forming progenitors. As these colonies express the alpha-1 integrin (CD49a), here we single-cell FACS sorted CD49a+ cells from bone marrow in order to create clones and then compared their colony forming efficiency and multilineage differentiation capacity to the unsorted cells. Following selection, 40% of the sorted CD49a+ cells formed colonies, whereas parental cells failed to form colonies following limited dilution plating at 1 cell/well. Following ex vivo expansion, clones shared a similar morphology to the parental cell line, and also demonstrated enhanced proliferation. Further analysis by flow cytometry using a panel of multilineage markers demonstrated that the CD49a+ clones had enhanced expression of CD90 and CD105 compared to unsorted cells. Culturing cells in adipogenic, osteogenic or chondrogenic medium for 7, 10 and 15 days respectively and then analysing them by quantitative PCR demonstrated that CD49a+ clones readily underwent multlineage differentiation into fat, bone and cartilage compared to unsorted cells. These results thus support the use of CD49a selection for the enrichment of mesenchymal stem cells, and describes a strategy for selecting the most multipotential cells from a heterogeneous pool of bone marrow mononuclear stem cells. PMID- 17694278 TI - Physiological stress induces the metastasis marker AGR2 in breast cancer cells. AB - As an approach to understanding the factors that activate expression of tumor progression genes, the role of physiological stress in the activation of a panel of tumor cell markers was investigated. These studies identify the developmental gene product, anterior gradient 2 (AGR2) as a cancer cell marker specifically up regulated in response to depletion of serum and oxygen. AGR2 has been identified as a tumor marker in primary and secondary cancer lesions, and as a marker for detection of circulating tumor cells (CTCs). Elevated levels of AGR2 are known to increase the metastatic potential of cancer cells, but conditions leading to increased expression of AGR2 are not well understood. The present results identify novel physiological parameters likely to contribute to AGR2 induction in situ. PMID- 17694279 TI - Sapphire platinum detachable coil experience in a tertiary-care facility. AB - BACKGROUND: The Guglielmi Detachable Coil introduced by the Boston Scientific Corporation has been widely used for endovascular coiling of aneurysm. Recently, Sapphire platinum detachable coils (eV3, Irvine, CA) have been introduced for aneurysm coiling. Herein, we report our clinical experience with the Sapphire coil to evaluate the incidence of coil related complications and the rate of aneurysm occlusion. METHODS: Consecutive patients who underwent embolization with Sapphire detachable coils were prospectively enrolled from January 2004 to September 2004 and the data were retrospectively analyzed. Patient demographics, including age, gender, presenting symptoms, Hunt and Hess grade, Fisher grade and locations of the vascular anomalies were collected. Additionally, complications associated with the coils and rates of aneurysm occlusion were observed and the data compiled. RESULTS: 29 patients underwent Sapphire coil embolization for intracranial aneurysms. Mean age was 50 +/- 18 (mean +/- SD) years with 81% being females. Aneurysm neck reconstruction was required in 7 cases, 6 with Neuroform stent (5 unruptured aneurysms) and 1 with balloon assistance (ruptured aneurysm). In 7 cases, Sapphire coils were used along with other coils. There were no events of thromboembolism or ruptures of aneurysms during coil embolization. However, multi-diameter coils demonstrated stretching in 4 stent-assisted cases without any adverse consequences. Complete occlusion of the aneurysm was achieved in 79.31% of the patients, neck remnant in 6.89, and partial coiling was achieved in 13.79%. CONCLUSION: The Sapphire coil could safely be used in the treatment of both ruptured and unruptured aneurysms. However, multi-diameter non-stretch resistant coils may be associated with coil stretching when used in conjunction with a stent. Further study is still required for definitive results. PMID- 17694280 TI - [Analysis of hospital admissions associated with digitalis glycosides]. AB - BACKGROUND: Although the value of digitalis glycosides in the treatment of heart failure is limited, approximately 255 million DDDs of digitalis glycosides (DGs) were prescribed in Germany in 2004. METHOD: The authors analyzed data from adverse drug reactions (ADRs) resulting in hospitalization in the four German Pharmacovigilance Centers (PVCs) associated with DGs between 2000 and 2004. All patients with an at least "probable" ADR were included. RESULTS: Out of 3,092 ADR patients, in 314 patients (10.2%, 244 women) admission was caused by a DG-related ADR. Patients with DG-related ADR had a significantly lower body weight and were significantly older than patients with other ADRs. Per 1,000 patients exposed to DGs the incidence [95% CI] was calculated to 1.9 [1.0; 3.3] ADRs per 3 months exposition. Oral digitoxin was involved in 296 patients (228 women). 70.6% of women but only 29.3% of men were overdosed (> 1 mug/kg body weight per day). Women received significantly higher body weight-related digitoxin doses and had significantly higher digitoxin plasma levels than men. ADRs in patients with nonelevated digitoxin serum level were mainly caused by pharmacodynamic drug-drug interactions (e.g., beta-blockers). Overall, 42.4% of the ADRs were supposed to be preventable. CONCLUSION: Body weight-adapted dosing of digitoxin is essential for preventing DG-ADRs, particularly in elderly women with low body weight. Beyond giving attention to pharmacodynamic and pharmakokinetic drug-drug interactions, regular measurements of digitoxin plasma concentrations are crucial accounting for the increased half-life of digitoxin in the very old. PMID- 17694282 TI - [Novel indications for phosphodiesterase type 5 inhibitors]. AB - Phosphodiesterase type 5 (PDE5) induces the breakdown of cyclic guanosine monophosphate (cGMP) in smooth muscle cells. Hence, PDE5 inhibitors promote vasodilative effects by enhancing intracellular cGMP levels. Three PDE5 inhibitors, sildenafil, vardenafil, and tadalafil, have been approved for the treatment of "erectile dysfunction" (ED). All three show an excellent effectiveness regarding ED therapy, but differ from one another regarding their pharmacokinetic properties. Recent experimental studies and clinical trials indicate that PDE5 inhibitors are also effective in the treatment of various other diseases such as pulmonary arterial hypertension (PAH), Raynaud's disease, gastrointestinal disorders, and stroke, and furthermore exert cardioprotective effects. This review describes the cardiovascular safety of PDE5 inhibitors and provides an overview of the current literature regarding potential novel indications. PMID- 17694281 TI - [Evaluation of an internal guideline for the diagnostics of deep vein thrombosis]. AB - BACKGROUND AND PURPOSE: In line with the application of evidence-based medicine as part of the day-to-day clinical practice of a community hospital internal guidelines concerning relevant diagnostic or therapeutic problems were developed. The authors retrospectively compared all data of patients with the tentative diagnosis of deep vein thrombosis (DVT), who underwent further diagnostics before and after implementation of an internally developed guideline for the diagnostics of DVT. The aim was to evaluate if the internal guideline was applied by the doctors in the daily routine and if the implementation led to a change and rationalization of the diagnostic process, in particular with regard to reducing invasive examinations. METHODS: In a retrospective controlled cohort study the medical records of in- and outpatients (n = 371) receiving further diagnostics following a tentative diagnosis of DVT were screened. The kind of examinations, the duration of the diagnostic process and the rate of hospitalization for DVT were compared between the intervention group (n = 185), treated in the initial 10 months following guideline implementation, and the control group (n = 186), treated in the 10 months prior to implementation. Furthermore, the physicians' compliance with the internal guideline was assessed. RESULTS: After implementation in 114 of 185 cases (62%) the treating doctors based their diagnostic procedure on the internal guideline. There was a significant decrease of phlebographies (45.4% vs. 74.2%; RR 0.61 [95% CI 0.51; 0.73]). By contrast, the number of D-dimer tests (81.6% vs. 33.3%; RR 2.45 [95% CI 1.98; 3.03]) and of duplex sonographies (42.2% vs. 21.5%; RR 1.96 [95% CI 1.42; 2.71]) increased significantly. A reduction of the hospitalization rate for further diagnostics of primary ambulant patients (51.3% vs. 60.4% of the tentative cases; RR 0.85 [95% CI 0.69; 1,04]) without a significant change in the final number of DVT diagnoses (33.3% vs. 27.6%; RR 0,83 [95% CI 0,61; 1,13]) was found. There was a slight increment in the mean length of diagnostic process (2.12 vs. 1.84 days). CONCLUSION: The implementation of an internal guideline for the diagnostics of DVT led to a significant reduction of the hospitalization rate and to a considerable change of the diagnostic procedure in favor of noninvasive diagnostic tests, for patients presenting with a diagnosis of suspected DVT. PMID- 17694283 TI - [Doping in sport]. AB - The misuse of therapeutics for doping purposes has always been a serious issue in professional as well as amateur sport. With the introduction of lists containing prohibited substances and methods of doping by international sports federations as well as the International Olympic Committee, doping controls were established that have resulted in numerous adverse analytic findings. Due to the dynamic nature of the pharmaceutical market and constantly growing pool of new therapeutics, sports drug-testing authorities have been urged to expand and improve doping control analytical strategies. Referring to the current list of prohibited substances and methods of doping, effects and side effects of classes of drugs are summarized, and statistics are presented describing positive test results reported during the years 2003-2005. PMID- 17694284 TI - [Update cardiology 2006/2007]. AB - This article reviews advances in cardiovascular medicine published last year. The following issues are reported in detail: (1) risk factors and lifestyle, (2) computed tomography in coronary artery disease, (3) revascularization in cardiogenic shock, (4) long-term anticoagulation in venous thrombosis, (5) anemia in heart failure, (6) optimism and cardiovascular death, (7) mortality after drug eluting stents, (8) diabetes and cardiovascular disease, (9) new guidelines atrial fibrillation, (10) dopamine agonists and cardiac valve regurgitation, (11) beta-blockers and hypertension, (12) angiotensin-converting enzyme inhibitors and aortic rupture, (13) statin therapy, (14) adherence to pharmacotherapy. PMID- 17694285 TI - [Financial incentives and dialysis]. AB - Chronic renal replacement therapy by hemodialysis costs 55,000 Euros per year and constitutes the upper limit of a cost-effective treatment. Since reimbursement for dialysis is high, every patient who is in need of it will receive dialysis. Nephrology outside the hospital, however, is moving into a progress trap. Financial incentives tempt physicians to avoid complex or delicate treatments such as immunosuppression of IgA nephritis. The decision to forgo or withdraw dialysis and the referral to kidney transplantation conflict with the nephrologists' economic interests. High-tech medicine needs a shift in thinking since not all medically possible diagnostic and therapeutic procedures can be financed anymore. The costs urge to do more for prevention and treatment of kidney disease. Alternative possibilities to extend the cost-effective kidney transplantation should be discussed without moral rigorism. Since it is in competition with other cost-intensive disciplines, it is hard for nephrologists to start with the required mind-changing process. PMID- 17694286 TI - [Clinical diagnostics of pulmonary tuberculosis]. PMID- 17694287 TI - [The German program for disease management guidelines: evaluation by use of quality indicators]. AB - The Program for National Disease Management Guidelines (German DM-CPG Program) in Germany aims at the implementation of best-practice recommendations for prevention, acute care, rehabilitation and chronic care in the setting of disease management programs and integrated health-care systems. Like other guidelines, DM CPG need to be assessed regarding their influence on structures, processes and outcomes of care. However, quality assessment in integrated health-care systems is challenging. On the one hand, a multitude of potential domains for measurement, actors and perspectives need to be considered. On the other hand, measures need to be identified that assess the function of the diagnostic and therapeutic chain in terms of cooperation and coordination of care. The article reviews methods and use of quality indicators in the context of the German DM-CPG Program. PMID- 17694288 TI - [Procedure of implementation of new methods of examination and treatment in the G DRG system (NUB procedure)]. PMID- 17694289 TI - [Recurrent melena in a 75-year-old man with gastrointestinal stromal tumor]. PMID- 17694291 TI - [Developmental dyslexia: the role of phonological processing for the development of literacy]. AB - Successful early reading and spelling acquisition depends on a number of different skills. Of considerable importance is phonological processing, which is the processing of acoustic signals with linguistic content. Three areas of phonological processing have been found to be most important for reading and writing competence: phonological awareness, naming speed, and phonological working memory. Research on these components suggests that specific interventions tailored to individual phonological processing deficits may prevent later dyslexia. Therefore, it appears mandatory that ear-nose-throat physicians have at least a basic knowledge of the theory of phonological processing. This will enable proper consultation with parents of affected children. PMID- 17694290 TI - [Angioneurotic orolingual edema associated with the use of rt-PA following a stroke]. AB - Angioneurotic orolingual edema associated with the use of rt-PA (recombinant tissue plasminogen activator) for systemic thrombolysis are described in the literature, but only as isolated case reports. Strangely, the rate of anaphylactic reactions to rt-PA is higher (1.9%) when they are used in the treatment of acute stroke than when they are given to treat acute myocardial infarction (0.02%). Patients who are taking ACE inhibitors seem to be at increased risk of such a potentially life-threatening event. We now report on two patients, in each of whom asymmetric angioneurotic edema was observed following successful thrombolysis with rt-PA. Both these patients were taking ACE inhibitors. It was possible to avoid intubation and ventilation in both cases. Therapy with ranitidine, clemastine, and a C1 esterase inhibitor resulted in the resolution of symptomatic angioneurotic edema within hours. PMID- 17694292 TI - Accumulation of dietary glycotoxins in the reproductive system of normal female rats. AB - The aim of the present study was to investigate whether dietary advanced glycation end-products (AGEs) can be detected in the ovarian tissue of normal female rats and whether they can affect their metabolic or hormonal profile. Sixty normal rats (20 animals in each group) were randomly assigned to regular diet, either high (H-AGE) or low (L-AGE) in AGE content for 6 months. H-AGE rats demonstrated higher levels of fasting glucose (P < 0.001), insulin (P < 0.069), and serum AGEs (P < 0.001) than control and L-AGE rats. Additionally, the H-AGE group showed increased AGE localization in the theca interna cells of the ovarian tissue compared to control/L-AGE rats (P = 0.003). Furthermore, increased receptor for AGE (RAGE) staining was also observed in granulosa cells compared to control/L-AGE samples (P = 0.038). In the H-AGE group, plasma testosterone was higher than in control rats (P < 0.001) and in the L-AGE group (P < 0.001). However, H-AGE rats did not exhibit higher body weight compared with normal (P = 0.118) and L-AGE-fed rats (P = 0.35). These results demonstrate for the first time that administration of high AGE diet in female rats for a prolonged period is associated with increased deposition of AGEs in the theca cells and of RAGE in the granulosa and theca interna cells of the ovarian tissue compared with the corresponding ovarian compartments of the control and L-AGE-fed animals. The metabolic alterations in conjuction with the increased deposition in ovarian tissues of dietary glycotoxins and elevated levels of testosterone in H-AGE-fed animals compared to the controls suggest an impact of environmental factors on ovarian tissue and these findings need further exploration. PMID- 17694293 TI - [Percutaneous plate osteosynthesis for clavicular fractures. Initial description]. AB - Insertion of titanium nails for type A and B clavicular fractures can fail intraoperatively due to the small diameter or irregular nature of the medullary canal. At present, such failures lead to open reduction and fixation (ORIF) with plates. In type C fractures (comminuted fractures), a telescoping effect is observed so that ORIF is the only suitable alternative besides nonoperative therapy. A suitable minimally invasive solution for type C fractures and as a salvage procedure for failed intramedullary nailing of type A and B fractures is presented here for the first time with a percutaneous application of an LC plate to the clavicle. PMID- 17694294 TI - [Establishing a protein signature from prostate tissue biopsies]. AB - The prostate-specific antigen test (PSA) has been a major factor contributing to a better management of prostate cancer. The low specificity limits its use in diagnosis especially in early detection of prostate cancer. Multiply expressed proteins need to be identified to establish a disease-specific protein signature that distinguishes between cancerous and noncancerous tissue. The first aim of our study is to identify differentially expressed proteins in both tissues using two-dimensional gel electrophoresis and subsequent mass spectrometry. We elucidated whether prostate biopsies are useful. First results have shown a different protein expression pattern in cancerous and noncancerous tissue. PCR revealed an increasing amount of mRNA for some upregulated proteins. We conclude that biopsies are useful material to establish protein expression patterns. PMID- 17694295 TI - [Adjuvant therapy of locally advanced prostate carcinoma with ibandronate]. PMID- 17694296 TI - Anthropometry, carbohydrate and lipid metabolism in the East Flanders Prospective Twin Survey: heritabilities. AB - AIMS/HYPOTHESIS: We determined the genetic contribution of 18 anthropometric and metabolic risk factors of type 2 diabetes using a young healthy twin population. METHODS: Traits were measured in 240 monozygotic (MZ) and 138 dizygotic (DZ) twin pairs aged 18 to 34 years. Twins were recruited from the Belgian population-based East Flanders Prospective Twin Survey, which is characterised by its accurate zygosity determination and extensive collection of perinatal and placental data, including information on chorionicity. Heritability was estimated using structural equation modelling implemented in the Mx software package. RESULTS: Intra-pair correlations of the anthropometric and metabolic characteristics did not differ between MZ monochorionic and MZ dichorionic pairs; consequently heritabilities were estimated using the classical twin approach. For body mass, BMI and fat mass, quantitative sex differences were observed; genetic variance explained 84, 85 and 81% of the total variation in men and 74, 75 and 70% in women, respectively. Heritability estimates of the waist-to-hip ratio, sum of four skinfold thicknesses and lean body mass were 70, 74 and 81%, respectively. The heritability estimates of fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance and beta cell function, as well as insulin-like growth factor binding protein-1 levels were 67, 49, 48, 62 and 47%, in that order. Finally, for total cholesterol, LDL-cholesterol, HDL-cholesterol, total cholesterol:HDL-cholesterol ratio, triacylglycerol, NEFA and leptin levels, genetic factors explained 75, 78, 76, 79, 58, 37 and 53% of the total variation, respectively. CONCLUSIONS/INTERPRETATION: Genetic factors explain the greater part of the variation in traits related to obesity, glucose intolerance/insulin resistance and dyslipidaemia. PMID- 17694297 TI - GLUT2 protein at the rat proximal tubule brush border membrane correlates with protein kinase C (PKC)-betal and plasma glucose concentration. AB - AIMS/HYPOTHESIS: GLUT2 is the main renal glucose transporter upregulated by hyperglycaemia, when it becomes detectable at the brush border membrane (BBM). Since glucose-induced protein kinase C (PKC) activation in the kidney is linked to diabetic nephropathy, we investigated the effect of glycaemic status on the protein levels of PKC isoforms alpha, betaI, betaII, delta and epsilon in the proximal tubule, as well as the relationship between them and changes in GLUT2 production at the BBM. METHODS: Plasma glucose concentrations were modulated in rats by treatment with nicotinamide 15 min prior to induction of diabetes with streptozotocin. Levels of GLUT2 protein and PKC isoforms in BBM were measured by western blotting. Additionally, the role of calcium signalling and PKC activation on facilitative glucose transport was examined by measuring glucose uptake in BBM vesicles prepared from proximal tubules that had been incubated either with thapsigargin, which increases cytosolic calcium, or with the PKC activator phorbol 12-myristate,13-acetate (PMA). RESULTS: Thapsigargin and PMA enhanced GLUT-mediated glucose uptake, but had no effect on sodium-dependent glucose transport. Diabetes significantly increased the protein levels of GLUT2 and PKC betaI at the BBM. Levels of GLUT2 and PKC-betaI correlated positively with plasma glucose concentration. Diabetes had no effect on BBM levels of alpha, betaII, delta or epsilon isoforms of PKC. CONCLUSIONS/INTERPRETATION: Enhanced GLUT2 mediated glucose transport across the proximal tubule BBM during diabetic hyperglycaemia is closely associated with increased PKC-betaI. Thus, altered levels of GLUT2 and PKC-betaI proteins in the BBM may be important factors in the pathogenic processes underlying diabetic renal injury. PMID- 17694298 TI - DNA aptamers against the MUC1 tumour marker: design of aptamer-antibody sandwich ELISA for the early diagnosis of epithelial tumours. AB - Aptamers are functional molecules able to bind tightly and selectively to disease markers, offering great potential for applications in disease diagnosis and therapy. MUC1 is a well-known tumour marker present in epithelial malignancies and is used in immunotherapeutic and diagnostic approaches. We report the selection of DNA aptamers that bind with high affinity and selectivity an MUC1 recombinant protein containing five repeats of the variable tandem repeat region. Aptamers were selected using the SELEX methodology from an initial library containing a 25-base-long variable region for their ability to bind to the unglycosylated form of the MUC1 protein. After ten rounds of in vitro selection and amplification, more than 90% of the pool of sequences consisted of target binding molecules, which were cloned, sequenced and found to share no sequence consensus. The binding properties of these aptamers were quantified using ELISA and surface plasmon resonance. The lead aptamer sequence was subsequently used in the design of an aptamer-antibody hybrid sandwich ELISA for the identification and quantification of MUC1 in buffered solutions. Following optimisation of the operating conditions, the resulting enzyme immunoassay displayed an EC50 value of 25 microg/ml, a detection limit of 1 microg/ml and a linear range between 8 and 100 microg/ml for the MUC1 five tandem repeat analyte. In addition, recovery studies performed in buffer conditions resulted in averaged recoveries between 98.2 and 101.7% for all spiked samples, demonstrating the usability of the aptamer as a receptor in microtitre-based assays. Our results aim towards the formation of new diagnostic assays against this tumour marker for the early diagnosis of primary or metastatic disease in breast, bladder and other epithelial tumours. PMID- 17694299 TI - Adverse events of blood-pressure-lowering drugs: evidence of high incidence in a clinical setting. AB - OBJECTIVES: Our primary objective was to determine the incidence of AEs of antihypertensive drugs in a cohort of outpatients attending a specialized clinic. The secondary objectives were to determine the incidence of AEs by classes of blood-pressure-lowering drugs used in monotherapy and to identify risk factors for the occurrence of AEs. METHODS: In a prospectively planned cohort study, patients attending a hypertension outpatient clinic were systematically interrogated about the occurrence of AEs of blood-pressure-lowering drugs. We compared the incidence of AEs by classes of drugs employed in monotherapy and identified risk factors for the occurrence of AEs in a logistic regression model. RESULTS: Participants were followed for 12.3 +/- 12.2 months. In total, 534 (35.4%) of 1,366 patients treated with blood pressure drugs complained of at least one AE during the follow-up, corresponding to an incidence of 31.3 AEs per 1,000 patients/month [95% confidence interval (CI) 28.6-33.9). The systolic blood pressure in the initial evaluation (P = 0.002) and use of two or more drugs (P < 0.001) were associated with higher incidence of AEs. The incidence of AEs was higher among patients treated with calcium channel blockers in monotherapy than in patients treated with diuretics (47.2 vs. 7.6%, P < 0.001). CONCLUSION: Adverse events of blood-pressure-lowering drugs are quite frequent in a clinical context, and may influence the adherence to treatment. Patients under treatment with diuretics in monotherapy have the lower incidence of AEs. PMID- 17694300 TI - Population pharmacokinetic analysis of lamivudine, stavudine and zidovudine in controlled HIV-infected patients on HAART. AB - OBJECTIVE: This work aimed at building a population pharmacokinetic (PK) model for lamivudine (LMV), stavudine (STV) and zidovudine (ZDV), estimating their inter and intraindividual PK variability and investigating the influence of different covariates. METHODS: Population PK of LMV, STV and ZDV was separately evaluated from plasma concentrations obtained in 54, 39 and 27 HIV1-infected patients, respectively, enrolled in the COPHAR1-ANRS102 trial. The primary objective of this trial was to study the pharmacokinetics of indinavir (IDV) and nelfinavir (NFV) in treated patients with a sustained virological response. Concentrations of nucleoside analogs (NA) were measured in plasma as a secondary objective. A one-compartment model with first-order elimination was used, with zero-order absorption for LMV and first-order absorption for STV and ZDV. RESULTS: Mean parameters [interpatient variability in coefficient of variation (CV%)] of LMV, STV and ZDV were: oral volume of distribution (V/F) 145 l (52%), 24 l (81%) and 248 l (80%), oral clearance (Cl/F) 32 l/h, 16 l/h (74%) and 124 l/h (51%), respectively. For LMV, absorption duration (Ta) was 1.46 h (64%). For STV and ZDV, ka was 0.46 h(-1) and 2.9 h(-1), respectively. We found a systematic effect of combination with NFV vs. IDV. We found that intrapatient variability was greater than interpatient variability (except for STV) and greater than 55% for the three drugs. CONCLUSION: This trial enabled the estimation of the population PK parameters of three NA in patients with a sustained virological response, and the median curves could be used as references for concentration controlled strategies. We observed, as for the protease inhibitors, a great variability of PK parameters. PMID- 17694301 TI - Biodegradation of diphenyl ether and transformation of selected brominated congeners by Sphingomonas sp. PH-07. AB - Polybrominated diphenyl ethers (PBDEs) are common flame-retardant chemicals that are used in diverse commercial products such as textiles, circuit boards, and plastics. Because of the widespread production and improper disposal of materials that contain PBDEs, there has been an increasing accumulation of these compounds in the environment. The toxicity and bioavailability of PBDEs are variable for different congeners, with some congeners showing dioxin-like activities and estrogenicity. The diphenyl ether-utilizing bacterium Sphingomonas sp. PH-07 was enriched from activated sludge of a wastewater treatment plant. In liquid cultures, this strain mineralized 1 g of diphenyl ether per liter completely within 6 days. The metabolites detected and identified by gas chromatography/mass spectrometry (MS) and electrospray ionization/MS analysis corresponded with a feasible degradative pathway. However, the strain PH-07 even catabolized several brominated congeners such as mono-, di-, and tribrominated diphenyl ethers thereby producing the corresponding metabolites. PMID- 17694302 TI - Coexpression of rumen microbial beta-glucanase and xylanase genes in Lactobacillus reuteri. AB - The aim of this study was to clone and coexpress two rumen fibrolytic enzyme genes in Lactobacillus reuteri. The ability of the genetically modified strain to degrade beta-glucan and xylan was evaluated. The Fibrobacter succinogenes beta glucanase (1,3-1,4-beta-D: -glucan 4-glucanohydrolase [EC 3.2.1.73]) gene and the Neocallimastix patriciarum xylanase gene, xynCDBFV, were constructed to coexpress and secrete under control of the Lactococcus lactis lacA promoter and its secretion signal and then transformed into L. reuteri Pg4, a strain isolated from the gastrointestinal tract of broiler chickens. The transformed L. reuteri strain acquired the capacity to break down soluble beta-glucan and xylan. The introduction of the recombinant plasmids and production of beta-glucanase and xylanase did not affect cell growth. To the best of our knowledge, this is the first report of coexpression of rumen microbial fibrolytic enzyme genes in L. reuteri. PMID- 17694303 TI - A new kinetic approach to microbial storage process. AB - In this work, a new kinetic approach was proposed to describe the microbial growth, substrate consumption, and formation and utilization of the intracellular storage products (X(STO)) in activated sludge. It was found that the formation of X(STO) was coupled with energy generation and respiration and that the X(STO) formation rate was proportional to the substrate utilization rate. A high amount of external substrate resulted in a relatively rapid storage process with a large fraction of substrate electrons for X(STO) formation. The maximum growth rate of active biomass on X(STO) and the yield coefficient for growth on the storage polymers were estimated as 0.12 h(-1) and 0.60 g chemical oxygen demand (COD)(X) g(-1) COD(STO), respectively. This established model was verified with the experimental results from two different case studies with pure and mixed cultures. Results showed that this kinetic model was able to accurately and mechanistically describe the microbial storage processes. PMID- 17694304 TI - Lipid accumulation in Schizochytrium G13/2S produced in continuous culture. AB - Lipid and docosahexaenoic acid (DHA) accumulation into Schizochytrium G13/2S was studied under batch and continuous culture. Different glucose and glutamate concentrations were supplemented in a defined medium. During batch cultivation, lipid accumulation, 35% total fatty acids (TFA) occurred at the arithmetic growth phase but ceased when cell growth stopped. When continuous culture was performed under different glutamate concentrations, nitrogen-growth-limiting conditions induced the accumulation of 30-28% TFA in Schizochytrium. As the dilution rate decreased from 0.08 to 0.02 h(-1), both cell dry weight and TFA content of the cell increased. Under a constant dilution rate of 0.04 h(-1), carbon-limiting conditions decreased the TFA to 22%. Fatty acid profile was not affected by the different nutrient concentrations provided during continuous culture. Consequently, lipid accumulation can be induced through the carbon and nitrogen source concentration in the medium to maximise the TFA and subsequently DHA productivity by this microorganism. PMID- 17694305 TI - Magnetic resonance imaging in the evaluation of osteochondritis dissecans of the patella. AB - OBJECTIVE: The objective was to evaluate the magnetic resonance (MR) appearance of patellar osteochondritis dissecans (OCD). MATERIALS AND METHODS: We retrospectively analyzed MR images of 16 patients (18 cases, mean age 20 years) using OCD of the patella. In 5 cases surgery was carried out, and we compared the surgical findings with the MR imaging findings in these cases. RESULTS: In all 18 cases, OCD was located central-inferiorly on the patella, and the average size was 11 x 11 x 7 mm. Subchondral deformities were present in 16 out of 18 cases (88.9%), subchondral cyst formation in 4 cases (22.2%), reactive bone marrow signal in 8 cases (44.4%), overlying patellar cartilage abnormality in 14 cases (77.8%), loose body in 2 cases (11.1%), patella alta in 8 cases (44.4%), hypoplastic sulcus in 7 cases (38.9%), and synovitis in 4 cases (22.2%). In all 5 cases in which surgery was carried out, the cartilage abnormality classified on the MR images was confirmed, and a loose body was removed at arthroscopy in 2 of the 5 cases. CONCLUSION: Magnetic resonance imaging of patellar OCD typically shows subchondral deformity and variable abnormalities of the overlying patellar cartilage located central-inferiorly on the patella. PMID- 17694307 TI - A new PET tracer specific for vascular endothelial growth factor receptor 2. AB - PURPOSE: Noninvasive positron emission tomography (PET) imaging of vascular endothelial growth factor receptor 2 (VEGFR-2) expression could be a valuable tool for evaluation of patients with a variety of malignancies, and particularly for monitoring those undergoing antiangiogenic therapies that block VEGF/VEGFR-2 function. The aim of this study was to develop a VEGFR-2-specific PET tracer. METHODS: The D63AE64AE67A mutant of VEGF(121) (VEGF(DEE)) was generated by recombinant DNA technology. VEGF(121) and VEGF(DEE) were purified and conjugated with DOTA for (64)Cu labeling. The DOTA conjugates were tested in vitro for VEGFR 2 specificity and functional activity. In vivo tumor targeting efficacy and pharmacokinetics of (64)Cu-labeled VEGF(121) and VEGF(DEE) were compared using an orthotopic 4T1 murine breast tumor model. Blocking experiments, biodistribution studies, and immunofluorescence staining were carried out to confirm the noninvasive imaging results. RESULTS: Cell binding assay demonstrated that VEGF(DEE) had about 20-fold lower VEGFR-1 binding affinity and only slightly lower VEGFR-2 binding affinity as compared with VEGF(121). MicroPET imaging studies revealed that both (64)Cu-DOTA-VEGF(121) and (64)Cu-DOTA-VEGF(DEE) had rapid and prominent activity accumulation in VEGFR-2-expressing 4T1 tumors. The renal uptake of (64)Cu-DOTA-VEGF(DEE) was significantly lower than that of (64)Cu DOTA-VEGF(121) as rodent kidneys expressed high levels of VEGFR-1 based on immunofluorescence staining. Blocking experiments and biodistribution studies confirmed the VEGFR specificity of (64)Cu-DOTA-VEGF(DEE). CONCLUSION: We have developed a VEGFR-2-specific PET tracer, (64)Cu-DOTA-VEGF(DEE). It has comparable tumor targeting efficacy to (64)Cu-DOTA-VEGF(121) but much reduced renal toxicity. This tracer may be translated into the clinic for imaging tumor angiogenesis and monitoring antiangiogenic treatment efficacy. PMID- 17694308 TI - Renal accumulation of [111In]DOTATOC in rats: influence of inhibitors of the organic ion transport and diuretics. AB - AIM: Radiation exposure to the kidney limits therapy with radiometal labelled DOTATOC. This study evaluates the organic anion and cation transport (inhibitors: probenecid and cimetidine/dexamethasone) as well as diuresis (furosemide and mannitol) regarding renal uptake of [(111)In]DOTATOC. METHODS: One hundred eight male Fisher rats were injected with [(111)In]DOTATOC via the tail vein. Prior to activity injection a total of 84 rats underwent injection with probenecid vs. sodium chloride 0.9% (48 rats), cimetidine vs. dexamethasone vs. sodium chloride 0.9% (18 rats), and furosemide vs. mannitol vs. sodium chloride 0.9% (18 rats). Rats were sacrificed at predetermined time points up to 48 h after activity injection. Kidneys, adrenal glands, pancreas, spleen, blood, liver, and muscle were harvested and injected activity per gram tissue was determined. Autoradiographic images of the kidneys were acquired in a total of 24 rats. RESULTS: Probenecid led to a reduction in renal uptake by up to 30% while not significantly changing the activity accumulation in the other organs investigated. This reduction was attributable to the renal cortex (ratio cortex/medulla 1.72 vs. 1.99; p = 0.006). Cimetidine and dexamethasone had no effect in any of the organs. Furosemide led to a 44% increase in renal activity accumulation attributable to enhanced renal medullary uptake (ratio cortex/medulla 1.44 versus 1.69; p = 0.006). Mannitol had no effect on renal activity uptake. CONCLUSION: Inhibition of the organic anion transport by probenecid may help reduce renal uptake regarding therapy with radiometal labelled DOTATOC. The enhancing effect of furosemide may be unfavourable for therapy. The results must be confirmed by human studies. PMID- 17694309 TI - Does chemotherapy influence the quantification of SUV when contrast-enhanced CT is used in PET/CT in lymphoma? AB - PURPOSE: In patients with lymphoma, we investigated the impact of contrast enhanced CT on PET attenuation correction in lesions and normal tissues, particularly when PET/CT was performed after chemotherapy. METHODS: Fifty patients (51+/-18 years) with Hodgkin's disease (n=17) or non-Hodgkin lymphomas (n=33) were studied before and after chemotherapy. PET/CT scans were performed 60 min after injection of FDG. Iopamiron 300 (iopamidol, 1.5 cc/kg) was injected immediately afterwards, followed 50 s later by a second craniocaudal CT (CT+). PET images were successively reconstructed using the unenhanced CT (PET-) and the CT+ (PET+) for attenuation correction, using iterative reconstruction (4 iterations, 8 subsets, 5 mm post-filtering). HU(mean), SUV(max) and SUV(mean) were measured before and after chemotherapy in ten non-tumoural ROIs [aorta, femur, kidney, lung, iliopsoas muscle, occipital cortex, T12 vertebra, liver, spleen and inferior vena cava (IVC)] and in tumoural lymphadenopathies or malignant tissues (n=397 and 51 VOIs respectively before and after chemotherapy) using a 3D-thresholding method (identical threshold for PET- and PET+). ROIs were defined on the PET- and automatically applied on the unenhanced CT (CT-), the CT+ and the PET+. RESULTS: In the non-tumoural tissues, HU(mean) increased significantly in the CT+ compared with the CT- in the vessels and the highly vascularised organs, and slight increases were observed in the occipital cortex (+11%), the iliopsoas muscle (+6%) and the femur (+3%). SUV(max) increased significantly in the PET+ compared with the PET- in the aorta (+14%), the liver (+10%), the spleen (+10%) and the IVC (+12%). SUV(mean) increased significantly in the PET+ compared with the PET- in the aorta (+15%), the kidney (+13%), the liver (+11%), the spleen (10%) and the IVC (+12%). In the lesions, HU(mean) was not significantly different before and after chemotherapy, whatever the normal region considered. SUV(max) increased significantly after treatment in the T12 vertebra (+12%). SUV(mean) increased significantly after treatment in the T12 vertebra (+13%) and in the liver (+12%). HU(mean) increased significantly in the CT+ compared with the CT- in the lesions (+55%) before chemotherapy. SUV(max) and SUV(mean) increased significantly in the PET+ compared with the PET- in the lesions (+4%) only before chemotherapy. No significant difference was seen in measurements (HU(mean), SUV(max) and SUV(mean)) after chemotherapy. CONCLUSION: Our study demonstrates that use of enhanced CT for attenuation correction has a negligible effect on quantification at staging and after chemotherapy. A "single shot" enhanced PET/CT may thus be performed in the evaluation of patients with lymphoma at staging, during treatment and at follow-up. PMID- 17694311 TI - FR3D: finding local and composite recurrent structural motifs in RNA 3D structures. AB - New methods are described for finding recurrent three-dimensional (3D) motifs in RNA atomic-resolution structures. Recurrent RNA 3D motifs are sets of RNA nucleotides with similar spatial arrangements. They can be local or composite. Local motifs comprise nucleotides that occur in the same hairpin or internal loop. Composite motifs comprise nucleotides belonging to three or more different RNA strand segments or molecules. We use a base-centered approach to construct efficient, yet exhaustive search procedures using geometric, symbolic, or mixed representations of RNA structure that we implement in a suite of MATLAB programs, "Find RNA 3D" (FR3D). The first modules of FR3D preprocess structure files to classify base-pair and -stacking interactions. Each base is represented geometrically by the position of its glycosidic nitrogen in 3D space and by the rotation matrix that describes its orientation with respect to a common frame. Base-pairing and base-stacking interactions are calculated from the base geometries and are represented symbolically according to the Leontis/Westhof basepairing classification, extended to include base-stacking. These data are stored and used to organize motif searches. For geometric searches, the user supplies the 3D structure of a query motif which FR3D uses to find and score geometrically similar candidate motifs, without regard to the sequential position of their nucleotides in the RNA chain or the identity of their bases. To score and rank candidate motifs, FR3D calculates a geometric discrepancy by rigidly rotating candidates to align optimally with the query motif and then comparing the relative orientations of the corresponding bases in the query and candidate motifs. Given the growing size of the RNA structure database, it is impossible to explicitly compute the discrepancy for all conceivable candidate motifs, even for motifs with less than ten nucleotides. The screening algorithm that we describe finds all candidate motifs whose geometric discrepancy with respect to the query motif falls below a user-specified cutoff discrepancy. This technique can be applied to RMSD searches. Candidate motifs identified geometrically may be further screened symbolically to identify those that contain particular basepair types or base-stacking arrangements or that conform to sequence continuity or nucleotide identity constraints. Purely symbolic searches for motifs containing user-defined sequence, continuity and interaction constraints have also been implemented. We demonstrate that FR3D finds all occurrences, both local and composite and with nucleotide substitutions, of sarcin/ricin and kink-turn motifs in the 23S and 5S ribosomal RNA 3D structures of the H. marismortui 50S ribosomal subunit and assigns the lowest discrepancy scores to bona fide examples of these motifs. The search algorithms have been optimized for speed to allow users to search the non-redundant RNA 3D structure database on a personal computer in a matter of minutes. PMID- 17694310 TI - Phase-1 trial of gefitinib and temozolomide in patients with malignant glioma: a North American brain tumor consortium study. AB - PURPOSE: This is a phase-I study of gefitinib in combination with temozolomide in patients with gliomas. The goal of the study was to define the maximum tolerated dose (MTD) and to characterize the pharmacokinetics of gefitinib when combined with temozolomide. PATIENTS AND METHODS: Patients were stratified according to co administration of enzyme-inducing anti-epileptic drugs (EIAEDs). There were 26 evaluable patients enrolled (16 on EIAEDs, 10 not on EIAEDs). All but seven patients had Glioblastoma Multiforme (GBM), and only six cases had a Karnosfsky Performance Status (KPS) of less than 80; median age was 51 years. All had received prior radiotherapy and 14 patients had no prior chemotherapy. The starting dose of temozolomide was 150 mg/m(2)/day for 5 days every 28 days and could be escalated to a maximum dose of 200 mg/m(2)/day in subsequent cycles. The starting dose of gefitinib was 500 mg/day given by mouth on a continuous basis. Dose-limiting toxicity was assessed in cycle one only. RESULTS: For patients on EIAEDs, the MTD of gefitinib was 1,000 mg/day in combination with temozolomide. Dose-limiting toxicity (DLT) was due to diarrhea, nausea and vomiting. For patients not on EIAEDs, the MTD was 250 mg/day in combination with temozolomide. The DLT was due to increases in liver transaminases. Rash was not a significant toxicity at these dose levels. The peak concentration and AUC(0-24hr) at the 500 mg dose level was 1.8 and 2.5-fold lower, respectively, in the EIAED group compared to the non-EIAED group; trough levels of gefitinib increased in both groups consistent with the reported terminal half-life ranging from 27 to 51 h. CONCLUSION: The recommended phase-2 dose of gefitinib when used in combination with temozolomide is 1,000 and 250 mg/day, respectively, for patients on or not on EIAEDs. PMID- 17694312 TI - Computerized transrectal ultrasound (C-TRUS) of the prostate: detection of cancer in patients with multiple negative systematic random biopsies. AB - This study was designed to compare the diagnostic yield of computerized transrectal ultrasound (C-TRUS) guided biopsies in the detection of prostate cancer in a group of men with a history of multiple systematic random biopsies with no prior evidence of prostate cancer. The question was asked: Can we detect cancer by C-TRUS that has been overlooked by multiple systematic biopsies? The entrance criteria for this study were prior negative systematic random biopsies regardless of number of biopsy sessions or number of individual biopsy cores. Serial static TRUS images were evaluated by C-TRUS, which assessed signal information independent of visual gray scale. Five C-TRUS algorithms were utilized to evaluate the information of the ultrasound signal. Interpretation of the results were documented and the most suspicious regions marked by C-TRUS were biopsied by guiding the needle to the marked location. Five hundred and forty men were biopsied because of an elevated PSA or abnormal digital rectal exam. 132 had a history of prior negative systematic random biopsies (1-7 sessions, median: 2 and between 6 and 72 individual prostate biopsies, median: 12 cores). Additionally, a diagnostic TUR-P of the prostate with benign result was performed in four patients. The PSA ranged from 3.1-36 ng/ml with a median of 9.01 ng/ml. The prostate volume ranged from 6-203 ml with a median of 42 ml. Of the 132 patients with prior negative systematic random biopsies, cancer was found in 66 (50%) by C-TRUS targeted biopsies. In this group the median number of negative biopsy sessions was two and a median of 12 biopsy cores were performed. From literature we would expect a cancer detection rate in this group with systematic biopsies of approximately 7%. We only found five carcinomas with a Gleason Score (GS) of 5, 25 with GS 6, 22 with GS 7, 8 with GS 8 and even 7 with GS 9. The results of this prospective clinical trail indicates that the additional use of the C-TRUS identifies clinical significant cancerous lesions that could not been visualized or detected by systematic random biopsies in a very high percentage. In addition, the results of the study support the efforts to search for strategies that utilize expertise and refinement of imaging modalities rather than elevating the number of random biopsies (f.e. 141 cores in one session) in the detection of prostate cancer. PMID- 17694313 TI - Bilateral staged total knee arthroplasty in obese patients. AB - INTRODUCTION: The purpose of this study was to compare the clinical and functional results and complications associated with staged bilateral total knee arthroplasty (TKA) performed 4-11 days apart during a single hospitalization in patients who were obese and patients who were not obese. METHODS: We retrospectively evaluated 48 (96 knees) patients who were obese and divided into two groups based on their body mass indices (BMI). Morbidly obese patients (group A1, BMI > or = 40 kg/m2) consisted of 21 patients (42 knees), and obese patients (group A2, BMI > or = 30 kg/m2) consisted of 27 patients (54 knees). The control group (group B, BMI < 30 kg/m2) consisted of 20 non-obese patients (40 knees), who were undergoing staged bilateral procedure within the same time frame. All patients had cemented TKAs with use of posterior cruciate sparing prosthesis without patellar resurfacing. If medically stable after the first arthroplasty the patients then underwent the second arthroplasty 4-11 days later. The data on major complications and minor complications were evaluated. RESULTS: Although, there was no statistically significant difference in overall complication rates in any of the groups, the non-obese group had fewer wound complications than the other groups (P > 0.05). No significant differences in preoperative or postoperative Knee Society score, and functional score could be demonstrated between the three groups (P > 0.05). Both obese and nonobese patients showed improvements in pain and function from pre-surgery to a minimum 2 years follow up. CONCLUSION: Results of bilateral staged TKAs in obese patients have low complication and high success rates and increased BMI has no negative effect on the early outcome. Bilateral staged TKA might be a good treatment alternative for the improvement of the patient's quality of life and functional and clinical outcomes. PMID- 17694314 TI - Caesarean or vaginal delivery for preterm very-low-birth weight (< or =1,250 g) infant: experience from a district general hospital in UK. AB - OBJECTIVE: To determine whether delivery by caesarean is associated with a better neuro-developmental outcome at two years for preterm infants born weighing 1,250 g or less. SETTING: District General Hospital, United Kingdom. DESIGN: All inborn infants weighing <1,250 g born at St Helier University Hospital between January 1995 and December 2003 were identified from contemporaneously collected computer database. All hospital records were retrieved. Details of the mother, delivery route, Apgar score, details of resuscitation and details of the baby, neonatal progress and neuro-developmental status at two years was transcribed on a pre designed proforma. Neuro-developmental status assessment at two years of age was carried out by an independent neurodevelopmental paediatrician. Neuro developmental status was classified as normal, severe, moderate or mild disability. STATISTICAL ANALYSIS: Analysis was done by creating a simple two by two table. Statistical significance was set at p = 0.05. Multivariate and univariate analysis was carried out for a number of confounding variables. SAMPLE: Total of 411 babies were identified from the data-base. Of these 59 were still born and fourteen though born alive died in the delivery suit. 125 (37%) were excluded from analysis as they were returned to their referring hospitals prior to discharge from hospital. Information about their two-year follow-up was either incomplete or not robust enough to be included in the analysis. Analysis was carried out on 213(63%) for whom we had complete data set at two years of age (103 infants born via vaginal delivery and 110 infants were born by caesarean section). OUTCOME MEASURE: Primary outcome measure was to compare survival at discharge and neurodevelopmental status at two years of age of this cohort. Secondary outcome included determining the incidence of grade III or IV intraventricular haemorrhage (IVH), chronic lung disease and necrotising enterocolitis (NEC). RESULTS: The overall caesarean delivery rate for this cohort was 51.6% while the overall caesarean rate for all births at our hospital during the study period varied between 20 and 23%. Neonatal mortality for those delivered by caesarean was 12.7% compared to 14.5% for those delivered vaginally (p = ns). Overall incidence of any neuro-disability at two years of age was 46.8% for those delivered by caesarean compared to 47.7% for those delivered vaginally (p = ns). There was no difference in those with severe (23.5% vs. 25.0%), moderate (10.4% vs. 9%) or mild (12.5% vs. 13.6%) neuro-disability between the groups nor was there any difference in the number of babies with IVH, chronic lung disease and NEC. Neuro-disability was equally greater in both groups for babies born weighing 750 grams or less and/or born at 26 weeks or less gestation. CONCLUSION: Despite the increasing tendency to deliver extremely preterm babies by caesarean, we did not find that it was associated with either reduced mortality or neuro-disability at two years of age. Therefore the method of delivery of very-low-birth weight premature infants should be based on obstetric or maternal indications rather than the perceived outcome of the baby. PMID- 17694315 TI - Measuring contrast sensitivity in normal subjects with OPTEC 6500: influence of age and glare. AB - BACKGROUND: The purpose of this study was to develop age-related curves for contrast sensitivity (CS) in normal subjects under day and night conditions with and without glare. METHODS: Sixty-one healthy eyes from 61 subjects were measured with the OPTEC(R) 6500 P under day and night conditions (luminance levels: 85 cd/m(2) and 3.0 cd/m(2) with and without glare; spatial frequencies: 1.5, 3, 6, 12 and 18 cycles/degree). A reliability analysis with five repeated measurements of six persons on 4 days was performed to examine the repeatability. The influence of age on contrast sensitivity, forward and backward scatter was examined by means of linear regression. RESULTS: Contrast sensitivity was significantly reduced under night conditions with glare, whereas glare had less influence under daylight illumination. Mean reliability coefficients are 0.87 (day), 0.77 (day with glare), 0.69 (night) and 0.81 (night with glare), which suggests sufficient retest reliability of the device. Regression analyses showed a highly significant influence of age, but the variance of the measurement values is not explained by age alone. The coefficients of determination for the regression of area under the log contrast sensitivity function (AULCSF) on age are 0.33 (photopic), 0.34 (photopic with glare), 0.29 (mesopic) and 0.36 (mesopic with glare, p < 0.0001 in all cases). CONCLUSION: A significant relationship between age, CS and scatter was confirmed in our study. The results provide baseline values for the examination of patients with different diseases in which contrast sensitivity is impaired (such as glaucoma, cataracts and amblyopia) and might be useful in studies of roadworthiness or in investigation of the impact of intraocular lenses. PMID- 17694316 TI - Low temperature (15 degrees C) induces COPII dissociation from membranes and slow exit from the endoplasmic reticulum in HeLa cells. AB - Low temperature induces a transport blockade at the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) in cultured cells. Our previous studies support that the primary effect of low temperature is the detachment of COPI complexes from membranes. In the present study, we have used immunofluorescence and cryoimmunoelectron microscopy to investigate the effects of low temperature on both COPII and clathrin coat complexes in HeLa cells. Strikingly, COPII proteins moved from membranes to the cytosol at 15 degrees C, accumulating into electron dense areas. In agreement with this observation, we also showed that ER exit is delayed in cells cultured at this temperature. In contrast, clathrin coat is not affected. Together, our results demonstrate that low temperature induces COPII dissociation from membranes and slow exit from the endoplasmic reticulum. PMID- 17694317 TI - Production of silicon alloys is associated with respiratory symptoms among employees in Norwegian smelters. AB - OBJECTIVES: To develop a qualitative exposure classification of employees in Norwegian smelters and to investigate the relationship between respiratory symptoms and occupational exposure using this classification. METHODS: The 3,924 participants completed a standardised questionnaire including questions of respiratory symptoms, familial asthma, allergy, doctor-diagnosed asthma, smoking habits, previous exposure and occupation. The employees were classified according to their current job function: (1) line operators were employed full time on the production line, (2) non-exposed employees did not work in production, (3) the remaining employees were classified as non-line operators. The association between the prevalence of respiratory symptoms and job category was examined using multivariate logistic regression. RESULTS: The mean age of the participants was 38.6 years (standard deviation 9.2 years), 88.5% were males. The odds ratios (OR) (95% confidence intervals in parenthesis) for dyspnoea, cough and phlegm regarding previous exposure compared with no previous exposure were 1.4 (1.1 1.7), 1.4 (1.2-1.8) and 1.3 (1.0-1.7), respectively. The OR in line operators compared with non-exposed employees was 1.2 (0.9-1.7) for dyspnoea, 1.3 (1.0-1.8) for cough and 1.9 (1.4-2.7) for phlegm. The OR for respiratory symptoms was higher in relation to previous exposure than current job function except for phlegm. CONCLUSION: In Norwegian smelters respiratory symptoms appear to be positively related to both current job function and previous exposure. Previous exposure appears to be more important than current job function. PMID- 17694318 TI - Overall and peripheral ratings of perceived exertion during a graded exercise test to volitional exhaustion in individuals of high and low fitness. AB - This study assessed the relationship between differentiated ratings of perceived exertion (RPE) and heart rate with oxygen uptake (VO2) during two graded exercise tests (GXT) to exhaustion on a cycle ergometer in 49 men and women (19-50 years) of high and low fitness. The study also assessed whether sub-maximal RPE values elicited during the GXTs could provide appropriate estimates of maximal aerobic power (VO2max) Peripheral RPE (RPEP) was higher than overall RPE (RPEO) at exhaustion in both groups (P<0.001), but the reliability of the terminal RPEO was higher (0.75 and 0.40, respectively). Fitness did not moderate the relationship of RPEO and RPEP with VO2 during the GXTs (P>0.05). However, the correlation for RPEP and VO2 was higher for women compared to men (0.98 and 0.96, respectively, P<0.05), although this is of little practical significance. In both groups, RPEO was almost as highly correlated with VO2 as heart rate during GXTs terminated at exhaustion (approximately 0.955-0.980). There were no differences between predicted and measured VO2max when VO2 values were extrapolated from sub-maximal RPEO (13, 15 and 17) intensities (42.1+/-12.5, 43.4+/-11.5, 44.2+/-11.3 and 43.3+/-10.0 ml kg(-1) min(-1), respectively). However, VO2max predicted from sub maximal RPEP intensities was significantly lower (P<0.05). In conclusion, terminal RPEO was a more reliable measure of the RPE, and provided more accurate estimates of VO2max in healthy participants of high and low fitness when elicited from sub-maximal exercise intensities. PMID- 17694319 TI - Specific role of LeMAN2 in the control of seed germination exposed by overexpression of the LeMAN3 gene in tomato plants. AB - Endo-beta-mannanase is one of the key enzymes involved in the hydrolysis of the mannan-rich cell walls of tomato (Solanum lycopersicon) seeds. Two isoforms of endo-beta-mannanase have been characterized in tomato seeds: LeMAN2 is active in the micropylar area prior to germination and LeMAN1 is active after germination in all endosperm cells surrounding the cotyledons. To explore whether general mannanase activity in the endosperm cap is sufficient to promote germination, the gene encoding LeMAN3 was inserted into transgenic tomato plants under the control of a CaMV-35S promoter. Expression of LeMAN3 was evident in the endosperm cap and in the lateral endosperm of the transgenic seeds 10 min after imbibition. An activity test indicated increased activity of endo-beta-mannanase in the transgenic lines relative to the control line in all seed parts, during the first 20 h of imbibition. However, overexpression of LeMAN3 in transgenic seeds inhibited seed germination at both optimal and suboptimal temperatures. Detailed RT-PCR analyses revealed the transcription patterns of the genes encoding the various mannanase isoforms, and indicated a delay in LeMAN2 transcription in the endosperm cap of the transgenic seeds. Interestingly, tissue-print assays indicated similar mannanase activity in the micropylar areas for both transgenic and control seeds. These results indicate that overexpression of active endo-beta mannanase in the endosperm cap is not sufficient to enable hydrolysis of the cell walls or to promote germination of tomato seeds. Cell-wall hydrolysis in these endosperm cells is under tight control and requires the specific activity of LeMAN2. PMID- 17694320 TI - Water deficits accelerate ripening and induce changes in gene expression regulating flavonoid biosynthesis in grape berries. AB - Water deficits consistently promote higher concentrations of anthocyanins in red winegrapes and their wines. However, controversy remains as to whether there is any direct effect on berry metabolism other than inhibition of growth. Early (ED) and late (LD) season water deficits, applied before or after the onset of ripening (veraison), were imposed on field grown Vitis vinifera "Cabernet Sauvignon", and the responses of gene expression in the flavonoid pathway and their corresponding metabolites were determined. ED accelerated sugar accumulation and the onset of anthocyanin synthesis. Both ED and LD increased anthocyanin accumulation after veraison. Expression profiling revealed that the increased anthocyanin accumulation resulted from earlier and greater expression of the genes controlling flux through the anthocyanin biosynthetic pathway, including F3H, DFR, UFGT and GST. Increases in total anthocyanins resulted predominantly from an increase of 3'4'5'-hydroxylated forms through the differential regulation of F3'H and F3'5'H. There were limited effects on proanthocyanidin, other flavonols, and on expression of genes committed to their synthesis. These results demonstrate that manipulation of abiotic stress through applied water deficits not only modulates compositional changes during berry ripening, but also alters the timing of particular aspects of the ripening process. PMID- 17694321 TI - Myxoinflammatory fibroblastic sarcoma: investigations by comparative genomic hybridization of two cases and review of the literature. AB - Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare low-grade sarcoma of the distal extremities characterized by a myxohyaline stroma, a dense inflammatory infiltrate and virocyte- and lipoblast-like giant cells. Up to now, only two cases have been investigated cytogenetically, showing complex and heterogeneous karyotypes, in part with supernumerary ring chromosomes. We characterized two further cases of MIFS immunohistochemically and performed comparative genomic hybridization as well as DNA image cytometry analyses. Both tumors showed the characteristic histomorphological pattern of MIFS and were positive for Vimentin and CD68. Moreover, both cases presented aberrant karyotypes including distinct DNA copy number changes involving chromosome 7 and disclosed DNA aneuploidy. PMID- 17694323 TI - Reference levels for 17-hydroxyprogesterone, 11-desoxycortisol, cortisol, testosterone, dehydroepiandrosterone sulfate and androstenedione in infants from birth to six months of age. AB - Reference plasma adrenal steroid levels during early infancy are frequently used to verify hormone measurements when any adrenal abnormality is suspected. We aim to obtain longitudinal reference plasma levels for 17-hydroxyprogesterone (17OHP), 11-desoxycortisol (11DOC), cortisol, dehydroepiandrosterone sulfate (DHEAS), testosterone, and androstenedione in healthy infants from birth to 6 months of age. In 138 term infants, 80 males and 58 females, plasma steroid levels were measured using specific RIA procedures at birth and on the 3rd, 15th, 30th, 60th, 90th, 120th, 150th, and 180th days of life. Smoothed percentiles for each variable were calculated according to the LMS method (LMS program version 1.16, Institute of Child Health, London). Except for cortisol, plasma levels of adrenal steroids decreased progressively from birth to 6 months of age. Plasma concentrations of 17OHP, 11DOC, and cortisol did not show gender differences, but testosterone and androstenedione were significantly higher in boys, and DHEAS levels were higher in girls. Longitudinal reference plasma levels for 17OHP, 11DOC, cortisol, DHEAS, testosterone, and androstenedione have been described in an adequate sample of healthy infants from birth to 6 months of age. These standards, displayed as smoothed percentiles, may be used as reference values in the management of congenital endocrine (adrenal or gonadal) abnormalities that appear in the first weeks of life. PMID- 17694322 TI - Changes in the profile of simple mucin-type O-glycans and polypeptide GalNAc transferases in human testis and testicular neoplasms are associated with germ cell maturation and tumour differentiation. AB - Testicular germ cell tumours (TGCT) exhibit remarkable ability to differentiate into virtually all somatic tissue types. In this study, we investigated changes in mucin-type O-glycosylation, which have been associated with somatic cell differentiation and cancer. Expression profile of simple mucin-type O-glycans (Tn, sialyl-Tn, T), histo-blood group H and A variants and six polypeptide GalNAc transferases (T1-4, T6, T11) that control the site and density of O-glycosylation were analysed by immunohistochemistry during human testis development and in TGCT. Normal testis showed a restricted pattern; gonocytes expressed abundant sialyl-Tn and sialyl-T, and adult spermatogonia were devoid of any glycans, whereas spermatocytes and spermatids expressed exclusively glycans Tn and T and the GalNAc-T3 isoform. A subset of mature ejaculated spermatozoa expressed an additional glycan sialyl-T. The pattern found in testicular neoplasms recapitulated the developmental order: Pre-invasive carcinoma in situ (CIS) cells and seminoma expressed fetal type sialylated glycans in keeping with their gonocyte-like phenotype. Neither simple mucin-type O-glycans nor GalNAc transferase isoforms were found in undifferentiated nonseminoma, i.e. embryonal carcinoma, whereas teratomas expressed them all to some extent but in a disorganized manner. We concluded that simple mucin-type O-glycans and their transferases are developmentally regulated in the human testis, with profound changes associated with neoplasia. The restricted O-glycosylation pattern in haploid germ cells suggests a role in their maturation or egg recognition/fertilization warranting further studies in male infertility, whereas the findings in TGCT provide new diagnostic tools and support our hypothesis that testicular cancer is a developmental disease of germ cell differentiation. PMID- 17694324 TI - The importance of angiogenesis markers in the outcome of patients with diffuse large B cell lymphoma: a retrospective study of 97 patients. AB - PURPOSE: The role of angiogenesis has been extensively evaluated in solid tumors and more recently in hematologic malignancies. Several surrogate markers of angiogenesis including tumor VEGF, VEGF receptors, and microvessel density have correlated with outcome in some lymphoma studies. This is a single institution retrospective study evaluating the role of angiogenesis markers in the clinical outcome of patients with diffuse large B cell lymphoma (DLBCL). PATIENTS AND METHODS: A total of 97 patients with DLBCL diagnosed and managed at Indiana University between 1993 and 2001 were included. Archived tumor samples were stained for VEGF-A, VEGF-C, VEGF-R1, and CD31 and graded as negative or positive (1+, 2+, 3+). The relationship between the expression of these markers and the international prognostic variables as well as the progression free survival (PFS) and the overall survival (OS) was evaluated. RESULTS: VEGF-A, VEGF-C, VEGF-R1 were expressed in 77, 98, and 18% of tumors, respectively. VEGF-A negative patients had an improved OS compared to VEGF-A (1+) (P = 0.0502). VEGF-C correlated with both LDH (r = 0.28, P = 0.0502) and IPI score (r = 0.25, P = 0.013). VEGF-R1 negative patients had a superior survival compared to those with VEGF-R1 (2+) (P = 0.0154). CONCLUSIONS: The presence of tumor associated angiogenesis may alter the outcome of patients with DLBCL and could be a prognostic factor. Further clinical studies are needed to correlate the degree of angiogenesis with response to anti-angiogenesis agents. PMID- 17694325 TI - Expression of the polycomb group protein EZH2 and its relation to outcome in patients with urothelial carcinoma of the bladder. AB - PURPOSE: The polycomb group protein Enhancer of Zeste Homolg 2 (EZH2), a repressor of gene transcription, has been linked to the progression of various malignancies. This study was done to examine a potential correlation of EZH2 mRNA expression with clinicopathological parameters and outcome in patients with urothelial carcinoma (UC) of the bladder. METHODS: We determined the relative EZH2 gene expression by quantitative RT-PCR in tumor specimens from a cohort of 100 patients with UC (mean follow-up 44.2 months). EZH2 expression levels were correlated to pathological tumor features and outcome. RESULTS: Enhancer of Zeste Homolg 2 was expressed in 90% of the tumor samples. Expression levels increased in parallel with tumor stage (P = 0.002). High grade UC displayed significantly elevated EZH2 levels compared to low grade disease (P < 0.0001). High EZH2 expression was related to an abbreviated time to recurrence in muscle invasive carcinomas (pT >/= 2) (P = 0.028). No such correlation was detected in the group of superficial tumors (pT A mutation was detected in one allele in the proband. The ratio of +KTS/-KTS was 0.67 in the proband's cDNA. The expression of podocyte molecules (WT1, nephrin, podocin, alpha-actinin 4 and CD2AP) were also investigated in a renal specimen of this FS patient. WT1 expression showed diffuse nuclear staining, with less obvious speckles in the patient's glomeruli than in those of controls. The distribution and intensity of podocyte molecules were altered both in normal- and abnormal-appearing glomeruli. In conclusion, the study presented a case of FS by clinical manifestation, renal pathology, karyotype analysis and genetic testing. A lower ratio of +KTS/-KTS and an abnormal distribution of WT1, as well as abnormal expressions of other podocyte molecules, were also revealed. The mechanisms of WT1 mutation causing FS still need to be investigated. PMID- 17694337 TI - Posterior reversible encephalopathy syndrome in the pediatric renal population. AB - Posterior reversible leukoencephalopathy syndrome (PRES) clinically presents with seizures, severe headaches, and mental and visual changes. Our goal was to describe the clinical features, triggering factors, neuro-imaging findings, and electroencephalogram (EEG) findings in a pediatric cohort with renal disease. We retrospectively analyzed the records of 18 children with the diagnosis of PRES between January 2001 and June 2006 at the University of Miami/Holtz Children's Hospital, USA. There were 22 PRES episodes. The most common clinical presentation was generalized tonic-clonic seizures in 59% (13/22). The most common identified trigger of PRES was hypertensive crisis in 59% (13/22). Almost half of the children had no evidence of on-going uncontrolled hypertension; 44% (8/18) had normal funduscopic examination findings, and 50% (9/18) had no or mild left ventricular hypertrophy. Two of the 18 patients had recurrent PRES episodes, three episodes each. Diffuse slowing was the most common finding on the EEGs. Atypical magnetic resonance imaging (MRI) findings were more prevalent in the imaged cases (62% vs 25%, P < 0.05). All the computerized tomography (CT) scans were normal, despite the positive MRI findings in four cases when both types of imaging was used. All the episodes had total clinical resolution. In conclusion, despite the diverse initial trigger, acute hypertension seems to be the common pathogenic pathway for pediatric PRES. MRI seems superior to CT, with better sensitivity due to its high resolution and diffusion-weighted imaging. The lesions do not necessarily have to be in the posterior white matter and may not be totally reversible. PMID- 17694338 TI - Cystinuria in children and young adults: success of monitoring free-cystine urine levels. AB - Medical treatment of cystinuria is often disappointing. Patients undergo frequent surgery, which is often followed by early relapse. The aim of our study was to evaluate the efficacy of medical treatment of cystinuria, to prevent formation or to reduce the numbers and dimensions of renal stones. Twenty cystinuric patients were treated with a combined approach, including cystine-binding drugs. Free and bound urine cystine levels were measured every 4 months. Drug dosage was adjusted to maintain free urine cystine level below 100 micromol/mmol creatinine. Eighteen patients completed the study; detection of new stones was reduced from 0.28 per year to 0.03 per year, and, in six patients, the numbers and dimensions of pre existing renal stones were reduced. Surgery was required in one subject, and no relapse was observed 12 months afterwards. The dosage required to achieve target levels was closely correlated with patient body weight: older children required a lower dose. Medical management of cystinuria is feasible. The treatment must be personalised in children, as the amount of drug required is strictly dependent on body size. PMID- 17694339 TI - Prognostic factors in adult community-acquired bacterial meningitis: a 4-year retrospective study. AB - The aim of this 4-year, observational, single-center study was to identify prognostic factors and evaluate the need for intensive care in cases of bacterial meningitis. During the study period, 60 cases of adult bacterial meningitis were identified. Fifty-one patients were transferred to the intensive care unit at various times during their hospital stay. In the multivariate analysis, factors significantly associated with the need for mechanical ventilation and/or vasopressive drugs included comorbidity and a Glasgow coma score of less than 12 at hour 6 following presentation. The results indicate patients with a decreased level of consciousness, neurological deficit or comorbidity should be admitted to the intensive care unit at an early stage of illness. When patients lack these criteria 6 h following presentation, admission to the medical ward is reasonable. PMID- 17694340 TI - The cranberry and the urinary tract. AB - Cranberry products have been heralded as natural treatments for urinary tract infections (UTIs) and have been widely used for this purpose. Current evidence favours an antibacterial role for the cranberry's natural polyphenols or tannins. Although limited species- and strain-specific direct inhibition has been determined in vitro, it has been suggested that a key mechanism of inhibition, especially for the abundant uropathogenic E. coli, relies on anti-adhesion properties. Many studies of prevention have been complicated due to the enrollment of patients who have had complicated urinary tracts, and outcomes have not been consistently favourable. In contrast, significant prevention has been shown for acute cystitis among high-risk young females. While reasonably well tolerated and deplete from side effects, further scientific work is required to better place the role of cranberry products in the management of UTIs. Progress in this area has set the stage for further hypothesis testing studies. PMID- 17694341 TI - Temporal evolution of mechanical properties of skeletal tissue regeneration in rabbits: an experimental study. AB - Various mathematical models represent the effects of local mechanical environment on the regulation of skeletal regeneration. Their relevance relies on an accurate description of the evolving mechanical properties of the regenerating tissue. The object of this study was to develop an experimental model which made it possible to characterize the temporal evolution of the structural and mechanical properties during unloaded enchondral osteogenesis in the New Zealand rabbit, a standard animal model for studies of osteogenesis and chondrogenesis. A 25 mm segment of tibial diaphysis was removed sub-periosteally from rabbits. The defect was repaired by the preserved periosteum. An external fixator was applied to prevent mechanical loading during osteogenesis. The regenerated skeletal tissues were studied by CT scan, histology and mechanical tests. The traction tests between 7 and 21 days post-surgery were done on formaldehyde-fixated tissue allowing to obtain force/displacement curves. The viscoelastic properties of the regenerating skeletal tissues were visualized throughout the repair process. PMID- 17694342 TI - Rapid preparation of fluorescent 9-anthrylmethyl esters for fatty acid analysis of small amount of triacylglycerols. AB - This paper proposes a one-step method for preparation of fluorescent 9 anthrylmethyl esters from triacylglycerols (TAG) ranging in amount from 0.1 to 5 microg. It involves base-catalyzed transesterification using potassium 9 anthracenemethoxide, prepared by proton exchange between 9-anthracenemethanol and potassium tert-butoxide. Transesterification for 10 min at room temperature gave the fatty acid 9-anthrylmethyl esters in nearly maximal yields (82-85%). The products could be analyzed by reversed-phase HPLC without purification. Excellent linear relationships were observed for standard curves of 10-250 pmol of TAG standards (16:0, 19:0, 18:2 and 22:6), and differences in the slopes were less than 5% among the standards. Almost consistent compositions of the esters were observed for the products formed from 0.5 to 5 microg or less of fish oils TAG, and they were similar to those obtained by HPLC of ordinary multi-step synthesis products and by GLC of methyl esters. The present method is a great improvement of derivatization time, and is powerful for fatty acid analysis of small amounts of natural TAG. PMID- 17694344 TI - Consumption of c9,t11-18:2 or t10,c12-18:2 enriched dietary supplements does not influence milk macronutrients in healthy, lactating women. AB - Substantial research suggests that the t10,c12-18:2, but not the c9,t11-18:2, isomer of conjugated linoleic acid (CLA) reduces milk fat synthesis in lactating bovine and rodent species. Because fat is the major energy-yielding component in human milk, we were interested in whether this is true for women as well. Thus, the effects of c9,t11-18:2 and t10,c12-18:2 on milk fat were examined in breast feeding women (n = 12) in a double-blind, placebo-controlled, crossover study with latin-square design. The study was divided into six periods: baseline (3 days), three intervention periods (5 days each), and two washout periods (9 days each). During each intervention period, women consumed 750 mg/day of a supplement containing predominantly c9,t11-18:2, t10,c12-18:2, or 18:1 (olive oil placebo). Milk was collected by complete breast expression on the final day of each period. Infant milk consumption was estimated by 24 h weighing on the penultimate day of each intervention and washout period, and maternal adiposity (% body fat) was determined at baseline using dual energy X-ray absorptiometry. Milk c9,t11-18:2 and t10,c12-18:2 concentrations were greater (P < 0.05) during the corresponding CLA treatment periods as compared to the placebo period, providing strong evidence of subject compliance. Both CLA isomers were transferred into milk fat at relatively high efficiency; average transfer efficiency was estimated to be 23.3%. Compared to the placebo treatment, milk fat content was not reduced during either CLA treatment. Data indicate that body fatness did not modify any putative effect of isomeric CLA consumption on milk fat concentration. The evidence from this study suggests that the sensitivity of lactating women's mammary tissue to an anti-lipogenic effect of the t10,c12-18:2 isoform of CLA may be less than previously hypothesized. PMID- 17694343 TI - The diversity of health effects of individual trans fatty acid isomers. AB - There are multiple adverse effects of trans fatty acids (TFA) that are produced by partial hydrogenation (i.e., manufactured TFA), on CVD, blood lipids, inflammation, oxidative stress, endothelial health, body weight, insulin sensitivity, and cancer. It is not yet clear how specific TFA isomers vary in their biological activity and mechanisms of action. There is evidence of health benefits on some of the endpoints that have been studied for some animal TFA isomers, such as conjugated linoleic acid; however, these are not a major TFA source in the diet. Future research will bring clarity to our understanding of the biological effects of the individual TFA isomers. At this point, it is not possible to plan diets that emphasize individual TFA from animal sources at levels that would be expected to have significant health effects. Due to the multiple adverse effects of manufactured TFA, numerous agencies and governing bodies recommend limiting TFA in the diet and reducing TFA in the food supply. These initiatives and regulations, along with potential TFA alternatives, are presented herein. PMID- 17694347 TI - Effect of predators of juvenile rodents on the spread of the hantavirus epidemic. AB - Effects of predators of juvenile mice on the spread of the Hantavirus are analyzed in the context of a recently proposed model. Two critical values of the predation probability are identified. When the smaller of them is exceeded, the hantavirus infection vanishes without extinguishing the mice population. When the larger is exceeded, the entire mice population vanishes. These results suggest the possibility of control of the spread of the epidemic by introducing predators in areas of mice colonies in a suitable way so that such control does not kill all the mice but lowers the epidemic spread. PMID- 17694346 TI - Dissection of a genetically complex cluster of growth and obesity QTLs on mouse chromosome 2 using subcongenic intercrosses. AB - In a previous study we characterized the B6.CAST-(D2Mit329-D2Mit457)N(6) (B62D) congenic strain, which possesses CAST/EiJ (CAST) chromosome 2 donor alleles from 74 to 180 Mbp on a C57BL6/J (B6) background. This strain exhibited significant decreases in body weight and adiposity attributable to the weight gain 2 (Wg2) quantitative trait locus (QTL). To refine the location of Wg2, we used a two stage genetic dissection strategy consisting of a B62D x B6 backcross, which mapped Wg2 to the proximal portion of the B62D donor region, followed by the development of seven overlapping subcongenic F(2) intercrosses targeting the Wg2 genomic interval. Surprisingly, five of the seven intercrosses displayed significant differences, dependent on genotype, in body weight and/or fat pad mass. These effects were the result of at least four independent QTLs that were named Wg2a, b, c, and d. In contrast to the lean and low body weight phenotype of the B62D parental strain, mice homozygous for CAST congenic alleles (cast/cast) at Wg2a were significantly heavier at 6 and 9 weeks of age, while cast/cast mice at Wg2c had higher levels of total fat. Consistent with the prior observed effects of Wg2, cast/cast mice at Wg2b displayed significant decreases in 6- and 9-week body weight as well as a decrease in total fat pad mass. All of the QTLs had additive effects on body composition except Wg2d, which displayed underdominance for total fat mass. Significant differences in weight and adiposity were also observed in genetically identical b6/b6 homozygous mice across the panel of subcongenics, suggesting either maternal or paternal contributions to body composition. These data represent a significant advancement toward the identification of mouse chromosome 2 growth and obesity quantitative trait genes. PMID- 17694348 TI - Outcome of beta-interferon treatment in relapsing-remitting multiple sclerosis: a Bayesian analysis. AB - Observational studies of the effect of beta-interferon (IFNbeta) on accumulation of fixed disability in relapsing remitting multiple sclerosis (RRMS) in clinical practice have been difficult to interpret due to bias. The aim of this study of 175 RRMS patients was to use Bayesian analysis to establish whether IFNbeta attenuates disability relative to a cohort of matched historical control subjects from the Sylvia Lawry Centre for MS Research. A sensitivity analysis was based on a range of prior probability distributions for IFNbeta efficacy derived from a published meta-analysis of randomised controlled trials (RCTs) of IFNbeta, and the data were interpreted both unmodified and using variance inflation and point estimate bias correction; the corrected data interpreted in the light of the most likely prior probability distribution yielded a 95 % posterior credible interval for the odds ratio of accumulation of fixed disability after two years of IFNbeta therapy of 0.52, 0.94. It is concluded that two years of IFNbeta therapy for RRMS reduces accumulation of fixed disability in clinical practice. PMID- 17694349 TI - Wilson's disease in two consecutive generations in a Bulgarian Roma family. PMID- 17694350 TI - Cerebellar ataxia and congenital disorder of glycosylation Ia (CDG-Ia) with normal routine CDG screening. AB - Cerebellar ataxia can have many genetic causes among which are the congenital disorders of glycosylation type I (CDG-I). In this group of disorders, a multisystem phenotype is generally observed including the involvement of many organs, the endocrine, hematologic and central nervous systems. A few cases of CDG-Ia have been reported with a milder presentation, namely cerebellar hypoplasia as an isolated abnormality. To identify patients with a glycosylation disorder, isofocusing of plasma transferrin is routinely performed. Here, we describe two CDG-Ia patients,who presented with mainly ataxia and cerebellar hypoplasia and with a normal or only slightly abnormal transferrin isofocusing result. Surprisingly, the activity of the corresponding enzyme phosphomannomutase was clearly deficient in both leucocytes and fibroblasts. Therefore, in patients presenting with apparently recessive inherited ataxia caused by cerebellar hypoplasia and an unknown genetic aetiology after proper diagnostic work-up, we recommend the measurement of phosphomannomutase activity when transferrin isofocusing is normal or inconclusive. PMID- 17694351 TI - The multidisciplinary clinic, quality of life and survival in motor neuron disease. PMID- 17694352 TI - Enrichment and fractionation of heavy metals in bed sediments of River Narmada, India. AB - A metal fractionation study on bed sediments of River Narmada in Central India has been carried out to examine the enrichment and partitioning of different metal species between five geochemical phases (exchangeable fraction, carbonate fraction, Fe/Mn oxide fraction, organic fraction and residual fraction). The river receives toxic substances through a large number of tributaries and drains flowing in the catchment of the river. The toxic substances of particular interest are heavy metals derived from urban runoff as well as municipal sewage and industrial effluents. Heavy metals entering the river get adsorbed onto the suspended sediments, which in due course of time settle down in the bottom of the river. In this study fractionation of metal ions has been carried out with the objective to determine the eco-toxic potential of metal ions. Although, in most cases (except iron) the average trace/heavy metal concentrations in sediments were higher than the standard shale values, the risk assessment code as applied to the present study reveals that only about 1-3% of manganese, <1% of copper, 16 19% of nickel, 4-20% of chromium, 1-4% of lead, 8-13% of cadmium and 1-3% of zinc exist in exchangeable fraction and therefore falls under low to medium risk category. According to the Geo-accumulation Index (GAI), cadmium shows high accumulation in the river sediments, rest of other metals are under unpolluted to moderately polluted class. PMID- 17694354 TI - Direct comparison of enzyme measurements from dried blood and leukocytes from male and female Fabry disease patients. AB - Anderson-Fabry disease is an X-linked disorder that is caused by deficiency of the lysosomal enzyme alpha-galactosidase A. Symptoms include chronic progressive painful small-fibre neuropathy, cornea verticillata, renal failure and heart disease. Interestingly, female heterozygous patients may also show severe symptoms. After clinical suspicion, usually the determination of alpha galactosidase activity in leukocytes is requested first. Alternatively, an enzymatic assay using dried blood specimens has been described. Dried blood samples require less material and are substantially more stable (several months at room temperature) than whole-blood specimens. To validate the new method and to asses its usefulness for diagnosis of female patients, enzyme activities of alpha-galactosidase, beta-galactosidase and beta-glucuronidase from 78 known Fabry patients were compared (29 males, 47 females) between both materials. In summary, the determination of alpha-galactosidase activity using dried blood and leukocytes as well as the ratio of alpha-galactosidase to beta-glucuronidase in dried blood can improve the diagnostic specificity in cases of female patients who are difficult to identify when only leukocyte enzyme activities are considered. PMID- 17694353 TI - Congenital adrenal hyperplasia: diagnostic advances. AB - Congenital adrenal hyperplasia is a group of autosomal recessive disorders resulting from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex. The most frequent is steroid 21 hydroxylase deficiency, accounting for more than 90% of cases. Much has been learned about the genetics of the various clinical forms of 21-hydroxylase deficiency, and correlations between the genotype and the phenotype have been studied extensively. Gene-specific diagnosis is now feasible and neonatal screening and prenatal treatment have been widely implemented. This discussion will be limited to the most common form of congenital adrenal hyperplasia, with focus on the diagnostic advances in this disease. PMID- 17694355 TI - Structures for clinical follow-up: newborn screening. AB - Clinical follow-up of children identified by newborn screening is critical in ensuring that the short-term and long-term needs of the newborn infant are managed. Within the United States, one of the biggest challenges in the newborn screening programme is clinical follow-up, and there still remains wide variation in practice patterns among states on how infants are followed up. In addition, there is lack of consistency in the treatment and diagnostic protocols used by health care providers. There is growing interest in the establishment of a systematic process for follow-up and for the development of a nationwide infrastructure that will ensure that all children will be provided consistent and effective treatment in a timely manner. Within this framework of optimal diagnosis and therapy, there must also be opportunities to study the natural history of these conditions, to monitor short- and long-term health outcomes, to assist with policy decision-making, to validate the effectiveness of screening, to define the clinical spectrum of the diseases, and to provide opportunities for the advancement of novel therapeutic interventions and screening/diagnostic technologies. It will only be through the development of a structured clinical follow-up system that we will be able to make certain these newborn infants are provided the most appropriate treatment for their disease variants and allow researchers to make more rapid advances in improving the clinical management of these conditions. PMID- 17694357 TI - Newborn screening: a national public health programme in Brazil. AB - The newborn screening programme started in Brazil (1976) through isolated initiatives, without governmental directions and/or policies. According to Health Ministry (2000) data the coverage was 55% and unevenly distributed. Only 17 out of 27 Brazilian states had more than 30% coverage. Public budgets covered only diagnostic examinations. There were no official data about assistance, patient follow-up or detected disorders. The creation of the National Programme (2001) has provided new perspective for newborn screening (NBS) in the public health system. It has provided important official data and established management and care units for each state: Reference Services in Newborn Screening. The programme screened about 13 million newborns from October 2001 to December 2005. The coverage increased to 80.2% (2005) and 74% of the states presented coverage of over 70%. Within 34 accredited Reference Services in 27 Brazilian states, all provide screening for PKU and CH. Ten of them provide screening for haemoglobinopathies as well, and three of them provide also for CF. The Reference Services altogether count on at least 170 health professionals, such as paediatricians, endocrinologists, nutritionists, psychologists and social workers. They are qualified to assist positive cases, within the policies established by the National Programme. There has been significant increase in NBS coverage and follow-up assuredness, including detected cases before the National Programme (10,935 positive cases) mostly in those regions where the programme did not exist. There has been significant evolution in the Newborn Screening as a Public Health Program in Brazil due to the government's commitment (federal and each component state). PMID- 17694356 TI - Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults. AB - Inborn errors of metabolism (IEMs) may present in adolescence or adulthood as a psychiatric disorder. In some instances, an IEM is suspected because of informative family history or because psychiatric symptoms form part of a more diffuse clinical picture with systemic, cognitive or motor neurological signs. However, in some cases, psychiatric signs may be apparently isolated. We propose a schematic classification of IEMs into three groups according to the type of psychiatric signs at onset. Group 1 represents emergencies, in which disorders can present with acute and recurrent attacks of confusion, sometimes misdiagnosed as acute psychosis. Diseases in this group include urea cycle defects, homocysteine remethylation defects and porphyrias. Group 2 includes diseases with chronic psychiatric symptoms arising in adolescence or adulthood. Catatonia, visual hallucinations, and aggravation with treatments are often observed. This group includes homocystinurias, Wilson disease, adrenoleukodystrophy and some lysosomal disorders. Group 3 is characterized by mild mental retardation and late onset behavioural or personality changes. This includes homocystinurias, cerebrotendinous xanthomatosis, nonketotic hyperglycinaemia, monoamine oxidase A deficiency, succinic semialdehyde dehydrogenase deficiency, creatine transporter deficiency, and alpha and beta mannosidosis. Because specific treatments should be more effective at the 'psychiatric stage' before the occurrence of irreversible neurological lesions, clinicians should be aware of atypical psychiatric symptoms or subtle organic signs that are suggestive of an IEM. Here we present an overview of IEMs potentially revealed by psychiatric problems in adolescence or adulthood and provide a diagnostic strategy to guide metabolic investigations. PMID- 17694358 TI - Tandem mass spectrometric determination of succinylacetone in dried blood spots enables presymptomatic detection in a case of hepatorenal tyrosinaemia. AB - Tyrosinaemia type I, or fumarylacetoacetase deficiency, causes hepatorenal damage by accumulation of fumarylacetoacetate. Patients are generally in good condition at birth, but are at risk of developing serious metabolic crises with liver failure and hepatic coma. An early start of treatment with NTBC and a tyrosine balanced diet can prevent harm to the patients. The application of tandem mass spectrometry to newborn screening allows for easy determination of tyrosine to detect the presence of hypertyrosinaemia in the neonate, but most patients with tyrosinaemia type I do not present with high tyrosine levels at the time of newborn screening. We report on a 7-week-old girl presenting with acute hepatopathy and severe coagulopathy due to tyrosinaemia type I. The metabolic screening, which was performed by tandem mass spectrometry at the age of 48 h, had revealed normal values for tyrosine and methionine that were well within ranges observed in the general population and equally normal ratios of methionine/tyrosine and tyrosine/serine. In this patient even lowering the cut off levels for tyrosine and methionine would not have provided better sensitivity. Residual blood spots from the newborn screening filter paper were retrospectively analysed using a specific mass-spectrometric method for the detection of succinylacetone and revealed a 5-fold elevated succinylacetone concentration. This indicates that identification of all newborns with hepatorenal tyrosinaemia is only possible by determination of succinylacetone as part of the newborn screening process. PMID- 17694359 TI - Prostaglandin H synthase isoenzyme distribution in the gingival tissue of patients with periodontitis: pronounced expression adjacent to gram-positive bacteria. AB - Prostaglandin (PGE(2)) is an inflammatory mediator that plays a critical role in the pathogenesis of periodontal disease. Prostaglandin H synthase (PGHS) a rate limiting enzyme in PGE(2) biosynthesis exists as two separate isoforms (PGHS-1 and PGHS-2). We have previously demonstrated that both isoforms are generally present in the gingival tissue of periodontitis patients. This study explores in greater detail the variable distribution of each isoenzyme in both inflamed and non-inflamed gingival tissues of patients with periodontitis, and the relationship to adjacent bacteria. Although the positive staining for PGHS-1 was never as intense as for PGHS-2 in the same tissue specimen, either in inflamed or non-inflamed tissues, there was strong staining for both isoenzymes in the epithelium. The keratin layer did not stain. Non-keratinizing crevicular and junctional epithelium contained both isoenzymes through their full thickness in both inflamed and non-inflamed tissues. Pronounced staining of PGHS-2 was evident in the epithelia adjacent to Gram-positively stained organisms. In non-inflamed tissue, PGHS-1 and PGHS-2 were particularly evident in the spinous cell layer; however, fewer of the fibroblasts, endothelial cells, and resident mononuclear inflammatory cells stained positively for PGHS-1 as compared to PGHS-2, but this was less apparent in the inflamed tissues. The immunohistochemical staining patterns indicate that both crevicular and gingival epithelium are important sources of prostaglandin production in the gingival tissue of patients with periodontitis and that bacteria entrapped near to these sites may be important in promoting expression of inducible PGHS-2. PMID- 17694360 TI - Selective prostaglandin G/H synthase (PGHS)-2 inhibitors show greater inhibitory activities on human PGHS-2 than on murine PGHS-2 in intact cells. AB - Excess eicosanoid formation during inflammation has been attributed to the expression of the gene coding for the inducible isoform of prostaglandin G/H synthase (PGHS-2). Human and murine PGHS-2 proteins differ in 73 out of the 604 amino acids. When comparing the inhibitory effects of a panel of PGHS-inhibitors in a whole cell human and murine PGHS-2 assay carried out under identical conditions, classical NSAIDs with the exception of aspirin and tenoxicam showed similar inhibitory effects on both human and murine PGHS-2 enzymes. However, the PGHS-2 selective inhibitors nimesulide, flosulide and NS398 showed a much greater inhibition of human PGHS-2. We suggest that these differences could be due to the genetic differences of human and murine PGHS-2. PMID- 17694361 TI - Anti-inflammatory activity of emu oils in rats. AB - The anti-inflammatory activities of five different preparations of emu (Dromais Novae-Hollandiae) oil, applied topically, have been examined using an experimental polyarthritis- in rats. Four of the preparations were found to be active against adjuvant-induced arthritis in rats. The efficacies of the emu oils acting transdermally are compared with that of orally administered ibuprofen (40 mg/kg). PMID- 17694362 TI - Coordination of copper with aspirin enhances its anti-platelet aggregation activity. AB - Anti-platelet aggregation of copper aspirinate, a copper complex of aspirin, has been studied in vitro and in vivo. The result shows that copper aspirinate is much more effective than aspirin against AA-, ADP- and PAF-induced platelet aggregation. Its mechanism is related to the inhibition of platelet cyclooxygenase and release of active substances from platelets, and to the promotion of PGI(2) level in plasma. PMID- 17694363 TI - Etodolac in the management of pain: a clinical review of a multipurpose analgesic. AB - Etodolac is a non-steroidal anti-inflammatory drug with analgesic properties. Its primary anti-inflammatory mechanism of action is through a selective effect on cyclo-oxygenase-2 (COX-2). It is rapidly absorbed after oral administration, and maximum plasma concentration (C(max)) is reached in 1-2 h, with an elimination half-life (t1/2 ) of 6-8 h.Etodolac has been widely applied in the treatment of inflammatory arthritides such as rheumatoid arthritis, ankylosing spondylitis and gout and in osteoarthritis and has been shown to be efficacious and well tolerated.However, etodolac has other applications which rely primarily on its efficacy as an analgesic. In particular, etodolac has been evaluated in the treatment of a variety of different pain states. Etodolac has been observed to be efficacious in the treatment of acute pain following dental extraction, orthopaedic and urological surgery, and episiotomy, as well as in the treatment of pain due to acute sports injuries, primary dysmenorrhoea, tendonitis, bursitis, periarthritis, radiculalgia and low back pain.These studies indicate that etodolac is a multipurpose analgesic with many clinical applications in addition to its use in the treatment of inflammatory and degenerative forms of arthritis. PMID- 17694364 TI - Management of diarrhoeic type of irritable bowel syndrome with exclusion diet and disodium cromoglycate. AB - Several studies have stressed the role of food intolerance as one of the major factors in the pathogenesis of irritable bowel syndrome (IBS). The purpose of this study was to determine the proportion of patients with IBS that can respond well to an exclusion diet with/without oral disodium cromoglycate and to document the effects of this combination. We selected 120 ambulatory patients with diarrhoeic type IBS; 66 of them (55%) had a concomitant food intolerance (assessed by skin prick test), showing a positive reaction to one (32%) or more foods (68%). Sixty-three (52.5%) tested by cytotoxic test showed more positive reactions. The results were evaluated by means of semiquantitative subjective and objective scores. Thirty patients were randomly treated with a strict exclusion diet, while the other 36 were treated with both exclusion diet and oral disodium cromoglycate (250 mg four times daily) for four months. We observed an improvement of symptoms in 18 (60%) of the 30 patients that had received the only exclusion diet, whereas thirty-two of 36 patients (89%) who had undergone both dietary and cromoglycate treatments showed an improvement that was clinically and statistically significant (p = 0.01).Thus it is concluded that dietary exclusion in association with disodium cromoglycate is most effective in carefully selected patients with diarrhoeic type IBS, with a very high probability of prolonged symptomatic benefit in those subjects that do respond. PMID- 17694367 TI - Pharmacology of benzydamine. AB - Benzydamine is a topical anti-inflammatory drug which is widely available and used topically for the treatment of the mouth. It is also used as a gel for application to inflamed joints. It has physicochemical properties and pharmacological activities which differ markedly from those of the aspirin-line non-steroidal anti-inflammatory drugs. Benzydamine is a weak base unlike the aspirin-like drugs which are acids or metabolized to acids. A major contrast with the aspirin-like drugs is that benzydamine is a weak inhibitor of the synthesis of prostaglandins but it has several properties which may contribute to its anti inflammatory activity. These properties include inhibition of the synthesis of the inflammatory cytokine, tumour necrosis factor-alpha (EC(50), 25 micromol/L). Inhibition of the oxidative burst of neutrophils occurs under some conditions at concentrations of 30 to 100 micromol/L, concentrations which may be produced within oral tissues after local application. A further activity of benzydamine is a general activity known as membrane stabilization which is demonstrated by several actions including inhibition of granule release from neutrophils at concentrations ranging from 3 to 30 micromol/L and stabilization of lysosomes. Lack of knowledge of the tissue concentrations of benzydamine limit the correlation between pharmacological activities in vitro and in vivo. The concentration of benzydamine in the mouthwash is 4 mmol/L but the concentrations in oral tissues have not been studied adequately. Limited data in the rat indicates that concentrations of benzydamine in oral tissues are approximately 100 micromol/L. PMID- 17694368 TI - Relationship between mucosal levels of interleukin 8 and toxinogenicity of Helicobacter pylori. AB - AIM OF STUDY: To investigate if an association exists between in-vivo mucosal levels of IL-8 and bacterial expression of cytotoxin and cagA gene of H. pylori. METHODS: Seventy-two dyspeptic patients referred for endoscopy were studied, including 36 patients with peptic ulcer (PU) and 36 with non-ulcer dyspepsia (NUD). Biopsies were taken for histology, H. pylori culture and measurement of IL 8 by ELISA. To test the ability of H. pylori to produce cytotoxin (VacA), broth culture supernatants were assayed on Vero cells and vacuolation measured. PCR was used to detect the cagA gene of H. pylori. RESULTS: H. pylori was isolated in 52 of 72 patients studied. Among the 52 strains, 25 (49%) were VacA+ve/cagA+ve; 12 (23%) were VacA-ve/cagA-ve; the remaining 15 strains (28%) were either VacA+ve/cagA-ve or VacA-ve/cagA+ve. IL-8 levels (median (interquartile) pg/mg) in patients infected with VacA+ve (1.5 (0.64, 2.84)) or cagA+ve strains (1.25 (0.72, 2.34) were significantly higher than in those with VacA-ve (0.76 (0.4, 1.0)) or cagA-ve strains (0.5 (0.4, 1.5); p<0.05). The neutrophil infiltration score was also higher in patients infected with VacA+ve or cagA+ve strains than in those infected with VacA-ve or cagA-ve strains (p<0.05). CONCLUSION: VacA+ve/cagA+ve strains were associated with an enhanced production of mucosal IL-8 in vivo and correlated with a stronger infiltration of neutrophils. Enhanced mucosal production of IL-8 and its role in neutrophil chemotaxis and activation could be important in H. pylori-induced gastroduodenal inflammation and in the development of peptic ulcer disease. PMID- 17694369 TI - Anti-uveitis and inhibition of fibroblast-like corneal and conjunctival cells by interleukin-1 blockers. AB - Effects of interleukin-1 (IL-1) blockers, CK130 and CK131, on IL-1-induced uveitis and proliferation of fibroblast-like corneal and conjunctival cells were investigated in this study. It was found that CK130 and CK131 inhibited IL-1 induced uveitis in rat eyes effectively at 3 mg/kg and 10 mg/kg, respectively. Further, CK130 and CK131 inhibited fibroblast-like corneal and conjunctival cell growth effectively at 10-300 microg/ml and 30-300 microg/ml, respectively. It was also found that DNA synthesis was markedly reduced by CK130 and CK131 at 30-100 microg/ml. RNA synthesis was also inhibited by these CK compounds but protein synthesis was little affected or enhanced. PMID- 17694370 TI - The role of calcium in paracetamol (acetaminophen) cytotoxicity in PC12 cells transfected with CYP4502E1. AB - Paracetamol-induced toxicity is mainly due to the accumulation of its CYP450 mediated N-hydroxylation product - N-acetylimidoquinone. We examined cell viability, proliferation rates and intracellular calcium in PC12 cells and in a PC12 cell line transfected with cytochrome P4502E1 exposed to paracetamol. This drug had a concentration-related effect on cell survival and a LD(50) which was significantly different between both cell types. A 48% decrease of PC12 cells was found following application of 5 mmol/L paracetamol for 48 h. A total 73% decrease in cell numbers was found in cells metabolizing the drug. Culture protein levels were diminished in a similar manner. Paracetamol increased intracellular calcium (by 662%) only in CYP4502E1-transfected cells. The protective role of EGTA and verapamil modulating calcium homeostasis was more evident in CYP4502E1-transfected cells. These results suggest that biotransformation of paracetamol by CYP2E1 increases its cytotoxicity and that a calcium imbalance may have a key role in the initiation of cell injury. PMID- 17694371 TI - Paracetamol (acetaminophen) esters of some non-steroidal anti-inflammatory carboxylic acids as mutual prodrugs with improved therapeutic index. AB - Paracetamol (acetaminophen) esters [4a-f] of some acidic NSAIDs were synthesized and evaluated as mutual prodrug forms with the aim of improving the therapeutic index through prevention of the gastrointestinal toxicity. The structures of the synthesized esters were confirmed by IR and (1)H-NMR spectroscopy and their purity was established by elemental analyses and TLC. In-vitro stability studies revealed that the synthesized ester prodrugs 4a-f are sufficiently chemically stable in non-enzymatic simulated gastric fluid (hydrochloric acid buffer of pH 1.3 (t (1/2) approximately 15-45 h)) and in phosphate buffer of pH 7.4 (t (1/2) approximately 4-40 h). In 80% human plasma and 10% rat liver homogenate, the mutual prodrugs were found to be susceptible to enzymatic hydrolysis releasing the corresponding NSAID and paracetamol at relatively faster rates (t (1/2) approximately 15-385 min and 1-140 min, respectively). Calculated log P values indicated that the prodrugs 4a-f are more lipophilic than the parent drugs.In vivo experiments in rabbits showed higher plasma levels of ibuprofen after oral administration of its ester prodrug 4b compared with those resulting from an equivalent amount of the corresponding physical mixture. Moreover, significant improvement in latency of pain threshold in mice has been observed up to 4 h after po administration of 0.02 mmol/kg of the prodrugs, compared with the corresponding physical mixtures. Gross observations and scanning electromicrographs of the stomach showed that the prodrugs induced very little irritancy in the gastric mucosa of mice after oral administration for 4 days. These results suggest that the synthesized mutual ester prodrugs were characterized by a better therapeutic index than the parent drugs. PMID- 17694372 TI - Influence of atrial natriuretic peptide, brain natriuretic peptide and urodilatin on the histamine-induced bronchoconstriction in the conscious guinea pig. AB - The influence of human atrial natriuretic peptide (ANP) and of two related peptides, human brain natriuretic peptide (BNP) and urodilatin (URO) on the bronchoconstriction induced by inhalation of histamine in conscious, non anaesthetized guinea pigs was tested.Changes in lung function were registered using two independent methods, one operating in a closed body-plethysmographic system, the other in an open system based on the time lag of air flow curves. The peptides were infused (0.25 ml/min) into the jugular vein for a period from 10 min before until 15 min after the histamine inhalation.ANP displayed virtually no effect on the bronchoconstriction. URO showed some inibition at 1280ng kg(-1) min(-1), but not at lower doses. BNP (640ng kg(-1) min(-1)) inhibited the bronchoconstriction markedly for the total registration period.It can be concluded from these results that BNP exerts bronchoprotective effects in the conscious guinea pig, which are superior to those of ANP or URO. PMID- 17694373 TI - From the H(2) receptor gene to reclassification of the H(2) receptor antagonists. AB - From previous studies it is known that long-term stimulation of the histamine H(2) receptor results in receptor downregulation. Two different pathways are involved in the downregulation process of the H(2) receptor: a cAMP-dependent and cAMP-independent agonist-dependent pathway. Recently, it became evident that in the absence of an agonist the H(2) receptor expressed in CHO cells already stimulate cAMP production, also referred to as spontaneous activity. The spontaneous activity can be inhibited by several H(2) antagonists, previously thought to act as competitive antagonists, and these antagonists are referred to as inverse agonists. Some antagonists, e.g. burimamide, are not able to inhibit the spontaneous activity and are referred to as neutral antagonists. Inverse agonism appears to be the mechanistic basis of upregulation. Only inverse agonists and not neutral antagonists induce receptor upregulation after long-term treatment as these compounds inhibit the spontaneous receptor activity and thus the basal receptor downregulation. Moreover it might also explain previously reported observations after long-term treatment of gastric ulcers, such as intragastric hyperacidity. PMID- 17694374 TI - Helping and cooperation in children with autism. AB - Helping and cooperation are central to human social life. Here, we report two studies investigating these social behaviors in children with autism and children with developmental delay. In the first study, both groups of children helped the experimenter attain her goals. In the second study, both groups of children cooperated with an adult, but fewer children with autism performed the tasks successfully. When the adult stopped interacting at a certain moment, children with autism produced fewer attempts to re-engage her, possibly indicating that they had not formed a shared goal/shared intentions with her. These results are discussed in terms of the prerequisite cognitive and motivational skills and propensities underlying social behavior. PMID- 17694375 TI - Evaluating the process of polishing borosilicate glass capillaries used for fabrication of in-vitro fertilization (iVF) micro-pipettes. AB - In this paper we investigate a number of gas flames for fire polishing borosilicate glass capillaries used in the manufacturing of IVF micro-pipettes. Hydrofluoric acid (HF) was also used as an alternative to finish the pipette end. Glass micro tools in the IVF industry are drawn from hollow glass capillaries of diameter 1 mm. These capillaries are cut manually to a length of 100 mm from hollow glass rods resulting in sharp and chipped edges. These capillaries are held in a customised holder having padding of soft silicone or rubber. Sharp and uneven edges of these capillaries pick up particles of rubber or soft silicone shavings, rendering them ineffective for IVF treatments. The working range of borosilicate glass is 800-1,200 degrees C. The experiments involved analysis of fire polishing process for borosilicate glass capillaries using candle, butane, propane, 2350 butane propane, oxyacetylene gas flames, finding the optimum distance of the capillary relative to the flame, optimum time for which the capillary should be held in the flame and optimum region of the flame which gives the required temperature range. The results show that 2350 butane propane gas mix is optimum for fire polishing of borosilicate glass capillaries. The paper is concluded by comparing the results of fire polishing with the results of acid polishing, in which HF of 1.6% concentration is used to etch the ends of the borosilicate glass pipettes. PMID- 17694376 TI - Effect of selective and non-selective beta-blockers on body weight, insulin resistance and leptin concentration in chronic heart failure. AB - BACKGROUND: Chronic heart failure (CHF) is characterized by increased insulin resistance and hyperleptinaemia. We aimed to study effects of selective and non selective beta-blockers on body weight, insulin resistance, plasma concentrations of leptin and resistin in patients with CHF. METHODS: Twenty-six non-cachectic beta-blocker-naive patients with CHF were randomized and treated with either carvedilol or bisoprolol. Body weight, plasma concentrations of leptin, resistin, fasting glucose and insulin were measured at baseline and after 6 months of therapy. Insulin resistance was estimated by homeostasis model assessment- estimated insulin resistance (HOMA-IR). RESULTS: Body weight increased significantly in the carvedilol group (mean change + 2.30 kg, p = 0.023) while it did not change in the bisoprolol group (mean change -0.30 kg, p = 0.623) (ns between groups). Plasma leptin concentration increased only in the carvedilol group (mean change + 4.20 ng/ml, p = 0.019) (ns between groups). Fasting glucose and resistin remained unchanged in both groups. After 6 months, mean plasma insulin concentration changed significantly differently (p = 0.015) in the bisoprolol (mean change +3.1 microU/ml) compared to the carvedilol group (mean change -6.3 microU/ml) and HOMA-IR was consequently higher in the bisoprolol compared to the carvedilol group (5.2 +/- 4.2 vs 2.8 +/- 1.6, p = 0.046). CONCLUSION: This study found different metabolic effects of carvedilol and bisoprolol in non-cachectic patients with CHF. With unchanged fasting plasma glucose concentration after 6 months of treatment, carvedilol significantly decreased plasma insulin concentration and insulin resistance compared to bisoprolol. PMID- 17694377 TI - Multi-vessel stenting during primary percutaneous coronary intervention for acute myocardial infarction. A single-center experience. AB - BACKGROUND: Recanalization of the culprit lesion is the main goal of primary angioplasty for acute ST-segment elevation myocardial infarction (STEMI). Patients presenting with acute myocardial infarction and multivessel disease are, therefore, usually subjected to staged procedures, with the primary percutaneous coronary intervention (PCI) confined to recanalization of the infarct-related artery (IRA). Theoretically at least, early relief of stenoses of non-infarct related arteries could promote collateral circulation, which could help to limit the infarct size. However, the safety and feasibility of such an approach has not been adequately established. METHODS: In this single-center prospective study we examined 73 consecutive patients who had an acute STEMI and at least one or more lesions > or = 70% in a major epicardial vessel other than the infarct-related artery. In the first 28 patients, forming the multi-vessel (MV) PCI group, all lesions were treated during the primary procedure. In the following 45 patients, forming the culprit-only (CO) PCI group, only the culprit lesion was treated during the initial procedure, followed by either planned-staged or ischemia driven revascularization of the non-culprit lesions. Fluoroscopy time and contrast dye amount were compared between both groups, and patients were followed up for one year for major adverse cardiac events (MACE) and other significant clinical events. RESULTS: The two groups were well balanced in terms of clinical characteristics, number of diseased vessels and angiographic characteristics of the culprit lesion. In the MV-PCI group, 2.51 lesions per patient were treated using 2.96 +/- 1.34 stents (1.00 lesions and 1.76 +/- 1.17 stents in the CO-PCI group, both p < 0.001). The fluoroscopy time increased from 10.3 (7.2-16.9) min in the CO-PCI group to 12.5 (8.5-19.3) min in the MV-PCI group (p = 0.22), and the amount of contrast used from 200 (180-250) ml to 250 (200-300) ml, respectively (p = 0.16). Peak CK and CK-MB were significantly lower in patients of the MV-PCI group (843 +/- 845 and 135 +/- 125 vs 1652 +/- 1550 and 207 +/- 155 U/l, p < 0.001 and 0.01, respectively). Similar rates of major adverse cardiac events at one year were observed in the two groups (24% and 28% in multi-vessel and culprit treatment groups, p = 0.73). The incidence of new revascularization in both infarct- and non-infarct-related arteries was also similar (24% and 28%, respectively, p = 0.73). CONCLUSION: We may state from this limited experience that a multi-vessel stenting approach for patients with acute STEMI and multi vessel disease is feasible and probably safe during routine clinical practice. Our data suggest that this approach may help to limit the infarct size. However, larger studies, perhaps using drug-eluting stents, are still needed to further evaluate the safety and efficiency of this procedure, and whether it is associated with a lower need of subsequent revascularization and lower costs. PMID- 17694378 TI - Transplantation of autologous mononuclear bone marrow stem cells in patients with peripheral arterial disease (the TAM-PAD study). AB - OBJECTIVES: For patients with severe, chronic limb ischemia in many cases interventional or surgical treatment is not possible anymore. In the past, both intramuscular and intraarterial transplantation of autologous BMCs had been proved therapeutically beneficial. The TAM-PAD study is the first one to analyze combined intraarterial and intramuscular BMC transplantation in its acute and long-term effects. METHODS: 13 patients with chronically ischemic limbs due to peripheral arterial disease (Fontaine stage IIb) were recruited and underwent follow-up examinations after 2 and 13 months. Mononuclear cells from bone marrow were injected intramuscular and intraarterial into the ischemic limb. RESULTS: In contrast to the control group, after 2 months the pain-free walking distance of the transplanted patients significantly increased (from 147 +/- 90 to 500 +/- 614 m, p = 0.001). Furthermore the ankle-brachial index was significantly improved (at rest from 0.66+/-0.18 to 0.80+/-0.15, p = 0.003, after stress from 0.64 +/- 0.19 to 0.76 +/- 0.16, p = 0.006). Similar improvement was documented in capillary-venous oxygen-saturation (thigh from 59 +/- 9 to 66 +/- 5, p = 0.005, lower leg from 56 +/- 14 to 63 +/- 5, p = 0.021) and venous occlusion plethysmography (rest from 2.1 +/- 0.7 to 2.5 +/- 0.7, p = 0.009, mean reactive hyperemia from 5.3 +/- 1.8 to 7.2 +/- 1.8, p = 0.003, and peak flow from 7.2 +/- 3.2 to 10.8 +/- 2.8, p = 0.002). After 13 months these positive effects persisted at their improved level. No side effects or complications were monitored. CONCLUSIONS: Combined intraarterial and intramuscular transplantation of autologous mononuclear bone marrow stem cells is a clinically feasible and minimally invasive therapeutic option for patients with severe chronic peripheral occlusive arterial disease. PMID- 17694379 TI - Heart failure and malignant ventricular tachyarrhythmias due to hereditary hemochromatosis with iron overload cardiomyopathy. PMID- 17694380 TI - Severe cardiomyopathy in a patient with renal cell carcinoma after treatment with the novel tyrosine kinase inhibitor sunitinib. PMID- 17694381 TI - In vitro evaluation of coronary stents and in-stent stenosis using a dynamic cardiac phantom and a 64-detector row CT scanner. AB - INTRODUCTION: The aim of the study was to examine the ability of a 64-slice MDCT to detect in-stent stenoses in an ex vivo model of coronary stents. METHODS: Five different stents (Liberte, Boston Scientific; Driver, Medtronic; Multi-Link Vision, Guidant; Taxus Express, Boston Scientific; Cypher, Cordis) were examined using a dynamic cardiac phantom. The stents were pulled over a vessel model that consists of a polymer tube with diameters of 3.0, 3.5, and 4.0 mm and four different degrees of stenoses (0%; 30%; 50%; 70-80%). This model was moved with a rate of 60 bpm to mimic cardiac motion. To assess the degree of artificial signal reduction (artificial reduction of attenuation (ARA)) by the different stents, attenuation values were measured in the vessel outside the stent, and in the non stenotic vessel inside the stent. Furthermore the grade of stenosis was assessed by two clinical observers. RESULTS: Highest ARA was found for the Cypher Stent (35 HU), whereas the Liberte Stent presented the lowest ARA (16 HU). Depending on the stent and the vessel diameter, up to 87.5% of the stenoses were correctly diagnosed. In the 3.0 and 3.5 mm vessels, a nonstenotic or low-grade stenotic vessel was diagnosed as intermediate or high-grade stenosis in 22.5%, whereas in the 4.0 mm vessels, this kind of overestimation did not occur. A 50% stenosis was diagnosed as a 30% stenosis in 30%. On the other hand, high-grade stenoses were underestimated in only 10%. On a four-point scale, the average deviation from the real grade of stenosis was 0.21 for the Liberte stent, 0.54 for the Taxus Express stent, 0.29 for Driver stent, 0.62 for the Multi-Link Vision stent, and 0.37 for the Cypher stent. CONCLUSIONS: In a dynamic cardiac phantom model, high grade stenoses in vessels with a diameter of 4 mm could be reliably detected irrespective of the stent type used in this study. Vice versa, high grade stenoses (> or = 50%) could only be ruled out with certainty in vessels with a diameter of 4 mm. In smaller vessels, the ability to correctly diagnose high grade stenoses was dependent on the type of stent and the imaging artifacts associated with it. PMID- 17694382 TI - Short- and long-term outcome after carotid artery stenting with neuroprotection: single-center experience within a prospective registry. AB - BACKGROUND: Carotid artery stenting is an alternative method to surgical endarterectomy for treatment of carotid artery stenosis. METHODS AND RESULTS: Three hundred and seventy-one consecutive patients (71+/-9 years) undergoing 405 carotid artery interventions at a single cardiologic center were studied prospectively within a therapy registry. In general, the interventional procedure was performed using neuroprotective devices to prevent distal embolization. Stents were used routinely whenever possible. Independent neurological assessment took place prior to and after carotid stenting. The neurological event rate was assessed in the early (<30 days) and late post interventional period. In asymptomatic patients, 286 interventions were done with a 30-day stroke rate of 1.3% (ipsilateral 1.0%). In symptomatic patients, strokes occurred in a significantly (p<0.005) higher rate of 5.0% after 119 interventions (all ipsilateral). At long-term follow-up (mean 728+/-548 days) additional strokes occurred ipsilateral to the side of carotid intervention in 0.4% of asymptomatic patients (1.7% of symptomatic patients); contralateral strokes were seen at long term follow-up in 1.1% of asymptomatic (1.7% of symptomatic) patients. Due to their comorbidities, 1.6% of patients died early, and an additional 11.1% late after carotid stenting. CONCLUSION: Carotid artery stenting with the general use of neuroprotective devices yields acceptable shortterm results with respect to neurological events. Asymptomatic patients have significantly less periprocedural strokes than symptomatic patients. Neurological events during long-term follow-up are rare, in particular ipsilateral to the side of carotid stenting. Thus, carotid artery stenting with neuroprotection is a safe method for carotid revascularization, with acceptable periprocedural events, particularly in asymptomatic patients, and a good long-term neurologic outcome. PMID- 17694383 TI - Utility of endomyocardial biopsy guided by delayed enhancement areas on magnetic resonance imaging in the diagnosis of cardiac sarcoidosis. PMID- 17694384 TI - Distal embolic protection during percutaneous intervention of aorto-coronary venous bypass grafts: the FIRST Trial. AB - OBJECTIVE: Interventions in aorto-coronary venous bypass grafts (CABG) can cause acute procedural complications due to distal embolization of debris. In the FIRST (First European Investigation Regarding the Systematic use of the TriActiv device) multicenter trial the distal endovascular protection system TriActiv (Kensey Nash) was evaluated during intervention of CABG. METHODS: 195 patients in 17 centers in Germany with significant disease of a vein graft were enrolled. Inclusion and exclusion criteria were comparable to the SAFER trial. RESULTS: Acute procedural success was achieved in 98% of cases. Aspirated debris was found in 96.5% of patients. Primary endpoints (MACE at 30 days) occurred in 8.7% of all pts. (ITT). No patient died and 7.2% of patients suffered from MI. The rate of early revascularization was 1.5%. Secondary endpoints (MACCE at 30 days) were found in 9.2% and at hospital discharge in 8.7% of patients. CONCLUSIONS: The TriActiv system is safe and effective. Normal post procedural flow can be preserved and the MACE rate is with 8.7% considerably low. The FIRST trial supports the growing belief that PCI of CABG should be performed with protection systems. PMID- 17694385 TI - Saccade induced cortical activation in patients with post-stroke visual field defects. AB - Substantial disability in patients with hemianopia results from reduced visual perception. Several studies have shown that these patients have impaired saccades but may improve search strategies with appropriate training of saccades. We used fMRI to study the representation of saccades in patients with post-stroke hemianopia to the left. Brain activation during visually guided saccades was measured in 10 patients with a pure occipital cortical lesion causing homonymous hemianopia and in 10 healthy control subjects. Differences in activation between rest and saccades and between controls and patients were assessed with statistical parametric mapping (SPM'99). In normal subjects, significant activation was found in the frontal and parietal eye fields bilaterally and in the supplementary eye field. These areas were also activated in patients, however, to a lesser degree. In contrast, an area of increased activation in patients was found in the posterior parietal cortex of the (non-affected) left hemisphere. Visual field defects after striate lesions are associated with changes in the frontoparietal network underlying the cortical control of saccades. PMID- 17694386 TI - Comparative efficacy of low dose, daily versus alternate day plasma exchange in severe myasthenia gravis: a randomised trial. AB - OBJECTIVE: To evaluate the comparative efficacy of low dose daily versus alternate day plasma exchange in patients with severe myasthenia. METHODS: Thirty three patients with myasthenia gravis (Osserman's stage II b and III) were randomized to receive alternate day (n = 17) or daily low dose plasma exchange (n = 16). Plasma exchange were carried on each patient, number of exchanges varying subject to their requirements and 20-25 ml/kg plasma was removed during each session. Myasthenia gravis disease scale (MGDS) score was evaluated before and after the procedure. Time to wean off ventilator, removal of nasogastric tube and total duration of hospital stay were also assessed. RESULTS: There was no statistically significant difference between daily vs. alternate day group with regards to change in MGDS score, percentage change in MGDS score, and complication rates. A decreased hospital stay was observed in patients on daily plasma exchange which almost reached statistical significance. CONCLUSION: We conclude from our study that daily and alternate day plasma exchange are similar in their efficacy and complication rates, however the daily schedule could be a preferred modality due to decreased hospital stay. PMID- 17694387 TI - Erythropoietin has no effect on hippocampal response during memory retrieval 3 days post-administration. PMID- 17694388 TI - Evaluation of serotonin, noradrenaline and dopamine reuptake inhibitors on light induced phase advances in hamster circadian activity rhythms. AB - RATIONALE: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for the treatment of anxiodepressive states that are often associated with perturbed circadian rhythms including, in certain patients, phase advances. Surprisingly, the influence of SSRIs upon circadian activity rhythms has been little studied in experimental models. OBJECTIVES: Accordingly, this study examined the ability of SSRIs to modulate the phase-setting properties of light on circadian activity rhythms in hamsters. Their actions were compared to those of the mixed serotonin/noradrenaline reuptake inhibitor (SNRI), venlafaxine, the selective noradrenaline reuptake inhibitor, reboxetine, and the dopamine reuptake inhibitor, bupropion. MATERIALS AND METHODS: Wheel-running activity rhythms were recorded in male Syrian hamsters. Drugs were administered systemically before a light stimulus that was used to advance the timing of the hamster running rhythms. RESULTS: Four chemically diverse SSRIs, citalopram (1-10 mg/kg, intraperitoneally), fluvoxamine (1-10), paroxetine (1-10), and fluoxetine (10 and 20), all robustly and significantly inhibited the ability of light to phase advance hamster circadian wheel-running activity rhythms. Their actions were mimicked by venlafaxine (1-10) that likewise elicited a marked reduction in phase advances. Conversely, reboxetine (1-20) and bupropion (1-20) did not exert significant effects. CONCLUSIONS: These data suggest that suppression of serotonin (but not noradrenaline or dopamine) reuptake by SSRIs and SNRIs modifies circadian locomotor activity rhythms in hamsters. Further, they support the notion that an inhibitory influence upon the early-morning light-induced advance in circadian activity contributes to the therapeutic effects of serotonin uptake inhibitors in certain depressed patients. PMID- 17694389 TI - Endocannabinoid modulation of male rat sexual behavior. AB - RATIONALE: Synthetic and plant-derived cannabinoid CB(1) receptor agonists have consistently been shown to impair sexual behavior in male rodents; however, the role of the endocannabinoid system in regulating copulatory processes is largely unknown. The aim of this experiment was to determine the effect of pharmacological facilitation or antagonism of endocannabinoid signaling on male rat sexual behavior. MATERIALS AND METHODS: Male Long-Evans rats were administered a single injection of either the cannabinoid CB(1) receptor antagonist AM251 (1, 2, or 5 mg/kg), the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.1, 0.3, or 0.5 mg/kg), or the anandamide uptake inhibitor/FAAH inhibitor AM404 (1, 2, and 5 mg/kg), or their respective vehicles, and examined on parameters of appetitive and consummatory sexual behavior. RESULTS: Inhibition of anandamide metabolism through URB597 had no effect on any parameter of sexual behavior. However, the highest dose of AM404 increased the latency to engage in intromitting behavior, but had no other effect on sexual behavior, suggesting that this effect may be due to the sedative-suppressive effects of this drug. AM251 produced a dose-dependent facilitation of ejaculation, such that the number of intromissions required to achieve ejaculation and the ejaculation latency were reduced by AM251 administration. CONCLUSIONS: These data suggest that antagonism of the CB(1) receptor facilitates ejaculatory processes, an effect which may be due to interactions with neuropeptidergic systems in the hypothalamus, and further, suggest a novel target for pharmacological agents aimed at treating ejaculatory-based sexual dysfunction. PMID- 17694390 TI - Can the ice-water test predict the outcome of intradetrusor injections of botulinum toxin in patients with neurogenic bladder dysfunction? AB - The aim of this project was to evaluate the ice-water test as a predictor of the response to intradetrusor botulinum toxin injection in patients with neurogenic detrusor overactivity. We retrospectively evaluated the urodynamic parameters in 22 patients with neurogenic bladder dysfunction and positive ice-water test. Maximum cystometric capacity (MCC), reflex volume (RV), maximum detrusor pressure during voiding (MVP) and bladder compliance (BC) were compared before and after intradetrusor injection of 300 units botulinum toxin and calculated as a quotient. The ice-water test was performed before the injection, and the maximum pressure rise and the time to maximum pressure were measured. Furthermore, the ratio between maximum pressure and time to reach maximum pressure was calculated as the velocity of pressure rise. Correlations between the ice-water test criteria and the quotients of the cystometric data before and after injection were determined by the Spearmen's Rho coefficient. The increase in MCC and RV after botulinum toxin A injection showed a small positive, but insignificant correlation of 0.25 and 0.2 to the velocity of pressure rise of the ice-water test. A small negative, but insignificant correlation was found in change of BC and MVP with -0.17 and -0.2, respectively. Based on our population the ice-water test cannot predict the efficacy of intradetrusor botulinum toxin injections in patients with neurogenic detrusor overactivity. PMID- 17694391 TI - Prospective evaluation of candidate urine and cell markers in patients with interstitial cystitis enrolled in a randomized clinical trial of Bacillus Calmette Guerin (BCG). AB - We measured candidate urine biomarkers and bladder cell DNA cytometry in interstitial cystitis (IC) patients randomized to receive intravesical Bacillus Calmette Guerin (BCG) or placebo in a multicenter trial. Participants received 6 weekly instillations and were followed for 34 weeks. Urine was collected at baseline, prior to fourth treatment, and at study end. Antiproliferative factor (APF) activity was determined by 3H-thymidine incorporation assay; heparin binding epidermal growth factor-like growth factor (HB-EGF) and epidermal growth factor-like growth factor (EGF) levels were determined by ELISA. Cellular DNA content was measured by image analysis to determine the mean hyperdiploid fraction (HDF) of the urine cell pellet. Associations between marker levels, and treatment or symptoms, were examined. Baseline APF positivity rate and mean levels of the other biomarkers were similar to previous smaller studies. During the week 34 follow-up, mean HDF decreased (P = 0.0003) and HB-EGF increased (P < 0.0001); both correlated weakly with decreased urgency. There was no difference in any biomarker between symptom responders and non-responders, but the percentage of responders was low and not significantly different for BCG versus placebo. APF positivity, decreased HB-EGF, increased EGF, and increased HDF were confirmed at baseline in IC patients. Changes in HDF and HB-EGF levels correlated weakly with changes in urgency, but the low BCG response rate prevented identification of additional associations between biomarker changes and treatment or symptoms. PMID- 17694392 TI - Effect of maternal ethanol consumption during pregnancy and lactation on kinetic parameters of folic acid intestinal transport in suckling rats. AB - Ethanol ingestion is known to interfere with folate absorption and metabolism. A fostering/crossfostering analysis of maternal ethanol exposure effects on jejunum and ileum kinetic parameters in vivo of offspring rat folic acid absorption at 21 days postpartum was carried out. The rats were divided into four groups: CP, control pups; GP, pups exposed to ethanol only during gestation; LP, pups exposed to ethanol only during lactation; GLP, pups exposed to ethanol during gestation and lactation. Jejunal and ileal loop transport studies were performed using in vivo perfusion at a flow rate of 3 ml/min for 5 min. Folic acid concentrations of 0.25, 0.5, 1, 1.5 and 2.5 microM: were used. Jejunal and ileal absorption values were determined by the difference between the initial and the final amounts of substrate in the perfusate and expressed as picomoles per square centimeter of intestinal surface every 5 min. The results indicated that ethanol consumption by the dams during gestation and/or lactation led to significant changes in V(max), with no significant changes in apparent K(m). These findings suggest that exposure to ethanol during gestational and suckling periods leads to a general delay in postnatal body weight and that intestinal folate absorption appears to be upregulated in suckling rats, this effect being higher in the LP group. PMID- 17694393 TI - Occurrence of two cytotypes in Bryconamericus aff. iheringii (Characidae): karyotype analysis by C- and G-banding and replication bands. AB - Cytogenetic analyses of Bryconamericus aff. iheringii specimens from the upper Parana River basin (State of Parana, Brazil) are provided. They had 2n = 52 chromosomes and two cytotypes with variations in their karyotypic formulae: cytotype I with 12 metacentric, 18 submetacentric, 8 subtelocentric and 14 acrocentric chromosomes with a fundamental number (FN) of 90; cytotype II with 8 metacentric, 28 submetacentric, 6 subtelocentric and 10 acrocentric chromosomes with a fundamental number (FN) of 94. Differences in C- and G-band patterns between the cytotypes, distinguishing marker chromosomes for each karyotype, were reported. The R-band pattern by 5-bromodeoxyuridine incorporation was obtained in chromosomes of the cytotype II sample. In some metaphases, the second pair of submetacentric chromosomes is distinctive: its short arm is heterochromatic (positive C-band), corresponding to a late replication region. In the same cytotype, a G- and R-band size heteromorphism w as recorded in the long arm of pair 9 (submetacentric). These methodologies revealed an actual karyotypic differentiation in the B. aff. iheringii population analyzed. Morphometrical comparative analyses and a discussion of evolutionary aspects of chromosome diversification in species of this genus are provided as well. PMID- 17694394 TI - Two novel elements (CFG1 and PYG1) of Mag lineage of Ty3/Gypsy retrotransposons from Zhikong scallop (Chlamys farreri) and Japanese scallop (Patinopecten yessoensis). AB - Two novel elements (CFG1 and PYG1) of Mag lineage of Ty3/Gypsy retrotransposons were cloned from Zhikong scallop (Chlamys farreri) and Japanese scallop (Patinopecten yessoensis). The total length of the CFG1 element is 4826 bp, including 5'-LTR (192 bp), the entire ORF (4047 bp) and 3'-LTR (189 bp). The entire ORFs of both CFG1 and PYG1 elements are composed of 1348 aa and do not have any frameshifts. Their closest relative is Jule element from the poeciliid fish (Xiphophorus maculatus). On average, the diploid genome of C. farreri contains approximately 84 copies of CFG1 elements. We summarize the major features of CFG1, PYG1 and other elements of Mag lineage of the Ty3/Gypsy group. mRNA expression of CFG1 element in larvae increases gradually before the gastrulae stage and decreases gradually afterward, whereas in adductor such expression in adductor muscle and digestive gland are lower than those in other tissues. Overall, mRNA expression of CFG1 element in the early larvae is significantly higher than that in adult tissues. In muscle tissue, while the promoter and partial GAG domain of CFG1 element are unmethylated, the partial RT domain is highly methylated. These results suggest that CFG1 expression may be controlled by a post-transcriptional gene silencing mechanism that is associated with coding-region (RT domain) methylation. PMID- 17694395 TI - In situ-forming oleogel implant for rivastigmine delivery. AB - PURPOSE: To provide a simplified dosing schedule and potentially reduce side effects associated to peak plasma concentrations, an in situ-forming oleogel implant was studied for the sustained-release of rivastigmine. MATERIALS AND METHODS: The gel was prepared by dissolving 5-10% (w/w) N-stearoyl L: -alanine methyl ester (SAM) organogelator in safflower oil containing either dissolved rivastigmine or its dispersed hydrogen tartrate salt. Rheological analysis, differential scanning calorimetry, and infrared spectroscopy were carried out to assess the impact of drug incorporation on the oleogel; this was followed by in vitro and in vivo release studies. RESULTS: A weakening of intermolecular interactions was suggested by gel-sol transition temperature drops of 10-15 degrees C upon incorporation of dissolved drug. Meanwhile, the dispersed drug salt induced minimal or no changes in transition temperature. Gels containing dispersed rivastigmine had the lowest burst in vitro (<15% in 24 h). In vivo, the 10% SAM formulation containing dispersed rivastigmine provided prolonged drug release within the therapeutic range for 11 days, with peak plasma levels well below the toxic threshold and up to five times lower than for the control formulation. CONCLUSIONS: This study established SAM gels to be a promising option for sustained-release formulations in the treatment of Alzheimer's Disease. PMID- 17694396 TI - What I wish I knew then...reflections from personal experiences in counseling about Down syndrome. AB - Sharing the news about a newborn baby's diagnosis of Down syndrome with families is a scenario genetic counselors frequently face. Yet often we may feel uncomfortable or unsure how to best support families in this setting in a way that will foster competence and resilience. This commentary is a reflection of one genetic counselor's experiences in counseling about Down syndrome over the course of her career and how her thinking has transitioned from a medical based model of disability to a more individual and family-focused model. Ideas and suggestions are offered that genetic counselors can incorporate into their practice. PMID- 17694398 TI - The influence of cancer-related distress and sense of coherence on anxiety and depression in patients with hereditary cancer: a study of patients' sense of coherence 6 months after genetic counseling. AB - This study examines the association between Sense of Coherence and anxiety and depression amongst patients at risk of hereditary cancer receiving genetic counseling. When writing this article, 144 patients referred for genetic counseling due to a suspicion of hereditary cancer in the family were recruited for this multicentered longitudinal study on the psychosocial aspects of genetic counseling in Norway. A total of 96 (66%) patients responded to the follow-up survey distributed 6 months after genetic counseling. This survey included the Sense of Coherence-29 Scale, Impact of Event Scale, and Hospital Anxiety and Depression Scale. Multiple regression analyses were applied. Our results show association between cancer-related distress and symptoms of anxiety and depression. Sense of Coherence is significantly associated with both anxiety and depression. The hypothesis of Sense of Coherence buffering cancer-related distress and the possible impact of these findings for genetic counseling are discussed. PMID- 17694397 TI - Assessment of psychosocial outcomes in genetic counseling research: an overview of available measurement scales. AB - The aim of the present paper was to describe and evaluate many of the measurement scales currently used in genetic counseling outcomes research. A team of three researchers reviewed the available literature and selected a variety of validated instruments suitable for measurement of genetic counseling outcomes. There are numerous scales to assess each of the following outcomes among counselees: satisfaction with genetic counseling; knowledge; decision-making; psychological adjustment; coping; perceived personal control; perceptions of disease risk; and family communication about genetic risk. However, the strengths and limitations inherent to each instrument warrant careful consideration prior to implementation. In the genetic counseling context, scale selection should be undertaken with thought directed towards the characteristics of the research sample (e.g. levels of literacy, culture, medical condition), the practicalities of the research setting (e.g. available funding and resources, time restrictions, researcher expertise), the purpose of the research (i.e. the specific aspect of the genetic counseling experience to be studied), and the science underlying the scale (e.g. theoretical framework, psychometric properties). PMID- 17694400 TI - Benefit of preformed silos in the management of gastroschisis. AB - Gastroschisis is traditionally managed by primary closure (PC) or delayed closure after surgical silo placement. Bedside insertion of preformed silos (PFS) and delayed closure has become more widespread, although its benefits remain unclear. To identify differences in outcome of infants managed with PFS compared with traditional closure (TC) techniques. Single-centre retrospective review of 53 consecutive neonates admitted between February 2000 and January 2006. Data expressed as median (range). Non-parametric statistical analysis used with P < 0.05 regarded as significant. Forty infants underwent TC and 13 had PFS and delayed closure. Median ventilation time in both groups was 4 days (P = 0.19) however this was achieved with higher mean airway pressures (MAPs) (day 0, 10 (5 16) versus 8 (5-10) cmH(2)O; P = 0.02) and inspired oxygen (40 (21-100) versus 30 (21-60)%; P = 0.03) in TC group. Urine output on day-1 of life was significantly higher in PFS group (1.1 (0.16-3.07) versus 0.45 (0-2.8) ml/kg/h; P = 0.02). Inotrope support was required in 17/40 (43%) of TC versus 0/13 (0%) in PFS (P < 0.01). After exclusion of infants with short bowel syndrome and/or intestinal atresia (n = 9), there was a shorter time to full enteral feeds in the TC group (22 (12-36) versus 27 (17-45); P = 0.07), although there was no difference in the period of parenteral nutrition (PN) (P = 0.1) or overall hospital stay (P = 0.34). No deaths or episodes of necrotizing enterocolitis occurred. The use of PFS for gastroschisis closure is associated with a reduction in pulmonary barotrauma, better tissue perfusion and improved early renal function, consistent with a reduction in abdominal compartment syndrome. PMID- 17694401 TI - Magnetic attraction leading to a small bowel obstruction in a child. AB - Foreign body ingestion in small children is common yet only 1% of cases require operative management of associated complications (Arana et al. in Eur J Pediatr 160:468-472, 2001). A 6-year-old boy was referred to our institution with a 12 h history of abdominal pain. This pain was diffuse and crampy in nature and associated with multiple episodes of non-bilious, non-bloody emesis. On evaluation he was stable and his abdomen demonstrated slight distention and tenderness without peritoneal signs. Plain abdominal radiographs demonstrated some distended loops of small bowel and a radio-opaque foreign object within the mid-abdomen. A small bowel obstruction secondary to foreign body ingestion was diagnosed and an emergent laparotomy performed. Upon exploration, a transition zone was noted near the ileocecal valve. Further exploration revealed the obstruction to be caused secondary to the apposition of two small (8 mm) magnets, one in the proximal ileum and the other near the ileocecal valve, resulting in an internal hernia. The magnets were easily separated relieving the obstruction and both were removed via two small bowel enterotomies. After being presented with the magnets, his parents suspected that they came from the clothes of a Polly Pocket (Mattel, Inc., El Segundo, CA) doll. The patient had an uneventful post operative course and was discharged to home on the second post-operative day. This case demonstrates the complications that may occur with multiple magnet ingestion. It highlights the need for close observation and early surgical intervention in children with a suspected history of foreign body ingestion, a clinical picture of gastrointestinal distress, and radiographic evidence of a radio-opaque foreign object. PMID- 17694399 TI - Interaction of bone morphogenetic proteins with cells of the osteoclast lineage: review of the existing evidence. AB - The present review evaluates the existing scientific proofs of this supplementary role of the BMPs and summarises its clinical implications. Bone regeneration is a process consisting of bone formation and bone resorption, two different but closely coupling pathways, which in most circumstances proceed simultaneously. Plenty of evidence has also characterised the bone morphogenetic proteins (BMPs) as inducing factors of bone formation. However, there is also evidence that these multifunctioning proteins affect bone resorption and the osteoclast homeostasis utilising various pathways. The present review evaluates the existing scientific evidence of this supplementary role of the BMPs, and summarises its clinical implications. PMID- 17694402 TI - Hematological and biochemical changes in organically farmed sheep naturally infected with Fasciola hepatica. AB - A naturally occurring outbreak of fasciolosis in a group of 20 Merinolandschaf (German Merino) sheep was studied. Hematological and blood biochemical values in sheep spontaneously infected with liver fluke Fasciola hepatica were compared with equivalent values in 20 parasite-free sheep from organically farmed flock. Investigated animals were kept in outdoor system, on pastures covered with swamps, which remain flooded after rainy season. Significantly lower red blood cell (RBC) count, lymphocytes, hemoglobin (Hb), packed cell volume (PCV), mean corpuscular hemoglobin concentration (MCHC), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine, and albumin were recorded in sheep from the infected herd, whereas white blood cell (WBC) count, eosinophil, segmented and band neutrophil count, mean corpuscular volume (MCV), gamma-glutamyl transferase (GGT), concentrations of glucose, and globulins were significantly higher than in the parasite free herd. No significant correlation between the investigated blood parameters and the number of F. hepatica eggs in the feces was detected. This study shows that hematological and biochemical values can be useful in early diagnosis and prognosis of sheep fasciolosis. PMID- 17694403 TI - Identification of anisakid nematodes with zoonotic potential from Europe and China by single-strand conformation polymorphism analysis of nuclear ribosomal DNA. AB - Using genetic markers defined previously in the second internal transcribed spacer (ITS-2) of nuclear ribosomal DNA (rDNA), isotopic, and non-isotopic polymerase-chain-reaction-coupled single-strand conformation polymorphism (SSCP) were utilized to identify each of three anisakid species [Anisakis simplex (s.l.), Contracaecum osculatum (s.l.), and Hysterothylacium aduncum] from different host species and geographical locations in Poland and Sweden. While subtle microheterogeneity was observed within each of Anisakis simplex (s.l.) and H. aduncum, distinct SSCP profiles were displayed for each of the three species, allowing identification and differentiation of the three taxa. Subsequent sequencing of the ITS-1 and ITS-2 rDNA revealed that A. simplex (s.l.) represented Anisakis simplex s.s. and Contracaecum osculatum (s.l.) represented C. osculatum C. Application of the non-isotopic SSCP assay of ITS-2 to larval anisakid samples from different hosts and geographical locations in China revealed three distinct SSCP profiles, one of which was consistent with that of A. simplex (s.l.), and the other two had different SSCP profiles from that of C. osculatum C and H. aduncum. Sequencing of the ITS-1 and ITS-2 rDNA for representative Chinese anisakid samples examined revealed three anisakid species in China, i.e., Anisakis typica, Anisakis pegreffii, and Hysterothylacium sp. These molecular tools will be useful for identification and investigation of the ecology of anisakid nematodes in China and elsewhere. PMID- 17694404 TI - Mitochondrial DNA variation of a natural population of Gyrodactylus thymalli (Monogenea) from the type locality River Hnilec, Slovakia. AB - The monogenean flatworm Gyrodactylus thymalli (Zitnan, Helminthologia, 2:266-269, 1960) is considered a harmless ectoparasite on grayling (Thymallus thymallus). The species is closely related to G. salaris Malmberg, 1957 that causes severe gyrodactylosis on Atlantic salmon (Salmo salar) in many Norwegian rivers. In this paper, we study the mitochondrial diversity of a G. thymalli population from one of the type localities Hrable on River Hnilec, Slovakia. By sequencing parts of the mitochondrial NADH dehydrogenase subunit 5 gene, we detected three haplotypes that differ from each other by 2.1-4.1%. The haplotype HnilecI was found most common. Our data suggest that River Hnilec has been colonized independently at least three times with G. thymalli. PMID- 17694405 TI - Effects of the inoculant strain Sphingomonas paucimobilis 20006FA on soil bacterial community and biodegradation in phenanthrene-contaminated soil. AB - The effects of the inoculant strain Sphingomonas paucimobilis 20006FA (isolated from a phenanthrene-contaminated soil) on the dynamics and structure of microbial communities and phenanthrene elimination rate were studied in soil microcosms artificially contaminated with phenanthrene. The inoculant managed to be established from the first inoculation as it was evidenced by denaturing gradient gel electrophoresis analysis, increasing the number of cultivable heterotrophic and PAH-degrading cells and enhancing phenanthrene degradation. These effects were observed only during the inoculation period. Nevertheless, the soil biological activity (dehydrogenase activity and CO(2) production) showed a late increase. Whereas gradual and successive changes in bacterial community structures were caused by phenanthrene contamination, the inoculation provoked immediate, significant, and stable changes on soil bacterial community. In spite of the long-term establishment of the inoculated strain, at the end of the experiment, the bioaugmentation did not produce significant changes in the residual soil phenanthrene concentration and did not improve the residual effects on the microbial soil community. PMID- 17694406 TI - Portal vein thrombosis: CT features. AB - There are many causative diseases to produced portal vein thrombosis (PVT) with the most common being liver cirrhosis with hepatocellular carcinoma. Visualization of abnormalities associated with PVT is crucial to diagnosis and appropriate intervention. Dynamic contrast enhanced CT is the best means of diagnosis of PVT and evaluation of various causative diseases. The findings of PVT of the dynamic CT are filling defect partially or totally occluding the vessel lumen and rim enhancement of the vessel wall. Signs and symptoms of PVT may be subtle or nonspecific and overshadowed by the underlying illness. Radiologists should be aware of the clinical situations that predispose a patient to portal or mesenteric vein thrombosis. PMID- 17694408 TI - Effect of aging on tongue protrusion forces in rats. AB - The purpose of this study was to ascertain the effect of aging on muscle contractile properties associated with tongue protrusion in a rat model. Fischer 344/Brown Norway hybrid rats, ten young (9 months old) and ten old (32 months old), were used to measure protrusive contractile properties. Results showed a significant reduction in tetanic forces in the old animals. The following measures of muscle contraction were not different between age groups: mean twitch contraction force, twitch contraction time, twitch contraction half-decay time, and a calculated measure of fatigability. In conclusion, aging influenced protrusive tongue muscle contractions in a rat model such that tetanic forces were reduced. The reduction of tetanus force may parallel findings in human subjects relative to isometric tongue force generation and may be associated with age-related disorders of swallowing. PMID- 17694407 TI - The effect of an effortful swallow on the normal adult esophagus. AB - The effect of an effortful swallow on the healthy adult esophagus was investigated using concurrent oral and esophageal manometry (water perfusion system) on ten normal adults (5 males and 5 females, 20-35 years old) while swallowing 5-ml boluses of water. The effects of gender, swallow condition (effortful versus noneffortful swallows), and sensor site within the oral cavity, esophageal body, and lower esophageal sphincter (LES) were examined relative to amplitude, duration, and velocity of esophageal body contractions, LES residual pressure, and LES relaxation duration. The results of this study provide novel evidence that an effortful oropharyngeal swallow has an effect on the esophageal phase of swallowing. Specifically, effortful swallowing resulted in significantly increased peristaltic amplitudes within the distal smooth muscle region of the esophagus, without affecting the more proximal regions containing striated muscle fibers. The findings pertaining to the LES are inconclusive and require further exploration using methods that permit more reliable measurements of LES function. The results of this study hold tremendous clinical potential for esophageal disorders that result in abnormally low peristaltic pressures in the distal esophageal body, such as achalasia, scleroderma, and ineffective esophageal motility. However, additional studies are necessary to both replicate and extend the present findings, preferably using a solid-state manometric system in conjunction with bolus flow testing on both normal and disordered populations, to fully characterize the effects of an effortful swallow on the esophagus. PMID- 17694409 TI - Rigid spine syndrome: a radiologic and manometric study of the pharynx and esophagus. AB - The rigid spine syndrome (RSS) is not a recognized cause of dysphagia. The "vacuolar variant" of RSS causes mild, generalized, and slowly progressive weakness. Respiratory evaluation detected severe restrictive chest wall defect and significant respiratory muscle weakness. We identified nine patients at our Neuromuscular Clinic over a period of years. The aim of this evaluation was to ascertain whether pharyngoesophageal dysfunction caused cough (2/9), intermittent oropharyngeal dysphagia (4/9), and aspiration pneumonia (3/9). Pharyngeal and esophageal functions were evaluated separately by conventional cineradiography and intraluminal esophageal manometry over a one-year study period. An age- and gender-matched volunteer group without swallowing complaints partook in the manometric component of the study. There were seven male and two female patients. The mean age of patients was 19.1 years (17.8 years for controls), and the age range was 11-36 years (13-32 years for controls). The mean disease duration was 17.2 years (range=8-31 years). Patients were commonly underweight (7/9). Cineradiology detected abnormal swallow physiology of pharyngeal striated muscle (1/9) and of esophageal smooth muscle (2/9). Mean manometric pressures in patients were not significantly different from control data. Manometry detected "nonspecific" contractility abnormalities (3/9) that were not reflected in the mean data. The relative lack of instrumental findings suggested minor upper alimentary tract dysmotility in patients with the RSS. The myopathy that underlies this syndrome likely caused dysfunction of the striated muscle of the pharyngeal constrictors and upper esophageal sphincter. The documented abnormalities of esophageal smooth muscle motility were nonspecific and tenuously associated with the muscle disorder. The incongruity between complaints of intermittent dysphagia and study results was perhaps due to transient pharyngoesophageal dysmotility, altered swallowing mechanics of limited cervical spine mobility, altered swallowing perception after previous intubation/tracheostomy, or a "functional" upper intestinal complaint. PMID- 17694410 TI - Oral and pharyngeal transit of a paste bolus in Chagas' disease. AB - We measured the oral and pharyngeal transit of a paste bolus in 20 patients with Chagas' disease and 21 controls. Each subject swallowed of a 10-ml paste bolus prepared with 50 ml of water and 4.5 g of instant food thickener labeled with 55.5 MBq of 99m technetium phytate. After the scintigraphic recording of the transit, we delineated regions of interest (ROI) corresponding to mouth, pharynx, and proximal esophagus. Time-activity curves were generated for each ROI. There was no difference between patients with Chagas' disease and controls with respect to the duration of oral and pharyngeal transit, amount of pharyngeal residue, or flux of bolus entry into the proximal esophagus. The amount of oral residue was higher in patients with Chagas' disease (median = 0.71 ml) than in controls (median = 0.45 ml). The pharyngeal clearance duration was longer in patients with Chagas' disease (median = 0.85 s) than in controls (median = 0.60 s). The oral transit duration of the patients with Chagas' disease and dysphagia (median = 0.55 s, n = 14) was shorter than the oral transit duration of chagasic patients without dysphagia (median = 0.80 s, n = 6). We conclude that when swallowing a paste bolus, patients with Chagas' disease may have an increased amount of oral residue and a longer pharyngeal clearance duration than asymptomatic volunteers. PMID- 17694411 TI - The impact of aging on eating, drinking, and swallowing function in people with Down's syndrome. AB - Many people with Down's syndrome (DS) experience eating, drinking, and swallowing (EDS) difficulties, which can potentially lead to life-threatening conditions such as malnutrition, dehydration, and aspiration pneumonia. As the life expectancy of people with DS continues to improve, there is an increasing need to examine how the aging process may further affect these conditions. Published research studies have yet to address this issue; therefore, this article draws on the literature in three associated areas in order to consider the dysphagic problems that might develop in aging people with DS. The areas examined are EDS development in children and adolescents with DS, EDS changes associated with aging, and EDS changes associated with dementia of the Alzheimer's type (DAT) because this condition is prevalent in older adults with DS. This article concludes that unlike in the general population, the aging process is likely to cause dysphagic difficulties in people with DS as they get older. Therefore, it is suggested that longitudinal studies are needed to examine the specific aspects of EDS function that may be affected by aging and concomitant conditions in DS. PMID- 17694412 TI - Effects of the time interval between clamping and linear stapling for resection of porcine small intestine. AB - BACKGROUND: Although a wait of several seconds after clamping is recommended when an automatic stapler is used to achieve adequate hemostasis, this wait has not been experimentally clarified. METHODS: To determine whether waiting is necessary between clamping and firing of a linear stapler, this study evaluated the number of staple line bleeding points and histologic changes in stapling sites of porcine small intestine (n = 46). It also assessed the ratio of dry to wet tissue weight (DW ratio) (n = 20) of porcine small intestine clamped between the prongs of a linear stapler. The sites were studied separately as follows: no wait with a four-row device (n = 12), no wait with a six-row device (n = 11), wait with a four-row device (n = 12), and wait with a six-row device (n = 11). The linear stapler was fired immediately after clamping in the no wait group and 1 min after clamping in the wait group. RESULTS: The mean number of staple line bleeding points in 2 to 5 min with the six-row device and in 3 to 5 min with the four-row device after firing were significantly less in the wait group than in the no wait group using the same device (p < 0.05). Cross sections of staple lines showed a higher frequency of mucosal cutting in the no wait group than in the wait group for both the four-row and the six-row devices (both significant at p < 0.01). Although the mean wet tissue weights of anastomotic sites did not change in either group, the mean DW ratio was significantly less in the wait group than in the no wait group (p < 0.01). CONCLUSIONS: A 1-min interval after clamping decreases the amount of clamped tissue. Waiting may thus be necessary to reduce bleeding from stapling sites, which may be related to a decrease in mucosal cutting. PMID- 17694413 TI - Phytoplankton-group specific quantitative polymerase chain reaction assays for RuBisCO mRNA transcripts in seawater. AB - The gene for the large subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase (rbcL) has been shown to be a useful target for molecular assays that quantify form- or clade-specific RNA transcript concentrations as a proxy for the carbon fixation activity of marine phytoplankton. To improve the phylogenetic specificity and sensitivity of RNA probe hybridization methods, a quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay has been reported for diatom and pelagophyte rbcL RNA. Here we detail enhancements made to this PCR method and development of additional assays to specifically quantify rbcL expression from haptophytes, Synechococcus and high-light Prochlorococcus. In vitro RNA transcripts were tested to demonstrate specificity and quantitative accuracy. Application of these methods on seawater samples from two depth profiles in the northern Gulf of Mexico showed a fair degree of agreement between PCR and hybridization results, with results for the chromophytic or form ID rbcL containing organisms having better agreement between the two methods. Diatoms and other heterokonts were shown to be the primary carbon fixers at these locations by PCR, in agreement with greater form ID rbcL RNA measured by hybridization. PMID- 17694415 TI - Appropriateness of colonoscopy in the era of colorectal cancer screening: a prospective, multicenter study in a private-practice setting (Berlin Colonoscopy Project 1, BECOP 1). AB - PURPOSE: The introduction of reimbursement for screening colonoscopy in Germany more than one year ago raised concerns that the consequent workload might lead to underuse of diagnostic colonoscopy for symptomatic patients. Available appropriateness criteria for diagnostic colonoscopy have been rarely tested in a realistic outpatient setting. This study was designed to test current appropriateness criteria for diagnostic colonoscopy to better select patients and potentially provide more capacity for screening cases. Secondary goals were yield and quality control in both the diagnostic and screening cases. METHODS: A prospective study was initiated in 39 private-practice offices to collect data on consecutive colonoscopies conducted during a 6-day study period. A detailed questionnaire was developed to define indications and symptoms, and all findings at colonoscopy were recorded. Colonoscopies were further analyzed and stratified into a screening and a diagnostic group. In the diagnostic group, indications were assessed according to the current guidelines for appropriateness (American Society for Gastrointestinal Endoscopy, European Panel for the Appropriateness of Gastrointestinal Endoscopy), and the results were correlated with the percentage of relevant findings (tumors, inflammatory conditions). RESULTS: During the study period, 1,397 colonoscopies (57 percent screening, 43 percent diagnostic) were analyzed (male/female ratio = 39/61 percent; mean age, 61 years). Fourteen percent and 37 percent, respectively, of the 605 diagnostic colonoscopies were regarded as inappropriate relative to the criteria of the American Society for Gastrointestinal Endoscopy and the European Panel for the Appropriateness of Gastrointestinal Endoscopy. However, the percentage of relevant inflammatory and neoplastic findings (polyps, cancer, inflammatory bowel disease, benign strictures) was only 5 to 10 percent higher in the appropriate group than in the inappropriate group. On the basis of these data, a hypothetical model for selecting appropriate indications was developed: if patients older than aged 50 years with pain, bleeding, and diarrhea, but not constipation, are regarded as having an appropriate indication, such an approach would save 20 percent of colonoscopies in these main indication groups (bleeding, pain, diarrhea, constipation), with a hypothetical miss rate for relevant findings (as defined above) of 5 percent. CONCLUSIONS: Currently used appropriateness criteria for diagnostic colonoscopy increase the yield of relevant findings but lead to a miss rate for relevant findings in the range of 10 to 15 percent. Simple selection criteria based on age and symptoms could be more suitable and should be tested in a larger group of patients. PMID- 17694414 TI - Apparent involvement of a beta1 type integrin in coral fertilization. AB - Integrins are involved in a wide variety of cell adhesion processes, and have roles in gamete binding and fusion in mammals. Integrins have been also discovered in the scleractinian coral Acropora millepora (Cnidaria: Anthozoa). As a first step toward understanding the molecular basis of fertilization in corals, we examined the effect of polyclonal antisera raised against recombinant coral integrins on gamete interactions in A. millepora. Antiserum raised against integrin betacn1 dramatically decreased the binding of Acropora sperm to eggs and significantly decreased fertilization rates relative to preimmune serum and seawater controls. However, the antiserum against AmIntegrin alpha1 did not affect significantly either sperm-egg binding or fertilization. One possible explanation for this is that AmIntegrin alpha1 may preferentially mediate interactions with RGD-containing ligands, whereas mammalian alpha6 integrin (which is most directly implicated in gamete interactions) preferentially interacts with laminin-related ligands. Our results suggest that beta1 type integrins are involved in the fertilization process in Acropora and that some functions of these molecules may have been conserved between corals and mammals. PMID- 17694416 TI - Surgical outcome of intraductal papillary mucinous neoplasms of the pancreas. AB - OBJECTIVE: An increasing number of intraductal papillary mucinous neoplasms of the pancreas have been reported in recent years. However, the clinicopathologic features and surgical outcome of this neoplasm are not fully understood because of the limited number of cases. The objective of this study is to clarify the clinicopathologic features of intraductal papillary mucinous neoplasm of the pancreas and evaluate prognostic factors influencing survival. METHODS: Eighty two patients with intraductal papillary mucinous neoplasm undergoing surgical resection at the National Cancer Center Hospital East between April 1994 and October 2006 were retrospectively analyzed. RESULTS: There were 31 patients with adenoma and 51 patients with carcinoma. Carcinomas were subdivided into noninvasive carcinoma (n = 14), minimally invasive carcinoma (n = 6), and invasive carcinoma (n = 31). The postoperative mortality rate was 0%. The 5-year survival rate for patients with intraductal papillary mucinous adenoma, noninvasive carcinoma, minimally invasive carcinoma, and invasive carcinoma was 80%, 78%, 83%, and 24%, respectively. Regardless of the margin status, no patient with adenoma developed recurrent disease. There were significant differences in survival between noninvasive carcinoma and invasive carcinoma (P = .016) and between minimally invasive carcinoma and invasive carcinoma (P = .030). Multivariate analysis confirmed that lymph node metastasis (P = .004) and age (P = .015) were significant prognostic factors after surgical resection of these neoplasms. CONCLUSIONS: Patients with intraductal papillary mucinous adenoma, noninvasive carcinoma, and minimally invasive carcinoma showed favorable survival. In contrast, invasive intraductal papillary mucinous carcinoma was associated with poor survival regardless of the margin status. Nodal involvement was the strongest predictor of poor survival. PMID- 17694417 TI - Compensation in academic medicine: progress toward gender equity. AB - BACKGROUND: Studies have documented substantial salary disparities between women and men in academic medicine. While various strategies have been proposed to increase equity, to our knowledge, no interventions have been evaluated. OBJECTIVE: This paper aims to assess the effect of an identity-conscious intervention on salary equity. DESIGN: This study shows comparison of adjusted annual salaries for women and men before and after an intervention. PARTICIPANTS/SETTING: We studied full time faculty employed in FY00 (n = 393) and FY04 (n = 462) in one College of Medicine. INTERVENTION: Compensation data were obtained from personnel databases for women and men, and adjusted for predictors. After verification of data accuracy by departments, comparable individuals within the same department who had different salaries were identified. The Dean discussed apparent disparities with department heads, and salaries were adjusted. MEASUREMENTS: Total adjusted annualized salaries were compared for men and women for the year the project began and the year after the intervention using multivariate models. Female faculty members' salaries were also considered as a percent of male faculty members' salaries. RESULTS: Twenty-one potential salary disparities were identified. Eight women received equity adjustments to their salaries, with the average increase being $17,323. Adjusted salaries for women as a percent of salary for men increased from 89.4% before the intervention to 93.5% after the intervention. Disparities in compensation were no longer significant in FY2004 in basic science departments, where women were paid 97.6% of what men were paid. CONCLUSIONS: This study shows that gender disparities in compensation can be reduced through careful documentation, identification of comparable individuals paid different salaries, and commitment from leadership to hold the appropriate person accountable. PMID- 17694418 TI - Analysis of anal sphincter preservation rate according to tumor level and neoadjuvant chemoradiotherapy in rectal cancer patients. AB - The anal sphincter preservation rate (ASPR) according to tumor level and neoadjuvant chemoradiotherpy (CRT) has not been fully evaluated. Therefore, the aim of this study was to evaluate the correlation between the tumor level, neoadjuvant CRT, and the ASPR in rectal cancer patients. We studied 544 patients (tumor level, 0-6 cm) who underwent curative resection for rectal cancer between 1991 and 2005. Patients were divided six into groups according to tumor level over 1-cm intervals, and the ASPR was evaluated in patients with and without neoadjuvant CRT according to tumor level. Sphincter preservation surgery was performed in 191 patients, and 86 patents underwent neoadjuvant CRT. The overall ASPR was 43.0% (37/86) in patients with neoadjuvant CRT and 33.6% (154/458) in patients without neoadjuvant CRT (P=0.094). In an analysis according to tumor level, the ASPR was 0.0 vs 0.0% in 10 pancreatic resections annually. OBJECTIVE: To evaluate the extent of regionalization of pancreatic resection and the factors predicting resection at high-volume centers (>10 cases/year) in Texas. METHODS: Using the Texas Hospital Inpatient Discharge Public Use Data File, we evaluated trends in the percentage of patients undergoing pancreatic resection at high-volume centers (>10 cases/year) from 1999 to 2004 and determined the factors that independently predicted resection at high-volume centers. RESULTS: A total of 3,189 pancreatic resections were performed in the state of Texas. The unadjusted in-hospital mortality was higher at low-volume centers (7.4%) compared to high-volume centers (3.0%). Patients resected at high-volume centers increased from 54.5% in 1999 to 63.3% in 2004 (P = 0.0004). This was the result of a decrease in resections performed at centers doing less than five resections/year (35.5% to 26.0%). In a multivariate analysis, patients who were >75 (OR = 0.51), female (OR = 0.86), Hispanic (OR = 0.58), having emergent surgery (OR = 0.39), diagnosed with periampullary cancer (OR = 0.68), and living >75 mi from a high-volume center (OR = 0.93 per 10-mi increase in distance, P < 0.05 for all OR) were less likely to be resected at high-volume centers. The odds of being resected at a high-volume center increased 6% per year. CONCLUSIONS: Whereas regionalization of pancreatic resection at high-volume centers in the state of Texas has improved slightly over time, 37% of patients continue to undergo pancreatic resection at low-volume centers, with more than 25% occurring at centers doing less than five per year. There are obvious demographic disparities in the regionalization of care, but additional unmeasured barriers need to be identified. PMID- 17694421 TI - Chronic lymphocytic leukemia radiogenicity: a systematic review. AB - OBJECTIVE: Chronic lymphocytic leukemia (CLL) is generally considered to be non radiogenic and is excluded from several programs that compensate workers for illnesses resulting from occupational exposures. Questions about whether this exclusion is justified prompted a Congressional mandate to the National Institute for Occupational Safety and Health (NIOSH) to, further, examine the radiogenicity of CLL. This study revisits the question of CLL radiogenicity by examining epidemiologic evidence from occupationally and medically-exposed populations. METHODS: A systematic review of radiation-exposed cohorts was conducted to investigate the association between radiation and CLL. Exploratory power calculations for a pooled occupational study were performed to examine the feasibility of assessing CLL radiogenicity epidemiologically. RESULTS: There is a bias against reporting CLL results, because of the disease's presumed non radiogenicity. In medical cohort studies that provide risk estimates for CLL, risk is elevated, though non-significantly, in almost all studies with more than 15 years average follow-up. The results of occupational studies are less consistent. CONCLUSIONS: Studies with adequate follow-up time and power are needed to better understand CLL radiogenicity. Power analyses show that a pooled study might detect risk on the order of radiation induced non-CLL leukemia, but is unlikely to detect smaller risks. PMID- 17694420 TI - IL6 genotypes and colon and rectal cancer. AB - Inflammation appears to play a key role in the development of colorectal cancer (CRC). In this study we examine factors involved in the regulation of inflammation and risk of CRC. Data from a multi-center case-control study of colon (N = 1579 cases and N = 1977 controls) and rectal (N = 794 cases and N = 1005 controls) cancer were used to evaluate the association between the rs1800795 and rs1800796 IL6 polymorphisms and CRC. We evaluated the joint effects of IL6 single nucleotide polymorphisms and regular use of aspirin/NSAIDs and vitamin D receptor (VDR) genotype. Having a C allele of the rs1800796 IL6 polymorphisms and the GG genotype of the rs1800795 IL6 polymorphisms was associated with a statistically significantly reduced the risk of colon (OR 0.76 95% CI 0.57, 1.00), but not rectal (OR 1.49 95% CI 1.02,2.16) cancer. Both IL6 polymorphisms were associated with significant interaction with current use of aspirin/NSAIDs to alter risk of colon cancer: individuals with a C allele in either polymorphism who were current users of aspirin/NSAIDs had the lowest colon cancer risk. CRC risk also was associated with an interaction between VDR and IL6 genotypes that was modified by current use of aspirin/NSAIDs. This study provides further support for inflammation-related factors in the etiology of CRC. Other studies are needed to explore other genes in this and other inflammation-related pathways. PMID- 17694422 TI - Diet and risk of multiple myeloma in Connecticut women. AB - Multiple myeloma accounts for an estimated 19,900 incident cancer cases per year in the United States. A population-based case-control study, consisting of 179 incident cases and 691 controls, was conducted to examine the impact of diet on multiple myeloma risk. Diet was assessed using a food frequency questionnaire and odds ratios, 95% confidence intervals, and P-trends were calculated across quartiles of consumption. After controlling for potential confounders, we observed inverse associations for cooked tomatoes (P-trend = 0.002), cruciferous vegetables (P-trend = 0.01), fresh fish (P-trend < 0.001), alcohol (P-trend < 0.001), and vitamin A (P-trend < 0.001) with multiple myeloma risk. In contrast, consumption of cream soups (P-trend = 0.01), jello (P-trend = 0.01), ice cream (P trend = 0.01), and pudding (P-trend < 0.001) were positively associated with multiple myeloma. Furthermore, there was a suggestion that carbohydrate intake may be positively associated, whereas vitamin D and calcium intake may be inversely associated, with multiple myeloma risk. Despite very limited data on dietary factors in relation to multiple myeloma, the findings from this study concur with previously published studies, suggesting an inverse association for consumption of fish, cruciferous vegetables and green vegetables, and a positive association for some dairy products. PMID- 17694423 TI - Soil contamination of heavy metals in the Katedan Industrial Development Area, Hyderabad, India. AB - Studies on quantitative soil contamination due to heavy metals were carried out in Katedan Industrial Development Area (KIDA), south of Hyderabad, Andhra Pradesh, India under the Indo-Norwegian Institutional Cooperation Programme. The study area falls under a semi-arid type of climate and consists of granites and pegmatite of igneous origin belonging to the Archaean age. There are about 300 industries dealing with dyeing, edible oil production, battery manufacturing, metal plating, chemicals, etc. Most of the industries discharge their untreated effluents either on open land or into ditches. Solid waste from industries is randomly dumped along roads and open grounds. Soil samples were collected throughout the industrial area and from downstream residential areas and were analysed by X-ray Fluorescence Spectrometer for fourteen trace metals and ten major oxides. The analytical data shows very high concentrations of lead, chromium, nickel, zinc, arsenic and cadmium through out the industrial area. The random dumping of hazardous waste in the industrial area could be the main cause of the soil contamination spreading by rainwater and wind. In the residential areas the local dumping is expected to be the main source as it is difficult to foresee that rain and wind can transport the contaminants from the industrial area. If emission to air by the smokestacks is significant, this may contribute to considerable spreading of contaminants like As, Cd and Pb throughout the area. A comparison of the results with the Canadian Soil Quality Guidelines (SQGL) show that most of the industrial area is heavily contaminated by As, Pb and Zn and local areas by Cr, Cu and Ni. The residential area is also contaminated by As and some small areas by Cr, Cu, Pb and Zn. The Cd contamination is detected over large area but it is not exceeding the SQGL value. Natural background values of As and Cr exceed the SQGL values and contribute significantly to the contamination in the residential area. However, the availability is considerably less than anthropogenic contaminants and must therefore be assessed differently. The pre- and post-monsoon sampling over two hydrological cycles in 2002 and 2003 indicate that the As, Cd and Pb contaminants are more mobile and may expect to reach the groundwater. The other contaminants seem to be much more stable. The contamination is especially serious in the industrial area as it is housing a large permanent residing population. The study not only aims at determining the natural background levels of trace elements as a guide for future pollution monitoring but also focuses on the pollution vulnerability of the watershed. A plan of action for remediation is recommended. PMID- 17694424 TI - Increasing cognitive load to facilitate lie detection: the benefit of recalling an event in reverse order. AB - In two experiments, we tested the hypotheses that (a) the difference between liars and truth tellers will be greater when interviewees report their stories in reverse order than in chronological order, and (b) instructing interviewees to recall their stories in reverse order will facilitate detecting deception. In Experiment 1, 80 mock suspects told the truth or lied about a staged event and did or did not report their stories in reverse order. The reverse order interviews contained many more cues to deceit than the control interviews. In Experiment 2, 55 police officers watched a selection of the videotaped interviews of Experiment 1 and made veracity judgements. Requesting suspects to convey their stories in reverse order improved police observers' ability to detect deception and did not result in a response bias. PMID- 17694425 TI - Urban and rural differences in pregnancy weight gain in Guilan, northern Iran. AB - OBJECTIVES: This study aimed to compare pregnancy weight gain and weight gain patterns in a group of Iranian women who attended urban and rural public health centers for prenatal care in Guilan, Iran. DESIGN: A secondary data analysis using routinely collected health centers data. SETTING: 12 randomly selected health centers in urban and rural areas in Guilan. PARTICIPANTS: A total of 2,047 pregnant women (1,097 in urban areas and 950 in rural areas) who regularly attended health centers for prenatal care and delivered between June 2003 and August 2006. MEASUREMENTS: Data on prepregnancy weight, height, pregnancy weight gain, mother's age, parity, education and infant birth weight were extracted from the health records. The women were categorized based on their prepregnancy body mass index as underweight, normal weight and overweight. FINDINGS: These results showed that among normal weight women, 41.1% of urban and 56.6% of rural women had weight gains below the Institute of Medicine (IOM) recommendation (P<0.0001). Among underweight women, 48.1% of urban and 65.8% of rural women had weight gains below the IOM recommendation (P<0.0001). Rural women with normal prepregnancy weight gained less weight than the urban women in the second trimester of their pregnancy (5.7+/-2.9 kg vs. 4.6+/-2.5 kg, P<0.0001). The underweight rural women gained less weight in both the second and the third trimesters of their pregnancy than the urban women. While the overall prevalence of having low birth weight (LBW) infants for underweight women were 5.2% only 1.9 % of those who gained adequate pregnancy weight gain had LBW infants. CONCLUSION: This study indicated that a considerable proportion of the women both in urban and rural areas in Guilan, Iran had inadequate pregnancy weight gain. These results showed that prenatal care in terms of pregnancy weight gain in the present health system is not satisfactory. PMID- 17694426 TI - Heterogeneity within Asian subgroups: a comparison of birthweight between infants of US and non-US born Asian Indian and Chinese mothers. AB - OBJECTIVES: Birthweight distributions and proportions of low birthweight (LBW) are commonly used to assess the health of populations. However, the "population" is difficult to define due to differences by race, socioeconomic status, age distribution, and cultural identity. This study analyzes birth outcomes in two Asian subgroups to examine variation within the Asian population. METHODS: Analysis of the 1998-2003 National Center for Health Statistics' natality file for 293,211 singleton births in Asian Indian and Chinese mothers compared birthweight distributions, mean birthweights, proportions of very low birthweight (VLBW) and moderately low birthweight (MLBW) infants, and the influence of maternal nativity on these outcomes. A multiple logistic regression analysis, stratified by maternal nativity, was done to control for established confounders of maternal age, marital status, education, and parity. RESULTS: Maternal characteristics and birthweight distributions varied by race subgroup and nativity. Infants of Asian Indian mothers had a lower mean birthweight and higher proportions of VLBW and MLBW than Chinese. After controlling for differences in maternal characteristics, infants of US born Asian Indian mothers were more likely to be VLBW (AOR 1.87, 95% CI: 1.27-2.75) or MLBW (AOR 1.59, 1.39-1.82) than infants of US born Chinese mothers. Similarly, infants of non-US born Asian Indian mothers were more likely to be VLBW (AOR 2.13, 2.06-2.21) or MLBW (AOR 2.26, 2.18-2.35) then infants of non-US born Chinese mothers. CONCLUSIONS: Our study demonstrates variation in birth outcomes by maternal race and nativity in two Asian subgroups. The heterogeneity within a single commonly used "population" is likely not limited to these two Asian subgroups, but is probably applicable to many populations in the United States. Analyses should try to account for these differences to ensure a more accurate representation of various populations in the US. The difficulty of defining a population by race adds to the complexity of examining disparities in birth outcomes. PMID- 17694427 TI - The plight of older persons as caregivers to people infected/affected by HIV/AIDS: evidence from Uganda. AB - This paper describes the challenges faced by elderly persons (50 years and above) in Uganda, as parents and/or relatives of persons infected by HIV and as caregivers of the infected relatives and their uninfected children. Little is known regarding these indirect impacts of HIV/AIDS on the elderly in sub-Saharan Africa. Yet, the elderly are most often the main caregivers of HIV-infected persons and their families. Data used in this study were obtained from focus group discussions and in-depth interviews conducted among elderly respondents in 10 rural and urban communities within two Ugandan districts, Luwero and Kamuli. Findings indicate that the elderly do provide care to patients with AIDS at the terminal stage of the illness-when patients most need constant care. In most cases, the challenge of caring for the sick patients is compounded by the responsibility to care for the children affected by HIV/AIDS, which also starts when their parents are still living, not when the children become orphans. This demanding work was reported to negatively affect the elderly in various dimensions (economic, emotional, physical, and nutritional), all of which impacts their health and well-being. The responsibility for day-to-day patient care is borne primarily by elderly females, who reported a higher rate of physical ailments than male respondents-perhaps an indication of their disproportionate contribution to the care responsibilities. Most of the elderly respondents interviewed have a lot of anxiety about their future health and well-being, which they attributed in most part to the HIV/AIDS epidemic. These challenges do appear to exacerbate the aging process of the elderly whose health and well-being are already affected by the poor resource base and weak health infrastructure in this setting. PMID- 17694429 TI - Estimating HIV prevalence and risk behaviors of transgender persons in the United States: a systematic review. AB - Transgender populations in the United States have been impacted by the HIV/AIDS epidemic. This systematic review estimates the prevalence of HIV infection and risk behaviors of transgender persons. Comprehensive searches of the US-based HIV behavioral prevention literature identified 29 studies focusing on male-to-female (MTF) transgender women; five of these studies also reported data on female-to male (FTM) transgender men. Using meta-analytic approaches, prevalence rates were estimated by synthesizing weighted means. Meta-analytic findings indicated that 27.7% (95% confidence interval [CI], 24.8-30.6%) of MTFs tested positive for HIV infection (four studies), while 11.8% (95% CI, 10.5-13.2%) of MTFs self-reported being HIV-seropositive (18 studies). Higher HIV infection rates were found among African-American MTFs regardless of assessment method (56.3% test result; 30.8% self-report). Large percentages of MTFs (range, 27-48%) reported engaging in risky behaviors (e.g., unprotected receptive anal intercourse, multiple casual partners, sex work). Prevalence rates of HIV and risk behaviors were low among FTMs. Contextual factors potentially related to increased HIV risk include mental health concerns, physical abuse, social isolation, economic marginalization, and unmet transgender-specific healthcare needs. Additional research is needed to explain the causes of HIV risk behavior of transgender persons. These findings should be considered when developing and adapting prevention interventions for transgender populations. PMID- 17694428 TI - Herpes simplex virus protein UL11 but not UL51 is associated with lipid rafts. AB - The UL11 and UL51 gene products of herpes simplex virus (HSV) are membrane associated tegument proteins that are incorporated into the HSV virion. UL11 and UL51 are conserved throughout the herpesvirus family. Both UL11 and UL51, either singly or in combination, are involved in virion envelopment and/or egress. Both proteins are fatty acylated: UL11 is both acylated by myristoic and palmitoic acids and UL51 is monoacylated by palmitoic acid. Using confocal microscopy and sucrose gradient fractionations in transfected or HSV-infected cells, we found that HSV-2 UL11 but not UL51 was associated with lipid rafts. The dual acylation of UL11 was necessary for lipid raft association, as mutations in the myristoylation or palmitoylation sites prevented lipid raft association. These differences in lipid raft association may contribute to the functional differences between UL11 and UL51. PMID- 17694430 TI - Human immunodeficiency virus infection and associated factors among specific population subgroups in Cameroon. AB - The objective of this study was to identify factors associated with HIV infection among specific population subgroups and complement the HIV surveillance system in Cameroon. Five subgroups (truck drivers, female-sex-workers, university students, health service providers, and residents along Chad-Cameroon petroleum pipeline) were targeted in 2004. Potential participants were approached at their geographically diverse areas and consented to participate in the study. Anonymous blood samples were collected. 4,011 participants were surveyed (35% students, 25% sex-workers, 20% pipeline residents, 12.5% health service providers, 7.5% truck drivers). HIV prevalence was highest among sex-workers [26.4%, (95% CI, 23.6 29.2)], pipeline residents [19.9% (95% CI, 17.1-22.7)] and truck drivers [16.3% (95% CI, 12.3-20.9)] and lowest among health service providers [5.2% (95% CI, 3.4 7.5)] and university students [3.8% (95% CI, 2.9-5.0)]. Risky sexual behaviours were practiced in all subpopulations. Multivariable analysis shows in female-sex workers that; older age, residing in the grassland region (Northwest and West Provinces) and inconstant condom use were significantly associated with HIV infection. Despite a moderate HIV prevalence in the general Cameroonian population, some subgroups are at much higher risk for HIV transmission and practicing risky sexual behaviours. There is need for expanded prevention and care programs with emphasis on truck drivers, sex-workers and pipeline residents. PMID- 17694431 TI - Behavioral studies of female sex workers in China: a literature review and recommendation for future research. AB - Commercial sex plays a critical role in the heterosexual transmission of HIV in China. This study reviews behavioral studies in English literature on female sex workers (FSWs) in China from 1990 to 2006. Existing studies indicate that FSWs in China are young, mobile, most of them have both commercial and non-commercial sex partners; they have low rates of consistent condom use and high rates of STD infection. Some FSWs are also engaged in drug abuse. There is a great variation of sexual practices and HIV risks among FSWs across different work settings. Limited numbers of intervention studies have reported positive effects on increasing condom use and/or decreasing STD infections. Literature gaps and lessons learned from existing studies are identified and future research needs are discussed. Future behavioral intervention programs need to be multi-faceted and incorporate environmental and structural factors for different groups of FSWs. PMID- 17694432 TI - Should a statin be prescribed to every patient with heart failure? AB - Chronic heart failure (HF) represents an emerging epidemic since its prevalence is continuously increasing despite advances in treatment. Many recent clinical studies have clearly demonstrated that statin therapy is associated with improved outcomes in HF irrespective of aetiology (ischaemic or not) or baseline cholesterol levels. Indeed, most of the conducted large statin trials and trials in HF have demonstrated a positive effect of statins in HF patients. Furthermore, the use of statins in HF seems to be safe as none of the recent trials has resulted in worse outcomes for HF patients treated with statins. Potential mechanisms through which statins could benefit the failing myocardium include non sterol effects of statins, as well as effects on nitric oxide and endothelial function, inflammation and adhesion molecules, apoptosis and myocardial remodelling and neurohormonal activation. This review discusses the pathophysiological basis of statin effects on HF and focuses on clinical data for the benefit from statin use in this setting. Until today there are no official recommendations in both the American and the European guidelines regarding the use of statins in HF patients, as the available data come from small observational or larger but retrospective, non-randomised studies. Therefore, HF patients should be treated according to current lipid guidelines. Large randomised clinical trials are underway and will further delineate the role of statin therapy in HF patients. Until more data are available, we could not recommend statin use to every patient with HF irrespective of HF aetiology and baseline cholesterol levels. PMID- 17694433 TI - Differentiation decreased telomerase activity in rat glioblastoma C6 cells and increased sensitivity to IFN-gamma and taxol for apoptosis. AB - Glioblastoma is the deadliest and most prevalent brain tumor, which is not yet amenable to any treatments. Therefore, new and innovative therapeutic strategies need to be developed for treating this deadly disease. We found that all-trans retinoic acid (ATRA) or 13-cis retinoic acid (13-CRA) induced astrocytic differentiation with down regulation of telomerase activity in rat glioblastoma C6 cells and enhanced sensitivity of the cells to interferon-gamma (IFN-gamma) or taxol (TXL) for apoptosis. Sensitivity of differentiated cells to IFN-gamma or TXL was greatly increased for apoptosis with increases in calcineurin expression, Bax:Bcl-2 ratio, mitochondrial release of cytochrome c, and expression and activity of calpain and caspases. Treatment with IFN-gamma activated caspase-8 indicating induction of apoptosis via the receptor-mediated pathway. Notably, IFN gamma activated the signal transducer and activator of transcription-1 (STAT-1) for signaling via binding to gamma activator sequence (GAS), whereas TXL activated Raf-1 kinase for inactivation of Bcl-2 by its phosphorylation. We confirmed involvement of different proteolytic mechanisms in cell death by pretreating the cells with caspase-8 inhibitor II, calpeptin (calpain inhibitor), and caspase-9 inhibitor I, and caspase-3 inhibitor IV. Results demonstrated that retinoids induced astrocytic differentiation with down regulation of telomerase activity and worked synergistically to enhance sensitivity of cells to the cytotoxic agent IFN-gamma and the cytostatic agent TXL for apoptosis. This combination therapy for differentiation and apoptosis could be highly effective for controlling the malignant growth of glioblastoma. PMID- 17694434 TI - Functional consequences of iron overload in catecholaminergic interactions: the Youdim factor. AB - The influence of postnatal iron overload upon implications of the functional and interactive role of dopaminergic and noradrenergic pathways that contribute to the expressions of movement disorder and psychotic behaviours in mice was studied in a series of experiments. (1) Postnatal iron overload at doses of 7.5 mg/kg (administered on Days 10-12 post partum) and above, invariably induced a behavioural syndrome consisting of an initial (1st 20-40 min of a 60-min test session) hypoactivity followed by a later (final 20 min of a 60-min test session) hyperactivity, when the mice were tested at adult ages (age 60 days or more). (2) Following postnatal iron overload, subchronic treatment with the neuroleptic compounds, clozapine and haloperidol, dose-dependently reversed the initial hypoactivity and later hyperactivity induced by the metal. Furthermore, DA D(2) receptor supersensitivity (as assessed using the apomorphine-induced behaviour test) was directly and positively correlated with iron concentrations in the basal ganglia. (3) Brain noradrenaline (NA) denervation, using the selective NA neurotoxin, DSP4, prior to administration of the selective DA neurotoxin, MPTP, exacerbated both the functional (hypokinesia) and neurochemical (DA depletion) effects of the latter neurotoxin. Treatment with L-Dopa restored motor activity only in the animals that had not undergone NA denervation. These findings suggest an essential neonatal iron overload, termed "the Youdim factor", directing a DA NA interactive component in co-morbid disorders of nigrostriatal-limbic brain regions. PMID- 17694435 TI - Swiss psychiatrists beliefs and attitudes about cannabis risks in psychiatric patients: ideologically determined or evidence-based? AB - The objective of this survey was to assess the beliefs of Swiss psychiatrists about the risks associated with cannabis, and to assess their prohibitive attitudes toward their patients. Eighty-two doctors agreed to fill-up the questionnaire. Cluster analysis retained a 3-cluster solution. Cluster 1: "Prohibitionists" believed that cannabis could induce and trigger all forms of psychiatric disorder, and showed a highly prohibitive attitude. Cluster 2: "Causalists" believed that schizophrenia, but not other psychiatric disorders, could be induced and triggered. Cluster 3: "Prudent liberals" did not believe that psychiatric disorders could be induced by cannabis, and were generally less prohibitive. PMID- 17694437 TI - Issues encountered in a qualitative secondary analysis of help-seeking in the prodrome to psychosis. AB - Primary data are rarely used explicitly as a source of data outside of the original research purpose for which they were collected. As a result, qualitative secondary analysis (QSA) has been described as an "invisible enterprise" for which there is a "notable silence" amongst the qualitative research community. In this paper, we report on the methodological implications of conducting a secondary analysis of qualitative data focusing on parents' narratives of help seeking activities in the prodrome to psychosis. We review the literature on QSA, highlighting the main characteristics of the approach, and discuss issues and challenges encountered in conducting a secondary analysis. We conclude with some thoughts on the implications for conducting a QSA in children's mental health services and research. PMID- 17694438 TI - The Fas/Fas-ligand pathway does not mediate the apoptosis in elastase-induced emphysema in mice. AB - Porcine pancreatic elastase (PPE), which induces emphysema via apoptosis, was administered to wild-type and Fas-deficient (lpr) mice. On days 3 and 28 after administration, the mean linear intercepts within lung tissues were significantly higher in PPE-treated wild-type and lpr mice than in control mice, though there were no significant differences between the PPE-treated groups. Likewise, the numbers of TUNEL-positive cells were increased in the lungs of PPE-treated wild type and lpr mice, and again the effect was similar in the two PPE-treated groups. These findings suggest that apoptosis associated with PPE-induced emphysema is not mediated via the Fas/Fas-ligand pathway. PMID- 17694436 TI - Neurocognitive effects of methamphetamine: a critical review and meta-analysis. AB - This review provides a critical analysis of the central nervous system effects of acute and chronic methamphetamine (MA) use, which is linked to numerous adverse psychosocial, neuropsychiatric, and medical problems. A meta-analysis of the neuropsychological effects of MA abuse/dependence revealed broadly medium effect sizes, showing deficits in episodic memory, executive functions, information processing speed, motor skills, language, and visuoconstructional abilities. The neuropsychological deficits associated with MA abuse/dependence are interpreted with regard to their possible neural mechanisms, most notably MA-associated frontostriatal neurotoxicity. In addition, potential explanatory factors are considered, including demographics (e.g., gender), MA use characteristics (e.g., duration of abstinence), and the influence of common psychiatric (e.g., other substance-related disorders) and neuromedical (e.g., HIV infection) comorbidities. Finally, these findings are discussed with respect to their potential contribution to the clinical management of persons with MA abuse/dependence. PMID- 17694439 TI - Microsatellite analysis of induced sputum DNA in patients with lung cancer in heavy smokers and in healthy subjects. AB - Abnormality in the fragile histidine triade (FHIT), a candidate tumor suppressor gene located in chromosome region 3 (3p14.2), has been frequently found in multiple tumor types, including lung cancer. In this study, the authors assessed the consistency of DNA microsatellite analysis of induced sputum (IS), as compared to that of blood and plasma. They also evaluated the loss of heterozigosity (LOH) and microsatellite instability (MSI) in 3 different loci, D3S1300, D3S1313, and D3S1234, all internal to the FHIT gene, in IS, blood, and plasma from patients with lung cancer, smokers, and healthy subjects. Eighteen patients with lung cancer (3 females, age mean +/- SD: 63 +/- 7 years), 39 smokers (23 females, age mean +/- SD: 57 +/- 6 years and cigarette pack-years mean +/- SD: 34 +/- 12), and 22 healthy nonsmoking subjects (13 females, age mean +/- SD: 63 +/- 5 years) were studied. DNA was extracted from blood, plasma, and IS, by means of a standard method. Analysis of LOH and MSI were performed using a fluorescent polymerase chain reaction (PCR)-based approach, followed by capillary electrophoresis. The ratios between the peak heights (phs), expressed as random fluorescence units, from plasma/blood (p/b) and induced sputum/blood (is/b) in all three loci were considered. The biases (agreement limits) between the mean ph ratio from p/b and is/b of D3S1300, D3S1313, and D3S1234 were respectively 0.07 ( 0.39 to 0.53), 0.016 (- 0.32 to 0.35), - 0.10 (- 0.51 to 0.30) in the patients; 0.04 (- 0.52 to 0.43), - 0.06 (- 0.31 to 0.18), - 0.08 (- 0.48 to 0.30) in smokers; and - 0.11 (- 0.40 to 0.17), - 0.05 (- 0.53 to 0.43), - 0.09 (- 0.51 to 0.33) in healthy subjects. LOH and MSI in at least one locus were observed in 55% of patients, in 18% of smokers, and in 4.5% of healthy subjects (P < 0.001). These results showed that IS DNA provided data that were consistent with those from blood and plasma. These findings highlight new prospects for early tumor detection by a noninvasive technique based on the analysis of genetic alterations in induced sputum. PMID- 17694440 TI - Platelet-derived growth factor, transforming growth factor-beta, and connective tissue growth factor in a porcine bronchial model of obliterative bronchiolitis. AB - The expression of platelet-derived growth factor (PDGF), transforming growth factor (TGF)-beta, and connective tissue growth factor (CTGF) and the effect of imatinib, an agent inhibiting PDGF receptors, were assessed in a porcine bronchial transplantation model of obliterative bronchiolitis (OB). Up-regulation of PDGF-A, PDGF receptors alpha and beta, and TGF-beta expression occurred in allografts, whereas PDGF-B and CTGF expression was similar in allo- and autografts. Imatinib modified the inflammatory responses and expression patterns of PDGF-A and PDGF receptors. This study further confirms PDGF and TGF-beta as mediators of OB and supports the concept of the importance of the pathways signaled through PDGF receptors in post-transplant OB. PMID- 17694441 TI - Characterization of pulmonary cell growth parameters in a continuous perfusion microfluidic environment. AB - In vitro models of the alveolo-pulmonary barrier consist of microvascular endothelial cells and alveolar epithelial cells cultured on opposing sides of synthetic porous membranes. However, these simple models do not reflect the physiological microenvironment of pulmonary cells, wherein cells are exposed to a complex milieu of mechanical and soluble stimuli. In this report, we studied alveolar epithelial (A549) and microvascular endothelial (HMEC-1) cells within varying microfluidic environments as a first step towards building a microfluidic analog of the gas-exchange interface. We fabricated polydimethylsiloxane (PDMS) microdevices for parallel studies of cell growth under multiple flow rates. Cells adhered and proliferated in the microculture chambers for shear stresses up to approximately 2 x 10(-3) dynes/cm(2), corresponding to media turnover rates of approximately 53 seconds. Proliferation of these cells into confluent monolayers and expression of cell-specific markers (SP-A and CD-31) demonstrated successful pulmonary cell culture in microscale devices, a first for alveolar epithelial cells. These results represent the initial steps towards the development of microfluidic analogs of the alveolo-pulmonary barrier and tissue engineering of the lung. PMID- 17694442 TI - Evaluation of preventive and control measures for lead exposure in a South African lead-acid battery recycling smelter. AB - In South Africa, new lead regulations released in February 2002 served as motivation for a cross-sectional study investigating the effectiveness of preventive and control measures implemented in a lead smelter that recycles lead acid batteries. Twenty-two workers were observed and interviewed. Structured questionnaires were used to gather workers' personal information, perception about their work environment, health risks, and work practices. Retrospective data from air monitoring and medical surveillance programs were obtained from the plant's records. The smelter implemented a number of control measures for lead exposure, including engineering controls, administrative controls, and, as a last resort, personal protective equipment. Engineering controls were rated the best control measure and included local exhaust ventilation systems and wet methods. Positive pressure systems were used in the offices and laboratory. The local exhaust ventilation system was rated the best engineering control measure. Although control measures were used, areas such as smelting and refinery had average lead in air levels above 0.15 mg/m(3), the occupational exposure limit for lead. This was a concern especially with regard to the smelting area because those workers had the second highest mean blood lead levels; workers in the battery breaking area had the highest. Regular use of personal protective equipment by some workers in the "lead exposure zones" was not observed. Although the mean blood lead levels had been below 40 micro g/dL for more than 90% of the workers since 2001, more than 70% of workers reported concerns about their health while working in the smelter. Even though control measures were implemented, they were not adequate because in some areas lead in air exceeded the occupational exposure limit. Therefore, improvement of existing measures and regular monitoring of personal protective equipment use were included in the recommendations given to the smelter. PMID- 17694443 TI - Monoclonal antibodies: why look at anything else? PMID- 17694444 TI - Recombinant bispecific antibodies for cellular cancer immunotherapy. AB - Bispecific antibodies recognizing two different antigens present on different cells have been developed for cellular cancer therapy in which cytotoxic effector cells are recruited to tumor cells. Initial studies with bispecific antibodies have not reached satisfactory clinical endpoints, mainly due to low efficacy, Fc mediated side effects and immunogenicity. This has resulted in a declining interest in bispecific antibodies for cancer therapy. However, growing knowledge in effector cell biology and the implementation of antibody engineering technologies has led to a revival and the development of novel or improved strategies. Various recombinant bispecific antibodies have demonstrated efficacy in vitro andin vivo, with the first recombinant antibody molecule currently in clinical trials for the treatment of B-cell malignancies. PMID- 17694445 TI - Nanobodies in therapeutic applications. AB - Over the years, many antibodies have been successfully generated to treat patients with life-threatening diseases, most notably cancer. While the first generation of antibodies, originating from mice, caused severe side effects and were relatively inefficient, technological advances have made it possible to obtain fully human antibodies for therapeutic use. 'Heavy-chain only' antibodies have recently been discovered in the blood of camelids. Because of their size, the antigen-binding units of these antibodies comprising only a single Ig fold are called Nanobodies. These antibody fragments have several remarkable features that make them ideal candidates as next-generation cancer therapeutics. Particularly appealing is their ability to simultaneously inhibit various crucial growth factor receptors or their ligands with a single molecule. In addition, they are easy to clone and express on the tip of filamentous phage, which opens the possibility to select for Nanobodies inducing particular biological effects. Nanobodies have potential to become important cancer therapeutics in the near future, displaying unequalled and unprecedented efficacies in treatment. PMID- 17694446 TI - Anticalins as alternative binding proteins for therapeutic use. AB - Members of the human lipocalin protein family exhibit four structurally hypervariable loops that form a ligand pocket, similar to the six complementarity determining regions of antibodies. Using targeted random mutagenesis and selection, novel binding proteins, the so-called anticalins, have been engineered for the specific and tight complexation of low-molecular weight compounds as well as protein antigens, in particular medically relevant cell-surface targets. Based on recent in vitro and in vivo data, anticalins offer three mechanisms for application in human therapy: (i) as antagonists, for example, by binding to cellular receptors and blocking them from interaction with natural signaling molecules; (ii) as tissue-targeting vehicles, by localizing toxic molecules, cytokines or enzymes to disease-related cell-surface receptors; and (iii) as antidotes, by rapidly scavenging toxic or otherwise irritant compounds from the body. Compared with antibodies, anticalins provide several practical advantages because they are much smaller, consist of a single polypeptide chain, do not require disulfide bonds, and can easily be produced in microbial host cells. PMID- 17694447 TI - Nonviral in vivo delivery of therapeutic small interfering RNAs. AB - Since its discovery in the late 1990s, RNA interference (RNAi) has gained much attention as a powerful strategy for silencing activity. Instrumental for this naturally occurring targeting mechanism is the intracellular presence of a target gene-specific small interfering RNA (siRNA). Therefore, the in vivo delivery of highly specific siRNA molecules represents one major goal in the further development of RNAi-based approaches for clinical applications. For the non-viral delivery of siRNAs, except for local or topical administration, various routes of application and delivery vehicles/strategies have been explored so far, including the systemic injection of pure, unmodified or chemically modified siRNAs, physical methods such as hydrodynamic injection or electropulsation, encapsulation of siRNAs in liposomes, lipoplexes or cationic lipids, formation of nanoplexes through complexation of siRNAs in cationic or other carriers, or chemical coupling of siRNAs to specific carrier molecules. Therefore, approaches to establish the clinical application of RNAi may rely on a combination of biosciences and nanotechnology; in particular, for the identification of optimal siRNAs against optimal target molecules, and the development of sophisticated delivery systems. PMID- 17694448 TI - Treating HIV-1 infection with dendritic cells. AB - The orchestration of a coordinated immune response by dendritic cells (DCs) make them an attractive target for pathogens to exploit to evade host immunity, as well as for use in therapeutic strategies to overcome this exploitation. Because HIV-1 infection is predominantly a disease of the immune system, targeting DCs for therapeutic strategies to counter the effects of HIV-1 on DCs and other immune effector cells is a timely and extremely dynamic endeavor. Our knowledge of DC function and the interaction between HIV-1 and DCs is rapidly increasing. This review focuses on HIV-1-DC interactions, the impact of these on DC therapeutics for the treatment of HIV-1-infected individuals and the current status of DC-based therapeutic vaccines for HIV-1 infection. PMID- 17694449 TI - Anti-proteinuric effects of glycosaminoglycan-based drugs. AB - Heparan sulfate (HS) is a member of the family of glycosaminoglycans (GAGs) that is generally bound to a core protein to form a proteoglycan (PG). HSPGs may be cell-membrane associated (glypicans and syndecans) or located within the extracellular matrix (agrin, perlecan and type XVIII collagen). The sulfate and carboxylic groups in HS are responsible for the negative charge of the sugar chain. HS is abundantly present in the filter unit of the kidney, especially in the glomerular basement membrane (GBM), and is assumed to repel negatively charged proteins, including albumin, thereby preventing their filtration. Alterations in HS expression in the GBM have been reported in a number of renal pathologies, including diabetic nephropathy, minimal change nephropathy and membranous glomerulopathy.A decreased HS expression in the GBM generally correlates with an increase in the level of proteinuria. Progressive proteinuria may result in end-stage renal failure when untreated. Based on these findings, GAG-based drugs have been used to treat proteinuria and some, notably sulodexide, have shown beneficial effects. The biosynthesis of HS and its possible role in renal filtration are discussed, an overview of GAG-based drugs and their effect on proteinuria is provided, and possible mechanisms by which GAG-based drugs ameliorate proteinuria are discussed. PMID- 17694450 TI - Current approaches in the transcriptional-guided gene therapy of human hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC), the predominant histological subtype of primary human liver cancer, is one of the most prevalent cancer types worldwide, accounting for an estimated 500,000 deaths annually. The clinical management of HCC is challenging on many counts. HCC is a phenotypically and genetically heterogeneous polyclonal disease and is resistant to most conventional chemotherapy. Early manifestation of HCC is characteristically silent and slow growing with few symptoms, and HCC is therefore often diagnosed at an advanced stage, when potentially curative surgical or local ablative therapy is not feasible. Therefore, clinically validated biomarkers that could confer pathological and functional changes associated with the formation and progression of HCC are urgently needed to provide important molecular basis for the development of novel treatments. Recently, comprehensive molecular gene profiling of primary liver cancer tissues has been employed to identify specific genes that are linked to hepatocarcinogenesis. Current attempts to translate molecular knowledge to design strategies for the experimental gene therapy of HCC are reviewed. PMID- 17694451 TI - Hsp-based tumor vaccines: state-of-the-art and future directions. AB - Hsp-based tumor vaccines, autologous tumor-derived Hsp-peptide complexes, have been applied to cancer immunotherapy for the treatment of cancer patients with a variety of advanced malignancies. Data from clinical trials, including those from phase III, have so far demonstrated that the immunization strategy can induce significant tumor-specific immune responses. Some improved clinical outcomes have also been observed but the clinical utility of this strategy awaits further investigations. In addition, preclinical studies have been conducted to design a variety of novel Hsp-based tumor vaccines with improved therapeutic potentials. These approaches include development of Hsp fusion proteins and genetic vaccines using plasmid DNA and adenoviruses. Successful cancer immunotherapy with Hsp based tumor vaccines will depend on the results obtained from both clinical trials and preclinical studies. PMID- 17694452 TI - Therapeutic cloning: status and prospects. AB - Embryonic stem cells (ESCs) offer a new and remarkable potential for treating and curing a wide range of genetic diseases such as diabetes and muscular dystrophy, degenerative diseases such as Parkinson's disease, renal disease and heart disease, and traumatic injury such as spinal cord injury. Therapeutic cloning, wherein patient-specific ESCs can be derived from pre-implantation stage embryos produced by somatic cell nuclear transfer, constitutes one approach of obtaining histocompatible cells for engraftment. Recent improvements in the production of cloned embryos in non-human primate models, combined with advances in the ability to establish human ESC lines and direct their differentiation along specific pathways support the notion that therapeutic cloning may soon be feasible. This review summarizes the status and current feasibility of the approach and the technical hurdles that must be addressed, and discusses the ethical issues that have arisen as a result. PMID- 17694453 TI - MBP-8298, a synthetic peptide analog of myelin basic protein for the treatment of multiple sclerosis. AB - BioMS Medical Corp, under license from the University of Alberta, is developing MBP-8298, a synthetic peptide analog of myelin basic protein, for the potential treatment of multiple sclerosis. Phase II and III clinical trials of MBP-8298 are underway. PMID- 17694454 TI - Linaclotide, a new direction in the treatment of irritable bowel syndrome and chronic constipation. AB - Microbia Inc is developing the oral guanylate cyclase C agonist linaclotide, a 14mer peptide for the potential treatment of constipation-predominant irritable bowel syndrome and chronic idiopathic constipation. Phase II clinical trials are underway for both indications. PMID- 17694456 TI - Atrial fibrillation characteristics in patients with ischaemic stroke. AB - BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia and an important risk factor for ischaemic stroke (IS). AIM: To assess the frequency of AF, including paroxysmal (pxAF), persistent (psAF) and permanent AF (pmAF), in patients hospitalised due to IS as well as to establish the natural course of AF and IS prognosis. METHODS: A prospective, non-interventional study of consecutive acute stroke patients with AF with a 6-month follow-up. A favourable stroke outcome was defined when a patient survived or had no disabling stroke during follow-up. RESULTS: Within 24 months of recruitment, 838 patients were hospitalised due to IS or transient ischaemic attack. Concomitant AF was diagnosed in 200 (24.4%) of these patients. Permanent AF was observed in 108 (54%), pxAF in 70 (35%), psAF in 9 (4.5%), and AF of unknown duration in 13 (6.5%) patients. Mean age, demographics and concomitant treatment did not differ significantly among groups. The pxAF patients had less often a disabling stroke on admission (81 and 91 vs. 50%, p <0.001) and discharge (55 and 31 vs. 19%, p <0.001) than pmAF and psAF patients, respectively. In-hospital (13 and 9 vs. 3%, p <0.001) and 6-month mortality rates (35 and 40 vs. 14%, p <0.001) were also significantly higher in pmAF and psAF patients than in the pxAF group. Lack of chronic anticoagulation tended to be a risk factor for death (OR 2.1, 95% CI 0.8-5.1, p=0.09). In 20 (66%) patients with pxAF who experienced recurrence of spontaneous AF during hospitalisation, a successful pharmacological cardioversion was performed, whereas in 10 (34%) patients sinus rhythm was not restored. Restoration of sinus rhythm was a risk factor for unfavourable stroke outcome in the 6-month observation period (OR 2.14; 95% CI 1.07-4.29; p=0.03). During the study 29 (40%) patients with pxAF experienced at least one AF recurrence, and 20 (29%) developed psAF. Transformation of psAF to pmAF was observed in 8 (36%) patients. Disabling stroke on admission was a risk factor (OR 4.5, 95% CI 0.9-22.9, p=0.05) for transformation of pxAF to pmAF. CONCLUSION: Atrial fibrillation was present in 24.4% of acute IS patients. Paroxysmal AF was diagnosed in 35%, pmAF in 54% and psAF in 11% of patients. During follow-up 29% of pxAF progressed to psAF and 36% psAF to pmAF. In-hospital and 6-month mortality rates and the number of patients with disabling stroke were significantly lower in pxAF than in pmAF and psAF patients. A trend towards unfavourable outcome was observed among patients not receiving chronic anticoagulation. PMID- 17694457 TI - Femoral rather than carotid artery ultrasound imaging predicts extent and severity of coronary artery disease. AB - BACKGROUND: Pathological, epidemiological and clinical studies indicate that there is coexistence between peripheral vascular disease and coronary artery disease (CAD). B-mode ultrasound of superficial arteries is a non-invasive, valid and reproducible method of directly visualising and assessing carotid and femoral intima-media thickness (IMT) and focal atherosclerosis. AIM: To evaluate the prognostic importance of carotid and femoral vascular changes in predicting CAD severity. METHODS: 410 patients--300 (73.2%) males and 110 (26.8%) females--aged 29-75 years (mean age 55.9+/-9.5 years), referred for elective coronary arteriography, were studied. Clinical examination and laboratory tests were performed, and ultrasound assessments of IMT and atherosclerotic plaque thickness in the common carotid arteries and common femoral arteries were evaluated. RESULTS: Coronary angiography revealed CAD in 81% of patients (85% of males, 70% of females). Cox multiple hazards regression analyses showed a significant relationship between size of atherosclerotic plaques in peripheral arteries and CAD. Odds ratio of CAD associated with every 1-mm plaque thickening ranged from 1.7 to 3.0 (p <0.001) depending on examined artery. Using multiple stepwise regression analysis, the following parameters were found to be independent predictors of one-vessel CAD: myocardial infarction (MI) in anamnesis (OR=22.3; 95% CI 4.0-122.9), typical chest pain (OR=6.4; 95% CI 1.2-34.2), femoral IMT (OR=5.0; 95% CI 1.4-18.4), ex-smoking (OR=5.6; 95% CI 1.1-28.7), and pulse pressure (OR=1.8; 95% CI 1.0-3.2). Independent predictors of multi-vessel CAD were: MI (OR=3.7; 95% CI 1.8-7.5), typical angina (OR=3.3; 95% CI 1.7-6.5), age (OR=1.05; 95% CI 1.01-1.08), number of cigarettes smoked (OR=0.8; 95% CI 0.6 0.9), total cholesterol level (OR=1.1; 95% CI 1.0-1.2), and left femoral plaque thickness (OR=1.4; 95% CI 1.0-2.0). CONCLUSION: Femoral IMT is an independent predictor of a single-vessel disease, whereas femoral atherosclerotic plaque presence indicates advanced CAD. PMID- 17694458 TI - Patients with non-ST-elevation myocardial infarction and without chest pain are treated less aggressively and experience higher in-hospital mortality. AB - BACKGROUND: Lack of chest pain or atypical pain does not exclude acute coronary syndrome (ACS). AIM: To assess demographic and clinical characteristic as well as treatment strategies in patients with atypical chest pain on admission in hospitals without on-site invasive facility (IF). METHODS: Twenty-nine community hospitals participated in the Registry of Acute Coronary Syndromes. A total of 2382 patients with ACS were enrolled. Patients admitted to hospitals with suspected ACS were stratified according to their pain symptoms as either typical (TS) or atypical which also included lack of pain (ATS). RESULTS: Of all patients with initial ACS diagnosis 152 (6.4%) presented without chest pain on admission. Patients from group ATS in comparison to group TS were more often women (49 vs. 39%; p=0.01), and less frequently had past medical history of coronary artery disease (54.3 vs. 72.5%; p <0.0001), myocardial infarction (15.2 vs. 32.1%; p <0.0001), arterial hypertension (65.6 vs. 74.5; p <0.0001) or renal insufficiency (1.3 vs. 5%; p=0.04). Invasive treatment was undertaken in 9.2% of patients from group ATS and in 14.6% from group TS (p=0.049). In-hospital mortality among all patients remaining in community hospitals for conservative treatment was similar in both groups (ATS vs. TS: 8.7 vs. 5.9%; p=NS). Among patients with typical and atypical symptoms the occurrence of ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina (UA) was similar. Patients with NSTEMI and UA with atypical symptoms were less likely transferred for invasive diagnostic, for NSTEMI 9.4 vs. 18.1% (p=0.03) and for UA 6.1 vs. 12.9% (p=0.04). In-hospital mortality was similar among typical and atypical groups in STEMI and UA patients. However, it was significantly higher among NSTEMI patients with atypical chest pain treated conservatively (3.6 vs. 0%; p=0.05). CONCLUSIONS: There is a significant group of ACS patients without chest pain on admission who are usually women with less severe past medical history. This subset of patients is treated less aggressively in terms of antiplatelet therapy and invasive approach. It is patients with diagnosis of NSTEMI who due to being misdiagnosed due to their atypical chest pain have poorer outcome. PMID- 17694459 TI - Haemorheological factors and myocardial reperfusion in patients with ST-elevation myocardial infarction undergoing primary coronary intervention. AB - INTRODUCTION: The no-reperfusion phenomenon occurs in a considerable number of patients despite restoration of the infarct-related artery (IRA) patency. Factors responsible for this phenomenon include myocardial structural changes, whereas haemorheological parameters that significantly contribute to microvascular resistance, have not been studied so far. AIM: To determine the possible relationship between blood and plasma viscosity, red blood cell aggregation and their deformability, and myocardial reperfusion following effective mechanical intervention of IRA. METHODS: The analysis included 23 patients with myocardial infarction treated with primary coronary angioplasty with resultant TIMI (Thrombolysis in Myocardial Infarction) grade 3 flow. Myocardial reperfusion was found effective if myocardial perfusion grade (MPG) was 3. Blood and plasma viscosity were assessed using a Brookfield rotation viscometer. Red blood cell aggregation and deformability were measured with a Laser Optical Rotational Cell Analyzer (LORCA). Patients were divided into two groups with respect to obtained MPG: reperfusion group (14 subjects) and no-reperfusion group (9 patients). RESULTS: Corrected whole blood viscosity and plasma viscosity were significantly higher in the no-reperfusion group and exceeded the values obtained in the reperfused patients by 14% (p <0.05) and 10.5% (p <0.01), respectively. Red blood cell deformability index at shear stress ranging from 1.75 Pa to 60.03 Pa was significantly lower in the no-reperfusion group. Red blood cell aggregation index was significantly higher (by 14.3%, p <0.05), whereas aggregation halftime was significantly shorter (by 58%, p <0.05) in the no-reperfusion group. CONCLUSIONS: Our results indicate that haemorheological disturbances may be an important factor contributing to no-reperfusion after effective mechanical opening of IRA. PMID- 17694460 TI - TIMI Risk Score accurately predicts risk of death in 30-day and one-year follow up in STEMI patients treated with primary percutaneous coronary interventions. AB - BACKGROUND: TIMI Risk Score for ST-elevation myocardial infarction (STEMI) was developed in a cohort of patients treated with fibrinolysis. It was though to predict in-hospital and short-term prognosis. Later studies validated this approach in large cohorts of patients, regardless of the applied treatment and presented its good power to predict 30-day mortality. AIM: We applied the TIMI Risk Score to our registry of STEMI patients treated with primary percutaneous intervention (pPCI) to validate the possibility to predict one-year survival. METHODS: Our registry comprised 494 consecutive patients (mean age 58.5+/-11.3 years) with STEMI treated with pPCI who were followed for approximately one year. STEMI was diagnosed based on typical criteria: chest pain, ECG changes and rise in myocardial necrosis markers. In all patients TIMI Risk Score for STEMI was calculated and they were divided into three groups: low risk (0-5 points), medium risk (6-7) and high risk (>7 points). Multivariate logistic regression analysis, Kaplan-Meier survival analysis with Cox and log-rank tests as well as c statistics from receiver-operator curves (ROC) were used for statistical analysis. RESULTS: TIMI 3 flow was obtained in 95.5% of patients. Median TIMI risk score was 4 (ranging from 0 to 10). During follow-up there were 47 deaths (9.5%). There was a statistically significant difference in survival between all risk groups both in 30-day and one-year follow-up (p <0.001 log-rank test). TIMI Risk Score had good power to predict 30-day (c statistic 0.834, 95% CI 0.757 0.91, p <0.0001) as well as one-year mortality (c statistic 0.809, 95% CI 0.739 0.878, p <0.0001). Interestingly, when we excluded from the analysis all patients who died during the first 30 days, TIMI Risk score maintained its very good prognostic value. All analysed risk groups significantly differed between each other with respect to mortality (p <0.05, log-rank test) and the c statistic was 0.745 (95% CI 0.612-0.879, p <0.0002). In multivariate logistic regression analysis TIMI Risk Score was one of the independent risk factors of death during one-year follow-up (OR 1.59, p <0.001). CONCLUSIONS: TIMI Risk Score accurately defines the population of STEMI patients who are at high risk of death not only during the first 30 days, but also during a long-term follow-up. This simple score should be included in the discharge letters because it contains very useful information for further care. PMID- 17694461 TI - Nitroglycerin infusion after percutaneous coronary intervention does not influence short- and long-term outcome--a prospective NAPI (Nitroglycerin Administration after Percutaneous Intervention) study. AB - BACKGROUND: Although the benefit of nitroglycerin infusion in patients after elective coronary angioplasty has not been established, this regimen is routinely used in some centres. AIM: The Nitroglycerin Administration after Percutaneous Intervention (NAPI) study tested the efficacy of routine nitroglycerin infusion on the 1st day after percutaneous coronary intervention (PCI) in a double-blind randomised single-centre clinical trial. METHODS: We randomly assigned 200 patients scheduled for elective PCI to treatment with nitroglycerin (100 patients, age 58+/-6 years, infusion up to 100 microg/min) or placebo (100 patients, age 57+/-5 years, p=NS, NaCl 0.9%) for 12 hours after PCI. Patients with acute myocardial infarction, haemodynamic instability during PCI and known intolerance to nitrates were excluded. Patients who were randomised to the placebo group had the possibility to receive nitroglycerin infusion according to the attending physician's decision. Clinical endpoints (cardiac death, myocardial infarction, postprocedural chest pain, unstable angina and repeated PCI) were assessed in hospital and out of hospital with follow-up extended to 24 months. RESULTS: There were no differences during in-hospital stay between those receiving nitroglycerin and receiving placebo, regarding mortality (0 vs. 0%, NS), myocardial infarction (0 vs. 2%, NS), postprocedural chest pain (10 vs. 8%, NS) or repeated PCI (0 vs. 2%, NS). Similarly, 24-month follow-up also revealed no significant differences between those receiving nitroglycerin and placebo (mortality: 0 vs. 0%, NS; myocardial infarction: 4 vs. 4%, NS; repeated PCI: 10 vs. 8%, NS or CABG: 0 vs. 0%, NS). CONCLUSIONS: Routine use of intravenous nitroglycerin after elective PCI has no influence on in-hospital and long-term outcome, including cardiac death, myocardial infarction, postprocedural chest pain, unstable angina and repeated PCI. PMID- 17694462 TI - [Exudative pericarditis due to secondary kidney amyloidosis--a case report]. AB - Non-infective pericarditis in some cases may be caused by secondary amyloidosis. Amyloidosis is a metabolic disorder in which amyloid protein is deposited in various organs and destroys them. The most frequent location of systemic amyloidosis are the kidneys. In this case study we report a 74-year-old man who was admitted to hospital due to very poor condition, generalised oedema and severe dyspnoea. Since 2003 the patient had been hospitalised many times due to pericarditis of unknown aetiology. In this case we diagnosed exudative pericarditis due to nephrotic syndrome caused by secondary kidney amyloidosis which occurs very rarely. PMID- 17694463 TI - [Suspected clopidogrel resistance associated with recurrent coronary stent thrombosis--a case report]. AB - We describe a case of an 81-year-old man with acute ST-elevation myocardial infarction (STEMI), who received a loading dose of clopidogrel (300 mg) and aspirin (ASA) (300 mg) prior to primary coronary intervention of critical left anterior descending coronary artery stenosis. Three days later he developed recurrent acute STEMI due to the in-stent thrombosis and a second stent implantation was performed. The dose of clopidogrel (75 mg) remained unchanged, while the dose of ASA was increased from 75 mg to 150 mg. Three days later the patient had an other STEMI due to the in-stent thrombosis and additional stent implantation with IIb/IIIa blocker was performed. Clopidogrel resistance was suspected. Therefore, clopidogrel was replaced by ticlopidine, the dose of ASA was increased and low-molecular heparin was administered. Since then, the patient has been clinically stable. Our case indicates the existence of a subgroup of patients with combined clopidogrel and ASA resistance. PMID- 17694464 TI - [Coronary artery bypass grafting in a patient after percutaneous left main angioplasty with DES stent implantation]. AB - We present surgical treatment of acute coronary syndrome due to the left main stenosis in a patient in whom 6 months earlier percutaneous left main angioplasty with DES-stent implantation was performed. We discuss indications for percutaneous angioplasty and for coronary artery bypass grafting in patients with left main stenosis. PMID- 17694465 TI - From Ludwik Fleck's leukergy to the present-day rheology of leukocytes in heart and vascular diseases. PMID- 17694466 TI - [Slow coronary flow phenomenon]. PMID- 17694467 TI - [Rosiglitazone--under fire]. PMID- 17694468 TI - [Atrial tachycardia or atrial flutter]. PMID- 17694469 TI - [Thrombus entrapped in the foramen ovale in an 80-year-old woman with chronic pulmonary embolism manifested by recurrent syncope--a case report]. AB - We present a case of an 80-year-old female admitted to hospital because of recurrent syncope. The echocardiogram revealed a large thrombus in the left and right atria, entrapped in the patent foramen ovale, right heart enlargement and pulmonary hypertension. Magnetic resonance confirmed significant pulmonary embolism. The patient was successfully treated with fractioned heparin. PMID- 17694470 TI - [Stent rupture with subsequent balloon catheter failure and entrapment under stent during elective angioplasty at the right coronary artery]. PMID- 17694471 TI - [Atrioventricular nodal reentrant tachycardia triggering atrial fibrillation--a case report]. AB - We describe a case of an otherwise healthy 50-year-old man with frequent attacks of heart palpitations. During electrophysiological study two episodes of atrial fibrillation (AF) were induced. In both cases AF was preceded by a few seconds of atrioventricular nodal reentrant tachycardia (AVNRT). Ablation of atrioventricular node slow pathway successfully eliminated both tachyarrhythmias during 6 months follow-up. Since during AVNRT a few short coupled atrial ectopic beats appeared, we hypothesized that AVNRT did not trigger AF directly but by inducing ectopic beats form a pulmonary vein or an atrial focus that became a direct trigger of AF. PMID- 17694472 TI - [Treatment of cardiogenic shock in acute coronary syndrome. Do logistics follow logic?]. PMID- 17694473 TI - Improvement of insulin sensitivity in obese Zucker rats by myricetin extracted from Abelmoschus moschatus. AB - In an attempt to develop new substances for treating insulin resistance, obese Zucker rats were employed to screen the effect of myricetin, an active principle of Abelmoschus moschatus (Malvaceae), on insulin resistance. Myricetin purified from the aerial portion of the plant was administered intravenously ( I. V.) into animals. A dose-dependent decrease in the plasma glucose concentration of obese Zucker rats was observed 30 min following an I. V. injection. Moreover, repeated I. V. injection of myricetin (1 mg/kg) into obese Zucker rats 3 times daily for 1 week reduced the value of the glucose-insulin index, an index of insulin resistance calculated from the areas under the curve of glucose and insulin during the intraperitoneal glucose tolerance test. Additionally, repeated myricetin treatments overturned the inability of insulin to increase the expression of glucose transporter subtype 4 (GLUT 4) and to increase the protein levels and phosphorylation of insulin receptor substrate-1 (IRS-1) in soleus muscle of these obese rats. The inability of insulin to increase expression of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase) and to promote Akt serine phosphorylation in soleus muscle of these rats were also overturned by repeated myricetin treatments. These findings indicate that myricetin improves insulin sensitivity through increased post-receptor insulin signaling mediated by enhancements in IRS-1-associated PI3-kinase and GLUT 4 activity in muscles of obese Zucker rats. Myricetin might be used as a model substance for the development of antidiabetic compounds. PMID- 17694474 TI - Changes in cortical volume with olanzapine in chronic schizophrenia. AB - INTRODUCTION: Atypical antipsychotics can affect cortical volume differently from traditional drugs. The study of the outcome of grey matter deficits in schizophrenia with olanzapine may be of particular interest in this context. METHODS: In this study, we evaluated the changes in the volume of gray matter in the cortex of 11 schizophrenic patients treated with olanzapine and in 11 healthy controls after three years of follow-up. After MR imaging, acquisition data were processed with a volumetric quantification method based on the Talairach atlas. The longitudinal change of volumetric data was corrected for differences in overall brain size. RESULTS: Patients showed greater reduction than controls in cortical volume in the frontal and parietal regions during follow-up. No relationship was observed between clinical and volumetric changes. CONCLUSION: Our data suggest that the profile of action of olanzapine on the cortical volume of chronically ill patients may be similar to that of typical antipsychotics. Other explanations, however, cannot be completely discarded for that outcome with our data. PMID- 17694475 TI - Sexual dysfunction in psychiatric inpatients the role of antipsychotic medication. AB - INTRODUCTION: Sexual dysfunction is a common side effect of antipsychotic medication. Although increased prolactin levels caused by antipsychotic agents are believed to play a major role with regard to sexual side effects, the underlying mechanism of antipsychotic agent-induced sexual dysfunction remains poorly understood. METHODS: In a multicentric study 587 psychiatric inpatients were assessed by means of a self-rating sexual questionnaire. Focussing on antipsychotic treatment three subgroups were drawn from the original sample. One group was treated with prolactin-increasing antipsychotics (n=119), the other with prolactin-neutral medication (n=109) and the third patient group was comprised of non-medicated clinical controls (n=105). RESULTS: The majority of all patients (50-75%) reported at least minor sexual dysfunction. On comparison of the subgroups, only female patients treated with prolactin-increasing medication reported more severe sexual dysfunction. However, multiple regression analysis did not confirm an association between the type of treatment and sexual impairment. DISCUSSION: Sexual dysfunction frequently occurs in psychiatric inpatients treated with antipsychotics. Our findings only partly support the assumptions concerning a major role of prolactin-increasing neuroleptics for medication-induced sexual impairment. PMID- 17694476 TI - Chronic paranoid psychosis and dementia following interferon-alpha treatment of hepatitis C: a case report. AB - Low-dose interferon-alpha is a standard therapy for hepatitis C. Psychotic disorders have been described as a rare complication of such treatments that resolve with its termination. Here, we present a patient without significant risk factors for interferon-alpha-induced serious mental disorders who developed a psychotic disorder with a cognitive impairment achieving the level of dementia after seven months of interferon-alpha therapy. The disturbances have persisted for three years despite cessation of interferon and introduction of antipsychotic treatment. The possibility of severe neuropsychiatric adverse effects of interferon-alpha therapy in a susceptible individual may necessitate regular psychiatric consultations during the treatment. PMID- 17694477 TI - Memantine-associated reversal of clozapine-induced weight gain. AB - INTRODUCTION: Weight gain is a frequently observed adverse event in the treatment with atypical antipsychotics that significantly affects the patients' physical health and treatment compliance. METHODS: We report on a treatment-resistant schizophrenic patient who received an add-on treatment with the low-affinity NMDA antagonist memantine because of cognitive disturbances. RESULTS: During this treatment we observed a marked decrease of clozapine-induced weight gain. The causal relationship to memantine could be demonstrated using an on-off-on design with a significant increase of weight after discontinuation and again a substantial weight loss after re-exposition with memantine. Beside weight, also negative symptoms improved. DISCUSSION: Prospective controlled trials evaluating the safety and possible positive effects of memantine on antipsychotic induced weight gain are needed. PMID- 17694478 TI - Improvement of quality of life in panic disorder with escitalopram, citalopram, or placebo. AB - BACKGROUND: It has been argued that measurement of outcome in panic disorder should not be limited to monitoring the number of panic attacks, but should include all domains that affect patient quality of life. METHODS: Data from a randomized prospective comparison of escitalopram, citalopram, and placebo in patients with DSM-IV panic disorder were analyzed with regard to measurements of impairment of quality of life. The subscales of the Panic and Agoraphobia Scale (P&A) (Panic Attacks, Agoraphobic Avoidance, Anticipatory Anxiety, Functional and Social Disability, and Worries about Health) and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) were analyzed. RESULTS: Treatment with escitalopram was associated with significant improvement on all 5 subscales of the P&A. Citalopram was significantly different from placebo in 3 subscales. Escitalopram and citalopram were significantly better than placebo in improving quality of life (measured by the total score of the Q-LES-Q Scale). Escitalopram was superior to placebo on 12 of 16 items of the Q-LES-Q, while citalopram was superior on 7 items. CONCLUSION: The P&A scale was more robust than measurement of panic frequency in differentiating medication from placebo. Escitalopram treatment was associated with improvement on all assessed domains that impair quality of life in panic disorder. Measurement of clinical improvement should not be solely based on panic attack frequency, but should also include assessment of a broad range of domains that affect patient quality of life. PMID- 17694479 TI - Marked hypofrontality in clozapine-responsive patients. AB - Previous data show that the effects of clozapine on regional brain activity are different from those of other antipsychotic agents. It seemed of interest to study the brain activity patterns after treatment with clozapine, since this drug might correct basal deficits directly related to schizophrenia or instead induce changes that would in some way compensate distant abnormalities. In order to study the activity pattern resulting from clozapine treatment we have used FDG PET and statistical parametric mapping (SPM) to explore the functional status of patients after chronic treatment with this drug, We compared their metabolic activity with normal controls and neuroleptic-naive (NN) patients, with the aim to identify if a reversion of pre-existing deficits or a induction of different changes was the result of clozapine administration. We compared metabolic patterns in 23 treatment-resistant (TR) patients after 6 months of treatment with clozapine, eighteen healthy subjects, and 17 NN schizophrenia patients. After treatment with clozapine, TR patients showed a clear hypofrontality and caudate hypometabolism in comparison with both the controls and NN patients, and also a lower thalamic activity than the healthy controls. In conclusion, our results support a preferential role for prefrontal regions and their subcortical connections in the mechanism of action of clozapine, resulting in a clearly hypofrontal state as compared to both controls and schizophrenia patients without previous treatment. PMID- 17694480 TI - Dose-response relationship of pregabalin in patients with generalized anxiety disorder. A pooled analysis of four placebo-controlled trials. AB - BACKGROUND: Pregabalin has been evaluated in randomised clinical trials in patients with generalised anxiety disorder (GAD) in a fixed-dose design and with the Hamilton Anxiety Scale (HAM-A) as outcome measure. Four of the available six placebo-controlled trials were found acceptable for a pooled analysis of dose response relationship. METHOD: Both the full HAM-A (14) and the six-item subscale covering the core items of GAD (HAM-A (6)) were analysed. The unbiased effect size statistic was used to evaluate the advantage of pregabalin over placebo. An effect size of 0.40 or higher was used to indicate a clinically significant effect. RESULTS: Four placebo-controlled trials running over four weeks and covering the dose range from 150 mg to 600 mg pregabalin were sufficiently homogeneous to be pooled for the analysis. Both HAM-A (6) and HAM-A (14) showed that for the dose of 150 mg pregabalin daily the effect size was clearly below 0.40. For the dose range of 200-450 mg daily, the effect sizes exceeded 0.40, with a plateau-like curve. The maximum dose of 600 mg daily did not increase effect size. On the HAM-A (14) as well as the item of sleep, effect size was generally higher, but followed the same pattern as the HAM-A (6). DISCUSSION: The dose of 150 mg pregabalin over the four weeks of the trials was found insufficient for the treatment of GAD. In the dose range of 200-450 mg daily, a clinically significant effect was obtained, although with a plateau-like curve which was not increased for the maximum dose of 600 mg daily. PMID- 17694481 TI - Hypomania induced by atypical antipsychotics among schizophrenic patients: report of three cases. AB - Induction of mania or hypomania related to the use of atypical antipsychotics among patients with no history of mood disorders has been previously reported. We reported the cases of three schizophrenic patients with no previous history of mood disorders (including no history of mania or hypomania episodes) who developed hypomania associated to the use of atypical antipsychotics. PMID- 17694482 TI - Electroconvulsive monotherapy in confusion psychosis: a potential standard regimen? AB - We report on the successful use of continuation electroconvulsive therapy (ECT) as prophylactic treatment of relapse in a case of confusion psychosis. The 20 year-old patient exacerbated in an almost annual rhythm and had been characterized as pharmacologically treatment-resistant since he failed to respond to any psychopharmacological therapy including sufficient clozapine as well as mood-stabilizing and sedating pharmacological treatments. After the diagnosis of confusion psychosis, the patient received ECT as monotherapy and showed a marked reduction of symptoms. Continuation ECT was then conducted for 7 months after the patient was discharged from hospital. Two years later, our patient is still in remission while continuation ECT has been tapered; no prophylactic psychotropic medication was prescribed in the last 2 years. Implications of this case on the therapy of confusion psychosis as well as on the diagnostic classification of confusion psychosis within our current systems are discussed. PMID- 17694483 TI - [Child and adolescent psychiatry: a profession and its identity II]. AB - BACKGROUND: Up till the 1970s child and adolescent psychiatry had no distinctive diagnostic system of its own. From the 1980s onwards qualitative information gathering (e.g. via discussion or play-situations) was no longer regarded as adequate and the standardised gathering of (quantitative) information became the cornerstone of the diagnostic process. This development fundamentally changed the child psychiatrist's profession and its identity. AIM: To investigate the specific features that are required in current child and adolescent psychiatry. METHOD: In this article we will clarify the change in the child psychiatrist's profession and identity by outlining how child an adolescent psychiatry evolved as from the early 1980s. We will do this by concentrating on the diagnostic process. The treatment aspect will be discussed only briefly. RESULTS: Over the last 25 years the role of the child psychiatrist has undoubtedly changed. From being mainly a diagnostician and/or being personally responsible for treating the child or adolescent the child psychiatrist has become increasingly the person who controls the diagnostic process and plans treatment. CONCLUSION: Over the last two decades the diagnostic technique of the child psychiatrist has developed in a new direction. The child psychiatrist has chosen instead to elucidate a patient's referral and to discuss the reasons for a request for assistance and/or care. The psychiatrist uses many types of information and a multitude of informants and methods. This development has led to a fundamental change in the child psychiatrist's profession and its identity. PMID- 17694484 TI - [The psychiatrist has to be supportive]. PMID- 17694485 TI - [Rational Rehabilitation in the treatment of post-traumatic stress disorder (PTSD). A pilot study]. AB - BACKGROUND: In a randomised controlled study, a type of cognitive behavior therapy known as Rational Rehabilitation proved effective in the treatment of patients with chronic mental symptoms. Post-traumatic stress disorder is a serious illness that occurs frequently and can last for many years. Rational Rehabilitation may also be an effective treatment for post-traumatic stress disorder. AIM: To investigate, via a pilot study, on the effect of Rational Rehabilitation in patients with post-traumatic stress disorder, whether a randomised controlled study is called for. METHOD: Nineteen patients with post traumatic stress disorder, who were awaiting regular treatment, opted to join the study. The effect of Rational Rehabilitation was studied in relation to: symptoms of post-traumatic stress disorder, degree of happiness experienced, autonomy, social support and need for further treatment. results Rational Rehabilitation seems to have a positive effect on all outcome measures, except flashbacks. CONCLUSION: A controlled study of the effect of Rational Rehabilitation in patients with post-traumatic stress disorder seems justified. PMID- 17694486 TI - [Aetiology of prolonged fatigue among workers. An overview of findings from the Maastricht Cohort Study]. AB - BACKGROUND: Considerable attention is being given to prolonged fatigue among workers because it occurs so frequently and is alleged to have serious consequences. AIM: To present an overview of the magnitude, causes and consequences of prolonged fatigue in the workplace with a view to preventing its occurrence. METHOD: On the basis of of the articles written as part of the Maastricht Cohort Study we present an overview of this study, a prospective cohort study (n=12,140) that covered a period of 4 years. results Prolonged fatigue seems to occur frequently among workers. Risk factors in the aetiology of prolonged fatigue were found in subjective and objective work-related factors, as well as in factors related to the health and private situation of the employee. CONCLUSION: The assumed multifactorial aetiology of prolonged fatigue was confirmed by means of prospective analyses in the Maastricht Cohort Study. The observed risk factors can be applied as tools for the development of effective preventive measures against prolonged fatigue. PMID- 17694487 TI - [Course, consequences and treatment of prolonged fatigue among workers: an overview of findings from the Maastricht Cohort Study]. AB - summary background Although prolonged fatigue is a common complaint among workers, relatively little is known about its course and consequences. AIM: To present an overview of the course, consequences and treatment of prolonged fatigue in the work force. METHOD: We present an overview of the findings from the Maastricht Cohort Study, which was a prospective cohort (n=12.140) that covered a period of 4 years. results Fatigue runs an unfavourable course. In many workers symptoms of fatigue are present for a long time, and in some workers the symptoms even develop into those of chronic fatigue syndrome. The consequences of prolonged fatigue are also serious and are manifested in various ways: sick leave, work disability, accidents, immunological effects and reduction in work participation. A brief cognitive behaviour therapy administered by general practitioners to employees with prolonged fatigue proved ineffective. CONCLUSION: The severe consequences of prolonged fatigue and the current lack of effective therapies underline the importance of preventing the development of fatigue complaints, for which the Maastricht Cohort Study may provide the basic tools. PMID- 17694488 TI - [Fatigue, myalgic encephalomyelitis/chronic fatigue syndrome and work]. PMID- 17694489 TI - [How can the results of primary-care treatment for depression be improved?]. AB - BACKGROUND: The results of treatment for depression are frequently disappointing. The main reasons for this are inadequate treatment and non-compliance. AIM: This article attempts to deal with the question of how patient compliance and the results of treatment for depression can be improved. METHOD: We performed a critical analysis of the literature. We searched Medline (1966- January 2002), psycinfo (1984-January 2002), Embase (1980-January 20002) and the Cochrane Controlled Trials Register (1966-Janaury 2002) for reports of randomised controlled trials. In our search we used the terms 'patient compliance', 'adherence', patient dropout', 'depression', 'depressive disorder', and 'affective disorder'. On the basis of the results of our search we compared two interventions that could be applied in Dutch practices. results We found 11 articles, all relating to treatment in primary care settings. Usual care proved to be inadequate. The quality of the usual care currently provided can be improved by extra interventions. So far there are no indications that complex interventions benefit the patient more than simple interventions, such as regular follow-up procedures. Therefore, for the time being, simple interventions are to be preferred. CONCLUSION: Treatment for depression can be improved by means of relatively simple interventions. PMID- 17694490 TI - [Do we really still need psychiatric case registers?]. AB - SUMMARY: A question frequently raised in the Netherlands is whether regional case registers have added value compared to national information systems. Research in regional case registers, however, has shown that they have added value based on longitudinal data-gathering, specialised knowledge of the region concerned and data-processing. Regional case registers reflect developments in the total range of services available (cure and care, including clinics to treat alcoholism and drug addiction). Case register research can also aim at developing outcome measures and creating links between mental health care and other health care areas. PMID- 17694491 TI - [Granulocytopenia while using clozapine: continuing or stopping treatment]. AB - BACKGROUND: This article describes four patients using clozapine, with neutropenia. Clozapine-induced neutropenia can be one of three types: pseudo, benign or malignant. The malignant type can give cause for serious concern; in that case treatment with clozapine must be stopped. Pseudo-neutropenia and benign neutropenia, however, occur frequently. In these cases it is probably unnecessary to stop clozapine medication, particularly if clozapine is clearly indicated. PMID- 17694492 TI - [Interactions of epilepsy and psychiatric problems: life-threatening situations]. AB - Epilepsy and psychiatric problems can occur simultaneously and can, quite unexpectedly, trigger interactions that may lead to life-threatening situations. This became obvious in the case of a female patient who suddenly developed a status epilepticus while admitted to hospital. The seizure was probably connected with secret self-induced vomiting which led to a low intake of antiepileptic medication. She used the vomiting to control emotionally charged post-traumatic intrusions. Both the vomiting and the number of seizures were triggered by a life event (in this case emigration). In case of epilepsy, early screening for psychopathology seems advisable because there may be interactions with epileptic variables. PMID- 17694493 TI - Labelling of the anti-III-neurotubulin monoclonal antibody by 99mTc and its binding to responsible antigen. AB - BACKGROUND: beta-III-neurotubulin is a characteristic degradation protein of cellular cytoskeleton of nervous tissues, which originates with disorders that lead to the loss of peripheral neurons or neurons of the central nervous system. For the diagnostics of neuropathic and neurodegenerative processes, beta-III neurotubulin is therefore the goal structure, and radioactive labelled antibody TU-20 (99m)Tc could theoretically enable diagnostic application in vivo. MATERIAL AND METHODS: In our case, were selected three ways of labelling monoclonal antibody IgG1-TU-20, which shows a high affinity towards beta-III-neurotubulin with (99m)Tc. The indirect labelling was ensured through the bifunctional chelator HYNIC, the direct labelling by electrolytic means, and the direct labelling of antibody TU-20 reduced by 2-mercaptoethanol. To observe each single feature, the appropriate chemical and biochemical control methods were used. Chemical purity was ensured by gel filtration and, together with chemical stability, it was checked by paper chromatography. To control the biological stability, SDS electrophoresis was used. The immunoreactivity was checked using ELISA-tests. RESULTS: The results have shown that the optimal method for labelling the antibody TU-20 is indirect labelling through the bifunctional chelator HYNIC, and the least effective method of labelling the antibody TU-20 is reduced by 2-mercaptoethanol. DISCUSSION: The results of labelling the monoclonal antibody towards antigen TU-20 with (99m)Tc confirmed that structure of the monoclonal antibody is destroyed by 2-mercaptoethanol, and in the case of electrolytic labelling, there are not enough binding places for radionuclide (99m)Tc on the monoclonal antibody. PMID- 17694494 TI - Production and tumour uptake of [64Cu]Pyruvaldehyde-bis (N4 methylthiosemicarbazone) for PET and/or therapeutic purposes. AB - BACKGROUND: Copper-64 (T(1/2)=12.7 degrees h) is an important radionuclide used both in PET imaging and therapy. [(64)Cu]-pyruvaldehyde- bis(N(4) methylthiosemicarbazone) ([64Cu]-PTSM) has already been used in the detection of cerebral and myocardial blood flow. In this study, a simple production method and tumor accumulation of [(64)Cu]-PTSM in fibrosarcoma-bearing mice were reported. MATERIAL AND METHODS: Cu-64 was produced via the 68Zn(p, alpha n)(64)Cu nuclear reaction. [(64)Cu]-PTSM was prepared using in-house made PTSM ligand and [(64)Cu]cuprous acetate and injected to fibrosarcoma-bearing mice. RESULTS: Copper-64 was prepared in chloride form ( approximately 200 mCi, > 95% chemical yield at 180 degrees microA for 1.1 h irradiation, radionuclidic purity > 96%, copper-67 as impurity). The solution of (64)Cu- PTSM was prepared in > 80% radiochemical yield and more than 98% radiochemical purity. A significant tumor uptake was observed 2 hours post injection in tumor-bearing mice (tumor/muscle: 9, tumor/blood: 6). CONCLUSION: [(64)Cu]-PTSM was prepared on a radiopharmaceutical scale using readily available zinc-68, with high quality and was shown to possess application in the therapy and/or imaging of fibrosarcoma. PMID- 17694495 TI - Utility of 18F-FDG PET and contrast-enhanced CT scan in the assessment of residual liver metastasis from colorectal cancer following adjuvant chemotherapy. AB - BACKGROUND: Neoadjuvant chemotherapy has been successfully used in the treatment of patients with colorectal liver metastases. The selection of patients for surgical resection after chemotherapy still poses a significant clinical challenge. (18)F-FDG PET is a useful tool in the assessment of liver metastases but the data regarding its sensitivity after chemotherapy is scarce. Our aim was to assess the value of this imaging modality in the selection of patients with colorectal liver metastasis for surgery following adjuvant chemotherapy. MATERIAL AND METHODS: We reviewed the diagnostic performances of (18)F-FDG PET and contrast-enhanced CT scan data from patients with colorectal liver metastases following treatment with chemotherapy. Nineteen patients (12 males, 7 females; median age 61 years; range 41-79) were evaluated. Chemotherapy regimens were: FOLFOX (14 patients), FOLFIRI (3 patients), 5-FU/FA (1 patient) and UFT irinotecan-oxaliplatin (1 patient). Median time between end of chemotherapy and CT scan was 3.4 weeks, between end of chemotherapy and PET was 5.9 weeks and between end of chemotherapy and surgery was 9.9 weeks. All patients underwent surgery and had histopathological confirmation of liver lesions. Nine patients had segmentectomy, 2 patients had wedge resection, 5 patients had right hepatectomy and 3 patients had explorative laparotomy with liver biopsies. RESULTS: Data from all 19 patients, comprising 65 liver lesions, were confirmed by histo-pathology. Results on a per-lesion basis showed a sensitivity of 62% for (18)F-FDG PET and 70% for CT scan. A complete agreement between (18)F-FDG PET or CT scan and histology was documented in 5 and 3 patients, respectively. The sensitivity of (18)F-FDG PET was shown to increase for lesions larger than 1 cm (74% vs. 18%). CONCLUSIONS: These results suggest that (18)F-FDG PET and CT scan have sub-optimal sensitivity in the evaluation of colorectal liver lesions after neo-adjuvant chemotherapy, especially for lesions < 1 cm. The combined use of the two imaging techniques does not significantly increase the sensitivity of lesion detection. PMID- 17694496 TI - Parametric clearance kidney scintigrams; diagnostic potential in diabetes. AB - BACKGROUND: The diagnostic usefulness of parametric clearance kidney images was studied in the early diagnosis of diabetic nephropathy, juxtaposed with conventional dynamic urinary investigation (renoscintigraphy) combined with deconvolution procedure of renal and blood time activity curves and determination of plasma clearance of (99m)Tc-ethylenedicysteine ((99m)Tc-EC). MATERIAL AND METHODS: The investigation was performed on a group of 70 individuals (41 males, 29 females) in whom diabetes type 1 was diagnosed (age 10 to 30 y.; mean 19 y.) and on a control group of 35 healthy individuals (15 males, 20 females) in the age-bracket of 18-25 years (mean 19 y.). In all subjects studied, renoscintigraphy was performed after administration of (99m)Tc-EC (activity 40 120 MBq) combined with determination of urinary clearance (ERPF) of the radiopharmaceutical. The renographic curves were evaluated taking into account their shape and individual share of each kidney, and the clearance function was calculated (RClr). From analysis of the time-activity, kidney curves T(max) and T(1/2) were assessed. In addition, the mean (99m)Tc-EC transport time through the complete kidney (MTT) and organ's parenchyma (PTT) were calculated from results of deconvolution of the curve. From the dynamic urinary system study, conventional images of radiopharmaceutical distribution in the kidneys in the secretion phase were obtained. The parametric clearance images were also computed on the basis of relative clearance values in all the pixels of both kidney regions of interest. The disturbances in kidney function were assessed separately by means of conventional scintigram analysis and of corresponding parametric images. A three-stage classification was used in both cases for the evaluation of abnormal findings in the kidneys RESULTS AND CONCLUSIONS: In all studied individuals, the (99m)Tc-EC (ERPF) clearance values were within the normal range. When renographic time activity curves were considered the flattening of the curves (III phase) was more frequent in diabetic individuals than in the controls (39.3% vs. 15.7%; p = 0.001). The shape of the curves in phases I and II were normal in all studied individuals of both groups. There were no differences observed between mean values of T(max), T(1/2) and PTT in diabetics and controls. However, mean MTT values were significantly higher in diabetics than in controls (p = 0.02). In conventional summation images (phase II of the renograms), there were no significant differences in frequency of defects in kidney parenchyma diabetics and controls (4.3% vs. 2.9%). In contrast, analysis of parametric kidney clearance images revealed that parenchyma defects were found with significantly greater frequency in diabetic individuals (35.7%) than in control subjects (8.6%; p < 0.001). Summarizing the findings, it appears that parametric clearance kidney images reveal local deviations of renal uptake and secretory function while conventional indicators of renal function are still in the normal range. This observation points to the fact that clearance parametric images may have potential value in the early diagnosis of diabetic nephropathy, and perhaps in other types of renal damage. Incorporation of parametric images into the dynamic study of the urinary system may be promising when early detection of kidney damage seems vital. PMID- 17694497 TI - Gallium citrate uptake is a marker of breast malignancy: true or false? AB - A 34-year old lady had a (67)Gallium citrate scan and demonstrated uptake by both of her breasts--diffuse in the right breast, but focal in the left breast at the "9 o'clock position". Core biopsy from both breasts showed fibroadenoma and no malignant cells were found. Though uptake of (67)Gallium citrate is normally associated with malignancy or infection there may be other causes of uptake and follow-up biopsy should be performed. PMID- 17694498 TI - FDG-PET detection of primary bone marrow large B-cell lymphoma in a patient with hairy cell leukemia. AB - We describe a case of hairy cell leukaemia (HCL) coexistent with non-Hodgkin's lymphoma (NHD). This combination is reported to be extremely rare with no clear demonstration of the clonal relationship between the two conditions. After a previous failure of purine analogue therapy, our patient was successfully treated with rituximab resulting in normalisation of blood cell count cessation of blood transfusion and negative iliac crest biopsy. Unfortunately, the patient developed intense and persistent bone pain during the 1(st) line treatment for HCL. Skeletal X-rays, neck-thorax-abdomen CT scan and repeated bone MRI were unremarkable and bone scintigraphy showed non-specific changes. Laboratory examinations were normal. To better evaluate bone scintigraphy results, we finally performed FDG-PET/CT, which showed multiple foci of intense abnormal radiotracer uptake involving the bone marrow. An FDG-PET/CT guided bone marrow biopsy showed primary bone marrow diffuse large B-cell lymphoma (LBCL). Despite 2(nd) and 3(rd) line treatment, the patient died shortly after for central nervous system involvement by NHD. The role of FDG-PET/CT in identifying bone and bone marrow localization of NHD is reviewed and an earlier use is suggested in poorly understood bone pain. PMID- 17694499 TI - Acrometastasis to the foot: an unusual presentation of transitional cell carcinoma of the bladder. AB - Metastases from bladder cancer to the bones of the hands or feet are rare and usually present after the diagnosis of the primary lesion has been made. This case report describes a 76-year-old man presenting with initial signs of infection of the right foot. Subsequent bone scan revealed multiple bony metastases and hydronephrosis raising the possibility of a primary bladder tumour that was later confirmed by urine cytology and fine needle aspiration of the foot. PMID- 17694500 TI - Cerebral hemodynamics and investigations of cerebral blood flow regulation. AB - To maintain adequate cerebral blood flow despite frequent changes in systemic arterial blood pressure and to constantly adjust blood supply to the current metabolic demand dictated by neuronal electrical activity, brain developed a myriad of mechanisms. These are designed to protect central nervous system from fatal consequences of hypoxia and energy deficit and are collectively called "cerebral autoregulation". Despite years of research mechanisms responsible for regulation of CBF functioning under physiologic and pathologic conditions are still not clear. When these mechanisms are damaged or exhausted, patients life is in danger, as even slight, negligible under normal conditions, systemic hemodynamic disturbances might lead to cerebral infarct. Even perfect imaging of the irreversible brain damage with MR for the particular patient is too late action. Thus, detection of cerebral blood flow disturbances and impaired autoregulation, which are known to be associated with high risk of stroke, are extremely important in clinical practice. Several methods have been developed to quantify this process and thus evaluate risk of cerebral ischemia and guide therapeutic process. This review focuses on current knowledge on physiology of regulation of cerebral blood flow, mechanisms responsible for brain damage resulted from cerebral ischemia and reviews noninvasive diagnostic tests to assess cerebral autoregulation. PMID- 17694503 TI - Low-energy collision-induced fragmentation of negative ions derived from ortho-, meta-, and para-hydroxyphenyl carbaldehydes, ketones, and related compounds. AB - Collision-induced dissociation (CID) mass spectra of anions derived from several hydroxyphenyl carbaldehydes and ketones were recorded and mechanistically rationalized. For example, the spectrum of m/z 121 ion of deprotonated ortho hydroxybenzaldehyde shows an intense peak at m/z 93 for a loss of carbon monoxide attributable to an ortho-effect mediated by a charge-directed heterolytic fragmentation mechanism. In contrast, the m/z 121 ion derived from meta and para isomers undergoes a charge-remote homolytic cleavage to eliminate an *H and form a distonic anion radical, which eventually loses CO to produce a peak at m/z 92. In fact, for the para isomer, this two-step homolytic mechanism is the most dominant fragmentation pathway. The spectrum of the meta isomer on the other hand, shows two predominant peaks at m/z 92 and 93 representing both homolytic and heterolytic fragmentations, respectively. (18)O-isotope-labeling studies confirmed that the oxygen in the CO molecule that is eliminated from the anion of meta-hydroxybenzaldehyde originates from either the aldehydic or the phenolic group. In contrast, anions of ortho-hydroxybenzaldehyde and 2-hydroxy-1 naphthaldehyde, both of which show two consecutive CO eliminations, specifically lose the carbonyl oxygen first, followed by that of the phenolic group. Anions from 2-hydroxyphenyl alkyl ketones lose a ketene by a hydrogen transfer predominantly from the alpha position. Interestingly, a very significant charge remote 1,4-elimination of a H(2) molecule was observed from the anion derived from 2,4-dihydroxybenzaldehyde. For this mechanism to operate, a labile hydrogen atom should be available on the hydroxyl group adjacent to the carbaldehyde functionality. PMID- 17694504 TI - Circulating advanced glycation end products (AGEs) and soluble form of receptor for AGEs (sRAGE) are independent determinants of serum monocyte chemoattractant protein-1 (MCP-1) levels in patients with type 2 diabetes. AB - BACKGROUND: Atherosclerosis is an inflammatory disease. Monocyte chemoattractant protein-1 (MCP-1) is an essential chemokine responsible for the recruitment of monocytes to inflammatory lesions in the vasculature, an initial step of atherosclerosis. Since serum levels of MCP-1 are higher in patients with type 2 diabetes, inhibition of MCP-1 may be a novel therapeutic target for prevention of accelerated atherosclerosis in diabetes. However, little is known about the regulation and determinants of serum MCP-1 levels in patients with diabetes. In this study, we examined the determinants of serum MCP-1 levels in type 2 diabetic patients. METHODS: Eighty-six consecutive outpatients with type 2 diabetes (36 male and 50 female; mean age 68.4+/-9.6) underwent a complete history and physical examination, determination of blood chemistries, MCP-1, tumour necrosis factor-alpha, adiponectin, advanced glycation end products (AGEs), and soluble form of receptor for AGEs (sRAGE). We examined the association between MCP-1 levels and those in anthropometric, metabolic and inflammatory variables in these subjects. RESULTS: Univariate regression analysis showed that serum levels of MCP 1 were positively associated with AGEs (r=0.386, p<0.001) and sRAGE (r=0.315, p<0.001). After adjusting for age and sex, AGEs (p<0.001) and sRAGE (p<0.05) still remained significant. CONCLUSION: The results demonstrate for the first time that circulating levels of AGEs and sRAGE are independent determinants of serum MCP-1 levels in patients with type 2 diabetes. Our present observations suggest the AGEs-RAGE system may be mainly involved in the elevation of MCP-1 in type 2 diabetic patients. PMID- 17694505 TI - Pramlintide reduced markers of oxidative stress in the postprandial period in patients with type 2 diabetes. AB - BACKGROUND: The production of oxidative stress as a result of postprandial hyperglycaemia is now recognized as an important contributing factor in the development of diabetes complications. The objective of this study was to examine the effects of pramlintide on plasma concentrations of glucose and several markers of oxidative stress in patients with type 2 diabetes following a standardized meal. METHODS: This was a randomized, single-blind, placebo controlled, crossover study conducted at two clinical research centres in the United States. A total of 19 subjects (9 men and 10 women) with type 2 diabetes using mealtime insulin participated in the study. Pramlintide (120 microg), or placebo, and rapid-acting mealtime insulin were administered prior to a standardized meal on two separate study days. Plasma concentrations of glucose, nitrotyrosine (NT), oxidized-LDL cholesterol (OxLDL-C), and total radical trapping parameter (TRAP) were assessed during the 4-h postprandial period. RESULTS: Compared to placebo, pramlintide treatment reduced postprandial excursions of glucose, NT, and OxLDL-C and protected TRAP from consumption. Correlation analysis revealed positive associations between placebo-corrected glucose incremental AUC(0-4 h) and both NT and OxLDL-C and a negative association between placebo-corrected glucose incremental AUC(0-4h) and TRAP. CONCLUSIONS: The reduction in postprandial glucose excursions achieved with addition of pramlintide to rapid-acting insulin in type 2 diabetes was associated with a reduction in postprandial markers of oxidative stress. PMID- 17694506 TI - LMAN lesions prevent song degradation after deafening without reducing HVC neuron addition. AB - In some songbirds perturbing auditory feedback can promote changes in song structure well beyond the end of song learning. One factor that may drive vocal change in such deafened birds is the ongoing addition of new vocal-motor neurons into the song system. Without auditory feedback to guide their incorporation, the addition of these new neurons could disrupt the established song pattern. To assess this hypothesis, the authors determined if neuronal recruitment into the vocal motor nucleus HVC is affected by neural signals that influence vocal change in adult deafened birds. Such signals appear to be conveyed via LMAN, a nucleus in the anterior forebrain that is necessary for vocal change after deafening. Here the authors tested whether LMAN lesions might restrict song degradation after deafening by reducing the addition or survival of new HVC neurons that would otherwise corrupt the ongoing song pattern. Using [3H]thymidine autoradiography to identify neurons generated in adult zebra finches, it was shown here that LMAN lesions do not reduce the number or percent of new HVC neurons surviving for either several weeks or months after [3H]thymidine labeling. However, the authors confirmed previous reports that LMAN lesions restrict vocal change after deafening. These data suggest that neurons incorporated into the adult HVC may form behaviorally adaptive connections without requiring auditory feedback, and that any role such neurons may play in promoting vocal change after adult deafening requires anterior forebrain pathway output. PMID- 17694507 TI - Attributable fractions with survival data. AB - Attributable fraction (AF) is an important concept in clinical and epidemiological studies. The concept has mainly been discussed in relation to case-control studies, cross-sectional studies, and follow-up studies of fixed length. Here, we propose and discuss several ways of defining and estimating AFs with right-censored survival data, and thus with varying lengths of follow-up. In particular, we define the attributable hazard fraction, the AF before time t, and the AF within study. These measures have different interpretations and may give different numerical values, as illustrated in an application to real data on time to the first receiving of cash benefits for hearing impairment in children. The results underline the need for careful selection of the type of measure and interpretation when reporting AFs for survival data. PMID- 17694511 TI - gem-Dihalocyclopropanes as building blocks in natural-product synthesis: enantioselective total syntheses of ent-erythramine and 3-epi-erythramine. AB - ent-Erythramine ((-)-1), the enantiomer of the alkaloid erythramine, was prepared in 15 steps from known compounds. The first of three pivotal bond-forming steps in the synthesis was a Suzuki-Miyaura cross-coupling reaction of the starting materials to give a bis-silyl ether. The second involved silver(I)-induced electrocyclic ring opening of the gem-dichlorocyclopropane formed in the next step and trapping of the ensuing pi-allyl cation by the tethered nitrogen atom to give, following cleavage of the allyloxycarbonyl protecting group, an approximately 5:6 mixture of the chromatographically separable diastereoisomeric spirocyclic products. In the third critical bond-forming reaction, the iodide formed from one of the diastereoisomers underwent a radical-addition/elimination reaction sequence that led to (-)-1 in 89 % yield. The application of the same sequence of transformations to the other diastereoisomer afforded 3-epi-(+) erythramine (3-epi-(+)-1). PMID- 17694512 TI - Biovalidation of an SPE-HPLC-UV-fluorescence method for the determination of valsartan and its metabolite valeryl-4-hydroxy-valsartan in human plasma. AB - A simple and fast method for the simultaneous determination of the antihypertensive drug Valsartan and its metabolite in human plasma has been validated. The proposed method deals with SPE, followed by an HPLC separation coupled with fluorimetric and photometric detection. The optimization of the SPE HPLC method was achieved by an experimental design. The separation was performed on an RP C18 Atlantis 100 mmx3.9 mm column. The mobile phase consisted of a mixture of ACN 0.025% TFA and phosphate buffer (5 mM, pH = 2.5) 0.025% TFA and was delivered in gradient mode at a flow rate of 1.30 mL/min. The eluent was monitored with a fluorescence detector at 234 and 378 nm excitation and emission wavelengths, respectively, and at 254 nm using a photometric detector. The full analytical validation was performed according to the Food and Drug Administration (FDA) 'guidance for industry: bioanalytical method validation' and the recoveries obtained for Valsartan and its metabolite ranged from 94.6 to 108.8%. The validated method was successfully applied to 12 plasma samples obtained from patients under antihypertensive treatment with Valsartan. PMID- 17694513 TI - Development of a two-step screening ESI-TOF-MS method for rapid determination of significant stress-induced metabolome modifications in plant leaf extracts: the wound response in Arabidopsis thaliana as a case study. AB - To study the stress-induced effects caused by wounding under a new perspective, a metabolomic strategy based on HPLC-MS has been devised for the model plant Arabidopsis thaliana. To detect induced metabolites and precisely localise these compounds among the numerous constitutive metabolites, HPLC-MS analyses were performed in a two-step strategy. In a first step, rapid direct TOF-MS measurements of the crude leaf extract were performed with a ballistic gradient on a short LC-column. The HPLC-MS data were investigated by multivariate analysis as total mass spectra (TMS). Principal components analysis (PCA) and hierarchical cluster analysis (HCA) on principal coordinates were combined for data treatment. PCA and HCA demonstrated a clear clustering of plant specimens selecting the highest discriminating ions given by the complete data analysis, leading to the specific detection of discrete-induced ions (m/z values). Furthermore, pool constitution with plants of homogeneous behaviour was achieved for confirmatory analysis. In this second step, long high-resolution LC profilings on an UPLC-TOF MS system were used on pooled samples. This allowed to precisely localise the putative biological marker induced by wounding and by specific extraction of accurate m/z values detected in the screening procedure with the TMS spectra. PMID- 17694514 TI - Drug-induced Myc-mediated apoptosis of cancer cells is inhibited by stress protein Hsp70. AB - The Myc oncoprotein serves a dual function by stimulating cells both towards growth and apoptosis. The latter functions are often abrogated during tumor development. The Hsp70 stress protein is a potent anti-apoptotic molecule, but its potential role in protecting cells from Myc-mediated apoptosis has not been investigated. Our results show that activated Myc potentiated apoptosis induced by the cancer drugs etoposide (ETO) and camptothecin (CAMP) in v-Myc-expressing human U-937 monoblastic cells and in Rat1 cells containing a conditionally active Myc/estrogen receptor (MycER) fusion protein. However, both heat shock and ectopic Hsp70 expression protected the cells from Myc-mediated apoptosis after drug treatment in both systems. The increased susceptibility to the anti-tumor drugs by activated Myc was enhanced by siRNA-mediated knockdown of Hsp70 expression in U-937 cells. Addressing the mechanisms by which Myc and Hsp70 promotes and inhibits drug-induced apoptosis, respectively, we found that v-Myc stimulated cytochrome c release and activation of effector caspase-9, -3 and -7, but not of initiator caspase-8. Inhibition of caspase-9 specifically reduced v Myc-stimulated apoptosis, whereas inhibition of caspase-8 and -3/7 reduced apoptosis both in v-myc-expressing and parental ETO-treated U-937 cells. Interestingly, Myc-stimulated activation of effector caspases was inhibited, but cytochrome c release was not affected by Hsp70 expression, suggesting that Hsp70 interferes with the proapoptotic function of Myc downstream of mitochondria, at the level of caspase-9 and downstream caspases. In conclusion, Hsp70 seems to have key function in inhibition of apoptosis mediated by Myc and may therefore play an important role in Myc-driven oncogenesis. PMID- 17694515 TI - Lack of promotion effects of 50 Hz magnetic fields on 7,12 dimethylbenz(a)anthracene-induced malignant lymphoma/lymphatic leukemia in mice. AB - New-born CD-1 mice were initiated with a single subcutaneous injection of 60 microg 7,12-dimethylbenz(a)anthracene (DMBA) within 24 h after birth. After weaning, the mice were randomly divided into five groups of 100, 50 males and 50 females each. One group served as a cage control. The other four groups of mice were exposed to either 0 (sham-exposed), 7, 70, or 350 microT(rms) circularly polarized 50 Hz magnetic fields (MFs) for 22 h/day, 7 days/week for 30 weeks. Animals were observed daily and the development of malignant lymphoma/lymphatic leukemia was examined histopathologically. The experiment was conducted twice. There was no observed sexual difference in the cumulative proportions of mice with malignant lymphoma/lymphatic leukemia and a 3-way analysis of deviance using the Cox regression model revealed no interactions between experiment, sex, or group. The cumulative proportions of mice with malignant lymphoma/lymphatic leukemia in the MF-exposed groups were not significantly higher than those in the sham-exposed group of each sex in individual experiments and in males and females combined in each experiment, and in all the animals from the two experiments combined. These data provide no evidence to support the hypothesis that power frequency MFs is a significant risk factor for hematopoietic neoplasia. PMID- 17694516 TI - Mobile phone base station radiation does not affect neoplastic transformation in BALB/3T3 cells. AB - A large-scale in vitro study focusing on low-level radiofrequency (RF) fields from mobile radio base stations employing the International Mobile Telecommunication 2000 (IMT-2000) cellular system was conducted to test the hypothesis that modulated RF fields affect malignant transformation or other cellular stress responses. Our group previously reported that DNA strand breaks were not induced in human cells exposed to 2.1425 GHz Wideband Code Division Multiple Access (W-CDMA) radiation up to 800 mW/kg from mobile radio base stations employing the IMT-2000 cellular system. In the current study, BALB/3T3 cells were continuously exposed to 2.1425 GHz W-CDMA RF fields at specific absorption rates (SARs) of 80 and 800 mW/kg for 6 weeks and malignant cell transformation was assessed. In addition, 3-methylcholanthrene (MCA)-treated cells were exposed to RF fields in a similar fashion, to assess for effects on tumor promotion. Finally, the effect of RF fields on tumor co-promotion was assessed in BALB/3T3 cells initiated with MCA and co-exposed to 12-O tetradecanoylphorbol-13-acetate (TPA). At the end of the incubation period, transformation dishes were fixed, stained with Giemsa, and scored for morphologically transformed foci. No significant differences in transformation frequency were observed between the test groups exposed to RF signals and the sham-exposed negative controls in the non-, MCA-, or MCA plus TPA-treated cells. Our studies found no evidence to support the hypothesis that RF fields may affect malignant transformation. Our results suggest that exposure to low-level RF radiation of up to 800 mW/kg does not induce cell transformation, which causes tumor formation. PMID- 17694517 TI - Acyclic stereocontrol in the Ireland-Claisen rearrangement of alpha-branched esters. PMID- 17694518 TI - Exploring the nickel-catalyzed oxidation of alkenes: a diamination by sulfamide transfer. PMID- 17694519 TI - Engineering a selective small-molecule substrate binding site into a deoxyribozyme. PMID- 17694520 TI - Dual catalysis: a combined enantioselective Bronsted acid and metal-catalyzed reaction--metal catalysis with chiral counterions. PMID- 17694521 TI - A paramagnetic contrast agent for detecting tyrosinase activity. PMID- 17694522 TI - Labeling tetracysteine-tagged proteins with a SplAsH of color: a modular approach to bis-arsenical fluorophores. PMID- 17694523 TI - No marked kinetic isotope effect in the peroxone (H2O2/D2O2+O3) reaction: mechanistic consequences. PMID- 17694524 TI - Artesunate and dihydroartemisinin (DHA): unusual decomposition products formed under mild conditions and comments on the fitness of DHA as an antimalarial drug. AB - Artesunate drug substance, for which a rectal capsule formulation is under development for the treatment of severe malaria, when heated at 100 degrees C for 39 h gives beta-artesunate, artesunate dimers, 9,10-anhydrodihydroartemisinin (glycal), a DHA beta-formate ester, and smaller amounts of other products that arise via intermediate formation of dihydroartemisinin (DHA) and subsequent thermal degradation. Solid DHA at 100 degrees C provides an epimeric mixture of a known peroxyhemiacetal, arising via ring opening to a hydroperoxide and re closure, smaller amounts of a 3:1 mixture of epimers of a known tricarbonyl compound, and a single epimer of a new dicarbonyl compound. The latter arises via homolysis of the peroxide and an ensuing cascade of alpha-cleavage reactions which leads to loss of formic acid incorporating the C10 carbonyl group of DHA exposed by this 'unzipping' cascade. The tricarbonyl compound that arises via peroxide homolysis and extrusion of formic acid from a penultimate hydroxyformate ester incorporating C12 of the original DHA, is epimeric at the exocyclic 1'' aldehyde, and not in the cyclohexanone moiety. It is converted into the dicarbonyl compound by peroxide-induced deformylation. The dicarbonyl compound is not formed during anhydrous ferrous bromide mediated decomposition of DHA at room temperature, which provides the 1''-R epimer of the tricarbonyl compound as the dominant product; this equilibrates at room temperature to the 3:1 mixture of epimers of the tricarbonyl compound obtained from thermolysis. Each of artesunate and DHA decomposes readily under aqueous acidic conditions to provide significant amounts of the peroxyhemiacetal, which, like DHA, decomposes to the inert end product 2-deoxyartemisinin under acidic or basic conditions. DHA and the peroxyhemiacetal are the principal degradants in aged rectal capsule formulations of artesunate. TGA analysis and thermal degradation of DHA reveals a thermal lability which would pose a problem not only in relation to ICH stability testing guidelines, but in the use of DHA in fixed formulations currently under development. This thermolability coupled with the poor physicochemical properties and relative oral bioavailability of DHA suggests that it is inferior to artesunate in application as an antimalarial drug. PMID- 17694525 TI - Functional classification of protein kinase binding sites using Cavbase. AB - Increasingly, drug-discovery processes focus on complete gene families. Tools for analyzing similarities and differences across protein families are important for the understanding of key functional features of proteins. Herein we present a method for classifying protein families on the basis of the properties of their active sites. We have developed Cavbase, a method for describing and comparing protein binding pockets, and show its application to the functional classification of the binding pockets of the protein family of protein kinases. A diverse set of kinase cavities is mutually compared and analyzed in terms of recurring functional recognition patterns in the active sites. We are able to propose a relevant classification based on the binding motifs in the active sites. The obtained classification provides a novel perspective on functional properties across protein space. The classification of the MAP and the c-Abl kinases is analyzed in detail, showing a clear separation of the respective kinase subfamilies. Remarkable cross-relations among protein kinases are detected, in contrast to sequence-based classifications, which are not able to detect these relations. Furthermore, our classification is able to highlight features important in the optimization of protein kinase inhibitors. Using small molecule inhibition data we could rationalize cross-reactivities between unrelated kinases which become apparent in the structural comparison of their binding sites. This procedure helps in the identification of other possible kinase targets that behave similarly in "binding pocket space" to the kinase under consideration. PMID- 17694526 TI - Optical nanosensor design with uniform pore geometry and large particle morphology. AB - Appropriate design of nanosensors for optically selective, sensitive sensing systems is needed for naked-eye detection of pollutants for environmental cleanup of toxic heavy-metal ions. Mesostructured materials with two- or three dimensional (2D or 3D) geometries and large particle morphologies show promise as probe carriers, and can therefore be used to reproducibly fabricate uniformly packed nanosensors. This is the first report on the effects of significant key properties of the mesostructured carriers, such as morphology, geometry, and pore shape, on the functionality of optical nanosensor designs. Such mesostructured sensors with superior physical characteristics can be used as components in sensing systems with excellent stability and sensitivity, and with rapid detection response. The nanosensor design can enhance the selectivity even at low concentrations of the pollutant target ions (nanomolar level). Among the nanosensors developed here, the large pore-surface grains of highly ordered 3D monoliths (HOM) exhibited a high adsorption capability of the Pyrogallol Red probe and high accessibility to analyte ion transport, leading to possible naked eye detection of Sb(III) ions at concentrations as low as 10(-9) mol dm(-3) and at a wide detection range of 0.5 ppb to 3 ppm. A key finding in our study was that our mesostructured nanosensor designs retained highly efficient sensitivity without a significant increase in kinetic hindrance, despite the slight decrease of the specific activity of the electron acceptor/donor strength of the probe functional group after several regeneration/reuse cycles. The results, in general, indicate that large-scale reversibility of optical nanosensors is feasible in such metal-ion sensing systems. PMID- 17694527 TI - The reactivity of calicheamicin gamma(1)(I) in the minor groove of DNA: the decisive role of the environment. AB - Triggering and Bergman cyclization of calicheamicin gamma(1) (I) outside and inside the minor groove of the duplex 9mer-B-DNA sequence d(CACTCCTGG).d(CCAGGAGTG) were investigated by using density functional theory and molecular mechanics (DFT and MM) descriptions in which the ligand is completely described at the DFT and the receptor at the MM level. The calculated docking energy of calicheamicin gamma(1) (I) (-12.5 kcal mol(-1)) is close to the measured value of -9.7 kcal mol(-1) and the site specificity is in line with experimental observations. Calicheamicin is triggered in the minor groove in such a way that out of a cyclohexenone by Michael addition an E rather than a Z form of a cyclohexanone is formed, which in turn adopts a chair rather than a twistboat form. Decisive for the stereochemistry of the Michael addition is the orientation of the carbamate substituent at the headgroup of calicheamicin. Triggered calicheamicin can undergo the Bergman cyclization at body temperature only if present in its E chair form (activation enthalpy 16.4 kcal mol(-1)). An intermediate biradical is formed (docking energy -13.6 kcal mol(-1)), which has a sufficient lifetime to abstract two hydrogen atoms. Hydrogen abstraction is a two rather than one-step process and involves the C5(H5') atom first and then the T22(H4') atom in line with experimental observations. The decisive role of using a DFT rather than an MM description for the ligand is documented. PMID- 17694528 TI - Asymmetric hydrogenations one by one: differentiation of up to three beta ketocarboxylic acid derivatives based on Ruthenium(II)-binap catalysis. AB - Noyori-type reductions of pairs of beta-ketoamides and beta-ketoesters with elemental hydrogen (4 bar) proceeded substrate by substrate. When Et(2)NH(2) (+)[{RuCl(S)-binap}(2)](mu-Cl)(3)(-) was employed as a catalyst in a methanol or ethanol solution, the substrates were reduced at room temperature in the order beta-ketopyrrolidide > or = beta-ketopiperidide > or = beta-keto(N,N diethylamide) > beta-keto(alkyl esters) > beta-keto(oligofluoroalkyl esters). This is the first time that beta-ketoamides have been reduced asymmetrically (91 to >98 % ee) under such mild conditions. Monitoring the concentrations of these beta-ketocarboxyl acid derivatives and their respective hydrogenation products over the course of time showed that the most electron-rich substrate is captured by the catalyst preferentially and exothermically; whether this occurs reversibly or irreversibly remains to be determined. The hydrogenation product is subsequently formed. The last transformation includes the rate-determining step. The combination of these events explains why starting from appropriate mixtures of substrates a "first-choice substrate" reacted from early on while the "second choice substrate" stayed virtually untouched over an extended period of time and reacted no earlier than after the "first-choice substrate" had disappeared. From then onward, however, the "second-choice substrate" also reacted relatively rapidly. PMID- 17694529 TI - Synthesis of a bis-macrocycle containing two back-to-back rigidly connected 1,10 phenanthroline units as a central core and its incorporation in a handcuff-like catenane. AB - A bis-macrocycle containing two back-to-back connected 1,10-phenanthroline chelates has been prepared. The synthetic strategy involves the preparation of a monocyclic precursor consisting of a 1,10-phenanthroline-5,6-dione fragment incorporated in a 30-membered ring. This important intermediate has been prepared via two distinct routes, both strategies relying on the use of a ketal as a 1,2 dione protective group. A four-component condensation reaction between two molecules of the macrocyclic dione and two equivalents of ammonia (used in large excess) in the presence of a reducing agent (Na(2)S(2)O(4)) leads to the desired bis-ring in good yield. The most direct synthetic route allows preparation of the bis-macrocycle in seven steps from 1,10-phenanthroline in an overall yield of 14 %. Using the now well-established "gathering and threading" effect of copper(I), a doubly threaded species could be obtained in quantitative yield, in which each ring of the bis-macrocycle is threaded by a "molecular string". These fragments bear terminal allylic groups, which are used to prepare the final catenane by performing a double ring-closing metathesis reaction. This final cyclisation reaction is high yielding and affords the desired catenane consisting of a bis macrocycle of which the two cyclic units are threaded by a large ring. The compound has been fully characterised by classical techniques. Electronic spectroscopy and electrochemical measurements suggest that the two copper complex subunits do not interact electronically, in spite of the aromatic nature of the bridging ligand between the two metal centres. PMID- 17694530 TI - Organocatalysed asymmetric beta-amination and multicomponent syn-selective diamination of alpha,beta-unsaturated aldehydes. AB - An easy and affordable route for obtaining chiral beta-aminated- and alpha,beta diaminated aldehydes, 1,3-aminoalcohols, and related compounds by using organocatalysis is presented. The chiral secondary amine (S)-2-[bis(3,5 bistrifluoromethylphenyl)trimethylsilanyloxymethyl]pyrrolidine is used as the catalyst to activate alpha,beta-unsaturated aldehydes, which allows succinimide to add in a 1,4-regio- and stereoselective fashion thereby forming N-protected 1,3-aminoaldehydes in good yields and enantioselectivities. This is followed by two easy transformations giving rise to optically active 1,3-aminoalcohols, a common motif in many biologically active compounds, for example, fibrinogen receptor antagonists. Furthermore, optically active alpha,beta-syn-diaminated aldehydes were obtained by the addition of diethyl azodicarboxylate in a one-pot reaction. PMID- 17694531 TI - Ring opening of the cyclobutane in a thymine dimer radical anion. AB - The reactions of hydrated electrons (e(aq) (-)) with thymine dimer 2 and thymidine have been investigated by radiolytic methods coupled with product studies, and addressed computationally by means of BB1K-HMDFT calculations. Pulse radiolysis revealed that one-electron reduction of the thymine dimer 2 affords the radical anion of thymidine (5) with t(1/2)<35 ns. Indeed, the theoretical study suggests that radical anion 3, in which the spin density and charge distribution are located in both thymine rings, undergoes a fast partially ionic splitting of the cyclobutane with a half-life of a few ps. This model fits with the in vivo observation of thymine dimer repair in DNA by photolyase. gamma Radiolysis of thymine dimer 2 demonstrates that the one-electron reduction and the subsequent cleavage of the cyclobutane ring does not proceed by means of a radical chain mechanism, that is, in this model reaction the T(-)* is unable to transfer an electron to the thymine dimer 2. PMID- 17694532 TI - Determining factors for cryoprotectant accumulation in the freeze-tolerant earthworm, Dendrobaena octaedra. AB - The freeze-tolerant earthworm Dendrobaena octaedra is found in most of the European forest and tundra, Siberia, North America and Greenland where it over winters in the top soil and encounters winter frost. In response to freezing this earthworm rapidly synthesises glucose which acts as a cryoprotectant. Frost tolerance varies extensively between geographical populations, and of the populations studied so far, the Finnish worms are most and the Danish worms least frost tolerant. Little is known about the determining factors for glucose synthesis and this study therefore investigated possible roles of acclimation and the cues for synthesis of glucose, in Finnish and Danish worms. The Finnish population had significantly larger glycogen reserves than the Danish during acclimation and in all worms, glucose synthesis was the result of an almost stoichemical reduction in glycogen stores. Maximum glucose levels were reached after the onset of freezing and were significantly higher in Finnish worms where the sugar accounted for as much as 5% of the fresh weight. On average, both the total glycogen phosphorylase activity and the active enzyme pool increased during acclimation in the Finnish but not the Danish populations. However, the increase in this enzyme was only significant during the freezing process. In this study, we show contrary to previous theory that glucose synthesis is initiated before the onset of freezing and that in this species, cryoprotectant synthesis is sensitive to very small temperature changes below 0 degrees C without the presence of ice. PMID- 17694533 TI - A preliminary study of food transfer in Sichuan snub-nosed monkeys (Rhinopithecus roxellana). AB - Food transfer happens regularly in a few nonhuman primates species that are also characterized by remarkable social tolerance. Sichuan snub-nosed monkeys (Rhinopithecus roxellana), or golden monkeys, which exhibit high social tolerance in their social relationships are thus of interest to see whether tolerance would extend to food transfer. In this study, branch feeding activity was observed in a semi-captive group of Sichuan snub-nosed monkeys, which consisted of 10 subjects that included a one-male unit (OMU) and an all-male unit (AMU). We recorded 1,275 food interactions over 27 days, and 892 instances of food transfer. The most commonly observed types of food transfer behavior were co-feeding (62.1%) and relaxed claim (22.8%). Of 892 food transfers, 756 (84.8%) took place in the OMU, most of which were among adults (34.7%) and among juveniles (42.1%). The transfer success rate was high in both the cases (87.9% for adults and 78.9% for juveniles). Food transfer in the AMU took place less often than that among adults in the OMU though with similar high transfer success. Food transfer between the OMU and AMU was limited to juvenile males from the OMU and adults from the AMU. These results provide the first evidence of food transfer in golden monkeys and suggest that tolerant social relationships in golden monkeys make transfer possible. PMID- 17694534 TI - A mechanistic view on the evolutionary origin for centrin-based control of centriole duplication. AB - Mounting evidence implicates the protein centrin as a key regulator of centriole duplication, yet it remains to be determined just how centrin functions in this process. Recent studies suggest that centrin exerts both spatial and temporal control over centriole duplication through its role as a component of centriole precursor structures and through periodic cell-cycle specific changes in its abundance. Here, an overview of centrin and its role in centrosome dynamics is presented. Finally, a speculative model for just how centrin may operate to control centriole duplication is proposed with the intention to stimulate future advances in this area. This model provides an evolutionary basis for the preservation of essential features of the yeast spindle pole body (SPB) with the origin of the complex structure of the mammalian centriole. PMID- 17694535 TI - Effects of magnetic field on the antioxidant defense system of recirculation cultured Chlorella vulgaris. AB - Little is known about the influence of magnetic fields (MF) on growth of microalgae such as Chlorella vulgaris, which has been consumed as health food for various nutritional and pharmacological effects. This preliminary study investigated whether static MF can modulate the antioxidant system in C. vulgaris by exposing the cells to static MF generated by dual yoke electromagnets with magnetic flux density of 10-50 mT for 12 h. After exposure to 10-35 mT for 12 h, the activity of superoxide dismutases and peroxidase increased significantly compared to control cells. However, a remarkable increase of catalase activity occurred at 45 and 50 mT. The lipid peroxidation of algae cells determined by production of thiobarbituric acid-reactive substances was much increased when exposed to 35, 45, and 50 mT of MF. The scavenging ability of 2,2-diphenyl-1 picrylhydrazyl radical was decreased markedly while there was no variation of total carotenoids content in C. vulgaris cells. Assay of specific growth rate in 72 h cultivation after MF exposure was also conducted. In groups after exposure to 10-35 mT of MF, specific growth rate was significantly increased. These results suggest that 10-35 mT of static MF exposure could promote the growth of C. vulgaris and regulate its antioxidant defense system to protect cells efficiently, which could possibly enhance the growth of C. vulgaris in industrialized cultivation by MF. PMID- 17694536 TI - Dosimetric evaluation and comparison of different RF exposure apparatuses used in human volunteer studies. AB - The aim of this study was to provide the information necessary to enable the comparison of exposure conditions in different human volunteer studies published by the research groups at the Universities of Turku, Swinburne, and Zurich. The latter applied a setup optimized for human volunteer studies in the context of risk assessment while the first two applied a modified commercial mobile phone for which detailed dosimetric data were lacking. While the Zurich Setup exposed the entire cortex of the target hemisphere, the other two setups resulted in only very localized exposure of the upper cheek, and concentrated on a limited area of the middle temporal gyrus just above the ear. The resulting peak spatial SAR averaged over 1 g of the cortex was 0.19 W/kg of the Swinburne Setup, and 0.31 W/kg for the Turku Setup, compared to 1 W/kg for the Zurich Setup. The average exposure of the thalamus was 5% and 9% of the Zurich Setup results for the Swinburne and Turku Setups, respectively. In general, the phone-based setup results in only reasonably defined exposures in a very limited area around the maximum exposure; the exposure of the rest of the cortex was low, and may vary greatly as a function of the setup, position, and local anatomy. The analysis confirms the need for a carefully designed exposure setup that exposes the relevant brain areas to a well-defined level in human volunteer studies, and shows that studies can only be properly compared and replicated if sufficiently detailed dosimetric information is available. PMID- 17694537 TI - Does the nonsense-mediated mRNA decay mechanism prevent the synthesis of truncated BRCA1, CHK2, and p53 proteins? AB - The nonsense-mediated mRNA decay (NMD) mechanism is an evolutionarily conserved process ensuring the degradation of transcripts carrying premature termination codon(s). NMD is believed to prevent the synthesis of truncated proteins that could be detrimental to the cell. However, although numerous studies have assessed the efficiency of this mechanism at the mRNA level, data are lacking in regard to whether NMD fulfills its expected goal at the protein level. In this study, we have investigated whether endogenous alleles of breast cancer predisposing genes carrying nonsense codons were able to produce detectable amounts of truncated proteins in lymphoblastoid cell lines. A total of 20 truncating BRCA1 mutations were analyzed, along with the 1100delC CHEK2 and the 770delT TP53 mutations. All the studied alleles triggered NMD, the amount of mutant transcript ranging from 16 to 63% of that of the wild-type species. We found that BRCA1 and CHK2 truncated proteins could not be detected, even when NMD was inhibited. This suggests that BRCA1 and CHK2 truncated proteins are highly unstable. Conversely, the p53 protein encoded by the 770delT allele is as abundant as the wild-type protein, as removal of the C-terminal p53 domain leads to a stabilized mutant protein, whose abundance is markedly increased when NMD is inhibited. Therefore, our results show that it is not possible to infer the presence of truncated proteins in cells from carriers of a truncated mutation without experimental verification, as each case is expected to be different. PMID- 17694538 TI - Gd(III)-EPTPAC16, a new self-assembling potential liver MRI contrast agent: in vitro characterization and in vivo animal imaging studies. AB - The recently reported amphiphilic chelate, [Gd(EPTPAC16)(H2O)]2-, forms supramolecular aggregates in aqueous solution by self-assembly of the monomers with a relaxometrically determined critical micellar concentration (CMC) of 0.34 mM. The effect of sonication on the aggregate size was characterized by dynamic light scattering and relaxometry, indicating the presence of premicellar aggregates and an overall decrease in aggregate size and polydispersity upon sonication, slightly below the CMC. [[153Sm](EPTPAC16)(H2O)]2- radiotracer was evaluated in vivo from gamma scintigraphy and biodistribution in Wistar rats. It was found to depend strongly on the sample concentration, below or above the CMC, and its sonication, in a way that correlates with the effect of the same factors on the size of the aggregates formed in solution. Below CMC, the very large aggregates of the [153Sm]3+ -labeled chelate were persistently and mainly taken up by the lungs, and also by the macrophage-rich liver and spleen. Sonication of this solution led to loss of the lung uptake. Above CMC, the metal chelate was mainly taken up by the liver, with very little uptake by the spleen and lungs. In vivo, dynamic contrast-enhanced (DCE)-MRI evaluation of the micellar [Gd(EPTPAC16)(H2O)]2- compound in Wistar rats showed a persistent hepatic positive-contrast effect in T1-weighted images, qualitatively similar to the clinically established Gd(III)-based hepatobiliary-selective agents. No enhancement effect was observed in the lungs because of the scarcity of mobile protons in this organ, despite the scintigraphic evidence of significant lung retention of the [153Sm]3+ -labeled chelate at concentrations below the CMC. PMID- 17694539 TI - Longer you play, the more hostile you feel: examination of first person shooter video games and aggression during video game play. AB - This study investigated the effects of video game play on aggression. Using the General Aggression Model, as applied to video games by Anderson and Bushman, [2002] this study measured physiological arousal, state hostility, and how aggressively participants would respond to three hypothetical scenarios. In addition, this study measured each of these variables multiple times to gauge how aggression would change with increased video game play. Results showed a significant increase from baseline in hostility and aggression (based on two of the three story stems), which is consistent with the General Aggression Model. This study adds to the existing literature on video games and aggression by showing that increased play of a violent first person shooter video game can significantly increase aggression from baseline. PMID- 17694540 TI - Representational oligonucleotide microarray analysis (ROMA) and comparison of binning and change-point methods of analysis: application to detection of del22q11.2 (DiGeorge) syndrome. AB - DiGeorge (del22q11.2) syndrome is estimated to occur in 1:4,000 births, is the most common contiguous-gene deletion syndrome in humans, and is caused by autosomal dominant deletions in the 22q11.2 DiGeorge syndrome critical region (DGCR). Multiple microarray methods have been developed recently for analyzing such copy number changes, but data analysis and accurate deletion detection remains challenging. Clinical use of these microarray methods would have many advantages, particularly when the possibility of a chromosomal disorder cannot be determined simply on the basis of history and physical examination data alone. We investigated the use of the microarray technique, representational oligonucleotide microarray analysis (ROMA), in the detection of del22q11.2 syndrome. Genomic DNA was isolated from three well-characterized cell lines with 22q11.2 DGCR deletions and from the blood of a patient suspected of having del22q11.2 syndrome, and analyzed using both the binning and change-point model algorithms. Though the 22q11.2 deletion was easily identified with either method, change-point models provide clearer identification of deleted regions, with the potential for fewer false-positive results. For circumstances in which a clear, a priori, copy-number change hypothesis is not present, such as in many clinical samples, change-point methods of analysis may be easier to interpret. PMID- 17694541 TI - Physical and biological considerations for the use of nonaqueous solvents in oral bioavailability enhancement. AB - This review addresses the use of nonaqueous solvents as components of oral formulations in discovery and preclinical studies. Pharmacology, pharmacokinetic, and safety studies are frequently conducted with solution formulations that use a solvent to solubilize poorly aqueous soluble drugs. The physical chemical basis for solubilization and the precipitation of solubilized drug following administration both contribute to the utility of nonaqueous solvent solutions as oral vehicles. While many of these solvents are considered nontoxic, they are not completely inert biologically. The effects of common nonaqueous solvents on the structural integrity of the epithelia, the inherent permeability of and flux across the GI membrane, the activity of efflux and metabolic enzymes, and the effects on GI motility and GI transit times will be described through an examination of available literature. The practical relevance of these factors to the development of early formulations will be examined critically and suggestions made for the suitability of nonaqueous solvents for a variety of purposes. PMID- 17694542 TI - Calorimetric and spatial characterization of polymorphic transitions in caffeine using quasi-isothermal MTDSC and localized thermomechanical analysis. AB - We describe a novel integrated approach to the study of polymorphic transformation that includes quasi-isothermal modulated temperature differential scanning calorimetry (QI-MTDSC) and microthermal analysis (MTA), with a view to studying the thermal, kinetic and spatial characteristics of the process. Form II and I caffeine was prepared and conventional DSC and hot stage microscopy performed. The Form II to I transition at circa 413 K was associated with a change in crystal habit to needle shaped crystals. QI-MTDSC was used to measure the heat capacity of the system as a function of temperature, while MTA was able to spatially differentiate between the two polymorphs in compressed systems. We present a novel extension of the reduced temperature method whereby we apply it for the first time to linear rising temperature data corresponding to the transition; the analysis suggests a close approximation to Arrhenius behavior. We also describe a heat transfer model that allows calculation of the thermal gradients within a hermetically sealed pan for the first time. The combined approach has therefore allowed the characterization of the thermodynamics and kinetics of the transformation process as well as spatial identification of the distribution of the transformation in compressed systems. PMID- 17694543 TI - Influence of intravesicular pH drift and membrane binding on the liposomal release of a model amine-containing permeant. AB - Accurate determination of intrinsic permeability coefficients is critical to the development of structure-permeability relationships and liposomal delivery systems. The apparent release rate of a drug from liposomes may reflect not only its intrinsic permeability coefficient and barrier properties but also a variety of underlying equilibria including drug ionization, membrane binding or complexation, and kinetic processes such as buffer exchange. Additionally, transport of ionizable drugs that are initially at high concentrations in liposomes can generate or dissipate pH gradients across the barrier causing deviations from classical pH-permeability profiles. In this study, the liposomal release of a model amine (tyramine) is determined as a function of drug loading, intravesicular pH, and buffer composition. Kinetic models are derived to study effects of such equilibria (e.g., ionization, membrane binding) and kinetic processes (e.g., pH drift and acid/base carriers). All equilibrium constants needed for the models were independently measured and used. The barrier properties of the lipid bilayers under the experimental conditions were assessed by monitoring the transport of mannitol and bretylium as a function of pH. A corrected intrinsic permeability coefficient of 0.04 cm/s was in close agreement with the value predicted from the barrier domain model for bilayer permeability, suggesting that all perturbing factors were properly addressed. PMID- 17694544 TI - Relative bioavailability of salicylic acid following dermal application of a 30% salicylic acid skin peel preparation. AB - A single-center, single-sequence, two-period crossover study was performed to compare the systemic exposure to salicylic acid (SA) following facial application of a 30% SA cosmetic skin peel formulation applied for 5 min and an oral dose of 650 mg aspirin in nine healthy male and female subjects. The mean (SD) maximum SA concentration (Cmax) was 0.81 (0.32) microg/mL and 56.4 (14.2) microg/mL. The AUC based safety margin ratio was 50:1. A depot effect was observed during topical application of the skin peel solution as the absorption of SA continued beyond the 5-min application period. Plasma SA Cmax values were achieved from 1.4 to 3.5 h after topical application and from 0.5 to 1.5 h after oral aspirin. The plasma concentrations in the present study (30%; 5 min) were similar to that of a low concentration (2%) applied in a leave-on product to the same body surface area. In conclusion, our results suggest that the use of this SA facial peel should not pose any significant systemic health risks. PMID- 17694545 TI - Research advances in the development of peptide antibiotics. AB - Bacterial resistance to antibiotics is a growing concern in both nosocomial and community acquired infections. Resistance began to emerge as early as the 1950s. Much research has been dedicated to the improvement of existing classes of antibiotics. Antimicrobial peptides (AMPs) are part of the innate immune system, and an important component of immune defense. They are produced by plants, animals, insects, and single celled organisms, and possess anti-microbial properties. As such, they are an ideal target for future antibiotic production. Bacteriocins are a subgroup of AMPs, produced by various bacteria. It has been shown that the production of chimeric peptides consisting of bacteriocins and pheromones can be targeted toward the killing of specific bacterial species. In contrast to the clonal, acquired adaptive immunity, endogenous peptide antibiotics provide a fast and energy-effective mechanism as front line defense. This review will provide an overview of AMPs and their potential for target specific anti-infective therapy. PMID- 17694546 TI - Is PAMPA a useful tool for discovery? AB - Experimental PAMPA data generated for 40 low molecular weight commercial drugs is reviewed in the context of its utility in the drug discovery process. Several experimental variables that have been introduced in the literature as additions or improvements to the PAMPA were also evaluated. The relationship between PAMPA data and both calculated and measured octanol/water distribution coefficients was examined. From this assessment, it was concluded that the PAMPA yields information about the lipophilicity as measured by the octanol/water partitioning of a compound, but that this same information could be derived in a simpler manner from calculated log D values. PMID- 17694547 TI - Development of anaplastic lymphoma kinase (ALK) small-molecule inhibitors for cancer therapy. AB - Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) involved in the genesis of several human cancers; indeed, ALK was initially identified in constitutively activated and oncogenic fusion forms--the most common being nucleophosmin (NPM)-ALK--in a non-Hodgkin's lymphoma (NHL) known as anaplastic large-cell lymphoma (ALCL) and subsequent studies identified ALK fusions in the human sarcomas called inflammatory myofibroblastic tumors (IMTs). In addition, two recent reports have suggested that the ALK fusion, TPM4-ALK, may be involved in the genesis of a subset of esophageal squamous cell carcinomas. While the cause-effect relationship between ALK fusions and malignancies such as ALCL and IMT is very well established, more circumstantial links implicate the involvement of the full-length, normal ALK receptor in the genesis of additional malignancies including glioblastoma, neuroblastoma, breast cancer, and others; in these instances, ALK is believed to foster tumorigenesis following activation by autocrine and/or paracrine growth loops involving the reported ALK ligands, pleiotrophin (PTN) and midkine (MK). There are no currently available ALK small molecule inhibitors approved for clinical cancer therapy; however, recognition of the variety of malignancies in which ALK may play a causative role has recently begun to prompt developmental efforts in this area. This review provides a succinct summary of normal ALK biology, the confirmed and putative roles of ALK fusions and the full-length ALK receptor in the development of human cancers, and efforts to target ALK using small-molecule kinase inhibitors. PMID- 17694548 TI - Mutations in the MPV17 gene are responsible for rapidly progressive liver failure in infancy. AB - MPV17 is a mitochondrial inner membrane protein of unknown function recently recognized as responsible for a mitochondrial DNA depletion syndrome. The aim of this study is to delineate the specific clinical, pathological, biochemical, and molecular features associated with mitochondrial DNA depletion due to MPV17 gene mutations. We report 4 cases from 3 ethnically diverse families with MPV17 mutations. Importantly, 2 of these cases presented with isolated liver failure during infancy without notable neurologic dysfunction. CONCLUSION: We therefore propose that mutations in the MPV17 gene be considered in the course of evaluating the molecular etiology for isolated, rapidly progressive infantile hepatic failure. PMID- 17694549 TI - Therapeutics targeting tumor immune escape: towards the development of new generation anticancer vaccines. AB - Despite the evidence that immune effectors can play a significant role in controlling tumor growth under natural conditions or in response to therapeutic manipulation, it is clear that malignant cells evade immune surveillance in most cases. Considering that anticancer vaccination has reached a plateau of results and currently no vaccination regimen is indicated as a standard anticancer therapy, the dissection of the molecular events underlying tumor immune escape is the necessary condition to make anticancer vaccines a therapeutic weapon effective enough to be implemented in the routine clinical setting. Recent years have witnessed significant advances in our understanding of the molecular mechanisms underlying tumor immune escape. These mechanistic insights are fostering the development of rationally designed therapeutics aimed at reverting the immunosuppressive circuits that undermine an effective antitumor immune response. In this review, the best characterized mechanisms that allow cancer cells to evade immune surveillance are overviewed and the most debated controversies constellating this complex field are highlighted. In addition, the latest therapeutic strategies devised to overcome tumor immune escape are described, with special regard to those entering clinical phase investigation. PMID- 17694550 TI - Positional lumbar imaging using a positional device in a horizontally open configuration MR unit - initial experience. AB - PURPOSE: To evaluate whether positional MR images of the lumbar spine, obtained with a horizontally open-configuration MR unit, demonstrate positional changes of the dural sac, and to assess whether there are significant differences in positional changes between healthy volunteers and patients with chronic low back pain. MATERIALS AND METHODS: The study population consisted of 15 patients with chronic low back pain and 14 healthy volunteers. MR images were obtained using a horizontally open-configuration 0.4-T MR unit. After conventional lumbar MR examinations, images were obtained in the flexion, neutral, and extension positions, using a positioning device. The anteroposterior diameter of the dural sac at the level of each lumbar disk was measured in the three positions and quantitative data were compared. RESULTS: Our MR protocol was tolerated by all patients. In both patients and volunteers, the mean anteroposterior diameter of the dural sac was smaller in the extension positions than in the flexion positions. In the mean rate of change (RC) in the dural sac diameter at the site of the degenerated disks, the difference between the volunteers and patients was significant (P < 0.05). There was no significant difference in the mean RC between patients and volunteers without degenerative disks. CONCLUSION: Using a horizontally open-configuration MR unit, positional MR imaging provided position dependent change of the dural sac. Positional changes at the site of the degenerated disks may be different in patients with and without chronic low back pain. PMID- 17694551 TI - Expression of granulocyte-colony-stimulating factor and its receptor in human Ewing sarcoma cells and patient tumor specimens: potential consequences of granulocyte-colony-stimulating factor administration. AB - BACKGROUND: Ewing sarcoma (ES) is a highly vascular malignancy. It has been demonstrated that both angiogenesis and vasculogenesis contribute to the growth of ES tumors. Granulocyte-colony-stimulating factor (G-CSF), a cytokine known to stimulate bone marrow (BM) stem cell production and angiogenesis, is routinely administered to ES patients after chemotherapy. Whether ES cells and patient tumor samples express G-CSF and its receptor (G-CSFR) and whether treatment with this factor enhances tumor growth was examined. METHODS: Human ES cell lines were analyzed for expression of G-CSF and G-CSFR in vitro and in vivo. Sixty-eight paraffin-embedded and 15 frozen tumor specimens from patients with ES were also evaluated for the presence of G-CSF and G-CSFR. The in vivo effect of G-CSF on angiogenesis and BM cell migration was determined. Using a TC/7-1 human ES mouse model, the effect of G-CSF administration on ES tumors was investigated. RESULTS: G-CSF and G-CSFR protein and RNA expression was identified in all ES cell lines and patient samples analyzed. In addition, G-CSF was found to stimulate angiogenesis and BM cell migration in vivo. Tumor growth was found to be significantly increased in mice treated with G-CSF. The average tumor volume for the group treated with G-CSF was 1218 mm(3) compared with 577 mm(3) for the control group (P = .006). CONCLUSIONS: The findings that ES cells and patient tumors expressed both G-CSF and its receptor in vitro and in vivo and that the administration of G-CSF promoted tumor growth in vivo suggest that the potential consequences of G-CSF administration should be investigated further. PMID- 17694552 TI - Assessing symptom burden using the M. D. Anderson symptom inventory in patients with chemotherapy-induced anemia: results of a multicenter, open-label study (SURPASS) of patients treated with darbepoetin-alpha at a dose of 200 microg every 2 weeks. AB - BACKGROUND: Patients with cancer who are receiving chemotherapy often experience chemotherapy-induced anemia (CIA), which is associated with symptoms that reduce quality of life. The M. D. Anderson Symptom Inventory (MDASI) is a brief, self rating assessment scale that measures the severity of core symptoms and symptom interference with function. The current study used the MDASI to prospectively assess the correlation between hemoglobin and self-perceived cancer-related symptoms in a large patient population with CIA who were receiving darbepoetin alpha at a dose of 200 mug every 2 weeks. METHODS: Eligible patients enrolled in this multicenter, open-label study were age > or =18 years, had a nonmyeloid malignancy, were receiving multicycle chemotherapy, and were anemic (hemoglobin < or = 11 g/dL). Hemoglobin was measured every 2 weeks; the MDASI was administered weekly. For hemoglobin-based endpoints, patients were stratified by baseline hemoglobin (< 10 g/dL or > or =10 g/dL). RESULTS: Of 2422 enrolled patients, 2401 received > or =1 dose of darbepoetin-alpha. Eighty percent of patients (95% confidence limit, 78-82 patients) achieved target hemoglobin levels (> or =11 g/dL) during the study. Patients with a baseline hemoglobin < 10 g/dL had a greater increase in hemoglobin, took longer to achieve the target hemoglobin, and received more red blood cell transfusions than patients with a baseline hemoglobin > or =10 g/dL. The percentage of patients with moderate to severe MDASI scores (> or =5 points) for fatigue, distress, loss of appetite, disturbed sleep, and interference with function was reduced during the study. Improvement in symptom burden was associated with an increase in hemoglobin concentration. CONCLUSIONS: Treatment with darbepoetin-alpha at a dose of 200 mug every 2 weeks is associated with improvement in symptom burden as measured by the MDASI, a simple tool that may improve symptom management for cancer patients with CIA. PMID- 17694553 TI - Patient selection, cancer control, and complications after salvage local therapy for postradiation prostate-specific antigen failure: a systematic review of the literature. AB - Among men who experience prostate-specific antigen (PSA) failure after external beam radiation or brachytherapy (RT), many will harbor occult micrometastases; however, a significant minority will have a true local-only failure and, thus, potentially may benefit from a salvage local therapy. Those most likely to have a local-only failure initially have low-risk disease (PSA < 10 ng/mL, Gleason score < or =6, clinical T1c or T2a tumor status), pretreatment PSA velocity < 2.0 ng/mL per year at the time of initial presentation, interval to PSA failure > 3 years, PSA doubling time > 12 months, negative bone scan and pelvic imaging, and positive rebiopsy. In addition, men with presalvage PSA levels > 10 ng/mL, presalvage T3/T4 disease, or presalvage Gleason scores > or =7 on a rebiopsy sample without significant RT effects are unlikely to be cured by salvage local therapy. Based on a review of all series of post-RT salvage prostatectomy, cryosurgery, and brachytherapy published in English since 1990, morbidity can be substantial. Although urinary incontinence appeared to be greater after salvage prostatectomy (41%) or cryosurgery (36%) than after brachytherapy (6%), patients who received salvage brachytherapy faced a 17% risk of grade 3 or 4 genitourinary complications and a fistula risk that averaged 3.4% across all series. From this review, the authors concluded that prospective randomized studies are needed to determine the relative efficacy of the 3 major local salvage modalities and that additional research is needed to identify factors associated with an increased risk of significant complications to improve patient selection and to augment the benefit/risk ratio associated with attempts to cure local-only recurrences after radiation therapy. PMID- 17694554 TI - Inflammatory breast cancer (IBC) and patterns of recurrence: understanding the biology of a unique disease. AB - BACKGROUND: Inflammatory breast cancer (IBC) is the most aggressive manifestation of primary breast cancer. The authors compared the prognostic features of IBC and non-IBC locally advanced breast cancer (LABC) to gain insight into the biology of this disease entity. METHODS: This retrospective analysis consisted of 1071 patients, comprising 240 patients with IBC and 831 patients with non-IBC LABC who were enrolled in 10 consecutive clinical trials (5 from each disease group). All patients received similar multidisciplinary treatment. The authors measured time to disease recurrence for each individual site from the start of treatment to the date of disease recurrence or last follow-up (recurrence-free survival) and overall survival rates to the date of last follow-up or death. RESULTS: The median follow-up period was 69 months (range, 1-367 months). Pathologically complete response rates were 13.9% and 11.7% in the IBC and non-IBC LABC groups, respectively (P = .42). The 5-year estimates of cumulative incidence of recurrence were 64.8 % and 43.4% (P < .0001), respectively, for IBC and non-IBC LABC. IBC had significantly higher cumulative incidence of locoregional recurrence and distant soft-tissue and bone disease. The 5-year overall survival (OS) rate was 40.5% for the IBC group (95% CI, 34.5%-47.4%) and 63.2% for the non IBC LABC group (95% CI, 60.0%-66.6%; P < .0001). CONCLUSIONS: IBC was associated with a worse prognosis and a distinctive pattern of early recurrence compared with LABC. These data suggested that investigating factors affecting "homing" of cancer cells may provide novel treatment strategies for IBC. PMID- 17694555 TI - Predictive factors for complications in elderly patients who underwent head and neck oncologic surgery. AB - BACKGROUND: Postoperative complications are relevant outcomes in patients with head and neck tumor who have undergone surgery. Few trials have assessed predictive factors in older patients. We assessed the predictive effect of preoperative clinical factors on postoperative complications. METHODS: We conducted a cohort study with 242 patients older than 70 years with head and neck cancer who underwent surgery. Logistic regression identified predictive factors for postoperative complications. Significant variables were used to build a predictive index. RESULTS: Comorbidities were present in 87.6% of patients, and 56.6% had some type of complication (44.6% local and 28.5% systemic). Male sex, bilateral neck dissection, presence of 2 or more comorbidities, reconstruction, and clinical stage IV were associated with postoperative complications. The predictive index showed a receiver operating characteristics curve (ROC) area of 0.69. CONCLUSION: It is possible to predict postoperative complications in older patients with head and neck tumors who underwent oncologic surgery using clinical preoperative variables. PMID- 17694556 TI - Interpretability of PET/CT imaging in head and neck cancer patients following composite mandibular resection and osteocutaneous free flap reconstruction. AB - BACKGROUND: We investigated positron emission tomography (PET)/CT scanning following segmental resections and osteocutaneous free-flap reconstruction. The interpretability of PET/CT imaging with healing osteotomies and reconstruction hardware was analyzed. METHODS: Patient scans within 18 months of surgery were interpreted for malignancy. Interpretations were compared with clinical data to determine sensitivity/specificity. Standardized uptake values (SUVs) were determined for bony controls, osteotomies, and tumors and were analyzed using paired t test. RESULTS: Fifteen scans were visually interpreted, 13 underwent SUV analysis. Reconstruction hardware did not interfere with interpretability. Sensitivity and specificity were 88% and 86%, respectively. Osteotomy sites averaged 25% higher SUVs compared with bony controls (vs sternum p = .003, vs mandible p = .008). Tumor SUVs were higher than osteotomies (p = .023) and controls (vs sternum p = .013, vs mandible p = .025). CONCLUSION: Although osteotomies were characterized by an increased fluorodeoxyglucose signal, scan interpretability was unimpaired. Our study suggests that PET/CT imaging can be utilized to survey free-flap patients at acceptable levels of sensitivity/specificity. PMID- 17694557 TI - Squamous cell carcinoma of the head and neck in never smoker-never drinkers: a descriptive epidemiologic study. AB - BACKGROUND: While the attributed risk factors for the vast majority of patients with squamous cell carcinoma of the head and neck (SCCHN) are smoking and alcohol abuse, there appears to be a rising proportion of SCCHN patients who report no significant smoking or drinking history. This study reports the demographic and potential risk factors of a large series of never smoker-never drinker (NSND) patients. METHODS: All subjects were participants in a prospective epidemiologic study of incident SCCHN. We obtained demographic data, clinical characteristics, and potential etiologic factors for 172 NSND patients and 1131 ever smoker-ever drinker (ESED) patients. RESULTS.: NSND patients were more likely to be female and to present at extremes of age, but overall were significantly younger than ESED patients. NSND patients had a higher proportion of oral cavity and oropharyngeal cancers than ESED patients had. Eleven percent of NSND patients (17% of NSND men) reported regular use of noncigarette tobacco products or marijuana, 41% (45% of NSND women) reported regular environmental exposure to tobacco smoke, 24% (36% of NSND men) reported regular occupational exposures to carcinogens/toxins, and 30% had a history of gastroesophageal reflux disease. More than half the NSND patients with an oropharyngeal primary were serologically positive for human papillomavirus type 16. CONCLUSION: NSND patients with SCCHN are commonly young women with oral tongue cancer, elderly women with gingival/buccal cancer, or young to middle-aged men with oropharyngeal cancer. While several exposures studied may be important to the etiology of a subset of these cancers in NSND patients, it is likely that no single known factor is responsible for a majority of SCCHN in NSNDs. PMID- 17694558 TI - Cost of care for early- and late-stage oral and pharyngeal cancer in the California Medicaid population. AB - BACKGROUND: This study documents the direct medical costs associated with treating oral and pharyngeal squamous cell carcinoma (OSCC) as early- or late stage disease according to the current standard of care. METHODS: This retrospective analysis of California Medicaid claims data calculated direct payments for patients diagnosed with OSCC. Patients were defined as being treated for early- or late-stage disease based on treatment modality. Regression determined significant predictors of year-1 cost of care following diagnosis. RESULTS: Median year-1 cost of care following initial diagnosis was $25,319 for the 229 patients identified. Regression results determined that treatment modality and medical comorbidities were significant in predicting costs (p < .05). Costs for patients treated as having early-stage OSCC were approximately 36% less than for those treated as having late-stage disease (p = .002). CONCLUSION: Treatment for OSCC is a significant cost from Medicaid's perspective, and these data suggest early detection may ease its economic burden. PMID- 17694559 TI - Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency. AB - Steroidogenic factor 1 (SF1, NR5A1) is a nuclear receptor that regulates multiple genes involved in adrenal and gonadal development, steroidogenesis, and the reproductive axis. Human mutations in SF1 were initially found in two 46,XY female patients with severe gonadal dysgenesis and primary adrenal failure. However, more recent case reports have suggested that heterozygous mutations in SF1 may also be found in patients with 46,XY partial gonadal dysgenesis and underandrogenization but normal adrenal function. We have analyzed the gene encoding SF1 (NR5A1) in a cohort of 27 patients with 46,XY disorders of sex development (DSD) from the German network of DSD. Heterozygous SF1 mutations were found in 5 out of 27 (18.5%) of cases. Four patients with SF1 mutations presented with the similar phenotype of mild gonadal dysgenesis, severe underandrogenization, and absent Mullerian structures. Of these, two patients harbored missense mutations within the DNA-binding region of SF1 (p.C33S, p.R84H), one patient had a nonsense mutation (p.Y138X) and one patient had a frameshift mutation (c.1277dupT) predicted to disrupt RNA stability or protein function. One additional patient ([c.424_427dupCCCA]+[p.G146A]) displayed a more marked phenotype of severe gonadal dysgenesis, normal female external genitalia, and Mullerian structures. Functional studies of the missense mutants (p.C33S, p.R84H) and of one nonsense mutant (p.Y138X) revealed impaired transcriptional activation of SF1-responsive target genes. To date, adrenal insufficiency has not occurred in any of the patients. Thus, SF1 mutations are a relatively frequent cause of 46,XY DSD in humans. PMID- 17694560 TI - Static magnetic fields enhance skeletal muscle differentiation in vitro by improving myoblast alignment. AB - Static magnetic field (SMF) interacts with mammal skeletal muscle; however, SMF effects on skeletal muscle cells are poorly investigated. The myogenic cell line L6, an in vitro model of muscle development, was used to investigate the effect of a 80 +/- mT SMF generated by a custom-made magnet. SMF promoted myogenic cell differentiation and hypertrophy, i.e., increased accumulation of actin and myosin and formation of large multinucleated myotubes. The elevated number of nuclei per myotube was derived from increased cell fusion efficiency, with no changes in cell proliferation upon SMF exposure. No alterations in myogenin expression, a modulator of myogenesis, occurred upon SMF exposure. SMF induced cells to align in parallel bundles, an orientation conserved throughout differentiation. SMF stimulated formation of actin stress-fiber like structures. SMF rescued muscle differentiation in the presence of TNF, a muscle differentiation inhibitor. We believe this is the first report showing that SMF promotes myogenic differentiation and cell alignment, in the absence of any invasive manipulation. SMF-enhanced parallel orientation of myotubes is relevant to tissue engineering of a highly organized tissue such as skeletal muscle. SMF rescue of muscle differentiation in the presence of TNF may have important therapeutic implications. PMID- 17694561 TI - Transcriptional analysis of polydnaviral genes in the course of parasitization reveals segment-specific patterns. AB - Polydnaviruses are symbiotic viruses of endoparasitic wasps, which are formed in their ovary and injected along with the eggs into the host. They manipulate the host in a way to allow successful parasitoid development. A hallmark of polydnaviruses is their segmented genome consisting of several circles of double stranded DNA. We are studying the solitary egg-larval parasitoid Chelonus inanitus (Braconidae) parasitizing Spodoptera littoralis (Noctuidae). The polydnavirus of Chelonus inanitus (CiV) protects the parasitoid larva from encapsulation by the host's immune system, slightly modifies host nutritional physiology, and induces a developmental arrest of the host in the prepupal stage. Here we present data on newly identified CiV genes and their expression patterns in the course of parasitization. None of these genes has similarity to other genes and so far no gene families could be found. A rough estimation of transcript quantities revealed that even the most highly expressed CiV genes reach maximal values, which are 250 times lower than actin. This indicates that the CiV-induced alterations of the host are brought about by a concerted action of low levels of transcripts. In an overview, we show the expression patterns of all CiV genes analysed up to now; they indicate that several genes with similar expression patterns (early, persistent, intermediate, or late) are grouped together on the same segment. This is the first observation of this type. It suggests that one function of the segmentation of the polydnavirus genome may be the grouping together of genes, which are regulated in a similar manner. PMID- 17694562 TI - The effects of boric acid-induced oxidative stress on antioxidant enzymes and survivorship in Galleria mellonella. AB - Larvae of the wax moth, Galleria mellonella (L.), were reared from first instar on a diet supplemented with 156, 620, 1,250, or 2,500 ppm boric acid (BA). The content of malondialdehyde (MDA, an oxidative stress indicator), and activities of the antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), and glutathione peroxidase (GPx)] were determined in the fat body and hemolymph in the 7th instar larvae and newly emerged pupae. Relative to control larvae, MDA was significantly increased in larval hemolymph, larval and pupal fat body, but decreased in the pupal hemolymph. Insects reared on diets with 156- and 620-ppm BA doses yielded increased SOD activity but 1,250- and 2,500-ppm doses resulted in decreased SOD activity in larval hemolymph. SOD activity was significantly increased but CAT was decreased in the larval fat body. High dietary BA treatments led to significantly decreased GST activity. However, they increased GPx activity in larval hemolymph. Dietary BA also affected larval survival. The 1,250- and 2,500 ppm concentrations led to significantly increased larval and pupal mortality and prolonged development. In contrast, the lowest BA concentration increased longevity and shortened development. We infer that BA toxicity is related, at least in part, to oxidative stress management. PMID- 17694563 TI - Effects of the compounds 2-methoxynaphthoquinone, 2-propoxynaphthoquinone, and 2 isopropoxynaphthoquinone on ecdysone 20-monooxygenase activity. AB - The effects of the natural compound 2-methoxy-1,4-naphthoquinone, isolated from the leaves of Impatiens glandulifera and the synthetic compounds 2-propoxy-1,4 naphthoquinone and 2-isopropoxy-1,4-naphthoquinone on ecdysone 20-monooxygenase (E-20-M) activity were examined in three insect species. Homogenates of wandering stage third instar larvae of Drosophila melanogaster, or abdomens from adult female Aedes aegypti, or fat body or midgut from fifth instar larvae of Manduca sexta were incubated with radiolabelled ecdysone and increasing concentrations (from 1 x 10(-8) to 1 x 10(-3) M) of the three compounds. All three compounds were found to inhibit in a dose-dependent fashion the E-20-M activity in the three insect species. The concentration of these compounds required to elicit a 50% inhibition of this steroid hydroxylase activity in the three insect species examined ranged from approximately 3 x 10(-5) to 7 x 10(-4) M. PMID- 17694564 TI - Significance of the 19-kDa hemolymph protein HP19 for the development of the rice moth Corcyra cephalonica: morphological and biochemical effects caused by antibody application. AB - The hemolymph protein HP19 of the rice moth, Corcyra cephalonica, mediates the 20 hydroxyecdysone (20E)-dependent acid phosphatase (ACP) activity at a nongenomic level. Affinity-purified polyclonal antibody against HP19 (alphaHP19-IgG) was used in the present study to understand the role of HP19 during the postembryonic development of Corcyra. In the in vitro studies, HP19 action was blocked either by immuno-precipitation using alphaHP19-IgG, prior to its addition to the fat body culture or by the addition of the antibody directly to the culture, along with 20E and hemolymph containing HP19. The alphaHP19-IgG blocked the HP19 mediated 20E-dependent ACP activation. In the in vivo studies, the alphaHP19-IgG was injected into the fully developed last (final/Vth) instar larvae of Corcyra, to complex the HP19 in vivo, in order to block the action of HP19. The injection of alphaHP19-IgG resulted in defective development of larvae, which grew either into non-viable larvae or larval-pupal/pupal-adult intermediates relative to the effect of pre-immune IgG injected controls. The present study shows that HP19 plays an important role in controlling the metamorphosis of Corcyra by regulating the 20E-dependent ACP activity. Coupled with the earlier findings, the ecdysteroid hormone regulates this action at a nongenomic level. PMID- 17694565 TI - Cotesia kariyai larvae need an anchor to emerge from the host Pseudaletia separata. AB - Mature larvae of the gregarious endoparasitoid Cotesia kariyai construct cocoons for pupation approximately 10 days after parasitization and emerge from their host Pseudaletia separata under a long day photo-regime (16L8D) at 25 +/- 1 degrees C. The parasitoid larvae make capsules in the host hemocoel just prior to their emergence. These capsules function as "anchors," which enable them to press against the host integument from inside the host. It was predicted that this anchor might be composed of silk proteins secreted from the parasitoid larvae, because a previous study showed that the anchor was made up of a glycoprotein and that the silk gland of parasitoid larvae developed from 2nd larval stage. Fibroin like proteins in C. kariyai larva mainly consist of two proteins with molecular masses of the 300.6 and 46.7 kDa estimated by SDS-PAGE. The fibroin-like proteins with the same molecular mass were detected from the anchor proteins just prior to parasitoid emergence. These results indicate that the anchor was assembled with fibroin-like proteins and was formed just before parasitoid emergence while in the host body cavity. Injection of bovine pancreatic trypsin inhibited the emergence of parasitoid larvae from the host because the anchor was decomposed by trypsin. Trypsin activity in the parasitized host hemolymph increased only after parasitoid emergence. PMID- 17694566 TI - Delivering genes to the organ-localized immune system: long-term results of direct intramarrow transduction. AB - We studied the distribution of transgene-expressing cells after direct gene transfer into the bone marrow (BM). Rats received direct injection into the femoral BM of SV(Nef-FLAG), a Tag-deleted recombinant SV40 carrying a marker gene (FLAG epitope). Controls received an unrelated rSV40 or saline. Blood cells (5%) and femoral marrow cells (25%) expressed FLAG throughout. FLAG expression was assessed in different organs at 1, 4 and 16 months. FLAG+ macrophages were seen throughout the body, and were prominent in the spleen. FLAG+ cells were common in pulmonary alveoli. The former included alveolar macrophages and type II pneumocytes. These cells were not detected at 1 month, occasional at 4 months and common at 16 months after intramarrow injection. Rare liver cells were positive for both FLAG and ferritin, indicating that some hepatocytes also expressed this BM-delivered transgene. Control animals were negative. Thus: (a) fixed tissue phagocytes may be accessible to gene delivery by intramarrow transduction of their progenitors; (b) transduced BM-resident cells or their derivatives may migrate to other organs (lungs) and may differentiate into epithelial cells; and (c) intramarrow injection of rSV40s does not detectably transduce parenchymal cells of other organs. PMID- 17694567 TI - Spot arrays on modified glass surfaces for efficient SPOT synthesis and on-chip bioassay of peptides. AB - To make SPOT synthesis of peptides and their assays on glass surfaces more convenient, a simple method for making spot arrays on a slide glass was designed through patterning with a photoresist and perfluorination followed by amination with various silane compounds and polymers. With these spot-arrayed glass surfaces, we could measure the coupling completion of each Fmoc amino acid on the glass surface by direct fluorescence analysis after fluorescence-labeling the amino groups on the surface of each spot. Then we synthesized several types of decapeptides and HPQ-pentapeptides on the spot-arrayed glasses and identified the optimal surface condition for stepwise peptide coupling and on-chip bioassay. After optimizing the surface conditions, we synthesized a model library of biotin Gly-Ala-P(1)-Gly (P(1): one of 19 amino acids) and successfully replicated the well-known alpha-chymotrypsin subsite specificities through Cy5-streptavidin binding to the remaining biotin on the surface after the enzymatic digestion. PMID- 17694568 TI - Bioinformatics-based discovery and identification of new biologically active peptides for GPCR deorphanization. AB - Owing to their involvement in many physiological and pathological processes, G protein-coupled receptors (GPCRs) are interesting targets for drug development. Approximately, 100 endoGPCRs lack their natural ligands and remain orphan (oGPCRs). Consequently, oGPCR deorphanization appears a promising research field for the development of new therapeutics. On the basis of the knowledge of currently known GPCR/ligand couples, some oGPCRs may be targeted by peptides. However, to find new drugs for GPCRs, Genepep has developed a dedicated bioinformatics platform to screen transcriptomic databases for the prediction of new GPCR ligands. The peptide lists generated include specific data, such as chemical and physical properties, the occurrence of post-translational modifications (PTMs) and an annotation referring to the location and expression level of the related putative genes. This information system allows a selection through series of biological criteria of approximately 10 000 natural peptides including already known GPCR ligands and potential new candidates for GPCR deorphanization. The most promising peptides for functional assay screening and future development as therapeutic agents are under evaluation. PMID- 17694569 TI - Evaluating the amino acid CF3-bicyclopentylglycine as a new label for solid-state 19 F-NMR structure analysis of membrane-bound peptides. AB - The conformation, alignment and dynamic behavior of membrane-bound peptides is readily accessible by solid-state (19)F-NMR spectroscopy, but it has been difficult to incorporate suitable (19)F-labelled amino acids into synthetic peptides. To avoid the drawbacks of previously used labels, we have rationally designed and synthesized a novel amino acid that suits all theoretical and practical requirements for peptide synthesis and subsequent (19)F-NMR structure analysis [Mikhailiuk et. al, Angew. Chem. 2006, 118, 5787-5789]. The enantiomerically pure L-form of 3-(trifluoromethyl)bicyclopent-[1.1.1]-1 ylglycine (CF(3)-Bpg) carries a CF(3) group that is rigidly attached to the peptide backbone and does not racemize during peptide synthesis. It could be demonstrated for several different peptides that their biological activity is usually not affected by a single label, nor the conformation, as monitored by circular dichroism. Here, we carry out a more detailed structure analysis to evaluate the potential and reliability of CF(3)-Bpg for solid-state NMR, using the well-known alpha-helical antimicrobial peptide PGLa as a test case. We have collected several orientational constraints from the anisotropic (19)F--(19)F dipolar couplings of CF(3)-Bpg in various positions of PGLa embedded in lipid bilayers. These resulting structural parameters are then compared with those previously determined from 4-CF(3)-phenylglycine and 3,3,3-d(3)-alanine labels on the same peptide. The analysis confirms that CF(3)-Bpg does not perturb the alpha helical conformation of PGLa. Likewise, the helix alignment is shown to follow the established concentration-dependent pattern in realigning from a surface bound S-state to an obliquely tilted T-state. Hence, the advantages of CF(3)-Bpg over all previously used (19)F-labeled side chains are evident, as they combine ease of chemical incorporation and peptide purification with high NMR sensitivity and absent background signals, allowing a straightforward analysis of the dipolar splittings with no need for chemical shift referencing without any ambiguity in the sign of the couplings. PMID- 17694570 TI - Automated structure verification based on a combination of 1D (1)H NMR and 2D (1)H - (13)C HSQC spectra. AB - A method for structure validation based on the simultaneous analysis of a 1D (1)H NMR and 2D (1)H - (13)C single-bond correlation spectrum such as HSQC or HMQC is presented here. When compared with the validation of a structure by a 1D (1)H NMR spectrum alone, the advantage of including a 2D HSQC spectrum in structure validation is that it adds not only the information of (13)C shifts, but also which proton shifts they are directly coupled to, and an indication of which methylene protons are diastereotopic. The lack of corresponding peaks in the 2D spectrum that appear in the 1D (1)H spectrum, also gives a clear picture of which protons are attached to heteroatoms. For all these benefits, combined NMR verification was expected and found by all metrics to be superior to validation by 1D (1)H NMR alone. Using multiple real-life data sets of chemical structures and the corresponding 1D and 2D data, it was possible to unambiguously identify at least 90% of the correct structures. As part of this test, challenging incorrect structures, mostly regioisomers, were also matched with each spectrum set. For these incorrect structures, the false positive rate was observed as low as 6%. PMID- 17694571 TI - Characterisation of the expression and function of the GM-CSF receptor alpha chain in mice. AB - The granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine able to regulate a variety of cell functions including differentiation of macrophages and granulocytes, dendritic cell development and the maintenance of homeostasis. It binds specifically to its receptor, which is composed of a cytokine-specific alpha-chain (GM-CSF receptor alpha-chain, GMRalpha) and a beta chain shared with the receptors for interleukin-3 and interleukin-5. In this report, we present a comprehensive study of GMRalpha in the mouse. We have found that the mouse GMRalpha is polymorphic and alternatively spliced. In the absence of specific antibodies, we generated a novel chimeric protein containing the Fc fragment of human IgG1 coupled to mouse GM-CSF, which was able to specifically bind to GMRalpha and induce proliferation of GMRalpha-transduced Ba/F3 cells. We used this reagent to perform the first detailed FACS study of the surface expression of mouse GMRalpha by leucocytes. Highest expression was found on monocytes and granulocytes, and variable expression on tissue macrophages. The GM CSF receptor in mice is specifically expressed by myeloid cells and is useful for the detection of novel uncharacterised myeloid populations. The ability to detect GM-CSF receptor expression in experimental studies should greatly facilitate the analysis of its role in immune pathologies. PMID- 17694572 TI - Inhibition of calcineurin-NFAT signaling by the pyrazolopyrimidine compound NCI3. AB - Dephosphorylation of NFAT by the Ca(2+)-calmodulin-dependent Ser/Thr protein phosphatase calcineurin is a bottleneck of T cell receptor-dependent activation of T cells. In dimeric complexes with immunophilins, the immunosuppressants cyclosporine A (CsA) and tacrolimus (FK506) block this process by inhibition of the enzymatic activity of calcineurin. We have identified the pyrazolopyrimidine compound NCI3 as a novel inhibitor of calcineurin-NFAT signaling. Similar to CsA and FK506, NCI3 inhibits dephosphorylation and nuclear translocation of NFAT, IL 2 production and proliferation of stimulated human primary T cells with IC(50) values from 2 to 4.5 microM. However, contrary to CsA and FK506, NCI3 neither blocks calcineurin;s phosphatase activity nor requires immunophilins for inhibiting NFAT activation. Our data suggest that NCI3 binds to calcineurin and causes an allosteric change interfering with NFAT dephosphorylation in vivo but not in vitro. NCI3 acts not only on the endogenous calcineurin but also on a C terminally truncated, constitutively active version of calcineurin. The novel inhibitor described herein will be useful in better defining the cellular regulation of calcineurin activation and may serve as a lead for the development of a new type of immunosuppressants acting not by direct inhibition of the calcineurin phosphatase activity. PMID- 17694573 TI - Redefining epithelial progenitor potential in the developing thymus. AB - Cortical and medullary epithelium represent specialised cell types that play key roles in thymocyte development, including positive and negative selection of the T cell repertoire. While recent evidence shows that these epithelial lineages share a common embryonic origin, the phenotype and possible persistence of such progenitor cells in the thymus at later stages of development remain controversial. Through use of a panel of reagents including the putative progenitor marker Mts24, we set out to redefine the stages in the development of thymic epithelium. In the early embryonic day (E)12 thymus anlagen we find that almost all epithelial cells are uniformly positive for Mts24 expression. In addition, while the thymus at later stages of development was found to contain distinct Mts24(+) and Mts24(-) epithelial subsets, thymus grafting experiments show that both Mts24(+) and Mts24(-) epithelial subsets share the ability to form organised cortical and medullary thymic microenvironments that support T cell development, a function shown previously to be lost in the Mts24(-) cells by E15 when lower cell doses were used. Our data help to clarify stages in thymic epithelial development and provide important information in relation to currently used markers of epithelial progenitors. PMID- 17694574 TI - The chemokine receptor CCR6 is an important component of the innate immune response. AB - In our initial studies we found that naive CCR6-deficient (CCR6(-/-)) C57BL/6 mice possessed significantly lower number of both F4/80(+) macrophages and dendritic cells (DC), but higher number of B cells in the peritoneal cavity, as compared to naive wild type (WT) controls. Furthermore, peritoneal macrophages isolated from CCR6(-/-) mice expressed significantly lower levels of inflammatory cytokines and nitric oxide following lipopolysaccharide (LPS)stimulation, as compared to WT macrophages. In a severe experimental peritonitis model induced by cecal ligation and puncture (CLP), CCR6(-/-) mice were protected when compared with WT controls. At 24 h following the induction of peritonitis, CCR6(-/-) mice exhibited significantly lower levels of inflammatory cytokines/chemokines in both the peritoneal cavity and blood. Interestingly, DC recruitment into the peritoneal cavity was impaired in CCR6(-/-) mice during the evolution of CLP induced peritonitis. Peritoneal macrophages isolated from surviving CCR6(-/-) mice 3 days after CLP-induced peritonitis exhibited an enhanced LPS response compared with similarly treated WT peritoneal macrophages. These data illustrate that CCR6 deficiency alters the innate response via attenuating the hyperactive local and systemic inflammatory response during CLP-induced peritonitis. PMID- 17694575 TI - DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. AB - The transcription factor FOXP3 is critical for development and function of regulatory T cells (Treg). Their number and functioning appears to be crucial in the prevention of autoimmunity and allergy, but also to be a negative prognostic marker for various solid tumors. Although expression of the transcription factor FOXP3 currently constitutes the best-known marker for Treg, in humans, transient expression is also observed in activated non-Treg. Extending our recent findings for the murine foxp3 locus, we observed epigenetic modification of several regions in the human FOXP3 locus exclusively occurring in Treg. Importantly, activated conventional CD4(+) T cells and TGF-beta-treated cells displayed no FOXP3 DNA demethylation despite expression of FOXP3, whereas subsets of Treg stable even upon extended in vitro expansion remained demethylated. To investigate whether a whole set of genes might be epigenetically imprinted in the Treg lineage, we conducted a genome-wide differential methylation hybridization analysis. Several genes were found displaying differential methylation between Treg and conventional T cells, but none beside FOXP3 turned out to be entirely specific to Treg when tested on a broad panel of cells and tissues. We conclude that FOXP3 DNA demethylation constitutes the most reliable criterion for natural Treg available at present. PMID- 17694576 TI - Activation of retinoic acid receptor-alpha favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. AB - Autoimmunity is thought to reflect an imbalance between regulatory T helper lymphocytes (Treg) and pathogenic, IL-17-secreting T helper (Th17) cells. Induction of both adaptive Treg and Th17 cells requires signalling from TGF-beta. We now show that, in the context of TGF-beta signalling, all-trans retinoic acid (ATRA) leads to increased induction of CD4(+) T cells expressing the Treg specification factor forkhead box protein P3 (FoxP3) and decreased frequency of cells expressing IL-17, even in the presence of IL-6. Using a specific agonist and antagonist, as well as retroviral over-expression, we also provide evidence that the effects of ATRA are likely to be at least partially mediated by the nuclear retinoic acid receptor-alpha (RARalpha). These findings indicate that signalling through a specific nuclear retinoic acid receptor can favour the decision to adopt the Treg fate at the expense of Th17 fate. Specific agonists of RARalpha could, therefore, be considered candidates for the treatment of autoimmunity. PMID- 17694577 TI - Ruptured omphalocele with extracorporeal intestines mimicking gastroschisis in a fetus with Turner syndrome. PMID- 17694578 TI - Treatment with amniopatch of premature rupture of membranes after first-trimester chorionic villus sampling. AB - OBJECTIVE: To assess the amniopatch procedure when premature rupture of membranes occurs after first-trimester chorionic villus sampling (CVS). STUDY DESIGN: From May 2001 to June 2004, the amniopatch procedure was offered in cases of premature rupture of membranes after CVS when severe oligohydramnios was present (largest vertical pocket < 2 cm) and persistent (more than 1 week). RESULTS: The amniopatch was placed in five pregnancies at 12-18 weeks of gestation, resulting in amniotic fluid restoration in all but one pregnancy. In three pregnancies, fetal demise was observed at 1, 2 and 36 days after the procedure. The last procedure resulted in a healthy newborn. CONCLUSION: Although the amniopatch restored normal amniotic fluid levels in all cases, 4 of the 5 cases resulted in fetal demise. PMID- 17694579 TI - Risk of recurrence in major central nervous system malformations between 1976 and 2005. AB - OBJECTIVE: The goal of the current publication is to review isolated central nervous system malformations (CSMs) using a database in excess of 75 000 cases, with special regard to the risk of recurrence of these malformations alone or in combination. METHODS: In the period between 1 January 1976 and 31 December 2005, among the 75 320 documented cases, consultations were requested due to earlier isolated CSMs in the patients' histories in 3030 cases (4.2%). Processing the data we only considered disorders of genetic origin, and that was why we excluded the cases due to intrauterine infection. Monogenically inherited malformations were also excluded from the analysis. The diagnosis of the malformations was based on the prenatal diagnosis of ultrasonography as well as the findings of the foetopathological examination. RESULTS: In 65% of the cases, the couples sought counselling because of malformation in a previous pregnancy. In these cases, the risk of recurrence was thought to be 5.2%, while in the case of two affected children this figure stood at 21.9%. Analysing the values for the risk of recurrence in 5-year periods, neural tube defects (NTDs) (particularly anencephaly and spina bifida) showed a detectable decrease, which could be attributed to a growing use of folic acid supplementation around the time of conception and during pregnancy. CONCLUSION: There is a clear decrease of risk of recurrence of NTDs, while in the case of the other CSMs in this study, there is no noteworthy chronological change in their risk of recurrence. PMID- 17694580 TI - Presenting results of probabilistic sensitivity analysis: the incremental benefit curve. AB - Cost-effectiveness acceptability curves have become a common way of presenting the results of probabilistic sensitivity analysis. However, these curves do not provide information on what the loss of welfare or net benefit (NB) is for cases where a given intervention is not the optimal one. We describe an alternate approach to presenting the results of probabilistic sensitivity analysis called the incremental benefit curve that presents the entire distribution of incremental NB of each intervention for a given WTP value. The incremental benefit curve provides the decision maker information regarding the potential welfare loss with a given intervention for scenarios in which it is not the optimal intervention, and thus would be a useful complement to the acceptability curve. PMID- 17694585 TI - Hierarchical nanomanufacturing: from shaped zeolite nanoparticles to high performance separation membranes. AB - Despite more than a decade of intense research on the high-resolution selectivity of thin zeolite films as alternatives to energy-intensive industrial separations, membranes consisting of intergrown, oriented zeolite crystals have fallen short of gaining wide commercial application. Factors including poor performance, high cost, and difficulties in scale up have contributed to this, and have also stunted their application in other niche markets. Until recently, rational design of these materials was limited because of the elusive mechanism of zeolite growth, and forced more empirical approaches. New understanding of zeolite growth along with recent advances in the molecular engineering of crystal microstructure and morphology, assembly of crystal monolayers, and synthesis of ordered films constitute a strong foundation for meeting stringent industrial demands in the future. Together with new processing capabilities, such a foundation should make it possible to synthesize commercially viable zeolite membranes through hierarchical approaches. Such advances open exciting prospects beyond the realm of separations for assembly of novel and complex functional materials including molecular sensors, mechanically stable dielectrics, and novel reaction-diffusion devices. PMID- 17694586 TI - Synthesis, characterization, and chirality of dimeric N-confused porphyrin-zinc complexes: toward the enantioselective synthesis of bis(porphyrinoid) systems. PMID- 17694587 TI - Chiral recognition inside a chiral cucurbituril. PMID- 17694588 TI - Direct enrichment of metallic single-walled carbon nanotubes induced by the different molecular composition of monohydroxy alcohol homologues. PMID- 17694589 TI - Monitoring single-cell infectivity from virus-particle nanoarrays fabricated by parallel dip-pen nanolithography. PMID- 17694590 TI - Design and synthesis of cyclopeptide analogues of the potent histone deacetylase inhibitor FR235222. AB - Various structurally modified analogues of FR235222 (1), a natural tetrapeptide inhibitor of mammalian histone deacetylases, were prepared in a convergent approach. The design of the compounds was aimed to investigate the effect of structural modifications of the tetrapeptide core involved in enzyme binding in order to overcome some synthetic difficulties connected with the natural product 1. The modifications introduced could also help identify key structural features involved in the mechanism of action of these compounds. The prepared molecules were subjected to in vitro pharmacological tests, and their potency was tested on cultured cells. Two of the components of the array were found to be more potent than the parent compound 1 and almost as efficient as trichostatin A (TSA). These results demonstrate that it is possible to synthesize highly active cyclic tetrapeptides using commercially available amino acids (with the exception of 2 amino-8-oxodecanoic acid, Ahoda). The nature of the residue in the second position of the cyclic peptide and the stereochemistry of the Ahoda tail are important for the inhibitory activity of this class of cyclic tetrapeptide analogues. PMID- 17694591 TI - Differential EI fragmentation pathways for peracetylated C-glycoside ketones as a consequence of bicyclic ketal ring structures. AB - Several C-glycoside ketones and peracetylated C-glycoside ketones have been synthesized from 13 structurally-diverse aldoses sugars (including isotope labeled [1-(13)C]Glc, [U-(13)C]Glc, and [6, 6'-(2)H(2)]Glc) via an aqueous-based Knoevanagel condensation with aliphatic 1,3-diketones. Sodium adduct molecular ions observed by MALDI-TOF MS confirmed that the reactions are essentially quantitative, and that the acetylation products are the expected peracetylated C glycoside ketones, rather than cyclized ketofurans. Analysis of the peracetylated C-glycoside ketones by gas chromatography-EI-MS show characteristic fragment ions that have been assigned to four distinct fragmentation pathways. Peracetylated aldohexose-, aldopentose-, and 6-deoxyaldohexose-C-glycoside ketones fragment via gas phase furanoid intermediates. These data, and DFT calculations, indicate that the furanoid intermediates arise because the peracetylated C-glycoside ketones adopt a bicyclic structure containing a 5-member ketal ring. This ketal ring is the precursor of the furanoid rings in the gas phase. The 2-deoxyhexose-C glycoside ketones are unable to form an intramolecular 2-ketal bond, and therefore undergo ion fragmentations via nonfuranoid pathways. PMID- 17694592 TI - Self-assembled-monolayer-modified silicon substrate to enhance the sensitivity of peptide detection for AP-MALDI mass spectrometry. AB - A self-assembled-monolayer-modified silicon substrate was successfully used to enhance the sensitivity of peptide detection for atmospheric pressure-matrix assisted laser desorption/ionization mass spectrometry (AP-MALDI/MS). The effect of surface modification of silicon wafer samples with NH(2) and OH functional groups was investigated. In addition, solvent effects for the preparation of modified NH(2)-functionalized surfaces were examined. The sensitivities for the two peptides were significantly improved, increasing between 12 and 160 times, for bradykinin and gramicidin, respectively, on an NH(2)-modified silicon surface prepared in toluene, over that on a conventional gold substrate. The limits of detection (LODs) for bradykinin and gramicidin using the conventional gold substrate in AP-MALDI/MS experiments were > 0.011 microM and 110 microM, respectively. Using our SAM approach, the LODs for bradykinin and gramicidin in AP-MALDI/MS can be improved to 0.93 nM and 0.33 microM, respectively. This SAM approach for AP-MALDI/MS is simple and sensitive, and can be used for high throughput analysis. PMID- 17694593 TI - Study of the phase I and phase II metabolism of a mixture containing multiple tanshinones using liquid chromatography/tandem mass spectrometry. AB - Metabolism of a mixture containing four dominant components in lipid solubles of Danshen was studied both in vitro and in vivo. The parent compounds and their metabolites were simultaneously detected by using liquid chromatography coupled with ion trap mass spectrometry. The results indicated that oxidation was the major pathway in phase I metabolism. O-Glucuronidation of the hydroxylated tanshinones was identified in the rat urine samples collected after the oral administration of the tanshinone components. The metabolic rates obtained from the in vitro metabolism study of each individual component were significantly different from those obtained from the incubation study of the four components in a cassette. Metabolite identification showed that tanshinone IIA and tanshinone I were the major metabolites of cryptotanshinone and dihydrotanshinone I, respectively. The obtained results demonstrated the metabolic change between the active components in Danshen and suggested the need to study the multiple components or even the extract from the herbal medicines. PMID- 17694594 TI - A Bayesian analysis of doubly censored data using a hierarchical Cox model. AB - Two common statistical problems in pooling survival data from several studies are addressed. The first problem is that the data are doubly censored in that the origin is interval censored and the endpoint event may be right censored. Two approaches to incorporate the uncertainty of interval-censored origins are developed, and then compared with more usual analyses using imputation of a single fixed value for each origin. The second problem is that the data are collected from multiple studies and it is likely that heterogeneity exists among the study populations. A random-effects hierarchical Cox proportional hazards model is therefore used. The scientific problem motivating this work is a pooled survival analysis of data sets from three studies to examine the effect of GB virus type C (GBV-C) coinfection on survival of HIV-infected individuals. The time of HIV infection is the origin and for each subject this time is unknown, but is known to lie later than the last time at which the subject was known to be HIV negative, and earlier than the first time the subject was known to be HIV positive. The use of an approximate Bayesian approach using the partial likelihood as the likelihood is recommended because it more appropriately incorporates the uncertainty of interval-censored HIV infection times. PMID- 17694595 TI - Behavioral regulation: factor analysis and application of the Behavioral Dyscontrol Scale in dementia and mild cognitive impairment. AB - BACKGROUND: Executive dysfunction is a hallmark of both Dementia of the Alzheimer's Type (AD) and Vascular Dementia (VaD). A complete neuropsychological battery contains measures of executive function, but the focus tends to be on cognitive processes with verbal or written output. The Behavioral Dyscontrol Scale (BDS) is purported to be a measure of executive function that addresses control over voluntary motor behavior. Previous factor analyses revealed three factor solutions using a variety of patient populations. Our goals were to examine the factor structure in a sample of geriatric outpatients and to apply that factor structure to detect possible differences between AD, VaD, amnestic Mild Cognitive Impairment (MCI), non-amnestic MCI, and normal controls. METHODS: An exploratory factor analysis was performed on 260 outpatient evaluations from 2002-2006. Only the seven items requiring motor responses were included. RESULTS: A two-factor solution emerged. We named the factors Motor Problem-Solving and Simple Motor Repetitive Behaviors. For the first factor, the AD and VaD groups differed from the MCI groups and normal controls, but did not differ from each other. There were no differences between the control, amnestic MCI, and non amnestic MCI groups. There were no differences between the groups for the second factor. CONCLUSION: It was concluded that voluntary control of behavior that requires problem-solving for complex tasks may help differentiate dementia from mild cognitive impairment and normal aging. PMID- 17694596 TI - Religion and the war in Sudan. PMID- 17694597 TI - Measurements of the cyclic variation of myocardial backscatter from two dimensional echocardiographic images as an approach for characterizing diabetic cardiomyopathy. PMID- 17694598 TI - Mesh repairs in hiatal surgery. The case for mesh repairs in hiatal surgery. PMID- 17694599 TI - Post-discharge symptomatic thromboembolic events in hip fracture patients. AB - INTRODUCTION: The aim of this study was to audit referral rates for post discharge symptomatic thromboembolic events following hip fracture surgery to assess the extent of the clinical problem and to initiate discussion on prolonged chemoprophylaxis. PATIENTS AND METHODS: All patients who underwent surgery for proximal hip fractures in one year (2001-2002) were followed up. Patient case notes were used to identify all morbidity episodes within 3 months following discharge. Patients with suspected symptomatic thromboembolic episodes were investigated to confirm the diagnoses objectively. Reasons for hospital readmission and causes of death were identified. RESULTS: A total of 267 patients who underwent surgery for proximal hip fractures were included in the study. Forty-three patients died during initial admission episode. Of the 224 patients discharged, 46 (20.54%) patients were referred back to hospital within 3 months, for unplanned emergency management. Of these, 8 patients (3.57%) were referred back for suspected thromboembolic events. Of these, 6 (2.67%) were referred with a clinical diagnoses of deep vein thrombosis (DVT) but only 1 patient (0.45%) was confirmed to have DVT. Two patients (0.89%) were referred with features of pulmonary embolism (PE). Both were confirmed on ventilation-perfusion scans and both patients died. One patient died following PE in the community.Thus, overall, 3 deaths (1.34%) following discharge were recorded to be due to pulmonary embolism. CONCLUSIONS: Suspected thromboembolic events constitute a major proportion of unplanned referrals back to the hospital. Three deaths due to delayed pulmonary embolism may justify prolonged universal chemoprophylaxis following hip fracture surgery. PMID- 17694600 TI - Abstracts from the Bone Research Society Annual Meeting, 3-5 July 2007, Southampton, United Kingdom. PMID- 17694602 TI - Consumer-driven health plans: early evidence and potential impact on hospitals. AB - Consumer-driven health plans-tax--advantaged accounts paired with high-deductible coverage--represent a small but rapidly growing part of insurance offerings. Supporters believe that such plans will encourage consumers to become better informed, more cost-conscious users of health care. Opponents worry that patients will obtain fewer necessary and nonessential services alike. Early evidence suggests that consumer-driven plans result in lower costs and increased use of preventive and chronic care services, but these findings are preliminary. The biggest effect for hospitals might be the pressure produced for increased price transparency and greater uniformity in pricing, although high-deductible plans also could reduce hospital spending by reducing use. PMID- 17694603 TI - Plea for privacy. PMID- 17694604 TI - Collapsing focal segmental glomerulosclerosis as a possible complication of valproic acid. PMID- 17694605 TI - Surprise 'social status' finding in rape study. PMID- 17694606 TI - [The role of desensitization of glucocorticoid receptors in the development of vascular resistance to endogenous vasoconstrictors in traumatic shock]. AB - The fact that the activity of cytosol glucocorticoid receptors decreases in shock have been shown before [Golikov P. P. et al., 2001]. The connection between the development of vascular hyporeactivity to endogenous vasoconstrictors and desensitization of glucocorticoid receptors was studied in this investigation. On Kenton traumatic model in a rat experiment, it was shown that the strength of the isometric constriction of the isolated aorta in response to angiotensin II, endothelin-1, phenylephrine, noradrenaline, and vasopressin falls on the second day after a severe mechanical injury (3.3, 2.1, 1.7, 1.6, and 1.5 times, respectively; p < 0.01). On the contrary, the strength of the constriction in response to serotonin increases more then twice. Artificial desensitization of glucocorticoid receptors by long-term administration of dexamethasone (3 mg per kg during five days) results in similar changes of vascular reactivity i.e. a 2.5, 2, 7, and 1.4-fold decrease in the strength of aortal constriction in response to angiotensin II, vasopressin, and endothelin-1, respectively. The strength of the constriction in response to serotonin tended to increase as well. Carbahol-induced relaxation of the aorta pre-constricted with noradrenaline did not change compared with control, being 70 to 80%, both in shock and after desensitization of glucocorticoid receptors with dexamethasone. Presumably, the pathogenetic mechanism of pressor reaction suppression, connected with a decrease in cytosol glucocorticoid receptor activity and thus with inhibition of glucocorticoid-induced expression of the membrane receptors of endogenous vasoconstrictors, is realized in traumatic shock together with other mechanisms. PMID- 17694607 TI - Tuberculin skin test (TST) conversion rates for the US Navy and Marine Corps. PMID- 17694609 TI - What triggers heart attacks? Sudden stress--whether it's from anger, a heat wave, or getting out of bed--can be the final "insult" that sets off a heart attack, stroke, or cardiac arrest. PMID- 17694610 TI - Guidelines offer women a change of heart. Focusing on prevention is the best way to halt heart disease in women. PMID- 17694611 TI - A road map to life in the fat lane. PMID- 17694612 TI - Drive-through angioplasty? PMID- 17694613 TI - Ask the doctor. Is warfarin turning my toes purple? PMID- 17694614 TI - Ask the doctor. Can you really prevent heart disease? PMID- 17694615 TI - HIPAI and animal welfare on the agenda in Krakow. PMID- 17694616 TI - Fewer cases of neonatal septicaemia in Scottish calves. PMID- 17694617 TI - Revised recommendations of the Advisory Committee on Immunization Practices to Vaccinate all Persons Aged 11-18 Years with Meningococcal Conjugate Vaccine. PMID- 17694619 TI - Bibliography. Current world literature. Allergy. PMID- 17694618 TI - Bibliography. Current world literature. Facial plastic surgery. PMID- 17694620 TI - Bibliography. Current world literature. Anaphylaxis and insect allergy. PMID- 17694621 TI - A technique to avoid leg-length discrepancy in total hip arthroplasty. PMID- 17694622 TI - A cuff of a flatus tube -- an aid to the endoscopic removal of small, sharp ingested foreign bodies. PMID- 17694623 TI - DEFRA seeks views on a wildlife health strategy. PMID- 17694624 TI - Welsh Assembly appeals against overturn of TB slaughter notice. PMID- 17694625 TI - Equine disease surveillance, January to March 2007. PMID- 17694626 TI - Outbreak of highly pathogenic avian influenza caused by Asian lineage H5N1 virus in turkeys in Great Britain in January 2007. PMID- 17694627 TI - Abstracts of the International Symposium on Interdisciplinary Life Science: From Genome to Function, Zhengzhou, Henan, China, 12-15 October 2005. PMID- 17694628 TI - Abstracts of the International Symposium on Cell Biology: From Basic Research to Clinical Applications, Chongqing, China, 14-16 October 2004. PMID- 17694629 TI - Abstracts of the International Symposium on Cell Signaling--From Disease to Drug Discovery, Hong Kong, 15-17 October 2001. PMID- 17694630 TI - AHA scientific statement: new blood pressure targets for high-risk and established coronary artery disease patients. PMID- 17694631 TI - [The New International Health Regulations (2005 IHR)]. PMID- 17694632 TI - [Bibliometric study of the original articles published in Revista Espanola de Salud Puiblica (1991-2000). Part III: reference analysis]. AB - BACKGROUND: The advancement of knowledge is based on the results of previously conducted research studies, which are reflected in the reference sources listed in a scientific article. This study is aimed at studying the scientific information used in the Revista Espanola de Salud Publica based on the references cited in the original articles published during the 1991-2000 period. METHODS: The data regarding the year and where published, document type, language and country in which published was taken from the reference sources listed in the 290 original articles published, the obsolescence, Price and isolation indexes being calculated, and the Bradford core distribution being established according to the source journals. The self-citing rate was also calculated. RESULTS: A total of 7465 references were cited in the Reference section of the 290 original articles. An average of 25.7 references were cited per article. The Price index was 40.7. The scientific articles showed an obsolescence index of 5, the books and book chapters having an index of 6. A total 50.6% of the citations were from studies published in Spanish. The isolation index of the references was 48.1. The first Bradford core is comprised of 10 journals, the first four of which are Spanish. The self-citing rate was 3.8%. CONCLUSIONS: The information consumption of the original articles published in the Revista Espanola de Salud Publica show parameters similar to those of other Spanish health sciences journals for those same years, and the parameters regarding which this Journal differs from other Spanish health sciences journals seem to be justified by those particular aspects unique to public health, which does not fall within the patterns inherent to the clinical disciplines. PMID- 17694633 TI - [Estimate of the mortality rate attributable to occupational diseases in Spain, 2004]. AB - BACKGROUND: Occupational diseases are not registered in Spain to a sufficient degree so as to be able to evaluate the impact thereof in our country. In this study, the occupational disease-related mortality and the costs thereof are estimated based on attributable risks calculated in international literature. METHODS: Attributable risk estimates are applied for the occupationally-caused deaths rate calculated by Nurminen and Karjalainen (Finland, 2001) are applied to the total number of deaths by the relevant diseases and age groups in Spain and in Autonomous Communities in 2004. The potential years of life and working life lost are calculated. Based upon the years of working life lost, the updated costs of the loss of productive life due to deaths caused by occupational diseases in Spain are estimated. RESULTS: According to our estimates, nearly 16,000 deaths would have occurred in Spain due to occupational exposure-related diseases, the majority in males (87%). These deaths could have caused nearly 152,000 potential years of life lost and somewhat over 47,000 potential years of working life lost, which would entail an updated cost in productivity losses of 580 million - 1 billion euros. CONCLUSIONS: In 2004, the occupational disease register in Spain included solely two deaths due to this cause. The results of this study however reveal the importance of working conditions as determining factors in preventable deaths among the population and the imminent need for adequate surveillance and prevention systems for dealing with this public health problem in its full magnitude. PMID- 17694634 TI - [Marked hypertransaminasemia incidence in a health department in the autonomous community of Valencia, Spain (2002-2003)]. AB - BACKGROUND: Marked hypertransaminasemia (HT) is not an infrequent situation within clinical practice, which is usually interpreted as primary acute liver damage. The objectives of this study were to determine the incidence, mortality rate and aetiology of marked HT among the general population, and the use therefore as an indicator of primary acute liver damage. METHODS: A retrospective study was made of all patients with marked HT (ALT >400 IU/L) which were attended over a two-year period at the Healthcare Department n 11 in the Autonomous Community of Valencia. The computerized medical records and the results of the different supplementary examinations made were reviewed, and an analysis was made of different variables: clinical diagnosis and evolution, other liver function related biochemical parameters and autoimmune and infection serology markers. RESULTS: A total of 414 patients with marked HT were identified (incidence of 88 cases/100,000 inhab./year), 73 of whom died (mortality rate of 16 deaths/100,000 inhab./year). Of the twenty aetiologies found, the most frequent were extrahepatic cholestasis (28.3%), hypoxic hepatopathy (14.6%) and sepsis (11.9%). The positive predictive value of marked HT as an indicator of primary acute liver damage was 27.7%. CONCLUSIONS: Marked HT is a disorder having a remarkable incidence rate among the general population, entailing a high mortality rate. Its aetiology is widely varied, being however the extrahepatic origin predominant. PMID- 17694635 TI - [Trend in platelet antiaggregants utilization in the autonomous community of Valencia, Spain (2000-2005)]. AB - BACKGROUND: Platelet antiaggregants are basic drugs for preventing ischemic arterial diseases. This study is aimed at ascertaining the trend in their use in Primary Care in the Autonomous Community of Valencia during the 2000-2005 period. METHODS: Descriptive study of the use of platelet antiaggregants (ATC code: B01AC) dispensed charged to the National Health System in the Autonomous Community of Valencia in Primary Care. Data given in defined daily doses (DDD) per 1000 inhabitants per day. RESULTS: In 2005, three drugs totalled 98% of all those prescribed overall (acetyl salicylicacid (ASA) 66%, clopidogrel 23% and triflusal 9%). Oral antiaggregant use rose by 23% within the 2000-2005 period (from 29.6 to 36.5 DDD/1000 inhab./day). Clopidogrel showed a 218% increase, whilst ASA was the most used drug, with quite a stable percentage of use throughout said time period (nearing 70%). The expense generated by this group of drugs doubled, clopidogrel having been the highest-cost drug/DDD (2.14 EUROS), its use having totalled 23% of all antiaggregants yet the expense thereof having totalled 76% of the total expenditure. CONCLUSIONS: The use of antiaggregants increased in the Autonomous Community of Valencia during the time period under study. The utilization of ASA remained stable, whilst clopidogrel increased its market share despite the treatment guide recommendations and the restrictions on its use. The consumption of clopidogrel noticeably contributed to the drug spending for this group. PMID- 17694636 TI - [Comprension of a document informing citizens as to the benefits and risks of prostate cancer screening. A semistructured interview-based study]. AB - BACKGROUND: The development of tools to aid in prostate cancer screening-related decision-making is a challenge for healthcare professionals and institutions. This study is aimed at evaluating citizen comprehension of a document prepared by experts informing as to prostate cancer screening benefits and risks. METHODS: Phenomenological qualitative study conducted in Barcelona (November 2004-January 2005). The data was gathered by means of seven interviews with males within the 50-70 age range of different educational levels attended in primary care. A descriptive-narrative theme-based categorical content analysis was made of the narrative discourse. RESULTS: This document provides knowledge regarding the aforementioned aspects, although the males possessing a lower level of education point out words and concepts found difficult to understand. In all of the educational strata, the screening-related doubts entertained are due to the prostate-specific antigen not having been precisely stated, the concept most difficult to understand being that of early cancer detection possibly not being beneficial. They are of the opinion that this document is useful for what they consider as being a decision which must be made by the patient with the collaboration of the professionals. Those interviewed are satisfied with the decision made following the information furnished. CONCLUSIONS: The educational level, the locus of control and health beliefs-attitudes condition the comprehension-assimilation of the information. Citizen participation in the preparation of tools to aid in decision-making processes concerning prostate cancer screening affords the possibility of attaining more useful documents. Further research is necessary on the effects this type of information has on citizens. PMID- 17694637 TI - [Relationship of the degree of physical activity, blood pressure and body fat among teenagers in Madrid]. AB - BACKGROUND: It is throughout childhood and adolescence that many behavior patterns which are going to have a powerful influence on health during adult life are established. This study is aimed at analysing the influence physical activity has on the health of adolescents and at determining the relationship thereof with blood pressure (BP) and body composition. METHODS: The research was conducted from November 2002 to February 2003, using the Modifiable Physical Activity Questionnaire for Adolescents, which measures the degree of physical activity. The anthropometric variables and blood pressure were also measured for the sample comprised of 554 adolescents within the 12-18 age range from 35 schools in Madrid. RESULTS: A total of 13.2% of the males and 36.4% of the females were found to be inactive. The averages for the systolic/diastolic BP were 125.6/71.3 mmHg in the males and 118/69.4 mmHg in the females, but physical activity was found to have an influence solely on the diastolic BP for the males. A total of 48.27% of the females showed a tendency toward being overweight, as compared to 13.53% of the males. In the case of the females, a relationship was found to exist between body fat and degree of physical activity. CONCLUSIONS: The degree of physical activity shows itself to be a factor related to the health of adolescents, although taking on a different focus in each gender. Among the males, it has a significant bearing on the diastolic BP, whilst among the females, its influence is seen in the degree of body fat. PMID- 17694638 TI - [Trend and seasonal variations of Campylobacter gastroenteritis in Valladolid, Spain. A five-year series, 2000-2004]. AB - BACKGROUND: Campylobacter is one of the main enteric pathogens, nevertheless many aspects of its epidemiology still are not well known. This study aims to analyze the trend and seasonal pattern in Valladolid. METHODS: A time series analysis was developed using an additive model. The information sources were the reports to the Microbiological Information System from the main hospitals in Valladolid. Patients who showed a positive coproculture to Campylobacter spp. in the period 2000-2004 were considered cases. Trend, seasonal coefficients, incidence rates by age, sex and year of notification and incidence rate ratios were calculated. RESULTS: A decreasing trend in reported cases was observed. A significant seasonal coefficient was obtained in the 6th four-week period (c=12,854, p = 0.023). The incidence rate was higher among those under five years of age and among males, rising up to 1841.9 cases (95% CI: 1797.2-1889.6) and 99.7 cases (95% CI: 96.9-102.4) per 100,000 inhabitants-year respectively. CONCLUSIONS: Campylobacter infections occurs to a greater extent in late springtime, affecting mainly children. It is necessary to delve deeper into the knowledge of the epidemiology of this microorganism at the local level with a multidisciplinary approach, taking both microbiological and epidemiological aspects into account. PMID- 17694639 TI - Pyrogen testing of lipidic parenterals with a novel in vitro test--application of the IPT based on cryopreserved human whole blood. AB - The European Pharmacopoeia has made the testing of small volume parenterals (< 15) obligatory since 2004. This concerns many formulations, e.g. vitamins, steroids and hormones, many of which are applied intramuscularly using a lipidic carrier. Lipopolysaccharides, the best established endotoxins from Gram-negative bacteria, bind strongly to lipophilic substances, which mask them in Limulus amebocyte lysate assays. End-product testing, therefore, can only be carried out in rabbit pyrogen tests. This will lead to a pronounced increase in animal experiments if no alternative procedures become available. We have described a novel in vitro pyrogen test (IPT) based on human whole blood, which has recently been validated in a collaborative study including the European Pharmacopoeia. Here, the utility of the IPT for lipophilic substances and lipid-containing end products was assessed. For a variety of lipids commonly added to formulations of injectable endproducts, namely peanut oil, sesame oil, miglyol and paraffin, a protocol which allows interference-free testing was established applying the pharmacopoeial criterion of 50 to 200% retrieval of an LPS spike. Furthermore, end-product testing for three sample formulations was possible. In all, a method could be established which allows the determination of given or calculated ELC (endotoxin limit concentrations) according to Pharmacopoeia. It is concluded that monocytes do react to lipid-bound LPS, indicating that immune responses to contaminated endproducts must be anticipated, and that the IPT is suitable for endproduct control of these formulations. PMID- 17694640 TI - Evaporative light scattering detection (ELSD): a tool for improved quality control of drug substances. AB - Thanks to the recent technological advancements, evaporative light-scattering detection (ELSD) is regarded as a valuable alternative to UV detection for liquid chromatographic analysis of substances that do not contain a chromophore. In the field of substances for pharmaceutical use, LC-ELSD appears to be suitable for aminoglycosides, most of which (for ex. gentamicin) are presently controlled in the Ph. Eur. by pulsed amperometric detection. Other substances (ex sugars, triglycerides) presently employing refractometrric detection, could be conveniently analysed by LC-ELSD. ELS detection is regarded as robust and relatively simple, although not particularly sensitive. A key feature of ELSD is that - unlike refractometry - it can operate in gradient mode, thus allowing application of more selective liquid chromatographic methods. ELSD can also be used to set up MS-compatible methods, as the mobile phase constraints are essentially the same. Due to all the above, ELSD is becoming increasingly used in pharmacopoeial methods. PMID- 17694641 TI - In vitro pyrogenicity of Gram-positive bacteria--validation of the kit using fresh human whole blood. AB - The two conventional tests to detect pyrogen contaminants in injectable pharmaceutical drugs are the Rabbit Model and the Limulus amoebocyte lysate (LAL) test. To replace these models, a new system on human whole blood is developed, using the release of Interleukin 1 beta (IL1beta) after cell stimulation with gram-positive and gram negative pyrogens. The purpose of this study was to validate the ENDOSAFE-IPT kit using the quantitative ELISA enzyme immunoassay. The assay is divided into two parts: blood cell stimulation with Lipopolysaccharides (LPS) and Lipoteichoic acid (LTA) and quantitation of IL1beta using the ELISA method. In each assay, blood from a particular donor were stimulated with the Endotoxin Standard, and with a sample of a commercial antibiotic preparation (Clavulanic acid/Ticarcillin) spiked with the Endotoxin Standard. LTA from Bacillus subtilis and a sample of diphtheria toxoid were also used. At least, six assays were tested. A polynomial regression of the Endotoxin Standard series showed a correlation coefficient greater than 0.99. The spiked antibiotic sample recoveries were 50-121%. The LTA quantitation limit was 0.1 microg/ml and the range of detection of pyrogens from Gram positive diphtheria toxoid was 0.77 to 2.5 EEU/ml. The IL1beta production varied markedly between donors. However the coefficient of variation was less than 20 % intra-assay. In conclusion, the ENDOSAFE-IPT kit can be used for the quantitative and qualitative detection of pyrogens from Gram negative and Gram positive bacteria. PMID- 17694642 TI - Possible alternative to European Pharmacopoeia's method of analysis Test for Fc Function of Immunoglobulin (2.7.9) by using tetanus toxoid as antigen. AB - Preparations of intravenous immunoglobulins must keep functional integrity throughout the purification process. In order to assess Fc fragment functionality, the European Pharmacopoeia proposes the Test for Fc function of immunoglobulin (2.7.9), which is based on a rubella antigen of high titre. Sometimes, such antigen is difficult to obtain. In the present study, we develop the same assay using tetanus toxoid instead of rubella antigen, adapting the procedure for the use of tetanus toxoid. The comparison between rubella-based and tetanus-based assays showed that the slopes of the haemolysis curves were higher if red blood cells had been sensitised with the rubella antigen than with tetanus toxoid. Nonetheless, the tetanus-based assay gave satisfactory results and it could be a good alternative antigen target. PMID- 17694643 TI - Large variations in the ovalbumin content in six European influenza vaccines. AB - Since influenza vaccines are propagated in embryonated chicken eggs, they contain residual egg proteins (mostly ovalbumin). This could lead to the induction of allergic reactions in vaccinated individuals that are allergic to egg. The ovalbumin content in six influenza vaccines, available on the Swedish market in the autumn of 2004, was studied using a commercial ELISA kit. The results show a high degree of variation in ovalbumin content between the different influenza vaccines, ranging between 28 ng/ml and 1.1 microg/ml. No vaccine, however, had an ovalbumin concentration above the limit of 1.0 microg per dose (i.e. 2.0 microg/ml) set by the European Pharmacopoeia for the actual types of influenza vaccines. Thus results presented here clearly show that a tightening of the limit is fully possible. PMID- 17694644 TI - Effect of temperature on plasma freezing under industrial conditions. AB - The European Pharmacopoeia monograph on Human plasma for fractionation does not define the freezing process time but does define the freezing temperature (- 30 degrees C or below). Initial freezing conditions are crucial for the quality of plasma. These conditions were intended to preserve labile proteins such as fVIIl, but they can also be considered favourable for the plasma quality in general. This study evaluates the way the industrial plasma freezing affects labile coagulation factors. We have studied the freezing of plasma in industrial-size chambers at temperatures close to - 30 degrees C, - 25 degrees C and - 20 degrees C, and the possible differences between performing the freezing process in a chamber or in a freezer, in order to elucidate whether or not these parameters affect the quality of plasma. For this study, plasma bottles were frozen in industrial chambers set at - 30 degrees C, - 25 degrees C and - 20 degrees C, and in a freezer set at - 20 degrees C. The freezing rates were followed by means of probes in plasma control bottles. From this plasma, coagulation factors (fVIII, fIX and fibrinogen) were analysed before and after freezing, and cryoprecipitate was obtained in some cases. Statistically significant differences exist in fVIII:C recovery in thawed plasma between freezing at - 30 degrees C and at - 20 degrees C (n = 11; 85.4 +/- 4.3 % versus 74.6 +/- 6.0 % (chamber) or 79.3 +/- 6.3 % (freezer)). There is no difference between - 30 degrees C and - 25 degrees C, or between freezing at - 20 degrees C in a chamber or in a freezer. No significant loss of activity in thawed plasma is observed for fIX and fibrinogen at - 25 degrees C or - 20 degrees C versus - 30 degrees C. The fVIII and vWF recovery in cryoprecipitates does not show differences (464.2 IU fVIII/ml at - 30 degrees C, 446.7 IU fVIII/ml at - 25 degrees C, and 475.8 IU fVIII/ml at - 20 degrees C). The results obtained from this study support that plasma might also be frozen at - 25 degrees C or below without any impact on its quality, and that sporadic and short term deviations, from - 30 degrees C or below up to - 25 degrees C, in the currently required freezing temperature, would not have an effect on the labile factors recovery. PMID- 17694645 TI - Isoform number I--a new tool to evaluate the quality of erythropoietin. AB - The overall isoform number I, calculated from capillary zone electrophoresis (CZE) data, is introduced as a new parameter that enables the assessment of the quality of erythropoietin (EPO) in a simple, yet efficient manner. I is defined as the sum of the products of the individual CZE peak area percent shares (pn) of the EPO isoforms (n = 1-8) and the corresponding individual isoform numbers (n): I=p1x1+p2x2+p3x3+ p4x4+p5x5+p6x6+p7x7+p8x8 The results from an internal collaborative study were used to calculate I-numbers for 2 successive batches of EPO Biological Reference Preparations (BRPs) established by the European Pharmacopoeia (Ph. Eur.) Commission. Based on the results of 6 participating laboratories each, the I-numbers calculated for batch 1 (BRP1) and candidate batch 2 (cBRP2) were I = 518.7 +/- 3.5 (coefficient of variation (CV) = 0.7 %) and I = 542.4 +/- 2.2 (CV = 0.4 %) respectively. Thus, the I-numbers of the 2 EPO preparations clearly indicated the difference between BRP1 and cBRP2 described in the literature, but in a much more apparent and simple manner. Notably, one of the 7 laboratories participating in the study with cBRP2 yielded an outlier value of I = 525.6, pointing towards a suboptimal CZE analysis, and was therefore excluded from the cBRP2 mean value calculation. It is suggested that the overall isoform number I of erythropoietin provides a new and highly valid quality control measure that makes it possible to ensure the batch-to-batch consistency of the active pharmaceutical ingredient of EPO market products. PMID- 17694646 TI - Viral safety evaluation of biopharmaceuticals and homoeopathic preparations of human or animal origin. AB - In order to meet the generally high quality requirements for the pharmaceutical manufacturing process, medicaments of animal or human origin specifically have to undergo a substantial viral safety test program. This procedure has been narrowly defined in numerous internationally valid guidelines; in addition, registration authorities are available in an advisory capacity. In order to bring about the experimental evidence, thorough planning, virological expertise and infrastructure, as well as close cooperation between process engineers and virologists, is necessary. Generally, generic studies are not accepted by the registration authorities. However, in coordination with the German Federal Institute for Drugs and Medicinal Devices (BfArM), a special arrangement for homoeopathic preparations could be agreed upon and the efficacy of selected production stages proven beyond doubt. Therefore, combined with the careful execution and evaluation of the validation studies, a high technical status for biopharmaceuticals including homoeopathic preparations guarantees a very high degree of viral safety. PMID- 17694647 TI - The use of a two-way analysis of variance to compare the methods for the assay of anhydrous dibasic calcium phosphate in the European, Japanese and United States Pharmacopoeias. AB - Tri-PEC (IPEC-Americas, IPEC-Europe and JPEC) carried out a two-way analysis of variance (Round Robin testing) for the assay of Anhydrous Dibasic Calcium Phosphate (CaHPO4) at the request of the Pharmacopoeial Discussion Group (PDG). On the basis of the result obtained, the difference in the assay results for anhydrous CaHPO4 using the different methods of the 3 Pharmacopoeias was not significant, while the difference in the results for the 3 different batch samples tested by 3 different methods was significant (p < 0.05). On the basis of these results, the methods from the 3 Pharmacopoeias, did not give different results, and thus the methods themselves should be considered equivalent. PMID- 17694648 TI - Chromogenic assay of human coagulation factor VIII: statistical comparison of 2 working dilution procedures (Pharmeuropa Scientific Notes 2005-1). PMID- 17694649 TI - [Reconstruction of femoral artery with external jugular vein graft]. AB - OBJECTIVE: To introduce the treatment and clinical result of reconstructing femoral artery with external jugular vein graft. METHODS: From June 2002 to April 2Q06, 22 cases of femoral artery defects caused hy pseudoaneurysm resection, were reconstructed with external jugular vein graft hy microsurgical technique. There were 20 males and 2 females, aging 25-46 years (mean 31.2 years). The length of femoral artery defects was 5-9 cm, with an average of 6.8 cm. The location was left in 14 cases and right in 8 cases. RESULTS: Ten cases achieved healing hy the first intention, and 4 cases hy the second intention. The other 8 cases need the regional flap repair hecause the wound splited open and hecame ulcer. Femoral artery defects were reconstructed successfully and the pulse of dorsal arteries of foot could he felt except 1 case of bleeding of anastomotic rupture. Eighteen patients were followed up 1-30 months, and no pseudoaneurysm recurred. Color ultrasound Doppler detection showed that the external jugular veins took place of the femoral artery defects in 12 cases. CONCLUSION: External jugular vein is stahle at anatomy and easy-to-ohtain. Its calihre is close to that of the femoral artery. It can he osed for reconstructing femoral artery defects as the vein material. The operation is easy and the clinical result is sure. PMID- 17694650 TI - [Individual revascularization for treatment of multilevel arterial occlusive disease of lower extremity]. AB - OBJECTIVE: To determine the clinical effect of sequence and cross bypass or combined with endovascular procedure for mutilevel arterial occlusive disease of lower extremity so as to investigate the credible treatment for mutilevel arterial occlusive disease of lower extremity. METHODS: Between April 2004 and July 2005, 11 patients (14 limbs)underwent sequence and cross bypass, thromboendarterectomy or combined with endovascular procedure. Among of them, 10 cases were male and 1 case was female, aging 62-79 years(mean 70. 5 years), and including 8 cases of intermittent claudications (Fontaine stage II), 3 cases of rest pain (Fontaine stage III) and 1 case of toe ulcer with gangrene (Fontaine stage IV). Colour Doppler ultrasonography showed that 14 lower limbs were diagnosed as having multilevel arterial occlusive disease and the preoperation and ankle brachial index (ABI) was 0.36 +/- 0. 11 . Lower limb digital subtraction angiography (DSA) showed 3 cases of bilateral iliac artery stenosis, extrailiac artery occlusion and bilateral superficial femoral artery occlusions, 1 case of right common iliac artery stenosis, extrailiac artery occlusion and bilateral superficial femoral artery occlusions and 8 cases of unilateral extrailiac artery stenosis and superficial femoral artery occlusions. Postoperation tests of DSA,colour Doppler ultrasonography and ABI were done to observe cumulative patency rate after operation. RESULTS: The follow-up period was from 3 to 26 months (mean 14.5 months ). All patients survived. The symptoms of intermittent claudication and rest pain disappeard in all patients. ABI was improved by 0.89 +/- 0.13 after procedure (P < 0.01). The overall salvage rate of limb was 100%. DSA was performed from 3 to 280 days after operation, the overall primary graft patency rate was 92.86% (13/14). CONCLUSION: Sequence and cross bypass, thromboendarterectomy or combined with endovascular procedure in treatment of mutilevel occlusive disease of lower extremity was effective, less invasive and safe. PMID- 17694651 TI - [Comparative study on autologous implantation between bone marrow stem cells and peripheral blood stem cells for treatment of lower limb ischemia]. AB - OBJECTIVE: To compare the effectiveness of autologous implantation between bone marrow stem cells and peripheral blood stem cells for treatment of lower limb ischemia. METHODS: From December 2004 to December 2005, 42 patients with unilateral lower limb ischemia were treated with both autologous bone marrow stem cell implantation (group A, n=21) and autologous peripheral blood stem cell implantation (group B, n=21). Forty-two patients included 32 males and 10 females. The age ranged from 34 to 80 years, with a mean of 65. 6 years. Of the patients, there were 28, 8 and 6 patients suffered from diabetic lower limb ischemia, Burger's disese and atherosclotic occlusion, respectively. Ischemic history was from 3 months to 5 years, with a mean of 2.1 years. A series of subjective indexes (such as improvement of pain, cold sensation and numbness) and objective indexes such as increase of ankle brachial index (ABI), transcutaneous oxygen pressure (TcPO2), angiography, amputation rate, and improvement of foot wound healing, were used to evaluate the effect. RESULTS: After 4 weeks of implantation, the rate of pain relief was 88.2% in group A and 89.5% in group B (P > 0.05); the rate of cold sensation relief was 94.4% in group A and 94.7% in group B (P > 0.05); improvement of numbness was 69.2% and 66.7% respectively in groups A and B (P > 0.05). Increase of ABI was 38.1% in group A and 33.3% in group B (P > 0.05); increase of TcPO, was 85.7% and 90.5% respectively in groups A and B (P > 0.05); angiography was performed in 12 patients (group A) and 9 patients (group B), and the new formed collateral vessel rate was 83.3% in group A and 77.8% in group B (P > 0.05); the amputation rate was 9.1% in groups A and B (P > 0.05); the rate of improvement of foot wound healing was 60.0% in group A and 66.7% in group B (P > 0.05). Forty patients were followed up 3-15 months (mean 8 months). The improvement rate of subjective symptoms was 75.0% in group A and 70.0% in group B (P > 0.05); increase of ABI was 60.0% in group A and 65.0% in group B; increase of TcPO was 80.0% and 75.0% respectively in groups A and B; the new formed collateral vessel rate was 90.0% in group A and 84.6% in group B. All ulcers healed except 1 case in group B. CONCLUSION: Bone marrow stem cell graft and peripheral blood stem cell graft are all effective in treating lower limb ischemia. PMID- 17694652 TI - [Repair and reconstruction of femoral pseudoaneurysm caused by drug injection]. AB - OBJECTIVE: To evaluate repair and reconstruction of the femoral pseudoaneurysm caused by drug injection. METHODS: From May 2000 to May 2005, 15 cases of femoral pseudoaneurysm caused by drug injection underwent operation treatment. All patients were male, aging 20-36 years. The disease course was 18-52 days (mean 35 days) and the course of drug injection was 3-17 months. The locations were the left side in 5 cases and the right side in 10 cases. After having been bandaged with pressure and supported with nutrition, they had been all operated. One case received fistula repair, and 14 cases received vascular grafting with ePTFE man made blood vessel. RESULTS: The wounds healed by the first intention in 14 cases. All limbs survived. The complexion, temperature and response of involved leg were in gear. The postoperative color ultrasound Doppler detection showed that all the vascular grafts were of patency. The function of the involved limbs restored to normal. CONCLUSION: Complete debridement, vascular reconstruction and better microsurgery skill were the key factors of treating successfully the femoral pseudoaneurysm caused by drug injection. PMID- 17694653 TI - [Surgical treatment of traumatic subclavian artery]. AB - OBJECTIVE: To explore the treatment of traumatic subclavian artery. METHODS: From July 1990 to January 2006, 12 cases of traumatic subclavian artery were treated by using of combined incision of superior-inferior clavian. All patients were male, aging 18-36 years (mean 22.6 years). The locations were section 1 of subclavian artery in 1 case, section 2 in 4 cases and section 3 in 7 cases. All patients had incomplete rupture and defect. Time from injury to operation was 3 hours to 1.5 months. The methods of vascular repair included primary repair, end to-end anastomosis and artificial vascular prosthesis grafts. RESULTS: There was no death. Extremities survived in all cases and got good function in 10 cases. All patients were followed up 2 months to 12 years (mean 5 yeras and 2 months). The pulse of radial artery restored to normal in 10 cases and did not be felt in 2 cases. The function of extremities restored to normal in 2 cases with partial injury of brachial plexus nerve and did not improve in 2 cases with complete injury of brachial plexus nerve. CONCLUSION: The exposure of subclavian artery is difficult because of its particular anatomy region. The repair and reconstruction of subclavian artery should be selected according to the type of vascular injuries. Combined superior-inferior clavian approach can satisfy the exposure and repair for the subclavian artery. PMID- 17694654 TI - [Treatment of delayed popliteal artery trauma of knees]. AB - OBJECTIVE: To summarize the experience in treatment and diagnosis of popliteal artery trauma and to determine the factors for amputation. METHODS: From February 1995 to January 2006, 28 patients with popliteal artery trauma were treated. The disease course was more than 8 hours. Of them, there were 25 males and 3 females, aging from 3 to 53 years. Trauma was caused by traffic accident in 12 cases, by falling from height in 3 cases, by firearm in 2 cases, by sharp instruments in 3 cases, by strangulation in 2 cases and by others in 6 cases. No arteriopalmus or weak arteriopalmus were observed in 18 cases and in 8 cases respectively. Popliteal artery exposure or active bleeding was seen in 2 cases; the popliteal arteries were examined by operation in 8 cases; color ultrasound Doppler flow imaging showed color flood flow signals were through popliteal artery and its branches in 20 cases. Defect size of popliteal artery was less than 5 cm in 7 cases and more than 5 cm in 9 cases. End to end anastomosis reconstruction by saphenous vein graft and direct suture was performed in 16 cases and ampulation in 12 cases. The time of the revascularization of the leg was 8-150 hours (mean 31. 8 hours). RESULTS: All patients were followed up 6 months to 11 years with an average of 4.2 years. In 16 cases given end to end anastomosis reconstruction, 15 cases achieved revascularization and limb survival; lower limb function restored to normal within 1 year in 12 cases; foot drop and ankle joint contracture occurred in 3 cases and the survival rate of limbs was 94%. Amputation was given in 12 of 28 cases because of severe trauma. The rate of amputation was 43% and the rate of disability was 54%. CONCLUSION: Popliteal artery trauma should be treated as soon as the diagnosis is made. If the revascularization is more than 8 hours or circulatory compensation is not complete, it will affect the leg survival. Delayed diagnosis and severe traumas are the cause of high rate of amputation in popliteal artery trauma. PMID- 17694655 TI - [Experimental study on umbilical vascular compliance and expression of antigen after removing endothelial cell]. AB - OBJECTIVE: To evaluate which is better method zymogen or low temperature frozen in removing vascular endothelial cell so as to lay a foundation for creating a kind of brace which is not to be rejected and the same as own blood vessel. METHODS: Fresh and not damaged umbilical blood vessel was collected from natural labour women, human umbilical blood vessel was remove carefully from normal foetus, then was put into disinfectant at 37 C for 24 hours. They were divided into 3 groups:normal group (NG), zymogen group (ZG) and low temperature frozen group (LG). ZG: 0.1% collagen II enzyme was added in umbilical blood vessel and closed the both sides and the vascular endothelial cell was removed in 37 C water. LG:Umbilical blood vessel was put into liquid nitrogen for 24 hours after frozened step by step, and then it was put into 37 C water for 30-60s and the vascular endothelial cells were washed away by normal saline. NG:Umbilical blood vessel was kept into 4 C Kerb's liquid. The bacteria were cultured in each group. The samples were stained by HE, elastic fiber and collagen fiber were observed by light and scanning electron microscope. The difference of compliance was compared. Human leukocyte antigen ABC (HLA-ABC) and HLA-DR were observed by immunohistochemical method and the expression of antigen of umbilical blood vessel was analysed. Results In LG, umbilical vascular endothelial cells were removed completely; artery showed vertical smooth muscle and vein showed elastic membrane. In ZG, umbilical vascular endothelial cells were removed completely after 20 minutes; artery showed vertical smooth muscle cells and vein showed lower endothelial layer. The vascular compliance in LG was higher than that in NG, and the latter was also higher than that in ZG, but showing no significant differences (P > 0.05). The compliance of umbilical vein was 2-3 times as much as that of umbilical artery. The expression of HLA-ABC and HLA-DR in LG and ZG were lower than that in NG, showing significant differences (P < 0.01). CONCLUSION: Low temperature frozen method and zymogen method (0.1% collagen II enzyme for 20 min) can remove vascular endothelial cells of human umbilical blood vessel completely. Low temperature frozen method was better than zymogen method. PMID- 17694656 TI - [Dynamic change of epidermal stem cells in the wound healing course of diabetic rats]. AB - OBJECTIVE: To observe the epidermal width, the amount variation and distribution character of epidermal stem cells(ESCs) and the wound healing rate at different periods of diabetes mellitus(DM) rats after trauma, then to study the correlation of them. METHODS: Forty-eight Wistar rats were divided into DM group and normal control group randomly (n=24). The DM rats were induced by streptozocin (STZ) and then made chronic healing wound by special perforex. At the 3rd, 4th, 7th, 14th and 21st days after trauma, the healing rate was calculated, the wound edge and granulation tissue were obtained for haematoxylin-eosin (HE) staining and immunohistochemical staining of keratin 19 (K19) and beta1 integrin. Then the epidermal width, the area and the gradation value of positive unit (PU) were measured. RESULTS: At the 3rd, 7th, 14th and 21st days after trauma, the wound healing rates of normal rats were 24. 48% +/- 3.37%, 50.46% +/- 1.26%, 92.82% +/- 2.12% and 99.41% +/- 0.66% respectively, while those of DM rats were 2.43% +/- 1.02%, 40.59% +/- 1.65%, 80.77% +/- 3.57% and 85.40% +/- 0.94% respectively, showing significant differences (P < 0.01). Before trauma, there was no significant difference in the epidermal width between normal rats and DM rats (P > 0.05). However, at the 3rd, 7th, 14th and 21st days after trauma, the epidermal widths of normal rats were 26.43 +/- 3.21, 33.29 +/- 3.52, 31.53 +/- 3.35 and 26.01 +/- 3.19 microm respectively, while those of DM rats were 23.58 +/- 2.33, 31.02 +/- 3.38, 33.72 +/- 5.49 and 21.80 +/- 4.02 microm respectively, the epidermal widths in DM rats were significantly lower than those in normal rats (P < 0.01). The average PU value of K19 in normal rats were 91.68%, 93.14%, 72.27% and 70.31% respectively, while those in DM rats were 40.29%, 40.79%, 29.94% and 10.37% respectively. The average PU value of beta1 integrin in normal rats were 49.6%, 91.16, 77.13% and 57.17% respectively, while those in DM rats were 38.94%, 24.16%, 61.36% and 38.83%. The results indicated that the average PU values of K19 and beta1 integrin in DM rats were significantly lower than those in normal rats (P < 0.05). CONCLUSION: The amount and activity decrease of ESCs may be one of the important mechanisms of difficult recovering wounds of DM rats. PMID- 17694657 TI - [Experimental study on fas gene death domain mutations in keloid pedigrees]. AB - OBJECTIVE: To detect gene mutations of Fas gene death domain (exons 79) in 2 Chinese keloid pedigrees and to investigate the significance of Fa gene mutations in the keloid formation. METHODS: The samples were selected from keloid pedigrees A and B in 2005. The polymerase chain reaction and DNA sequencing analysis technique were used to detect the sequence of exons 7-9 of Fas gene from keloid tissues of 2 male patients in pedigree A, their peripheral vein blood and their surrounding normal skin served as their own contrast, their spouses' peripheral vein blood served as normal contrast, the peripheral vein blood of 2 patients in pedigree B served as a contrast between different keloid pedigrees. RESULTS: No gene mutations and single nucleotide polymorphism in Fas gene exons 7, 8 were found in all samples from pedigrees A and B. But point mutations and single nucleotide polymorphism in Fas gene exon 9 were identified in 11 bp and 53 bp in 2 keloid tissue samples from Chinese keloid pedigree A. CONCLUSION: Fas gene point mutations maybe indicate some relations in Fas protein function and keloid formation. PMID- 17694658 TI - Effect of wt-P53 protein on telomerase activity in keloid fibroblasts. AB - OBJECTIVE: To evaluated the role of wt-P53 protein in telomerase regulation in keloid fibroblasts (KFBs). METHODS: The fibroblasts were derived from human keloid tissue which was proved by pathological diagnosis. KFBs were divided into 2 groups, the transfection group and the untransfection group. wt-p53 gene was transfected into the fibroblasts by adenovirus vectors in the transfection group. The KFBs untransfected with wt-p53 gene served as control (untransfection group). After 48 hours of transfection, the expression of wt-P53 protein was analyzed by both Western blotting and immunofluorescence method, respectively. The telomerase activity was evaluated by TRAP-ELISA after 1-7 days of transfection. RESULTS: All the KFBs from 2 groups expressed wt-P53 protein. But the expression level of wt P53 protein in the transfection group was significantly higher than that in the untransfection group. At the same time of high expression of wt-P53 protein, the telomerase activity of KFBs in transfection group was significantly lower than that in the untransfection group (P < 0.05). CONCLUSION: High level expression of wt-P53 protein can transiently inhibit the telomerase activity of KFBs. PMID- 17694659 TI - [Reconstruction of scar constractures in axilla and chest with local scar skin flap]. AB - OBJECTIVE: To investigate a suitable way to reconstruct sear constractures in the axilla and chest. METHODS: From January 2001 to December 2005, 52 patients (57 episodes) with scar constractures in the axilla and chest were treated, including 31 males and 21 females with an age range of 1-44 years. The deformities of scar constractures in the axilla and chest were reconstructed with posterior part of axillary scar skin flaps (44 epidsodes), anterior part of axillary scar skin flaps (10 episodes) and lateral part of upper arm's scar skin flaps (3 episodes). The flaps were sutured to the surrounding tissues in 19 episodes, the donor sites in other 38 cases were covered with split thickness skin grafts. RESULTS: Fifty four scar skin flaps survived completely by the first intention except 3 flaps, which margin necrosed and healed with dressing changes. All patients were followed up 1 month to 5 years. All patients gained a good functional recovery and cosmetic appearance after the operation, and the unfolding function of shoulder restored to 1500. CONCLUSION: Axillary local scar skin flap is a good alternative method to reconstruct scar constractures in the axilla and chest. PMID- 17694660 TI - [Cross-bridge vascular anastomosis free tissue transplantation in repairing tissue defects of extremities]. AB - OBJECTIVE: To investigate the application and effect of the cross-bridge vascular anastomosis free flap transplantation for tissue defects of extremities. METHODS: From May 1982 to November 2005, 110 cases of tissue defects of extremities were treated with cross-bridge vascular anastomosis free tissue transplantation. Of 110 patitents, 80 were male and 30 were female with a median age of 30 years(5 to 54 years). Tissue defects were caused by traffic accidents (59 cases), machine injuries (32 cases) and mangled injuries (19 cases). The locations were the forearms in 2 cases and the legs in 108 cases. And 69 cases had simple soft tissue defects, 6 cases had simple bone defects, and 35 cases had complicated defects. The length of bone defect ranged from 5 cm to 19 cm and the area of soft tissue defect ranged from 6 cm x 10 cm to 15 cm x 35 cm. The graft tissue included latissimus dorsi musculocutaneous flap, vastus anterolateral flap,cutaneous fibula flap, osseous fibula flap, and cutaneous iliac flap. The cross-bridge of the two lower extremities was performed in 106 cases, the cross bridge of the two upper extremities in 2 cases, and the cross-bridge of the upper lower extremities in 2 cases. The composite tissue transplantation was used if the graft tissues were two or more. The wounds of donor site was directly sutured in 67 cases, and partly sutured with skingrafting in 43 cases. RESULTS: Vascular crisis occurred in 9 cases. Vascular crisis was relieved in 5 cases and grafting tissues was survival after exploring the vessel; 4 cases failed. The graft tissue was survival in 101 cases, and the survival rate was 96.4%. The follow-up time was 4 months to 22 years with an average of 6.3 years. Graft bone healed and mean healing time was 4 months. The flap appearance was satisfactory and extremity function was restored to normal. One case became necrosis in the edge of the flap and cured by debridement, dressing and skingrafting, the other got primary healing at 2-3 weeks after operation. CONCLUSION: The application of the cross bridge vascular anastomosis free tissue transplantation for tissue defects of extremities is an effective method, when extremities have no vessel anastomosed. PMID- 17694661 TI - [Reconstruction of nasal defect after tumor excision]. AB - OBJECTIVE: To introduce the experience and comprehension to reconstruct nasal defect after tumor excision. METHODS: From April 1996 to April 2006, based on the aesthetic subunit principle and according to the size, shape, location of nasal defect and the conditions of surrounding skin, homologous local flap was selected to cover the nasal defect in 428 cases which nasal tumors were removed. Among 428 cases, there were 273 men and 155 women, with a median age of 52 years (12-78 years); including 146 cases of basal cell carcinoma, 83 cases of squamous cell carcinoma, 54 cases of epidermal cyst, and 145 cases of pigmented naevus. The clinical stage of malignant tumor was 0-I stage, the course of disease was 1 week to 3 months. The locations were nasal tip in 51 cases, nasal ala in 102 cases, dorsum of nose in 138 cases, and nasal side in 137 cases, across 2 nasal subunits in 83 cases. The area of the defect ranged between 0.6 cm x 0.6 cm and 3.0 cm x 4.0 cm. The origin of flaps was frontonasal flap in 58 cases, bilobed flap in 67 cases, reforming rhomboid flap in 152 cases, nasolabial flap in 118 cases, forehead falp in 33 cases. The secondary defect of donor site was directly sutured. RESULTS: Among 428 cases, 423 cases acquired complete recovery; 3 cases which had epiderm necrosis over the far end of the flap achieved healing by the first intention and 2 cases which had suffered low-grade infection of incision achieved healing by the second intention after regional change dressings. The nasal defect was successfully repaired in all patients, and the all flaps survived. A total of 385 patients were available for follow-up of 1 to 60 months, no tumor recurrence occurred, and the repaired tissue were good match with surrounding tissue, good nasal contour was obtained, the cosmetic results were satisfactory. CONCLUSION: Based on the nasal aesthetic subunit principle, the local flap can reconstruct the nasal above medial defect, and a good color, contour and texture match with the surrounding skin can be obtained, the cosmetic results are satisfactory. PMID- 17694662 TI - [Clinical study on effect of keeping perioperative normal body temperature on skin flap survival]. AB - OBJECTIVE: To investigate the effect of perioperative body temperature on the survival of skin flap grafting. METHODS: From July 2005 to November 2006, 50 cases of I-II grade patients undergoing elective skin flap grafting were randomly divided 2 groups. Pharyngeal temperature (PT) and skin temperature (ST) were monitored and recorded every 15 minutes. Operative time, anesthetic time, time from the end of operation to extubation, the volume of blood transfusion, the volume of fluid transfusion and the flap survival 7 days after operation were recorded. In the experimental group, the body temperature was maintained in normal range with water market and forced air heater. In the control group, the body temperature was only monitored without any treatment. Results There were no significant differences in operating room temperature, operative time, anesthetic time, the volume of blood transfusion and fluid transfusion between 2 groups (P > 0.05). After induction, PT decreased gradually in both groups during the first 45 minutes, compared with the time point of intubation (P < 0.05), but there were no significant differences between the 2 groups (P > 0.05); and ST rose in both groups during the first 45 minutes, compared with the time point of intubation (P < 0.05). After 45 minutes of induction, in the experimental group, PT was in the normal range (36 C), and ST didn't change compared with that of the time point of induction (P > 0.05). In the control group, both PT and ST decreased gradually and time-dependently compared with the time point of intubation (P < 0.05). In the experimental group, PT and ST at each time point were higher than those in the control group (P < 0.05). All the skin flap grafts survived in the experimental group, and skin flap grafts necrosed in 2 cases in the control group. CONCLUSION: Keeping normal body temperature can improve the survival of skin flap grafting. Therefore, the body temperature should be monitored and maintained in a normal range. PMID- 17694663 TI - [Clinical characteristics of Bochdalek hernia in neonates and infants]. AB - OBJECTIVE: To summarize the clinical characteristics, diagnosis and treatment of Bochdalek hernia in neonates and infants. METHODS: The data of 15 neonates and 10 infants with Bochdalek hernia,undergoing the normal diagnosis and surgical repair from August 1983 to June 2004, were retrospectively reviewed. Location was left in 22 cases and right in 3 cases. Twenty-four cases were treated by operation and 1 case died of respiratory failure before operation. RESULTS: Before April 1998, 7 of 8 (5 neonates, 3 infants) cases of Bochdalek hernia stayed healthy and respiratory symptom-free 1 year after operation; they were followed up 1 year and 3 months to 11 years. One premature neonate with Bochdalek hernia died of respiratory failure before operation, and his lung volume was found to be dysplasia. From April 1998 to June 2004, 15 (8 neonates,7 infants) of 17 (10 neonates, 7 infants)cases of Bochdalek hernia survived postoperatively, while 2 neonates died of respiratory failure. CONCLUSION: The earlier dyspnoea of neonates of Bochdalek hernia occur, the worse their healthy status appear. The standard and timely surgical repairs could improve the curative ratio. Whether the operation was suspended depended on the healthy states of babies. PMID- 17694664 TI - [Ventral urethroplasty for postoperative urethral stricture in patients with hypospadias]. AB - OBJECTIVE: To investigate the effect of ventral urethroplasty for postoperative anastomotic stricture in patients with hypospadias. METHODS: From August 2000 to December 2005, 20 patients with anastomotic stricture after hypospadias repair were treated with ventral urethroplasty. The age ranged from 2 to 27 years with an average of 6.4 years. All patients showed dysuria after operation. Main clinical manifestation included dysuria and acraturesis. Interruption of urinary stream occurred in 17 cases; of them, 3 cases had urinary stasis and 4 cases had frequent micturition, urgent micturition and pain in urination. Urethrography and cystourethrography showed 0. 5-1. 0 cm stricture with proximal dilation of urethra in 16 cases and obvious diverticularization in 9 cases. Urine routine examination showed that white blood cell was ++ to ++++ in 16 cases and pus cell was +/+ to ++ in 13 cases. RESULTS: Twenty cases were followed up 2 months to 4 years (mean 2.3 years). All the cases achieved good results in urination with normosthenuria and normal force of urinary stream. No recurrent stricture, urethrocutaneous fistula, or penile curvature occurred. The cosmesis was satisfactory, and the results of urine routine examination was normal. CONCLUSION: Ventral urethroplasty for postoperative anastomotic stricture in patients with hypospadias is a simple and effective procedure. PMID- 17694665 TI - [Effects of immunosuppressants on proliferation of pheochromocytoma 12 and L929 cells]. AB - OBJECTIVE: To explore the effects of several immunosuppressants on the proliferation of pheochromocytoma 12 (PC12) and L929 cells. METHODS: Different concentrations of methylprednisolone (10(-3), 10(-4), 10(-6) and 10(-8) mol/L), cyclosporin A (CsA, 10(-5), 10(-6), 10(-7) and 10(-8) mol/L) and FK506 (10(-6), 10(-7), 10(-8) and 10(-9) mol/L) were administrated to the PC12 and L929 cells, while control group was given no drugs. At 24, 48 and 72 hours after administration, the cell proliferation was measured with MTT methods respectively. The results were compared and analyzed statistically. RESULTS: High concentration methylprednisolone (10(-3) mol/L) and low concentration CsA (10(-8) 10(-7) mol/L) could promote the proliferation of PC12 cells within 48 hours after administration, after that, the proliferation effects were no longer significant. There were no promotion effects for different concentrations of FK506. Under high concentrations, both CsA (10(-6)-1 x 10(-5) mol/L) and methylprednisolone (10(-3) mol/L) could significantly inhibit the proliferation of L929 cells after 24 hours of administration. And high concentration (10(-6) mol/L) FK506 could promote the proliferation of L929 cells transitorily (only for 48 hours after administration). CONCLUSION: 10(-3) mol/L methylprednisolone and 10(-8)-10(-7) mol/L CsA can promote the proliferation of PC12 cells for a short period of time. Both 10(-3) mol/L methylprednisolone and 10(-6)-10(-5) mol/L CsA can significantly inhibit proliferation of L929. PMID- 17694666 TI - [Effects of exogenous basic fibroblast growth factor on in-sheathed tendon healing and adhesion formation]. AB - OBJECTIVE: To explore the effects of exogenous basic fibroblast growth factor (bFGF) on in-sheathed tendon healing and adhesion formation. METHODS: Ninety Leghorn chickens were randomly divided into 3 groups (groups A, B and C), 30 animals for each group, and the right third digitorum longus tendon of the chicken was transected to make defect models. In group A, the tendon was sutured in situ after transection. In group B, the tendon was sutured after 0.6 microl fibrin sealant (FS) was applied at repair site. In group C, the tendon was sutured after 0.6 microl FS mixed with 500 ng bFGF was applied at repair site. At 1, 2, 4 and 8 weeks after operation, the tendons of 6 chickens in each group were harvested for morphological and histological evaluation. Six specimens of each group was obtained for biomechanical test at 8 weeks. RESULTS: The gross observation showed that the differences of grading of tendon adhesion were not significant between groups A, B, and C 8 weeks after operation (P > 0.05). Histological evaluation showed that there were no significant differences in fibroblast counting and the content of collagen fibers between groups A and B (P > 0.05). The angiogenesis, fibroblast proliferation and collagen production in the sheath, epitendon and parenchyma at repair site in group C occurred earlier and were more than those in groups A and B, showing significant differences (P < 0.05). The biomechanical tests showed that the gliding excursion of the tendon in group A, B and C were 3.44 +/- 0.43, 3.51 +/- 0.56 and 2.84 +/- 0.42 mm respectively; the work of flexion were 14.87 +/- 1.72, 14.08 +/- 1.85 and 20.62 +/- 3.52 Nmm respectively; the ultimate tensile strength of the tendon was 10.34 +/- 1.45, 11.26 +/- 1.83 and 15.02 +/- 2.20 N respectively; showing no significant differences between groups A and B (P > 0.05), but showing significant differences between group C and groups A, B (P < 0.05). CONCLUSION: The exogenous bFGF at tendon repair site can facilitate in-sheathed tendon healing, but also increase the tendon adhesion formation. PMID- 17694667 TI - [Construction of recombinant adeno-associated virus vector with human bone morphogenetic protein]. AB - OBJECTIVE: To construct the recombinant adeno-associated virus vector with human bone morphogenetic protein 4 gene (AAV-hBMP-4). METHODS: The hBMP-4 gene primer was designed basing on the corresponding gene sequence in GenBank. EcoR I site was introduced into the upstream of the primer and Sal I site into downstream. The hBMP-4 gene was amplified with the template of EX-A0242-M01-hBMP-4, then was cloned into pUC18 vector to construct recombinant plasmid pUC18-hBMP-4. The plasmids pUC18-hBMP-4 and plasmid pSNAV cut by EcoR I and Sal I enzyme, the fragments were collected and linked with T4 DNA ligase at 16 C over night, recombinant plasmid pSNAV-hBMP-4 was obtained. The recombinant plasmid was then transfected into BHK21 cells using Lipofectamine TM2000. The G418 resistant cells were obtained consequently. These cells were infected with HSV1-rc/deltaUL2 which has the function of packaging and copying the recombinant AAV. After purification, the construction of recombinant AAV-hBMP-4 was completed. RESULTS: The construction of the recombinant pSNAV-hBMP-4 was confirmed by PCR electrophoresis and digestion with restriction enzyme. The gene sequence in the recombinant pSNAV-hBMP-4 was correct. The virus titer was about 1.5 x 10(12) microg/ml. The purity of the virus was more than 95% using the SDS-PAGE method. CONCLUSION: With this method, high virus titers and purity of AAV-hBMP-4 can be acquired successfully and it is useful to bone tissue engineering. PMID- 17694668 TI - [Comparison of acellular bovine pericardium material with collagen membrane in guiding bone regeneration]. AB - OBJECTIVE: To compare the effect of guiding bone regeneration between 1-ethyl-3(3 diaminopropyol)-carbodiimide (EDAC)-crosslinked acellular bovine pericardium (ABP) and medical collagen membrane (CM). METHODS: Defects of 7 mm X 7 mm x 5 mm were created in both mandibles of 24 rabbits, which weighted 2.6-3.5 kg. One side defect was covered with EDAC-crosslinked ABP(EDAC-crosslinked ABP group), the other side defect with medical CM as control(CM group). The ability of bone defect repair and change of both membrane materials were evaluated by gross observation, histological study and computer graphic analysis in the 4th, 8th, 16th and 24th weeks after operation. RESULTS: The surface of bone defects was even, consistent with adjacent normal bone in EDAC-crosslinked ABP group, while that of bone defects was of no evenness in CM group in the 16th and the 24th weeks. The histological observation showed that bone trabecula formed in the EDAC crosslinked ABP group and fibrous connective tissue was seen in CM group in the 16th and the 24th weeks. There were no significant differences in new bone percentage of bone defects between 2 groups in the 4th and the 8th weeks (P > 0.05). In the 16th week new bone percentage of bone defects was 81.99% +/- 3.92% in EDAC-crosslinked ABP group and 76.35% +/- 4.29% in CM group, showing significant difference (P < 0.05). The average percentage of absorption in EDAC crosslinked ABP group was 16.57%, 27.94%, 65.61 and 85.72% in the 4th, 8th, 16th and 24th weeks respectively, while that in CM group was more than 50% in the 4th week and completely degraded at the end of 8 weeks. CONCLUSION: EDAC-crosslinked ABP has a better effect on guiding bone regeneration than CM in the repair of bone defects. PMID- 17694669 TI - [An experimental study on effect of astragalus polysaccharides on chitosan/polylactic acid scaffolds for repairing alveolar bone defects in dogs]. AB - OBJECTIVE: To investigate the effect of astragalus polysaceharides (AP) on chitosan polylactic acid (AP/C/PLA)scaffolds and marrow stromal cells (MSCs)tissue engineering on periodontal regeneration of horizontal alveolar hone defects in dogs. METHODS: MSCs were isolated from the bone marrow and then cultured in conditioned medium to be induced to become osteogenic. The MSCs were harvested and implanted into AP/C/PLA and C/PLA scaffolds. A horizontal alveolar bone defect(5 mm depth, 2 mm width)were produced surgically in the buccal side of the mandibular premolar 3 and 4 of 10 dogs. The defects were randomly divided into 4 groups (n=10): Group A, root planning only (blank control); group B, AP/C/PLA with conditioned medium (medium control); group C C/PLA with MSCs (scaffolds control); and group D, AP/C/PLA with MSCs (experimental group). Eight weeks after surgery, block sections of the defects were collected for gross, histological and X-ray analysis. RESULTS: MSCs induced in vitro exhibited an osteogenic phenotype with expressing collagen I and alkaline phosphatase. X-ray film observation showed that the bone density and height had no changes in group A; in group B, the bone density was increased to a certain extent and furcation area reached a few height, but no height was increased in interdental septum; in group C, the bone density was increased and furcation area nearly reached the native height, but interdental septum reached a few height; in group D, the bone density was increased significantly and furcation area and interdental septum reached the native height. Histological evaluation showed that there was greater tissue formation in group D than that in groups A, B and C, in which new alveolar bone, new cementum, periodontal ligament with Sharpey's fibers, and new bone tissue was similar to native periodontal tissues. In group A,B, C and D respectively, the amount of new alveolar bone regeneration was 0.83 +/- 0.30, 1.46 +/- 0.55, 2.67 +/- 0.26 and 2.90 +/- 0.41 mm; new cementum regeneration was 0.78 +/- 0.45, 1.30 +/- 0.60, 2.29 +/- 0.18 and 2.57 +/- 0.22 mm; the amount of connective tissue adhesion was 0.80 +/- 0.22, 1.33 +/- 0.34, 2.23 +/- 0.42 and 2.64 +/- 0.27 mm; all showing significant differenecs between group D and groups A, B and C (P < 0.05). CONCLUSION: The technology of tissue engineering with AP/C/PLA scaffolds and induced MSCs may contribute to periodontal regeneration. PMID- 17694670 TI - [Experimental study on repair of articular cartilage defects with homograft of marrow mesenchymal stem cells seeded onto poly-L-lactic acid/gelatin]. AB - OBJECTIVE: To investigate the effect of homograft of marrow mesenchymal stem cells (MSCs) seeded onto poly-L-lactic acid (PLLA)/gelatin on repair of articular cartilage defects. METHODS: The MSCs derived from 36 Qingzilan rabbits, aging 4 to 6 months and weighed 2.5-3.5 kg were cultured in vitro and seeded onto PLLA/gelatin. The MSCs/PLLA/gelatin composite was cultured and transplanted into full thickness defects on intercondylar fossa. Thirty-six healthy Qingzilan rabbits were made models of cartilage defects in the intercondylar fossa. These rabbits were divided into 3 groups according to the repair materials with 12 in each group: group A, MSCs and PLLA/gelatin complex (MSCs/PLLA/gelatin); group B, only PLLA/gelatin; and group C, nothing. At 4, 8 and 12 weeks after operation, the gross, histological and immunohistochemical observations were made, and grading scales were evaluated. RESULTS: At 12 weeks after transplantation, defect was repaired and the structures of the cartilage surface and normal cartilage was in integrity. The defects in group A were repaired by the hyline-like tissue and defects in groups B and C were repaired by the fibrous tissues. Immunohistochemical staining showed that cells in the zones of repaired tissues were larger in size, arranged columnedly, riched in collagen II matrix and integrated satisfactorily with native adjacent cartilages and subchondral bones in group A at 12 weeks postoperatively. In gross score, group A (2.75 +/- 0.89) was significantly better than group B (4.88 +/- 1.25) and group C (7.38 +/- 1.18) 12 weeks after operation, showing significant differences (P < 0.05); in histological score, group A (3.88 +/- 1.36) was better than group B (8.38 +/- 1.06) and group C (13.13 +/- 1.96), and group B was better than group C, showing significant differences (P < 0.05). CONCLUSION: Transplantation of mesenchymal stem cells seeded onto PLLA/gelatin is a promising way for the treatment of cartliage defects. PMID- 17694671 TI - [Adult stem cells and stem cell disease]. AB - OBJECTIVE: To summarize the characteristics of adult stem cells and to introduce the definition and the features of stem cell disease. METHODS: Literature concerning adult stem cells and stem cell disease was extensively reviewed. RESULTS: Adult stem cells were localized in tissues and organs, and were able to generate function cells to replace cell loss during a lifetime of wear and tear. The stem cells had self-renewal to maintain themselves and undergo aging within the lifespan of an organism. The dysfunction of stem cells was capable to cause diseases, which could be defined as stem cell disease in human. The disorder of self renewal and differentiation in stem cells could increase the cellular proliferation, produce proliferative diseases such as tumors. The stem cells with self renewal defect, differentiation blockage, or aged stem cells could not supply enough function cells for tissue refreshment. The defect of tissue refreshment caused degenerative diseases. CONCLUSION: Studies on the stem cell self renew, differentiation, and aging can provide knowledge to understand the mechanism of stem cell diseases and develop technique to diagnose and treat these diseases. PMID- 17694672 TI - [Experimental and clinical research on repair of growth plate injury]. AB - OBJECTIVE: To sum up the experimental and clinical history as well as latest development of repair of growth plate injury. METHODS: Recent articles ab safe and effective methoout repair of growth plate injury were extensively reviewed and major reparative methods were introduced, especially including tissue engineering research on growth plate. RESULTS: Repair of growth plate injury was a great difficulty in experimental study and clinical treatment of pediatric orthopediis. Transplantation of free growth plate and cartilage were unfavorably used because of lack of blood supplement. Although circulation problem was solved by transplantation of vascularized growth plate, autografts of epiphyseal cartilage were involved in limitation of donor, and allografts of epiphyseal cartilage induced immunological reaction. Noncartilaginous tissue and material could only prevent formation of bony bridge in small defect of growth plate and lacked ability of regenerative repair. Transplantation of tissue engineered cartilage and chondrocytes might be a choice for repair of growth plate injury. CONCLUSION: Owing to lack of safe and effective methods of repairing growth plate injury, research on chondrocyte and tissue engineered cartilage should be further done. PMID- 17694673 TI - [Present and future of clinical application of myoblast]. AB - OBJECTIVE: To introduce the current situation and future of myoblast transfer therapy (MTT) in clinical application. METHODS: The latest fifteen-year literatures were extensively reviewed, concerning gene therapy for Duchenne's muscular dystrophy, Parkinson's disease, myelopathy, permanent facial paralysis, angiocardiopathy, injuries of bone, joint and muscle, hematopathy, and pituitary dwarf. RESULTS: In medical field, MTT is an ideal method to treat some common diseases. The problems were immunologic rejection and better carriers for myoblasts implantation. CONCLUSION: It is the focus on the use of myoblast as a vector to carry exogenous gene in some disease therapy. The major problems of MTT include transplantation immunity, cell fusion and target protein expression. It is easy to gain, culture and transfuse to the host for myoblasts, these merits are beneficial to clinical application. PMID- 17694674 TI - Development of drug resistance mutations in patients on highly active antiretroviral therapy: does competitive advantage drive evolution. AB - Most physicians that treat individuals with HIV-1 disease are able to successfully suppress viral replication with the pharmacologic armamentarium available today. For the majority of patients this results in immune reconstitution and improved quality of life. However, a large fraction of these patients have transient elevations in their viral burden and even persistence of low-level viremia. In fact, many individuals whose viral load is suppressed to < 50 c/ml have evidence of low-level viral replication. The impact of low-level viremia and persistent viral replication is an area of significant study and interest owing to the potential for the development of drug resistance mutations. Here the fundamental question is whether and perhaps what factors provide a venue for the development of resistant virus. The concern is clearly the eventual progression of disease with the exhaustion of treatment options. The purpose of this review is to evaluate the current literature regarding the effect of low level viremia on the development of drug resistance mutations. Herein, we discuss the impact of different levels of viral suppression on the development of mutations. In addition, we look at the role that resistance and fitness play in determining the survival of a breakthrough mutation within the background of drug. PMID- 17694675 TI - HIV diversity, recombination and disease progression: how does fitness "fit" into the puzzle? AB - HIV appears to have diverged into several lineages upon multiple zoonotic introductions from the nonhuman primates. The HIV-2 and HIV-1 groups M, N, and O likely represent different cross-species transmission events. The radial evolution of group M in multiple clades or subtypes is likely due to adaptation and expansions in the human hosts. It is not well understood why HIV strains such as HIV-1 subtype C in particular or group M in general have spread disproportionately as compared to other subtypes, groups, or types, which often remained geographically constrained to local epidemics. Host genetic effects, transmission bottlenecks, social/behavioral and environmental limitations, founder effect and other viral factors could have contributed to variable spread through the human population. Even after transmission, viruses evolve at different rates during disease progression. Recent studies have explored phenotypic differences between HIV types, groups, and subtypes in attempts to explain or understand this radial evolution and expansion. This review explores some of the important aspects relating to fitness during disease progression, during global distribution of different HIV subtypes, and related to circulation of recombinant forms in the epidemic. PMID- 17694676 TI - HIV and malaria. AB - Malaria and HIV infection are both prevalent in the areas of the world where these diseases have the largest burden. Both diseases interact with one another and this interaction is especially important in areas with non-continuous malaria transmission, in pregnant women, and in patients with more severe immunodeficiency. Malaria has been implicated in transitory higher viral load and in low CD4 counts, so it could have an influence on higher transmission rates of HIV and perhaps in the course of HIV infection. Infection with HIV has been shown to cause more clinical malaria and higher parasitemia in patients living in perennial transmission areas, and higher rates of severe malaria episodes and mortality in areas where malaria is transmitted with seasonal frequency. The HIV infected patients have also higher rates of malaria treatment failures. Co trimoxazole prophylaxis has been shown to be effective in the prevention of some opportunistic infections in HIV-infected patients, but also in prevention of malaria episodes. Antiretroviral protease inhibitors demonstrate antimalarial effects that could have important clinical and therapeutic implications. For all of these reasons, HIV and malaria should be considered together as part of healthcare programs for both diseases in countries where their co-presence favors an interaction with important clinical consequences. PMID- 17694677 TI - Update on the treatment of chronic hepatitis C in HIV-infected patients. AB - Liver disease is currently the second leading cause of death in HIV-infected persons in Western countries. Hepatitis C virus infection accounts for the majority of cases of hepatic illness in this population. Although great progress has been made in the treatment of chronic hepatitis C in HIV-positive patients, many challenges still remain unsolved. The combination of pegylated interferon plus ribavirin is the current treatment of choice in hepatitis C virus/HIV coinfected patients, regardless of hepatitis C virus genotype. However, the limited efficacy of this therapy in the HIV setting makes necessary the development of new strategies and/or drugs for the treatment of hepatitis C infection. Several anti-hepatitis C virus compounds are currently under investigation, although most are still in the early stages of clinical development. There is a relatively large group of patients who will be unable to be treated with the current hepatitis C virus medication based on interferon, mainly due to contraindications such as serious neuropsychiatric or cardiovascular history. However, for those without contraindications, treatment should be provided with no restrictions at the start (e.g. asking unnecessarily for a liver biopsy), and reassessed at weeks 4 and 12, considering virologic responses. Treatment should only be continued in early virologic responders. The use of standard doses of ribavirin (1000-1200 mg/day) and for at least 12 months seems crucial to maximize the effect of current hepatitis C treatment in the HIV setting, while no further benefit seems to derive from using higher than recommended pegylated interferon dosages. In patients with rapid virologic response (undetectable viremia at week 4) to anti-hepatitis C therapy, shorter periods of therapy (24 weeks) may be advisable in hepatitis C genotypes 2 and 3. Finally, adequate selection of candidates and careful selection of concomitant antiretroviral medications must be encouraged. Patients with low CD4 percentages (< 15%) should be deferred for treatment and HAART prioritized in order to improve CD4 counts. When possible, nucleoside analogs such as zidovudine, stavudine, and abacavir should be replaced by others having no deleterious interactions with ribavirin (e.g. tenofovir, lamivudine, or emtricitabine). Didanosine should never be coadministered with ribavirin due to potential life threatening complications. PMID- 17694678 TI - A brief history of TRIM5alpha. AB - In spite of the fact that the first isolates of HIV-1 became available more than 20 years ago, there is still no robust animal model for HIV-1 replication and pathogenesis. This is largely due to the existence of multiple genetic barriers to HIV-1 replication in most nonhuman primates, including a severe block targeting the early, post-entry phase of the viral replication cycle. It is now known that a protein called TRIM5alpha mediates this early restriction in nonhuman primate cells. Tissue culture experiments, together with genetic association studies involving multiple HIV/AIDS cohorts, indicate that the human orthologue of TRIM5alpha does not have a significant impact on HIV-1 replication. However, most human alleles encode a functional protein that can restrict at least one retrovirus unrelated to HIV-1 (N-tropic murine leukemia virus), although one deleterious mutation (H43Y) is present at high frequency in human populations. Phylogenetic analyses of the TRIM5 locus reveal that prehistoric retroviral epidemics, not unlike the current HIV/AIDS pandemic, played a significant role in the evolutionary history of humans and their primate relatives. The discovery of TRIM5alpha's antiretroviral activity sparked the imaginations of many laboratories, and considerable effort has now been channeled into characterizing the protein and determining its possible mechanism(s) of action. It is hoped that research on TRIM5alpha will contribute to the establishment of new and improved models for HIV replication and AIDS pathogenesis, point the way towards novel therapeutic targets to stem the tide of the human AIDS epidemic, provide an experimental window onto the early, post entry stages of the retroviral replication cycle, and even inspire the search for other cellular factors that modulate retroviral infection. PMID- 17694679 TI - Discovery of VIRIP--a natural HIV entry inhibitor. PMID- 17694680 TI - A novel mechanism involved in TLR4 expression during inflammation. AB - The p47phox- and Rac 1-dependent NADPH oxidase activation, ROS production, and MAPK signaling pathways play critical roles in endotoxin-enhanced TLR4 expression and TLR4 mRNA stabilization in VSMCs. These evidences provide for the direct involvement of VSMCs in endotoxin-mediated inflammatory activation, which may contribute to the progression of cardiovascular disorders, although targeting TLR4 will prove to be a successful approach for the treatment of these devastating diseases remains to be determined. PMID- 17694681 TI - Effect of intrathecal NG-nitro-L-arginine methyl ester administration on Fos expression in the spinal dorsal horn in rats following sciatic nerve ligation. AB - BACKGROUND: In the available literature, the pro- or antinociceptive role of nitric oxide (NO) is warmly disputed. As a marker of neuronal activation of the central nervous system, Fos expression has been widely used to assess the change in central neuronal activity evoked by peripheral input. In this study, we examined the effect of intrathecal L-NAME, a non-selective nitric oxide synthase (NOS) inhibitor, on nociceptive behavior and spinal Fos expression in rats following chronic constriction injury (CCI) of sciatic nerve, a model of neuropathic pain similar to that observed in clinical setting. METHODS: Eighty adult male SD rats showing no neurological deficiency a week after intrathecal catheterization were used in this study. L-NAME 250 microg of 10 microl (an equivalent or 0.9% saline) was injected intrathecally 15 min prior to CCI or sham operation. In addition to examination of thermal hyperalgesia by paw withdrawal latency (PWL), measurement of Fos protein staining neurons in the lumbar spinal cord using an immunohistochemistry technique were made at 1, 3, 7 and 14 days after operation. RESULTS: As compared with untreated animals, both CCI and sham operations evoked an early and long-term Fos expression, whereas a significant decrease in PWL was demonstrated only in rats receiving CCI. On days 3, 7 and 14 after CCI, the number of FLI neurons in the spinal dorsal horn ipsilateral to the injury decreased by 54%, 57% and 43%, respectively, in CCI-L-NAME group when compared with CCI-saline group, corresponding to the significant attenuation of thermal hyperalgesia. However, intrathecal L-NAME preadministration had no effect on the spinal Fos expression evoked by sham operation. CONCLUSIONS: Spinal Fos expression could be induced by different mechanisms, and it should not regarded as a reliable marker of pain sensation disorders. NO plays an important role in the development of nociception and spinal Fos expression through central sensitization mediated by peripheral nerve injury. PMID- 17694682 TI - Ultrasound examination for the optimal head position for interscalene brachial plexus block. AB - BACKGROUND: Surface anatomic landmarks have traditionally been used to locate the brachial plexus in the interscalene groove. Head rotation can affect the orientation of neck vessels and may possibly affect the brachial plexus. The optimal degree of head rotation has been specified for better internal jugular vein cannulation but not for interscalene brachial plexus block. The purpose of this study was to evaluate the influence of head rotation on interscalene brachial plexus block. METHODS: We simulated the needle insertion in interscalene approach to brachial plexus with the ultrasound probe to mimic the needle in the manner of actual block in 53 volunteers. Ultrasound-derived measurements were recorded to evaluate the influence of head rotation on the approach including deviation from the imitative needle path to plexus center, depth of brachial plexus and vessel intersection. RESULTS: Medial deviation of the imitative needle path to the center of brachial plexus was found from all angles of head rotation. Increased head rotation angle of 0 degree, 15 degrees, 30 degrees, 45 degrees and 60 degrees from the midline was associated with increasing medial deviation. The brachial plexus became more superficial if head rotation was over 30 degrees than within the realm of 15 degrees. The likelihood of the stimulated needle path intersecting the internal jugular vein was lower than 5% for head rotation within 30 degrees and would become significantly higher for head rotation over 45 degrees. CONCLUSIONS: Whenever we perform interscalene brachial plexus block, the head rotation angle should not exceed 30 degrees. The measured medial deviation of surface landmark should be considered when it is used to approach interscalene brachial plexus. PMID- 17694683 TI - The use of portable computer for information acquirement during anesthesiologist's ward round in acute pain service. AB - BACKGROUND: The Acute Pain Service Information Management System (APSIMS), as we coined, is the utilization of a portable computer to register the data of the patients who need acute pain management during anesthesiologist's ward round. Initially, the data of the daily acute pain assessment at the ward are recorded on a sheet of paper by the rounding anesthesiologist, which are subsequently entered into the hospital main frame computer by an anesthetic nurse. In order to save manpower in data entry, we planned to introduce the personal digital assistant (PDA) into acute pain assessment. The anesthesiologist can record a patient's data directly into the PDA device at the bedside. After acute pain assessment is finished, we can directly up load the data from the PDA to the hospital mainframe computer without the need of further manpower for doing data input. This study was to evaluate the use of PDA for acute pain assessment and compare the PDA-based method with that of the current paper-transcription method in work efficiency. METHODS: Two computer applications were developed: the APS Mobile Assistant and the Data Transformation Wizard (DTW). The APS Mobile Assistant is a PDA application running on a portable computer with Windows Mobile 2003 operation system. The anesthesiologist can use this application to perform APS assessment at the bedside. The Data Transformation Wizard is a PC application which can transfer data from the PDA device to the hospital mainframe computer, by which the data in the PDA system can be integrated into the hospital information system. The evaluation included the reckoning of the timings of two periods i.e. the time spent by the physician to perform acute pain assessment at the bedside and the time required for data management by the nurse. To compare the paper-transcription method with the PDA-based technique, the Student's t test was performed to assess the data of time of each category collected. A P value less than 0.05 was considered to be significant. RESULTS: When the time required for assessment of acute pain was determined, no statistically significant difference was observed between the use of the paper-transcription-based system and the PDA system (P = 0.258). In comparison the PDA system was clearly shown to facilitate faster management of data (Paper-transcription method: 1.57 +/- 0.08 min per patient compared with PDA-based method: 0.24 +/- 0.01 min per patient, P < 0.0001). CONCLUSIONS: Implementation of PDA device during APS assessment can provide the anesthesiologists with more time to acquire information during APS visits. Using the PDA technology in clinical settings can increase work efficiency. We can save manpower and are convinced that data collection is more complete with the use of a PDA system. PMID- 17694684 TI - Magnesium infusion and postoperative atrial fibrillation: a randomized clinical trial. AB - BACKGROUND: Postoperative arrhythmias are among the most common complications of cardiac surgery. Total serum magnesium concentration will change after coronary bypass surgery but compensatory prophylactic administration of magnesium has remained a controversial issue. We studied whether prophylactic administration of magnesium could prevent post-coronary artery bypass grafting (CABG) arrhythmias and evaluated the effects of diabetes mellitus on prophylactic magnesium administration. METHODS: In a clinical trial, 345 consecutive CABG candidates were randomly assigned to study (n = 166, 48.1%) and control groups. Patients in study group received supplemental magnesium infusion as following: 2 g [corrected] after induction of anesthesia until cardio-pulmonary bypass and then 8 g upon arrival in Intensive Care Unit (ICU) until 24 hr. Total serum magnesium concentration was measured at four designated time points: onset of induction, and 0, 24 and 48 hr after ICU admission. Cardiac arrhythmias were sought with a 12-lead electrocardiogram (ECG) from the end of surgery up till discharge. RESULTS: Atrial Fibrillation (Af) occurred in 34 patients (9.9%). Total serum magnesium concentration was significantly higher in patients who received supplemental magnesium (P < 0.001) and significantly lower in Af patients (P= 0.02). Among non-diabetics, Af incidence was significantly lower in study group compared with control group. CONCLUSIONS: The occurrence of atrial fibrillation correlates with serum magnesium level. Diabetes mellitus probably hampers prophylactic effect of supplemental magnesium in preventing the occurrence of Af. PMID- 17694685 TI - Clinical experience of pain treatment for postherpetic neuralgia in elderly patients. AB - BACKGROUND: Postherpetic neuralgia (PHN) is a neuropathic pain syndrome that occurs following acute herpes zoster infection. The main clinical problem is intractable pain which interferes with activity of daily life and reduces the quality of life in the elderly patients. This retrospective study was to evaluate the outcome of pain treatment for the elderly patients with PHN at the Pain Clinic of Kaohsiung Medical University Hospital. METHODS: Fifty-eight elderly outpatients with PHN were studied from January 2004 to June 2006. The pain intensity before and after treatment were assessed by patients themselves with numeric pain scale (NPS). The pain treatment included (1) medication with anticonvulsants, opioids and nonsteroidal anti-inflammatory drugs (NSAIDs); (2) nerve block with 0.25% bupivacaine or 1% lidocaine twice a week at the beginning of the treatment. The therapeutic outcome was expressed by pain relief. The reduction of pain and residual pain intensity were evaluated subjectively by the patients themselves with patients' global impression and NPS, respectively, after treatment for one and three months (or last visit). The adverse events throughout the treatment course were analyzed. RESULTS: (1) The mean age of the patients was 75.1 yr. The number of female PHN sufferers was higher than that of male in all aged groups and the highest incidence was found in the age group of 70-79 (65.5%). The most commonly involved dermatomes were in the thoracic region (82.7%). (2) All patients suffered from severe pain (NPS 8-10) before treatment. (3) The pain management was a combination of medication and nerve block at the beginning of the treatment. Among the medications, gabapentin was prescribed to all the patients and almost all of them (98.3%) required opioids simultaneously and some of them needed additional NSAIDs at the beginning of the treatment. (4) The most common adverse event was somnolence (24.1%). (5) Among the sympathetic blocks, the intercostal nerve block was performed commonly (84.5%). (6) The therapeutic outcome was expressed by pain relief. As to the reduction of pain, 46 cases (79.3%) and 57 cases (98.3%) felt moderate and much improvement after treatment for one and three months (or last visit), respectively. As to residual pain intensity, although none of them got complete pain relief, however, there were 12 cases (20.7%) and 45 cases (77.6%) felt the pain intensity was mild (NPS 1-3) after treatment for one and three months respectively. (7) There was a statistically significant decrease in the pain intensity between before treatment and after treatment for one month and three months. CONCLUSIONS: Our study results showed that the concurrent combination therapy with proper medications and appropriate nerve blocks could offer satisfactory pain relief in the majority of elderly patients with PHN. PMID- 17694686 TI - Cellular mechanisms of neuroinflammatory pain: the role of interleukin-1beta. AB - Dorsal horn of the spinal cord is important in the transduction and modulation of various pain signals. Interleukin-1beta (IL-1beta) not only plays an important role in the nociceptive modulation but also enhances the spinal cord nociceptive neuron wind-up. Intrathecal (i.t.) administration of IL-1beta activates p38 mitogen-activated protein kinase (MAPK), and leads to induction of inducible nitric oxide synthase (iNOS) and release of nitric oxide (NO), which sensitizes the spinal nociceptors and produces thermal hyperalgesia and allodynia. I.t. pretreatment of IL-1 receptor antagonist (IL-1ra), p38 MAPK inhibitor or iNOS inhibitor, inhibits the i.t. IL-1beta-induced NO levels and thermal hyperalgesia in rats, likely via either inhibiting the IL-1beta-mediated p38 MAPK activation and subsequent iNOS induction, or direct attenuation of the central iNOS activity, which therefore reduces the central sensitization of inflammatory pain. I.t. administration of IL-1beta in rats provides an attractive model for studying the mechanisms and development of the treatment strategy of neuroinflammatory pain. PMID- 17694687 TI - Methemoglobinemia induced by exposure to topical benzocaine for an awake nasal intubation--a case report. AB - Topical benzocaine and lidocaine are widely used in general anesthesia to minimize the stimulation by awake intubation and in very rare occasion they may induce methemoglobinemia. Although this complication is uncommon, it may be potentially lethal. Here we report a 29-year-old female who was scheduled to receive correction of malocclusion and developed acute methemoglobinemia soon after induction of general anesthesia. Three weeks ago, she had received open reduction for fracture of mandible with intermaxillary fixation under general anesthesia, for which awake fiberoptic intubation was smoothly performed after premedication with 2% topical lidocaine and intravenous fentanyl. This time, trachomucosal block with 4 mL of 4% topical lidocaine and spray of 20% topical benzocaine over the oral cavity and nostrils were carried out before intubation. Awake blind intubation was performed because she could not open her mouth for more than 1 cm. A 6.5 mm-sized nasal endotracheal tube was smoothly placed in first attempt. About 10 min later, an unexplained cyanosis occurred and SpO2 fell to about 70%. Based on a high oxygen tension by arterial blood gas analysis (PaO2) with a contradictory fall of oxygen saturation by pulse oximetry (SpO2), acute methemoglobinemia was highly suspected. The diagnosis was confirmed by multiple-wavelength CO-oximetry. The methemoglobinemia was resolved gradually after methylene blue was given. In conclusion, we must always take the possibility of methemoglobinemia into consideration for differential diagnosis in case of unexplained cyanosis, particularly when patients have prior exposure to methemoglobin-inducing agents. PMID- 17694688 TI - Massive pulmonary embolism during orthopedic surgery. AB - A 90-year-old female patient undergoing surgery for knee and hip fractures under general anesthesia sustained cardiac arrest intraoperatively. The transesophageal echocardiography performed during resuscitation revealed massive pulmonary embolism with a 2 x 3 cm oval-shaped thrombus in the bifurcation of pulmonary artery. Anticoagulant therapy was administered immediately. Clinical symptoms were gradually improved, and transthoracic echocardiography performed 5 days later revealed no evidence of residual thromboemboli. Subsequently the patient developed liver and acute renal failures in consequence of hypoperfusion during the intraoperative resuscitation, and died of multiple organ failure 21 days after the procedure. We conclude that transesophageal echocardiography is a useful diagnostic instrument and should be utilized in high risk patient as early as possible, even before and during surgery. PMID- 17694689 TI - Syndrome of inappropriate antidiuretic hormone secretion and diabetes insipidus in an infant following surgery. AB - Syndrome of inappropriate secretion of antidiuretic hormone and diabetes insipidus occurring in very short order in the same patient is rare. We report a 9 month-old male infant suffering form holoprosencephaly developed syndrome of inappropriate secretion of antidiuretic hormone followed by diabetes insipidus within a relative short time postoperatively after his third operation. Inability to suppress as well as to stimulate arginine vasopressin secretion and anesthetic and surgical stresses, were thought to be the possible causes of this event. PMID- 17694690 TI - Postoperative pulmonary edema after lower thoracic spinal tumor surgery--a case report. AB - Cardiovascular instability is a common manifestation of spinal cord injury, especially if the upper thoracic or cervical spine is involved. Here we report a case of lower thoracic spinal tumor who developed acute pulmonary edema postoperatively at post-anesthesia room following surgery. This might be caused by injudicious fluid administration after trying to correct intraoperative hypotension due to neurogenic shock. Therefore, meticulous calculation in fluid resuscitation together with vasopressors or inotropics support is important in dealing with neurogenic shock. Comprehensive monitoring of hemodynamic parameters, such as with central venous catheter or pulmonary catheter in this sort of surgery should be established for drastic fluid management. PMID- 17694691 TI - Usefulness of the skin index in predicting the outcome of oral challenges in children. AB - BACKGROUND: The diagnostic accuracy of the skin prick test (SPT) for food allergies remains to be fully accepted and substantial individual differences in the prevalence of skin test reactivity have been reported. OBJECTIVE: The aim of this study was to assess the diagnostic value of absolute wheal size and skin index (SI; ratio of food allergen-induced wheal to histamine-induced wheal) according to the outcome of controlled oral food challenges. METHODS: Eighty seven controlled oral challenges were performed with cow's milk, hen eggs, wheat, buckwheat, peanuts, seafood, and/or fruit in 51 children (median age, 35 months). The wheal diameters in SPT, the SI, and the serum specific immunoglobulin (Ig) E concentrations were determined. RESULTS: Thirty-three oral challenges were assessed as being positive. SI and wheal diameter in SPT were both significantly different according to the outcome of food challenge (P < .001 and P = .03, respectively); the greatest difference was found in the case of SI. Serum specific IgE concentration did not differ significantly according to the outcome of food challenge. CONCLUSION: SI may be helpful for predicting a positive outcome of food challenge. PMID- 17694692 TI - Peak expiratory flow monitoring to screen for asthma in patients with allergic rhinitis. AB - AIM: To investigate the benefit of using peak expiratory flow (PEF) monitoring to screen for asthma in allergic rhinitis patients. METHODS: Eighty-nine consecutive patients with allergic rhinitis but never assessed for asthma were included in this prospective study. Their allergic status was determined by skin prick tests. All of the subjects filled in a questionnaire on asthma-like symptoms. If they reported such symptoms, pulmonary function tests were carried out. Then, PEF was checked twice daily for 3 weeks. RESULTS: Thirty-six percent of our study group were male and 64% were female patients with a mean (SD) age of 36.3 (14.0) years. Skin prick tests were positive to grass mixture in 71 (79.8%) patients, to tree mixture in 51 (57.3%), to mite in 46 (51.7%), and to epidermal mix in 26 (29.2%) patients. Thirty-six patients (41%) reported 3 or more asthma symptoms. Lung function test results for these 36 patients showed obstruction for 11.1% (4 patients); the remaining patients (88.9%) had normal function parameters. The subjects who reported 3 or more asthma symptoms but had normal lung function monitored their PEF for 3 weeks. Sixteen (50%) patients from this group and the 4 patients with demonstrated airway obstruction had more than 20% diurnal variation in PEF. These 20 patients' asthma symptoms disappeared after they received 3 months of low-dose inhaled corticosteroid therapy. CONCLUSION: It is necessary to look for asthma in patients suffering from allergic rhinitis. PEF monitoring is a low-cost, objective approach to asthma diagnosis that can be performed by a patient with allergic rhinitis even if spirometry is normal. Knowledge of this technique is of utmost importance because delay in diagnosis will result in the unsatisfactory treatment of the disease. PMID- 17694693 TI - Group education on asthma for children and caregivers: a randomized, controlled trial addressing effects on morbidity and quality of life. AB - OBJECTIVE: To establish the efficacy in terms of morbidity and quality of life of a group education program on asthma aimed at children and caregivers. METHODS: An open, randomized, controlled trial was undertaken in 13 primary health care centers in Spain, Cuba, and Uruguay and involved 245 children with active asthma aged 9 to 13 years and their caregivers. The intervention consisted of 3 educational sessions lasting 45 to 60 minutes each and was performed with 3 intervention groups: children alone, caregivers alone, and both children and caregivers. The outcome measures were difference between intervention and control groups in the rate of asthma attacks and hospital admission, as well as the quality of life of children and caregivers in the 6 months following the intervention. RESULTS: The rate of asthma attacks per patient-year decreased when the intervention was given only to children (mean difference, -1.61; 95% confidence interval [CI], -2.87 to -0.34) or to both children and caregivers ( 1.60; 95% CI, -2.88 to -0.31). Hospital admissions per patient-year decreased in the intervention groups children alone (-0.28; 95% CI, -0.51 to -0.05) and both children and caregivers (-0.25; 95% CI, -0.49 to -0.02). Education provided to caregivers alone was not associated with any changes in morbidity. No differences were observed in terms of quality of life between controls and any of the intervention groups. CONCLUSIONS: Group education on asthma reduces morbidity but does not improve quality of life. The benefits are apparent when education is aimed at children but no additional benefit is obtained if the intervention is also aimed at their caregivers. Finally, group education for adult caregivers alone is not effective. PMID- 17694694 TI - The influence of bedroom environment on sensitization and allergic symptoms in schoolchildren. AB - BACKGROUND: Bedroom conditions have been associated with an increased risk of allergy. OBJECTIVE: The aim of this study was to evaluate the relationship between sleeping environment and sensitization and allergic symptoms in schoolchildren. METHODS: A cross-sectional study, the Aalst Allergy Study, was performed in an unbiased community population of 2021 Belgian schoolchildren, aged 3.4 to 14.8 years. Skin prick testing was performed with the most common aeroallergens and bedroom conditions (presence of stuffed toys, type of flooring, and bedding material) were documented through a parental questionnaire. RESULTS: The presence of stuffed toys in the bedroom was associated with a lower prevalence of overall sensitization and a lower prevalence of conjunctivitis and allergic respiratory symptoms. That effect was almost exclusively present in children with a positive family history of atopy and was more pronounced as the number of stuffed toys increased. A significantly lower prevalence of overall sensitization, sensitization to house dust mite, and wheezing was documented in children with nonsynthetic bedding materials. That effect was exclusive to children with a positive family history of atopy. Type of flooring was not associated with sensitization or allergic symptoms. CONCLUSION: Our data suggest that bedroom exposure to stuffed toys and nonsynthetic bedding materials may have a protective effect against sensitization and allergic symptoms in genetically predisposed children. Confirmation of these findings will require further prospective studies that include measurement of levels of mite allergens and endotoxins and assessment of the time, degree, and duration of the exposure. PMID- 17694695 TI - Duration of asthma and lung function in life-long nonsmoking adults. AB - BACKGROUND: The airways of adult or elderly asthmatics are likely candidates for airway remodeling, resulting in persistent airflow obstruction. This population can provide a good model for cross-sectional evaluation of the effect of asthma duration on airflow. METHODS: We evaluated postbronchodilator airflow and lung volumes at baseline and after a short course of oral prednisone in a group of 42 never-smokers with persistent mild or moderate asthma aged 55 years or older. Patients were grouped as having short duration asthma (SDA, <14 years) or long duration asthma (LDA, > or =14 years) according to the median duration of the disease (14 years) of the sample. RESULTS: There were no significant differences in patient characteristics or asthma severity indices between the groups. After a short course of prednisone, forced expiratory volume in 1 second (FEV1) and the ratio of FEV to forced vital capacity (FVC) were significantly higher for the SDA group. Only 3 patients presented persistent airflow limitation (FEV1/FVC% < 75%). An inverse correlation was demonstrated between duration of asthma and postbronchodilator FEV1 (% predicted) (r = -0.43, P = .01) and FEV1/FVC% (r = 0.50, P = .003). CONCLUSION: Our data show a close relationship between duration of disease and loss of lung function, supporting the concept of asthma as a slow, progressive disease at least among those patients with a mild-to-moderate severity. Permanent airflow obstruction in mild or moderate asthma is unusual, but can occur in a small number suffering from the disease for years. PMID- 17694696 TI - Dipyrone improves small airway function in asthmatic patients with moderate obstruction. AB - BACKGROUND: Dipyrone is an analgesic and antipyretic agent with a distinctive spasmolytic effect on smooth muscles. We recently showed that dipyrone significantly relaxed precontracted tracheal smooth muscle in guinea pig. OBJECTIVE: To investigate whether this in vitro observation could be observed in vivo in the respiratory function parameters of asthma patients. METHOD: Twenty two patients, aged 18 to 75 years and diagnosed with asthma according to the American Thoracic Society criteria were enrolled at the time they had any indication for dipyrone use. Pulmonary function tests were performed before and 30, 60, 90, and 120 minutes after oral intake of 1 g of dipyrone. The tests were repeated without dipyrone intake in a situation of spontaneous recovery after a minimum washout period of 2 days. RESULTS: Patients were classified according to their baseline forced expiratory volume in 1 second (FEV1) as having mild obstruction (FEV > or =80% predicted) or moderate obstruction (FEV1 60%-80% predicted). Significant improvement with dipyrone was seen in FEV1 and peak expiratory flow rates at 25%, 50% and 75%) of forced vital capacity and in maximum midexpiratory flow rate only in patients with moderate asthma. No significant change was observed on the spontaneous recovery day except in FEV1. CONCLUSION: Dipyrone had a significant effect leading to an improved small airway function in asthmatic patients with moderate airway obstruction, confirming our recent in vitro findings. PMID- 17694697 TI - Seasons and other factors affecting the quality of life of asthmatic children. AB - OBJECTIVE: To study the effect of seasons on the health-related quality of life (HRQL) of asthmatic children. METHODS: Four groups of asthmatic children 7 to 14 years old were recruited by pediatricians during each season of the year. Their HRQL was assessed by means of the Paediatric Asthma Quality of Life Questionnaire (PAQLQ). Other factors surveyed were asthma severity, atopy, medical treatment, immunotherapy, obesity, parental smoking, and anti-allergic measures. RESULTS: The mean (SD) overall PAQLQ score was highest in summer at 6.2 (1.0) and lowest in autumn at 5.5 (1.2). The same trend was found for domains in summer and autumn, respectively: symptoms, 6.2 (1.0) vs 5.4 (1.4); emotions, 6.5 (0.8) vs 6.0 (1.0); and activities, 5.9 (1.4) vs. 5.0 (1.5). Factors such as male gender (odds ratio [OR], 0.60; 95% confidence interval [CI], 0.41-0.87), being on immunotherapy (OR, 0.59; 95% CI, 0.38-0.92), living in an urban environment (OR, 0.56; 0.33-0.93), and residing on the northern coast of Spain along the Bay of Biscay (OR, 0.56; 0.36-0.89) were independent protective factors against having a total PAQLQ score in the lower tertile. Conversely, being recruited in a primary care setting (OR, 1.55; 1.01-2.38) and having more severe asthma were risks for being in the lower tertile. CONCLUSIONS: Irrespective of the severity of the disease, season has a significant influence on the HRQL of asthmatic children. PMID- 17694699 TI - Anaphylaxis after eating Italian pizza containing buckwheat as the hidden food allergen. AB - A 20-year-old woman developed anaphylaxis after eating pizza on 4 different occasions in 2 restaurants. Both restaurants made their pizza dough with a mixture of wheat and buckwheat flours. A prick-to-prick test with buckwheat flour was positive. Skin prick tests and specific immunoglobulin E responses to soybean and peanut were weakly positive while the response to buckwheat was negative. We ruled out a pathogenic role for peanut and soybean because the patient usually eats both with no signs of allergic reaction. Double-blind, placebo-controlled food challenges with buckwheat flour were positive after the administration of a cumulative dose of 2.3 g of the culprit flour. To our knowledge, our report describes the first case of anaphylaxis after intake of buckwheat flour as the hidden allergen in pizza dough. PMID- 17694698 TI - Assessment of a new brand of determinants for skin testing in a large group of patients with suspected beta-lactam allergy. AB - BACKGROUND: Skin testing with major and minor determinants of benzylpenicillin is recommended standard practice for the evaluation of patients with immediate hypersensitivity reactions to beta-lactams. However, commercial reagents for this purpose were recently dropped from the European market. OBJECTIVE: In the present study, we assessed a new brand of reagents for use in skin testing in patients with suspected penicillin allergy. METHODS: Prick tests and intradermal tests were performed with benzylpenicilloyl polylysine (PPL) and minor determinant mixture (MDM). Penicillin G, amoxicillin, and the culprit beta-lactam were also tested. If skin tests were negative, a single-blind oral challenge test was performed with the culprit active principle or penicillin. If both skin tests and challenge tests were negative, the same procedure was repeated between 2 and 4 weeks later. RESULTS: A total of 636 patients were assessed. The allergy study was positive in 69 patients. Skin tests with PPL were positive in 30 patients (46.8%) and with MDM in 28 (43.7%). Sixteen patients displayed a positive reaction to both PPL and MDM (25%), while 42 patients (65.6%) had a positive reaction to either PPL or MDM alone. Thirty-two patients had positive skin test reactions to penicillin G or another p-lactam antibiotic. Five patients in whom a negative result was obtained in skin tests had a positive reaction to oral challenge. CONCLUSIONS: Our results indicate that a new brand of determinants that is commercially available in Europe is a reliable and useful tool for the diagnosis of beta-lactam allergy. The new reagents are a safe alternative to the previously available brand. PMID- 17694700 TI - Recurrent angioedema due to lysozyme allergy. AB - A 54-year-old woman suffered an episode of dyspnea and edema affecting her eyelids, tongue, and lips a few minutes after intake of Lizipaina (bacitracin, papain, and lysozyme). She was treated with intravenous drugs and her symptoms improved within 2 hours. She had experienced 3 to 4 bouts of similar symptoms related to the ingestion of cured cheeses or raw egg. Specific serum immunoglobulin (Ig) E against lysozyme was present at a concentration of 0.45 kU/L, and no specific IgE was found against egg white and yolk, ovalbumin, or ovomucoid. Skin prick tests were positive with commercial extracts of egg white and lysozyme but doubtful with yolk, ovalbumin, and ovomucoid. Prick-to-prick tests with raw egg white and yolk gave positive results, but negative results were obtained with cooked egg white and yolk and 5 brands of cheese (3 of them containing lysozyme and the other 2 without lysozyme). Controlled oral administration of papain, bacitracin, and cheeses without lysozyme was well tolerated. We suggest that the presence of lysozyme in a pharmaceutical preparation, cured cheese, and raw egg was responsible for the symptoms suffered by our patient, probably through an IgE-mediated mechanism. PMID- 17694702 TI - Selective hypersensitivity to boiled razor shell. AB - Many types of seafood require cooking before ingestion and it has been demonstrated that this cooking process may affect the antigenicity and allergenicity of the food. We describe a case of anaphylaxis caused by selective sensitization to razor shell, a mollusc. In vivo and in vitro studies confirmed sensitization to boiled razor shell. Analysis of the nature of the allergen yielded results that were consistent with the findings of other authors and suggested that allergens involved in seafood allergy are commonly high molecular weight proteins that, in most cases, are heat stable. PMID- 17694701 TI - Severe asthma associated with myasthenia gravis and upper airway obstruction. AB - An unusual association of asthma and myasthenia gravis (MG) complicated by tracheal stenosis is reported. The patient was a 35-year-old black woman with a history of severe asthma and rhinitis over 30 years. A respiratory tract infection triggered a life-threatening asthma attack whose treatment required orotracheal intubation and mechanical ventilatory support. A few weeks later, tracheal stenosis was diagnosed. Clinical manifestations of MG presented 3 years after her near-fatal asthma attack. Spirometry showed severe obstruction with no response after inhalation of 400 microg of albuterol. Baseline lung function parameters were forced vital capacity, 3.29 L (105% predicted); forced expiratory volume in 1 second (FEV1), 1.10 L (41% predicted); maximal midexpiratory flow rate, 0.81 L/min (26% predicted). FEV1 after administration of albuterol was 0.87 L (32% predicted). The patient's flow-volume loops showed flattened inspiratory and expiratory limbs, consistent with fixed extrathoracic airway obstruction. Chest computed tomography scans showed severe concentric reduction of the lumen of the upper thoracic trachea. PMID- 17694703 TI - Severe immediate reaction to nabumetone. AB - Nabumetone is a nonsteroidal antiinflammatory (NSAID) prodrug that inhibits cyclooxygenase-2. It has been recommended as a safe alternative in most patients with hypersensitivity reactions to NSAIDs. Systemic reactions caused by nabumetone are not frequent. We report 2 cases of immediate systemic reactions due to nabumetone. The first case involved a 68-year-old woman who developed immediate generalized pruritus, erythema, morbilliform eruption, swollen tongue sensation, diarrhea, and hypotension after the ingestion of a single dose of nabumetone. In the second case, a 77-year-old woman developed generalized pruritus, palm erythema, colic abdominal pain, diarrhea, dizziness, tightness of the chest, dyspnea, and hypotension immediately after oral intake of nabumetone. Both patients had previously tolerated this drug. Since these episodes, they have avoided nabumetone. Skin prick tests with nabumetone (10 and 100 mg/mL) were negative. Oral challenge tests with other NSAIDs, even of the same group as nabumetone, were negative in both patients. The mechanisms responsible for the reaction were not established. PMID- 17694704 TI - Pompholyx induced by intravenous immunoglobulin therapy. PMID- 17694705 TI - Montelukast in 2 atopic patients with intolerance to nonsteroidal anti inflammatory drugs and paracetamol: 5-year follow-up. PMID- 17694706 TI - Anaphylactic shock caused by tick (Rhipicephalus sanguineous). PMID- 17694707 TI - Severe anaphylaxis to royal jelly attributed to cefonicid. PMID- 17694708 TI - Detection of a 12-kilodalton lipid transfer protein allergen in parsley. PMID- 17694709 TI - Anaphylaxis induced by lupine as a hidden allergen. PMID- 17694710 TI - Immediate hypersensitivity to corticosteroids: finding an alternative. PMID- 17694711 TI - An analysis of the definitions and elements of recovery: a review of the literature. AB - As mental health recovery gains traction, many people have put forward varying definitions. Few attempts have been made to create a dimensional analysis of the recovery literature that assesses the growing consensus about what recovery is or what its definition should entail. This paper incorporates an ecological framework to take the individual's life context into account while emphasizing both the reestablishment of one's mental health (i.e., first order change) and the mitigation of the oppressive nature of barriers imposed by the greater community (i.e., second order change) so that people may experience social integration and community inclusion. PMID- 17694712 TI - Creating a recovery-oriented system of behavioral health care: moving from concept to reality. AB - This article describes challenges and successes seen in the first four years of efforts the state of Connecticut has made to reorient its behavioral health system to promoting recovery. Beginning in 2000, the Connecticut initiative was conceptualized as a multi-year, systemic process that involved the following interrelated steps: a) developing core values and principles based on the input of people in recovery; b) establishing a conceptual and policy framework based on this vision; c) building workforce competencies and skills; d) changing programs and service structures; e) aligning fiscal and administrative policies; and, finally, f) monitoring, evaluating, and adjusting these efforts. Following descriptions of the first four steps, the authors offer a few lessons that might benefit other states engaged in similar processes of transformation. PMID- 17694713 TI - Recovery: a common vision for the fields of mental health and addictions. AB - The vision of recovery is reshaping the fields of mental health and addiction services. This paper reviews how this broad vision is shaping common goals, principles, values and strategies across the two fields. We further examine how a common vision of recovery can positively impact the treatment of co-occurring disorders and speculate on how this vision can bridge the seeming differences between these two fields and reshape a mutual understanding of the essentials of recovery from severe mental illness and addiction. PMID- 17694714 TI - Recovery and resilience in children's mental health: views from the field. AB - This article explores the questions, "What does recovery mean in the context of children's mental health?" "How do recovery and resilience fit with the system of care values that underpin current transformation efforts in the children's mental health field?" And, "What implications flow from the answers to these questions?" The author details a process designed to gather the perspectives of family members, service providers, administrators, researchers, and advocates, summarizes the results of these discussions, and concludes with recommendations for next steps. PMID- 17694715 TI - Cultural competency and recovery within diverse populations. AB - Recovery for diverse populations with mental health problems includes communities of color, those with limited English proficiency and individuals who are lesbian, gay, bisexual or transgender (LGBT). The process of healing and recovery must take into consideration the critical role of culture and language and look at the individual within the context of an environment that is influenced by racism, sexism, colonization, homophobia, and poverty as well as the stigma and shame associated with having a mental illness. Recovery must assess the impact of isolation brought about by cultural and language barriers and work towards reducing the negative influence it has on the emotional and physical well-being of the person. It is imperative that recovery occur at multiple levels and involves the person in recovery, the service provider, the larger community and the system that establishes policies that often work against those who do not fit the mold of what mainstream society considers being "the norm." Recovery must respect the cultural and language backgrounds of the individual. PMID- 17694716 TI - Promoting the value and practice of shared decision-making in mental health care. AB - Active consumer participation is critical in contemporary mental health care and treatment planning and has been a staple of the field of psychiatric rehabilitation for the last three decades. Providing the opportunity for consumers to chose interventions that fit personal preferences and recovery increase the likelihood that these interventions will enhance personal meaning, satisfaction and quality of life (Improving the Quality of Health Care for Mental and Substance Use Conditions, 2006). Similarly, self-determination and shared decision-making are critical components of recovery. As stated in the President's New Freedom Commission on Mental Health Final Report, recovery from mental illnesses should be the expectation in mental health care with services and treatments that are consumer and family-driven. Mental health care should be planned and delivered to ensure that consumers and families with children with mental health problems receive real and meaningful choices about treatment options and providers. The purpose of this paper is to explore the value and use of shared decision-making in health and mental health care, briefly examine the advantages and disadvantages of shared decision making and propose next steps in advancing use of shared decision-making in mental health care. PMID- 17694717 TI - The lived experience of using psychiatric medication in the recovery process and a shared decision-making program to support it. AB - Decision making related to the use of psychiatric medication in the recovery process is complex. This paper describes some of the challenges involved in making decisions about using psychiatric medications. It also details an innovative intervention to support shared decision making in psychiatry. The program includes a peer-run decision support center and a software program to support the activation of medical staff and clients in shared decision making. PMID- 17694718 TI - Psychiatric advance directives: a tool for consumer empowerment and recovery. AB - Individuals with psychiatric disabilities identify choice and self-direction as central elements of recovery. During times of psychiatric crisis people may experience a frightening loss of choice and self-direction, which can be damaging and traumatic. Psychiatric advance directives (PADs) are legal documents created to address this loss of autonomy and choice during crises by allowing individuals to communicate in the present wishes for care during a future crisis. This paper examines the ways in which PADs support and can be a tool for recovery and discusses future recovery-oriented directions for PAD research and intervention. PMID- 17694719 TI - Consumer-operated self-help centers. AB - Consumer-operated services (COS) are viewed as a legitimate alternative for mental health consumers living in the community. This article provides an overview of, outlines a consumer-operated self-help center model that has evolved in New Jersey, and illustrates how it has become a viable component of the mental health system. The goal is to inspire psychiatric rehabilitation practitioners to create COS alternatives as part of their state-run services transformation efforts. PMID- 17694720 TI - Doctor, do you have a minute? The dilemma posed by physician interaction with the pharmaceutical industry. PMID- 17694721 TI - Is the silent epidemic keeping patients awake? PMID- 17694722 TI - Prevalence and consequences of sleep disorders in traumatic brain injury. AB - STUDY OBJECTIVES: Determine prevalence and consequences of sleepiness and sleep disorders after traumatic brain injury (TBI). METHODS: Prospective evaluation with polysomnography (PSG), multiple sleep latency test (MSLT), Epworth Sleepiness Scale (ESS) and neuropsychological testing including Psychomotor Vigilance Test (PVT), Profile of Mood States (POMS), and Functional Outcome of Sleep Questionnaire (FOSQ). SETTING: Three academic medical centers with level I trauma centers, accredited sleep disorders centers, and rehabilitative medicine programs. Participants; Eighty-seven (87) adults at least 3 months post TBI. MEASUREMENTS AND RESULTS: Abnormal sleep studies were found in 40 subjects (46%), including 20 (23%) with obstructive sleep apnea (OSA), 10 (11%) with posttraumatic hypersomnia (PTH), 5 (6%) with narcolepsy, and 6 (7%) with periodic limb movements in sleep (PLMS). Among all subjects, 22 (25%) were found to have objective excessive daytime sleepiness with MSLT score <10 minutes. There was no correlation between ESS score and MSLT (r = 0.10). There were no differences in age, race, sex, or education between the sleepy and non-sleepy subjects. Likewise, there were no differences in severity of injury or time after injury between sleepy and non-sleepy subjects. Sleepy subjects had a greater body mass index (BMI) than those who were not sleepy (p = 0.01). OSA was more common in obese subjects (BMI > or =30, p < 0.001). Sleepy subjects demonstrated poorer PVT scores (p < 0.05), better self-reported sleep related quality of life (FOSQ scores [p < 0.05]), and no differences in POMS. CONCLUSIONS: There is a high prevalence of sleep disorders (46%) and of excessive daytime sleepiness (25%) in subjects with TBI. Sleepy subjects may be more impaired than comparable non sleepy TBI subjects, yet be unaware of problems. Given the high prevalence of OSA (23%), PTH (11%), and narcolepsy (7%) in this population, there is a clinical indication for NPSG and MSLT. PMID- 17694723 TI - Sleep disorders in chronic traumatic brain injury. AB - STUDY OBJECTIVE: To examine the spectrum of sleep disorders in patients with chronic traumatic brain injury (TBI) and determine if the severity of sleep disorder is related to severity of chronic TBI. METHODS: Patients who underwent evaluation for sleep disorder/s following a TBI were included in this retrospective analysis. Sixty adult patients with TBI (age 20-69 yr; 38 M and 22 F), who presented with sleep-related complaints 3 months to 2 years following TBI, were studied. None had sleep complaints prior to the TBI. Orophrayngeal, chin, and TMJ examinations were considered benign. The severity of injury was assessed by the Global Assessment of Functioning (GAF) scale. Polysomnograms (PSGs) were performed on 54 patients (90%), 28 of whom underwent multiple sleep latency tests (MSLTs) because they scored >11 on the Epworth Sleepiness Scale (ESS). The Beck Depression Inventory (BDI) scale was administered if there was sleep maintenance insomnia, and the Hamilton Anxiety Scale (HAS) was administered if there was sleep onset insomnia. RESULTS: The TBI severity was mild in 40%, moderate in 20%, and severe in 40%. The Epworth Sleepiness Scale (ESS) score was elevated (>11) in 52%. Hypersomnia was the presenting complaint in 50%, mostly due to sleep apnea, narcolepsy, and periodic limb movement disorder (PLMD). Insomnia was the presenting complaint in 25%, half with sleep maintenance insomnia and high BDI scores, and the remainder with sleep onset insomnia and high HAS scores. Parasomnia was the presenting complaint in 25%; the most frequent parasomnia was REM behavior disorder (RBD). GAF scores were significantly correlated (p < 0.05) with some of the measures of sleep disruption (stage 1, sleep efficiency, and wake during sleep), but not with others (wake before sleep, stage-shifts, PLMI, PLMA and AHI) on the PSG. Fifty-three percent (15/28) had a mean sleep onset latency <5 minutes, and 32% (9/28), also had two or more sleep onset rapid eye movement periods (SOREMPs) on the MSLT. CONCLUSION: The results of this study demonstrate that a full spectrum of common sleep disorders occurs in patients with chronic TBI. The severity of chronic TBI as measured by GAF scores is correlated with some of the measures of sleep disruption but not others, indicating a complex and multifactorial pathogenesis. PMID- 17694725 TI - The treatment of parasomnias with hypnosis: a 5-year follow-up study. AB - STUDY OBJECTIVES: This study involves a replication and extension of a previous one reported by Hurwitz et al (1991) on the treatment of certain parasomnias with hypnosis. METHODS: Thirty-six patients (17 females), mean age 32.7 years (range 6 71). Four were children aged 6 to 16. All had chronic, "functionally autonomous" (self-sustaining) parasomnias. All underwent 1 or 2 hypnotherapy sessions and were then followed by questionnaire for 5 years. RESULTS: Of the 36 patients, 45.4% were symptom-free or at least much improved at the 1-month follow-up, 42.2% at the 18-month follow-up, and 40.5% at the 5-year follow-up. CONCLUSIONS: One or 2 sessions of hypnotherapy might be an efficient first-line therapy for patients with certain types of parasomnias. PMID- 17694724 TI - Hypersomnia following traumatic brain injury. AB - STUDY OBJECTIVES: To evaluate the prevalence and natural history of sleepiness following traumatic brain injury. METHODS: This prospective cohort study used the Sickness Impact Profile to evaluate sleepiness in 514 consecutive subjects with traumatic brain injury (TBI), 132 non-cranial trauma controls, and 102 trauma free controls 1 month and 1 year after injury. RESULTS: Fifty-five percent of TBI subjects, 41% of non-cranial trauma controls, and 3% of trauma-free controls endorsed 1 or more sleepiness items 1 month following injury (p < .001). One year following injury, 27% of TBI subjects, 23% of non-cranial trauma controls, and 1% of trauma-free controls endorsed 1 or more sleepiness items (p < .001). Patients with TBI were sleepier than non-cranial trauma controls at 1 month (p < .02) but not 1 year after injury. Brain-injured subjects were divided into injury-severity groups based on time to follow commands (TFC). At 1 month, the non-cranial trauma controls were less sleepy than the 1- to 6-day (p < .05), 7- to 13-day (p < .01), and 14-day or longer (p < .01) TFC groups. In addition, the < or = 24-hour group was less sleepy then the 7- to 13-day and 14-day or longer groups (each p < .05). At 1 year, the non-cranial trauma control group (p < .05) and the < or = 24-hour TFC group (p < .01) were less sleepy than the 14-day or longer TFC group. Sleepiness improved in 84% to 100% of subjects in the TBI TFC groups, as compared with 78% of the non-cranial trauma control group (p < .01). CONCLUSIONS: Sleepiness is common following traumatic injury, particularly TBI, with more severe injuries resulting in greater sleepiness. Sleepiness improves in many patients, particularly those with TBI. However, about a quarter of TBI subjects and non-cranial trauma control subjects remained sleepy 1 year after injury. PMID- 17694726 TI - Efficacy and tolerability of indiplon in transient insomnia. AB - OBJECTIVE: The efficacy of indiplon was evaluated by polysomnography (PSG) in an experimental model of transient insomnia consisting of the first night effect combined with a 2-hour phase advance. METHODS: Healthy volunteers age 21-64 years (N=593; 62% female; mean +/- SEM) years, 32 +/- 0.39) were randomized to double blind treatment with a single nighttime dose of indiplon (10 mg or 20 mg) or placebo. PSG assessments included latency to persistent sleep (LPS, primary endpoint) and total sleep time (TST); self-report assessments included sleep quality (SQ); next day residual effects were evaluated by the Digit Symbol Substitution Test (DSST), Symbol Copying Test (SCT), and a Visual Analog Scale of sleepiness (VAS). RESULTS: LPS mean (+/- SEM) values were significantly reduced on indiplon 10 mg (21.2 +/- 1.5 minutes) and indiplon 20 mg (16.8 +/- 1.1 minutes) compared to placebo (33.1 +/- 2.5 minutes; p < 0.0001 for both comparisons to placebo). TST mean (+/- SEM) values were significantly increased on indiplon 10 mg (414.5 +/- 3.9 minutes) and indiplon 20 mg (423.5 +/- 3.1 minutes) compared to placebo (402.9 +/- 3.9 minutes; p <0.005 for the 10 mg dose; p < 0.0001 for the 20 mg dose). SQ was also significantly improved on both doses. There were no differences between indiplon and placebo on next day DSST, SCT, or VAS. CONCLUSIONS: Indiplon was effective in inducing sleep, increasing sleep duration, and improving overall sleep quality without next day residual effects in healthy volunteers in a model of transient insomnia. PMID- 17694727 TI - Neuropsychological effects of 2-week continuous positive airway pressure treatment and supplemental oxygen in patients with obstructive sleep apnea: a randomized placebo-controlled study. AB - STUDY OBJECTIVES: To determine predictors of neuropsychological functioning in patients with obstructive sleep apnea (OSA) and whether treatment with 2-week continuous positive airway pressure (CPAP) or supplemental oxygen would improve cognitive functioning. DESIGN: Randomized placebo-controlled design. SETTING: University-based clinical research center. PATIENTS: Forty-six patients with untreated OSA. INTERVENTIONS: Two-week CPAP, supplemental oxygen, or placebo CPAP. MEASUREMENTS AND RESULTS: Participants underwent polysomnography and completed a neuropsychological test battery before and after treatment. Prior to treatment, patients with OSA showed diffuse impairments, particularly in terms of speed of information processing, attention and working memory, executive functioning, learning and memory, as well as alertness and sustained attention. A global deficit score at baseline was positively correlated with percentage of stage 1 sleep (p = .049) only and was not correlated with obesity, daytime sleepiness, depression, fatigue, OSA severity, and the other polysomnography variables. The 3 treatment groups (therapeutic-CPAP, supplemental oxygen, and placebo-CPAP) were compared using repeated-measures analysis of variance (ANOVA). There was no significant Time x Treatment interaction for the global deficit score. When examining individual neuropsychological test scores, two thirds of them improved with time regardless of treatment, although only Digit Vigilance Time (p = .020) showed significant improvement specific to CPAP treatment. CONCLUSION: The present results suggest that Digit Vigilance-Time might be the most sensitive neuropsychological test for measuring the effects of the treatments. In general, 2 weeks of CPAP or oxygen-supplementation treatment was insufficient to show overall beneficial cognitive effects, as compared with placebo-CPAP. However, 2 weeks of CPAP treatment might be helpful in terms of speed of information processing, vigilance, or sustained attention and alertness. PMID- 17694728 TI - Validation of the ApneaLink for the screening of sleep apnea: a novel and simple single-channel recording device. AB - STUDY OBJECTIVES: Screening for sleep apnea may be useful in a number of settings, such as preoperative testing, clinical research, and evaluation for referral to a sleep center. The purpose of the study was to validate the ApneaLink device (ResMed Corporation, Poway, Calif) for use as a screening tool for sleep apnea in clinical practice. METHODS: The ApneaLink device is a single channel screening tool for sleep apnea that measures airflow through a nasal cannula connected to a pressure transducer, providing an apnea-hypopnea index (AHI) based on recording time. We compared the AHI from the ApneaLink device to that obtained during simultaneously conducted attended sleep-laboratory polysomnography to assess the sensitivity and specificity of the device in consecutive subjects with type 2 diabetes mellitus referred from a diabetes clinic. We also compared the AHI obtained from the ApneaLink device during a study in the subjects' homes to that obtained during the in-laboratory study. The laboratory study was performed within 2 weeks of the home study. RESULTS: Fifty nine subjects completed the study. Mean age of subjects was 57 years; mean body mass index was 33 kg/m2. The results demonstrate a high sensitivity and specificity of the at-home ApneaLink AHI compared with the AHI from the simultaneous polysomnographic study at all AHI levels, with the best results at an AHI of > or =15 events per hour (sensitivity 91%, specificity 95%). The AHI comparison from the home and laboratory studies also demonstrates good sensitivity and specificity at AHI levels of > or =15 and > or =20 events per hour (sensitivity 76%, specificity 94%, for both). CONCLUSIONS: Given the prevalence of sleep apnea in the adult population and in specific comorbid conditions, a screening tool may be useful in many diagnostic settings. This study demonstrates that the ApneaLink device provides reliable information, is a simple, easy-to-use device, and is highly sensitive and specific in calculating AHI, when compared with the AHI obtained from full polysomnography. PMID- 17694729 TI - Prior authorization of newer insomnia medications in managed care: is it cost saving? AB - STUDY OBJECTIVES: New pharmacotherapeutic treatment options are available to treat patients with 1 or more insomnia symptoms. However, these new pharmaceuticals are subject to a variety of managed-care tools, such as prior authorizations, that may restrict access to these medications. The objective of this study was to evaluate the economic consequences to a health plan that requires prior authorization for nonbenzodiazepine medications approved for the treatment of insomnia characterized by difficulties both falling and staying asleep. METHODS: An economic model was constructed to determine the effects of a typical prior-authorization program across a hypothetical managed-care population. Model parameters were derived from national estimates and a literature review. RESULTS: Economic consequences of a prior-authorization program were based on a hypothetical managed-care plan with 500,000 insured patients. An estimated acquisition cost of $300 per 100 tablets of medication requiring prior authorization, $40 to process each priorauthorization request, and prior-authorization rejection rates of 2% to 5% were considered. Using the default-model inputs of the hypothetical plan characteristics and costs, the economic model estimated a loss of $600,000 to $700,000 per year to the health plan. In a 3-way threshold sensitivity analysis when prior-authorization rejection rate was increased to 5%, the cost of each request in the prior authorization program was decreased to $20, and the cost of a first-generation nonbenzodiazepine was decreased to a generic price (i.e. $100 per prescription), the model continued to show a net loss to managed care in each case. CONCLUSIONS: This model showed that requiring prior authorization for newer sleep treatments might not be a cost-saving strategy for managed-care organizations. PMID- 17694730 TI - Coexistence of epileptic nocturnal wanderings and an arachnoid cyst. AB - Episodic nocturnal wanderings (ENWs) have rarely been associated with gross abnormalities of brain structures. We describe the case of a patient with ENWs in coexistence with an arachnoid cyst (AC). The patient was a 15-year-old boy who presented with nocturnal attacks characterized by complex motor behaviors. An MRI revealed a left temporal cyst and a SPECT Tc99 scan showed left temporal hypoperfusion and bilateral frontal hyperperfusion, more evident on the right side. During an all-night polysomnographic recording with audiovisual monitoring, dystonic posture followed by sleepwalking-like behavior was documented. The sleepwalking-like behavior was preceded by a spike discharge over the left frontocentral region with contralateral projection and secondary generalization during stage 2 sleep. Treatment with levetiracetam produced a striking remission of seizures. This supports a conservative management of an AC, considering that it may be an incidental finding. In epileptic patients, an AC may not necessarily be related to the location of the seizure focus. PMID- 17694732 TI - Assessment and policy for commercial driver license referrals. AB - This report describes experiences, subsequent action, and policy recommendations regarding sleep disorders assessment of veterans in relation to a commercial driver medical examiner referral. A series of 6 veterans were seen in our sleep clinic, presenting with an order from a commercial driver medical examiner (CDME) for polysomnography and/or Multiple Sleep Latency Testing (PSG/MSLT). We searched the literature for an evidence-based justification for handling this referral, and we concluded that there is neither federal policy nor current evidence to suggest that any current diagnostic test, including PSG/MSLT and/or MWT, is capable of predicting which individual drivers are at risk for fall-asleep crashes. The best indicator of risk is self-reported sleepiness, regardless of cause. Thus, we concluded that an administrative request for a "PSGIMSLT" is not a rational use of VA resources. Procedures and a policy for the Cleveland VA system were developed to respond to the request for evaluation, recognizing that sleep problems and disorders other than sleep apnea may be present in this population. An educational component was an important feature of this response. We suspect that this approach may be appropriate for managed care systems in general. PMID- 17694733 TI - A full term infant with cyanotic episodes. Congenital central hypoventilation syndrome. PMID- 17694731 TI - Endothelial dysfunction in obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is a common disorder and is associated with adverse cardiovascular consequences, including hypertension and coronary artery disease. While the mechanisms responsible for increased risk of cardiovascular events in OSA have not yet been fully elucidated, hypoxia, inflammation, obesity, metabolic dysregulation, and sympathetic activation, may contribute to these consequences. Endothelial dysfunction may be another link between OSA and cardiovascular disease. Dysfunctional endothelium is characterized by an imbalance in production of vasoactive hormones, increased adherence of inflammatory mediators to endothelial cells and hypercoagulability, and is a known risk factor for cardiovascular events. Studies have directly measured vascular endothelial function in patients with OSA and found a muted response compared to controls. Other studies have evaluated biochemical markers of endothelial function including circulating levels of vasoactive and thrombosis mediators and provide further proof of endothelial dysfunction in this disorder. A better appreciation of the role of the dysfunctional endothelium in OSA will help shed light on the pathogenesis of cardiovascular disease in this disorder and may lead to development of novel therapies aimed at preventing untoward outcomes. PMID- 17694734 TI - The man who fought in sleep. Rapid eye movement (REM) sleep behavior disorder (RBD). PMID- 17694735 TI - Physician light therapy. PMID- 17694736 TI - Light intensity evaluation of laser-induced fluorescence after caries removal using an experimental caries staining agent. AB - OBJECTIVE: The purpose of this study was to evaluate the intensity of fluorescent light reflected from cavity wall dentin, after dentin stained by an experimental caries detecting liquid was removed. BACKGROUND DATA: The conventional caries detecting liquid tends to penetrate dentin too deeply. On the other hand, DIAGNOdent has gradually gained recognition and established itself as a caries detection device using a laser beam. METHOD: An experimental caries staining liquid or the conventional caries staining liquid was applied in the same cavity to observe for differences in dye penetration. Intensity of fluorescence reflected from treated dentin was measured by DIAGNOdent. RESULTS: The mean DIAGNOdent value after removing the tooth substance stained by the experimental liquid was 17.9+/-4.1, compared with 7.7+/-2.7 by conventional one. CONCLUSION: Light intensity evaluation of laser-induced fluorescence suggested that the experimental caries detecting liquid did not penetrate the dentin which should be preserved, hence avoiding overtreatment. PMID- 17694737 TI - Guinea Pig Maximization Test of tri-ethylene glycol mono-methacrylate. AB - The aim of this study was to evaluate tri-ethylene glycol mono-methacrylate (TEGMA) in terms of dermatological allergic reaction using a Guinea Pig Maximization Test. Skin reaction was evaluated according to the criteria of International Contact Dermatitis Research Group. TEGMA, as a constituent in new primers, has been reported to contribute to a priming ability similar to that of highly purified glyceryl mono-methacrylate (GM). In this study, it was found that its adverse effect was less than that of 2-hydroxy ethyl methacrylate (2-HEMA), but similar to that of highly purified GM. In conclusion, it was anticipated that TEGMA would hereafter replace 2-HEMA as a primer, as it posed a lower risk of triggering dermatological allergic reaction. PMID- 17694738 TI - Effects of thermal cycling on surface texture of restorative composite materials. AB - The purpose of this study was to evaluate the effect of thermal cycling on the surface texture of restorative materials. Disk-shaped specimens made of seven resin composites (Beautifil: BF; Esthet-X: EX; Filtek Supreme: FS; Inten-S: IS; Point 4: PT; Solare: SR; and Venus: VS) were finished with 1-microm alumina suspension, and then thermocycled between 4 and 60 degrees C in distilled water for 20,000 or 50,000 cycles with a dwell time of 60 seconds. Staining susceptibility and mean surface roughness, Ra, were examined, and surface texture was observed by scanning electron microscopy. Dye penetration test showed that the surfaces of all resin composites were more stained after thermal cycling. Mean Ra of all resin composites, except PT, significantly increased after 50,000 thermal cycles. Dislodgement of filler particles was observed for all resin composites after thermal cycling, except FS. It was concluded that thermal cycling significantly affected the surface texture of the seven examined resin composites. PMID- 17694739 TI - Tensile bond strength between custom tray and elastomeric impression material. AB - The aim of this study was to investigate how to achieve sufficient and stable adhesive strength between impression material and tray. Impression materials were molded between autopolymerizing resin columns, and tensile strength was measured as a function of these factors: tray storage time (1, 2, 4, 7, and 10 days), adhesive drying time (0, 1, 5, 10, and 15 minutes), and tray surface roughness (air abrasion, bur-produced roughness, and no treatment). Tensile bond strength was not affected by tray storage time throughout the entire evaluation period of 10 days. As for tray adhesive drying time, Reprosil and Exaimplant yielded extremely low values for drying times of 10 minutes or less (P<0.05), while Imprint II and Impregum were not influenced by drying time. Vinyl polysiloxane achieved the highest adhesive strength with bur-produced roughness, which was significantly higher than with air abrasion or no treatment (P<0.05), whereas polyether achieved the lowest value with bur-produced roughness (P<0.05). It was concluded that surface treatment of custom tray should be adapted to the type of impression material used to achieve optimum bond strength. PMID- 17694740 TI - Structure-property relation of a soft liner material used in denture applications. AB - With a view to understanding the structure-property relation of a silicone-based soft lining denture material after polymerization, its chemical composition and viscoelastic properties were investigated. Chemical compositions of the cured and uncured polymers of a commercial silicone permanent soft liner were determined by infrared spectroscopic analysis, nuclear magnetic resonance (NMR), and X-ray photoelectron spectroscopy. Dynamic mechanical analysis (DMA) method was used to investigate the viscoelastic behavior of the cured polymer of liner. Spectroscopic analysis showed that the main component of soft liner was vinyl terminated poly(dimethylsiloxane), and the adhesive was 3 methacryloxypropyltrimethoxy silane. NMR results revealed that other components included benzoyl peroxide as initiator for polymerization and also silicilic acid. Surface analysis by XPS provided interesting insights about the nature of adhesive bonding, as well as diffusion of silicilic acid through the matrix of the processed material and leaching-out. DMA results showed a two-phase character, and that the cured polymer was highly elastic. PMID- 17694741 TI - Compressive strength, surface roughness, fluoride release and recharge of four new fluoride-releasing fissure sealants. AB - The aim of this study was to investigate the compressive strength and surface roughness of two glass ionomer cements and two resin-based fissure sealants before and after fluoride release and recharge. Twenty-one specimens were prepared and divided into three groups for each material. First group was loaded in compression until failure. Fluoride released was measured from the remaining specimens, and then the second group of seven specimens was loaded at 28th day. The remaining seven specimens were exposed to 0.05% NaF solution and 1.23% APF gel. Fluoride amount was measured, and the last group was loaded at 70th day. Surface roughness measurement of five more disk-shaped specimens from each material was also carried out. After exposure to APF gel, all materials were recharged. At the end of experimental period, it was found that surface roughness increased, whereas compressive strength decreased, over time. In conclusion, fluoride-releasing fissure sealants could act as show, rechargeable fluoride release systems. However, if a fissure sealant exhibited high fluoride release, it had inferior mechanical properties. PMID- 17694742 TI - Comparison of the effects of added alpha- and beta- tricalcium phosphate on the basic properties of apatite cement. AB - Effects of added alpha-tricalcium phosphate (alpha-TCP) and beta-TCP were investigated to shed light on the setting reaction of apatite cement (AC) consisting of tetracalcium phosphate (TTCP) and dicalcium phosphate anhydrous8 (DCPA). Added beta-TCP showed no reactivity, and thus resulted in extended setting time and decreased mechanical strength. In contrast, alpha-TCP dissolved to supply calcium and phosphate ions after initial apatite crystal formation by the reaction of TTCP and DCPA. Although setting time was delayed because alpha TCP was involved only in the latter reaction of apatite cement, larger apatite crystals were formed due to its addition. As a result of larger apatite crystal formation, the mechanical strength of alpha-TCP-added apatite cement increased by approximately 30%, as compared to alpha-TCP-free apatite cement. PMID- 17694743 TI - Tensile strength and durability of bovine dentin. AB - This study investigated the effects of thermal cycling on the tensile strength of dentin. Bovine dentin were divided into 10 groups, which were then subjected to various conditions: intact after preparation, thereby serving as a control; heating in boiling water for 45 minutes; 10,000 thermal cycles in water; 10,000 thermal cycles in PBS; storage in water at 5, 23, or 55 degrees C for two weeks; and storage in PBS at 5, 23, or 55 degrees C for two weeks. Subsequently, bovine dentin were trimmed into dumbbell-shaped specimens and the tensile test performed in distilled water at 37 degrees C. Mean tensile strengths were compared statistically by one-way ANOVA and Fisher's PLTD test (p<0.05). Fracture surfaces were observed by scanning electron microscopy, and reliability of the results was analyzed with Weibull distribution. Tensile strength did not significantly change after thermal cycling or storage in water and PBS at all temperatures tested (71.2-77.0 MPa) but decreased after treatment with boiling water (65.5 MPa). PMID- 17694744 TI - Micro-shear bond strength of two all-in-one adhesive systems to unground fluorosed enamel. AB - The aim of this study was to evaluate the micro-shear bond strengths of two all in-one adhesive systems to unground fluorosed enamel. Buccal surfaces of 24 normal and 24 moderately fluorosed teeth (Thylstrup and Fejerskov index, TFI=4-6) were bonded using G-Bond and Clearfil Tri-S Bond. The surfaces were then restored with a resin composite, stored for 24 hours in water, and tested for micro-shear bond strength (MSBS). Fracture modes, etching patterns, and adhesive interfaces were studied under a scanning electron microscope (SEM). Data were analyzed with two-way ANOVA, whereby no significant differences in MSBS were found among the four groups (p>0.05). Through SEM examination, it was shown that 1 microm of resin tag-like extensions had penetrated into the enamel for both adhesives at the enamel-adhesive interface. Based on the results obtained, it was concluded that MSBS was not influenced by the severity of fluorosis. Furthermore, there were no differences in enamel bond strength between G-Bond and Clearfil Tri-S Bond. PMID- 17694745 TI - Adhesion of Streptococcus sanguinis to dental implant and restorative materials in vitro. AB - Bacterial adhesion to tooth surfaces or dental materials starts immediately upon exposure to the oral environment. The aim of this study, therefore, was to compare the adhesion of Streptococcus sanguinis to saliva-coated human enamel and dental materials - during a one-hour period - using an in vitro flow chamber system which mimicked the oral cavity. After fluorescent staining, the number of adhered cells and their vitality were recorded. The dental materials used were: titanium (Rematitan M), gold (Neocast 3), ceramic (Vita Omega 900), and composite (Tetric Ceram). The number of adherent bacterial cells was higher on titanium, gold, and ceramic surfaces and lower on composite as compared to enamel. As for the percentage of adherent vital cells, it was higher on enamel than on the restorative materials tested. These results suggested that variations in the number and vitality of the adherent pioneer oral bacteria, S. sanguinis, in the in vitro system depended on the surface characteristics of the substratum and the acquired salivary pellicle. The in vitro adhesion model used herein provided a simple and reproducible approach to investigate the impact of surface-modified dental materials on bacterial adhesion and vitality. PMID- 17694746 TI - Fracture resistance of Nd:YAG laser-welded cast titanium joints with various clinical thicknesses and welding pulse energies. AB - The purpose of this study was to evaluate the fracture resistance of Nd:YAG laser welded cast titanium (Ti) joints with various clinical thicknesses and welding pulse energies. A four-point bending test was used to assess the effects of various specimen thicknesses (1-3 mm) and welding pulse energies (11-24 J) on the fracture resistance of Nd:YAG laser-welded Ti dental joints. Fracture resistance was evaluated in terms of the ratio of the number of fractured specimens to the number of tested specimens. As for the fracture frequencies, they were compared using the Cochran-Mantel-Haenszel test. Morphology of the fractured Ti joints was observed using a scanning electron microscope. Results showed that decreasing the specimen thickness and/or increasing the welding pulse energy, i.e., increasing the welded area percentage, resulted in an increase in the fracture resistance of the Ti joint. Where fracture occurred, the fracture site would be at the center of the weld metal. PMID- 17694747 TI - New index for the stability of a type I collagen affected by hydrophobic environment. AB - Effects of hydrophobic environment adjusted by various alcohols on the structural stability of calfskin collagen (CSC) were studied to elucidate the nature of collagen-monomer interaction in adhesion. The stability of CSC in aqueous alcohol solutions was represented by its denaturation temperature, Td, measured by DSC. The hydrophobicity of the alcohol solutions was quantified with their specific dielectric constants, epsilon(r), calculated from their concentrations. The effect of each alcohol to stabilize or destabilize CSC was evaluated by the initial slope of each Td vs. epsilon(r) plot, denoted as -(dTd/d epsilon(r))ini and termed as stabilization power. Results showed that a hydrophobic environment with a smaller epsilon(r) lowered the stabilization power. Stabilization power ranged from -3 (strong destabilization) for phenol (epsilon(r) =12) to +0.3 (weak stabilization) for glycerol (epsilon(r)=47). In view of the encouraging results obtained in this study, the new index was therefore helpful in predicting the effects of new dental materials of known epsilon(r) values on the stability of dentinal collagen. PMID- 17694748 TI - NMR study on the adhesion efficacy of experimental phosphonic acid monomers. AB - Three experimental self-etching primers - consisting of N-methacryloyl-omega aminoalkyl phosphonic acid (NMomegaP) with different methylene chain lengths and N-methacryloyl glycine (NMGly) - were formulated. The influence of methylene chain length in NMomegaP derivatives on the chemical nature of calcium salts was examined following their application to tooth components. Bond strengths of experimental self-etching primers created with these monomers to enamel and dentin were also investigated. Nuclear magnetic resonance spectroscopy showed that NMomegaPs decalcified tooth components with formation of calcium salts, which changed from calcium hydrogen phosphonate to calcium phosphonate with increase in methylene chain length within the NMomegaP structure. Disparity in calcium salt formation was related to increases in bond strength to enamel from 18 to 24 MPa. However, bond strength to dentin remained unchanged (22 MPa). The relative dependency of bond strength on monomer methylene chain length was probably attributable to the sites where these NMomegaP calcium salts had deposited on the bonding substrates. PMID- 17694749 TI - The effect of antibacterial monomer MDPB on the growth of organisms associated with root caries. AB - MDPB, 12-methacryloyloxydodecylpyridinium bromide, was tested for its ability to inhibit the growth of organisms associated with active root caries lesions and to modify the growth characteristics of these organisms at sub-MICs. MICs and MBCs of MDPB for independent isolates (n=5) of the following taxa: Streptococcus mutans, Streptococcus oralis, Streptococcus salivarius, Actinomyces naeslundii, Actinomyces israelii, Actinomyces gerensceriae, Actinomyces odontolyticus, Lactobacillus spp., and Candida albicans were determined, and the effects at sub MIC on microbial growth kinetics were assessed. All isolates were sensitive to inhibition by MDPB. The median MICs and MBCs of MDPB for these organisms were in the range of 3.13 to 25.0 microg/ml and 6.25 to 50.0 microg/ml, respectively. As for the influence of pH, inhibition was sensitive to acidic pH. Even at sub-MICs, the growth of all strains, measured as cell yield and doubling time, was significantly reduced. Based on the results of this study, MDPB exhibited the potential to inhibit the growth of microbiota associated with active root caries lesions. PMID- 17694750 TI - Relation between attractive force and keeper surface characteristics of iron neodymium-boron magnetic attachment systems. AB - The purpose of this study was to evaluate the influence of heating, cast bonding, and subsequent polishing procedures on attractive force of magnetic attachments. Two magnetic attachment systems with keepers of different chemical compositions (Hicorexslim 3013, 447J1; Magfit EX400, AUM20) were employed. Keepers examined were: (1) untreated; (2) heated; (3) cast-bonded with Ag-Pd alloy; (4) cast bonded with Ag-Pd alloy and polished; (5) cast-bonded with gold alloy; and (6) cast-bonded with gold alloy and polished. Attractive force was determined with a force gauge, and surface structure was evaluated with scanning laser and electron microscopes. Attractive force of the Hicorex system was reduced by cast bonding, whereas that of the Magfit system was reduced by both heating and cast bonding. However, attractive force of both systems was somewhat recovered through the polishing process. Based on the findings of this study, it was suggested that careful polishing after cast bonding was indispensable to the recovery of attractive force for both attachment systems. PMID- 17694751 TI - Influence of adhesive systems on bond strength between fiber posts and composite resin cores in a pull-out test design. AB - The aim of this study was to evaluate the effects of post surface conditioning with adhesive systems on tensile bond strength between two composite resin core systems and FRP posts (ER DentinPost). Forty-eight posts were trimmed at the coronal part, and the upper part of 3 mm was covered with a standardized composite resin core build-up. Twenty-four posts were treated with the respective adhesive systems. Four groups were formed: G1 - ClearfilCore; G2 - Clearfil New Bond + ClearfilCore; G3 - MultiCore Flow; and G4 - AdheSE + MultiCore Flow. Mean (SD) bond strengths in MPa were 7.53 (0.89) for ClearfilCore and 8.08 (0.93) for New Bond + ClearfilCore; 5.80 (0.39) for MultiCore Flow and 5.92 (0.43) for AdheSE + MultiCore Flow. ClearfilCore achieved significantly higher bond strengths than MultiCore Flow (two-way ANOVA; p<0.0001). In conclusion, composite resin core materials exerted a significant influence on tensile bond strength, while adhesive systems did not significantly affect the results. PMID- 17694752 TI - The effect of bleaching on the elastic modulus of bovine enamel. AB - The purpose of this study was to determine the elastic modulus of enamel during bleaching procedure with the use of an ultrasonic device. Enamel sections were obtained from freshly extracted bovine incisors. Specimens were exposed to 10% carbamide peroxide for two hours, followed by an application of a fluoride containing toothpaste for five minutes and stored in artificial saliva (pH 7.0). An ultrasonic device was used to measure the sound velocities of longitudinal and shear waves as well as elastic modulus. The mean elastic modulus of bleached enamel decreased with time, from 15.5 GPa to 10.1 GPa. Conversely, the elastic modulus of bleached enamel followed by application of a fluoride-containing toothpaste increased with time, from 15.2 GPa to 20.2 GPa. Results of this study indicated that a decrease in elastic modulus associated with bleaching occurred, and that fluoride-containing toothpaste reversed this effect. PMID- 17694753 TI - Development of new software as a convenient analysis method for dental microradiography. AB - To the end of developing a convenient research tool to calculate the mineralization status of teeth in detail, a new program was developed using Visual Basic for Applications combined with Microsoft Excel 2004. To demonstrate the usefulness of this program, it was used to analyze tooth enamel mineralization after acid exposure. Transverse microradiography images (TMR) of specimens were digitalized with a charge-coupled device camera with a microscope (CCD camera) and a digital film scanner (FS). Subsequently, the mineral content profile of each specimen after de- and remineralization studies were calculated using the Angmar's formula. The newly developed program was applied to calculating the mineral loss (DeltaZ), lesion depth (Ld), surface zone depth (SZd), and lesion body depth (LBd) of tooth specimens. In addition, the outer surface zone (OSZ), inner lesion body (ILB), and sandwich area (SA) between OSZ and ILB- which together constituted DeltaZ - were calculated by the newly developed program. Data obtained with the newly developed program were in good agreement for both CCD camera and FS, indicating that the program was reliable for tooth enamel mineralization research studies. PMID- 17694754 TI - Analysis of Er:YAG lased dentin using attenuated total reflectance Fourier transform infrared and X-ray diffraction techniques. AB - The purpose of this study was to investigate the chemical characteristics of dentin after Er:YAG laser irradiation using various output energies with or without water irrigation. Analysis was carried out by means of attenuated total reflectance Fourier transform infrared spectroscopy (FT-IR/ATR) and X-ray diffraction (XRD). Furthermore, the relative infrared peak intensities of dentin specimens were compared statistically. Results showed that Er:YAG laser with an output energy of 100 mJ/pulse with water irrigation did not cause any detectable change in dentin. However, a higher energy output or the absence of water irrigation affected the organic portion of dentin. With XRD, no obvious phase changes were observed between the XRD pattern of the control (non-irradiated) dentin powder and those after Er:YAG irradiation - regardless of Er:YAG laser output energy or dehydration condition. It was suggested that the intrinsic water content of dentin - together with extrinsic water irrigation - were important factors to achieving the desired outcome of dentin ablation by Er:YAG laser. PMID- 17694755 TI - Antifungal effect of acrylic resin containing apatite-coated TiO2 photocatalyst. AB - The purpose of this study was to develop an acrylic resin with antifungal properties by leveraging the photocatalytic activity of apatite-coated titanium dioxide (Ap-TiO2). Candida albicans was used for antifungal activity assay of the specimen plates under ultraviolet A (UVA) with a black light source. Statistically significant decreases in cell viability in acrylic resins containing 5 wt% and 10 wt% Ap-TiO2 were observed after irradiation for two, four, and six hours (P<0.01), when compared to the control. As for the flexural strength and modulus values of acrylic resins mixed with Ap-TiO2 and TiO2 particles, they varied before and after irradiation. Among the tested specimens, a 5 wt% content of Ap-TiO2 in acrylic resin exceeded the requirements of ISO 1567. It was thus suggested that acrylic resin containing 5 wt% Ap-TiO2 could exert antifungal effects on C. albicans, while at the same time maintain adequate mechanical properties for clinical use. PMID- 17694756 TI - The effect of thermal stress on bonding durability of resin composite adaptation to the cavity wall. AB - This study evaluated the effect of thermal stress on marginal sealing and cavity wall adaptation using two adhesive systems. Cylindrical cavities were prepared in superficial dentin of bovine incisors and bonded with Clearfil SE Bond or Single Bond adhesive. Cavities were bulk-filled with Photo Clearfil Bright or Filtek Flow resin composite and light-cured for 40 seconds. Specimens were thermocycled for 0, 500, or 5000 times. A dye penetration test was carried out to determine adaptation to the cavity wall. Dye penetration length was calculated as a percentage of the total cavity wall length. Clearfil SE Bond showed excellent marginal sealing and cavity wall adaptation regardless of composite type up to 500 cycles of thermal stress. As for the Single Bond groups, significantly greater marginal leakage occurred after 500 cycles. At 5000 cycles of thermal stress, both adhesive systems showed significantly decreased marginal integrity compared with the 0 cycle group. PMID- 17694757 TI - Controlled release of simvastatin acid using cyclodextrin inclusion system. AB - Simvastatin acid (SVA) has been reported to stimulate bone formation by increasing expression of BMP-2 in osteoblasts. Due to their multi-functional characteristics and bioadaptability, cyclodextrins (CDs) are capable of forming inclusion complexes with many drugs by including a whole drug molecule inside their cavity. In the present study, we prepared SVA/CD inclusion complex solutions with different pH values. These were then used to determine their SVA release behavior after coating on titanium substrates, as well as to clarify the characteristics of SVA/CD complexes per se. Results showed that the lower the pH value of the solution, the lower the release kinetics of SVA. Besides, the amount of crystalline complexes in the coatings increased with decrease in pH. These results suggested that the release rate of SVA depended on two factors: pH of the solution and concomitant crystallinity of the coating. PMID- 17694758 TI - Effects of disinfection of combined agar/alginate impressions on the dimensional accuracy of stone casts. AB - This study investigated the effects of disinfection of combined agar/alginate impressions on the dimensional accuracy of resultant stone casts. Impressions of a master cast designed to simulate an abutment tooth were prepared by combining each of two brands of cartridge-form agar impression materials with an alginate impression material. The impressions were immersed in 1% sodium hypochlorite for 10 minutes or 2% glutaraldehyde for 30 minutes. The remaining impressions were sprayed with these two disinfectants and then stored in sealed bags for 10, 30, 60, and 120 minutes. Stone casts obtained from the non-disinfected impressions were also prepared as control. Changes in diameter of the stone casts were then measured. Results indicated that storage for 10 minutes after spraying with 1% sodium hypochlorite was an appropriate disinfection method for combined agar/alginate impressions, as well as immersion in 1% sodium hypochlorite for 10 minutes. PMID- 17694759 TI - A review of soft tissue sarcoma. AB - BACKGROUND: Soft tissue sarcomas (STS) are a heterogeneous group of rare tumours that arise predominantly from the embryonic mesoderm. They present most commonly as an asymptomatic mass originating in an extremity but can occur anywhere in the body, particularly the trunk, retroperitoneum, or the head and neck. They account for about 0.7% of all adult malignancies. METHOD: A review of the literature of STS was undertaken with emphasis on current approach in management. RESULT: Despite recent advances in the knowledge of the molecular biology of STS, there is yet no identifiable aetiology in most cases. Tru-cut biopsy is a safe, accurate and economical procedure for diagnosing STS. Enough tissue is usually obtained for use in several diagnostic tests such as electron microscopy and cytogenetic analysis. With the advent of Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and Magnetic Resonance Angiography (MRA), tumours can easily be delineated from muscle groups, bone and neurovascular structures. Surgery remains the main potentially curative therapy for STS. In the last two decades, the role of adjuvant radiotherapy has revolutionized the treatment from a situation where amputation was the standard treatment for extremity STS to the present time where limb sparing surgery is appropriate in more than 90% of patients. Postoperative adjuvant chemotherapy significantly improves the overall and disease free survival for patients with large size and high grade sarcomas. CONCLUSION: Optimal results of treatment require multidisciplinary interaction between the referring practitioner, the treating surgeon, the pathologist, the radiotherapist and the chemotherapist. PMID- 17694760 TI - Pharmacotherapy for chronic heart failure. AB - BACKGROUND: Heart failure is a chronic and progressive disorder which results due to inability of the heart to pump adequate blood to meet up the metabolic demands of the body. Detecting patients with heart failure could be simple but rather complex of clinical decisions as presentation could be classical or non-specific with minimal symptoms and orsigns. Management is aimed at relieving symptoms, improving quality of life, preventing hospitalisation and arresting disease progression thus prolonging survival. In addition to pharmacologic measures, non pharmacologic ones are also employed. METHOD: Relevant literature was reviewed using medical journals and also via internet. The key words employed were: Heart failure, Chronic heart failure, Diuretics, Vasodilators, Angiotensin receptor blockers (ARBS) and Angiotensin converting enzyme inhibitors (ACEI). The National Heart, Lung and Blood Institute, Canadian Cardiovascular Society, American College of Cardiology websites were also used in the course of this review. RESULTS: This review was able to support the use of betablockers, ACEI, ARBS, digitalis, diuretics, vasodilators and aldosterone antagonists in the management of chronic heart failure. CONCLUSION: The objectives of drug therapy in heart failure includes the short-term goals of stabilising the patient, improving haemodynamic function and conferring symptomatic improvement, as well as the long term goal of limiting disease progression, decreasing hospital re-admission rates and improving survival. The cause needs to be established and aggravating factors identified (and where possible treated). Most of the drugs, if not all, are used in combination with one another to achieve maximal therapeutic goal. Use of some drugs could be entertained as an add-on therapy depending on any co-existing medical condition. PMID- 17694761 TI - Management of postoperative morbidity after third molar surgery: a review of the literature. AB - BACKGROUND: Patients' complaints of pain, swelling and limitation in mouth opening following lower third molar surgery is an important factor affecting their daily life. The aim of this study was to review the different methods of minimizing postoperative morbidity following lower third molarsurgery. METHODS: Relevant literatures from Scirus, Pubmed and Medline computerized search on management of postoperative morbidity following third molar surgery were evaluated and highlighted. Information was also obtained from texts and journals in the medical libraries of Federal School of Dental Technology and the University of Nigeria both in Enugu. RESULTS: studies reviewed have not pointed to the effectiveness of the routine use of any systemic or local agent for minimizing postoperative morbidity after third molar surgery without other undesirable effects. Oral surgeons across the world have devised several methods, which include the use of drugs, different surgical techniques, laser therapy and the use of drains. CONCLUSION: Postoperative morbidity after the surgical removal of impacted lower third molar still remains an important factor in patients' recovery and comfort. The awareness of different methods of reducing morbidity after lower third molar surgery would help both the surgeon and the patients in the management of impacted lower third molar. PMID- 17694762 TI - Gastric histopathological findings in mucosal biopsies of symptomatic patients in jos central Nigeria. AB - BACKGROUND: Dyspepsia is a common disease worldwide. It is a cause of great absenteeism from work with a lot of economic loss. In Jos, it is one of the most common complaints encountered in both general outpatient and specialist clinics. AIM: To evaluate the histopathological changes in gastric mucosa of patients presenting with symptoms of dyspepsia. METHODS: Cross sectional study. Gastric endoscopic biopsy specimens from 100 consecutive patients with symptoms of dyspepsia were histologically evaluated using the criteria of the updated Sydney system. RESULTS: There were 50 males and 50 females. Their overall mean age was 39.6 +/- 12.2 (S.D). The prevalence of Helicobacter pylori colonization was 79%. Males were 53.2% and females 46.8% respectively giving a sex ratio of 1.4:1. Gastritis, neutrophil activity, glandular atrophy and intestinal metaplasia were observed in 95%, 83%, 38% and 28% respectively. Gastric carcinoma was found in 3% ofthe patients. CONCLUSION: From our study, we conclude that the majority of our patients with dyspeptic symptoms have significant histopathological changes in their gastric mucosa with implications for the development of further gastric lesions, and that the most common cause of dyspepsia in our environment is Helicobacter pylori infection. PMID- 17694763 TI - Cardiovascular risk factors in Nigerians with systemic hypertension. AB - BACKGROUND: Hypertension is the commonest risk factor for cardiovascular disease, and it frequently coexists together with other risk factors, thereby increasing the absolute cardiovascular risk. This study is primarily aimed at assessing cardiovascular risk factors in patients with hypertension in comparison with controls. It is also aimed at assessing target organ damage and absolute cardiovascular risk among the hypertensives. STUDY DESIGN: The study was case control in design, conducted at the General outpatient and Cardiology Clinics of Aminu Kano Teaching Hospital, Kano, Nigeria. Three groups of patients (treated hypertensives, untreated hypertensives and controls), each 70 in number, were matched for age and sex. Patients were selected by balloting, using simple random sampling method. RESULTS: The most prevalent cardiovascular risk factor was Increased Body Mass Index, which was significantly more prevalent among treated (70%) than untreated (45.7%) hypertensives and controls (44.3%). Left Ventricular Hypertrophy was the most prevalent Target Organ Damage, found in 54.3% of treated and 42.9% of untreated hypertensives, and 0% of controls. Very high cardiovascular risk was detected in 75.6% of treated and 68.5% of untreated hypertensives. CONCLUSION: Even before the commencement of treatment, hypertenisves had high prevalence of cardiovascular risk factors and evidence of target organ damage. These were more pronounced in treated hypertensives. The basis and prognosis are discussed. PMID- 17694764 TI - Austin-moore hemiarthroplasty; the Enugu experience. AB - BACKGROUND: Femoral neck fracture is the commonest fracture among the elderly who frequently have co-morbid medical conditions. It commonly follows trivial falls at home. Prosthetic replacement with Austin Moore prothesis is one of the treatment options open to Orthopaedic Surgeons in this age group who need to be mobilised as early as possible to prevent the complications of prolonged immobilization. This study shows our experience with Austin Moore hemiarthroplasty [AMH] as a treatment option for femoral neck fractures over a 10 year period. METHOD: Hospital records of 46 out of 59 patients who had AMH in NOHE between 1995-2004 (10 year period) were reviewed retrospectively. The 13 patients who had incomplete records were excluded. RESULTS: The age range of the patients was 26-99 yrs with 67:2 yrs as the mean. There was a slight female to male preponderance [F:M = 1.1:1]. Most of the patients clustered between 61 and 80yrs. Majority presented late [76%], with only 2 patients presenting within 24hrs of injury. Fracture neck of femur was the commonest indication for AMH [89.1%] with domestic falls and RTA having 54.3% & 32% respectively as aetiological factors. Hypertension was the most prevalent co morbid medical condition [76%]. Majority of the patients had preoperative traction, 58% (skin: 32.6%, skeletal 26.1%) while general anaethesia was used in 63% of patients. Blood transfusion was common; 87.1. 58.7% of patients were mobilized within 2-3 wks of operation while 26.9% were delayed for more than 3 wks. 2 patients [4.3%] died while on admission. 76.1% were mobilized initially on Zimmer frames, 13.0% on crutches, 6.5% on wheel chair. 80% were able to walk with walking stick[cane] in 6 weeks while 87% achieved this in 12 weeks. Follow up time of patients was poor as patients default frequently after few visits. Wound infection was the commonest complication 26.1%, mostly treated by dressing and antibiotics. 13.0% were hospitalized for 2-3 weeks, 36%-4-6 wks while 50% stayed beyond 6 wks. Mortality rate was 4.3% [2]. PMID- 17694765 TI - A comparison of booked and unbooked patients with ruptured uterus in A referral hospital in the Niger Delta region of Nigeria. AB - OBJECTIVE: To document differences in characteristics and outcome between booked and unbooked patients with ruptured uterus METHODS: A 10 year retrospective comparative analysis of booked and unbooked patients with ruptured uterus at the Baptist medical center, Eku, Delta State. RESULTS: The overall incidence of ruptured uterus was 1 in 271 deliveries while the incidence among booked and unbooked patients was 1 in 556 and 1 in 140 respectively. There were a statistically significant difference in number of booked patients with formal education beyond the primary level compared with the unbooked patients (p = 0.0206; 95% CI 1.92-14.79). A higher proportion of booked patients with ruptured uterus had history of previous uterine scar. All the three maternal deaths occured in the unbooked patients. The overall case fatality rate for ruptured uterus was 23% or 1 in 4.3. CONCLUSION: Booked and unbooked patients with ruptured uterus have different characteristics and outcome. Subsequent studies on ruptured uterus should disaggregate their data according to the booking category of the patients. This will assist in making effective intervention plans that will impact both groups. PMID- 17694766 TI - Reduced thyrotropin in euthyroid goitrous patients suggesting subclinical hyperthyroidism. AB - BACKGROUND: Subclinical hyperthyroidism, a biochemical finding of low serum thyrotropin (TSH) with the serum levels of thyroxine (T4) and triiodothyronine (T3) within the reference range, could easily be ignored by clinicians, as it, usually, does not manifest with any thyroid specific symptoms. It is of two types: endogenous and exogenous. However, patients with the findings of low TSH, normal T4 and T3 develop some abnormalities in the cardiovascular system, such as atrial fibrillation, increase in left ventricular mass and diastolic dysfunction. It is believed that treatment intervention may reduce or halt the progression of the cardiac abnormalities. The main objective of the study was to determine how frequent subclinical hyperthyroidism was occurs and to serve as a reminder to the existence of the disorder. METHODS: It was a hospital-based study carried out at the Jos University Teaching Hospital (JUTH). Consecutive clinically euthyroid goitre patients attending the outpatient department of JUTH, were studied for various parameters including TSH, T4 and T3 The serum concentrations of T4 and T3 were determined by enzyme-linked immunosorbent assay (ELISA) technique. The serum TSH concentration was estimated using a 2nd generation ELISA technique. RESULTS: 98 patients participated in the study. Nine patients had non-specific symptoms not referable to the thyroid and found to have high levels of thyroid hormone concentration with depressed TSH and were excluded from further analysis, while 7 had subclinical hyperthyroidism giving a prevalence rate of 7.9% among these clinical euthyroid goitre patients. The subjects with this condition were mainly above 60 years of age and mainly had long-standing goitre. CONCLUSION: Endogenous subclinical hyperthyroidism was present in 7.9% of these clinically euthyroid goitre patients mainly 60 years and above, with long-standing goitre. This high prevalence rate calls for high index of suspicion as this condition is associated with morbidities that can raise mortality. PMID- 17694767 TI - Rehabilitation of children after elbow injuries. AB - OBJECTIVES: To review the efficiency of early physical therapy to achieve successful rehabilitation after elbow injuries in children. SETTING: Tertiary medical institution, Department of Physical Therapy, University Clinical Center of Kosovo, rr. Spitalit pn. 10000 Prishtina, Kosovo. METHODS: We retrospectively reviewed the patients with elbow injuries, (ICD, Rev. 10, Elbow Fractures code) merely as a consequence of trauma, who had undergone rehabilitation program from June 2000 December 2001. RESULTS: In this study 140 cases with elbow injuries are analyzed. The majority of the injured are with fracture 132 cases (94.29%), whereas only 8 cases or 5.72% are with non displaced fracture or dislocation. Analysis based on the most frequent injury localization in the elbow region, among all fractures, supracondylar fracture is present with 78 cases or 56%. The majority of cases, 49 or 35% have had injuries caused by fall from height, up to 6 cases or 4.3% injured in MVA. Timely initiation of rehabilitation program is influential factor in successful rehabilitation, whereas correlation between time of initiation and rehabilitation success have demonstrated important statistical significance, very high correlation r = 0.75 p < 0.01. CONCLUSION: The children that did not have continuous rehabilitation program, due to huge interruptions during rehabilitation, have not achieved excellent success in rehabilitation. Early start of rehabilitation, since the arm is immobilized, can cause complete regaining of elbow functions, therefore any delay in the beginning of rehabilitation will leave consequences, from the must minor ones up to disability. PMID- 17694768 TI - Bacterial isolates from necrotizing fasciitis: a clinico-pathological perspective. AB - BACKGROUND: Necrotizing fasciitis (NF) is a progressive, polymicrobial, potentially fatal soft tissue infection that can affect both sexes, all age groups and any anatomical region of the body. Identification of the offending microorganisms is important, since the eventual outcome of treatment is dependent on aggressive surgical, chemotherapeutic and supportive therapy. AIM: To determine the spectrum of aerobic bacterial organisms responsible for NF in Sokoto, Northwestern Nigeria, and to establish a baseline for which further studies can be conducted. PATIENTS AND METHODS: A 5-year prospective study of aerobic bacteria isolated from all consecutive patients with NF seen at the Usmanu Danfodiyo University Teaching Hospital, Sokoto, Nigeria from January 2001 to December 2005. All necessary information from each patient was fed into the computer for analysis. RESULTS: There were 62 patients, of which 33 (53.2%) were males while the remaining 29 (46.8%) were females. The ages ranged from six days to 70 years (mean = 21.4 years). One or more precipitating factors were identified in 32 (51.6%) patients, while 40 (64.5%) patients had identifiable pre morbid pathology. The body surface area (BSA) involved ranged from 1 31% (mean = 5.2%). The commonest anatomical region involved was the trunk in 23 (37.1%) patients; this was followed by the lower limbs, upper limbs, head and neck, perineum and buttocks in that order. From the 62 patients, 176 aerobic cultures were carried out. Of this, 147 cultures (83.5%) were positive, while the remaining 29 (16.5%) grew no organisms after 48 hours of incubation. The commonest offending organisms were Staphylococcus aureus and Pseudomonas aeruginosa. Infection was polymicrobial in 64% of patients. Cephalosporins, quinolones and aminoglycosides were the most sensitive antibiotics. Multiple wound debridements were required in nearly half of the patients. The duration of hospital stay ranged from 3 132 days (mean=39 days). The overall mortality was 14.5%. CONCLUSION: NF is essentially polymicrobial, deriving significant contributions from both gram-negative and gram-positive bacteria. The cultural characteristics of the disease, and sensitivity to antibiotics, require periodic assessments. PMID- 17694769 TI - Tuberculosis treatment outcomes in State Hospital, Osogbo, southwestern Nigeria: a four year review. AB - BACKGROUND: A retrospective review of all cases of tuberculosis (TB) enrolled in the directly observed treatment-short course chemotherapy (DOT-SCC) between June 2000 and June 2004 at a General Hospital in Southwestern Nigeria was undertaken. The aim is to determine treatment outcomes and ascertain the effectiveness of the programme for TB control. METHODOLOGY: Case registers of all TB patients enrolled were reviewed and data obtained analyzed by statistical methods. RESULTS: A total of 879 TB patients (467 males, 412 females; M: F ratio 1.13:1) aged 1 to 80 years (mean age 33.0 +/- 14.0 years) were enrolled. The disease was pulmonary in 98.4% and extrapulmonary in 1.6%. Seven hundred and thirty four (83.6%) patients complied with the DOTS-SCC regimen, 127 (14.4%) defaulted while 18 (2%) transferred out. The overall treatment success rate was 76.3% while 3.8% had treatment failures. Outcome was not significantly affected by types of TB lesion (P = 0.1103), patient category (P = 0.4968), age (P = 0.7198), gender (P = 0.1726) or smear positivity (P = 0.5497). CONCLUSION: Although the currently advocated DOT-SCC regimen achieved a high success rate in this locality, it fell below the 85% recommended target. There is need to step up health education campaign on compliance with therapy and aggressively follow up defaulters to forestall the emergence of multidrug resistant M. tuberculosis. PMID- 17694770 TI - Diabetes co-existing with chronic liver disease: clinical features and response to therapy. AB - BACKGROUND AND OBJECTIVES: Diabetes mellitus (DM) and chronic liver disease (cirrhosis) may co-exist in the same individual. Diabetes may cause non-alcoholic steatohepatitis with necroinflammatory changes and granuloma formation leading to hepatic fibrosis. Cirrhosis of the liver from alcohol and hepatitis C infection, on the other hand, may give rise to insulin resistance or may result in progressive impairment of insulin secretion leading to DM. We studied the clinical features and response to therapy of diabetic patients with the two conditions to determine if there are differences in the clinical features and effects of the chronic liver disease (CLD) on the management of DM. METHODS: This was a prospective study conducted at the Diabetes Clinic at the Jos University Teaching Hospital (JUTH) over a period of two years. Newly diagnosed diabetics with features of CLD (cirrhosis) were enrolled into the study after obtaining a consent. Age, sex, body mass index (BMI), family history of diabetes were recorded, as well as symptoms and signs of DM or CLD. Serum fasting blood glucose (FBS), prothrombin time ratio (PTR), and serum fasting lipids (serum lipoproteins and serum triglycerides) were measured. Urinalysis was done. The responses to therapy were classified as very rapid, rapid and gradual based on our previous unpublished observations that diabetic patients with CLD responded briskly to antidiabetes therapy. RESULTS: 26 patients(19 men, and 7 women) were seen with both diseases agreed to participate in the study This accounted for 8.6% of the diabetic population attending the diabetes clinic. The mean age of the patients was 54.6 (9.2) years spanning a range of 34-75 years. Mean BMI was 21.6 (6.0) kg/m2. The mean serum albumin concentration was 25.5 (8.5) g/l, mean FBS was 15.5 ( 3.4) mmol/l and PTR was 1.6 (0.43). Urinalysis showed glycosuriain all patients with only one patient showing trace of ketonuria. Clinical features of DM and CLD were few each. There was a brisk response to insulin therapy so that one needs to be cautious with insulin administration. CONCLUSION: Diabetes in patients with CLD has similar but fewer features compared to patients with type2 DM. CLD affects the response to therapy, particularly insulin therapy and calls for caution, as these patients may be sensitive to therapy. PMID- 17694771 TI - The perception of health professions on causes of interprofessional conflict in a tertiary health institution in Abakaliki, southeast Nigeria. AB - BACKGROUND: Interprofessional conflict in university teaching hospitals in Nigeria is on the increase. This study was aimed at assessing the health professions' perception of factors responsible forconflict. METHODOLOGY: A cross sectional descriptive survey among six health professions. RESULTS: The perceived causes of conflict include differential salary between doctors and others, physician intimidation and discrimination of other professions, "inordinate ambition" of the other professions to lead the health team, and envy of the doctor by the other professions. Doctors differed significantly from the other professions on the role of each of these in causing conflict. Mutual respect for each other's competence, proper remuneration and clear delineation of duties for all, and other groups appreciating the salary differential between them and doctors were perceived as means of resolving the conflict. While all accepted mutual respect and proper remuneration as effective, other health workers differed significantly from doctors on the effectiveness of appreciating salary differential between them and doctors in resolving the conflict. CONCLUSION: Differential salary between the doctor and the other health workers is the main factor perceived to cause interprofessional conflict. The government and all health professions should accept, and maintain the relativity in salary differential between doctors and other health professions. PMID- 17694772 TI - Pedestrian injuries resulting from road traffic accidents: the Azare experience. AB - BACKGROUND: Road traffic accident (RTA) is a leading cause of serious morbidity and mortality world wide. The pedestrians are not spared from this epidemic. OBJECTIVE: The aim of this study is to identify factors that puts the pedestrian at risk of injuries from RTA and the anatomical regions most commonly involved in our environment and suggest ways of curbing them. METHODS: This was a one-year retrospective study of 122 pedestrian casualties resulting from road traffic accident attending the Accident and Emergency (A/E) Unit of the Federal Medical Centre, Azare. RESULTS: Majority of the patients (72%) were males with a male to female ratio of 2.6:1. Children and adolescents constitute 54.1% of the casualties. Motorcycles were responsible for most of the pedestrian injuries (73%). The head and neck was the most frequently injured anatomical region of the body (43.4%), followed by the extremities (37%). The months of August and January were the peak periods of injuries. CONCLUSION: The safety of pedestrian is seriously threatened by the growing popularity of commercial motorcycles on our roads. Preventive measures are advocated to ensure only licensed cyclists are allowed on the roads. Adequate personnel training to manage head injury in our centers is also advised. More patrol by the road safety agents is advised in the months of January and August. PMID- 17694773 TI - When the inheritance of two heterozygote states become a diagnostic problem: misdiagnosis of the sickle cell trait. AB - BACKGROUND: The sickle cell trait is a benign asymptomatic condition that should not ordinarily be associated with clinical manifestations of a haemoglobinopathy. METHOD: This is a case control study of sickle cell trait patients who presented with symptomatology of a haemoglobinopathy. HbA2, HbF and HbS levels as well as the haematocrit and the peripheral film pictures of 10 symptomatic individuals (patients) with the sickle cell trait were compared with those of 20 asymptomatic individuals (controls) with the sickle cell trait. RESULTS: The mean HbA, of the cases was 4.9% compared to the mean of 2.2% for the controls (p < 0.0001). Nine of the patients and none of the controls had a raised HbA, (> 3.5%). The mean HbF of the patients was 5.6% with a range of 1.2-14.0% while the mean of the control was 2.0% and a range of 0. 7-8.4% (p = 0.006). Six (30%) of the controls had normal HbF level (<1%) while none of the patients had a normal HbF level. The mean haematocrit of the patients and controls were 0.33 and 0.37 respectively (p = 0.009). HbS level was below 40% in both groups. Pregnancy did not significantly affect the mean HbF, the mean HbF for pregnant and non-pregnant cases were 2.1% and 3.8% respectively. CONCLUSION: These findings suggest that the prevalence of the thalassaemia trait may be higher among Nigerians than previously thought with the clinical severity masked by the co-inheritance of other genes like thalassaemia that occur frequently in the same population. PMID- 17694774 TI - Disseminated intravascular coagulopathy in a neonate: management challenges. AB - BACKGROUND: Newborns are vulnerable to developing disseminated intravascular coagulopathy (DIC) following infections because of immaturity of their coagulation system. This case report highlights the diagnostic and management challenges encountered in neonates with DIC. METHOD/RESULT: The case notes of an eight day old male who presented with a three-day history of fever, convulsion, excessive crying, refusal to suck and intermittent gum bleeding was reviewed. On examination, he had signs of meningeal irritation and a grade 4 machinery murmur maximal at the 2nd left intercostal space. Investigations showed severe thrombocytopenia and deranged coagulation profile. He received intravenous antibiotics as well as three exchange blood transfusions to correct his coagulation profile and improve his clinical condition before discharge. The underlying cause of his condition was presumably an intrauterine infection. CONCLUSION: The survival of neonates with DIC depends on vigorous treatment of the underlying disorders so as to curtail the triggers of blood coagulation as well as replacement of the consumed coagulation factor. PMID- 17694775 TI - Anterior abdominal wall hydatid cyst; an unusual presentation. AB - BACKGROUND: Hydatid disease is common in sheep rearing communities, often presenting with hepatic cysts in a majority of cases. Musculo-skeletal involvement as occurred in our patient is an unusual manifestation. Hydatid disease should be considered a differential of superficial and soft tissue swellings in our environment. METHOD: A 27-year-old HIV positive widow on antiretroviral therapy, who presented with intramuscular hydatid cyst in the right lower quadrant of the anterior abdominal wall is presented. RESULT: Following total excision and chemotherapy with albendazole, the patient did well and remained symptom free two years later. CONCLUSION: Though a rarity, hydatid cyst does occur in the musculo-skeletal system, presenting as a superficial swelling. Correct surgical management, including the intra-operative avoidance of spillage of cyst fluid demands pre-operative diagnosis or at least a high index of suspicion. Hydatid cyst should therefore be kept in mind in the differential diagnosis of superficial swellings of musculo-skeletal origin in sheep rearing communities such as ours. PMID- 17694776 TI - Abscess of the deep cervical fascial space in adults: a report of 3 cases and review of anatomy. AB - Deep cervical space abscess is a disease with the potential for grave consequences if not managed properly. Even though since the antibiotic era it has been on the decline, it still occurs. Better imaging techniques have made the management of this disease better such that it is possible to treat the abscesses conservatively reserving surgical drainage for cases that fail to respond to treatment. We present 3 cases of deep cervical space abscess that were surgically drained and wide spectrum antibiotic administered. In one of the patients, there was coexisting pulmonary tuberculosis. PMID- 17694777 TI - Bilateral pneumoblepharon/palpebral emphysema in Nigeria--a case report. AB - BACKGROUND: Bilateral pneumoblepharon or palpebral emphysema is an unusual presentation of tuberculosis which is a fairly common disease condition. METHOD: The case record of a four year old Nigerian female presenting with bilateral pneumoblepharon secondary to tuberculosis with a review of literature on the subject is presented. RESULT: Palpebral emphysema is one of the ocular complications of tuberculosis, which is not commonly reported in our environment. CONCLUSION: There is a need for the ophthalmologist to be more aware of the ocular complications of tuberculosis such as palpebral emphysema, in order to avoid misdiagnosis and to ensure proper treatment of this condition. PMID- 17694778 TI - Targeted therapies: aiming for the bull's-eye. PMID- 17694779 TI - Relationships with patients have a deep impact on oncology nurses. Interview by Camille A Servodidio. PMID- 17694780 TI - Immune-boosting prostate cancer vaccine endorsed by FDA advisors. PMID- 17694781 TI - Drugs offer new hope for patients with CML who are resistant to imatinib. PMID- 17694782 TI - Oncology nursing issues are common across cultures and continents. PMID- 17694783 TI - Mentors can help nurses advance their careers. PMID- 17694784 TI - Living donor kidney transplantation--is it safe? PMID- 17694785 TI - Risk of live kidney donation--Indian perspective. AB - INTRODUCTION: Live kidney donation is an established form of organ donation but carries the risk of an unnecessary surgery in a normal individual for the benefit of the recipient. Long term effects of nephrectomy have not been studied in Indian donors so far. AIM: The aim of this pilot study was to review the effects of kidney donation on morbidity (renal function, BP and proteinuria), psychosocial outcome and mortality. MATERIAL AND METHODS: Fifty donors who had nephrectomy 3 months to 20 years prior formed the material of this study. Medical history (donor age at nephrectomy, duration post-nephrectomy, family history), physical examination including anthropometry and systolic and diastolic blood pressure (SBP and DBP) measurement pre and post nephrectomy were recorded. Evaluation of renal function included pre and post-nephrectomy urinalysis, determination of microalbuminuria, serum creatinine, blood urea, 24 hr urinary protein and creatinine estimation and calculation of creatinine clearance. Renal length was measured by ultrasonography. Quality of life (QOL) was assessed by a standard questionnaire. Donors with co-morbidities not related to nephrectomy were excluded from the analysis. Data was statistically analyzed. RESULTS: Twenty two donors (44%) were males and 28 (56%) females. Parents constituted the majority 39 (78%); 10 were siblings (20%) and 1 was a spousal donor. The mean age at donation was 41.26 +/- 8.12 years (25-54.16 years). Since kidney donation a mean time interval of 63 months (3-264 months) had elapsed. There was a mean rise of 9.96 mm Hg in SBP and 7.18 mm Hg in DBP. Hypertension was noted in 23(46%). 20 donors (40%) developed microalbuminuria (MAU) post nephrectomy and 7 (14%) developed overt proteinuria (> 300 mg/day). Mean GFR pre and post nephrectomy was 102.74 +/- 6.91 ml/min and 74.54 +/- 14.64 ml/min with a mean reduction of 28.2 +/- 13.57 ml/min. There was no significant change in serum creatinine after donation (0.97 +/- 0.09 mg/dl vs 1.22 +/- 0.82 mg/dl). There was an increase in renal length of 1.14 +/- 0.73 cm. None of the donors regretted donation. CONCLUSION: This pilot study reaffirms the safety of live kidney donation. There was a fall in GFR with consequent increase in renal length postnephrectomy. The long-term implications of the minimal increase in proteinuria and rise in blood pressure need to be evaluated in larger cohort of donors over a longer period of time. This study underscores the need for initiating a donor registry to achieve this objective. PMID- 17694786 TI - Hospital-based case series of 175 cases of serologically confirmed brucellosis in Bikaner. AB - OBJECTIVE: To study the clinical spectrum of brucellosis in Bikaner (Northwest India). METHODS: A total of 175 cases were diagnosed as brucellosis during the period of six year (June 1997 to May 2003). They were studied for clinical profile and treated by rifampicin and doxycyclin and additionally streptomycin for initial 14 days in patients of neurobrucellosis. These patients were followed up to 3 months. RESULTS: Patients of brucellosis presented with a wide spectrum of clinical manifestations. Out of 175 cases 155 were from rural area. Age ranged between 12-60 years (124 males, 51 females). Analysis of risk factors revealed history of raw milk ingestion (86.86%), occupational contact with animals (81.14%), handling of infected material (62.28%), household contact (16%) and 2 patients were veterinarian. Joint pain (83.43%) and fever (77.71%) were the commonest presenting feature. Sacroiliac joint was most commonly involved (46.86%). 31 cases had involvement of multiple joints. Other mode of presentation were neurobrucellosis (18.86%), manifested as polyradiculoneuropathy, myeloradiculopathy, meningoencephalopathy and polyradiculomyeloencephalopathy; predominant pulmonary involvement (4.0%) presented as bronchitis, pneumonia and pleural effusion; epididymoorchitis, infective endocarditis, nephrotic syndrome and recurrent abortion. All patients responded well to the treatment. CONCLUSION: Brucellosis is an important emerging zoonotic disease but it is often under diagnosed due to lack of suspicion and diagnostic facilities despite the fact that cattle farming (an important high risk group) is one of the main occupation in rural area. This report should infuse the awareness about this reemerging disease specifically in high-risk group. PMID- 17694787 TI - Myocardial dysfunction in rheumatic carditis--does it really exist? AB - OBJECTIVES: Acute rheumatic fever (ARF) continues to affect millions of children in developing countries. Aim of the present study was to evaluate the role of myocardial dysfunction in the genesis of heart failure in patients with rheumatic carditis. There are limited studies on this subject. METHODS AND RESULTS: In this prospective study, 108 consecutive patients of ARF were evaluated by echocardiography and assay of cardiac troponin I blood levels. The patients were divided into three groups. Group A (n = 30): patients with no evidence of carditis; Group B (n = 45): patients with first attack of carditis; and group C (n = 33): patients with recurrent attacks of carditis. Left ventricular dimensions tended to be larger in Group B and C patients. Left ventricular ejection fraction did not differ between the groups (Group A: 63 +/- 8.1%, Group B: 58 +/- 7.9%, Group C: 61.2 +/- 9%, p = ns). Heart failure was present in 37.7% patients of Group B, and in 60.6% patients of Group C (p = < 0.05). Ejection fraction was normal in majority of heart failure patients (75.7%). It was reduced in 29.4% of patients in Group B and in 20% of Group C patients with heart failure (p = ns). All patients with low ejection fraction had hemodynamically significant regurgitant valvular lesions. Mean cardiac troponin I values, an index of myocardial damage, did not differ between the three groups (Group A: 0.062 +/- 0.027 ng/ml, Group B: 0.068 +/- 0.019 ng/ml, Group C: 0.071 +/- 0.031 ng/ml, p = ns). CONCLUSION: The present study did not demonstrate any echocardiographic abnormalities or cardiac troponin I elevation suggesting significant myocardial involvement during acute rheumatic fever. This lends credence to the view that myocardial involvement does not play any significant role in the genesis of heart failure in patients with rheumatic carditis. PMID- 17694788 TI - Binswanger's disease. PMID- 17694789 TI - A case of giant subclavian aneurysm. PMID- 17694790 TI - Coronary artery bypass surgery or drug eluting stent for unprotected left main coronary artery disease. AB - Coronary artery bypass surgery (CABG) is the treatment of choice in unprotected left main coronary artery disease (ULMCA). However drug eluting stent (DES) implantations in ULMCA have ushered a revolution in the field of percutaneous coronary interventions (PCI) for left main coronary artery (LMCA) by reducing peri-procedural mortality and incidence of major adverse cardiac events (MACE). More randomized trials and follow-up studies are required before PCI with DES can be chosen as alternative to CABG. PMID- 17694791 TI - Investigations proposed to accurately classify chronic gastritis. AB - Patients of chronic gastritis should be investigated with gastric mucosal biopsy, parietal cell antibody, intrinsic factor antibody, Helicobacter pylori antibody, urea breath test or faecal antigen test for Helicobacter pylori, to accurately classify them. The results of these tests will indicate Helicobacter pylori infection (present or past), the role of hereditary factor (intrinsic factor antibody present or absent) and the success or failure of Helicobacter pylori eradication treatment. PMID- 17694792 TI - Descending thoracic aortic aneurysm presenting as left sided hemorrhagic pleural effusion. AB - Aneurysm of descending thoracic aorta, in majority of cases is diagnosed either by chance in routine chest imaging for some other reasons or rarely due to it's symptomatic presentation like chest pain and other mediastinal compression symptoms. In this case report we present a case of 69 year old smoker who presented with cough, hemoptysis and left sided massive painless hemorrhagic pleural effusion. Further investigation revealed a large aneurysm of descending thoracic aorta which infiltrated the left lung. We suggest descending thoracic aneurysm be included in the differential diagnosis of this sort of clinical presentation which otherwise imperative with the clinical scenario of bronchogenic carcinoma. PMID- 17694793 TI - Pseudotumor--like presentation of neurobrucellosis. AB - Brucellosis is bacterial zoonoses. In endemic areas brucellosis can present with clinical features of nearly any neurological illness. Meningitic presentation is most common, with patient presenting with either acute or chronic meningitis. Pseudotumor--like presentation is also documented and accounts for only 4% of cases of neurobrucellosis. Here we are documenting a case of neurobrucellosis with presentation similar to pseudotumor cerebri but with abnormal CSF. This highlights the fact that being a potentially treatable condition brucellosis should always come in the differential diagnosis of neurotuberculosis especially if there are atypical features e.g. pseudotumor presentation with abnormal CSF. PMID- 17694794 TI - Type 1 renal tubular acidosis with sensorineural deafness. AB - We report a case of Type 1 Renal Tubular Acidosis (RTA) in association with sensorineural deafness. Inherited Type 1 RTA is usually autosomal dominant, though there is a rarer recessive form associated with nerve deafness. Simple alkali replacement can correct the systemic metabolic defect, but does not appear to ameliorate hearing loss. PMID- 17694795 TI - Medical philately (Medical Theme on Stamps) Joseph Skoda (1805-1881). PMID- 17694796 TI - Aspirin-induced non-cardiogenic pulmonary edema. PMID- 17694797 TI - Hypoglycemia and catatonia. PMID- 17694798 TI - Cardiorenal syndrome and later-onset Fabry disease: is there a connection? PMID- 17694799 TI - Brain natriuretic peptide--the biological marker in the diagnosis of overt congestive heart failure and myocardial ischemia. AB - Brain natriuretic peptide (BNP) is one of the cardiac peptide hormones that are involved in water and electrolyte homeostasis in heart failure. There are two mechanisms for increased BNP gene expression: cardiomyocyte stretching and neurohormonal activation. Many recent studies reported an increase in BNP gene expression with elevated plasma concentrations of BNP/NT-proBNP and its precursor, proBNP, in overt heart failure as well as in myocardial ischemia or acute coronary syndrome. In addition, the elevated plasma concentrations of BNP and NT-proBNP are a prognostic marker of morbidity, mortality and later development of heart failure in patients with acute coronary syndrome. In the management of children with congenital heart disease the role of BNP as a diagnostic tool is less evident. This review summarizes recently known facts about the role of BNP in the diagnosis, management and prognosis of congestive heart failure, myocardial ischemia and congenital heart disease (Ref. 33). Full Text (Free, PDF) www.bmj.sk. PMID- 17694800 TI - In vitro contractile response of human myometrium to oxytocin, PGF2alpha, bradykinin and ET-1. AB - BACKGROUND: The imbalance in the sex hormones levels is the limited factor which induces disturbances in the uterus function and elevates uterine contractile activity. OBJECTIVES: The aim of our study was to evaluate and compare the direct contractile responsiveness of myometrium to the effects of uterotonic agents- oxytocin, PG2alpha, ET-1, and bradykinin--in the strips of human non-pregnant myometrium during different phases of menstrual cycle. METHODS: Reactivity of human myometrial strips, obtained from the pre-menopausal woman undergoing total hysterectomy for benign gynaecological indications such as leiomyomas, was evaluated in vitro. RESULTS: Our results showed an increased reactivity of myometrium to contractile mediators during follicular phase of the cycle. Our findings support the idea that estrogens might have a positive influence on the expression of various types of receptors (FP, OTR, BK2R and ET(A)R) and thus promote the contractility in response to uterotonic agents. On the contrary, minimal myometrial response to oxytocin, PG2alpha, ET-1, and bradykinin were observed during luteal phase when progesterone levels are increased. CONCLUSION: Our results indicate that the contractile activity of myometrium is mostly influenced by changes in sex steroid hormones during menstrual cycle. In future, this experimental model can be used for the study of mechanism regulating myometrial smooth muscle reactivity and its pharmacological modulation (Fig. 4, Ref. 20). Full Text (Free, PDF) www.bmj.sk. PMID- 17694801 TI - Lipoprotein (a) and apolipoprotein (a) phenotypes in healthy Macedonian children. AB - BACKGROUND: Plasma levels of lipoprotein(a) [Lp(a)] are determined largely by genetic variation in the gene encoding apolipoprotein(a) [apo(a)], the unique protein component of Lp(a). High plasma levels of Lp(a) increase the risk of premature atherosclerosis. However, the association of apo(a) phenotypes with the development of these diseases remains largely unexplored. OBJECTIVES: Determination of Lp(a) levels and apo(a) isoforms (phenotypes) in 100 (51 boys, 49 girls) Macedonian healthy children aged 9-18. METHODS: We used 3-15 % gradient SDS-PAGE for separation of apo(a) isoforms. According to the different apo(a) electrophoretic mobilities, Apo(a) was classified into five single and respective double-band phenotypes. RESULTS: Each individual expressed a single (homozygotic), double-band (heterozygotic) or no band (null phenotype). The apo(a) phenotype frequencies revealed that the frequency of single-band phenotype expression (64 %) was higher than that of double bands (32 %) and that the frequency of phenotypes representative of low molecular weight was very low (4%). The most frequent phenotype was S4 (42.65%). The distribution of plasma Lp(a) levels was skewed, with the highest frequencies at low levels. The mean Lp(a) concentration was 11.95 (SD of 5.98 and median of 9.62 mg/dL). We did not find differences in the mean and median plasma Lp(a) levels between boys and girls (p > 0.05). A strong inverse relationship was found between the apparent molecular weight of apo(a) phenotypes and plasma Lp(a) concentration (r = -0.4257). CONCLUSIONS: Determination of Lp(a) levels and apo(a) phenotypes in children, may help in preventing and reducing the risk of atherosclerotic development (Tab. 6, Ref 32). Full Text (Free, PDF) www.bmj.sk. PMID- 17694802 TI - Comparison of a preincisional and postincisional small dose of ketamine for postoperative analgesia in children. AB - BACKGROUND: The aim of this randomized, double blind, placebo controlled prospective study was to investigate the preventive action of N-methyl-D aspartate (NMDA) receptor antagonist ketamine on postoperative analgesia by comparing its administration preincisionally, at the end of operation and placebo in the management of postoperative pain in children. METHODS: 90 children ASA I or II, scheduled for hernia repairs, circumcisions and orchydopexy, aged 4.5-14 years were randomly assigned in three groups: first received low dose ketamine 0.3 mg/kg intravenously before the start of operation, second the same dose at the end of operation and the third group got placebo saline i.v. before the incision. The intensity of postoperative pain was measured by visual-analogue scale (VAS) at 2, 6, 12 and 24 h postoperatively. The rescue analgesic consumption, the time of the first request of postoperative analgesia and side effects were noted. RESULTS: There were not any significant differences in VAS, the time of the first request of analgesia and analgesics' consumption in postoperative period between the preincisional and postincisional ketamine and placebo group. The side effects as sleep disturbances, hallucinations, and nightmares were equal in both ketamine groups. CONCLUSIONS: No significant difference was found between analgesic effects of preincisional ketamine, ketamine administered at the end of operation and of control group in postoperative analgesia in children (Tab. 1, Fig. 1, Ref. 21). Full Text (Free, PDF) www.bmj.sk. PMID- 17694803 TI - Combination of two anti-stress procedures: our original 4-corner deltoid-like vaginal suspension and suburethral duplication sec. Lazarevski in patients with genital prolapse. AB - AIM: The effectiveness of the combination of two anti-stress procedures: 1) our original 4-corner deltoid-like vaginal suspension; and 2) suburethral duplication sec. Lazarevski are analysed. STUDY DESIGN: 144 women, undergoing vaginal hysterectomy, combined with our original 4-corner deltoid-like vaginal suspension and suburethral duplication sec. Lazarevski were divided into: SUIGP group (n = 48) with stress urinary incontinence (SUI) and genital prolapse (GP); and GP group (n = 96) with GP. All operations were performed by the first author of this study. RESULTS: At the last follow-up (mean 18.3 months for GP, and 18.7 months for SUIGP), point C was significantly higher in both groups and total vaginal length (tvl) longer in GP vs. preoperative positions (p < 0.05; p < 0.05; p < 0.05 respectively). There were no postoperative significant differences between groups. Regarding the severity of prolapse: stage I for anterior segment and stage 0 for most severe segment predominated in SUIGP (p < 0.05; p < 0.05 respectively). The recurrent prolapse was: 1) in anterior segment: stage I 6.25% in GP and 18.7% in SUIGP; stage II 6.25% in GP and 2.1% in SUIGP; 2) in posterior segment: stage I 18.7% in GP and 18.7% in SUIGP. There was no recurrent prolapse of the apical segment, and only one patient with stage III anterior segment. The recurrent SUI was 8.3% in SUIGP, and de novo SUI 1% in GP. CONCLUSION: This proposed combination seems to be safe and effective (Tab. 8, Fig. 2, Ref. 24). Full Text (Free, PDF) www.bmj.sk. PMID- 17694804 TI - Video-assisted thoracoscopic surgery for spontaneous pneumothorax in children-our experience. AB - The aim of this case report was to analyse the efficiency of video-assisted thoracic surgery (VATS) in the treatment of spontaneous pneumothorax. Spontaneous pneumothorax occurs subsequently to a disruption of visceral pleura and escape of air into pleural space. A retrospective study was performed in 5 patients from December 2001 until May 2006. Four procedures for recurrent spontaneous pneumothorax and one procedure for primary spontaneous pneumothorax were performed. The main symptoms in our patients included chest pain (100%), shortness of breath (60%) and cough (10%) In all patients we made routine X-rays and CT scans. With CT scans in four patients we detected apical bullae. In one patient we had not appropriate diagnosis and we made VATS as diagnostic and later therapeutic procedure. In all patients bullae were in apical zone and resected with endostapler device. There was no postoperative mortality or any complications after VATS. The median duration of the operation was 75 minutes (65 120 minutes), and postoperative hospital stay was 6 days (range 5 to 8 days). On the basis of our results and results from literature we conclude that VATS allows effective, safe performance of standard surgical procedures, avoiding a formal thoracotomy incision (Ref. 15). Full Text (Free, PDF) www.bmj.sk. PMID- 17694805 TI - Neuropsychological outcome in children with hypoplastic left heart syndrome. AB - OBJECTIVES: The purpose of this study is to review a single-institutional experience gained over one decade, to assess late neuropsychological outcome in patients as well as to determine Norwood operation risk factors that are related to patient and procedure and influence these results. BACKGROUND: The reports of first successful staged operation of hypoplastic left heart syndrome (HLHS) and its numerous modifications have improved the early survival also in patients with complex forms. Specifically, the identification of other specific risk factors related to patient or procedure in the first stage of palliation for HLHS may play a role in cognitive deficit. METHODS: Single-institutional, cross-sectional study of neurodevelopmental outcome. The mean age at testing was 6.9 +/- 0.3 years. There were 19 patients enrolled with completed psychological testing Standford-Binet test. RESULTS: The mean neurocognitive results were significantly below the population normative values. The mean full-scale IQ for the entire cohort was 84.1 +/- 8.2. The predictive factors are strongly associated with severe metabolic acidosis, low birth weight, hospital stay over 35 days, prolonged duration of DHA and aortic valve diameter playing an important role in the subsequent psychological outcome, especially in differential subsections of IQ scale (Tab. 2, Ref. 15). Full Text (Free, PDF) www.bmj.sk. PMID- 17694806 TI - The prevalence of female obesity in the world and in the Slovak Gypsy women. AB - OBJECTIVES: Paper is focused (1) on the comparison of some parameters (body height, body weight, blood pressure, BMI values) in Gypsy and non-Gypsy women from eastern and western Slovakia; (2) on the comparison of biochemical parameters in the Gypsy minority and majority of western Slovakia. BACKGROUND: There is not enough of available reliable data on health status of Slovak Gypsy minority. METHODS: Gypsy and non-Gypsy women (57 and 56 subjects) from the western region of Slovakia (Zlate Klasy, Gbely) as well as Gypsy and non-Gypsy women (393 and 444 subjects) from the eastern region of Slovakia (Presov region) were investigated. Values of body height, body weight, blood pressure and calculated values of BMI (body mass index) were performed. Biochemical parameters of 269 Gypsies and 346 non-Gypsy persons from western Slovakia were measured. The statistically significant cut-off point was p < 0.05. RESULTS: In all age groups, the BMI values of Gypsy women were higher than those of non-Gypsy women. The occurrence of obesity, overweight, and hypertension was higher in the Gypsy population from both eastern and western regions of Slovakia. In the group of Gypsy minority of western Slovakia, the parameters of metabolic syndrome (dyslipidemia--high concentrations of triglycerides, low concentrations of HDL cholesterol, high concentrations of fasting insulin, and high values of insulin resistance) were found to be significantly changed. CONCLUSION: These findings suggest that the risk of atherogenesis in Gypsy minority has considerably increased and this is caused by unfavourable factors such as an increase in the prevalence of obesity, hypertension, smoking and the deficiency in protective substances leading to dyslipidemia, hyperinsulinemia, cardiovascular diseases, metabolic syndrome and diabetes (Fig. 2, Tab. 4, Ref 10). Full Text (Free, PDF) www.bmj.sk. PMID- 17694807 TI - Some indicators of quality of life in senior age in two regions international comparative study--the Czech Republic and the Slovak Republic. AB - Some characteristics of quality and way of life were examined in the group of persons aged over 60 years. One group was in the West region of the Czech Republic--1028 people living in the city of Plzen. The other group was in the East region of Slovakia--125 senior citizens from the town of Presov. The investigations were carried out in general practitioners' offices in 2005/2006. The groups consisted of patients visiting GPs. The reason of their visits was usually a general check of their health state and prescription of medications. An anonymous questionnaire was used. Students of medicine asked the respondents. They tried to find out some characteristics of seniors* life style and other aspects of seniors' life determining the quality of life. Diet, free time activities, physical activity, way of life, including smoking and alcohol consumption were investigated. Some questions were aimed on the respondents opinion about their way of life, their worries and wishes (Tab. 11, Ref. 10). Full Text (Free, PDF) www.bmj.sk. PMID- 17694808 TI - Current multidisciplinary treatment of gastric cancer. AB - The aim of our study was to optimise current therapy of gastric tumours. The studied population consisted of 92 patients treated at the 1st Department of Surgery, St. Anne's Teaching Hospital, Brno, Czech Republic, and at the Department of Radiation Oncology of the same hospital during 1994-2000. We have proven that, nowadays, a radical surgical procedure still remains the best method used for the treatment of malignant illnesses of the stomach. Results from clinical studies show that preoperative chemotherapy is effective and that postponed surgical therapy has no impact on survival (Fig. 4, Ref. 21). Full Text (Free, PDF) www.bmj.sk. PMID- 17694809 TI - Infra red photocoagulation of early grades of hemorrhoids--5-year follow-up study. AB - BACKGROUND: Infra-red photocoagulation is used as an instrumental treatment for bleeding hemorrhoids. During this procedure the tissue is coagulated by infrared radiation. For treatment, mechanical pressure and radiation energy are applied simultaneously to ablate the blood supply to the hemorrhoidal mass. MATERIAL AND METHOD: This study describes the results of infrared photocoagulation of Grade I and II bleeding hemorrhoids with 5-year follow-up. RESULTS: 300 patients treated by infrared coagulation were followed up for a period of 60 months. 39 patients had persistence or recurrence of bleeding. Other post procedure complaints included post defecation discomfort, pruritus and discharge per anus. No patient had any septic or infective complication. CONCLUSION: This retrospective study shows that infra red coagulation for hemorrhoids in early stages could be an easy and effective alternative to conventional methods as it is quick, painless and safe. The procedure can be repeated in case of recurrence and should be considered as an alternative to conventional treatment in hemorrhoids (Ref. 30). Full Text (Free, PDF) www.bmj.sk. PMID- 17694810 TI - Health care in patients with primary Sjogren's syndrome. AB - The aim of the present study was to define more accurately the necessary health care in patients with the primary Sjogren's syndrome and to compare it to those necessary for patients with another autoimmune disease--rheumatoid arthritis without a concomitant Sjogren's syndrome (Tab. 1, Ref. 5). Full Text (Free, PDF) www.bmj.sk. PMID- 17694811 TI - The rare benign liver tumors. AB - As opposed to malignant secondary tumors, metastases of the colorectal carcinoma are benign tumors of the liver that are quite rare in the Czech Republic. From the 55 patients operated on since 2000 at our department for benign liver tumors, the most frequent are haemangiomas, focal nodular hyperplasia (FNH) and hepatocelular adenoma. Only 7.3% of them form a different histological type of a tumor than this most frequently occurring trio of tumors. The authors describe three cases of rather rare liver tumors with benign behavior that have the potential of becoming malignant. It concerns mucin producing biliary tumors, which correspond to the pancreatic intraductal papillary mucin tumor, hepatic cystadenoma with ovarian stroma and a liver hamartoma in an adult patient (Ref 13). Full Text (Free, PDF) www.bmj.sk. PMID- 17694812 TI - Seemingly or partially negative prefixes in medical English. AB - In this article we will try to find out if the prefixes anti-, contra-, counter-, de-, dys-, ex-, extra-, mal- can negate the words they combine with (Ref. 9). Full Text (Free, PDF) www.bmj.sk. PMID- 17694813 TI - [Study of the impact of intramyocardial implantation of stem cells on myocardial perfusion and contractility in patients with coronary heart disease concurrent with postinfarct cardiosclerosis and chronic heart failure]. AB - OBJECTIVE: to study of intramyocardial implantation of cultured bone marrow stem cells on myocardial perfusion and contractility in the surgical treatment of patients with coronary heart disease (CHD) and chronic heart failure (CHF), by synchronized single-photon emission computed tomography (SSPECT) of the myocardium. SUBJECTS AND METHODS: The study included 11 patients. Intramyocardial injection of cell injections into the myocardial periscarring areas was made at coronary bypass surgery. All the patients underwent 99mTc myocardial SSPECT MIBI before and 3, 6, 12 months after surgery. RESULTS AND CONCLUSIONS: Implantation of bone marrow stem cells into the left ventricular myocardium favorably affects left ventricular remodeling and contributes to the improvement of myocardial perfusion and contractility, as evidenced by 99mTc. PMID- 17694814 TI - [Topographic anatomic features of radiocarpal joints and carpal articulations]. AB - Ultrasound study of the musculoskeletal system has become one of the new areas in the development of echography. This radiation diagnostic technique allows evaluation of the status of soft tissue and cartilaginous components of the joint with a high precision. Knowledge of the echoanatomy of upper limb diarthrosis makes it possible to detect abnormalitles in due time and to specify their nature. PMID- 17694815 TI - [Gastric and intestinal scintigraphy in the complex diagnosis of small bowel obstruction]. AB - An algorithm has been developed for radiation diagnosis of small bowel obstruction, which involves abdominal X-ray and ultrasound studies at the first stage and radionuclide evaluation of gastrointestinal transit, by using 100-150 ml of aqueous 99mTc-technefite or 99mTc-bromeside solution in a dose of 50-100 MBq (radiation load 0.7-1.4 MeV) per os. The sensitivity, specificity, and diagnostic efficiency of the whole radiation diagnostic complex and each procedure separately were determined by the results of examination in 180 patients with suspected small bowel obstruction, of whom 104 patients were operated on, but obstruction ceased during medical treatment. Inclusion of the radionuclide technique into the diagnostic complex involving plain radiography and ultrasonography was shown to enhance diagnostic efficiency up to 97-98%. PMID- 17694816 TI - [Controversial points of estimation of the thickness of the anterior wall of the pregnant uterus]. AB - OBJECTIVE: to study reasons for the discrepancy between clinical and echographic estimates of the thickness of the pregnant uterine wall during cesarean section. MATERIALS AND METHODS: 175 labors running physiologically, during labor induction and delivery stimulation and 22 cases of late abortions (19-27-week gestation) when clinically indicated, were studied. RESULTS: while incising the anterior uterine wall during planned cesarean section, practitioners noted its thickness to be about 2 cm or more. Ultrasonography showed that the thickness was 5.5-8.5 cm. The reason for this discrepancy was the development of traumatic local hypertone at the moment of dissection of the anterior uterine wall. CONCLUSIONS: the different estimation of the myometrial thickness is associated not only with methodological differences (clinical and echographic), but also with the physiological features of the uterus as a muscular organ that is able to rapidly alter its thickness during labor pains and its traumatization during cesarean section or amniocentesis. PMID- 17694817 TI - [Late color duplex scanning diagnosis of the areas of endovascular intervention into arteries and lower extremity shunts]. AB - The purpose of the study was to assess the areas of balloon angioplasty (BAP) and stenting of lower extremity arteries and femoral, popliteal, mainly, in situ autovenous shunts, by using color duplex scanning (CDS) in the late period of a follow-up. Materials and methods. The CDS technique could diagnose 344 (64%) areas of BAP and stenting of lower extremity arteries and shunts. The echosemiotics of complications typical of a late period was determined. Based on the specified echosemiotics of late complications, the author detected 99 (28.8%) cases of hemodynamically significant complications: BAP and stenting area stenosis (n=25 (7.3%)); BAP area restenosis (reocciusion) (n=33 (9.6%)); stent restenosis (n=19 (5.5%), arterial stenosis proximal and distal to a stent (n=17 4.9%)), and stent breakage (n=5 (1.5%)). Hemodynamically insignificant complications were revealed in 90 (26.2%) cases: intimal dissection in 16 (4.7%) cases, BAP area restenosis in 35 (10%), stent restenosis in 15 (4.4%), and arterial stenosis proximal or distal to the stent and between the stents. In the late period following BAP and stenting aortoiliac patency was 87.50 + 3.18% during a mean follow-up o 27.58 + 1.50 months. In the late period, the patency of the superficial femoral artery (SFR) was 55.41 + 14.43% during a mean follow-up of 22.60 + 2.73 months, that of the popliteal artery (PA) was 67.34 + 15.98% during a mean follow-up of 43.08 + 5.81 months, that of shin arteries was 44.96 + 19.77% during a mean follow-up of 18.76 + 2.58 months, and that of shunts, was 40.89 + 18.47% during a mean follow-up of 23.32 + 2.29 months. Thus, changes caused by the progression of the underlying disease--atherosclerosis were found in the areas of BAP and stenting of lower extremity arteries and shunts. Stent breakage may be due to "metal deterioration" and the presence of a stent in the superficial femoral artery with greatest functional load on extremity movement and flexion. The blood flow spectrum mode recording a local hemodynamic shift with > 2.0-2.5-fold linear blood flow velocity increase in the complication area was leading in the operation of an ultrasound apparatuses in the differential diagnosis of hemodynamically significant and insignificant complications. The results of good late patency of the areas of BAP and stentming of SFR and PA may be accounted for by strict criteria for selecting patients for endovascular surgery, by taking into account the indications for and contraindications to TASC (2001). In our study, 20 endovascular reinterventions (repeated balloon angioplasty, additional stenting stent balloon angioplasty) in complicated areas were performed, which maintained and prolonged the function of segments. The detection of hemodynamically insignificant complications revealed patients who need further meticulous follow-up ultrasound studies. PMID- 17694818 TI - [Radiation diagnosis for tuberculous gonitis in children]. AB - Tuberculous knee joint lesion in children is the most common form of articular pathology. The high sociomedical significance of this disease in modern society is determined by not only its prevalence, but also economic losses caused by high disability rates in children. The purpose of the study was to determine the possibilities and place of a comprehensive radiation study in the diagnosis of tuberculous gonitis in children. Sixty patients aged 10 months to 18 years were examined. Clinical studies were comprehensively assessed, by taking into account the collected history data and orhthopedic and laboratory findings. Surgery was made in 26 children. All the patients underwent mutiprojection X-ray study, knee joint ultrasound study being made in 48 patients. Knee joint X-ray study was performed on Siregraph (Siemens) apparatuses. Real-time ultrasonography was conducted on Aloka SSD-1100 and Aloka--3500+ apparatuses, by employing a 7.5-MHz linear transducer. According to P.G. Kornev (1971), three phases were identified in the course of tuberculous gonitis. These included prearthritic (the development of primary ostitis); arthritic (articular cartilage destruction, followed by the development of secondary arthritis; and postarthritic (sequels of prior tuberculous osteomyelitis) phases. Analysis indicated that the use of the routine X-ray study in combination with ultrasound scanning in the diagnosis of tuberculous gonitis in children yielded more adequate information on tissue and knee joint structural changes and made it possible to define further policy treatment and to predict the outcomes of the disease. PMID- 17694819 TI - [Characteristics of three-dimensional surgical correction of scoliotic deformity, as evidenced by x-ray studies]. PMID- 17694820 TI - [Radiation diagnostic studies and their efficiency in closed injury of the lower cervical spine]. PMID- 17694821 TI - [Theories of the pathogenesis of adverse reactions caused by x-ray contrast agents]. PMID- 17694822 TI - Necrotizing Pseudomonas infection of the ocular adnexa in an infant with leukocyte adhesion defect. PMID- 17694823 TI - Symptomatic convergence insufficiency. Interview by Leonard B. Nelson. PMID- 17694824 TI - What's your diagnosis? Sporadic oculocutaneous albinism associated with Chen's iridal rings (secondary to equatorial lenticular shadows). PMID- 17694825 TI - Molecular genetics for the pediatric ophthalmologist. AB - The field of molecular genetics is evolving to encompass techniques that are directly relevant to the diagnosis and management of eye disease. Therefore, pediatric ophthalmologists must have a knowledge base that includes basic genetic concepts and their application to current clinical care. PMID- 17694826 TI - Effect of central corneal thickness and radius of the corneal curvature on intraocular pressure measured with the Tono-Pen and noncontact tonometer in healthy schoolchildren. AB - PURPOSE: To determine the effect of central corneal thickness and radius of the corneal curvature on intraocular pressure (IOP) measurements using the Tono-Pen and a noncontact tonometer in healthy Turkish schoolchildren. SUBJECTS AND METHODS: IOP was measured with the Tono-Pen and a noncontact tonometer in 602 eyes of 602 healthy schoolchildren with a mean age of 10.1 +/- 1.6 years. Central corneal thickness was measured using an ultrasonic pachymeter after all IOP determinations had been made. The effect of central corneal thickness, radius of the corneal curvature, and sex on measured IOP was explored by linear regression analysis. RESULTS: The mean central corneal thickness was found to be 564.92 +/- 32 microm. The mean IOP readings were 17.9 +/- 2 mm Hg using the Tono-Pen, and 16.7 +/- 2 mm Hg using a noncontact tonometer. The Tono-Pen measured IOP values slightly greater than the noncontact tonometer (P < .0001). A significant association between measured IOP and central corneal thickness was found with each device. The IOP increased 2.1 and 4.2 mm Hg with every 100-microm increase in central corneal thickness for the Tono-Pen and the noncontact tonometer, respectively. The dependence of IOP on central corneal thickness did not differ between boys and girls. There was a significant association between the Tono-Pen and noncontact tonometer differences and central corneal thickness; the noncontact tonometer tended to overestimate IOP in eyes with thicker corneas. CONCLUSIONS: The Tono-Pen readings appeared to be less affected by corneal thickness than those of the noncontact tonometer. The corneal radius of curvature had no significant effect on measured IOP with each device. Because the Tono-Pen was relatively easy to use and less affected by corneal thickness, it may be an alternative method for measuring IOP in children. PMID- 17694827 TI - Rarebit perimetry and optic disk topography in pediatric glaucoma. AB - PURPOSE: To determine the relationship between visual field and optic nerve topography findings in a cohort of children with pediatric glaucoma and an age matched and sex-matched control SUBJECTS AND METHODS: Fifteen children, aged 6 to 15 years, with pediatric glaucoma in at least one eye and 15 age-matched and sex matched healthy children were examined with best-corrected visual acuity and perimetry. When possible, scanning laser topography of the optic disk (ie, Heidelberg retinal tomography) was performed. RESULTS: Of 27 eyes in 15 children with pediatric glaucoma examined with Goldmann perimetry, 15 eyes (55%) had a normal visual field. Of 24 eyes examined with Rarebit perimetry, 8 eyes (33%) showed normal results and 16 eyes (67%) showed an abnormally low hit rate (ie, the fraction of seen targets vs presented targets). Nine of the 15 eyes showing normal Goldmann visual fields had a subnormal Rarebit hit rate. All children in the control group had normal Rarebit visual fields. Heidelberg retinal tomography could be performed in all healthy children and in 22 eyes of 13 children with pediatric glaucoma. The concordance between the Heidelberg retinal tomography classification (ie, normal or glaucoma) and the Rarebit results was high (Cohen's kappa = 0.79). A statistically significant correlation (r = 0.66, P = .006) between Rarebit hit rate and Heidelberg retinal tomography glaucoma index was found in the glaucoma group. CONCLUSIONS: Rarebit perimetry detected glaucomatous damage in various types of pediatric glaucoma, and can be assumed to be of value in both diagnosis and follow-up. In 13 children with glaucoma, Heidelberg retinal tomography could be performed. The results conformed well to Rarebit findings. PMID- 17694828 TI - Causes of visual impairment in children: a study of 3,210 cases. AB - PURPOSE: To determine causes of visual impairment in children at the Low Vision Service of the Ophthalmic Clinic at the University of Sao Paulo and at the Brazilian Association for the Visually Impaired People (Laramara), located in Sao Paulo, Brazil. PATIENTS AND METHODS: This study evaluated 3,210 visually impaired children (49% female, 51% male; average age, 5.9 years). Visual impairment was present in 57% (visually impaired group) and 43% presented another associated disability (multiple disability group). RESULTS: The main causes of visual impairment in the visually impaired group were toxoplasmic macular retinochoroiditis (20.7%), retinal dystrophies (12.2%), retinopathy of prematurity (11.8%), ocular malformation (11.6%), congenital glaucoma (10.8%), optic atrophy (9.7%), and congenital cataracts (7.1%). The main causes of visual impairment in the multiple disability group were optic atrophy (37.7%), cortical visual impairment (19.7%), toxoplasmic macular retinochoroiditis (8.6%), retinopathy of prematurity (7.6%), ocular malformation (6.8%), congenital cataracts (6.1%), and degenerative disorders of the retina and macula (4.8%). The retina was the most frequently affected anatomic site in the visually impaired group (49.2%) and the optic nerve in the multiple disability group (39%). CONCLUSION: Primary, secondary, and tertiary prevention efforts for childhood blindness and visual rehabilitation must be considered in Latin America. PMID- 17694829 TI - Free-floating unilateral pigmented vitreous cyst in a child. AB - Free-floating vitreous cysts have been ocular curiosities, especially in children. Various etiologies have been proposed. Most of these cysts are asymptomatic except for subtle symptoms of visual floaters. When the visual axis is obscured, treatment options include surgery and laser treatment. We report a case of a unilateral pigmented vitreous cyst in a child. PMID- 17694830 TI - An unusual cause of acute bilateral optic disk swelling with macular star in a 9 year-old girl. AB - We report a rare case of bilateral optic disk swelling with macular exudates and cottonwool spots secondary to a pheochromocytoma in a 9-year-old girl. Malignant hypertensive changes in the eyes are uncommon and may sometimes resemble neuroretinitis. Overaggressive treatment of malignant hypertension can cause optic nerve infarction, leading to blindness. PMID- 17694831 TI - Use of the ex-press miniature glaucoma implant in a child with Sturge-Weber syndrome. AB - A two-stage antiglaucoma operation was planned for the left eye of an 11-year-old boy with bilateral Sturge-Weber syndrome to avoid intraoperative and postoperative choroidal and retinal effusion as with previous trabeculectomy. The Ex-Press miniature glaucoma implant was placed 10 days before trabeculectomy with mitomycin C. There were no complications with either procedure. PMID- 17694832 TI - Visual manifestations of craniofrontonasal dysplasia. AB - In this sample of craniofrontonasal dysplasia, a 44.4% prevalence of visual impairment was observed, with more than half being due to potentially correctable causes of visual loss, including amblyopia and anisometropia. High prevalences of strabismus (88.9%) and V-pattern (55.5%) in craniofrontonasal dysplasia were also demonstrated. All three patients who underwent strabismus surgery showed improvement in ocular alignment postoperatively. This group needs regular eye examinations to assess for visual impairment and provide timely intervention for modifiable causes of visual loss. PMID- 17694833 TI - Corneal blood staining after traumatic hyphema. PMID- 17694834 TI - Long time follow up of implant therapy and treatment of peri-implantitis. AB - Dental implants have become an often used alternative to replace missing teeth, resulting in an increasing percentage of the adult population with implant supported prosthesis. Although favourable long-term results of implant therapy have been reported, infections occur. Until recently few reports included data on peri-implant infections, possibly underestimating this complication of implant treatment. It is possible that some infections around implants develop slowly and that with time peri-implantitis will be a common complication to implant therapy as an increasing number of patients have had their implants for a long time (>10 years). Data on treatment of peri-implant lesions are scarce leaving the clinician with limited guidance regarding choice of treatment. The aim of this thesis was to study the frequency of implant loss and presence of peri-implant lesions in a group of patients supplied with Branemark implants 9-14 years ago, and to relate these events to patient and site specific characteristics. Moreover three surgical treatment modalities for peri-implantitis were evaluated. The thesis is based on six studies; Studies I-III included 218 patients and 1057 implants followed for 9-14 years evaluating prevalence of, and factors related to implant loss (Paper I) and prevalence of peri-implant infections and related factors (Paper I-III). Study IV is a review describing different treatment modalities of peri-implant infections. Study V is a prospective cohort study involving 36 patients and 65 implants, evaluating the use of a bone substitute with or without the use of a resorbable membrane. Study VI is a case series with 12 patients and 16 implants, evaluating a bone substitute in combination with a resorbable membrane and submerged healing. This thesis demonstrated that: After 9 14 years the survival rates of dental implants are high (95.7%). Implant loss seems to cluster within patients and are related to periodontitis evidenced as bone loss on radiographs at remaining teeth before implant placement. (Paper I) Peri-implantitis is a common clinical entity after 9-14 years. (Paper II) Using the implant as the statistical unit the level of keratinized mucosa and pus were explanatory for a bone level at > or =3 threads (1.8 mm). When the patient was used as a statistical unit a history of periodontitis and smoking were explanatory for peri-implantitis. (Paper III) Animal research has demonstrated that re-osseointegration can occur. The majority of human studies were found to be case reports. Using submerged healing and bone transplants, bone fill can occur in peri-implant defects. (Paper IV) Surgical treatment of peri-implantitis using a bone substitute with or without a resorbable membrane resulted in similar pocket depth reduction, attachment gain and defect fill. (Paper V) Bone substitute in combination with a resorbable membrane and a submerged healing resulted in defect fill > or =2 threads (1.2 mm) in 81% of the implants. (Paper VI) In conclusion: 9-14 years after implant installation peri-implant lesions are a common clinical entity. Smokers and patients with a history of periodontal disease are at higher risk to develop peri-implantitis. Clinical improvements and defect fill can be obtained with various surgical techniques using a bone substitute. PMID- 17694835 TI - The importance of screening for intimate partner violence (IPV). PMID- 17694837 TI - Overview of emergency medical services in North Carolina. PMID- 17694836 TI - Awareness of the bicycle helmet law in North Carolina. AB - BACKGROUND: One in 3 bicyclists killed in North Carolina is under the age of 16. Since enactment of a mandatory bicycle helmet law for children in 2001, there has been no observed increase in helmet use in North Carolina. The goal of this study was to assess perceptions of helmet effectiveness and the level ofawareness of the North Carolina bicycle helmet law. METHODS: A written survey was distributed to parents, physicians, teachers, and emergency medical services (EMS) personnel throughout Pitt County, North Carolina, to ask their knowledge of the bicycle helmet law, the frequency of their helmet use, their perceptions of the effectiveness of helmets, their opinions of who should be providing education about bicycle helmets, and their knowledge ofpr oper bicycle helmet use. RESULTS: The survey response rate was 72% (n=43). Seventy-five percent of teachers and EMS personnel, 69% ofparents, and 580% of physicians were aware of the North Carolina helmet law. Nineteen percent of parents responded that their children wore helmets "always", 1% answered "often", and 18% answered "never". The effectiveness of helmets in preventing head injuries was underestimated by many respondents with 49% estimating 50%-75% effectiveness. LIMITATIONS: This survey was distributed only in Pitt County and does not reflect helmet awareness for the state as a whole. CONCLUSIONS: The majority ofparents, teachers, physicians, and EMS personnel in Pitt County, North Carolina, are aware of the mandatory bicycle helmet law for children. Enforcement of and education about the bicycle helmet law should be increased . PMID- 17694838 TI - Emergency medical services legislation in North Carolina. PMID- 17694839 TI - Federal policy leading the way in emergency medical services. PMID- 17694841 TI - Research and evaluation in out-of-hospital emergency medical services. PMID- 17694840 TI - Recalling the birth of emergency medical services in North Carolina. PMID- 17694842 TI - Emergency medical services education: past, present, and future. PMID- 17694843 TI - Responding to the educational needs of our emergency medical services responders. PMID- 17694844 TI - Baccalaureate emergency medical services education in North Carolina: history, challenges, and opportunities. PMID- 17694845 TI - Management and financing of emergency medical services. PMID- 17694846 TI - Service integration and workforce trends in emergency medical services. PMID- 17694847 TI - Emergency medical services information systems. AB - The future of EMS and the U.S. health care system is dependent on interactive, real-time data systems that can be used to design, develop, implement, evaluate, and maintain quality evidence-based systems of care. North Carolina is a national and international leader in EMS given its support of the PreMIS System, the EMS Toolkit Project, EMS Bioterrorism Surveillance, and participation in the National EMS Database. PMID- 17694848 TI - Medical oversight for emergency medical services: defining success. PMID- 17694849 TI - Paramedic endotracheal intubation. PMID- 17694850 TI - Emergency preparedness in North Carolina: leading the way. PMID- 17694851 TI - Emergency medical communication in North Carolina: past, present, and future challenges. AB - Ifthe best equipped ambulance arrives unannounced at the emergency room door and the hospital is unprepared for the arrival, the system has broken down and patients can be lost because of it. There must be good reliable communications between the person reporting the accident, the dispatcher of the appropriate vehicle and personnel, the police and fire departments (when called for), the hospital emergency department, the medical specialists available to the hospital and those bigger hospitals (trauma centers) to which the patient might in some cases be sent directly. PMID- 17694852 TI - The future of emergency medical services communications systems: time for a change. PMID- 17694853 TI - Spotlight on the safety net. Mecklenburg Emergency Medical Services Agency. AB - Mecklenburg Emergency Medical Services Agency, better known as Medic, provides emergency and nonemergency paramedic level medical services to the citizens of Mecklenburg County. Medic is part of a unique partnership between Mecklenburg County, Carolinas HealthCare System, and Presbyterian Health Care/Novant Health. Since fiscal year 1997, Medic has reduced ambulance response times, implemented higher clinical standards, and reduced the taxpayer subsidy per call by half The agency will answer more than 85,000 calls for medical help this year. Medic also conducts frequent community education programs on health, safety, injury prevention, and emergency-related issues. PMID- 17694854 TI - Running the numbers. North Carolina Emergency Department visit data available for public health surveillance. PMID- 17694855 TI - Scotland Memorial Hospital Emergency Center improvements. PMID- 17694856 TI - Modelling fibrillation potentials--analysis of time parameters in the muscle intracellular action potential. AB - A single fiber action potential (SFAP) can be modelled as the convolution of a biolectrical source and a filter impulse response. In the Dimitrov-Dimitrova (D D) convolutional model, the first temporal derivative of the intracellular action potential (IAP) is used as the source, and Tspl is a time parameter related to the duration of the IAP waveform. This paper is centred on the relation between Tspl and the main spike duration (MSD), defined as the time interval between the first and third phases of the SFAP. We show that Tspl essentially determines the MSD parameter. As experimental data, we used fibrillation potentials (FPs) of two different muscles to study the D-D model. We found that Tspl should have a certain statistical variability in order to explain the variability in the MSD of our FPs. In addition, we present a method to estimate the Tspl values corresponding to a given SFAP from its measured MSD. PMID- 17694857 TI - Estimation of the hemodynamic response of fMRI Data using RBF neural network. AB - Functional magnetic resonance imaging (fMRI) is an important technique for neuroimaging. The conventional system identification methods used in fMRI data analysis assume a linear time-invariant system with the impulse response described by the hemodynamic responses (HDR). However, the measured blood oxygenation level-dependent (BOLD) signals to a particular processing task (for example, rapid event-related fMRI design) show nonlinear properties and vary with different brain regions and subjects. In this paper, radial basis function (RBF) neural network (a powerful technique for modelling nonlinearities) is proposed to model the dynamics underlying the fMRI data. The equivalence of the proposed method to the existing Volterra series method has been demonstrated. It is shown that the first- and second-order Volterra kernels could be deduced from the parameters of the RBF neural network. Studies on both simulated (using Balloon model) as well as real event-related fMRI data show that the proposed method can accurately estimate the HDR of the brain and capture the variations of the HDRs as a function of the brain regions and subjects. PMID- 17694858 TI - Expanding the bioheat equation to include tissue internal water evaporation during heating. AB - We propose a new method to study high temperature tissue ablation using an expanded bioheat diffusion equation. An extra term added to the bioheat equation is combined with the specific heat into an effective (temperature dependent) specific heat. It replaces the normal specific heat term in the modified bioheat equation, which can then be used at temperatures where water evaporation is expected to occur. This new equation is used to numerically simulate the microwave ablation of bovine liver and is compared to experimental ex vivo results. PMID- 17694859 TI - Predictions of psychophysical measurements for sinusoidal amplitude modulated (SAM) pulse-train stimuli from a stochastic model. AB - Two approaches have been proposed to reduce the synchrony of the neural response to electrical stimuli in cochlear implants. One approach involves adding noise to the pulse-train stimulus, and the other is based on using a high-rate pulse-train carrier. Hypotheses regarding the efficacy of the two approaches can be tested using computational models of neural responsiveness prior to time-intensive psychophysical studies. In our previous work, we have used such models to examine the effects of noise on several psychophysical measures important to speech recognition. However, to date there has been no parallel analytic solution investigating the neural response to the high-rate pulse-train stimuli and their effect on psychophysical measures. This work investigates the properties of the neural response to high-rate pulse-train stimuli with amplitude modulated envelopes using a stochastic auditory nerve model. The statistics governing the neural response to each pulse are derived using a recursive method. The agreement between the theoretical predictions and model simulations is demonstrated for sinusoidal amplitude modulated (SAM) high rate pulse-train stimuli. With our approach, predicting the neural response in modern implant devices becomes tractable. Psychophysical measurements are also predicted using the stochastic auditory nerve model for SAM high-rate pulse-train stimuli. Changes in dynamic range (DR) and intensity discrimination are compared with that observed for noise modulated pulse-train stimuli. Modulation frequency discrimination is also studied as a function of stimulus level and pulse rate. Results suggest that high rate carriers may positively impact such psychophysical measures. PMID- 17694860 TI - Noninvasive ECG as a tool for predicting termination of paroxysmal atrial fibrillation. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia and entails an increased risk of thromboembolic events. Prediction of the termination of an AF episode, based on noninvasive techniques, can benefit patients, doctors and health systems. The method described in this paper is based on two-lead surface electrocardiograms (ECGs): 1-min ECG recordings of AF episodes including N-type (not terminating within an hour after the end of the record), S-type (terminating 1 min after the end of the record) and T-type (terminating immediately after the end of the record). These records are organised into three learning sets (N, S and T) and two test sets (A and B). Starting from these ECGs, the atrial and ventricular activities were separated using beat classification and class averaged beat subtraction, followed by the evaluation of seven parameters representing atrial or ventricular activity. Stepwise discriminant analysis selected the set including dominant atrial frequency (DAF, index of atrial activity) and average HR (HRmean, index of ventricular activity) as optimal for discrimination between N/T-type episodes. The linear classifier, estimated on the 20 cases of the N and T learning sets, provided a performance of 90% on the 30 cases of a test set for the N/T-type discrimination. The same classifier led to correct classification in 89% of the 46 cases for N/S-type discrimination. The method has shown good results and seems to be suitable for clinical application, although a larger dataset would be very useful for improvement and validation of the algorithms and the development of an earlier predictor of paroxysmal AF spontaneous termination time. PMID- 17694861 TI - Characterization of interdependency between intracranial pressure and heart variability signals: a causal spectral measure and a generalized synchronization measure. AB - Causal coherence and generalized synchronization (GS) index were extracted from beat-to-beat mean intracranial pressure (ICP) and intervals between consecutive normal sinus heart beats (RR interval) that were recorded from 12 patients undergoing normal pressure hydrocephalus diagnosis. Data were organized into two groups including an ICP B-Wave group and a baseline control group. Maximal classic coherence (CC) between ICP and RR interval within [0.04, 0.15] Hz was found to be significantly greater than zero for both B-Wave and control groups with B-Wave CC greater than that of the baseline group. Causal coherence analysis further revealed that feedforward coherence due to RR interval's effect on ICP always exists for both B-Wave and baseline ICP state and no significant difference exists between two groups. On the other hand, feedback coherence from ICP to RR interval was enhanced during the occurrence of B-Wave. This finding regarding the enhanced directional, from ICP to RR interval, coupling between ICP and RR interval was also confirmed by a modified GS measure. PMID- 17694862 TI - Contact-free measurement of cardiac pulse based on the analysis of thermal imagery. AB - We have developed a novel method to measure human cardiac pulse at a distance. It is based on the information contained in the thermal signal emitted from major superficial vessels. This signal is acquired through a highly sensitive thermal imaging system. Temperature on the vessel is modulated by pulsative blood flow. To compute the frequency of modulation (pulse), we extract a line-based region along the vessel. Then, we apply fast Fourier transform (FFT) to individual points along this line of interest to capitalize on the pulse's thermal propagation effect. Finally, we use an adaptive estimation function on the average FFT outcome to quantify the pulse. We have carried out experiments on a data set of 34 subjects and compared the pulse computed from our thermal signal analysis method to concomitant ground-truth measurements obtained through a standard contact sensor (piezo-electric transducer). The performance of the new method ranges from 88.52% to 90.33% depending on the clarity of the vessel's thermal imprint. To the best of our knowledge, it is the first time that cardiac pulse has been measured several feet away from a subject with passive means. PMID- 17694863 TI - Automatic identification of retinal arteries and veins from dual-wavelength images using structural and functional features. AB - This paper presents an automated method to identify arteries and veins in dual wavelength retinal fundus images recorded at 570 and 600 nm. Dual-wavelength imaging provides both structural and functional features that can be exploited for identification. The processing begins with automated tracing of the vessels from the 570-nm image. The 600-nm image is registered to this image, and structural and functional features are computed for each vessel segment. We use the relative strength of the vessel central reflex as the structural feature. The central reflex phenomenon, caused by light reflection from vessel surfaces that are parallel to the incident light, is especially pronounced at longer wavelengths for arteries compared to veins. We use a dual-Gaussian to model the cross-sectional intensity profile of vessels. The model parameters are estimated using a robust M-estimator, and the relative strength of the central reflex is computed from these parameters. The functional feature exploits the fact that arterial blood is more oxygenated relative to that in veins. This motivates use of the ratio of the vessel optical densities (ODs) from images at oxygen sensitive and oxygen-insensitive wavelengths (ODR = OD600/OD570) as a functional indicator. Finally, the structural and functional features are combined in a classifier to identify the type of the vessel. We experimented with four different classifiers and the best result was given by a support vector machine (SVM) classifier. With the SVM classifier, the proposed algorithm achieved true positive rates of 97% for the arteries and 90% for the veins, when applied to a set of 251 vessel segments obtained from 25 dual wavelength images. The ability to identify the vessel type is useful in applications such as automated retinal vessel oximetry and automated analysis of vascular changes without manual intervention. PMID- 17694864 TI - Integrated analysis of vascular and nonvascular changes from color retinal fundus image sequences. AB - Algorithms are presented for integrated analysis of both vascular and nonvascular changes observed in longitudinal time-series of color retinal fundus images, extending our prior work. A Bayesian model selection algorithm that combines color change information, and image understanding systems outputs in a novel manner is used to analyze vascular changes such as increase/decrease in width, and disappearance/appearance of vessels, as well as nonvascular changes such as appearance/disappearance of different kinds of lesions. The overall system is robust to false changes due to inter-image and intra-image nonuniform illumination, imaging artifacts such as dust particles in the optical path, alignment errors and outliers in the training-data. An expert observer validated the algorithms on 54 regions selected from 34 image pairs. The regions were selected such that they represented diverse types of vascular changes of interest, as well as no-change regions. The algorithm achieved a sensitivity of 82% and a 9% false positive rate for vascular changes. For the nonvascular changes, 97% sensitivity and a 10% false positive rate are achieved. The combined system is intended for diverse applications including computer-assisted retinal screening, image-reading centers, quantitative monitoring of disease onset and progression, assessment of treatment efficacy, and scoring clinical trials. PMID- 17694865 TI - Geometry-adapted hexahedral meshes improve accuracy of finite-element-method based EEG source analysis. AB - Mesh generation in finite-element- (FE) method-based electroencephalography (EEG) source analysis generally influences greatly the accuracy of the results. It is thus important to determine a meshing strategy well adopted to achieve both acceptable accuracy for potential distributions and reasonable computation times and memory usage. In this paper, we propose to achieve this goal by smoothing regular hexahedral finite elements at material interfaces using a node-shift approach. We first present the underlying theory for two different techniques for modeling a current dipole in FE volume conductors, a subtraction and a direct potential method. We then evaluate regular and smoothed elements in a four-layer sphere model for both potential approaches and compare their accuracy. We finally compute and visualize potential distributions for a tangentially and a radially oriented source in the somatosensory cortex in regular and geometry-adapted three compartment hexahedra FE volume conductor models of the human head using both the subtraction and the direct potential method. On the average, node-shifting reduces both topography and magnitude errors by more than a factor of 2 for tangential and 1.5 for radial sources for both potential approaches. Nevertheless, node-shifting has to be carried out with caution for sources located within or close to irregular hexahedra, because especially for the subtraction method extreme deformations might lead to larger overall errors. With regard to realistic volume conductor modeling, node-shifted hexahedra should thus be used for the skin and skull compartments while we would not recommend deforming elements at the grey and white matter surfaces. PMID- 17694866 TI - Three-dimensional cardiac electrical imaging from intracavity recordings. AB - A novel approach is proposed to image 3-D cardiac electrical activity from intracavity electrical recordings with the aid of a catheter. The feasibility and performance were evaluated by computer simulation studies, where a 3-D cellular automaton heart model and a finite-element thorax volume conductor model were utilized. The finite-element method (FEM) was used to simulate the intracavity recordings induced by a single-site and dual-site pacing protocol. The 3-D ventricular activation sequences as well as the locations of the initial activation sites were inversely estimated by minimizing the dissimilarity between the intracavity potential "measurements" and the model-generated intracavity potentials. Under single-site pacing, the relative error (RE) between the true and estimated activation sequences was 0.03 +/- 0.01 and the localization error (LE) (of the initiation site) was 1.88 +/- 0.92 mm, as averaged over 12 pacing trials when considering 25 microV additive measurement noise using 64 catheter electrodes. Under dual-site pacing, the RE was 0.04 +/- 0.01 over 12 pacing trials and the LE over 24 initial pacing sites was 2.28 +/- 1.15 mm, when considering 25 microV additive measurement noise using 64 catheter electrodes. The proposed 3-D cardiac electrical imaging approach using intracavity electrical recordings was also tested under various simulated conditions and robust inverse solutions obtained. The present promising simulation results suggest the feasibility of obtaining 3-D information of cardiac electrical activity from intracavity recordings. The application of this inverse method has the potential of enhancing electrocardiographic mapping by catheters in electrophysiology laboratories, aiding cardiac resynchronization therapy, and other clinical applications. PMID- 17694867 TI - Reduction of artifacts induced by misaligned geometry in cone-beam CT. AB - The quality of computed tomography (CT) images frequently suffers from artifacts caused by scanner misalignments. In this paper, we discuss the results of our improved approximate cone-beam reconstruction formula, which corrects for the mechanical misalignment of the scanner. Based on the general filtered back projection (FBP) algorithm proposed by Feldkamp, the new formula reduces the artifacts in reconstructed images. Six parameters are employed to describe the scanner misalignment. Experimental results show that the images reconstructed by using the new formula are clearer than those reconstructed by using the general FBP algorithm in a misaligned system. Through the new formula, we have reduced the artifacts caused by misalignment. PMID- 17694868 TI - An automated system for 24-h monitoring of cough frequency: the leicester cough monitor. AB - The objective monitoring of cough for extended periods of time has long been recognized as an important step towards a better understanding of this symptom, and a better management of chronic cough patients. In this paper, we present a system for the automatic analysis of 24-h, continuous, ambulatory recordings of cough. The system uses audio recordings from a miniature microphone and the detection algorithm is based on statistical models of the time-spectral characteristics of cough sounds. We validated the system against manual counts obtained by a trained observer on 40 ambulatory recordings and our results show a median sensitivity value of 85.7%, median positive predictive value of 94.7% and median false positive rate of 0.8 events/h. An analysis application was developed, with a graphical user interface, allowing the use of the system in clinical settings by technical or medical staff. The result of the analysis of a recording session is presented as a concise, graphical-based report. The modular nature of the system interface facilitates its enhancement with the integration of further modules. PMID- 17694869 TI - Volume catheter parallel conductance varies between end-systole and end-diastole. AB - In order for the conductance catheter system to accurately measure instantaneous cardiac blood volume, it is necessary to determine and remove the contribution from parallel myocardial tissue. In previous studies, the myocardium has been treated as either purely resistive or purely capacitive when developing methods to estimate the myocardial contribution. We propose that both the capacitive and the resistive properties of the myocardium are substantial, and neither should be ignored. Hence, the measured result should be labeled admittance rather than conductance. We have measured the admittance (magnitude and phase angle) of the left ventricle in the mouse, and have shown that it is measurable and increases with frequency. Further, this more accurate technique suggests that the myocardial contribution to measured admittance varies between end-systole and end diastole, contrary to previous literature. We have tested these hypotheses both with numerical finite-element models for a mouse left ventricle constructed from magnetic resonance imaging images, and with in vivo admittance measurements in the murine left ventricle. Finally, we propose a new method to determine the instantaneous myocardial contribution to the measured left ventricular admittance that does not require saline injection or other intervention to calibrate. PMID- 17694870 TI - Theoretical study on the effect of sensor contact force on pulse transit time. AB - Pulse transit time (PTT) has been widely used for noninvasive examination of the arterial viscoelastic properties, such as elasticity, compliance, and stiffness of the vessel walls. PTT is usually determined as the time interval between the peak of the electrocardiogram R wave and the foot of the photoplethysmogram (PPG). However, it was observed that the PPG is affected by the applied contact force between the photoplethysmographic sensor and the measurement site, e.g., finger. In this study, the nonlinear biomechanical properties of the finger arterial wall were considered when investigating the changes in PTT with varying contact force. Emphasis was placed on the changes in the shape of the arterial wall pressure-volume curve. The simulation results indicated that at positive transmural pressure, PTT increased with the applied contact force, reaching the maximum at zero transmural pressure and remaining at a constant level at negative transmural pressure. The theoretical analysis was further verified by the experiments carried out on thirty young subjects and six elderly subjects using twelve discrete levels of contact force. PMID- 17694872 TI - Impact studies of high-speed micro-particles following biolistic delivery. AB - The powdered injection system is a novel biomedical device for needle-free adminstration of DNA vaccines. One system, call the Venturi device, uses the venturi effect to entrain DNA-coated micron gold particles into an established quasi-steady supersonic helium jet flow and accelerate them into an appropriate momentum in order to penetrate the outer layer of the skin or mucosal tissue to achieve a biological effect. In this paper, computational fluid dynamics is utilized to simulate the complete operation of a prototype Venturi system. The key features of the gas dynamics and gas-particle interactions are presented. In particular, the mechanism for the particle entrainment is explored. The overall capability of the Venturi system to deliver the particles into modelled targets is discussed. The statistical analysis shows that a mean impact velocity of 695 m/s is achieved for representative gold particles (1.8 microm in diameter), with a penetration depth of 29.8 microm for epidermal DNA delivery. PMID- 17694871 TI - Automatic brachytherapy seed placement under MRI guidance. AB - The paper presents a robotic method of performing low dose rate prostate brachytherapy under magnetic resonance imaging (MRI) guidance. The design and operation of a fully automated MR compatible seed injector is presented. This is used with the MrBot robot for transperineal percutaneous prostate access. A new image-registration marker and algorithms are also presented. The system is integrated and tested with a 3T MRI scanner. Tests compare three different registration methods, assess the precision of performing automated seed deployment, and use the seeds to assess the accuracy of needle targeting under image guidance. Under the ideal conditions of the in vitro experiments, results show outstanding image-guided needle and seed placement accuracy. PMID- 17694873 TI - Differences in the activity of the muscles in the forearm of individuals with a congenital absence of the hand. AB - The spectral content of the myoelectric signals from the muscles of the remnant forearms of three persons with congenital absences (CA) of their forearms was compared with signals from their intact contra-lateral limbs, similar muscles in three persons with acquired losses (AL) and seven persons without absences [no loss (NL)]. The observed bandwidth for the CA subjects was broader with peak energy between 200 and 300 Hz. While the signals from the contra-lateral limbs and the AL and NL subjects was in the 100-150 Hz range. The mean skew of the signals from the AL subjects was 46.3 +/- 6.7 and those with NL of 45.4 +/- 8.7, while the signals from those with CAs had a skew of 11.0 +/- 11. The structure of the muscles of one CA subject was observed ultrasonically. The muscle showed greater disruption than normally developed muscles. It is speculated that the myographic signal reflects the structure of the muscle which has developed in a more disorganized manner as a result of the muscle not being stretched by other muscles across the missing distal joint, even in the muscles that are used regularly to control arm prostheses. PMID- 17694874 TI - The muscle activation method: an approach to impedance control of brain-machine interfaces through a musculoskeletal model of the arm. AB - Current demonstrations of brain-machine interfaces (BMIs) have shown the potential for controlling neuroprostheses under pure motion control. For interaction with objects, however, pure motion control lacks the information required for versatile manipulation. This paper investigates the idea of applying impedance control in a BMI system. An extraction algorithm incorporating a musculoskeletal arm model was developed for this purpose. The new algorithm, called the muscle activation method (MAM), was tested on cortical recordings from a behaving monkey. The MAM was found to predict motion parameters with as much accuracy as a linear filter. Furthermore, it successfully predicted limb interactions with novel force fields, which is a new and significant capability lacking in other algorithms. PMID- 17694875 TI - Convolutive blind source separation algorithms applied to the electrocardiogram of atrial fibrillation: study of performance. AB - The analysis of the surface electrocardiogram (ECG) is the most extended noninvasive technique in medical diagnosis of atrial fibrillation (AF). In order to use the ECG as a tool for the analysis of AF, we need to separate the atrial activity (AA) from other cardioelectric signals. In this matter, statistical signal processing techniques, like blind source separation (BSS), are able to perform a multilead statistical analysis with the aim to obtain the AA. Linear BSS techniques can be divided in two groups depending on the mixing model: algorithms where instantaneous mixing of sources is assumed, and convolutive BSS (CBSS) algorithms. In this work, a comparison of performance between one relevant CBSS algorithm, namely Infomax, and one of the most effective independent component analysis (ICA) algorithms, namely FastICA, is developed. To carry out the study, pseudoreal AF ECGs have been synthesized by adding fibrillation activity to normal sinus rhythm. The algorithm performances are expressed by two indexes: the signal to interference ratio (SIRAA) and the cross-correlation (RAA) between the original and the estimated AA. Results empirically prove that the instantaneous mixing model is the one that obtains the best results in the AA extraction, given that the mean SIRAA obtained by the FastICA algorithm (37.6 +/- 17.0 dB) is higher than the main SIRAA obtained by Infomax (28.5 +/- 14.2 dB). Also the RAA obtained by FastICA (0.92 +/- 0.13) is higher than the one obtained by Infomax (0.78 +/- 0.16). PMID- 17694876 TI - Use of genetic algorithms to optimize fiber optic probe design for the extraction of tissue optical properties. AB - This paper outlines a framework by which the optimal illumination/collection geometry can be identified for a particular biomedical application. In this paper, this framework was used to identify the optimal probe geometry for the accurate determination of tissue optical properties representative of that in the ultraviolet-visible (UV-VIS) spectral range. An optimal probe geometry was identified which consisted of a single illumination and two collection fibers, one of which is insensitive to changes in scattering properties, and the other is insensitive to changes in the attenuation coefficient. Using this probe geometry in conjunction with a neural network algorithm, the optical properties could be extracted with root-mean-square errors of 0.30 cm(-1) for the reduced scattering coefficient (tested range of 3-40 cm(-1)), and 0.41 cm(-1) for the absorption coefficient (tested range of 0-80 cm(-1)). PMID- 17694878 TI - CARNA awards. PMID- 17694877 TI - Smart microrobots for mechanical cell characterization and cell convoying. AB - This paper deals with the effective design of smart microrobots for both mechanical cell characterization and cell convoying for in vitro fertilization. The first microrobotic device was developed to evaluate oocyte mechanical behavior in order to sort oocytes. A multi-axial micro-force sensor based on a frictionless magnetic bearing was developed. The second microrobotic device presented is a cell convoying device consisting of a wireless micropusher based on magnetic actuation. As wireless capabilities are supported by this microrobotic system, no power supply connections to the micropusher are needed. Preliminary experiments have been performed regarding both cell transporting and biomechanical characterization capabilities under in vitro conditions on human oocytes so as to demonstrate the viability and effectiveness of the proposed setups. PMID- 17694879 TI - Passion's purpose. PMID- 17694880 TI - Closing perspectives. RNs excel in PCN role--going to the doctor was never like this. PMID- 17694881 TI - Laparoscopic bowel surgery. AB - Bowel surgery is performed on a daily basis in many hospitals around the world. With the introduction of laparoscopic surgery in the 1990s, laparoscopic bowel surgery has become an option for patients to consider. This article will briefly review the anatomy of the large bowel and identify indications, contraindications, preoperative preparations, and intraoperative considerations for laparoscopic bowel surgery. A brief description of the various types of laparoscopic bowel resection procedures will be presented along with the advantages and complications. The future of laparoscopic bowel surgery will also be presented. PMID- 17694882 TI - The joys of perioperative nursing. AB - When we join perioperative nursing we enter the swinging doors of the operating suite and never leave. Have we come home? Are we drawn by--Student experience? A job to go to by random assignment? A long desire to work in the OR? For a career change? Regardless of the reason for our arrival, many things keep us in the OR including the teamwork, friendships formed, the challenges, the camaraderie, and the constant learning of new skills. For some it is the adrenaline rushes with each crisis and trauma that comes through the door. Or maybe it's because we feel we truly are nursing and able to act for the patient. We realize that patients have placed their trust in our care during a very vulnerable time when they are unable to speak for themselves. What creates and keeps a perioperative nurse? Using a qualitative research questionnaire, given to nurses attending a national perioperative conference, the author obtained feedback from nurses on their feelings, attitudes and knowledge in an effort to determine what makes a perioperative nurse and what it is that keeps them there for so many years. The results, along with the author's personal observations, are outlined in this article. PMID- 17694883 TI - Walk or be driven? A study on walking patients to the operating theatre. AB - The objective of this study was to determine patients' perception on the possibility of changing a tradition-based practice to a more patient empowering service, thus demonstrating that nurses can make a difference in providing a more patient-centred environment. The study revealed that the patients themselves wanted to be included in the decision-making process and actively embrace change. PMID- 17694884 TI - Clinical guidelines: what do they have to do with us? PMID- 17694885 TI - Consent and the law. PMID- 17694886 TI - Now and then. 'Wanted, SRN'. PMID- 17694887 TI - Assessment of a child with fever. PMID- 17694888 TI - Perceptions of young people about decision making in the acute healthcare environment. AB - AIM: This study explored young people's perceptions of their involvement in healthcare decisions affecting their management of care. METHOD: A phenomenological approach was used to allow in-depth examination of the young people's personal accounts of their experiences. Data were obtained from 10 hospitalised young people between the ages of 12-16 years from both genders and from different medical and surgical specialities using focused interviews. Transcribing, reading and listening to the data enabled data analysis through reflection and analysis. FINDINGS: Three themes were identified: level of involvement in decision-making; psychological impact of involvement in decision making; and communication. CONCLUSION: Professional practice in the care of young people should include effective communication, a policy of inclusion and active assessment of competence. PMID- 17694890 TI - Risk management and clinical governance for complex home-based health care. AB - Healthcare professionals have an obligation to enable children with complex needs to lead 'ordinary lives' at home but the views of professionals and family members often diverge in relation to the management of risks. Nurses are increasingly taking on the clinical responsibility for children with complex needs within a multidisciplinary, multi-agency team, yet have little training or experience in adapting risk management and clinical governance frameworks to home based settings. Risk management frameworks for home-based care for children with complex health and social care needs are introduced in this article. Best practice guidance and resources for adapting risk management frameworks are presented to meet this identified gap in knowledge and experience. Children, young people and their parents have increasing expectations relating to the type and quality of home-based support they receive. Developing and applying clinical governance and risk management frameworks are part of improving outcomes for children with complex needs and their families. PMID- 17694889 TI - Transitional care for young people with diabetes: policy and practice. AB - Young people with diabetes inevitably require transfer to adult services. Adult clinics differ from paediatric clinics and therefore a smooth, planned process of transition is required. Adolescence can be especially difficult for young people with diabetes and research evidence highlights the need for individualised approaches to this transition. Health policy related to diabetes services emphasises the importance of good transition and guidelines are available to inform service development and improvement. Local services in one district in England appear to reflect policy, guidelines and evidence but there a number of actions that could be taken to further improve transitional care both locally and nationally. PMID- 17694891 TI - Abuse of children with disabilities in hospital: issues and implications. AB - Children with disabilities are among the most vulnerable in our society and are more likely to be abused or neglected than non-disabled children. Health professionals in all settings have an important role in child protection as they are often the first to see the signs of abuse and are in a position to identify risk of abuse. Aside from intentional abuse, there are a number of healthcare practices that can be construed as abuse or neglect. Such practices may have become shrouded under normal clinical routines and continue unchallenged, for example, assuming that disabled children cannot give informed consent or that their privacy and dignity do not have to be maintained as they do not feel embarrassed at having their bodies examined. A health professional or student is guilty of abusive practice if he or she intentionally carries out such practices, allows them to continue by not speaking up or does not learn about the signs and symptoms of abuse in children with disabilities and how to understand their communications. Identifying and stopping both intentional and subtle abusive practices is a complex task requiring changes in attitudes held by many in the health services. PMID- 17694892 TI - Reducing the risk of wrong route errors. AB - Infants in the neonatal intensive care unit are at particular risk from clinical errors because of their fragility and vulnerability, as well as the complex nature of medication and other treatment regimes. Wrong route errors have been well documented, particularly related to enteral nutrition and medication. Published guidance for preventing such errors should inform changes in practice at the local level. In 2005, the Regional Neonatal Intensive Care Unit at the University Hospital of Wales Cardiff undertook a change in clinical practice to improve standards of care for all babies requiring enteral nutrition and medication, thus reducing the risk of a wrong route error. A routine revision of departmental policy resulted in a review of available evidence to inform the practice changes. Colour-coded enteral/oral syringes with a new style nasogastric tube were introduced. By promoting best practice through networking with other colleagues, staff have worked towards standardising the delivery of care in order to minimise the risk wrong route errors. PMID- 17694893 TI - Theory focused practice: enhancing student learning in children's nursing practice. PMID- 17694894 TI - Participation in a clinical trial: views of children and young people with diabetes. AB - AIM: To investigate whether involvement in research can have a positive effect on the education and management of disease of children and young people with diabetes. METHOD: Children's and young people's experiences of exposure to intensified intervention during a clinical trial were examined by a questionnaire given to 44 young patients with type 1 diabetes from the UK and Ireland. The young people had participated in a trial comparing specific insulin regimes. Most patients were obliged to increase injection frequency, clinic attendance, glucose monitoring and diary entries. FINDINGS: Of the 44 patients, 36 completed the questionnaire. Most, including the younger children, did not regard basal-bolus therapy, additional injections or intensified self-monitoring as barriers to self management. They also believed that the management of their diabetes was further supported as a result of increased contact and intensive insulin management. Many of the children participating in this study felt they had learned something about their diabetes, and, furthermore, almost all opted to remain on an intensive treatment regimen. CONCLUSION: These results suggest that trial involvement benefits the young person's approach to self-management of diabetes. PMID- 17694895 TI - Physiology of fever. AB - Knowing how the body reacts to the presence of pathogens allows healthcare professionals to make informed decisions about what action to take in caring for the child with fever. A raised body temperature raises the metabolic rate and makes the immune response more efficient. It also stimulates naturally occurring anti-pyretics but can also have harmful effects. Careful monitoring based on risk of serious illness is recommended in new guidelines on the management of feverish illness in young children provide (National Institute of Health and Clinical Excellence (NICE 2007), which also provide an opportunity for standardising fever management. PMID- 17694896 TI - The maternal-fetal conflict: the right of a woman to refuse a Cesarean section versus the state's interest in saving the life of the fetus. PMID- 17694897 TI - Does a pharmacist have the right to refuse to fill a prescription for birth control? PMID- 17694898 TI - Applying cognitive psychology to education. PMID- 17694899 TI - Enhancing learning and retarding forgetting: choices and consequences. AB - Our research on learning enhancement has been focusing on the consequences for learning and forgetting of some of the more obvious and concrete choices that arise in instruction, including questions such as these: How does spacing of practice affect retention of information over significant retention intervals (up to 1 year)? Do spacing effects generalize beyond recall of verbal materials? Is feedback needed to promote learning, and must it be immediate? Although retrieval practice has been found to enhance learning in comparison with additional study, does it actually reduce the rate of forgetting? Can retrieval practice effects be extended to nonverbal materials? We suggest that as we begin to find answers to these questions, it should become possible for cognitive psychology to offer nonobvious advice that can be applied in a variety of instructional contexts to facilitate learning and reduce forgetting. PMID- 17694900 TI - The memorial consequences of multiple-choice testing. AB - The present article addresses whether multiple-choice tests may change knowledge even as they attempt to measure it. Overall, taking a multiple-choice test boosts performance on later tests, as compared with non-tested control conditions. This benefit is not limited to simple definitional questions, but holds true for SAT II questions and for items designed to tap concepts at a higher level in Bloom's (1956) taxonomy of educational objectives. Students, however, can also learn false facts from multiple-choice tests; testing leads to persistence of some multiple-choice lures on later general knowledge tests. Such persistence appears due to faulty reasoning rather than to an increase in the familiarity of lures. Even though students may learn false facts from multiple-choice tests, the positive effects of testing outweigh this cost. PMID- 17694901 TI - Generalizing test-enhanced learning from the laboratory to the classroom. AB - Test-enhanced learning refers to the fact that taking an initial test on studied material enhances its later retention relative to simply studying the material and then taking a final test. Most research on the testing effect has been done with materials such as word lists, and the general finding has been that the benefits of testing are greater when the initial test is a recall (production) test rather than a recognition test. We briefly summarize three experiments that extend these results to educationally relevant materials, namely brief articles, lectures, and materials in a college course. All three experiments demonstrated a robust testing effect and also revealed that an initial short-answer test produced greater gains on a final test than did an initial multiple-choice test. Furthermore, one experiment revealed a positive effect of immediate feedback given with the initial test. The educational implications are that production tests (short answer or essay) and feedback soon after learning increase learning and retention. In addition, frequent testing probably has the indirect positive effects of keeping students motivated and leading them to space out periods of study. PMID- 17694902 TI - Learning how to learn: can experiencing the outcome of different encoding strategies enhance subsequent encoding? AB - Research on how individuals monitor their level of comprehension during study paint a picture of learners as insensitive to many of the factors or conditions of learning that can enhance long-term retention and transfer. In the present article, we discuss research examining the sensitivity, or lack thereof, of learners to one such factor: generation. More specifically, we discuss research addressing the question of learners' sensitivity to the memorial benefits of generation and whether--if given the opportunity to experience this benefit in their own recall performance--they might then go on to develop enhanced encoding strategies in the processing of new to-be-learned information. PMID- 17694903 TI - Metacomprehension for educationally relevant materials: dramatic effects of encoding-retrieval interactions. AB - As the metacomprehension literature has grown, important discoveries pertinent to education havebeen made. For example, as students are better able to assess their knowledge and implement appropriate study strategies, presumably their acquisition and retention of course material improves. Accordingly, we consider the metacomprehension literature with an emphasis on factors that impact metacomprehension accuracy. Several studies have demonstrated that metacomprehension prediction accuracy will improve to the extent that people engage in enriched-encoding activities. More recently, research by Thomas and McDaniel (in press) has suggested that enriched-encoding manipulations interact with retrieval to impact both retention and metacomprehension and, in turn, the effectiveness of controlling subsequent study. Thus, matching enriched-encoding activities with the criterial test plays a critical role in metacomprehension accuracy and control of studying. PMID- 17694904 TI - The promise and perils of self-regulated study. AB - Self-regulated study involves many decisions, some of which people make confidently and easily (if not always optimally) and others of which are involved and difficult. Good study decisions rest on accurate monitoring of ongoing learning, a realistic mental model of how learning happens, and appropriate use of study strategies. We review our research on the decisions people make, for better or worse, when deciding what to study, how long to study, and how to study. PMID- 17694905 TI - Principles of cognitive science in education: the effects of generation, errors, and feedback. AB - Principles of cognitive science hold the promise of helping children to study more effectively, yet they do not always make successful transitions from the laboratory to applied settings and have rarely been tested in such settings. For example, self-generation of answers to questions should help children to remember. But what if children cannot generate anything? And what if they make an error? Do these deviations from the laboratory norm of perfect generation hurt, and, if so, do they hurt enough that one should, in practice, spurn generation? Can feedback compensate, or are errors catastrophic? The studies reviewed here address three interlocking questions in an effort to better implement a computer based study program to help children learn: (1) Does generation help? (2) Do errors hurt if they are corrected? And (3) what is the effect of feedback? The answers to these questions are: Yes, generation helps; no, surprisingly, errors that are corrected do not hurt; and, finally, feedback is beneficial in verbal learning. These answers may help put cognitive scientists in a better position to put their well-established principles in the service of children's learning. PMID- 17694906 TI - Counting the cost of an absent mind: mind wandering as an underrecognized influence on educational performance. AB - Successful learning requires that individuals integrate information from the external environment with their own internal representations. In this article, we consider the role that mind wandering plays in education. Mind wandering represents a state of decoupled attention because, instead of processing information from the external environment, our attention is directed toward our own private thoughts and feelings. In principle, because mind wandering is a state of decoupled attention, it represents a fundamental breakdown in the individual's ability to attend (and therefore integrate) information from the external environment. We consider evidence that mind wandering impairs the encoding of information, leading to failures in building a propositional model of a sentence and, ultimately, impairing the building of a narrative model with sufficient detail to allow generating inferences. Next, because recognizing and correcting for mind wandering is a metacognitive skill, certain client groups, such as those suffering from dysphoria or attention deficit disorder, may be unable to correct for the deficits associated with mind wandering, and so may suffer greater negative consequences during education. Finally, we consider how to apply this research to educational settings. PMID- 17694907 TI - Improving the writing skills of college students. AB - Advanced writing skills are an important aspect of academic performance as well as of subsequent work-related performance. However, American students rarely attain advanced scores on assessments of writing skills (National Assessment of Educational Progress, 2002). In order to achieve higher levels of writing performance, the working memory demands of writing processes should be reduced so that executive attention is free to coordinate interactions among them. This can in theory be achieved through deliberate practice that trains writers to develop executive control through repeated opportunities to write and through timely and relevant feedback. Automated essay scoring software may offer a way to alleviate the intensive grading demands placed on instructors and, thereby, substantially increase the amount of writing practice that students receive. PMID- 17694908 TI - Working memory, math performance, and math anxiety. AB - The cognitive literature now shows how critically math performance depends on working memory, for any form of arithmetic and math that involves processes beyond simple memory retrieval. The psychometric literature is also very clear on the global consequences of mathematics anxiety. People who are highly math anxious avoid math: They avoid elective coursework in math, both in high school and college, they avoid college majors that emphasize math, and they avoid career paths that involve math. We go beyond these psychometric relationships to examine the cognitive consequences of math anxiety. We show how performance on a standardized math achievement test varies as a function of math anxiety, and that math anxiety compromises the functioning of working memory. High math anxiety works much like a dual task setting: Preoccupation with one's math fears and anxieties functions like a resource-demanding secondary task. We comment on developmental and educational factors related to math and working memory, and on factors that may contribute to the development of math anxiety. PMID- 17694909 TI - Cognitive tutor: applied research in mathematics education. AB - For 25 years, we have been working to build cognitive models of mathematics, which have become a basis for middle- and high-school curricula. We discuss the theoretical background of this approach and evidence that the resulting curricula are more effective than other approaches to instruction. We also discuss how embedding a well specified theory in our instructional software allows us to dynamically evaluate the effectiveness of our instruction at a more detailed level than was previously possible. The current widespread use of the software is allowing us to test hypotheses across large numbers of students. We believe that this will lead to new approaches both to understanding mathematical cognition and to improving instruction. PMID- 17694910 TI - Amnesia, rehearsal, and temporal distinctiveness models of recall. AB - Classical amnesia involves selective memory impairment for temporally distant items in free recall (impaired primacy) together with relative preservation of memory for recency items. This abnormal serial position curve is traditionally taken as evidence for a distinction between different memory processes, with amnesia being associated with selectively impaired long-term memory. However recent accounts of normal serial position curves have emphasized the importance of rehearsal processes in giving rise to primacy effects and have suggested that a single temporal distinctiveness mechanism can account for both primacy and recency effects when rehearsal is considered. Here we explore the pattern of strategic rehearsal in a patient with very severe amnesia. When the patient's rehearsal pattern is taken into account, a temporal distinctiveness model can account for the serial position curve in both amnesic and control free recall. The results are taken as consistent with temporal distinctiveness models of free recall, and they motivate an emphasis on rehearsal patterns in understanding amnesic deficits in free recall. PMID- 17694911 TI - Retrograde facilitation under midazolam: the role of general and specific interference. AB - In a double-blind, placebo-controlled experiment that used midazolam, a benzodiazepine that creates temporary amnesia, we compared acquisition and retention of paired associates of different types. Some word pairs were studied before the injection of saline or midazolam, and two lists of word pairs were studied after the injection. Critical comparisons involved retention of pairs that were practiced on all three lists, pairs studied on only one list, and pairs that involved recombining cue and response terms from one list to the next, as a function of drug condition. Previous research with benzodiazepines had found retrograde facilitation for material acquired prior to injection, compared with the control condition. One explanation for this facilitation is that the anterograde amnesia produced by the benzodiazepine frees up the hippocampus to better consolidate previously learned material (Wixted, 2004, 2005). We accounted for a rich data set using a simple computational model that incorporated interference effects (cue overload) at retrieval for both general (experimental context) interference and specific (stimulus term) interference without the need to postulate a role for consolidation. The computational model as an Excel spreadsheet may be downloaded from www.psychonomic.org/archive. PMID- 17694912 TI - Properties of the organization of memory for people: evidence from dream reports. AB - Steyvers and Tenenbaum (2005) showed that semantic networks for words have three organizational properties: short average path lengths, high clustering, and power law degree distribution. If these are general properties of memory organization, they would apply to memory for other complex material, including people and relations between them. In addition, if during dreaming, characters are generated via knowledge in the dreamer's memory, the three properties would be found in a relational network of characters in dreams. In dream reports from three individuals, two characters in the same dream were considered affiliated. Resulting social networks have the three properties, with the power law holding when low degrees are omitted. One network with a tree-like outline is different from the other two. Results suggest associative memory has the three properties, and demonstrate that dream reports are a potentially valuable source for information about social networks. PMID- 17694913 TI - Did you witness demonic possession? A response time analysis of the relationship between event plausibility and autobiographical beliefs. AB - This study tested the hypothesis that the search for information pertinent to answering the question "Did event x happen to you?" is preceded by a preliminary plausibility assessment, the outcome of which affects the amount of effort invested in the search. Undergraduate students were asked to assess the plausibility of six events and subsequently to rate their belief that each event had happened to them before the age of 6. Unknown to them, response times (RTs) for answering the belief questions were also recorded. RTs for making belief judgments were more highly correlated with plausibility than with belief, and were significantly associated with plausibility even when belief ratings were controlled. As predicted, RTs were very short when the event was deemed highly implausible and increased sharply if the event was deemed at least somewhat plausible; significant but less pronounced increases in RTs followed as plausibility increased further. PMID- 17694914 TI - Does remembering emotional items impair recall of same-emotion items? AB - In the part-set cuing effect, cuing a subset of previously studied items impairs recall of the remaining noncued items. This experiment reveals that cuing participants with previously-studied emotional pictures (e.g., fear-evoking pictures of people) can impair recall of pictures involving the same emotion but different content (e.g., fear-evoking pictures of animals). This indicates that new events can be organized in memory using emotion as a grouping function to create associations. However, whether new information is organized in memory along emotional or nonemotional lines appears to be a flexible process that depends on people's current focus. Mentioning in the instructions that the pictures were either amusement- or fear-related led to memory impairment for pictures with the same emotion as cued pictures, whereas mentioning that the pictures depicted either animals or people led to memory impairment for pictures with the same type of actor. PMID- 17694915 TI - Iterated learning: intergenerational knowledge transmission reveals inductive biases. AB - Cultural transmission of information plays a central role in shaping human knowledge. Some of the most complex knowledge that people acquire, such as languages or cultural norms, can only be learned from other people, who themselves learned from previous generations. The prevalence of this process of "iterated learning" as a mode of cultural transmission raises the question of how it affects the information being transmitted. Analyses of iterated learning utilizing the assumption that the learners are Bayesian agents predict that this process should converge to an equilibrium that reflects the inductive biases of the learners. An experiment in iterated function learning with human participants confirmed this prediction, providing insight into the consequences of intergenerational knowledge transmission and a method for discovering the inductive biases that guide human inferences. PMID- 17694916 TI - Is the mind inherently forward looking? Comparing prediction and retrodiction. AB - It has been suggested that prediction may be an organizing principle of the mind and/or the neocortex, with cognitive machinery specifically engineered to detect forward-looking temporal relationships, rather than merely associating temporally contiguous events. There is a remarkable absence of behavioral tests of this idea, however. To address this gap, we showed subjects sequences of shapes governed by stochastic Markov processes, and then asked them to choose which shape reliably came after a probe shape (prediction test) or before a probe shape (retrodiction test). Prediction was never superior to retrodiction, even when subjects were forewarned of a forward-directional test. PMID- 17694918 TI - Distractor interference stays constant despite variation in working memory load. AB - Previous studies have shown that working memory (WM) plays an important role in selective attention, sothat high WM load leads to inefficient distractor inhibition, in comparison with low WM load. In the present study, we examined the effect of WM on distractor processing while the extent of attentional focus was held constant. Our results show that WM load affected distractor processing only when it was positively correlated with the extent of attentional focus. When the latter was held constant, the effect ofWM became negligible. Furthermore, when low WM load was paired with a wide attentional focus and high WM load was matched with a narrow attentional focus, greater distractor processing was found when the WM load was low than when it was high. These results suggest that efficient distractor inhibition may require only minimal WM resources and that the effect of WM on distractor processing is more complex than has previously been assumed. PMID- 17694917 TI - Aging and a benefit of distractibility. AB - Under instructions to ignore distraction, younger and older adults read passages with interspersed distracting words. Some of the distractors served as solutions to a subsequent set of verbal problems in which three weakly related words could be related by retrieving a missing fourth word (i.e., the Remote Associates Test [RAT]; Mednick, 1962). Older adults showed significant priming from the distraction, whereas younger adults did not. In this study, we present a case in which age-related reductions in attentional control over information that was not initially relevant can actually lead to superior performance for older adults. The RAT materials may be downloaded from www.psychonomic.org/archive. PMID- 17694919 TI - Simon says: reliability and the role of working memory and attentional control in the simon task. AB - The Simon effect refers to the observation that subjects identify targets (e.g., colors) faster when the irrelevant spatial location of the target corresponds to the location of the response key. Theoretical accounts of the Simon effect typically explain performance in terms of automatic and controlled processes. Furthermore, the relative contributions of automatic and controlled processes are held to change as a function of the proportion of compatible to incompatible trials (compatibility proportion). Data are presented demonstrating that the reliability of the Simon effect, indexed by correlating its magnitude within subjects across blocks of trials, varied substantially as a function of the compatibility proportion. When the compatibility proportion was high, so was reliability. When the compatibility proportion was low, reliability was low as well. The results are discussed in terms of the relative reliability of automatic and controlled processes and the role of working memory and attentional control in goal maintenance. PMID- 17694920 TI - Inhibitory tagging in inhibition of return: evidence from flanker interference with multiple distractor features. AB - Fuentes, Vivas, and Humphreys (1999) proposed a distinction between inhibition of return (IOR) and inhibitory processing taking place at a location subject to IOR. This latter mechanism, inhibitory tagging (IT), would act at a late level of processing related to response selection. In the present study, we examined whether IT was applied only to the target-relevant properties of the stimuli (e.g., to its color) or whether it was applied to other features of the stimulus as well (e.g., to its shape). Both when the task was to respond to the target's color (Experiment 1) as well as when it was to respond to the target's shape (Experiment 2), there was evidence of IT (reversal of the typical flanker effect at the cued location, relative to the uncued location) only to task-relevant features of the target. These findings suggest that IT is a central process of control constrained by task demands and current goals. PMID- 17694921 TI - The time required for perceptual (nonmotoric) processing in IOR. AB - In an inhibition of return (IOR) paradigm, we used a threshold-tracking procedure combined with backward masking to measure the speed of perceptual processing in IOR independent of motoric factors. Instead of the conventional reaction time measure, this procedure yielded the critical exposure duration (DURc) that is required in order for a target to be identified reliably before the onset of a trailing mask. In Experiment 1, the facilitation effects conventionally found at short cue-target onset asynchrony (CTOA) were evidenced by shorter values of DURc at cued relative to uncued locations. Conversely, the retardation effects conventionally found at long CTOA were evidenced by correspondingly longer values of DURc. In Experiment 2, the DURc results strongly suggest that the directional reading bias previously observed in IOR studies is due, at least in part, to perceptual rather than motoric factors. PMID- 17694922 TI - Nontarget objects can influence perceptual processes during object recognition. AB - Previous experiments have shown that objects are recognized more readily in a semantically consistent visual context. However, the benefit from context could be explained by response bias, and may not reflect the influence of context on the perceptual processes of recognition. We conducted a six-alternative forced choice experiment to measure semantic and perceptual errors. A target object appeared briefly, surrounded by four context objects. The target was more accurately identified when the context consisted of objects semantically related to the target. The large number of semantic errors, which increased when the context presentation preceded the target, showed that response bias did account for a proportion of the context effect. Nevertheless, significant facilitation was still present after a bias correction. Recognition of an object can be affected by context not only when it is embedded in a coherent naturalistic scene, but also when it is simply near other related objects. Materials associated with this article may be accessed at www.psychonomic.org/archive. PMID- 17694923 TI - New objects can capture attention without a unique luminance transient. AB - Recent evidence has suggested that new objects capture attention solely because they are typically accompanied by a unique luminance transient. In the present study, we presented a stationary pattern mask after an array of placeholders but before a subsequent search display. This allowed all of the search elements to be presented simultaneously, thereby eliminating the unique luminance transient associated with the appearance of any new objects. Under these circumstances, new objects still captured attention. In another experiment, we jiggled the mask. This caused new objects to lose their advantage. We discuss implications for the importance of new objects, and the attentional consequences of motion. PMID- 17694924 TI - Multiple object juggling: changing what is tracked during extended multiple object tracking. AB - The multiple object tracking (MOT) task has been a useful tool for studying the deployment of limited-capacity visual resources over time. Since it involves sustained attention to multiple objects, this task is a promising model for real world visual cognition. However, real-world tasks differ in two critical ways from standard laboratory MOT designs. First, in real-world tracking, it is unusual for the set of tracked items to be identified all at once and to remain unchanged over time. Second, real-world tracking tasks may need to be sustained over a period of minutes, and not mere seconds. How well is MOT performance maintained over extended periods of time? In four experiments, we demonstrate that observers can dynamically "juggle" objects in and out of the tracked set with little apparent cost, and can sustain this performance for up to 10 min at a time. This performance requires implicit or explicit feedback. In the absence of feedback, performance tracking drops steadily over the course of several minutes. PMID- 17694925 TI - Visual layout modulates Fitts's law: the importance of first and last positions. AB - When a target in the last position of a structured visual array is aimed for, movement times (MTs) are shorter than predicted by Fitts's law (Adam, Mol, Pratt, & Fischer, 2006). That study, however, confounded relative target position with absolute target location. To determine whether target position does, indeed, produce changes in the speed-accuracy trade-off function, the present experiment manipulated relative target position (e.g., first or last) independently of absolute target location (e.g., nearest or farthest). This was accomplished by presenting connected placeholders at three adjacent locations from a set of five possible locations (i.e., the middle location could be the first, middle, or last placeholder position in an array). The results of a speeded manual-pointing task showed that relative position is important for Fitts's law; when absolute location was held constant, shorter MTs were found for last-position than for middle-position targets. In addition, a similar effect was found for first position targets. These results suggest that Fitts's law holds within, but not between, relative target positions in visible structured arrays. PMID- 17694926 TI - Illusory colors promote interocular grouping during binocular rivalry. AB - When dissimilar monocular images are presented separately to each of a person's eyes, these images compete for visual dominance, with dominance of one image or the other alternating over time. While this phenomenon, called binocular rivalry, transpires, local image features distributed over space and between the eyes can become visually dominant at the same time; the resulting global figure implicates interocular grouping. Previous studies have suggested that color tends to influence the incidence of global dominance; in this study, we assess whether illusory color can also influence interocular grouping. To test this, we exploited the McCollough effect, an orientation-contingent color aftereffect induced by prolonged adaptation to different colors paired with different orientations. Results show that during binocular rivalry, illusory colors induced by the McCollough adaptation enhance strong interocular grouping relative to preadaptation testing, to an extent comparable in strength with the enhancement induced by real colors. Thus, illusory colors that are present only in an observer's mind are sufficiently potent to influence low-level visual processes such as binocular rivalry. PMID- 17694927 TI - Rotational kinematics influence multimodal perception of heaviness. AB - Perceived heaviness has been shown to be specific to an object's rotational inertia (I), its resistance to rotational acceleration. According to the kinematic specification of dynamics (KSD) principle, we hypothesized that I is optically specified by rotational kinematics. Using virtual depictions of wielded objects, we investigated whether the visually detected rotational kinematics of wielded objects would influence perceived heaviness in a manner consistent with the inertial model of heaviness perception. We scaled the virtual object's movement so that it rotated more or less than its wielded counterpart, specifying lower and higher I, respectively. Perceived heaviness was inversely related to the rotational scaling factor, consistent with a KSD interpretation of the inertial model. PMID- 17694928 TI - "Just another pretty face": a multidimensional scaling approach to face attractiveness and variability. AB - Findings on both attractiveness and memory for faces suggest that people should perceive more similarity among attractive than among unattractive faces. A multidimensional scaling approach was used to test this hypothesis in two studies. In Study 1, we derived a psychological face space from similarity ratings of attractive and unattractive Caucasian female faces. In Study 2, we derived a face space for attractive and unattractive male faces of Caucasians and non-Caucasians. Both studies confirm that attractive faces are indeed more tightly clustered than unattractive faces in people's psychological face spaces. These studies provide direct and original support for theoretical assumptions previously made in the face space and face memory literatures. PMID- 17694929 TI - Controlling lexical contributions to the reading of pseudohomophones. AB - Reynolds and Besner (2005) presented a computational account of six effects that emerge when readers are asked to pronounce pseudohomophones (nonwords--e.g., brane-that sound like words when pronounced). In the dual route cascaded (DRC) model of reading, they varied a parameter controlling the rate of inhibition from letter units to the orthographic lexicon to mimic strategic control over the extent of specific lexical processing. In this article, we provide an account in which the effects are simulated by varying the DRC's reading-aloud criterion--a parameter that sets the minimal level of phonemic activation required to pronounce a letter string. We show that varying this parameter provides another means of controlling lexical contributions to reading aloud. PMID- 17694930 TI - ECG of the month. Chest tightness and electrocardiographic changes during a dipyridamole-technetium-99m-sestamibi myocardial perfusion study. Myocardial ischemia. PMID- 17694931 TI - Radiology case of the month. Acute left thigh pain and weakness. Diabetic amyotrophy. PMID- 17694932 TI - A middle-aged man with newly diagnosed HIV infection and rash. AB - TEN is a rare cutaneous drug reaction associated with high morbidity and mortality. The underlying pathogenic mechanisms are poorly understood. Development of an effective treatment algorithm has been hampered by the low incidence of this disorder, incomplete knowledge of the mechanisms of epidermal death, and lack of large controlled trials to evaluate therapeutic interventions. PMID- 17694933 TI - Disparities in schizophrenic disorders and associated co-morbidities among inpatient discharges in Louisiana hospitals from the years 2000 to 2003. AB - National and international studies have suggested in the past that there are disparities based on the race of the patient for the diagnoses of schizophrenic disorders. The purpose of this study was to look for the same disparities in Louisiana inpatient population based on LAHIDD (Louisiana Hospital Inpatient Discharge Database) data from the years 2000 to 2003. We also looked for co morbid substance and alcohol-related mental disorders in the same patient population. Our study concluded that for the years 2000-2003, 50.52 % of patients were African American/black as compared to 30.09 % Caucasian/white; 56.73 % were between the ages of 18-44 years, 56.17 % were males and 43.83 % were females; 71.48 % were single. Further research is required to determine the underlying causes for the disparities in the diagnoses of schizophrenic disorders. PMID- 17694934 TI - Colo-rectal duplication: a case report and review of the literature. PMID- 17694935 TI - Hymenopterid bites, stings, allergic reactions, and the impact of hurricanes on hymenopterid-inflicted injuries. AB - Hymenopterid stings and subsequent allergic reactions are a common indication for emergency department visits worldwide. Unrecognized anaphylactic reactions to hymenopterid stings by apids, or bees, and vespids, or wasps, are a significant cause of sudden and unanticipated deaths outdoors in young people, with and without atopic histories. Insect bites and stings, often complicated by allergic reactions or skin infections, by community-acquired pathogens, such as methicillin-resistant Staphylococcus aureus, are common sources of morbidity following hurricanes, tropical storms, and prolonged flooding. This article will review and critically analyze the descriptive epidemiology and outcomes of hymenopterid bites, stings, and allergic reactions, especially following hurricanes and prolonged flooding disasters; stratify the immunologic reactions to hymenopterid stings by clinical severity and outcomes; and present current recommendations for management, prophylaxis, and prevention of hymenopterid stings and reactions. PMID- 17694936 TI - Double endoscopic technique for operative dilation of esophageal strictures resistant to conventional therapy. AB - Esophageal strictures are a common problem causing significant morbidity for affected patients. Most can be treated safely and successfully with esophageal dilation. We have treated two patients with post-radiation esophageal strictures so tight that standard dilation technique failed even with an aggressive approach. We utilized a technique for operative dilation of these strictures using both antegrade and retrograde endoscopes. This approach for refractory esophageal strictures has only twice been previously reported. In both patients, a gastrostomy was placed and an endoscope was subsequently passed from the stomach retrograde up to the level of the stricture. Another endoscope was passed from above down to the proximal portion of the stricture. Illuminating the stricture, using fluoroscopy, carefully passing a wire, and grasping and pulling the wire with forceps from the opposite endoscope allowed for safe passage through the stricture. Savary dilators were utilized to effectively dilate the strictures. A method for protection of the lumen for subsequent dilations by passing a small catheter through the stricture was also developed. This technique offers an option for patients with otherwise untreatable strictures, with the major advantage of visualization from above and below. PMID- 17694937 TI - The effect of Katrina on clinical research: lessons learned. PMID- 17694938 TI - The case report of staphylococcal scalded skin syndrome. PMID- 17694939 TI - Case report of hantavirus pulmonary syndrome and review. AB - A previously healthy 29-year-old male presented to the emergency department with pleuritic chest pain, nonproductive cough, and dyspnea. He was treated empirically for community acquired pneumonia and discharged to home. Two days later, the patient presented with respiratory distress along with neutrophilia, thrombocytopenia, elevated liver function tests, and hemoconcentration. Radiographs of his chest showed bilateral lung infiltrates and pleural effusions. He was admitted to the hospital and developed cardiopulmonary failure and died the following day. Serologic tests for hantavirus pulmonary syndrome confirmed the diagnosis. PMID- 17694940 TI - Treatment of type 2 diabetes mellitus and the incretin system. PMID- 17694941 TI - Pay for performance: evaluating incentive plans. PMID- 17694943 TI - Continuing dental education on the Internet. PMID- 17694942 TI - Quality focus: Welcome to Medicare exams--a great opportunity for South Dakota seniors. PMID- 17694944 TI - Influence of a nanometer-scale surface enhancement on de novo bone formation on titanium implants: a histomorphometric study in human maxillae. AB - In this prospective randomized controlled clinical study, small titanium implants were placed in posterior maxillae for the purpose of assessing the rate and extent of new bone development. Nine pairs of site evaluation implants were placed in posterior areas of maxillae and retrieved with trephine drills after 4 or 8 weeks of unloaded healing. The amount of bone in linear contact (%) with the implant surface was used to determine the osteoconductive potential of the implant surface. Implant surfaces were dual acid etched (n = 9) (controls) or dual acid etched and further conditioned with nanometer-scale crystals of calcium phosphate (n = 9) (test implants), and the surfaces were compared. The implants and surrounding tissues were processed for histologic analysis. The mean bone-to implant contact value for the test surface was significantly increased over that of the control implants at both time intervals (P <.01). For the implants/patients included in this study, the addition of a nanometer-scale calcium phosphate treatment to a dual acid-etched implant surface appeared to increase the extent of bone development after 4 and 8 weeks of healing. PMID- 17694945 TI - Nine-year results following treatment of intrabony periodontal defects with an enamel matrix derivative: report of 26 cases. AB - Treatment of intrabony periodontal defects with an enamel matrix derivative (EMD) has been demonstrated, in the short term, to result in periodontal regeneration and to significantly improve clinical parameters such as probing depth (PD) and clinical attachment level (CAL). The present study evaluated deep intrabony defect sites at 9 years after treatment with EMD. Twenty-one patients with a total of 26 deep intrabony defects with PD > or = 6 mm and intrabony depth > or = 3 mm, as identified by probing and radiographs, were consecutively treated with EMD. PD, recession of the gingival margin (GR), and CAL were evaluated prior to treatment and at 1 and 9 years after treatment. At 1 year, mean PD was significantly reduced. At 9 years, mean PD was statistically significantly increased versus the 1-year results but still significantly improved versus baseline. After I year, mean GR had increased significantly; at 9 years, measurements showed statistically significant improvements compared to the 1-year results and baseline. The mean CAL changed from 10.0 +/- 2.3 mm at baseline to 6.8 +/- 2.3 mm at 1 year and to 7.0 +/- 1.9 mm at 9 years. No treated teeth were lost during the observation period. The clinical improvements obtained following treatment with EMD can be maintained over a period of 9 years. PMID- 17694946 TI - A telescopic crown concept for the restoration of partially edentulous patients with aggressive generalized periodontitis: a 3-year prospective longitudinal study. AB - This prospective longitudinal 3-year study compared clinical parameters and implant success rates of removable superstructures supported by both teeth and implants in patients with treated generalized aggressive periodontitis (GAP) and of cemented, implant-retained fixed superstructures in periodontally healthy patients. A total of 17 partially edentulous patients with 54 implants took part in the study. Nine patients with treated GAP received removable superstructures according to the Marburg double crown system, and eight periodontally healthy patients received fixed superstructures. Teeth were examined 2 to 4 weeks before extraction of the nonretainable teeth (baseline) and 3 weeks after insertion of the definitive abutments. Every 3 months over a 3-year period, clinical parameters were recorded and the composition of the subgingival microflora was determined. Intraoral radiographs were obtained at baseline, just after insertion of the superstructure, and 1 and 3 years later. Both groups showed mean plaque and gingival indices below 0.43 at implants and teeth. Mean probing depths around implants increased by approximately 0.7 mm and remained virtually constant for the teeth. Mean attachment loss at implants was 0.9 mm in GAP patients and 0.5 mm in healthy patients. The morphologic distribution of microorganisms in both groups showed healthy conditions. Moderate bone loss at teeth and implants was registered. Implant success rates were 100% in the healthy patients and 97.6% in the GAP patients. No significant differences were seen in the results between the groups. PMID- 17694947 TI - Use of a piezoelectric surgical device to harvest bone grafts from the mandibular ramus: report of 40 cases. AB - Forty patients (12 men, 28 women; mean age 44.9 +/- 13.95 years) with inadequate bone volume for implant placement in either the maxilla or the mandible were scheduled for bone-grafting procedures. Bone grafts were harvested with a piezoelectric surgical device (Piezosurgery, Mectron) from 45 donor sites and grafted into recipient sites prior to implant placement. After healing of the grafted sites, 109 implants were placed. Clinical evaluations were performed to assess the size and quality of the obtained grafts, complications at the donor and recipient sites, integration of the grafts, bone quality, resorption of the grafts, and ability to properly place implants. Piezosurgery allowed precise, clean, and smooth cutting with excellent visibility. Mean graft size was 1.15 cm3 (SD 0.5), with a maximum of 2.4 cm3. The quality of the obtained grafts was mainly cortical (71%), 42 of the 45 donor sites healed uneventfully (93.33%), and 50 of the 52 grafted sites healed uneventfully (96.15%). PMID- 17694948 TI - In vitro color changes of soft tissues caused by restorative materials. AB - A crucial factor influencing implant esthetics is the color of the peri-implant mucosa. This in vitro study analyzed the effect of titanium and zirconia with and without veneering ceramic on the color of mucosa of three different thicknesses. Ten pig maxillae were used, and the palatal area was chosen as the test region. To simulate different mucosa thicknesses, connective tissue grafts, 0.5 mm and 1.0 mm thick, were harvested from three additional jaws. Defined mucosa thicknesses were created by placing the grafts under a palatal mucosa flap. Four different test specimens (titanium, titanium veneered with feldspathic ceramic, zirconia, and zirconia veneered with feldspathic ceramic) were placed under the mucosa, and the color of the tissue was evaluated with a spectrophotometer for three different soft tissue thicknesses (1.5, 2.0, and 3.0 mm). The color was compared to mucosa without test specimens, and the color difference (DeltaE) was calculated. All restorative materials induced overall color changes (DeltaE), which diminished with increases in soft tissue thickness. Titanium induced the most prominent color change. Zirconia did not induce visible color changes in 2.0 mm-thick and 3.0-mm-thick mucosa, regardless of whether it was veneered. However, with a mucosa thickness of 3.0 mm, no change in color could be distinguished by the human eye on any specimen. Mucosa thickness is a crucial factor in terms of discoloration caused by different restorative materials. In patients with thinner mucosa, zirconia will show the least color change. PMID- 17694949 TI - Removable prosthesis supported by implants according to the Cagliari modified conometry technique: case report. AB - This report describes the rehabilitation of a patient who was completely edentulous in the mandible with a removable prosthesis supported by implants on four Straumann Wide-Neck implants placed in the positions of the canines and second molars. The Cagliari modified conometry technique was developed to improve and simplify anchorage systems based on conical copings in a removable prosthesis supported by implants. The connection of the removable prosthesis to the implants is obtained by primary conical copings, which are screwed to the implants, coupled to secondary copings equipped with plastic friction devices (Arch Friction-Soft, Dental Konos). After the secondary copings are positioned on the primary copings, the secondary copings are fixed with acrylic resin to the removable prosthesis in the mouth, with the goal of passive fit. The prosthesis produced with this method is not a classic implant-supported overdenture but is a removable prosthesis completely supported by implants that is shaped like a fixed prosthesis. This type of prosthesis is extremely stable and has modular retention (plastic friction), creating ideal conditions for oral hygiene. The stability of this type of prosthesis results in psychologic comfort and masticatory performance similar to that of a fixed prosthesis but with the hygiene, esthetics, and lower expense of an overdenture. PMID- 17694950 TI - The ray setting procedure: a new method for implant planning and immediate prosthesis delivery. AB - This paper introduces a new system for planning implant positions directly on the working cast, called the ray setting procedure. It allows clinicians to obtain, on a master cast, the correct implant positions through the correction of previously planned expected positions. The device used is the Ray Set, a machine that can be used to precisely define, on the plaster working cast of the mouth, hard and soft tissue anatomy and correlate it with an articulator and computed tomographic data from the patient. This cast is used to build an individual surgical stent that perfectly matches the teeth and soft tissues as well as a provisional or definitive implant-supported prosthesis for partially or completely edentulous patients. A clinical case is presented to explain the procedure. A definitive all-ceramic cemented and screw-retained prosthesis, fabricated from a rigid material and with passive fit, was created before implant surgery and was placed with an immediate occlusal load applied a few minutes after implant placement. The prosthesis was retained with both cement and screws so as to make removal easy for accurate finishing of the margins immediately before cementation. The prosthesis was built, before implant surgery, according to the PIP method (presurgical implant prosthesis). The ray setting procedure can be used for planning immediate or delayed loading of implants. PMID- 17694951 TI - Immediate function with NobelPerfect implants in the anterior dental arch. AB - This study examined the clinical performance of the scalloped NobelPerfect implant in a one-stage procedure (immediate provisionalization in the esthetic zone). In 20 patients, immediate prosthetic restorations were placed on 31 NobelPerfect implants and followed for up to 27 months. Outcome variables were success rates, marginal bone levels, and Pink Esthetic Score (PES) assessed per implant. One implant failed (success rate: 96.8%). Marginal bone levels averaged 1.7 mm above the first thread and remained stable during the observation period. Mean PES ratings were 11.3 (range, 8 to 14). Survival rates, marginal bone levels, and esthetic results suggest proof of principle for the preservation of the interproximal bony lamella with a scalloped implant design. PMID- 17694952 TI - Osseointegration of titanium implants following guided bone regeneration using expanded polytetrafluoroethylene membrane and various bone fillers. AB - The purpose of this study was to evaluate the percentage of bone-to-implant contact following guided bone regeneration using expanded polytetrafluoroethylene (e-PTFE) membranes and various bone fillers in a beagle dog model. A staged approach was used for initial bone regeneration of surgically created defects and subsequent implant placement in newly regenerated ridges. Three months after bilateral extraction of the mandibular premolars and first molars, rectangular, distal-extension defects that included the entire width of the ridge buccolingually were surgically created in the alveolar processes. All defects were covered with an e-PTFE membrane, and several bone fillers were placed, in a randomized fashion, under the membrane: autogenous bone, demineralized freeze dried bone, anorganic bovine bone, tricalcium phosphate granules, and collagen sponge. One site in each animal was treated with e-PTFE barrier membrane alone as control. Following an 8-month healing period, nonsubmerged titanium implants (36 total) were placed in regenerated bone following membrane removal. Three months later, the animals were sacrificed, and nondecalcified buccolingual sections were evaluated histometrically for bone-to-implant contact. All sites demonstrated high percentages (50% to 65%) of bone-to-implant contact, with no significant differences across the various treatment groups. In addition, all tested bone fillers formed a complex that supported and maintained the osseointegrated implants in a healthy state, with no apparent signs of peri-implantitis. Using a staged approach, the present study provided histologic and histometric evidence that implants placed in entirely regenerated bone can achieve and maintain osseointegration, regardless of the type of bone fillers used. PMID- 17694953 TI - Significance of Bcl-2 and Bax proteins in cervical carcinogenesis: an immunohistochemical study in squamous cell carcinoma and squamous intraepithelial lesions. AB - Sixteen low grade (LSIL), 22 high grade (HSIL) squamous intraepithelial lesions, 28 invasive (13 stage I and 15 stage II-IV) squamous cell carcinoma (SCC) and 15 benign cervices were immunohistochemically studied for involvement of Bcl-2 and Bax proteins in cervical carcinogenesis. 4-microm sections of the cases were immunostained for Bcl-2 (Clone 124: Dako) and Bax (Dako) and staining intensity was rated as 1 (light), 2 (moderate) and 3 (strong) and percentage cellular staining as 0 (negative), 1 (1-25%), 2 (26-50%), 3 (51-75%) and 4 (>75%) with score derived by multiplying staining intensity and percentage positivity. The cut-off value, indicating upregulated expression, was computed as >2 for Bcl-2 and >8 for Bax. Bcl-2 was upregulated (p < 0.05) in HSIL and Bax in SCC when compared with benign cervical squamous epithelium. Bcl-2 expression was confined to the lower third of the epithelium in the benign cervices and LSIL. In HSIL, expression reached the middle and upper thirds. 4 (30.8%) HSIL with upregulated Bcl-2 demonstrated intensification of staining around the basement membrane. SCCs showed "diffuse" (evenly distributed) or "basal" (intensified staining around the periphery of the invading tumour nests) expression of Bcl-2. Of the 5 SCCs with upregulated Bcl-2, 1 of 2 (50%) stage I and 3 (100%) stage II-IV tumours exhibited the "basal" pattern. Benign cervical squamous epithelium, LSIL, HSIL and SCC showed a generally diffuse Bax expression. Thus, Bcl-2 and Bax appeared to be upregulated at different stages of cervical carcinogenesis, Bcl-2 in HSIL and Bax after invasion. Intensification of staining of Bcl-2 at the basement membrane in some HSIL and SCC is interesting and may augur for increased aggressiveness. PMID- 17694954 TI - Use of the denaturing gradient gel electrophoresis (DGGE) method for mutational screening of patients with familial hypercholesterolaemia (FH) and Familial defective apolipoprotein B100 (FDB). AB - Familial hypercholesterolaemia (FH) and Familial defective apolipoprotein B100 (FDB) are autosomal dominant inherited diseases of lipid metabolism caused by mutations in the low density lipoprotein (LDL) receptor and apolipoprotein B 100 genes. FH is clinically characterised by elevated concentrations of total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C), presence of xanthomata and premature atherosclerosis. Both conditions are associated with coronary artery disease but may be clinically indistinguishable. Seventy-two (72) FH patients were diagnosed based on the Simon Broome's criteria. Mutational screening was performed by polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE). Positive mutations were subjected to DNA sequencing for confirmation of the mutation. We successfully amplified all exons in the LDL receptor and apo B100 genes. DGGE was performed in all exons of the LDL receptor (except for exons 4-3', 18 and promoter region) and apo B100 genes. We have identified four different mutations in the LDL receptor gene but no mutation was detected in the apo B 100 gene. The apo B100 gene mutation was not detected on DGGE screening as sequencing was not performed for negative cases on DGGE technique. To our knowledge, the C234S mutation (exon 5) is a novel mutation worldwide. The D69N mutation (exon 3) has been reported locally while the R385W (exon 9) and R716G (exon 15) mutations have not been reported locally. However, only 4 mutations have been identified among 14/72 patients (19.4%) in 39 FH families. Specificity (1-false positive) of this technique was 44.7% based on the fact that 42/76 (55.3%) samples with band shifts showed normal DNA sequencing results. A more sensitive method needs to be addressed in future studies in order to fully characterise the LDLR and apo B100 genes such as denaturing high performance liquid chromatography. In conclusion, we have developed the DNA analysis for FH patients using PCR-DGGE technique. DNA analysis plays an important role to characterise the type of mutations and forms an adjunct to clinical diagnosis. PMID- 17694955 TI - Molecular characterisation and frequency of Ggamma Xmn I polymorphism in Chinese and Malay beta-thalassaemia patients in Malaysia. AB - The molecular basis of variable phenotypes in P-thalassaemia patients with identical genotypes has been associated with co-inheritance of alpha-thalassaemia and persistence of HbF production in adult life. The Xmn I restriction site at 158 position of the Ggamma-gene is associated with increased expression of the Ggamma-globin gene and higher production of HbF This study aims to determine the frequency of the digammaferent genotypes of the Ggamma Xmn I polymorphism in P thalassaemia patients in two ethnic groups in Malaysia. Molecular characterisation and frequency of the Ggamma Xmn I polymorphism were studied in fifty-eight Chinese and forty-nine beta-thalassaemia Malay patients by Xmn I digestion after DNA amplification of a 650 bp sequence. The in-house developed technique did not require further purification or concentration of amplified DNA before restriction enzyme digestion. The cheaper Seakem LE agarose was used instead of Nusieve agarose and distinct well separated bands were observed. Genotyping showed that the most frequent genotype observed in the Malaysian Chinese was homozygosity for the absence of the Xmn I site (-/-) (89.7%). In the Malays, heterozygosity of the Xmn I site (+/-) was most common (63.3%). Homozygosity for the Xmn I site (+/+) was absent in the Chinese, but was confirmed in 8.2% of the Malays. The ratio of the (+) allele (presence of the Xmn I site) to the (-) allele (absence of the Xmn I site)) was higher in the Malays (0.66) compared to the Chinese (0.05). The (+/-) and (+/+) genotypes are more commonly observed in the Malays than the Chinese in Malaysia. PMID- 17694956 TI - Linkage and association studies in a Malaysian family with autosomal recessive non-syndromic hearing loss. AB - Hearing loss is a common sensory deficit in humans. The hearing loss may be conductive, sensorineural, or mixed, syndromic or nonsyndromic, prelingual or postlingual. Due to the complexity of the hearing mechanism, it is not surprising that several hundred genes might be involved in causing hereditary hearing loss. There are at least 82 chromosomal loci that have been identified so far which are associated with the most common type of deafness--non-syndromic deafness. However, there are still many more which remained to be discovered. Here, we report the mapping of a locus for autosomal recessive, non-syndromic deafness in a family in Malaysia. The investigated family (AC) consists of three generations- parents who are deceased, nine affected and seven unaffected children and grandchildren. The deafness was deduced to be inherited in an autosomal recessive manner with 70% penetrance. Recombination frequencies were assumed to be equal for both males and females. Using two-point lod score analysis (MLINK), a maximum lod score of 2.48 at 0% recombinant (Z = 2.48, theta = 0%) was obtained for the interval D14S63-D14S74. The haplotype analysis defined a 14.38 centiMorgan critical region around marker D14S258 on chromosome 14q23.2-q24.3. There are 16 candidate genes identified with positive expression in human cochlear and each has great potential of being the deaf gene responsible in causing non-syndromic hereditary hearing loss in this particular family. Hopefully, by understanding the role of genetics in deafness, early interventional strategies can be undertaken to improve the life of the deaf community. PMID- 17694957 TI - Mutational analysis of p53 and RB2/p130 genes in Malaysian nasopharyngeal carcinoma samples: a preliminary report. AB - This study reports the results of mutation detection of tumour suppressor genes, p53 and RB2/p130 genes in Malaysian nasopharyngeal carcinoma (NPC) studied by PCR CSGE analysis and direct DNA sequencing method. Frequent sites of mutation in both genes (exons 5-8 of p53 and exons 19-21 of RB2/p130) were examined. Thirty six NPC blood samples and three NPC cell lines were investigated for the presence of mutations. No mutation of p53 and RB2/p130 genes was identified in any of the blood samples. Nonetheless, there was an identical G-->4 C nucleotide change at codon 280 of p53 gene in all the cell lines. A larger study that includes biopsy tissues should be carried out to provide a more in-depth look into the pathogenesis of NPC in Malaysia. PMID- 17694958 TI - Elevated plasma tissue factor levels in neonates with umbilical arterial catheter associated thrombosis. AB - Catheterization of the umbilical artery has been a useful aid in the management of sick neonates for the past few decades. However, it is associated with various complications. Reported studies strongly suggest a significant role of intravascular catheterization in the development of aortic thrombi. Increase in thrombosis of large vessels is believed to be related to mechanical injury in the catheterized vessels, which provide direct exposure of blood to tissue factor (TF), the primary cellular initiator of the extrinsic coagulation pathway. This study was conducted to determine the levels of plasma TF, tissue factor pathway inhibitor (TFPI) and D-dimer (DD) in infants with umbilical arterial catheter (UAC)-associated thrombosis. Quantification of TF was carried out using an in house sandwich ELISA, whereas TFPI and DD levels were measured with commercial immunoassay kits. Infants with UAC inserted were found to have significantly higher levels of plasma TF (p < 0.001) than baseline levels. However, there were no significantly elevated levels of TFPI or DD. Infants with UAC-associated thrombosis demonstrated a greater increase of TF level (median: 414.5 pg/mL; range: -76.0, 6667.0) than infants without UAC-associated thrombosis (105.0 pg/mL; -976.0, 9480.0; p = 0.009) following UAC insertion. Our findings indicate that quantification and monitoring of TF levels could predict thrombus formation in infants with indwelling UAC. Following umbilical arterial catheterisation, infants with an approximately 3-fold rise in plasma TF levels were most at risk of developing abdominal aorta thrombosis as confirmed by real-time abdominal ultrasonography. PMID- 17694959 TI - Edwardsiella tarda septicemia with underlying multiple liver abscesses. AB - Edwardsiella tarda has recently been described as a member of the family Enterobacteriaceae. The genus Edwardsiella contains three species; E. hoshinae, E. ictaluri and E. tarda. Edwardsiella tarda is the only species which has been recognised as pathogenic to humans, especially in those with an underlying disease. The most common presentation is watery diarrhoea. Extra intestinal infections have been reported infrequently. Humans seem to be infected or colonised with Edwardsiella through ingestion or inoculation of a wound. This report is of a patient with multiple liver abscesses due to E. tarda who later developed bacterial peritonitis and septicaemic shock. PMID- 17694960 TI - Extensive myelofibrosis responsive to treatment for acute erythroblastic leukaemia. AB - Intense myelofibrosis is rarely associated with de novo acute myeloid leukaemia (AML) except in acute megakaryoblastic leukaemia (AML-M7) where there is diffuse marrow fibrosis as a consequence of proliferation of neoplastic myeloid cells. AML associated with significant myelofibrosis developing both de novo or secondary to primary (idiopathic) myelofibrosis is characterised by a fulminant course and extremely poor prognosis, primarily due to treatment-resistant disease. The prognostic value of degree of marrow fibrosis in de novo AML has been poorly investigated. We describe a case of extensive myelofibrosis associated with acute erythroblastic leukaemia (AML-M6) that responded to induction therapy of the leukaemia. PMID- 17694961 TI - Diagnosis of gestational diabetes mellitus: is it time for a new critical value? AB - OBJECTIVE: To identify the value for the 1-hour glucose tolerance test (GTT) that would maintain 100%, 90% and 75% sensitivity for identifying abnormal 3-hour GTT results in prenatal patients from an East Coast, urban, university hospital setting. STUDY DESIGN: Two hundred forty-two women who underwent the 3-hour GTT during pregnancy between January 1, 2004, and February 1, 2005, at a university hospital laboratory and private laboratories were included. The preceding 1-hour GTT results were obtained from these women, and a receiver operating characteristic (ROC) curve was constructed to identify a 1-hour GTT cutoff value that would maintain 100%, 90% and 75% sensitivity. A subgroup analysis was performed of patients of Asian ethnicity. This study was approved by the institutional review board. RESULTS: To maintain 100% sensitivity of the 1-hour GTT in predicting an abnormal 3-hour GTT, the 1-hour GTT cutoff value could be raised to 144 mg/dL in our population. For 90% and 75% sensitivities, the values were 150 and 156 mg/dL, respectively. There was no clinically significant difference in ROC curve evaluation between Asian and non-Asian groups. CONCLUSION: Raising the current level of 135 mg/dL for a 1-hour GTT to potentially decrease the need for the 3-hour GTT should be considered if larger patient series yield findings similar to those in our population. PMID- 17694962 TI - An impedance-controlled system for endometrial ablation: five-year follow-up of 107 patients. AB - OBJECTIVE: To assess the safety, efficacy and data durability of the NovaSure endometrial ablation system 5 years after the procedure in women with severe menorrhagia secondary to dysfunctional uterine bleeding (DUB). STUDY DESIGN: A prospective, single-arm, pilot study of 107 women undergoing endometrial ablation using the NovaSure system (Canadian Task Force classification II-1) at a specialized center for gynecologic endoscopy. The premenopausal women, with menorrhagia secondary to DUB unresponsive to medical therapy, had completed childbearing. A Pictorial Blood-Loss Assessment Chart was used to conduct a posttreatment evaluation of menstrual blood loss and bleeding pattern. Ablation was performed without any type of endometrial pretreatment. RESULTS: No intraoperative or postoperative complications were observed. Treatment time averaged 94 seconds. At the 5-year follow-up, amenorrhea was reported by 75% of patients and successful reduction of bleeding was achieved in 98%, with hysterectomy and retreatment rates of 2.9% and 3.8%, respectively. CONCLUSION: Long-term clinical results indicate that the NovaSure system is a safe and effective method for treatment of women with menorrhagia secondary to DUB. NovaSure yields high amenorrhea and success rates and low surgical reintervention rates 5 years after treatment. PMID- 17694963 TI - Vaginal vs. cesarean delivery for preterm breech presentation of singleton infants in California: a population-based study. AB - OBJECTIVE: To examine the morbidity and mortality associated with vaginal breech delivery (VBD) of premature, low-birth-weight (LBW) (< 2.5 kg) newborns as compared to delivery by cesarean section. STUDY DESIGN: A retrospective cohort study of singleton, preterm (< 37 weeks), LBW, nonanomalous newborns in California (January 1, 1991-December 31, 1999) was performed. Neonatal morbidity and mortality by route of delivery were compared. RESULTS: Overall, 14,417 LBW, preterm, breech newborns were delivered (14% vaginally and 86% by cesarean). There were 150,570 LBW, preterm, cephalic newborns, of whom 82% were delivered vaginally. VBD of LBW newborns in nulliparous women was associated with increased neonatal mortality in newborns weighing 500-1,000 g (OR 11.7; 95% CI 7.9, 17.2), 1,001-1,500 g (OR 17.0; 95% CI 6.8, 42.7), 1,501-2,000 g (OR 7.2; 95% CI 2.4, 21.4), and 2,001-2,500 g (OR 6.6; 95% CI 2.1, 21.2) as compared with breech delivery by cesarean in nulliparous women. Birth trauma was increased in VBD of newborns weighing 1,500-2,000 g (OR 3.8; 95% CI 1.4, 10.1) and 2,001-2,500 g (OR 4.5; 95% CI 2.6, 7.9) as compared to breech delivery by cesarean in nulliparous women. Birth asphyxia was increased in breech newborns weighing 2,001-2,500 g (OR 3.5; 95% CI 2.2, 5.6) delivered vaginally in nulliparous women as compared to cephalic vaginal deliveries. CONCLUSION: VBD of the preterm, LBW newborn is associated with significantly increased neonatal mortality as compared to cesarean section at similar birth weights. Birth trauma (> 1,500 g) was greater with VBD as compared to breech delivery by cesarean, and asphyxia (> 2,000 g) was greater with VBD as compared to cephalic vaginal delivery, suggesting that cesarean delivery may be a safer route of delivery for preterm breech fetuses. PMID- 17694964 TI - Management of group B Streptococcus in pregnant women with penicillin allergy. AB - OBJECTIVE: To determine whether group B Streptococcus (GBS)-colonized pregnant women who report a history of penicillin allergy can safely undergo diagnostic evaluation to rule out or confirm the potential for an IgE-mediated (allergic) reaction to penicillin. STUDY DESIGN: Over 18 months, all pregnant women with GBS positive vaginal/rectal cultures and a history of penicillin allergy were referred to the Department of Allergy and Immunology for a history and possible skin testing. Patients who had experienced anaphylaxis were advised to continue avoiding penicillin and were not skin tested. Women without such a history underwent immediate hypersensitivity (percutaneous and intradermal) testing using 2 penicillin reagents with controls. If skin testing was negative, intrapartum antimicrobial prophylaxis with intravenous penicillin was administered. RESULTS: Of 28 patients with both GBS colonization and "penicillin allergy," 25 (89%) had negative skin testing to penicillin and received intrapartum penicillin for GBS prophylaxis without adverse reactions. Skin testing was positive in 2 patients, and intrapartum penicillin was not administered. Penicillin skin testing was not performed on 1 patient due to a history of anaphylaxis from penicillin. CONCLUSION: These results indicate that most pregnant women reporting penicillin allergy undergo negative skin tests and are able to safely receive intrapartum penicillin GBS prophylaxis. PMID- 17694965 TI - Human papillomavirus in vulvar vestibulitis syndrome. AB - OBJECTIVE: To investigate the prevalence of human papillomavirus (HPV) in patients with vulvar vestibulitis syndrome by using a recently developed polymerase chain reaction (PCR) primer set that detects known papillomavirus types. STUDY DESIGN: We retrospectively identified 38 patients with vulvar vestibulitis who underwent therapeutic surgical excision of the vestibule. Eleven controls without vestibulitis who underwent vestibular excision for conditions unrelated to HPV infection were identified prospectively. Surgical specimens were examined for the presence of HPV DNA by PCR amplification. DNA sequencing was used to determine HPV type. RESULTS: The prevalence of HPV among patients with vestibulitis was 21% vs. 36% among controls. Group B HPV types accounted for 4 of the 10 (40%) HPV types found in patients with vestibulitis. Overall, in both patient and control samples, a spectrum of HPV types was identified, encompassing many branches of the HPV phylogenetic tree. No etiologic association was apparent. CONCLUSION: This study did not support an association of HPV with vulvar vestibulitis. The low rate of observed infection in women with and without vestibulitis and the diversity of HPV types identified suggest incidental virus carriage rather than direct cause and effect. The underlying cause of this debilitating condition remains unknown. PMID- 17694966 TI - Uterine weight as a predictor of morbidity after a benign abdominal and total laparoscopic hysterectomy. AB - OBJECTIVE: To determine if an enlarged uterus is associated with an increased rate of intraoperative and postoperative complications and prolonged hospital length of stay (LOS) after benign total abdominal hysterectomy (TAH) or total laparoscopic hysterectomy (TLH). STUDY DESIGN: Women who underwent TAH or TLH were stratified, according to uterine weight, into 3 groups: group 1, uterine weight < 200 g; group 2, 201-500 g; and group 3, > 500 g. Indications included uterine leiomyomas, chronic pelvic pain, prolapsed uterus, endometriosis and adenomyosis, dysfunctional uterine bleeding; all had benign final pathology. Statistical analysis compared risks of intraoperative and postoperative morbidity and prolonged hospital stay. RESULTS: Prolonged hospital stay risk increased for uterine weight > 500 g (p < or = 0.001). There was a significant association between postoperative complications and uterine size (p < or = 0.001). Mean estimated blood loss (EBL) also increased with uterine weight > 500 g (p < or = 0.001). TLH was associated with fewer postoperative complications, shorter LOS and reduced EBL (p < or = 0.001). CONCLUSION: Average LOS and risk of blood loss, blood transfusion and other postoperative complications after hysterectomy for benign disease increased with increasing uterine weight. TLH is an excellent alternative for enlarged uteri; it was strongly associated with decreased morbidity, shorter LOS, and reduced EBL and blood transfusion rate in all uterine weight groups when adjusted for other variables. PMID- 17694967 TI - Thrombophilia and antithrombotic therapy in women with recurrent spontaneous abortions. AB - OBJECTIVE: To investigate the association between thrombophilia and recurrent spontaneous abortions (RSAs) and to evaluate the efficacy of anticoagulant treatment. STUDY DESIGN: All couples with a history of RSAs were studied by immunologic tests and determination of coagulation factors. Low-molecular-weight heparin and low-dose aspirin daily during pregnancy were used in 29 selected cases with acquired and inherited thrombophilia. The control group included 23 women with a history of RSAs and tests positive for thrombophilia who declined to receive medication during pregnancy. RESULTS: All couples with a history of RSAs were studied by immunologic tests and determination of coagulation factors. Low molecular-weight heparin and low-dose aspirin daily during pregnancy were used in 29 selected cases with acquired and inherited thrombophilia. The control group included 23 women with a history of RSAs and tests positive for thrombophilia who declined to receive medication during pregnancy. CONCLUSION: All couples with RSAs require screening for thrombophilia. Low-molecular-weight heparin and low dose aspirin daily during pregnancy appear to have a favorable effect on pregnancy outcome in selected women with RSAs and acquired or inherited thrombophilia. PMID- 17694968 TI - Light and electron microscopic study of epithelial cells from the human oviduct and uterus subcultured on extracellular matrix gel. AB - OBJECTIVE: To investigate the structure of epithelial cells from the human oviduct and uterus on extracellular matrix (ECM) gel in the first passage. STUDY DESIGN: Human oviducts and endometrial tissues were obtained from patients undergoing total hysterectomy; the epithelial cells, having been isolated by enzyme digestion, were cultured on polystyrene plastic surfaces. The epithelial nature of the cells was confirmed by immunocytochemistry, and their morphology was examined by microscopy. Cells of an epithelial nature were then trypsinized and cultured on an ECM gel-coated filter insert for 5 days. The cells, in parallel with the tissues, were subsequently prepared for transmission electron microscopy. RESULTS: Plastic-cultured cells had no sign of differentiation and appeared as elongated spindle cells in sections. These cells looked columnar and highly polarized after being cultured on ECM gel surfaces. They were similar to epithelial cells from the corresponding tissue fragment. Cultured on ECM gel, the ciliated epithelial cells of human oviducts appeared ultrastructurally similar to glandular cells from the human uterus. Cilia did not form under culture conditions. CONCLUSIONS: It seems that human uterine and oviduct epithelial cells can acquire polarized morphology and differentiated states on ECM gel after having lost it on plastic surfaces and that ECM gel by itself is not enough to induce cilia formation in culture. PMID- 17694969 TI - Effect of estrogen-progestin and estrogen on mammographic density. AB - OBJECTIVE: To assess the different effects between non-treatment, estrogen and estrogen-progestin regimens on changes in mammographic density in postmenopausal women. STUDY DESIGN: A historical cohort of 105 postmenopausal women who attended the Menopause Clinic, Srinagarind Hospital, Khon Kaen, Thailand, and received 1 of 3 regimens: nontreatment, estrogen or estrogen-progestin (35 in each group). Mammographic examinations were done before and after a 12-24-month period of hormone therapy. Breast density (mammographic density, recorded in the medical records) between the 2 examinations in each group were compared. RESULTS: An increase in mammographic density occurred among women receiving hormone therapy: 40% (14 of 35) in the estrogen-progestin group and 20% (7 of 35) in the estrogen only group, but no variation in density was observed in the nontreatment group. The increase in mammographic density occurring in women on hormone therapy, as compared to the nontreatment group, was statistically significant (estrogen progestin, 95% CI 20.91-59.09; estrogen, 95% CI 3.89-36.11). When the different treatment types were compared, the estrogen-progestin group tended to have a higher prevalence of mammographic density change than the estrogen-only group, but the difference was not statistically significant (95% CI -3.81-43.81). CONCLUSION: Hormone therapy was associated with increased mammographic density. Apparently the estrogen-progestin regimen affects breast density more than estrogen-only does. PMID- 17694970 TI - Therapeutic value of trichloroacetic acid in the treatment of isolated genital warts on the external female genitalia. AB - OBJECTIVE: To evaluate the value of 85% trichloroacetic acid (TCA) in the treatment of human papillomavirus (HPV)-associated genital warts of the external genitalia and to detect the recurrence rate and side effects of this therapeutic regimen. STUDY DESIGN: All patients with a suspected HPV-related papillary vulvar lesion after initial examination underwent vulvoscopic evaluation with a magnification of 8-20x using acetic acid and toluidine blue. Under local anesthesia, biopsies were taken from acuminate or papillary warts for histopathologic confirmation and from suspicious areas to exclude preinvasive or invasive diseases. Following histopathologic diagnosis, patients were treated with 85% TCA. RESULTS: Overall, 51 patients with isolated vulvar and/or perianal genital warts were included. Of those patients, 11 (21.5%) had acuminate and 40 (78.5%) had papular genital warts. All the women had lesions of the labia minora. The other localizations were as follows: labia majora, 18 (35.3%); lateral vulva, 5 (9.8%); clitoris, 9 (17.6%); fourchette, 16 (31.3%); and perianal area, 7 (13.7%). All lesions were successfully treated by the end of the treatment period (median, 4; range 2-5). None of the patients had recurrence or new lesions during the 6-month follow-up period. In the second 6 months, 9 patients (17.6%) were diagnosed with recurrent lesions. Although all the patients experienced transient burning pain during therapy, none of them discontinued the therapy. Ulceration was observed in 8 patients (15.6%). Of those patients only 3 had permanent scarring (5.8%). CONCLUSION: We recommend the use of TCA in patients with external genital warts, especially for mild to moderate cases. It is associated with a high success rate and low morbidity if sufficient care is taken during application. PMID- 17694971 TI - Pregnancy-induced bone marrow aplasia mimicking idiopathic thrombocytopenia: a case report. AB - BACKGROUND: Pregnancy has been associated with aplastic anemia, but a causal relationship has been questioned. CASE: A case of aplastic anemia was diagnosed during pregnancy and initially mimicked immune-mediated thrombocytopenic purpura. CONCLUSION: Pregnant women with aplastic anemia are at high risk. The severity of the disease and choice of the patient have to be considered before treatment. PMID- 17694972 TI - Neonate with a single umbilical vessel: a case report. AB - BACKGROUND: The respiratory, metabolic and excretory functions of the placenta provide maintenance of fetuses in utero even in the presence of severe malformations that preclude postnatal survival. CASE: A 17-year-old secundigravida delivered a 1,075-g liveborn in the 30th week of gestation. The infant was severely malformed, with gastroschisis and a short umbilical cord, and survived for 62 minutes after birth. The placenta was examined pathologically, and a complete an autopsy was performed. The cord measured 13.0 cm long, the limit for absolute shortness. An 8.0-cm segment was found to contain only 1 umbilical vessel, basically a vein, with segmental arterial pads. CONCLUSION: The concurrence in a liveborn infant of malformations so severe it could not be sustained, a segment of umbilical cord with only 1 vessel and postnatal survival of 62 minutes emphasizes the biologic distinction between existence and vitality. PMID- 17694973 TI - Fibroma of the vulva: a case report. AB - BACKGROUND: It is rare to see large vulvar growths that are not trauma related in young women. The largest vulvar mass recorded dates back to 1851. Fibroma of the vulva is not common but, if not seen early and removed, can be emotionally draining for the patient. CASE: A large vulvar mass was found in an 18-year-old woman and was expeditiously excised. The patient was emotionally withdrawn and would not participate in any school or social activities. She would carry moist paper towels with her to prevent maceration of the lower abdomen and lesion wall. CONCLUSION: An extraordinary physical finding can embarrass and alter a patient's demeanor and should be addressed without delay. The emotional condition of our patient prior to surgery consisted of depression and emotional stress due to the large vulvar mass. Following surgery the patient was comfortable, and her demeanor is now excellent. PMID- 17694974 TI - Syncopal episode as the presenting symptom of jugular vein thrombosis in pregnancy: a case report. AB - BACKGROUND: Jugular vein thrombosis has been reported to occur in pregnant women who conceived with assisted reproductive technology (ART). CASE: A 28-year-old woman at 17 weeks' gestation presented to the emergency room with a syncopal episode. She reported no arm pain or swelling, no neck pain or swelling, and no dyspnea or difficulty swallowing. Doppler sonography of the neck vasculature revealed acute bilateral internal jugular vein thromboses. Thrombophilia workup was normal. Intravenous anticoagulation with heparin was initiated, and the patient was discharged on low-molecular-weight heparin. CONCLUSION: Though rare, jugular vein thrombosis should be considered in the differential diagnosis of syncopal episodes even in women who conceive without ART. PMID- 17694975 TI - Extensive iliac vein thrombosis as a rare complication of a uterine leiomyoma: a case report. AB - BACKGROUND: Lower leg thombosis can occur in association with a large uterine leiomyoma. CASE: We report a case of extensive lower extremity thromboembolic disease secondary to large uterine myomas. The patient presented with sudden onset of lower extremity swelling in the absence of risk factors for thrombosis. Workup revealed extensive thrombosis involving iliac, femoral, popliteal, posterior tibial and peroneal veins secondary to vena caval compression by large uterine fibroids. Hysterectomy was performed after vena caval filter placement. CONCLUSION: In women with large uterine leiomyomas, the preoperative workup should include testing to rule out potential asymptomatic thrombi. PMID- 17694976 TI - Herpes in the peripartum period: a case report. AB - BACKGROUND: Despite the tremendous advances made in the management of genital herpes, neonatal herpes has not been completely eradicated. In addition, the time from the onset of symptoms in the neonate to the diagnosis of herpes and institution of antiviral medication has remained unchanged in the past 20 years. CASE: Neonatal herpes infection resulted from primary, first-episode peripartum genital herpes in the mother. Due to a high index of suspicion, herpes testing was performed on the infant and neonatal herpes diagnosed. Subsequently, the mother developed evidence of primary herpes infection. CONCLUSION: This case report illustrates the problems with current management strategies for prevention of neonatal herpes. PMID- 17694977 TI - Rupture of ectopic pregnancy with minimally detectable beta-human chorionic gonadotropin levels: a report of 2 cases. AB - BACKGROUND: Several studies have demonstrated that 25-77% of ectopic pregnancies spontaneously resolve with expectant management. However, expectant management is controversial and should be considered only for patients with small, unruptured gestational sacs, low beta-human chorionic gonadotropin (beta-hCG) levels and absence of symptoms. There is no consensus on how long to follow such patients. CASES: Two patients with beta-hCG levels < 10 mIU/mL presented with ruptured ectopic pregnancy and hemoperitoneum. CONCLUSION: While expectant management of a suspected ectopic pregnancy may allow spontaneous resolution of such an ectopic pregnancy, rupture may occur at any time and even with extremely low beta-hCG levels. Patients need to be counseled about the risks of rupture and symptoms, immediate action should be taken if symptoms develop, and serum beta-hCG levels should be followed to zero. PMID- 17694978 TI - Broad ligament lipoma presenting as a pelvic mass: a case report. AB - BACKGROUND: Pelvic masses can arise from gynecologic, nongynecologic, intraperitoneal and retroperitoneal structures. A retroperitoneal lipoma presenting as an adnexal mass is exceedingly rare. CASE: A 27-year-old, healthy woman had pelvic discomfort and was found to have pelvic organ displacement to the left side and a right adnexal mass. Ultrasonography revealed an echogenic adnexal mass, and computed tomography suggested a lipoma. At laparotomy a large, right, retroperitoneal broad ligament lipoma was found and excised completely without difficulty. DISCUSSION: Gynecologists should be aware of the possibility of retroperitoneal broad ligament lipomatous tumors presenting as adnexal masses. PMID- 17694979 TI - Strangulation of a prolapsed rectal cancer in labor: a case report. AB - BACKGROUND: Colorectal cancer during pregnancy is uncommon. Most patients present in late pregnancy, and the tumor is localized to rectum in up to 85% of cases. Delayed diagnosis due to confusing significant lower gastrointestinal symptoms with pregnancy-associated gastrointestinal changes is a common feature. From the increasing intraabdominal pressure during delivery, a tumor can prolapse throu the anus and develop incarceration and strangulation, but that is seen a extremely rarely, CASE: A 33-year-old woman was found to have a prolapsing rectal cancer through the anus during delivery, and it progressed to incarceration, CONCLUSION: Colorectal cancer during pregnancy is rare and mostly localized to the rectum. To manage a strangulated rectal prolapse that occurs in labor, consideration should be given to perineal rectosigmoidectomy under general anesthesia. The choice of surgical procedure is controversial if the preoperative diagnosis is not clear. PMID- 17694980 TI - Endometrial ablation in a woman with a persistent uterine hemorrhage due to acute promyelocytic leukemia: a case report. AB - BACKGROUND: Life-threatening uterine hemorrhage can be a presenting symptom in patients with acute promyelocytic leukemia (APML), of which one of the complications is disseminated intravascular coagulopathy. CASE: A 44-year-old, previously healthy woman, gravida 3, para 3, presented with a life-threatening uterine hemorrhage. She was subsequently diagnosed with APML by bone marrow biopsy. The uterine hemorrhage was treated with hormonal therapy and uterine artery embolization (UAE), which failed to control the bleeding. Radiofrequency, impedance-controlled endometrial ablation was successfully utilized. CONCLUSION: Endometrial ablation can be used to effectively treat a life-threatening uterine hemorrhage in patients with APML after failed medical therapy and UAE. PMID- 17694981 TI - Recurrent umbilical endometriosis after laparoscopic treatment of minimal pelvic endometriosis: a case report. AB - BACKGROUND: Umbilical endometriosis is extremely rare. The majority of cases occur spontaneously. There have been a few reported cases following laparoscopy but none for the treatment of pelvic endometriosis. CASE: Umbilical endometriosis occurred 20 months after laparoscopic treatment of stage 1 pelvic endometriosis. The symptoms recurred 7 months following excision of the lesion and were successfully treated with silver nitrate cautery. CONCLUSION: This is the first reported case of umbilical endometriosis following laparoscopic treatment of pelvic endometriosis as well as the first to demonstrate that chemical cautery may cure small lesions. PMID- 17694982 TI - Small bowel infarction secondary to volvulus during pregnancy: a case report. AB - BACKGROUND: Pregnancy masks the signs and symptoms of intestinal obstruction. A high index of suspicion is required for proper and timely diagnosis. CASE: A 26 year-old, primiparous woman, 32 weeks pregnant, presented with a 1-day history of pain in the upper abdomen. The pain was sudden in onset and was mostly in the epigastric region. Initially the patient was managed conservatively on the suspicion of gastritis, but she did not respond. Subsequent abdominal ultrasound suggested intestinal obstruction. The decision for laparotomy was made. On entering the abdominal cavity, examination of the intestine revealed volvulus of the jejunum with a complete twist at the base of the mesentery and around 20 cm of bluish black, foul-smelling, infarcted and necrosed bowel. CONCLUSION: Resection of the infarcted bowel was done with primary end-to-end anastomosis of the remaining part. The patient made an uneventful recovery and delivered a male infant vaginally at 41 weeks. PMID- 17694983 TI - Prolonged obstructed labor causing a severe obstetric fistula: a case report. AB - BACKGROUND: Severe obstructed labor with a pelvic fistula is associated with significant fetal and maternal morbidity and mortality. It is rare in the developed world due to access to health care and availability of cesarean section for labor dystocia. CASE: A 25-year-old primigravida in denial of her pregnancy due to a psychotic disorder experienced prolonged obstructed labor at home with fetal death, necrosis of her bladder and uterus, sepsis and profound neuropathy. Aggressive surgical and medical management, including hysterectomy and urinary diversion, resulted in survival and an enhanced potential for a good quality of life. CONCLUSION: Severe urogenital fistula secondary to prolonged obstructed labor can occur in a metropolitan area. In the setting of psychiatric disease, physicians must be prepared for the most remote clinical situations and complications. PMID- 17694984 TI - Stage II squamous cell carcinoma of the vagina in a patient with Bloom syndrome: a case report. AB - BACKGROUND: Bloom syndrome (BS) is a rare autosomal recessive disorder characterized by dwarfism and a predisposition to cancer. Squamous cell vaginal cancer is also quite rare and has not before been reported in association with BS. CASE: A 37-year-old woman, para 0-0-2-0, with BS was referred to the gynecologic oncology service for a suspicious mass in the vagina associated with dyspareunia and vaginal bleeding. Previous biopsies were consistent with high grade vaginal dysplasia, however, thorough surgical evaluation ultimately demonstrated stage II vaginal cancer. After consultation with a gynecologic oncologist and radiation oncologist, an adjuvant treatment plan was created for external beam radiation with cisplatin potentiation followed by intracavitary brachytherapy. CONCLUSION: BS is an excellent model of human cancer in general. These patients are diagnosed with cancers at an earlier age and higher rate than is the general population, but the distribution of cancer type seems to be similar to that in the general population. Treatment of cancers in this population is largely similar to that of the general population. There is no known treatment to decrease the occurrence of neoplasia in BS patients other than strict adherence to all known cancer surveillance screening modalities. PMID- 17694985 TI - Tension-free vaginal tape sling with a porcine interposition graft in an irradiated patient with a past history of a urethrovaginal fistula and urethral mesh erosion: a case report. AB - BACKGROUND: Patients with previous irradiation are at high risk for complications following pelvic reconstructive surgery. The treatment of these complications and the patient's initial disorder can be complex and difficult, especially when the use of various graft materials, including mesh, is involved in the original complication. CASE: A 49-year-old woman with a history of anal and vulvar cancer treated with pelvic irradiation underwent a tension-free vaginal tape (TVT) sling for stress urinary incontinence (SUI) and experienced complications of urethral mesh erosion and urethrovaginal fistula (UVF). The mesh was removed and the urethra repaired, but the repair failed, and she continued to have a persistent UVF. The patient presented to our center, and the UVF was repaired successfully with a Martius flap. Secondary to persistent SUI with intrinsic sphincter deficiency (ISD), the patient underwent a repeat TVT sling with a porcine interposition graft between the mesh and urethra to help prevent urethral mesh erosion. The patient healed without complications and achieved 80% improvement in her symptoms at 3 months, with only occasional SUI. She was eventually able to achieve 100% cure with the addition of periurethral collagen injections. CONCLUSION: Porcine interposition grafts while constructing a TVT sling may help reduce urethral erosion rates in patients with previous irradiation. PMID- 17694986 TI - Spontaneous vaginal expulsion of an infected necrotic cervical fibroid through a cervical fistula after uterine artery embolization: a case report. AB - BACKGROUND: Uterine artery embolization (UAE) is promising, minimally invasive therapy being offered to women for treatment of fibroids. Although it seems to be safe and effective, major complications and adverse outcomes have been reported. CASE: A patient treated with UAE for a huge cervical fibroid presented with an infected, necrotic cervical mass lesion 4 weeks after the procedure. Spontaneous vaginal expulsion of the infected cervical fibroid from the left lateral cervical fistula tract occurred 3 weeks later while the patient was receiving antibiotic therapy. After 6 months of intervention, an approximately 99% regression rate in the fibroid volume was achieved. The patient gave birth to a healthy, female infant following a spontaneous, uneventful pregnancy and vaginal delivery. CONCLUSION: UAE appears to be associated with a significant reduction in fibroid volume. Expulsion of the infected, necrotic parts of the fibroid after UAE may be accepted as a natural process. Warning the patient about this potential risk, early recognition of infective complications and lose follow up seem to be crucial to avoiding potentially fatal septic shock. PMID- 17694987 TI - Complete hydatidiform mole with a surviving coexistent twin in a woman with sickle cell disease: a case report. AB - BACKGROUND: Twin pregnancy with an apparently healthy fetus and complete hydatidiform mole (CHMTF) is a rare condition. We present the first reported case in a woman with sickle cell disease. CASE: An 18-year-old woman, para 1, gravida 0, with sickle cell disease was diagnosed at 19 weeks as having a complete molar pregnancy with a coexistent live fetus. The patient presented with abdominal pain, nausea, headaches, body aches, joint pain and chest pain on 2 different occasions. She denied having vaginal bleeding. Whether the patient was having a sickle cell crisis or molar pregnancy symptoms (i.e., thyrotoxicosis) was not clear. She was given intravenous hydration and pain management. All her symptoms resolved, confirming sickle cell crisis as the final diagnosis. The pregnancy was uneventful until 35 weeks, when oligohydramnios prompted induction of labor. Suction curettage was performed after delivery for removal of the molar pregnancy. The patient did not show any evidence of persistent trophoblastic disease 2 months after delivery. CONCLUSION: CHMTF in sickle cell disease patients is challenging. Adequate intravenous hydration and pain management should be started when one suspects a crisis. If the symptoms resolved, thyrotoxicosis due to the molar pregnancy is unlikely. In addition to proper medical management, proper counseling of the patient and close monitoring of both fetus and mother should be undertaken. PMID- 17694988 TI - Laparoscopic resection of a noncommunicating, rudimentary uterine horn using the harmonic scalpel: a report of 3 cases. AB - BACKGROUND: Noncommunicating, rudimentary uterine horns are often removed to prevent potential pregnancy complications or to treat patients who develop pain from functional endometrium within the horn. Historically, these have been removed via laparotomy. Recently, resections of noncommunicating uterine horns have been performed laparoscopically using many different devices. We report 3 patients who underwent laparoscopic resection using the harmonic scalpel. CASES: Three patients were diagnosed with this condition at our institution between 2000 and 2003. All underwent laparoscopic resection using the harmonic scalpel without complications. All patients were discharged from the hospital on the day of surgery. Two patients subsequently had term vaginal deliveries. CONCLUSION: Resection of a rudimentary uterine horn by laparoscopy using the harmonic scalpel is an option for patients diagnosed with noncommunicating, rudimentary uterine horns. This modality might offer some advantages for patients who must undergo resection. PMID- 17694989 TI - Microphthalmos associated with Dartmouth combination chemotherapy in pregnancy: a case report. AB - BACKGROUND: Use of Dartmouth combination chemotherapy in pregnancy is scarcely reported, with only 1 report of its use in the late second and third trimesters and no report of its use in the first trimester. CASE: This is the first reported case in which the Dartmouth combination chemotherapy regimen was inadvertently used in a pregnant woman during the first and second trimesters for treatment of metastatic melanoma. The infant was found to have isolated microphthalmos and severe hypermetropia at 1 year of age. CONCLUSION: Although a causal relationship cannot be established from a single case, this report does provide useful information to discourage the use of this chemotherapy regimen in the first trimester, which is the critical period for organogenesis. PMID- 17694990 TI - Recommendations for antenatal surveillance in fetal gastroschisis. PMID- 17694991 TI - Chronic pelvic pain. PMID- 17694992 TI - Melding or meddling: compliance and ethics programs. PMID- 17694993 TI - Why compliance programs fail: economics, ethics and the role of leadership. PMID- 17694994 TI - Persuasion and coercion: a critical review of philosophical and empirical approaches. PMID- 17694995 TI - The slippery slope of the middle ground: reconsidering euthanasia in Britain. PMID- 17694996 TI - An innovative, inclusive process for meso-level health policy development. PMID- 17694997 TI - Review essay: John Meadowcroft, The ethics of the market (London: Palgrave Macmillian, 2005). ix + 173pp. PMID- 17694998 TI - [South-North]. PMID- 17695000 TI - [Qualitative study on factors influencing the choice to work with the elders]. AB - INTRODUCTION: Geriatric settings are not attractive for italian nurses that rather prefer other areas, valued as more stimulating and rewarding. No italian studies attempted to analyse the reasons for the lack of interest of nurses for geriatric care, therefore an explorative study was conducted. METHOD: A qualitative study was conducted collecting data through focus groups with nurses involved in different clinical settings. The focus groups were type-recorded and transcribed. Content analysis was used to analyse data. A researcher identified the main codes (this process was independently reviewed by a second researcher). The codes with similar meaning were grouped in main categories. The process was independently reviewed by a third researcher. RESULTS: Several factors (individual, educational, organizative and sociocultural influence the choice of working with elderly people. The main reasons are related to: the needs of the family and of the organization, the quality of interpersonal relationship and values of the team, the previous educational experiences, the personal values, the association between old age and death, the physical characteristics of the working environment, the opportunity of giving personalized care, the perception of complexity of needs and of the necessary skills to answer those needs. CONCLUSIONS: The choice of the nursing profession is value loaden and nurses favour a choice of setting that reflects their values, rather than a priory selecting the clinical area. Geriatric care is perceived as generalist, less professionalizing compared to critical care. The education can play a major role in motivating nurses to consider and privilege geriatric care. PMID- 17694999 TI - [The implementation of a pathway for Romanian medical assistants to obtain the Italian nursing degree]. AB - AIMS: This article describes management and outcomes of an academic pathway for the transition from Medical Assistant Diploma to Bachelor Science of Nursing (BSN) of Padua University for a group of Romanian nurses. METHODS: The course, repeated for two academic years, (2004-05, 2005-06), was 15 months long and it was performed mainly in Timisoara. It was managed by a partnership of public and private Italian and Romanian institutions. RESULTS: Forty-three nurses attended to the full course and 42 obtained the BSN with good results. Lectures were delivered locally and via long distance courses. Students attended Italian wards for their practical training. CONCLUSION: This project was performed in the framework of an international cooperation project for academic nursing knowledge diffusion in East-European countries, and for recognition and integration of nursing studies. PMID- 17695001 TI - [Towards a multidisciplinary participating epidemiology: the OMG (Osteoarthrosis pathology in General Medicine)]. AB - AIM: Aim of study is to collect data on a cohort of patients chronically exposed to NSAIDS and, on a sub-sample of patients, representative of the range severity and co-morbid conditions, to collect qualitative data with interviews, on patients' perceptions of their illness and treatments. METHOD: Patients with osteoarticular problems will be included in the cross sectional study and prospective surveillance. Cross sectional study: all the eligible patients followed by the MD in 4 months. Prospective surveillance. All the eligible patients with moderate-severe problems, requiring long term care. Doctors will be required to visit the patient at inclusion, after the inclusion (when clinically needed) and at the end of the surveillance period. Data will be collected on concomitant problems, severity and duration of osteoartrosis, drug and non-drug treatments prescribed, quality of life (SF-12 at entry and at each follow-up); WOMAC scale on severity of osteoarticular pathology, and problems with drugs (collected through interview). RESULTS: Expected results are the incidence and prevalence of chronic care burden for each doctor, the number of patients with not controlled symptoms, the frequency and reasons for changes in drug treatments and the characteristics and variability of patients. PMID- 17695002 TI - [Clinical-caring epidemiology of pain at the hospital--the ECAD-O project]. AB - Pain continues to be underreported and undertreated, and resistances to the administration of morphine and opioids are one of the major drawbacks. AIMS: a. to activate a surveillance as part of routine care; b. to produce periodical reports to follow-up any improvement or changes in oppioid and specifically treatment of pain; c. to the groups of patients whose pain is undertreated; d. to create a multicentre network of hospitals willing and able to promote a permanent surveillance on pain and its treatment. METHOD: A cross sectional survey will be conducted in index days to collect data on the number of patients exposed to analgesics; the perception of health workers on the effectiveness of treatments administered; patients' satisfaction on pain control. A prospective surveillance on: a. adverse events; b. incident difficult cases (patients whose pain is not controlled or difficult to treat, e.g. because of comorbidities or contraindications to opioids). EXPECTED RESULTS: Data produced will be analysed and presented for each participating centre and will be used for education, audit and quality improvement. PMID- 17695003 TI - [Does the electronic prescription reduce drugs errors? Comparison between electronic and manual prescription]. AB - BACKGROUND: Medication errors are the major responsible for adverse events in hospitals. Although computerized prescription systems are widely considered the best option to decrease the medication errors, this belief is not evidence based since only few studies assessed their effectiveness. AIM: The aim of this study is to compare the effectiveness on reducing medication errors of the manual prescription system (drugs transcribed in the clinical records) with a computerized system. METHOD: Drugs prescriptions (manual and electronic) were retrospectively analyzed to identify medication errors. A medication error is the lack of clarity and completedness of the prescription. RESULTS: 1587 prescriptions were analyzed with the manual prescription system (phase 1), 1500 with the provisional electronic system (phase 2) and 1034 with the final one (phase 3). Between phase 1 and 2 an increase of incomplete prescriptions for dose (+17%) and lack of completedness of prescription (+49%) was observed. After some modifications a decrease of "errors" was observed, respectively -39% and -23.5% (p<0.001). CONCLUSIONS: The study shows that the informatization of the drug prescriptions reduces medication errors but requires a close planning, monitoring and tailoring of the system according to local problems and needs. PMID- 17695004 TI - [The subcutaneous administration of drugs]. PMID- 17695005 TI - [An Italian or European way to the emancipation of nursing]. PMID- 17695006 TI - [Inequalities in health in Europe]. PMID- 17695007 TI - Environmental factors associated with spatial and temporal distribution of Anopheles (Diptera: Culicidae) larvae in Sukabumi, West Java, Indonesia. AB - A 12-mo ecological study of the spatial-temporal distribution of immature stages of Anopheles species was conducted in Sukabumi District, West Java, Indonesia. The study characterized 1,600 sites from a contiguous coastal and hill zone (0 800-m elevation) of which 64% contained Anopheles larvae. Principal component and multiple logistic regression analyses identified ecological parameters associated with presence of nine [Anopheles aconitus Doenitz, Anopheles annularis Van de Wulp, Anopheles barbirostris Van der Wulp, Anopheles flavirostris (Ludlow), Anopheles insulaeflorum (Swellengrebel and Swellengrebel de Graaf), Anopheles kochi Doenitz, Anopheles maculatus Theobald, Anopheles sundaicus (Rodenwaldt), and Anopheles vagus Doenitz] of 15 Anopheles species collected. Combined data for all nine species showed increased Anopheles presence associated with wet season periods and higher elevation habitats exhibiting reduced tree canopy coverage, higher water temperatures, and shallower water depths. Habitat variables measured included topography (elevation), water conditions (temperature, pH, salinity depth, and velocity), habitat characteristics (substrate and canopy cover), density and type of aquatic vegetation coverage (riparian, floating, and emergent), and distance from nearest human habitation. Significant relationships were found for nine species when using all habitats in the analysis. Habitat characteristics for three species were refined. An. aconitus and An. barbirostris were associated with higher elevation rice, Oryza savita L., paddies with relatively shallow water depths, higher water temperatures, higher acidity and salinity concentrations, and a greater average distance from human habitation. An. vagus presence in rice paddies was associated with lower elevation fields, deeper and cooler water, less acidic and saline conditions, and habitats closer to human dwellings. Overall, the distribution of Anopheles species in Sukabumi was found to be nonrandom and predictable on the basis of habitat characteristics. PMID- 17695008 TI - Insight into global mosquito biogeography from country species records. AB - To advance our limited knowledge of global mosquito biogeography, we analyzed country occurrence records from the Systematic Catalog of the Culicidae (http://www.mosquitocatalog. org/main.asp), and we present world maps of species richness and endemism. A latitudinal biodiversity gradient was observed, with species richness increasing toward the equator. A linear log-log species (y)-area (x) relationship (SAR) was found that we used to compare observed and expected species densities for each country. Brazil, Indonesia, Malaysia, and Thailand had the highest numbers of species, and Brazil also had the highest taxonomic output and number of type locations. Brazil, Australia, the Philippines, and Indonesia had the highest numbers of endemic species, but excluding small island countries, Panama, French Guiana, Malaysia, and Costa Rica had the highest densities of total species and endemic species. Globally, 50% of mosquito species are endemic. Island countries had higher total number of species and higher number of endemic species than mainland countries of similar size, but the slope of the SAR was similar for island and mainland countries. Islands also had higher numbers of publications and type locations, possibly due to greater sampling effort and/or species endemism on islands. The taxonomic output was lowest for some countries in Africa and the Middle East. A consideration of country estimates of past sampling effort and species richness and endemism is proposed to guide mosquito biodiversity surveys. For species groups, we show that the number of species of Anopheles subgenus Anopheles varies with those of subgenus Cellia in a consistent manner between countries depending on the region. This pattern is discussed in relation to hypotheses about the historical biogeography and ecology of this medically important genus. Spatial analysis of country species records offers new insight into global patterns of mosquito biodiversity and survey history. PMID- 17695009 TI - Reproduction and development of laboratory and wild house dust mites (Acari: Pyroglyphidae) and their relationship to the natural dust ecosystem. AB - Life histories of "wild" house dust mites, Dermatophagoides pteronyssinus (Trouessart) (Acari: Pyroglyphidae), were compared with laboratory cultures by using a diet consisting of skin and dust or a laboratory diet consisting of dried liver and yeast. Under constant conditions of 25 degrees C and 75% RH, fecundity and rate of reproduction were higher in laboratory cultures on both diets compared with wild mites. There were also trends for a shorter prereproductive period and more rapid egg development of laboratory mites compared with wild mites. Overall, there was little effect of diet on either strain of mites at 75% RH. At low RH (64%), fecundity was significantly lower (for both strains on both diets), and there were also trends for longer prereproductive period, reduced rate of reproduction, reduced adult survival, prolonged egg and juvenile development, or a combination compared with 75% RH. Additionally egg and juvenile mortality were significantly higher on the liver and yeast diet. Overall, the skin and dust diet favored both strains of mites at 64% RH. On the liver and yeast diet at 64% RH, wild mite adults performed significantly better than laboratory mites, and egg mortality was lower. These results suggest that laboratory mites have stronger reproduction and development than wild mites, except when under environmental stress and that diet is a significant factor, particularly in suboptimal conditions. This could have important implications for predictive models of house dust mite populations in their natural habitat. Ideally, such models should be developed using data from wild dust mite populations reared on a natural diet. PMID- 17695010 TI - Seasonal change in habitat use by Haemaphysalis longicornis (Acari: Ixodidae): plant, litter, and soil. AB - Habitat use of Hemaphysalis longicornis Neumann (Acari: Ixodidae) was observed from February 1998 to January 2000 in Boso Peninsula, central Japan. The number of ticks collected from plants (by hand) and from litter and soil (by the vinyl method) was compared seasonally. Laboratory experiments showed that the vinyl method effectively collected 97% of adults, 98% of nymphs, and 95% of larvae from soil and litter samples. Field studies showed that habitat use of all stages varied during the species' active period. Larvae were seen on plants from August to October, and the number of larvae on plants peaked in September. Nymphs were on plants from March to May in 1998 or July in 1999 and again in August and September in 1998 and 1999. The number of nymphs collected from the litter was large in October and March. Nymphs shifted from litter and soil to plants both in spring and autumn. Adults were on plants from March to July, although they were collected from litter and soil from September to July. Adults shifted from litter and soil to plants during their activity period. It was shown that all stages were uncommon (low percentages) on plants early in the active period and very abundant (high percentages) late in the active period. PMID- 17695011 TI - Direct and indirect effects of animal detritus on growth, survival, and mass of invasive container mosquito Aedes albopictus (Diptera: Culicidae). AB - Compared with plant detritus, animal detritus yields higher growth rates, survival, adult mass, and population growth of container-dwelling mosquitoes. It is unclear whether the benefit from animal detritus to larvae results from greater microorganism growth, direct ingestion of animal detritus by larvae, or some other mechanism. We tested alternative mechanisms by which animal detritus may benefit the invasive container-dwelling mosquito Aedes albopictus (Skuse) (Diptera: Culicidae). In the laboratory, larvae were reared under three conditions with access to 1) detritus, but where microorganisms in the water column were reduced through periodic flushing; 2) water column microorganisms, but larvae had no direct access to detritus; or 3) both water column microorganisms and detritus. Access treatments were conducted for three masses of animal detritus: 0.005, 0.010, and 0.020 g. Water column bacterial productivity (measured via incorporation of [3H] leucine) decreased significantly with flushing and with larval presence. Removing microorganisms through flushing significantly reduced mass of adult mosquitoes (both sexes), and it significantly prolonged developmental times of females compared with treatments where water column microorganisms or microorganisms and detritus were available. Survival to adulthood was greatest when larvae had access to both water column microorganisms and 0.020 g of detritus, but it declined when only water column microorganisms were available or when 0.005 g of detritus was used. These findings indicate both direct (as a food source) and indirect (assisting with decomposition of detritus) roles of microorganisms in producing the benefit of animal detritus to container mosquito larvae. PMID- 17695012 TI - Decaying invertebrate carcasses increase growth of Aedes triseriatus (Diptera: Culicidae) when leaf litter resources are limiting. AB - Treeholes are detritus-based communities, and resource quantity and quality play a large role in structuring such communities. The primary resource is leaf litter, but decaying invertebrates also are a resource to treehole inhabitants. These communities are subject to a variety of disturbances, which may affect resources or cause widespread mortality. When dead inhabitants decay, they provide a potentially high-quality resource to survivors or subsequent colonists. We predicted that variation in decaying larvae (0, 7.3, and 29.2 mg/liter) and leaf litter (1, 5, and 10 g/liter) would influence the performance of populations of Aedes triseriatus (Say), the eastern treehole mosquito. We tested this prediction in field mesocosms, which were subjected to a freezing event causing widespread mortality of the scirtid beetle Helodes pulchella Guerin. We then added a cohort of first instar mosquitoes to mesocosms, and we monitored their development from March until June 2005. At the highest leaf litter level, survival, adult mass, and time to complete development were unaffected by decaying scirtids, and they were different from treatments with lower levels of leaf litter. In treatments with 1 and 5 g/liter leaf litter and decaying scirtids, mosquito survival and adult mass were higher than in treatments with 1 and 5 g/liter leaf litter and no decaying scirtids. At 5 g/liter leaf litter, a higher mass of dead scirtids was required to significantly increase adult mass. Faster decay of carcasses and release of limiting nutrients likely spur growth of microorganisms, upon which mosquitoes feed. Invertebrate populations in high disturbance communities may be subject to high mortality, and mosquitoes hatching after the disturbance will benefit, but only when other resources are limiting. PMID- 17695013 TI - Biology of Phlebotomus papatasi (Diptera: Psychodidae) in the laboratory. AB - Details on the productivity and developmental times of a colony of Phlebotomus papatasi Scopoli (Diptera: Psychodidae) over 14 generations are reported and compared with findings of previous studies. The average productivity (percentage of eggs laid that were reared to adults) over six generations at 26-27 and at 29 30 degrees C was 44.08 and 59.53%, respectively. The maximum productivity was 69.5%. The average developmental time over six generations at 26-27 and at 29 -30 degrees C was 35 and 26 d, respectively. The minimum developmental time from egg to adults was 25 d. The Tunisian strain of P. papatasi can reproduce autogenously or anautogenously, depending on the availability of a suitable bloodmeal source. PMID- 17695014 TI - Population structure and gene flow of Anopheles farauti s.s. (Diptera: Culicidae) among ten sites on five islands of Vanuatu: implications for malaria control. AB - The Anopheles punctulatus (Diptera: Culicidae) group is the main vector for malaria and Bancroftian filariasis in Vanuatu. Anopheles larvae were collected from 10 localities on five islands of Vanuatu during the 2004 dry season for species identification as well as for estimating population structure and gene flow within and among islands. Species identification was determined using polymerase chain reaction-restriction fragment length polymorphism analysis of the internal transcribed spacer 2 region. Population structure and gene flow were examined by sequencing a portion of the ND4/ND5 region of the mitochondrial genome. Only one species of the An. punctulatus group, An. farauti s.s., was identified, consistent with previous studies in Vanuatu. A nonrandom distribution of An. farauti s.s. lineages was observed with one cosmopolitan lineage shared by eight sites on all five islands and a preponderance of island-specific lineages (36/40), indicating the introduction of a single main lineage into Vanuatu followed by dispersal, diversification, and limited lineage exchange between islands. Network analysis suggests a possible second introduction of An. farauti s.s. into the northern islands of Gaua and Malekula. Gene flow was high on three of the five islands, whereas Tanna and Santo have significant population structure. Among islands, gene flow was limited, indicating active mosquito dispersal only over short distances and a paucity of passive human-mediated dispersal over long distances. Minimal risk of active dispersal among these islands indicates that vector control can be effectively initiated at the island level within the archipelago of Vanuatu. PMID- 17695015 TI - The C-terminal extension that characterizes mosquito (Diptera: Culicidae) ribosomal protein S6 is widespread among the Culicomorpha. AB - Eukaryotic ribosomal proteins, which participate in the structure and function of the translational machinery, are generally well conserved. In Aedes and Anopheles mosquitoes (Diptera: Culicidae), however, ribosomal protein S6 (RpS6) contains a low-complexity, C-terminal extension that is absent from its homolog in Drosophila melanogaster Meigen and Manduca sexta (L.). To explore the distribution of RpS6 C-terminal extensions in genera phylogenetically closer to mosquitoes than is Drosophila, we recovered cDNAs encoding RpS6 from a phantom midge (Chaoborus sp.), a midge (Chironomus sp.), a blackfly (Simulium sp.), and a phantom crane fly [Bittacomorpha clavipes (F.) ]. Sequences of deduced translation products showed that RpS6 extensions occurred only in members of the Culicomorpha, and they were absent from B. clavipes, a member of the Ptychopteromorpha, which forms the sister group to the Culicomorpha. Likewise, the extension did not occur in Telamtoscopus sp., a moth fly classified among the more distantly related Psychodomorpha. The C-terminal extensions on RpS6 ranged in length from 81 to 190 amino acids, they were highly enriched for lysine and alanine, and they seem to be evolving more rapidly than the conventional portion of the RpS6 protein shared by all eukaryotes. Although analysis of RpS6 protein was consistent with analyses based on ribosomal DNA, suggesting that Chironomidae is the sister group to the remaining families in the Culicomorpha, trees generated from RpS6 amino acid sequences were largely congruent with accepted phylogenies based on morphological characters. Our results suggest that a C terminal, lysinerich extension on RpS6 is a potential molecular synapomorphy for the Culicomorpha. PMID- 17695016 TI - Age-related changes in female mosquito carbon dioxide detection. AB - Mosquitoes rely on carbon dioxide (CO2) as a primary component in host-seeking behavior. CO2 is detected by specialized receptor neurons in basiconic sensilla located on the maxillary palps of the mosquito. The sensitivity and specificity of these sensors can be studied using single-cell electrophysiological methods. Such electrophysiological data reveal that certain aspects of the sensitivity of these sensors change during the maturation of adult female Aedes aegypti (L.) (Diptera: Culicidae). Although the mean threshold of response is similar between the ages examined, the overall sensitivity and temporal pattern of discharge of the neurons vary with age. Older females, which are likely to engage in host seeking behavior, are more responsive to CO2 than very young females that are unlikely to seek hosts. Male mosquitoes did not show a similar pronounced pattern of sensitivity. The implications of such differences are discussed with respect to behavior. PMID- 17695017 TI - Field evaluation of traditionally used plant-based insect repellents and fumigants against the malaria vector Anopheles darlingi in Riberalta, Bolivian Amazon. AB - Inexpensive insect repellents may be needed to supplement the use of impregnated bed-nets in the Amazon region, where the primary malaria vector, Anopheles darlingi (Root), is exophilic and feeds in the early evening. Three plants that are traditionally used to repel mosquitoes in Riberalta, Bolivian Amazon, were identified by focus group, and then they were tested against An. darlingi as well as Mansonia indubitans (Dyar & Shannon)/Mansonia titillans (Walker). Cymbopogon citratus (Staph), Guatemalan lemongrass, essential oil at 25% was used as a skin repellent, and it provided 74% protection for 2.5 h against predominantly An. darlingi and 95% protection for 2.5 h against Mansonia spp. Attalea princeps (name not verified) husks, burned on charcoal in the traditional way provided 35 and 51% protection against An. darlingi and Mansonia spp., respectively. Kerosene lamps, often used to light rural homes, were used as a heat source to volatilize 100% Mentha arvensis (Malinv ex. Bailey) essential oil, and they reduced biting by 41% inside traditional homes against Mansonia spp., although they were ineffective outdoors against An. darlingi. All three plant-based repellents provided significant protection compared with controls. Plant-based repellents, although less effective than synthetic alternatives, were shown by focus groups to be more culturally acceptable in this setting, in particular para-menthane-3, 8, idol derived from lemon eucalyptus, Corymbia citriodora (Hook). Plant-based repellents have the potential to be produced locally and therefore sold more cheaply than synthetic commercial repellents. Importantly, their low cost may encourage user compliance among indigenous and marginalized populations. PMID- 17695019 TI - Structural characterization of acetylcholinesterase 1 from the sand fly Lutzomyia longipalpis (Diptera: Psychodidae). AB - Acetylcholinesterase (AChE) plays a key role in cholinergic impulse transmission, and it is the target enzyme for organophosphorus and carbamate insecticides. Two genes, AceI and AceII, have been characterized from different insect species, and point mutations in either gene can lead to significant resistance to these classes of insecticides. In this report, we describe the partial characterization of the AceI gene from Lutzomyia longipalpis (Lutz & Neiva) (Diptera: Psychodidae), and we show that the possibility exists for the development of a resistant phenotype to organophosphates and carbamates in sand flies. Our results point to the presence of a single AceI gene in L. longipalpis (LlAce1) and that AChE activity is inhibited by organophosphorus at a concentration of 5 x 10(-5) M. Regarding insecticide resistance, analysis of the truncated LlAce1 cDNA suggests that a single missense mutation leading to a glycine-to-serine substitution at amino acid position 119 (G119S) may arise in L. longipalpis, similar to what has been detected in Anopheles gambiae s.s. Another missense mutation involved in resistant phenotypes, F331W, detected in Culex tritaeniorhynchus Giles, is less likely to occur in L. longipalpis, because it faces codon constraint in this sand fly species. Comparison of the three dimensional structures of the deduced amino acid sequence of the truncated LLAChE1 with that of An. gambiae and Cx. tritaeniorhynchus also suggests that similar structural modifications due to the missense amino acid changes in the active site gorge are detected in all three insects. PMID- 17695018 TI - Spinosad, a naturally derived insecticide, for control of Aedes aegypti (Diptera: Culicidae): efficacy, persistence, and elicited oviposition response. AB - The naturally derived insecticide spinosad is a reduced-risk material that is neurotoxic to Diptera. The 24-h 50% lethal concentration by laboratory bioassay in third instars of Aedes aegypti (L.) (Diptera: Culicidae) (Rockefeller strain) was estimated at 0.026 ppm. Two identical field trials were performed in an urban cemetery in southern Mexico during the dry and wet seasons. Water containers treated with 1 or 5 ppm spinosad suspension concentrate (Tracer, Dow Agrosciences) were as effective in preventing the development of Aedes spp. (mostly Ae. aegypti) as temephos granules during both trials, whereas the bacterial insecticide VectoBac 12AS performed poorly. The half-life of aqueous solutions of spinosad (10 ppm) placed in a warm sunny location was 2.1 d, compared with 24.5 d for solutions in a shaded location. Spinosad, temephos, and VectoBac were not repellent to gravid Ae. aegypti at the concentrations tested, and no ovicidal properties were observed. The 24-h survival of neonate larvae but was reduced by 94-100% in the presence of residues carried over from the spinosad treatments, but it was not affected by residues of temephos or VectoBac. The toxicological properties of spinosad, combined with its favorable environmental profile, should encourage the detailed evaluation of spinosad as a mosquito larvicide in domestic and urban environments. PMID- 17695020 TI - Preliminary field testing of a long-lasting insecticide-treated hammock against Anopheles gambiae and Mansonia spp. (Diptera: Culicidae) in West Africa. AB - The efficacy of an experimental long-lasting insecticide-treated hammock (LLIH) with a long-lasting treated net used as a blanket and made of the same fabric (polyethylene) was tested in a concrete block experimental hut, against the malaria vector Anopheles gambiae s.l. and the arbovirus vectors and nuisance mosquitoes Mansonia africana (Theobald) and Mansonia uniformis (Theobald). The LLIH was treated with the pyrethroid insecticide permethrin. It was evaluated concurrently with ignited mosquito coils over 20 successive weeks. In total, 2,227 mosquitoes (130 An. gambiae and 2,097 Mansonia spp.) corresponding to 27.8 mosquitoes per trap-night were collected in the untreated hut (control). The repellent effect of both coils and LLIH significantly reduced the number of mosquitoes entering the huts (35- 60%). There was no significant difference between LLIH and mosquito coils in blood-feeding inhibition (93-97%) or in mortality (88-98%). The LLIH is more cost-effective and user-friendly than mosquito coils, which need to be replaced nightly to protect people sleeping indoors from mosquito bites. The effects of LLIH on exophagic vectors also need to be investigated because most people that sleep in hammocks are outdoors. PMID- 17695021 TI - Effects of avermectins on olfactory responses of Culicoides imicola (Diptera: Ceratopogonidae). AB - The aim of this study was to examine the role of the olfactory system of the midge Culicoides imicola Kieffer as the major system mediating repellency to antihelminthic avermectins. Incidental observations indicate that treatment with Dectomax or Ivomec (commercial formula of the avermectins doramectin and ivermectin, respectively) protects sheep from infection by bluetongue (BT) viruses. Our electrophysiological data from midge antennae showed that the stimulating effectiveness of L- (+)-lactic acid, butanone, and sheep fleece odor decreased after addition of avermectins. The results show that these antihelminthics affect the olfactory sensitivity of the insect toward the animal host by reducing the response to those compounds that attract the insect, consequently reducing the possibility of biting the sheep and thereby transferring the BT virus. PMID- 17695022 TI - Refractoriness in tsetse flies (Diptera: Glossinidae) may be a matter of timing. AB - Tsetse flies (Diptera: Glossinidae: Glossina spp.) are vectors for African trypanosomiasis, a devastating disease that kills both people and animals in sub Saharan Africa. Trypanosomes ingested with an infected bloodmeal reside within the gut of tsetse and eventually move to the salivary glands where they become transmissible during blood feeding. Although tsetses are efficient vectors for disease transmission, infection prevalence in the field is surprisingly low, a trait referred to as refractoriness. Refractoriness is relatively more pronounced in palpalis subgroup flies, although certain species within the susceptible morsitans species complex are also highly refractory, such as Glossina pallidipes Austen. We examined the role of the humoral immune response in refractoriness to infection by comparing the expression of the antimicrobial peptide gene attacin across three species with varied vector competence. Gene expression was measured both temporally (time after feeding and fly age) and spatially (tissue specificity). Although microbial immune challenge induces attacin expression in all three species, "refractory" fly species showed an uninduced, baseline level of systemic (fat body) attacin, whereas the "susceptible" flies did not. In addition, refractory species had a higher level of attacin expression in the proventriculus and midgut. We also found that blood feeding alone up-regulated attacin expression in refractory species but not in the susceptible species. Finally, reverse genetics showed that repression of attacin by double-stranded RNA-mediated RNA interference increased susceptibility to trypanosome infection in G. pallidipes. The role of early, uninduced attacin expression, and its role in relative refractoriness in tsetse, is discussed. PMID- 17695023 TI - Experimental evaluation of Musca domestica (Diptera: Muscidae) as a vector of Newcastle disease virus. AB - House flies, Musca domestica L. (Diptera: Muscidae), were examined for their ability to harbor and transmit Newcastle disease virus (family Paramyxoviridae, genus Avulavirus, NDV) by using a mesogenic NDV strain. Laboratory-reared flies were experimentally exposed to NDV (Roakin strain) by allowing flies to imbibe an inoculum consisting of chicken embryo-propagated virus. NDV was detected in dissected crops and intestinal tissues from exposed flies for up to 96 and 24 h postexposure, respectively; no virus was detected in crops and intestines of sham exposed flies. The potential of the house fly to directly transmit NDV to live chickens was examined by placing 14-d-old chickens in contact with NDV-exposed house flies 2 h after flies consumed NDV inoculum. NDV-exposed house flies contained approximately 10(4) 50% infectious doses (ID50) per fly, but no transmission of NDV was observed in chickens placed in contact with exposed flies at densities as high as 25 flies per bird. Subsequent dose-response studies demonstrated that oral exposure, the most likely route for fly-to-chicken transmission, required an NDV (Roakin) dose > or =10(6) ID50. These results indicate that house flies are capable of harboring NDV (Roakin) but that they are poor vectors of the virus because they carry an insufficient virus titer to cause infection. PMID- 17695024 TI - Temporal dynamics of early-phase transmission of Yersinia pestis by unblocked fleas: secondary infectious feeds prolong efficient transmission by Oropsylla montana (Siphonaptera: Ceratophyllidae). AB - Plague, a flea-borne zoonotic disease, is characterized by rapidly spreading epizootics. Rate of infectious spread is thought to be related to daily biting rate of the vector, the extrinsic incubation period, vector efficiency, and the duration of infectivity. A recent study of Oropsylla montana (Baker) (Siphonaptera: Ceratophyllidae), the primary vector of Yersinia pestis (Yersin) to humans in North America, revealed that this flea feeds readily on a daily basis, has a very short extrinsic incubation period, and efficiently transmits plague bacteria for at least 4 d postinfection (p.i.). Earlier studies based on fleas receiving a single infectious bloodmeal showed that transmission efficiency wanes after 4 d p.i. In our study, we simulate a naturally occurring scenario in which fleas are exposed repeatedly to septicemic hosts, and we evaluate vector efficiency of O. montana 6-9 d after the initial infectious bloodmeal for 1) fleas given a "booster" infectious bloodmeal 5 d after initial exposure and 2) fleas that received an uninfected maintenance bloodmeal 5 d p.i. Transmission of Y. pestis was not observed beyond 7 d after initial exposure in the fleas that received a single infectious bloodmeal, whereas fleas given a booster infectious bloodmeal could transmit throughout the 9-d duration of the study. The proportion of flea pools transmitting Y. pestis was significantly higher for fleas receiving multiple, rather than single infectious bloodmeals. Surprisingly, transmission success was not directly related to bacterial loads in fleas. Our data indicated that the duration of time over which O. montana reliably transmitted plague bacteria was longer than previously thought, and this may help to explain rapid rates of epizootic spread. PMID- 17695025 TI - Early-phase transmission of Yersinia pestis by unblocked Xenopsylla cheopis (Siphonaptera: Pulicidae) is as efficient as transmission by blocked fleas. AB - For almost a century, the oriental rat flea, Xenopsylla cheopis (Rothschild) (Siphonaptera: Pulicidae), was thought to be the most efficient vector of the plague bacterium Yersinia pestis (Yersin). Approximately 2 wk after consuming an infectious bloodmeal, a blockage often forms in the flea's proventriculus, which forces the flea to increase its biting frequency and consequently increases the likelihood of transmission. However, if fleas remain blocked and continue to feed, they usually die within 5 d of blocking, resulting in a short infectious window. Despite observations of X. cheopis transmitting Y. pestis shortly after pathogen acquisition, early-phase transmission (e.g., transmission 1-4 d postinfection [ p.i.]) by unblocked fleas was viewed as anomalous and thought to occur only by mass action. We used an artificial feeding system to infect colony reared X. cheopis with a fully virulent strain of Y. pestis, and we evaluated transmission efficiency 1- 4 d p.i. We demonstrate 1) that a single infected and unblocked X. cheopis can infect a susceptible host as early as 1 d p.i., 2) the number of fleas per host required for unblocked fleas to drive a plague epizootic by early-phase transmission is within the flea infestation range observed in nature, and 3) early-phase transmission by unblocked fleas in the current study was at least as efficient as transmission by blocked fleas in a previously published study using the same colony of fleas and same bacterial strain. Furthermore, transmission efficiency seemed to remain constant until block formation, resulting in an infectious period considerably longer than previously thought. PMID- 17695026 TI - Phenology of Ixodes ricinus and infection with Borrelia burgdorferi sensu lato along a north- and south-facing altitudinal gradient on Chaumont Mountain, Switzerland. AB - Questing Ixodes ricinus L. ticks were collected monthly from 2003 to 2005 on the north- and south-facing slopes of Chaumont Mountain in Neuchatel, Switzerland, at altitudes varying from 620 to 1,070 m. On the south-facing slope, questing tick density was higher than on the north-facing slope, and it decreased with altitude. Density tended to increase with altitude on the north-facing slope. Saturation deficit values higher than 10 mmHg and lasting for >2 mo were often recorded on the south-facing slope, explaining seasonal patterns of questing tick activity. The overall prevalence of Borrelia burgdorferi sensu lato was 22.4%, and prevalence differed according to exposure and among years. No difference was noticed between nymphs and adults. Four Borrelia species were identified. Mixed infections were detected in 52 ticks, B. garinii and B. valaisiana (n = 21) and B. afzelii and B. burgdorferi s.s. (n = 20) were the most frequent associations observed. The density of infected ticks varied from 3.6 to 78.7 infected nymphs per 100 m2 and from 0.6 to 16.9 infected adults per 100 m2, both slopes combined. The study on the south-facing slope was a follow-up of a previous study carried out at the same location during 1999-2001. Comparison of climatic data between the two periods showed a marked increase in saturation deficit. Substantial differences in density and phenology of ticks also were observed. At high elevations, ticks were significantly more abundant during the current study. This can be explained by rising temperatures recorded during summer at altitude, reaching values similar to those registered in the first study beneath. At the lowest altitude, adults were significantly less abundant, probably due to long lasting high saturation deficits that impaired nymphal survival. The density of Borrelia-infected ticks was higher than in the previous study. PMID- 17695027 TI - Climate-based model predicting acarological risk of encountering the human-biting adult life stage of Dermacentor andersoni (Acari: Ixodidae) in a key habitat type in Colorado. AB - We exploited an elevation (climate) gradient ranging from 1,700 to 2,500 m in Poudre Canyon of Larimer County, CO, to determine climatic correlates of abundance per 15-s drag sampling time unit (hereafter referred to as abundance) of the human-biting adult life stage of the Rocky Mountain wood tick, Dermacentor andersoni Stiles (Acari: Ixodidae), in a key risk habitat for tick exposure: south/west-facing, rocky hillsides with mixed grass-brush-conifer vegetation. The relationship between elevation and abundance was parabolic, with peak tick abundances occurring at mid-range elevations (2,200-2,400 m) and tick abundances approaching zero at approximately 2,100 and 2,500 m. Regression modeling demonstrated that abundance of host-seeking adult ticks in south/west-facing exposures was accurately predicted by several climate variables related to temperature (e.g., mean annual minimum temperature, maximum temperature, and base 10 degrees C growing degree-days, and median length of annual freeze-free period; r2 values ranging from 0.771 to 0.864), whereas mean annual precipitation, snowfall, or relative humidity were uninformative in this respect (r2 values ranging from 0.020 to 0.316). Abundance of D. andersoni adults peaked at a mean annual maximum temperature of approximately 10 degrees C and a mean annual growing degree-day value of approximately 650. Relationships between climate variables and abundance of D. andersoni adults were used to create geographic information system (GIS)-based models for predicted tick abundance in south/west facing exposures in Larimer County. This is the first GIS-based model developed for spatial patterns of abundance of D. andersoni. Finally, preliminary data from Poudre Canyon indicate a shift toward peak abundances of D. andersoni adults occurring in sheltered northern/eastern exposures, rather than in drier and hotter southern/ western exposures, at elevations below 2,100 m. PMID- 17695028 TI - Effect of salinity on temephos toxicity to larvae of Aedes sollicitans (Diptera: Culicidae). AB - Aedes sollicitans (Walker) (Diptera: Culicidae) is an important vector of eastern equine encephalitis as well as several other mosquito-borne brain fevers. The larvae are salt-tolerant and develop in salt marshes with highly varying salinity. The effect of salinity on the toxicity of one of the major larvicidal organophosphates, temephos, was evaluated in two groups of larvae raised either in freshwater or water with salinity ranging from 1 to 3.5%. When larvae were raised in freshwater, low salinity (1-3.5%) decreased the toxicity and high salinity (5%) increased the toxicity. In contrast, salinity did not change the toxicity to larvae raised in saltwater. Temephos treatment and salinity seemed to have cross-interaction for the larvae raised in freshwater. High salinity also caused reduction in larval body size, and 5% salinity alone caused mortality for larvae raised in freshwater, suggesting that preadaptation to saltwater in the early instars is essential for survival in later instars at high salinity. PMID- 17695029 TI - Host records for Ornithonyssus sylviarum (Mesostigmata: Macronyssidae) from birds of North America (Canada, United States, and Mexico). AB - The northern fowl mite, Ornithonyssus sylviarum (Canestrini and Fanzago, 1877) (Mesostigmata: Macronyssidae) is a broadly distributed blood-feeding parasite that has been collected from many birds of temperate regions. Previously, the most complete host list was published in 1938, and it included 15 North American (Canada, United States, and Mexico) host species. In the process of a general survey of bird-associated mites in Alberta, Canada, we recovered many O. sylviarum specimens. Herein, we update the previous host list with these observations and records published since 1938. We collected mites by washing the bodies of salvaged birds and examining the filtrate. Northern fowl mites were collected from 26 host species, with 16 of these species being the first host records for North America. Including results from the current study, O. sylviarum has been reported from 72 species of North American birds from 26 families. This updated host list will be useful to anyone interested in the role of O. sylviarum in transmission of avian disease. PMID- 17695030 TI - Evaluation of novaluron as a feed-through insecticide for control of immature sand flies (Diptera: Psychodidae). AB - The development and survival of sand fly Phlebotomus papatasi Scopoli (Diptera: Psychodidae) larvae fed feces of Syrian hamsters, Mesocricetus auratus, that had been fed a diet containing novaluron were evaluated. In total, six larval diets were used in sand fly larval bioassays. Four groups of larvae were fed feces of hamsters that had been maintained on a diet containing either 0, 9.88, 98.8, or 988 ppm novaluron. Two additional groups were fed a larval diet composed of equal parts composted rabbit feces and rabbit chow containing either 0 or 988 ppm novaluron. No pupation, hence no adult emergence, occurred when larvae were fed feces of hamsters that were fed diets containing novaluron. The mortality of sand flies fed feces of treated hamsters occurred during larval molts. The results of this study suggest that a control strategy using rodent baits containing novaluron to control phlebotomine sand flies and zoonotic cutaneous leishmaniasis may be possible. PMID- 17695032 TI - [Surgery--the science or craft?]. PMID- 17695031 TI - Repellent efficacy of formic acid and the abdominal secretion of carpenter ants (Hymenoptera: Formicidae) against Amblyomma ticks (Acari: Ixodidae). AB - Formic acid is a substance produced by some ants for defense, trail marking, and recruitment. Some animals are known to rub ants or other arthropods on parts of their plumage or fur to anoint themselves with released substances. A recent study with a semifree-ranging group of capuchin monkeys, Cebus apella L., in the Tiete Ecological Park, Sao Paulo, Brazil, an area of occurrence of the tick species Amblyomma cajennense (F.), revealed that "anting" with carpenter ants, Camponotus rufipes F. (Hymenoptera: Formicidae), occurs frequently, especially during the A. cajennense subadult season. Based on these observations, we tested the repellent effect of the formic acid and the ants themselves against A. cajennense and Amblyomma incisum Neumann nymphs, and Amblyomma parcum Aragdo adult ticks in the laboratory. The results revealed a significant repellent effect of formic acid and ant secretion, and a significant duration of the repellent effect. The results suggest that the anting behavior of capuchin monkeys, and other vertebrates, may be related with repellence of ticks and other ectoparasites. PMID- 17695033 TI - [Pyogenic abscesses of the liver]. AB - Pyogenic abscesses of the liver represent a serious nosologic unit with high morbidity and mortality rates. Their diagnostics is based on ultrasonography, computer tomography or MRI, or positrone emission tomography. The principal treatment procedure includes percutaneous draining of the abscess cavity under the ultrasound or CT control. The authors present a group of 83 subjects hospitalized from 2000 to 2006 for pyogenic abscesses of the liver. Obstruction of the bile ducts, acute cholecystitis and resections of the liver or pancreas for malignancies were recorded as the commonest causes of the abscesses. Percutaneous drainage was the treatment method of choice in 67.5% of the subjects and it included management of the causative factors and administration of antibiotics. The hospitalization period was affected by the following factors: septic conditions (p < 0.04), ALT levels (p < 0.003) - cut off 3.0 mkat/l, the abscess diameter, which may have required reoperation, (p < 0,05), diabetes mellitus (p < 0.05) and septic conditions (p < 0.001). The need for re hospitalization due to a relaps of the pyogenic abscess of the liver correlated significantly with the following: a number (> 2) of abscesses (p < 0.04), C reactive protein levels (p < 0.005) - cut off> 100 mg/l and septic conditions (p < 0.007). Furthermore, significat correlation was detected between the mortality rates and sepsis (p < 0.05). PMID- 17695034 TI - [Complications of the laparoscopic appendectomy]. AB - 706 appendectomic procedures using laparoscopy were performed in the Surgical Clinic of the FTN hospital during 2003-2005. The group's mortality rate was nil, the morbidity rated 3.54%. The following complications were recorded: nine patients (1.27%) experienced infiltration in the right hypogastric region, which was confirmed on CT or ultrasound examinations, nine subjects (1.27%) suffered wound infections, two subjects (0.28%) developed subileus, in two subjects (0.28%) intraabdominal abscesses, and in one subject (0.14%) diffuse suppurative peritonitis were diagnosed, one subject (0.14%) developed intraabdominal hemorrhaging, in one subject (0.14%) intraabdominal hematoma was detected. Rates of complications in our group are similar to those presented in literature [1, 2, 3]. Based on their study group analysis, the authors found the laparoscopic appendectomy more beneficial for a patient than the open appendectomy. PMID- 17695035 TI - [Controversy in the indication of surgical treatment of acute bleeding for peptic ulcers in gastroduodenum]. AB - INTRODUCTION: Bleeding in the upper part of GI tract is a serious condition requiring careful investigation and adequate treatment. The surgical treatment is irreplaceable in the case of unsuccessful conservative treatments. The timing of a surgical intervention in diagnostic-therapeutic algorithm is still controversial, although there are a lot of identification factors. MATERIAL: 538 patients with bleeding I and IIA according to Forrest classification were hospitalized in surgical ICU in the period from July 2001 till December 2006. There were 310 men and 228 women together. RESULT: 34 patients with mortality 17.6% were surgically treated after unsuccessful conservative and endoscopic treatment. CONCLUSION: The early surgical intervention for patients with bleeding from peptic ulcus decreases its mortality. The emergency surgical intervention is necessary for patients when bleeding continues in an adequate conservative treatment or in the excessive recurrent bleeding. It is also necessary when the active bleeding is not endoscopicaly treatable or approachable. The number of emergency surgical interventions can be decreased by effective endoscopical treatment and by stabilization of patients. In the case of the location of bleeding in the back wall of duodenal bulbus or in the location of little curvature and especially in bigger peptical lesions the elective surgical intervention should be concerned because of the high risk of recurrence of bleeding. The mortality rate in emergency surgical intervention for excessive bleeding ranges from 10 till 50% compared with elective operations according to literature. PMID- 17695036 TI - [Delayed reconstructions of soft tissue defects of the face]. AB - The author describes a non-standard approach to the management of facial soft tissue defects. Significance of delayed reconstructions in defect face injuries and options for their employment in indicated cases are highlighted. PMID- 17695037 TI - [Surgical harvesting of small bowel intended for transplantation]. AB - The small intestine transplantations represent a logical alternative to final total parenteral nutrition in patients with chronic intestinal failures. It is considered a life- saving procedure in patients with intestinal failure, where standard treatment procedures cannot be further implemented. Perfect harvesting technique is very important for succesful clinical small bowel transplantation. The authors studied the surgical view of the small intestinal transplant harvesting and monitored differences in ischemic injuries to jejunum and ileum depending on duration of the cold ischemia time. The study is one of the inital works in the planned intestinal transplantation clinical programme. PMID- 17695038 TI - [Benign lymphoepithelial cyst of the pancreas: a case report]. AB - Lymphoepithelial cyst of the pancreas represents an extremely rare and benign entity of undetermined pathogenesis. This lesion must be taken into consideration in the differential diagnosis of pancreatic cystic lesions. A case of resected lymphoepithelial cyst of pancreas in 59-year-old man with an attack of acute pancreatitis in anamnesis is reported. The postoperative period was uneventful, and the histolopathological examination revealed the structures of lymphoepithelial cyst. The aim of this report is to describe the clinical and pathological features of this unusual true cyst of the pancreas. PMID- 17695039 TI - [Acute massive hemorrhage from the recanalized umbilical vein as a complication of portal hypertension]. AB - Portal hypertension is very often complicated by severe and a life threatening bleeding in GIT in most cases from oesophageal varices. Another complication of PH is dilatation of portosystemic shunts in abdominal wall so-called caput medusae. We describe a case of a man, that was admitted to our surgical department with massive bleeding from recanalisated umbilical vein as complication of portal hypertension. After couple of the recurrence of the haemorrhage and precise diagnosis of the source we have indicated surgical treatment. We cat off the lig. teres hepatis by laparoscopic approach to decrease tension in blood vessels in the abdominal wall. After surgery there were no evidence of rebleeding and the patient was forwarding for monitoring of oesophageal varices in gastroenterological center. PMID- 17695040 TI - [A synchronous tumor of the rectum and kidney. A case review]. AB - Incidence of multiple synchronic carcinomas is on rise. It may be attributed to improvements in diagnostic technology and other factors, as well. The authors wish to share their experience in this case review dealing with the synchronic colorectal carcinoma and carcinoma of the left kidney, with literature data added. The causative factors of the multiple tumors should be searched for at subcellural levels. They result from genetic transformations in a particular patient and may also be affected by environmental factors. It must be remembered, that cancer need not affect a single organ system. However, a single organ system may be affected by cancer in several locations, which must be born in mind when a diagnosis is made. PMID- 17695041 TI - [Infected brachial artery pseudoaneurysm--infrequent complication secondary to parenteral drug abuse]. AB - INTRODUCTION: Intravenous drug abuse brings many infectious and surgical complications. Considering the duration of a drug scene in Czech Republic, pseudoaneurysms are not frequent complications, but we can expect their increased frequency with time. METHODS: A 27-year-old patient with known history of parenteral drug abuse (heroin, pervitin) was treated at our department during the autumn of 2006. He had self-injected heroin into an armpit four days before his appearance in our outpatient department. An abscess of his left arm and armpit resulting from cellulitis was his admission diagnosis based on a clinical ground. We did not validate that diagnosis with any radiology test. The operation made clear that pseudoaneurysm in a proximal part of brachial artery was a correct diagnosis. Because of severe inflammation of his left upper extremity, the pseudoaneurysm was dealt with resection, ligation of the brachial artery above and below the defect and leaving the incision to heal by secondary intention. RESULTS AND CONCLUSIONS: The pseudoaneurysm was treated with excision, tying the proximal and distal ends of brachial artery without urgent revascularization, extensive debridement of all necrotic tissues and leaving the incision to heal by secondary intention. Our approach did not threaten viability of the limb, which did not show any signs of ischemia during close postoperative monitoring. Our way seems to be appropriate and in agreement with current literature. The peroperative finding stresses the necessity of standard and Doppler ultrasound in every intravenous drug abuser with clinical picture of "a typical abscess" located in groin, elbow and armpit. PMID- 17695042 TI - [Laparoscopic management of epidermoid spleen cyst]. AB - Spleen cysts are rare in the surgical practice. They may be primary or secondary. Primary cysts (true, with own lining) represent 30-40% of all cysts and occur mostly in children and young adults. Secondary cysts (pseudocysts, with no lining) are more frequent. Primary cysts are mostly asymptomatic and usually occur as accidental findings during ultrasound examinations. Cysts over 50 mm or cysts with clinical symptomatology should be managed surgicaly. Laparoscopy may be used. The authors present laparoscopic management of a spleen epidermoid cyst in a young female. PMID- 17695043 TI - [Disorder of vertebral metastasis]. AB - The aim of this article is putting near problems of treatment vertebral metastasis to professional public. Because of improving of imagine methods the diagnosis of this disorder is early making and that is way patient benefit of early initiation of adequate therapy. Authors of this paper rate literary studies concerning of therapeutic methods for treatment of vertebral metastasis and comper to their group of patients. PMID- 17695044 TI - [Oral hygienic, nutritional habits and dental surgeon attendance of Hungarian adult population]. AB - The aim of the study was to reveal the oral hygienic, nutritional and behavioral habits of Hungarian adult population in different regions of Hungary. The study was performed by the Department of Prosthetic Dentistry (Semmelweis University, Budapest) in 2003-2004. Altogether 4606 persons (mean age: 46.37 +/- 7.89ys), 2923 women (mean age: 48,09 +/- 18,36 ys), 1683 men (mean age: 44.41 +/- 17.14 ys) participated in the study. Probands were selected randomly from the population attending the compulsory lung screening examinations. To make a representative sample of the whole population in the country, the chosen localities covered all regions, the capital, the large towns and villages as well. The data were coded on special sheets by computer in place. Statistical analysis was performed using SPSS for Windows 10.0 statistical software version. The daily consumption of sweets was the highest (34%) in the Western Central Region. It was the highest in the age group under 19 ys (40%). In relation to daily consumption of coke and soft drinks, the frequency was 13% in the whole population. The highest frequency was registered in the North Eastern Region (17.5%) and in the age group of 19-year-olds. The results showed that the consumption of soft drinks was significantly lower in women comparing to men (p < 0.001). The consumption of sweets and soft drinks was significantly decreased by the increase of age (p < 0.001). The asked population cleaned their teeth twice a day, mostly using only toothbrush and dentifrice, and only 12% of them used mouthwash, 11% toothpick, and 7% dental floss. The majority of the examined population (68%) visited dental service on an irregular base (only in case of acute complaints). PMID- 17695045 TI - [Prognostic significance of type 2 diabetes in patients treated with surgery and irradiation for gingival cancer]. AB - Type 2 diabetes may be regarded as a risk factor for cancers in different sites. The aim of this study was to compare the progression of primary gingival cancers in type 2 diabetic and non-diabetic patients. This retrospective follow-up study involved 48 diabetic and 52 non-diabetic control patients with gingival squamous cell carcinoma in stage T2-3N0M0. Their treatment comprised surgical tumor extirpation, block resection of the mandible, functional cervical dissection and 60 Gy adjuvant irradiation. Progression data was recorded after a 2-year period of clinical follow-up. Surgical samples were assessed histopathologically from the aspect of tumor spread. At the end of a 2-year follow-up period, there were significantly worse clinical results in the diabetic group concerning the cervical lymph node metastases (P <0.05) and the rate of deaths (P< 0.001). Histologically, the degree of tumor invasion was significantly different in the diabetic group compared to the controls (P < 0.01). Type 2 diabetes can be regarded as a possible prognostic factor in cases of gingival carcinoma, forecasting an unfavorable course. PMID- 17695047 TI - [Synthesis of nanoparticles for dental drug delivery systems]. AB - Modern drug delivery systems are designed for targeted controlled slow drug release. Up to now polymer based hydrogels have been applied in dentistry, which systems can affect the rate of the release due to their structure. Recently, intensive research for other methods is performed all over the world in order to improve the effectiveness of delivery systems. Nanotechnology is one of the most dynamically developing disciplines and is a powerful tool to increase the bioavailability of drugs. The aim of this work is to synthesise biocompatible nanoparticles by free radical initiated copolymerization of the monomers, 2 hydroxyethyl methacrylate (HEMA) and polyethyleneglycol dimethacrylate (PEGDMA) in aqueous solution, which can support the formation of nanoparticles that can be used as a drug delivery system for dental applications. The polymer-based nanoparticles were prepared via micellar polymerisation, which resulted a well dispersible white powder material. The size of particles was determined by Dynamic Laser Light Scattering (DLS) and Scanning Electron Microscopy (SEM). The size of particles is in range of 50-180 nm, measured by SEM. These values are commensurable with the results obtained by DLS experiments, where two size ranges were observed, as 40 +/- 15 nm and 180 +/- 30 nm. The nanoparticles are suitable for incorporation into a hydrogel matrix and to design new drug delivery devices for dental applications. PMID- 17695046 TI - [Changes in the indications for oral surgical implants based on statistical analysis]. AB - Journals, books and lectures on oral implantology are concerned less and less with the various fields of indication and their changes. The reason for this is in part that from a surgical point of view we consider the lack of contraindication as the indication of dental implant placement, while from a prosthetic point of view implant supported prosthetic work can be done in any prosthetic situation. Despite of this it is an interesting question, how the ratios of the various fields of indication have changed in view of the age groups and genders in Hungary in the past twenty years. In the present study a part of the patients reporting to the outpatient clinic of the Department of Oral and Maxillofacial Surgery and Dentistry of Semmelweis University for dental implant placement in the past 22 years were analyzed using statistical methods. Various age groups, genders and types of implants were compared in view of the indication of placement. The results were compared to data published in international literature. PMID- 17695048 TI - [Osteonecrosis of the jaws by using bisphosphonates]. AB - The new generation of bisphosphonates are often used in the treatment of osteoporosis or for certain tumors with bone defects. Between the period of September 2005 and May 2006 we have treated 8 patients at our clinic with a bisphosphonate-induced osteonecrosis in the maxillofacial region. All of these patients went through intravenous bisphosphonate treatment earlier. We have chosen two cases, where the appearance of side effects can be named as typical. Based upon the increasing number of international articles reporting and our own experiences in this matter, we would like to draw attention to the importance of prevention in treating these patients. In case of symptoms, if temporary suspension of the bisphosphonate therapy does not have severe consequences, combination of surgical and long-term antibiotic therapy could be the solution. PMID- 17695049 TI - [Determination and practical application of articulator related individual functional parameters. New method of measurement: virtual articulator and face bow]. AB - The aim of each occlusal surface reconstruction is to take the functionally developed biomorphologic aspects into consideration while restoring occlusal conditions. In order to fulfil these conditions, it is necessary to represent individual mandible movement as accurately as possible. In addition to physiological knowledge, it is indispensable for us to be able to simulate spatial mandible movement and determine individual parameters in an utmost precise way. By correcting projecting mistakes, the articulator should reproduce static and dynamic occlusal conditions according to reality. This is a difficult task. The advance of technology, spreading of computers and the idea of 'virtual articulator' have all helped to fulfil all these conditions by quick digital data processing instead of complicated and slow mechanical gadgets. The aim of our publication is to present the programming possibilities of the articulator of individual value belonging to the system and the advantages of the method. PMID- 17695050 TI - Comparison of individual prediction of treatment outcome made by a TMD specialist and a TMD-trained general dental practitioner in patients with temporomandibular disorders. AB - The aim of this study was to investigate if a TMD-trained general dental practitioner could individually predict actual treatment outcome in selected patients diagnosed with temporomandibular disorders (TMD) with similar results as a TMD specialist. The patients were examined, individually predicted, treatment planned, treated and had their treatment outcome evaluated by the therapist, respectively. Out of 2618 patients referred to a TMD specialist clinic, 1086 patients started treatment. They were all divided into Muscle or Mainly TMJ symptoms. Prediction of the treatment outcome as Good or Dubious was based on the patient's history, the clinical and, sometimes, radiological findings. The degree of improvement was graded using a Numeric Rating Scale 0-100. A clinical important improvement, defined as an improvement of initial complaints of 50% or more, was judged as a correct prediction of Good treatment outcome. Seven-hundred sixty-nine patients treated by the TMD specialist (Sample 1) was compared with 164 patients treated by the TMD-trained general dental practitioner (Sample 2). For patients with Muscle symptoms in Sample 1, a 50% improvement or more was reached by 93% of those predicted Good and 57% of those predicted Dubious. The corresponding figures in Sample 2 were 100% and 82%, respectively. In Sample 1, patients with Mainly TMJ symptoms reached a 50% improvement or more in 94% of those with prediction Good and 73% of those predicted Dubious. In Sample 2 the figures were 100% and 87%, respectively. ATMD-trained general dental practitioner could individually predict treatment outcome with similar results as a TMD specialist in selected patients diagnosed with TMD. Whether the method is possible to generalize has to be investigated further. PMID- 17695051 TI - A longitudinal study of dental health from the age of 14 to 41. AB - The aim of present study was to longitudinally follow dental health from the age of 14 to 41. Originally an entire age group attending one of the compulsory schools in the city of Orebro, Sweden was selected and 115 children born in 1962 were included in the study. At the last examination 27 years later, 73 (63%) individuals, 35 males and 38 females, could still be located and were willing to participate. The drop out analysis did not show any statistical difference between the drop-outs and this final material. All participants had experienced a comprehensive whole population based preventive dental care, free of charge, during the first 19 years of their lives, and after that the increment of dental diseases had been limited. Only two individuals were diagnosed with chronic periodontitis at 41, and 70% of all DMFS registered at 41 were present already at 19. This positive development during adulthood seemed to be unrelated to socio economic status. In addition, the dental health at 41 did not seem to be obviously influenced by if the participants, as adults, had paid yearly visits to the dentist or not, and there was no evidence supporting that regularly seeing a dental hygienist or using daily inter-dental cleaning would improve dental health. The most obvious difference in dental health at 41 was due to gender where e.g. the experience of proximal caries and bleeding after probing were twice as frequent in males as in females. Based on the results of the present study it can be concluded that uncritically abandoning whole population preventive strategies might not be in the best interest of public dental health. Furthermore, if already existing dental care resources should be reallocated for a better long-term dental health investment it should be on the expense of the young adults to the benefit of the young teenagers (as population sub-groups) and not the other way around based on individual indications. PMID- 17695052 TI - Development and evaluation of a comprehensive screening for orofacial dysfunction. AB - The aim was to develop a comprehensive screening instrument for evaluation of orofacial dysfunction that was easy to perform for different health professionals without special equipment. The Nordic Orofacial Test--Screening (NOT-S), consisting of a structured interview and clinical examination,was developed with a picture manual illustrating the different tasks in the examination. It was first tested in a Swedish version, and later translated to other Nordic languages, and to English. The interview reflected six domains, (I) Sensory function, (II) Breathing, (III) Habits, (IV) Chewing and swallowing, (V) Drooling, and (VI) Dryness of the mouth, and the examination included six domains representing (1) The face at rest, and tasks regarding (2) Nose breathing, (3) Facial expression, (4) Masticatory muscle and jaw function, (5) Oral motor function, and (6) Speech. One or more "yes" for impairment in a domain resulted in one point (maximum NOT-S score 12 points). The mean NOT-S score (+/- SD) in 120 patients (3-86 yr), referred to five centers for specialized dental care or speech and language pathology in Sweden, Norway and Denmark, was 4.1 +/- 2.6, and 0.4 +/- 0.6 in 60 control subjects (3-78 yr). The screening was easy to administer and the time spent 5-13 min. The scores from the clinic-referred sample differed significantly from the controls, and the sensitivity of the screening was 0.96 and specificity 0.63. Repeated evaluations of videotapes of 200 patients by 3 examiners, speech-language pathologists and dentists, with at least two-week intervals, showed inter- and intraexaminer agreement on the points given in the domains at respectively 83% and 92-95% which increased after recalibration to 85% and 95-99%. Kappa values for interexaminer agreement on the NOT-S scores were 0.42-0.44 (i.e. fair), and the method error was 5.3%. To conclude, NOT-S gave a reliable and valid screening for orofacial dysfunction. PMID- 17695053 TI - Experience of dental care for children with congenital heart disease among Swedish dentists. AB - This study was conducted in order to examine the experience of and attitudes to dental care for children with congenital heart disease (CHD) among Swedish general dentists. 183 general dentists employed in the Public Dental Health Service in the counties of Vasterbotten and Uppsala, and private practitioners listed with dentistry for children in the county of Vasterbotten, Sweden, were enrolled in the study. Data were collected with a questionnaire with 18 questions. Eighteen per cent of the dentists stated that they had received special education or information except the graduate training to treat children with CHD. Forty-eight per cent of the dentists had one or more patients with CHD. Seventy-two per cent of these stated that their CHD-patients had a caries problem. Statistically significant differences were displayed between answers on the questions "who in the dental team perform the major part of the dental care for children with CHD" and "what is your opinion on which personal category that should perform the major part of the dental care for this group of children" (p < 0.001). Among dentists whose clinical time mainly was used for dentistry for children, it was more common to treat children with CHD (p < 0.001) than for dentists with a lower degree of dentistry for children. The study showed that the Swedish dental care for children with CHD today mainly is performed by dental nurses, dental hygienists and general dentists. This strongly differs from the dentist's opinion on who should perform the major part of the dental care for this group of children. These findings taken together with the very low number of dentists that had received special education or information except the graduate training to treat children with CHD indicates that the Swedish dentists are unsettled and insecure in the dental treatment of children with heart defects. An early and close cooperation between specialists in pediatric dentistry, dentists with special training and general dentists is strongly desirable to support the dentists and facilitate the dental care for children with CHD. PMID- 17695054 TI - Evaluation of a Swedish version of the OHIP-14 among patients in general and specialist dental care. AB - The aim of this study was to investigate the Swedish version of an oral health related quality of life (OHRQL) instrument, the short form of the Oral Health Impact Profile (OHIP-14), and to assess OHRQL among patients in general dental care and specialist clinics (periodontics, TMD and implant dentistry) in Goteborg, Sweden. Consecutively selected patients were asked to answer the OHIP 14, the General Oral Health Assessment Index (GOHAI) and a questionnaire including socio-demographic, general health and oral health questions. 153 patients (50-89 years old) out of 237 (65%) returned the questionnaires. Cronbach's Alpha among the OHIP items was high (0.93) and the corrected item scale correlation varied between 0.51 and 0.79. The correlation between the OHIP 14 score and the GOHAI was high (-0.83) indicating good criterion validity. The mean additive OHIP-14 score was 22.6 (SD = 10.5). Implant patients scored significantly higher than other patient groups with respect to missing teeth, dentures and mobile teeth. High scores were also associated with perceived poor general health and dissatisfaction with life-situation. The test-retest reliability was assessed in a separate sample (n = 47) and the correlation coefficient was 0.85. The Swedish version of OHIP-14 demonstrated good reliability and validity. The poorer OHRQL reported by the implant patients reflects the strong association found between OHIP score and dentures and missing teeth, while OHIP-14 did not show similar sensitivity to other impacts of oral disorders. PMID- 17695055 TI - Patient satisfaction with dental care in one Swedish age cohort. Part 1- descriptions and dimensions. AB - The aim of this study were to investigate the dimensionality of satisfaction with dental care, to control the reproducibility of the analysis over time, to investigate changes between the two studied years and to relate satisfaction with elapsed time since the most recent visit to dental care. All persons born in 1942 in two counties in Sweden, Orebro and Ostergotland, were surveyed by post in 1992 at the age of 50 and resurveyed at the age of 55. There were 5363 persons responding at both times, constituting the study group. In this study, opinions are analysed about general satisfaction with dental care and about the most recent dental visit. Factor analysis, one-way ANOVA and contingency tables were used. Overall satisfaction was high both as to general satisfaction and as to the most recent dental care visit. Those with their most recent dental visit more than a year ago felt more pain, anxiety and unpleasantness and were also more generally dissatisfied. Of those having experiences of pain, anxiety and unpleasantness at most recent visit, there was an overrepresentation of non regular attenders. Factor analysis showed that the questions used revealed a stable pattern. In conclusion, the overall satisfaction with dental care was high. Differences between the two studied years were small. Persons not visiting dental care within the last year were more dissatisfied both generally and with the most recent visit. A greater number of regular attenders had no feelings of anxiety, pain or unpleasantness at all. PMID- 17695056 TI - Applying cardiac advances saves lives. PMID- 17695057 TI - Migraine, heart disease linked. PMID- 17695058 TI - Ask the doctor. What causes C-reactive protein levels to vary? PMID- 17695059 TI - Ask the doctor. Why does my father feel wires poking him in the chest months after open-heart surgery? PMID- 17695060 TI - Toxicological highlights. PMID- 17695061 TI - [Integrated treatment of depression in Aachen]. PMID- 17695062 TI - Using an extracorporeal suture loop to aid retroperitoneal pelvi-ureteric anastomotic suturing during laparascopic pyeloplasty. PMID- 17695063 TI - Scientists tackle water contamination in Bangladesh. PMID- 17695064 TI - In Venezuela, two public-health systems grow apart. PMID- 17695065 TI - SPRING: a new trial to evaluate tipranavir in heterogeneous treatment-experienced HIV populations. PMID- 17695066 TI - Ramsay Hunt syndrome presenting as cranial polyneuropathy. PMID- 17695067 TI - [Time course of osseous changes in early functional load using dental implants in x-ray imaging]. AB - The paper deals with X-ray parameters in indirect implantation and with the impact of early functional load on osteointegration in the experimental and clinical settings. Analysis of cases suggests that implant installation just after tooth extraction accelerates implant osteointegration and causes no complications. PMID- 17695068 TI - [Ultrasound diagnosis in endoprosthesis of lower extremity arterial aneurysms with "Hemobahn"- and "Viabahn"-eluted stents]. AB - The paper presents the results of color duplex scanning (CDS) in 7 patients treated at the Unit of Vascular Surgery, Clinical Hospital No. 83, from 2002 to 2006, in whom 5 Hemobahn grafting stents and 2 Viabahm ones were implanted into the lower limb arterial aneurysms and the proximal anastomoses of the iliofemoral alloshunts "Gore-tex". A grafting stent was individually selected for each specific case. All the examinees were males. The patients' age was 60 to 70 years. The results of endovascular interventions were assessed, by analyzing color duplex scanning (CDS) of a grafting stent implantation area in early postoperative periods (days 1-3), further by the scheme following 1, 3, 6, and 12 months and then twice a year. Endovascular intervention areas were studied by the standard procedure on Logic-500 and Vivid-700 ultrasound apparatuses (USA) with a 7.5-MHz linear transducer and a 3.5-MHz convection transducer. In the postoperative period, multiprojection scanning was used to detect stent configuration impairments. According to the data of examination using the CDS technique, a surgical success was noted in 100% of cases. In all cases, stage, adequate aneurysmal stenting along with the restoration of the geometry of proximal anastomoses of iliofemoral alloshunts, iliac and superficial femoral arteries with exclusion of aneurysms from blood flow was diagnosed at a hospital stage. Follow-up ultrasonography revealed no changes in the area of endovascular intervention. Thus, as a highly informative, noninvasive technique, CDS can assess the results of implantation of grafting stents into the arteries and shunts of the lower extremities in both early and late postoperative periods. PMID- 17695071 TI - Emergency contraception. PMID- 17695072 TI - Influences that affect Maori women breastfeeding. AB - This project aimed to identify the factors that influence Maori women's decision to breastfeed or not. During 2004-2005, a diverse demographic of Maori women and family members was selectively recruited from within a major urban area, small towns, and rural areas. Thirty women who had cared for a newborn within the previous three years were interviewed, alone or together with other family members. All participants self-identified as Maori and were over 16. Women who had artificially fed their babies were underrepresented. Most of the participants had breastfed and their determination to breastfeed was strong. This research proposes a new model for understanding how Maori women are diverted from breastfeeding. Five influences were identified: interruption to a breastfeeding culture; difficulty establishing breastfeeding within the first six weeks; poor or insufficient professional support; perception of inadequate milk supply; and returning to work. These influences occur in a temporal sequence and highlight opportunities for intervention. Factors that encourage breastfeeding are also discussed. PMID- 17695073 TI - Creating a breastfeeding culture: a comparison of breastfeeding practises in Australia and Iran. AB - Breastfeeding is an unequalled way of providing ideal food for the healthy growth and development of infants and has a unique biological and emotional influence on the health of both mother and child. However, despite the well documented health benefits of breastfeeding, most Australian women discontinue breastfeeding before the recommended time. This study attempts to identify variables influencing breastfeeding practices in Australia by comparing Australia with Iran, which enjoys a comparatively high breastfeeding rate. The study found a range of variables which appeared to negatively influence breastfeeding practices in Australia including: a comparatively inadequate national program for the promotion of breastfeeding; less uptake of the Baby Friendly Hospital Initiative; less supported return to paid work; and cultural issues. PMID- 17695074 TI - An analysis of Australia's changing context: the breastfeeding mother, motivation and free community-based education. AB - Breastfeeding promotion, support, and education by volunteer peer activists have improved breastfeeding duration rates in various low socio-economic populations. In Australia however, breastfeeding rates at six months are low despite peer support, as provided by the Australian Breastfeeding Association, being available to mothers since 1964. Immigration over the last 40 years has changed the identity of Australian mothers and altered the country's fertility rate. The discourses that are currently circulated to motivate the breastfeeding mother are reviewed and questioned. PMID- 17695075 TI - A longitudinal evaluation of sulfide concentration as a marker for the progression of periodontitis. PMID- 17695076 TI - A three-dimensional analysis method for edentulous mandibular ridge shape. AB - The aim of this study was to develop a three-dimensional method to analyze edentulous ridge shapes. A laser projection method was used to record the shape of edentulous plaster models. Contour of residual ridge on the reconstructed image was then subdivided into small triangles, and a 'normal line' representing the center of gravity of each triangle was determined buccolingually and anteroposteriorly. Angle between the normal line on the residual ridge and the tentative occlusal plane was calculated for each triangle. These angles were then used to analyze the ridge shape. This method was used to analyze the ridges of 20 edentulous patients with excessive bone resorption. The results suggested that this method was useful for analyzing edentulous ridges regardless of ridge shape and degree of resorption. PMID- 17695077 TI - [Treatment of latent tuberculosis infection: update of guidelines, 2006]. AB - The Tuberculosis Working Group of the Portuguese Society of Pulmonology, feeling the need to develop guidelines for the diagnosis and treatment of latent tuberculosis infection, compiled a set of recommendations, in view to standardize procedures on this area. This document was prepared in collaboration with the Portuguese Societies of Internal Medicine, Pediatrics and Infectious Diseases, A review and update of guidelines for tracing and treatment of latent tuberculosis infection was made, concerning immunocompetent children and adults, as well as immunocompromised children and adults due to HIV infection. It is understood that these guidelines are to be used as general recommendations, and they should not replace the individual analysis of each case. PMID- 17695078 TI - [Consensus document on nosocomial pneumonia]. PMID- 17695079 TI - [Teamwork: a challenge for family health strategy consolidation]. AB - Teamwork is one of the main pillars of Family Health Care projects, although it is not a strategy exclusively applied to such programs. It is not frequently discussed in current collective health research studies, but the perspective resulting from the full range of its action favors interdisciplinary and transdisciplinary actions. Thus, when building a Family Health Project, teamwork should be guided by a common health care purpose and the players involved should develop an interaction movement within the team itself as well as in relation to the community. It is therefore critical to establish communication practices for mutual understanding. This paper presents some preliminary considerations on the teamwork strategy in Family Health Care actions, indicating barriers and potentials in the construction of this health care model. PMID- 17695080 TI - Purine metabolism in heterozygous carriers of hypoxanthine-guanine phosphoribosyltransferase deficiency. AB - The urate pool and daily turnover of urate, together with the rate of incorporation of glycine into urate, were measured in three asymptomatic mothers who had sons with various degrees of deficiency of hypoxanthine-guanine phosphoribosyltransferase activity. Two of these mothers had abnormally increased values for the urate pool, urate turnover, and 24-hour urinary excretion of uric acid. These two mothers also had reduced hypoxanthine-guanine phosphoribosyltransferase activity and increased adenine phosphoribosyltransferase activity in erythrocyte lysates. All three mothers showed an abnormal increase in urate production, as judged by the rate of incorporation of glycinie into urate. PMID- 17695081 TI - Eye movement-retina delayed feedback. AB - Time delays between ocular movement and retinal input have been studied by yoking a visual target to eye movement by experimental programming methods and a laboratory real-time computer system. The subject's task was to manipulate this eye movement-yoked target cursor to perform either compensatory or pursuit eye tracking. The computer thereafter was programmed to store input eye-movement signals and read them out after a delay interval to control the yoked visual target cursor controlled by the eye movements. Delay time constants of 0.1 second significantly affected tracking. Eye movement-retinal feedback delays appeared to have an even more marked effect on positive pursuit eye tracking. PMID- 17695083 TI - [Recommendation of the surgical specialty college for the correction of the financing for inguinal hernia repairs]. PMID- 17695082 TI - [Use of implants for the tension-free surgical treatment of hernias]. PMID- 17695084 TI - [Care of the eyes in patients in the intensive care]. PMID- 17695085 TI - Oxidized low density lipoproteins induce apoptosis in human lymphocytes: involvement of mitogen-activated protein kinases. AB - Oxidized low density lipoproteins (oxLDL), macrophages and T-lymphocytes are present in atherosclerotic lesions. We and others have shown that oxLDL is cytotoxic for macrophages, endothelial, smooth muscle and activated T-lymphocytes and induce apoptosis. Here we demonstrate that (i) oxidized LDL (oxLDL), oxidized VLDL (oxVLDL) and hydrogen peroxide (H2O2) induce apoptosis in human T lymphocytes and (ii) mitogen-activated protein kinases are involved in this process. Apoptosis was monitored by immunofluorescence microscopy and flow cytometry for annexin V binding, Apo 2.7 expression, the TUNEL reaction and caspase 3 activity. In the presence of oxLDL (100 microg/ml), oxVLDL (50 microg/ml) and H2O2 (5 mM), the fraction of apoptotic cells increased within 6 hours to more than 70%. Preincubation of lymphocytes with the MAPKK inhibitor PD 98059 and the p38MAPK inhibitor SB-203580 almost completely abolished these effects. Furthermore, oxLDL and H2O2 but not native LDL strongly enhanced phosphorylation of JNK, p38MAPK and p42/44MAPK. The results suggest that in the resting lymphocyte apoptosis triggered by oxidized lipoproteins and oxidative stress depends on the activation of p44/42MAPK and p38MAPK cascades. PMID- 17695086 TI - In vitro study of biofunctional indicators after exposure to asbestos-like fluoro edenite fibres. AB - The in vitro biological response to fluoro-edenite (FE) fibres, an asbestos-like amphibole, was evaluated in lung alveolar epithelial A549, mesothelial MeT-5A and monocyte-macrophage J774 cell lines. The mineral has been found in the vicinity of the town of Biancavilla (Catania, Sicily), where an abnormal incidence of mesothelioma has been documented. Cell motility, distribution of polymerized actin, and synthesis of vascular endothelial growth factor (VEGF) and of beta catenin, critical parameters for tumour development, progression and survival, were investigated in A549 and MeT-5A cells exposed to 50 microg/ml FE fibres for 24 hr and 48 hr. The levels of cyclooxygenase (COX-2) and prostaglandin (PGE2), two molecules involved in cancer pathogenesis by affecting mitogenesis, cell adhesion, immune surveillance and apoptosis, were measured in J774 cells treated with FE fibres under the same experimental conditions. Finally, FE fibres were studied by SEM and EDS analysis to investigate their chemical composition. Exposure of A549 and MeT-5A cells to FE fibres affected differentially phalloidin stained cytoplasmic F-actin networks, cell motility and VEGF and beta-catenin expression according to the different sensitivity of the two cell lines. In J774 cells it induced a significant increase in COX-2 expression, as assessed by Western blot analysis, and in the concentration of PGE2, measured in culture media by ELISA. SEM-EDS investigations demonstrated two types of FE fibres, edenite and fluoro-edenite, differing in chemical composition and both recognizable as calcic amphiboles. Fibre width ranged from less than 1 microm (prevalently 0.5 microm) to 2-3 microm (edenite) up to several microm (fluoro edenite); length ranged from about 6 to 80 microm (edenite) up to some hundred microm (fluoro-edenite). Results provide convincing evidence that FE fibres are capable of inducing in vitro functional modifications in a number of parameters with crucial roles in cancer development and progression. Inhaled FE fibres have the potential to induce mesothelioma, even though their ability to penetrate lung alveoli depends on their aerodynamic diameter. PMID- 17695088 TI - Destiny led him to dentistry, dedication made him president. PMID- 17695087 TI - Observations of barbers' activities in Oyo State Nigeria: implications for HIV/AIDS transmission. AB - In Nigeria, most studies concerning HIV/AIDS transmission have looked at the sexual route from both epidemiological and behavioral perspectives. A few have examined the role of blood transfusion and the potential for indigenous surgical practices. None have specifically looked at the transmission of potential barbers. This study distinguished between indigenous barbers who function as surgeons and "modern" barbers who cut hair, and focused on the latter through observations of barbering practices in 77 shops in Igbo-Ora and Apete communities in Oyo State. Igbo-Ora is headquarters of a rural local government, while Apete is a peri-urban community near Ibadan, the state capital. Five barbering sessions were observed in each shop using a checklist during evening hours when shops are busiest. All barbers used clippers to cut hair, either electric or manual. On average, barbers sterilized the clippers in a commercial disinfectant, Jik, or with methylated spirits prior to 4.2 barberings. Sex and age of customer were not associated with wether the clippers were sterilized. Three shop characteristics appeared to influence sterilization behavior. Clippers were more likely to be sterilized if the shop was in Apete, if the shop owner was male, and if the shop had two or more of the following electrical appliances: fan, TV, or radio/cassette layer. There were only two observed cases of the barbers causing a cut, and in both cases the clippers had been sterilized. Overall, 63 (16.3%) of the 385 customers were barbed with non-sterilized clippers. The relatively short time gap between customers implies that the potential for disease transmission exists, though it was not within the scope of this study to study disease transmission itself. In-service training that involves the barbers themselves and addresses both gender and town differences is recommended. PMID- 17695089 TI - Report from the XVI International HIV Drug Resistance Workshop. PMID- 17695090 TI - Entecavir in HIV/HBV coinfection: possible HIV activity and resistance risk. PMID- 17695091 TI - On the oxycontin scandal: don't abandon patients in pain. PMID- 17695092 TI - Treatment of STDs: updated guidelines from the CDC. PMID- 17695093 TI - Acute Charcot's arthropathy: a difficult diagnosis. PMID- 17695094 TI - Lumbar artery avulsion after a low-energy chance fracture. PMID- 17695095 TI - A rare, opportunistic disease in a patient with AIDS. PMID- 17695096 TI - What are the best screening instruments for PPD? PMID- 17695097 TI - Hypochondriasis: meeting the management challenge. PMID- 17695098 TI - What is the impact of postgraduate education for PAs? PMID- 17695099 TI - Should I get the shingles vaccine? PMID- 17695100 TI - Patient information. Should I get the shingles vaccine? PMID- 17695101 TI - A man with an unusual sequela of alcoholism. PMID- 17695102 TI - What is your diagnosis? Multiple evanescent white dot syndrome. PMID- 17695103 TI - The status of pollinators. PMID- 17695104 TI - Typological review of environmental performance metrics (with illustrative examples for oil spill response). AB - An intensification of interest in environmental assessment during the last 2 decades has driven corporate efforts to better document environmental goals, improve environmental management systems, and increase awareness of the environmental and ecological effects of business operations. This trend has been motivated partly by regulatory requirements (such as the Toxics Release Inventory in the United States) and partly by the inclination of some large manufacturing firms to embrace a broader social and environmental mission characterized as "sustainability" or "ecoefficiency." Moreover, the importance of measurable objectives in the US government has been recognized at least since the Government Performance Results Act of 1993, which was intended to both improve the efficiency of government and the confidence of the American public in government managers. However, in management of environmental crises - such as catastrophic oil or chemical spills - development of measurable performance standards has lagged. Consequently, government spill managers are unable to define success in terms that are easily communicated to public and other stakeholder groups, and they could be disadvantaged in their efforts to deploy response resources with maximum efficiency. In this paper, we present a typological review of environmental assessment measures and summarize some of the current practices and strategic goals among federal agencies with regard to oil and chemical spills. A general approach to organizing metrics for oil spill response, restoration, and recovery is also presented. The results could improve planning efforts and communication among different federal, state, and local agencies and public or stakeholder groups involved in spill management. PMID- 17695105 TI - Insight into the variation in calculated human exposure to soil contaminants using seven different European models. AB - In order to get insight into the variation in calculated human exposure, the outputs of 7 European exposure models have been compared. Twenty scenarios, differing with respect to land use, soil type, and contaminant, formed the basis for calculating human exposure to soil contaminants. All calculations were performed twice: Once with a standardized set of parameters for all models and once with the own default parameters. This led to the conclusion that the variation in calculated total exposure (combining all exposure pathways) is large (the majority of the outputs is in between a factor of 100 higher and a factor of 100 lower than the scenario medians). In addition, variation for exposure due to indoor air inhalation is also large. The variation for exposure due to crop consumption is substantial (the majority of the outputs is in between a factor of 10 higher and a factor of 10 lower than the scenario medians) and limited for exposure due to soil ingestion (limited = the majority of the outputs is within a factor of 5 higher and a factor of 5 lower than the scenario medians). The variation in calculated exposure increases when a contaminant is more mobile and, particularly, more volatile. The variation due to selection of input parameters does only yield an additional variation over the variation due to model algorithms for exposure due to soil ingestion and, to a lesser extent, for exposure due to crop consumption. The variation in calculated exposure is not dependent on the soil type and hardly dependent (only for exposure due to soil ingestion) on land use. The choice of model is a very significant factor for the absolute value of calculated exposure. For the promotion of uniformity it was recommended to construct a toolbox for the calculation of human exposure, for general use, including standardized tools and flexible tools, the latter to account for region-specific or country-specific (geographical, ethnological, and cultural) elements and national policy decisions. PMID- 17695106 TI - Improving uncertainty analysis in European Union risk assessment of chemicals. AB - Handling uncertainty in curren European Union (EU) risk assessment of new and existing substances is problematic for several reasons. The known or quantifiable sources of uncertainty are mainly considered. Uncertainty is insufficiently, explicitly communicated to risk managers and decision makers but hidden and concealed in risk quotient numbers that appear to be certain and, therefore, create a false sense of certainty and protectiveness. The new EU chemical policy legislation, REACH, is an opportunity to learn from interdisciplinary thinking in order to evolve to smart risk assessment: an assessment in which awareness and openness to uncertainty is used to produce better characterizations and evaluations of risks. In a smart risk assessment context, quantifying uncertainty is not an aim but just a productive means to refine the assessment or to find alternative solutions for the problem at stake. Guidance and examples are given on how to differentiate, assess, and use uncertainty. PMID- 17695107 TI - An integrated health risk assessment approach to the study of mining sites contaminated with arsenic and lead. AB - In order to test the value of an integrated approach for the analysis of health risks at contaminated sites, an integrated health risk assessment in a mining area was performed following 3 steps: 1) Environmental monitoring of surface soil, 2) assessment of exposure to metals in children and native rodents, and 3) DNA damage evaluation (comet assay) in children and rodents. These aspects also were studied in less exposed populations. Our results in humans showed that children living in the most polluted area (Villa de la Paz, Mexico) had higher lead blood concentrations (geometric mean of 13.8 microg/dL) and urinary arsenic levels (geometric mean of 52.1 microg/g creatinine) compared to children living in a control area (Matehuala, Mexico; blood lead of 7.3 microg/dL; urinary arsenic of 16.8 microg/g creatinine). Furthermore, the exposed children also had increased DNA damage (tail moment mean in Villa de la Paz of 4.8 vs 3.9 in Matehuala; p < 0.05). Results in rodents were identical. Animals captured in the polluted area had higher levels of arsenic (geometric mean of 1.3 microg/g in liver and 1.8 microg/g in kidney), lead (0.2 microg/g in liver and 0.9 microg/g in kidney), and cadmium (0.8 microg/g in liver and 2.2 microg/g in kidney), and increased DNA damage (tail moment mean of 18.2) when compared to control animals (arsenic in liver of 0.08 microg/g and kidney of 0.1 microg/g; lead in liver of 0.06 microg/g and kidney of 0.3 microg/g; cadmium in liver of 0.06 microg/g and kidney of 0.6 microg/g; and tail moment of 14.2). With the data in children and rodents, the weight-of-evidence for health risks (in this case DNA damage) associated with metal exposure in Villa de la Paz was strengthened. Therefore, a remediation program was easier to justify, and a feasibility study at this site is under way. PMID- 17695108 TI - Chronic exposure to polynuclear aromatic hydrocarbons in natal habitats leads to decreased equilibrium size, growth, and stability of pink salmon populations. AB - The immediate and delayed effects of embryonic exposure to low levels of polynuclear aromatic hydrocarbons (PAHs) have been shown to reduce survival to maturity by 50% in exposed pink salmon populations. This suggests that chronically exposed populations could be extirpated over relatively few generations, but the effect of density dependence on extirpation rate is unknown. This study examines the interaction of PAH effects and randomly varying density dependence on a simulated population. The simulation derives from 70 years of observations made on a single pink salmon population and toxicity studies involving a hatchery population in the same watershed. Results from simulations involving exposure of 100% of the population to effects consistent with an aqueous PAH concentration of 18 nL/L indicate an 80% decrease in population productivity and an 11% probability of extinction after 35 generations. In contrast, population growth rate declined by only 5%. Further decreases in survival relative to that of observed PAH effects rapidly increase the probability of extinction. Data from these simulations demonstrate that, at low levels of exposure, density dependence can compensate for reduced population size and buffer the population against extinction. However, if equilibrium size is depressed sufficiently, random environmental variation overcomes the buffering effect of density dependence and extinction probability increases. These data demonstrate that extinction probability and population size are more sensitive measures of population effects than growth rate for wild populations regulated by density dependence. PMID- 17695109 TI - How well can we predict the toxicity of pesticide mixtures to aquatic life? AB - Results of publised pesticide mixure toxicity experiments conducted with aquatic organisms were compiled and evaluated to assess the accuracy of predictive mixture models. Three types of models were evaluated: Concentration addition (CA), independent action (IA), and simple interaction (SI). The CA model was the most often tested (207 experiments), followed by SI (59) and IA (37). The reviewed experiments are listed in the Supplemental material to provide a resource for future investigators. The predictive accuracy of each model was quantified for each experiment by the model deviation ratio (MDR), which was calculated by dividing the predicted toxicity by the observed toxicity. Eighty eight percent of all experiments that evaluated the CA model had observed effective concentrations within a factor of 2 of predicted values (MDR values from 0.5-2.0). The median MDR was 1, about 5% of MDRs were less than 0.5, and about 5% were greater than 2, indicating unbiased estimates overall. The predictive accuracy of CA and IA models was influenced, however, by the different modes of action (MOA) of the pesticides. For experiments with pesticides with the same MOA, CA more accurately predicted effective concentrations for more experiments compared to IA, which tended to underpredict toxicity. The IA model was somewhat more accurate than the CA model for most mixtures with different MOAs, but in most cases there were relatively small differences between the models. Additionally, 80% of SI experiments had an MDR value below 2.0 despite a bias towards experiments that are likely to have an interaction. Thus, results indicate that the CA model may be used as a slightly conservative, but broadly applicable model with a relatively small likelihood of underestimating effects due to interactions. PMID- 17695110 TI - An ecological risk assessment for insecticides used in adult mosquito management. AB - West Nile virus (WNV) has been a concern for people across the United States since the disease was initially observed in the summer of 1999. Since 1999, WNV has caused the largest arboviral encephalitis epidemic in US history. Vector control management programs have been intensively implemented to control mosquitoes that carry WNV. Our deterministic ecological risk assessment focused on 6 common mosquito adulticides used in vector control, including 3 pyrethroids (d-phenothrin, resmethrin, and permethrin), pyrethrins, and 2 organophosphates (malathion and naled). Piperonyl butoxide, a synergist for the pyrethroids, was also assessed. Both aquatic and terrestrial nontarget organisms were considered for acute and chronic exposures to the adulticides. Tier I exposure estimates were derived from ISCST3 and AERMOD for deposition and air concentrations affecting terrestrial organisms and PRZM-EXAMS for standard pond concentrations affecting aquatic organisms. Nontargets exposed to adulticides included small mammals, birds, as well as aquatic vertebrates and invertebrates in a pond subject to receiving the chemical via drift and runoff. Risk quotients were obtained by comparing exposures to toxic endpoints. All risk quotients were low indicating that risks to ecological receptors most likely were small. PMID- 17695111 TI - Screening procedure to assess the impact of urban stormwater temperature to populations of brown trout in receiving water. AB - The discharge of urban stormwater may cause a sudden temperature increase in receiving waters that may be harmful to fish and other aquatic organisms. A screening procedure is proposed with temperature thresholds for the runoff from roofs and roads as well as for the receiving water system to protect brown trout from thermal damage. The stormwater temperature is calculated on the basis of a simple thermodynamic estimate for different latitudes. Only receiving waters with maximum daily mean temperatures of 22 degrees C (T1) are considered potential habitats for brown trout. The maximum temperature for a 1-h exposure time with a safety margin for 100% survival is 25 degrees C (T2), the sudden temperature change at the beginning of a rain event must not exceed 7 degrees C (T3), and fish-egg development requires the daily maximum temperature in winter to be below 12 degrees C (T4). Examples of stormwater runoff from roof or road surfaces from Switzerland validate our approach within +/-0.5 degrees C. Effects of runoff into receiving waters without detailed data can be predicted within +/-0.8 degrees C. With the restriction by T1, T2 seems not to be an acute problem at Swiss latitudes. T3 could play a role, especially if a large amount of runoff is discharged in small and rather cool rivers and streams. Finally, T4 deserves more attention than hitherto given. The proposed procedure may be a useful tool for assessing the influence of urban stormwater on the temperature of the receiving waters, particularly with regard to predicting the thermal impacts of urban or suburban runoff to populations of brown trout. PMID- 17695112 TI - The sediments of the Venice Lagoon (Italy) evaluated in a screening risk assessment approach: part I--application of international sediment quality guidelines. AB - A number of studies carried out in recent years have shown the presence of a wide range of contaminants in the Venice Lagoon. It is important to have a good understanding of the ecological quality of Venice Lagoon sediments in order to 1) define and locate areas where a threat to the environment is present and therefore an intervention is needed (i.e., in situ assessment and management); and 2) define sustainable and environmentally correct ways of managing sediments that are to be dredged for navigational purposes or in relation to other interventions (i.e., ex situ management). This study reports on a critical comparison of chemical quality of sediments in Venice Lagoon and its subregions. Data on the Venice Lagoon were compiled from several studies conducted during the past decade on surface sediment contamination; temporal variation and risks for contaminants at depth were not addressed. The comparison of observed pollutant concentrations with local and internationally used sediment quality guidelines (SQGs) was used as a tool to benchmark different sites and for a tier I (screening) ecological risk assessment. Meaning and relevance of a number of SQGs are discussed, together with the options available for carrying out the comparison with sediment data. The screening of the Venice Lagoon sediment quality is discussed from a risk-assessment perspective and appropriate values for use in an in situ-ex situ management framework are suggested. Although there were some differences depending upon which specific SQGs were applied, different SQGs provided the same general picture of screening risk in Venice Lagoon: Although there are geographic differences, median levels for several contaminants in surface sediments exceeded a number of SQGs. Many contaminants exceed threshold effects SQGs, and Hg exceeds probable effects SQGs in most sub-basins except the southern Lagoon. Venice Lagoon south has the lowest screening risk levels, Venice Lagoon central/north has the highest (and is nearest to the Porto Marghera and Venice City Canals sites). Ranges are high in all areas, therefore any remedial or disposal decision should use site-specific data. PMID- 17695113 TI - The sediments of the Venice Lagoon (Italy) evaluated in a screening risk assessment approach: part II--lagoon sediment quality compared to hot spots, regional, and international case studies. AB - The objective of this study was to carry out a critical comparison of data on the screening quality of surface sediments in Venice Lagoon (VL; main lagoon and its subbasins, Porto Marghera [PM], and Venice City Canals) and in other transitional and coastal ecosystems with various levels of human impact (urbanization and industrialization). To put VL in terms of reference and industrialized sites in the region, case studies were selected from the North Adriatic Region; to gain insight into how VL sediments compared to transitional areas throughout the world, case studies also were selected from a number of regions internationally. In order to compare regional levels of contamination, statistically processed sediment contaminant levels within a region (minimum, maximum, mean, and median), not individual sample values, are compared. The screening quality (relative to a variety of sediment quality guidelines) and the drivers of screening risk (based upon contaminant mixtures) of the VL sediments and other coastal and transitional sites are compared and discussed. The VL sediments have hazard quotients on the low end of the range typical of moderately urbanized and industrialized sites and higher than background conditions among the case studies reviewed. The Hg levels in the VL were generally higher than at other sites, and other contaminants were either equivalent or lower. Although sediments have somewhat higher levels of some contaminants and lower levels of other contaminants in PM and Venice City (VC) canals, levels for most contaminants are comparable to case studies with high levels of anthropogenic impact. For many contaminants of interest, PM (and for some, VC) sediments have some of the highest levels of any case study reviewed. How PM and VC rank when compared to other highly industrialized sites depends upon how data are synthesized and how ranges are taken into account. Actual risk must be evaluated using a weight-of-evidence approach, because natural background levels and site-specific bioavailability will differ both regionally and internationally. PMID- 17695114 TI - The Exxon Valdez oil spill revisited and the dangers of normative science. AB - In the July 2006 issue of Integrated Environmental Assessment and Management, a paper by Harwell and Gentile was published assessing the present ecological significance of the impacts from the Exxon Valdez oil spill (EVOS). First, this paper compares the major conclusions of Harwell and Gentile and a paper reviewing the current impacts of EVOS by Peterson et al as published by Science in 2003. Stark differences exist between the conclusions of the 2 papers regarding continuing impacts. Part of the difference appears to be the infusion of different social values or policy goals into each. Normative science is the use or interpretation of data in support of specific values or policies. Examples of values or policies intertwined with science are constructs such as ecosystem health, ecosystem integrity, ecological significance, and recovery. Examination of the environmental risk assessment and toxicology literature reveals that the symptoms of normative science are common and the implications widespread. Separation of science from policy or at a minimum a transparent acknowledgment of the science-policy interaction is clearly necessary in order to obtain a clear picture of the ecological system under investigation. PMID- 17695115 TI - Separating the wheat from the chaff: the effective use of mathematical models as decision tools. AB - The purpose of this paper is to discuss the effective use of quantitative modeling in environmental decision making, with a particular focus on problems of contaminated sediment and surface water. The intended audience includes both model developers and model users. Our goal is to facilitate more effective communication among model developers and those using the information produced by models to aid decision making. We provide a series of observations or conclusions we have reached in our experience that are as follows. A model is a tool for evaluating alternate hypotheses; a model itself is not a hypothesis. All decisions are actually based upon models, either explicitly or implicitly. Models are used to address diagnostic and prognostic questions. Models can provide value added when applied throughout the lifetime of a project. Uncertainty, and therefore the need for models, is greater in systems near background. Models can provide useful information even when based on relatively small data sets. The utility of a model depends on the strength of the constraints placed upon it. The calibration process can be only partially specified a priori. Model calibration and evaluation require multiple lines of evidence. Uncertainty analysis is both qualitative and quantitative. Validation is provided by the application of the model under a wide range of conditions. Communication of the strength of model constraints is critical to model acceptance. We conclude that while models are often used in the evaluation of contaminated sediment problems, distrust in the use of models remains strong. The assessment of uncertainty is the factor most limiting acceptability. PMID- 17695116 TI - Population-scale assessment endpoints in ecological risk assessment part II: selection of assessment endpoint attributes. AB - Because ecological services often are tied to specific species, the risk to populations is a critical endpoint and important feature of ecological risk assessments. In Part 1 of this series it was demonstrated that population scale assessment endpoints are important expressions of the valued components of ecological structures. This commentary reviews several of the characteristics of populations that can be evaluated and used in population scale risk assessments. Two attributes are evaluated as promising. The 1st attribute is the change in potential productivity of the population over a specified time period. The 2nd attribute is the change in the age structure of a population, expressed graphically or as a normalized effects vector (NEV). The NEV is a description of the change in age structure due to a toxicant or other stressor and appears to be characteristic of specific stressor effects. PMID- 17695117 TI - Ecotoxicity of nanomaterials to fish: challenges for ecotoxicity testing. PMID- 17695118 TI - Selenium: deterrence, toxicity, and adaptation. PMID- 17695119 TI - Cadmium transfer to humans from soils via soybeans. PMID- 17695120 TI - Is food grown in urban gardens safe? PMID- 17695121 TI - The search for the "ideal" soil toxicity test reference substance. PMID- 17695122 TI - Improving regulatory risk assessment--using aquatic macrophytes. PMID- 17695123 TI - Error propagation framework for diffusion tensor imaging via diffusion tensor representations. AB - An analytical framework of error propagation for diffusion tensor imaging (DTI) is presented. Using this framework, any uncertainty of interest related to the diffusion tensor elements or to the tensor-derived quantities such as eigenvalues, eigenvectors, trace, fractional anisotropy (FA), and relative anisotropy (RA) can be analytically expressed and derived from the noisy diffusion-weighted signals. The proposed framework elucidates the underlying geometric relationship between the variability of a tensor-derived quantity and the variability of the diffusion weighted signals through the nonlinear least squares objective function of DTI. Monte Carlo simulations are carried out to validate and investigate the basic statistical properties of the proposed framework. PMID- 17695124 TI - Spatiotemporal independent component analysis for the detection of functional responses in cat retinal images. AB - In the early stages of some retinal diseases, such as glaucoma, loss of retinal activity may be difficult to detect with current clinical instruments. Because current instruments require unattainable levels of patient cooperation, high sensitivity and specificity are difficult to attain. We have devised a new retinal imaging system that detects intrinsic optical signals which reflect functional changes in the retina and that do not require patient cooperation. Measured changes in reflectance in response to the visual stimulus are on the order of 0.1%-1% of the total reflected intensity level, which makes the functional signal difficult to detect by standard methods. The desired functional signal is masked by other physiological signals and by imaging system noise. In this paper, we quantify the limits of independent component analysis (ICA) for detecting the low intensity functional signal and apply ICA to 60 video sequences from experiments using an anesthetized cat whose retina is presented with different patterned stimuli. The results of the analysis show that using ICA, in principle, signal levels of 0.1% can be detected. The study found that in 86% of the animal experiments the patterned stimuli effects on the retina can be detected and extracted. PMID- 17695125 TI - A maximum likelihood approach to parallel imaging with coil sensitivity noise. AB - Parallel imaging is a powerful technique to speed up magnetic resonance (MR) image acquisition via multiple coils. Both the received signal of each coil and its sensitivity map, which describes its spatial response, are needed during reconstruction. Widely used schemes such as SENSE assume that sensitivity maps of the coils are noiseless while the only errors are in coil outputs. In practice, however, sensitivity maps are subject to a wide variety of errors. At first glance, sensitivity noise appears to result in an errors-in-variables problem of the kind that is typically solved using total least squares (TLSs). However, existing TLS algorithms are in general inappropriate for the specific type of block structure that arises in parallel imaging. In this paper, we take a maximum likelihood approach to the problem of parallel imaging in the presence of independent Gaussian sensitivity noise. This results in a quasi-quadratic objective function, which can be efficiently minimized. Experimental evidence suggests substantial gains over conventional SENSE, especially in nonideal imaging conditions like low signal-to-noise ratio (SNR), high g-factors and large acceleration, using sensitivity maps suffering from misalignment, ringing, and random noise. PMID- 17695126 TI - Effect of spatial alignment transformations in PCA and ICA of functional neuroimages. AB - It has been previously observed that independent component analysis (ICA), if applied to data pooled in a particular way, may lessen the need for spatial alignment of scans in a functional neuroimaging study. In this paper, we seek to determine analytically the conditions under which this observation is true, not only for spatial ICA, but also for temporal ICA and for principal component analysis (PCA). In each case, we find conditions that the spatial alignment operator must satisfy to ensure invariance of the results. We illustrate our findings using functional magnetic-resonance imaging (fMRI) data. Our analysis is applicable to both intersubject and intrasubject spatial normalization. PMID- 17695127 TI - Automatic correction of level set based subvoxel precise centerlines for virtual colonoscopy using the colon outer wall. AB - Virtual colonoscopy (VC) is becoming a more prevalent method to detect and diagnose colorectal cancer. An essential component of using VC to detect cancerous polyps, especially in conjunction with computer-aided diagnosis, is the accurate calculation of the centerline of the colon. While the colon is often modeled as a simple cylinder, the amount of colonic distention may vary between patients and within the same patient often causing loops and multiple disconnected segments to be present in the colon segmentation. These variations have caused previous centerline algorithms to fail to capture a complete and accurate centerline for all colons. We have developed an automatic method to determine from a computed tomography (CT) VC a subvoxel precise centerline that is accurate even in cases of over-distended or under-distended colons. In this algorithm, the loops in the colon caused by over-distention are detected and removed when the centerline calculation is performed. Also, a newly developed method for the detection and segmentation of the outer wall of the colon is used to connect collapsed portions of the colon where the lumen segmentation fails to produce a continuous centerline. These two methods allow for a complete and accurate centerline to be calculated in uniformly distended colons as well as in colons containing segments which are over-distended and/or under-distended. We have demonstrated successfully the effectiveness of our algorithm on 50 cases, 25 of which resulted in erroneous solutions by previous centerline algorithms due to variability in the colon distention. PMID- 17695128 TI - Real-time vessel segmentation and tracking for ultrasound imaging applications. AB - A method for vessel segmentation and tracking in ultrasound images using Kalman filters is presented. A modified Star-Kalman algorithm is used to determine vessel contours and ellipse parameters using an extended Kalman filter with an elliptical model. The parameters can be used to easily calculate the transverse vessel area which is of clinical use. A temporal Kalman filter is used for tracking the vessel center over several frames, using location measurements from a handheld sensorized ultrasound probe. The segmentation and tracking have been implemented in real-time and validated using simulated ultrasound data with known features and real data, for which expert segmentation was performed. Results indicate that mean errors between segmented contours and expert tracings are on the order of 1%-2% of the maximum feature dimension, and that the transverse cross-sectional vessel area as computed from estimated ellipse parameters a, b as determined by our algorithm is within 10% of that determined by experts. The location of the vessel center was tracked accurately for a range of speeds from 1.4 to 11.2 mm/s. PMID- 17695129 TI - Diffusion basis functions decomposition for estimating white matter intravoxel fiber geometry. AB - In this paper, we present a new formulation for recovering the fiber tract geometry within a voxel from diffusion weighted magnetic resonance imaging (MRI) data, in the presence of single or multiple neuronal fibers. To this end, we define a discrete set of diffusion basis functions. The intravoxel information is recovered at voxels containing fiber crossings or bifurcations via the use of a linear combination of the above mentioned basis functions. Then, the parametric representation of the intravoxel fiber geometry is a discrete mixture of Gaussians. Our synthetic experiments depict several advantages by using this discrete schema: the approach uses a small number of diffusion weighted images (23) and relatively small b values (1250 s/mm2), i.e., the intravoxel information can be inferred at a fraction of the acquisition time required for datasets involving a large number of diffusion gradient orientations. Moreover our method is robust in the presence of more than two fibers within a voxel, improving the state-of-the-art of such parametric models. We present two algorithmic solutions to our formulation: by solving a linear program or by minimizing a quadratic cost function (both with non-negativity constraints). Such minimizations are efficiently achieved with standard iterative deterministic algorithms. Finally, we present results of applying the algorithms to synthetic as well as real data. PMID- 17695130 TI - Characteristic quantities of microvascular structures in CLSM volume datasets. AB - A method for fully automated morphological and topological quantification of microvascular structures in confocal laser scanning microscopy (CLSM) volume datasets is presented. Several characteristic morphological and topological quantities are calculated in a series of image-processing steps and can be used to compare single components as well as whole networks of microvascular structures to each other. The effect of the individual image-processing steps is illustrated and characteristic quantities of measured volume datasets are presented and discussed. PMID- 17695131 TI - Minimal shape and intensity cost path segmentation. AB - A new generic model-based segmentation algorithm is presented, which can be trained from examples akin to the active shape model (ASM) approach in order to acquire knowledge about the shape to be segmented and about the gray-level appearance of the object in the image. Whereas ASM alternates between shape and intensity information during search, the proposed approach optimizes for shape and intensity characteristics simultaneously. Local gray-level appearance information at the landmark points extracted from feature images is used to automatically detect a number of plausible candidate locations for each landmark. The shape information is described by multiple landmark-specific statistical models that capture local dependencies between adjacent landmarks on the shape. The shape and intensity models are combined in a single cost function that is optimized noniteratively using dynamic programming, without the need for initialization. The algorithm was validated for segmentation of anatomical structures in chest and hand radiographs. In each experiment, the presented method had a significant higher performance when compared to the ASM schemes. As the method is highly effective, optimally suited for pathological cases and easy to implement, it is highly useful for many medical image segmentation tasks. PMID- 17695132 TI - [Practice guidelines 2007 for the treatment of arterial hypertension]. PMID- 17695133 TI - Optimal outpatient appointment scheduling. AB - In this paper optimal outpatient appointment scheduling is studied. A local search procedure is derived that converges to the optimal schedule with a weighted average of expected waiting times of patients, idle time of the doctor and tardiness (lateness) as objective. No-shows are allowed to happen. For certain combinations of parameters the well-known Bailey-Welch rule is found to be the optimal appointment schedule. PMID- 17695134 TI - A Bayesian approach to assess heart disease mortality among persons with diabetes in the presence of missing data. AB - Some states' death certificate form includes a diabetes yes/no check box that enables policy makers to investigate the change in heart disease mortality rates by diabetes status. Because the check boxes are sometimes unmarked, a method accounting for missing data is needed when estimating heart disease mortality rates by diabetes status. Using North Dakota's data (1992-2003), we generate the posterior distribution of diabetes status to estimate diabetes status among those with heart disease and an unmarked check box using Monte Carlo methods. Combining this estimate with the number of death certificates with known diabetes status provides a numerator for heart disease mortality rates. Denominators for rates were estimated from the North Dakota Behavioral Risk Factor Surveillance System. Accounting for missing data, age-adjusted heart disease mortality rates (per 1,000) among women with diabetes were 8.6 during 1992-1998 and 6.7 during 1999 2003. Among men with diabetes, rates were 13.0 during 1992-1998 and 10.0 during 1999-2003. The Bayesian approach accounted for the uncertainty due to missing diabetes status as well as the uncertainty in estimating the populations with diabetes. PMID- 17695135 TI - A linear programming model for allocating HIV prevention funds with state agencies: a pilot study. AB - Given the initiatives to improve resource allocation decisions for HIV prevention activities, a linear programming model was designed specifically for use by state and local decision-makers. A pilot study using information from the state of Florida was conducted and studied under a series of scenarios depicting the impact of common resource allocation constraints. Improvements over the past allocation strategy in the number of potential infections averted were observed in all scenarios with a maximal improvement of 73%. When allocating limited resources, policymakers must balance efficiency and equity. In this pilot study, the optimal allocation (i.e., most-efficient strategy) would not distribute resources in an equitable manner. Instead, only 12% of at-risk people would receive prevention funds. We find that less efficient strategies, where 58% fewer infections are averted, result in significantly more equitable allocations. This tool serves as a guide for allocating funds for prevention activities. PMID- 17695136 TI - A mixed integer programming model to locate traumatic brain injury treatment units in the Department of Veterans Affairs: a case study. AB - For the Department of Veterans Affairs (VA), traumatic brain injury (TBI) is a significant problem facing active duty military personnel, veterans, their families, and caregivers. The VA has designated TBI treatment as one of its physical medicine and rehabilitation special emphasis programs, thereby providing a comprehensive array of treatment services to those military personnel and veterans with TBI. Timely treatment of TBI is critical in achieving maximal recovery, and being in geographical proximity to a medical center with specialized TBI treatment services is a major determinant of whether such treatment is utilized. We present a mixed integer programming model for locating TBI treatment units in the VA. This model was developed for the VA Rehabilitation Strategic Healthcare Group to assist in locating new TBI treatment units. The optimization model assigns TBI treatment units to existing VA medical centers while minimizing the sum of patient treatment costs, patient lodging and travel costs, and the penalty costs associated with foregone treatment revenue and excess capacity utilization. We demonstrate our model with VA TBI admission data from one of the VA's integrated service networks, and discuss the expected service and cost implications for a range of TBI treatment unit location options. PMID- 17695137 TI - Surgical block scheduling in a system of hospitals: an application to resource and wait list management in a British Columbia health authority. AB - Scheduling surgical specialties in a medical facility is a very complex process. The choice of schedules and resource availability impact directly on the number of patients treated by specialty, cancellations, wait times, and the overall performance of the system. In this paper we present a system-wide model developed to allow management to explore tradeoffs between OR availability, bed capacity, surgeons' booking privileges, and wait lists. We developed a mixed integer programming model to schedule surgical blocks for each specialty into ORs and applied it to the hospitals in a British Columbia Health Authority, considering OR time availability and post-surgical resource constraints. The results offer promising insights into resource optimization and wait list management, showing that without increasing post-surgical resources hospitals could handle more cases by scheduling specialties differently. PMID- 17695138 TI - What determines a patient's treatment? Evidence from out of hours primary care co op data in the Republic of Ireland. AB - This study explores consistency in healthcare. It investigates whether vulnerable groups in the population receive the most appropriate care. This is achieved by considering the case study of individuals who present to out of hours (OOH) primary care services in the Republic of Ireland with gastroenteritis. Specifically an individual can potentially receive four services; nurse advice, doctor advice, a treatment centre consultation or a home visit. Results show that service choice is influenced by patient, call and seasonal characteristics to varying degrees. Patient symptoms are the primary driver of the type of service the patients receives. Results also indicate that the OOH primary care facilities individual characteristics do not affect service choice. This suggests a degree of consistent care across these organisations. It also provides evidence that service choice is exogenous to the organisation. PMID- 17695139 TI - Staggered work shifts: a way to downsize and restructure an emergency department workforce yet maintain current operational performance. AB - Starting from the last decade of the twentieth century, most hospital Emergency Department (ED) budgets did not keep up with the demand for ED services made by growing populations and aging societies. Since labor consumes over 50% of the total monies invested in EDs and other healthcare systems, any downsizing, streamlining and reorganization plan needs to first address staffing issues such as determining the correct size of the workforce and its work shift scheduling. In this context, it is very important to remember that downsizing certainly does not mean a general cut-across-the-board. This study shows that a selective downsizing process in which each resource is treated separately (increasing the work capacity of some resources is also possible), based on its unique contribution to the overall ED operational performance, can approximately maintain current ED operational measures in terms patient length of stay (LOS) despite an overall reduction in staff hours. A linear optimization model (S model) and a heuristic iterative simulation based algorithm (SWSSA) are used in this study for scheduling the resources' work shifts, one resource at a time. The algorithm was tested using data that was gathered from five general hospital EDs. By leveling the workload of the different resources in the ED, SWSSA was able to achieve LOS values within -19 to 4% of the original values despite a reduction of 8-17.5% in physicians' work hours and a reduction of 13-47% in the nurses' work hours. PMID- 17695140 TI - Determination of lipophilicity and pKa measurement of some 4-imino-1,4 dihydrocinnoline-3-carboxylic acid and 4-oxo-1,4-dihydrocinnoline-3-carboxylic acid derivatives--isosteric analogues of quinolones. AB - As a continuation of our study, physicochemical properties of some antibacterial active 4-imino-1,4-dihydrocinnoline-3-carboxylic acid and 4-oxo-1,4 dihydrocinnoline-3-carboxylic acid derivatives were investigated. Partition coefficient (log P), and dissociation constant (pKa) were experimentally determined and also calculated by the use of ACDLabs system software. The obtained values were correlated with experimental data. PMID- 17695141 TI - Inhibition of lipid peroxidation induced by hydroxyprogesterone caproate by some conventional antioxidants in goat liver homogenates. AB - Among the cellular molecules, lipids containing unsaturated fatty acids with more than one double bond are particularly susceptible to action of free radicals. The resulting reaction, known as lipid peroxidation, has deleterious effect on biological membranes, leading sometimes even to disrupting them, or influencing their structure and function. Different toxic products are formed during this process. In this context, the present study was made to explore the suppressive actions of some conventional antioxidant compounds e.g., ascorbic acid, alpha tocopherol and probucol on lipid peroxidation induced by hydroxyprogesterone caproate (HP), a progestogenic compound. The study has been performed using goat liver homogenate. It was found that HP increased thiobarbituric acid reactive substance i.e., malondialdehyde (MDA) and also other major toxic end product of lipid peroxidantion - 4-hydroxynonenal (4-HNE). HP decreased significantly the levels of reduced glutathione (GSH) and nitric oxide (NO) in the liver homogenates. This suggests that HP caused lipid peroxidation to a significant extent, which may be related to the toxic potential of the drug. It was further found that all of the above mentioned antioxidants could suppress HP-induced lipid peroxidation to the significant extent. PMID- 17695142 TI - Exploring effects of different nonsteroidal antiinflammatory drugs on lipid peroxidation. Part II. 4-HNE profile. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are common in alleviating pain, pyrexia and inflammation, in patients with rheumatoid arthritis and osteoarthritis. As these drugs are associated with high incidence of gastrointestinal ulceration, bleeding and kidney damage which may be linked with lipid peroxidation. our study was aimed to examine lipid peroxidation induction capacity of NSAIDs (diclofenac sodium, ibuprofen, flurbiprofen, paracetamol, nimesulide, celecoxib and indomethacin) by determining 4-hydroxy-2-nonenal (4 HNE) concentration as an index of lipid peroxidation and to see the suppressive potential of ascorbic acid on NSAID induced lipid peroxidation. The results suggest that diclofenac sodium, ibuprofen, flurbiprofen, paracetamol, nimesulide and celecoxib exerted mild antioxidant activity. Indomethacin exerted statistically significant increase in 4-HNE content, indicating statistically significant peroxidation activity. Ascorbic acid could significantly reduce indomethacin-induced lipid peroxidation. PMID- 17695143 TI - Ginger extract ameliorates paraben induced biochemical changes in liver and kidney of mice. AB - The present investigation was undertaken to evaluate the effect of paraben (p hydroxybenzoic acid) on acidic, basic, and neutral proteins content, as well as carbohydrate and cholesterol contents in liver and kidney of mice. Adult female albino mice were orally administrated with 2.25 and 4.5 mg of paraben in 0.2 mL of olive/animal/day for thirty days. The results revealed dose dependent, significant reduction in acidic, basic, and neutral protein, carbohydrate contents and an increase in cholesterol content of the investigated liver and kidney. Oral administration of aqueous extract of Zinziber officinale (3 mg/animal/day) along with paraben for thirty days caused significant amelioration in all the protein types, carbohydrate and cholesterol of liver and kidney. PMID- 17695144 TI - Amelioration by black tea of sodium fluoride-induced changes in protein content of cerebral hemisphere, cerebellum and medulla oblongata in brain region of mice. AB - Oral administration of sodium fluoride (NaF, 6 and 12 mg/kg body weight/day) to Swiss strain male albino mice for 30 days caused significant dose-dependant reduction in the content of acidic, basic, neutral, and total protein in cerebral hemisphere, cerebellum and medulla oblongata region of brain. After 30 days of NaF treatment, followed by withdrawal of treatment for 30 days, partial but significant amelioration occurred. Administration of 2% black tea extract alone for 30 days did not cause any significant effect. However, concurrent administration of NaF and black tea extract for 30 days caused significant amelioration in all parameters studied. PMID- 17695145 TI - Cyclization of thiosemicarbazide derivatives of 5-arylidene-2,4-dioxothiazolidine 3-acetic acids to 1,3,4-thiadiazoles and their pharmacological properties. AB - By the reaction of (5-arylidene-2,4-dioxothiazolidin-3-yl)acetyl chlorides with 4 phenylthiosemicarbazide, acylthiosemicarbazide derivatives 4-6 were obtained. The cyclization of 4-6 in acid medium led to 1,3,4-thiadiazole derivatives 7-9. The structure of the compounds was confirmed by elemental analysis and IR, H NMR, 13C NMR and MS spectra. The effects of compounds 7 and 9 on the central nervous system (CNS) of mice were studied. PMID- 17695146 TI - New derivatives of 5-amino-3-methyl-4-isothiazolecarboxylic acid and their immunological activity. AB - Several new compounds - 4 and 5-substituted derivatives of 3-methyl-4 isothiazolecarboxylic acid were synthesized. These compounds have aminoacylamino groups in position 5 of the isothiazole ring. In position 4, the carboxylic group was replaced by ethyl ester. The biological activites of the obtained compounds were analyzed in the humoral immune response and delayed type hypersensitivity reaction to sheep red blood cells (SRBC) in the mouse model, as well as in the proliferative response of splenocytes to T-cell and B-cell mitogens in vitro. PMID- 17695148 TI - Flavonoids and phenolic acids of Nepeta cataria L. var. citriodora (Becker) Balb. (Lamiaceae). AB - Luteolin 7-O-glucuronide, luteolin 7-O-glucurono-(1-->6)-glucoside, apigenin 7-O glucuronide as well as free aglycones luteolin and apigenin have been isolated from lemon catnip herb (Nepeta cataria L. var citriodora). Luteolin 7-O-glucurono (1-->6)-glucoside is probably a new compound, for the first time described. Two minor constituents of flavonoid fraction have been identified as apigenin 7-O glucoside and luteolin 7-O-glucoside by means of HPLC method. The percentage of total flavonoids determined by use of spectrophotometric method was in the range from 0.30 to 0.46% of dry mass. In phenolic acid fraction, caffeic, rosmarinic and p-coumaric acids have been identified. Total amount of phenolic acids determined by spectrophotometric method was in the range of 0.75% to 1.4 % and the content of rosmarinic acid quantified by HPLC method fluctuated in the wide range from 0.06% to 0.15% depending on the sample. The results of the investigations showed that the composition of flavonoid compounds and phenolic acids in lemon catnip are similar to those in lemon balm (Melissa officinalis L.). The amount of flavonoids are similar in both plants, and the percentage of rosmarinic acid is about ten times lower in lemon catnip than in lemon balm. The presence of luteolin, apigenin and their glycosides, caffeic acid as well as the previously described terpenoids (ursolic acid, citral, nerol. geraniol) suggests the possibility of the use of lemon catnip herb as a constituent of phytopharmaceutical preparations with mild sedative, antispasmodic, antioxidative and antiinflammatory action. PMID- 17695147 TI - Polyphenolic compounds in Scopolia caucasica Kolesn. ex Kreyer (Solanaceae). AB - The qualitative and quantitative determinations of coumarins, phenolic acids and flavonoids in the leaves and underground parts of Scopolia caucasica using paper chromatography and HPLC methods were described. From the leaves of this plant, kaempferol 3-O-(2-glucosyl)-galactoside-7-O-glucoside, kaempferol 3-O-(2 glucosyl)-galactoside and quercetin 3-O-glucoside were isolated and identified by spectroscopic methods (UV, 1H- and 13C-NMR). PMID- 17695149 TI - Evaluation of furosemide-loaded alginate microspheres prepared by ionotropic external gelation technique. AB - Alginate microspheres containing furosemide were prepared by the ionotropic external gelation technique using Ca2+, Al3+ and Ba2+ ions. The incorporation efficiency of the prepared microspheres ranged between 65% and 93%. The effect of sodium alginate concentration, cross-linking ions and drying conditions was evaluated with respect to entrapment efficiency, particle size, surface characteristics and in vitro release behavior. Infrared spectroscopic study confirmed the drug-polymer compatibility. Differential scanning calorimetric analysis revealed that the drug was molecularly dispersed in the alginate microsphere matrices. Scanning electron microscopic study of microspheres showed the rough surface due to higher concentration of drug molecules dispersed at molecular level in the alginate matrices. The mean particle size and entrapment efficiency were found to be varied by changing various formulation parameters. The in vitro release profile could be altered significantly by changing various formulation parameters to give a sustained release of drug from the microspheres. The kinetic modeling of the release data indicate that furosemide release from the alginate microspheres follow anomalous transport mechanism after an initial lag period when the drug release mechanism was found to be Fickian diffusion controlled. PMID- 17695150 TI - Influence of tiagabine on the antinociceptive action of morphine, metamizole and indomethacin in mice. AB - The influence of tiagabine at a dose of 3.2 mg/kg (single administration) and at a dose of 1.2 mg/kg (multiple administration - 10 days) on the antinociceptive effect of morphine (10 mg/kg), metamizole (500 mg/kg) and indomethacin (10 mg/kg single dose and 1.4 mg/kg - multiple doses) was investigated in mice using the hot-plate and tail-flick tests. All drugs were injected intraperitoneally. Tiagabine was administered to mice 30 min before the analgesic drugs. Measurement of the reaction to a noxious stimulus was performed 60, 90 and 120 min after administration of tiagabine. The study was further conducted for 10 days with repeated drug doses. Tiagabine and morphine administered in single doses demonstrate an additive antinociceptive effect in the hot-plate test and a slightly synergistic effect in the tail-flick test. A single administration of tiagabine slightly increased the antinoceptive action of metamizole and indomethacin in both tests, but that effect is less pronounced than the antinociceptive action of tiagabine alone. Repeated administration of tiagabine with morphine abolishes the tolerance to morphine analgesia. Both single and repeated administration of tiagabine alone exerted the antinociceptive effect in the hot-plate test. PMID- 17695151 TI - Omega-3 fatty acids have antidepressant activity in forced swimming test in Wistar rats. AB - Forced swimming test is used to induce a characteristic behavior of immobility in rats, which resembles depression in humans to some extent. We evaluated the effect of omega-3 fatty acids alone as well as compared it with the standard antidepressant therapy with fluoxetine in both acute and chronic studies. In both the studies, rats were divided into 4 groups and subjected to the following drug interventions - Group 1- control: Group 2- fluoxetine in dose of 10 mg/kg subcutaneously 23.5, 5 and 1 h before the test: Group 3- omega-3 fatty acids in dose of 500 mg/kg orally; Group 4- fluoxetine plus omega-3 fatty acids both. In acute study, omega-3 fatty acids were given in single dose 2 h prior to the test while in chronic study omega-3 fatty acids were given daily for a period of 28 days. All animals were subjected to a 15-min pretest followed 24 h later by a 5 min test. A time sampling method was used to score the behavioral activity in each group. The results revealed that in acute study, omega-3 fatty acids do not have any significant effect in forced swimming test. However, in chronic study, omega-3 fatty acids affect the immobility and swimming behavior significantly when compared with control (p < 0.01) without any significant effect on climbing behavior and the efficacy of combination of omega-3 fatty acids and fluoxetine is significantly more than that of fluoxetine alone in changing the behavioral activity of rats in forced swimming test. It leads to the conclusion that omega-3 fatty acids have antidepressant activity per se, and the combination of fluoxetine and omega-3 fatty acids has more antidepressant efficacy than fluoxetine alone in forced swimming test in Wistar rats. PMID- 17695152 TI - Determination of oxytetracycline in biological matrix. PMID- 17695153 TI - Reactions of azaisatoic anhydrides: formation of pyridopyrimidinones. PMID- 17695154 TI - Engineering management. PMID- 17695155 TI - Patient care. Study: grieving parents want to connect with clinicians; few do. PMID- 17695156 TI - Quality. New clinical research often leads to questions about treatment plans. PMID- 17695157 TI - Physician recruitment. Encouraging med students to return to rural areas. PMID- 17695158 TI - Other voices. Can banks be trusted to handle health records? Interview by Haydn Bush. PMID- 17695160 TI - Quality. Web sites start reporting hospital mortality data. PMID- 17695159 TI - Storyboard. Big questions loom for big health care deal. PMID- 17695161 TI - Access & coverage. A new approach to prevention: linking lawyers and patients. PMID- 17695162 TI - Patient safety. Fragmented care heightens error risk for surgical patients. PMID- 17695163 TI - Notes from the trail [part 4]. PMID- 17695164 TI - The new era CFO. AB - Once upon a time, hospital chief financial officers were almost exclusively number crunchers. Nowadays, the ideal CFO must have a broad understanding of all aspects of health care, including the clinical side, operations, and marketing. One prominent member of the profession puts it bluntly: "CFOs who are overly focused on finance won't succeed." PMID- 17695165 TI - The board's role in capital financing. AB - Trustees must pay more attention to capital financing as oversight intensifies, rating agencies ask more questions, and the need for new funding sources grows. PMID- 17695166 TI - Financial imperative: physician relations. AB - At an annual investors' conference in New York City, top not-for-profit health systems outline their challenges and strategies for the future. PMID- 17695167 TI - Medicaid is the new Medicare. AB - Medicare fraud has long been a favorite target of government investigators. Now, with beefed-up funding and staffing, they've set their sights on Medicaid. PMID- 17695168 TI - Shock absorbers. Hospital residency programs smooth the bumps for new nurses. AB - Residency programs aim to help RNs transition from nursing school to the hectic reality of the hospital, and to keep them from fleeing for the exits. PMID- 17695169 TI - Telemedicine's adolescent angst. AB - Ten years after telemedicine hit the mainstream, growing pains are evident, robotic surgery and other "wows" relatively rare. But home-based care is set to explode. PMID- 17695170 TI - U.S. still last among industrialized nations in key health measures. PMID- 17695171 TI - Urological diseases cost Americans $11 billion a year, NIH reports. PMID- 17695172 TI - Survey reveals worry ever access to care and support for universal coverage. PMID- 17695173 TI - Infection prevention, energy savings top construction trends. PMID- 17695174 TI - Datapage. Nurses: satisfaction not guaranteed. PMID- 17695175 TI - Applauding the innovative work of Maori nurses. PMID- 17695180 TI - Passionately caring for her community. Interview by Teresa O'Connor. PMID- 17695181 TI - Remote area nursing requires an open mind and sense of humour. PMID- 17695182 TI - Hutt Valley DHB achieves Magnet recognition. PMID- 17695183 TI - Why should NZNO belong to ICN? PMID- 17695184 TI - Intramuscular injections--what's best practice? PMID- 17695185 TI - Using new research skills. PMID- 17695186 TI - A vision for nursing. PMID- 17695187 TI - Maori student nurses' hui nurture spiritual, academic and cultural needs. PMID- 17695188 TI - New network for student nurses. PMID- 17695189 TI - [Diagnosis and therapy of lymphomas--Croatian consensus]. PMID- 17695190 TI - [Specialty preferences among final-year medical students at Zagreb University Medical School]. AB - The aim of this study was to investigate the sixth-year medical students' specialty preferences, at the Zagreb University Medical School. A total of 603 students were recruited during a three-year period (2003-2005), with a response rate of 83.3%. One third had a preferred specialty upon enrolment at the Medical School. Three most desirable specialties few months prior to graduation were internal medicine (12.6%), paediatrics (10.2%), and surgery (8.7%), while one fourth of students (24.4%) reported one of the controllable life-style specialties as their specialty choice. Students who were interested in internal medicine reported the best academic performance, while those who were interested in the family medicine (general practice) reported the poorest academic performance. The study indicates that family medicine, anaesthesiology, and radiology were the least commonly reported as specialties of the students' choice, compared to percentage of specialists employed in Croatian health care service. The most wanted specialties were ear-nose-throat and orthopaedics. PMID- 17695191 TI - [Osteoporosis prevalence in Croatian males--the results of calcaneus ultrasound]. AB - The aim of the study was to establish the normative QUS data in a healthy sample of Croatian males and estimate the prevalence of osteoporosis. A total of 1002 male participants, aged 20-99, were recruited in seven study centers (Zagreb, Ivanic-grad, Koprivnica, Sibenik, Pula, Slavonski Brod, Vukovar). In each subject broadband ultrasound attenuation (BUA), speed of sound (SOS) and quantitative ultrasound index (QUI) of the calcaneus were measured using the Sahara ultrasound device. Significant declining with age was found for all three parameters (p < 0.001). The peak SOS (1562.8 +/- 28.5 m/s) and QUI (103.6 +/- 16.5) values were observed in the third decade, whereas the peak BUA value (86.2 +/- 19.2 db/MHz) was observed in the fourth decade of life. Using the World Health Organization diagnostic criteria for DXA the rates of osteoporosis in the males aged 50 and older were 5.8%, 3.4 and 4.2% for QUI, BUA, and SOS respectively. However, when we used the cut-off value of the T < or = -l.8, prevalence of osteoporosis in Croatian males older than 50 years was 16.2%, 11.7% and 17.2%. PMID- 17695192 TI - [Three-year-old boy--a homozygote for familiar hypercholesterolemia]. AB - Homozygous familial hypercholesterolemia (FH) is a rare autosomal dominant disorder caused by mutations in the low-density-lipoprotein (LDL) receptor gene. It occurs with a frequency of approximately 1 per million persons world-wide. Clinically, homozygous FH is associated with extremely elevated levels of LDL cholesterol and cutaneous xanthomas that develop in early childhood. These children are at risk of extremely early coronary events and death from myocardial infarction caused by premature generalized atherosclerosis. Their medical treatment is very complex, associated with various problems and complications. We describe a 3-year-old boy with clinical signs of homozygous FH (elevated LDL cholesterol levels and xanthomas). Heterozygous hypercholesterolemia was found in his parents and some other family members. The boy has been treated with simvastatin and atorvastatin, but without reaching the treatment goals. LDL apheresis is planned as the treatment of choice for homozygous children with FH. PMID- 17695193 TI - [Leukocytoclastic vasculitis in primary Sjogren syndrome: a case report]. AB - We report a case of primary Sjogren's syndrome (SSjo with cutaneous leukocytoclastic vasculitis. The accurate diagnosis of SSjo was established based on objective signs and symptoms of ocular and oral dryness and characteristic appearance of a biopsy sample from a minor salivary gland, and presence of anti SS-A autoantibody. Another autoimmune disorder was not present, so diagnosis of primary SSjo was established. Histologic finding of skin biopsy of purpuric lesion was typical for leukocytoclastic vasculitis. The patient was treated with small doses of glucocorticoids and with local symptomatic therapy for ocular and oral dryness. SSjo is one of the most common autoimmune disorders and vasculitis is one of the most characteristic extraglandular manifestations, but wide spectrum of cutaneous involvement in primary SSjo has been little studied. PMID- 17695194 TI - [Laparoscopic transgastric cystogastrostomy of pancreatic pseudocyst: a case report]. AB - Pancreatic pseudocyst is one of the most common complications of acute pancreatitis. Symptomatic or complicated pseudocysts require treatment. The basic principle of pseudocyst treatment is its drainage. The best method is internal drainage by establishing communication between pseudocyst and stomach or small intestine. With advances in endoscopic technology it is now possible to drain pseudocyst efficently in neighboring stomach or duodenum, however the surgical internal drainage of pancreatic pseudocysts that has been carried out as open operation for decades, remains the criterion standard against which all other therapies are measured. In recent years, several methods of laparoscopic internal drainage of pancreatic pseudocysts have been published. Initial results are encouraging, although the number of patients operated using these methods is still small and there is no clear evidence that laparoscopic internal drainage is beneficial for the patients. In this case report we present our first case of laparoscopic internal drainage of pancreatic pseudocyst. The pseudocyst developed as a complication of acute pancreatitis. Laparoscopic internal drainage with cholecystectomy was carried out on 4th of April, 2005. The patient recovered without complications and during first year of follow-up no recurrence of pseudocyst was observed. PMID- 17695195 TI - [Severe chronic illness and liaison psychiatry]. AB - The paper reviews three cases treated for somatic diseases on the clinical wards for dialysis, haematology and gynaecology. Patients suffereing from somatic diseases often have psychological disturbances, too. As a connection between somatic and psychological, a relatively new branch of psychiatry developed - liaison psychiatry. Liaison psychiatrist, on the one hand, halps the patient to cope with the illness more easily, and on the other hand, helps the members of the healing team to understand better the patient's psychological needs. In the described cases, psychological disturbances occurred at the end of somatic treatment. The liaison psychiatrist's role was to enable the patients to adapt to the new situation, and not to lose their quality of life. The aim of this paper is pointing out the importance of liaison psychiatrist in the treatment of physically ill patients. PMID- 17695196 TI - [Infections due to nontuberculous mycobacteria]. AB - The best known members of genus Mycobacterium belong to M. tuberculosis complex. Other mycobacteria are known as nontuberculous mycobacteria (NTM). NTM less commonly cause a disease (mycobacteriosis), more often colonising respiratory tract. The presence of NTM is more common in immunocompromised patients and in those with a previous lung disease. The decrease in the incidence of tuberculosis is followed by increased incidence of NTM. Since tuberculosis has been declining in Croatia over the last 50 years, increasing incidence of NTM is expected. Growing incidence of chronic obstructive pulmonary disease (COPB) is contributing to this increase. NTM are ubiquitous and inhaling of aerosol particles constitutes the dominant route of infection. They are not transmitted via interhuman contact. In addition to pulmonary and skin infections, disseminated infections are also described. The treatment of mycobacteriosis is difficult and long. Besides using antituberculotic drugs such as rifampin and ethambutol, the therapies use fluoroquinolones; the introduction of macrolides has significantly improved the outcome of treatment. PMID- 17695197 TI - [Arthroscopic surgery of the ankle]. AB - Arthroscopic surgery of the ankle has become indispensable method in the armamentarium of the modern orthopaedic surgeon. Technological advancement and thorough understanding of the anatomy have resulted in improved ability to perform arthroscopy of the ankle. The method is minimally invasive and it allows the direct visualization of intra-articular structures without arthrotomy or malleolar osteotomy. Anterior or posterior approach may be used, and various indications have become generally accepted: anterior soft tissue or bony impingement, loose bodies, osteochondral defects, synovitis (rheumatoid arthritis, infective arthritis, and hemophilic arthropathy), posterior impingement syndrome, posttraumatic conditions, osteoarthritis (arthrosis), ankle arthrodesis, tumor-like lesions (synovial osteochondromatosis, pigmented villonodular synovitis) and many combinations of these pathological entities. In this paper we will discuss technique, indications, complications and future perspective of the ankle arthroscopy. In addition we will review the most recent literature data regarding this appealing technique. PMID- 17695198 TI - [Proposal of cervical cancer early detection programme in Croatia]. AB - Opportunistic screening by Pap smear was introduced in Croatia in 1950s, with a consequent decrease of cervical cancer incidence and mortality. Since 1990s, no further decrease has been observed, and there are still about 370 new cases and 100 deaths of cervical cancer yearly in Croatia. In scope of the proposed early detection programme, all Croatian women aged 25-64 years should be screened. In the first phase of the programme, the target population would be tested by Pap smear every third year. In the second phase, HPV-testing would also be introduced for women over 30 years. Organization of the programme at county level is proposed, while the evaluation and monitoring would be performed both at county level and centrally. Regarding the present costs of treatment and sick-leave of cervical cancer patients, it is estimated that the introduction of cervical cancer screening programme in Croatia would be cost-effective already after the first decade. PMID- 17695199 TI - [Improving knowledge and awareness about tuberculosis in a middle incidence country such as Croatia as a potential response to extensively drug-resistant tuberculosis global spread]. PMID- 17695200 TI - [2007 "a challenge for orthopedics"]. PMID- 17695201 TI - [Quality of life of patients with paraplegia secondary to traumatic spine injury]. AB - INTRODUCTION: The quality of life of paraplegic patients is complex, given the interaction that takes place among various factors that include severity of the injury, the degree of independence, the available resources, the acceptance of the injury, and the health-promotion activities. A patient with a history of spinal cord injury is at risk of developing secondary conditions that impair quality of life. OBJECTIVE: Determine the quality of life of patients seen at HTOLV with a diagnosis of traumatic paraplegia. Material and methods. Twenty three paraplegic patients were assessed using the Functional Independence Measure (FIM) scale and the EuroQoL. RESULTS: Mean age was 42.2 years; males were predominant and represented 78%. According to the FIM, mean independence was 88% (65 to 97%). The EuroQoL score was 0.4879 in a scale where 0 represents the worst status and 1 the best. The most frequent complications were: urinary tract infections, depression, pain, and pressure sores. Fifty-seven percent of patients remained married after the injury; 39% of patients were and have remained single, and 82.61% of patients receive a pension. CONCLUSIONS: The quality of life of paraplegic patients is below the mean quality of life of individuals without any disabilities. PMID- 17695202 TI - [Experience with the locking compression plates (LCP) in the Hospital Susana Lopez de Valencia--Popayan, Colombia]. AB - The LCP (locking compression plate) system is a new type of extramedullary fixation for the management of fractures. A special design allows the surgeon to use it as a standard plate or as an internal fixator. The combined hole permits the use of standard screws, such as "locking" screws, that produce angular stability. We present the experience with this implant at Hospital Susana Lopez de Valencia in Popayan, Colombia, from November 2003 to August 2005. The LCP system was used to treat different types of fractures, according to the Orthopedic Trauma Association (OTA) classification. A total of 68 patients (54 males and 14 females) were enrolled in the study. Descriptive statistics was used for data analysis. The results show that 63 fractures (93%) healed within the expected time frame. Complications occurred in 11 patients (16%), with the major ones being infection, loosening, implant rupture, and non-union. Some of them were associated with technical problems and non-observance of the internal fixation principles. In conclusion, the LCP system is an excellent alternative for osteosynthesis which provides new possibilities for the stabilization of simple and complex lesions. However, same as standard osteosynthesis, it is not free of complications. PMID- 17695203 TI - [Preoperative management with skeletal traction in distal tibial fractures]. AB - OBJECTIVE: To describe the immediate management of distal tibial fractures as well as the complications of soft and bony tissues. MATERIAL AND METHODS: Prospective review of 45 patients with distal tibial fractures during an 8-month period (August 1st 2005 to March 31st 2006). They were classified according to Ruedi and Allgower. Seventy-one percent were managed with transcalcaneal skeletal traction and 28% with Jones bandage. The neovascular status of the affected anatomical segment was reviewed and analyzed before and after the surgical procedure. RESULTS: Type II distal fractures were the most frequent ones, with the left size and the male gender as predominant. Skeletal traction was used in 32 patients (71%); osteosynthesis was performed in all cases. CONCLUSIONS: When compared with Jones bandage, transcalcaneal skeletal traction improved the clinical conditions of the distal segment of the leg before and after the surgical procedure. PMID- 17695204 TI - [Larsen syndrome: clinical course and treatment of 22 cases]. AB - In 1950 Joseph Larsen described patients with facial dysmophism, joint hyperelasticity and multiple dislocations. Frequency is 1/ 100,000 live births. Sporadic cases have been reported in the literature in recent years. We analyzed a total of 22 patients with Larsen syndrome, all of them treated in our institution. We report their alterations and management, whether surgical or orthopedic, with a minimum follow-up of three years. After the follow-up we concluded that conservative treatment is fundamental and surgical interventions are indicated for: adduct club foot, patellofemoral dislocation, and unilateral hip dislocation. PMID- 17695205 TI - [Treatment of tibial non-union with a large bone defect with half-tubular fibular graft, centromedullary nailing and bone graft]. AB - INTRODUCTION: Non-union is most frequent in the tibia. It may occur with bone loss and is most often seen in the mid-third, mainly as a result of high-energy trauma. Our purpose is to present a treatment alternative. MATERIAL AND METHODS: Prospective, longitudinal, experimental trial conducted between 1999 and 2004. Five patients classified according to Judet and Paley were included. A half tubular fibular graft plus an autologous and/or heterologous iliac crest graft were used with a UTN nail for stabilization purposes; mean follow-up was 24 months. RESULTS: All patients were male. High energy trauma was the cause in 100%; 5 were Gustilo III fractures; Paley B1 type was present in 60%; the mean bone defect was 7.8 cm. Grade III Montoya bone healing was observed on average at 13.6 months. There were two complications; one infection that required removal of the synthesis without disrupting the healing, and one re-fracture which was managed at a different service. CONCLUSIONS: An autologous half-tubular fibular graft, plus autologous and/or heterologous graft, stabilized with a UTN nail, restores the loss caused by the bone defect and allows achieving an appropriate bone healing. PMID- 17695206 TI - [Use of a xenoimplant for the treatment of bone defects, benign tumors, pseudoarthrosis and arthrodesis. Preliminary report]. AB - OBJECTIVE: To show that the ceramic produced at the Institute for Materials Research, National Autonomous University of Mexico, is an appropriate replacement of bone graft in patients with bone tumors, benign tumors, pseudoarthrosis and arthrodesis treated at "General Ignacio Zaragoza" Regional Hospital. MATERIAL AND METHODS: An experimental, longitudinal study using bovine ceramic xenoimplants in patients covered by the Security and Social Services Institute for Civil Servants (ISSSTE), regardless of age and gender, all of whom consented to receiving the ceramic xenoimplant. Patients who did not consent or who discontinued treatment were excluded. A total of 24 patients were enrolled from March 1st to August 31st, 2006; two patients were withdrawn due to treatment discontinuation. They underwent X-ray evaluation of bone healing using the Montoya classification. RESULTS: The sample is composed of 14 male and 8 female patients, with a mean age of 46.6 years, and a standard deviation (s=) of 13.8. The most frequent indication was arthrodesis in 10 patients (45.45%), pseudoarthrosis in 6 (27.27%), benign tumors in 3 (13.63%), and bone defects in 3 (13.63%). Type II to type IV bone healing was observed in the sample. DISCUSSION: The use of ceramic xenoimplants is appropriate as a replacement of bone graft in patients with arthrodesis and bone defects, thus avoiding the need for autologous bone graft. This results in a decreased patient morbidity. PMID- 17695207 TI - [Minimally invasive surgery for total hip arthroplasty. A review of 36 cases]. AB - INTRODUCTION: A new approach has been developed recently that considerable decreases the size of the skin incision and that has led to controversy around the advantages it offers. OBJECTIVE: To analyze the immediate postoperative course of patients considering the following parameters: operative time, blood loss, postoperative pain. To report the complications that occurred. MATERIAL AND METHODS: Thirty six patients, with a mean age of 48 years, with a diagnosis of grade IV coxarthrosis. Twenty-four patients underwent uncemented total hip arthroplasty, and 12 total hybrid hip arthroplasty. The preoperative Harris clinical assessment was applied and a lateral approach was used in all cases. The initial incision was 6 cm long (100%). RESULTS: The final incision was 6.5 cm in 26 patients (72.22%), 7 cm in 10 patients. Necrosis of wound commissures occurred in 12 patients, superficial necrosis of wound margins in 10 patients; no wound infections were reported. The mean operative time was 65 minutes for uncemented hips and 80 minutes for hybrid hips. Mean intraoperative bleeding was 150 ml. Mean postoperative pain was 3 in the VAS. Complications included performing a neo acetabulum in one case, and a false passage of the femur component in one case. CONCLUSION: The minimally invasive approach for total hip replacement is indicated for patients with special characteristics. It is less invasive, safe, involves minimal bleeding, shorter operative time, and is reproducible. Moreover, it offers significant benefits during the immediate postoperative period when compared with the standard incision, since it involves ess pain and mobility is resumed sooner. PMID- 17695208 TI - [Cutaneous lobular capillary hemangioma of the hand during pregnancy. A case report]. AB - Hemangiomas are abnormal blood vessel proliferations representing the 4th most common tumor of the hand and are frequent among women in their twenties. The case of a 27-year-old woman with a lobular capillary hemangioma in the index finger that appeared during the second month of pregnancy is presented. There are reports stating that these tumors may change their course as a result of various factors such as estrogen or progesterone. They have not been much studied and it is important to know that even though they are benign neoplasias, their course may be aggressive an therefore appropriate treatment is mandatory. PMID- 17695209 TI - [Martin Kirschner (1879-1942)]. PMID- 17695210 TI - [Mouthguards: a difficult choice?]. AB - It is the dentists' task to advise their patients what type of mouthguard grants the best possible protection. It is generally accepted that off-the-counter mouthguards are not sufficiently protective. These mouthguards are usually ill fitting and not worn in the mouth but in the sporting shorts' pocket instead. A custom-fabricated mouthguard is proven to offer maximal protection. A mouthguard has to offer adequate protection with high comfort. A composite laminate construction and space between the inner surface of the mouthguard and the labial surface of the upper front teeth are essential for adequate protection. Transitional dentition and/or orthodontic appliances are no limitation to fabricate a custom-formed mouthguard. PMID- 17695211 TI - [Implants and prosthesis. Never to forget!]. PMID- 17695212 TI - [Dissertations 25 years after date 16. The mutilated dentition]. AB - The lack of scientific basis for the treatment of mutilated dentition and the lack of a correlation between the loss of molar teeth and oral function were the reasons for carrying out a doctoral research project into mutilated dentitions. According to the thesis, loss of teeth was increased with age and loss of teeth followed a similar pattern in all socio-economic classes. No correlation was found between the number of teeth lost and oral function. Only a weak correlation could be demonstrated between the number of occluding pairs of maxillary and mandibular teeth and subjective chewing ability. Subsequent clinical trials and questionnaire studies revealed that, basically, hardly any convincing reason is available for prosthetic replacement of posterior teeth, providing the presence of 3 occluding pairs of maxillary and mandibular teeth. On the strength of scientific evidence available, one may assume that a sound dentition containing at least 20 teeth, maxillary and mandibular frontal teeth and premolars, is satisfactory functionally and aesthetically. For these cases, any reason for prosthetic replacement is absent. PMID- 17695213 TI - [The N-of-1 trial: the ideal study design that is underused]. AB - The randomised experiment in a single patient, the N-of-1 trial, is the best study design for demonstrating causality, for example between agent and effect. Despite this, this type of study is only encountered sporadically in medical journals. One reason for this is that even this type of design cannot definitively demonstrate causality, because different points in time are compared with one another. Moreover, the design is rather inefficient, since the results correspond with those from observation without randomisation, placebo control or blinding. Even so, the N-of-1 trial is the ultimate form of verification in, for example, the individualisation of treatment. For this reason, this form of study might be used more often. PMID- 17695214 TI - [Restless legs due to ingestion of 'light' beverages containing saccharine. Results of an N-of-1 trial]. AB - To determine whether there was a connection between the complaint of restless legs and the ingestion of artificial sweeteners in a patient with these symptoms after drinking certain 'light' beverages, a randomised, double-blind, placebo controlled N-of-1 trial with a crossover design was used. During a period of 48 days, the patient took 4 capsules per day containing either 150 mg of cyclamate, 22.5 mg of saccharine, both sweeteners, or placebo on two successive days. Between each of these 2-day periods there was a 2-day rest period during which no capsules were taken. The hospital pharmacist had prepared the capsules and determined the sequence of the 2-day periods on a random basis. The patient did not know which capsules he was taking. Every day on arising, starting 3 weeks before the trial period, the patient noted the intensity and duration of the symptoms in the late evening and previous night. For this notation he used an 11 point scale, from 0 (= no restless legs) to 10 (= almost total inability to sleep because of restless legs). A score of 1-3 corresponded to mild symptoms that had no effect on the patient's sleep; at a score of 4-6 his sleep was disturbed and at a score of 7-10 the patient hardly slept at all. The patient had symptoms more often while using saccharine or the combination of saccharine and cyclamate than when taking the placebo (4 and 4 versus 2 of the 6 nights); moreover, the average score was then statistically significantly higher (5.2 and 5.8 versus 3-3). It was concluded that there was a connection between the patient's complaints of restless legs and the use of saccharine, but not the use of cyclamate. PMID- 17695215 TI - [Mediastinitis and cervical fasciitis necroticans post extraction of 2 molars]. AB - A 38-year-old man developed dysphagia, fever and marked trismus, resulting in an abcess of the parafaryngeal region, soon after the surgical extraction of 2 mandibular molars. Despite systemic antibiotics and surgical drainage, the abcess spread to the mediastinum. Within a short space of time, cervical fasciitis necroticans and descending necrotizing mediastinitis developed. Because of the life-threatening health condition, the patient was admitted to a hospital for further treatment. He underwent surgical exploration of the cervical and sternal region, thoracotomy for mediastinal drainage, debridement, and daily mediastinal rinsing with hydrogen peroxide and betadine iodine. After 5 weeks intensive treatment, the patient could be discharged from the hospital in a fairly good condition of health. PMID- 17695216 TI - [Skin diseases of the face; an overview for dental practitioners]. AB - Dental practitioners are supposed to have some knowledge of skin diseases, particularly those occurring in the face. They should encourage a patient to see his physician or a dermatologist for further evaluation and possible treatment. Diseases of the skin can be classified in various ways. In this overview, diseases are classified as infectious diseases, inflammatory diseases, autoimmune diseases, benign neoplasms, premalignant lesions, and malignant lesions. In the Dutch health care system, family doctors play an important role and, until recently, they have been the obvious persons to whom a patient with a detected skin disease was referred by dental practitioners. The general practitioner then determined whether a referral to a dermatologist was indicated. However, because of changes in the health care system it has become possible for a dentist to refer patients directly to a dermatologist in case of the presence of a skin disease. PMID- 17695217 TI - A material curiosity. Interview by Alison Stoddart. PMID- 17695218 TI - Enantioselective catalytic syntheses of alpha-branched chiral amines. PMID- 17695219 TI - Fluorescent dyes of the esculetin and alizarin families respond to zinc ions ratiometrically. AB - Commercially available dyes of the esculetin and alizarin families are identified as lead structures for constructing ratiometric fluorescent probes for zinc ions. PMID- 17695220 TI - A tailored organometallic gelator with enhanced amphiphilic character and structural diversity of gelation. AB - A cholesterol-appended titanocene gelator was synthesised which forms twisted fibers able to gelate a variety of solvents of different polarity as demonstrated by spectroscopic and microscopic techniques. PMID- 17695221 TI - Adenosine residues in the template do not block spontaneous replication steps of RNA. AB - Sub-freezing temperatures, azabenzotriazolide activation, multiple monomer addition, and helper displacement help to overcome what seemed like an intrinsic block of adenine-templated RNA replication steps in the absence of enzymes. PMID- 17695222 TI - Photoinduced reduction of catalytically and biologically active Ru(II)bisterpyridine-cytochrome c bioconjugates. AB - Ruthenium(II)bisterpyridine chromophores were covalently linked to iso-1 cytochrome c from yeast to create light-activated donor-acceptor bioconjugates. PMID- 17695223 TI - Synthesis and characterization of pi-extended bowl-shaped pi-conjugated molecules. AB - A series of pi-extended bowl-shaped pi-conjugated compounds were synthesized from sumanene and characterized, and among them the terthiophene derivative showed a remarkable red-shifted absorption and small band gap, which wa rationalized by molecular orbital calculation. PMID- 17695224 TI - Ba7Mn5Cr2O20: charge and chemical order. AB - Ba7Mn5Cr2O2O20 adopts a structure containing an ordered array of Mn(IV), Mn(II) and Cr(V) cations and exhibits complex magnetic behaviour at low temperature. PMID- 17695225 TI - Cyclometalated ruthenium complexes for sensitizing nanocrystalline TiO2 solar cells. AB - Cyclometalated ruthenium complexes of [Ru(C--arrow--N) (N--N--N)] configuration are a promising new class of molecular sensitizers for dye-sensitized solar cells, as a result of their broad and red-shifted visible absorption in comparison to the analogous [Ru(N--N--N)2] type coordinative complexes. PMID- 17695226 TI - A rotaxane mimic of the photoactive yellow protein chromophore environment: effects of hydrogen bonding and mechanical interlocking on a coumaric amide derivative. AB - Hydrogen bonding in a [2]rotaxane is shown to stabilise the phenolate anion of a coumaric amide chromophore by almost 3 pKa units; however, the effect on the UV spectral shift in the anion is small and, significantly given the photochemistry of PYP, despite the hydrogen bonding olefin photoisomerisation in the anionic rotaxane remains heavily suppressed. PMID- 17695227 TI - Directed evolution and axial chirality: optimization of the enantioselectivity of Pseudomonas aeruginosa lipase towards the kinetic resolution of a racemic allene. AB - Directed evolution of Pseudomonas aeruginosa lipase by the use of combinatorial active site saturation test (CAST) criteria provided a highly enantioselective mutant (Leu162Phe) for kinetic resolution of an axially chiral allene, p nitrophenyl 4-cyclohexyl-2-methylbuta-2,3-dienoate (E=111); the high enantioselectivity of the Leu162Phe mutant was rationalized by pi-pi stacking. PMID- 17695228 TI - Commercial Fe- or Co-containing carbon nanotubes as catalysts for NH3 decomposition. AB - Fresh commercial carbon nanotubes (CNTs) containing residual Co or Fe nanoparticles are highly active for NH3 decomposition while the microstructure of CNTs remains unchanged. The catalysts are promising for elimination of NH3 from coal gasification stream and for production of H2 from NH3. PMID- 17695229 TI - Facile fabrication of superhydrophobic surface from micro/nanostructure metal alkanethiolate based films. AB - A series of superhydrophobic surfaces with micro/nanostructure have been successfully achieved by a simple process via the reaction between metal (such as Cd and Zn) salts and alkanethiolates. PMID- 17695230 TI - Formal synthesis of (+/-)-platensimycin. AB - A formal total synthesis of (+/-)-platensimycin [(+/-)-1] is reported involving an intramolecular Stetter reaction and a radical cyclization. PMID- 17695231 TI - A high-performance selective oxidation system for the facile production of fine chemicals. AB - Mn(III)AlPO-5 and Cr(VI)AlPO-5 redox (microporous) catalysts are effective, in the presence of dissolved acetylperoxyborate (APB) under mild conditions (333-373 K), and much superior to the titanosilicate, TS-1 (also a single-site heterogeneous catalyst), in the selective oxidation of primary, secondary, benzylic and other unsaturated alcohols, p-cymene, methyl cyclohexene and other speciality organics which are of value in the fine-chemical and pharmaceutical industries. PMID- 17695232 TI - Stereospecific aziridination of olefins via electrophile-induced cyclization of gamma,delta-unsaturated imines and subsequent hydrolytic rearrangement. AB - The olefinic bond of gamma,delta-unsaturated aldehydes underwent a net aziridination through electrophile-induced cyclization and subsequent rearrangement of the resulting cyclic iminium salts: this methodology allows the stereospecific introduction of aziridine moieties into cyclic systems. PMID- 17695233 TI - Co2+/ Co(0) redox couple revealed by EPR spectroscopy triggers preferential coordination of reactants during SCR of NOx with propene over cobalt-exchanged zeolites. AB - Catalytic reduction of NOx with propene over Co2+ -exchanged beta and ZSM-5 zeolites occurs with formation of zero-valent cobalt; NOx preferentially adsorbed on Co2+ plays the role of a metal reducing agent while ligation of propene is favored for Co(0) centers. PMID- 17695234 TI - Aqueous-biphasic hydroformylation of higher alkenes promoted by alkylimidazolium salts. AB - Aqueous-biphasic hydroformylation of higher alkenes (>C5) can be greatly accelerated by addition of 1-octyl-3-methylimidazolium bromide without affecting the phase separation and with good catalyst retention in the aqueous phase. PMID- 17695235 TI - Hybrid lipid bilayers in nanostructured silicon: a biomimetic mesoporous scaffold for optical detection of cholera toxin. AB - Cholera toxin levels are optically detected by affinity capture within hybrid lipid bilayer membranes formed in the nanostructures of porous silicon photonic crystals. PMID- 17695236 TI - Poly(ethylene glycol) stabilized Co nanoparticles as highly active and selective catalysts for the Pauson-Khand reaction. AB - PEG-stabilized cobalt nanoparticles were prepared by thermal decomoposition of [Co2(CO)8] in PEG and were shown to be highly active and selective catalysts, for intra- and intermolecular Pauson-Khand reactions (PKR), in organic solvents or aqueous media. PMID- 17695237 TI - Metal template assembly of highly functionalized octacyanoporphyrazine framework from TCNE structural units. AB - A new route to the octacyanoporphyrazine framework based on the interaction of metal sandwich pi-complexes with TCNE has been developed. PMID- 17695238 TI - An electrochemically driven molecular shuttle controlled and monitored by C60. AB - Herein we describe a fullerene rotaxane, in which shuttling between two well defined and distant co-conformations is both induced and monitored by the C60 stopper. PMID- 17695239 TI - Magnetite ferrofluids stabilized by sulfonato-calixarenes. AB - Magnetite (Fe304) nanoparticles stabilised by sulfonatocalixarene macrocycles are readily accessible by a rapid in situ co-precipitation, and exhibit ferro-fluidic and superparamagnetic behaviour. PMID- 17695240 TI - New coordination modes at molybdenum for 2-diphenylphosphinoaniline derived ligands. AB - The complexes [MoCl3(1-N,2-Ph2P-C6H4)2] (1) and {MoCl(Nt-Bu)[1-micro(N),2 (Ph2P)C6H4]}2 (2) have been obtained from the reaction of 2 diphenylphosphinoaniline [1,2(NH2)(Ph2P)C6H4] with either sodium molybdate [Na2MoO4] (in the presence of Et3N and Me3SiCl) or [MoCl2(Nt-Bu)2(DME)]; the crystal structure of 1 reveals a novel MoNC2PN six-membered conjugated ring system derived from a P-N coupling reaction between two ligands, whilst that of 2 reveals bridging imido/terminal phosphine ligation. PMID- 17695241 TI - Iron-catalyzed aryl-aryl cross-coupling reaction tolerating amides and unprotected quinolinones. AB - The iron(III)-catalyzed cross-coupling reaction between functionalized arylcopper reagents and aromatic iodides bearing an amide function or an unprotected quinolinone leads smoothly to polyfunctionalized biphenyls in excellent yields due to an intramolecular chelating effect of the amide group. PMID- 17695242 TI - Nanoscopic hybrid systems with a polarity-controlled gate-like scaffolding for the colorimetric signalling of long-chain carboxylates. AB - Hybrid mesoporous systems containing a gate-like ensemble functionalised with imidazolium groups and a dye are used for the selective colorimetric sensing of long-chain carboxylates. PMID- 17695243 TI - Sidearm effects in the enantioselective cyclopropanation of alkenes with aryldiazoacetates catalyzed by trisoxazoline/Cu(I). AB - A highly enantioselective cyclopropanation of alkenes with phenyldiazoacetates catalyzed by CuPF6(CH3CN)4/trisoxazoline has been developed. PMID- 17695244 TI - One-pot synthesis of a pentasaccharide with antibiotic activity against Helicobacter pylori. AB - A pentasaccharide that contains the alpha-1,4-GlcNAc mucin core two-branched O glycan has been synthesized by a one-pot, two-step glycosylation strategy; this particular carbohydrate motif may provide protection against H. pylonri induced pathologies since the synthetic pentasaccharide inhibits cholesterol alpha glucosyltransferase (IC50 of 0.47 mM). PMID- 17695245 TI - Tandem C-C coupling--intramolecular acetylenic Schmidt reaction under Pd/C-Cu catalysis. AB - A new one-pot reaction for the regioselective construction of a six-membered fused N-heterocyclic ring leading to isoquinolones under Pd/C-Cu catalysis is described. PMID- 17695246 TI - Human gamma delta T cells: candidates for the development of immunotherapeutic strategies. AB - A numerically small subset of human T lymphocytes expresses a gamma delta T cell receptor (TCR). These gamma delta T cells share certain effector functions with alpha beta T cells as well as with NK cells and NKT cells. The major peripheral blood gamma delta T cell subset in healthy adults expresses a Vgamma9Vdelta2 TCR, which recognizes small phosphorylated metabolites referred to as phosphoantigens. Vdelta1 gamma delta T cells mainly occur in the intestine. They recognize the stress-induced MICA/B and CD1c. Furthermore, gamma delta T cells express a variety of NK cell and pattern-recognition receptors which are responsible for the "fine-tuning" of effector functions. In recent years, gamma delta T cells start to emerge as a rewarding target for immunotherapeutic strategies against viral infections and cancer. A better understanding of factors that modulate gamma gamma delta T cell function will further eluminate the potential of these cells. PMID- 17695247 TI - Initiation of primary anti-vaccinia virus immunity in vivo. AB - The primary focus of our work is the initiation of an antiviral immune response. While we employ many experimental systems to address this fundamental issue, much of our work revolves around the use of vaccinia virus. Concerns over the negative effects of vaccination have prevented the return of the smallpox immunization program to the general population and underscored the importance of understanding the primary immune response to vaccinia virus. This response is comprised of a complex symphony of immune system components employing a variety of different mechanisms. In this review, we will both highlight the roles of many of these components and touch on the applications of vaccinia virus in the laboratory and the clinic. PMID- 17695249 TI - Flt3-ligand plasmid prevents the development of pathophysiological features of chronic asthma in a mouse model. AB - Airway inflammation and remodeling are primary characteristics of long-standing asthma. A balance between the T(H)1/T(H)2 cytokines regulates the accumulation and activation of inflammatory cells, including mast cells and eosinophils. Recently, we demonstrated that pUMVC3-hFLex, an active plasmid, mammalian expression vector for the secretion of Flt3-L, reversed established airway hyperresponsiveness (AHR) in a murine model of acute allergic airway inflammation. The present experiments were undertaken to examine the effect of pUMVC3-hFLex in a chronic model of allergic airway inflammation that was established in Balb/c mice by sensitization and challenge with ovalbumin (OVA). pUMVC3-hFLex or the control plasmid, pUMVC3, were administered by injection into the muscle interior tibialis. Treatment with pUMVC3-hFLex completely reversed established AHR (p < 0.05), and this effect continued even after several exposures to the allergen (p < 0.05). pUMVC3-hFLex treatment prevented the development of goblet cell hyperplasia and subepithelial fibrosis, and significantly reduced serum levels of IL-4 and IL-5, and increased serum IL-10 levels (p < 0.05) with no effect on serum IL-13. Serum IgE or serum total and anti-OVA IgG1 and IgG2a levels did not change. Total BALF cellularity and BALF IL 5 levels were reduced (p < 0.05), but there was no significant effect on BALF IL 10 and IL-13. These results suggest that pUMVC3-hFLex treatment can prevent the development of airway remodeling and maintain airway protection in chronic experimental asthma model, and might provide a novel approach for treating chronic asthma. PMID- 17695250 TI - At the interface of physics and biology. PMID- 17695248 TI - Dendritic cells and the immunopathogenesis of systemic lupus erythematosus. AB - Over the last decade, the role of dendritic cells (DCs) in the immunopathogenesis of systemic lupus erythematosus (SLE) has become apparent. As unique mediators of both tolerance and immunity, aberrant myeloid and plasmacytoid DC function can promote autoimmune responses via a number of mechanisms and proinflammatory pathways. This review provides an overview of DC function, the potential role of DCs in promoting autoimmune responses in SLE, and how other abnormalities in lupus can lead to an enhanced engagement of DCs in immune responses. How medications used to treat SLE and other autoimmune conditions may exert effects on DCs is also explored. PMID- 17695251 TI - Tissue preparation for laser capture microdissection and RNA extraction from fresh frozen breast tissue. PMID- 17695252 TI - Whole-mount techniques to evaluate subepithelial cellular populations in the adult mouse intestine. PMID- 17695253 TI - Improved DNA sequencing quality and efficiency using an optimized fast cycle sequencing protocol. PMID- 17695254 TI - Concomitant quantification of targeted drug delivery and biological response in individual cells. AB - Targeted therapies result in heterogeneous drug delivery, often with highly variable drug uptake in the targeted cells and significant numbers of cells that are essentially untargeted. However both the variably targeted cells and neighboring bystander cells may respond to the treatment. Using ionizing radiation as an example of a targeted therapeutic agent, we describe a quantitative immunofluorescence-based approach for concomitant quantification of exposure and measurement of biological responses in both targeted and bystander cells. Cultures of human skin fibroblasts are co-pulse-labeled with 3H deoxycytidine (3H-dC) and bromodeoxyuridine (BrdU). The labeled cells, identified by BrdU immunofluorescence, are internally irradiated by low-energy beta particles emitted by incorporated 3H-dC. BrdU immunofluorescence intensity is proportional to radioactivity incorporated and, therefore, to radiation dose rate. Cell-cycle arrest in G2 is measured in labeled cells as function of dose rate. Stress responses in bystander cells, indicated by a G1 checkpoint, are concomitantly measured with a flow cytometric-cumulative labeling index (FCM-CLI) assay. The overall approach presented herein may be useful in the context of evaluating responses to targeted drug delivery. PMID- 17695255 TI - Quantification of human angiogenesis in immunodeficient mice using a photon counting-based method. AB - Testing new antiangiogenic drugs for cancer treatment requires the use of animal models, since stromal cells and extracellular matrices mediate signals to endothelial cells that cannot be fully reproduced in vitro. Most methods used for analysis of antiangiogenic drugs in vivo utilized histologic examination of tissue specimens, which often requires large sample sizes to obtain reliable quantitative data. Furthermore, these assays rely on the analysis of murine vasculature that may not be correlated with the responses of human endothelial cells. Here, we engineered human blood vessels in immunodeficient mice with human endothelial cells expressing luciferase, demonstrated that these cells line functional blood vessels, and quantified angiogenesis over time using a photon counting-based method. In a proof-of-principle experiment with PTK/ZK, a small molecule inhibitor of vascular endothelial growth factor (VEGF) tyrosine kinase receptors, a strong correlation was observed between the decrease in bioluminescence (9.12-fold) in treated mice and the actual decrease in microvessel density (9.16-fold) measured after retrieval of the scaffolds and immunohistochemical staining of endothelial cells. The method described here allows for quantitative and noninvasive investigation into the effects of anti cancer drugs on human angiogenesis in a murine host. PMID- 17695256 TI - PCR-based procedures to isolate insertion sites of DNA elements. AB - During the past several years, retroviral insertional mutagenesis has been fruitfully applied to search for genes/pathways involved in tumorigenesis. Techniques used to identify proviral insertion sites are critical for fulfilling these projects. Although a variety of approaches have been described, an improvement over existing methods is required to recover every possible insertion site for cancer gene discovery, so-called saturation analysis. Here, we have described the development of two ligation-mediated PCR variants, SplinkTA-PCR (STA-PCR) and SplinkBlunt-PCR, for efficient isolation of insertion sites in retrovirus-induced leukemia. Our results demonstrated that these two protocols are complementary to each other and that they are better employed in combination for maximal cloning efficiency. These protocols are easy-to-use, reliable and efficient, and are readily applicable to large-scale cloning of insertion sites of provirus and other integrated DNA elements, as well as for detection and cloning of differential insertions unique to drug-resistant cells. PMID- 17695257 TI - Closed-tube genotyping of apolipoprotein E by isolated-probe PCR with multiple unlabeled probes and high-resolution DNA melting analysis. AB - Isolated-probe PCR (IP-PCR) is a method that combines asymmetric PCR, unlabeled probes, and high-resolution DNA melting while maintaining a closed tube system. A double-stranded DNA (dsDNA) dye LCGreen I was used to detect the unlabeled probes. LCGreen I is also used to detect the 277-base pair PCR product peak as an internal amplification control. To accomplish this, IP-PCR separates the asymmetric PCR amplification step and the detection step of the unlabeled probes. This prevents the probes from interfering with the amplification of the DNA target. The samples are then melted using a high-resolution DNA melting instrument: the HR-1. The closed tube system virtually eliminates PCR product contamination or sample carryover The target apolipoprotein E (APOE) was chosen to test the IP-PCR technique. APOE contains two single nucleotide polymorphisms (SNPs) located 139 base pairs apart in a GC-rich region of the human genome. The results from this study show that the IP-PCR technique was able to determine the correct APOE genotype for each of the 101 samples. The IP-PCR technique should also be useful in detecting SNPs in other high-GC regions of the human genome. PMID- 17695258 TI - Fluorescence resonance energy transfer-based method for detection of DNA binding activities of nuclear factor kappaB. AB - The DNA binding protein nuclear factor kappaB (NF-kappaB) and the cellular signaling pathways in which it participates are the central coordinators of many biological processes, including innate and adaptive immune responses, oxidative stress response, and aging. NF-kappaB also plays a key role in diseases, for example, cancer A simple, convenient, and high-throughput detection of NF-kappaB activation is therefore important for systematically studying signaling pathways and for screening therapeutic drug targets. We describe a method based on fluorescence resonance energy transfer (FRET) to directly measure the amount of activated NF-kappaB. More specifically, a double-stranded DNA (dsDNA) probe was designed to contain a pair of FRET fluorophores at the same end of the probe and an endonuclease binding site within the NF-kappaB consensus sequence. The activated NF-kappaB was detected by FRET following the restriction enzyme digestion. Using three different analyte materials--(i) purified recombinant NF- kappaB p50, (ii) nuclear extracts, and (iii) whole cell lysates--we demonstrated that this assay is as sensitive as the traditional, widely used electrophoretic mobility shift assay (EMSA), but much less labor-intensive for measuring NF kappaB DNA binding activities. In addition, this FRET-based assay can be easily adapted for high-throughput screening of NF-kappaB activation. PMID- 17695259 TI - New tissue microarray technology for analyses of gene expression in frozen pathological samples. AB - Tissue microarrays (TMAs) are widely used to analyze gene expression in multiple pathological samples on a single slide. Currently, most TMA slides are made by coring paraffin-embedded tissues and arraying them into a paraffin block, from which TMA sections are cut. However paraffin-based TMA technology may not be compatible with frozen clinical tissue samples, which have a higher quality of RNAs and proteins for preparing TMAs than paraffin-embedded tissue samples. In this study, we developed an alternative TMA technology that is applicable to a broader range of frozen tissue samples. Our method takes advantage of a newly developed array recipient block that can be used to array small tissue cores. After arraying tissue cores, the tissue block can be immediately sectioned on a cryostat microtome to make TMA slides. TMAs made using this method have well defined array configurations and good tissue/cell morphology. Immunohistochemistry and in situ hybridization study also revealed well-preserved proteins and mRNAs on TMA slides. Our method significantly simplifies TMA preparation and assembly when frozen pathological tissues are used. Our technology provides an alternative tool for creating high-quality TMAs for the general research community to study gene expressions in pathological samples. PMID- 17695260 TI - Characterizing the spatio-temporal behavior of cell populations through image auto- and cross-correlation microscopy. AB - We propose two methods for characterizing the spatio-temporal behavior of cell populations in culture. The first method, image auto-correlation microscopy (IACM), allows us to characterize the variation in the number of objects as a function of time, thus enabling the quantification of the clustering properties of cell populations to be performed. The second method, image cross-correlation microscopy (ICCM), allows us to characterize the migration properties of cell populations. The latter method does not require estimation or measurement of the trajectories of individual cells, which is very demanding when populations of >100 cells are examined. The capabilities of the two methods are demonstrated with simulated cell populations, and their usefulness is illustrated with experiments involving invasive and noninvasive tumor cell populations. PMID- 17695261 TI - Novel high content multi-parametric cell-based assays. PMID- 17695262 TI - [Evaluating health state and professional adaptation of young workers and students on aircraft-construction plant]. AB - The article deals with materials on parameters of health and functional cardiovascular resources, some psychophysiologic functions, social and psychologic characteristics in young workers of aircraft-construction plant and in potential workers - technical school and college students. The authors evaluate efficiency of occupational adaptation of the youth. PMID- 17695263 TI - [Biochemical criteria of occupationally related diseases formation in firemen]. AB - Results of medical examination among working firemen and firemen with diagnosed occupational disease prove changes in protein and lipid metabolism. Decreased alpha-globulin fractions and increased beta-globulins could result from toxic chemical load and stress. Thus early changes in cholesterol metabolism without hepatic involvement are seen. PMID- 17695264 TI - [Influence of dioxines on firemen]. AB - The authors analysed dioxines sources and reasons supporting dioxines influence on firemen. Highlevels of dioxines in the firemen who participated in industrial fire extinguishing on JSC "Irkoutskcable" in 1992 assume possible occupational exposure. PMID- 17695265 TI - [Methodic aspects of evaluating occupational risk in workers]. AB - The authors present results of testing the method of occupational risk evaluation exemplified by workers of major enterprises of East Siberia and Far North. The article proves that complex evaluation of main pathologic syndromes risk with social and psychologic characteristics consideration should be included into criteria of occupational risk evaluation. PMID- 17695266 TI - [Methyl sulphides and their metabolites in biologic materials of workers engaged into sulfate pulping]. AB - The authors studied serum and urine levels of methyl sulphides in workers engaged into sulfate pulping and exposed to methyl sulphides. Blood serum was studied only for dimethyldisulfide. Urine appeared to contain no methyl sulphides, but finding was increased urinary excretion of sulfates which are metabolites of methyl sulphides. Sulfates content of urine correlated with intensity and duration of exposure to methyl sulphides, so this exposure test could be used as a biologic marker in monitoring work conditions and health state of workers exposed to methyl sulphides. PMID- 17695267 TI - [Features of nervous system involvement under stress influence by occupational physical factors]. AB - Somatosensory and auditory evoked potentials prove central and peripheral nervous system disorders in patients long exposed to vibration. Those disorders are altered impulse conductivity at all levels including peripheral neuron to nerve trunk, from the trunk to primary somatosensory cortex. Vibration is potent chronic stressor causing complicated neuroreflectory and neurohumoral disorders. PMID- 17695268 TI - [Slow virus infections characterized by the mode of onset]. PMID- 17695269 TI - [Disease concept of the slow virus infection]. AB - This article gives a brief history of the terminology of slow virus infection, the conceptual change that occurred in it, the features common to slow infection and the current concept of slow virus infection. Bjorn Sigurdsson from the field of veterinary medicine proposed slow virus infection as unique mode of infection in 1954. Its initial concept was remodeled along with the general acceptance of prion theory of sheep scrapie that was proposed in 1982. The features common to slow infection include very long latency, unanimous poor prognosis, central nervous system involvement, etc. Currently the slow infection comprises those caused by slow conventional viruses that is the slow virus infection (for example subacute sclerosing panencephalitis and progressive multifocal encephalopathy in human and visna-maedi in sheep) and prion diseases (for example kuru, Creutzfeldt Jakob disease, Gerstmann-Straussler-Scheinker syndrome in human, scrapie and bovine spongiform encephalopathy). PMID- 17695270 TI - [Research progress in slow virus infections in Japan and the diagnostic points]. AB - There have been many progresses of researches on slow virus infections including sub-acute sclerosing panencephalitis (SSPE), progressive multifocal leukoencephalopathy (PML) and prion diseases. In Japan, many researches were conducted in relation with the research group on prion disease and slow virus infection sponsored by the Ministry of Health, Welfare and Labor. Particularly in prion disease, the nation-wide surveillance has shown many important epidemiological and clinical results. However the elucidation of pathomechanisms and development of effective treatments of prion disease, SSPE and PML are far from contentment and we the mankind need further efforts to overcome these diseases. PMID- 17695271 TI - [Establishment of the concept of prion diseases]. AB - The history of prion diseases is derived from descriptions of scrapie of sheep and goats in the eighteenth century. In 1920, Creutzfeldt-Jakob disease was reported as the first case of human prion diseases, which was recognized as subacute spongiform encephalopathy, one of neurodegenerative diseases. Afterwards, many transmission experiments were performed, which lead to the establishment of the fundamental concept, transmissible spongiform encephalopathy(TSE). The infectious agent was supposed to be a novel virus, so TSE was classified into slow virus infection. In 1982, Prusiner investigated the infectious fraction of scrapie-infected brain homogenate, defined the infectious agent as proteinaceous infectious particles that resist inactivation by procedures that modify nucleic acid and newly designated as prion after virion in viral infection. PMID- 17695272 TI - [Epidemiology and surveillance system of prion disease in Japan]. AB - The current surveillance system by the Creutzfeldt-Jakob disease (CJD) Surveillance Committee, Japan, started in April 1999, and 836 patients with prion diseases had been registered until September 2006, including sporadic CJD (78 %), inherited prion disease (14 %), and infectious prion disease (8 %). The infectious prion disease included a patient with variant CJD and 68 patients with dura mater graft-associated CJD (dCJD). Combined with the dCJD patients identified by previous surveillance systems, the total number of dCJD was counted to be 124. PMID- 17695273 TI - [Elusive function of prion protein]. AB - Prion protein is a highly conserved glycoprotein tethered to cell membranes by a glycosylphosphatidylinositol(GPI) anchor that is expressed in many tissues including brain, heart, and muscle. Although misfolding of the cellular prion protein (PrP(c)) into alternative form, denoted (PrP(Sc)), is a key event in prion infections, the normal function of PrPc remains to be clearly defined. Many PrP(c)-binding proteins have been identified, and several roles for PrP(c) have been suggested, including oxidative stress, cell adhesion, copper uptake, cell survival, protection against oxidative stress, but authentication of these interactions in functional assays is incomplete. In this article, we pick out some researches that pertain to the biology of mammalian prion protein functions. PMID- 17695274 TI - [Mechanisms of prion transmission]. AB - Prions, the causative agents of prion diseases, consist of the abnormal isoform of prion protein, PrP(Sc). PrP(Sc) is generated by conformational conversion of the normal isoform of prion protein, PrPc, a glycosyl-phosphatidyl-inositol anchored glycoprotein abundantly expressed on the surface of neurons. Prions or PrP(Sc) having invaded the body interact with PrP(c) and induce changes in structure of the interacting PrP(c) into that of PrP(Sc), leading to prion replication. At the same time, this constitutive conversion causes the detrimental accumulation of PrP(Sc) in the brain tissue. Here, I will introduce the structural and biochemical properties of PrP(c) and PrP(Sc) and discuss the nature of prions and the mechanisms of prion replication in more detail. PMID- 17695275 TI - [Notch-1 is involved in neurodegeneration in prion diseases]. AB - Prion diseases are caused by disease -causing isoform of the prion protein (PrP(Sc)) accumulation in the central nervous system. Accumulation of PrP(Sc) induces synaptic dysfunctions, dendritic atrophy, neuronal vacuolation and reactive gliosis. Clinical symptoms are observed after neuronal cell loss. Recently we have reported that Notch-1, which plays important roles in neuronal development is activated in animal and cell models of prion diseases. It is well known that the activation of the Notch signaling pathway induces gliogenesis and suppresses neurogenesis. I will review the previous reports about neurodegeneraion of prion diseases and discuss the possible involvement of Notch 1 in the dendritic atrophy. PMID- 17695276 TI - [Neuropathological diagnosis of prion disease]. AB - Neuropathological diagnosis of prion disease consists of sequence analysis of PRNP (prion protein gene), located on chromosome 20 and characterization and visualization of deposited proteinase K-resistant prion protein (PrP(Sc)). SNP at 129 locus (M/V) and Type 1 and Type 2 difference in Western blot analysis of PrP(Sc) from the postmortem brain influence the clinical and pathological presentations. Prion disease is classified into sporadic, hereditary and infectious subtypes, but PrP(Sc) from almost all the subtypes can transmit the disease to transgenic mice expressing human PRNP. Variant CJD, apparently derived from bovine spongiformic encephalopathy, requires shift in disease control strategy, in that PrP(Sc) is present in peripheral lymphatic organs. PMID- 17695277 TI - [Clinical characteristics and laboratory findings in prion diseases]. AB - Acutely progressing dementia, generalized myoclonus, and periodic synchronous discharge (PSD) on EEG are thought to be characteristic features of Creutzfeldt Jakob disease (CJD). However, recent surveillance studies in European countries and Japan have revealed several uncommon variants that run relatively long clinical course, demonstrate atypical myoclonus, and show no PSD. Brain specific proteins such as 14-3-3 protein, tau protein, and neuron specific enolase (NSE) are detected in the CSF of CJD patients. Clinical features and laboratory findings of sporadic CJD are related well to the combination of polymorphism at codon 129 of prion protein gene(PRNP) (Methionine/Methionine, Methionine/Valine, and Valine/Valine) and type of pathogenic prion protein (type 1 and type 2). Those of genetic prion disease depend on pathogenic mutation in PRNP. Positive rates of PSD and 14-3-3 protein in the CSF differ among subtypes of sporadic CJD and genetic prion diseases. Diffusion-weighted MRI is very useful for an early clinical diagnosis of CJD and some subtypes show their own characteristic findings. PMID- 17695278 TI - [Recent advances in the diagnosis and therapeutics for human prion diseases]. AB - Prion diseases, or transmissible spongiform encephalopathies, are fatal, neurodegenerative disorders associated with the accumulation of a misfolded infectious prion protein which is made by a posttranslational conformational change of the host-encoded cellular prion protein. A large number of studies to reveal the pathogenesis of prion diseases have been done using such experimental models as animals, cell cultures and cell-free systems over the past 30 years. The prion pathogenesis is still enigmatic, but current explosion of the knowledge about prion biology has led to the discovery of either more reliable diagnostic measurements or more beneficial therapeutic candidates. Here, the recent advances are reviewed in the diagnostics and the therapeutics for prion diseases. PMID- 17695279 TI - [Clinical typing and diagnosis of sporadic human prion diseases (classic sproadic CJD, MM2-cortical form CJD, MM2-thalamic form CJD)]. AB - We described recent knowledge and outline about a diagnosis and clinical typing of sporadic prion disease. Diagnostic procedure and classification based on a pattern of Western blotting of PrP(Sc), neuropathologic findings, and clinical features. In addition, we described a clinical significance of total tau protein, significance of a diffusion-weighted images of MRI. Analysis of 112 cases of sporadic prion diseases showed 92.3% at positive rate. Sensitivity and specificity were 95.5% and 95.7%, respectively by total tau protein assay of 44 cases of prion diseases. PMID- 17695280 TI - [Familial prion disease (GSS, familial CJD, FFI)]. AB - We described clinically features of inherited prion disease (GSS, familial CJD and FFI). In addition, we found new useful findings of GSS patients for early diagnosis. Generally, clinicians believe that the main features of GSS (P102L) are cerebellar symptoms and dementia; however, our patients showed other features. Most showed mild gait disturbance, dysesthesia and hyporeflexia of the lower legs, proximal leg muscle weakness, and truncal ataxia during the early stage of the disease. Dementia was not a main symptom during the early stage. The key features for the early diagnosis of GSS102 are truncal ataxia, dysesthesia and hyporeflexia of the lower legs, and mild dysarthria. Normal cerebellar MRI and abnormal cerebral SPECT findings should be useful for early diagnosis of GSS (P102L). PMID- 17695281 TI - [Acquired Creutzfeldt-Jakob disease (CJD)--Kuru, iatrogenic CJD, variant CJD]. AB - Human prion diseases can be classified as sporadic, hereditary or acquired. The acquired forms are known to be caused by the transmission to human from human or animal, via medical appliances, oral intake or parenteral solutions. Usually, peripheral infection such as oral(Kuru) or parenteral (human pituitary hormones) transmission causes cerebellar degenerative form, and central nervous system infection such as neurosurgical treatment, dura mater grafts or corneal grafts transmission causes clinical features similar to sporadic form of Creutzfeldt Jakob disease (CJD). The variant CJD (vCJD) is considered to be transmitted bovine spongiform encephalopathy(BSE) to human through dietary exposure. The early clinical features of vCJD are dominated by psychiatric symptoms, and minor number of patients have neurological symptoms from the onset. After about 6 months, there are frank neurological signs, including ataxia, cognitive impairment and involuntary movements. PMID- 17695282 TI - [Counseling families and patients with prion disease]. AB - It is critical to provide sufficient information and psychosocial support to people who have concerns and questions related with prion disease, especially families and patients. The processes of information provision and psychological counseling require professional skills based on theories, and people' s needs should be considered. Grief counseling is also helpful for not only those who have lost their families but also people who are facing difficult diagnosis and rapid development of illness. With regard to familial prion disease, which is about 10 % of all cases, genetic counseling is useful to discuss genetics and genetic testing with people who are at risk. As a system of peer-support, there are prion disease family support groups available in Japan and other countries. PMID- 17695283 TI - [Prevention of prion disease transmission]. AB - Prion infections lead to fatal diseases of the CNS, including Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy(BSE) in cows. Iatrogenic CJD which have been transmitted through dura-matter transplantation, administration of pituitary tissue extracts, corneal transplantation, or neurosurgical procedures. There are not thought to be infectious agents in blood of sporadic CJD patients. However three recipients of blood donated by individuals who subsequently developed variant CJD in United Kingdam. We introduce the guideline for CJD infection through medical procedure made in 2003 and arouse attention to risk of blood in variant CJD patients. PMID- 17695284 TI - [Epidemiological aspects of SSPE]. AB - SSPE is neurodegenerative complication of slow measles infection in young children. In developing countries, SSPE has become rare disease because of widespread immunization for measles. However, in under developing countries, it is not rare disease. In Japan, widespread measles vaccination started in 1978. From 1981 SSPE cases declined to about 5 patients per year. We studied 114 cases with SSPE who were still alive in 2003. Incidence of SSPE elevated to near 10 cases per year in 1993-1998 coincident with decline of the rate of immunization for measles. After 1999, the incidence is under 5 cases per year. The immunization rate of young children increased to over 90%, SSPE will become rare disease near future. Future problem will be adult or infant onset of SSPE because of decreasing of anti measles virus titer, SSPE in immunosuppressive state including AIDS or post measles vaccination SSPE. PMID- 17695285 TI - [Host genetic factors for the development of SSPE]. AB - Subacute sclerosing panencephalitis(SSPE) is a progressive and fatal neurological illness without established treatment. As the precise mechanism how measles virus (MV) causes SSPE is still unknown, full clarification of pathogenesis and pathophysiology is essential to establish effective strategy to treat the illness. Viral, host and environmental factors are involved in the development of SSPE. As host factors, immaturity of immune system and central nervous system are well recognized. Recently, we demonstrated that functional polymorphisms of MxA, interleukin(IL)-4 and interferon regulatory factor-1 (IRF-1) genes are associated with the development of SSPE in Japanese. High-density oligonucleotide microarray and subsequent quantitative reverse transcriptase-polymerase chain reaction demonstrated that the mRNA levels of granulysin were decreased in SSPE patients and were increased in measles patients, suggesting that granulysin might play a role in the host defense against MV and possibly be involved in the pathogenesis or pathophysiology of SSPE. In a Turkish study, association between angiotensin converting enzyme (ACE) gene polymorphism and SSPE was shown. PMID- 17695286 TI - [SSPE virus and pathogenesis]. AB - Subacute sclerosing panencephalitis (SSPE) is caused by particular mutants of measles virus, which are often referred to as SSPE virus. SSPE virus is characterized by (i) the inability to produce infectious viral particles, (ii) the neuropathogenicity in animal models as well as in humans, and (iii) the prolonged persistence in vivo over many years. The viral genome exhibits particular mutations, called biased hypermutation, most notably in the M gene, followed by the F and H genes. Consequently, the M, F and H proteins are mutated, which is thought to account for the characteristic features of SSPE virus. The possible mechanism of long-term persistence of the virus after the recovery of measles is also discussed. PMID- 17695287 TI - [Clinical course and findings in and differential diagnosis of subacute sclerosing panencephalitis]. AB - The clinical features of subacute sclerosing panencephalitis (SSPE) include the following : stage I, behavioral changes; stage II, myoclonus and motor deterioration; stage III, mental and motor deterioration to coma; stage IV, a vegetative state. Anti-measles titers of serum and cerebrospinal fluid (CSF) are elevated in the patients with SSPE. CSF IgG levels and IgG index are also elevated in SSPE. The characteristic electroencephalography in stage II of SSPE shows periodic high voltage slow wave bursts. In the early stage, psychiatric diseases and epilepsy should be ruled out. Neurodegenerative diseases and other encephalitis/encephalopathy should be also excluded. PMID- 17695288 TI - [Therapy and prognosis in subacute sclerosing panencephalitis]. AB - Subacute sclerosing panencephalitis (SSPE) is a progressive and fatal central nervous system disorder that results from a persistent SSPE virus infection. Compound which inhibits the replication of SSPE virus might be a candidate for the specific drug for SSPE. Out of several compounds which had been tried for the treatment of SSPE, two drugs, i.e., inosiplex and interferon-a were reported to be effective. Those drugs, however, could not cure the disease. Recently, ribavirin therapy has been proposed as novel antiviral chemotherapy for SSPE. By intraventricular administration, ribavirin level in CSF reaches a concentration at which ribavirin could completely inhibit the replication of SSPE virus. Thus, intraventricular ribavirin therapy might eradicate SSPE virus from the CNS and stop the progression of SSPE syndrome. The therapeutic efficacy should be evaluated in the patients who are treated with the therapy at an early stage of SSPE. PMID- 17695289 TI - [Review of progressive multifocal leukoencephalopathy]. AB - Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system caused by a reactivation of the JC virus (JCV). PML occurs almost exclusively in the setting of cellular immune deficiency and its prevalence has recently increased greatly, in line with the AIDS (acquired immunodeficiency syndrome) epidemic in Western countries. A Japanese epidemiological survey showed an increasing trend in the number of AIDS-PML cases. To date, there are no effective and specific therapies for PML. As patients with AIDS-PML may benefit from combined antiretroviral therapy, efforts to improve the immune status of such patients is therefore considered to be a key factor in achieving a successful outcome for PML cases. However, PML deficits are nevertheless expected to be permanent and most cases of PML result in death within a few months. It is therefore hoped that improvements in diagnostic modalities can be made which can eventually allow for the earlier detection of PML while, at the same time, improved curative therapies for PML can also be developed in the near future. PMID- 17695290 TI - [Etiological agent and pathogenicity mechanism of PML]. AB - JC virus (JCV) is a causative agent of progressive multifocal leukoencephalopathy (PML) that occurs mainly in immunosuppressed patients, especially those with HIV/AIDS. JCV belongs to the Polyomavirus that are characterized by non-enveloped icosahedral capsids containing small, circular, double-stranded DNA genomes. JCV is widely distributed among the population world-wide. However, infections are usually restricted by the immune system. In this article we briefly provide an overview of the interaction between JCV and host immunity. We also review the biological and physical characteristics and the lifecycle, receptors interaction, intracellular trafficking, viral transcription and replication, progeny virus propagation of JCV to examine the pathogenicity mechanism of PML. PMID- 17695291 TI - [Clinical characteristics, diagnostic criteria and treatment of progressive multifocal leukoencephalopathy]. AB - The clinical characteristics, diagnostic criteria and treatment of progressive multifocal leukoencephalopathy (PML) are reviewed. PML is characterized by rapid progression and poor outcome, and therefore requires the diagnosis and treatment as early as possible. Diffusion-weighted and diffusion tensor MRI were reported to be useful for the evaluation of disease activity of PML. The detection of JCV DNA in the cerebrospinal fluid by PCR has replaced the brain biopsy. Highly active antiretroviral therapy has improved both the survival rate and the neurological functions in HIV-associated PML. However, the treatment for immune reconstitution inflammatory syndrome, which often deteriorates neurological functions, has never been solved. PMID- 17695292 TI - [Development of animal model for understanding of pathogenesis of subacute sclerosing panencephalitis using non-human primates]. AB - Many animal models using experimental small animals for subacute sclerosing panencephalitis (SSPE) had been reported. But these models were not enough for understanding of pathogenesis of SSPE. After pathogenic measles virus was isolated with highly susceptible B95a cells, mimic infection of measles in human beings became easily produced in non-human primates. In this article, our attempt to develop SSPE model using cynomolgus monkeys will be introduced. PMID- 17695293 TI - [Prion diseases in animals--bovine spongiform encephalopathy]. AB - It has been two decades since bovine spongiform encephalopathy(BSE) was first recognized in UK. After the emergence in UK, BSE cases reported in European countries, North America, Israel and Japan. In UK, number of BSE cases turned to decline after 1993, and BSE cases are now decreasing in many European countries, suggesting the occurrence of BSE is hopefully coming to an end in near future. Although there are limitations on performing experiments such as long incubation periods and the use of cattle for pathogenetic studies, there are many research outcomes on BSE during the two decades and those are adapted for control measures for BSE. Extensive active surveillance of prion diseases in ruminants in European countries and Japan clarified the exact incidence of the diseases in ruminants, however, the surveillance also disclosed other concerns, for instance, the existence of atypical BSE cases and possibly BSE prion -infected goats in the field. PMID- 17695294 TI - [Dura mater related Creutzfeldt-Jakob disease in Japan: relationship between sites of grafts and clinical features]. AB - A nation wide survey demonstrated 129 case of CJD with cadaveric dura mater grafts in Japan to February 2007. These patients were identified to have received Lyodura during period between 1978 and 1991. Incubation period from grafting to the onset of symptoms varied from 16 months to 24.5 years. We conducted a retrospective review of the full medical records of 107 of these patients. Patients were divided into two groups by site of neurosurgical or orthopedic procedures (supratentorial vs. infratentorial). Hemiparesis or hemianopsia developed as an initial manifestation in 31.9% of 47 patients with supratentorial grafts but did not develop among nay of the infratentorial group (p<0.0001). Conversely, brainstem symptoms (nystagmus, diplopia, ipsilateral hearing loss, facial paresis or paresthesia) were noted in 25.0% of the infratentorial group, but were not seen in the supratentorial group (p<0.0001). PMID- 17695295 TI - [Novel approaches for therapeutic kidney regeneration]. AB - The discovery of tissue stem cells has launched the current boom in the field of regenerative research, which is tremendously exciting and holds enormous therapeutic potential. However, despite such optimism, recent findings have tempered the potential for medical practice especially in case of anatomically complicated and functionally sophisticated organs such as kidney and lung. This article reviews recent findings on renal stem cells and their possible application in therapeutic intervention for acute renal failure, as well as the intensive attempts to build a functional kidney de novo for chronic renal failure, which may truly progress the next stage from "regenerative medicine" to "regenerative therapy". PMID- 17695296 TI - [QOL of Japanese patients with GERD]. AB - Gastroesophageal reflux disease(GERD) has been reported to be a pathological condition that decreases quality of life(QOL) of patients because of the various troublesome symptoms. To measure QOL, generic and disease specific instruments have been used in western countries. In Japan, some of these instruments are translated into the Japanese and are used for the measurement of QOL of various diseases. QOL of the Japanese patients with GERD are measured with the Japanese version of SF-36 and GSRS. As reported in western countries, QOL of the Japan patients with GERD are reported to be significantly decreased in comparison with those of healthy individuals. PMID- 17695297 TI - [Clinical application of real-time tissue elastography to head and neck cancer- evaluation of cervical lymph node metastasis with real-time tissue elastography]. AB - Real-time tissue elastography (elastography) is a new ultrasonography procedure that display tissue elasticity. We evaluated the usefulness of elastography in the diagnosis of cervical lymph node metastasis and its treatment results in patients with head and neck cancer. Metastatic lymph nodes tended to produce little distortion when displayed as hard tumors, and produced distortion, displayed as soft tumors, after radiation therapy and/or chemotherapy. Elastography thus is useful as a potential new diagnostic procedure in the diagnosis of neck lymph node metastasis in head and neck cancer. PMID- 17695298 TI - [Clinical study of 28 cases of cervical lymph node metastasis from an unknown primary carcinoma]. AB - From 1989 to 2005, 28 patients--20 men and 8 women--with cervical lymph node metastasis from an unknown primary carcinoma were treated and studied retrospectively. In histological diagnosis, open biopsy was conducted in 11 patients and non-open biopsy (FNA or frozen section diagnosis during surgery) in 17. Blind biopsy under general anesthesia was conducted in 10 patients, showing one primary tumor in the nasopharynx. Tonsillectomy for diagnosis was not done. In region of maximum-size lymph node metastasis, the upper cervical region accounted for 22 cases (79%). The N stage of cervical lymph nodes was as follows: N2a in 4, N2b in 14, N2c in 3, and N3 in 7. The histopathological diagnosis of cervical lymph node was as follows: squamous cell carcinoma in 21, adenocarcinoma in 3, mucoepidermoid carcinoma in 2, and others in 2. Therapy was as follows: only neck dissection in 7, neck dissection with postoperative radiation therapy in 13, and irradiation and chemotherapy in 8. All patients treated with irradiation and chemotherapy had been judged to be inoperable. Seven patients were found to have a subsequent primary tumor. Primary tumor sites were as follows: tonsils in 3 and upper gingiva, base of tongue, lung, and nasopharynx in 1 each. FDG-PET was conducted in 7 patients but revealed no primary tumor. Overall 5-year survival in this study was 46%. We should pay particular attention to the tonsils for detecting primary tumors in patients with cervical metastasis from an unknown primary carcinoma. PMID- 17695299 TI - [A clinical study of 71 cases of acute epiglottitis]. AB - Acute epiglottitis causes sudden upper airway obstruction that may become lethal, and must be diagnosed and treated quickly and precisely. We review clinical features of 71-cases of acute epiglottitis in 6 years, focusing in cases requiring emergency airway management. Retrospective analysis was done for 1) age and gender, 2) month of onset, 3) symptoms, 4) smoking history, 5) diabetes history, 6) cause and background, 7) first medical institution visit, 8) duration from symptom onset to hospital visit, 9) oropharyngeal findings, 10) laryngendoscopic findings, 11) pharyngeal culture, and 12) deterioration after hospitalization. We found that 2 cases deteriorated in laryngendoscopic findings after hospitalization despite treatment. Even if the first medical findings are mild, it is necessary to respond to patients with the possibility to deterioration in mind. Five cases required emergency airway management-3 with tracheostomy and 2 cases with endotracheal intubation. If symptoms of laryngeal edema, oxygen desaturation, and dyspnea are present, emergency airway management should be prepared soon after hospitalization. PMID- 17695300 TI - [Clinical statistics of recurrent acute low-tone senseorineural hearing loss]. AB - Recently, acute low-tone senseorineural hearing loss (ALHL) has become common, and its good prognosis is known well. On the other hand, several reports have suggested that ALHL is frequently associated with Meniere's disease. We retrospectively examined the clinical course of 357 cases that were diagnosed and treated as ALHL at our hospitals. Forty-four of these cases that showed high-tone hearing loss in association with age-related changes were classified as atypical cases. The clinical futures of 49 "poor prognosis cases", who experienced recurrent hearing loss and/or profound hearing loss, are reported. Eight of the 49 cases who experienced recurrences had progressive hearing loss upto middle or high tones. Seventeen cases complained of vertiginous sensation, and 8 of these cases experienced recurrent attacks of vertigo and were diagnosed as having Meniere's disease. The former seventeen cases accounted for 34.7% of the "poor prognosis cases", and the latter eight accounted for 16.3% of these cases. Our results suggest that the hearing loss is more frequently associated with Meniere's disease in cases who experience recurrent hearing loss. Thus, cases initially diagnosed as ALHL may include some cases of progressive hearing loss and Meniere's disease. Even in cases in which hearing improvement is obtained, careful clinical observation is necessary, especially in older patients with bilateral affliction and atypical presentation. ALHL has been generally considered to have a good prognosis, however our examination revealed a relatively high frequency of recurrences, progressive hearing loss and complication by vertigo. We recommend, based on this evidence, that careful explanation of this disease is necessary at time of initial informed consent. PMID- 17695301 TI - [Picture in clinical hematology: NK/T-cell lymphoma showing intravascular lymphomatosis]. PMID- 17695302 TI - [Distinct genetic pathway in the molecular pathogenesis of MDS/AML with AML1/RUNX1 point mutations]. PMID- 17695303 TI - [Clinical analysis of HLA-DR-negative non-M3 AML]. AB - The type of leukemia was defined as HLA-DR(-) non-M3-AML, when HLA antigens were detected by flow cytometry at an incidence of < 20% of the blast population excluding M3-AML. Out of 109 patients with de novo acute myeloid leukemia, 8 patients had HLA-DR(-) non-AML-M3. According to the French-American-British criteria, 7 patients could be subdivided into 3 patients with M1, 4 patients with M2 and 1 patient with M4. The morphological features of bone marrow aspiration demonstrated no dysplasia and peroxidase stain positivity was noted in over 86% of the blast cells in all patients, the blast cells with fine granularity in 7 patients. The cytogenetic analysis revealed a normal karyotype. There was no expression marker of the blast antigens except CD13, CD14, CD33, CD34 and CD56. All of 7 patients who underwent induction therapy attained complete remission. Overall survival and disease-free survival showed no significant differences between the HLA-DR(-) non- M3-AML group and the HLA-DR(+) AML group. PMID- 17695304 TI - [Superior mesenteric and portal vein thrombosis in a polycythemia vera patient with JAK2 mutation]. AB - A 47-year-old woman was admitted to our hospital in December 1994 with polycythemia. The patient's red blood cell volume was 33 ml/kg and bone marrow cytology was able to rule out other myeloproliferative diseases such as chronic myelogenous leukemia, essential thrombocytosis and myelofibrosis. The patient was diagnosed as having polycythemia vera. She had undergone only phlebotomy until 1999 when the thrombocytosis appeared, subsequent to which she was treated with oral hydroxyurea. However, in March 2006, she developed upper abdominal pain and was admitted to our hospital on March 14th, 2006. Computed tomography scan revealed thromboses in the portal and superior mesenteric veins. Anticoagulation therapy delivered intravenously via the superior mesenteric vein dramatically improved her symptoms and liver function. She is currently on anticoagulation therapy in our outpatient clinic. PMID- 17695305 TI - [Hypercalcemia and multiple osteolytic lesions associated with proinflammatory cytokines in a patient with acute lymphoblastic leukemia]. AB - A 70-year-old man was admitted to the hospital with left ankle pain, also exhibiting severe consciousness disturbance. Laboratory findings showed not only hypercalcemia, but also increased serum levels of PTHrP and a few of proinflammatory cytokines, such as TNF-alpha, and IL-6. The X-ray and CT examinations revealed multiple osteolytic lesions, including the left tibia and fibula. Bone marrow aspiration revealed increased lymphoblasts (48%), and the patient was diagnosed as having acute lymphoblastic leukemia (ALL, L2). The hypercalcemia was successfully treated with calcitonin and bisphosphonate, and subsequently his consciousness status recovered rapidly. The bone marrow lymphoblast count decreased following combination chemotherapy, and a tendency towards improvement of the left ankle pain was also noted. However, he died of acute pneumonia and gastrointestinal bleeding. The postmortem findings showed leukemic cell involvement of the left tibia. The present case suggested that not only humoral hypercalcemia or local osteolytic hypercalcemia, but also proinflammatory cytokines were associated with multiple osteolysis and hypercalcemia. PMID- 17695306 TI - [Aggressive phase multiple myeloma with post-renal acute renal failure due to multiple extramedullary plasmacytomas]. AB - A 63-year-old woman was diagnosed as having multiple myeloma (MM), IgG-kappa type, stage IIIA, in October 2003. She achieved partial response after receiving three courses of VAD therapy and one course of high dose dexamethasone therapy (HDD); maintenance therapy consisted of melphalan and prednisolone. In November 2004, the patient developed spinal canal stenosis that required surgery. At the end of December 2004, the patient developed renal dysfunction that progressed to anuria. A CT scan showed multiple retroperitoneal masses that impinged on and obstructed both ureters and caused bilateral hydronephroses. Renal function improved after a right percutaneous nephrostomy and chemotherapy consisting of HDD, cyclophosphamide, vincristine, and doxorubicin. Nevertheless, the patient died due to MM in February 2005. On autopsy, multiple retroperitoneal and pelvic plasmacytomas with 13q- and t(4;14) (p16;q32) were found. Our patient is a rare case that, in the terminal stage of MM, developed aggressive phase multiple myeloma with extramedullary plasmacytomas that caused acute renal failure due to compression on both ureters. PMID- 17695307 TI - [Primary diffuse large B-cell lymphoma of the bone marrow complicated with autoimmune hemolytic anemia and erythroid hypoplasia]. AB - A 75-year-old woman was admitted for general fatigue. Diagnostic investigations showed no lymphadenopathy or hepatosplenomegaly. Laboratory examinations revealed severe anemia and an undetectable level of haptoglobin in the peripheral blood. A direct Coombs test was positive. Bone marrow examination showed abnormal, large, CD20-positive lymphocytes and erythroid hypoplasia. Accordingly, a diagnosis of primary diffuse large B-cell lymphoma (DLBCL) of the bone marrow with autoimmune hemolytic anemia (AIHA) and erythroid hypoplasia was made. The patient was treated with prednisolone and 3 courses of rituximab, followed by 6 courses of R CHOP. AIHA and erythroid hypoplasia subsided after prednisolone and 3 courses of rituximab. Treatment with 6 courses of R-CHOP resulted in complete remission. Isolated bone marrow disease as a presenting feature of DLBCL is very rare. Although malignant lymphomas are often associated with immunologic disorders, this is the first report of diffuse large B-cell lymphoma with isolated bone marrow disease and simultaneous autoimmune hemolytic anemia and erythroid hypoplasia. This case provides valuable information concerning the pathophysiology of an immunologic anomaly with malignant lymphoma. PMID- 17695308 TI - [Bone marrow-restricted involvement of T-cell granular lymphocyte leukemia]. AB - A 66-year-old female was referred to our hospital with bone pain and progressive pancytopenia with granular lymphocyte infiltration only in the bone marrow (BM). Flow cytometric and histological analyses revealed that these cells were positive for CD3, TCRalphabeta, granzyme B, and the diagnosis of T-cell granular lymphocyte leukemia (T-GLL) with myelofibrosis was made. These BM granular lymphocytes were greatly ruffled and showed the CD3/CD20 double positive phenotype, which was not detected in the peripheral blood. The patient was treated with a single course of fludarabine followed by a favorable clinical course for 3 months. Many of the BM lymphocytes displayed almost normal appearance after treatment, however, the number of lymphocytes in the BM did not decrease and these were still CD3/CD20 double positive. This is an overlap case of T-GLL and peripheral T-cell lymphoma, unspecified (PTCLu). PMID- 17695309 TI - [Recombinant factor VIII-CVP therapy for acquired factor VIII inhibitors]. AB - A 78-year-old man and an 81-year-old woman without hemophilia suddenly developed giant ecchymoses and intramuscular hemorrhage. Prolonged activated partial thromboplastin time and low factor VIII activity were observed, and the patients were subsequently diagnosed as having acquired factor VIII inhibitors. The patients were infused with one dose of recombinant factor VIII, 50 to 100 U/kg body weight, followed by cyclophosphamide, 500 mg on day 1 and 200 mg/day on days 2 to 5; vincristine, 2 mg on day 1; and prednisolone, 100 mg/day on days 1 to 5 (recombinant factor VIII-CVP therapy). Both patients responded after one course of therapy. Disappearance of inhibitors was achieved after three to four courses of therapy without subsequent recurrence. Recombinant factor VIII-CVP therapy is safe and effective in the eradication of factor VIII inhibitors. PMID- 17695310 TI - Sensitivity of cholinesterase of the Pacific squid Todarodes pacificus to organophosphorus inhibitors of various structure. PMID- 17695311 TI - Monoamine oxidase activity in chum salmon (Oncorhynchus keta) liver: substrate inhibitor specificity. PMID- 17695312 TI - Induction of double-stranded DNA breaks in mouse blood leukocytes by treating cells with iron-nitrosyl complexes. PMID- 17695313 TI - Antistress properties of melafen. PMID- 17695314 TI - A study of the composition of organic compounds in mouse reproductive organs at early pregnancy stages by proton magnetic resonance. PMID- 17695315 TI - The ion-radical mechanism of degradation of nucleoside triphosphate to nucleoside monophosphate in the presence of Mg2+ and the radical nature of synthesis of single-stranded DNA. PMID- 17695316 TI - Contribution of inducible and constitutive mechanisms to radioresistance acquisition by hamster malignant fibroblasts. PMID- 17695317 TI - Visualization of cancer cells by means of the fluorescent EGFP-barnase protein. PMID- 17695318 TI - Prediction of antigenically active regions in the OmpF-like porin of Yersinia pseudotuberculosis. PMID- 17695319 TI - Segment NS of influenza A virus contains an additional gene NSP in positive-sense orientation. PMID- 17695320 TI - Gonadotropins influence alkaline phosphatase activity in Drosophila virilis. PMID- 17695321 TI - Oxygen channels of erythrocyte membrane. PMID- 17695322 TI - Effect of diazoxide and Ca2+ on rat heart mitochondria loaded with Na+. PMID- 17695323 TI - The peptaibol antibiotic zervamicin displays neurotropic activity. PMID- 17695324 TI - Interaction of calcium-independent latrotoxin receptor with intracellular adapter protein TRIP8b. PMID- 17695325 TI - Amyloidogenic peptide homologous to beta-domain region of alpha-lactalbumin. PMID- 17695326 TI - Extreme properties of the genetic code markup. PMID- 17695327 TI - The specificity of thiosubstrates of cholinesterases of various origin. PMID- 17695328 TI - The metapsychology of the analyst. 1942. PMID- 17695329 TI - On "The metapsychology of the analyst," by Robert Fliess. PMID- 17695330 TI - The meanings and uses of countertransference. 1957. PMID- 17695331 TI - Racker's contribution to the understanding of countertransference revisited. PMID- 17695332 TI - The delicate balance of work and illusion in psychoanalysis. AB - One might say that the analyst counts on the patient's unconscious work, while conscious work is, to some extent, just one more thing to be deconstructed (analyzed). Analyst and patient, however, cannot avoid thinking that they are working on a common project, partly because the image of a mutual work distracts from the painfully uncertain illusion that the analyst is really offering a lasting, familial sort of bond, and partly because the sense of being involved in a joint project actually fosters the specific unconscious psychoanalytic work, provided that it is delicately balanced against the necessary illusion of the relationship. If, however, we choose to tilt the balance one way or the other, we must be prepared to make some sacrifices. PMID- 17695333 TI - On dreaming one's patient: reflections on an aspect of countertransference dreams. AB - This paper explores the phenomenon of the countertransference dream. Until very recently, such dreams have tended to be seen as reflecting either unanalyzed difficulties in the analyst or unexamined conflicts in the analytic relationship. While the analyst's dream of his/her patient may represent such problems, the author argues that such dreams may also indicate the ways in which the analyst comes to know the patient on a deep, unconscious level by processing the patient's communicative projective identifications. Two extended clinical examples of the author's countertransference dreams are offered. The author also discusses the use of countertransference dreams in psychoanalytic supervision. PMID- 17695334 TI - Neutrality and curiosity: elements of technique. AB - In the past three decades, neutrality has come under increasing criticism. The idea that a psychoanalyst can leave himself out of the therapeutic exchange has come to be seen as either an impossible dream or a myth. We propose that examining neutrality through the lens of curiosity allows for a new appreciation of the ongoing and vital importance of this psychoanalytic attitude. Our hypothesis is that curiosity and neutrality are linked, and that to maintain a neutral stance, the analyst must be able to direct a relatively conflict-free curiosity toward the workings of the analysand's mind as well as his own. PMID- 17695335 TI - Thinking about psychoanalytic curricula: an epistemological perspective. AB - The author discusses the role that curriculum development can play in preparing psychoanalytic candidates to understand the challenges created by theoretical pluralism in our field and by the growth of knowledge in neighboring disciplines. Curriculum design can be used to encourage the development of epistemological perspectives that can serve as organizing frameworks to help candidates think critically about psychoanalytic knowledge. It is possible to teach these complex matters in a way that students find accessible and useful. The author presents exemplars taken from the curriculum at the Columbia University Center for Psychoanalytic Training and Research in New York. PMID- 17695336 TI - On the fate of psychoanalysis and political theory. AB - The author explores the present structure of the relationship between psychoanalysis and political theory, finding that the two often attempt to integrate each other's findings as mere resources within the pursuit of fundamentally self-determined projects. This radically misconstrues the force and meaning of the insights upon which they draw. Especially when psychoanalytic interpretations of collective subjects (nations, regions, etc.) occur, the relationship between psychoanalysis and political theory may not be appropriately mediated, promoting suspiciousness about the interpretive and therapeutic efficacy of such nonclinical "interventions." The author proposes an alternative paradigm for a new working relationship between psychoanalysis and political theory. PMID- 17695337 TI - A note on notes: note taking and containment. AB - In extreme situations of massive projective identification, both the analyst and the patient may come to share a fantasy or belief that his or her own psychic reality will be annihilated if the psychic reality of the other is accepted or adopted (Britton 1998). In the example of' Dr. M and his patient, the paradoxical dilemma around note taking had highly specific transference meanings; it was not simply an instance of the generalized human response of distracted attention that Freud (1912) had spoken of, nor was it the destabilization of analytic functioning that I tried to describe in my work with Mr. L. Whether such meanings will always exist in these situations remains a matter to be determined by further clinical experience. In reopening a dialogue about note taking during sessions, I have attempted to move the discussion away from categorical injunctions about what analysis should or should not do, and instead to foster a more nuanced, dynamic, and pair-specific consideration of the analyst's functioning in the immediate context of the analytic relationship. There is, of course, a wide variety of listening styles among analysts, and each analyst's mental functioning may be affected differently by each patient whom the analyst sees. I have raised many questions in the hopes of stimulating an expanded discussion that will allow us to share our experiences and perhaps reach additional conclusions. Further consideration may lead us to decide whether note taking may have very different meanings for other analysts and analyst-patient pairs, and whether it may serve useful functions in addition to the one that I have described. PMID- 17695338 TI - Four roadblocks in approaching Masud Khan. PMID- 17695339 TI - Review of Masud Khan: The myth and the reality, by Roger Willoughby. PMID- 17695340 TI - Review of false self: The life of Masud Khan, by Linda Hopkins. PMID- 17695341 TI - Psychoanalytic ethics and psychoanalytic competence: lessons from the biographies of Masud Khan. PMID- 17695342 TI - CAPAS 2.0: a computer tool for coding transcribed and digitally recorded verbal reports. AB - A new computer software tool for coding and analyzing verbal report data is described. Combining and extending the capabilities of earlier verbal report coding software tools, CAPAS 2.0 enables researchers to code two different types of verbal report data: (1) verbal reports already transcribed and stored in text files and (2) verbal reports in their original digitally recorded audio format. For both types of data, individual verbal report segments are presented in random order and coded independently of other segments in accordance with a localized encoding principle. Once all reports are coded, CAPAS 2.0 converts the coded reports to a formatted file suitable for analysis by statistical packages such as SPSS. PMID- 17695343 TI - G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. AB - G*Power (Erdfelder, Faul, & Buchner, 1996) was designed as a general stand-alone power analysis program for statistical tests commonly used in social and behavioral research. G*Power 3 is a major extension of, and improvement over, the previous versions. It runs on widely used computer platforms (i.e., Windows XP, Windows Vista, and Mac OS X 10.4) and covers many different statistical tests of the t, F, and chi2 test families. In addition, it includes power analyses for z tests and some exact tests. G*Power 3 provides improved effect size calculators and graphic options, supports both distribution-based and design-based input modes, and offers all types of power analyses in which users might be interested. Like its predecessors, G*Power 3 is free. PMID- 17695344 TI - Word naming and psycholinguistic norms: Chinese. AB - In this article, we present normative data for 2,423 Chinese single-character words. For each word, we report values for the following 15 variables: word frequency, cumulative frequency, homophone density, phonological frequency, age of learning, age of acquisition, number of word formations, number of meanings, number of components, number of strokes, familiarity, concreteness, imageability, regularity, and initial phoneme. To validate the norms, we collected word-naming latencies. Factor analysis and multiple regression analysis show that naming latencies of Chinese single-character words are predicted by frequency, semantics, visual features, and consistency, but not by phonology. These analyses show distinct patterns in word naming between Chinese and alphabetic languages and demonstrate the utility of normative data in the study of nonalphabetic orthographic processing. PMID- 17695345 TI - Assessing the format of the presentation of text in developing a Reading Strategy Assessment Tool (R-SAT). AB - We are constructing a new computerized test of reading comprehension called the Reading Strategy Assessment Tool (R-SAT). R-SAT elicits and analyzes verbal protocols that readers generate in response to questions as they read texts. We examined whether the amount of information available to the reader when reading and answering questions influenced the extent to which R-SAT accounts for comprehension. We found that R-SAT was most predictive of comprehension when the readers did not have access to the text as they answered questions. PMID- 17695346 TI - A multimethod approach to examining usability of Web privacy polices and user agents for specifying privacy preferences. AB - Because all research methods have strengths and weaknesses, a multimethod approach often provides the best way to understand human behavior in applied settings. We describe how a multimethod approach was employed in a series of studies designed to examine usability issues associated with two aspects of online privacy: comprehension of privacy policies and configuration of privacy preferences for an online user agent. Archival research, user surveys, data mining, quantitative observations, and controlled experiments each yielded unique findings that, together, contributed to increased understanding of online-privacy issues for users. These findings were used to evaluate the accessibility of Web privacy policies to computer-literate users, determine whether people can configure user agents to achieve specific privacy goals, and discover ways in which the usability of those agents can be improved. PMID- 17695347 TI - Using temporal cohesion to predict temporal coherence in narrative and expository texts. AB - We investigated the linguistic features of temporal cohesion that distinguish variations in temporal coherence. In an analysis of 150 texts, experts rated temporal coherence on three continuous scale measures designed to capture unique representations of time. Coh-Metrix, a computational tool that assesses textual cohesion, correctly predicted the human ratings with five features of temporal cohesion. The correlations between predicted and actual scores were all statistically significant. In a complementary study, we explored the importance of temporal cohesion in characterizing genre. A discriminant function analysis, using Coh-Metrix temporal indices, successfully distinguished the genres of science, history, and narrative texts. The results suggested that history texts are more similar to narrative texts than to science texts in terms of temporal cohesion. PMID- 17695348 TI - iSTART 2: improvements for efficiency and effectiveness. AB - iSTART (interactive strategy training for active reading and thinking) is a Web based reading strategy trainer that develops students' ability to self-explain difficult text as a means to improving reading comprehension. Its curriculum consists of modules presented interactively by pedagogical agents: an introduction to the basics of using reading strategies in the context of self explanation, a demonstration of self-explanation, and a practice module in which the trainee generates self-explanations with feedback on the quality of reading strategies contained in the self-explanations. We discuss the objectives that guided the development of the second version of iSTART toward the goals of increased efficiency for the experimenters and effectiveness in the training. The more pedagogically challenging high school audience is accommodated by (1) a new introduction that increases interactivity, (2) a new demonstration with more and better focused scaffolding, and (3) a new practice module that provides improved feedback and includes a less intense but more extended regimen. Version 2 also benefits experimenters, who can set up and evaluate experiments with less time and effort, because pre- and posttesting has been fully computerized and the process of preparing a text for the practice module has been reduced from more than 1 person-week to about an hour's time. PMID- 17695349 TI - Sleep, sex, and the Web: surveying the difficult-to-reach clinical population suffering from sexsomnia. AB - One major advantage of Web-based research lies in its ability to reach and study people who have rare conditions of interest. Another advantage is that, due to the anonymity of the survey situation, the Internet is particularly suited for surveys on sensitive topics. Sexsomnia is a newly identified medical condition whose sufferers engage in sexual behavior during their sleep. Problematic cases are highly distressing and have forensic implications. The consensus among opinion leaders in sleep medicine is that sexsomnia may be quite common but that it often goes unreported because of shame and embarrassment. Thus, little is known about this condition's demographics and clinical features. This article reports findings from a sample analysis of 20 years of research on sexsomnia and discusses the results, strengths, and weaknesses of a recent Web-based survey conducted on the difficult-to-reach clinical population that suffers from sexsomnia. PMID- 17695350 TI - Using a computer simulation of three slot machines to investigate a gambler's preference among varying densities of near-miss alternatives. AB - The present article describes a software program in Visual Basic .NET designed to simulate three slot machines on a computer screen. This software is described in detail regarding utility, downloading, and usage; and data are presented illustrating the software's potential for researchers interested in gambling behavior. A simulation of multiple slot machines such as this enables researchers to evaluate players' preferences across various machines. In the highlighted experiment, 18 recreational slot machine players played the software for extra course credit and a chance at cash prizes. All participants played a version of the simulation in which every 5th response on average was a win, whereas the remaining trials were a loss. However, on those loss trials, a varying distribution of almost wins or near misses (i.e., two winning symbols on the payoff line and the final winning symbol directly above or below the payoff line) were presented in percentages of 15, 30, or 45. While no preferences across the three options could be predicted on the basis of reinforcement history alone, deviations from equal choices across the games were noted and appeared to be the result of the presentations of near-miss losing trials. Implications for a greater understanding of pathological gambling are presented. PMID- 17695351 TI - PC_Eyewitness: evaluating the New Jersey method. AB - One important variable in eyewitness identification research is lineup administration procedure. Lineups administered sequentially (one at a time) have been shown to reduce the number of false identifications in comparison with those administered simultaneously (all at once). As a result, some policymakers have adopted sequential administration. However, they have made slight changes to the method used in psychology laboratories. Eyewitnesses in the field are allowed to take multiple passes through a lineup, whereas participants in the laboratory are allowed only one pass. PC_Eyewitness (PCE) is a computerized system used to construct and administer simultaneous or sequential lineups in both the laboratory and the field. It is currently being used in laboratories investigating eyewitness identification in the United States, Canada, and abroad. A modified version of PCE is also being developed for a local police department. We developed a new module for PCE, the New Jersey module, to examine the effects of a second pass. We found that the sequential advantage was eliminated when the participants were allowed to view the lineup a second time. The New Jersey module, and steps we are taking to improve on the module, are presented here and are being made available to the research and law enforcement communities. PMID- 17695352 TI - DEWEX: a system for designing and conducting Web-based experiments. AB - DEWEX is a server-based environment for developing Web-based experiments. It provides many features for creating and running complex experimental designs on a local server. It is freeware and allows forboth using default features, for which only text input is necessary, and easy configurations that can be set up by the experimenter. The tool also provides log files on the local server that can be interpreted and analyzed very easily. As an illustration of how DEWEX can be used, a recent study is presented that demonstrates the system's most important features. This study investigated learning from multiple hypertext sources and shows the influences of task, source of information, and hypertext presentation format on the construction of mental representations of a hypertext about a historical event. PMID- 17695353 TI - An introduction to association rule mining: an application in counseling and help seeking behavior of adolescents. AB - Association rule mining (ARM) is a technique used to discover relationships among a large set of variables in a data set. It has been applied to a variety of industry settings and disciplines but has, to date, not been widely used in the social sciences, especially in education, counseling, and associated disciplines. This article thus introduces ARM and presents aspects of existing work that will be relevant and useful to researchers practitioners in the social sciences. Definitions and concepts are presented, and examples of ARM applications are highlighted to strengthen these ideas. We also discuss an example from our existing research to show that ARM can be used to investigate help-seeking behavior in a sample of secondary school students in Singapore. We also present some guidelines and recommendations for using ARM. PMID- 17695354 TI - HMMTree: a computer program for latent-class hierarchical multinomial processing tree models. AB - Latent-class hierarchical multinomial models are an important extension of the widely used family of multinomial processing tree models, in that they allow for testing the parameter homogeneity assumption and provide a framework for modeling parameter heterogeneity. In this article, the computer program HMMTree is introduced as a means of implementing latent-class hierarchical multinomial processing tree models. HMMTree computes parameter estimates, confidence intervals, and goodness-of-fit statistics for such models, as well as the Fisher information, expected category means and variances, and posterior probabilities for class membership. A brief guide to using the program is provided. PMID- 17695355 TI - Validating the Restricted Focus Viewer: a study using eye-movement tracking. AB - Investigation of cognitive processes and visual attention during problem-solving tasks is an important part of understanding human reasoning. Eyetracking technology has proven to have many benefits in revealing visual attention patterns. However, the high price of accurate eyetrackers and the difficulties associated with using them represent major obstacles to their wider application. Therefore, previous studies have sought to find alternatives to eyetracking. The Restricted Focus Viewer (RFV) brings a small part of an otherwise blurred display to the focus of visual attention: A user controls what part of the screen is in focus by using a computer mouse and explicitly selecting the area to be shown in focus. Recently, some studies have employed the RFV to investigate cognitive behavior of users, and some researchers have even enhanced the tool to study usability. We replicated a previous RFV-based study while also recording gaze data. We compared the attention allocation in time and space as reported by the RFV and an eyetracker. Further, we investigated the effects of RFV's display blurring on the visual attention allocation of 18 novice and expert programmers. Our results indicate that the data obtained from the two tools differ. Also, the RFV-blurring interferes with the strategies utilized by experts, and has an effect on fixation duration. However, task performance was preserved. PMID- 17695356 TI - EMuJoy: software for continuous measurement of perceived emotions in music. AB - An adequate study of emotions in music and film should be based on the real-time measurement of self-reported data using a continuous-response method. The recording system discussed in this article reflects two important aspects of such research: First, for a better comparison of results, experimental and technical standards for continuous measurement should be taken into account, and second, the recording system should be open to the inclusion of multimodal stimuli. In light of these two considerations, our article addresses four basic principles of the continuous measurement of emotions: (1) the dimensionality of the emotion space, (2) data acquisition (e.g., the synchronization of media and the self reported data), (3) interface construction for emotional responses, and (4) the use of multiple stimulus modalities. Researcher-developed software (EMuJoy) is presented as a freeware solution for the continuous measurement of responses to different media, along with empirical data from the self-reports of 38 subjects listening to emotional music and viewing affective pictures. PMID- 17695357 TI - Testing the race model inequality: an algorithm and computer programs. AB - In divided-attention tasks, responses are faster when two target stimuli are presented, and thus one is redundant, than when only a single target stimulus is presented. Raab (1962) suggested an account of this redundant-targets effect in terms of a race model in which the response to redundant target stimuli is initiated by the faster of two separate target detection processes. Such models make a prediction about the probability distributions of reaction times that is often called the race model inequality, and it is often of interest to test this prediction. In this article, we describe a precise algorithm that can be used to test the race model inequality and present MATLAB routines and a Pascal program that implement this algorithm. PMID- 17695358 TI - Automated measure of conditioned orienting behavior in rats. AB - The behavioral and neural mechanisms of orienting behavior have interested experimental psychologists for the last several decades. For example, in the framework of associative learning, examining the brain substrates of orienting behavior has yielded significant insight into the neural basis of attentional function and learning. The present study describes a procedure by which the orienting response to a visual stimulus (rearing on the hind legs) can be monitored automatically, and it validates the procedure by comparing data generated by the automated procedure with data generated by the typical observational procedure. The automated procedure provides an inexpensive means of obtaining immediate, online assessment of rearing behavior during a conditioning session, reduces the possibility of experimenter bias, and significantly reduces the time required to evaluate observational data. PMID- 17695359 TI - A methodology for the capture and analysis of hybrid data: a case study of program debugging. AB - This article describes a methodology for the capture and analysis of hybrid data. A case study in the field of reasoning with multiple representations- specifically, in computer programming--is presented to exemplify the use of the methodology. The hybrid data considered comprise computer interaction logs, audio recordings, and data about visual attention focus. The capture of the focus of visual attention data is performed with software. The software employed tracks the user's visual attention by blurring parts of the stimuli presented on the screen and allowing the participant to see only a small region of it at any one time. These hybrid data are analyzed via a methodology that combines qualitative and quantitative approaches. The article describes the software tool employed and the analytic methodology, and also discusses data capture issues and limitations of the approach. PMID- 17695360 TI - Applying the bootstrap to the multivariate case: bootstrap component/factor analysis. AB - The bootstrap method, which empirically estimates the sampling distribution for either inferential or descriptive statistical purposes, can be applied to the multivariate case. When conducting bootstrap component, or factor, analysis, resampling results must be located in a common factor space before summary statistics for each estimated parameter can be computed. The present article describes a strategy for applying the bootstrap method to conduct either a bootstrap component or a factor analysis with a program syntax for SPSS. The Holzinger-Swineford data set is employed to make the discussion more concrete. PMID- 17695361 TI - Multidimensional normative ratings for the International Affective Picture System. AB - The purpose of the present investigation was to replicate and extend the International Affective Picture System norms (Ito, Cacioppo, & Lang, 1998; Lang, Bradley, & Cuthbert, 1999). These norms were developed to provide researchers with photographic slides that varied in emotional evocation, especially arousal and valence. In addition to collecting rating data on the dimensions of arousal and valence, we collected data on the dimensions of consequentiality, meaningfulness, familiarity, distinctiveness, and memorability. Furthermore, we collected ratings on the primary emotions of happiness, surprise, sadness, anger, disgust, and fear. A total of 1,302 participants were tested in small groups. The participants in each group rated a subset of 18 slides on 14 dimensions. Ratings were obtained on 703 slides. The means and standard deviations for all of the ratings are provided. We found our valence ratings to be similar to the previous norms. In contrast, our participants were more likely to rate the slides as less arousing than in the previous norms. The mean ratings on the remaining 12 dimensions were all below the midpoint of the 9-point Likert scale. However, sufficient variability in ratings across the slides indicates that selecting slides on the basis of these variables is feasible. Overall, the present ratings should allow investigators to use these norms for research purposes, especially in research dealing with the interrelationships among emotion and cognition. The means and standard deviations for emotions may be downloaded as an Excel spreadsheet from www.psychonomic.org/archive. PMID- 17695362 TI - Predictors of timed picture naming in Chinese. AB - We report normative data collected from Mainland Chinese speakers for 232 objects taken from Snodgrass and Vanderwart (1980). These data include adult ratings of concept familiarity, age of acquisition (AoA), printed-word frequency, and word length (in syllables), as well as measures of rated visual complexity, image agreement, and name agreement. We then examined timed picture naming of these objects with native Chinese speakers in Beijing in two experiments using line drawings and colored pictures. In both experiments, the variables name agreement, rated concept familiarity, and AoA made significant independent contributions to naming latency in multiple regression analyses. We observed a correlation of r = .85 between naming latency with line drawings and colored pictures and a reduced effect of image agreement on naming when colored pictures were presented. We discuss the implications of our findings for the study of lexical processing in Chinese. Normative data for 232 Chinese nouns may be downloaded from www.psychonomic.org/archive. PMID- 17695363 TI - Topsy-turvy, loud and clear. PMID- 17695364 TI - Universal health care. PMID- 17695365 TI - Universal health care--the states take the lead. PMID- 17695366 TI - The 2007 session of the Maryland General Assembly: a focus on universal health care legislation. PMID- 17695367 TI - The 2007 session of the General Assembly with a compendium of Maryland insurance law. PMID- 17695368 TI - Task force seeks cure for inadequate physician reimbursement in Maryland. PMID- 17695369 TI - Picking the best employees for the job. AB - I have earned my gray hair honestly and have come to realize that one of the things that everyone wants and needs is respect. I hear it over and over again, on the street and in the office. So, I would close by saying that to be successful with employees is to respect them and expect them to respect others. PMID- 17695370 TI - The Irish contribution to modern medicine--19th century Dublin. PMID- 17695371 TI - Personalized nutrition: nutritional genomics as a potential tool for targeted medical nutrition therapy. AB - An emerging goal of medical nutrition therapy is to tailor dietary advice to an individual's genetic profile. In the United States and elsewhere, "nutrigenetic" services are available over the Internet without the direct involvement of a health care professional. Among the genetic variants most commonly assessed by these companies are those found in genes that influence cardiovascular disease risk. However, the interpretation of DNA-based data is complex. The goal of this paper is to carefully examine nutritional genomics as a potential tool for targeted medical nutrition therapy. The approach is to use heart health susceptibility genes and their common genetic variants as the model. PMID- 17695372 TI - Probiotics: a critical review of their potential role as antihypertensives, immune modulators, hypocholesterolemics, and perimenopausal treatments. AB - The conventional use of probiotics to modulate gastrointestinal health, such as in improving lactose intolerance, increasing natural resistance to infectious diseases in the gastrointestinal tract, suppressing traveler's diarrhea, and reducing bloating, has been well investigated and documented. Most of the mechanisms reported to date are mainly caused by the suppression of pathogenic bacteria. Currently, the potential applications of probiotics are being expanded beyond alleviating gastrointestinal disorders to include benefits involving antihypertension, immunomodulation, improving serum lipid profiles, and the alleviation of postmenopausal disorders. Although they seem promising, most of these postulated benefits are based on in vitro evaluations, and the lack of in vivo evidence and/or incompatible outcomes between in vitro experiments and in vivo trials has led to inconclusive claims. This present review highlights some of the previous roles of probiotics on gut health and addresses several potential roles currently being investigated. PMID- 17695373 TI - The importance of nutrition status assessment: the case of severe acute pancreatitis. AB - Severe acute pancreatitis is associated with high mortality. Adequate nutrition support improves clinical outcome. Nevertheless, several recent trials have focused primarily on the route of nutrition support and neglected the role of nutrition status assessment in tailoring nutrition support to individual needs. PMID- 17695374 TI - Steap proteins: implications for iron and copper metabolism. AB - Erythroid cells of the bone marrow, the most avid consumers of iron in the body, acquire ferric (Fe3+) iron exclusively via the transferrin cycling pathway. A long-standing fundamental molecular question of how ferric iron is handled in this pathway has been recently resolved by the identification of Steap3 (sixtransmembrane epithelial antigen of the prostate 3) as an endosomal ferrireductase needed for efficient utilization of transferrin-delivered iron. Further characterization of Steap3 and other Steap proteins reveals a possible greater role of Steap proteins in iron and copper metabolism. PMID- 17695375 TI - Flatiron mice and ferroportin disease. AB - Flatiron mice provide the first genetic model that fully recapitulates the iron loading disorder ferroportin disease. Unlike the other known genetic causes of hemochromatosis, missense mutations in the ferroportin gene are autosomal dominant. These new findings show that ferroportin disease results from dominant negative effects rather than haplo-insufficiency. PMID- 17695376 TI - Antiepileptic drugs and subarachnoid hemorrhage. PMID- 17695377 TI - Outcome in patients with subarachnoid hemorrhage treated with antiepileptic drugs. AB - OBJECT: Prophylactic use of antiepileptic drugs (AEDs) in patients admitted with aneurysmal subarachnoid hemorrhage (SAH) is common practice; however, the impact of this treatment strategy on in-hospital complications and outcome has not been systematically studied. The goal in this study was twofold: first, to describe the prescribing pattern for AEDs in an international study population; and second, to delineate the impact of AEDs on in-hospital complications and outcome in patients with SAH. METHODS: The authors examined data collected in 3552 patients with SAH who were entered into four prospective, randomized, double blind, placebo-controlled trials conducted in 162 neurosurgical centers and 21 countries between 1991 and 1997. The prevalence of AED use was assessed by study country and center. The impact of AEDs on in-hospital complications and outcome was evaluated using conditional logistic regressions comparing treated and untreated patients within the same study center. RESULTS: Antiepileptic drugs were used in 65.1% of patients and the prescribing pattern was mainly dependent on the treating physicians: the prevalence of AED use varied dramatically across study country and center (intraclass correlation coefficients 0.22 and 0.66, respectively [p < 0.001]). Other predictors included younger age, worse neurological grade, and lower systolic blood pressure on admission. After adjustment, patients treated with AEDs had odds ratios of 1.56 (95% confidence interval [CI] 1.16-2.10; p = 0.003) for worse outcome based on the Glasgow Outcome Scale; 1.87 (95% CI 1.43-2.44; p < 0.001) for cerebral vasospasm; 1.61 (95% CI 1.25-2.06; p < 0.001) for neurological deterioration; 1.33 (95% CI 1.01 1.74; p = 0.04) for cerebral infarction; and 1.36 (95% CI 1.03-1.80; p = 0.03) for elevated temperature during hospitalization. CONCLUSIONS: Prophylactic AED treatment in patients with aneurysmal SAH is common, follows an arbitrary prescribing pattern, and is associated with increased in-hospital complications and worse outcome. PMID- 17695378 TI - Intraventricular hemorrhage from ruptured aneurysm: clinical characteristics, complications, and outcomes in a large, prospective, multicenter study population. AB - OBJECT: In this study the authors analyzed the relationship of intraventricular hemorrhage (IVH) to in-hospital complications and clinical outcome in a large population of patients with aneurysmal subarachnoid hemorrhage (SAH). METHODS: Data from 3539 patients with aneurysmal SAH were evaluated, and these data were obtained from four prospective, randomized, double-blind, placebo-controlled trials of tirilazad that had been conducted between 1991 and 1997. Clinical characteristics, in-hospital complications, and outcome at 3 months post-SAH (Glasgow Outcome Scale score) were analyzed with regard to the presence or absence of IVH. RESULTS: Patients with SAH and IVH differ in demographic and admission characteristics from those with SAH but without IVH and are more likely to suffer in-hospital complications and a worse outcome at 3 months post-SAH. CONCLUSIONS: The presence of IVH in patients with SAH has an important predictive value with regard to these aspects. PMID- 17695379 TI - World's first magnetic resonance imaging/x-ray/operating room suite: a significant milestone in the improvement of neurosurgical diagnosis and treatment. AB - OBJECT: In February 2006, the magnetic resonance/x-ray/operating room (MRXO) suite opened at the authors' institution. This is the first hybrid neurosurgical procedure suite to combine magnetic resonance (MR) imaging, computed tomography (CT), and angiography within a neurosurgical operating room (OR). In the present paper the authors describe the concept of the MRXO as well as their first 10 months of experience using this suite, and discuss its advantages and limitations. METHODS: In the MRXO suite, the combined OR and angiography (OR angiography) station is located in the middle of the suite, and the MR imaging and CT scanning stations are each installed in an adjoining bay connected to the OR-angiography station by shielded sliding doors. The surgical, MR imaging, angiography, and CT tables are positioned in order of use. The patient lies on a fully MR imaging- and radiography-compatible mobile patient tabletop that is used to move the patient quickly and safely among the tables in the imaging and operating components of the MRXO suite. RESULTS: The authors performed all interventional procedures safely. The specially designed operating tabletop of the MRXO suite reduced the limitations on neurosurgeons during standard neurosurgical procedures. This hybrid suite helps to provide high-quality intraoperative imaging, greatly reducing the risk of unexpected events during the procedure. CONCLUSIONS: The MRXO suite, which combines OR and imaging equipment, represents a significant milestone in the improvement of neurosurgical diagnosis and treatment and other interventional procedures. Another advantage of the MRXO suite is its cost-effectiveness, which is partly due to its streamlined imaging procedure. PMID- 17695380 TI - Enhancement of cerebral blood flow using systemic hypertonic saline therapy improves outcome in patients with poor-grade spontaneous subarachnoid hemorrhage. AB - OBJECT: Systemic administration of 23.5% hypertonic saline enhances cerebral blood flow (CBF) in patients with poor-grade spontaneous subarachnoid hemorrhage (SAH). Whether the increment of change in CBF correlates with changes in autoregulation of CBF or outcome at discharge remains unknown. METHODS: Thirty five patients with poor-grade spontaneous SAH received 2 ml/kg 23.5% hypertonic saline intravenously, and they underwent bedside transcranial Doppler (TCD) ultrasonography and intracranial pressure (ICP) monitoring. Seventeen of them underwent Xe-enhanced computed tomography (CT) scanning for measuring CBF. Outcome was assessed using the modified Rankin Scale (mRS) at discharge from the hospital. The data were analyzed using repeated-measurement analysis of variance and Dunnett correction. A comparison was made between patients with favorable and unfavorable outcomes using multivariate logistic regression. RESULTS: The authors observed a maximum increase in blood pressure by 10.3% (p < 0.05) and cerebral perfusion pressure (CPP) by 21.2% (p < 0.01) at 30 minutes, followed by a maximum decrease in ICP by 93.1% (p < 0.01) at 60 minutes. Changes in ICP and CPP persisted for longer than 180 and 90 minutes, respectively. The results of TCD ultrasonography showed that the baseline autoregulation was impaired on the ipsilateral side of ruptured aneurysm, and increments in flow velocities were higher and lasted longer on the contralateral side (48.75% compared with 31.96% [p = 0.045] and 180 minutes compared with 90 minutes [p < 0.05], respectively). The autoregulation was briefly impaired on the contralateral side during the infusion. A dose-dependent effect of CBF increments on favorable outcome was seen on Xe-CT scans (mRS Score 1-3, odds ratio 1.27 per 1 ml/100 g tissue x min, p = 0.045). CONCLUSIONS: Bolus systemic hypertonic saline therapy may be used for reversal of cerebral ischemia to normal perfusion in patients with poor-grade SAH. PMID- 17695381 TI - Assessment of brain aneurysms by using high-resolution magnetic resonance angiography after endovascular coil delivery. AB - OBJECT: Digital subtraction (DS) angiography is the current gold standard of assessing intracranial aneurysms after coil placement. Magnetic resonance (MR) angiography offers a noninvasive, low-risk alternative, but its accuracy in delineating coil-treated aneurysms remains uncertain. The objective of this study, therefore, is to compare a high-resolution MR angiography protocol relative to DS angiography for the evaluation of coil-treated aneurysms. METHODS: In 2003, the authors initiated a prospective protocol of following up patients with coil-treated brain aneurysms using both 1.5-tesla gadolinium-enhanced MR angiography and biplanar DS angiography. Using acquired images, the subject aneurysm was independently scored for degree of remnant identified (complete obliteration, residual neck, or residual aneurysm) and the surgeon's ability to visualize the parent vessel (excellent, fair, or poor). RESULTS: Thirty-seven patients with 42 coil-treated aneurysms were enrolled for a total of 44 paired MR angiography-DS angiography tests (median 9 days between tests). An excellent correlation was found between DS and MR angiography for assessing any residual aneurysm, but not for visualizing the parent vessel (K = 0.86 for residual aneurysm and 0.10 for parent vessel visualization). Paramagnetic artifact from the coil mass was minimal, and in some cases MR angiography identified contrast permeation into the coil mass not revealed by DS angiography. An intravascular microstent typically impeded proper visualization of the parent vessel on MR angiography. CONCLUSIONS: Magnetic resonance angiography is a noninvasive and safe means of follow-up review for patients with coil-treated brain aneurysms. Compared with DS angiography, MR angiography accurately delineates residual aneurysm necks and parent vessel patency (in the absence of a stent), and offers superior visualization of contrast filling within the coil mass. Use of MR angiography may obviate the need for routine diagnostic DS angiography in select patients. PMID- 17695382 TI - The role of exudation in chronic subdural hematomas. AB - OBJECT: Chronic subdural hematomas (SDHs) are a local inflammatory process that causes the formation of a granulation tissue often referred to as the external or outer membrane. This membrane has abnormally permeable macrocapillaries. Therefore, exudation from the macrocapillaries in the outer membrane of chronic SDH may play an important role in the enlargement of chronic SDH. In this study the authors investigated the role of exudation in chronic SDH. METHODS: The authors examined 24 patients (16 men and eight women; age range 38-86 years [mean age 61.4 years]) with 27 chronic SDHs. The clinical status of the patients was evaluated according to the classification described by Markwalder. The diagnosis was established on computed tomography (CT) scans in all cases. The authors also used the Nomura Classification for judging the lesion's appearance on CT scans. Immediately after the diagnosis, all patients were administered 20 mCi (740 mBq) technetium-99m human serum albumin. Four hours later, blood and SDH samples were taken and radioactivity levels were measured in each. The ratio of activity of the samples taken from chronic SDH to the radioactivity of blood was determined as a percentage and defined as the exudation rate. On the follow-up CT scan obtained on postoperative Day 20, subdural collections thicker than 5 mm were determined to be a reaccumulation. RESULTS: The correlations between the exudation rate and age of the patients, clinical grades, CT appearances, and amount of reaccumulation were investigated. In this series the average exudation rate was 13.24% (range 2.05-28.88%). The mean exudation rates according to the clinical grades assigned to patients were as follows: Grade 0, 8.67 +/- 5.64% (three patients); Grade 1, 5.07 +/- 1.43% (eight patients); Grade 2, 17.87 +/- 3.73% (seven patients); and Grade 3, 19.65 +/- 7.67% (six patients). Exudation rates in patients with Grades 2 and 3 were significantly higher than those in Grades 0 and 1 (p < 0.05). The mean exudation rates according to the lesion's appearance on CT scans were found as follows: hypodense appearance, 6.55 +/- 4.52% (eight patients); isodense appearance, 11.07 +/- 6.32% (five patients); hyperdense appearance, 19.47 +/- 13.61% (three patients); and mixed-density appearance, 17.40 +/- 5.80% (nine patients). The differences among the groups were significant (p < 0.05). The average exudation rate was statistically higher in the patients with reaccumulation (16.30 +/- 8.16%) than that in the patients without reaccumulation (9.96 +/- 6.84%) (p < 0.05). CONCLUSIONS: The exudation rate in chronic SDH is correlated with a higher clinical grade (Markwalder Grade 2 or 3), mixed-density CT appearance, and reaccumulation. Therefore, exudation from macrocapillaries in the outer membrane of chronic SDH probably plays an important role in the pathophysiology and the growth of chronic SDH. PMID- 17695383 TI - Dynamic phases of peroneal and tibial intraneural ganglia formation: a new dimension added to the unifying articular theory. AB - OBJECT: The pathogenesis of intraneural ganglia has been a controversial issue for longer than a century. Recently the authors identified a stereotypical pattern of occurrence of peroneal and tibial intraneural ganglia, and based on an understanding of their pathogenesis provided a unifying articular explanation. Atypical features, which occasionally are observed, have offered an opportunity to verify further and expand on the authors' proposed theory. METHODS: Three unusual cases are presented to exemplify the dynamic features of peroneal and tibial intraneural ganglia formation. RESULTS: Two patients with a predominant deep peroneal nerve deficit shared essential anatomical findings common to peroneal intraneural ganglia: namely, 1) joint connections to the anterior portion of the superior tibiofibular joint, and 2) dissection of the cyst along the articular branch of the peroneal nerve and proximally. Magnetic resonance (MR) images obtained in these patients demonstrated some unusual findings, including the presence of a cyst within the tibial and sural nerves in the popliteal fossa region, and spontaneous regression of the cysts, which was observed on serial images obtained weeks apart. The authors identified a clinical outlier, a case that could not be understood within the context of their previously reported theory of intraneural ganglion cyst formation. Described 32 years ago, this patient had a tibial neuropathy and was found at surgery to have tibial, peroneal, and sciatic intraneural cysts without a joint connection. The authors' hypothesis about this case, based on their unified theory, was twofold: 1) the lesion was a primary tibial intraneural ganglion with proximal extension followed by sciatic cross-over and distal descent; and 2) a joint connection to the posterior aspect of the superior tibiofibular joint with a remnant cyst within the articular branch would be present, a finding that would help explain the formation of different cysts by a single mechanism. The authors proved their hypothesis by careful inspection of a recently obtained postoperative MR image. CONCLUSIONS: These three cases together with data obtained from a retrospective review of the authors' clinical material and findings reported in the literature provide firm evidence for mechanisms underlying intraneural ganglia formation. Thus, expansion of the authors' unified articular theory permits understanding and elucidation of unusual presentations of intraneural cysts. Whereas an articular connection and fluid following the path of least resistance was pivotal, the authors now incorporate dynamic aspects of cyst formation due to pressure fluxes. These basic principles explain patterns of ascent, cross-over, and descent down terminal nerve branches based on articular connections, paths of diminished resistance to fluid flow within recognized anatomical compartments, and the effects of fluctuating pressure gradients. PMID- 17695384 TI - Brachial plexus injuries: outcome following neurotization with intercostal nerve. AB - OBJECT: Brachial plexus root avulsion injuries, which are devastating, usually result from high-speed accidents. Nerve transfer provides hope for successful treatment of this difficult set of injuries. Nevertheless, the controversies regarding indications, techniques, and outcome of the various available surgical procedures continue. METHODS: A retrospective analysis was performed in 51 patients (43 male and eight female patients) with brachial plexus injuries who underwent neurotization at the authors' institute between 1997 and 2003. Clinical, electrophysiological, and imaging data were used to identify the type and pattern of involvement of the various elements of the plexus. The mean duration of denervation was 6.4 months (range 2-24 months). Outcome was computed in terms of the overall improvement in power of the target muscle as well as the functional usefulness of such recovery. RESULTS: There were 50 supraclavicular injuries (25 preganglionic, eight postganglionic, and 17 mixed). One patient had an infraclavicular (posterior spinal cord) injury. Pan-brachial plexus injury with a flail upper limb was the most common pattern. Overall, 55 nerves were neurotized-33 musculocutaneous, 18 axillary, and two each for ulnar and radial nerves (47 single and four double neurotizations-by using intercostal nerve donors in the majority of cases. Adequate follow-up data were available in 36 patients (38 nerves) and these were used for the analysis of outcome. Overall, 58.3% of patients had improvement, and of these 62% achieved useful recovery. This accounted for 36% of overall useful recovery. Multiple logistic regression analysis revealed that regardless of age, sex, mode and pattern of injury, and recipient nerve, the duration of denervation showed a trend toward significance that correlated with overall (but not useful) improvement. The critical duration of denervation was 5.5 months. CONCLUSIONS: Neurotization for brachial plexus root avulsion injuries is a viable option. Early detection and intervention (within 5.5 months) leads to a better overall recovery. PMID- 17695385 TI - Patient outcome after common peroneal nerve decompression. AB - OBJECT: This study examines common peroneal nerve decompression and its effect on nerve function. METHODS: Fifty-one peroneal nerve decompressions were retrospectively reviewed. All patients were evaluated preoperatively and postoperatively for motor and sensory function of the peroneal nerve as well as for pain. RESULTS: Postoperatively, 40 (83%) of 48 patients who had preoperative motor weakness had improvement in motor function. Likewise, 23 (49%) of 47 patients who had sensory disturbances and 26 (84%) of 31 patients who had preoperative pain improved after surgical decompression of the peroneal nerve. CONCLUSIONS: Common peroneal nerve decompression is a useful procedure to improve sensation and strength as well as to decrease pain. PMID- 17695386 TI - Chordomas of the skull base: surgical management and outcome. AB - OBJECT: The goal of this study was to report on the surgical management of skull base chordomas and to evaluate both the short- and long-term treatment outcomes. METHODS: The authors retrospectively studied data from 49 patients who had undergone consecutive surgeries at a single institution. They also analyzed patterns of chordoma extension. Complications and surgery-related morbidity were recorded. A Kaplan-Meier analysis was performed to determine survival rates in patients 5 and 10 years after their first surgery. Operative approaches were selected on the basis of the predominant tumor extension. RESULTS: The approach used most frequently was the transethmoidal in 36.3%, followed by the pterional in 23.4% and the retrosigmoid in 23.4%. The tumor was totally removed in 49.4% and subtotally in 50.6%. The rate of total removal was highest at initial surgery (78%) and progressively declined thereafter. In 11.8% of cases a new neurological deficit developed, while the preoperative deficit remained unchanged. In 20% of cases the preoperative deficits improved, but new deficits also appeared. The 5- and 10-year survival rates are 65 and 39%, respectively. CONCLUSIONS: With an individually tailored surgical approach, total tumor removal in 78% of the cases was achieved at the initial surgery. Radical surgery appears to increase slightly the surgical morbidity, but at the same time prolongs the recurrence-free interval. Chordomas cannot be regarded as surgically curable tumors given the 5- and 10-year survival rates in patients harboring such lesions. PMID- 17695387 TI - Gamma Knife surgery for benign meningioma. AB - OBJECT: Meningioma is the most frequent benign tumor treated with Gamma Knife surgery (GKS); however, the assessment of its efficacy and safety in slow-growing tumors is an ongoing process, requiring analysis of long-term results. METHODS: Three hundred sixty-eight patients harboring 400 meningiomas treated between 1992 and 1999 at Na Homolce Hospital were evaluated. The median patient age was 57 years (range 18-84 years). The median tumor volume was 4.4 cm3 (range 0.11-44.9 cm3). The median tumor margin dose to the 50% isodose line was 12.55 Gy (range 6.5-24 Gy). Descriptive analysis was performed in 331 patients (90%); 325 patients had a follow-up longer than 24 months (median 60 months), and six patients were included because of posttreatment complications. The volume of treated tumors decreased in 248 cases (69.7%), remained the same in 99 (27.8%), and increased in nine (2.5%). The actuarial tumor control rate was 97.9% at 5 years post-GKS. Perilesional edema after radiosurgery was confirmed on neuroimaging in 51 patients (15.4%). The temporary and permanent morbidity rates after radiosurgery were 10.2 and 5.7%, respectively. RESULTS: A significantly higher incidence of tumor volume increase was observed in men compared with women and in tumors treated with a margin dose lower than 12 Gy. Significant risk factors for edema included an age greater than 60 years, no previous surgery, perilesional edema before radiosurgery, a tumor volume greater than 10 cm3, a tumor location in the anterior fossa, and a margin dose greater than 16 Gy. CONCLUSIONS: Stereotactic radiosurgery is a safe method of treatment for meningiomas. A minimum margin dose of 12 to 16 Gy seems to represent the therapeutic window for benign meningiomas with a high tumor control rate in a mid term follow-up period. PMID- 17695388 TI - Postoperative improvement in visual function in patients with tuberculum sellae meningiomas: results of the extended transsphenoidal and transcranial approaches. AB - OBJECT: Recently, extended transsphenoidal surgery (ETSS) has become an alternative to transcranial surgery (TCS) for suprasellar meningiomas, although the relative benefits of ETSS have yet to be established. To evaluate the effectiveness of ETSS, the authors analyzed surgical outcomes of TCS and ETSS. METHODS: During a 12-year period, 28 patients with meningiomas arising from the tuberculum sellae underwent tumor removal at Kinki University Hospital. The first 12 patients underwent TCS, and the remaining 16 underwent ETSS. In the TCS group, the optic canal on the approach side was unroofed in all cases. In the ETSS group bilateral optic canals were opened, and the dural and bone defects of the skull base were repaired using abdominal fascia and hydroxyapatite cement. In half of the cases, lumbar drainage of cerebrospinal fluid (CSF) was also performed. RESULTS: In a retrospective analysis of this consecutive series of patients, improvement in visual acuity and intraoperative blood loss were significantly better in the ETSS group (p = 0.010 and p = 0.011, respectively), whereas improvement in visual field defects, operative times, and the tumor removal rate were not significantly different between the two groups. Nonvisual surgical complications such as CSF leakage (one patient) and infarction of a perforating artery (three patients) were observed in the TCS group. In the ETSS group, CSF leakage (two patients), anosmia (two patients), and infarction of a perforating artery (two patients) were observed. CONCLUSIONS: Given the encouraging results in improvement in visual acuity, ETSS may be acceptable for the treatment of tuberculum sellae meningiomas. PMID- 17695389 TI - Reduction of cerebrospinal fluid rhinorrhea after vestibular schwannoma surgery by reconstruction of the drilled porus acusticus with hydroxyapatite bone cement. AB - OBJECT: Cerebrospinal fluid (CSF) rhinorrhea remains a significant cause of morbidity after resection of vestibular schwannomas (VSs), with rates of rhinorrhea after this procedure reported to range between 0 and 27%. The authors investigated whether reconstruction of the drilled posterior wall of the porus acusticus with hydroxyapatite cement (HAC) would decrease the incidence of postoperative CSF rhinorrhea. METHODS: A prospective observational study of 130 consecutive patients who underwent surgery for reconstruction of the posterior wall of the drilled porus acusticus with HAC was conducted between October 2002 and September 2005. All patients underwent a retrosigmoid transmeatal approach for VS resection and were followed up to document cases of CSF rhinorrhea, incisional CSF leak, meningitis, or rhinorrhea-associated meningitis. A cohort of 150 patients with VSs who were treated with the same surgical approach but without HAC reconstruction served as a control group. RESULTS: The authors found that HAC reconstruction of the porus acusticus wall significantly reduced the rate of postoperative CSF rhinorrhea in their patients. In the patients treated with HAC, rhinorrhea developed in only three patients (2.3%) compared with 18 patients (12%) in the control group. This was a statistically significant finding (p = 0.002, odds ratio = 5.8). CONCLUSIONS: The use of HAC in the reconstruction of the drilled posterior wall of the porus acusticus, occluding exposed air cells, greatly reduces the risk of CSF rhinorrhea. PMID- 17695390 TI - Usefulness of 123I-iomazenil single-photon emission computed tomography in discriminating between mesial and lateral temporal lobe epilepsy in patients in whom magnetic resonance imaging demonstrates normal findings. AB - OBJECT: To provide greater accuracy in determining the epileptogenic zone during preoperative evaluation, the authors retrospectively examined 123I-iomazenil single-photon emission computed tomography (IMZ SPECT) studies obtained in patients with temporal lobe epilepsy (TLE) in whom there was no evidence of an abnormality on magnetic resonance (MR) images. METHODS: Twelve patients, seven with mesial TLE (MTLE) and five with lateral TLE (LTLE), satisfied the criteria for inclusion in the study. The IMZ SPECT findings in these patients were reviewed retrospectively, and a comparison was made between findings in patients with MTLE and those in patients with LTLE. RESULTS: The IMZ SPECT studies demonstrated decreased IMZ uptake in the ipsilateral mesial temporal region and the anterobasal temporal lobe in all patients who had MTLE on only one side. On the other hand, IMZ SPECT examinations revealed low IMZ uptake in the ipsilateral lateral temporal lobe in four of five patients with LTLE in whom abnormal findings were restricted to the lateral neocortex. In the remaining patient with LTLE, abnormally low IMZ uptake was found in both mesial and lateral temporal lobes, although pure LTLE was diagnosed by an invasive electroencephalographic evaluation; this patient's habitual seizures continued even after temporal lobectomy, although his mesial structures were spared. CONCLUSIONS: The authors report characteristics of IMZ SPECT findings that differed between patients with MTLE and those with LTLE. The IMZ SPECT examinations proved useful for preoperative evaluation and, to a certain extent, for discrimination between MTLE and LTLE in cases in which MR imaging demonstrated normal findings. The results of this study suggest that IMZ SPECT findings may reflect localization of the epileptogenic zone. PMID- 17695391 TI - Incidence and pattern of direct blunt neurovascular injury associated with trauma to the skull base. AB - OBJECT: Skull base fractures are often associated with potentially devastating injuries to major neural arteries in the head and neck, but the incidence and pattern of this association are unknown. METHODS: Between April and September 2002, 1738 Level 1 trauma patients were admitted to St. Joseph's Hospital and Medical Center in Phoenix, Arizona. Among them, a skull base fracture was diagnosed in 78 patients following computed tomography (CT) scans. Seven patients had no neurovascular imaging performed and were excluded. Altogether, 71 patients who received a diagnosis of skull base fractures after CT and who also underwent a neurovascular imaging study were included (54 men and 17 women, mean age 29 years, range 1-83 years). Patients underwent CT angiography, magnetic resonance angiography, or digital subtraction angiography of the head and craniovertebral junction, or combinations thereof. RESULTS: Nine neurovascular injuries were identified in six (8.5%) of the 71 patients. Fractures of the clivus were very likely to be associated with neurovascular injury (p < 0.001). A high risk of neurovascular injury showed a strong tendency to be associated with fractures of the sella turcica-sphenoid sinus complex (p = 0.07). CONCLUSIONS: The risk of associated blunt neurovascular injury appears to be significant in Level 1 trauma patients in whom a diagnosis of skull base fracture has been made using CT. The incidence of neurovascular trauma is particularly high in patients with clival fractures. The authors recommend neurovascular imaging for Level 1 trauma patients with a high-risk fracture pattern of the central skull base to rule out cerebrovascular injuries. PMID- 17695392 TI - Axillary nerve repair by triceps motor branch transfer through an axillary access: anatomical basis and clinical results. AB - OBJECT: Grafting or nerve transfers to the axillary nerve have been performed using a deltopectoral approach and/or a posterior arm approach. In this report, the surgical anatomy of the axillary nerve was studied with the goal of repairing the nerve through an axillary access. METHODS: The axillary nerve was bilaterally dissected in 10 embalmed cadavers to study its variations. Three patients with axillary nerve injuries then underwent surgical repair through an axillary access; the axillary nerve was repaired by transfer of the triceps long head motor branch. RESULTS: At the lateral margin of the subscapularis muscle, the axillary nerve was found in the center of a triangle bounded medially by the subscapular artery, laterally by the latissimus dorsi tendon, and cephalad by the posterior circumflex humeral artery. At the entrance of the quadrangular space, the axillary nerve divisions were loosely connected to each other, and could be clearly separated and correctly identified. Surgery for the axillary nerve repair through the axillary access was straightforward. Eighteen months after surgery, all three patients had recovered deltoid strength to a score of M4 on the Medical Research Council scale and had improved abduction strength by 50%. No deficit was evident in elbow extension. CONCLUSIONS: The axillary nerve and its branches can be safely dissected and repaired by triceps motor nerve transfer through an axillary access. PMID- 17695393 TI - Selection of the donor nerve for end-to-side neurorrhaphy. AB - OBJECT: The authors of other studies have reported that the selection of an agonistic donor nerve is required for recovering voluntary motor control after end-to-side nerve repair. In this experimental investigation, the authors' goal was to verify this assumption by performing end-to-side neurorrhaphy of the rat median nerve on its antagonistic radial nerve. METHODS: The left median nerve in 10 adult female rats was repaired by end-to-side neurorrhaphy after epineuriotomy on the radial nerve at the middle of the brachium. The time course of median nerve functional recovery was then assessed using the grasping test until postoperative Week 30. Before removing the nerve, the surgical site was carefully explored to exclude contamination by the proximal nerve stump, and the functional anatomy of median and radial nerves was assessed by electrical stimulation. Repaired nerves were then processed for resin embedding, and semithin sections were obtained for nerve fiber histomorphometry by using the dissector method. RESULTS: Repaired median nerves were repopulated by nerve fibers regenerating from the radial donor nerve as previously shown. Moreover, voluntary motor control of the flexor muscles innervated by the median nerve was progressively recovered beginning in postoperative Week 10 and reaching 42% of normal by Week 30. CONCLUSIONS: Contrary to previously reported data, recovery of voluntary motor function after end-to-side nerve repair can also be expected when an antagonistic nerve is used as a donor nerve. PMID- 17695394 TI - Survival of transplanted neural progenitor cells enhanced by brain irradiation. AB - OBJECT: Authors of previous studies have reported that adult transplanted neural progenitor cells (NPCs) are suitable for brain cell replacement or gene delivery. In this study, the authors evaluated survival and integration of adult rat derived NPCs after transplantation and explored the potential impact on transplant survival of various mechanical and biological factors of clinical importance. METHODS: Adult female Fischer 344 rats were used both as a source and recipient of transplanted NPCs. Both 9L and RG2 rat glioma cells were used to generate in vivo brain tumor models. On the 5th day after tumor implantation, NPCs expressing green fluorescent protein (GFP) were administered either intravenously (3.5 x 10(7) cells) or by stereotactic injection (1 x 10(4)-1 x 10(6) cells) into normal or tumor-bearing brain. The authors evaluated the effect of delivery method (sharp compared with blunt needles, normal compared with zero volume needles, phosphate-buffered saline compared with medium as vehicle), delivery sites (intravenous compared with intratumoral compared with intraparenchymal), and pretreatment with an immunosuppressive agent (cyclosporin) or brain irradiation (20-40 Gy) on survival and integration of transplanted NPCs. RESULTS: Very few cells survived when less than 10(5) cells were transplanted. When 10(5) cells or more were transplanted, only previously administered brain irradiation significantly affected survival and integration of NPCs. Although GFP containing NPCs could be readily detected 1 day after injection, few cells survived 4 days to 1 week unless preceded by whole-brain radiation (20 or 40 Gy in a single fraction), which increased the number of GFP-containing NPCs within the tissue more than fivefold. CONCLUSIONS: The authors' findings indicate that most NPCs, including those from a syngeneic autologous source, do not survive at the site of implantation, but that brain irradiation can facilitate subsequent survival in both normal and tumor-bearing brain. An understanding of the mechanisms of this effect could lead to improved survival and clinical utility of transplanted NPCs. PMID- 17695395 TI - Treatment of traumatic brain injury in rats with erythropoietin and carbamylated erythropoietin. AB - OBJECT: This study was designed to investigate the neuroprotective properties of recombinant erythropoietin (EPO) and carbamylated erythropoietin (CEPO) administered following traumatic brain injury (TBI) in rats. METHODS: Sixty adult male Wistar rats were injured with controlled cortical impact, and then EPO, CEPO, or a placebo (phosphate-buffered saline) was injected intraperitoneally. These injections were performed either 6 or 24 hours after TBI. To label newly regenerating cells, bromodeoxyuridine was injected intraperitoneally for 14 days after TBI. Blood samples were obtained on Days 1, 2, 3, 7, 14, and 35 to measure hematocrit. Spatial learning was tested using the Morris water maze. All rats were killed 35 days after TBI. Brain sections were immunostained as well as processed for the enzyme-linked immunosorbent assay to measure brain-derived neurotrophic factor (BDNF). RESULTS: A statistically significant improvement in spatial learning was seen in rats treated with either EPO or CEPO 6 or 24 hours after TBI (p < 0.05); there was no difference in the effects of EPO and CEPO. Also, these drugs were equally effective in increasing the number of newly proliferating cells within the dentate gyrus at both time points. A statistically significant increase in BDNF expression was seen in animals treated with both EPO derivatives at 6 or 24 hours after TBI. Systemic hematocrit was significantly increased at 48 hours and 1 and 2 weeks after treatment with EPO but not with CEPO. CONCLUSIONS: These data demonstrate that at the doses used, EPO and CEPO are equally effective in enhancing spatial learning and promoting neural plasticity after TBI. PMID- 17695396 TI - Malignant transformation-related genes in meningiomas: allelic loss on 1p36 and methylation status of p73 and RASSF1A. AB - OBJECT: Analysis of meningiomas supports the suggestion that loss of heterozygosity (LOH) of chromosome arm 1p plays an important role in malignancy. The aim of this study was to identify genes related to meningioma progression from the benign state to the atypical and anaplastic states by examining 1p LOH and the promoter methylation of RASSF1A and p73. METHODS: The authors studied 40 surgical specimens (22 WHO Grade I, 11 Grade II, and seven Grade III) obtained in 37 patients with meningioma. The LOH at 1p36 was analyzed using microsatellite markers, and promoter methylation of p73 and RASSFIA was analyzed using methylation-specific polymerase chain reaction. RESULTS: No 1p LOH was detected in the Grade I tumors, whereas it was detected in more than 80% of the Grade II and III tumors. Methylation of the p73 promoter was observed in 81.8 and 71.4% of the Grade II and III tumors, respectively, but it was not observed in any of the Grade I tumors; methylation of the RASSF1A promoter was observed in 18.2, 63.6, and 42.9% of the Grade I, II, and III tumors, respectively. Interestingly, 1p LOH and p73 promoter hypermethylation were detected in the malignantly transformed tumors but not in the lower-grade primary ones. CONCLUSIONS: Based on the hypothesis that meningiomas cumulatively acquire genetic alterations and thus progress from the benign to the atypical and anaplastic states, genetic alterations in the methylation status of p73 or RASSF1A along with 1p LOH may result in the malignant transformation of a meningioma. This type of genetic fingerprint may play both diagnostic and therapeutic roles. PMID- 17695397 TI - Endothelial injury and inflammatory response induced by hemodynamic changes preceding intracranial aneurysm formation: experimental study in rats. AB - OBJECT: Intracranial aneurysms are the leading cause of subarachnoid hemorrhage, which is associated with high morbidity and mortality rates. Despite advances in the microsurgical and endovascular treatment of intracranial aneurysms, little is known about the mechanisms by which they originate, grow, and rupture. To clarify the series of early events leading to formation of intracranial aneurysms, the authors compared aneurysmal morphological changes on vascular corrosion casts with parallel pathological changes in the cerebral arteries of rats. METHODS: The authors induced cerebral aneurysms by renal hypertension and right common carotid artery ligation in 40 male Sprague-Dawley rats; 10 intact rats served as the controls. The anterior cerebral artery-olfactory artery bifurcation was assessed morphologically by using vascular corrosion casts of Batson plastic reagent and immunohistochemically by using antibodies against endothelial nitric oxide synthase, alpha-smooth muscle actin, macrophages, and matrix metalloproteinase-9. RESULTS: Surgically treated rats manifested different degrees of aneurysmal changes. Based on these staged changes, the authors propose that the formation of intracranial aneurysms starts with endothelial injury at the apical intimal pad (Stage I); this leads to the formation of an inflammatory zone (Stage II), followed by a partial tear or defect in the inflammatory zone. Expansion of this defect forms the nidus of the intracranial aneurysm (Stage III). CONCLUSIONS: This is the first study to demonstrate the in vivo mechanisms of intracranial aneurysm formation. The inflammatory response that follows endothelial injury is the basic step in the pathogenesis of these lesions. In this study the investigators have expanded the understanding of the origin of intracranial aneurysms and have contributed to the further development of measures to prevent and treat aneurysms. PMID- 17695398 TI - Reversible tonsillar prolapse and syringomyelia after embolization of a tectal arteriovenous malformation. Case report and review of the literature. AB - The authors report the case of a 21-year-old woman who presented with headaches, frequent sensations of loss of equilibrium, and intermittent strabismus. A tectal arteriovenous malformation (AVM) was diagnosed based on magnetic resonance (MR) imaging findings. The AVM drained toward the straight sinus and was associated with a tonsillar prolapse (Chiari malformation Type I [CM-I]) and cervical syringomyelia. The tectal AVM was embolized with N-butyl cyanoacrylate, and disconnection of about 80% of the lesion was obtained. All clinical symptoms resolved after embolization, and radiosurgery was proposed to treat the malformation remnant. A control MR image confirmed the regression of the tonsillar prolapse and the disappearance of the syrinx. This report emphasizes that CM-I and syringomyelia may be acquired and related to hydrovenous disorders. PMID- 17695399 TI - Endoscopic stent placement for treatment of secondary bilateral occlusion of the Monro foramina following endoscopic third ventriculostomy in a patient with aqueductal stenosis. Case report. AB - Nontumoral bilateral occlusion of the Monro foramina is a rare clinical condition. Treatment includes shunt placement, endoscopic procedures, or both. The authors describe the case of a 22-year-old woman who had previously undergone placement of a ventriculoperitoneal shunt via a right frontal approach for management of triventricular dilation due to aqueductal stenosis. Six years postoperatively she presented with right-sided slit-ventricle syndrome and stenosis of the right Monro foramen, which was treated with an endoscopic third ventriculostomy and fenestration of the septum pellucidum. Two years later she presented with bilateral lateral ventricular dilation. Inspection of the right lateral ventricle with a fiberscope revealed occlusion of the septum pellucidum fenestration; on observation, the right Monro foramen was covered by thick, tough granulation tissue and the left was occluded by thin membranous tissue. Repeated fenestration of the septum pellucidum and left Monro foraminoplasty were therefore performed by perforating this thin tissue. A stent was then introduced into the third ventricle via the right lateral ventricle, the fenestration in the septum pellucidum, and the left Monro foramen. The authors note that fiberscopes are in general more maneuverable than rigid endoscopes and conclude that they are particularly useful for the treatment of this type of hydrocephalus. PMID- 17695400 TI - Endolymphatic sac tumor demonstrated by intralabyrinthine hemorrhage. Case report. AB - Endolymphatic sac tumors (ELSTs) are locally invasive neoplasms that arise in the posterior petrous bone and are associated with von Hippel-Lindau (VHL) disease. These tumors cause symptoms even when microscopic in size (below the threshold for detectability on imaging studies) and can lead to symptoms such as hearing loss, tinnitus, vertigo, and facial nerve dysfunction. While the mechanisms of audiovestibular dysfunction in patients harboring ELSTs are incompletely understood, they have critical implications for management. The authors present the case of a 33-year-old man with VHL disease and a 10-year history of progressive tinnitus, vertigo, and left-sided hearing loss. Serial T1-weighted magnetic resonance (MR) imaging and computed tomography scans revealed no evidence of tumor, but fluid attenuated inversion recovery (FLAIR) MR imaging sequences obtained after hearing loss demonstrated evidence of left intralabyrinthine hemorrhage. On the basis of progressive disabling audiovestibular dysfunction (tinnitus and vertigo), FLAIR imaging findings, and VHL disease status, the patient underwent surgical exploration of the posterior petrous region, and a small (2-mm) ELST was identified and completely resected. Postoperatively, the patient had improvement of the tinnitus and vertigo. Intralabyrinthine hemorrhage may be an early and the only neuroimaging sign of an ELST in patients with VHL disease and audiovestibular dysfunction. These findings support tumor-associated hemorrhage as a mechanism underlying the audiovestibular dysfunction associated with ELSTs. PMID- 17695401 TI - Extradural dermoid tumor of the petrous apex. Case report. AB - Dermoid cysts are rare, benign, congenital tumors. Most case series thus far have featured intradural tumors. The authors report on a case of an extradural dermoid tumor of the middle cranial fossa with osseous invasion, successfully removed using a left subtemporal extradural approach. The clinical presentation, histological features, radiological findings, and management of this unique case are described. PMID- 17695402 TI - Infraoptic course of anterior cerebral arteries associated with abnormal gyral segmentation. Case report. AB - The authors report the case of a 34-year-old woman who presented with increasing headaches. Neuroimaging revealed bilateral anomalous vessels arising at the level of each ophthalmic artery, coursing rostromedially to join the anterior communicating artery (ACA), which harbored an aneurysm. Intraoperatively, the authors identified an abnormal gyral segmentation of the frontoorbital region, with a median gyrus separated from the olfactory tracts on each side by the gyrus rectus. No interhemispheric fissure was observed in the exposed area. This is the first report in the literature of an abnormal gyral segmentation in association with an infraoptic course of an ACA. Recognition of this possible gyral abnormality in association with this vascular anomaly is relevant for surgical exposure and treatment of aneurysms by clip placement. PMID- 17695403 TI - Colocalized cellular schwannoma and plexiform neurofibroma in the absence of neurofibromatosis. Case report. AB - The authors report on a patient without neurofibromatosis Type 1 or 2 (NF1 or NF2) and without evidence of schwannomatosis, who was found to have an unusual combination of nerve sheath tumors-a large cellular schwannoma and multifascicular involvement of a plexiform neurofibroma arising from the same site within the radial nerve and posterior cord of the infraclavicular brachial plexus. This case broadens the spectrum of combined pathological features of nerve sheath tumors. Genetic studies revealed a combined loss of neurofibromin and merlin in both regions and chromosome arm 22q deletion within the neurofibroma component only. The latter finding supports the suggestion that these were two different clonal neoplasms, and is consistent with a collision tumor pattern. PMID- 17695404 TI - Ethylene oxide gas sterilization: a simple technique for storing explanted skull bone. Technical note. AB - The authors evaluated the effectiveness of a simple technique using ethylene oxide (EtO) gas sterilization and room temperature storage of autologous bone grafts for reconstructive cranioplasty following decompressive craniectomy. The authors retrospectively analyzed data in 103 consecutive patients who underwent cranioplasty following decompressive craniectomy for any cause at the University of Illinois at Chicago between 1999 and 2005. Patients with a pre-existing intracranial infection prior to craniectomy or lost to follow-up before reconstruction were excluded. Autologous bone grafts were cleansed of soft tissue, hermetically sealed in sterilization pouches for EtO gas sterilization, and stored at room temperature until reconstructive cranioplasty was performed. Cranioplasties were performed an average of 4 months after decompressive craniectomy, and the follow-up after reconstruction averaged 14 months. Excellent aesthetic and functional results after single-stage reconstruction were achieved in 95 patients (92.2%) as confirmed on computed tomography. An infection of the bone flap occurred in eight patients (7.8%), and the skull defects were eventually reconstructed using polymethylmethacrylate with satisfactory results. The mean preservation interval was 3.8 months in patients with uninfected flaps and 6.4 months in those with infected flaps (p = 0.02). A preservation time beyond 10 months was associated with a significantly increased risk of flap infection postcranioplasty (odds ratio [OR] 10.8, p = 0.02). Additionally, patients who had undergone multiple craniotomies demonstrated a trend toward increased infection rates (OR 3.0, p = 0.13). Data in this analysis support the effectiveness of this method, which can be performed at any institution that provides EtO gas sterilization services. The findings also suggest that bone flaps preserved beyond 10 months using this technique should be discarded or resterilized prior to reconstruction. PMID- 17695405 TI - A novel treatment approach to cholesterol granulomas. Technical note. AB - The authors report a novel technique for the treatment of cholesterol granulomas. An extradural middle fossa approach was used to access the granuloma, with drainage through silastic tubes into the sphenoid sinus via the anteromedial triangle between V1 and V2. Cholesterol granulomas occur when the normal aeration and drainage of temporal bone air cells is occluded, resulting in vacuum formation and transudation of blood into the air cells. This process results in anaerobic breakdown of the blood with resulting cholesterol crystal formation and an inflammatory reaction. Traditional treatment of this lesion involves extensive drilling of the temporal bone to drain the granuloma cyst and establish a drainage tract into the middle ear. Such drainage procedures can be time consuming and difficult, and potentially involve structural damage to the inner ear and facial nerve. An extradural middle fossa approach provides easy access to the granuloma and anterior petrous bone entry into the granuloma for resection. Granuloma drainage is then achieved using shunt tubing in the sphenoid sinus via a small hole in the anteromedial triangle between V1 and V2. Five patients with symptomatic cholesterol granuloma were treated without complication using this novel extradural middle fossa approach. One patient required reoperation 1-year postoperatively for cyst regrowth and occlusion of the drainage tube. At the 5 year follow-up examination, no patient reported recurrent symptoms. Extradural middle fossa craniotomy and silastic tube drainage into the sphenoid sinus is a viable alternative method for treatment of cholesterol granuloma. PMID- 17695406 TI - Otfrid Foerster, the great neurologist and neurosurgeon from Breslau (Wroclaw): his influence on early neurosurgeons and legacy to present-day neurosurgery. AB - As a result of the turbulences of World War II, Wroclaw, Poland (formerly Breslau, Germany) lost its internationally acknowledged position in the field of neurosurgery, which it once had thanks to Otfrid Foerster. This innovative German doctor and scientist made a considerable contribution to the development of neurological and neurosurgical research worldwide. He also made Breslau a renowned center for scientific study, luring researchers from around the world. His achievements influenced many neurosurgeons during his lifetime, above all those from the US and England, including, for example, such well-known men as Fulton, Bucy, Bailey, and Penfield (who worked with Foerster in Breslau for quite a long time). Together Foerster and Penfield searched for the causes of epilepsy and the surgical methods to treat it. For young American neurosurgeons it was a very significant step in their careers to be able to train in Breslau under the guidance of Otfrid Foerster. In 1937 the British Association of Neurological Surgeons visited Breslau and awarded him with the honor of "Member Emeritus," which could be seen as the culmination of Foerster's career. In this paper the authors give an overview of Foerster's work and evaluate its significance. They also elucidate the difficult historical background during fascism in Germany using the sources of the Polish National Archives. Dr. Foerster's remaining traces in today's Wroclaw are meticulously reported. PMID- 17695407 TI - Transsphenoidal hypophysectomy. 1971. PMID- 17695408 TI - Desmoid-type fibromatosis. PMID- 17695409 TI - Introduction to chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS). AB - Prostatitis is the most frequently diagnosed illness in men under 50, accounting for about 8% of all consultations with urologists. Estimates based on published studies suggest that the incidence of prostatitis in the population is somewhere between 4% and 11%. In 1995 the National Institutes of Health (NIH) classified prostatitis into 4 main categories: 1) acute bacterial; 2) chronic bacterial; 3) pelvic pain syndrome; 4) asymptomatic inflammatory. The aetiological agent most often involved is bacterial, particularly the category of Gram (-) bacteria, followed by Gram (+), chlamydiae and mycoplasmas; however many cases of prostatitis are caused by bacteria which are difficult to isolate or by aetiopathogenic mechanisms which are immunological, neurological, psychosomatic or anatomical in nature. An observational study was recently done on the Italian territory in order to estimate the incidence and risk factors of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). The disease incidence estimation was 13.8%. Cigarette smoking, high caloric diet with low consumption of fruit and vegetables, constipation, meteorism, slow digestion, sexual relationship with more than one partner and coitus interruptus were more likely in CP/CPPS patients than in controls (p < 0.001). CP/CPPS had a negative influence on sexual desire, erectile dysfunction and premature ejaculation (p < 0.001). The Meares Stamey test was positive in 13.3% of patients and 2.9% of controls. PMID- 17695410 TI - The AISPEP (Associazione Italiana Sindromi Pelvico Prostatiche) chronic prostatitis questionnaire (AISPEP-Q). focus on the disease: anamnestic data, life activities, symptoms, sexual habits, quality of life and knowledge about prostatitis from 93 questions answered on the Internet. AB - Chronic prostatitis (CP) has been described as one of the most common illnesses men aged < or = 50, showing a significant impact on patients' quality of life comparable with other chronic diseases, such as unstable angina or Crohn's disease. CP also is a social and economic problem due to its high incidence in the young male population and to the absence of evidence for the effectiveness of treatment. Today, however, although validated outcome questionnaires are available to follow prostatitis patients, diagnostic and treatment options are based on experience, expert opinion and poor clinical trial data. More extensive and better-designed epidemiological studies are needed to evaluate and describe prostatitis patient clinical characteristics, in order to carry out correct and useful treatment. The aim of this report is to present the new Associazione Italiana Sindromi Pelvico Prostatiche questionnaire (AISPEP-Q) in order to provide a tool for increasing knowledge in prostatitis patient characteristics and design future epidemiological studies. PMID- 17695411 TI - Prevalence of sexual dysfunction in men with chronic prostatitis/chronic pelvic pain syndrome. AB - OBJECTIVE: The aim of this study was to assess the prevalence of sexual dysfunction in men with chronic prostatitis/chronic pelvic pain syndrome. MATERIALS AND METHODS: A group of 399 patients with symptoms suggesting prostatitis without urethral discharge attending an outpatient Prostatitis Clinic was considered. All were evaluated by the same urologist according to a protocol comprising medical history, physical and transrectal ultrasound examination. Patients had a urethral swab, a four-specimen study and culture of the seminal fluid. Patients were classified according to NIDDK/NIH on the basis of the results of the microbiologic and microscopic four-specimen study and of the culture of the seminal fluid. Subjective symptoms were scored by CPSI questionnaire and by non validated general assessment questions inquiring loss of libido, quality of erection, premature loss of erection, pain on ejaculation, hemo-spermia, pyo-spermia, premature ejaculation, and presence of semen abnormalities. RESULTS: Of all the patients evaluated, 138 (34%) had erectile and 220 ejaculatory dysfunctions (55%). Loss of libido, premature ejaculation and presence of semen abnormalities were more frequent in subjects younger than 50 years. Rates of impaired erection and of semen abnormalities were significantly higher in patients with bacterial chronic prostatitis with respect to patients with chronic pelvic pain syndrome. Premature ejaculation was more frequent (p = 0.02) in patients with 10-30 leukocytes (36%) or > 30 leukocytes (32%) in VB3 urine than in those with 10 or less leukocytes (22%). Painful ejaculation was significantly associated to the sonographic demonstration of enlargement (p = 0.000), asymmetry (p = 0.001) or inflammatory changes (p = 0.038) of the seminal vesicles, whereas hemo-spermia was significantly associated to asymmetry (p = 0.000) or inflammatory changes (p = 0.013, respectively) of the seminal vesicles. Men with erectile (p = 0.001) and ejaculation dysfunction (p = 0.001) had more severe CPSI scores than men without such complaints. The presence of erectile and ejaculation dysfunction was related to significantly higher scores for domains of pain and quality of life. CONCLUSIONS: Although mental distress and impaired quality of life related to illness could contribute to sexual dysfunction observed in patients with CP/CPPS, the presence of erectile and ejaculatory disorders is more frequently related to symptoms and imaging suggestive of a more severe inflammatory condition. PMID- 17695412 TI - Conventional bacteriology in prostatitis patients: microbiological bias, problems and epidemiology on 1686 microbial isolates. AB - Prostatitis is one of the most common illnesses in men aged < or = 50 with different clinical presentation such as pelvic pain, Lower Urinary Tract Symptoms or sexual disfunction. Problems in the diagnosis and classification of this condition, however, have delayed epidemiologic research and consequently, our understanding of the natural history of prostatitis is limited. Nowadays, the Meares & Stamey test (M&S Test) in bacterial prostatitis is considered the most important test for diagnosis of bacterial prostatitis, even if several problems have been identified in running the M&S Test. The aim of the present study is to perform a review of the microbiological diagnosis approach to prostatitis patients and illustrate a new protocol, a modification of the standard Meares and Stamey test for the microbiological diagnosis of prostatitis, which includes total ejaculate (TE) from each patient. PMID- 17695413 TI - Chronic prostatitis (CP)/chronic pelvic pain syndrome (CPPS): what do we know? AB - To dissertate about chronic prostatitis/chronic pelvic pain syndrome is, in the beginning of the XXI century, more difficult and complex than before. Indeed the therapeutical and pathogenetic hypothesis chase, below and often contradict each other. In this review we have tried to underline the opinions of the most accredited researcher, leaving to the reader the possibility to throw one's due conclusions. PMID- 17695414 TI - Reduction of PSA values by combination pharmacological therapy in patients with chronic prostatitis: implications for prostate cancer detection. AB - We identified from our clinical database a total of 471 patients affected by cat. II chronic bacterial prostatitis (CBP), cat. III (IIIa and IIIb) chronic pelvic pain syndrome (CP/CPPS), or cat. IV asymptomatic inflammatory prostatitis (AIP), according to NIH criteria. 132 intent-to-treat patients, showing levels of PSA > or =4 ng/mL, were subjected to a 6-week course of combination pharmacological therapy with 500 mg/day ciprofloxacin, 500 mg/day azithromycin (3 days/week), 10 mg/day alfuzosin and 320 mg b.i.d. Serenoa repens extract. At the end of treatment, 111 per-protocol patients belonging to all categories of prostatitis showed a total 32.5% reduction of PSA levels. In the same group, 66 patients (59.4%) showed "normalization" of PSA values under the 4 ng/mL limit. Patients affected by cat. IIIb CP/CPPS showed the highest PSA reduction and normalization rates (40% and 68.4%, respectively). Follow-up data show that, after a marked, significant reduction at completion of therapy, PSA levels, urine peak flow rates and NIH-CPSI symptom scores remained constant or decreased throughout a period of 18 months in patients showing normalization of PSA values. Prostatic biopsy was proposed to 45 patients showing persistently high PSA values (> or = 4 ng/mL) at the end of treatment. Fourteen patients rejected biopsy; of the remaining 31, 10 were diagnosed with prostate cancer. Four months after a first biopsy, a second biopsy was proposed to the 21 patients with a negative first diagnosis and persistently elevated PSA levels. Three patients rejected the procedure; of the remaining 18, four were diagnosed with prostatic carcinoma. In summary, combination pharmacological therapy decreased the number of patients undergoing prostatic biopsy from 111 to 45. Normalization of PSA values in 59.4% of patients -not subjected to biopsy--increased the prostate cancer detection rate from 12.6% (14/111) to 31.1% (14/45). The reduction of PSA after a 6-week course of therapy was calculated in patients affected by cat. II, IIIa, IIIb and IV prostatitis after stratification with respect to the concomitant presence or absence of benign prostatic hyperplasia (BPH). PSA was reduced by 41% in cat. II CBP patients without BPH, compared to a 12.7% reduction in patients affected by BPH. Cat. IIIa CP/CPPS patients without BPH showed a 58.3% reduction of PSA levels, compared to a 20.7% reduction observed in CPPS/BPH patients. These data show that the presence of BPH may prevent the reduction of PSA induced by combination pharmacological therapy, and suggest that care has to be taken in the adoption of PSA as a marker of therapeutic efficacy in the presence of confounding factors like BPH. PSA should in our opinion be used as a significant component of a strategy integrating multiple diagnostic approaches. PMID- 17695415 TI - Eradication of unusual pathogens by combination pharmacological therapy is paralleled by improvement of signs and symptoms of chronic prostatitis syndrome. AB - We performed a comparative analysis of microbiological and clinical responses to combination therapy in 104 symptomatic patients showing evidence of infection by traditional uropathogens (TU) or by unusual pathogens (UP) at the prostatic level. Eighty-two pathogens out of a total of 104 isolated microorganisms were eradicated at the end of a 6-week course of combination therapy with ciprofloxacin, azithromycin, alfuzosin and a S. repens extract. The TU and UP groups showed eradication rates of 75.5% and 82.3%, and clinical success rates of 78.8% and 85.7%, respectively. Thus, a similar response to therapy was observed in patients infected by TU or by UP. Intergroup differences were not significantly different, with the exception of higher scores relative to the impact of the disease on quality of life in TU-patients. Long-term improvement of signs and symptoms of prostatitis indicates that combination therapy is beneficial for symptomatic patients showing evidence of infection by unusual pathogens at the prostatic level. Our data support the hypothesis that organisms other than the traditionally recognized uropathogens may play a role in the onset of prostatitis. PMID- 17695416 TI - Pharmacoanalytical assays of Erwinia asparaginase (erwinase) and pharmacokinetic results in high-risk acute lymphoblastic leukemia (HR ALL) patients: simulations of erwinase population PK-PD models. AB - BACKGROUND: Asparaginases are the cornerstone therapy of many successful combination regimens for the treatment of acute lymphoblastic leukemia (ALL), the most common malignancy in children and adolescents. Currently, two asparaginase formulations are available in the US, native Escherichia coli asparaginase (ASNase) and pegaspargase. A third formulation native Erwinia asparaginase (Erwinase, ERW) has recently been made available under a licensing exception for personal use. We report here the development and validation process of ERW pharmacoanalytical assays and the results in a few patients. MATERIALS AND METHODS: We developed and systematically validated the ERW enzyme activity and ERW concentration, anti-ERW antibody and related assays. Pharmacokinetic and pharmacodynamic (PK-PD) studies were performed in a limited number of patients who received 6,000 IU/m2 x 3 per week x 2 courses, and 4 patients who received 25,000 IU/m2 x 3 per week x 2 courses of ERW. RESULTS: The linearity and range of the Erwinase calibration lines for the pharmacoanalytical assays were excellent. The accuracy and precision were better than the FDA limit allows for oncology biological products (<30%) coefficient of variation (%CV) and related parameters in the quantification of ERW concentration. The validation of these parameters was equal to or better than during the assay development. PK-PD analyses of ERW in a few patients yielded an average half-life of elimination of 15.8+/-1.64 hours. There was an excellent PD response post ERW administration resulting in an ERW concentration-dependent asparagine (ASN, <0.5 microM) and glutamine (GLN, <50 microM) deamination. Pharmacodynamic correlations demonstrated that 0.1 to 0.2 IU/ml of ERW in serum were sufficient for 90% GLN and/or ASN deamination for up to 2 weeks. No anti-ERW antibody [Ab(+)] was seen among those few patients. None of the other 5 patients had an adverse event. Based on these post hoc results, simulations on various doses and schedules of this drug have been made. CONCLUSION: The pharmacoanalytical assays were excellent tools to evaluate the PK and PD data of ERW in pediatric patients with HR ALL. However, this initial PK-PD evidence needs further validation in future clinical trials. Insights into the PD contributions of ERW in anti-E. coli ASNase Ab(+) patients will guide us in optimal design and use of ERW as part of combination chemotherapy regimens in future clinical trials. PMID- 17695417 TI - Fibrosarcoma of the jaws: two cases of primary tumors with intraosseous growth. AB - Fibrosarcoma (FS) is a malignant mesenchymal neoplasm of the fibroblasts that rarely affects the oral cavity. Two cases of primary FS of the jaws with intraosseous growth (2 men, aged 53 and 71 years) are described. Microscopically, in one case the tumor showed an intense proliferation of spindle-shaped cells, varying little in size and shape and arranged in parallel bands, partly crossing each other, with significant mitotic activity and nuclear pleomorphism; the second case was characterized by low cellularity comprising spindle-shaped cells, deposited in a variably fibrous and myxoid stroma. On immunohistochemistry, cells in both cases were strongly immunoreactive for MIB-1 and vimentin, focally positive for CD68, and negative for S-100 protein, pancytokeratin, HMB45, CD34, desmin, smooth muscle actin (SMA) and epithelial membrane antigen (EMA). Based on clinical, histological and immunohistochemical findings, the final diagnosis was FS in the first case, myxofibrosarcoma in the second. Treatment was radical surgery with mandibular reconstruction. After two years, the first patient displayed multiple metastases and died during the third year after the initial diagnosis; the second patient was still alive and doing well five years after treatment. We discuss the differential diagnosis versus other forms of sarcoma, examining the morphological appearance that is frequently very similar, the immunohistochemical expression of MIB-1, vimentin, S-100, CD-34, CD68, EMA, as well as conventional clinicopathological features that may help to distinguish FS from other sarcomas. PMID- 17695418 TI - Expression of endostatin in merkel cell carcinoma. AB - BACKGROUND: The aim of this study was to examine the expression of endostatin in Merkel cell carcinoma (MCC) and to correlate the expression with tumour growth and the development of metastasis. PATIENTS AND METHODS: The study comprised 19 patients treated for MCC at the Helsinki University Hospital, Helsinki, Finland between 1987 and 2003. Endostatin expression was studied by immunohistochemistry. The correlations between the quantitative expression of endostatin and tumour parameters were analysed statistically. RESULTS: The expression of endostatin was documented in only 40% of the samples. Endostatin correlated negatively with tumour size, and was expressed in 30% of the large and 56% of the small tumours. There was no difference in expression between tumours expanding to metastases and tumours with more indolent behaviour. The simultaneous expression of vascular endothelial growth factor receptor-2 and endostatin was distinguished in small sized tumours. CONCLUSION: This study showed a correlation between endostatin expression and small tumour size in Merkel cell carcinoma. This finding was further confirmed by the finding that tumours positive for VEGFR-2, but not for endostatin, seemed to be larger than tumours that showed simultaneous expression of VEGFR-2 and endostatin. PMID- 17695419 TI - Expression of vascular endothelial growth factor receptor-2 in Merkel cell carcinoma. AB - BACKGROUND: The aim of this study was to examine the expression of vascular endothelial growth factor receptor-2 (VEGFR-2) in Merkel cell carcinoma (MCC) and to correlate the expression with tumour growth and the development of metastasis. PATIENTS AND METHODS: The study included 21 patients treated for MCC at Helsinki University Hospital, Helsinki, Finland between 1987 and 2003. The VEGFR-2 expression was studied by immunohistochemistry. The correlations between the quantitative expression of VEGFR-2 and tumour size and metastatic dissemination were analyzed statistically. RESULTS: VEGFR-2 was expressed in 91% of the large (> or =2 cm) and 70% of the small (<2 cm) tumours. There was a stronger positive correlation between expression of VEGFR-2 and tumour size than between VEGFR-2 and metastatic potential. CONCLUSION: A correlation between the expression of pro angiogenic marker and tumour size was established. Our results indicate that inhibiting angiogenesis could be a treatment option for MCC. The role of neovascularization in the metastatic process in MCC remains to be determined. PMID- 17695420 TI - Urinary cyclic GMP after treatment of gynecological cancer. A prognostic marker of clinical outcome. AB - BACKGROUND: The search for biological markers to predict malignant disease and its recurrence, or to monitor the effectiveness of treatment is a continuous process in medicine. Several years ago, urinary excretion of cGMP in urine was found to be a sensitive predictor in the follow-up of ovarian cancer and of monitoring treatment of cancer of the uterine cervix. PATIENTS AND METHODS: In the present study, 27 patients with gynecological cancer, including cancer of the uterine cervix (n=13), cancer of the uterine corpus (n=8) and cancer of the ovaries (n=6), were monitored for 10 years. Blood and urinary samples were taken before primary treatment (baseline sample) and three months thereafter (three month sample). The serum levels of CEA, CA-125 and PIIINP and urine excretion of cGMP and cAMP were determined. Creatinine levels in serum and urine were employed to determine renal clearance. RESULTS: After 10 years' observation of women with cancer of the uterine cervix, seven patients showed no relapse and cGMP levels in baseline samples and three-month samples were 36.8+/-4.1 and 24.9+/-4.4 nmol cGMP/micromol creatinine (mean+/-SEM, p<0.01), respectively. The levels in patients (n=6) with relapse after 10 years' observation were 32.8+/-4.0 (baseline sample) and 43.5+/-4.2 (three-month sample) nmol cGMP/micromol creatinine (mean+/ SEM, p<0.02). Among the patients treated for cancer of the uterine corpus (n=9), none showed recurrent disease within the observation period of 10 years. The cGMP levels fell from 37.9+/-6.3 (baseline sample) to 22.3+/-2.3 (three-month sample) nmol cGMP/micromol creatinine (p<0.005). In the patients with ovarian cancer (n=6), 4 patients relapsed during the observation period of 10 years. In these women the cGMP levels increased from 34.5+/-2.7 (baseline sample) to 46.3+/-4.7 nmol cGMP/micromol creatinine whilst in both patients without relapse the levels decreased from 31.8 (range: 26.5-37.1) to 27.3 (range: 25.7-28.8) nmol cGMP/micromol creatinine, respectively. The changes in levels of cAMP, CEA, CA 125 and PIINP did not show statistically significant differences. Early changes in cGMP levels appear to predict long-term prognosis in gynecological cancers. PMID- 17695421 TI - Phase I study of docetaxel (TXT) and 5-fluorouracil (5-FU) with concurrent radiotherapy in patients with advanced esophageal cancer. AB - This phase I study was designed to determine the maximum-tolerated dose (MTD) of docetaxel (TXT) and toxicities of combining weekly administration of TXT and continuous infusion of 5-fluorouracil (5-FU) with concomitant radiotherapy for advanced esophageal cancer. PATIENTS AND METHODS: Patients received TXT by i.v. infusion over 1 h on days 1, 8, 22 and 29. They were also given 5-FU 250 mg/m2/day by continuous infusion for 24 h on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40 and 43-45. Fractionated radiotherapy was performed on days 1-5, 8-12, 15 19, 22-26, 29-33, 36-40 and 43-45, and a total dose of 60 to 66 Gy was delivered. The starting dose level (Level 1) of TXT was set at 7.5 mg/m2. Dose escalation was conducted in increments of 25 mg/m2, until the dose reached Level 4 (15 mg/m2). At least three patients were enrolled at each level. RESULTS: Seven patients (median age, 64 years) were enrolled. Six patients had stage III (T4NIMO) and one had stage IVb (T4N1M1b) esophageal cancer; six had squamous cell carcinoma and one had carcinosarcoma. No patient had received prior chemotherapy or radiotherapy, and two patients had undergone esophageal bypass surgery using a whole stomach tube without resection of primary or metastatic lesions. In the 7patients, the regimen was well-tolerated, with esophagitis as the most common toxicity (grade 3: n=1; grade 4: n=3). In general, hematological toxicity was mild. Dose-limiting toxicity (DLT) was observed at Level 2 (TXT 10 mg/m2) when three patients developed grade 4 esophagitis and this dose was deemed the MTD for this regimen. In the 7 assessable patients, the overall clinical response rate was 85.7%. CONCLUSION: The MTD of TXT in this regimen was 10 mg/m2 and the recommended dose of TXT was 7.5 mg/m2. Although esophagitis was the dose-limiting and the most frequent toxicity, the regimen was safe and well-tolerated, and demonstrated the possibility of good efficacy in patients with advanced esophageal cancer. PMID- 17695422 TI - Significance of thymidine phosphorylase in metronomic chemotherapy using CPT-11 and doxifluridine for advanced colorectal carcinoma. AB - BACKGROUND: A phase II study was designed to evaluate the efficacy, safety and predictors for response of metronomic chemotherapy using weekly low-dosage CPT-11 and doxifluridine (5'-DFUR) in 45 patients with metastatic colorectal cancer. PATIENTS AND METHODS: Forty mg/m2 of CPT-11 was administered for 3 consecutive weeks in a 4-week treatment cycle, with 5'-DFUR (800 mg/day) given orally. RESULTS: One or more adverse effects were seen in 42 patients. However, most of these were mild at grade 1 or 2, including only leucopenia in 2, neutropenia in 1, diarrhea in 1 and nausea in 1 as grade 3. The objective response rate was 36% with a median overall survival of 452 days. The response rate in patients with a high expression of thymidine phosphorylase (dThdPase) in tumor cells (47%) was higher (p=0.092) than that (19%) in patients with a low expression. CONCLUSION: The efficacy of metronomic chemotherapy using low-dosage weekly CPT-1 and 5'-DFUR is worthy of further clinical study, especially in patients with a high expression of dThdPase in primary tumor cells. PMID- 17695423 TI - Prognostic significance of TGFbeta-1 and pSmad2/3 in breast cancer patients with T1-2,N0 tumours. AB - BACKGROUND: The transforming growth factor beta (TGFbeta) signaling pathway has been shown to exert divergent effects and to cross-talk with estrogen pathways in mammary gland tumorigenesis. TGF signaling in early stage breast cancer was investigated by examining the expression of TGFbeta-1 and the signaling mediators pSmad2/3 and Smad4. Their association with oestrogen and progesterone receptors, as well as with clinical and pathological features was also analyzed. PATIENTS AND METHODS: Sixty-one tumor specimens from surgically treated patients with primary T12,N0 breast cancer were examined. The expression of TGFbeta-1, pSmad2 and Smad4 was assessed implementing immunohistochemical assays. RESULTS: TGFbeta I, pSmad2/3 and Smad4 were expressed in 50.9%, 74.0% and 61.0% of specimens, respectively. The degree of expression of the three molecules was significantly associated with each other. Loss of pSmad2/3 expression indicated a shorter disease-free survival in all patients, including those with oestrogen receptor positive tumors. Patients not expressing TGFbeta-1 were 4.6 times more likely to experience distant recurrence. CONCLUSION: Our results demonstrate that pSmad2/3 and TGFP-1 may be promising novel prognostic markers for T1.2,N0 breast carcinomas. PMID- 17695424 TI - Quality assurance of radiotherapy in a clinical trial for lymphoma: individual case review. AB - BACKGROUND: A multi-institutional clinical trial was conducted for localized lymphoma. This study evaluated whether a quality assurance (QA) program could clarify the source of variation in radiotherapy treatment between the institutions. MATERIALS AND METHODS: Two- or three-dimensional treatment planning is required to cover the target volumes adequately and to minimize doses to organs at risk. An original QA tool was used to compare pretreatment images with portal images and dose distribution, concurrently. RESULTS: In two of the first 12 cases, there was a deviation in the delineation of planning target volume (PTV). The QA committee clarified that there were ambiguities in the definition of PTV The study office distributed a memorandum outlining the definition of PTV in order to reduce deviations. Thereafter, a minor deviation was identified in one of the latter 11 cases. CONCLUSION: This QA program clarified the source of variation, and adapted the policy to reduce these problems. PMID- 17695426 TI - Combined low-dose cytarabine, melphalan and mitoxantrone for older patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. AB - BACKGROUND: Low-dose cytarabine (ara-C) has been used to treat older patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), but has resulted in complete remission for <20% of cases. A pilot study of the efficacy of a combination chemotherapy using low-dose ara-C, melphalan (Mel), and mitoxantrone (Mit) was conducted. PATIENTS AND METHODS: The treatment comprised ara-C (10 mg/m2) twice daily, melphalan (2 mg/body) every other day, and mitoxantrone (3 mg/m2) every 3 days. The treatment was discontinued if the nuclear cell count was <15,000/microl with <20% blast count in the bone marrow. The primary end-points were initial response and tolerability. RESULTS: The study comprised 9 patients with AML or high-risk MDS (median age, 75 years). Complete remission was achieved in 3 patients. All the patients displayed grade 4 neutropenia and thrombocytopenia. One patient died from sepsis. CONCLUSION: The present regimen was more effective and displayed similar safety, compared with low-dose ara-C alone. PMID- 17695425 TI - Prediction of response to definitive chemoradiotherapy in esophageal cancer using positron emission tomography. AB - BACKGROUND: Positron emission tomography (PET) with 18-F-fluorodeoxyglucose (FDG) has already proven useful in assessing the extension of esophageal carcinomas, detecting tumor recurrence and monitoring responses to therapy. The current study aims to assess the potential role of FDG-PET in predicting the response of esophageal squamous cell carcinoma (SCC) to definitive chemoradiotherapy (CRT). PATIENTS AND METHODS: Twenty-seven patients with thoracic esophageal SCC who received definitive CRT between January 2001 and December 2005 underwent PET before and after CRT. The clinical evaluation of the primary tumor response to treatment was classified as either complete response (CR) or non-CR. RESULTS: All patients had intensive FDG uptake in the primary tumor prior to CRT. The standardized uptake value (SUV) averaged 8.2+/-4.7 before CRT and decreased significantly to 2.8+/-1.8 after CRT (p<0.0001). The SUV before CRT averaged 10.2 in the non-CR group (n=17) and 4.9 in the CR group (n= 10). The SUV after CRT averaged 3.7 in the non-CR group and 1.4 in the CR group. The change in SUV for the CR group was higher than that in the non-CR group (p<0.05). The relationship between clinical features and clinical CR was analyzed using logistic regression analysis which revealed significant correlations between clinical CR and the longitudinal dimension of the tumor (p <0.05), SUV before CRT (p<0.05), SUV after CRT (p<0.01) and tumor classification (p <0.05). If the clinical features before CRT were limited, multivariate analysis revealed that the SUV before CRT was an independent predictor for clinical CR (p<0.05). CONCLUSION: In predicting clinical evaluation of therapy prior to CRT, we suggest that SUV prior to definitive CRT is one of the most reliable predictors of response, along with tumor dimensions and classification. PMID- 17695427 TI - Predictive value of thymidylate synthase and dihydropyrimidine dehydrogenase expression in tumor tissue, regarding the efficacy of postoperatively administered UFT (tegafur+uracil) in patients with non-small cell lung cancer. AB - BACKGROUND: UFT (tegafur + uracil) has been reported to be effective as an adjuvant in postoperative chemotherapy for non-small cell lung cancer (NSCLC) in a randomized prospective study. Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) expression were investigated in resected tumors and the relationship between their expression and clinical factors in NSCLC patients was examined. PATIENTS AND METHODS: Fifty-four NSCLC patients had undergone complete surgical resection and lymph node dissection, and had been administered UFT post surgery. The TS and DPD expression in the tumor tissues was evaluated by immunohistochemical staining. The relationship between TS and/or DPD expression and clinicopathological factors was examined. RESULTS: There were 38 TS-negative and 16 TS-positive cases, and 22 DPD-negative and 32 DPD-positive cases. There was no significant difference between the patients with TS or DPD and those without TS or DPD in age, gender, histological type or p-stage. The 5-year survival rates of patients positive and negative for TS were 50.0 and 89.5%, while 10-year survival rates were 23.3 and 79.7%, respectively (p<0.001). The 5 year survival rates of TS-positive and TS-negative patients in p-stage I were 54.6 and 95.5%, while 10-year survival rates were 22.7 and 95.5%, respectively (p<0.001). There was no significant difference between DPD-positive and DPD negative patients in prognosis. CONCLUSION: The oral administration of UFT after surgery might improve the survival of NSCLC patients when TS levels in tumor tissues are low. Immunohistochemical evaluation of TS and DPD expression may be useful for predicting the efficacy of UFT after complete resection in NSCLC. PMID- 17695428 TI - Chemosensitivity-related genes of breast cancer detected by DNA microarray. AB - BACKGROUND: The feasibility of a preoperative docetaxel/5'-deoxy-5-fluorouridine (5'-DFUR) regimen for breast cancer patients was examined and the genes related to the response to it was investigated. PATIENTS AND METHODS: Women with advanced breast cancer were treated with docetaxel (60 mg/m2, day 1) and 5'-DFUR (800 mg/day, on days 1-14) q3 weeks by 4 cycles. Microarray analysis was carried out using preoperative core biopsy samples. Based on the mRNA expression levels, genes related to clinical and pathological responses were selected. RESULTS: The docetaxel/5'-DFUR regimen showed a 86% clinical response rate including 42% complete response, one pathological complete response and one ductal carcinoma in situ component. In microarray analysis, we identified 6 genes, including IGF-1, and derived a predictive formula with 67% accuracy. In addition, x2 analysis revealed a tendency for good response in ER-negative and Her2/neu-positive cases. CONCLUSION: Microarray analysis enabled us to predict the pathological response to docetaxel/5'-DFUR chemotherapy. PMID- 17695429 TI - Phase I study of combination therapy with S-1 and weekly docetaxel for advanced gastric cancer. AB - BACKGROUND: The primary objective of this study was to determine the maximum tolerated dose (MTD), the toxicity profile and the recommended dose (RD) for phase II of a combination of S-1 and weekly administration of docetaxel. PATIENTS AND METHODS: Patients with histologically diagnosed recurrent or unresectable locally advanced gastric cancer were enrolled. A fixed oral dose of 80 mg/m2 S-1 was given for 3 weeks. Docetaxel was infused intravenously on day 1, 8 and 15, repeated every 5 weeks. A pharmacokinetic study was also performed. RESULTS: A total of 14 patients were enrolled. One dose-limiting toxicity (DLT) (grade 3 diarrhea with febrile neutropenia) occurred at level 2. DLTs occurred in 3/5 patients at level 3, (grade 3 stomatitis, with febrile neutropenia or continuous grade 4 neutropenia). The pharmacokinetic study suggested no drug interactions. Overall response and disease control rates were 20% and 80%, respectively. The response rate at the RD (level 2) was 50%. Overall survival was 9.4 months. CONCLUSION: RD was level 2 (80 mg/m2 of S-1 for 3 weeks and 20 mg/m2 of docetaxel on day 1, 8 and 15, every 5 weeks). Dose intensities of S-1 and docetaxel were 48 mg/m2/week and 12 mg/m2/week, respectively. This regimen showed promising activity for advanced gastric cancer. PMID- 17695430 TI - A phase II study of weekly paclitaxel as second-line chemotherapy for advanced gastric Cancer (CCOG0302 study). AB - BACKGROUND: Although paclitaxel was given triweekly in phase II trials prior to its approval for gastric cancer in Japan, it is currently more often delivered by a weekly schedule in the second-line setting. PATIENTS AND METHODS: A phase II trial with response rate as the primary end-point was conducted. Patients with metastatic or unresectable gastric adenocarcinoma who had measurable lesions and had disease progression with the front-line chemotherapy were treated by weekly administration of paclitaxel at a dose of 80 mg/m2. RESULTS: Forty-five patients were accrued and 44 were assessable for response. Partial responses were observed in 7 patients (16%). Stable disease was documented in further 14 patients (48%). Median progression-free survival of all patients enrolled was 2.6 months and median overall survival was 7.8 months. Toxicity was mild and manageable, the most frequent > or = grade 3 toxicity being neutropenia occurring in 16% of the patients. CONCLUSION: With modest response rate, favorable toxicity profile, and progression-free or overall survival similar to those of more intense combination regimens, weekly paclitaxel remains a rational therapeutic option for gastric cancer refractory to the first-line chemotherapy. PMID- 17695431 TI - Phase I/II study of irinotecan and UFT for advanced or metastatic colorectal cancer. AB - The aim of this study was to determine the recommended dose of irinotecan in combination with the fixed dose of oral UFT as first-line therapy in patients with advanced or recurrent colorectal cancer, and to evaluate the response rate and overall survival as a phase II study. PATIENTS AND METHODS: Thirteen patients were recruited into a phase I trial. Four doses of irinotecan ranging from 60 to 150 mg/m2/day were administered intravenously on day 1 and day 16 in combination with UFT given orally from day 2 to day 15. In a phase II study, 53 patients received at least one cycle of this therapy. RESULTS: The recommended dose of this combination was determined as irinotecan 120 mg/m2/day and UFT 400 mg/m2/day. Dose-limiting toxicities were neutropenia and prolonged leucopenia. On an intent-to-treat analysis, the response rate in the phase II study was 24.5% (95% confidence interval 13.8% to 38.2%). The median overall survival time was 20.3 months (95% confidence interval, 15.0-22.8 months). Out of 20 patients with stable disease, 17 who received more than 4 cycles of the regimen lived longer than the other 3 patients who received fewer than 3 cycles (p = 0.0353). Hematological adverse events were mainly grade 3/4 neutropenia observed in 6 out of 53 patients. Grade 3 non-hematological toxicities, such as diarrhea, anorexia, nausea/vomiting and alopecia were observed in 6 patients. CONCLUSION: Irinotecan combined with oral UFT was effective and well-tolerated. This regimen may be considered as a first-line therapy for advanced or metastatic colorectal cancer and may result in fairly long survival, even for patients with stable disease. PMID- 17695432 TI - S100A10 expression in thyroid neoplasms originating from the follicular epithelium: contribution to the aggressive characteristic of anaplastic carcinoma. AB - BACKGROUND: S100A10, a member of the S100 family, forms a heterotetramer with annexin IIH and promotes carcinoma invasion and metastasis by plasminogen activation. In this study, S100A10 and annexin II expression in thyroid neoplasms were demonstrated. PATIENTS AND METHODS: The expression levels of S100A10 and annexin II in 193 thyroid neoplasms were immunohistochemically investigated. RESULTS: S10A10 and annexin II were not expressed in normal follicular cells or any follicular adenomas. Cells stained positively in 14.6% and 20.8% of follicular carcinomas for S100A10 and annexin II, respectively, but their expression levels were always low. S100A10 and annexin II were expressed in all papillary carcinomas, but 88.2% and 82.8% ofpapillary carcinomas were classified in the low group. These expression levels were not linked to any clinicopathological features. S100S10 and annexin II were also expressed in all anaplastic carcinomas, with 83.3% of these lesions were classified in the high group. CONCLUSION: These findings suggest that S100A10 and annexin II contribute to the aggressive characteristics of anaplastic carcinoma, while playing a constitutive role in papillary carcinoma. PMID- 17695433 TI - Complete remission of ovarian small cell carcinoma treated with irinotecan and cisplatin: a case report. AB - BACKGROUND: Small cell carcinoma of the ovary is a rare type of ovarian carcinoma with a very poor prognosis. CASE REPORT: We report here a case of a 55-year-old woman with small cell carcinoma of the left ovary. The patient underwent cytoreductive surgery with residual tumors of 6 cm at the cul-de-sac and was found to have stage IIIc disease. After six courses of irinotecan (CPT-11) and cisplatin (CDDP) combination therapy, secondary cytoreductive surgery was performed. The patient showed no evidence of residual tumors. After an additional three courses of chemotherapy, the patient is still alive and well without evidence of disease. CONCLUSION: CPT-11 and CDDP combination chemotherapy may be effective and safe for patients with small cell carcinoma of the ovary. PMID- 17695434 TI - Exemestane as neoadjuvant hormonotherapy for locally advanced breast cancer: results of a phase II trial. AB - BACKGROUND: Neoadjuvant hormonotherapy has recently been used for downstaging large or locally advanced (LA) breast cancer in postmenopausal women. PATIENTS AND METHODS: A phase II study was conducted in postmenopausal, hormone-receptor (HR) positive, T2-T4 patients, receiving 25 mg/day exemestane for 16 weeks. RESULTS: Among 42 patients, 57.1% underwent conservative surgery. The clinical objective response rate (ORR) was 73.3%, without progression. A pathological partial response was achieved in 16.7% of the patients. Exemestane significantly reduced the expression of Ki-67 and progesterone receptors (PgR) (p<0.001). A significant decrease in PgR was correlated with clinical ORR (p=0.028). The responders presented higher baseline PgR levels (p=0.017). No relationship was found between ORR and mRNA expression of aromatase or oestrogen receptors beta (ER-beta). CONCLUSION: Neoadjuvant exemestane provided satisfactory efficacy and safety profiles in LA breast cancer. The main biological effects consisted of a reduction in PgR expression for responders and a decrease in Ki-67 expression. PMID- 17695435 TI - Human papillomavirus infections in lung cancer. Detection of E6 and E7 transcripts and review of the literature. AB - Lung cancer is the leading cause of cancer related death in Western countries. Several factors have been implicated in its aetiology: cigarette smoking, environmental pollution, asbestos and genetic factors. The possible involvement of human papillomavirus (HPV) in bronchial squamous cell lesions was first suggested in 1979 by Syrjanen. Since then, several studies have confirmed the presence of HPV DNA in about 20% of lung cancer cases examined, with HPV16 and 18 as the two most frequently found oncogenic viral types. More recently, these data have been supported by the detection of E6 and E7 transcripts in HPV-positive lung cancer cases, reinforcing the hypothesis that oncogenic HPVs could act as cofactors in bronchial carcinogenesis. This published literature is briefly reviewed and new data of the authors on detection of E6 and E7 transcripts in lung cancer samples are presented. PMID- 17695436 TI - Palliative chemotherapy for recurrent and metastatic esophageal cancer. AB - More than two-thirds of patients diagnosed with esophageal cancer will have unresectable disease. The objective of this article is to review the clinical trials utilizing cytotoxic chemotherapy in patients with recurrent and metastatic esophageal cancer. A computerized (MEDLINE) search was performed to identify papers published on this topic between 1966 and 2007. A total of 96 trials were subsequently identified. Two randomized trials compared palliative chemotherapy with best supportive care in 180 patients with advanced esophageal cancer. Effectiveness and side-effects were evaluated in 49 phase II studies and 3 randomized phase III trials. Combination chemotherapy as compared to monochemotherapy is associated with significantly higher response rates but nevertheless results in similar survival. CF (cisplatin and 5-fluorouracil) currently represents one of the most effective regimens for advanced esophageal cancer, while among the newer combinations, irinotecan or taxane-based regimens have also given promising results. Prognosis for the majority of patients, however, remains poor as increases in survival were moderate at best. PMID- 17695437 TI - Microsatellite instability and sensitivitiy to FOLFOX treatment in metastatic colorectal cancer. AB - BACKGROUND: Microsatelite instability (MSI) is the consequence of the inactivation of a mismatch repair gene and is observed in approximately 15% of colon cancer cases. Patients with MSI colon cancer do not benefit from 5 fluorouracil (5-FU)-based chemotherapy. A current treatment of reference for colon cancer is a combination of 5-FU and oxaliplatin (FOLFOX). The aim of this study was to determine the efficiency of the FOLFOX treatment in patients with metastatic MSI colon cancer. PATIENTS AND METHODS: Tumour specimens were collected from patients with metastatic colon cancer treated with FOLFOX 4 modified or FOLFOX 6; these two regimens are based on 85 mg/m2 and 100 mg/m2 oxaliplatin, respectively. The MSI status was assessed by measuring the length of five monomorphic mononucleotide markers. The FOLFOX regimen was evaluated as a first-line treatment according to WHO criteria. RESULTS: Forty patients (22 men, 18 women), median age 63.5 years (27-83 years) were treated with FOLFOX 4 or 6. Nine patients had tumours exhibiting high MSI (MSI group) and 31 patients had tumours exhibiting microsatellite stability (MSS group). In the MSS group, 11 partial responses (36%) were observed, while there were only two in the MSI group (22%) (no significant difference). The two patients who were responders in the MSI group were treated with FOLFOX 6. The overall survival was not significantly different for MSI and MSS patients. CONCLUSION: No significant differences in the overall response rate or overall survival between the two groups of patients were observed. However, these results suggest that patients with MSI colon cancer are more sensitive to a higher dose of FOLFOX. PMID- 17695438 TI - Neoadjuvant chemotherapy with irinotecan and mitomycin-C for locally advanced squamous cell carcinoma of the uterine cervix. AB - BACKGROUND: The efficacy and toxicity of combined therapy with irinotecan (CPT 11) and mitomycin-C (MMC) in a neoadjuvant setting were evaluated in patients with locally advanced squamous cell carcinoma (SCC) of the uterine cervix. PATIENTS AND METHODS: Eligibility included patients with previously untreated cervical carcinoma. CPT-11 (100 mg/m2) was administered on days 1, 8 and 15 intravenously (i.v.), while MMC (10 mg/m2 i.v.) was given on day 1. Survival curves were generated using the Kaplan-Meier method. RESULTS: Among 35 eligible patients, 3 showed a complete response and 27 a partial response, with an overall response rate of 85.7%. No patient showed progressive disease. Thirty-three patients were able to undergo radical surgery after neoadjuvant chemotherapy and only 2 patients (stage IIIb) received radiotherapy without the optimal surgery. The median disease-free survival (DFS) period was 42 months (range 5-73). The median overall survival (OAS) period was 44 months (range 17-74). Two-year DFS and OAS rates were 74.3% and 91.4%, respectively. Of the 58 treatment cycles administered, grade 3 or 4 neutropenia and thrombocytopenia were observed in 50% and 9% of the treatment cycles, respectively. Grade 3 or 4 diarrhea was observed in 6%. CONCLUSION: Neoadjuvant chemotherapy with CPT-11 and MMC can be effective and well-tolerated against locally advanced SCC of the uterine cervix. PMID- 17695439 TI - Combination therapy with thalidomide, temozolomide and tamoxifen improves quality of life in patients with malignant astrocytomas. AB - BACKGROUND: Patients with malignant astrocytomas (MA) have a poor survival rate despite surgery, radiation therapy (RT), and chemotherapy (CT). Patients deteriorate rapidly with decreasing quality of life (QoL). The purpose of the current study was to determine the safety and efficacy, including QoL evaluation, of oral therapy with temozolomide, thalidomide, and tamoxifen (TTT) in patients with MA in an Institutional Review Board (IRB)-approved, prospective trial. PATIENTS AND METHODS: Twenty-three patients met the eligibility requirements and were enrolled after informed consent was signed. After baseline testing, patients received temozolomide 75 mg/m2 orally (p.o.) for the first 21 days, thalidomide 100 mg p.o. daily, and tamoxifen 100 mg p.o. daily for each 28-day cycle. Treatment continued until disease progression. Primary outcome measurements were survival (Kaplan-Meier analysis), response to treatment, toxicity (National Cancer Institute's Common Toxicity Criterion) and QoL evaluation. RESULTS: The Kaplan-Meier analysis showed that survival time from diagnosis was 78.4+/-15 weeks with a median survival of 54.6 weeks and from date of enrollment was 46.1+/ 10 weeks with median survival of 33.3 weeks. Toxicity was limited to 5 patients with deep venous thrombosis (DVT), 2 of whom had pulmonary emboli (PE). All recovered with anticoagulation therapy and none suffered long term sequelae. Several QoL measures, including the global health status scores (p=0.003), were significantly improved after 2 cycles of treatment compared to the baseline assessment. CONCLUSION: The combination of temozolomide, thalidomide and tamoxifen administered as outpatient oral therapy resulted in significantly improved QoL for patients with MA without significant toxicity. PMID- 17695440 TI - Quantification of circulating plasma DNA fragments as tumor markers in patients with esophageal cancer. AB - The quantity and quality of circulating DNA fragments was analyzed by quantitative real-time polymerase chain reactions (qPCR) in plasma from patients with esophageal carcinomas, in order to assess their diagnostic value. PATIENTS AND METHODS: Plasma was collected preoperatively from 24 patients with esophageal cancer and 21 healthy controls. qPCR was performed using two primer sets for the beta-actin gene, amplifying short and long segments. RESULTS: The DNA concentrations in both the short and long assays of esophageal cancer patients were significantly higher than the controls (p<0.001). The area under the receiver-operating characteristic curve was 0.83 (short) and 0.91 (long) for esophageal cancer patients versus the controls. There was also a significant difference in DNA integrity (short/long) between esophageal cancer patients and the control group (p= 0.001). CONCLUSION: qPCR assays for plasma DNA concentrations and their integrity can serve as new diagnostic markers for screening and monitoring patients with esophageal cancer. PMID- 17695441 TI - Clinical management and follow-up of squamous intraepithelial cervical lesions during pregnancy and postpartum. AB - BACKGROUND: The incidence of cervical cancer in pregnancy is estimated to be 1 10/10000 pregnancies. Approximately 3% of cervical cancers are diagnosed during pregnancy. The incidence of abnormal Pap smears has been reported to be 5%-8%. Data on the spontaneous evolution of an intraepithelial neoplasia during pregnancy are quite diverse. Of dysplasia cases diagnosed during pregnancy, 10% 70% regress and sometimes even disappear postpartum, while persistence in the severity of cervical neoplasia is reported in 25%-47% and progression occurs in 3%-30%. However, adequate follow-up and definitive management in the postpartum period is important. The objective of the study was to assess proper management of squamous intraepithelial lesion (SIL) during and after pregnancy, to assess regression, persistence and risk of progression and the predictive role of HPV tests. MATERIALS AND METHODS: Thirty-one out of 721 pregnant women with a diagnosis of low- and high-grade SIL were observed. All patients were triaged using standard colposcopy. The histological diagnosis was assessed by colposcopic direct biopsies. In patients affected by high-SIL with colposcopic findings of suspected micro-invasive lesions, a loop electrosurgical excisional procedure (LEEP) was carried out in pregnancy. High risk HPV tests were performed using PCR. The patients were followed up with cytology and colposcopy every 6-8 weeks during gestation and nine weeks postpartum. They were re-evaluated using cytology, colposcopy and histology for a final diagnosis and, when necessary, submitted to treatment. The patients were followed up for a minimum of 5 years. The HPV test was performed once at 6-8 weeks during gestation and annually during the follow-up. RESULTS: Of the 31 patients with abnormal cytology, histological analysis revealed 10 cervical intraepithelial neoplasia (CIN) 1, 5 CIN 2 and 16 CIN 3. The HPV test at diagnosis was positive for HPV 16 type in 22 cases and negative in 9. Five patients with CIN 2 and 11 with CIN 3 were followed up; 5 patients with CIN 3 with colposcopic findings of suspected microinvasive lesions were submitted to an excisional procedure with LEEP before the 16th week of pregnancy. CONCLUSION: Performing high-risk HPV tests may improve the follow-up of patients with SIL in pregnancy and postpartum in addition to cytology and colposcopy to indicate persistence/progression of the lesions. Proper management and adequate follow-up could be proposed in pregnancy and postpartum. PMID- 17695442 TI - Quantification of plasma cell-free DNA in patients with gastric cancer. AB - BACKGROUND: The circulating DNA concentration and integrity was examined by a quantitative polymerase chain reaction (qPCR) in the plasma from patients with gastric cancer and their diagnostic value for the detection of gastric cancer assessed. PATIENTS AND METHODS: Plasma samples were collected preoperatively from 53 patients with gastric cancer and 21 healthy controls. qPCR was performed using two different primer sets for the beta-actin gene, amplifying short and long segments. DNA integrity was calculated as the ratio of concentrations in both assays. RESULTS: The DNA concentrations in the short and long assays of the gastric cancer patients were significantly higher (p=0.03 and p<0.0001, respectively) than those of the control group. The DNA integrity was also higher in cancer patients than that of the controls, however the difference was not significant (p=0.07). CONCLUSION: The plasma DNA concentration assay may serve as a new diagnostic marker for the screening and monitoring of patients with gastric cancer. PMID- 17695443 TI - Matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) and their tissue inhibitors (TIMP-1 and TIMP-2) in differential diagnosis between low malignant potential (LMP) and malignant ovarian tumours. AB - BACKGROUND: Matrix metalloproteinase-2 (MMP-2) (gelatinase A) and MMP-9 (gelatinase B) have the ability to degrade several extracellular matrix components. This study aimed to evaluate whether matrix metalloproteinases (MMP 2, MMP-9, MMP-2-TIMP-2 complex) or their tissue inhibitors (TIMP-1, TIMP-2) could be used as preoperative serum markers in differentiating between low malignant potential (LMP) and malignant ovarian tumours. PATIENTS AND METHODS: The study population consisted of 61 patients with ovarian neoplasms (28 benign, 11 LMP and 22 malignant). MMP-2, MMP-9, MMP-2-TIMP-2 complex, TIMP-1 and TIMP-2 were analysed from serum samples using enzyme-linked immunoassay (ELISA). RESULTS: Serum TIMP-1 values significantly increased from benign (median 250 microg/l, range 137-616 microg/l) to LMP (median 357 microg/l, range 63-587 microg/l) and further to malignant (median 443 microg/l, range 199-983 microg/l) ovarian neoplasms (p<0.001). There was a significant difference in the ratios of TIMP-1 to MMP-2 and TIMP-1 to MMP-2-TIMP-2 complex between the patients with benign vs. malignant and an LMP vs. malignant tumour. CONCLUSION: The value of circulating TIMP-1 and the ratios of TIMP-1 to MMP-2 and TIMP-1 to MMP-2-TIMP-2 complex may be valuable for differentiating between LMP and malignant ovarian tumours. PMID- 17695444 TI - Prognosis and treatment of primary deep soft tissue sarcomas. AB - The objective of this study was to define the prognostic factors for survival of patients with soft tissue sarcomas (STS) of the extremities located below the muscular fascia. PATIENTS AND METHODS: One hundred and twenty-seven consecutive patients, resected in our Institution between March 1988 and December 2002, were reviewed. RESULTS: On univariate analysis, the prognostic factors for survival were tumor size, nodal status, adequate surgery, tumor malignancy grade and administered chemotherapy. Additionally, local failure, metastasis after resection and residual tumor after incomplete resection followed by complete resection were adverse prognostic factors for survival. The tumor size, nodal status and metastasis after resection were factors indicating worse survival on multivariate analysis. CONCLUSION: Our results indicate that most factors influencing the course of the disease cannot be controlled by the surgeon. Complete resection is imperative for local control and allows the patient the chance of a cure. New treatment procedures should be evaluated in prospective trials to optimize therapy. Surgery without sufficient information on the malignancy or expansion of the tumor might be detrimental for the patient. PMID- 17695445 TI - Measurement of estrone sulfate in postmenopausal women: comparison of direct RIA and GC-MS/MS methods for monitoring response to endocrine therapy in women with breast cancer. AB - BACKGROUND: High concentrations of estrone sulfate (EIS) are present in serum of pre- and postmenopausal women. Most assays for this estrogen conjugate involve enzyme hydrolysis and chromatographic purification prior to RIA. We have compared concentrations of serum EIS in postmenopausal women measured by direct RIA or GC MS/MS methods. PATIENTS AND METHODS: We analysed serum EIS concentrations using a direct 'ultrasensitive' RIA. Serum EIS concentrations were also measured by GC MS/MS in which estrone conjugates are isolated using a solid-phase technique after which enzyme hydrolysis is employed to liberate estrone prior to GC-MS/MS analysis. RESULTS: We analysed 32 serum samples collected from 8 postmenopausal women participating in a Phase I trial of the steroid sulfatase inhibitor 667 COUMA TE. Concentrations of E1S were 998+/-86 pmol/l (mean +/- sem) and 912+/-114 pmol/l as measured by direct RIA and GC-MS/MS methods respectively. There was a highly significant correlation (r=0.96, p<0.001) between concentrations of EIS measured by the different methods. CONCLUSION: We conclude that the direct 'ultrasensitive' RIA for the measurement of serum EIS provides a reliable method for assaying serum concentrations of this estrogen conjugate and should be useful in monitoring the response to endocrine therapy in postmenopausal women with hormone-dependent breast cancer. PMID- 17695446 TI - Intraoperative quantitative detection of CEA mRNA in the peritoneal lavage of gastric cancer patients with transcription reverse-transcription concerted (TRC) method. A comparative study with real-time quantitative RT-PCR. AB - BACKGROUND: Real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) for detection of carcinoembryonic antigen (CEA) mRNA in the peritoneal lavage of gastric cancer patients is now recognized as a useful method for the prediction of peritoneal recurrence after curative surgery. One problem with this method is that it is time-consuming and difficult to perform an intraoperative diagnosis, which is essential for intraperitoneal adjuvant chemotherapy. PATIENTS AND METHODS: In order to overcome these problems, we introduced a transcription-reverse transcription concerted reaction (TRC), which is a non-PCR-based, isothermal mRNA amplification method, as an ultrarapid diagnostic method, and compared its diagnostic power with qRT-PCR for peritoneal washes from 112 gastric cancer patients. RESULTS: TRC measurement could be completed within 1.0-1.5 h and showed the same detection sensitivity ranging from 10(2) to 10(6) copies for standard CEA mRNA as qRT-PCR. The CEA mRNA copy number, as determined by TRC, was well correlated with the depth of tumor invasion (pT category), similar to the result obtained using qRT-PCR. With CEA mRNA copy numbers of 100 as a TRC cut-off value, the resultant sensitivity and specificity of TRC (85% and 100%, respectively) were higher than for cytology (62%, 100%) and comparable to qRT-PCR (92%, 100%). CONCLUSION: TRC has a diagnostic power almost equivalent to qRT-PCR but with the advantage of ultra-rapid detection. TRC would therefore be available for intraoperative sensitive diagnosis of occult tumor cells in the peritoneal cavity of gastric cancer patients. PMID- 17695447 TI - A methionine-free diet associated with nitrosourea treatment down-regulates methylguanine-DNA methyl transferase activity in patients with metastatic cancer. AB - BACKGROUND: Methionine (MET) depletion used in association with chemotherapy improves the therapeutic index in animal models. This potentiating effect may be due to tumor cell sensitization to chloroethylnitrosoureas through their MET dependency and the down-regulation of O6- methylguanine-DNA methyltransferase (MGMT). Our purpose was to evaluate the impact of the association of a dietary MET restriction with nitrosourea treatment on MGMT activity in peripheral blood mononuclear cells (PBMCs). PATIENTS AND METHODS: Six patients with metastatic cancer (melanoma and glioma) received 4 cycles of a MET-free diet with cystemustine (60 mg/m2). RESULTS: MGMT activity in PBMCs decreased by an average of 13% from 553+/-90 fnol/mg before the diet to 413+/-59 fmol/mg after the diet + chemotherapy period (p=0.029). The decrease of MGMT activity was not affected by the duration of the MET-free diet period but seems to be correlated to the plasma MET depletion induced by the MET-free diet. PMID- 17695448 TI - Ulex europeus agglutinin-I binding as a potential prognostic marker in ovarian cancer. AB - BACKGROUND: Ovarian cancer represents the malignant tumour of the female genital tract with the worst prognosis, mainly caused by early intraperitoneal spread. Cell-to-cell and cell-to-matrix interactions play a functionally important role in this spread and are both mediated by the cell membrane. Changes in the glycosylation of the cell membrane, as detected by lectin histochemistry, are sometimes associated with a poor prognosis. PATIENTS AND METHODS: The expression of lectin binding of 164 ovarian cancer patients was analysed and the staining results were correlated with the clinical data of the patients. RESULTS: The univariate and multivariate statistical analysis revealed an independent prognostic significance for Ulex europeus agglutinin-I (UEA-I) binding. CONCLUSION: These findings indicate that UEA-I binding can serve as a prognostic factor in ovarian cancer. PMID- 17695449 TI - Expression of MMP-10 in lung cancer. AB - BACKGROUND: Matrix metalloproteinase (MMP)-mediated degradation of the extracellular matrix is a key point in tumor development and expansion. MMP-10 is one of the most important and well-characterized members of the MMP family. In the present study, we examined MMP-10 mRNA and protein levels in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Three endogenous reference genes including GAPDH, beta-actin and 18S rRNA, and MMP-10 mRNA levels were determined using real-time RT-PCR. Immunohistochemical staining was applied to examine MMP 10 protein levels. Both tumor and adjacent normal lung tissues were collected from 32 NSCLC patients. The mRNA levels of GAPDH, beta-actin and 18S rRNA exhibited great differences in tumor tissues and in the adjacent normal tissues. The ratio of mRNA levels in the tumor tissues compared to the adjacent normal tissues followed the pattern GAPDH > beta-actin > 18S rRNA. Thereafter, we chose 18S rRNA as the reference gene for MMP-10 mRNA level determinations. MMP-10 mRNA levels in tumor tissues were significantly lower than those in the adjacent normal tissues (p =0.0423). However, the MMP-10 protein levels were higher in the tumor tissues than in the adjacent normal tissues (p=0.0055). The MMP-10 mRNA level was positively-correlated to the MMP-10 protein level in tumor tissues (r=0.4672, p=0.0161), but this correlation was not seen in the adjacent normal tissues (r=-0.0030, p=0.9891). CONCLUSION: There were no statistical differences in MMP-10 mRNA levels and protein levels in relation to patient's gender, age, tumor stages, tumor size, lymph node metastasis or tumor histological type. PMID- 17695450 TI - Evaluation of prognostic value of VEGF-C and VEGF-D in breast cancer--10 years follow-up analysis. AB - The aim of the study was to evaluate the prognostic value of vascular endothelial growth factor C (VEGF-C) and VEGF-D expression in stage II, grade 2 and 3, ductal breast cancer patients. PATIENTS AND METHODS: The immunohistochemical staining of 98 tumor samples and 5- and 10-year overall (OS) and disease-free survival (DFS) were analyzed. RESULTS: A significant relationship between VEGF-C and VEGF-D expression (p=0.000002) was noted. No correlations between protein expression and clinical parameters (tumor size, grade, estrogen receptor status, axillaty lymph node metastases and age) or 5- and 10-year DFS or OS were demonstrated. A close to significant correlation (p=0.084) was observed between high expression of VEGF C and 5-year OS. CONCLUSION: Our study did not reveal any prognostic value of VEGF-C or VEGF-D. Therefore they are not useful as markers for patients with poor prognosis. Unlike in other studies, our patient group was homogenous which might have contributed to the results obtained. PMID- 17695451 TI - Survivin expression predicts early recurrence in early-stage breast cancer. AB - BACKGROUND: The apoptosis inhibitor survivin is one of the most specific proteins in breast cancer patients. The role of this protein in predicting prognosis is still controversial. PATIENTS AND METHODS: Survivin mRNA was measured using quantitative TaqMan reverse transcription-PCR in 76 samples, including 48 early stage breast cancer tissues and adjacent normal tissues, from patients with operable tumors, and was tested for correlation with established clinicopathological factors, or disease-free survival (DFS). RESULTS: Comparing the survivin expression in 78 breast cancer patients with the clinicopathological factors (age, menopausal status, nodal category, tumor histology, tumor size, histological grade, ER and PgR status, and type of operation), T factor (T1-T4) was significantly associated with a high survivin mRNA ratio (p=0.0104). The proportion of tumors with a high survivin mRNA ratio was greater in node-positive than in node-negative tumors (p=0.0001), and in grade III tumors compared to grade I or grade II tumors (p =0.0001). Patients with low survivin expression showed significantly better disease-free survival than patients with high survivin expression in stage I and II breast cancer (p<0.0001, log-rank). Survivin expression alone is a powerful prognostic factor for disease-free survival of breast cancer patients without nodal involvement (HR: 0.024, 95% CI: 0.001-0.446, p=0.0123) using Cox multivariate regression analysis. CONCLUSION: Survivin is an indicator of the recurrence of early-stage breast cancer. Survivin might be used as a new marker to stratify early-stage breast cancer patients for more optimal treatment modalities, or it could be a promising target for therapy. PMID- 17695452 TI - Risk factors for different patterns of recurrence after resection of hepatocellular carcinoma. AB - BACKGROUND: Long-term survival of patients with hepatocellular carcinoma after hepatectomy is unsatisfactory because of the high recurrence rate. PATIENTS AND METHODS: Among 396 patients who underwent curative resection of hepatocellular carcinoma, there were 228 patients with clinical recurrence: 85 with solitary intrahepatic recurrence (group A), 109 with two or more intrahepatic recurrences (group B), and 34 who had extrahepatic recurrence (group C). The clinical and pathological factors for each group were investigated for association with long term survival of each group. RESULTS: The survival rate of group C was significantly lower than that of the other groups. Patients in group C were significantly younger than those in groups A or B, with higher levels of protein induced by absence/antagonism of vitamin K-II, larger tumors, more poorly differentiated tumors, intravascular invasion and a lower incidence of cirrhosis than the other groups. Group A showed a significantly longer period until recurrence and maintained good liver function at recurrence. In group B, the survival rate of Child-Pugh class A patients was significantly higher than that of class B and C patients. Class A patients received significantly more treatments for recurrence than patients in the other classes. CONCLUSION: Postoperative adjuvant chemotherapy should be performed as early as possible after hepatectomy if the patient is younger, has a large tumor and/or has a high level of protein induced by absence/antagonism of vitamin K-II. Patients with solitary intrahepatic recurrence and adequate liver function should receive further curative therapy. It is important to maintain the postoperative nutritional status of patients with multiple intrahepatic recurrences in order to allow repeated and aggressive therapy to be performed. PMID- 17695453 TI - Serum tPSA, cPSA, related density parameters and chromogranin A as predictors of positive margins after radical prostatectomy. AB - Serum levels of total prostate specific antigen (t-PSA) and PSA complexed to antichymotrypsin (PSA-ACT), as well as their corresponding density parameters were measured in prostate cancer (PC) candidates for radical prostatectomy. In these patients blood Chromogranin A (CgA) values were also recorded. The PSA-ACT recordings in presurgically characterized organ-confined disease were assumed to predict post-surgical staging better than t-PSA. If this proved correct the novel approach might contribute to the positive predictive value of Partin nomograms. In this prospective study 50 patients with clinically localized PC underwent staging pelvic lymphadenectomy and radical prostatectomy. The numerical values of the tPSA and PSA-ACT parameters were presurgically measured. The PSA and PSA-ACT densities (PSAD and ACTD) of the whole prostate were calculated by using transurethral ultrasound (TRUS) data. These preoperative results together with the CgA values were correlated with post-surgical pathological staging data. The relationships between serum tPSA, PSA-ACT, PSAD, ACTD, CgA and the final stage of prostatectomy specimens derived from the pathological data were analyzed. This preliminary study was performed on a relatively small number of patients who were characterized by a serum PSA <20 and a Gleason score (GS) < or =7. Nevertheless, the application of the logistic regression model showed both t-PSA and PSA-ACT to be superior to their density derivatives in predicting postsurgical pathological stage in PC patients who initially seemed to have localized prostate cancer. An elevation in serum CgA level, although rather infrequent at the early stages of PC is principally found in patients with higher Gleason score PC and was mostly associated with extracapsular tumor spread. Our results do not justify the substitution of PSA-ACT for t-PSA data in the Partin nomogram approach. PMID- 17695454 TI - Developments in the treatment of non-small cell lung cancer. AB - Lung cancer remains the leading cause of cancer-related deaths among men and women in the civilized world. Although there have been major improvements over the recent decades in surgical techniques and the role of chemotherapy radiotherapy in the treatment of non-small cell lung cancer (NSCLC), the long term outlook for these patients has not changed significantly. The median survival for patients with advanced-stage NSCLC treated with platinum-based chemotherapy is a disappointing 8-10 months. In current clinical practice, chemotherapy is used as a combined modality with radiotherapy as an adjuvant or neoadjuvant therapy. Moreover, combination chemotherapy is regarded as the standard care in the treatment of unresectable locally advanced (stage IIIb), metastatic (stage IV), or recurrent disease. The recent developments in the treatment of NSCLC have been focused on the emerging role of adjuvant therapy in the early stages of NSCLC. The clinical activity of pemetrexed, a multitargeted antifolate anticancer agent, as a second-line chemotherapy agent and the impact of new biological agents, such as bevacizumab and erlotinib, have been investigated in phase III trials in the first- and second-line setting. Even though these options have been available in the last few years, there is a clear need for improvement in the current standard of care. No definite survival benefit has yet been demonstrated. An abundant amount of research is still required in the field of lung cancer therapy with well-designed clinical trials and appropriate patient selection. PMID- 17695455 TI - Prospective malignancy grading of invasive squamous carcinoma of the uterine cervix. Prognostic significance in a long-term follow-up. AB - A multifactorial grading score (MGS) for invasive squamous cell carcinoma of the uterine cervix has demonstrated its capacity to predict survival in a 5-10 year perspective and metastasis frequencies, and is a valuable tool for treatment schedules. In this study it was shown that the power of prognosis is valid even up to 20 years. In this material from 619 cervical carcinoma patients the MGS scores turned out to remain as strong as earlier proven. Earlier studies have shown that MGS is superior to other mono- and multifactorial grading systems, histological differentiation into cell types, age, clinical stage, irradiation and DNA-analysis. Treatment of cervical squamous cell carcinoma is more specific today to meet the patients' need for instance to preserve fertility or to minimize operation and eventually radiotherapy. The MGS score is a strong prognostic tool in patients with cervical carcinoma. PMID- 17695456 TI - A population-based study of age-related variation in clinicopathological features, molecular. Markers and outcome from colorectal cancer. AB - BACKGROUND: To investigate age-related differences in clinicopathological features, molecular alterations and patient survival in a large, population-based series of CRC. PATIENTS AND METHODS: The study cohort consisted of 5,971 cases diagnosed between 1993 and 2003 representing over 90% of the CRCs diagnosed in the state of Western Australia. RESULTS: Patients aged < or =30, < or =40, < or =50 and < or =60 years comprised 0.9%, 3.1%, 10.6% and 27.8% of all cases, respectively. The proportion of rectal cancers and tumors with poor differentiation was higher in < or =30-year-old patients and decreased progressively with age. The incidence of tumors with microsatellite instability was significantly higher in patients aged 540 years (18.3%) compared to those aged 41-60 years (6.6%; p<0.0001). TP53 mutations were also more frequent (p=0.002), however K-ras mutations were less common (p =0.0001) when comparing the same age groups. CONCLUSION: These results provide evidence for major age related differences in the clinical and molecular features of CRC. PMID- 17695457 TI - Prognostic value of HER2 and progesterone receptor expression in endometrial carcinoma with positive peritoneal washing. AB - BACKGROUND: Although the majority of endometrial cancer (EC) patients can be cured by surgery, unexpected recurrent disease may also occur in early stage patients. In the present study, whether or not the analysis of multiple biopathological parameters might lead to more accurate predictions of the clinical outcome of EC patients with long-term follow-up (FU) was investigated. PATIENTS AND METHODS: Estrogen and progesterone receptor (ER and PgR) positivity and HER2 overexpression by immunohistochemistry were evaluated. The peritoneal washings (PWs) were analyzed by cytology and immunocytochemistry employing AR-3 and B72.3 monoclonal antibodies. RESULTS: The patients with positive PW and HER2 positive tumors showed shorter overall survival compared to those bearing HER2 negative tumors (p =0.004). HER2 overexpression also influenced the patient outcome in the group with tumors lacking PgR (p = 0.004). At multivariate analysis PgR and HER2 overexpression emerged as independent prognostic factors. CONCLUSION: The combined analysis of these biopathological markers could provide useful information for the selection of patients to be enrolled in innovative therapeutic strategies. PMID- 17695458 TI - A phase II trial of weekly irinotecan in cisplatin-refractory esophageal cancer. AB - BACKGROUND: This study investigated the efficacy and toxicity of weekly single agent irinotecan in patients with metastatic disease relapsing after cisplatin based chemotherapy. PATIENTS AND METHODS: Fourteen patients were enrolled. A total number of 29 cycles (one cycle consisted of CPT-11 100 mg/m2 on days 1, 8, 15, qd 28) were applied. Irinotecan was continued until disease progression or unacceptable toxicity occurred. Where toxicity was less than WHO grade 3, the dose of irinotecan was escalated in 20 mg steps in subsequent cycles up to a maximum dose of 140 mg/m2. Patients were assessed for response according to WHO criteria every second cycle. RESULTS: Of the 13 evaluable patients, 2 achieved a partial response (PR) and 3 disease stabilisation (NC); progressive disease (PD) was noted in 8 patients. Median time to progression was 2 months (range: 1-8 months) and median survival from start of study treatment was 5 months (range: 2 16 months). Grade 3 toxicity consisted of diarrhea (n=3), fever (n=1) and pain (n=1). CONCLUSION: Single-agent irinotecan has moderate activity in cisplatin refractory esophageal cancer. PMID- 17695459 TI - Primary melanoma of the esophagus with non-metastatic dark lymph nodes in a female breast cancer patient. AB - BACKGROUND: Primary melanoma of the esophagus is a very rare and aggressive neoplasm; only a small number of patients survive more than 1 year after initial diagnosis. CASE REPORT: We describe a case of primary melanoma of the esophagus in a woman with a history of invasive breast cancer. The patient suffered from dysphagic and dyspeptic disorders. The abdomen ultrasonography and the esophagogastroscopy showed a lesion located at the esophago-gastric junction extending to the gastric fundus. Histological and immunohistochemical studies revealed a primary esophageal infiltrating melanoma. A total gastrectomy and regional lymphadenectomy with a partial resection of the distal esophagus was performed. RESULTS: During laparotomic exploration, numerous dark lymp hnodes were found. On frozen sections, surprisingly neither malignant cells nor melanin were detected in the lymph nodes. Resection margins were not involved with the tumor. CONCLUSION: Patient is still alive with no evidence of recurrence at 24 months after surgical treatment, alone. PMID- 17695460 TI - Value of RT-PCR analysis of sentinel nodes in determining the pathological nodal status in colon cancer. AB - BACKGROUND: Pathological examination of sentinel lymph nodes (SLNs) and non-SLNs in colon cancer is frequently not performed to the same extent. We examined whether non-SLNs were truly negative in tumors with tumor-negative SLNs using reverse transcriptase-polymerase chain reaction (RT-PCR). PATIENTS AND METHODS: RT-PCR with carcinoembryonic antigen (CEA) was performed in hematoxylin-eosin (H&E) and immunohistochemical (IHC) tumor-negative SLNs. In RT-PCR negative SLNs, we also performed RT-PCR on non-SLNs. Statistical analyses indicated the requirement for a minimum of 72 accurate comparisons of non- SLNs and SLNs, which could be fulfilled using tissues from 12 patients. RESULTS: Negative and positive controls were performed. In nine of the 12 colon tumors, H&E and IHC-negative SLNs were also negative with CEA-RT-PCR. A total of 102 lymph nodes, including 99 non-SLNs were retrieved in these nine specimens and none of the non-SLNs were CEA RT-PCR-positive. CONCLUSION: In this study, all CEA RT-PCR tumor-negative SLNs correctly reflect the tumor-negative status of the non-SLN's in primary colon tumors. The reliability of this method in colon cancer seems promising. PMID- 17695461 TI - Dynamics of serum levels of tumour markers and prognosis of recurrence and survival after liver surgery for colorectal liver metastases. AB - BACKGROUND: The authors present a statistical analysis of the dynamics of tumour markers and compare these with single serum levels in patients before and after liver surgery for colorectal liver metastases (CLM). PATIENTS AND METHODS: The serum levels of tumor markers conventionally used in clinical practice (CA19-9, CEA, CA72-4) and markers informing of the proliferation activity of malignancy (TKI TPA, TPS) were statistically analysed. The authors studied 144 patients who underwent liver surgery for colorectal liver metastases between September 1999 and June 2005. Serum levels of tumor markers before surgery (maximally two weeks before the operation), after surgery (maximally one month after the operation - usually on the day of dismission), six months (+/- one month) and twelve months after the surgery (+/- one month) were determined. The Log Rank test and the Wilcoxon test were used for statistical evaluation. The survival rate and disease free intervals (DFI) were computed using the Kaplan-Meier method. RESULTS: The statistical analysis of tumour marker dynamic after liver surgery (speed and power of recurrence) supported the dynamics of CA 19-9 and CEA as excellent prognostic factors of early recurrence of CLM in contrast to proliferative tumor markers. CONCLUSION: The results of the study suggest the importance of tumour markers for the prediction of a short survival rate or DFI. This approach would be very helpful for the planning of palliative oncological treatment for patients with liver malignancies that cannot be treated by surgical therapy. Current patients with a high tendency of recurrence of CLM after liver surgery should be followed up more thoroughly to increase the possibility of successful reoperation. PMID- 17695462 TI - Brain metastases in patients with advanced breast cancer. AB - BACKGROUND: The incidence of brain metastases (BM) is apparently rising in patients with advanced breast cancer (ABC). We performed a case control study to define current features of breast cancer related to central nervous system (CNS) metastases. PATIENTS AND METHODS: From March 1999 to May 2006, we identified 72 patients with symptomatic BM of breast cancer. A comparison group was randomly selected assigning to each case two patients with primary breast cancer and no BM, matched for year of diagnosis, age and tumour stage (pT status and nodal status). RESULTS: Cases had a significantly higher rate of negative estrogen receptors (ERs) (60% in cases vs. 29% in controls), negative progesterone receptors (PgRs) (79% vs. 43%), HER2/neu over expression (44% vs. 13%) and immunostaining for Ki-67 > or =20% (84% vs. 55%), with p-value <0.001 for all four parameters in univariate analyses. On multivariate analysis, HER2/neu over expression and Ki-67 -20% were independent predictive factors of brain relapse (Odds Ratio (OR) 2.55, 95% confidence intervals (CI) 1.10-5.94 and OR 2.97, 95% CI 1.01-8.73, respectively). Endocrine unresponsive tumours (both ER and PgR <10%) showed an increased risk of relapse with BM of borderline significance (OR 1.91, 95% CI 0.87-4.12). CONCLUSION: Patients with ER and PgR negative tumours either with or without HER-2/neu over expression should be considered at higher risk of BM. PMID- 17695463 TI - Mitomycin C plus capecitabine (mixe) in anthracycline- and taxane-pretreated metastatic breast cancer. A multicenter phase II study. AB - BACKGROUND: Capecitabine is considered the treatment of choice for anthracycline- and taxane-pretreated metastatic breast cancer. Mitomycin C seems to improve the activity of capecitabine by up-regulation of thymidine phosphorylase. PATIENTS AND METHODS: Fifty-five women with metastatic breast cancer previously treated with anthracyclinetaxane were treated with mitomycin C 10 mg/m2 on day 1 every six weeks and capecitabine 1000 mg/m2 on days 2-15 every three weeks. RESULTS: An overall response rate of 38% was found, consisting of 3 (5%) complete responses (CR) and 18 (33%) partial responses (PR); 8 patients (14%) had a stable disease (SD) for more than 4 months. The combination was well-tolerated, with the main toxicities being neutropenia, diarrhea and fatigue; other toxicities were of mild to moderate intensity without impairment in the quality of life of the patients. CONCLUSION: Capecitabine is confirmed as the drug of choice in the treatment of anthracycline- and taxane-pretreated metastatic breast cancer and its combination with mitomycin appears to improve its efficacy. PMID- 17695464 TI - A phase II study of oral UFT and leucovorin concurrently with pelvic irradiation as neoadjuvant chemoradiation for rectal cancer. AB - BACKGROUND: Neoadjuvant chemoradiation with continuous infusion (CI) of 5 fluorouracil (5FU) is widely used in rectal cancer. The aim of this study was to evaluate the use of oral tegafur-uracil (UFT) and leucovorin (LV) instead of CI 5FU. PATIENTS AND METHODS: Patients had resectable T3-4 or low T2 rectal adenocarcinoma. Chemoradiation consisted of pelvic irradiation (45 Gy in fractions of 1.8 Gy) and oral UFT (240 mg/m2/day) and LV (30 mg/day) given during the first 28 days of radiotherapy. RESULTS: Thirty-two patients were treated; 81% had T3-4 tumors and 25% had N+ disease. Toxicity, predominantly gastrointestinal, was generally mild. Grade 3 toxicity occurred in only one patient. Pathological down-staging was noted in 13 patients (42%) and pathological complete response in 3 (10%). Sphincter preservation was possible in 71% of patients undergoing surgery. CONCLUSION: Neoadjuvant chemoradiation with oral UFT/LV is well tolerated and active against rectal cancer. Formal comparison with the current standard treatment is warranted. PMID- 17695465 TI - Qualitative DNA differences between two structurally different lesions: high grade dysplasia and carcinoma in situ in colorectal adenomas. AB - BACKGROUND: Despite the fact that the Vienna classification of neoplasias in the gastrointestinal (GI) tract acknowledged low-grade dysplasia (LGD), high-grade dysplasia (HGD) and carcinoma in situ (CIS) and that most Western pathologists recognize CIS in many organs, both CIS and HGD are still used synonymously in colorectal adenomas. Differences between CIS and HGD in colorectal adenomas are reported. MATERIALS AND METHODS: Five large colorectal adenomas (measuring >20 mm) having areas of both HGD and CIS were stained with hematoxylin and eosin (H&E) and with Feulgen stains. RESULTS: The HGD areas showed tightly packed, spindle shaped, hyperchromatic cells with slight to moderate pleomorphic nuclei having coarse chromatin. In contrast, the CIS cells displayed marked pleomorphism, large vesicular nuclei and a prominent nucleolus. In H&E stain the hyperchromasia found in HGD nuclei was much less evident in CIS nuclei. The HGD nuclei were intensively stained (+++) with the DNA-specific Feulgen reaction but the CIS nuclei were not. CONCLUSION: It would appear that following the completion of chromosomal mutations in the nuclei of HGD-cells, their DNA, carrying the new genetic information, is transcribed into RNA in the nuclei of CIS. Thus, through messenger-RNA, the production of mutated cytoplasmic proteins, required for the ultimate invasion of the lamina propria mucosa (and beyond), would be triggered. PMID- 17695467 TI - Association of XPD polymorphisms with prostate cancer in Taiwanese patients. AB - BACKGROUND: The DNA repair gene XPD, an important caretaker of the overall genome stability, is thought to play a major role in the development of human malignancy. Polymorphic variants of XPD, at codon 312, 751, and other sites, have been associated with cancer susceptibility, but few studies have investigated their effect on prostate cancer risk. PATIENTS AND METHODS: In this hospital based case-control study, the association of XPD codon 312, 751 and promoter-114 polymorphisms with prostate cancer risk in a Taiwanese population were investigated. In total, 123 patients with prostate cancer and 479 healthy controls recruited from the China Medical Hospital in Central Taiwan were genotyped. RESULTS: We found a significant difference in the frequency of the XPD codon 312 genotype, but not the XPD codon 751 or promoter-114 genotypes, between the prostate cancer and control groups. Those who had GIA or A/A at XPD codon 312 showed a 1.81-fold (95% confidence interval=1.21-2.69) increased risk of prostate cancer compared to those with GIG. As for XPD codon 312 or promoter-114, there was no difference in distribution between the prostate cancer and control groups. CONCLUSION: Our findings suggest that the heterozygous and homozygous A allele of the XPD codon 312 may be associated with the development of prostate cancer and may be a useful marker for primary prevention and anticancer intervention. PMID- 17695466 TI - Biweekly administration of docetaxel and gemcitabine as adjuvant therapy for stage II and IIIA non-small cell lung cancer: a phase II study. AB - BACKGROUND: The aim of this study was to determine the overall survival, progression-free survival, and toxicity associated with adjuvant administration of docetaxel and gemcitabine for completely resected patients with stage II and IIIA non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty-nine eligible patients had surgical resection for pathological stage II or IIIA disease and received postoperative gemcitabine 1000 mg/m2 followed by docetaxel 80 mg/m2 on days 1 and 14. Cycles were repeated every 28 days. RESULTS: Treatment compliance was acceptable, at 83%. The median duration of follow-up, time to disease progression, and overall survival was 36.7 months, 17 months and 21 months, respectively. Toxicities were acceptable. Treatment failure revealed brain metastasis (15%), intrathoracic recurrence (24%) and systemic metastasis (36%). CONCLUSION: The biweekly administration of docetaxel and gemcitabine is a safe, well-tolerated and convenient chemotherapy regimen in the adjuvant setting of completely resected NSCLC stage II and III, with efficacy similar to that reported in other regimens. Hence, this nonplatinum based regimen appears promising and warrants further evaluation. PMID- 17695468 TI - Value of repeat resection for survival in pulmonary metastases from soft tissue sarcoma. AB - BACKGROUND: Pulmonary metastasectomy in soft tissue sarcoma (STS) can lead to long-term survival. The aim of our study was to report on prognostic factors and the value of repeat resection in recurrent disease. PATIENTS AND METHODS: Seventy eight pulmonary metastasectomies were performed on 42 STS patients from 1990 to 2005. Overall survival time and 3-year survival rate were evaluated. Subgroup analysis was performed on age, primary tumor stage, histological type and grade, occurrence and recurrence pattern, systemic treatment and number of resections. RESULTS: The 3-year actuarial survival rate was 31%. Primary tumor grade and repeat resections were shown to be independent prognostic factors for survival. CONCLUSION: Patients with repeat resections due to recurrent metastasis show a significantly better prognosis than those with only one resection. Thus, lacking randomised controlled data of the natural course of patients with unresected lung metastases to compare these results, metastasectomy in STS patients is also recommended in recurrent disease. PMID- 17695469 TI - Course of mitogen-stimulated T lymphocytes in cancer patients treated with Viscum album extracts. AB - BACKGROUND: In a prospective observational study, the impact of two different dose regimes of a commercially available fermented Viscum album L. extract (VA-E, Iscador) on the function of T lymphocytes from cancer patients was investigated. PATIENTS AND METHODS: A total of 71 cancer patients were enrolled. These patients attended two different sections of a tumor outpatient clinic which are used to apply different VA-E escalation schemes. Our hypothesis was that a rapid dose escalation of subcutaneously applied VA-E may induce strong local reactions at the injection side (>3 cm diameter) and may have an effect on the functional competence of T lymphocytes (mitogen-activated interleukin-2 receptor alpha chain), which was recorded over an observation period of six month. RESULTS: Within this observation period, a decline of stimulated T cell function was observed, particularly in patients with colorectal or prostate cancer; this decline was not seen in patients with breast cancer (who received lower mean concentrations per month) nor in patients with dose adaptation in response to too strong local reactions. CONCLUSION: With respect to T-cell function, our results indicate that in patients without local reactions, a long lasting mistletoe extract application should be withheld periodically to allow T-cell reactivity to recover. PMID- 17695470 TI - Complications of percutaneous radiofrequency thermal ablation of primary and secondary lesions of the liver. AB - Hepatocellular carcinoma is one of the most common malignancies in the world, with the liver being the second most frequently involved organ in metastatic disease. Although the gold standard treatment for malignant liver disease is surgical resection, only few patients can undergo such an intervention. This explains the current great interest in various loco-regional therapies, of which radiofrequency thermal ablation (RFA) is the most common. To date, only a few studies have evaluated the complications associated with this treatment. The aim of this study was to determine the rate of complications, divided into major and minor, in patients treated with RFA. A total of 373 hepatic lesions in 250 patients were treated with 292 sessions of percutaneous ultrasound-guided RFA. According to our data, ten patients (4%) had major, complications, twelve patients (4.8%) had minor complications, no deaths occurred. Around 30% of patients had a body temperature increase of up to 38 'C. All complications, except one, were treated with nonsurgical therapies. One patient with massive hemoperitoneum required surgery. In conclusion, percutaneous RFA is a loco regional therapy associated with a low incidence of side-effects and a negligible risk of death. PMID- 17695471 TI - Occurence of stromal myofibroblasts in the invasive ductal breast cancer tissue is an unfavourable prognostic factor. AB - BACKGROUND: Numerous experimental studies have described the capacity of myofibroblasts to stimulate mammary cancer cells in a paracrine manner. Until now, the prognostic significance of myofibroblasts present in breast cancer has not been examined. PATIENTS AND METHODS: In paraffin sections, originating from 45 patients with primary invasive breast cancer, immunohistochemical reactions were performed using antibodies directed against smooth muscle actin, Ki-67, VEGF, bFGF and UPA. RESULTS: The cases with higher content of myofibroblasts in the tumour tissue manifested higher grade, more pronounced expression of Ki-67, VEGF and bFGF and shorter overall survival and relapse-free survival. CONCLUSION: The present study for the first time documents the unfavourable prognostic significance of myofibroblasts in tissues of invasive ductal mammary carcinomas. PMID- 17695472 TI - Chondrosarcoma of the larynx and review of the literature. AB - Chondrosarcoma (CS) of the larynx was first described in 1935. Cartilaginous tumours of the larynx are largely rare and there is little literature concerning them. Laryngeal CS manifest with a different pathological behaviour to other malignancies of the larynx and as such the treatment of these neoplasias are different. The purpose of this review is to present a detailed report of the laryngeal CS in recent literature. We present a case of laryngeal CS of the cricoid cartilage and a case of a sarcomatous neoplasm of the vocal cord as a potential differential diagnosis. Although representing a rare malignancy, the last decade has brought new insights in surgical treatment of laryngeal CS and subsequent reduction in recurrence rates, whereas progress in tumour biology and etiological agents is still scarce. We concentrate on new insights in classification, radiologic and pathologic features, and treatment modalities in the last two decades. Based on the literary evidence the authors recommend a conservative laryngeal function-preserving surgery. Total laryngectomy should be reserved to recurrent CS and rare cases of voluminous high-grade CS of the larynx. PMID- 17695473 TI - Association between allelic polymorphisms of metabolizing enzymes (CYP 1A1, CYP 1A2, CYP 2E1, mEH) and occurrence of colorectal cancer in Hungary. AB - BACKGROUND: Genetic polymorphisms of metabolizing enzymes may affect the risk of cancer formation in humans. Since the diet can contain polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HAs), the relationship between polymorphisms of enzymes involved in PAH and HA metabolism and the occurrence of sporadic colorectal cancer was studied. PATIENTS AND METHODS: Five hundred colorectal cancer patients and 500 controls were genotyped for cytochrome P450 enzymes (CYP) 1A1 Ile/Val, CYP 1A2*1F, CYP 2E1 c1/c2, microsomal epoxy hydrolase (mEH) exon 3 Tyr113His and exon 4 His139Arg polymorphisms by allele-specific polymerase chain reaction (PCR) or PCR-restriction fragment length polymorphism (RFLP). RESULTS: The presence of CYP 1A1 Val, CYP 2E1 c2 and mEH exon 3 His alleles was statistically significantly associated with the occurrence of colorectal cancer (OR: 1.44 95% CI: 1.04-2.00; OR: 1.74 95% CI: 1.15-2.65; OR: 1.79 95% CI: 1.10-2.92, respectively). CONCLUSION: These findings suggest that allelic polymorphism of metabolizing enzymes play an important role in human colorectal carcinogenesis by affecting the metabolism of dietary carcinogens. PMID- 17695474 TI - Clinical and dermoscopic criteria related to melanoma sentinel lymph node positivity. AB - BACKGROUND: The early detection of lymph node metastases may have important prognostic and therapeutic implications in melanoma patients. The purpose of this study was to investigate whether specific clinical and/or dermoscopic features could be "in vivo" predictors of sentinel lymph node (SLN) positivity in melanomas >1 mm thick. MATERIALS AND METHODS: Five Italian centres (Istituto Dermopatico dell'Immacolata, IDI, Rome; Skin Cancer Unit, Oncologia Dermatologica, CPO, Ravenna; Istituto Europeo Oncologico, Milan; Centro di Riferimento Oncologico, Aviano; Istituto Nazionale Tumori, Naples) carried out a blind retrospective study on 508 melanomas observed from January 1994 to December 2002. The clinical and dermoscopic features of 78 melanomas >1 mm thick with the SLN biopsied were reviewed. RESULTS: The tumour palpability was the only factor correlated to SLN positivity in melanomas >1 mm thick. Palpability was found in 46.2% of nodal positive melanomas and in 18.5% of nodal negative melanomas (p=0.03). The patients with palpable melanomas showed a higher risk of nodal metastasis (OR=3.8). Dermoscopy failed to recognize predictive criteria for SLN positivity. Some clinical and dermoscopic features, although not statistically significant, showed interesting differences between nodal-negative and nodal positive melanomas. CONCLUSION: Melanoma palpability may suggest the presence of nodal metastasis in >1 mm thick tumours. PMID- 17695475 TI - Performance status (PS): a simple predictor of short-term outcome of cancer patients with solid tumors admitted to the intensive care unit (ICU). AB - BACKGROUND: Admission of cancer patients with serious medical complications to the Intensive Care Unit (ICU) remains controversial. The aim of this study was to examine the 30-day all-cause mortality in cancer patients with solid tumors admitted to the ICU and to identify factors predicting 30-day mortality. PATIENTS AND METHODS: A retrospective study was conducted in 69 consecutive cancer patients with solid tumors admitted to the ICU of a 400-bed general hospital in Greece, between October 2001 and October 2005. Demographics, ECOG performance status (PS) prior to hospitalization, stage of cancer, metastases, number of metastatic sites, prior chemotherapy, primary site of tumor, APACHE II score on ICU admission, development of ICU acquired infection, sepsis, multiple organ failure (MOF), need for mechanical ventilation (MV), length of ICU stay, hospital stay and 30-day mortality were examined. RESULTS: The observed 30-day hospital mortality rate was 66.6% (n=46) with most deaths (n=32) occurring in the ICU. Univariate negative predictors of 30-day mortality were PS 3-4 (p=0.03), APACHE II score (p=0.001), MOF (p=0.001) and need for MV (p=0.001). Only PS 3-4 was an independent predictor in multivariate analysis (p=0.02). CONCLUSION: ECOG PS 3-4 prior to hospitalization was found to be a simple negative predictor of short term outcome of cancer patients with solid tumors admitted to the ICU. PMID- 17695476 TI - Axillary lymph node metastases detection with 99mTc-sestamibi scintimammography in patients with breast cancer undergoing curative surgery. AB - BACKGROUND: Axillary lymph node (AN) status is the primary prognostic discriminant in patients with breast cancer (BC). Although axillary dissection represents the method of choice for obtaining such information, less invasive procedures have been suggested. The aim of this study was to evaluate the usefulness of 99mTc-sestamibi scintimammography (SSM) in detecting AN involvement in patients with confirmed primary BC undergoing surgery. PATIENTS AND METHODS: A series of 159 consecutive women (median age 54 years, range 36-78 years) with confirmed BC undergoing curative surgery were enrolled in the study. Each patient underwent SSM, from 4 to 12 days prior to surgery. According to the tumour staging, modified radical mastectomy was performed in 41 (25.8%) patients, while 118 (74.2%) patients underwent breast conserving surgery with dissection of the axilla. The results of SSM were compared against the final histological evaluation of the axillary nodes. RESULTS: The final pathology showed 33 (20.8%) pT1b, 90 (56.6%) pT1c, and 36 (22.6%) pT2 breast carcinomas. The greatest diameter of the tumour ranged from 8 to 30 mm (median 16 mm). Sixty patients (37.7%) had axillary node metastases (N1), and 99 (60.3%) had negative nodes (NO). The age of the patients significantly correlated with both size of the tumour (R=0.24, p<0.01) and number of positive nodes (R=0.33, p<0.01). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of SSM in detecting AN metastases were 81.4%, 91.0%, 84.2%, 91.0% and 87.4%, respectively. The sensitivity was higher in patients with three or more positive nodes (27 out of 28, 96.4%), while in patients with two (n=25) or one (n=7) positive nodes, the sensitivity decreased to 80% and 28.6%, respectively. CONCLUSION: SSM may be useful in patients undergoing surgery for BC when a preoperative assessment of axillary lymph node status is required. Unfortunately, the sensitivity of SSM in detecting node metestases in patients with BC is low when the number of involved nodes is two or less. This suggests that other imaging techniques should be used is conjunction with SSM, with the aim of increasing both sensitivity and specificity. PMID- 17695477 TI - Expression of mRNA MMP-7 and mRNA TIMP-1 in non-small cell lung cancer. AB - BACKGROUND: Destruction of the extracellular matrix is a necessary precondition for metastasis and invasion of tumour cells. Metalloproteinases (MMPs) are involved in this process, matrilysin being one of them (MMP-7). The results of our pilot study with patients operated on for non-small cell lung carcinoma (NSCLC), with the assessment of MMP-7 and the tissue inhibitor of matrix metalloproteinase (TIMP-1), are presented here. PATIENTS AND METHODS: The group consisted of 34 patients who had been operated on in the course of 2005. Messenger RNA MMP- 7 and TIMP-1 were assessed in 20 cases (58%). Tissue samples were frozen to -70 degrees C, total RNA was subsequently isolated and a reverse transcription was performed from it. The quantitative assessment itself was performed using a real-time PCR method. The resulting expression level was determined as the expression ratio of the assessed gene and the housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). RESULTS: A higher expression of mRNA MMP-7 was found in the NSCLC tissue than in non-tumourous lung tissue. On the other hand, a higher expression of mRNA TIMP-1 in the non tumourous surrounding lung tissue was demonstrated. The expression of mRNA MMP-7 and TIMP-1 was higher in adenocarcinoma than in the epidermoid form of NSCLC. CONCLUSION: The value of our results should not be overestimated since we had only a small group of patients and assessed only one of the whole range of metalloproteinases (MMP-7). We consider the assessment and ratio quantification of metallorpoteinases in normal lung and NSCLC to be the first step in a further application of these parameters. PMID- 17695478 TI - The distribution and pathological staging of colorectal cancers in ethnic groups. AB - BACKGROUND: There is little data on the distribution and histological staging of colorectal cancer in ethnic groups in the United Kingdom. A study to investigate this was undertaken at a hospital serving a multi-ethnic population. PATIENTS AND METHODS: Case analysis from a prospective database of all colorectal cancers between 2000-2004 was performed. Data was recorded on the distribution of cancer, operative procedures and Dukes' staging. RESULTS: A total of 256 patients (118 females) were diagnosed with colorectal cancer, of whom 214 (83.6%) underwent resection. There were 39 Afro-Caribbeans 66.2 years +/- 12.6 years; mean [age +/- s.d.], 14 Asians 64 years +/- 12.6 years, 34 Mediterraneans 67.7 years +/- 9.9 years and 176 Caucasian British 74.3 years +/- 11.3 years. Right-sided colonic lesions were more frequent in Afro-Caribbeans, whilst left-sided lesions were more frequent in Mediterraneans. The incidence of Dukes'A cancer was high in Mediterraneans whilst Dukes' C cancer was commoner in Caucasians and Afro Caribbeans. CONCLUSION: Ethnic patients present with colorectal cancer at significantly younger ages. Afro-Caribbeans have significantly more right-sided and Mediterraneans more left-sided cancer. Afro-Caribbean and Caucasian patients present with more advanced cancer compared to Mediterraneans. This has implications on the investigation, as well as screening in ethnic minority patients. PMID- 17695479 TI - Vertical platysma myocutaneous flap reconstruction for T2-staged oral carcinoma. AB - The surgical resection of tumour-affected oral soft tissue structures often leads to tissue defects. Various techniques can be used for reconstruction. Our experience of using a vertical platysma myocutaneous flap in a group of patients who underwent reconstruction after T2-staged oral cancer surgical resection associated with neck dissection is described. Only one patient required a surgical revision, due to flap detachment, with a pectoralis major myocutaneous flap. No other major complications, such as nerve lesions or orocutaneous fistulas, were observed. Satisfactory swallowing function was achieved within two weeks in all cases. A platysma myocutaneous flap is a versatile, easy-to-perform, one-stage procedure, and the outcome is best in adequately selected patients; it should not be adopted in patients who have undergone previous neck surgery or radiotherapy, or if radical neck dissection is planned. Care is required to preserve the external jugular vein and the submental artery, particularly when level I is dissected. PMID- 17695480 TI - Dummy run for a phase II multi-institute trial of chemoradiotherapy for unresectable pancreatic cancer: inter-observer variance in contour delineation. AB - The aim of this study was to examine the interobserver variance in delineating the contour of unresectable pancreatic cancer for chemoradiotherapy. PATIENTS AND METHODS: CT images of two cases of unresectable pancreatic tumors (head and body cancer) were sent to eight radiation therapy facilities in a CD-ROM. Gross tumor volume (GTV) and planning target volume (PTV) were delineated using the radiotherapy treatment planning system (RTP) of the respective facilities. The mean and variance of the GTV and PTV of 11 plans by the eight facilities were analyzed. RESULTS: The respective mean volumes of the GTV of pancreatic head and body cancer cases were 34.8 cm3 (SD, 30.4; median, 31.8; range, 13.5-122 cm3) and 73.4 cm3 (SD, 28.1; median, 67.9; range, 46.3-152 cm3). The ratios of the largest to the smallest contoured GTV were 9 and 3, respectively. The corresponding average volumes of PTV were 148 cm3 (SD, 84.3; median, 129; range, 69.6-363 cm3) and 240 cm3 (SD, 79.8; median, 227; range, 148-420 cm3). The ratios of the largest to the smallest contoured volume were 5 and 2.8 for PTV delineation, respectively. CONCLUSION: Dummy run using CD-ROM is possible on a multi-institute scale but also disclosed interobserver variance. Unified protocol interpretation to reduce inter-observer variance is therefore essential for successful multi institute clinical trials. PMID- 17695481 TI - Expression of a molecular marker panel as a prognostic tool in gastric cancer patients treated postoperatively with docetaxel and irinotecan. A study of the Hellenic Cooperative Oncology Group. AB - INTRODUCTION: This study evaluated the prognostic role of vascular epidermal growth factor (VEGF), thymidylate synthase (TS), topoisomerase I (Topo-I), topoisomerase IIalpha (Topo-IIalpha) and E-cadherin (E-cadh) tumor expression, in patients with resectable gastric cancer, who were treated postoperatively with the docetaxel/irinotecan combination. PATIENTS AND METHODS: Forty-five patients with resectable gastric cancer were treated with 6 cycles of docetaxel 30 mg/m2 and irinotecan 110 m/m2 on day 1 and d8 every 21 days. All specimens were examined by using immunohistochemistry (IHC) for the expression of VEGF, TS, Topo I, Topo-IIalpha and E-cadh. RESULTS: Positivity for TS was significantly correlated with age and for VEGF with diffuse histological type and good PS. No significant correlation was observed among Topo-I, Topo-IIalpha and E-cadh positivity with any of the clinicopathological parameters studied. Median overall survival (OS) was 31.7, and disease-free survival (DFS) 26 months, respectively. None of the above-investigated molecular markers were significantly associated with OS and DFS. Finally, according to the univariate analysis for survival, only advanced stages (III, IV) of the disease implied risk of death, mainly due to lymph node involvement and, to a lesser extent, tumor size. None of the studied molecular markers were found to be independent prognostic markers. CONCLUSION: These results should be interpreted very cautiously, due to the limited number of patients studied, as well as the limitations of the IHC technique. PMID- 17695482 TI - Efficacy of IL-2 immunotherapy in metastatic renal cell carcinoma in relation to the psychic profile as evaluated using the Rorschach test. AB - BACKGROUND: Despite the well-documented importance of the psycho-emotional status in modulating the anticancer immunity, at present no study has been performed to analyse the influence of the psychological condition on the efficacy of IL-2 cancer immunotherapy. Previous clinical studies have already suggested that the evidence of anxiety may negatively affect the therapeutic efficacy of IL-2 immunotherapy of cancer. Moreover, previous psycho-oncological investigations showed that the suppression of sexual pleasure and sexual identity would represent one of the most frequent psychological profiles in cancer patients. On this basis, a study was planned in an attempt to evaluate relations existing between psychological status, analysed using the Rorschach test and efficacy of IL-2 immunotherapy in the treatment of metastatic renal cell cancer patients. PATIENTS AND METHODS: The study included 30 consecutive metastatic RCC patients. IL-2 was injected s.c. at a dose of 3 million IU twice/day 5 days/week for 4 consecutive weeks, corresponding to one complete immunotherapeutic cycle, followed by a second cycle after a 21-day rest period. RESULTS: A complete response (CR) was achieved in only 1/30 (3%) patients; a partial response (PR) was obtained in 6/30 (20%) patients. The tumor response rate (CR +PR) was 7/30 (23%) patients. The performance of a psychological analysis was accepted by 24/30 (80%) patients. A normal sexual identity was present in 7/24 (29%) patients. The tumor response rate achieved in patients with sexual identity was significantly higher compared to these who had no sexual identity or who refused the psychological investigation (p<0.05 and p<0.01, respectively). In the same way, the increase in mean lymphocyte number obtained in patients with sexual identity was significantly higher compared to that found in the other two groups of patients. CONCLUSION: This study demonstrated that the psychological status prior to treatment may be associated with the clinical response to IL-2 cancer immunotherapy. PMID- 17695483 TI - Gemcitabine and oral vinorelbine as salvage treatment in patients with advanced anthracycline- and taxane-pretreated breast cancer. AB - BACKGROUND: Despite progress achieved with new chemotherapeutic and endocrine agents, advanced breast cancer (ABC) remains a disease with poor prognosis. We sought to determine the efficacy of gemcitabine (GC) and oral vinorelbine (VB) in heavily preatreated ABC. PATIENTS AND METHODS: Patients previously treated with anthracyclines and taxanes in the metastatic setting with progressive disease were eligible. Treatment consisted of VB (60 mg/m2, orally) and GC (1000 mg/m2, intravenous infusion), every two weeks of a 28- day cycle. RESULTS: Thirty-one patients with ABC were enrolled. Toxicity was acceptable, mainly haematological. Three and 8 patients achieved a complete (9.6%) and partial (25.8%) response, respectively; ten patients (32.2%) had stable disease. Median time-to-progression was 5.3 months, while in responders 8.6 months. Median overall survival was 14 months. CONCLUSION: Oral VB and GC is an active and well-tolerated combination in anthracycline/taxane-pretreated ABC, representing an interesting option in this poor prognosis group of patients. PMID- 17695484 TI - Analysis of long-term survivors of glioblastoma multiforme in a single institution with aggressive local retreatment protocol. AB - Current treatment methods result in survival beyond 2 years in just a minority of adult patients with glioblastoma multiforme (GBM). Our institution has used an aggressive policy of local retreatment, including surgery and radiotherapy, at first relapse. Long-term survival (>2 years) after such an approach was evaluated. PATIENTS AND METHODS: A retrospective analysis was carried out of all patients with confirmed histological diagnosis of GBM at relapse. Patients with oligodendroglial component or progression from low-grade glioma were not included. RESULTS: Out of the 30 patients managed with aggressive local retreatment, 8 survived for more than 2 years, but no 5-year survivors were observed. All were younger than 60 years, had a good performance status, RPA class III or IV and a long interval to relapse. Those with the longest survival times had also received two different chemotherapy regimens. However, two of the patients were never treated with chemotherapy. Survival from retreatment was 5-17 months. CONCLUSION: When selecting patients on the basis of the factors associated with long-term survival, the same sequence of surgery, radiotherapy and chemotherapy that should be considered at first diagnosis might provide a moderate survival extension. PMID- 17695485 TI - Effects of intralesional 32-P chromic phosphate in refractory patients with head and neck tumours. AB - BACKGROUND: The clinical outcome of refractory head and neck (H&N) cancer patients remains poor despite novel treatment strategies. In this pilot study the efficacy of intratumoral injection of 32-P chromic phosphate in 14 patiehts with refractory H&N carcinomas was investigated in terms of response rates and overall survival. PATIENTS AND METHODS: Fourteen patients (median age: 59 years) with either cytostatic drug-resistant tumours or tumours known to be primarily chemotherapy-resistant were entered into the study. After sonographic determination of the tumour volume, 32-P chromic phosphate (74-444 MBq) was injected into the central part of the tumour under sonographic guidance. Follow up investigations included serial scintigraphy, sonographic examinations and hematological studies. RESULTS: Injection of 32-P chromic phosphate into refractory H&N tumours resulted in remarkable regression. The median survival of all patients was 7.8 months (range: 4-16). Eight patients exhibited a partial response, while 6 patients did not respond to the treatment. In 3 patients thrombocytopenia (grade I/II) was observed, but no other significant side-effects were apparent. Significant pathological and anatomical changes within the tumour tissue were demonstrated. In all cases examined, formation of a cyst within the area of central activity, surrounded by a centrifugal necrotic ring and a marginal fibrotic structure, was found. CONCLUSION: A lack of persistent systematic or local side-effects, as well as noteworthy efficacy, are properties of this novel regional treatment modality with 32-P chromic phosphate. This modality deserves consideration for further clinical trials. PMID- 17695486 TI - Preoperative serum C-reactive protein level in non-small cell lung cancer. AB - We evaluated the significance of the preoperative serum C-reactive protein (CRP) level as a prognostic indicator in patients with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Two hundred and three patients who had undergone a curative resection of NSCLC were retrospectively reviewed. RESULTS: The proportion of the tumor size over 3 cm per patient in the CRP-positive group (> or =0.5 mg/dL: n=38) was significantly higher than that in the CRP-negative group (<0.5 mg/dL: n = 165). The proportion of the adenocarcinoma in CRP-positive group was significantly lower than that in CRP-negative group. The overall and disease specific survival rates in the CRP-positive group were significantly lower than the rates in the CRP-negative group. Based on a multivariate analysis, the preoperative serum CRP level was selected as one of the unfavorable indicators regarding survival. CONCLUSION: The preoperative serum CRP level is an independent and significant indicator predictive of a poor prognosis in patients with NSCLC. PMID- 17695487 TI - Second-line chemotherapy of platinum compound plus CPT-11 following ADOC chemotherapy in advanced thymic carcinoma: analysis of seven cases. AB - BACKGROUND: Optimal chemotherapeutic regimen in thymic carcinoma remains uncertain and the efficacy of second line chemotherapy has not been established either. PATIENTS AND METHODS: We retrospectively evaluated the efficacy of an irinotecan plus cisplatin or carboplatin (IP) regimen as a salvage treatment for patients with unresectable thymic carcinoma that progressed after cisplatin, doxorubicin, vincristine and cyclophosphamide (ADOC) chemotherapy. Seven patients with histologically confirmed thymic carcinoma that was resistant to or who had relapsed after initial chemotherapy with ADOC were treated with IP. The treatment consisted of irinotecan (CPT-11, 60 mg/m2, days 1, 8 and 15) and cisplatin (80 mg/m2, day 1) or carboplatin (AUC 4) intravenously every 4 weeks, for at least 2 cycles. RESULT: Two patients achieved partial responses. Although another two patients showed a significant reduction of the primary thoracic lesion, the appearance of a new lesion was found in one and a metastatic lesion was unchanged in the other. Neutropenia over grade 3 was observed in all patients but none of the patients developed serious infections. There were no severe non-hematological toxicities, including diarrhea. CONCLUSION: We conclude that salvage chemotherapy may be useful in certain patients with thymic carcinoma and irinotecan may be a novel and alternative agent for relapsed thymic carcinoma. PMID- 17695488 TI - Capecitabine plus hepatic intra-arterial epirubicin and cisplatin in unresectable biliary cancer: a phase II study. AB - The aim of the present study was to evaluate the activity of hepatic intra arterial infusion of epirubicin and cisplatin combined with oral capecitabine, in patients with unresectable biliary carcinomas. PATIENTS AND METHODS: Twenty patients were treated by bolus infusion of epirubicin 50 mg/m2 and cisplatin 60 mg/m2 in the hepatic artery on day 1, combined with oral capecitabine 1000 mg/m2 bid, from day 2 to day 15. RESULTS: Partial responses (PR) were observed in 6 patients (31.5%), stable disease (SD) in 9 (47.5%) and progression (PD) in 4 (21%). The median progression-free and overall survival periods were 11.6 and 18.0 months, respectively, and 1-year survival was 74%. One patient died after the first cycle because of G4 diarrhea. The other patients had good tolerance, with minimal hematological toxicity and only 1 G3 vomiting. CONCLUSION: This combined intra-arterial and oral approach to patients with biliary carcinomas was found to be active and safe and seems to produce an encouraging survival response. PMID- 17695489 TI - Germline NBS1 mutations in families with aggregation of Breast and/or ovarian cancer from north-east Poland. AB - BACKGROUND: NBS1 gene, which product participates in DNA repair, has been postulated to be a susceptibility factor for a number of types of cancer, including breast cancer. The carrier frequency of the 657del5 and I171V NBS1 gene mutations among Polish patients with familial breast and/or ovarian cancer was compared with that of randomly selected newborns. PATIENTS AND METHODS: Using allele-specific amplification-polymerase chain reaction (ASAPCR) and restriction fragment length polymorphismpolymerase chain reaction (RFLP-PCR) techniques, blood samples were analysed from 250 patients with breast or/and ovarian cancer and a total number of 4,000 for 657del5 mutation and 1,300 for I1171V mutation controls. RESULTS: Although an increased frequency of both mutations in cancer cases - 0.8% of 657del5 and 2.4% of I171V, compared to controls - 0.52% and 1.38%, respectively, was found, the differences were not statistically significant. CONCLUSION: Our results indicate that NBS1 mutations do not contribute significantly to breast or ovarian cancer development. PMID- 17695490 TI - 5-year results of cisplatin-epirubicin-vinorelbine (PEV) combination as primary chemotherapy in T2-3, N0-2 breast cancer patients: a multicentre phase II study. AB - The aim this study was to assess the efficacy of cisplatin-epirubicin vinorelbine, as primary chemotherapy, in reducing the tumour burden in T2-3 N0-2 breast carcinomas. Breast conservative surgery (BCS) rate, clinical and pathological complete response (pCR), toxicity and 5-year disease-free survival (DFS) and overall survival (OS) were evaluated. PATIENTS AND METHODS: Eighty eight women with tumours > or =2.5 cm were treated with cisplatin (P) 50 mg/m2, epirubicin (E) 100 mg/m2 and vinorelbine (V) 25 mg/m2, every 3 weeks. RESULTS: Fifty-six out of the 88 patients (63.6%) underwent BCS, notably including 12/23 patients with initial tumours >5 cm. The overall clinical response was 72.8% (cCR=11.4%), pCR 20.5% and pTO+pNO 17%. No cardiac toxicity was observed. Grade 3/4 adverse events were leukopenia (9.4%), neutropenia (7.9%), nausea and vomiting (7.3%). After a median follow-up of 5 years, 24 patients (27.3%) had developed local or distant metastases. The mean DFS and OS were 51.7 (SE 2.38) and 57.02 (SE 1.98) months, respectively, and were significantly higher in pCR patients in comparison to the others (63.05 vs. 48.76, p<0.01 and 64.59 vs. 55.04, p<0.05, respectively). CONCLUSION: The PEV regimen was highly effective in reducing the tumour burden, especially for large tumours. The rate of pCR was similar to that obtained by other, including taxane-based regimens, and was well tolerated. The study demonstrated the feasibility of such a regimen even in small centres, and being of low cost this combination could be of value in the application of primary therapy. PMID- 17695491 TI - Successful treatment with cyclosporine of thymoma-related aplastic anemia. AB - Aplastic anemia is a rare immune-mediated complication of thymoma. Thymomas, especially of the cortical type, have the capacity to generate mature T-cells from their immature precursors. Furthermore, mature intratumorous T-cells have an increased autoantigen-specific potential. We present the case of a 75-year-old patient with an inoperable cortical thymoma who developed aplastic anemia 7 years after the initial diagnosis. The infiltration of the bone marrow by these cells was accompanied by the production of cytokines such as tumor necrosis factor alpha (TNF-alpha) in the microenvironment of bone marrow and in the serum sample. The patient was successfully treated with oral cyclosporine A for 14 months and when she died due to progression of the thymoma, 9 months after the discontinuation of cyclosporine, the aplastic anemia had not recurred. PMID- 17695492 TI - Clinical significance of nm23 gene expression in gastric cancer. AB - BACKGROUND: The expression of the nm23 gene has been associated with the development of metastasis. Numerous studies have shown down-regulation of nm23 expression in metastatic breast and colon cancer. The expression of the putative metastasis-suppressor gene nm23 in gastric carcinoma is controversial. The aim of this study was the analysis of nm23 expression in a large series of gastric cancer patients. PATIENTS AND METHODS: In a retrospective immunohistochemical study specimens obtained from 116 gastric cancer patients (mean age 64 years; range: 33-85) who had undergone gastrectomy with extended lymphadenectomy were analyzed. Nm23 expression in the tumor epithelium was studied by immunohistochemistry followed by a semi-quantitative (score 0-3) evaluation. Statistical analysis including Chi-square test, uni- and multivariate survival analyses were performed. RESULTS: The nm23 staining pattern was positive (score 2 3) in 100 (86.2%) specimens and negative (score 0-1) in 16 (13.8%) samples. Lymph node metastasis was found in 65% of the patients. No significant correlations could be determined between nm23 expression and other variables such as gender, age, tumor differentiation, WHO-, Lauren-, Goseki-, or Ming-classification. The intensity of nm23 staining in the tumor cells was not significantly correlated with depth of tumor infiltration (T-stage), lymph node metastasis (N-stage), distant metastasis (M-stage), UICC-stage, or prognosis. CONCLUSION: Our series did not show a correlation of nm23 expression in terms of lymph node and distant metastasis or prognosis in gastric cancer patients. PMID- 17695493 TI - Differential resistance of melanoma cells to treatment with recombinant IFN alpha2b and leukocyte IFN. AB - BACKGROUND: Interferon-alpha (IFN-alpha) subtypes bind to the same receptor and are expected to have the same biological functions. Whether or not leukocyte IFN, containing six major IFN-alpha proteins had the same anti-tumor effect as one subtype, recombinant IFN-alpha2b, was investigated. MATERIALS AND METHODS: Three melanoma lines were treated with both types of IFN, and the effect on proliferation and survival was estimated both after short-term and prolonged treatment. RESULTS: All the melanoma cell lines were sensitive to the antiproliferative effects of both IFN species during short-term treatment. However, upon prolonged culture, the frequency of resistant colony formation was significantly higher in cultures treated with IFN-alpha2b compared to those treated with leukocyte IFN. There was a qualitative difference between the resistant colonies selected by the two IFN species with respect to morphology, growth rate and sensitivity to apoptosis. CONCLUSION: The development of resistant clones occurred at a lower rate during long-term treatment with leukocyte IFN containing six major subtypes of IFN-alpha as compared to IFN alpha2b. PMID- 17695494 TI - MDR1/P-glycoprotein and MRP-1 drug efflux pumps in pancreatic carcinoma. AB - BACKGROUND: Pancreatic cancer is one of the most challenging solid organ malignancies. This is due to its aggressiveness, frequent late presentation as advanced disease and chemoresistance. A better understanding of the molecular basis of its drug resistance is needed. MATERIALS AND METHODS: In this study, the first of its kind, the expression of both MDR1 P-gp and MRP-1 protein in pancreatic tumour specimens was examined by immunohistochemistry. Expression of these drug efflux pumps was examined using semi-quantitative immunohistochemistry according to the percentage of cells within the tumour, demonstrating another staining intencity. RESULTS: Overall, 93.3% of pancreatic carcinomas expressed MDR1 P-gp, approximately 31% co-expressed MRP-1 with MDR1 P-gp, while 6.7% expressed neither of these proteins. CONCLUSION: Our results show that drug efflux pumps, in particular that of MDR1 P-gp, are frequently expressed in pancreatic cancer. While a causative role for these efflux pumps in pancreatic cancer chemoresistance cannot necessarily be concluded, the information presented here should be considered when selecting chemotherapy/drug efflux pump inhibitors for future therapies. PMID- 17695495 TI - Antigen loading of dendritic cells with apoptotic tumor cell-preparations is superior to that using necrotic cells or tumor lysates. AB - BACKGROUND: Loading of dendritic cells (DCs) with tumor cell (TC) preparations is an attractive method for vaccine preparation because the entire antigen repertoire of a tumor is processed and presented by the DCs, thus allowing the simultaneous stimulation of T-helper cells and cytotoxic T-lymphocytes. However, optimal loading conditions have still to be defined. MATERIALS AND METHODS: DCs were pulsed either with tumor lysates, apoptotic or necrotic preparations of a breast cancer cell line and subsequently used to stimulate autologous T lymphocytes. Antigen loading was quantified using immunofluorescent-based methods. RESULTS: Four hours co-incubation of apoptotic TCs or tumor lysates with DCs undergoing maturation resulted in effective DC-loading. However, the DCs pulsed with apoptotic TCs were best in stimulating interferon-gamma (INF-gamma) secretion as the effector function of autologous T-cells. CONCLUSION: Tumor lysates are in common use for DC-based vaccine manufacturing. However, our data indicate an advantage of apoptotic TC-preparations in regard to antigen loading effectiveness as well as the loaded DC's capacity to activate T-cells. PMID- 17695496 TI - Growth/adhesion-regulatory tissue lectin galectin-3: stromal presence but not cytoplasmic/nuclear expression in tumor cells as a negative prognostic factor in breast cancer. AB - BACKGROUND: The endogenous lectin galectin-3 can regulate cell adhesion and proliferation in vitro, thus prompting the examination of its clinical relevance in breast cancer. MATERIALS AND METHODS: Immunohistochemical processing of tissue sections (n = 273; drop-out rate 20.4%) was used for the assessment of galectin-3 expression. Cytoplasmic/nuclear staining and presence in the tumor stroma were analyzed in human breast cancer patients. RESULTS: A weak correlation with positive steroid receptor status was revealed for cytoplasmic positivity. Nuclear staining was correlated to the lobular type of invasive carcinoma, and tumor stroma expression to high-grade malignancy. Multiple testing of cut-off points to divide the cases into groups based on different levels of immunopositivity combined with univariate Kaplan-Meier survival analysis and computations following the multivariate Cox regression model disclosed no prognostic correlation to either cytoplasmic or nuclear expression of galectin-3. The presence of galectin-3 in the stroma, however, indicated an unfavorable prognosis. Prediction of overall survival was feasible using a model consisting of stage and c-erbB2 status. CONCLUSION: These data signify that caution should be exercised in extrapolating from the anti-apoptotic/prometastatic activity of galectin-3 in model systems to the clinical situation. PMID- 17695497 TI - Does homeobox-related "positional" genomic information contribute to implantation of metastatic cancer cells at non-random sites? AB - Reasons for the lodgment of metastases from several types of solid cancer at apparently non-random sites have not been established. Recently, a group of genes expressed in human fibroblasts obtained from different anatomic locations was implicated in "positional" genomic information. Essentially, a Cartesian coordinate system identifying fibroblasts originally resident at anterior or more posterior, proximal or distal and dermal or non-dermal (heart, lung, etc.) locations was proposed. The determinants used for these identifications included HOX genes, central to embryonic segmental development, some of which are expressed in differentiated, post-embryonic cells. To the extent that HOX or other homeobox genes are expressed in ectodermal, mesodermal or endodermally derived, malignantly transformed cells, they might contribute "positional" information to nidation of specific malignant clones at non-random sites. As understood in the past, interdiction of HOX or homeobox-related gene expression might reduce the probability of cancer cell implantation or alter their destinations in complex ways. Ideally, by interfering with HOX or other homeobox gene-related expression of antigenic determinants potentially contributing to their "homing" and nidation, reduced implantation of circulating cancer cells could render them more susceptible to systemic chemotherapy or immunotherapy, as demonstrated in mice. Furthermore, HOX or other homeobox genes or their products could provide novel intra- or extracellular targets for therapy. PMID- 17695498 TI - 2-Deoxy-2-[18F] fluoro-D-glucose uptake and correlation to intratumoral heterogeneity. AB - The aim of this study was to investigate the pattern of 2-deoxy-2-[18F]fluoro-D glucose (FDG) uptake in relation to the intratumoral histopathological appearance. MATERIALS AND METHODS: Intratumoral distribution of FDG in nude mice with xenografted tumours originating from an established head and neck squamous cell carcinoma was studied. FDG uptake and the correlation to histopathological appearance was evaluated in four separate quarters of each tumour. RESULTS: Variations in FDG uptake correlating to the presence of tumour cells was demonstrated. Quarters containing more than 50% tumour cells showed a significantly higher FDG uptake (p = 0.028) than quarters with more stromal tissue and necrosis. CONCLUSION: This study shows that the heterogenic FDG uptake within a tumour correlates to histopathological findings and that the variable appearance of tracer uptake on the PET scan depends on distribution of different tissue components in the tumour. This intratumoral heterogeneity calls for caution when evaluating a PET scan where median values of larger areas will be misguiding and thus small areas with high uptake should be regarded as the regions of interest. PMID- 17695499 TI - Exogenous platelet-derived growth factor (PDGF) induces human astrocytoma cell line proliferation. AB - Platelet-derived growth factor receptors (PDGFR) regulate several processes in normal cells including cellular proliferation, differentiation and migration, and are widely expressed in a variety of malignancies. In astrocytoma, PDGF ligand and receptor are often overexpressed and PDGFR activity deregulation has been linked to pathogenesis. The issue of the functional capacity of PDGFR has only occasionally been addressed in glioma cells by measuring the proliferative response induced by exogenous PDGF. In the present study, PDGFRalpha expression was evaluated in human grade 2 and 4 astrocytoma cell lines and tissue specimens by immunocytochemistry. The receptor responsiveness to exogenous PDGF was determined in astrocytoma cells with an MTT assay. It was found that astrocytoma cells express PDGFRalpha and respond to PDGF mitogenic action in a grade dependent manner. The receptor was found to be functional since it induced cell proliferation at different ligand concentrations. We can thus conclude that the proliferative response of human astrocytoma cells is related to their malignancy and receptor status before PDGF stimulation, suggesting a role for PDGFRalpha inhibitors as blockers of malignant cell proliferation. PMID- 17695500 TI - Expression of cyclin D1 and Ki-67 in squamous cell carcinoma of the penis. AB - BACKGROUND: Cyclin D1 plays an important role in regulating the progression of cells through the G1-phase of the cell cycle. The aim of the study was to investigate the expression of cyclin D1 and Ki-67 in squamous cell carcinomas (SCC) and in some premalignant lesions of the penis and to correlate it with clinicopathological parameters and patient survival. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded tissues from 21 SCC, 7 lichen sclerosus, 5 condyloma acuminatum and 2 erythoplasia of Queyrat were stained by immunohistochemistry for cyclin D1 and Ki-67. RESULTS: Cyclin D1-positive nuclear staining was overexpressed in 13/21 SCC (61.9%) and in one case of erythoplasia of Queyrat. Strong reactivity for Ki-67 was found in 16 (76.2%) SCC, in 3 condyloma acuminatum and in one case of erythoplasia of Queyrat. A tendency for an association between cyclin D1 expression and tumour differentiation (p = 0.07) but not the level of tumour invasion (p = 0.50) was found. The Ki-67 expression was notably increased with the advance of tumour grade, but the difference did not reach a statistically significant level (p = 0.46). A slight tendency towards a relationship between Ki-67 and cyclin D1 protein expression was observed (p = 0.32). Two patients relapsed and one died from the disease over a median follow up period of 4.6 years (range 0.1-10.3 years). CONCLUSION: Ki-67 antibody and cyclin D1 overexpression seem to parallel each other, supporting the concept that cyclin D1 serves as a cell cycle activator. Cyclin D1 overexpression may be used as a prognostic factor of poor outcome in penile carcinoma. PMID- 17695501 TI - Silvestrol, a potential anticancer rocaglate derivative from Aglaia foveolata, induces apoptosis in LNCaP cells through the mitochondrial/apoptosome pathway without activation of executioner caspase-3 or -7. AB - The novel cyclopenta[b]benzofuran, silvestrol, isolated from the fruits and twigs of Aglaia foveolata, has been found to exhibit very potent in vitro cytotoxic activity against several human cancer cell lines. Furthermore, it was active in the in vivo P388 murine leukemia model. In this study, the mechanism of cytotoxicity mediated by silvestrol in the LNCaP (hormone-dependent human prostate cancer) cell line was investigated. Silvestrol induced an apoptotic response, disrupted the mitochondrial trans-membrane potential and caused cytochrome c release into the cytoplasm. Immunoblot analysis indicated that, at the protein level, silvestrol produced an increase of Bcl-xl phosphorylation with a concomitant increase of bak. Furthermore, caspase-2, -9 and -10 appeared to be involved in silvestrol-mediated apoptosis. In contrast, the involvement of caspase-3 and -7 was not detected, either by immunoblot or caspase-3/-7-like activity analysis, indicating that these pathways do not play a crucial role in silvestrol-induced apoptosis. To investigate the relative contribution of the caspases, inhibition of apoptosis with four different cell-permeable inhibitors was studied (Boc-D-Fmk, Z-VDVAD-FMK Z-LEHD-FMK and Z-AEVD-FMK). Only the general caspase inhibitor, Boc-D-Fmk, completely inhibited the formation of apoptotic bodies. In contrast, caspase-2 and caspase-9 selective inhibitors induced about a 40% reduced apoptotic response, whereas the caspase-10 selective inhibitor caused about a 60% reduction in apoptosis compared to silvestrol only treated cells. Taken together, the studies described herein demonstrate the involvement of the apoptosome/mitochondrial pathway and suggest the possibility that silvestrol may also trigger the extrinsic pathway of programmed cell death signaling in tumor cells. PMID- 17695503 TI - Decreased expression of connexin-30 and aberrant expression of connexin-26 in human head and neck cancer. AB - BACKGROUND: The relation of connexins and carcinogenesis has been studied in various organs and cell lines, with connexins currently being considered tumor suppressors. MATERIALS AND METHODS: The expression of connexin-26 (Cx26) and connexin-30 (Cx30) in human head and neck carcinomas, as well as in adjacent normal mucosa, was evaluated by immunohistochemistry. Furthermore, the expression of these connexins with regard to apoptosis and cell differentiation was investigated. RESULTS: In the cancer tissues, Cx30 expression was drastically reduced compared to apparently normal mucosa while Cx26 expression was almost the same. The intracellular distribution patterns of Cx26 and Cx30 in cancer cells differed between cancer locations. In the cancer tissues, expression of Cx26 and Cx30 was not related to apoptosis assessed by TdT-mediated dUTP-biotin nick end labeling (TUNEL) reaction or to cell differentiation assessed by immunoreaction to involucrin. CONCLUSION: The present results suggest that connexins may play a role in the carcinogenesis of head and neck cancer. PMID- 17695502 TI - Chemoprevention by alpha-santalol on UVB radiation-induced skin tumor development in mice. AB - Studies have shown the chemopreventive effects of alpha-santalol on chemically and UVB-induced skin cancer in mice. The objective of the present investigation was to find the lowest effective concentration of alpha-santalol for the chemopreventive effects on UVB-induced skin tumor development in mice and to determine antiperoxidant effect of alpha-santalol in order to elucidate its possible mechanism of action. Female SKH-1 mice were divided into different groups receiving either vehicle alone or different concentrations of alpha santalol. Mice in all the groups were initiated and promoted with UVB radiation for skin tumor development. The promotion phase continued for 30 weeks. Skin tumors were counted once a week for 30 weeks. Lipid peroxidation was assayed in skin and liver microsomes by measuring malonaldehyde formed using thiobarbituric acid method. Topical administration of alpha-santalol reduced UVB-induced skin tumor development in a concentration-dependent manner. Application of alpha santalol (5%) significantly (p < 0.05) delayed skin tumor development for 25 weeks and reduced tumor multiplicity. alpha-Santalol also inhibited in vitro lipid peroxidation in skin and liver microsomes. alpha-Santalol application prevents UVB-induced skin tumor development possibly by acting as an antiperoxidant. PMID- 17695504 TI - Evaluation of carcinogenic potential of 17alpha-ethinylestradiol in a host mediated in vivo/in vitro assay system. AB - A host-mediated assay system for detection of the transforming activity of different chemical carcinogens on peritoneal macrophages has been previously established. Directly, as well as indirectly acting carcinogenic substances administered intraperitoneally to NMRI mice could be examined in this way. Resident macrophages were recovered by peritoneal lavage from treated and untreated mice and cultured in soft agar. After 5-6 days normal and transformed cells could be distinguished. By the use of this system an immortalized macrophage-like cell line was derived from the peritoneal cells of NMRI mice treated with 17alpha-ethinylestradiol. This cell line enabled us to perform additional investigations on the underlying molecular effects of 17alpha ethinylestradiol, such as detection of the transformation specific polypeptides as surrogate markers for transformation. The investigation reported here describes the cell-transforming and oncogenic potential of 17alpha ethinylestradiol. PMID- 17695505 TI - Effect of copper and role of the copper transporters ATP7A and CTR1 in intracellular accumulation of cisplatin. AB - An investigation was carried out as to whether copper affected the intracellular accumulation of cisplatin (cis-diamminedichloroplatinum(II); CDDP) and whether changes in the expression of ATP7A and CTR1 were related to acquired resistance using CDDP-sensitive (KB) and -resistant (KBR/0.8, KBR/1.2) cells. Intracellular platinum accumulation and platinum-DNA adducts were significantly lower in the CDDP-resistant sublines compared with KB cells. Treatment with 750 microM CuSO4 increased the amount of intracellular platinum 1.8-, 3.2-, and 3.9-fold in KB, KBR/0.8, and KBR/1.2 cells respectively, and increased the platinum-DNA adducts by 1.9-fold in KB cells and by 3.2-fold in KBR/1.2 cells. The level of ATP7A was greatly reduced and CTR1 expression slightly decreased in KBR/1.2 cells compared with KB cells. ATP7A expression was markedly increased by exposure to CDDP with or without copper in KB cells but not in KBR/1.2 cells. CDDP and copper did not increase the level of CTR1 in KB or KBR/1.2 cells. These results indicate that a high concentration of copper causes a significant increase in the cellular accumulation of CDDP and binding of platinum to DNA independently of CTR1 expression in KB cells and CDDP-resistant sublines thereof and that the acquisition of CDDP resistance is associated with a greatly reduced level of ATP7A and a marginally lower expression of CTR1. PMID- 17695506 TI - Biodistribution, pharmacokinetics and microSPECT/CT imaging of 188Re-bMEDA liposome in a C26 murine colon carcinoma solid tumor animal model. AB - Nanoliposomes are useful carriers in drug delivery. Radiolabeled nanoliposomes have potential applications in radiotherapy and diagnostic imaging. In this study, the biodistribution and pharmacokinetics of 188Re-BMEDA-labelled pegylated liposomes (RBLPL) and unencapsulated 188Re-BMEDA administered by the i.v. route in murine C26-colon tumour-bearing mice were investigated. MicroSPECT/CT images were performed to evaluate the distribution and tumor targeting of RBLPL in mice. For the biodistribution study, the highest uptake of liposome in tumors was 3.62% +/- 0.73% at 24 h after RBLPL administration, and the tumor to muscle ratio of RBLPL was 7.1-fold higher than that of 188Re-BMEDA. With image analysis, the highest SUV in tumor was 2.81 +/- 0.26 at 24 h after injection of RBLPL. The Pearson correlation analysis showed a positive correlation of tumor targeting or uptake of RBLPL between biodistribution and microSPECT semi-quantification imaging analysis (r = 0.633). The results of the pharmacokinetics revealed that the area under the tissue concentration-time curve (AUC) of RBLPL was 4.7-fold higher than that of unencapsulated 188Re-BMEDA. These results suggested the potential benefit and advantage of 188Re-labeled nanoliposomes for imaging and treatment of malignant diseases. PMID- 17695507 TI - Different expression of thymidylate synthase in primary tumour and metastatic nodes in breast cancer patients. AB - BACKGROUND: To date an accurate evaluation of predictive markers in breast cancer is mainly conducted at the primary site, although the main goal of the adjuvant therapy is the control of micrometastases. Adjuvant therapy drugs need a high proliferative cell rate to be effective. The proliferating activity can be evaluated by the Ki-67 marker and even by thymidylate synthase (TS), a cell cycle enzyme present in proliferating cells. In this study the TS levels in primary tumours were compared to those of their metastases. PATIENTS AND METHODS: The TS expression and Ki-67 were evaluated by means of immunohistochemistry in 80 primary breast tumours (PTs) and in their matched axillary metastatic lymph-nodes (ALNs). RESULTS: In 16% of patients, malignant cells of involved nodes showed a lower TS expression than the PTs. In the same group, we also found a lower number of Ki-67 immunoreactive cells in lymph node metastases when compared with primary tumours. CONCLUSION: The group of patients with lower TS and Ki-67 expression in lymph node metastatic cells may be less sensitive to 5-fluorouracil and high dose methotrexate requiring them to be treated with other drug combinations. PMID- 17695508 TI - Somatostatin receptor subtypes in human non-functioning neuroendocrine tumors and effects of somatostatin analogue SOM230 on cell proliferation in cell line NCI H727. AB - Well-differentiated neuroendocrine tumors (NT) expresses somatostatin receptors (sstr). A composition of sstr subtype determines biological behavior. We therefore evaluated their immunolocalization in 71 NT cases using immunohistochemistry. Sstr immunoreactivity was demonstrated as follows: sstr1 39.4% of all cases, sstr2A 90.1%, sstr2B 39.4%, sstr3 50.7% and sstr5 76.1%. Based on these findings, the effects of the recently developed sstr subtype specific somatostatin analogue SOM230 on the NT cell line NCI-H727 were examined. SOM230 significantly reduced cell proliferation while the conventional analogue SMS201-995 did not. Therefore, SOM230 has advantages in controlling the cell proliferation of these tumors but the status of sstr subtypes should be determined, possibly using immunohistochemistry, in order to confer its maximum benefits. PMID- 17695509 TI - Human equilibrative nucleoside transporter 1, as a predictor of 5-fluorouracil resistance in human pancreatic cancer. AB - BACKGROUND: The purpose of this study was to find a novel biomarker to predict 5 fluorouracil (5-FU) or gemcitabine (2',2'-difluoro-deoxycytidine) sensitivity in pancreatic cancer. MATERIALS AND METHODS: The relationship between 5-FU and gemcitabine sensitivity and the mRNA levels of human equilibrative nucleoside transporter 1 (hENT1), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) was investigated using seven types of human pancreatic carcinoma cell line (AsPC1, BxPC3, MiaPaCa-2, PSN1, Panc1, PCI6, and KMP-4). Quantitative mRNA expression was measured by LightCycler. A [3H] gemcitabine cellular uptake assay was performed to examine the inhibition of hENT1 by nitrobenzylmercaptoprine ribonucleoside (NBMPR). RESULTS: The expression levels of hENT1 mRNA significantly correlated with the IC50 value of 5-FU in all seven lines and also correlated with gemcitabine resistance in six lines (except AsPC1). No significant association was observed between TS or DPD mRNA levels and 5-FU sensitivity. In the PSN1 cells, [3H] gemcitabine uptake via hENT1 was significantly inhibited by NBMPR, and 5-FU sensitivity was significantly increased when the cells were pretreated with NBMPR. CONCLUSION: Our results suggest that hENT1 plays an important role in 5-FU resistance and that hENT1 mRNA levels might be a useful marker to predict 5-FU sensitivity in pancreatic cancer. PMID- 17695510 TI - Clarification of the functional significance of human folate-binding protein alpha, peptide 191-199, based on a correct GenBank sequence and on other FBP (191 199) sequences. AB - It has been brought to our attention that one of the folate binding protein (FBP) peptides, which we reported first as antigenic and immunogenic in cancer patients, the FBP 191-199, is "off by one amino acid from the amino acid sequence that is listed in GenBank". We searched the published information on FBP and found that the FBP 191-199, which we reported contains threonine 197 instead of the GenBank tyrosine 197. In addition, we found mutations in the FBP (191-199) in other positions, as well as in the flanking residues which direct processing. The potential significance of these changes for cancer vaccines is discussed. It is highly recommended that future human studies with FBP will analyze both GenBank and published sequences in the literature. The large number of mutations in immunogenic FBP-tumor antigens, reported more recently, should be considered during preclinical testing for vaccine and gene therapy in human cancers. PMID- 17695511 TI - Mutant epidermal growth factor receptor undergoes less protein degradation due to diminished binding to c-Cbl. AB - Gefitinib (Iressa) sensitivity in non-small cell lung cancer (NSCLC) is associated with activating mutations in epidermal growth factor receptor (EGFR). It was reported that autophosphorylation of the mutant EGFR is prolonged compared with wild-type EGFR. To explore the mechanism of sustained autophosphorylation, the mutant and wild-type EGFR degradation activities were examined in NSCLC cell lines. EGFR degradation activity was measured by 125I-EGF. The degradation rate of EGFR was lower in the PC-9 NSCLC cell line, which expressed 15-bp deletion mutant EGFR, compared with that in the PC-14 NSCLC (wild-type EGFR). To clarify the mechanism, the stable transfected cell lines, 293_pEGFR and 293_pdelta15, expressing wild-type and mutant EGFR, respectively, were used. In 293_pdelta15, EGFR degradation and binding of c-Cbl ubiquitin ligase to this receptor were reduced compared with 293_pEGFR. Based on these results, we conclude that the mutant EGFR underwent less protein degradation due to diminished binding to c Cbl. PMID- 17695512 TI - HTERT mRNA expression correlates with matrix metalloproteinase-1 and vascular endothelial growth factor expression in human breast cancer: a correlative study using RT-PCR. AB - BACKGROUND: Telomerase activity has been significantly associated with nodal metastasis and cellular proliferation in human breast cancer, indicating that its degree of expression has some form of vital control over the invasive nature of the malignancy concerned. Of the telomerase subunits, the reverse transcriptase (hTERT) is the main determinant of enzyme activity. Vascular endothelial growth factors (VEGF)-C and (VEGF)-D, matrix metalloprotease type 1 (MMP-1) and protease activated receptors (PARs) have all been linked to promotion of tumour invasiveness and metastatic dissemination. This study aims to examine the association between hTERT transcription and that of VEGF-D, VEGF-C, MMP-1, PAR1a and PAR1b through a correlative analysis of the mRNA transcripts of these genes in human breast cancer. MATERIALS AND METHODS: Breast cancer tissues (n = 116) and normal tissues (n-31) were collected immediately after surgery and stored at 80 degrees C until use. The level of hTERT transcripts from the prepared DNA from the above samples was determined using real time-quantitative PCR based on the Amplifluor technology. The levels of the transcript were generated from a standard that was simultaneously amplified with the samples. Normalisation against cytokeratin 19 (CK19) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was also carried out. RESULTS: There was a positive correlation between hTERT mRNA expression (after CK19 normalisation) with both VEGF-D and MMP-1 in human breast cancer. PAR1 was seen to correlate with hTERT (after GAPDH normalisation) with a highly significant correlation with PAR1a alone. However there was no correlation between hTERT transcription and VEGF-C or with PAR1b alone. CONCLUSION: Our findings suggest that hTERT is a potential up-regulator of MMP-1, PAR1 and VEGF-D expression and this may explain its apparent control over the invasiveness and metastasis of the malignancy concerned. PMID- 17695513 TI - Frequent promoter methylation of M-cadherin in hepatocellular carcinoma is associated with poor prognosis. AB - BACKGROUND: Many cadherins (CDH) are associated with various types of cancer and their genetic and epigenetic alterations might be involved in carcinogenesis. MATERIALS AND METHODS: We examined the methylation status of CDH genes in primary hepatocellular carcinoma (HCC) and corresponding noncancerous liver tissues derived from 47 patients, and evaluated the correlation with clinicopathological parameters. RESULTS: Hypermethylation was detected at a ratio ranging from 0% to 55.3%. In particular, M-cadherin (CDH15) was the most hypermethylated of 7 CDH genes. Patients with methylated M-cadherin had shorter 5-year survival rates than patients with unmethylated M-cadherin (overall survival rates, 67.4% vs. 82.7%; p = 0.0167) when assessed using Kaplan-Meier curves. Multivariate analysis revealed that M-cadherin methylation status was an independent predictor of survival. CONCLUSION: We found that M-cadherin methylation status has prognostic significance for the poorer survival of patients with HCC. This is the first definitive report of a correlation between M-cadherin and the prognosis of patients with HCC. PMID- 17695514 TI - Distribution of radioiodinated estramustine binding protein antibody in mice with DU-145 prostate cancer xenograft. AB - BACKGROUND: Estramustine phosphate (EMP) and estramustine binding protein antibody (EMBP-AB) accumulate in the mouse prostate. The distribution of radioiodinated EMBP-AB in tumor mice was investigated to assess its therapeutic potential against prostate cancer. MATERIALS AND METHODS: Mice with DU-145 prostate cancer xenografts received 243 microCi of I-125-labeled EMBP-AB (RI-EMBP AB). The concentration of activity in different organs was measured 4 h after the injection. RESULTS: The blood contained 0.45% of the injected dose per gram, the prostate 2.4%, the testes 0.95% and the tumor 0.65%. Radioactivity in these organs decreased more rapidly than in other organs. The doses of radiation absorbed by the prostate and the tumor, assuming a 1 mCi injected dose, were 1.81 and 0.92 cGy, respectively. CONCLUSION: Most other organs would receive relatively high doses of radioactivity, were I-125 to be used in therapeutic doses. Therefore, RI-EMBP-AB is not beneficial in radionuclide treatment as compared to possible EMP applications. PMID- 17695515 TI - Antitumor activity of capecitabine and bevacizumab combination in a human estrogen receptor-negative breast adenocarcinoma xenograft model. AB - BACKGROUND: Capecitabine and bevacizumab have each been shown to inhibit tumor growth. Their combination failed to improve survival in a phase III trial of metastatic breast cancer (MBC), although it should be noted patients had been heavily pretreated with anthracyclines and taxanes. Our aim was to evaluate whether combination treatment would increase tumor growth inhibition and survival in a breast cancer model. MATERIALS AND METHODS: Mice bearing KPL-4 human estrogen receptor-negative breast adenocarcinoma xenografts were given capecitabine orally daily for 14 days at the maximum tolerated dose (MTD) or half MTD, alone or with 5 mg/kg intraperitoneal bevacizumab twice weekly. RESULTS: Tumor growth inhibition (TGI) and increased life span (ILS) were superior in the combination groups versus monotherapy (p < 0.05). TGI and ILS were significantly improved in the high- versus low-dose capecitabine combination (p < 0.05). CONCLUSION: Capecitabine in combination with bevacizumab provides a basis for pursuing the combination for first-line treatment of MBC. PMID- 17695516 TI - Galectin-3 expression in colorectal cancer: relation to invasion and metastasis. AB - BACKGROUND: Galectin-3, a beta-galactoside-binding protein, has been associated with various biological processes, such as cell adhesion, recognition, proliferation, differentiation and apoptosis. The aim of this study was to determine the relationship of galectin-3 expression to clinicopathological findings in patients with colorectal cancer. Furthermore, the correlation between the expression of galectin-3 and beta-catenin, and the Ki-67 labeling index were investigated. MATERIALS AND METHODS: Immunohistochemical assessment of galectin 3, beta-catenin and Ki-67 expression was performed on samples from 108 patients with colorectal cancer. The expression of galectin-3 was classified at the tumor surface and the invasive front, and its relationship with clinicopathological factors was considered from a statistical viewpoint. RESULTS: There was significant liver metastasis when the expression of galectin-3 was lower at the invasive front of a tumor compared to its surface (p = 0.04). There were also significant correlations between beta-catenin expression at the tumor surface and liver metastasis and tumor stage (p = 0.03, p = 0.04 respectively). CONCLUSION: The reduction of galectin-3 expression is associated with the invasion and metastasis of colorectal cancer. A possible involvement of galectin-3 expression in tumor invasion, metastasis and proliferation in patients with colorectal cancer is suggested. PMID- 17695517 TI - A new mechanism for primary resistance to gefitinib in lung adenocarcinoma: the role of a novel G796A mutation in exon 20 of EGFR. AB - Subsets of non-small cell lung cancer (NSCLC) patients who carry activating somatic mutations of the epidermal growth factor receptor (EGFR) have demonstrated an increased probability of obtaining objective responses to the receptor tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib. However, a substantial proportion of the cases with somatic mutations, which suggest sensitivity to gefitinib, are primary resistant to it. A primary resistant case of lung adenocarcinoma that was found to carry both delE746-A750 and a G796A mutation in the EGFR is reported. In vitro, a stable clone of cells bearing the G796A mutation was approximately 50,000-fold less sensitive to gefitinib in comparison to cells carrying the delE746-A750 mutant EGFR. This study suggests that screening tumour samples for a range of EGFR mutations may improve our ability to identify the patients most likely to benefit from EFGR TKIs. PMID- 17695518 TI - Combinatory gene therapy with electrotransfer of midkine promoter-HSV-TK and interleukin-21. AB - We examined the effect of the combination of herpes simplex virus type1-thymidine kinase (HSV-TK)-suicide gene therapy and interleukin-21 (IL-21) immune gene therapy. MATERIALS AND METHODS: To improve tumor specificity and the safety of gene therapy, we designed the suicide gene (HSV-TK) to be driven by midkine (MK) minimal promoter (MKp-TK). Plasmid DNA containing HSV-TK-suicide gene or IL-21 gene was injected into TE2 and Colon26 tumors developed in nude mice and electric pulses were then delivered. RESULTS: Tumors transduced with the MKp-TK gene demonstrated increased sensitivity to ganciclovir (GCV) in vitro and in vivo. MK minimal promoter conferred efficient transcriptional activity to the HSV-TK suicide gene and in vivo electroporation was an effective method for transducing the MKp-TK gene. IL-21-transduced tumors disappeared completely in syngeneic BALB/c mice. However, the tumors were not suppressed completely in T-cell depleted nude mice, and antitumor effects were absent in NK-cell-depleted mice. These data suggest that IL-21 induces T- and NK-cell-dependent antitumor effects. Furthermore, the growth of IL-21-producing tumors subsequently transduced with MKp-TK by electroporation was significantly retarded compared with control groups. CONCLUSION: Using the minimal promoter region of MK to drive the HSV-TK gene and in vivo electroporation to transduce IL-21 DNA into the tumors produced an efficient gene therapy with improved safety. To our knowledge, this is the first report of a combination gene therapy using HSV-TK/GCVand IL-21. PMID- 17695519 TI - Adenovirus type 5 substituted with type 11 or 35 fiber structure increases its infectivity to human cells enabling dual gene transfer in CD46-dependent and independent manners. AB - Infectivity of adenovirus type 5 (Ad5) to cells depends primarily on its fiber mediated binding to the coxsackievirus and adenovirus receptor (CAR) on target cells. Down-regulated CAR expression, often found in human tumors, hampered Ad5 mediated gene transfer. Ad 11 and Ad 35, belonging to a subtype B group, use CD46 as their cellular receptors; accordingly, chimeric Ad5 whose fiber structure was substituted with that of the type 11 or 35 (Ad5/11 or Ad5/35) could infect human cells in a different manner from Ad5. We found that Ad5/35 infected human tumors, including pancreatic and breast cancer, and human fibroblasts better than Ad5 and Ad5/11. Infectivity of Ad5/35 to these cells was correlated with that of Ad5/11, but efficacy of Ad5/35- and Ad5/11-mediated transduction was not directly correlated with the expression level of CD46 in the target cells. Infection of human hepatoma cells with measles virus, whose cellular receptor is CD46, down regulated the CD46 expression and reduced subsequent infectivity of Ad5/35 but not Ad5/11. Infection of Ad5 suppressed subsequent gene transfer by Ad5 but not by Ad5/11 orAd5/35. Likewise infection of Ad5/35 decreased following gene transduction by Ad5/35 and Ad5/11, but to a lesser extent by Ad5. These data collectively showed that combinatory use of Ad5 and the chimeric Ad enables dual gene transfer into target cells and suggest that infectivity of subtype B Ad does not completely depend on CD46 expression and that other receptors possibly influence the infectivity. PMID- 17695520 TI - Effect of vascular targeting agent Oxi4503 on tumor cell kinetics in a mouse model of colorectal liver metastasis. AB - BACKGROUND: Oxi4503 has been shown to inhibit tumor growth and improve survival in an animal model of colorectal (CRC) liver metastases. This agent appears to selectively target the endothelial cytoskeleton with resultant vessel occlusion and tumor necrosis. MATERIALS AND METHODS: This study evaluated the pattern of tumor necrosis caused by Oxi4503, with particular emphasis on patterns of cell proliferation and apoptosis in a murine model of CRC liver metastases. RESULTS: A single dose of Oxi4503 caused immediate tumor vasculature collapse and subsequently tumor necrosis. There was widespread central necrosis with evidence of viable tumor cells at the periphery. Alterations in the number and spatial pattern of tumor cells undergoing apoptosis and the rate of cellular proliferation were also observed following treatment. Microvessel density was reduced following treatment, however patent vessels were still observed within the necrotic core. CONCLUSION: Although Oxi4503 caused significant tumor destruction, synergistic treatment with cytotoxic and/or anti-angiogenic agents should be considered in order to achieve complete tumor eradication and long-term survival. PMID- 17695521 TI - Effect of CDT6 on factors of angiogenic balance in tumour cell lines. AB - BACKGROUND: Cornea-derived transcript 6 (CDT6, also known as AngX) is an angiopoietin-related factor resulting in anti-tumour effect in vivo. However, a recent abstract reported that CDT6 can also induce angiogenesis and promotes tumour growth. In our previous work, CDT6 had failed to show pro- or anti angiogenic effects. It is unknown if CDT6 expression occurs in human cancer. MATERIALS AND METHODS: An array of human tumour cell lines and tumour tissues was tested for CDT6-gene expression using RT-PCR. To address the controversial role of CDT6 on angiogenesis in different tumour models, the expression levels of four factors of the angiogenic balance (VEGF, endostatin, TIMP-1 and PAI-1) were determined in CDT6-transfected and control cells of the human and murine melanoma cell lines BLM and B16-F10. Endostatin was significantly up-regulated by CDT6 expression in the human model and significantly down-regulated in the mouse model. None of 18 cell lines or 23 tumours expressed CDT6. CONCLUSION: This contradictory effect on endostatin expression in human and mouse models may be an explanation for the conflicting results for the effect of CDT6 expression on angiogenesis. PMID- 17695522 TI - A simple non-destructive test of cellular activity (NTCA) for in vitro assessment of cancer cell chemosensitivity/resistance. AB - Determination of chemosensitivity/chemoresistance is becoming increasingly important for individualization of breast cancer chemotherapy. We developed a simple non-destructive test of cellular activity (NTCA) for assessment of the cytopathic effect of antitumour drugs in vitro. Contrary to routinely used methods (e.g. MTT), besides the comparative evaluation of metabolic activity using pH (given by the medium colour), the NTCA enables the simultaneous assessment of proliferation and morphology of cultured cells (phase-contrast microscopy) at any time during the incubation with cytostatics. Moreover, the regenerative potential of the cells can be examined by cell recovery and growth after drug removal. We provide evidence for the relevance of NTCA in chemosensitivity testing of primary breast cancer cells and breast cancer cell lines for cisplatin, gemcitabine and tamoxifen. NTCA represents a simple addition to the chemosensitivity assessment and could also serve for rapid screening of new antitumour strategies. PMID- 17695523 TI - Decreased expression of DARPP-32 in oral premalignant and malignant lesions. AB - BACKGROUND: DARPP-32 is a neuronal protein that plays a central role in dopaminergic neurotransmission. Although DARPP-32 may contribute to the pathogenesis of several human malignancies, its expression has never been investigated in oral premalignant and malignant lesions. MATERIALS AND METHODS: DARPP-32 expression was examined using immunohistochemistry in 14 normal oral mucosa, 5 normal lower lip mucosa, 41 oral leukoplakia (OL), 30 oral squamous cell carcinoma (OSCC) and 20 lower lip squamous cell carcinoma (LLSCC) specimens. Differences of its expression between groups were analyzed. RESULTS: OSCC and OL with moderate or severe dysplasia showed lower DARPP-32 expression in relation to normal oral mucosa. LLSCC showed lower DARPP-32 expression than normal lower lip mucosa and OSSC. CONCLUSION: The decreased expression of DARPP-32 in oral premalignant and malignant lesions suggests a tumor suppressor role for this protein in the tumorigenesis of these lesions. PMID- 17695524 TI - Alterations of the p53, Rb and p27 tumor suppressor pathways in diffuse large B cell lymphomas. AB - Diffuse large B-cell lymphomas (DLBCL) display defects in cell cycle and apoptosis regulation. Therefore, the immunohistochemical expression patterns of the proteins p14, p21, Hdm2 and cyclin D2 were analyzed in relation to the previously reported expression of other major cell cycle proteins (p53, Rb, p16, p27, Ki-67 and cyclins A, B1, D2, D3 and E), apoptosis-associated proteins (bcl2, bcl-xl, bax, bak, bad and bid) and the B-cell differentiation immunophenotypes. Expression of the proteins p14, p21, Hdm2 and cyclin D2 was observed in 62/71 (87%), 22/76 (29%), 35/74 (47%) and 11/77 (14%) cases, respectively. Immunohistochemical alterations of the p53 (p53-Hdm2-p21-p14), Rb (Rb-p16-cyclin D [D2 or D3]) and p27 (p27-cyclin E) pathways were found in 56/77 (73%), 53/79 (67%) and 54/79 (68%) cases, respectively. Concomitant alterations of the p53-Rb, p53-p27 and Rb-p27 pathways were found in 40/77 (52%), 38/77 (50%) and 36/79 (46%) cases, respectively. Three concomitant alterations of the p53-Rb-p27 pathways were found in 28/79 (35%) cases. The main findings of the present study were the following: alterations of the p27 pathway were associated with higher expression of Ki-67 (p = 0.023); concomitant alterations of the p53Rb pathways and the p53-p27 pathways were associated with higher expression of cyclin A (p = 0.015 and p = 0.021, respectively) and concomitant alterations of the p53, Rb and p27 pathways were associated with higher expression of cyclin A (p = 0.013). Since cyclin A supports DNA replication, centrosome duplication and mitosis, these findings indicate that concomitant alterations of the p53, Rb and p27 pathways in DLBCL may have cooperative effects resulting in increased neoplastic cell proliferation. This might explain, at least partially, the association between concurrent aberrations of the p53, Rb and p27 pathways and aggressive clinical behavior in DLBCL. PMID- 17695525 TI - Detrimental effects of an antibody directed against tumor necrosis factor alpha in experimental kidney irradiation. AB - Antibodies directed against tumor necrosis factor (TNF)-alpha are clinically used for Crohn's disease, rheumatoid arthritis and psoriasis. TNF-alpha is also an important cytokine in radiotherapy because it mediates inflammatory responses in normal tissues. To study the influence of TNF-alpha inhibition on radiation toxicity, we used a well-established mouse model of kidney irradiation, where the portal also includes parts of the intestine. Mice were treated with single fraction radiotherapy to the right kidney with doses of 8 or 10 Gy with or without the monoclonal TNF-alpha antibody infliximab injected i.v. in three doses. The kidney function was assessed by means of repeated 99mTc dimercaptosuccinate scans during a maximum follow-up of 49 weeks. Treatment with infliximab significantly exacerbated radiation nephropathy at all time points, both in the 8 Gy and 10 Gy groups. The drug itself is not known to cause renal impairment. In the control group irradiated with 10 Gy, one mouse died from delayed radiation-induced intestinal toxicity. Skin reactions and general performance status were also similar across the groups. These data suggest that administration of infliximab concomitant to radiotherapy causes profound alterations in the development of kidney dysfunction. Importantly, other radiation-related toxicities were similar across all groups. PMID- 17695526 TI - VP-16 resistance in the NCI-H460 human lung cancer cell line is significantly associated with glucose-regulated protein78 (GRP78) induction. AB - AIM: To investigate the relationship between the expression of glucose-regulated protein (GRP78) and resistance to VP-16 in the NCI-H460 cell line. METHODS: RT PCR, real-time RT-PCR and Western blotting were used in analyzing the expression of GRP78 at mRNA and protein levels in the NCI-H460 cell line induced by A23187 at different concentrations. Cell survival with VP-16 was determined using a colony-formation assay with the account of IC50. RESULTS: The expression of GRP78 at both the mRNA and protein levels was higher in the NCI-H460 cell line induced by A23187. A23187 treatment resulted in up to 4.8-fold elevation of GRP78 mRNA and up to 3.2-fold elevation of GRP78 protein in the experimental cells compared to the controls, all in a dose-dependent manner. The IC50s for VP-16 in the cells pretreated with different concentrations of A23187 (0, 1, 2, 4 and 6 microM) were: 12.11 +/- 0.83, 12.68 +/- 1.04, 25.82 +/- 1.83, 37.46 +/- 1.89 and 45.19 +/ 2.34 microM, respectively. Compared to the control, there was a significant elevation of IC50 for VP-16 in the cells pretreated with A23187. Survival curve analysis also showed that the induction of A23187 caused a significantly longer survival for the cells subjected to VP-16 treatment (p < 0.05). CONCLUSION: A23187 treatment is highly effective for the induction of GRP78 and subsequent development of resistance to VP-16 in the human lung cancer NCI-H460 cell line. Based on the trend of the change in IC50 and the expression of GRP78 in differently exposed cells, we conclude that the induction of GRP78 by A23187 is significantly associated with the resistance to VP-16. PMID- 17695527 TI - Effects of tumor necrosis factor-related apoptosis-inducing ligand alone and in combination with fluoropyrimidine anticancer agent, S-1, on tumor growth of human oral squamous cell carcinoma xenografts in nude mice. AB - BACKGROUND: Chemotherapy has shown little antitumor activity against advanced oral squamous cell carcinoma (OSCC) patients. Therefore, there is an urgent need to develop more effective therapeutic methods for patients with advanced OSCC. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor ligand family that selectively induces apoptosis of cancer cells. S-1 is a new oral antineoplastic agent that can induce apoptosis in various types of cancer cells, including OSCC. Hence, combined treatment of cancer cells with TRAIL and S-1 might exert dramatic antitumor effects on OSCC cells. MATERIALS AND METHODS: In this study, the response of human OSCC cells to TRAIL alone and in combination with S-1 was examined using nude mouse xenograft models. S-1 (10 mg/kg/day, 5 times/week) was administered orally and TRAIL (1 mg/kg, 5 times/week) was injected into peritumoral tissue for three weeks. Apoptotic cells were detected by a TUNEL method. The protein expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and orotate phosphoribosyl transferase (OPRT) were assessed using immunohistochemistry; their gene expression was determined using microdissection and RT-PCR, and their protein levels using ELISA. RESULTS: Combined therapy of TRAIL and S-1 exerted antitumor effects on human OSCC xenografts markedly and significantly induced apoptotic cells in tumors treated with TRAIL plus S-1. Immunohistochemistry showed that the expressions of TS and DPD were down-regulated, and that OPRT expression was up-regulated in tumors treated with TRAIL plus S-1. In the same way, microdissection and RT-PCR revealed that the expression of TS and DPD mRNA was down-regulated and that expression of OPRT mRNA was up-regulated in tumors administered the combined treatment. Moreover, ELISA indicated that the protein levels of TS and DPD were down-regulated, and that OPRT was up-regulated in tumors treated with the combined therapy. During the experimental period, no loss of body weight was observed in mice treated with the combined therapy. CONCLUSION: These findings demonstrate that the combination of TRAIL and S-1 is effective against OSCC and has the potential of being a new therapeutic tool for future treatment of these tumors. PMID- 17695528 TI - Crude extracts of Euchresta formosana radix inhibit invasion and migration of human hepatocellular carcinoma cells. AB - Crude extracts of Euchresta formosana radix (EFR) have previously been observed to induce the suppression of liver cancer Hep3B cell growth and induce apoptosis in response to overexpression of reactive oxygen species, GADD153, Bax and caspase-3, and to decrease the levels of mitochondrial membrane potential in vitro. In this study, the effect of EFR on cell migration and invasion by the human liver hepatocellular carcinoma (HCC) cell line Hep3B was examined. Hep3B cells treated in vitro with EFR migrated and invaded less than cells treated with phosphate-buffered saline (PBS) as a control. EFR inhibited migration and invasion by down-regulating the production of RhoA and ROCK1, FAK, and matrix metalloproteinase-1, -2, -9 and -10 relative to PBS only. These results show that EFR inhibits invasion and migration by liver cancer cells by down-regulating proteins associated with these processes, resulting in reduced metastasis. Thus, EFR should be considered as a possible therapeutic agent for inhibiting primary tumor growth and preventing metastasis. PMID- 17695529 TI - In vitro antitumor lymphocyte generation using dendritic cells and innate immunity mechanisms as tumor cell treatments. AB - Dendritic cells play a central role in the initiation and regulation of acquired and innate immunity, playing an important role in immunosurveillance and antitumor reaction. This reaction is mediated by effector cells and soluble factors. We chose to investigate four dendritic cell loading methods by mimicking innate immunity mechanisms and using whole tumor cell treatments in order to stimulate lymphocytes: sodium hypochlorite, TNFalpha and IFNgamma and IgG opsonization. These methods were compared in an HLA.A2 model of healthy donors and with the M74 melanoma cell line. Treated tumor cell-loaded DC were able to increase proliferation of lymphocytes. Moreover, a CTL population was stimulated, as shown by their specific cytotoxicity against tumor cells (with w6/32 antibody assays), against MelanA/MART-1 loaded T2 cells and using MelanA/MART-1 tetramer. IgG opsonization seemed to be less efficient than other tumor cell treatments. These loaded DC, or the obtained effector cells, could be interesting for therapeutic applications in antitumor cell therapy. PMID- 17695530 TI - Anticancer effects of licofelone (ML-3000) in prostate cancer cells. AB - BACKGROUND: Licofelone, a potent antiinflammatory agent has been reported to interfere with the cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) signaling pathways with few side-effects. However, the underlying mechanism of licofelone against human cancer is not understood. MATERIALS AND METHODS: Human and mouse prostate cancer cells were exposed to licofelone in a time- and dose-dependent manner. Cell growth/cell viability, apoptosis, and expression of COX-2 and 5-LOX at the gene and protein levels were investigated. RESULTS: For the first time, it was demonstrated that licofelone inhibited prostate cancer cell growth and significantly down-regulated COX-2 and 5-LOX expression. A weak inhibitory effect on COX-1 protein was also observed. CONCLUSION: Licofelone inhibited COX-2 and 5 LOX simultaneously and prevented overall cancer cell growth by enhancing apoptosis in both androgen-dependent and androgen-independent prostate cancer cells. Validating the dual role of licofelone in animal models of prostate cancer is critical for promoting its use as a potential chemopreventive or therapeutic agent. PMID- 17695531 TI - Cytotoxic effects of treosulfan on prostate cancer cell lines. AB - OBJECTIVE: Despite various therapeutical options in metastatic prostate cancer, the lack of a curative approach motivates further investigations. Treosulfan is an alkylating agent that has proven its indication in the treatment of e.g. ovarian carcinoma. This study focused on the objective of evaluating the effect of in vitro intoxication of human prostate carcinoma cell lines with treosulfan. MATERIALS AND METHODS: Human prostate cancer cell lines LNCaP, DU145 and PC3 were treated with treosulfan concentrations from 0.5-500 microM for up to six days. Analysis of cell viability was performed using colorimetric WST-1 assay. Control data were obtained from identical cell lines cultivated without treosulfan. RESULTS: Incubation with treosulfan inhibited cell viability and led to cell death in all cell lines in a dose- and time-dependent manner. After one day, viability of LNCaP, DU145 and PC3 cells was constantly reduced with a dose rate of at least 10 microM (p < 0.001), 10 microM (p < 0.0001) and 100 microM (p < 0.0001) treosulfan, respectively. Minimum dose rates leading to death of nearly all LNCaP, DU145 and PC3 cells were 250 microM, 100 microM and 200 microM treosulfan, respectively. CONCLUSION: The results demonstrate a sensitivity of prostate carcinoma cells to the cytotoxic activity of treosulfan. Therefore, treosulfan might be a promising compound for novel treatment protocols for prostate cancer. PMID- 17695532 TI - Prognostic significance of platelet-derived growth factor-BB expression in human esophageal squamous cell carcinomas. AB - BACKGROUND: Cancer metastases are commonly found in the lymphatic system and tumor lymphangiogenesis requires the interplay of several growth factors. The expression of platelet-derived growth factor (PDGF)-BB and vascular endothelial growth factor (VEGF)-C in esophageal cancer was investigated to define their clinicopathological significance. MATERIALS AND METHODS: Using immunohistochemistry, the expression of PDGF-BB and VEGF-C was examined, along with lymphatic vessel density (LVD) in 53 patients with esophageal cancer. RESULTS: PDGF-BB and VEGF-C expression was positive in 31 cases (58.5%) and 38 cases (71.7%), respectively, and expression correlated with lymph node metastasis and lymphatic invasion. Furthermore, PDGF-BB expression correlated with the depth of tumor invasion and the size of the tumor, and PDGF-BB-positive patients had a significantly poorer prognosis than PDGF-BB-negative patients. The LVD in positive PDGF-BB or VEGF-C tumors was higher than in negative tumors. CONCLUSION: PDGF-BB may play a pivotal role in lymphangiogenesis and tumor growth in esophageal cancer. PMID- 17695533 TI - Crude extracts of Euchresta formosana radix induce cytotoxicity and apoptosis in human hepatocellular carcinoma cell line (Hep3B). AB - In this study, the effects of 95% ethanol extracts of Euchresta formosana radix (EFR) on the cell cycle and apoptosis in human hepatocellular carcinoma (HCC) Hep3B cells were investigated. The results indicated that EFR decreased DNA synthesis and viable Hep3B cell numbers in a concentration-dependent manner. EFR induced a p21- and p27-dependent cell cycle arrest in S-phase and apoptosis of the Hep3B cells. The induction of apoptosis by EFR treatment was also confirmed by DAPI staining. EFR inhibited cyclin-dependent kinase (CDK)-1 and -2 expression and decreased cyclin B1 and E levels, resulting in S-phase arrest. EFR induced reactive oxygen species (ROS) production followed by endoplasmic reticulum (ER) stress that was based on the increase of GADD153 and GRP78 which led to the release of Ca2+ in the Hep3B cells. The EFR-promoted apoptosis was associated with increasing activation of caspases 3, 7, and 9 and enhanced poly(ADP-ribose) polymerase cleavage and increased expression of p21(CIP1/WAF1), p27(KIP1), Bax and Bad. Furthermore, the levels of Bcl-xl decreased after EFR treatment. Alteration of these key anti- and pro-apoptotic proteins could contribute to the increase in p53-independent apoptosis that was observed in the Hep3B cells. PMID- 17695534 TI - Induction of apoptosis in human hepatocellular carcinoma cells by synthetic antineoplaston A10. AB - Antineoplaston A10 (3-phenylacetylamino-2,6-piperidinedion) is a naturally occurring substance and was the first antineoplaston in the human body to be chemically identified. The effect of antineoplaston A10 on human hepatocellular carcinoma cell lines HepG2 and HLE has been examined. Antineoplaston A10 displayed anti-proliferative action inhibiting cell growth in a dose- and time dependent manner in vitro as measured by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide (MTT) and clonogenic assays. Incubation with antineoplaston A10 for 48 h induced apoptotic events such as a typical apoptotic morphology, formation of a characteristic ladder pattern of DNA migration and accumulation of sub-G1 phase cells. Next, hepatoma xenografts in nude mice were employed to study the antitumor effects of antineoplaston A10 in vivo. Oral administration of antineoplaston A10 delayed the growth of HepG2 and HLE cells in the mice without a reduction in body weight. A higher proportion of apoptotic cells in xenografts was observed by means of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. In addition, the level of expression of apoptotic marker p53 increased while that of anti apoptotic protein bcl-2 decreased, as evaluated with immunohistochemical staining in the xenografts. These results suggested that antineoplaston A10 may inhibit the growth of human hepatoma cells through the induction of apoptosis. PMID- 17695535 TI - Tobacco and inflammation effects in immunoexpression of hMSH2 and hMLH1 in epithelium of oral mucosa. AB - BACKGROUND: Both hMSH2 and hMLH1 are integrated in the DNA mismatch repair (MMR) system. Reduced expression of these proteins has been reported in head and neck carcinoma; however, few studies have examined the normal levels of these proteins in oral tissues or investigated factors which could interfere with this expression. The aim of this study was to detect the expression pattern of hMSH2 and hMLH1 in normal oral mucosa and to correlate this with demographic data, smoking and local inflammation. MATERIALS AND METHODS: The expression of hMSH2 and hMLH1 was evaluated in 38 samples of normal mucosa epithelium using immunohistochemistry. RESULTS: No relationship was observed between hMSH2 and hMLH1 and demographic data. The hMLH1 but not hMSH2 expression was altered in smokers and in the presence of inflammation. CONCLUSION: Both hMSH2 and hMLH1 are highly expressed in the normal epithelium of oral mucosa. In addition, hMLH1 expression is directly influenced by tobacco use and inflammation. PMID- 17695536 TI - Andrographolide inhibits the adhesion of gastric cancer cells to endothelial cells by blocking E-selectin expression. AB - BACKGROUND: Andrographolide, an active component isolated from the Chinese official herbal Andrographis paniculata, has recently been reported to have anticancer activity. However the molecular mechanism responsible for its anticancer action has not been fully defined. In this study, we investigated the effect of andrographolide on the adhesion of gastric cancer cells to the activated endothelial cells and the expression of some cell adhesion molecules. MATERIALS AND METHODS: Human endothelial cells were preincubated with andrographolide for 6 h and then incubated with the cytokine tumor necrosis factor for 4 h. Endothelial surface expression of E-selectin was evaluated by flow cytometry, immunostaining and ELISA. Further, we investigated E-selectin mRNA expression by RT-PCR. Surface expression of sialyl Lewis(X) of three gastric cancer cell lines (SGC7901, MGC803, BGC823) and a normal gastric epithelial cell line GES-1 was evaluated by flow cytometry and immunostaining. Adherence of CFSE labeled gastric cancer cells and GES-1 cells to endothelial cell monolayers was then determined. RESULTS: Andrographolide significantly reduced E-selectin expression of activated endothelial cells, and inhibited the E-selectin expression on mRNA level. Three gastric cancer cell lines expressed high levels of sialyl Lewis(X), whereas GES-1 did not. Andrographolide also significantly decreased gastric cancer cells adherence to stimulated endothelial cells. The inhibition of E-selectin expression corresponded to the reduction of tumor cell adherence. The effects of andrographolide on tumor adhesion were almost nullified by pre-incubation with E-selectin and sialyl Lewis(X) antibody. CONCLUSION: These findings demonstrate that andrographolide suppresses the adhesion of gastric cancer cells which express high level sialyl Lewis(X) to human vascular endothelial cells by blocking E-selectin expression and, thus, may represent a candidate therapeutic agent for cancer. PMID- 17695537 TI - Coagulation-related factors, thrombomodulin and protein Z, are not associated with risk for oral cancer. AB - BACKGROUND: The link between thrombosis and cancer has been well established. Levels of protein Z and thrombomodulin indirectly regulate thrombin productionl and therefore may affect cancer susceptibility. PATIENTS AND METHODS: The functional polymorphisms -13A/G and -33G/A in protein Z and thrombomodulin genes (respectively) influence transcription. The two polymorphisms were investigated in 160 oral cancer patients and 168 controls of equivalent age, gender and ethnicity using restriction fragment length polymorphism typing. RESULTS: The frequency of the -13G allele, which results in lower expression of protein Z gene, was not significantly elevated in patients compared to controls (8.1% and 6.3%, respectively; odds ratio 1.35, 95% confidence interval 0.72-2.56). No carriers of the thrombomodulin low expression -33A allele were identified, underscoring the rarity of this allele in Caucasians. CONCLUSION: Inherited predisposition affecting protein Z or thrombomodulin levels does not modulate susceptibility to oral cancer. Any possible contribution of thrombin to oral oncogenesis may involve other factors. PMID- 17695538 TI - Lack of association of XRCC1 codon 399Gln polymorphism with chronic myelogenous leukemia. AB - BACKGROUND: Recent studies suggest that single nucleotide polymorphisms in different genes may modulate the susceptibility to chronic myelogenous leukaemia (CML). Here, the association of the common XRCC1 gene polymorphism Arg399Gln at codon 399 in CML was investigated. PATIENTS AND METHODS: Genotyping was performed by melting curve analysis in samples from peripheral blood or bone marrow. RESULTS: The frequency of the variant allele 399Gln was similar between the control group and the patients (35.2% and 34.9%, respectively; p = 0.21). Similarly, the heterozygote and homozygote variant genotypes displayed a homogenous distribution in both groups (p > 0.05 for all comparisons). Moreover, distribution of the variant allele and subgenotypes did not significantly differ between the patient subgroups with a diagnosis age below or above 50 years. CONCLUSION: To our knowledge, this is the first study to investigate the role of any XRCC1 polymorphism in CML and our findings do not support a role of codon 399Gln polymorphism in CML. PMID- 17695539 TI - Immunophenotypic profile of biomarkers related to anti-apoptotic and neural development pathways in the Ewing's family of tumors (EFT) and their therapeutic implications. AB - BACKGROUND: Ewing's family of tumors (EFT) comprises a broad spectrum of tumors composed of primitive committed cells with neuroectodermal capacity. The degree of neural differentiation within EFT, as measured with morphological features and expression of neural markers, delimits two members: Ewing's sarcoma (ES) and peripheral primitive neuroectodermal tumor (pPNET). Molecules such as c-kit and its ligand (Stem cell factor, SCF), CD95 (FAS), CD95L (FASL), IGF-IR, protect EFT cells from apoptosis, whereas c-erb-B2, erythropoietin (EPO) and its receptor (EPO-R) participate in the maturation of primitive committed neuroectodermal cells and in the normal embryonal brain development. The aim of the present study was to analyse the expression of these molecules in paraffin-embedded material from a series of EFT. MATERIALS AND METHODS: Forty-five cases of EFT (23 typical ES, 4 atypical and 18 pPNET) were analysed following the immunohistochemical LSAB method, with antigen retrieval heating using an autoclave, citrate buffer pH 6.0 and the following primary antibodies: FAS (APO-CD 95), FAS-L, c-kit, SCF, IGF-IR and c-erbB2. The expression was evaluated independently by three of the authors and the final score (0 to 3+) was based on the intensity and percentage of positively stained cells. In a second cooperative analysis, tissues from 30 cases of EFT (15 typical, 3 atypical and 12 PNET) were immunostained with EPO and EPO R. RESULTS: High expression of c-kit/SCF (2+, 3+) was detected in 28/45 cases of EFT (62.2%), whereas FAS-FAS-L and IGF-IR were observed in 16/45 (37.7%) and 9/45 (20%), respectively. Regarding the neuroectodermal pathway, membranous and cytoplasmic expression of c-erb-B2 was observed in 9/45 (20%) EFT, regardless of the morphological and immunohistochemical expression of conventional neural markers. High expression of EPO and EPO-R was observed in 20/30 EFT (66.6%). CONCLUSION: C-kit/SCF and EPO/EPO-R seem to participate in the pathway of anti apoptotic and proliferative advantage, while c-erb-B2 does not play an important role in the neuroectodermal differentiation pathway in EFT cells. PMID- 17695540 TI - Mast cells in invasive ductal breast cancer: different behavior in high and minimum hormone-receptive cancers. AB - BACKGROUND: Studies on the role of mast cells (MC) in cancer have given contrasting results. In order to contribute to the clarification of their role, research on breast cancer was carried out, because some aspects of its carcinogenesis, such as the diversity of the hormonal component, differ greatly. MATERIALS AND METHODS: This study included 50 cases of invasive ductal breast cancer not otherwise specified (NOS): 25 of them were high hormone-receptive (HHR) cancers with estrogen and progesterone receptor values not lower than 50%, 25 were minimum hormone-receptive (MHR) cancers (< 5%). In both groups, mast cells were quantified in the peritumoral area. Twenty cases of surgical interventions for non-neoplastic esthetic prosthesis in healthy women were examined as controls. The proliferation index Ki-67 (MIB1) and the c-erb B2 receptor protein were also considered in cancer patients. Mast cells were detected using Giemsa and Alcian blue stains. RESULTS: The results obtained showed that there was a highly significant increase in the number of mast cells mainly in the peritumoral area in HHR cancer cases (p < 0.0001) compared to MHR cancers and controls (p < 0.0001). Comparison between mast cells in MHR cancer and control cases was not significant (p = 0.114). Hormone-receptive cancers have a less severe prognosis for their higher responsiveness to therapy. This element may suggest that the higher mast cell number present in these types of cancer is a favorable prognostic factor. Moreover, mast cells tend to accumulate around the cancer area and this can be seen as an attempt to oppose the progression of the anomalous tissue. Mast cells were reported to exhibit cytolytic activity against tumor cells. PMID- 17695541 TI - A novel cycloheptapeptide exerts strong anticancer activity via stimulation of multiple apoptotic pathways in caspase-3 deficient cancer cells. AB - BACKGROUND: VR3848 is a novel cycloheptapeptide, isolated from a Euphorbiaceae plant, which can suppress proliferation of various tumor cells at nanomolar concentration. Due to its novelty and potency, the molecular process of tumor cell growth inhibition was investigated intensively. MATERIALS AND METHODS: MCF-7 cells, a caspase-3 deficient cancer cell line, were treated with VR3848. The genetic response was monitored using cDNA array analysis. RESULTS: Expression alterations of caspase, bcl-2 family members, death receptor, death adaptor, death ligands, stress response, cell cycle machinery, mitogen-activated protein kinases (MAPKs) and proto-oncogene were found which can be linked into three apoptotic pathways. The first was the death receptor-mediated pathway, which was confirmed by functional inhibition of caspase-8 and -10. The second pathway was via ER-stress apoptosis demonstrated by up-regulation of ER-stress genes and the release of caspase-12 into the cytoplasm. The third pathway involved mitochondrial membrane leakage which was elucidated by down-regulation of anti apoptotic bcl-2 and an increased level of cytosolic apoptosis-inducing factor (AIF). Cell cycle arrest was observed which may have been a direct effect of VR3848 or a consequence of DNA strand breaks which in turn stimulated cell cycle arrest. CONCLUSION: VR3848 inhibited MCF-7 cancer cell growth through an activation of three related apoptotic pathways. PMID- 17695542 TI - Signal transducer and activator of transcription 1 in breast cancer: analysis with tissue microarray. AB - BACKGROUND: Constitutively activated signal transducer and activator of transcription (STAT) proteins are found in various types of tumors. However, there is still very limited information about the role of STATs in breast cancer. The power of the tissue microarray analysis (TMA) technique is the capability of performing a series of analyses of thousands of specimens in a parallel fashion with minimal damage to the original blocks. This study was designed to use TMA in determing the STAT1 status in breast cancer tissues. MATERIALS AND METHODS: Archival tissue specimens from 102 patients with primary invasive breast cancer were selected and STAT1 expression was analyzed using immunohistochemical staining with tissue microarray. The data of primary tumor staging, age, estrogen receptor status, lymph node status, histological grading and TNM staging were also collected. RESULTS: There were 18 patients (17.6%) with 0 expression in STAT1, 29 patients (28.4%) with 1 expression in STAT1, 21 patients (20.6%) with 2 expression in STAT1 and 34 patients (33.4%) with 3 expression in STAT1. There was no significant relationship between STAT1 expression and age (p = 0.203), estrogen receptor status (p = 0.221), histological grading (p = 0.861), primary tumor staging (p = 0.918), lymph node status (p = 0.53), or TNM staging (p = 0.826). There was no survival difference noted among the four groups with different STAT1 expression (p = 0.859). CONCLUSION: Immuno-histochemical staining with tissue microarray analysis was convenient and feasible for the analysis of STAT1 expression status in breast cancer. STAT1 expression did not show significant correlation with the overall survival rate. PMID- 17695543 TI - Dichlorotetra-mu-Isobutyratodirhenium(III): enhancement of cisplatin action and RBC-stabilizing properties. AB - BACKGROUND: Previous investigations showed antitumor properties of dirhenium carboxylate introduced to tumor-bearing animals at high doses. The development of liposomal forms of rhenium substances and the activity of dichlorotetra-mu isobutyratodirhenium (III) (Re1) in stabilizing red blood cells (RBC) shown in experiments in vitro and in vivo enabled the use of this substance in the present study. The aim of the work was to investigate the antitumor properties of Re1 in liposomal form alone and together with cisplatin, and to analyze whether Re1 can support RBC in the model of tumor growth. MATERIALS AND METHODS: Introduction of a single dose of cisplatin and liposomal forms of Re1 according to a scheme of antioxidant therapy was tested in a rat model of specific Guerink (T-8) carcinoma. The dynamics of tumor growth, weights of isolated tumors, RBC morphology and hemoglobin levels were measured. RESULTS: The cluster rhenium compound, Re1, with carboxylic ligands had its own anticancer properties and enhanced cisplatin action on tumor growth. Introduction of the rhenium substance led to an increase in quantities of normal RBC forms in blood of tumor-bearing animals. Possible mechanisms of enhancement of cisplatin efficiency by Re1 according to its structural peculiarities are discussed. CONCLUSION: A novel antitumor system including the use of a cluster rhenium compound and cisplatin is presented. Enhancement of cisplatin action and antitumor properties of rhenium compound initially took place due to the properties of quadruple metal-to-metal bond between two atoms of rhenium. PMID- 17695544 TI - High gene expression of matrix metalloproteinase-7 is associated with early stages of oral cancer. AB - BACKGROUND: In the light of the recently found contribution of matrix metalloproteinases (MMPs) to oral oncogenesis, the correlation of MMP-7 with risk for oral cancer was investigated. MATERIALS AND METHODS: The MMP-7 -181A/G polymorphism in 159 German and Greek patients with oral squamous cell carcinoma and 120 healthy controls of equivalent gender and ethnicity was studied. RESULTS: The detected carrier frequency of the high expression G allele was significantly higher in patients compared to controls (74.8% versus 61.7%, p = 0.0257). This significant difference was more pronounced in patients with early stages of cancer and absent in those with advanced stages. A/G heterozygotes have a double relative risk (OR 2.07, 95%, CI 1.17-3.67) of developing early stages of oral cancer than low expression A/A homozygotes. CONCLUSION: MMP-7 gene expression is associated with increased risk only for early stages of oral cancer, possibly due to the inhibitory effect of MMP-7 in angiogenesis. PMID- 17695545 TI - The missing kiss of life: transcriptional activity of the metastasis suppressor gene KiSS1 in early breast cancer. AB - BACKGROUND: KiSS-1 is a metastasis suppressor gene encoding a neuropeptide with potent antimetastatic activities in tumour cell lines. The transcriptional activity of the gene and its associations in resected breast cancer were analysed. MATERIALS AND METHODS: Tumour messenger RNA (mRNA) of the KiSS1 exon I/II boundary was extracted from paraffin-embedded stage II or III node-positive breast adenocarcinomas of 272 women. KiSS1 mRNA was examined for associations with outcome, disease and molecular characteristics. RESULTS: Only 8 out of 272 tumours (3%) yielded detectable KiSS1 mRNA levels. There was no evidence of correlation of KiSS1 transcription with the number of involved axillary nodes, grade, hormone receptor status or tumour size. Of women with increased KiSS1 mRNA tumour levels, 87.5% were postmenopausal, whereas only 48% were postmenopausal among patients without detectable KiSS1 mRNA (p = 0.03). No association of KiSS1 transcription was found with transcription of the cell cycle-regulators HER2, VEGF, p53, BCL2, PAEP, or BIRC5. At a median follow-up of 62 months, there was no statistically significant difference between women harbouring KiSS1 mRNA-negative versus-positive tumours in terms of disease-free and overall survival (log-rank test p = 0.54 and p = 0.55, respectively). CONCLUSION: The metastasis suppressor gene KiSS1 is silenced in the vast majority of resected node-positive breast adenocarcinomas. These findings support the antimetastatic role of the gene and warrant its study as a prognostic marker and a therapeutic target. PMID- 17695546 TI - Ethyl 2- [N-m-chlorobenzyl- (2'-methyl)] anilino-4-oxo-4,5-dihydrofuran-3 carboxylate (JOT01006) induces apoptosis in human cervical cancer HeLa cells. AB - Human cervical cancer is potentially lethal, and therefore the development of effective and tolerable therapeutic options is vital. In the present study, the in vitro effect of the synthetized compound JOT01006 (C21H20C1NO4) on human cervical epithelioid carcinoma cell line (HeLa) was examined. The results demonstrated that JOT01006 induced morphological changes and cytotoxicity (decreased the percentage of viable cells) in a dose-dependent manner. JOT01006 induced apoptosis which was analyzed by flow cytometric methods and confirmed by DAPI staining and DNA fragmentation analyzed by DNA gel electrophoresis. JOT01006 also induced reactive oxygen species (ROS) overproduction before causing endoplasmic reticulum (ER) stress which was also confirmed by the increased levels of Grp78 and Gadd153. Western blotting was selected to demonstrate that JOT010006 promoted p53, Bak, PARP, caspase-3 levels and decreased the levels of Bcl-2 and Bcl-xL. Our results also showed that JOT01006 also promoted caspase-12 production followed by apoptosis. The results also showed that JOT01006 inhibited the migration of HeLa cells potentially through inhibition of MMP-2 and -9. PMID- 17695547 TI - Radioiodide imaging and treatment of ARO cancer xenograft in a mouse model after expression of human sodium iodide symporter. AB - BACKGROUND: Most undifferentiated and anaplastic thyroid carcinomas are not sensitive to 131I therapy due to their lost ability for iodide accumulation. This study aims to restore the iodide uptake by transferring and expressing human sodium iodide symporter (hNIS) in these cancer cells for 131I gene therapy. MATERIALS AND METHODS: hNIS cDNA expression vector was transfected into wild-type anaplastic thyroid cancer cells (ARO-W) which do not concentrate iodide. Stable trasfected cells were isolated (ARO-S) and analyzed by RT-PCR, radioiodide uptake and immunocyto-chemistry staining. 131I imaging and treatment were performed on mice bearing ARO-W and ARO-S xenograft tumors and tumor volume was recorded. RESULTS: The ARO-S cells showed clear hNIS expression on the cell membrane and accumulated 87-fold and 4.4-fold radioiodide of that of wild-type cells in vitro and in vivo, respectively. Radioiodide uptake was dependent on cell number and reached a maximum level at 20 minutes in vitro. The half life of radioiodide efflux was 12 minutes and 12 hours in vitro and in vivo, respectively. Administration of a therapeutic dose of 131I into mice bearing ARO-S tumors effectively inhibited tumor growth as compared to control mice. CONCLUSION: Our results suggest the potential of hNIS-mediated 131I gene therapy on anaplastic thyroid cancer cells. PMID- 17695548 TI - Immunohistochemical expression and prognostic significance of fatty acid synthase in pancreatic carcinoma. AB - BACKGROUND: The aim of this study was to evaluate immunohistochemical markers in pancreatic cancer and to determine the association of their expression with clinicopathological features and prognosis. PATIENTS AND METHODS: Thirty pancreatic adenocarcinoma patients were followed-up for an average period of 5 years. FAS, bcl-2, p53 and Ki-67 expression were detected immunohistochemically to determine their prognostic value. RESULTS: FAS was statistically associated with p53 (p = 0.002), Ki-67 (p = 0.003), higher histological grade (p = 0.001 and recurrence and overall survival (p = 0.001). CONCLUSION: The newly found overexpression of FAS in highly aggressive pancreatic carcinomas may help us stratify patients into different prognostic groups and indicate new therapeutic strategies. PMID- 17695549 TI - Apoptosis and cytolysis induced by giganteosides and hederacolchisides in HL-60 cells. AB - The viability, cytolysis and apoptosis-mediated cellular death induced by giganteosides D and E (Gig-D and Gig-E) and hederacolchisides A and A1 (Hcol-A and Hcol-A1) were analysed in HL-60 cells. MATERIALS AND METHODS: The end-point metabolic (WST1) and lactate dehydrogenase (LDH) assays were used. Cell cycle analysis and apoptosis were measured by flow cytometry, DNA laddering and caspase 3 analyses. RESULTS: the HL-60 cell line was more sensitive to Hcol-A1 and Gig-D (IC50 3-5 microM) than to Gig-E and Hcol-A (IC50 8-13 microM; WST1 assay). This was related to LDH release. The induction of apoptosis could be detected without caspase-3 activation after 24 h of treatment. DNA fragmentation could be detected only with Gig-D. With Hcol-A1 and Gig-D, an accumulation of cells in the S-phase and an increase of cells in sub-G1 peak were observed. By the annexinV fluorescein isothiocyanate (FITC)/7-amino-actinomycin D (AAD) assay, the majority of cells were in late apoptosis with Gig-D, and in necrosis with Hcol-A1. CONCLUSION: Hcol-A1 is more cytotoxic than Gig-D, followed by Gig-E and finally Hcol-A. This is related to a membrane permeabilization effect, leading to cytolysis. PMID- 17695550 TI - Gender-specific association of the VEGF -2578C > A polymorphism in Korean patients with colon cancer. AB - BACKGROUND: Angiogenesis is involved in the development of cancer, promoting tumor growth, invasiveness and metastasis. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. The present case control study was carried out, to determine whether there is an association between the VEGF -2578C > A polymorphism and colon cancer. PATIENTS AND METHODS: DNA samples taken from 246 patients with colon cancer and 203 healthy controls were amplified by polymerase chain reaction for VEGF -2578C > A polymorphism. RESULTS: Genotype frequencies of the VEGF -2578C > A polymorphism were not significantly different between patient and control groups. However, when the data were stratified by gender, the frequency of the -2578CA + AA (A allele-bearing) genotype was marginally significant different with protective effect for colon cancer in women (odds ratio, OR, 0.60; 95% confidence interval, CI, 0.36-0.99; p = 0.056). The -2578CA + AA genotype was also associated with reduced risk in patients with proximal colon cancer (OR, 0.55; 95% CI, 0.31-0.97; p = 0.049). This association also remained in women with proximal colon cancer. CONCLUSION: Although the VEGF 2578C > A polymorphism had no influence on susceptibility to colon cancer, some genotypes showed a significant difference between the case and control groups when the data were stratified by gender and the original location of tumor, suggesting that the VEGF -2578C > A polymorphism, at least in Koreans, is a genetic determinant of colon cancer risk. PMID- 17695551 TI - STEALTH liposomal CKD-602, a topoisomerase I inhibitor, improves the therapeutic index in human tumor xenograft models. AB - BACKGROUND: CKD-602, a topoisomerase I inhibitor, has antitumor activity in a broad spectrum of tumor types. STEALTH liposomal CKD-602 (S-CKD602) prolongs circulation of CKD-602 in plasma, increases drug exposure in tumors and improves efficacy compared with free drug. MATERIALS AND METHODS: Different dosing regimens of S-CKD602, free CKD-602 and topotecan were compared for antitumor activity in female athymic nude mice bearing human A375 melanoma, ES-2 ovarian, H82 SCLC or HT-29 colon tumor xenografts. RESULTS: S-CKD602 was more efficacious than free drug in all tumor types studied. The therapeutic index (TI) of S-CKD602 was estimated to be approximately 6-fold greater than that of free CKD-602 in ES 2 and approximately 3-fold greater in H82 tumors. TI of S-CKD602 was approximately 2-fold greater than that of free CKD-602 and approximately 5-fold greater than that of topotecan in A375, and > or = 3-fold greater in HT-29 tumors. In A375 tumors, once-weekly dosing of S-CKD602 was superior to once every 2 weeks or twice weekly schedules. CONCLUSION: The therapeutic index of S-CKD602 was greater than that of free CKD-602 and topotecan in several human tumor types. PMID- 17695552 TI - Celecoxib increased expression of 14-3-3sigma and induced apoptosis of glioma cells. AB - BACKGROUND: Celecoxib, a cyclooxygenase-2 inhibitor, has been found to inhibit the proliferation of several kinds of cancer cells; however, the effects of celecoxib on glioma cells are not clear. MATERIALS AND METHODS: A172 glioma cells were treated with various concentrations of celecoxib for 4, 24 or 48 h. Cytotoxic drug effects were studied by MTT (3-[4,5-dimethylthiazole-2-yl]-2,5- diphenyltetrazolium bromide)-based colorimetric assay, and celecoxib-induced apoptosis of glioma cells was investigated by FACScan. Western blot analysis was used to study celecoxib effects on the expression of mitogen-activated protein kinases (MAPKs), p53, p21, 14-3-4sigma, Bcl-2 and Bax. Caspace-3 activity in glioma cells was analyzed by caspase activity assay. RESULTS: Celecoxib exerted cytotoxic effects upon and induced apoptosis of the A172 glioma cells in a concentration and time-dependent manner (p < 0.05). Celecoxib had no effects on expression of MAPKs, Bax, or p21; however, it increased expression of p53 and 14 3-4sigma, and reduced expression of Bcl-2. Celecoxib also increased the activity of caspace-3 in glioma cells. The apoptotic fraction of A172 cells induced by 24 h treatment with 100 microM celecoxib was reduced from 39% to 23% by pretreatment with caspace-3 inhibitor (DEVD-CHO) (p < 0.001). CONCLUSION: The results suggest that celecoxib induced cytotoxicity and apoptosis in this line of glioma cells and that such effects might be related to activation of p53 and 14-3-3sigma, reduced Bcl-2 and Bcl-2/Bax ratio, and increased caspace-3 activity. PMID- 17695553 TI - Effects of anti-malarial drugs on MCF-7 and Vero cell replication. AB - BACKGROUND: Previous in vivo studies performed in our laboratories demonstrated that anti-malarial drugs may or enhance or slow down Ehrlich's ascites tumour progression in infected mice. In the light of these observations, an in vitro study was undertaken to assess the response of human tumour cells to various anti malarial drugs and consequently the safety of the anti-malarial therapy. MATERIALS AND METHODS: MCF-7 cells and Vero cells (control line) were cultured in Eagle's minimum Essential medium (EMEM) and then subjected to graded concentrations of different anti-malarial drugs. Trypan-blue exclusion, MTT and Western blotting tests were performed. RESULTS: The findings showed that pyrimethamine (12.5 mg/L), chloroquine (12.5 mg/L) and primaquine (1.56 mg/L) stimulated MCF-7 cell growth. The proliferative effect was inhibited by doxorubicin only in cultures treated with chloroquine and primaquine. These results might indicate that some anti-malarial drugs have a worrying tumour promoting effect which should not be underestimated when undertaking anti malarial prophylactic measures. PMID- 17695554 TI - Renal specific secondary hypertension. AB - Chronic kidney disease (CKD) is now understood to affect over 5% of all adult patients and it conveys a risk of reduced survival in those affected. At least 80% of those patients with stages 3-5 CKD (i.e. GFR <60 ml/min) suffer with hypertension, and in most the major cause is due to pertubation of an important renal endocrine system, the renin-angiotensin-aldosterone (RAA) axis. In this article the epidemiology of renal-related hypertension and its importance in pre disposing to the increased cardiovascular risk in renal disease are discussed. Hypertension is known to be a major cause of progressive loss of renal function in CKD, particularly because of activation of the RAA, and hence the case for blockade of this system with ACE inhibitors and Angiotensin receptor blockers is highlighted. PMID- 17695555 TI - Improving the nutritional condition of infants and young children undergong hemodialysis. AB - The growing number of infants receiving HD treatment has led to an increased awareness among the nursing staff of the unique and complex needs of children undergoing chronic treatment. As part of the overall treatment, nurses must broaden their knowledge of medical advancements in numerous areas: Increased knowledge in the area of child growth and development and unique formulas and "supplements". PMID- 17695556 TI - Education of transplanted women for prevention of unplanned pregnancy following kidney transplantation. AB - Reproductive function in female patients (pts) with advanced kidney disease is decreased and characterised by diminished libido, ovulation and infertility. The underlying cause is hypothalamic-hypophysis-gonadal axis dysfunction in women with chronic kidney disease which usually results in high levels of prolactin and.ammenorrhea In women with end stage kidney disease requiring replacement therapy in fertile period conception is very rare. Even in case of conception successful pregnancy and delivery are not likely, on most occasions spontaneous abortion occurs. Should a newly pregnant woman on haemodialysis wish to deliver the baby, intensive dialysis is required, everyday until childbirth. In the haemodialysis center in University Clinical Center in Ljubljana, only one woman in the chronic dialysis programme gave birth, in 1996. PMID- 17695557 TI - Client attitudes towards home dialysis therapy. AB - BACKGROUND: There are many studies about the professional problem of renal patient non-compliance and a number describing the experience of living on dialysis. To date studies have not examined client attitudes toward their therapy. OBJECTIVES: This paper reports a study seeking to describe characteristic attitudes towards their treatment regimen among a group living on home dialysis. METHODS: The study used a critical interpretive methodology, enabling a distinction between the professional viewpoint and the renal client perspective. Twenty home dialysis clients from one renal service in New Zealand were interviewed for an hour each in November 2004 and January 2005. Texts of the taped interviews were analysed to discover the client perspective towards their therapy in this group. RESULTS: During the initial period of adjustment to treatment many participants discovered their need for treatment by experimenting with the therapeutic prescription. They then used what they had learned about the therapy to alter their treatment regimen in order to maintain, as far as possible, their normal lifestyle. After modifying their therapeutic prescription to suit themselves, participants' motivation to continue meeting the ongoing demands of the treatment regimen was influenced by their perception of their individual life situation, including their relationships, work and personal attitudes towards life. DISCUSSION: Health professionals have interpreted renal client behaviour in relation to their therapy in terms of compliance, because effectiveness of treatment depends on their cooperation. From a client perspective their attitudes are better understood in terms of negotiation. Renal clients do not simply follow professional advice but, through a process of negotiation, seek to integrate therapy into their pattern of regular activities to maintain their normal lifestyle. Renal clients' motivation to meet the ongoing demands of treatment is not related solely to their health status, but is also affected by their general life situation. Understanding client attitudes towards therapy enables nurses to better support people living on dialysis. PMID- 17695558 TI - Quality of life research: a valuable tool for nephrology nurses. AB - Findings from quality of life research provide nurses with valuable information for planning care. However, the instrument for measuring quality of life has to be carefully selected to ensure that it assesses accurately the impact on the patients' lives. The research tools reviewed in this article (QLI-H, and KDQOLTM) are well-established instruments that have contributed significantly to understanding issues surrounding quality of life in the end-stage renal disease population. This understanding will lead to improved patient care in the field of nephrology nursing practice. PMID- 17695559 TI - An exploratory study of patient's feelings about asking healthcare professionals to wash their hands. AB - The purpose of this study was to explore patient opinion about asking healthcare professionals to wash their hands prior to a clinical procedure and to explore if MRSA status and access to patient information about infection control would influence anxiety about asking. A descriptive survey was undertaken using a semi structured questionnaire. The questionnaire was distributed to a randomised convenience sample of 185 in-patients across all departments of an acute NHS Trust hospital (response rate 59.4%). Spearman's rank order and Kendall Tau-b tests were used to analyse specific correlations. Respondents were more confident than anxious to be involved in a campaign that asked patients to ask staff to wash their hands. Patients were more anxious to ask if previous admission episodes were fewer, if their knowledge of MRSA was high and if there was less information about infection control available. Less anxiety was associated with patients who had MRSA in the past and the suggestion that staff wore badges saying 'It's OK to ask'. PMID- 17695560 TI - Dialysis nurses for palliative care. AB - The palliative approach offers significant and practical care throughout the treatment of the dialysis patient until death. Varied aspects of quality of life for patients can be improved. It is possible to relieve symptoms such as sleep disorders, pain, constipation and pruritus, which, according to the present survey, are common symptoms. The treatment of dying dialysis patients or the possibility and legitimization of discontinuing treatment are complex, controversial issues with ethical and legal implications. But these issues have not yet been adequately dealt with by the nephrological community. The nurses who encounter patients daily, who constantly deal with great suffering and who lack tools to help, can lead the practice in this field within the framework of inter disciplinary team work. In light of the obvious need for progress in this area, appropriate training courses should be considered. The implementation of the palliative approach in dialysis units could be a challenge for all of us in the coming years. PMID- 17695561 TI - The need for care co-ordination in an ageing dialysis population. AB - Over the past ten year period, there has been a sharp increase in the age distribution of dialysis patients. The mean age of patients entering dialysis therapy in 1995 was 69 years, rising to 75 years by 2005 (Figure 1). Of this group of patients, there is a 20% mortality rate within 6 months of commencing dialysis (Figure 2). Renal replacement therapy (RRT) is considered a bridge to transplantation. However, what if the patient is not eligible for transplantation because of age, co-morbidity or refusal? PMID- 17695562 TI - On line UV-adsorbance measurements. Summary of the EDTNA/ERCA journal club discussion. Summer 2006. AB - The discussion was initiated by a paper comparing the measurement of dialysis dose (Kt/V) and solute clearance using on-line ultra-violet absorbance, blood and dialysate urea and ionic dialysance by Uhlin et al (NDT 2006). Participants from 14 countries discussed the theory behind the UV absorbance technique and the potential for its use in routine practice, the correlation between Kt/V measured using different methods, the use of ionic dialysance and the optimisation of dose monitoring. The 'take-home' messages from the discussion were that UV-absorbance could help ensure the delivery of dialysis dose as it provides real time feedback on the effect interventions such as repositioning of needles. The technology is relatively inexpensive and requires no consumables but changes in the dialysis machine settings could lead to misleading measurements if not communicated to the UV monitor. Session-to-session variation in dialysis dose can be measured using on-line clearance monitoring. If it is already on the machine and costs nothing, why not use it? Alternatively, regular access recirculation checks and a record of the total blood volume processed at each session allow problems with delivered dialysis dose to be picked up between routine blood tests. PMID- 17695563 TI - The grapefruit-drug interaction debate: role of statins. PMID- 17695564 TI - Key practice points in the management of fibromyalgia. PMID- 17695565 TI - Rural origins and choosing family medicine predict future rural practice. PMID- 17695566 TI - Medical school expansion: an immediate opportunity to meet rural health care needs. PMID- 17695567 TI - Letting go. PMID- 17695568 TI - Common problems in endurance athletes. AB - Endurance athletes alternate periods of intensive physical training with periods of rest and recovery to improve performance. An imbalance caused by overly intensive training and inadequate recovery leads to a breakdown in tissue reparative mechanisms and eventually to overuse injuries. Tendon overuse injury is degenerative rather than inflammatory. Tendinopathy is often slow to resolve and responds inconsistently to anti-inflammatory agents. Common overuse injuries in runners and other endurance athletes include patellofemoral pain syndrome, iliotibial band friction syndrome, medial tibial stress syndrome, Achilles tendinopathy, plantar fasciitis, and lower extremity stress fractures. These injuries are treated with relative rest, usually accompanied by a rehabilitative exercise program. Cyclists may benefit from evaluation on their bicycles and subsequent adjustment of seat height, cycling position, or pedal system. Endurance athletes also are susceptible to exercise-associated medical conditions, including exercise-induced asthma, exercise-associated collapse, and overtraining syndrome. These conditions are treatable or preventable with appropriate medical intervention. Dilutional hyponatremia is increasingly encountered in athletes participating in marathons and triathlons. This condition is related to overhydration with hypotonic fluids and may be preventable with guidance on appropriate fluid intake during competition. PMID- 17695569 TI - Fibromyalgia. AB - Fibromyalgia is an idiopathic, chronic, nonarticular pain syndrome with generalized tender points. It is a multisystem disease characterized by sleep disturbance, fatigue, headache, morning stiffness, paresthesias, and anxiety. Nearly 2 percent of the general population in the United States suffers from fibromyalgia, with females of middle age being at increased risk. The diagnosis is primarily based on the presence of widespread pain for a period of at least three months and the presence of 11 tender points among 18 specific anatomic sites. There are certain comorbid conditions that overlap with, and also may be confused with, fibromyalgia. Recently there has been improved recognition and understanding of fibromyalgia. Although there are no guidelines for treatment, there is evidence that a multidimensional approach with patient education, cognitive behavior therapy, exercise, physical therapy, and pharmacologic therapy can be effective. PMID- 17695570 TI - Home monitoring of glucose and blood pressure. AB - Home monitoring of blood glucose and blood pressure levels can provide patients and physicians with valuable information in the management of diabetes mellitus and hypertension. Home monitoring allows patients to play an active role in their care and may improve treatment adherence and clinical outcomes. Glucose meters currently on the market produce results within 15 percent of serum blood glucose readings and offer a variety of features. Although the data are somewhat conflicting, home glucose monitoring has been associated with improved glycemic control and reduced long-term complications from diabetes. These effects are more pronounced in patients who take insulin. Home blood pressure values predict target organ damage and cardiovascular outcomes better than values obtained in the office. Home blood pressure measurements are also effective at detecting borderline hypertension and monitoring the effectiveness of antihypertensive drugs. Validated arm cuffs are the preferred blood pressure devices for home use. Information from home monitoring should always be used in conjunction with that from regular office visits and other data to make appropriate therapeutic decisions. PMID- 17695571 TI - Lnformation from your family doctor. Monitoring your blood pressure at home. PMID- 17695572 TI - Information from your family doctor. Monitoring your blood sugar at home. PMID- 17695573 TI - Screening and treatment for sexually transmitted infections in pregnancy. AB - Many sexually transmitted infections are associated with adverse pregnancy outcomes. The Centers for Disease Control and Prevention recommends screening all pregnant women for human immunodeficiency virus infection as early as possible. Treatment with highly active antiretroviral therapy can reduce transmission to the fetus. Chlamydia screening is recommended for all women at the onset of prenatal care, and again in the third trimester for women who are younger than 25 years or at increased risk. Azithromycin has been shown to be safe in pregnant women and is recommended as the treatment of choice for chlamydia during pregnancy. Screening for gonorrhea is recommended in early pregnancy for those who are at risk or who live in a high-prevalence area, and again in the third trimester for patients who continue to be at risk. The recommended treatment for gonorrhea is ceftriaxone 125 mg intramuscularly or cefixime 400 mg orally. Hepatitis B surface antigen and serology for syphilis should be checked at the first prenatal visit. Benzathine penicillin G remains the treatment for syphilis. Screening for genital herpes simplex virus infection is by history and examination for lesions, with diagnosis of new cases by culture or polymerase chain reaction assay from active lesions. Routine serology is not recommended for screening. The oral antivirals acyclovir and valacyclovir can be used in pregnancy. Suppressive therapy from 36 weeks' gestation reduces viral shedding at the time of delivery in patients at risk of active lesions. Screening for trichomoniasis or bacterial vaginosis is not recommended for asymptomatic women because current evidence indicates that treatment does not improve pregnancy outcomes. PMID- 17695574 TI - Information from your family doctor. STIs in pregnancy: protecting yourself and your baby. PMID- 17695575 TI - Predicting hip fracture risk in older women. PMID- 17695576 TI - Persistent anterior knee pain. PMID- 17695577 TI - Walk-in HIV testing clinic proves great success. PMID- 17695578 TI - Professionalism and courage in the heat of a desert. PMID- 17695579 TI - Barriers to the expression of sexuality in the older person. PMID- 17695580 TI - Eating for recovery. AB - Susan Holmes argues that prevention of hospital-related malnutrition should be a primary aim for nurses. PMID- 17695581 TI - Helping nature along. AB - Many couples who face infertility just need health information to make simple life changes. In one area of the country, two nurses have stepped in. PMID- 17695582 TI - Reforming cancer care. PMID- 17695583 TI - Developing a nursing service for patients with hepatitis C. AB - Hepatitis C is a chronic viral infection, which can progress to cirrhosis, liver failure, liver cancer and death. This article describes a model implemented to improve the care of people with hepatitis C in Calderdale and Huddersfield. The aim was to design a model of care based on patient need and create a flexible hepatitis C testing service for current and former injecting drug users. The new service concentrated on three elements: developing the local hepatitis C support group; introducing an integrated care pathway and booklet for assessing patients on treatment for hepatitis C; and implementing a viral hepatitis clinical nurse specialist role in the local drug and alcohol action team. PMID- 17695584 TI - A practical guide to using pulmonary artery catheters. AB - This article reviews the physiological principles underlying the use of the pulmonary artery (PA) catheter. The procedure for PA catheter insertion, PA pressure monitoring, PA catheter removal and complications associated with the PA catheter are discussed, as are nursing management of the catheter and nursing care of the patient. PMID- 17695586 TI - Advanced liver cirrhosis. PMID- 17695585 TI - Erectile dysfunction: physiology, causes and patient management. AB - This article examines the prevalence, causes, identification, assessment and treatment options for men with erectile dysfunction. Erectile dysfunction is thought to affect one in ten men across the UK and is often a consequence of pathology and/or pharmacology. Treatment can be offered to all patients, but the keys to management are identification, accurate assessment and focused therapy. Nurses are well placed to identify and support men who have this distressing problem. PMID- 17695587 TI - When disaster strikes. PMID- 17695588 TI - Virtual wards, real nursing. PMID- 17695589 TI - Optimization of a spectrophotometric method for quantification of acid-soluble glycoprotein in porcine serum. AB - The concentration of acid-soluble glycoprotein (ASG) in serum can be measured by selective precipitation with perchloric acid and then spectrophotometric quantification of the protein content in the supernatant. The purpose of this work was to standardize and optimize this procedure in pigs and to establish an automated protocol for quantification of the protein content in the supernatant with the use of bicinchoninic acid and copper sulfate. The greatest concentration of ASG was obtained when serum was incubated with 0.6 M perchloric acid at a 1:20 dilution. A minimum of 10 min of incubation at 37 degrees C or 25 degrees C was needed for complete selective precipitation. This method provided intra-assay coefficients of variation (CVs) of 5.14% and 5.12% and interassay CVs of 7.11% and 7.53% for samples with high and low ASG concentrations, respectively. The technique of linearity under dilution showed linear regression coefficients greater than 0.99. The limit of detection of ASG was 0.23 mg/mL, which is low enough to allow discrimination between normal and pathological states. A more than 2-fold increase in ASG concentration was found in pigs with postweaning multisystemic wasting syndrome when compared with healthy pigs. These results indicate that ASG could be considered a moderate acute-phase protein that would be easily measured and useful in assessing health status or the presence of inflammation in pigs. However, there was some overlap of results between groups of healthy and diseased animals. PMID- 17695590 TI - Characterization of canine monocyte-derived dendritic cells with phenotypic and functional differentiation. AB - For therapeutic purposes, large numbers of dendritic cells (DCs) are essential. In this study, we used 2% autologous canine plasma, granulocyte/macrophage colony stimulating factor (GM-CSF), fms-like tyrosine kinase 3 ligand (Flt3L), and interleukin 4 (IL-4) in generating monocyte-derived DCs from peripheral blood mononuclear cells of dogs. The plasma enriched the population of CD14-positive monocytes by greatly enhancing the efficiency of monocyte adherence, the proportion of adherent cells increasing from 6.6% with 10% fetal bovine serum to 15.3% with 2% autologous canine plasma. Culturing the adherent monocytes for 6 d with human GM-CSF, canine IL-4, and human Flt3L significantly increased the yield of DCs, more than 90% of which were CD14-negative. Because, in the presence of lipopolysaccharide (LPS), monocytes that were CD14-positive expressed tumor necrosis factor ac much more than DCs with low levels of CD14, it is important to decrease the numbers of CD14-positive cells in generating monocyte-derived DCs. With flow cytometry and real-time reverse-transcriptase-mediated polymerase chain reaction assays, we found that in canine immature DCs (iDCs) the expression of DLA class II molecules, CD1a, CD11c, CD40, and CD86 was high and the expression of CD80, CD83, and CD14 either low or negative. During maturation (stimulated by LPS), the expression of CDla, CD40, CD83, and CD80 was upregulated. However, the expression of DLA class II molecules, CD11c, and CD86 was not increased in mature DCs. Incubating the iDCs with LPS decreased antigen uptake and increased the cells' immunostimulatory capacity (assessed by the allogeneic mixed-lymphocyte reaction), indicating that LPS accelerates the functional maturation of DCs. This protocol may facilitate the use of DCs in cellular immunotherapy. PMID- 17695591 TI - In vitro 3-dimensional kinematic evaluation of 2 corrective operations for cranial cruciate ligament-deficient stifle. AB - The objective of this study was to determine the immediate postoperative effect of 2 corrective operations for cranial cruciate ligament (CCL)-deficient stifle by evaluating 3-dimensional (3-D) stifle kinematics. Ten hindlimbs from large breed canine cadavers were used. Range of motion was induced by applying 100 N of traction on the quadriceps tendon and recorded with electromagnetic movement sensors for each situation: intact stifle (control), CCL-sectioned stifle, and surgical correction of the sectioned ligament with the modified retinacular imbrication technique (MRIT) and then with a tibial plateau leveling osteotomy- Montavon (TPLO-M). The results for the experimental situations were compared with the results for the control situation by 1-way repeated-measures analysis of variance and with each other by post-hoc analysis with the least-significant difference method. Range of motion was significantly decreased by MRIT as compared with the other situations. Normal cranial tibial translation was restored after MRIT, whereas TPLO-M resulted in significant caudal translation. A significant increase in external rotation was observed after both MRIT and TPLO M. A significant increase in tibial adduction throughout the range of motion was observed with TPLO-M, whereas a significant increase in tibial abduction was observed after MRIT. This study allowed us to better understand objectively the effects on 3-D canine stifle kinematics of MRIT and TPLO-M. We suggest that this type of in vitro study would be useful to evaluate established and upcoming surgical techniques and potentially improve corrective surgery. PMID- 17695592 TI - Differential expression of Haemophilus parasuis genes in response to iron restriction and cerebrospinal fluid. AB - Haemophilus parasuis is an important opportunistic pathogen in swine of high health status, but to date no proven virulence factors have been described. As virulence factors are known to be regulated during disease, the objective of this study was to identify genes of a virulent serovar 5 strain with altered expression after iron restriction or in the presence of porcine cerebrospinal fluid (CSF), conditions that reflect in vivo growth conditions. Using differential-display reverse-transcriptase-mediated polymerase chain reaction, we found that homologues of genes encoding fructose bisphosphate aldolase (fba), adenylosuccinate synthetase (purA), 2',3'-cyclic nucleotide phosphodiesterase (cpdB), lipoprotein signal peptidase (lspA), pyrophosphate reductase (lytB), superoxide dismutase (sodC), tyrosyl t-RNA synthetase (tyrS), cysteine synthetase (cysK), an unknown protein, and a homologue of a hydrolase of the haloacid dehydrogenase superfamily were upregulated in response to iron restriction. In addition, the purA, cpdB, lspA, lytB, and sodC homologues, cDNAs homologous with a Na+/alanine symporter, fatty acid ligase (fadD), diadenosine tetraphosphatase (apaH), and an unknown protein were upregulated in response to CSF. In screening for the presence of these differentially expressed genes to assess their usefulness as diagnostic markers of high virulence potential, we detected homologues of all of these genes in all of the reference strains of the 15 established serovars. The hydrolase homologue, however, was expressed only in representative H. parasuis strains associated with a high virulence potential, suggesting that this enzyme may play a role in pathogenesis. PMID- 17695593 TI - Prevalence of resistance to 11 antimicrobials among Campylobacter coill isolated from pigs on 80 grower-finisher farms in Ontario. AB - We carried out a cross-sectional study to investigate antimicrobial resistance patterns of Campylobacter coli isolated from Ontario grower-finisher pigs. From January to June 2004, 1200 samples were collected from 80 farms by obtaining a constant number (15) of fecal samples per farm. Susceptibility of the isolates to 11 antimicrobial drugs was determined by the agar-dilution technique. The overall prevalence of resistance to 1 or more antimicrobials among the isolates was 99.2%. High levels of resistance were observed for azithromycin, clindamycin, erythromycin, streptomycin, and tetracycline: 91.7%, 82.5%, 81.4%, 70.7%, and 63.7%, respectively. For sulfamethoxazole, ampicillin, and nalidixic acid, resistance was observed in 40.3%, 26.6%, and 22.7% of the isolates, respectively. Although at very low levels, resistance was observed for ciprofloxacin (a fluoroquinolone), chloramphenicol, and gentamicin: in 2.4%, 1.7%, and 0.2%, respectively. Many of the isolates (29.7%) were resistant to 5 antimicrobials, the most common being azithromycin, clindamycin, erythromycin, streptomycin, and tetracycline. Isolates from the same farm showed at least 5 patterns of resistance. Results from this study indicate high levels of resistance to the antimicrobial drugs most commonly used in the Canadian swine industry (macrolides, lincosamides, and tetracyclines) among C. coli isolated from grower finisher pigs in Ontario. Macrolides and fluoroquinolones are the drugs most commonly used to treat severe human campylobacteriosis. Fortunately, at present, there is little resistance to fluoroquinolones among C. coli from pigs in Ontario. PMID- 17695594 TI - Effect of Mycoplasma hyopneumoniae colonization at weaning on disease severity in growing pigs. AB - To determine whether Mycoplasma hyopneumoniae colonization at weaning in off-site weaning systems is associated with the severity of respiratory disease due to this agent in growing pigs, we studied 20 groups, each group representing a different week in production, in sow herds at 3 farms of 3000 sows each that had a prevalence of M. hyopneumoniae colonization at weaning higher than 5%. The calculated sample size for assessment at weaning was 39 piglets for each group under study; 39 litters were randomly selected, and 1 piglet was randomly selected from each litter for testing and ear-tagged. In total, 780 piglets were tested. The presence of M. hyopneumoniae in nasal swabs at weaning was established by nested polymerase chain reaction (PCR). All groups were followed until slaughter, at which time blood samples were collected from each ear-tagged pig to test for M. hyopneumoniae antibodies, bronchial swabs were collected for detection of M. hyopneumoniae DNA by nested PCR, and the lung lesion score and percentage of affected lungs in the same animals were calculated. Correlation analyses showed a positive correlation between colonization at weaning and all 4 dependent variables indicating infection at slaughter: average lung lesion score, percentage of affected lungs, presence of M. hyopneumoniae on the bronchial epithelium, and seroconversion. This study provides evidence that severity of the disease can be predicted by the prevalence at weaning in segregated systems. Therefore, strategies focused on reducing colonization at weaning seem to be important elements in the global control of M. hyopneumoniae in segregated production systems. PMID- 17695595 TI - Serologic and genetic characterization of North American H3N2 swine influenza A viruses. AB - The H3N2 subtype of influenza A viruses isolated from pigs in the United States and Canada has shown both genetic and antigenic diversity. The objective of this study was to determine the serologic and genetic characteristics of contemporary strains of these viruses. Genetic analysis of 18 reference strains and 8 selected strains demonstrated differences in 1% to 9% of the nucleotides of the hemagglutinin (HA) gene. Phylogenetic analysis of the HA gene revealed 3 genetic clusters, as well as divergence of cluster III viruses from a cluster III prototype virus (A/Swine/Illinois/21587/99). By means of 1-way cross hemagglutination inhibition with antiserum against 5 field isolates and 3 vaccine viruses, most of 97 isolates tested could be placed in 1 of 3 serogroups. The several isolates that did not react with any antiserum were in genetic cluster III, which suggests that continuous antigenic drift in cluster III may have resulted in virus variants. The efficacy of commercial vaccines against these virus variants should be evaluated with vaccination and challenge studies. PMID- 17695596 TI - Efficacy of swine influenza A virus vaccines against an H3N2 virus variant. AB - We compared the efficacy of 3 commercial vaccines against swine influenza A virus (SIV) and an experimental homologous vaccine in young pigs that were subsequently challenged with a variant H3N2 SIV, A/Swine/Colorado/00294/2004, selected from a repository of serologically and genetically characterized H3N2 SIV isolates obtained from recent cases of swine respiratory disease. The experimental vaccine was prepared from the challenge virus. Four groups of 8 pigs each were vaccinated intramuscularly at both 4 and 6 wk of age with commercial or homologous vaccine. Two weeks after the 2nd vaccination, those 32 pigs and 8 nonvaccinated pigs were inoculated with the challenge virus by the deep intranasal route. Another 4 pigs served as nonvaccinated, nonchallenged controls. The serum antibody responses differed markedly between groups. After the 1st vaccination, the recipients of the homologous vaccine had hemagglutination inhibition (HI) titers of 1:640 to 1:2560 against the challenge (homologous) virus. In contrast, even after 2nd vaccination, the commercial-vaccine recipients had low titers or no detectable antibody against the challenge (heterologous) virus. After the 2nd vaccination, all the groups had high titers of antibody to the reference H3N2 virus A/Swine/Texas/4199-2/98. Vaccination reduced clinical signs and lung lesion scores; however, virus was isolated 1 to 5 d after challenge from the nasal swabs of most of the pigs vaccinated with a commercial product but from none of the pigs vaccinated with the experimental product. The efficacy of the commercial vaccines may need to be improved to provide sufficient protection against emerging H3N2 variants. PMID- 17695597 TI - Low-dose ginseng (Panax quinquefolium) modulates the course and magnitude of the antibody response to vaccination against equid herpesvirus I in horses. AB - The purpose of this study was to determine if ginseng fed at low levels enhances a horse's antibody response to vaccination against Equid herpesvirus 1 (EHV-1). For 28 d, 5 horses received ground, powdered ginseng (35 mg/kg body weight, 1.7 mg/kg total ginsenosides) in molasses as a carrier, and 5 received molasses only. On day 14, each horse was vaccinated against EHV-1. The time course of the antibody response to vaccination was significantly altered in the horses receiving ginseng, a clinically relevant increase in antibody titer being observed by postvaccination day 2 compared with day 6 in the control horses. The horses receiving ginseng also had a significant decrease in serum levels of sodium and a significant increase in serum levels of potassium. No adverse effects of ginseng treatment were identified by hematologic and blood biochemistry profiles. Thus, low-dose dietary supplementation with ginseng in healthy horses may be a useful adjunct to vaccination. PMID- 17695598 TI - Effect of fat supplementation on leptin, insulin-like growth factor I, growth hormone, and insulin in cattle. AB - We investigated the effect of fat supplementation on plasma levels of hormones related to metabolism, with special attention to leptin, in cows in early lactation and in feedlot steers. In experiment 1, 34 lactating cows received no fat or else 0.5 or 1.0 kg of partially hydrogenated oil per day in addition to their basal diet from day 20 before the expected calving date to day 70 postpartum. In experiment 2, part of the corn in the basal concentrate was replaced with 0.7 kg of the same oil such that the diets were isocaloric; 18 cows received the fat-substituted diet and 18 a control diet from day 20 before the expected calving date to day 75 postpartum. In experiment 3, calcium salts of fatty acids were added to the basal diet of 14 feedlot steers for 80 d; another 14 steers received a control diet. The basal plasma levels of leptin were higher in the cows than in the steers. Dietary fat supplementation did not affect the leptin levels in the lactating cows but lowered the levels in the feedlot steers despite greater energy intake and body fatness (body weight) in the steers receiving the supplement than in those receiving the control diet. The levels of insulin-like growth factor I and insulin were decreased with dietary fat supplementation in the lactating cows but were unaffected in the steers, suggesting that responses to fat ingestion depend on the physiological state of the animal, including age and sex. Finally, no effects of supplementary fat on the level of growth hormone were demonstrated in any of the models. PMID- 17695599 TI - Detection of bovine herpesvirus 4 DNA in aborted bovine fetuses. AB - The presence of Bovine herpesvirus 4 (BoHV-4) was investigated by several methods in 24 aborted bovine fetuses. Polymerase chain reaction (PCR) and in situ DNA hybridization proved the presence of BoHV-4 DNA in 7 (29%) of the fetuses. The BoHV-4 genome was detected in the cytoplasm of splenic lymphocytes and monocytes, and sometimes in renal tubular epithelial cells or hepatic Kupffer cells, in all 7 PCR-positive fetuses. However, BoHV-4-specific monoclonal antibody failed to detect viral antigen in the formalin-fixed, paraffin-embedded tissue samples. No bacterial pathogens were found in the tissues of the BoHV-4-positive fetuses. Fungi were detected in 1 sample, and antibody to bovine viral diarrhea virus was detected in another. These results indicate that BoHV-4 could play a role in reproductive disorders of cattle, including abortion. PMID- 17695600 TI - Presence of non-O157 Shiga toxin-producing Escherichia coli in feces from feedlot cattle in Alberta and absence on corresponding beef carcasses. AB - The study objectives were to determine the prevalence and serotypes of non-O157 Shiga toxin-producing Escherichia coli (STEC) in pens of feedlot cattle and on corresponding beef carcasses. We collected 25 fecal samples from 84 pens in 21 Alberta feedlots and 40 carcass swabs from each preslaughter pen for analysis by culture and polymerase chain reaction (PCR). Non-O157 STEC were recovered from feces from 12 (14%) of the 84 pens and 12 (57%) of the 21 feedlots by examination of 1 E. coli isolate positive for 4-methylumbelliferyl-beta-beta-glucuronide per sample. Twelve non-O157 serotypes were detected, but 7 of the 15 STEC isolates lacked the accessory virulence genes eae and hlyA. Although 115 (7%) of the carcass broths were PCR-positive, no STEC isolates were recovered from the 1650 carcasses sampled. Our data indicate that multiple non-O157 STEC serotypes may be present in cattle feces, yet are unlikely to be recovered from the corresponding beef carcasses when 20 colonies per sample from PCR-positive broth cultures are analyzed. PMID- 17695601 TI - Prevalence and genetic characterization of hepatitis E virus in paired samples of feces and serum from naturally infected pigs. AB - This study describes the distribution of Hepatitis E virus (HEV) in a naturally infected swine population and the genetic relatedness of HEV strains on swine farms in Spain. Of fecal and serum samples collected from 131 pigs and manure ditch samples collected from 17 farms, HEV was detected in 16%, 14%, and 59%, respectively, for an overall prevalence rate of 23%. The maximum prevalence rates for feces and serum were in pigs 5 to 12 wk old. A high prevalence of the virus in feces (18%) was observed in sows. Gene sequencing was performed on 6 strains from feces, serum, and manure ditch: the nucleotide identities varied from 81.5% to 99% when compared with those of other strains of genotype 3 isolated from swine. This is the first study in Europe to show the variation in virus distribution by age in feces and serum in a naturally infected swine population. PMID- 17695602 TI - Clinical evaluation of flowable resins in non-carious cervical lesions: two-year results. AB - This study evaluated the two-year clinical performance of one microhybrid composite and three different types of flowable resin materials in non-carious cervical lesions. A total of 252 noncarious cervical lesions were restored in 37 patients (12 male, 25 female) with Admira Flow, Dyract Flow, Filtek Flow and Filtek Z250, according to manufacturers' instructions. All the restorations were placed by one operator, and two other examiners evaluated the restorations clinically within one week after placement and after 6, 12, 18 and 24 months, using modified USPHS criteria. At the end of 24 months, 172 restorations were evaluated in 26 patients, with a recall rate of 68%. Statistical analysis was completed using the Pearson Chi-square and Fisher-Freeman-Halton tests (p < 0.05). Additionally, survival rates were analyzed with the Kaplan-Meier estimator and the Log-Rank test (p < 0.05). The Log-Rank test indicated statistically significant differences between the survival rates of Dyract Flow/Admira Flow and Dyract Flow/Filtek Z250 (p < 0.05). While there was a statistically significant difference between Dyract Flow and the other materials for color match at 12 and 18 months, no significant difference was observed among all of the materials tested at 24 months. Significant differences were revealed between Filtek Z250 and the other materials for marginal adaptation at 18 and 24 months (p < 0.05). With respect to marginal discoloration, secondary caries, surface texture and anatomic form, no significant differences were found between the resin materials (p > 0.05). It was concluded that different types of resin materials demonstrated acceptable clinical performance in non-carious cervical lesions, except for the retention rates of the Dyract Flow restorations. PMID- 17695603 TI - Eight in-office tooth whitening systems evaluated in vivo: a pilot study. AB - This in vivo pilot study evaluated eight products with hydrogen peroxide (HP) concentrations ranging from 15% to 35%. The treatment contact time varied from 15 minutes to 60 minutes. Patients were evaluated for color at baseline, immediately after treatment and at one, two, four and six weeks after treatment using a colorimeter, shade guide and photos. All eight products were effective in bleaching teeth. Colorimeter data for deltaE immediately after treatment was 6.77. At one and six weeks after bleaching, there were 51% and 65% reductions in deltaE, respectively. PMID- 17695604 TI - Effect of pH variations in a cycling model on the properties of restorative materials. AB - This study evaluated the effect of cycling various pH demineralizing solutions on the surface hardness, fluoride release and surface properties of restorative materials (Ketac-Fil Plus, Vitremer, Fuji II LC, Freedom and Fluorofil). Thirty specimens of each material were made and the surface hardness measured. The specimens were randomized into five groups according to the pH (4.3; 4.6; 5.0; 5.5 and 6.2) of the demineralizing solution. The specimens were submitted to pH cycling for 15 days. The specimens remained in the demineralizing solution for six hours and in the remineralizing solution for 18 hours. Then, the surface hardness (SH) was remeasured and the surface properties were assessed. Fluoride release was determined daily. Data from SH and the percentage of alteration in surface hardness were analyzed by analysis of variance (p < 0.05); the Kruskal Wallis test was performed for the fluoride release results. When hardness was compared, the variation in pH led to a positive correlation for glass ionomer cements and a negative correlation for fluoride release. For polyacid-modified resin composites, a negative correlation was found with regards to fluoride release; no significant correlation was observed for hardness. Surface properties were influenced: an acidic pH led to a greater alteration, except for polyacid modified resin composites. The pH of the demineralizing solution influenced fluoride release from the tested materials. The pH variation altered hardness and surface properties of glass ionomer cements but did not influence polyacid modified resin composites. PMID- 17695605 TI - A study of microleakage in Class II composite restorations using four different curing techniques. AB - There are several incremental techniques for the placement of posterior composites in Class II cavities that were introduced to overcome clinical failures associated with these restorations. This study evaluated microleakage in Class II cavities restored with four different curing techniques. On 40 non carious, freshly extracted human premolars, Class II cavities were prepared following a standard pattern in which the mesial cavities had a cervical margin 1.0 mm above the CEJ, and for distal cavities, 1.0 mm below the CEJ. The specimens were randomly divided into four groups. Each cavity surface was conditioned with 35% phosphoric acid and rinsed to remove the excess water, followed by a dental bonding agent (PQ1) being used for all the cavities. The teeth were then restored with a fiber reinforced resin-based composite (Neulite F), using four different techniques: Group 1, metal matrix with wooden wedge; Group 2, transparent matrix with reflective wedge; Group 3, metal matrix with wooden wedge and light tip and Group 4, metal matrix with wooden wedge and bio glass cylinder. Then, the restorations were finished and polished, rebonded, thermocycled (2000 times, 5 degrees C to 55 degrees C, 30 second dwell time), stained, sectioned vertically and viewed under a stereomicroscope (40x). They were then scored on a 0-4 scale based on microleakage at the gingival margins. The data were analyzed using the Kruskal-Wallis and Mann-Whitney U tests. The results showed that Group 1 demonstrated the most leakage, while the other three groups showed less leakage than Group 1. There was no significant difference between the enamel and dentin gingival margin groups. As a result of these findings, the authors concluded that restoration with metal matrices, using light conducting instruments, results in significantly less microleakage at the gingival margins of Class II resin composite restorations. PMID- 17695606 TI - Shear bond strength of the amalgam-resin composite interface. AB - OBJECTIVE: This study compared the initial and one year shear bond strengths (SBS) of resin composite bonded to amalgam using Amalgambond-Plus. METHODS: Resin composite cylinders (Point 4, Kerr Corporation) were bonded to either etched enamel (A), 50% etched enamel-50% polished amalgam (B), airborne-particle abraded amalgam (C), carbide bur prepared amalgam (D) and airborne-particle abraded 50% amalgam-50% etched-enamel (E). Shear bond strengths were determined using a standardized testing device (Ultradent Products) in a universal testing machine (Instron model 4204). The failed interfaces were evaluated with SEM to obtain visual evidence of the failure mode. RESULTS: ANOVA indicated significant differences among the groups (p < 0.0001). SBS in MPa (Mean/SD) were for A at year 0: (24.63/4.19), A at year 1: (16.84/7.25), B at year 0: (9.13/2.18), B at year 1: (15.54/6.41), C at year 0: (16.82/3.60), C at year 1: (15.26/3.90), D at year 0: (9.27/4.03), D at year 1: (7.97/7.17), E at year 0: (16.67/4.87) and E at year 1: (8.63/3.64). CONCLUSION: In vitro testing demonstrated that resin composite masking has the strongest, most durable SBS on airborne-particle abraded amalgam and airborne-particle abraded enamel-amalgam surfaces and could be used as a method to improve the esthetics of amalgam restorations. PMID- 17695607 TI - Surface geometry of four nanofiller and one hybrid composite after one-step and multiple-step polishing. AB - This study assessed the surface quality of four nanoparticle composites and one hybrid composite after polishing with three different techniques. Nanocomposites Premise (KerrHawe), Tetric EvoCeram (Ivoclar Vivadent), Filtek Supreme (3M ESPE) and Ceram X Duo (Dentsply) and the hybrid composite Herculite XRV (KerrHawe) were selected. Sixty specimens 7x7 mm each were fabricated from these materials. After light curing, the specimens were treated with 600 grit sandpaper discs. Fifteen specimens of each composite were polished using flexible Sof-Lex discs (3M ESPE). The remaining 45 specimens of each material were prepared with three finishing protocols: a single 30 microm diamond (n=15), a sequence of a 30 microm and a 20 microm diamond (n=15) and a 30 microm diamond followed by a tungsten carbide finishing bur (n=15). Each series of 15 specimens was then subdivided into three groups of five and polished with the Astropol system (Ivoclar Vivadent), OptiShine brushes (KerrHawe) and the Enhance/PoGo system (Dentsply). Quantitative evaluation of surface roughness was done with the help of optical laser stylus profilometry. Average roughness (Ra) was calculated, and the effect of the materials, the finishing regimen and the polishing methods on surface roughness were analyzed by three-way and two-way Anova and Scheffe post-hoc tests. Qualitative evaluation of the surfaces was done with the help of scanning electron microscopy (PSEM 500, Phlipps). Photomicrographs were assessed with respect to surface quality in four gradings. Surface roughness after polishing was significantly influenced by three factors: composite material (p < 0.001), finishing protocol (p < 0.001) and polishing method (p < 0.001). There were strong interactions between the finishing and polishing methods (p < 0.001). Two of the nanocomposites were significantly smoother (p < or = 0.001), while the other two had a surface quality similar to that of a hybrid composite. Astropol achieved the lowest average roughness on all composites. Except for a combination of a 30 microm diamond and OptiShine brushes, which caused severe roughness, all the polishing methods produced surfaces that were significantly smoother than using the Sof-Lex discs. PMID- 17695608 TI - The influence of C-factor, flexural modulus and viscous flow on gap formation in resin composite restorations. AB - This study analyzed the influence of C-factor, flexural modulus and viscous flow on gap formation in resin composite restorations. Two resin composites, a mini filled hybrid (P 60) and a nanofilled (Supreme), were used. The flexural modulus was obtained from bar-shaped specimens submitted to three-point bending. Viscous flow was obtained from the difference between the initial and final diameter of resin composite disks submitted to a load of 10 N for 120 seconds. Gap analysis was conducted in three types of cylindrical cavities (C-factor of 1.8, 2.6 and 3.4) that were prepared on the occlusal surfaces of human molars. The gap width at the dentin-resin composite interface was measured using a 3D scanning system (Talyscan 150). The data were analyzed by ANOVA and Student-Newman-Keuls' test, t test and linear regression analysis (alpha = 0.05). The cavities with C-factor 3.4 presented the highest Gap formation (p < 0.0001). The lowest Gap formation was found in cavities restored with Supreme resin composite (p < 0.0001). P 60 presented significantly higher flexural modulus and lower viscous flow than Supreme (p < 0.0001). Regression analyses detected a significant influence of flexural modulus and viscous flow on gap formation (p < 0.05). PMID- 17695609 TI - Effect of intermediate agents and pre-heating of repairing resin on composite repair bonds. AB - This study investigated the composite-to-composite microtensile bond strength and interfacial quality after using different combinations of intermediate agents and pre-curing temperatures of repairing resin. Forty-five composite discs (8x4 mm) of Gradia Direct Anterior (GC Corp), stored in a saline solution at 37 degrees C for one month, were sandblasted (50 microm aluminum oxide), cleaned (35% phosphoric acid) and randomly divided into three groups (n=15) according to the intermediate agent applied: (1) no treatment; (2) unfilled resin (Scotchbond Multi-Purpose Adhesive, 3M ESPE); (3) flowable composite (Gradia LoFlo, GC Corp). Each disc was incrementally repaired (8x8 mm) with the same resin as the substrate. For each group, three subgroups (n=5) were created, depending on the pre-curing temperature of the repairing resin-4 degrees C, 23 degrees C or 37 degrees C. Two bonded specimens per group were prepared to evaluate the composite to-composite interfacial quality via scanning electron microscope. Microtensile bond strength measurements were performed with the remaining three specimens and failure mode was examined by stereomicroscopy. Two-way ANOVA revealed that temperature (p < 0.001), intermediate agent (p < 0.001) and the interaction (p = 0.002) significantly affected the repair strength. Post-hoc comparisons revealed that bond strengths were significantly lower using a 4 degrees C repairing resin in groups where intermediate agents were used. The highest bond strengths were recorded when flowable composite was used as an intermediate agent under each of the three temperature conditions. Interfacial quality improved by raising the resin temperature from 4 degrees C to 37 degrees C. PMID- 17695610 TI - Bond durability of composite luting agents to ceramic when exposed to long-term thermocycling. AB - PURPOSE: This study evaluated the effect of thermocycling on the microtensile bond strength of four adhesive luting agents to GN-I CAD-CAM ceramic. The hypothesis tested was that thermocycling did not affect bonding effectiveness, irrespective of the luting agents used. MATERIALS AND METHODS: Ceramic specimens of two different sizes (6x8x3 mm; 13x8x4 nm) were fabricated from GN-I CAD-CAM ceramic blocks (GC) using a low-speed diamond saw. Two different sized porcelain discs were bonded with one of the four composite luting agents (Linkmax [LM], Panavia [PN], RelyX Unicem [UN] and Variolink II [VL]) according to the manufacturer's instructions. The specimens were stored for 24 hours in distilled water at 37 degrees C and subjected to 0; 10,000; 20,000 and 40,000 thermocycles prior to microTBS testing. Two-way analysis of variance was used to test the influence of luting cement, thermocycling and interaction between both (p < 0.05). The Tukey HSD test determined statistical differences in microTBS for each luting composite between the different thermocycling conditions (p < 0.05). The mode of failure was determined at a magnification of 50x using a stereomicroscope (Wild M5A). RESULTS: Two-way ANOVA revealed that microtensile bond strength was affected by the luting cement, thermocycling and a combination of both. No difference in bond strength between Linkmax, Panavia F and Variolink II was noticed after 24 hours of water storage (LM: 47.6 MPa; PN: 41 MPa; VL: 36 MPa). RelyX Unicem scored significantly lower than Linkmax and Panavia F (UN: 24.2 MPa). The influence of thermocycling on bond strength was different for the four luting cements. Using Variolink II, the bond strength remained stable after 40,000 thermocycles (43.6 MPa). Linkmax showed a significant decrease in bond strength after 10,000 (26 MPa) and 40,000 thermocycles (14.8 MPa). Panavia F and RelyX Unicem were the most negatively influenced, as all specimens failed prior to testing (pre-testing failures) when the specimens were thermocycled 10,000 and 20,000 times or longer, respectively. Regarding the failure mode, there was a correlation between bond strength and type of failure. Initially, a combination of adhesive and mixed adhesive-cohesive failures was noticed. The percentage of adhesive failures increased, together with a decrease in bond strength. CONCLUSION: It was concluded that there were significant differences among the four resin composite cements in terms of their bonding effectiveness to CAD-CAM ceramic after thermocycling. The varying degrees of bonding effectiveness of these adhesive luting agents highlight the need for material specifications. PMID- 17695611 TI - Impact of adhesive application to wet and dry dentin on long-term resin-dentin bond strengths. AB - This study compared the effects of moisture and rubbing action on the immediate and one-year microtensile bond strength (BS) of an ethanol/water-based adhesive system (Single Bond [SB]) and an acetone-based system (One Step [OS]) to dentin. A flat superficial dentin surface on 60 human molars was exposed by wet abrasion. Two coats of the adhesives were applied on either a dry (D) or rewetted surface (W) with no (NRA), slight (SRA) or vigorous rubbing action (VRA). After light curing (600 mW/cm2/10 seconds), composite buildups were constructed incrementally and the specimens were stored in water (37 degrees C/24 hours). They were longitudinally sectioned in the "x" and "y" directions to obtain bonded sticks (0.8 mm2) to be tested in tension at 0.5 mm/minute. The sticks from each tooth were then divided, stored in water at 37 degrees C and tested immediately and after 12 months (12 M) at 0.5 mm/minute. The bond strength values of sticks from the same hemitooth were averaged for statistical purposes. The prematurely debonded specimens were included in the hemi-tooth mean. The data from each adhesive was analyzed by three-way ANOVA and Tukey's multiple comparison tests (alpha = 0.05). In the dry groups, high bond strength values were obtained under VRA. When the dentin was kept moist, both SRA and VRA provided high resin-dentin bond strength values. Reductions in bond strength values after one year of water storage were not observed for the SB adhesive or were less pronounced for the OS adhesive when it was vigorously rubbed onto the dentin surface. PMID- 17695613 TI - In vitro evaluation of tooth-color change using four paint-on tooth whiteners. AB - The effectiveness of four paint-on tooth whiteners was evaluated and compared in this in vitro study. Sixty extracted anterior teeth were selected and randomly assigned to five groups: 1-(AS) Artificial Saliva (Roxane); 2-(MSW) Sparkling White (Meijer); 3-(CNE) Crest Night Effects (Procter & Gamble); 4-(ABB) Beautifully Bright (Avon) and 5-(CSWN) Simply White Night Gel (Colgate Palmolive). The teeth were cleaned with a soft bristle toothbrush and toothpaste (Procter & Gamble) to remove any residue from the storage solution. The bleaching gels were painted onto the surface of the teeth, and they were then wrapped in gauze moistened with artificial saliva and kept in 100% humidity at 98 degrees F in a laboratory oven (Precision Scientific model 18EG) for 24 hours. The treatment was repeated once a day for 14 days. Visual color assessment was done using a value-oriented Vitapan Classical Shade Guide (Vident) and a colorimeter (Minolta Chroma Meter CR 321). PVS jigs (Exaflex, GC America) were fabricated for each tooth. Visual and colorimetric readings were recorded at baseline, 7 and 14 days. One-way ANOVA and Tukey multiple comparisons test were used to assess differences between groups. CNE and CSWN presented the highest mean number of shade changes and deltaE*ab Colorimeter readings. ABB and MSW did not significantly lighten the teeth, as measured by either method of evaluation after two weeks of the bleaching regimen. PMID- 17695612 TI - In vitro inhibition of bacterial growth using different dental adhesive systems. AB - OBJECTIVES: This study evaluated the antibacterial potential of four different adhesive systems. METHODS & MATERIALS: Gluma Comfort Bond + Desensitizer, Gluma Comfort Bond, iBond and One-Up Bond F were tested against Streptococcus mutans, Streptococcus sobrinus, Lactobacillus acidophilus and Actinomyces viscosus. The inhibition of growth by calibrated preparations was quantified by the measurement of zones of inhibition on bacterial lawns. Bactericidal activity was determined as reductions in recoverable colony-forming units in bacterial suspensions exposed to test preparations. RESULTS: All the preparations exhibited detectable zones of inhibition for all target bacteria through six months. When the bactericidal action was evaluated, all the materials were able to kill all the tested bacteria when tested immediately after polymerization. After one week of aging, iBond was the only material that continued to kill all of the test strains. PMID- 17695614 TI - Bond strengths of two adhesive systems to dentin contaminated with a hemostatic agent. AB - This study evaluated the bond strength of a total-etch and a self-etch adhesive to dentin contaminated with a hemostatic agent containing aluminum chloride (AlCl3). Eighteen occlusal dentin discs were prepared from human molars. Each disc was ground and sectioned into two halves, one for normal dentin and the other for contaminated dentin. The specimens of both normal and contaminated dentin were randomly divided into three groups and treated with the following materials: (1) Excite (EX); (2) Clearfil SE Bond with 20-second primer application time (CB 20) and (3) Clearfil SE Bond with 40-second primer application time (CB 40). The microshear bond strength specimens were prepared using the resin composite Clearfil APX. The bond strengths were evaluated on a universal testing machine. Statistical analysis was performed at alpha = 0.05. The surface micromorphology and aluminum content of the different dentin conditions were also examined. In EX, no significant difference was found between the bond strengths of normal dentin and contaminated dentin. The bond strength of CB20 to contaminated dentin was significantly lower than that to normal dentin. The extension of primer application time from 20 to 40 seconds significantly increased the bond strength of CB to contaminated dentin. PMID- 17695616 TI - Additional uses for the classic matrix band. PMID- 17695615 TI - Color stability and degree of cure of direct composite restoratives after accelerated aging. AB - PURPOSE: This study evaluated the color changes and amount of remaining C = C bonds (%RDB) in three dental composites after hydrothermal- and photoaging. METHODS AND MATERIALS: The materials tested were Estelite sigma, Filtek Supreme and Tetric Ceram. Specimens were fabricated from each material and subjected to L* a* b* colorimetry and FTIR spectroscopy before and after aging. Statistical evaluation of the deltaL,* deltaa,* deltab,* deltaE and %deltaRDB data was performed by one-way ANOVA and Tukey's test. The %RDB data before and after aging were statistically analyzed using two-way ANOVA and Student-Newman-Keuls test. In all cases an alpha = 0.05 significance level was used. RESULTS: No statistically significant differences were found in deltaL*, deltaa*, deltaE and %deltaRDB among the materials tested. Tetric Ceram demonstrated a significant difference in deltab*. All the materials showed visually perceptible (deltaE >1) but clinically acceptable values (deltaE < 3.3). Within each material group, statistically significant differences in %RDB were noticed before and after aging (p < 0.05). Filtek Supreme presented the lowest %RDB before aging, with Tetric Ceram presenting the lowest %RDB after aging (p < 0.05). The %deltaRDB mean values were statistically significantly different among all the groups tested. No correlation was found between deltaE and %deltaRDB. PMID- 17695617 TI - The ethics of enabling technology. PMID- 17695618 TI - The bodily incorporation of mechanical devices: ethical and religious issues (part 2). PMID- 17695619 TI - Wired patients: implantable microchips and biosensors in patient care. PMID- 17695620 TI - Becoming borg to become immortal: regulating brain implant technologies. PMID- 17695621 TI - Design and engineering ethics considerations for neurotechnologies. PMID- 17695622 TI - Neurosurgical implants: clinical protocol considerations. PMID- 17695623 TI - "Currents of hope": neurostimulation techniques in U.S. and U.K. print media. PMID- 17695624 TI - Ethics in the clinical application of neural implants. PMID- 17695625 TI - CQ Sources/Bibliography. PMID- 17695626 TI - Rights and procreative liberty. PMID- 17695627 TI - Parental love and the ethics of sex selection. PMID- 17695628 TI - The moral imperative for ectogenesis. PMID- 17695629 TI - Who reviews the projects of unaffiliated researchers for ethics? A case study from Alberta. PMID- 17695630 TI - Disaster planning. Florida hospitals combat high property insurance rates. PMID- 17695638 TI - [Industrial hygiene for firemen: results and prospects of research]. AB - The authors present results of the Institute work on industrial hygiene for firemen, including hygienic evaluation of work conditions, health state and improving concept of occupational health for risky job individuals. PMID- 17695639 TI - [Electroneuromyography in diagnosis of vibration disease and occupational polyneuropathy]. AB - Electroneuromyography in workers exposed to local vibration revealed disordered functional state of nerves in lower and upper limbs, more significant in arms. Individuals exposed to local and general vibration combined with occupational hazards demonstrated more frequent axonal type of ulnar nerve disorder, with less length of service in comparison with group 1 members. PMID- 17695640 TI - [Behavioral activity of white rats under inhalation of metallic mercury]. AB - Prolonged inhalation of metallic mercury vapors by white rats appeared to result in toxic encephalopathy manifesting in disorders of orientative and investigatory, emotional behavior - increased anxiety, aggressiveness, negative e motionalism, higher locomotion activity. Throughout the experiment the animals had increased aggressiveness and muscular tone. PMID- 17695641 TI - [Role of environmental pollution with lead in children health state]. AB - Evidence is that high environmental pollution with lead causes accumulation of the metal amounts exceeding allowable levels (10 g/dl) in serum of children, and further on to neuropsychologic disorders. The authors defined correlations between lead content of environment, serum lead level in children and changes of some neuropsychologic parameters. PMID- 17695642 TI - High-content screening. PMID- 17695643 TI - High-throughput profiling of posttranslational modification enzymes by phage display. AB - Phage display has been used as a high-throughput platform for identifying proteins or peptides with desired binding or catalytic activities from a complex proteome. Recently, phage display has been applied to profile the catalytic activities of posttranslational modification (PTM) enzymes. Here, we highlight recent work elucidating the downstream targets of PTM enzymes by phage display, including the genome-wide profiling of biosynthetic enzymes subject to phosphopantetheinyl transferase (PPTase) modification. PMID- 17695644 TI - [MR imaging in congenital disorders of the brain]. AB - MR imaging is an excellent tool for use in diagnosing congenital malformations of the brain. Such malformations cannot be reliably recognized or classified without an insight into the basic processes of the fetal development of the brain. Cortical malformations are classically divided into (1) malformations of neuronal proliferation, i.e. of stem cell proliferation in the periventricular germinal matrix zone, (2) disorders of neuronal migration, i.e. of the radial migration of the neurons from the periventricular germinal matrix zone to the cortical surface, and (3) disorders of cortical organization. Other cerebral malformations are agenesis or dysgenesis of the corpus callosum, encephaloceles, and various kinds of holoprosencephaly. Chiari malformation ans disorders on the Dandy-Walker spectrum are relatively common, primarily infratentorial disorders. Rarer infratentorial disorders are Joubert syndrome, rhombencephalosynapsis and Lhermitte Duclos syndrome. PMID- 17695645 TI - Growing threat of superbugs. PMID- 17695646 TI - Raising moth awareness. PMID- 17695647 TI - Tackling communicable diseases in prisons. PMID- 17695648 TI - More emphasis needed on HIV prevention, warn experts. PMID- 17695649 TI - New guidance issued on HIV data collection. PMID- 17695650 TI - Kazakh medical workers guilty of causing HIV outbreak. PMID- 17695651 TI - Multiple bumps seen on the heels. Piezogenic pedal papules. PMID- 17695652 TI - Stenting or bypass--which is right for you? Knowing which intervention is best for your condition may improve your odds of survival and reduce the need for a follow-up. PMID- 17695653 TI - Tests that predict your cardiac future. Several tests assess risk of coronary heart disease, heart attack and death from heart disease, but can better prediction lead to successful prevention? PMID- 17695654 TI - Protect your heart by relieving stress. Stress is associated with high blood pressure and other contributors to heart disease. Learn how to recognize and manage the problem. PMID- 17695655 TI - It's not too late to reverse metabolic syndrome. Lifestyle changes, such as losing weight, may save your life. PMID- 17695656 TI - Add more fiber to your diet and see a bounty of health benefits. Fiber is loaded with advantages, from increased regularity to lowering cholesterol. Here's how you can get more. PMID- 17695657 TI - Ezetimibe combines with simvastatin to tackle cholesterol. New drugs attack "bad" cholesterol in the liver and intestine. PMID- 17695658 TI - Niacin plus statin: powerful anti-cholesterol partnership. Use of the B vitamin niacin may help keep your cholesterol under control, but there are certain things you should know before starting therapy. PMID- 17695659 TI - New medications help those with diabetes avoid heart trouble. Drugs mimic the body's natural insulin and glucose controls, but diet and exercise are still keys to controlling the disease. PMID- 17695660 TI - Ask the doctors. I have previously received stents in my heart arteries. My cardiologist recommended a stress test.. I would like to avoid that if possible. Couldn't I just have a computed tomography (CT) scan of my heart instead? PMID- 17695661 TI - Even light exercise has benefit. Resistance training can restore muscle composition and strength at any age. PMID- 17695662 TI - Advances in diagnostic radiology and RFA aid cancer detection and treatment. Recent innovations enable earlier treatment with shorter hospital stays and less post-procedure pain. PMID- 17695663 TI - Enlarged prostate: BPH could be two diseases, one more severe. Diagnostic breakthrough could identify new form of prostate disease sooner, enabling earlier therapy. PMID- 17695664 TI - Chronic pain disrupts memory, concentration. Pain can go beyond discomfort to affect important mental functions. PMID- 17695665 TI - Living with atherosclerosis is more serious than previously thought. Outpatients are at significant risk for heart attack and stroke. PMID- 17695666 TI - Rheumatoid arthritis and early death risk. In patients with RA, the mutated HLA DRB1-SE gene is the suspect for higher incidence of heart disease and cancer. PMID- 17695667 TI - I have osteoarthritis in my knees. I also have a blood-clotting disorder and have been put on Coumadin, which means I can't take NSAIDs. I take a daily dose of Tylenol, but it doesn't have much effect. What do you suggest? PMID- 17695669 TI - Primary hyperparathyroidism. PMID- 17695668 TI - A kinetic and dynamic analysis of Foxp3 induced in T cells by TGF-beta. AB - TGF-beta induces Foxp3 expression in stimulated T cells. These Foxp3+ cells (induced regulatory T cells (iTreg)) share functional and therapeutic properties with thymic-derived Foxp3+ regulatory T cells (natural regulatory T cells (nTreg)). We performed a single-cell analysis to better characterize the regulation of Foxp3 in iTreg in vitro and assess their dynamics after transfer in vivo. TGF-beta up-regulated Foxp3 in CD4+Foxp3- T cells only when added within a 2- to 3-day window of CD3/CD28 stimulation. Up to 90% conversion occurred, beginning after 1-2 days of treatment. Foxp3 expression strictly required TCR stimulation but not costimulation and was independent of cell cycling. Removal of TGF-beta led to a loss of Foxp3 expression after an approximately 4-day lag. Most iTreg transferred into wild-type mice down-regulated Foxp3 within 2 days, and these Foxp3- cells were concentrated in the blood, spleen, lung, and liver. Few of the Foxp3- cells were detected by 28 days after transfer. However, some Foxp3+ cells persisted even to this late time point, and these preferentially localized to the lymph nodes and bone marrow. CXCR4 was preferentially expressed on Foxp3+ iTreg within the bone marrow, and CD62L was preferentially expressed on those in the lymph nodes. Like transferred nTreg and in contrast with revertant Foxp3- cells, Foxp3+ iTreg retained CD25 and glucocorticoid-induced TNFR family-related gene. Thus, Foxp3 expression in naive-stimulated T cells is transient in vitro, dependent on TGF-beta activity within a highly restricted window after activation and continuous TGF-beta presence. In vivo, a subset of transferred iTreg persist long term, potentially providing a lasting source for regulatory activity after therapeutic administration. PMID- 17695670 TI - Addiction: a nurse's story. Opioids became an obsession--until he was caught. PMID- 17695671 TI - [Primary hyperparathyroidism]. AB - For thirty years, primary hyperparathyroidism is recognized as a frequent endocrine disease which is, most often, "non symptomatic" that is without nephrolithiasis or osteitis fibrosa cystica. Our knowledge in the pathophysiology has greatly grown and diagnosis of primary hyperparathyroidism is frequently easy. The only curative treatment is surgery and the indications have been codified by several consensus conferences. PMID- 17695672 TI - [POEMS syndrome]. PMID- 17695673 TI - [Osteoarticular infections. New mangement challenges]. PMID- 17695674 TI - [Osteoarticular infection diagnosis]. AB - Diagnosis of osteitis/arthritis requires clinical, microbiological and radiological data. Good quality samples must be obtained before antibiotic therapy is introduced to identify causative microorganisms. New technical methods such as PCR can improve the diagnosis. X-ray radiograph is always performed when osteitis is suspected, even if the diagnosis can be difficult since abnormalities are present late in the course of the disease. MRI is the best method to establish the diagnosis of osteitis or arthritis. Scintigraphy can be an interesting investigation since it can be promptly performed even in patients with foreign material. New technical such as PET-Scan could be interesting to establish the diagnosis. Collaboration between clinicians, microbiologists and radiologists is essential to establish the diagnosis in order to target the appropriate treatment and to improve the prognosis. PMID- 17695675 TI - [Bone and joint prosthesis infections]. AB - Despite the advances made in the surgical management and the optimization of anti infective treatments, bacterial infections on bone and joint prosthesis remain a diagnostic and especially therapeutic issue. Infections can be either early (postoperative) or late (hematogenous) acute infections, or late chronic infections. Typically, the diagnosis of hematogenous acute infections is usually easy to establish. However, diagnosing chronic infections is more complex and mostly requires complementary examinations. In any case, no element can indicate with certainty the existence of an infection, aside from the identification of germs in the samples, properly collected. Treatment combines one of the various surgical strategies (surgical scrub with prosthesis maintenance, 1- or 2-step prosthesis replacement, prosthesis removal without reimplantation or head-neck resection, therapeutic abstention) and an extended antibiotherapy. In any scenario, a close collaboration between physicians and surgeons is essential to stop the infectious process. PMID- 17695676 TI - [Infectious spondylodiscitis]. AB - Vertebral osteomyelitis (VO) is an infection of the intervertebral disc with a possible extension to adjacent vertebrae. Annual incidence of VO in France is 2.4/100,000 inhabitants. It increases with age, above 6/100,000 over 70 years old. Eighty percent are hematogenous, and 20% developed after spinal surgery. The main unspecific symptoms are inflammatory spine pain, associated or not with fever. Diagnosis is performed with MRI, then blood cultures and disco-vertebral biopsy. The main causative organisms are staphylococci (40 to 60%), even though tuberculosis can be observed in 20%. Specific antimicrobial therapy, immobilisation and reeducation are needed. Clinical practice guidelines for management of infectious spondylodiscitis have been edited in 2007. PMID- 17695677 TI - [Infection associated with orthopaedic fixation devices]. AB - Infection associated with orthopaedic fixation devices are suspected on clinical and radiological findings, and confirmed by microbiological studies. Antimicrobial therapy should be avoided before tissues sampling for culture. The goals of treatment are consolidation of fracture and preservation of chronic osteomyelitis. Retention of the internal fixation device combined with long-term antibiotic treatment is only reasonable in some acute cases (if the implant is stable). In other cases, implant should be removed, replaced by an external fixator. Secondary, bone and soft tissues reconstruction could be done. Antimicrobial treatment according to the pathogen and its antimicrobial susceptibility is administered for 6 to 12 weeks. Long-term prognosis is good but with some long-term resurgences. PMID- 17695678 TI - [Acute septic arthritis]. AB - Acute septic arthritis is a medical emergency both for its diagnosis and its treatment. There are numerous predisposing factors of this condition. Staphylococcus aureus is the most frequent isolated bacteria. In 15% of cases, the clinical picture is not a monoarticular involvement, but rather a polyarticular one. Diagnosis is based on the identification of the micro-organism by joint aspiration and/or blood cultures. These bacteriological samples have to be realized before antibiotics administration. Cultures remain negative in 10 to 20% of true cases of septic arthritis. The antibiotic treatment has to be started when the direct Gram stain examination is positive (50% of cases) or if the suspicion is high but the Gram stain negative. It is frequently necessary to search for an associated endocarditis. It is necessary to remember the possibility of a gonococcal arthritis (tenosynovitis, skin lesions). Joint drainage can be achieved either by closed-needle aspiration or by surgical drainage (hip, destructive lesions on radiographs, no satisfactory response to medical aspirations). Duration of antibiotic treatment varies between 6 and 12 weeks, with the exception of gonococcal arthritis (10 days). PMID- 17695679 TI - [Diabetic foot osteomyelitis]. AB - Bone and joint infections associated with chronic wound of the diabetic foot are frequent and severe complications that should be considered in most cases. Early diagnosis and aggressive treatment are likely to limit bad outcome. Clinical studies with acceptable methodology addressing the relative role of medical and surgical approaches are needed. Bone biopsy available in routine in a diabetic foot clinic represents a marker of good quality of management of such patients. Given the global burden and potential severity of osteomyelitis of the diabetic foot, every measure that can prevent the occurrence and persistence of a foot wound in a diabetic patient remain major objectives. PMID- 17695680 TI - [Antibiotic therapy of osteoarticular infections in the adult]. AB - The treatment of bone and joint infections remains difficult. A combination of prolonged antibiotic therapy and surgery is generally required. However, antibiotic and surgical treatment strategies lack standardisation. The optimal antimicrobial therapy must be adjusted both to the isolated microorganism(s) and to the patient, and must be diffused into the bone. It is difficult to make evidence-based recommendations on the treatment of these infections, as very little high quality clinical evidence exists. PMID- 17695681 TI - [Patients' card. What is ambulatory parenteral antibiotic therapy?]. PMID- 17695682 TI - [Assessment: trainees, medical education and beyond...(2)]. PMID- 17695683 TI - [Fit, faint and blackout in the adults]. PMID- 17695684 TI - [Breastfeeding and complications]. PMID- 17695685 TI - [HIV infection]. PMID- 17695686 TI - [Genital infections in men. Urethral discharge]. PMID- 17695687 TI - [At the very begining of the Salpetriere, Paris, the locking up of beggar and debauched women]. PMID- 17695688 TI - Post-intubation tracheal stenoses: what is the curative yield of the interventional pulmonology procedures? PMID- 17695689 TI - Management of post-intubation tracheal stenoses using the endoscopic approach. AB - BACKGROUND AND AIM: Tracheal stenosis is a common complication of intubation with or without subsequent tracheotomy whose management remains poorly defined. Over 600 post-intubation tracheal stenoses have been treated in our centre since 1982: the aim of this study was to determine the safety and efficacy of our endoscopic approach. METHODS: This retrospective study includes 113 new cases treated between 1998 and 2001. We chose this period to have a standardised technique and a significant number of cases with a sufficiently long follow up (28-78 months). Forty patients who did not meet the criteria for "true stenosis" (granulomas, pseudoglottic stenosis, etc.) were excluded from the study. RESULTS: 73 patients (50+/-21 years) entered the study: 13 (18%) web-like and 60 (82%) complex stenoses. Most web-like stenoses were successfully treated with Laser Assisted Mechanical Dilation (LAMD) alone; among complex stenoses LAMD was sufficient to treat 13 patients (22%), whereas 47 patients (78%) required stent placement: 22 had their stent removed after one year and did not require any further therapy, 13 inoperable patients required permanent stent and 12 were referred to surgery after failure of multiple endoscopic treatments. No permanent complications secondary to endoscopic treatment were observed. 48 patients (66%) obtained a stable, good result with the endoscopic procedure, 13 (18%) required a permanent stent while 12 patients (16%) were referred to surgery. CONCLUSIONS: Our results indicate that the endoscopic treatment of post-intubation tracheal stenoses performed in an expert setting can be considered a safe first-line therapy, leaving some selected cases and the relapsing stenoses, for surgical resection. PMID- 17695690 TI - Some factors influencing quality of spontaneous or induced sputum for inflammatory cell analysis. AB - AIM: To find some simple clinical factors which can predict the quality of the sputum samples obtained in a large group of asthmatic subjects. METHODS: We compared the presence of sputum productive cough in the days preceding the test, easiness in expectoration during the test, and sputum macroscopic aspect (presence of visible plugs) with the quality of slides obtained from sputum processing. We also monitored changes in the quality in patients who repeated sputum collection several times, comparing those whose first sample was adequate with those whose first sample was inadequate. We analysed 547 sputum samples obtained from 238 asthmatic patients. Sputum was processed using the whole sample method. RESULTS: Patients with productive cough in the days preceding the test and easy expectoration during the test produced a higher percentage of adequate samples than those without productive cough (86% vs 76 %, p=0.01) and with difficulty in expectoration (85% vs 63%, p=0.0001). "Good" macroscopic samples were associated with better quality of slides (91% vs 38%, p=0.0001). Patients with inadequate first sample (n=40) had a higher percentage of inadequate samples (55%) in the subsequent tests than patients (n=115) with adequate first sample (8%). CONCLUSIONS: Patients with increased airway secretions in the days preceding the test, easy expectoration and "good" macroscopic aspect of the sputum are more likely to produce sputum sample adequate for inflammatory cell analysis. If the first sputum sample is adequate, subsequent samples are very likely to be adequate as well. If the first sputum sample is inadequate, the quality of subsequent samples cannot be predicted, since there are similar probabilities of having adequate or inadequate samples. PMID- 17695691 TI - PIKO-1, an effective, handy device for the patient's personal PEFR and FEV1 electronic long-term monitoring. AB - BACKGROUND AND AIM: Subjects with airway obstruction are strongly recommended to monitor their lung function, which is particularly variable in asthma. Unlike PEFR, other personal measurements (such as FEV1) are still difficult to perform. PIKO-1 is the first electronic device for both PEFR and FEV1 personal check, but its precision has not yet been assessed. The aim of this study was to compare PEFR and FEV1 values from PIKO-1 and from a conventional spirometer in subjects with airway obstruction. METHODS: In total, 352 subjects (217 men; 47.6 +/- 19.0 years; 72.6 +/- 15.0 kg; 168.1 +/- 11.9 cm) performed sequential measurements using a PIKO-1 device and a spirometer. Wilcoxon signed-rank test and sign test were used as statistical tests. RESULTS: Mean FEV1 values from the spirometer and PIKO-1, respectively, were 2.9 L +/- 1.1 and 3.0 L +/- 1.1, and mean PEFR values were 466.1 L/min +/- 164.5 SD and 426.3 L/min +/- 151.6 SD. PIKO-1 proved to overestimate FEV1 values by 4% (p<0.0001) and to underestimate PEFR values by 8% (p<0.000) systematically. CONCLUSIONS: The precision of both PIKO-1 measurements (such as FEV1 and PEFR) have been assessed. PEFR and FEV1 measures should be reset by two different constants. Nevertheless, PIKO-1 is a suitable and reliable device for the personal monitoring of obstructive patients in real life. PMID- 17695692 TI - Chronic productive cough in young adults is very often due to chronic rhino sinusitis. AB - BACKGROUND: Chronic productive cough is a common clinical problem; often potential causes outside the lower respiratory tract are forgotten or ignored. The aim of this study was to make a precise etiopathogenetic diagnosis of chronic productive cough in young adults. METHODS: In a clinical setting, 212 subjects (mean age 41+/-5 years) who had reported chronic productive cough in a previous postal survey of a young adult population underwent within two years clinical and functional investigations following a rational diagnostic approach. Two pulmonologists independently established the diagnosis using a clinically structured interview on nasal and respiratory symptoms, spirometry and other tests when appropriate (bronchodilator test or methacholine bronchial challenge, chest radiography); if rhino-sinusitis was suspected, subjects underwent an ENT examination with nasal endoscopy and/or sinus computed tomography. RESULTS: At the end of the diagnostic procedure, 87 subjects (41%) no longer had chronic productive cough and had normal function. Fifty-eight subjects (27%) had chronic rhino-sinusitis; seventeen subjects (8%) had asthma, and of these fourteen also had chronic rhino-sinusitis; 50 subjects (24%) had COPD stage 0+, of these seven also had chronic rhino-sinusitis. Chronic rhino-sinusitis was more frequent in females than in males (p<0.05). CONCLUSIONS: Both in clinical practice and in epidemiological studies, it is important to consider that the origin of chronic productive cough could be frequently outside the lower respiratory tract; a consistent percentage of young adults with persistent productive cough has indeed chronic rhino-sinusitis. PMID- 17695693 TI - The united airways concept: from bench to bedside. PMID- 17695694 TI - Brittle asthma. AB - Brittle asthma is a clinical phenotype of the disease at the severe end of the spectrum. Type 1 brittle asthma is characterised by a maintained wide PEF variability (> 40% diurnal variation for > 50% of the time over a period of at least 150 days) despite considerable medical therapy including a dose of inhaled steroids of at least 1500 pg of beclomethasone or equivalent. Type 2 brittle asthma is characterised by sudden acute attacks occurring in less than three hours without an obvious trigger on a background of apparent normal airway function or well controlled asthma. Mechanisms behind the development of brittle asthma include smooth muscle contraction and edema of the airways, which are supported by chronic airway inflammation. Allergy reactions, impairment of local immunity, respiratory infections, psycho-social disorders and reduced perception of worsening airway function are the risk factors for brittle asthma. The diagnosis is based on the analysis of specific symptoms, role of triggers, personal or family history, measurement of lung function and PEF monitoring. Pharmacological treatment of type 1 brittle asthma in addition to the high doses of inhaled and/or oral steroids and bronchodilators includes subcutaneous injections of beta2 agonist and inhalation of long acting beta2 agonist. The treatment of patients with type 2 brittle asthma includes exclusion of allergen exposure, identification of triggers, self management and management of acute attacks. PMID- 17695695 TI - Acebrophylline: an airway mucoregulator and anti-inflammatory agent. AB - Acebrophylline is an airway mucus regulator with antiinflammatory action. The drug's approach involves several points of attack in obstructive airway disease. The molecule contains ambroxol, which facilitates various steps in the biosynthesis of pulmonary surfactant, theophylline-7 acetic acid whose carrier function raises blood levels of ambroxol, thus rapidly and intensely stimulating surfactant production. The resulting reduction in the viscosity and adhesivity of the mucus greatly improves ciliary clearance. By deviating phosphatidylcholine towards surfactant synthesis, making it no longer available for the synthesis of inflammatory mediators such as the leukotrienes, acebrophylline also exerts an inflammatory effect. This is confirmed in vivo by the reduction in aspecific bronchial hyper-responsiveness in patients with stable bronchial asthma. On a clinical level, acebrophylline is therapeutically effective in patients with acute or chronic bronchitis, chronic obstructive or asthma-like bronchitis and recurrence of chronic bronchitis; it reduces the frequency of episodes of bronchial obstruction and reduces the need for beta2-agonists, and improves indexes of ventilatory function. PMID- 17695696 TI - What happens when oral tuberculosis is not treated? AB - Pulmonary tuberculosis (TB) is the most important form of the disease, although infection may also occur by way of the intestinal tract, tonsils and skin. Oral lesions consist of persistent ulcers or granulomatous masses. A 50 year old man had been diagnosed "necrotising granulomatous inflammation" following a biopsy of a lesion on lower lip, 21 months before at a medical centre. A chest-X-ray had not been performed and he had not been given any advise in respect of treatment. He was admitted to the hospital with cough, sputum, weakness, weight loss and lesions on his lower lip. In radiology, it was detected that he had supraclavicular, submental, cervical, mediastinal lymphadenopathies, pulmonary infiltrations with cavities, thickening and roughness on left oropharengial tonsil, thickenning on inner parts of larynx and bilateral surrenal thickening. The biopsy of lesions on larynx, tonsil and epiglottis revealed "necrotising granulomatous inflammation" and histopathology supported TB infection. Sputum acid-fast bacilli was positive and culture was positive for Mycobacterium tuberculosis complex. Two months of combination treatment resulted in a gradual relief of the symptoms, radiological response, disappearing of neck swelling and healing of lesions on lip, tonsil and larynx. Although unusual oral cavity manifestations of TB are rare, clinicians should be aware of possible occurrance. PMID- 17695697 TI - Secondary bronchial botryomycosis due to foreign body aspiration. AB - Botryomycosis is recognised mainly as a visceral disorder with rare cases of pulmonary manifestation. The most frequent cause of pulmonary Botryomycosis is aspiration of a foreign body which induces bacteria to group together instead of spreading out forming conglomerates resembling the granules of Actinomyces. Here we report on the clinical and pathologic findings of a 38-year-old patient without any further predisposing factors. It should be mentioned that the disease was cured following the extraction of a foreign body without the need for any surgery or antibiotic therapy. Factors influencing the course of the disease are discussed below. PMID- 17695698 TI - [Atrial fibrillation: a question of sheep]. PMID- 17695699 TI - [Computed tomography angiography: how to choose between fear of change and fanatic excess?]. PMID- 17695700 TI - [Antihypertensive therapy and cardiovascular prevention. The role of angiotensin II receptor blockers]. AB - Angiotensin II receptor blockers (ARBs) are widely used in patients with hypertension, heart failure, diabetic nephropathy, and other conditions. Over stimulation of AT2 receptor as a result of AT1 blockade may contribute to the beneficial effects of ARBs through vasodilation and inhibition of cardiac and vascular hypertrophy and fibrosis. Some experimental studies, however, suggested that AT, receptor overstimulation, in addition to beneficial effects, might trigger inhibition of angiogenesis and apoptosis. In a review, some authors suggested that ARBs may increase the risk of myocardial infarction. This position triggered a hot scientific debate and further analyses of existing data. We completed a meta-analysis of randomized clinical trials comparing ARBs with either placebo or active drugs different from ARBs. ARBs were not associated with an excess risk of myocardial infarction (odds ratio 1.03 in a random-effect model and 1.02 in a fixed-effect model). Cardiovascular mortality did not differ between ARBs and drugs different from ARBs (odds ratio 1.00 in a random-effect model and 0.99 in a fixed-effect model) and it was slightly lesser with ARBs than with placebo (odds ratio 0.91; 95% confidence interval 0.83-0.99; p = 0.042) in a prespecified subgroup analysis. Other meta-analyses confirmed these data. In conclusion, evidence from randomized trials does not support the hypothesis that AT2 receptor over-stimulation produces harmful clinical effects. Current indications and contraindications to the use of ARBs in patients with hypertension, heart failure, and diabetic nephropathy should be maintained and probably extended to the entire class of these drugs. PMID- 17695701 TI - [Mitral regurgitation and left ventricular dysfunction: pathophysiology and surgical therapy]. AB - Functional mitral regurgitation (FMR) is a distinctive valve disease in which the left ventricle is the "culprit" and the mitral valve is the "victim". It differentiates from organic regurgitation because the structure of the valve and subvalvar apparatus are not affected, hence abnormalities of the left ventricle are not the consequence but the cause of valve disease. It is at present well known that FMR conveys adverse prognosis in patients with left ventricular dysfunction, with a graded relationship between severity and reduced survival. Recent important advances in the understanding of pathophysiology of this complex valve disease have recognized that FMR results from changes in the geometry of the left ventricle, the mitral annulus and papillary muscles. Assessment of the degree of FMR, by Doppler echocardiography, has allowed to identify patients with adverse prognosis and predictors of death, drawing guidelines for therapy. Standard surgical restrictive annuloplasty represents the treatment of choice, although improvement in long-term survival had not been clearly demonstrated yet. New surgical and interventional therapies are currently under development. In this paper we reviewed the most important published literature, trying to define the mechanisms of regurgitation, diagnosis and therapeutic options, making an update of future perspectives for the treatment of FMR. PMID- 17695702 TI - [Forty-slice multidetector computed tomography for non-invasive diagnostic approach to coronary artery disease]. AB - BACKGROUND: Multidetector computed tomography coronary angiography (MDCT-CA) is a non-invasive technique that clearly shows coronary anatomy and correctly identifies plaque location and morphology. In this study we assessed diagnostic accuracy of MDCT-CA in detectiong significant stenosis in patients with clinically relevant coronary tree disease. METHODS: . Fifty patients (38 males, 12 females, mean age 60.9 +/- 9.2 years) with atypical chest pain, stable or unstable angina pectoris, or non-ST-elevation myocardial infarction underwent MDCT-CA (Brilliance 40, Philips Medical Systems, Cleveland, OH, USA) within 3 days before diagnostic conventional coronary angiography. Inclusion criteria were sinus rhythm, heart rate <70 b/min, and ability to hold breath for more than 12 s. Exclusion criteria were known intolerance to contrast medium, serum creatinine >2 mg/dl, pregnancy, respiratory insufficiency, unstable clinical conditions, and severe heart failure. Beta-blockers were administered if heart rate was >70 b/min. To synchronize arrival of the contrast bolus (Iomeron 400, Bracco, Milan) in the coronary arteries with the start of the scan the bolus-tracking technique was used. Diagnostic accuracy was evaluated per segment, per vessel, and per patient. RESULTS: Mean heart rate during examination was 61.9 +/- 6.2 b/min; 618 segments were evaluated. The assessment was impaired by respiratory artifacts only in 1 patient (2%). MDCT-CA showed good sensitivity, specificity, and positive and negative predictive values in detecting significant coronary artery stenosis (94, 94, 91, and 96% per segment; 91, 97, 95, and 92% per vessel; 100, 100, 100, and 100% per-patient, respectively). CONCLUSIONS: Forty-slice MDCT-CA showed a good diagnostic capability in detecting significant coronary artery stenosis in patients referred to our institution for suspected or known significant coronary artery disease. PMID- 17695703 TI - [The project "Don Carlo Gnocchi Foundation--Cardio-Thoracic Department De Gasperis--Lombardy Region" for the care of children from socio-economically deprived areas affected by cardiac disease]. AB - BACKGROUND: In 2001 the Cardiac Rehabilitation Unit IRCCS S. Maria Nascente Center and the International Area of Don Carlo Gnocchi Foundation, in collaboration with the Cardiac Surgery Department "De Gasperis" of Niguarda Ca' Granda Hospital in Milan, planned a project to treat children from impoverished countries. The "Fondo Sanitario Regionale" of the Lombard Region cosponsored the program. METHODS: From October 2001 to November 2006, 32 patients (25 from Zimbabwe and 7 from Albania) were selected and submitted to cardiac surgery: 22 patients were affected by acquired valvular heart disease in NYHA class III-IV, 10 by congenital heart disease. After surgery the patients admitted to our rehabilitation unit underwent a period of comprehensive cardiac rehabilitation. Afterwards, the patients were in the care of selected Italian families for about 3 months. In both populations the problems faced in the selection, management and surgical approach are discussed. RESULTS: At 21 months the survival of the whole study population was 93 % (2 valvular patients died during the follow-up); 2 patients who initially underwent mitral valve repair were submitted to valve replacement for late appearance of severe regurgitation. In 3 patients with mitral valve bioprosthesis a significant structural valve deterioration occurred in the follow-up and 2 of them underwent valve replacement. CONCLUSIONS: The advantage of the excellent performance in durability of mechanical prosthetic valves (with respect to the limited durability of porcine bioprostheses), the problems with long-term anticoagulation have to be taken into consideration in the management of patients coming from socio-economically deprived areas. PMID- 17695704 TI - [Role of multidetectori compted tomography angiography and three-dimensional post processing in a case of a Valsalva graft in aortic valve repair and replacement with the Cabrol procedure]. AB - Patients with combined valvular-aortic disease undergo surgical reconstruction of the aortic root with a valved composite graft. Two of the techniques used to replace the aortic valve and ascending aorta are Bentall and Cabrol procedures. Cabrol surgical procedure uses a Dacron tube that enables coronary artery revascularization. Graft limb occlusion may however occur. Digital subtraction angiography, magnetic resonance angiography and multidetector computed tomography angiography are useful imaging methods for the evaluation of surgical-related complications. We report the case of a patient treated by the Cabrol technique, who was studied with contrast-enhanced multidetector computed tomography angiography to evaluate long-term post-surgical complications and coronary vessels patency. PMID- 17695705 TI - [An atypical case of tako-tsubo syndrome presenting with symptomatic bradycardia]. AB - The tako-tsubo syndrome (transient left ventricular apical ballooning with normal coronary arteries), initially described in Japanese patients, is now being increasingly observed worldwide and should be considered in the differential diagnosis of acute coronary syndromes. Angina-like chest pain, electrocardiographic changes and an increase in myocardial markers are often present, as well as history of acute stressful events preceding symptom onset. We report the case of an Asiatic woman in whom typical, reversible abnormalities in left ventricular motion were associated with symptomatic junctional bradycardia. Nevertheless, the patient was completely free from angina and excluded acute pain or emotions in the previous weeks. Coronary angiography showed absence of significant disease and left ventricular function was found to be unremarkable 1 month after the acute event. Although infrequent, atypical presentations of tako tsubo syndrome have occasionally been reported and, in our opinion, they could provide interesting insights into the ill-defined pathophysiology of the disease. PMID- 17695706 TI - [Clinical correlation between congestive failure and hepatic percussion dullness]. PMID- 17695707 TI - Microreactors as tools in the hands of synthetic chemists. AB - Recent developments in the construction of microstructured reaction devices and their wide-ranging applications in many different areas of chemistry suggest that microreactors may significantly impact the way chemists conduct experiments. Miniaturizing reactions offers many advantages for the synthetic organic chemist: high-throughput scanning of reaction conditions, precise control of reaction variables, the use of small quantities of reagents, increased safety parameters, and ready scale-up of synthetic procedures. A wide range of single and multiphase reactions has been performed in microfluidic-based devices. Certainly, microreactors cannot be applied to all chemistries yet and microfluidic systems also have disadvantages. Limited reaction time ranges, high sensitivity to precipitating products, and analytical challenges have to be overcome. An overview of microfluidic devices available for chemical synthesis is provided and some specific examples, mainly from our laboratory, are discussed to illustrate the potential of microreactors. PMID- 17695708 TI - Micro-fluidic and lab-on-a-chip technology. AB - By reducing the operational dimensions of a conventional macrofluidic-based system down to the micron scale, one can not only reduce the sample volume, but also access a range of unique characteristics, which are not achievable in conventional macro-scale systems. This chapter will discuss the unique properties of miniaturised systems based on micro-fluidic and Lab-on-a-Chip technology and consider how these may influence the overall performance associated with chemical and biological processing. Some consideration will also be given to the selection of materials and/or surface modifications that will be proactive in exploiting the high surface area and thermal and mass transfer properties, to enhance process performance. PMID- 17695709 TI - Microreactors as new tools for drug discovery and development. AB - In common with other producers of fine chemicals, the pharmaceutical industry can deploy flow microreactors to provide a more flexible production regime than is achievable with large-scale batch reactors. With monitoring of output flow, microreactors can be adjusted exquisitely to give enhanced and inherently safer protocols. Bulk production can be achieved through long run times or parallel reactors. However, microreactors can also be used advantageously in pharmaceutical R&D in other ways. This paper describes their use in the creation of a tool for rapid discovery and optimisation of leads to new drugs. Here microreactors are used to create an integrated micro-scaled chemical synthesis and bioassay system able to conduct fast-cycling iterative searches of diverse chemical space as an enhanced method for identifying and optimising novel lead chemotypes. The use of a microreactor to provide point-of-use access to PET ligands is also described. This significant down-scaling and acceleration of the synthesis of potent but short-lived biomarkers of disease could provide a means of significantly shortening the time and resources required to achieve a drug approval. PMID- 17695710 TI - Microchemical systems for discovery and development. AB - Applications of silicon-based microreactors are summarized starting with systems for single-phase organic transformations and progressing through multiphase catalytic systems to microsystems for multistep chemical synthesis. The latter systems involve extraction and gas-liquid separation processes designed to take advantage of the dominance of surface tension effects in microfluidic devices. Integration of physical sensors (e.g., for pressure, temperature, and flow) and measurements of chemical species further enhances the utility of microreactors by enabling chemical kinetic studies and optimization of optimal operating conditions. A brief description of synthesis and handling of solid particulates is included, with particular emphasis on multistep processing of colloidal nanoparticles. Finally, scale-up issues and challenges to the adoption of microreaction technology are discussed. PMID- 17695711 TI - Isoindolones and related N-heterocycles via palladium nanoparticle-catalyzed 3 component cascade reactions. AB - Non-phosphine-containing cyclopalladated N-heterocycles possessing either sp2 C Pd(II) or sp3 C-Pd(II) bonds and simple Pd(II) salts are precursors of Pd(0) nanoparticles whose initial morphology is dependent on the nature of the precursor. Addition of polyvinylpyrrolidone (pvp) dramatically increases catalyst lifetime. Nanoparticle generation can be achieved at ambient temperature in the presence of carbon monoxide by a process akin to the water-gas shift reaction. Allene also lowers the temperature required for nanoparticle generation. 3 Component catalytic cascades employing one or both of these substrates provide access to a variety of 5- and 6-membered N-heterocycles including isoindolones, N aminoisoindolones, phthalazones, dihydroisoquinolines, and isoquinolones. PMID- 17695712 TI - Applying homogeneous catalysis for the synthesis of pharmaceuticals. AB - This article describes recent achievements of my research group in the Leibniz Institut fur Katalyse e.V. in the area of applied homogeneous catalysis for the synthesis of biologically active compounds. Special focus is given on the development of novel and practical palladium and copper catalysts for the functionalization of haloarenes and haloheteroarenes. PMID- 17695713 TI - An integrated approach to developing chemoenzymatic processes at the industrial scale. AB - Biocatalysis is becoming a transformational technology for chemical synthesis as a result of recent advances in enzyme discovery, structural biology, protein expression, high-throughput screening, and enzyme evolution technologies. To truly impact chemical synthesis at the industrial scale, biotransformations and chemical research and development must be integrated to develop cost-effective and environmentally friendly solutions for drug manufacture. In this chapter, some recent applications of chemoenzymatic synthesis of pharmaceutically active ingredients or advanced intermediates were selected to illustrate the principle of this integrated approach. PMID- 17695714 TI - Scale-up in microwave-accelerated organic synthesis. AB - Microwave-assisted organic chemistry has received strong exposure in the literature over the last decade, and nowadays more and more research chemists are successfully applying microwave technology to organic reactions on a small scale. However, the efficient application of this technology to cover the specific needs of larger-scale preparations, e.g., in a kilo lab, remains to be shown. We therefore initiated a study to investigate the scalability of microwave technology. Two different microwave systems designed for large-scale operation were evaluated in order to characterize strengths and weaknesses of each instrument with regard to scale-up. Special focus was directed on temperature/pressure limits, handling of suspensions, ability to rapidly heat and cool, robustness, and overall processing time. Based on the results of this study, a batch microwave reactor with a reaction volume of approximately 1.1 1 was purchased and installed in the kilo lab. Several reactions have been performed successfully on a 50- to 100-g scale in our laboratory, showing that a scale-up from a 15 ml scale to a 1-1 scale is feasible. In general, a significant reduction of reaction time was achievable, in some cases yields and selectivity were also improved. Nevertheless, a major weakness of the available systems is the limited vessel size, which is, in most cases, far below a suitable reaction volume required for work in a kilo lab. PMID- 17695715 TI - Solid supported reagents in multi-step flow synthesis. AB - The frequently overlooked benefits that considerably simplify and enrich our standard of living are most often hinged upon chemical synthesis. From the development of drugs in the ongoing fight against disease to the more aesthetic aspects of society with the preparation of perfumes and cosmetics, synthetic chemistry is the pivotally involved science. Furthermore, the quality and quantity of our food supply relies heavily upon synthesised products, as do almost all aspects of our modern society ranging from paints, pigments and dyestuffs to plastics, polymers and other man-made materials. However, the demands being made on chemists are changing at an unprecedented pace and synthesis, or molecular assembly, must continue to evolve in response to the new challenges and opportunities that arise. Responding to this need for improved productivity and efficiency chemists have started to explore new approaches to compound synthesis. Flow-based synthesis incorporating solid supported reagents and scavengers has emerged as a powerful way of manipulating chemical entities and is envisaged to become a core laboratory technology of the future. PMID- 17695716 TI - Solid-phase supported synthesis: a possibility for rapid scale-up of chemical reactions. AB - The direct scale-up of a solid-phase synthesis has been demonstrated with 4-(2 amino-6-phenylpyrimidin-4-yl)benzamide and an arylsulfonamido-substituted hydroxamic acid derivative as examples. These compounds were obtained through combinatorial chemistry and solution-phase synthesis was used in parallel to provide a comparison. By applying highly loaded polystyrene-derived resins as the solid support, a good ratio between the product and the starting resin is achieved. We have demonstrated that the synthesis can be scaled up directly on the solid support, successfully providing the desired compounds easily and quickly in sufficient quantities for early development demands. PMID- 17695717 TI - Microstructured reactors for development and production in pharmaceutical and fine chemistry. AB - The true potential of microprocess technology for process intensification is not yet fully clear and needs to be actively explored, although more and more industrial case stories provide information. This paper uses a shortcut cost analysis to show the major cost portions for processes conducted by microstructured reactors. This leads to predicting novel chemical protocol conditions, which are tailored for microprocess technology and which are expected to highly intensify chemical processes. Some generic rules to approach this are termed new process windows, because they constitute a new approach to enabling chemistry. Using such process intensification together with scaled-out microstructured reactors, which is demonstrated by the example of gas-liquid microprocessing, paves the road to viable industrial microflow processes. Several such commercially oriented case studies are given. Without the use of new process windows conditions, microprocess technology will probably stick to niche applications. PMID- 17695718 TI - Comparison of DNA replication in Xenopus laevis and Simian Virus 40. AB - DNA replication is a fundamental process within the cell cycle. The exact duplication of the genetic information ensures genome stability. Extensive research has identified the principal players required for the sequential processes: origin-licensing (a controlled order of events giving a chromosome site the potential to be initiated within the S phase of the same cell cycle); initiation (by removing the license a previous licensed site is transformed into a site where the DNA helix starts to melt); and DNA replication (copying the parental DNA by leading and lagging strand DNA-synthesis). The present report compares the advantages and limitations of studying DNA replication in the model systems Xenopus laevis (X. laevis) and in Simian Virus 40 (SV40). PMID- 17695719 TI - A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. AB - Endogenous small RNAs (miRNAs) regulate gene expression by mechanisms conserved across metazoans. While the number of verified human miRNAs is still expanding, only few have been functionally annotated. To perform genetic screens for novel functions of miRNAs, we developed a library of vectors expressing the majority of cloned human miRNAs and created corresponding DNA barcode arrays. In a screen for miRNAs that cooperate with oncogenes in cellular transformation, we identified miR-372 and miR-373, each permitting proliferation and tumorigenesis of primary human cells that harbor both oncogenic RAS and active wild-type p53. These miRNAs neutralize p53-mediated CDK inhibition, possibly through direct inhibition of the expression of the tumorsuppressor LATS2. We provide evidence that these miRNAs are potential novel oncogenes participating in the development of human testicular germ cell tumors by numbing the p53 pathway, thus allowing tumorigenic growth in the presence of wild-type p53. PMID- 17695720 TI - An investigation into 53BP1 complex formation. AB - Loss of the control over cellular proliferation can lead to cell death or result in the abnormal proliferation characteristic of the cancerous state. Among the controls used to achieve normal cellular proliferation is the DNA damage checkpoint pathway that monitors genome integrity (Hartwell and Kastan 1994). 53BP1 was identified as a protein that interacts with the DNA-binding core domain of the tumor suppressor p53. The p53-binding region of 53BP1 maps to the C terminal BRCT domains which are homologous to those found in the breast cancer protein BRCA1 and in other proteins involved in the DNA damage response, notably budding yeast Rad9. In addition to its recently reported role in sensing double strand breaks, 53BP1 is believed to have roles, currently ill understood, in many aspects of DNA metabolism ranging from transcription and class switch recombination to 'mediating' the DNA damage checkpoint response (Chai et al. 1999; Huyen et al. 2004; Sengupta et al. 2004; Ward et al. 2004). Here, we investigate 53BP1 complex formation. We investigate 53BP1 oligomerization and show that this is not dependent on the presence of disulfide bridges. PMID- 17695721 TI - Tumor promotion by tumor-associated macrophages. AB - Recent years have seen a renaissance of the inflammation-cancer connection stemming from different lines of work and leading to a generally accepted paradigm (Balkwill and Mantovani 2001; Mantovani et al. 2002; Coussens and Werb 2002; Balkwill et al. 2005). An inflammatory component is present in the microenvironment of most neoplastic tissues, including those not causally related to an obvious inflammatory process Cancer-associated inflammation includes: the infiltration of white blood cells, prominently phagocytic cells called macrophages (TAM) (Paik et al. 2004); the presence of polipeptide messengers of inflammation (cytokines such as tumor necrosis factor (TNF) or interleukin-1 (IL 1), chemokines such as CCL2); the occurrence of tissue remodelling and angiogenesis. Chemokines have emerged as a key component of the tumor microenvironment which shape leukocyte recruitment and function (Pollard 2004). Strong direct evidence suggests that cancer associated inflammation promotes tumor growth and progression. Therapeutic targeting of cancer promoting inflammatory reactions is in its infancy, and its development is crucially dependent on defining the underlying cellular and molecular mechanisms in relevant systems. PMID- 17695722 TI - The AP-2alpha transcription factor regulates tumor cell migration and apoptosis. AB - AP-2 proteins are a family of developmentally-regulated transcription factors. They are encoded by five different genes (alpha, beta, gamma, delta, and epsilon) but they share a common structure. AP-2 plays relevant roles in growth, differentiation, and adhesion by controlling the transcription of specific genes. Evidence shows that the AP-2 genes are involved in tumorigenesis and for instance, they act as tumor suppressors in melanomas and mammary carcinomas. Here we investigated the function of the AP-2alpha protein in cancer formation and progression focusing on apoptosis and migration. We introduced AP-2alpha-specific siRNA (as oligos or in retroviruses) in HeLa or MCF-7 human tumor cells and obtained a pronounced down-modulation of AP-2a mRNA and protein levels. In these cells, we observed a significant reduction of chemotherapy-induced apoptosis, migration, and motility and an increase in adhesion suggesting a major role of AP 2a during cancer treatment and progression (migration and invasion). We have data suggesting that migration is, at least in part, regulated by secreted factors. By performing a whole genome microarray analysis of the tumor cells expressing AP 2alpha siRNA, we identified several AP-2alpha-regulated genes involved in apoptosis and migration such as FAST kinase, osteopontin, caspase 9, members of the TNF family, laminin alpha 1, collagen type XII, alpha 1, and adam. PMID- 17695723 TI - Modulatory actions of neuropeptide Y on prostate cancer growth: role of MAP kinase/ERK 1/2 activation. AB - Neuroendocrine molecules play a significant role in the progression of human prostate cancer (PCa) and its neuroendocrine differentiation has been associated to a worse prognosis. Evidence exists that, among these molecules, the pleiotropic neuropeptide Y (NPY) and the related receptors may play a role in the normal prostate as well as in the progression of human PCa, which represents one of the most common malignant diseases among men in the Western world. The role of NPY in PCa biology appears to vary in different in vitro human PCa cell systems, since it has been found to reduce the proliferation of LNCaP and DU145 cells, but to stimulate the growth of PC3 cells. These effects are mediated mainly by the NPY Y1 receptor and are associated with a clone-specific pattern of intracellular signaling activation, including a peculiar time-course of MAPK/ERK1/2 phosphorylation (long-lasting in DU145 and transient in PC3 cells). In conclusion, several studies support the concept that NPY and the related receptors are overexpressed in PCa and may play a relevant role in PCa progression. The diagnostic and therapeutical value of targeting the NPY system in PCa will be evaluated in future studies. PMID- 17695724 TI - The ARF tumor suppressor in acute leukemias: insights from mouse models of Bcr Abl-induced acute lymphoblastic leukemia. AB - The prototypical Bcr-Abl chimeric oncoprotein is central to the pathogenesis of chronic myelogenous leukemias (CMLs) and a subset of acute lymphoblastic leukemias (Ph+ ALLs). The constitutive tyrosine kinase transforms either hematopoietic stem cells (in CML) or committed pre-B lymphoid progenitors (in Ph+ ALL) to generate these distinct diseases. The INK4A/ARF tumor suppressor locus is frequently deleted in both B- and T-lineage ALLs, including Ph+ ALL, whereas the locus remains intact in CML. In murine bone marrow transplant models and after transfer of syngeneic Bcr-Abl-transformed pre-B cells into immunocompetent recipient animals, Arf gene inactivation dramatically decreases the latency and enhances the aggressiveness of Bcr-Abl-induced lymphoblastic leukemia. Targeted inhibition of the Bcr-Abl kinase with imatinib provides highly effective therapy for CML, but Ph+ ALL patients do not experience durable remissions. Despite exquisite in vitro sensitivity of Arf-null, BCR-ABL+ pre-B cells to imatinib, these cells efficiently establish lethal leukemias when introduced into immunocompetent mice that receive continuous, maximal imatinib therapy. Bcr-Abl confers interleukin-7 (IL-7) independence to pre-B cells, but imatinib treatment restores the requirement for this cytokine. Hence, IL-7 can reduce the sensitivity of Bcr-Abl+ pre-B cells to imatinib. Selective inhibitors of both Bcr Abl and the IL-7 transducing JAK kinases may therefore prove beneficial in treating Ph+ ALL. PMID- 17695725 TI - Identification and validation of the anaplastic large cell lymphoma signature. AB - Anaplastic large cell lymphomas (ALCL) represent a subset of lymphomas in which the anaplastic lymphoma kinase (ALK) gene is fused to several partners, most frequently to the NPM gene. We have previously demonstrated that the constitutive expression and phosphorylation of ALK chimeric proteins is sufficient for cellular transformation, and its activity is strictly required for the survival of ALCL cells. To unravel signaling pathways required for NPM-ALK-mediated transformation and tumor maintenance, we analyzed the transcriptomes of ALK positive ALCL cell lines through experimentally controlled approaches in which ALK signaling was abrogated by an inducible ALKshRNA or by ALK inhibitors. Transcripts derived from the gene expression profiling analyses uncovered a reproducible signature, which includes a novel group of ALK-regulated genes. A functional RNAi screening identified new ALK transcriptional targets instrumental to cell transformation and/or to sustain the growth and survival of ALK positive ALCL cells. Thus, we prove that an experimentally controlled and functionally validated gene expression profiling analysis represents a powerful tool to identify novel pathogenetic networks and to validate biologically suitable target genes for therapeutic interventions. PMID- 17695726 TI - Cell-cycle inhibitor profiling by high-content analysis. AB - The discovery of agents which disrupt cancer cell division by specifically targeting key components of the cell-cycle machinery represents a major focus of recent drug discovery efforts in Oncology. The drug discovery process can be greatly enhanced by multiparametric cellular analysis which can assist in confirmation, often in a few multiplexed assays, of the mechanism of action (MOA) of compounds identified through biochemical screening or similar in vitro methods. High-Content Analysis (HCA) is a technique based on automated microscopy which enables multiparametric analysis of fluorescent indicators to define cellular responses to compound treatment. Several distinct fluorescence channels can be acquired and analyzed within a single measure in the same cell population. Here we present a multiparametric HCA approach to characterize potential cell cycle inhibitors in osteosarcoma U-2 OS adherent cell cultures. This approach allows monitoring of compound-induced cell-cycle perturbations by analyzing specific cellular markers such as nuclear morphology, DNA content or histone H3 phosphorylation. Moreover, the induction of DNA damage response or apoptosis can also be readily evaluated. By considering the profile of the investigated cellular markers at different compound concentrations, a fingerprint defines the cellular and molecular phenotype associated with each compound. PMID- 17695727 TI - Regulation for nuclear targeting of the Abl tyrosine kinase in response to DNA damage. AB - Abl is a ubiquitously expressed nonreceptor tyrosine kinase that is involved in diverse cellular signaling cascades. The cellular response mediated by Abl depends upon its subcellular localization. Expression of Abl in the cytoplasm results in cell proliferation and survival. In contrast, nuclear Abl is activated and induces apoptosis after genotoxic stress. Recent studies have demonstrated the molecular mechanisms by which c-Abl moves into the nucleus in the response to DNA damage. In normal cells, 14-3-3 proteins sequester c-Abl in the cytosol. Upon exposure of cells to genotoxic agents, c-jun N-terminal kinase is activated and phosphorylates 14-3-3, resulting in the release of c-Abl into the nucleus. Moreover, nuclear targeting of c-Abl is required for the induction of apoptosis in response to DNA-damaging agents. Thus, c-Abl may determine cell fate via its subcellular localization. This review summarizes the implications of these findings on our understanding of Abl-regulated cellular functions and potential therapeutic strategies to modulate the aberrant kinase. PMID- 17695728 TI - Use of nitroglycerin in the active phase of tilt testing: is there a difference in elderly patients? AB - INTRODUCTION: The importance of tilt testing has been demonstrated in the evaluation of patients with syncope of unknown cause, and it is the gold standard technique for the diagnosis of neurocardiogenic syncope, particularly with the use of pharmacological provocative agents to improve diagnostic accuracy. Stimulation with sublingual nitroglycerin is generally well tolerated and increases test sensitivity, shortening the test duration; this also allows the test to be applied in elderly patients. OBJECTIVES: To evaluate, in a population referred for syncope of unknown etiology, the value of tilt testing with sublingual nitroglycerin and to compare the responses obtained in elderly and younger patients. METHODS: We studied 158 patients who underwent tilt testing using nitroglycerin as a provocative agent. We compared patients aged <65 years (Group A, n=74) and > or =65 years (Group B, n=84). Tilt testing was performed according to the Italian protocol, with continuous monitoring of the electrocardiogram and blood pressure (Task Force Monitor, CNSystems). Only patients who were asymptomatic in the passive phase of the test were included. The test was considered positive for neurocardiogenic response when symptoms were reproduced with bradycardia and/or hypotension; the responses were classified as cardioinhibitory, vasodepressor or mixed. A gradual and parallel decrease in blood pressure after nitroglycerin administration, followed by syncope, was considered an exaggerated response to nitrates. RESULTS: There were no differences in gender distribution between groups. Tilt testing was positive in 57% of group A and 51% of group B patients (p=NS), with an exaggerated response to nitrates in 11% and 16% respectively (p=NS). With regard to neurocardiogenic responses, vasodepression was more frequent in group B (53% vs. 24%; p=0.001), while a mixed response tended to be more frequent in group A (59% vs. 40%; p=0.07), with no significant difference in cardioinhibitory responses (17% in group A vs. 7% in group B; p=NS). CONCLUSIONS: In a population with syncope of unknown origin, tilt testing potentiated with nitroglycerin: a) makes a significant contribution to clarifying diagnosis and is of equal value in both elderly and younger patients; and b) is associated with a higher incidence of neurocardiogenic vasodepressor response in the elderly, although with a similar rate of exaggerated responses to nitrates. PMID- 17695729 TI - Impact of a specialized outpatient heart failure follow-up program on hospitalization frequency and functional status of patients with advanced heart failure. AB - BACKGROUND: High rates of morbidity and mortality are observed in patients with advanced heart failure (AHF). AHF is now considered the most costly syndrome in cardiology owing to the substantial economic burden associated with hospitalizations for acute decompensation. A management program that involves specialized follow-up by a multidisciplinary team has been suggested as a desirable strategy for improving outcomes for these patients. OBJECTIVE: To evaluate the impact of a specialized outpatient heart failure (HF) follow-up program for patients with AHF on frequency and duration of hospitalization for HF and functional status. METHODS: We retrospectively studied 167 consecutive patients with AHF who were referred to the outpatient HF follow-up program in our institution between January and November 2002, of whom 147 followed for > or =30 days were included in the analysis. In addition to demographic and baseline clinical characteristics, HF medication and NYHA functional class, the number and duration of hospitalizations for HF during the previous 12 months were recorded and compared at the time of referral and after a follow-up period of 6.5+/-3 months. RESULTS: Of the 147 patients analyzed (aged 60.8+/-13 years; 79% male; left ventricular ejection fraction 27+/-11%), 67% were in NYHA functional class III, 20% in class II and 13% in class IV at the time of referral. There was a significant improvement in functional class during the mean follow-up period: 55% of the patients were in class III, 37% in class II, 5% in class I and 3% in class IV (p<0.0001). The proportion of patients on beta-blockers or spironolactone increased from 33% and 51% at the time of referral to 69% and 71% respectively after referral (p<0.0001). In the 12 months before referral, 39% of the patients had been hospitalized for acute decompensation of HF (87 hospitalizations - mean 7.2/month) versus 13% of the patients during the mean follow-up period (25 hospitalizations - 3.8/month, p<0.0001). No significant differences were found in the proportion of patients on angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, digoxin or diuretics, or in the mean duration of hospitalization before and after referral. CONCLUSION: The specialized follow up of patients with AHF by a team with expertise in HF resulted in significant therapeutic optimization. Increased use of beta-blockers and spironolactone was associated with significant improvement in functional capacity and significant reduction in hospitalizations. PMID- 17695730 TI - Heart failure after acute coronary syndrome: identify to treat better! AB - INTRODUCTION: The development of heart failure (HF) following acute coronary syndromes (ACS) significantly worsens short- and long-term prognosis. The present study aimed to identify clinical characteristics, detectable at admission for ACS, that could predict HF development during hospitalization, and to evaluate its impact on in-hospital mortality. METHODS: This was a retrospective cohort study that included 601 patients consecutively admitted with ACS. Demographic, clinical and laboratory data at admission were collected and HF was defined as maximum Killip class II or III. Logistic regression analysis was performed to identify independent predictors of HF and, additionally, in-hospital death. RESULTS: 29.3% of the population developed HF, mostly older patients (69.52+/ 11.9 years vs. 61.81+/-12.4 years, p<0.0001), women, hypertensive, diabetic and non-smokers. On admission, this subgroup of patients presented with higher heart rate and glycemia, and lower glomerular filtration rate (eGFR) and hemoglobin. The percentage of patients with left ventricular systolic dysfunction (LVSD) was significantly higher in the group of patients with HF (74.4% versus 48.7%, p<0.0001); however, no significant differences were found in the type of ACS or its location. In the present study, we found that patients with HF were stratified less invasively (less likely to undergo cardiac catheterization or percutaneous coronary intervention). The development of HF was associated with longer hospitalization and higher in-hospital mortality (7.4% versus 2.1%, p=0.004) on univariate analysis, but not on multivariate analysis. On multivariate analysis, only age (OR=1.04; 95% CI 1.02-1.06), diabetes mellitus (OR=1.77; 95% CI 1.05-2.96), glycemia (OR=1.05; 95% CI 1.01-1.08), eGFR <60 ml/min/1.73m2 (OR=2.90, 95% CI 1.73- 4.84), heart rate (OR=1.03, 95% CI 1.02 1.04) and LVSD (OR=2.48, 95% CI 1.59-3.85) were independent predictors of HF. CONCLUSIONS: HF is a frequent complication in ACS and is associated with higher in-hospital mortality. Identifying risk of HF development on admission, through easily acquired clinical characteristics (older age, diabetes and/or elevated glycemia, renal failure and higher heart rate), will certainly influence immediate therapeutic choices and permit an individualized approach to each patient. PMID- 17695731 TI - Rupture of a submitral ventricular aneurysm into the left atrium diagnosed by transesophageal echocardiography. AB - Submitral ventricular aneurysm is a thoroughly studied pathology but is not well known due to its rarity. Clinically, it is manifested by symptoms and signs of heart failure, mitral regurgitation and/or ventricular arrhythmias, and may be associated with thromboembolic phenomena and myocardial ischemia due to compression of the coronary arteries by the aneurysm. A rare complication of this type of aneurysm is rupture into the left atrium. Transthoracic echocardiography plays an important role in the definitive diagnosis of this pathology, although the role of transesophageal echocardiography in the evaluation of these patients is less known. We report a case of a submitral ventricular aneurysm complicated by rupture into the left atrium, which was diagnosed by transesophageal echocardiography. PMID- 17695732 TI - Myxoma in the right ventricular outlow tract. AB - We present a patient with dyspnea, cyanosis and presyncope during exercise related to intermittent obstruction of the right outflow tract by a myxoma of the right ventricle attached to the membranous interventricular septum by its pedicle. We also review the specific medical and surgical features of such tumors. Right ventricular myxomas are rare benign tumors and clinical manifestations depend mainly on size and site of attachment. They can cause obstructive events, and embolism is also possible. Both forms of clinical presentation are potentially fatal and surgical removal should be urgently scheduled. This is usually curative, although recurrences have been reported, generally when these tumors are part of the Carney complex. The best surgical approach is individualized, and transesophageal echocardiography is an important tool in the decision. In our case right atriotomy was considered the best option. PMID- 17695733 TI - [ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation--excutive summary]. PMID- 17695734 TI - Left atrial myxoma associated with severe mitral regurgitation and patent foramen ovale. PMID- 17695735 TI - Fracture strength of teeth with flared root canals restored with glass fibre posts. AB - OBJECTIVE: To investigate the fracture strength and pattern of failure of teeth with weakened roots reconstructed by different procedures. METHODS: In an in vitro study root posts were placed in 50 endodontically treated canines, divided into 5 groups (n=10) as follows: cast metallic post; glass fibre post with smaller diameter than the root canal; glass fibre post with smaller diameter than the root canal + glass fibre strips; glass fibre post with smaller diameter than the root canal + accessory glass fibre posts; anatomical post (glass fibre post with smaller diameter than the root canal, relined with low viscosity composite resin). Posts were luted with resin cement and the coronal portion of posts was constructed with composite resin. Metallic crowns were cemented on the posts. Specimens were submitted to compressive load in a universal testing machine. Fracture strength values of each group were compared. RESULTS: Fracture strength values were for Groups 1-5 respectively: 1087.06; 745.69; 775.41; 920.64; 876.12kgf, with significant differences between Groups 1 and 2 and between Groups 1 and 3 (p<0.05). Observed patterns of fracture were: Group 1 - 100% of roots fractured; Groups 2 and 4 - variable fracture modes; Group 3 - 60% of fractures occurred in the cervical root third; Group 5 - 50% of failures occurred in the coronal portion of the post. CONCLUSIONS: The fracture strength of teeth with cast metallic posts, teeth with anatomical posts or teeth with glass fibre posts combined with accessory posts was similar. All teeth restored with cast metallic posts presented fractures and were unfavourable to maintenance of the remaining tooth structure. Teeth with fibre posts (Groups 2 to 5) presented variable fracture modes; however, the maximum percentage of unfavourable fractures was 30%. PMID- 17695736 TI - Dental erosion amongst 13- and 14-year-old Brazilian schoolchildren. AB - OBJECTIVES: To assess the prevalence of dental erosion in a sample of 13- and 14 year-old Brazilian schoolchildren and to assess the relationship of dental erosion and socio-demographic characteristics. METHODS: A convenience sample of 458 children (190 boys and 268 girls) from 14 schools in Tres Coracoes, south east Brazil, was examined. Socio-demographic data were collected by self completion questionnaires. RESULTS: Dental erosion was observed in 34.1% of subjects, involving enamel only and showing a symmetrical distribution. The palatal surfaces of the upper incisors were the most commonly affected surfaces. Erosion experience was higher in boys; pupils from Government funded schools; those resident in rural areas and those from the high economic class, but none of these were statistically significant. CONCLUSION: These data are the first to show that in a cohort of 13-14-year old Brazilian schoolchildren, approximately one third of those examined showed mild erosion, requiring clinical preventive counselling. No statistically significant association was observed between erosion, gender and socioeconomic factors. PMID- 17695737 TI - Informed consent in dental malpractice claims. A retrospective study. AB - With the introduction of informed consent in dental practice in Spain during the last ten years activity has been focused on avoiding complaints rather than on giving adequate information to the patient. However, in the eyes of many professionals the document by which patients accept the cost or estimated charge of treatment is the equivalent of informed consent. Although Spanish law permits verbal consent in some cases (low risk therapeutic activities), some dentists interpret this law in a very broad way. The aim of this paper was to study the fulfilment of informed consent in relation to professional malpractice claims presented to the College of Dentists of the province of Murcia, south east Spain (regional professional association) during the last twelve years (n=52). Evaluation of the complaints pointed to adequate professional behaviour in 14 cases and malpractice in 38 cases (in 29 of which the treatment applied was technically correct but with inadequate information provided during the process, while nine cases represented technical errors). The written document of informed consent was absent in 40 cases, although the verbal information supplied was considered adequate in 14 cases. When the document of informed consent was present (12 cases) it was considered unsuitable, although adequately complemented by oral information. PMID- 17695738 TI - Uncommon radiological findings: a case report. AB - A 50-year-old friendly and attractive Chinese lady was examined by the Primary Care Unit, Faculty of Dentistry, University of Malaya. Her requests for treatment included implants and crowns. Two periapical radiographs of teeth 16 and 48 were taken to aid diagnosis. Interestingly, pin-like radio-opaque objects were found over the crown of the impacted tooth 15 and also tooth 17. These objects were initially interpreted as silver points or radiographic artifacts but further investigation employing panoramic radiography revealed the distribution of more radio-opaque objects in the orofacial region. Based on a review of the literature and the opinion of experienced radiology and oral surgery lecturers, these foreign radio-opaque objects were diagnosed as susuks or charm needles. PMID- 17695739 TI - Caries risk assessment in Bosnian children using Cariogram computer model. AB - AIM: To examine caries risk using the Cariogram model, interactive PC program for caries risk evaluation in 12-year-old children and to correlate caries risk in children of different socioeconomic backgrounds. MATERIAL AND METHODS: 109, Sarajevo 12-year-olds in three groups based on socioeconomic background. Baseline data on general health condition, diet frequency and use of fluoride were obtained. DMFT and plaque scores were calculated. Saliva analyses included lactobacillus and mutans streptococci levels in saliva, saliva secretion and buffer capacity. Scores were entered into the Cariogram model and risk was calculated for each child. RESULTS: Most 12-year-old children have a medium risk of caries, with a 59.4% chance of avoiding future caries. In an average caries risk profile of children from Sarajevo the dominant sector is diet, with 12.5% risk; bacteria sector (plaque and mutans streptococci level) 10.8% risk; susceptibility (fluoride, saliva secretion and buffering capacity) 9.7% risk; circumstances (caries experience and medical history) 7.4% risk. Caries risk profiles showed that there are differences in the socioeconomic status of children with significantly greater risk in children with poor living conditions who also have the most unfavourable caries risk profiles. CONCLUSIONS: The Cariogram model can successfully determine caries risk profiles for 12-year-old children of different socioeconomic status and can be used in developing preventive strategies for reducing caries risk in children. PMID- 17695740 TI - A case report of patient practising yoga leading to dental erosion. AB - The article presents the case of a patient who was practising Yoga (Kunjal kriya) which led to dental erosion. Dental erosion can be due to extrinsic or intrinsic causes. The intrinsic causes include vomiting due to anorexia nervosa, regurgitation due to abnormality in gastro-intestinal tract or rumination. A 38 year-old male patient presented with a rare aetiology of dental erosion. He had practiced kunjal kriya one of the yogic exercises described in ancient India. In kunjal kriya the patient vomits on an empty stomach in order to clean his or her gastro-intestinal tract. The patient had practiced this form of exercise for over 12 years which had led to severe dental erosion. A proper case history should be evaluated for every patient so that they can be counselled for any factors that could be detrimental to dental health. Early diagnosis is paramount in recognising the aetiology of dental erosion so that detrimental effects on the dentition can be prevented. PMID- 17695741 TI - Changing use and knowledge of fluoride toothpaste by schoolchildren, parents and schoolteachers in Beijing, China. AB - OBJECTIVE: To assess the oral hygiene practices, current use of and knowledge about fluoride toothpaste among schoolchildren, parents, and schoolteachers; to describe the attitudes of parents and schoolteachers in relation to improving schoolchildren's oral health. DESIGN: Cross-sectional study. PARTICIPANTS: 1,557 schoolchildren, 1,132 parents, and 352 schoolteachers were recruited by multistage stratified sampling procedure in a district of Beijing, China. METHODS: Self-completed questionnaire. RESULTS: The percentage of schoolchildren, parents, and schoolteachers who actually used fluoride toothpaste was 88%, 86%, and 87%, respectively, and 74-78% of the respondent groups brushed their teeth twice a day or more. 64% of schoolchildren, 73% of parents, and 74% of schoolteachers confirmed the caries preventive effect of fluoride toothpaste. Toothpaste recommended by oral health professional organisations was preferred by respondents - particularly by schoolchildren - when purchasing toothpaste (86%). 93% of parents and 56% of schoolteachers recognised their important role in promoting children's oral health; however, their lack of knowledge seemed to be a major obstacle in fulfilling this role. CONCLUSIONS: The use of fluoride toothpaste in Beijing appears to have increased during the past decade. In addition to mass communication comprehensive school-based oral health programmes are needed to continuously promote the use of fluoride toothpaste among schoolchildren. PMID- 17695742 TI - Fractured incisors: a judicious restorative approach--part 3. AB - AIM: To consider different conservative options in the literature to restore fractured anterior teeth. MATERIALS AND METHODS: Only anterior tooth fractures not involving the pulp were considered, without limitation on age. Treatment options were chosen depending on the clinical situation of patients at first visit. The authors considered 15 cases each of: reattachment; porcelain veneers; direct composites. RESULTS AND CONCLUSIONS: The techniques analysed were revealed to be valid during the period of observation. No failures were recorded with vital teeth keeping their vitality and no radiographic signs of apical or root pathology. With reattachment, two cases have shown the visibility of fracture line after 2 years, depending on the angle of light incidence on the tooth surface. For direct restorations, three adult cases have shown partial discolouration at 24, 28 and 40 months. No fractures or debonding have occurred among porcelain veneers. The authors suggest, whenever possible, to utilise the reattachment technique. Direct restorations are suitable for young patients: they have a higher chance of sustaining further trauma than adults, and composites have a favourable failure mode compared to ceramics. In adults, where long lasting restorations are needed, restoration of with porcelain veneers is the treatment of choice. PMID- 17695743 TI - A multiagent system for retrieving bioinformatics publications from web sources. AB - Due to the enormous amount of information available on the Internet, extracting and classifying it has become one of the most important tasks. This principle is valid also while searching for scientific publications. This paper describes a system able to retrieve scientific publications from the Web throughout a text categorization process. To this end, a generic multiagent architecture has been customized according to the requirements imposed by the specific task. Experiments have been performed on publications extracted from BMC Bioinformatics and PubMed digital archives. PMID- 17695744 TI - GGM: efficient navigation and mining in distributed genomedical data. AB - The integration of genomics and patient related data is considered as one of the most promising investigation topic in health care research. Started in 2004, the Grid for Geno Medicine (GGM) project aims at providing a comprehensive grid software infrastructure designed to allow biologists to mine and analyze relationships between medical, genetic, and genomic data stored in distributed datawarehouses. The proposed layered service oriented architecture offers a number of independent but compliant services that can be deployed in a grid environment. This paper presents these services insisting on their integration into a common software platform, the use case that is carried out. It also presents the current state of the developments and of the performance evaluations. PMID- 17695745 TI - A grid environment for high-throughput proteomics. AB - We connect in a grid-enabled pipeline an ontology-based environment for proteomics spectra management with a machine learning platform for unbiased predictive analysis. We exploit two existing software platforms (MS-Analyzer and BioDCV), the emerging proteomics standards, and the middleware and computing resources of the EGEE Biomed VO grid infrastructure. In the setup, BioDCV is accessed by the MS-Analyzer workflow as a Web service, thus providing a complete grid environment for proteomics data analysis. Predictive classification studies on MALDI-TOF data based on this environment are presented. PMID- 17695746 TI - A grid-enabled protein secondary structure predictor. AB - We present an integrated Grid system for the prediction of protein secondary structures, based on the frequent automatic update of proteins in the training set. The predictor model is based on a feed-forward multilayer perceptron (MLP) neural network which is trained with the back-propagation algorithm; the design reuses existing legacy software and exploits novel grid components. The predictor takes into account the evolutionary information found in multiple sequence alignment (MSA); the information is obtained running an optimized parallel version of the PSI-BLAST tool, based on the MPI Master-Worker paradigm. The training set contains proteins of known structure. Using Grid technologies and efficient mechanisms for running the tools and extracting the data, the time needed to train the neural network is dramatically reduced, whereas the results are comparable to a set of well-known predictor tools. PMID- 17695747 TI - Replication and update of molecular biology databases. AB - Update of molecular biology databases is a growing burden on the biomedical research community. As the grid allows to share and replicate data, we propose a service to automatically update the molecular biology databases from a single changing reference using Web services. In this paper we report the components, the architecture, and the deployment of the update service on the french RUGBI grid infrastructure. RUGBI is a computing grid infrastructure based on existing middleware and technologies for the community of scientists in bioinformatics. PMID- 17695748 TI - A service-oriented grid infrastructure for biomedical data and compute services. AB - Service-oriented Grid technologies are increasingly utilized for the realization of future biomedical IT infrastructures since they offer unprecedented opportunities for the integration of advanced analysis and simulation applications as well as distributed heterogeneous data sources and information systems. The European Union's @neurIST project is developing a Grid-based IT infrastructure for the management of all processes linked to research, diagnosis, and treatment development for complex and multifactorial diseases encompassing data repositories, computational analysis services, and information systems handling multiscale, multimodal information at distributed sites. This paper provides an overview of the @neurIST Grid middleware and outlines the infrastructure offered for the provision of advanced compute and data services to support computationally demanding modeling and simulation tasks and to access heterogeneous distributed data sources through semantic integration. PMID- 17695749 TI - An agent-based multilayer architecture for bioinformatics grids. AB - Due to the huge volume and complexity of biological data available today, a fundamental component of biomedical research is now in silico analysis. This includes modelling and simulation of biological systems and processes, as well as automated bioinformatics analysis of high-throughput data. The quest for bioinformatics resources (including databases, tools, and knowledge) becomes therefore of extreme importance. Bioinformatics itself is in rapid evolution and dedicated Grid cyberinfrastructures already offer easier access and sharing of resources. Furthermore, the concept of the Grid is progressively interleaving with those of Web Services, semantics, and software agents. Agent-based systems can play a key role in learning, planning, interaction, and coordination. Agents constitute also a natural paradigm to engineer simulations of complex systems like the molecular ones. We present here an agent-based, multilayer architecture for bioinformatics Grids. It is intended to support both the execution of complex in silico experiments and the simulation of biological systems. In the architecture a pivotal role is assigned to an "alive" semantic index of resources, which is also expected to facilitate users' awareness of the bioinformatics domain. PMID- 17695750 TI - A fast job scheduling system for a wide range of bioinformatic applications. AB - Bioinformatic tools are often used by researchers through interactive Web interfaces, resulting in a strong demand for computational resources. The tools are of different kind and range from simple, quick tasks, to complex analyses requiring minutes to hours of processing time and often longer than that. Batteries of computational nodes, such as those found in parallel clusters, provide a platform of choice for this application, especially when a relatively large number of concurrent requests is expected. Here, we describe a scheduling architecture operating at the application level, able to distribute jobs over a large number of hierarchically organized nodes. While not contrasting and peacefully living together with low-level scheduling software, the system takes advantage of tools, such as SQL servers, commonly used in Web applications, to produce low latency and performance which compares well and often surpasses that of more traditional, dedicated schedulers. The system provides the basic functionality necessary to node selection, task execution and service management and monitoring, and may combine loosely linked computational resources, such as those located in geographically distinct sites. PMID- 17695751 TI - The mepsMAP server. Mapping epitopes on protein surface: mining annotated proteins. AB - For a growing number of biologists DNA or protein data are typically retrieved and managed on the Web, and not in the laboratory. A large number of bioinformatics datasets from primary and (thousands of) secondary databases are scattered on the Web in various formats. A biologist end-user might need to access and use tens of databases and tools every day. For this reason, the bioinformatics community is developing more and more service-oriented architectures (SOAs): software architecture of loosely coupled software services that can be accessed without knowledge of, or control over, their internal architecture. Data-processing and analysis tasks can be automated by having free access to bioinformatics Web services (WSs) that are the building blocks of the SOAs. In this paper we introduce a new bioinformatics Web server, mepsMAP (mapping epitopes on protein surface: Mining Annotated Proteins), developed to identify the recognition sites between antibodies and their cognate antigens. In some cases, the recognition site is represented by a continuous segment of the antigen sequence, but much more often the epitope is "conformational," i.e., the antibody recognizes the location and type of exposed antigen side chains that are not necessarily contiguous in the antigen's sequence, but brought together by its three-dimensional structure. A facility on the server allows the user to search putative conformational epitopes on protein surface, querying the system for proteins with a given annotation. The mepsMAP server has been implemented as a SOA composed by a database and a set of four WSs. We present here the software architecture of the system with a detailed description of the WS dataflow that has been optimized to provide the best computing performance while maintaining the easiest end-user access to the system via a Web interface. PMID- 17695752 TI - Grid methodology for identifying co-regulated genes and transcription factor binding sites. AB - The identification of the genes that are coordinately regulated is an important and challenging task of bioinformatics and represents a first step in the elucidation of the topology of transcriptional networks. We first compare the performances, in a grid setting, of the Markov clustering algorithm with respect to the k-means using microarray test data sets. The gene expression information of the clustered genes can be used to annotate transcription binding sites upstream co-regulated genes. The methodology uses a regression model that relates gene expression levels to the matching scores of nucleotide patterns allowing us to identify DNA-binding sites from a collection of noncoding DNA sequences from co-regulated genes. Here we discuss extending the approach to multiple species exploiting the grid framework. PMID- 17695753 TI - To be or not to be: predicting soluble SecAs as membrane proteins. AB - SecA is an important component of protein translocation in bacteria, and exists in soluble and membrane-integrated forms. Most membrane prediction programs predict SecA as being a soluble protein, with the exception of TMpred and Top Pred. However, the membrane associated predicted segments by TMpred and TopPred are inconsistent across bacterial species in spite of high sequence homology. In this paper we describe a new method for membrane protein prediction, PSSM_SVM, which provides consistent results for integral membrane domains of SecAs across bacterial species. This PSSM encoding scheme demonstrates the highest accuracy in terms of Q2 among the common prediction methods, and produces consistent results on blind test data. None of the previously described methods showed this kind of consistency when tested against the same blind test set. This scheme predicts traditional transmembrane segments and most of the soluble proteins accurately. The PSSM scheme applied to the membrane-associated protein SecA shows characteristic features. In the set of 223 known SecA sequences, the PSSM_SVM prediction scheme predicts eight to nine residue embedded membrane segments. This predicted region is part of a 12 residue helix from known X-ray crystal structures of SecAs. This information could be important for determining the structure of SecA proteins in the membrane which have different conformational properties from other transmembrane proteins, as well as other soluble proteins that may similarly integrate into lipid bi-layers. PMID- 17695754 TI - Mathematical modeling of retinal mosaic formation by mechanical interactions and dendritic overlap. AB - The retina is a complex assembly of neurons packed into a three-layer structure containing five classes of cells. Each class of retinal cells is regularly arranged within its layer in an orderly configuration called the retinal mosaic. We have set up a mathematical model of retinal mosaic formation focusing on the actions of local mechanical forces on the neuron's cytoskeleton. The cytoskeleton has been modeled according to two approaches, one based on the tensegrity concept (a structure made of elastic and rigid elements), and the other based on a simple model with viscoelastic features. We have assumed causing deformation of their cytoskeleton, overlap of dendritic areas and movement of the neuron. Simulations based on these two models indicate that a random distribution of neurons reaches an orderly configuration by local and mechanical neuron interaction in the case in which the cytoskeleton is modeled using the tensegrity approach, but not when the neuron is modeled as a purely viscoelastic system. Considering that the main structural difference between the Maxwell model and the tensegrity model is that the latter model contains rigid elements whereas the former does not, this suggests that the presence of rigid components in the cytoskeleton of retinal neurons plays a key role in the formation processes of the retinal mosaic. PMID- 17695755 TI - Feature selection and combination criteria for improving accuracy in protein structure prediction. AB - The classification of protein structures is essential for their function determination in bioinformatics. At present, a reasonably high rate of prediction accuracy has been achieved in classifying proteins into four classes in the SCOP database according to their primary amino acid sequences. However, for further classification into fine-grained folding categories, especially when the number of possible folding patterns as those defined in the SCOP database is large, it is still quite a challenge. In our previous work, we have proposed a two-level classification strategy called hierarchical learning architecture (HLA) using neural networks and two indirect coding features to differentiate proteins according to their classes and folding patterns, which achieved an accuracy rate of 65.5%. In this paper, we use a combinatorial fusion technique to facilitate feature selection and combination for improving predictive accuracy in protein structure classification. When applying various criteria in combinatorial fusion to the protein fold prediction approach using neural networks with HLA and the radial basis function network (RBFN), the resulting classification has an overall prediction accuracy rate of 87% for four classes and 69.6% for 27 folding categories. These rates are significantly higher than the accuracy rate of 56.5% previously obtained by Ding and Dubchak. Our results demonstrate that data fusion is a viable method for feature selection and combination in the prediction and classification of protein structure. PMID- 17695756 TI - [Old age: present epidemic, reality in the future or the skeletal muscle degeneration]. PMID- 17695757 TI - [Unicompartment knee arthroplasty with an Oxford prosthesis]. AB - INTRODUCTION: Unicompartmental knee replacement is a procedure increasingly used in patients with osteoarthritis of the medial knee compartment. The purpose of this study is to report the short- and long-term clinical outcomes of patients undergoing unicompartmental knee arthroplasty with the "Oxford" prosthesis. MATERIALS AND METHODS: This is a descriptive and cross-sectional study of 24 medial unicompartmental arthroplasties performed in 22 patients. Two cases were bilateral due to medial compartment arthrosis caused by genu varum with X-ray evidence of total loss of the medial joint space in the standing X-ray evidence of total loss of the medial joint space in the standing X-rays in ages 55 t0 74 years. Fifteen females and 7 males were included. Ligament integrity was proven clinically and radiologically. A cemented Oxford prosthetic design was used (Biomet) with a minimally invasive medial approach. RESULTS: A clinical and radiological evaluation of all patients was performed in the immediate postoperative period, at 2 and 4 weeks and every 3 months thereafter. Pain, knee range of motion and gait autonomy were evaluated for a three-year period in the first 7 patients, and eight months in the last one. In 21 patients (95.4%) pain subsided completely and one has intermittent pain in the medial aspect of the operated knee; the flexion range achieved was 90 degrees to 100 degrees in 13 patients (59%) and 8 patients achieved more than 110 degrees. Independent gait occurred at day 7 in 21 patients (95.4%); no complications were reported. CONCLUSION: Unicompartmental arthroplasty with the "Oxford" implant provides full pain relief in well selected patients. It is a reliable procedure with excellent functional outcomes, low morbidity, short hospital stay and rapid recovery. PMID- 17695758 TI - [Scooter-related injuries in pediatrics patients]. AB - The authors undertook an analysis of all the pediatric patients who presented at their hospital with scooter-related injuries. A total of 37 patients seen at Dr. Victorio de la Fuente Narvaez Trauma Hospital were studied. Findings included a wide variety of injuries, from skull fracture to limb factures, as well as one open fracture and a chondral knee fracture. Diagnoses were made clinically and radiologically and various treatments were provided, both conservative and surgical. Findings showed a high frequency of scooter-related fractures in children. The use of protective equipment by children and their supervision are necessary to prevent these injuries. PMID- 17695759 TI - [Bone tissue response to the echelon-type uncemented femoral component in revision total hip arthroplasty (THA)]. AB - INTRODUCTION: We present the preliminary, short-term results of a cohort study of revision THA focused on aseptic loosening and aimed at assessing the metadiaphyseal bone ingrowth biological response of an uncemented femoral implant with an extensive porous coating. MATERIAL AND METHODS: The clinical, X-ray and personal satisfaction outcomes (SF-36) of four patients were assesessed. We had performed four exchange THAs due to a diagnosis of clinical and radiographic aseptic prosthetic loosening, with symptoms of anterior thigh pain. Three THAs were primary and one was a hemiarthroplasty. Mean follow-up after the prosthetic exchange was 41.5 weeks. RESULTS: As of postoperative week six, a radiographic improvement of the bone appearance was seen due to mineralization and decrease in the radiolucent areas in the interfaces. As of week 20, variable degrees of bone ingrowth were seen. No femoral subsidence has occurred and anterior thigh pain was relieved in all cases. DISCUSSION: Stem size, stiffness,stiffness, the geometry and the extension of the porous coating seem to affect bone remodeling. Implants with an extensive porous-coated surface seem to assure a reliable, long term fixation and provide a circumferential seal against debris. PMID- 17695760 TI - [Treatment of traumatic clavicular pseudoarthrosis with the Hunec Colchero nail]. AB - INTRODUCTION: Post-traumatic clavicular pseudoarthrosis occurs as a complication of mid third fractures, particularly of those with an important displacement that leads to failure of conservative treatment. Most reports on the management of this complication use various plates and grafts. We used the Hunec nail as an implant and an iliac crest graft. MATERIAL AND METHODS: We report the results obtained in 17 patients with a diagnosis of clavicular pseudoarthrosis treated with the Hunec nail and an iliac crest graft. Patients were 9 males and 8 females; mean age was 38 years. Ten pseudoarthrosis were located on the right side and seven on the left side. Eleven were classified as atrophic and six as hypertrophic. Only one case had undergone previous surgery. Regardless of the type of pseudoarthrosis, an iliac crest graft placed as "barrel ribs" was used. RESULTS: In all cases bone healing occurred in a period of approximately 12 weeks; there was complete recovery of the ranges of motion. Only one case had nail migration, but this happened after bone healing and no other complications occurred. The nail was removed from 10 patients one year after surgery. We conclude that the Colchero Hunec nail provides enough stability to achieve healing of the traumatic clavicular pseudoarthrosis. PMID- 17695761 TI - [Capsular retensioning in anterior unidirectional glenohumeral instability]. AB - OBJECTIVE: To present the experience of the Orthopedics Service PEMEX South Central Hospital in the management of anterior unidirectional shoulder instability with an arthroscopic technique consisting of capsular retensioning either combined with other anatomical repair procedures or alone. MATERIAL AND METHODS: Thirty-one patients with anterior unidirectional shoulder instability operated-on between January 1999 and December 2005 were included. Fourteen patients underwent capsular retensioning and radiofrequency, and in 17 patients, capsular retensioning was combined with suture anchors. Patients with a history of relapsing glenohumeral dislocations and subluxations, with anterior instability with or without associated Bankart lesions were selected; all of them were young. RESULTS: The results were assessed considering basically the occurrence of instability during the postoperative follow-up. No cases of recurring instability occurred. Two cases had neuroma and one experienced irritation of the suture site. Six patients had residual limitation of combined lateral rotation and abduction movements, of a mean of 10 degrees compared with the healthy contralateral side. The most frequent incident was the leak of solutions to the soft tissues. CONCLUSIONS: Capsular retensioning, whether combined or not with other anatomical repair techniques, has proven to result in a highly satisfactory rate of glenohumeral stabilization in cases of anterior unidirectional instabilities. The arthroscopic approach offers the well-known advantages of causing less damage to the soft tissues, and a shorter time to starting rehabilitation therapy and exercises. PMID- 17695762 TI - [Radiologic correlation between the cortical-shaft index and bone mineral density in the diagnosis of osteoporosis]. AB - OBJECTIVE: To know if radiological relationship exists among the index corticodiaphyseal of Lizaur Utrilla (ICD) and the corticofemoral diaphyseal of Gomez Garcia (ICDF) with the density bony (DMO) mineral column power station and hip for the diagnosis of osteoporosis; with the purpose of optimizing the simple X-ray of hip well during the valuation of the bony quality. MATERIAL AND METHOD: One carries out a study of field, traverse, comparative, descriptive and observational, where you study a representative sample of 90 feminine patients divides in three equal groups: group 1:30 healthy (control) patients from 20 to 40 years of age; group 2: patient postmenopausal and group 3:30 patients with the diagnose of hip fracture; same that were subjected to studies of simple X-ray of hip including the femur proximal as well as central DMO, stops later to obtain those mentioned indexes before mentioned. RESULTS: For effects of this study decided to implement a new index on the base of the smallest trocanter, to which is assigned the name of index corticometaphyseal (ICM); hurtling the following results: the quantity of the bony mineral is bigger in the column (mediates: 0.973 +/- 0.168 g/cm2) that in the hip (mediates: 0.852 +/- 0.164 g/cm2); significant (p < 0.001) difference exists among each one of the indexes; the index that bigger (35 cases) correlation had with DMO was lCM with 75.5%, (68 cases) continued by ICD with 60% and (54 cases) for I finish ICDF 38%, CONCLUSIONS: Radiological relationship of 75.5% exists between IMC and central DMO of column and hip for the diagnosis of osteoporosis. PMID- 17695763 TI - [Evocative lumbar discography]. AB - Even though lumbar discography was described in 1948 by Lind Bloom as a useful diagnostic method to identify ruptures of the anulus fibrosus of the intervertebral disc, it was neglected for many years as an unreliable method. This happened especially after a publication by Holt, who in 1968 reported a 37% false-positive rate in a study done among inmates, with a very irritating contrast medium (hypaque) that was administered intrathecally. OBJECTIVE: To show that lumbar discography is a dynamic and safe method and even more reliable than magnetic resonance imaging to detect intervertebral disc ruptures. MATERIAL AND METHODS: Thirty-three patients with a clinical history of lumbosciatic pain lasting more than 6 months and an MRI-proven diagnosis of herniated disc were studied. Fifty discographies were performed at the L3-4, L4-5, L5-S1 spaces. They were considered as negative: (1) When the contrast had an oval or cotton-ball shape. (2) When the disc admitted 2-2.5 cm of contrast medium without causing any pain. They were considered as positive: When the contrast dye diffused with an irregular pattern. (2) When the administration of the contrast dye was painful. All negative discographies were followed-up for 6 months. RESULTS: Thirty-three patients; 22 males, 11 females; 50 discographies as follows: 5 at L3-4; 27 at L4 5; and 18 at L5-S1. Five discographies were negative, At six months, the patients were asymptomatic. The discography detected 5 patients, equivalent to a 10% false/positive rate for the magnetic resonance imaging. Two patients developed diskitis. CONCLUSIONS: Discography is more effective than magnetic resonance imaging for detecting intervertebral disc ruptures. Patients with diskitis were related with minimally invasive surgery, probably more due to the infectious process than to discography. PMID- 17695764 TI - [Fulkerson osteotomy in patients with patellofemoral pain and malalignment]. PMID- 17695765 TI - [Rupture of extensor tendons due to chronic post-traumatic distal radio-ulnar dislocation. Case report]. AB - INTRODUCTION: We report a case of extensor tendon rupture due to chronic post traumatic distal radioulnar dislocation. These lesions are frequent in rheumatic and arthrotic wrists due to dorsal capsule rupture and tendon erosion by the ulnar head. An identical mechanism was involved in this case. MATERIAL AND METHODS: The involved tendons were the extensor of the fifth digit and the common extensor of the fourth and fifth digits, which coincides with most of the reported cases. They were sutured to each other and all of them to the extensor of the third digit. Nothing was done to the ulnar head because the patient refused that part of the procedure. RESULTS: After six weeks of immobilization with a brace and two months of rehabilitation the patient recovered the ranges of motion, with the exception of the last ten degrees of extension. Pain on the cubital aspect did not change. CONCLUSIONS: These lesions are frequent in certain risk groups, as mentioned above. Once the tendons have been sutured or grafted, the distal aspect of the ulna should be resected in case of arthrosis or deformity to prevent new ruptures and relief pain. PMID- 17695766 TI - [Li-Fraumeni familial cancer syndrome: case report and review of the literature]. AB - INTRODUCTION: Multiple familial cancer is a rare entity as is also Li-Fraumeni Syndrome (LFS), which involves a mutation in the germ cell line of Tp53 suppresor gene that is expressed in chromosome 17p13.1 and occurs as an autosomal dominant condition. OBJECTIVE: Presentation of one case of LFS. CLINICAL CASE: Family history: maternal grandfather had melanoma and maternal aunt had osteoblastic osteosarcoma of the left distal femur. Eight-and-a-half year-old child with a history of a CNS tumor (choroid plexus carcinoma) and two years later, a melanoma (Spitz nevus). SYMPTOMS: impaired motor function of the left half of the body and pain upon ipsilateral gait. The physical exam showed swelling of the left iliac crest. The X-rays showed osteoblastic osteosarcoma and the fine needle aspiration biopsy (FNAB) was positive. The diagnosis was made according to the clinical criteria for LFS. DISCUSSION: We report a case of LFS diagnosed based on clinical criteria. We suggest that the questioning of patients with cancer be aimed at finding out the family history of neoplasias. The case presented herein shows an evident association between both choroid plexus carcinoma and osteoblastic osteosarcoma and the patient's family history. We think that any physician treating children with cancer should consider these multiple familial cancer syndromes. PMID- 17695768 TI - [Guidelines for diagnosis and therapy, 3rd edition]. PMID- 17695767 TI - [Spinal stenosis-related risk factors: case and control study]. AB - OBJECTIVE: To determine whether the risk factors described in the literature are applicable to our population or not. MATERIAL AND METHODS: A case and control study was undertaken. Seventy patients with an imaging-confirmed diagnosis of lumbar stenosis were included as well as 70 controls that denied having any of the following symptoms: chronic lumbar pain, claudication, sensory alterations and muscle weakness of the lower limbs. A survey to identify risk factors possibly associated with lumbar stenosis was carried out. The statistical analysis was done with non-conditional logistic regression and the risks were determined by means of an odds ratio (OR) in both a univariate and a multivariate modality. RESULTS: One hundred and forty individuals of both genders were included; 70 cases and 70 controls. The factors that were found to be significant in the univariate analysis were included in the multivariate analysis. The OR for age was 7.6 (CI 95% = 2.81-20.93; p = 0.0001), for scoliosis, 5.14 (IC 95% = 1.27 20.77; p = 0.021), for SAH, 1.82 (IC 95% = 0.74-4.48; p = 0.19) and for neoplasias, 2.55 (IC 95% = 0.22-29.23; p = 0.45). CONCLUSION: This study showed that age over 65 years, scoliosis and systemic arterial hypertension are risk factors for lumbar stenosis. The multivariate analysis showed that age increases the risk in the presence of scoliosis. PMID- 17695769 TI - [Socio-moral reasoning in boys with conduct disorder--the influence of cognitive, educational and psychosocial factors]. AB - OBJECTIVES: The study explores whether conduct-disordered children differ from healthy children in reference to their moral development and to what extent cognitive and education factors, respectively psychosocial stress factors mediate the level of socio-moral development. METHODS: Sixteen boys aged nine to fourteen years with an ICD-10 diagnosis of Conduct Disorder were compared to sixteen age matched healthy controls. The level of socio-moral maturity was assessed by means of the German version of the Sociomoral Reflection Measure (Gibbs et al., 1992). RESULTS: Results show that conduct-disordered boys tended to differ from their healthy counterparts in terms of the level of socio-moral maturity of judgement. According to the theory of Gibbs and co-workers, the moral judgement of healthy children (characterized by a pro-social and mutually moral attitude) is more mature than that of conduct-disordered boys. While the latter remain at an interim level between immature and mature socio-moral reasoning, the former adhere to more rational, exchange-oriented morals. The factors "intelligence" and "maternal support" exercise a decisive influence on socio-moral development. CONCLUSIONS: It should be investigated whether or not the current results can be generalized in a larger sample. PMID- 17695770 TI - [Precursors of hyperactive disorders: potential early diagnosis in infants?]. AB - OBJECTIVES: Are there any differences (organic, psychosocial, psychopathological, cognitive or educational, respectively differences in the motor or neurological development) between infants who later on at the age of 8 years suffer from a hyperactive disorder and those who later on at the same age are undisturbed? Are there specific harbingers for hyperactive disorders in the group concerned? METHODS: With regard to their developmental risk load at the age of 3 months, 26 primary school children with hyperactive disorders were compared with 241 healthy children, 25 children with emotional disturbances, and 30 children with socially disruptive behaviour, all of the same age. RESULTS: Identified as the most important predictors for the onset of hyperactive disorders were a reduced birth weight, the mother's origin from a shattered family, early contact impairments on the part of the child, and the mother's neglect of the infant. CONCLUSIONS: Altogether, however, the prediction of later hyperactivity in primary school children on the basis of salient features in the infant children remains unsatisfactory and unspecific. PMID- 17695771 TI - [Anger regulation in boys with attention deficit hyperactivity disorder (ADHD)]. AB - OBJECTIVES: We explored the reaction of boys with ADHD when they are angry at a friend. Due to their impulsivity and difficulty in focussing their attention, it may be expected that such boys be inclined to resort more frequently to confrontational and harmful strategies of anger regulation and less often to negotiation, reappraisal, or distancing strategies. METHODS: A sample of 23 boys diagnosed with ADHD (without co-morbid Oppositional Defiant Disorder or Conduct Disorder) between eight and thirteen years of age were compared to an age-matched sample of 23 boys with non-clinical behaviour. Strategies of anger regulation were assessed by means of a self-report questionnaire: Strategies of Anger Regulation for Children (SAR-C). RESULTS: The self-report reveals no difference between boys with ADHD and those without in terms of confrontation and harmful strategies. As expected, boys with ADHD reported less frequent use of distancing strategies. They also indicated less frequent negotiation of the event with the friend or re-appraisal thereof. CONCLUSIONS: Results indicate that boys with ADHD tend to report anger regulation strategies that require impulse control less often than their counterparts without ADHD. The groups did not differ in terms of their use of confrontational strategies that involved the acting out of their aggressive anger impulse because boys with ADHD (but without a co-morbid ODD or CD) may not intend to harm their friends in the long run and thus do not consider their behaviour to be aggressive. PMID- 17695772 TI - [Procedures of Austrian authorised experts in custodial and visiting rights--a survey of current practice]. AB - OBJECTIVES: Within the framework of an Austria-wide comprehensive evaluation study, all legally authorised experts in the field of family law active as evaluators were contacted, and a survey of prevailing evaluation practice was carried out by means of a written questionnaire. METHODS: A questionnaire based on the rules of test theory was developed for this purpose. RESULTS: The response rate of 33% (n = 25) served to demonstrate a fundamentally homogenous weighting for each individual custody criterion amongst the experts, even though a variety of methods and testing procedures were used and no uniform approach relating to particular theoretical concepts was applied. The majority of authorised experts regard the solution and process-oriented evaluation method as a desirable supplement to the procedural status diagnostics used to date. CONCLUSIONS: Because the procedures applied in authorised evaluations are not standardised, psychological testing procedures to examine the individual criteria used in making decisions should be developed according to the rules of test theory. The feasibility of applying a solution and process-oriented approach to authorised evaluations, under the formulation of general methodological-theoretical and normative conditions, is a matter for discussion by authorised experts and the legal profession. PMID- 17695773 TI - [The dilemma of court expertise--commentary on the SSRI-tapering verdict by the Saxonian social court]. AB - We comment on a Social Court verdict that sentenced a German health insurance carrier to pay for the tapering of fluoxetine in a case of adolescent depression but not to payment for ongoing SSRI treatment in view of their off-label status. Evidence presented to the competent court, including a statement by the German Association for Child and Adolescent Psychiatry (DGKJP), was inadequately interpreted or else misunderstood. The court abstained from substantiating its own competence, e.g. by means of an external expertise. Even though an earlier verdict by the Federal Social Court was taken into account, there were shortcomings with regard to its realisation. The physician in charge of such a case is confronted with therapeutical and ethical dilemmata, as well as with problems of liability, as the court-ordered discontinuation of pharmacological treatment could conceivably compromise the well-being of the patient. Due to the recent marketing authorisation by the EMEA for the use of fluoxetine in the treatment of depressed children above the age of eight years in Europe, the case may be settled. Yet the implications of juridical intrusions into medical practice and therapy regimes must still be addressed. PMID- 17695774 TI - [Parent artery occlusion with bypass surgery for the treatment of aneurysms of the internal carotid artery]. PMID- 17695775 TI - [Postoperative patterns of improvement of symptoms and degrees of satisfaction in families of patients after operations for definite idiopathic normal pressure hydrocephalus: a long-term follow-up study]. AB - PURPOSE: To clarify the patterns of improvement of pre- and post-operative symptoms and family satisfaction in patients with definite idiopathic normal pressure hydrocephalus (iNPN) who responded well to shunt intervention. SUBJECTS AND METHODS: The subjects included 40 patients definitively diagnosed with iNPH and who were followed up for one year or longer (age, 61-85; male-to-female ratio, 18: 22). The study focused on (1) preoperative clinical symptoms, (2) improvements in symptoms at 1, 3, 5, and 12 months after surgery, and the satisfaction of the families based on medical results of the Zarit caregiver burden interview, and infomation through questionnaires to medical personnel. RESULTS: (1) The major symptoms were gait disturbance (G, n=38), dementia (D, n=10), and urinary incontinence (U, n=23). G and D appeared as initial symptoms in 30 and 10 cases, respectively. (2) The rates of postoperative improvement at 1, 3, 5, and 12 months were 94.7%, 94.7%, 97.4%, and 94.7% for G, 43.8%, 62.5%, 71.9%, and 84.4% for D, and 78.3%, 86.96%, 86.96%, and 91.3% for U, respectively. G and U cases improved during the postoperative early stage, and D improved gradually from after the third postoperative month. The family satisfaction before surgery and at 1, 3, 5, and 12 months after surgery was 72.5 +/- 12.8, 68.1 +/- 15.4, 55.7 +/- 9.6, 52.9 +/- 11.4, and 47.3 +/- 7.9 points, respectively. The rate of improvement in satisfaction was higher for D. The satisfaction of the medical personnel was 88 percent (+) at 1 month and tended to remain high for 12 months. CONCLUSION: (1) Preoperative gait disturbance is a major initial symptom in definitively diagnosed iNPN. (2) Postoperative improvement of G and U is obtained at an early stage. In contrast, D tends to improve gradually from after the third postoperative month. The family satisfaction increases as the symptom of D improve. The satisfaction of the medical personnel tends to remain high after the first postoperative month. This study investigated the results of quantitative analyses of the patients symptoms. PMID- 17695776 TI - [Frontofacial monobloc advancement using the Rigid External Distraction (RED-II) system]. AB - One-stage frontofacial monobloc advancement has been used to treat patients with craniofacial synostosis including Crouzon disease. Nishimoto et al. first applied a rigid external distraction system for two patients. However, precise surgical techniques and proper indication for this gradual distraction method have not yet been established. This report describes the advantages and detailed surgical methods of frontofacial monobloc advancement using a Rigid External Distraction (RED- II) System. Three patients with severe craniofacial synostosis including Crouzon disease and Treacher Collins syndrome were treated. The ages of patients were 9, 9, and 8 year old, respectively. The RED- II System was safely applied for these young children and cosmetic results were sufficient. No major postoperative complications occurred. PMID- 17695777 TI - [Proximal ligation of the parent artery for symptomatic tandem stenosis of the extradural internal carotid artery: a case report]. AB - A 72-year-old man suffered blindness due to right central retinal artery occlusion. Cerebral angiography revealed tandem stenosis in the cervical, petrosal and cavernous portions of the right internal carotid artery (ICA). Blood flow from the vertebrobasilar artery via the right posterior communicating artery mainly perfused the right cerebral hemisphere. In addition, significant stenosis was observed in the left cervical carotid artery and the origin of the left vertebral artety. First, the patient underwent left carotid endarterectomy and vertebral artery to subclavian artery transposition. Two months later, ligation of the right ICA at its origin was performed. Postoperative course was uneventful and the patient has not experienced further ischemic events. We suggest that proximal ligation of the parent artery is a useful procedure for medically refractory extradural ICA stenosis when surgical direct revascularization and percutaneous transluminal angioplasty cannot be performed. PMID- 17695778 TI - [Extracranial internal carotid artery aneurysm associated with Marfan syndrome: case report]. AB - Marfan syndrome is a heritable disorder of connective tissue characterized by autosomal dominant inheritance. Cerebrovascular disorders associated with Marfan syndrome are known to be rare. In this report, we described a rare case of a 64 year-old woman with an extracranial internal carotid artery (ICA) aneurysm associated with Marfan syndrome. The extracranial ICA was very tortuous and a 3 cm-diameter aneurysm was observed at the distal portion of the carotid bifurcation. Through anterior neck incision, the aneurysm was dissected from the surrounding tissue. The carotid artery was clamped, and external shunting was performed using a 3-way shunt tube. The aneurysm was excised, and an end-to-end anastomosis of the ICA was made. Postoperative course was uneventful except for mild swallowing disturbance lasting for 2 weeks. The surgical indication and technique are discussed. PMID- 17695779 TI - [Refractory chronic subdural hematoma due to spontaneous intracranial hypotension]. AB - Spontaneous intracranial hypotension (SIH) is reported to cause chronic subdurai hematoma (SDH), however diagnosis of SIH in patients with SDH is not always easy. We report a case of chronic SDH refractory to repeated drainage, which was attributed to SIH. A forty-five-year-old man who had been suffering from orthostatic headache for one month was admitted to our hospital presenting with unconsciousness and hemiparesis. CT on admission revealed a chronic subdural hematoma, which was successfully treated once with subdural drainage. However, the patient fell into unconscious again with recurrence of the hematoma within several days. After two more sessions of drainage, SIH due to cerebrospinal fluid leakage was diagnosed with spinal magnetic resonance imaging (MRI) and radionuclide cisternography. Spinal MRI demonstrated abnormal fluid accumulation in the thoracic epidural space, and the radionuclide cisternogram showed early excretion of tracer into urine as well as absence of intracranial tracer filling. After treatment with epidural blood patching, the hematoma rapidly disappeared and he was discharged without symptoms. In the treatment of chronic SDH, especially in young to middle aged patient without preceding trauma or hematological disorders, physicians should pay attention to underlying SIH to avoid multiple surgery. MRI of the spine as well as radionuclide cisternography is useful in evaluation of this condition. PMID- 17695780 TI - [Case report of cholesterol crystal embolism 1 month after carotid stenting]. AB - Cholesterol crystal embolism (CCE) is a systemic disease resulting from shedding of cholesterol crystals into the small vessels of multiple organs, including skin, kidney, gastrointestinal tract and others. Recently, neuroendovascular therapeutic procedures for athrosclerosis disease is increasing. We report a case of CCE after carotid stenting (CAS). A 73-year-old man with asymptomatic carotid stenosis was treated by percutanenous transluminal angioplasty with stenting. CAS was achieved in a short time without trouble. About 1 month after CAS, his renal function deteriorated and purpura appeared on both toe tips (blue toe syndrome) with muscle pain of the lower extremities. Under diagnosis of CCE, he was treated by Predonisolone 20 mg/day and Valsartan 160 mg/day, Pravastatin 10 mg/day. His symptom's dramatically improved, with partial recovery of renal function. CCE rarely occurs after angiographic or interventional procedures, but is difficult to diagnose clinically and there is no established therapy. For early diagnosis of CCE strict follow-up of a patients clinical presentation and laboratory data, especially in high risk patients, is needed. PMID- 17695781 TI - [Case of a ruptured vertebral artery dissecting aneurysm recanalized after internal trapping]. AB - A 35-year-old male experienced a sudden onset of severe headache. A CT scan revealed subarachnoid hemorrhage. By cerebral angiography, he was diagnosed as having a ruptured right vertebral artery dissecting aneurysm (VADA). It was successfully treated by endovascular occlusion of the affected site, including the aneurysm and parent artery, by using detachable coils. A follow-up angiography obtained seven months after the first treatment revealed the recanalization of the right vertebral artery and dissected aneurysm in an antegrade fashion. A skull X-ray image was useful for detecting the change in appearance of the coils. The second embolization was successfully performed in the same manner. Based on this rare case, the authors emphasize that a careful angiographic analysis and complete internal trapping of the dissecting site are important in the treatment of the ruptured VADA. PMID- 17695782 TI - [Autologous transplantation of adult derived neural stem cells]. PMID- 17695783 TI - [Magnetic resonance imaging and pathology in epilepsy (3). Dysembryoplastic neuroepithelial tumor and neoplastic lesions]. PMID- 17695784 TI - [What's the difference? Comparison of American and Japanese practice of medicine- 2]. PMID- 17695785 TI - [Use of QuantiFeron TB-2G test on high-risk groups for tuberculosis infection at our hospital]. AB - PURPOSE: To investigate the infection rate of tuberculosis in high-risk employees at our hospital. METHODS: We measured interferon gamma levels in 40 employees and evaluated the infection rate in doctors working in the Tuberculosis Ward (D group), nurses in the Tuberculosis Ward (N group), and other high-risk employees (O group). RESULTS: The overall infection rate including probable infection was 6/40 (15.0%). The infection rate in the N group was 0%, while those in the D and O groups were 27.3% and 20.0% respectively. No new infection of tuberculosis was observed after the introduction of tuberculosis infection measure manual of our hospital. CONCLUSION: Our hospital's tuberculosis infection measure manual was effective in decreasing the new tuberculosis infection despite a high infection rate in high-risk employees at our hospital. PMID- 17695786 TI - [Examination of administrative dosage of cyclosporine during anti-tuberculosis chemotherapy including rifampicin]. AB - AIMS: In the treatment of tuberculosis with rifampicin in patients treated with prednisolone and cyclosporine, we have to increase the dosage of these drugs. Although prednisolone dosage is recommended to be doubled, there is no established consensus about cyclosporine dosage. Our aim is to review the current situation at our institution regarding the dosage of cyclosporine administered to tuberculous patients after the addition of rifampicin to the treatment regimen. METHODS AND RESULTS: We reviewed patients' clinical status and how dosages of cyclosporine were altered during a course of tuberculosis treatment including rifampicin in 4 patients (2 interstitial pneumonitis, 2 collagen vascular disease) who were being treated with cyclosporine between 2001 and 2003. Prednisolone had been also administrated in all patients and the dosage was doubled from the beginning of the treatment. The appropriate dosage of cyclosporine was found to be 2.5-3.5 (average 3) times that of initial dosage, and it required 5-12 weeks (average 8.3) measurements of trough levels and 6-27 (average 12) weeks until appropriate trough levels were obtained. CONCLUSIONS: The appropriate dosage of cyclosporine was found to be approximately 3 times that of the initial dosage in all patients, but it required a long-term and frequent measurements of trough levels before reaching this goal. It seems that trebling the dosage of cyclosporine from the start of anti-tuberculosis chemotherapy will be an efficient way to achieve good clinical outcome. PMID- 17695787 TI - [Reevaluation of pathogenesis of epituberculosis in infants and children with tuberculosis]. AB - OBJECT: We try to reevaluate the pathogenesis of epituberculosis in infants and children with tuberculosis, because most studies on epituberculosis were done more than 50 years ago. SUBJECT AND METHODS: Nineteen children (less than 1 y/o: 12, 1 y/o: 2, 2 y/o: 3, and 4 y/o: 2) were studied by CT imaging and bronchofiberscopy in addition to gastric Mycobacterium tuberculosis examination and regular chest XP. RESULTS: In 13 of total 19 patients (68%), lobar or segmental epituberculosis occured after starting antituberculous chemotherapy, including a case in which epituberculosis of right upper lobe was recognized at the time of diagnosis of tuberculosis and after starting chemotherapy, epituberculosis of right middle lobe was observed. CT imaging revealed that all 19 patients had enlargement of mediastinal and/or hilar lymphonodes compressing neighboring bronchi, and 16 of total 19 patients (84%) demonstrated relevant parenchymal infiltration. Gastric Mycobacterium tuberculosis was positive in 15 out of 19 patients (79%). Bronchofiberscopy was done in 16 patients, and it demonstrated mass lesion of various size on the bronchial wall in 13 patients (81%). CONCLUSION: The present study demonstrated that epituberculosis predominantly occured in tuberculosis infants less than one year old, which was different from the previous reports. The CT imaging also makes clear that epituberculosis may be the atelectasis of lobe or segment which occurs mostly due to compression of bronchi by the enlargement of mediastinal and/or hilar lymphonodes and their early exacerbation after starting chemotherapy. Bronchofiberscopy also elucidated that bronchial wall mass lesion resulted from perforation of lynphonodes may partially contribute to the formation of epituberculosis. PMID- 17695788 TI - [Case of pulmonary multi-drug resistant tuberculosis with left destroyed lung, treated with pneumonectomy]. AB - A 31-year-old woman complained of cough and fever for 2 months. She was admitted to a hospital and was diagnosed as pulmonary tuberculosis. She received combination therapy with isoniazid, rifampicin, ethambutol, and pyrazinamide. As the drug susceptibility test revealed that the isolated strain was multi-drug resistant, the regimen was changed to pyrazinamide, ethionamide, cycloserine, enviomycin, and levofloxacin. The chemotherapy was not effective, so she received pneumonectomy for left destroyed lung. After surgical treatment, her sputa converted to negative for tubercle bacilli. Surgical treatment such as pneumonectomy is considered to be useful in a case of multi-drug resistant pulmonary tuberculosis. PMID- 17695789 TI - [Drug sensitivity test of Campylobacter jejuni strains isolated from human diarrheal stools, chicken meat, and chicken feces, and gene mutation of quinolone resistant strains]. AB - In basic studies on campylobacteriosis, we tested 53 strains from human diarrhea stools and 102 strains from chicken meat and feces obtained between 2002 and 2006 for drug sensitivity to different drugs and gene mutation in quinolone-resistant strains. 1) Of 15 drugs tested, all were resistant to one or more of the following 10 drugs: CEX, 99.4%: ABPC, 59.4%; NA, 40.6%; NFLX, 40.0%; TC and CPFX, 39.4%; PIPC, 38.1%; MINO, 30.3%; KM, 3.2%; and SM, 2.6%. 2) Of 155 drug-resistant strains, 28 (18.1%) were resistant to single drugs and 127 (81.9%) were resistant to multiple drugs. The most frequent pattern of multipledrug resistance was ABPC/PIPC/CEX, followed by ABPC/PIPC/CEX/TC/MINO/NA/NFLX/CPFX. 3) Mutation of GyrA (Thr86 --> Ile) was detected in 43 (97.7%) of 44 quinolone-resistant strains. We found that resistance to beta-lactams, quinolones, and tetracycline antibiotics was high, and most resistant strains were resistant to multiple drugs. We also found that most quinolone-resistant strains had GyrA mutation. PMID- 17695790 TI - [Genesis of methicillin-resistant Staphylococcus aureus and selective antibacterial injection pressure]. AB - We reported previously that cefazolin was related to an increase in methicillin resistant Staphylococcus aureus (MRSA) between 1998 and 2000 at Yamagata University Hospital. The incidence of MRSA decreased, however, between 2001 and 2003. We examined the relationship between the use of antibacterial injection and MRSA incidence. MRSA increased in surgical and medical wards between 1998 and 2000, but decreased mainly in surgical wards between 2001 and 2003. We statistically analyed the number of inpatients detected with MRSA (MRSA patients) and the use of antibiotics per month. MRSA patients positively correlated with cephems and carbapenems, the highest positive correlation with cefazolin at a correlation coefficient (R) of 0.45 (p<0.001). In multiple linear regression analysis, cefazolin and carbapenems were chosen as independent variables of a regression equation predicting MRSA patients, during the MRSA decrease and in surgical wards. We thought, it was because carbapenems increased with cefazolin that only cefazolin was chosen as an independent variable during the MRSA increase. We found that the antibiotics as independent variables were associated with about 50% of MRSA by the multiple regression model contribution ratio. Cefazolin was used most for presurgical prophylaxis in surgical wards, and about 20% of surgical wards in medical wards. Carbapenems were use almost equally in surgical and medical wards, but the correlation with MRSA in medical wards was 0.21 (p<0.1) and in surgical wards 0.38 (p<0.005), showing a significant correlation with carbapenems in surgical wards. In conclusion, cefazolin and carbapenems were related to the incidence of MRSA, and carbapenems showed a significant correlation in the presence of cefazolin. This strongly suggests that MRSA is significantly generated when inpatients are given carbapenems after administration of cefazolin. PMID- 17695791 TI - [Influenza telephone consultation target the general public--2003-2004, 2004 2005]. AB - The NPO Biomedical Science Association provided telephone consultation, including contacts by fax and email, targeting the general public within the framework of influenza control measures worked out by the Japanese Ministry of Health, Labor and Welfare (MHLW). We received 2,813 inquiries during the 2003-2004 flu season and 2,444 inquiries during the 2004-2005 season. By month, the highest number was in October-November, accounting for 42.6%. The preceding season showed a similar trend. By gender, 72.5% of those seeking advice were women. By area of residence, the highest number was living in metropolitan Tokyo, and the remainder lived in the prefectures of Kanagawa, Chiba, Saitama, Nagano, Shizuoka, and Ibaraki in this order. We received no inquiries from the prefectures of Shimane or Saga. By occupation, housewives accounted for 1,114 inquiries (45.6%), followed by private companies with 447 inquiries (18.3%) and health-care providers with 227 inquiries (9.3%), similar to the 2003-2004 flu season. By subject, 1,545 inquiries concerned vaccines (62.2%) mainly, the pros and cons of vaccination, adverse reactions, and the number of inoculations required. Inquiries about pregnancy, infants and young children, and breast-feeding accounted for 19.2%. Inquiries on vaccine shortages during the 2004-2005 flu season (7), SARS (22), and bird flu (22) decreased compared to the previous season, while the number of consultations on antiviral agents increased (209). In discussing how information on influenza should be communicated to the public, we propose that "Influenza Q & A" provided by the Infectious Diseases Surveillance Center of the NIID, MHLW, should include information on influenza specifically addressing pregnant woman and breast feeding or child-rearing mothers. PMID- 17695792 TI - Lactobacillus reuteri tablets suppress Helicobacter pylori infection--a double blind randomised placebo-controlled cross-over clinical study. AB - We studied the effect of Lactobacillus reuteri strain SD2112 Tablets Reuterina (ERINA Co., Inc.), in suppressing H. pylori urease activity and to use the urea breath test (UBT) as a marker for the burden of infection. Method 1: Assessment of UBT and H. pylori density. Subjects were 33 H. pylori-positive patients from whom were obtained gastric biopsy specimens by upper gastrointestinal endoscopy. The correlation between UBT and H. pylori density was investigated. Individual UBT was established for each patient. Patients were divided by H. pylori density was 3 groups: Group I (low-density), Group II (moderate-density), and Group III (high-density). The individual UBTs were then correlated to the established H. pylori quantity. Method 2: Assessment of suppressive effect of L. reuteri on H. pylori urease activity. Subjects were 40 asymptomatic volunteers with an UBT exceeding 15 per thousand, randomly allocated to four groups: Subjects in Group A underwent active treatment for 4 weeks (period 1) and placebo treatment for the following 4 weeks (period 2). These in Group B underwent treatment in reverse order. Those in Group C underwent placebo. Group D consisted of volunteers with negative UBT undergoing active treatment for the full 8 weeks. Result 1: UBT was 11.6+/-2.0 per thousand, 22.1+/-2.6 per thousand, and 35.4+/-7.6 per thousand in Groups I, II, and III, showing UBT that increased significantly (I vs. II: p< 0.01 and I vs. III: p<0.05) based on H. pylori density. Result 2:Significant differences were seen in the decrease in UBT before versus after medication in Groups A and B. In Group A, lower UBT was maintained until the end of the full 8 week period. The overall decrease in UBT due to medication with L. reuteri Tablets was 69.7+/-4.0% (p<0.05). CONCLUSION: Administration of L. reuteri Tablets [Reuterina (ERINA Co.,Inc.)] significantly decreased UBT in H. pylori positive subjects, demonstrating that L. reuteri suppresses H. pylori urease activity and H. pylori density. PMID- 17695793 TI - [Serovars and epidemiological properties of Salmonella isolated from patients with sporadic diarrhea in Yamanashi prefecture during the last 22 years (1985 2006)]. AB - We studied the serovars, yearly and monthly frequency of isolates, and drug susceptibility of 3,028 strains of Salmonella isolated from patients with sporadic diarrhea during April 1985 to December 2006 in Yamanashi Prefecture. Results are as follows : 1) Isolates were serologically classified into 72 different serovars. Predominant serovars were S. Enteritidis (59.3%), S. Typhimurium (10.5%), S. Oranienburg (2.9%), S. Hadar (2.4%), S. Litchfield (2.3%), and S. Infantis (2.0%). 2) Serovars of S. Haifa, S. Schleissheim, S. Livingstone, S. Mikawasima, S. Manhattan, S. Muenchen, S. Emek, S. Dublin, S. Javiana, S. Miami, S. Miyazaki, S. Weltevreden, S. Orion, S. Give, S. Aberdeen, S. Surat and S. Orientalis were isolated from human sources for the first time since 1995 in Yamanashi Prefecture. 3) Yearly frequency of isolation was 305 strains (10.1%) for 1996, 283 strains (9.3%) for 1999, 273 strains (9.0%) for 2000, 238 strains (7.9%) for 1989 and 228 strains (7.5%) for 1997. 4) Monthly frequency of isolation was 567 strains (18.7%) for August, 471 strains (15.6%) for September, 430 strains (14.2%) for July, 340 strains (11.2%) for October and 266 strains (8.8%) for June. 5) Predominant ages of patients from whom Salmonella strains were isolated were 2 years for 199 strains (6.6%), 1 year for 192 strains (6.4%), 3 years for 169 strains (5.6%), 4 years for 161 strains (5.3%), and under 1 year for 110 strains (3.6%). 6) The rate of isolation from males was higher at 56.3% than for females at 43.7%. 7) The isolation frequency of drug-resistant strains was 64.8% in 1985-2006. The most predominant resistance pattern was SM single resistance because of the increase in S. Enteritidis. 8) The number of resistant strains of was 1,435 of 1,780 strains (80.6%) for S. Enteritidis, and 214 of 322 strains (66.5%) for S. Typhimurium, 1 of 87 strains (1.1%) for S. Oranienburg and 73 of 73 strains (100%) for S. Hadar. 9) The serovar S. Typhimurium had much multiple drug resistance strains, being resistant ever to fluoroquinolone. PMID- 17695794 TI - [Primary pulmonary cryptococcosis: a case series of 9 patients]. AB - We retrospectively reviewed 9 consecutive cases of primary pulmonary cryptococcosis having no comorbidity. At diagnosis, seven had no subjective symptoms and two had subtle symptom. Chest CT scan showed nodular shadows in 8, while 3 cases had infiltrative shadows. Eight of the nine were diagnosed with histopathology obtained by transbronchial lung biopsy or CT-guided needle aspiration biopsy. We also assessed PHA and Con A lymphocyte stimulation tests to measure cellular immune function in 6, four of whom showed decreased reaction of lymphocytes. We successfully treated seven of the nine with fluconazole alone and used fluconazole as a maintenance regimen in two. No relapse or treatment failure was seen after completion of antifungal treatment. Six cases were seropositive for serum cryptococcus antigen titer at diagnosis and only one showed seroconversion. We concluded that the duration of therapy for primary pulmonary cryptococcosis should not be necessarily determined by serum cryptococcus antigen seroconversion. PMID- 17695795 TI - [Studies of influenza vaccination among elderly nursing home residents]. AB - We conducted a questionnaire survey of influenza vaccination among elderly nursing home residents, and investigated the actual condition and the view of vaccination of elderly people. There was 272 elderly residents in Nagoya-shi, Kouseiin Medical Welfare Center, they were classified into the bed ridden group; 195cases (71.7%) according to the independence in activities of daily living, and 132cases (48.5%) were evaluated as the disturbance of community ability group. The number of vaccination in 2002/2003 was 163 residents (59.9%). When the vaccination group (163cases) was compared with the non-vaccination group (109cases), it becomes clear that the later has much bedridden or dementia. The reply of questionnaire was obtained from 139 cases (51.1%) among 272 residents. As a reason of the residents who received vaccine, a prevention was 70.2%, mostly over whelmingly. The following were 17.0% of a custom of annual vaccination, and the recommendation by doctor and family were 5.3% and 3.2%, respectively. The main reasons for having not received a vaccine was inability of recoganization 22.2%. The afraid of adverse reaction or allergy, the ache of a injection was following 17.8%, respectively. In order to raise the rate of the vaccination in elderly nursing home residents, we should make into consideration that the educational campaign of the safety of vaccine and how to develop motivation for vaccination to the elderly with cognitive decline. PMID- 17695796 TI - [Measurement of rifampicin and clarithromycin in serum by high-performance liquid chromatography with electrochemical detection]. AB - Rifampicin (RFP) induces hepatic drug-metabolizing enzymes, making drug interactions a very important clinical problem. Clarithromycin (CAM) metabolism is reportedly enhanced by induction of hepatic drug-metabolizing enzymes (CYP3A4) by RFP, so that the blood lend of CAM decreases when RFP is administered concurrently. We connected an electrochemical detector to a high-performance liquid chromatograph (HPLC) for simple, rapid, easy measurement of blood concentrations of RFP and CAM. Using samples of patient serum, normal serum, and reference standards, we compared HPLC by an external laboratory and the results of LC/MS/MS analysis with those of this new assay. A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels (r=0.975, p<0.01). A strong correlation was also seen between results we obtained for CAM with the electrochemical detector in this assay and values measured by LC/MS/MS analysis (r=0.995, p<0.01). Our method enabled simple, rapid measurement of RFP and CAM by connecting the HPLC and electrochemical detector in tandem. This system was used to modulate dosage during combined therapy with RFP and CAM. The therapeutic effect for nontuberculous mycobacteriosis is expected to improve, and our HPLC is expected to be useful for simple, rapid, easy measurement of blood concentrations. PMID- 17695797 TI - [Relationship between time taken from collection of blood to incubation and measurement in whole-blood interferon gamma assay for diagnosis of Mycobacterium tuberculosis infection]. AB - BACKGROUND: The introduction of second-generation QuantiFERON-TB (QFT) enables the diagnosis of Mycobacterium tuberculosis (TB) infection with high specificity and sensitivity. This in vitro diagnostic test uses 2 TB-specific proteins (ESAT 6 and CFP-10) to stimulate cells in heparinized whole blood and detects interferon-gamma (IFN-gamma) produced from blood cells. When QFT is done in laboratories outside of the hospital, several hours may be required to transport blood samples. We studied the relationship between QFT results and the time taken from collection of blood to incubation (preincubation time). METHODS: Heparinized whole blood drawn from TB suspects was immediately transported to a laboratory. We started to incubate 4 aliquots of blood with ESAT-6, CFP-10, mitogen (phytohemagglutinin), and nil control, at 1, 3, 6, 9, and 12 h after blood was drawn. After incubation, the concentration of IFN-gamma in each plasma sample was determined by ELISA, and values E and C were expressed as the concentration of IFN-gamma with ESAT-6 or CFP-10, minus the concentration of IFN-gamma in the nil control. Value E or C > or =0.35IU/mL was considered positive, > or =0.10 and<0.35IU/mL as equivocal (gray zone), and<0.10IU/mL as negative. We analyzed 8 patients with value E or C > or =0.10IU/mL at a preincubation time of 1 h. RESULTS: Value E and C decreased especially for preincubation time >6 h. As a result, the interpretation of value E changed from "positive" to "equivocal" in 2 cases and from "equivocal" to "negative" in 2 cases. Interpretation of value C also changed from "positive" to "equivocal" or "negative" in 2 cases and from "equivocal "to "negative" in 1 case. Even if the higher of value E or C were used for analysis, QFT results changed in half of patients when preincubation time was>6 h. CONCLUSION: Since QFT results in half of patients changed when preincubation time was>6 h, incubation of whole blood should start < or =6 h after blood drawing. PMID- 17695798 TI - [IgM antibody detection in acute viral diseases, 1995-2004: analysis of data collected at a commercial diagnostic laboratory in Japan]. AB - We analyzed data from tests for virus-specific IgM in 376,000 serum specimens sent to a commercial diagnostic laboratory from clinics nationwide between 1995 and 2004. IgM antibodies to measles, rubella, mumps, parvo B19, and varicella zoster viruses were tested using IgM-capture ELISA kits. Among specimens, 254,000 (68%) had documentation of age, of which 56% were sera from persons<20 and 44%> or = 20 years of age. Monthly or yearly trends in IgM antibody-positive tests in<20 year-old persons were similar to those in pediatric patients per sentinel clinic reported by the National Epidemiological Surveillance of Infectious Diseases (NESID), which collects weekly numbers of patients with designated infectious diseases from 3000 pediatrics clinics nationwide. Patterns of changes in monthly IgM positive tests in both < 20 and > or = 20 y specimens were similar, indicating that infections occur simultaneously in both children and adults. Adult IgM-positive specimens came from internal medicine clinics and from dermatology clinics for measles; from dermatology and obstetrics clinics for rubella and parvo B19; from otolaryngology clinics for mumps; and from dermatology and otolaryngology clinics for varicella-zoster virus. Analysis of large numbers of IgM test results at regular intervals may contribute to understanding of the epidemiology of these viral diseases in Japan. PMID- 17695799 TI - [Epidemic status of influenza virus between 2004-2005 and 2005-2006 at Kawasaki Medical School Hospital]. AB - Of patients with influenza-like symptoms such as fever, myalgia and arthralgia 2399 visited Kawasaki Medical School Hospital in 2004-2005 and 2171 in 2005-2006. Among those patients over 16 years old, laboratory examinations using the rapid antigen test or the serum HI test were positive for 366 (A: 86, B : 280) in 2004 2005 and 372 (A :370, B:2) in 2005-2006. Influenza B achieved epidemic status first in 2004-2005, followed by influenza A (H3N2) after April 2005. Only influenza A was epidemic in 2005-2006. The slight difference in frequency or complication between these strains was not statistically significant. In spite of influenza vaccination inoculation in 20% of patients with influenza in 2004-2005 and 2005-2006, influenza spread. The prognosis of these patients, however, was comparatively good. PMID- 17695800 TI - [Evaluation of antigen diagnostic kit in group A streptococcus mass infection]. AB - We report a Food-borne group A streptococcus epidemic at Kitasato University campus on July 30 and 31, 2005, believed caused by lunch. A current mass group A streptococcus infection differing from the food-borne epidemic above occurred at Kitasato University East Hospital, also believed caused by lunch. Group A streptococcus was detected using a prompt diagnostic kit and bacterial culture from 116 clinical specimens taken from 116 patients with group A streptococcus pharyngitis at Kitasato University East Hospital on August 5, 2005. To investigate the utility of immunochromatographic detection of group A streptococcus antigen, 116 clinical specimens obtained from pharyngeal membranes by swab were examined using a prompt diagnostic kit for group A streptococcus (ImmunoCard STAT! STREP A TEST) and conventional bacterial culture. Group A streptococcus positivity differed between the two methods. Fourteen patients were found to be positive by the prompt diagnostic kit and 23 by bacterial culture. Four patients showing 1.0 x 10(6) cfu/mL estimated by the culture were difficult to diagnose with the prompt diagnostic kit,even though the detection sensitivity of this kit was 1.0 x 10(6) cfu/mL or more. Conventional bacterial culture should therefore be used in addition to the prompt diagnostic kit to detect group A streptococcus, especially in pharyngeal samples obtained from patients with pharyngitis. PMID- 17695801 TI - [Investigation of Streptococcus pneumoniae and Haemophilus influenzae isolated from pediatric outpatients nationwide with a respiratory tract infection at the first consultation (2002-2003)--with special reference to the results of nasopharyngeal culture in pediatric patients with no previous history of antibacterial drug administration]. AB - We previously reported that penicillin-resistant Streptococcus pneumoniae (PRSP) and beta-lactamase-nonproducing ampicillin-resistant (BLNAR) were detected at a frequency of 27% and 35% in 468 strains of Streptococcus pneumoniae and 557 strains of Haemophilus influenzae isolated from pediatric patients diagnosed with respiratory infection in 20 pediatric outpatient facilities throughout Japan between November 2002 and June 2003. Here, we have added additional considerations regarding results of nasopharyngeal culture from 558 pediatric patients diagnosed with pneumonia, bronchitis, or otitis media and having no previous history of antibacterial drug administration. No significant difference was seen in the detection of S. pneumoniae or H. influenzae between nasal and oral specimens, or between patients with pneumonia, bronchitis, and otitis media. The detection of S. pneumoniae in pediatric patients 4 years old was significantly higher, however than that in pediatric patients 5 years old. The detection of H. influenzae in pediatric patients with a history of attending group childcare facilities was significantly higher than that in pediatric patients with no such history. No significant differences were seen among groups in the percentage of PSRP and BLNAR isolated among S. pneumoniae and H. influenzae strains. Nasopharyngeal culture of pediatric patients with respiratory infection yielded a higher frequency of S. pneumoniae in younger than older patients and a higher frequency of H. influenzae in pediatric patients with a history of attending group childcare facilities. The detection of resistant bacteria was considered related to other factors, such as the type of antibacterial drugs used, that are not discussed here. PMID- 17695802 TI - [Dipylidium caninum infection in an infant]. AB - Dipylidium caninum, the dog tapeworm, is a common intestinal cestode of domestic dogs and cats, but few cases have been reported of human infection by this parasite in Japan. We repot a case of D. caninum infection in a 17 month-old girl, who sometimes had symptoms of abdominal pain, diarrhea, and dysphoria at night. Her mother noted the appearance of small white worms in her stool, and she was seen by a local pediatrician. Despite antiparasitic therapy wiht pyrantel pamoate, the problem persisted and was eventually referred for further workup to Kurume University Hospital. The diagnosis was made by microscopic examination of the excreted proglottids, which contained characteristic egg capsules. She was successfully treated with a singledose of praziquantel and four adult parasites were recovered. The longest intact worm was 32cm. Her family had household pets (a dog and a cat). The pets were seen by the local veterinary and both were evidenced D. caninum. Humans, primarily children, become infected when they accidentally ingest fleas. Parents usually find proglottids as multiple white objects, often described as cucumber, melon, or pumpkin seeds, in stool, diapers, or on the perineum. Most general practitioners and pediatricians may treat children with enterobiasis (pinworm) infection, and in case the treatment fails, other parasite infection should be considered such as this worm. A history of dog or cat pets, fleas, and flea bites may be important clues to diagnosis. Pets found to be infected should also be treated. PMID- 17695803 TI - [A case of disseminated candidiasis as an initial presentation of AIDS]. AB - A 44-year-old woman referred for skin eruptions and an altered mental status was confirmed to have HIV infection on Western Blot analysis. Her CD4+ T cell count was 15/microl. On admission, she appeared quite ill with respiratory distress. Chest X-ray showed bilateral patchy infiltration and pleural effusions. She was treated with cefotaxime, pentamidine, and antituberculosis drugs, but her condition worsened and dopamine was initiated. Intensive treatment failed, and she died the following day. An autopsy showed purplish papules on her face and trunk and multiple white nodules in her liver, spleen and lungs. Culture was positive for Candida Albicans, yielding a diagnosis and of disseminated candidiasis. It is rare for HIV patients to be diagnosed with disseminated candidiasis, since the pathogenesis usually requires disruption of the mucosal barrier. The defense mechanism against disseminated candidiasis is mainly neutrophils and macrophages, and its dysfunction is not a primary characteristic of HIV infection. To the best of our knowledge, this is the first report in Japan of a HIV patient to have disseminated candidiasis. PMID- 17695805 TI - [Recent advances in studies on susceptibility genes in diabetic nephropathy]. PMID- 17695806 TI - [Molecular understanding of adverse effects of hyperglycemia in diabetic nephropathy]. PMID- 17695807 TI - [Microinflammation in the pathogenesis of diabetic nephropathy]. PMID- 17695808 TI - [Early diagnosis is essential to inhibit the progression of diabetic nephropathy]. PMID- 17695809 TI - [New findings with RAS inhibitors in diabetic nephropathy]. PMID- 17695810 TI - [Novel therapeutic approaches to diabetic nephropathy]. PMID- 17695811 TI - [Present status and the future of diabetic nephropathy]. PMID- 17695812 TI - [Evaluation of urinary factor H excretion in patients with idiopathic membranous nephropathy]. AB - BACKGROUND: The complement system plays an important role in renal pathogenesis, and C5b-9, a terminal complement complex, is regarded as the principal mediator of proteinuria in idiopathic membranous nephropathy(MN). Since factor H regulates complement activation at the C3 step and is a crucial factor in complement mediated tissue injury, the urinary excretion of factor H in patients with idiopathic MN was investigated. METHODS: Seven patients with biopsy-proven idiopathic MN were studied for twenty-four weeks. Urinary factor H levels were measured by ELISA from regularly collected urine samples, and then evaluated and compared with assays of urinary protein and C5b-9 excretion. RESULTS: During the study, five patients were treated with steroid therapy. All seven patients maintained stable renal function and showed a decline in urinary protein excretion. The mean level of urinary factor H was markedly elevated (156.1 +/- 47.1 U/mg U-Cr) before treatment (0 week), and gradually declined to 127.2 +/- 43.5 U/mg U-Cr at 12 weeks, and to 64.7 +/- 26.9 U/mg U-Cr) at 24 weeks. This followed decreases in urinary protein and urinary C5b-9 excretion. Percent change in urinary factor H level significantly decreased 24 weeks after treatment without affecting the plasma factor H level. CONCLUSION: These results suggest that factor H contributes to the regulatory mechanism of in situ complement activation, and thus the study of urinary factor H levels, as well as urinary C5b 9, may be significant in idiopathic MN. PMID- 17695813 TI - [Current management of renal anemia in patients with chronic kidney disease at the predialysis stage]. AB - OBJECTIVE: Patients with chronic kidney disease (CKD) are frequently complicated by renal anemia as renal function declines. However, clinical guidelines on erythrocyte stimulating agents (erythropoietin : EPO) for such patients have not been established. Current clinical practice for EPO administration is based on the recommendations of the Japanese health insurance regulations, which have not always been supported by clinical evidence. MATERIALS & METHODS: The study subjects were 49 patients with CKD staged above 3 who had developed renal anemia requiring EPO. These patients were treated with EPO S. C. at the dose of 6,000 IU/week together with iron supplementation as deemed necessary for more than 24 weeks. RESULTS: The hemoglobin (Hb) value was 9.2 +/- 1.0 g/dL at the start, 10.9 +/- 1.6 g/dL at the peak (n = 49, p < 0.001 the start vs. the peak), and 9.0 +/- 1.6 g/dL at the commencement of dialysis (n = 49, p < 0.001 the peak vs. the commencement of dialysis). Seventy-one percent (35/49) of the patients achieved Hb levels over 10 g/dL, and 51% (25/49) achieved Hb levels over 11 g/dL. Conversely, 28% (14/49) of the patients failed to reach an Hb level over 10 g/dL. Factors explaining the good response to EPO (good responders were defined as those achieving Hb levels over 11 g/dL) had shown high Hb levels at the start (Logistic multiple regression analysis, p = 0.03) along with low creatinine concentration at the start (Cox's proportional hazard models, p = 0.015). Transferrin saturation (TSAT) at the start was 33.6 +/- 13.6%, 34.0 +/- 19.9% at the peak, and 24.7 +/- 11.6% at the commencement of dialysis, showing a significant reduction in TSAT at the commencement of dialysis compared to that at the start (n = 49, p = 0.0383, the start vs. the commencement of dialysis). Serum ferritin concentration was 140.7 +/- 139.5 pg/mL at the start, 107.9 +/- 110.8 pg/mL at the peak, and 131.9 +/- 112.4 pg/mL at the commencement of dialysis, indicating an absence of significant differences among the three time points. CONCLUSION: The current health insurance regulations in Japan seem to be inappropriate in that the permitted EPO dosage of 6,000 IU/week might not be sufficient to achieve the target Hb level of more than 11 g/dL in most patients with CKD. To more efficiently achieve renoprotection, both early and timely initiation of EPO and reconsideration of the recommended EPO dosage appear to be warranted. PMID- 17695815 TI - Emergencies first. HL7 develops the first unique clinical profile for the ED, based on its EHR umbrella standard. PMID- 17695816 TI - Getting what you pay for. PricewaterhouseCoopers report finds that value from IT investment does not come quickly or easily. PMID- 17695814 TI - [Case of immune complex crescentic glomerulonephritis with consistently high titers of MPO-ANCA for 6 years]. AB - A male patient, now 65 years old, experienced fever, hemoptysis, and respiratory failure about six years ago. Soon thereafter, he developed rapid progressive renal dysfunction with pulmonary hemorrhage and positive findings for MPO-ANCA. We commenced methylprednisolone pulse (MP) therapy followed by oral prednisolone (PSL) and intravenous cyclophosphamide (CY) for the treatment of ANCA-associated microscopic polyangiitis (MPA). Therapeutic efficacy was obtained comparatively rapidly. Light microscopic findings of a percutaneous renal biopsy demonstrated focal necrotizing and crescentic glomerulonephritis. Immunofluorescent microscopy indicated diffuse deposition of IgG and C3 along the periphery of the tufts and in the mesangium. On the basis of these findings, the condition was diagnosed as immune complex crescentic glomerulonephritis associated with MPO-ANCA. MPO-ANCA titers were high (714 EU) at onset and remained high (250-450 EU) over the ensuing 6 years with oral administration of PSL 5 mg. Though his condition remitted completely, his MPO-ANCA titers recently increased to above 600 EU once more. We conducted a follow-up renal biopsy to ascertain if the fluctuation of MPO-ANCA titers reflected an early stage of relapse. Light microscopic findings of the biopsied tissue revealed no signs of necrosis or crescentic formation of the glomeruli. Immunofluorescent microscopic findings were negative. The elevated MPO-ANCA titers were not valuable for the early prediction of relapse in our case, and the immune complex may have played an important role. When judging relapse and remission in ANCA-associated glomerulonephritis, it is important to evaluate the overall clinical findings and histopathological findings in addition to the serial ANCA titers. PMID- 17695817 TI - Hospital goes robotic. Six months since embracing robots to deliver medication and supplies, Providence Hospital has seen futuristic results. PMID- 17695818 TI - Without wires. St. Joseph Health System signs a $1 million contract to implement wireless at three hospitals. PMID- 17695819 TI - Off the front lines. Building an inter-hospital PACS network may improve business efficiency, just as it has improved care. PMID- 17695820 TI - Is HHS going private? Three firms are tasked with devising competing business plans for taking AHIC private. PMID- 17695821 TI - A stark future? Recent tweaks to the law give hospitals a freer hand in donating IT to physicians, but structuring these complex relationships is another story. PMID- 17695822 TI - The long run. As the P4P race continues, providers integrate EBM with data gathering systems to cross the finish line. PMID- 17695823 TI - At work on an EMR in Dallas. A leading academic medical center is bringing an EMR to its 450-bed health system. PMID- 17695824 TI - Does e-prescribing lower prices? Southwest Medical Associates found eRx helped arm physicians with pertinent information at the point of care. PMID- 17695825 TI - A time of change. New technology-enhanced care models may change everything. Will you be able to adapt? PMID- 17695826 TI - The price cut. M&A activity abounds in a market where hospitals outsource to the tune of billions. PMID- 17695827 TI - Implementation methodology matters. Successful electronic health record RFPs must include malleable methodologies that change over time. PMID- 17695828 TI - The threat from within. Implementing secure access controls helps organizations protect sensitive patient information from insider threat. PMID- 17695829 TI - Predicting health. A six step implementation process may help providers improve patient care, best practices and ROI. PMID- 17695830 TI - Picture perfect. Care providers see diagnostic imaging, digital data capture and PACS as more than just radiology-related systems. PMID- 17695831 TI - Warming to law. After the U.S. Supreme Court ruling, how stiff will greenhouse gas regulations be? PMID- 17695832 TI - Reasonable doubt. Data secrecy clouds judgments of lethal injection. PMID- 17695834 TI - An ear for spacetime. Pulsars provide an alternative way to detect gravitational waves. PMID- 17695833 TI - Treading water. The levees are patched up, but the flood risk remains high. PMID- 17695835 TI - Jam session. A design to block RFID tags. PMID- 17695836 TI - All in the family. Paternity shocker: marmoset twins pass on each other's genes. PMID- 17695837 TI - Bad execution. Lethal injection can cause undue suffering to the condemned. Wha's to be done? PMID- 17695838 TI - The promise of the blue revolution. Aquaculture can maintain living standards while averting the ruin of the oceans. PMID- 17695839 TI - The limited appeal of nuclear energy. To developing nations, the new arguments for nuclear power are far from compelling. PMID- 17695841 TI - Warmer oceans, stronger hurricanes. Evidence is mounting that global warming enhances a cyclone's damaging winds and flooding rains. PMID- 17695840 TI - The prospects for Homo economicus. A new fMRI study debunks the myth that we are rational-utility money maximizers. PMID- 17695842 TI - The memory code. Researchers are closing in on the rules that the brain uses to lay down memories. Discovery of this memory code could lead to the design of smarter computers and robots and even to new ways to peer into the human mind. PMID- 17695843 TI - A malignant flame. Understanding chronic inflammation, which contributes to heart disease, Alzheimer's and a variety of other ailments, may be a key to unlocking the mysteries of cancer. PMID- 17695844 TI - The evolution of cats. Genomic paw prints in the DNA of the world's wild cats have clarified the cat family tree and uncovered several remarkable migrations in their past. PMID- 17695845 TI - An earth without people. A new way to examine humanity's impact on the environment is to consider how the world would fare if all the people disappeared. Interview with Alan Weisman. Interview by Steve Mirsky. PMID- 17695846 TI - Broadband room service by light. Encoded light transmissions can provide the wireless devices in a room with multimedia web services such as videoconferencing, movies on demand and more. PMID- 17695847 TI - Should science speak to faith? PMID- 17695848 TI - A little privacy, please. Computer scientist latanya sweeney helps to save confidentiality with "anonymizing" programs, "deidentifiers" and other clever algorithms. Whether they are enough, however, is another question. PMID- 17695849 TI - In or out? PMID- 17695851 TI - Does premium gasoline deliver premium benefits to your car? PMID- 17695850 TI - Why do the ice cubes in my freezer often develop stalagmitelike spikes? PMID- 17695852 TI - Case history 1: Mr. C. PMID- 17695853 TI - Tooth surface loss: causes and effects. PMID- 17695854 TI - Vertical dimension of occlusion. PMID- 17695855 TI - Endodontics and tooth retention. PMID- 17695856 TI - Surgical periodontal interventions: long-term outcomes. PMID- 17695857 TI - Tooth wear and occlusion: friends or foes? PMID- 17695858 TI - Overdenture therapy and worst-case scenarios: alternative management strategies. PMID- 17695859 TI - Case history 2: Mrs K. PMID- 17695860 TI - Sequelae of partial edentulism. PMID- 17695861 TI - Osteoarthrosis/osteoathritis in the temporomandibular joints. PMID- 17695862 TI - Cantilevers in dentistry. PMID- 17695864 TI - Time-dependent intraoral ecologic changes and prosthodontic interventions. PMID- 17695863 TI - Gender-specific dental health issues and treatment considerations. PMID- 17695865 TI - Implant management of posterior partial edentulism. PMID- 17695866 TI - On diverse approaches to prosthodontic research: the case series approach to clinical research. PMID- 17695867 TI - The evidence-based approach to prosthodontic practice and research. PMID- 17695868 TI - Where science fails prosthodontics. PMID- 17695869 TI - Five-year clinical results of zirconia frameworks for posterior fixed partial dentures. AB - PURPOSE: The aim of this prospective clinical cohort study was to determine the success rate of 3- to 5-unit zirconia frameworks for posterior fixed partial dentures (FPDs) after 5 years of clinical observation. MATERIALS AND METHODS: Forty-five patients who needed at least 1 FPD to replace 1 to 3 posterior teeth were included in the study. Fifty-seven 3- to 5-unit FPDs with zirconia frameworks were cemented with 1 of 2 resin cements (Variolink or Panavia TC). The following parameters were evaluated at baseline, after 6 months, and 1 to 5 years after cementation at test (abutments) and control (contralateral) teeth: probing pocket depth, probing attachment level, Plaque Index, bleeding on probing, and tooth vitality. Intraoral radiographs of the FPDs were taken. Statistical analysis was performed using descriptive statistics, Kaplan-Meier survival analysis, and the McNemar test. RESULTS: Twenty-seven patients with 33 zirconia FPDs were examined after a mean observation period of 53.4 +/- 13 months. Eleven patients with 17 FPDs were lost to follow-up. After the 3-year recall visit, 7 FPDs in 7 patients were replaced because they were not clinically acceptable due to biologic or technical complications. After 5 years of clinical observation, 12 FPDs in 12 patients had to be replaced. One 5-unit FPD fractured as a result of trauma after 38 months. The success rate of the zirconia frameworks was 97.8%; however, the survival rate was 73.9% due to other complications. Secondary caries was found in 21.7% of the FPDs, and chipping of the veneering ceramic in 15.2%. There were no significant differences between the periodontal parameters of the test and control teeth. CONCLUSIONS: Zirconia offers sufficient stability as a framework material for 3- and 4-unit posterior FPDs. The fit of the frameworks and veneering ceramics, however, should be improved. PMID- 17695870 TI - An up to 16-year prospective study of 304 porcelain veneers. AB - PURPOSE: This study aimed to prospectively analyze the outcomes of 304 feldspathic porcelain veneers prepared by the same operator, in 100 patients, that were in situ for up to 16 years. MATERIALS AND METHODS: A total of 304 porcelain veneers on incisors, canines, and premolars in 100 patients completed by one prosthodontist between 1988 and 2003 were sequentially included. Preparations were designed with chamfer margins, incisal reduction, and palatal overlap. At least 80% of each preparation was in enamel. Feldspathic porcelain veneers from refractory dies were etched (hydrofluoric acid), silanated, and cemented (Vision 2, Mirage Dental Systems). Outcomes were expressed as percentages (success, survival, unknown, dead, repair, failure). The results were statistically analyzed using the chi-square test and Kaplan-Meier survival estimation. Statistical significance was set at P < .05. RESULTS: The cumulative survival for veneers was 96% +/- 1% at 5 to 6 years, 93% +/- 2% at 10 to 11 years, 91% +/- 3% at 12 to 13 years, and 73% +/- 16% at 15 to 16 years. The marked drop in survival between 13 and 16 years was the result of the death of 1 patient and the low number of veneers in that period. The cumulative survival was greater when different statistical methods were employed. Sixteen veneers in 14 patients failed. Failed veneers were associated with esthetics (31%), mechanical complications (31%), periodontal support (12.5%), loss of retention >2 (12.5%), caries (6%), and tooth fracture (6%). Statistically significantly fewer veneers survived as the time in situ increased. CONCLUSIONS: Feldspathic porcelain veneers, when bonded to enamel substrate, offer a predictable long-term restoration with a low failure rate. The statistical methods used to calculate the cumulative survival can markedly affect the apparent outcome and thus should be clearly defined in outcome studies. PMID- 17695871 TI - Frequency and location of traumatic ulcerations following placement of complete dentures. AB - PURPOSE: To determine the location of mucosal injuries that appear following placement of complete dentures, as well as the number of adjustments necessary to achieve patient comfort. The frequency of mucosal injuries in female and male patients and their connection with clinical anatomic features were also investigated. MATERIALS AND METHODS: Sixty-one completely edentulous healthy patients who wore dentures (47 women and 14 men) took part in the study; 122 newly fabricated complete maxillary and mandibular dentures were investigated. All patients were seen for a 1-week adjustment appointment. Areas where signs of denture-induced mucosal injuries appeared were marked on an anatomic illustration. The follow-up period was in 1-week increments as deemed necessary by the patient. Associations between variables were analyzed with analysis of variance. Results were recorded as mean + SD. Statistical significance was set at P < or = .05. RESULTS: Eighty-seven percent of the dentures required adjustment at week 1, 50% at week 2, and only 7% at week 3. No patients required a further visit. Most frequently injured maxillary areas were the vestibular sulcus (41%), maxillary tuberosity (21%), and hamular notch (12%). In the mandible, the most frequently injured areas were the retromylohyoid area (17%), lingual sulcus (14%), and vestibular sulcus (13%). Denture-induced irritations were detected in a higher ratio in the mandible (P < .001), especially in male denture wearers at the first adjustment (P < .05). Men had a higher ratio of lesions at the region of the maxillary vestibular sulcus between the labial and buccal frenum and at the mandibular vestibular sulcus of the buccal shelf region (P < .001). CONCLUSIONS: Denture-induced irritations appeared most often in the vestibular sulcus of the maxilla and mandible, indicating that it is necessary to evaluate the area of the facial seal of the prosthesis by applying a medium- or a heavy pressure indicator paste to the borders, and to make adjustments at the delivery stage and subsequent adjustment appointments. Denture placement must not be the final patient-clinician encounter when treating with complete dentures. Denture adjustments are very important clinical phases of denture fabrication and essential in patient care. PMID- 17695872 TI - Impact of osseointegrated implants on the selection of treatment options in relation to tooth extraction: comparison between 1995 and 2005. AB - This study aimed to examine the influence of osseointegrated implants on decision making for prosthodontic treatments. Twenty-five randomly selected Japanese dental clinicians in 1995 and 2005 with 5 to 15 years of clinical experience were requested to define bone support levels for prosthodontic treatment options. Comparison of the results expressed with the fuzzy function between 1995 and 2000 showed that indications for extraction have expanded with the prevalence of osseointegration concepts. Further, the definition of poor bone quality has changed. Osseointegration has influenced the decision-making process in prosthodontic treatments related to extraction. PMID- 17695873 TI - Effect of different mucosal and acrylic resin surface treatments in a denture retention model for patients with radiotherapy-induced xerostomia. AB - The purpose of this study was to determine the effect of oral moisturizing agents, denture adhesives, and surface treatments on the retention of an acrylic resin test base dislodged from the maxillary alveolar ridges of xerostomic radiotherapy patients. Acrylic resin test bases prepared for 10 edentulous xerostomia patients were subjected to 8 surface treatment methods: method 1 = untreated dry surface; method 2 = use of Biotene oral moisturizer; method 3 = use of Protefix denture adhesive; method 4 = combination of Biotene and Protefix; method 5 = sandblasting of test bases; method 6 = use of Biotene on sandblasted surface; method 7 = use of Protefix on sandblasted surface; method 8 = combination of Protefix and Biotene on sandblasted surface. After each treatment, a tensile testing apparatus was used to dislodge the inserted test bases, and force values (N) were recorded. A significant difference in retentive force was observed between the 4 Protefix groups and those that did not use denture adhesive (P < .001). There were no differences among the 4 combinations of denture adhesive treatments (P > .05). Sandblasting the denture surfaces did not increase retentive forces alone or in combination with any other treatments. Biotene oral moisturizing agent was used in 4 treatment methods, but only had a significant effect on increasing retentive force when used with a nonsandblasted surface (P < .05). Biotene had no effect on retentive force compared to a nonsandblasted surface without moisturizer or when it was used in combination with any other methods. Protefix denture adhesive offered the greatest improvement in retentive force. Sandblasting the intaglio surface did not improve retentive force. Biotene was reported to improve patient comfort but had minimal effect on retentive force; however, Biotene can be assumed to be a more advantageous method of increasing retention compared to sandblasting (P < .05). PMID- 17695874 TI - Patterns of missing teeth in a population of oligodontia patients. AB - PURPOSE: The purpose of this study was to characterize a population of oligodontia patients and identify patterns of tooth agenesis. MATERIALS AND METHODS: A total of 116 patients with nonsyndromic oligodontia were studied, and the Tooth Agenesis Code (TAC) per quadrant was calculated. Oligodontia was defined as the congenital absence of 6 or more permanent teeth, excluding the third molars. The TAC is a unique number, consistent with a specific pattern of tooth agenesis. The authors suggest the use of an overall TAC with which the dentition throughout the mouth can be presented by a single number. Frequency analysis was used to study the prevalence of various patterns. RESULTS: There was a great diversity of TACs. In the maxilla, agenesis of both premolars and the lateral incisor or the presence of only the central incisor and first molar were the most common patterns. In the mandible, agenesis of the second premolar or both premolars occurred most frequently. CONCLUSIONS: No single pattern of agenesis occurred more than twice when the full mouth was viewed. Hence, the presentation of the dentition in oligodontia is very heterogeneous. Evaluation of treatment strategies in oligodontia patients is a methodologic challenge because homogenous, comparable subgroups of patients are not available. PMID- 17695875 TI - Evaluation of visual and spectrophotometric shade analyses: a clinical comparison of 3758 teeth. AB - This study aimed to evaluate the performance of visual and spectrophotometric tooth shade analysis. Two operators independently selected the best match of 3758 anterior teeth of 106 patients at 3 different dates, using the Chromascop Complete shade guide. Additionally, tooth color was analyzed 3 consecutive times using a reflectance spectrophotometer. Spectrophotometry showed high agreement values (89.6%); both examiners agreed in 49.7% of the measurements. Visual assessment resulted in significantly darker ratings than spectrophotometry (P < .0005). However, a positive association was observed for both procedures (P = .548). Spectrophotometric shade determination seems to be significantly more reproducible than the visual procedure. PMID- 17695876 TI - Shear bond strength of a new resin bonding system to different ceramic restorations. AB - This study evaluated the shear bond strength of a newly developed resin bonding system, including single-liquid ceramic primer and dual-cured resin luting agent, to 5 ceramic materials (feldspathic porcelain, machinable ceramic, In-Ceram Alumina, Procera AllCeram alumina, and Cercon). Ceramic specimens were cleaned with phosphoric acid, treated with primer, and bonded with a resin luting agent. Shear bond strength was determined after 24 hours of immersion in water and/or 10,000 thermocycles. There were no significant differences in bond strength before and after thermocycling for the 5 ceramic materials (P > .05). The findings indicate that the resin bonding system may offer an acceptable performance in terms of clinical success for the 5 ceramic restorations. PMID- 17695877 TI - SEM evaluation of in situ early bacterial colonization on a Y-TZP ceramic: a pilot study. AB - This study aimed to evaluate the effect of surface glazing and polishing of yttrium-stabilized tetragonal zirconia polycrystal ceramic on early dental biofilm formation, as well as the effect of brushing on the removal of adhered bacteria. Two subjects used oral appliances with polished and glazed samples fixed to the right and left sides. After 20 minutes, 1 hour, and 6 hours, the subjects manually brushed the samples on the right side. The samples were analyzed using scanning electron microscopy. Granular material was verified on the samples, especially on irregular surfaces. After 1 hour, there was no significant difference between glazed and polished surfaces in terms of bacterial presence. However, glazed surfaces tended to accumulate more biofilm, and brushing did not completely remove the biofilm. Polished surfaces seem to present a lower tendency for biofilm formation. PMID- 17695878 TI - Perception thresholds for electrical stimulation of the palatal mucosa. AB - PURPOSE: To define the normative ranges of the Current Perception Threshold (CPT) of the palatal mucosa and to correlate it with the subjects' attributes. MATERIALS AND METHODS: A group of 129 informed healthy subjects consented to participate in the study. A Neurometer NS3000 device was used to evaluate the CPTs of the nasopalatine nerve (NPN) and the greater palatine nerve (GPN) by using 2000-, 250-, and 5-Hz stimulations. After confirming the relationships with regard to gender, age, weight, height, alcohol consumption, duration of sleep, weight percentage of water content, smoking, and CPT, the normative ranges of the CPT measurements were obtained. RESULTS: Correlations were observed between age and CPTs obtained with the 2000- and 250-Hz stimulations of the GPN. The CPTs of the GPN were higher than those of the NPN. With the exception of the 5-Hz stimulation of the NPN, the CPTs in men were higher than those in women; however, the within- and between-site ratios exhibited no differences between the male and female subjects. No significant effects of smoking and alcohol consumption on CPT were observed. Range analysis revealed an increase in the CPTs as the frequency increased from 5 to 250 to 2,000 Hz. Within-site ratio analysis revealed increasing and spreading CPT ratios in the following order: 250/5 Hz, 2000/250 Hz, and 2,000/5 Hz. In the order of 5-, 250-, and 2000-Hz stimulations, decreasing ratios were observed for the between-site ratio analysis. CONCLUSION: This study provides useful diagnostic criteria for CPTs in the palatal mucosa. PMID- 17695879 TI - A prefabricated precision attachment: 3 years of experience with the Swiss Mini SG system. A prospective clinical study. AB - The aim of this prospective long-term clinical trial was to verify the clinical success of prefabricated precision attachments with regard to periodontal condition, wearing comfort, and stability of attachment friction. Twenty-eight patients were fitted with 35 prostheses with Swiss Mini-SG precision attachments. Following clinical investigation and monitoring over a 3-year period, 80% of the prostheses were functioning well. The average pocket depth of the abutment teeth at the buccal sites and the periodontal parameters Approximal Plaque Index and Sulcus Bleeding Index showed statistically significant improvements. The abutment tooth mobility (Periotest measurements) decreased. It is not advisable to support the attachments on single abutment teeth. PMID- 17695880 TI - Atrazine ban premature. PMID- 17695881 TI - Models underestimate global warming impacts. PMID- 17695882 TI - Past PFOA sources in the Arctic Ocean. PMID- 17695884 TI - E-waste campaign begins in the UK. PMID- 17695883 TI - Perchlorate is widespread in U.S. Southwest. PMID- 17695885 TI - Redirecting autism research. PMID- 17695886 TI - Tiny filters fix big water problems. PMID- 17695887 TI - PFOA in people. PMID- 17695888 TI - Assessing extended producer responsibility laws in Japan. PMID- 17695889 TI - Mercury in crude oil processed in the United States (2004). AB - The mean and range of concentrations of mercury in crude oil processed by U.S. refineries in 2004 were determined using two analytical methods. One hundred seventy separate crude oil streams were sampled repetitively to obtain 328 individual samples. Samples were retrieved immediately upstream of refinery tank farms. Losses of mercury during production, separation, and transportation were not examined. The arithmetic mean and median of 170 oil streams were 7.3 and 1.5 microg/kg in total mercury, respectively. The total mercury concentration of oil processed in the United States in year 2004, including all species and both dissolved and suspended forms, expressed as a volume-weighted mean was calculated to be 3.5 +/- 0.6 microg/kg. The range of measured concentrations extended from below the analytical detection limit (0.5 microg/kg) to approximately 600 microg/kg. Good agreement was found with other recent and independent studies of mercury in crude oil refined in North America. The total amount of mercury in crude oil processed in the U.S annually is less than five percent of the amount contained in U.S. coal produced annually. PMID- 17695890 TI - Beach sands along the California coast are diffuse sources of fecal bacteria to coastal waters. AB - Fecal indicator bacteria (FIB) are nearly ubiquitous in California (CA) beach sands. Sands were collected from 55 beaches along the CA coast. Ninety-one percent of the beaches had detectable enterococci (ENT) while 62% had detectable E. coli (EC) in their sands. The presence of a putative bacterial source (such as a river), the degree of wave shelter, and surrounding land use explained a significant (p < 0.05) fraction of the variation in both ENT and EC densities between beaches. Sand characteristics including moisture content, organic carbon, and percentfines, significantly (p < 0.05) influenced only EC densities in beach sand. We assayed 34 of 163 sand samples for salmonellae, but did not detect this bacterial pathogen. The potential for FIB to be transported from the sand to sea was investigated at a single wave-sheltered beach with high densities of ENT in beach sand: Lovers Point, CA (LP). We collected samples of exposed and submerged sands as well as water over a 24 h period in order to compare the disappearance or appearance of ENT in sand and the water column. Exposed sands had significantly higher densities of ENT than submerged sands with the highest densities located near the high tide line. Water column ENT densities began low, increased sharply during the first flood tide and slowly decreased over the remainder of the study. During the first flood tide, the number of ENT that entered the water column was nearly equivalent to the number of ENT lost from exposed sands when they were submerged by seawater. The decrease in nearshore ENT concentrations after the initial influx can be explained by ENT die-off and dilution with clean ocean water. While some ENT in the water and sand at LP might be of human origin because they were positive for the esp gene, others lacked the esp gene and were therefore equivocal with respect to their origin. Follow-up sampling at LP revealed the presence of the human specific Bacteroides marker in water and sand. PMID- 17695891 TI - Widespread natural perchlorate in unsaturated zones of the southwest United States. AB - A substantial reservoir (up to 1 kg ha(-1)) of natural perchlorate is present in diverse unsaturated zones of the arid and semi-arid southwestern United States. The perchlorate co-occurs with meteoric chloride that has accumulated in these soils throughout the Holocene [0 to 10-15 ka (thousand years ago)] and possibly longer periods. Previously, natural perchlorate widely believed to be limited to the Atacama Desert, now appears widespread in steppe-to-desert ecoregions. The perchlorate reservoir becomes sufficiently large to affect groundwater when recharge from irrigation or climate change flushes accumulated salts from the unsaturated zone. This new source may help explain increasing reports of perchlorate in dry region agricultural products and should be considered when evaluating overall source contributions. PMID- 17695892 TI - A global mass balance analysis of the source of perfluorocarboxylic acids in the Arctic Ocean. AB - Whereas the pervasive and abundant presence of perfluorinated carboxylic acids (PFCAs) in the Arctic marine food chain is clearly established, their origin and transport pathway into the Arctic Ocean are not. Either the atmospheric oxidation of volatile precursor compounds, such as the fluorotelomer alcohols (FTOHs), or the long-range oceanic transport of directly emitted PFCAs is seen as contributing the bulk of the PFCA input to the Arctic. Here simulations with the zonally averaged global fate and transport model Globo-POP, in combination with historical emission estimates for FTOHs and perfluorooctanoic acid (PFOA), are used to evaluate the relative efficiency and importance of the two transport pathways. Estimates of the emission-independent Arctic Contamination Potential reveal that the oceanic transport of directly emitted PFCAs is more than 10-fold more efficient than the atmospheric degradation of FTOHs in delivering PFCAs to the Arctic, mostly because of the low yield of the reaction. The cumulative historic emissions of FTOHs are lower than those estimated for PFOA alone by a factor of 2-3, further limiting the contribution that precursor oxidation makes to the total PFCAs load in the Arctic Ocean. Accordingly, when fed only with FTOH emissions, the model predicts FTOH air concentrations in agreement with the reported measurements, but yields Arctic seawater concentrations for the PFOA that are 2 orders of magnitude too low. Whereas ocean transport is thus very likely the dominant pathway of PFOA into the Arctic Ocean, the major transport route of longer chain PFCAs depends on the size of their direct emissions relative to those of 10:2 FTOH. The predicted time course of Arctic seawater concentrations is very similar for directly emitted and atmospherically generated PFCAs, implying that neither past doubling times of PFCA concentrations in Arctic marine mammals nor any future time trends are likely to resolve the question of the dominant source of PFCAs. PMID- 17695893 TI - Distribution and fate of inorganic and organic arsenic species in landfill leachates and biogases. AB - The arsenic release from landfills requires special attention both due to its potential toxicity and due to the increasing global municipal solid waste production. The determination of arsenic species in both leachates and biogases has been performed in this work to determine the fate of arsenic in landfills. Both inorganic and methylated arsenic species occur in leachates with concentrations varying from 0.1 to 80 microg As L(-1). These species are representative of the leachate arsenic composition, as the mean recovery obtained for the speciation analyses is 67% of the total arsenic determined in elementary analyses. In biogases, both methylated and ethylated volatile arsenic species have been identified and semiquantified (0-15 microg As m(-3)). The landfill monitoring has emphasized close relationships between the concentrations of mono , di-, and tri-methylated arsenic compounds in leachates. A biomethylation pathway has thus been proposed as a source of these methylated compounds in the leachates from waste arsenic, which is supposed to be in major part under inorganic forms. In addition, peralkylation mechanisms of both biomethylation and bioethylation have been suggested to explain the occurrence of the identified volatile species. This combined speciation approach provides a qualitative and quantitative characterization of the potential emissions of arsenic from domestic waste disposal in landfills. This work highlights the possible formation of less harmful organoarsenic species in both leachates and biogases during the waste degradation process. PMID- 17695894 TI - Quantitative identification of unknown exposure pathways of phthalates based on measuring their metabolites in human urine. AB - Humans are exposed to ubiquitous phthalates via multiple pathways. Exposures to phthalates have been estimated in some previous risk assessments in Japan based on point-of-contact measurement or scenario evaluation approaches. While the Japanese national government has regulated the use of di(2-ethylhexyl)phthalate (DEHP) and excluded several other phthalates from its regulation based on some of them, it is unclear whether such past exposure assessment studies fully assessed total human exposure to phthalates. In the present study, we measured their urinary metabolites, which show direct evidence of human exposure to phthalates. We recruited voluntary participants (N = 36) who agreed to donate urine samples, and measured the urinary concentrations of phthalate metabolites using enzymatic deconjugation, solid-phase extraction, and high-performance liquid-chromatography isotope-dilution tandem mass spectrometry. We then derived the daily intakes of their respective phthalates based on steady state assumption and finally compared them with the corresponding estimated daily intakes of each phthalate via diet and air derived from previous exposure or risk assessments in Japan. These comparisons showed that exposures to dimethyl phthalate, diethyl phthalate, and di-n-butyl phthalate via diet and air accounted for less than half of their respective total exposures. On the other hand, it appears that dietary intake was more predictive for the total exposure to n-butyl-benzyl phthalate and DEHP. The probabilities that the log normal distribution of each phthalate daily intake estimated from the present study exceeds the corresponding tolerable daily intake were estimated to be less than 10(-4). PMID- 17695895 TI - Quinone emissions from gasoline and diesel motor vehicles. AB - Gas- and particle-phase emissions from gasoline and diesel vehicles operated on chassis dynamometers were collected using annular denuders, quartz filters, and PUF substrates. Quinone species were measured using O-(2,3,4,5,6 pentafluorobenzyl)hydroxylamine derivatization in conjunction with gas chromatography-mass spectrometry and high-performance liquid chromatography-mass spectrometry. Nine quinones were observed, ranging from C6 to C16. New species identified in motor vehicle exhaust include methyl-1,4-benzoquinone, 2-methyl-1,4 naphthoquinone (MNQN), and aceanthrenequinone. Gas-phase motor vehicle emissions of quinones are also reported for the first time. Six gas-phase quinones were quantified with emission rates of 2-28 000 microg L(-1) fuel consumed. The most abundant gas-phase quinones were 1,4-benzoquinone (BON) and MNQN. The gas-phase fraction was > or = 69% of quinone mass for light-duty gasoline emissions, and > or = 84% for heavy-duty diesel emissions. Eight particle-phase quinones were observed between 2 and 1600 microg L(-1), with BQN the most abundant species followed by 9,10-phenanthrenequinone and 1,2-naphthoquinone. Current particle phase quinone measurements agree well with the few available previous results. Further research is needed concerning the gas-particle partitioning behavior of quinones in ambient and combustion source conditions. PMID- 17695896 TI - Occurrence and air-sea exchange of phthalates in the Arctic. AB - Air and seawater samples were taken simultaneously to investigate the distribution and air-sea gas exchange of phthalates in the Arctic onboard the German Research Ship FS Polarstern. Samples were collected on expeditions ARK XX1&2 from the North Sea to the high Arctic (60 degrees N-85 degrees N) in the summer of 2004. The concentration of sigma6 phthalates (dimethyl phthalate (DMP), diethyl phthalate (DEP), di-i-butyl phthalate (DiBP), di-n-butyl phthalate (DnBP), butylbenzyl phthalate (BBP), and diethylhexyl phthalate (DEHP)) ranged from 30 to 5030 pg L(-1) in the aqueous dissolved phase and from 1110 to 3090 pg m(-3) in the atmospheric gas phase. A decreasing latitudinal trend was present in the seawater and to a lesser degree in the atmosphere from the Norwegian coast to the high Arctic. Overall, deposition dominated the air-sea gas exchange for DEHP, while volatilization from seawater took place in the near-coast environment. The estimated net gas deposition of DEHP was 5, 30, and 190 t year(-1) for the Norwegian Sea, the Greenland Sea, and the Arctic, respectively. This suggests that atmospheric transport and deposition of phthalates is a significant process for their occurrence in the remote Atlantic and Arctic Ocean. PMID- 17695897 TI - Current-use flame retardants in the eggs of herring gulls (Larus argentatus) from the Laurentian Great Lakes. AB - Of the 13, current-use, non-polybrominated diphenyl ether (PBDE) flame retardants (FRs) monitored, hexabromobenzene (HBB), pentabromoethylbenzene (PBEB), pentabromotoluene (PBT), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE) and alpha- and gamma-isomers of hexabromocyclododecane (HBCD), and the syn- and anti-isomers of the chlorinated Dechlorane Plus (DP) were quantified in egg pools of herring gulls (Larus argentatus) collected in 2004 from six sites in all five of the Laurentian Great Lakes of North America. alpha-HBCD concentrations ranged from 2.1 to 20 ng/g (wet weight (ww)). Other "new" FR levels ranged from 0.004 to 1.4 ng/g ww and were much lower than those of the major BDE congeners that are in technical mixtures (namely BDE-47, -99, -100), where sigma3PBDE ranged from 186 to 498 ng/g ww. Nineteen hepta-BDEs (sigma(hepta) = 4.9-11 ng/g ww), octa-BDEs (alpha(octa) = 2.6-9.1 ng/g ww), and nona-BDEs (sigma(nona) = 0.12-5.6 ng/g ww) were detectible at all six colonies, while BDE-209 was low but quantifiable (< 0.1-0.21 ng/g ww) at two colonies. sigma-DP (syn- and anti-isomers) concentrations in eggs from all sites ranged from 1.5 to 4.5 ng/g ww. Our findings indicate that mother herring gulls are exposed to several, current-use flame retardants via their diet, and in ovo transfer occurred to their eggs. Given the aquatic diet of herring gull, this suggests that there are non-PBDE BFRs present in the gull-associated aquatic food web of the Great Lakes. PMID- 17695898 TI - Time trends of methylmercury in walleye in northern Wisconsin: a hierarchical Bayesian analysis. AB - Methylmercury data from walleye fillets collected by multiple agencies from northern Wisconsin lakes from 1982 to 2005 were examined for regional time trends. Hierarchical Bayesian methods were used to model dependencies and provide probability statements for parameters pertaining to individual lakes and the region as a whole. A missing data mechanism allowed the sex of the fish to be included as a predictor since the sexes grow at different rates. A slight regional decrease in methylmercury of 0.60% annually was found, consistent with declining atmospheric mercury deposition. Methylmercury was estimated to have decreased in 77% of the 420 lakes from which walleye were sampled, although uncertainty regarding time trends was greater for most individual lakes than for the region as a whole. Methylmercury in walleye varied widely from lake to lake, but generally accumulated in the fish at similar rates by length after accounting for differences in sex. Slower-growing male walleye had higher methylmercury concentrations than females for a given length, and skin-on fillets were 16% lower in methylmercury than skin-off fillets. PMID- 17695899 TI - Personal exposure to polybrominated diphenyl ethers (PBDEs) in residential indoor air. AB - We used personal air samplers to measure indoor air exposure to polybrominated diphenyl ethers (PBDEs) for 20 residents of the Greater Boston Area (Massachusetts). Area air measures were simultaneously collected from two rooms in each participant's home. Total personal air concentrations (particulate + vapor) were 469 pg/m3 for non-209 BDEs and 174 pg/m3 for BDE 209, significantly higher than bedroom and main living room concentrations (p = 0.01). The ratio of personal air to room air increased from 1 for vapor-phase congeners to 4 for fully particulate-bound congeners, indicating a personal cloud effect. Bedroom and main living area air samples were moderately correlated for non-209 BDEs (r = 0.45, p = 0.045) and BDE 209 (r = 0.58, p = 0.008). Use of personal air concentrations increased estimates of inhalation exposure over those previously reported. Inhalation may account for up to 22% of the total BDE 209 exposure in U.S. adults. PMID- 17695900 TI - Asian Mussel Watch Program: contamination status of polybrominated diphenyl ethers and organochlorines in coastal waters of Asian countries. AB - Mussel samples were used in this study to measure the levels of polybrominated diphenyl ethers (PBDEs) and organochlorines (OCs) in the coastal waters of Asian countries like Cambodia, China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, the Philippines, and Vietnam. PBDEs were detected in all the samples analyzed, and the concentrations ranged from 0.66 to 440 ng/g lipid wt. Apparently higher concentrations of PBDEs were found in mussels from the coastal waters of Korea, Hong Kong, China, and the Philippines, which suggests that significant sources of these chemicals exist in and around this region. With regard to the composition of PBDE congeners, BDE-47, BDE-99, and BDE-100 were the dominant congeners in most of the samples. Among the OCs analyzed, concentrations of DDTs were the highest followed by PCBs > CHLs > HCHs > HCB. Total concentrations of DDTs, PCBs, CHLs, and HCHs in mussel samples ranged from 21 to 58 000, 3.8 to 2000, 0.93 to 900, and 0.90 to 230 ng/g lipid wt., respectively. High levels of DDTs were found in mussels from Hong Kong, Vietnam, and China; PCBs were found in Japan, Hong Kong, and industrialized/urbanized locations in Korea, Indonesia, the Philippines, and India; CHLs were found in Japan and Hong Kong; HCHs were found in India and China. These countries seem to play a role as probable emission sources of corresponding contaminants in Asia and, in turn, may influence their global distribution. PMID- 17695901 TI - Uranium reoxidation in previously bioreduced sediment by dissolved oxygen and nitrate. AB - Flow-through sediment column experiments examined the reoxidation of microbially reduced uranium with either oxygen or nitrate supplied as the oxidant. The uranium was reduced and immobilized via long-term (70 days) acetate biostimulation resulting in 62-92% removal efficiency of the 20 microM influent uranium concentration. Uranium reduction occurred simultaneously with iron reduction as the dominant electron accepting process. The columns were reoxidized by discontinuing the supply of acetate and either replacing the anaerobic gas used to purge the influent media with a gas mixture containing 20% oxygen (resulting in a dissolved oxygen concentration of 0.27 mM) or adding 1.6 mM nitrate to the influent media. Both oxygen and nitrate resolubilized the majority (88 and 97%, respectively) of the uranium precipitated during bioreduction within 54 days. Although oxygen is more thermodynamically favorable an oxidant than nitrate, nitrate-dependent uranium oxidation occurred significantly faster than oxygen-dependent uranium oxidation at the beginning of our experiment due, in part, to oxygen reacting more strongly with other reduced compounds. Nitrate breakthrough at the effluent of the column occurred within 12 h, which was significantly earlier than when oxygen was detected at the effluent (26 days). Although, over time, the majority of uranium was reoxidized by either oxidant, these results indicate that the type of oxidant and its reactivity with other reduced compounds will influence the fate of reduced uranium during a short-term oxidation event that may occur during a uranium bioremediation scenario. PMID- 17695902 TI - Influence of engine operating conditions on diesel particulate matter emissions in relation to transient and steady-state conditions. AB - Airborne particulate matter is an important pollutant affecting air quality. Currently, diesel PM regulations are based on emitted particle mass; however, the particle size distributions are also important factors in air quality. While the distributions of particulate emissions under steady-state conditions are well known and have been generalized, varying distributions undertransient conditions are not well-understood. This study investigates the size distributions of PM, focusing on the nuclei- and accumulation-modes, emitted from diesel engines under transient operations. Some engine conditions during transient testing produced particle size distributions that were notably different from those produced under steady-state conditions. During transient operation, the size distributions were either mono- or bimodal with peaks that were able to switch quickly between the nuclei- and accumulation-modes. These distributions have not been observed during steady-state testing but are significant because environmental and health effects and emission control solutions are highly dependent on particle size. PMID- 17695903 TI - Bioaccumulation of perfluorochemicals in sediments by the aquatic oligochaete Lumbriculus variegatus. AB - Bioaccumulation of perfluoroalkyl sulfonates, perfluorocarboxylates, and 2-(N ethylperfluorooctane sulfonamido) acetic acid (N-EtFOSAA) from laboratory-spiked and contaminated field sediments was assessed using the freshwater oligochaete, Lumbriculus variegatus. Semistatic batch experiments were conducted to monitor the biological uptake of these perfluorochemicals (PFCs) over 56 days. The elimination of PFCs was measured as the loss of PFCs in L. variegatus exposed to PFC-spiked sediment for 28 days and then transferred to clean sediment. The resultant data suggest that PFCs in sediments are readily bioavailable and that bioaccumulation from sediments does not continually increase with increasing perfluorocarbon chain length. Perfluorooctane sulfonate (PFOS) and perfluorononanoate were the most bioaccumulative PFCs, as measured by laboratory based estimated steady-state biota sediment accumulation factors (BSAFs) and BSAFs measured using contaminated field sediments. Elimination rate constants for perfluoroalkyl sulfonates and perfluorocaroboxylates were generally smaller than those previously measured for other organic contaminants. Last, a PFOS precursor, N-EtFOSAA, accumulated in the worm tissues and appeared to undergo biotransformation to PFOS and other PFOS precursors. This suggests that N EtFOSAA, which has been detected in sediments and sludge often at levels exceeding PFOS, may contribute to the bioaccumulation of PFOS in aquatic organisms. PMID- 17695904 TI - Carbon disulfide removal by zero valent iron. AB - The use of zero valent iron (Fe0) for the remediation of water contaminated with carbon disulfide (CS2), a common groundwater contaminant, has been evaluated in this study. Mineralogical analysis of Fe0 filings and polished Fe0 cross-sections indicates that iron sulfide is formed due to the removal of carbon disulfide from solution by Fe0. The kinetics of CS2 removal by Fe0 was examined through both batch and column testing, and it is demonstrated that CS2 is removed rapidly from solution. A linear relationship was observed, through batch testing, between the pseudo-first-order rate constant (k(obs)) and the surface area concentration of Fe0 (rho(a)). Data obtained from kinetic batch tests performed at four temperature levels conformed to the Arrhenius equation, and the calculated apparent activation energy (E(a)) was 37 +/- 2.3 kJ mol(-1), indicating that the kinetics of CS2 removal by Fe0 is controlled by a chemical surface reaction. The temperature correction factors for CS2 from a reference of 25 degrees C were x 1.4 for 18 degrees C, x 1.7 for 15 degrees C, x 2.0 for 12 degrees C, and x 2.3 for 9 degrees C. Surface area normalization of k(obs) obtained through batch and column testing gives specific reaction rate constants (k(SA)) within 1 order of magnitude, indicating that k(SA) values are useful as a general descriptor of CS2 Fe0 reaction kinetics and that these values provide a clear starting point for design calculations prior to commencing site-specific treatability studies for permeable reactive barrier design. PMID- 17695905 TI - Removal mechanism of As(III) by a novel Fe-Mn binary oxide adsorbent: oxidation and sorption. AB - A novel Fe-Mn binary oxide adsorbent was developed for effective As(III) removal, which is more difficult to remove from drinking water and much more toxic to humans than As(V). The synthetic adsorbent showed a significantly higher As(III) uptake than As(V). The mechanism study is therefore necessary for interpreting such result and understanding the As(III) removal process. A control experiment was conducted to investigate the effect of Na2SO3-treatment on arsenic removal, which can provide useful information on As(III) removal mechanism. The adsorbent was first treated by Na2SO3, which can lower its oxidizing capacity by reductive dissolution of the Mn oxide and then reacted with As(V) or As(III). The results showed that the As(V) uptake was enhanced while the As(III) removal was inhibited after the pretreatment, indicating the important role of manganese dioxide during the As(III) removal. FTIR along with XPS was used to analyze the surface change of the original Fe-Mn adsorbent and the pretreated adsorbent before and after reaction with As(V) or As(III). Change in characteristic surface hydroxyl groups (Fe-OH, 1130, 1048, and 973 cm(-1)) was observed by the FTIR. The determination of arsenic oxidation state on the solid surface after reaction with As(III) revealed that the manganese dioxide instead of the iron oxide oxidized As(III) to As(V). The iron oxide was dominant for adsorbing the formed As(V). An oxidation and sorption mechanism for As(III) removal was developed. The relatively higher As(III) uptake may be attributed to the formation of fresh adsorption sites at the solid surface during As(III) oxidation. PMID- 17695906 TI - DLVO approach to the flocculability of a photosynthetic H2-producing bacterium, Rhodopseudomonas acidophila. AB - The DLVO theory was used to explore the flocculation characteristics of a H2 producing photosynthetic bacterium, Rhodopseudomonas acidophila. The relationship between the surface characteristics of this strain and itsflocculability was evaluated. Its flocculability was governed by both electrolyte concentration and pH, and the appropriate electrolyte concentration and pH were found to be 0.1 M NaCl solution and pH 7.0, respectively. In addition, the extracellular polymeric substances produced by R. acidophila were observed to have a significant effect on its flocculation. The effective Hamaker constant between R. acidophila and water was only 2.27 x 10(-23) J, suggesting that the contribution of van der Waals interaction energy to the total interaction energy could be neglected. As a result, the bacterial particles could not overcome the total energy barrier to flocculate effectively. Otherwise, because the repulsive total interfacial free energy between the bacterial cells and water was positive, the cell particles of R. acidophila repelled each other, resulting in a great stability of the cell suspensions. PMID- 17695907 TI - Association with natural organic matter enhances the sunlight-mediated inactivation of MS2 coliphage by singlet oxygen. AB - MS2 coliphage, a surrogate for human enteric viruses, is inactivated by singlet oxygen (1O2) produced via sunlight-mediated excitation of natural organic matter (NOM) in surface waters. The 1O2 concentration within a NOM macromolecule or supramolecular assembly ([1O2]internal) is orders of magnitude higher than in the bulk solution ([1O2]bulk). In close proximity of NOM, MS2 is thus exposed to an elevated 1O2 concentration ([1O2]NOM), and inactivation is likely to be enhanced as compared to the bulk solution. In experiments using a solar simulator, we determined [1O2]bulk, [1O2]internal, as well as the association of MS2 with four NOMs (Fluka humic acid, FHA; Suwannee river humic acid, SRHA; Aldrich humic acid, AHA; Pony lake fulvic acid, PLFA), and studied their effect on the MS2 inactivation rate constant, k(obs), over a range of 1-25 mg NOM/L. The k(obs) values were modeled as the sum of the inactivation rate constants in close proximity to the NOM and in the bulk solution, assuming Langmuir-type adsorption of NOM onto MS2. FHA and SRHA exhibited 13-22 fold greater adsorption equilibrium constants than AHA and PLFA. Inactivation in the bulk solution contributed between 2% (20 mg/L FHA) and 39% (5 mg/L AHA) toward the overall k(obs). Thus, even for the less adsorbing NOM, inactivation was dominated by [1O2]NOM rather than [1O2]bulk. Changes in solution chemistry to promote closer interactions between MS2 and NOM also enhanced k(obs). Addition of Mg2+ to neutralize the negative surface charge of MS2 and NOM increased k(obs) up to 4.1-fold. Similarly, lowering the solution pH closer to the isoelectric point of MS2 (pl = 3.9) enhanced k(ob), 51-fold in 5 mg/L AHA. PMID- 17695908 TI - Spectroscopic evidence for uranium bearing precipitates in vadose zone sediments at the Hanford 300-area site. AB - Uranium (U) solid-state speciation in vadose zone sediments collected beneath the former North Process Pond (NPP) in the 300 Area of the Hanford site (Washington) was investigated using multi-scale techniques. In 30 day batch experiments, only a small fraction of total U (approximately 7.4%) was released to artificial groundwater solutions equilibrated with 1% pCO2. Synchrotron-based micro-X rayfluorescence spectroscopy analyses showed that U was distributed among at least two types of species: (i) U discrete grains associated with Cu and (ii) areas with intermediate U concentrations on grains and grain coatings. Metatorbernite (Cu[UO2]2[PO4]2 x 8H2O) and uranophane (Ca[UO2]2[SiO3(OH)]2 x 5H2O) at some U discrete grains, and muscovite at U intermediate concentration areas, were identified in synchrotron-based micro-X-ray diffraction. Scanning electron microscopy/energy dispersive X-ray analyses revealed 8-10 microm size metatorbernite particles that were embedded in C-, Al-, and Si-rich coatings on quartz and albite grains. In mu- and bulk-X-ray absorption structure (mu-XAS and XAS) spectroscopy analyses, the structure of metatorbernite with additional U-C and U-U coordination environments was consistently observed at U discrete grains with high U concentrations. The consistency of the mu- and bulk-XAS analyses suggests that metatorbernite may comprise a significant fraction of the total U in the sample. The entrapped, micrometer-sized metatorbernite particles in C-, Al , and Si-rich coatings, along with the more soluble precipitated uranyl carbonates and uranophane, likely control the long-term release of U to water associated with the vadose zone sediments. PMID- 17695909 TI - Electron pulse radiolysis determination of hydroxyl radical rate constants with Suwannee River fulvic acid and other dissolved organic matter isolates. AB - Pulse radiolysis experiments were conducted on dissolved organic matter (DOM) samples isolated as hydrophobic and hydrophilic acids and neutrals from different sources (i.e., stream, lake, wastewater treatment plant). Absolute bimolecular reaction rate constants for the reaction of hydroxyl radicals (*OH) with DOM (k*(OH), DOM) were determined. k*(OH, DOM) values are expressed as moles of carbon. Based on direct measurement of transient DOM radicals (DOM*) and competition kinetic techniques, both using pulse radiolysis, the k*(OH, DOM) value for a standard fulvic acid from the Suwannee River purchased from the International Humic Substances Society was (1.60 +/- 0.24) x 10(8) M(-1) s(-1). Both pulse radiolysis methods yielded comparable k*(OH, DOM) values. The k*(OH, DOM) values for the seven DOM isolates from different sources ranged from 1.39 x 10(8) M(-1) s(-1) to 4.53 x 10(8) M(-1) s(-1), and averaged 2.23 x 108 M(-1) s( 1) (equivalent to 1.9 x 10(4) (mgC/L)(-1) s(-1)). These values represent the first direct measurements of k*(OH, DOM,) and they compare well with literature values obtained via competition kinetic techniques during ozone or ultraviolet irradiation experiments. More polar, lower-molecular-weight DOM isolates from wastewater have higher k*(OH, DOM) values. In addition, the formation (microsecond time scale) and decay (millisecond time scale) of DOM* transients were observed for the first time. DOM* from hydrophobic acids exhibited broader absorbance spectra than transphilic acids, while wastewater DOM isolates had narrower DOM* spectra more skewed toward shorter wavelengths than did DOM* spectra for hydrophobic acids. PMID- 17695910 TI - On the source of organic acid aerosol layers above clouds. AB - During the July 2005 Marine Stratus/Stratocumulus Experiment (MASE) and the August-September 2006 Gulf of Mexico Atmospheric Composition and Climate Study (GoMACCS), the Center for Interdisciplinary Remotely-Piloted Aircraft Studies (CIRPAS) Twin Otter probed aerosols and cumulus clouds in the eastern Pacific Ocean off the coast of northern California and in southeastern Texas, respectively. An on-board particle-into-liquid sampler (PILS) quantified inorganic and organic acid species with < or = 5-min time resolution. Ubiquitous organic aerosol layers above cloud with enhanced organic acid levels were observed in both locations. The data suggest that aqueous-phase reactions to produce organic acids, mainly oxalic acid, followed by droplet evaporation is a source of elevated organic acid aerosol levels above cloud. Oxalic acid is observed to be produced more efficiently relative to sulfate as the cloud liquid water content increases, corresponding to larger and less acidic droplets. As derived from large eddy simulations of stratocumulus underthe conditions of MASE, both Lagrangian trajectory analysis and diurnal cloudtop evolution provide evidence that a significant fraction of the aerosol mass concentration above cloud can be accounted for by evaporated droplet residual particles. Methanesulfonate data suggest that entrainment of free tropospheric aerosol can also be a source of organic acids above boundary layer clouds. PMID- 17695911 TI - Temperature dependence of the air concentrations of polychlorinated biphenyls and polybrominated diphenyl ethers in a forest and a clearing. AB - Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) were quantified in 67 high volume air samples taken concurrently in a forest and a clearing in southern Ontario, Canada from October 2001 to November 2002. Air concentrations were comparable between the two sites. Gaseous PCBs ranged from 6.4 to 150 pg x m(-3), and gaseous PBDEs ranged from below method detection limit (BDL) to 55 pg x m(-3) (with two extreme events up to 290 pg x m(-3)). Particulate PBDEs ranged from BDL to 40 pg x m(-3). Gaseous concentrations of PCBs and PBDEs were highly temperature dependent, suggesting a relatively strong influence of re-evaporation. Air concentrations of highly chlorinated PCBs in the forest were more temperature dependent than those in the clearing, whereas no difference was observed for the less-chlorinated PCBs. Forest filtering may have enriched highly chlorinated PCBs in the forest soil relative to the soil in the clearing, resulting in a higher contribution of re-evaporation for highly chlorinated PCBs at the forest. Compared to measurements conducted a decade earlier at a nearby site, PCB air concentrations were generally less temperature dependent, indicative of a reduction in the contribution of re-evaporation in the region. Furthermore, a significant correlation was found between temperature dependence and degree of chlorination, which had not been apparent in the previous study. This is presumably because depuration from soils occurred slower for highly chlorinated PCBs, resulting in their relatively higher abundance in terrestrial surfaces and, therefore, higher contribution from re-evaporation. Contrasting with the PCBs, the temperature dependence of PBDE air concentrations did not differ between congeners or between forest and clearing site. This could be a result of different usage and emission history: PCBs were banned approximately three decades ago, whereas PBDEs are currently still in use. Consequently, the influence of primary emissions on air concentrations is expected to be more important for PBDEs than for PCBs. PMID- 17695912 TI - Carbon and chlorine isotope effects during abiotic reductive dechlorination of polychlorinated ethanes. AB - We investigated the extent and variability of C and Cl isotope fractionation during the reduction of polychlorinated ethanes to evaluate the potential use of Cl isotope analysis for the assessment of contaminant transformation in subsurface environments. Kinetic isotope effects (KIE) for C and Cl for the reductive beta-elimination of 1,1,2,2-tetrachloroethane (1,1,2,2-TeCA), pentachloroethane (PCA), and hexachloroethane by Cr(II) used as model reductant in homogeneous solution were compared to KIEs measured for dehydrochlorination of 1,1,2,2-TeCA and PCA. Since isotopic reactions of polychlorinated compounds are complicated by the simultaneous presence of several Cl isotopologues and intramolecular isotopic competition, we present a procedure for the determination of KIEs for Cl from the initial reactant and final product Cl isotope ratios. Despite different reaction mechanisms, that is reduction via dissociative inner sphere electron transfer by Cr(H2O)6(2+) and base-catalyzed, concerted elimination, respectively, apparent KIEs for C of both pathways fall within a similar range (1.021-1.031). In contrast, KIEs for Cl are significantly higher for reductive beta-elimination (1.013-1.021) than for dehydrochlorination (1.000 1.006). These results suggest that reductive transformations of polychlorinated contaminants might be identified on the basis of combined C and Cl isotope analysis. PMID- 17695913 TI - Selecting scenarios to assess exposure of surface waters to veterinary medicines in Europe. AB - Registering a veterinary medicinal product (VMP) in the European Union requires assessing its potential to contaminate surface waters (SW) on a European scale. VMP are spread to land in manure or excreted during grazing and may enter SW through runoff, erosion, or leaching. Since the factors driving these processes vary largely across Europe, it is necessary to identify characteristic conditions, so-called scenarios, under which VMP enter SW. These scenarios may guide the parameterization of mechanistic fate models to predict environmental concentrations for environmental risk assessment. A number of such scenarios for pesticides and VMP have been developed rather pragmatically. Here, we describe how a geo-referenced European database of driving factors was used to divide the European environment into groups with similar conditions for SW contamination by VMP. Out of these groups, relevant exposure scenarios in Europe were selected by a simple scoring system. Comparing these to the existing scenarios showed that a number of situations are not well covered. The newly identified scenarios are primarily located in hilly areas of Central Europe and the Mediterranean, and in Eastern European plains with a continental climate. We recommend that they are included in the technical guidelines for higher-tier assessment of VMP. PMID- 17695914 TI - Regional air quality: local and interstate impacts of NO(x) and SO2 emissions on ozone and fine particulate matter in the eastern United States. AB - While the U.S. air quality management system is largely designed and managed on a state level, many critical air quality problems are now recognized as regional. In particular, concentrations of two secondary pollutants, ozone and particulate matter, are often above regulated levels and can be dependent on emissions from upwind states. Here, impacts of statewide emissions on concentrations of local and downwind states' ozone and fine particulate matter are simulated for three seasonal periods in the eastern United States using a regional Eulerian photochemical model. Impacts of ground level NO(x) (e.g., mobile and area sources), elevated NO(x) (e.g., power plants and large industrial sources), and SO2 emissions are examined. An average of 77% of each state's ozone and PM(2.5) concentrations that are sensitive to the emissions evaluated here are found to be caused by emissions from other states. Delaware, Maryland, New Jersey, Virginia, Kentucky, and West Virginia are shown to have high concentrations of ozone and PM(2.5) caused by interstate emissions. When weighted by population, New York receives increased interstate contributions to these pollutants and contributions to ozone from local emissions are generally higher. When accounting for emission rates, combined states from the western side of the modeling domain and individual states such as Illinois, Tennessee, Indiana, Kentucky, and Georgia are major contributors to interstate ozone. Ohio, Indiana, Tennessee, Kentucky, and Illinois are the major contributors to interstate PM(2.5). When accounting for an equivalent mass of emissions, Tennessee, Kentucky, West Virginia, Virginia, and Alabama contribute large fractions of these pollutants to other states. PMID- 17695915 TI - Seasonal and regional variations of primary and secondary organic aerosols over the continental United States: semi-empirical estimates and model evaluation. AB - Seasonal and regional variations of primary (OC(pri)) and secondary (OC(sec)) organic carbon aerosols across the continental United States for the year 2001 were examined by a semi-empirical technique using observed OC and elemental carbon (EC) data from 142 routine monitoring sites in mostly rural locations across the country, coupled with the primary OC/EC ratios, obtained from a chemical transport model (i.e., Community Multiscale Air Quality (CMAQ) model). This application yields the first non-mechanistic estimates of the spatial and temporal variations in OC(pri) and OC(sec) over an entire year on a continental scale. There is significant seasonal and regional variability in the relative contributions of OC(pri) and OC(sec) to OC. Over the continental United States, the median OC(sec) concentrations are 0.13, 0.36, 0.63, 0.44, and 0.42 mictrog C m(-3) in winter (DJF), spring (MAM), summer (JJA), fall (SON), and annual, respectively, making 21, 44, 51, 42, and 43% contributions to OC, respectively. OC(pri) exceeds OC(sec) in all seasons except summer. Regional analysis shows that the southeastern region has the highest concentration of OC(pri) (annual median = 1.35 microg C m(-3)), whereas the central region has the highest concentration of OC(sec) (annual median = 0.76 microg C m(-3)). The mechanistic OC(sec) estimates from the CMAQ model were compared against the independently derived semi-empirical OC(sec) estimates. The results indicate that the mechanistic model reproduced the monthly medians of the semi-empirical OC(sec) estimates well over the northeast, southeast, midwest, and central regions in all months except the summer months (June, July, and August), during which the modeled regional monthly medians were consistently lower than the semi-empirical estimates. This indicates that the CMAQ model is missing OC(sec) formation pathways that are important in the summer. PMID- 17695916 TI - Ocean sequestration of carbon dioxide: modeling the deep ocean release of a dense emulsion of liquid Co2-in-water stabilized by pulverized limestone particles. AB - The release into the deep ocean of an emulsion of liquid carbon dioxide-in seawater stabilized by fine particles of pulverized limestone (CaCO3) is modeled. The emulsion is denser than seawater, hence, it will sink deeper from the injection point, increasing the sequestration period. Also, the presence of CaCO3 will partially buffer the carbonic acid that results when the emulsion eventually disintegrates. The distance that the plume sinks depends on the density stratification of the ocean, the amount of the released emulsion, and the entrainment factor. When released into the open ocean, a plume containing the CO2 output of a 1000 MW(el) coal-fired power plant will typically sink hundreds of meters below the injection point. When released from a pipe into a valley on the continental shelf, the plume will sink about twice as far because of the limited entrainment of ambient seawater when the plume flows along the valley. A practical system is described involving a static mixer for the in situ creation of the CO2/seawater/pulverized limestone emulsion. The creation of the emulsion requires significant amounts of pulverized limestone, on the order of 0.5 tons per ton of liquid CO2. That increases the cost of ocean sequestration by about $13/ ton of CO2 sequestered. However, the additional cost may be compensated by the savings in transportation costs to greater depth, and because the release of an emulsion will not acidify the seawater around the release point. PMID- 17695917 TI - Mechanistic relationships among PCDDs/Fs, PCNs, PAHs, CIPhs, and CIBzs in municipal waste incineration. AB - An extensive investigation was conducted to understand polychlorinated dibenzo-p dioxin and furan (PCDD/F) formation mechanisms and their relationship with other organic compounds. PCDD/F, chlorophenols (CIPhs), chlorobenzenes (CIBzs), polyaromatic hydrocarbons (PAHs), and polychlorinated naphthalenes (PCNs) were analyzed in the boiler exit gases of a field-scale municipal solid waste incinerator under various operating conditions. The TEQ value and the concentration of target compounds changed with incinerator operating conditions. Low mass PAHs and 246-triCIPh increased dramatically during shut downs; the latter was associated with increased 1368- and 1379-TeCDD. A strong correlation was observed between PCNs and PCDFs and adjacent PCNs homologue group were closely related to each other. This suggested that PCN formation is related with chlorination/dechlorination mechanisms similar to PCDFs. PCDDs were related with most of the CIPhs and the high chlorinated benzenes. Most of target compounds except PAHs had a positive correlation (R2 > 0.5) with TEQ and half of them showed a good relationship (R2 > 0.8) with PCDDs/Fs toxic equivalency (TEQ). PMID- 17695918 TI - The chronic toxicity of alcohol alkoxylate surfactants on anaerobic granular sludge in the pulp and paper industry. AB - The chronic toxicity of an alcohol alkoxylate surfactant used in the pulp and paper industry was observed in methanogenic consortia under unfed conditions. Methanogenic inhibition was not observed until 250 h of famine conditions while in the presence of the surfactant. The delayed onset of inhibition is likely due to the amount of time necessary for the surfactant to partition into the cellular membrane which uncouples cellular energy conservation mechanisms and exhausts internal energy reserves necessary to maintain homeostasis. PMID- 17695919 TI - Photoassisted degradation of azodyes over FeOxH2x-3/Fe0 in the presence of H2O2 at neutral pH values. AB - Fe0 was calcined in air at 200 degrees C and showed enhanced activity in three cycling runs for the degradation of acid red B (ARB) in the presence of H2O2 under UVA irradiation. Subsequently, the catalyst's activity was maintained effectively after 10 successive cycling experiments. Moreover, the catalyst was found to be highly effective for the degradation of nonbiodegradable azodyes ARB, reactive brilliant red X-3B, reactive red K-2G, cationic red X-GRL, and cationic blue X-GRL at neutral pH values. On the basis of characterization by X-ray diffraction, X-ray photoelectron spectroscopy, and Fourier transform infrared spectra, the surface layer of the catalyst was mainly composed of alpha-FeOOH and gamma-Fe2O3, and the core was Fe0 (FeOxH2x-3/ Fe0). Fe,OxH2x3/Fe0 was very easily recovered from the reaction system by magnetic separation. The degradation of azodyes came from the synergistic effect of the catalysis of galvanic cells and the oxidation of heterogeneous photo-Fenton reaction on the basis of all information obtained under different experimental conditions. By the total organic carbon and GC-MS analysis, the degradation process of ARB was shown to proceed with decolorization and naphthalene ring openings into CO2 and small organic acid. PMID- 17695920 TI - Visible-light-Mediated TiO2 photocatalysis of fluoroquinolone antibacterial agents. AB - This study reports on the photocatalytic transformation of fluoroquinolone antibacterial agents (ciprofloxacin, enrofloxacin, norfloxacin, and flumequine) in aqueous titanium dioxide (TiO2) suspensions irradiated with ultraviolet (UV; lambda > 324 nm) or visible light (lambda > 400, > 420, or > 450 nm). Visible light-mediated fluoroquinolone degradation is unexpected from direct photolysis or established TiO2 band gap photoexcitation mechanisms, which both require UV light. Visible-light-mediated photocatalysis requires an appropriate conduction band electron acceptor (e.g., O2, BrO3-), but is not dependent upon hydroxyl radical, superoxide, or other reactive oxygen species generated upon TiO2 band gap excitation. The process slows considerably when fluoroquinolone adsorption is inhibited. Whereas fluoroquinolone decomposition in UV-irradiated TiO2 suspensions is accompanied by mineralization, no changes in dissolved organic carbon occur during visible-light-photocatalyzed degradation. Results are consistent with a proposed charge-transfer mechanism initiated by photoexcitation of surface-complexed fluoroquinolone molecules. Complexation to the TiO2 surface causes a red shift in the fluoroquinolone absorption spectrum (via ligand-to metal charge transfer), enabling photoexcitation by visible light. Fluoroquinolone oxidation then occurs by electron transfer into the TiO2 conduction band, which delivers the electron to an adsorbed electron acceptor. The lack of organic carbon mineralization indicates formation of stable organic byproducts that are resistant to further degradation by visible light. In UV irradiated TiO2 suspensions, the charge-transfer mechanism acts in parallel with the semiconductor band gap photoexcitation mechanism. PMID- 17695921 TI - Community structure analysis of reverse osmosis membrane biofilms and the significance of Rhizobiales bacteria in biofouling. AB - The biofilm community structure of a biofouled reverse osmosis (RO) membrane was examined using a polyphasic approach, and the dominant phylotypes retrieved were related to the order Rhizobiales, a group of bacteria that is hitherto not implicated in membrane biofouling. A comparison with two other membrane biofilms using T-RFLP fingerprinting also revealed the dominance of Rhizobiales organisms. When pure culture RO biofilm isolates were cultivated aerobically in BIOLOG microplates, most Rhizobiales were metabolically versatile in their choice of carbon substrates. Nitrate reduction was observed in five RO isolates related to Castellaniella, Ochrobactrum, Stenotrophomonas, and Xanthobacter. Many of the key Rhizobiales genera including Bosea, Ochrobactrum, Shinella, and Rhodopseudomonas were detected by PCR to contain the nirK gene responsible for nitrite reductase activity. These findings suggest that Rhizobiales organisms are ecologically significant in membrane biofilm communities under both aerobic and anoxic conditions and may be responsible for biofouling in membrane separation systems. PMID- 17695922 TI - Some critical structure factors of titanium oxide nanotube array in its photocatalytic activity. AB - A highly ordered TiO2 nanotube array on Ti substrate was fabricated by using an electrochemical anodic oxidation method. The morphology, crystalline phase, and photoelectrochemical property of the nanotube array were characterized. The photocatalytic activity of the nanotube array was evaluated by the decolorization of methyl orange in aqueous solution using the different light sources. The effects of structure and morphology of the nanotube array on its photocatalytic activity were investigated. It was found that the photoabsorption behavior of the TiO2 nanotube film depended on the structures of the nanotube array. The nanotube array films exhibited a drastically enhanced photocurrent, and a higher photocatalytic activity compared with the TiO2 nanoparticle film prepared by the regular sol-gel method. The experimental results indicated that the film thickness markedly influenced the photocatalytic activity of nanotube array film, and the 2.5 microm-thick TiO2 nanotube array film appeared a maximum photodegradation efficiency to methyl orange. However, for a given nanotube length, the tube diameter was only very slightly affected the photocatalytic efficiency in this work. The explanation for some critical structure factors of TiO2 nanotube array in the photocatalytic activity was discussed as well. PMID- 17695923 TI - Preparation of biotic and abiotic iron oxide nanoparticles (IOnPs) and their properties and applications in heterogeneous catalytic oxidation. AB - Iron oxide nanoparticles (IOnPs) as solid catalyst were prepared using a biotic method, i.e., biomineralization, and abiotic methods, i.e., thermal decomposition and electrochemical methods, for use as solid catalysts in the heterogeneous catalytic ozonation of para-Chlorobenzoic acid (pCBA). It was determined that characteristics of IOnPs, including particle size, morphology, surface area, electrokinetic mobility, basic group content, and chemical composition were significantly influenced by the preparation methods. TEM and FE-SEM analyses showed that the thermal decomposition method produced monodispersed and regularly spherical particles. The smallest iron oxide was also prepared by the thermal decomposition method, whereas the electrochemical method produced the largest iron oxide in terms of mean particle size. The specific surface area was found to be inversely proportional to the mean particle size. In catalytic ozonation at acidic pH levels, it was clearly observed that IOnPs enhanced the degradation of pCBA by the production of *OH radicals resulting from the catalytic decomposition of ozone. Additionally, functional groups and surface area were found to play an important role in the catalytic activity of IOnPs. To this extend, in a comparison of particle types, IOnPs prepared by the thermal decomposition method (IO(TD)) showed the greatest catalytic activity in terms of R(ct) value representing the ratio of hydroxyl radicals and ozone. This result may be due to the relatively higher surface area and basic group content of IO(TD) than other IOnPs. PMID- 17695924 TI - Cr(VI) removal from aqueous solution by activated carbon coated with quaternized poly(4-vinylpyridine). AB - A composite sorbent (GAC-QPVP) was prepared by coating poly(4-vinylpyridine) onto a granular activated carbon, followed by cross-linking and quaternization processes. The sorbent was characterized by scanning electron microscopy, point of zero charge measurement, and BET analysis. Batch experiments with variable pH, ionic strength, and concentrations of Cr(VI), sorbent, and competing anions were conducted to evaluate the selective sorption of Cr(VI) from aqueous solutions. The results showed that Cr(VI) sorption rates could be described by a reversible second-order kinetics, and equilibrium uptake of Cr(VI) increased with decreasing pH, decreasing ionic strength, and increasing sorbent concentration. The estimated maximum equilibrium uptake of chromium was 53.7 mg/g at pH = 2.25, 30.7 mg/g at pH = 3.65, and 18.9 mg/g at pH = 6.03, much higher than the maximum capacity of PVP-coated silica gel, an adsorbent for Cr examined previously. When compared with the untreated granular activated carbon, sorption onto GAC-QPVP resulted in much less Cr(VI) reduction and subsequent release of Cr(III). The effect of phosphate, sulfate, and nitrate was minor on the selective sorption of Cr(VI). An ion exchange model that was linked with aqueous speciation chemistry described Cr(VI) sorption reasonably well as a function of pH, ionic strength, and Cr(VI) concentration. Model simulations suggested that sorbed Cr(VI) was partially reduced to Cr(III) on the sorbent when pH was less than 4. The presence of Cr(III) on the sorbent was confirmed by the X-ray photoelectron spectroscopic analysis. Overall, the study has demonstrated that GAC-QPVP can effectively remove Cr(VI) from aqueous solutions under a wide range of experimental conditions, without significant Cr(III) release associated with the virgin GAC treatment. PMID- 17695925 TI - Methanol oxidation using ozone on titania-supported vanadia catalyst. AB - Ozone-enhanced catalytic oxidation of methanol has been conducted at mild temperatures of 100-250 degrees C using a V2O5/ TiO2 catalyst prepared by the sol gel method. The catalyst was characterized using XRD, surface area measurements, and temperature-programmed desorption of methanol. The oxidation of methanol with ozone in the absence of a catalyst gave about 30% conversion at 100 degrees C. Methanol oxidation over a V2O5/TiO2 catalyst at 100 degrees C gave very little conversion with oxygen, whereas the conversion increased to 80% with ozone. Methanol, having an inlet stream concentration of 15 000 ppmv, can be completely oxidized to CO(x) with an ozone-to-methanol ratio of 1.2, a temperature of 150 degrees C, and a gas hourly space velocity (GHSV) of 60 000 h(-1). The apparent activation energy with ozone was calculated to be ca. 40 kJ/mol, which is much lower than that calculated with oxygen (60 kJ/mol). At low methanol conversion methyl formate was the main product, whereas higher conversions favored oxidation to CO(x). The results imply a consecutive reaction of adsorbed methanol species, favoring selectivity toward methyl formate at lower temperatures and ozone-to methanol ratios and CO(x) at higher temperatures and ozone-to-methanol ratios. Langmuir-Hinshelwood kinetics was used to model the reaction with and without ozone in the feed. The model parameters were obtained using least-squares fit to a selected set of experimental data, and the model was subsequently compared to all experimental data obtained in this study. PMID- 17695926 TI - Applications of pore-expanded mesoporous silica. 7. Adsorption of volatile organic compounds. AB - Three different varieties of mesoporous silicas were synthesized by varying the postsynthesis treatment of an as-synthesized ordered mesoporous material type MCM 41. The resulting materials consisted of a purely siliceous MCM-41, a pore expanded MCM-41 (PE-MCM-41C), and a surfactant-laden pore-expanded MCM-41 (PE-MCM 41E) and were evaluated as adsorbents for two types of volatile organic compounds, i.e., chlorinated and aromatic hydrocarbons. Values of heat of adsorption and Henry's law constant were determined by pulse chromatography. Additionally, adsorption capacities were calculated with a dynamic method using breakthrough curves for single components in dry and humid environments. The surfactant-containing material exhibited good compatibility with chlorinated compounds in terms of heat of adsorption and efficiency in gaseous streams containing moisture. Purely siliceous mesoporous materials, i.e., MCM-41 and PE MCM-41C, were more selective toward aromatic hydrocarbons but also gave rise to exceptionally strong adsorption. PMID- 17695927 TI - Membrane independent limiting flux for RO and NF membranes fouled by humic acid. AB - The flux decline of reverse osmosis and nanofiltration membranes was investigated under constant pressure conditions during humic acid fouling tests. For a given membrane type under a given feedwater composition, increasing pressure resulted in increased flux reduction and foulant accumulation. A limiting flux seems to exist beyond which the membrane flux cannot be sustained. Membranes with initial fluxes greater than the limiting flux experienced severe fouling and their pseudo stable fluxes approached the limiting flux. Flux reduction was much milder when the initial flux was lower than the limiting flux. Furthermore, the limiting flux seems to be independent of membrane properties, probably due to the dominance of foulant--deposited-foulant interaction upon complete foulant coverage over membrane surfaces. On the other hand, strong dependence of the limiting flux on the feedwater composition was observed. The limiting flux was reduced at higher proton, calcium, and/or background electrolytes concentrations, likely due to reduced electrostatic repulsion under these conditions. PMID- 17695928 TI - PCB bioavailability control in Lumbriculus variegatus through different modes of activated carbon addition to sediments. AB - PCB bioavailability to a freshwater oligochaete (Lumbriculus variegatus) was studied using sediments from a PCB-impacted river that was treated with different modes of granular activated carbon (GAC) addition. For sedimenttreated with 2.6% GAC and mixed for 2 min prior to L. variegatus addition, the reduction in total PCB biouptake was 70% for 75-300 microm size carbon, and 92% for the 45-180 microm size carbon. For the case where the GAC was placed as a thin layer on top of the sediments without mixing, the reduction in total PCB uptake was 70%. PCB biouptake kinetics study using treated and untreated sediment showed that the maximum PCB uptake in tissue was achieved at 28 days and decreased after that time. Although the absolute uptake of PCB changed over time, the percent reduction in total PCB uptake upon GAC amendment remained constant after the first few days. Our results indicated that PCB bioavailability was reduced upon the addition and little or no mixing of GAC into sediments. PCB aqueous equilibrium concentration and desorption rates were greatly reduced after GAC amendment, indicating reductions in the two primary mechanisms of PCB bioavailability in sediments: chemical activity and chemical accessibility. PMID- 17695929 TI - Electricity production from cellulose in a microbial fuel cell using a defined binary culture. AB - Microbial fuel cells (MFCs) convert biodegradable materials into electricity, potentially contributing to an array of renewable energy production strategies tailored for specific applications. Since there are no known microorganisms that can both metabolize cellulose and transfer electrons to solid extracellular substrates, the conversion of cellulosic biomass to electricity requires a syntrophic microbial community that uses an insoluble electron donor (cellulose) and electron acceptor (anode). Electricity was generated from cellulose in an MFC using a defined coculture of the cellulolytic fermenter Clostridium cellulolyticum and the electrochemically active Geobacter sulfurreducens. In fed batch tests using two-chamber MFCs with ferricyanide as the catholyte, the coculture achieved maximum power densities of 143 mW/ m2 (anode area) and 59.2 mW/m2 from 1 g/L carboxymethyl cellulose (CMC) and MN301 cellulose, respectively. Neither pure culture alone produced electricity from these substrates. The coculture increased CMC degradation from 42% to 64% compared to a pure C. cellulolyticum culture. COD removal using CMC and MN301 was 38 and 27%, respectively, with corresponding Coulombic efficiencies of 47 and 39%. Hydrogen, acetate, and ethanol were the main residual metabolites of the binary culture. Cellulose conversion to electricity was also demonstrated using an uncharacterized mixed culture from activated sludge with an aerobic aqueous cathode. PMID- 17695930 TI - Degradation of well cement by CO2 under geologic sequestration conditions. AB - Experiments were conducted to assess the durability of cements in wells penetrating candidate formations for geologic sequestration of CO2. These experiments showed a significant variation in the initial degradation (9 days of exposure) based on the curing conditions. The high-temperature (50 degrees C) and high-pressure (30.3 MPa) curing environment increased the degree of hydration and caused a change in the microstructure and distribution of the Ca(OH)2(s) phase within the cement. Cement cured at 50 degrees C and 30.3 MPa (representing sequestration conditions) proved to be more resistant to carbonic acid attack than cement cured at 22 degrees C and 0.1 MPa. The cement cured at 50 degrees C and 30.3 MPa exhibited a shallower depth of degradation and displayed a well defined carbonated zone as compared to cement cured under ambient conditions. This is likely due to smaller, more evenly distributed Ca(OH)2(s) crystals that provide a uniform and effective barrier to CO2 attack. PMID- 17695931 TI - Assessment of exposure of workers and swimmers to trihalomethanes in an indoor swimming pool. AB - A simultaneous study on workers' and swimmers' exposure to trihalomethanes (THMs) in an indoor swimming pool has been carried out by analyzing urine samples using the headspace and gas chromatography-mass spectrometry technique. The subjects of this study were male and female workers of an indoor swimming pool as well as swimmers regularly attending the pool. The results reported show that only chloroform and bromodichloromethane were detected in the urine of those people exposed, which can be used as a specific index of exposure to these compounds. THM uptake of swimmers after 1 h of swimming was higher than that of workers after a 4 h work shift since THM levels in the workers' urine were associated only with inhalation, while levels in swimmers' urine were mainly associated with dermal absorption, apart from inhalation and occasional ingestion, as well as increased uptake due to the physical stress (swimming). The kinetics of THM excretion in the urine of the participants exposed has been calculated after termination of the exposure to select the sampling time and determine the elimination process. An interval of 15 min after exposure was selected as the sampling time, and the absorbed dosage was eliminated by 2 h after exposure. A good correlation between THM concentrations found in the swimming pool water and the urinary THM concentrations of the people affected after exposure has also been obtained. PMID- 17695932 TI - Production of perfluorinated carboxylic acids (PFCAs) from the biotransformation of polyfluoroalkyl phosphate surfactants (PAPS): exploring routes of human contamination. AB - Perfluorinated acids are detected in human blood world-wide, with increased levels observed in industrialized areas. The origin of this contamination is not well understood. A possible route of exposure, which has received little attention experimentally, is indirect exposure to perfluorinated acids through ingestion of chemicals applied to food contact paper packaging. The current investigation quantified the load of perfluorinated acids to Sprague-Dawley rats upon exposure to polyfluoroalkyl phosphate surfactants (PAPS), nonpolymeric fluorinated surfactants approved for application to food contact paper products. The animals were administered a single dose at 200 mg/kg by oral gavage of 8:2 fluorotelomer alcohol (8:2 FTOH) mono-phosphate (8:2 monoPAPS), or the corresponding di-phosphate (8:2 diPAPS), with blood taken over 15 days post dosing to monitor uptake, biotransformation, and elimination. Upon completion of the time-course study the animals were redosed using an identical dosing procedure, with sacrifice and necropsy 24 h after the second dosing. Increased levels of perfluorooctanoic acid (PFOA), along with both 8:2 PAPS congeners, were observed in the blood of the dosed animals. In the 8:2 monoPAPS-dosed animals, 8:2 monoPAPS and PFOA blood concentrations peaked at 7900 +/- 1200 ng/g and 34 +/ 4 ng/g respectively. In the 8:2 diPAPS-dosed animals, 8:2 diPAPS peaked in concentration at 32 +/- 6 ng/g, and 8:2 monoPAPS and PFOA peaked at 900 +/- 200 ng/g and 3.8 +/- 0.3 ng/g, respectively. Several established polyfluorinated metabolites previously identified in 8:2 FTOH metabolism studies were also observed in the dosed animals. Consistent with other fluorinated contaminants, the tissue distributions showed increased levels of both PFOA and the 8:2 PAPS congeners in the liver relative to the other tissues measured. Previous investigations have found that PAPS can migrate into food from paper packaging. Here we link ingestion of PAPS with in vivo production of perfluorinated acids. PMID- 17695933 TI - Quantitative structure-activity relationship model for prediction of genotoxic potential for quinolone antibacterials. AB - Antibiotics are of concern because of their widespread usage, their potential role in the spread and maintenance of bacterial resistance, and because of the selection pressure on microbes. In this study, the genotoxic potential of 20 quinolone antibacterials, including 5 first-generation, 8 second-generation, and 7 third-generation quinolones, was determined. While all of the antibacterials studied showed genotoxic potential, the molar concentration for each antibacterial that produces 10% (EC10) of the maximum response of corresponding antibacterial ranged from 0.61 to 2917.0 nM, and was greatly dependent on chemical structures. A quantitative structure-activity relationship (QSAR) was established by applying a quantum chemical modeling method to determine the factors required for the genotoxic potential of quinolone antibacterials. The octanol-water coefficient (logP(ow)) adjusted bythe pH and energies of the highest occupied molecular orbital (epsilon(HOMO)) and lowest unoccupied molecular orbital (epsilon(LUMO)) were selected as hydrophobic and electronic chemical descriptors, respectively. The genotoxic potentials of quinolone antibacterials were found to be dependent on their logP(ow) and epsilon(HOMO), while the effects of epsilon(LUMO) on the genotoxic potentials could not be identified. The QSAR model was also used to predict the genotoxic potentials for 14 quinolone antibacterials, including 1 second-generation, 2 third-generation, and 11 fourth-generation quinolone antibacterials. A correlation between the genotoxic potentials and their minimal inhibition concentrations (MIC50) against Streptococcus pneumoniae from the literature for 18 quinolone antibacterials was observed, providing a potential method to estimate MIC50. PMID- 17695934 TI - Assessment of the solubility and bioaccessibility of barium and aluminum in soils affected by mine dust deposition. AB - Barium is a heavy metal to which human and animal receptors may be exposed in various settings--for example, in mineral extraction industries where the mining and milling of ores occurs. Aluminum is also an element abundant in soil and dust to which human and animal receptors may be exposed in association with such industries. This study investigated the solubility and bioaccessibility of barium and aluminum in simulated gastric fluids using an in vitro test method previously validated for lead. Soil samples were collected from the vicinity of a mine and transport road that generated fugitive dust containing barium as barite (BaSO4). It was found that barium bioaccessibility in different tundra soil and fugitive dust source materials varied greatly, between 0.07 and 66.0%, depending on sample location, grain size, solid-to-fluid ratio used in the in vitro experiments, and the analytical method selected for determining total barium concentrations in the sample substrates. For X-ray fluorescence spectrometry (XRF) analytical methods and a solid-to-fluid ratio of 1:100, barium bioaccessibility from the barite-rich mine waste rock and gyro crusher ore dust source materials was very low (0.07 0.36%). By contrast, the bioaccessibility of barium in tundra soil samples affected by fugitive dust deposition ranged from 3.8 to 19.5%. The relative solubility of barium measured in the simulated gastric fluids of this study is consistent with time-dependent dissolution of barite in mine waste rock and ore dust, and the presence of more soluble chemical forms in tundra soil. Laboratory XRF analysis was the only analytical method used in this study that accurately characterized total barium concentrations for all sample substrates. Aluminum bioaccessibility was distinguished from barium bioaccessibility by its generally lower values and smaller dependence on grain size and solid-to-fluid ratios. The range of aluminum bioaccessibility values (0.31-4.0%) is consistent with the predominance of aluminum in relatively insoluble aluminosilicate minerals. PMID- 17695935 TI - Using biodynamic models to reconcile differences between laboratory toxicity tests and field biomonitoring with aquatic insects. AB - Aquatic insects often dominate lotic ecosystems, yet these organisms are under represented in trace metal toxicity databases. Furthermore, toxicity data for aquatic insects do not appear to reflect their actual sensitivities to metals in nature, because the concentrations required to elicit toxicity in the laboratory are considerably higher than those found to impact insect communities in the field. New approaches are therefore needed to better understand how and why insects are differentially susceptible to metal exposures. Biodynamic modeling is a powerful tool for understanding interspecific differences in trace metal bioaccumulation. Because bioaccumulation alone does not necessarily correlate with toxicity, we combined biokinetic parameters associated with dissolved cadmium exposures with studies of the subcellular compartmentalization of accumulated Cd. This combination of physiological traits allowed us to make predictions of susceptibility differences to dissolved Cd in three aquatic insect taxa: Ephemerella excrucians, Rhithrogena morrisoni, and Rhyacophila sp. We compared these predictions with long-term field monitoring data and toxicity tests with closely related taxa: Ephemerella infrequens, Rhithrogena hageni, and Rhyacophila brunea. Kinetic parameters allowed us to estimate steady-state concentrations, the time required to reach steady state, and the concentrations of Cd projected to be in potentially toxic compartments for different species. Species-specific physiological traits identified using biodynamic models provided a means for better understanding why toxicity assays with insects have failed to provide meaningful estimates for metal concentrations that would be expected to be protective in nature. PMID- 17695936 TI - Comment on "Conservation of cancer genes in the marine invertebrate Mytilus edulis". PMID- 17695937 TI - Gold star. Oregon hospital becomes first to earn gilded LEED rating. PMID- 17695938 TI - Vision of the future. Patient portals advance the environment of care. PMID- 17695939 TI - Accommodating the aged. What hospitals can learn from long-term care facilities. PMID- 17695940 TI - Small decisions, big savings. Avoiding omissions and seizing opportunities in hospital project planning. PMID- 17695941 TI - Moving forward. What's in store for the next edition of the FGI/AIA guidelines? PMID- 17695942 TI - Ready for inspection. ES and the environment of care. PMID- 17695943 TI - [Clinical trials published in Revista Espanola de Anestesiologia y Reanimacion: characteristics and quality of design]. AB - OBJECTIVE: To identify and assess the quality of controlled clinical trials published in Revista Espanola de Anestesiologia y Reanimacion during the period 1967-2004. MATERIAL AND METHODS: We identified and classified clinical trials following the criteria adopted by the International Cochrane Collaboration. Each trial was described and its design assessed. RESULTS: We identified 640 controlled clinical trials: 233 (36.4%) were published as original articles, 398 (62.2%) were conference presentations, and 9 (1.4%) were in other publication formats. The most common type of trial design, found in 398 (62.2%) cases, was drug-to-drug comparison. The main outcome was of clinical interest in 464 (72.5%) cases. The system of randomization used was considered adequate in only 37 (5.8%) of the studies. The funding source for 432 (67.5%) trials was not specified. CONCLUSIONS: It is noteworthy that Revista Espanola de Anestesiologia y Reanimacion has published a large number of controlled clinical trials in comparison with other Spanish journals covered by Index Medicus. We observed that important information on how the trials were carried out was missing and that trial quality was low in terms of current standards. The editorial board's adoption of the CONSORT statement may help to improve the quality of trials currently being published, and that question should be analyzed after a reasonable period of time has passed. PMID- 17695944 TI - [Perceived quality of resident training in anesthesiology and postoperative recovery care]. AB - OBJECTIVE: To carry out an opinion survey on the quality of residency training in the specialty of anesthesiology and postoperative recovery care. To propose improvements to be made based on the results. METHOD: All training programs in the specialty of anesthesiology and postoperative recovery care within the Spanish National Public Health System were provided with an opinion questionnaire designed by the national professional association (Sociedad Espaiiola de Anestesia, Reanimacion y Terapeutica del Dolor). The aspects assessed were sense of welcome and integration; curriculum; training sessions; external rotations (outside the anesthesiology department); surgical anesthesia; emergency and on call training; specific practical training objectives; research; other aspects; annual assessment and evaluation of the assigned supervisor and the educational committee; overall opinion of the education received; the structure of the anesthesiology department. RESULTS: Questionnaires were returned between May and November 2005, with a response rate of 30%. Specialized residency training was considered satisfactory overall but there was great interest in measures to improve it. The most highly assessed features were the sense of departmental welcome and integration and the work performed during duty assignments in the specialty. Deficiencies that generated the most dissatisfaction were external rotations, training in certain techniques (chest drainage and management of a bronchoscope), research, complementary training (computer skills, bioethics, and communication skills). CONCLUSIONS: Despite a poor rate of return, the results can help indicate directions to take in making improvements at different levels of the specialty's organization. PMID- 17695945 TI - [Orotracheal intubation training: assessment with the cumulative sum method]. AB - OBJECTIVES: Orotracheal intubation is one of the first techniques a new resident learns. The cumulative sum (cusum) method has been shown to be a useful tool for the assessment of learning, as it provides qualitative and quantitative information that allows technical competence to be certified. The aim of this study was to use the cusum method to assess the learning of orotracheal intubation by a group of first year residents. METHODS: The residents were evaluated at 2 stages. In the first, the acceptable failure rate was set at 10% and in the second it was reduced to 5%. Learning curves were constructed for each resident for both stages. RESULTS: Eight residents were evaluated. They performed 868 intubations, 330 at the first stage and 538 at the second. Forty (4.6%) of the intubations failed: 26 (7.9%) in the first stage and 14 (2.6%) in the second. All residents achieved the acceptable failure rate of 10% in the first 3 months with a mean (SD) number of intubations of 41.3 (6). All achieved the 5% acceptable failure rate within the 11 months of study, after a mean of 67.3 (28) intubations. CONCLUSIONS: The cusum method proved a useful tool for training residents to perform tracheal intubation. It afforded objective information on performance and facilitated evaluation while learning was taking place. PMID- 17695946 TI - [Music versus diazepam to reduce preoperative anxiety: a randomized controlled clinical trial]. AB - OBJECTIVES: To compare the effectiveness of music to that of diazepam in reducing preoperative anxiety. PATIENTS AND METHODS: Patients were randomized to 2 groups to receive diazepam or listen to music on the day of surgery and the previous day. Just before the operation, anxiety was assessed with the State-Trait Anxiety Inventory. Cortisol levels, heart rate, and blood pressure were also recorded. RESULTS: Two hundred seven patients were enrolled. No significant differences in any of the outcome measures (anxiety, cortisol level, heart rate, or blood pressure) were found between the 2 groups (music vs sedative). CONCLUSIONS: Our findings indicate that music is as effective as sedatives for reducing preoperative anxiety. PMID- 17695947 TI - [Abdominal compartment syndrome]. AB - The measurement of intra-abdominal pressure (IAP) is gaining importance in critical care units because of its prognostic value. The standard method of measurement is intravesical. When the IAP is high, the condition is referred to as intra-abdominal hypertension. The elevation may be compensated for if it is not excessive or if the increase was not rapid, or it might have various repercussions, in which case abdominal compartment syndrome (ACS) is diagnosed. The pathogenic mechanism that underlies ACS is the response of a territory predisposed to a process of ischemia and reperfusion, with release of inflammatory cytokines and formation of free radicals (anaerobic metabolism). Clinical manifestations comprise elevated IAP, oliguria, difficult mechanical ventilation with hypoxia and hypercapnia, and diminished cardiac output. ACS leads to multisystem dysfunction and, if not treated, to multiple organ failure and death. The rapid establishment of appropriate treatment measures is important. The first line of treatment is medical but definitive surgical treatment should not be delayed. PMID- 17695948 TI - [Anesthesia in urology: notes on its history and development in Spain, 1847 to 1950]. AB - This review of the historical course of anesthesia performed in the context of urology in Spain relies on primary sources: doctoral theses, dissertations, published articles, inaugural addresses, conference proceedings, and books belonging to various archives and libraries. We collected a large number of documents relating to urology and of particular interest regarding anesthesia, classified them, and subjected them to critical analysis. This allowed us to carefully follow the development of anesthesia and urology itself, both of which attained notable clinical and scientific importance in Spain. Anesthesia with chloroform and incomplete anesthesia were the norm during the second half of the 19th century. However, during the first half of the 20th century, the most widely used techniques were the application of ether or spinal or local infusions, although epidural and intravenous techniques were also mentioned. PMID- 17695950 TI - [Anesthesia in a patient with narcolepsy]. PMID- 17695949 TI - [Delayed perforation of the cecum and sigmoid colon after blunt abdominal trauma in a patient with multiple injuries]. AB - Blunt abdominal trauma can damage the intestinal vasculature and may occasionally lead to delayed intestinal perforation, associated with a combined rate of morbidity and mortality of 25%. The diagnosis of such complications is hindered by sedation in critical patients, however, and morbimortality in this population is therefore higher. We report the case of a man with multiple injuries admitted to the intensive care unit, where delayed perforations of the sigmoid colon and cecum were diagnosed. The management of blunt abdominal trauma is reviewed and the possible causes, diagnostic approaches, and treatment options for colon injuries are discussed. PMID- 17695951 TI - [Cardiac arrhythmia during general anesthesia in a former cocaine user]. PMID- 17695952 TI - [Jet ventilation (Manujet) in fiberoptic bronchoscopy treatment of postoperative atelectasis]. PMID- 17695953 TI - [Relatives' experience during intensive care unit hospitalization]. PMID- 17695954 TI - [Pulsus paradoxus and the pulse oximetry waveform]. PMID- 17695955 TI - Interview with Jack O. Bovender, Jr., FACHE, chairman and chief executive officer, Hospital Corporation of America. Interview by Kyle L. Grazier. PMID- 17695956 TI - Effective management of technology implementation. PMID- 17695957 TI - A systems approach to culturally and linguistically competent care. PMID- 17695958 TI - Retail medicine: the cure for healthcare disparities? AB - Healthcare disparities are a growing concern for the U.S. healthcare system. These disparities are found at all levels of quality, access, and cost and greatly affect those segments of the population that most need affordable, quality, and accessible healthcare. The populations most in need are rural, ethnic, racial, and minority populations, who do not usually receive the highest quality of care. A new healthcare delivery model has recently emerged--retail medical clinics. This article describes current disparities in the healthcare system and presents one possible solution: the use of retail medical clinics. PMID- 17695959 TI - Hospital-physician informed consent: new use for an old doctrine. AB - The relationship between hospitals and physicians has changed dramatically in recent years because of the increasingly competitive healthcare environment. Many healthcare executives have struggled to find a balance between collaborating and competing with the new breed of physicians. A relationship familiar to the healthcare leader may provide a useful framework for effectively addressing physician relations in today's healthcare setting. The physician-patient relationship experienced tensions similar to those facing the hospital-physician relationship, and informed consent arose to establish clear expectations between physicians and patients. Healthcare leaders might consider adopting an informed consent philosophy in their physician relations. Four basic components of informed consent govern the physician-patient context: (1) an assessment of the situation, (2) an explanation of the treatment, (3) an exploration of the alternatives, and (4) a documentation of any agreement. These four components can be adapted to the hospital-physician context to foster productive partnerships in today's healthcare landscape. PMID- 17695960 TI - The "new economics" of clinical quality improvement: the case of community acquired pneumonia. AB - Hospitals and health systems have developed substantial infrastructure, at significant expense, to improve care quality and support the collection and distribution of quality metrics. Yet providers often have little understanding of what return, if any, they have earned on the investment because they typically view quality improvement efforts simply as a cost of doing business. After analyzing data from 10,512 patients with community-acquired pneumonia, we found that better performance on two quality measures was associated with shorter length of stay and improved financial performance. For example, a one-day decrease in the time until patients were shifted from intravenous to oral antibiotics was associated with a 0.8-day reduction in length of stay and a nearly 60 percent increase in margins. Providers can adapt the methods we used to derive these findings to identify other quality metrics that simultaneously increase care quality and generate economic value. To derive maximum clinical and financial benefit, however, providers must ensure that clinical quality staff members are adequately supported and skilled to set priorities and to implement effective initiatives. PMID- 17695961 TI - Mentoring junior healthcare administrators: a description of mentoring practices in 127 U.S. hospitals. AB - A survey instrument about mentoring junior healthcare administrators was mailed to 485 senior-level executives-chief executive officers, hospital administrators, and presidents. Completed surveys were returned by 127 senior executives (26 percent response rate). On average, the respondents were 53 years old, had nine years of organizational tenure in their current position, and had 16.5 years of career tenure as a senior healthcare executive. The mean age of when the respondents first had a mentor was 28 years old. The average length of the respondents' relationship with their mentor was 3.56 years. Although healthcare executives believed mentoring benefits the healthcare industry as a whole, they reported that the benefits were even greater for the hospital where mentoring was done. Personal satisfaction was cited as the primary reason for serving as a mentor. In the 127 organizations represented by the respondents, informal mentoring programs were more prevalent than formal mentoring programs. Our findings suggest that healthcare executives in formal mentoring programs may be more likely to support mentoring than individuals who entered informal mentoring relationships. Those who reported being mentors or engaging in mentoring supportive activities had a longer job tenure and career tenure than did individuals who had not served as mentors. The study suggests that mentoring--in particular, informal mentoring--is a popular activity in U.S. hospitals and is carried out by experienced healthcare executives whose primary motivation is personal satisfaction. PMID- 17695962 TI - Government-sponsored health plan acquisition integration: decisions and dynamics. PMID- 17695963 TI - Rant du jour. PMID- 17695964 TI - Here is where all the MTs have gone. PMID- 17695965 TI - More tributes... PMID- 17695966 TI - Potential and pitfalls of NBS, and the reference lab's role. PMID- 17695967 TI - Pain reduction during infant and pediatric phlebotomy. PMID- 17695968 TI - Rising prevalence of variant HIV-1 subtypes poses new diagnostic challenge. PMID- 17695969 TI - Trend in therapeutic monitoring of immunosuppressive drugs. PMID- 17695970 TI - Advance and contingency preparations meet changed inspection system. PMID- 17695971 TI - A perfect score. PMID- 17695972 TI - POCT for POLs: a POL consultant's view. PMID- 17695973 TI - Hakim's SCC still making history. PMID- 17695974 TI - Be a volunteer in medicine. PMID- 17695978 TI - Expanding your options. Registering with more than one staffing agency. PMID- 17695979 TI - Syphillis. Still a public health danger. PMID- 17695980 TI - Bedside emergency. Respiratory distress. 2. PMID- 17695981 TI - Patient flow: a staff nurse's perspective. PMID- 17695982 TI - Identity theft. PMID- 17695983 TI - On the development, morphology and function of the temporomandibular joint in the light of the orofacial system. AB - The temporomandibular joint has a key role in the biocybernetic functional cycle of the orofacial system. It has developed as a "secondary joint" and displays a number of features relating to the articular tubercle, the mandibular condyle, the articular disc, the joint cartilage and the retroarticular pad. The joint cartilage of the mandibular condyle is a primary compensatory growth centre also comprising distant effects. The coordinate course of the mandibular movements is controlled by a complex reflex mechanism and neuronal controller cycles. Morphology, function and clinical aspects are of equal interest to both physicians and dentists. PMID- 17695984 TI - Factors affecting the variation in the adult temporomandibular joint of archaeological human populations. AB - To elucidate factors that may affect the variation in the bony components of temporomandibular joint (TMJ), a preliminary study was conducted on the temporal articular surface of the TMJ of 30 skulls from Iron Age and medieval populations from Lithuania and a mixed Neolithic and Bronze Age population from the Central Elbe-Saale region (CESR). Using three-dimensional (3D) photos of the skulls, length and width measurements of the TMJ were obtained and compared with external skull measurements. Distinct, random variation between the TMJ values from opposite sides of the cranium were identified as fluctuating asymmetry. ANOVA results suggest significant differences in the length of the TMJ between the population of the CESR and the two Lithuanian populations, but not between the two Lithuanian populations. Environmental factors, including geography, may be responsible for the variation in the TMJ form. PMID- 17695985 TI - Regulatory effects of biophysical strain on rat TMJ discs. AB - Recent studies have revealed that dynamic biomechanical forces can exert antiinflammatory and antiproteolytic effects on fibrocartitage. Whether the effects of mechanical strain also involve stimulation of the insulin-like growth factor (IGF) system and, therefore, of growth and repair of fibrocartilage has yet to be determined. The objective of this in vitro study was to determine if continuous biophysical strain regulates the gene expression of IGF1, IGF2, IGF1 receptor (IGF1R), insulin receptor substrate (IRS1), and IGF-binding proteins (IGFBP) 3 and 5 in cells from the fibrocartilaginous disc of the temporomandibular joint (TMJ). Rat TMJ disc cells were subjected to continuous biophysical strain (3% and 20%) for 4 and 24 h. Subsequently, RNA was extracted and real-time PCR was performed using an iCycler iQ detection system to analyze the gene expression of the IGF system. The gene expression of IGF1, IGF2, IGF1R, IRS1, IGFBP3, and IGFBP5 was significantly (p < 0.05) inhibited when cells were subjected to continuous biophysical strain, as compared to control at both time points. High strain induced a stronger inhibition of these molecules as compared to strain of Low magnitude. In conclusion, continuous biophysical strain seems to downregulate the expression of the IGF system and may, therefore, reduce the potential of fibrocartilage for growth and repair. PMID- 17695986 TI - Biomechanical analysis of stress distribution in the temporomandibular joint. AB - The positions of the head of the mandible, the articular disc and the outline of the temporal surface are digitised from sagittal MRT-scans of the mandibular joint of a 32-year-old subject in five different positions of occlusion. The stress distribution in the joint is calculated on the basis of these data. For each position of the condyle, the momentary point of rotation in the head of the mandible and the tangent attached to the temporal surface are determined. The line connecting these two points indicates the direction of the resulting bearing force. Furthermore, the extension of the area available to the force transmission is estimated. By means of these parameters, the stress distribution is calculated independently of the position. The analyses show that the mandibular joint is slightly eccentrically loaded in all positions. The increase in stress is in all cases oriented caudo-ventrally. The results are verified in an anatomical specimen of the articular tuberculum. The trabecular structures as well as the subchondral bone-lamella of the articular tuberculum are functionally adapted to the analysed stress situations. PMID- 17695987 TI - Morphological structures and protrusive cranial border guidance of the temporomandibular joint of Cercopithecus mona. AB - Morphological parameters of the temporomandibular joint (TMJ) of Cercopithecus mona were analyzed by sagittal medial/lateral slicing of the entire joint. The slice contours of the osseous structures of the joint surfaces were approximated by circles. In this manner, the main parameter of the protrusive cranial border guidance, the protrusive dimeric Link chain (DLC), could be measured. In each joint, all slices yielded protrusive DLCs which were nearly parallel to each other. In medial/lateral direction all parts of the joints participate in force transmission in initial protrusive cranial border function. PMID- 17695988 TI - Aspects of morphology and guidance of the human temporomandibular joint. AB - Examinations of the curvature morphology of the temporomandibular joints (TMJs) in macerated human skulls yielded that in initial protrusive cranial border motion, parts of the condylar articulating surfaces are only functional under force transmission. These areas were found on the lateral-central side of the condyle. In contrast to the Cercopithecus mona, a monkey species, the human TMJ apparently possesses a distinctly higher spatial performance range. PMID- 17695989 TI - Prevalence and clinical signs of degenerative temporomandibular joint changes validated by magnetic resonance imaging in a non-patient group. AB - The aim of this study is to investigate associations between degenerative bony changes of the temporomandibular joint (TMJ) evaluated by magnetic resonance imaging (MRI) and signs and symptoms of temporomandibular disorders (TMD) in a non-patient group. A total of 307 subjects (140 males and 167 females) were selected from the cross-sectional epidemiological study "Study of Health in Pomerania" (SHIP) for this evaluation. A clinical functional examination of the masticatory muscles and the TMJs was performed as well as an MRI examination of the TMJs. Another 77 subjects (25%) exhibited degenerative changes of one or both TMJs in the MRI. Clinical analysis revealed pain on palpation of the masticatory muscles in 113 subjects. Some 39 subjects had pain during palpation of the TMJs. There were significant associations between the MRI confirmed diagnosis of osteoarthrosis and some clinical signs (joint noises, joint palpation pain, reduced mouth opening) and symptoms (reported pain in the jaw and masticatory muscles) of TMD as well as further MRI diagnoses (disc displacement with and without reduction, fibrosis of the posterior ligament). Although there were some associations, clinical examination alone is not sufficient for diagnosing degenerative joint diseases. MRI is a necessary diagnostic adjunct for estimating the prevalence of TMD subgroups in non-patient populations. PMID- 17695990 TI - Distribution of insulin-like growth factors in condylar hyperplasia. AB - Condylar hyperplasia (CH) is a local overgrowth of the condylar process of the temporomandibular joint (TMJ) of unknown etiology. Probably, growth factors like the insulin-like growth factors (IGFs) are involved in its pathogenesis. Specimens from 12 patients were investigated histologically and immunohistochemically to obtain the distribution of the IGFs-I and -II and the IGF1 receptor. The results revealed juvenile and adult subtypes. While generally IGF-II could only be detected weakly, in the juvenile cases strong immunostaining for IGF-I in cartilage and bone supposes an influence on pathological growth processes. PMID- 17695991 TI - Bone welding--a histological evaluation in the jaw. AB - The expansion of biodegradable osteosynthesis systems in clinical application correlates well to the progress in development of new materials as to the improvement of application methods. One of those new application methods is the ultrasound-aided insertion of Resorb-X pins. The aim of this study was the histological evaluation of possible thermal damage to bone due to the ultrasound insertion. For this purpose, condylar neck fractures in 12 sheep were produced, repositioned and fixed by Resorb-X plates and pins. The animals were sacrificed in two groups, one after 2 weeks and one after 9 weeks. The bone-pin interlinkage and the structure of the bone were histologically evaluated. After 2 weeks a tight bone-polymer interlinkage was seen. Neither a pronounced foreign body reaction nor an interposition of fibrous tissue at the interface or a thermally induced necrosis was observed. The late phase of wound healing after 9 weeks showed pathomorphological characteristics within the normal range of bone healing. The bone seemed to be free of any alteration caused by process engineering. We conclude that thermal stress caused by ultrasound-aided pin insertion does not lead to cellular reaction in the bone. The fast and easy application of this improved biodegradable osteosynthesis system will bring a clear advantage in clinical use. PMID- 17695992 TI - Correlation of MRT imaging with real-time axiography of TMJ clicks. AB - There is a series of tools useful for gathering diagnostic information on patients with temporomandibular joint disorders. Tracings of the joint movement (axiography) provide useful information about the motion of the joints. Since the availability of electronic axiographic tracers, the movement of the condyles can be resolved with high resolution both in space and in time. In order to obtain information about the anatomical relation of the joint surfaces and the disc, magnetic resonance tomography imaging (MRI) is routinely carried out. It is common practice to take MR images of the joints with the mouth closed and fully open. In order to correlate the MR images with the axiographic tracings, a series of images can provide much more information. In this study we examined patients with distinct temporomandibular joint (TMJ) clicks. In one case, the click occurs once a day, while in the other case the click happens every time the mouth is opened. In order to obtain information about both motion and anatomical relation of the TMJ at and around the position where the clicks occur, we recorded a series of MRI scans with the mouth gradually opened and before and after joint clicks. Real-time axiographic tracings during the click were taken with an optimized system where the polar moments were reduced as much as possible to follow the movement during the click. These tracings were correlated with the MRI scans to determine the exact internal conditions of the TMJ and the changes during the click. In particular cases, the additional information provided by this procedure can be useful in deciding whether and which therapeutic intervention is advisable. PMID- 17695993 TI - A michigan-type occlusal splint with spring-loaded mandibular protrusion functionality for treatment of anterior disk dislocation with reduction. AB - For treatment of temporomandibular disorders Michigan-type splints are frequently used, as are mandibular advancement appliances for patients diagnosed with anterior disk dislocation. As both types show good results, the combination of these two mechanisms into one bimaxillary appliance was tested on eight patients where splint therapy had brought reduction but not complete elimination of the symptoms. An existing maxillary Michigan splint was modified so that advancement springs could be fitted and the generated forces were transmitted to a mandibular retainer, which did not interfere with the function of the splint. Treatment progress was monitored with computerized axiography and in all cases the axiographic tracings after the bimaxillary treatment showed no pattern indicative of disk dislocation under normal jaw movements. Myofascial pain symptoms, already improved by the pre-treatment with the Michigan splint, were found to be reduced further or eliminated completely. The approach of retrofitting a Michigan splint with the springs allowed for a versatile appliance, which required no occlusal alteration to the finely adapted splint but could as easily be brought back to the simple splint-functionality either for daytime use or for a period of stabilization of the result after successful treatment. Compliance was found to be very good and the short treatment period, together with the small force levels did not produce any detectable dental side effects. PMID- 17695994 TI - Metric analysis of the upper space of the temporomandibular joint (TMJ) in pigs (Sus scrofa domestica) for evaluation of the pig as a model for arthroscopic TMJ surgery. AB - Minimally invasive arthroscopic surgery of the temporomandibular joint (TMJ) is more technically demanding than procedures in Larger joints. The acquisition of adequate arthroscopic skills for TMJ surgery requires extensive specialized training that can hardly be obtained from patients. In order to introduce a proper animal model for TMJ arthroscopy, this study focuses on the morphology of the upper joint cavity of pigs at different ages. Plastic casts of the upper joint cavity were obtained from a mixed-sex sample of eight unfixed juvenile pig heads. The morphometric evaluation of these plastic casts revealed that the TMJ of pigs with a body weight of about 30 kg resemble the situation of the human TMJ best, and thus may serve as a model for arthroscopic exercises and examinations of the TMJ. PMID- 17695995 TI - Functional magnetic resonance imaging of brain activity during chewing and occlusion by natural teeth and occlusal splints. AB - Brain imaging based on functional magnetic resonance (fMRI) is a useful tool for examination of neuronal networks and cerebral structures subserving visiospatial function. The purpose of this study was to compare the brain activity during chewing and occlusal function in centric occlusion on natural teeth or on occlusal splints. Four tasks were performed by 13 healthy, fully dentate subjects (21-32 years old, 6 female and 7 male): occlusal tap-tap movements in centric occlusion by natural teeth, after application of a maxillary occlusal splint and chewing movements on left and right sided rubberdam strips. In order to reveal which areas of the brain were more strongly activated, conjunction analyses between the different tasks were performed for each subject and for the average values of brain signal activity of all subjects. Whilst several known foci of activity were subtracted, differences of significant activity rested in areas of the sensorimotor cortex. Mainly ipsitaterality of hemispheres concerned the left and right sided chewing, whereas the conjunction between tap-tap movements on natural teeth and splint occlusion indicated only one weak, but significant activation foci. The study confirms fMRT as one of the most useful developing methods to clear up neuro-cortical effectiveness of occlusion and occlusal therapy. PMID- 17695996 TI - Study on treatment of condylar process fractures of the mandible. AB - Treatment of mandibular condylar process fractures may be conservative or surgical. Both treatment approaches aim to reconstruct the articulating joint surfaces in a physiological position to the discoligamentary structures. The study comprised 1812 patients of Wuerzburg University who presented with a fracture of the mandibular condylar process between 1981 and 2001. Besides conservative management options, surgical interventions using mini-plate osteosynthesis and the Wuerzburg lag screw plate were studied for post-treatment changes. Statistical analysis revealed that surgical osteosynthesis is superior to merely conservative therapy in terms of post-treatment dysgnathic severity. Hence, surgical osteosynthesis is advocated especially in patients with high condylar fractures or dislocated fractures in order to ideally achieve 'restitutio ad integrum'. PMID- 17695997 TI - The mandibularly fixed hinge axis--investigation of patients with sound and pathological jaws. AB - In former works, we had proved that test persons with sound temporomandibular joints (TMJs) used a mandibularly fixed hinge axis (MFHA) and were able to pilot the mandible by solely two kinematical degrees of freedom. We wondered if we could evaluate the MFHA the same way for patients who had problems with their TMJs. Actually, the MFHA could be determined likewise. The results could provide information on the reason for the distortion of the movement of the TMJs, which cannot be yielded by X-ray radiographs. PMID- 17695998 TI - The movement structure of the mandible and alignment of the neck. AB - The motion patterns of mandibular points were recorded in vivo in closed free movements of the mandible in the sagittal-vertical plane. The points ran along closed loops, which were evaluated by their area and length. All points whose loops showed areas of the same size regarding the sense of circulation formed straight lines. When the absolute area of the loops was taken into account, a valley with two minima was found in the function "absolute area versus position of the point", the point which showed the deepest minimum tallied with the position of the neuromuscular mandibular rotation axis. The points with loop lengths of same size formed elliptical lines, the perimeter of which was minimal for a point below the condyle. Morphological relations: the row of teeth in the upper jaw was found to be located below the line of minimal path lengths on the straight lines with constant areas, and the cervical spine was found to be arranged along the valley of the minimal absolute areas where the path lengths have their maximum. PMID- 17695999 TI - Dimeric link chain and instantaneous centers of rotation of the mandible. AB - The primary aim of the study was to reveal whether the free opening movement of the mandible can be determined by only 2 rotational axes as suggested in recent literature. For this purpose, the free opening movement of the mandible was registered in 20 asymptomatic patients using an ultrasonic measuring system. Subsequently, the locations of the instantaneous centers of rotation (ICR) were determined directly from the raw data. In a second approach, the same data were used to construct a mandibular and maxillar rotational axis according to the dimeric link chain (DLC) concept. On the basis of the angular velocities around these 2 axes, the positions of the ICR were calculated in the sagittal-vertical plane. Calculating the ICR by the DLC method provides similar results to that of the conventional approaches. It can be concluded that the DLC method is a valid approach and that considering the planar mandibular movement as a movement with 2 degrees of freedom is justified. PMID- 17696000 TI - Functional state of the mandible and rolling-gliding characteristics in the TMJ. AB - For the physiological intact stomatognathic system, the three main functional states (occlusat articular functions, free mandibular movements, and ideal bolus function) were biomechanically discussed concerning the structure of movement, rolling-gliding characteristics, and force transfer in the temporomandibular joint (TMJ). In all three cases, rolling is not possible in the TMJ since the instantaneous rotational axis is positioned outside of the joint-rolling is not necessary because the TMJ is not loaded by appreciable forces. In the aged stomatognathic system with a lost discus and considerable Loads in the TMJ, however, the attrition of the joint is eased by rolling movement at the articulating surfaces. The destruction of the discus can be seen as a physiological adaptation which brings back the joint to an original odontogen condition. PMID- 17696001 TI - Effects of centric relation prematurities of the frontal teeth. AB - Centric relation prematurities of frontal teeth are frequently found with patients who have severe orthodontic anomalies or received extensive restorative treatment. They can cause a range of symptoms ranging from loosening of the teeth to temporomandibular disorders (TMD). The objective of this work has been to derive a mathematical description of the mandibular and periodontal forces generated by anterior prematurities for different incisor relations. In order to quantify the effect of contact area (location and inclination) and the tooth inclination, a two-dimensional mathematical approach was used. Vectorisation of the forces and bending moments makes it possible to predict under which conditions the load increase mainly affecting the anterior teeth can and may cause localized pain and eventually loosening and flaring/crowding of the upper/lower incisors and under which conditions the temporomandibular joint will suffer a large increase in retrusive force, which potentially leads to TMD. For 10 patients with anterior prematurities, analysis of the incisor relation was carried out. For all cases the conclusions drawn from the mathematical model were in full agreement with the reported symptoms, which could be successfully treated. PMID- 17696002 TI - Biomechanical aspects of mandibular growth. AB - The subject of this study was to analyse how functional parameters of stomatognathic systems are influenced by growth. For this purpose, two cephalometric radiographs of 65 patients with class-II-relation treated with functional appliances were superimposed on the occlusal plane. The two patient groups consisted of 32 open bite and 33 deep bite cases. The direction of the condylar growth significantly differed for both cases. Nevertheless the hypothesis could be confirmed that the original functional structure was hardly affected by growth. PMID- 17696003 TI - Occlusal contact patterns--population-based data. AB - The reconstruction of functionally appropriate contacts between antagonistic teeth substantially determines the quality of prosthetic-restorative work. In a population-based sample comprising 2597 subjects, static occlusal contacts were registered and analysed using the GEDAS (Greifswald Digital Analyzing System), which digitally represents the contact point situation by means of silicone bite impressions. The number of contacting teeth is approximately equal on the Left- and right-hand side amounting to 8.3 on the left and 8.4 on the right. Furthermore, it was shown that 39% of the maxillary bridge pontics and 33% of the mandibular bridge units are not in contact. Antagonistic contacts are missing in 41% of the maxillary and 39% of the mandibular removable denture teeth. These results show that the fabrication of fixed dentures, particularly in bridge pontics, and the inspection of removable dentures needs to be done with more care to this detail. PMID- 17696004 TI - Plate osteosynthesis of the mandibular condyle. AB - The aim of this study is to evaluate and compare the biomechanical stability of various osteosynthesis materials for mandible condylar-process fractures. On 160 porcine mandibles, four different monocortical plating techniques (40 per group) were investigated. Condyles were fractured at a defined location from the incisure to the posterior border. After correct anatomical reduction the fractures were plated, using four different techniques. Osteosynthesis materials used were the delta plate, the trapezoid plate, the dynamic compression plate and double mini-plates. Each group was subjected to linear loading in lateral to medial, medial to lateral, anterior to posterior and posterior to anterior directions by a universal mechanical testing machine TIRAtest 2720. Yield load, yield displacement were measured for the different plates. Statistically significant differences were noted between the fixation groups in all four directions. Rigid internal fixation with double mini plates showed the best stability in all directions except posterior to anterior. In this direction, the delta-plate resisted the highest loads. In the three other directions, the delta plate was second best with data similar to double miniplates but lower in magnitude. PMID- 17696005 TI - Remarks on the morphology of the human temporomandibular joint in the fetal period. AB - Skeletons of human fetuses of different ages allow the study of the considerable transformations of the mandibular joint and the mandible in this relative short stage of life. The condyle is anchored in the mandible by a conical process. The tip of this cone extends to the anLage of the 2nd milk molar. The conical process can be recognized macroscopically up to newborn age. It can also be identified by modern imaging methods. The cone can be well distinguished from the surrounding bone of the mandible. The mandibular joints of fetuses in the 31st, the 32nd, the 39th week and of a newborn were dissected, removed, and histologically investigated. The conical process of the condyle was clearly observed. The cartilage on the condyle is characterised by a layered structure which is typical for a center of growth. In the cartilage of young fetuses, blood vessels were found, reaching from the trabecular bone to the articular space. At this stage of life, blood vessels are also present in the central part of the discus articularis. PMID- 17696006 TI - Simultaneous preconcentration of copper, nickel, cobalt and lead ions prior to their flame atomic absorption spectrometric determination. AB - A sensitive and simple method for the simultaneous preconcentration of nutritionally important minerals in real samples has been reported. The method is based on the adsorption of Cu2+, Ni2+, Co2+ and Pb2+ on 4-propyl-2-thiouracil (PUT) loaded on activated carbon. The metals on the complexes are eluted using 5 mL 3 M HNO3 in acetone. The influences of the analytical parameters including pH and sample volume were investigated. The effects of matrix ions on the retentions of the analytes were also examined. The recoveries of analytes were generally higher than 95%. The detection limits for Cu2+, Ni2+, Co2+ and Pb2+ were 1.6, 1.3, 1.2, 2.3 ng ml(-1), respectively. The method has been successfully applied for these metals content evaluation in some real samples including natural water samples. PMID- 17696007 TI - Synthesis, characterization and structure effects on extractability and selectivity of N,N'-bis(salicylaldehydene)-1,4-bis-(m-aminophenoxy)butane towards some divalent cations. AB - The extraction of copper(II), nickel(II) and cobalt(II) from the aqueous phase with N,N'-bis(salicylaldehydene)-1,4-bis-(m-aminophenoxy)butane (MAS), which was synthesized from 1,4-bis(m-aminophenoxy)butane and salicylaldehyde, was studied. Microanalytical data, elemental analysis, UV-visible 1H and 13C n.m.r. spectra and IR-spectra were used to confirm the structures. The extractability and selectivity of divalent cations were evaluated as a function of relationship between distribution ratio of the metal and pH or ligand concentration. Cu+2 showed the highest extractability and selectivity at pH 6.0, whereas Ni+2 and Co+2 showed at pH 9.2. The stoichiometries of the compounds formed were estimated to be CuL, CoL, NiL, where L is N,N'-bis(salicylaldehydene)-1,4-bis-(m aminophenoxy)butane. It was concluded that MAS can effectively be used in solvent extraction of copper(II), nickel(II) and cobalt(II) from the aqeous phase to the organic phase. PMID- 17696008 TI - Efficient high-performance liquid chromatography with liquid-liquid partition cleanup method for the determination of pymetrozine in tobacco. AB - For the first time, a novel, simple and reliable method for analysis of pymetrozine residues in flue-cured tobacco leaves has been developed utilizing HPLC-UV with liquid-liquid partition cleanup. Pre-treatment with ultrasonic extraction and liquid-liquid partition procedures gave preferable baseline separation and clean chromatograms by removing water-soluble and fat-soluble components which interfere with pymetrozine in the test. The performance of the method was evaluated and validated: the detection limit (LOD) was 0.005 microg x mL(-1), the relative standard deviation (RSD) was 1.2% (n = 5), and the overall recovery was above 90% at fortification levels of 0.200, 0.500, 1.000, and 5.000 mg x kg(-1). The proposed method was successfully employed for the determination of pymetrozine residues in twelve flue-cured tobacco samples collected from different regions of China. PMID- 17696009 TI - Spectrophotometric simultaneous determination of manganese(II) and iron(II) in pharmaceutical by orthogonal signal correction-partial least squares. AB - The simultaneous determination of manganese(II) and iron(II) mixtures by using spectrophotometric methods is a difficult problem in analytical chemistry, due to spectral interferences. By multivariate calibration methods, such as partial least squares (PLS), it is possible to obtain a model adjusted to the concentration values of the mixtures used in the calibration range. Orthogonal signal correction (OSC) is a preprocessing technique used to remove the information unrelated to the target variables based on constrained principal component analysis. OSC is a suitable preprocessing method for partial least squares calibration of mixtures without loss of prediction capacity using spectrophotometric method. In this study, the calibration model is based on absorption spectra in the 450-600 nm range for 21 different mixtures of manganese(II) and iron(II). Calibration matrices were containing 0.05-1.2 and 0.1 2.3 microg mL(-1) Mn(II) and Fe(II), respectively. The RMSEP for manganese(II) and iron(II) with OSC and without OSC were 0.0316, 0.0291, and 0.0907, 0.115, respectively. This procedure allows the simultaneous determination of manganese(II) and iron(II) in synthetic and real matrix samples with good reliability of the determination. PMID- 17696010 TI - Layer-by-layer assembly of silicotungstate multilayer films modified on glassy carbon electrode and their electrochemical behaviors. AB - A new electrode was modified by multilayer films composed of heteropolyanion (SiW12) and cationic polymer poly(diallyldimethylammonium chloride) through electrochemical growth. The modified electrode electrochemical behavior, the effect of solution pH and electrocatalytic response to the reduction of BrO3- and NO2- have been investigated. The result shows that the electrochemical process of multilayer films modified electrode including SiW12 is a reversible process by electrochemical step. One-electron process has no proton participation in the first step, and one-electron process is accompanied by one proton participation in the second step and two-electron process is accompanied by two protons participation in the third step. The films grow uniformly, and the peak currents increase with increasing layer numbers. The peak currents increase with scan rate, and the reduced potentials of multilayer films shift negatively with increasing pH. The electrochemical mechanism of multilayer films was suggested. PMID- 17696011 TI - Dynamic ultrasound-assisted extraction of catechins and caffeine in some tea samples. AB - A novel dynamic ultrasound-assisted extraction (DUAE) device has been constructed for extraction of five catechins and caffeine in solid sample. The accurate, simple, reproducible and sensitive method for the determination of five catechins and caffeine has been developed and validated. A comparison has been made of the efficiencies by employing DUAE and conventionally static ultrasound-assisted extraction (UAE). The proposed method can not only improve extraction efficiency but also decrease time and solvent consumption. The commercial Chinese tea samples, involving green and black teas, are rapidly analyzed by the proposed DUAE method. The linearity, range, selectivity, precision, accuracy, and robustness also showed acceptable values. PMID- 17696013 TI - Pahs and trace elements in PM(2.5) at the Venice Lagoon. AB - The results of an experimental analysis carried out to investigate PM(2.5) concentration levels and the content of polycyclic aromatic hydrocarbons, as well as inorganic trace elements in the atmospheric particles are presented. Measurements were taken with a micrometeorological station equipped with an optical PM(2.5) detector, and simultaneously, particles were collected on filters for subsequent chemical analyses. The average value of daily PM(2.5) concentration is 21.5 ug/m3 and real-time measurements indicate that the average concentration during the day (8 am to 8 pm) is about 25% lower than the nocturnal average. Short-time averages of PM2.5 decrease when the wind speed increases as consequence of the more efficient mixing. Meteorological measurements indicate the presence of a local daily (breeze) circulation with wind blowing from the Alps or the Adriatic Sea and, during this circulation, larger concentrations were observed, with wind coming from the Alps. Days of high PM(2.5) concentration with dominant anthropic or with prevalent crustal contributions were identified. Regarding trace metals, their average concentrations are comparable to those found in others urban areas, except for Cd (3 ng m(-3)), probably due to the presence of glass-works in Murano. The highest concentrations are observed for K (99 ng m(-3)) and Na (73 ng m(-3)), which are the main constituents of marine spray, while the lowest concentrations are observed for elements such as Cs and Co (respectively 0.01 and 0.02 ng m(-3)). Also the concentrations of PAH are comparable with those of other industrial areas, as their sum ranges from 0.16 ng m(-3) to 3.73 ng m(-3), but if considered as B(a)P toxicity equivalent, they are largely lower (0.036 +/- 0.026 ng m(-3)). From the analyses of discriminating ratios, it has been found that the main origin of PAH in PM(2.5) samples may be petrogenic, probably related to the presence of refinery and petrochemical plants on the mainland, although the contribution of combustion processes cannot be excluded. PMID- 17696014 TI - GC/MS analysis of pesticides in the Ferrara area (Italy) surface water: a chemometric study. AB - The development of a network to monitor surface waters is a critical element in the assessment, restoration and protection of water quality. In this study, concentrations of 42 pesticides--determined by GC-MS on samples from 11 points along the Ferrara area rivers--have been analyzed by chemometric tools. The data were collected over a three-year period (2002-2004). Principal component analysis of the detected pesticides was carried out in order to define the best spatial locations for the sampling points. The results obtained have been interpreted in view of agricultural land use. Time series data regarding pesticide contents in surface waters has been analyzed using the Autocorrelation function. This chemometric tool allows for seasonal trends and makes it possible to optimize sampling frequency in order to detect the effective maximum pesticide content. PMID- 17696012 TI - Preparation of aminylferrocene/nanogold modified glassy carbon electrode and its electrocatalysis on dopamine. AB - Aminylferrocene(FcAI)-Nanogold(NG) modified glassy carbon electrode (FcAI/NG/GCE) was prepared by the Au-N bond between Au and FcAI. Electrochemical impedance spectroscopy (EIS) was employed to study the surface of the modified electrode. The electrochemical behavior of dopamine (DA) on the modified electrode was investigated and it was found that the modified electrode had an obvious electrocatalytic effect on DA. Compared with a bare GCE, the modified electrode exhibited an apparent shift of the oxidation peak potential in the negative potential direction and a marked enhancement in the current response for DA. We investigated the determination of DA on the modified electrode by differential pulse voltammetry (DPV). Linear calibration curve was obtained in the range of 7.0 x 10(-7) mol/L to 6x10(-4) mol/L of DA in 0.1 mol/L phosphate buffer solution (pH = 7.0) with a correlation coefficient of 0.9989. The detection limit (S/N = 3) of DA was estimated to be 1.0 x 10(-7) mol/L. Especially, by using the modified electrode, we can separate the oxidation peaks of ascorbic acid (AA) and DA in the PBS and it was satisfactory for the determination of DA with the interference of AA. PMID- 17696015 TI - Platinum(II), palladium(II), rhodium(III) and lead(II) voltammetric determination in sites differently influenced by vehicle traffic. AB - The present work reports analytical results relevant to voltammetric determination of Pt(II), Pd(II), Rh(III) [Platinum Group Metals (PGMs)] and Pb(II) in superficial water sampled in sites differently influenced by vehicle traffic, especially considering their temporal behaviour. For all the elements, in addition to detection limits, precision, expressed as relative standard deviation (s(r) %) and accuracy, expressed as percentage recovery (R %) are also reported. In all cases they show to be good, being the former lower than 6% and the latter in the range 94-105%. A critical comparison with spectroscopic measurements is also discussed. PMID- 17696016 TI - Heavy metal removal from aqueous solution by Pseudevernia furfuracea (L.) Zopf. AB - The present study was carried out in a batch system using a lichen (Pseudevernia furfuracea (L.) Zopf) for the sorption of nickel(II) and copper(II) ions from water. Particularly, the effect of pH, contact time and temperature were considered. Pseudevernia furfuracea exhibited nickel(II) and copper(II) uptake of 49.87 and 60.83 mg/g at an initial pH of 4 and 5-6 at 35 degrees C respectively. Both the Freundlich and Langmuir adsorption models were suitable for describing the biosorption of nickel(II) and copper(II) by the biosorbent. Biosorption showed pseudo first order rate kinetics for nickel and copper ions. Using the equilibrium constant values obtained at 25 and 35 degrees C, the thermodynamics properties of the biosorption (deltaG degrees, deltaH degrees and deltaS degrees) were determined. The biosorption of nickel(II) and copper(II) onto Pseudevernia furfuracea was found to be endothermic. PMID- 17696018 TI - Mental illness and the workplace: a national concern. PMID- 17696017 TI - Covalent modification of glassy carbon electrode with aspartic acid for simultaneous determination of hydroquinone and catechol. AB - Glassy carbon electrode (GCE) is covalently modified with aspartic acid (Asp). The modified electrode is used for the simultaneous electrochemical determination of hydroquinone (HQ) and catechol (CC) and shows an excellent electrocatalytical effect on the oxidation of HQ and CC by cyclic voltammetry (CV) in 0.1 mol/L acetate buffer solution (pH 4.5). In differential pulse voltammetric (DPV) measurements, the modified electrode could separate the oxidation peak potentials of HQ and CC present in binary mixtures by about 101 mV though the bare electrode gave a single broad response. A successful elimination of the fouling effect by the oxidized product of HQ on the response of CC has been achieved at the modified electrode. The determination limit of HQ in the presence of 0.1 mmol/L CC was 9.0 x 10(-7) mol/L and the determination limit of CC in the presence of 0.1 mmol/L HQ was 5.0 x 10(-7) mol/L. The proposed method has been applied to the simultaneous determination of HQ and CC in a water sample with simplicity and high selectivity. PMID- 17696019 TI - Interventions to improve employment outcomes for workers who experience mental illness. AB - OBJECTIVE: To review employment interventions for individuals who experience mental illness. METHOD: I reviewed employment interventions described in the mental health, disability, and rehabilitation literature for the period 1990 to 2005 and organized these interventions into a framework. RESULTS: The framework develops 7 distinct individual-level employment interventions as well as interventions directed at the employer and at workplace organization. It also considers factors that will affect access to these interventions. Although there is a sense of optimism about the potential of these interventions, research in the area is limited. CONCLUSION: Physicians who are knowledgeable about the nature and scope of employment interventions for individuals with mental illness are in a good position to effect positive change in the work lives of the individuals they serve. PMID- 17696020 TI - An international perspective on worker mental health problems: who bears the burden and how are costs addressed? AB - OBJECTIVE: To discuss the burden of poor mental health in workers, who currently bears it, and how the associated rising costs are being addressed, from an international perspective. METHOD: We identify the stakeholder groups and the costs they incur as a result of problems related to mental health in 6 different domains. In addition, we offer examples of programs, services, and strategies being used to either decrease costs or enhance benefits. RESULTS: Mental illness is associated with a wide range of costs distributed across multiple stakeholders including government, employers, workers and their families, and the health care system. The costs incurred by the groups are interrelated; an attempt to decrease the burden for one group of stakeholders will inevitably affect other stakeholders. Thus the answer to the question of who bears the costs of poor mental health is "everyone." CONCLUSIONS: Everyone could benefit from investment in improved mental health in the workplace. However, because the benefits associated with improved worker mental health are often distributed among several stakeholders, the incentives for any single stakeholder to pay for additional services for workers may be diluted. As a consequence, no one invests. Nevertheless, there is a role for all stakeholders, just as there are potential benefits for all. Along with government, employers, employees, and the health care system must invest in promoting good workplace health. PMID- 17696021 TI - Longitudinal diagnostic efficiency of DSM-IV criteria for borderline personality disorder: a 2-year prospective study. AB - OBJECTIVE: To examine the longitudinal diagnostic efficiency of the DSM-IV criteria for borderline personality disorder (BPD). METHODS: At baseline, we used semistructured diagnostic interviews to determine criteria and diagnoses; blinded assessments were performed 24 months later with 550 participants. Diagnostic efficiency indices (specifically, conditional probabilities, total predictive power, and kappa) were calculated for each criterion determined at baseline, with the independent BPD diagnosis at follow-up used as the standard. RESULTS: Longitudinal diagnostic efficiencies for the BPD criteria varied, with the criteria of suicidality or self-injury and unstable relationships demonstrating the most predictive utility. CONCLUSIONS: BPD criteria differ in their predictive utility for the diagnosis of BPD when considered longitudinally. These findings have implications both for clinicians who are considering diagnoses and for researchers concerned with forthcoming revisions of our nosological system. PMID- 17696022 TI - Survey of atypical antipsychotic prescribing by Canadian child psychiatrists and developmental pediatricians for patients aged under 18 years. AB - OBJECTIVE: To describe self-reported patterns of prescribing atypical antipsychotics (ATAs) and monitoring practices of child psychiatrists and developmental pediatricians in Canada. METHOD: We surveyed members of the Canadian Academy of Child and Adolescent Psychiatry and members of the Developmental Paediatrics Section of the Canadian Paediatric Society regarding the types and frequencies of ATAs they prescribed, the ages and diagnoses of patients for whom they prescribed these medications, and the types and frequencies of monitoring used. RESULTS: Ninety-four percent of the child psychiatrists (95% CI, 90% to 97%) and 89% of the developmental pediatricians (95% CI, 75% to 96%) prescribed ATAs, most commonly risperidone (69%). Diagnoses included psychotic, mood, anxiety, externalizing, and pervasive developmental disorders. Prescribing for symptoms such as aggression, low frustration tolerance, and affect dysregulation was also common. Twelve percent of all prescriptions were for children under age 9 years. Most clinicians monitored patients, but there were wide variations in the type and frequency of tests performed. CONCLUSIONS: Despite the lack of formal indications, ATAs were prescribed by this group of clinicians for many off-label indications in youth under age 18 years, including very young children. Neither evidence-based guidelines nor a consensus on monitoring exist for this age group. PMID- 17696023 TI - A consecutive series of treated affected offspring of parents with bipolar disorder: is response associated with the clinical profile? AB - OBJECTIVE: In adults with established bipolar disorder (BD), differential response to mood stabilizers has been associated with the clinical profile. Long term treatment studies of youth with BD are lacking. This paper provides longitudinal observations of response to mood stabilizers early in the course of illness in youth with BD. METHOD: We report on 15 research patients who, as adolescents, met DSM-IV lifetime criteria for a bipolar spectrum disorder and required long-term treatment. These youths derived from families with one parent having BD whose course and long-term treatment response were determined in accordance with research criteria. The patients were offered lithium, and if they failed to respond or refused it, they were treated with either an anticonvulsant or an atypical antipsychotic. Using a validated scale, an independent rater retrospectively blindly scored the response to long-term treatment. RESULTS: Those patients who stabilized on lithium derived from lithium-responsive families, whereas those who stabilized on an antipsychotic derived from lithium nonresponsive families. The clinical course in the youths stabilized by lithium differed from that in the youths stabilized by an atypical antipsychotic. CONCLUSIONS: Our findings suggest that the clinical profile may help in selecting effective stabilizing treatment and that a proportion of youth can be stabilized on monotherapy. This is a small case series with nonrandom treatment assignment, and the findings should be considered tentative. PMID- 17696024 TI - Clozapine-induced hypersalivation: a review of treatment strategies. AB - OBJECTIVE: Clozapine-induced hypersalivation (CIH) is a significant side effect affecting about one-third of patients treated with clozapine. CIH can be stigmatizing, can affect quality of life, and can result in discontinuation of clozapine treatment. The purpose of this review is to provide an understanding of CIH, specifically, its pathophysiology, measurement, and the evidence for CIH treatment alternatives. METHODS: We searched MEDLINE from 1980 to June 2006 for all reported pharmacologic treatment studies related to CIH. We identified additional references by a manual search of the bibliographies of retrieved articles. RESULTS: Several studies reported improvement of CIH with both selective and nonselective anticholinergic medications. However, with the exception of local anticholinergic agents such as ipratropium bromide and atropine eye drops, potential systemic adverse effects limit the effectiveness of this class of medications. Open-label studies of clonidine, an alpha2 antagonist, suggest that it may be beneficial in managing CIH. Other pharmacologic treatments, such as amisulpride and botulinum toxin, may be useful in refractory CIH cases. CONCLUSION: Although few randomized controlled trials were found in the literature, this review highlights potential treatment alternatives for this common and disabling cause of hypersalivation. Prompt and effective treatment of CIH may assist with treatment tolerability, adherence, and outcomes in patients with treatment-refractory schizophrenia. Information on funding and support and author affiliations appears at the end of the article. PMID- 17696025 TI - A shortcut to rejection: how not to write the results section of a paper. AB - This article discusses common errors in writing up the results of papers. It covers the following: (1) giving details about irrelevant topics, such as what program was used to enter the data, while ignoring important ones (for example, which options were chosen for various statistical tests); (2) reporting P levels of 0.0000 and negative values for t tests; (3) giving the P levels but not the actual values of the statistical tests; (4) not including confidence intervals and measures of the magnitude of an effect; (5) testing irrelevant hypotheses, such as whether reliability or validity coefficients are significantly different from zero; (6) attributing reliability and validity to tests rather than to the circumstances under which they are given; and (7) reporting levels of accuracy that cannot be supported by the data. Suggestions are made regarding the proper way to report findings. PMID- 17696026 TI - Starson v. Swayze: the Supreme Court speaks out (not all that clearly) on the question of "capacity". AB - OBJECTIVES: The decision in Starson v. Swayze interpreting the "understanding" requirement for capacity in the Ontario Health Care Consent Act (HCCA) provoked concern and criticism from psychiatric quarters. This article seeks to explain the decision and its implications for Ontario and other provinces. METHOD: The majority and minority opinions in the Starson case, and 4 cases decided in Ontario since Starson, were closely analyzed. The literature on capacity was examined. The decision's constitutional implications were considered. RESULTS: Patients need not be able to understand that their condition constitutes an illness to be found capable of consenting to or refusing treatment. The focus should be on their ability to understand that they are affected by the condition's manifestations. A patient's "best interests" are not relevant to the capacity determination. The majority opinion departed from the traditional role accorded to a patient's denial of illness in determining capacity. Contrary to the views of some commentators, the Court's discussion of the actual benefits and risks of the treatments prescribed for Starson had no bearing on the capacity issue. Three of the post-Starson cases examined complied with the Court's holding; one did not. The majority's distinction regarding what patients must be able to understand about their condition is likely not a "principle of fundamental justice" under the Canadian Charter of Rights and Freedoms (the Charter). The right of the capable patient to refuse treatment and the irrelevance of the patient's best interests likely do constitute such principles. CONCLUSIONS: Patients in Ontario cannot be found incapable because they deny they are ill. Ability to recognize the manifestations of their condition suffices. This distinction is probably only binding in Ontario. The capable patient's right to refuse treatment and the irrelevance of the patient's best interests likely are binding throughout Canada. PMID- 17696027 TI - Psychiatric advance directives and the right to refuse treatment in Canada. AB - OBJECTIVE: To provide a Canadian perspective on psychiatric advance directives (PADs) and assess whether these documents can be implemented as an adjunct to mental health services to empower people with mental illness. METHOD: We reviewed Canadian jurisprudence over the past 15 years related to people with mental illness and the right to refuse medical treatment. Provincial mental health legislation is explained to discern PADs' possible effect in Canada. RESULTS: Evidence is accumulating that legal and mental health professionals see PADs as useful documents to promote patient autonomy. Canadian jurisprudence, mental health legislation, and psychological research suggest that PADs could be implemented by legal and mental health professionals. Mental health legislation has the power to prohibit or facilitate choices regarding the right to refuse medical treatment. CONCLUSIONS: This review suggests the need for greater empirical research to be conducted in Canada to determine stakeholders' perceptions of whether PADs could successfully be implemented and their interaction with legislation. PMID- 17696028 TI - Re: How spiritual values and worship attendance relate to psychiatric disorders in the Canadian population. PMID- 17696029 TI - A better tomorrow begins today. PMID- 17696030 TI - A modern day David meets Goliath. PMID- 17696032 TI - The transmission of masticatory forces and nasal septum: structural comparison of the human skull and Gothic cathedral. AB - This study extrapolates the transmission of masticatory forces to the cranium based on the architectural principles of Gothic cathedrals. The most significant finding of the study, obtained by analysis of coronal CT scans, is the role of the hard palate, and especially the vomer and the perpendicular plate of the ethmoid in masticatory force transmission. The study also confirms, experimentally, the paths of masticatory forces, cited in literature but based purely on morphological observations. Human skulls and Gothic cathedrals have similar morphological and functional characteristics. The load exerted by the roof of the cathedral is transmitted to the ground by piers and buttresses. These structures also resist the shearing forces exerted by high winds. Similarly, the mid-facial bones of the skull transmit the vertical as well as the lateral masticatory forces from the maxillary dentition to the skull base. The nonload bearing walls and stained glass windows of the cathedral correspond to the translucent wall of the maxilla. The passageway between the aisle and the nave of the cathedral is equivalent to the meatal openings in the lateral wall of the nasal cavity. PMID- 17696031 TI - Macroscopic anatomy of the sphenomandibular ligament related to the inferior alveolar nerve block. AB - We performed macroscopic observations of the sphenomandibular ligaments, and measured the space that is surrounded by the mandibular ramus and the ligament by using computed tomography. The materials used in this study were 40 heads of 40 adult cadavers. The cadaver head was cut on the mid sagittal plane. The medial pterygoid muscles of the cadavers were removed to observe the ligaments. The attaching style of the sphenomandibular ligament to the mandibular ramus was classified into three types: Type I (5 in 40 samples; attached only to the mandibular lingula), Type II (12 in 40 samples; attached to the mandibular lingula and extended toward the rear part of the internal surface of the mandibular ramus), and Type III (23 in 40 samples; attached to the mandibular lingula and toward the posterior border of the mandibular ramus). There was no statistical difference in the length of the ligament among the three types. However, Type III showed the largest width, and the space was approximately eight and three times as large as those of Type I and II, respectively. This indicated that the Type III ligament covered a larger area over the mandibular foramen than Type I. These results suggest that the three-dimensional morphology of the sphenomandibular ligament, as represented by Type III, may affect the effectiveness of anesthesia. PMID- 17696033 TI - Comorbidity of pterygoid hamular area pain and TMD. AB - Often craniofacial pain subjects report a number of conflicting and overlapping symptoms that can present a confusing clinical picture. Reaching a diagnosis on these individuals can prove to be a frustrating and difficult event for both the examiner and the patient. Thus, it is incumbent on clinicians treating patients with pain in the head, face and neck areas to be familiar with the less common pain disorders to assist in the differential review. This retrospective study examines the comorbidity of pterygoid hamulus pain with temporomandibular disorders (TMD). To acquire this information, the charts of 464 subjects with TMD in a private setting were examined to determine if pterygoid hamular pain was found at the evaluation. Ninety-two patients (N=92) had positive findings. Areas of referred pain that were elicited during the examination were charted. The pterygoid hamular area should be evaluated in individuals with TMD and especially those presenting with posterior palate and throat pain. PMID- 17696034 TI - Effects of anterior cruciate ligament (ACL) injury on muscle activity of head, neck and trunk muscles: a cross-sectional evaluation. AB - This study evaluated the that effects a pathology of the knee, due to an anterior cruciate ligament (ACL) injury, has on muscular activity of neck, head, and trunk muscles. Twenty-five (25) subjects (mean age 28+/-9 years) with ACL injury of the left knee were compared with a control no-pathology group. Surface electromyography (sEMG) at mandibular rest position and maximal voluntary clenching (MVC) wasused to evaluate muscular activity of the areas: masseter, anterior temporalis, posterior cervicals, sternocleidomastoid (SCM), and upper and lower trapezius. The sEMG activity of each muscle, as well as the asymmetry index between the right and the left sides, were compared between the two groups. Subjects in the study group showed a significant increase in the asymmetry index of the sEMG activity of the anterior temporalis at mandibular rest position (p<0.05). At rest, the areas of anterior temporalis and masseter in the control group showed a significantly lower sEMG activity compared with subjects in the study group, both in the right and the left sides (p<0.05). The same was found for the sEMG activity of the areas of SCM and lower trapezius. At MVC, the right areas of anterior temporalis and masseter in the study subjects showed a significantly lower sEMG activity compared with the control group. The same was observed for the lower trapezius area, both in the right and the left sides. In general, ACL injury appears to provide a change in the sEMG activity of head, neck and trunk muscles. PMID- 17696035 TI - Low intensity laser application in temporomandibular disorders: a phase I double blind study. AB - The purpose of this study was to evaluate the effectiveness of low intensity laser therapy (LILT) for the control of pain from temporomandibular disorder (TMD) in a random and double-blind research design. Forty-eight (48) patients presenting temporomandibular joint (TMJ) pain were divided into an experimental group (GI) and a placebo group (GII). The sample was submitted to the treatment with infrared laser (780 nm, 70 mW, 10 s, 89.7 J/cm2) applied in continuous mode on the affected temporomandibular region, at one point: inside the external auditive duct toward the retrodiskal region, twice a week, for four weeks. For the control group, two identical probes (one active and one that does not emit radiation) were used unknown by the clinician and the subjects. A tip planned for laser acupuncture was used and connected to the active point of the probe. The parameter evaluated was the intensity of pain after palpation of the condylar lateral pole, pre-auricular region and external auditive duct, according to the Visual Analogue Scale (VAS). Four evaluations were performed: Ev1 (before laser application), Ev2 (after 4th application), Ev3 (after 8th application) and Ev4 (30 days after the last application). Data were submitted to statistical analysis. The results showed a decrease in the pain level mainly for the active probe. Among the evaluations, the Ev3 exhibited lower sensitivity to palpation. In conclusion, the results show that low intensity laser is an effective therapy for the pain control of subjects with TMD. PMID- 17696036 TI - Muscular activity disorders in relation to intentional occlusal interferences. AB - The electromyographic activity (EMG) of the anterior temporal (AT), masseter (M), trapezius (T) muscles and anterior aspect of the digastric (D) was measured in 50 subjects, during six seconds of maximum contraction, bilaterally with and without unilateral premature contacts and individually for each tooth. Special occlusal interferences were designed to assess muscular activity. Muscular activity was measured simultaneously by placing premature contacts on each tooth, under T-Scan monitoring. Premature contacts reduced EMG activity during maximum contraction of the AT, D and M muscles, the highest disruption is in the AT muscle, at the level of upper right 2nd molar, with a 56% reduction in activity. Conversely, there was an increase of activity of the T muscle in all teeth when placing artificial occlusal premature contacts, with the highest difference in the upper right 1st bicuspid. Therefore, occlusal interferences can cause neuromuscular disruptions, thus inducing important muscular discrepancy. Both the EMG and T-Scan monitoring can be considered suitable methods to use in daily dental practice to identify premature contacts and to measure EMG activity. PMID- 17696037 TI - Determination of range of mandibular movements in children without temporomandibular disorders. AB - Mandibular movement values are an important parameter within the clinical evaluation of the temporomandibular joint. Limited or increased movement is a sign of dysfunction. Normal values used as reference correspond to adult populations, and information on child populations is scant. The aim of this study was to establish reference measurements of children with primary (Group A) and mixed dentition (Group B) without signs of temporomandibular disorders. The study population comprised 212 boys and girls, aged 3 to 11 years, attending a state school in the San Martin district in the province of Buenos Aires, who presented no joint sounds, clicking or pain. A calibrated operator determined maximal opening, protrusion, and lateral movements. Group A (n=105): mean age 4.61+/-0.9; maximal opening 38.59 mm +/- 4.03; protrusion 3.71 mm+/-1.79; right lateral movement 5.43 mm+/-1.83 and left lateral movement 5.52 mm +/- 1.73. Group B (n= 107): mean age 6.9+/-1.65; maximal opening 41.97 mm +/- 5.27; protrusion 3.96 mm+/-1.92; right lateral movement 6.05 mm+/-1.99 and left lateral movement 6.13 mm+/-2.21. Opening and lateral movements were found to increase with age. Comparison between groups using Welch t Test showed significant differences in maximal opening (p<0.0001), right (p= 0.0191) and left (p=0.0262) lateral movement. CONCLUSIONS: Mandibular movements are associated with growth. Mandibular movements of pediatric patients must be assessed in relation to age and type of dentition. PMID- 17696038 TI - The orthodontic treatment of TMD patients: EMG effects of a functional appliance. AB - The aim of this work was to test the effects of the Function Generator Bite (FGB) on the masticatory muscles of temporomandibular joint dysfunction (TMD) subjects. Two groups were selected for the study. A group of 20 TMD patients (group F) requiring orthodontic treatment and treated with FGB and a group of 10 healthy subjects (group H) were considered. Both groups were evaluated before the therapy began (TO) and then after 18 months of therapy (T1). An electromyographic analysis of the masseter and temporalis anterior muscles and a clinical evaluation according to the Research Diagnostic Criteria for TMD (RDC/TMD) were performed. A statistical difference between the two groups was observed at TO with respect to the activity index. TMD subjects showed a lower value of the index. Further studies are necessary to fully understand the utility of this EMG index as a diagnostic indicator. PMID- 17696039 TI - Nervus intermedius neuralgia: a case report. AB - Nervus intermedius neuralgia (NIN) is an uncommon disorder that affects a sensory branch of the facial nerve. This condition usually provokes a very intense and stabbing pain localized in the depth of the ear canal. Due to the close anatomical proximity, temporomandibular joint (TMJ) pathologies should be included in the differential diagnosis. The treatment of NIN has not been established, although it seems reasonable that the therapeutic approaches used in other more common craniofacial neuralgias, such as trigeminal neuralgia, should be effective. In this paper, the authors present a case report of a female patient diagnosed with NIN who was successfully managed with pharmacological treatment. PMID- 17696040 TI - Objective discrimination between mandibular open/close excursion patterns: a clinical case report. AB - The purpose of this clinical case report was to describe the kinematic variables of movement that best discriminated between asymmetrical and symmetrical mandibular excursion patterns in a patient with myogenic temporomandibular dysfunction. Two mandibular movements (deemed to be asymmetrical and symmetrical by both patient and physiotherapist) were each recorded six times on three occasions at six, twelve, and 15 weeks after commencement of an exercise programme. The mandibular movements were captured with a 12-camera Motion Analysis System (Motion Analysis Corp., Santa Rosa, CA) with kinematic variables expressed in six degrees-of-freedom. A two-way analysis of variance (ANOVA) for repeated measures was used to analyze the data. The asymmetrical pattern was characterized by increased axial rotation and decreased sagittal rotation but with no differences in translation values when compared to those of the symmetrical pattern. The results support the clinician's and patient's judgment regarding differences in quality of mandibular excursion patterns made over the course of time. PMID- 17696041 TI - Current issues in pediatric lupus nephritis: role of revised histopathological classification. AB - Childhood-onset systemic lupus erythematosus (SLE) has an unpredictable natural history with variable clinical manifestations. The prognosis of SLE is linked closely to renal involvement with lupus nephritis (LN), which is more severe in patients with childhood-onset compared with adult-onset disease. The histopathological classification of LN facilitates treatment decisions, protocols, and clinical research. After the World Health Organization and modified WHO classifications of LN from 1974 to 1995, the International Society of Nephrology and Renal Pathology Society Working Group revised the histopathological classification of LN. The reclassification was published in 2004 after their consensus conference held at Columbia University in New York in May 2002. The aims of the reclassification were to standardize definitions, emphasize clinically relevant lesions, and encourage uniform and reproducible reporting among centers. Although the revised classification is time-consuming, it is important for future international collaboration on multicenter trials of disease-modifying agents. The prognosis of SLE and LN is linked to the histopathology of the renal lesion, but the clinical manifestations of LN, including nephrotic syndrome and hypertension, cannot predict the degree of renal involvement. However, we are many years away from completely understanding the etiopathogenesis of LN and the predictive role of the revised histological classification for direction of patient management. PMID- 17696042 TI - Prevention of meningococcal disease. AB - Neisseria meningitidis is the most common cause of meningitis in children aged 2 18 with a mortality rate ranging from 4-40% and substantial morbidity in 11-19% of survivors. Of the four serogroups ofNeisseria meningitidis, serogroups B and C are the most common causes in the United States, with serogroup C causing most disease among adolescents, a population at risk for invasive meningococcal disease. The meningococcal polysaccharide vaccine was developed in response to increasing rates of bacterial meningitis among military recruits. With widespread use of the vaccine in the military, there was a dramatic decreased incidence in invasive meningococcal disease. However, there may be limitations to the polysaccharide vaccine including lack of durable protection, lack of induction of T-cell-dependent immune response, and lack of immunogenicity in children less than 2 years of age. Based on the success of other conjugate vaccines in pediatrics, a new conjugate polysaccharide vaccine, Menactra, has been approved by the Food and Drug Administration and recommended for routine vaccination in adolescents by the Advisory Committee on Immunization Practices. PMID- 17696043 TI - Prevalence of viral and mycobacterial co-infections in perinatally HIV-infected children. AB - The progression of HIV disease may be affected by co-infection with other viruses. This study investigates the prevalence of Epstein-Barr virus (EBV); cytomegalovirus (CMV); herpes simplex virus (HSV) types 1 and 2; hepatitis A, B, and C (HA, HB, HC); and tuberculosis in perinatally HIV-infected children. Electrochemiluminescence Immunoassay (EIA) against EBV, CMV, HSV 1 and 2, HAV HBV HCV, and skin testing with purified protein derivative was performed on 45 perinatally HIV-infected children. CMVwas positive in 51%, EBVin 93.3%, HSV-1 in 62.2%, HSV-2 in 48.9%, HAV in 15.6%, HBVand HCV in 6.7% and PPD in 0%. HSV-2 prevalence was higher in females and Hispanics. The prevalence of CMV, EBV HSV-1, and tuberculosis was equivalent to rates reported in the general population. Prevalence of HSV-2 was significantly higher than in the general population (p < 0.001). Higher rates of HSV-2 infection and hepatitis may be secondary to high maternal co-infection rate and subsequent vertical transmission. PMID- 17696044 TI - Pathology teach and tell disseminated candidiasis in an infant with acute myeloid leukemia without prior chemotherapy. AB - Opportunistic fungal infections are significant problems for neutropenic patients who are undergoing cytotoxic therapy for acute leukemia. Systemic and hepatosplenic candidiasis have been reported in acute leukemic patients who are on chemotherapy. Gastrointestinal tract involvement is a rare phenomenon in disseminated candidiasis, especially in acute leukemia. We report one such rare case of acute myeloid leukemia in an infant who died of disseminated candidiasis with gastrointestinal tract involvement prior to the institution of chemotherapy. PMID- 17696045 TI - Pituitary adenomas in childhood: development and diagnosis. AB - Pituitary adenomas account for approximately 2.7% of all supratentorial tumors in the pediatric age range, and children are more likely than adults to develop a functioning adenoma. X chromosome inactivation studies indicate that pituitary adenomas arise from the clonal expression of a single mutated cell, and various intracellular mechanisms contribute to tumoral transformation. Functional pituitary tumors in childhood result in physical and biochemical effects of excess production of the oversecreted hormone, such as ACTH, prolactin, human growth hormone, TSH, LH, or FSH. In the clinical approach to pituitary adenomas, it is important to establish the presence of hormonal excess prior to undertaking imaging studies. PMID- 17696047 TI - Effects of a brief educational program on knowledge and willingness to accept treatment among patients with hepatitis C at inner-city hospitals. AB - Hepatitis C is the most common cause of chronic liver disease in the United States. The prevalence of HCV infection is higher in African Americans and Hispanics than among non-Hispanic whites. African Americans not only have a high prevalence of HCV but they also show lower response rates to treatment with pegylated interferon and Ribavirin. Studies have shown that HCV patients often have low levels of knowledge about the disease, including knowledge about modes of transmission and available treatment options. This study was based in two inner-city hospitals in Brooklyn, New York, Kings County Medical Center and The University Hospital of Brooklyn. The goal of this study was to evaluate the change in knowledge of patients with HCV and their willingness to accept treatment after a single session of on-site education which was delivered as part of a clinic visit. Our patients were from minority ethnic groups, with the majority being African Americans. There was a substantially low knowledge among patients with HCV about the etiologic agent being a virus amongst the twenty five patients who completed the study. After the educational intervention there was an increase in knowledge about risk factors for transmitting HCV, such as unprotected sexual intercourse (100% vs. 88% at baseline), tattooing and body piercing (88% vs. 64% at baseline), and sharing personal items like razors. Knowledge of the risk of developing liver cancer in patients with HCV also increased substantially (96% vs. 77% at baseline). There was a marked increase in the expressed willingness to accept treatment (88% vs. 41% baseline). The results of the educational intervention were very encouraging. These results have implication in setting up a structured educational intervention in liver clinics for HCV patients. PMID- 17696048 TI - Providing contraceptive care to low-income, African American teens: the experience of urban community health centers. AB - Recently, attention has been drawn to the quality of the patient-provider relationship as a mediator of health outcomes for racial and ethnic minorities. The purpose of this study was to examine the provider-patient relationship in reproductive health care for low income African American teens and to identify effective techniques they use in caring for teens. We conducted focus groups with providers at two clinics serving six low-income neighborhoods on the Southside of Chicago. Sessions were audio-taped then transcribed verbatim. ATLAS/ti 5.0 (a qualitative data analysis software program), was used for coding, text retrieval, data management and analysis of data. Providers in community clinics use a number of tactics when working with teens. First, they forge strong relationships through the use of language, shared background experiences, honesty and spending extra time with teens. Second, clinic employees work collectively to care for the patients with all staff members, both professional and clerical, contributing to the provider-patient relationship. Third, providers seek opportunities for contraceptive counseling even attempting to reach males outside of clinic. Techniques used by providers in neighborhood clinics may provide important insights for providing reproductive health care to low income, African American teens. PMID- 17696050 TI - Environmental and economic evaluation of the Massachusetts Smoke-Free Workplace Law. AB - An environmental and economic evaluation of the smoke-free law in Massachusetts provides a broad appreciation of how a state-wide smoking ban affects the health of patrons and workers as well as the industries that are commonly concerned about the effects of smoking bans on business. The aim of this study is to evaluate environmental and economic effects of the statewide Massachusetts statewide Smoke-Free Workplace Law. Before and after the smoking ban, air quality testing was conducted in a sample (n = 27) of hospitality venues and state-wide economic changes were assessed. Compliance, in terms of patronage was measured by person-counts. Environmental outcomes were respirable suspended particles (RSP) less than 2.5 microns in diameter (PM2.5). Economic outcomes were meals tax collections, employment in the food services and drinking places and accommodations industries. On average, levels of respirable suspended particles (RSPs) less than 2.5 microns in diameter (PM2.5) decreased 93% in these venues after the Massachusetts Smoke-free Workplace Law went into effect. No statistically significant changes were observed among the economic indicators. This evaluation demonstrates that the state-wide Massachusetts law has effectively improved indoor air quality in a sample of Massachusetts venues and has not negatively affected several economic indicators. PMID- 17696049 TI - Assessment of the nutrition and physical activity education needs of low-income, rural mothers: can technology play a role? AB - The purpose of this study was to examine the perceptions of low-income, rural mothers regarding their need for nutrition and physical activity education and the role of technology in addressing those needs. Quantitative and qualitative research was combined to examine the nature and scope of the issues faced by this target population. Women who were currently receiving food stamps and had children in nursery school to eighth grade were recruited through a state database to participate in a telephone survey (N = 146) and focus groups (N = 56). Low-income, rural mothers were aware of and practiced many health behaviors related to nutrition and physical activity, but they faced additional barriers due to their income level, rural place of residence, and having children. They reported controlling the fat content in the food they cooked and integrating fruits and vegetables but showed less interest in increasing fiber consumption. They reported knowing little about physical activity recommendations, and their reported activity patterns were likely inflated because of seeing housework and child care as exercise. To stretch their food budget, the majority reported practicing typical shopping and budgeting skills, and many reported skills particularly useful in rural areas: hunting, fishing, and canning. Over two thirds of the survey respondents reported computer access and previous Internet use, and most of those not yet online intended to use the Internet in the future. Those working in rural communities need to consider technology as a way to reach traditionally underserved populations like low-income mothers. PMID- 17696052 TI - Passion: the power of family medicine. PMID- 17696051 TI - Local health department responses during the 2004-2005 influenza vaccine shortage. AB - During the 2004-2005 influenza vaccine shortage, the Centers for Disease Control and Prevention (CDC) coordinated distribution of post-October 5th 2004 doses of influenza vaccine to state and local health departments (LHDs), who subsequently distributed vaccine to community providers. The National Association of County and City Health Officials (NACCHO) conducted three Web-based surveys throughout the 2004-2005 influenza season to assess in real-time how LHDs were 1) dealing with the vaccine shortage, 2) implementing the interim recommendations from the Advisory Committee on Immunization Practices (ACIP), and 3) making efforts to reallocate and redistribute doses of influenza vaccine toward high-priority populations within their communities. This paper highlights LHD responses that alleviated adverse impacts during this public health emergency. The first survey asked LHDs to quantify their community's vaccine supply; the second survey asked them to describe their specific responses to the crisis; and the third survey asked them to reflect and evaluate the effectiveness of their efforts to vaccinate high-priority groups during the crisis. Six hundred five (605) of 717 (84%) LHDs in 44 states responded to the three surveys. Results show that LHDs leveraged preparedness plans, formed strategic community partnerships, and practiced vaccination drills to address the problems of vaccinating high-priority and hard-to-reach populations that arose out of the vaccine shortage. The practices used by LHDs during this shortage may provide valuable response lessons to minimize the impact of future influenza vaccine shortages and other public health emergencies. PMID- 17696053 TI - More on high-low agreements. PMID- 17696054 TI - Managing your panel size. PMID- 17696055 TI - Are you ready to discuss complementary and alternative medicine? PMID- 17696056 TI - Billing for Medicare Part D vaccines. PMID- 17696057 TI - Improving care with an automated patient history. PMID- 17696058 TI - The art of apology: when and how to seek forgiveness. PMID- 17696059 TI - Making the most of the daily commute. PMID- 17696060 TI - Cracked and broken teeth--definitions, differential diagnosis and treatment. AB - Cracked and broken teeth present a diagnostic dilemma to the dentist and the sooner a correct diagnosis is made the greater are the chances to save the tooth. As the location, direction and size of the crack or fracture dictates the choice of treatment, it is important to first define the types of cracks and fractures in the coronal and radicular tooth structure. Cracks and fractures can be classified as follows: 1. craze lines 2. fractured cusps 3. cracked teeth 4. split teeth 5. vertical root fractures. The vertical root fracture has been described recently in two articles in this publication, and therefore will not be discussed here. Diagnosis of a cracked tooth is not always initially obvious. The patient's response to clinical testing is the primary diagnostic tool along with the dental history provided by the patient. Radiographs are secondary in making a diagnosis. Clinical aids for reproducing the patient's symptoms such as occlusal bite devices, observing occlusal wear facets and the application of cold water to one tooth at a time may isolate the offending tooth. In situations where an irreversible pulpitis is diagnosed, endodontic treatment is indicated. In the case of a questionable diagnosis, or one in which a potential reversible pulpitis is made, a provisional restoration can be placed for an unspecified time as a diagnostic aid. If endodontic therapy were indicated, consultation with the patient as to the compromised prognosis and the alternatives to endodontic treatment is essential. PMID- 17696061 TI - ["Flare-up" during endodontic treatment--etiology and management]. AB - "Flare-ups" during or following endodontic treatment are not uncommon. A "Flare up" refers to post-operative pain and/or swelling resulting from bacterial, mechanical or chemical irritation. Prompt diagnosis and treatment are essential for reducing patients' pain and discomfort. Prevention of bacterial, chemical or mechanical invasion to the periapical tissues is the best approach. Other treatment modalities which reduce the probability of periradicular tissue irritation should also be adopted. Etiology, prevention, diagnosis and treatment options of "flare-up" cases are discussed as well as indications for analgesics, in accordance with the severity of the pain. PMID- 17696062 TI - Mechanical behavior of major connectors--part 2: influence of denture teeth height and loading direction. AB - STATEMENT OF THE PROBLEM: When force is applied on a denture the moments may develop at the denture major connector (MC) interface and thus enabling more framework deformation. PURPOSE: To determine the influence of crown height and loading directions on the stiffness of different MC designs when supported by an oral cavity simulating model. MATERIAL AND METHODS: Oral cavity models were used as support for different major connector's designs. A set of metal tooth casted crowns, 8, 10, and 12 mm in height, was prepared from molar plastic phantom teeth. The crowns were connected to premolar or molar regions of the major connectors and loaded vertically or in 45 to the occlusal plane. The stiffness of the system was measured. RESULTS: Changing tooth-crown height resulted in small changes in stiffness values when loaded vertically to the occlusal plane. Loading in oblique to the occlusal plane, the mean stiffness value decreased 30% when crown height increased from 8 mm to 12 mm. A reduction in stiffness values of 80 90% compared to vertical loading was found. CONCLUSION: Long denture crowns reduce the rigidity of the removable partial dentures. CLINICAL IMPLICATIONS: The removable partial denture should be supported by the maximal oral tissues. This stresses the importance of periodical examinations for any need of denture-base relining to maintain good support. PMID- 17696063 TI - [Partial orthodontic treatment--a case report and its implications]. AB - Several theories lie behind the development of lower incisors crowding. Nowadays, many adults are seeking for treatment to resolve this problem. The present case report describes development of mild lower incisor crowding during one year of partial orthodontic treatment in the maxillary arch of a young adult patient. In trying to explain what was behind the speedy process, which forced the orthodontist to add the lower arch to the treatment, we found that narrowing the upper arch in the canine's area was the best explanation to this pathological process. The effect of the upper arch width on the lower one is quoted in many publications but it is not related to the lower incisors crowding phenomenon. PMID- 17696064 TI - [Is there a tendency for professional saturation in orthodontics in Israel?]. AB - OBJECTIVES: The purpose of the present study is to evaluate the demand for orthodontic treatment in Israeli society, and determine the adequacy of the profession to provide service. In addition, a database of Israeli orthodontic specialist demographics will be compiled. METHODS: There is no statistical information available as to the orthodontic treatment needs and demands in Israel. Furthermore, no survey exists measuring response to orthodontics by the Israeli patient population (i.e. attitudes, treatment time etc). In order to gauge these parameters, a written questionnaire was distributed to all the orthodontists in Israel (specialists, post graduate students and dentists who have completed their orthodontic training but have not yet earned specialist certification). The survey contained questions regarding work hours (full or partial time), the numbers of orthodontic care facilities and the distance travelled to each office, the orthodontist's claim of "free time", and whether there is a desire to increase the time spent treating patients. RESULTS: A total of 89 orthodontists complied with the conditions of the study. Sixty nine (77.5%) were male, and 65 (73%) of them were certified specialists. It was found that 9% of the responding orthodontists practiced general dentistry in addition to orthodontics during at least 25% of their clinic time. A majority of the orthodontists (60/89) work in more than one office and 27% work in four or more different offices. About a quarter (25.8%) of the responding orthodontists report having less work than they desire and 16.9% of the orthodontists would like to work 10 or more additional hours per week. The majority of the orthodontists (80.9%) live in the central part of Israel and they travel long distances to work. Almost half of the offices (47.6%) are located 30 km or more away from their homes. CONCLUSIONS: The present survey indicates that the demographics within the orthodontic specialty tend towards that of professional over-supply (saturation). It was also found that the majority of the orthodontists live in the central region of Israel, therefore, travelling to satellite offices is inherently time consuming. PMID- 17696065 TI - [Dentistry--in the eyes of the court--Integrated overview of verdicts that were given regarding dentistry]. PMID- 17696066 TI - New dental products and the dentists. PMID- 17696067 TI - Deming revisited, part 3: variations. PMID- 17696068 TI - But what do I bill...CT or CTA? PMID- 17696069 TI - Radiology operations: what you don't know could be costing you millions. AB - Rapid growth in advanced imaging procedures has left hospital radiology departments struggling to keep up with demand, resulting in loss of patients to facilities that can offer service more quickly. While the departments appear to be working at full capacity, an operational analysis of over 400 hospital radiology departments in the US by GE Healthcare has determined that, paradoxically, many departments are in fact underutilized and operating for below their potential capacity. While CT cycle time in hospitals that were studied averaged 35 minutes, top performing hospitals operated the same equipment at a cycle time of 15 minutes, yielding approximately double the throughput volume. Factors leading to suboptimal performance include accounting metrics that mask true performance, leadership focus on capital investment rather than operations, under staffing, under scheduling, poorly aligned incentives, a fragmented view of operations, lack of awareness of latent opportunities, and lack of sufficient skills and processes to implement improvements. The study showed how modest investments in radiology operations can dramatically improve access to services and profitability. PMID- 17696070 TI - Implementing PACS doesn't guarantee productivity gains. AB - Consulting services based on "lean thinking" help optimize workflow and achieve the efficiency expected from a PACS implementation. Training referring physicians is essential to eliminating the production and distribution of film-based studies. Marketing the benefits of PACS to physicians and patients can earn market share and boost patient volumes. PMID- 17696071 TI - Managing the marketing program. PMID- 17696072 TI - Developing and implementing a career ladder program. AB - A career ladder program is a formal management tool used not only by managers looking to recognize and retain employees, but also by employees seeking growth opportunities. A career ladder program involves careful development, frequent and effective communication during implementation, and activities focused on measuring program effectiveness. Career ladders are a way to increase productivity and staff versatility; improve morale, clinical quality, and staff satisfaction; reduce turnover; promote professional growth and job enrichment; and improve patient care. PMID- 17696073 TI - Benefits of protocol-driven ultrasound exams. AB - From financial benefits to saving time, protocol-driven ultrasound offers numerous options to the radiology department. Protocols enable sonographers to take command of workflow by providing a customizable exam guide. Protocols offer the radiology department greater exam consistency across all sonographers. PMID- 17696074 TI - Employee recognition. PMID- 17696075 TI - Intermittent pneumatic compression devices. AB - Intermittent pneumatic compression (IPC) devices are used to aid circulation in the lower limbs as a means of preventing deep vein thrombosis--a condition that can be dangerous and even fatal if it results in a pulmonary embolism. To be effective, IPC devices need to be safe, easy to use, and comfortable. Our Evaluation tells you which products meet these qualifications and how you can select one that best suits your needs. We tested and rated the following products: the VenaFlow, supplied by Aircast/DJO; the Flowtron Excel and Flowtron Universal, supplied by Huntleigh Healthcare; the PlexiPulse and Pulse SC, supplied by Kinetic Concepts Inc. (KCI); the A-V Impulse System, SCD Express, and SCD Response, supplied by Tyco Healthcare/Kendall. PMID- 17696076 TI - Hazard report. Storage of endoscopes in shipping cases continues to put patients at risk. PMID- 17696077 TI - Short history of mammography: a Belgian perspective. AB - It took the surgery community more than half a century to accept mammography. Three periods can be observed in the history of the evolution of mammography. The first one goes from 1913 to 1940, the second one from 1940 to 1970, and the third period from 1970 to the end of the century, when a high quality of mammography with an even lower dose is achieved by digital systems for both diagnostic and screening purpose. PMID- 17696079 TI - Is there a role for sonography in breast cancer screening? AB - Sonography can disclose tumors that remain mammographically occult. As a result, many have suggested to perform sonography in addition to screening mammography, especially in women with dense breasts. This approach, however, should be dealt with very cautiously. First of all, the term "mammographically occult" should be used carefully, because lesions that are missed because of suboptimal mammographic image quality or bad positioning or because no attempt has been made to compare with previous mammograms must not automatically be considered as mammographically occult. Secondly, introduction of sonography in mammographic screening is not straightforward because (1) it is extremely difficult to detect small malignant lesions with sonography without concurrently causing an excess of false positive results, (2) it is unclear how sonographic screening should be organized and quality-assured, (3) it is not unreasonable to expect that the excess costs of sonographic screening would favor other prevention strategies with more favorable cost/benefit ratio to decrease overall mortality. But most importantly, no large-scale trials have unequivocally proven the validity of sonography screening so far, neither in the general population, nor in subgroups with dense mammograms and/or at increased risk of breast cancer. Therefore, mammography remains currently the only screening tool that is associated with a decrease of breast cancer specific mortality and that should be used for mass screening. PMID- 17696080 TI - Typetesting of physical characteristics of digital mammography systems: first experiences within the Flemish breast cancer screening programme. AB - To avoid the purchase of a digital mammography system by radiologists with intrinsic characteristics not able to fulfil the physical-technical quality requirements of the acceptance tests of the European guidance document, typetesting of digital equipment was introduced in the organisation and legislation of the Flemish breast cancer screening programme. Typetesting is performed for two types of instrumentation: systems for image capture and processing and systems for image presentation. Typetesting is finalised or ongoing for eight DR systems and four CR systems. Eight workstations were or are submitted to the typetesting for image presentation. Experiences gained in typetesting of systems for image capture and -processing up to now show that the contrast-detail analysis of CDMAM phantom imaging and the homogeneity tests are most stringent. In general DR performs better than CR in imaging performance. Typetesting for image presentation has shown no difference in quality between CRT and LCD monitors. Furthermore, 3 MP monitors also pass the tests. However, to get the full resolution capabilities of the image capture system zooming in and scrolling over the image is necessary, which is time-consuming in clinical practice. Finally, we emphasize that typetesting involves also an evaluation of a set of clinical images by the working party of radiologists and that succeeding in typetesting does not mean that a particular system passes automatically the acceptance testing. A perfect tuning of the system and the coupling to a high quality X-ray system is necessary as well. PMID- 17696081 TI - Digital mammography for screening and diagnosis of breast cancer: an overview. AB - Digital mammography is an emerging technique for the evaluation of the breast. Unless the low spatial resolution, the systems performs very well in diagnostic imaging because they improve lesion conspicuity through their better efficiency of absorption of x-ray photons and a linear response over a wide range of radiation intensities and the inherent high contrast resolution. With digital imaging, separation of the process of x-ray detection from the image display and storage is possible and makes optimization of each of these steps possible. In this regard, applying image processing can have a high impact on image quality. Different clinical trials are available to evaluate the accuracy of digital mammography. To control the image quality, dedicated quality parameters are developed and approved by the European Commission. However, unless the experience in diagnostic imaging with digital mammography, introduction in a screening environment still has difficulties. As telemammography is an advantage of digital imaging, practical implementation of different imaging systems in one large screening network is not solved yet. The radiologist also must be aware with the different kind of images coming from the different systems. The disadvantage of digital imaging is the high cost and the sharing of digital images with other facilities which not have a similar technology. Future technology is tomosynthesis, dual energy mammography and cone beam CT of the breast. PMID- 17696082 TI - Diffusion restriction in a superficial breast lesion. AB - OBJECTIVE: To report the imaging findings of a 22-year-old Asian woman with a freely movable retro-areolar nodule in the right breast, first noticed after a holiday in The Philippines. MATERIAL AND METHODS: We preformed clinical examination, mammography and ultrasound with color Doppler imaging. A differential diagnosis of epidermal inclusion cyst, complex cyst, well demarcated carcinoma and echinococcus cyst was proposed. For further differential diagnosis, a MRI of the breasts was performed on a 1.5 superconducting system, with a bilateral breast coil. T2- and T1 weighted images, followed by axial echo-planar diffusion-weighted MRI (DW-MRI) were performed with b values of 0, 500, and 1000 mm2/s (trace images and ADC maps). RESULTS: The high signal intensity on T2 weighted images confirmed the cystic character of the lesion. The high signal intensity on T1 FS weighted images can be seen in complex cysts and inclusion cysts, but is less likely in an echinococcus cyst. On DW-MRI there is a marked diffusion restriction in the nodule, which can be seen in complex cysts and inclusion cysts. A well demarcated carcinoma is less likely, unless a tumour with a very high cellularity. Because neither carcinoma nor echinococcus cyst could be ruled out, a surgical excision was performed. Pathological examination revealed normal squamous epithelium with stratification and lamellated keratin, consistent with an epidermal inclusion cyst. CONCLUSION: We argue that in selected cases DW MRI can be useful to narrow the differential diagnosis and notable differentiate epidermal inclusion cysts from echinococcus cysts. PMID- 17696083 TI - Eosinophilic mastitis. AB - In this report a case with eosinophilic mastitis is described. The non specific radiologic findings of eosinophilic mastitis are illustrated. Diagnosis was established by histopathological exam of needle biopsy material. Knowledge of this rare entity may be helpful in diagnosis and clinical management. PMID- 17696084 TI - Clip migration after vacuum-assisted stereotactic breast biopsy: a pitfall in preoperative wire localization. AB - Vacuum-assisted stereotactic breast biopsy has become an irreplaceable instrument in the management of suspicious mammographic lesions. If the initial mammographic lesion becomes obscured or absent following the biopsy, a clip is commonly placed by interventional breast radiologists at the biopsy site. This enables future wire localization if atypical or malignant histology warrants excision. Currently, clip malposition or migration has become increasingly recognized in the literature as a possible complication of stereotactic breast biopsy. As in this case, recognition of migration of the clip was crucial in the planning of the patient's subsequent wire localization procedure. This article aims to increase the awareness of radiologists and surgeons of this potential pitfall to prevent false-negative biopsies and minimize positive surgical margins after wire guided breast conservation surgery. Routine evaluation of pre- and postbiopsy mammograms and prospective identification of inaccurate clip placement before stereotactic wire localization and excision should be performed. PMID- 17696085 TI - Congenital thymic cyst. PMID- 17696086 TI - Cystic adventitial disease with secondary occlusion of the popliteal artery. PMID- 17696087 TI - Juvenile metachromatic leukodystrophy. PMID- 17696088 TI - Acute calcific retropharyngeal tendonitis. PMID- 17696089 TI - Spontaneous spinal epidural hematoma. PMID- 17696090 TI - Transient osteoporosis of the hip in a 38-year-old man. PMID- 17696091 TI - Abdominal wall desmoid tumor. PMID- 17696092 TI - Mucoid degeneration of the anterior cruciate ligament. PMID- 17696093 TI - Chronic osseous sarcoidosis. PMID- 17696094 TI - Anterior femoro-acetabular impingement of the left hip. PMID- 17696095 TI - Thoracic extramedullary hematopoiesis secondary to enzymatic deficiency. PMID- 17696096 TI - Varicose abdominal mass due to congenital absence of inferior vena cava. PMID- 17696097 TI - Craniofacial dysmorphism in Apert syndrome. PMID- 17696098 TI - Primary malignant peritoneal mesothelioma associated with Metsovo lung. PMID- 17696099 TI - Hematemesis due to pseudoaneurysm complicating acute pancreatitis. PMID- 17696100 TI - Left pain due to ectopic thymoma. PMID- 17696101 TI - Aspergilloma in bronchogenic cyst. PMID- 17696102 TI - Chronic recurrent multifocal osteomyelitis associated to psoriasis. PMID- 17696103 TI - Nail-patella syndrome associated with Ewing sarcoma. PMID- 17696104 TI - Chest gossypiboma after coronary surgery. PMID- 17696105 TI - Cannabis-induced brain ischemia. PMID- 17696106 TI - Unusual presentation of a ureteral calculus. PMID- 17696107 TI - CT imaging of acute thoracic aortic dissection. PMID- 17696108 TI - Cubital tunnel syndrome of right elbow. PMID- 17696109 TI - Acute splenic infarction. PMID- 17696110 TI - 64-row MDCT diagnosis of intimal hyperplasia causing restenosis of renal arterial stent. PMID- 17696111 TI - Hedonistic or suicidal? PMID- 17696112 TI - Keeping cool. PMID- 17696113 TI - Analysing aggression. PMID- 17696114 TI - Glastonbury: mud, sweat and tears. PMID- 17696115 TI - Follow the leader. PMID- 17696116 TI - Dehydration in older people: assessment and management. PMID- 17696117 TI - Caring for families during critical illness: a reflective case study. PMID- 17696118 TI - Get rid of the pen pushers. PMID- 17696119 TI - Differences in predictors of cervical and breast cancer screening by screening need in uninsured Latino women. AB - BACKGROUND: Latino women experience higher mortality for cervical cancer and lower 5-year survival for breast cancer than non-Latino White women. Adherence with screening recommendations can increase chances of survival, yet the factors that influence screening behaviors in uninsured women are not well documented. METHODS: Uninsured Latino women (N = 467) recruited in four US cities participated in the study. Logistic regression was used to model adherence to recommendations by screening type (cervical or breast cancer) and screening need (needs to obtain initial screening, overdue for rescreening, up-to-date with rescreening). RESULTS: Predictors differed by type of screening and screening need. Women who reported exposure to cancer education were more likely to have had a mammogram and to be up-to-date with Pap smear screening than women without such exposure. Women who were younger, had more than a sixth grade education, and/or had children were more likely to have had a Pap smear. Older women who had been in the US the longest were more likely to be overdue for a Pap smear. Women with incomes 5000 to 7000 were more likely to have obtained a mammogram. Regional differences were found with respect to mammography screening and maintenance behaviors. CONCLUSIONS: Exposure to cancer education is an important predictor of screenings among uninsured urban Latino women. The potential of creating educational interventions that can increase screening rates among women who evidence health disparities is encouraging. Recruitment strategies to reach women in need of screenings are provided. PMID- 17696120 TI - Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. AB - OBJECTIVE: The relationship between genetic variation in the T-type calcium channel gene CACNA1H and childhood absence epilepsy is well established. The purpose of this study was to investigate the range of epilepsy syndromes for which CACNA1H variants may contribute to the genetic susceptibility architecture and determine the electrophysiological effects of these variants in relation to proposed mechanisms underlying seizures. METHODS: Exons 3 to 35 of CACNA1H were screened for variants in 240 epilepsy patients (167 unrelated) and 95 control subjects by single-stranded conformation analysis followed by direct sequencing. Cascade testing of families was done by sequencing or single-stranded conformation analysis. Selected variants were introduced into the CACNA1H protein by site-directed mutagenesis. Constructs were transiently transfected into human embryo kidney cells, and electrophysiological data were acquired. RESULTS: More than 100 variants were detected, including 19 novel variants leading to amino acid changes in subjects with phenotypes including childhood absence, juvenile absence, juvenile myoclonic and myoclonic astatic epilepsies, as well as febrile seizures and temporal lobe epilepsy. Electrophysiological analysis of 11 variants showed that 9 altered channel properties, generally in ways that would be predicted to increase calcium current. INTERPRETATION: Variants in CACNA1H that alter channel properties are present in patients with various generalized epilepsy syndromes. We propose that these variants contribute to an individual's susceptibility to epilepsy but are not sufficient to cause epilepsy on their own. The genetic architecture is dominated by rare functional variants; therefore, CACNA1H would not be easily identified as a susceptibility gene by a genome-wide case-control study seeking a statistical association. PMID- 17696121 TI - Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions. AB - OBJECTIVE: To determine the role of bone morphogenetic proteins (BMPs) in stimulating glial scar formation in demyelinating lesions of the adult spinal cord. METHODS: The dorsal columns of adult rats were injected with lysolecithin to induce a local demyelinating lesion. Levels of BMP4 and BMP7 proteins were assayed and compared with glial fibrillary acidic protein expression in the injury area. BMP-responsive cells were identified by expression of phosphorylated Smad1/5/8. Cultures of mature spinal cord astrocytes were treated with BMP4, and levels of chondroitin sulphate proteoglycans (CSPGs) were measured. The effect of BMP4 on CSPG gene regulation was determined by real-time polymerase chain reaction for CSPG core proteins. RESULTS: BMP4 and BMP7 increase rapidly at the site of demyelination, and astrocytes surrounding the lesion increase expression of phosphorylated Smad1/5/8. Cultured mature astrocytes respond directly to BMPs with Smad1 translocation to the nucleus, increased phosphorylated Smad1/5/8, and increases in glial fibrillary acidic protein and CSPG expression. BMP treatment also increased CSPG messenger RNA for CSPG core proteins, including aggrecan and neurocan. Increases in CSPG expression in astrocytes by BMPs were blocked by the inhibitor noggin. Injections of BMP4 or BMP7 into the dorsal columns in the absence of demyelination led to increases in CSPG expression. INTERPRETATION: Local increases in BMPs at the site of a demyelinating lesion causes upregulation of gliosis, glial scar formation, and heightened expression of CSPGs such as neurocan and aggrecan that may inhibit remyelination. PMID- 17696122 TI - Compulsive singing: another aspect of punding in Parkinson's disease. AB - We report on two patients with advanced Parkinson's disease who were exhibiting a peculiar and stereotyped behavior characterized by an irrepressible need to sing compulsively when under high-dose dopamine replacement therapy. Sharing many features with punding, this singing behavior is proposed as a distinct manifestation of the dopamine dysregulation syndrome in Parkinson's disease. PMID- 17696123 TI - Mutations in the cyclic adenosine monophosphate response element of the tyrosine hydroxylase gene. AB - Tyrosine hydroxylase (TH) deficiency (OMIM 191290) is one cause of early-onset dopa-responsive dystonia. We describe seven cases from five unrelated families with dopa-responsive dystonia and low homovanillic acid in cerebrospinal fluid who were suspected to suffer from TH deficiency. Analysis of part of the TH promotor showed five homozygous and two heterozygous mutations in the highly conserved cyclic adenosine monophosphate response element. Our data suggest that, if no mutations are found in the coding regions of the gene in patients strongly suspected of TH deficiency, the search for pathogenic mutations should be extended to regulatory promotor elements. PMID- 17696124 TI - Two unique patients with novel microdeletions in 4p16.3 that exclude the WHS critical regions: implications for critical region designation. AB - Wolf-Hirschhorn syndrome (WHS) is characterized by growth delay, developmental delay, hypotonia, seizures, feeding difficulties, and characteristic facial features. Deletion of either of two critical regions (WHSCR and WHSCR-2) within chromosome band 4p16.3 has been proposed as necessary for the minimal clinical manifestations of WHS and controversy remains regarding their designation. We describe two patients with novel terminal microdeletions in 4p16.3 who lack the characteristic facial features but do show some of the more nonspecific manifestations of WHS. The first patient had a ring chromosome 4 with an intact 4q subtelomere and a terminal 4p microdeletion of approximately 1.27-1.46 Mb. This deletion was distal to both proposed critical regions. The second patient had a normal karyotype with a terminal 4p microdeletion of approximately 1.78 Mb. This deletion was distal to WHSCR and the breakpoint was near or within the known distal boundary for WHSCR-2. Both patients showed significant postnatal growth delay, mild developmental delays and feeding difficulties. Their facial features were not typical for WHS. The phenotype of the first patient may have been influenced by the presence of a ring chromosome. Seizures were absent in the first patient whereas the second patient had a complex seizure disorder. Characterization of these patients supports the hypothesis that a gene in WHSCR 2, LETM1, plays a direct role in seizure development, and demonstrates that components of the WHS phenotype can be seen with deletions distal to the known boundaries of the two proposed critical regions. These patients also emphasize the difficulty of mapping clinical manifestations common to many aneusomy syndromes. PMID- 17696125 TI - Distal 3p deletion syndrome: detailed molecular cytogenetic and clinical characterization of three small distal deletions and review. AB - The distal 3p deletion syndrome is characterized by developmental delay, low birth weight and growth retardation, micro- and brachycephaly, ptosis, long philtrum, micrognathia, and low set ears. We have used FISH and BACs in order to map three 3p deletions in detail at the molecular level. The deletions were 10.2 11 Mb in size and encompassed 47-51 known genes, including the VHL gene. One of the deletions was interstitial, with an intact 3p telomere. In nine previously published patients with 3p deletions, the size of the deletion was estimated using molecular or molecular cytogenetic techniques. The genotype, including genes of interest, and the phenotype of these cases are compared and discussed. The localization of the proximal breakpoint in one of our patients suggests that the previously identified critical region for heart defects may be narrowed down, now containing three candidate genes. We can also conclude that deletion of the gene ATP2B2 alone is not enough to cause hearing impairment, which is frequently found in patients with 3p deletion. This is the third reported case with an interstitial deletion of distal 3p. PMID- 17696126 TI - Health-related quality of life in multiple sclerosis: effects of natalizumab. AB - OBJECTIVE: To report the relationship between disease activity and health-related quality of life (HRQoL) in relapsing multiple sclerosis, and the impact of natalizumab. METHODS: HRQoL data were available from 2,113 multiple sclerosis patients in natalizumab clinical studies. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study, patients received natalizumab 300 mg (n = 627) or placebo (n = 315); in the Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) study, patients received interferon beta 1a (IFN-beta-1a) plus natalizumab 300 mg (n = 589), or IFN-beta-1a plus placebo (n = 582). The Short Form-36 (SF-36) and a subject global assessment visual analog scale were administered at baseline and weeks 24, 52, and 104. Prespecified analyses included changes from baseline to week 104 in SF-36 and visual analog scale scores. Odds ratios for clinically meaningful improvement or worsening on the SF-36 Physical Component Summary (PCS) and Mental Component Summary were calculated. RESULTS: Mean baseline SF-36 scores were significantly less than the general US population and correlated with Expanded Disability Status Scale scores, sustained disability progression, relapse number, and increased volume of brain magnetic resonance imaging lesions. Natalizumab significantly improved SF-36 PCS and Mental Component Summary scores at week 104 in AFFIRM. PCS changes were significantly improved by week 24 and at all subsequent time points. Natalizumab-treated patients in both studies were more likely to experience clinically important improvement and less likely to experience clinically important deterioration on the SF-36 PCS. The visual analog scale also showed significantly improved HRQoL with natalizumab. INTERPRETATION: HRQoL was impaired in relapsing multiple sclerosis patients, correlated with severity of disease as measured by neurological ratings or magnetic resonance imaging, and improved significantly with natalizumab. PMID- 17696127 TI - Lymphocytic choriomeningitis virus infection of the developing brain: critical role of host age. AB - OBJECTIVE: Lymphocytic choriomeningitis virus (LCMV) is a common human pathogen that causes substantial injury to the developing brain when the infection occurs during pregnancy. However, among children with congenital LCMV infection, there is considerable variability in the site, nature, and severity of neuropathology and in the clinical outcome. We hypothesize that the variability in neuropathology and outcome is due to differences in the gestational timing of LCMV infection. METHODS: We utilized an animal model of human congenital LCMV infection, in which developing rat pups were inoculated with LCMV at a series of postnatal ages, including postnatal days 1, 4, 6, 10, 21, 30, and 60. Cellular targets of infection were determined immunohistochemically, viral titers were determined by plaque assay, and pathology was determined by histological analysis, neuronal quantification, and immunostaining for lymphocytic subclasses. RESULTS: Host age at the time of infection profoundly affected the cellular targets of infection, maximal viral titers, immune response to the viral infection, and the severity, nature, and location of the neuropathology. All of the pathological changes observed in children with congenital LCMV infection were reproduced in the rat model by infecting the rat pups at different ages. INTERPRETATION: The effect of LCMV infection on the developing brain strongly depends on host age at the time of infection. Much of the variability in neuropathology and outcome among children with congenital LCMV infection probably depends on the gestational age at which the infection occurs. PMID- 17696128 TI - Early growth in brain volume is preserved in the majority of preterm infants. AB - OBJECTIVE: Preterm infants have reduced cerebral tissue volumes in adolescence. This study addresses the question: Is reduced global brain growth in the neonatal period inevitable after premature birth, or is it associated with specific medical risk factors? METHODS: Eighty-nine preterm infants at term equivalent age without focal parenchymal brain lesions were studied with 20 full-term control infants. Using a deformation-based morphometric approach, we transformed images to a reference anatomic space, and we used the transformations to calculate whole brain volume and ventricular volume for each subject. Patterns of volume difference were correlated with clinical data. RESULTS: Cerebral volume is not reduced compared with term born control infants (p = 0.765). Supplemental oxygen requirement at 28 postnatal days is associated with lower cerebral tissue volume at term (p < 0.001), but there were no significant differences in cerebral volumes attributable to perinatal sepsis (p = 0.515) and quantitatively defined diffuse white matter injury (p = 0.183). As expected, the ventricular system is significantly larger in preterm infants at term equivalent age compared with term control infants (p < 0.001). INTERPRETATION: Cerebral volume is not reduced during intensive care for the majority of preterm infants, but prolonged supplemental oxygen dependence is a risk factor for early attenuation of global brain growth. The reduced cerebral tissue volume seen in adolescents born preterm does not appear to be an inevitable association of prematurity, but rather caused by either specific disease during intensive care or factors operating beyond the neonatal period. PMID- 17696129 TI - Climatic variability and the population dynamics of historical hunter-gatherers: the case of Sami of Northern Finland. AB - Our current knowledge on climate-mediated effects on human population dynamics is based on preindustrial agrarian societies where climate-induced crop failures had a major impact on fertility and mortality rates. However, because most of the human evolutionary history has been shaped by hunter-gatherer lifestyle relying on diverse plant and animal food sources, it is also important to understand how climate affected the population dynamics of hunter-gatherers. We thus studied whether climate, measured as a reconstructed annual mean temperature, had concurrent or delayed effects on the key components of population dynamics, annual births and deaths, in three historical (1722-1850) Sami populations of Northern Finland that depended mainly on fishing, hunting, and reindeer herding for their livelihood. We found only weak concurrent effects of mean temperature on annual births and deaths, although in general warm years correlated with increased birth and reduced mortality rates. Likewise, temperature-mediated delayed effects were mainly absent: in one population only, a warm previous year tended to reduce the number of births. By contrast, annual numbers of births and deaths were more closely associated, as indicated by negative correlations between births and deaths up to three previous years. To summarize, in contrast to historical agrarian societies, the population dynamics of historical Sami seemed to be only weakly associated with annual mean temperature, which may indicate that these populations, probably due to their dietary breadth, were rather unaffected by climatic variation. PMID- 17696130 TI - Seasonal evaluation of reproductive status and exposure to environmental estrogens in hornyhead turbot at the municipal wastewater outfall of Orange County, CA. AB - Seasonal changes in developmental stages, condition factor (CF), gonadosomatic index, and plasma vitellogenin (Vtg) concentrations in male and female hornyhead turbot were examined at the wastewater outfall (T1) of the Orange County Sanitation District, and two farfield sites T11 (7.7 km northwest of the outfall) and Dana Point (35 km south of the outfall) between February 2005 and May 2006. Fish collected from the three sites exhibited male-oriented sex ratios. With few exceptions, developmental stages, CF, and GSI of both genders and plasma Vtg concentrations of females were not significantly different in samples collected from different sites at the same sampling period. More advanced gonad developmental stages and higher plasma Vtg concentrations in females were observed in August, indicating the seasonality of the reproductive cycle for this species. Plasma Vtg concentrations in males were observed in all of the sampling sites with the highest prevalence at T11 relative to T1 and Dana Point. The Vtg expression in males from the three sampling sites indicated widespread exposure to estrogenic compounds in waters of coastal California. However, the histopathological and reproductive relevance of the responses appeared to be insignificant and may not affect the population in these locations. PMID- 17696131 TI - Hepatoprotective efficacy of certain flavonoids against microcystin induced toxicity in mice. AB - Toxic cyanobacteria (blue-green algae) water blooms have become a serious problem in several industrialized areas of the world. Microcystin-LR (MC-LR) is a cyanobacterial heptapeptide that represents acute and chronic hazards to animal and human health. Identification of suitable chemprotectants against microcystin is essential considering human health hazards. In the present study, we have evaluated the protective efficacy of three flavanoids namely quercetin (200 mg/kg), silybin (400 mg/kg), and morin (400 mg/kg)] pretreatment against microcystin toxicity (0.75 LD(50), 57.5 microg/kg) in mice. Various biochemical variables were measured to study the recovery profile of protected animals at 1- and 3-days post-toxin treatment. The serum alanine amino transferase (ALT) shows 17-fold increase in MC-LR treated animals compared with control group at 1 day. The silybin and quercetin group showed a decrease in level of ALT compared with MC-LR group but still higher than control group. No significant protection was observed with aspartate aminotransaminase (AST) and lactate dehydrogenase (LDH) levels in flavanoid-treated groups at 1-day post-treatment. But at 3 days, the serum levels of AST and ALT were normalized to control values, but the serum LDH levels were still significantly higher than the control group. No significant changes were observed in glutathione peroxidase and reduced glutathione levels at both 1- and 3-day postexposure. The catalase activity shows a significant decrease in quercetin-treated animals at 3-day postexposure. The protein phosphatase was significantly inhibited in MC-LR group compared to control. The silybin pretreated group showed recovery after 1 day. At 3 days, the PPAse activity was reversed to control values in all the flavanoid-treated groups. Immunoblotting analysis showed microcystin-PPAse adduct in liver tissues of toxin treated as well as flavanoid-treated mice even after 3 days. The results of this study show that flavanoids, quercetin, silybin, and morin could reverse the hepatotoxic effects of MC-LR in vivo. PMID- 17696132 TI - Effects of aqueous extracts from five species of the family Papaveraceae on selected aquatic organisms. AB - The effects of aqueous root extracts from five species of the family Papaveraceae on the growth of cyanobacteria, algae, and other non-target aquatic organisms were investigated to evaluate their potential use as algicides or cyanocides in the aquatic environment. Dicranostigma lactucoides and Sanguinaria canadensis featured the highest toxicity while Macleaya microcarpa was found to be the least toxic to all aquatic organisms tested. The Chelidonium majus extract had the best properties as a potential algicide or cyanocide because of its significant toxicity to phytoplankton and lower toxicity to non-target aquatic organisms as compared with the other Papaveraceae family members. PMID- 17696133 TI - Release of hydrogen sulfide by asteroid impacts in Black Sea and risks for inland human population. AB - The hydrogen sulfide rich waters of the Black Sea pose a potential danger for the surrounding land regions. The impact of an asteroid may cause a catastrophic poisonous gas release in the atmosphere. Some effects of this last phenomenon on the Eastern Black Sea coastal regions are evaluated in this article. Two simple models are proposed to describe the generation of the H(2)S cloud. The initial diameter of the cloud depends on asteroid size. The initial thickness of the cloud depends, in addition, on sea depth at impact location. The wind speed plays an important role in H(2)S cloud dynamics. At 10 m/s wind-speed the cloud margins may be seen at about 150 km from impact location in about 3.2 h. The maximum distance traveled by the hydrogen sulfide cloud increases by increasing the asteroid size and wind speed. The influence of the impact position on the distance traveled by hydrogen sulfide clouds is rather weak, as far as the seawater depth does not change significantly. Two values are considered when referring to the effect of hydrogen sulfide concentrations on humans: the lower concentration limit of 19.88 ppm (which corresponds to fatigue, loss of appetite, headache, irritability, poor memory, dizziness) and the upper concentration limit of 497 ppm (which corresponds to death after single exposures). The land surface area covered by the H(2)S cloud generated by a 1000 m size asteroid during the run-in ranges between about 6080 and 11,520 km(2). This may affect between 145,000 and 276,000 people. When a 250 m size asteroid is considered, the covered land surface area ranges between about 840 and 1,890 km(2) and between 20,000 and 45,000 people may be affected. In case of a 70 m size asteroid, the cloud covers up to 105 km(2) of land during the run-in. This may affect about 2500 people. These are moderate estimates. They do not include the urban population and may be 10 times underestimated for some particular wind directions. General recommendations to diminish the social effects of the impacts are presented. PMID- 17696134 TI - Acute toxicities of trace metals and common xenobiotics to the marine copepod Tigriopus japonicus: Evaluation of its use as a benchmark species for routine ecotoxicity tests in Western Pacific coastal regions. AB - Marine copepods have recently been recognized as important organisms in ecotoxicity testing for regulatory purposes. The harpacticoid copepod Tigriopus japonicus has a wide geographical distribution along the coast in the Western Pacific including Japan, South Korea, Taiwan, and Hong Kong. This study evaluated the acute toxicity sensitivity profile of Tigriopus japonicus against 12 common toxic substances including six endocrine disrupting chemicals (EDCs), three biocides and three trace metals. Through standard acute toxicity test procedures, toxicity endpoints LC(50), LC(10), and no observed effect concentration (NOEC) of each chemical were obtained. Although T. japonicus depicted different sensitivities towards different chemicals, a dose-response relationship was consistent in all cases. T. japonicus was particularly sensitive to most of the EDCs, but relatively less sensitive to molinate (a thiocarbate herbicide). Across all tested chemicals, tributyltin (TBT) was the most toxic to the copepod with the LC(50), LC(10), and NOEC of 0.05, 0.03, and 0.02 mg/L, respectively. A comparison made with available data on acute toxicities of these chemicals to other marine copepod species revealed that T. japonicus is generally more sensitive to EDCs and in particular to TBT. We, therefore, strongly advocate that T. japonicus shall be adopted as a benchmark marine species for routine ecotoxicity testing and ecotoxicological studies in Western Pacific coasts. PMID- 17696135 TI - Octylphenol reduces the expressions of steroidogenic enzymes and testosterone production in mouse testis. AB - 4-tert-octylphenol (OP) is known to disrupt testicular development and reduce male fertility. In the present study, male mice were exposed to OP at two different developmental stages, and the expression of steroidogenic enzymes and testosterone production were evaluated. Juvenile (15-day-old) and adult (8-week old) male mice were injected with 2, 20, or 200 mg/kg of OP or 0.2 microg/kg of estradiol valerate for 5 days. Testosterone concentration was measured by radioimmunoassay and the expressions of the testicular genes were determined by RT-PCR analysis and immunohistochemistry. In the animals exposed with 20 mg/kg of OP during juvenile stage, histochemical analysis of the testis showed that number of pyknotic germ cells inside the tubule was increased, while the number of oil red O positive Leydig cells was decreased. Moreover, the lumen formation was remarkably delayed. A reduced serum testosterone concentration and down-regulated expressions of the mRNAs for steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage enzyme (P450scc), and 17alpha-hydroxylase/C(17 20) lyase (P450(17alpha)) were also observed after juvenile exposure to OP. Immunohistochemical staining for P450scc was mainly detected in interstitial Leydig cells, and a slightly reduced expression of P450scc protein was observed in the testis exposed to 20 mg/kg of OP during juvenile stage. The present study demonstrates that juvenile exposure to OP inhibits steroidogenesis by decreasing the expressions of steroidogenic enzymes in the testis. Diminished lipid content in Leydig cells and reduced transcriptional expression of the cholesterol transport gene, StAR, also support altered cholesterol metabolism and/or transport as a potential mechanism for the decreased testosterone production following exposure to OP. Altogether, the alteration of steroidogenesis by exposure to OP may adversely affect the normal development of the testis and spermatogenesis. PMID- 17696136 TI - Effect of temperature on heavy metal toxicity to earthworm Lumbricus terrestris (Annelida: Oligochaeta). AB - Earthworms (Lumbricus terrestris) acclimated at 2 degrees C above their habitat temperature (10-12 degrees C) showed about 5% increase in basal rate of oxygen consumption, which increased to about 38% in 14-16 degrees C- and 40% in 16-18 degrees C-, but decreased by 84% in 20-22 degrees C-acclimated worms. Temperature also increased the blood hemoglobin (Hb) concentration, which decreased slightly in 20-22 degrees C-acclimated worms. The worms acclimated at 20-22 degrees C showed their blood to be hypovolemic than that of 10-12 degrees C worms indicating dehydration. Pre-exposure of 10-14 degrees C-acclimated worms to sublethal concentrations of zinc, copper, and lead did not significantly affect the rate of respiration. However, at higher temperatures all these metals inhibited oxygen consumption; zinc, lead, and cadmium by approximately 11% and copper by approximately 18% of that at 14-16 degrees C. At 20-22 degrees C, the respiration was further inhibited, 36% by copper, 18% by cadmium, and approximately 10% by lead and zinc. Copper, lead, and zinc decreased the temperature-enhanced increase in blood Hb concentration at all temperatures. In 20-22 degrees C-acclimated worms heavy metal exposure slightly lowered the oxygen affinity of Hb as well as caused shifts in carbon monoxide difference spectra. The acute toxicity of these metals was not affected by a 2 degrees C rise in acclimation temperature but increased by 17% (lead), 33% (copper), and 5% (zinc) in 14-16 degrees C- and by 40% (lead), 149% (copper), and 132% (zinc) in 20-22 degrees C-acclimated worms. The increase in toxicity of metals caused by high temperatures may be due to limiting the scope of aerobic metabolism (oxygen extraction, transport, and utilization) via quantitative and qualitative effects on Hb. This terrestrial species appears to be tolerant of slight increases in habitat temperature, such as that expected with current global climate change. PMID- 17696137 TI - Toxicity of phenanthrene and lindane mixtures to marine invertebrates. AB - Surface waters near industrialized and agricultural areas are contaminated with hundreds of different pollutants from a variety of sources. Methods for measurement of sediment, surface water, and porewater toxicity in marine environments include the sea urchin (Arbacia punctulata) fertilization and embryological development tests and copepod (Schizopera knabeni) survival and hatching success assessment. The concentration addition model was applied to determine whether toxicity of two compounds, phenanthrene (polycyclic aromatic hydrocarbon) and lindane (organochlorine pesticide), when combined can be accurately assessed because of similar modes of action. Mixture analysis determined the sea urchin fertilization test to exhibit additivity (TU(mix) = 1.13), while the copepod test exhibited a synergistic effect (TU(mix) = 0.22). Mixture toxicity data for the sea urchin embryological test were not conclusive because of the lack of toxicity of the individual chemicals. The synergistic effect to copepods is a concern as it indicates that greater toxic effects may occur when the compounds are present in mixtures. Results from this research suggest that increased toxicity to some categories of organisms should be expected near agricultural and industrial areas where pesticides and other types of compounds may occur simultaneously. PMID- 17696138 TI - Toxicological effects and bioaccumulation in the freshwater clam (Corbicula fluminea) following exposure to trivalent arsenic. AB - Contamination of aquatic environments by arsenic is a serious worldwide problem. The main objective of this work was to evaluate the response of a freshwater clam (Corbicula fluminea) to arsenic (As III) exposure and infer its potential as a biological indicator of contamination. Metallothioneins (MTs) were used as indicators of metalloid toxicity in combination with an histological and histochemical evaluation. After a period of acclimatization in the laboratory, 50 C. fluminea (0.4 g +/- 0.1) were exposed to different nominal concentrations of arsenic (100, 300, 500, and 1000 microg L(-1)) for 7 days. The concentration of total As III in the water and in the tissues of the organisms was determined by atomic absorption spectrometry, and MTs were quantified through differential pulse polarography. Results suggest that the organisms exposed to the concentrations of 300 and 1000 microg As L(-1) accumulated the highest levels of As III in the tissues (17 +/- 9 and 15 +/- 3 microg g(-1) distilled water, respectively), which was confirmed through histochemical analysis. An apparent induction of MTs was also observed in the organisms exposed to As III, suggesting that C. fluminea possesses some capacity for arsenic regulation. The results suggest that the induction of MTs may be of high interest as a biomarker for arsenic contamination in aquatic environments, and confirms the potential of C. fluminea as a biological indicator. PMID- 17696139 TI - Biomonitoring of heavy metals using Mytilus galloprovincialis in Safi coastal waters, Morocco. AB - Heavy metal concentrations of mercury, cadmium, lead, zinc, cooper, nickel, manganese, and chromium in Mytilus galloprovincialis were investigated to provide information on pollution of Safi coastal area, since these metals have the highest toxic potential. The concentration of Hg and Pb was determined by AFS and ICP-MS methods, respectively, whilst the remaining metals (Cd, Cr, Cu, Mn, Zn, and Ni) were quantified by AAS. High lead, cadmium, chromium, and mercury levels were registered in tissue samples collected from two stations near the Jorf Lihoudi and Safi city, while elevated concentration of manganese and zinc (14.70 25.30 mg kg(-1) and 570-650 mg kg(-1) dry wt, respectively) were found in mussel specimens from Cap Cantin. The high levels of nickel found respectively in the areas near the industrial area being of concern in terms of environmental health need frequent monitoring. The metal concentrations recorded at the clean stations may be considered as useful background levels to which to refer for comparison within the Atlantic coast. M. galloprovincialis are suitable biomonitors to investigate the contamination levels of heavy metals pollution face a different human activity in this coastal area of the Atlantic coast. PMID- 17696141 TI - Early life influences on adult leg and trunk length in the 1958 British birth cohort. AB - OBJECTIVES: Short leg length has been associated with increased disease risk. We investigated (1) whether taller childhood stature predicts longer adult leg than trunk length; (2) the effects of early life factors on adult leg/trunk length. METHODS: We used data from the 1958 British birth cohort on height in childhood and at 45 years, leg and trunk length at 45 years and early life factors (n approximately 5,900). RESULTS: For a SD increase in height at 7 years, adult leg length increased more than trunk length (2.5-2.8 cm vs. 1.9 cm). Parental height had a stronger association with adult than childhood height, and leg than trunk length. Prenatal factors were associated with leg (maternal smoking) and trunk length (birth order); birth weight had a similar effect on leg and trunk lengths. Large family size, overcrowding, and social housing were more strongly associated with leg than trunk length: deficits in adult height (0.4-0.8 cm) were mostly due to shorter legs. CONCLUSIONS: Socio-economic adversity in childhood is associated with delayed early growth, shorter adult leg length, and stature. Leg length is the height component most sensitive to early environment. Studies of early life and adult disease could usefully assess adult leg length in addition to height. PMID- 17696140 TI - Prevalence of overweight and cardiovascular risk factors in rural and urban children from Central Asia: the Kazakhstan health and nutrition examination survey. AB - Kazakhstan is undergoing a rapid modernization process, which carries the risk of an epidemic of obesity and cardiovascular disease. We enrolled a sample of about 50 children for every combination of gender, environment (urban vs. rural), ethnic group (Kazakh vs. Russian), and age group from 7 to 18 years, for a total of 4,808 children. Anthropometry and blood pressure were measured on all children while fasting blood cholesterol and glucose were measured only in 2,616 children aged > or =12 years. The prevalence of overweight and risk of overweight ranged from 2.8 (rural male Kazakhs) to 9.1% (urban male Russians). The prevalence of prehypertension and hypertension ranged from 8.3 (urban females) to 15.9% (rural females); that of hypercholesterolemia from 11.5 (male rural Russians) to 26.5% (female rural Kazakhs); and the overall prevalence of impaired fasting glucose was 0.1%. We conclude that overweight and cardiovascular risk factors are less prevalent in children living in Kazakhstan than in those living in Western countries. However, these figures are not negligible and suggest that preventive measures are needed to contain the epidemic of overweight and cardiovascular disease that will most likely accompany the modernization of Kazakhstan in the next years. PMID- 17696142 TI - Serologic evaluation of human microcystin exposure. AB - Microcystins are among the most commonly detected toxins associated with cyanobacteria blooms worldwide. Two episodes of intravenous microcystin exposures occurred among kidney dialysis patients during 1996 and 2001. Analysis of serum samples collected during these episodes suggests that microcystins are detectable as free and bound forms in human serum. Our goal was to characterize the biochemical evidence for human exposure to microcystins, to identify uncertainties associated with interpretation of these observed results, and to identify research needs. We analyzed serum samples using enzyme-linked immunosorbent assay (ELISA) methods to detect free microcystins, and gas chromatography/mass spectrometry (GC/MS) to detect 2-methyl-3-methoxy-4 phenylbutyric acid (MMPB). MMPB is derived from both free and protein-bound microcystins by chemical oxidation, and it appears to represent total microcystins present in serum. We found evidence of free microcystins in patient serum for more than 50 days after the last documented exposure. Serum concentrations of free microcystins were consistently lower than MMPB quantification of total microcystins: free microcystins as measured by ELISA were only 8-51% of total microcystin concentrations as detected by the GC/MS method. After intravenous exposure episodes, we found evidence of microcystins in human serum in free and protein-bound forms, though the nature of the protein-bound forms is uncertain. Free microcystins appear to be a small but variable subset of total microcystins present in human serum. Research is needed to elucidate the human toxicokinetics of microcystins, in part to determine how observed serum concentrations can be used to estimate previous microcystin exposure. PMID- 17696143 TI - Combined 4D-fingerprint and clustering based membrane-interaction QSAR analyses for constructing consensus Caco-2 cell permeation virtual screens. AB - A set of 30 structurally diverse molecules, for which Caco-2 cell permeation coefficients were determined, formed the training set for construction of Caco-2 cell permeation models based upon membrane-interaction (MI) QSAR analysis and a new QSAR method called 4D-fingerprint QSAR analysis. The descriptor terms of the 4D-fingerprints equation are molecular similarity eigenvalues, and this set of descriptors is being evaluated as a potential "universal" QSAR descriptor set. The 4D-fingerprint model suggests that Caco-2 cell permeation is governed by the spatial distribution of hydrogen bonding and nonpolar groups over the molecular shape of a molecule. Moreover, a complementary resampling of the original Caco-2 cell permeation training set, followed by the construction of several "clustered" MI-QSAR models, led to a consensus model consistent in interpretation with the 4D fingerprint model. PMID- 17696144 TI - Review fluorescence correlation spectroscopy for probing the kinetics and mechanisms of DNA hairpin formation. AB - This article reviews the application of fluorescence correlation spectroscopy (FCS) and related techniques to the study of nucleic acid hairpin conformational fluctuations in free aqueous solutions. Complimentary results obtained using laser-induced temperature jump spectroscopy, single-molecule fluorescence spectroscopy, optical trapping, and biophysical theory are also discussed. The studies cited reveal that DNA and RNA hairpin folding occurs by way of a complicated reaction mechanism involving long- and short-lived reaction intermediates. Reactions occurring on the subnanoseconds to seconds time scale have been observed, pointing out the need for experimental techniques capable of probing a broad range of reaction times in the study of such complex, multistate reactions. PMID- 17696145 TI - Margin failures in crown-like brittle structures: off-axis loading. AB - The effect of off-axis loading of compliant indenters on the initiation of cracks at the margins of dental crown-like dome structures consisting of glass shells back-filled with an epoxy resin is examined. As in previous studies on similar structures but with strictly axial loading, cracks can be made to initiate and propagate from the margins around the dome faces into a "semi-lunar" fracture pattern characteristic of some all-ceramic crown failures. In this study, balsa wood and teflon disk indenters are used to provide the off-axis loading, at 45 degrees to the dome axis. The soft indenters, considered representative of food bolus, spread the contact at the top surface, suppressing otherwise dominant radial cracks that ordinarily initiate at the dome undersurface directly along the load axis beneath harder indenters. Finite element modeling is used to show that off-axis loading dramatically increases the tensile stresses at the near side dome margin, strongly diminishing the loads required to generate the lunar fracture mode. PMID- 17696146 TI - Genetic effect of anatase on osteoblast-like cells. AB - Titanium is the gold standard among materials used for prosthetic devices, because of its good mechanical and chemical properties. When exposed to oxygen, titanium becomes an oxide that is biocompatible and able to induce osseointegration. Three allotropic forms of titanium dioxide exist, that is brookite, rutile, and anatase. Anatase can be prepared as a colloidal suspension and then used to coat surfaces. Anatase coating (AC) can potentially have specific biological effects. Here we are testing the effect of AC on osteoblast like cells (MG63) by using microarray techniques to identify genes that are differently regulated in osteoblasts exposed to AC. By using DNA microarrays containing 20,000 genes, we identified in osteoblast-like cell lines (MG-63) cultured on AC, several genes whose expression was significantly up- or downregulated. They cover a broad range of functional activities: signaling transduction, immunity, cell cycle regulation, lysosomes composition and vesicular transport, cell adhesion, cytoskeleton and extracellular matrix components, proliferation, and apoptosis. The data reported constitute, to our knowledge, the first genetic portrait of AC effects. They can be relevant to a better understanding of the molecular mechanism of bone regeneration and as a model for comparing other materials with similar clinical effects. PMID- 17696147 TI - Titanium particles that have undergone phagocytosis by macrophages lose the ability to activate other macrophages. AB - Titanium particles derived from the wear of the orthopaedic implant surfaces can activate macrophages to secrete cytokines and stimulate osteoclastic bone resorption, causing osteolysis around orthopaedic implants. However, what happens to the titanium particles after being phagocytosed by macrophages is not known. We prepared titanium particles (as received, clean, and LPS-coated), and exposed them to macrophages in culture. Free particles were washed away after 24 h and the intracellular particles were kept in culture for additional 48 h until being harvested by lysing the cells. Particles that had been cell treated or noncell treated were examined by scanning electronic microscopy to analyze the shape, size, and concentration of the particles. The cell treated and noncell treated particles were exposed to macrophages in culture with a particle to cell ratio of 300:1. After 18 h, the levels of TNF-alpha in culture medium and the viability of the cells were examined. Clean particles did not stimulate TNF-alpha secretion by macrophages, while LPS-coated particles dramatically increased that response. Phagocytosis by macrophages did not change the shape and size of the particles, but depleted the ability of the particles to stimulate TNF-alpha secretion by macrophages. This indicates that macrophages are capable of rendering titanium particles inactive without degrading the particles, possibly by altering the surface chemistry of the particles. PMID- 17696148 TI - Adhesion of Streptococcus sanguinis to glass surfaces measured by isothermal microcalorimetry (IMC). AB - Bacterial adhesion is the first step in the development of the oral biofilm, called dental plaque. Plaque is the cause of caries, periodontal diseases, and periimplantitis. Investigations of dental plaque, including bacterial adhesion, employ various in vivo and in vitro models using microscopic methods. Microcalorimetry offers another direct approach. The model organism Streptococcus sanguinis is one of the first colonizers adhering to the saliva-coated human tooth surfaces or dental materials within minutes after tooth cleaning. TAM III thermostats, equipped with microcalorimeters, were used for isothermal microcalorimetric (IMC) measurements of heat production as a function of time, expressed by power-time (p-t) curves. Continuous measurements of heat production of growing S. sanguinis cells showed their overall metabolic activity and were highly reproducible. For the adhesion experiments the bacteria were allowed to adhere to different amounts of glass beads. Growing S. sanguinis cells produced a characteristic p-t curve with a maximum of 500 microW at 4.5 h when reaching 10(9) cells ml(-1). The same number of stationary S. sanguinis cells, suspended in PBS produced only approximately 30 microW at 0.5 h due to adhesion. But the amount of heat increased with available glass surface area, indicating that a portion of the heat of adhesion was measured. Similar results were obtained with stationary S. sanguinis cells suspended in human saliva. This study shows that microcalorimetric evaluation of initial bacterial adhesion is indeed possible and may become a rapid, reproducible screening method to study adhesion of different bacteria to different dental materials or to modified surfaces. PMID- 17696149 TI - Finite element analysis of subsurface damage of ceramic prostheses in simulated intraoral dental resurfacing. AB - Finite element analysis (FEA) was used to investigate the stress fields and the degrees of subsurface damage of ceramic prostheses in simulated intraoral dental resurfacing operations using clinical diamond burs. A two-dimensional finite element model was established with the dental operational parameters and the material properties as input variables. This model enabled to predict the stress fields and to evaluate the depths of subsurface damage in ceramic prostheses as functions of the dental resurfacing operational conditions. The results indicate that the tensile, shear, compressive, and equivalent von Mises stresses were all centered under the diamond bur-specimen contact zone. The maximum values of these stresses were concentrated at the diamond grit exit point, decreasing with an increase in depth of cut. The predicted depths of subsurface damage increased with an increase in both the depth of cut and the maximum chip thickness, in the range of 30-140 microm. Also, the depths of subsurface damage were experimentally measured using scanning electron microscopy (SEM). The FEA predictions were found to be in agreement with the SEM experimental observations. PMID- 17696150 TI - Effect of substrate temperature on mechanical properties of calcium phosphate coatings. AB - The effect of substrate temperature and processing parameters on mechanical properties of nanoscale calcium phosphate coatings are being studied in order to refine the processing technique for Functionally Graded Hydroxyapatite (FGHA) coatings. Coatings were deposited on titanium substrates with a set substrate temperature of 450, 550, 650, or 750 degrees C in an Ion Beam Assisted Deposition (IBAD) system using a sintered hydroxyapatite (HA) target. Mechanical properties of the coatings deposited with a set substrate temperature such as, bonding/adhesion strength to the substrate, nanohardness, and Young's Modulus as well as coating thickness were evaluated and compared with commercial plasma spray HA coatings. It is concluded that depositing FGHA coatings would better be started at 550-650 degrees C to maintain superior properties of the film at the interface. It can also be concluded that the residual stresses caused by different Coefficient of Thermal Expansions (CTEs) between the substrate and coatings are not the only factor controlling the bonding strength and mechanical properties of these samples. Other parameters such as the nature of the interface layers and their bonding to each other as well as the density and grain structure of the coatings must be taken into consideration for an appropriate evaluation of mechanical properties of calcium phosphate coatings deposited on heated substrate. PMID- 17696151 TI - Human iliac crest cancellous bone elastic modulus and hardness differ with bone formation rate per bone surface but not by existence of prevalent vertebral fracture. AB - The goals of this study were to measure tissue-level elastic moduli and hardness of human cancellous bone using nanoindentation, and determine the relationship between nanoindentation results and previously measured bone histomorphometric variables and bone mineralization. Forty iliac crest biopsies were used in this study, which were collected from Caucasian females with vertebral fracture or from a normal healthy female Caucasian population. They were also categorized into two groups according to high or low bone formation rate per bone surface (BFR/BS). Thirty-two sites were randomly selected on each specimen for nanoindentation with a Berkovich diamond indenter. Two sets of elastic moduli and hardness were calculated using the continuous stiffness measurement method and the Oliver-Pharr method, respectively. Relationships between nanoindentation results and donor age, bone mineralization, and histomorphometric variables were examined. No difference in elastic moduli or hardness was observed between the normal and fracture groups. Significantly lower elastic moduli were observed in the high BFR/BS group. The elastic moduli and hardness measurements were not significantly correlated with the bone mineralization measured independently in a previous study. Linear correlation between elastic modulus and hardness calculated using the Oliver-Pharr method was not different between the normal and fracture groups or between the high and low BFR/BS groups. Nanoindentation hardness was a very good predictor of bone tissue elastic modulus for both normal and osteoporotic bone tissues. Osteoporosis may not change the relationship between bone tissue elastic modulus, bone hardness, and bone mineralization. PMID- 17696152 TI - Effect of chain modifications on the physicomechanical properties of silsesquioxane-based dental nanocomposites. AB - The objective of this study was to evaluate the physicomechanical properties of a series of polyhedral silsesquioxane (SSQ) methacrylate monomers developed for dental applications. The effect of chain modifications on the properties of the SSQ-based monomers was also evaluated. Physicomechanical properties that are investigated include polymerization shrinkage, degree of conversion, hardness, and modulus. Results obtained were compared with unfilled 1:1 (control) bis GMA/TEGDMA materials (typical monomers used in dental composites). All samples investigated were cured using 400-500 nm light at 500 mW/cm(2) for 40 s. Shrinkage associated with curing and post-gel reactions for all synthesized SSQ compounds were found to range from (0.04 +/- 0.01)% to (0.33 +/- 0.03)% with degree of conversion ranging from (56.68 +/- 2.81)% to (84.53 +/- 2.62)%. At all time intervals, post-gel shrinkage associated with control was found to be significantly greater than all SSQ compounds. No significant difference in degree of conversion was observed for control, and all SSQ compounds except for SSQ attached with eight equivalents of short-chain methacrylate. Mechanical properties associated with SSQ compounds were found to be significantly lower than control. However, through chain modifications, mechanical properties of SSQ compounds can be improved by approximately 50%. PMID- 17696153 TI - Efficacy of ciprofloxacin implants in treating experimental osteomyelitis. AB - Ciprofloxacin (CFX) implants containing poly(D,L-lactide) and calcium phosphates (tricalcium phosphate and hydroxyapatite) was evaluated in 50 rabbits in an experimental osteomyelitis model. Their femoral cavity was inoculated with Staphylococcus aureus. After 2 weeks, the infected focus was cleaned out and the delivery system implanted. The infection and subsequent response to treatment were evaluated by microbiological analysis, biochemical and hematological markers, body weight, temperature, clinical signs, X-rays, and histology. Infected bone cultures, treated with CFX implants, showed reduced bacterial growth against controls. All CFX was released within 6 weeks. All animals recovered within 4 weeks. Even 12 weeks after implantation, no recurrence of infection was observed. Serum C-reactive protein, platelet, and leukocyte levels increased in all animals before treatment, and 4 weeks after it were maintained or rose in control animals, while decreased to normal levels in treated ones. Body weight was characterized by pretreatment losses, then gains during recuperation, or further loss in untreated animals; with no significant intraindividual differences in body temperature. Body weight, leucocytes, platelets, and C-reactive protein turned out to be highly useful markers for monitoring this kind of infection and its treatment. CFX implants demonstrated to be an effective therapy for S. aureus bone infection. Their efficacy was also reflected in decreasing severity of clinical signs, nonprogress of radiological signs indicative of infection, and good integration into bone structure. Histological examination revealed repair, with new bone formation extending into implants. PMID- 17696154 TI - LUTS treatment: future treatment options. AB - Lower urinary tract symptoms (LUTS) are commonly divided into storage, voiding, and postmicturition symptoms, and may occur in both men and women. Male LUTS have historically been linked to benign prostatic hyperplasia (BPH), but are not necessarily prostate related. The focus of treatment for LUTS has thus shifted from the prostate to the bladder and other extraprostatic sites. LUTS include symptoms of the overactive bladder (OAB), which are often associated with detrusor overactivity. Treatment for LUTS suggestive of BPH has traditionally involved the use of alpha(1)-adrenoceptor (AR) antagonists; 5alpha-reductase inhibitors; and phytotherapy-however, several new therapeutic principles have shown promise. Selective beta(3)-adrenoceptor agonists and antimuscarinics are potentially useful agents for treating LUTS, particularly for storage symptoms secondary to outflow obstruction. Other agents of potential or actual importance are antagonists of P2X(3) receptors, botulinum toxin type A, endothelin (ET) converting enzyme inhibitors, and drugs acting at vanilloid, angiotensin, and vitamin D(3) receptor sites. Drugs interfering with the nitric oxide/cGMP-cAMP pathway, Rho-kinase and COX inhibitors, as well as drugs targeting receptors and mechanisms within the CNS, are also of interest and deserving of further study for the treatment of LUTS. PMID- 17696155 TI - Catalase overexpression does not impair extensor digitorum longus muscle function in normal mice. AB - Catalase is a major antioxidant enzyme. Increasing catalase expression represents a promising avenue to improve muscle function in certain physiological conditions and in some muscle diseases. We hypothesized that catalase overexpression should not impair normal muscle contraction. We delivered a hemagglutinin (HA)-tagged human catalase gene to normal mouse muscle by an adeno-associated viral vector (AAV). Western blot and immunostaining revealed efficient expression of HA-tagged catalase. Enzymatic assay demonstrated an approximately threefold increase in catalase activity in AAV-infected muscles. Catalase overexpression impaired neither twitch nor tetanic tension in the extensor digitorum longus (EDL) muscle. Furthermore, EDL fatigue response was not altered. Taken together, we have developed a novel AAV vector to enhance catalase expression. Lack of apparent toxicity in normal muscle strongly supports further exploration of this vector to reduce oxidative stress-induced muscle damage. PMID- 17696156 TI - A bFGF/TCP-composite inhibits bone formation in a sheep model. AB - Basic fibroblast growth factor is a well known osteostimulative protein. The effects of basic fibroblast growth factor are dose-dependent and, when used with a carrier, influenced by the release kinetics. Aim of our study was to determine the effects of a composite of basic fibroblast growth factor and a newly developed, in situ setting tricalcium phosphate (TCP) cement. A trepanation defect in the distal femoral epiphysis of Merino-Mix sheep with a diameter of 9.4 mm and 10 mm depth was filled with the in situ setting TCP cement combined with 0 or 200 microg of bFGF/cm(3) TCP, autologous bone graft or left empty. The sheep were euthanized after 3 months. The defect and the periimplant area were examined by microradiography, histology, and histomorphometry. The data was analyzed with the help of the Wilcoxon and Kruskal-Wallis tests. Defects filled with TCP with or without bFGF showed a close bone-cement contact. The histomorphometric analysis revealed that the addition of bFGF inhibited the ingrowth of bone significantly, while the resorption of the cement was not influenced. In conclusion, the clinical application of this bFGF/TCP-composite does not seem promising. The reason for the inhibition of new bone formation will be discussed, but requires further investigation. PMID- 17696157 TI - Demonstration of intrinsic innervation of the guinea pig upper urinary tract using whole-mount preparation. AB - AIMS: The morphology and functional importance of the autonomic nervous system in the upper urinary tract is still not completely understood. Previous histological studies investigating the innervation of the urinary tract have mainly used conventional sections in which the three-dimensional structure of the intramural innervation is difficult to achieve. In contrast, the whole-mount preparation technique is a suitable method for visualizing the distribution of the mesh-like neuronal networks within the urinary tract. METHODS: The distribution and regional variation of neurofilament (NF), tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), and substance P-immunoreactive (SP-IR) neurons, as well as acetylcholinesterase (AChE) and nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d)-positive neurons were investigated using whole-mount preparations of the guinea pig upper urinary tract. RESULTS: Two distinct nervous plexuses were detected within the muscle layers containing NF, TH, ChAT, and SP IR nerves. AChE-positive nerves were seen in all layers. Only moderate NADPH-d positive innervation was found. Renal pelvis, upper and lower part of the ureter showed an overall increased innervation compared to the middle portion of the ureter. Ganglia were found at the pelviureteric border displaying NF and TH immunoreactivity. CONCLUSION: The whole-mount preparation technique provides an elegant method for assessing the three-dimensional architecture of ureteral innervation. The guinea pig upper urinary tract is richly supplied with adrenergic, cholinergic, nitrergic, and sensory nerves which suggest that the autonomous nervous system plays an important role in controlling ureteral motility and blood flow. PMID- 17696158 TI - Dynamic magnetic resonance imaging for grading pelvic organ prolapse according to the International Continence Society classification: which line should be used? AB - AIMS: To assess and compare the reliability of dynamic MRI to quantify pelvic organ prolapse (POP) according to the International Continence Society (ICS) using two different reference lines, and to determine which line gives the best concordance with clinical examination. METHODS: Forty-seven patients with genital prolapse underwent physical examination and dynamic MRI. Five nulliparous, symptom-free female volunteers underwent dynamic MRI as control subjects. Two distinct observers performed the MRI measurements of POP according to the ICS using two distinct reference lines: the mid-pubic line and a new one, the perineal line that provides a better match with the hymen plane. Measurements were repeated twice according to each line. The intra-class coefficient was used to estimate intra-observer and inter-observer reliability; the Altman and Bland plot was used to assess the agreement between MRI and clinical measurements. RESULTS: The intra-observer and inter-observer reliability of MRI measurements were in general excellent. Intra-class coefficients were better for the mid-pubic line than the perineal line. Although the MRI measurements correlate significantly with the physical measurements, the Altman and Bland plot shows an unacceptable magnitude of discrepancy between clinical and MRI examinations. CONCLUSIONS: Although dynamic MRI shows excellent inter- and intra-observer reliability, its agreement with clinical examination is poor whatever the line used. PMID- 17696159 TI - Rho-kinase and effects of Rho-kinase inhibition on the lower urinary tract. AB - Altered smooth muscle cell contractility/tone contributes, at least in part, to the lower urinary tract symptoms (LUTS) seen in men with benign prostatic obstruction (BPO). Accordingly, many of the therapies to date have focused largely on blockade of individual membrane receptors to diminish smooth muscle contractility and provide symptomatic relief. This pharmacologic approach has been associated with variable results, limited efficacy, and untoward side effects. Such limited clinical success is not surprising given the plethora of neurotransmitters, neuromodulators, and hormones that are now known to modulate LUT smooth muscle cell tone. In the pursuit of improved treatment options, more recent investigations have focused attention on intracellular signal transduction events that represent convergence points for membrane receptor activation. In particular, calcium sensitization and the role of the Rho-kinase pathway has received much attention. In this report, we review the literature on the role of the Rho-kinase pathway in the modulation of LUT smooth muscle cell tone. In short, the available data support an important role for Rho-kinase in the physiologic and pathophysiologic regulation of LUT smooth muscle cell tone. Rho kinase inhibitors thus appear to represent a potentially attractive therapeutic possibility for the treatment of LUTS. PMID- 17696160 TI - Molecular phylogeny of the three paedomorphic Mediterranean gobies (Perciformes: Gobiidae). AB - Pelagic gobies are considered of particular zoological interest because the acquisition of a pelagic lifestyle is achieved through the persistence of larval anatomical features. The Mediterranean Sea is inhabited by three goby species (Aphia minuta, Crystallogobius linearis and Pseudaphya ferreri) characterized by paedomorphic traits. Owing to the shared larval morphological features, these species have generally been considered as a monophyletic group. This study aimed at establishing the phylogenetic relationships of these paedomorphic species within the family Gobiidae to ascertain whether the pelagic lifestyle achieved through paedomorphosis is due to an event that took place in a common ancestor or not. For this purpose, we amplified by polymerase chain reaction and sequenced the mitochondrial 12S rDNA (complete sequence) and 16S rDNA (partial sequence) of 15 Mediterranean gobies. The phylogenetic analysis strongly supported the polyphyletic origin of the three paedomorphic gobies, indicating that the heterochronic change leading to the retention of larval features seems to have occurred independently in the ancestors of these species. Thus, the sharing of morphological traits can be considered homoplasious and the classification of these species in the same taxonomic group is rejected on the basis of molecular data. PMID- 17696161 TI - Congenital defects among liveborn infants with Down syndrome. AB - BACKGROUND: Many infants with Down syndrome (DS) have co-occurring congenital malformations requiring intensive surgical and medical management. To anticipate the care needed by these infants, providers and parents require accurate information about birth defects that may be present. This article uses a unique national hospital discharge dataset to identify the rate at which structural birth defects are identified among liveborn infants with DS. METHODS: ICD-9-CM diagnosis codes for data from the Healthcare Cost and Utilization Project were used to identify infants with and without DS, and to classify birth defects. The study population consisted of liveborn infants discharged from the hospital from 1993 through 2002. ORs for the association between the occurrence of congenital malformations and the presence of DS were computed using logistic regression models for survey data. RESULTS: Discharge data included 11,372 DS and 7,884,209 non-DS births, representing national estimates of 43,463 DS and 39,716,469 non-DS births respectively. In addition to congenital heart defects that co-occurred most often in DS infants compared to infants without DS, the risks for gastrointestinal malformations (OR 67.07), genitourinary malformations (OR 3.62), orofacial malformations (OR 5.63), and abdominal wall malformations (OR 3.25) were also elevated in infants with DS. There was no difference in the risk of spina bifida between infants with and without DS. CONCLUSIONS: This is the first nationally representative compilation of the co-occurrence of congenital malformations associated with DS. This information may assist providers and parents in their attempts to understand and prepare for the true burden of this condition. PMID- 17696162 TI - Microemulsions--modern colloidal carrier for dermal and transdermal drug delivery. AB - Microemulsions are modern colloidal drug carrier systems. They form spontaneously combining appropriate amounts of a lipophilic and a hydrophilic ingredient, as well as a surfactant and a co-surfactant. Due to their special features, microemulsions offer several advantages for pharmaceutical use, such as ease of preparation, long-term stability, high solubilization capacity for hydrophilic and lipophilic drugs, and improved drug delivery. The article summarizes the level of research with respect to dermal and transdermal application. A large number of in vitro as well as some in vivo studies demonstrated that drugs incorporated into microemulsions penetrate efficiently into the skin. The enhancing activity seems to be attributable to a variety of factors depending on the composition and the resulting microstructure of the formulations. However, an extended use in practice depends on the choice of well-tolerated ingredients, mainly surfactants, and the restriction of their amounts in order to guarantee skin compatibility. PMID- 17696163 TI - Relaxation and crystallization of amorphous carbamazepine studied by terahertz pulsed spectroscopy. AB - At the example of carbamazepine the crystallization of a small organic molecule from its amorphous phase was studied using in situ variable temperature terahertz pulsed spectroscopy (TPS). Even though terahertz spectra of disordered materials in the glassy state exhibit no distinct spectral features we demonstrate subtle changes in the spectra with increasing temperature and discuss the findings in respect to the density of vibrational states. The crystallization leads to distinct spectral features allowing the crystallization and subsequent polymorphic phase transition at higher temperatures to be studied in detail. It is possible to study both relaxation and crystallization processes by variable temperature TPS. PMID- 17696164 TI - Attention-deficit/hyperactivity disorder and callous-unemotional traits as moderators of conduct problems when examining impairment and aggression in elementary school children. AB - Examined whether attention-deficit/hyperactivity disorder (ADHD) and callous unemotional (CU) traits moderate the association between conduct problems (CPs) and impairment and aggression. Participants were 214 children who were rated by their elementary school classroom teachers. Results indicated that the association between CP and impairment and aggressive outcomes is almost always moderated by ADHD and/or CU. Moreover, in many instances, the association between CP and outcomes was moderated by both ADHD and CU such that the moderating effects of CU on CP were more pronounced at lower levels of ADHD. Results are discussed with respect to developmental taxonomies and trajectories of the disruptive behavior disorders. PMID- 17696165 TI - Effect of polymer molecular weight on the production of drug nanoparticles. AB - Stable, polymer-coated nanoparticles of two hydrophobic drugs, namely nabumetone and halofantrine, have been prepared by a wet-bead milling process performed in the presence of a stabilizing homopolymer, either hydroxypropylmethylcellulose (HPMC) or polyvinylpyrrolidone (PVP), of differing molecular weights and concentrations. Although nabumetone nanoparticles could only be produced when HPMC was used as stabilizing polymer, halofantrine nanoparticles could be prepared using either HPMC or PVP. Stable nanoparticles of nabumetone could be produced using a HPMC solution of viscosity average molecular weight, M(v), of 5 kg/mol over an approximate four fold polymer concentration range (0.63-2.5% w/w) when a drug loading of 20% w/w was used. Increasing the molecular weight of HPMC up to a limiting M(v) of 89 kg/mol did not result in the formation of nanoparticles at any of the polymer concentrations examined. The amount of polymer absorbed onto the nanoparticles was determined by measuring the depletion of polymer from solution based on either an ultra-violet (PVP) or optical rotatory dispersion (ORD) (HPMC) assay. The slightly lower concentration of HMPC found to be present on the surface of the halofantrine nanoparticles compared with the nabumetone nanoparticles suggested a differing affinity of the polymer for the surface of the two drugs. PMID- 17696166 TI - Prodrugs of nucleoside analogues for improved oral absorption and tissue targeting. AB - Nucleoside analogues are widely used for the treatment of antiviral infections and anticancer chemotherapy. However, many nucleoside analogues suffer from poor oral bioavailability due to their high polarity and low intestinal permeability. In order to improve oral absorption of these polar drugs, prodrugs have been employed to increase lipophilicity by chemical modification of the parent. Alternatively, prodrugs targeting transporters present in the intestine have been exploited to facilitate the transport of the nucleoside analogues. Valacyclovir and valganciclovir are two successful valine ester prodrugs transported by the PepT1 transporter. Recently, research efforts have focused on design of prodrugs for tissue specific delivery to improve efficacy and safety. This review presents advances of prodrug approaches for improved oral absorption of nucleoside analogues and recent developments in tissue targeting. PMID- 17696167 TI - Estradiol enhances long term potentiation in hippocampal slices from aged apoE4 TR mice. AB - Hormone replacement therapy to treat or prevent Alzheimer Disease (AD) in postmenopausal women is controversial because it may pose other health risks such as cancer and thromboembolism. ApoE status is thought to influence the nootropic efficacy of hormone therapy, but findings are neither consistent nor well understood. We used a known in vitro memory model (long-term potentiation, LTP) in aged (24-27 month) female targeted replacement mice expressing human apoE3 or E4 to compare the effects of exogenous estradiol. Recording medial perforant path evoked field potentials in dentate gyrus of hippocampal slices, we found that both strains exhibited comparable basal synaptic transmission as assessed by input/output functions and paired pulse depression, and that these measures were not affected by estradiol. Vehicle-treated groups from both strains showed comparable LTP. Estradiol had no effect on LTP in apoE3-TR, but selectively increased LTP magnitude in apoE4-TR. The estradiol induced enhancement of LTP in aged female apoE4-TR is consistent with recent clinical observations that estrogen replacement decreases AD risk in some women with apoE4. Elucidating the mechanism of this selective enhancement may lead to more informed treatment decisions as well as to the development of safer alternatives to hormone therapy. PMID- 17696168 TI - Differential involvement of the dorsal hippocampus in passive avoidance in C57bl/6J and DBA/2J mice. AB - The inferior performance of DBA/2 mice when compared to C57BL/6 mice in hippocampus-dependent behavioral tasks including contextual fear conditioning has been attributed to impaired hippocampal function. However, DBA/2J mice have been reported to perform similarly or even better than C57BL/6J mice in the passive avoidance (PA) task that most likely also depends on hippocampal function. The apparent discrepancy in PA versus fear conditioning performance in these two strains of mice was investigated using an automated PA system. The aim was to determine whether these two mouse strains utilize different strategies involving a different contribution of hippocampal mechanisms to encode PA. C57BL/6J mice exhibited significantly longer retention latencies than DBA/2J mice when tested 24 h after training irrespective of the circadian cycle. Dorsohippocampal NMDA receptor inhibition by local injection of the selective antagonist DL-2-amino-5 phosphonovaleric acid (AP5, 3.2 microg/mouse) before training resulted in impaired PA retention in C57BL/6J but not in DBA/2J mice. Furthermore, nonreinforced pre-exposure to the PA system before training caused a latent inhibition-like reduction of retention latencies in C57BL/6J, whereas it improved PA retention in DBA/2J mice. These pre-exposure experiments facilitated the discrimination of hippocampal involvement without local pharmacological intervention. The results indicate differences in PA learning between these two strains based on a different NMDA receptor involvement in the dorsal hippocampus in this emotional learning task. We hypothesize that mouse strains can differ in their PA learning performance based on their relative ability to form associations on the basis of unisensory versus multisensory contextual/spatial cues that involve hippocampal processing. PMID- 17696169 TI - Dysregulation of growth factor receptor-bound protein 2 and fascin in hippocampus of mice polytransgenic for chromosome 21 structures. AB - Nonchimeric polytransgenic 152F7 mice encompassing four human chromosome 21 genes (DSCR3, DSCR5, TTC3, and DYRK1A) within the Down syndrome critical region present with learning and memory impairment. However, no abnormalities were shown by in vitro electrophysiological or neuroanatomical findings in hippocampus of 152F7 mice. To search for molecular changes that may be linked to cognitive impairment, we compared hippocampal protein levels between nontransgenic (WT) and 152F7 mice by a proteomic approach. Protein extracts were run on two-dimensional gel electrophoresis, protein spots were analyzed by mass spectrometry (MALDI-TOF-TOF) followed by quantification by specific software. Three hundred and nineteen different gene products were identified, and 48 proteins were assigned as signaling-related proteins. Stringent statistical analysis considering P < 0.005 as statistically significant based upon multiple testing revealed that growth factor receptor-bound protein 2 (Grb2) levels were decreased and an expression form of fascin 1 was increased in 152F7 mice when compared with WT. A series of proteins showed trends for increased and decreased hippocampal levels (P > 0.005 and P < 0.05). Only 2 out of 319 different gene products were dysregulated, pointing to the specificity of the analysis. Decreased Grb2 levels in the hippocampus of 152F7 mice may contribute to impaired cytoskeleton functions because dynamin 1 binds to Grb2 and involved in the formation of the endocytic process. Fascin dysregulation is of relevance for actin bundling in vesicle trafficking and may represent or lead to impaired neurotransmission that, in turn, may lead to the cognitive defect observed in this mouse model of Down syndrome. PMID- 17696170 TI - The hippocampal indexing theory and episodic memory: updating the index. AB - A little over 20 years ago, (Teyler and DiScenna,1986; Behav Neurosci 100:147 152) proposed the hippocampal memory index theory. It offered an account of episodic memory based on the intrinsic organization of the hippocampus, its synaptic physiology and its anatomical relationship to other regions of the brain. The essence of their idea was that the hippocampus was functionally designed and anatomically situated to capture information about neocortical activity generated by the individual features of behavioral episode. Moreover, because the hippocampus projects back to these neocortical regions the information it stored could serve as an index to the pattern of neocortical activity produced by the episode. Consequently, a partial cue that activated the index could activate the neocortical patterns and thus retrieve the memory of the episode. In this article we revisit and update indexing theory. Our conclusion is that it has aged very well. Its core ideas can be seen in many contemporary theories and there is a wealth of data that support this conceptual framework. PMID- 17696171 TI - Perirhinal and hippocampal contributions to visual recognition memory can be distinguished from those of occipito-temporal structures based on conscious awareness of prior occurrence. AB - The ability of humans to distinguish consciously between new and previously encountered objects can be probed with visual recognition memory tasks that require explicit old-new discriminations. Medial temporal-lobe (MTL) lesions impair performance on such tasks. Within the MTL, both perirhinal cortex and the hippocampus have been implicated. Cognitive processes can also be affected by past object encounters in the absence of conscious recognition, as in repetition priming tasks. Past functional neuroimaging findings in healthy individuals suggest that even in tasks that require conscious recognition decisions for visual stimuli, posterior cortical structures in the ventral visual pathway distinguish between old and new objects at a nonconscious level. Conclusive evidence that differentiates the neural underpinnings of conscious from nonconscious processes in recognition memory, however, is still missing. In particular, functional magnetic resonance imaging (fMRI) findings for the MTL have been inconsistent towards this end. In the present fMRI study, we tested whether perirhinal and hippocampal contributions to recognition memory can be distinguished from those of occipito-temporal structures in the ventral visual pathway based on the participants' reported conscious awareness of prior occurrence. Images of objects with a large degree of feature overlap served as stimuli; they were selected to ensure an involvement of perirhinal cortex in the present recognition task, based on evidence from past lesion-based research. We found that both perirhinal cortex and occipito-temporal cortex showed a differential old-new response that reflected a repetition-related decrease in activity (i.e., new > old). Whereas in perirhinal cortex this decrease was observed with respect to whether subjects reported objects to be old or new, irrespective of the true item status, in occipito-temporal cortex it occurred in relation to whether objects were truly old or new, irrespective of the participants' conscious reports. Hippocampal responses differed in their exact pattern from those of perirhinal cortex, but were also related to the conscious recognition reports. These results indicate that both perirhinal and hippocampal contributions can be distinguished from those of occipito-temporal structures in the ventral visual pathway based on the participants' reported conscious awareness of prior occurrence. PMID- 17696172 TI - Disruption of cerebral cortex MET signaling in autism spectrum disorder. AB - OBJECTIVE: Multiple genes contribute to autism spectrum disorder (ASD) susceptibility. One particularly promising candidate is the MET gene, which encodes a receptor tyrosine kinase that mediates hepatocyte growth factor (HGF) signaling in brain circuit formation, immune function, and gastrointestinal repair. The MET promoter variant rs1858830 allele "C" is strongly associated with ASD and results in reduced gene transcription. Here we examined expression levels of MET and members of the MET signaling pathway in postmortem cerebral cortex from ASD cases and healthy control subjects. METHODS: Protein, total RNA, and DNA were extracted from postmortem temporal cortex gray matter samples (BA 41/42, 52, or 22) belonging to eight pairs of ASD cases and matched control subjects. MET protein expression was determined by Western blotting; messenger RNA expression of MET and other related transcripts was assayed by microarray and quantitative reverse transcriptase polymerase chain reaction. RESULTS: MET protein levels were significantly decreased in ASD cases compared with control subjects. This was accompanied in ASD brains by increased messenger RNA expression for proteins involved in regulating MET signaling activity. Analyses of coexpression of MET and HGF demonstrated a positive correlation in control subjects that was disrupted in ASD cases. INTERPRETATION: Altered expression of MET and related molecules suggests dysregulation of signaling that may contribute to altered circuit formation and function in ASD. The complement of genes that encode proteins involved in MET activation appears to undergo long-term compensatory changes in expression that may be a hallmark contribution to the pathophysiology of ASD. PMID- 17696173 TI - Evidence for episodic memory in a pavlovian conditioning procedure in rats. AB - In an effort to evaluate episodic memory processes in the rat, we developed a novel Pavlovian conditioning procedure. Rats explored two distinctive contexts, one in the morning and the other in the evening. Subsequently, either in the morning or the evening, they received a foot shock immediately upon entry into a third context that equally resembled the two explored contexts. When conditioned freezing was measured at an intermediate time of day, rats showed significantly more fear of the context congruent with the time of day of the foot shock. Thus, rats automatically form an integrated time-place memory that can be flexibly updated by future events, essential characteristics of episodic memory. PMID- 17696174 TI - Calcium-independent phospholipase A(2) influences AMPA-mediated toxicity of hippocampal slices by regulating the GluR1 subunit in synaptic membranes. AB - We have recently documented that phosphorylation of the GluR1 subunit of alpha amino-3-hydroxy-5-methylisoxazole-propionate (AMPA) glutamate receptors is influenced by calcium-independent forms of phospholipase A(2) (iPLA(2)) activity in the brain. Given the importance of GluR1 subunit phosphorylation in the control of AMPA receptor delivery to synaptic membranes, we tested the influence of iPLA(2) activity on AMPA receptor distribution between neuronal compartments, using organotypic cultured hippocampal slices. In agreement with earlier reports, the iPLA(2) inhibitor bromoenol lactone (BEL) markedly enhanced the phosphorylation of the GluR1 subunit at both Ser831 and Ser845 residues. GluR1 subunit phosphorylation levels were selectively increased by (R)-BEL, an enantio selective inhibitor of iPLA(2)gamma, but not by (S)-BEL, an iPLA(2)beta inhibitor. The iPLA(2)gamma inhibitor R-BEL also promoted the insertion of new GluR1 subunits into synaptic membranes and exacerbated AMPA-mediated cell death in the CA1 region of the hippocampus. The latter effect was selectively abolished by IEM 1460 and philanthotoxin-433, two antagonists specific for AMPA receptors lacking GluR2 subunits. These results provide evidence that iPLA(2)gamma-related regulation of AMPA receptor GluR1 subunit phosphorylation could represent an important mechanism modulating hippocampal cell death induced by AMPA receptor overstimulation. PMID- 17696175 TI - COL4A1 mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. AB - OBJECTIVE: Several hereditary ischemic small-vessel diseases of the brain have been reported during the last decade. Some of them have ophthalmological, mainly retinal, manifestations. Herein, we report on a family affected by vascular leukoencephalopathy and variable abnormalities of the anterior chamber of the eye. METHODS: After the occurrence of a small, deep infarct associated with white matter lesions in a patient with a medical history of congenital cataract and amblyopia, we conducted clinical and neuroradiological investigations in 10 of her relatives. RESULTS: Diffuse leukoencephalopathy associated with ocular malformations of the Axenfeld-Rieger type was observed in five individuals. Familial genetic analyses led to the identification of a novel missense mutation in the COL4A1 gene, p.G720D, which cosegregates with the disease. INTERPRETATION: Our data corroborate previous observations demonstrating the role of COL4A1 in cerebral microangiopathy and expand the phenotypic spectrum associated with mutations in this gene. We delineate a novel association between the Axenfeld Rieger anomaly and leukoencephalopathy and stroke. Ann Neurol 2007. PMID- 17696176 TI - Saccadic palsy after cardiac surgery: characteristics and pathogenesis. AB - OBJECTIVE: To characterize the syndrome of saccadic palsy that may follow cardiac surgery, and to interpret the findings using current concepts of the neurobiology of fast eye movements. METHODS: Using the magnetic search coil technique, we measured eye, eyelid, and head movements of 10 patients who developed selective palsy of saccades after cardiac surgery. RESULTS: Patients showed varying degrees of slowing and hypometria of saccades in the vertical plane or both horizontal and vertical planes, with complete loss of all saccades in one patient. Quick phases of nystagmus were also affected, but smooth pursuit, vergence, and the vestibuloocular reflex were usually spared. The smallest saccades were less slowed than larger saccades. Affected patients were visually disabled by loss of ability to voluntarily shift their direction of gaze. Blinks and head thrusts modestly improved the range and speed of voluntary movement. The syndrome usually followed aortic valve replacement. Common accompanying features included dysarthria, labile emotions, and unsteady gait. The saccadic palsy either improved during the early part of the course or remained static. INTERPRETATION: Selective loss of all forms of saccades, with sparing of other eye movements, indicates malfunction of the brainstem machinery that generates saccades. A current model of brainstem circuits could account for both hypometria and slowing. This syndrome and the visual disability it causes often go unrecognized unless saccades are systematically tested at the bedside. PMID- 17696177 TI - Smart "turn-on" magnetic resonance contrast agents based on aptamer functionalized superparamagnetic iron oxide nanoparticles. PMID- 17696178 TI - Controlled stability of the triple-stranded helical structure of a beta-1,3 glucan with a chromophoric aromatic moiety at a peripheral position. AB - We synthesized a semiartificial beta-1,3-glucan, curdlan with dialkylaniline groups (CUR-DA), that bears chromophoric aromatic groups at its peripheral positions. Spectroscopic studies as well as microscopic observations indicate that CUR-DA adopts a triple-stranded helical structure in water- or methanol-rich solutions of dimethyl sulfoxide (DMSO). This triple-stranded helical structure exhibits high thermal stability and resistance to base, attributes that are similar to those of the triple-stranded helical structure of native beta-1,3 glucans such as schizophyllan. Moreover, we found that the stability of the triple-stranded helical structure can be easily modulated by solvent composition and metal-ion (Zn2+) binding. As beta-1,3-glucan polysaccharides are known to serve as "polymeric" hosts, including certain DNA molecules, carbon nanotubes, and conjugated polymers, and complexation occurs only with the single-stranded structure, this information is very useful for the creation of these attractive polymeric composites, the controlled release of DNA, and so on. PMID- 17696179 TI - Bright blue-emitting Ce3+ complexes with encapsulating polybenzimidazole tripodal ligands as potential electroluminescent devices. PMID- 17696181 TI - Metal-free catalytic hydrogenation. PMID- 17696180 TI - Rational design of a fluorescence-turn-on sensor array for phosphates in blood serum. PMID- 17696184 TI - Early barriers in the matrix photochemical formation of syn-anti randomized FC(O)SeF from the OCSe:F(2) complex. AB - The photochemically induced reaction of OCSe and F(2), isolated together in an Ar matrix at about 15 K, leads to formation of the hitherto-unknown fluorocarbonylselenyl fluoride FC(O)SeF. The reaction occurs via a van der Waals complex O=C=Se...F-F that favors very early formation of the anti conformer. The presence and subsequent decay of a band assigned to the F-F vibration correlated with perturbed OCSe bands seems to confirm this hypothesis. Subsequent irradiation of the matrix leads to randomized FC(O)SeF by a photochemically induced conformational equilibrium between syn and anti forms. Another photochemical reaction channel is the formation of CO and SeF(2) molecules, which are produced in the same matrix cage and then form a loose complex. The changes were monitored and the products characterized experimentally by their IR spectra, and the spectra analyzed in the light of the results of theoretical calculations. PMID- 17696185 TI - Coexistence of hydrogen-bonded loop and extended tetrapeptide conformations. AB - The conformations of a protected tetrathiopeptide have been analysed by isotope labelling and two-dimensional infrared spectroscopy (2D-IR). It has been found that Boc-Ala-Gly(=S)-Ala-Aib-OMe in acetonitrile, as well as its oxopeptide analogue, can adopt a hydrogen-bonded loop conformation in coexistence with less restricted structures. The two types of conformations interconvert too quickly to be resolved on the nuclear magnetic resonance (NMR) timescale, but give rise to different cross peaks in two-dimensional infrared spectra. The hydrogen bond between the Boc terminal group and the amide proton of Aib can be broken by photoisomerisation of the thioamide bond. PMID- 17696186 TI - Dispersion interactions govern the strong thermal stability of a protein. AB - Rubredoxin from the hyperthermophile Pyrococcus furiosus (Pf Rd) is an extremely thermostable protein, which makes it an attractive subject of protein folding and stability studies. A fundamental question arises as to what the reason for such extreme stability is and how it can be elucidated from a complex set of interatomic interactions. We addressed this issue first theoretically through a computational analysis of the hydrophobic core of the protein and its mutants, including the interactions taking place inside the core. Here we show that a single mutation of one of phenylalanine's residues inside the protein's hydrophobic core results in a dramatic decrease in its thermal stability. The calculated unfolding Gibbs energy as well as the stabilization energy differences between a few core residues follows the same trend as the melting temperature of protein variants determined experimentally by microcalorimetry measurements. NMR spectroscopy experiments have shown that the only part of the protein affected by mutation is the reasonably rearranged hydrophobic core. It is hence concluded that stabilization energies, which are dominated by London dispersion, represent the main source of stability of this protein. PMID- 17696187 TI - Evidence for spontaneous release of acrylates from a transition-metal complex upon coupling ethene or propene with a carboxylic moiety or CO(2). AB - The development of a new synthetic approach to acrylates based on the formation of alkyl esters of acrylic acids has been studied. A preformed Pd-COOMe moiety is used as a model system to investigate the insertion of an olefin into the Pd--C bond. The fast elimination of acrylate is observed. Density functional calculations support the experimental findings and allow the characterization of transition states along the reaction pathway. The first example of olefin/CO(2) coupling with facile release of ethyl acrylate is also presented. PMID- 17696188 TI - Highly diastereoselective palladium-catalyzed cyclizations of 3,4-allenylic hydrazines and organic halides -- highly stereoselective synthesis of optically active pyrazolidine derivatives and the prediction of the stereoselectivity. AB - Pyrazolidines containing two chiral centers, an interesting class of heterocyclic compounds possessing a range of biological activities, have been prepared highly diastereoselectively (up to 95:5) through asymmetric Pd(OAc)(2)-catalyzed cyclizations between the easy available optically active allenylic hydrazines and organic halides in THF in the presence of (R,R)-Bn-Box (L2) as the ligand. It was observed 1) that in most cases (3R,5S)-pyrazolidines were obtained in good yields with very high enantiopurities (>99%) and high diastereoselectivities (up to 95:5) in the presence of (R,R)-Bn-Box (L2), 2) that aryl halides containing electron-donating or -withdrawing groups, heteroaryl, and 1-alkenyl iodides are all suitable substrates for this diastereoselective cyclization, 3) that the absolute configurations of the newly formed chiral centers in the pyrazolidines depend on the structure of substrate 1, and 4) that the enantio- and diastereopurities of the trans-pyrazolidines are co-controlled by the chiralities of the chiral catalysts and the substrates. A model for prediction of the enantiopurities of the products and the diastereoselectivities of the reactions based on an HPLC study of the starting hydrazines and the products was established. PMID- 17696191 TI - [(dpp-bian)Ga-Ga(dpp-bian)] and [(dpp-bian)Zn-Ga(dpp-bian)]: synthesis, molecular structures, and DFT studies of these novel bimetallic molecular compounds. AB - 1,2-Bis[(2,6-diisopropylphenyl)imino]acenaphthene) (dpp-bian) stabilizes gallium gallium and zinc-gallium bonds (compounds 1-3). The compound [(dpp-bian)Ga-Ga(dpp bian)] (2) was prepared by the reaction of GaCl3 with K3[dpp-bian] and the heterometallic [(dpp-bian)Zn-Ga(dpp-bian)] (3) was prepared by a simple one-pot reaction of [{(dpp-bian)ZnI}(2)] with GaCl3 and K4[dpp-bian]. In contrast to [(dpp-bian)Zn-Zn(dpp-bian)] (1) and 3, compound 2 is ESR silent, thus proving the dianionic character of both dpp-bian ligands. The solution ESR spectrum of 3 reveals the coupling of an unpaired electron with the gallium nuclei (69)Ga and (71)Ga (A((69)Ga)=0.97, A((71)Ga)=1.23 mT), thus confirming the presence of Zn-Ga bonds in solution. According to the results of the X-ray crystal structure analyses the metal-metal bond lengths in 2 (2.3598(3) A) and 3 (2.3531(8) A) are close to that found in 1 (2.3321(2) A). The electronic structures of compounds 2 and 3 were studied by DFT (B3 LYP/6-31G* level). The metal-metal pi bond in 2 is mainly formed by overlap of the p orbitals of Ga in the HOMO and HOMO-1, the latter showing a stronger interaction. The s and p orbitals of Ga overlap in the deeper located HOMO-17 producing a Ga-Ga sigma bond. In contrast to the Zn-Zn bond in 1, which has 95 % s character, the NBO (natural bond order) analysis of 2 reveals 67.8 % s, 32.0 % p, and 0.2 % d character for the Ga-Ga bond. Compound 3 has a doublet electronic ground state. The unpaired electron occupies the alpha HOMO-1 localized at the Zn-containing fragment. The Ga-Zn bond is mainly formed by overlap of the metal orbitals in the alpha HOMO-6 and beta HOMO-5. According to the results of the NBO analysis, the Zn wave functions are responsible for 28.7 % of the Zn-Ga bond, with 96.7 % s, 1.0 % p, and 2.3 % d character. PMID- 17696192 TI - HIV-1 protease and HIV-1 integrase inhibitory substances from Eclipta prostrata. AB - The bioassay-guided fractionation for anti-HIV-1 integrase activity led to the isolation of six compounds from the whole plant extract of Eclipta prostrata extract. They were identified as 5-hydroxymethyl-(2,2':5',2'')-terthienyl tiglate (1), 5-hydroxymethyl-(2,2':5',2'')-terthienyl agelate (2), 5-hydroxymethyl (2,2':5',2'')-terthienyl acetate (3), ecliptal (4), orobol (5) and wedelolactone (6). Of these, compound 6 showed the highest activity against HIV-1 integrase (IN) with an IC50 value of 4.0+/-0.2 microm, followed by compound 5 (IC50=8.1+/ 0.5 microm), whereas the four terthiophene compounds (1-4) were inactive (IC50>100 microm). Regarding HIV-1 protease (PR) inhibitory activity, compound 1 exhibited appreciable activity against HIV-1 PR with an IC50 of 58.3+/-0.8 microm, followed by compound 4 (IC50=83.3+/-1.6 microm) and compound 3 (IC50=93.7+/-0.8 microm), while compounds 2, 5 and 6 were inactive against HIV-1 PR (IC50>100 microm). This is the first report of anti-HIV-1 IN activities for wedelolactone (6), a coumarin derivative, and orobol (5), an isoflavone derivative. This study supports the use of E. prostrata in AIDS patients, which is in accord with its traditional use by Thai traditional doctors for curing blood related diseases. PMID- 17696193 TI - PVRL2 is translocated to the TRA@ locus in t(14;19)(q11;q13)-positive peripheral T-cell lymphomas. AB - Very few recurrent chromosomal abnormalities have been identified in T-cell non Hodgkin lymphomas. These involve the TRA@/TRD@ gene at chromosome band 14q11 in up to 15% of cases. We recently reported a novel and recurrent translocation, t(14;19)(q11;q13), in peripheral T-cell lymphoma (PTCL). Fluorescence in situ hybridization analysis performed in three cases suggested an involvement of the TRA@/TRD@ locus at 14q11 and of a region telomeric to BCL3 on 19q13. We now report the molecular cloning of these translocations. Sequence analysis confirmed the involvement of the TRA@/TRD@ and indicated that the breakpoints were located mainly in the TRAJ region. On chromosome 19, our results revealed a new clustering of breakpoints outside the region involved in t(14;19)(q32;q13) positive B-cell malignancies. Remarkably, all three breaks were located downstream or within the PVRL2 gene, in a small 10.3 kb interval, suggesting a nonrandom location of the breakpoints. For two patients, a high mRNA expression of both PVRL2 and BCL3 was found. In conclusion, we identified PVRL2 as a new recurrent partner gene of the TRA@ locus in PTCL. These results suggest that both BCL3 and PVRL2 may participate in the pathogenesis of these PTCLs, but further studies should be undertaken to investigate the precise role of these genes. PMID- 17696194 TI - Genomic profile of chronic myelogenous leukemia: Imbalances associated with disease progression. AB - The expression of the chimeric BCR/ABL1 fusion gene resulting from t(9;22)(q34;q11) in chronic myelogenous leukemia (CML) is necessary for malignant transformation, but not sufficient to maintain disease progression. The appearance of various chromosomal and molecular alterations in the accelerated and terminal phase of CML is well documented, but evidence for causal relationship is largely lacking. We carried out a genome wide screening at a resolution of 1 Mb of 54 samples at different stages of CML together with 12 CML cell lines and found that disease progression is accompanied by a spectrum of recurrent genome imbalances. Among the most frequent are losses at 1p36, 5q21, 9p21, and 9q34 and gains at 1q, 8q24, 9q34, 16p, and 22q11, all of which were located with higher precision within the genome than previously possible. These genome imbalances are unique to CML cases with clinically manifested or suspected accelerated/blast stage alike, but not seen in chronic phase samples. Previously unrecognized cryptic imbalances occurring within the Ph-chromosome were also detected, although further scrutiny is required to pin-point gene involvement and seek association with disease features. Importantly, some of these imbalances were seen in the CD34(+) cells but not in the whole BM samples of patients in accelerated phase. Taken together, these findings highlight the potential of screening CD34(+) cells for genome wide imbalances associated with disease progression. Finally, the numerous single copy number variations recorded, many unique to this cohort of patients, raise the possible association of genome polymorphism and CML. PMID- 17696195 TI - Differential gene expression in melanocytic nevi with the V600E BRAF mutation. AB - We studied gene expression in 18 melanocytic nevi with and four nevi without the V600E mutation in the BRAF gene using HG-U133A 2.0 microarray with 22,277 transcripts. Data analysis revealed 92 genes up-regulated and 105 genes down regulated in nevi with the mutation compared to nevi without mutation. Pathway analysis showed that differentially regulated genes mapped to 10 genetic networks. The major network included genes involved in cell death, cell cycle, and cellular growth and proliferation. Up-regulated genes in nevi with the mutation included CDKN2A, CDKN1C, and MITF; whereas down-regulated genes included those involved in apoptotic and other pathways. Principal component analysis identified 22 probe sets (20 genes) that caused separate segregation of nevi with and without mutations. In conclusion, our data showed differences in gene expression between nevi with and without the V600E BRAF mutation. Moreover, nevi with mutations showed over-expression of genes involved in melanocytic senescence and cell cycle inhibition. PMID- 17696196 TI - FGFR1 over-expression in primary rhabdomyosarcoma tumors is associated with hypomethylation of a 5' CpG island and abnormal expression of the AKT1, NOG, and BMP4 genes. AB - Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma likely results from abnormal proliferation and differentiation during skeletal myogenesis. Multiple genetic alterations are associated with the three RMS histopathological subtypes, embryonal, alveolar, and pleomorphic adult variant. Recently, we reported the novel amplification of the FGFR1 gene in a RMS tumor. The involvement of FGFR1 in RMS was now further studied in primary tumors and RMS cell lines by mutation screening, quantitative RNA expression, and methylation analyses. No mutation was found by DHPLC and sequencing of the entire FGFR1 coding sequence and exon-intron boundaries. However, FGFR1 over-expression was detected in all primary RMS tumors and cell lines tested. A hypomethylation of a CpG island upstream to FGFR1 exon 1 was identified in the primary RMS tumors, using sodium bisulfite modification method, suggesting a molecular mechanism to FGFR1 over-expression. Expression analysis of additional genes, AKT1, NOG and its antagonist BMP4, which interact downstream to FGFR1, demonstrated expression differences between primary RMS tumors and normal skeletal muscles. Our data suggest an important role for FGFR1 and FGFR1-downstream genes in RMS tumorigenesis and a possible association with the deregulation of proliferation and differentiation of skeletal myoblasts in RMS. PMID- 17696197 TI - Malaria and hereditary elliptocytosis. PMID- 17696199 TI - Cerebral nocardiosis in a patient with NHL treated with rituximab. PMID- 17696198 TI - Relative systemic hypertension in patients with sickle cell disease is associated with risk of pulmonary hypertension and renal insufficiency. AB - We analyzed entry data from 163 adult hemoglobin SS and Sbeta(0) thalassemia patients enrolled in the prospective Sickle Cell Pulmonary Hypertension Screening Study and stratified their ECHO-determined tricuspid regurgitant jet velocity (TRV) and serum creatinine concentration according to three systemic blood pressure categories. TRV was >or= 2.5 m/sec in 27% of the patients with systolic blood pressure (SBP) <120 mmHg and diastolic blood pressure (DBP) <70 mmHg, in 37% with SBP 120-139 mmHg or DBP 70-89 mmHg, and in 93% with SBP 140 mmHg or DBP 90 mmHg or higher (P<0.0005 for trend). Serum creatinine concentration was 1.0 mg/dL or higher in 7% of patients with SBP <120 mmHg and DBP <70 mmHg, in 17% with SBP 120-139 mmHg or DBP 70-89 mmHg and 50% with SBP 140 mmHg or DBP 90 mmHg or higher (P<0.0005 for trend). Over 2 years of follow-up, there were trends for more frequent progression to elevated TRV (P=0.073) or creatinine (P=0.037) values according to the higher systemic blood pressure categories. Our findings suggest that systemic SBP 120-139 mmHg or DBP 70-89 mmHg defines a category of relative systemic hypertension in patients with sickle cell disease that is associated with increased risk for pulmonary hypertension and renal dysfunction. Whether antihypertensive and/or nitric oxide donor therapy in sickle cell disease patients with relative hypertension prevents these and other complications should be determined by clinical trials. PMID- 17696200 TI - Therapeutic use of Rituximab for sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). PMID- 17696201 TI - Children with hyperdiploid but not triple trisomy (+4,+10,+17) acute lymphoblastic leukemia have an increased incidence of extramedullary relapse on current therapies: a single institution experience. AB - To evaluate the outcome of children with high hyperdiploid acute lymphoblastic leukemia (hHDALL) treated at the author's institution. One hundred thirty-five consecutive children with B-precursor ALL were diagnosed between 1991 and 2002: 38 (28.1%) hHDALL and 97 (71.9%) non-hHDALL. In the hHDALL group, 11/38 (28.9%) relapsed at a median interval of 2.8 years (range: 0.8-5.0 years) with 9/11 relapses occurring at the end or after the completion of therapy. Three (27.3%) relapses were isolated hematopoietic (BM), while eight (72.7%) were either isolated extramedullary (EM) relapses (n=6; Testis: 4; CNS: 2) or combined hematopoietic and extramedullary relapses (n=2; BM + CNS: 1; BM + Testis: 1). For the non-hHDALL group, 29/97 (29.9%) relapsed. Unlike the hHDALL group, the non hHDALL group experienced hematopoietic relapses (62%; n=18) more frequently than isolated extramedullary (27.5%; n=8: Testis: 1; CNS: 7) or combined hematopoietic and extramedullary relapses (10.3%; CNS + BM: 3), with 24/29 (82.8%) of the relapses occurring on therapy. Relapses in hHDALL frequently involved EM sites (P=0.053). Presence of triple trisomy of +4,+10,+17 at diagnosis had a protective effect against relapse (P<0.05). Five-year EFS for the hHDALL and non-hHDALL patients was similar, 70.5+/-7.5% and 66.4+/-4.9%, respectively. Five-year OS for the hHDALL patients was significantly higher than for the non-hHDALL patients, 92+/-4.5% vs. 74.1+/-4.5%, P=0.038. Biologically significant differences exist between relapse patterns of hHDALL and non-hHDALL cases related to relapse sites and time periods when relapses occur. hHDALL relapses continue to be chemo sensitive. PMID- 17696202 TI - Azathioprine-associated acute myeloid leukemia in a patient with Crohn's disease and thiopurine S-methyltransferase deficiency. AB - Immunosuppressive thiopurines like azathioprine, 6-mercaptopurine, and thioguanine are commonly used in inflammatory and neoplastic disorders. A subset of these patients are genetically slow metabolizers due to point-mutations in enzyme thiopurine S-methyltransferase (TPMT), and are at a higher risk of hematologic toxicity and leukemogenesis. We present such a patient who was a slow metabolizer for azathioprine, and developed a rapidly lethal form acute myeloid leukemia after relatively low dose exposure to the drug. There was prominent hemophagocytic activity in the bone marrow, and cytogenetic analysis showed a complex karyotype with monosomy 7, but no involvement of chromosome 8. PMID- 17696203 TI - Phase II evaluation of an intensified induction therapy with standard daunomycin and cytarabine followed by high dose cytarabine for adults with previously untreated acute myeloid leukemia: a Southwest Oncology Group study (SWOG-9500). AB - Induction therapy for acute myeloid leukemia (AML) usually consists of 7 days of cytarabine at 100-200 mg/m(2)/day and an anthracycline. Such combinations produce complete response (CR) rates of 60-80% in patients with de novo AML. On the basis of a previous report, suggesting a higher CR rate using a regimen of standard daunomycin and cytarabine followed by 3 days of high-dose cytarabine (HDAC), 101 eligible patients received this regimen in a phase II trial. Sixty patients [59%, 95% confidence interval (CI) 49-69%] achieved a CR, and 10 patients died of infection during induction. Although cytogenetic risk group affected overall survival (P = 0.0016) and relapse-free survival (P = 0.0043), it had no impact on CR rate (P = 0.63). Patients received postremission therapy with repetitive courses of alternate day high-dose cytarabine; this was associated with considerable toxicity and the majority of patients could not receive all of the scheduled postremission therapy. The estimated median survival was 23 months (95% CI 15-34 months), and the estimated probability of surviving 5 years was 34% (95% CI 24-43%). The results of this intensive induction regimen were similar to that seen in previous trials and were not as promising as reported in the previous pilot study. PMID- 17696204 TI - Post-transplant outcomes of induction therapy for myeloma: thalidomide and dexamethasone versus doxorubicin, vincristine, and dexamethasone prior to high dose melphalan with autologous stem cell support. AB - High-dose melphalan with autologous stem cell support improves survival as part of initial therapy for myeloma. Previous studies of pre-transplant induction regimens have compared paraprotein response rates but not long-term outcomes after transplant. We reviewed the records of all patients with multiple myeloma who received an autologous stem cell transplant at the University of Pennsylvania Medical Center. We compared outcomes for 69 patients who received high-dose melphalan conditioning after January 1, 2003 as part of initial therapy for myeloma, including 41 patients who received anthracycline-based induction (VAD or DVD) and 28 patients who received thalidomide and dexamethasone induction. Baseline characteristics in these two groups were not different, though potentially clinically important differences were apparent in assignment to post transplant consolidation and maintenance therapy. Despite similar response rates during induction therapy, thalidomide and dexamethasone induction was associated with better progression-free survival (hazard ratio 0.18, P = 0.011) after transplant. This effect persisted in multivariable regression models including baseline characteristics and post-transplant treatment. Overall survival was not different between the two groups. These results suggest that the use of thalidomide during induction therapy may lead to improved long-term outcomes after transplant. Future trials comparing induction therapies should examine progression-free and overall survival after transplant to confirm this benefit. PMID- 17696205 TI - Successful treatment of adult T-cell leukemia with unrelated cord blood transplantation. AB - This study reports the first well-documented case of adult T-cell leukemia (ATL) successfully treated with unrelated cord blood transplantation (UCBT). A 49-year old woman was diagnosed with acute-type of ATL. Chemotherapy induced complete remission, but the human T-cell leukemia virus type 1 (HTLV-1) proviral load was detected in mononuclear cells of her peripheral blood. The patient received UCBT with a conditioning regimen consisting of total body irradiation, cytarabine, and cyclophosphamide. She remains in remission 30 months after UCBT and the HTLV-1 proviral load has fallen to undetectable levels. This result suggests that UCBT should be a therapeutic option for ATL patients who do not have suitable donors and those who urgently require treatment. PMID- 17696206 TI - Nonfamilial hemophagocytic lymphohistiocytosis. PMID- 17696207 TI - Predictors of response to reinduction chemotherapy for patients with acute myeloid leukemia who do not achieve complete remission with frontline induction chemotherapy. AB - Eighty-one patients with acute myeloid leukemia who had persistent leukemia following standard induction therapy with cytarabine plus daunorubicin (7+3 regimen) underwent reinduction therapy with a combination of mitoxantrone, etoposide, and high-dose cytarabine (HiDAC). Patients achieving complete remission (CR) then received consolidation therapy with HiDAC plus mitoxantrone. Patients with matched sibling donors were referred for allogeneic bone marrow transplantation (BMT) in CR-1. The overall response rate to reinduction was 53%. The major adverse predictors of CR on multivariate analysis were poor risk cytogenetics, a higher % bone marrow blasts prior to reinduction therapy and increased age. The median relapse-free survival (RFS) was 9 months and the estimated 2-year RFS was 30%. No significant predictors of RFS or overall survival (OS) were found among the patients achieving CR. Patients undergoing allogeneic BMT in CR-1 after double induction had a 50% 2-year OS. Patients relapsing after achieving CR with double induction had a poor outcome with a 4% 1 year OS. The results indicate that patients with poor risk cytogenetics or marrow blast percentage >or= 60% following 7+3 induction have a low probability of achieving CR with reinduction and should be considered for novel approaches to improve CR rates. Patients achieving CR are at high risk of relapse and should be considered for allogeneic BMT or novel strategies to attempt to reduce relapse rates. PMID- 17696208 TI - Oral decitabine reactivates expression of the methylated gamma-globin gene in Papio anubis. AB - The silencing of tumor suppressor genes associated with increased DNA methylation of the promoter regions is a frequent observation in many forms of cancer. Reactivation of these genes using pharmacological inhibitors of DNA methyltransferase such as 5-aza-2'-deoxycytidine (decitabine) is a worthwhile therapeutic goal. The effectiveness and tolerability of low-dose intravenous and subcutaneous decitabine regimens to demethylate and reactivate expression of the methylated gamma-globin gene in baboons and in patients with sickle cell disease led to successful trials of low-dose regimens of this drug in patients with myelodysplastic syndrome. Since these low-dose regimens are well-tolerated with minimal toxicity, they are suitable for chronic dosing to maintain promoter hypomethylation and expression of target genes. The development of an orally administered therapy using DNA methyltransferase inhibitors would facilitate such chronic approaches to therapy. We tested the ability of decitabine and a new salt derivative, decitabine mesylate, to reactivate the methylated gamma-globin gene in baboons when administered orally. Our results demonstrate that oral administration of these drugs at doses 17-34 times optimal subcutaneous doses of decitabine reactivates fetal hemoglobin, demethylates the epsilon- and gamma globin gene promoters, and increases histone acetylation of these promoters in baboons (Papio anubis). PMID- 17696209 TI - Erythrophagocytosis in hemolytic disease of the newborn. PMID- 17696210 TI - Novel somatic mutations of the VHL gene in an erythropoietin-producing renal carcinoma associated with secondary polycythemia and elevated circulating endothelial progenitor cells. AB - Mutation of the VHL tumor suppressor gene is a frequent genetic event in the carcinogenesis of renal-cell carcinoma (RCC). Circulating endothelial progenitor cells (EPCs) have important role in neoangiogenesis, and mobilization of these cells is induced by various growth factors including erythropoietin (EPO). With this regard, we analyzed a patient with EPO-producing clear-cell RCC and polycythemia. DNA extraction and sequencing analysis of the VHL gene were performed from the tumor and the adjacent normal renal tissue. Isolated and cultured circulating EPCs from the blood taken with phlebotomy were characterized by flow cytometry and immunofluorescence analysis. This RCC had two novel somatic mutations of the VHL gene, p.Leu128Pro and p.Asn131Lys. Culture of blood mononuclear cells revealed a strikingly high number of endothelial cell colonies derived from EPCs (nearly 10-fold more than in controls). Elevated number of circulating EPCs seems to be related to high EPO production from RCC with novel double somatic mutation of the VHL gene in this patient. PMID- 17696211 TI - Cerebrovascular accident in beta-thalassemia major (beta-TM) and beta-thalassemia intermedia (beta-TI). AB - Chronic hypercoagulable state expressed clinically by thromboembolic events has been described in thalassemia. One of the affected organs is the brain where symptomatic and asymptomatic damage has been reported. The present report describes seven cases who presented with the signs of cerebrovascular accident (CVA), five ischemic and two with hemorrhage. Two of them died. All patients were splenectomized, five received regular blood transfusions, and their ferritin levels were between 1,200 and 3,000 mg %. In addition, four patients had congestive heart failure and atrial fibrillation, and three had "Bronze diabetes," The recommendation on the basis of the results is that well-designed clinical trials are indicated to monitor asymptomatic brain damage by magnetic resonance imaging in splenectomized patients over the age of 20 years, who are not regularly transfused and have a high risk to develop thromboembolic events. In this subset of patients, anticoagulant and/or antiplatelet therapy should be considered. Moreover, treatment of additional complications resulting from iron overload, which may contribute to the etiology of CVA such as cardiac failure and arrhythmia with or without "bronze diabetes," is mandatory. PMID- 17696212 TI - On-line sample stacking and short-end injection CE for the determination of fluoxetine and norfluoxetine in plasma: Method development and validation using experimental designs. AB - A short-end injection CE method combining field-amplified sample stacking (FASS) is presented for the analysis of fluoxetine (FL) and norfluoxetine in plasma. In this study, FASS enhanced the sensitivity about 1100-fold, while short-end injection reduced the analysis time to less than 4 min. Parameters involved in the separations were investigated using a central composite design (CCD) and response surface methodology to optimize the separation conditions in a total of only 32 runs. Samples injected into the capillary for 99.9 s at a voltage of -5 kV were stacked in a water plug (0.5 psi, 9 s). Baseline resolution of FL and its major metabolite was achieved using a BGE formulation consisting of phosphate triethanolamine at low pH, and a separation voltage of -10 kV. Five percent methanol was added as organic modifier to enhance selectivity and resolution. The linear range was between 10 and 500 ng/mL (r >0.9946), covering the expected plasma therapeutic ranges. The LOD in plasma were 4 ng/mL (S/N = 3), a value comparable to that obtained using LC-MS, showing the success of the on-line stacking technique. Our method was also successfully validated in quantification and pharmacokinetic studies with three volunteer plasma samples and could be applied to pharmacogenetic studies. PMID- 17696213 TI - A study of comparability in amplified fragment length polymorphism profiling using a simple model system. AB - A simple amplified fragment length polymorphism (AFLP) model, using the bacteriophage lambda genome, was developed to test the reproducibility of this technique in an international comparative study. Using either non-selective or selective primers, nine fragments or subsets of two or three fragments, respectively, were predicted using in silico software. Under optimized conditions, all predicted fragments were experimentally generated. The reproducibility of the AFLP model was tested by submitting both "unknown" DNA template that had been restricted and ligated with AFLP linkers (R/L mixture) and corresponding primer pairs to nine laboratories participating in the study. Participants completed the final PCR step and then used either slab gel electrophoresis or CE to detect the AFLP fragments. The predicted fragments were identified by the majority of participants with size estimates consistently up to 3 base pair (bp) larger for slab gel electrophoresis than for CE. Shadow fragments, 3 bp larger than the predicted fragments, were often observed by study participants and organizers. The nine AFLP fragments exhibited relative intensities ranging from less than 3% to 22% and, apart from the two weakest fragments, with a % CV of 16 to 25. Fragments containing the highest guanine cytosine (GC) content of 50-56% showed the greatest stability in the AFLP profiles. PMID- 17696214 TI - Experimental renal preservation by normothermic resuscitation perfusion with autologous blood. AB - BACKGROUND: Normothermic perfusion (NP) has the potential to improve metabolic support and maintain the viability of ischaemically damaged organs. This study investigated the effects of NP compared with current methods of organ preservation in a model of controlled non-heart-beating donor (NHBD) kidneys. METHODS: Porcine kidneys (n = 6 in each group) were subjected to 10 min warm ischaemia and then preserved as follows: 2 h cold storage (CS) in ice (CS2 group), 18 h CS (CS18 group), 18 h cold machine perfusion (CP group) or 16 h CS + 2 h NP (NP group). Renal haemodynamics and function were measured during 3 h reperfusion with autologous blood using an isolated organ perfusion system. RESULTS: Increasing CS from 2 to 18 h reduced renal blood flow (mean(s.d.) area under the curve (AUC) 444(57) versus 325(70) ml per 100 g; P = 0.004), but this was restored by NP (563(119) ml per 100 g; P = 0.035 versus CS18). Renal function was also better in CS2, CP and NP groups than in the CS18 group (mean(s.d.) serum creatinine fall 92(6), 79(9) and 64(17) versus 44(13) per cent respectively; P = 0.001). The AUC for serum creatinine was significantly lower with CS for 2 h than for 18 h (mean(s.d.) 1102(2600) versus 2156(401) micromol/l.h; P = 0.001), although values in CP and NP groups were not significantly different from those in the CS2 group (1354(300) and 1756(280) micromol/l.h respectively). Two hours of NP increased the adenosine 3'-triphosphate : adenosine 3'-diphosphate ratio to a significantly higher level than the preperfusion values in all other groups (P = 0.046). CONCLUSION: NP with oxygenated blood was able to restore depleted ATP levels and reverse some of the deleterious effects of CS. PMID- 17696215 TI - Patient factors influencing conversion from laparoscopically assisted to open surgery for colorectal cancer. AB - BACKGROUND: Intraoperative conversion from laparoscopically assisted to open surgery for colorectal cancer is thought to be influenced by several patient factors. Analysis of the Conventional versus Laparoscopic-Assisted Surgery In Colorectal Cancer (CLASICC) Trial data aimed to identify these risk factors. METHODS: Of 488 laparoscopically assisted procedures attempted, 143 (29.3 per cent) were converted to open operation. Patient factors considered in multivariable analyses were age, sex, previous abdominal incisions, body mass index (BMI), tumour site, tumour diameter, pathological tumour (pT) and pathological node (pN) stage, extent of tumour spread from the muscularis propria, liver and peritoneal metastases, and American Society of Anesthesiologists (ASA) grade. As BMI was missing for 30.7 per cent of patients, two approaches were employed: one considered BMI as a possible risk factor and one did not. RESULTS: When BMI was taken into consideration, male sex (odds ratio (OR) 2.07; P = 0.020), BMI (OR 1.10; P = 0.006) and extent of tumour spread from the muscularis propria (OR 1.08; P < 0.001) were independent predictors of conversion. When BMI was not considered, extent of tumour spread (OR 1.07; P < 0.001) and male sex (OR 2.05; P = 0.004) were again identified, as were tumour site (OR 2.11; P = 0.005) and ASA grade (II versus I, OR 0.92; III versus I, OR 2.74; P = 0.012). CONCLUSION: Intraoperative conversion is more likely with larger BMI, in men, patients with rectal cancer, those graded ASA III or when there is greater local tumour spread. PMID- 17696216 TI - Life-saving therapy for haemorrhaging liver adenomas using selective arterial embolization. AB - BACKGROUND: Emergency treatment for patients with a ruptured hepatocellular adenoma is controversial. The aim of this study was to evaluate management with selective arterial embolization. METHODS: The study included 11 consecutive patients treated for ruptured hepatocellular adenomas between 2001 and 2006. After initial haemodynamic support, all patients received selective embolization of branches of the hepatic artery. The primary outcome was effectiveness in stopping the bleeding. Secondary outcomes were complications and changes in tumour size after embolization. RESULTS: A single embolization brought haemorrhaging under control in ten patients; one patient needed three embolizations. None of the patients required emergency surgery. In the follow-up of 19 (range 7-49) months, no general or hepatobiliary complications were observed. All 25 adenomas, including those without signs of haemorrhaging in the same liver lobe, were either smaller or not detectable on computed tomography or magnetic resonance imaging after embolization, with the median diameter decreasing from 7.0 to 2.5 cm (P < 0.001). CONCLUSION: Selective embolization of the hepatic artery is a safe and adequate first approach in the management of patients with haemorrhaging hepatocellular adenomas. Furthermore, arterial embolization reduces the size of adenomas in the liver. PMID- 17696217 TI - Long-term neurological and functional outcome in Nipah virus infection. AB - OBJECTIVE: Nipah virus (NiV) is an emerging zoonosis. Central nervous system disease frequently results in high case-fatality. Long-term neurological assessments of survivors are limited. We assessed long-term neurologic and functional outcomes of 22 patients surviving NiV illness in Bangladesh. METHODS: During August 2005 and May 2006, we administered a questionnaire on persistent symptoms and functional difficulties to 22 previously identified NiV infection survivors. We performed neurologic evaluations and brain magnetic resonance imaging (MRI). RESULTS: Twelve (55%) subjects were male; median age was 14.5 years (range 6-50). Seventeen (77%) survived encephalitis, and 5 survived febrile illness. All but 1 subject had disabling fatigue, with a median duration of 5 months (range, 8 days-8 months). Seven encephalitis patients (32% overall), but none with febrile illness had persistent neurologic dysfunction, including static encephalopathy (n = 4), ocular motor palsies (2), cervical dystonia (2), focal weakness (2), and facial paralysis (1). Four cases had delayed-onset neurologic abnormalities months after acute illness. Behavioral abnormalities were reported by caregivers of over 50% of subjects under age 16. MRI abnormalities were present in 15, and included multifocal hyperintensities, cerebral atrophy, and confluent cortical and subcortical signal changes. INTERPRETATION: Although delayed progression to neurologic illness following Nipah fever was not observed, persistent fatigue and functional impairment was frequent. Neurologic sequelae were frequent following Nipah encephalitis. Neurologic dysfunction may persist for years after acute infection, and new neurologic dysfunction may develop after acute illness. Survivors of NiV infection may experience substantial long-term neurologic and functional morbidity. PMID- 17696218 TI - Efficient cyclic system to yield ectoine using Brevibacterium sp. JCM 6894 subjected to osmotic downshock. AB - Brevibacterium sp. JCM 6894 cells grown in the presence of 1.5-2.5 M NaCl for 24 h at 30 degrees C were subjected to the osmotic downshock. Downshocked cells after ectoine release were grown for further 24 h in the fresh medium with same salinity as before shock. When this cyclic system was applied to the strain JCM 6894, the amount of ectoine in the cells increased with an increase of incubation time, which indicates that the cells manipulated by the present conditions were enough active to survive and synthesize ectoine after several times of osmotic downshock. In the presence of 2 M NaCl, the highest yield of ectoine released was achieved in this cyclic system, more than 2.4 g/L during 7 days of incubation. (1)H and (13)C-NMR analyses of solutes released from the cells by the osmotic downshock showed the presence of only ectoine with high purity. Release of ectoine from the cells was carried out within 5 min and its rates were increased by the dilution in the downshock treatment. For the convenience of operations, non-sterilized medium containing 2 M NaCl was examined for the cell growth in the present system, in which almost same level of ectoine yield, release rates, and cell viability were observed as those of sterilized medium. PMID- 17696219 TI - Enteric glial cells and their role in gastrointestinal motor abnormalities: introducing the neuro-gliopathies. AB - The role of enteric glial cells has somewhat changed from that of mere mechanical support elements, gluing together the various components of the enteric nervous system, to that of active participants in the complex interrelationships of the gut motor and inflammatory events. Due to their multiple functions, spanning from supporting elements in the myenteric plexuses to neurotransmitters, to neuronal homeostasis, to antigen presenting cells, this cell population has probably more intriguing abilities than previously thought. Recently, some evidence has been accumulating that shows how these cells may be involved in the pathophysiological aspects of some diseases. This review will deal with the properties of the enteric glial cells more strictly related to gastrointestinal motor function and the human pathological conditions in which these cells may play a role, suggesting the possibility of enteric neuro-gliopathies. PMID- 17696220 TI - Endoscopic approach to malignant strictures at the hepatic hilum. AB - Hilar tumors have proven to be a challenge to treat and manage because of their poor sensitivity to conventional therapies and our inability to prevent or to detect early tumor formation. Endoscopic stent drainage has been proposed as an alternative to biliary-enteric bypass surgery and percutaneous drainage to palliate malignant biliary obstruction. Prosthetic palliation of patients with malignant hilar stenoses poses particular difficulties, especially in advanced lesions (type II lesions or higher). The risk of cholangitis after contrast injection into the biliary tree in cases where incomplete drainage is achieved is well known. The success rate of plastic stent insertion is around 80% in patients with proximal tumors. Relief of symptoms can be achieved in nearly all patients successfully stented. PMID- 17696221 TI - Hepatorenal syndrome. AB - Hepatorenal syndrome (HRS) is a "functional" and reversible form of renal failure that occurs in patients with advanced chronic liver disease. The distinctive hallmark feature of HRS is the intense renal vasoconstriction caused by interactions between systemic and portal hemodynamics. This results in activation of vasoconstrictors and suppression of vasodilators in the renal circulation. Epidemiology, pathophysiology, as well as current and emerging therapies of HRS are discussed in this review. PMID- 17696222 TI - Outcomes of patients with cirrhosis undergoing non-hepatic surgery: risk assessment and management. AB - The reported mortality rates in patients with cirrhosis undergoing various non transplant surgical procedures range from 8.3% to 25%. This wide range of mortality rates is related to severity of liver disease, type of surgery, demographics of patient population, expertise of the surgical, anesthesia and intensive care unit team and finally, reporting bias. In this article, we will review the pathophysiology, morbidity and mortality associated with non-hepatic surgery in patients with cirrhosis, and then recommend an algorithm for risk assessment and evidence based management strategy to optimize post-surgical outcomes. PMID- 17696223 TI - Pancreatic sphincterotomy: technique, indications, and complications. AB - Pancreatic sphincterotomy serves as the cornerstone of endoscopic therapy of the pancreas. Historically, its indications have been less well-defined than those of endoscopic biliary sphincterotomy, yet it plays a definite and useful role in diseases such as chronic pancreatitis and pancreatic-type sphincter of Oddi dysfunction. In the appropriate setting, it may be used as a single therapeutic maneuver, or in conjunction with other endoscopic techniques such as pancreatic stone extraction or stent placement. The current standard of practice utilizes two different methods of performing pancreatic sphincterotomy: a pull-type sphincterotome technique without prior stent placement, and a needle-knife sphincterotome technique over an existing stent. The complications associated with pancreatic sphincterotomy are many, although acute pancreatitis appears to be the most common and the most serious of the early complications. As such, it continues to be reserved for those endoscopists who perform a relatively high volume of therapeutic pancreaticobiliary endoscopic retrograde cholangio pancreatography. PMID- 17696224 TI - Antiviral efficacy of adefovir dipivoxil versus lamivudine in patients with chronic hepatitis B sequentially treated with lamivudine and adefovir due to lamivudine resistance. AB - AIM: To compare the antiviral efficacy of adefovir (ADV) in lamivudine (LMV) resistant patients with LMV treatment in nucleoside-naive patients, using serum samples collected sequentially during the course of treatment progressing from LMV to ADV. METHODS: Forty-four patients with chronic hepatitis B (CHB) were included. The patients were initially treated with LMV and then switched to ADV when LMV resistance developed. Antiviral efficacy was assessed by measuring the following: reduction in serum HBV DNA from baseline, HBV DNA negative conversion (defined as HBV DNA being undectable by the hybridization assay), and HBV DNA response (either HBV DNA level or= 2 log10 reduction from baseline HBV DNA level). RESULTS: After two and six months of treatment, HBV DNA reduction was greater with LMV compared to ADV treatment (P = 0.021). HBV DNA negative conversion rates were 64% and 27% after one month of LMV and ADV treatment respectively (P = 0.001). Similarly, HBV DNA response rates were 74% and 51% after two months of LMV and ADV treatment respectively (P = 0.026). The time taken to HBV DNA negative conversion and to HBV DNA response were both delayed in ADV treatment compared with LMV. CONCLUSION: The antiviral efficacy of ADV in LMV-resistant patients is slower and less potent than that with LMV in nucleoside-naive patients during the early course of treatment. PMID- 17696225 TI - Hepatitis C virus non-structural 5A abrogates signal transducer and activator of transcription-1 nuclear translocation induced by IFN-alpha through dephosphorylation. AB - AIM: To study the effect of Hepatitis C virus non-structural 5A (HCV NS5A) on IFNalpha induced signal transducer and activator of transcription-1 (STAT1) phosphorylation and nuclear translocation. METHODS: Expression of STAT1 Tyr701 phosphorylation at different time points was confirmed by Western blot, and the time point when p-STAT1 expressed most, was taken as the IFN induction time for further studies. Immunocytochemistry was used to confirm the successful transient transfection of NS5A expression plasmid. Immunofluorescence was performed to observe if there was any difference in IFNalpha-induced STAT1 phosphorylation and nuclear translocation between HCV NS5A-expressed and non-HCV NS5A-expressed cells. Western blot was used to compare the phosphorylated STAT1 protein of the cells. RESULTS: Expression of HCV NS5A was found in the cytoplasm of P(CNS5A transfected ) Huh7 cells, but not in the PRC/CMV transfected or non-transfected cells. STAT1 Tyr701 phosphorylation was found strongest in 30 min of IFN induction. STAT1 phosphorylation and nuclear import were much less in the presence of HCV NS5A protein in contrast to P( RC/CMV-transfected ) and non transfected cells under fluorescent microscopy, which was further confirmed by Western blot. CONCLUSION: HCV NS5A expression plasmid is successfully transfected into Huh7 cells and HCV NS5A protein is expressed in the cytoplasm of the cells. IFN-alpha is able to induce STAT1 phosphorylation and nuclear translocation, and this effect is inhibited by HCV NS5A protein, which might be another possible resistance mechanism to interferon alpha therapy. PMID- 17696226 TI - Baseline HBV DNA level is the most important factor associated with virologic breakthrough in chronic hepatitis B treated with lamivudine. AB - AIM: To identify the factors associated with virologic breakthrough and to select a subgroup of patients who respond well to lamivudine without developing virologic breakthrough (VBT). METHODS: Of 79 patients who had received lamivudine therapy for 9-57 mo, 34 were HBeAg-positive and 45 were HBeAg-negative, 24 developed virologic breakthrough and 55 did not. Clinical and virologic factors were compared between the two groups. RESULTS: The median duration of therapy was 25 (9-57) mo. Virologic breakthrough was defined as a > 1 log HBV DNA increase following initial suppression. When several factors, including gender, duration of infection, baseline HBV DNA, and baseline ALT in HBeAg-positive chronic hepatitis patients were analyzed by logistic regression, the most important predictor of virologic breakthrough was the baseline HBV DNA (r2 = 0.12, P < 0.05). When HBeAg-positive chronic hepatitis patients were divided into two groups by a point of 6.6 log HBV DNA, the incidence of virologic breakthough between two groups was significantly different. CONCLUSION: Lamivudine may remain an effective first line therapy for those HBeAg-positive patients with a baseline HBV DNA < 6.6 log10 copies/mL. PMID- 17696227 TI - Bravo (wireless) ambulatory esophageal pH monitoring: how do day 1 and day 2 results compare? AB - AIM: To investigate if differences exist for patients' gastroesophageal reflux as measured by the Bravo ambulatory esophageal pH system between d 1 and d 2. METHODS: A retrospective study of 27 consecutive adult patients who underwent Bravo esophageal pH monitoring was performed. Patients underwent EGD under IV conscious sedation prior to Bravo placement. Acid reflux variables and symptom scores for d 1 were compared to d 2. RESULTS: The mean doses of fentanyl and midazolam were 90.4 microg and 7.2 mg, respectively. D 1 results were significantly more elevated than d 2 with respect to total time pH < 4, upright position reflux, and mean number of long refluxes. No statistical difference was noted between the two days for supine position reflux, number of refluxes, duration of longest reflux, episodes of heartburn, and symptom score. CONCLUSION: Patients undergoing Bravo esophageal pH monitoring in association with EGD and moderate conscious sedation experience significantly more acid reflux on d 1 compared to d 2. The IV sedation may be responsible for the increased reflux on d 1. Performed this way, 48-h Bravo results may not be entirely representative of the patients' true GE reflux profile. PMID- 17696228 TI - Low-dose tenofovir is more potent than adefovir and is effective in controlling HBV viremia in chronic HBeAg-negative hepatitis B. AB - AIM: To study the efficacy of tenofovir disoproxil fumarate (TDF) at low dose in a small open trial of chronic hepatitis B patients with advanced stage disease. METHODS: Eleven patients were treated with TDF 75 mg for a median period of 80 (range, 24-576) wk and then 7 cases were shifted to an adefovir 10 mg treatment group. All patients had been pre-treated with lamivudine: 5 had YMDD resistant mutants and 6 wild-type virus. When TDF was started, 4 patients had low-level viremia and 6 were PCR-negative. RESULTS: During TDF treatment, PCR remained negative in 10 patients, transaminase levels were normal and no significant viral breakthrough was observed. The drug was well tolerated in all cases. When TDF 75 mg was substituted with adefovir 10 mg, 3 out of 7 patients had a persistent viral rebound (2700-130,000 copies/mL), in whom lamivudine had to be reintroduced. CONCLUSION: Low-dose TDF monotherapy can control HBV viremia for an extended period of time without the emergence of resistance and is more potent than adefovir at the standard dosage. The use of a reduced dose of TDF could diminish the cost of therapy in low-income countries, but further studies in a larger population and in HBeAg-positive subjects are needed. PMID- 17696229 TI - Randomized, double-blind, comparative study of dexrabeprazole 10 mg versus rabeprazole 20 mg in the treatment of gastroesophageal reflux disease. AB - AIM: To compare the efficacy and safety of dexrabeprazole 10 mg versus rabeprazole 20 mg in the treatment of gastroesophageal reflux disease (GERD). METHODS: This was a randomized, double-blind clinical study. Fifty patients with GERD were randomly assigned to receive dexrabeprazole 10 mg or rabeprazole 20 mg once daily. Efficacy was assessed by evaluating improvement in visual analog scale (VAS) scores of heart-burn and regurgitation and safety was assessed by recording incidence of any adverse drug reactions. Laboratory investigations and upper gastro-intestinal endoscopy was conducted at baseline and after 28 d of therapy. RESULTS: A total of 50 patients (n = 25 in dexrabeprazole group and rabeprazole group each) completed the study. There were no significant differences in the baseline characteristics between the two groups. The VAS score (mean +/- SD) of heartburn and regurgitation in dexrabeprazole (64.8 +/- 5.1 and 64 +/- 8.1, respectively) and rabeprazole (64.4 +/- 8.7 and 57.6 +/- 9.7, respectively) groups significantly reduced (P < 0.0001) to 30 +/- 11.5, 24 +/- 10 and 32 +/- 9.5, 29.2 +/- 11.9, respectively on d 28. A significantly higher (P = 0.002) proportion of patients showed >or= 50% improvement in regurgitation with dexrabeprazole 10 mg (96%) compared to rabeprazole 20 mg (60%). Onset of symptom improvement was significantly earlier with dexrabeprazole than with rabeprazole (1.8 +/- 0.8 d vs 2.6 +/- 1.4 d; P < 0.05). The incidences of esophagitis in the dexrabeprazole group and rabeprazole group before therapy were 84% and 92%, respectively (P = 0.38). The incidence of improvement/healing of esophagitis after therapy was more (P = 0.036) in the dexrabeprazole group (95.2%) compared to the rabeprazole group (65.2%). No adverse drug reaction was seen in either group. CONCLUSION: In the treatment of GERD, efficacy of dexrabeprazole 10 mg is better than rabeprazole 20 mg, with regards to improvement/healing of endoscopic lesions and relief from symptoms of regurgitation. PMID- 17696230 TI - Safety and efficacy of oral HD-03/ES given for six months in patients with chronic hepatitis B virus infection. AB - AIM: To investigate the safety and efficacy of the formulation HD-03/ES capsules in the management of patients with chronic hepatitis B infection. METHODS: A total of 25 patients were recruited to the study and were given HD-03/ES, two capsules twice daily for six months. Clinical assessment of symptoms and signs were done using the " clinical observation table" once a month before and after the treatment. Biochemical investigations of total bilirubin, ALT, AST, serum protein for liver function tests were done every month after initiating treatment. Serum was analyzed for HBV markers for HBsAg, HBeAg and HBV DNA at baseline, 4 and 6 mo after therapy using ELISA kits from Roche. RESULTS: After 6 mo of therapy with HD-03/ES, a significant reduction of ALT values from 66.5 +/- 11.1 to 39.1 +/- 5.2 (P < 0.01) and a significant HBsAg loss (52%, P < 0.001), HBeAg loss (60%, P < 0.05) and HBV DNA loss (60%, P < 0.05) was observed. Adverse effects were mild and never warranted withdrawal of the drug. CONCLUSION: The results of this pilot study indicate that HD-03/ES might be a safe and effective treatment for chronic hepatitis B infection and a long-term multicentric comparator trial is warranted and under way. PMID- 17696231 TI - Detection and treatment of synchronous lesions in colorectal cancer: the clinical implication of perioperative colonoscopy. AB - AIM: To evaluate the clinical significance of pre- and intra-operative colonoscopy for the detection of synchronous lesions in colon cancer. METHODS: Two hundred and sixty-five pre-operative and 51 intra-operative colonoscopic evaluations were performed in 316 colorectal cancer patients who underwent curative resection from January 2001 to June 2006. The incidence and characteristics of synchronous lesions and their influence on surgery were evaluated. RESULTS: Two hundred and eighty-two synchronous lesions were detected in 124 (39.2%) of 316 patients including all lesions regardless of their histologic type. True adenomatous polyps were found in 91 (28.8%) of 316 patients, and 17 (5.4% of all patients) patients had synchronous colon cancers. The preoperative identification of synchronous lesions altered the planned surgery in 37 (14.0%) of 265 patients. In 18 patients among the surgically removed cases, the lesions were removed by extending the resection range. Further segmental resection or polypectomy through enterotomy was necessary in 19 patients. Nineteen (37.2%) of 51 intraoperative colonoscopy cases had synchronous lesions. Additional surgical procedures including segmental bowel resection and polypectomy with enterotomy were necessary in 7 (13.7%) of 51 intraoperative colonoscopy cases to remove the lesions. CONCLUSION: Synchronous colorectal polyps or cancer are frequent and their preoperative detection is important for optimal surgical planning and treatment. Intraoperative colonoscopy is a useful option in cases where a preoperative colonoscopy is not feasible. PMID- 17696232 TI - Duodeno-jejunal junction dyssynergia: description of a novel syndrome. AB - AIM: To investigate the hypothesis that duodeno-jejunal dyssynergia existed at the duodeno-jejunal junction. METHODS: Of 112 patients who complained of epigastric distension and discomfort after meals, we encountered nine patients in whom the duodeno-jejunal junction did not open on duodenal contraction. Seven healthy volunteers were included in the study. A condom which was inserted into the 1st duodenum was filled up to 10 mL with saline in increments of 2 mL and pressure response to duodenal distension was recorded from the duodenum, duodeno jejunal junction and the jejunum. RESULTS: In healthy volunteers, duodenal distension with 2 and 4 mL did not produce pressure changes, while 6 and up to 10 mL distension effected significant duodenal pressure increase, duodeno-jejunal junction pressure decrease but no jejunal pressure change. In patients, resting pressure and duodeno-jejunal junction and jejunal pressure response to 2 and 4 mL duodenal distension were similar to those of healthy volunteers. Six and up to 10 mL 1st duodenal distension produced significant duodenal and duodeno-jejunal junction pressure increase and no jejunal pressure change. CONCLUSION: Duodeno jejunal junction failed to open on duodenal contraction, a condition we call 'duodeno-jejunal junction dyssynergia syndrome' which probably leads to stagnation of chyme in the duodenum and explains patients' manifestations. PMID- 17696233 TI - Histopathological profile of gastritis in adult patients seen at a referral hospital in Kenya. AB - AIM: To conduct a detailed histological study of gastritis in adult patients attending an endoscopy clinic at a Kenyan teaching and referral hospital. METHODS: Biopsy specimens from consecutive patients were examined and graded according to the Updated Sydney System for H pylori infection, chronic inflammation, neutrophil activity, glandular atrophy and intestinal metaplasia. Also documented were gastric tissue eosinophil counts and presence of lymphoid follicles. RESULTS: The rate of the graded variables, in the antrum and corpus respectively, were as follows: H pylori infection (91%, 86%), chronic inflammation (98%, 93%), neutrophil activity (91%, 86%), glandular atrophy (57%, 15%) and intestinal metaplasia (11%, 2%). Lymphoid follicles were noted in 11% of cases. Duodenal and gastric ulcers were documented in 32% and 2% respectively. The mean eosinophil count was 5.9 +/- 0.74 eosinophils/HPF and 9.58 +/- 0.93 eosinophils/HPF in the corpus and antrum respectively. Significant association was found between the degree of H pylori colonisation with chronic inflammation, neutrophil activity and antral glandular atrophy. Biopsies from the antrum and corpus showed significant histopathological discordance for all the graded variables. H pylori negative cases were associated with recent antibiotic use. CONCLUSION: The study reaffirms that H pylori is the chief cause of gastritis in this environment. The majority of patients show a moderate to high degree of inflammation but a low degree of glandular atrophy and intestinal metaplasia. The study shows that inter-relationships between the histological variables in this African population are similar to those found in other populations worldwide including non-African populations. PMID- 17696234 TI - Effect of lymph node micrometastases on prognosis of gastric carcinoma. AB - AIM: To evaluate the relationship between lymph node micrometastases and prognosis of patients with gastric carcinoma and to evaluate the significance of the new assessment of nodal status in determining the pN categories in the 5th edition of the UICC TNM classification. METHODS: A total of 850 lymph nodes from 30 patients with gastric carcinoma who underwent gastrectomy with lymphadenectomy were assessed by reverse transcription polymerase chain reaction assay in addition to histologic examination. Cytokeratin-20 gene marker was used in this assay. RESULTS: Routine examination by HE staining confirmed metastasis in 233 lymph nodes from 20 patients. All these 233 lymph nodes were cytokeratin-20 positive. Moreover, lymph node micrometastases were detected in an additional 67 lymph nodes in 12 of these 20 patients. Lymph node micrometastases were also detected in 10 lymph nodes from 2 of 10 patients who had no obvious metastases identified by HE staining. Totally, lymph node micrometastases were identified by the reverse transcription polymerase chain reaction assay in 77 (12.5%) lymph nodes from 14 (46.7%) patients with gastric carcinoma. Of 27 patients who underwent curative resection, 7 (25.9%) were up-staged (from IB stage to II stage in 1 patient, from IB stage to IIIA stage in 1 patient, from II stage to IIIA stage in 1 patient, from IIIA stage to IIIB stage in 1 patient, from IIIA stage to IV stage in 1 patient, from IIIB stage to IV stage in 2 patients). In a median follow-up of 32 (range 8-36) mo, Kaplan-Meier survival analysis showed significant improvements in median survival (22.86 +/- 3.17 mo, 95% CI: 16.64 29.08 mo vs 18.00 +/- 7.4 mo, 95% CI: 3.33-32.67 mo) of patients with negative lymph node micrometastases over patients with positive lymph node micrometastases (log-rank, P < 0.05). CONCLUSION: Lymph node micrometastases have a significant impact on the current staging system of gastric carcinoma, and are significant risk factors for prognosis of patients with gastric carcinoma. PMID- 17696235 TI - Expression of G3BP and RhoC in esophageal squamous carcinoma and their effect on prognosis. AB - AIM: To investigate the expression and significance of G3BP and RhoC proteins in esophageal squamous carcinoma (ESC). METHODS: The expression of G3BP and Rhoc proteins in 80 cases of ESC was detected by immunohistochemistry. The relationship was studied between the expression of the two proteins and tumor size, differentiation degree, TNM stage, lymph node metastasis and prognosis of ESC. RESULTS: The positive expression rate of G3BP in ESC was 71.25%; and the rate in the lymph node metastasis group was significantly higher than that in the non-lymph node metastasis group (Z = -2.283, P = 0.022), but no relations were found between G3BP expression and tumor size, differentiation degree and TNM stage (P > 0.05). The group with G3BP positive expression had shorter survival time than the group with G3BP negative expression (P = 0.000). The positive expression rate of RhoC in ESC was 66.25%; and the rate in the lymph node metastasis group was significantly higher than that in the non-lymph node metastasis group (Z = -2.115, P < 0.05), but no relations were found between RhoC expression and tumor size, differentiation degree and TNM stage (P > 0.05). The RhoC positive expression group had a shorter survival time than the RhoC negative expression group (P < 0.001. The expression of G3BP protein correlated positively with the expression of RhoC in ESC tissues (rs = 0.656, P < 0.001). CONCLUSION: The expression of G3BP and RhoC protein is closely related to the lymph node metastasis and survival in ESC patients. G3BP and RhoC proteins can be considered as predictors of prognosis in ESC patients. PMID- 17696236 TI - Molecular mechanisms of paclitaxel and NM-3 on human gastric cancer in a severe combined immune deficiency mice orthotopic implantation model. AB - AIM: To explore the molecular mechanisms of action of paclitaxel and NM-3 on human gastric cancer in severe combined immune deficiency (SCID) mice. METHODS: Human gastric cancer cells SGC-7901 were implanted into SCID mice and mice were treated with paclitaxel and NM-3. The effects of paclitaxel and NM-3 on apoptosis of human gastric cancer cells were analyzed using flow cytometry, TUNEL assays, and DNA fragment analyses. RESULTS: Apoptosis of SGC-7901 cells was successfully induced by paclitaxel, NM-3, and the combination of paclitaxel and NM-3 24 h after injection as shown by the presence of apoptotic hypodiploid peaks on the flow cytometer before G1-S and a characteristic apoptotic band pattern in the DNA electrophoresis. The apoptotic rate detected by TUNEL assay was found to be significantly higher in the paclitaxel/NM-3 compared to the control group (38.5% +/- 5.14% vs 13.2% +/- 1.75%, P < 0.01). CONCLUSION: Paclitaxel in combination with NM-3 is able to induce apoptosis of the human gastric cancer cells in SCID mice effectively and synergistically. PMID- 17696237 TI - Effects of nutritional and psychological status in gastrointestinal cancer patients on tolerance of treatment. AB - AIM: To assess the effects of poor nutritional and psychological status on tolerance of cancer treatment and the recovery of physical performance status in patients with gastrointestinal cancer. METHODS: An epidemiological survey with respect to nutritional and psychological status in patients with gastrointestinal cancer was conducted among 182 operated patients in four provincial-level hospitals from December 2005 to June 2006. The food frequency survey method, state-trait anxiety inventory (STAI) and depression status inventory (DSI) were used to obtain information about the diet and psychological status in the patients. Nutritional status in the participants was reflected by serum albumin (Alb), hemoglobin (HB) and body mass index (BMI). RESULTS: Alb, protein intake and anxiety were associated with the severity of side effects of treatment. The adjusted relative risk (RR) for Alb, protein intake and anxiety was 3.30 (95% CI: 1.08, 10.10, P = 0.03), 3.25 (95% CI: 1.06, 9.90, P = 0.04) and 1.48 (95% CI: 1.29, 1.70, P < 0.0001), respectively. Moreover, calorie intake, HB and depression were associated with the recovery of physical performance status in the patients. Adjusted relative risk was 2.12 (95% CI: 1.09, 4.03, P = 0.028), 2.05 (95% CI: 1.08, 3.88, P = 0.026) and 1.07 (95% CI: 1.02, 1.12, P = 0.007), respectively. CONCLUSION: Both poor nutrition status and psychological status are independent risk factors for severe side effects of cancer treatment, and have impact on the recovery of physical performance status in patients after treatment. PMID- 17696238 TI - Assessment of T staging and mesorectal fascia status using high-resolution MRI in rectal cancer with rectal distention. AB - AIM: To determine the accuracy of high-resolution magnetic resonance imaging (MRI) using phased-array coil for preoperative assessment of T staging and mesorectal fascia infiltration in rectal cancer with rectal distention. METHODS: In a prospective study of 67 patients with primary rectal cancer, high-resolution magnetic resonance imaging (in-plane resolution, 0.66 multiply 0.56) with phased array coil were performed for T-staging and measurement of distance between the tumor and the mesorectal fascia. The assessment of MRI was compared with postoperative histopathologic findings. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were evaluated. RESULTS: The overall magnetic resonance accuracy was 85.1% for T staging and 88% for predicting mesorectal fascia involvement. Magnetic resonance sensitivity, specificity, accuracy, positive predictive value, and negative predictive value was 70%, 97.9%, 89.6%, 93.3% and 88.5% for 7). However, there were only 45 consultations (1.1%) for typical GERD symptoms. Although GERD symptoms are common in adults of all ages, the prevalence of GERD was highest in the 20-29 years age group and the age group 70-79 years had the lowest prevalence for both males and females. CONCLUSION: Although there was a high rate indicating GERD in our primary care population, only 1.1% of outpatients attended our hospital with a chief complaint of GERD symptoms. Since about one-third of GERD patients are affected by atypical symptoms, general physicians need to be cautious about extrapolating these results to patients with a chief complaint other than typical GERD symptoms. PMID- 17696252 TI - Spontaneous elimination of hepatitis C virus infection: a retrospective study on demographic, clinical, and serological correlates. AB - AIM: To find correlates to spontaneous clearance of hepatitis C virus (HCV) infection, this study compared individuals with self-limited and chronic infection with regard to clinical, demographic, and serological parameters. METHODS: Sixty-seven anti-HCV positive and repeatedly HCV RNA negative individuals were considered to have resolved HCV infection spontaneously. To determine the viral genotype these patients had been infected with HCV serotyping was performed. For comparison reasons, 62 consecutive patients with chronic hepatitis C were enrolled. Cases and controls were compared stratified for age and sex. RESULTS: Retrospective analysis showed (1) a lower humoral reactivity to HCV in patients with self-limited compared to chronic HCV-infection and (2) that younger age, history of iv drug use, and acute/post-acute hepatitis A or B co infections, but not viral genotypes, are independent correlates for spontaneous HCV clearance. CONCLUSION: The stronger humoral reactivity to HCV in patients with persistent infections and in those with a history of iv drug use is supposed to be due to continuous or repeated contact(s) to the antigen. Metachronous hepatitis A or hepatitis B infections might favor HCV clearance. PMID- 17696253 TI - Lithocholic acid induction of the FGF19 promoter in intestinal cells is mediated by PXR. AB - AIM: To study the effect of the toxic secondary bile acid lithocholic acid (LCA) on the expression of fibroblast growth factor 19 (FGF19) in intestinal cells and to characterize the pregnane-X-receptor (PXR) response of the FGF19 promoter region. METHODS: The intestinal cell line LS174T was stimulated with various concentrations of chenodeoxy-cholic acid and lithocholic acid for several time points. FGF19 mRNA levels were determined with quantitative realtime RT-PCR. FGF19 deletion promoter constructs were generated and the LCA response was analzyed in reporter assays. Co-transfections with PXR and RXR were carried out to study FGF19 regulation by these factors. RESULTS: LCA and CDCA strongly up regulate FGF19 mRNA expression in LS174T cells in a time and dose dependent manner. Using reporter gene assays with several deletion constructs we found that the LCA responsive element in the human FGF19 promoter maps to the proximal regulatory region containing two potential binding sites for PXR. Overexpression of PXR and its dimerization partner retinoid X receptor (RXR) and stimulation with LCA or the potent PXR ligand rifampicin leads to a significant induction of FGF19 promoter activity in intestinal cells. CONCLUSION: LCA induced feedback inhibition of bile acid synthesis in the liver is likely to be regulated by PXR inducing intestinal FGF19 expression. PMID- 17696254 TI - Risk factors and prevention of biliary anastomotic complications in adult living donor liver transplantation. AB - AIM: To evaluate risk factors of biliary anastomotic complications (BACs) and outcomes according to type of biliary reconstruction. METHODS: A total of 33 consecutive adult living donor liver transplantation (LDLT) were reviewed, 17 of which had undergone Duct-to-Duct anastomosis (D-D). The remaining 16 patients received Roux-en-Y anastomosis (R-Y). The perioperative factors, such as the type of graft and the number of graft bile ducts, were analyzed retrospectively. RESULTS: The overall incidence of BACs was 39.4%. The incidence of BACs was significantly higher in the patients with than without neoadjuvant chemotherapy (71.4% vs 10%, P = 0.050). There was no significant difference in the incidence of biliary leakage in patients with D-D vs those with R-Y. The incidence of biliary strictures following the healing of biliary leakage was significantly higher in D-D (60%) than in R-Y (0%) (P = 0.026). However, the incidence of BACs related bacteremia was significantly higher in R-Y than in D-D (71.4% vs 0%, P = 0.008). In D-D, use of T-tube stent remarkably reduced the incidence of BACs, compared with straight tube stent (0% vs 50%, P = 0.049). CONCLUSION: Our experience showed an increase of BACs related bacteremia in the patients with R Y. Therefore, D-D might be a preferred biliary reconstruction. However, the surgical refinement of D-D should be required because of the high incidence of biliary strictures. Use of the T-tube stent might lead to a significant reduction of BACs in D-D. PMID- 17696255 TI - Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease. AB - AIM: To investigate the role of gene variants and derived haplotypes of the CLOCK transcription factor in nonalcoholic fatty liver disease (NAFLD) and their relation with the disease severity. METHODS: A total of 136 patients with NAFLD and 64 healthy individuals were studied. Liver biopsy was performed in 91 patients. Six tag SNPs showing a minor allele frequency > 10% (rs1554483 C/G; rs11932595 A/G; rs4580704 C/G; rs6843722 A/C; rs6850524 C/G and rs4864548 A/G) encompassing 117 kb of chromosome 4 and representing 115 polymorphic sites (r(2) > 0.8) were genotyped. RESULTS: rs11932595 and rs6843722 showed significant associations with NAFLD (empiric P = 0.0449 and 0.023, respectively). A significant association was also observed between clinical or histologic spectrum of NAFLD and rs1554483 (empiric P = 0.0399), rs6843722 (empiric P = 0.0229) and rs6850524 (empiric P = 0.00899) and between fibrosis score and rs1554483 (empiric P = 0.02697), rs6843722 (empiric P = 0.01898) and rs4864548 (empiric P = 0.02697). Test of haplotypic association showed that CLOCK gene variant haplotypes frequencies in NAFLD individuals significantly differed from those in controls (empiric P = 0.0097). CONCLUSION: Our study suggests a potential role of the CLOCK polymorphisms and their haplotypes in susceptibility to NAFLD and disease severity. PMID- 17696256 TI - Inhibition of p38 mitogen-activated protein kinase attenuates experimental autoimmune hepatitis: involvement of nuclear factor kappa B. AB - AIM: To investigate the role of p38 mitogen-activated protein kinase (p38MAPK) in murine experimental autoimmune hepatitis (EAH). METHODS: To induce EAH, the syngeneic S-100 antigen emulsified in complete Freud's adjuvant was injected intraperitoneally into adult male C57Bl/6 mice. Liver injury was assessed by serum ALT and liver histology. The expression and activity of p38 MAPK were measured by Western blot and kinase activity assays. In addition, DNA binding activities of nuclear factor kappa B (NF-kappaB) were analyzed by electrophoretic mobility shift assay. The effects of SB203580, a specific p38 MAPK inhibitor, on liver injuries and expression of proinflammatory cytokines (interferon-gamma, IL 12, IL-1beta and TNF-alpha) were observed. RESULTS: The activity of p38 MAPK and NF-kappaB was increased and reached its peak 14 or 21 d after the first syngeneic S-100 administration. Inhibition of p38 MAPK activation by SB203580 decreased the activation of NF-kappaB and the expression of proinflammatory cytokines. Moreover, hepatic injuries were improved significantly after SB203580 administration. CONCLUSION: p38 MAPK and NF-kappaB play an important role in an animal model of autoimmune hepatitis (AIH) induced by autoantigens. PMID- 17696257 TI - Apoptotic effect of Epigallocatechin-3-gallate on the human gastric cancer cell line MKN45 via activation of the mitochondrial pathway. AB - AIM: To investigate whether Epigallocatechin-3-gallate (EGCG) can induce apoptosis of the gastric cancer cell line MKN45 and its apoptotic pathway. METHODS: To determine this, apoptotic rates of MKN45 cells after EGCG treatment with or without caspase-3 inhibitor were evaluated by Annexin V-FITC + PI staining The influence of EGCG on the activity of caspase-3 in the MKN45 cells was determined by ELISA. By Rhodamine123 staining, the membrane potential change of the mitochondrion was also investigated, and mRNAs and protein expression of the bcl-2 family were analyzed by RT-PCR and Western blot. RESULTS: EGCG can induce apoptosis of MKN45 cells in time- and dose-dependent manner. Eight hours after EGCG treatment, the activity of caspase-3 in the MKN45 increased, especially 12 h after treatment. The mitochondrial membrane potential was significantly weakened 4 h after EGCG insult. The mRNA and protein expression levels of pro-apoptotic members, such as Bax, Bid and Bad, were upregulated gradually as treated time increased. Moreover, the mRNA and protein expression levels of anti-apoptotic members, such as Bcl-xL and Bcl-2, were inhibited. CONCLUSION: These data support that EGCG can induce apoptosis of the human gastric cancer cell line MKN45, and the effect is in a time- and dose-dependent manner. The apoptotic pathway triggered by EGCG in MKN45 is mitochondrial dependent. PMID- 17696258 TI - Oligonucleotide chip, real-time PCR and sequencing for genotyping of hepatitis B virus. AB - AIM: To compare the oligonucleotide chip, real-time PCR and sequencing for genotyping of hepatitis B virus in Chinese patients with chronic hepatitis B. METHODS: Mixture of samples with different genotypes and clinical serum samples from 126 chronic hepatitis B patients was tested for hepatitis B virus genotypes by oligonucleotide chip, real-time PCR and sequencing of PCR products, respectively. Clinical performances, time required and costs of the three assays were evaluated. RESULTS: Oligonucleotide chips and real-time PCR detected 1% and 0.1% genotypes, respectively, in mixed samples. Of the 126 clinical samples from patients with chronic hepatitis B, genotype B was detected in 41 (33%), 41 (33%) and 45 (36%) samples, and genotype C in 76 (60%), 76 (60%) and 81 (64%) samples, by oligonucleotide chip, real-time PCR and sequencing, respectively. Oligonucleotide chip and real-time PCR detected mixed genotypes B and C in 9 samples. Real-time PCR was the rapidest and cheapest among the three assays. CONCLUSION: Oligonucleotide chip and real-time PCR are able to detect mixed genotypes, while sequencing only detects the dominant genotype in clinical samples. PMID- 17696259 TI - A one-year trial of entecavir treatment in patients with HBeAg-positive chronic hepatitis B. AB - AIM: To evaluate the efficacy and safety of entecavir (ETV) in hepatitis Be antigen (HBeAg)-positive chronic hepatitis B (CHB) patients who had not received a nucleoside analogue and who had failed in lamivudine (LVD) therapy. METHODS: Sixty-one patients were divided into three groups. Forty-two patients who had not received a nucleoside analogue were randomized into two groups: group A (n = 21) received LVD 100 mg/d and group B (n = 21) received ETV 0.5 mg/d. The remaing 19 patients treated with LVD (n = 19), who switched to ETV 1.0 mg/d served as group C. All patients were treated for 48 wk. HBV DNA levels were measured with polimerase-chain-reaction (PCR) analysis. Liver function tests, HBV serology and safety assessments were also conducted. RESULTS: Significantly more patients in group B (52.1% and 71.4%) had undetectable HBV DNA levels than in groups A (35.8% and 38%; P < 0.0001) and C (10.6% and 21.1%, P < 0.0001) at wk 24 and 48, respectively. At wk 48, ALT levels were normalized in more patients in group B (85.7%) than in groups A (76.2%) and C (74%). CONCLUSION: ETV had a significantly higher response rate than LVD in patients with HBeAg-positive CHB who had not previously received a nucleoside analogue; ETV can effectively inhibit the replication of HBV DNA and normalize the levels of ALT in refractory CHB patients treated with LVD; and ETV is safe in clinical application. PMID- 17696260 TI - Resolution of chronic hepatitis C following parasitosis. AB - An inefficient cellular immune response likely leads to chronic hepatitis C virus (HCV) infection. Resolution of chronic HCV infection in the absence of treatment is a rare occurrence. We report the case of a 39-year old white male with a 17 year history of chronic HCV infection, who eradicated HCV following a serious illness due to co-infection with Babesia (babesiosis), Borriela Borgdorferi (Lyme disease) and Ehrlichia (human granulocytic ehrlichiosis). We hypothesize that the cellular immune response mounted by this patient in response to his infection with all three agents but in particular Babesia was sufficient to eradicate HCV. PMID- 17696261 TI - Ectopic hepatocellular carcinoma arising from pancreas: a case report and review of the literature. AB - A 56-year-old man was found to have a pancreatic tail tumor. His blood chemistry showed no infection with hepatitis B or C virus and no elevations of tumor markers or pancreatic hormones. Abdominal ultrasound showed an encapsulated, rather heterogeneous, hypoechoic tumor, 6.5 cm in maximum diameter, with a beak sign. Helical dynamic CT revealed an irregularly enhanced tumor with pooling of contrast medium in the delayed phase. Abdominal angiography showed a hypervascular tumor. With a tentative diagnosis of non-functional islet-cell tumor, the patient underwent resection of the pancreatic body and tail with splenectomy. The contour of the liver and its surface were normal. In microscopic examination, tumor cells arranged in a trabecular pattern with focal bile pigment resembling hepatocellular carcinoma (HCC). Immunohistochemically, these tumor cells were positivefor HEPPAR-1, CAM5.2, cytokeratin 18 and COX-2, but negative for MUC-1, and cytokeratins 7, 20 and 8. These results supported a diagnosis of HCC without any adenocarcinoma component. The patient is currently doing well without any signs of recurrence in either the remaining pancreas or liver three years after surgery. We report the rare case with ectopic HCC in the pancreas with a review of the literature. PMID- 17696262 TI - Colonoscopic diagnosis of appendiceal intussusception in a patient with intermittent abdominal pain: a case report. AB - Intussusception of the appendix is a rare condition. Most cases are diagnosed during operation of the patients suspected to have appendicitis. In this report we present a seventy one year-old man with a history of periumbilical intermittent abdominal pain for several months. None of the paraclinical tests were useful for determining the diagnosis. Colonoscopy performed during the last episode of abdominal pain revealed the prolapsed appendix in the cecum and the patient was sent to the operating room. Macroscopic appearance of the appendix was normal and microscopic examination revealed follicular hyperplasia and acute focal appendicitis. Appendiceal intussusception should be considered in differential diagnosis of intermittent abdominal pain and colonoscopic diagnosis could be very important to avoid dangerous or unnecessary decision making. PMID- 17696263 TI - Correct diagnosis and successful treatment for pericardial effusion due to toothpick injury: a case report and literature review. AB - We reported a 55-year-old man who suffered from chest pain and dyspnea on exertion for two weeks associated with night sweating, general malaise, poor appetite, and body weight loss. Physical examination revealed friction rub with distant heart sound, bilateral clear breathing sound, no abdomen tenderness, and normal bowel sound. Subsequent chest X-ray revealed cardiomegaly and cardiac echo showed massive pericardial and pleural effusion with normal left ventricular function. Constrictive pericarditis was diagnosed based on clinical information. Tuberculosis (TB), malignancy, autoimmune disease, infection, hypothyroidism, and idiopathic could be the causes but excluded by further study. High-resolution lung CT scan after reconstruction revealed a moderate amount pericardial effusion with possible superimposed infection. Thickness of pericardium and left lobe liver abscess were found. A straight tubular structure about 6 cm in length transverses the lateral segment of liver to pericardial space and unknown foreign body was suspected. Laparotomy was performed, 6.5 cm toothpick was found through the liver into pericardium. Post-operative course was uneventful and he discharged one week later. The patient could not remember swallowing the toothpick before. He had no chest pain and dyspnea on exertion during a 6-mo follow-up period. PMID- 17696264 TI - Lupus erythematosus tumidus induced by sex reassignment surgery. AB - OBJECTIVE: We describe a case of sex reassignment surgery and the subsequent development of lupus erythematosus tumidus (LET). LET is characterized clinically by erythematous, succulent, edematous, nonscarring plaques in sun-exposed areas. Results of histological examination show perivascular and periadnexal lymphocytic infiltration and interstitial mucin deposition. This report emphasizes that environmental triggers, including prolonged exposure to significant doses of estrogens as part of sex reassignment surgery, may lead to the development of lupus in a nonpredisposed individual. PMID- 17696265 TI - Temporomandibular joint arthritis in juvenile idiopathic arthritis: prevalence, clinical and radiological signs, and relation to dentofacial morphology. AB - OBJECTIVE: To perform a prospective, comprehensive, clinical, and radiological evaluation of temporomandibular joint (TMJ) involvement and its influence on craniofacial growth, in a cohort of patients with juvenile idiopathic arthritis (JIA), representing all JIA subtypes. METHODS: Clinical rheumatologic and orthodontic evaluations were performed in 100 patients with JIA [12 systemic arthritis, 24 rheumatoid factor (RF)-negative polyarthritis, 1 RF-positive polyarthritis, 39 oligoarthritis, 22 enthesitis-related arthritis, 2 psoriatic arthritis]. An orthopantomogram and lateral cephalogram were performed in 46 patients. The prevalence of TMJ arthritis was studied in relation to JIA subtype and disease characteristics; cephalometric measurements were compared to those from age- and sex-matched healthy controls. RESULTS: Whereas 55% of patients with JIA had at least one symptom/sign of TMJ arthritis, 78% of the radiographed group exhibited condylar lesions. The presence of condylar damage was not related to clinical orthodontic findings or to JIA subtype, disease activity, severity, or duration. Patients with JIA exhibited larger mandibular plane and A-nasion-B angles, larger total anterior facial height, smaller interincisal and sella nasion-B angles, and shorter mandibular ramus lengths than their age- and sex matched controls. Craniofacial alterations were clearly related to the presence of condylar damage, even when present at a minimal degree. CONCLUSION: Our data show that TMJ condylar damage occurs very frequently in JIA, and irrespective of JIA subtype; condylar lesions can present early, progress insidiously, and -- even at a minimal degree -- can severely alter the craniofacial profile. We propose that the followup of patients with JIA should include early and regular evaluation by an orthodontist, supplemented with radiographic TMJ imaging. PMID- 17696266 TI - The rate of pyrin mutations in critically ill patients with systemic inflammatory response syndrome and sepsis: a pilot study. AB - OBJECTIVE: The role of individual genetic differences in susceptibility to systemic inflammatory response syndrome (SIRS) and sepsis is generally unrecognized or underestimated. We investigated the rate of pyrin mutations in critically ill patients with SIRS and sepsis, and compared whether carriers for pyrin mutations are associated with respect to the frequency of and certain features of sepsis and SIRS. METHODS: We tested M694V, M680I, V726A, R761H, and M694I mutations in critically ill patients. RESULTS: Twenty-four of 80 (30%) critically ill patients were found to carry some pyrin mutations; none had a history compatible with familial Mediterranean fever. We also found a high frequency of carriers in patients having pneumonia (30.3%), urinary tract infection (29.4%), and acute pancreatitis (30.8%). When we compared our results with the pyrin mutation carrier rate of a healthy Turkish population (10%), the rate of pyrin mutations in all patients (p < 0.001), and patients with urinary tract infection (p <0.001), acute pancreatitis (p <0.001), and pneumonia (p < 0.001) were found to be significantly high. The white blood cell count, erythrocyte sedimentation rate, lactic dehydrogenase, and rate of fever and pulse were significantly higher, whereas systolic and diastolic blood pressure and albumin levels were significantly lower in patients with pyrin mutation compared to those without the mutation. CONCLUSION: Our results showed that critically ill patients with SIRS and sepsis have increased prevalence of pyrin mutations, and patients with SIRS and sepsis carrying the pyrin mutation seem to be highly susceptible for a severe disease course. PMID- 17696267 TI - Determinants of reduced walking speed in people with musculoskeletal pain. AB - OBJECTIVE: Maintenance of good walking speed is essential to independent living. People with musculoskeletal disease often have reduced walking speed. We investigated determinants of slower walking, other than musculoskeletal disease, that might provide valuable additional targets for therapy. METHODS: We analyzed data from the Somerset and Avon Survey of Health, a community based survey of people aged over 35 years. A total of 2703 participants who reported hip or knee pain at baseline (1994/1995) were studied, and reassessed in 2002-2003; 1696 were available for followup, and walking speed was tested in 1074. Walking speed (m/s) was used as outcome measure. Baseline characteristics, including comorbidities and socioeconomic factors, were tested for their ability to predict reduced walking speed using multiple linear regression analysis. RESULTS: Age, female sex, and immobility at baseline were predictive of slower walking speed. Other independent risk factors included the presence of cataract, low socioeconomic status, intermittent claudication, and other cardiovascular conditions. Having a cataract was associated with a decrease of 0.10 m/s (95% CI 0.03, 0.16). Those in social class V had a walking speed 0.22 m/s (95% CI 0.126, 0.31) slower than those in social class I. CONCLUSION: Comorbidities, age, female sex, and lower socioeconomic position determine walking speed in people with joint pain. Issues such as poor vision and social-economic disadvantage may add to the effect of musculoskeletal disease, suggesting the need for a holistic approach to management of these patients. PMID- 17696268 TI - Improving informed decision-making for patients with knee pain. AB - OBJECTIVE: Studies have shown that patients with knee pain are not well informed of their potential treatment options and that patient preferences are often discordant with physician practices. The objective of this pilot study was to test the efficacy of a computer tool to improve informed decision-making for patients with knee pain in an outpatient primary care clinic setting. METHODS: Patients with knee pain were randomized to receive an information pamphlet or to perform a computer task. The latter was designed to elicit preferences based on patient tradeoffs for route of administration, benefits, and side effects of commonly used treatment options for knee pain. After performing the task, participants were given a printed handout illustrating their preferences. RESULTS: In total, 87 patients were randomized. Decisional self-efficacy, preparedness to participate in decision-making, and arthritis self-efficacy were greater in participants randomized to the intervention arm compared to those receiving the information pamphlet (p < 0.05 for all comparisons). CONCLUSION: Participants using a tool designed to increase patient awareness of choice and evaluate the tradeoffs related to available treatment options were more confident in their ability to obtain information about available treatment options, were better prepared to participate in their visit, and had better arthritis related self-efficacy compared to patients receiving an information pamphlet. The results of this pilot study justify future large-scale trials to determine the effectiveness of similar interventions. PMID- 17696269 TI - Serum uric acid levels and risk for vascular diseases in patients with metabolic syndrome. AB - OBJECTIVE: Gout and increased serum uric acid (SUA) levels are often seen in patients with components of the metabolic syndrome. Increased SUA levels are associated with increased vascular risk, as is the metabolic syndrome. We investigated the association between SUA levels and the metabolic syndrome in a population of patients with manifest vascular disease to determine whether SUA levels convey an independent risk for vascular disease in patients with the metabolic syndrome. METHODS: A nested case-cohort study of 431 patients with 220 cases with a new vascular event during followup, originating from the Second Manifestations of Arterial Disease (SMART) study. All patients had manifest vascular diseases, consisting of cerebral, coronary, or peripheral artery disease or abdominal aortic aneurysm. The relationship of SUA with the metabolic syndrome was analyzed with linear regression and adjusted for age, sex, creatinine clearance, and alcohol and diuretic use. The relationship of SUA levels with new vascular disease was investigated with Cox regression and adjusted for age and sex. RESULTS: The metabolic syndrome was present in 50% of patients. SUA levels were higher in 214 patients with the metabolic syndrome than in 217 patients without (0.36 +/- 0.08 mmol/l vs 0.32 +/- 0.09 mmol/l). SUA concentrations increased with the number of components of the metabolic syndrome (0.30 mmol/l to 0.38 mmol/l) adjusted for age, sex, creatinine clearance, and alcohol and diuretic use. Increased SUA concentrations were independently associated with risk for vascular events in patients without the metabolic syndrome (age and sex adjusted hazard ratio 2.4, 95% CI 1.0-5.5), in contrast to patients with the metabolic syndrome (adjusted hazard ratio 1.9, 95% CI 1.0-3.9). CONCLUSION: Elevated SUA levels are strongly associated with the metabolic syndrome, yet are not an independent risk factor for vascular disease in patients with the metabolic syndrome. In patients without the metabolic syndrome, elevated SUA levels are associated with increased risk for vascular disease. PMID- 17696270 TI - Psoriatic arthritis in Reykjavik, Iceland: prevalence, demographics, and disease course. AB - OBJECTIVE: To determine the prevalence, demographics, and course of psoriatic arthritis (PsA) in the Reykjavik area of Iceland. METHODS: In total 220 patients >/= 18 years of age living in the Reykjavik area of Iceland were located in a community registry of psoriatic patients and in hospital records. Of these, 156 (71%) were interviewed and examined for verification of skin and joint disease according to published criteria. RESULTS: Prevalence of PsA in the adult population was estimated to be 164 per 100,000 (95% CI 143-187), adjusted to 139 per 100,000 (95% CI 112-169) after exclusion of 25 individuals. The female to male ratio was close to 2:1. The mean age at skin disease onset was 23 years, with significantly earlier onset in women (age 20 yrs in women vs 26 yrs in men; p = 0.01), but there was no significant difference for age at the time of onset of joint disease. Mean duration of PsA was 20 years. Oligoarthritis was the most common (44%), followed by polyarthritis (31%), enthesitis (8%), and inflammatory back pain (7%). According to patients' recall of clinical features at onset, 78 patients (60%) had changed categories of PsA at the time of the study, most frequently from polyarthritis to oligoarthritis (48%), followed by oligoarthritis to polyarthritis (36%). These changes seemed independent of use of disease modifying drugs, which 54% had received. CONCLUSION: PsA in Reykjavik, Iceland, has a prevalence of at least 0.14% and is strikingly more common in women. The majority of patients reported a change in the pattern of affected joints during the course of their disease. PMID- 17696271 TI - Classification criteria for systemic sclerosis subsets. AB - OBJECTIVE: To evaluate the measurement properties of criteria for systemic sclerosis (SSc) subsets for classification of patients in SSc trials, and to determine if any one criteria set confers measurement advantage over others. METHODS: A systematic review of articles describing classification criteria for SSc subsets was performed. Evidence supporting the sensibility (statement of purpose for which the criteria will be used, population, setting, face and content validity, and feasibility), validity, and reliability of the criteria was evaluated. RESULTS: Fourteen sets of criteria for SSc subsets were identified. There is variability in the intended purpose and setting for which criteria sets are to be applied. Although face validity improves with the addition of less commonly encountered subsets or disease manifestations as criteria, the feasibility of implementing such criteria is conversely limited. Content validity for most criteria sets has not been evaluated due to lack of an explicitly stated conceptual framework for SSc. The criteria with 3 or more subsets do not provide incremental predictive validity over the 2-subset criteria. Our ability to compare subset criteria on divergent validity and reliability is limited by a lack of data. CONCLUSION: The 2-subset criteria of LeRoy, et al have good feasibility, acceptable face validity, and good predictive validity. Further research is needed to compare the content validity, divergent validity, and reliability of these with other subset criteria for use in SSc trials. PMID- 17696272 TI - Medical insurance, socioeconomic status, and age of onset of endstage renal disease in patients with lupus nephritis. AB - OBJECTIVE: Limited access to care may hasten progression to endstage renal disease (ESRD) in patients with lupus nephritis. We examined associations between type of medical insurance, socioeconomic status (SES), and age at onset of ESRD in a national, population-based cohort. METHODS: Using the United States Renal Data System, incident cases of ESRD due to lupus nephritis in the US from January 1, 1996, to June 30, 2004, were examined in this cross-sectional study (n = 7971). Age at onset of ESRD was compared among patients with different types of medical insurance and by SES. RESULTS: In each ethnic group, patients with private insurance were older at the onset of ESRD than those with no insurance or Medicaid. For example, whites with private insurance were on average 7.5 years older than those with no insurance and 8.2 years older than those with Medicaid. There were no differences in age at onset of ESRD between those with no insurance and those with Medicaid. SES, based on the socioeconomic characteristics of the patient's area of residence, was associated with age of onset of ESRD only in whites. CONCLUSION: Among patients with lupus nephritis who develop ESRD, those with private medical insurance are older when they begin ESRD treatment than those with Medicaid or no insurance. Given that medical insurance is unrelated to the age at onset of lupus nephritis, these findings suggest that progression to ESRD varies with medical insurance status, possibly because of differences in quality of care or access to care. PMID- 17696273 TI - Clinical manifestations of human T lymphotropic virus type I-infected patients with systemic lupus erythematosus. AB - OBJECTIVE: Human T lymphotropic virus type I (HTLV-I) may be associated with some connective tissue autoimmune diseases, including systemic lupus erythematosus (SLE). To determine the relationship between HTLV-I infection and SLE, we examined the clinical manifestations of SLE patients with HTLV-I infection. METHODS: Eighty-nine patients with SLE were screened for antibodies to HTLV-I by electrochemiluminescence immunoassay. The presence of HTLV-I proviral sequences in peripheral blood mononuclear cells (PBMC) was determined by real-time polymerase chain reaction (PCR) quantification and Southern blotting analysis. The differences in clinical manifestations between HTLV-I-seropositive and seronegative patients with SLE were analyzed statistically. RESULTS: Fourteen of 89 (15.7%) patients were HTLV-I seropositive. All PBMC samples from 11 patients tested by PCR and 3 samples from 10 patients tested by Southern blotting analysis were positive for HTLV-I-related sequences. The age of HTLV-I-seropositive patients with SLE was significantly higher than that of seronegative patients (median 60 vs 42 yrs; p < 0.0005). The age at onset of SLE in HTLV-I-seropositive patients was also significantly higher than that of seronegative patients (median 45.5 vs 30 yrs; p <0.0005). The lymphocyte count in HTLV-I-seropositive SLE patients was significantly higher than that of seronegative patients (median 1740 vs 1066/microl; p = 0.027). The maintenance dose of prednisolone in HTLV-I seropositive patients with SLE was significantly lower than that in seronegative patients (median 5 vs 9 mg/day; p = 0.012). CONCLUSION: This is the first report of the differences in clinical manifestations between SLE patients with and without HTLV-I infection. Our results suggest some involvement of HTLV-I in the pathogenesis of SLE. PMID- 17696275 TI - Association of PTPN22 with rheumatoid arthritis among South Asians in the UK. AB - OBJECTIVE: To compare the distribution and assess genetic associations of the PTPN22 R620W single-nucleotide polymorphism among South Asian (Asiatic Indian) patients with rheumatoid arthritis (RA) and ethnically matched controls. METHODS: DNA samples from 133 rheumatoid factor-positive South Asian RA patients and 149 control subjects from the East Midlands of the UK were genotyped for PTPN22 R620W polymorphism. Genotyping was performed by the polymerase chain reaction restriction fragment length polymorphism method. RESULTS: The PTPN22 *T allele frequency was lower than in the Caucasian populations, but the disease association was significant (odds ratio 5.87, 95% confidence interval 1.68 20.52). Similar association was observed for genotypes containing *T allele. CONCLUSION: Our results suggest that the T variant acts as a susceptibility allele for autoantibody-positive RA among South Asians. PMID- 17696276 TI - Gold therapy in women planning pregnancy: outcomes in one center. AB - OBJECTIVE: To review the experience and outcome of pregnancies in women taking gold while planning pregnancy. METHODS: We undertook a chart review of patients attending for gold injection and monitoring between January 1992 and April 2006. For women who became pregnant while being followed taking gold therapy, we extracted demographic, treatment, and disease activity data, information regarding pregnancy complications, outcome, and postpartum course. For details missing from the clinic records, patients were interviewed by the clinic nurse. RESULTS: Fourteen women experienced 20 pregnancies while being followed in the gold monitoring clinic. Mean age at the time of conception was 34.5 years (range 24-41), disease duration 8.5 years (1-16). Rheumatoid factor was positive in 9 of 14 women. Duration taking gold prior to conception was < 12 months in 7 pregnancies, 13-24 months in 4, 25-34 months in 2, and 2-10 years in 7 pregnancies. Four women continued taking gold until delivery. The rest of the women discontinued gold when they knew they were pregnant, with the exception of one who held her gold 4 weeks prior to conception. There were 5 spontaneous abortions in the first trimester; included were 2 spontaneous abortions in a woman with known Robertsonian chromosomal translocation. Sixteen babies were healthy including a pair of twins. One baby was born with weakness of one extraocular muscle requiring surgery; one had blocked tear ducts at birth. Rheumatoid arthritis (RA) flared during 3/15 completed pregnancies and postpartum and post-spontaneous abortion in 18/20 pregnancies. CONCLUSION: Our clinic experience and the published literature support the current practice that in patients with RA, gold may still be considered a treatment option in women planning pregnancy. PMID- 17696277 TI - Effects of low-dose prednisolone on endothelial function, atherosclerosis, and traditional risk factors for atherosclerosis in patients with rheumatoid arthritis--a randomized study. AB - OBJECTIVE: To determine the influence of low-dose prednisolone on atherosclerosis, endothelial function, and risk factors for atherosclerosis in patients with early rheumatoid arthritis (RA). METHODS: At start of the first disease modifying antirheumatic drug, 67 patients with early, active RA were randomized to either 7.5 mg prednisolone daily (n = 34) or no prednisolone (n = 33). In the prednisolone group, 21 were treated for 2 years and 13 continuously. After a mean of 5 years intima-media thickness (IMT) and calculated intima-media area (cIMa) of the carotid arteries were determined by B-mode ultrasound. Endothelial function was determined by flow-mediated dilatation (FMD) of the brachial artery. RESULTS: IMT [median (interquartile range) 0.675 mm (0.58-0.82) vs 0.673 mm (0.0.62-0.80)], cIMa [13.7 mm2 (11.45-20.37) vs 14.1 mm2 (12.34 17.38)], prevalence of atherosclerotic plaques (82.3% vs 81.9%), and endothelial function [FMD% (mean +/- SD) 3.88% +/- 2.8 vs 3.74% +/- 2.9] did not differ between patients treated with and those not treated with prednisolone. There were no differences in lumen diameter of carotid arteries, or levels of lipoproteins, glucose, and blood pressure. Patients treated for at least 4 years (and currently treated) with prednisolone had a trend to higher systolic blood pressure (157 +/- 29 mm Hg) compared with untreated patients (141 +/- 28 mm Hg; p = 0.06) and had higher cholesterol levels (5.6 mmol/L +/- 1.39 vs 4.9 +/- 28; p = 0.03). In the whole cohort, age and HDL were independently associated with IMT; age, HDL, and blood pressure with cIMa; and age and serum creatinine with presence of atherosclerotic plaques. CONCLUSION: Low-dose prednisolone did not influence endothelial function and atherosclerosis in patients with RA. However, total cholesterol was higher in patients treated with prednisolone. PMID- 17696278 TI - Peripheral blood expression of nuclear factor-kappab-regulated genes is associated with rheumatoid arthritis disease activity and responds differentially to anti-tumor necrosis factor-alpha versus methotrexate. AB - OBJECTIVE: To evaluate peripheral blood expression of genes regulated by nuclear factor-kappaB (NF-kappaB), a key mediator of tumor necrosis factor-alpha (TNF alpha) signaling, in patients with rheumatoid arthritis (RA) before and during treatment with anti-TNF-alpha or methotrexate (MTX). We analyzed association of gene expression with disease activity, rheumatoid factor (RF), age, sex, disease duration, treatment modality, and clinical response. METHODS: Sixty patients consented for RNA analysis at baseline and after 2 and 6 weeks of treatment. Disease activity was quantified using Disease Activity Score (DAS28) and C reactive protein (CRP). Expression of 67 TNF-alpha-responsive, NF-kappaB regulated genes was measured using Affymetrix arrays and RT-PCR. RESULTS: Expression of 34 genes was associated with DAS28-CRP, notably S100A12/calgranulin C, IL7R, and aquaporin 3. No association was observed with age, sex, RF, or disease duration. Expression of 16 genes changed in a manner that differed significantly between treatment groups. Eleven were reduced in anti-TNF-alpha treated patients relative to MTX, while 5 were increased. The majority of these observations were confirmed using RT-PCR. Gene expression was not associated significantly with change in disease activity. CONCLUSION: NF-kappaB-dependent gene expression in peripheral leukocytes is highly correlated with RA activity as measured by DAS28-CRP. Expression of many genes responds differentially to anti TNF-alpha versus MTX, suggesting fundamentally different effects on the NF-kappaB pathway. This peripheral blood expression signature provides candidate markers that could lead to development of a simple, minimally invasive pharmacodynamic assay for RA treatments directed at the NF-kappaB pathway. Combination of gene expression data with clinical scores and serum markers may provide more sensitive and predictive measures of RA disease activity. PMID- 17696279 TI - Vanadate, an inhibitor of stromelysin and collagenase expression, suppresses collagen induced arthritis. AB - OBJECTIVE: Collagen induced arthritis (CIA) is a model of chronic inflammatory synovitis with pannus, neovascularization, and joint destruction similar to rheumatoid arthritis (RA). Matrix metalloproteinases (MMP) are involved in degradation of the extracellular matrix and joint destruction in RA. c-fos and c jun are protooncogenes whose products combine to form activating protein (AP-1), a regulatory protein that is required for cell proliferation and the transcription of a variety of genes, including MMP such as collagenase and stromelysin. Administration of vanadium compounds suppresses c-fos/c-jun expression and AP-1 activity, resulting in inhibition of MMP expression in response to factors such as interleukin 1 (IL-1). We evaluated whether a vanadium AP-1 inhibitor could reduce MMP expression and subsequent joint damage in CIA. METHODS: Vanadate [bis (maltolato) oxovanadium (IV) (BMOV; 10 mg/kg/day)] and the reducing agent N-acetyl cysteine (NAC; 100 mg/kg/day) were given subcutaneously daily in an attempt to suppress established CIA in rats. NAC in combination with vanadate appeared to increase the efficacy of c-fos/c-jun inhibition, while decreasing toxicity. Controls were given NAC alone. Clinical, radiographic, and histologic measures were evaluated as well as synovial MMP and IL-1a expression. RESULTS: BMOV therapy, initiated on the day of onset of clinical arthritis, significantly reduced clinical arthritis within 2 days (p <0.05) compared to controls. Significance was maintained to the termination of the study on Day 18 post-arthritis onset (p < 0.005), with a maximum difference seen on Day 5 (p < 0.00001). Blinded radiographic scores at the completion of the protocols indicated less joint destruction in the experimental group compared to the control group (p < 0.005). Scanning and transmission electron microscopy confirmed the preservation of articular cartilage with therapy. In BMOV-treated rats, synovial mRNA expression of collagenase, stromelysin, and IL-la were reduced by 78%, 58%, and 85%, respectively, compared to controls. CONCLUSION: This is the first study of vanadate as a potential antirheumatic agent. Further study of this AP-1 and MMP inhibitor may lead to new treatment options in RA. PMID- 17696280 TI - Do Toll-like receptors contribute to the pathogenesis of lupus? PMID- 17696281 TI - New perspectives from China on HIV rheumatic manifestations. PMID- 17696282 TI - If knowledge is power, why don't rheumatoid arthritis education programs show better outcomes? PMID- 17696283 TI - Bone and matrix remodeling markers: a new tool for assessment of treatment efficacy in ankylosing spondylitis? PMID- 17696284 TI - Causes of death in patients with rheumatoid arthritis: comparison with siblings and matched osteoarthritis controls. AB - OBJECTIVE: Survival of patients with rheumatoid arthritis (RA) is reduced when compared to the general population. We assessed differences in causes and age of death between patients with RA and their siblings. Comparisons were also made with a control group of subjects with lower limb osteoarthritis (OA). METHODS: A population of 257 patients with RA studied in 1991 was compared to 371 of their same-sex siblings and 485 patients with hip and knee OA who were also attending the department at this time. Death certificates were obtained and compared. RESULTS: Among patients with RA, 54% (139/257) were deceased, compared to 28% (105/371) of the siblings and 32% (154/485) of OA patients (RA vs siblings or OA, p < 0.05). There were more deaths due to ischemic heart disease (IHD) in both the RA and OA groups compared to those expected; ratio observed/expected, 1.66 (95% CI 1.01, 2.79) and 1.96 (95% CI 1.21, 3.25), respectively, but not for siblings: observed/expected = 1.05 (95% CI 0.53, 2.08). There was a significant deficit in cancer related deaths in RA patients, observed/expected = 0.62 (95% CI 0.36, 1.03). CONCLUSION: Significantly more patients with RA had died than in either of the comparator populations. RA and OA patients died more frequently of IHD than the siblings. The RA population had a 40% reduced rate of cancer related deaths than expected and compared to their siblings. PMID- 17696285 TI - Rheumatology in the developing countries--challenges and solutions: 11th Annual Conference of the Pakistan Society for Rheumatology in collaboration with the Baqai Rheumatology Unit. PMID- 17696286 TI - Wegener's granulomatosis mimicking a thoracic spondylodiscitis. PMID- 17696287 TI - Online learning of objects in a biologically motivated visual architecture. AB - We present a biologically motivated architecture for object recognition that is capable of online learning of several objects based on interaction with a human teacher. The system combines biological principles such as appearance-based representation in topographical feature detection hierarchies and context-driven transfer between different levels of object memory. Training can be performed in an unconstrained environment by presenting objects in front of a stereo camera system and labeling them by speech input. The learning is fully online and thus avoids an artificial separation of the interaction into training and test phases. We demonstrate the performance on a challenging ensemble of 50 objects. PMID- 17696288 TI - A model of grid cells based on a twisted torus topology. AB - The grid cells of the rat medial entorhinal cortex (MEC) show an increased firing frequency when the position of the animal correlates with multiple regions of the environment that are arranged in regular triangular grids. Here, we describe an artificial neural network based on a twisted torus topology, which allows for the generation of regular triangular grids. The association of the activity of pre defined hippocampal place cells with entorhinal grid cells allows for a highly robust-to-noise calibration mechanism, suggesting a role for the hippocampal back projections to the entorhinal cortex. PMID- 17696289 TI - Adaptive thresholds for neural networks with synaptic noise. AB - The inclusion of a macroscopic adaptive threshold is studied for the retrieval dynamics of both layered feedforward and fully connected neural network models with synaptic noise. These two types of architectures require a different method to be solved numerically. In both cases it is shown that, if the threshold is chosen appropriately as a function of the cross-talk noise and of the activity of the stored patterns, adapting itself automatically in the course of the recall process, an autonomous functioning of the network is guaranteed. This self control mechanism considerably improves the quality of retrieval, in particular the storage capacity, the basins of attraction and the mutual information content. PMID- 17696290 TI - Recurrent Neural Networks are universal approximators. AB - Recurrent Neural Networks (RNN) have been developed for a better understanding and analysis of open dynamical systems. Still the question often arises if RNN are able to map every open dynamical system, which would be desirable for a broad spectrum of applications. In this article we give a proof for the universal approximation ability of RNN in state space model form and even extend it to Error Correction and Normalized Recurrent Neural Networks. PMID- 17696291 TI - A neural network model of metaphor understanding with dynamic interaction based on a statistical language analysis: targeting a human-like model. AB - The purpose of this paper is to construct a model that represents the human process of understanding metaphors, focusing specifically on similes of the form an "A like B". Generally speaking, human beings are able to generate and understand many sorts of metaphors. This study constructs the model based on a probabilistic knowledge structure for concepts which is computed from a statistical analysis of a large-scale corpus. Consequently, this model is able to cover the many kinds of metaphors that human beings can generate. Moreover, the model implements the dynamic process of metaphor understanding by using a neural network with dynamic interactions. Finally, the validity of the model is confirmed by comparing model simulations with the results from a psychological experiment. PMID- 17696292 TI - Attention and visual search. AB - Selective Tuning (ST) presents a framework for modeling attention and in this work we show how it performs in covert visual search tasks by comparing its performance to human performance. Two implementations of ST have been developed. The Object Recognition Model recognizes and attends to simple objects formed by the conjunction of various features and the Motion Model recognizes and attends to motion patterns. The validity of the Object Recognition Model was first tested by successfully duplicating the results of Nagy and Sanchez. A second experiment was aimed at an evaluation of the model's performance against the observed continuum of search slopes for feature-conjunction searches of varying difficulty. The Motion Model was tested against two experiments dealing with searches in the visual motion domain. A simple odd-man-out search for counter clockwise rotating octagons among identical clockwise rotating octagons produced linear increase in search time with the increase of set size. The second experiment was similar to one described by Thorton and Gilden. The results from both implementations agreed with the psychophysical data from the simulated experiments. We conclude that ST provides a valid explanatory mechanism for human covert visual search performance, an explanation going far beyond the conventional saliency map based explanations. PMID- 17696293 TI - An embedded saliency map estimator scheme: application to video encoding. AB - In this paper we propose a novel saliency-based computational model for visual attention. This model processes both top-down (goal directed) and bottom-up information. Processing in the top-down channel creates the so called skin conspicuity map and emulates the visual search for human faces performed by humans. This is clearly a goal directed task but is generic enough to be context independent. Processing in the bottom-up information channel follows the principles set by Itti et al. but it deviates from them by computing the orientation, intensity and color conspicuity maps within a unified multi resolution framework based on wavelet subband analysis. In particular, we apply a wavelet based approach for efficient computation of the topographic feature maps. Given that wavelets and multiresolution theory are naturally connected the usage of wavelet decomposition for mimicking the center surround process in humans is an obvious choice. However, our implementation goes further. We utilize the wavelet decomposition for inline computation of the features (such as orientation angles) that are used to create the topographic feature maps. The bottom-up topographic feature maps and the top-down skin conspicuity map are then combined through a sigmoid function to produce the final saliency map. A prototype of the proposed model was realized through the TMDSDMK642-0E DSP platform as an embedded system allowing real-time operation. For evaluation purposes, in terms of perceived visual quality and video compression improvement, a ROI-based video compression setup was followed. Extended experiments concerning both MPEG-1 as well as low bit-rate MPEG-4 video encoding were conducted showing significant improvement in video compression efficiency without perceived deterioration in visual quality. PMID- 17696294 TI - Nonnegative tensor factorization for continuous EEG classification. AB - In this paper we present a method for continuous EEG classification, where we employ nonnegative tensor factorization (NTF) to determine discriminative spectral features and use the Viterbi algorithm to continuously classify multiple mental tasks. This is an extension of our previous work on the use of nonnegative matrix factorization (NMF) for EEG classification. Numerical experiments with two data sets in BCI competition, confirm the useful behavior of the method for continuous EEG classification. PMID- 17696295 TI - Does abnormal spinal reciprocal inhibition lead to co-contraction of antagonist motor units? A modeling study. AB - It is suggested that co-contraction of antagonist motor units perhaps due to abnormal disynaptic I(a) reciprocal inhibition is responsible for Parkinsonian rigidity. A neural model of Parkinson's disease bradykinesia is extended to incorporate the effects of spindle feedback on key cortical cells and examine the effects of dopamine depletion on spinal activities. Simulation results show that although reciprocal inhibition is reduced in DA depleted case, it doesn't lead to co-contraction of antagonist motor neurons. Implications to Parkinsonian rigidity are discussed. PMID- 17696296 TI - Towards reasoning and coordinating action in the mental space. AB - Unlike a purely reactive system where the motor output is exclusively controlled by the actual sensory input, a cognitive system must be capable of running mental processes which virtually simulate action sequences aimed at achieving a goal. The mental process either attempts to find a feasible course of action compatible with a number of constraints (Internal, Environmental, Task Specific etc) or selects it from a repertoire of previously learned actions, according to the parameters of the task. If neither reasoning process succeeds, a typical backup strategy is to look for a tool that might allow the operator to match all the task constraints. This further necessitates having the capability to alter ones own goal structures to generate sub-goals which must be successfully accomplished in order to achieve the primary goal. In this paper, we introduce a forward/inverse motor control architecture (FMC/IMC) that relaxes an internal model of the overall kinematic chain to a virtual force field applied to the end effector, in the intended direction of movement. This is analogous to the mechanism of coordinating the motion of a wooden marionette by means of attached strings. The relaxation of the FMC/IMC pair provides a general solution for mentally simulating an action of reaching a target position taking into consideration a range of geometric constraints (range of motion in the joint space, internal and external constraints in the workspace) as well as effort related constraints (range of torque of the actuators, etc.). In case, the forward simulation is successful, the movement is executed; otherwise the residual "error" or measure of inconsistency is taken as a starting point for breaking the action plan into a sequence of sub actions. This process is achieved using a recurrent neural network (RNN) which coordinates the overall reasoning process of framing and issuing goals to the forward inverse models, searching for alternatives tools in solution space and formation of sub-goals based on past context knowledge and present inputs. The RNN + FMC/IMC system is able to successfully reason and coordinate a diverse range of reaching and grasping sequences with/without tools. Using a simple robotic platform (5 DOF Scorbot arm + Stereo vision) we present results of reasoning and coordination of arm/tool movements (real and mental simulation) specifically directed towards solving the classical 2-stick paradigm from animal reasoning at a non linguistic level. PMID- 17696297 TI - Developing role of forensics in deterring violence and genocide. PMID- 17696298 TI - Role of law enforcement response and microbial forensics in investigation of bioterrorism. AB - The risk and threat of bioterrorism and biocrime have become a large concern and challenge for governments and society to enhance biosecurity. Law enforcement plays an important role in assessing and investigating activities involved in an event of bioterrorism or biocrime. Key to a successful biosecurity program is increased awareness and early detection of threats facilitated by an integrated network of responsibilities and capabilities from government, academic, private, and public assets. To support an investigation, microbial forensic sciences are employed to analyze and characterize forensic evidence with the goal of attribution or crime scene reconstruction. Two different molecular biology-based assays--real time polymerase chain reaction (PCR) and repetitive element PCR--are described and demonstrate how molecular biology tools may be utilized to aid in the investigative process. Technologies relied on by microbial forensic scientists need to be properly validated so that the methods used are understood and so that interpretation of results is carried out within the limitations of the assays. The three types of validation are preliminary, developmental, and internal. The first is necessary for rapid response when a threat is imminent or an attack has recently occurred. The latter two apply to implementation of routinely used procedures. PMID- 17696299 TI - Y-chromosome short tandem repeat DYS458.2 non-consensus alleles occur independently in both binary haplogroups J1-M267 and R1b3-M405. AB - AIM: To determine the human Y-chromosome haplogroup backgrounds of non-consensus DYS458.2 short tandem repeat alleles and evaluate their phylogenetic substructure and frequency in representative samples from the Middle East, Europe, and Pakistan. METHODS: Molecular characterization of lineages was achieved using a combination of Y-chromosome haplogroup defining binary polymorphisms and up to 37 short tandem repeat loci, including DYS388 to construct haplotypes. DNA sequencing of the DYS458 locus and median-joining network analyses were used to evaluate Y-chromosome lineages displaying the DYS458.2 motif. RESULTS: We showed that the DYS458.2 allelic innovation arose independently on at least two distinctive binary haplogroup backgrounds and possibly a third as well. The partial allele length pattern was fixed in all haplogroup J1 chromosomes examined, including its known rare sub-haplogroups. Within the alternative R1b3 associated M405 defined sub-haplogroup, both DYS458.0 and DYS458.2 allele classes occurred. A single chromosome also allocated to the R1b3-M269*(xM405) classification. The physical position of the partial insertion/deletion occurrence within the normal tetramer tract differed distinctly in each haplogroup context. CONCLUSIONS: While unusual DYS458.2 alleles are informative, additional information for other linked polymorphic loci is required when using such non-conforming alleles to infer haplogroup background and common ancestry. PMID- 17696300 TI - Development of a multiplex single base extension assay for mitochondrial DNA haplogroup typing. AB - AIM: To provide a screening tool to reduce time and sample consumption when attempting mitochondrial DNA (mtDNA) haplogroup typing. METHODS: A single base primer extension assay was developed to enable typing, in a single reaction, of twelve mtDNA haplogroup specific polymorphisms. For validation purposes a total of 147 samples were tested including 73 samples successfully haplogroup typed using mtDNA control region (CR) sequence data, 20 samples inconclusively haplogroup typed by CR sequence data, 21 samples previously haplogroup typed using RFLP analysis, and 31 samples of known ancestral origin without previous haplogroup typing. Additionally, two highly degraded human bones embalmed and buried in the early 1950s were analyzed using the SNP multiplex. RESULTS: When the SNP multiplex was used to type the 96 previously CR sequenced specimens, an increase in haplogroup or macrohaplogroup assignment relative to conventional CR sequence analysis was observed. The single base extension assay was also successfully used to assign a haplogroup to decades-old, embalmed skeletal remains dating to World War II. CONCLUSION: The SNP multiplex was successfully used to obtain haplogroup status of highly degraded human bones, and demonstrated the ability to eliminate possible contributors. The SNP multiplex provides a low cost, high throughput method for typing of mtDNA haplogroups A, B, C, D, E, F, G, H, L1/L2, L3, M, and N that could be useful for screening purposes for human identification efforts and anthropological studies. PMID- 17696301 TI - Allele frequencies for 15 short tandem repeat loci in representative sample of Croatian population. AB - AIM: To study the distribution of allele frequencies of 15 short tandem repeat (STR) loci in a representative sample of Croatian population. METHODS: A total of 195 unrelated Caucasian individuals born in Croatia, from 14 counties and the City of Zagreb, were sampled for the analysis. All the tested individuals were voluntary donors. Buccal swab was used as the DNA source. AmpFlSTR Identifiler was applied to simultaneously amplify 15 STR loci. Total reaction volume was 12.5 microL. The PCR amplification was carried out in PE Gene Amp PCR System Thermal Cycler. Electrophoresis of the amplification products was preformed on an ABI PRISM 3130 Genetic Analyzer. After PCR amplification and separation by electrophoresis, raw data were compiled, analyzed, and numerical allele designations of the profiles were obtained. Deviation from Hardy-Weinberg equilibrium, observed and expected heterozygosity, power of discrimination, and power of exclusion were calculated. Bonferroni's correction was used before each comparative analysis. RESULTS: We compared Croatian data with those obtained from geographically neighboring European populations. The significant difference (at P<0.01) in allele frequencies was recorded only between Croatian and Slovenian populations for vWA locus. There was no significant deviation from Hardy-Weinberg equilibrium for all the observed loci. CONCLUSION: Obtained population data concurred with the expected "STR data frame" for this part of Europe. PMID- 17696302 TI - Highly effective DNA extraction method for nuclear short tandem repeat testing of skeletal remains from mass graves. AB - AIM: To quantitatively compare a silica extraction method with a commonly used phenol/chloroform extraction method for DNA analysis of specimens exhumed from mass graves. METHODS: DNA was extracted from twenty randomly chosen femur samples, using the International Commission on Missing Persons (ICMP) silica method, based on Qiagen Blood Maxi Kit, and compared with the DNA extracted by the standard phenol/chloroform-based method. The efficacy of extraction methods was compared by real time polymerase chain reaction (PCR) to measure DNA quantity and the presence of inhibitors and by amplification with the PowerPlex 16 (PP16) multiplex nuclear short tandem repeat (STR) kit. RESULTS: DNA quantification results showed that the silica-based method extracted on average 1.94 ng of DNA per gram of bone (range 0.25-9.58 ng/g), compared with only 0.68 ng/g by the organic method extracted (range 0.0016-4.4880 ng/g). Inhibition tests showed that there were on average significantly lower levels of PCR inhibitors in DNA isolated by the organic method. When amplified with PP16, all samples extracted by silica-based method produced 16 full loci profiles, while only 75% of the DNA extracts obtained by organic technique amplified 16 loci profiles. CONCLUSIONS: The silica-based extraction method showed better results in nuclear STR typing from degraded bone samples than a commonly used phenol/chloroform method. PMID- 17696303 TI - Success rates of nuclear short tandem repeat typing from different skeletal elements. AB - AIM: To evaluate trends in DNA typing success rates of different skeletal elements from mass graves originating from conflicts that occurred in the former Yugoslavia (Bosnia and Herzegovina and Kosovo) during the 1990s, and to establish correlation between skeletal sample age and success of high throughput short tandem repeat (STR) typing in the large data set of the International Commission on Missing Persons. METHOD: DNA extraction and short tandem repeat (STR) typing have been attempted on over 25000 skeletal samples. The skeletal samples originated from different geographical locations where the conflicts occurred and from different time periods from 1992 to 1999. DNA preservation in these samples was highly variable, but was often significantly degraded and of limited quantity. For the purpose of this study, processed samples were categorized according to skeletal sample type, sample age since death, and success rates tabulated. RESULTS: Well-defined general trends in success rates of DNA analyses were observed with respect to the type of bone tested and sample age. The highest success rates were observed with samples from dense cortical bone of weight bearing leg bones (femur 86.9%), whereas long bones of the arms showed significantly lower success (humerus 46.2%, radius 24.5%, ulna 22.8%). Intact teeth also exhibited high success rates (teeth 82.7%). DNA isolation from other skeletal elements differed considerably in success, making bone sample selection an important factor influencing success. CONCLUSION: The success of DNA typing is related to the type of skeletal sample. By carefully evaluating skeletal material available for forensic DNA testing with regard to sample age and type of skeletal element available, it is possible to increase the success and efficiency of forensic DNA testing. PMID- 17696304 TI - Variant alleles, triallelic patterns, and point mutations observed in nuclear short tandem repeat typing of populations in Bosnia and Serbia. AB - AIM: To present a compendium of off-ladder alleles and other genotyping irregularities relating to rare/unexpected population genetic variation, observed in a large short tandem repeat (STR) database from Bosnia and Serbia. METHODS: DNA was extracted from blood stain cards relating to reference samples from a population of 32800 individuals from Bosnia and Serbia, and typed using Promega's PowerPlex16 STR kit. RESULTS: There were 31 distinct off-ladder alleles were observed in 10 of the 15 STR loci amplified from the PowerPlex16 STR kit. Of these 31, 3 have not been previously reported. Furthermore, 16 instances of triallelic patterns were observed in 9 of the 15 loci. Primer binding site mismatches that affected amplification were observed in two loci, D5S818 and D8S1179. CONCLUSION: Instances of deviations from manufacturer's allelic ladders should be expected and caution taken to properly designate the correct alleles in large DNA databases. Particular care should be taken in kinship matching or paternity cases as incorrect designation of any of these deviations from allelic ladders could lead to false exclusions. PMID- 17696305 TI - Contribution of forensic anthropology to identification process in Croatia: examples of victims recovered in wells. AB - AIM: To describe the contribution of forensic anthropology to the recovery, analysis, and identification of victims from the 1991-1995 war in Croatia recovered in wells. METHODS: From 1996 to the present, human remains of a total of 61 individuals have been recovered from 13 wells. Six wells contained the remains of a single individual, one well contained the remains of 2 individuals, and 6 wells contained the remains 3 or more individuals. The majority of wells, containing 90.2% (55/61) of recovered individuals, were located within a 4 km radius of the Croatian-Serbian border. RESULTS: Forensic anthropologists re individualized 26/61 (42.6%) individuals out of skeletonized and commingled remains, provided basic biological data on sex, age-at-death, and stature in all identifications (n=37), as well as established positive identification by recognizing unique skeletal features (antemortem fractures and skeletal evidence of antemortem surgical interventions) in 3/37 (8.1%) cases. Trauma analyses carried out by forensic anthropologists contributed to the determination of the cause of death in 38/61 (62.3%) individuals and to the probable cause of death in an additional 18/61 (29.5%) individuals. The most frequent (27/38, 71.0%) type of trauma causing death in individuals recovered from wells was a single gunshot wound. CONCLUSION: Forensic anthropologists, collaborating closely with forensic pathologists, forensic odontologists, forensic radiologists, criminologists, and molecular biologists contributed significantly to trauma analysis and identification of war victims recovered from wells. PMID- 17696306 TI - DNA identification of skeletal remains from the World War II mass graves uncovered in Slovenia. AB - AIM: To present the joint effort of three institutions in the identification of human remains from the World War II found in two mass graves in the area of Skofja Loka, Slovenia. METHODS: The remains of 27 individuals were found in two small and closely located mass graves. The DNA was isolated from bone and teeth samples using either standard phenol/chloroform alcohol extraction or optimized Qiagen DNA extraction procedure. Some recovered samples required the employment of additional DNA purification methods, such as N-buthanol treatment. Quantifiler Human DNA Quantification Kit was used for DNA quantification. PowerPlex 16 kit was used to simultaneously amplify 15 short tandem repeat (STR) loci. Matching probabilities were estimated using the DNA View program. RESULTS: Out of all processed samples, 15 remains were fully profiled at all 15 STR loci. The other 12 profiles were partial. The least successful profile included 13 loci. Also, 69 referent samples (buccal swabs) from potential living relatives were collected and profiled. Comparison of victims' profile against referent samples database resulted in 4 strong matches. In addition, 5 other profiles were matched to certain referent samples with lower probability. CONCLUSION: Our results show that more than 6 decades after the end of the World War II, DNA analysis may significantly contribute to the identification of the remains from that period. Additional analysis of Y-STRs and mitochondrial DNA (mtDNA) markers will be performed in the second phase of the identification project. PMID- 17696307 TI - Skeletal remains from World War II mass grave: from discovery to identification. AB - AIM: To present the process of identification of skeletal remains from a mass grave found on a Dalmatian mountain-range in 2005, which allegedly contained the remains of civilians from Herzegovina killed in the World War II, including a group of 8 Franciscan monks. METHODS: Excavation of a site in Dalmatian hinterland, near the village of Zagvozd, was accomplished according to archeological procedures. Anthropological analysis was performed to estimate sex, age at death, and height of the individuals, as well as pathological and traumatic changes of the bones. Due to the lack of ante-mortem data, DNA typing using Y-chromosome was performed. DNA was isolated from bones and teeth samples using standard phenol/chloroform/isoamyl alcohol extraction. Two Y-chromosome short tandem repeats (STR) systems were used for DNA quantification and amplification. Typing of polymerase chain reaction (PCR) products was performed on an ABI Prism 310 Genetic Analyzer. PCR typing results were matched with results from DNA analysis of samples collected from the relatives of supposed victims--blood samples from the living relatives and bone samples collected during further exhumation of died parents or relatives of the supposed victims. RESULTS: The remains contained 18 almost complete skeletons, with considerable post-mortal damage. All remains were men, mainly middle-aged, with gunshot wounds to the head. DNA analysis and cross-matching of the results with relatives' data resulted in three positive identifications using the Y-chromosomal short tandem repeat (Y-STR) systems. All of the positively identified remains belonged to the Franciscan friars allegedly killed in Herzegovina and buried at the analyzed site. CONCLUSION: Our analysis of remains from a mass grave from the World War II confirmed the value of patrilineal lineage based on Y-STRs, even when missing persons had left no offspring, as is the case with Franciscan monks. Although this report is primarily focused on the identification of remains from a mass grave, it also emphasizes the role of forensic approach in documenting human right violations. PMID- 17696308 TI - Repatriation and identification of the Finnish World War II soldiers. AB - AIM: To present a summary of the organization, field search, repatriation, forensic anthropological examination, and DNA analysis for the purpose of identification of Finnish soldiers with unresolved fate in World War II. METHODS: Field searches were organized, executed, and financed by the Ministry of Education and the Association for Cherishing the Memory of the Dead of the War. Anthropological examination conducted on human remains retrieved in the field searches was used to establish the minimum number of individuals and description of the skeletal diseases, treatment, anomalies, or injuries. DNA tests were performed by extracting DNA from powdered bones and blood samples from relatives. Mitochondrial DNA sequence comparisons, together with circumstantial evidence, were used to connect the remains to the putative family members. RESULTS: At present, the skeletal remains of about a thousand soldiers have been found and repatriated. In forensic anthropological examination, several injuries related to death were documented. For the total of 181 bone samples, mtDNA HVR-1 and HVR-2 sequences were successfully obtained for 167 (92.3%) and 148 (81.8%) of the samples, respectively. Five samples yielded no reliable sequence data. Our data suggests that mtDNA preserves at least for 60 years in the boreal acidic soil. The quality of the obtained mtDNA sequence data varied depending on the sample bone type, with long compact bones (femur, tibia and humerus) having significantly better (90.0%) success rate than other bones (51.2%). CONCLUSION: Although more than 60 years have passed since the World War II, our experience is that resolving the fate of soldiers missing in action is still of uttermost importance for people having lost their relatives in the war. Although cultural and individual differences may exist, our experience presented here gives a good perspective on the importance of individual identification performed by forensic professionals. PMID- 17696309 TI - DNA analysis of early mediaeval individuals from the Zvonimirovo burial site in Northern Croatia: investigation of kinship relationships by using multiplex system amplification for short tandem repeat loci. AB - AIM: To perform initial DNA analysis of four selected early mediaeval individuals from the Zvonimirovo burial site in Northern Croatia. METHODS: Investigation of genetic matching of individuals from a "double burial" and of individuals with shared cranial non-metric/metric traits from two single inhumations, located in another block of the cemetery complex, was carried out. DNA from four teeth samples was extracted, quantified, and amplified by polymerase chain reaction (PCR) for short tandem repeat loci, using AmpFlSTR Profiler PCR Amplification Kit. RESULTS: Autosomal STR genotyping generated high parentage probability (PP) as to the matching of the two individuals from the "double burial" site (PP 98.63%), and of two women with shared cranial non-metric/metric traits from neighboring single burials (PP 90.07%). Parentage probability calculations of a possible genetic matching of the subadult from a "double burial" with the adults from single burials 4 and 3, were significantly lower (PP 60.45% and 38.52%). DNA typing for amelogenin confirmed the sex of the three female individuals, estimated previously by morphology. The unknown sex of a subadult was also identified as female. CONCLUSION: Increased parentage probability for autosomal STR loci matches and the presence of a rare allele shared among matched individuals support their possible kinship relationship, in accordance with bioarchaeological data. We assume an intentional double burial based on a close familial relationship, ie two single neighboring inhumations based on consanguinity, rather than a strong social relationship. The kinship lineages remain unknown at this point. PMID- 17696310 TI - Validation of a short tandem repeat multiplex typing system for genetic individualization of domestic cat samples. AB - AIM: To conduct developmental validation studies on a polymerase chain reaction (PCR) based short tandem repeat (STR) multiplex typing system, developed for the purpose of genetic individualization and parentage testing in domestic cat samples. METHODS: To evaluate reproducibility of the typing system, the multiplex was amplified using DNA extracted from hair, blood, and buccal samples obtained from the same individual (n=13). Additional studies were performed to evaluate the system's species' specificity, using 26 North American mammalian species and two prokaryotes Sacchromyces and Escherichia coli, sensitivity, and ability to identify DNA mixtures. Patterns of Mendelian inheritance and mutation rates for the 11 loci were directly examined in a large multi-generation domestic cat pedigree (n=263). RESULTS: Our studies confirm that the multiplex system was species-specific for feline DNA and amplified robustly with as little as 125 picograms of genomic template DNA, demonstrating good product balance. The multiplex generated all components of a two DNA mixture when the minor component was one tenth of the major component at a threshold of 50 relative fluorescence units. The multiplex was reproducible in multiple tissue types of the same individual. Mutation rates for the 11 STR were within the range of sex averaged rates observed for Combined DNA Index System (CODIS) loci. CONCLUSION: The cat STR multiplex typing system is a robust and reliable tool for the use of forensic DNA analysis of domestic cat samples. PMID- 17696311 TI - Forensic botany: potential usefulness of microsatellite-based genotyping of Croatian olive (Olea europaea L.) in forensic casework. AB - AIM: To assess genotyping with microsatellite-based markers of the olive (Olea europaea L.) for potential application of olive as legal case evidence, with regard to the degree of variability within the Croatian olive genomic pool and to the effectiveness of the chosen set of microsatellite-based markers in revealing olive divergence. METHODS: The total of 44 autochthonous Croatian olive specimens were subjected to genotyping with 16 previously described and developed microsatellite-based markers. According to previous morphological analyses, 44 specimens were classified into 30 cultivars with the exception of an additional, previously unassigned specimen. RESULTS: Genotyping of 44 specimens distinguished a total of 44 different genotype profiles by 16 microsatellite-based loci. Average expected heterozigosity amounted to 0.758, which points to significant diversity of Croatian olives. CONCLUSION: Croatian olive genotyping showed strong varietal discrimination up to the single tree and considerable potential application of olive as evidence in investigation of crime, accident, and suicide circumstances. PMID- 17696312 TI - Genetic analysis of individual seeds by amplified fragment length polymorphism. PMID- 17696313 TI - Moderation in all things. PMID- 17696314 TI - Status of scholarly productivity among nursing academics in Malawi. PMID- 17696315 TI - Bioterrorism or natural disasters: what shall we worry about next? PMID- 17696317 TI - Self-assembled nano-bioreactor from block ionomers with elevated and stabilized enzymatic function. AB - Core-cross-linked polyion complex (PIC) micelles entrapping trypsin in the core were prepared by mixing trypsin and poly(ethylene glycol)-block-poly(alpha,beta aspartic acid) in aqueous medium, followed by the introduction of glutaraldehyde cross-linkages. Trypsin incorporated into the core-cross-linked micelles showed high storage stabilities, and the initial enzymatic activity of trypsin was maintained even after standing for one week at ambient temperature. Further, stable compartmentalization of trypsin into the core-cross-linked micelles led to a unique modulation in the enzymatic functions including an improved thermal tolerability with an increased maximum reaction rate compared to native trypsin. PMID- 17696316 TI - A steric block in translation caused by the antibiotic spectinomycin. AB - The widely used antibiotic spectinomycin inhibits bacterial protein synthesis by blocking translocation of messenger RNA and transfer RNAs on the ribosome. Here, we show that in crystals of the Escherichia coli 70S ribosome spectinomycin binding traps a distinct swiveling state of the head domain of the small ribosomal subunit. Spectinomycin also alters the rate and completeness of reverse translocation in vitro. These structural and biochemical data indicate that in solution spectinomycin sterically blocks swiveling of the head domain of the small ribosomal subunit and thereby disrupts the translocation cycle. PMID- 17696318 TI - Non-proximate detection of small and large molecules by desorption electrospray ionization and desorption atmospheric pressure chemical ionization mass spectrometry: instrumentation and applications in forensics, chemistry, and biology. AB - Ambient surfaces are examined by mass spectrometry at distances of up to 3 m from the instrument without any prior sample preparation. Non-proximate versions of the desorption electrospray ionization (DESI) and desorption atmospheric pressure chemical ionization experiments are shown to allow rapid, sensitive, and selective detection of trace amounts of active ingredients in pharmaceutical drug formulations, illicit drugs (methamphetamine, cocaine, and diacetylmorphine), organic salts, peptides, chemical warfare agent simulants, and other small organic compounds. Utilizing an ion transport tube to transport analyte ions to the mass spectrometer, nonproximate DESI allows one to collect high-quality, largely interference-free spectra with signal-to-noise (S/N) ratios of more than 100. High selectivity is achieved by tandem mass spectrometry and by reactive DESI, a variant experiment in which reagents added into the solvent spray allow bond-forming reactions with the analyte. Ion/molecule reactions were found to selectively suppress the response of mixture components other than the analyte of interest in nonproximate-DESI. Flexible ion transport tubing is also investigated, allowing performance similar to stainless steel tubing in the transport of ions from the sample to the mass spectrometer. Transfer tube temperature effects are examined. A multiple sprayer DESI source capable of analyzing a larger sample area was evaluated to decrease the sampling time and increase sample throughput. Low nanogram detection limits were obtained for the compounds studied from a wide variety of surfaces, even those present in complex matrixes. PMID- 17696319 TI - Residue G346 in transmembrane segment six is involved in inter-domain communication in P-glycoprotein. AB - Multidrug transporters such as P-glycoprotein require considerable inter-domain communication to couple energy utilization with substrate translocation. Elucidation of the regions or residues involved in these communication pathways is a key step in the eventual molecular description of multidrug transport. We used cysteine-scanning mutagenesis to probe the functional involvement of residues along the cytoplasmic half of transmembrane segment 6 (TM6) and its extension toward the nucleotide binding domain. The mutation of one residue (G346C) in this segment adversely affected drug transport in cells. Further investigation using purified protein revealed that the underlying biochemical effect was a reduction in basal ATP hydrolysis. This G346C mutation also affected the stimulation of ATPase activity in a drug dependent manner but had no effect on drug binding, ATP binding, or ADP release. Homology modeling of P-glycoprotein indicated that the G346C mutation caused a steric interaction between TM5 and TM6, thereby precluding a helical movement required to support ATP hydrolysis. PMID- 17696321 TI - Al7Ag and Al7Au clusters with large highest occupied molecular orbital-lowest unoccupied molecular orbital gap. AB - The candidate structures for the ground-state geometry of the Al(7)M (M = Li, Cu, Ag, and Au) clusters are obtained within the spin-polarized density functional theory. Absorption energy, vertical ionization potential, vertical electron affinity, and the energy gap between the highest occupied molecular orbital (HOMO) level and the lowest unoccupied molecular orbital (LUMO) level have been calculated to investigate the effects of doping. Doping with Ag or Au can lead to a large HOMO-LUMO gap, low electron affinity, and increased ionization potential of Al(7) cluster. In the lowest-energy structure of the Al(7)Au cluster, the Al atom binding to the Al(6)Au acts monovalent and the other six Al atoms are trivalent. Thus, the Al(7)Au cluster has 20 valence electrons, and its enhanced stability may be due to the electronic shell closure effect. PMID- 17696320 TI - Univalent binding of the Cry1Ab toxin of Bacillus thuringiensis to a conserved structural motif in the cadherin receptor BT-R1. AB - The Cry1Ab toxin produced by Bacillus thuringiensis (Bt) exerts insecticidal action upon binding to BT-R1, a cadherin receptor localized in the midgut epithelium of the tobacco hornworm Manduca sexta [Dorsch, J. A., Candas, M., Griko, N. B., Maaty, W. S., Midboe, E. G., Vadlamudi, R. K., and Bulla, L. A., Jr. (2002) Cry1A toxins of Bacillus thuringiensis bind specifically to a region adjacent to the membrane-proximal extracellular domain of BT-R1 in Manduca sexta: involvement of a cadherin in the entomopathogenicity of Bacillus thuringiensis, Insect Biochem. Mol. Biol. 32, 1025-1036]. BT-R1 represents a family of invertebrate cadherins whose ectodomains (ECs) are composed of multiple cadherin repeats (EC1 through EC12). In the present work, we determined the Cry1Ab toxin binding site in BT-R1 in the context of cadherin structural determinants. Our studies revealed a conserved structural motif for toxin binding that includes two distinct regions within the N- and C-termini of EC12. These regions are characterized by unique sequence signatures that mark the toxin-binding function in BT-R1 as well as in homologous lepidopteran cadherins. Structure modeling of EC12 discloses the conserved motif as a single broad interface that holds the N- and C-termini in close proximity. Binding of toxin to BT-R1, which is univalent, and the subsequent downstream molecular events responsible for cell death depend on the conserved motif in EC12. PMID- 17696322 TI - Diamagnetic currents in the neutral He atoms. AB - The mechanism of the occurrence of intraatomic diamagnetic currents in the neutral He atoms with microscopic sizes is investigated. It is found that most of all electrons can form electron pairs originating from attractive Coulomb interactions between two electrons with opposite spins occupying the 1s atomic orbital in the neutral He atom at 298 K. Intraatomic diamagnetic currents in the neutral He atoms with microscopic sizes can be explained by such electron pairing. The transition temperature Tc(He),(1s) value at which intraatomic diamagnetic currents can disappear in each He atom is estimated. The Tc(He),(1s) values for the neutral He atoms with microscopic sizes are estimated to be much larger than the superconducting transition temperatures Tc,BCS values for the conventional superconductors with macroscopic sizes. This result can be understood from continuous energy levels of electronic states in conventional superconductivity with macroscopic sizes, and from discrete energy levels of electronic states in the neutral He atoms with microscopic sizes. The energy difference between the occupied and unoccupied orbitals decreases with an increase in material size and thus the second-order perturbation effect becomes more important with an increase in material size. Therefore, the mechanism of the occurrence of intraatomic diamagnetic current in the neutral He atoms suggested in this research would not be true for materials with large sizes. The dependence of electronic properties on temperature in the diamagnetic currents in the neutral He atoms with microscopic sizes is studied and compared with that in the conventional superconductivity with macroscopic sizes. PMID- 17696323 TI - On the chaperon mechanism: application to ClO + ClO (+N2) --> ClOOCl (+N2). AB - The dynamics of the ClO + ClO (+N(2)) radical complex (or chaperon) mechanism is studied by electronic structure methods and quasi-classical trajectory calculations. The geometries and frequencies of the stationary points on the potential energy surface (PES) are optimized at the B3LYP/6-311+G(3df) level of theory, and the energies are refined at the CCSD(T)/6-311+G(3df) (single-point) level of theory. Basis set superposition error (BSSE) corrections are applied to obtain 1.5 kcal mol(-1) for the binding energy of the ClO.N(2) van der Waals (VDW) complex. A model PES is developed and used in quasi-classical trajectory calculations to obtain the capture rate constant and nascent energy distributions of ClOOCl* produced via the chaperon mechanism. A range of VDW binding energies from 1.5 to 9.0 kcal mol(-1) are investigated. The anisotropic PES for the ClO.N(2) complex and a separable anharmonic oscillator approximation are used to estimate the equilibrium constant for formation of the VDW complex. Rate constants, branching ratios to produce ClOOCl, and nascent energy distributions of excited ClOOCl* are discussed with respect to the VDW binding energy and temperature. Interestingly, even for weak VDW binding energies, the N(2) usually carries away enough energy to stabilize the nascent ClOOCl*, although the VDW equilibrium constant is small. For stronger binding energies, the stabilization efficiency is reduced, but the capture rate constant is increased commensurately. The resulting rate constants for forming ClOOCl* from the title reaction are only weakly dependent on the VDW binding energy and temperature. As a result, the relative importance of the chaperon mechanism is mostly dependent on the VDW equilibrium constant. For the calculated ClO.N(2) binding energy of 1.5 kcal mol( 1), the VDW equilibrium constant is small, and the chaperon mechanism is only important at very high pressures. PMID- 17696325 TI - Spectral and photophysical characterization of donor-pi-acceptor arylthienyl- and bithienyl-benzothiazole derivatives in solution and solid state. AB - A comprehensive study has been made in solution at room temperature (293 K), low temperature (77 K), and in thin films (Zeonex matrixes) of the spectral and photophysical properties of six arylthienyl- and bithienyl-benzothiazole derivatives functionalized with different donor groups. Similar experiments have been carried out with two related precursors (containing the arylthienyl and aryl bithienyl conjugated systems), and results are compared. Singlet-singlet and triplet-triplet absorption spectra, emission spectra together with lifetimes and quantum yields have been obtained, and from these data the rates for all the radiative and nonradiative processes determined, providing information on the dominant decay processes. The arylthienyl-benzothiazole derivatives show high fluorescence quantum yields (phi(F)) with negligible internal conversion (phi(IC)), whereas the bithienyl-benzothiazoles display lower but still significant phi(F) values, but now radiationless processes (phi(IC) and phi(ISC)) are competitive. A comparison with the analogous oligothiophenes is made. Singlet oxygen yields were also determined and the triplet energy transfer to (3)O2 to produce (1)O2 was found to be highly efficient with values of S(Delta)(= phi(Delta)/phi(T)) varying from 0.4 to 1. PMID- 17696324 TI - A solution study on the local and global structure changes of cytochrome c: an unfolding process induced by urea. AB - The local and global structural changes of cytochrome c induced by urea in aqueous solution have been studied using X-ray absorption spectroscopy (XAS) and small-angle X-ray scattering (SAXS). According to the XAS result, both the native (folded) protein and the unfolded protein exhibit the same preedge features taken at Fe K-edge, indicating that the Fe(III) in the heme group of the protein maintains a six-coordinated local structure in both the folded and unfolded states. Furthermore, the discernible differences in the X-ray absorption near edge structure (XANES) of these two states are attributed to a possible spin transition of the Fe(III) from a low-spin state to a high-spin state during the unfolding process. The perseverance of six-coordination and the spin transition of the iron are reconciled by a proposed ligand exchange, with urea and water molecules replacing the methionine-80 and histidine-18 axial ligands, respectively. The SAXS result reveals a significant morphology change of cytochrome c from a globular shape of a radius of gyration R(g) = 12.8 A of the native protein to an elongated ellipsoid shape of R(g) = 29.7 A for the unfolded protein in the presence of concentrated urea. The extended X-ray absorption fine structure (EXAFS) data unveil the coordination geometries of Fe(III) in both the folded and unfolded state of cytochrome c. An initial spin transition of Fe(III) followed by an axial ligand exchange, accompanied by the change in the global envelope, is proposed for what happened in the protein unfolding process of cytochrome c. PMID- 17696326 TI - Theoretical study of very high spin organic pi-conjugated polyradicals. AB - Different forms of pi-conjugated polyarylmethyl systems, such as diradicals, polyradicals, spin clusters, and polymers, were studied with valence bond (VB) calculations within the density matrix renormalization group (DMRG) framework. For these systems, the energy gap between the high-spin ground state and the lowest low-spin excited state (DeltaE(L-H)) was computed and found to correlate well with their stability. On the basis of our analysis, medium-sized polyarylmethyl cycles are suggested to be potential key building blocks of very high spin spin clusters and polymers. PMID- 17696327 TI - Atomic correlation energy from the electron density at the nucleus. AB - Ground-state atomic correlation energies, and their kinetic energy and potential energy components, are shown to be well-represented by empirical formulas of the form CNrho(0)Z(-gamma), where C and gamma are constants that are largely invariant within various sets of atoms and positive ions, Z is the atomic number, N is the number of electrons, and rho(0) is the electron density at the nucleus. Results are given for neutral atoms, singly charged positive ions, and many isoelectronic series-315 atomic species in all. PMID- 17696328 TI - Efficient simulation of three-pulse photon-echo signals with application to the determination of electronic coupling in a bacterial photosynthetic reaction center. AB - A time-nonlocal quantum master equation coupled with a perturbative scheme to evaluate the third-order polarization in the phase-matching direction k(s) = k(1) + k(2) + k(3) is used to efficiently simulate three-pulse photon-echo signals. The present method is capable of describing photon-echo peak shifts including pulse overlap and bath memory effects. In addition, the method treats the non-Markovian evolution of the density matrix and the third-order polarization in a consistent manner, thus is expected to be useful in systems with rapid and complex dynamics. We apply the theoretical method to describe one- and two-color three-pulse photon-echo peak shift experiments performed on a bacterial photosynthetic reaction center and demonstrate that, by properly incorporating the pulse overlap effects, the method can be used to describe simultaneously all peak shift experiments and determine the electronic coupling between the localized Q(y) excitations on the bacteriopheophytin (BPhy) and accessory bateriochlorophyll (BChl) in the reaction center. A value of J = 250 cm(-1) is found for the coupling between BPhy and BChl. PMID- 17696329 TI - Boron dipyrromethene analogs with phenyl, styryl, and ethynylphenyl substituents: synthesis, photophysics, electrochemistry, and quantum-chemical calculations. AB - Seven fluorescent boradiazaindacene-based compounds with one or two phenyl, ethenylphenyl, and ethynylphenyl substituents at the 3- (or 3,5-) position(s) were synthesized via palladium-catalyzed coupling reactions with the appropriate 3,5-dichloroBODIPY derivative. The effect of the various substituents at the 3- (or 3,5-) position(s) on the spectroscopic and photophysical properties were studied as a function of solvent by means of UV/vis absorption, steady-state, and time-resolved fluorometry, and theoretical modeling. The emission maxima of the symmetrically 3,5-disubstituted dyes are shifted to longer wavelengths (by 30 to 60 nm) relative to the related asymmetrically 3,5-disubstituted ones. Introduction of styryl substituents causes the largest red shift in both the absorption and emission spectra. BODIPY derivatives with ethynylaryl groups also shift the spectral maxima to longer wavelengths compared to aryl-substituted ones but to a lesser degree than the styryl compounds. The quantum-chemical calculations confirm these trends and provide a rationale for the spectral shifts induced by substitution. The fluorescence quantum yields of the ethenylaryl and ethynylaryl analogs are significantly higher that those of the aryl-substituted dyes. The 3,5-diethynylaryl dye has the highest fluorescence quantum yield (approximately 1.0) and longest lifetime (around 6.5 ns) among the BODIPY dyes studied. The differences in the photophysical properties of the dyes are also reflected in their electrochemical properties where the symmetrically 3,5 disubstituted dyes display much lower oxidation potentials when compared to their asymmetric counterparts. PMID- 17696330 TI - A time-dependent quantum dynamical study of the H + HBr reaction. AB - Time-dependent wave packet calculations were carried out to study the exchange and abstraction processes in the title reaction on the Kurosaki-Takayanagi potential energy surface (Kurosaki, Y.; Takayanagi, T. J. Chem. Phys. 2003, 119, 7838). Total reaction probabilities and integral cross sections were calculated for the reactant HBr initially in the ground state, first rotationally excited state, and first vibrationally excited state for both the exchange and abstraction reactions. At low collision energy, only the abstraction reaction occurs because of its low barrier height. Once the collision energy exceeds the barrier height of the exchange reaction, the exchange process quickly becomes the dominant process presumably due to its larger acceptance cone. It is found that initial vibrational excitation of HBr enhances both processes, while initial rotational excitation of HBr from j(0) = 0 to 1 has essentially no effect on both processes. For the abstraction reaction, the theoretical cross section at E(c) = 1.6 eV is 1.06 A(2), which is smaller than the experimental result of 3 +/- 1 A(2) by a factor of 2-3. On the other hand, the theoretical rate constant is larger than the experimental results by about a factor of 2 in the temperature region between 220 and 550 K. It is also found that the present quantum rate constant is larger than the TST result by a factor of 2 at 200 K. However, the agreement between the present quantum rate constant and the TST result improves as the temperature increases. PMID- 17696331 TI - Geometric dependence of the B3LYP-predicted magnetic shieldings and chemical shifts. AB - We perform a systematic investigation of how the B3LYP/6-311+G(2d,p) calculated 13C nuclear magnetic shielding constants depend on the 6-31G(d)-optimized geometries for a set of 18 molecules with various chemical environments. For absolute shieldings, the Hartree-Fock (HF)-optimized geometries lead to a mean absolute deviation (MAD) of 5.65 ppm, while the BLYP- and B3LYP-optimized geometries give MADs of 13.07 and 10.14 ppm, respectively. For chemical shifts, the HF, BLYP and B3LYP geometries lead to MADs of 2.36, 5.80, and 4.43 ppm, respectively. We find that the deshielding tendency of B3LYP can be effectively compensated by using the HF-optimized geometries. When we apply the B3LYP//HF protocol to versicolorin A and 5alpha-androstan-3,17-dione, MADs of 1.86 and 1.41 ppm, respectively, are obtained for chemical shifts, in satisfactory agreement with the experiment. PMID- 17696332 TI - Lysosome and HER3 (ErbB3) selective anticancer agent kahalalide F: semisynthetic modifications and antifungal lead-exploration studies. AB - Kahalalide F (1) shows remarkable antitumor activity against different carcinomas and has recently completed phase I clinical trials and is being evaluated in phase II clinical studies. The antifungal activity of this molecule has not been thoroughly investigated. In this report, we focused on acetylation and oxidation of the secondary alcohol of threonine, as well as reductive alkylation of the primary amine of ornithine, and each product was evaluated for improvements in antifungal activity. 1 and analogues do not exhibit antimalarial, antileishmania, or antibacterial activity; however, the antifungal activity against different strains of fungi was particularly significant. This series of compounds was highly active against Fusarium spp., which represents an opportunistic infection in humans and plants. The in vitro cytotoxicity for the new analogues of 1 was evaluated in the NCI 60 cell panel. Analogue 5 exhibited enhanced potency in several human cancer cell lines relative to 1. PMID- 17696333 TI - Crystal structure of the anthrax drug target, Bacillus anthracis dihydrofolate reductase. AB - Spores of Bacillus anthracis are the infectious agent of anthrax. Current antibiotic treatments are limited due to resistance and patient age restrictions; thus, additional targets for therapeutic intervention are needed. One possible candidate is dihydrofolate reductase (DHFR), a biosynthetic enzyme necessary for anthrax pathogenicity. We determined the crystal structure of DHFR from B. anthracis (baDHFR) in complex with methotrexate (MTX; 1) at 2.4 Angstrom resolution. The structure reveals the crucial interactions required for MTX binding and a putative molecular basis for how baDHFR has natural resistance to trimethoprim (TMP; 2). The structure also allows insights for designing selective baDHFR inhibitors that will have weak affinities for the human enzyme. Additionally, we have found that 5-nitro-6-methylamino-isocytosine (MANIC; 3), which inhibits another B. anthracis folate synthesis enzyme, dihydropteroate synthase (DHPS), can also inhibit baDHFR. This provides a starting point for designing multi-target inhibitors that are less likely to induce drug resistance. PMID- 17696334 TI - CYP2C9 structure-metabolism relationships: optimizing the metabolic stability of COX-2 inhibitors. AB - The cytochrome P450 (CYP) family is composed of a large group of monooxygenases that mediate the metabolism of xenobiotics and endogenous compounds. CYP2C9, one of the major isoforms of the CYP family, is responsible for the phase I metabolism of a variety of drugs. The aim of the present investigation is to use rational design together with MetaSite, a metabolism site prediction program, to synthesize compounds that retain their pharmacological effects but that are metabolically more stable in the presence of CYP2C9. The model compound for the study is the nonsteroidal anti-inflammatory drug celecoxib, a COX-2 selective inhibitor and known CYP2C9 substrate. Thirteen analogs of celecoxib were designed, synthesized, and evaluated with regard to their metabolic properties and pharmacologic effects. The docking solutions and the predictions from MetaSite gave useful information leading to the design of new compounds with improved metabolic properties. PMID- 17696335 TI - Design, synthesis, and estrogenic activity of a novel estrogen receptor modulator -a hybrid structure of 17beta-estradiol and vitamin E in hippocampal neurons. AB - We recently discovered that ICI 182,780 (1), an antagonist of estrogen receptor (ER)-dependent proliferation in reproductive tissues, functions as an estrogenic agonist in primary neurons. The present study investigated whether the agonist properties of 1 in neurons could be translated into structural analogs. 7alpha [(4R,8R)-4,8,12-trimethyltridecyl]estra-1,3,5-trien-3,17beta-diol (2), a hybrid structure of 17beta-estradiol and vitamin E, was synthesized and found to bind to both ERalpha and ERbeta. In vitro analyses demonstrated that 2 was neuroprotective and effective in activating molecular mechanisms associated with estrogenic agonist activity in rat primary hippocampal neurons. Collectively, the data support an estrogenic agonist profile of 2 action comparable to 1 in primary neurons, confirming that estrogenic activity of 1 in neurons is not a unique phenomenon. These results provide support for the development of a brain selective ER modulator, with potential as an efficacious and safe estrogen alternative to prevent Alzheimer's disease and cognitive decline in postmenopausal women. PMID- 17696337 TI - Selective low-temperature syntheses of facial and meridional tris-cyclometalated iridium(III) complexes. AB - We have developed a selective low-temperature synthesis of fac and mer tris cyclometalated Ir(III) complexes. The chloro-bridged dimers [Ir(CwedgeN)2Cl]2 (CwedgeN = cyclometalating ligand) are cleaved in coordinating solvents like acetonitrile to give neutral Ir(CwedgeN)2(NCCH3)Cl species which in turn are reacted with AgPF6 to give hexafluorophosphate salts of the bis-acetonitrile species [Ir(CwedgeN)2(NCCH3)2]PF6 for CwedgeN = 2,2'-thienylpyridine (thpy) and 2 phenylpyridine (ppy). These bis-acetonitrile complexes are excellent starting materials for the synthesis of tris-Ir(III) complexes. The complexes of the general formula fac-Ir(CwedgeN)3 were synthesized with the ligands thpy and ppy at 100 degrees C in o-dichlorobenzene from the corresponding [Ir(CwedgeN)2(NCCH3)2]PF6 complexes. The reaction of [Ir(CwedgeN)2(NCCH3)2]PF6 with thpy at room temperature did not give the expected tris complex but instead gave [Ir(thpy)2(N,S-thpy)]PF6, with the third chelating ligand complexed through the sulfur atom of the thiophene ring. [Ir(thpy)2Cl]2, [Ir(ppy)2Cl]2, Ir(thpy)2(NCCH3)Cl, [Ir(thpy)2(NCCH3)2]PF6, [Ir(ppy)2(NCCH3)2]PF6, and [Ir(thpy)2(N,S-thpy)]PF6 were structurally characterized by X-ray crystallography. Additionally, hydroxy-bridged dimers, [Ir(CwedgeN)2(OH)]2, were synthesized as starting materials for the selective synthesis of mer-Ir(CwedgeN)3 complexes at 100 degrees C in o-dichlorobenzene. A mechanism is proposed that may account for the selectivity observed in the formation of the mer-Ir(CwedgeN)3 and fac-Ir(CwedgeN)3 isomers in previous studies and the studies presented here. PMID- 17696336 TI - Supramolecular self-assembled polynuclear complexes from tritopic, tetratopic, and pentatopic ligands: structural, magnetic and surface studies. AB - Polymetallic, highly organized molecular architectures can be created by "bottom up" self-assembly methods using ligands with appropriately programmed coordination information. Ligands based on 2,6-picolyldihydrazone (tritopic and pentatopic) and 3,6-pyridazinedihydrazone (tetratopic) cores, with tridentate coordination pockets, are highly specific and lead to the efficient self-assembly of square [3 x 3] Mn9, [4 x 4] Mn16, and [5 x 5] Mn25 nanoscale grids. Subtle changes in the tritopic ligand composition to include bulky end groups can lead to a rectangular 3 x [1 x 3] Mn9 grid, while changing the central pyridazine to a more sterically demanding pyrazole leads to simple dinuclear copper complexes, despite the potential for binding four metal ions. The creation of all bidentate sites in a tetratopic pyridazine ligand leads to a dramatically different spiral Mn4 strand. Single-crystal X-ray structural data show metallic connectivity through both mu-O and mu-NN bridges, which leads to dominant intramolecular antiferromagnetic spin exchange in all cases. Surface depositions of the Mn9, Mn16, and Mn25 square grid molecules on graphite (HOPG) have been examined using STM/CITS imagery (scanning tunneling microscopy/current imaging tunneling spectroscopy), where tunneling through the metal d-orbital-based HOMO levels reveals the metal ion positions. CITS imagery of the grids clearly shows the presence of 9, 16, and 25 manganese ions in the expected square grid arrangements, highlighting the importance and power of this technique in establishing the molecular nature of the surface adsorbed species. Nanoscale, electronically functional, polymetallic assemblies of this sort, created by such a bottom-up synthetic approach, constitute important components for advanced molecule-based materials. PMID- 17696338 TI - O-O bond cleavage in dinuclear peroxo complexes of iron porphyrins: a quantum chemical study. AB - To gain insight into the mechanisms of O2 activation and cleavage in metalloenzymes, biomimetic metal complexes have been constructed and experimentally characterized. One such model complex is the dinuclear peroxo complex of iron porphyrins observed at low temperature in a non-coordinating solvent. The present theoretical study examines the O-O bond cleavage in these complexes, experimentally observed to occur either at increased temperature or when a strongly coordinating base is added. Using hybrid density functional theory, it is shown that the O-O bond cleavage always occurs in a state where two low-spin irons (S = +/-1/2) are antiferromagnetically coupled to a diamagnetic state. This state is the ground state when the strong base is present and forms an axial ligand to the free iron positions. In contrast, without the axial ligands, the ground state of the dinuclear peroxo complex has two high-spin irons (S = +/-5/2) coupled antiferromagnetically. Thus, the activation barrier for O-O bond cleavage is higher without the base because it includes also the promotion energy from the ground state to the reacting state. It is further found that this excitation energy, going from 10 unpaired electrons in the high-spin case to 2 in the low-spin case, is unusually difficult to determine accurately from density functional theory because it is extremely sensitive to the amount of exact exchange included in the functional. PMID- 17696339 TI - In situ hydrothermal synthesis of nanolamellate CaTiO3 with controllable structures and wettability. AB - Nanolamellate structures of CaTiO3 were fabricated by using an in situ hydrothermal synthesis method on titanium for the first time. The number of nanolamellas and the morphology completely or mainly depend on the reaction time and NaOH concentrations, and the wettability of the resulting CaTiO3 surfaces can be successively turned from superhydrophilic to superhydrophobic after modification with a thin layer of hydrophobic silicone, mainly depending on the surface morphology. The proposed formation mechanism of the nanolamellate CaTiO3 structures has also been discussed. PMID- 17696340 TI - Solvent effects on the spectroscopic and photophysical properties of the trans (1,4,8,11-tetraazacyclotetradecane)diisothiocyanatochromium(III) ion, trans [Cr(cyclam)(NCS)(2)]+. AB - The spectroscopy and photophysics of trans-[Cr(cyclam)(NCS)2]+ (where cyclam is 1,4,8,11-tetraazacyclotetradecane) were studied in a range of solvents. The cyclam NH stretching vibration [nu(NH)] wavenumber correlates with the Gutmann donor number, whereas the thiocyanate CN stretching vibration [nu(CN)] wavenumber correlates with the Snyder solvent strength (P') scale. These results signify that there is a difference in the solvent interactions with the two types of ligands. The energy of the ligand-to-metal charge transfer absorption maximum between 310 and 320 nm and the energy of the spin-forbidden (doublet-quartet) absorption and emission bands above 700 nm correlate with the nu(CN) wavenumber. This establishes the dominant role of solvent effects at the NCS- ligand in "tuning" the energy of these spectroscopic features. Quantum yields phirx for photosubstitution are <0.02 at 54 degrees C and <0.002 at 22 degrees C, demonstrating that photochemical reaction is a very minor pathway. The effects of solvent and temperature on the nonradiative decay of the doublet excited-state were investigated by observing the time-resolved phosphorescence between 700 and 750 nm. Below 30 degrees C, the lifetimes are relatively temperature-independent, whereas at higher temperatures, a strong Arrhenius-type dependence is observed. Values for the preexponential factor (A) and the activation energy (Ea) are solvent-dependent and follow a Barclay-Butler-type correlation. These observations are consistent with a dominant back-intersystem crossing pathway for nonradiative decay in the higher-temperature region. From trends observed between ln(A) and the nu(CN) frequency, it appears that solvent effects at the thiocyanate ligand play a dominant role in influencing the rate of nonradiative decay in the high-temperature region. PMID- 17696341 TI - A convergent coordination chemistry-based approach to dissymmetric macrocyclic cofacial porphyrin complexes. AB - We report a highly convergent and modular approach for the synthesis of dissymmetric cofacial porphyrin complexes, which is based upon the weak-link approach to supramolecular coordination chemistry. Specifically, we have utilized a halide-induced ligand rearrangement reaction, which is capable of providing heteroligated mixed-metal porphyrin complexes in quantitative yield. Significantly, the adoption of a coordination chemistry based approach for the synthesis of these complexes allows for facile in situ regulation of the porphyrin-porphyrin interactions through the addition of external chemical stimuli. PMID- 17696342 TI - The conformational free energy landscape of beta-D-glucopyranose. Implications for substrate preactivation in beta-glucoside hydrolases. AB - Using ab initio metadynamics we have computed the conformational free energy landscape of beta-D-glucopyranose as a function of the puckering coordinates. We show that the correspondence between the free energy and the Stoddard's pseudorotational itinerary for the system is rather poor. The number of free energy minima (9) is smaller than the number of ideal structures (13). Moreover, only six minima correspond to a canonical conformation. The structural features, the electronic properties, and the relative stability of the predicted conformers permit the rationalization of the occurrence of distorted sugar conformations in all the available X-ray structures of beta-glucoside hydrolase Michaelis complexes. We show that these enzymes recognize the most stable distorted conformers of the isolated substrate and at the same time the ones better prepared for catalysis in terms of bond elongation/shrinking and charge distribution. This suggests that the factors governing the distortions present in these complexes are largely dictated by the intrinsic properties of a single glucose unit. PMID- 17696343 TI - Dual nanomolar and picomolar Zn(II) binding properties of metallothionein. AB - Each of the seven Zn(II) ions in the Zn(3)S(9) and Zn(4)S(11) clusters of human metallothionein is in a tetrathiolate coordination environment. Yet analysis of Zn(II) association with thionein, the apoprotein, and analysis of Zn(II) dissociation from metallothionein using the fluorescent chelating agents FluoZin 3 and RhodZin-3 reveal at least three classes of sites with affinities that differ by 4 orders of magnitude. Four Zn(II) ions are bound with an apparent average log K of 11.8, and with the methods employed, their binding is indistinguishable. This binding property makes thionein a strong chelating agent. One Zn(II) ion is relatively weakly bound, with a log K of 7.7, making metallothionein a zinc donor in the absence of thionein. The binding data demonstrate that Zn(II) binds with at least four species: Zn(4)T, Zn(5)T, Zn(6)T, and Zn(7)T. Zn(5)T and Zn(6)T bind Zn(II) with a log K of approximately 10 and are the predominant species at micromolar concentrations of metallothionein in cells. Central to the function of the protein is the reactivity of its cysteine side chains in the absence and presence of Zn(II). Chelating agents, such as physiological ligands with moderate affinities for Zn(II), cause dissociation of Zn(II) ions from metallothionein at pH 7.4 (Zn(7)T <==> Zn(7-n)T + nZn(2+)), thereby affecting the reactivity of its thiols. Thus, the rate of thiol oxidation increases in the presence of Zn(II) acceptors but decreases if more free Zn(II) becomes available. Thionein is such an acceptor. It regulates the reactivity and availability of free Zn(II) from metallothionein. At thionein/metallothionein ratios > 0.75, free Zn(II) ions are below a pZn (-log[Zn(2+)](free)) of 11.8, and at ratios < 0.75, relatively large fluctuations of free Zn(II) ions are possible (pZn between 7 and 11). These chemical characteristics match cellular requirements for Zn(II) and suggest how the molecular structures and redox chemistries of metallothionein and thionein determine Zn(II) availability for biological processes. PMID- 17696344 TI - Mechanistic twist of the [8+2] cycloadditions of dienylisobenzofurans and dimethyl acetylenedicarboxylate: stepwise [8+2] versus [4+2]/[1,5]-vinyl shift mechanisms revealed through a theoretical and experimental study. AB - Recently, it was reported that both dienylfurans and dienylisobenzofurans could react with dimethyl acetylenedicarboxylate (DMAD) to give [8+2] cycloadducts. Understanding these [8+2] reactions will aid the design of additional [8+2] reactions, which have the potential for the synthesis of 10-membered and larger carbocycles. The present Article is aimed to understand the detailed mechanisms of the originally reported [8+2] cycloaddition reaction between dienylisobenzofurans and alkynes at the molecular level through the joint forces of computation and experiment. Density functional theory calculations at the (U)B3LYP/6-31+G(d) level suggest that the concerted [8+2] pathway between dienylisobenzofurans and alkynes is not favored. A stepwise reaction pathway involving formation of a zwitterionic intermediate for the [8+2] reactions between dienylisobenzofurans that contain electron-donating methoxy groups present in their diene moieties and DMAD has been predicted computationally. This pathway is in competition with a Diels-Alder [4+2] reaction between the furan moieties of dienylisobenzofurans and DMAD. When there is no electron-donating group present in the diene moieties of dienylisobenzofurans, the [8+2] reaction occurs through an alternative mechanism involving a [4+2] reaction between the furan moiety of the tetraene and DMAD, followed by a [1,5]-vinyl shift. This computationally predicted novel mechanism was supported experimentally. PMID- 17696346 TI - Hydrogen-bond interaction in organic conductors: redox activation, molecular recognition, structural regulation, and proton transfer in donor-acceptor charge transfer complexes of TTF-imidazole. AB - Hydrogen-bond interaction in donor-acceptor charge-transfer complexes of TTF imidazole demonstrated the electronic effects in terms of control of component ratio and redox activation. These unprecedented effects of hydrogen bonds renewed the criteria giving "a high probability of being organic metals" and produced a number of highly conductive complexes with various acceptors having a wide range of electron-accepting ability. In p-chloranil complex, both molecules were linked by hydrogen bonds and formed a D-A-D triad, regulating the donor-acceptor composition to be 2:1. Theoretical calculations have revealed that the polarizability of hydrogen bonds controls the redox ability of the donor and p benzoquinone-type acceptors and afforded different ionicity in complexes from those expected by the difference of redox potentials between donor and acceptors. In the p-chloranil complex, this electronic and structural regulation by hydrogen bond realized the first metallic donor-acceptor charge-transfer complex based on hydrogen bond functionalized TTF. Hydrogen bonds controlled also molecular arrangements in charge-transfer complexes, giving diverse and highly ordered assembled structures, D-A-D triad in the p-chloranil complex, one-dimensional zigzag chain in I(5) salt, alternating donor-acceptor chain in chloranilic acid complex, and D-A-D-A cyclic tetramer in nitranilic acid complex. Furthermore, TTF imidazole acted as electron donor as well as proton acceptor in anilic acid complexes and realized the simultaneous charge- and proton-transfer complexes. These investigations demonstrated the new and intriguing potentials of the hydrogen bond in the development of organic conductors and multifunctional molecular materials. PMID- 17696345 TI - Electrochemical generation of glycosyl triflate pools. AB - Glycosyl triflates, which serve as important intermediates in glycosylation reactions, were generated and accumulated by the low-temperature electrochemical oxidation of thioglycosides such as thioglucosides, thiogalactosides, and thiomannosides in the presence of tetrabutylammonium triflate (Bu(4)NOTf) as a supporting electrolyte. Thus-obtained solutions of glycosyl triflates (glycosyl triflate pools) were characterized by low-temperature NMR measurements. The thermal stability of glycosyl triflates and their reactions with glycosyl acceptors were also examined. PMID- 17696347 TI - Enzymatic synthesis of fluorinated mechanistic probes for sialidases and sialyltransferases. PMID- 17696349 TI - Formation of monodisperse and shape-controlled MnO nanocrystals in non-injection synthesis: self-focusing via ripening. AB - Formation of nearly monodiperse MnO nanocrystals by simple heating of Mn stearate in octadecene was studied systematically and quantitatively as a model for non injection synthesis of nanocrystals. For controlling the shape of the nanocrystals, that is, rice, rods, peanuts, needles, and dots, either an activation reagent (ocadecanol) or an inhibitor (stearic acid) might be added prior to heating. The quantitative results of this typical non-injection system reveal that the formation of nearly monodisperse nanocrystals did not follow the well-known "focusing of size distribution" mechanism. A new growth mechanism, self-focusing enabled by inter-particle diffusion, is proposed. Different from the traditional "focusing of size distribution", self-focusing not only affects the growth process of the nanocrystals, but may also play a role in controlling nucleation. Because of the simplicity of the reaction system, it was possible to also identify the chemical reactions associated with the growth and ripening of MnO nanocrystals with a variety of shapes. Through a recycling reaction path, water was identified as a decisive component in determining the kinetics for both growth and ripening in this system, although the reaction occurred at around 300 degrees C. PMID- 17696348 TI - RNA probes of steric effects in active sites: high flexibility of HIV-1 reverse transcriptase. PMID- 17696350 TI - Photocatalytic hydrogen production from water employing a Ru, Rh, Ru molecular device for photoinitiated electron collection. PMID- 17696351 TI - Charge density waves in the square nets of tellurium of AMRETe4 (A = K, Na; M = Cu, Ag; RE = La, Ce). PMID- 17696352 TI - Stresses at the interface of micro with nano. PMID- 17696353 TI - Exceptional coupling of tetrachloroperylene bisimide: combination of Ullmann reaction and C-H transformation. PMID- 17696355 TI - Total synthesis of (+)-suaveolindole: establishment of its absolute configuration. PMID- 17696354 TI - Enzymatic synthesis of aromatic polyketides using PKS4 from Gibberella fujikuroi. PMID- 17696357 TI - An original redox-responsive ligand based on a pi-extended TTF framework. AB - The synthesis of the first pi-extended tetrathiafulvalene (TTF) ligand featuring a furanoquinonoid spacer and pyridyl functional groups is described. This compound shows an unprecedented electrochemical sensing behavior and excellent coordinating properties toward selected divalent metal ions. Solid-state structures of the free ligand and its Ni(II)Cl2 complex are described. PMID- 17696358 TI - Discovery of an amylose-free starch mutant in cassava (Manihot esculenta Crantz). AB - One of the objectives of the cassava-breeding project at CIAT is the identification of clones with special root quality characteristics. A large number of self-pollinations have been made in search of useful recessive traits. During 2006 harvests an S1 plant produced roots that stained brownish-red when treated with an iodine solution, suggesting that it had lower-than-normal levels of amylose in its starch. Colorimetric and DSC measurements indicated low levels (3.4%) and an absence of amylose in the starch, respectively. SDS-PAGE demonstrated the absence of GBSS enzyme in the starch from these roots. Pasting behavior was analyzed with a rapid visco-analyzer and resulted in larger values for peak viscosity, gel breakdown, and setback in the mutant compared with normal cassava starch. Solubility was considerably reduced, while the swelling index and volume fraction of the dispersed phase were higher in the mutant. No change in starch granule size or shape was observed. This is the first report of a natural mutation in cassava that drastically reduces amylose content in root starch. PMID- 17696359 TI - Use of near-infrared spectroscopy and feature selection techniques for predicting the caffeine content and roasting color in roasted coffees. AB - Near-infrared spectroscopy (NIRS), combined with diverse feature selection techniques and multivariate calibration methods, has been used to develop robust and reliable reduced-spectrum regression models based on a few NIR filter sensors for determining two key parameters for the characterization of roasted coffees, which are extremely relevant from a quality assurance standpoint: roasting color and caffeine content. The application of the stepwise orthogonalization of predictors (an "old" technique recently revisited, known by the acronym SELECT) provided notably improved regression models for the two response variables modeled, with root-mean-square errors of the residuals in external prediction (RMSEP) equal to 3.68 and 1.46% for roasting color and caffeine content of roasted coffee samples, respectively. The improvement achieved by the application of the SELECT-OLS method was particularly remarkable when the very low complexities associated with the final models obtained for predicting both roasting color (only 9 selected wavelengths) and caffeine content (17 significant wavelengths) were taken into account. The simple and reliable calibration models proposed in the present study encourage the possibility of implementing them in online and routine applications to predict quality parameters of unknown coffee samples via their NIR spectra, thanks to the use of a NIR instrument equipped with a proper filter system, which would imply a considerable simplification with regard to the recording and interpretation of the spectra, as well as an important economic saving. PMID- 17696360 TI - Identification of TLC markers and quantification by HPLC-MS of various constituents in noni fruit powder and commercial noni-derived products. AB - The composition of noni (Morinda citrifolia) products has been investigated. TLC profiles of several commercial juices and capsules were compared. 3-Methyl-1,3 butanediol was identified as a typical marker in noni juices. The presence of sorbic acid (E200) was detected in one juice declared as additive free. Quantitative data have been obtained by HPLC-MS. A method for the quantification of characteristic noni constituents, such as iridoid glucosides, scopoletin, rutin, fatty acid glucosides, and anthraquinones, was developed and validated. The separation was performed on a C18 column with a gradient of acetonitrile in water containing 0.1% formic acid. Detection was carried out with ESI-MS in the negative ion mode. Significant differences were observed between the products. Asperulosidic acid, deacetylasperulosidic acid, and rutin were present in all samples analyzed, but their concentrations differed considerably between the products. Fatty acid glucosides, noniosides B and C, were present in capsules and most juices. Scopoletin was mainly found in juices. The anthraquinone alizarin, which has been reported from roots and leaves, was not detected in the samples investigated. PMID- 17696361 TI - Structure-activity relationship development of dihaloaryl triazole compounds as insecticides and acaricides. 1. Phenyl thiophen-2-yl triazoles. AB - An extended lipophilic system that incorporated some key elements of first generation 2,6-dihaloaryl actives, such as 1, demonstrated desirable efficacy against chewing insects as well as sap-feeding insects. These four-ring systems, based on 2, were accessed primarily via Suzuki couplings of halothiophene derivatives with appropriately substituted boronic acids. In particular, phenylthiophene systems that incorporated haloxyether groups, such as those in 3, 4, and 5, had the broadest spectrum of activity across chewing and sap-feeding insect pests. Expansion of this structure-activity relationship to include compounds with differing substitution patterns on the thiophene-C-ring and aryl-D rings was undertaken. The synthesis and insecticidal activity of 3-aryl-5 (thiophen-2-yl)-1-methyl-1H-[1,2,4]triazoles will be described. PMID- 17696363 TI - Observation of an intermediate tryptophanyl radical in W306F mutant DNA photolyase from Escherichia coli supports electron hopping along the triple tryptophan chain. AB - DNA photolyases repair UV-induced cyclobutane pyrimidine dimers in DNA by photoinduced electron transfer. The redox-active cofactor is FAD in its doubly reduced state FADH-. Typically, during enzyme purification, the flavin is oxidized to its singly reduced semiquinone state FADH degrees . The catalytically potent state FADH- can be reestablished by so-called photoactivation. Upon photoexcitation, the FADH degrees is reduced by an intrinsic amino acid, the tryptophan W306 in Escherichia coli photolyase, which is 15 A distant. Initially, it has been believed that the electron passes directly from W306 to excited FADH degrees , in line with a report that replacement of W306 with redox-inactive phenylalanine (W306F mutant) suppressed the electron transfer to the flavin [Li, Y. F., et al. (1991) Biochemistry 30, 6322-6329]. Later it was realized that two more tryptophans (W382 and W359) are located between the flavin and W306; they may mediate the electron transfer from W306 to the flavin either by the superexchange mechanism (where they would enhance the electronic coupling between the flavin and W306 without being oxidized at any time) or as real redox intermediates in a three-step electron hopping process (FADH degrees * <-- W382 < - W359 <-- W306). Here we reinvestigate the W306F mutant photolyase by transient absorption spectroscopy. We demonstrate that electron transfer does occur upon excitation of FADH degrees and leads to the formation of FADH- and a deprotonated tryptophanyl radical, most likely W359 degrees. These photoproducts are formed in less than 10 ns and recombine to the dark state in approximately 1 micros. These results support the electron hopping mechanism. PMID- 17696362 TI - Structure and sodium channel activity of an excitatory I1-superfamily conotoxin. AB - Conotoxin iota-RXIA, from the fish-hunting species Conus radiatus, is a member of the recently characterized I1-superfamily, which contains eight cysteine residues arranged in a -C-C-CC-CC-C-C- pattern. iota-RXIA (formerly designated r11a) is one of three characterized I1 peptides in which the third last residue is posttranslationally isomerized to the d configuration. Naturally occurring iota RXIA with d-Phe44 is significantly more active as an excitotoxin than the l-Phe analogue both in vitro and in vivo. We have determined the solution structures of both forms by NMR spectroscopy, the first for an I1-superfamily member. The disulfide connectivities were determined from structure calculations and confirmed chemically as 5-19, 12-22, 18-27, and 21-38, suggesting that iota-RXIA has an ICK structural motif with one additional disulfide (21-38). Indeed, apart from the first few residues, the structure is well defined up to around residue 35 and does adopt an ICK structure. The C-terminal region, including Phe44, is disordered. Comparison of the d-Phe44 and l-Phe44 forms indicates that the switch from one enantiomer to the other has very little effect on the structure, even though it is clearly important for receptor interaction based on activity data. Finally, we identify the target of iota-RXIA as a voltage-gated sodium channel; iota-RXIA is an agonist, shifting the voltage dependence of activation of mouse NaV1.6 expressed in Xenopus oocytes to more hyperpolarized potentials. Thus, there is a convergence of structure and function in iota-RXIA, as its disulfide pairing and structure resemble those of funnel web spider toxins that also target sodium channels. PMID- 17696364 TI - The conformation of H,K-ATPase determines the nucleoside triphosphate (NTP) selectivity for active proton transport. AB - The gastric H,K-ATPase is related to other cation transport ATPases, for example, Na,K-ATPase and Ca-ATPase, which are called E1-E2 ATPases in recognition of conformational transitions during their respective transport and catalytic cycles. Generally, these ATPases cannot utilize NTPs other than ATP for net ion transport activity. For example, under standard assay conditions, rates of NTP hydrolysis and H+ pumping by the H,K-ATPase for CTP are about 10% of those for ATP and undetectable with GTP, ITP, and UTP. However, we observed that H,K-ATPase will catalyze NTP/ADP phosphate exchange at similar rates for all of these NTPs, suggesting that a common phosphoenzyme intermediate is formed. The present study was undertaken to evaluate the specificity of nucleotides to power the H,K-ATPase and several of its partial reactions, including NTP/ADP exchange, K+-catalyzed phosphatase activity, and proton pumping. Results demonstrate that under conditions that promote the conformational change of the K+ bound form of the enzyme, K.E2, to E1, all NTPs tested support K+-stimulated NTPase activity and H+ pumping up to 30-50% of that with ATP. These conditions include (1) the presence of ADP as well as the NTP energy source and (2) reduced K+ concentration on the cytoplasmic side to approximately 0. These data conform to structural models for E1-E2 ATPases whereby adenosine binding promotes the K.E2 to E1 conformational change and K+ deocclusion. PMID- 17696366 TI - Dynamic surface properties of polyelectrolyte/surfactant adsorption films at the air/water interface: poly(diallyldimethylammonium chloride) and sodium dodecylsulfate. AB - The dynamic surface elasticity, dynamic surface tension, and ellipsometric angles of mixed aqueous poly(diallyldimethylammonium chloride)/sodium dodecylsulfate solutions (PDAC/SDS) have been measured as a function of time and surfactant concentration. This system represents a typical example of polyelectrolyte/surfactant complex formation and subsequent aggregation on the nanoscale. The oscillating barrier and oscillating drop methods sometimes led to different results. The surface viscoelasticity of mixed PDAC/SDS solutions are very close to those of mixed solutions of sodium polystyrenesulfonate and dodecyltrimethylammonium bromide but different from the results for some other polyelectrolyte/surfactant mixtures. The abrupt drop in surface elasticity when the surfactant molar concentration approaches the concentration of charged polyelectrolyte monomers is caused by the formation of microparticles in the adsorption layer. Aggregate formation in the solution bulk does not influence the surface properties significantly, except for a narrow concentration range where the aggregates form macroscopic flocks. The mechanism of the observed relaxation process is controlled by the mass exchange between the surface layer and the flocks attached to the liquid surface. PMID- 17696365 TI - The effector domain of human Dlg tumor suppressor acts as a switch that relieves autoinhibition of kinesin-3 motor GAKIN/KIF13B. AB - The activity of motor proteins must be tightly regulated in the cells to prevent unnecessary energy consumption and to maintain proper distribution of cellular components. Loading of the cargo molecule is one likely mechanism to activate an inactive motor. Here, we report that the activity of the kinesin-3 motor protein, GAKIN, is regulated by the direct binding of its protein cargo, human discs large (hDlg) tumor suppressor. Recombinant GAKIN exhibits potent microtubule gliding activity but has little microtubule-stimulated ATPase activity in solution, suggesting that it exists in an autoinhibitory form. In vitro binding measurements revealed that defined segments of GAKIN, particularly the MAGUK binding stalk (MBS) domain and the motor domain, mediate intramolecular interactions to confer globular protein conformation. Direct binding of the SH3 I3-GUK module of hDlg to the MBS domain of GAKIN activates the microtubule stimulated ATPase activity of GAKIN by approximately 10-fold. We propose that the cargo-mediated regulation of motor activity constitutes a general paradigm for the activation of kinesins. PMID- 17696367 TI - Protein release from biodegradable dextran nanogels. AB - The use of drugs with intracellular targets will strongly depend on the availability of delivery systems that are able to deliver them to specific intracellular sites at an optimal rate. Biodegradable dextran nanogels were prepared using liposomes as a nanoscaled reactor.1,2 These nanogels were obtained by UV polymerization of dextran hydroxyethylmethacrylate (dex-HEMA) containing 1 stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC) liposomes. We found the encapsulation efficiency of bovine serum albumin (BSA) and lysozyme in the dextran nanogels to be about 50%. Specifically, the release of BSA and lysozyme from the dextran nanogels was clearly governed by the cross-link density of the tiny gels. Depending on the size of the encapsulated protein, the cross-link density of the dextran network, and the presence or absence of a lipid coating, proteins were released from the nanogels over days to weeks. Interestingly, when sufficiently diluted, dextran nanogels did not aggregate in human serum, which is of major importance when one considers intravenous administration of such nanogels. Also, reconstitution of lyophilized dextran nanogels seemed perfectly possible, which is also an important finding since dextran nanogels will have to be stored in dry form. Because dextran nanogels can be taken up by cells, they are promising materials for controlled intracellular release of proteins. PMID- 17696368 TI - Control of TiO2 structures from robust hollow microspheres to highly dispersible nanoparticles in a tetrabutylammonium hydroxide solution. AB - A new process for controlling the structure of TiO2 from hollow microspheres to highly dispersible nanoparticles has been developed by altering the concentration of tetrabutylammonium hydroxide (TBAH) in the solvothermal reaction of titanium isopropoxide. Robust and size-controllable hollow TiO2 microspheres, constructed by the assembly of 18 nm TiO2 nanoparticles, were synthesized at relatively high TBAH concentration. The diameters of hollow spheres, with a shell thickness of approximately 250 nm, were controlled to 1.5-4 microm by varying the concentration of TBAH in the range of 0.1-0.5 M. After calcination at 450 degrees C, the hollow microspheres were not appreciably deformed and were still floating on the surface of the water. However, highly dispersible TiO2 nanoparticles with an average diameter of 13 nm were obtained at a low TBAH concentration such as 9.2 mM. The colloidal particle size of TiO2 in an aqueous suspension at pH 2 was 12.5-13.5 nm, which indicates that the each nanoparticle is completely separated. The overall procedure is simple and highly reproducible, and large-scale synthesis is available at low cost. PMID- 17696369 TI - Mesoscale simulations of the behavior of charged polymer brushes under normal compression and lateral shear forces. AB - Dissipative particle dynamics (DPD) was used to investigate the behavior of two opposing end-grafted charged polymer brushes in aqueous media under normal compression and lateral shear. The effect of polymer molecular weight, degree of ionization, grafting density, ionic strength, and compression on the polymer conformation and the resulting shear force between the opposing polymer layers were investigated. The simulations were carried out for the poly(tert-butyl methacrylate)-block-poly(sodium sulfonate glycidyl methacrylate) copolymer, referred as PtBMA-b-PGMAS, end-attached to a hydrophobic surface for comparison with previous experimental data. Mutual interpenetration of the opposing end grafted chains upon compression is negligible for highly charged polymer brushes for compression ratios ranging from 2.5 to 0.25. Under electrostatic screening effects or for weakly charged polymer brushes, a significant mutual interpenetration was measured. The variation of interpenetration thickness with separation distance, grafting density, and polymer size follows the same scaling law as the one observed for two opposing grafted neutral brushes in good solvent. However, compression between two opposing charged brushes results in less interpenetration relative to neutral brushes when considering equivalent grafting density and molecular weight. The friction coefficient between two opposing polymer-coated surfaces sliding past each other is shown to be directly correlated with the interpenetration thickness and more specifically to the number of polymer segments within the interpenetration layer. PMID- 17696370 TI - Conductance switching in an organic material: from bulk to monolayer. AB - Fluorescein sodium, which does not exhibit electrical bistability in thin films, can be switched to a high conducting state by the introduction of carbon nanotubes as channels for carrier transport. Thin films based on fluorescein sodium/carbon nanotubes display memory switching phenomenon among a low conducting state and several high conducting states. Read-only and random-access memory applications between the states resulted in multilevel memory in these systems. Results in thin films and in a monolayer (deposited via layer-by-layer assembly) show that instead of different molecular conformers, multilevel conducting states arise from the different density of high conducting fluorescein molecules. PMID- 17696371 TI - Structural and rheological investigation of Fd3m inverse micellar cubic phases. AB - In the present study we demonstrate that a bulk inverse micellar cubic phase of Fd3m structure can be obtained by adding a hydrophobic component, such as the food-grade limonene, to the binary system monolinolein/water in a well-defined composition. The Fd3m structure studied in this work had a very slow kinetics of formation, as a consequence of partitioning of water into two types of micelle populations with different sizes. The Fd3m structure formed at a ratio of limonene oil to total lipids of alpha = 0.4 is stable in the bulk up to a maximum hydration of 12.68 wt % water, beyond which it starts to coexist with dispersed water. At full hydration, by combining small-angle X-ray scattering and available topological models, the inverse micellar cubic phase of Fd3m structure was shown to be formed by 16 small micelles and 8 larger micelles per cubic lattice cell (Q227 group), with radii of the micellar polar cores ranging between 1 and 3 nm and 149-168 monolinolein molecules per micelle depending on the water content. The temperature dependence of the structural and rheological properties of the Fd3m mesophase was investigated using SAXS, rheology, and turbidimetry. It appeared that the Fd3m phase underwent crystallization below 18 degrees C and began melting in an inverse microemulsion (L2 phase) coexisting with water above 28.5 degrees C with complete melting obtained at 40-45 degrees C, as evidenced by SAXS and rheology. Macroscopic phase separation between the L2 phase and excess water was observed with time at higher temperatures. The investigation of the viscoelastic properties of the Fd3m inverse discrete micellar cubic phase revealed a rheological signature similar to that of the bicontinuous cubic phases Pn3m and Ia3d observed in homologous binary systems. However, the Fd3m phase presented a complex set of slower relaxation mechanisms leading to a shift by 1 order of magnitude of the dominant relaxation times and whole relaxation spectrum, as compared to those of inverse bicontinuous cubic phases. These findings have been tentatively explained by (i) the multiple relaxation of micelles upon deformation, (ii) the small hydration level of the Fd3m phase, and (iii) the low temperature at which this phase can be observed. PMID- 17696372 TI - Cellulose nanocrystal submonolayers by spin coating. AB - Dilute concentrations of cellulose nanocrystal solutions were spin coated onto different substrates to investigate the effect of the substrate on the nanocrystal submonolayers. Three substrates were probed: silica, titania, and amorphous cellulose. According to atomic force microscopy (AFM) images, anionic cellulose nanocrystals formed small aggregates on the anionic silica substrate, whereas a uniform two-dimensional distribution of nanocrystals was achieved on the cationic titania substrate. The uniform distribution of cellulose nanocrystal submonolayers on titania is an important factor when dimensional analysis of the nanocrystals is desired. Furthermore, the amount of nanocrystals deposited on titania was multifold in comparison to the amounts on silica, as revealed by AFM image analysis and X-ray photoelectron spectroscopy. Amorphous cellulose, the third substrate, resulted in a somewhat homogeneous distribution of the nanocrystal submonolayers, but the amounts were as low as those on the silica substrate. These differences in the cellulose nanocrystal deposition were attributed to electrostatic effects: anionic cellulose nanocrystals are adsorbed on cationic titania in addition to the normal spin coating deposition. The anionic silica surface, on the other hand, causes aggregation of the weakly anionic cellulose nanocrystals which are forced on the repulsive substrate by spin coating. The electrostatically driven adsorption also influences the film thickness of continuous ultrathin films of cellulose nanocrystals. The thicker films of charged nanocrystals on a substrate of opposite charge means that the film thickness is not independent of the substrate when spin coating cellulose nanocrystals in the ultrathin regime (<100 nm). PMID- 17696373 TI - Interactions of 4-chlorophenol with TiO2 polycrystalline surfaces: a study of environmental interfaces by NEXAFS, XPS, and UPS. AB - Despite a significant body of literature on the photocatalytic decomposition of 4 chlorophenol by TiO2 at liquid/solid and gas/solid interfaces, a fundamental understanding of the interaction of 4-chlorophenol with TiO2 is lacking. We present the first study of this interaction under well-defined UHV conditions by means of NEXAFS, time-dependent XPS, and UPS. XPS data show that the molecule adsorbs with the carbon framework intact and no scission of the C-Cl bond. The NEXAFS results indicate a coverage-dependent tilted geometry for the adsorbed molecule that is attached to the surface via a phenolate link. In contrast, because of the absence of an OH functionality, 1,2,4-trichlorobenzene lies flat. The adsorption of 4-chlorophenol is accompanied by a decrease in the TiO2 work function pointing to adsorbate --> substrate charge transfer. Interestingly, the UPS data suggest that 4-chlorophenol adsorption leads to the photosensitization of TiO2, thus providing a basis for understanding recent results on the visible light photocatalytic activity of TiO2 for 4-chlorophenol decomposition. It is also found that the molecule is stable against thermal decomposition at temperatures of up to approximately 473 K, which is well above the temperature range used for photocatalytic decomposition studies. PMID- 17696374 TI - Fluorocarbon crowning: Langmuir-Blodgett deposition versus self-assembly at molecularly rough surfaces. AB - Langmuir-Blodgett deposition of a single monolayer of 1,2,4,5-tetrakis[(N (perfluoroundecanoamidoethyl)-N,N-dimethylammonium)methyl]benzene tetrabromide (1) onto a thin film made from alternating layers of poly(diallydimethylammonium chloride) (PDADMA) and poly(4-styrenesulfonate) (PSS) ions affords a uniform fluorinated surface of low energy. An analogous surface that has been constructed by self-assembly shows the same critical surface tension of 16.5 dyn/cm. A comparison of Zisman plots for these two modified films, in combination with analysis by X-ray photoelectron spectroscopy, indicates that Langmuir-Blodgett deposition produces a higher quality and more densely packed fluorocarbon surface that is very hydrophobic. In sharp contrast, the use of a single-chain analog (i.e., N-(perfluoroundecanoamidoethyl)-N,N,N-trimethylammonium bromide) (2)) affords relatively high energy surfaces by Langmuir-Blodgett deposition and by self-assembly. PMID- 17696375 TI - Mechanism of electrochemical reduction of hydrogen peroxide on copper in acidic sulfate solutions. AB - Hydrogen peroxide is a commonly used oxidizer component in chemical mechanical planarization slurries, used in the processing of Cu metallization in microelectronics applications. We studied the electrochemical reduction of hydrogen peroxide on Cu in 0.1 M H2SO4 solutions using methods including cyclic voltammetry, rotating disk electrode experiments, surface-enhanced Raman spectroscopy, and density functional theory (DFT) calculations. The spectroscopy reveals that the hydrogen peroxide molecule is reduced at negative potentials to form a Cu-OH surface species in acidic solutions, a result consistent with the insight from Tafel slope measurements. DFT calculations support the instability of peroxide relative to the surface-coordinated hydroxide on both Cu(111) and Cu(100) surfaces. PMID- 17696376 TI - The biologically important surfactin lipopeptide induces nanoripples in supported lipid bilayers. AB - Under specific conditions, lipid membranes form ripple phases with intriguing nanoscale undulations. Here, we show using in situ atomic force microscopy (AFM) that the biologically important surfactin lipopeptide induces nanoripples of 30 nm periodicity in dipalmitoyl phosphatidylcholine (DPPC) bilayers at 25 degrees (i.e. well below the pretransition temperature of DPPC). Whereas most undulations formed the classical straight orientation with characteristic angle changes of 120 degrees , some of them also displayed unusual circular orientations. Strikingly, ripple structures were formed at 15% surfactin but were rarely or never observed at 5 and 30% surfactin, emphasizing the important role played by the surfactin concentration. Theoretical simulations corroborated the AFM data by revealing the formation of stable surfactin/lipid assemblies with positive curvature. PMID- 17696377 TI - Si/SiO2-templated formation of ultraflat metal surfaces on glass, polymer, and solder supports: their use as substrates for self-assembled monolayers. AB - This paper describes the use of several methods of template stripping (TS) to produce ultraflat films of silver, gold, palladium, and platinum on both rigid and polymeric mechanical supports: a composite of glass and ultraviolet (UV) curable adhesive (optical adhesive, OA), solder, a composite of poly(dimethyl siloxane) (PDMS) and OA, and bare OA. Silicon supporting its native oxide layer (Si/SiO2) serves as a template for both mechanical template stripping (mTS), in which the metal film is mechanically cleaved from the template, and chemical template stripping (cTS), in which the film-template composite is immersed in a solution of thiols, and the formation of the SAM on the metal film causes the film to separate from the template. Films formed on all supports have lower root mean-square (rms) roughness (as measured by atomic force microscopy, AFM) than films used as-deposited (AS-DEP) by electron-beam evaporation. Monolayers of n dodecanethiolate formed by the mTS and cTS methods are effectively indistinguishable by scanning tunneling microscopy (STM); molecularly resolved images could be obtained using both types of surfaces. The metal surfaces, before being cleaved, are completely protected from contact with the atmosphere. This protection allows metal surfaces intended to support SAMs to be prepared in large batch lots, stored, and then used as needed. Template stripping thus eliminates the requirement for evaporation of the film immediately before use and is a significant extension and simplification of the technology of SAMs and other areas of materials science requiring clean metal surfaces. PMID- 17696378 TI - Halogen bonding as a new driving force for layer-by-layer assembly. AB - A new approach for fabricating a layer-by-layer polymer film was explored, which was based on the halogen bonding between poly(4-(4-iodo-2,3,5,6 tetrafluorophenoxy)-butyl acrylate) and poly(4-vinylpyridine). Layer-by-layer assembly of two polymers was confirmed by UV-vis spectroscopy and quartz crystal microbalance measurements. The interaction between the two polymers was identified as halogen bonding by X-ray photoelectron spectroscopy. The surface of the multilayer film is flat, and the thickness of one bilayer is about 1.3 nm. We also compared the stability of a halogen-bonded multilayer film in methanol with that of a hydrogen-bonded multilayer film. PMID- 17696379 TI - The glycine max xylem sap and apoplast proteome. AB - Molecular signaling interactions in the plant apoplast are important for defense and developmental responses. We examined the soybean proteome of the apoplastic conduit of root-to-shoot communication, the xylem stream, using gel electrophoresis combined with two types of tandem mass spectrometry. We examined soybeans for the presence of a Bradyrhizobium japonicum-induced, long distance developmental signal that controls autoregulation of nodulation (AON) to determine if xylem proteins (XPs) were involved directly or indirectly in AON. The xylem and apoplast fluids collected in hypocotyl, epicotyl, and stem tissue contained a highly similar set of secreted proteins. The XPs were different from those secreted from imbibing seed implying they play important basic roles in xylem function. The XPs of wild-type and nts1007 plants were indistinguishable irrespective of plant age, inoculation status, or time after inoculation suggesting that none was directly involved in AON. XPs were continuously loaded into the xylem stream, as they were present even 28 h after shoot decapitation. These results were consistent with semiquantitative RT-PCR studies that examined the expression of genes corresponding to the XPs under inoculated or uninoculated conditions. Monitoring the expression of XP genes by RT-PCR showed that four possessed root biased expression. This suggested that the corresponding protein products could be produced in roots and travel long distances to shoots. Of these, a species of lipid transfer protein is a candidate for a water-soluble, long-distance signal-carrier due to the presence of hydrophobic clefts that bind known plant signals in vitro. Two soybean XPs identified in this study, lipid transfer protein and Kunitz trypsin inhibitor (KTI), have known roles in plant signaling. PMID- 17696380 TI - The optimization of protocols for proteome difference gel electrophoresis (DiGE) analysis of preneoplastic skin. AB - Difference gel electrophoresis (DiGE) allows the reliable comparison of proteome differences between two or three samples within a single gel, by way of a CyDye fluorescent labeling system. This facilitates identification of protein differences avoiding the difficulties associated with gel-to-gel variation. A drawback of this approach is the necessity for high-purity protein samples, since contaminants can interfere with the labeling process, affecting subsequent analysis. Thus far, DiGE has been applied to the study of various sample types derived from relatively simple starting materials such as serum, cell lines, or primary cells. Herein, we describe optimization of protein extraction and purification from a complex tissue (the murine ear) of which a major component is skin, which is compatible with the CyDye labeling system and DiGE. Protein samples obtained by this method from preneoplastic, transgenic tissue have been effectively compared to normal tissue samples to reveal bona fide differences, verifiable by Western blotting. In total, 41 protein differences (21 up- and 20 down-regulated in the pathological samples) were identified by mass spectrometry (MS). This method can therefore form a guide for those wishing to perform DiGE on complex tissues, and is especially useful for samples with relatively insoluble components such as skin. PMID- 17696381 TI - Reliable detection of deamidated peptides from lens crystallin proteins using changes in reversed-phase elution times and parent ion masses. AB - Identifying deamidated peptides using low-resolution mass spectrometry is difficult because traditional database search programs cannot accurately detect modified peptides when the mass differences are only 0.984 Da. In this study, we utilized differential reversed-phase elution behavior of deamidated and corresponding unmodified peptide forms to significantly improve deamidation detection on a low-resolution LCQ ion trap instrument. We also improved the mass measurements of unmodified and deamidated peptide forms by averaging survey scans across each chromatogram peak. Tryptic digests of a series of normal (3-day old, 2-year old, 18-year old, 35-year old, and 70-year old) and cataractous (93-year old) human lens samples were used to produce large numbers of potentially deamidated peptides. The complex peptide mixtures were separated by strong cation exchange (SCX) chromatography followed by reversed-phase (RP) chromatography. Synthetic peptides were used to show that unmodified and deamidated peptides coeluted during the SCX separation and were completely resolved with the RP conditions used. Retention time shifts (RTS) and mass differences (DeltaM) of deamidated lens peptides and their corresponding unmodified forms were manually determined for the 70-year old lens sample. These values were used to assign correct or incorrect deamidation identifications from SEQUEST searches where deamidation was specified as a variable modification. Manual validation of SEQUEST identifications from synthetic peptides, 3-day old, and 70-year old samples had an overall 42% deamidation detection accuracy. Filtering SEQUEST identifications using RTS and DeltaM constraints resulted in >93% deamidation detection accuracy. An algorithm was developed to automate this method, and 72 Crystallin deamidation sites, 18 of which were not previously reported in human lens tissue, were detected. PMID- 17696382 TI - Amphibian skin secretomics: application of parallel quadrupole time-of-flight mass spectrometry and peptide precursor cDNA cloning to rapidly characterize the skin secretory peptidome of Phyllomedusa hypochondrialis azurea: discovery of a novel peptide family, the hyposins. AB - This study reports the variety of peptides present in the skin secretory peptidome of Phyllomedusa hypochondrialis azurea. Peptide structures, along with post-translational modifications, were elucidated by QTOF MS/MS analysis, cDNA sequencing, or a combination of both. Twenty-two peptides, including 19 novel structures, were identified from six different structural classes, including tryptophyllins, dermorphins, and a novel group of peptides termed hyposins. The study demonstrates the power of this combined approach to mine the rich peptidome compliment of the amphibian defensive skin secretome. PMID- 17696383 TI - Microscale solution isoelectric focusing as an effective strategy enabling containment of hemeoglobin-derived products for high-resolution gel-based analysis of the Plasmodium falciparum proteome. AB - The high hemeozoin (beta-hemeatin) content of Plasmodium falciparum lysates imposes severe limitations on the analysis of the malarial proteome, in particular compromising the loading capacities of two-dimensional gels. Here we report on the adaptation of a recently developed solution-phase isoelectric focusing-based fractionation technique as a prefractionation strategy for efficient containment of hemeoglobin-derived products and complexity reduction, to facilitate the high-resolution gel-based quantitative analysis of plasmodial lysates. PMID- 17696384 TI - Bistability in doped organic thin film transistors. AB - Organic thin film transitors (TFTs) with the conducting polymer poly(3,4 ethylenedioxythiophene):poly(styrene sulfonic acid), PEDOT:PSS, as the active layer and cross-linked, layer-by-layer assembled poly(allylamine hydrochloride)/poly(acrylic acid) (PAH/PAA) multilayers as the gate dielectric layer were investigated. A combination of spectroscopic data and device performance characteristics was used to study the behavior of these TFT devices under a variety of controlled environmental test conditions. It was shown that depletion and recovery of the device can be induced to occur by a means that is consistent with the electrochemical oxidation and reduction of water contained in the film. In addition to acting as a reactant, moisture also acts as a plasticizer to control the mobility of other species contained in the film and thereby permits bistable operation of these devices. Raman spectroscopy was used to show that the observed device switching behavior is due to a change in the PEDOT doping level. PMID- 17696385 TI - 6MAP, a fluorescent adenine analogue, is a probe of base flipping by DNA photolyase. AB - Cyclobutylpyrimidine dimers (CPDs) are formed between adjacent pyrimidines in DNA when it absorbs ultraviolet light. CPDs can be directly repaired by DNA photolyase (PL) in the presence of visible light. How PL recognizes and binds its substrate is still not well understood. Fluorescent nucleic acid base analogues are powerful probes of DNA structure. We have used the fluorescent adenine analogue 6MAP, a pteridone, to probe the local double helical structure of the CPD substrate when bound by photolyase. Duplex melting temperatures were obtained by both UV-vis absorption and fluorescence spectroscopies to ascertain the effect of the probe and the CPD on DNA stability. Steady-state fluorescence measurements of 6MAP-containing single-stranded and doubled-stranded oligos with and without protein show that the local region around the CPD is significantly disrupted. 6MAP shows a different quenching pattern compared to 2-aminopurine, another important adenine analogue, although both probes show that the structure of the complementary strand opposing the 5'-side of the CPD lesion is more destacked than that opposing the 3'-side in substrate/protein complexes. We also show that 6MAP/CPD duplexes are substrates for PL. Vertical excitation energies and transition dipole moment directions for 6MAP were calculated using time-dependent density functional theory. Using these results, the Forster resonance energy transfer efficiency between the individual adenine analogues and the oxidized flavin cofactor was calculated to account for the observed intensity pattern. These calculations suggest that energy transfer is highly efficient for the 6MAP probe and less so for the 2Ap probe. However, no experimental evidence for this process was observed in the steady-state emission spectra. PMID- 17696386 TI - Refinement of a structural model of a pigment-protein complex by accurate optical line shape theory and experiments. AB - Time-local and time-nonlocal theories are used in combination with optical spectroscopy to characterize the water-soluble chlorophyll binding protein complex (WSCP) from cauliflower. The recombinant cauliflower WSCP complexes reconstituted with either chlorophyll b (Chl b) or Chl a/Chl b mixtures are characterized by absorption spectroscopy at 77 and 298 K and circular dichroism at 298 K. On the basis of the analysis of these spectra and spectra reported for recombinant WSCP reconstituted with Chl a only (Hughes, J. L.; Razeghifard, R.; Logue, M.; Oakley, A.; Wydrzynski, T.; Krausz, E. J. Am. Chem. Soc. U.S.A. 2006, 128, 3649), the "open-sandwich" model proposed for the structure of the pigment dimer is refined. Our calculations show that, for a reasonable description of the data, a reduction of the angle between pigment planes from 60 degrees of the original model to about 30 degrees is required when exciton relaxation-induced lifetime broadening is included in the analysis of optical spectra. The temperature dependence of the absorption spectrum is found to provide a unique test for the two non-Markovian theories of optical spectra. Based on our data and the 1.7 K spectra of Hughes et al. (2006), the time-local partial ordering prescription theory is shown to describe the experimental results over the whole temperature range between 1.7 K and room temperature, whereas the alternative time-nonlocal chronological ordering prescription theory fails at high temperatures. Modified-Redfield theory predicts sub-100 fs exciton relaxation times for the homodimers and a 450 fs time constant in the heterodimers. Whereas the simpler Redfield theory gives a similar time constant for the homodimers, the one for the heterodimers deviates strongly in the two theories. The difference is explained by multivibrational quanta transitions in the protein which are neglected in Redfield theory. PMID- 17696387 TI - Probing the environment of cu(b) in heme-copper oxidases. AB - Time-resolved step-scan FTIR (TRS2-FTIR) and density functional theory have been applied to probe the structural dynamics of CuB in heme-copper oxidases at room temperature. The TRS2-FTIR data of cbb3 from Pseudomonas stutzeri indicate a small variation in the frequency of the transient CO bound to CuB in the pH/pD 7 9 range. This observation in conjunction with density functional theory calculations, in which significant frequency shifts of the nu(CO) are observed upon deprotonation and/or detachment of the CuB ligands, demonstrates that the properties of the CuB ligands including the cross-linked tyrosine, in contrast to previous reports, remain unchanged in the pH 7-9 range. We attribute the small variations in the nu(CO) of CuB to protein conformational changes in the vicinity of CuB. Consequently, the split of the heme Fe-CO vibrations (alpha-, beta-, and gamma-forms) is not due to changes in the ligation and/or protonation states of the CuB ligands or to the presence of one or more ionizable groups, as previously suggested, but the result of global protein conformational changes in the vicinity of CuB which, in turn, affect the position of CuB with respect to the heme Fe. PMID- 17696388 TI - Assembly of lipids and proteins into lipoprotein particles. AB - The self-assembly of reconstituted discoidal high-density lipoproteins, known as nanodiscs, was studied using coarse-grained molecular dynamics and small-angle X ray scattering. In humans, high-density lipoprotein particles transport cholesterol in the blood and facilitate the removal of excess cholesterol from the body. Native high-density lipoprotein exhibits a wide variety of shapes and sizes, forming lipid-free/poor, nascent discoidal, and mature spherical particles. Little is known about how these lipoprotein particles assemble and transform from one state to another. Multiple 10 micros coarse-grained simulations reveal the assembly of discoidal high-density lipoprotein particles from disordered protein-lipid complexes. Small-angle X-ray scattering patterns were calculated from the final assembled structures and compared with experimental measurements carried out for this study to verify the accuracy of the coarse-grained simulations. Results show that hydrophobic interactions assemble, within several microseconds, the amphipathic helical proteins and lipids into roughly discoidal particles, while the proteins assume a final approximate double-belt configuration on a slower time scale. PMID- 17696389 TI - Small angle scattering and zeta potential of liposomes loaded with octa(carboranyl)porphyrazine. AB - In this work, the physicochemical characterization of liposomes loaded with a newly synthesized carboranyl porphyrazine (H2HECASPz) is described. This molecule represents a potential drug for different anticancer therapies, such as boron neutron capture therapy and for photodynamic therapy or photothermal therapy. Different loading methods and different lipid mixtures were tested. The corresponding loaded vectors were studied by small angle scattering, light scattering, and zeta potential. The combined analysis of structural data at various lengths of scales and the measurement of the surface charge allowed us to obtain a detailed characterization of the investigated systems. The mechanisms underlying the onset of differences in relevant physicochemical parameters (size, polydispersity, and charge) were also critically discussed. PMID- 17696390 TI - Control of the interchain pi-pi interaction and electron density distribution at the surface of conjugated poly(3-hexylthiophene) thin films. AB - Interchain interaction, i.e., pi-pi stacking, can benefit the carrier transport in conjugated regio-regular poly(3-hexylthiophene) (P3HT) thin films. However, the existence of the insulating side hexyl chains in the surface region may be detrimental to the charge transfer between the polymer backbone and overlayer molecules. The control of the molecular orientation in the surface region is expected to alter the distribution of the pi electron density at the surface to solve such problems, which can be achieved by controlling the solvent removal rate during solidification. The evidence that the pi-electron density distribution at the outermost surface can be controlled is demonstrated by the investigation using the powerful combination of near edge X-ray absorption fine structure spectroscopy, ultraviolet photoelectron spectroscopy, and the most surface-sensitive technique: Penning ionization electron spectroscopy. From the spectroscopic studies, it can be deduced that the slower removal rate of the solvent makes the polymer chains even at the surface have sufficient time to adopt a more nearly equilibrium structure with edge-on conformation. Thus, the side hexyl chains extend outside the surface, which buries the pi-electron density contributed from the polymer backbone. Contrarily, the quench of obtaining a thermo-equilibrium structure in the surface region due to the faster removal of the solvent residual can lead to the surface chain conformation without persisting to the strong bulk orientation preference. Therefore, the face on conformation of the polymer chain at the surface of thin films coated with high spin coating speed facilitate the electron density of the polymer backbone exposed outside the surface. Finally, thickness dependence of the surface electronic structure of P3HT thin films is also discussed. PMID- 17696391 TI - Synthesis and photophysical properties of nonbenzoid ended fluorophores. AB - A series of pi-conjugated compounds (1-23) were successfully synthesized by the Sonogashira, Suzuki, and Wittig-Horner reactions. The structure-property relationship about photoluminescence based on these synthesized compounds was systematically discussed in detail. In addition, energy gaps between ground and excited states of these compounds, which were in good agreement with the experimental observation, were calculated by the semiempirical parametrized PM3 method. It was revealed that emission efficiency largely depends on molecular structure, aggregation type, and size of nanoaggregates. PMID- 17696392 TI - Simultaneous presence of diverse molecular patterns in humic substances in solution. AB - The chemical and structural nature of humic substances (HS) is the object of an intense debate in the literature involving two main theoretical positions: the classical view defending the macromolecular pattern, and the new, more recent, view proposing a supramolecular pattern. In this study, we observe that both molecular patterns are present in different whole humic systems in solution. We also identify these molecular patterns with a specific fraction of HS. Thus, the HS family formed by the gray humic acids studied presented a clear macromolecular pattern, whereas the HS family formed by the fulvic acids studied presented the coexistence of supramolecular assemblies and individual molecules. The third HS family studied, the brown humic acids, presented both the macromolecular pattern and the supramolecular pattern. We also find that molecular aggregation disaggregation has a strong influence in the fluorescence pattern of HS, thus indicating that the current concepts of HS structure derived from fluorescence studies need revision. PMID- 17696393 TI - Direct observation of aminyl radical intermediate during single-crystal to single crystal photoinduced Orton rearrangement. AB - A photoinduced analogue of the thermal Orton rearrangement reaction by which an N chlorine atom from a side amino group is transferred to a phenyl ring was studied in the solid state. Contrary to the mixture of products obtained in solution, in the N-chloro-N-acetylaminobenzene crystals the photoreaction proceeds with complete preservation of crystallinity, affording selectively and quantitatively the para isomer of chloroacetanilide. Study of the reaction mechanism by in situ steady-state photodiffraction, a combination of photoexcitation by UV light and single-crystal X-ray diffraction analysis, provided evidence for creation of N acetyl-N-phenylaminyl (AcPhN*) radical as a metastable reaction intermediate. The structure of the aminyl radical produced in 9.2% yield from the major disordered component in the statically 85.6:14.4 disordered crystal was directly observed for the first time. The unprecedented stability of the radical is prescribed to the solid-state cage effect, the reactive center of the radical species being locked away from the reactive target molecules. The creation of the radical and its head-to-tail chain reaction within the undulated hydrogen-bonded ribbons involving the acetyl carbonyl group are employed to explain the high selectivity of the photoinduced single-crystal to single-crystal Orton rearrangement. On the basis of the change of the crystal structure and the physicochemical data, a three-center five-atom mechanism involving homolytic cleavage of the N-Cl bond followed by hydrogen abstraction by the carbonyl group is suggested for the solid state photoinduced Orton rearrangement. PMID- 17696394 TI - Self-assembly of recombinant amphiphilic oligopeptides into vesicles. AB - The aim of the present study was to design amphiphilic oligopeptides that can self-assemble into vesicular structures. The ratio of hydrophilic to hydrophobic block length was varied, and peptides were designed to have a hydrophobic tail in which the bulkiness of the amino acid side groups increases toward the hydrophilic domain (Ac-Ala-Ala-Val-Val-Leu-Leu-Leu-Trp-Glu(2/7)-COOH). These peptides were recombinantly produced in bacteria as an alternative to solid-phase synthesis. We demonstrate with different complementary techniques (dynamic and static light scattering, tryptophan fluorescence anisotropy, and electron microscopy) that these amphiphilic peptides spontaneously form vesicles with a radius of approximately 60 nm and a low polydispersity when dispersed in aqueous solution at neutral pH. Morphology and size of the vesicles were relatively insensitive to the variations in hydrophilic block length. Exposure to acidic pH resulted in formation of visible aggregates, which could be fully reversed to vesicles upon pH neutralization. In addition, it was demonstrated that water soluble molecules can be entrapped inside these peptide vesicles. Such peptide vesicles may find applications as biodegradable drug delivery systems with a pH dependent release profile. PMID- 17696395 TI - A model for the structure of the C-terminal domain of dragline spider silk and the role of its conserved cysteine. AB - Dragline spider silk fibers have extraordinary attributes as biomaterials of superior strength and toughness. Previously we have shown that the conserved C terminal domain of a dragline spider silk protein is necessary for directing oriented microfiber formation. Here we present for the first time a state-of-the art model of the three-dimensional structure of this domain, and, by comparing several dragline proteins, identify its key evolutionarily conserved features. Further, using the baculovirus expression system, we produced recombinant proteins that are mutated in the unique cysteine residue present in the domain. While a conservative mutation to serine allows fiber formation, thus demonstrating that there is no need for disulfide bond formation in this system, a mutation to arginine significantly alters the local surface properties, preventing fiber formation. These experimental results are in agreement with our model, wherein the cysteine is localized in a highly conserved hydrophobic loop that we predict to be important for the protein-protein interactions of this domain and hence also for fiber formation. PMID- 17696396 TI - A nanoparticle-based solution DNA sandwich assay using ICP-AES for readout. AB - We report herein a nanoparticle-based methodology for detecting DNA in solution using inductively coupled plasma atomic emission spectrometry (ICP-AES) as a readout tool. This represents the first homogeneous solution assay of biologically significant targets by employing ICP-related techniques. Two types of particles are employed: silica nanoparticles or gold nanoparticles functionalized with oligonucleotides that are capable of hybridizing with half of the target DNA sequence as signal readout components, and magnetic microparticles functionalized with oligonucleotides that are capable of hybridizing with the other half of the sequence as capture components. In the presence of target DNA, three components form typical sandwich structures, and the application of a magnetic field could effectively separate them from the rest of the solution. Subsequent application of ICP-AES effectively provides an inorganic elemental readout for the diagnosis of target DNA. PMID- 17696397 TI - Excellent thermal conductivity of transparent cellulose nanofiber/epoxy resin nanocomposites. PMID- 17696398 TI - Synthesis of hyaluronan haloacetates and biology of novel cross-linker-free synthetic extracellular matrix hydrogels. AB - Hyaluronan (HA) derivatives containing thiol-reactive electrophilic esters were prepared to react with thiol-modified macromolecules to give cross-linker-free hydrogels. Specifically, HA was converted to two haloacetate derivatives, HA bromoacetate (HABA) and HA iodoacetate (HAIA). In cytotoxicity assays, these reactive macromolecules predictably induced cell death in a dose-dependent manner. Cross-linker-free synthetic extracellular matrix (sECM) hydrogels were prepared by thiol alkylation using HAIA and HABA as polyvalent electrophiles and thiol-modified HA (CMHA-S) with or without thiol-modified gelatin (Gtn-DTPH) as polyvalent nucleophiles. When primary human fibroblasts were seeded on the surface of the sECMs containing only the electrophilic HA haloacetate and nucleophilic CMHA-S components, no significant cytoadherence was observed. Cell attachment and viability was 17% (HABA) to 30% (HAIA) lower on HA haloacetate cross-linked hydrogels than on CMHA-S that had been oxidatively cross-linked via disulfide-bonds. In contrast, sECMs that included Gtn-DTPH allowed fibroblasts to attach, spread, and proliferate. Taken together, the HA haloacetates are attractive candidates for producing cross-linker-free sECM biomaterials that can function either as anti-adhesive barriers or as cytoadhesive sECMs for cell culture in pseudo-3-D. PMID- 17696399 TI - Interaction between casein and the oppositely charged surfactant. AB - The interactions between the classical cationic surfactant dodecyltrimethylammonium bromide (DTAB) and 2.0 mg/mL casein were investigated using isothermal titration calorimetry (ITC), turbidity, dynamic light scattering (DLS), and fluorescence spectra measurements. The results suggest that the cationic headgroup of the surfactant individually binds to the negatively charged amino acid sites on the casein chains because of the electrostatic attraction upon the addition of DTAB. When the surfactant concentration reaches a critical value c1, DTAB forms micelle-like aggregates on the casein chain, resulting in the formation of insoluble casein/DTAB complexes. Further addition of DTAB leads to the redissolution of casein/DTAB complexes because of the net positive charge on casein/DTAB complexes and the formation of DTAB free micelles. The addition of salt screens the repulsion between the surfactant headgroups and the attraction between casein and surfactant molecules, which weakens the binding of surfactant onto the casein chain, favoring the formation of free surfactant micelles. PMID- 17696400 TI - One-step electrospinning of cross-linked chitosan fibers. AB - Chitin is a nitrogen-rich polysaccharide that is abundant in crustaceans, mollusks, insects, and fungi and is the second most abundant organic material found in nature next to cellulose. Chitosan, the N-deacetylated derivative of chitin, is environmentally friendly, nontoxic, biodegradable, and antibacterial. Fibrous mats are typically used in industries for filter media, catalysis, and sensors. Decreasing fiber diameters within these mats causes many beneficial effects such as increased specific surface area to volume ratios. When the intrinsically beneficial effects of chitosan are combined with the enhanced properties of nanofibrous mats, applications arise in a wide range of fields, including medical, packaging, agricultural, and automotive. This is particularly important as innovative technologies that focus around bio-based materials are currently of high urgency, as they can decrease dependencies on fossil fuels. We have demonstrated that Schiff base cross-linked chitosan fibrous mats can be produced utilizing a one-step electrospinning process that is 25 times faster and, therefore, more economical than a previously reported two-step vapor-cross linking method. These fibrous mats are insoluble in acidic, basic, and aqueous solutions for 72 h. Additionally, this improved production method results in a decreased average fiber diameter, which measures 128 +/- 40 nm. Chemical and structural analyses were conducted utilizing Fourier transform infrared spectroscopy, solubility studies, and scanning electron microscopy. PMID- 17696401 TI - Total synthesis of pumiliotoxins 209F and 251D via late-stage, nickel-catalyzed epoxide-alkyne reductive cyclization. AB - Pumiliotoxins 209F and 251D were synthesized using highly selective nickel catalyzed epoxide-alkyne reductive cyclizations as the final step. The exocyclic (Z)-alkene found in the majority of the pumiliotoxins was formed stereospecifically and regioselectively, without the use of a directing group on the alkyne, and the epoxide underwent ring opening exclusively at the less hindered carbon to provide the requisite tertiary alcohol. The epoxides were prepared using diastereoselective addition of a sulfoxonium anion to a proline derived methyl ketone. PMID- 17696402 TI - An efficient and scalable one-pot double Michael addition-Dieckmann condensation for the synthesis of 4,4-disubstituted cyclohexane beta-keto esters. AB - A simple, scalable, and efficient one-pot methodology for the synthesis of 4,4 disubstituted cyclohexane beta-keto esters from benzylic nitriles or esters and methyl acrylate promoted by potassium tert-butoxide is described. The process relies on a tandem double Michael addition-Dieckmann condensation reaction, which results in the formation of three discrete carbon-carbon bonds in a single pot, including a quaternary center. The method allows for the convenient and rapid synthesis of a variety of 4-aryl-4-cyano-2-carbomethoxycyclohexanone and 4-aryl 2,4-biscarbomethoxycyclohexanone building blocks for use in natural products synthesis and medicinal chemistry. PMID- 17696403 TI - Moving nanoparticles with Raman scattering. AB - We show how to change optically the distance between two protein-linked gold nanoparticles by Raman-induced motion of the linker protein. Rayleigh scattering spectroscopy of the coupled-particle plasmon allows us to compare the inter nanoparticle distance of individual protein-linked gold nanoparticle dimers before and after surface-enhanced Raman scattering (SERS). We find that low intensity (50 microW/microm2) laser light in resonance with the nanoparticle dimer plasmon provokes a change of the inter-nanoparticle distance on the order of 0.5 nm whenever SERS from the proteins connecting the nanoparticles can be observed. PMID- 17696404 TI - Electrochemical detection of DNA hybridization via bis-intercalation of a naphthylimide-functionalized viologen dimer. AB - The synthesis and DNA binding properties of a bis-naphthyl imide tetracationic diviologen compound NI(CH2)3V(2+)(CH2)6V(2+)(CH2)3NI (where V(2+) = 4,4' bipyridinium and NI = naphthyl imide, NIV) are described. Binding to thiolated ssDNA and dsDNA immobilized at Au electrodes was characterized using the electrochemical response for reduction of the V(2+) state to the V+ (viologen radical cation) state. Isotherms and binding constants for this molecule to both forms of immobilized DNA were generated in this fashion. The character of the binding isotherm for dsDNA suggests bis-intercalation. Under high saline conditions, the diviologen molecule dissociated 160 times slower from dsDNA compared to ssDNA. Slow dissociation kinetics from dsDNA (kd =7.0 x 10-5 s(-1)) allow this molecule to be used as an effective DNA hybridization indicator. PMID- 17696405 TI - Electrochemical imaging of localized sandwich DNA hybridization using scanning electrochemical microscopy. AB - Imaging of localized hybridization of nucleic acids immobilized on gold-DNA chip was performed by means of the feedback mode of scanning electrochemical microscopy (SECM). Thiol-tethered oligodeoxynucleotide (HS-ODN) probes, spotted on a gold surface, were hybridized with unmodified target sequence via sandwich hybridization with a biotinylated signaling probe. Spots where sequence-specific hybridization had occurred were developed by adding a streptavidin-alkaline phosphatase conjugate and biocatalyzed precipitation of an insoluble and insulating product. As a consequence, the surface conductivity of the spotted region of the chip where hybridization had taken place changed. These changes in conductivity were sensitively detected by the SECM tip. The proposed method allows imaging of a DNA array in a straightforward way. Analysis of real samples was also performed coupling this method with polymerase chain reaction. The imaging of 60 nM PCR amplicon (255 bp) was demonstrated. PMID- 17696406 TI - Screening the sequence selectivity of DNA-binding molecules using a gold nanoparticle-based colorimetric approach. AB - We have developed a novel competition assay that uses a gold nanoparticle (Au NP) based, high-throughput colorimetric approach to screen the sequence selectivity of DNA-binding molecules. This assay hinges on the observation that the melting behavior of DNA-functionalized Au NP aggregates is sensitive to the concentration of the DNA-binding molecule in solution. When short, oligomeric hairpin DNA sequences were added to a reaction solution consisting of DNA-functionalized Au NP aggregates and DNA-binding molecules, these molecules may either bind to the Au NP aggregate interconnects or the hairpin stems based on their relative affinity for each. This relative affinity can be measured as a change in the melting temperature (Tm) of the DNA-modified Au NP aggregates in solution. As a proof of concept, we evaluated the selectivity of 4',6-diamidino-2-phenylindone (an AT-specific binder), ethidium bromide (a nonspecific binder), and chromomycin A (a GC-specific binder) for six sequences of hairpin DNA having different numbers of AT pairs in a five-base pair variable stem region. Our assay accurately and easily confirmed the known trends in selectivity for the DNA binders in question without the use of complicated instrumentation. This novel assay will be useful in assessing large libraries of potential drug candidates that work by binding DNA to form a drug/DNA complex. PMID- 17696407 TI - The K15 protein of Kaposi's sarcoma-associated herpesvirus recruits the endocytic regulator intersectin 2 through a selective SH3 domain interaction. AB - Kaposi's sarcoma-associated herpesvirus, also known as human herpesvirus 8, is closely associated with several cancers including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. The rightmost end of the KSHV genome encodes a protein, K15, with multiple membrane-spanning segments and an intracellular carboxy-terminal tail that contains several conserved motifs with the potential to recruit interaction domains (i.e., SH2, SH3, TRAF) of host cell proteins. K15 has been implicated in downregulating B cell receptor (BCR) signaling through its conserved motifs and may thereby play a role in maintaining viral latency and/or preventing apoptosis of the infected B cells. However, K15's mode of action is largely unknown. We have used mass spectrometry, domain and peptide arrays, and surface plasmon resonance to identify binding partners for a conserved proline-rich sequence (PPLP) in the K15 cytoplasmic tail. We show that the PPLP motif selectively binds the SH3-C domain of an endocytic adaptor protein, Intersectin 2 (ITSN2). This interaction can be observed both in vitro and in cells, where K15 and ITSN2 colocalize to discrete compartments within the B cell. The ability of K15 to associate with ITSN2 suggests a new role for the K15 viral protein in intracellular protein trafficking. PMID- 17696408 TI - Redox-dependent sodium binding by the Na(+)-translocating NADH:quinone oxidoreductase from Vibrio harveyi. AB - Relaxation characteristics of the 23Na nuclei magnetization were used to determine the sodium-binding properties of the Na+-translocating NADH:quinone oxidoreductase from Vibrio harveyi (NQR). The dissociation constant of Na+ for the oxidized enzyme was found to be 24 mM and for the reduced enzyme about 30 microM. Such large (3 orders in magnitude) redox dependence of the NQR affinity to sodium ions shows that the molecular machinery was designed to use the drop in redox energy for creating an electrochemical sodium gradient. Redox titration of NQR monitored by changes in line width of the 23Na NMR signal at 2 mM Na+ showed that the enzyme affinity to sodium ions follows the Nernst law for a one-electron carrier with Em about -300 mV (vs SHE). The data indicate that energy conservation by NQR involves a mechanism modulating ion affinity by the redox state of an enzyme redox cofactor. PMID- 17696409 TI - Identification and thermodynamic characterization of molten globule states of periplasmic binding proteins. AB - Molten globule-like intermediates have been shown to occur during protein folding and are thought to be involved in protein translocation and membrane insertion. However, the determinants of molten globule stability and the extent of specific packing in molten globules is currently unclear. Using far- and near-UV CD and intrinsic and ANS fluorescence, we show that four periplasmic binding proteins (LBP, LIVBP, MBP, and RBP) form molten globules at acidic pH values ranging from 3.0 to 3.4. Only two of these (LBP and LIVBP) have similar sequences, but all four proteins adopt similar three-dimensional structures. We found that each of the four molten globules binds to its corresponding ligand without conversion to the native state. Ligand binding affinity measured by isothermal titration calorimetry for the molten globule state of LIVBP was found to be comparable to that of the corresponding native state, whereas for LBP, MBP, and RBP, the molten globules bound ligand with approximately 5-30-fold lower affinity than the corresponding native states. All four molten globule states exhibited cooperative thermal unfolding assayed by DSC. Estimated values of DeltaCp of unfolding show that these molten globule states contain 28-67% of buried surface area relative to the native states. The data suggest that molten globules of these periplasmic binding proteins retain a considerable degree of long range order. The ability of these sequentially unrelated proteins to form highly ordered molten globules may be related to their large size as well as an intrinsic property of periplasmic binding protein folds. PMID- 17696410 TI - Ab initio thermochemistry of the hydrogenation of hydrocarbon radicals using silicon-, germanium-, tin-, and lead-substituted methane and isobutane. AB - A series of reactions of the type Y. + XH(4) --> YH + .XH(3) and Y'. + HX(CH(3))(3) --> Y'H + .X(CH(3))(3), where Y = H, CH(3); Y' = CH(3), C(CH(3))(3); and X = Si, Ge, Sn, Pb are studied using state-of-the-art ab initio electronic structure methods. Second-order Moller-Plesset perturbation theory; the coupled cluster singles, doubles, and perturbative triples method; and density functional theory are used with correlation-consistent basis sets (cc-pVNZ, where N = D, T, Q) and their pseudopotential analogs (cc-pVNZ-PP) to determine the transition state geometries, activation barriers, and thermodynamic properties of these reactions. Trends in the barrier heights as a function of the group IVA atom (Si, Ge, Sn, and Pb) are examined. With respect to kinetics and thermodynamics, the use of a hydrogen attached to a group IVA element as a possible hydrogen donation tool in the mechanosynthesis of diamondoids appears feasible. PMID- 17696411 TI - Quantum trajectories from a discrete-variable representation method. AB - A method for obtaining quantum trajectories from a discrete-variable representation computation of the quantum potential is presented. The method exploits the linearity of the Schrodinger equation, deals smoothly with the quantum potential singularities, and readily performs the time propagation up to fairly large total elapsed times. A one-dimensional test of the general n dimensional formulation is included. PMID- 17696412 TI - Nonisothermal decomposition kinetics and computational studies on the properties of 2,4,6,8-tetranitro-2,4,6,8-tetraazabicyclo[3,3,1]onan-3,7-dione (TNPDU). AB - The thermal decomposition and the nonisothermal kinetics of the thermal decomposition reaction of 2,4,6,8-tetranitro-2,4,6,8-tetraazabicyclo[3,3,1]onan 3,7-dione (TNPDU) were studied under the nonisothermal condition by differential scanning calorimetry (DSC) and thermogravimetry-derivative thermogravimetry (TG DTG) methods. The kinetic model function in differential form and the value of Ea and A of the decomposition reaction of TNPDU are f(alpha) = 3(1 - alpha)[-ln(1 - alpha)](2/3), 141.72 kJ mol(-1), and 10(11.99) s(-1), respectively. The critical temperature of thermal explosion of the title compound is 232.58 degrees C. The values of DeltaS(++), DeltaH(++), and DeltaG(++) of this reaction are -15.50 J mol(-1) K(-1), 147.65 kJ mol(-1), and 155.26 kJ mol(-1), respectively. The theoretical investigation on the title compound as a structure unit was carried out by the DFT-B3LYP/6-311++G** method. The IR frequencies and NMR chemical shift were performed and compared with the experimental results. The heat of formation (HOF) for TNPDU was evaluated by designing isodesmic reactions. The detonation velocity (D) and detonation pressure (P) were estimated by using the well-known Kamlet-Jacobs equation, based on the theoretical densities and HOF. The calculation on bond dissociation energy suggests that the N-N bond should be the trigger bond during the pyrolysis initiation process. PMID- 17696413 TI - Vibrational structure of vinyl chloride cation studied by using one-photon zero kinetic energy photoelectron spectroscopy. AB - The vibrational structure of vinyl chloride cation, CH(2)CHCl+ (X(2)A' '), has been studied by vacuum ultraviolet (VUV) zero-kinetic energy (ZEKE) photoelectron spectroscopy. Among nine symmetric vibrational modes, the fundamental frequencies of six modes have been determined. The first overtone of the out-of-plane CH(2) twist vibrational mode has been also measured. In addition to these, the combination and overtone bands of the above vibrational modes about 4500 cm(-1) above the ground state have been observed in the ZEKE spectrum. The vibrational band intensities of the ZEKE spectrum can be described approximately by the Franck-Condon factors with harmonic approximation. The ZEKE spectrum has been assigned based on the harmonic frequencies and Franck-Condon factors from theoretical calculations. The ionization energy (IE) of CH(2)CHCl is determined as 80705.5 +/- 2.5 (cm(-1)) or 10.0062 +/- 0.0003 (eV). PMID- 17696414 TI - Secondary kinetics of methanol decomposition: theoretical rate coefficients for 3CH2 + OH, 3CH2 + 3CH2, and 3CH2 + CH3. AB - Direct variable reaction coordinate transition state theory (VRC-TST) rate coefficients are reported for the (3)CH(2) + OH, (3)CH(2) + (3)CH(2), and (3)CH(2) + CH(3) barrierless association reactions. The predicted rate coefficient for the (3)CH(2) + OH reaction (approximately 1.2 x 10(-10) cm(3) molecule(-1) s(-1) for 300-2500 K) is 4-5 times larger than previous estimates, indicating that this reaction may be an important sink for OH in many combustion systems. The predicted rate coefficients for the (3)CH(2) + CH(3) and (3)CH(2) + (3)CH(2) reactions are found to be in good agreement with the range of available experimental measurements. Product branching in the self-reaction of methylene is discussed, and the C(2)H(2) + 2H and C(2)H(2) + H2 products are predicted in a ratio of 4:1. The effect of the present set of rate coefficients on modeling the secondary kinetics of methanol decomposition is briefly considered. Finally, the present set of rate coefficients, along with previous VRC-TST determinations of the rate coefficients for the self-reactions of CH(3) and OH and for the CH(3) + OH reaction, are used to test the geometric mean rule for the CH(3), (3)CH(2), and OH fragments. The geometric mean rule is found to predict the cross combination rate coefficients for the (3)CH(2) + OH and (3)CH(2) + CH(3) reactions to better than 20%, with a larger (up to 50%) error for the CH(3) + OH reaction. PMID- 17696415 TI - Polarization selectivity of third-order and fifth-order Raman spectroscopies in liquids and solids. AB - Polarization selectivity of third-order and fifth-order Raman spectroscopies is examined for both isotropic liquids and periodic lattices. Our approach directly applies the symmetry property of the probed system to decompose the polarization tensor elements into independent components. The polarization selectivity predicted by symmetry analysis is rigorous and applicable to higher-order Raman spectroscopy. The different polarization selectivities of isotropic systems and periodic lattices can be used as a signature of the liquid-solid phase transition. PMID- 17696416 TI - Design, synthesis, and evaluation of orally active benzimidazoles and benzoxazoles as vascular endothelial growth factor-2 receptor tyrosine kinase inhibitors. AB - Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. Guided by X-ray crystallography and molecular modeling, a series of 2-aminobenzimidazoles and 2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVEC cellular proliferation assays. In this report we describe the synthesis and structure-activity relationship of a series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22 as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22 demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observed at 100 mg/kg) and the rat corneal angiogenesis model (ED(50) = 16.3 mg/kg). PMID- 17696417 TI - Synthesis and biological evaluation of the mitochondrial complex 1 inhibitor 2-[4 (4-fluorobutyl)benzylsulfanyl]-3-methylchromene-4-one as a potential cardiac positron emission tomography tracer. AB - A series of fluorinated chromone analogs with IC50 values ranging from 9 to 133 nM for the mitochondrial complex 1 (MC-I) has been prepared. A structure-activity relationship (SAR) study of the most potent fluorinated chromone analog 10 demonstrated the linkage heteroatom preference of the side chain region of the molecule while maintaining potent MC-I inhibitory activity. Tissue distribution studies 30 min after [(18)F]10 administration to Sprague-Dawley (SD) rats demonstrated high uptake of the radiotracer from the blood pool into the myocardium (2.24% ID/g), kidney (1.93% ID/g), and liver (2.00% ID/g). After 2 h about 66% of the activity in the myocardium at 30 min had been retained, whereas approximately 70% had been cleared from the liver and kidney. MicroPET images of SD rats after [(18)F]10 administration allowed easy assessment of the myocardium through 60 min with minimal lung or liver interference. PMID- 17696418 TI - Nitrated indenoisoquinolines as topoisomerase I inhibitors: a systematic study and optimization. AB - The biological activity of indenoisoquinoline topoisomerase I (Top1) inhibitors can be greatly enhanced depending on the choice of substituents on the aromatic rings and lactam side chain. Previously, it was discovered that a 3-nitro group and a 9-methoxy group afforded enhanced biological activity. In the present investigation, indenoisoquinoline analogues were systematically prepared using combinations of nitro groups, methoxy groups, and hydrogen atoms in an effort to understand the contribution of each group toward cytotoxicity and Top1 inhibition. Analysis of the biological results suggests that the nitro group is important for Top1 inhibition and the methoxy group improves cytotoxicity. In addition, previously identified structure-activity relationships were utilized to select favorable lactam side chain functionalities for incorporation on the aromatic skeleton of analogues in this study. As a result, this investigation has provided optimal Top1 inhibitors equipotent to camptothecin that demonstrate low nanomolar cytotoxicities toward cancer cells. PMID- 17696419 TI - 3,17-disubstituted 2-alkylestra-1,3,5(10)-trien-3-ol derivatives: synthesis, in vitro and in vivo anticancer activity. AB - Estradiol-3,17-O,O-bis-sulfamates inhibit steroid sulfatase (STS), carbonic anhydrase (CA), and, when substituted at C-2, cancer cell proliferation and angiogenesis. C-2 Substitution and 17-sulfamate replacement of the estradiol-3,17 O,O-bis-sulfamates were explored with efficient and practical syntheses developed. Evaluation against human cancer cell lines revealed the 2-methyl derivative 27 (DU145 GI(50) = 0.38 microM) as the most active novel bis sulfamate, while 2-ethyl-17-carbamate derivative 52 (GI(50) = 0.22 microM) proved most active of its series (cf. 2-ethylestradiol-3,17-O,O-bis-sulfamate 4 GI(50) = 0.21 microM). Larger C-2 substituents were deleterious to activity. 2-Methoxy-17 carbamate 50 was studied by X-ray crystallography and was surprisingly 13-fold weaker as an STS inhibitor compared to parent bis-sulfamate 3. The potential of 4 as an orally dosed anti-tumor agent is confirmed using breast and prostate cancer xenografts. In the MDA-MB-231 model, dramatic reduction in tumor growth or regression was observed, with effects sustained after cessation of treatment. 3-O Sulfamoylated 2-alkylestradiol-17-O-carbamates and sulfamates have considerable potential as anticancer agents. PMID- 17696420 TI - Conformation-activity relationship of neuropeptide S and some structural mutants: helicity affects their interaction with the receptor. AB - Neuropeptide S (NPS) is the endogenous ligand of the previously orphan G-protein coupled receptor now named NPSR. The NPS-NPSR receptor system regulates important biological functions such as sleep/waking, locomotion, anxiety and food intake. Recently, exhaustive Ala scan and d-amino acid scan studies, together with systematic N- and C-terminal truncation, led to the identification of key residues for biological activity. Because conformational preferences might also play an important role, we undertook a detailed conformational analysis of NPS and several analogues in solution. We show that helicity induced by substitution of three flexible residues in the 5-13 regulatory region abolishes biological activity. A parallel pharmacological and conformational study of single and multiple substitutions of glycines 5, 7, and 9 showed that helicity can be tolerated in the C-terminal part of the peptide but not around Gly7. The identification of hNPSR partial agonists heralds the possibility of designing pure NPS receptor antagonists. PMID- 17696421 TI - Mixed-valence iron(II, III) trimesates with open frameworks modulated by solvents. AB - Solvothermal reactions with different solvents produced two iron trimesates [Fe2(H2O)2(BTC)4/3]Cl x 4.5(DMF) (1) and [Fe4Cl(BTC)8/3]Cl2 x H2O x 2.5(DEF) (2) (BTC = 1,3,5-benzenetricarboxylate, DMF = N,N'-dimethylformamide, DEF = N,N' diethylformamide). The framework of 1 is a (3,4)-connected net constructed from mixed-valence paddlewheel Fe2(II, III) units and BTC linkers, while the framework of 2 is a (3,8)-connected net built from mixed-valence square-planar Fe4(III, III, III, II) units and BTC linkers. The large volume inside the framework of 1 (or 2) is occupied by disordered Cl- anions and guest DMF (or DEF) molecules. The mixed-valence character of the frameworks of 1 and 2 was confirmed by Mossbauer spectroscopy studies. The active electronic property of iron cations may be the origin of the variability of the iron-organic frameworks, which are readily affected by some synthetic factors, such as solvents. Magnetic studies reveal that there are antiferromagnetic exchange interactions among the Fe atoms in 1 and 2. Ion-exchange studies for 1 show that the Cl- anions inside the framework of 1 can be exchanged by CNS- anions. PMID- 17696422 TI - Exploring the interaction of mercury(II) by N(2)S(2) and NS(3) anthracene containing macrocyclic ligands: photophysical, analytical, and structural studies. AB - The complexation properties toward Hg(II) of six macrocyclic ligands, 3,11-dithia 7,17-diazabicyclo[11.3.1]heptadeca-1(17),13,15-triene (L1), 7-(9 anthracenylmethyl)-3,11-dithia-7,17-diazabicyclo[11.3.1]heptadeca-1(17),13,15 triene (L2), 7-(10-methyl-9-anthracenylmethyl)-3,11-dithia-7,17 diazabicyclo[11.3.1]heptadeca-1(17),13,15-triene (L3), 7,7'-[9,10 anthracenediylbis(methylene)]bis-3,11-dithia-7,17-diazabicyclo[11.3.1]heptadeca 1(17),13,15-triene (L4), 1,4,7-trithia-11-azacyclotetradecane (L5), and 11, (anthracen-9-ylmethyl)-1,4,7-trithia-11-azacyclotetradecane (L6), were studied. The stoichiometries of the formed species were determined from absorption and fluorescence titrations. In these anthracene-containing macrocycles, a fluorescent quenching of the emission was found upon Hg(II) addition. The X-ray crystal structure of [HgCl2(L2)] x 1/2CH2Cl2 was determined. The asymmetric unit contains two independent [HgCl2(L2)] molecules and one dichloromethane molecule. Each Hg(II) ion is coordinated by the pyridine nitrogen, the two sulfur atoms of one L2 molecule, and two chloride ions. Analytical studies using solvent extraction separation of Hg(II) from aqueous solutions were performed to determine the Hg(II) extraction capability of ligands L1, L2, and L5. PMID- 17696423 TI - Transition-metal-induced fluorescence resonance energy transfer in a cryptand derivatized with two different fluorophores. AB - A laterally nonsymmetric aza cryptand has been derivatized with one 7-nitrobenz-2 oxa-1,3-diazole (fluorophore(1)) and one/two anthracenes (fluorophore(2)) to obtain 1 and 2. Their emission characteristics are probed in the presence of a number of transition metals and proton. In the case of 1, Cu(II), Zn(II), Cd(II), and proton afford a large enhancement of fluorescence, whereas Fe(II) and Ag(I) exhibit one order of magnitude less enhancement. In contrast, 2 gives a large enhancement with Cu(II), Ag(I), and proton. The enhancement is observed in the diazole moiety even when the anthracene fluorophore is excited because of substantial fluorescence resonance energy transfer from anthracene to the diazole moiety. Compounds 1 and 2 can be termed as the second-generation fluorescence signaling systems. PMID- 17696424 TI - The first hexanuclear copper(I) carboxylate: X-ray crystal structure and reactivity in solution and gas-phase reactions. AB - The carboxylate ligand-exchange reaction of copper(I) trifluoroacetate by 3,5 difluorobenzoate yielded a new product, [Cu(O2C(3,5-F)2C6H3)] (1). Single crystals of 1 suitable for X-ray structural characterization were obtained by sublimation-deposition procedures at 230 degrees C. An X-ray diffraction study revealed a remarkable planar hexanuclear copper(I) core supported by bridging carboxylates, the first such structural type among other known copper(I) carboxylates. The Cu...Cu distances within the core range from 2.7064(8) to 2.8259(8) A and fall into the category of cuprophillic interactions. The hexacopper unit remains intact upon gas-phase deposition with a planar polyarene, coronene (C24H12), to give [Cu6(O2C(3,5-F)2C6H3)6](C24H12) (2). Density functional theory calculations suggest the latter compound to be a cocrystallization product having electrostatic interactions between the hexacopper complex and coronene. However, cocrystallization affects the photophysical properties of 2. While copper(I) 3,5-difluorobenzoate (1) exhibits photoluminescence at ca. 554 nm (lambda(ex) = 350 nm) in the solid state, compound 2 is nonluminescent at room temperature in the visible region. Gas-phase and solution reactions of 1 with alkyne ligands, diphenylacetylene (C14H10) and 1,4-bis(p-tolylethynyl)benzene (C24H18), result in the rupture of the [Cu6] core to afford dinuclear organometallic copper(I) complexes. The latter have a dimetal core cis-bridged by two carboxylate groups with acetylene ligands eta(2) coordinated to each copper(I) center. PMID- 17696425 TI - Spin transition at the mesophase transition temperature in a cobalt(II) compound with branched alkyl chains. AB - A cobalt(II) compound, [Co(C5C12C10-terpy)2](BF4)2 [C5C12C10-terpy = 4',5' '' decyl-1' ''-(heptadecyloxy)-2,2':6',2' '-terpyridine] with branched alkyl chains, based on a terpyridine frame, was synthesized. The cobalt(II) compound exhibits a spin transition between low-spin and high-spin with a thermal hysteresis loop (T(1/2) upward arrow = 288 K and T(1/2) downward arrow = 284 K) at the liquid crystal transition temperature. It is the first example in the cobalt(II) compounds in which the spin transition occurs at the crystal-liquid crystal transition temperature. PMID- 17696426 TI - Adventures in crystallization. Crystalline salts containing one, two, or even three chemically distinct cations obtained from solutions of [(cyclohexyl isocyanide)(4)Rh(I)]+. AB - By judicious selection of crystallization conditions, it has been possible to obtain the salts of a common building block, [(RNC)4Rh(I)]+, in single-crystal form suitable for X-ray diffraction. Salts that contain a single type of cation include deep green [(C6H11NC)12Rh(I)3](SbF6)3, deep green [(C6H11NC)12Rh(I)3](AsF6)3, and straw yellow [(C6H11NC)8Rh(II)2Cl2](BF4)2 (in addition to the previously isolated trimeric deep green [(i-PrNC)12RhI3]Cl3 x 4.5 H2O, monomeric, [(C6H11NC)4 Rh(I)](BPh4), and [(i-PrNC)4Rh(I)](BPh4) (both yellow), and red, dimeric [(C6H11NC)8Rh(I)2]Cl2 x 0.5C6H6 x 2H2O). Ordered crystals of [(C6H11NC)12Rh(I)3](SbF6)3 contain linear Rh3 units, while those of [(C6H11NC)12Rh(I)3](AsF6)3 show disorder which is consistent with the presence of linear or bent Rh3 units. The formation of green [(C6H11NC)12Rh(V/III)3Cl2][(C6H11NC)12Rh(I)3]Cl6, and brown [(C6H11NC)12Rh(V/III)3Cl2][(C6H11NC)8Rh(I)2][(C6H11NC)4RhI]Cl6 x 16H2O x 3C6H6 along with unidentified red-brown cubes from an air-exposed solution of [(C6H11NC)4Rh(I)]Cl is reported. As their formulas indicate, green [(C6H11NC)12Rh(V/III)3Cl2][(C6H11NC)12Rh(I)3]Cl6, and brown [(C6H11NC)12Rh(V/III)3Cl2][(C6H11NC)8Rh(I)2][(C6H11NC)8Rh(I)]Cl6 x 16H2O x 3C6H6 contain two or three chemically distinct cations, respectively, but again are built from a common precursor, [(C6H11NC)4Rh(I)]+. PMID- 17696427 TI - Pore-size tunable mesoporous zirconium organophosphonates with chiral L-proline for enzyme adsorption. AB - Mesoporous zirconium organophosphonates with a tunable mesopore (pore diameter: from 4.8 to 16.3 nm) were synthesized through co-condensation of ZrCl4 and 1 phosphomethylproline (H3PMP) with the aid of organic additives in the presence of an anionic surfactant (sodium dodecyl sulfate) under weak acidic conditions. The organic additives, tetrahydrofuran, can effectively strengthen the assembly of ZrCl4 and H3PMP around the surfactant micelles through decreasing the hydrolysis and condensation rate of ZrCl4. The results of the N2 sorption isotherm and SEM image show that zirconium phosphate with a bimodal structure is formed by calcination of mesoporous zirconium organophosphonate. Mesoporous zirconium organophosphonates can effectively adsorb lysozyme (Lz) and papain, and the adsorption equilibrium for Lz can be reached within 30 min. The adsorption capacity for Lz and papain can reach as high as 438 and 297 mg/g, respectively. Furthermore, Lz adsorbed on mesoporous zirconium organophosphonates can retain its structural conformation as in its free state, and no leaching of Lz from the solid was observed when shaking the Lz-loaded solid in a buffer solution. Also, the existence of L-proline in the mesopore could help the adsorption of papain at a pH value lower than the pI of papain. PMID- 17696428 TI - Synthesis, structure, and electrochemistry of di- and zerovalent nickel, palladium, and platinum monomers and dimers derived from an enantiopure (S,S) tetra(tertiary phosphine). AB - The ligand (S,S)-1,1,4,7,10,10-hexaphenyl-1,4,7,10-tetraphosphadecane, (S,S) tetraphos, reacts with hexa(aqua)nickel(II) chloride in the presence of trimethylsilyl triflate (TMSOTf) in dichloromethane to give the yellow square planar complex [Ni{(R,R)-tetraphos}](OTf)2, which has been crystallographically characterized as the square-pyramidal, acetonitrile adduct [Ni(NCMe){(R,R) tetraphos}]OTf. Cyclic voltammograms of the nickel(II) complex in dichloromethane and acetonitrile at 20 degrees C showed two reduction processes at negative potentials with oxidative (E(p)(ox)) and reductive (E(p)(red)) peak separations similar to those observed for ferrocene/ferrocenium under identical conditions, suggesting two one-electron steps. The cyclic voltammetric data for the divalent nickel complex in acetonitrile at temperatures below -20 degrees C were interpreted according to reversible coordination of acetonitrile to the nickel(I) and nickel(0) complexes. The divalent palladium and platinum complexes [M{(R,R) tetraphos}](PF6)2 and [M2{(R,R)-tetraphos}2](OTf)4 have been prepared. The reduction potentials for the complexes [M{(R,R)-tetraphos}](PF6)2 increase in the order nickel(II) < palladium(II) < platinum(II). The reaction of (S,S)-tetraphos with bis(cycloocta-1,5-diene)nickel(0) in benzene affords orange [Ni{(R,R) tetraphos}], which slowly rearranges into the thermodynamically more stable, yellow, double-stranded helicate [Ni2{(R,R)-tetraphos}2]; the crystal structures of both complexes have been determined. The reactions of (S,S)-tetraphos with [M(PPh3)4] in toluene (M = Pd) or benzene (M = Pt) furnish the double-stranded helicates [M2{(R,R)-tetraphos}2]; the palladium complex crystallizes from hot benzene as the 2-benzene solvate and was structurally characterized by X-ray crystallography. In each of the three zerovalent complexes, the coordinated (R,R) tetraphos stereospecifically generates tetrahedral M(PP)2 stereocenters of M configuration. PMID- 17696429 TI - Steric stabilization of a monomeric proalumatrane: experimental and theoretical studies. AB - Treatment of tripodal tris(3-tert-butyl-2-hydroxy-5-methylbenzyl)amine (L) with 1 equiv of trimethylaluminum in toluene gave the stable proalumatrane (AlL) (1) [wherein L = tris(3-tert-butyl-5-methyl-2-oxidobenzyl)amine] featuring a distorted trigonal monopyramidal four-coordinate aluminum geometry. An analogous reaction uses the less sterically congested isomer of L, namely, tris(5-tert butyl-2-hydroxy-3-methylbenzyl)amine provided dimeric (AlL')2 (2) [wherein L' = tris(5-tert-butyl-3-methyl-2-oxidobenzyl)amine], which contains two bridging alumatrane moieties possessing five-coordinate TBP aluminum geometries. Reaction of AlL with water provided the adduct H2O. AlL (3), a species that is representative of a coordinatively stabilized intermediate in the hydrolysis of an aluminum alkoxide. Theoretical calculations revealed that considerable stabilization energy is obtained by the coordination of a water molecule to the tetracoordinate aluminum in AlL and that this result is consistent with the postulate that the Lewis acidity of AlL exceeds that of boron trifluoride, despite the presence of the transannular N-->Al bond in AlL. PMID- 17696430 TI - Mechanism of ammonia detection by chemically functionalized single-walled carbon nanotubes: in situ electrical and optical study of gas analyte detection. AB - We provide definitive evidence for the mechanism of electronic detection of ammonia by monitoring in situ changes in the electrical resistance and optical spectra of films of poly(m-aminobenzenesulfonic acid)-functionalized SWNTs (SWNT PABS). The increase of resistance during exposure to ammonia is associated with deprotonation of the PABS side chain that in turn induces electron transfer between the oligomer and the valence band of the semiconducting SWNTs. Near IR spectroscopy is used to demonstrate that the charge transfer is a weakly driven process, and this accounts for the high reversibility of the sensor. We show that the sensitivity of the chemiresistors increases as the film thickness is reduced to the percolation threshold and that the SWNT-PABS film thickness provides a simple means to enhance the electronic response. PMID- 17696431 TI - Mechanistic investigation of the cobalt-catalyzed selective conversion of diallylanilines to quinolines involving C-N and C-H activations. AB - 2,3-Substituted quinolines were readily prepared from diallylanilines in good yields under mild conditions by using Co2(CO)(8) as catalyst. Regioselectivity has been explored by examining a series of electron-donating and electron withdrawing functional groups at ortho, meta, and para positions of the diallylanilines. The results show that both steric and electronic effects influence the isolated yields. Electron-withdrawing groups inhibit the reaction. Solvent effects, temperature effects, and catalyst loadings have also been investigated. Isotopic labeling experiments were devised to permit delineation of the mechanism of reaction. PMID- 17696432 TI - Ultrafast energy transfer and strong dynamic non-condon effect on ligand field transitions by coherent phonon in gamma-Fe2O3 nanocrystals. AB - Relaxation dynamics of an optically excited ligand field state and strong modulation of oscillator strengths of ligand field transitions by coherent acoustic phonon in gamma-Fe(2)O(3) nanocrystals were investigated through transient absorption measurements. A near-infrared pump beam prepared the lowest excited ligand field state of Fe(3+) ions preferentially on the tetrahedral coordination site. A time-delayed visible probe beam monitored the dynamics of various ligand field transitions and modification of their oscillator strengths by a coherent lattice motion. Transient absorption data exhibited dynamic features of a few distinct time scales, 100 fs, 1 ps, and 17-100 ps, as well as intense oscillatory features resulting from a coherent acoustic phonon. The initial decay of the induced absorption in 100 fs has been attributed to the exchange interaction-mediated energy transfer from the tetrahedral to octahedral Fe(3+) sites. The dynamics of slower time scales were assigned to the vibrational and electronic relaxations. Excitation of the ligand field state created a coherent acoustic phonon resulting in unusually intense modulation of the transient absorption signal despite its predominantly local nature and relatively small vibronic coupling. Excitation of each Fe(3+) ion in the nanocrystal was estimated to modulate up to 60% of its contribution to the total absorption intensity of the nanocrystal. The intense modulation of the absorption has been attributed to the strongly modulated oscillator strength of the ligand field transitions rather than oscillating Frank-Condon overlap. Dynamic modification of the metal-ligand orbital overlap and exchange interaction between the neighboring metal ions are the main factors responsible for the modulation of the oscillator strength. PMID- 17696433 TI - Synthesis, crystal structure, characterization, and catalytic properties of TNU 9. AB - The synthesis, crystal structure, characterization, and catalytic properties of the novel medium-pore zeolite TNU-9 (framework type TUN), one of the most crystallographically complex zeolites known to date, are described. TNU-9 was found to crystallize under hydrothermal conditions at the expense of a lamellar precursor over a very narrow range of SiO(2)/Al(2)O(3) and NaOH/SiO(2) ratios and in the presence of 1,4-bis(N-methylpyrrolidinium)butane and Na+ ions as structure directing agents. A combination of molecular modeling and Rietveld refinement using synchrotron powder diffraction data confirms the proposed topology of as made TNU-9 and suggests three or possibly four different sites for the organic within the complex pore structure. The proton form (H-TNU-9) of this new medium pore zeolite exhibits exceptionally high hydrothermal stability, as well as very strong acidity. When compared to H-ZSM-5, H-MCM-22, H-mordenite, and H-Beta, H TNU-9 displays unique shape selectivities for the acid-catalyzed reactions of monoaromatic hydrocarbons such as the disproportionation of toluene and the isomerization and disproportionation of m-xylene. In particular, for the isomerization of m-xylene, the ratio of isomerization to disproportionation increases steadily to values in excess of 50 with prolonged time on stream and a high p/o xylene ratio is observed in the products, achieving a value of ca. 6 after only a short time on stream. These results are rationalized on the basis of the unique pore topology of TNU-9. PMID- 17696434 TI - Self-organization of room-temperature ionic liquids exhibiting liquid-crystalline bicontinuous cubic phases: formation of nano-ion channel networks. PMID- 17696435 TI - Synthesis of a Dy@C82 derivative bearing a single phosphorus substituent via a zwitterion approach. PMID- 17696438 TI - Upper rim appended hybrid calixarenes via click chemistry. AB - We report the application of "click" chemistry for the synthesis of hybrid calixarenes appended on the upper rim with carbohydrate and N,C-protected alpha amino acids. The chemoselective N- or C-deprotection of the alpha-amino acids and their subsequent transformation into dipeptides is described. The first example of a chemo-enzymatic synthesis on upper rim derived calix[4]arenes using trans sialidase affords sialylated lactose calix[4]arenes. Our innovative chemo enzymatic process paves the way for further applications. PMID- 17696439 TI - Self-supported oligomeric Grubbs/Hoveyda-type Ru-carbene complexes for ring closing metathesis. AB - On the basis of the release-return metathesis mechanism, self-supported oligomeric Grubbs/Hoveyda-type Ru-carbene complexes have been designed and synthesized as a new type of recoverable catalyst for ring-closing metathesis. The catalytic activities of the self-supported oligomeric Ru-carbene complex in ring-closing metathesis are comparable to those of their homogeneous counterpart as they work homogeneously and are recovered heterogeneously. PMID- 17696440 TI - Echinacea species and alkamides inhibit prostaglandin E(2) production in RAW264.7 mouse macrophage cells. AB - Inhibition of prostaglandin E(2) (PGE(2)) production in lipopolysaccharide stimulated RAW264.7 mouse macrophage cells was assessed with an enzyme immunoassay following treatments with Echinacea extracts or synthesized alkamides. Results indicated that ethanol extracts diluted in media to a concentration of 15 microg/mL from E. angustifolia, E. pallida, E. simulata, and E. sanguinea significantly inhibited PGE2 production. In further studies, PGE2 production was significantly reduced by all synthesized alkamides assayed at 50 microM, by Bauer alkamides 8, 12A analogue, and 14, Chen alkamide 2, and Chen alkamide 2 analogue at 25 microM and by Bauer alkamide 14 at 10 microM. Cytotoxicity did not play a role in the noted reduction of PGE2 production in either the Echinacea extracts or synthesized alkamides. High-performance liquid chromatography analysis identified individual alkamides present at concentrations below 2.8 microM in the extracts from the six Echinacea species (15 microg/mL crude extract). Because active extracts contained <2.8 microM of specific alkamide and the results showed that synthetic alkamides must have a minimum concentration of 10 microM to inhibit PGE2, it is likely that alkamides may contribute toward the anti-inflammatory activity of Echinacea in a synergistic or additive manner. PMID- 17696441 TI - Determination of theaflavins including methylated theaflavins in black tea leaves by solid-phase extraction and HPLC analysis. AB - A quantitative method for four theaflavins and two methylated theaflavin derivatives in black tea leaves was developed by solid-phase extraction and a high-performance liquid chromatographic method with photodiode array detection. The theaflavins in black tea leaves were extracted three times with 40 vol 50% aqueous ethanol (mg dry tea powder/mL) containing 2% ascorbic acid. The ethanol extracts were diluted 4-fold with distilled water. All diluted extracts were directly applied to the solid-phase C18 cartridge column without concentration. The fraction of theaflavins was obtained by 40% ethanol extraction after rinsing with water followed with 15% ethanol extraction. An aliquot of theaflavins after concentration was injected onto an ODS C18 reversed-phase column, and four theaflavins and two methylated theaflavins were sufficiently separated by a linear gradient system using distilled water and acetonitrile with 0.5% acetic acid. This analytical method is sensitive for the determination of a small amount of methylated theaflavins, since various interfering substances produced during the fermentation process were eliminated in advance by solid-phase extraction. Using this analytical method, we also demonstrated that methylated theaflavins were easily produced during the manufacture of black tea. PMID- 17696442 TI - Inhibition of prostaglandin E(2) production by anti-inflammatory hypericum perforatum extracts and constituents in RAW264.7 Mouse Macrophage Cells. AB - Hypericum perforatum (Hp) is commonly known for its antiviral, antidepressant, and cytotoxic properties, but traditionally Hp was also used to treat inflammation. In this study, the anti-inflammatory activity and cytotoxicity of different Hp extractions and accessions and constituents present within Hp extracts were characterized. In contrast to the antiviral activity of Hp, the anti-inflammatory activity observed with all Hp extracts was light-independent. When pure constituents were tested, the flavonoids, amentoflavone, hyperforin, and light-activated pseudohypericin, displayed anti-inflammatory activity, albeit at concentrations generally higher than the amount present in the Hp extracts. Constituents that were present in the Hp extracts at concentrations that inhibited the production of prostaglandin E(2) (PGE(2)) were pseudohypericin and hyperforin, suggesting that they are the primary anti-inflammatory constituents along with the flavonoids, and perhaps the interactions of these constituents and other unidentified compounds are important for the anti-inflammatory activity of the Hp extracts. PMID- 17696443 TI - Properties of cast films from hemp (Cannabis sativa L.) and soy protein isolates. A comparative study. AB - The properties of cast films from hemp protein isolate (HPI) including moisture content (MC) and total soluble mass (TSM), tensile strength (TS) and elongation at the break (EAB), and surface hydrophobicity were investigated and compared to those from soy protein isolate (SPI). The plasticizer (glycerol) level effect on these properties and the interactive force pattern for the film network formation were also evaluated. At some specific glycerol levels, HPI films had similar MC, much less TSM and EAB, and higher TS and surface hydrophobicity (support matrix side), as compared to SPI films. The TS of HPI and SPI films as a function of plasticizer level (in the range of 0.3-0.6 g/g of protein) were well fitted with the exponential equation with coefficient factors of 0.991 and 0.969, respectively. Unexpectedly, the surface hydrophobicity of HPI films (including air and support matrix sides) increased with increasing the glycerol level (from 0.3 to 0.6 g/g of protein). The analyses of protein solubility of film in various solvents and free sulfydryl group content showed that the disulfide bonds are the prominent interactive force in the HPI film network formation, while in the SPI case, besides the disulfide bonds, hydrogen bonds and hydrophobic interactions are also to a similar extent involved. The results suggest that hemp protein isolates have good potential to be applied to prepare protein film with some superior characteristics, e.g., low solubility and high surface hydrophobicity. PMID- 17696444 TI - Quantitative analysis of phytate globoids isolated from wheat bran and characterization of their sequential dephosphorylation by wheat phytase. AB - Wheat phytase was purified to investigate the action of the enzyme toward its pure substrate (phytic acid - myo-inositol hexakisphosphate) and its naturally occurring substrate (phytate globoids). Phytate globoids were purified to homogeneity from wheat bran, and their nutritionally relevant parameters were quantified by ICP-MS. The main components of the globoids were phytic acid (40% w/w), protein (46% w/w), and several minerals, in particular, K > Mg > Ca > Fe (in concentration order). Investigation of enzyme kinetics revealed that K(m) and V(max) decreased by 29 and 37%, respectively, when pure phytic acid was replaced with phytate globoids as substrate. Time course degradation of phytic acid or phytate globoids using purified wheat phytase was followed by HPIC identification of inositol phosphates appearing and disappearing as products. In both cases, enzymatic degradation initiated at both the 3- and 6-positions of phytic acid and end products were inositol and phosphate. PMID- 17696445 TI - Quantitative analysis of red wine tannins using Fourier-transform mid-infrared spectrometry. AB - Tannin content and composition are critical quality components of red wines. No spectroscopic method assessing these phenols in wine has been described so far. We report here a new method using Fourier transform mid-infrared (FT-MIR) spectroscopy and chemometric techniques for the quantitative analysis of red wine tannins. Calibration models were developed using protein precipitation and phloroglucinolysis as analytical reference methods. After spectra preprocessing, six different predictive partial least-squares (PLS) models were evaluated, including the use of interval selection procedures such as iPLS and CSMWPLS. PLS regression with full-range (650-4000 cm(-1)), second derivative of the spectra and phloroglucinolysis as the reference method gave the most accurate determination for tannin concentration (RMSEC = 2.6%, RMSEP = 9.4%, r = 0.995). The prediction of the mean degree of polymerization (mDP) of the tannins also gave a reasonable prediction (RMSEC = 6.7%, RMSEP = 10.3%, r = 0.958). These results represent the first step in the development of a spectroscopic methodology for the quantification of several phenolic compounds that are critical for wine quality. PMID- 17696446 TI - Optimization of simultaneous flavanol, phenolic acid, and anthocyanin extraction from grapes using an experimental design: application to the characterization of champagne grape varieties. AB - Optimization of polyphenol extraction from grape skin, seed, and pulp was performed on Vitis vinifera L. cv. Pinot Noir, by response surface methodology using a Doehlert design. An acidified mixture of acetone/water/methanol was the best solvent for simultaneous extraction of major polyphenol groups from all berry parts, while optimum extraction times and solid-to-liquid ratios varied according to the part. The determined composition from the model agreed with independent experimental results. Analysis of the three Champagne grape varieties showed that proanthocyanidins were the major phenolic compounds in each part (60 93%). The total berry proanthocyanidin content was highest in Pinot Meunier (11 g kg(-1)) and lowest in Chardonnay (5 g kg(-1)), but Pinot Meunier pulp contained lower amounts of proanthocyanidins and phenolic acids (210 and 127 mg kg(-1) berry, respectively) than that of the other two varieties. The berry anthocyanin content was equivalent in both Pinot Noir and Pinot Meunier (632 and 602 mg kg( 1), respectively). PMID- 17696447 TI - Improved GC/MS method for quantitation of n-alkanes in plant and fecal material. AB - A gas chromatography-mass spectrometry (GC/MS) method for the quantitation of n alkanes (carbon backbones ranging from 21 to 36 carbon atoms) in forage and fecal samples has been developed. Automated solid-liquid extraction using elevated temperature and pressure minimized extraction time to 30 min per sample as compared to more than 24 h for traditional GC-flame ionization detection methods that use saponification and liquid-liquid extraction. Extraction solvent requirements were also minimized to 10 mL per sample. Under optimal conditions, complete method recoveries, including extraction efficiency, were greater than 91%. The linear dynamic range was 5 to 100 nmol injected onto the column, with a limit of quantitation of 5 nmol. Intra-assay coefficients of variation for the analysis of annual ryegrass (Lolium rigidum), subterranean clover (Trifolium subterranean), and bovine feces ranged from 0.1%-12.9%, where lower concentrations of n-alkane produced a higher degree of imprecision. The reported GC/MS method permits simple, rapid, and precise quantitation of n-alkanes in plant and fecal material and reduces reagent and labor requirements. PMID- 17696448 TI - Inhibition of trypsin by condensed tannins and wine. AB - Phenolic compounds are abundant vegetable secondary metabolites in the human diet. The ability of procyanidin oligomers and wine polyphenols to inhibit trypsin activity was studied using a versatile and reliable in vitro method. The hydrolysis of the chromogenic substrate N-benzoyl-d,l-arginine-p-nitroanilide (BApNA) by trypsin was followed by spectrophotometry in the presence and absence of condensed tannins and wine. A clear relationship between the degree of polymerization of procyanidins and enzymatic inhibition was observed. Trypsin activity inhibition was also detected in several types of wine. In general, the inhibition increased with the concentration of phenolic compounds in wines. These results may be relevant when considering these compounds as antinutritional factors, thereby contributing to a reduced absorption of nutrients. PMID- 17696449 TI - Influence of agronomic variables on the macronutrient and micronutrient contents and thermal behavior of mate tea leaves (Ilex paraguariensis). AB - The influence of agronomic variables (light intensity, age of leaves, and fertilization type) on the content of macronutrients and micronutrients (potassium, calcium, sodium, magnesium, manganese, iron, zinc, and copper) of tea leaves was assessed by acid digestion, followed by flame atomic absorption spectrometry (FAAS). The thermal behavior of mate tea leaves (Ilex paraguariensis) was also studied in this work. Samples of mate (Ilex paraguariensis) were collected in an experiment conducted under agronomic control at Erva-Mate Barao Commerce and Industry LTD (Brazil). The results showed that the mineral content in mate is affected by the agronomic variables investigated. In general, the content of mineral compounds analyzed is higher for younger leaves and for plants cultivated in shadow. Thermal analysis of samples indicated a similar behavior, with three typical steps of decomposition: loss of water, degradation of low-molecular weight compounds, and degradation of residual materials. PMID- 17696450 TI - Identification and comparison of phenolic compounds in the preparation of oolong tea manufactured by semifermentation and drying processes. AB - Oolong tea manufactured via a semifermentation process possesses a taste and color somewhere between green and black teas. Alteration of constituents, particularly phenolic compounds, in the infusion of oolong tea resulting from its manufacture, was analyzed by high-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry. The identified constituents contained 2 alkaloids, 11 flavan-3-ols, 8 organic acids and esters, 11 proanthocyanidin dimers, 3 theaflavins, and 22 flavonoid glycosides, including 6 novel acylated flavonol glycosides. The tentative structures of these 6 novel compounds were depicted according to their mass fragmentation patterns in MS(n) (n = 1-4). In comparison with caffeine as an internal standard, relative contents of the constituents in the infusions of fresh tea shoot and different oolong tea preparations were examined. Approximately, 30% catechins and 20% proanthocyanidins were oxidized during the manufacture of oolong tea from fresh tea shoots, and 20% of total flavonoids were decomposed in a follow-up drying process. Gallocatechin-3-O-gallate and theaflavins putatively produced in the semifermentation process of oolong tea were not detected in fresh tea shoots, and the majority of theaflavins were presumably transformed into thearubigins after drying. PMID- 17696451 TI - Mechanistic studies on norcoclaurine synthase of benzylisoquinoline alkaloid biosynthesis: an enzymatic Pictet-Spengler reaction. AB - Norcoclaurine synthase catalyzes an asymmetric Pictet-Spengler condensation of dopamine and 4-hydroxyphenylacetaldehyde to give (S)-norcoclaurine. This is the first committed step in the biosynthesis of the benzylisoquinoline alkaloids that include morphine and codeine. In this work, the gene encoding for the Thalictrum flavum norcoclaurine synthase is highly overexpressed in Escherichia coli and the resulting His-tagged recombinant enzyme is purified for the first time. A continuous assay based on circular dichroism spectroscopy is developed and used to monitor the kinetics of the enzymatic reaction. Dopamine analogues bearing a methoxy or hydrogen substituent in place of the C-1 phenolic group were readily accepted by the enzyme whereas those bearing the same substituents at C-2 were not. This supports a mechanism involving a two-step cyclization of the putative iminium ion intermediate that does not proceed via a spirocyclic intermediate. The reaction of [3,5,6-2H]dopamine was found to be slowed by a kinetic isotope effect of 1.7 +/- 0.1 on the value of kcat/KM. This is interpreted as showing that the deprotonation step causing rearomatization is partially rate determining in the overall reaction. PMID- 17696452 TI - Adenosine deaminase 1 and concentrative nucleoside transporters 2 and 3 regulate adenosine on the apical surface of human airway epithelia: implications for inflammatory lung diseases. AB - Adenosine is a multifaceted signaling molecule mediating key aspects of innate and immune lung defenses. However, abnormally high airway adenosine levels exacerbate inflammatory lung diseases. This study identifies the mechanisms regulating adenosine elimination from the apical surface of human airway epithelia. Experiments conducted on polarized primary cultures of nasal and bronchial epithelial cells showed that extracellular adenosine is eliminated by surface metabolism and cellular uptake. The conversion of adenosine to inosine was completely inhibited by the adenosine deaminase 1 (ADA1) inhibitor erythro-9 (2-hydroxy-3-nonyl)adenine (EHNA). The reaction exhibited Km and Vmax values of 24 microM and 0.14 nmol x min(-1) x cm(-2). ADA1 (not ADA2) mRNA was detected in human airway epithelia. The adenosine/mannitol permeability coefficient ratio (18/1) indicated a minor contribution of paracellular absorption. Adenosine uptake was Na+-dependent and was inhibited by the concentrative nucleoside transporter (CNT) blocker phloridzin but not by the equilibrative nucleoside transporter (ENT) blocker dipyridamole. Apparent Km and Vmax values were 17 microM and 7.2 nmol x min(-1) x cm(-2), and transport selectivity was adenosine = inosine = uridine > guanosine = cytidine > thymidine. CNT3 mRNA was detected throughout the airways, while CNT2 was restricted to nasal epithelia. Inhibition of adenosine elimination by EHNA or phloridzin raised apical adenosine levels by >3-fold and stimulated IL-13 and MCP-1 secretion by 6-fold. These responses were reproduced by the adenosine receptor agonist 5'-(N-ethylcarboxamido)adenosine (NECA) and blocked by the adenosine receptor antagonist, 8-(p-sulfophenyl) theophylline (8-SPT). This study shows that adenosine elimination on human airway epithelia is mediated by ADA1, CNT2, and CNT3, which constitute important regulators of adenosine-mediated inflammation. PMID- 17696454 TI - Internal structure of nanoporous TiO2/polyion thin films prepared by layer-by layer deposition. AB - The internal structure of porous TiO2 films prepared by electrostatic layer-by layer deposition was investigated. The films were prepared by alternate dipping of solid substrates into dispersions of TiO2 nanoparticles and polycations, polyanions, or pure buffer solution, respectively. The surface charge of the amphoteric TiO2 particles was controlled by the pH of the aqueous dispersions. The morphology of the film surface was investigated by means of scanning electron microscopy. It was found that the surface roughness strongly depends on the polymeric material used for the deposition process but is independent of the ionic strength of the solution or the molecular weight of the polyions. The samples with rough surfaces feature strong light scattering. The porosity and internal structure of the TiO2/polyelectrolyte films were investigated by adsorption/desorption of dye molecules. A crude estimate yields an internal surface that is up to 160 times the plane surface of the substrate for a film thickness of 1 microm. The composition of the films was investigated by X-ray photoelectron spectroscopy (XPS). Detection of the XPS signal after each deposition step of the first three dipping cycles shows a significant increase of the relative surface coverage of Ti after the TiO2 deposition step and of PSS after the PSS deposition step. For later dipping cycles, such an increase was also detectable but less prominent. PMID- 17696453 TI - Effects of cell volume regulating osmolytes on glycerol 3-phosphate binding to triosephosphate isomerase. AB - During cell volume regulation, intracellular concentration changes occur in both inorganic and organic osmolytes in order to balance the extracellular osmotic stress and maintain cell volume homeostasis. Generally, salt and urea increase the Km's of enzymes and trimethylamine N-oxide (TMAO) counteracts these effects by decreasing Km's. The hypothesis to account for these effects is that urea and salt shift the native state ensemble of the enzyme toward conformers that are substrate-binding incompetent (BI), while TMAO shifts the ensemble toward binding competent (BC) species. Km's are often complex assemblies of rate constants involving several elementary steps in catalysis, so to better understand osmolyte effects we have focused on a single elementary event, substrate binding. We test the conformational shift hypothesis by evaluating the effects of salt, urea, and TMAO on the mechanism of binding glycerol 3-phosphate, a substrate analogue, to yeast triosephosphate isomerase. Temperature-jump kinetic measurements promote a mechanism consistent with osmolyte-induced shifts in the [BI]/[BC] ratio of enzyme conformers. Importantly, salt significantly affects the binding constant through its effect on the activity coefficients of substrate, enzyme, and enzyme substrate complex, and it is likely that TMAO and urea affect activity coefficients as well. Results indicate that the conformational shift hypothesis alone does not account for the effects of osmolytes on Km's. PMID- 17696456 TI - Reversing DNA-mediated adhesion at a fixed temperature. AB - Recognition-based assembly of micron- to nano-sized colloidal particles functionalized with DNA has generated great interest in the past decade; however, reversing the assembly process is typically achieved by thermal denaturation of the oligonucleotide duplexes. Here, we report an alternative disassembly approach at a fixed temperature using competitive hybridization events between immobilized and soluble oligonucleotide strands. Microspheres are first aggregated via primary hybridization events between immobilized DNA strands with a weak, but sufficient, affinity for partner strands to link complementary surfaces together. To reverse the aggregation process, soluble oligonucleotides are then added to competitively displace the original hybridization partners through secondary hybridization events. Using flow cytometry to quantify hybridization events and microscopy to examine DNA-mediated aggregation and redispersion, we found that the efficiency of competitive displacement is based upon (1) the difference in base pair matches between the primary and secondary target for the same probe sequence and (2) the concentration of hybridizing oligonucleotides participating in microsphere aggregation. To the best of our knowledge, this study is the first to employ DNA hybridization events to mediate reversible adhesion between colloidal particles at a fixed temperature. PMID- 17696455 TI - Langmuir monolayer properties of perfluorinated double long-chain salts with divalent counterions of separate electric charge at the air-water interface. AB - The novel perfluorinated double long-chain salts with divalent counterions of separate electric charge, 1,1-(1,omega-alkanediyl)-bispyridinium perfluorotetradecane- carboxylate [CnBP(FC14)2 : n = 2, 6, 10, 14], were newly synthesized and their interfacial behavior was investigated by Langmuir monolayer methods. Surface properties [surface pressure (pi)-, surface potential (DeltaV)-, dipole moment (micro perpendicular)-area (A) isotherms] and morphological images of CnBP(FC14)2 monolayers on a subphase of water and on various NaCl concentrations were measured by employing the Wilhelmy method, the ionizing electrode method, fluorescence microscopy (FM), and Brewster angle microscopy (BAM). CnBP(FC14)2 formed a stable monolayer on water at 298.2 K, where these pi A isotherms shifted to a larger molecular area with increasing charge separation and had no transition point from a disordered phase to an ordered one. On the contrary, the pi-A isotherms on NaCl solutions moved to the smaller areas, showed the transition and higher collapse pressures compared to the pi-A isotherms on water. These results suggested that a sodium chloride subphase induced the condensation of CnBP(FC14)2 molecules upon compression. In addition, it is quite noticeable that a dissociation of CnBP counterion from CnBP(FC14)2 occurs on NaCl solutions, depending on the extent of charge separation. This phenomenon was supported by the changes of the limiting area, transition pressure, collapse pressure, repeated compression-expansion cycle curve, and DeltaV behavior of perfluorotetradecanoic acid (FC14). Furthermore, temperature dependence of these monolayers was investigated, and an apparent molar quantity change on the phase transition was evaluated on 0.15 M NaCl. The morphological behavior of CnBP(FC14)2 and FC14 monolayers was also confirmed by FM and BAM images. PMID- 17696457 TI - Amorphous drug nanosuspensions. 3. Particle dissolution and crystal growth. AB - In the present paper, we have studied particle dissolution and crystal growth of the poorly water soluble drug felodipine, using fluorescence as a probe for the amount of crystalline material. Dissolution kinetics is essentially diffusion controlled, while the rate of crystal growth is significantly slower compared to the diffusion-controlled limit. The deviation from diffusion control was characterized by the effective length, lambda, related to the kinetics of a surface integration process. Amorphous nanoparticles may be highly unstable in the presence of small amounts of crystalline particles. This is due to the fact that the molecular solubility from the amorphous nanoparticles often is at least an order of magnitude higher than the corresponding crystalline solubility. In a mixed system where crystalline nanoparticles have been added to an amorphous nanosuspension, the bulk will have a monomer concentration intermediate between the amorphous and crystalline solubilities, and is thus supersaturated with respect to the crystalline particles while being undersaturated with respect to the amorphous particles. As a consequence, the amorphous particles spontaneously dissolve, while crystalline particles grow, in a combined process which is similar to Ostwald ripening. By knowing the parameters describing dissolution and crystal growth, respectively, it was possible to simulate the outcome of controlled seeding experiments, where a small amount of crystalline nanoparticles was added to a dispersion of amorphous nanoparticles. A good agreement between model calculations and experiments was obtained including how the crystal growth rate varied with the amounts of added crystalline seeds. PMID- 17696458 TI - Mode of heavy meromyosin adsorption and motor function correlated with surface hydrophobicity and charge. AB - The in vitro motility assay is valuable for fundamental studies of actomyosin function and has recently been combined with nanostructuring techniques for the development of nanotechnological applications. However, the limited understanding of the interaction mechanisms between myosin motor fragments (heavy meromyosin, HMM) and artificial surfaces hampers the development as well as the interpretation of fundamental studies. Here we elucidate the HMM-surface interaction mechanisms for a range of negatively charged surfaces (silanized glass and SiO2), which is relevant both to nanotechnology and fundamental studies. The results show that the HMM-propelled actin filament sliding speed (after a single injection of HMM, 120 microg/mL) increased with the contact angle of the surfaces (in the range of 20-80 degrees). However, quartz crystal microbalance (QCM) studies suggested a reduction in the adsorption of HMM (with coupled water) under these conditions. This result and actin filament binding data, together with previous measurements of the HMM density (Sundberg, M.; Balaz, M.; Bunk, R.; Rosengren-Holmberg, J. P.; Montelius, L.; Nicholls, I. A.; Omling, P.; Tagerud, S.; Mansson, A. Langmuir 2006, 22, 7302-7312. Balaz, M.; Sundberg, M.; Persson, M.; Kvassman, J.; Mansson, A. Biochemistry 2007, 46, 7233 7251), are consistent with (1) an HMM monolayer and (2) different HMM configurations at different contact angles of the surface. More specifically, the QCM and in vitro motility assay data are consistent with a model where the molecules are adsorbed either via their flexible C-terminal tail part (HMMC) or via their positively charged N-terminal motor domain (HMMN) without other surface contact points. Measurements of zeta potentials suggest that an increased contact angle is correlated with a reduced negative charge of the surfaces. As a consequence, the HMMC configuration would be the dominant configuration at high contact angles but would be supplemented with electrostatically adsorbed HMM molecules (HMMN configuration) at low contact angles. This would explain the higher initial HMM adsorption (from probability arguments) under the latter conditions. Furthermore, because the HMMN mode would have no actin binding it would also account for the lower sliding velocity at low contact angles. The results are compared to previous studies of the microtubule-kinesin system and are also discussed in relation to fundamental studies of actomyosin and nanotechnological developments and applications. PMID- 17696459 TI - Radiation-induced synthesis and cryo-TEM characterization of silver nanoshells on linoleate spherical micelles. AB - We combine the self-assembly properties of amphiphilic molecules with the radiolysis method to produce specific sizes and shapes of metallic nano-objects. Radiolysis is used to synthesize core--shell structures consisting of nanometric linoleate spherical micelles as the core and silver as the shell. The validity of the technique is asserted by cryoelectron microscopy, which is an adequate technique for low density contrasts and core--shell structures. The shells are found to be homogeneous with a size of a few nanometers. Images are used to bring forward the hypothesis of the fabrication process. PMID- 17696460 TI - Pickering stabilization as a tool in the fabrication of complex nanopatterned silica microcapsules. AB - Complex silica-based microcapsules with nanopatterned features were made using Pickering stabilization as a fabrication tool. A sequential two-step liquid liquid interface-driven assembly process was employed using Laponite clay discs and Laponite armored polystyrene latex particles as solids to stabilize emulsion droplets on two different length scales. The discotic Laponite particles and poly(diethoxysiloxane) were used as silica sources. The ethoxy groups of the poly(diethoxysiloxane) were removed via a triethylamine-catalyzed interfacial hydrolysis and sol-gel reaction. The organic components were removed via a calcination step. The two-stage templating route provided siliceous microcapsules of which the capsule walls were decorated on either the outside or inside with nanocapsules composed of Laponite clay. PMID- 17696461 TI - Interactions between charged surfaces immersed in a polyelectrolyte solution. AB - With grand canonical simulations invoking a configurationally weighted scheme, we have calculated interactions between charged surfaces immersed in a polyelectrolyte solution. In contrast to previous simulations of such systems, we have imposed full equilibrium conditions (i.e., we have included diffusive equilibrium with a bulk solution). This has a profound impact on the resulting interactions: even at modest surface charge densities, oppositely charged chains will, at sufficiently large separations, adsorb strongly enough to overcompensate for the nominal surface charge. This phenomenon, known as charge inversion, generates a double-layer repulsion and a free-energy barrier. Simpler canonical approaches, where the chains are assumed to neutralize the surfaces perfectly, will not capture this stabilizing barrier. The barrier height increases with the length of the polyions. Interestingly enough, the separation at which the repulsion becomes attractive is independent of chain length. The short chains here are unable to reach across from one surface to the other. We therefore conclude that the transition to an attractive regime is not provided by the formation of such "intersurface" bridges. With long chains and at large separations, charge inversion displays decaying oscillatory behavior (i.e., the apparent surface charge switches sign once again). This is due to polyion packing effects. We have also investigated responses to salt addition and changes in polyelectrolyte concentration. Our results are in qualitative and semiquantitative agreement with experimental findings, although it should be noted that our chains are comparatively short, and the experimental surface charge density is poorly established. PMID- 17696462 TI - An inflammatory arthritis-associated metabolite biomarker pattern revealed by 1H NMR spectroscopy. AB - Rheumatoid arthritis, a debilitating, systemic inflammatory joint disease, is likely accompanied by alterations in circulating metabolites. Here, an 1H NMR spectroscopy-based metabolomics approach was developed to establish a metabolic 'biomarker pattern' in a model of rheumatoid arthritis, the K/BxN transgenic mouse. Sera obtained from arthritic K/BxN mice (N = 15) and a control population (N = 19) having the same genetic background, but lacking the arthritogenic T-cell receptor KRN transgene, were compared by 1H NMR spectroscopy. A unique method was developed by combining technologies such as ultrafiltration to remove proteins from serum samples, quantitative 'targeted profiling' of known metabolites, pseudo-quantitative profiling of unknown resonances, a supervised O-PLS-DA pattern recognition analysis, and a metabolic-pathway based network analysis for interpretation of results. In total, 88 spectral features were profiled (59 metabolites and 28 unknown resonances). A highly significant subset of 18 spectral features (15 known compounds and 3 unknown resonances) was identified (p = 0.00075 using MANOVA) that we term a 'metabolic bioprofile'. We identified metabolites relating to nucleic acid, amino acid, and fatty acid metabolism, as well as lipolysis, reactive oxygen species generation, and methylation. Pathway analysis suggested a shift from metabolites involved in numerous reactions (hub metabolites) toward intermediates and metabolic endpoints associated with arthritis. The results attest to the metabolic complexity of systemic inflammation and to the power of the experimental approach for identifying a wide variety of disease-associated marker candidates. The diagnostic and prognostic implications of monitoring a spectrum of metabolic events simultaneously using serum samples is discussed with respect to the potential for individualized medicine. PMID- 17696463 TI - Bioinformatics processing of protein and transcript profiles of normal and transformed cell lines indicates functional impairment of transcriptional regulators in buccal carcinoma. AB - Normal and two transformed buccal keratinocyte lines were cultured under a standardized condition to explore mechanisms of carcinogenesis and tumor marker expression at transcript and protein levels. An approach combining three bioinformatic programs allowed coupling of abundant proteins and large-scale transcript data to low-abundance transcriptional regulators. The analysis identified previously proposed and suggested novel protein biomarkers, gene ontology categories, molecular networks, and functionally impaired key regulator genes for buccal/oral carcinoma. PMID- 17696464 TI - Proteomic and biochemical studies of calcium- and phosphorylation-dependent calmodulin complexes in Mammalian cells. AB - Protein conformational changes due to cofactor binding (e.g., metal ions, heme) and/or post-translational modifications (e.g., phosphorylation) modulate dynamic protein complexes. Calmodulin (CaM) plays an essential role in regulating calcium signaling and homeostasis. Herein, we report a straightforward and systematic approach to identify potential calcium- and phosphorylation-dependent CaM complexes in a proteome-wide manner. We have identified over 120 CaM-associated proteins encompassing four different classes of CaM binding in HeLa cells, namely, calcium-dependent and phosphorylation-dependent (e.g., EDD1), calcium dependent and phosphorylation-independent (e.g., myosin IE), calcium-independent and phosphorylation-dependent (e.g., DDX3), and calcium-independent and phosphorylation-independent (e.g., DDX5). To demonstrate the utility of our method in understanding biological pathways, we showed that in vivo phosphorylation of inositol 1,4,5-triphosphate receptor type 1 (IP3R1) at Ser1598 significantly reduced the affinity of its Ca2+-dependent CaM binding. However, phosphorylation of IP3R1 did not substantially affect its Ca2+-independent CaM binding. These results shed new lights on the mechanism underlying the marked increase of Ca2+ release due to IP3R1 phosphorylation. We further showed that staurosporine-sensitive kinase(s) and phosphatase PP1 play a critical role in modulating the phosphorylation-dependent CaM binding of IP3R1. Our method may serve as a general strategy to identify and characterize phosphorylation dependent protein complexes, to pinpoint the phosphorylation sites and associated kinase(s) and phosphatase(s) involved in the protein-protein interactions, and to functionally characterize these complexes in mammalian cells. PMID- 17696465 TI - Investigating side chain mediated electroluminescence from carbazole-modified polyfluorene. AB - In molecular design of electroluminescent (EL) conjugated polymers, introducing a charge transport moiety on a side chain is found to be a promising method for balancing electron and hole fluxes in EL devices without changing the emitting color if there is no interaction between moiety and main chain. In the case of grafting a carbazole (Cz) moiety (hole transporting) on blue emitting polyfluorene, a green emission appears with intensity comparable to the blue emission, which was attributed to a possible interaction between main chain and Cz as previously reported by us. Here, a detailed study of its EL mechanism was carried out by means of time-resolved EL with the assistance of molecular simulation and thermally stimulated current measurements; exploration of how main chain segments interact with the transport moiety was performed. We found the Cz groups in Cz100PF play multiple roles: they act as (1) hole transporter to improve hole injection, (2) hole trapping site for efficient electron-hole recombination to yield blue-emitting excitons, and (3) source of green emission from electroplex formed via electric field-mediated interaction of the Cz/Cz radical cation with an electron in the nearby PF backbone. In combination, these observations suggest that integrated consideration for both intramolecular and intermolecular interactions provides a new route of molecular design of efficient EL polymers. PMID- 17696466 TI - Temperature-induced collapse of alkaline Earth cation-polyacrylate anion complexes. AB - Polyacrylate anions are used to inhibit CaCO3 precipitation and may be a promising additive to control formation of inorganic nanoparticles. The origin of this applicability lies in specific interactions between the alkaline earth cations and the carboxylate functions along the polyacrylate chains. In the absence of CO32- anions, these interactions eventually cause precipitation of polyelectrolytes. Extended investigation of dilute sodium polyacrylate solutions approaching this precipitation threshold revealed a dramatic shrinking of the PA coil dimensions once the threshold is reached (Eur. Phys. J. E 2001, 5, 117). Recent isothermal calorimetric titration experiments by Antonietti et al. (Macromolecules 2004, 37, 3444) indicated that the driving force of this precipitation is entropic in nature. In the present work, we investigated the impact of temperature on the structural changes of dissolved polyacrylate chains decorated with alkaline earth cations. To this end, large polyacrylate chains were brought close to the precipitation threshold by the addition of distinct amounts of Ca2+ or Sr2+ cations. The resulting structural intermediates were then subjected to temperature variations in the range of 15 degrees C or=90%) in the reactions with most early transition-metal cations (Sc+, Ti+, V+, Y+, Zr+, Nb+, Mo+, Hf+, Ta+, and W+) and to a minor extent (10%) with one main-group cation (As+). OD transfer is observed to occur only with three cations (Sr+, Ba+, and La+). Other cations, including most late transition and main-group cations, were observed to react with D2O exclusively and slowly by D2O addition or not at all. O-Atom transfer proceeds with rate coefficients in the range of 8.1 x 10(-13) (As+) to 9.5 x 10(-10) (Y+) cm3 molecule(-1)(s-1) and with efficiencies below 0.1 and even below 0.01 for the fourth-row atomic cations V+ (0.0032) and As+ (0.0036). These low efficiencies can be understood in terms of the change in spin required to proceed from the reactant to the product potential energy surfaces. Higher order reactions are also measured. The primary products, NbO+, TaO+, MoO+, and WO+, are observed to react further with D(2)O by O-atom transfer, and ZrO+ and HfO+ react further through OD group abstraction. Up to five D(2)O molecules were observed to add sequentially to selected M+ and MO+ as well as MO2+ cations and four to MO(2)D+. Equilibrium measurements for sequential D(2)O addition to M+ are also reported. The periodic variation in the efficiency (k/k(c)) of the first addition of D(2)O appears to be similar to the periodic variation in the standard free energy (DeltaG degrees) of hydration. PMID- 17696504 TI - Reductive halogen elimination from phenols by organic radicals in aqueous solutions; chain reaction induced by proton-coupled electron transfer. AB - Gamma-radiolysis and measurements of halide ions by means of ion chromatography have been employed to investigate reductive dehalogenation of chloro-, bromo-, and iodophenols by carbon-centered radicals, *CH(CH(3))OH, *CH(2)OH, and *CO(2)-, in oxygen-free aqueous solutions in the presence of ethanol, methanol, or sodium formate. While the reactions of 4-IC(6)H(4)OH with *CH(CH(3))OH and *CH(2)OH radicals are endothermic in water/alcohol solutions, the addition of bicarbonate leads to iodide production in high yields, indicative of a chain reaction. The maximum effect has been observed with about 10 mM sodium bicarbonate present. The complex formed from an alpha-hydroxyalkyl radical and a bicarbonate anion is considered to cause the enhancement of the reduction power of the former to the extent at which the reduction of the iodophenol molecule becomes exothermic. No such effect has been observed with phosphate, which is a buffer with higher proton affinity, when added in the concentration of up to 20 mM at pH 7. This indicates that one-electron reduction reactions by alpha-hydroxyalkyl radicals occur by the concerted proton-coupled electron transfer, PCET, and not by a two step ET/PT or PT/ET mechanisms. The reason for the negative results with phosphate buffer could be thus ascribed to a less stable complex or to the formation of a complex with a less suitable structure for an adequate support to reduce iodophenol. The reduction power of the carbonate radical anion is shown to be high enough to reduce iodophenols by a one-electron-transfer mechanism. In the presence of formate ions as H-atom donors, the dehalogenation also occurs by a chain reaction. In all systems, the chain lengths depend on the rate of reducing radical reproduction in the propagation step, that is, on the rate of H-atom abstraction from methanol, ethanol, or formate by 4-*C(6)H(4)OH radicals liberated after iodophenol dehalogenation. The rate constants of those reactions were determined from the iodide yield measurements at a constant irradiation dose rate. They were estimated to be 6 M(-1)(s-1) for methanol, 140 M(-1)(s-1) for ethanol, and 2100 M(-1)(s-1) for formate. Neither of the tested reducing C centered radicals was able to dehalogenate the bromo or chloro derivative of phenol. PMID- 17696505 TI - Theoretical studies on structures and spectroscopic properties of a series of novel cationic [trans-(C/N)2Ir(PH3)2]+ (C/N = ppy, bzq, ppz, dfppy). AB - The geometries, electronic structures, and spectroscopic properties of a series of novel cationic iridium(III) complexes [trans-(C/N)(2)Ir(PH(3))(2)]+ (C/N = 2 phenylpyridine, 1; benzoquinoline, 2; 1-phenylpytazolato, 3; 2-(4,6 difluorophenyl)pyridimato, 4) were investigated theoretically. The ground- and excited-state geometries were optimized at the B3LYP/LANL2DZ and CIS/LANL2DZ levels, respectively. The optimized geometry structural parameters agree well with the corresponding experimental results. The unoccupied molecular orbitals are dominantly localized on the C/N ligand, while the occupied molecular orbitals are composed of Ir atom and C/N ligand. Under the time-dependent density functional theory (TDDFT) level with the polarized continuum model (PCM) model, the absorption and phosphorescence in acetonitrile (MeCN) media were calculated based on the optimized ground- and excited-state geometries, respectively. The calculated results showed that the lowest-lying absorptions at 364 nm (1), 389 nm (2), 317 nm (3), and 344 nm (4) are all attributed to a {[d(yz)(Ir) + pi(C/N)] - > [pi*(C/N)]} transition with metal-to-ligand and intraligand charge transfer (MLCT/ILCT) characters; moreover, the phosphorescence at 460 (1) and 442 nm (4) originates from the 3{[d(yz)(Ir) + pi(C/N)] [pi*(C/N)]} (3)MLCT/(3)ILCT excited state, while that at 505 (2) and 399 nm (3) can be described as originating from different types of (3)MLCT/(3)ILCT excited state (3){[d(xy)(Ir) + pi(C/N)] [pi*(C/N)]}. The calculated results also revealed that the absorption and emission transition character can be altered by adjusting the pi electron withdrawing groups and, furthermore, suggested that the phosphorescent color can be tuned by changing the pi-conjugation effect of the C/N ligand. PMID- 17696506 TI - Unified derivation of Bohmian methods and the incorporation of interference effects. AB - We present a unified derivation of Bohmian methods that serves as a common starting point for the derivative propagation method (DPM), Bohmian mechanics with complex action (BOMCA), and the zero-velocity complex action method (ZEVCA). The unified derivation begins with the ansatz psi = eiS/Planck's where the action (S) is taken to be complex, and the quantum force is obtained by writing a hierarchy of equations of motion for the phase partial derivatives. We demonstrate how different choices of the trajectory velocity field yield different formulations such as DPM, BOMCA, and ZEVCA. The new derivation is used for two purposes. First, it serves as a common basis for comparing the role of the quantum force in the DPM and BOMCA formulations. Second, we use the new derivation to show that superposing the contributions of real, crossing trajectories yields a nodal pattern essentially identical to that of the exact quantum wavefunction. The latter result suggests a promising new approach to deal with the challenging problem of nodes in Bohmian mechanics. PMID- 17696507 TI - Reciprocating motion on the nanoscale. AB - This paper analyzes the confined motion of a Brownian particle fluctuating between two conformational states with different potential profiles and different position-dependent rate constants of the transitions, the fluctuations arising from both thermal (equilibrium) and external (nonequilibrium) noise. The model illustrates a mechanism to transduce, on the nanoscale, the energy of nonequilibrium fluctuations into mechanical energy of reciprocating motion. Expressions for the reciprocating velocity and the efficiency of energy conversion are derived. These expressions are treated in more detail in the slow fluctuation (quasi-equilibrium) regime, by simple perturbation theory arguments, and in the fast fluctuation limit, in terms of the potential of mean force. A notable observation is that the generalized driving force of the reciprocating motion is caused by two sources: the energy contribution due to the difference between the potential profiles of the states and the entropic contribution due to the difference between the position-dependent rate constants. Two illustrative examples are presented, where one of the two sources can be ignored and an exact solution is allowed. Among other aspects, we also discuss the ways to construct a molecular motor based on the reciprocating engine. PMID- 17696508 TI - Thermochemical studies of N-methylpyrazole and N-methylimidazole. AB - The 351.1 nm photoelectron spectra of the N-methyl-5-pyrazolide anion and the N methyl-5-imidazolide anion are reported. The photoelectron spectra of both isomers display extended vibrational progressions in the X2A' ground states of the corresponding radicals that are well reproduced by Franck-Condon simulations, based on the results of B3LYP/6-311++G(d,p) calculations. The electron affinities of the N-methyl-5-pyrazolyl radical and the N-methyl-5-imidazolyl radical are 2.054 +/- 0.006 eV and 1.987 +/- 0.008 eV, respectively. Broad vibronic features of the A(2)A' ' states are also observed in the spectra. The gas-phase acidities of N-methylpyrazole and N-methylimidazole are determined from measurements of proton-transfer rate constants using a flowing afterglow-selected ion flow tube instrument. The acidity of N-methylpyrazole is measured to be Delta(acid)G(298) = 376.9 +/- 0.7 kcal mol(-1) and Delta(acid)H(298) = 384.0 +/- 0.7 kcal mol(-1), whereas the acidity of N-methylimidazole is determined to be Delta(acid)G(298) = 380.2 +/- 1.0 kcal mol(-1) and Delta(acid)H(298)= 388.1 +/- 1.0 kcal mol(-1). The gas-phase acidities are combined with the electron affinities in a negative ion thermochemical cycle to determine the C5-H bond dissociation energies, D(0)(C5-H, N-methylpyrazole) = 116.4 +/- 0.7 kcal mol(-1) and D(0)(C5-H, N-methylimidazole) = 119.0 +/- 1.0 kcal mol(-1). The bond strengths reported here are consistent with previously reported bond strengths of pyrazole and imidazole; however, the error bars are significantly reduced. PMID- 17696509 TI - Modeling competitive interactions in proteins: vibrational spectroscopy of M+(n methylacetamide)1(H2O)n=0-3, M=Na and K, in the 3 microm region. AB - To properly understand the preferred structures and biological properties of proteins, it is important to understand how they are influenced by their immediate environment. Competitive intrapeptide, peptide...water, ion...water, and ion...peptide interactions, such as hydrogen bonding, play a key role in determining the structures, properties, and functionality of proteins. The primary types of hydrogen bonding involving proteins are intramolecular amide...amide (N-H...O=C) and intermolecular amide...water (O-H...O=C and H-O...H N). n-Methylacetamide (NMA) is a convenient model for investigating these competitive interactions. An analysis of the IR photodissociation (IRPD) spectra of M+(n-methylacetamide)1(H2O)n=0-3 (M=Na and K) in the O-H and N-H spectral regions is presented. Ab initio calculations (MP2/cc-pVDZ) are used as a guide in identifying both the type and location of hydrogen bonds present. In larger clusters, where several structural isomers may be present in the molecular beam, ab initio calculations are also used to suggest assignments for the observed spectral features. The results presented offer insight to the nature of ion...NMA interactions in an aqueous environment and reveal how different ion...ligand pairwise interactions direct the extent of water...water and water...NMA hydrogen bonding observed. PMID- 17696510 TI - Direct measurements of intersystem crossing rates and triplet decays of luminescent conjugated oligomers in solutions. AB - Photothermal calorimetry and fluorescence spectroscopy were used to determine the relaxations of the photoexcited singlet state of two PPV and polyfluorene oligomers, (E,E)-1,4-bis[(2-benzyloxy)styryl]benzene (PVDOP) and ter(9,9' spirobifluorene) (TSBF). The decay rates of different S1 relaxation channels, which include intersystem crossing (ISC), radiative, and nonradiative decay can be determined by the combination of photoacoustic calorimetry (PAC) and the time correlated single photon counting (TCSPC) technique. The triplet state energy level is determined by the phosphorescence (Ph) spectra recorded at 77 K. The ISC yields are approximately 3% and 6% for PVDOP and TSBF, respectively. The T1 to S0 transition decay rate is acquired by PAC and photothermal beam deflection (PBD) measurements. The triplet state decay rate is 17 and 21 ms(-1) at room temperature. The Ph intensity decay at 77 K shows that the triplet state lifetime increases by 4 orders of magnitude, as compared to room temperature. PMID- 17696511 TI - Cytosine in context: a theoretical study of substituent effects on the excitation energies of 2-pyrimidinone derivatives. AB - The ultrafast radiationless decay mechanism for cytosine has been shown to be in part dependent upon high vertical excitation, while slower fluorescence displayed in some cytosine analogs is generally linked to lower vertical excitation energies. To probe how excitation energies relate to pyrimidine structure, substituent effects on the vertical excitation energies for a number of derivatives of 2-pyrimidin-(1H)-one (2P) have been calculated using multireference configuration-interaction ab initio methods. Substitutions using groups with pi electron donating, withdrawing and conjugation-extending properties at the C(4) and C(5) positions on the 2P system give predictive trends for the first three singlet excited-state energies. The S(1) pipi* energies of 2P derivatives involving C4 substitution vary linearly with the Hammett substituent parameter sigma(P)+. Cytosine is shown to have the highest bright pipi* energy of the 2P derivatives presented, with that energy being strongly dependent on the position, orientation, and geometry of the C4-amino. A simple description of the predictive energetic trends for the bright pipi* energies using frontier molecular orbital theory is presented, based on the character of the HOMO and LUMO orbitals for each derivative. The results of this study expand the current understanding of the photophysical behavior of the DNA pyrimidine bases and could be useful in the design of analogs where particular spectral properties are desired. PMID- 17696513 TI - An NMR-based antagonist induced dissociation assay for targeting the ligand protein and protein-protein interactions in competition binding experiments. AB - We present an NMR-based antagonist induced dissociation assay (AIDA) for validation of inhibitor action on protein-protein interactions. As opposed to many standard NMR methods, AIDA directly validates the inhibitor potency in an in vitro NMR competition binding experiment. AIDA requires a large protein fragment (larger than 30 kDa) to bind to a small reporter protein (less than 20 kDa). We show here that a small fragment of a protein fused to glutathione S-transferase (GST) can effectively substitute the large protein component. We successfully used a GST-tagged N-terminal 73-residue p53 domain for binding studies with the human MDM2 protein. Other interactions we studied involved complexes of CDK2, cyclin A, p27, and the retinoblastoma protein. All these proteins play a key role in the cell division cycle, are associated with tumorigenesis, and are thus the subject of anticancer therapy strategies. PMID- 17696512 TI - Design and synthesis of HIV-1 protease inhibitors incorporating oxazolidinones as P2/P2' ligands in pseudosymmetric dipeptide isosteres. AB - A series of novel HIV-1 protease inhibitors based on two pseudosymmetric dipeptide isosteres have been synthesized and evaluated. The inhibitors were designed by incorporating N-phenyloxazolidinone-5-carboxamides into the hydroxyethylene and (hydroxyethyl)hydrazine dipeptide isosteres as P2 and P2' ligands. Compounds with (S)-phenyloxazolidinones attached at a position proximal to the central hydroxyl group showed low nM inhibitory activities against wild type HIV-1 protease. Selected compounds were further evaluated for their inhibitory activities against a panel of multidrug-resistant protease variants and for their antiviral potencies in MT-4 cells. The crystal structures of lopinavir (LPV) and two new inhibitors containing phenyloxazolidinone-based ligands in complex with wild-type HIV-1 protease have been determined. A comparison of the inhibitor-protease structures with the LPV-protease structure provides valuable insight into the binding mode of the new inhibitors to the protease enzyme. Based on the crystal structures and knowledge of structure activity relationships, new inhibitors can be designed with enhanced enzyme inhibitory and antiviral potencies. PMID- 17696514 TI - Inhibition of Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium avium by novel dideoxy nucleosides. AB - The prevalence of tuberculosis (TB) and mutidrug-resistant tuberculosis (MDR-TB) has been increasing, leading to serious infections, high mortality, and a global health threat. Here, we report the identification of a novel class of dideoxy nucleosides as potent and selective inhibitors of Mycobacterium bovis, Mycobacterium tuberculosis, and drug-resistant Mycobacterium tuberculosis. A series of 5-acetylenic derivatives of 2',3'-dideoxyuridine (3-8) and 3'-fluoro 2',3'-dideoxyuridine (22-27) were synthesized and tested for their antimycobacterial activity against M. bovis, M. tuberculosis, and M. avium. 2',3' Dideoxyuridine possessing 5-decynyl, 5-dodecynyl, 5-tridecynyl, and 5 tetradecynyl substituents (4-7) exhibited the highest antimycobacterial activity against all three mycobacteria. In contrast, in the 3'-fluoro-2',3' dideoxyuridine series, a 5-tetradecynyl analogue (26) displayed the most potent activity against these mycobacteria. Among other derivatives, 5-bromo-2',3' dideoxycytidine (11), 5-methyl-2',3'-dideoxycytidine (12), and 5-chloro-4-thio 2',3'-dideoxyuridine (19) exhibited modest inhibition of M. bovis and M. tuberculosis. In the series of dideoxy derivatives of adenosine, guanosine, and purines, 2-amino-6-mercaptoethyl-9-(2,3-dideoxy-beta-d glyceropentofuranosyl)purine (32) and 2-amino-4-fluoro-7-(2,3-dideoxy-beta-d glyceropentofuranosyl)pyrrolo[2,3-d]pyrimidine (35) were the most efficacious against M. bovis and M. tuberculosis, and M. avium, respectively. PMID- 17696515 TI - Potent new antiviral compound shows similar inhibition and structural interactions with drug resistant mutants and wild type HIV-1 protease. AB - The potent new antiviral inhibitor GRL-98065 (1) of HIV-1 protease (PR) has been studied with PR variants containing the single mutations D30N, I50V, V82A, and I84V that provide resistance to the major clinical inhibitors. Compound 1 had inhibition constants of 17-fold, 8-fold, 3-fold, and 3-fold, respectively, for PR(D30N), PR(I50V), PR(V82A), and PR(I84V) relative to wild type PR. The chemically related darunavir had similar relative inhibition, except for PR(D30N), where inhibitor 1 was approximately 3-fold less potent. The high resolution (1.11-1.60 Angstrom) crystal structures of PR mutant complexes with inhibitor 1 showed small changes relative to the wild type enzyme. PR(D30N) and PR(V82A) showed compensating interactions with inhibitor 1 relative to those of PR, while reduced hydrophobic contacts were observed with PR(I50V) and PR(I84V). Importantly, inhibitor 1 complexes showed fewer changes relative to wild type enzyme than reported for darunavir complexes. Therefore, inhibitor 1 is a valuable addition to the antiviral inhibitors with high potency against resistant strains of HIV. PMID- 17696517 TI - Design of recombinant antibody microarrays for serum protein profiling: targeting of complement proteins. AB - Antibody-based microarrays is a novel technology with great promise for high throughput proteomics. The process of designing high-performing arrays has, however, turned out to be challenging. Here, we have designed the next generation of a human recombinant scFv antibody microarray platform for protein expression profiling of nonfractionated biotinylated human plasma and serum proteomes. The setup, based on black polymer Maxisorb slides interfaced with a fluorescent-based read-out system, was found to provide specific, sensitive (subpicomolar (pM) range) and reproducible means for protein profiling. Further, a chip-to-chip normalization protocol critical for comparing data generated on different chips was devised. Finally, the microarray data were found to correlate well with clinical laboratory data obtained using conventional methods, as demonstrated for a set of medium abundant (micromolar (microM) to nanomolar (nM) range) protein analytes in serum and plasma samples derived from healthy and complement deficient individuals. PMID- 17696516 TI - Doxazolidine induction of apoptosis by a topoisomerase II independent mechanism. AB - The mechanism of doxorubicin is compared with that of doxazolidine, a doxorubicin formaldehyde conjugate. The IC(50) for growth inhibition of 67 human cancer cell lines, but not cardiomyocytes, is 32-fold lower with doxazolidine than with doxorubicin. Growth inhibition by doxazolidine correlates better with growth inhibition by DNA cross-linking agents than with growth inhibition by doxorubicin. Doxorubicin induces G2/M arrest in HCT-116 colon cancer cells and HL 60 leukemia cells through a well-documented topoisomerase II dependent mechanism. Doxazolidine fails to induce a G2/M arrest in HCT-116 cells but induces apoptosis 4-fold better than doxorubicin. The IC(50) for doxazolidine growth inhibition of HL-60/MX2 cells, a topoisomerase II deficient derivative of HL-60 cells, is 1420 fold lower than the IC(50) for doxorubicin, and doxazolidine induces apoptosis 15 fold better. Further, doxazolidine has little effect in a topoisomerase II activity assay. These data indicate that doxorubicin and doxazolidine induce apoptosis via different mechanisms and doxazolidine cytotoxicity is topoisomerase II independent. PMID- 17696518 TI - Examining the proteome of Drosophila across organism lifespan. AB - A survey of the proteome of Drosophila melanogaster at nine time points across the adult lifespan based on several mass-spectrometry-based techniques is presented. In total, there is evidence for 5902 unique peptides corresponding to 1699 different proteins. Of hundreds of relatively abundant components, many appear to be highly dynamic as the adult fly ages. Of those proteins that we observe changing with age, a majority, associated with metabolism, reproduction, and development, are down-regulated. Other biological pathways such as defense response also show variable changes, where some proteins are down-regulated and others are up-regulated. The observed variations are compared with a report of genome-wide changes at the transcriptome level at different ages and the similarities and differences are presented. PMID- 17696519 TI - Contribution of protein fractionation to depth of analysis of the serum and plasma proteomes. AB - In-depth analysis of the serum and plasma proteomes by mass spectrometry is challenged by the vast dynamic range of protein abundance and substantial complexity. There is merit in reducing complexity through fractionation to facilitate mass spectrometry analysis of low-abundance proteins. However, fractionation reduces throughput and has the potential of diluting individual proteins or inducing their loss. Here, we have investigated the contribution of extensive fractionation of intact proteins to depth of analysis. Pooled serum depleted of abundant proteins was fractionated by an orthogonal two-dimensional system consisting of anion-exchange and reversed-phase chromatography. The resulting protein fractions were aliquotted; one aliquot was analyzed by shotgun LC-MS/MS, and another was further resolved into protein bands in a third dimension using SDS-PAGE. Individual gel bands were excised and subjected to in situ digestion and mass spectrometry. We demonstrate that increased fractionation results in increased depth of analysis based on total number of proteins identified in serum and based on representation in individual fractions of specific proteins identified in gel bands following a third-dimension SDS gel analysis. An intact protein analysis system (IPAS) based on a two-dimensional plasma fractionation schema was implemented that resulted in identification of 1662 proteins with high confidence with representation of protein isoforms that differed in their chromatographic mobility. Further increase in depth of analysis was accomplished by repeat analysis of aliquots from the same set of two dimensional fractions resulting in overall identification of 2254 proteins. We conclude that substantial depth of analysis of proteins from milliliter quantities of serum or plasma and detection of isoforms are achieved with depletion of abundant proteins followed by two-dimensional protein fractionation and MS analysis of individual fractions. PMID- 17696522 TI - Mean first passage time for the contact between the ends of a chain polymer. AB - We investigate the first passage times for the contact between the ends of a Rouse chain, whose initial separation is greater than a predefined contact distance, sigma, and equilibrium-distributed. An approximate analytic expression for the mean first passage time is obtained and compared with the results of previous theories and Brownian dynamics simulations. We find that the results of the present theory are in better agreement with Brownian dynamics simulation results than those of previously reported theories. PMID- 17696520 TI - A comparative proteomic analysis of human and rat embryonic cerebrospinal fluid. AB - During vertebrate central nervous system development, the apical neuroepithelium is bathed with embryonic Cerebrospinal Fluid (e-CSF) which plays regulatory roles in cortical cell proliferation and maintenance. Here, we report the first proteomic analysis of human e-CSF and compare it to an extensive proteomic analysis of rat e-CSF. As expected, we identified a large collection of protease inhibitors, extracellular matrix proteins, and transport proteins in CSF. However, we also found a surprising suite of signaling and intracellular proteins not predicted by previous proteomic analysis. Some of the intracellular proteins are likely to represent the contents of microvesicles recently described within the CSF (Marzesco, A. M., et al. J. Cell Sci. 2005, 118 (Pt. 13), 2849-2858). Defining the rich composition of e-CSF will enable a greater understanding of its concerted actions during critical stages of brain development. PMID- 17696521 TI - Assessment approach for evaluating high abundance protein depletion methods for cerebrospinal fluid (CSF) proteomic analysis. AB - Optimal proteomic analysis of human cerebrospinal fluid (CSF) requires depletion of high-abundance proteins to facilitate observation of low-abundance proteins. The performance of two immunodepletion (MARS, Agilent Technologies and ProteoSeek, Pierce Biotechnology) and one ultrafiltration (50 kDa molecular weight cutoff filter, Millipore Corporation) methods for depletion of abundant CSF proteins were compared using a graphical method to access the depth of analysis using "marker proteins" with known normal concentration ranges. Two dimensional LC/MS/MS analysis of each depleted sample yielded 171 and 163 unique protein identifications using the MARS and ProteoSeek immunodepletion methods, respectively, while only 46 unique proteins were identified using a 50 kDa molecular weight cutoff filter. The relative abundance of the identified proteins was estimated using total spectrum counting and compared to the concentrations of 45 known proteins in CSF as markers of the analysis depth. Results of this work suggest a clear need for methodology designed specifically for depletion of high abundance proteins in CSF, as depletion methods designed to deplete high abundance serum proteins showed little improvement in analysis depth compared to analysis without depletion. The marker protein method should be generally useful for assessing depth of analysis in the comparison of proteomic analysis methods. PMID- 17696523 TI - Signals in solid-state photochemically induced dynamic nuclear polarization recover faster than signals obtained with the longitudinal relaxation time. AB - During the photocycle of quinone-blocked photosynthetic reaction centers (RCs), photochemically induced dynamic nuclear polarization (photo-CIDNP) is produced by polarization transfer from the initially totally electron polarized electron pair and can be observed by 13C magic-angle spinning (MAS) NMR as a strong modification of signal intensities. The same processes creating net nuclear polarization open up light-dependent channels for polarization loss. This leads to coherent and incoherent enhanced signal recovery, in addition to the recovery due to light-independent longitudinal relaxation. Coherent mixing between electron and nuclear spin states due to pseudosecular hyperfine coupling within the radical pair state provides such a coherent loss channel for nuclear polarization. Another polarization transfer mechanism called differential relaxation, which is based on the long lifetime of the triplet state of the donor, provides an efficient incoherent relaxation path. In RCs of the purple bacterium Rhodobacter sphaeroides R26, the photochemical active channels allow for accelerated signal scanning by a factor of 5. Hence, photo-CIDNP MAS NMR provides the possibility to drive the NMR technique beyond the T1 limit. PMID- 17696524 TI - Molecular dynamics simulations of Cu(II) and the PHGGGWGQ octapeptide. AB - The interaction between Cu2+ and the copper-binding octapeptide region in the human prion protein has been investigated by molecular dynamics simulations. In total four different nonbonded and bonded models were used in the study. Charge sets containing atomic partial charges were developed for these models. Out of the considered models, the bonded model performed physically in the most correct way. The simulations with the bonded model showed that the water molecules in the axial position are very labile. The tryptophan indole ring can remain in a stable position on top of the equatorial coordination plane of copper without water mediation. Strong aromatic interaction was observed between the imidazole and indole rings. The nonbonded models showed a tendency for water-mediated interaction between the copper ion and different carbonyl oxygen atoms. In the case of the bonded model, a carbonyl group could also interact directly with the copper ion in one of the apical position. PMID- 17696525 TI - Puckering transition of proline residue in water. AB - The puckering transition of the proline residue with trans and cis prolyl peptide bonds was explored by optimizations along the torsion angle chi1 of the prolyl ring using quantum-chemical methods in water. By analyzing the potential energy surfaces and local minima in water, it is observed that the puckering transition of the proline residue proceeds from a down-puckered conformation to an up puckered one and vice versa through the transition state with an envelope form having the N atom at the top of the envelope and not a planar one, as seen in the gas phase, although the backbone conformations are different in the gas phase and in water. The barriers to the puckering transition DeltaGup-->down are estimated to be 3.12 and 3.00 kcal/mol for trans and cis conformers at the B3LYP/6 311++G(d,p) level of theory in water, respectively, which are about 1.7 kcal/mol higher than those in the gas phase. Out of 2197 prolines from the 241 high resolution PDB chains, four transition-state-like structures with the envelope ring puckering are identified. Three of them have the trans prolyl peptide bonds and one has the cis one. The favorable or steric interactions by neighboring residues may be responsible for the stabilization of these transition-state-like ring structures in the proteins. PMID- 17696526 TI - Dynamics of water in the hydration shells of C60: molecular dynamics simulation using a coarse-grained model. AB - Dynamics of water in the solvation shells of a fullerene molecule as obtained from a coarse-grained (CG) model for the C60-water interaction has been presented and compared with the same obtained from the atomistic model. While in the CG model the interaction between a fullerene and a water has been represented by a simple two-body central potential as obtained from a coarse-graining of the interactions of a C60 molecule with water, in the atomistic description all the interactions between the atoms of a C60 and a water molecule have been explicitly taken into account. Extensive molecular dynamics simulations of a C60 molecule in water have been performed in isothermal-isobaric ensembles. Translational and reorientational mobilities as well as residence time of water in the solvation shells of a fullerene molecule have been obtained by calculating the corresponding time correlation functions from simulation trajectories. Comparison of the dynamical behaviors obtained from the CG and the atomistic models shows overall good agreement. The nature of the relaxation and the trend that the dynamics becomes slower with the decreasing solute-water distance as obtained from the atomistic model have, in general, been reproduced by the CG model. PMID- 17696527 TI - Wormlike micelles in mixed surfactant systems: effect of cosolvents. AB - We have studied the structure and rheological behavior of viscoelastic wormlike micellar solutions in the mixed nonionic surfactants poly(oxyethylene) cholesteryl ether (ChEO15)-trioxyethylene monododecyl ether (C12EO3) and anionic sodium dodecyl sulfate (SDS)-C12EO3 using a series of glycerol/water and formamide/water mixed solvents. The obtained results are compared with those reported in pure water for the corresponding mixed surfactant systems. The zero shear viscosity first sharply increases with C12EO3 addition and then decreases; i.e., there is a viscosity maximum. The intensity (viscosity) and position (C12EO3 fraction) of this maximum shift to lower values upon an increase in the ratio of glycerol in the glycerol/water mixed solvent, while the position of the maximum changes in an opposite way with increasing formamide. In the case of the SDS/C12EO3 system, zero-shear viscosity shows a decrease with an increase of temperature, but for the ChEO15/C12EO3 system, again, the zero-shear viscosity shows a maximum if plotted as a function of temperature, its position depending on the C12EO3 mixing fraction. In the studied nonionic systems, worm micelles seem to exist at low temperatures (down to 0 degrees C) and high glycerol concentrations (up to 50 wt %), which is interesting from the viewpoint of applications such as drag reduction fluids. Rheology results are supported by small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS) measurements on nonionic systems, which indicate micellar elongation upon addition of glycerol or increasing temperature and shortening upon addition of formamide. The results can be interpreted in terms of changes in the surface curvature of aggregates and lyophobicity. PMID- 17696528 TI - Study of the Calix[4]resorcinarene--dopamine interactions in monolayers by measurement of pressure--area isotherms and Maxwell displacement currents. AB - The mechanisms of interactions between calix[4]resorcinarene and dopamine in monolayers formed at the air-water interface were studied by analyzing their mechanical, thermodynamic, and electrical properties evaluated from measurements of pressure-area isotherms and Maxwell displacement currents (MDCs). An increased concentration of dopamine in the water subphase resulted in an increase in the area per calix[4]resorcinarene molecule, an increase in the collapse pressure, and a shift in the monolayer phase transitions from the gaseous to the liquid state and from the liquid to the solid state toward higher molecular areas. A contactless method of recording MDCs enabled the monitoring of changes in the charge state of the monolayer-constituting molecules and the determination of a relationship between the phase state of the monolayer and the structural transitions of calix[4]resorcinarene. The changes of the MDC recordings started already in the gaseous state of the monolayer. On the basis of MDC values, we determined the normal component of the dipole moment of calix[4]resorcinarene, as well as that of its complex with dopamine. The dipole moment reached a maximum value of 1040 mD in the region of the phase transition from the liquid to the solid state of the monolayer. The results obtained suggest that the binding of dopamine with calix[4]resorcinarene depends on the orientation of the calixarene molecules in the monolayer. The calix[4]resorcinarene-dopamine interactions were also quantified in terms of the excess of Gibbs free energy, thereby allowing the evaluation of the energy of the calix [4]resorcinarene-dopamine bond, which was in the range from 1.95 to 8.54 kJ/mol depending on the surface pressure. This value implies weak interactions between these molecules. PMID- 17696529 TI - Ab initio prediction of tryptophan fluorescence quenching by protein electric field enabled electron transfer. AB - We report quantum mechanical-molecular mechanical (QM-MM) predictions of fluorescence quantum yields for 20 tryptophans in 17 proteins, whose yields span the range from 0.01 to 0.3, using ab initio computed coupling matrix elements for photoinduced electron transfer from the 1La excited indole ring to a local backbone amide. The average coupling elements span the range 140-1000 cm-1, depending on tryptophan rotamer conformation. The matrix elements were from the singles configuration interaction matrix, and were largely insensitive to which of the three basis sets was used. Large fluctuations were seen on the time scale of tens of femtoseconds, caused primarily by side chain and backbone torsional variations for 150 ps of dynamics at 300 K. The largest coupling occurs for the chi1 = -60 degrees rotamer and is purely through-bond. There is no apparent correlation between the coupling magnitude and quantum yield, which is still dominated by energy gap and reorganization energy. The source of error bars for predicted quenching rates using the weak coupling golden rule may be due to inaccurate averaged Franck-Condon weighted densities because of inadequate simulation times and parameters and/or to failure of the weak coupled golden rule used in these predictions because of the broad distribution of Landau-Zener probabilities arising from the large variable coupling. PMID- 17696530 TI - Atomic-scale detection of organic molecules coupled to single-walled carbon nanotubes. PMID- 17696531 TI - Photoswitchable dendritic hosts: a dendrimer with peripheral azobenzene groups. AB - We have studied the adducts formed by eosin (E) with a fourth generation dendrimer (D) that comprises 30 tertiary amine units in the interior and 32 naphthyl and 32 trans azobenzene units in the periphery. We have found that: (i) the all trans dendrimer D(32t) can be converted by irradiation with 365 nm light (Phi=0.12) into species containing, as an average, 4 trans and 28 cis azobenzene units, D(4t28c), that at 313 K undergoes a D(4t28c) --> D(32t) thermal back reaction (k = 7.0 x 10(-5) s(-1)); (ii) D(32t) and D(4t28c) extract 8 and, respectively, 6 eosin molecules from water at pH 7, yielding the species D(32t) subset 8E and D(4t28c) subset 6E; (iii) eosin uptake is significantly faster for D(32t) than for D(4t28c); (iv) irradiation at 365 nm of the D(32t) subset 8E species at 298 K leads to the release of two eosin molecules with formation of a photostable D(15t17c) subset 6E species (Phi = 0.15) that is also obtained from the back thermal reaction of D(4t28c) subset6E at 313 K (k = 2.7 x 10(-5) s(-1)); (v) thermal release of E from D(32t) subset 6E is much faster than from D(4t28c) subset 6E; and (vi) excitation of E in the adducts sensitizes the cis --> trans (but not the trans --> cis) isomerization. The results obtained show that the isomerization of the 32 peripheral azobenzene units controls to some extent the hosting capacity of the dendrimer and, viceversa, eosin molecules hosted in the dendrimer affect the isomerization process of its azobenzene units. PMID- 17696532 TI - Calcium-induced phospholipid ordering depends on surface pressure. AB - The effect of sodium and calcium ions on zwitterionic and anionic phospholipids monolayers is investigated using vibrational sum-frequency generation in conjunction with surface pressure measurements and fluorescence microscopy. Sodium ions only subtly affect the monolayer structure, while the effect of calcium is large and depends strongly on the surface pressure. At low surface pressures (approximately 5 mN/m), the presence on Ca2+ results in the unexpected appearance of ordered domains. For pressures between approximately 5 and approximately 25 mN/m, Ca2+ ions induce disorder in the monolayer. For pressures exceeding 25 mN/m, calcium cations expand the monolayer, while simultaneously ordering the lipid chains. Interestingly, effects are similar for both zwitterionic lipids and negatively charged lipids. In both vibrational sum frequency generation and surface tension measurements, the molecular signature of the association of Ca2+ with the lipids is evident from Ca2+-induced changes in the signals corresponding to area changes of 4 A2/lipid-precisely the surface area of a Ca2+ ion, with evidence for a change in lipid Ca2+ complexation at high pressures. PMID- 17696533 TI - DNA polymerase beta catalysis: are different mechanisms possible? AB - DNA polymerases are crucial constituents of the complex cellular machinery for replicating and repairing DNA. Discerning mechanistic pathways of DNA polymerase on the atomic level is important for revealing the origin of fidelity discrimination. Mammalian DNA polymerase beta (pol beta), a small (39 kDa) member of the X-family, represents an excellent model system to investigate polymerase mechanisms. Here, we explore several feasible low-energy pathways of the nucleotide transfer reaction of pol beta for correct (according to Watson-Crick hydrogen bonding) G:C basepairing versus the incorrect G:G case within a consistent theoretical framework. We use mixed quantum mechanics/molecular mechanics (QM/MM) techniques in a constrained energy minimization protocol to effectively model not only the reactive core but also the influence of the rest of the enzymatic environment and explicit solvent on the reaction. The postulated pathways involve initial proton abstraction from the terminal DNA primer O3'H group, nucleophilic attack that extends the DNA primer chain, and elimination of pyrophosphate. In particular, we analyze several possible routes for the initial deprotonation step: (i) direct transfer to a phosphate oxygen O(Palpha) of the incoming nucleotide, (ii) direct transfer to an active site Asp group, and (iii) transfer to explicit water molecules. We find that the most probable initial step corresponds to step (iii), involving initial deprotonation to water, which is followed by proton migration to active site Asp residues, and finally to the leaving pyrophosphate group, with an activation energy of about 15 kcal/mol. We argue that initial deprotonation steps (i) and (ii) are less likely as they are at least 7 and 11 kcal/mol, respectively, higher in energy. Overall, the rate determining step for both the correct and the incorrect nucleotide cases is the initial deprotonation in concert with nucleophilic attack at the phosphate center; however, the activation energy we obtain for the mismatched G:G case is 5 kcal/mol higher than that of the matched G:C complex, due to active site structural distortions. Taken together, our results support other reported mechanisms and help define a framework for interpreting nucleotide specificity differences across polymerase families, in terms of the concept of active site preorganization or the so-called "pre-chemistry avenue". PMID- 17696534 TI - Interparticle charge transfer mediated by pi-pi stacking of aromatic moieties. PMID- 17696535 TI - Tungsten(II) monocarbonyl bis(acetylacetonate): a fourteen-electron docking site for eta2 four-electron donor ligands. PMID- 17696536 TI - Conversion of cyclic vinyl sulfones to transposed vinyl phosphonates. AB - Functionalized cyclic vinyl sulfones were directly converted to the "polarity reversed" vinyl phosphonates through an efficient one pot procedure. Ozonolysis of these vinyl sulfones and vinyl phosphonates furnish complementary sets of termini-differentiated ester-aldehydes. This strategy has been applied for preparation of segments needed for the synthesis of Aplyronine A. The scope and limitations of this transformation were defined. PMID- 17696537 TI - Self-assembly of chiral luminescent lanthanide coordination bundles. PMID- 17696538 TI - Dopant ion concentration dependence of growth and faceting of manganese-doped GaN nanowires. PMID- 17696539 TI - Refolding foldamers: triazene-arylene oligomers that change shape with chemical stimuli. AB - We describe the preparation of five triazene-arylene oligomers (3, 4, 7, 8, and 11) and investigations of their folding properties in aqueous solution. These oligomers contain four 2-fold rotors and populate a conformational ensemble comprising at least 10 states. Extensive 1D and 2D NMR studies as well as X-ray crystallography establish that the presence of three members of the cucurbit[n]uril family (CB[n]), CB[10], CB[7], and CB[8], results in the selective population of the (a,a,a,a)-, (a,s,s,a)-, and (a,a,a,s)-conformers. As a result of the high affinity and highly selective binding properties of the CB[n] family, it is possible to fold a single foldamer strand (3) into the CB[8].(a,a,a,s)-3 conformer by the addition of CB[8], then unfold and refold it into the CB[7].(a,s,s,a)-3.CB[7] conformer by addition of CB[7] and 3,5 dimethylaminoadamantane (17), then unfold and refold it again into the CB[10].(a,a,a,a)-3 conformer by addition of CB[10].CB[5] and aminoadamantane (18). The transformation of CB[8].(a,a,a,s)-3 into CB[7].(a,s,s,a)-3.CB[7] proceeds through the intermediacy of CB [8].(a,a,s,a)-3.CB[7], which enhances the rate of dissociation of strand 3 from CB[8]. PMID- 17696540 TI - Facile synthesis of well-defined block copolymers containing regioregular poly(3 hexyl thiophene) via anionic macroinitiation method and their self-assembly behavior. PMID- 17696541 TI - Ultrafast deactivation channel for thymine dimerization. PMID- 17696542 TI - Understanding the formation of N-H tautomers from alpha-substituted pyridines: tautomerization of 2-ethylpyridine promoted by osmium. PMID- 17696543 TI - Control of bacterial aggregation by thermoresponsive glycopolymers. PMID- 17696544 TI - Reverse selectivity in m-CPBA oxidation of oligothiophenes to sulfones. AB - Oligothiophene sulfones of up to six rings can be conveniently prepared by the direct oxidation of butyl-substituted thiophene oligomers with m-CPBA in dichloromethane. Reverse selectivity of oxidized rings is observed relative to previously reported systems without beta-substitution. The selectivity in the trimer and hexamer is confirmed with single-crystal X-ray structure data. The sulfones possess red-shifted absorptions and increased electron affinities relative to the parent oligomers. PMID- 17696545 TI - Improved and efficient synthesis of chiral N,P-ligands via cyclic sulfamidates for asymmetric addition of butyllithium to benzaldehyde. AB - A robust and scaleable route to chiral 1-isopropylamino-2 (diphenylphosphino)ethanes is described via the ring-opening of chiral, cyclic sulfamidates with potassium diphenylphosphide (KPPh(2)). The novel protocol offers a robust access to gram quantities of chiral amino phosphinoethanes in high yields. The Li-amides of the chiral aminophosphines were evaluated as chiral ligands in the asymmetric addition of n-butyllithium (BuLi) to benzaldehyde, yielding 1-phenylpentanol up to 98% ee. PMID- 17696546 TI - Iodinane- and metal-free synthesis of N-cyano sulfilimines: novel and easy access of NH-sulfoximines. AB - The synthesis of N-cyanosulfilimines can readily be achieved by reaction of the corresponding sulfides with cyanogen amine in the presence of a base and NBS or I2 as halogenating agents. Oxidation followed by C-N bond cleavage affords synthetically useful NH-free sulfoximines. PMID- 17696547 TI - Copper-catalyzed amidation of sp3 C-H bonds adjacent to a nitrogen atom. AB - We have developed a novel copper-catalyzed amidation of unactivated sp(3) C-H bonds adjacent to a nitrogen atom by using an inexpensive catalyst-oxidant (CuBr/(t)BuOOH) system under mild conditions. The dephenylation was first found for N-benzylaniline, and the new class of products provide diverse structures for pharmaceuticals and combinatorial chemistry. PMID- 17696548 TI - Synthesis and enzyme inhibitory activity of the s-nucleoside analogue of the ribitylaminopyrimidine substrate of lumazine synthase and product of riboflavin synthase. AB - Lumazine synthase and riboflavin synthase catalyze the last two steps in the biosynthesis of riboflavin. To obtain structural and mechanistic probes of these two enzymes, as well as inhibitors of potential value as antibiotics, a sulfur analogue of the pyrimidine substrate of the lumazine synthase-catalyzed reaction and product of the riboflavin synthase-catalyzed reaction was designed. Facile syntheses of the S-nucleoside 5-amino-6-(D-ribitylthio)pyrimidine-2,4(1H,3H) dione hydrochloride (15) and its nitro precursor 5-nitro-6-(D ribitylthio)pyrimidine-2,4(1H,3H)-dione (14) are described. These compounds were tested against lumazine synthase and riboflavin synthase obtained from a variety of microorganisms. Compounds 14 and 15 were found to be inhibitors of both riboflavin synthase and lumazine synthase. Compound 14 is an inhibitor of Bacillus subtilis lumazine synthase (Ki 26 microM), Schizosaccharomyces pombe lumazine synthase (Ki 2.0 microM), Mycobacterium tuberculosis lumazine synthase (Ki 11 microM), Escherichia coli riboflavin synthase (Ki 2.7 microM), and Mycobacterium tuberculosis riboflavin synthase (Ki 0.56 muM), while compound 15 is an inhibitor of B. subtilis lumazine synthase (Ki 2.6 microM), S. pombe lumazine synthase (Ki 0.16 microM), M. tuberculosis lumazine synthase (Ki 31 microM), E. coli riboflavin synthase (Ki 47 microM), and M. tuberculosis riboflavin synthase (Ki 2.5 microM). PMID- 17696549 TI - The methyl group as a source of structural diversity in heterocyclic chemistry: side chain functionalization of picolines and related heterocycles. AB - The reaction of 2-picoline at the methyl group with NDA and KDA followed by dimethyldisulfide trapping furnished, respectively, dithioacetals and trithioortho esters with high selectivity. The method was successfully applied to other methyl-substituted pyridines, quinolines, and pyrazines. Dithioketals were prepared by a one-pot procedure involving the reaction of metalated 2-picoline with 2 equiv of dimethyldisulfide followed by in situ trapping with a second electrophile. All of the generated thio-substituted compounds were efficiently transformed in presence of mercury salts or under oxidizing conditions to other functional groups comprising aldehydes, ketones, ketals, thiol esters, orthoesters, and esters. PMID- 17696550 TI - Tandem bis-aldol reaction of ketones: a facile one-pot synthesis of 1,3-dioxanes in aqueous medium. AB - A novel tandem bis-aldol reaction of ketone with paraformaldehyde catalyzed by polystyrenesulfonic acid in aqueous medium delivers 1,3-dioxanes in high yield. This one-pot, operationally simple microwave-assisted synthetic protocol proceeds efficiently in water in the absence of organic solvent, with excellent yield. PMID- 17696551 TI - Directed electrodeposition of polymer films using spatially controllable electric field gradients. AB - We report a method for the directed electrodeposition of polymer films in various patterns using spatially controllable electric field gradients. One- and two- dimensional surface electric field gradients were produced by applying different potential values at spatially distinct locations on an electrode surface. Variations in the resulting local electrochemical potentials were used to spatially manipulate the rate of electrodeposition of several polymers. By controlling the electric field gradient in the presence of sequentially varying deposition solutions, complex polymer patterns could be produced. One-dimensional structures consisting of alternating bands of polyaniline and either poly(phenylene) oxide or poly(aminophenylene) oxide were produced, as well as more complex two-dimensional structures. Film characterization was achieved through optical imaging, UV-vis spectroscopy, and ellipsometry. Results indicate that this directed deposition technique is a simple strategy to create complex, millimeter-sized surface patterns of electrodeposited materials. PMID- 17696552 TI - Growth and structure of water on SiO2 films on Si Investigated by Kelvin probe microscopy and in Situ X-ray spectroscopies. AB - The growth of water on thin SiO2 films on Si wafers at vapor pressures between 1.5 and 4 Torr and temperatures between -10 and 21 degrees C has been studied in situ using Kelvin probe microscopy and X-ray photoemission and absorption spectroscopies. From 0 to 75% relative humidity (RH), water adsorbs forming a uniform film 4-5 layers thick. The surface potential increases in that RH range by about 400 mV and remains constant upon further increase of the RH. Above 75% RH, the water film grows rapidly, reaching 6-7 monolayers at around 90% RH and forming a macroscopic drop near 100%. The O K-edge near-edge X-ray absorption spectrum around 75% RH is similar to that of liquid water (imperfect H-bonding coordination) at temperatures above 0 degrees C and is ice-like below 0 degrees C. PMID- 17696553 TI - A mechanistic study of the formation of mesoporous structures from in situ AC conductivity measurements. AB - The purpose of this work is to study the kinetics of self-assembly in the formation mechanism of anionic templated mesoporous solids (AMS-n) during the first few seconds of the synthesis as well as to demonstrate the use of alternating ion current (AIC) conductivity measurements to follow the self assembly in complex hybrid systems. The formation of different AMS-n caged-type mesostructures through the delayed addition of the silica source is demonstrated and explained in terms of the interaction between the co-structure-directing agent (CSDA) and the oppositely charged surfactant headgroup regions. Our findings, supported by transmission electron microscopy, 29Si magic angle spinning nuclear magnetic resonance (MAS NMR) spectroscopy, dynamic light scattering (DLS) measurements, and powder X-ray diffraction suggest that the interaction of the CSDA with the surfactant headgroup occurs within seconds after its addition to the synthesis gel leading to interaction between the polymerizing CSDAs and the oppositely charged micelle and to an increase in the micelle-CSDA aggregate size. Both DLS and AIC measurements agree that this process occurs within the first 1000 s after addition of the CSDA to the synthesis gel at room temperature. In addition to the mechanistic study it was found that the intermediate materials are comprised of a three-layer entity. Time-dependent 29Si MAS NMR studies reveal that an organo-silica layer forms around the micelles prior to a condensed outer inorganic shell of silica. PMID- 17696554 TI - The effect of changing the microstructure of a microemulsion on chemical reactivity. AB - A kinetic study was carried out on various solvolytic reactions in water/ NH4OT /isooctane microemulsions. The NH4OT surfactant is a derivative of the sodium salt of bis(2-ethylhexyl) sulfosuccinate (NaOT or AOT), where the Na+ counterion has been replaced by NH4+. The counterion substitution effects the phase diagram of the system, and therefore, NH4OT-based microemulsions with high water content reaching values of W = 350 (W = [H2O]/[NH4OT]) can be obtained. The presence of high W values suggests a transition in the microemulsion microstructure from water-in-oil (w/o) to oil-in-water (o/w), as was confirmed by conductivity and 1H NMR self-diffusion measurements. The interpretation of the kinetic studies in terms of pseudophase formalism allows us to analyze the effect of the microemulsion on chemical reactivity, regardless of its microstructure. It has been confirmed that the values of the solvolytic rate constants at the interphase of oil-in-water microemulsions are similar to those obtained for aqueous SDS systems, showing that the hydration degree of the interphase of the oil-in-water microemulsions is independent of W. The influence of the surfactant counterion on the solvolytic rate constants was analyzed by comparing HOT-, NaOT-, and NH4OT based microemulsions. An important influence on the rate constants caused by the changes in the structural properties of water has been observed as was confirmed by the water 1H NMR signals. PMID- 17696555 TI - High-density encapsulation of Fe3O4 nanoparticles in lipid vesicles. AB - We report a morphological study of the encapsulation of 12-nm Fe3O4 nanoparticles (NPs) in large unilamellar vesicles of dipalmitoylphosphatidylcholine (DPPC). Preparation was done by reverse-phase evaporation. Phase behavior of the NP-lipid system was studied so that the loading of NPs in vesicles could be maximized. Increasing NP concentration significantly affects the resulting lipid morphology in a manner similar to increasing lipid concentration. Optimal production of high density NP-loaded vesicles (HNLVs) requires temperatures of 50 degrees C, higher than the main phase transition (Tm) of DPPC. The formation of fully enclosed HNLVs requires incubation times of at least hours. PMID- 17696557 TI - Self-directed growth of AlGaAs core-shell nanowires for visible light applications. AB - Al0.37Ga0.63As nanowires (NWs) were grown in a molecular beam epitaxy system on GaAs(111)B substrates. Micro-photoluminescence measurements and energy dispersive X-ray spectroscopy indicated a core--shell structure and Al composition gradient along the NW axis, producing a potential minimum for carrier confinement. The core--shell structure formed during growth as a consequence of the different Al and Ga adatom diffusion lengths. PMID- 17696556 TI - Aging investigation of cobalt ferrite nanoparticles in low pH magnetic fluid. AB - In this study, we report on how surface-passivated and nonpassivated cobalt ferrite nanoparticles (8 nm diameter), suspended as ionic magnetic fluids and aged under low pH conditions, revealed different behavior as far as the time evolution of the iron/cobalt cation distribution, crystal quality, coercivity, and saturation magnetization are concerned. Different techniques were used to perform a detailed study regarding the chemical stability, structural stability, and surface and magnetic properties of the suspended nanoparticles as a function of the aging time. Properties of surface-passivated and nonpassivated nanoparticles were investigated by transmission electron microscopy, X-ray diffraction, atomic absorption spectrometry, magnetic measurements, Raman spectroscopy, and Mossbauer spectroscopy. Our data showed that the employed nanoparticle surface passivation process, besides the formation of an iron-rich surface layer, modifies the nanoparticle core as well, improving the crystal quality while modifying the Fe/Co cation distribution and the nanoparticle dissolution rate profile. Magnetic data showed that the saturation magnetization increases for surface-passivated nanoparticles in comparison to the nonpassivated ones, though coercivity decreases after passivation. These two observations were associated to changes in the cation distribution among the available tetrahedral and octahedral sites. PMID- 17696558 TI - Selective plating for junction delineation in silicon nanowires. AB - The in situ growth of p-n junctions in silicon nanowires enables the fabrication of a variety of nanoscale electronic devices. We have developed a method for selective coating of Au onto n-type segments of silicon nanowire p-n junctions. Selective plating allows for quick verification of the position of p-n junctions along the nanowire using electron microscopy and allows for measurement of segment length. PMID- 17696559 TI - Single-walled carbon nanotubes in the intact organism: near-IR imaging and biocompatibility studies in Drosophila. AB - The ability of near-infrared fluorescence imaging to detect single-walled carbon nanotubes (SWNTs) in organisms and biological tissues has been explored using Drosophila melanogaster (fruit flies). Drosophila larvae were raised on food containing approximately 10 ppm of disaggregated SWNTs. Their viability and growth were not reduced by nanotube ingestion. Near-IR nanotube fluorescence was imaged from intact living larvae, and individual nanotubes in dissected tissue specimens were imaged, structurally identified, and counted to estimate a biodistribution. PMID- 17696560 TI - Parallel fabrication of nanogap electrodes. AB - We have developed a technique for simultaneously fabricating large numbers of nanogaps in a single processing step using feedback-controlled electromigration. Parallel nanogap formation is achieved by a balanced simultaneous process that uses a novel arrangement of nanoscale shorts between narrow constrictions where the nanogaps form. Because of this balancing, the fabrication of multiple nanoelectrodes is similar to that of a single nanogap junction. The technique should be useful for constructing complex circuits of molecular-scale electronic devices. PMID- 17696561 TI - One- and two-photon excited optical ph probing for cells using surface-enhanced Raman and hyper-Raman nanosensors. AB - We demonstrate spatially resolved probing and imaging of pH in live cells by mobile and biocompatible nanosensors using surface-enhanced Raman scattering (SERS) of 4-mercaptobenzoic acid (pMBA) on gold nanoaggregates. Moreover, we also show that this concept of pH nanosensors can be extended to two-photon excitation by using surface-enhanced hyper-Raman scattering (SEHRS). In addition to the advantages of two-photon excitation, the SEHRS sensor enables measurements over a wide pH range without the use of multiple probes. PMID- 17696562 TI - Perylenediimide nanowires and their use in fabricating field-effect transistors and complementary inverters. AB - Perylenetetracarboxyldiimide (PTCDI) nanowires self-assembled from commercially available materials are demonstrated as the n-channel semiconductor in organic field-effect transistors (OFETs) and as a building block in high-performance complementary inverters. Devices based on a network of PTCDI nanowires have electron mobilities and current on/off ratios on the order of 10(-2) cm2/Vs and 10(4), respectively. Complementary inverters based on n-channel PTCDI nanowire transistors and p-channel hexathiapentacene (HTP) nanowire OFETs achieved gains as high as 8. These results demonstrate the first example of the use of one dimensional organic semiconductors in complementary inverters. PMID- 17696563 TI - Wafer-scale assembly of highly ordered semiconductor nanowire arrays by contact printing. AB - Controlled and uniform assembly of "bottom-up" nanowire (NW) materials with high scalability presents one of the significant bottleneck challenges facing the integration of nanowires for electronic applications. Here, we demonstrate wafer scale assembly of highly ordered, dense, and regular arrays of NWs with high uniformity and reproducibility through a simple contact printing process. The assembled NW pitch is shown to be readily modulated through the surface chemical treatment of the receiver substrate, with the highest density approaching approximately 8 NW/mum, approximately 95% directional alignment, and wafer-scale uniformity. Such fine control in the assembly is attained by applying a lubricant during the contact printing process which significantly minimizes the NW-NW mechanical interactions, therefore enabling well-controlled transfer of nanowires through surface chemical binding interactions. Furthermore, we demonstrate that our printing approach enables large-scale integration of NW arrays for various device structures on both rigid silicon and flexible plastic substrates, with a controlled semiconductor channel width ranging from a single NW ( approximately 10 nm) up to approximately 250 microm, consisting of a parallel array of over 1250 NWs and delivering over 1 mA of ON current. PMID- 17696564 TI - Anemia in patients undergoing percutaneous coronary intervention: current issues and future directions. AB - Anemia is common among patients with coronary artery disease (CAD) and portends a higher risk of short- and long-term mortality, major adverse cardiac events, and bleeding complications. Blood transfusion has long been the cornerstone of therapy for anemia; however, its benefit in patients with CAD is controversial and the appropriate threshold for transfusion has been widely debated. In this review, we summarize the studies evaluating the impact of anemia in patients with CAD undergoing percutaneous coronary intervention and address several issues regarding the use of transfusion in anemic patients. In addition, we discuss alternative options for the management of anemia, such as the use of erythropoietin, aqueous oxygen, and hemoglobin-based oxygen carriers. PMID- 17696565 TI - Pharmacologic therapy of chronic heart failure. AB - Over the past 2 decades, investigators have learned more about the pathophysiologic changes that occur in systolic and diastolic dysfunction. Ironically, in some cases, the biologic pathways that have protected the heart during acute dysfunction are the same pathways that cause progressive deleterious effects with chronic activation. In particular, it is the activation of the neurohormonal system that has a significant impact on disease progression. As a result, the neurohormonal system has provided a key target for pharmacologic therapy in patients with heart failure secondary to systolic dysfunction. These targets include the renin-angiotensin-aldosterone system as well as the sympathetic nervous system. Neurohormonal manipulation, however, is often ineffective in the pharmacologic therapy of patients with endstage heart failure, therefore other treatment strategies - including the use of inotropic agents to improve pump function and diuretics to control fluid balance are needed. PMID- 17696566 TI - Direct antithrombins: mechanisms, trials, and role in contemporary interventional medicine. AB - Direct thrombin inhibitors have several potential advantages over indirect thrombin inhibitors such as heparin. Bivalirudin, a bivalent direct thrombin inhibitor, is most commonly used in clinical practice and has a proven role in contemporary interventional medicine with elective percutaneous coronary intervention (PCI) as well as in patients with non-ST-elevation acute coronary syndrome (NSTEACS). Results from well-controlled clinical trials have shown that bivalirudin is associated with an approximate 50% reduction in major bleeding while having similar effects on incidence of death and myocardial infarction (MI) compared with herapin or enoxaparin and glycoprotein IIb/IIIa inhibitors. Bivalirudin has been successfully used in off- and on-pump cardiac surgery. Argatroban is the most evaluated among the univalent direct thrombin inhibitors inhibiting only the catalytic site of thrombin. It has been associated with similar rates of major bleeding compared with heparin in patients with acute MI receiving either streptokinase or alteplase with no effects on clinical endpoints. In a meta-analysis of 11 randomised trials where direct thrombin inhibitors (hirudin, bivalirudin, argatroban, efegatan or inogatran) were compared with unfractionated heparin in >35,000 patients with ST-elevation MI (STEMI) or NSTEACS there was no mortality difference between treatment groups but the incidence of MI at 30 days was significantly reduced in patients treated with direct thrombin inhibitors compared with heparin (4.7% vs 5.3%; p < 0.004). The role of direct thrombin inhibitors in both primary angioplasty for STEMI and angioplasty after fibrinolytic therapy needs to be established. Overall, the efficacy and improved safety profile make bivalirudin an attractive first-line anticoagulant for elective PCI and in patients with NSTEACS undergoing an invasive strategy. PMID- 17696567 TI - Metabolic syndrome: cardiovascular risk assessment and management. AB - The metabolic syndrome (MetS) is a clustering of risk factors known to promote or increase the risk for development of diabetes mellitus and cardiovascular disease (CVD). Approximately one-third of the adult population of developed countries can be categorized as having MetS by different definitions. MetS, even in the absence of diabetes mellitus, is associated with an increased risk of CVD and total mortality. Those with diabetes mellitus are considered a cardiovascular risk equivalent and warrant aggressive management of underlying risk factors to optimize prevention of CVD. Initial evaluation of coronary heart disease risk involves global risk estimation using Framingham or other algorithms for risk prediction. Consideration of screening for novel risk factors such as C-reactive protein, as well as subclinical atherosclerosis (from carotid ultrasound, computed tomography, or ankle-brachial index), can further refine the estimation of future CVD risk. The presence of subclinical atherosclerosis or elevated levels of C-reactive protein can potentially modify recommended treatment goals for lipid and other cardiovascular risk factors. The American Heart Association and US National Heart Lung and Blood Institute have released guidelines for the clinical management of MetS, which focus on lifestyle management for abdominal obesity and physical inactivity, and clinical management of atherogenic dyslipidemia, elevated BP, elevated glucose, and prothrombotic state. PMID- 17696568 TI - Impact of weight-loss medications on the cardiovascular system: focus on current and future anti-obesity drugs. AB - Overweight and obesity have been rising dramatically worldwide and are associated with numerous co-morbidities such as cardiovascular disease (CVD), type 2 diabetes mellitus, hypertension, certain cancers, and sleep apnea. In fact, obesity is an independent risk factor for CVD and CVD risks have also been documented in obese children. The majority of overweight and obese patients who achieve a significant short-term weight loss do not maintain their lower bodyweight in the long term. This may be due to a lack of intensive counseling and support from a facilitating environment including dedicated healthcare professionals such as nutritionists, kinesiologists, and behavior specialists. As a result, there has been a considerable focus on the role of adjunctive therapy such as pharmacotherapy for long-term weight loss and weight maintenance. Beyond an unfavorable risk factor profile, overweight and obesity also impact upon heart structure and function. Since the beginning, the quest for weight loss drugs has encountered warnings from regulatory agencies and the withdrawal from the market of efficient but unsafe medications. Fenfluramine was withdrawn from the market because of unacceptable pulmonary and cardiac adverse effects. Nevertheless, there is extensive research directed at the development of new anti-obesity compounds. The effect of these molecules on CVD risk factors has been studied and reported but information regarding their impact on the cardiovascular system is sparse. Thus, instead of looking at the benefit of weight loss on metabolism and risk factor management, this article discusses the impact of weight loss medications on the cardiovascular system. The potential interaction of available and potential new weight loss drugs with heart function and structure is reviewed. PMID- 17696569 TI - Incremental effect of clopidogrel on important outcomes in patients with cardiovascular disease: a meta-analysis of randomized trials. AB - OBJECTIVES: To quantify the impact of clopidogrel plus aspirin on the individual outcomes of death, myocardial infarction, or stroke in patients with established cardiovascular disease, or in patients with multiple risk factors for vascular disease. BACKGROUND: Randomized trials have demonstrated a reduction in composite outcomes when clopidogrel is added to aspirin therapy in patients with coronary artery disease; however, the magnitude of benefit on individual outcomes is unknown. METHODS: We conducted a meta-analysis on randomized, controlled trials that compared aspirin plus clopidogrel with aspirin plus placebo for the treatment of coronary artery disease. RESULTS: This analysis included five randomized trials (CURE, CREDO, CLARITY, COMMIT, and CHARISMA) in 79 624 patients. The incidence of all-cause mortality was 6.3% in the aspirin plus clopidogrel group versus 6.7% in the aspirin group (odds ratio [OR] 0.94; 95% CI 0.89, 0.99; p = 0.026). The incidence of myocardial infarction was 2.7% and 3.3% (OR 0.82; 95% CI 0.75, 0.89; p < 0.0001), and stroke was 1.2% and 1.4% (OR 0.82; 95% CI 0.73, 0.93; p = 0.002). Similarly, the incidence of major bleeding was 1.6% and 1.3% (OR 1.26; 95% CI 1.11, 1.41; p < 0.0001), and fatal bleeding was 0.28% and 0.27% (OR 1.04; 95% CI 0.76, 1.43; p = 0.79). CONCLUSION: The addition of clopidogrel to aspirin results in a small reduction in all-cause mortality in patients with ST-elevation myocardial infarction and a modest reduction in myocardial infarction and stroke in patients with cardiovascular disease. The overall incidence of major bleeding however is increased, although there is no excess of fatal bleeds or hemorrhagic strokes. PMID- 17696570 TI - Should we encourage over-the-counter statins? A population perspective for coronary heart disease prevention. AB - BACKGROUND: Prescribed statin therapy has contributed to a dramatic reduction in primary and secondary coronary heart disease (CHD). In the UK, simvastatin is currently available without prescription; however, the US FDA rejected an application for nonprescription lovastatin in 2005. OBJECTIVE AND METHODS: We used population impact measures for three hypothetical levels of CHD risk to estimate the number of CHD events that would be prevented in the US over 5 years under three scenarios: (i) prescription-only regulations; (ii) approval of over the-counter (OTC) statins; and (iii) implementation of lifestyle interventions. RESULTS: For people at very low risk of CHD, 429,299 CHD events could be prevented by the availability of OTC statins and 560,243 CHD events could be prevented among this group by implementing lifestyle interventions. For those at moderate risk of CHD, 244,388 CHD events could be prevented by OTC statins compared with 318 866 by lifestyle interventions. For people at high risk of CHD, prescription statins could prevent 374,897 CHD events over the next 5 years. CONCLUSIONS: Provision of OTC statins to US adults at low or moderate risk of CHD would have a greater impact on CHD prevention than providing prescription statins for those at high risk of CHD. Provision of OTC statins alongside lifestyle interventions among those at low or moderate risk of CHD could substantially reduce the number of CHD events in the population. PMID- 17696571 TI - Conceptual and methodological issues in the design of clinical trials of antipsychotics for the treatment of schizophrenia. AB - Schizophrenia is one of the most severe and disabling psychiatric disorders. Antipsychotic drugs offer considerable benefits in controlling symptoms and preventing relapse. The strategy for the present review of clinical trials was to ask 'What are the features of schizophrenia and the existing treatments of the illness that have implications for future clinical trials'? Six key facts were identified.First, schizophrenia is genetically 'complex'. Trials may benefit from designs including genetically related illnesses, by focussing on cross-cutting aspects of the phenotype such as psychosis or cognitive dysfunction, and by collecting information on possible moderators and mediators of treatment response.Second, schizophrenia affects multiple neurotransmitter systems. Multiple signalling pathways may need to be considered, with different time courses of response. Outcome measures from clinical trials could be collected at more frequent intervals, particularly in the early phase of response.Third, the clinical features used to define the illness are a mix of symptoms and social occupational dysfunction, yet treatment response is often defined only by changes in symptoms. Multiple measures of functioning need to be collected at baseline and at the endpoint of trials. Consensus definitions for response, remission, relapse, recovery and recurrence need to be developed.Fourth, schizophrenia is often highly disabling. Linking treatment response in clinical trials to measures of quality-adjusted life-years will allow comparison with other medical illnesses using common metrics.Fifth, the general health and care of individuals with schizophrenia is often poor. 'Complex' interventions, which include, but are not limited to, antipsychotic medications, need to be designed and tested for the problems facing these patients.Finally, large gaps exist between clinical trials, practice guidelines and patterns of practice. Trials need to be designed to investigate widely used approaches such as antipsychotic polypharmacy, where actual practice diverges from evidence-based guidelines. PMID- 17696572 TI - Neurogenic actions of atypical antipsychotic drugs and therapeutic implications. AB - Brain imaging and postmortem studies have reported a reduction in the volume of discrete brain regions, as well as cellular abnormalities in schizophrenic patients. In addition, basic research studies have demonstrated effects of antipsychotic drugs on cell morphology and number. Of particular interest is adult neurogenesis, which has been linked to cognitive and memory improvements, and is also associated with the behavioural actions of antidepressants. While the action of antidepressant treatment is restricted mainly to the hippocampus, long term administration of antipsychotics is reported to increase neurogenesis in the subventricular zone (SVZ), as well as the subgranular zone (SGZ) of the hippocampus. In addition, antipsychotic drugs increase the proliferation of non neuronal cell types in the prefrontal cortex and could thereby influence the function of this brain region. Typical and atypical antipsychotic drugs differentially regulate neurogenesis in the SVZ and SGZ. Although the therapeutic relevance remains speculative, the results are consistent with the hypothesis that the actions of antipsychotic agents could be mediated, in part, by increased proliferation of neuronal as well as glial cells. Additional animal studies and postmortem analyses are required to further test this possibility and to investigate the relevance of this work in the pathophysiology and treatment of schizophrenia. PMID- 17696573 TI - Bipolar II disorder : epidemiology, diagnosis and management. AB - Bipolar II disorder (BP-II) is defined, by DSM-IV, as recurrent episodes of depression and hypomania. Hypomania, according to DSM-IV, requires elevated (euphoric) and/or irritable mood, plus at least three of the following symptoms (four if mood is only irritable): grandiosity, decreased need for sleep, increased talking, racing thoughts, distractibility, overactivity (an increase in goal-directed activity), psychomotor agitation and excessive involvement in risky activities. This observable change in functioning should not be severe enough to cause marked impairment of social or occupational functioning, or to require hospitalisation. The distinction between BP-II and bipolar I disorder (BP-I) is not clearcut. The symptoms of mania (defining BP-I) and hypomania (defining BP II) are the same, apart from the presence of psychosis in mania, and the distinction is based on the presence of marked impairment associated with mania, i.e. mania is more severe and may require hospitalisation. This is an unclear boundary that can lead to misclassification; however, the fact that hypomania often increases functioning makes the distinction between mania and hypomania clearer. BP-II depression can be syndromal and subsyndromal, and it is the prominent feature of BP-II. It is often a mixed depression, i.e. it has concurrent, usually subsyndromal, hypomanic symptoms. It is the depression that usually leads the patient to seek treatment.DSM-IV bipolar disorders (BP-I, BP II, cyclothymic disorder and bipolar disorder not otherwise classified, which includes very rapid cycling and recurrent hypomania) are now considered to be part of the 'bipolar spectrum'. This is not included in DSM-IV, but is thought to also include antidepressant/substance-associated hypomania, cyclothymic temperament (a trait of highly unstable mood, thinking and behaviour), unipolar mixed depression and highly recurrent unipolar depression.BP-II is underdiagnosed in clinical practice, and its pharmacological treatment is understudied. Underdiagnosis is demonstrated by recent epidemiological studies. While, in DSM IV, BP-II is reported to have a lifetime community prevalence of 0.5%, epidemiological studies have instead found that it has a lifetime community prevalence (including the bipolar spectrum) of around 5%. In depressed outpatients, one in two may have BP-II. The recent increased diagnosing of BP-II in research settings is related to several factors, including the introduction of the use of semi-structured interviews by trained research clinicians, a relaxation of diagnostic criteria such that the minimum duration of hypomania is now less than the 4 days stipulated by DSM-IV, and a probing for a history of hypomania focused more on overactivity (increased goal-directed activity) than on mood change (although this is still required for a diagnosis of hypomania). Guidelines on the treatment of BP-II are mainly consensus based and tend to follow those for the treatment of BP-I, because there have been few controlled studies of the treatment of BP-II. The current, limited evidence supports the following lines of treatment for BP-II. Hypomania is likely to respond to the same agents useful for mania, i.e. mood-stabilising agents such as lithium and valproate, and the second-generation antipsychotics (i.e. olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole). Hypomania should be treated even if associated with overfunctioning, because a depression often soon follows hypomania (the hypomania-depression cycle). For the treatment of acute BP-II depression, two controlled studies of quetiapine have not found clearcut positive effects. Naturalistic studies, although open to several biases, have found antidepressants in acute BP-II depression to be as effective as in unipolar depression; however, one recent large controlled study (mainly in patients with BP-I) has found antidepressants to be no more effective than placebo. Results from naturalistic studies and clinical observations on mixed depression, while in need of replication in controlled studies, indicate that antidepressants may worsen the concurrent intradepression hypomanic symptoms. The only preventive treatment for both depression and hypomania that is supported by several, albeit older, controlled studies is lithium. Lamotrigine has shown some efficacy in delaying depression recurrences, but there have also been several negative unpublished studies of the drug in this indication. PMID- 17696575 TI - Extended-release formulations for the treatment of epilepsy. AB - This review analyses the concept of extended-release (ER) formulations in epilepsy and evaluates ER formulations of carbamazepine, valproic acid and a modified-release (MR) formulation of oxcarbazepine. ER formulations are usually designed to reduce dose frequency and maintain relatively constant or flat plasma drug concentration. It is questionable whether flat plasma concentrations of an antiepileptic drug (AED) improve antiepileptic efficacy compared with fluctuating plasma concentrations. More certainly, they minimise concentration-related adverse effects, and the dosing flexibility and consistency of plasma concentrations may simplify the management of antiepileptic drug therapy. Neurologists would like ER formulations that can be administered once- and/or twice-daily to tailor therapy for the individual patient; however, switching dosage schedules from multiple dosages per day to once daily, although more convenient, will not generally improve therapeutic coverage (maintenance of effective drug concentration in biological fluids and tissue). Pharmacokinetically, the impact of a missed dose is greater the larger the dose and the less frequent the administration. Therefore, the risk of breakthrough seizure is higher during AED once-daily administration than twice-daily administration. Consequently, the increased compliance observed with fewer dosages per day should be weighed against the impact or forgiveness of omitted dose(s) and the shorter 'forgiveness' period associated with once-daily administration. Currently, the trend is to treat patients with epilepsy with ER formulations because of the better compliance, convenience and flat plasma concentration versus time curve. Thus, it seems that the term 'flatter is better' for AED plasma profiles has precipitated in the last 10-15 years among neurologists and epilepsy caregivers, and is being promoted by marketing forces of pharmaceutical companies. Data from the literature support the trend to treat epileptic patients with twice-daily administration of the existing ER formulations of valproic acid and carbamazepine, and oxcarbazepine-MR; however, the author of this article is not convinced that these ER formulations can guarantee a complete therapeutic coverage throughout the 24-hour dosing interval following once-daily administration. Epilepsy is a single-episode disease, and the convenience and possible better compliance associated with once-daily administration must be weighed against the shorter 'forgiveness' period and possible higher risk of breakthrough seizure due to sub-therapeutic plasma levels and/or omitted doses. Data suggest just a small difference in compliance between once- and twice-daily administration, with no significant difference in efficacy. Therefore, the increased compliance following once-daily administration may be counter-productive in minimising the occurrence of sub-therapeutic drug concentrations. Weighing up the advantages and disadvantages for once- versus twice-daily administration of ER formulations in epilepsy leads to a conclusion in favour of twice-daily administration. PMID- 17696576 TI - Clinical impact of adjuvant chemotherapy in glioblastoma multiforme : a meta analysis. AB - BACKGROUND: A meta-analysis of chemotherapy for glioblastoma multiforme (GBM) was performed. We sought to update prior analyses by focusing exclusively on GBM, including new trials of novel treatments, assessing effectiveness of individual treatment categories and presenting data in a clinically useful format. METHODS: A search of MEDLINE and EMBASE was conducted for randomised controlled trials of chemotherapy in GBM. RESULTS: Relative risks (RRs) for survival in 16 trials comparing chemotherapy with no chemotherapy were 1.18 (95% CI 1.08, 1.30) at 6 months, 1.53 (95% CI 1.26, 1.86) at 12 months and 2.12 (95% CI 1.60, 2.80) at 24 months. Nitrosourea compounds, local therapy (e.g. carmustine [1,3-bis [2 chloroethyl]-1-nitrosourea] wafers) and temozolomide were all more effective than no chemotherapy. Absolute increases in survival at 6, 12 and 24 months were 11%, 8% and 1%, respectively, for nitrosourea compounds; 8%, 24% and 5%, respectively, for local therapy; and 4%, 15% and 17%, respectively, for temozolomide. Efficacy of local therapy and temozolomide peaked at 12 and 18 months, respectively. After 2 years, nitrosourea compounds no longer provided clinically relevant benefit (number needed-to-treat [NNT] = 100; effect size [ES] = 0.17 SD), local therapy had diminishing returns (NNT = 20) that remained clinically relevant (ES = 0.71 SD) and temozolomide continued to show good efficacy (NNT = 5.9; ES = 0.74 SD). Survival was not significantly improved with multi-agent versus single-agent nitrosourea-based therapy in five trials: 6-month RR 0.91 (95% CI 0.71, 1.16); 24 month RR 1.33 (95% CI 0.72, 2.46). CONCLUSION: Although nitrosourea compounds, local therapy and temozolomide are all effective in the treatment of GBM, local therapy and temozolomide may be associated with greater response, with clinically significant benefits extending to 24 months. The timing of peak benefits of local and temozolomide therapy suggests this combination may be more effective than single-agent chemotherapy and warrants further study. PMID- 17696574 TI - Diagnosis and treatment of agoraphobia with panic disorder. AB - Agoraphobia with panic disorder is a phobic-anxious syndrome where patients avoid situations or places in which they fear being embarrassed, or being unable to escape or get help if a panic attack occurs. During the last half-century, agoraphobia has been thought of as being closely linked to the recurring panic attack syndrome, so much so that in most cases it appears to be the typical development or complication of panic disorder. Despite the high prevalence of agoraphobia with panic disorder in patients in primary-care settings, the condition is frequently under-recognised and under-treated by medical providers. Antidepressants have been demonstrated to be effective in preventing panic attacks, and in improving anticipatory anxiety and avoidance behaviour. These drugs are also effective in the treatment of the frequently coexisting depressive symptomatology. Among antidepressant agents, SSRIs are generally well tolerated and effective for both anxious and depressive symptomatology, and these compounds should be considered the first choice for short-, medium- and long-term pharmacological treatment of agoraphobia with panic disorder. The few comparative studies conducted to date with various SSRIs reported no significant differences in terms of efficacy; however, the SSRIs that are less liable to produce withdrawal symptoms after abrupt discontinuation should be considered the treatments of first choice for long-term prophylaxis. Venlafaxine is not sufficiently studied in the long-term treatment of panic disorder, while TCAs may be considered as a second choice of treatment when patients do not seem to respond to or tolerate SSRIs. High-potency benzodiazepines have been shown to display a rapid onset of anti-anxiety effect, having beneficial effects during the first few days of treatment, and are therefore useful options for short-term treatment; however, these drugs are not first-choice medications in the medium and long term because of the frequent development of tolerance and dependence phenomena. Cognitive-behavioural therapy is the best studied non-pharmacological approach and can be applied to many patients, depending on its availability. PMID- 17696577 TI - Gold standards in pharmacovigilance: the use of definitive anecdotal reports of adverse drug reactions as pure gold and high-grade ore. AB - Anecdotal reports of adverse drug reactions are generally regarded as being of poor evidential quality. This is especially relevant for postmarketing drug safety surveillance, which relies heavily on spontaneous anecdotal reports. The numerous limitations of spontaneous reports cannot be overemphasised, but there is another side to the story: these datasets also contain anecdotal reports that can be considered to describe definitive adverse reactions, without the need for further formal verification. We have previously defined four categories of such adverse reactions: (i) extracellular or intracellular tissue deposition of the drug or a metabolite; (ii) a specific anatomical location or pattern of injury; (iii) physiological dysfunction or direct tissue damage demonstrable by physicochemical testing; and (iv) infection, as a result of the administration of an infective agent as the therapeutic substance or because of demonstrable contamination. In this article, we discuss the implications of these definitive ('between-the-eyes') adverse effects for pharmacovigilance. PMID- 17696578 TI - Safety profile of meropenem: an updated review of over 6,000 patients treated with meropenem. AB - Meropenem is a broad-spectrum carbapenem antibacterial with potent antimicrobial activity against a broad range of Gram-negative, Gram-positive and anaerobic bacteria. The second parenteral carbapenem to be introduced worldwide, meropenem has been in clinical use since 1994. Two previous safety reviews have established that meropenem has a favourable and acceptable safety profile. This new review was conducted after the approval of meropenem in the US in 2005 for the treatment of patients with complicated skin and skin-structure infections, in addition to the previously approved indications of intra-abdominal infections and paediatric bacterial meningitis. The analysis includes the clinical trial data from the previous safety reviews, updated with expanded experience across a number of serious bacterial infections, including a large international study in patients with skin or skin-structure infections and further experience in patients with intra-abdominal infections and bacterial meningitis. A total of 6154 patients with 6308 meropenem exposures were compared with 4483 patients treated with comparator agents (4593 exposures), and the paediatric population base for which safety data are available has doubled to over 1000 patients. The data presented reinforce the favourable safety profile of meropenem. In general, the incidence and pattern of adverse events occurring with meropenem were similar to those of the first carbapenem, imipenem/cilastatin, and to those of the cephalosporin- and clindamycin-based regimens to which it had been compared. The most common adverse events reported for meropenem were diarrhoea (2.5%), rash (1.4%) and nausea/vomiting (1.2%). No adverse event occurred in more than 3% of patient exposures to meropenem, indicating a low overall frequency of adverse events as well as excellent gastrointestinal tolerability. Furthermore, no unexpected adverse events were identified, and the very low incidence of seizures in patients with meningitis was not considered to be drug related. In infections other than meningitis, the incidence of seizures considered by investigators to be related to meropenem treatment was 0.07%. In the new studies that updated the earlier safety data, no new cases of drug-related seizure were reported for any treatment or patient group (meningitis/non-meningitis infections). In conclusion, meropenem is well tolerated and has good CNS and gastrointestinal tolerability when used for the treatment of serious bacterial infections in a wide range of adult and paediatric patient populations. PMID- 17696579 TI - Physician response to patient reports of adverse drug effects: implications for patient-targeted adverse effect surveillance. AB - OBJECTIVE: Using a patient targeted survey, we sought to assess patient representations of how physicians responded when patients presented with possible adverse drug reactions (ADRs). As a demonstration case, we took one widely prescribed drug class, the HMG-CoA reductase inhibitors ('statins'). This information was used to assess whether a patient-targeted ADR surveillance approach may complement provider reporting, potentially fostering identification of additional patients with possible or probable ADRs. METHODS: A total of 650 adult patients taking statins with self-reported ADRs completed a survey. Depending on the problems reported, some patients completed additional surveys specific to the most commonly cited statin ADRs: muscle, cognitive or neuropathy related. Patients were asked to report drug, dose, ADR character, time course of onset with drug, recovery with discontinuation, recurrence with rechallenge, quality-of-life impact, and interactions with their physician in relation to the perceived ADR. This paper focuses on patients' representation of the doctor patient interaction and physicians' attribution, when patients report perceived ADRs. RESULTS: Eighty-seven percent of patients reportedly spoke to their physician about the possible connection between statin use and their symptom. Patients reported that they and not the doctor most commonly initiated the discussion regarding the possible connection of drug to symptom (98% vs 2% cognition survey, 96% vs 4% neuropathy survey, 86% vs 14% muscle survey; p < 10( 8) for each). Physicians were reportedly more likely to deny than affirm the possibility of a connection. Rejection of a possible connection was reported to occur even for symptoms with strong literature support for a drug connection, and even in patients for whom the symptom met presumptive literature-based criteria for probable or definite drug-adverse effect causality. Assuming that physicians would not likely report ADRs in these instances, these patient-submitted ADR reports suggest that targeting patients may boost the yield of ADR reporting systems. CONCLUSIONS: Since low reporting rates are considered to contribute to delays in identification of ADRs, findings from this study suggest that additional putative cases may be identified by targeting patients as reporters, potentially speeding recognition of ADRs. PMID- 17696580 TI - Allergic reactions to medicines derived from Pelargonium species. AB - Pelargonium (Pelargonium sidoides DC and P. reniforme Curtis) is reported to have immune modulating properties and antibacterial activity, and Pelargonium extracts have been used for the treatment of respiratory tract and gastrointestinal infections. Introduced in the early 1980s in Germany, Umckaloabo (ISO Arzneimittel), an ethanolic extract of the roots of P. sidoides and P. reniforme, was the first Pelargonium-derived product to be commonly used in a country in the EU. According to the Umckaloabo product information, this extract has no known adverse effects. However, there is a theoretical risk of interactions with anticoagulants such as warfarin, and antiplatelet drugs, such as aspirin (acetylsalicylic acid). To date, the Uppsala Monitoring Centre has, through the WHO international pharmacovigilance programme, received 34 case reports of allergic reactions suspected to be associated with the use of Pelargonium extract, all originating from Germany. In a number of these reports, the description and timing of the event was indicative of an acute Coombs and Gell Type I hypersensitivity reaction; two of these patients needed treatment for circulatory failure. So far, the experience of such reactions is limited to Germany. Since Pelargonium-containing herbal products have recently been approved in a number of other countries, the possibility of the occurrence of allergic reactions has become of more general interest and further information regarding these products is needed. PMID- 17696581 TI - A modified prescription-event monitoring study to assess the introduction of Seretide Evohaler in England: an example of studying risk monitoring in pharmacovigilance. AB - INTRODUCTION: Monitoring was required for the introduction of non chlorofluorocarbon (CFC) propellants in metered dose inhalers (MDIs) to ensure that there were no unexpected adverse events due to the new products. A postmarketing surveillance study has been conducted to evaluate the introduction of the MDI Seretide Evohaler (hydrofluoroalkane-134a inhaler containing salmeterol and fluticasone propionate). OBJECTIVES: To summarise the modified prescription-event monitoring (PEM) study conducted to evaluate the introduction of Seretide Evohaler and discuss the relevance of this type of study towards pharmacovigilance risk-management planning. METHODS: Modified PEM methodology was used to examine the introduction of Seretide Evohaler into general practice in England. Patients were identified from the first National Health Service prescriptions dispensed in England for Seretide Evohaler. One postal questionnaire was sent to the prescribing doctor, requesting demographic information, severity of the indication, concomitant medication for this condition, smoking history, event data 3 months prior to and 3 months after the first prescription for Seretide Evohaler and also reason for stopping if it had been stopped. Pregnancies, deaths and selected events were followed up. Incidence density ratios were calculated to compare event rates 3 months prior to and 3 months after the introduction of Seretide Evohaler. A matched cohort analysis examined oral corticosteroid use and hospital admissions between the pre- and post-exposure periods. RESULTS: The cohort comprised 13,464 patients prescribed Seretide Evohaler, with a response rate of 62%. There was no significant difference in the length of courses of oral corticosteroid use when the pre- and post-exposure periods were compared. A matched cohort analysis showed there was no increase in the use of oral corticosteroids (relative risk [RR] 0.95; 95% CI 0.90, 0.99) or hospital admissions in the post-exposure period (RR 0.87; 95% CI 0.73, 1.04). When the number of patients with events were compared for the periods 3 months before and 3 months after exposure, fewer events were reported in the post-exposure period. There were 64 patients who experienced adverse events within an hour of using Seretide Evohaler, including one report of paradoxical bronchospasm and one of myocardial infarction with fatal outcome that were both assessed as possibly related to treatment. DISCUSSION: The results of the study suggest that the introduction of Seretide Evohaler was generally well tolerated. The modified methodology has allowed a comparison of the event rates before and after the introduction of this CFC-free inhaler into general practice. PMID- 17696582 TI - Telithromycin use and spontaneous reports of hepatotoxicity. AB - BACKGROUND AND OBJECTIVE: Recent reports have described cases of telithromycin related hepatotoxicity. The objective of this study is to quantify the effect of telithromycin use on the risk of hepatotoxicity. METHODS: We conducted a spontaneous-report case-control study of hepatotoxicity in telithromycin recipients using reports from the US FDA Adverse Event Reporting System. Reports from between 1 January 2005 and 30 June 2005 were examined. Cases included reports of patients with abnormal liver function tests, hepatocellular damage and hepatic impairment, while patients with reported conditions with similar reporting probabilities were considered as controls. The primary outcome measure of the analysis was the reporting odds ratio (ROR) evaluating the a priori hypothesis that telithromycin use confers an elevated risk of hepatotoxicity relative to other agents. RESULTS: A total of 2219 cases and 20,667 controls were identified. We estimated an ROR for hepatotoxicity associated with telithromycin compared with other agents of 1.82 (95% CI 1.12, 2.96) after controlling for age and gender, approximating an 82% excess risk in users of telithromycin relative to users of other agents. CONCLUSIONS: This analysis is the first to specifically quantify the effect of telithromycin on the risk of hepatotoxicity. Telithromycin use may increase the risk of hepatotoxicity by >80%. Biases inherent in spontaneous reports include under-reporting of events and differential or time varying reporting due to enhanced clinician awareness. Future studies should employ alternative data sources because of the inherent limitations of passive surveillance systems. PMID- 17696583 TI - Incidence of allergic reactions associated with antibacterial use in a large, managed care organisation. AB - BACKGROUND: Data on the incidence of serious allergic reactions to fluoroquinolone antibacterials are mainly derived from spontaneous reports that cannot be used to accurately estimate incidence. METHODS: This study estimated the drug-specific incidence of serious allergic reactions after fluoroquinolone, cephalosporin and phenoxymethylpenicillin potassium exposure, using claims for healthcare services with confirmation through medical record abstraction within a large health insurer database. Cohorts exposed to each antibacterial of interest (moxifloxacin, levofloxacin, ciprofloxacin, gatifloxacin, cephalosporins and penicillin) were identified, and followed for 14 days for anaphylaxis (9th revision of the International Classification of Diseases [ICD-9] code 995.0), other allergic drug reactions (ICD-9 995.2, 995.3) or cardiopulmonary resuscitation. RESULTS: The incidence per 10,000 first dispensings of any allergic diagnosis made in the hospital or emergency department was similar for moxifloxacin (4.3; 95% CI 3.5, 5.3), penicillin (4.7; 95% CI 3.8, 5.7) and ciprofloxacin (5.4; 95% CI 4.4, 6.5). The incidence for moxifloxacin was lower than that for levofloxacin (8.7; 95% CI 7.4, 10.0), gatifloxacin (6.7; 95% CI 5.6, 7.9) and the cephalosporins (7.5; 95% CI 6.3, 8.8). The incidence of anaphylaxis/anaphylactoid reactions after first dispensings was similar for the fluoroquinolones: 0.1 (95% CI 0.0, 0.3) for ciprofloxacin, 0.3 (95% CI 0.1, 0.5) for moxifloxacin, 0.3 (95% CI 0.1, 0.6) for gatifloxacin and 0.5 (95% CI 0.3, 0.9) for levofloxacin; and comparable with that of the cephalosporins (0.2; 95% CI 0.0, 0.4) and penicillin (0.1; 95% CI 0.0, 0.3). CONCLUSIONS: Anaphylactic reactions were rare and their incidence did not differ substantially among the drug groups studied. By determining the occurrence of reactions following defined exposures, these results provide a context for the interpretation of spontaneous reports of allergic reactions. PMID- 17696584 TI - Criteria revision and performance comparison of three methods of signal detection applied to the spontaneous reporting database of a pharmaceutical manufacturer. AB - BACKGROUND AND OBJECTIVE: Several statistical methods exist for detecting signals of potential adverse drug reactions in spontaneous reporting databases. However, these signal-detection methods were developed using regulatory databases, which contain a far larger number of adverse event reports than the databases maintained by individual pharmaceutical manufacturers. Furthermore, the composition and quality of the spontaneous reporting databases differ between regulatory agencies and pharmaceutical companies. Thus, the signal-detection criteria proposed for regulatory use are considered to be inappropriate for pharmaceutical industry use without modification. The objective of this study was to revise the criteria for signal detection to make them suitable for use by pharmaceutical manufacturers. METHODS: A model comprising 40 drugs and 1000 adverse events was constructed based on a spontaneous reporting database provided by a pharmaceutical company and used in a simulation to investigate appropriate criteria for signal detection. In total, 1000 pseudo datasets were generated with this model, and three statistical methods (proportional reporting ratio [PRR], Bayesian Confidence Propagation Neural Network [BCPNN] and multi-item gamma Poisson shrinker [MGPS]) for signal detection were applied to each dataset. The sensitivity and specificity of each method were evaluated using these pseudo datasets. The optimum critical value for signal detection (i.e. the value that achieved the highest sensitivity with 95% specificity) was identified for each method. The optimum values were also examined with the adverse events classified into two categories according to frequency. The three original detection methods and their revised versions were applied to a real pharmaceutical company database to detect 173 known adverse reactions of four drugs. RESULTS: The 1000 pseudo datasets consisted of an average of 81 862 reports and 11,407 drug-event pairs, including 1192 adverse drug reactions. The sensitivities of PRR, BCPNN and MGPS methods were 49%, 45% and 26%, respectively, whereas their specificities were 95%, 99.6% and 99.99%, respectively; these sensitivities were unacceptably low for pharmaceutical manufacturers, whereas the specificities were acceptable. The highest sensitivity for each method, obtained by changing critical values and maintaining specificity at 95%, was 44%, 62% and 62%, respectively. When adverse events were classified into two categories, sensitivities as high as 75% for regular events and 39% for rare events were achieved with the revised BCPNN method. The critical values of the information component minus two standard deviations (IC - 2SD) index of the revised BCPNN method were greater than -0.7 for regular events and greater than -0.6 for rare events. The revised BCPNN method yielded 51% sensitivity and 89% specificity for the real dataset. CONCLUSION: A lower critical value may be needed when signal-detection methodology is applied to the spontaneous reporting databases of pharmaceutical manufacturers. For example, it is recommended that pharmaceutical manufacturers use the BCPNN method with IC - 2SD criteria of greater than -0.7 for regular events and greater than -0.6 for rare events. PMID- 17696585 TI - Drug-induced endocrine and metabolic disorders. PMID- 17696588 TI - Overview on pathophysiology and newer approaches to treatment of peripheral neuropathies. AB - Peripheral neuropathies are extremely heterogeneous nosological entities. One of the most common symptoms is pain, the underlying mechanisms of which are numerous and complex. Inflammation, reparative processes, and anatomical and gene expression alterations lead to chronic pain, the persistence of which is sustained by peripheral and central sensitisation mechanisms. Treatment of peripheral neuropathies is targeted to its symptomatic and aetiological features. For pain relief, several types of drugs may be used, notably antidepressants (e.g. tricyclic antidepressants, selective serotonin reuptake inhibitors, and both serotonin and noradrenaline [norepinephrine] reuptake inhibitors), antiepileptic drugs (e.g. carbamazepine, phenytoin, lamotrigine, valproic acid, gabapentin, topiramate and pregabalin), NSAIDs and opioid analgesics. Aetiological therapy is aimed at modifying the pathophysiological mechanisms underlying the neuropathy, some of which are common in different neuropathic conditions. Certain drugs are known to exert more than one action on different pathophysiological mechanisms. This is the case with acetyl-L-carnitine (ALC), which can be considered both a symptomatic therapy that can be used in any kind of painful neuropathy, and an aetiological therapy, at least in diabetic neuropathy and neuropathies induced by nucleoside reverse transcriptase inhibitors and cancer chemotherapeutic agents. ALC acts via several mechanisms, inducing regeneration of injured nerve fibres, reducing oxidative stress, supporting DNA synthesis in mitochondria, and enhancing nerve growth factor concentrations in neurons. PMID- 17696589 TI - Acetyl-L-carnitine in diabetic polyneuropathy: experimental and clinical data. AB - Diabetic polyneuropathy (DPN) is the most common late complication of diabetes mellitus. The underlying pathogenesis is multifaceted, with partly interrelated mechanisms that display a dynamic course. The mechanisms underlying DPN in type 1 and type 2 diabetes mellitus show overlaps or may differ. The differences are mainly due to insulin deficiency in type 1 diabetes which exacerbates the abnormalities caused by hyperglycaemia. Experimental DPN in rat models have identified early metabolic abnormalities with consequences for nerve conduction velocities and endoneurial blood flow. When corrected, the early functional deficits are usually normalised. On the other hand, if not corrected, they lead to abnormalities in lipid peroxidation and expression of neurotrophic factors which in turn result in axonal, nodal and paranodal degenerative changes with worsening of nerve function. As the structural changes progress, they become increasingly less amendable to metabolic interventions. In the past several years, experimental drugs--such as aldose reductase inhibitors, antioxidants and protein kinase C inhibitors--have undergone clinical trials, with disappointing outcomes. These drugs, targeting a single underlying pathogenetic factor, have in most cases been initiated at the advanced stage of DPN. In contrast, substitution of acetyl-L-carnitine (ALC) or C-peptide in type 1 DPN target a multitude of underlying mechanisms and are therefore more likely to be effective on a broader spectrum of the underlying pathogenesis. Clinical trials utilising ALC have shown beneficial effects on nerve conduction slowing, neuropathic pain, axonal degenerative changes and nerve fibre regeneration, despite relatively late initiation in the natural history of DPN. Owing to the good safety profile of ALC, early initiation of ALC therapy would be justified, with potentially greater benefits. PMID- 17696590 TI - Acetyl-L-carnitine in HIV-associated antiretroviral toxic neuropathy. AB - Nucleoside analogue reverse transcriptase inhibitors (NRTIs), used as part of highly active antiretroviral therapy for the treatment of HIV and AIDS, disrupt neuronal mitochondrial DNA synthesis, resulting in antiretroviral toxic neuropathy (ATN). Acetyl-L-carnitine (ALC) enhances neurotrophic support of sensory neurons, potentially causing symptom relief and nerve regeneration, and in addition has numerous other effects on metabolic function that might be of benefit in such patients.ALC has been given to HIV patients with symptomatic ATN in a number of clinical studies administered either twice daily intramuscularly or as oral sachets or tablets. It has been shown to significantly reduce a variety of validated pain ratings, and is generally safe and well tolerated. Using a measure of neuronal innervation in standardised skin biopsies of the affected area, cutaneous nerve density has been improved by the administration of ALC in subjects with symptomatic ATN and reduced epidermal and dermal innervation, associated with clinical improvement, which was maintained over a 4 year period. Improvements were seen in both the structure and function of small sensory fibres, which were sustained over time whilst subjects received ALC. Other open-label, non-randomised studies have shown similar benefits in patients with ATN in terms of pain reduction over the short term. Further placebo controlled studies of both treatment and prophylaxis have been completed and are under analysis to characterise further the usefulness of this pathogenesis-based therapy for ATN. PMID- 17696591 TI - Acetyl-L-carnitine in neuropathic pain: experimental data. AB - Acetyl-L-carnitine (ALC) has gained clinical interest for its analgesic effect in different forms of neuropathies associated with chronic pain, such as diabetic and HIV-related peripheral neuropathies. The antinociceptive effect of ALC has been confirmed in several experimental models of neuropathic pain, including streptozotocin- and chemotherapy-induced neuropathy, and the sciatic nerve chronic constriction injury model. In these models, prophylactic administration of ALC has proven to be effective in preventing the development of neuropathic pain. In addition, ALC is known to produce a strong antinociceptive effect when given after neuropathic pain has been established. ALC can also improve the function of peripheral nerves by increasing nerve conduction velocity, reducing sensory neuronal loss, and promoting nerve regeneration. Analgesia requires repeated administrations of ALC, suggesting that the drug regulates neuroplasticity across the pain neuraxis. Recent evidence indicates that ALC regulates processes that go beyond its classical role in energy metabolism. These processes involve the activation of muscarinic cholinergic receptors in the forebrain, and an increased expression of type-2 metabotropic glutamate (mGlu2) receptors in dorsal root ganglia neurons. Induction of mGlu2 receptors is mediated by acetylation mechanisms that involve transcription factors of the nuclear factor (NF)-kappaB family. PMID- 17696592 TI - Acetyl-L-carnitine for the treatment of chemotherapy-induced peripheral neuropathy: a short review. AB - Peripheral neurotoxicity is a major complication associated with the use of chemotherapeutic agents such as platinum compounds, taxanes and vinca alkaloids. The neurotoxicity of chemotherapy depends not only on the anticancer agent(s) used, the cumulative dose and the delivery method, but also on the capacity of the nerve to cope with the nerve-damaging process. The sensory and motor symptoms and signs of neurotoxicity are disabling, and have a significant impact on the quality of life of cancer patients. Moreover, the risk of cumulative toxicity may limit the use of highly effective chemotherapeutic agents. Therefore, prophylaxis and treatment of peripheral neurotoxicity secondary to chemotherapy are major clinical issues. Acetyl-L-carnitine (ALC), the acetyl ester of L-carnitine, plays an essential role in intermediary metabolism. Some of the properties exhibited by ALC include neuroprotective and neurotrophic actions, antioxidant activity, positive actions on mitochondrial metabolism, and stabilisation of intracellular membranes. ALC has demonstrated efficacy and high tolerability in the treatment of neuropathies of various aetiologies, including chemotherapy-induced peripheral neuropathy (CIPN). In several experimental settings, the prophylactic administration of ALC prevented the occurrence of peripheral neurotoxicity commonly induced by chemotherapeutic agents. In animal models of CIPN, ALC administration promoted the recovery of nerve conduction velocity, restored the mechanical nociceptive threshold, and induced analgesia by up-regulating the expression of type-2 metabotropic glutamate receptors in dorsal root ganglia. These results, plus the favourable safety profile of ALC in neuropathies of other aetiologies, have led to the effects of ALC on CIPN being investigated in cancer patients. Preliminary results have confirmed the reasonably good tolerability profile and the efficacy of ALC on CIPN. The present studies support the use of ALC in cancer patients with persisting neurotoxicity induced by paclitaxel or cisplatin treatment. PMID- 17696603 TI - Automated discovery of functional generality of human gene expression programs. AB - An important research problem in computational biology is the identification of expression programs, sets of co-expressed genes orchestrating normal or pathological processes, and the characterization of the functional breadth of these programs. The use of human expression data compendia for discovery of such programs presents several challenges including cellular inhomogeneity within samples, genetic and environmental variation across samples, uncertainty in the numbers of programs and sample populations, and temporal behavior. We developed GeneProgram, a new unsupervised computational framework based on Hierarchical Dirichlet Processes that addresses each of the above challenges. GeneProgram uses expression data to simultaneously organize tissues into groups and genes into overlapping programs with consistent temporal behavior, to produce maps of expression programs, which are sorted by generality scores that exploit the automatically learned groupings. Using synthetic and real gene expression data, we showed that GeneProgram outperformed several popular expression analysis methods. We applied GeneProgram to a compendium of 62 short time-series gene expression datasets exploring the responses of human cells to infectious agents and immune-modulating molecules. GeneProgram produced a map of 104 expression programs, a substantial number of which were significantly enriched for genes involved in key signaling pathways and/or bound by NF-kappaB transcription factors in genome-wide experiments. Further, GeneProgram discovered expression programs that appear to implicate surprising signaling pathways or receptor types in the response to infection, including Wnt signaling and neurotransmitter receptors. We believe the discovered map of expression programs involved in the response to infection will be useful for guiding future biological experiments; genes from programs with low generality scores might serve as new drug targets that exhibit minimal "cross-talk," and genes from high generality programs may maintain common physiological responses that go awry in disease states. Further, our method is multipurpose, and can be applied readily to novel compendia of biological data. PMID- 17696604 TI - SimulFold: simultaneously inferring RNA structures including pseudoknots, alignments, and trees using a Bayesian MCMC framework. AB - Computational methods for predicting evolutionarily conserved rather than thermodynamic RNA structures have recently attracted increased interest. These methods are indispensable not only for elucidating the regulatory roles of known RNA transcripts, but also for predicting RNA genes. It has been notoriously difficult to devise them to make the best use of the available data and to predict high-quality RNA structures that may also contain pseudoknots. We introduce a novel theoretical framework for co-estimating an RNA secondary structure including pseudoknots, a multiple sequence alignment, and an evolutionary tree, given several RNA input sequences. We also present an implementation of the framework in a new computer program, called SimulFold, which employs a Bayesian Markov chain Monte Carlo method to sample from the joint posterior distribution of RNA structures, alignments, and trees. We use the new framework to predict RNA structures, and comprehensively evaluate the quality of our predictions by comparing our results to those of several other programs. We also present preliminary data that show SimulFold's potential as an alignment and phylogeny prediction method. SimulFold overcomes many conceptual limitations that current RNA structure prediction methods face, introduces several new theoretical techniques, and generates high-quality predictions of conserved RNA structures that may include pseudoknots. It is thus likely to have a strong impact, both on the field of RNA structure prediction and on a wide range of data analyses. PMID- 17696605 TI - Helicobacter pylori evolution: lineage- specific adaptations in homologs of eukaryotic Sel1-like genes. AB - Geographic partitioning is postulated to foster divergence of Helicobacter pylori populations as an adaptive response to local differences in predominant host physiology. H. pylori's ability to establish persistent infection despite host inflammatory responses likely involves active management of host defenses using bacterial proteins that may themselves be targets for adaptive evolution. Sequenced H. pylori genomes encode a family of eight or nine secreted proteins containing repeat motifs that are characteristic of the eukaryotic Sel1 regulatory protein, whereas the related Campylobacter and Wolinella genomes each contain only one or two such "Sel1-like repeat" (SLR) genes ("slr genes"). Signatures of positive selection (ratio of nonsynonymous to synonymous mutations, dN/dS = omega > 1) were evident in the evolutionary history of H. pylori slr gene family expansion. Sequence analysis of six of these slr genes (hp0160, hp0211, hp0235, hp0519, hp0628, and hp1117) from representative East Asian, European, and African H. pylori strains revealed that all but hp0628 had undergone positive selection, with different amino acids often selected in different regions. Most striking was a divergence of Japanese and Korean alleles of hp0519, with Japanese alleles having undergone particularly strong positive selection (omegaJ > 25), whereas alleles of other genes from these populations were intermingled. Homology based structural modeling localized most residues under positive selection to SLR protein surfaces. Rapid evolution of certain slr genes in specific H. pylori lineages suggests a model of adaptive change driven by selection for fine-tuning of host responses, and facilitated by geographic isolation. Characterization of such local adaptations should help elucidate how H. pylori manages persistent infection, and potentially lead to interventions tailored to diverse human populations. PMID- 17696606 TI - Mechanisms of firing patterns in fast-spiking cortical interneurons. AB - Cortical fast-spiking (FS) interneurons display highly variable electrophysiological properties. Their spike responses to step currents occur almost immediately following the step onset or after a substantial delay, during which subthreshold oscillations are frequently observed. Their firing patterns include high-frequency tonic firing and rhythmic or irregular bursting (stuttering). What is the origin of this variability? In the present paper, we hypothesize that it emerges naturally if one assumes a continuous distribution of properties in a small set of active channels. To test this hypothesis, we construct a minimal, single-compartment conductance-based model of FS cells that includes transient Na(+), delayed-rectifier K(+), and slowly inactivating d-type K(+) conductances. The model is analyzed using nonlinear dynamical system theory. For small Na(+) window current, the neuron exhibits high-frequency tonic firing. At current threshold, the spike response is almost instantaneous for small d current conductance, gd, and it is delayed for larger gd. As gd further increases, the neuron stutters. Noise substantially reduces the delay duration and induces subthreshold oscillations. In contrast, when the Na(+) window current is large, the neuron always fires tonically. Near threshold, the firing rates are low, and the delay to firing is only weakly sensitive to noise; subthreshold oscillations are not observed. We propose that the variability in the response of cortical FS neurons is a consequence of heterogeneities in their gd and in the strength of their Na(+) window current. We predict the existence of two types of firing patterns in FS neurons, differing in the sensitivity of the delay duration to noise, in the minimal firing rate of the tonic discharge, and in the existence of subthreshold oscillations. We report experimental results from intracellular recordings supporting this prediction. PMID- 17696607 TI - Coronavirus non-structural protein 1 is a major pathogenicity factor: implications for the rational design of coronavirus vaccines. AB - Attenuated viral vaccines can be generated by targeting essential pathogenicity factors. We report here the rational design of an attenuated recombinant coronavirus vaccine based on a deletion in the coding sequence of the non structural protein 1 (nsp1). In cell culture, nsp1 of mouse hepatitis virus (MHV), like its SARS-coronavirus homolog, strongly reduced cellular gene expression. The effect of nsp1 on MHV replication in vitro and in vivo was analyzed using a recombinant MHV encoding a deletion in the nsp1-coding sequence. The recombinant MHV nsp1 mutant grew normally in tissue culture, but was severely attenuated in vivo. Replication and spread of the nsp1 mutant virus was restored almost to wild-type levels in type I interferon (IFN) receptor-deficient mice, indicating that nsp1 interferes efficiently with the type I IFN system. Importantly, replication of nsp1 mutant virus in professional antigen-presenting cells such as conventional dendritic cells and macrophages, and induction of type I IFN in plasmacytoid dendritic cells, was not impaired. Furthermore, even low doses of nsp1 mutant MHV elicited potent cytotoxic T cell responses and protected mice against homologous and heterologous virus challenge. Taken together, the presented attenuation strategy provides a paradigm for the development of highly efficient coronavirus vaccines. PMID- 17696608 TI - Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. AB - Shigella infection, the cause of bacillary dysentery, induces caspase-1 activation and cell death in macrophages, but the precise mechanisms of this activation remain poorly understood. We demonstrate here that caspase-1 activation and IL-1beta processing induced by Shigella are mediated through Ipaf, a cytosolic pattern-recognition receptor of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, and the adaptor protein apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC). We also show that Ipaf was critical for pyroptosis, a specialized form of caspase-1-dependent cell death induced in macrophages by bacterial infection, whereas ASC was dispensable. Unlike that observed in Salmonella and Legionella, caspase-1 activation induced by Shigella infection was independent of flagellin. Notably, infection of macrophages with Shigella induced autophagy, which was dramatically increased by the absence of caspase-1 or Ipaf, but not ASC. Autophagy induced by Shigella required an intact bacterial type III secretion system but not VirG protein, a bacterial factor required for autophagy in epithelial-infected cells. Treatment of macrophages with 3-methyladenine, an inhibitor of autophagy, enhanced pyroptosis induced by Shigella infection, suggesting that autophagy protects infected macrophages from pyroptosis. Thus, Ipaf plays a critical role in caspase-1 activation induced by Shigella independently of flagellin. Furthermore, the absence of Ipaf or caspase-1, but not ASC, regulates pyroptosis and the induction of autophagy in Shigella-infected macrophages, providing a novel function for NLR proteins in bacterial-host interactions. PMID- 17696609 TI - Functional genomics highlights differential induction of antiviral pathways in the lungs of SARS-CoV-infected macaques. AB - The pathogenesis of severe acute respiratory syndrome coronavirus (SARS-CoV) is likely mediated by disproportional immune responses and the ability of the virus to circumvent innate immunity. Using functional genomics, we analyzed early host responses to SARS-CoV infection in the lungs of adolescent cynomolgus macaques (Macaca fascicularis) that show lung pathology similar to that observed in human adults with SARS. Analysis of gene signatures revealed induction of a strong innate immune response characterized by the stimulation of various cytokine and chemokine genes, including interleukin (IL)-6, IL-8, and IP-10, which corresponds to the host response seen in acute respiratory distress syndrome. As opposed to many in vitro experiments, SARS-CoV induced a wide range of type I interferons (IFNs) and nuclear translocation of phosphorylated signal transducer and activator of transcription 1 in the lungs of macaques. Using immunohistochemistry, we revealed that these antiviral signaling pathways were differentially regulated in distinctive subsets of cells. Our studies emphasize that the induction of early IFN signaling may be critical to confer protection against SARS-CoV infection and highlight the strength of combining functional genomics with immunohistochemistry to further unravel the pathogenesis of SARS. PMID- 17696610 TI - Mouse pachytene checkpoint 2 (trip13) is required for completing meiotic recombination but not synapsis. AB - In mammalian meiosis, homologous chromosome synapsis is coupled with recombination. As in most eukaryotes, mammalian meiocytes have checkpoints that monitor the fidelity of these processes. We report that the mouse ortholog (Trip13) of pachytene checkpoint 2 (PCH2), an essential component of the synapsis checkpoint in Saccharomyces cerevisiae and Caenorhabditis elegans, is required for completion of meiosis in both sexes. TRIP13-deficient mice exhibit spermatocyte death in pachynema and loss of oocytes around birth. The chromosomes of mutant spermatocytes synapse fully, yet retain several markers of recombination intermediates, including RAD51, BLM, and RPA. These chromosomes also exhibited the chiasmata markers MLH1 and MLH3, and okadaic acid treatment of mutant spermatocytes caused progression to metaphase I with bivalent chromosomes. Double mutant analysis demonstrated that the recombination and synapsis genes Spo11, Mei1, Rec8, and Dmc1 are all epistatic to Trip13, suggesting that TRIP13 does not have meiotic checkpoint function in mice. Our data indicate that TRIP13 is required after strand invasion for completing a subset of recombination events, but possibly not those destined to be crossovers. To our knowledge, this is the first model to separate recombination defects from asynapsis in mammalian meiosis, and provides the first evidence that unrepaired DNA damage alone can trigger the pachytene checkpoint response in mice. PMID- 17696611 TI - SREBP controls oxygen-dependent mobilization of retrotransposons in fission yeast. AB - Retrotransposons are mobile genetic elements that proliferate through an RNA intermediate. Transposons do not encode transcription factors and thus rely on host factors for mRNA expression and survival. Despite information regarding conditions under which elements are upregulated, much remains to be learned about the regulatory mechanisms or factors controlling retrotransposon expression. Here, we report that low oxygen activates the fission yeast Tf2 family of retrotransposons. Sre1, the yeast ortholog of the mammalian membrane-bound transcription factor sterol regulatory element binding protein (SREBP), directly induces the expression and mobilization of Tf2 retrotransposons under low oxygen. Sre1 binds to DNA sequences in the Tf2 long terminal repeat that functions as an oxygen-dependent promoter. We find that Tf2 solo long terminal repeats throughout the genome direct oxygen-dependent expression of adjacent coding and noncoding sequences, providing a potential mechanism for the generation of oxygen-dependent gene expression. PMID- 17696612 TI - The role of AtMUS81 in interference-insensitive crossovers in A. thaliana. AB - MUS81 is conserved among plants, animals, and fungi and is known to be involved in mitotic DNA damage repair and meiotic recombination. Here we present a functional characterization of the Arabidopsis thaliana homolog AtMUS81, which has a role in both mitotic and meiotic cells. The AtMUS81 transcript is produced in all tissues, but is elevated greater than 9-fold in the anthers and its levels are increased in response to gamma radiation and methyl methanesulfonate treatment. An Atmus81 transfer-DNA insertion mutant shows increased sensitivity to a wide range of DNA-damaging agents, confirming its role in mitotically proliferating cells. To examine its role in meiosis, we employed a pollen tetrad based visual assay. Data from genetic intervals on Chromosomes 1 and 3 show that Atmus81 mutants have a moderate decrease in meiotic recombination. Importantly, measurements of recombination in a pair of adjacent intervals on Chromosome 5 demonstrate that the remaining crossovers in Atmus81 are interference sensitive, and that interference levels in the Atmus81 mutant are significantly greater than those in wild type. These data are consistent with the hypothesis that AtMUS81 is involved in a secondary subset of meiotic crossovers that are interference insensitive. PMID- 17696613 TI - Global dissemination of a single mutation conferring white pericarp in rice. AB - Here we report that the change from the red seeds of wild rice to the white seeds of cultivated rice (Oryza sativa) resulted from the strong selective sweep of a single mutation, a frame-shift deletion within the Rc gene that is found in 97.9% of white rice varieties today. A second mutation, also within Rc, is present in less than 3% of white accessions surveyed. Haplotype analysis revealed that the predominant mutation originated in the japonica subspecies and crossed both geographic and sterility barriers to move into the indica subspecies. A little less than one Mb of japonica DNA hitchhiked with the rc allele into most indica varieties, suggesting that other linked domestication alleles may have been transferred from japonica to indica along with white pericarp color. Our finding provides evidence of active cultural exchange among ancient farmers over the course of rice domestication coupled with very strong, positive selection for a single white allele in both subspecies of O. sativa. PMID- 17696615 TI - Quality of life after balloon angioplasty versus stent implantation in the superficial femoral artery: findings from a randomized controlled trial. AB - PURPOSE: To investigate whether primary nitinol stenting in the superficial femoral artery (SFA) is beneficial to patients' quality of life (QoL). METHODS: One hundred four patients (55 men; mean age 66+/-19 years) with chronic limb ischemia and SFA disease were randomly assigned to primary stent implantation (n=51) or balloon angioplasty (n=53) with optional stenting for a suboptimal angioplasty result (17 of 53). QoL was measured by the SF-36 questionnaire at baseline and at 3, 6, and 12 months post intervention. RESULTS: QoL was significantly improved post intervention and up to 12 months in both treatment groups. Significant inverse associations were observed between QoL parameters and restenosis. Comparing primary stenting (n=51) versus balloon angioplasty with optional stenting (n=53) by the intention to treat, no significant differences in QoL were observed. Analyses of stented patients (n=68) versus balloon angioplasty (n=36) patients, however, demonstrated significantly improved measures of QoL after stenting. CONCLUSION: Endovascular revascularization of SFA disease improves QoL, and restenosis negatively affects QoL outcomes. After stent implantation, whether primary or secondary, QoL was significantly ameliorated compared to balloon angioplasty alone. However, it remains to be proven in larger cohorts whether primary stenting yields a QoL benefit compared to balloon angioplasty with optional secondary stenting. PMID- 17696614 TI - A screen for suppressors of gross chromosomal rearrangements identifies a conserved role for PLP in preventing DNA lesions. AB - Genome instability is a hallmark of cancer cells. One class of genome aberrations prevalent in tumor cells is termed gross chromosomal rearrangements (GCRs). GCRs comprise chromosome translocations, amplifications, inversions, deletion of whole chromosome arms, and interstitial deletions. Here, we report the results of a genome-wide screen in Saccharomyces cerevisiae aimed at identifying novel suppressors of GCR formation. The most potent novel GCR suppressor identified is BUD16, the gene coding for yeast pyridoxal kinase (Pdxk), a key enzyme in the metabolism of pyridoxal 5' phosphate (PLP), the biologically active form of vitamin B6. We show that Pdxk potently suppresses GCR events by curtailing the appearance of DNA lesions during the cell cycle. We also show that pharmacological inhibition of Pdxk in human cells leads to the production of DSBs and activation of the DNA damage checkpoint. Finally, our evidence suggests that PLP deficiency threatens genome integrity, most likely via its role in dTMP biosynthesis, as Pdxk-deficient cells accumulate uracil in their nuclear DNA and are sensitive to inhibition of ribonucleotide reductase. Since Pdxk links diet to genome stability, our work supports the hypothesis that dietary micronutrients reduce cancer risk by curtailing the accumulation of DNA damage and suggests that micronutrient depletion could be part of a defense mechanism against hyperproliferation. PMID- 17696616 TI - Treatment of critical limb ischemia using ultrasound-enhanced thrombolysis (PARES Trial): final results. AB - PURPOSE: To evaluate the safety and performance of ultrasound-enhanced thrombolysis in the treatment of acute thrombotic or embolic occlusion of the lower limb arteries. METHODS: From April 2005 to July 2006, 25 patients (15 men; mean age 64.1 years, range 37-82) presenting with acute (<14 days old) occlusions of the lower limb arteries were treated with local thrombolysis [recombinant tissue plasminogen activator (rtPA)] in a dosage of 1.0 mg/h using the EKOS Lysus Peripheral Catheter System with an ultrasound core. No bolus injection of rtPA was given. The mean occlusion length was 25.1 cm (range 2-70). RESULTS: The technical success rate was 100%. Total clot removal was achieved in 22 (88%) patients after 16.9 hours (range 5-24) using a mean 17 mg (range 5-25) of rtPA. In 8 cases, total clot removal of the main lesion was achieved after 6 hours (6 mg of rtPA). In 1 patient, lysis was stopped after 2.5 hours because of bleeding due a dislocation of the introducer sheath. In 2 cases, total clot removal could not be achieved; these patients were successfully treated with thromboaspiration. At the 1-month follow-up, the treated vessel was still patent in 20 patients. Two reocclusions occurred; 1 was treated with a bypass graft and the other with conservative therapy. There were no cases of amputation or death during follow up. There were no side effects related to rtPA or the catheter system. CONCLUSION: This study demonstrates that local lysis of acute arterial occlusions using the Lysus Peripheral Catheter System is safe and effective. Blood flow is restored quickly. PMID- 17696617 TI - Subintimal angioplasty of infrainguinal arterial occlusions for critical limb ischemia: long-term patency and clinical efficacy. AB - PURPOSE: To evaluate long-term patency and clinical efficacy of subintimal angioplasty (SAP) of occluded infrainguinal arteries 3 years post procedure. METHODS: One hundred eighty-one patients (92 men; median age 79 years) underwent attempted SAP in 193 limbs with occluded infrainguinal arteries during the period 1999 to 2001. Nearly half (83, 46%) of the patients had diabetes. Most (172, 95%) had critical ischemia (Fontaine classification>II). All patients surviving at least 3 years after the procedures were followed in January 2005 with questionnaires, clinical examinations, ankle-brachial index measurements, and duplex ultrasonography. All data were collected prospectively and analyzed retrospectively. RESULTS: The primary technical success in the entire cohort was 77% (148/193). Thirty-day mortality was 10% (19/181); 113 (62%) patients died before the 3-year follow-up. In the 68 (38%) survivors (71 limbs), patency at 49.2 months (IQR 40.8-57.6) was 40% (26/65 limbs imaged by duplex). The TASC classification did not affect technical or clinical outcomes. Forty-six (68%) of the survivors presented with clinical improvement (lower Fontaine classification at postoperative follow-up versus baseline). The limb salvage at >3 years was 86% in the 58 primarily successful SAPs and 38% in the 13 procedures that failed initially. CONCLUSION: SAP is a minimally invasive option for patients with critical limb ischemia. A primary technical success is essential for good clinical outcome and primary technical failure is more devastating than late occlusion. TASC classification and length of the SAP are of poor predictive value. More data are needed to confirm the efficacy of SAP. PMID- 17696618 TI - Duplex sonography versus angiography for assessment of femoropopliteal arterial disease in a "real-world" setting. AB - PURPOSE: To evaluate the agreement of duplex ultrasound (DUS) versus digital subtraction angiography (DSA) for assessment of femoropopliteal arterial disease in a real-world clinical setting. METHODS: Consecutive patients with peripheral artery disease who were scheduled for a percutaneous intervention were included in this retrospective study. During an 18-month period, 491 patients (276 men; median age 73 years, interquartile range 64-81) were enrolled. A peak systolic velocity ratio (PSVR)>2.4 was the optimal cutoff for detecting a >50% stenosis by DSA. Findings of preprocedural DUS in the proximal, middle, and distal ipsilateral superficial femoral artery and in the popliteal segment were analyzed for agreement with preprocedural femoropopliteal DSA using kappa statistics. Only the target limb in each patient was analyzed, for a total of 1964 vascular segments. RESULTS: Agreement for the degree of stenosis in 10% increments was only moderate (weighted kappa 0.67, 95% CI 0.65 to 0.69). Using the PSVR>2.4 cutoff, agreement between DUS and DSA for a >50% stenosis was good (kappa 0.79, 95% CI 0.77 to 0.81). Sensitivity, specificity, positive predictive value, and negative predictive value for correctly detecting a >50% stenosis by DUS were 0.81 (0.78 to 0.84), 0.93 (0.91 to 0.94), 0.84 (0.81 to 0.87), and 0.91 (0.87 to 0.95), respectively. Comparable findings were observed within different patient subgroups. CONCLUSION: Agreement between DUS and DSA in the femoropopliteal segment is only moderate with respect to the absolute degree of stenosis. However, detection of a >50% stenosis can be done with acceptable precision in routine clinical practice using PSVR>2.4 as a threshold. PMID- 17696619 TI - Sirolimus-eluting versus bare-metal low-profile stent for renal artery treatment (GREAT Trial): angiographic follow-up after 6 months and clinical outcome up to 2 years. AB - PURPOSE: To evaluate the patency of sirolimus-eluting stents (SES) compared to bare-metal stents (BMS) in the treatment of atherosclerotic renal artery stenosis (RAS). METHODS: Between November 2001 to June 2003, 105 consecutive symptomatic patients (53 men; mean age 65.7 years) with RAS were treated with either a bare metal (n=52) or a drug-eluting (n=53) low-profile Palmaz-Genesis peripheral stent at 11 centers in a prospective nonrandomized trial. The primary endpoint was the angiographic result at 6 months measured with quantitative vessel analysis by an independent core laboratory. Secondary endpoints were technical and procedural success, clinical patency [no target lesion revascularization (TLR)], blood pressure and antihypertensive drug use, worsening of renal function, and no major adverse events at 1, 6, 12, and 24 months. RESULTS: At 6 months, the overall in stent diameter stenosis for BMS was 23.9%+/-22.9% versus 18.7%+/-15.6% for SES (p=0.39). The binary restenosis rate was 6.7% for SES versus 14.6% for the BMS (p=0.30). After 6 months and 1 year, TLR rate was 7.7% and 11.5%, respectively, in the BMS group versus 1.9% at both time points in the SES group (p=0.21). This rate remained stable up to the 2-year follow-up but did not reach significance due to the small sample. Even as early as 6 months, both types of stents significantly improved blood pressure and reduced antihypertensive medication compared to baseline (p<0.01). After 6 months, renal function worsened in 4.6% of the BMS patients and in 6.9% of the SES group. The rate of major adverse events was 23.7% for the BMS group and 26.8% for the SES at 2 years (p=0.80). CONCLUSION: The angiographic outcome at 6 months did not show a significant difference between BMS and SES. Renal artery stenting with both stents significantly improved blood pressure. Future studies with a larger patient population and longer angiographic follow-up are warranted to determine if there is a significant benefit of drug-eluting stents in treating ostial renal artery stenosis. PMID- 17696620 TI - Highlights of the guidelines for screening of extracranial carotid artery disease: a statement for healthcare professionals from the Multidisciplinary Practice Guidelines Committee of the American Society of Neuroimaging; cosponsored by the Society of Vascular and Interventional Neurology. PMID- 17696621 TI - Angiographic analysis of intravascular thrombus volume in patients with acute ischemic stroke. AB - PURPOSE: To investigate the role that intravascular thrombus volume plays in mechanical thrombectomy and dose-titrated algorithms using pharmaceutical thrombolytic therapies. METHODS: The angiographic studies of 33 consecutive patients (19 women; mean age 66+/-11 years) who underwent endovascular treatment for acute ischemic stroke were reviewed. A double-injection technique was utilized that involved 2 catheters for simultaneous injection of contrast proximal and distal to the thrombus to delineate its boundaries. The thrombus volume was calculated using the formula for cylindrical objects after measuring its length and diameter. RESULTS: The volume of the 36 thrombi measured in the study group was 46+/-59 mm3. The mean length and diameter were 10+/-6 and 2+/-1 mm, respectively. The time between symptom onset and acquisition of angiographic images ranged from 167 to 589 minutes (mean 336+/-109). In a multivariate analysis, thrombus volume was not associated with any recanalization (odds ratio 2.4, 95% CI 0.02-191) after adjusting for initial occlusion grade, time between symptom onset and angiography, and previous intravenous use of thrombolytic agents. Volume capacities for retrieval devices to retain 50% and 75% of the thrombi were estimated as 29.2 mm3 and 55.3 mm3, respectively. CONCLUSION: The large variation in thrombi volume must be considered in designing retrieval devices to optimize their performance. PMID- 17696622 TI - TCD evaluation before and after stenting in patients with severe primary carotid artery stenosis versus restenosis. AB - PURPOSE: To evaluate cerebral hemodynamics before and after carotid angioplasty and stenting (CAS) using transcranial Doppler (TCD). METHODS: Sixty-eight patients (52 men; mean age 69+/-9.5 years) with severe carotid stenosis (83.4%+/ 10.2%) were examined by TCD before and 2 months after CAS. Thirty-two (47%) patients had primary carotid stenosis and 36 (53%) had restenosis after carotid endarterectomy (CEA). A broad TCD protocol was employed to estimate cerebral hemodynamics, including assessment of velocities (V) and asymmetry of cerebral blood flow velocity (CBFV) in the middle cerebral artery, (MCA) anterior cerebral artery (ACA), and basilar artery (BA); the pulsatility indexes; and flow acceleration. RESULTS: Ipsilateral MCA mean velocities before stenting were 46.3+/-12.6 cm/s in the primary stenosis group and 47.1+/-12.3 cm/s in restenosis group; after stenting, the velocities were 53.8+/-12.1 and 52.7+/-9.6 cm/s, respectively (p<0.005 for both groups). MCA asymmetry by Vmean before CAS was higher in the primary stenosis group (27.6%+/-2.4% versus 19.8%+/-2.3%, p<0.05). After stenting, this index was significantly lower in both groups: 16.4%+/-2.4% and 12.3%+/-2.3%, respectively (p<0.0001 for each group). All other TCD parameters improved significantly in both groups after CAS as well (p<0.05), showing the strong hemodynamic effect of this procedure. CONCLUSION: CAS effectively improves cerebral hemodynamics in patients with severe primary and restenosis of the internal carotid artery. PMID- 17696623 TI - CT angiography of stented carotid arteries: comparison with Doppler ultrasonography. AB - PURPOSE: To determine whether computed tomographic angiography (CTA) is a feasible modality for assessing stented carotid arteries and whether in-stent restenosis based on CTA concurs with ultrasonography (US). METHODS: A retrospective review was conducted of 37 follow-up CTA and US images from 27 patients (23 men; median age 70 years, range 56-77) who received 34 nitinol carotid stents. CTA and US images were compared with respect to assessability and percent stenosis. Both visual estimation (>or=50% or not) and the NASCET method were used to determine percent stenosis in CTA images. For US, a determination of >or=50% stenosis was based on peak systolic velocity (>or=200 cm/s) and an internal carotid artery to common carotid artery ratio >or=2.5. Percent stenosis values by CTA were also compared to values (n=7, 21%) determined by catheter angiography. RESULTS: CTA and US images were "totally assessable" in 27 (73%) and 15 (41%), "totally non-assessable" in 0 (0%) and 3 (8%), and "partially assessable" in 10 (27%) and 19 (51%), respectively. Assessability of CTA images was equal to or better than that of US images in 33 (89%). The percent stenoses by CTA and US were comparable in 20 cases. CTA found >or=50% stenosis using the NASCET method in 4 of 20 stents; none of these showed >or=50% stenosis by visual estimation of CTA or by spectral Doppler US. Compared with catheter angiography, CTA overestimated percent stenosis from 34% to 66% (mean 53%). US confirmed 2 angiographically proven restenoses, but CTA identified only 1. CONCLUSION: CTA provides better image quality for stented carotid arteries than US, but it might be inferior to US in determining restenosis in assessable cases. Therefore, CTA is likely to be an alternative to US in cases of non-assessability. A large-scale study including more restenosis cases is warranted to reveal which modality is more reliable for diagnosis of restenosis. PMID- 17696624 TI - Multicenter safety and efficacy analysis of assisted closure after antegrade arterial punctures using the StarClose device. AB - PURPOSE: To evaluate the safety and efficacy of the StarClose device for closure of antegrade punctures following infrainguinal endovascular interventions. METHODS: A retrospective review was conducted of 221 consecutive patients treated with the StarClose device in a 12-month period at 5 centers (4 French and 1 British). Of these, 107 patients (69 men; median age 75 years, range 44-93) were from the UK cohort (111 closures), and 94 patients (75 men; median age 67 years, range 32-95) were from the French cohort (111 closures). Technical success, complication rates, demographic data, medical history, and procedural details were gathered for all patients. Residual bleeding and the requirement for additional manual compression were recorded when the device failed. Clinical evaluation was performed at discharge; color-coded duplex ultrasonography was done in a subset of French patients. RESULTS: The overall technical success rate was 94.6% (210/222; 95% CI 3.1%-9.2%). The results were similar in the 2 cohorts: 95.5% (106/111; 95% CI 1.9%-10.1%) in the UK and 93.7% (104/111; 95% CI 3.1% 12.4%) in France. The 12 failures (5 UK and 7 France) were due to several mechanisms: device failure (n=5), obesity (n=1), groin scarring (n=2), and unexplained (n=4). In 2 failed cases, open surgical closure of the arteriotomy was performed because pressure hemostasis failed. Two pseudoaneurysms were observed: one after immediate failure was successfully treated by prolonged pressure; the other, after apparent success of the device, required surgical therapy. The incidence of serious vascular complication was 1.8% (4/222; 95% CI 0.7%-4.5%); 2 patients from each cohort. CONCLUSION: The StarClose device safely and effectively closes antegrade punctures after infrainguinal endovascular intervention, even in patients who would be considered to be at high risk for puncture-site bleeding. However, a randomized trial would be required to support any definitive recommendations. PMID- 17696625 TI - Rapid pacing for better placing: comparison of techniques for precise deployment of endografts in the thoracic aorta. AB - PURPOSE: To investigate the safety, efficacy, impact on positioning, and neurocognitive outcomes of 3 conceptually different methods of avoiding the "windsock" effect during thoracic stent-graft placement. METHODS: A retrospective review was conducted of 70 patients (48 men; mean age 63 years) who underwent elective or emergency stent-graft placement in the thoracic aorta for various pathologies. Twenty-seven patients (18 men; mean age 64+/-12 years) had stent graft positioning during rapid right ventricular (RV) pacing at 180 to 200 beats per minute. Another 27 patients (18 men; mean age 62+/-12 years) had stent-graft placement under controlled hypotension (25% in 1 (10%); the latter returned to baseline on day 5. At 30 days, 7 (70%) patients had improved CrCl and 3 (30%) remained unchanged. CONCLUSION: TRT is feasible during EVAR in high-risk patients. Further investigation is warranted to determine the safety and efficacy of TRT in preserving renal function during EVAR. PMID- 17696628 TI - Role of the Hardman index in predicting mortality for open and endovascular repair of ruptured abdominal aortic aneurysm. AB - PURPOSE: To correlate the Hardman prognostic index with perioperative mortality in patients undergoing open and endovascular repair of ruptured abdominal aortic aneurysm (rAAA). METHODS: Over a 5-year period, 126 patients (109 men; mean age 74 years, range 51-91) underwent open (n=74) or endovascular (n=52) repair of rAAA in a single unit. Five Hardman factors (age>76 years, history of loss of consciousness, ECG evidence of ischemia, hemoglobin<9.0 g/dL, and serum creatinine>0.19 mmol/L) were assessed, and their association with in-hospital or 30-day mortality was evaluated retrospectively by chi-square or logistic regression analysis. RESULTS: The mortality for open repair was 51.4% (38/74) in comparison to 32.7% (17/52) for the endovascular group (p=0.05). On multivariate analysis, loss of consciousness (p=0.03, OR 2.9, 95% CI 1.1 to 7.5) was the only significant predictor of mortality in both groups. The mortality rates for open repair patients with Hardman scores<2 were 43.5% (20/46) in comparison to 22.9% (8/35) for the endovascular group (p=0.06), whereas mortality rates for patients with scores>or=2 were 64.3% (18/28) and 52.9% (9/17) for the respective groups (p=0.54). CONCLUSION: The Hardman index correlates well with mortality in both the open and endovascular groups. Those with a score<2 have a trend toward better survival following endovascular repair compared to open repair, while this benefit is not obvious in patients with a score>or=2. PMID- 17696629 TI - Impact of randomized trials comparing conventional and endovascular abdominal aortic aneurysm repair on clinical practice. AB - PURPOSE: To report a retrospective study into the effects of trials on clinical decision-making regarding abdominal aortic aneurysm (AAA) patients suitable for both conventional open (OR) and endovascular aneurysm repair (EVAR). METHODS: A questionnaire was sent to 1400 Dutch surgeons and trainees. Interviewees had to choose between OR and EVAR for AAA patients with and without comorbidity. Specifically, their preferences before and after the publication of 2 randomized trials (EVAR-1 and DREAM) were polled. RESULTS: Of the 524 (37%) questionnaires returned, 223 (43%) respondents treated AAA patients. Before publication of the trials, 160 (72%) preferred OR for the patient without comorbidity and 169 (76%) preferred EVAR for the patient with comorbidity. In total, 72 (32%) respondents changed their preference after the trials were published; however, there was no overall major shift. Focusing on the different cases revealed that the OR preference was significantly enhanced for the patient without comorbidity (p<0.01), while the EVAR preference was significantly enhanced for the patient with comorbidity (p<0.05). CONCLUSION: The randomized trials have not induced major overall changes in surgical decision-making for AAA patients suitable for both EVAR and OR. PMID- 17696630 TI - Commentary: impact of EVAR and DREAM trials on clinical practice. PMID- 17696631 TI - Changes in coronary flow reserve following stent implantation in the swine descending thoracic aorta. AB - PURPOSE: To evaluate coronary flow reserve (CFR) changes following stent implantation in the descending thoracic aorta (DTA) of a porcine model. METHODS: Six pigs (3 males; 40 to 44 kg) were anesthetized and kept on mechanical ventilation. A 6-F guiding right Judkins catheter was advanced under fluoroscopy to the right coronary artery, and a pressure wire with a temperature sensor was placed within the vessel lumen at a distance of 4 cm from the ostium. CFR was estimated by the thermodilution method before and after maximal coronary vasodilation with 20 mg of intracoronary papaverine. Aortography was also performed to measure aortic diameter. Subsequently, a self-expanding vascular stent was deployed into the DTA just below the left subclavian artery (LSA), and CFR was measured again. All animals were maintained for 3 weeks; at the end of this period, a further CFR was calculated using the same procedure. RESULTS: The mean aortic diameter below the LSA was 12.15+/-0.15 mm. Following stent deployment, the mean aortic diameter measured at the stented segment was 12.58+/ 0.11 (p=0.001 versus baseline). The mean CFR value was 4.70+/-2.00 before stent implantation, 2.68+/-0.86 immediately after, and 4.05+/-1.15 at 3 weeks after stenting. Accordingly, CFR values were significantly depressed immediately after stent placement compared with baseline (p=0.027). However, CFR values obtained 3 weeks following stent deployment were similar to the initial values (p=0.59). CONCLUSION: Stent deployment in the normal swine DTA produces a significant immediate decrease in CFR, which is attenuated 3 weeks later. The clinical impact of CFR changes following DTA endografting remain to be elucidated. PMID- 17696632 TI - Toward endografting of the ascending aorta: insight into dynamics using dynamic cine-CTA. AB - PURPOSE: To evaluate pulsatility and movement along the ascending thoracic aorta using dynamic electrocardiographically-gated 64-slice cine computed tomographic angiography (CTA). METHODS: Diameter and area change and center of mass (COM) movement of the ascending thoracic aorta was determined per cardiac cycle in 15 patients at surgically relevant anatomical levels: (A) 5 mm distal to the coronary arteries, (B) 5 mm proximal to the innominate artery, and (C) halfway up the ascending aorta. Additionally, COM movement was determined 1 cm (level P) and 2 cm (level Q) distal from the origins of the innominate, left carotid, and left subclavian arteries. Eight gated datasets covering the cardiac cycle were used to reconstruct images at each level perpendicular to the aortic lumen. The distance between important anatomical landmarks was determined. RESULTS: All levels showed significant cardiac cycle-induced diameter and area changes (p<0.001), with the largest pulsatility 5 mm distal to the coronary arteries. Mean maximum diameter changes were (A) 17.4%+/-4.8% (range 7.5%-27.5%), (B) 13.9%+/-3.5% (range 10.6% 25.0%), and (C) 12.9%+/-3.4% (8.3%-19.6%). Mean area changes were (A) 12.7%+/ 5.5% (range 4.3%-21.8%), (B) 7.5%+/-2.0% (range 4.1%-11.0%), and (C) 5.6%+/-2.2% (range 1.9%-11.4%). Mean maximum COM movements were (A) 6.1+/-2.0 mm (range 2.7 9.0), (B) 2.3+/-1.1 mm (range 1.1-5.6), and (C) 3.6+/-1.5 mm (range 1.4-6.5). Mean COM movements of the innominate, left carotid, and left subclavian arteries, respectively, were (P) 1.9+/-0.7 mm (range 0.9-3.7), 2.4+/-0.6 mm (range 1.4 3.3), and 1.9+/-0.6 mm (range 0.8-2.8), and (Q) 1.8+/-0.7 mm (range 0.8-3.5), 1.8+/-0.6 mm (range 0.8-2.7), 1.9+/-0.6 mm (range 1.1-3.4). CONCLUSION: The dynamics of the ascending thoracic aorta and the arch vessels are impressive, showing a wide range of 3-dimensional motions. Future ascending arch branched and fenestrated thoracic endograft designs must consider this active local environment, as it may have implications for durability, sealing, and ultimate clinical success. PMID- 17696633 TI - Risk factors for developing postprocedural microemboli following carotid interventions. AB - PURPOSE: To determine risk factors predictive of microemboli found on diffusion weighted magnetic resonance imaging (DW-MRI) following carotid angioplasty and stenting (CAS) with distal protection and carotid endarterectomy (CEA). METHODS: A retrospective review was conducted of all carotid interventions at a single institution between 2004 and 2006. In that time frame, 64 carotid interventions (34 CAS, 30 CEA) were performed in 63 male patients (mean age 69.5 years, range 52 to 91) with DW-MRI scans available for review. Patient characteristics, including age, gender, smoking history, diabetes mellitus, hypertension, hyperlipidemia, obesity (body mass index >30), coronary artery disease (CAD), chronic obstructive pulmonary disease, peripheral vascular disease, and atrial fibrillation, were documented. For the CAS patients, anatomical and procedural characteristics, including fluoroscopy time, contrast volume, performance of an arch angiogram, and lesion anatomy, were recorded. Bivariate analyses were performed to determine which parameters were associated with the occurrence of acute postprocedural microemboli found on DW-MRI by 2 blinded neuroradiologists. RESULTS: Twenty-four (71%) of the 34 CAS patients and 1 (3%) of the 30 CEA patients demonstrated new cerebral microemboli postoperatively. In the bivariate analyses of all patient, anatomical, and procedural characteristics, only a history of CAD was associated with an increased risk of microemboli; 20 (80%) of the 25 patients who had postprocedure microemboli had CAD compared to 18 (46%) of 39 patients without microemboli (p=0.007). Twenty (53%) of the 38 (59%) patients with CAD developed microemboli compared to 5 (19%) of the 26 patients without CAD (p=0.007). All other patient, procedural, and anatomical characteristics were not found to be independent risk factors predictive of postprocedure microemboli. CONCLUSION: CAS with distal protection carries a significantly greater risk for developing new microemboli compared to CEA. Of all the risk factors analyzed, only a history of CAD emerged as an independent risk factor for the development of microemboli following carotid intervention. This finding may influence the decision to perform CAS in patients deemed high risk solely due to the presence of CAD. PMID- 17696634 TI - Risk factors for perioperative stroke during thoracic endovascular aortic repairs (TEVAR). AB - PURPOSE: To determine the clinical and anatomical risk factors for cerebrovascular accidents (CVA) in patients undergoing thoracic endovascular aortic repair (TEVAR). METHODS: Between September 2000 and December 2006, 196 patients (135 men; mean age 68.6+/-13.5 years, range 17-92) underwent TEVAR for a variety of aortic pathologies. The majority (156, 79.6%) were treated with the TAG stent-graft. Demographics, pathologies, intraoperative procedure-related measures, device usage, and postoperative outcomes were assessed. CVA was defined as a new focal or global neurological (motor or sensory) deficit lasting >48 hours associated with acute intracranial abnormalities on computed tomography or magnetic resonance brain imaging. Spinal cord ischemia was excluded. In a subset of patients with planned left subclavian artery (LSA) coverage and an incomplete circle of Willis or a dominant left vertebral artery, prophylactic carotid subclavian bypasses were performed. RESULTS: Nine (4.6%) patients suffered a CVA. Factors not predictive of a CVA on univariate analysis included aortic pathology, urgency of repair, ASA classification, type of anesthesia, blood loss, procedure time, and device used. Proximal extent of repair (with or without extra anatomical revascularization) was significantly associated with a higher incidence of strokes (zones 0-2 versus 3-4, p=0.025). Five (55.6%) patients with a CVA had documented intraoperative hypotension (systolic blood pressure<80 mmHg). Additionally, while 2 patients had hemispheric infarcts, 5 had acute posterior circulation infarcts involving the cerebellum and brainstem; a single patient had both anterior and posterior circulation infarcts. Seven of the CVA patients had proximal coverage of the thoracic aorta in zones 0-2; of these, 6 had posterior circulation infarcts. Selective LSA revascularization based on preoperative cerebrovascular imaging resulted in lower rates of CVA (6.4% to 2.3%, p=0.30) and posterior circulation infarcts (5.5% to 1.2%, p=0.13). CONCLUSION: Proximal extent of repair may serve as a surrogate marker for greater severity of degenerative disease of the aortic arch. Avoidance of intraoperative hypotension and preservation of antegrade vertebral perfusion may be important in prevention of posterior circulation strokes. PMID- 17696635 TI - Increased anterior abdominal aortic wall motion: possible role in aneurysm pathogenesis and design of endovascular devices. AB - PURPOSE: To determine whether variations in aortic wall motion exist in mammalian species other than humans and to consider the potential implications of such variations. METHODS: M-mode ultrasound was used to measure abdominal aortic wall motion in 4 animal species [mice (n=10), rats (n=8), rabbits (n=7), and pigs (n=5)], and humans (n=6). Anterior wall displacement, posterior wall displacement, and diastolic diameter were measured. The ratio of displacement to diameter and cyclic strain were calculated. RESULTS: Body mass varied from 24.1+/ 2.4 g (mouse) to 61.8+/-13.4 kg (human); aortic diameter varied from 0.53+/-0.07 mm (mouse) to 1.2+/-1 mm (human). Anterior wall displacement was 2.5 to 4.0 times greater than posterior among the species studied. The ratios of wall displacement to diastolic diameter were similar for the anterior (range 9.40%-11.80%) and posterior (range 2.49%-3.91%) walls among species. The ratio of anterior to posterior displacement (range 2.47-4.03) and aortic wall circumferential cyclic strain (range 12.1%-15.7%) were also similar. An allometric scaling exponent was experimentally derived relating anterior wall (0.377+/-0.032, R2=0.94) and posterior wall (0.378+/-0.037, R2=0.93) displacement to body mass. CONCLUSION: Abdominal aortic wall dynamics are similar in animals and humans regardless of aortic size, wih more anterior than posterior wall motion. Wall displacement increases linearly with diameter, but allometrically with body mass. These data suggest increased dynamic strain of the anterior wall. Increased strain, corresponding to increased elastin fatigue, may help explain why human abdominal aortic aneurysms initially develop anteriorly. Aortic wall motion should be considered when developing endovascular devices, since asymmetric motion may affect device migration, fixation, and sealing. PMID- 17696636 TI - Device-specific resistance to in vivo displacement of stent-grafts implanted with maximum iliac fixation. AB - PURPOSE: To compare the in vivo device-specific downward displacement force of various externally supported endografts implanted with maximum iliac fixation. METHODS: Twenty female sheep had aneurysms created with a graft patch in the infrarenal aorta. In 12 animals, a fully supported modular bifurcated stent-graft [AneuRx (n=4), Talent (n=4), or Zenith (n=4)] was deployed; in the other 8, a bifurcated aortic graft was surgically anastomosed to the infrarenal aorta. All grafts were displaced in vivo by applying downward traction to a guidewire brought out both femoral arteries. The peak force to cause initial stent-graft migration or disruption of the sutured anastomosis was recorded and compared. RESULTS: There was no difference in animal size, aortic neck diameter or length, aneurysm size, or iliac artery diameter for animals receiving the AneuRx, Talent, or Zenith stent-grafts and those undergoing surgical repair. The mean length of iliac fixation was 31.0+/-0.3 mm, 30.8+/-0.5 mm, and 31.3+/-0.6 mm for the AneuRx, Talent, and Zenith devices, respectively (p=NS). Peak force to initiate migration was 30.2+/-5.5 N (range 25-38) for the AneuRx, 44.8+/-5.6 N (range 40 53) for the Talent, 46.7+/-5.4 N (range 38-55) for the Zenith, and 40.6+/-7.5 N (range 31-50) for the surgical anastomosis (p=0.01). There was no difference detected in the peak force to initiate migration between the suprarenally affixed Talent and Zenith stent-grafts and the surgical anastomosis (p=0.55). CONCLUSION: Devices with a suprarenal component require significantly greater force to cause downward displacement compared to infrarenal devices. The force required to displace a suprarenal device with maximal iliac fixation was equivalent to the force required to disrupt a surgical anastomosis. PMID- 17696637 TI - Influence of wall compliance on hemodynamics in models of abdominal aortic aneurysm. AB - PURPOSE: To determine complementary criteria to existing morphological criteria, which are not reliable but are used to justify surgical intervention to treat abdominal aortic aneurysm (AAA). METHODS: An experimental study was conducted in which 2 models of AAA, 1 rigid and 1 soft, were used to study the influence of compliance on aneurysm dynamics. The heart rate was 70 beats per minute, and the mean flow rate was 1.02 L/min. Velocity measurements were made with particle image velocimetry in 2 planes parallel to flow (1 vertical and 1 horizontal). RESULTS: The general flow patterns generated in the rigid AAA model were in agreement with the literature. In both models, a vortex occurred at the beginning of systolic deceleration in the proximal part of the AAA, near the anterior wall. The vortex remained confined to the proximal part during the entire cycle in the rigid model, whereas in the soft model, the vortex migrated to the distal segment during the cycle and impacted the AAA walls. This impact generated a local pressure increase on the wall. In the soft model, another vortex was created near the posterior wall. These vortices eroded and weakened the walls of the distal segment, which can cause rupture. CONCLUSION: Compliance of the aneurysm wall might become another criterion to justify surgical intervention. PMID- 17696638 TI - Endovascular rescue of a fused monorail balloon and cerebral protection device. AB - PURPOSE: To present a case of successful endovascular retrieval of a monorail predilation balloon fused to an embolic protection device (EPD) in the distal internal carotid artery (ICA) of a high-risk symptomatic patient. CASE REPORT: A 60-year-old man with documented systemic atherosclerotic disease had a severe (>70%) restenosis in the left ICA 3 years after endarterectomy. He was scheduled for carotid artery stenting (CAS) with cerebral protection; however, he developed unstable angina and was transferred to our facility, where the admitting team decided that staged CAS followed by coronary bypass grafting would be the best option. During the CAS procedure, a 6-mm AccuNet filter was passed across the lesion via a 6-F carotid sheath and deployed in the distal ICA without incident. However, the 4-x20-mm predilation monorail balloon was then advanced without visualizing the markers, resulting in inadvertent aggressive interaction that trapped the balloon's tip in the filter. Several maneuvers to separate the devices were unsuccessful. Finally, the filter/balloon combination was moved gently retrograde until the balloon was straddling the subtotal ICA lesion. The lesion was dilated to 4 mm with the balloon, and the sheath was gently advanced across the lesion as the balloon was deflated. Angiography excluded interval occlusion of the filter from the embolic debris during the aforementioned aggressive maneuvers and documented antegrade flow. The filter was slowly withdrawn into the 6-F sheath with simultaneous aspiration. A second 6-mm filter was deployed, and the procedure was completed satisfactorily. The patient did well, with no neurological sequelae. CONCLUSION: EPDs are an essential in carotid artery stenting and, keeping in mind the potential risks associated with their use, will help the operator avoid complications such as this one. PMID- 17696639 TI - Endovascular treatment of aneurysmal deterioration in peripheral arterial allografts. AB - PURPOSE: To report endovascular treatment of 2 patients with aneurysmal deterioration of peripheral arterial allografts. CASE REPORT: Two men (65 and 64 years old) who had undergone an arterial allograft reconstruction for infection of prosthetic infrapopliteal bypass grafts 5 and 7 years ago, respectively, were diagnosed with asymptomatic aneurysmal deterioration of the allografts. Stent graft repair was successful in both cases, completely excluding the aneurysms. At >or=1 year, continued aneurysm exclusion was confirmed by duplex scan, with no evidence of endoleak, migration, or stenosis. CONCLUSION: Endovascular treatment may be a useful therapeutic option when treating patients with late peripheral allograft deterioration. PMID- 17696641 TI - Anaemia: a useful indicator of neglected disease burden and control. PMID- 17696640 TI - Translating pharmacogenomics: challenges on the road to the clinic. AB - Pharmacogenomics is one of the first clinical applications of the postgenomic era. It promises personalized medicine rather than the established "one size fits all" approach to drugs and dosages. The expected reduction in trial and error should ultimately lead to more efficient and safer drug therapy. In recent years, commercially available pharmacogenomic tests have been approved by the Food and Drug Administration (FDA), but their application in patient care remains very limited. More generally, the implementation of pharmacogenomics in routine clinical practice presents significant challenges. This article presents specific clinical examples of such challenges and discusses how obstacles to implementation of pharmacogenomic testing can be addressed. PMID- 17696642 TI - Expansion of regulatory T cells in patients with Langerhans cell histiocytosis. AB - BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare clonal granulomatous disease that affects mainly children. LCH can involve various tissues such as bone, skin, lung, bone marrow, lymph nodes, and the central nervous system, and is frequently responsible for functional sequelae. The pathophysiology of LCH is unclear, but the uncontrolled proliferation of Langerhans cells (LCs) is believed to be the primary event in the formation of granulomas. The present study was designed to further investigate the nature of proliferating cells and the immune mechanisms involved in the LCH granulomas. METHODS AND FINDINGS: Biopsies (n = 24) and/or blood samples (n = 25) from 40 patients aged 0.25 to 13 y (mean 7.8 y), were studied to identify cells that proliferate in blood and granulomas. We found that the proliferating index of LCs was low ( approximately 1.9%), and we did not observe expansion of a monocyte or dendritic cell compartment in patients. We found that LCH lesions were a site of active inflammation, tissue remodeling, and neo-angiogenesis, and the majority of proliferating cells were endothelial cells, fibroblasts, and polyclonal T lymphocytes. Within granulomas, interleukin 10 was abundant, LCs expressed the TNF receptor family member RANK, and CD4(+) CD25(high) FoxP3(high) regulatory T cells (T-regs) represented 20% of T cells, and were found in close contact with LCs. FoxP3(+) T-regs were also expanded compared to controls, in the blood of LCH patients with active disease, among whom seven out of seven tested exhibited an impaired skin delayed-type hypersensitivity response. In contrast, the number of blood T-regs were normal after remission of LCH. CONCLUSIONS: These findings indicate that LC accumulation in LCH results from survival rather than uncontrolled proliferation, and is associated with the expansion of T-regs. These data suggest that LCs may be involved in the expansion of T-regs in vivo, resulting in the failure of the host immune system to eliminate LCH cells. Thus T-regs could be a therapeutic target in LCH. PMID- 17696643 TI - Are autumn foliage colors red signals to aphids? PMID- 17696645 TI - No forest left behind. PMID- 17696644 TI - The p75 neurotrophin receptor is a central regulator of glioma invasion. AB - The invasive nature of cancers in general, and malignant gliomas in particular, is a major clinical problem rendering tumors incurable by conventional therapies. Using a novel invasive glioma mouse model established by serial in vivo selection, we identified the p75 neurotrophin receptor (p75(NTR)) as a critical regulator of glioma invasion. Through a series of functional, biochemical, and clinical studies, we found that p75(NTR) dramatically enhanced migration and invasion of genetically distinct glioma and frequently exhibited robust expression in highly invasive glioblastoma patient specimens. Moreover, we found that p75(NTR)-mediated invasion was neurotrophin dependent, resulting in the activation of downstream pathways and producing striking cytoskeletal changes of the invading cells. These results provide the first evidence for p75(NTR) as a major contributor to the highly invasive nature of malignant gliomas and identify a novel therapeutic target. PMID- 17696646 TI - Adaptive variation in beach mice produced by two interacting pigmentation genes. AB - Little is known about the genetic basis of ecologically important morphological variation such as the diverse color patterns of mammals. Here we identify genetic changes contributing to an adaptive difference in color pattern between two subspecies of oldfield mice (Peromyscus polionotus). One mainland subspecies has a cryptic dark brown dorsal coat, while a younger beach-dwelling subspecies has a lighter coat produced by natural selection for camouflage on pale coastal sand dunes. Using genome-wide linkage mapping, we identified three chromosomal regions (two of major and one of minor effect) associated with differences in pigmentation traits. Two candidate genes, the melanocortin-1 receptor (Mc1r) and its antagonist, the Agouti signaling protein (Agouti), map to independent regions that together are responsible for most of the difference in pigmentation between subspecies. A derived mutation in the coding region of Mc1r, rather than change in its expression level, contributes to light pigmentation. Conversely, beach mice have a derived increase in Agouti mRNA expression but no changes in protein sequence. These two genes also interact epistatically: the phenotypic effects of Mc1r are visible only in genetic backgrounds containing the derived Agouti allele. These results demonstrate that cryptic coloration can be based largely on a few interacting genes of major effect. PMID- 17696647 TI - Three-dimensional analysis of a viral RNA replication complex reveals a virus induced mini-organelle. AB - Positive-strand RNA viruses are the largest genetic class of viruses and include many serious human pathogens. All positive-strand RNA viruses replicate their genomes in association with intracellular membrane rearrangements such as single- or double-membrane vesicles. However, the exact sites of RNA synthesis and crucial topological relationships between relevant membranes, vesicle interiors, surrounding lumens, and cytoplasm generally are poorly defined. We applied electron microscope tomography and complementary approaches to flock house virus (FHV)-infected Drosophila cells to provide the first 3-D analysis of such replication complexes. The sole FHV RNA replication factor, protein A, and FHV specific 5-bromouridine 5'-triphosphate incorporation localized between inner and outer mitochondrial membranes inside approximately 50-nm vesicles (spherules), which thus are FHV-induced compartments for viral RNA synthesis. All such FHV spherules were outer mitochondrial membrane invaginations with interiors connected to the cytoplasm by a necked channel of approximately 10-nm diameter, which is sufficient for ribonucleotide import and product RNA export. Tomographic, biochemical, and other results imply that FHV spherules contain, on average, three RNA replication intermediates and an interior shell of approximately 100 membrane-spanning, self-interacting protein As. The results identify spherules as the site of protein A and nascent RNA accumulation and define spherule topology, dimensions, and stoichiometry to reveal the nature and many details of the organization and function of the FHV RNA replication complex. The resulting insights appear relevant to many other positive-strand RNA viruses and support recently proposed structural and likely evolutionary parallels with retrovirus and double-stranded RNA virus virions. PMID- 17696649 TI - What makes us human (Homo sapiens)? The challenge of cognitive cross-species comparison. AB - Two major theoretical approaches have dominated the quest for uniquely human cognitive abilities: a developmentalist approach stressing the importance of environmental and social conditions, and a predominant approach in experimental and comparative psychology, the deterministic approach suggesting the effect of environmental and social conditions to be minimal. As a consequence, most claims of human cognitive uniqueness are based on comparisons of White middle class Westerner humans (Homo sapiens) with captive chimpanzees (Pan troglodytes). However, humans are much more than only White middle class Westerners, and chimpanzees are much more than only captives. A review of some data available on different populations of humans and chimpanzees reveals that only the predictions of the developmentalist approach are supported. In addition, systematic biases are too often introduced in experiment protocols when comparing humans with apes that further cast doubts on cross-species comparisons. The author argues that only with consideration of within-species population differences in the cognitive domains and the use of well-matched cross-species experimental procedures will an objective understanding of the different cognitive abilities between species emerge. This will require a shift in the theoretical approach adopted by many in experimental and comparative psychology. PMID- 17696648 TI - An actin-based wave generator organizes cell motility. AB - Although many of the regulators of actin assembly are known, we do not understand how these components act together to organize cell shape and movement. To address this question, we analyzed the spatial dynamics of a key actin regulator--the Scar/WAVE complex--which plays an important role in regulating cell shape in both metazoans and plants. We have recently discovered that the Hem-1/Nap1 component of the Scar/WAVE complex localizes to propagating waves that appear to organize the leading edge of a motile immune cell, the human neutrophil. Actin is both an output and input to the Scar/WAVE complex: the complex stimulates actin assembly, and actin polymer is also required to remove the complex from the membrane. These reciprocal interactions appear to generate propagated waves of actin nucleation that exhibit many of the properties of morphogenesis in motile cells, such as the ability of cells to flow around barriers and the intricate spatial organization of protrusion at the leading edge. We propose that cell motility results from the collective behavior of multiple self-organizing waves. PMID- 17696650 TI - Discrete quantity judgments in the great apes (Pan paniscus, Pan troglodytes, Gorilla gorilla, Pongo pygmaeus): the effect of presenting whole sets versus item by-item. AB - The authors examined quantity-based judgments for up to 10 items for simultaneous and sequential whole sets as well as for sequentially dropped items in chimpanzees (Pan troglodytes), gorillas (Gorilla gorilla), bonobos (Pan paniscus), and orangutans (Pongo pygmaeus). In Experiment 1, subjects had to choose the larger of 2 quantities presented in 2 separate dishes either simultaneously or 1 dish after the other. Representatives of all species were capable of selecting the larger of 2 quantities in both conditions, even when the quantities were large and the numerical distance between them was small. In Experiment 2, subjects had to select between the same food quantities sequentially dropped into 2 opaque cups so that none of the quantities were ever viewed as a whole. The authors found some evidence (albeit weaker) that subjects were able to select the larger quantity of items. Furthermore, the authors found no performance breakdown with the inclusion of certain quantities. Instead, the ratio between quantities was the best performance predictor. The authors conclude that quantity-based judgments rely on an analogical system, not a discrete object file model or perceptual estimation mechanism, such as subitizing. PMID- 17696651 TI - Serial list linking by macaque monkeys (Macaca mulatta): list property limitations. AB - Four sophisticated macaque monkeys (Macaca mulatta) learned 6 different, 15-item ordinal lists (via conditional, 2-choice discriminations) as part of a study assessing some properties of serial list memory in monkeys. After assuring that the first 3 lists were well retained, the researchers attempted to link these by training only the 2 end-item pairs that ordered all 45 items into an inclusive series. A 20-day test of possible pairings among these 45 items was then conducted. Subsequently, the other 3 lists were trained and tested for retention, but no link training was provided. Then, a test like the one that had followed linking was administered. Unlike previous outcomes with three 5-item lists, linking did not yield immediate merger of three 15-item lists into a 45-item list, although 45-item lists were acquired after sufficient exposure to the testing/training regimen under both linking and nonlinking conditions. List length as a limiting factor in linking suggested processing restrictions analogous to those observed in human list memory. Results supported further investigation of list-linking characteristics. PMID- 17696652 TI - Response strategies in list learning by orangutans (Pongo pygmaeus x P. abelii). AB - Rhesus monkeys (Macaca mulatta) develop strategies to acquire and execute serial lists (K. B. Swartz & S. A. Himmanen, 2001). Serial probe recognition studies of list memory have demonstrated similarities across monkeys and humans (S. F. Sands & A. A. Wright, 1980). The present study extended the investigation of list learning and memory to determine whether orangutans (Pongo pygmaeus x P. abelii) would show evidence of subjective organization of photographic lists in a manner similar to that shown by humans learning a list of unrelated words (E. Tulving, 1962). No evidence for the effective use of a subjective organization strategy was found, but the orangutans developed a right-to-left spatial response strategy, which emerged during the acquisition of 5-item lists. This strategy was an effective way to reduce the load on working memory when presented with a complex array of items. PMID- 17696653 TI - Cognitive decline and human (Homo sapiens) aging: an investigation using a comparative neuropsychological approach. AB - Using a comparative neuropsychological approach, the authors compared performance of younger and healthy older adults ages 65 and over on tasks originally developed to measure cognition in animals. A battery of 6 tasks was used to evaluate object discrimination, egocentric spatial abilities, visual and spatial working memory, and response shifting. Older adults performed more poorly than younger adults on tasks that evaluate egocentric spatial abilities, response shifting, and to a lesser extent object recognition. The two groups did not differ for tasks that evaluate spatial working memory and object discrimination. The impairments the authors observed in tasks that evaluate response shifting and object recognition are consistent with those found in canines and primates as well as those found in Alzheimer's disease. The results are consistent with the notion that cognitive processes supported by the amygdala and the orbitofrontal cortex are among the first to decline with increasing age in both humans and animals. PMID- 17696654 TI - A short-term longitudinal study of preschoolers' (Homo sapiens) sex segregation: the role of physical activity, sex, and time. AB - The interactive influence of preschool children's level of physical activity, sex, and time on the degree of sex segregation was assessed. A sample of nursery school children was observed across much of a school year, and levels of physical activity and sex segregation were sampled during their free play periods. Following sexual selection theory, we predicted a Sex X Time X Physical Activity interaction on segregation such that high-activity girls early in the school year would interact with boys but, with time, the high-activity girls would be segregated among themselves. Boys (both high- and low-activity) should remain segregated across the year. The hypothesis was supported, and results are discussed in terms of the interactive role of biology and socialization on sex segregation. PMID- 17696655 TI - Effects of spatial food distribution on search behavior in rats (Rattus norvegicus). AB - To analyze how search strategies are adapted according to the geometric distribution of food sources, the authors submitted rats to a search task in which they had to explore 9 food trays in an open field and avoid visiting already-depleted trays. Trays were spatially arranged in 4 independent configurations: a cross, a 3 x 3 matrix, 3 clusters of 3 trays each, and a random configuration. Rats exhibited differential search efficiency as a specific effect of the susceptibility of the configurations to being explored in a principled way: crosses were first, matrices or clusters were in the middle, and random configurations were last. Although no exhaustive searches or highly principled patterns were observed in any of the configurations, performances improved as the sessions went by. Thus, structural affordances of the environment influence the construction not only of search strategies but also of information linked to where the reward is. PMID- 17696656 TI - The packaging problem: bivalve prey selection and prey entry techniques of the octopus Enteroctopus dofleini. AB - Many predators face a complex step of prey preparation before consumption. Octopuses faced with bivalve prey use several techniques to penetrate the shells to gain access to the meat inside. When given prey of mussels Mytilus trossulus, Manila clams Venerupis philippinarum, and littleneck clams Protothaca staminea, Enteroctopus dofleini solved the problem differently. They pulled apart V. philippinarum and M. trossulus, which had the thinnest shells and the least pulling resistance. P. staminea were eaten after the shells had been chipped or had been penetrated by drilling, presumably to inject a toxin. Likely because of these differences, octopuses consumed more V. philippinarum and M. trossulus than P. staminea when the mollusks were given to them either 1 species at a time or all together. However, when the shells were separated and the penetration problem removed, the octopuses predominantly chose P. staminea and nearly ignored M. trossulus. When V. philippinarum were wired shut, octopuses switched techniques. These results emphasize that octopuses can learn on the basis of nonvisual information and monitor their body position to carry out feeding actions. PMID- 17696657 TI - Human listeners provide insights into echo features used by dolphins (Tursiops truncatus) to discriminate among objects. AB - Echolocating bottlenose dolphins (Tursiops truncatus) discriminate between objects on the basis of the echoes reflected by the objects. However, it is not clear which echo features are important for object discrimination. To gain insight into the salient features, the authors had a dolphin perform a match-to sample task and then presented human listeners with echoes from the same objects used in the dolphin's task. In 2 experiments, human listeners performed as well or better than the dolphin at discriminating objects, and they reported the salient acoustic cues. The error patterns of the humans and the dolphin were compared to determine which acoustic features were likely to have been used by the dolphin. The results indicate that the dolphin did not appear to use overall echo amplitude, but that it attended to the pattern of changes in the echoes across different object orientations. Human listeners can quickly identify salient combinations of echo features that permit object discrimination, which can be used to generate hypotheses that can be tested using dolphins as subjects. PMID- 17696658 TI - Interactive and vicarious acquisition of auditory preferences in Northern bobwhite (Colinus virginianus) chicks. AB - Studies examining the effects of stimulus contingency on filial imprinting have produced inconsistent findings. In the current study, day-old bobwhite chicks (Colinus virginianus) received individual 5-min sessions in which they were provided contingent, noncontingent, or vicarious exposure to a variant of a bobwhite maternal assembly call. Chicks given contingent exposure to the call showed a significant preference for the familiar call 24 hr following exposure and significantly greater preferences than chicks given noncontingent exposure. Chicks given vicarious exposure to recordings of another chick interacting with the maternal call showed significant deviations from chance responding; however, the direction of chick preference (toward the familiar or unfamiliar) depended on the particular call used. These results indicate that both direct and indirect (vicarious) exposure to stimulus contingency can enhance the acquisition of auditory preferences in precocial avian hatchlings. Precocial avian hatchlings thus likely play a more active role in directing their own perceptual and behavioral development than has typically been thought. PMID- 17696659 TI - Activity of common marmosets (Callithrix jacchus) in limited spaces: hand movement characteristics. AB - The increasing popularity of marmoset monkeys (Callithrix jacchus) in anatomical, behavioral, and electrophysiological studies has called for a detailed analysis of their natural behavior within limited spaces. In the present study, the authors analyzed hand movements during horizontal and vertical progressions in a cylinder. The trajectory of each hand covered the entire cylinder floor during horizontal progressions and the entire cylinder wall during vertical progressions. Different marmosets have different patterns of hand movement. The average maximum angle of hand movements for all marmosets during horizontal and vertical progressions oscillates, although the average over time is constant and similar for both hands, whereas head movements during horizontal progressions become smaller with successive progressions. Another observed difference between rats and monkeys was in the size of head and hand movements at the beginning of each experimental session. During the 1st horizontal progression, all marmosets moved their heads to a greater extent than their hands. This sequential head and hand movement is referred as bistable behavior. The bistable pattern of motor behavior, which was also observed in successive progressions, may be derived from an inherent fear of predators or exploratory interest of a novel environment. PMID- 17696660 TI - Residential treatment for children and youth: time for reconsideration and reform. PMID- 17696661 TI - Ensuring the preconditions for transformation through licensing, regulation, accreditation, and standards. AB - Residential treatment is a potentially powerful intervention for children and families, currently facing the imperative to fundamentally change practice models to achieve greater quality efficacy, efficiency, and effectiveness. Such transformation is best accomplished from a solid foundation which is created by licensing, regulation, accreditation, and internal standards. PMID- 17696662 TI - Definition and accountability: a youth perspective. AB - This paper reviews the systemic flaws of residential treatment facilities from a youth perspective concerning the lack of transparency, definition and accountability, and the subsequent mistreatment and human rights violations of youth experiencing emotional, behavioral, and cognitive challenges. PMID- 17696663 TI - A review of the literature on the effectiveness of housing and support, assertive community treatment, and intensive case management interventions for persons with mental illness who have been homeless. AB - A review of 16 controlled outcome evaluations of housing and support interventions for people with mental illness who have been homeless revealed significant reductions in homelessness and hospitalization and improvements in other outcomes (e.g., well-being) resulting from programs that provided permanent housing and support, assertive community treatment (ACT), and intensive case management (ICM). The best outcomes for housing stability were found for programs that combined housing and support (effect size = .67), followed by ACT alone (effect size = .47), while the weakest outcomes were found for ICM programs alone (effect size = .28). The results of this review were discussed in terms of their implications for policy, practice, and future research. PMID- 17696664 TI - Families affected by parental mental illness: a multiperspective account of issues and interventions. AB - A multiperspective account of the issues and subsequent interventions for families affected by parental mental illness is reviewed in this article, including those involving the children, the parent with mental illness, other family members, agencies, and society in general. An overview of various issues and interventions for families affected by parental mental illness is seen as potentially useful for practitioners and program developers as well as providing a resource bank for systematic evaluation, research, and policy. PMID- 17696665 TI - Impact of perceived racial discrimination and collective self-esteem on psychological distress among Vietnamese-American college students: sense of coherence as mediator. AB - This study examined whether sense of coherence mediated relationships of perceived racial discrimination and of collective self-esteem to psychological distress (depression and anxiety) among 122 Vietnamese American college students. Higher levels of perceived racial discrimination (PRD) were associated with a reduced sense of coherence (SOC) and with higher levels of depression and anxiety. Path analysis found that SOC partially mediated the relationship of PRD to depression as well as to anxiety. Higher collective self-esteem (CSE) was associated with a stronger SOC, which in turn was associated with lower depression and anxiety. SOC mediated the relationship between CSE and depression, and part of the relationship between CSE and anxiety. PMID- 17696666 TI - Family systems psychiatry: principles, good practice guidelines, clinical examples, and challenges. AB - This article describes a collaborative action research project, carried out in Germany and designed to promote the integration of family systems thinking and methods into the core practices of everyday psychiatric care. During 1997-2002, "good practice" guidelines were compiled in an initial research project, involving 17 in- and outpatient psychiatric services. In the second phase of the project (2002-2008), the approach is now well established, being taught and evaluated in three state hospitals in Germany. This article outlines the development of the project and the application of family systems psychiatry principles, demonstrating their feasibility and value in a number of different psychiatric hospitals. Two clinical vignettes illustrate the usefulness of the family systems approach as a comprehensive framework for delivering recovery focused inpatient care. PMID- 17696667 TI - Acculturation and acculturative stress as indicators for suicide risk among African Americans. AB - The literature on African American suicide and the acculturation literature were examined to derive a possible explanation for increases in suicide deaths for African American men and apparent resilience for African American women. Historically, African Americans were believed to be unaffected by suicide because of protective factors (e.g., strong religious values and cohesive familial support systems) embedded in the culture. However, minority mental health investigators have found that acculturation sometimes leads to negative consequences for individuals from ethnic minority backgrounds. Accordingly, acculturation and acculturative phenomena are proposed as a model to shed light on African American male suicide as African Americans increasingly engage mainstream values, beliefs, and practices in the absence of traditional protective factors. PMID- 17696668 TI - Psychiatric housing: locational patterns and choices. AB - This study investigated locational patterns and choices in recently sited psychiatric housing. It examined the socioeconomic attributes of the neighborhoods of a sample of supervised houses and apartments for persons with severe mental illness in seven states, and the factors associated with the choice of those locations. Using data drawn from the U.S. Census and interviews with mental health administrators and residential staff, the study identified siting patterns that linked housing affordability to development in mixed use, walkable neighborhoods that provided residents with access to community resources in a variety of small towns and metropolitan areas. Although residences were located in neighborhoods with a range of socioeconomic attributes including low and high poverty rates, mean municipal poverty levels were significantly higher than those of the states in which they were located. PMID- 17696669 TI - Mental health screening of preschool children: validity and reliability of ABLE. AB - Children with behavioral, emotional or language problems struggle to do well at school often with limited success. ABLE (Attention, Behavior, Language, and Emotions), a new screening tool, was used to estimate the prevalence and the severity of concerns parents and teachers have about children's school adjustment and evaluate their need for services. Data obtained from the parents and teachers of children randomly selected from public Pre-K classrooms in 6 states (N = 415) and from a mental health screening of rural and urban children (N = 5,577) support the validity and reliability of ABLE. Parents identified severe problems in 18.4% of children and Pre-K teachers identified 10.5%. By kindergarten, the proportion of children identified by their teachers with serious problems more than doubled to 23%. Inattention/overactivity and behavior problems were identified most often. These children were 3.4 times more likely to be certified later for special education services by kindergarten than children not identified with problems by ABLE. However, fewer than 14% of children in public Pre-K identified with serious problems in Pre-K had received mental health services by the end of Kindergarten. PMID- 17696670 TI - Posttraumatic distress and growth among wives of prisoners of war: the contribution of husbands' posttraumatic stress disorder and wives' own attachments. AB - This study examined distress and growth among wives of former combat veterans and prisoners of war (POWs), and the contribution of their husband's posttraumatic stress disorder (PTSD) and the wives' own attachment style to these outcomes. Two groups of wives participated in the study: 87 wives of former POWs, and 74 wives of control veterans. The wives of POWs reported significantly higher levels of distress and growth than did the wives of the controls. Husbands' PTSD symptomatology, as well as higher levels of avoidance and anxiety dimensions of attachment, contributed positively to distress and to growth. Further studies on the unique predictors of growth are needed. PMID- 17696671 TI - Tomorrow's players under occupation: an analysis of the association of political violent with psychological functioning and domestic violence, among Palestinian youth. AB - A 2005 survey of 2,328 youth (ages 12 to 18) in the West Bank, Palestine, revealed an association between exposure to politically violent events, domestic violence, and school violence and with psychological symptomatology. Results also found associations between family violence, family economic status, and psychological symptomatology. Respondents reported low levels of family functioning. Data revealed some geographic variability in experiences of politically violent events, domestic violence, school violence, and psychological symptomatology. Implications for practice are discussed. PMID- 17696672 TI - Do urban adolescents become desensitized to community violence? Data from a national survey. AB - This study explored whether the response of urban adolescents to community violence exposure differs from their response to family violence and sexual assault. More specifically, the authors explored whether desensitization to community violence exposure was more common compared with desensitization to other violence-related stressors. Participants included 1,245 urban adolescents drawn from a national probability sample of 4,023 youth (aged 12-17 years) who were interviewed about their history of interpersonal violence exposure, symptoms of posttraumatic stress disorder (PTSD), and delinquency. A negative curvilinear effect of community violence exposure on PTSD combined with a positive linear effect of exposure on delinquency was considered evidence for desensitization. Results provided minimal support for the desensitization hypothesis and revealed increasing levels of PTSD symptoms and delinquent behaviors among boys and girls exposed to higher levels of all three violence types. PMID- 17696673 TI - Treating depression in vulnerable urban women: a feasibility study of clinical outcomes in community service settings. AB - There is a paucity of literature on direct treatment outcomes for impoverished minority populations. The current study supports the feasibility of successfully treating women for depressive symptoms in community settings where they typically seek care, adding to the small but growing direct knowledge base in this area. The sample of the 2-site study consisted of 91 women seeking treatment for depressive complaints at a homeless shelter program and a municipal hospital psychiatric clinic for Latino patients. Participants were randomly assigned to either a 16-week cognitive-behavioral group or a 16-week supportive/exploratory group for depression. Best-practice features with this population were integrated throughout. Findings showed that both treatment conditions were equally effective in decreasing depressive symptoms (BDI, CES-D) up to 4 months after treatment termination. These changes were paralleled by improvements in self-reported physical health (Duke Physical Profile). No significant differences between treatment conditions were found. Directives for next steps in the current research agenda are offered in efforts to broaden the direct evidence base for treating vulnerable urban women at high risk for depression and other forms of mental illness. PMID- 17696674 TI - Children's self-report about violence exposure: an examination of the Things I Have Seen and Heard Scale. AB - Children's exposure to violence is often found to be an important predictor of child outcomes. The measures most frequently used to assess it have not been systematically examined, and there is little consensus about how to use these measures. This study examined a version of the Things I Have Seen and Heard Scale in a sample of 784 children who completed the scale at both age 6 and 8. There was only modest support for the use of the scale as a set of single-item measures or as a simple sum of items. Exploratory factor analyses suggested that the scale consisted of two factors: a global/community violence scale and a home violence scale. The evidence for validity of the scales was stronger at age 8 than at age 6. These findings suggest that there may be some limits to the utility of self reports of violence exposure in very young children. However, there is initial evidence that the global/community scale is a reliable and valid indicator of young children's exposure to violence. Further use and exploration of the subscales is warranted. PMID- 17696675 TI - Longitudinal helpseeking patterns among victims of intimate partner violence: the relationship between legal and extralegal services. AB - Current theory assumes that intimate partner violence (IPV) victims' helpseeking is a process that unfolds over time rather than a one-time event, but this assumption has never been explored with longitudinal data. This study describes the pattern of formal helpseeking efforts in a sample of 406 IPV victims over the course of a year. Further, we explore the relationship between legal and extralegal helpseeking, reflecting current controversy over how these two types of interventions should be coordinated. We constructed and tested latent growth curve models using structural equation modeling to explore helpseeking patterns, and found that repeated helpseeking was common, with 80% seeking additional help during follow-up. Results also showed that legal and extralegal helpseeking decreased together over time, and that this similarity in pattern can best be described as a connection between behaviors that are similarly influenced by time specific events like re-abuse, rather than a connection between overarching trajectories. Results suggest that time varying factors are more important than stable characteristics in predicting helpseeking patterns, and support coordination through a one-stop-shopping model rather than primarily through referral systems. PMID- 17696676 TI - Gender differences in the mediated relationship between alcohol use and academic motivation among late adolescents. AB - This study utilized structural equation modeling to examine the relationship between alcohol use and academic motivation controlling for potentially mediating variables of deviant behavior, depressive cognitions, family communication, and peer relations. The study also examined the manner in which these relationships were moderated by gender. Results indicated that alcohol use was directly related to deviance for both males and females, but was not associated with depressive cognitions for either males or females. Deviant behavior was directly associated with depressive cognitions for both males and females, but this effect was significantly stronger for females. Deviance was significantly, inversely related to family communication among males, but not females. Depressive cognitions were significantly, inversely related to family communication for both males and females. Family communication and peer relations were directly related to academic motivation for both males and females, and the relationship between family communication and academic motivation was also mediated through peer relations. The necessity of providing information that focuses on minimizing involvement in deviant behaviors for females and the differential importance of family and peer relations is discussed. PMID- 17696677 TI - Adolescent female murderers: characteristics and treatment implications. AB - This study examines individual and family characteristics of a population of 29 adolescent females charged with homicide or attempted homicide in the juvenile justice system. The purpose of this study is to contribute to the limited knowledge about adolescent females charged with homicide. Data were collected including the MAYSI-2, a risk classification instrument, and social, educational and family histories. Findings include high rates of reported substance use, delinquent peers, early indicators of mental health problems, and limited control and supervision by parents. The most common weapon used was a car and the most common victim was a known person. A comparison was conducted on girls charged with homicide during the commission of another crime or committed during a conflict. The conflict group was found to victimize friends and family significantly more often than the crime group. The crime group showed higher use of alcohol and drugs, used a gun more and had co-offenders at a higher rate. A profile was developed to describe the typical adolescent female homicide offender found in this study. Treatment recommendations and future research were discussed. PMID- 17696678 TI - The value of nonhuman primates in drug abuse research. AB - The use of nonhuman primates (NHP) is invaluable for drug abuse research. The laboratory animals most closely related to humans are NHP. The phylogeny, anatomy, physiology, neurochemistry, and behavior of NHP are more similar to humans than other laboratory species. There is now an extensive body of literature documenting the neuroanatomical, neurochemical, and neuropharmacological similarities between NHP and humans and the differences between NHP and other laboratory species in dopamine, norepinephrine, serotonin, opioid, and gamma aminobutyric acid systems. Comprehensive studies comparing pharmacokinetics in humans, monkeys, dogs, and rats have shown that data in monkeys are the most predictive of human pharmacokinetic parameters. The long life span and extended adolescent period for NHP permits intensive, long-term investigations and the use of within-subject experimental designs similar to those used in human laboratory studies. Within-subject designs require fewer subjects than standard between-group designs and permit the careful evaluation of individual differences. NHP have been used extensively in drug abuse research for over 40 years and have provided useful information on the behavioral processes associated with drug abuse and addiction as well as drug abuse liability in humans. This review focuses on important species differences between rodents and NHP and on the value of NHP in bridging the gap between rodents and humans to enhance the ability to generalize preclinical findings to human drug abuse. PMID- 17696679 TI - Comparison of zolpidem and midazolam self-administration under progressive-ratio schedules: consumer demand and labor supply analyses. AB - Progressive ratio (PR) schedules of intravenous drug self-administration are useful for establishing the relationships between reinforcing effectiveness and pharmacological actions of abused drugs. The authors compared the reinforcing effects of 2 short-duration benzodiazepine-type drugs differing in their receptor selectivity: zolpidem (selective for gamma aminobutyric acid Type A [GABA(A)] receptors containing alpha1 subunits) and midazolam (nonselective). Reinforcing effectiveness was evaluated using a PR schedule of intravenous drug injection in rhesus monkeys in which the response requirement increased across the experimental session and the initial response requirement (IRR) was varied. Analyses based on consumer demand and labor supply models of behavioral economics revealed that the relative reinforcing effectiveness of zolpidem was greater than that of midazolam. For consumer demand analyses, the degree of difference between zolpidem and midazolam depended on whether price was calculated on the basis of different IRRs or different doses of drug. According to labor supply analysis, the reinforcing effects of midazolam were influenced by the economic concept referred to as a price effect to a greater degree than those of zolpidem. These findings suggest that a compound with selectivity for GABA(A) receptors containing alpha1 subunits has greater reinforcing effectiveness than a nonselective compound with similar pharmacokinetics, albeit under a limited range of conditions (high response costs). Differences in price effects may play a key role in determining the relative reinforcing effectiveness of selective versus nonselective benzodiazepine agonists. PMID- 17696680 TI - Contingency management in cocaine abusers: a dose-effect comparison of goods based versus cash-based incentives. AB - Goods-based contingency management interventions (e.g., those using vouchers or prizes as incentives) have demonstrated efficacy in reducing cocaine use, but cost has limited dissemination to community clinics. Recent research suggests that development of a cash-based contingency management approach may improve treatment outcomes while reducing operational costs of the intervention. However, the clinical safety of providing cash-based incentives to substance abusers has been a concern. The present 16-week study compared the effects of goods-based versus cash-based incentives worth $0, $25, $50, and $100 on short-term cocaine abstinence in a small sample of cocaine-dependent methadone patients (N = 12). A within-subject design was used; a 9-day washout period separated each of 8 incentive conditions. Higher magnitude ($50 and $100) cash-based incentives (checks) produced greater cocaine abstinence compared with the control ($0) condition, but a magnitude effect was not seen for goods-based incentives (vouchers). A trend was observed for greater rates of abstinence in the cash based versus goods-based incentives at the $50 and $100 magnitudes. Receipt of $100 checks did not increase subsequent rates of cocaine use above those seen in control conditions. The efficacy and safety data provided in this and other recent studies suggest that use of cash-based incentives deserves consideration for clinical applications of contingency management, but additional confirmation in research using larger samples and more prolonged periods of incentive delivery is needed. PMID- 17696681 TI - Abstinence-based incentives in methadone maintenance: interaction with intake stimulant test results. AB - Baseline drug use detected in urine toxicology has been shown to predict drug abuse treatment outcome, including response to contingency management interventions with drug abstinence as their target. This study examined the association between baseline urine test result and treatment outcome in stabilized methadone maintenance patients with ongoing stimulant use to determine whether abstinence incentives were differentially effective in those testing stimulant negative versus positive at study entry. Participants were 386 methadone-maintained patients who took part in a National Drug Abuse Treatment Clinical Trials Network multisite study aimed at reducing stimulant abuse during treatment (J. M. Peirce et al., 2006). At study intake, 24% of participants tested stimulant negative and 76% tested positive. Those testing negative at entry submitted 82% negative urines during the study versus 36% for those testing positive at entry (odds ratio [OR] = 8.67; confidence interval [CI] = 5.81 12.94). Compared with those receiving usual care, the addition of abstinence incentives resulted in a significant increase in stimulant-negative urine samples submitted during the study both for those testing negative at study entry (OR = 2.27; CI = 1.13- 4.75) and for those testing positive (OR = 1.84; CI = 1.25 2.71). These findings suggest that abstinence incentives have significant clinical benefits independent of initial drug use severity among methadone maintenance patients with ongoing stimulant drug use. PMID- 17696682 TI - Ecstasy (MDMA) does not have long-term effects on aggressive interpretative bias: a study comparing current and ex-ecstasy users with polydrug and drug-naive controls. AB - +/-3, 4-methylenedioxymethamphetamine (MDMA or ecstasy) remains a widely used recreational drug, which, in animals, can produce long-lasting changes to the brain's serotonergic system. As serotonin has been implicated in human aggression, it is possible that ecstasy users are at risk of increased aggression even after prolonged abstention from the drug. The objective of this study was to indirectly assess aggression in current and abstinent ecstasy users using an information-processing paradigm that measures cognitive bias toward material with aggressive content. The task employed has previously shown increased aggressive bias 3-4 days after ecstasy use. An interpretative bias task was administered to 105 male participants: 26 ex-ecstasy users, 25 current ecstasy users, 29 polydrug using controls, and 25 drug-naive controls. Accuracy and response times to process and recognize ambiguous sentences were tested. There were no group differences in aggressive interpretative bias. All 4 groups processed neutral sentences faster than aggressive sentences and were subsequently faster and more confident in recognizing neutral compared with aggressive sentences. Further, self-ratings of aggression also showed no group differences, even though self rated impulsivity was significantly higher in current ecstasy users than in drug naive controls. The findings that all groups were biased toward neutral and away from aggressive interpretations of ambiguous sentences add to the existing body of knowledge in suggesting that increased aggression found in ecstasy users a few days after taking the drug is a transient phenomenon and not a long-term, persisting effect. PMID- 17696683 TI - Reduction of cocaine seeking by a food-based inhibitor in rats. AB - Environmental stimuli can exert a powerful influence over drug seeking and taking. For example, previous experiments found that combining multiple drug related stimuli tripled drug seeking and doubled drug intake (L. V. Panlilio, S. J. Weiss, & C. W. Schindler, 1996, 2000), whereas a signal for the absence of cocaine (i.e., a drug-related inhibitor) dramatically reduced cocaine seeking in rats by over 90% (D. N. Kearns, S. J. Weiss, C. W. Schindler, & L. V. Panlilio, 2005). In the present experiment, a signal for the absence of food created through the A+/AB- conditioned inhibition paradigm also suppressed responding for cocaine by approximately 90%. Symmetrically, a signal for the absence of cocaine (i.e., a cocaine-based inhibitor) suppressed food seeking to a similar degree. These findings, consistent with the appetitive-aversive interaction theory of motivation, suggest that using inhibitors based on nondrug appetitive reinforcers might be a practical method of reducing drug seeking in human drug abusers and should be seriously considered for clinical test and application. PMID- 17696684 TI - Naltrexone alteration of the nicotine-induced EEG and mood activation response in tobacco-deprived cigarette smokers. AB - The neural mechanisms contributing to the arousal-eliciting actions of smoking and nicotine involve multiple neurotransmitter systems. The current study examined the role of opioid neurotransmission in modulating the neuroelectric- and mood-activating response to acute nicotine administration in overnight tobacco-deprived smokers. In a randomized, double-blind, placebo-controlled design involving 18 (10 male, 8 female) overnight tobacco-abstinent smokers, spectrally analyzed electroencephalographic (EEG) activity and subjective reports of mood, euphoria, and smoking withdrawal were assessed in response to nicotine gum (4 mg) after pretreatment with placebo or with 50 mg of the opioid antagonist naltrexone. In addition to reducing withdrawal symptoms and increasing euphoria ratings, as well as subjective alertness in male participants, nicotine induced an EEG arousal response consisting of diffuse slow wave (delta, theta) amplitude reductions, frontal fast alpha wave amplitude increments, and elevations in beta wave amplitude, which were greater in female than in male smokers. Naltrexone attenuated the alerting and euphoric actions of nicotine but did not affect nicotine's ameliorating effects on withdrawal symptoms. Nicotine-induced frontal reductions in delta and global reductions in theta were prevented by naltrexone pretreatment, as were increases in anterior recordings of relative fast alpha. These findings suggest that the opioid system is involved in nicotine-induced subjective and neuroelectric arousal and implicate opioid-cholinergic interactions in the elicitation of these arousal responses to nicotine. PMID- 17696685 TI - Evaluating reactivity to ecological momentary assessment during smoking cessation. AB - Ecological momentary assessment (EMA) consists of assessing phenomena in real time in the natural environment. EMA allows for more fine-grained analyses of addictive behavior and minimizes threats to internal validity, such as recall biases and errors. However, because of the intensive monitoring involved in EMA, measurement reactivity is a concern. To test whether EMA with palmtop personal computers induces reactivity, the authors compared smoking-related outcomes between smokers using EMA and those not using EMA during a quit attempt. The use of no-EMA control groups has been rare in reactivity investigations to date. The EMA protocol included event-contingent assessments (smoking episodes, urge episodes) and random assessments. Outcomes included biologically confirmed abstinence and self-report measures of withdrawal, self-efficacy, motivation, affect, and temptations. Participants were smokers motivated to quit (N = 96). They were randomized to 1 of 3 groups: EMA for the week preceding a planned quit date, EMA for the week following the quit date, and no EMA. Abstinence rates did not differ between the groups at Day 7 or at Day 28 postcessation. For the 20 subscales assessed at each of 3 assessment times, there were significant differences between participants with and without EMA experience for 3 subscales at the 1st of 3 assessment times, and significant differences for 3 different subscales at the 3rd assessment time. These differences suggest some reactivity to EMA, although the inconsistent pattern across time indicates that further research is needed to definitively conclude that EMA induces reactivity. PMID- 17696686 TI - Facial EMG as an index of affective response to nicotine. AB - Negative affect reduction has been postulated to be a key feature of cigarette smoking. In the present study, facial electromyography (EMG), heart rate (HR), and skin conductance response (SCR) were used to evaluate the affective significance of acute nicotine administration and overnight withdrawal. Smokers (N = 115) attended four 90-min laboratory assessment sessions scheduled approximately 3 days apart. The sessions provided a complete crossing of 2 prelaboratory deprivation conditions (12-hr deprived vs. nondeprived) with 2 drug conditions (nicotine vs. placebo nasal spray). During each session, smokers viewed affective slides while facial EMG, HR, and SCR were recorded. Results indicated that for women, nicotine nasal spray resulted in lower corrugator EMG activity during both smoking-deprived and nondeprived sessions, compared with placebo. However, nondeprived women also showed an increase in zygomaticus EMG when given nicotine compared with placebo spray, whereas smoking-deprived women demonstrated a decrease in the zygomaticus response to nicotine compared with placebo. With men, nicotine also appeared to lower corrugator during deprivation, but not nondeprivation, compared with placebo spray, though the contrast only approached significance. With zygomaticus EMG, nicotine spray decreased men's zygomaticus responding during nondeprivation but not during deprivation, compared with placebo spray. The HR results reflected the stimulatory properties of the drug rather than nicotine's affective properties, whereas SCR was unresponsive to our experimental manipulations. The corrugator EMG results support negative reinforcement models of smoking that postulate that acute nicotine use reduces withdrawal-driven negative affect. PMID- 17696687 TI - Automatic affective responses to smoking cues. AB - The authors examined automatic emotional reactions to smoking cues among 35 smokers and 25 nonsmokers (32 women and 28 men), using a novel implicit measure, the Affect Misattribution Procedure. Associative-learning theories of addiction suggest that smokers develop positive responses to cues linked to the rewarding effects of nicotine. Prior research, however, has yielded mixed evidence for whether smokers have favorable or unfavorable automatic responses to smoking cues. These findings may depend on the methods used to measure implicit responses. Using the Affect Misattribution Procedure, the authors found that nonsmokers responded to smoking cues with clear negative affect, whereas smokers' responses depended on individual differences in current smoking withdrawal. Smokers having withdrawal symptoms and those most motivated to smoke showed favorable emotional responses to smoking cues, but those with no withdrawal or low motivation to smoke showed negative responses. These results help integrate previous studies finding that smokers have negative automatic responses to cigarettes with those studies finding that smokers' responses were relatively positive. The results are important for theories that emphasize the role of cue conditioning in maintaining addiction because these theories assume, consistent with the current findings, that smoking cues can take on positive reward value. PMID- 17696688 TI - Processing of unattended emotional visual scenes. AB - Prime pictures of emotional scenes appeared in parafoveal vision, followed by probe pictures either congruent or incongruent in affective valence. Participants responded whether the probe was pleasant or unpleasant (or whether it portrayed people or animals). Shorter latencies for congruent than for incongruent prime probe pairs revealed affective priming. This occurred even when visual attention was focused on a concurrent verbal task and when foveal gaze-contingent masking prevented overt attention to the primes but only if these had been preexposed and appeared in the left visual field. The preexposure and laterality patterns were different for affective priming and semantic category priming. Affective priming was independent of the nature of the task (i.e., affective or category judgment), whereas semantic priming was not. The authors conclude that affective processing occurs without overt attention--although it is dependent on resources available for covert attention--and that prior experience of the stimulus is required and right-hemisphere dominance is involved. PMID- 17696689 TI - Discretionary task interleaving: heuristics for time allocation in cognitive foraging. AB - When participants allocated time across 2 tasks (in which they generated as many words as possible from a fixed set of letters), they made frequent switches. This allowed them to allocate more time to the more productive task (i.e., the set of letters from which more words could be generated) even though times between the last word and the switch decision ("giving-up times") were higher in the less productive task. These findings were reliable across 2 experiments using Scrabble tasks and 1 experiment using word-search puzzles. Switch decisions appeared relatively unaffected by the ease of the competing task or by explicit information about tasks' potential gain. The authors propose that switch decisions reflected a dual orientation to the experimental tasks. First, there was a sensitivity to continuous rate of return--an information-foraging orientation that produced a tendency to switch in keeping with R. F. Green's (1984) rule and a tendency to stay longer in more rewarding tasks. Second, there was a tendency to switch tasks after subgoal completion. A model combining these tendencies predicted all the reliable effects in the experimental data. PMID- 17696690 TI - A model of the go/no-go task. AB - In this article, the first explicit, theory-based comparison of 2-choice and go/no-go variants of 3 experimental tasks is presented. Prior research has questioned whether the underlying core-information processing is different for the 2 variants of a task or whether they differ mostly in response demands. The authors examined 4 different diffusion models for the go/no-go variant of each task along with a standard diffusion model for the 2-choice variant (R. Ratcliff, 1978). The 2-choice and the go/no-go models were fit to data from 4 lexical decision experiments, 1 numerosity discrimination experiment, and 1 recognition memory experiment, each with 2-choice and go/no-go variants. The models that assumed an implicit decision criterion for no-go responses produced better fits than models that did not. The best model was one in which only response criteria and the nondecisional components of processing changed between the 2 variants, supporting the view that the core information on which decisions are based is not different between them. PMID- 17696691 TI - Individual differences in components of reaction time distributions and their relations to working memory and intelligence. AB - The authors bring together approaches from cognitive and individual differences psychology to model characteristics of reaction time distributions beyond measures of central tendency. Ex-Gaussian distributions and a diffusion model approach are used to describe individuals' reaction time data. The authors identified common latent factors for each of the 3 ex-Gaussian parameters and for 3 parameters central to the diffusion model using structural equation modeling for a battery of choice reaction tasks. These factors had differential relations to criterion constructs. Parameters reflecting the tail of the distribution (i.e., tau in the ex-Gaussian and drift rate in the diffusion model) were the strongest unique predictors of working memory, reasoning, and psychometric speed. Theories of controlled attention and binding are discussed as potential theoretical explanations. PMID- 17696692 TI - The role of causality in judgment under uncertainty. AB - Leading accounts of judgment under uncertainty evaluate performance within purely statistical frameworks, holding people to the standards of classical Bayesian (A. Tversky & D. Kahneman, 1974) or frequentist (G. Gigerenzer & U. Hoffrage, 1995) norms. The authors argue that these frameworks have limited ability to explain the success and flexibility of people's real-world judgments and propose an alternative normative framework based on Bayesian inferences over causal models. Deviations from traditional norms of judgment, such as base-rate neglect, may then be explained in terms of a mismatch between the statistics given to people and the causal models they intuitively construct to support probabilistic reasoning. Four experiments show that when a clear mapping can be established from given statistics to the parameters of an intuitive causal model, people are more likely to use the statistics appropriately, and that when the classical and causal Bayesian norms differ in their prescriptions, people's judgments are more consistent with causal Bayesian norms. PMID- 17696693 TI - Object categorization: reversals and explanations of the basic-level advantage. AB - People are generally faster and more accurate to name or categorize objects at the basic level (e.g., dog) relative to more general (animal) or specific (collie) levels, an effect replicated in Experiment 1 for categorization of object pictures. To some, this pattern suggests a dual-process mechanism, in which objects first activate basic-level categories directly and later engage more general or specific categories through the spread of activation in a processing hierarchy. This account is, however, challenged by data from Experiment 2 showing that neuropsychological patients with impairments of conceptual knowledge categorize more accurately at superordinate levels than at the basic level--suggesting that knowledge about an object's general nature does not depend on prior basic-level categorization. The authors consider how a parallel distributed processing theory of conceptual knowledge can reconcile the apparent discrepancy. This theory predicts that if healthy individuals are encouraged to make rapid categorization responses, the usual basic > general advantage should also reverse, a prediction tested and confirmed in Experiment 3. Implications for theories of visual object recognition are discussed. PMID- 17696694 TI - Causal relations and feature similarity in children's inductive reasoning. AB - Four experiments examined the development of property induction on the basis of causal relations. In the first 2 studies, 5-year-olds, 8-year-olds, and adults were presented with triads in which a target instance was equally similar to 2 inductive bases but shared a causal antecedent feature with 1 of them. All 3 age groups used causal relations as a basis for property induction, although the proportion of causal inferences increased with age. Subsequent experiments pitted causal relations against featural similarity in induction. It was found that adults and 8-year-olds, but not 5-year-olds, preferred shared causal relations over strong featural similarity as a basis for induction. The implications for models of inductive reasoning and development are discussed. PMID- 17696695 TI - Scope of linguistic influence: does a classifier system alter object concepts? AB - Whether and to what extent conceptual structure is universal is of great importance for understanding the nature of human concepts. Two major factors that might affect concepts are language and culture. The authors investigated whether these 2 factors affect concepts of everyday objects in any significant ways. Specifically, they tested (a) whether the system of grammatical categorization by classifiers influenced the conceptual structure of speakers of classifier languages, and (b) whether Westerners organized object concepts around taxonomic relations whereas Easterners organized them around thematic relations, as proposed by R. E. Nisbett (2003). The relative importance of 3 types of relations -taxonomic, thematic, and classifier--for Chinese and German speakers was tested using a range of tasks, including categorization, similarity judgment, property induction, and fast-speed word-picture matching. Some support for linguistic relativity as well as for the cultural-specific cognition proposal was found in some tasks, but these effects were miniscule compared with the importance of taxonomic and thematic relations for both language-culture groups. The authors conclude that the global structure of everyday object concepts is strikingly similar across different cultures and languages. PMID- 17696696 TI - Estimating stimuli from contrasting categories: truncation due to boundaries. AB - In this article, the authors present and test a formal model that holds that people use information about category boundaries in estimating inexactly represented stimuli. Boundaries restrict stimuli that are category members to fall within a particular range. This model posits that people increase the average accuracy of stimulus estimates by integrating fine-grain values with boundary information, eliminating extreme responses. The authors present 4 experiments in which people estimated sizes of squares from 2 adjacent or partially overlapping stimulus sets. When stimuli from the 2 sets were paired in presentation, people formed relative size categories, truncating their estimates at the boundaries of these categories. Truncation at the boundary of separation between the categories led to exaggeration of differences between stimuli that cross categories. Yet truncated values are shown to be more accurate on average than unadjusted values. PMID- 17696697 TI - Tracking the mind during reading via eye movements: comments on Kliegl, Nuthmann, and Engbert (2006). AB - R. Kliegl, A. Nuthmann, and R. Engbert reported an impressive set of data analyses dealing with the influence of the prior, present, and next word on the duration of the current eye fixation during reading. They argued that outcomes of their regression analyses indicate that lexical processing is distributed across a number of words during reading. The authors of this comment question their conclusions and address 4 different issues: (a) whether there is evidence for distributed lexical processing, (b) whether so-called parafoveal-on-foveal effects are widespread, (c) the role of correlational analyses in reading research, and (d) problems in their analyses because they use only cases in which words are fixated exactly once. PMID- 17696700 TI - Memory for emotionally neutral information in posttraumatic stress disorder: A meta-analytic investigation. AB - Studies have come to conflicting conclusions about whether posttraumatic stress disorder (PTSD) is associated with poorer memory for emotionally neutral information. The authors report a meta-analysis of 27 studies that investigated verbal and/or visual memory in samples with PTSD and healthy controls. The results indicated that the association between PTSD and memory impairment appears to be robust, small to moderate in size, and stronger for verbal than for visual memory. Effect sizes did not vary according to whether recall was immediate or delayed. The association is found in both civilian and military samples and cannot be readily explained as being due to the use of nontraumatized healthy control groups or concurrent head injury. The findings are placed in the context of recent neurobiological and experimental cognitive research. PMID- 17696699 TI - Gender differences and developmental change in externalizing disorders from late adolescence to early adulthood: A longitudinal twin study. AB - Using data from over 1,000 male and female twins participating in the Minnesota Twin Family Study, the authors examined developmental change, gender differences, and genetic and environmental contributions to the symptom levels of four externalizing disorders (adult antisocial behavior, alcohol dependence, nicotine dependence, and drug dependence) from ages 17 to 24. Both men and women increased in symptoms for each externalizing disorder, with men increasing at a greater rate than women, such that a modest gender gap at age 17 widened to a large one at age 24. Additionally, a mean-level gender difference on a latent Externalizing factor could account for the mean-level gender differences for the individual disorders. Biometric analyses revealed increasing genetic variation and heritability for men but a trend toward decreasing genetic variation and increasing environmental effects for women. Results illustrate the importance of gender and developmental context for symptom expression and the utility of structural models to integrate general trends and disorder-specific characteristics. PMID- 17696702 TI - Examining a dimensional representation of depression and anxiety disorders' comorbidity in psychiatric outpatients with item response modeling. AB - The current study replicated, in a sample of 2,300 outpatients seeking psychiatric treatment, a previous study (R. F. Krueger & M. S. Finger, 2001) that implemented an item response theory approach for modeling the comorbidity of common mood and anxiety disorders as indicators along the continuum of a shared latent factor (internalizing). The 5 disorders examined were major depressive disorder, social phobia, panic disorder/agoraphobia, specific phobia, and generalized anxiety disorder. The findings were consistent with the prior research. First, a confirmatory factor analysis yielded sufficient evidence for a nonspecific factor underlying the 5 diagnostic indicators. Second, a 2-parameter logistic item response model showed that the diagnoses were represented in the upper half of the internalizing continuum, and each was a strongly discriminating indicator of the factor. Third, the internalizing factor was significantly associated with 3 indexes of social burden: poorer social functioning, time missed from work, and lifetime hospitalizations. Rather than the categorical system of presumably discrete disorders presented in DSM-IV, these 5 mood and anxiety disorders may be alternatively viewed as higher end indicators of a common factor associated with social cost. PMID- 17696703 TI - Dysfunctional attitudes and episodes of major depression: Predictive validity and temporal stability in never-depressed, depressed, and recovered women. AB - In a large, community-based sample of women (N = 750), the authors examined the nature of associations between dysfunctional attitudes and depression. Dysfunctional attitudes were evaluated both as a vulnerability factor for depression and as a consequence of depression. A link was found between past depression and baseline elevations in dysfunctional attitudes that was independent of current subsyndromal symptoms, but intensification of dysfunctional attitudes following prospectively evaluated episodes of depression (depressive "scarring") was not observed. Although baseline dysfunctional attitudes predicted an episode of major depression over 3 years of prospective study, this prediction, considered alone or in interaction with negative life events, was redundant with that offered by history of past depression. Further, no significant prediction was evident for the Dysfunctional Attitude Scale (A. N. Weissman & A. T. Beck, 1978) when the formerly depressed and never-depressed cohorts were considered separately. Implications for cognitive theories are discussed. PMID- 17696704 TI - Mood regulation in depression: Differential effects of distraction and recall of happy memories on sad mood. AB - Recent research suggests that the recall of positive memories plays an important role in mood regulation. In this study, the authors examined the ability of currently depressed, formerly depressed, and never-depressed participants to regulate sad mood through the recall of positive memories or through distraction. Although improvement in mood was found for all participants in response to distraction, under instructions to recall positive memories, never-depressed participants' moods improved, whereas formerly depressed participants' sad moods remained unchanged. It is important to note that depressed participants exhibited a worsening of their sad moods after recalling positive memories. These results suggest both that depression is associated with an impaired ability to use positive recall to regulate a sad mood and that this impairment continues to be evident following recovery. PMID- 17696705 TI - Biases in visual orienting to negative and positive scenes in dysphoria: An eye movement study. AB - The study investigated biases for negative information in component processes of visual attention (initial shift vs. maintenance of gaze) in dysphoric and nondysphoric individuals. Eye movements were recorded while participants viewed a series of picture pairs depicting negative, positive, and neutral scenes (each pair presented for 3 s). Biases in initial orienting were assessed from the direction and latency of the initial shift in gaze, whereas biases in the maintenance of attention were assessed from the duration of gaze on the picture that was initially fixated. Results indicated that the dysphoric group showed a significantly greater bias to maintain gaze longer on negative pictures, relative to control pictures, compared with the nondysphoric group. There was no evidence of a dysphoria-related bias in initial shift of orienting to negative cues. Results are consistent with a depression-related bias that operates in the maintenance of attention on negative material. PMID- 17696706 TI - Posttraumatic stress disorder symptoms, physiological reactivity, alcohol problems, and aggression among military veterans. AB - This study examined the association between posttraumatic stress disorder (PTSD) symptomatology and aggressive behavior among a sample of male Vietnam veterans (N = 1,328). Results indicated that the hyperarousal PTSD symptom cluster evidenced the strongest positive association with aggression at the bivariate level when compared with the other PTSD symptom clusters. When the PTSD symptom clusters were examined together as predictors, hyperarousal symptoms evidenced a significant positive relationship with aggression, and avoidance/numbing symptoms were negatively associated with aggression. Examination of potential mediators indicated that hyperarousal symptoms were directly associated with aggression and indirectly related to aggression via alcohol problems. Reexperiencing symptoms were associated with aggression only indirectly and through their positive association with physiological reactivity and negative association with alcohol problems. Study results highlight the complexity of the relationship between PTSD symptoms and aggression, and suggest possible mechanisms explaining this association. PMID- 17696707 TI - Early temperamental and psychophysiological precursors of adult psychopathic personality. AB - Emerging research on psychopathy in children and adolescents raises the question of whether indicators, such as temperament or psychophysiology, exist very early in life in those with a psychopathic-like personality in adulthood. This study tests the hypothesis that individuals who are more psychopathic in adulthood would be less fearful and inhibited and more stimulation seeking/sociable at age 3 and that they would also show reduced age 3 skin-conductance (SC) responsivity. In a community sample of 335 3-year-olds, behavioral measures of temperament were taken and electrodermal activity was recorded in response to both orienting and aversive tones. R. D. Hare's (1985) Self-Report Psychopathy scale (SRP-II) was administered at follow-up at age 28. Individuals scoring higher on the measure were significantly less fearful and inhibited, were more sociable, and displayed longer SC half-recovery times to aversive stimuli compared with controls at age 3. Contrary to predictions, they also showed increased autonomic arousal and SC orienting. Findings appear to be the first to suggest that a prospective link may exist between temperament and psychophysiology in very young children and psychopathic personality in adulthood. PMID- 17696708 TI - Axis I and II comorbidity in adults with ADHD. AB - Ongoing debate over the validity of the attention-deficit/hyperactivity disorder (ADHD) construct in adulthood is fueled in part by uncertainty regarding implications of potentially extensive yet incompletely described comorbid Axis I and II psychopathology. Three hundred sixty-three adults ages 18 to 37 completed semistructured clinical interviews; informants were also interviewed, and best estimate diagnoses were obtained. Results were as follows: First, ADHD combined type (ADHD-C) had an excess of externalizing and internalizing Axis I disorders, suggesting a gradient-of-severity relationship between it and ADHD inattentive type (ADHD-I). Second, ADHD-C and ADHD-I did not differ in frequency of Axis II disorders. Third, however, ADHD overall was associated with increased rates of Axis II disorders, compared with rates in non-ADHD control participants, including both Cluster B (primarily borderline personality disorder) and Cluster C disorders. Fourth, ADHD incrementally accounted for clinician-rated global assessment of functioning scores above and beyond comorbid conditions or symptoms on either Axis I or Axis II. Results further inform nosology of ADHD in adults. PMID- 17696709 TI - Externalizing symptoms among children of alcoholic parents: Entry points for an antisocial pathway to alcoholism. AB - The authors examined heterogeneity in risk for externalizing symptoms in children of alcoholic parents, as it may inform the search for entry points into an antisocial pathway to alcoholism. That is, they tested whether the number of alcoholic parents in a family, the comorbid subtype of parental alcoholism, and the gender of the child predicted trajectories of externalizing symptoms over the early life course, as assessed in high-risk samples of children of alcoholic parents and matched controls. Through integrative analyses of 2 independent, longitudinal studies, they showed that children with either an antisocial alcoholic parent or 2 alcoholic parents were at greatest risk for externalizing symptoms. Moreover, children with a depressed alcoholic parent did not differ from those with an antisocial alcoholic parent in reported symptoms. These findings were generally consistent across mother, father, and adolescent reports of symptoms; child gender and child age (ages 2 through 17); and the 2 independent studies examined. Multialcoholic and comorbid-alcoholic families may thus convey a genetic susceptibility to dysregulation along with environments that both exacerbate this susceptibility and provide few supports to offset it. PMID- 17696710 TI - The acute effects of nicotine on positive and negative affect in adolescent smokers. AB - Although adolescent cigarette smoking remains a critical public health concern, little is known about the reinforcing mechanisms governing smoking in this vulnerable population. To assess predictions derived from both positive and negative reinforcement models of drug use, the authors measured the acute effects of nicotine, as administered via tobacco cigarettes, on both positive and negative affect in a group of 15- to 18-year-old smokers. A matched group of nonsmokers served as a comparison group. Findings revealed that whereas adolescents who smoked a cigarette experienced reductions in both positive and negative affect, the observed reductions in negative affect were moderated by nicotine content of the cigarette (high yield vs. denicotinized), level of nicotine dependence, level of baseline craving, and smoking expectancies pertinent to negative affect regulation. Nonsmokers experienced no change in affect over the 10-min assessment period, and no interaction effects were observed for positive affect. Overall, the findings conform to a negative reinforcement model of nicotine effects and strongly suggest that, even among young light smokers, nicotine dependence and resultant withdrawal symptomatology may serve as motivating factors governing smoking behavior. PMID- 17696711 TI - Delinquent peer affiliation and conduct problems: A twin study. AB - Many putative environmental risks correlate with individuals' genotypes. The association between delinquent peer affiliation and conduct problems may occur because of shared genetic liability. Five hundred fifty three monozygotic and 558 dizygotic twin pairs, aged 11 to 18 years, were assessed for delinquent peer affiliation and conduct problems. The authors investigated whether genes contribute to both delinquent peer affiliation and the correlation between delinquent peer affiliations and conduct problems. Delinquent peer affiliation was influenced by genetic, shared environmental, and nonshared environmental factors; genetic factors also contributed to the correlation between delinquent peer affiliations and conduct problems, providing evidence for genotype environment correlation. The magnitude of the genetic variance of conduct problems was contextually dependent on levels of delinquent peer affiliation and was greater at higher levels of delinquent peer affiliation. PMID- 17696712 TI - P300 amplitude, externalizing psychopathology, and earlier- versus later-onset substance-use disorder. AB - P300 amplitude predicts substance use or disorder by age 21. Earlier- versus later-onset substance disorders may reflect different levels of an externalizing psychopathology dimension. P300 in adolescence may not be as strongly related to later-onset substance problems as it is to earlier-onset ones. In the present study, visual P300 amplitude was measured at age 17 in a community-representative sample of young men. Substance and externalizing disorders were assessed at approximately ages 17, 20, and 24. Earlier-onset (by age 20) substance disorder was associated with higher rates of externalizing disorders than were later-onset problems. P300 amplitude was reduced in subjects with earlier-onset substance disorders, relative to later-onset and disorder-free subjects. Amplitude was also reduced in subjects with an externalizing disorder but no substance disorder. Earlier-onset subjects had reduced P300, even in the absence of an externalizing disorder. The results could not be attributed to a concurrent disorder or to recent substance use at the time of the P300 recording. The findings are consistent with P300 indexing an externalizing spectrum. Earlier-onset substance disorders are more strongly related to P300 and externalizing than are later onset problems. PMID- 17696713 TI - Stability and variability of affective experience and interpersonal behavior in borderline personality disorder. AB - This study examined both mean levels and intraindividual variability in the mood and interpersonal behavior of individuals with borderline personality disorder (BPD) and nonclinical control participants over a 20-day event-contingent recording period. Individuals in the BPD group experienced more unpleasantly valenced affect and were less dominant, more submissive, more quarrelsome, and more extreme in overall levels of behavior than control participants. In addition to these mean-level differences, individuals with BPD also reported more intraindividual variability in overall affect valence and in pleasantly valenced affect; displayed greater variability in dominant, quarrelsome, and agreeable behaviors; and exhibited an increased tendency to "spin" among interpersonal behaviors relative to nonclinical control participants. The findings document behavioral and affective manifestations of BPD in the context of naturally occurring interpersonal situations. PMID- 17696714 TI - Gaze strategies during planning in first-episode psychosis. AB - Eye movements were measured during the performance of a computerized Tower of London task to specify the source of planning abnormalities in patients with 1st episode schizophrenia or schizoaffective disorder. Subjects viewed 2 arrays of colored balls in the upper and lower parts of the screen. They were asked to plan the shortest sequence of moves required to rearrange the balls in the lower screen to match the upper arrangement. Compared with healthy controls, patients made more planning errors, and decision times were longer. However, the patients showed the same gaze biases as controls prior to making a response, indicating that they understood the requirements of the task, approached the task in a strategic manner by identifying the nature of the problem, and used appropriate fixation strategies to plan and elaborate solutions. The patients showed increased duration of long-gaze periods toward both parts of the screen. This suggests that the patients had difficulty in encoding the essential features of the stimulus array. This finding is compatible with slowing of working memory consolidation. PMID- 17696715 TI - Acute dissociation after 1 night of sleep loss. AB - Recent research has shown that dissociative symptoms are related to self-reports of deviant sleep experiences. The present study is the 1st to explore whether sleep loss can fuel dissociative symptoms. Twenty-five healthy volunteers were deprived of sleep for 1 night. Sleepiness and dissociative symptoms were assessed every 6 hr. The authors measured both spontaneous dissociative symptoms and dissociative symptoms induced by dot-staring during sensory deprivation. Sleepiness as well as spontaneous and induced dissociative symptoms were stable throughout the day but increased during the night. These findings provide further evidence for a robust relationship between disruptions in sleep patterns and dissociative symptoms. PMID- 17696716 TI - Gender differences in the sensitivity to posttraumatic stress disorder: An epidemiological study of urban young adults. AB - The authors examine the relationship between 2 separate but interrelated findings in the epidemiology of posttraumatic stress disorder (PTSD): women's greater PTSD risk following traumatic events and the sensitizing effects of a prior trauma on the PTSD response to a subsequent trauma. Data come from a representative sample of 1,698 young adults from a large U.S. city. Analysis was conducted on the subset exposed to traumatic events. Women's risk for PTSD following assaultive violence was higher than men's. When assaultive violence preceded a later nonassaultive trauma in women, there was an increased risk (relative risk = 4.9) for PTSD, which was not observed in men. The relative risk estimate in women was significantly higher than in men. These findings suggest that assaultive violence elicits women's PTSD response directly and by sensitizing them to the effects of subsequent traumatic events of lesser magnitude. PMID- 17696717 TI - Fear conditioning in panic disorder: Enhanced resistance to extinction. AB - Enhanced conditionability has been proposed as a crucial factor in the etiology and maintenance of panic disorder (PD). To test this assumption, the authors of the current study examined the acquisition and extinction of conditioned responses to aversive stimuli in PD. Thirty-nine PD patients and 33 healthy control participants took part in a differential aversive conditioning experiment. A highly annoying but not painful electrical stimulus served as the unconditioned stimulus (US), and two neutral pictures were used as either the paired conditioned stimulus (CS+) or the unpaired conditioned stimulus (CS-). Results indicate that PD patients do not show larger conditioned responses during acquisition than control participants. However, in contrast to control participants, PD patients exhibited larger skin conductance responses to CS+ stimuli during extinction and maintained a more negative evaluation of them, as indicated by valence ratings obtained several times throughout the experiment. This suggests that PD patients show enhanced conditionability with respect to extinction. PMID- 17696718 TI - The Shedler and Westen Assessment Procedure from the perspective of general personality structure. AB - The Shedler and Westen Assessment Procedure (SWAP-200; J. Shedler & D. Westen, 2004) has received increasing support as a dimensional model of personality pathology. However, only 1 prior study has related empirically the SWAP-200 with any other measure of personality or personality disorder. The purpose of the current study was to determine whether the SWAP-200 personality disorder and personality dimension scales relate meaningfully to the domains and facets of the five-factor model (FFM; J. M. Digman, 1990) of general personality structure. Individuals (n = 94) with significant personality pathology were described on instruments of general personality and personality pathology. The results of the current study suggest that most of the SWAP-200 personality and personality disorder scales relate to the domains and facets of the FFM in a manner consistent with FFM theory and previous FFM personality disorder research. Inconsistent findings and limitations are discussed, along with suggestions for future research. PMID- 17696719 TI - Effects of situational demand upon social enjoyment and preference in schizotypy. AB - The socioemotional functioning of schizophrenic and schizotypic individuals is marked by withdrawal, poor organization, and limited emotional displays. Such behavioral tendencies and lack of social enjoyment in schizotypy could be linked to the relative situational demands or role ambiguity inherent in specific social activities. To determine whether high-schizotypy individuals prefer more clearly role-defined social activities (e.g., visiting relatives) to more ambiguous, novel situations (e.g., going alone to a party), the authors gathered reports from 52 high-schizotypy and 60 low-schizotypy individuals on their enjoyment and frequency of engaging in social situations varying in relative situational demand. Parallel reports were obtained from knowledgeable others. Group x Situational Demand interactions revealed the hypothesized pattern of reduced frequency and enjoyment ratings for ambiguous or novel situations by the high schizotypy participants in both self and others' reports. Groups were more comparable in their reported frequency and enjoyment of less ambiguous situations. Results suggest the importance of situational demands in the socioemotional experience and behavioral withdrawal in schizotypy. PMID- 17696720 TI - Response perseveration in psychopaths: Interpersonal/affective or social deviance traits? AB - In order to clarify the role of the two broad components of psychopathy (interpersonal/affective and social deviance; R. D. Hare, 2003) in explaining maladaptive response perseveration in psychopaths, as well as the role of reflection after punished responses in this deficit, the authors administered a card perseveration task to 47 Spanish male inmates assessed using the Hare Psychopathy Checklist-Revised (PCL-R; R. D. Hare, 1991). Hierarchical regressions showed that psychopaths' maladaptive perseveration (more cards played and less money earned) was uniquely predicted by the social deviance features of psychopathy (PCL-R Factor 2)--particularly by its impulsive and irresponsible lifestyle facet (PCL-R Facet 3)--and not by its interpersonal/affective features (PCL-R Factor 1). Moreover, perseveration was related to a lack of reflection both after punishment and after reward feedback. The authors' results, in conjunction with previous evidence indicating perseverative deficits in several impulse control disorders, suggest that response perseveration may not be specific to psychopathy but rather is associated more generally with the externalizing dimension of psychopathology. PMID- 17696721 TI - Marital distress and DSM-IV psychiatric disorders in a population-based national survey. AB - The associations between marital distress and Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) Axis I psychiatric disorders were evaluated in a United States population-based survey of married individuals in which there was no upper age exclusionary criterion (N = 2,213). Marital distress was associated with (a) broad-band classifications of anxiety, mood, and substance use disorders and (b) all narrow band classifications of specific disorders except for panic disorder, with the strongest associations obtained between marital distress and bipolar disorder, alcohol use disorders, and generalized anxiety disorder. The association between marital distress and major depressive disorder increased in magnitude with increasing age; there was no evidence that the association between marital distress and other psychiatric disorders was moderated by gender or age. Results support continued research on the association between couple functioning and mental health. PMID- 17696722 TI - Survival from hepatocellular carcinoma at a cancer hospital in Pakistan. AB - OBJECTIVES: To determine the tumour and general characteristics, especially survival, of patients presenting with hepatocellular carcinoma at our tertiary care cancer hospital. PATIENTS AND METHODS: We retrospectively studied 584 charts of patients consecutively registered between 1995 and 2004 at the Shaukat Khanum Memorial Cancer Hospital and Research Centre, in Lahore, Pakistan. Descriptive statistics were obtained for gender, age, tumour size and morphology, alpha fetoprotein level, means of diagnosis, Child-Pugh status, risk factors, treatment given and follow-up. Survival analysis was conducted using the Kaplan-Meier method. RESULTS: Mean age at presentation was 56 years. Four hundred and forty four (76%) were male. Average tumour diameter evaluable in 412 patients was 8 cm. HCC was unifocal in 194 (33%), multifocal in 303 (52%) and unevaluable in 106. Mean AFP was 4,198 u/ml (range 1 - 278,560). Methods of diagnosis were FNA in 71, biopsy in 26, imaging/AFP > 200 in 70, lipiodol angiogram in 42, combinations of two of these in 365 and biphasic CT scans in 10. Initial Child-Pugh available for 400/584 was A in 216, B in 147 and C in 37. Evidence of prior hepatitis B infection was found in 114, and for hepatitis C in 254. Other than the four patients who had TACE followed by surgical resection, treatment was offered to 79/584 patients: among the 48 who had TACE, 26 experienced cancer progression whereas 11 had stable disease ranging from 6 - 20 months; another 11 were lost to follow-up. Of the 14 patients who underwent local resection, 2 were lost to follow-up, 7 developed recurrences but 5 remained disease free for a mean of 33 months. Following ethanol ablation in 17 patients, disease progressed in 5 but remained stable in 2 for a mean of 13 months; 10 were lost to follow-up. At the time of writing, 56 patients are alive (mean follow-up 20 months), 210 are known to have died (mean follow-up 9 months), and 318 were lost to follow-up within 3 months. Median overall survival was 10.5 months, death being the point of interest for survival analysis. Child-Pugh class stratified analysis (400/584) revealed median survival of 12 months for class A, 7.7 months for class B and 4 months for class C (p < 0.001). CONCLUSIONS: Most patients present with large, multifocal tumours, with poor liver function. Sixty one percent had evidence of prior infection with hepatitis B or C. The advanced stage at presentation, poor background liver function in many and the absence of a national liver transplantation program limit treatment options. Only 14% of patients were considered suitable for definitive treatment. Survival correlated with Child-Pugh status at presentation. Overall prognosis remains bleak. There is an urgent need to educate the public about the risks of hepatitis B and C and health professionals about early diagnosis and treatment, including possible development of a sustainable national liver transplant program. PMID- 17696724 TI - The JICA training course, community-based cancer prevention for the Asian and Pan Pacific countries, fiscal year 2006 (epidemiological approach). AB - Communicable diseases are still major causes of deaths in developing countries. Cancer incidence, however, increased 19% between 1990 and 2000, mainly in this same developing world (Stewart and Kleihaus, 2003), and malignant neoplasms are now the second leading cause of mortality in these countries (WHO, 2003). Limitations of medical facilities and equipment mean that prevention is indispensable for cancer control (Mikheev et al., 1994). However, human resources concerning cancer prevention are also limited, and encouragement of their development should be taken as a first priority. To assist in this aim, the present training course was designed by the Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Japan, and has been annually conducted since 1999, supported by the Japan International Cooperation Agency (JICA) (Takezaki, 2001; 2002; 2003; Wakai, 2004; 2006). The course targets doctors and public health workers who are responsible for community-based cancer prevention in developing countries to promote the introduction of comprehensive procedures, focusing mainly on primary prevention but also including screening for secondary prevention of cancer. PMID- 17696725 TI - Tea and cancer chemoprevention: a comprehensive review. AB - Dietary components that are capable of inhibiting the growth of cancer cells without affecting the growth of normal cells are receiving considerable attention in developing novel cancer-preventive approaches. Tea, made from young leaves and leaf buds of the tea plant, 'Camellia sinensis', and the world's second most consumed beverage, has received a great deal of attention both from the general public and the scientific community because tea polyphenols are strong antioxidants, and tea preparations have inhibitory activity against tumorigenesis. Besides this, the wide spread consumption of tea throughout the world evoked the interest of the scientific community in the possibility of its use in cancer prevention. There are three main types of tea, all coming from the tea plant viz. black tea (fermented,) green tea (unfermented), or oolong tea (semi-fermented), classified based on the methods of brewing and processing. Inhibition of tumorigenesis by green or black tea preparations has been demonstrated in various animal models in different organs. Various epidemiological studies substantiate the correlation between tea consumption and cancer prevention; however, they have not yielded clear conclusions pertaining to the protective effects of tea consumption against cancer development in humans. Many mechanisms have been proposed for the inhibition of carcinogenesis by tea, including the modulation of signal transduction pathways (including growth factor mediated, mitogen-activated protein kinase (MAPK)-dependent, and ubiquitin/proteasome degradation pathways ) that lead to the inhibition of cell proliferation and transformation; induction of apoptosis of preneoplastic and neoplastic cells, and inhibition of tumor invasion as well as angiogenesis. These mechanisms need to be evaluated, verified and corroborated in animal models and humans in order to gain more understanding on the effects of tea consumption on human cancer. Because the causative factors are different for different populations, tea consumption may affect carcinogenesis only in selected situations rather than having the general effect on all cancers. Although, on the basis of many epidemiological observations and numerous laboratory studies, it can be concluded that tea consumption is likely to have beneficial effects in reducing cancer risk in different populations, yet there is a need to define the population that could benefit from tea consumption. After careful evaluation of additional studies, it may be possible to recommend consumption of tea polyphenols by humans. Although considerable accumulating information provides a compelling body of evidence for the preventive potential of tea against cancer, naturally occurring tea polyphenols have yet to be evaluated in clinical intervention in human trials. PMID- 17696726 TI - Impact of C-reactive protein on disease risk and its relation to dietary factors. AB - C-reactive protein (CRP) is one of the acute-phase proteins in inflammation and CRP serum concentrations are therefore of interest. Data for high-sensitivity CRP (hs-CRP) with a low detection limit of approximately 0.04 mg/L have become available over the past decade and research has shown a link between high concentrations of hs-CRP and obesity as well as smoking. Expanded adipose tissue is in fact known to secrete proinflammatory cytokines which enhance hepatic synthesis of CRP. Moderate alcohol consumption and high physical activity have been associated with low levels of hs-CRP, but the evidence in these cases is not conclusive. It has been suggested that hs-CRP is an independent marker of the risk of cardiovascular disease, but the predictive capacity remains controversial. However, many prospective studies have observed increased risk of type 2 diabetes mellitus associated with high concentrations of hs-CRP, independent of obesity and other cardiovascular risk factors. On the other hand, no measurable increase in the risk associated with high levels of hs-CRP was observed with multivariate adjustment in several studies. A number of authors have reported that high concentrations of hs-CRP are associated with increased risks of colorectal and other cancers, but the findings again are inconsistent. Diet and hs-CRP are also of increasing research interest. High intakes of carotenoids and vitamin C, but not of vitamin E, seem to decrease the level of circulating hs-CRP. In addition, high consumption of vegetables and fruit are associated with lower levels of circulating hs-CRP, perhaps by exerting anti inflammatory effects. Both mechanistic and epidemiologic studies regarding dietary factors and low-grade inflammation are necessary to add to our knowledge of dietary influence on chronic disease development. PMID- 17696727 TI - Secondhand smoke in the home and Pap testing among Vietnamese American women. AB - The purpose of this study was to report the prevalence of Vietnamese households with smokers and examine Papanicolau (Pap) testing among Vietnamese American women living in households with and without smokers. In 2002, we surveyed Vietnamese between 18 and 64 years of age from a population-based sample of randomly selected households in Seattle, Washington zip codes known to have a high density of Vietnamese residents. The response rate among eligible households was 82%, and our sample included 418 households. We used two measures of Pap testing: ever had a Pap test and had one in the last two years. Household smoking status was categorized as current smoker in the house vs. no current smoker in the house. Overall, 47% of Vietnamese American women lived with a current smoker in the household, 73% had ever received a Pap test, and 63% received one in the last two years. Pap testing behavior varied only slightly by household smoking status, and the findings were not statistically significant. With nearly half of Vietnamese women in our study currently living with smokers, future studies should examine the relationship between secondhand smoke at home and other health behaviors in Vietnamese American households. PMID- 17696728 TI - Cancer pattern in Western Nepal: a hospital based retrospective study. AB - Information on cancer patterns is an important basis for determining the priorities for cancer control in different countries worldwide. There is no reliable information about the incidence or pattern of cancer in Nepal and hence an attempt was made to assess the situation based on hospital data which is the only source in the western region of Nepal. Cancer cases diagnosed by all methods or treated in Manipal Teaching Hospital, affiliated to Manipal College of Medical Sciences, Pokhara, during 1st January 2003 to 30th May 2005 were used for the present study. A total of 957 cancer cases were identified with a male to female ratio of 1.1:1. The median age of male and female patients was 63 and 60 years, respectively. The proportion of microscopically confirmed cases, both from primary and metastatic sites was 87.5% and tobacco-related cancers constituted 48% of all cancers among males and 28% among females. For males the leading cancer sites were lung (22.2%), larynx (9.8%) and stomach (9%) and that for females was lung (20%), cervix (19.7%) and breast (7.8%). Among males, 33.1% of all cancers were in the respiratory system followed by digestive organ cancers (23.2%). Among females, 28.4% cancers were related to the reproductive system, 22.8% to the respiratory system and 14.1% to digestive organs. The cancer pattern revealed by the present study provides valuable leads to cancer epidemiology in Nepal, particularly in the western region, and provides useful information for health planning and future research. PMID- 17696729 TI - Cancer registration in Basrah 2005: preliminary results. AB - Cancer is a disease which shows significant variation with time and across geographical entities. In Basrah, Iraq, despite the widespread impression that cancer is increasing, researchers are not yet able to draw clear boundaries as to the extent of cancer and its determinants. In this paper, we make a start in that direction; the aim was to measure as accurately as possible the incidence of cancer (all types) in Basrah, to assess age specific incidence rates and to map the cases across different areas of the governorate. For this purpose we compiled data on every accessible case of cancer. The cancer registry in Basrah was used as the prime source of data on newly diagnosed cancer cases, supported by three other sources: the Cancer Registration Section at the Department of Pathology and Forensic Medicine, College of Medicine, University of Basrah; the Oncology Centre at Al-Sadr Teaching Hospital; and the Oncology Ward in Basrah Maternity and Child Hospital. Other minor sources were also utilized. Information on cases from these sources was subjected to meticulous verification regarding repetition, place of residence and other potential errors. The overall incidence rate was 74.3/100,000 population with a higher rate for females (80.5/100,000) than for males (68.1/100,000). The results indicate clear increase in registered cancer cases with increasing age. The lowest incidence rate was among females aged 5-14 years (10.5/100,000) and the highest was among males aged 65 years and above (660.2/100,000). The results show no major variation in the annual incidence rates of cancer in different areas of Basrah governorate. This finding may suggest a common exposure to cancer risk factors. To reach sound conclusions about extent and determinants of cancer in Basrah, immense multi-spectrum efforts are now needed. PMID- 17696730 TI - The role of lifestyle risk factors on mortality from colorectal cancer in populations of the Asia-Pacific region. AB - Although colorectal cancer is one of the leading malignancies worldwide, there are few data on aetiological relationships from the Asia-Pacific region. Therefore, a collaborative study was conducted involving over half a million subjects from 33 cohort studies in the region. Age-adjusted death rates from colorectal cancer, over an average of 6.8 years follow-up, were 12 and 14 per 100,000 person-years among Asian women and men, respectively; corresponding values in Australasia were 31 and 41. Height was strongly associated with death from colorectal cancer: an extra 5 cm of height was associated with 10% (95%confidence interval, 3% - 18% additional risk, after adjustment for other factors. Smoking increased risk by 43% (9% - 88%), although no significant dose response relationship was discerned (p>0.05). Other significant (p <0.05) risk factors were body mass index and lack of physical activity. There was no significant effect on colorectal cancer mortality for alcohol consumption, waist circumference, fasting blood glucose or diabetes, although the latter conferred a notable 26% additional risk. Height may be a biomarker for some currently unknown genetic, or environmental, risk factors that are related both to skeletal growth and mutanogenesis. Understanding such mechanisms could provide opportunities for novel preventive and therapeutic intervention. PMID- 17696732 TI - How can the overtreatment rate of "see and treat" approach be reduced in women with high-grade squamous intraepithelial lesion on cervical cytology? AB - BACKGROUND: The aim of this study was to determine the incidence and predictors of overtreatment in "see and treat" approach using loop electrosurgical excision procedure (LEEP) in women with high-grade squamous intraepithelial lesion (HSIL) on cervical cytology. The overtreatment was considered when LEEP specimens contained no cervical pathology. Between January 2001 and April 2006, 446 women with HSIL on Pap smear underwent colposcopy followed by LEEP at Chiang Mai University Hospital. Mean age of these patients was 45.6 years with a range of 25 78 years. One hundred and twenty-one (27.1%) women were menopausal. Unsatisfactory colposcopy was observed in 357 (80.0%) women. Of 446 women, histologically-confirmed HSIL, invasive cancer, low-grade squamous intraepithelial lesions, and adenocarcinoma in situ were detected in 330 (74.0%), 76 (17.0%), 9 (2.0%), and 5 (1.1%), respectively. The overtreatment rate on LEEP specimens was noted in 26 women or 5.8% (95% confidence interval [CI] = 3.8 to 8.4) of 446 women. By multivariate analysis, postmenopausal status was the only significant independent predictor of overtreatment with an adjusted odds ratio of 2.89 (95% CI = 1.30 to 6.43, P = 0.009). When postmenopausal women were excluded from analysis, the overtreatment rate was reduced to only 4.0%. In conclusion, "see and treat" approach appears to be an appropriate strategy in managing women with HSIL cytology. The overtreatment rate could be reduced when such policy is limited for premenopausal women. PMID- 17696733 TI - Ethnic differences in survival for female cancers of the breast, cervix and colorectum in British Columbia, Canada. AB - BACKGROUND: Chinese and South Asians are among the fastest growing minority populations in Canada; however little is known about the burden of cancer in these populations. OBJECTIVE: The objective is to examine survival rates for breast, cervical and colorectal cancers in women within these two ethnic populations, as compared to the BC general population. METHODS: Survival rates were calculated for three time periods in the Chinese, South Asian and BC general populations, using the BC cancer registry. Ethnicity within the registry was determined using surnames. RESULTS: Survival rates for female breast, cervical and colorectal cancers have improved over time in all three population groups, however general differences were found among the groups. Chinese women had higher survival rates than both South Asians and all BC women for breast and cervical cancer, and intermediate survival rates between South Asians and all BC women for colorectal cancer. South Asian women had the highest survival rates for colorectal cancer, similar survival rates to all BC women for breast cancer, and lower survival rates for cervical cancer. INTERPRETATION: Differences in the observed survival rates may be explained by variations in screening and early detection, treatment practices, and cancer biology. This is discussed more fully for each cancer site. PMID- 17696731 TI - The impact of modifiable risk factors on mortality from prostate cancer in populations of the Asia-Pacific region. AB - Mortality from cancer of the prostate is increasing in the Asia-Pacific, when much of this region is undergoing a transition to a Western lifestyle. The role that lifestyle factors play in prostate cancer appears limited, but existing data mainly are from the West. We conducted an individual participant data analysis of 24 cohort studies involving 320,852 men (83% in Asia). Cox proportional hazard models were used to quantify associations between risk factors and mortality from prostate cancer. There were 308 deaths from prostate cancer (14% in Asia) during 2.1 million person-years of follow-up. The age-adjusted hazard ratio (95% confidence interval; CI) for men with body mass index (BMI) 28 kg/m2 or more, compared with below 25, was 1.55 (1.12 - 2.16); no such significant relationship was found for height or waist circumference. The BMI result was unchanged after adjustment for other variables, was consistent between Asia and Australia/New Zealand (ANZ) and did not differ with age. There was no significant relationship with diabetes, glucose or total cholesterol (p > or = 0.18). Smoking, alone, showed different effects in the two regions, possibly due to the relative immaturity of the smoking epidemic in Asia. In ANZ, the multiple-adjusted hazard ratio for an extra 5 cigarettes per day was 1.12 (95%CI: 1.03 - 1.22), whereas in Asia it was 0.77 (0.56 - 1.05). Body size is an apparently important determinant of prostate cancer in the Asia-Pacific. Evidence of an adverse effect of smoking is conclusive only in the predominantly Caucasian parts of the region. PMID- 17696734 TI - Patho-epidemiology of breast cancer in Karachi '1995-1997'. AB - OBJECTIVE: Provide an overview of the demographics and pathology of breast cancer in the female population of Karachi South during a 3 year period, 1995-1997. METHODS: Epidemiological data for 709 incident breast cancer cases, ICD-10 category C50 registered at Karachi Cancer Registry during 1st January 1995 to 31st December 1997 were reviewed. RESULTS: Breast cancer accounted for approximately one-third of the cancers in females. The age standardized incidence rate (ASR) world per 100,000 was 53.8, the crude incidence rate was 30.9. In KS 60% of the newly diagnosed breast cancers were observed in women below 50 years. The age-specific curves showed a gradual increase in risk from the third up till the seventh decade, followed by an actual/apparent decrease in risk. The socio economic distribution was 24.9% in category I the financially deprived class, 38.9% in category II the middle class and 35.9% in category III, the affluent class. Microscopic confirmation of malignancies was 99%. Invasive breast cancers predominated with 99.4%, with in-situ cancers contributing to 0.6% of the malignancies. The morphology of cancers was tilted towards duct cell carcinoma (DCC), pure DCC (92%), combinations of DCC /Paget's disease (0.6%) and lobular carcinoma (0.4%). Approximately 45% of duct cell carcinoma were seen in the premenopausal age group (<45 years). All bilateral breast cancers were duct cell carcinoma with a family history of first degree relative with breast cancer. The majority of the cases presented as moderately differentiated or grade 2 lesions (59.0%). Approximately 56% cancers had spread to the regional lymph nodes and 8.3% to a distant site at the time of diagnosis. A family history of first degree relative with breast cancer was present in 3% and second degree relatives in 7% of the cases. Odds ratio (OR) for 680 breast cancer cases with complete demographic information was calculated with 675 gender matched controls. A slightly higher risk was observed in non-Muslims and migrant ethnicities: two to three fold elevation in the Indian migrants (Gujrati speaking Mohajirs OR 3.86 (95% CI 2.51; 5.92) Urdu speaking Mohajirs OR 2.85 (95% CI 2.05; 3.96), Memon Mohajirs OR 2.21 (95% CI 1.48; 3.29) and Afghan migrants [OR 2.99 (95% CI 11.20; 7.44)]. The risk was also high in the females of Punjabi ethnicity settled in KS [OR 2.73 (95% CI 1.87; 3.99)]. The risk seems much less for the ethnicities belonging to North Western Pakistan i.e. Pathans [OR 1.684 (95% CI 0.89; 3.17)] and Baluchs [OR 0.90 (95% CI 0.58; 1.39)]. A marginally higher risk was observed in the higher socio-economic categories. The risk of developing breast cancer increased gradually for each age category from illiterate [OR 1.2 (95% CI 0.94; 1.55)] to college graduates [OR 13.12 (95% CI 7.31; 23.73)]. CONCLUSIONS: The incidence of breast cancer in Karachi South (KS) for the period 1995-1997 was the third highest in Asia. The hallmarks were a high reproductive age malignancy involving a higher socio-economic class, an invasive duct cell carcinoma diagnosed at an advanced stage, in younger more educated females and a low in situ malignancy. More studies are required to obtain a deeper insight into this breast cancer epidemic in Karachi. Implementation of breast cancer screening with stress on public health education is today a major responsibility of the government. PMID- 17696735 TI - Aberrant promoter methylation profile in pleural fluid DNA and clinicopathological factors in patients with non-small cell lung cancer. AB - The aim of this study was to investigate the prognostic value of hypermethylation of tumor suppressor genes in patients with non-small cell lung cancer (NSCLC). In samples from 34 lung patients with malignant pleural effusions, we used a methylation-specific polymerase chain reaction to detect aberrant hypermethylation of the promoters of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT), p16INK4a, ras association domain family 1A (RASSF1A), apoptosis-related genes, death-associated protein kinase (DAPK), and retinoic acid receptor beta(RARbeta). There is no association between methylation status of five tumor suppressor genes including MGMT, p16INK4a, RASSF1A, DAPK and RARbeta in pleural fluid DNA and clinicopathological parameters including clinical outcome. Aberrant promoter methylation of tumor suppressor genes in pleural fluid DNA could not be a valuable prognostic marker of NSCLC patients with malignant pleural effusion. PMID- 17696736 TI - Factors affecting residual lesion in women with cervical adenocarcinoma in situ after cone excisional biopsy. AB - The objective of this study was undertaken to evaluate the factors affecting residual lesion in women with adenocarcinoma in situ (AIS) on cervical conization specimens. The medical records of women with AIS who had no associated invasive carcinoma after cervical conization and underwent subsequent hysterectomy at Chiang Mai University Hospital were reviewed. During March 1998 and March 2006, 45 women were included for analysis. The mean age was 45.2 years (range, 30-66 years). Thirteen (28.9%) women presented with AIS on Pap smear. Thirty (66.7%) underwent loop electrosurgical excision procedure and the remaining 15 (33.3%) underwent cold-knife conization. Twenty (44.4%) women had mixed lesions of AIS and squamous intraepithelial lesion on cervical specimens. Surgical cone margins were clear in 25 (55.6%) women. Eighteen (40%) and two (4.4%) women had involved and non-evaluable cone margins, respectively. Residual lesion was noted in 14 (31.1%) hysterectomy specimens. There was no residual lesion in women with clear cone margins while 72% and 50% of women with involved and non-evaluable cone margins, had residual lesion, respectively. These differences were statistically significant (P<0.001). No significant association between the ECC results and the residual lesion was noted (P=0.29). In conclusion, approximately one-third of women with AIS on cervical conization have residual lesion on subsequent hysterectomy specimens. Only cone margin status is a significant predictor for residual lesion. PMID- 17696737 TI - Utility of urinary biomarkers in oral cancer. AB - OBJECTIVE: Oral cancer is the leading malignancy in India, with tobacco playing a major role in the etiology. The aim of the present study was to quantify nitrate+nitrite (NO2+NO3) in tobacco products as well as to study tobacco exposure related biomarkers in controls, patients with oral precancers (OPC) and oral cancer patients. MATERIALS & METHODS: Healthy individuals (n=90) were grouped into without habit of tobacco (NHT, n=30) and healthy individuals with habit of tobacco (WHT, n=60). Oral cancer patients with a tobacco habit were classified into abstinence (n=62) and non-abstinence (n=64) groups according to status at the study time. Urinary nicotine and cotinine levels were analyzed by modified high-pressure liquid chromatography (HPLC) using a UV detector. Levels of NO2+NO3 in tobacco and urine, and urinary thioether levels were estimated by spectrophotometry. RESULTS: NO2+NO3 levels in different types of tobacco product ranged between 0.13 to 3.39 mg/g. The Odds Ratio (OR) analysis indicated positive associations of both smoking and chewing habits of tobacco with high risk of development of oral cancer. Urinary nicotine, cotinine and NO2+NO3 levels were significantly elevated in WHT, patients with OPC and oral cancer patients as compared with the NHT group. This was also the case for urinary thioether levels. Levels of urinary nicotine and cotinine were also higher in the non-abstinence group with oral cancers. CONCLUSION: The results confirmed that tobacco chewing and smoking habits are prominent risk factors for development of oral cancer in the western part of India (Gujarat). Urinary nicotine, cotinine, NO2+NO3 and thioether levels can be helpful for screening programs for oral cancer. PMID- 17696738 TI - Does solar ultraviolet irradiation affect cancer mortality rates in China? AB - Solar ultraviolet B (UVB) has been found to correlate with reduced risk for 14 types of cancer in three or more observational studies and another 14 in one-to two observational studies. The beneficial role of UVB is thought to be mediated through vitamin D production. Few such studies have been conducted in Southeast Asia. Data on cancer mortality rates for 65 counties in China in 1978 and approximately 300 geographic, dietary, serum, occupation, and lifestyle factors from 1983-4 are available in Diet, Life-style and Mortality in China (Chen et al., Oxford University Press, 1990). The data for 39 counties away from the east coast of China were used in multiple linear regression analyses. The indices of solar UV radiation (UVR), latitude and heat index, were correlated with reduced mortality rates for cervical, colorectal (females), esophageal, gastric, and lung (males) cancer. Latitude was inversely correlated with liver cancer (males) and nasopharyngeal carcinoma (NPC). Lung cancer, the index used for smoking, was correlated with all less lung (males), cervical, liver (males), and NPC. Several other factors were also correlated with some of the cancers. However, no other factors could explain the latitudinal variation for these seven cancers. Thus, it is concluded that solar UVB, through production of vitamin D, reduces the risk of some types of cancer in China. Liver cancer and NPC are linked to viruses, and UVR may increase the risk through immunosuppression. Further studies are warranted. PMID- 17696739 TI - Reassessment of risk factors for oral cancer. AB - A total of 140 cases of histologically confirmed oral cancer were evaluated for their demographic details, dietary habits and addiction to tobacco and alcohol using a pre-designed structured questionnaire at the Mahatma Gandhi Institute of Medical Sciences, Sevagram in Central India. These cases were matched with three sets of age and sex matched controls. Oral cancer was predominant in the age group of 50-59 years. Individuals on a non-vegetarian diet appeared to be at greater risk of developing oral cancer. Cases were habituated to consuming hot beverages more frequently and milk less frequently than controls. Consumption of ghutka, a granular form of chewable tobacco and areca nut, was significantly associated with oral cancer cases. Cases had been using oral tobacco for longer duration than controls, and were habituated to sleeping with tobacco quid in their mouth. Most cases were also addicted to smoking tobacco and alcohol consumption. Bidi (a crude cigarette) smoking was most commonly associated with oral cancer. On stratified analysis, a combination of regular smoking and oral tobacco use, as well as a combination of regular alcohol intake and oral tobacco use were significantly associated with oral cancer cases. Synergistic effects of all three or even two of the risk factors - oral tobacco use, smoking and alcohol consumption- was more commonly seen in cases when compared to controls. PMID- 17696740 TI - Renal involvement in non-Hodgkin's lymphoma: the Shaukat Khanum experience. AB - BACKGROUND: Primary lymphoma of genitourinary system is rare as these organs do not contain lymphoid tissue, however secondary involvement often occurs. The most commonly affected genitourinary organ is the kidney. METHODS: Medical records of 901 patients with documented NHL seen at Shaukat Khanum Memorial Cancer Hospital & Research Center during 1995-2003 were studied for the incidence, histopathological, clinical and radiological correlation of renal involvement in NHL. RESULTS: 19(2.1%) patients had renal involvement. Male to female ratio was 3.75:1. Histology was diffuse large cell lymphoma in 12(63%) patients. IPI was High, High intermediate and Low intermediate in 17(89.5%) patients. Radiologically, 5(26.5%) patients had the disease above the diaphragm, 2(10.5%) patients had disease below the diaphragm while 12(63%) had disease on both sides of the diaphragm. 11(58%) showed complete response, 1(5.5%) showed partial response while 7(36.8%) showed progressive disease. CONCLUSION: Majority of patients with renal involvement had low intermediate or higher IPI compatible with significant progression rate. The findings and disease behavior in our population is comparable to those quoted in English literature. Radiological tools have made it easier to monitor disease response and renal biopsy is seldom required. PMID- 17696741 TI - Role of GSTM1 (Null/Present), GSTP1 (Ile105Val) and P53 (Arg72Pro) genetic polymorphisms and the risk of breast cancer: a case control study from South India. AB - The present study was undertaken to examine the frequencies of GSTM1 (Null/Present), GSTP1 (Ile105Val) and p53 (Arg72Pro) genotypes and their relations to breast cancer susceptibility in South Indian women. This case - control study involved 250 consecutive breast cancer cases and 500 healthy controls matched in five-year age categories in the ratio of 1:2. Genotyping was performed by PCR for GSTM1, Real-Time Allelic discrimination assay for GSTP1 and PCR-CTPP for p53. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression after adjusting for the known risk factors for breast cancer. The frequencies for the GSTM1 Null genotype were 26% in the cases and 22% in the controls; for GSTP1 Ile/Ile, Ile/Val, Val/Val the frequencies were 46.6%, 41.9% and 11.5%, respectively, in cases and 46.0%, 43.8% and 10.2% in controls; for p53 Arg/Arg, Arg/Pro & Pro/Pro the frequencies were 26.4%, 50.0% and 23.6% in cases and 27.0%, 44.8% and 28.2% in controls. A nonsignificant elevation in breast cancer risk was observed among women who had the GSTM1 Null genotype (OR=1.24; 95% CI=0.83-1.84), the p53 Arg/Arg genotype (OR=1.28; 95% CI=0.81-2.03) and the Pro/Arg genotype (OR=1.49; 95% CI=0.99-2.25), and the GSTP1 Val/Val genotype (OR=1.1; 95% CI=0.64-1.91). PMID- 17696742 TI - Attitudes of Japanese primary care physicians toward publicly endorsed periodic health examinations: a cross sectional survey. AB - BACKGROUND: Despite the lack of evidence for efficacy, an annual health examination has been advocated for the general population by the Japanese government. We conducted a cross-sectional survey to understand the attitudes of Japanese physicians toward the annual examinations. METHODS: In October 2003, a questionnaire was mailed to 1971 physicians registered with Aichi Prefecture Medical Association as internists. The survey was designed to determine their opinions about the effectiveness of the periodic health examination and each of its components. RESULTS: The response rate was 37%. Eighty-five percent believed that a periodic health examination was effective. Nearly 80% believed that height and weight should be measured, and more than 90% supported blood pressure measurements. Nearly 70% supported a physical examination of chest and abdomen. About half believed that vision and hearing tests should be performed for all ages. More than 90% considered performing a variety of laboratory tests valuable. Three-quarters supported hepatitis B surface antigen and hepatitis C antibody determinations. Seventy to eighty percent valued the screening tests for lung, stomach, colon, breast and cervical cancer. CONCLUSIONS: Most Japanese primary care physicians believe that a comprehensive annual health examination as currently endorsed by public health authorities is effective. PMID- 17696743 TI - Influence of regular black tea consumption on tobacco associated DNA damage and HPV prevalence in human oral mucosa. AB - Black tea is more widely consumed than green tea worldwide, particularly in India. Therefore, it is necessary to focus attention on black tea with respect to its health promoting and anti-cancer actions. In order to establish the concept that black tea is a potential candidate for cancer prevention, it is important to provide epidemiological evidence derived from investigations of human populations. In view of this, the objective of the present study was to determine the correlation between nature of black tea consumption and DNA damage in normal subjects with or without tobacco habit and oral cancer patients, taking the latter as positive controls. Much experimental evidence points to associations between tobacco habit and HPV 16 and HPV 18 (Human Papilloma virus) infection. But no studies have taken into account the possible confounding effect of black tea consumption on DNA damage along with HPV infection. A pilot study was therefore undertaken. Comet assay was used to evaluate the DNA damage among normal subjects including tobacco users (n = 86), non-tobacco users (n = 45) and Oral cancer patients (n = 37). Percentage of damaged cells was scored in the buccal squamous cells of all subjects mentioned above. HPV analysis was performed on 79 samples (including 37 oral cancer patients). The evaluation of various confounding factors like age, tenure of tobacco habit and tea habit showed significant associations with DNA damage. The observations strongly indicate that regular intake of black tea at least above four cups can reduce tobacco associated DNA damage among normal tobacco users. HPV prevalence was not seen to be associated with age, tenure of tobacco habit or the tea drinking habit. PMID- 17696744 TI - Intestinal phenotypes of stomach cancers arising after Helicobacter pylori eradication in carcinogen-treated Mongolian gerbils. AB - AIMS: We have previously demonstrated the importance of gastric and intestinal phenotypic expression for the histogenesis of stomach cancer. However, the phenotypes of stomach cancers arising after Helicobacter pylori (Hp) eradication have hitherto remained unclear. We therefore examined a series of lesions occurring after Hp eradication in the Mongolian gerbil (MG) model. METHODS: Totals of 6 and 20 advanced glandular stomach cancers were evaluated in Hp eradicated and Hp-infected MGs treated with N-methyl-N-nitrosourea (MNU-MGs), using several gastrointestinal epithelial phenotypic markers. The lesions were divided phenotypically into gastric (G type), gastric-and-intestinal mixed (GI type), intestinal (I type), and null (N type) phenotypes. RESULTS: All 4 differentiated type lesions in Hp-eradicated MNU-MGs were classified as G type, while both of the undifferentiated lesions exhibit the GI type. In Hp-infected MNU-MGs, the lesions were classified as 10 G, 8 GI, and 2 I types, with undifferentiated type lesions having more intestinal phenotypic expression than their differentiated counterparts (P< 0.01). CONCLUSIONS: Our data suggest that the differentiated stomach cancers exhibit the G type in Hp-eradicated MNU-MGs, suggesting that a kind of non-neoplastic G type gland may be precancerous. Intestinalization may still occur, especially in undifferentiated stomach cancers, even if Hp eradication is successful. PMID- 17696745 TI - Role of an androgen receptor gene polymorphism in development of hormone refractory prostate cancer in Indian population. AB - BACKGROUND: Androgen receptors play critical roles in the development of primary as well as advanced hormone-refractory prostate cancers. Since the growth of prostate cancer is androgen-sensitive, metastatic disease has been treated by hormonal therapy in the form of androgen ablation. Prostate cancer cells rely on androgen receptor (AR) for proliferation and survival. AIM: To evaluate the prognostic significance of androgen receptor polymorphism in patients under hormonal therapy in any form. METHODS: Complete follow up data were available for 87 patients out of 130 patients enrolled for study. DNA was extracted from blood samples using salting out method and then subjected to PCR Genscan for CAG and GGN genotyping. The mean follow up was 10.12+/-8.83 months. RESULTS: Out of 87 patients, 64 experienced clinical as well as biochemical recurrence. The overall hormone refractory rates were 73.4% after one year. We observed a significant shorter median CAG repeats in HRPC patients (20 vs 22). The hazard ratio for HRPCs with the < or =20 CAG repeat genotype was 0.602 (0.33-1.08, p=0.09). Kaplan Meier analysis showed that HRPC rates were not significantly associated with CAG repeat (p=0.06) but a trend was observed with short CAG repeats. No significant association was observed with AR-GGN repeats. CONCLUSIONS: A trend for association of AR-CAG repeats with HRPC patients in north Indian population was observed, suggesting this to be a prognostic factor for determining the therapeutic regimen. PMID- 17696746 TI - Evaluation of primers and PCR performance on HPV DNA screening in normal and low grade abnormal cervical cells. AB - High risk human papillomaviruses (HR-HPVs) are associated with increased risk of normal cervical cells developing to dysplasia and cervical carcinoma. Therefore, HR-HPV DNA testing can predict an endpoint of cervical carcinogenesis that is earlier than the development of cervical abnormalities. Not only the sensitivity of methods but also the amount of HPV DNA are very important and might be parameters to distinguish HPV detection. In this study, we evaluated the effects of primer sets and the polymerase chain reaction (PCR) performance with low viral load samples with normal cervical cytology (140 samples) and mild dysplasia (140 samples) using two consensus primers MY09/MY11 and GP5+/6+. The PCR was performed with single and nested PCR. Positive samples with both primer sets were then HPV genotyped by dot blot hybridization. Results showed higher sensitivity of single PCR using primer GP5+/GP6+ than primer MY09/MY11. HPV DNA was detected in 15% (21 of 140)and 20.7% (29 of 140) of normal cervical samples, respectively. For mild dysplasia samples, HPV DNA was detected in 37.1% (52 of 140) with MY09/MY11 and 50% (70 of 140) using GP5+/GP6+. In normal cervical samples, the positivity rate was increased to 38.5% (54 of 140) by nested PCR using primer GP5+/6+, but only 2 mild dysplasia samples that were negative by single GP5+/6+ were positive by auto nested PCR. These results suggested that, in low viral load samples, the sensitivity of HPV DNA detection depends not only on primer sets but also PCR performance. HPV 16 was the most common in mild dysplasia samples (20.8%), whereas HPV type 58 was found in 11.1%. This study suggested that nested PCR might be necessary for HPV DNA detection in cervical samples of women participating in cervical cancer screening. PMID- 17696747 TI - XRCC1 and XPD gene polymorphisms in a South Indian population. AB - DNA repair systems play an important role in maintaining the integrity of the human genome. Deficiency in the repair capacity due to either mutations or inherited polymorphisms in DNA repair genes may contribute to variations in the DNA repair capacity and subsequently susceptibility to cancer. The interindividual variability as well as ethnic differences in DNA repair polymorphisms, stress the importance to establish genotype profiles unique to a population. Hence the present study aimed to determine the frequencies of XRCC1 and XPD gene polymorphisms in 255 healthy random unrelated individuals from South India. DNA was isolated from the peripheral blood sample of these individuals and the XRCC1 and XPD genotypes were determined by PCR- RFLP with Msp1 and Pst1 enzymes respectively. The XRCC1 genotype frequencies revealed 36% Arg/Arg, 47% Arg/Gln and 17% Gln/Gln with Gln allele frequency of 0.41. Analysis of XPD genotypes revealed 51% Lys/Lys, 41% Lys/Gln and 8% Gln/Gln with Gln allele frequency of 0.29. No significant difference in the distribution of genotypes was seen based on gender. Comparison of the frequencies of XRCC1 and XPD polymorphisms observed in the present study with other populations revealed a distinctive nature of the South Indian population. An understanding of DNA repair gene polymorphisms might not only enable risk assessment of humans exposed to environmental carcinogens but also response to therapy, which target the DNA repair pathway. PMID- 17696748 TI - Cost effectiveness of cervical cancer screening among Chinese women in North America. AB - BACKGROUND: Chinese North American women have high invasive cervical cancer rates and low screening rates. The cost-effectiveness of strategies to improve Pap testing rates for Chinese women living in Seattle, Washington and Vancouver, British Columbia was examined. OBJECTIVES: To calculate the costs and cost effectiveness of implementing two strategies to motivate women to obtain a Pap smear. RESEARCH DESIGN: A three-armed randomized, controlled trial was conducted. Women in each of two interventions (high-intensity outreach and low-intensity mailing intervention) were compared to a group of women who received usual care. MEASURES: Costs were captured via a group discussion of costs, accounting records, sampling of staff time logs, and estimation of costs and task times. Effectiveness was measured as the proportion of women in each intervention arm who reported receiving a Pap smear since the trial began. Cost-effectiveness was calculated as the incremental cost of screening each additional woman between an intervention arm and the control arm. RESULTS: A greater percentage of women who received the outreach intervention had a Pap test than women who received mailed materials or women who were in the usual care arm. The intent-to-treat cost for each additional woman to be screened for a Pap test was $415 in the Outreach arm and $676 for the Direct Mailing arm. The outreach worker intervention, though more expensive overall, was more cost-effective than the mailing intervention. CONCLUSIONS: Outreach intervention is cost-effective for sponsors and should be considered as a strategy to motivate Chinese women living in North America to seek cervical cancer screening. PMID- 17696749 TI - Glutathione S-transferase P1 genotypes, genetic susceptibility and outcome of therapy in thai childhood acute lymphoblastic leukemia. AB - Glutathione S-transferases (GSTs) are enzymes that involved in bio- transformation by conjugation of electrophillic compounds to glutathione. Polymorphisms within genes that encode GSTs may affect the function of the enzymes. Polymorphisms of GSTP1 at codon 105 residue forms GSTP1 active site for binding of hydrophobic electrophiles, and the Ile-Val substitution affect substrate specific catalytic activity of this enzyme and may associate with susceptibility to malignant human disease, especially acute lymphoblastic leukemia (ALL), which is the most common leukemia in children younger than 15 years old. Genetic polymorphisms within the GSTP1 gene of childhood ALL patients were studied. In addition, the association of genetic polymorphism of GSTP1 and genetic susceptibility of acute lymphoblastic leukemia (ALL) was also determined using Chi-square and Odds ratio. PCR-RFLP was used to study genetic polymorphism of GSTP1 in 100 ALL patients and 100 healthy individuals.The results show that there is no statistically significant association between each genotypes and genetic susceptibility of acute lymphoblastic leukemia (ALL) (OR=0.92, P value=0.886). Moreover, there is no statistically significant association between each genotypes and demographic data of acute lymphoblastic leukemia (ALL). However, there are 2 cases of ALL with BM relapse show the polymorphic genotypes of GSTP1. It may suggest that GSTP1*V105 may be involved in relapse of ALL. PMID- 17696750 TI - Factors affecting survival of cervical cancer patients treated at the radiation unit of Srinagarind Hospital, Khon Kaen University, Thailand. AB - This retrospective longitudinal study aimed to evaluate factors for survival of cervical cancer patients treated with radiation therapy. Information was retrieved from the medical records of 1,180 cervical cancer patients and pathologic material was reviewed to confirm the diagnosis who treated with radiation therapy at Srinagarind Hospital, Khon Kaen University between 1 January 1994 to 31 December 1999. And they were followed up until December 31, 2004. The patients current vital status was searched through hospital-based registry, the population-based cancer registry of Khon Kaen Province, the civil registration database, the Ministry of Interior and mails were sent to them. Data were analysed with the Kaplan-Meier, Log-rank test and Cox proportion hazard model. Results were found that mortality rate of 70 per 1,000 person-year. The overall 5 years survival rate was 62.5%. Median time survival was <10 years. From multivariate analyses, the factors that were statistically affected survival of cervical cancer patients included staging (p-value<0.001), hemoglobin level (p value<0.001), interval between external and intracavitary radiation (p value<0.001) and fractionation (p-value=0.024). Stage III was the most important risk factors of mortality risk with 1.65-fold mortality risk compared with stage I (95% CI=1.05-2.59). Patients with low hemoglobin level (< or = 10 g./dl.) was associated with 1.85-fold mortality risk compared with patients who had level >12 g./dl. (95% CI=1.40-2.44). The interval between external and intracavitary radiation >28 days was associated with 2.28-fold mortality risk compared with patients who had duration <1 day (95% CI= 1.40-2.44). The fractionation 2 faction was associated with 0.25-fold mortality risk compared with 1 fraction (95% CI=0.07-0.96). The results of study show that stage of disease, hemoglobin level, interval between external- intracavitary radiation and fractionations were factors affected survival cervical patients treated with radiation. Future prospective trials should be undertaken to confirm the validity of these factors and to elucidate their therapeutic implications. PMID- 17696751 TI - Modulation of metastatic potential of B16F10 melanoma cells by acivicin: synergistic action of glutaminase and potentiation of cisplatin cytotoxicity. AB - Treatment for metastatic melanoma has mostly been unsatisfactory despite advances in ongoing medical research. Here we investigated the role of acivicin, a glutamine analogue, singly and in combination with either E. coli glutaminase or cisplatin, on the growth, angiogenic activity and invasiveness of B16F10 cells in vitro and after allografting in C57BL/6 mice. B16F10 melanoma colonization in the lungs of mice was measured by monitoring colony counts. Host toxicity was assessed with reference to tumor bearing host's weight and survivability. Acivicin promoted melanoma dormancy and reduced melanoma associated angiogenic factors like VEGF level and vessel diameter. Acivicin in combination with glutaminase significantly suppressed tumor growth by 66.7% and increased life span by 43.5% without host toxicity. Tumor VEGF content was significantly lowered by combination therapy as assessed by ELISA. Accelerated cytotoxicity, reduced invasion and enhanced apoptosis of melanoma cells were exhibited in vitro by combined than by single agent treatment. Moreover, invasion of melanoma cells through matrigel chambers was reduced in presence of acivicin and glutaminase combination. These findings support future studies of acivicin in combination with other anticancer agents for prevention of melanoma metastasis. PMID- 17696752 TI - Line-1 hypomethylation in multistage carcinogenesis of the uterine cervix. AB - OBJECTIVE: To evaluate characteristics of global hypomethylation in evolution of cervical cancer. MATERIALS AND METHODS: Eight cases of squamous cell carcinoma (SCC) and seven cases of carcinoma in situ (CIS) were studied. Each of the SCC samples contained CIS, and all SCC and CIS samples contained normal ectocervical epithelium. Microdissection was performed to separate normal epithelium, CIS and SCC prior to DNA extraction. Hypomethylation levels of long interspersed nuclear elements (LINE-1 or L1) were measured with a combined bisulfite restriction analysis (COBRA) PCR (polymerase chain reaction) protocol. The percentage of L1 hypomethylation for SCC, CIS and normal epithelium was compared. RESULTS: In the SCC cohort, the L1 hypomethylation level showed progressive increase comparing normal epithelium (59.4 +/- 8.86%) to CIS (64.37 +/- 7.32%) and SCC (66.3 +/- 7.26%) (repeated measurement ANOVA, P = 0.005). A significantly greater L1 hypomethylation level was found in CIS (62.06 +/- 3.44 %) compared to normal epithelium (60.03 +/- 3.69 %) (paired t-Test, P = 0.03). No significant difference in L1 hypomethylation level was noted between CIS of the two sample groups (unpaired t-Test, P = 0.2). CONCLUSIONS: In our study, there was a significant correlation between the degree of hypomethylation and progression from normal ectocervical mucosa to CIS and invasive cancer. Laboratory assessment of biopsies for this molecular event may have clinical significance. PMID- 17696753 TI - When should MRI be recommended for the accurate clinical staging of base of tongue carcinoma? AB - BACKGROUND AND PURPOSE: According to the American Joint Committee on Cancer (AJCC) cancer staging criteria (6th edition), cross-sectional imaging for base of tongue carcinoma is recommended when the deep tissue extent of a primary tumor is in question. The aim of this study was to establish which group of patients MRI might most benefit from accurate clinical staging of base of tongue carcinomas. PATIENTS AND METHODS: The clinical stagings of 33 patients with pathologically proven squamous cell carcinomas of the base of tongue were performed by two otorhinolaryngologic surgeons. Their results were compared with the results from MRI interpreted by a neuroradiologist and the numbers of patients being upstaged, downstaged or with an unchanged stage were recorded and analyzed. RESULTS: The tumor stages were changed in 13 of 33 patients (39.4%, 95% CI: 23.9-57.87%) and the overall stage groupings were changed in 10 (30.3 %, 95%CI: 15.6-48.7%) after performing MRI. Mis-staging by clinical examination in the overall stage grouping was as high as 83.3% (95%CI: 35.9-99.6%) in stages II and III and 85.7% (95% CI: 42.1-99.6%) in T3. CONCLUSION: MRI should be recommended in base of tongue carcinoma whenever clinical examination suggests overall stage groupings II, III or tumor stage T3. PMID- 17696754 TI - Intramolecular antigenicity of MUC1, a candidate for cancer vaccines. AB - Cancer is a big public health problem as well as a medical challenge. The tumor associated carbohydrate antigens and glycopeptide antigens derived from, for example, the MUC1 mucin glycoprotein or tumor mucin antigen, are attractive targets for the immunotherapy of cancer, owing to their expression by malignant cells. MUC1 glycoprotein is present in endometriotic lesions and over-expressed in many cancers and the MUC1 immune response is known to provide a protective host defense mechanism against cancer. In this work, the author studied the antigenicity pattern within the MUC1 molecule by an advanced bioinformatics method. It can be seen that the amino acid in the middle portion of the sequence pose high antigenicity. This part could be selected for further vaccine development. PMID- 17696755 TI - The Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study) to detect gene-environment interactions for cancer. AB - The Japan Multi-institutional Collaborative Cohort Study (J-MICC Study) launched in 2005, supported by a research grant for Scientific Research on Special Priority Areas of Cancer from the Japanese Ministry of Education, Culture, Sports, Science and Technology. Although the main purpose is to confirm and detect gene-environment interactions of lifestyle-related diseases, mainly of cancer, through the cohort analyses, it includes cross-sectional analyses on lifestyle factors, biomarkers, and genotypes, as well as confirmation/ screening of new biomarkers usable for early diagnosis of cancer. The endpoints are cancer diagnosis and death. The participants diagnosed as cancer will be identified through population-based cancer registries, hospital cancer registries, mail questionnaires, questionnaires at repeated visits, death certificates, health insurance data, and second survey questionnaires. Subjects are individuals aged 35 to 69 years enrolled from respondents to study announcements in specified areas, inhabitants attending health checkup examinations by local governments, visitors at health checkup centers, and patients at a cancer hospital. The number of subjects was set to be 100,000 throughout Japan. The enrollment period is from April 2005 to March 2010. The second survey is scheduled 5 years after their enrollment. The participants will be followed until 2025. The J-MICC Central Office is placed at Nagoya University Graduate School of Medicine. Ten participating research groups (Cohort Study Executing Groups) send baseline data and blood samples (buffy coat, serum, and plasma) anonymized with an identification number (J-MICC ID) to the Central Office. The data of second survey and follow-up will be linked using J-MICC ID. This study is expected to produce many findings on lifestyle and genetic traits associated with lifestyle related diseases including cancer among Japanese. PMID- 17696756 TI - Polyarticular septic arthritis following septic circumcision. AB - Ritual circumcision during an initiation ceremony for young adults is common practice in parts of South Africa. We report on a case of polyarticular septic arthritis in a seventeen-year-old man following septicaemia after circumcision, resulting in severe fixed flexion deformities of both knees. This case illustrates an unusual cause of polyarticular septic arthritis and the treatment difficulties associated with delayed presentation. It is also a reminder of the consequences of untreated acute septic arthritis. PMID- 17696757 TI - The researcher development program: how to extend the involvement of Australian general practitioners in research? AB - CONTEXT: This article reviews the Researcher Development Program (RDP) component of the Australian Government's Primary Health Care Research, Evaluation, and Development (PHC RED) strategy, examining critical aspects of program performance and suggesting strategies that might increase the involvement of rural GPs in research. ISSUE: Primary health care research capacity can only be built by providing sustainable, dedicated funding and a dedicated redistribution of workload from practice to research. The PHC RED funds and program supports only provide incentives to redirect existing capacity within primary health care from patient care to research for the time during which incentives are in place, generally as a part-time funded position for less than one-year's duration. The one-year time constraint is the most serious impediment to the success of the program. There is no formal provision for the continuing status of clinician/researchers. Continuation depends on the capacity of the mentor agencies, academic departments of general practice or university departments of rural health, to continue to support them, and on the time they can make available from their practice. Existing measures of program success, published research and new knowledge incorporated into practice settings, are too ambitious for researchers given a one-year time frame, working part time. Clinician/researchers have a demonstrated willingness to devote time to developing and answering a research question, but often lack the time and administrative support to get through the processes required, including ethics application and writing for publication. LESSONS LEARNED: A better way to capture success of the RDP program might be through a multi-objective composite set of measures of research performance that captures different types of outputs, with weighting factors assigned to different measures of research output. Development of peer-review panels to replace or augment annual reporting to assess the progress of PHC RED programs might also serve both to measure success and to promote collaborative ventures. Small scale research projects are more conducive to practising GPs than randomised controlled trials or large scale observational studies. Smaller projects can still lead to important discoveries and improvements to the healthcare system. Examples include guideline development, descriptive studies, and small-number analytical epidemiological studies. In order to engage the rural primary care community in redirecting clinical time to research, the needs of clinicians must be met, as well as those of funders, academic mentors and collaborators. Structures and systems that can be developed through PHC RED, including research networks, will determine whether efforts to increase research in primary-care settings succeed and are sustainable. Sustainable networks need sustainable funding. PMID- 17696758 TI - An innovation in Australian dental education: rural, remote and Indigenous pre graduation placements. AB - Anticipating the looming crisis in access to dental services in rural and remote areas, the Western Australian Centre for Rural and Remote Oral Health developed an undergraduate rural placement program to provide dental students of The University of Western Australia opportunities for direct experience of rural and remote practice during the final year of the undergraduate curriculum. The Rural, Remote and Indigenous Placement program started in 2002 and, to the end of 2005, had placed 78 final year dental students in supervised clinical practice in rural, remote or Indigenous practice. In this study, the evolution of the program (2002-2005) is described and student evaluation of the program is reported. While involved in the rural placement program, students were assessed by experienced dental practitioners and provided program evaluation. This structured feedback allowed continuous improvement of the program. Data from each year's graduates was also analysed to examine the question of influence of placements on practice location during the first 6 months after graduation. Although it will be many years before the effects of outplacement programs can be specifically attained, the evidence to date indicates that the program may be a valuable tool among the plethora of strategies being investigated to augment Australia's rural oral health workforce. PMID- 17696760 TI - Phenotype of a calbindin-D9k gene knockout is compensated for by the induction of other calcium transporter genes in a mouse model. AB - CaBP-9k may be involved in the active calcium absorption and embryo implantation. Although we generated CaBP-9k KO mice to explore its function, no distinct phenotypes were observed in these KO mice. It can be hypothesized that TRPV5 and 6 and plasma membrane calcium ATPase 1b may play a role in the regulation of calcium transport to compensate CaBP-9k deficiency in its KO model. INTRODUCTION: Active calcium transport in the duodenum and kidney is carried in three steps: calcium entry through epithelial Ca2+ channels (TRPV5 and TRPV6), buffering and/or transport by calbindin-D9k (CaBP-9k) and -D28k (CaBP-28k), and extrusion through the plasma membrane calcium ATPase 1b (PMCA1b) and sodium/calcium exchanger 1. Although the molecular mechanism of calcium absorption has been studied using knockouts (KOs) of the vitamin D receptor and CaBP-28k in animals, the process is not fully understood. MATERIALS AND METHODS: We generated CaBP-9k KO mice and assessed the phenotypic characterization and the molecular regulation of active calcium transporting genes when the mice were fed different calcium diets during growth. RESULTS: General phenotypes showed no distinct abnormalities. Thus, the active calcium transport of CaBP-9k-null mice proceeded normally in this study. Therefore, the compensatory molecular regulation of this mechanism was elucidated. Duodenal TRPV6 and CaBP-9k mRNA of wildtype (WT) mice increased gradually during preweaning. CaBP-9k is supposed to be an important factor in active calcium transport, but its role is probably compensated for by other calcium transporter genes (i.e., intestinal TRPV6 and PMCA1b) during preweaning and renal calcium transporters in adult mice. CONCLUSIONS: Depletion of the CaBP-9k gene in a KO mouse model had little phenotypic effect, suggesting that its depletion may be compensated for by calcium transporter genes in the intestine of young mice and in the kidney of adult mice. PMID- 17696759 TI - Control of the SOST bone enhancer by PTH using MEF2 transcription factors. AB - Expression of the osteocyte-derived bone formation inhibitor sclerostin in adult bone requires a distant enhancer. We show that MEF2 transcription factors control this enhancer and mediate inhibition of sclerostin expression by PTH. INTRODUCTION: Sclerostin encoded by the SOST gene is a key regulator of bone formation. Lack of SOST expression is the cause for the progressive bone overgrowth disorders sclerosteosis and Van Buchem disease. We have previously identified a distant enhancer within the 52-kb Van Buchem disease deletion downstream of the SOST gene that is essential for its expression in adult bone. Furthermore, we and others have reported that SOST expression is suppressed by PTH. The aim of this study was to identify transcription factors involved in SOST bone enhancer activity and mediating PTH responsiveness. MATERIALS AND METHODS: Regulation of the SOST enhancer and promoter was studied by luciferase reporter gene assays. Transcription factor binding sites were mapped by footprint analysis and functional mutation analyses using transient transfections of osteoblast-like UMR-106 cells that exhibit endogenous SOST expression. Specific transcription factor binding was predicted by sequence analysis and shown by gel retardation assays and antibody-induced supershifts. Expression of myocyte enhancer factors 2 (MEF2) was detected by in situ hybridization, quantitative RT-PCR (qPCR), and immunohistochemistry. The role of MEF2s in SOST expression was assessed by reporter gene assays and siRNA-mediated RNA knockdown. RESULTS: PTH completely suppressed the transcriptional activity of the SOST bone enhancer but did not affect the SOST promoter. A MEF2 response element was identified in the bone enhancer. It was essential for transcriptional activation, bound MEF2 transcription factors, and mediated PTH responsiveness. Expression of MEF2s in bone was shown by qPCR, in situ hybridization, and immunohistochemistry. MEF2s and sclerostin co-localized in osteocytes. Enhancer activity was stimulated by MEF2C overexpression and inhibited by co-expression of a dominant negative MEF2C mutant. Finally, siRNA-mediated knockdown of MEF2A, C, and D suppressed endogenous SOST expression in UMR-106 osteoblast-like cells. CONCLUSIONS: These data strongly suggest that SOST expression in osteocytes of adult bone and its inhibition by PTH is mediated by MEF2A, C, and D transcription factors controlling the SOST bone enhancer. Hence, MEF2s are implicated in the regulation of adult bone mass. PMID- 17696761 TI - Knee loading accelerates bone healing in mice. AB - Knee loading is an anabolic loading modality that applies lateral loads to the knee. This study shows that loads applied to the proximal tibial epiphysis stimulate healing of surgically generated wounds in the tibial diaphysis. INTRODUCTION: Wound healing is sensitive to mechanical stimulation such as various forms of stress and different magnitudes of strain. Knee loading has been shown to induce anabolic responses to murine tibias and femora when a strain of 10-20 mustrain is applied at the site of new bone formation. The object of this study was to address a question: does knee loading accelerate closure of open wounds in the tibia? MATERIAL AND METHODS: Fifty-three C57/BL/6 female mice were used. A surgical wound (0.5 mm in diameter) was generated in the left tibia (loaded) and the right tibia (sham-loaded control). From the fourth postoperative day, knee loading was performed to the left knee with a custom-made piezoelectric loader for 3 min/d for 3 consecutive days. The peak-to-peak force was 0.5 N. Animals were killed 1, 2, or 3 wk after surgery, and the healing process was evaluated with muCT, pQCT, and bone histomorphometry with calcein labeling. RESULTS: The measured strain was <20 mustrain with 0.5-N force regardless of the presence or absence of surgical wounds. Compared with sham-loaded controls, the results showed load-driven acceleration of wound healing. First, muCT data revealed that knee loading reduced the size of surgical wounds by 13% (p < 0.01; 1 wk), 25% (p < 0.001; 2 wk), and 15% (p < 0.01; 3 wk). Second, pQCT data indicated that total BMD and BMC and cortical BMD and BMC were significantly increased in the third postoperative week. Last, bone histomorphometry revealed that bone formation was stimulated from the site proximal (close to the knee) to the wound. CONCLUSIONS: The reparative and remodeling phases of wound healing were enhanced by loads applied to the knee without inducing significant in situ strain at the site of wounds. Noninvasive knee loading might therefore be useful clinically to stimulate bone healing in the entire tibia along its length (including cast immobilized wounds). PMID- 17696762 TI - Bone regeneration is regulated by wnt signaling. AB - Tissue regeneration is increasingly viewed as reactivation of a developmental process that, when misappropriated, can lead to malignant growth. Therefore, understanding the molecular and cellular pathways that govern tissue regeneration provides a glimpse into normal development as well as insights into pathological conditions such as cancer. Herein, we studied the role of Wnt signaling in skeletal tissue regeneration. INTRODUCTION: Some adult tissues have the ability to regenerate, and among these, bone is one of the most remarkable. Bone exhibits a persistent, lifelong capacity to reform after injury, and continual bone regeneration is a prerequisite to maintaining bone mass and density. Even slight perturbations in bone regeneration can have profound consequences, as exemplified by conditions such as osteoporosis and delayed skeletal repair. Here, our goal was to determine the role of Wnts in adult bone regeneration. MATERIALS AND METHODS: Using TOPgal reporter mice, we found that damage to the skeleton instigated Wnt reporter activity, specifically at the site of injury. We used a skeletal injury model to show that Wnt inhibition, achieved through adenoviral expression of Dkk1 in the adult skeleton, prevented the differentiation of osteoprogenitor cells. RESULTS: As a result, injury-induced bone regeneration was reduced by 84% compared with controls. Constitutive activation of the Wnt pathway resulting from a mutation in the Lrp5 Wnt co-receptor results in high bone mass, but our experiments showed that this same point mutation caused a delay in bone regeneration. In these transgenic mice, osteoprogenitor cells in the injury site were maintained in a proliferative state and differentiation into osteoblasts was delayed. CONCLUSIONS: When considered together, these data provide a framework for understanding the roles of Wnt signaling in adult bone regeneration and suggest a feasible approach to treating clinical conditions where enhanced bone formation is desired. PMID- 17696763 TI - Expression of acid-sensing ion channel 3 (ASIC3) in nucleus pulposus cells of the intervertebral disc is regulated by p75NTR and ERK signaling. AB - Although a recent study has shown that skeletal tissues express ASICs, their function is unknown. We show that intervertebral disc cells express ASIC3; moreover, expression is uniquely regulated and needed for survival in a low pH and hypoeromsotic medium. These findings suggest that ASIC3 may adapt disc cells to their hydrodynamically stressed microenvironment. INTRODUCTION: The nucleus pulposus is an avascular, hydrated tissue that permits the intervertebral disc to resist compressive loads to the spine. Because the tissue is hyperosmotic and avascular, the pH of the nucleus pulposus is low. To determine the mechanisms by which the disc cells accommodate to the low pH and hypertonicity, the expression and regulation of the acid sensing ion channel (ASIC)3 was examined. MATERIALS AND METHODS: Expression of ASICs in cells of the intervertebral disc was analyzed. To study its regulation, we cloned the 2.8-kb rat ASIC3 promoter and performed luciferase reporter assays. The effect of pharmacological inhibition of ASICs on disc cell survival was studied by measuring MTT and caspase-3 activities. RESULTS: ASIC3 was expressed in discal tissues and cultured disc cells in vitro. Because studies of neuronal cells have shown that ASIC3 expression and promoter activity is induced by nerve growth factor (NGF), we examined the effect of NGF on nucleus pulposus cells. Surprisingly, ASIC3 promoter activity did not increase after NGF treatment. The absence of induction was linked to nonexpression of tropomyosin-related kinase A (TrkA), a high affinity NGF receptor, although a modest expression of p75NTR was seen. When treated with p75NTR antibody or transfected with dominant negative-p75NTR plasmid, there was significant suppression of ASIC3 basal promoter activity. To further explore the downstream mechanism of control of ASIC3 basal promoter activity, we blocked p75NTR and measured phospho extracellular matrix regulated kinase (pERK) levels. We found that DN-p75NTR suppressed NGF mediated transient ERK activation. Moreover, inhibition of ERK activity by dominant negative-mitogen activated protein kinase kinase (DN-MEK) resulted in a dose-dependent suppression of ASIC3 basal promoter activity, whereas overexpression of constitutively active MEK1 caused an increase in ASIC3 promoter activity. Finally, to gain insight in the functional importance of ASIC3, we suppressed ASIC activity in nucleus pulposus cells. Noteworthy, under both hyperosmotic and acidic conditions, ASIC3 served to promote cell survival and lower the activity of the pro-apoptosis protein, caspase-3. CONCLUSIONS: Results of this study indicate that NGF serves to maintain the basal expression of ASIC3 through p75NTR and ERK signaling in discal cells. We suggest that ASIC3 is needed for adaptation of the nucleus pulposus and annulus fibrosus cells to the acidic and hyperosmotic microenvironment of the intervertebral disc. PMID- 17696764 TI - Oral respiratory syncytial virus (RSV) DNA vaccine expressing RSV F protein delivered by attenuated Salmonella typhimurium. AB - Human respiratory syncytial virus (RSV) is a major viral pathogen of the lower respiratory tract of infants and young children worldwide. No effective prevention measure is available. Attenuated Salmonella strains expressing heterologous antigens can be delivered by the oral route, triggering efficient antigen-specific humoral, cellular, and mucosal immunity. In this study, we orally administered attenuated Salmonella strain SL7207, carrying the plasmid pcDNA3.1/F expressing the RSV F gene, to BALB/c mice and showed significant elevations of serum anti-RSV IgG and bronchoalveolar lavage secretory IgA as compared with the control group carrying empty plasmid (p<0.001). The ratio of IgG1 and IgG2a was 0.96. The experimental group also showed a stronger cytotoxic T cell response (p<0.01 at effector:target ratios of 100:1 and 50:1) and a higher stimulation index value of T cell proliferation (p<0.05) than the respective control group. RSV titers in the lung homogenates of the experimental group on day 3 and day 5 postchallenge were lower than in the control group (p<0.05). Histopathological analysis showed obvious differences in infiltration of inflammatory cells and pulmonary alveolar wall thickness (p<0.01) between the two groups. In summary, our results demonstrate the potential of orally administered SL7207-based DNA vaccines against RSV infection. PMID- 17696765 TI - Continuous wave EPR oximetric imaging at 300 MHz using radiofrequency power saturation effects. AB - A novel continuous wave (CW), radiofrequency (RF), electron paramagnetic resonance (EPR) oximetric imaging technique is proposed, based on the influence of oxygen concentration on the RF power saturation of the EPR resonance. A linear relationship is demonstrated between the partial oxygen pressure (pO(2)) and the normalized signal intensity (I(N)), defined as, I(N) = (I(HP) - I(LP))/I(LP), where I(LP) and I(HP) refer to signal intensities at low (P(L)) and high (P(H)) RF power levels, respectively. A formula for the determination of pO(2), derived on the basis of the experimental results, reliably estimated various oxygen concentrations in a five-tube phantom. This new technique was time-efficient and also avoided the missing angle problem associated with conventional spectral spatial CW EPR oximetric imaging. In vivo power saturation oximetric imaging in a tumor bearing mouse clearly depicted the hypoxic foci within the tumor. PMID- 17696766 TI - The many flavors of hyperhomocyst(e)inemia: insights from transgenic and inhibitor-based mouse models of disrupted one-carbon metabolism. AB - Mouse models that perturb homocysteine metabolism, including genetic mouse models that result in deficiencies of methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase, and cystathionine beta-synthase, and a pharmaceutically induced mouse model with a transient deficiency in betainehomocysteine methyl transferase, have now been characterized and can be compared. Although each of these enzyme deficiencies is associated with moderate to severe hyperhomocyst(e)inemia, the broader metabolic profiles are profoundly different. In particular, the various models differ in the degree to which tissue ratios of S-adenosylmethionine to S-adenosylhomocysteine are reduced in the face of elevated plasma homocyst(e)ine, and in the distribution of the tissue folate pools. These different metabolic profiles illustrate the potential complexities of hyperhomocyst(e)inemia in humans and suggest that comparison of the disease phenotypes of the various mouse models may be extremely useful in dissecting the underlying risk factors associated with human hyperhomocyst(e)inemia. PMID- 17696767 TI - Mitochondrial dysfunction in aging and Alzheimer's disease: strategies to protect neurons. AB - Recent structural and functional studies of mitochondria have revealed that abnormalities in mitochondria may lead to mitochondrial dysfunction in aged individuals and those with neurodegenerative diseases, including Alzheimer's disease (AD). Molecular, cellular, and biochemical studies of animal models of aging and AD have provided compelling evidence that mitochondria are involved in AD development and progression. Further, a role for mitochondrial dysfunction in AD is supported by studies of neurons from autopsy specimens of patients with AD, transgenic AD mice, and neuronal cells expressing human AD mutation, which have revealed that amyloid beta (Abeta) enters mitochondria early in the disease process and disrupts the electron-transport chain, generates reactive oxygen species, and inhibits the production of cellular ATP, which in turn prevents neurons from functioning normally. Although AD researchers are actively involved in understanding Abeta toxicity and trying to develop strategies to reduce Abeta toxicity, one route they have yet to take is to investigate the molecules that activate nonamyloidogenic alpha-secretase activity that may reduce Abeta production and toxicity. In addition, it may be worthwhile to develop mitochondrially targeted antioxidants to treat AD. This article discusses critical issues of mitochondria causing dysfunction in aging and AD and discusses the strategies to protect neurons caused by mitochondrial dysfunction. PMID- 17696769 TI - Paper of the Year 2006: award to Pamela Hamill. PMID- 17696770 TI - The endosymbiotic origin of organelles: an ancient process still very much in fashion. PMID- 17696771 TI - Solute channels of the outer membrane: from bacteria to chloroplasts. AB - Chloroplasts, unique organelles of plants, originated from endosymbiosis of an ancestor of today's cyanobacteria with a mitochondria-containing host cell. It is assumed that the outer envelope membrane, which delimits the chloroplast from the surrounding cytosol, was thus inherited from its Gram-negative bacterial ancestor. This plastid-specific membrane is thus equipped with elements of prokaryotic and eukaryotic origin. In particular, the membrane-intrinsic outer envelope proteins (OEPs) form solute channels with properties reminiscent of porins and channels in the bacterial outer membrane. OEP channels are characterised by distinct specificities for metabolites and a quite peculiar expression pattern in specialised plant organs and plastids, thus disproving the assumption that the outer envelope is a non-specific molecular sieve. The same is true for the outer membrane of Gram-negative bacteria, which functions as a permeability barrier in addition to the cytoplasmic membrane, and embeds different classes of channel pores. The channels of these prokaryotic prototype proteins, ranging from unspecific porins to specific channels to ligand-gated receptors, are exclusively built of beta-barrels. Although most of the OEP channels are formed by beta-strands as well, phylogeny based on sequence homology alone is not feasible. Thus, the comparison of structural and functional properties of chloroplast outer envelope and bacterial outer membrane channels is required to pinpoint the ancestral OEP 'portrait gallery'. PMID- 17696772 TI - Diverse mechanisms and machineries for import of mitochondrial proteins. AB - Mitochondria are ubiquitous organelles that play an essential role in energy conversion and biosynthetic pathways in eukaryotic cells. Most mitochondrial proteins must be imported from the cytosol and sorted into one of the four mitochondrial subcompartments, the outer membrane, the intermembrane space, the inner membrane and the matrix. Studies in recent years revealed a remarkable diversity of mechanisms and machineries that are required for the import of proteins into mitochondria. At least four different pathways for the sorting and assembly of nuclear-encoded mitochondrial proteins have been identified. PMID- 17696773 TI - Transport of nuclear-encoded proteins into secondarily evolved plastids. AB - Many algal groups evolved by engulfment and intracellular reduction of a eukaryotic phototroph within a heterotrophic cell. Via this process, so-called secondary plastids evolved, surrounded by three or four membranes. In these organisms most of the genetic material encoding plastid functions is localized in the cell nucleus, with the result that many proteins have to pass three, four, or even five membranes to reach their final destination within the plastid. In this article, we review recent models and findings that help to explain important cellular mechanisms involved in the complex process of protein transport into secondary plastids. PMID- 17696774 TI - Mechanisms of protein import into thylakoids of chloroplasts. AB - The thylakoid membrane of chloroplasts contains the major photosynthetic complexes, which consist of several either nuclear or chloroplast encoded subunits. The biogenesis of these thylakoid membrane complexes requires coordinated transport and subsequent assembly of the subunits into functional complexes. Nuclear-encoded thylakoid proteins are first imported into the chloroplast and then directed to the thylakoid using different sorting mechanisms. The cpSec pathway and the cpTat pathway are mainly involved in the transport of lumenal proteins, whereas the spontaneous pathway and the cpSRP pathway are used for the insertion of integral membrane proteins into the thylakoid membrane. While cpSec-, cpTat- and cpSRP-mediated targeting can be classified as 'assisted' mechanisms involving numerous components, 'unassisted' spontaneous insertion does not require additional targeting factors. However, even the assisted pathways differ fundamentally with respect to stromal targeting factors, the composition of the translocase and energy requirements. PMID- 17696775 TI - Molecular machinery of mitochondrial dynamics in yeast. AB - Mitochondria are amazingly dynamic organelles. They continuously move along cytoskeletal tracks and frequently fuse and divide. These processes are important for maintenance of mitochondrial functions, for inheritance of the organelles upon cell division, for cellular differentiation and for apoptosis. As the machinery of mitochondrial behavior has been highly conserved during evolution, it can be studied in simple model organisms, such as yeast. During the past decade, several key components of mitochondrial dynamics have been identified and functionally characterized in Saccharomyces cerevisiae. These include the mitochondrial fusion and fission machineries and proteins required for maintenance of tubular shape and mitochondrial motility. Taken together, these findings reveal a comprehensive picture that shows the cellular processes and molecular components required for mitochondrial inheritance and morphogenesis in a simple eukaryotic cell. PMID- 17696776 TI - Chloroplast photorelocation movement mediated by phototropin family proteins in green plants. AB - Chloroplasts gather in areas irradiated with weak light to maximize photosynthesis (the accumulation response). They move away from areas irradiated with strong light to minimize damage of the photosynthetic apparatus (the avoidance response). The processes underlying these chloroplast movements can be divided into three parts: photoperception, signal transduction, and chloroplast movement. Photoreceptors for chloroplast movement have been identified recently in various plant species. A blue light receptor phototropin (phot) mediates chloroplast photorelocation movement in the seed plant Arabidopsis thaliana, the fern Adiantum capillus-veneris, the moss Physcomitrella patens and possibly the green alga Mougeotia scalaris. A chimeric photoreceptor between phytochrome and phototropin, neochrome (neo), was found in some advanced ferns and in the green alga M. scalaris. While the mechanism of chloroplast movement is not well understood, it is known that actin filaments play an important role in this process. To understand the molecular mechanisms associated with chloroplast movement, several mutants were isolated in A. thaliana (jac1 and chup1) and the corresponding genes were cloned. In this review, recent progress in photoreceptor research into chloroplast movement in various plant species and the possible factors functioning in signal transduction or the regulation of actin filaments identified in A. thaliana is discussed. PMID- 17696777 TI - Plastid division in an evolutionary context. AB - Plastids are derived from free-living cyanobacteria that were engulfed by eukaryotic host cells through the process of endosymbiosis and, like their cyanobacterial ancestors, divide by binary fission. Over the last decade the continued identification and functional analysis of plastid division components, coupled with ever-increasing genomic resources, have yielded insights into the origins and evolution of the plastid division mechanism in higher plants. Here we review the current understanding of the evolution of the chloroplast division proteins and present a model of how the machinery has developed to execute plastid division in Arabidopsis. PMID- 17696778 TI - Variability of the mitochondrial genome in mammals at the inter-species/intra species boundary. AB - Genomic variations represent the molecular basis of the biodiversity of living organisms on which selection operates to generate evolution. In eukaryotes, genomic variability can be experienced in both nuclear and organellar, i.e. mitochondrial and plastid (where present), genomes, which can follow completely different evolution pathways, as revealed by comparative genomics analyses. In Metazoa, for which a substantial number of complete genome sequences are available (nuclear, but mainly mitochondrial), we are just starting to grasp the selective pressures operating on some basic features of the genome as a whole. In this brief review, we discuss the variability of the mitochondrial metazoan genome, with particular reference to mitochondrial DNA in mammals. In light of the recent assumption that a small segment of mitochondrial DNA may be used, particularly in Metazoa, as a species marker, some data on mitochondrial gene variability at the inter-species/intra-species boundary are reported. Intra species variability has been evaluated in four mammalian species, Homo sapiens, Bos taurus, Sus scrofa and Canis familiaris, whereas the relationship between intra- and inter-species variability has been investigated in Bos taurus and Bos indicus. PMID- 17696779 TI - Diversity of proteasomal missions: fine tuning of the immune response. AB - The majority of cellular proteins are degraded by proteasomes within the ubiquitin-proteasome ATP-dependent degradation pathway. Products of proteasomal activity are short peptides that are further hydrolysed by proteases to single amino acids. However, some peptides can escape this degradation, being selected and taken up by major histocompatibility complex (MHC) class I molecules for presentation to the immune system on the cell surface. MHC class I molecules are highly selective and specific in terms of ligand binding. Variability of peptides produced in living cells arises in a variety of ways, ensuring fast and efficient immune responses. Substitution of constitutive proteasomal subunits with immunosubunits leads to conformational changes in the substrate binding channels, resulting in a modified protein cleavage pattern and consequently in the generation of new antigenic peptides. The recently discovered event of proteasomal peptide splicing opens new horizons in the understanding of additional functions that proteasomes apparently possess. Whether peptide splicing is an occasional side product of proteasomal activity still needs to be clarified. Both gamma-interferon-induced immunoproteasomes and peptide splicing represent two significant events providing increased diversity of antigenic peptides for flexible and fine-tuned immune response. PMID- 17696780 TI - Cellular expression of plasma prekallikrein in human tissues. AB - Plasma prekallikrein (PPK) is synthesised in hepatocytes and secreted into the blood, where it participates in the surface-dependent activation of blood coagulation, fibrinolysis, kinin generation and inflammation. Recently we demonstrated by quantitative RT-PCR that the human PPK gene is transcribed not only in the liver, but also in various non-hepatic human tissues at significant levels. However, up to now no reliable information is available concerning protein synthesis in the corresponding human tissues. Here we demonstrate by immunohistochemical studies that PPK or plasma kallikrein (PK) is localised in cells of different embryologically derived human tissues. In the human nephron, single cells of the distal tubules stained intensely, while the cytoplasm of cells forming proximal tubules and collecting ducts stained uniformly. PPK/PK was localised in hepatic epithelial cells of the liver, in cells of the pancreatic islet of Langerhans, in the interstitial Leydig cells of the testes, in the follicular and thecal granulosa cells of the ovary, and in the parotid gland, oesophagus, skin, respiratory tract, prostate and breast. We conclude that the cellular localisation of PPK/PK in multiple different progenitor-derived cells indicates specific cellular functions of this enzyme, in addition to its known function in the blood. PMID- 17696781 TI - Sumoylation of the zinc finger protein ZXDC enhances the function of its transcriptional activation domain. AB - The transcription of major histocompatibility complex class II (MHC II) genes is dependent on the co-activator protein class II trans-activator (CIITA). We have recently identified a protein known as zinc finger X-linked duplicated family member C (ZXDC) that, along with its binding partner ZXDA, forms a complex that interacts with CIITA and regulates MHC II transcription. Western blot analysis with anti-ZXDC antibodies identified two species of the ZXDC protein, one migrating near its predicted molecular mass and one with slower electrophoretic mobility. We report here that the slower migrating form is the result of sumoylation at a single lysine residue within the transcriptional activation domain of ZXDC. Three SUMO proteins (SUMO-1, -2 and -3) can modify the ZXDC protein. Multiple SUMO E3 ligase enzymes and HDAC4 can facilitate ZXDC sumoylation, and one ligase, PIASy, interacts with a specific region of the ZXDC protein. We found that sumoylation does not appear to disrupt or modulate the interaction of ZXDC with its binding partners. Rather, sumoylation of ZXDC is required for full activity of the transcriptional activation domain. Our findings suggest that sumoylation is an important regulator of ZXDC. PMID- 17696782 TI - Josephin domain-containing proteins from a variety of species are active de ubiquitination enzymes. AB - The neurodegenerative disease spinocerebellar ataxia type 3 (SCA3) is caused by the presence of an extended polyglutamine stretch (polyQ) in the unstructured C terminus of the human ataxin-3 (AT3) protein. The structured N-terminal Josephin domain (JD) of AT3 is conserved within a novel family of potential ubiquitin proteases, the JD-containing proteins, which are sub-divided into two groups termed ataxins and Josephins. These AT3 orthologs are encoded by the genomes of organisms ranging from Plasmodium falciparum to humans, with most species possessing more than one homolog. While Josephins consist of JDs alone, ataxins contain additional functional domains that may influence their enzyme activity. Here, we show that the enzyme activity of human AT3 (hAT3) is not affected by the length of polyQ in its C-terminus, even when it is in the range associated with SCA3. We also show that JDs of all human proteins with homology to AT3 and its homologs from various species possess de-ubiquitination activity. These results establish JD-containing proteins as a novel family of active de-ubiquitination enzymes with wide phylogenic distribution. PMID- 17696783 TI - Cysteine protease inhibitors reduce brain beta-amyloid and beta-secretase activity in vivo and are potential Alzheimer's disease therapeutics. AB - Beta-secretase inhibitors that lower brain beta-amyloid peptides (Abeta) are likely to be effective for treating Alzheimer's disease (AD). Irreversible epoxysuccinyl cysteine protease inhibitors are known to reduce brain Abeta and beta-secretase activity in the guinea pig model of human Abeta production. In this study, acetyl-L-leucyl-L-valyl-L-lysinal (Ac-LVK-CHO) is also shown to significantly reduce brain Abeta and beta-secretase activity and brain Abeta in the same model. Ac-LVK-CHO is structurally distinct from the epoxysuccinyl inhibitors and is a reversible cysteine protease inhibitor. The results suggest that cysteine protease inhibitors generally, and reversible cysteine protease inhibitors specifically, have potential for development as AD therapeutics. PMID- 17696784 TI - Pharmacogenetics and paediatric drug development: issues and consequences to labelling and dosing recommendations. AB - The area of pharmacogenetics (PGt) is evolving rapidly. However, ongoing efforts in this field are not aligned with the requirements for the inclusion of clinically relevant findings into the label, especially with reference to paediatric indications. Clinical research in children poses unique issues from a practical and technical perspective, but many challenges can be overcome by applying advanced study design and data analysis methods. When investigating the role of PGt factors on treatment effect, all features that influence drug response must be taken into account. Yet, PGt often has a privileged status in research protocols, with PGt factors evaluated independently from other determinants of response, instead of being regarded as other demographic or clinical covariates (e.g., age, renal function). At present, guidelines to incorporate PGt findings into label statements are lacking in part because this is a new and incompletely understood area. This situation is no longer acceptable. To achieve the potential that PGt can offer to drug development and ultimately to drug prescription, academia, industry and regulatory agencies need to pool resources on the revision of study design and data analysis requisites, bringing in model-based methodologies to enable accurate interpretation of results and provide appropriate labelling recommendations. PMID- 17696785 TI - Pharmacotherapeutic strategies for pediatric bipolar disorder. AB - There has been a recent increase in recognition and diagnosis of pediatric bipolar disorder (PBD), along with an increase in prescriptions for psychotropic medications for treating children suffering from this chronic, potentially disabling disorder. Lithium remains the only FDA-approved mood stabilizer for use in children > 12 years of age and along with valproic acid and carbamazepine, forms the triad of traditional mood stabilizers used for initiation of treatment for PBD. There has been a recent surge in the use of atypical antipsychotics in PBD, which may be due to their relative ease of administration and lack of requirement for serum level monitoring. A combination of traditional mood stabilizers along with atypical antipsychotics is commonly used in clinical practice, despite a lack of compelling empirical data. Although there is an urgent need for controlled studies on the available treatment options and strategies in PBD, recent expert consensus guidelines and emerging controlled pharmacotherapy data on PBD will lay the platform for future scientific research in the area. PMID- 17696786 TI - A pharmacogenomic evaluation of migraine therapy. AB - Migraine is a common idiopathic primary headache disorder with significant mental, physical and social health implications. Accompanying an intense unilateral pulsating head pain other characteristic migraine symptoms include nausea, emesis, phonophobia, photophobia and in approximately 20-30% of migraine cases, neurologic disturbances associated with the aura phase. Although selective serotonin (5-HT) receptor agonists (i.e., 5-HT(1B/1D)) are successful in alleviating migrainous symptoms in < or = 70% of known sufferers, for the remaining 30%, additional migraine abortive medications remain unsuccessful, not tested or yet to be identified. Genetic characterization of the migrainous disorder is making steady progress with an increasing number of genomic susceptibility loci now identified on chromosomes 1q, 4q, 5q, 6p, 11q, 14q, 15q, 17p, 18q, 19p and Xq. The 4q, 5q, 17p and 18q loci involve endophenotypic susceptibility regions for various migrainous symptoms. In an effort to develop individualized pharmacotherapeutics, the identification of these migraine endophenotypic loci may well be the catalyst needed to aid in this goal. In this review the authors discuss the present treatment of migraine, known genomic susceptibility regions and results from migraine (genetic) association studies. The authors also discuss pharmacogenomic considerations for more individualized migraine prophylactic treatments. PMID- 17696787 TI - Combined intravenous and intra-arterial approach in acute stroke treatment. AB - Despite the significant improvement in the outcome of ischaemic stroke with the use of intravenous recombinant tissue plasminogen activator, experience has shown limitations of the sole use of this approach in acute stroke treatment. This has encouraged the search for alternative managements for acute stroke. The combined use of intravenous/intra-arterial therapy is one such alternate treatment, if used in the right setting. In this review, the authors discuss the advantages and limitations of using this approach, together with an overview of the available therapies used through each route. The authors discuss the process of patient selection using clinical, as well as state of the art imaging modalities. PMID- 17696788 TI - Stroke prevention in the high-risk patient. AB - Strokes are increasing in number due to an ageing population and are largely preventable. In the highest risk patients, a 90% relative risk reduction for stroke is attainable by appropriately using all the measures proven to reduce stroke: smoking cessation, a Mediterranean diet, control of hypertension, anticoagulants or antiplatelet agents, lipid lowering drugs and appropriate carotid endarterectomy. Vitamin therapy to lower homocysteine and carotid stenting are additional measures that may yet prove beneficial. Diet, smoking cessation and appropriate carotid endarterectomy reduce stroke by more than do pharmacotherapies. Blood pressure control depends more on selecting appropriate therapy individualised for the patient, than on using any particular drug class. This review, therefore, places pharmacotherapy in perspective as part of, but not all of, stroke prevention. PMID- 17696789 TI - Post-traumatic stress disorder: an evaluation of existing pharmacotherapies and new strategies. AB - Post-traumatic stress disorder (PTSD) is often a chronic and disabling anxiety disorder that develops after exposure to a traumatic event. Researchers have demonstrated efficacy for both pharmacologic and psychosocial interventions in the treatment of PTSD. First-line pharmacotherapeutic options are the selective serotonin re-uptake inhibitors and serotonin noradrenaline re-uptake inhibitors. Older antidepressant agents, such as the tricyclic antidepressants and the monoamine oxidase inhibitor, phenelzine, have also proven efficacy in PTSD among more established agents. However, concerns for side effects have limited frequent use of these. Existing pharmacologic agents produce meaningful results and bear the advantage of treating depression and other co-morbid disorders, yet still fall short of being ideal due to limited response and remission rates and tolerability issues. The need for improving pharmacotherapy of PTSD remains compelling and directions for further research are discussed. PMID- 17696790 TI - Strategies in the treatment of HIV-1-associated adipose redistribution syndromes. AB - HIV-1/highly active antiretroviral therapy-associated lipodystrophy syndrome (HALS) is presently the most common long-term adverse effect limiting the doubtless efficacy of antiretroviral therapy. It has a great impact on the quality of life of patients, it is stigmatising and its psychologically devastating consequences may ultimately impact on the adherence to treatment of patients, eventually leading to treatment failure. Despite considerable advances in recent times, the pathogenesis of HALS remains elusive. Factors involved belong to three categories: those intrinsic to the host, some of them modifiable and some not, those associated with antiretroviral therapy, that are sometimes modifiable as well, and finally those related to HIV-1 infection and its consequences, most often not modifiable. The most commonly used strategies for HALS reversion have included host-dependent factors such as lifestyle and dietary modifications and antiretroviral-dependent factors such as switching or avoiding the use of drugs more prone to promote HALS. Lifestyle modifications and switching thymidine analogues have been associated with moderate success. Pharmacological interventions have included the use of insulin-sensitising agents and hormone therapy with disappointing results, whereas treatment with pravastatin or pioglitazone, and uridine supplementation seem to be associated with fat gain in preliminary studies. The only interventions with almost immediate results that may render a patient's appearance similar to his past one have included filling techniques for facial lipoatrophy and ultrasound-assisted liposuction for cervical fat pad hypertrophy. Among the filling options, semipermanent reabsorbable materials and autologous fat transfer have been associated with acceptable outcomes. As of now, the best hope should rely on the use of drugs friendly for fat, on defining the appropriate timing for starting antiretroviral and on continuing the research effort to understand the basic mechanisms underlying HALS pathogenesis. Only through this effort can the best chances for preventing or reverting established HALS be recognised. PMID- 17696791 TI - Giardiasis: a pharmacotherapy review. AB - Giardia lamblia, the cause of human giardiasis, is among the most common intestinal protozoa worldwide. Human infection may range from asymptomatic shedding of giardial cysts to symptomatic giardiasis, being responsible for abdominal cramps, nausea, acute or chronic diarrhoea, with malabsorption and failure of children to thrive. At present, treatment options include the nitroimidazoles derivatives; especially metronidazole, which has been the mainstay of treatment for decades and is still widely used. The increasing number of reports of refractory cases with this group of drugs and other antigiardial agents, has raised concern and led to a search for other compounds, some of which have arisen due to the introduction of drugs initially addressed to other diseases. The present article examines some of the most important points of antigiardial pharmacotherapy available at present and the future prospects of development of new agents. PMID- 17696792 TI - Management strategies for acute infective conjunctivitis in primary care: a systematic review. AB - A systematic review of the literature on all aspects of the management of acute infective conjunctivitis is undertaken. Acute infective conjunctivitis is a common presentation in primary healthcare. It is usually a mild condition and serious complications are rare. Clinical signs are a poor discriminator of bacterial and viral causes. Studies of treatment show that there is a high rate of clinical cure without any treatment (65% within 2-5 days). Treatment with topical antibiotics improves the rate of clinical recovery and this is more marked in the first 2-5 days after presentation (number needed to treat [NNT] = 6), but less by 6-10 days (NNT = 13). Studies comparing treatment with different antibiotics do not demonstrate that any one antibiotic is superior; the choice of antibiotic should be based on consideration of cost and bacterial resistance. The present practice of prescribing antibiotics to most cases is not necessary. PMID- 17696793 TI - The economics of temozolomide in brain cancer. AB - For 30 years, nitrosourea was the only adjuvant treatment available for aggressive glioma patients, despite its severe side effects; and, therefore, radiotherapy was often the therapy of choice. Survival prospect in these patients was, however, low with generally few patients surviving beyond 2 years. Recently, temozolomide was successfully tested in a number of randomised clinical trials and showed an increased survival. As many countries are considering reimbursement or have granted a market authorisation for temozolomide, a number of studies have been published in various countries in order to assess the cost-effectiveness of temozolomide for glioma patients in first- or second-line treatment. These studies show that in general, the incremental cost-effectiveness of temozolomide as adjuvant treatment, albeit at the higher end of commonly accepted thresholds, falls in line with other accepted cancer treatments. PMID- 17696794 TI - Rufinamide: a new anti-epileptic medication. AB - Rufinamide (1-[2,6-difluorobenzyl]-1H-1,2,3-triazole-4-carboxamide) is a new anti epileptic drug with a novel triazole derivative structure. The suspected mechanism of action is limitation of sodium-dependent action potentials, thought to result in a membrane stabilizing effect. Rufinamide is extensively metabolized in the liver by non-CYP450 enzymes with an elimination half-life of 8 - 12 h. Three randomized, placebo-controlled trials have shown that rufinamide is effective against partial seizures in adults. Efficacy in the Lennox-Gastaut syndrome, a severe, disabling childhood onset epilepsy syndrome, was shown in a single, randomized, placebo-controlled trial. It has recently been approved for treatment of Lennox-Gastaut syndrome in Europe. In the US it is under regulatory review. Most common adverse effects are somnolence, fatigue, dizziness, dipolopia, nausea and ataxia. Rufinamide has shown promise as adjunctive treatment for Lennox-Gastaut syndrome and may have some role in localization related epilepsies as well. PMID- 17696795 TI - Apomorphine in the treatment of Parkinson's disease. AB - Motor fluctuations, refractory to conventional medical management, are one of the most troubling aspects of Parkinson's disease. Apomorphine is a dopaminergic agent that has been known to the medical community for more than a century, but has only recently been developed to treat such motor fluctuations. In this article, the authors review the historical background, structure, mechanism of action, pharmacologic properties, clinical trials, indications and side effects, as well as avenues of further research, of apomorphine. PMID- 17696796 TI - Darunavir (TMC114): a new HIV-1 protease inhibitor. AB - Effective combination therapy for HIV/AIDS is now available and has made a major impact on HIV-related mortality and morbidity. The effects of even the most active of antiretroviral drugs are hampered by drug resistance and tolerability issues. Darunavir (TMC114), coadministered with low-dose ritonavir (darunavir/r), is a new HIV-1 protease inhibitor that has been designed to be active against both wild-type and multi-resistant virus. Darunavir/r 600/100 mg b.i.d. in a combination antiretroviral regimen in the POWER trials has provided treatment experienced patients with substantially greater virological and immunological benefits compared with standard of care. This article reviews the presently available data on darunavir, its pharmacology, pharmacokinetics, drug-drug interactions and clinical trial results, as well as examining darunavir from a health economic perspective. PMID- 17696797 TI - Letrozole: present and future role in the treatment of breast cancer. AB - State of the art hormonal therapy for women with breast cancer has evolved over the last few years. Tamoxifen used to be the gold standard for adjuvant treatment of postmenopausal women with hormone-sensitive early breast cancer and also for patients with metastatic disease in whom hormonal manipulation was considered, but the introduction of third generation aromatase inhibitors has changed this concept. This article discusses the clinical implications of recent trials with one of the aromatase inhibitors letrozole, including pharmacokinetic and pharmacodynamic data as well as recent data on relative benefits and side effects compared with other available hormonal agents. Relevant ongoing clinical translational trials evaluating this agent are also discussed. PMID- 17696798 TI - PEG-asparaginase. AB - L-asparaginases have been established components in the treatment of acute leukemias for nearly 40 years. Their antitumor effect results from the depletion of asparagine, an amino acid essential to leukemic cells, and subsequent inhibition of protein synthesis leading to considerable cytotoxicity. The efficacy of L-asparaginases has been limited by a high rate of hypersensitivity reactions and development of anti-asparaginase antibodies, which neutralize their activity. PEG-asparaginase, a form of Escherichia coli L-asparaginase covalently linked to polyethylene glycol, was rationally synthesized to decrease immunogenicity of the enzyme and prolong its half-life. In recent years, clinical trials have established the importance of intramuscular PEG-asparaginase in frontline pediatric and adult acute lymphoblastic leukemia therapy. Present studies are evaluating the feasibility of intravenous PEG-asparaginase administration. PMID- 17696799 TI - Pioglitazone: update on an oral antidiabetic drug with antiatherosclerotic effects. AB - Pioglitazone, a member of the PPAR-gamma agonist drug family, has been demonstrated to improve both metabolic and vascular insulin resistance when applied to patients with Type 2 diabetes mellitus. The drug is well tolerated with fluid retention and weight gain being the most frequently described side effects. The observed effects (e.g., improvements in glucose and lipid metabolism, improvements of endothelial function and microcirculation, reduction of surrogate markers of atherosclerosis and inflammation and an improvement in hypertension) have made pioglitazone one of the frequently prescribed antidiabetic drugs in the US and Europe. Several trials have shown its potency to reduce carotid intima-media thickness, and outcome studies with pioglitazone have shown its potential to delay the progression of Type 2 diabetes and atherosclerosis and even reduce cardiovascular mortality. The purpose of this review is to provide an overview about recently published clinical results with pioglitazone. They underline the value of this drug when used alone or in combination with other antidiabetic drugs for a successful management of Type 2 diabetes mellitus. PMID- 17696800 TI - Impact of physiological, physicochemical and biopharmaceutical factors in absorption and metabolism mechanisms on the drug oral bioavailability of rats and humans. AB - The onset, intensity and duration of therapeutic response to a compound depend on the intrinsic pharmacological activity of the drug and pharmacokinetic factors related to its absorption, distribution, metabolism and elimination that are inherent to the biological system. The process of drug transfer from the site of administration to the systemic circulation and the interspecies factors that impact this process are the scope of this review. In general, the factors that influence oral drug bioavailability via absorption and metabolism can be divided into physicochemical/biopharmaceutical and physiological factors. Physicochemical and biopharmaceutical factors that influence permeability and solubility tend to be species independent. Although there are significant differences in the anatomy and physiology of the gastrointestinal tract, these are not associated with significant differences in the rate and extent of drug absorption between rats and humans. However, species differences in drug metabolism in rats and humans did result in significant species differences in bioavailability. Overall, this review provides a better understanding of the interplay between drug physicochemical/biopharmaceutical factors and species differences/similarities in the absorption and metabolism mechanisms that affect oral bioavailability in rats and humans. This will enable a more rational approach to perform projection of oral bioavailability in human using available rat in vivo data. PMID- 17696801 TI - Predictive models for oral drug absorption: from in silico methods to integrated dynamical models. AB - Poor oral absorption is one of the most common reasons for a drug to be terminated during development. Oral drug absorption is a complex process affected by many competing factors related to the compound, the formulation and the gastrointestinal physiology. Throughout drug development, in silico, computational and mathematical models play important roles in the support of drug development and decision making in absorption-related issues. These models range from simple empirical rule of thumb tools to sophisticated dynamic systems. This article reviews the different computational methods for oral drug absorption for the various processes, with emphasis on solubility, permeability, dissolution and release rates, and gastrointestinal transit, but also on the modern integrated absorption prediction systems and computer software. PMID- 17696802 TI - New cell models and assays in cardiac safety profiling. AB - Drug-induced prolongation of the QT interval in the electrocardiogram has been associated with life-threatening ventricular tachycardia of the Torsades de Pointes type. To prevent this risk to patients, all new drug entities must undergo thorough in vitro and preclinical in vivo testing. Because a hERG channel block is the primary reason for ventricular repolarisation, disturbances causing a QT interval prolongation, established in vitro test systems focus on the analysis of drug action on hERG channel function. More sophisticated assays study ventricular repolarisation directly with cardiac tissue preparations. In addition, in the future, novel biological models, such as stem-cell-derived cardiomyocytes and cardiac tissue slices, may allow the design of innovative assay systems to address relevant cardiac safety pharmacology parameters. In this review, established as well as innovative assays and cell models used in these assays are discussed. PMID- 17696803 TI - Role of osteopontin in regulating hepatic inflammatory responses and toxic liver injury. AB - Osteopontin (OPN) produced by cells of the immune system, epithelial tissue, smooth muscle cells, osteoblasts and tumor cells has been implicated in various pathophysiological functions such as cell binding, spreading and migration, and tumor metastasis. OPN is known to bind to integrins expressed on macrophages through the arginine-glycine-aspartic acid (RGD) motif and promote migration of cells resulting in granuloma. In the liver, it has been reported that hepatic Kupffer cells secrete OPN facilitating macrophage infiltration in necrotic areas following carbon tetrachloride liver toxicity. Recent work has underlined the importance of OPN as a pivotal cytokine/chemokine in the generated hepatic neutrophil response during early phase alcoholic liver injury. Increased hepatobiliary OPN expression correlated well with higher neutrophil infiltration in a rat model of alcoholic steatohepatitis. In the same model of alcoholic steatohepatitis, higher hepatic expression of OPN in females was attributed to the higher neutrophil infiltration and consequent higher female sensitivity to liver damage. OPN as a potential biomarker for inflammatory liver disease has also been recently assessed. This review will focus on studies demonstrating the role of OPN in mediating hepatic inflammation (neutrophils, monocytes/macrophages and lymphocytes) and the ensuing liver toxicity. PMID- 17696804 TI - Biochemical mechanisms of nephrotoxicity: application for metabolomics. AB - This review describes biochemical pathways of nephrotoxicity and the application of metabolic biomarkers as they relate to nephrotoxicity. Specific and sensitive biomarkers constitute the missing link in the continuum of exposure to toxins and susceptibility, disease development and possible therapeutic intervention. Important requirements for biomarker development are a detailed understanding of biochemical pathways involved in nephrotoxicity, minimal invasiveness and capacity to screen large at-risk populations. Lastly, possible biomarker candidates should be organ specific and equally applicable in preclinical drug testing as well as in clinical care of patients. This review discusses four major metabolic pathways associated with disturbed renal homeostasis: i) direct metabolic evidence of abnormal excretion of endogenous metabolites; ii) disturbances in kidney osmolarity and renal osmolyte homeostasis; iii) impaired energy state followed by dysregulation of glucose, fatty acid and ketone body metabolism; and iv) oxidative stress in renal tissues. Each of these pathways can be monitored by specific surrogate markers in urine and blood using modern metabolomics technologies. PMID- 17696805 TI - In vitro models for processes involved in intestinal absorption. AB - The abundance of different techniques and protocols available reflects the need for reliable in vitro methods to assess intestinal absorption of potentially bioactive compounds. Physicochemical assays try to pinpoint the molecular properties contributing to the absorption process. The end points of biologically based methods, such as cell cultures and excised tissues, account for all processes undergone by a molecule that traverses a 'living' biological membrane, a cell or tissue. On top of fundamental physical processes (e.g., solubility, diffusion) such biological methods incorporate physiological responses such as active transport and metabolism. In this review, an account of in vitro methods for the assessment of molecular properties (lipophilicity, solubility, permeability) influencing intestinal absorption is given. Their advantages and limitations and the possibilities offered by this area of research are also evaluated. The combination of results from both classes of assays (physicochemical and biological) and integration with computational models will guide future developments in this field. Finally, possible future developments including stem cell research and multiple-end point assays are discussed. PMID- 17696806 TI - Alterations in drug disposition during pregnancy: implications for drug therapy. AB - The disposition of many medications is altered during pregnancy. Due to changes in many physiological parameters as well as variability in the activity of maternal drug-metabolizing enzymes, the efficacy and toxicity of drugs used by pregnant women can be difficult to predict. Enzymatic activity exhibited by the placenta and fetus may affect maternal drug distribution and clearance also. In addition, efflux transporters have been detected in high amounts within placental tissue, potentially limiting fetal exposure to xenobiotics. Dosage adjustments of antiepileptic drugs, antidepressants and anti-infectives administered during pregnancy have been required due to these changes in drug metabolism and disposition. As such, pregnant women may require different dosing regimens than both men and non-pregnant women. PMID- 17696807 TI - CNS pharmacokinetics of antifungal agents. AB - The goal in treatment of infections is to achieve a beneficial effect while minimizing toxicity. It is widely recognized that the principles of pharmacokinetics and pharmacodynamics are critical to determining an adequate dose-response relationship. There has been an increased involvement of the CNS to infection from opportunistic and endemic fungi over the last several decades due to establishment of solid-organ and bone marrow transplantation as well as immunosuppression from HIV. In this regard it has become critical to define optimal dosing regimens by an understanding of the processes which govern delivery of an antifungal agent to the targeted CNS site of involvement. The objective of this review is to: i) summarize published experimental and clinical antifungal pharmacokinetics; and ii) examine the relationship between CNS antifungal pharmacokinetics and efficacy. Examination of these studies reveal marked variability among antifungal drugs with regard to cerebrospinal fluid and brain parenchymal penetration. Formal examination of the relationship between CNS antifungal pharmacokinetics and efficacy are limited. The few experimental studies available suggest that brain parenchymal kinetics is a superior predictor of antifungal efficacy than cerebrospinal fluid concentrations. PMID- 17696808 TI - The role of cytochrome P450 in antiretroviral drug interactions. AB - As millions of patients with HIV/AIDS are put on treatment with the highly active antiretroviral therapy (HAART), drug interactions have become a major concern for healthcare providers. The use of HAART as a combination of 3 - 4 drugs creates potential for antiretroviral (ARV) drug interactions, and this is complicated by the addition of other drugs for treatment of other ailments such as comorbid chronic conditions and/or opportunistic infections. It has been observed that most ARV drug interactions involve drugs that interact with CYP enzymes. Specifically, protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the most implicated in ARV drug interactions and are metabolised by CYP isoenzymes. Because PIs and NNRTIs can also inhibit and induce some of the CYP isoenzymes, they often interfere with the metabolism of several drugs eliminated by CYP isoenzymes, and the converse is true. The drug groups most implicated in CYP-mediated interactions with ARV drugs include: rifamycins; statins; antibiotics; antifungals; antiulcer drugs; contraceptives; immunosuppressant drugs; drugs for erectile dysfunction; drugs of abuse; drugs for treatment of addiction; benzodiazepines; anticonvulsants; psychotropic agents; herbal products; antiarrhythmias; antimalarials; anticoagulants; and antiasthma drugs. Unfortunately, this information is published in different resources where it may not be accessible to many, and is also liable to misinterpretation if read in isolation. Here, this information has been pooled and discussed with a hope that it will enable appropriate use in patients with HIV/AIDS. The review was confined to CYP-associated ARV drug interactions to emphasise that prevention of ARV drug interactions requires thorough knowledge of CYP function and regulation by healthcare providers. PMID- 17696809 TI - Novel and future applications of microarrays in toxicological research. AB - Microarray technologies have both fascinated and frustrated the toxicological community since their introduction around a decade ago. Fascination arose from the possibility offered by the technology to gain a profound insight into the cellular response to chemically mediated stress, and the potential that this genomic signature would be indicative of the biological mechanism by which that stress was induced. Frustrations have arisen primarily from technical factors such as data variance, the requirement for the application of advanced statistical and mathematical analysis, and difficulties associated with actually recognising signature gene expression patterns, and discerning mechanisms. Toxicogenomics was predicted to make toxicological assessment and extrapolation easier, faster and cheaper. The reality has been somewhat different; toxicogenomics is difficult. However, its potential when properly applied has been indicated by some well designed toxicogenomics studies, particularly in the differentiation of genotoxins from non-genotoxins. Technology waits though for no man. While the toxicological community has been working to apply transcriptomics (mRNA levels) in toxicology, the technology has moved beyond this application into new arenas. Some have application to toxicology and are reviewed here, except transcriptomics which has been extensively written about before. This review discusses the application of microarray technologies applied to the genome per se (amplifications, deletions, epigenetic change), mRNA translation and its control mechanisms through miRNA. Which of the new genomics technoi?(1/2)logies will find most application in toxicology? In the opinion of the author there are three potentially major applications: i) arrayCGH in assessment and recognition of genotoxicity; ii) epigenetic assessment in developmental and transgenerational toxicology; and iii) miRNA assessment in all toxicology types, but particularly developmental toxicology. PMID- 17696811 TI - Clopidogrel: an updated and comprehensive review. AB - The risk of adverse events in patients with acute coronary syndrome remains substantial despite the use of regular aspirin. The addition of clopidogrel to regular aspirin therapy has been shown to be associated with significantly better outcomes in a variety of clinical settings within the spectrum of acute coronary syndromes. In this article, the evidence and therapeutic implications for the use of clopidogrel in patients with non-ST-elevation and ST elevation acute coronary syndromes is discussed, and also in those undergoing percutaneous coronary intervention. The use of clopidogrel in combination with other antithrombotics in the acute setting is considered, including glycoprotein IIb/IIIa receptor antagonists and direct thrombin inhibitors. Clopidogrel has changed the way in which patients with non-ST-elevation and, more recently, ST elevation acute coronary syndromes are treated. PMID- 17696810 TI - Direct thrombin inhibition with bivalirudin as an antithrombotic strategy in general and interventional cardiology. AB - Antithrombotic therapy is a crucial component of interventional cardiology and currently involves the administration of both anticoagulant and antiplatelet agents. The implementation of standard dual or triple antiplatelet therapies has allowed percutaneous coronary intervention (PCI) with stent implantation to become the treatment of choice in most patients with acute coronary syndromes (ACS), particularly in patients with ST-segment elevation myocardial infarction. However, the combined use of antithrombotic agents increases the bleeding risk associated with coronary intervention, which is a concern due to the increasing evidence that bleeding complications are associated with a higher risk of ischaemic events and death. The shortcomings of currently available anticoagulant drugs have promoted the ongoing development of new, powerful anticoagulant agents that have both efficacy in the setting of PCI and a reduced risk of bleeding; one of these classes of agents targets the thrombin molecule, a key factor in the coagulation cascade, and belongs to the class of anticoagulants known as direct thrombin inhibitors (DTIs). Bivalirudin, a synthetic peptide, is a DTI with unique, favourable pharmacological properties that include predictable linear pharmacokinetics. Bivalirudin was approved as an anticoagulant in patients undergoing routine PCI in 2000 by the FDA (in 2004 in Europe and Australia) and more recently in patients with ACS undergoing PCI. The pharmacological properties of bivalirudin, along with current indications for its use, are discussed in this review, with a focus on the major completed and ongoing clinical trials with bivalirudin. PMID- 17696812 TI - Tissue engineering with the aid of inkjet printers. AB - Tissue engineering holds the promise to create revolutionary new therapies for tissue and organ regeneration. This emerging field is extremely broad and eclectic in its various approaches. However, all strategies being developed are based on the therapeutic delivery of one or more of the following types of tissue building-blocks: cells; extracellular matrices or scaffolds; and hormones or other signaling molecules. So far, most work has used essentially homogenous combinations of these components, with subsequent self-organization to impart some level of tissue functionality occurring during in vitro culture or after transplantation. Emerging 'bioprinting' methodologies are being investigated to create tissue engineered constructs initially with more defined spatial organization, motivated by the hypothesis that biomimetic patterns can achieve improved therapeutic outcomes. Bioprinting based on inkjet and related printing technologies can be used to fabricate persistent biomimetic patterns that can be used both to study the underlying biology of tissue regeneration and potentially be translated into effective clinical therapies. However, recapitulating nature at even the most primitive levels such that printed cells, extracellular matrices and hormones become integrated into hierarchical, spatially organized three dimensional tissue structures with appropriate functionality remains a significant challenge. PMID- 17696813 TI - Brain tumour stem cells: possibilities of new therapeutic strategies. AB - Cancers are composed of heterogeneous cell populations, including highly proliferative immature precursors and differentiated cells, which may belong to different lineages. Recent advances in stem cell research have demonstrated the existence of tumour-initiating, cancer stem cells (CSCs) in non-solid and solid tumours. These cells are defined as CSCs because they show functional properties that resemble those of their normal counterpart to a significant extent. This concept applies to CSCs from brain tumours and, particularly, to glioblastoma stem-like cells, which self-renew under clonal conditions and differentiate into neuron- and glia-like cells, and into aberrant cells, with mixed neuronal/astroglia phenotypes. Notably, across serial transplantation into immunodeficient mice, glioblastoma stem-like cells are able to form secondary tumours which are a phenocopy of the human disease. A significant effort is underway to identify both CSC-specific markers and the molecular mechanism that underpin the tumorigenic potential of these cells, for this will have a critical impact on the understanding of the origin of malignant brain tumour and the discovery of new and more specific therapeutic approaches. Lately, the authors have shown that some of the bone morphogenetic proteins can reduce the tumorigenic ability of CSCs in GBMs. This suggests that mechanisms regulating the physiology of normal brain stem cells may be still in place in their cancerous siblings and that this may lead to the development of cures that selectively target the population CSCs found in the patients' tumour mass. PMID- 17696814 TI - Corticosteroid withdrawal in kidney transplantation: the present status. AB - Corticosteroids (CS) have played a vital role in organ transplantation, both for prevention and treatment of allograft rejection. However, the use of CS is associated with a wide range of adverse effects. With advances in immunosuppressive drug therapy, attempts have been made to minimize the use of CS to avoid or alleviate their side effects. Withdrawal of CS months after transplantation has transitioned to days. In low to intermediate risk renal allograft recipients, use of induction therapy and modern maintenance drug combinations allows safe withdrawal of CS within the first week of transplantation. In other groups, existing potent maintenance agents permit tapering of CS to low doses over the first few months. Withdrawal of these small doses may not add to the benefits. PMID- 17696815 TI - Therapeutic potential of adult progenitor cells in cardiovascular disease. AB - Cardiovascular diseases are responsible for high morbidity/mortality rates worldwide. Advances in patient care have significantly reduced deaths from acute myocardial infarction. However, the cardiac remodeling processes induced after ischaemia are responsible for a worsening in the heart condition, which in many cases ends up in failure. In the last decade, a novel therapy based on stem cell transplantation is being intensively studied in animal models and some stem cell types (i.e., skeletal myoblasts and bone marrow-derived cells) are already being tested in clinical trials. A novel stem cell population isolated from the bone marrow, termed multipotent adult progenitor cells was characterised a few years ago by its ability to differentiate, at the single cell level, towards cells derived from the three embryonic germ layers. Later on, other pluripotent cell populations have been also derived from the bone marrow. In this overview, the authors outline different stem cell sources that have been tested for their cardiovascular potential and put the regenerative potential of multipotent adult progenitor cells in animal models of acute and chronic myocardial infarction into perspective. PMID- 17696816 TI - Genetic modification of T cells for immunotherapy. AB - Adoptive transfer of antigen-specific T cells is a promising approach for preventing progressive viral infections in immunosuppressed hosts. By contrast, effective T-cell therapy of malignant disease has proven to be much more difficult to achieve. This, in part, reflects the difficulty of isolating high avidity T cells specific for tumor-associated antigens, many of which are self antigens that have induced some level of tolerance in the host. Even when tumor reactive T cells can be isolated, the ability of these cells to survive in vivo and traffic to tumor sites is often impaired. Additionally, most tumors employ multiple mechanisms to escape T-cell recognition, including interference in antigen presentation, secretion of inhibitory factors and recruitment of regulatory or immunosuppressive cells. The genetic modification of T cells prior to transfer provides a potential means to overcome many of these obstacles and enhance the efficacy of T-cell therapy. This review article discusses the rationale for genetic modification of T cells, the critical steps involved in gene transfer, and potential advantages and disadvantages of strategies that are now being examined to engineer improved effector T cells for the treatment of human infectious and malignant disease. PMID- 17696817 TI - Engineering blood vessels by gene and cell therapy. AB - Cardiovascular-related syndromes are the leading cause of morbidity and mortality worldwide. Arterial narrowing and blockage due to atherosclerosis cause reduced blood flow to the brain, heart and legs. Bypass surgery to improve blood flow to the heart and legs in these patients is performed in hundreds of thousands of patients every year. Autologous grafts, such as the internal thoracic artery and saphenous vein, are used in most patients, but in a significant number of patients such grafts are not available and synthetic grafts are used. Synthetic grafts have higher failure rates than autologous grafts due to thrombosis and scar formation within graft lumen. Cell and gene therapy combined with tissue engineering hold a great promise to provide grafts that will be biocompatible and durable. This review describes the field of vascular grafts in the context of tissue engineering using cell and gene therapies. PMID- 17696818 TI - Novel candidate disease for gene therapy: metachromatic leukodystrophy. AB - Metachromatic leukodystrophy (MLD) is a rare, fatal, inherited, autosomal recessive, lysosomal storage disorder, characterized by severe and progressive demyelination affecting the central and peripheral nervous systems. Despite some initial expectations in hematopoietic stem cell transplantation, and despite the ameliorated supportive therapy, MLD remains a life-threatening disease, with an extremely poor quality of life and a severe prognosis for all affected patients. Prospectively, in children affected by MLD, who have no other therapeutic option and an extremely poor prognosis, the potential risks associated with the use of a novel technology, such as gene therapy, might be well balanced by the potential benefit of a positive outcome. Thus, MLD might be considered an optimal candidate disease for testing innovative and potentially efficacious therapeutic approaches. Some of the gene therapy approaches discussed here, such as hematopoietic stem cells gene therapy, are likely to enter clinical testing in the near future. PMID- 17696819 TI - T-cell receptor gene therapy for cancer: the progress to date and future objectives. AB - In the last decade research has begun into the use of T-cell receptor (TCR) gene therapy as a means to control and eradicate malignancies. There is now a large body of evidence to demonstrate that through the use of this technology one can redirect T-cell antigen specificity to produce both cytotoxic and helper T cells, which are functionally competent both in vitro and in vivo and show promising antitumour effects in humans. This review focuses on the means by which TCR gene transfer is achieved and the recent advances to modify the TCRs and vector delivery systems which aim to enhance the efficiency and safety of TCR gene transfer protocols. PMID- 17696820 TI - New peptide nucleic acid analogues: synthesis and applications. AB - Peptide nucleic acids are oligonucleotide mimics characterised by high chemical and enzymatic stability, high specificity and affinity toward complementary DNA/RNA. The lack of charge and polar groups in the backbone decrease their solubility in aqueous environment and their ability to cross cell membranes, reducing their performance in in vivo applications. To improve solubility, increase affinity and specificity of binding and to control recognition between nucleic acids, several analogues bearing modifications on the nucleobase, nucleobase-backbone linker and on the backbone were synthesised. This paper describes the synthesis and applications of Peptide nucleic acid analogues and discusses the potential of analogues for which no application is reported. PMID- 17696821 TI - Biologics in Crohn's disease: searching indicators for outcome. AB - New insights into the underlying mechanism of Crohn's disease is enabling the development of new therapies. Even though the mechanisms of these drugs have been studied extensively, reliable indicators for implementation of new biologic drugs are still needed. This review presents biologics in Crohn's disease focusing on efficacy, steroid sparing, mucosal healing and safety, including immunogenicity. PMID- 17696822 TI - Update on anti-CTLA-4 antibodies in clinical trials. AB - Breaking immune tolerance against tumor self-antigens is presently an area of intense research in the design of cancer therapies. One possible method to enhance immune system activation against tumor antigens is by blocking the inhibitory co-stimulatory signals mediated by cytotoxic T lymphocyte antigen 4, (CTLA-4) expressed on activated T cells. The fully human monoclonal antibodies that are directed against human CTLA-4, ipilimumab (Medarex/Bristol-Myers Squibb) and CP-675,206 (Pfizer/Abgenix, now Amgen), have demonstrated activity against metastatic melanoma, hormone refractory prostate cancer and other malignancies. They have also uncovered unusual immune-related adverse events manifesting as self-limiting inflammatory reactions of the bowel, skin and pituitary. This article reviews preclinical development and data generated from Phase I, II and III studies with regard to the end points reported and immune-related adverse events. PMID- 17696823 TI - CPG-7909 (PF-3512676, ProMune): toll-like receptor-9 agonist in cancer therapy. AB - Stimulation of toll-like receptor (TLR)9 activates human plasmacytoid dendritic cells and B cells, and induces potent innate immune responses in preclinical tumor models and in patients. CpG oligodeoxynucleotides (ODNs) are TLR9 agonists that show promising results as vaccine adjuvants and in the treatment of cancers, infections, asthma and allergy. PF-3512676 (ProMune) was developed as a TLR9 agonist for the treatment of cancer as monotherapy and as an adjuvant in combination with chemo- and immunotherapy. Phase I and II trials have tested this drug in several hematopoietic and solid tumors. Pfizer has initiated Phase III trials to test PF-3512676 in combination with standard chemotherapy for non-small cell lung cancer. PMID- 17696824 TI - Heat-shock protein-peptide complex-96 for the treatment of cancer. AB - Heat-shock proteins (HSPs) are the most abundant and ubiquitous soluble intracellular proteins. Members of the HSP family bind peptides, including antigenic peptides generated within cells. HSPs also interact with antigen presenting cells (APCs) through CD91 and other receptors, eliciting a cascade of events that includes representation of HSP-chaperoned peptides MHC, translocation of NF-kappaB into the nuclei, and maturation of dendritic cells. These consequences point to a key role of HSPs in fundamental immunologic phenomena such as activation of APCs, indirect presentation (or crosspriming) of antigenic peptides, and chaperoning of peptides during antigen presentation. The properties of HSPs also allow them to be used for immunotherapy of cancers and infections in novel ways. This paper reviews the development and clinical trial progress of vitespen, an HSP peptide complex vaccine based on tumor-derived glycoprotein 96. PMID- 17696825 TI - Immunotherapy for prostate cancer using antigen-loaded antigen-presenting cells: APC8015 (Provenge). AB - Dendritic cells are deficient both in number and function in patients with cancer. Loaded dendritic cell therapies aim to overcome this deficiency by delivering antigens to antigen-presenting cells under ex vivo conditions, improving dendritic cell function. APC8015 (Provenge; Dendreon Corp., Seattle, WA) is a novel immunotherapeutic, which consists of autologous dendritic cells pulsed ex vivo with PA2024, a recombinant fusion protein consisting of granulocyte macrophage colony-stimulating factor and prostatic acid phosphatase, as an immunogenic agent. A Phase III randomized clinical trial has demonstrated a survival benefit in patients with metastatic hormone-refractory prostate cancer. This review summarizes the clinical trials using APC8015 in prostate cancer and discusses its future role in the treatment of prostate cancer. PMID- 17696826 TI - 32(nd) Annual Meeting of the European Thyroid Association in Leipzig, Germany. PMID- 17696827 TI - Immunohistochemistry differentiates papillary thyroid carcinoma arising in ectopic thyroid tissue from secondary lymph node metastases. AB - OBJECTIVE: To verify whether immunohistochemistry might be useful in the distinction between a true laterocervical metastasis of an undetected thyroid carcinoma and a primary tumor outside the gland. DESIGN: Galectin-3, cytokeratin 19, and HBME-1 were assessed in six cases (group A) of laterocervical masses harboring papillary thyroid carcinoma (PTC) but without a thyroid tumor, and in eight cases (group B) showing PTC both in the thyroid and in the laterocervical masses. In both groups, normal-looking follicles adjacent to the laterocervical neoplasia were present. MAIN OUTCOME: We found that the apparently normal follicles in group A were negative for all the antibodies, while group B showed strong and diffuse positive immunostaining. The neoplastic areas were always positive for all the antibodies in both groups. CONCLUSION: Even if immunohistochemical patterns of residual follicles of group B are very well differentiated that they resemble normal thyroid parenchyma, they may well be metastatic carcinomas. On the contrary, the presence of morphologically and immunohistochemically normal-looking follicles in group A, with no intrathyroid tumor, suggests that the primary PTC might possibly develop in the ectopic thyroid tissue. In cases showing morphologically and immunohistochemically normal looking follicles in laterocervical masses, these findings might lead to a reduction of the overdiagnosis of metastatic disease of an undetected carcinoma. PMID- 17696828 TI - Effects of 12 months treatment with L-selenomethionine on serum anti-TPO Levels in Patients with Hashimoto's thyroiditis. AB - OBJECTIVE: We studied the effects of selenium (Se) treatment on serum anti thyroid peroxidase (TPO) levels in Greek patients with Hashimoto's thyroiditis (HT). DESIGN: We prospectively studied 80 women with HT, median age 37 (range 24 52) years, for 1 year. All patients received 200 microg Se in the form of l selenomethionine orally for 6 months. At the end of the 6-month period, 40 patients continued taking 200 microg Se (Group A) and 40 patients stopped (Group B). Serum thyrotropin (TSH), free triiodothyronine (FT(3)), free thyroxine (FT(4)), anti-TPO, and anti-thyroglobulin (Tg) levels were measured at baseline and at the end of each 3-month period. MAIN OUTCOME: There was a significant reduction of serum anti-TPO levels during the first 6 months (by 5.6% and 9.9% at 3 and 6 months, respectively). An overall reduction of 21% (p < 0.0001) compared with the basal values was noted in Group A. In Group B, serum anti-TPO levels were increased by 4.8% (p < 0.0001) during the second 6-month period. CONCLUSIONS: Our study showed that in HT patients 6 months of Se treatment caused a significant decrease in serum anti-TPO levels, which was more profound in the second trimester. The extension of Se supplementation for 6 more months resulted in an additional 8% decrease, while the cessation caused a 4.8% increase, in the anti-TPO concentrations. PMID- 17696830 TI - Treatment of hypothyroidism in elderly patients and in patients with cardiac disease. AB - Hypothyroidism is often associated with adverse cardiovascular risk factors such as high cholesterol together with hypertension, endothelial dysfunction, and other atherosclerotic cardiovascular risk factors. The changed hemodynamic characteristics result in reduced cardiac index, and the renal perfusion is impaired with hyponatremia, and low renin and aldosterone production. The ischemic abnormalities are probably related to long-term consequences of a slow development of hypothyroidism, while the hemodynamic changes can develop in very short-term hypothyroidism. Replacement of hypothyroidism with levothyroxine is associated with a normalization of basal metabolic rate. Most patients with preexisting angina experience a gradual amelioration of symptoms, but in some cases the initial therapy may precipitate an unrecognized ischemic state, worsen a preexisting angina, or even result in myocardial infarction. It is therefore advisable to start replacement slowly and if needed perform a stress test and/or coronary angiography before. It may also in some cases be necessary to monitor the patients closely in a hospital setting during initiation of levothyroxine. Elderly hypothyroid patients with unstable angina pose a particular challenging problem, especially if coronary vascular surgery is indicated. No increased risk of peri- or postoperative death has been noted in small studies, although more complications have been described. It may be relevant to treat the cardiac vascular occlusion before starting replacement with levothyroxine in some cases, after careful weighting of pros and cons in each individual case. PMID- 17696829 TI - hNIS protein in thyroid: the iodine supply influences its expression and localization. AB - OBJECTIVE: Nonfunctioning thyroid nodules (NFTNs) display a diminished iodide concentrating ability, owing to defective expression and cell membrane targeting of the sodium-iodide symporter (NIS). Since NIS expression is primarily modulated by thyroid iodine content in vitro and in animal models, we attempted to determine whether iodine supply influences the expression and localization of human NIS (hNIS) in NFTNs. DESIGN: Using immunohistochemistry, we analyzed cold hyperplastic nodules and nonnodular thyroid samples (controls) from patients living in iodine-sufficient (n = 19) or severely iodine-deficient (n = 15) areas. MAIN OUTCOME: Nodules from the iodine-sufficient area exhibited weak or absent hNIS immunostaining whereas almost all nodules from the iodine-deficient area were hNIS positive. Heterogeneous hNIS staining was common among the iodine deficient samples (p = 0.028). hNIS was localized on membrane in all nodular samples from the iodine-deficient area and in less than 40% in the iodine sufficient area. CONCLUSIONS: hNIS is adequately expressed and appropriately localized in NFTNs cell membrane from iodine-deficient areas and its expression in vivo is modulated by iodine supply. PMID- 17696831 TI - Cardiovascular effects of mild hypothyroidism. AB - The cardiovascular risk is increased in patients with overt hypothyroidism, and several potential cardiovascular risk factors were similarly reported in patients with subclinical hypothyroidism. Only recently have more data become available about the effects of mild hypothyroidism on the cardiovascular system. An impaired left ventricular diastolic function, which is characterized by slowed myocardial relaxation and impaired ventricular filling, is the most consistent cardiac abnormality in patients with mild thyroid hormone deficiency. Impaired left ventricular diastolic function on effort was also documented by radionuclide ventriculography. Studies performed by ultrasonic myocardial textural analysis suggest an altered myocardial composition in patients with mild hypothyroidism. Moreover, pulsed tissue Doppler analysis revealed that patients with mild hypothyroidism had changes in myocardial time intervals in several left ventricular segments. Finally, alterations in cardiac hemodynamic were documented by cardiac magnetic resonance imaging in presence of mild disease. Vascular function is impaired in patients with mild and subclinical hypothyroidism, as documented by the increase in systemic vascular resistance and arterial stiffness and by the impaired endothelial function. The negative effect induced by mild hypothyroidism on cardiovascular system can be reverted restoring euthyroidism with levothyroxine (L-T4) therapy. Based on the data available, it appears that L T4 replacement should be considered in patients with mild hypothyroidism in presence of associated cardiovascular risk factors in the attempt to reverse these negative prognostic factors and improve the cardiovascular risk. PMID- 17696832 TI - Predicting the development of Cushing's syndrome in medullary thyroid cancer: utility of proopiomelanocortin messenger ribonucleic acid in situ hybridization. AB - OBJECTIVE: To determine the ability to predict the development of Cushing's syndrome (CS) by immunostaining prior to its clinical recognition. DESIGN: In the current report, we demonstrated that a medullary thyroid carcinoma (MTC) patient had the ability to develop CS several years before its clinical recognition. Special stains on tumor tissue confirmed the presence of ectopic adrenocorticotropic hormone (ACTH) 3 years before his clinical presentation of CS. Subsequently, we identified eight MTC patients and reviewed their records to determine whether there was clinical or laboratory evidence of CS. Tissue blocks were obtained from the primary tumor and metastasic lesions for ACTH staining and for proopiomelanocortin messenger ribonucleic acid (POMC mRNA) in situ hybridization. Chromogranin A staining was also performed. MAIN OUTCOME: ACTH staining did not detect ectopic ACTH. However, measuring ACTH precursor (POMC mRNA) by in situ hybridization confirmed the diagnosis, which preceded the patient's clinical presentation by 3 years. We also found that in a small series of eight MTC patients, most with metastatic disease, there was no histologic evidence of ACTH or POMC production. CONCLUSION: Our current report demonstrates that ACTH staining may not detect ACTH, but measuring POMC mRNA by in situ hybridization is very helpful in confirming the source of ectopic ACTH production. PMID- 17696833 TI - Diagnosis of medullary thyroid carcinoma by calcitonin measurement in fine-needle aspiration biopsy specimens. AB - Medullary thyroid carcinoma (MTC) is a thyroid malignancy originating from C cells. To date, serum calcitonin measurement and fine-needle aspiration biopsy (FNAB) have been prominent diagnostic approaches to these lesions. Although an elevated serum calcitonin level strongly suggests the presence of MTC, this examination cannot identify the origin of the calcitonin overexpression, especially in patients demonstrating multiple thyroid nodules. For the treatment planning, it is important to know which nodule is MTC, especially in nonhereditary MTC. In this study, we propose calcitonin measurement in the washout of FNAB needles after sampling each tumor (FNAB-CT) as a new approach to diagnosis of MTC. We performed FNAB-CT for five MTC cases. Although only one of these cases was definitively diagnosed as having MTC by FNAB cytology, FNAB-CT values ranged from 17,000 to 560,000 pg/mL, which were exceedingly higher than those of 11 controls (seven papillary carcinomas, two adenomatous nodules, one chronic thyroiditis, and one normal thyroid), which showed values ranging from <10 to 67 pg/mL. In patients with MTC, FNAB-CT values were 74 to 1888 times greater than serum calcitonin values. These findings suggest that FNAB-CT can be an additional approach to diagnosis of MTC. PMID- 17696834 TI - Poorly differentiated follicular thyroid carcinoma: prognostic factors and relevance of histological classification. AB - OBJECTIVE: Poorly differentiated follicular thyroid carcinoma (PDFC) is a tumor of follicular cell origin with attributes intermediate between well differentiated carcinomas and anaplastic carcinomas, but neither a clear histological description nor an established definition of prognostic indicators are available. DESIGN: This study correlates the clinical outcome and survival of 40 PDFC patients with histological architecture, cytological characteristics, and expression of various markers of cell proliferation and differentiation (cyclin A, cyclin B1, cyclin D1, cyclin E, Ki67, thyroperoxidase, galectin 3, dual oxidase [Duox], vascular endothelial growth factor, epidermal growth factor receptor, and p53). MAIN OUTCOME: At 5 years, the overall survival rate was 63% and the metastasis-free survival rate was 57%. An older age at the time of diagnosis and a larger tumor size were associated with an increased risk of distant metastases and of cancer-related death. Polymorph architecture was associated with a reduced risk of metastases, whereas a high expression of Duox was associated with a reduced risk of death. In these patients with PDFC, no other histological features or expression of any other marker had a prognostic significance. CONCLUSION: PDFC has a more aggressive behavior than well differentiated carcinomas; prognosis is related to indicators that are also relevant in patients with well-differentiated carcinomas. PMID- 17696835 TI - Which domains of thyroid-related quality of life are most relevant? Patients and clinicians provide complementary perspectives. AB - OBJECTIVE: To identify how thyroid diseases impact the patients' lives and to select the most relevant quality of life (QoL) issues for a thyroid-specific questionnaire. DESIGN: Fifteen thyroid experts and 80 thyroid outpatients (14 with nontoxic goiter, 12 nodular toxic goiter, 21 Graves' disease, 17 thyroid associated ophthalmopathy, and 16 primary hypothyroidism) were interviewed. METHODS: The relevance of 138 thyroid disease-related issues was rated during interviews. For each issue, three relevance measures were obtained: a diagnosis specific patient rating, a diagnosis-specific expert rating, and a combined overall patient/expert rating. The 75 most relevant issues overall and the 15 most relevant issues in each patient category were selected. RESULTS: Based on the above, 92 issues were selected, covering a broad range of clinical and QoL domains. Across patient groups, broader QoL domains were most relevant, especially fatigue and emotional susceptibility. However, when focusing on individual patient groups, diagnosis-related physical symptoms were very relevant too. Patients rated issues about psychosocial problems and impact on daily life as more relevant, whereas clinicians focused on thyroid-characteristic issues. CONCLUSIONS: A broad range of QoL issues and physical symptoms are relevant for thyroid patients, particularly fatigue and emotional susceptibility. Patients and clinicians offer complementary perspectives on relevance. PMID- 17696836 TI - Tall cell variant of papillary thyroid carcinoma without extrathyroid extension: biologic behavior and clinical implications. AB - BACKGROUND: The tall cell variant (TCV) is a histologic subtype of papillary thyroid carcinoma (PTC) that is more aggressive than "classical" PTC. Most authors believe that TCV's worse prognosis is related to older age at presentation, larger tumor size, and high frequency of extrathyroid tumor extension (ETE). To assess the biologic and clinical behavior of TCV without ETE, we performed a detailed comparative clinicopathologic analysis of classical PTC and TCV without ETE. METHODS: TCV was defined as a PTC harboring >50% tall cells, while classical PTC was restricted to those tumors containing >1% papillae and <30% tall cells. Microscopic analysis and chart review identified 62 cases of TCV and 83 classical PTC without ETE. These patients were analyzed for various pathologic, imaging, and clinical parameters including outcome. RESULTS: There was no statistical difference between TCV and classical PTC in relation to age, gender, tumor size, risk stratification, type of therapy, and length of follow up. TCV displayed more invasion of the tumor capsule and more often infiltrated into the thyroid capsule (p = 0.047 and 0.0004, respectively). Among patients with microscopically assessable regional lymph node (LN), 33 of 49 (67.3%) patients with TCV had LN metastasis at presentation, while only 24 of 60 (40%) classical PTC had positive nodes (p = 0.004). In multivariate analysis, histologic subtype (TCV vs. classical PTC) was the only independent factor associated with LN metastases (p = 0.007). In patients with adequate follow-up, 4 of 62 (6.5%) classical PTC and 7 of the 47 (14.9%) TCV had thyroid cancer recurrence (p = 0.202). TCV recurred at a distant site (3 of 47, 6.4%) while none of the 62 classical PTC developed distant metastases (p = 0.077). CONCLUSION: TCV without ETE is biologically a more aggressive tumor than classical PTC without ETE independent of age, gender, and tumor size. PMID- 17696837 TI - Phase II trial of thalidomide for therapy of radioiodine-unresponsive and rapidly progressive thyroid carcinomas. AB - BACKGROUND: There are no known effective therapies for distantly metastatic, rapidly progressive thyroid carcinomas unresponsive to radioiodine. OBJECTIVE: Since thyroid carcinomas are hypervascular and thalidomide is antiangiogenic, we assessed thalidomide's tumoristatic effects and toxicity in a phase II trial. DESIGN: Thirty-six patients with follicular, papillary, insular, or medullary thyroid carcinomas and distant, radioiodine-unresponsive metastases (volumes increasing >or= 30% per year before entry) were accrued between July 2001 and December 2002. Daily thalidomide started at 200 mg, increasing over 6 weeks to 800 mg or maximum tolerated dose. Toxicities and responses were assessed at 8 week intervals with tumor volume assessments. MAIN OUTCOMES: Twenty-eight of 36 patients were evaluable, 5 with partial responses (PR: 18%; 95% confidence interval [95% CI]: 6-37%) and 9 patients with stable disease (SD: 32%; 95% CI: 12 42%) for overall 50% response (95% CI: 31-69%). Median PR duration was 4 months (range: 2-6 months), and SD duration was 6 months (range: 2-14 months). Median survival was 23.5 months for responders (PR + SD) and 11 months for nonresponders. Most frequent toxicity was fatigue (69% grade 1-2, 8% grade 3-4). Four patients had grade 3-4 infections (without neutropenia), one had pericardial effusion, and one had pulmonary embolus. CONCLUSIONS: Thalidomide confers therapeutic benefit in subsets of thyroid cancer patients with rapidly progressive, distantly metastatic disease. PMID- 17696838 TI - Recurrent silent thyroiditis: a report of four patients and review of the literature. AB - Silent thyroiditis, excluding postpartum thyroiditis and destructive amiodarone thyroiditis, is a relatively uncommon cause of thyrotoxicosis and recurrent cases are even rarer. We present four patients with recurrent silent thyroiditis. The number of episodes ranged from two to nine. All four patients had episodes that were similar in duration (4-6 weeks) as well as in their clinical (no viral prodrome or neck pain), biochemical (high total triiodothyronine [T(3)], free thyroxine [T(4)], and low thyrotropin [TSH] presence of antibodies to thyroid antigens), and scintigraphic (low radioiodine uptake) findings. Individual symptoms and symptom-free duration (from 1 to 4 years) were more variable. No associations were found with regard to medications, pregnancies, or other disease states previously implicated in thyroiditis. One patient was unsuccessfully prescribed thyroid hormone to prevent recurrence. Three were treated with radioablative iodine therapy during the recovery phase of an episode; they became hypothyroid and take replacement l-thyroxine. They have remained symptom free. PMID- 17696839 TI - A new case of familial nonautoimmune hyperthyroidism caused by the M463V mutation in the TSH receptor with anticipation of the disease across generations: a possible role of iodine supplementation. AB - OBJECTIVE: Hereditary (familial) nonautoimmune hyperthyroidism (FNAH) is caused by activating thyroid-stimulating hormone (thyrotropin) receptor (TSHR) germline mutations. We describe a family with recurrent thyrotoxicosis and goiter across three generations, including an 8-year-old girl. MAIN OUTCOME: Sequences of the TSHR gene in the index patient, her father, her paternal grandmother, and a paternal uncle demonstrated the presence of an identical germline TSHR mutation. The mutation was heterozygous and determined the substitution of valine for methionine (codon 463; ATG-->GTG) in the second transmembrane domain of the TSHR in all the affected patients, but in none of the unaffected family members. CONCLUSIONS: We compared the clinical presentation of FNAH in the family reported by us with the other cases harboring the same mutation reported in the literature. This analysis revealed high variability in the phenotypical expression of the disease. In the family reported by us, we also observed a clear anticipation of the onset of the disease across generations, and we discussed whether such a phenomenon can be the consequence of the increased iodine supplementation in the area where the family lives. PMID- 17696840 TI - Transient thyroiditis after treatment with lenalidomide in a patient with metastatic renal cell carcinoma. AB - Lenalidomide, a recently developed immunomodulatory drug, shares the antiangiogenic and antitumor properties of thalidomide. While there is a known association between thalidomide and hypothyroidism, to our knowledge, there have been no prior reports of thyrotoxicosis associated with thalidomide or lenalidomide treatment. Herein, we report the case of a patient who developed transient thyrotoxicosis while receiving lenalidomide in a clinical trial for metastatic renal cell carcinoma. The time course and biochemical features of this patient's presentation are most consistent with immune-mediated subacute destructive thyroiditis. This case highlights the importance of monitoring thyroid function in the growing number of patients being treated with lenalidomide. PMID- 17696841 TI - Incidental metastatic microcarcinoma of the thyroid identified after total parathyroidectomy. AB - Papillary microcarcinoma of the thyroid comprises 10-20% of all thyroid malignancies. Most microcarcinomas are slow growing and have a favorable prognosis. Lymph node metastasis caused by thyroid microcarcinoma is uncommon, and distant metastasis to lung or bone is even rarer. Thyroid microcarcinoma with metastasis to a thymic lymph node was not previously reported. We describe a case of incidental 1 mm micropapillary thyroid cancer identified within a thymic lymph node following total parathyroidectomy for secondary hyperparathyroidism. PMID- 17696842 TI - Increased uptake of technetium-99m HDP in the subcortical area of both femurs in a patient with Graves' disease. PMID- 17696843 TI - Goitrous Hashimoto's thyroiditis presenting as obstructive sleep apnea. PMID- 17696844 TI - Multinodular goiter of unusual shape and location. PMID- 17696847 TI - New building to advance study of tuberculosis in cattle, wildlife. PMID- 17696848 TI - Looking for solutions in foie gras debate. PMID- 17696849 TI - What is your diagnosis? Moderate soft tissue swelling and widening of the antebrachiocarpal joint. PMID- 17696850 TI - What is your diagnosis? Mineralized-opaque-rimmed soft tissue mass in the right caudoventral portion of the abdomen. PMID- 17696851 TI - Theriogenology question of the month. Bilateral testicular neoplasia. PMID- 17696852 TI - Animal behavior case of the month. Canine compulsive disorder. PMID- 17696853 TI - Rabies surveillance in the United States during 2006. AB - During 2006, 49 states and Puerto Rico reported 6,940 cases of rabies in animals and 3 cases in humans to the CDC, representing an 8.2% increase from the 6,417 cases in animals and 1 case in a human reported in 2005. Approximately 92% of the cases were in wildlife, and 8% were in domestic animals. Relative contributions by the major animal groups were as follows: 2,615 raccoons (37.7%), 1,692 bats (24.4%), 1,494 skunks (21.5%), 427 foxes (6.2%), 318 cats (4.6%), 82 cattle (1.2%), and 79 dogs (1.1%). Compared with numbers of reported cases in 2005, cases in 2006 increased among all groups except cattle. Increases in numbers of rabid raccoons during 2006 were reported by 11 of the 20 eastern states where raccoon rabies was enzootic, and reported cases increased by 3.2% overall, compared with 2005. On a national level, the number of rabies cases in skunks during 2006 increased by 6.1% from the number reported in 2005. Once again, Texas reported the greatest number (n = 351) of rabid skunks and the greatest overall state total of animal rabies cases (889). No cases of rabies associated with the dog/coyote rabies virus variant were reported. The last identified case of this canine rabies virus variant was identified in March 2004, along the US/Mexico border. With 2006 marking the second year of no apparent transmission of the dog/coyote variant, these findings from surveillance data support the contention that the canine rabies virus variant is no longer in circulation in the United States. Total number of cases of rabies reported nationally in foxes increased 13.6%, compared with 2005. Increases in the number of reported rabid foxes were attributable to greater numbers of foxes reported with the Arctic fox rabies virus variant in Alaska, the Texas gray fox rabies virus variant in Texas, and the raccoon rabies virus variant in Virginia. The 1,692 cases of rabies reported in bats represented a 14.5% increase, compared with numbers reported in 2005, making bats the second most reported rabid animal behind raccoons. Cases of rabies in cats, dogs, horses and mules, and sheep and goats increased 18.2%, 3.9%, 12.8%, and 22.2%, respectively, whereas cases reported in cattle decreased 11.8%. In Puerto Rico, reported cases of rabies in mongooses increased 9.2%, and rabies in domestic animals, presumably attributable to spillover infection from mongooses, increased 20%. Three cases of human rabies were reported from Texas, Indiana, and California during 2006. The cases in Indiana and Texas were attributed to bat rabies virus variants, whereas the case in California was attributed to an exposure to a dog in the Philippines. PMID- 17696854 TI - Effects of preadoption counseling for owners on house-training success among dogs acquired from shelters. AB - OBJECTIVE: To determine the effect of preadoption counseling for owners on house training success among dogs acquired from shelters. DESIGN: Prospective study. SAMPLE POPULATION: 113 dog owners. PROCEDURES: Participants were randomly assigned to a treatment (n = 54) or a control (59) group. Dog owners in the treatment group received counseling (5 minutes' duration) regarding house training. Owners in the control group did not receive counseling, but all other adoption procedures were otherwise identical to those applied to the treatment group. All participants were contacted by telephone 1 month after adoption of a dog for assessment of house-training status and related issues by use of a standardized survey method; data were compared between groups. RESULTS: Most shelter dogs were considered successfully house-trained by their owners 1 month after adoption. Furthermore, dogs were considered house-trained by significantly more owners who received preadoption counseling than control group owners (98.1% vs 86.4%). Owners who received counseling used verbal punishment on their dogs during house-training less frequently and applied enzymatic cleaners to urine- or feces-soiled areas more frequently than owners in the control group. CONCLUSIONS AND CLINICAL RELEVANCE: Results have suggested that brief preadoption counseling for owners enhances successful house-training of dogs adopted from shelters. Counseling owners at the time of pet acquisition may thus have beneficial effects in the prevention of inappropriate elimination behaviors. Veterinarians and animal care staff should be encouraged to devote time to counsel new pet owners on successful house-training, as well as other healthcare and behavioral needs. PMID- 17696856 TI - Efficacy of temozolomide or dacarbazine in combination with an anthracycline for rescue chemotherapy in dogs with lymphoma. AB - OBJECTIVE: To compare results of treatment with temozolomide or dacarbazine, in combination with an anthracycline, in dogs with relapsed or refractory lymphoma. DESIGN: Nonrandomized, controlled clinical trial. ANIMALS: 63 dogs with relapsed or refractory lymphoma. PROCEDURES: Chemotherapy was administered in 21-day cycles. A combination of temozolomide and an anthracycline (doxorubicin or dactinomycin) was administered to 21 dogs and a combination of dacarbazine and an anthracycline was administered to 42 dogs. Efficacy and toxicoses were assessed. Results-Thirteen of the 18 (72%) dogs treated with the temozolomide-anthracycline combination and 25 of the 35 (71%) dogs treated with the dacarbazine anthracycline combination had a complete or partial response. Median duration of response to rescue chemotherapy was 40 days (range, 0 to 217 days) for dogs in the temozolomide group and 50 days (range, 0 to 587 days) for dogs in the dacarbazine group. The incidence of high-grade hematologic toxicoses was significantly higher among dogs in the dacarbazine group than among dogs in the temozolomide group, but the incidence of gastrointestinal tract toxicoses was not significantly different between groups. There were no significant differences between groups in regard to proportion of dogs with a complete or partial response, duration of response to rescue chemotherapy, survival time following rescue chemotherapy, or overall survival time. CONCLUSIONS AND CLINICAL RELEVANCE: Both combinations had promise in the treatment of dogs with relapsed or refractory lymphoma, although administration of temozolomide was more convenient than administration of dacarbazine and caused fewer hematologic toxicoses. PMID- 17696857 TI - Evaluation of trends in urolith composition in cats: 5,230 cases (1985-2004). AB - OBJECTIVE: To determine trends in urolith composition in cats. DESIGN: Retrospective case series. SAMPLE POPULATION: 5,230 uroliths. PROCEDURES: The laboratory database for the Gerald V. Ling Urinary Stone Analysis Laboratory was searched for all urolith submissions from cats from 1985 through 2004. Submission forms were reviewed, and each cat's age, sex, breed, and stone location were recorded. RESULTS: Minerals identified included struvite, calcium oxalate, urates, dried solidified blood, apatite, brushite, cystine, silica, potassium magnesium pyrophosphate, xanthine, and newberyite. During the past 20 years, the ratio of calcium oxalate stones to struvite stones increased significantly. When only the last 3 years of the study period were included, the percentage of struvite stones (44%) was higher than the percentage of calcium oxa-late stones (40%). The most common location for both types of uroliths was the bladder. The number of calcium oxalate-containing calculi in the upper portion of the urinary tract increased significantly during the study period. The number of apatite uroliths declined significantly and that of dried solidified blood stones increased significantly, compared with all other stone types. No significant difference in the number of urate stones was detected. CONCLUSIONS AND CLINICAL RELEVANCE: The increasing proportion of calcium oxalate uroliths was in accordance with findings from other studies and could be a result of alterations in cats' diets. However, the decreased percentage of calcium oxalate calculi and increased percentage of struvite calculi observed in the last 3 years may portend a change in the frequency of this type of urolith. PMID- 17696859 TI - Prevalence of equine herpesvirus-1 infection among Thoroughbreds residing on a farm on which the virus was endemic. AB - OBJECTIVE: To determine the incidence of equine herpesvirus-1 (EHV-1) infection among Thoroughbreds residing on a farm on which the virus was known to be endemic. DESIGN: Prospective cohort study. ANIMALS: 10 nonpregnant mares, 8 stallions, 16 weanlings, 11 racehorses, and 30 pregnant mares and their foals born during the 2006 foaling season. PROCEDURES: Blood and nasopharygeal swab samples were collected every 3 to 5 weeks for 9 months, and placenta and colostrum samples were collected at foaling. All samples were submitted for testing for EHV-1 DNA with a PCR assay. A type-specific EHV-1 ELISA was used to determine antibody titers in mares and foals at birth, 12 to 24 hours after birth, and every 3 to 5 weeks thereafter. RESULTS: Results of the PCR assay were positive for only 4 of the 1,330 samples collected (590 blood samples, 590 nasopharyngeal swab samples, 30 placentas, and 30 colostrum samples), with EHV-1 DNA detected in nasal secretions from 3 horses (pregnant mare, stallion, and racehorse) and in the placenta from 1 mare. Seroconversion was detected in 3 of 27 foals during the first month of life. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that there was a low prevalence of EHV-1 infection among this population of Thoroughbreds even though the virus was known to be endemic on the farm and that pregnant mares could become infected without aborting. Analysis of nasopharyngeal swab samples appeared to be more sensitive than analysis of blood samples for detection of EHV-1 DNA. PMID- 17696860 TI - Biosecurity practices and travel history of individuals exhibiting livestock at the 2005 California State Fair. AB - OBJECTIVE: To determine biosecurity practices and travel history of individuals exhibiting livestock at the 2005 California State Fair. DESIGN: Survey. STUDY POPULATION: 137 individuals exhibiting livestock at the fair. PROCEDURES: Exhibitors were asked to complete a survey to gather information about the animals they exhibited, the biosecurity practices they used, and the distances they traveled to exhibit their animals. RESULTS: 132 of the 137 (96%) respondents came from California, with respondents representing 40 of California's 58 counties. Median number of livestock exhibitions attended by respondents during the past 12 months was 3 (range, 1 to 7). Respondents indicated that 787 of the 812 (97%) animals they exhibited would be returned home after the fair. Nine (7%) respondents indicated that they did not take any particular biosecurity precautions before arriving at the fair, and 14 (10%) indicated that they did not take any particular biosecurity precautions while at the fair. Only 36 (26%) respondents indicated that they quarantined their animals when returning to their farm of residence after the fair. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that there was extensive movement of livestock among exhibitions in California, posing a potential threat for widespread dispersion of disease throughout the state and beyond, particularly given the low percentages of exhibitors who used various biosecurity measures. PMID- 17696861 TI - Copper toxicosis in a dairy goat herd. AB - CASE DESCRIPTION: A closed herd of 400 mixed-breed dairy goats was examined because of a decrease in milk production and increase in mortality rate. Nine animals had died within a 1-month period. CLINICAL FINDINGS: Clinical signs were evident only in lactating goats and included anorexia and recumbency. In the most severely affected goats, signs progressed to neurologic abnormalities and death. Serum aspartate aminotransferase activity, gamma-glutamyltransferase activity, and total bilirubin concentration were high in clinically affected does, but no evidence of hemolysis was found. A diagnosis of copper toxicosis was made on the basis of high liver and kidney copper concentrations and histologic evidence of hepatic necrosis. Goats were found to have been fed a mineral mix containing 3,050 ppm copper for 9 months prior to the onset of copper toxicosis. Overall, there was no consistent relationship between serum hepatic enzyme activities, serum copper concentration, and liver copper concentration. TREATMENT AND OUTCOME: Clinically affected goats were treated with penicillamine, ammonium molybdate, sodium thiosulfate, and vitamin E. Penicillamine increased urine copper excretion in treated does versus untreated control animals. An increased incidence of infectious disease was identified in the herd 9 months later. Liver vitamin E concentration was low in 10 of the 12 goats that underwent necropsy. CLINICAL RELEVANCE: Findings suggested that penicillamine may be an effective treatment for goats with copper toxicosis. Production losses months after the diagnosis was made suggested that the intoxication had a prolonged animal welfare and economic impacts. PMID- 17696862 TI - Tolerance of benzalkonium chloride, formalin, malachite green, and potassium permanganate in goldfish and zebrafish. AB - OBJECTIVE: To determine tolerance of goldfish and zebrafish to benzalkonium chloride, formalin, malachite green, and potassium permanganate. DESIGN: Tolerance study. ANIMALS: Adult goldfish (Carassius auratus) and zebrafish (Danio rerio). PROCEDURES: Groups of fish (n = 10/group) were exposed to each disinfectant at the therapeutic dosage; at 0.25, 0.5, 3, and 5 times the concentration used for the therapeutic dosage; and at the concentration used for the therapeutic dosage but for 3 or 5 times the recommended exposure time. RESULTS: In both species, exposure to malachite green at the therapeutic dosage resulted in toxic effects, including death. Exposure to formalin at the therapeutic dosage resulted in toxic effects in goldfish, but not zebrafish, and exposure to potassium permanganate resulted in toxic effects in zebrafish, but not goldfish. On the basis of the ratio of therapeutic dosage to median lethal dosage, in goldfish, formalin was more toxic than benzalkonium chloride, which was more toxic than malachite green, which was more toxic than potassium permanganate. In zebrafish, potassium permanganate was more toxic than formalin and benzalkonium chloride, which were approximately equally toxic and more toxic than malachite green. Extending treatment time increased the toxicity of potassium permanganate in zebrafish and the toxicity of formalin and malachite green in goldfish, but did not alter the toxicity of the other disinfectants. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that there was no consistency between zebrafish and goldfish in their tolerance to disinfectants, and that therapeutic dosages reported in the literature for these disinfectants were not always safe. PMID- 17696863 TI - Effects of age and sex on clinicopathologic reference ranges in a healthy managed Atlantic bottlenose dolphin population. AB - OBJECTIVE: To establish reference ranges for hematologic and serum biochemical variables in healthy Atlantic bottlenose dolphins (Tursiops truncatus) of known age and sex that were housed in open ocean water. DESIGN: Original study. SAMPLE POPULATION: 1,113 blood samples collected from 52 healthy bottlenose dolphins housed in open ocean water during 1998 to 2005. PROCEDURES: Data obtained from analyses of blood samples that had been collected for routine purposes from dolphins were analyzed with respect to sex and age of the dolphins. Each dolphin was categorized into 1 of 4 groups: 1 to 5 years (calf), > 5 to 10 years (juvenile), > 10 to 30 years (adult), or > 30 years (geriatric). Retrospective ANCOVA was performed for 30 hematologic and serum biochemical variables, with age and sex as cofactors. RESULTS: Among healthy bottlenose dolphins, age and sex significantly affected 23 of 30 (76.7%) and 11 of 30 (36.7%) hematologic and serum biochemical variables, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that age and sex significantly affected clinicopathologic reference ranges in our healthy bottlenose dolphin population. When assessing clinicopathologic variables in bottlenose dolphins, age and sex should be taken into consideration. The data obtained suggested reference ranges for healthy man aged bottlenose dolphin populations housed in open ocean water by age and sex. PMID- 17696866 TI - Structure-based drug design: docking and scoring. AB - This review gives an introduction into ligand - receptor docking and illustrates the basic underlying concepts. An overview of different approaches and algorithms is provided. Although the application of docking and scoring has led to some remarkable successes, there are still some major challenges ahead, which are outlined here as well. Approaches to address some of these challenges and the latest developments in the area are presented. Some aspects of the assessment of docking program performance are discussed. A number of successful applications of structure-based virtual screening are described. PMID- 17696867 TI - Virtual screening in drug discovery -- a computational perspective. AB - Virtual screening emerged as an important tool in our quest to access novel drug like compounds. There are a wide range of comparable and contrasting methodological protocols available in screening databases for the lead compounds. The number of methods and software packages which employ the target and ligand based virtual screening are increasing at a rapid pace. However, the general understanding on the applicability and limitations of these methodologies is not emerging as fast as the developments of various methods. Therefore, it is extremely important to compare and contrast various protocols with practical examples to gauge the strength and applicability of various methods. The review provides a comprehensive appraisal on several of the available virtual screening methods to-date. Recent developments of the docking and similarity based methods have been discussed besides the descriptor selection and pharmacophore based searching. The review touches upon the application of statistical, graph theory based methods machine learning tools in virtual screening and combinatorial library design. Finally, several case studies are undertaken where the virtual screening technology has been applied successfully. A critical analysis of these case studies provides a good platform to estimate the applicability of various virtual screening methods in the new lead identification and optimization. PMID- 17696868 TI - Structure-based approaches in the design of GSK-3 selective inhibitors. AB - Glycogen Synthase Kinase-3 (GSK-3) is a serine/threonine kinase with varied number of actions in cellular signalling systems making it an emerging target for diseases such as diabetes mellitus, cancer, chronic inflammation, bipolar affective disorders and Alzheimer's disease. Various efforts have produced many potent small molecule inhibitors of GSK-3, which are being tested for modulation of glycogen metabolism, gene transcription, apoptosis and enhancement of insulin stimulated glucose transport. Majority of the reported inhibitors show their inhibitory effects towards other phylogenetically related kinases also, like cyclin dependant kinases (CDKs). Thus it is important to develop inhibitors that can inhibit GSK-3 selectively. Rational approaches based on the knowledge of the receptor are best suited to address the selectivity problem. Several crystal structures of GSK-3beta with different ligands are being reported. These are providing the necessary clues regarding the interaction in the ligand binding domain. Several molecular docking efforts are being taken up to identify the clues for enhancing selectivity towards GSK-3. In this review we present current efforts and future opportunities in designing selective GSK-3 inhibitors. PMID- 17696869 TI - Structure-based approaches to drug discovery against tuberculosis. AB - Tuberculosis has become one of the deadliest global emergencies due to the widespread existence of multiple drug resistance strains of Mycobacterium tuberculosis and the increase of immuno-compromised populations in large parts of the world. Although the complete genome of M. tuberculosis became available in 1998, opening unprecedented opportunities for target-specific drug development, the progress since then has been slow, mainly due to a lack of a sufficiently strong interest by pharmaceutical and biotechnology industries. One of the most promising tools for future drug discovery lies in the elucidation of the molecular structures of potential drug targets from the M. tuberculosis proteome. During the last five years, the structures of about 200 unique targets have already been determined, which comprise about 5% of the entire M. tuberculosis proteome. As an example, we present the approach and some of the key achievements of the X-MTB consortium based in Germany. We summarize and discuss some recent highlights of potential drug targets of M. tuberculosis involved in lipid metabolism, protein phosphorylation/dephosphorylation and amino acid biosynthesis. The achievements of several structural genomics consortia that focus on targets from the M. tuberculosis proteome are now providing a solid framework to support coordinated international approaches for future structure based drug discovery programs at the interface between industrial enterprises and academic research. One of the objectives will be to focus on target complexes, in addition to single targets that dominate the present repository of structures from the M. tuberculosis proteome. PMID- 17696870 TI - Structural biology, protein conformations and drug designing. AB - Structure based drug designing is now a popular technique used for increasing the speed of drug designing process. This was made possible by the availability of many protein structures which helped in developing tools to understand the structure function relationships, automated docking and virtual screening. Knowledge of structure based functional properties of a drug target is very essential for a successful in silico designing of drugs. However, some problems associated with the structure determination process and lack of knowledge of conformational freedom associated with available protein structures are the hurdles involved in structure based drug designing. Docking and virtual screening processes depend on the active site structure of the receptor molecule and subtle differences in the conformations of these molecules due to flexibility pose a serious threat to the drug designing process. In this review problems associated with the conformations of proteins and homology models was reviewed. PMID- 17696871 TI - Free resources to assist structure-based virtual ligand screening experiments. AB - In today's research environment, a wealth of experimental/theoretical structural data is available and the number of therapeutically relevant macromolecular structures is growing rapidly. This, coupled with the huge number of small non peptide potential drug candidates easily available (over 7 million compounds), highlight the need of using computer-aided techniques for the efficient identification and optimization of novel hit compounds. Virtual (or in silico) ligand screening based on the three-dimensional structure of macromolecular targets (SB-VLS) is firmly established as an important approach to identify chemical entities that have a high likelihood of binding to a target molecule to elicit desired biological responses. A myriad of free applications and services facilitating the drug discovery process have been posted on the Web. In this review, we cite over 350 URLs that are useful for SB-VLS projects and essentially free for academic groups. We attempt to provide links for in silico ADME/tox prediction tools, compound collections, some ligand-based methods, characterization/simulation of 3D targets and homology modeling tools, druggable pocket predictions, active site comparisons, analysis of macromolecular interfaces, protein docking tools to help identify binding pockets and protein ligand docking/scoring methods. As such, we aim at providing both, methods pertaining to the field of Structural Bioinformatics (defined here as tools to study macromolecules) and methods pertaining to the field of Chemoinformatics (defined here as tools to make better decisions faster in the arena of drug/lead identification and optimization). We also report several recent success stories using these free computer methods. This review should help readers finding free computer tools useful for their projects. Overall, we are confident that these tools will facilitate rapid and cost-effective identification of new hit compounds. The URLs presented in this review will be updated regularly at www.vls3d.com in the coming months, "Links" section. PMID- 17696872 TI - Recent advances with TLR2-targeting lipopeptide-based vaccines. AB - The next generation of vaccines are being rationally designed according to rules that govern the way in which antigen is recognised by and stimulates the immune system. Amongst the first cells that encounter potentially dangerous agents such as viruses and bacteria are cells of the innate immune system, such as dendritic cells, that are widely distributed throughout the body including the skin. These cells patrol most tissues and have on their surface an array of receptors that have evolved to recognise many of the surface features of pathogens including the lipids and carbohydrates of structural lipoproteins, glycolipids and glycoproteins. Once encountered, recognised and engaged by a particular receptor on the dendritic cell, pathogenic material may then be transported inside the cell and processed for presentation to cells of the adaptive immune system. The result of this concert of events is a specific cellular or antibody response to particular epitopes of the invading pathogen. If then ways can be found to specifically target dendritic cells, through their specific receptors, then the efficacy and potency of vaccines could well be greatly improved. This review covers some of the approaches that we and others are pursuing in order to achieve this result. PMID- 17696873 TI - Human wild-type alanine:glyoxylate aminotransferase and its naturally occurring G82E variant: functional properties and physiological implications. AB - Human hepatic peroxisomal AGT (alanine:glyoxylate aminotransferase) is a PLP (pyridoxal 5'-phosphate)-dependent enzyme whose deficiency causes primary hyperoxaluria Type I, a rare autosomal recessive disorder. To acquire experimental evidence for the physiological function of AGT, the K(eq),(overall) of the reaction, the steady-state kinetic parameters of the forward and reverse reactions, and the pre-steady-state kinetics of the half-reactions of the PLP form of AGT with L-alanine or glycine and the PMP (pyridoxamine 5'-phosphate) form with pyruvate or glyoxylate have been measured. The results indicate that the enzyme is highly specific for catalysing glyoxylate to glycine processing, thereby playing a key role in glyoxylate detoxification. Analysis of the reaction course also reveals that PMP remains bound to the enzyme during the catalytic cycle and that the AGT-PMP complex displays a reactivity towards oxo acids higher than that of apoAGT in the presence of PMP. These findings are tentatively related to possible subtle rearrangements at the active site also indicated by the putative binding mode of catalytic intermediates. Additionally, the catalytic and spectroscopic features of the naturally occurring G82E variant have been analysed. Although, like the wild-type, the G82E variant is able to bind 2 mol PLP/dimer, it exhibits a significant reduced affinity for PLP and even more for PMP compared with wild-type, and an altered conformational state of the bound PLP. The striking molecular defect of the mutant, consisting in the dramatic decrease of the overall catalytic activity (approximately 0.1% of that of normal AGT), appears to be related to the inability to undergo an efficient transaldimination of the PLP form of the enzyme with amino acids as well as an efficient conversion of AGT-PMP into AGT-PLP. Overall, careful biochemical analyses have allowed elucidation of the mechanism of action of AGT and the way in which the disease causing G82E mutation affects it. PMID- 17696874 TI - Identification of a conserved motif required for Vps35p/Vps26p interaction and assembly of the retromer complex. AB - The retromer complex is a conserved cytoplasmic coat complex that mediates the endosome-to-Golgi retrieval of vacuole/lysosome hydrolase receptors in yeast and mammals. The recognition of cargo proteins by the retromer is performed by the Vps35p/VPS35 (where Vps is vacuolar protein sorting) component, which together with Vps26p/VPS26 and Vps29p/VPS29, forms the cargo-selective subcomplex. In this report, we have identified a highly-conserved region of Vps35p/VPS35 that is essential for the interaction with Vps26p/VPS26 and for assembly of the retromer complex. Mutation of residues within the conserved region results in Vps35p/VPS35 mutants, which cannot bind to Vps26p/VPS26 and are not efficiently targeted to the endosomal membrane. These data implicate Vps26p/VPS26 in regulating Vps35p/VPS35 membrane association and therefore suggest a role for Vps26p/VPS26 in cargo recognition. PMID- 17696875 TI - Evaluation of pH during cytostomal endocytosis and vacuolar catabolism of haemoglobin in Plasmodium falciparum. AB - The DV (digestive vacuole) of the malaria parasite, Plasmodium falciparum, is the site of Hb (haemoglobin) digestion and haem detoxification and, as a consequence, the site of action of CQ (chloroquine) and related antimalarials. However, the precise pH of the DV and the endocytic vesicles that feed it has proved difficult to ascertain. We have developed new methods using EGFP [enhanced GFP (green fluorescent protein)] to measure the pH of intracellular compartments. We have generated a series of transfectants in CQ-sensitive and -resistant parasite strains expressing GFP chimaeras of the DV haemoglobinase, plasmepsin II. Using a quantitative flow cytometric assay, the DV pH was determined to be 5.4-5.5. No differences were detected between CQ-sensitive and -resistant strains. We have also developed a method that relies on the pH dependence of GFP photobleaching kinetics to estimate the pH of the DV compartment. This method gives a pH estimate consistent with the intensity-based measurement. Accumulation of the pH sensitive probe, LysoSensor Blue, in the DV confirms the acidity of this compartment and shows that the cytostomal vesicles are not measurably acidic, indicating that they are unlikely to be the site of Hb digestion or the site of CQ accumulation. We show that a GFP probe located outside the DV reports a pH value close to neutral. The transfectants and methods that we have developed represent useful tools for investigating the pH of GFP-containing compartments and should be of general use in other systems. PMID- 17696876 TI - Molecular characterization of the thi3 gene involved in thiamine biosynthesis in Zea mays: cDNA sequence and enzymatic and structural properties of the recombinant bifunctional protein with 4-amino-5-hydroxymethyl-2-methylpyrimidine (phosphate) kinase and thiamine monophosphate synthase activities. AB - A thiamine biosynthesis gene, thi3, from maize Zea mays has been identified through cloning and sequencing of cDNA and heterologous overexpression of the encoded protein, THI3, in Escherichia coli. The recombinant THI3 protein was purified to homogeneity and shown to possess two essentially different enzymatic activities of HMP(-P) [4-amino-5-hydroxymethyl-2-methylpyrimidine (phosphate)] kinase and TMP (thiamine monophosphate) synthase. Both activities were characterized in terms of basic kinetic constants, with interesting findings that TMP synthase is uncompetitively inhibited by excess of one of the substrates [HMP PP (HMP diphosphate)] and ATP. A bioinformatic analysis of the THI3 sequence suggested that these activities were located in two distinct, N-terminal kinase and C-terminal synthase, domains. Models of the overall folds of THI3 domains and the arrangements of active centre residues were obtained with the SWISS-MODEL protein modelling server, on the basis of the known three-dimensional structures of Salmonella enterica serotype Typhimurium HMP(-P) kinase and Bacillus subtilis TMP synthase. The essential roles of Gln98 and Met134 residues for HMP kinase activity and of Ser444 for TMP synthase activity were experimentally confirmed by site-directed mutagenesis. PMID- 17696878 TI - Halting a cellular production line: responses to ribosomal pausing during translation. AB - Cellular protein synthesis is a complex polymerization process carried out by multiple ribosomes translating individual mRNAs. The process must be responsive to rapidly changing conditions in the cell that could cause ribosomal pausing and queuing. In some circumstances, pausing of a bacterial ribosome can trigger translational abandonment via the process of trans-translation, mediated by tmRNA (transfer-messenger RNA) and endonucleases. Together, these factors release the ribosome from the mRNA and target the incomplete polypeptide for destruction. In eukaryotes, ribosomal pausing can initiate an analogous process carried out by the Dom34p and Hbs1p proteins, which trigger endonucleolytic attack of the mRNA, a process termed mRNA no-go decay. However, ribosomal pausing can also be employed for regulatory purposes, and controlled translational delays are used to help co-translational folding of the nascent polypeptide on the ribosome, as well as a tactic to delay translation of a protein while its encoding mRNA is being localized within the cell. However, other responses to pausing trigger ribosomal frameshift events. Recent discoveries are thus revealing a wide variety of mechanisms used to respond to translational pausing and thus regulate the flow of ribosomal traffic on the mRNA population. PMID- 17696877 TI - Effect of glycation on alpha-crystallin structure and chaperone-like function. AB - The chaperone-like activity of alpha-crystallin is considered to play an important role in the maintenance of the transparency of the eye lens. However, in the case of aging and in diabetes, the chaperone function of alpha-crystallin is compromized, resulting in cataract formation. Several post-translational modifications, including non-enzymatic glycation, have been shown to affect the chaperone function of alpha-crystallin in aging and in diabetes. A variety of agents have been identified as the predominant sources for the formation of AGEs (advanced glycation end-products) in various tissues, including the lens. Nevertheless, glycation of alpha-crystallin with various sugars has resulted in divergent results. In the present in vitro study, we have investigated the effect of glucose, fructose, G6P (glucose 6-phosphate) and MGO (methylglyoxal), which represent the major classes of glycating agents, on the structure and chaperone function of alpha-crystallin. Modification of alpha-crystallin with all four agents resulted in the formation of glycated protein, increased AGE fluorescence, protein cross-linking and HMM (high-molecular-mass) aggregation. Interestingly, these glycation-related profiles were found to vary with different glycating agents. For instance, CML [N(epsilon)-(carboxymethyl)lysine] was the predominant AGE formed upon glycation of alpha-crystallin with these agents. Although fructose and MGO caused significant conformational changes, there were no significant structural perturbations with glucose and G6P. With the exception of MGO modification, glycation with other sugars resulted in decreased chaperone activity in aggregation assays. However, modification with all four sugars led to the loss of chaperone activity as assessed using an enzyme inactivation assay. Glycation-induced loss of alpha-crystallin chaperone activity was associated with decreased hydrophobicity. Furthermore, alpha-crystallin isolated from glycated TSP (total lens soluble protein) had also increased AGE fluorescence, CML formation and diminished chaperone activity. These results indicate the susceptibility of alpha-crystallin to non-enzymatic glycation by various sugars and their derivatives, whose levels are elevated in diabetes. We also describe the effects of glycation on the structure and chaperone-like activity of alpha crystallin. PMID- 17696879 TI - The diverse biofunctions of LIM domain proteins: determined by subcellular localization and protein-protein interaction. AB - The LIM domain is a cysteine- and histidine-rich motif that has been proposed to direct protein-protein interactions. A diverse group of proteins containing LIM domains have been identified, which display various functions including gene regulation and cell fate determination, tumour formation and cytoskeleton organization. LIM domain proteins are distributed in both the nucleus and the cytoplasm, and they exert their functions through interactions with various protein partners. PMID- 17696880 TI - Enhancement by lithium of cAMP-induced CRE/CREB-directed gene transcription conferred by TORC on the CREB basic leucine zipper domain. AB - The molecular mechanism of the action of lithium salts in the treatment of bipolar disorder is not well understood. As their therapeutic action requires chronic treatment, adaptive neuronal processes are suggested to be involved. The molecular basis of this are changes in gene expression regulated by transcription factors such as CREB (cAMP-response-element-binding protein). CREB contains a transactivation domain, in which Ser119 is phosphorylated upon activation, and a bZip (basic leucine zipper domain). The bZip is involved in CREB dimerization and DNA-binding, but also contributes to CREB transactivation by recruiting the coactivator TORC (transducer of regulated CREB). In the present study, the effect of lithium on CRE (cAMP response element)/CREB-directed gene transcription was investigated. Electrically excitable cells were transfected with CRE/CREB-driven luciferase reporter genes. LiCl (6 mM or higher) induced an up to 4.7-fold increase in 8-bromo-cAMP-stimulated CRE/CREB-directed transcription. This increase was not due to enhanced Ser119 phosphorylation or DNA-binding of CREB. Also, the known targets inositol monophosphatase and GSK3beta (glycogen-synthase kinase 3beta) were not involved as specific GSK3beta inhibitors and inositol replenishment did not mimic and abolish respectively the effect of lithium. However, lithium no longer enhanced CREB activity when the CREB-bZip was deleted or the TORC-binding site inside the CREB-bZip was specifically mutated (CREB R300A). Otherwise, TORC overexpression conferred lithium responsiveness on CREB bZip or the CRE-containing truncated rat somatostatin promoter. This indicates that lithium enhances cAMP-induced CRE/CREB-directed transcription, conferred by TORC on the CREB-bZip. We thus support the hypothesis that lithium salts modulate CRE/CREB-dependent gene transcription and suggest the CREB coactivator TORC as a new molecular target of lithium. PMID- 17696881 TI - CTCF mediates insulator function at the CFTR locus. AB - Regulatory elements that lie outside the basal promoter of a gene may be revealed by local changes in chromatin structure and histone modifications. The promoter of the CFTR (cystic fibrosis transmembrane conductance regulator) gene is not responsible for its complex pattern of expression. To identify important regulatory elements for CFTR we have previously mapped DHS (DNase I hypersensitive sites) across 400 kb spanning the locus. Of particular interest were two DHS that flank the CFTR gene, upstream at -20.9 kb with respect to the translational start site, and downstream at +15.6 kb. In the present study we show that these two DHS possess enhancer-blocking activity and bind proteins that are characteristic of known insulator elements. The DHS core at -20.9 kb binds CTCF (CCCTC-binding factor) both in vitro and in vivo; however, the +15.6 kb core appears to bind other factors. Histone-modification analysis across the CFTR locus highlights structural differences between the -20.9 kb and +15.6 kb DHS, further suggesting that these two insulator elements may operate by distinct mechanisms. We propose that these two DHS mark the boundaries of the CFTR gene functional unit and establish a chromatin domain within which the complex profile of CFTR expression is maintained. PMID- 17696882 TI - A structural basis for differential cell signalling by PAI-1 and PAI-2 in breast cancer cells. AB - PAI-1 and PAI-2 (plasminogen-activator inibitor types 1 and 2) are inhibitors of cell surface uPA (urokinase plasminogen activator). However, tumour expression of PAI-1 and PAI-2 correlates with poor compared with good patient prognosis in breast cancer respectively. This biological divergence may be related to additional functional roles of PAI-1. For example, the inhibition of uPA by PAI-1 reveals a cryptic high-affinity site within the PAI-1 moiety for the VLDLr (very low-density-lipoprotein receptor), which sustains cell signalling events initiated by binding of uPA to its receptor. These interactions and subsequent signalling events promote proliferation of breast cancer cells. Biochemical and structural analyses show that, unlike PAI-1, the PAI-2 moiety of uPA-PAI-2 does not contain a high-affinity-binding site for VLDLr, although uPA-PAI-2 is still efficiently endocytosed via this receptor in breast cancer cells. Furthermore, global protein tyrosine phosphorylation events were not sustained by uPA-PAI-2 and cell proliferation was not affected. We thus propose a structurally based mechanism for these differences between PAI-1 and PAI-2 and suggest that PAI-2 is able to inhibit and clear uPA activity without initiating mitogenic signalling events through VLDLr. PMID- 17696883 TI - Heightened alpha1A-adrenergic receptor activity suppresses ischaemia/reperfusion induced Ins(1,4,5)P3 generation in the mouse heart: a comparison with ischaemic preconditioning. AB - Reperfusion of ischaemic rat or mouse hearts causes NE [noradrenaline ('norepinephrine')] release, stimulation of alpha(1)-ARs (alpha(1)-adrenergic receptors), PLC (phospholipase C) activation, Ins(1,4,5)P(3) generation and the development of arrhythmias. In the present study, we examined the effect of increased alpha(1A)-AR drive on these responses. In hearts from non-transgenic mice (alpha(1A)-WT), Ins(1,4,5)P(3) generation was observed after 2 min of reperfusion following 30 min of zero-flow ischaemia. No Ins(1,4,5)P(3) response was observed in hearts from transgenic mice with 66-fold overexpression of alpha(1A)-AR (alpha(1A)-TG). This was despite the fact that alpha(1A)-TG hearts had 8-10-fold higher PLC responses to NE than alpha(1A)-WT under normoxic conditions. The immediate phospholipid precursor of Ins(1,4,5)P(3), PtdIns(4,5)P(2), responded to ischaemia and reperfusion similarly in alpha(1A)-WT and alpha(1A)-TG mice. Thus the lack of Ins(1,4,5)P(3) generation in alpha(1A)-TG mice is not caused by limited availability of PtdIns(4,5)P(2). Overall, alpha(1) AR-mediated PLC activity was markedly enhanced in alpha(1A)-WT mice under reperfusion conditions, but responses in alpha(1A)-TG mice were not significantly different in normoxia and post-ischaemic reperfusion. Ischaemic preconditioning prevented Ins(1,4,5)P(3) generation after 30 min of ischaemic insult in alpha(1A) WT mice. However, the precursor lipid PtdIns(4,5)P(2) was also reduced by preconditioning, whereas heightened alpha(1A)-AR activity did not influence PtdIns(4,5)P(2) responses in reperfusion. Thus preconditioning and alpha(1A)-AR overexpression have different effects on early signalling responses, even though both prevented Ins(1,4,5)P(3) generation. These studies demonstrate a selective inhibitory action of heightened alpha(1A)-AR activity on immediate post-receptor signalling responses in early post-ischaemic reperfusion. PMID- 17696885 TI - Fingerprinting and diversity of bacterial copA genes in response to soil types, soil organic status and copper contamination. AB - A molecular fingerprinting assay was developed to assess the diversity of copA genes, one of the genetic determinants involved in bacterial resistance to copper. Consensus primers of the copA genes were deduced from an alignment of sequences from proteobacterial strains. A PCR detection procedure was optimized for bacterial strains and allowed the description of a novel copA genetic determinant in Pseudomonas fluorescens. The copA DNA fingerprinting procedure was optimized for DNA directly extracted from soils differing in their physico chemical characteristics and in their organic status (SOS). Particular copA genetic structures were obtained for each studied soil and a coinertia analysis with soil physico-chemical characteristics revealed the strong influence of pH, soil texture and the quality of soil organic matter. The molecular phylogeny of copA gene confirmed that specific copA genes clusters are specific for each SOS. Furthermore, this study demonstrates that this approach was sensitive to short term responses of copA gene diversity to copper additions to soil samples, suggesting that community adaptation is preferentially controlled by the diversity of the innate copA genes rather than by the bioavailability of the metal. PMID- 17696887 TI - The role of Dsb proteins of Gram-negative bacteria in the process of pathogenesis. AB - Tertiary and quaternary structures of extracytoplasmic proteins containing more than one cysteine residue often require introduction of disulfide bonds. This process takes place in an oxidative environment, such as the periplasm of Gram negative bacteria, and is catalyzed by Dsb (disulfide bond formation) proteins. Mutations in dsb genes influence the conformation and stability of many extracytoplasmic proteins. Thus, many pathogens become partially or fully attenuated due to improper folding of proteins that act as virulence factors. This review summarizes the current knowledge on Dsb proteins and their effect on the pathogenicity of Gram-negative bacteria. The potential application of Dsb proteins in biotechnology is also discussed. PMID- 17696888 TI - The supercentenarians and how to get the most out of life. PMID- 17696886 TI - Carnobacterium: positive and negative effects in the environment and in foods. AB - The genus Carnobacterium contains nine species, but only C. divergens and C. maltaromaticum are frequently isolated from natural environments and foods. They are tolerant to freezing/thawing and high pressure and able to grow at low temperatures, anaerobically and with increased CO(2) concentrations. They metabolize arginine and various carbohydrates, including chitin, and this may improve their survival in the environment. Carnobacterium divergens and C. maltaromaticum have been extensively studied as protective cultures in order to inhibit growth of Listeria monocytogenes in fish and meat products. Several carnobacterial bacteriocins are known, and parameters that affect their production have been described. Currently, however, no isolates are commercially applied as protective cultures. Carnobacteria can spoil chilled foods, but spoilage activity shows intraspecies and interspecies variation. The responsible spoilage metabolites are not well characterized, but branched alcohols and aldehydes play a partial role. Their production of tyramine in foods is critical for susceptible individuals, but carnobacteria are not otherwise human pathogens. Carnobacterium maltaromaticum can be a fish pathogen, although carnobacteria are also suggested as probiotic cultures for use in aquaculture. Representative genome sequences are not yet available, but would be valuable to answer questions associated with fundamental and applied aspects of this important genus. PMID- 17696889 TI - Relationship between symptoms of temporomandibular disorders and dental status, general health and psychosomatic factors in two cohorts of 70-year-old subjects. AB - OBJECTIVE: To study the prevalence of symptoms of temporomandibular disorders (TMD) in two cohorts of 70-year-old subjects examined 8 years apart and analyse the relationship between such symptoms and dental status, general health and various background factors. MATERIALS AND METHODS: Two cohorts of 70-year-old subjects, born in 1922 (n = 422) and 1930 (n = 491) respectively, were examined with an interval of 8 years. A TMD symptom index (0-5) was established on answers to five questions related to TMD symptoms. RESULTS: There were no statistically significant differences between the two cohorts for prevalence of TMD symptoms and TMD index, neither for headache, neck ache, bruxism and chewing ability. TMJ sounds was the most prevalent symptom, 14%, whereas other TMD symptoms had low prevalence. The distribution of the TMD symptom index showed that 81% reported no symptoms, 15% one symptom, 3% two symptoms and 1% three to five symptoms. Single TMD symptoms and the TMD index exhibited significant associations (p < 0.001) with bruxism, headache, neck pain and several general health and psychosomatic factors, but with dental status only in women. Logistic regression showed that bruxism, neck pain, mouth dryness and a number of psychosomatic factors were associated with the TMD index. CONCLUSIONS: Besides TMJ sounds (14%), other TMD symptoms were rarely reported by the 70-year-old subjects. The TMD index was significantly associated with bruxism and several general health and psychosomatic complaints but with dental status only in women. PMID- 17696890 TI - General health of elderly institutionalised and community-dwelling Brazilians. AB - OBJECTIVE: To evaluate the heart rate, blood pressure, blood glucose and other important indicators of the general health of an elderly population of Sao Jose dos Campos, Brazil. MATERIALS AND METHODS: A cross-sectional study was conducted among 150 institutionalised and 150 community-dwelling individuals aged 60 years or more. The parameters evaluated were heart rate, blood pressure and blood glucose. The elderly also answered a questionnaire about osteoporosis, falls, physical exercising, participation in social events, type of foods ingested, Alzheimer and Parkinson's diseases and medication. RESULTS: The institutionalised elderly showed an average heart rate of 75.1, while that of the community dwelling elderly was 76.7. The percentage of systolic hypertension in the institutionalised and community-dwelling groups was 36% and 30% respectively, while diastolic hypertension showed a percentage of 40% and 57%, and diabetes was 32% and 30%. Among the institutionalised and community-dwelling groups, 13.3% and 21.3% respectively, reported osteoporosis, 31.3% and 42.7% falls, 7.3% and 24% exercised regularly, 4% and 69.3% participated regularly in social events, 58.7% and 51.3% reported eating solid foods, and 13.3% and 2%, respectively, suffered from Alzheimer's disease. Parkinson's disease was reported by 2% in both groups. The institutionalised elderly reported taking an average of 3.2 medications, while among community-dwelling elderly this number was 1.8. CONCLUSION: The entire sample presented a high prevalence of hypertension, diabetes and osteoporosis. No significant differences were found in the systemic health of the elderly institutionalised and community-dwelling groups. However, the latter group reported more frequent falls, participation in social events and exercised regularly. PMID- 17696891 TI - Influence of bite force and tongue pressure on oro-pharyngeal residue in the elderly. AB - OBJECTIVE: To investigate the influence of maximal bite force, maximal tongue pressure, number of mastications and swallowing on the oro-pharyngeal residue in the elderly. BACKGROUND: Oro-pharyngeal residue in the elderly is an indication of dysphagia. Pharyngeal residue is especially critical as it may cause aspiration pneumonia, which is one of the major causes of death in elderly. MATERIALS AND METHODS: Videofluorographic recordings were performed on 14 elderly volunteers (six males, eight females, age range 65-93 years) without any history or symptoms of dysphagia. The subjects were instructed to consume 9 g of barium containing bread in two manners; free mastication and swallow (FMS: masticate and swallow freely), and limited mastication and swallow (LMS: swallow once after 30 chewing actions). The amount of oral and pharyngeal residue was evaluated using a 4-point rating scale. Maximal occlusal force was measured by a pressure sensitive sheet, and maximal tongue pressure using a handy probe. Multiple regression analysis was performed to examine the influence of these items on the amount of oral and pharyngeal residue in FMS and LMS. RESULTS: In FMS, age was found to be a factor which increased oral residue (p = 0.053), and the number of swallowing (p = 0.017) and the state of the prosthesis (p = 0.030) reduced the pharyngeal residue. In LMS, tongue pressure was a factor which reduced oral residue (p = 0.015) and increased pharyngeal residue (p = 0.008). CONCLUSION: It is suggested that in the elderly tongue pressure contributed to propulsion of the food bolus from oral cavity into the pharynx, and multiple swallowing contributed to the reduction in the amount of pharyngeal residue. PMID- 17696892 TI - Oral health-related quality of life: a critical appraisal of assessment tools used in elderly people. AB - OBJECTIVE: The purpose of this study was to undertake a critical appraisal of oral health-related quality of life (OHRQoL) measurements used for research in the elderly. BACKGROUND: A variety of OHRQoL measurements have been developed in the past 20 years as a result of increased concern about the impact of oral conditions on a person's quality of life. There is need for an assessment aimed at prioritising the recommended measurements to be used for different purposes in the elderly. MATERIALS AND METHODS: Original English language papers using measurements to assess OHRQoL in the elderly were identified from Web of Science, EMBASE, PubMed, Medline and Lilacs databases. The search included all papers published from 1985 to February 2007. The criteria of assessment were: (i) measurement criteria (number of items and domains, and classification of the results found for each measurement); (ii) quantitative-qualitative criteria (frequency, acceptability, reproducibility, reliability, sensitivity and capability of being reproduced in other language versions). RESULTS: In a total of 152 papers selected, 20 measurements were identified. However, only seven fulfilled all the measurement and quantitative-qualitative criteria. CONCLUSION: Geriatric Oral Health Assessment Index, Subjective Oral Health Status Indicators, Oral Health Impact Profile-49, Dental Impact on Daily Living, Oral Health Impact Profile-14, Oral Impact on Daily Performances and German Version of the Oral Heath Impact Profile were considered as instruments of choice to assess OHRQoL in the elderly. The other 13 instruments identified require further research aimed at a validation process and the use of a language other than English. PMID- 17696893 TI - Distribution of biofilm on internal and external surfaces of upper complete dentures: the effect of hygiene instruction. AB - OBJECTIVES: The purpose of this study was to evaluate biofilm distribution over internal and external surfaces of upper complete dentures. It was also aimed at assessing the effect of oral hygiene instructions before and after home use of a disclosing solution. MATERIALS AND METHODS: The sample consisted of 29 complete denture wearers whose upper prostheses were evaluated. Surface biofilm was disclosed by means of a 1% neutral red solution and quantified with regard to internal and external surfaces. Oral hygiene information was provided on an individual basis. During the second stage, an amount of disclosing solution was given for domestic use. RESULTS: Internal and external surfaces presented a similar amount of biofilm, which was concentrated over the area of the posterior teeth area, palatal rugae and the internal vestibular incline of the distobuccal flange. This pattern was maintained during the study. However, overall amounts were reduced following denture hygiene information. The use of disclosing solution by subjects at home resulted in a further reduction. CONCLUSIONS: It was concluded that biofilm deposits were similar over assessed surfaces, regardless of the type of procedure but irregular areas presented greater amounts. Oral health instruction was effective in reducing the biofilm, in particular when associated with home use of a disclosing agent. PMID- 17696894 TI - Quantitative study of ageing epiglottal taste buds in humans. AB - OBJECTIVES: This investigation aimed to demonstrate age-related changes of taste buds on the human epiglottis using histomorphometrical analysis. METHODS: Histological observation and measurement of taste bud density were performed on oral and laryngeal surfaces of 237 human epiglottises (138 male and 99 females). The cases were divided into two age groups: 67 cases in the younger group, for subjects aged 10-39 years and 170 cases in the older group, for those aged 70-98 years. Each epiglottis was investigated at the upper and middle height levels. RESULTS: The mean density of taste buds significantly decreased on the laryngeal surfaces in the older group. Most taste buds were present in the upper height level on the laryngeal surfaces which were covered with thin and flat stratified squamous epithelium. The covering epithelium revealed developed epithelial ridges on the oral surfaces without taste buds. These results suggest a relationship between the existence of taste buds and the thickness of the covering epithelium. CONCLUSIONS: The presence of taste buds in the epiglottises of elderly people was demonstrated. In addition, the decrease of these taste buds with advancing age was clarified. PMID- 17696895 TI - Burning mouth syndrome (BMS): sialometric and sialochemical analysis and salivary protein profile. AB - OBJECTIVE: The aim of the present study was to analyse the characteristics of salivary production and its composition in individuals with burning mouth syndrome (BMS). STUDY DESIGN: Salivary flow rate, concentrations of potassium, iron, chloride, thiocyanate, magnesium, calcium, phosphorus, glucose, total protein and urea, as well as the expression profile of salivary proteins were analysed by SDS-PAGE. RESULTS: The mean salivary flow rate among control patients was lower than that of BMS patients. Chloride, phosphorus and potassium levels were elevated in patients with BMS (p = 0.041, 0.001 and 0.034, respectively). Total salivary protein concentration was reduced in individuals with BMS (p = 0.223). Analysis of the expression of salivary proteins by Coomassie blue SDS PAGE revealed a lower expression of low molecular weight proteins in individuals with BMS compared to healthy controls. CONCLUSIONS: These results indicate that the identification and characterisation of low molecular weight salivary proteins in BMS may be important in understanding BMS pathogenesis, thus contributing to its diagnosis and treatment. PMID- 17696896 TI - Geriatric dentistry: a new specialty in Brazil. AB - OBJECTIVE: To present the current status of geriatric dentistry in Brazil. BACKGROUND: In 2001, the Brazilian Dental Council established a new specialty: geriatric dentistry. This decision was based on the increase in both the elderly population and the demand for dental treatment of this cohort. MATERIALS AND METHODS: Data were obtained through online searches of the Brazilian Dental Council and the Brazilian Institute of Geography and Statistics. RESULTS: Brazil has 170 dental schools offering around 14 000 undergraduate vacancies every year. At the postgraduate level, there are 19 recognised dental specialties, one of which is geriatric dentistry, comprising 18 certificate programmes, with the potential to produce 216 new specialists every 18 months. The dentist/habitant ratio was 1:870, higher than that recommended by the Word Health Organization. The Brazilian population consists of around 14.5 million elderly people (8.6%). There were 124 specialists in geriatric dentistry distributed irregularly throughout the country. The specialist/elderly population rate was 1:117 249. At the undergraduate level, this new specialty is not included in the curricula of most dental schools in Brazil. CONCLUSIONS: Geriatric dentistry should be included in the undergraduate curricula of dental schools in Brazil. Postgraduate degree courses should be developed to produce more clinical academics and researchers in this field. PMID- 17696897 TI - Accelerated rehabilitation of an edentulous patient with an implant retained dental prosthesis: a case report. AB - This case report details the successful rehabilitation of an edentulous patient using a complete upper prosthesis and a lower implant retained overdenture. The provision of care was split between a specialist centre and a primary care setting. This approach reduced inconvenience to the patient. Modern surgical and prosthodontic techniques also reduced the total delivery time. After initial consultation a new set of complete dentures was prescribed with changes in design to the originals. The patient was also planned for placement of two mandibular implants to stabilise and retain the mandibular denture. The first line of treatment involved provision of a new set of dentures constructed by the patient's general dental practitioner. Dental implants were then placed in a specialist centre and the patient returned to the dental practice for attachment of the lower denture to the dental implants. The benefits and success of mandibular implant retained dentures are well documented. With delivery of the overdenture, the patient reported increased satisfaction with his prostheses which allowed him to eat a greater range of foods and enabled him to feel confident when speaking and socialising. PMID- 17696900 TI - From collagen chemistry towards cell therapy - a personal journey. AB - The Fell-Muir Award requires the recipient to deliver a lecture and a review manuscript which provides a personal overview of significant scientific developments in the field of matrix biology over the period of the recipient's career. In this context, this review considers the collagen family of structural proteins and the advances in biochemical, molecular biological and genetic techniques which led to the elucidation of the structure, synthesis and function of this important group of extracellular matrix constituents. Particular attention is focussed on early research on the identification and assembly of the soluble precursors of collagen types I and II, and the identification of the precursor of basement membrane collagen type IV. In subsequent studies investigating the maintenance of the chick chondrocyte phenotype in culture, the influence of the extracellular milieu was found to influence markedly both cell morphology and collagen gene expression. These studies led to the discovery of collagen type X whose expression is restricted to hypertrophic chondrocytes at sites of endochondral ossification. Such research provided a prelude to investigations of mammalian endochondral ossification which is known to be aberrant in a variety of human chondrodysplasias and is reactivated in bone fracture repair and in osteoarthritis. The cloning of bovine and then human collagen type X genes facilitated studies in relevant human diseases and contributed to the discovery of mutations in the COL10A1 gene in families with metaphyseal chondrodysplasia type Schmid. Clustering of mutations in the C terminal domain of the type X collagen molecule has now been widely documented and investigations of the pathogenic mechanisms in animal models are beginning to suggest the prospect of novel treatment strategies. PMID- 17696901 TI - Symposium: tendon and ligament remodelling and regeneration. PMID- 17696902 TI - The mechanobiological aetiopathogenesis of tendinopathy: is it the over stimulation or the under-stimulation of tendon cells? AB - While there is a significant amount of information available on the clinical presentation(s) and pathological changes associated with tendinopathy, the precise aetiopathogenesis of this condition remains a topic of debate. Classically, the aetiology of tendinopathy has been linked to the performance of repetitive activities (so-called overuse injuries). This has led many investigators to suggest that it is the mechanobiologic over-stimulation of tendon cells that is the initial stimulus for the degradative processes which have been shown to accompany tendinopathy. Although several studies have been able to demonstrate that the in vitro over-stimulation of tendon cells in monolayer can result in a pattern(s) of gene expression seen in clinical cases of tendinopathy, the strain magnitudes and durations used in these in vitro studies, as well as the model systems, may not be clinically relevant. Using a rat tail tendon model, we have studied the in vitro mechanobiologic response of tendon cells in situ to various tensile loading regimes. These studies have led to the hypothesis that the aetiopathogenic stimulus for the degenerative cascade which precedes the overt pathologic development of tendinopathy is the catabolic response of tendon cells to mechanobiologic under-stimulation as a result of microscopic damage to the collagen fibres of the tendon. In this review, we examine the rationale for this hypothesis and provide evidence in support of this theory. PMID- 17696903 TI - Cell phenotypic variation in normal and damaged tendons. AB - Injuries to tendons are common in both human athletes as well as in animals, such as the horse, which are used for competitive purposes. Furthermore, such injuries are also increasing in prevalence in the ageing, sedentary population. Tendon diseases often respond poorly to treatment and require lengthy periods of rehabilitation. The tendon has a unique extracellular matrix, which has developed to withstand the mechanical demands of such tensile-load bearing structures. Following injury, any repair process is inadequate and results in tissue that is distinct from original tendon tissue. There is growing evidence for the key role of the tendon cell (tenocyte) in both the normal physiological homeostasis and regulation of the tendon matrix and the pathological derangements that occur in disease. In particular, the tenocyte is considered to have a major role in effecting the subclinical matrix degeneration that is thought to occur prior to clinical disease, as well as in the severe degradative events that occur in the tendon at the onset of clinical disease. Furthermore, the tenocyte is likely to have a central role in the production of the biologically inadequate fibrocartilaginous repair tissue that develops subsequent to tendinopathy. Understanding the biology of the tenocyte is central to the development of appropriate interventions and drug therapies that will either prevent the onset of disease, or lead to more rapid and appropriate repair of injured tendon. Central to this is a full understanding of the proteolytic response in the tendon in disease by such enzymes as metalloproteinases, as well as the control of the inappropriate fibrocartilaginous differentiation. Finally, it is important that we understand the role of both intrinsic and extrinsic cellular elements in the repair process in the tendon subsequent to injury. PMID- 17696904 TI - The adaptability of tendon to loading differs in men and women. AB - The reason why women sustain more soft tissue injury than men during physical activity is unknown. Connective tissue properties and extracellular matrix adaptability in human tendon were investigated in models that addressed biochemical, physiological and biomechanical aspects of tendon connective tissue in response to mechanical loading. Habitual training resulted in a larger patellar tendon in men but not in women. Following an acute bout of exercise, men had an elevated tendon collagen synthesis rate and this effect was less pronounced or absent in women. Moreover, levels of circulating oestrogen affected the acute exercise-related increase in collagen synthesis. Finally, the mechanical strength of isolated tendon collagen fascicles in men surpassed that of women. Thus, compared to men, women have (i) an attenuated tendon hypertrophy response to habitual training; (ii) a lower tendon collagen synthesis rate following acute exercise; (iii) a rate of tendon collagen synthesis which is further attenuated with elevated estradiol levels; and (iv) a lower mechanical strength of their tendons. These data indicate that tendons in women have a lower rate of new connective tissue formation, respond less to mechanical loading, and have a lower mechanical strength, which may leave the tissue more susceptible to injury. PMID- 17696905 TI - Tendon matrix composition and turnover in relation to functional requirements. AB - Tendons are dense regular connective tissue structures that are defined based on their anatomical position of connecting muscle to bone. Despite these obvious commons features tendons from different locations within the body show remarkable variation in terms of their morphological, molecular and mechanical properties which relates to their specialized function. An appreciation of these differences is necessary to understand all aspects of tendon biology in health and disease. In our work, we have used a combination of mechanical assessment, histological measurements and molecular analysis of matrix in functionally distinct tendons to determine relationships between function and structure. We have found significant differences in material and molecular properties between spring-like tendons that are subjected to high strains during locomotion and positional tendons which are subjected to much lower strains. Furthermore, we have data to suggest that not only is the matrix composition different but also the ability of cells to synthesize and degrade the matrix (matrix turnover) varies between tendon types. We propose that these differences relate to the magnitude of strain that the tendon experiences during normal activities in life. Tendon cells may be preprogrammed during embryological development for the strain they will encounter in life or may simply respond to the particular strain environment they are subjected to. The elucidation of controlling mechanisms resulting in tendon cell specialization will have important consequences for cell based therapies and engineering strategies to repair damaged tendons. PMID- 17696906 TI - Relationship between plasma cholesterol, von Willebrand factor concentrations, extent of atherosclerosis and antibody titres to heat shock proteins-60, -65 and 70 in cholesterol-fed rabbits. AB - Epidemiological studies have shown an association between atherosclerosis, Heat shock protein (Hsp) expression, and Hsp antibody titres. We aimed to investigate the time course of appearance of Hsp-60, -65 and -70 antibodies in the cholesterol-fed rabbit and to relate antibody titres to serum concentrations of von Willebrand factor (vWF), a marker of endothelial injury. Rabbits were fed with 0.25-1.0% cholesterol diet for 13 weeks. Plasma levels of anti Hsp-60, -65 and -70 IgG titres, were measured using in-house enzyme-linked immunosorbent assays (ELISAs) together with plasma vWF concentrations. Plasma titres of anti Hsp-60, -65 and -70 antibodies were all significantly increased by weeks 5, 7 and 9 following commencement of the experimental diet compared with baseline (P < 0.05 for all). In non-cholesterol-fed rabbits, plasma levels of anti-Hsp titres were unchanged over this period. Increased plasma vWF concentrations were also found in the cholesterol-fed rabbits, reaching a maximum at approximately week 8, and falling thereafter. Furthermore, plasma vWF concentrations at 13 weeks correlated strongly with antibody titres to all three Hsps (r = 0.90, P = 0.002; r = 0.80, P = 0.017; r = 0.86, P = 0.006 for Hsp 60, -65 and -70 respectively) and titres were also strongly correlated with final plasma cholesterol concentrations in cholesterol-fed animals (r = 0.95, P = 0.002; r = 0.8, P = 0.001; r = 0.84, P = 0.01 respectively). In cholesterol-fed rabbits, antibody titres to Hsp-60, -65 and -70 appear to rise in association with a marker of endothelial injury, peaking at approximately the same time (8 weeks) after starting a high cholesterol diet. PMID- 17696907 TI - Investigation of intratumoural and peritumoural lymphatics expressed by podoplanin and LYVE-1 in the hybridoma-induced tumours. AB - Tumour-associated lymphatics contribute to a key component of metastatic spread, however, the biological interaction of tumour cells with intratumoural and peritumoural lymphatics (ITLs and PTLs) has remained unclear. To address this important issue, we have focused on the morphological and molecular aspects of newly formed lymphatics (lymphangiogenesis) and pre-existing lymphatics in the intratumoural and peritumoural tissues by using a hybridoma-induced tumour model. In the present study, ITLs with very high vessel density within the tumour mass showed small and flattened contours that varied from non-solid-to-solid tumours, whereas PTLs were relatively disorganized and tortuous, and packed with a cluster of tumour cells at the tumour periphery. Lymphatic endothelial cells (LECs) both in ITLs and PTLs were expressed with LYVE-1 and podoplanin in various tumour tissues, in which initial lymphatics were extremely extended and dilated. The tumour cells were frequently detected adhering to or penetrating lymphatic walls, especially near the open junctions. In the metastatic tissues, lymphangiogenic vasculatures occurred within the tumour matrix, and collecting PTLs represented abnormal twisty valve leaflets. The Western blot and RT-PCR analysis showed local variations of LEC proliferating potentials and lymphatic involvement in metastasis by a distinct profile of the protein and mRNA expression by LYVE-1, podoplanin, Prox-1 and vascular endothelial growth factor-3 (VEGFR-3). These findings indicated that both ITLs and PTLs, including enlarged pre-existing and newly formed lymphatics, may play a crucial role in metastasis with an active tumour cell adhesion, invasion, migration and implantation. PMID- 17696908 TI - Vascular endothelial growth factor (VEGF), VEGF receptors expression and microvascular density in benign and malignant thyroid diseases. AB - Angiogenesis is critical for the growth and metastatic spread of tumours. Vascular endothelial growth factor (VEGF) is the most potent inducer of neovasculature, and its increased expression has been related to a worse clinical outcome in many diseases. The purpose of this study was to evaluate the relation between VEGF, its receptors (VEGFR-1 and VEGFR-2) and microvessel density (MVD) in thyroid diseases. Immunostaining for VEGF and VEGF receptors was performed in 66 specimens of thyroid tissue, comprising 17 multinodular goitre (MNG), 14 Graves' disease, 10 follicular adenoma, 8 Hashimoto's thyroiditis, 7 papillary carcinoma and 10 normal thyroid specimens. Thyrocyte positivity for VEGF and VEGF receptors was scored 0-3. Immunohistochemistry for CD31, and CD34 on the same sections was performed to evaluate MVD. Immunohistochemical staining of VEGF in thyrocytes was positive in 92% of all the thyroid tissues studied. Using an immunostaining intensity cut off of 2, increased thyrocyte staining was seen in follicular adenoma specimens, MNG and normal thyroids compared with Hashimoto's thyroiditis and Graves' disease (P < 0.05). Similarly, VEGF thyrocyte expression in Graves' disease was less than other pathologies (P < 0.05). VEGFR-1 expression and the average MVD score did not differ between the different thyroid pathologies. VEGF expression was lower in autoimmune pathologies compared to autonomous growth processes. Conversely, both VEGFR-1 and VEGFR-2 were widely expressed in benign and neoplastic thyroid disease, suggesting that the up regulation of VEGF and not its receptors occurs as tissue becomes autonomous. There was no clear relationship between MVD measurement and thyroid pathology. PMID- 17696909 TI - Low coronary driving pressure early in the course of myocardial infarction is associated with subendocardial remodelling and left ventricular dysfunction. AB - Subendocardial remodelling of the left ventricular (LV) non-infarcted myocardium has been poorly investigated. Previously, we have demonstrated that low coronary driving pressure (CDP) early postinfarction was associated with the subsequent development of remote subendocardial fibrosis. The present study aimed at examining the role of CDP in LV remodelling and function following infarction. Haemodynamics were performed in Wistar rats immediately after myocardial infarction (MI group) or sham surgery (SH group) and at days 1, 3, 7 and 28. Heart tissue sections were stained with HE, Sirius red and immunostained for alpha-actin. Two distinct LV regions remote to infarction were examined: subendocardium (SE) and interstitium (INT). Myocyte necrosis, leucocyte infiltration, myofibroblasts and collagen volume fraction were determined. Compared with SH, MI showed lower CDP and LV systolic and diastolic dysfunction. Necrosis was evident in SE at day 1. Inflammation and fibroplasia predominated in SE as far as day 7. Fibrosis was restricted to SE from day 3 on. Inflammation occurred in INT at days 1 and 3, but at a lower grade than in SE. CDP correlated inversely with SE necrosis (r = -0.65, P = 0.003, at day 1), inflammation (r = 0.76, P < 0.001, at day 1), fibroplasia (r = -0.47, P = 0.04, at day 7) and fibrosis (r = -0.83, P < 0.001, at day 28). Low CDP produced progressive LV expansion. Necrosis at day 1, inflammation at days 3 and 7, and fibroplasia at day 7 correlated inversely with LV function. CDP is a key factor to SE integrity and affects LV remodelling and function following infarction. PMID- 17696910 TI - Infiltration of polymorphonuclear cells into the post-ischaemic myocardium is dependent on beta2 and alpha4 integrins. AB - Polymorphonuclear cells (PMN) are believed to be important effector cells responsible the myocardial damage seen following ischaemia. However, the exact kinetics of their migration remains controversial. Isolated PMN (10 x 10(6) cells) labelled with (51)Cr were injected into four groups of Lewis rats: 0 h (T0h; n = 13), 2 h (T2h; n = 7), 4 h (T4h; n = 7) or 6 h following ischaemia (T6h; n = 4). In all recipients, a left thoracotomy and ligation of the left anterior descending coronary was performed. Control animals underwent sham thoracotomy (n = 10). All animals were killed at 24 h and the radioactivity in the tissue measured to estimate labelled PMN migration. Monoclonal antibody blockade was also performed in experimental animals to assess the contribution of beta2 and alpha4 integrins to the PMN migration (n = 32). Labelled PMN migration to the myocardium was similar in all experimental groups, T0-T6h (7.2-11 x 10(5) labelled PMN) and significantly higher than sham controls (2.2 x 10(5) labelled PMN; P = 0.03). In contrast PMN migration to dermal inflammatory sites was highest in T0h group, and reached background level in the T4h and T6h groups. beta2 integrin blockade inhibited labelled PMN migration by 32%. Blockade of alpha4 integrin inhibited PMN migration by 30% while the combined beta2 + alpha4 blockade resulted in 63% inhibition of labelled PMN migration compared to treatment with isotype control antibody (P = 0.035). PMN migration following myocardial ischaemia persists over several hours after myocardial infarction and does not follow similar migration kinetics to dermal inflammation. Our findings also suggest that PMN migration is dependent equally on beta2 and alpha4 integrins. PMID- 17696911 TI - Cardiac and aortic structural alterations due to surgically-induced menopause associated with renovascular hypertension in rats. AB - Menopause and hypertension independently alter cardiovascular remodelling, but little is known about their effect on left ventricular and aortic wall remodelling. Eight-weeks-old Wistar rats were divided into four groups of six animals each: Sham group, OVX group (ovariectomized rats), 2K1C (two-kidneys, one clip rats) and OVX + 2K1C group and kept until 19 weeks. Blood pressure (BP) increased 12% in OVX group, 35% in 2K1C and OVX + 2K1C groups compared with sham group. Vaginal cytology showed Sham and 2K1C rats cycling normally, whereas OVX and OVX + 2K1C rats were persistently in dioestrus or proestrus. At euthanasia, left ventricle (LV) and thoracic aorta were removed and analysed (immunohistochemistry and stereology). LV mass/tibia length ratio and cross sectional area of cardiomyocytes increased in all groups except Sham. The intramyocardial vascularization reduced 30% in comparison with Sham group, with no difference among OVX, 2K1C and OVX + 2K1C groups. The cardiac interstitium increased more than 45% in both 2K1C and OVX + 2K1C groups compared with Sham, but there was no significant difference between Sham and OVX groups. Nuclei number of LV cardiomyocyte diminished in OVX group, followed by 2K1C group and OVX + 2K1C group, with no difference between the 2K1C and the OVX + 2K1C groups. There was positive immunostaining for angiotensin II AT1 receptor in smooth muscle cell layer of aortic tunica media in all groups. These results show that both ovariectomy and renovascular hypertension enhance BP as a single stimulus and therefore produce adverse cardiac remodelling. However, renovascular hypertension exerts a far greater influence than surgically-induced menopause in this parameter. PMID- 17696912 TI - Predominant formation of heavily pigmented dermal melanocytomas resembling 'animal-type' melanomas in hepatocyte growth factor (C57BL/6 x C3H)F1 mice following neonatal UV irradiation. AB - BACKGROUND: Transgenic mice expressing hepatocyte growth factor (HGF) develop cutaneous melanocytic tumors following neonatal UV exposure. Here, we examined the histologic spectrum of UV-induced melanocytic tumors in HGF mice on a pigmented (C57BL/6 x C3H/HeN)F(1) background. METHODS: Neonatally irradiated (4000 J/m(2)) mice were monitored for 43 weeks, and 31/34 (91%) animals developed a total of 163 melanocytic tumors. RESULTS: Of 54 primary tumors analyzed, most (49/54, 91%) demonstrated exclusively dermal collections of epithelioid cells with voluminous densely pigmented cytoplasm. Seven of these also demonstrated a population of spindled cells with mitoses. Several (3/54, 6%) tumors exhibited a junctional component with melanocytes present in the epidermis. Staining with PEP8 confirmed the presence of interfollicular melanocytes at the dermal epidermal junction in neonatal skin. CONCLUSIONS: In contrast to HGF animals on an albino (FVB) background, HGF animals on the pigmented (C57BL/6 x C3H/HeN)F(1) background do not develop classic radial growth phase melanoma but rather predominantly develop dermal melanocytomas resembling the 'animal-type' melanoma occasionally seen in humans. These results demonstrate the influence of genetic background on histologic pattern of UV-induced melanomas in mice. PMID- 17696913 TI - Cytokeratin expression in squamous cell carcinoma arising from hidradenitis suppurativa (acne inversa). AB - We have studied cytokeratin (CK) expression in two cases of well-differentiated and poorly differentiated squamous cell carcinoma (SCC) arising from hidradenitis suppurativa (HS) (acne inversa). In both cases, type A (infundibular-like keratinized) epithelia were observed. In type A epithelia, CK 1 and 10 expressions were decreased, and CK 14 and 17 were detectable in the whole layers. CK 7, 8, 15, 16 and 18 were not detected in type A epithelia. In tumor nests of well-differentiated SCC, CK 1 and 10 expressions were downregulated, and CK 14 expression was upregulated. In tumor nests of poorly differentiated SCC, CK 1 and 10 were not expressed, but simple epithelial keratins (CK 8, 18 and 19) were expressed. These changes of CK expression are related to malignant transformation from the sinus tract (type A epithelium) in HS to SCC. PMID- 17696914 TI - Melanophages reside in hypermelanotic, aberrantly glycosylated tumor areas and predict improved outcome in primary cutaneous malignant melanoma. AB - BACKGROUND: Previously, hypermelanotic regions of cutaneous malignant melanoma (CMM) were found to contain a mixture of highly melanized melanoma cells and melanophages. Both cell types produced beta1,6-branched oligosaccharides. These sugars are used for motility by myeloid cells and cancer cells alike and are associated with poor survival in carcinomas of the breast, colon and lung. This study further investigated associations between melanophages and beta1,6-branched oligosaccharides and their potential contributions to patient outcome. METHODS: Individual archival melanomas and high-throughput melanoma tissue microarrays were stained for melanophages with azure blue/S100 and for beta1,6-branched oligosaccharides with the lectin leukocytic phytohemagglutinin (LPHA, a selective marker for beta1,6-branched oligosaccharides). RESULTS: In primary CMM, melanophages were highly enriched in hypermelanotic, LPHA-positive tumor regions and correlated with improved outcome at 10- and 20-year follow ups. While the combination of melanophages, LPHA positivity and high pigmentation indicated better outcome, a subset of LPHA-positive cells not associated with melanophages indicated worse outcome. CONCLUSION: This is the first report of an anti-tumor role for the melanophage in melanoma biology. There appeared to be two classes of beta1,6-branched oligosaccharide-producing melanoma cells with opposing effects on outcome: one that attracted melanophages (better) and another that did not (worse). The findings disclose new aspects of the immune system and aberrant glycosylation in CMM. PMID- 17696915 TI - Characteristics of dermatologists who read dermatopathology slides. AB - BACKGROUND: The characteristics and prevalence of dermatologists reading dermatopathology slides are not well understood. METHODS: We surveyed 1406 members of the American Academy of Dermatology (AAD), including all 497 who were also members of the American Society of Dermatopathology (ASDP) along with a random sample of the remaining AAD members who were not ASDP members. Seven hundred and thirty of 1406 (51.9%) responded with a usable survey. Logistic regression was used to analyze responses by ASDP member dermatologists, non-ASDP member dermatologists and in a weighted analysis for dermatologists as a whole. RESULTS: A total of 32.7% of dermatologists as a whole generated at least one final microscopic diagnosis in the preceding year. Multivariate analysis demonstrated that men were significantly more likely to read dermatopathology slides (odds ratio (OR) = 1.90; 95% confidence interval (CI) 1.16-3.12; p = 0.01). Additionally, there was significant variation by region (p < 0.001); compared with dermatologists in the Midwest, dermatologists in the Southeast (OR = 0.39; 95% CI 0.19-0.80) were significantly less likely to read slides, while those in the Mountain (OR = 3.09; 95% CI 1.10-8.72) and West (OR = 2.01; 95% CI 1.04-3.90) regions were significantly more likely. There were no significant associations found between reading slides and the year of residency completion, the number of patients seen per week or being primarily in academics. CONCLUSIONS: The practice of dermatologists reading dermatopathology slides is relatively common, with significant regional and sex differences. PMID- 17696916 TI - The expression of CD23 in cutaneous non-lymphoid neoplasms. AB - BACKGROUND: Cluster designation 23 (CD23) is generally used as a lymphoid marker. Its utility in cutaneous epithelial tumors has never been studied. In our routine practice, we observed that CD23 reacted strongly with eccrine and apocrine secretory coils. METHODS: Immunohistochemical staining of CD23 was performed in a total of 131 cases of apocrine, eccrine, follicular and other cutaneous non lymphoid tumors. RESULTS: CD23 expression was detected in all benign apocrine tumors and in half of benign eccrine tumors, particularly those derived from secretory coils. CD23 staining was seen in 42% (8/19) of microcystic adnexal carcinoma (MAC), while no staining was observed in tumor cells of desmoplastic trichoepithelioma, morpheaform basal cell carcinoma and syringoma. All mammary and extramammary Paget's disease were labeled with CD23. In comparison, pagetoid Bowen's disease, melanoma in situ and sebaceous carcinoma exhibited negative staining. In addition, CD23 reacted diffusely with cutaneous mucinous eccrine carcinoma in a manner similar to breast or colonic adenocarcinoma. CONCLUSION: CD23 appears to be a reliable immunohistochemical marker of the eccrine/apocrine secretory coil and helpful in identifying sweat gland tumors of such origin. It is of ancillary value in differentiating MAC from its mimicker. CD23 is a useful addition to the diagnostic immunohistochemical panels for Paget's disease. PMID- 17696917 TI - Bitumen products alter bax, bcl-2 and cytokeratin expression: an in vivo study of chronically exposed road pavers. AB - BACKGROUND: The skin of road pavers is chronically exposed to bitumen fumes, a mixture of volatile compounds and particles, containing several carcinogenic and non-carcinogenic polycyclic aromatic hydrocarbons. Bitumen fumes can alter cutaneous barrier integrity in various ways and induce skin diseases. The present study was devised to investigate the expression of apoptosis proteins (bax and bcl-2) and the cytokeratin pattern in skin specimens from road paving workers exposed to bitumen fumes using immunohistochemical techniques. METHODS: Skin forearm punch biopsies from 16 occupationally exposed workers and an unexposed control group were processed for immunohistochemistry using a broad-spectrum anti cytokeratin antibody and monoclonal antibodies for bax and bcl-2 immunostaining. Urinary 1-hydroxypyrene (1-OHP) was also determined. RESULTS: Morphological specimen evaluation showed epidermal thinning of exposed skin and flattened dermal papillae. In sections from exposed subjects, grade 3 bax overexpression and cytokeratin immunoreaction was detected in all layers, while bcl-2 expression was downregulated (grade 1) and confined to the basal layer. There was a significant difference in 1-OHP values between road pavers and the control group (p < 0.05). CONCLUSION: Overexpression of the cytokeratin pattern and bax and underexpression of bcl-2 in chronically bitumen-exposed skin suggest that bitumen fumes induce activation of apoptosis as a defense mechanism. PMID- 17696918 TI - Dermatopathological indicators of poor melanoma prognosis are significantly inversely correlated with the expression of NM23 protein in primary cutaneous melanoma. AB - BACKGROUND: Some dermatopathological parameters are recognized as dominant indicators of high metastatic potential in melanoma, especially Breslow thickness, ulceration, Clark's level of invasion and mitotic rate. Because NM23 protein is the product of a melanoma metastasis suppressor gene, the aim of this study was to compare such dermatopathological indicators of melanoma prognosis with NM23 protein expression in primary cutaneous melanoma. METHODS: The immunohistochemical NM23 expression was semiquantitatively assessed in 30 primary cutaneous melanomas. Ten dermatopathological parameters were evaluated and compared with NM23 expression. RESULTS: A significant inverse correlation was found for NM23 expression in comparison with Breslow thickness (p < 0.01), ulceration (p < 0.05), Clark's level (p < 0.01), mitotic rate (p < 0.05), and vertical growth phase (p < 0.05). By contrast, no significant correlation was found for NM23 expression in comparison with cell morphology, presence of adjacent nevus, pigmentation, tumor-infiltrating lymphocytes, and regression was impossible to evaluate. CONCLUSIONS: The expression of NM23 protein in primary cutaneous melanoma is significantly inversely correlated with dermatopathological parameters currently recognized as powerful indicators of melanoma prognosis. NM23 may be therefore considered in the dermatopathological evaluation of primary cutaneous melanoma. PMID- 17696919 TI - Mitoses in conventional melanocytic nevi. AB - Given that nevi may grow in size, mitotic figures may be expected in melanocytic nevi. We reviewed the literature for studies addressing this issue. We sought to determine the number of mitotic figures we might discover upon review of a group of randomly collected, conventional nevi. We reviewed 157 nevi from patients and found seven nevi exhibiting mitotic figures, comprising 4% of our sample. We noted the location of the mitoses within the nevi, the presence of any congenital features, as well as other features such as signs of inflammation or irritation. Through this study we have shown that occasional mitoses occur within unremarkable, conventional nevi. PMID- 17696920 TI - Langerhans cell hyperplasia in scabies: a mimic of Langerhans cell histiocytosis. AB - AIM: In the absence of mites, the histologic diagnosis of human scabies can be difficult. Scabies can mimic a variety of inflammatory and lymphoproliferative disorders. It is under-recognized that scabies can also mimic Langerhans cell histiocytosis. METHODS: Sixteen examples of scabies were reviewed histologically and immunohistochemically (CD1a, CD3, CD20, CD30 and S100). RESULTS: Immunohistochemical labeling showed florid CD1a and S100 positivity in most cases, indicative of Langerhans cell hyperplasia. Scattered CD30+ lymphocytes were also typically present, within a dense infiltrate, primarily composed of T lymphocytes and eosinophils. CONCLUSION: Because of the prominent CD1a+/S100+ component, scabies can mimic Langerhans cell histiocytosis. This finding should be considered in conjunction with scattered CD30+ cells and clinical features to avoid misdiagnosis. PMID- 17696921 TI - Viral-associated trichodysplasia in a patient with lymphoma: a case report and review. AB - Viral-associated trichodysplasia is a recently described entity associated with immunosuppression. We describe a 68-year-old man with a history of treated lymphoma who developed numerous, disfiguring, papular and spiny lesions involving most of the central face. Both facial and body alopecia was noted. Histopathologic findings of a facial papule showed dramatic alterations of the hair bulbs, including bulbar distention, lack of hair shaft formation and a marked expansion of inner root sheath type epithelium. These findings were identical to those of previously described cases, so electron microscopy was performed. Numerous intranuclear virus particles were identified. Shortly after the diagnosis of trichodysplasia was made, the patient was found to have a relapse of his lymphoma, which may represent the source of his immunosuppression. Based on his skin biopsy findings, successful antiviral therapy was initiated. This case and a review of previously reported cases are discussed in this study. PMID- 17696922 TI - Soft-tissue perineurioma in a 20-year-old patient with neurofibromatosis type 1 (NF1): report of a case and review of the literature. AB - BACKGROUND: Perineurioma is a rare benign soft-tissue tumor composed of cells showing differentiation toward the perineurial cells of the nerve sheath. Although mutations in the neurofibromatosis 2 (NF2) gene have been documented in this tumor, there is no known association between perineuriomas and type 1 or 2 NF. METHODS: This is the first report of a case of soft-tissue perineurioma occurring in a patient with NF1. RESULTS: Histopathologic examination revealed a 2.0-cm well-circumscribed, spindle-cell neoplasm with slender, elongated, bipolar, wavy cytoplasmic processes and wavy, elongated nuclei in a hyalinized stroma with focal myxoid areas. The architecture was composed predominantly of short fascicles with areas exhibiting a storiform pattern. Immunohistochemistry showed positive labeling for epithelial membrane antigen (EMA) but no staining for S-100 and smooth muscle actin (SMA). CONCLUSION: This case illustrates that perineurioma can occur in association with NF1. Perineuriomas can be confused with other spindle-cell neoplasms, and relevant features and immunohistochemistry of these lesions are outlined. The patient has not had a recurrence with limited follow-up. PMID- 17696923 TI - Combined malignant melanoma and basal cell carcinoma tumor of the intermingled type. AB - BACKGROUND: The combination of malignant melanoma (MM) and basal cell carcinoma (BCC) within a single tumor is an unusual finding. CASE REPORT: An 84-year-old white man with a pigmented tumor on the back showing a combination of MM and BCC. RESULTS: A 1.5 x 1.5-cm irregular brown lesion on the back was clinically suggestive of MM. Histopathologically, the lesions turned out to be a combined tumor consisting of a superficial BCC and a regressive MM with a tumor thickness of 1.25 mm. The conglomerates of the BCC lay within the MM and were admixed with a high number of Melan-A-positive melanocytic cells. CONCLUSION: By reviewing the low number of published cases, we found that a combined MM-BCC tumor exists in two variants: a collision type in which components of each cell type are clearly demarcated and an intermingled type in which both cell types grow intimately together. Although both types occur as a mere incidence, in particular, the intermingled type may be diagnostically challenging and the evaluation of its dignity may be questionable. PMID- 17696924 TI - Compound melanocytic nevus associated with dermatofibroma: an additional case. PMID- 17696925 TI - Traditional Chinese herbal medicines for treatment of liver fibrosis and cancer: from laboratory discovery to clinical evaluation. AB - Liver disease afflicts over 10% of the world population. This includes chronic hepatitis, alcoholic steatosis, fibrosis, cirrhosis and hepatocellular carcinoma (HCC), which are the most health-threatening conditions drawing considerable attention from medical professionals and scientists. Patients with alcoholism or viral hepatitis are much more likely to have liver cell damage and cirrhosis, and some may eventually develop HCC, which is unfortunately, and very often, a fatal malignancy without cure. While liver surgery is not suitable in many of the HCC cases, patients are mostly given palliative support cares or transarterial chemoembolization or systemic chemotherapies. However, HCC is well known to be a highly chemoresistant tumour, and the response rate is <10-20%. To this end, alternative medicines are being actively sought from other sources with hopes to halt the disease's progression or even eliminate the tumours. Traditional Chinese herbal medicine has begun to gain popularity worldwide for promoting healthcare as well as disease prevention, and been used as conventional or complementary medicines for both treatable and incurable diseases in Asia and the West. In this article, we discuss the laboratory findings and clinical trial studies of Chinese herbal medicines (particularly small molecule compounds) for the treatment of liver disease ranging from fibrosis to liver cancer. PMID- 17696926 TI - Liver: an alarm for the heart? AB - BACKGROUND/AIMS: Fatty liver (FL) and coronary artery disease (CAD) have several risk factors in common, which are usually considered to account for their frequent coexistence. The independent association between FL and angiographic CAD was assessed in this case-control study by considering the contribution of their shared risk factors. METHODS: Three hundred and seventeen adult patients who underwent elective coronary angiography (CAG) were recruited immediately after CAG and classified into either of the two groups A (normal or mildly abnormal CAG; n=85) or B (clinically relevant CAD; n=232). A liver sonography was performed on the same day as CAG. RESULTS: The groups were significantly different in terms of gender, fasting blood glucose, low-density lipoproteins, diabetes (DM), hypertension and FL. In binary logistic regression, FL was the strongest independent predictor of CAD [P<0.001, odds ratio (OR)=8.48%, 95% confidence interval (CI)=4.39-16.40], followed by DM (P=0.002, OR=2.94) and male gender (P=0.014, OR=2.31). This pattern of associations did not change after clinically significant variables (waist-to-hip ratio, body mass index, triglycerides and high-density lipoproteins) were added to analysis. CONCLUSION: Fatty liver seems to be a strong independent alarm for the presence of significant CAD. PMID- 17696927 TI - Prediction of coronary atherosclerotic disease with liver transaminase level. AB - BACKGROUND/AIMS: Recent studies have shown that liver transaminases are associated with components of the metabolic syndrome including central obesity, type 2 diabetes, dyslipidaemia and high blood pressure, but their direct influence on coronary atherosclerosis has not been investigated before. We conducted this study to evaluate the predictive value of liver transaminases for angiography-documented coronary atherosclerosis in patients with coronary heart disease. METHODS: Six hundred and thirty consecutive patients with suspicious coronary artery disease (CAD) who were candidates for coronary angiography were enrolled. In addition to coronary angiography, measurements of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations, C reactive protein (CRP) level and assessment of the traits of the metabolic syndrome were performed in all patients. RESULTS: ALT and ALT/AST ratios were significantly correlated with angiographic atherosclerosis score in women (r=0.17 and 0.24 respectively). Logistic regression analysis showed that the ALT/AST ratio in women could predict severe CAD [odds ratio (OR) 3.93, 95% confidence interval (CI) 1.76-8.76]. After adjustment for components of the metabolic syndrome and CRP concentration, the OR remained significant (4.00 [1.76-9.14]). Although significant in univariate analysis, neither ALT (OR 0.98, 95% CI 0.77 1.15) nor AST (OR 0.99, 95% CI 0.72-1.22) could predict severe CAD in men. CONCLUSION: An elevated ALT/AST ratio in women predicts coronary atherosclerosis independently of the metabolic syndrome and serum CRP concentration, and should warrant further diagnostic and therapeutic interventions. PMID- 17696928 TI - Acid-base disturbances in critically ill patients with cirrhosis. AB - BACKGROUND/AIMS: The equilibrium of offsetting metabolic acid-base disorders in stable cirrhosis might be lost during episodes of hepatic decompensation, haemorrhage or sepsis. The purpose of this study was to determine whether the acid-base state is destabilized in critically ill patients with cirrhosis and whether this is associated with mortality. PATIENTS AND METHOD: One-hundred and eighty-one consecutive patients with cirrhosis were investigated in a prospective observational cohort study on admission to a medical intensive care unit (ICU) of a university hospital. Arterial acid-base state was assessed according to the Gilfix methodology. Clinical data, ICU mortality and hospital mortality were recorded. MAIN RESULTS: Patients had net metabolic acidosis owing to unmeasured anions and owing to hyperchloraemic, dilutional and lactic acidosis. Lactic acidosis, acidemia and acute renal failure on ICU admission were associated with increased mortality. Lactate and pH discriminated survivors from non-survivors. The presence of lactic acidosis could not always be recognized by customary acid base parameters. CONCLUSION: The stable equilibrium of acid-base disorders is lost when patients with cirrhosis become critically ill. Lactic acidosis and acidaemia are associated with increased ICU mortality caused by severe underlying organ dysfunction. PMID- 17696929 TI - Investigation of the Lith6 candidate genes APOBEC1 and PPARG in human gallstone disease. AB - BACKGROUND: Genetic susceptibility contributes to the aetiology of gallbladder diseases as shown by multiple epidemiological studies. A major gallstone susceptibility locus (Lith6) was identified in 2003 by quantitative trait locus mapping in mice. Two attractive positional and functional candidate genes in apolipoprotein B mRNA-editing protein (APOBEC1) and peroxisome proliferator activated receptor gamma (PPARG) are located in this interval. AIMS: To investigate APOBEC1 and PPARG as candidate genes for common symptomatic gallstone disease in humans. PATIENTS AND METHODS: Eight hundred and ten patients who underwent cholecystectomy for symptomatic gallstone disease (median age of onset 50) were compared with 718 sex-matched control individuals. An independent additional sample included 368 gallstone patients and 368 controls. Control individuals were sonographically free of gallstones. Haplotype tagging and all known coding single nucleotide polymorphisms were genotyped for PPARG (N=32) and APOBEC1 (N=11). RESULTS: The investigated high-risk patient sample provides a power of greater than 80% for the detection of odds ratios down to 1.45. No evidence of association of the two genes in the single-point tagging markers, coding variants and in the sliding window haplotype analysis was detected (all nominal single point P-values >0.04). A logistic regression analysis including age, sex and BMI as covariates was also negative (nominal P-values > or =0.08). CONCLUSIONS: In the investigated German samples, no evidence of association of APOBEC1 and PPARG with gallstone susceptibility was detected. Systematic fine mapping of the complete Lith6 region is required to identify the causative genetic variants for gallstone in mice and humans. PMID- 17696930 TI - Expression of bile acid synthesis and detoxification enzymes and the alternative bile acid efflux pump MRP4 in patients with primary biliary cirrhosis. AB - BACKGROUND: Bile acid synthesis, transport and metabolism are markedly altered in experimental cholestasis. Whether such coordinated regulation exists in human cholestatic diseases is unclear. We therefore investigated expression of genes for bile acid synthesis, detoxification and alternative basolateral export and regulatory nuclear factors in primary biliary cirrhosis (PBC). MATERIAL/METHODS: Hepatic CYP7A1, CYP27A1, CYP8B1 (bile acid synthesis), CYP3A4 (hydroxylation), SULT2A1 (sulphation), UGT2B4/2B7 (glucuronidation), MRP4 (basolateral export), farnesoid X receptor (FXR), retinoid X receptor (RXR), short heterodimer partner (SHP), hepatocyte nuclear factor 1alpha (HNF1alpha) and HNF4alpha expression was determined in 11 patients with late-stage PBC and this was compared with non cholestatic controls. RESULTS: CYP7A1 mRNA was repressed in PBC to 10-20% of controls, while CYP27 and CYP8B1 mRNA remained unchanged. SULT2A1, UGT2B4/2B7 and CYP3A4 mRNA levels were unaltered or only mildly reduced in PBC. MRP4 protein levels were induced three-fold in PBC, whereas mRNA levels remained unchanged. Expression levels of FXR, RXR, SHP, PXR, CAR, HNF1alpha and HNF4alpha were moderately reduced in PBC without reaching statistical significance. SUMMARY/CONCLUSIONS: Repression of bile acid synthesis and induction of basolateral bile acid export may represent adaptive mechanisms to limit bile acid burden in chronic cholestasis. As these changes do not sufficiently counteract cholestatic liver damage, future therapeutic strategies should aim at stimulation of bile acid detoxification pathways. PMID- 17696931 TI - Apolipoprotein AI and apolipoprotein E mRNA expression in peripheral white blood cells from patients with orthotopic liver transplantation. AB - BACKGROUND: Apolipoprotein AI/apolipoprotein E (apo-AI/apo-E) ratio change and its induction in non-hepatic tissues have been reported during liver development, regeneration, and several pathophysiologic states. The clinical implication of such changes is unclear, but these could reflect recovery and/or severity of liver damage. METHODS AND RESULTS: Using RT-PCR we analysed the mRNA expression of apo-AI and apo-E in peripheral white blood cells (PWBC) of patients with different liver diseases who underwent orthotopic liver transplantation (OLT) and compared its expression with the lipid profile and liver function tests. We found that patients showed higher levels of apo-AI mRNA without detection of apo-E mRNA on PWBC at the preoperative day, compared with healthy volunteers (HV). We found an apo-AI/apo-E mRNA ratio of 2.7 during the anhepatic stage, followed by a decrease to 1.3, 0.95, and 0.55 at days 30, 60, and 90, respectively. At the last time point, the apo-AI/apo-E ratio was similar to HV. At day 3 post-OLT, the lowest levels of high-density lipoprotein (HDL)-cholesterol (17 mg/dl; P<0.05) and the highest levels of aspartate aminotransferase, total bilirubin and alkaline phosphatase (77.5 IU/l, 37.9 g/dl, 177.8 IU/l, respectively; P<0.05) were detected. CONCLUSION: These results indicate that changes of HDL-cholesterol and apo-AI/apo-E mRNA ratio could be a good indicator of liver damage and/or hepatic functional recovery post-OLT. PMID- 17696932 TI - Nodular regenerative hyperplasia: a deleterious consequence of chemotherapy for colorectal liver metastases? AB - AIMS: This report describes three patients suffering from nodular regenerative hyperplasia (NRH). METHODS: These patients have received six, 16 and 20 cycles of neoadjuvant 5-fluorouracil and oxaliplatin-based chemotherapy before planned extended hepatectomy. Two patients underwent uneventful portal vein embolization to hypertrophy the future remnant liver. RESULTS: At the end of chemotherapy, liver function tests deteriorated and portal hypertension appeared in two patients, including ascites, splenomegaly and oesophageal varices. Liver biopsy was performed through a percutaneous (two patients) or a transjugular approach (one patient) and allowed the diagnosis of NRH, which was considered to be a contraindication for major liver resection in all three patients, associated with extrahepatic disease progression in one patient. All patients died from neoplastic disease progression despite further chemotherapy at 6, 17 and 31 months following the diagnosis of NRH. One patient developed liver failure and ascites at the time of death. CONCLUSIONS: Physicians should be aware of the potential occurrence and therapeutic impact of NRH in patients suffering from CRLM and treated by neoadjuvant 5FU-oxaliplatin-based chemotherapy before major liver surgery. PMID- 17696933 TI - Monocyte-derived dendritic cells from chronic HCV patients are not infected but show an immature phenotype and aberrant cytokine profile. AB - BACKGROUND: Chronic hepatitis C virus (HCV) infection is characterized by an insufficient immune response, possibly owing to impaired function of antigen presenting cells such as myeloid dendritic cells (DCs). Therapeutic vaccination with in vitro generated DCs may enhance the immune response. Subsets of DCs can originate from monocytes, but the presence of HCV in monocytes that develop into DCs in vitro may impair DC function. Therefore, we studied the presence of HCV RNA in monocytes and monocyte-derived DCs from chronic HCV patients. METHODS: Monocytes were cultured with granulocyte macrophage colony-stimulating factor (GM CSF) and interleukin 4 (IL-4) for 6 days, and then with GM-CSF, IL-4, tumour necrosis factor-alpha (TNF-alpha), prostaglandin E2, IL-1beta and IL-6 for 2 days to generate mature DCs. HCV RNA was assessed by polymerase chain reaction. Surface molecules were assessed by flow cytometry. Cytokine production was assessed by cytokine bead array. RESULTS: HCV RNA was present in monocytes in 11 of 13 patients, but undetectable in mature DCs in 13 of 13 patients. The morphology of patient DCs was comparable with DCs from healthy controls, but the percentage of cells expressing surface molecules CD83 (P=0.001), CD86 (P=0.023) and human leucocyte antigen-DR (P=0.028) was lower in HCV patients. Compared with control DCs, patient DCs produced enhanced levels of IL-10 (P=0.0079) and IL-8 (P=0.0079), and lower levels of TNF-alpha (P=0.032), IL-6 (P=NS) and IL-1beta (P=0.0079). Patient and control DCs did not produce IL-12. CONCLUSIONS: Monocyte derived DCs from chronic HCV patients are not infected but show an immature phenotype and aberrant cytokine profile. PMID- 17696934 TI - Relapse to prior therapy is the most important factor for the retreatment response in patients with chronic hepatitis C virus infection. AB - BACKGROUND: Treatment options for hepatitis C have developed rapidly in the past decade. The current treatment of choice is a combination of pegylated-interferon alpha (PEG-IFN-alpha) and ribavirin. With the development of more therapy options, patients who failed in prior therapy hope to clear hepatitis C virus by undergoing a more effective retreatment regime. In this report, we investigated response rates to combination therapy [standard IFN-alpha or PEG-IFN-alpha and ribavirin] in patients who relapsed or failed in prior therapy. METHODS: Ninety three patients were included in this retrospective study. All patients failed to previous IFN-alpha monotherapy (n=55) or to a combination of standard IFN-alpha and ribavirin (n=38). Fifty-nine patients were nonresponders and 34 were relapsers. Thirty-five patients were retreated with standard IFN-alpha plus ribavirin and 58 received PEG-IFN-alpha combination therapy. RESULTS: Sustained virologic response (SVR) was induced in 31% of all patients. The highest SVR rate (58%) was observed in relapsers to standard IFN-alpha combination therapy who were retreated with PEG-IFN-alpha combination therapy. The SVR rate in relapsers to standard IFN-alpha monotherapy who received a standard IFN-alpha combination therapy was 50%. Relapsers responded in a significantly higher proportion to retreatment than nonresponders (56% vs. 17%, P<0.001). Relapse to previous therapy was identified as an independent predictor for therapy response. The lowest SVR rate was observed in nonresponders to standard IFN-alpha combination therapy who were retreated with PEG-IFN-alpha combination therapy (1/26; 4%). CONCLUSIONS: In relapsers, retreatment with the most effective therapy regime to date a combination of PEG-IFN-alpha and ribavirin, is promising. However, retreatment with PEG-IFN-alpha combination therapy in nonresponders to standard IFN combination therapy is not effective. PMID- 17696935 TI - Up-regulation of proproliferative genes and the ligand/receptor pair placental growth factor and vascular endothelial growth factor receptor 1 in hepatitis C cirrhosis. AB - BACKGROUND/AIMS: Cirrhosis can lead to hepatocellular carcinoma (HCC). Non diseased liver and hepatitis C virus (HCV)-associated cirrhosis with or without HCC were compared. METHOD: Proliferation pathway genes, immune response genes and oncogenes were analysed by a quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) and immunostaining. RESULTS: Real-time RT-PCR showed up-regulation of genes in HCV cirrhosis including the proliferation associated genes bone morphogenetic protein 3 (BMP3), placental growth factor 3 (PGF3), vascular endothelial growth factor receptor 1 (VEGFR1) and soluble VEGFR1, the oncogene FYN, and the immune response-associated genes toll-like receptor 9 (TLR9) and natural killer cell transcript 4 (NK4). Expressions of TLR2 and the oncogenes B-cell CLL/lymphoma 9 (BCL9) and PIM2 were decreased in HCV cirrhosis. In addition, PIM2 and TLR2 were increased in HCV cirrhosis with HCC compared with HCV cirrhosis. The ligand/receptor pair PGF and VEGFR1 was intensely expressed by the portal tract vascular endothelium. VEGFR1 was expressed in reactive biliary epithelial structures in fibrotic septum and in some stellate cells and macrophages. CONCLUSION: PGF and VEGFR1 may have an important role in the pathogenesis of the neovascular response in cirrhosis. PMID- 17696936 TI - Noninvasive models to predict liver cirrhosis in patients with chronic hepatitis B. AB - OBJECTIVES: Few noninvasive models of chronic hepatitis B (CHB) to predict liver cirrhosis have been studied. The aim of the current study is to investigate the diagnostic accuracy of two simple novel models of spleen-platelet ratio index (SPRI) and age-spleen-platelet ratio index (ASPRI) in patients with CHB. PATIENTS AND METHODS: A total of 346 consecutive treatment-naive patients with CHB were retrospectively studied. The aspartate to alanine aminotransferase ratio (AAR), age-platelet index (API), aspartate aminotransferase to platelet ratio index (APRI), SPRI, and ASPRI were compared with liver histology. RESULTS: AAR, APRI, SPRI, API, and ASPRI correlated significantly to fibrosis stage (all P<0.001). The diagnostic accuracy of ASPRI was the highest among five tests for prediction of cirrhosis (area under receiver operating characteristic curve, AUROC=0.893). Using a cutoff score of ASPRI>12, the presence of cirrhosis could be correctly identified with a high accuracy (96.3% positive predictive value) in 35 (10.1%) of 346 patients. Similarly, using a cutoff of <5, the presence of cirrhosis could be totally excluded with 100% of negative predictive value in 120 (34.7%) of 346 patients. CONCLUSION: ASPRI was accurate in predicting cirrhosis and screening with ASPRI has the potential to reduce the number of liver biopsies in CHB patients. PMID- 17696937 TI - Hepatitis B vaccination after living donor liver transplantation. AB - BACKGROUND: The efficacy of hepatitis B vaccination after living donor liver transplantation (LDLT) in patients transplanted anti-HBc-positive grafts or in patients who underwent LDLT for fulminant hepatitis B remains unknown. METHOD: A total of 11 recipients who underwent LDLT between October 1996 and October 2002 prospectively received hepatitis B vaccination three times within 6 months, starting a few weeks after the cessation of hepatitis B immunoglobulin (HBIG) prophylaxis. Serial quantification of the hepatitis B surface antibody (HBsAb) was performed. RESULTS: At the last follow-up, six out of 11 patients (54.5%) had seroconversion and were free from HBIG thereafter. Four out of those six responders had a peak HBsAb level of more than 1000 IU/L, while the other two patients had peak HbsAb levels below 1000 IU/L. Five patients never responded to the treatment and were back to HBIG prophylaxis. The average age of the six responders was 25.5 years, which was significantly younger than that of non responders (44.4 years, P<0.05). None had side effects or hepatitis B infection during the study period. CONCLUSIONS: In conclusion, the use of this treatment modality could be used to reduce the cost of HBIG. PMID- 17696938 TI - Subgenotypes of hepatitis B virus genotype C do not correlate with disease progression of chronic hepatitis B in Taiwan. AB - BACKGROUND: Hepatitis B virus (HBV) genotype C (HBV/C) has two subgenotypes: HBV/Cs and Ce. The prevalence and clinical implications of subgenotype Cs and Ce in Taiwanese HBV carriers remain unknown. METHODS: Subgenotypes of HBV/C were determined in 242 Taiwanese HBV carriers with various stages of liver disease. The clinical as well as virologic features between patients with HBV/Cs and HBV/Ce infection were further compared. RESULTS: HBV/Ce was the predominant subgenotype in Taiwan. The prevalence of HBV/Ce was 93.6% in the inactive carriers group, 84.2% in chronic hepatitis patients, 81.2% in cirrhosis patients, 92.5% in hepatocellular carcinoma (HCC) patients without cirrhosis and 91.9% in HCC patients with cirrhosis. There was no significant difference in the distribution of the HBV/C subgenotypes among patients with different stages of liver disease. CONCLUSIONS: Subgenotypes of HBV/C may not have a clinical impact on the disease progression of chronic hepatitis B in Taiwan. PMID- 17696939 TI - Expression of microsomal prostaglandin E synthase-1 in human hepatocelluar carcinoma. AB - BACKGROUND/AIMS: The objective of this study was to evaluate the expression of microsomal prostaglandin E synthase-1 (mPGES-1) in hepatocellular carcinoma (HCC) tissues. METHODS: Forty surgically resected HCC tissues with adjacent non tumorous liver tissues and 14 surgically resected, histologically normal liver tissues were used. The immunohistochemical expressions of the mPGES-1 protein in these HCC tissues and normal control livers were analysed. mPGES-1 mRNA expression was also analysed by the real-time polymerase chain reaction method using the same tissues. RESULTS: Microsomal prostaglandin E synthase-1 was not expressed in hepatocytes but instead in vascular endothelial cells and bile duct epithelial cells in normal liver tissues. The mPGES-1 expression in HCC tissues was significantly greater than its expression in the non-tumorous tissues. All types of HCC expressed more mPGES-1 than normal or hepatitis livers, and the levels of mPGES-1 expression in poorly differentiated HCC were similar to the levels in well-differentiated HCC. The mPGES-1 mRNA expression paralleled its protein expression in these tumorous and non-tumorous tissues. CONCLUSIONS: The present study is the first to demonstrate a high expression of mPGES-1 in well differentiated HCC as well as in poorly differentiated HCC. These findings suggest that mPGES-1 may play a role in the advanced as well as early stage of hepatocarcinogenesis. PMID- 17696940 TI - Aberrant Notch3 and Notch4 expression in human hepatocellular carcinoma. AB - BACKGROUND: Notch signalling is altered in several solid tumours and it plays a role in growth inhibition and apoptosis of hepatocellular carcinoma (HCC)-derived cell lines, bile duct development and hepatocyte regeneration. AIMS: This study aims to analyse the expression of Notch3, Notch4 and HES1 and HES6 as Notch target genes in HCC, matched non-neoplastic tissue and HEPG2 cells. RESULTS: Notch3 and Notch4 are not expressed in normal liver and in chronic hepatitis surrounding HCC. Cirrhotic tissue stains negative for Notch3, while Notch4 is expressed by hepatocytes at the edge of regenerative nodules and in cell planes adjacent to fibrous septa. HCC tissue displays Notch3 and Notch4 abnormal accumulation, respectively, in 78% and 68% of the cases. The endothelium of hepatic veins with neoplastic permeation is frequently Notch4 positive. An upregulation of Notch3 mRNA was found in 95% of HCCs vs cirrhosis (P=0.0001), while Notch4 mRNA was downregulated in 80% of HCCs. HES6 mRNA expression was higher in HCC tissue when compared with cirrhosis (P=0.007), paralleling Notch3 mRNA expression. The HEPG2 cell line displays high Notch3 and low Notch4 protein and mRNA levels. CONCLUSIONS: These descriptive findings suggest an aberrant expression of Notch3 and Notch4 in HCC and allow the hypothesis of an activation of Notch signalling by Notch3. PMID- 17696941 TI - Haplotype analysis of signal peptide (insertion/deletion) and XbaI polymorphisms of the APOB gene in gallbladder cancer. AB - PURPOSE: The incidence of gallbladder cancer (GBC) is usually paralleled by the prevalence of gallstone disease, and genes of cholesterol metabolism have been implicated in gallstone disease. The XbaI and insertion/deletion (ins/del) polymorphism of Apolipoprotein B (APOB) appears to influence cholesterol homoeostasis and possibly risk for gallstone disease. We examined the effect of these polymorphisms individually as well as their haplotypes on GBC and gallstone patients in North Indian population. METHODS: The study comprises 123 consecutive cases of proven GBC, 172 cases of gallstone and 232 healthy subjects of similar age and sex. The genomic DNA was extracted from peripheral blood leucocytes and genotyping was performed using polymerase chain reaction (PCR) and PCR restriction fragment length polymorphism. RESULTS: In a case-control study, APOB XbaI and ins/del polymorphisms were not significantly associated with risk of GBC. Using the expectation maximization algorithm, four haplotypes were obtained, and haplotype X(+),D was found to be significantly higher in GBC patients without stone in comparison with healthy subjects [odds ratio (OR) 2.9, 95% confidence interval 1.2-6.6 P=0.012]. CONCLUSIONS: The X(+),D haplotype of APOB is associated with increased risk for development of GBC and the risk is not modified in the presence of gallstones. PMID- 17696942 TI - Adrenal metastasis from intrahepatic cholangiocarcinoma. PMID- 17696943 TI - Black cohosh, safety, and public awareness. PMID- 17696944 TI - Quantification of biofilm in microtiter plates: overview of testing conditions and practical recommendations for assessment of biofilm production by staphylococci. AB - The details of all steps involved in the quantification of biofilm formation in microtiter plates are described. The presented protocol incorporates information on assessment of biofilm production by staphylococci, gained both by direct experience as well as by analysis of methods for assaying biofilm production. The obtained results should simplify quantification of biofilm formation in microtiter plates, and make it more reliable and comparable among different laboratories. PMID- 17696945 TI - Immunohistochemical and mutational analysis of FLASH in gastric carcinomas. AB - FLASH was initially identified as a pro-apoptotic protein that transmits an apoptosis signal during death receptor-induced apoptosis. Additionally, diverse biologic roles of FLASH, including TNF-induced NF-kappaB activation, cell-cycle progression and cell division, have been identified. Although such functions are important in cancer pathogenesis, little is known about the alterations of FLASH gene and FLASH protein expression in human cancers. In this study, we analyzed the expression of FLASH protein in 60 gastric adenocarcinomas by immunohistochemistry. We furthermore analyzed mutation of FLASH in exon 8, where two polyadenine tracts ((A)8 and (A)9) are present, by single-strand conformation polymorphism (SSCP) assay in 184 gastric adenocarcinomas. By immunohistochemistry, FLASH protein expression in cancer cells was detected positively in 42 gastric carcinoma tissues (70%), whereas its expression in epithelial cells of normal gastric mucosa was shown as no or very weak intensity. Mutational analysis detected one FLASH mutation in the gastric carcinomas (0.5%). The increased expression of FLASH in the malignant gastric epithelial cells compared to the normal mucosal epithelial cells suggests that FLASH expression may play a role in gastric tumorigenesis. Also, the data suggest that somatic mutation of FLASH is a rare event in gastric carcinomas. PMID- 17696946 TI - Expression of D2-40 in adjunct diagnosis of papillary thyroid carcinoma. AB - The clinical pathologic criteria for nuclear features of papillary thyroid carcinoma are subjective and sometimes cannot distinguish carcinoma from adenomatous goiter and follicular neoplasms. No single antibody has demonstrated high sensitivity or specificity in making these distinctions. Using quantitative analysis of immunohistochemical staining with D2-40, a recently available monoclonal antibody used as a lymphatic endothelial marker, we examined 72 cases of papillary carcinoma. Controls included 36 follicular adenomas, 36 follicular carcinomas, and 20 adenomatous goiters with papillary hyperplasia. Cytoplasmic D2 40 immunoreactivity was present in 60 of 72 papillary carcinomas, 2 cases of follicular adenoma and 2 cases of follicular carcinoma, whereas no adenomatous goiter or normal thyroid glands contained positive epithelial cells. Overexpression of D2-40 in papillary thyroid carcinomas thus has potential diagnostic utility in differentiating these tumors from their potential histologic mimics. PMID- 17696947 TI - Calcium channel antagonist (nifedipine) attenuates Plasmodium berghei-specific T cell immune responses in Balb/C mice. AB - Nifedipine and verapamil (Martin et al. Science 1987;235:899-901) are a class of calcium channel blockers involved in the reversal of chloroquine (CQ) drug resistance in CQ-sensitive Plasmodium spp. Nifedipine alters calcium-dependent functions of macrophages and neutrophils during Plasmodium berghei malaria. However, knowledge of nifedipine-induced immunomodulation of T cell functions during P. berghei malaria is still limited. We investigated the effect of nifedipine on the immune status of splenic T cells during P. berghei malaria. The intracellular calcium levels were determined in the FURA-2A/M loaded T cells by spectrofluorometry. Splenic T cell proliferation, phosphatidylserine (PS) externalization, Fas expression and Bcl2/Bax expression were determined by flow cytometry. We report a significant increase in mean percent parasitemia in nifedipine-treated and P. berghei-infected mice. Although nifedipine treatment alone did not affect the resting state free calcium levels in splenic T cells, the rise in intracellular calcium levels of T cells following P. berghei infection was significantly less in nifedipine-treated mice compared to untreated groups at various parasitemia levels. Antigen-specific splenic T cell proliferation and apoptosis was ablated in nifedipine-treated and untreated groups at various parasitemia levels. The study unequivocally reflects the suppression of P. berghei-specific T cell immune responses by nifedipine. PMID- 17696948 TI - Silver against Pseudomonas aeruginosa biofilms. AB - Silver has been recognized for its antimicrobial properties for centuries. Most studies on the antibacterial efficacy of silver, with particular emphasis on wound healing, have been performed on planktonic bacteria. Our recent studies, however, strongly suggest that colonization of wounds involves bacteria in both the planktonic and biofilm modes of growth. The action of silver on mature in vitro biofilms of Pseudomonas aeruginosa, a primary pathogen of chronic infected wounds, was investigated. The results show that silver is very effective against mature biofilms of P. aeruginosa, but that the silver concentration is important. A concentration of 5-10 mug/mL silver sulfadiazine eradicated the biofilm whereas a lower concentration (1 mug/mL) had no effect. The bactericidal concentration of silver required to eradicate the bacterial biofilm was 10-100 times higher than that used to eradicate planktonic bacteria. These observations strongly indicate that the concentration of silver in currently available wound dressings is much too low for treatment of chronic biofilm wounds. It is suggested that clinicians and manufacturers of the said wound dressings consider whether they are treating wounds primarily colonized either by biofilm-forming or planktonic bacteria. PMID- 17696949 TI - EMMPRIN and fascin overexpression associated with clinicopathologic parameters of pancreatobiliary adenocarcinoma in Chinese people. AB - The aim of this study was to test whether expression of EMMPRIN and fascin correlates with clinicopathologic parameters of pancreatobiliary adenocarcinoma. Immunohistochemical analysis of EMMPRIN and fascin was performed in 100 surgical specimens obtained from Chinese patients, including 18 well-differentiated, 62 moderately differentiated, and 20 poorly differentiated pancreatic and biliary adenocarcinomas. Neither EMMPRIN nor fascin was detectable in normal pancreatic and biliary glandular epithelia. However, EMMPRIN and fascin immunoreactivity was observed on the cell membrane and within the cytoplasm in pancreatobiliary adenocarcinomas. Higher immunostaining scores of EMMPRIN and fascin were strongly associated with advanced grades of pancreatobiliary adenocarcinomas (36.1 and 51.3 for grade I, 95.5 and 110.1 for grade II, and 133.7 and 165.8 for grade III). In addition, higher immunostaining scores of EMMPRIN and fascin were associated with advanced T stages (29.8 and 43.6 for T1, 86.3 and 93.2 for T2, 107.6 and 117.6 for T3, and 129.5 and 156.5 for T4). Higher EMMPRIN and fascin scores were associated with shorter survival times and more advanced M and N stages of pancreatiobiliary adenocarcinomas. A higher expression of EMMPRIN and fascin was found to correlate well with histologic grades and clinical stages of pancreatobiliary adenocarcinomas. PMID- 17696950 TI - CD40/CD40L expression in leukocytes from chronic granulomatous disease patients. AB - Chronic granulomatous disease (CGD) is an inherited disorder caused by defects in the NADPH oxidase complex, which generates superoxide, the precursor of hydrogen peroxide (H(2)O(2)) and other reactive oxygen derivatives with microbicidal activity. Because CGD patients are at risk of chronic inflammatory manifestations, including inflammatory bowel disease and autoimmune diseases, and it is not clear whether these pathologies are exclusively secondary to altered superoxide production, or whether distinct immunologic defects are involved, we explored cell proliferation, lymphocyte cell counts, immunoglobulin levels, presence of autoimmune antibodies and expression of costimulatory molecules in leukocytes from CGD patients. We found that CGD patients have a diminished phytohemagglutinin-induced proliferation of blood mononuclear cells. Following stimulation with PMA plus ionomycin, a reduced percentage of CD40L expression in T lymphocytes and a diminished expression of CD40 molecules in neutrophils were observed on leukocytes from these patients. Our results suggest an altered interplay between elements of innate and adaptive immunity in CGD patients, which may be reflected in an increased susceptibility to opportunistic infections. PMID- 17696951 TI - Thymic stromal lymphopoietin augments the cytolytic activity of the human natural killer cell line NK-92. AB - Culturing the human natural killer cell line NK-92 for 24 h in the presence of thymic stromal lymphopoietin (TSLP) potentiated its cytotoxic capacity against the erythroleukemia cell line K562. Longer incubation times did not augment the NK activity any further. No synergistic effects with respect to either proliferation or cytotoxicity were observed when TSLP was mixed with suboptimal concentrations of IL-2. FACS analysis of the NK-92 cells indicated expression of TSLPR but not the other component of the TSLP receptor complex, namely IL 7Ralpha. Some of the surface molecules known to be involved in NK cell-mediated cytotoxicity were also monitored. None of the receptors analyzed altered their expression to any major extent upon culture in TSLP or IL-2. However, a limited number of NK-92 cells were observed that had a rather low CD94/NKG2A expression, which increased upon stimulation with TSLP or IL-2. PMID- 17696952 TI - Antibiotic susceptibility of blood culture isolates of anaerobic bacteria at a Norwegian university hospital. AB - In the present study the susceptibility of 200 blood culture isolates of anaerobic bacteria to benzylpenicillin, clindamycin, metronidazole, imipenem and piperacillin-tazobactam was examined. Metronidazole, imipenem, and piperacillin tazobactam showed the highest activity, with 98.5% of the isolates being fully susceptible to either agent. A high rate of reduced susceptibility to clindamycin among both Bacteroides spp. (37%) and Clostridium spp. (28%) was found. Almost all Bacteroides isolates were resistant to penicillin, and only 60% of Prevotella spp. were susceptible to this agent. The antibiotic susceptibility of anaerobic bacteria in Norway should be surveyed regularly. PMID- 17696953 TI - Search for evidence of recurring or persistent viruses in Crohn's disease. AB - New-onset Crohn's disease and acute flares are often associated with viral infections. The aim of this study was to search for evidence of persistent or recurrent viruses in patients. Tissue blocks were obtained from surgical specimens from patients and a control population. 111 samples were tested by PCR or RT-PCR, for EBV, CMV, HSV 1, HSV 2, HHV 8, pestiviruses, and enteroviruses. Additionally, seven sets of serum samples, including pre-operative and post operative samples, from CD patients were analyzed serologically for antibodies to EBV. The tests revealed evidence of EBV nucleic acid in tissues of 11 patients from a total of 70 tested (15.7%) and in tissues of 3 of 41 control subjects (7.3%). Evidence of pestivirus was found in one CD patient, while one patient and one control were positive for CMV. No HSV 1 or 2, HHV 8 or enteroviruses were found. The serologic tests revealed that five of seven CD patients had antibodies against the early protein, the capsid protein and the EBV nuclear antigen (EBNA). The titers were not significantly altered post-surgically. None of the patients had antibodies of the IgM isotype. Our findings vary from those of Ruther et al. who demonstrated evidence of EBV in tissues from 7 of 11 (64%) German CD patients. Antibodies to early EBV viral antigen and to nuclear antigen in five of seven Belgian patients suggest persistent active viral infection. PMID- 17696954 TI - Elevated matrilysin levels in bronchoalveolar lavage fluid do not distinguish idiopathic pulmonary fibrosis from other interstitial lung diseases. AB - Microarray studies have shown that matrilysin or matrix metalloproteinase (MMP)-7 is highly upregulated in the lungs of patients with idiopathic pulmonary fibrosis (IPF), but MMP-7 protein expression has not been systematically compared between IPF and other interstitial lung diseases. MMP-7 levels in bronchoalveolar lavage fluid (BALF) were compared to corresponding samples from nonspecific interstitial pneumonia (NSIP), sarcoidosis, and healthy controls. MMP-7 levels in the BALF were determined by ELISA and localization of MMP-7 in the lung tissue by immunohistochemistry. MMP-7 was similarly elevated in the BALF of all these disorders compared to healthy controls (p=0.007). Even control subjects with prolonged cough displayed a tendency towards elevated MMP-7 expression. There was a negative correlation between BALF MMP-7 levels and forced expiratory vital capacity (r=-0.348, p=0.02, n=42). In IPF lung, MMP-7 immunoreactivity appeared predominantly in the fibrotic parenchyma and arterial wall. In sarcoidosis and NSIP, prominent MMP-7 immunoreactivity was found in areas of inflammation. These results demonstrate that elevated BALF MMP-7 is not restricted to IPF alone but is also observed in other interstitial lung diseases and cannot be used as a differential diagnostic marker for IPF. PMID- 17696955 TI - Immunohistochemical analysis of phospho-BAD protein and mutational analysis of BAD gene in gastric carcinomas. AB - Mounting evidence indicates that deregulation of apoptosis contributes to the development of human cancers. BAD, a proapoptotic Bcl-2 family protein, regulates the intrinsic apoptosis pathway. The aim of this study was to explore whether alterations of phospho-BAD (p-BAD) protein that antagonizes apoptosis function of BAD and mutation of BAD gene are characteristics of human gastric cancers. We analyzed expression of p-BAD in 60 gastric adenocarcinomas by immunohistochemistry. Also, we analyzed BAD gene for detection of somatic mutations by single-strand conformation polymorphism (SSCP) assay. p-BAD expression was detected well in normal gastric mucosal epithelial cells, whereas it was detected in only 51% (31 of the 60) of the cancers. There was no somatic mutation of BAD gene in the 60 gastric cancer samples. The decreased expression of p-BAD in malignant gastric epithelial cells compared to normal mucosal epithelial cells suggested that loss of p-BAD expression may play a role in gastric tumorigenesis. The data also suggest that BAD mutation may not be a direct target of inactivation in gastric tumorigenesis. PMID- 17696956 TI - Deletion mutation of BRAF in a serrated adenoma from a patient with familial adenomatous polyposis. AB - BRAF gene mutations in the colorectum have been associated with serrated adenomas and less frequently with hyperplastic polyps, villous adenomas, tubular adenomas, and carcinomas. Most BRAF mutations in the colon have been reported as a V600E substitution. We report a case with a very rare deletion mutation of BRAF (c.1799 1801delTGA, p.Val600_Lys601delinsGlu) in a serrated adenoma; the patient has familial adenomatous polyposis with a germline mutation of the APC gene (c.3578delA, p.Gln1193ArgfsX1264). Genetic studies on fundic gland polyps and tubular adenomas from the same patient failed to demonstrate BRAF mutation. This case is the first reported with a deletion mutation of BRAF found in the colon. PMID- 17696957 TI - Statins: a perspective for left ventricular hypertrophy treatment. AB - Left ventricular hypertrophy (LVH), despite its adaptive nature, is associated with an increased risk of cardiovascular morbidity and mortality. Achievement of LVH regression is thus considered a principal therapeutic aim. However, regression of LVH induced by various therapeutic means may exhibit differing patterns, with variable biological implications. Inhibitors of 3-hydroxy-3 methylglutaryl coenzyme A reductase (statins) have been shown to induce prevention or regression of LVH in different models of pathological myocardial growth. In addition to reduction of LV mass, statins were shown to reduce myocardial fibrosis, increase capillary density network and attenuate electrical instability of the hypertrophied heart. Most importantly, statins improved systolic and diastolic LV function and even decreased mortality. The inhibition of hypertrophic growth was only partly achieved by reduction of haemodynamic overload. Direct mechanisms, such as inhibition of neurohumoral activation in the myocardial tissue, attenuated production of growth factors and markers of inflammation and reduction of oxidative stress also seem to participate. The protective effect of statins was associated with the inhibition of expression and activation of small guanosintriphosphate-binding proteins such as Ras and Rho, which control the intensity of oxidative stress, the production and availability of nitric oxide, and the expression of genes involved in myocardial growth. In addition to reduction of LV mass, statins may also improve the prognosis of LVH independently of their lipid-lowering effect. PMID- 17696958 TI - Fatty acid incorporation in endothelial cells and effects on endothelial nitric oxide synthase. AB - BACKGROUND: The nature of fatty acids provided by the diet as well as plasma lipid metabolism can modify the composition and properties of plasma membrane and thus the activity of membrane proteins. In humans, as well as in experimental models, diabetes is associated with both an alteration in serum lipid profile and a documented endothelial dysfunction. This in vitro study investigated on an immortalized human endothelial cell line (EA.hy 926) the specific effects of several free fatty acids (FFAs) on the composition of cellular membranes and the regulation of endothelial nitric oxide synthase (eNOS). MATERIALS AND METHODS: 0.1% of lipid deprived serum was added to the incubation medium with 25 mM glucose in order to study the effects of individual fatty acids: myristic acid, palmitic acid, stearic acid, oleic acid or linoleic acid at 100 microM bound with albumin. The effects of the FFAs on the endothelial nitric oxide synthase were investigated on mRNA level by quantitative PCR, on protein level and Ser1177 phosphorylation by Western blot and on enzymatic activity on living cells using radiolabelled arginine. RESULTS: Free linoleic acid increased the membrane content in n-6 fatty acids (mainly C18: n-6 and its metabolites) with a decrease in saturated and monounsaturated fatty acids. These conditions decreased the basal eNOS activity and reduced the phosphorylation of eNOS-Ser1177 due to activation by histamine. Free palmitic acid enriched the membranes with 16 : 0 with a slight decrease in monounsaturated fatty acids. These conditions increased eNOS activation without increasing Ser1177 phosphorylation upon histamine activation. The addition of the other FFAs also resulted in modifications of membrane composition, which did not to affect eNOS-Ser1177 phosphorylation. CONCLUSION: Among the fatty acids used, only modification of the membrane composition due to linoleic acid supply disturbed the basal enzymatic activity and Ser1177 phosphorylation of eNOS in a way that limited the role of histamine activation. Linoleic acid might involve the dysfunction of both eNOS basal activity and its phosphorylation status and may then contribute to an impaired vasodilatation in vivo. PMID- 17696959 TI - In vitro antiangiogenic activity of selective somatostatin subtype-1 receptor agonists. AB - BACKGROUND: Endothelial cells of human blood vessels (arteries and veins) show high levels of somatostatin subtype-1 receptor (sst(1)). The aim of the present study is to investigate the inhibitory effects of novel somatostatin analogs, highly selective for human sst(1), on in vitro angiogenesis and their modulation of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) expression. MATERIALS AND METHODS: Somatostatin analogs BIM-23745 and BIM-23926 were tested for their ability to prevent proliferation and migration of human endothelial HMEC-1 cells, to modulate VEGF and VEGFR-2 expression and to inhibit sprouting of microvessels from cultured human placental vessel explants in fibrin matrix for 28 days. RESULTS: The somatostatin sst(1 )receptor-selective agonists, BIM-23745 and BIM-23926 showed a suppression of endothelial proliferation (e.g. 10(-6) M BIM-23475, 40.0 +/- 2.1% vs. 100% of controls; 10(-7) M BIM-23926, 55.3 +/- 3.3% vs. 100% of controls), migration (e.g. 10(-7) M BIM-23475, 35.0 +/- 1.56% vs. 100% of controls; 10(-7) M BIM-23926, 53.7 +/- 1.77% vs. 100% of controls) and microvessel sprouting (e.g. 10(-8) M BIM-23475, 42.8 +/- 5.6% vs. 100% of controls; 10(-7) M BIM-23926, 17.2 +/- 11.8% vs. 100% of controls). A small but significant percentage of cells exposed to BIM-23745 and BIM-23926 for 24 h and for 72 h presented typical apoptotic morphology. Moreover, both the analogs significantly inhibit VEGF and VEGFR-2 gene expression in endothelial cells grown for 144 h in a fibrin matrix and the VEGF secretion in conditioned media. CONCLUSIONS: The inhibition of endothelial activities suggests potential therapeutic utility for administration of somatostatin sst(1 )receptor-selective agonists in the proliferative diseases involving angiogenesis. PMID- 17696960 TI - Pioglitazone shift circadian rhythm of blood pressure from non-dipper to dipper type in type 2 diabetes mellitus. AB - BACKGROUND: Insulin resistance significantly correlated with a non-dipper type of essential hypertension. Thiazolidinediones (TZD), oral hypoglycaemic agents that act as insulin sensitizers, have been demonstrated in multiple in vivo and in vitro studies to possess antihypertensive properties. This study examined the efficacy of TZD therapy with pioglitazone at transforming the circadian rhythms of blood pressure from a non-dipper to a dipper type. MATERIALS: We examined 31 patients with type 2 diabetes mellitus during both a baseline period and a period of treatment with pioglitazone. Patients received 15 mg day(-1) pioglitazone for four weeks and 30 mg day(-1) for 12 weeks. Twenty-four hour ambulatory blood pressure monitoring (ABPM) and laboratory data (blood tests for cardiovascular risk factors) were obtained at the beginning and end of the study. RESULTS: In non-dippers (n = 16), but not dippers (n = 15), we observed a significant interaction between pioglitazone therapy and nocturnal falls in systolic and diastolic blood pressure. This examination indicated that the magnitude of the nocturnal blood pressure fall was affected by pioglitazone therapy. In non dippers, but not dippers, a significant correlation was observed between the percent decrease in nocturnal BP and the homeostasis model assessment (HOMA) index (r = 0.774, P = 0.0007). CONCLUSIONS: The present study demonstrated that pioglitazone can restore the nocturnal BP declines in parallel to reductions in the HOMA index, suggesting that insulin resistance may play an important role in the genesis of circadian BP rhythms. TZD-based treatment may thus have the additional therapeutic advantage of reducing the risk of cardiovascular complications by transforming the circadian rhythm of BP. PMID- 17696961 TI - Association of oxidative stress and PON1 with LDL and HDL particle size in middle aged subjects. AB - BACKGROUND: Alterations in plasma lipoprotein subclass distributions affect atherosclerosis risk. Smaller, denser low-density lipoprotein (LDL) particles (sdLDL) are more susceptible to oxidation. In contrast, most of the protective effects of high-density lipoproteins (HDL) are attributable to larger particles. This study investigates the connection between LDL and HDL particle heterogeneity and oxidative stress, antioxidative defence (AOD) and paraoxonase (PON1) status in a healthy middle-aged Serbian population. MATERIALS AND METHODS: LDL and HDL particle sizes and subclass distributions were measured by gradient gel electrophoresis in 104 men and 103 women, aged 53 +/- 9.4 years. PON1 activities and PON1(Q192R) phenotypes were determined with paraoxon and diazoxon as substrates. The oxidative stress/AOD status was estimated by measuring malondialdehyde (MDA) and superoxide-anion (O2*(-)) levels and superoxide dismutase (SOD) activity. RESULTS: Subjects with sdLDL had significantly higher MDA (P < 0.001) and O2*(-)(P < 0.05) levels and greater diazoxonase (DZOase) activity (P < 0.05) compared to subjects with larger LDL particles. A high MDA concentration was a significant predictor of the sdLDL phenotype (P < 0.005). Increased levels of and MDA were associated with smaller HDL(3) subclass abundance. Reduced HDL particle size was associated with lower DZOase activity (P < 0.01). CONCLUSIONS: Even in the absence of symptoms of atherosclerosis, sdLDL particles are associated with increased oxidative stress, which may stimulate a compensatory rise in PON1 DZOase activity. Elevated oxidative stress may significantly affect HDL subclass distribution, resulting in the accumulation of smaller, denser HDL particles with diminished antioxidative capacity. PMID- 17696962 TI - High-dose versus low-dose esomeprazole-based triple therapy for Helicobacter pylori infection. AB - BACKGROUND: This prospective, randomized, controlled study was conducted to compare the efficacies of high-dose and low-dose esomeprazole-based triple therapies for Helicobacter pylori eradication in Taiwan. MATERIALS AND METHODS: From January 2004 to June 2006, 240 H. pylori-infected patients were randomly assigned to undergo high-dose (40 mg b.d.) or low-dose (40 mg o.d.) esomeprazole combined with clarithromycin (500 mg b.d.) and amoxicillin (1 g b.d.) for one week. Follow-up endoscopy was performed at eight weeks after the end of treatment to evaluate the response to therapy. RESULTS: Intention-to-treat analysis demonstrated no differences between eradication rates of high-dose and low-dose groups (92% vs. 90%, respectively, P > 0.05). Per-protocol analysis yielded comparable results (95% vs. 93%). Both groups exhibited similar frequencies of adverse events (13% vs. 11%) and drug compliance (96% vs. 93%). Multivariate analysis indicated that only good compliance (odds ratio: 10.3, 95% CI, 3.0-35.7) was an independent predictor of treatment success. CONCLUSIONS: This work demonstrates that low-dose esomeprazole-based triple therapy yields a similar eradication rate as high-dose esomeprazole-based therapy in Taiwan. Since the cost of the low-dose regime is lower than that of the high-dose regime, low-dose esomeprazole-based triple therapy can reasonably be recommended for the first line eradication of H. pylori for Taiwanese and probably most Asians. PMID- 17696963 TI - Lipid peroxidation and mucin secretagogue activity in bile of gallstone patients. AB - BACKGROUND: Chronic inflammation of the gallbladder wall and mucin hypersecretion are considered to be important factors in the pathogenesis of cholesterol gallstone disease. The aim of the study was to compare mucin concentration and mucin secretagogue activity with lipid peroxidation in gallbladder bile of patients with cholesterol or pigment stones. MATERIAL AND METHODS: We studied mucin concentration and, as a marker of lipid peroxidation, malondialdehyde concentration in 11 rapid (1 to 3 days) and eight non-nucleating (> 21 days) gallbladder biles of patients with cholesterol or pigment stones. Furthermore, the mucin secretagogue activity of rapid and non-nucleating gallbladder biles, as well as 1-5 micromol L(-1) malondialdehyde on cultured gallbladder epithelial cells, was determined. RESULTS: Our data show an increased malondialdehyde (7.2 +/- 1.8 vs. 3.8 +/- 0.5 micromol L(-1), P = 0.01) and mucin concentration (0.9 +/ 0.09 vs. 0.41 +/- 0.03 mg mL(-1), P = 0.01) and an increased mucin secretagogue activity (2.0 +/- 0.5 vs. 1.1 +/- 0.3 mucin secretion/control, P = 0.04) and cholesterol saturation index (1.2 +/- 0.1 vs. 08 +/- 0.1, P = 0.04) in rapid as compared to non-nucleating gallbladder biles. Malondialdehyde stimulated mucin secretion of cultured gallbladder epithelial cells in a concentration dependent manner. CONCLUSIONS: Our results support a promoting effect of gallbladder mucin hypersecretion by lipid peroxidation leading to rapid formation of cholesterol crystals in gallbladder bile. These findings suggest that besides hypersecretion of cholesterol in bile, chronic inflammation of the gallbladder wall is implicated in the pathogenesis of cholesterol gallstone disease. PMID- 17696964 TI - Increased voluntary exercise in mice deficient for tumour necrosis factor-alpha and lymphotoxin-alpha. AB - BACKGROUND: The endogenous mediators playing a role in the sensing of fatigue and cessation of exercise are yet to be characterized. We hypothesized that proinflammatory cytokines, in particular tumour necrosis factor-alpha (TNFalpha) and lymphotoxin-alpha (LT) transmit signals leading to fatigue. MATERIALS AND METHODS: Mice were placed in a cage with a freely rotating exercise wheel and allowed to adapt for 24 h. The running distance was measured for two additional periods of 24 h. The effects of the administration of intravenous anti-TNF antibodies, intracerebral recombinant TNF, or intravenous lipopolysaccharide (LPS) were also determined. RESULTS: Compared to normal littermates, the voluntary daily running distance was 1.8-fold greater in mice with a disruption of the gene for TNFalpha, and 3-fold greater in mice with a gene disruption for both TNFalpha and LT. Intravenous administration of a monoclonal antibody against murine TNFalpha did not affect the running distance of wild-type mice, whereas administration of TNF intracerebrally reduced by 4-fold the voluntary running distance of the animals. This demonstrates that fatigue is mediated by TNFalpha expressed in the central nervous system (CNS) and not by increased peripheral TNFalpha concentrations. TNFalpha and LT are strong inducers of prostaglandins, but mice with disrupted prostaglandin or prostacyclin receptors exhibited running distances not significantly different from their wild-type littermates. Thus, signalling molecules other than prostaglandins mediate the effect of TNFalpha and LT on exercise capacity. CONCLUSIONS: Our finding that exercise capacity is controlled by TNFalpha is the first to define the endogenous mediators of fatigue, and may have important implications for diseases with impaired exercise tolerance. PMID- 17696965 TI - Increased TNF-alpha production by peripheral blood mononuclear cells in patients with Krabbe's disease: effect of psychosine. AB - BACKGROUND: Inflammatory and/or immune activation occurs both in animal models (twitcher mice) and in the brain of patients with Globoid cell leukodystrophy (GLD) or Krabbe's disease (KD). In this study we evaluated in vitro the cytokine profile of KD patients and the effect of psychosine, the toxic metabolite which plays a role in the demyelination process in these patients. MATERIALS AND METHODS: We studied cytokine production by peripheral blood mononuclear cells (PBMCs) isolated from four KD patients, diagnosed on the basis of clinical criteria. Cells were cultured and stimulated with appropriate agents and the supernatants collected before and after the addition of psychosine. Tumour necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8) and monocyte chemoattractant factor (MCP)-1) production was evaluated (ELISA method) and compared with a group of 10 normal subjects. RESULTS: We found a significant increase of TNF-alpha release by PBMCs of KD patients compared with healthy subjects; TNF-alpha production was significantly increased after LPS addition. Psychosine was able to induce a further significant increase (P < 0.05) only in cells obtained from KD patients and not from control subjects. No changes were found in IL-8 and MCP-1 production. CONCLUSIONS: The increased TNF-alpha production permits us to confirm the presence of an inflammatory-immune stimulus in KD patients, which may be induced and potentiated by the pathogenetic metabolite psychosine. PMID- 17696966 TI - Documentation of the nasal nitric oxide response to humming: methods evaluation. AB - RATIONALE: Nitric oxide (NO) is present at higher concentrations in the nasal cavity than in the lower airway, and at even higher concentrations within the paranasal sinuses proper. When the paranasal sinus ostia are patent, acoustic activity produced by vocalization with closed lips (humming) promotes mixing of sinus with nasal gases, producing a further increase in nasal NO. We wished to evaluate procedures for the documentation of the nasal NO response to humming. MATERIALS AND METHODS: We compared two ATS-recommended sampling methods: 1) active exhalation of lower airway gas (parallel technique) and 2) passive aspiration of nasal gas with closed velopharynx (series technique). Variables controlled for included sampling rate, external resistance (parallel method), humming frequency, humming duration, and intertrial interval. Prior to upper airway sampling, exhaled lower airway NO was determined utilizing ATS standardized technique. RESULTS: Ten volunteers (seven males and three females, aged 21-58) with no history of respiratory allergies or sino-nasal disease were studied in a single session each. The parallel technique documented an increase in nasal NO during the humming manoeuvre in all subjects (mean ratio of humming to-quiet NO, 4.2), whereas the series technique did so in eight of 10 subjects (mean ratio 2.1). Correcting for admixture from the lower airway, the ratio of humming-to-quiet NO was greater with the parallel than series sampling technique (P < 0.05). CONCLUSIONS: Documentation of the response of nasal NO to humming in subjects without sino-nasal disease was consistently achievable by parallel sampling using commercially available equipment. Specific operational procedures are proposed. PMID- 17696967 TI - Localization of vacuolar transport receptors and cargo proteins in the Golgi apparatus of developing Arabidopsis embryos. AB - Using immunogold electron microscopy, we have investigated the relative distribution of two types of vacuolar sorting receptors (VSR) and two different types of lumenal cargo proteins, which are potential ligands for these receptors in the secretory pathway of developing Arabidopsis embryos. Interestingly, both cargo proteins are deposited in the protein storage vacuole, which is the only vacuole present during the bent-cotyledon stage of embryo development. Cruciferin and aleurain do not share the same pattern of distribution in the Golgi apparatus. Cruciferin is mainly detected in the cis and medial cisternae, especially at the rims where storage proteins aggregate into dense vesicles (DVs). Aleurain is found throughout the Golgi stack, particularly in the trans cisternae and trans Golgi network where clathrin-coated vesicles (CCVs) are formed. Nevertheless, aleurain was detected in both DV and CCV. VSR-At1, a VSR that recognizes N-terminal vacuolar sorting determinants (VSDs) of the NPIR type, localizes mainly to the trans Golgi and is hardly detectable in DV. Receptor homology-transmembrane-RING H2 domain (RMR), a VSR that recognizes C-terminal VSDs, has a distribution that is very similar to that of cruciferin and is found in DV. Our results do not support a role for VSR-At1 in storage protein sorting, instead RMR proteins because of their distribution similar to that of cruciferin in the Golgi apparatus and their presence in DV are more likely candidates. Aleurain, which has an NPIR motif and seems to be primarily sorted via VSR-At1 into CCV, also possesses putative hydrophobic sorting determinants at its C terminus that could allow the additional incorporation of this protein into DV. PMID- 17696969 TI - Anatomical and experimental studies of brachial plexus, sciatic, and femoral nerve-location using peripheral nerve stimulation in the dog. AB - OBJECTIVE: To investigate the anatomy of the brachial plexus, sciatic, and femoral nerves for the use of a peripheral nerve-stimulator to perform nerve blocks in dogs. STUDY DESIGN: Prospective experimental trial. ANIMALS: Four canine cadavers and four healthy adult dogs weighing 23 +/- 2.5 kg. METHODS: Phase I: in four canine cadavers, an anatomical study was conducted to evaluate accurate needle-insertion techniques. Phase II: the utility of these techniques, and the value of electrostimulation, were evaluated in four anesthetized dogs in lateral recumbency (medetomidine, 5 microg kg(-1)/ketamine 5 mg kg(-1)) using an electrical stimulator and shielded needles. RESULTS: For the brachial plexus, the needle was inserted cranial to the acromion, medial to the subscapularis muscle, at an angle of approximately 20-30 degrees in relation to a plane vertical to the surface on which the animal was lying, oriented parallel to the long axis of the animal, in a ventro-caudal direction. For the sciatic nerve, the needle was inserted just cranial to the sacrotuberous ligament, through the gluteus superficialis muscle, at an angle of approximately 60 degrees in relation to the horizontal plane, in a ventro-cranial direction, and up to the level of the ischium. For the femoral nerve, the needle was inserted perpendicular to the skin, just cranial to the femoral artery, and directed a little caudally. Using a peripheral nerve-stimulator, all nerves were located, and muscle contractions were elicited at a current of 0.2-0.4 mA. No complications were observed during the procedures. CONCLUSION: Electrostimulation of peripheral nerves is useful in locating the branches of the brachial plexus as well as the sciatic and femoral nerves in dogs. CLINICAL RELEVANCE: Peripheral nerve stimulation increases the reliability of a nerve block when compared with blind needle-insertion. PMID- 17696968 TI - PalC, one of two Bro1 domain proteins in the fungal pH signalling pathway, localizes to cortical structures and binds Vps32. AB - PalC, distantly related to Saccharomyces cerevisiae peripheral endosomal sorting complexes required for transport III (ESCRT-III) component Bro1p and one of six Aspergillus nidulans pH signalling proteins, contains a Bro1 domain. Green fluorescent protein (GFP)-tagged PalC is recruited to plasma membrane-associated punctate structures upon alkalinization, when pH signalling is active. PalC recruitment to these structures is dependent on the seven transmembrane domain (7 TMD) receptor and likely pH sensor PalH. PalC is a two-hybrid interactor of the ESCRT-III Vps20/Vps32 subcomplex and binds Vps32 directly. This binding is largely impaired by Pro439Phe, Arg442Ala and Arg442His substitutions in a conserved region mediating interaction of Bro1p with Vps32p, but these substitutions do not prevent cortical punctate localization, indicating Vps32 independence. In contrast, Arg442Delta impairs Vps32 binding and prevents PalC GFP recruitment to cortical structures. pH signalling involves a plasma membrane complex including the 7-TMD receptor PalH and the arrestin-like PalF and an endosomal membrane complex involving the PalB protease, the transcription factor PacC and the Vps32 binding, Bro1-domain-containing protein PalA. PalC, which localizes to cortical structures and can additionally bind a component of ESCRT III, has the features required to bridge these two entities. A likely S. cerevisiae orthologue of PalC has been identified, providing the basis for a unifying hypothesis of gene regulation by ambient pH in ascomycetes. PMID- 17696970 TI - Effect of butorphanol administration on cardiovascular parameters in isoflurane anesthetized horses - a retrospective clinical evaluation. AB - OBJECTIVE: To determine cardiovascular responses to administration of butorphanol in isoflurane-anesthetized horses. STUDY DESIGN: Retrospective evaluation of anesthetic records. ANIMALS: Seventy-six horses anesthetized for a variety of clinical surgical procedures. METHODS: Anesthetic records of clinical equine patients anesthetized between January 1999 and December 2003 were searched. The records were reviewed for horses in which anesthesia was induced with ketamine and a benzodiazepine and maintained with isoflurane, and horses that received butorphanol intraoperatively. Exclusion criteria included horses in which the rate of infusion of an inotrope or end-tidal isoflurane concentration was changed 10 minutes before or after the butorphanol bolus. The horses were separated into two groups: group 1 horses received butorphanol at intervals as part of a balanced protocol, group 2 horses had > or = 10% increase in heart rate (HR) or blood pressure within 10 minutes prior to butorphanol administration. RESULTS: Eighty-nine butorphanol administration events matched the criteria for inclusion, 49 in group 1 and 40 in group 2. There were no significant changes after butorphanol administration in systolic arterial pressure (SAP), mean arterial pressure (MAP), diastolic arterial pressure (DAP), and heart rate (HR) in group 1, or in end-tidal carbon dioxide concentration or hemoglobin oxygen saturation in either group. There were significant decreases in SAP (p < 0.0001), MAP (p < 0.0005), and DAP (p < 0.0008) after butorphanol administration in group 2. CONCLUSIONS AND CLINICAL RELEVANCE: The results presented here confirm that butorphanol can be administered to horses during isoflurane anesthesia without adverse effects on HR and arterial blood pressure. The results imply that butorphanol can deepen the plane of anesthesia and obtund sympathetic stimulation from a surgical procedure. PMID- 17696971 TI - Lack of systemic absorption of lidocaine from 5% patches placed on horses. AB - OBJECTIVE: To measure concentrations of lidocaine serum after application of two 5% patches on horses. STUDY DESIGN: Prospective experimental trial ANIMALS: Six client-owned, systemically healthy horses. METHODS: The hair was clipped on the medial aspect above the carpus of both fore limbs and 2 patches of 5% lidocaine were applied within 30 minutes of jugular catheter placement and the area was then bandaged. Venous blood was drawn from a jugular vein catheter that was inserted using lidocaine as a local block. Samples were drawn immediately before and at 2, 4, 6, 8, and 12 hours after patch application. The presence of lidocaine in serum was determined using an ELISA test. RESULTS: Lidocaine was detected in the serum of three horses at 0 hours immediately following the local block for catheter placement. Lidocaine was not detected at any other time from 2 to 12 hours. There was mild erythema at the site of patch placement at 12 hours in one horse but this resolved within 1 hour of patch removal. There were no other apparent adverse effects from the patches on any other horse. CONCLUSION: Five percent lidocaine patches applied proximally to the carpus did not result in detectable systemic concentrations of lidocaine. CLINICAL RELEVANCE: Any analgesic effects that might be produced by application of 5% lidocaine patches on horses will not be due to systemic absorption of the drug. PMID- 17696972 TI - Electroacupuncture analgesia in dogs: is there a difference between uni- and bi lateral stimulation? AB - OBJECTIVE: To compare the analgesic effect of uni- and bi-lateral electroacupuncture (EA) in response to thermal and mechanical nociceptive stimuli and to investigate the cardiorespiratory, endocrine, and behavioral changes in dogs submitted to EA. STUDY DESIGN: Prospective, randomized cross-over experimental study. ANIMALS: Eight adult, clinically healthy, cross-breed dogs, weighing 13 +/- 4 kg. METHODS: Dogs underwent electrostimulation at false acupoints (T-false); bilateral EA at acupoints, stomach 36, gall bladder 34 and spleen 6 (T-EA/bil); unilateral EA at the same points (T-EA/uni) or were untreated (T-control). All animals received acepromazine (0.05 mg kg(-1)) IV; and heart rate, pulse oximetry, indirect arterial blood pressure, respiratory rate, Pe'CO(2), rectal temperature, and plasma cortisol concentration were measured before, during, and after EA. Analgesia was tested using thoracic and abdominal cutaneous thermal and mechanical stimuli, and an interdigital thermal stimulus. Behavior was classified as calm or restless. Analysis of variance for repeated measures followed by Tukey's test was used for analysis of the data. RESULTS: There were no cardiorespiratory differences among the treatments. The cutaneous pain threshold was higher after EA, compared with false points. The latency period was shorter and analgesia was more intense in T-EA/bil than T-EA/uni, when both were compared with T-false and T-control. Six out of eight animals treated with EA were calm during treatment, and 5/8 and 4/8 of the T-false and T-control animals, respectively, were restless. Latency to interdigital thermal stimulation increased in T-EA/bil compared with the others. There was no difference in plasma cortisol concentrations among the treatments. CONCLUSIONS: Bilateral EA produced a shorter latency period, a greater intensity, and longer duration of analgesia than unilateral stimulation, without stimulating a stress response. CLINICAL RELEVANCE: Bilateral EA produces a better analgesic effect than unilateral EA. PMID- 17696973 TI - Clinical evaluation of the Surgivet V60046, a non invasive blood pressure monitor in anaesthetized dogs. AB - OBJECTIVE: To compare the performance of the Surgivet Non-Invasive Blood Pressure (NIBP) monitor V60046 with an invasive blood pressure (IBP) technique in anaesthetized dogs. STUDY DESIGN: A prospective study. ANIMALS: Thirty-four dogs, anaesthetized for a variety of procedures. METHODS: Various anaesthetic protocols were used. Invasive blood pressure measurement was made using a catheter in the femoral or the pedal artery. A cuff was placed on the contralateral limb to allow non invasive measurements. Recordings of arterial blood pressures (ABPs) were taken at simultaneous times for a range of pressures. For analysis, three pressure levels were determined: high [systolic blood pressure (SAP) > 121 mmHg], normal (91 mmHg < SAP < 120 mmHg) and low (SAP < 90 mmHg). Comparisons between invasive and non invasive measurements were made using Bland-Altmann analysis. RESULTS: The NIBP monitor consistently underestimated blood pressure at all levels. The lowest biases and greatest precision were obtained at low and normal pressure levels for SAP and mean arterial pressure (MAP). At low blood pressure levels, the biases +/- 95% confidence interval (CI) were 1.9 +/- 2.96 mmHg (SAP), 8.3 +/- 2.41 mmHg diastolic arterial pressure (DAP) and 3.5 +/- 2.09 mmHg (MAP). At normal blood pressure levels, biases and CI were: 1.2 +/- 2.13 mmHg (SAP), 5.2 +/- 2.32 mmHg (DAP) and 2.1 +/- 1.54 mmHg (MAP). At high blood pressure levels, the biases and CI were 22.7 +/- 5.85 mmHg (SAP), 5.5 +/- 3.13 mmHg (DAP) and 9.4 +/- 3.52 mmHg (MAP). In 90.6% of cases of hypotension (MAP < 70 mmHg), the low blood pressure was correctly diagnosed by the Surgivet. CONCLUSIONS: Measurement of blood pressure with the indirect monitor allowed detection of hypotension using either SAP or MAP. The most accurate readings were determined for MAP at hypotensive and normal levels. The monitor lacked accuracy at high pressures. CLINICAL RELEVANCE: When severe challenges to the cardiovascular system are anticipated, an invasive method of recording ABP is preferable. For routine usage, the Surgivet monitor provided a reliable and safe method of NIBP monitoring in dogs, thereby contributing to the safety of anaesthesia by providing accurate information about the circulation. PMID- 17696974 TI - Cardiovascular effects of enoximone in isoflurane anaesthetized ponies. AB - OBJECTIVE: Enoximone is a phosphodiesterase III inhibitor frequently used to improve cardiac output (CO) in man. As the use of enoximone has not been reported in horses, the effects of this inodilator were examined in isoflurane anaesthetized ponies. STUDY DESIGN: Prospective, randomised, experimental study. ANIMALS: Six healthy ponies, weighing 286 (212-367) +/- 52 kg, aged 5.0 +/- 1.6 years (4-6.5). METHODS: After sedation with romifidine [80 microg kg(-1) intravenously (IV)], general anaesthesia was induced with midazolam (0.06 mg kg( 1) IV) and ketamine (2.2 mg kg(-1) IV) and maintained with isoflurane in oxygen (Et Iso 1.7%). The ponies were ventilated to maintain eucapnia (PaCO(2) 4.66-6.00 kPa). Each pony was anaesthetized twice with an interval of 3 weeks; receiving enoximone 0.5 mg kg(-1) IV (E) or saline (S) 90 minutes post-induction. Heart rate (HR), arterial (AP) and right atrial pressure (RAP) were measured before treatment, every 5 minutes between T0 (treatment) and T30 and then every 10 minutes until T120. Cardiac output measurements (lithium dilution technique) and blood gas analysis (arterial and central venous samples) were performed before T0 and at T5, T10, T20, T40, T60, T80, T100 and T120. Stroke volume (SV), systemic vascular resistance (SVR), venous admixture (Qs/Qt) and oxygen delivery (DO(2)) were calculated. RESULTS: Enoximone induced significant increases in HR, CO, SV, Qs/Qt and DO(2) and a significant decrease in RAP. No significant differences were detected for AP, SVR and blood gases. No cardiac arrhythmias or other side effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE: The present results suggest that in isoflurane anaesthetized ponies, enoximone has beneficial effects on CO and SV without producing significant changes in blood pressure. Despite an increase in Qs/Qt, DO(2) to the tissues was improved. PMID- 17696975 TI - Plasma colloid osmotic pressure and total protein in horses during colic surgery. AB - OBJECTIVE: To assess the changes in colloid osmotic pressure (COP) in horses undergoing surgery for colic. STUDY DESIGN: Prospective clinical evaluation. ANIMALS: Twenty-nine adult horses presented for emergency laparotomy. METHODS: Horses were premedicated with intravenous (IV) xylazine and anesthesia was induced with ketamine, diazepam and guaifenesin and was maintained with isoflurane as required. Lactated Ringer's solution (LRS) was given to all horses during anesthesia. Blood was collected in heparin before, and every 30 minutes during, anesthesia to measure COP, total protein concentration (TP), osmolality, packed cell volume, electrolytes, glucose and lactate. In addition, COP was estimated using different formulas previously described for horses. RESULTS: Before anesthesia, COP and TP were 18.7 +/- 2.2 mmHg (2.49 +/- 0.29 kPa) and 6.3 +/- 0.7 g dL(-1), respectively. The horses received a mean +/- SD of 19.5 +/- 3.9 mL kg(-1) hour(-1) (range 15-25 mL kg(-1)hour(-1)) of LRS during anesthesia. The COP and TP decreased linearly (R(2) = 0.99, p < 0.01) during anesthesia and reached the lowest point at the end of anesthesia with a COP of 11.6 +/- 1.6 mmHg (1.55 +/- 0.21 kPa) and TP of 4.4 +/- 0.4 g dL(-1). The Pearson correlation coefficient for COP versus TP was r(2) = 0.78. Calculation of COP from TP concentrations showed that two formulas could predict COP to within 1 mmHg (0.13 kPa) (Thomas & Brown 1992; Boscan et al. 2007). CONCLUSIONS AND CLINICAL RELEVANCE: Colloid osmotic pressure, like TP, decreased greatly over the course of crystalloid fluid infusion during anesthesia for laparotomy in horses with colic. This change may predispose the animal to tissue edema with subsequent morbidity. PMID- 17696976 TI - The cardiopulmonary effects of dobutamine and norepinephrine in isoflurane anesthetized foals. AB - OBJECTIVE: To evaluate the cardiovascular effects of norepinephrine (NE) and dobutamine (DB) in isoflurane-anesthetized foals. STUDY DESIGN: Prospective laboratory study. METHODS: Norepinephrine (0.05, 0.10, 0.20, and 0.40 microg kg( 1) minute(-1)) and dobutamine (2.5, 5.0, and 10 microg kg(-1) minute(-1)) were alternately administered to seven healthy, 1- to 2-week-old isoflurane anesthetized foals. Arterial and pulmonary arterial blood pressure, right atrial pressure, pulmonary artery occlusion pressure, heart rate, body temperature, cardiac output, arterial and mixed venous blood pH, partial pressure of carbon dioxide, partial pressure of oxygen [arterial partial pressure of oxygen (PaO(2)) and mixed venous partial pressure of oxygen (PvO(2))], and packed cell volume were measured. Standard base excess, bicarbonate concentration, systemic and pulmonary vascular resistance, cardiac index (CI), stroke volume, left and right stroke work indices, oxygen delivery (DO(2)), consumption, and extraction were calculated. Results Norepinephrine infusion resulted in significant increases in arterial and pulmonary arterial pressure, systemic and pulmonary vascular resistance indices, and PaO(2); heart rate was decreased. Dobutamine infusion resulted in significant increases in heart rate, stroke volume index, CI, and arterial and pulmonary arterial blood pressure. Systemic and pulmonary vascular resistance indices were decreased while the ventricular stroke work indices increased. The PaO(2) decreased while DO(2) and oxygen consumption increased. Oxygen extraction decreased and PvO(2) increased. CONCLUSIONS AND CLINICAL RELEVANCE: Norepinephrine primarily augments arterial blood pressure while decreasing CI. Dobutamine primarily augments CI with only modest increases in arterial blood pressure. Both NE and DB could be useful in the hemodynamic management of anesthetized foals. PMID- 17696977 TI - Chemical composition of the epicuticular and intracuticular wax layers on the adaxial side of Ligustrum vulgare leaves. AB - Previous research has shown that cuticular triterpenoids are exclusively found in the intracuticular wax layer of Prunus laurocerasus. To investigate whether this partitioning was species-specific, the intra- and epicuticular waxes were identified and quantified for the glossy leaves of Ligustrum vulgare, an unrelated shrub with similar wax morphology. Epicuticular wax was mechanically stripped from the adaxial leaf surface using the adhesive gum arabic. Subsequently, the organic solvent chloroform was used to extract the intracuticular wax from within the cutin matrix. The isolated waxes were quantified using gas chromatography with flame ionization detection and identified by mass spectrometry. The results were visually confirmed by scanning electron microscopy. The outer wax layer consisted entirely of homologous series of very-long-chain aliphatic compound classes. By contrast, the inner wax layer was dominated (80%) by two cyclic triterpenoids, ursolic and oleanolic acid. The accumulation of triterpenoids in the intracuticular leaf wax of a second, unrelated species suggests that this localization may be a more general phenomenon in smooth cuticles lacking epicuticular wax crystals. The mechanism and possible ecological or physiological reasons for this separation are currently being investigated. PMID- 17696978 TI - Microarray analysis of transcriptional responses to abscisic acid and osmotic, salt, and drought stress in the moss, Physcomitrella patens. AB - Dehydration tolerance was an adaptive trait necessary for the colonization of land by plants, and remains widespread among bryophytes: the nearest extant relatives of the first land plants. A genome-wide analysis was undertaken of water-stress responses in the model moss Physcomitrella patens to identify stress responsive genes. An oligonucleotide microarray was used for transcriptomic analysis of Physcomitrella treated with abscisic acid (ABA), or subjected to osmotic, salt and drought stress. Bioinformatic analysis of the Physcomitrella genome identified the responsive genes, and a number of putative stress-related cis-regulatory elements. In protonemal tissue, 130 genes were induced by dehydration, 56 genes by ABA, but only 10 and eight genes, respectively, by osmotic and salt stress. Fifty-one genes were induced by more than one treatment. Seventy-six genes, principally encoding chloroplast proteins, were drought down regulated. Many ABA- and drought-responsive genes are homologues of angiosperm genes expressed during drought stress and seed development. These ABA- and drought-responsive genes include those encoding a number of late embryogenesis abundant (LEA) proteins, a 'DREB' transcription factor and a Snf-related kinase homologous with the Arabidopsis ABA signal transduction component 'OPEN STOMATA 1'. Evolutionary capture of conserved stress-regulatory transcription factors by the seed developmental pathway probably accounts for the seed-specificity of desiccation tolerance among angiosperms. PMID- 17696979 TI - Identification of quantitative trait loci influencing foliar concentrations of terpenes and formylated phloroglucinol compounds in Eucalyptus nitens. AB - Leaves of eucalypt species contain a variety of plant secondary metabolites, including terpenoids and formylated phloroglucinol compounds (FPCs). Both terpene and FPC concentrations are quantitative traits that can show large variation within a population and have been shown to be heritable. The molecular genetic basis of this variation is currently unknown. Progeny from a field trial of a three-generation mapping pedigree of Eucalyptus nitens were assayed for terpenes and FPCs. Quantitative trait loci (QTL) analyses were conducted using a map constructed from 296 markers to locate regions of the genome influencing foliar concentrations of these plant secondary compounds. A large number of significant QTL for 14 traits were located across nine linkage groups, with significant clustering of QTL on linkage groups 7, 8 and 9. As expected, QTL for biosynthetically related compounds commonly colocated, but QTL for unrelated monterpenes and FPCs also mapped closely together. Colocation of these QTL with mapped candidate genes from the various biosynthetic pathways, and subsequent use of these genes in association mapping, will assist in determining the causes of variation in plant secondary metabolites in eucalypts. PMID- 17696980 TI - Pathways of infection of Brassica napus roots by Leptosphaeria maculans. AB - Infection of Brassica napus cotyledons and leaves by germinating ascospores of Leptosphaeria maculans leads to production of leaf lesions followed by stem cankers (blackleg). Leptosphaeria maculans also causes root rot but the pathway of infection has not been described. An L. maculans isolate expressing green fluorescent protein (GFP) was applied to the petiole of B. napus plants. Hyphal growth was followed by fluorescence microscopy and by culturing of sections of plant tissue on growth media. Leptosphaeria maculans grew within stem and hypocotyl tissue during the vegetative stages of plant growth, and proliferated into the roots within xylem vessels at the onset of flowering. Hyphae grew in all tissues in the stem and hypocotyl, but were restricted mainly to xylem tissue in the root. Leptosphaeria maculans also infected intact roots when inoculum was applied directly to them and hyphae entered at sites of lateral root emergence. Hyphal entry may occur at other sites but the mechanism is uncertain as penetration structures were not observed. Infection of B. napus roots by L. maculans can occur via above- and below-ground sources of inoculum, but the relative importance of the infection pathways under field conditions is unknown. PMID- 17696981 TI - Leaf photoacclimatory responses of the tropical seagrass Thalassia testudinum under mesocosm conditions: a mechanistic scaling-up study. AB - Here, the leaf photoacclimatory plasticity and efficiency of the tropical seagrass Thalassia testudinum were examined. Mesocosms were used to compare the variability induced by three light conditions, two leaf sections and the variability observed at the collection site. The study revealed an efficient photosynthetic light use at low irradiances, but limited photoacclimatory plasticity to increase maximum photosynthetic rates (P(max)) and saturation (E(k)) and compensation (E(c)) irradiances under high light irradiance. A strong, positive and linear association between the percentage of daylight hours above saturation and the relative maximum photochemical efficiency (F(V)/F(M)) reduction observed between basal and apical leaf sections was also found. The results indicate that T. testudinum leaves have a shade-adapted physiology. However, the large amount of heterotrophic biomass that this seagrass maintains may considerably increase plant respiratory demands and their minimum quantum requirements for growth (MQR). Although the MQR still needs to be quantified, it is hypothesized that the ecological success of this climax species in the oligotrophic and highly illuminated waters of the Caribbean may rely on the ability of the canopy to regulate the optimal leaf light environment and the morphological plasticity of the whole plant to enhance total leaf area and to reduce carbon respiratory losses. PMID- 17696982 TI - Attitudes of health sciences faculty members towards interprofessional teamwork and education. AB - OBJECTIVES: Faculty attitudes are believed to be a barrier to successful implementation of interprofessional education (IPE) initiatives within academic health sciences settings. The purpose of this study was to examine specific attributes of faculty members, which might relate to attitudes towards IPE and interprofessional teamwork. METHODS: A survey was distributed to all faculty members in the medicine, nursing, pharmacy and social work programmes at our institution. Respondents were asked to rate their attitudes towards interprofessional health care teams, IPE and interprofessional learning in an academic setting using scales adopted from the peer-reviewed literature. Information on the characteristics of the respondents was also collected, including data on gender, prior experience with IPE, age and years of practice experience. RESULTS: A total response rate of 63.0% was achieved. Medicine faculty members reported significantly lower mean scores (P < 0.05) than nursing faculty on attitudes towards IPE, interprofessional teams and interprofessional learning in the academic setting. Female faculty and faculty who reported prior experience in IPE reported significantly higher mean scores (P < 0.05). Neither age, years of practice experience nor experience as a health professional educator appeared to be related to overall attitudinal responses towards IPE or interprofessional teamwork. CONCLUSIONS: The findings have implications for both the advancement of IPE within academic institutions and strategies to promote faculty development initiatives. In terms of IPE evaluation, the findings also highlight the importance of measuring baseline attitudinal constructs as part of systematic evaluative activities when introducing new IPE initiatives within academic settings. PMID- 17696983 TI - Does ultrasound training boost Year 1 medical student competence and confidence when learning abdominal examination? AB - OBJECTIVES: Learning to perform physical examination of the abdomen is a challenge for medical students. Medical educators need to find engaging, effective tools to help students acquire competence and confidence in abdominal examination techniques. This study evaluates the added value of ultrasound training when Year 1 medical students learn abdominal examination. METHODS: The study used a randomised trial with a wait-list control condition. Year 1 medical students were randomised into 2 groups: those who were given immediate ultrasound training, and those for whom ultrasound training was delayed while they received standard instruction on abdominal examination. Standardised patients (SPs) used a clinical skills assessment (CSA) checklist to assess student abdominal examination competence on 2 occasions - CSA-1 and CSA-2 - separated by 8 weeks. Students also estimated SP liver size for comparison with gold-standard ultrasound measurements. Students completed skills confidence surveys. RESULTS: Proficiency in abdominal examination technique acquired from traditional instruction boosted with ultrasound training showed no advantage at CSA-1. However, at CSA-2 the delayed ultrasound training group showed significant improvement. Students uniformly underestimated SP liver sizes and the estimates were not affected by ultrasound training. Student confidence in both groups improved from baseline to CSA-1 and CSA-2. CONCLUSIONS: Ultrasound training as an adjunct to traditional means of teaching abdominal examination improves students' physical examination technique after students have acquired skills with basic examination manoeuvres. PMID- 17696984 TI - Assessing the relationship between peer and facilitator evaluations in case-based learning. AB - OBJECTIVES: Attempts to validate peer evaluation and to incorporate it into the curriculum have met with mixed results. The purpose of this study was to assess the use of peer evaluations in a Year 1 case-based learning course. METHODS: As part of the formal grading process for the course, all faculty facilitators (n = 69 over 3 years) completed a 12-item evaluation form for each student at the conclusion of each case. As part of a course assignment, students (n = 415 over 3 years) completed brief evaluations of their peers based on 2 criteria: the overall quality of written reports, and participation in group discussion. In addition, students provided anonymous feedback in the written end-of-course evaluation about the peer evaluation process, and faculty were asked to comment during the wrap-up luncheon for small-group facilitators. RESULTS: Response rates for the 3 Year 1 medical student classes ranged from 95% to 99%. The average number of peer evaluations completed for each student was 4.6. The G coefficients for the rater-nested-within-person generalisability study were 0.52 for written reports and 0.60 for group participation; both were based on an average of 4-5 ratings. Correlation coefficients between peer and faculty evaluations in each of the 3 consecutive years of the course ranged from 0.46 to 0.63; all were statistically significant at P < 0.001. A correction for attenuation suggests that the true score correlation between faculty and peer measures is near 1.0. DISCUSSION: This study provides strong evidence that facilitator and peer ratings measure similar constructs and shows that, even among Year 1 medical students, peer evaluation can be conducted in a valid manner. PMID- 17696985 TI - A systematic review of medical skills laboratory training: where to from here? AB - OBJECTIVES: The aim of this review was to evaluate the effectiveness of medical skills laboratories or simulators. In particular, it aimed to determine if performance in medical skills laboratories is transferable to actual clinical performance and maintained over time. METHODS: A range of databases was utilised to search for relevant papers published from 1998 to June 2006. Articles were included in the review if they met a number of criteria that included the evaluation of a skills laboratory or simulator for the purpose of procedural skills training, that participants were either undergraduate medical students or postgraduate medical trainees, and that the study used a randomised, controlled trial (RCT) research design in evaluation. RESULTS: A total of 44 RCTs were identified for inclusion in the review. Overall, 32 (70%) studies reported that simulator training significantly improved procedural skills performance in comparison with standard or no training. Twenty (45%) RCTs assessed the transfer of simulator performance to clinical skills performance; however, 8 of these used animal models, not real patients. Only 2 studies assessed the maintenance of skills post-intervention, both at 4-month follow-up periods. CONCLUSIONS: Medical skills laboratories do lead to improvement in procedural skills compared with standard or no training at all when assessed by simulator performance and immediately post-training. However, there is a lack of well designed trials addressing the crucial issues of transferability to clinical practice and retention of skills over time. Further research must be carried out to address these matters if medical skills laboratories are to remain an integral component of medical education. PMID- 17696986 TI - Assessment of professional behaviour in undergraduate medical education: peer assessment enhances performance. AB - OBJECTIVES: To examine whether peer assessment can enhance scores on professional behaviour, with the expectation that students who assess peers score more highly on professional behaviour than students who do not assess peers. METHODS: Undergraduate medical students in their first and second trimesters were randomly assigned to conditions with or without peer assessment. Of the total group of 336 students, 278 students participated in the first trimester, distributed over 31 tutorial groups, 17 of which assessed peers. The second trimester involved 272 students distributed over 32 groups, 15 of which assessed peers. Professional behaviour was rated by tutors on 3 dimensions: Task Performance; Aspects of Communication, and Personal Performance. The rating scale ranged from 1 (poor) to 10 (excellent). Data were analysed using multivariate repeated measures multilevel analysis. RESULTS: Assessment scores were found to have generally increased in the second trimester, especially the personal performance scores of students who assessed peers. In addition, female students were found to have significantly higher scores than male students. CONCLUSIONS: In undergraduate medical education, peer assessment has a positive influence on professional behaviour. However, the results imply that peer assessment is only effective after students have become adjusted to the complex learning environment. PMID- 17696987 TI - Prevalence and breed distribution of chronic pancreatitis at post-mortem examination in first-opinion dogs. AB - OBJECTIVES: To assess the prevalence of canine chronic pancreatitis in first opinion practice and identify breed associations or other risk factors. METHODS: Three sections of pancreas were taken from 200 unselected canine post-mortem examinations from first-opinion practices. Sections were graded for inflammation, fibrosis and other lesions. Prevalence and relative risks of chronic pancreatitis and other pancreatic diseases were calculated. RESULTS: The prevalence of chronic pancreatitis was 34 per cent omitting the autolysed cases. Cavalier King Charles spaniels, collies and boxers had increased relative risks of chronic pancreatitis; cocker spaniels had an increased relative risks of acute and chronic pancreatitis combined. Fifty-seven per cent of cases of chronic pancreatitis were classified histologically as moderate or marked. Forty-one per cent of cases involved all three sections. Dogs with chronic pancreatitis were more commonly female and overweight, but neither factor increased the relative risk of chronic pancreatitis. There were breed differences in histological appearances and 24.5 per cent of cases were too autolysed to interpret with an increased relative risk of autolysis in a number of large breeds. CLINICAL SIGNIFICANCE: Chronic pancreatitis is a common, under-estimated disease in the first-opinion dog population with distinctive breed risks and histological appearances. PMID- 17696988 TI - Influence of breast cancer resistance protein (Abcg2) and p-glycoprotein (Abcb1a) on the transport of imatinib mesylate (Gleevec) across the mouse blood-brain barrier. AB - Imatinib, a protein tyrosine kinase inhibitor, may prevent the growth of glioblastoma cells. Unfortunately, its brain distribution is restricted by p glycoprotein (p-gp or multidrug resistance protein Mdr1a), and probably by breast cancer resistance protein (Bcrp1), two efflux pumps expressed at the blood-brain barrier (BBB). We have used in situ brain perfusion to investigate the mechanisms of imatinib transport across the mouse BBB. The brain uptake of imatinib in wild type mice was limited by saturable efflux processes. The inhibition of p-gp, by valspodar and zosuquidar, increased imatinib uptake (2.5-fold), as did the deficiency of p-gp in Mdr1a/1b(-/-) mice (5.5-fold). Perfusing imatinib with the p-gp/Bcrp1 inhibitor, elacridar, enhanced the brain uptake of imatinib in wild type (4.1-fold) and Mdr1a/1b(-/-) mice (1.2-fold). However, the brain uptake of imatinib was similar in wild-type and Bcrp1(-/-) mice when it was perfused at a non-saturating concentration. The brain uptake of CGP74588, an active metabolite of imatinib, was low. It was increased by perfusion with elacridar (twofold), but not with valspodar and zosuquidar. CGP74588 uptake was 1.5 times greater in Bcrp1(-/-) mice than in wild-type mice. These data suggest that imatinib transport at the mouse BBB is limited by p-gp and probably by Bcrp1, and that CGP74588 transport is restricted by Bcrp1. PMID- 17696989 TI - Reelin signals survival through Src-family kinases that inactivate BAD activity. AB - Reelin plays an important role in the migration of embryonic neurons, but its continuing presence suggests additional functions in the brain. We now report a novel function where reelin protects P19 embryonal cells from apoptosis during retinoic acid-induced neuronal differentiation. This increased survival is associated with reelin activation of the phosphatidyl-inositol-3-kinase (PI3 K)/Akt pathway. When PI3 K was inhibited with LY294002, reelin failed to protect against this retinoic acid-induced apoptosis. The protective effect of reelin includes activating the Src-family kinases/PI3 K/Akt pathway which then led to selective phosphorylation of Bcl-2/Bcl-XL associated death promoter (BAD) at serine-136, while the phosphorylation-incompetent mutation of BAD (S136A) suppressed this protection. These and additional studies define a novel pathway where reelin binds apoE receptors, significantly activates the PI3 K/Akt pathway causing phosphorylation of BAD which helps to protect cells from apoptosing, thus serving an important role in promoting the survival of maturing neurons in the brain. PMID- 17696991 TI - Evolutionary biology and practical conservation: bridging a widening gap. AB - At the ecosystem, species and population level, available measures suggest that average rates of loss of populations and habitats are now around 1% per year and seem likely to increase in the future. Habitat conversion continues in most parts of the world, especially in areas of high species richness, and novel threats, especially climate change, will pose new challenges. With this pressure, maintaining evolutionary processes in natural populations will be critical to longer term persistence, and will often require specific planning relevant to the context. However, in many areas of policy and practice, urgent actions tend to focus on pattern-based analyses and considerations of evolutionary and ecological processes are neglected. At a variety of levels, from setting goals to implementing conservation management at the site or species level, there are simple adjustments that can be made. Improved methods for integrating the work of scientists and policymakers is recommended, from the beginning to end of the planning process. PMID- 17696990 TI - Synthesis of phosphatidylserine by base exchange in Triton-insoluble floating fractions from rat cerebellum. AB - Phosphatidylserine (PS), which is synthesized in mammalian tissues by the exchange between free serine and the nitrogen bases present in membrane glycerophospholipids, is strictly required for protein kinase C (PKC) activity. PKC, as other molecules involved in signal transduction, is present in lipid rafts, considered as a platform for molecular signaling. Membrane microdomains enriched in components of rafts can be isolated on the basis of their insolubility in Triton X-100 at 4 degrees C and their low density in sucrose density gradient. This study demonstrates the existence of serine base exchange enzyme (SBEE) in Triton-insoluble floating fractions containing associated PKC. Using two fractions of detergent-resistant membranes from rat cerebellum, we observed a correlation between the level of SBEE activity and that of membrane associated PKC. This suggests that SBEE, synthesizing PS in the binding area for PKC, participates to signal transduction. The capability of SBEE to utilize not only serine but also ethanolamine, as free exchanging base, suggests a mechanism for modulating in loco PS concentration. PMID- 17696992 TI - Biochemical and molecular characterization of methanotrophs in soil from a pristine New Zealand beech forest. AB - Methane (CH4) oxidation and the methanotrophic community structure of a pristine New Zealand beech forest were investigated using biochemical and molecular methods. Phospholipid-fatty acid-stable-isotope probing (PLFA-SIP) was used to identify the active population of methanotrophs in soil beneath the forest floor, while terminal-restriction fragment length polymorphism (T-RFLP) and cloning and sequencing of the pmoA gene were used to characterize the methanotrophic community. PLFA-SIP suggested that type II methanotrophs were the predominant active group. T-RFLP and cloning and sequencing of the pmoA genes revealed that the methanotrophic community was diverse, and a slightly higher number of type II methanotrophs were detected in the clone library. Most of the clones from type II methanotrophs were related to uncultured pmoA genes obtained directly from environmental samples, while clones from type I were distantly related to Methylococcus capsulatus. A combined data analysis suggested that the type II methanotrophs may be mainly responsible for atmospheric CH4 consumption. Further sequence analysis suggested that most of the methanotrophs detected shared their phylogeny with methanotrophs reported from soils in the Northern Hemisphere. However, some of the pmoA sequences obtained from this forest had comparatively low similarity (<97%) to known sequences available in public databases, suggesting that they may belong to novel groups of methanotrophic bacteria. Different methods of methanotrophic community analysis were also compared, and it is suggested that a combination of molecular methods with PLFA-SIP can address several shortcomings of stable isotope probing. PMID- 17696993 TI - Deficits in social behavior and sensorimotor gating in mice lacking phospholipase Cbeta1. AB - Abnormal phospholipid metabolism has been implicated in the pathogenesis of schizophrenia, and it was reported that phospholipase C (PLC) beta1 is reduced in specific brain areas of patients with schizophrenia. However, the causal relationship of the PLCbeta1 gene with behavioral symptoms of schizophrenia remains unclear. To address this issue, we have examined the mutant mice lacking PLCbeta1 for schizophrenia-related phenotypes by performing various behavioral tests, including general locomotor activity, sensorimotor gating, social behaviors, and learning and memory. Phospholipase C beta1 knockout mice showed hyperactivities in an open field. They showed impaired prepulse inhibition of acoustic startle response, which was ameliorated by a systemic administration of an antipsychotic D2-receptor antagonist, haloperidol. In addition, they showed abnormal social behaviors, such as lack of barbering behavior, socially recessive trait and lack of nesting behavior. Furthermore, they showed impaired performance in the delayed-non-match-to-sample T-maze test. The present results show that the PLCbeta1 mutant mice share some of the behavioral abnormalities that have been reported in patients with schizophrenia. Thus, the PLCbeta1-linked signaling pathways may be involved in the neural system whose function is disrupted in the pathogenesis of schizophrenia. PMID- 17696994 TI - Brain gene expression correlates with changes in behavior in the R6/1 mouse model of Huntington's disease. AB - Huntington's disease (HD) is an inherited neurodegeneration that causes a severe progressive illness and early death. Several animal models of the disease have been generated carrying the causative mutation and these have shown that one of the earliest molecular signs of the disease process is a substantial transcriptional deficit. We examined the alterations in brain gene expression in the R6/1 mouse line over the course of the development of phenotypic signs from 18 to 27 weeks. Changes in R6/1 mice were similar to those previously reported in R6/2 mice, and gene ontology analysis shows that pathways related to intracellular and electrical signaling are altered among downregulated genes and lipid biosynthesis and RNA processes among upregulated genes. The R6/1 mice showed deficits in rotarod performance, locomotor activity and exploratory behavior over the time-course. We have correlated the alterations in gene expression with changes in behavior seen in the mice and find that few alterations in gene expression correlate with all behavioral changes but rather that different subsets of the changes are uniquely correlated with one behavior only. This indicates that multiple behavioral tasks assessing different behavioral domains are likely to be necessary in therapeutic trials in mouse models of HD. PMID- 17696995 TI - Interval timing in genetically modified mice: a simple paradigm. AB - We describe a behavioral screen for the quantitative study of interval timing and interval memory in mice. Mice learn to switch from a short-latency feeding station to a long-latency station when the short latency has passed without a feeding. The psychometric function is the cumulative distribution of switch latencies. Its median measures timing accuracy and its interquartile interval measures timing precision. Next, using this behavioral paradigm, we have examined mice with a gene knockout of the receptor for gastrin-releasing peptide that show enhanced (i.e. prolonged) freezing in fear conditioning. We have tested the hypothesis that the mutants freeze longer because they are more uncertain than wild types about when to expect the electric shock. The knockouts however show normal accuracy and precision in timing, so we have rejected this alternative hypothesis. Last, we conduct the pharmacological validation of our behavioral screen using d-amphetamine and methamphetamine. We suggest including the analysis of interval timing and temporal memory in tests of genetically modified mice for learning and memory and argue that our paradigm allows this to be done simply and efficiently. PMID- 17696996 TI - Individual differences in allocation of funds in the dictator game associated with length of the arginine vasopressin 1a receptor RS3 promoter region and correlation between RS3 length and hippocampal mRNA. AB - Human altruism is a widespread phenomenon that puzzled evolutionary biologists since Darwin. Economic games illustrate human altruism by showing that behavior deviates from economic predictions of profit maximization. A game that most plainly shows this altruistic tendency is the Dictator Game. We hypothesized that human altruistic behavior is to some extent hardwired and that a likely candidate that may contribute to individual differences in altruistic behavior is the arginine vasopressin 1a (AVPR1a) receptor that in some mammals such as the vole has a profound impact on affiliative behaviors. In the current investigation, 203 male and female university students played an online version of the Dictator Game, for real money payoffs. All subjects and their parents were genotyped for AVPR1a RS1 and RS3 promoter-region repeat polymorphisms. Parents did not participate in online game playing. As variation in the length of a repetitive element in the vole AVPR1a promoter region is associated with differences in social behavior, we examined the relationship between RS1 and RS3 repeat length (base pairs) and allocation sums. Participants with short versions (308-325 bp) of the AVPR1a RS3 repeat allocated significantly (likelihood ratio = 14.75, P = 0.001, df = 2) fewer shekels to the 'other' than participants with long versions (327-343 bp). We also implemented a family-based association test, UNPHASED, to confirm and validate the correlation between the AVPR1a RS3 repeat and monetary allocations in the dictator game. Dictator game allocations were significantly associated with the RS3 repeat (global P value: likelihood ratio chi(2) = 11.73, df = 4, P = 0.019). The association between the AVPR1a RS3 repeat and altruism was also confirmed using two self-report scales (the Bardi-Schwartz Universalism and Benevolence Value-expressive Behavior scales). RS3 long alleles were associated with higher scores on both measures. Finally, long AVPR1a RS3 repeats were associated with higher AVPR1a human post-mortem hippocampal messenger RNA levels than short RS3 repeats (one-way analysis of variance (ANOVA): F = 15.04, P = 0.001, df = 14) suggesting a functional molecular genetic basis for the observation that participants with the long RS3 repeats allocate more money than participants with the short repeats. This is the first investigation showing that a common human polymorphism, with antecedents in lower mammals, contributes to decision making in an economic game. The finding that the same gene contributing to social bonding in lower animals also appears to operate similarly in human behavior suggests a common evolutionary mechanism. PMID- 17696997 TI - Characterization of the quantitative trait locus for haloperidol-induced catalepsy on distal mouse chromosome 1. AB - We report here the confirmation of the quantitative trait locus for haloperidol induced catalepsy on distal chromosome (Chr) 1. We determined that this quantitative trait locus was captured in the B6.D2-Mtv7a/Ty congenic mouse strain, whose introgressed genomic interval extends from approximately 169.1 to 191.3 Mb. We then constructed a group of overlapping interval-specific congenic strains to further break up the interval and remapped the locus between 177.5 and 183.4 Mb. We next queried single nucleotide polymorphism (SNP) data sets and identified three genes with nonsynonymous coding SNPs in the quantitative trait locus. We also queried two brain gene expression data sets and found five known genes in this 5.9-Mb interval that are differentially expressed in both whole brain and striatum. Three of the candidate quantitative trait genes were differentially expressed using quantitative real-time polymerase chain reaction analyses. Overall, the current study illustrates how multiple approaches, including congenic fine mapping, SNP analysis and microarray gene expression screens, can be integrated both to reduce the quantitative trait locus interval significantly and to detect promising candidate quantitative trait genes. PMID- 17696998 TI - Gene expression in lung and basal forebrain during influenza infection in mice. AB - Inbred mice develop strain-dependent changes in sleep during the first few days after inoculation with influenza virus. To identify genes with the potential to differentially modulate sleep under this condition, we performed complementary DNA microarray analysis of both lung and basal forebrain (BF) of infected (I) and uninfected BALB/cByJ (C) and C57BL/6J (B6) mice. This analysis showed significant variation in the expression pattern of 667 and 1217 of the surveyed genes in BF and lung, respectively (P < 0.01). Applying the additional criterion of an effect size >or=2, 495 genes differed in expression in lung compared with 204 in BF. In BF, more genes were differentially expressed as a function of mouse strain, whereas in lung, more genes were differentially expressed as a function of health status. Significant alterations in expression after infection were more numerous and robust in BALB/cByJ vs. C57BL/6J mice. Some genes showed significant variation in both tissues as a function of strain or condition, but the changes in general were not parallel. Genes that showed significant and robust variation as a function of strain, health status or tissue included those related to immune function, metabolism, signal transduction, cell cycle regulation, apoptosis and other miscellaneous categories. Different patterns of gene expression in BF of uninfected mice suggest the possibility of fundamental mechanistic differences in pathways that modulate vigilance in these strains, whereas differences in expression of lung of infected mice suggests different peripherally generated sleep-modulatory stimuli in the two strains. PMID- 17696999 TI - SopD acts cooperatively with SopB during Salmonella enterica serovar Typhimurium invasion. AB - The intracellular bacterial pathogen, Salmonella enterica serovar Typhimurium (S. typhimurium), causes disease in a variety of hosts. To invade and replicate in host cells, these bacteria subvert host molecular machinery using bacterial proteins, called effectors, which they translocate into host cells using specialized protein delivery systems. One of these effectors, SopD, contributes to gastroenteritis, systemic virulence and persistence of S. typhimurium in animal models of infection. Recently, SopD has been implicated in invasion of polarized epithelial cells and here we investigate the features of SopD-mediated invasion. We show that SopD plays a role in membrane fission and macropinosome formation during S. typhimurium invasion, events previously shown to be mediated by the SopB effector. We further demonstrate that SopD acts cooperatively with SopB to promote these events during invasion. Using live cell imaging we show that a SopD-GFP fusion does not localize to HeLa cell cytosol as previously described, but instead is membrane associated. Upon S. typhimurium infection of these cells, SopD-GFP is recruited to the invasion site, and this recruitment required the phosphatase activity of SopB. Our findings demonstrate a role for SopD in manipulation of host-cell membrane during S. typhimurium invasion and reveal the nature of its cooperative action with SopB. PMID- 17697000 TI - A 10-year prospective study of ITI dental implants placed in the posterior region. II: Influence of the crown-to-implant ratio and different prosthetic treatment modalities on crestal bone loss. AB - OBJECTIVE: To evaluate the influence of the crown-to-implant ratio (C/I) ratio and different implant prosthetic treatment modalities on crestal bone loss around dental implants placed in the posterior region. MATERIAL AND METHODS: A total of 192 ITI dental implants were consecutively placed in premolars and molars of 83 partially edentulous patients. All implants were restored by means of ceramic-to metal fused fixed partial dentures or a single crown. Patients were followed as part of a prospective longitudinal study focusing on implant success. Surgical, radiographic and clinical variables were collected at the 1-year recall after implant placement and at the most recent clinical evaluation. Radiographic parameters were evaluated on periapical radiographs taken with a standardized long-cone paralleling technique. Implant restorations were divided into three groups according to their respective clinical C/I ratios: (a) 0-0.99, (b) 1-1.99 and (c) >or=2. RESULTS: The mean clinical C/I ratio was 1.77+/-0.56 mm. A total of 51 implants (26.5%) showed a clinical C/I ratio equal to or greater than 2. In this group, three implants failed, giving a cumulative survival rate of 94.1%. Crestal bone loss was -0.34+/-0.27 mm in group a, -0.03+/-0.15 mm in group b and 0.02+/-0.26 mm in group c. Differences among groups were statistically significant (P=0.009). Mode of retention, splinting or presence of cantilever extensions did not have an effect on crestal bone loss around ITI dental implants. CONCLUSIONS: Implant restorations with C/I ratios between 2 and 3 may be successfully used in the posterior areas of the jaw. PMID- 17697001 TI - Multicentre determination of quality control strains and quality control ranges for antifungal susceptibility testing of yeasts and filamentous fungi using the methods of the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antimicrobial Susceptibility Testing (AFST-EUCAST). AB - A multicentre study involving seven laboratories was performed using techniques recommended by the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antimicrobial Susceptibility Testing (AFST-EUCAST) to evaluate and propose quality control ranges and strains for susceptibility testing of fermentative yeasts and filamentous fungi. Participating laboratories tested the susceptibilities of a panel of 12 encoded isolates to amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole and posaconazole. In total, 15 lots of assay medium were tested, with one lot being common to all laboratories, and 18 144 MIC values were determined. Intra- and inter-laboratory agreements and intra-class correlation coefficients (ICCs) of the results for each drug/strain/lot combination were calculated. An average value of 85% agreement was selected for validation purposes. The average percentage of intra laboratory agreement was 90-95%, with ICC values of 0.90-0.95 (p <0.01). Inter laboratory reproducibility was also high, with 92% agreement and an ICC of 0.97 (p <0.01). The reproducibility was somewhat better with the common lot of assay medium (96% agreement) than with the different lots (91% agreement), but this difference was not significant. Two isolates that showed trailing growth had agreement percentages below the 85% limit selected for validation purposes and were therefore excluded from the panel of quality control strains. The recommended EUCAST methodologies were found to be highly reproducible and reliable for susceptibility testing of yeasts and filamentous fungi. Ten isolates are proposed for use as quality control strains with these EUCAST procedures. PMID- 17697002 TI - Molecular characterisation of multidrug-resistant Salmonella enterica serovar Typhimurium isolates from Gomel region, Belarus. AB - This study describes the characterisation by pulsed-field gel electrophoresis (PFGE), multilocus variable number tandem repeat analysis (MLVA) typing and antimicrobial resistance profiles of 35 Salmonella enterica serovar Typhimurium isolates, mostly from infections in children who acquired an infection outside hospitals in the Gomel region of Belarus. Thirty-one isolates were highly similar according to PFGE and MLVA typing, were multidrug-resistant, including resistance to ceftiofur, and harboured the bla(CTX-M-5) gene. These results indicate that a common source may have been responsible for most of the infections. PMID- 17697003 TI - Replacement of methicillin-resistant Staphylococcus aureus clones in Hungary over time: a 10-year surveillance study. AB - The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in Hungary has been increasing and is now close to 20% among invasive isolates of S. aureus. In order to understand the evolution of MRSA in Hungary, two collections of isolates were studied: 22 representatives of a collection of 238 MRSA isolates recovered between 1994 and 1998, and a collection of 299 MRSA isolates recovered between 2001 and 2004. The isolates were first characterised by pulsed-field gel electrophoresis (PFGE) and were distributed into 19 different PFGE patterns. Representatives of each pattern were further characterised by spa typing, multilocus sequence typing (MLST) and staphylococcal cassette chromosome mec (SCCmec) typing. The Hungarian clone that was predominant in 1994-1998 (PFGE E, ST239-III) had almost disappeared in 2003-2004, being replaced by the Southern German clone (PFGE B, ST228-I) and the New York/Japan epidemic clone (PFGE A, ST5 II), which represented c. 85% of the 2001-2004 isolates. Thus, this study describes, for the first time, the co-dominance and extensive spread of the New York/Japan clone in a European country. PMID- 17697004 TI - Evidence for low risk of Clostridium difficile infection associated with tigecycline. AB - Broad-spectrum antibiotics are often associated with a relatively high risk of Clostridium difficile infection (CDI). However, exceptions to this rule, e.g., piperacillin-tazobactam, show that marked inhibition of gut flora is not synonymous with CDI risk. Tigecycline has marked broad-spectrum activity that includes Gram-positive and Gram-negative facultative and obligate anaerobes. Antibiotic susceptibility, gut model and clinical trial data suggest that tigecycline is associated with a relatively low risk of CDI. Further clinical data should be obtained to confirm the results of these initial studies. PMID- 17697005 TI - Survival of Mycobacterium ulcerans at 37 degrees C. AB - Bone infection and metastatic spread in cases of Buruli ulcer imply that Mycobacterium ulcerans is able to survive and multiply at 37 degrees C. This study investigated the survival at 37 degrees C of M. ulcerans isolates from diverse geographical and clinical sources. Although the viability of all isolates decreased after a few days at 37 degrees C, viable bacilli remained after 13 days at 37 degrees C in most instances. African isolates of M. ulcerans were more thermotolerant than isolates from temperate regions. Isolates from skin and bone lesions of the same patients showed no difference in thermotolerance. PMID- 17697006 TI - Discovery of insertion element ISCfe1: a new tool for Campylobacter fetus subspecies differentiation. AB - The species Campylobacter fetus is divided into the subspecies C. fetus subsp. venerealis (CFV) and C. fetus subsp. fetus (CFF). CFV is the causative agent of bovine genital campylobacteriosis, a highly contagious venereal disease that may lead to serious reproductive problems, including sterility and abortion. In contrast, CFF can be isolated from the gastrointestinal tract of a wide range of host species, is associated with abortion in sheep and cattle, and can also be isolated from local and systemic infections in humans. Despite differences in host and niche preferences, microbiological differentiation of the two subspecies of C. fetus is extremely difficult. This study describes the identification of a new insertion element, ISCfe1, which is present exclusively in CFV strains, with highly conserved specific ISCfe1 insertion sites. The results are useful for identification and differentiation of the two C. fetus subspecies and will help in understanding the evolution and pathogenesis of C. fetus. PMID- 17697007 TI - Insulin sensitivity, proinflammatory markers and adiponectin in young males with different subtypes of depressive disorder. AB - OBJECTIVE: This study was designed to evaluate insulin sensitivity, proinflammatory markers and adiponectin concentration in young males with different subtypes of depressive disorder. METHODS: Nonobese young males with depressive disorder (ages between 18 years and 30 years; body mass index, BMI < or = 25 kg/m(2)) were recruited and divided into reactive depression (RD, N = 14), major depression (MD, N = 21) and bipolar depression (BD, N = 15) based on clinical course and symptom changes in Hamilton rating scale for depression (HAM D). Fourteen age- and BMI-matched healthy males were enrolled as controls. All of the participants received a 75-g oral glucose tolerance test (OGTT). Insulin sensitivity and beta-cell function were calculated by minimal model method from the frequently sampled intravenous glucose tolerance test. Plasma C-reactive protein (CRP), adiponectin, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were determined. RESULTS: Compared to the controls, insulin sensitivity (S(I)) were significantly lower in MD and BD (0.78 +/- 0.09 min( 1)/pmol and 0.75 +/- 0.09 min(-1)/pmol vs. 1.09 +/- 0.08 x 10(-5) min(-1)/pmol, P < 0.05, respectively). Acute insulin response (AIR) to intravenous glucose was elevated in BD as compared to control and RD groups (6079.9 +/- 841.8 pmol vs. 3339.8 +/- 356.4 pmol and 3494.8 +/- 337.7 pmol, P < 0.05, respectively). Plasma adiponectin level was diminished in BD group as compared to the control and RD groups (7.41 +/- 0.45 microg/ml vs. 9.07 +/- 0.54 microg/ml and 9.38 +/- 0.46 microg/ml; P < 0.05 and P < 0.01, respectively). By regression analysis, a significantly negative correlation between HAM-D score and S(I) was found in MD (r = -0.60, P = 0.005) and BD groups (r = -0.57, P = 0.04). CONCLUSIONS: The results suggest that there is an inverse relationship between both major and bipolar depression and insulin resistance in nonobese young males. PMID- 17697008 TI - Identification of TSH receptor mutations in three families with resistance to TSH. AB - OBJECTIVE: Genetic analysis of the TSH receptor gene in seven subjects with subclinical hypothyroidism (SH), in whom the diagnosis of autoimmune thyroid disease had been excluded by laboratory and instrumental techniques currently available. PATIENTS: Three families where different members (2 children and 5 adults) affected by SH were studied. GENETIC ANALYSIS: Genomic DNA was extracted from peripheral lymphocytes and the entire coding sequence of the TSHr gene was sequenced. pSVL-TSHr construct harbouring a Q8fsX62 insertion was obtained by site-directed mutagenesis. COS-7 cells transfected with wild-type and mutant receptor were used for binding studies, flow cytometry, and cyclic AMP (cAMP) determination. RESULTS: A four base pair (bp) duplication in position 41 (41TGCAins), leading to a premature stop of translation at codon 62 (Q8fsX62), was found to be heterozygous in the proband, the father and the sister in Family 1. In Family 2 the proband and the sister were heterozygous for the mutation D410N. In Family 3 the proband and the father were heterozygous for the mutation P162A. After transfection in COS-7 cells, the mutant receptor Q8fsX62 displayed a low expression at the cell surface, and a reduced response to bovine TSH (bTSH) in terms of cAMP production. CONCLUSIONS: We identified TSH receptor mutations in seven members of three families with subclinical hypothyroidism. PMID- 17697009 TI - Acute ethanol exposure combined with burn injury enhances IL-6 levels in the murine ileum. AB - BACKGROUND: Recent studies suggest that ethanol use imposes a greater risk of trauma-associated intestinal injury than trauma alone. The initiating and regulatory factors for multiple organ dysfunction syndromes are not well defined, yet evidence points to the gut as a possible trigger of the systemic inflammatory cascade as well as a potential source of cytokines. In the current study, we hypothesized that ethanol administration would alter cytokine levels and intestinal infiltration by neutrophils within the ileum of mice exposed to burn injury (15% total body surface of dorsal skin). METHODS: Ileal samples were collected for histological assessment, myeloperoxidase quantitation and the protein presence of tumor necrosis factor alpha (TNFalpha), interleukin (IL-) 6, macrophage inflammatory protein-2 (MIP-2; CXCL2) and the anti-inflammatory cytokine, IL-10. Additional ileal tissue samples were examined for localization of the IL-6 immunoreactivity. RESULTS: We did not detect statistically significant cytokine/chemokine differences (MIP-2 and IL-10) between sham control and treatment conditions at either 2 or 24 hours. However, there was a significant decrease in TNFalpha at 24 hours in both burn injury alone and in combination with ethanol treatment conditions (p < 0.05). In addition, there was an increase in IL-6 levels at 24 hours in intestinal tissue obtained from mice subjected to a combination of acute ethanol and burn injury, compared to the mice receiving burn or sham injury (p < 0.001). Ileal homogenate increases in IL-6 at 24 hours were concurrent with decreased villus height in the ileum, but no discernable changes in neutrophil infiltration (myeloperoxidase activity levels) at either 2 or 24 hours. Additional immunocytochemical localization studies of ileal tissue revealed that there was a substantial increase of IL-6 in intestinal enterocytes subjected to both burn injury alone, or in combination with acute ethanol exposure. CONCLUSIONS: The present study suggests that acute ethanol exposure combined with burn injury enhances levels of IL-6 protein in the ileum. The enhanced levels of ileal IL-6 are likely due to enterocyte production of the cytokine. PMID- 17697011 TI - Hepatitis C virus directly associates with insulin resistance independent of the visceral fat area in nonobese and nondiabetic patients. AB - Insulin resistance (IR) is known to be associated with the visceral adipose tissue area. Elucidation of the relationship between hepatitis C virus (HCV) and IR is of great clinical relevance, because IR promotes liver fibrosis. In this study, we tested the hypothesis that HCV infection by itself may promote IR. We prospectively evaluated 47 patients with chronic HCV infection who underwent liver biopsy. Patients with obesity, type 2 diabetes mellitus (DM), or a history of alcohol consumption were excluded. IR was estimated by calculation of the modified homeostasis model of insulin resistance (HOMA-IR) index. Abdominal fat distribution was determined by computed tomography. Fasting blood glucose levels were within normal range in all the patients. The results of univariate analysis revealed a significant correlation between the quantity of HCV-RNA and the HOMA IR (r = 0.368, P = 0.0291). While a significant correlation between the visceral adipose tissue area and the HOMA-IR was also observed in the 97 control, nondiabetic, non-HCV-infected patients (r = 0.398, P < 0.0001), no such significant correlation between the visceral adipose tissue area and the HOMA-IR (r = 0.124, P = 0.496) was observed in the patients with HCV infection. Multiple regression analysis with adjustment for age, gender and visceral adipose tissue area revealed a significant correlation between the HCV-RNA and the HOMA-IR (P = 0.0446). HCV is directly associated with IR in a dose-dependent manner, independent of the visceral adipose tissue area. This is the first report to demonstrate the direct involvement of HCV and IR in patients with chronic HCV infection. PMID- 17697012 TI - Additive effect of ethanol and HCV subgenomic replicon expression on COX-2 protein levels and activity. AB - The mechanisms by which alcohol exacerbates liver injury in patients with hepatitis C are unknown. We used the hepatitis C virus (HCV) subgenomic replicon cell system to evaluate the effect of ethanol on HCV replication and viral protein synthesis. Our results demonstrate that alcohol stimulates HCV replicon expression at both HCV-RNA and protein levels. Furthermore, we observed that ethanol treatment showed an additive effect in cyclooxygenase-2 (COX-2) protein expression and activity already induced by HCV viral proteins, and in turn increased HCV viral expression. Our results suggest that COX-2 activity is involved in ethanol-induced HCV-RNA and NS5A protein expression, because acetylsalicylic acid (ASA), a COX-1/2 inhibitor, blocked this induction and downregulated COX-2 protein expression and activity. Therefore, we suggest that ethanol increases HCV replication expression, at least in part, by upregulating a key cellular regulator of oxidative stress pathway known as COX-2 or its products. PMID- 17697013 TI - HCV infection is a risk factor for gallstone disease in liver cirrhosis: an Italian epidemiological survey. AB - We assessed the prevalence of gallbladder disease (i.e. gallstones plus cholecystectomy) among patients with liver disease and its association with the severity and aetiology of hepatic injury. Subjects, referred to 79 Italian hospitals, were enrolled in a 6-month period. The independent effect of the severity and aetiology of liver disease on gallstone disease prevalence was assessed by multiple logistic regression analysis. Overall, 4867 subjects tested anti-hepatitis C virus (HCV) positive alone, 839 were hepatitis B virus surface antigen (HBsAg) alone, and 652 had an excessive alcohol intake. The prevalence of gallstone disease was 23.3% in anti-HCV-positive patients, 12.4% in HBsAg positive and 24.2% in subjects reporting excessive alcohol intake, respectively. Gallstone disease prevalence increased by age in each aetiological category. The proportion of patients with gallstone disease who had a cholecystectomy was the highest in HCV+ subjects. After adjusting for the confounding effect of age and body mass index, compared with patients with less severe liver disease, subjects with HCV-related cirrhosis, but not those with alcohol-related cirrhosis, were more likely to have gallstone disease. Subjects with HCV-related cirrhosis (OR 2.13, 95% CI: 1.38-3.26) were more likely to have gallstone disease when compared with those with HBV-related cirrhosis. HCV infection is a risk factor for gallstone disease. In Italy, the high prevalence of HCV infection among cirrhotic patients has important implications, as cholecystectomy in these subjects is associated with high risk of morbidity and mortality. PMID- 17697014 TI - Health professionals' attitudes toward caring for people with hepatitis C. AB - An estimated 170 million people worldwide have hepatitis C, which is a significant cause of morbidity and mortality. Therefore, health professionals (HPs) are likely to care for people with hepatitis C at some stage in their careers. However, little is known about HPs' attitudes towards treating people with hepatitis C. An analytical, cross-sectional survey was conducted to explore the inter-relationship among HPs' hepatitis C knowledge and attitudes towards treating people with hepatitis C and their self-reported clinical behaviour: Self administered questionnaires were distributed to 3675 complementary therapists, dentists, medical practitioners, nurses, pharmacists, undergraduate medical and nursing students and people with hepatitis C in Victoria, Australia. Forty-six per cent responded (n = 1510). Only HP (complementary therapists, dentists, medical practitioners, nurses and pharmacists) data is presented (n = 1347). Most HPs demonstrated adequate hepatitis C knowledge, but some displayed intolerant attitudes toward people with hepatitis C. Their self-reported compliance with infection control practices indicated that they frequently treated people with hepatitis C differently from other patients by using additional infection control precautions while treating patients with hepatitis C. In addition, fear of contagion and disapproval of injecting drug use emerged as barriers to their willingness to treat people with hepatitis C. The results suggest that focusing education strategies on changing HPs' attitudes toward people with hepatitis C, injecting drug users, and infection control guidelines rather than concentrating solely on medical information might ultimately improve patient care. PMID- 17697015 TI - Therapy outcome in patients with chronic hepatitis C: role of therapy supervision by expert hepatologists. AB - Previous large multicentre trials reported sustained virological response (SVR) rates of 45-80% in chronically infected hepatitis C virus (HCV) patients. However, it is unclear whether such a treatment success is also achieved in daily routine and to what extent it depends on expert hepatological supervision. This was retrospectively analysed in patients presenting at our outpatient department during May 1997 and March 2004 and receiving at least one treatment dose. A total of 302 treatment-naive HCV patients [72% genotypes 1 or 4 (n = 215), 25% genotypes 2/3 (n = 78) and 3% undetermined genotype (n = 9)] were included in the analysis. Out of these, 196 patients consulted an expert hepatologist at least once every 3 months during treatment [regular visitors (RV)], whereas in 106 patients treatment was performed and supervised by a general practitioner (irregular visitors). Both patient groups did not differ in their baseline characteristics. However, the virological response rates at the end of treatment (ETR; 146/196, 74%vs 51/106, 48%, P < 0.001) and 6 months thereafter (SVR; 129/196, 66%vs 36/106, 34%, P < 0.001) were significantly higher in RV. In patients treated with pegylated-interferon (PEG-IFN)/ribavirin, this difference was statistically highly significant (P < 0.001) for HCV genotypes 1 and 4 (treated patients: SVR: 62/101, 61%vs 14/51, 27%, P < 0.001), but not for genotypes 2/3. SVR rates were also significantly better in RV with advanced liver damage [SVR 69% (22/32) vs 25% (5/20), P = 0.004]. In regular and irregular visitors treatment was discontinued in 7% (14/196) and 15% (16/106) respectively (P = 0.015). Patients with unfavourable genotypes 1 and 4 or with advanced liver damage benefit from HCV therapy supervision by a specialist, probably because of less frequent treatment interruptions or dose reductions. PMID- 17697016 TI - Risk factors for anaemia in human immunodeficiency virus/hepatitis C virus coinfected patients treated with interferon plus ribavirin. AB - The most frequent and the most troublesome adverse effect of interferon plus ribavirin-based therapy is anaemia. The aim of this analysis was to determine the incidence and risk factors of anaemia (Hb < 10 g/dL) in human immunodeficiency virus/hepatitis C virus (HCV)-coinfected patients receiving anti-HCV therapy. We reviewed all cases of anaemia occurring among 416 patients participating in a randomized, controlled 48-week trial comparing peginterferon (peg-IFN) alpha 2b plus ribavirin with interferon alpha-2b plus ribavirin. Univariate and multivariate analyses were used to identify links with antiretroviral treatments, HCV therapy and clinical and laboratory findings. Sixty-one (15.9%) of the 383 patients who received at least one dose of anti-HCV treatment developed anaemia. In multivariate analysis the risk of anaemia was significantly associated with zidovudine (OR, 3.27 95% CI, 1.64-6.54, P = 0.0008) and peg-IFN (OR, 2.35; 95% CI, 1.16-4.57, P = 0.0179). The risk of anaemia was lower in patients with higher baseline haemoglobin levels (OR, 0.35 95% CI, 0.26-0.49, P < 0.0001) and in patients receiving protease inhibitor-based antiretroviral therapy (OR, 0.51 95% CI, 0.30-0.86, P = 0.0114). Zidovudine discontinuation could help to avoid anaemia associated with anti-HCV therapy. PMID- 17697017 TI - Hepatitis C virus (HCV) prevalence, and injecting risk behaviour in multiple sites in England in 2004. AB - We sought to corroborate geographical differences in hepatitis C virus (HCV) prevalence and assess whether these can be explained by differences in injecting risk behaviour. A community recruited interview survey of 1058 injecting drug users (IDU) - including a blood spot specimen for antibody testing - was undertaken in seven cities in England. HCV prevalence varied from 27% to 74% across sites (chi(2)(6) = 115.3, P < 0.001). There was a significant variation in crack-injection, prison history, injecting frequency, homelessness, groin injecting, syringe reuse and sharing between the sites. Adjustment for clustering by site and other covariates attenuated the odds ratios (OR) for most variables: e.g. crack injection changed from an unadjusted OR of >2 to an adjusted OR of 1.4 (95% CI 0.9-2.0). Remaining significant covariates included: homelessness (OR 2.2; 1.4-3.6); ever imprisonment (OR 1.7; 1.2-2.5); syringe sharing >18 months ago (OR 2.0; 1.3-3.0); injecting duration and age. Introducing site as a second level variable did not reach significance (P = 0.10). HCV prevalence among IDU reporting 'never sharing' was 48%. Geographical variation in HCV prevalence remains poorly explained, but should be the key focus of our surveillance effort. Measures of sharing and their interpretation require greater scrutiny. PMID- 17697018 TI - Hepatitis B vaccine uptake among injecting drug users in England 1998 to 2004: is the prison vaccination programme driving recent improvements? AB - In 1999, the Department of Health allocated additional funding to Health Authorities in England to expand hepatitis B immunization among injecting drug users (IDUs), with the aim of increasing coverage by 20%. In 2001, a vaccination programme for prison inmates in England was also instigated. Between 1998 and 2004 current IDUs participated in a series of annual unlinked anonymous surveys that recorded vaccine uptake (n = 11 383). The proportion self-reporting vaccine uptake rose significantly from 27% in 1998 to 59% in 2004 [adjusted odds ratio: 3.7 (95% CI 3.2-4.3); increase in uptake of 25% per annum (95% CI 22-27%)]. A second survey, which recruited 852 current IDUs from community settings in 2003/04, found that prisons were the most common source (38%) of vaccine doses, followed by drug services (28%) and general practitioners (17%), with only 14% receiving doses through needle exchanges. These data suggest that the 20% target of improving vaccination coverage has been met, with the prison vaccination programme likely to have made a substantive contribution in recent years. However, prevalence of antibodies to the hepatitis B core antigen was stable (21%) and is currently similar among the vaccinated and unvaccinated. Consideration needs to be given to improving community vaccination provision for IDUs, targeting recent initiates, and determining when surveillance data should indicate reductions in infection so that the effectiveness of the targeted strategy can be assessed. PMID- 17697019 TI - Association between lamivudine sensitivity and the number of substitutions in the reverse transcriptase region of the hepatitis B virus polymerase. AB - This study aimed to identify the viral factors responsible for poor sensitivity to lamivudine (LAM). We analyzed 49 LAM-treated chronic hepatitis B patients infected with hepatitis B virus (HBV) genotype C. Serum HBV DNA reached a level below the detection limit of the sensitive PCR assay in 31 (63.3%) within the first 24 weeks of LAM therapy (good responder group). Of the patients who did not achieve undetectable levels of HBV DNA within 24 weeks (poor responder group), 15 (83.3%) experienced virological breakthrough, whilst only four patients in the good responder group (12.9%) experienced virological breakthrough. Multivariate analysis revealed that failure to achieve a reduction in viral load to undetectable levels within 24 weeks was independently associated with the occurrence of virological breakthrough. Sequence analysis of the HBV genome revealed that point mutations in the precore region (G1896A) and enhancer I (A1287G/C) were observed more frequently in the good responder group than in the poor responder group (P = 0.002 and 0.019 respectively), and the number of substitutions in the reverse transcriptase domain of the polymerase was significantly higher in the good responders than in the poor responders (P = 0.026). In conclusion, determining the sequence of preexisting HBV, especially for enhancer I, the precore region, and the RT domain of the polymerase region, may be useful in predicting sensitivity to LAM therapy. PMID- 17697020 TI - Tracing hepatitis C and Delta viruses to estimate their contribution in HCC rates in Mongolia. AB - An estimated incidence of hepatocellular carcinoma (HCC) in Mongolia is currently one of the highest in the world. According to previous reports, the sero prevalence of hepatitis B (HBV) and hepatitis C (HCV) viruses in general population of the country is very high (HBV, 10% and HCV, 15%, respectively). Moreover, the majority (75-100%) of the HBV-infected individuals have co infection with hepatitis Delta virus (HDV). Despite reported observations that HBV + HDV/HCV co-infection have significantly stronger association with HCC when compared with HCV-monoinfection, the later is still frequently observed among Mongolian HCC patients (39%). In this study, an approach based on principles of population genetics and mathematical epidemiology was used to trace an epidemic history of HCV and HDV. In agreement with the sero-epidemiological and social historical background of the country, the results have demonstrated that the viruses had different epidemic dynamics in Mongolia; HCV was characterized by earlier epidemic expansion, whereas HDV spread with approximately 50 years lag. This may explain the comparable contribution of the HCV-monoinfection and HBV + HDV co-infection in current HCC rate despite different levels of risk of carcinogenesis. Used approach is useful in evaluation of current and prospective disease burden. PMID- 17697021 TI - Effects of sleep deprivation on anaerobic exercise-induced changes in auditory brainstem evoked potentials. AB - BACKGROUND: The present study was designed to assess how anaerobic exercise affects auditory brainstem response (ABR) parameters, and whether one night of sleep deprivation could alter these possible exercise-induced changes in ABRs. METHODS: Seven healthy, audiologically normal male students (mean age 22.4 +/- 1.0 years) participated in the study. All subjects underwent anaerobic Wingate test for three times: (i) baseline, (ii) following a full-night of habitual sleep and (iii) following one night of sleep deprivation. ABR measurements were performed before and after the second and the third Wingate tests. Oral body temperatures were recorded at the beginning of all ABR measurements. RESULTS: The latencies of wave III and V significantly shortened by anaerobic loading performed in the day after habitual sleep (4.13 +/- 0.10 versus 4.01 +/- 0.17 ms, P<0.02; and 5.84 +/- 0.26 versus 5.65 +/- 0.23 ms, P<0.03, respectively). One night of total sleep deprivation shortened pre-exercise latencies and altered exercise-induced changes in ABRs. CONCLUSION: The findings obtained in the present study show that acute anaerobic exercise is effective on ABR wave latencies independent from body temperature changes, and sleep deprivation has some modulatory effects on exercise-induced changes in ABR. PMID- 17697022 TI - Cardiovascular changes induced by cold water immersion during hyperbaric hyperoxic exposure. AB - The present study was designed to assess the cardiac changes induced by cold water immersion compared with dry conditions during a prolonged hyperbaric and hyperoxic exposure (ambient pressure between 1.6 and 3 ATA and PiO(2) between 1.2 and 2.8 ATA). Ten healthy volunteers were studied during a 6 h compression in a hyperbaric chamber with immersion up to the neck in cold water while wearing wet suits. Results were compared with measurements obtained in dry conditions. Echocardiography and Doppler examinations were performed after 15 min and 5 h. Stroke volume, left atrial and left ventricular (LV) diameters remained unchanged during immersion, whereas they significantly fell during the dry session. As an index of LV contractility, percentage fractional shortening remained unchanged, in contrast to a decrease during dry experiment. Heart rate (HR) significantly decreased after 5 h, although it had not changed during the dry session. The changes in the total arterial compliance were similar during the immersed and dry sessions, with a significant decrease after 5 h. In immersed and dry conditions, cardiac output was unchanged after 15 min but decreased by almost 20% after 5 h. This decrease was related to a decrease in HR during immersion and to a decrease in stroke volume in dry conditions. The hydrostatic pressure exerted by water immersion on the systemic vessels could explain these differences. Indeed, the redistribution of blood volume towards the compliant thoracic bed may conceal a part of hypovolaemia that developed in the course of the session. PMID- 17697023 TI - Comparison between aortic, mitral and tricuspid annular velocities measured with quantitative two-dimensional color Doppler tissue imaging in healthy subjects. AB - OBJECTIVES: To compare the systolic, early and late diastolic velocities of the aortic, mitral and tricuspid annuli in healthy subjects and to study the intraobserver and interobserver reproducibility (IIOR) of measuring the velocities at the aortic annulus. METHODS: Twenty healthy subjects with mean age 28 years were investigated with quantitative two-dimensional color Doppler tissue imaging and the systolic, early and late diastolic velocities were measured at the aortic, mitral and tricuspid annuli. RESULTS: The mitral annulus had significant higher systolic velocity and early diastolic velocity than the aortic annulus. The late diastolic velocity was significant lower at the aortic annulus compared with the both other annuli. At the different sites of the annuli the highest systolic velocity and early diastolic velocity were measured at the lateral site of the mitral annulus, whereas the lowest systolic velocity was measured at the septal site of the same annulus. The lowest early diastolic velocity was found at the septal site of the aortic annulus. The highest late diastolic velocity was measured at the lateral site of the tricuspid annulus and the lowest at the lateral site of the aortic annulus. CONCLUSIONS: The mitral annulus has statistical significant higher systolic and early diastolic velocities than the aortic annulus. There are significant differences in velocities between several of the different sites of the annuli. IIOR of measuring the systolic and early diastolic velocities of the aortic annulus is good. PMID- 17697024 TI - Alterations in the peripheral circulation in COPD patients. AB - RATIONALE: Although various factors influence peripheral circulation in chronic obstructive pulmonary disease (COPD) patients, little is known about the vasomotor changes in these subjects. OBJECTIVES: The present study was designed to assess alterations in the brachial circulation of COPD patients. METHODS: Twenty-five COPD patients and 25 healthy subjects were studied. Brachial artery (BA) blood flow and indices of BA stiffness were investigated by two-dimensional ultrasonography and pulsed Doppler. Cardiac dimensions, left ventricular (LV) function and cardiac output were assessed by pulsed Doppler echocardiography. MAIN RESULTS: A significant increase in LV mass was observed in the COPD group despite normal arterial pressure. Total arterial compliance and BA compliance were significantly decreased in COPD patients in comparison with healthy subjects. Heart rate was increased in COPD patients and was inversely correlated with PaO(2) and forced expiratory volume in the first second (FEV(1)). A decrease in LV preload was expressed by a reduction in LV diastolic diameters and LV stroke volume. Patients with severe COPD have a lower BA surface area than patients with moderate COPD. FEV(1) and PaO(2) were significantly related to BA compliance. CONCLUSION: In COPD patients, significant alterations in the peripheral circulation were observed. Moreover, the magnitude of changes in the peripheral circulation was related to the severity of COPD. PMID- 17697025 TI - Dehydration does not influence cardiovascular reactivity to behavioural stress in young healthy humans. AB - Enhanced hydration increases the human cardiovascular reactivity to mental stress. If reduced water intake has the opposite effect, this would suggest controlling for water deprivation when studying such responses. Blood pressure, heart rate and parasympathetically dominated beat-to-beat heart rate fluctuations were assessed during resting baseline and mental stress. Two challenging cognitive-motor tasks, a 5-Choice Reaction Time Task (CRTT) and a Paced Auditory Serial Addition Task (PASAT), served as mental stress tests. Eight female and eight male volunteers were examined twice, after 24 h of water deprivation and after normal water intake (counterbalanced order, 7-day interval). Water deprivation resulted in moderate dehydration with a mean 2.6% decrease of total body weight. Dehydration did neither affect baseline blood pressure, heart rate, nor blood pressure reactivity to mental stress. However, dehydration slightly ( 1.2 bpm) diminished heart rate reactivity to the PASAT (P = 0.03) and increased beat-to-beat heart rate fluctuations in response to the CRTT (P = 0.05). Dehydration intensified CRTT- and PASAT-induced reductions of beat-to-beat heart rate fluctuations in females (gender x dehydration interactions: P = 0.04-0.05). Moderate dehydration induced by water restriction has no effect on blood pressure reactivity to mental stress. The effects on heart rate reactivity are small. However, stress-induced parasympathetic withdrawal may be fortified during dehydration in females, which suggests controlling for water intake when studying such responses. PMID- 17697026 TI - Central fatigue of the first dorsal interosseous muscle during low-force and high force sustained submaximal contractions. AB - The aim of this study was to compare the extent of central fatigue in the first dorsal interosseous (FDI) muscle of healthy adults in low, moderate and high force submaximal contractions. Nine healthy adults completed four experimental sessions where index finger abduction force was recorded during voluntary contractions and in response to brief trains (five pulses at 100 Hz) of electrical stimulation. The ability to maximally activate FDI under volition, or voluntary activation, and its change with sustained activity (central fatigue) was assessed using the twitch interpolation technique. The fatigue tasks consisted of continuous isometric index finger abduction contractions held until exhaustion at four target force levels: 30%, 45%, 60% and 75% of the maximal voluntary contraction. The main finding was the presence of central fatigue for the 30% task, but not for the three other fatigue tasks. The extent of central fatigue was also associated with changes in a measure reflecting the status of peripheral structures/mechanisms. It appears that central fatigue contributed to task failure for the lowest force fatigue task (30%), but not for the other (higher) contraction intensities. PMID- 17697027 TI - Detection of left ventricular dysfunction by Doppler tissue imaging in patients with complete recovery of visual wall motion abnormalities 6 months after a first ST-elevation myocardial infarction. AB - AIMS: The aim of this study was to assess left ventricular (LV) systolic and diastolic function, using Doppler tissue imaging (DTI), in patients with complete recovery of visual wall motion abnormalities six months after a first ST elevation myocardial infarction (STEMI). METHODS: Out of 90 patients presenting with a STEMI, 68 patients without a history of heart disease were examined by echocardiography before discharge and after 6 months. The patients were compared to 41 age matched healthy subjects (HS). LV function was assessed by visual wall motion and mitral annular velocities using pulsed wave DTI. RESULTS: Sixty-eight patients had visual wall motion abnormalities at baseline. Of these, 19 patients showed complete recovery of wall motion at 6-months follow-up. Patients with complete recovery of wall motion abnormalities had significantly reduced peak systolic and peak early diastolic mitral annular velocities compared to HS at 6 months (8.3 cm s(-1) versus 9.9 cm s(-1), P<0.001 for systolic velocity and 9.3 cm s(-1) versus 13.1 cm s(-1), P<0.001 for diastolic velocity, respectively). CONCLUSION: In patients presenting with a first STEMI, mitral annular systolic and early diastolic velocities assessed by DTI at 6-months follow-up are significantly reduced compared to HS, despite normal standard echocardiographic parameters of LV function. This probably reflects a residual subendocardial damage not detected by conventional echocardiographic methods. PMID- 17697028 TI - Suppression of heart rate variability after supramaximal exertion. AB - Wingate test is short anaerobic exercise, performed with maximal power, whereas aerobic exercise at 85% maximal heart rate (HR(max)) may be performed for long period. Sustained HR elevations and changes in autonomic activity indices have been observed after latter kind of exercise. Several studies reported reduction in mean interval between consecutive R peaks in ECG (RRI) 1 h after Wingate test; however, underlying changes in autonomic activity remain elusive. In eight young males, RRI and heart rate variability (HRV) were measured daily over two 5-day trials. Subjects exercised on third day of each trial, measurements were taken 1 h after (i) two consecutive 30-s bouts of Wingate tests or (ii) after a 30-min exercise at 85% HR(max), with subjects in supine rest and breathing either spontaneously or at controlled rates of 6 and 15 breaths / min. RRI was significantly shorter after Wingate and submaximal exercise, reduction of high- and low-frequency components of HRV attained reliability only after Wingate tests. This pattern remained preserved for three modes of breathing: spontaneous, 6 and 15 breaths /min. After 24 and 48 h, no exercise effects were traceable. We hypothesize that (i) anaerobic exertion is followed by sustained inhibition of vagal activity, (ii) parasympathetic system plays dominant role in mediating suppression of high- and low-HRV frequency components during postexercise recovery, (iii) degree of alteration of autonomic activity caused by anaerobic and strenuous aerobic exercise may be similar and (iv) normalization of vagal activity precedes normalization of sympathetic cardiac nerves activity during final stage of postexercise recovery. PMID- 17697029 TI - Post-exercise abdominal, subcutaneous adipose tissue lipolysis in fasting subjects is inhibited by infusion of the somatostatin analogue octreotide. AB - To determine whether blockade of the exercise-induced increase in growth hormone (GH) secretion may affect the regional lipolytic rate in the post-exercise recovery period, the aim of the present experiments was to study the effect of infusion of the somatostatin analogue octreotide on the s.c., abdominal adipose tissue metabolism, before, during and after exercise in healthy, fasting, young male subjects. The adipose tissue net releases of fatty acids and glycerol were measured by arterio-venous catheterizations and simultaneous measurements of adipose tissue blood flow with the local Xe-clearance method. Nine subjects were studied during 1-h basal rest, and then during continuous octreotide infusion during 1-h rest, 1-h exercise at 50% of maximal oxygen consumption and 4-h post exercise rest. A control study on seven subjects was performed under similar conditions but without octreotide infusion. The results show that octreotide infusion during rest increased lipolysis and fatty acid release from the abdominal, s.c. adipose tissue. The exercise-induced increase in lipolysis and fatty acid release does not seem to be affected by octreotide when compared with the control study without octreotide infusion while the post-exercise increase in lipolysis is inhibited by octreotide, suggesting that the exercise-induced increase in GH secretion plays a role for the post-exercise lipolysis in s.c., abdominal adipose tissue. PMID- 17697030 TI - Bronchial responsiveness in bakery workers: relation to airway symptoms, IgE sensitization, nasal indices of inflammation, flour dust exposure and smoking. AB - BACKGROUND: Bronchial hyperresponsiveness (BHR) is common in bakery workers. The relation between bronchial responsiveness measured with a tidal breathing method and smoking, airway symptoms, IgE-sensitization, nasal indices of inflammation and flour dust exposure have been studied with bronchial responsiveness expressed as a continuous outcome. MATERIAL AND METHODS: Bakery workers (n = 197) were subjected to interviews, questionnaires, allergy tests, workplace dust measurements and bronchial metacholine provocation. Eosinophil cationic protein (ECP) and alpha(2)-macroglobulin were measured in nasal lavage. Bronchial responsiveness was expressed as slope(conc), a measurement based on regressing the per cent reduction in FEV(1) at each provocation step. RESULTS: BHR expressed as slope(conc) was associated with smoking (P = 0.009), asthma symptoms at work (P = 0.001), and occupational IgE sensitization (P = 0.048). After adjusting for baseline lung function the association between BHR and IgE sensitization was no longer present. We demonstrated an association between nasal ECP and BHR (slope(conc) < 3: P = 0.012), but not to alpha(2)-macroglobulin in nasal lavage. No association was seen between BHR and current exposure level of flour dust, number of working years in a bakery or a history of dough-making. CONCLUSION: BHR is related to baseline lung function, work-related asthma symptoms, smoking and nasal eosinophil activity, but not to occupational IgE sensitization and current flour dust exposure when measured with metacholine provocation. The slope(conc) expression seems to be a useful continuous outcome in bronchial responsiveness testing. PMID- 17697031 TI - Muscle metaboreflex contribution to resting limb haemodynamic control is preserved in older subjects. AB - Ageing is associated with tonic elevations in basal sympathetic vasoconstrictor outflow to skeletal muscle and a parallel decline in vascular function. The purpose of this study was to test the hypothesis that older individuals exhibit attenuated calf vascular resistance (CVR) responses to muscle metaboreflex activation in comparison with young subjects. Fourteen young (mean +/- SD age 23 +/- 3 years) and 13 older (62 +/- 7 years) sedentary subjects participated in the study. To evaluate muscle metaboreflex, we measured heart rate, mean blood pressure (MBP), calf blood flow (CBF) (venous occlusion plethysmography) and CVR responses to static handgrip exercise at 30% of maximal voluntary contraction, followed by recovery with [postexercise circulatory occlusion, (PECO+)] or without (PECO-) circulatory occlusion. Mean BP and CVR increased significantly (ANOVA P<0.05) throughout exercise and remained elevated during PECO+ when compared with PECO- in both groups. There were no significant differences between the two groups in BP and CVR relative changes from baseline during the entire protocol in both trials. CBF responses were also similar in the young and older subjects, except for the first minute of exercise, where young subjects had higher CBF responses. Our results demonstrate that older subjects have similar BP and calf haemodynamic responses to static handgrip exercise and selective action of the muscle metaboreflex when compared with young subjects, compatible with preserved muscle metaboreflex contribution to resting limb haemodynamic control with ageing in humans. PMID- 17697032 TI - Anti-emetic therapy in cancer chemotherapy: current status. AB - Nausea and vomiting are ranked as the most severe side effects to chemotherapy by cancer patients. Twenty years ago, treatment of nausea and vomiting from chemotherapy only had moderate effect and often unpleasant side effects. The drugs used included dopamine(2)-receptor antagonists and corticosteroids alone or combined. This review summarizes the development of anti-emetic therapy, but will focus on the importance of two new classes of anti-emetics: the serotonin(3)- and the neurokinin(1)-receptor antagonists. Furthermore, evidence-based guidelines for the treatment of chemotherapy-induced nausea and vomiting will be given. The serotonin(3)-receptor antagonists, the first group of drugs developed specifically as anti-emetics, have significantly improved the prophylaxis of chemotherapy-induced emesis especially in combination with a corticosteroid. The improvement in the prophylaxis of nausea with this combination is however modest. A new group of anti-emetics, the neurokinin(1)-receptor antagonists, has now been developed, and the first drug, aprepitant, was marketed in 2003. Aprepitant increases the effect of a serotonin(3)-receptor antagonist plus a corticosteroid against acute emesis induced by highly or moderately emetogenic chemotherapy and aprepitant is also active in the protection against delayed emesis. The importance of drug-drug interactions with anti-emetics and other drugs, especially cytotoxins, through their competition for cytochrome P450 enzymes, have been studied. At present, there is no evidence that such interactions are of major clinical importance. Evidence-based clinical guidelines are now available and regularly updated, but unfortunately clinical implementation is slow. Recommendations for some types of chemotherapy-induced emesis such as delayed emesis, is based on a low level of evidence. Furthermore, the majority of clinical trials include highly selected groups of patients not permitting definite conclusions for other and more heterogeneous patient groups. Development of new anti-emetics with other mechanisms of action is awaited with interest. PMID- 17697033 TI - Assessment of acute respiratory and cardiovascular toxicity of casiopeinas in anaesthetized dogs. AB - The 99 lethal dose in an acute toxicity study of two anticancer novel molecules named casiopeinas((R)) in dogs was calculated to be 200 mg/m(2) for casiopeina III-ia and 160 mg/m(2) for casiopeina IIgly. Considering therapeutic dose ranges from 3.6 to 18 mg/m(2) for the former and 1.2 to 3 mg/m(2) for the latter, true therapeutic margin of safety varies from 4.7 to 23.6 mg/m(2) and from 20 to 50 mg/m(2), respectively. For both casiopeinas intravenous administration of the corresponding lethal dose in 100 ml of 5% dextrose solution in a time period of 30 min. induced death after an almost uneventful latency time period of 30-50 min. Then, after an apparently sudden onset, changes in blood gases indicated respiratory distress (PO(2) from 82.5% to 26.5% for casiopeina III-ia and from 88.6% to 37.5% for casiopeina IIgly; end-tidal CO(2) from 38 to 8.1 mmHg for the first and from 35.1 to 11.2 mmHg for the second, this was almost simultaneously confirmed by the onset of tachypnoea (from 16 to almost 60 breaths/min. for both casiopeinas) and by a drop in arterial blood pressure (from 117 to 51 mmHg for casiopeina III-ia and from 108 to 49 mmHg for casiopeina IIgly). Reflex tachycardia occurs at the beginning of intravenous administration followed by bradycardia a few minutes later (from 158 to 63 beats/min. for casiopeina III-ia and from 148 to 56 beats/min. for casiopeina IIgly). Finally, cardiac arrest occurred no later than 25 min. towards the end of these events lung oedema appeared as fluid dripping from the endotracheal tube. Death occurred in a mean of 15 +/- 5 min. S.D. from the beginning of the end of the latency period. For both casiopeina's data allow the speculation that lung oedema is caused by a joined toxicity to the lung capillary bed, and particularly to the heart. Carvedilol premedication for 8 days delayed the outcome of lung oedema by approximately 8 hr but could not prevent it. PMID- 17697034 TI - Is bupropion a more specific substrate for porcine CYP2E than chlorzoxazone and p nitrophenol? AB - Porcine microsomes are able to hydroxylate chlorzoxazone and p-nitrophenol, the most commonly used human test substrates for CYP2E1. However, in pigs, CYP2E appears not to be the only enzyme involved in the hydroxylation of chlorzoxazone and p-nitrophenol, as the enzyme capacity and immunochemical level of the apoprotein do not correlate. The present study shows that the hydroxylation of chlorzoxazone and p-nitrophenol is inhibited 50-65% by anti-human CYP2A6, suggesting that these substrates are metabolized almost equally well by CYP2A and CYP2E in pigs. To find an alternative probe to porcine CYP2E, bupropion, another human substrate, was examined. Incubation with bupropion concentrations ranging from 0.05 to 20 mM and with various inhibitors revealed that this substrate is metabolized by both CYP2A and CYP2E. At the high substrate concentration (5 mM), however, the CYP2A6 inhibition decreased compared to inhibition percentages found using the low substrate concentration (0.5 mM). The opposite was found for CYP2E, as inhibition studies with antibodies and diethyldithiocarbamate indicate that it catalysed a negligible part of the reaction at the low substrate concentration and up to 84% at the high concentration. Thus, hydroxylation of bupropion follows the same pattern in pigs as in human beings and the activity measured in pigs is comparable with the human counterpart. Furthermore, bupropion is a more specific substrate for CYP2E than chlorzoxazone and p-nitrophenol although not perfect. PMID- 17697035 TI - Enteral exsorption of acetaminophen after intravenous injection in rats: influence of activated charcoal on this clearance path. AB - The fate of acetaminophen after intravenous injection in whole bowel-irrigated rats (n = 40) and the influence of activated charcoal on the kinetics were investigated. After randomization to four groups (n = 10, each group), plasma concentration and the quantities of acetaminophen and metabolites excreted into bile, urine and intestine were determined using an in vivo model with or without orally administered activated charcoal and with or without bile duct cannulation. The cumulative amount of acetaminiphen and metabolites exsorbed into the small intestine within 3.5 hr after intravenous injection was about 20% of dose in the animals with bile duct cannulation and about 7% of dose in the animals without. Correspondingly, about 13% of dose was detected in the externalized bile. Activated charcoal did not influence the amount exsorbed into the small intestine. Terminal half-life in plasma ranged from 35 to 51 min. within the four treatment groups without statistically significant difference (P = 0.152). Correspondingly, the area under the curve did not vary much and ranged between 2.6 and 3.3 g/min./l (P = 0.392). Deposition of acetaminophen and metabolites in liver and kidney after 3.5 hr was marginal and ranged between 0.02% and 0.6% of the dose within all groups. The excretion of acetaminophen and metabolites into urine varied strikingly between 31% and 56% of the dose within all groups and correlated with diuresis. The lack of effect of activated charcoal on the elimination of acetaminophen and metabolites may be due to the small amount of the drug being exsorbed into the intestine or the reduced adsorbent capacity of activated charcoal to acetaminophen and metabolites, which also could be influenced by inadequate luminal stirring. PMID- 17697036 TI - Effects of paracetamol combined with dextromethorphan in human experimental muscle and skin pain. AB - By combining drugs with different mechanisms of action, synergistic effects may be achieved. The aim of the present experimental pain study was to combine paracetamol with dextromethorphan for synergistic effects. Furthermore, the reproducibility of the pain assessment methods was evaluated. Eighteen volunteers completed all periods in a three-way cross-over study. Pain stimuli were assessed at baseline and 1, 2 and 3 hr after dosing. The aim was to compare the pain alleviating effect of 1 g paracetamol, 1 g paracetamol plus 30 mg dextromethorphan and placebo in response to a number of different stimuli in a human experimental volunteer model of skin and muscle pain. Repeated electrical stimulation of skin and muscle (temporal summation) modelled central integration and intramuscular hypertonic saline mimicked musculoskeletal pain. The method provided statistically stable pain recordings between repetitions on the same day and between days (all P > 0.05). Between repetitions on the same day, all tests were reproducible within the participants (intra-class correlation > 0.60). Between days all tests, except muscular pain pressure threshold, were reproducible within the participants (intra-class correlation > 0.60). There were no statistical differences (all P > 0.05) between paracetamol compared to placebo, and between the effect of paracetamol and dextromethorphan compared to placebo. The acute pain models were not sufficiently sensitive to detect an analgesic effect of paracetamol or the combination with dextromethorphan. The selected dose of dextromethorphan was low as the aim was to use commonly used doses, and a higher dose of dextromethorphan is most likely needed to attenuate the selected pain measures. PMID- 17697038 TI - The effect of potassium channel opener pinacidil on the non-pregnant rat uterus. AB - The effects of the K(+) channel opener, pinacidil on the spontaneous rhythmic contractions and contractions provoked by electrical field stimulation (50 Hz) or by oxytocin were investigated in the isolated uterus of the non-pregnant rat in oestrus. Pinacidil produced more potent inhibition of oxytocin-elicited contractions than of spontaneous rhythmic contractions or electrical field stimulation-induced contractions. Glibenclamide, a selective blocker of adenosine triphosphate (ATP)-sensitive K(+) (K(ATP)) channels, antagonized the pinacidil induced inhibition of contractions elicited by oxytocin in a competitive manner. However, the pinacidil-induced inhibition of electrical field stimulation elicited contractions and spontaneous rhythmic contractions was antagonized non competitively by glibenclamide. In the uterine strips pre-contracted with 80 mM K(+), the pinacidil-induced maximal relaxation was not affected. The present data show that pinacidil exhibits potent relaxant properties in the rat non-pregnant uterus in oestrus and therefore should be taken into account as a possible agent for treatment of dysmenorrhoea. Based on glibenclamide affinity, it appears that the inhibitory response to pinacidil involves K(ATP )channels. We need further investigations to explain why the interaction between glibenclamide and pinacidil in this experimental model depends on the nature of contractions. The ability of pinacidil to completely relax the rat non-pregnant uterus pre-contracted with K(+)-rich solution suggests that K(+) channel-independent mechanism(s) also play a part in its relaxant effect. PMID- 17697037 TI - Amelioration of corticosteroid-induced type 2 diabetes mellitus by rosiglitazone is possibly mediated through stimulation of thyroid function and inhibition of tissue lipid peroxidation in mice. AB - We investigated the possible involvement of thyroid hormones and lipid peroxidation in the antidiabetic potential of rosiglitazone (a peroxisome proliferator-activated receptors gamma-agonist) on corticosteroid-induced type 2 diabetes mellitus. Rosiglitazone was administered to dexamethasone-induced hyperglycaemic male mice and the alterations in serum concentrations of thyroid hormones insulin, total cholesterol, triglycerides and fasting glucose were studied. Simultaneously changes in lipid peroxidation, reduced glutathione (GSH) content, superoxide dismutase and catalase activities in renal and cardiac tissues (which are commonly affected in diabetes mellitus), were also investigated. Administration of dexamethasone (1.0 mg/kg/day intramuscularly for 28 days) caused hyperglycaemia with a parallel increase in serum insulin, total cholesterol, triglycerides and tissue lipid peroxidation with a decrease in serum levels of both the thyroid hormones (triiodothyronine, T(3) and thyroxine, T(4)) and in the activity of associated tissue antioxidants such as superoxide, catalase and glutathione. However, rosiglitazone administration (3.2 mg/kg/day orally for 21 days) along with an equivalent amount of dexamethasone reverted most of these changes, including a marked inhibition of tissue lipid peroxidation and an increase in the serum levels of both thyroid hormones. The present findings reveal that the test drug ameliorates corticosteroid-induced type 2 diabetes mellitus through an increase in serum thyroid hormone concentrations and inhibition in tissue lipid peroxidation. PMID- 17697039 TI - Effects of caffeic acid phenethyl ester on the histopathological changes in the lungs of cigarette smoke-exposed rabbits. AB - We aimed at evaluating the effects of caffeic acid phenethyl ester (CAPE) on the histopathological changes in the lungs of rabbits exposed to cigarette smoke exposure. Four groups with six rabbits each were as follows: cigarette smoke group, CAPE group, cigarette smoke + CAPE group and control group. The cigarette smoke group was exposed to cigarette smoke 1 hr daily for 1 month. The CAPE group was administered intraperitoneal CAPE. The CAPE + cigarette smoke group was both exposed to cigarette smoke and was administered intraperitoneal CAPE. The control group was exposed to clean air. After 1 month, the rabbits were killed and the lung tissues were examined histopathologically. Peribronchial and intraparenchymal inflammation, intraparenchymal vascular congestion and thrombosis, intraparenchymal haemorrhage, respiratory epithelial proliferation, number of macrophages in the bronchiolar and alveolar lumen, alveolar destruction, emphysematous changes and bronchoalveolar haemorrhage scores were significantly higher in the cigarette smoke group than in the control group. Administration of CAPE to cigarette smoke-exposed rabbits significantly prevented all these changes. CAPE seems to have significant preventive effects on the severe histopathological changes in the lungs associated with cigarette smoke exposure. However, in some instances, it may not alter the progression to fibrosis. PMID- 17697040 TI - Influence of endotoxin-induced sepsis on the requirements of propofol-fentanyl infusion rate in pigs. AB - Endotoxin-induced sepsis in pigs is a recognized experimental model for the study of human septic shock. Generally, pigs are brought into general anaesthesia before sepsis is induced. It is our experience that drug dosages of propofol and fentanyl need to be reduced during endotoxin-induced sepsis, in order to prevent respiratory and cardiovascular depression, but the scientific evidence for this observation is lacking. Therefore, we measured the consumption of propofol and fentanyl at equal level of anaesthesia in pigs with (n = 5) and without (n = 5) endotoxin-induced sepsis, using the cerebral state index (CSI) as measure of anaesthetic depth. Infusion rates of propofol (P < 0.01) and fentanyl (P < 0.05) were significantly lower in septic pigs. Pigs with endotoxin-induced sepsis had an infusion rate of 2.2 mg/kg/hr (S.D. 0.5) for propofol and 12 microg/kg/hr (S.D. 2) for fentanyl, whereas healthy pigs had infusion rates of 3.5 mg/kg/hr (S.D. 0.6) and 17 microg/kg/hr (S.D. 4), respectively. CSI was equal in both groups throughout the experiment, and had a lowest average value of 47 (S.D. 10) at t = 30 in healthy pigs and reached a highest average value of 67 (S.D. 19) at t = 240 in pigs with endotoxin-induced sepsis. Anaesthetic depth was sufficient, assessed clinically, throughout the experiment in both groups. We concluded that the consumption of propofol and fentanyl was significantly reduced in pigs with endotoxin-induced sepsis. In the present study, we adjusted the level of anaesthesia according to clinical signs, and found good agreement with CSI. PMID- 17697041 TI - Protective effect of quercetin on the homocysteine-injured human umbilical vein vascular endothelial cell line (ECV304). AB - Homocysteine is responsible for the occurrence of many cardiovascular diseases for instance by injuring the vascular endothelial cells. Quercetin has many beneficial effects on the cardiovascular system, but it is unknown whether it provides protection against homocysteine-injured vascular endothelial cells. The aim of the present study was to investigate the protective effect and mechanism of quercetin on the homocysteine-injured human umbilical vein vascular endothelial cell line (ECV304) (i.e. morphology, viability and nuclear factor kappa B (NF-kappaB) expression of ECV304 injured with 1.0 mM homocysteine) by determination of lipid peroxidant and endothelium-derived factors in the cultural medium of homocysteine-injured ECV304. Quercetin at 6.25, 12.5, 25, 50 and 100 microM attenuated the morphological changes and increased viability of homocysteine-injured ECV304 in a dose-dependent manner (P < 0.05 or P < 0.01 versus the homocysteine-injured group). At the same time, quercetin at 12.5, 25 and 50 microM decreased malondialdehyde level, endothelin release and NF-kappaB expression, and increased superoxide dismutase activity, nitric oxide and 6-keto prostaglandin F1alpha releases in homocysteine-injured ECV304 (P < 0.05 or P < 0.01 versus the homocysteine-injured group). These results suggest that quercetin has a protective effect on homocysteine-injured vascular endothelial cells by antioxidant and anti-inflammatory mechanisms. PMID- 17697042 TI - [(3)H] citalopram binding to serotonin transporter sites in minnow brains. AB - Mammalian serotonin (SERT) and norepinephrine transporters (NET) are target sites for antidepressants and are affected by pesticide exposures. Herein, we examined whether golden shiner (Notemigonus crysoleucas) or fathead minnow (Pimphales promelas) SERTs and catecholamine transporters respond comparably to mammalian SERTs and NETs. We compared the pharmacological profiles of central SERT and NET binding sites of the golden shiner minnow to those of rats. Homogenate binding with the radioligand [(3)H] citalopram indicated that golden shiner SERT has a K(D) of 7 +/- 3 nM and a B(max) of 226 +/- 46 fmol/mg protein. These values are similar to those of rat cortical SERT (K(D) 1.4 +/- 0.1 nM and B(max) 240 +/- 48 fmol/mg protein). We also examined SERT binding in fathead minnow brain, and found it similar to that of the golden shiner. A putative golden shiner NET, measured using [(3)H] nisoxetine, had K(D) = 12 +/- 5 nM and B(max) = 187 +/- 49 fmol/mg protein, whereas rat hippocampal NET had K(D) = 5 +/- 2 nM and B(max) = 93 +/- 8 fmol/mg protein. Minnow SERT and NET binding is displaceable by selective reuptake inhibitors. Finally, we exposed zebrafish (Danio rerio) to the serotonin reuptake inhibiting antidepressant sertraline or the organophosphate chlorpyrifos for 21 days. After either treatment, SERT binding was reduced by 50% (n = 3-6, P < 0.05). In summary, minnow central SERT and NET express slightly lower affinity for antidepressants than rats. However, magnitudes of affinity are similar, and minnow SERT binding is decreased by chronic sertraline or chlorpyrifos administration. PMID- 17697043 TI - Substrate-dependent modulation of UDP-glucuronosyltransferase 1A1 (UGT1A1) by propofol in recombinant human UGT1A1 and human liver microsomes. AB - Our previous study has shown that propofol, a probe substrate for human UDP glucuronosyltransferase (UGT) 1A9, activated the glucuronidation of 4 methylumbelliferone (4-MU) by recombinant UGT1A1 in a concentration-dependent manner. In the present study, we investigated the mechanism of activation, and whether the stimulatory effect occurs when another substrate is used with human liver microsomes. The glucuronidation of 4-MU followed Michaelis-Menten kinetics with a K(m) value of 101 microM in the absence of propofol. In the presence of 200 microM propofol, a concentration that causes heterotopic activation of 4-MU glucuronidation (4-MUG), the V(max) value increased to 1.5-fold, while the K(m) value decreased to 0.53-fold. In order to assess whether propofol activates UGT1A1 activity for a substrate other than 4-MU, the effect of propofol on oestradiol 3beta-glucuronidation by recombinant UGT1A1 and in human liver microsomes was evaluated. In contrast to 4-MUG activity, propofol inhibited UGT1A1-catalysed oestradiol 3beta-glucuronidation in recombinant UGT1A1 as well as in human liver microsomes with IC(50) values of 59 and 228 microM, respectively. In addition, a known UGT1A1 modulator, 17alpha-ethynyloestradiol, stimulated oestradiol 3beta-glucuronidation slightly at a concentration of 5 microM, while it inhibited 4-MUG in recombinant UGT1A1 at all concentrations tested (5-100 microM). These findings indicate that the modulation of UGT1A1 by propofol is substrate-dependent, and thus care should be taken when extrapolating the stimulatory effects of drugs for one glucuronidation substrate. PMID- 17697045 TI - IP3 receptor/Ca2+ channel: from discovery to new signaling concepts. AB - Inositol 1,4,5-trisphosphate (IP(3)) is a second messenger that induces the release of Ca(2+) from the endoplasmic reticulum (ER). The IP(3) receptor (IP(3)R) was discovered as a developmentally regulated glyco-phosphoprotein, P400, that was missing in strains of mutant mice. IP(3)R can allosterically and dynamically change its form in a reversible manner. The crystal structures of the IP(3)-binding core and N-terminal suppressor sequence of IP(3)R have been identified. An IP(3) indicator (known as IP(3)R-based IP(3) sensor) was developed from the IP(3)-binding core. The IP(3)-binding core's affinity to IP(3) is very similar among the three isoforms of IP(3)R; instead, the N-terminal IP(3) binding suppressor region is responsible for isoform-specific IP(3)-binding affinity tuning. Various pathways for the trafficking of IP(3)R have been identified; for example, the ER forms a meshwork upon which IP(3)R moves by lateral diffusion, and vesicular ER subcompartments containing IP(3)R move rapidly along microtubles using a kinesin motor. Furthermore, IP(3)R mRNA within mRNA granules also moves along microtubules. IP(3)Rs are involved in exocrine secretion. ERp44 works as a redox sensor in the ER and regulates IP(3)R1 activity. IP(3) has been found to release Ca(2+), but it also releases IRBIT (IP(3)R-binding protein released with IP(3)). IRBIT is a pseudo-ligand for IP(3) that regulates the frequency and amplitude of Ca(2+) oscillations through IP(3)R. IRBIT binds to pancreas-type Na, bicarbonate co-transporter 1, which is important for acid-base balance. The presence of many kinds of binding partners, like homer, protein 4.1N, huntingtin associated protein-1A, protein phosphatases (PPI and PP2A), RACK1, ankyrin, chromogranin, carbonic anhydrase-related protein, IRBIT, Na,K-ATPase, and ERp44, suggest that IP(3)Rs form a macro signal complex and function as a center for signaling cascades. The structure of IP(3)R1, as revealed by cryoelectron microscopy, fits closely with these molecules. PMID- 17697046 TI - The role of nucleotides in the neuron--glia communication responsible for the brain functions. AB - Accumulating findings indicate that nucleotides play an important role in cell-to cell communication through P2 purinoceptors, even though ATP is recognized primarily to be a source of free energy and nucleotides are key molecules in cells. P2 purinoceptors are divided into two families, ionotropic receptors (P2X) and metabotropic receptors (P2Y). P2X receptors (7 types; P2X(1)-P2X(7)) contain intrinsic pores that open by binding with ATP. P2Y (8 types; P2Y(1, 2, 4, 6, 11, 12, 13,) and (14)) are activated by nucleotides and couple to intracellular second-messenger systems through heteromeric G-proteins. Nucleotides are released or leaked from non-excitable cells as well as neurons in physiological and pathophysiological conditions. One of the most exciting cells in non-excitable cells is the glia cells, which are classified into astrocytes, oligodendrocytes, and microglia. Astrocytes express many types of P2 purinoceptors and release the 'gliotransmitter' ATP to communicate with neurons, microglia and the vascular walls of capillaries. Microglia also express many types of P2 purinoceptors and are known as resident macrophages in the CNS. ATP and other nucleotides work as 'warning molecules' especially through activating microglia in pathophysiological conditions. Microglia play a key role in neuropathic pain and show phagocytosis through nucleotide-evoked activation of P2X(4) and P2Y(6) receptors, respectively. Such strong molecular, cellular and system-level evidence for extracellular nucleotide signaling places nucleotides in the central stage of cell communications in glia/CNS. PMID- 17697047 TI - Regeneration of the central nervous system using endogenous repair mechanisms. AB - Recent advances in developmental and stem cell biology have made regeneration based therapies feasible as therapeutic strategies for patients with damaged central nervous systems (CNSs), including those with spinal cord injuries, Parkinson disease, or stroke. These strategies can be classified into two approaches: (i) the replenishment of lost neural cells and (ii) the induction of axonal regeneration. The first approach includes the activation of endogenous neural stem cells (NSCs) in the adult CNS and cell transplantation therapy. Endogenous NSCs have been shown to give rise to new neurons after insults, including ischemia, have been sustained; this form of neurogenesis followed by the migration and functional maturation of neuronal cells, as well as the responses of glial cells and the vascular system play crucial roles in endogenous repair mechanisms in damaged CNS tissue. In this review, we will summarize the recent advances in regeneration-based therapeutic approaches using endogenous NSCs, including the results of our own collaborative groups. PMID- 17697048 TI - Protective effects of 15-deoxy-Delta12,14-prostaglandin J2 against glutamate induced cell death in primary cortical neuron cultures: induction of adaptive response and enhancement of cell tolerance primarily through up-regulation of cellular glutathione. AB - There is increasing evidence to suggest that reactive oxygen species, including a variety of lipid oxidation products and other physiologically existing oxidative stimuli, can induce an adaptive response and enhance cell tolerance. In the present study, by using cultured cortical neurons, we investigated the effect of electrophilic lipids, such as 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d PGJ(2)) and 4-hydroxy-2-nonenal (4-HNE) against the cell death induced by H(2)O(2) and glutamate. Pre-treatment with both 15d-PGJ(2) and 4-HNE at sublethal concentrations resulted in a significant protective effect against oxidative stress, and 15d-PGJ(2), in particular, exhibited a complete protective effect against glutamate-induced neuronal cell death. Pre-treatment with 15d-PGJ(2) increased the intracellular glutathione (GSH) as well as the gene expression of glutamate-cysteine ligase (GCL), the rate-limiting enzyme of GSH synthesis. 15d PGJ(2) protected cells from glutamate-induced GSH depletion, while the inhibition of cellular GSH synthesis by buthionine sulfoximine abolished the adaptive response induced by 15d-PGJ(2). These findings indicate that at low levels, 15d PGJ(2) acts as a potent survival mediator against glutamate-induced insults via the induction of an adaptive response primarily through the up-regulation of the intracellular GSH synthesis. PMID- 17697049 TI - A novel PIP2 binding of epsilonPKC and its contribution to the neurite induction ability. AB - Protein kinase C-epsilon (epsilonPKC) induces neurite outgrowth in neuroblastoma cells but molecular mechanism of the epsilonPKC-induced neurite outgrowth is not fully understood. Therefore, we investigated the ability of phosphatidylinositol 4,5-bisphosphate (PIP(2)) binding of epsilonPKC and its correlation with the neurite extension. We found that full length epsilonPKC bound to PIP(2) in a 12 omicron-tetradecanoylphorbol-13-acetate dependent manner, while the regulatory domain of epsilonPKC (epsilonRD) bound to PIP(2) without any stimulation. To identify the PIP(2) binding region, we made mutants lacking several regions from epsilonRD, and examined their PIP(2) binding activity. The mutants lacking variable region 1 (V1) bound to PIP(2) stronger than intact epsilonRD, while the mutants lacking pseudo-substrate or common region 1 (C1) lost the binding. The PIP(2) binding ability of the V3-deleted mutant was weakened. Those PIP(2) bindings of epsilonPKC, epsilonRD and the mutants well correlated to their neurite induction ability. In addition, a chimera of pleckstrin homology domain of phospholipase Cdelta and the V3 region of epsilonPKC revealed that PIP(2) binding domain and the V3 region are sufficient for the neurite induction, and a first 16 amino acids in the V3 region was important for neurite extension. In conclusion, epsilonPKC directly binds to PIP(2) mainly through pseudo-substrate and common region 1, contributing to the neurite induction activity. PMID- 17697050 TI - Activation of cholecystokinin neurons in the dorsal pallium of the telencephalon is indispensable for the acquisition of chick imprinting behavior. AB - Chick imprinting behavior is a good model for the study of learning and memory. Imprinting object is recognized and processed in the visual wulst, and the memory is stored in the intermediate medial mesopallium in the dorsal pallium of the telencephalon. We identified chicken cholecystokinin (CCK)-expressing cells localized in these area. The number of CCK mRNA-positive cells increased in chicks underwent imprinting training, and these cells expressed nuclear Fos immunoreactivity at high frequency in these regions. Most of these CCK-positive cells were glutamatergic and negative for parvalbumin immunoreactivity. Semi quantitative PCR analysis revealed that the CCK mRNA levels were significantly increased in the trained chicks compared with untrained chicks. In contrast, the increase in CCK- and c-Fos-double-positive cells associated with the training was not observed after closure of the critical period. These results indicate that CCK cells in the dorsal pallium are activated acutely by visual training that can elicit imprinting. In addition, the CCK receptor antagonist significantly suppressed the acquisition of memory. These results suggest that the activation of CCK cells in the visual wulst as well as in the intermediate medial mesopallium by visual stimuli is indispensable for the acquisition of visual imprinting. PMID- 17697051 TI - Neurotensin type 2 receptor is involved in fear memory in mice. AB - Neurotensin receptor subtype 2 (Ntsr2) is a levocabastine-sensitive neurotensin receptor expressed diffusely throughout the mouse brain. Previously, we found that Ntsr2-deficient mice have an abnormality in the processing of thermal nociception. In this study, to examine the involvement of Ntsr2 in mouse behavior, we performed a fear-conditioning test in Ntsr2-deficient mice. In the contextual fear-conditioning test, the freezing response was significantly reduced in Ntsr2-deficient mice compared with that of wild-type mice. This reduction was observed from 1 h to 3 weeks after conditioning, and neither shock sensitivity nor locomotor activity was altered in Ntsr2-deficient mice. In addition, we found that Ntsr2 mRNA was predominantly expressed in cultured astrocytes and weakly expressed in cultured neurons derived from mouse brain. The combination of in situ hybridization and immunohistochemistry showed that Ntsr2 mRNA was dominantly expressed in glial fibrillary acidic protein positive cells in many brain regions including the hypothalamus, while Ntsr2 gene was co expressed with neuron-specific microtubule associated protein-2 in limited numbers of cells. These results suggest that Ntsr2 in astrocytes and neurons may have unique function like a modulation of fear memory in the mouse brain. PMID- 17697052 TI - Peripheral inflammatory hyperalgesia modulates morphine delivery to the brain: a role for P-glycoprotein. AB - P-glycoprotein (Pgp, ABCB1) is a critical efflux transporter at the blood-brain barrier (BBB) where its luminal location and substrate promiscuity limit the brain distribution of numerous therapeutics. Moreover, Pgp is known to confer multi-drug resistance in cancer chemotherapy and brain diseases, such as epilepsy, and is highly regulated by inflammatory mediators. The involvement of inflammatory processes in neuropathological states has led us to investigate the effects of peripheral inflammatory hyperalgesia on transport properties at the BBB. In the present study, we examined the effects of lambda-carrageenan-induced inflammatory pain (CIP) on brain endothelium regulation of Pgp. Western blot analysis of enriched brain microvessel fractions showed increased Pgp expression 3 h post-CIP. In situ brain perfusion studies paralleled these findings with decreased brain uptake of the Pgp substrate and opiate analgesic, [(3)H] morphine. Cyclosporin A-mediated inhibition of Pgp enhanced the uptake of morphine in lambda-carrageenan and control animals. This indicates that the CIP induced decrease in morphine transport was the result of an increase in Pgp activity at the BBB. Furthermore, antinociception studies showed decreased morphine analgesia following CIP. The observation that CIP modulates Pgp at the BBB in vivo is critical to understanding BBB regulation during inflammatory disease states. PMID- 17697053 TI - Minimal role for activating transcription factor 3 in the oligodendrocyte unfolded protein response in vivo. AB - To further our goal of identifying and characterizing the functions of major components of the unfolded protein response (UPR) in oligodendrocytes, the gene encoding the activator of transcription factor 3 protein (ATF3) has been ablated in mice expressing mutant forms of the Proteolipid protein 1 (Plp1) gene and the phenotype of double mutants characterized at several levels. Mature oligodendrocytes in Plp1 mutant mice undergo UPR-induced cell stress, induce ATF3 expression and exhibit a greater propensity to die by apoptosis, which is consistent with pro-death function of ATF3 proposed from in vitro studies. However, we find that the absence of ATF3 has no effect on the levels of apoptosis in Plp1 mutants. Furthermore, we find that oligodendrocyte function appears normal in Atf3(-/-) mice and that motor coordination and neural communication are similarly unaffected. Accordingly, we conclude that ATF3, at best, plays a minor role in UPR signaling and its expression is more likely induced by the UPR as a secondary event in oligodendrocytes that is unrelated to cell death. PMID- 17697054 TI - Dyslipidaemia in diabetic patients: time for a rethink. AB - Patients with type 2 diabetes have a marked increase in the risk of premature coronary heart disease (CHD). One of the underlying reasons for this increased risk is atherogenic dyslipidaemia, which is common in this patient group and characterized by low plasma levels of high-density lipoprotein cholesterol (HDL C), increased levels of serum triglycerides, specifically very low-density lipoprotein triglycerides, and an increase in small, dense low-density lipoprotein (LDL) particles. Current management strategies focus on the initial use of statin or fibrate therapy (the latter approach indicated in patients with pronounced hypertriglyceridaemia). Recent treatment guidelines also emphasize the need for reduction in LDL-cholesterol (LDL-C) below 100 mg/dl (2.6 mmol/l) in diabetic patients, as this patient group has a clustering of cardiovascular risk factors that collectively lead to an excess risk of premature mortality. Multidrug lipid-modifying therapy has been proposed to further reduce CHD risk in diabetic patients. Adding nicotinic acid to primary statin therapy would be a logical approach based on the complementary therapeutic benefits of these treatments. Nicotinic acid is the most potent agent currently available for raising HDL-C and is also effective in reducing triglycerides and LDL-C. Moreover, clinical trial data have shown that nicotinic acid can be safely used in diabetic patients. Data from the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER 2) study in patients with established CHD and low HDL-C (27% of whom had type 2 diabetes) show the atheroprotective effects of nicotinic acid/statin combination therapy. The clinical benefits of this combination therapy are indicated by subgroup analyses from the HDL-Atherosclerosis Treatment Study, which showed 40% reduction in coronary event frequency in patients with impaired glucose tolerance. Together, these data support the proposed strategy of aggressive multidrug treatment of diabetic dyslipidaemia to improve patient outcome. PMID- 17697056 TI - Premixed insulin treatment for type 2 diabetes: analogue or human? AB - The progressive nature of type 2 diabetes makes insulin initiation a necessary therapeutic step for many patients. Premixed insulin formulations containing both basal and prandial insulin (so called biphasic insulin) are often prescribed because they are superior to long- or intermediate-acting insulin in obtaining good metabolic control. In addition, they are considered as an attractive alternative to classical basal-bolus therapy as fewer daily injections are required. Premixed insulin formulations include conventional (e.g. biphasic human insulin 70/30, or 30/70 in European countries, BHI 30) and newer premixed human analogues (e.g. biphasic insulin aspart 70/30, or 30/70 in Europe, BIAsp 30; insulin lispro mix 75/25-Mix 75/25, or Mix 25/75 in Europe). Like conventional premixed human insulin, premixed insulin analogues contain a fixed proportion of soluble, rapid-acting insulin analogue, with protaminated analogue comprising the remainder. Unlike conventional premixes, analogue premixes have more physiological pharmacokinetic and therapeutically more desirable pharmacodynamic profiles than premixed human insulin. Consequently, postprandial glycaemic control is better with premixed insulin analogues than with premixed human insulin. In nontreat-to-target registration trials, the lowering of haemoglobin A(1c) with premixed insulin analogues was not inferior to that seen with premixed human insulin. Minor hypoglycaemia was similar for premixed analogue and premixed human insulins, while major hypoglycaemia appears to be rare with either formulation. The occurrence of adverse events, other than hypoglycaemia, was also similar between various premix insulins. The premixed insulin analogues, BIAsp 30 and Mix 75/25, like the fast-acting analogues from which they are derived, also allow flexible injection timing, relative to meal timing, thus improving adherence, compliance and quality of life compared with premixed human insulin. Overall, the evidence suggests that premixed insulin analogues are cost effective and have useful advantages over premixed human insulin for the treatment of type 2 diabetes. PMID- 17697055 TI - The role of angiotensin II type 1 receptor blockers in the prevention and management of diabetes mellitus. AB - Angiotensin II Receptor blockers (ARBs) are an important addition to the current range of medications available for treating a wide spectrum of diseases including cardiovascular diseases. Coronary heart disease (CHD) is the most common cause of death in the United Kingdom and worldwide. More importantly, the presence of the metabolic syndrome and the likelihood of diabetes mellitus taking on epidemic proportions in the years to come all threaten to maintain the mortality rate due to CHD. This review article focuses on the clinical studies that have helped define the trends in the usage of these agents in the prevention and treatment of diabetes mellitus and its complications and also explores possible mechanisms of action and future developments. PMID- 17697057 TI - Effects of pioglitazone on lipid and lipoprotein metabolism. AB - Type 2 diabetes is associated with an increased risk of cardiovascular disease (CVD). A major contributing factor to this risk is the abnormal lipid profile known as dyslipidaemia, which is characterized by low HDL cholesterol (HDL-C), raised triglycerides (TGs) and a predominance of small, dense LDL cholesterol (LDL-C) particles. Statins are now widely used first-line in patients with type 2 diabetes due to their proven efficacy in reducing LDL-C and cardiovascular risk. However, despite the use of statins, the absolute risk of CVD in patients remains elevated, highlighting the need to target all aspects of the diabetic lipid profile such as raised TGs or low HDL-C levels. Insulin resistance is thought to be central in the pathogenesis of diabetic dyslipidaemia; therefore, improving insulin sensitivity with a thiazolidinedione offers an attractive treatment option. Indeed, pioglitazone, a member of the peroxisome proliferator-activated receptor-gamma family, has been shown in clinical trials to improve both blood glucose levels and the lipid profile when used either as monotherapy or in combination with other oral antidiabetic agents. In the monotherapy setting, pioglitazone has been associated with greater decreases in TGs and increases in HDL-C when compared with glibenclamide or metformin. Studies investigating the effects of pioglitazone add-on therapy to either metformin or sulphonylurea treatments have shown sustained improvements in serum levels of TGs and HDL-C and favourable effects on LDL-C particle size. In comparison with rosiglitazone, pioglitazone has different and potentially favourable effects on plasma lipids. The recent PROspective pioglitAzone Clinical Trial In macroVascular Events study has given weight to the hypothesis that the beneficial metabolic effects of pioglitazone may be associated with reductions in cardiovascular risk in patients with type 2 diabetes. PMID- 17697058 TI - The implications of anthropometric, inflammatory and glycaemic control indices in the epidemiology of the metabolic syndrome given by different definitions: a classification analysis. AB - BACKGROUND: Individuals with the metabolic syndrome (MS) are at high risk for coronary heart disease. In this study, we evaluated the levels of inflammatory, lipidaemic and glycaemic control markers in subjects with and without MS, as given by different definitions. METHODS: During 2001-2002, we randomly enrolled 1,514 men (18-87 years old) and 1,528 women (18-89 years old), without any clinical evidence of cardiovascular disease, from the Attica area, Greece. Among several variables, we also measured inflammatory markers, total antioxidant capacity, glucose and insulin levels and various lipids. MS was defined according to either the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III criteria or the International Diabetes Federation (IDF) Epidemiology Task Force group. In all the analyses, subjects with diabetes were excluded. RESULTS: The prevalence of the MS was 17.9% according to the NCEP definition and 48.9% according to the IDF definition (p < 0.001). The prevalence of MS was higher in men compared with women according to both definitions (p for gender differences <0.001). Moreover, 3.9% of the total study sample fulfilled only the NCEP criteria, but not the IDF, while 38.6% fulfilled only the IDF criteria. Subjects who were defined as having MS using the IDF criteria were younger, had higher body mass index, C-reactive protein, fibrinogen, tumour necrosis factor alpha levels, total antioxidant capacity and lower glucose and insulin levels. CONCLUSIONS: Prevalence of the MS is very high among Greek adults when the IDF definition is used, while it is still considerable when we adopt the NCEP criteria. It is evident that subjects who fulfilled the IDF criteria showed increased levels of inflammatory markers compared with those who fulfilled the NCEP ATP III criteria. PMID- 17697059 TI - The effects of underfeeding on whole-body carbohydrate partitioning, thermogenesis and uncoupling protein 3 expression in human skeletal muscle. AB - AIM: Underfeeding is known to reduce resting energy expenditure (REE) as an energy-conserving mechanism and may also reduce insulin sensitivity. Uncoupling protein 1 is known to have a significant role in energy expenditure (EE) in small mammals, but the role of UCPs in humans is unclear. UCP3 is primarily expressed in human skeletal muscle, a significant site of whole-body EE in lean individuals and therefore has a potential role in human metabolism. Here, we examine the effects of short-term underfeeding on UCP3 skeletal muscle expression, and on whole-body insulin sensitivity, substrate utilization and thermogenesis. METHODS: Eleven non-obese men [age 22.8 +/- 1.34 years, body mass index 23.4 +/- 0.71 kg/m(2), mean +/- s.e.m.] were fed for two periods of 6 days, an underfeeding diet (UF) (50% predicted requirements for weight maintenance) and an eucaloric diet (EU), with the same macronutrient composition, in random order. Subjects visited the laboratory on four separate occasions, before and after each dietary period. REE, metabolites and muscle biopsies (vastus lateralis) were taken and the thermogenic response to a hyperinsulinaemic euglycaemic clamp was measured over a 2-h period. UCP3 mRNA levels were measured using Taqman. RESULTS: After underfeeding for 6 days, REE fell by 0.43 +/- 0.17 kJ/min (p = 0.032), with weight loss of 2.05 +/- 0.34 kg (p < 0.001). Baseline fasting glucose was significantly lower at 4.26 +/- 0.07 mmol/l (p = 0.005), with a corresponding fall in carbohydrate oxidation (0.08 +/- 0.03 g/min; p = 0.04). Fasting free fatty acids (FFA) increased by 0.13 +/- 0.03 mmol/l (p < 0.001), with an increase in beta-hydroxybutyrate concentrations of 0.41 +/- 0.07 mM (p < 0.001) compared with post-EU. There was no significant change in UCP3 mRNA levels pre- and post UF [10.4 +/- 6.8 arbitrary units (au); p = 0.16] compared with pre- and post-EU (3.2 +/- 7.3 au; p = 0.67). There was no thermogenic response to the clamp after 6 days of underfeeding and a significant reduction in glucose disposal rates (from 46.35 +/- 2.15 to 39.46 +/- 1.12 micromol/min/kg; p = 0.003). Carbohydrate oxidation rates were lower by 0.08 +/- 0.03 g/min (p = 0.011) compared with pre UF, with no change in glucose storage rates (28.2 +/- 2.4 micromol/min/kg pre-UF; 27.0 +/- 2.3 micromol/min/kg post-UF; p = 0.7). EU resulted in a mildly underfed state with marginal weight loss (0.55 +/- 0.28 kg; p = 0.08), and fasting FFA increased by 0.13 +/- 0.03 mmol/l (p < 0.001) and beta-hydroxybutyrate concentrations by 0.05 +/- 0.02 mM (p = 0.03) compared with pre-EU. There was no change in glucose disposal or storage rates compared with pre-EU. CONCLUSIONS: Underfeeding for 6 days has no significant effect on UCP3 mRNA expression in skeletal muscle in non-obese men but is associated with changes in carbohydrate fuel partitioning, REE and the thermogenic response to the glucose clamp. Mild underfeeding had no effect on insulin sensitivity, but more severe energy restriction reduced insulin-stimulated glucose oxidation without affecting glucose storage. PMID- 17697060 TI - Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome. AB - AIM: To observe the effect of constant positive airway pressure (CPAP) therapy on regional lipid deposition, muscle metabolism and glucose homeostasis in obese patients with obstructive sleep apnoea syndrome (OSAS). METHODS: A total of 29 obese patients underwent assessment before and after a minimum of 12-week CPAP therapy. Abdominal adipose tissue was assessed using magnetic resonance imaging. Intramyocellular lipid (IMCL) and skeletal muscle creatine were assessed using (1)H-magnetic resonance spectroscopy. Fasting venous and arterial blood were collected. Glucose control was assessed using the homeostatic model. A subgroup of six patients were also evaluated for skeletal muscle pH, phosphocreatine (PCr) and mitochondrial function using (31)P-magnetic resonance spectroscopy. The sample was divided according to CPAP therapy, with regular users defined as a minimum nightly use of >or=4 h; 19 subjects were regular and 10 were irregular CPAP users. RESULTS: Visceral adipose tissue volume and circulating leptin were reduced with regular CPAP use but not with irregular CPAP use. Regular CPAP use also produced an increase in skeletal muscle creatine and resting PCr and a decrease in muscle pH. Neither the regular nor irregular CPAP users showed any change in IMCL content, insulin sensitivity scores or mitochondrial function. CONCLUSIONS: These data show that regular CPAP therapy reduces visceral adipose tissue and leptin and improves skeletal muscle metabolites. In obese patients with severe OSAS, regular CPAP use does not improve glucose control, suggesting that the influence of obesity on glucose control dominates over any potential effect of OSAS. PMID- 17697061 TI - Diet-induced obesity and diabetes reduce coronary responses to nitric oxide due to reduced bioavailability in isolated mouse hearts. AB - AIM: The aim of the present study was to examine nitric oxide (NO)-mediated coronary vascular responses in a mouse model of obesity and diabetes induced by a high-fat, high-carbohydrate diet. We hypothesized that endogenous NO bioavailability would be reduced in obese/diabetic mouse hearts due to enhanced superoxide anion production, and that coronary smooth muscle responses to exogenous NO would be reduced. METHODS: Age-matched, male C57BL/6J mice were fed either a control diet or a high-fat, high-carbohydrate diet. After 15 weeks, the mice were anesthetized and their hearts were removed and perfused by the Langendorff method under constant flow conditions with an oxygenated buffer solution, and changes in coronary vascular resistance were quantified. RESULTS: Mice fed the high-fat, high-carbohydrate diet became obese, hyperglycaemic and hyperinsulinaemic. Coronary vasoconstrictor responses to NO synthase inhibition by N(omega)-nitro-L-arginine methyl ester were reduced in obese/diabetic mice; normal responses were restored by pretreatment with the superoxide dismutase mimetic 2,2,6,6-tetramethyl-1-piperidinyloxy (Tempol). Coronary endothelium independent vasodilation to the NO donor (+/-)-S-nitroso-N-acetylpenicillamine (SNAP) was reduced; however, 8-bromo-cyclic guanosine monophosphate (cGMP) induced vasodilation was unchanged in obese/diabetic hearts. CONCLUSIONS: These findings suggest that in a diet-induced mouse model of obesity and diabetes, NO bioavailability is reduced by increased superoxide NO scavenging leading to impaired NO-mediated vasodilation. Furthermore, the attenuation of SNAP-induced vasodilation may be due to increased reactive oxygen species scavenging of exogenous NO because normal vascular smooth muscle NO signalling is maintained as indicated by similar 8-bromo-cGMP responses in control and obese/diabetic hearts. PMID- 17697062 TI - Acute hyperglycaemia does not alter coronary vascular function in isolated, perfused rat hearts. AB - AIM: The purpose of this study was to evaluate the hypothesis that acute hyperglycaemia in hearts of rats without diabetes alters coronary vascular responses to nitric oxide (NO), adenosine (ADO) and phenylephrine (PHE). METHODS: Coronary function was studied in isolated, Langendorff-perfused, non-beating rat hearts that were perfused with an oxygenated Krebs-Henseleit solution containing 40 mM KCl to arrest the hearts. Changes in coronary vascular resistance were assessed by measuring changes in coronary perfusion pressure under constant flow conditions. Coronary responses to ADO, sodium nitroprusside (SNP), PHE and L-NAME (inhibitor of NO synthase) were studied either under normoglycaemic conditions (100 mg/dl d-glucose) or after 60 min of hyperglycaemic perfusion (500 mg/dl d glucose). d-mannitol was used as a hyperosmotic control. RESULTS: Hyperglycaemia did not alter vasodilator responses to ADO or SNP in the presence or absence of L NAME. Furthermore, hyperglycaemia, compared with normoglycaemia, did not alter vasoconstrictor responses induced by L-NAME or PHE. CONCLUSIONS: Sixty minutes of exposure to 500 mg/dl of d-glucose in an isolated, non-beating, buffer-perfused rat heart did not significantly affect coronary vascular smooth muscle vasodilator responses to NO and ADO or alter alpha(1)-adrenoceptor-mediated vasoconstrictor responses to PHE. Furthermore, an unchanged vasoconstrictor response to L-NAME suggests that acute hyperglycaemia did not alter NO bioavailability. PMID- 17697063 TI - Initiation of insulin glargine in suboptimally controlled patients with type 2 diabetes: sub-analysis of the AT.LANTUS trial comparing treatment outcomes in subjects from primary and secondary care in the UK. AB - AIM: The AT.LANTUS study compared insulin glargine initiation and titration using one of two algorithms in suboptimally controlled subjects with type 2 diabetes mellitus (T2DM) based on a primary outcome of severe hypoglycaemia. Secondary outcomes included other categories of hypoglycaemia, glycaemic control, weight changes and insulin dose. Here, we report the results of a subanalysis of the trial, which investigated whether insulin glargine can be initiated and titrated as effectively in primary [general practitioner (GP)] as secondary (hospital) care in patients with T2DM in the UK. METHODS: The main study was a multicentre (n = 611), multinational (n = 59), open-label, 24-week randomized trial in 4,588 suboptimally controlled subjects with T2DM. Insulin glargine was titrated to target fasting blood glucose (FBG) levels of 29 weeks and birthweight >1000 g, the neonatal mortality rate was lower in twins than in singletons. The limit of viability was gestational age 27 weeks and birthweight 1000 g, which was similar in singletons and twins regardless of gender. To improve the health of neonates in a country, it is imperative to investigate the characteristics of fetal growth and death under the particular circumstances of the country. When risk is defined for neonates account must be taken of differences in race, gender and plurality of birth, as the neonatal mortality rate varies depending on those factors. PMID- 17697071 TI - Growth outcomes for Australian Aboriginal children aged 11 years who were born with intrauterine growth retardation at term gestation. AB - Long-term poor growth outcomes are well documented for intrauterine growth retarded babies (IUGR) in developed populations but there is a paucity of IUGR studies from disadvantaged populations where the greatest burden of IUGR occurs. Using a Northern Territory, Aboriginal cohort recruited at birth and followed up at a mean age of 11.4 years, comparisons of body size were made between children born at term who had been IUGR (n = 121) and those non-IUGR (n = 341), and between those IUGR babies who had an appropriate ponderal index at birth (n = 72) and those with a low ponderal index (n = 49). Compared with non-IUGR children, at follow-up the IUGR children were almost 2 cm shorter (P = 0.10), 4 kg lighter (P < 0.01) and their head circumferences were almost a 1 cm smaller (P < 0.01). For the 121 term IUGR children, there were no significant differences in growth outcomes according to ponderal index measures at birth. These findings from an Australian Aboriginal sample are consistent with other comparisons of IUGR and non-IUGR children in developed populations and suggest there may be no additional effects of IUGR on growth in childhood for disadvantaged populations similar to the Aboriginal population in the Northern Territory. PMID- 17697072 TI - Risk factors for failure to thrive in infancy depend on the anthropometric definitions used: the Copenhagen County Child Cohort. AB - Failure to thrive (FTT) is the term widely used to describe poor weight gain in infancy, a condition associated with cognitive deficiency in later childhood. FTT has been investigated in earlier population studies, but little is known about risk factors for FTT or the sequence of events as this requires data to be collected prospectively within the first year of life. Furthermore, several different anthropometric criteria have been used to define FTT, and it is not known whether children identified by the different criteria are comparable. In the present population study we compared risk factors for FTT in a general infant population using different definitions of FTT. Three different criteria of FTT mirroring those used in previous population studies were applied to a birth cohort of 6090 infants. Sociodemographic data and prospectively collected information concerning physical and mental development of the children were obtained from National registries and standardised public health nurse records. Risk factors preceding each of the three 'types' of FTT were compared. The three criteria for FTT identified children with very different profiles and a prevalence of FTT ranging from around 2% to 21% in this affluent population. The criterion of slow weight gain conditional on birthweight (conditional weight gain) was associated with lower birthweight, small-for-gestational-age and deviant overall development. Adding low body mass index did not change this profile. In contrast, the commonly used criterion of downward crossing of centiles on an ordinary weight-for-age chart was associated with factors normally linked with low risk of adverse physical and mental development. Slow conditional weight gain, irrespective of additional thinness, seemed to identify infants with prenatal growth retardation and early developmental delays. In contrast, simple downward crossing of centiles seemed mainly to identify healthy low-risk infants, and thus, seems a poor screening measure of FTT in this affluent infant population. Thus, conditional weight gain appears to be the most sensible measure of FTT at present. However, only longitudinal studies including different anthropometric measures and different outcomes can unravel the discriminating power of the different FTT definitions concerning long-term prognosis. PMID- 17697073 TI - Effect of smoking and alcohol use during pregnancy on the occurrence of low birthweight in a farming region in South Africa. AB - The aim of this case-control study was to determine the risk factors for low birthweight in a farming region in South Africa, with particular attention to maternal alcohol use and smoking, both independently and in combination. Data collection was via structured postpartum interviews and review of antenatal and delivery records. The study setting was a regional referral hospital in a farming region. The study subjects were 200 infants with birthweight < 2500 g (cases) and 200 unmatched control infants of normal weight born during the same period as the cases. The outcome measure was low birthweight, i.e. infant birthweight <2500 g. Results showed the contribution of term low birthweight (as a measure of intrauterine growth retardation) to the total low-birthweight incidence was almost 50%, indicating a substantial intrauterine growth retardation component in this population. Sociodemographic factors were not as predictive of low birthweight in this predominantly low income population. Smoking (adjusted OR 2.67, [95% CI 1.69, 4.20]) was the strongest life style-related predictor of low birthweight. The alcohol low-birthweight relationship was not significant when adjusted for smoking status (crude OR 2.15, [95% CI 1.37, 3.39]; adjusted OR 1.32, [95% CI 0.80, 2.20]). However, there appeared to be an interaction with combined use of these two substances during pregnancy that increased the risk of low birthweight (adjusted OR increased to 4.24, [95% CI 1.01, 17.76]. It is clear that life style factors such as smoking and drinking are contributing to the occurrence of low birthweight in the target region. A comprehensive health promotion programme needs to be implemented as an integral part of antenatal and family planning services, to reduce smoking and drinking by women in this community. PMID- 17697074 TI - Maternal smoking, social class and outcomes of pregnancy. AB - Exposure to tobacco during pregnancy is an important risk factor for infant health. Recently the prevalence of smoking during pregnancy has declined in our area. The objective of this study was to analyse the association between several social variables and the fetal exposure to smoking, as well as the association between maternal smoking and some adverse gestational outcomes. Data collection was cross-sectional. The study population were women in the city of Barcelona (Catalonia, Spain) delivering a child without birth defects. The sample corresponded to the controls of the Birth Defects Registry of Barcelona, 2% of all pregnancy deliveries in the city from 1994 to 2003 (n = 2297). Information sources were hospital records and a personal interview of mothers. The analysis measured first the association between independent variables (instruction level, social class, occupation, nationality, planned pregnancy, parity, hospital funding and smoking status of the mother's partner) with two dependent variables: smoking at the initiation of pregnancy and quitting during pregnancy. Second, the persistence of smoking over pregnancy and all independent variables were studied with three variables indicating adverse outcomes of pregnancy: low gestation, low birthweight and intrauterine growth restriction (IUGR). Finally, the joint association between the persistence of smoking over pregnancy and social class taken as independent variables was determined with the three variables indicating adverse outcomes of pregnancy. Logistic regression models were fitted, adjusting for maternal age. Results are presented as odds ratios with their 95% confidence intervals. The prevalence of smoking at the onset of gestation was 41%, and 40% of these women quit during pregnancy, so that 25% delivered as active smokers. Fewer women with higher educational levels and from families with non-manual jobs smoked, as did immigrants, those planning pregnancy and women whose partner did not smoke. Smoking immigrants quit more frequently than nationals, as did those planning pregnancy, primiparae, and women whose partner did not smoke. Low gestation, low birthweight and IUGR were more frequent among smokers and women with a manual occupation, but manual occupation lost its significance when adjusting for smoking. The association between smoking and adverse results was higher for IUGR. In conclusion, the prevalence of smoking and quitting during pregnancy varied according to social factors. The influence of social factors on the outcome of pregnancy was mediated strongly by smoking in a country that provides access to health care free of cost. A priority in reducing inequalities in health is to help women from manual work backgrounds quit smoking. PMID- 17697075 TI - Maternal dental history, child's birth outcome and early cognitive development. AB - Prenatal exposure to high levels of mercury, radiation and inflammation have been associated with adverse reproductive outcomes such as increases in preterm delivery, low birthweight and delayed neurodevelopment. Few data are available to evaluate the potential effects of prenatal low-level exposure to these factors as may occur during dental care. We evaluated maternal dental history prior to and during pregnancy in relation to birth outcomes and early communicative development among offspring in a large cohort (n = 7375) of British children born in 1991-92. Dental history was assessed by questionnaire. The child's communicative development was assessed using the MacArthur Communicative Development Inventory at 15 months of age. Total mercury was measured in umbilical cord tissue for a subset of the children. Overall, dental care, including amalgam fillings, was not associated with birth outcomes or language development. Having X-rays taken during pregnancy was not associated with birthweight measured continuously (b = 14.7, P = 0.4), but was associated with slightly increased odds of having a term, low-birthweight baby (OR 1.9, [95% confidence interval 1.0, 3.4]). More detailed evaluation of the potential adverse effects of elective dental treatment during pregnancy, particularly dental X rays, may be warranted. PMID- 17697076 TI - Outcomes of preterm children according to type of delivery onset: a nationwide population-based study. AB - The objective of the study was to investigate whether spontaneous and iatrogenic preterm births are associated with different paediatric outcomes. A nationwide population-based study comprising 1 010 487 singletons used data from 1991 to 2001 from the Swedish Medical Birth Register and the Swedish Hospital Discharge Register. Intrauterine fetal deaths, unknown type of delivery onset and congenital malformations were excluded. Neonatal, perinatal and long-term neurological outcomes were studied. Spontaneous preterm births were compared with iatrogenic preterm births. Odds ratios (OR) and hazard ratios (HR) for outcome variables were obtained using the Mantel-Haenszel technique and Cox analyses respectively. Adjustments were made for gestational age at birth, maternal age, parity and smoking. The preterm population consisted of 34 215 (73.2%) spontaneous preterm infants and 12 511 (26.8%) iatrogenic preterm infants. Spontaneous preterm infants were at increased risk of cerebral palsy at gestational age 28-31 weeks (HR: 1.86 [95% CI: 1.12, 3.10]), and of sepsis at gestational age 32-33 weeks (HR: 1.58 [95% CI: 1.28, 1.96]). Other outcome variables were associated with iatrogenic preterm birth, especially respiratory and gastrointestinal diagnoses. In conclusion, spontaneous preterm birth and iatrogenic preterm birth are associated with different paediatric outcomes. PMID- 17697077 TI - Risks and causes of mortality among low-birthweight infants in childhood and adolescence. AB - The purpose of the study was to estimate the risks of mortality among infants with low birthweight (LBW, <2500 g) during their childhood and adolescence using a prospective cohort design. A total of 341 249 livebirths were registered in the 1985 Taiwan Birth Registry. We identified the 11 701 LBW singletons and randomly selected the same number of normal-birthweight (NBW) singletons. Study subjects of both LBW and NBW groups were linked, through the individual's unique personal identification number, to the Taiwan Death Registry to identify those who died between 1985 and 2003. Using the life-table method, we calculated the age specific and cumulative survival rate for both LBW and NBW groups. We used Cox's proportional hazard model with adjustment for potential confounders to estimate the age-specific hazard ratio (HR) of mortality. Age-specific causes of mortality were presented for both groups. The result showed that the cumulative survival rate over an 18-year period for the LBW and NBW subjects was estimated at 95.83% and 99.37%, respectively. Significantly increased adjusted HR of mortality associated with LBW was limited to ages <1 year (boys: 8.99; girls: 8.29) and 1-4 years (boys: 2.19; girls: 2.25). Conditions originating in the perinatal period and congenital anomalies were the most prevalent cause of death among LBW and NBW, respectively. Between ages 1 and 18 years, injury and poisoning became the top ranked causes of death irrespective of birthweight and gender. Although there were small numbers of congenital anomalies, they were still a leading cause of death for LBW subjects, but not for NBW subjects, at ages 5-18 years. The LBW subjects were also likely to suffer from respiratory causes at 5-18 years. This study suggested, therefore, that LBW infants tended to have significantly elevated mortality rates under the age of 5 years, and were vulnerable to more non-injury deaths in their childhood and adolescence. PMID- 17697078 TI - Primary cutaneous marginal zone B-cell lymphoma in a patient with chronic lymphocytic leukaemia. AB - Primary cutaneous marginal zone B-cell lymphoma (PCMZL) is a low-grade malignant lymphoma that presents in the skin with no evidence of extracutaneous localization at diagnosis. We present an 80-year-old woman with B-cell chronic lymphocytic leukaemia (CLL) who developed multifocal PCMZL lesions 14 months after CLL diagnosis. PCMZL was clonally similar to the original bone marrow (BM) CLL cells. The specific translocation t(14;18) (q32;q21) with breakpoints in IGH and BCL2 loci was found in a skin specimen, but was absent in BM and peripheral blood (PB) cells. In contrast, a 13q deletion was found in BM and PB CLL cells. The patient was treated with chlorambucil and complete response of PCMZL was achieved. To our knowledge this is the first patient with CLL in whom PCMZL has been diagnosed. PMID- 17697080 TI - Yeast diversity in rice-cassava fermentations produced by the indigenous Tapirape people of Brazil. AB - The Tapirape people of the Tapi'itawa tribe of Brazil produce several fermented foods and beverages, one of which is called 'cauim'. This beverage usually makes up the main staple food for adults and children. Several substrates are used in its production, including cassava, rice, corn, maize and peanuts. A fermentation using rice and cassava was conducted, and samples were collected at 4-h intervals for microbial analysis. The yeast population was low at the beginning of the fermentation and reached 6.9 x 10(7) CFU mL(-1) after 48 h. During the fermentation process common yeast species were identified by sequencing of the D1/D2 domain of the large-subunit (26S) rRNA gene. The predominant yeast species found was Candida tropicalis. Candida intermedia, Candida parapsilosis, Pichia guilliermondii, Saccharomyces cerevisiae and Trichosporon asahii were also found in high numbers during the fermentation. Exophiala dermatidis, often associated with blastomycosis, was found in the mass before inoculation and during the initial stages of the fermentation. Examination of these indigenous fermented foods may provide clues as to how food production and preservation can be expanded and thereby contribute to improve nutrition in native tribes in the region. PMID- 17697081 TI - Degradation of arylarsenic compounds by microorganisms. AB - Microorganisms were not directly accumulated when soil contaminated to about 0.5 mM with diphenylarsinic acid (DPAA) was used as the sole source of carbon. However, using toluene as the carbon source yielded several isolates, which were then used in cultivation with DPAA as the sole source of carbon. By these methods, Kytococcus sedentarius strain NK0508, which can grow in up to 0.038 mM DPAA, was isolated. The toxicity of DPAA retarded the growth of K. sedentarius and the direct accumulation of DPAA-utilizing microorganisms from environmental samples. This strain can utilize about 80% of DPAA and phenylarsonic acid as the sole source of carbon for 3 days. Degradation products of DPAA were determined to be cis, cis, muconate and arsenic acid. When K. sedentarius was cultivated with methylphenylarsinic acid and diphenylmethylarsine, about 90% and 10% degradation of the two compounds, respectively, were observed. Diphenylmethylarsine oxide, possibly synthesized by methylation of DPAA, was detected as one of the transformation products. These results suggest that degradation is initiated by splitting of the phenyl groups from the arylarsenic compounds with subsequent hydroxylation of the phenyl groups and ring opening to yield cis, cis, muconate. PMID- 17697082 TI - Molecular cloning of crustins from the hemocytes of Brazilian penaeid shrimps. AB - Crustins are antimicrobial peptides initially identified in the hemocytes of the crab Carcinus maenas (11.5-kDa peptide or carcinin) and recently also recognized in penaeid shrimps and other crustacean species. The aim of this study was to identify sequences encoding for crustins from the hemocytes of four Brazilian penaeid species: Farfantepenaeus paulensis, Farfantepenaeus subtilis, Farfantepenaeus brasiliensis and Litopenaeus schmitti. Using primers based on consensus nucleotide alignment of crustins from different crustaceans, cDNA sequences coding for crustins in all indigenous penaeid species were amplified. The obtained four crustin sequences encoded for peptides containing a hydrophobic N-terminal region rich in glycine repeats and a C-terminal part with 12 cysteine residues and a conserved whey acidic protein domain. All obtained crustin sequences showed high amino acidic similarity among each other and with crustins from litopenaeid shrimps (76-98%). This is the first report of crustins in native Brazilian penaeid shrimps. PMID- 17697083 TI - Mycoplasma insons sp. nov., a twisted mycoplasma from green iguanas (Iguana iguana). AB - Mycoplasma insons sp. nov., first cultured from the choanae and tracheae of healthy green iguanas (Iguana iguana) from El Salvador, was readily distinguished from all previously described mollicutes and assigned to the Mycoplasma fastidiosum phylogenetic cluster by 16S rRNA gene sequence comparisons. Growth inhibition assays distinguished the isolates serologically from the other two members of that cluster. Many M. insons cells exhibit a remarkable twisted rod morphology despite lacking a cell wall. The organism is nonmotile, produces acid from glucose, but does not hydrolyze arginine, esculin, or urea. Mycoplasma insons 16S rRNA gene was also detected by PCR in packed blood cells from culture negative iguanas. The type strain I17P1(T) has been deposited with the Mollicutes Collection at Purdue University and with the American Type Culture Collection (ATCC BAA-1435) in the USA. A limited number of cultures generated by the authors have also been deposited with the Culture Collection, University of Goteborg, in Sweden (CCUG 53461). PMID- 17697084 TI - Editorial: armed conflict, war and public health. PMID- 17697085 TI - Morbidity and associated factors in rural and urban populations of South Lebanon: a cross-sectional community-based study of self-reported health in 2000. AB - OBJECTIVE: To assess self-reported morbidity and its determining factors in South Lebanon, with an emphasis on the influence of the habitat location (urban vs. rural) and gender. METHODS: Cross-sectional survey in 2000 among 524 South Lebanon residents >/=14 years sampled from a random sample of households using a multi-level cluster sampling technique. Data on self-reported morbidity, lifestyle and socioeconomic status were collected through interviews, using a standardized questionnaire. To evaluate deprivation, a new index was created; the modified 'Living Conditions Index'. Stepwise logistic regression analysis was performed to test the effect of habitat and gender on self-reported morbidity. RESULTS: People in one-fifth of the households lived in precarious conditions. Illiteracy was significantly higher in rural than urban settings. Urban residents reported obesity, varicose veins, anxiety/depression and visual disorders more often. Illiteracy, headaches, lumbar pain, varicose veins and anxiety/depression were more frequently reported by women, whereas ulcers, hearing disorders, cardio vascular diseases and their risk factors were more frequently reported by men. Precarious living conditions were associated with headaches, lumbar pains and insomnia. Individuals covered by a health insurance sought care more often than the uninsured. CONCLUSION: Habitat location had only a minor influence on self reported morbidity; women perceived their health as poorer than men and a number of disease conditions were influenced by deprivation. Our study confirms that the epidemiological transition phenomenon had occurred in South Lebanon in 2000. Our community-based data can serve as a baseline for monitoring changes in health in South Lebanon in the future and especially those because of the war that emerged in July 2006. PMID- 17697086 TI - Effect of pregnancy on HIV disease progression and survival among women in rural Uganda. AB - OBJECTIVE: To investigate the effect of pregnancy on HIV disease progression and survival among HIV-infected women in rural Uganda, prior to the introduction of anti-retroviral therapy (ART). METHODS: From a clinical cohort established in 1990, we selected records from HIV-infected women of reproductive age. We conducted two analyses: (1) all HIV-infected cases contributing to analysis of CD4 decline, using a linear regression model with random intercepts and slopes; (b) incident cases with known date of seroconversion contributed to analyses of median time to CD4 <200 cells/microl, AIDS and death. RESULTS: A total of 139 women were included in the analysis of CD4 decline. Women who subsequently became pregnant had higher CD4 counts at enrolment and had a slower CD4 decline than those who did not become pregnant. In women who became pregnant, CD4 decline was faster after pregnancy than before (P < 0.0001). The survival analyses showed no significant differences between women who became pregnant and those who did not with respect to median time to CD4 count <200, AIDS or death. CONCLUSIONS: The initial comparative immunological advantage possessed by fertile women before they become pregnant is subsequently lost as a result of their pregnancy. Women should be informed about the potential negative effect of pregnancy on their immunological status and should be offered contraception. In resource-limited settings, women determined to become pregnant should be given priority for ART if eligible. PMID- 17697087 TI - Asymptomatic serum cryptococcal antigenemia and early mortality during antiretroviral therapy in rural Uganda. AB - OBJECTIVE: To evaluate the association between a positive serum cryptococcal antigen (CRAG) test at baseline and mortality during the first 12 weeks on antiretroviral therapy (ART). Cryptococcal meningitis is a leading cause of HIV related mortality in Africa, but current guidelines do not advocate CRAG testing as a screening tool. METHODS: Between May 2003 and December 2004, we enrolled HIV 1 infected individuals into a study of ART monitoring in rural Uganda. CRAG testing was conducted retrospectively on stored pre-ART serum samples of participants whose baseline CD4 cell count was <100 cells/mul and who were without symptoms suggestive of disseminated cryptococcal disease at enrolment. RESULTS: Of 377 participants, 5.8% had serum CRAG titre >/=1:2. Of these, 23% died during follow-up. Controlling for CD4 cell count, HIV-1 viral load, anaemia, active tuberculosis and body mass index, relative risk of death during follow-up among those with asymptomatic cryptococcal antigenemia at baseline was 6.6 [95% confidence interval (CI) 1.86-23.61, P = 0.0036]. The population attributable risk for mortality associated with a positive CRAG at baseline was 18% (CI 2 33%), similar to that associated with active tuberculosis (19%, CI 1-36%). CONCLUSION: Asymptomatic cryptococcal antigenemia independently predicts death during the first 12 weeks of ART among individuals with advanced HIV disease in rural Uganda. Routine screening and provision of azole antifungal therapy prior to or simultaneous with the start of ART should be evaluated for the potential to prevent mortality in this population. PMID- 17697088 TI - Spatial distribution of Burkitt's lymphoma in Kenya and association with malaria risk. AB - Endemic Burkitt's lymphoma (BL) is the most common paediatric malignancy in equatorial Africa and was originally shown to occur at high-incidence rates in regions where malaria transmission is holoendemic. New ecological models of malaria that are based on both parasite prevalence and disease have been described. In this study, we examined district level data collected from paediatric BL cases in Kenya from 1988 through 1997 and assessed whether the distribution of district level incidence rates could be explained by new ecologic estimates of malaria risk. Chi-square tests and log-linear regression models were used to evaluate these associations. An association with tribe of origin as a factor also was examined. The 10-year average annual incidence rate (IR) for Kenya was 0.61 per 100,000 children. Incidence rates varied by malaria transmission intensity as follows: low malaria risk (BL IR = 0.39), arid/seasonal (0.25), highland (0.66), endemic coast (0.68), and endemic lake (1.23) (chi(2) = 11.32, P = 0.002). In a log-linear model, BL rates were 3.5 times greater in regions with chronic and intense malaria transmission intensity than in regions with no or sporadic malaria transmission (odds ratio = 3.47, 95% confidence interval = 1.30-9.30), regardless of tribe. Although crude tribe-specific incidence rates ranged between 0.0 and 3.26, tribe was not associated with BL after controlling for malaria. These findings support the aetiologic role of intense malaria transmission intensity in BL. PMID- 17697089 TI - Sex differences in under and over nutrition among school-going Black teenagers in South Africa: an uneven nutrition trajectory. AB - OBJECTIVES: To investigate the nutritional status of Black South African teenagers by sex and compare it with nutritional profiles of teenagers from other countries. METHODS: The first South African Youth Risk Behaviour Survey (2002) was adapted to include anthropometric data and this paper reports on the prevalence of under and over nutrition among 5322 Black teenagers, aged 13.0-17.9 years, grades 8-11. Prevalence of over nutrition in this study was compared with other countries using a World Bank country economic classification. RESULTS: Significant sex differences were observed for under and over nutrition. Boys (18.4%) had a higher prevalence of underweight than girls (2.6%) (P < 0.005), who were more at risk of overweight than boys (20.9%vs. 4.2%) (P < 0.005). Boys (21.9%) were more stunted than girls (9.4%) (P < 0.05), but stunted girls were at greater risk of overweight than boys across all levels of stunting. The prevalence of overweight among boys (4.2%) was lower than in other countries while for girls (20.9%) was similar to several upper middle and high income countries. CONCLUSION: Gender sensitive strategies are required to address both under and over nutrition among South African teenagers to reduce stunting and future chronic disease epidemics in adulthood. This paper suggests that Black South African teenagers are experiencing an uneven nutritional transition across sex, from under nutrition to over nutrition. PMID- 17697090 TI - The effect of health care worker training on the use of intermittent preventive treatment for malaria in pregnancy in rural western Kenya. AB - BACKGROUND: In 1998, Kenya adopted intermittent preventive treatment (IPTp) with sulphadoxine-pyrimethamine (SP) for malaria prevention during pregnancy. We conducted a survey in 2002 among women who had recently delivered in the rural neighbouring areas Asembo and Gem and reported coverage of 19% of at least one dose and 7% of two or more doses of SP. Health care workers (HCW) in Asembo were retrained on IPTp in 2003. OBJECTIVES: To evaluate if IPTp coverage increased and if the training in Asembo led to better coverage than in Gem, and to identify barriers to the effective implementation of IPTp. METHODS: Community-based cross sectional survey among a simple random sample of women who had recently delivered in April 2005, interviews with HCW of antenatal clinics (ANC) in Asembo and Gem. RESULTS: Of the 724 women interviewed, 626 (86.5%) attended the ANC once and 516 (71.3%) attended two or more times. Overall IPTp coverage was 41% for at least one dose, and 21% for at least two doses of SP. In Asembo, coverage increased from 19% in 2002 to 61% in 2005 for at least one dose and from 7% to 17% for two doses of SP. In Gem, coverage increased from 17% to 28% and 7% to 11%, respectively. Interviews of HCW in both Asembo and Gem revealed confusion about appropriate timing, and lack of direct observation of IPTp. CONCLUSION: Training of HCW and use of simplified IPTp messages may be a key strategy in achieving Roll Back Malaria targets for malaria prevention in pregnancy in Kenya. PMID- 17697091 TI - Predictors of death from severe pneumonia among children 2-59 months old hospitalized in Bohol, Philippines: implications for referral criteria at a first level health facility. AB - OBJECTIVE: To determine predictors of death among children 2-59 months old admitted to hospital with severe pneumonia. METHODS: Prospective observational study from April 1994 to May 2000 to investigate serious infections in children less than 5 years old admitted to a tertiary care government hospital in a rural province in central Philippines. The quality of clinical and laboratory work was monitored. The WHO classification for severe pneumonia was used for patient enrolment. RESULTS: There were 1249 children with severe pneumonia and no CNS infection. Thirty children died. Using univariate analysis, the following factors were significantly associated with death: age 2-5 months, dense infiltrates on chest radiography and presence of definite bacterial pathogens in the blood. Stepwise logistic regression analysis revealed the following independent predictors of death: age 2-5 months, weight for age z-score less than -2 SD, dense infiltrates on chest radiography and definite pathogens isolated in the blood. When the results of chest radiographs and blood cultures were not included to mimic facilities available at first-level facilities, age 2-5 months and weight for age z-score less than -2 SD remained independent predictors of death. CONCLUSION: When resources are limited, children with lower chest wall indrawing (severe pneumonia) who are 2-5 months old or moderately to severely malnourished should be referred for immediate higher-level care. PMID- 17697092 TI - Reducing financial barriers to emergency obstetric care: experience of cost sharing mechanism in a district hospital in Burkina Faso. AB - OBJECTIVE: To describe the implementation of a cost-sharing system for emergency obstetric care in an urban health district of Ouagadougou, Burkina Faso and analyse its results after 1 year of activity. METHODS: Service availability and use, service quality, knowledge of the cost-sharing system in the community and financial viability of the system were measured before and after the system was implemented. Different sources of data were used: community survey, anthropological study, routine data from hospital files and registers and specific data collected on major obstetric interventions (MOI) in all the hospitals utilized by the district population. Direct costs of MOI were collected for each patient through an individual form and monitored during the year 2005. Rates of MOI for absolute maternal indications (AMI) were calculated for the period 2003-2005. RESULTS: The direct cost of a MOI was on average 136US$, including referral cost. Through the cost-sharing system this amount was shared between families (46US$), health centres (15US$), Ministry of Health (38US$) and local authority (37US$). The scheme was started in January 2005. The rate of cost recovery was 91.3% and the balance at the end of 2005 was slightly positive (4.7% of the total contribution). The number of emergency referrals by health centres increased from 84 in 2004 to 683 in 2005. MOI per 100 expected births increased from 1.95% in 2003 to 3.56% in 2005 and MOI for AMI increased from 0.75% to 1.42%. CONCLUSIONS: The dramatic increase in MOI suggests that the cost-sharing scheme decreased financial and geographical barriers to emergency obstetric care. Other positive effects on quality of care were documented but the sustainability of such a system remains uncertain in the dynamic context of Burkina Faso (decentralization). PMID- 17697093 TI - Effect of a large dam on malaria risk: the Koka reservoir in Ethiopia. AB - OBJECTIVE: To determine whether the Koka water reservoir in the Rift Valley of Ethiopia contributes to the malaria burden in its vicinity. METHODS: Frequency of malaria diagnosis in fever clinics was correlated with distance of residence from the margin of the Koka reservoir. Annual as well as seasonal malaria case rates were determined in cohorts residing < 3, 3-6 and 6-9 km from the reservoir. Plasmodium falciparum risk was compared with that of Plasmodium vivax. A multiple variable regression model was used to explore associations between malaria case rates and proximity to the reservoir, controlling for other suspected influences on malaria transmission. RESULTS: Malaria case rates among people living within 3 km of the reservoir are about 1.5 times as great as for those living between 3 and 6 km from the reservoir and 2.3 times as great for those living 6-9 km from the reservoir. Proximity to the reservoir is associated with greater malaria case rates in periods of more intense transmission. Plasmodium falciparum is most prevalent in communities located close to the reservoir and P. vivax in more distant villages. The presence of the reservoir, coupled with inter-annual climatic variations, explains more than half of the region's variability in malaria case rates. CONCLUSION: Large water impoundments are likely to exacerbate malaria transmission in malaria-endemic parts of sub-Saharan Africa. PMID- 17697094 TI - Factors determining use of pre-travel preventive health services by West African immigrants in The Netherlands. AB - OBJECTIVE: To determine for what reasons West African immigrants, who contribute the largest single group of malaria cases in the Netherlands, visit pre-travel preventive health services and whether use of such services is likely to improve use of preventive measures. METHODS: Semi-structured interviews with eligible participants recruited through West African churches and societies and at a large festival. RESULTS: A total of 70% of the total non-random sample of 292 participants said that they always use pre-travel preventive health services before travelling. Being from Ghana (OR = 2.5), having legal residency status (OR = 2.5), visiting friends and relatives rather than going for business or funeral (OR = 6.7), and living in Amsterdam (OR = 5.1) were all independently associated with using pre-travel preventive health services, as were taking general preventive measures (OR = 3.0), and self-reported use of malaria prophylaxis. Higher use of pre-travel preventive health services was not associated with better knowledge of malaria as such. CONCLUSIONS: West Africans, in particular non-Ghanaians, illegal immigrants and West African immigrants leaving at short notice should be encouraged to use pre-travel preventive health services. Adequate methods to reach these groups need to be developed, including health education on the importance of prevention in general. PMID- 17697095 TI - Migrants' access to antiretroviral therapy in Thailand. AB - OBJECTIVE: To investigate migrants' access to antiretroviral therapy (ART) and assess the applicability of ART guidelines to migrants. METHODS: Six focus group discussions (FGD) were conducted in Thailand with 74 Burmese migrants: factory workers in Mae Sot and Bangkok, construction site workers in Chiang Mai and unemployed and undocumented HIV-positive migrants in Mae Sot. Thirteen key stakeholders and migrants were interviewed for triangulation. RESULTS: (1) Present criteria for in-/exclusion restrict migrants' access to ART. (2) Leading ART guidelines are not applicable for migrants in general. (3) Migrants are likely to experience more problems with adherence to ART than local patients, which increases the importance of ART guidelines. CONCLUSIONS: Without ART guidelines that take into consideration the specific circumstances that limit migrants' access to ART, health care providers will continue to render HIV positive migrants ineligible. Interventions are needed to both make the ART guidelines applicable to migrants and to overcome obstacles restricting migrants' access to ART. This will greatly improve migrants' access to ART and help to save the lives of thousands of HIV-positive migrants. PMID- 17697096 TI - Involvement of cathepsin B in the plant disease resistance hypersensitive response. AB - A diverse range of plant proteases are implicated in pathogen perception and in subsequent signalling and execution of disease resistance. We demonstrate, using protease inhibitors and virus-induced gene silencing (VIGS), that the plant papain cysteine protease cathepsin B is required for the disease resistance hypersensitive response (HR). VIGS of cathepsin B prevented programmed cell death (PCD) and compromised disease resistance induced by two distinct non-host bacterial pathogens. It also suppressed the HR triggered by transient co expression of potato R3a and Phytophthora infestans Avr3a genes. However, VIGS of cathepsin B did not compromise HR following recognition of Cladosporium fulvum AVR4 by tomato Cf-4, indicating that plant PCD can be independent of cathepsin B. The non-host HR to Erwinia amylovora was accompanied by a transient increase in cathepsin B transcript level and enzymatic activity and induction of the HR marker gene Hsr203. VIGS of cathepsin B significantly reduced the induction of Hsr203 following E. amylovora challenge, further demonstrating a role for this protease in PCD. Whereas cathepsin B is often relocalized from the lysosome to the cytosol during animal PCD, plant cathepsin B is secreted into the apoplast, and is activated upon secretion in the absence of pathogen challenge. PMID- 17697097 TI - Structure and function of archaeal RNA polymerases. AB - RNA polymerases (RNAPs) are essential to all life forms and therefore deserve our special attention. The archaeal RNAP is closely related to eukaryotic RNAPII in terms of subunit composition and architecture, promoter elements and basal transcription factors required for the initiation and elongation phase of transcription. RNAPs of this class are large and sophisticated enzymes that interact in a complex manner with DNA/RNA scaffolds, substrates NTPs and a plethora of transcription factors - interactions that often result in an allosteric regulation of RNAP activity. The 12 subunits of RNAP play distinct roles including RNAP assembly and stability, catalysis and functional contacts with exogenous factors. Due to the availability of structural information of RNAPs at high-resolution and wholly recombinant archaeal transcription systems, we are beginning to understand the molecular mechanisms of archaeal RNAPs and transcription in great detail. PMID- 17697098 TI - A processive lipid glycosyltransferase in the small human pathogen Mycoplasma pneumoniae: involvement in host immune response. AB - The human pathogen Mycoplasma pneumoniae has a very small genome but with many yet not identified gene functions, e.g. for membrane lipid biosynthesis. Extensive radioactive labelling in vivo and enzyme assays in vitro revealed a substantial capacity for membrane glycolipid biosynthesis, yielding three glycolipids, five phosphoglycolipids, in addition to six phospholipids. Most glycolipids were synthesized in a cell protein/lipid-detergent extract in vitro; galactose was incorporated into all species, whereas glucose only into a few. One (MPN483) of the three predicted glycosyltransferases (GTs; all essential) was both processive and promiscuous, synthesizing most of the identified glycolipids. These enzymes are of a GT-A fold, similar to an established structure, and belong to CAZy GT-family 2. The cloned MPN483 could use both diacylglycerol (DAG) and human ceramide acceptor substrates, and in particular UDP-galactose but also UDP glucose as donors, making mono-, di- and trihexose variants. MPN483 output and processitivity was strongly influenced by the local lipid environment of anionic lipids. The structure of a major beta1,6GlcbetaGalDAG species was determined by NMR spectroscopy. This, as well as other purified M. pneumoniae glycolipid species, is important antigens in early infections, as revealed from ELISA screens with patient IgM sera, highlighting new aspects of glycolipid function. PMID- 17697099 TI - A comparison of computerized and pencil-and-paper tasks in assessing cognitive function in community-dwelling older people in the Newcastle 85+ Pilot Study. AB - OBJECTIVES: To compare the acceptability and feasibility of computerized and pencil-and-paper tests of cognitive function in 85-year-old people. DESIGN: Group comparison of participants randomly allocated to pencil-and-paper (Wechsler Adult Intelligence and Memory Scales) or computerized (Cognitive Drug Research) tests of verbal memory and attention. SETTING: The Newcastle 85+ Pilot Study was the precursor to the Newcastle 85+ Study a United Kingdom Medical Research Council/Biotechnology and Biological Sciences Research Council cohort study of health and aging in the oldest-old age group. PARTICIPANTS: Eighty-one community dwelling individuals aged 85. MEASUREMENTS: Participant and researcher acceptability, completion rates, time taken, validity as cognitive measures, and psychometric utility. RESULTS: Participants randomized to computerized tests were less likely to rate the cognitive function tests as difficult (odds ratio (OR)=0.16, 95% confidence interval (CI)=0.07-0.39), stressful (OR=0.18, 95% CI=0.07-0.45), or unacceptable (OR=0.18, 95% CI=0.08-0.48) than those randomized to pencil-and-paper tests. Researchers were also less likely to rate participants as being distressed in the computer test group (OR=0.19, 95% CI=0.07-0.46). Pencil-and-paper tasks took participants less time to complete (mean+/-standard deviation 18+/-4 minutes vs 26+/-4 minutes) but had fewer participants who could complete all tasks (91% vs 100%). Both types of task were equally good measures of cognitive function. CONCLUSION: Computerized and pencil-and-paper tests are both feasible and useful means of assessing cognitive function in the oldest-old age group. Computerized tests are more acceptable to participants and administrators. PMID- 17697100 TI - A population-based study of cholinesterase inhibitor use for dementia. AB - OBJECTIVES: To examine current utilization patterns of cholinesterase inhibitor (ChEI) therapy for dementia to determine treatment duration, use in long-term care, how often patients receive these drugs until death, and frequency of switching between the available ChEIs. DESIGN: A population-based healthcare administrative database study. SETTING: Patients aged 66 and older from the Canadian province of Ontario who received a new prescription for a ChEI between June 1, 2000, and December 31, 2002. Patients were followed until discontinuation of ChEI therapy, death, or end of the observation period (March 31, 2005). PARTICIPANTS: Twenty-eight thousand nine hundred and sixty-one patients, including 4,601 residing in long-term care, mean age 80, 63% female. MEASUREMENTS: Information on diagnosis, medical comorbidity, physician visits, and concomitant medication use was obtained. Estimates of duration of continuous use were determined. The percentage of patients who remained on the initial dose prescribed, the proportion who switched to a second ChEI, and the percentage who remained on ChEIs until death were calculated. RESULTS: Patients had on average more than 26 physician visits in the year before ChEI therapy, but only 28% had seen a dementia specialist. Concomitant use of potentially inappropriate medications (strongly anticholinergic medications and benzodiazepines) was noted in 37% of patients. The average length of treatment for all patients was 866 days. Many patients (43%) remained on the initial dose prescribed, 6% switched to another ChEI, and 19% died while on ChEI therapy. CONCLUSION: Elderly patients with dementia are treated for lengthy periods of time with ChEIs in the community and in long-term care facilities. Further research is required to determine whether these utilization patterns are appropriate. It is also unclear whether these results are generalizable to other populations without universal health coverage or drug formulary benefits. PMID- 17697101 TI - Identifying vulnerable older adults with cancer: integrating geriatric assessment into oncology practice. AB - OBJECTIVES: To integrate the principles of geriatric assessment into the care of older patients with cancer in order to identify vulnerable older adults and develop interventions to optimize cancer treatment. DESIGN: A brief, comprehensive, self-administered questionnaire and intervention algorithm were developed consisting of measures of geriatric assessment that are brief, reliable, validated, and predictive of mortality and morbidity in older patients. SETTING: Academic tertiary care cancer center and community-based satellite practice. PARTICIPANTS: Patients aged 65 and older with cancer. MEASUREMENTS: The questionnaire solicits information about the patient's functional status, comorbidity, psychological status, nutritional status, and social support. A scoring algorithm for referral to a multidisciplinary team was developed. RESULTS: Two hundred forty-five of 250 patients completed the questionnaire (mean age 76, range 65-95). The majority of patients were women (71%), white (95%), married (52%), and retired (90%), with a variety of tumor types and stages. Most patients (78%) completed the questionnaire on their own and reported acceptance of questionnaire length (91%), no difficult questions (94%), no upsetting questions (96%), and no missing questions (89%). The mean time to completion was 15 minutes, with a median of 12.5 (standard deviation 10, range 2-60). Information from this questionnaire helped identify physical and psychological impairments, poor nutrition, lack of social support, and untreated comorbidities. Appropriate referrals to a multidisciplinary team were made. CONCLUSION: This brief, comprehensive, self-administered questionnaire is feasible for use in the outpatient oncology setting and helped identify the needs of geriatric oncology patients. Prospective trials are needed to determine the effectiveness of the interventions offered. PMID- 17697102 TI - The relationship between self-rated health and mortality in older black and white Americans. AB - OBJECTIVES: To determine whether the association between self-rated health (SRH) and 4-year mortality differs between black and white Americans and whether education affects this relationship. DESIGN: Prospective cohort. SETTING: Communities in the United States. PARTICIPANTS: Sixteen thousand four hundred thirty-two subjects (14,004 white, 2,428 black) enrolled in the 1998 wave of the Health and Retirement Study (HRS), a population-based study of community-dwelling U.S. adults aged 50 and older. MEASUREMENTS: Subjects were asked to self-identify their race and their overall health by answering the question, "Would you say your health is excellent, very good, good, fair, or poor?" Death was determined according to the National Death Index. RESULTS: SRH is a much stronger predictor of mortality in whites than blacks (c-statistic 0.71 vs 0.62). In whites, poor SRH resulted in a markedly higher risk of mortality than excellent SRH (odds ratio (OR)=10.4, 95% confidence interval (CI)=8.0-13.6). In blacks, poor RSH resulted in a much smaller increased risk of mortality (OR=2.9, 95% CI=1.5-5.5). SRH was a stronger predictor of death in white and black subjects with higher levels of education, but differences in education could not account for the observed race differences in the prognostic effect of SRH. CONCLUSION: This population-based study found that the relationship between SRH and mortality is stronger in white Americans and in subjects with higher levels of education. Because the association between SRH and mortality appears weakest in traditionally disadvantaged groups, SRH may not be the best measure to identify vulnerable older subjects. PMID- 17697103 TI - Physical activity and leg strength predict decline in mobility performance in older persons. AB - OBJECTIVES: To assess the extent to which physical activity and leg strength are associated with change in mobility in older persons. DESIGN: Prospective, observational cohort study. SETTING: Retirement communities across the Chicago metropolitan area participating in the Rush Memory and Aging Project. PARTICIPANTS: Eight hundred eighty-six ambulatory older persons without dementia. MEASUREMENT: Rate of change in mobility. RESULTS: In a linear mixed-effects model that controlled for age, sex, education, and a term for baseline physical activity, a higher level of physical activity was associated with a slower rate of mobility decline (estimate=0.006, standard error (SE)=0.003, P=.03); each additional hour of physical activity at baseline was associated with an approximately 3% decrease in the rate of mobility decline. In a similar model, a higher level of baseline leg strength was associated with a slower rate of mobility decline (estimate=0.031, SE=0.132, P=.02); each additional unit of leg strength at baseline was associated with an approximately 20% decrease in the rate of mobility decline. In a final model, which included terms for physical activity and leg strength together, both were associated with decline in mobility. Furthermore, both remained associated with mobility even after controlling for body composition, balance, pulmonary function, cognition, history of joint pain, cardiovascular diseases and risk factors, and medications. CONCLUSION: Physical activity and leg strength are relatively independent predictors of mobility decline in older persons. Although physical activity may improve strength, the beneficial effect of physical activity on mobility is likely to involve other pathways. PMID- 17697104 TI - Chronic anemia and fatigue in elderly patients: results of a randomized, double blind, placebo-controlled, crossover exploratory study with epoetin alfa. AB - OBJECTIVES: To evaluate the effect of epoetin alfa treatment on hemoglobin (Hb), fatigue, quality of life (QOL), and mobility in elderly patients with chronic anemia. DESIGN: An exploratory, 32 week, randomized, double-blind, crossover treatment trial. PARTICIPANTS: Sixty-two community-dwelling individuals aged 65 and older with chronic anemia (Hb < or =11.5 g/dL). INTERVENTION: Subcutaneous epoetin alfa or placebo weekly for 16 weeks (Phase I) with crossover to the opposite treatment (Phase II). MEASUREMENTS: Hb and QOL scores from the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system. Mobility was assessed as a secondary outcome using the Timed Up and Go (TUG) test. RESULTS: Of the 62 subjects enrolled, complete data were analyzed for 58 in Phase I and 54 participants in Phase II. Of those enrolled, most were African American (95%) and female (85%) and had multiple comorbidities and a mean age+/ standard deviation of 76.1+/-7.2. Mean baseline Hb was 10.5+/-0.9 g/dL (7.3 11.5). In Phase I, 67% of those taking epoetin alfa, and in Phase II, 69% of those taking epoetin alfa had an increase in Hb of more than 2 g/dL, significantly more than those taking placebo (P<.001). Similarly, elderly participants significantly improved on the fatigue and anemia subscales of the FACIT across phases (all P<.05). No significant differences were found between treatment and placebo on TUG scores. Epoetin alfa was well tolerated. CONCLUSION: In this trial involving predominantly older African-American women with anemia, a direct relationship existed between increases in Hb during epoetin alfa therapy and improvements in fatigue and QOL. PMID- 17697105 TI - Effect of sodium hypochlorite on human root dentine--mechanical, chemical and structural evaluation. AB - AIM: To investigate the mechanical, chemical and structural alterations of human root dentine following exposure to ascending sodium hypochlorite concentrations. METHODOLOGY: Three-point bending tests were carried out on standardized root dentine bars (n = 8 per group, sectioned from sound extracted human third molar teeth) to evaluate their flexural strength and modulus of elasticity after immersion in 5 mL of water (control), 1% NaOCl, 5% NaOCl or 9% NaOCl at 37 degrees C for 1 h. Additional dentine specimens were studied using microelemental analysis, light microscopy following bulk staining with basic fuchsin, and scanning electron microscopy (SEM). Numerical data were compared using one-way ANOVA. Bonferroni's correction was applied for multiple testing. RESULTS: Immersion in 1% NaOCl did not cause a significant drop in elastic modulus or flexural strength values in comparison to water, whilst immersion in 5% and 9% hypochlorite reduced these values by half (P < 0.05). Both, carbon and nitrogen contents of the specimens were significantly (P < 0.05) reduced by 5% and 9% NaOCl, whilst 1% NaOCl had no such effect. Exposure to 5% NaOCl rendered the superficial 80-100 mum of the intertubular dentine permeable to basic fuchsin. Three-dimensional SEM reconstructions of partly demineralized specimens showed NaOCl concentration-dependent matrix deterioration. Backscattered electron micrographs revealed that hypochlorite at any of the tested concentrations left the inorganic dentine components intact. CONCLUSIONS: The current data link the concentration-dependent hypochlorite effect on the mechanical dentine properties with the dissolution of organic dentine components. PMID- 17697106 TI - A preliminary study investigating the survival of tetracycline resistant Enterococcus faecalis after root canal irrigation with high concentrations of tetracycline. AB - AIM: To compare the ability of two Enterococcus faecalis strains to survive exposure to an irrigation solution containing a high concentration of tetracycline in the root canals of bovine teeth. METHODOLOGY: The root canals of twelve bovine incisor root sections were chemo-mechanically prepared using commercially available drills, sodium hypochlorite and ethylenediamine tetra acetic acid. The root sections were divided into two groups and inoculated with either a tetracycline sensitive or resistant strain of E. faecalis. The strains are isogenic, however one contains a conjugative transposon related to Tn916 which confers resistance to tetracycline, and the other strain is sensitive to the antibiotic. After 26 days of incubation the root canals were irrigated using one of three solutions (sterile distilled water, 50% ethanol or tetracycline at a concentration of 30 mg mL(-1)). The roots were sampled by grinding dentine and canal contents and the debris collected were incubated in broth to assess growth. RESULTS: Irrigation with sterile distilled water or 50% ethanol did not remove all of the cells present. The tetracycline containing solution was efficient in preventing any growth of sensitive E. faecalis, however the resistant strain was able to survive a 5 min exposure at 30 mg mL(-1). CONCLUSIONS: The presence of the Tn916-like conjugative transposon containing the tetracycline resistance gene tet(M) allowed an E. faecalis strain to survive irrigation using a solution containing an extremely high concentration of tetracycline in a root canal model. PMID- 17697107 TI - Dentine removal in the coronal portion of root canals following two preparation techniques. AB - AIM: To measure the root canal area and the reduction of the mesial and buccal/lingual wall thickness at the level of the coronal interference in mesial roots of mandibular molars after instrumentation with a crown-down or a simultaneous root canal preparation technique. METHODOLOGY: Twenty mesial roots of first mandibular molars with a moderate root canal curvature were embedded in resin and sectioned horizontally at the level of the coronal interference, using a modification of the Bramante technique. After scanning and processing, the sections were reassembled. One root canal of each root was prepared using ProTaper instruments, while Mtwo instruments were used in the other root canal of the same mesial root. After scanning and processing, the data obtained were analysed for two parameters: changes in root canal area after instrumentation (Delta A) and reduction of the mesial and buccal/lingual wall thickness (Delta T). The data were subjected to Student's t-tests for statistical analysis at a significance level of P < 0.05. RESULTS: No statistically significant differences were found between the two groups with respect to the changes in the areas (Delta A) at the level considered (P = 0.410). No statistically significant differences were noticed between the two groups for dentine thickness (Delta T) of both the mesial wall (P = 0.077) and the buccal or lingual wall (P = 0.171). CONCLUSIONS: There was no difference between the ProTaper and Mtwo groups for the amount of dentine removed. PMID- 17697108 TI - The potential applications of cone beam computed tomography in the management of endodontic problems. AB - AIM: To provide core information on cone beam computed tomography (CBCT) technology and its potential applications in endodontic practice. SUMMARY: CBCT has been specifically designed to produce undistorted three-dimensional information of the maxillofacial skeleton as well as three-dimensional images of the teeth and their surrounding tissues. This is usually achieved with a substantially lower effective dose compared with conventional medical computed tomography (CT). Periapical disease may be detected sooner using CBCT compared with periapical views, and the true size, extent, nature and position of periapical and resorptive lesions can be assessed. Root fractures, root canal anatomy and the true nature of the alveolar bone topography around teeth may be assessed. CBCT scans are desirable to assess posterior teeth prior to periapical surgery, as the thickness of the cortical and cancellous bone can be accurately determined as can the inclination of roots in relation to the surrounding jaw. The relationship of anatomical structures such as the maxillary sinus and inferior dental nerve to the root apices may also be clearly visualized. KEY LEARNING POINTS: CBCT has a low effective dose in the same order of magnitude as conventional dental radiographs. CBCT has numerous potential applications in the management of endodontic problems. PMID- 17697109 TI - Parallel post-space preparation in different tooth types ex vivo: deviation from the canal centre and remaining dentine thickness. AB - AIM: To determine the deviation of parallel-sided twist-drills during post channel preparation and relate this to tooth type and position. METHODOLOGY: Human teeth with single root canals were selected: maxillary second premolars (group i); maxillary lateral incisors (group ii); mandibular canines (group iii); mandibular first premolars (group iv; all groups n = 16). The teeth were reduced to 17 mm length by sectioning the crown, and the root canals prepared and filled. Microradiographs were made in two directions. The teeth were individually embedded in a gypsum jaw and placed in a phantom head. Two operators performed parallel post-space preparation (12 mm length, 1.25 mm diameter) to the following protocol: gutta-percha removal with Gates Glidden drills numbers 2 and 3 and post space enlargement with parallel drills numbers 3, 4 and 5, consecutively. Subsequently, microradiographs were re-exposed. The original and post-operative microradiographs were digitized and superimposed, and deviation of the post-space from the filled canal and remaining dentine thickness measured. RESULTS: Overall, the mean deviation was 0.07 mm to the mesial (95% CI: 0.01-0.12), and 0.27 mm to the buccal (95% CI: 0.18-0.35). Group ii had significantly more buccal deviation than other groups (P = 0.004-0.008). A remaining dentine thickness of <0.5 mm occurred 16 times in 14 teeth, and of <1 mm occurred 97 times in 52 teeth. CONCLUSIONS: Deviation during parallel post-preparation was common, predominantly in mesial and buccal directions, especially in maxillary incisors. This deviation increased the risk of perforation considerably. PMID- 17697110 TI - vpsA- and luxO-independent biofilms of Vibrio cholerae. AB - The natural life cycle of Vibrio cholerae involves the transitioning of cells between different environmental surfaces such as the chitinous shell of Crustaceae and the epithelial layer of the human intestine. Previous studies using static biofilm systems showed a strict dependence of biofilm formation on the vps and lux genes, which are essential for exopolysaccharide formation and cell-cell signaling, respectively. The authors' report here that in biofilms grown under hydrodynamic conditions, DeltavpsA and DeltaluxO mutants of V. cholerae do form pronounced, three-dimensional biofilms that resemble all aspects of wild-type biofilms. By genetic experiments, it was shown that in hydrodynamically grown biofilms this independence of vpsA is due to the expression of rpoS, which is a negative regulator of vpsA expression. Biofilms also underwent substantial dissolution after 96 h that could be induced by a simple stop of medium flow. The studies indicate that metabolic conditions control the reversible attachment of cells to the biofilm matrix and are key in regulating biofilm cell physiology via RpoS. Furthermore, the results redefine the roles of vps and quorum-sensing in V. cholerae biofilms. PMID- 17697111 TI - Are depression and cognitive performance related in temporal lobe epilepsy? AB - PURPOSE: The degree to which depression interacts with the cognitive deficits of epilepsy to alter cognitive skill and general functioning is unknown. Depression has significant negative effects on adaptive functioning including cognitive skills. Temporal lobe epilepsy (TLE) patients are known to possess cognitive dysfunction. Thus, TLE patients who are depressed may suffer a double burden of cognitive deficits. METHODS: We examined whether depressed patients show increased cognitive deficits relative to nondepressed TLE patients (n = 59). We then sought to determine if this effect varied for left versus right TLE patients utilizing preoperative depression and neuropsychological data. To accurately study the lateralization of any observed effects, we selected only patients with definitive evidence of unilateral pathology and seizure focus and utilized a two year seizure-free postsurgical outcome to capture this. RESULTS: The data suggested that cognitive performance was not related to depression, and that depression did not reliably mediate the cognitive presentation of either our left or right TL patients. The notion of a double burden on cognition did not receive support from our data. The data did produce the expected advantage on verbal memory measures for right TLE patients. CONCLUSIONS: The reasons for the limited statistical effects are discussed and issues in unraveling the causal relationships between depression, cognition, and TLE are considered. We discussed the potential role depression may play in the cognitive skills of TLE patients, but the major implication is that depression and neurocognitive performance appear to bear a limited relationship in the context of TLE. PMID- 17697112 TI - Rotenone inhibits mammalian cell proliferation by inhibiting microtubule assembly through tubulin binding. AB - Rotenone, a widely used insecticide, has been shown to inhibit mammalian cell proliferation and to depolymerize cellular microtubules. In the present study, the effects of rotenone on the assembly of microtubules in relation to its ability to inhibit cell proliferation and mitosis were analyzed. We found that rotenone inhibited the proliferation of HeLa and MCF-7 cells with half maximal inhibitory concentrations of 0.2 +/- 0.1 microm and 0.4 +/- 0.1 microm, respectively. At its effective inhibitory concentration range, rotenone depolymerized spindle microtubules of both cell types. However, it had a much stronger effect on the interphase microtubules of MCF-7 cells compared to that of the HeLa cells. Rotenone suppressed the reassembly of microtubules in living HeLa cells, suggesting that it can suppress microtubule growth rates. Furthermore, it reduced the intercentrosomal distance in HeLa cells at its lower effective concentration range and induced multipolar-spindle formation at a relatively higher concentration range. It also increased the level of checkpoint protein BubR1 at the kinetochore region. Rotenone inhibited both the assembly and the GTP hydrolysis rate of microtubules in vitro. It also inhibited the binding of colchicine to tubulin, perturbed the secondary structure of tubulin, and reduced the intrinsic tryptophan fluorescence of tubulin and the extrinsic fluorescence of tubulin-1-anilinonaphthalene-8-sulfonic acid complex, suggesting that it binds to tubulin. A dissociation constant of 3 +/- 0.6 microm was estimated for tubulin rotenone complex. The data presented suggest that rotenone blocks mitosis and inhibits cell proliferation by perturbing microtubule assembly dynamics. PMID- 17697113 TI - Molecular cloning, expression and characterization of protein disulfide isomerase from Conus marmoreus. AB - The oxidative folding of disulfide-rich conotoxins is essential for their biological functions. In vivo, disulfide bond formation is mainly catalyzed by protein disulfide isomerase. To elucidate the physiologic roles of protein disulfide isomerase in the folding of conotoxins, we have cloned a novel full length protein disulfide isomerase from Conus marmoreus. Its ORF encodes a 500 amino acid protein that shares sequence homology with protein disulfide isomerases from other species, and 70% homology with human protein disulfide isomerase. Enzymatic analyses of recombinant C. marmoreus protein disulfide isomerase showed that it shared functional similarities with human protein disulfide isomerase. Using conotoxins tx3a and sTx3.1 as substrate, we analyzed the oxidase and isomerase activities of the C. marmoreus protein disulfide isomerase and found that it was much more efficient than glutathione in catalyzing oxidative folding and disulfide isomerization of conotoxins. We further demonstrated that macromolecular crowding had little effect on the protein disulfide isomerase-catalyzed oxidative folding and disulfide isomerization of conotoxins. On the basis of these data, we propose that the C. marmoreus protein disulfide isomerase plays a key role during in vivo folding of conotoxins. PMID- 17697114 TI - Serum components and activated Ha-ras antagonize expression of perivenous marker genes stimulated by beta-catenin signaling in mouse hepatocytes. AB - Hepatocytes of the periportal and perivenous zones of the liver lobule show marked differences in the contents and activities of many enzymes and other proteins. Previous studies from our and other groups have pointed towards an important role of beta-catenin-dependent signaling in the regulation of expression of genes encoding proteins with preferential perivenous localization, whereas, in contrast, signaling through Ras-dependent pathway(s) may induce a 'periportal' phenotype. We have now conducted a series of experiments to further investigate this hypothesis. In transgenic mice with scattered expression of an activated Ha-ras (Ha-ras(G12V)) mutant in liver, expression of the perivenous markers glutamine synthetase and two cytochrome P450 isoforms was completely abolished in those hepatocytes demonstrating constitutively activated extracellular signal-regulated kinase activity, even though they were located directly adjacent to central veins. Similarly, incubation of primary hepatocytes or hepatoma cells with increasing amounts of serum caused a concentration dependent attenuation of expression of perivenous marker mRNAs, whereas the expression of periportal markers was increased. The inhibitory effect of high amounts of serum on the expression of perivenous markers was also observed if their expression was stimulated by activation of beta-catenin signaling, and comparable inhibitory effects were seen in cells stably transfected with a T-cell factor/lymphoid-enhancing factor-driven luciferase reporter. Epidermal growth factor could partly mimic serum effects in hepatoma cells, and its effect could be blocked by an inhibitor of extracellular signal-regulated kinase activity. These data suggest that activation of the Ras/mitogen-activated protein kinase (extracellular signal-regulated kinase) pathway favors periportal gene expression while simultaneously antagonizing a perivenous phenotype of hepatocytes. PMID- 17697115 TI - Characterization of inhibitors of phosphodiesterase 1C on a human cellular system. AB - Different inhibitors of the Ca(2+)/calmodulin-stimulated phosphodiesterase 1 family have been described and used for the examination of phosphodiesterase 1 in cellular, organ or animal models. However, the inhibitors described differ in potency and selectivity for the different phosphodiesterase family enzymes, and in part exhibit additional pharmacodynamic actions. In this study, we demonstrate that phosphodiesterase 1C is expressed in the human glioblastoma cell line A172 with regard to mRNA, protein and activity level, and that lower activities of phosphodiesterase 2, phosphodiesterase 3, phosphodiesterase 4 and phosphodiesterase 5 are also present. The identity of the phosphodiesterase 1C activity detected was verified by downregulation of the mRNA and protein through human phosphodiesterase 1C specific small interfering RNA. In addition, the measured K(m) values (cAMP, 1.7 microm; cGMP, 1.3 microm) are characteristic of phosphodiesterase 1C. We demonstrate that treatment with the Ca(2+) ionophore ionomycin increases intracellular Ca(2+) in a concentration-dependent way without affecting cell viability. Under conditions of enhanced intracellular Ca(2+) concentration, a rapid increase in cAMP levels caused by the adenylyl cyclase activator forskolin was abolished, indicating the involvement of Ca(2+)-activated phosphodiesterase 1C. The reduction of forskolin-stimulated cAMP levels was reversed by phosphodiesterase 1 inhibitors in a concentration-dependent way. Using this cellular system, we compared the cellular potency of published phosphodiesterase 1 inhibitors, including 8-methoxymethyl-3-isobutyl-1 methylxanthine, vinpocetine, SCH51866, and two established phosphodiesterase 1 inhibitors developed by Schering-Plough (named compounds 31 and 30). We demonstrate that up to 10 microm 8-methoxymethyl-3-isobutyl-1-methylxanthine and vinpocetine had no effect on the reduction of forskolin-stimulated cAMP levels by ionomycin, whereas the more selective and up to 10 000 times more potent phosphodiesterase 1 inhibitors SCH51866, compound 31 and compound 30 inhibited the ionomycin-induced decline of forskolin-induced cAMP at nanomolar concentrations. Thus, our data indicate that SCH51866 and compounds 31 and 30 are effective phosphodiesterase 1 inhibitors in a cellular context, in contrast to the weakly selective and low-potency phosphodiesterase inhibitors 8-methoxymethyl 3-isobutyl-1-methylxanthine and vinpocetine. A172 cells therefore represent a suitable system in which to study the cellular effect of phosphodiesterase 1 inhibitors. 8-Methoxymethyl-3-isobutyl-1-methylxanthine and vinpocetine seem not to be suitable for the study of phosphodiesterase 1-mediated functions. PMID- 17697116 TI - Differential effects of Mxi1-SRalpha and Mxi1-SRbeta in Myc antagonism. AB - Mxi1 belongs to the Myc-Max-Mad transcription factor network. Two Mxi1 protein isoforms, Mxi1-SRalpha and Mxi1-SRbeta, have been described as sharing many biological properties. Here, we assign differential functions to these isoforms with respect to two distinct levels of Myc antagonism. Unlike Mxi1-SRbeta, Mxi1 SRalpha is not a potent suppressor of the cellular transformation activity of Myc. Furthermore, although Mxi1-SRbeta exhibits a repressive effect on the MYC promoter in transient expression assays, Mxi1-SRalpha activates this promoter. A specific domain of Mxi1-SRalpha contributes to these differences. Moreover, glyceraldehyde-3-phosphate dehydrogenase interacts with Mxi1-SRalpha and enhances its ability to activate the Myc promoter. Our findings suggest that Mxi1 gains functional complexity by encoding isoforms with shared and distinct activities. PMID- 17697117 TI - Transcriptional upregulation of inflammatory cytokines in human intestinal epithelial cells following Vibrio cholerae infection. AB - Coordinated expression and upregulation of interleukin-1alpha, interleukin-1beta, tumor necrosis factor-alpha, interleukin-6, granulocyte-macrophage colony stimulating factor, interleukin-8, monocyte chemotactic protein-1 (MCP-1) and epithelial cell derived neutrophil activator-78, with chemoattractant and proinflammatory properties of various cytokine families, were obtained in the intestinal epithelial cell line Int407 upon Vibrio cholerae infection. These proinflammatory cytokines also showed increased expression in T84 cells, except for interleukin-6, whereas a striking dissimilarity in cytokine expression was observed in Caco-2 cells. Gene expression studies of MCP-1, granulocyte macrophage colony-stimulating factor, interleukin-1alpha, interleukin-6 and the anti-inflammatory cytokine transforming growth factor-beta in Int407 cells with V. cholerae culture supernatant, cholera toxin, lipopolysaccharide and ctxA mutant demonstrated that, apart from cholera toxin and lipopolysaccharide, V. cholerae culture supernatant harbors strong inducer(s) of interleukin-6 and MCP-1 and moderate inducer(s) of interleukin-1alpha and granulocyte-macrophage colony stimulating factor. Cholera toxin- or lipopolysaccharide-induced cytokine expression is facilitated by activation of nuclear factor-kappaB (p65 and p50) and cAMP response element-binding protein in Int407 cells. Studies with ctxA mutants of V. cholerae revealed that the mutant activates the p65 subunit of nuclear factor-kappaB and cAMP response element-binding protein, and as such the activation is mediated by cholera toxin-independent factors as well. We conclude that V. cholerae elicits a proinflammatory response in Int407 cells that is mediated by activation of nuclear factor-kappaB and cAMP response element-binding protein by cholera toxin, lipopolysaccharide and/or other secreted products of V. cholerae. PMID- 17697118 TI - Mitochondrial targeting of intact CYP2B1 and CYP2E1 and N-terminal truncated CYP1A1 proteins in Saccharomyces cerevisiae--role of protein kinase A in the mitochondrial targeting of CYP2E1. AB - Previously we showed that intact rat cytochrome P450 2E1, cytochrome P450 2B1 and truncated cytochrome P450 1A1 are targeted to mitochondria in rat tissues and COS cells. However, some reports suggest that truncated cytochrome P450 2E1 is targeted to mitochondria. In this study, we used a heterologous yeast system to ascertain the conservation of targeting mechanisms and the nature of mitochondria targeted proteins. Mitochondrial integrity and purity were established using electron microscopy, and treatment with digitonin and protease. Full-length cytochrome P450 2E1 and cytochrome P450 2B1 were targeted both to microsomes and mitochondria, whereas truncated cytochrome P450 1A1 (+ 5 and + 33/cytochrome P450 1A1) were targeted to mitochondria. Inability to target intact cytochrome P450 1A1 was probably due to lack of cytosolic endoprotease activity in yeast cells. Mitochondrial targeting of cytochrome P450 2E1 was severely impaired in protein kinase A-deficient cells. Similarly, a phosphorylation site mutant cytochrome P450 2E1 (Ser129A) was poorly targeted to the mitochondria, thus confirming the importance of protein kinase A-mediated protein phosphorylation in mitochondrial targeting. Mitochondria-targeted proteins were localized in the matrix compartment peripherally associated with the inner membrane and their ethoxyresorufin O-dealkylation, erythromycin N-demethylase, benzoxyresorufin O dealkylation and nitrosodimethylamine N-demethylase activities were fully supported by yeast mitochondrial ferredoxin and ferredoxin reductase. PMID- 17697119 TI - Insights into the activation of brain serine racemase by the multi-PDZ domain glutamate receptor interacting protein, divalent cations and ATP. AB - Brain serine racemase contains pyridoxal phosphate as a prosthetic group and is known to become activated by divalent cations such as Ca(2+) and Mg(2+), as well as by ATP and ADP. In vivo, brain serine racemase is also activated by a multi PSD-95/discs large/ZO-1 (PDZ) domain glutamate receptor interacting protein (GRIP) that is usually coupled to the GluR2/3 subunits of the alpha-amino-3 hydroxy-5-methylisoxazole-4-propionic acid Ca(2+) channel. In the present study, we analysed the mechanisms by which serine racemase becomes activated by GRIP, divalent cations and ATP. We show that binding of PDZ6 of GRIP to serine racemase does not result in increased d-serine production. However, full-length GRIP does augment significantly enzymatic activity. We expressed various GRIP shorter constructs to map down the regions within GRIP that are necessary for serine racemase activation. We observed that, whereas recombinant proteins containing PDZ4-PDZ5-PDZ6 are unable to activate serine racemase, other constructs containing PDZ4-PDZ5-PDZ6-GAP2-PDZ7 significantly augment its activity. Hence, activation of serine racemase by GRIP is not a direct consequence of the translocation towards the calcium channel but rather a likely conformational change induced by GRIP on serine racemase. On the other hand, the observed activation of serine racemase by divalent cations has been assumed to be a side effect associated with ATP binding, which is known to form a complex with Mg(2+) ions. Because no mammalian serine racemase has yet been crystallized, we used molecular modelling based on yeast and bacterial homologs to demonstrate that the binding sites for Ca(2+), ATP and the PDZ6 domain of GRIP are spatially separated and modulate the enzyme through distinct mechanisms. PMID- 17697120 TI - Plasticity of S2-S4 specificity pockets of executioner caspase-7 revealed by structural and kinetic analysis. AB - Many protein substrates of caspases are cleaved at noncanonical sites in comparison to the recognition motifs reported for the three caspase subgroups. To provide insight into the specificity and aid in the design of drugs to control cell death, crystal structures of caspase-7 were determined in complexes with six peptide analogs (Ac-DMQD-Cho, Ac-DQMD-Cho, Ac-DNLD-Cho, Ac-IEPD-Cho, Ac-ESMD-Cho, Ac-WEHD-Cho) that span the major recognition motifs of the three subgroups. The crystal structures show that the S2 pocket of caspase-7 can accommodate diverse residues. Glu is not required at the P3 position because Ac-DMQD-Cho, Ac-DQMD-Cho and Ac-DNLD-Cho with varied P3 residues are almost as potent as the canonical Ac DEVD-Cho. P4 Asp was present in the better inhibitors of caspase-7. However, the S4 pocket of executioner caspase-7 has alternate regions for binding of small branched aliphatic or polar residues similar to those of initiator caspase-8. The observed plasticity of the caspase subsites agrees very well with the reported cleavage of many proteins at noncanonical sites. The results imply that factors other than the P4-P1 sequence, such as exosites, contribute to the in vivo substrate specificity of caspases. The novel peptide binding site identified on the molecular surface of the current structures is suggested to be an exosite of caspase-7. These results should be considered in the design of selective small molecule inhibitors of this pharmacologically important protease. PMID- 17697121 TI - Glutamate recognition and hydride transfer by Escherichia coli glutamyl-tRNA reductase. AB - The initial step of tetrapyrrole biosynthesis in Escherichia coli involves the NADPH-dependent reduction by glutamyl-tRNA reductase (GluTR) of tRNA-bound glutamate to glutamate-1-semialdehyde. We evaluated the contribution of the glutamate moiety of glutamyl-tRNA to substrate specificity in vitro using a range of substrates and enzyme variants. Unexpectedly, we found that tRNA(Glu) mischarged with glutamine was a substrate for purified recombinant GluTR. Similarly unexpectedly, the substitution of amino acid residues involved in glutamate side chain binding (S109A, T49V, R52K) or in stabilizing the arginine 52 glutamate interaction (glutamate 54 and histidine 99) did not abrogate enzyme activity. Replacing glutamine 116 and glutamate 114, involved in glutamate-enzyme interaction near the aminoacyl bond to tRNA(Glu), by leucine and lysine, respectively, however, did abolish reductase activity. We thus propose that the ester bond between glutamate and tRNA(Glu) represents the crucial determinant for substrate recognition by GluTR, whereas the necessity for product release by a 'back door' exit allows for a degree of structural variability in the recognition of the amino acid moiety. Analyzing the esterase activity, which occured in the absence of NADPH, of GluTR variants using the substrate 4-nitrophenyl acetate confirmed the crucial role of cysteine 50 for thioester formation. Finally, the GluTR variant Q116L was observed to lack reductase activity whereas esterase activity was retained. Structure-based molecular modeling indicated that glutamine 116 may be crucial in positioning the nicotinamide group of NADPH to allow for productive hydride transfer to the substrate. Our data thus provide new information about the distinct function of active site residues of GluTR from E. coli. PMID- 17697122 TI - Structural adaptation to low temperatures--analysis of the subunit interface of oligomeric psychrophilic enzymes. AB - Enzymes from psychrophiles show higher catalytic efficiency in the 0-20 degrees C temperature range and often lower thermostability in comparison with meso/thermophilic homologs. Physical and chemical characterization of these enzymes is currently underway in order to understand the molecular basis of cold adaptation. Psychrophilic enzymes are often characterized by higher flexibility, which allows for better interaction with substrates, and by a lower activation energy requirement in comparison with meso/thermophilic counterparts. In their tertiary structure, psychrophilic enzymes present fewer stabilizing interactions, longer and more hydrophilic loops, higher glycine content, and lower proline and arginine content. In this study, a comparative analysis of the structural characteristics of the interfaces between oligomeric psychrophilic enzyme subunits was carried out. Crystallographic structures of oligomeric psychrophilic enzymes, and their meso/thermophilic homologs belonging to five different protein families, were retrieved from the Protein Data Bank. The following structural parameters were calculated: overall and core interface area, characterization of polar/apolar contributions to the interface, hydrophobic contact area, quantity of ion pairs and hydrogen bonds between monomers, internal area and total volume of non-solvent-exposed cavities at the interface, and average packing of interface residues. These properties were compared to those of meso/thermophilic enzymes. The results were analyzed using Student's t-test. The most significant differences between psychrophilic and mesophilic proteins were found in the number of ion pairs and hydrogen bonds, and in the apolarity of their subunit interface. Interestingly, the number of ion pairs at the interface shows an opposite adaptation to those occurring at the monomer core and surface. PMID- 17697123 TI - A new sulfurtransferase from the hyperthermophilic bacterium Aquifex aeolicus. Being single is not so simple when temperature gets high. AB - Sulfur is a functionally important element of living matter. Rhodanese is involved in the enzymatic production of the sulfane sulfur which has been suggested as the biological relevant active sulfur species. Rhodanese domains are ubiquitous structural modules occurring in the three major evolutionary phyla. We characterized a new single-domain rhodanese with a thiosulfate : cyanide transferase activity, Aq-477. Aq-477 can also use tetrathionate and polysulfide. Thermoactivity and thermostability studies show that in solution Aquifex sulfurtranferase exists in equilibrium between monomers, dimers and tetramers, shifting to the tetrameric state in the presence of substrate. We show that oligomerization is important for thermostability and thermoactivity. This is the first characterization of a sulfurtransferase from a hyperthermophilic bacterium, which moreover presents a tetrameric organization. Oligomeric Aq-477 may have been selected in hyperthermophiles because subunit association provides extra stabilization. PMID- 17697124 TI - Absence of yKu/Hdf1 but not myosin-like proteins alters chromosome dynamics during prophase I in yeast. AB - Meiosis is central to the formation of haploid gametes or spores in that it segregates homologous chromosomes and halves the chromosome number. A prerequisite of this genome bisection is the pairing of homologous chromosomes during the first meiotic prophase. When budding yeast cells are induced to undergo meiosis, this has profound consequences for nuclear structure: after premeiotic DNA replication centromeres disperse, while telomeres move about the nuclear periphery and temporarily cluster during the leptotene/zygotene transition (bouquet stage) of the prophase to first meiotic division. In vegetative cells, Hdf1p (yKu) and the myosin-like proteins Mlp1p and Mlp2p have been suggested to contribute to the organization of silent chromatin, tethering of telomeres to the nuclear periphery, DNA repair, and telomere maintenance. Here, we investigated by molecular cytology whether yKu and Mlp proteins contribute to telomere and chromosome dynamics in meiosis. It was found that mlp1 Delta mlp2 Delta double-mutant cells undergo centromere dispersion, telomere clustering, homologue pairing, and sporulation like wild type. On the other hand, cells deficient for yKu underwent meiosis-specific chromosomal events with a delay, while they eventually sporulated like wild type. These results suggest that the absence of yKu not only affects vegetative nuclear architecture (Laroche et al., 1998) but also interferes with the ordered occurrence of chromosome dynamics during first meiotic prophase. PMID- 17697125 TI - Perichromatin fibrils as early markers of transcriptional alterations. AB - Perichromatin fibrils represent the morphological expression of transcription and co-transcriptional processing of pre-mRNA. They can be considered, hence, an example of work in progress. High resolution techniques such as electron microscopy demonstrate that perichromatin fibrils play a role as early markers of transcriptional alterations. In this paper, we review some experimental and physiological conditions impairing or modulating transcription as well as their effects on perichromatin fibrils. In all the situations reported, perichromatin fibrils show modifications in their amount and/or their associated proteins. Their movements are also affected, as well as their export or their intra-nuclear storage forms. Perichromatin fibrils therefore represent highly sensitive markers not only for monitoring transcriptional and processing rate but also for identifying the maturation level of pre-mRNA/mRNA occurring in the cell nucleus and the functional correlation with the cellular metabolic state. PMID- 17697126 TI - Aberrant fibroblast growth factor receptor signaling in bladder and other cancers. AB - Fibroblast growth factors (FGFs) are potent mitogens, morphogens, and inducers of angiogenesis, and FGF signaling governs the genesis of diverse tissues and organs from the earliest stages. With such fundamental embryonic and homeostatic roles, it follows that aberrant FGF signaling underlies a variety of diseases. Pathological modifications to FGF expression are known to cause salivary gland aplasia and autosomal dominant hypophosphatemic rickets, while mutations in FGF receptors (FGFRs) result in a range of skeletal dysplasias. Anomalous FGF signaling is also associated with cancer development and progression. Examples include the overexpression of FGF2 and FGF6 in prostate cancer, and FGF8 overexpression in breast and prostate cancers. Alterations in FGF signaling regulators also impact tumorigenesis, which is exemplified by the down-regulation of Sprouty 1, a negative regulator of FGF signaling, in prostate cancer. In addition, several FGFRs are mutated in human cancers (including FGFR2 in gastric cancer and FGFR3 in bladder cancer). We recently identified intriguing alterations in the FGF pathway in a novel model of bladder carcinoma that consists of a parental cell line (TSU-Pr1/T24) and two sublines with increasing metastatic potential (TSU-Pr1-B1 and TSU-Pr1-B2), which were derived successively through in vivo cycling. It was found that the increasingly metastatic sublines (TSU-Pr1-B1 and TSU-Pr1-B2) had undergone a mesenchymal to epithelial transition. FGFR2IIIc expression, which is normally expressed in mesenchymal cells, was increased in the epithelial-like TSU-Pr1-B1 and TSU-Pr1-B2 sublines and FGFR2 knock-down was associated with the reversion of cells from an epithelial to a mesenchymal phenotype. These observations suggest that modified FGF pathway signaling should be considered when studying other cancer types. PMID- 17697127 TI - MBNL3/CHCR prevents myogenic differentiation by inhibiting MyoD-dependent gene transcription. AB - Muscle differentiation is controlled by positive and negative signals. While much attention has been placed on proteins that promote muscle formation, the importance of negative regulators has been underemphasized. MBNL3/CHCR belongs to the muscleblind family of Cys3His zinc finger proteins implicated in myotonic dystrophy. MBNL3 is expressed in myoblasts, muscle precursor cells, and during the early stages of myogenesis, but is detected at very low levels in terminally differentiated myotubes. Constitutive expression of MBNL3 inhibits myotube formation and antagonizes myogenin and myosin heavy chain expression. To identify MBNL3 target genes, we compared the expression profile of C2C12 mouse myoblasts that constitutively express MBNL3 with control cells. From the 15,247 genes represented on the DNA microarray, classification by biological function indicated that genes involved in muscle development/contraction and cell adhesion were down-regulated by MBNL3 expression. mRNA and protein levels for the muscle transcription factor MyoD and E-box regulated transcription were reduced in C2C12 MBNL3 expressing cells. We hypothesize that MBNL3 serves to antagonize muscle differentiation by suppressing MyoD expression levels to prevent unwanted myogenic gene transcription. These findings are the first indication that a mammalian muscleblind-like (MBNL) protein plays a regulatory role in muscle differentiation under nonpathogenic conditions. PMID- 17697128 TI - Analysis of the callipyge phenotype through skeletal muscle development; association of Dlk1 with muscle precursor cells. AB - The callipyge mutation in sheep in the form of the paternal heterozygote results in skeletal muscle hypertrophy, which is most pronounced in the hindquarters. Overexpression of one of the genes in the region of the causative single nucleotide polymorphism, Dlk1, is postulated to be a primary cause of the muscle hypertrophy although the mechanism is not clear. This study examined the expression of Dlk1 mRNA and its encoded protein in skeletal muscles of callipyge and wild-type sheep. The muscles examined included those that demonstrate hypertrophy in callipyge sheep as well as an unaffected muscle. The expression pattern of Dlk1 protein in these muscles was also measured over a developmental time course ranging from 80 days of gestation to 12 weeks after birth. Quantitative reverse transcription-polymerase chain reaction demonstrated that Dlk1 mRNA was significantly increased in affected, but not unaffected, muscles from callipyge sheep at 120 days of gestation through to 12 weeks of age. Immuno localization of Dlk1 was pronounced in the interstitial connective tissue of fetal muscle but was less intense at later ages. No clear difference in Dlk1 immuno-localization was noted between genotypes in the fetal samples. Strong myofiber-specific Dlk1 immuno-localization was observed in hypertrophied callipyge muscles at 12 weeks of age. This staining was exclusively associated with fast type II myofibers and these had a significantly larger mean cross sectional area, compared with fast type II myofibers in control sheep that did not overexpress Dlk1. In addition, Dlk1 immuno-localization was associated with a sub-population of Pax7-positive mononucleated cells in all skeletal muscles examined during fetal development and at birth, but this was not apparent at 12 weeks. There were no genotype-dependent alterations in the mRNA expression patterns of a number of promyogenic transcription factors indicating that the callipyge mutation was not affecting muscle cell differentiation per se. We postulate that Dlk1 is implicated in the commitment and/or proliferation of fetal myoblasts as well as in the maintenance of hypertrophy in fully differentiated myofibers. PMID- 17697129 TI - Multilineage differentiation potential of equine blood-derived fibroblast-like cells. AB - Tissue engineering (TE) has emerged as a promising new therapy for the treatment of damaged tissues and organs. Adult stem cells are considered as an attractive candidate cell type for cell-based TE. Mesenchymal stem cells (MSC) have been isolated from a variety of tissues and tested for differentiation into different cell lineages. While clinical trials still await the use of human MSC, horse tendon injuries are already being treated with autologous bone marrow-derived MSC. Given that the bone marrow is not an optimal source for MSC due to the painful and risk-containing sampling procedure, isolation of stem cells from peripheral blood would bring an attractive alternative. Adherent fibroblast-like cells have been previously isolated from equine peripheral blood. However, their responses to the differentiation conditions, established for human bone marrow MSC, were insufficient to fully confirm their multilineage potential. In this study, differentiation conditions were optimized to better evaluate the multilineage capacities of equine peripheral blood-derived fibroblast-like cells (ePB-FLC) into adipogenic, osteogenic, and chondrogenic pathways. Adipogenic differentiation using rabbit serum resulted in a high number of large-size lipid droplets three days upon induction. Cells' expression of alkaline phosphatase and calcium deposition upon osteogenic induction confirmed their osteogenic differentiation capacities. Moreover, an increase of dexamethasone concentration resulted in faster osteogenic differentiation and matrix mineralization. Finally, induction of chondrogenesis in pellet cultures resulted in an increase in cartilage-specific gene expression, namely collagen II and aggrecan, followed by protein deposition after a longer induction period. This study therefore demonstrates that ePB-FLC have the potential to differentiate into adipogenic, osteogenic, and chondrogenic mesenchymal lineages. The presence of cells with confirmed multilineage capacities in peripheral blood has important clinical implications for cell-based TE therapies in horses. PMID- 17697130 TI - Dissecting in vitro host cell infection by Plasmodium sporozoites using flow cytometry. AB - The study of the liver stage of malaria has been hampered by limitations in the experimental approaches required to effectively dissect and quantify hepatocyte infection by Plasmodium. Here, we report on the use of flow cytometry, in conjunction with GFP-expressing Plasmodium sporozoites, to assess the various steps that constitute a successful malaria liver infection: cell traversal, hepatocyte invasion and intrahepatocyte parasite development. We show that this rapid, efficient and inexpensive method can be used to overcome current limitations in the independent quantification of those steps, facilitating routine or large-scale studies of host-pathogen molecular interactions. PMID- 17697131 TI - Burkholderia cenocepacia ET12 strain activates TNFR1 signalling in cystic fibrosis airway epithelial cells. AB - Burkholderia cenocepacia is an important pulmonary pathogen in individuals with cystic fibrosis (CF). Infection is often associated with severe pulmonary inflammation, and some patients develop a fatal necrotizing pneumonia and sepsis ('cepacia syndrome'). The mechanisms by which this species causes severe pulmonary inflammation are poorly understood. Here, we demonstrate that B. cenocepacia BC7, a potentially virulent representative of the epidemic ET12 lineage, binds to tumour necrosis factor receptor 1 (TNFR1) and activates TNFR1 related signalling pathway similar to TNF-alpha, a natural ligand for TNFR1. This interaction participates in stimulating a robust IL-8 production from CF airway epithelial cells. In contrast, BC45, a less virulent ET12 representative, and ATCC 25416, an environmental B. cepacia strain, do not bind to TNFR1 and stimulate only minimal IL-8 production from CF cells. Further, TNFR1 expression is increased in CF airway epithelial cells compared with non-CF cells. We also show that B. cenocepacia ET12 strain colocaizes with TNFR1 in vitro and in the lungs of CF patients who died due to infection with B. cenocepacia, ET12 strain. Together, these results suggest that interaction of B. cenocepacia, ET12 strain with TNFR1 may contribute to robust inflammatory responses elicited by this organism. PMID- 17697132 TI - The bundlin pilin protein of enteropathogenic Escherichia coli is an N acetyllactosamine-specific lectin. AB - Synthetic N-acetyllactosamine (LacNAc) glycoside sequences coupled to BSA competitively inhibit enteropathogenic Escherichia coli (EPEC) localized adherence (LA) to human intestinal biopsy specimens and tissue culture cell monolayers. The LacNAc-specific adhesin appears to be associated with the bundle forming pili (BFP) expressed by EPEC during the early stages of colonization. Herein, we report that recombinant bundlin inhibits EPEC LA to HEp-2 cells and binds to HEp-2 cells. Recombinant bundlin also binds, with millimolar association constants (K(assoc)), to synthetic LacNAc-Benzene and LacNAc-O(CH(2))(8)CONH(2) glycosides as assessed in the gas phase by nanoelectrospray ionization mass spectrometry. Furthermore, LacNAc-BSA inhibits LA only of EPEC strains that express alpha bundlin alleles, suggesting putative locations for the LacNAc binding pocket in the alpha bundlin monomer. Collectively, these results suggest that alpha bundlin possesses lectin-like properties that are responsible for LacNAc-specific initial adherence of alpha bundlin-expressing EPEC strains to host intestinal epithelial cells. PMID- 17697133 TI - West Nile virus capsid protein induces p53-mediated apoptosis via the sequestration of HDM2 to the nucleolus. AB - The capsid protein of the West Nile virus (WNV) functions as an apoptotic agonist via the induction of mitochondrial dysfunction and the activation of caspases-9 and -3. Here, we have determined that the WNV capsid (WNVCp) is capable of binding to and sequestering HDM2 into the nucleolus. WNVCp was shown to interfere with the formation of the HDM2 and p53 complex, thereby causing the stabilization of p53 and the subsequent induction of its target apoptotic protein, Bax. Whereas WNVCp was capable of inducing the p53-dependent apoptotic process in wild-type mouse embryonic fibroblasts (MEF) or SH-SY5Y cells, it exerted no significant effects on p53-null MEF or on p53-knockdown SH-SY5Y cells. This suggests that WNVCp-mediated apoptosis requires p53. Furthermore, when WNV was transfected into cells, endogenous Hdm2 and WNVCp were able to interact physically. WNVCp expressed in wild-type MEF proved able to induce the translocation of the endogenous Hdm2 into the nucleolus. Consistently, WNV was highly pathogenic in the presence of p53, and was less so in the absence of p53. The results of these studies suggest that the apoptotic mechanism mediated by WNV might occur in accordance in a fashion similar to that of the tumour-suppressing mechanism mediated by ARF. PMID- 17697134 TI - From QTL to QTN identification in livestock--winning by points rather than knock out: a review. AB - Many quantitative trait loci (QTL) affecting economic traits in livestock have now been identified. However, the confidence interval (CI) of individual QTL as determined by linkage analysis often spans tens of map units, containing hundreds of genes. Linkage disequilibrium (LD) mapping can reduce the CI to individual map units, but this reduced interval will still contain tens of genes. Methods suitable for model animals to find and validate specific quantitative trait nucleotides (QTN) underlying the QTL cannot be easily applied to livestock species because of their long generation intervals, the cost of maintaining each animal and the difficulty of producing transgenics or 'knock-outs'. Considering these limitations, we review successful approaches for identifying QTN in livestock and outline a schematic strategy for QTN determination and verification. In addition to linkage and LD mapping, the methods include positional cloning, selection of candidate genes, DNA sequencing and statistical analyses. Concordance determination and functional assays are the critical tests for validation of a QTN; we provide a generalized formula for the probability of concordance by chance. Three genes that meet the burden of proof for QTN identification--DGAT1 in cattle, IGF2 in swine and GDF8 in sheep--are discussed in detail. The genetic and economic ramifications of identified QTN and the horizon for selection and introgression are also considered. PMID- 17697135 TI - Associations of functional candidate genes derived from gene-expression profiles of prenatal porcine muscle tissue with meat quality and muscle deposition. AB - Ten genes (ANK1, bR10D1, CA3, EPOR, HMGA2, MYPN, NME1, PDGFRA, ERC1, TTN), whose candidacy for meat-quality and carcass traits arises from their differential expression in prenatal muscle development, were examined for association in 1700 performance-tested fattening pigs of commercial purebred and crossbred herds of Duroc, Pietrain, Pietrain x (Landrace x Large White), Duroc x (Landrace x Large White) as well as in an experimental F(2) population based on a reciprocal cross of Duroc and Pietrain. Comparative sequencing revealed polymorphic sites segregating across commercial breeds. Genetic mapping results corresponded to pre existing assignments to porcine chromosomes or current human-porcine comparative maps. Nine of these genes showed association with meat-quality and carcass traits at a nominal P-value of < or = 0.05; PDGFRA revealed no association reaching the P < or = 0.05 threshold. In particular, HMGA2, CA3, EPOR, NME1 and TTN were associated with meat colour, pH and conductivity of loin 24 h postmortem; CA3 and MYPN exhibited association with ham weight and lean content (FOM) respectively at P-values of < 0.003 that correspond to false discovery rates of < 0.05. However, none of the genes showed significant associations for a particular trait across all populations. The study revealed statistical-genetic evidence for association of the functional candidate genes with traits related to meat quality and muscle deposition. The polymorphisms detected are not likely causal, but markers were identified that are in linkage disequilibrium with causal genetic variation within particular populations. PMID- 17697136 TI - Regular sports activities decrease the risk of venous thrombosis. AB - BACKGROUND: Stasis of the blood has been postulated as a major cause of venous thrombosis. However, little is known about the effect of stimulating the blood flow in order to prevent venous thrombosis through, for example, sports activities. OBJECTIVES: In a large population-based case-control study (MEGA study), we studied whether participating in sports activities on a regular basis was associated with venous thrombosis risk. PATIENTS/METHODS: Consecutive patients with a first venous thrombosis of the leg or a pulmonary embolism, and control subjects, consisting of partners of the patients and randomly selected control subjects from the general population, were asked to participate. Sports activities and other risk factors for venous thrombosis were reported in a standardized mailed questionnaire. Participants with malignancy were excluded. RESULTS: Out of 3608 patients, 1136 (31.5%), and of our 4252 control subjects 1686 (39.7%), participated in sports activities. Participating in sports activities reduced the risk of venous thrombosis compared with not participating in sports activities [odds ratio (OR) 0.64; 95% CI 0.58-0.71]. Risk reductions were similar after adjustment for sex, age and body mass index (OR(adj) 0.71; 95% CI 0.64-0.78) and when the analysis was restricted to healthy individuals (OR(adj) 0.67; 95% CI 0.58-0.78). No differences in risk were found for various frequencies, intensities and types of sport. CONCLUSION: Regular sports activities reduce the risk of venous thrombosis. PMID- 17697137 TI - 4G4G genotype of the plasminogen activator inhibitor-1 promoter polymorphism associates with disseminated intravascular coagulation in children with systemic meningococcemia. AB - BACKGROUND: Meningococcal disease may present as sepsis, meningitis or a combination of both. Impaired fibrinolysis and massive elevation of the plasminogen activator inhibitor-1 (PAI-1) is a characteristic feature of meningococcal sepsis. We and others have reported an association between mortality and the functional 4G/5G promoter polymorphism of the PAI-1 gene in children with meningococcal sepsis. OBJECTIVE: Multicenter study to investigate the association of the 4G/5G PAI-1 polymorphism and disseminated intravascular coagulation (DIC) in children with meningococcal disease in a Central European population. PATIENTS/METHODS: Blood samples and clinical information of 326 previously healthy children with meningococcal infection were collected from 95 pediatric hospitals in Germany, Switzerland, Italy, and Austria from 2000 to 2002. RESULTS: DIC, defined as platelet counts below 100 G L(-1), increased D dimer levels and prolonged prothrombin time, was significantly associated with the 4G4G genotype [31 of 63 (49%) vs. 55 of 175 (31%), P = 0.014], resulting in a hazard ratio (HR) of 1.5 (95% confidence interval 1.1-2.1) to develop DIC. Carriers of the 4G4G genotype showed significantly lower platelet counts (183 G L(-1) vs. 227 G L(-1), P = 0.009) on admission. Fibrinogen and C-reactive protein levels were not associated with the PAI-1 4G/5G polymorphism, nor were white blood cell counts. CONCLUSIONS: Our data show a correlation between the 4G4G genotype of the PAI-1 gene and development of DIC in meningococcal infection. PMID- 17697138 TI - Performance characteristics of a rapid assay for anti-PF4/heparin antibodies: the particle immunofiltration assay. PMID- 17697139 TI - Influence of CYP2C19 and CYP3A4 gene polymorphisms on clopidogrel responsiveness in healthy subjects. PMID- 17697140 TI - Bridging therapy in patients on long-term oral anticoagulants who require surgery: the Prospective Peri-operative Enoxaparin Cohort Trial (PROSPECT). AB - BACKGROUND: The peri-operative management of patients on oral anticoagulants (OACs) is a common clinical problem. Our aim was to determine the incidence of major bleeding during peri-operative administration of treatment-dose enoxaparin and the impact of the extensiveness of the procedure on the risk of bleeding. METHODS: We performed a prospective cohort study of 260 patients at 24 North American sites on OACs for atrial fibrillation or a history of deep vein thrombosis (DVT) requiring invasive or surgical procedures whose treating physician felt that bridging therapy was required. Warfarin was withheld, and once-daily s.c. enoxaparin (1.5 mg kg(-1)) was given peri-operatively. Patients were followed for 28 days after OAC was therapeutic. RESULTS: Major bleeding was observed in nine of 260 patients (3.5%, 95% CI: 1.6-6.5). The bleeding risk varied markedly by extensiveness of procedure: the incidence of major bleeding for invasive procedures, minor surgery and major surgery was 0.7% (95% CI: 0.02 3.7), 0% (95% CI: 0-5.0), and 20.0% (95% CI: 9.1-35.7), respectively. There were five thromboembolic events in total (1.9%, 95% CI: 0.6-4.4). There were four arterial events (2.3%, 95% CI: 0.6-5.7) in 176 patients with atrial fibrillation, and one venous event (1.0%, 95% ci: 0.03-5.7) in 96 patients with prior DVT/ CONCLUSIONS: Bridging therapy with once-daily therapeutic-dose enoxaparin administered primarily in an outpatient setting has a low incidence of major bleeding for patients undergoing invasive procedures and minor surgery. Further studies are needed to optimize the bridging strategy for patients undergoing major surgery. PMID- 17697141 TI - Persistent platelet activation in patients with type 2 diabetes treated with low doses of aspirin. AB - BACKGROUND: The percentage of diabetic patients who do not benefit from the protective effect of aspirin is larger than in other populations at cardiovascular risk. OBJECTIVE: We compared the ability of aspirin to suppress TxA2 and platelet activation in vivo, in type-2 diabetics vs. high-risk non diabetic patients. METHODS: Urinary 11-dehydro-TXB2, plasma sCD40 L, and sP selectin were measured, together with indices of low-grade inflammation, glycemic control, and lipid profile, in 82 patients with type-2 diabetes and 39 without diabetes, treated with low doses of aspirin. RESULTS: Urinary 11-dehydro-TxB2, plasma sCD40L and sP-selectin were significantly higher in diabetics than in controls: [38.9 (27.8-63.3) vs. 28.5 (22.5-43.9) ng mmol(-1) of creatinine, P = 0.02], [1.06 (0.42-3.06) vs. 0.35 (0.22-0.95) ng mL(-1); P = 0.0001], [37.0 (16.8 85.6) vs. 20.0 (11.2-35.6) ng mL(-1), P = 0.0001], respectively. The proportion of individuals with diabetes increased across quartiles of 11-dehydro-TxB2, sCD40L, and sP-selectin, with the highest quartiles of 11-dehydro-TxB2, sCD40L and sP-selectin, including 66%, 93.3%, and 93.3% of individuals with diabetes. Markers of platelet activation positively correlated with indices of glycemic control but not with markers of low-grade inflammation. CONCLUSIONS: Platelet dysfunction associated with insufficient glycemic control, may mediate persistent platelet activation under aspirin treatment. PMID- 17697142 TI - The differential expression of proteins in the cortical cells of wool and hair fibres. AB - Three different cell types have been identified in the cortex of wool: orthocortex, mesocortex and paracortex. Fine wool fibres, particularly Merino sheep, are noted for their bilateral distribution of orthocortical and paracortical cells, with the latter following the concave side of the crimp wave. Furthermore, studies have indicated that the paracortex has a higher concentration of cysteine than the orthocortex. This has been supported by in situ hybridization studies in the follicle that have shown that sulphur-rich proteins are initially expressed on the paracortical side of the fibre, with some becoming more uniformly spread, laterally, over the entire fibre as the keratinization process progresses. In contrast, proteins high in glycine and tyrosine tend to be expressed initially on the orthocortical side of the follicle. While these in vitro studies have pointed to where specific proteins are located in the follicle, elucidating the situation for the mature fibre has been less easy. A range of approaches have been used to separate orthocortical and paracortical cells and these have only been able to provide evidence for a higher level of cysteine in the latter. Electrophoretic studies have found a number of differences in protein expression between the two sides but have not specifically identified which proteins. Thus, there appears to be good evidence for the paracortex containing a higher proportion of proteins in the ultra-high sulphur class but there is some uncertainty regarding the exact distribution of proteins high in glycine and tyrosine. PMID- 17697143 TI - Expression of the human Cathepsin L inhibitor hurpin in mice: skin alterations and increased carcinogenesis. AB - The serine protease inhibitor (serpin) hurpin (serpin B13) is a cross class specific inhibitor of the cysteine protease Cathepsin (Cat) L. Cat L is involved in lysosomal protein degradation, hair follicle morphogenesis, epidermal differentiation and epitope generation of antigens. Hurpin is a 44 kDa protein which is expressed predominantly in epidermal cells. In psoriatic skin samples, hurpin was strongly overexpressed when compared with normal skin. Keratinocytes overexpressing hurpin showed increased resistance towards UVB-induced apoptosis. To further analyse the functional importance of this inhibitor, we have generated transgenic mice with deregulated Cat L activity by expressing human hurpin in addition to the endogenous mouse inhibitor. The three independent transgenic lines generated were characterized by identical effects excluding insertional phenotypes. Macroscopically, mice expressing human hurpin are characterized by abnormal abdominal fur. The number of apoptotic cells and caspase-3 positive cells was reduced after UV-irradiation in transgenic animals compared with wild type mice. Interestingly, after chemical carcinogenesis, transgenic mice showed an increased susceptibility to develop skin cancer. Array analysis of gene expression revealed distinct differences between wild-type and hurpin-transgenic mice. Among others, differentially expressed genes are related to antigen presentation and angiogenesis. These results suggest an important role of Cat L regulation by hurpin which might be of clinical relevance in human skin diseases. PMID- 17697144 TI - Strong cellular and humoral immune responses induced by transcutaneous immunization with HBsAg DNA-cationic deformable liposome complex. AB - Transcutaneous immunization presents a major challenge on account of poor permeability of antigens through the skin barrier. To overcome this limitation, the deformable liposome could be a better method for transcutaneous delivery of these antigens. In this study, hepatitis B surface antigen (HBsAg) plasmid DNA cationic complex deformable liposome was utilized as a mode for enhanced immunity against the antigen. Deformable liposome was prepared by conventional rotary evaporation method and characterized for various parameters such as vesicles shape and surface morphology, size and size distribution, entrapment efficiency, elasticity and stability. The immune stimulating activity was studied by measuring serum anti-HBsAg titre and cytokines level (interleukin-4 and interferon-gamma) following topical application of liposome in BALB/c mice and results were compared with deformable liposome encapsulated DNA applied topically as well as naked DNA and pure recombinant HBsAg, administered intramuscularly. It was observed that deformable liposome elicited a comparable serum antibody titre and endogenous cytokines levels compared to other vaccinations. The study signifies the potential of deformable liposome as DNA vaccine carriers for effective transcutaneous immunization. PMID- 17697145 TI - Cytokine gene polymorphisms in hepatitis C virus-related oral lichen planus. AB - Cytokine polymorphisms may influence both the risk of developing oral lichen planus (OLP) and the outcome of hepatitis C virus (HCV)-infected patients and OLP has been frequently associated with HCV infection. The aim of the present study was to analyse whether cytokine polymorphisms may influence the susceptibility to HCV-related OLP. Thirty-five patients with OLP and chronic HCV infection (OLP HCV+ve) took part in the study. As controls, 44 patients with OLP but without HCV (OLP-HCV-ve) infection and 140 healthy donors were studied. Thirteen cytokine genes with 22 single nucleotide polymorphisms (SNP) were studied. IFN-gamma UTR 5644 genotype frequencies showed an increase in number of A/T heterozygote in OLP HCV+ve patients compared with OLP-HCV-ve that approached the statistical significance [P = 0.03, P-corrected (PC) = 0.66]. Contrarily, in OLP-HCV+ve patients, the frequency of genotype -308 G/A of the TNF-alpha was decreased, whereas the genotype -308 G/G was increased compared with OLP-HCV-ve (P = 0.0005, PC = 0.011 and P = 0.0016, PC = 0.0352, respectively). OLP patients with and without HCV infection showed a different genetic cytokine background suggesting distinct pathogenetic mechanisms. PMID- 17697146 TI - A transient unresponsive state of self-scratching behaviour is induced in mice by skin-scratching stimulation. AB - When mice were scratched with brushes on their dorsal skins, they began to scratch themselves with their hind paws. Thus, self-scratching behaviour was induced in mice in response to skin-scratching stimulation. If the second skin scratching stimulation was given within a few days, the induction of the second self-scratching behaviour was significantly suppressed compared with the first one. Thereafter, mice gradually recovered from this unresponsive state within a week. Thus, a transient unresponsive state of self-scratching behaviour is induced by skin-scratching stimulation. Pretreatment with a tachykinin receptor NK-1R antagonist L-703606 or capsaicin significantly suppressed self-scratching behaviour, while pretreatment with a neutral endopeptidase inhibitor phosphoramidon significantly enhanced it. Pretreatment with a calcitonin gene related peptide (CGRP) receptor antagonist CGRP(8-37) did not affect the following self-scratching behaviour. From these results, it is suggested that substance P (SP) signalling through its receptor NK-1R at least in part mediates the induction of self-scratching behaviour. After skin-scratching stimulation, immunoreactivity of SP both in the peripheral nerve fibres and in the dorsal root ganglion (DRG) neurons was significantly decreased and was well-correlated with suppression of self-scratching behaviour. From these findings, it is suggested that the induction of unresponsive states of self-scratching behaviour may be at least in part caused by the depleted states of SP in peripheral nerve fibres and/or in DRG neurons. The induction of a transient unresponsive state after skin scratching may possibly happen also in patients with pruritus. Thus, further studies to elucidate the precise mechanisms are required. PMID- 17697147 TI - Suppressive effect of orally administered copper(II)-aspirinate (Cu2(asp)4) complex on the generation of reactive oxygen species in the skin of animals subjected to UVA exposure. AB - As reactive oxygen species (ROS) are involved in the pathogenesis of various diseases, superoxide dismutase (SOD) and its mimetic complexes have been intensively studied. Recently, we found that Cu(2)(aspirinate)(4) (Cu(2)(asp)(4)) has both in vitro and in vivo antioxidative activities. We investigated the suppressive effect of Cu(2)(asp)(4) on ROS generation in the skin of hairless mice that were orally administered Cu(2)(asp)(4) and followed by UVA exposure. The results were compared with those obtained from mice that were orally administered Cu(salicylate)(2) (Cu(sal)(2)) or Cu(acetate)(2), (Cu(ace)(2)) and followed by UVA exposure. After confirming that Cu(2)(asp)(4) suppressed ROS generation in the skin, we measured both SOD activity and metallothionein (MT) and SOD protein levels in the whole proteins extracted from the skin of ICR mice that were orally administered Cu(II) compounds. The Cu(2)Zn(2)-SOD activity was enhanced by the administration of Cu(II) compounds; however, no alterations in the protein levels of MT and SOD were observed. Metallokinetics of the paramagnetic Cu(II) species in the circulating blood of rats, as estimated by electron spin resonance (ESR), revealed that among the Cu(II) compounds, the residence time of the Cu(II) species from Cu(2)(asp)(4) was the longest. On the basis of these results, we conclude that Cu(2)(asp)(4) is an orally potent antioxidative compound that suppresses ROS generation in the skin. The residence time of Cu(II) in the blood and the enhanced SOD activity in the skin following the oral administration of Cu(2)(asp)(4) support this conclusion. Here, we propose that Cu(2)(asp)(4) may be used to protect the skin against ROS generation. PMID- 17697148 TI - Superior nuclear receptor selectivity and therapeutic index of methylprednisolone aceponate versus mometasone furoate. AB - Although introduced more than 50 years ago, topical glucocorticoids are still the first line therapy for many inflammatory skin disorders such as atopic eczema, contact dermatitis and many others. Recently, significant improvements have been made to optimize the ratio of desired to unwanted effects. While with early compounds such as triamcinolone, topical side effects such as skin atrophy and telangiectasias can be observed rather frequently, newer drugs such as methylprednisolone aceponate or mometasone furoate have a significantly improved therapeutic index. The present study compared these two modern topical glucocorticoids, which possess the highest therapeutic index currently found, in terms of nuclear receptor selectivity in vitro and induction of the most important local side effects (skin atrophy and telangiectasias) in a relevant rodent model in vivo. We demonstrate that methylprednisolone aceponate displays higher specificity in nuclear receptor binding compared with mometasone furoate. Methylprednisolone aceponate was also markedly superior in terms of minimizing induction of skin atrophy or telangiectasias when compared with mometasone furoate. Based on these observations, methylprednisolone aceponate is expected to have a greater therapeutic index as compared with mometasone furoate, at least in the test systems used here. The degree to which this observation may translate into a clinical setting requires confirmation. PMID- 17697149 TI - Prostaglandin metabolism in human hair follicle. AB - Prostaglandins regulate a wide number of physiological functions. Recently PGF(2alpha) analogue such as latanoprost was shown to have a real impact on hair regrowth. The aim of this study was to investigate and describe the expression profile in human hair follicle of prostaglandin metabolism key enzymes, i.e. carbonyl reductase-1 (CBR1), microsomal prostaglandin E synthase-1 (mPGES-1) and microsomal prostaglandin E synthase-2 (mPGES-2), cytosolic prostaglandin E synthase (cPGES), the aldoketoreductase AKR1C1 and the prostaglandin F synthase AKR1C3. Quantitative RT-PCR on plucked hair follicles revealed some sex-related differences, mPGES-2 and AKR1C3 expression levels being higher in women. Cell and hair follicle compartment specificity was investigated using Western blot, PGE(2) and PGF(2alpha) ELISA assays and immunohistochemistry. Most of the hair cell types were endowed with prostaglandin metabolism machinery and were thus able to produce PGE(2) and/or PGF(2alpha). The epithelial part of the hair bulb was identified by immunohistology and EIA assays as the main source of prostaglandin synthesis and interconversion. All these observations support the concept that prostaglandins might be involved in hair growth and differentiation control. PMID- 17697150 TI - Enzyme-linked immunosorbent assay using multimers of the 16th non-collagenous domain of the BP180 antigen for sensitive and specific detection of pemphigoid autoantibodies. AB - Bullous pemphigoid (BP) and pemphigoid gestationis (PG) are acquired autoimmune subepidermal blistering diseases characterized by autoantibodies against the hemidesmosomal proteins BP180/type XVII collagen and BP230. In the vast majority of BP and PG patients, these autoantibodies bind to epitopes clustered within the 16th non-collagenous domain of BP180. An ELISA system for the detection of these autoantibodies was developed and evaluated using 16th non-collagenous domain (NC16A) tetramers instead of monomers. In contrast to antigens fused to large proteins used in the past for the detection of autoantibodies against type XVII collagen, tetrameric antigen fragments bearing a small hexahistidine tag allow for high expression levels without the need to cleave off the fusion partner. Using tetrameric BP180 NC16A, positive reactions were found in 106 (89.8%) of 118 randomly selected BP sera and in all of 20 (100%) randomly selected PG sera, whereas only 2.2% of a large cohort of control subjects were positive in this assay, including patients with rheumatoid arthritis (two of 107), progressive systemic sclerosis (two of 50), systemic lupus erythematosus (one of 72), and healthy blood donors (10 of 494). Thus, the sensitivity and specificity of the new anti-tetrameric NC16A ELISA were 89.9% and 97.8% respectively. Levels of circulating autoantibodies against BP180 paralleled disease activity in the pemphigoid patients. In conclusion, the use of tetrameric NC16A in ELISA results in a sensitive and specific tool for diagnosis and monitoring of BP and PG. PMID- 17697152 TI - Nonexercise activity thermogenesis--liberating the life-force. AB - Obesity occurs when energy intake exceeds energy expenditure over a protracted period of time. The energy expenditure associated with everyday activity is called NEAT (Nonexercise activity thermogenesis). NEAT varies between two people of similar size by 2000 kcal day(-1) because of people's different occupations and leisure-time activities. Data support the central hypothesis that NEAT is pivotal in the regulation of human energy expenditure and body weight regulation and that NEAT is important for understanding the cause and effective treatment for obesity. PMID- 17697153 TI - Immune tolerance: mechanisms and application in clinical transplantation. AB - The achievement of immune tolerance, a state of specific unresponsiveness to the donor graft, has the potential to overcome the current major limitations to progress in organ transplantation, namely late graft loss, organ shortage and the toxicities of chronic nonspecific immumnosuppressive therapy. Advances in our understanding of immunological processes, mechanisms of rejection and tolerance have led to encouraging developments in animal models, which are just beginning to be translated into clinical pilot studies. These advances are reviewed here and the appropriate timing for clinical trials is discussed. PMID- 17697154 TI - Aspects on pathophysiological mechanisms in COPD. AB - Chronic obstructive pulmonary disease (COPD) is a condition which is characterized by irreversible airway obstruction due to narrowing of small airways, bronchiolitis, and destruction of the lung parenchyma, emphysema. It is the fourth most common cause of mortality in the world and is expected to be the third most common cause of death by 2020. The main cause of COPD is smoking but other exposures may be of importance. Exposure leads to airway inflammation in which a variety of cells are involved. Besides neutrophil granulocytes, macrophages and lymphocytes, airway epithelial cells are also of particular importance in the inflammatory process and in the development of emphysema. Cell trafficking orchestrated by chemokines and other chamoattractants, the proteinase antiproteinase system, oxidative stress and airway remodelling are central processes associated with the development of COPD. Recently systemic effects of COPD have attracted attention and the importance of systemic inflammation has been recognized. This seems to have direct therapeutic implications as treatment with inhaled glucocorticosteroids has been shown to influence mortality. The increasing body of knowledge regarding the inflammatory mechanism in COPD will most likely have implications for future therapy and new drugs, specifically aimed at interaction with the inflammatory processes, are currently being developed. PMID- 17697155 TI - Links between arterial and venous disease. AB - An increasing body of evidence suggests the likelihood of a link between arterial and venous disease. According to the results of recent studies, atherosclerosis and venous thromboembolism (VTE) share common risk factors, including age, obesity, diabetes mellitus and metabolic syndrome. Atherosclerosis has the potential to promote the development of thrombotic disorders in the venous system. Another scenario assumes that the two clinical conditions are simultaneously triggered by biological stimuli responsible for activating coagulation and inflammatory pathways in both the arterial and the venous system. Several recent studies have consistently shown that patients with VTE of unknown origin are at a higher risk of cardiovascular diseases, including atherosclerotic complications, than patients with secondary VTE and matched control individuals. Future studies are needed to clarify the nature of this association, to assess its extent and to evaluate its implications for clinical practice. PMID- 17697156 TI - Long-term use of Swedish moist snuff and the risk of myocardial infarction amongst men. AB - BACKGROUND: The scientific evidence on cardiovascular risks associated with long term use of snuff is limited and inconclusive. The use of this smokeless tobacco has increased in recent decades, and adverse health effects associated with snuff use could be of great public health concern. OBJECTIVE: We aimed to study whether long-term use of snuff affects the risk of myocardial infarction. DESIGN: Between 1978 and 1993 all construction workers in Sweden were offered repeated health check-ups by the Swedish Construction Industry's Organization for Working Environment Safety and Health. A cohort was created with information on tobacco use and other risk factors, collected through questionnaires. SETTING: In total, 118,395 nonsmoking men without a history of myocardial infarction were followed through 2004. Information on myocardial infarction morbidity and mortality was obtained from national registers. Relative risk estimates were derived from Cox proportional hazards regression model, with adjustment for age, body mass index and region of residence. RESULTS: Almost 30% of the men had used snuff. In total, 118 395 nonsmoking men without a history of myocardial infarction were followed through 2004. The multivariable-adjusted relative risks for ever snuff users were 0.91 (95% confidence interval, 0.81-1.02) for nonfatal cases and 1.28 (95% confidence interval, 1.06-1.55) for fatal cases. Heavy users (>or=50 g day(-1)) had a relative risk of fatal myocardial infarction of 1.96 (95% confidence interval, 1.08-3.58). Snuff use increased the probability of mortality from cardiovascular disease amongst nonfatal myocardial infarction patients. CONCLUSION: Our results indicate that snuff use is associated with an increased risk of fatal myocardial infarction. PMID- 17697157 TI - The risk of myocardial infarction and sudden cardiac death amongst snuff users with or without a previous history of smoking. AB - OBJECTIVES: To investigate the risk of a first myocardial infarction (MI) and sudden cardiac death (SCD) amongst male snuff users. DESIGN: We used a prospective incident case-referent study design nested in the population-based Vasterbotten Intervention Program and the Northern Sweden MONICA study. SUBJECTS: Tobacco habits and cardiovascular risk factors were assessed at baseline screening and compared in 525 male MI cases (including 93 SCD cases) and 1798 matched referents. RESULTS: Myocardial infarction occurred on average 4 years and 2 months after the baseline screening. No increased risk for MI was found amongst snuff users without a previous history of smoking compared with nontobacco users after adjustments for body mass index, leisure time physical activity, educational level and cholesterol level (OR 0.82; 95% CI, 0.46-1.43). For snuff users with a previous history of smoking, the adjusted OR was 1.25 (95% CI, 0.80 1.96). Significantly increased risk for MI was found in current smokers with or without current snuff use. For SCD cases with survival time<24 h, the adjusted OR for snuff users without previous history of smoking was 1.18 (95% CI, 0.38-3.70) and for cases with survival time<1 h the OR was 0.38 (95% CI, 0.08-1.89). CONCLUSIONS: We found no increased risk for MI amongst snuff users without a previous history of smoking. Amongst snuff users with a previous history of smoking, the tendency towards an increased risk for MI may reflect the residual risk from former smoking. This study does not support the hypothesis that the risk for SCD is increased amongst snuff users. PMID- 17697158 TI - Size at birth and its relation to muscle strength in young adult women. AB - OBJECTIVE: To assess the relationship between development in utero, assessed by birth weight, and muscle strength in young adult women as assessed by grip strength. METHODS: A total of 1563 participants aged 20-40 years in the Southampton Women's Survey had their grip strength measured during pregnancy. At recruitment to the survey the women had been asked to recall their birth weight or obtain it from their parents. For 536 women born in Southampton, birth weight was obtained from hospital records. Grip strength was related to birth weight using multiple linear regression analysis, adjusting for age, height, weight and reported physical activity. RESULTS: Grip strength increased with age, height, weight, physical activity and birth weight. In the mutually-adjusted model, grip strength increased by 1.10 kg per kilogram of birth weight (95% CI: 0.58-1.61 kg). In women with hospital birth weight data the relationship strengthened to 1.44 kg per kilogram of birth weight (95% CI: 0.50-2.38 kg). CONCLUSIONS: Grip strength in women in their twenties and thirties is at or approaching its peak. The association between grip strength and birth weight was remarkably similar to findings from other studies of women at younger and older ages. This indicates that in utero development has consequences for muscle strength throughout the life course, even allowing for the increase to peak muscle strength and then its decline as a woman ages. PMID- 17697159 TI - Impaired cortisol response to acute stressors in patients with coronary disease. Implications for inflammatory activity. AB - OBJECTIVES: Inflammation is assumed to play a major role in the progress of atherosclerotic disease. We hypothesized that an altered hypothalamic-pituitary adrenal (HPA) axis activity was linked to a disinhibited inflammatory activity in patients with coronary artery disease (CAD). METHODS: Thirty CAD patients were assessed 12-14 weeks after a first-time acute coronary syndrome. Serum samples were assayed for C-reactive protein (CRP) and interleukin-6. Free cortisol was measured in a 24-h urine sample and in repeated saliva samples 30 min after awakening and at bedtime. The levels of inflammatory markers and cortisol were also determined before and after standardized physical and psychological stress tests. RESULTS: The CAD patients had a higher 24-h cortisol secretion and a flattened diurnal slope, resulting from significantly higher cortisol levels at bedtime, compared to clinically healthy controls. The levels of evening cortisol were strongly related to inflammatory markers in serum. When exposed to acute physical and psychological stressors, the CAD patients showed a significantly blunted cortisol response compared to controls. In addition, a stress-induced increase in CRP was only observed in the patient group. CONCLUSIONS: Patients with CAD exhibited a cortisol pattern that markedly differed from controls. The data indicate that a dysfunctional HPA axis response involves a failure to contain inflammatory activity in CAD patients, thus providing a possible link between stress and inflammation in disease. PMID- 17697160 TI - Matrix metalloproteinase-1 and its inhibitor, TIMP-1, in systolic heart failure: relation to functional data and prognosis. AB - BACKGROUND: Structural remodelling of left ventricle is a common feature in the progression of congestive heart failure (CHF). Matrix metalloproteinases (MMPs) have been directly implicated as they degrade extracellular proteins. To test the hypothesis that MMP-and its inhibitor, tissue type inhibitor of matrix metalloproteinases (TIMP-1), could be related to functional status and prognosis in CHF, we examined the relationship of MMP-1 and TIMP-1 to peak oxygen consumption (VO2) and peak minute ventilation/carbon dioxide production relationship (VE/VCO2), and assessed their prognostic value. METHODS: We studied 50 patients with CHF, who were compared with 53 controls echocardiogram and ergoespirometry were performed, and serum levels of MMP-1 and TIMP-1 were assayed by ELISA. Patients were followed up for 17.5+/-8.9 months, and total mortality, readmissions for heart failure and cardiac transplantation were recorded. RESULTS: Patients with CHF had lower levels of MMP-1 (P=0.027), and higher levels of TIMP-1 and TIMP-1/MMP-1 ratio (both P<0.01) than controls. TIMP-1 levels and the TIMP-1/MMP-1 ratio correlated negatively with peak VO2 (Spearman, r:-0.51; P=0.001 and r: -0.42; P=0.030, respectively). During the follow-up period, 23 patients (47.9%) suffered endpoints--these patients had higher baseline peak VE/VCO2 (P=0.001), TIMP-1 (P=0.004), and TIMP-1/MMP-1 ratio values (P=0.002), whereas MMP-1 levels were lower (P=0.027). On multivariate analysis, VE/VCO2, MMP 1 levels and age were the only variables independently related to prognosis (all P<0.05). CONCLUSION: Poor functional capacity in CHF can be related to abnormal extracellular matrix turnover. Patients who suffered endpoints had more abnormal indices of matrix turnover, where MMP-1 levels showed independent prognostic value. PMID- 17697161 TI - Acute liver failure in Sweden: etiology and outcome. AB - OBJECTIVE: To determine the causes and outcome of all patients with acute liver failure (ALF) in Sweden 1994-2003 and study the diagnostic accuracy of King's College Hospital (KCH) criteria and the model for end-stage liver disease (MELD) score with transplant-free deaths as a positive outcome. RESEARCH DESIGN AND METHODS: Adult patients in Sweden with international normalized ratio (INR) of >or=1.5 due to severe liver injury with and without encephalopathy at admission between 1994-2003 were included. RESULTS: A total of 279 patients were identified. The most common cause of ALF were acetaminophen toxicity in 42% and other drugs in 15%. In 31 cases (11%) no definite etiology could be established. The KCH criteria had a positive-predictive value (PPV) of 67%, negative predictive value (NPV) of 84% in the acetaminophen group. Positive-predictive value and negative-predictive value of KCH criteria in the nonacetaminophen group were 54% and 63% respectively. MELD score>30 had a positive-predictive value of 21%, negative-predictive value of 94% in the acetaminophen group. The corresponding figures for the nonacetaminophen group were 64% and 76% respectively. CONCLUSIONS: Acetaminophen toxicity was the most common cause in unselected patients with ALF in Sweden. KCH criteria had a high NPV in the acetaminophen group, and in combination with MELD score<30 predicts a good prognosis in acetaminophen patients without transplantation. PMID- 17697163 TI - Comparison of two laser fluorescence devices for the detection of occlusal caries in vivo. AB - Laser fluorescence measurements have been shown to be well suited for caries diagnosis. The aim of this study was to compare two laser fluorescence devices and to correlate the respective values with the visual and radiographic assessment and with the extent of the carious lesion. Ninety-four clinically non cavitated occlusal carious lesions in the premolars and molars of 82 patients were examined. Laser fluorescence values on the surface were measured with a conventional laser fluorescence system and a novel laser fluorescence pen device. When operative intervention at a site was indicated, the extent of caries was determined after its removal. Readings obtained with both systems were significantly different with an interdevice factor of 0.64. Sensitivity and specificity for operative care were 92.6% and 53.7%, respectively, for the conventional, and 88.9% and 53.7%, respectively, for the pen device. For both devices, a correlation between laser fluorescence values and the visual and radiographic assessment and with the extent of the lesion was shown. The study indicates that the novel laser fluorescence device seems to be suitable for occlusal caries diagnosis. However, proposed guidelines for the clinical use of laser fluorescence readings of the conventional device cannot be transferred to the novel pen system. PMID- 17697164 TI - Activity of superior head of human lateral pterygoid increases with increases in contralateral and protrusive jaw displacement. AB - The hypothesis was that the superior head of human lateral pterygoid muscle (SHLP) plays a similar role in jaw movement as the inferior head of human lateral pterygoid muscle (IHLP). The aims were to determine the functional properties of SHLP single motor units (SMUs) and root mean square activity (RMS) of the SHLP during contralateral and protrusive jaw movement tasks and to compare these features with those identified previously for the IHLP. In 22 human subjects, SMUs were recorded intramuscularly from computer tomography-verified sites within the SHLP during standardized contralateral and protrusive jaw movement tasks recorded by a jaw-tracking device. Of the 50 SMUs discriminated, 39 were active during contralateral and 29 during protrusive jaw movements. The firing rates and RMS of the SHLP motor units increased with an increase in jaw displacement. The RMS activity across the entire trial during contralateral jaw movement was significantly greater than that during protrusion. Similarly to conclusions previously identified for the IHLP, the data are consistent with an important role for the SHLP in the control of contralateral and protrusive jaw movements. The similarities in SHLP and IHLP functional properties support the proposal that both heads should be regarded as a system of fibers acting as one muscle. PMID- 17697165 TI - Chewing problems and dissatisfaction with chewing ability: a survey of older Tanzanians. AB - This study assessed the prevalence and correlates of reported chewing problems and dissatisfaction with chewing ability. Discrepancy between reported chewing problems and satisfaction/dissatisfaction with chewing ability was examined. A household survey was conducted in Tanzania in 2004/2005. A total of 1,031 adults (mean age 62.9 yr) underwent clinical examination and a personal interview. Forty per cent [95% confidence interval (CI): 37-43] reported problems with chewing at least one food item, and 25% (95% CI: 22-28) were dissatisfied with their chewing ability. Adjusted odds ratios (OR) for reporting problems with chewing any food were 1.6, 1.2, and 4.2 if having intact anterior/reduced posterior, reduced anterior/intact posterior, and reduced anterior/posterior occluding units, respectively. Subjects dissatisfied with their chewing ability were less likely to be female (OR = 0.6) and more likely to have reduced anterior/posterior occluding units (OR = 3.4), to report dental pain (OR =2.5), chewing problems (OR = 4.7), and oral impacts on daily performances (OIDP) (OR = 3.2). The OIDP scores discriminated between satisfied and dissatisfied groups, irrespective of confirmed chewing problems. Chewing problems and dissatisfaction with chewing ability was prevalent among older Tanzanians. Clinical measures of dentition status, together with reported functional and psychosocial impact scores, determined the subjects' evaluation of their chewing ability and should be taken into account when estimating treatment needs. PMID- 17697166 TI - Is there a gradient by job classification in dental status in Japanese men? AB - The objective of this study was to assess whether there is a gradient in dental health status by job classification in male Japanese workers. The study subjects were 16,261 male Japanese workers aged 20-69 yr. Jobs were classified into seven job groups. Oral examination was conducted using World Health Organization criteria for decayed, missing or filled teeth (DMFT). Professionals, managers, and office workers had a better oral status than those in service occupations and drivers. Professionals had significantly more natural and sound teeth than those in other job classes. The DMFT of professionals was significantly lower than in workers of other job classes. Professionals had a significantly higher restorative index than did workers of other job classes. The restorative index of office workers was significantly higher than that in managers, skilled workers, salespersons, those in service occupations, and drivers. Drivers were 1.8 times, and those in service occupations 1.3 times, more likely to have one or more carious teeth compared with professionals. Skilled workers, salespersons, those in service occupations, and drivers were 1.3, 1.3, 1.4, and 2.1 times, respectively, more likely to have a missing tooth compared with professionals. Skilled workers, those in service occupations, and drivers were 1.7, 1.9, and 3.1 times, respectively, more likely not to have 20 or more teeth compared with professionals aged 50-69 yr. PMID- 17697167 TI - Early development of the lower deciduous dentition and oral vestibule in human embryos. AB - The aim of this work was to investigate the early development of the deciduous dentition and oral vestibule in the human embryonic lower jaw. Histological sections and three-dimensional reconstructions from prenatal weeks 6-9 were used. A continuous anlage for the oral vestibule did not exist in the mandible. In contrast to the upper jaw, where we previously observed that the dental and vestibular epithelia developed separately, two dento-vestibular bulges differentiated in the incisor region of the mandible. The lingual parts of each bulge were found to give rise to the respective central and lateral incisors, whereas the labial parts differentiated into the vestibular epithelium. In the canine and molar areas, the dental and vestibular epithelia originated separately. Later, the segments of the vestibular epithelium fused into the labial vestibular ridge, giving rise to the lower oral vestibule in the lip region. In the cheek region, the oral vestibule was found to originate in the mucosal inflection between the developing jaw and the cheek. A similar heterogeneous developmental base for the oral vestibule was also observed in the upper jaw. There is thus no general scheme for the early development of the dental and vestibular epithelia that applies to both the upper and lower jaws, and to both their anterior and posterior regions. PMID- 17697168 TI - Enamel matrix proteins bind to wound matrix proteins and regulate their cell adhesive properties. AB - Enamel matrix proteins (EMP) induce periodontal regeneration and accelerate dermal wound healing, but the cellular mechanisms of these processes are unclear. We investigated the binding of EMP to the wound matrix proteins fibronectin, laminin-1, collagen type I, and collagen type IV and analyzed the interaction of epithelial cells and periodontal ligament fibroblasts (PDLF) with EMP and composite matrices of EMP + fibronectin or EMP + collagen. The adhesion of PDLF to EMP was concentration- and integrin-dependent and did not require de novo protein synthesis. EMP supported PDLF migration. In contrast, keratinocytes did not adhere to EMP if their protein synthesis was blocked. EMP showed concentration-dependent binding of fibronectin, peaking at 100 microg ml(-1) (before the precipitation point) of EMP. Type I collagen binding to EMP peaked at a low (1 microg ml(-1)) and narrow concentration range. Neither laminin-1 nor type IV collagen bound to EMP. Collagen and fibronectin, bound to EMP, showed significantly reduced (> 50%) binding of both epithelial cells and PDLF compared with the equivalent concentration of these proteins alone. PDLF, but not epithelial cell, adhesion was rescued by increasing the EMP concentration. These findings show that EMP binds to wound extracellular matrix proteins and regulates their adhesive properties. Such interactions may favor fibroblast adhesion over epithelial cells, potentially promoting connective tissue regeneration. PMID- 17697170 TI - Chitosan adsorption to salivary pellicles. AB - The salivary pellicle is a negatively charged protein film, to which oral bacteria readily adhere. Chitosans are cationic biomolecules with known antimicrobial properties that can be modified in different ways to enhance its antimicrobial activity. Here, we determined the changes in surface chemical composition using X-ray photoelectron spectroscopy (XPS), in hydrophobicity by analyzing water contact angles, in charge through measuring streaming potentials, and evaluated morphology using atomic force microscopy (AFM), of salivary pellicles upon adsorption of different chitosans. The adsorption of chitosans to pellicles was chemically evident from altered carbon functionalities and the presence of an N(1s) peak at 401.1 eV as a result of protonated amines in XPS. Chitosan adsorption made the pellicle (zeta potential of untreated pellicles 29 mV) positively charged and more hydrophobic. A chemically modified chitosan (CL) and an unmodified chitosan (UC) caused aggregation of adsorbed salivary proteins, and AFM revealed clumps of protein after treatment with these chitosans, yielding an increase in pellicle surface roughness from 5.1 nm to between 16.3 and 35.6 nm for CL and UC, respectively. In summary, chitosans have a clear tendency to adsorb to salivary pellicles with a profound effect on the surface properties of the pellicle. Therefore, chitosans may provide anchoring molecules to affix antimicrobials to pellicle surfaces. PMID- 17697169 TI - Changes in matrix phosphorylation during bovine dentin development. AB - Phosphorylation of the organic matrix proteins of dentin is important for the initiation of mineralization, but its relevance in later mineralization stages is controversial. The objective of this study was to analyze changes in the total matrix phosphate content during dentin development and to identify their origin. Amino acid and total matrix phosphate analyses of microdissected developing mantle and circumpulpal fetal bovine dentin specimens were performed. The amino acid composition showed few changes during mantle and circumpulpal dentin maturation. However, the total matrix phosphate content showed a significant, positive correlation with tissue maturation in both mantle and circumpulpal dentin, with a two- and a three-fold increase, respectively, being observed. The data indicate that changes occur in the pattern of phosphorylation of matrix proteins during dentin maturation, which we suggest may play a functional role in later stages of tooth mineralization. PMID- 17697171 TI - Lactobacillus-mediated interference of mutans streptococci in caries-free vs. caries-active subjects. AB - In order to assess whether naturally occurring oral lactobacilli have probiotic properties, lactobacilli were isolated from saliva and plaque from children and adolescents, with or without caries lesions. The interference capacities of these lactobacilli were investigated against a panel of 13 clinical isolates and reference strains of Streptococcus mutans and Streptococcus sobrinus, as well as against the subject's autologous mutans streptococci, using the agar-overlay technique. Lactobacillus-mediated inhibition differed significantly between the three subject groups (no caries, arrested caries, or active caries), demonstrating increased inhibition in subjects without present or previous caries experience compared to subjects with arrested caries or subjects presenting with frank lesions. Lactobacilli from subjects lacking S. mutans inhibited the growth of the test panel of mutans streptococci significantly better than lactobacilli from subjects who were colonized. Furthermore, subjects without caries experience harbored lactobacilli that more effectively repressed the growth of their autologous mutans streptococci. Twenty-three Lactobacillus spp. completely inhibited the growth of all mutans streptococci tested. Species with maximum interference capacity against mutans streptococci included Lactobacillus paracasei, Lactobacillus plantarum, and Lactobacillus rhamnosus. Naturally occurring oral lactobacilli significantly inhibited the growth of both test strains of mutans streptococci and the subject's autologous mutans streptococci in vitro, and this effect was more pronounced in caries-free subjects. PMID- 17697172 TI - Interleukin-17 plays a role in exacerbation of inflammation within chronic periapical lesions. AB - Interleukin (IL)-17 plays an important role in inflammation and certain autoimmune diseases. However, its role in the pathogenesis of chronic dental periapical lesions has not been studied. Periapical lesion mononuclear cells (PL MNC) were isolated from inflammatory cells and phenotypically analyzed by immunocytochemistry. The cells were cultured in vitro and IL-17 and IL-8 were measured in the culture supernatants. Controls were peripheral blood (PB) MNC. The level of IL-17 and the proportion of neutrophils were significantly higher in symptomatic lesions. In addition, the production of IL-17 was higher in culture supernatants of PL-MNC isolated from lesions with a predominance of T cells, and the IL-17 concentration correlated with the proportion of CD3+ and CD4+ cells. There was a positive correlation between the levels of IL-17 and IL-8 in the group of symptomatic lesions. The relationship between these cytokines was additionally confirmed on the basis of augmented production of IL-8 by both PL MNC and PB-MNC treated with IL-17. Our results suggest that IL-17, by stimulating the production of IL-8, may play a role in exacerbating inflammation within chronic periapical lesions. PMID- 17697173 TI - Dentine sealing provided by smear layer/smear plugs vs. adhesive resins/resin tags. AB - The aim of this study was to evaluate the ability of five experimental resins, which ranged from hydrophobic to hydrophilic blends, to seal acid-etched dentine saturated with water or ethanol. The experimental resins (R1, R2, R3, R4, and R5) were evaluated as neat bonding agents (100% resin) or as solutions solvated with absolute ethanol (70% resin/30% ethanol). Fluid conductance was measured at 20 cm H(2)O hydrostatic pressure after sound dentine surfaces were: (i) covered with a smear layer; (ii) acid-etched; or (iii) bonded with neat or solvated resins, which were applied to acid-etched dentine saturated with water or ethanol. In general, the fluid conductance of resin-bonded dentine was significantly higher than that of smear layer-covered dentine. However, when the most hydrophobic neat resins (R1 and R2) were applied to acid-etched dentine saturated with ethanol, the fluid conductance was as low as that produced by smear layers. The fluid conductance of resin-bonded dentine saturated with ethanol was significantly lower than for resin bonded to water-saturated dentine, except for resin R4. Application of more hydrophobic resins may provide better sealing of acid-etched dentine if the substrate is saturated with ethanol instead of with water. PMID- 17697174 TI - A novel nonsense mutation in PAX9 is associated with marked variability in number of missing teeth. AB - Tooth development is under strict genetic control. During the last decade, studies in molecular genetics have led to the identification of gene defects causing the congenital absence of permanent teeth. Analyses of PAX9 and MSX1 in nine families with hypodontia and oligodontia revealed one new PAX9 mutation. A LOD score of Z = 1.8 (theta = 0.0) was obtained for D14S75 close to PAX9 in one three-generation family, and sequencing of the gene identified the nonsense mutation c.433C>T. The mutation results in a truncated PAX9 protein containing the paired domain region as a result of the Q145X stop mutation. The family showed a marked phenotypic variability in the number of missing teeth, ranging from 2 to 15 missing teeth. The highest frequency of missing teeth was found for second molars followed by second premolars. PMID- 17697175 TI - Expression of peroxiredoxin I in plasma cells of oral inflammatory diseases. AB - The participation of reactive oxygen species (ROS) in the immune response, both as pathogen killers and as mediators of signaling pathways, is well established. However, little is known about the enzymes responsible for ROS elimination in immune cells. Peroxiredoxin I (PrdxI) is a multifunctional enzyme that exhibits thioredoxin-dependent peroxidase activity. It has been described as a major hydrogen peroxide (H(2)O(2))-inducible protein in mouse peritoneal macrophages. In order to characterize its participation in the antioxidant defense of inflammatory/immune cells in greater detail, we evaluated its expression at sites of the oral cavity affected by inflammatory disorders induced by different agents (infectious, chemical, mechanical or tumor). In this study we demonstrated, by immunohistochemistry, that PrdxI is expressed in plasma cells, but not in B lymphocytes, regardless of the inflammation-inducing agent. We suggest that PrdxI induction could be considered a crucial part of the cellular adaptive response to the B-cell differentiation process to cope with the additional H(2)O(2) associated with massive disulfide bond formation during immunoglobulin folding in the endoplasmic reticulum of plasma cells. PrdxI could diminish the tissue damage that accompanies inflammation. PMID- 17697177 TI - The promise of stem cell therapy for eye disorders. PMID- 17697178 TI - Clinical applications and new developments of optical coherence tomography: an evidence-based review. AB - Optical coherence tomography (OCT) is a new imaging modality that has increasingly become an indispensable tool in clinical practice for the diagnosis and management of ocular diseases involving the macula, optic nerve and anterior segment. The instrument is an advanced imaging technique that provides unprecedented high resolution and cross-sectional tomographic images of the ocular microstructure in situ, and in real time. Since its introduction about four years ago, a multitude of advantages has made OCT an essential instrument in ophthalmic imaging. The technique has fast image acquisition speed and non contact, non-invasive applicability, allowing a non-excisional 'optical biopsy' to be performed. The purpose of this paper is to provide an evidence-based review of the increasing role of OCT in the diagnosis and management of ocular disorders, particularly in age-related macular degeneration, diabetic macular oedema, macular hole, epiretinal membrane and glaucoma. Being one of the first users of OCT in Australia, our clinical experiences will be highlighted and clinical examples of various conditions will be presented to provide an overview of the immense implications of OCT in practice. The latest developments of the OCT revolution, in relation to combining OCT with fundus photography and scanning laser ophthalmoscopy, will also be described. New developments of three dimensional visualisation of tissue morphology with future models of ultra-high speed, ultra-high resolution OCT may further enhance the early diagnosis, monitoring of disease progression and assessment of treatment efficacy, facilitated by this powerful technology. PMID- 17697179 TI - Horner syndrome. AB - Horner syndrome is an uncommon but important clinical entity, representing interruption of the sympathetic pathway to the eye and face. Horner syndrome is almost always diagnosed clinically, though pharmacological testing can be used to confirm the diagnosis. Imaging modalities such as PET, CT and MRI are important components of work-up for patients presenting with acquired Horner syndrome. Our patient's presentation with Horner syndrome unmasked the causative superior sulcus squamous cell carcinoma and a coincidental lower lobe adenocarcinoma. Successful radical treatment of these cancers resulted in complete resolution of the syndrome and disease-free survival at 18 months. We review the anatomy and pathophysiology underlying this and other causes of Horner syndrome. PMID- 17697180 TI - Apparent time-dependent differences in inferior tear meniscus height in human subjects with mild dry eye symptoms. AB - PURPOSE: The aim of the study was to track the volume of tears contained in the inferior tear meniscus over the course of the day in subjects with symptoms of mild dry eye and a control asymptomatic group. METHODS: Forty non-contact lens wearing subjects (aged 27 +/- 6 years) were enrolled in this investigator-masked study. They were divided into 'dry eye' (DE) and 'non-dry eye' (NDE) individuals based on their responses to the Allergan Subjective Evaluation of Symptoms of Dryness (SESOD) questionnaire. Measurement of the tear meniscus height (TMH) was undertaken on the centre of the right eye at 9:00 am, noon, 3:00 pm, 6:00 pm and 9:00 pm on the lower lid using a non-contact, non-invasive optical coherence tomographer (OCT). The TMH was determined from scanned images using customised software. RESULTS: A monotonous and significant reduction in the central TMH occurred over the course of the day in both groups (p < 0.05), with the values constantly decreasing (NDE = 0.162 to 0.125 mm; DE = 0.154 to 0.121 mm). While the TMH values in the DE group were always lower than the NDE group, these were not significantly different at any time (p > 0.05). CONCLUSIONS: A diurnal reduction in tear volume, as assessed by evaluation of the inferior TMH, may be one of the reasons responsible for the common increase in end-of-day ocular dryness symptoms reported by many patients in clinical practice. PMID- 17697181 TI - Acanthamoeba keratitis and contact lens wear. AB - Acanthamoeba keratitis is a rare but serious complication of contact lens wear that may cause severe visual loss. The clinical picture is usually characterised by severe pain, sometimes disproportionate to the signs, with an early superficial keratitis that is often misdiagnosed as herpes simplex virus (HSV) keratitis. Advanced stages of the infection are usually characterised by central corneal epithelial loss and marked stromal opacification with subsequent loss of vision. In this paper, six cases of contact lens-related Acanthamoeba keratitis that occurred in Australia and New Zealand over a three-year period are described. Three of the patients were disposable soft lens wearers, two were hybrid lens wearers and one was a rigid gas permeable lens wearer. For all six cases, the risk factors for Acanthamoeba keratitis were contact lens wear with inappropriate or ineffective lens maintenance and exposure of the contact lenses to tap or other sources of water. All six patients responded well to medical therapy that involved topical use of appropriate therapeutic agents, most commonly polyhexamethylene biguanide and propamidine isethionate, although two of the patients also subsequently underwent deep lamellar keratoplasty due to residual corneal surface irregularity and stromal scarring. Despite the significant advances that have been made in the medical therapy of Acanthamoeba keratitis over the past 10 years, prevention remains the best treatment and patients who wear contact lenses must be thoroughly educated about the proper use and care of the lenses. In particular, exposure of the contact lenses to tap water or other sources of water should be avoided. PMID- 17697182 TI - Grading static versus dynamic images of contact lens complications. AB - BACKGROUND: This study was conducted to investigate grading performance when estimating the severity of static versus dynamic images of contact lens-related ocular pathology. METHODS: Thirty-eight subjects used the Efron Grading Scales for Contact Lens Complications to grade the severity of ocular pathological changes depicted in static and dynamic (movie clip) computer-displayed images of each of the following contact lens complications: bulbar conjunctival redness, limbal redness, papillary conjunctivitis, corneal staining, corneal infiltrates and meibomian gland dysfunction. The viewing of static and dynamic images was separated by seven weeks. RESULTS: Grades assigned to dynamic images were 0.6 and 0.7 grading scale units higher than those assigned to static images for limbal redness and papillary conjunctivitis, respectively (p < 0.0001 for both). No difference was observed for the other four complications. There was an apparent trend for grading variability to be reduced (that is, observers grading in closer agreement) when grading dynamic versus static images. CONCLUSIONS: Absolute grades based on an assessment of signs of pathology represented in static images may, in some instances, underestimate the true severity of the condition. PMID- 17697183 TI - Electron microscopic examination of the anterior lens capsule in a case of Alport's syndrome. AB - PURPOSE: To report a case of Alport's syndrome and to present electronmicroscopic examination findings of the anterior lens capsule of this patient. METHOD: A 21 year-old man was referred for low visual acuity and retinal pigment epithelial changes in the left eye. The patient and his relatives underwent detailed ophthalmological examination, including electrophysiological testing. The patient also underwent electronmicroscopic examination of the anterior lens capsule. RESULTS: His visual acuity was 6/18 OD and 6/15 OS. Anterior lenticonus and subcapsular opacities were observed in the left eye. Cataract extraction by phacoemulsification with intraocular lens implantation was performed for his poor visual performance. During the capsulorhexis, the remarkably thin and fragile anterior capsule was noted and removed. Ultrastructural analysis of the anterior lens capsule showed a thinner central zone compared with the periphery. CONCLUSIONS: The course of Alport's syndrome can be ameliorated by early diagnosis. Therefore, the ophthalmological examination of a patient with anterior lenticonus must be combined with a detailed medical evaluation. Ultrastructural analysis of the lens capsule can support the diagnosis of Alport's syndrome. PMID- 17697184 TI - Branch retinal artery occlusion during a migraine attack. AB - A 60-year-old male with a history of migraine presented with evidence of branch retinal arterial occlusion that developed at the time of an attack of retinal migraine. The diagnosis of branch arterial occlusion secondary to migraine was made after exclusion of numerous possible medical conditions. The possible role of vasospasm in this condition is discussed. PMID- 17697185 TI - When is glaucoma really glaucoma? AB - The approach to the diagnosis and management of glaucoma has undergone considerable changes in recent years. Current concepts of glaucoma diagnosis focus on structural assessment and structure-function correlation, and relies less on the finding of visual field abnormalities. In turn, contemporary approaches to management have also changed and revolve around earlier initiation of pressure lowering medication based on pre-perimetric findings. This article presents an approach to the assessment of the patient with suspected glaucoma, highlighting those structural and ancillary diagnostic investigations that will aid in the correct diagnosis. It also discusses the differentiation of glaucoma from other, non-glaucomatous disease processes. PMID- 17697189 TI - Acute anterior uveitis in primary care. PMID- 17697195 TI - Identification of the Salmonella enterica serotype typhimurium SipA domain responsible for inducing neutrophil recruitment across the intestinal epithelium. AB - In human intestinal disease induced by Salmonella enterica serotype Typhimurium (S. typhimurium) transepithelial migration of polymorphonuclear leukocytes (PMNs) rapidly follows attachment of the bacteria to the epithelial apical membrane. Previously, we have shown that the S. typhimurium effector protein, SipA, plays a pivotal role in signalling epithelial cell responses that lead to the transepithelial migration of PMNs. Thus, the objective of this study was to determine the functional domain of SipA that regulates this signalling event. SipA was divided into two fragments: the SipAb C-terminal fragment(426-684) (259 AA), which binds actin, and the SipAa fragment(2-425) (424 AA), which a role has yet to be described. In both in vitro and in vivo models of S. typhimurium induced intestinal inflammation the SipAa fragment exhibited a profound ability to induce PMN transmigration, whereas the SipAb actin-binding domain failed to induce PMN transmigration. Subsequent mapping of the SipAa domain identified a 131-amino-acid region (SipAa3(294-424)) responsible for modulating PMN transepithelial migration. Interestingly, neither intracellular translocation nor actin association of SipA was necessary for its ability to induce PMN transepithelial migration. As these results indicate SipA has at least two separate functional domains, we speculate that during infection S. typhimurium requires delivery of SipA to both extracellular and intracellular spaces to maximize pro-inflammatory responses and mechanisms of bacterial invasion. PMID- 17697197 TI - Review article: Bowel preparation for colonoscopy--the importance of adequate hydration. AB - BACKGROUND: Patient compliance with screening recommendations for colorectal cancer remains low, despite a 90% survival rate achieved with early detection. Bowel preparation is a major deterrent for patients undergoing screening colonoscopy. More than half of patients taking polyethylene glycol electrolyte lavage solution and sodium phosphate preparations experience adverse events, such as nausea and abdominal pain. Many adverse events may be associated with dehydration, including rare reports of renal toxicity in patients taking sodium phosphate products. Addressing dehydration-related safety issues through patient screening and education may improve acceptance of bowel preparations, promote compliance and increase the likelihood of a successful procedure. AIM: To evidence safety issues associated with bowel preparation are generally related to inadequate hydration. RESULTS: Dehydration-related complications may be avoided through proper patient screening, for example, renal function and comorbid conditions should be considered when choosing an appropriate bowel preparation. In addition, patient education regarding the importance of maintaining adequate hydration before, during and after bowel preparation may promote compliance with fluid volume recommendations and reduce the risk of dehydration-related adverse events. CONCLUSIONS: Proper patient screening and rigorous attention by patients and healthcare providers to hydration during bowel preparation may provide a safer, more effective screening colonoscopy. PMID- 17697196 TI - Translational mini-review series on immunodeficiency: molecular defects in common variable immunodeficiency. AB - Common variable immunodeficiency (CVID) is a primary immunodeficiency that typically affects adults and is characterized by abnormalities of quantative and qualitative humoral function that are heterogeneous in their immunological profile and clinical manifestations. The recent identification of four monogenic defects that result in the CVID phenotype also demonstrates that the genetic basis of CVID is highly variable. Mutations in the genes encoding the tumour necrosis factor (TNF) superfamily receptors transmembrane activator and calcium modulating ligand interactor (TACI) and B cell activation factor of the TNF family receptor (BAFF-R), CD19 and the co-stimulatory molecule inducible co stimulator molecule (ICOS) all lead to CVID and illustrate the complex interplay required to co-ordinate an effective humoral immune response. The molecular mechanisms leading to the immune defect are still not understood clearly and particularly in the case of TACI, where a number of heterozygous mutations have been found in affected individuals, the molecular pathogenesis of disease requires further elucidation. Together these defects account for perhaps 10-15% of all cases of CVID and it is highly likely that further genetic defects will be identified. PMID- 17697198 TI - Meta-analysis: Inosine triphosphate pyrophosphatase polymorphisms and thiopurine toxicity in the treatment of inflammatory bowel disease. AB - BACKGROUND: Thiopurines are widely used for the treatment of inflammatory bowel disease, but are associated with the development of side effects. It has been suggested that the enzyme inosine triphosphate pyrophosphatase (ITPA) plays a role in the digestion of thiopurines and that defective activity resulting from polymorphisms in the inosine triphosphate pyrophosphatase encoding genes may be associated with thiopurine-induced side effects. Current studies are controversial regarding this hypothesis. AIM: To perform a meta-analysis and gain more insight into a possible correlation between thiopurine-induced side effects and ITPA polymorphisms. METHODS: We explored Medline for articles on ITPA polymorphisms and thiopurine toxicity. Studies that compared ITPA polymorphism frequencies among thiopurine-tolerant and -intolerant adult inflammatory bowel disease patients were included in this meta-analysis. RESULTS: Nine published studies investigated associations between ITPA polymorphisms and thiopurine toxicity. Six studies (with 751 patients included) met our inclusion criteria and were processed in the meta-analysis. This analysis demonstrates that the ITPA 94C ->A polymorphism, is not significantly associated with any of the studied side effect parameters. CONCLUSIONS: This meta-analysis does not prove a correlation between the development of thiopurine toxicity and the ITPA 94C-->A polymorphism. This implies that there is no clinical relevance to determine ITPA polymorphisms in thiopurine-treated patients. PMID- 17697199 TI - Meta-analysis: The utility and safety of heparin in the treatment of active ulcerative colitis. AB - BACKGROUND: The use of heparin for the treatment of ulcerative colitis has been evaluated in several open and controlled trials, with varying outcomes. AIM: To evaluate the efficacy and safety of heparin as supplemental therapy compared with conventional therapy in patients with ulcerative colitis. METHODS: All randomized trials comparing heparin supplementation to conventional therapy were included from electronic databases. Statistical analysis was performed with review manager 4.2.8 (The Cochrane Collaboration, Oxford, UK). Sub-analysis and sensitivity analysis were also performed. RESULTS: Eight randomized-controlled trials, investigating a total of 454 participants, met the inclusion criteria. The odds ratio (OR) for the efficacy of heparin supplementation vs. conventional therapy was 0.78 (95% CI = 0.50-1.21). Few serious adverse events were observed. The OR for the efficacy of unfractionated heparin and low-molecular-weight heparin vs. conventional therapy was 0.26 (95% CI = 0.07-0.93) and 0.92 (95% CI = 0.57-1.47), respectively. The OR for the efficacy of heparin vs. conventional therapy with placebo was 0.87 (95% CI = 0.53-1.44). CONCLUSIONS: Our meta-analysis suggests that administration of heparin in patients with ulcerative colitis is safe, but no additive benefit over conventional therapy is indicated. PMID- 17697200 TI - One-week acid suppression trial in uninvestigated dyspepsia patients with epigastric pain or burning to predict response to 8 weeks' treatment with esomeprazole: a randomized, placebo-controlled study. AB - BACKGROUND: While empiric acid-suppressive therapy for uninvestigated dyspepsia patients with symptoms of epigastric pain or burning is standard practice, it is unknown whether an early response to therapy predicts outcome. AIM: To evaluate whether a 1-w acid suppression trial is effective for predicting 8-w response in such patients. METHODS: Helicobacter pylori-negative patients (aged 18-50 years) in primary care with uninvestigated epigastric pain or burning were randomized to esomeprazole 40 mg q.d.s. or b.d. for 1w, followed by esomeprazole 40 mg q.d.s. or placebo for 7w. Each day, patients rated the severity of their symptoms. RESULTS: Based on the last 3d, 1-w response rates were 39% (231 of 588) and 43% (258 of 596) with esomeprazole 40 mg q.d.s. and b.d., respectively. Based on the last 7d, response rates at 4w were 38% (283 of 738) and 25% (93 of 380) for esomeprazole and placebo, respectively, and 47% (339 of 716) and 34% (124 of 368), respectively, at 8w (both P < 0.001 vs. placebo). The sensitivity and specificity of esomeprazole treatment were 58% and 70%, respectively, at 8w. CONCLUSION: A 1-w acid suppression trial is of limited clinical value for predicting 8-w response in patients with symptoms of epigastric pain or burning. Esomeprazole provides greater symptom control than placebo at 4w and 8w. PMID- 17697201 TI - Randomized-controlled trial of esomeprazole in functional dyspepsia patients with epigastric pain or burning: does a 1-week trial of acid suppression predict symptom response? AB - BACKGROUND: Early identification of true responders to acid suppression in functional dyspepsia patients with symptoms of epigastric pain or burning may enable clinicians to optimally tailor treatment. AIM: To evaluate whether a 1-w acid suppression trial is useful for identifying true responders in this population. METHODS: Patients (18-70 years) were randomized to either esomeprazole 40 mg q.d.s., b.d. or placebo for 1w, and then esomeprazole 40 mg q.d.s. or placebo for 7w. Epigastric pain and/or burning were recorded on a 4 point scale (0 = none, 3 = severe). Trial-week response was defined as symptom score sum < or = 1 on last 3d of therapy; response at 8w was symptom score sum < or = 1 over preceding 7d. RESULTS: 1-w response rates were 33% (199 of 597), 29% (188 of 629) and 23% (71 of 315) with esomeprazole q.d.s., esomeprazole b.d. and placebo, respectively (P = 0.002 for esomeprazole groups vs. placebo). At 8w, trial week sensitivity and specificity were 46% and 80%, respectively, for esomeprazole (40 or 80 mg), and 33% and 87%, respectively, for placebo. The positive and negative predictive values for esomeprazole were 60% and 69%. CONCLUSION: Response to a 1-w acid suppression trial is of limited use for predicting symptom response at 8w in patients with unexplained epigastric pain or burning. PMID- 17697202 TI - Severe gastro-oesophageal reflux symptoms in relation to anxiety, depression and coping in a population-based study. AB - BACKGROUND: The association between psychiatric disorders and gastro-oesophageal reflux symptoms is uncertain, and few population-based studies are available. AIM: To examine the association between psychiatric and psychological factors and reflux symptoms. METHODS: Population-based, cross-sectional, case-control study based on two health surveys conducted in the Norwegian county Nord-Trondelag in 1984-1986 and 1995-1997. Reflux symptoms were assessed in the second survey, including 65,333 participants (70% of the county's adult population). 3153 subjects reporting severe reflux symptoms were defined as cases and 40,210 subjects without symptoms were defined as controls. Data were collected in questionnaires. Odds ratio with 95% confidence intervals were estimated using unconditional logistic regression, in adjusted models. RESULTS: Subjects reporting anxiety without depression had a 3.2-fold (95% CI: 2.7-3.8) increased risk of reflux, subjects with depression without anxiety had a 1.7-fold (95% CI: 1.4-2.1) increased risk and subjects with both anxiety and depression had a 2.8 fold (95% CI: 2.4-3.2) increased risk, compared to subjects without anxiety/depression. We observed a weak inverse association between one measure of covert coping and risk of reflux and a weak positive association between another coping measure and risk of reflux. CONCLUSIONS: This population-based study indicates that anxiety and depression are strongly associated with reflux symptoms, while no consistent association regarding coping and reflux was found. PMID- 17697203 TI - Effect of MDR1 C3435T polymorphism on cure rates of Helicobacter pylori infection by triple therapy with lansoprazole, amoxicillin and clarithromycin in relation to CYP 2C19 genotypes and 23S rRNA genotypes of H. pylori. AB - BACKGROUND: Polymorphism in MDR1 is associated with variation in the plasma level of a proton pump inhibitor. AIM: To investigate whether MDR1 polymorphism is associated with eradication rates of Helicobacter pylori by a triple therapy with lansoprazole, amoxicillin and clarithromycin in relation to CYP2C19 genotype status and bacterial susceptibility to clarithromycin. METHODS: A total of 313 patients infected with H. pylori completed the treatment with lansoprazole 30 mg b.d., clarithromycin 200 mg b.d. and amoxicillin 750 mg b.d. for 1 week. MDR1 C3435T polymorphism and CYP2C19 genotypes of patients and sensitivity of H. pylori to clarithromycin were determined. RESULTS: Logistic regression analysis revealed that the MDR1 polymorphism as well as CYP2C19 genotypes of patients and clarithromycin-resistance of H. pylori were significantly associated with successful eradication. Eradication rates for H. pylori were 82% (83/101: 95% CI = 73-89), 81% (112/139: CI = 73-87), and 67% (44/73: CI = 48-72) in patients with the MDR1 3435 C/C, C/T and T/T genotype, respectively (P = 0.001). CONCLUSIONS: Polymorphism of MDR1 is one of the determinants of successful eradication of H. pylori by the triple therapy with lansoprazole, amoxicillin and clarithromycin, together with CYP2C19 genotype and bacterial susceptibility to clarithromycin. PMID- 17697204 TI - Evaluating the cost of sustained virologic response in naive chronic hepatitis C patients treated a la carte. AB - BACKGROUND: There is a tendency to individualize treatment in chronic hepatitis C patients depending on viral load and rapid clearance of HCV-RNA. AIM: To evaluate the cost (euro, 2006) per sustained virologic response in naive patients with therapy a la carte compared with standard combination therapy. METHODS: A decision analysis model was used to compare standard therapy with peginterferon alpha and ribavirin for 24 weeks for genotype (G) 2/3, and 48 weeks for G1 and therapy a la carte with the same drugs but different durations: G1 high viral load for 48 weeks, G1 low viral load with rapid virologic response for 24 weeks, and without rapid virologic response for 48 weeks, and G2/3 with rapid virologic response for 12 weeks, and without rapid virologic response for 24 weeks. RESULTS: Sustained virologic response was similar in both strategies. The cost per successfully treated patient for standard therapy is 17,812 euros and for therapy a la carte 12,313 euros. Assuming that 13,309 patients with standard therapy and 14,450 patients with therapy a la carte achieve sustained virologic response, therapy a la carte has an overall cost-saving of 59.13 million euros. CONCLUSION: Therapy a la carte is a cost-saving strategy for chronic hepatitis C infection compared to standard therapy, with lower investment requirement per patient to achieve sustained virologic response. PMID- 17697205 TI - Acute systemic, splanchnic and renal haemodynamic changes induced by molecular adsorbent recirculating system (MARS) treatment in patients with end-stage cirrhosis. AB - AIM: To evaluate the acute effect of treatment with the molecular adsorbent recirculating system (MARS) on splanchnic, renal and systemic haemodynamics in patients with end-stage cirrhosis. METHODS: Twelve patients with end-stage cirrhosis, undergoing MARS treatment, were enrolled. The following haemodynamic parameters were measured by means of Doppler ultrasonography and thoracic electrical bioimpedance, before and after each session: portal velocity, renal and splenic resistance indices, cardiac output, cardiac stroke volume, heart rate, mean arterial pressure, systemic vascular resistance. RESULTS: Median portal velocity increased significantly after treatment (23.7 vs. 20.3 cm/s, P < 0.05) while renal resistance index (0.72 vs. 0.75, P < 0.05) and splenic resistance index (0.60 vs. 0.65, P < 0.05) decreased significantly. Mean arterial pressure (83 vs. 81 mmHg, P < 0.05) and vascular resistance (899 vs. 749 dyne. s/cm5, P < 0.05) increased significantly, while cardiac output and stroke volume showed no significant changes. CONCLUSIONS: Data emerging from this investigation suggest that MARS treatment improves significantly various haemodynamic alterations in cirrhotic patients in the short term. The observed decrease in renal vascular resistance and improvement in splenic resistance index, a parameter related to portal resistance, which leads us to hypothesize that these haemodynamic effects are probably mediated by clearance of vasoactive substances during MARS treatment. PMID- 17697206 TI - Virtual vs. optical colonoscopy in symptomatic gastroenterology out-patients: the case for virtual imaging followed by targeted diagnostic or therapeutic colonoscopy. AB - AIM: To compare virtual colonoscopy with optical colonoscopy findings in symptomatic patients. BACKGROUND: Computer tomographic colonography is an alternative to optical colonoscopy. Studies have shown that two-dimensional computer tomographic colonography does not have sufficient sensitivity. Three dimensional computerized tomographic virtual colonoscopy compares well with optical colonoscopy for colorectal neoplasia screening in asymptomatic individuals. METHODS: One hundred patients aged 50 and older underwent same day virtual colonoscopy and optical colonoscopy. The endoscopists were unaware of the radiologist's report until the withdrawal phase of the endoscopy when segmental unblinding occurred. The virtual colonoscopy and optical colonoscopy findings were compared by using the unblinded optical colonoscopy as the reference standard. RESULTS: Pancolonic endoluminal virtual colonoscopy was achieved in 99 patients. Optical colonoscopy caecal intubation occurred in 91 patients. Direct comparison was possible in 90 patients. Both techniques revealed the three cancers detected. Virtual colonoscopy revealed 11 polyps > or = 6 mm diameter in nine patients. Optical colonoscopy revealed 10 polyps > or = 6 mm diameter in nine patients with a further 15-mm polyp discovered after segmental unblinding. CONCLUSION: In symptomatic patients, three-dimensional virtual colonoscopy is equivalent to optical colonoscopy for diagnosing colon cancer and clinically significant polyps. A case can be made for three-dimensional virtual colonoscopy as a primary modality followed if necessary by same day-targeted optical colonoscopy. PMID- 17697207 TI - Sequential evaluation of thiopurine methyltransferase, inosine triphosphate pyrophosphatase, and HPRT1 genes polymorphisms to explain thiopurines' toxicity and efficacy. AB - AIM: To evaluate the polymorphisms of several genes involved in the azathioprine and mercaptopurine metabolism, in an attempt to explain their toxicity and efficacy in Crohn's disease and ulcerative colitis. METHODS: In 422 consecutive patients (250 with Crohn's disease and 172 with ulcerative colitis) and 245 healthy controls, single nucleotide polymorphisms of thiopurine methyltransferase, inosine triphosphate pyrophosphatase and hypoxanthine phosphoribosyl transferase (HPRT1) genes were related to the occurrence of adverse drug reactions (ADRs) and efficacy of therapy. RESULTS: Seventy-three patients reported 81 episodes of ADRs; 45 patients did not respond to therapy. Frequency of thiopurine methyltransferase risk haplotypes was significantly increased in patients with leucopenia (26% vs. 5.7% in patients without ADRs, and 4% of controls) (P < 0.001); no correlation with other ADRs and efficacy of therapy was found. Conversely, the frequency of inosine triphosphate pyrophosphatase and HPRT1 risk genotypes was not significantly different in patients with ADRs (included leucopenia). Non-responders had an increased frequency of inosine triphosphate pyrophosphatase risk genotypes (P = 0.03). CONCLUSIONS: The majority of azathioprine/mercaptopurine-induced ADRs and efficacy of therapy are not explained by the investigated gene polymorphisms. The combined evaluation of all three genes enhanced the correlation with leucopenia (43.5% vs. 23% in controls) (P = 0.008), at the expense of a reduced accuracy (60%). PMID- 17697208 TI - Infliximab in severe ulcerative colitis: short-term results of different infusion regimens and long-term follow-up. AB - BACKGROUND: Severe ulcerative colitis is a life-threatening disorder, despite i.v. glucocorticoids treatment. Infliximab has been proposed as a safe rescue therapy. AIM: To evaluate short- and long-term effectiveness and safety of infliximab in severe refractory ulcerative colitis. METHODS: Eighty-three patients with severe ulcerative colitis (i.v. glucocorticoids treatment refractory) were treated with infliximab in 10 Italian Gastroenterology Units. Patients underwent one or more infusions according to the choice of treating physicians. Short-term outcome was colectomy/death 2 months after the first infusion. Long-term outcome was survival free from colectomy. Safety data were recorded. RESULTS: Twelve patients (15%) underwent colectomy within 2 months. One died of Legionella pneumophila infection 12 days after infliximab. Early colectomy rates were higher in patients receiving one infusion (9/26), compared with those receiving two/more infusions (3/57, P = 0.001, OR = 9.53). Seventy patients who survived colectomy and did not experience any fatal complications were followed-up for a median time of 23 months; 58 patients avoided colectomy during the follow-up. Forty-two patients were maintained on immunosuppressive drugs. No clinical features were associated with outcomes. CONCLUSIONS: Infliximab is an effective and relatively safe therapy to avoid colectomy and maintain long-term remission for patients with severe refractory ulcerative colitis. In the short term, two or more infusions seem to be more effective than one single infusion. PMID- 17697209 TI - The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study. AB - BACKGROUND: Lifelong adherence to a strict gluten-free diet is the cornerstone of coeliac disease treatment. Elucidation of disease pathogenesis has created opportunities for novel therapeutic approaches to coeliac disease. AT-1001 is an inhibitor of paracellular permeability whose structure is derived from a protein secreted by Vibrio cholerae. AIM: To determine the safety and tolerability of 12 mg doses of AT-1001 in coeliac disease subjects challenged with gluten. METHODS: An in-patient, double-blind, randomized placebo-controlled safety study utilizing intestinal permeability, measured via fractional excretions of lactulose and mannitol, as an exploratory measure of drug efficacy. RESULTS: Compared to placebo, no increase in adverse events occurred in patients exposed to AT-1001. Following acute gluten exposure, a 70% increase in intestinal permeability was detected in the placebo group, while none was seen in the AT-1001 group. Interferon-gamma levels increased in four of seven patients (57%) of the placebo group, but only in four of 14 patients (29%) of the AT-1001 group. Gastrointestinal symptoms were more frequently detected in the placebo group when compared to the AT-1001 group (P = 0.018). CONCLUSIONS: AT-1001 is well tolerated and appears to reduce intestinal barrier dysfunction, proinflammatory cytokine production, and gastrointestinal symptoms in coeliacs after gluten exposure. PMID- 17697210 TI - Training for trauma. PMID- 17697211 TI - The effects of electromyographic activity on the accuracy of the Narcotrend monitor compared with the Bispectral Index during combined anaesthesia. AB - The Narcotrend is a monitor system for the assessment of depth of anaesthesia. The objective of this trial was to investigate the susceptibility of the Narcotrend to electromyographic (EMG) activity when compared with the Bispectral Index (BIS). We enrolled 33 patients undergoing major urological procedures under combined anaesthesia (thoracic epidural analgesia and general anaesthesia). Anaesthetic depth was assessed simultaneously by the BIS XP and Narcotrend. The intended anaesthetic depth ranged between 40 and 55 in the BIS and between D2 and D0 in the Narcotrend. BIS, but not Narcotrend, values correlated significantly (p < 0.0001) with EMG. BIS values between 70 and 80 occurred intermittently above an EMG activity of 35 dB, whereas the Narcotrend and the clinical signs remained unchanged during the period of elevated BIS values. None of the patients reported intra-operative awareness. Increased electromyographic activity does not affect Narcotrend values. Under combined anaesthesia, the Narcotrend monitor is more reliable when compared with the BIS regarding susceptibility to increased EMG activity. PMID- 17697212 TI - The utility of B-type natriuretic peptide in predicting postoperative cardiac events and mortality in patients undergoing major emergency non-cardiac surgery. AB - B-type natriuretic peptide (BNP) levels predict cardiovascular risk in several settings. We hypothesised that they would identify individuals at increased risk of complications and mortality following major emergency non-cardiac surgery. Forty patients were studied with a primary end-point of a new postoperative cardiac event, and/or development of significant ECG changes, and/or cardiac death. The main secondary outcome was all-cause mortality at 6 months. Pre operative BNP levels were higher in 11 patients who suffered a new postoperative cardiac event (p = 0.001) and predicted this outcome with an area under the receiver operating characteristic curve of 0.85 (CI = 0.72-0.98, p = 0.001). A pre-operative BNP value > 170 pg x ml(-1) has a sensitivity of 82% and a specificity of 79% for the primary end-point. In this small study, pre-operative BNP levels identify patients undergoing major emergency non-cardiac surgery who are at increased risk of early postoperative cardiac events. Larger studies are required to confirm these data. PMID- 17697213 TI - A minimally invasive metabolic test with intramuscular injection of halothane 5 and 6 vol% to detect probands at risk for malignant hyperthermia. AB - We hypothesised that intramuscular halothane injection increases local Pco(2) concentrations in malignant hyperthermia susceptible (MHS) but not in non susceptible (MHN) individuals. Pco(2) probes with attached microtubing catheters for halothane injection were placed into the lateral vastus muscle of eight MHS and eight MHN probands. Following equilibration, a single bolus of 200 microl halothane 5 and 6 vol% was injected. Pco(2) was measured spectrophotometrically. Baseline Pco(2) concentrations were similar between groups. Maximum Pco(2) and maximum rate of Pco(2) increase was significantly enhanced by halothane 5 and 6 vol% in MHS compared to MHN probands. Systemic haemodynamic and metabolic parameters did not differ between both groups. Local halothane application induces a hypermetabolic reaction with a significant Pco(2) increase in MHS compared to MHN probands, indicating a susceptibility to malignant hyperthermia. Intramuscular halothane injection with Pco(2) measurement seems to be a suitable method for the development of a minimally invasive metabolic test to diagnose malignant hyperthermia susceptibility. PMID- 17697214 TI - Pre-operative high sensitivity C-reactive protein and postoperative outcome in patients undergoing elective orthopaedic surgery. AB - High-sensitivity C-reactive protein (hsCRP) adds important prognostic information, not reflected by traditional risk factors, to the prediction of both the development and outcome of cardiovascular pathology. HsCRP levels also correlate inversely with cardiorespiratory fitness, an important determinant of peri-operative outcome. We hypothesised that pre-operative hsCRP should be associated with excess peri-operative morbidity and longer length of stay. Pre operative hsCRP was measured blinded to standardised postoperative outcomes in 129 elective orthopaedic patients. HsCRP levels were divided into high (> 3 mg x l(-1)) or low (< 3 mg x l(-1)) groups (Center for Disease Control stratification). High-CRP patients had significant cardiovascular history, received cardiac medication or steroid therapy (p < 0.05). Higher pre-operative hsCRP was associated with longer length of stay: mean 7.5 days (95% CI: 6.2-8.8) vs 6.0 days (95% CI: 5.5-6.5; p = 0.03; log rank test). In 21 patients with > 8 days length of stay, high pre-operative hsCRP patients were over-represented (p = 0.04). Pre-operative hsCRP is related to length of stay and delayed postoperative complications. PMID- 17697215 TI - The concept of surgical operating list 'efficiency': a formula to describe the term. AB - While numerous reports have sought ways of improving the efficiency of surgical operating lists, none has defined 'efficiency'. We describe a formula that defines efficiency as incorporating three elements: maximising utilisation, minimising over-running and minimising cancellations on a list. We applied this formula to hypothetical (but realistic) scenarios, and our formula yielded plausible descriptions of these. We also applied the formula to 16 consecutive elective surgical lists from three gynaecology teams (two at a university hospital and one at a non-university hospital). Again, the formula gave useful insights into problems faced by the teams in improving their performance, and it also guided possible solutions. The formula confirmed that a team that schedules cases according to the predicted durations of the operations listed (i.e. the non university hospital team) suffered fewer cancellations (median 5% vs 8% and 13%) and fewer list over-runs (6% vs 38% and 50%), and performed considerably more efficiently (90% vs 79% and 72%; p = 0.038) than teams that did not do so (i.e. those from the university hospital). We suggest that surgical list performance is more completely described by our formula for efficiency than it is by other conventional measures such as list utilisation or cancellation rate alone. PMID- 17697217 TI - BIS and Entropy in the elderly. AB - The interaction of many poorly defined, physiological, pharmacological, and pathological factors make titration of general anaesthesia in the elderly difficult. There may be a potential clinical benefit using the processed electroencephalogram (EEG) to monitor hypnotic level in this population. We prospectively studied 16 patients aged over 65 years having hip fractures repaired under general anaesthesia by experienced anaesthetists blinded to Bispectral Index (BIS(XP)) and Entropy values. Pre-induction EEG indices did not correlate with age or mini-mental state examination (MMSE). During maintenance of anaesthesia, BIS(XP) and Response Entropy (RE) values were within the recommended range of 40-60, 45% and 32% of the total time, respectively. BIS(XP) and Response Entropy (RE) values were above 60 for 11% and 13% of the total time, respectively, and below 40 for 44% and 55% of the total time, respectively. BIS(XP) correlated well with RE in 12 patients, but in the other four patients there was a difference of more than 20 points between BIS(XP) and RE. PMID- 17697216 TI - Bacterial contamination of anaesthetists' hands by personal mobile phone and fixed phone use in the operating theatre. AB - Following hand disinfection, 40 anaesthetists working in the operating room (OR) were asked to use their personal in-hospital mobile phone for a short phone call. After use of the cell phone, bacterial contamination of the physicians' hands was found in 38/40 physicians (4/40 with human pathogen bacteria). After repeating the same investigation with fixed phones in the OR anteroom 33/40 physicians showed bacterial contamination (4/40 with human pathogen bacteria). The benefit of using mobile phones in the OR should be weighed against the risk for unperceived contamination. The use of mobile phones may have more serious hygiene consequences, because, unlike fixed phones, mobile phones are often used in the OR close to the patient. PMID- 17697218 TI - A study of airway management using the ProSeal LMA laryngeal mask airway compared with the tracheal tube on postoperative analgesia requirements following gynaecological laparoscopic surgery. AB - In a randomised double blind prospective study, we tested the hypothesis that postoperative pain is lower in patients who receive an ProSeal LMA laryngeal mask airway compared with a tracheal tube. One hundred consecutive female patients (ASA I-II, 18-75 years) undergoing laparoscopic gynaecological surgery were divided into two equal-sized groups for airway management with the ProSeal LMA or tracheal tube. Anaesthesia management was identical for both groups and included induction of anaesthesia using propofol/fentanyl, and maintenance with propofol/remifentanil, muscle relaxation with rocuronium, positive pressure ventilation, gastric tube insertion, dexamethasone/tropisetron for anti-emetic prophylaxis, and diclofenac for pain prophylaxis. All types of postoperative pain were treated using intravenous patient-controlled analgesia (PCA) morphine. Patients and postoperative staff were unaware of the airway device used. Data were collected by a single blinded observer. We found that pain scores were lower for the ProSeal LMA at 2 h and 6 h but not at 24 h. Morphine requirements were lower for the ProSeal LMA by 30.4%, 30.6% and 23.3% at 2, 6 and 24 h, respectively. Nausea was less common with the ProSeal LMA than with the tracheal tube at 2 h and 6 h but not at 24 h. There were no differences in the frequency of vomiting, sore throat, dysphonia or dysphagia. We conclude that postoperative pain is lower for the ProSeal LMA than the tracheal tube in females undergoing gynaecological laparoscopic surgery. PMID- 17697219 TI - The effect of dilution and prolonged injection time on fentanyl-induced coughing. AB - This study was designed to evaluate the effect of diluting fentanyl 50 microg x ml(-1) to 25 or 10 microg x ml(-1) with 0.9% saline and prolonged injection time on fentanyl-induced cough. Two hundred patients requiring general anaesthesia were randomly allocated into four groups: 50 microg x ml(-1) (Group I), 25 microg x ml(-1) (Group II), 10 microg x ml(-1) (Group III) or 10 microg x ml(-1) combined with prolonged injection (Group IV). Fentanyl 3 microg x kg(-1) was administered within 5 s in Groups I, II, and III, or over 30 s in Group IV. Occurrence of cough was significantly reduced in Group IV (2% vs 32%, 16% and 12% in Groups I, II and III, respectively, p < 0.05). There were no statistically significant differences in the severity of coughing between the four groups (p > 0.05). We conclude that dilution of fentanyl to 10 microg x ml(-1) with 0.9% saline combined with a prolonged injection time eliminates fentanyl-induced cough. PMID- 17697220 TI - A randomised placebo-controlled trial of the effects of midazolam premedication on children's postoperative cognition. AB - This randomised, placebo-controlled study assessed the effects of midazolam premedication on children's postoperative cognition and physical morbidity. In all, 179 children aged 5-10 years were randomly assigned to receive buccal midazolam (0.2 mg x kg(-1)) or placebo before sevoflurane-nitrous oxide anaesthesia for multiple dental extractions. They performed tests of choice reaction time, attention, psychomotor co-ordination and memory pre-operatively (baseline), before discharge and at 48 h. The reaction time of both groups was significantly slower before discharge compared to baseline, with the midazolam group being significantly slower than placebo. Psychomotor co-ordination was also significantly impaired postoperatively after midazolam. Performance on both tests had recovered to baseline by 48 h. Midazolam was also associated with significant anterograde amnesia, both postoperatively and at 48 h, for information presented in the interval between premedication and surgery. The results show significant short-term impairment of children's cognitive function and amnesia enduring for 48 h after low-dose midazolam premedication. PMID- 17697221 TI - Effects of normobaric hyperoxia on haemodynamic parameters of healthy full-term parturients. AB - Fifteen healthy, full-term women with singleton pregnancies were exposed to an increased F(I)o(2) of 0.4 and their haemodynamic responses measured with a non invasive transthoracic bio-impedance monitor. There was a mean reduction in cardiac index from 3.18 to 3.03 l x min(-1) x m(-2) (4.7%, p = 0.004). The mean indexed systemic vascular resistance increased from 2049 to 2178 dynes x cm(-5) x m(-2) (5.7%, p = 0.005). There were no significant changes in stroke index, heart rate or mean arterial pressure. This study demonstrates that even a moderate increase in inspired oxygen fraction has significant effects on the cardiovascular system of the term parturient. PMID- 17697222 TI - Comparison of the Airway Scope, gum elastic bougie and fibreoptic bronchoscope in simulated difficult tracheal intubation: a manikin study. AB - We compared the Airway Scope with a gum elastic bougie and fibreoptic bronchoscope in a manikin with a simulated Cormack and Lehane Grade 3 laryngoscopic view. Twenty-seven anaesthetists intubated the trachea of the manikin with these devices and the time required for intubation was measured. They were then asked to rate the subjective difficulty of intubation (1 = very easy; 5 = very difficult). Mean (SD) intubation times were 16.6 (11.2) s with the Airway Scope, 29.4 (10.9) s with the gum elastic bougie (p < 0.0001), and 30.6 (20.0) s with the fibreoptic bronchoscope (p < 0.0001). The median (range) difficulty was 2 (1-4) with the Airway Scope, 3 (2-4) with the gum elastic bougie (p < 0.001), and 2 (1-5) with the fibreoptic bronchoscope (p = 0.014). In Cormack and Lehane grade 3 laryngoscopic views, the Airway Scope may enable faster and easier tracheal intubation than does a Macintosh laryngoscope with a gum elastic bougie or a fibreoptic bronchoscope. PMID- 17697223 TI - An evaluation of the TruView EVO2 laryngoscope. AB - The TruView EVO2 laryngoscope was compared with the traditional Macintosh laryngoscope in 200 patients who required tracheal intubation for elective surgery. Mallampati score determined prior to laryngoscopy was significantly related to the view of the glottis during laryngoscopy for both laryngoscopes. The view of the larynx was better with the TruView EVO2 laryngoscope than with the Macintosh laryngoscope in patients with a Cormack and Lehane grade greater than 1 (p < 0.01). The mean time to intubate was significantly shorter with the Macintosh laryngoscope (34 s) than with the TruView laryngoscope (51 s) (p < 0.01). PMID- 17697224 TI - Evaluation of the Basic Airway Model, a novel mask ventilation training manikin. AB - The Basic Airway Model is an airway manikin designed for training in mask ventilation. We investigated the ability of the Basic Airway Model to provide varying levels of difficulty for mask ventilation. Volunteers with three levels of experience (novice, intermediate and expert) attempted to ventilate the manikin at three levels of difficulty: easy, intermediate and difficult. The distribution of frequencies of successful ventilation by different groups at the three levels of difficulty were statistically significant (p < 0.0001). The median (IQR (range)) degree of difficulty was 3 (2-5 (1-7)), 4 (3-5.3 (2-7)) and 6 (5-7 (3-9)) for easy, intermediate and difficult settings, respectively. We conclude that the Basic Airway Model can provide different levels of difficulty for mask ventilation training. PMID- 17697225 TI - Awake insertion of the fibreoptic intubating LMA CTrach in three morbidly obese patients with potentially difficult airways. AB - The Intubating Laryngeal Mask Airway (ILMA) is a supraglottic airway that facilitates ventilation and blind tracheal intubation. The LMA CTrach is functionally identical to the ILMA, but has an integrated fibreoptic bundle that provides a view of the larynx. This enables visualisation of tracheal intubation while delivering 100% oxygen, with or without an inhalational anaesthetic. We report awake insertion of the CTrach in three morbidly obese patients (BMI 60-63) with known or anticipated difficult airways. Pre-operatively, patients were given midazolam and glycopyrrolate intravenously, and then in the operating theatre the airway was anaesthetised with topical lidocaine 4%. The CTrach was inserted into the oropharynx of the still-awake patient, the vocal cords were visualised, and anaesthetic induction was commenced with sevoflurane and spontaneous ventilation. Neuromuscular blockers were not used and we were able to see the vocal cords during the entire anaesthetic induction and intubation. PMID- 17697226 TI - Torsades de pointes and self-terminating ventricular fibrillation in a prescription methadone user. AB - Methadone is known to prolong the QT interval and precipitate torsades de pointes. A 54-year-old prescription methadone user with hypokalaemia was referred to Critical Care with acute confusion and respiratory distress. Alcohol withdrawal was the presumed precipitant. The real precipitant only became evident on analysis of a 24-h ECG (Holter monitor) attached to the patient at the time. The patient had suffered prolonged (10 min) ventricular arrhythmias including torsades de pointes and self-terminating ventricular fibrillation. The patient made a full recovery. Risk factors for acquired long QT syndrome and the treatment of torsades de pointes are discussed. PMID- 17697227 TI - Apnoeic spells following general anaesthesia in a patient with familial hemiplegic migraine. AB - Hemiplegic migraine is an unusual variant of migraine, characterised by a temporary hemiparesis or hemiplegia associated with headache. We report a patient with hemiplegic migraine who developed atypical migraine with apnoeic spells, aphasia and hemiparesis following general anaesthesia. We review the clinical features of hemiplegic migraine and the considerations for its anaesthetic management. PMID- 17697228 TI - Ketamine for emergency anaesthesia at very high altitude (4243 m above sea level). AB - A 22-year-old woman presenting with postpartum haemorrhagic shock at 4243 m altitude required anaesthesia to identify and treat the source of bleeding. Slow intravenous administration of ketamine (0.5 mg x kg(-1)) resulted in deep anaesthesia and apnoea requiring hand ventilation for 5 min. Haemodynamic stability was maintained throughout the procedure. Haemostasis was achieved following uterine packing and suture of a second-degree vaginal tear and small cervical tear. Confusion and visual hallucinations occurred upon awakening but recovery was otherwise uneventful. Ketamine can be used for emergency anaesthesia in a wilderness environment over 4000 m but it is probable that the benefits outweigh the risks only where life or limb are acutely threatened. Careful titration of the administered dose is strongly advised, particularly in patients where hypovolaemia and/or hypoxaemia are present. The availability of airway management equipment and the skills to use them may significantly reduce the risks associated with anaesthetic administration at very high altitude. PMID- 17697229 TI - Peri-operative respiratory failure in a cirrhotic patient: a misleading diagnosis. AB - Patients with chronic liver disease may present with different degrees of respiratory dysfunction whose differential diagnosis is important before elective surgery. We report the case of a misleading diagnosis of peri-operative respiratory failure in a cirrhotic patient who underwent mastectomy. Intra operative respiratory failure was ascribed by the anaesthetic team to pulmonary embolism and after the operation this diagnosis was still suspected. Despite postoperative heparin treatment, pulmonary gas exchange remained severely impaired. On the hypothesis of a right to left shunt, we performed transoesophageal echocardiography with a bubble test and confirmed hepatopulmonary syndrome. We administered anticoagulant therapy to the patient following surgery, increasing the risk of haemorrhage. We also continued orotracheal intubation and mechanical ventilation longer than was needed. Respiratory symptoms in a patient with liver disease should not be underestimated and up to 20% of these patients may have hepatopulmonary syndrome. PMID- 17697230 TI - Intubation via a laryngeal mask airway with an Aintree catheter - not all laryngeal masks are the same. PMID- 17697231 TI - Difficulty with intubation over a fibrescope vs over a bougie. PMID- 17697232 TI - Anaesthetic management of patients with Takotsubo cardiomyopathy. PMID- 17697233 TI - Pressure palsy mimicking brachial plexus injury after mastectomy. PMID- 17697235 TI - Tissue adhesive as an alternative to sutures for securing central venous catheters. PMID- 17697236 TI - Accidental use of glucose solution in an arterial cannula flush system. PMID- 17697237 TI - Low volume sub-Tenon's block. PMID- 17697238 TI - Cardiorespiratory arrest during trigeminal rhizolysis. PMID- 17697239 TI - An added benefit of bilateral blood pressure monitoring during carotid endarterectomy. PMID- 17697240 TI - Ultrasound-guided localisation of the trachea. PMID- 17697241 TI - 'False' teeth. PMID- 17697242 TI - Novel use of graded elastic compression stockings. PMID- 17697243 TI - Risk of air embolism from prefilled syringes. PMID- 17697244 TI - Editorial: bisphosphonates. PMID- 17697245 TI - Comparison of the percentage of gutta-percha-filled area obtained by Thermafil and System B. AB - The aim of this study was to determine the percentage of gutta-percha-filled area (GPFA) obtained by Thermafil and System B techniques using light microscopy and digital image processing. Forty-five human mandibular first molars were prepared and obturated as follows: Group 1: lateral condensation (n = 15); Group 2: System B (n = 15); and Group 3: Thermafil system (n = 15). Horizontal sections were cut 4 and 6 mm from the apical foramen of each tooth. The samples were metallographically prepared and taken through photomicrographs. Using digital analysis, the cross-sectional area of the canal and the gutta-percha areas were measured. The GPFA data obtained for the three groups were analysed using the non parametric Friedman and Wilcoxon Signed-Ranks tests. Significant differences were found between Group 3 and Group 2-Group 1. No significant difference was found between Group 2 and Group 1. The Thermafil system produced significantly higher GPFAs than lateral condensation and System B techniques (P < 0.01). This result suggests that the Thermafil system can reduce sealer and voids. PMID- 17697246 TI - Evaluation of ethylenediaminetetraacetic acid (EDTA) solution and gel for smear layer removal. AB - The purpose of this in vitro study was to compare the efficacy of 24% ethylenediaminetetraacetic acid (EDTA) gel and 17% EDTA solution in cleaning dentine walls after root canal instrumentation. Thirty human canine teeth were divided into three groups of 10 teeth each. In Group 1, 1% sodium hypochlorite was used as the irrigating solution; in Group 2, 1% sodium hypochlorite was used with 17% EDTA solution; and in Group 3, 1% sodium hypochlorite was used with 24% EDTA gel. The presence of a smear layer was analysed after instrumentation using scanning electron microscopy. The Kruskal-Wallis test revealed a statistical difference (P < 0.05) between Groups 1 and 2, and also between Groups 1 and 3. No difference was observed between Groups 2 and 3 (P > 0.05). The results indicate that 1% sodium hypochlorite alone does not remove the smear layer and that there was no statistical difference between EDTA gel and EDTA solution in smear layer removal. PMID- 17697247 TI - Spreading of root canal irrigants on root dentine. AB - The purpose of this study was to evaluate the spreading of root canal irrigants on human root dentine. The spreading of various solutions on dentine surfaces was measured after pre-treatment with various conditional solutions. Seven experimental groups were set based on the combination of conditioning solution test solution: none-distilled water; none-6% sodium hypochlorite (NaOCl); none 14.3% ethylenediaminetetraacetic acid containing surfactant 0.084% cetrimide (Morhonine); NaOCl-NaOCl; NaOCl-Morhonine; Morhonine-Morhonine and Morhonine NaOCl. After application of 0.1 mL of conditioning solution for 60 s, 0.5 microL of test solution was placed on dentine surfaces. Spreading of test solution was measured for 480 s to examine the size of the contact area ratio. Those at 300 s were compared among groups using Fisher's Protected Least Significant Difference (P < 0.05). It was concluded that the contact area ratio of Morhonine-NaOCl increased the most significantly among all the experimental groups. PMID- 17697248 TI - Root canal preparation with the NiTi systems K3, Mtwo and ProTaper. AB - The aim of this paper was to examine the result of rotary root canal preparation with the nickel-titanium (NiTi) systems K3, ProTaper and Mtwo. One hundred and fifty curved artificial root canals and 60 mesial canals of human mandibular molars were selected. In the group of curved artificial canals, all canals were prepared to size 35/0.04 taper with the three systems. In the group of human mandibular molars, the teeth with mature root canals were radiographed with silver points inserted in bucco-lingual and in mesio-distal positions. In the artificial root group, one K3 instrument separated. Mtwo (20%) showed significantly (P = 0.003) less zips than K3 (46.9%) or ProTaper (50%). There were no significant differences in ledge and elbow formation. K3 and Mtwo had the lowest percentage of canal transportation. There was no significant difference regarding the preparation length or the condition of the apical foramina following the preparation. Canals prepared with K3 (26.5%) were significantly (P < 0.001) less tapered than ProTaper (62%) and Mtwo (82%). In the human mandibular molar group, one Mtwo and one ProTaper instrument separated. No significant differences were found in the preparation length, transportation or taper. The three systems tested, K3, Mtwo and ProTaper, achieved good preparation results. PMID- 17697249 TI - Two palatal root canals in a maxillary second molar. AB - In this study, we report a case of two palatal root canals in a maxillary second molar that was endodontically treated. The possibility of two palatal root canals in maxillary second molars is quite small; however, it must be taken into account in clinical and radiographic evaluation during endodontic treatment. Often, their presence is noticed only after a canal treatment due to continuing post-operative discomfort. PMID- 17697250 TI - Four canals in the mesial root of a mandibular first molar. A case report under the operating microscope. AB - In this era of microscope-assisted endodontics, finding variations in root canal system anatomy is not uncommon. Operating microscopes combined with careful clinical examination and radiographic interpretation can aid the clinician to successfully treat cases with such internal anatomy. The understanding of this view enables the possible location of additional canals in any tooth requiring endodontic treatment. The present clinical article demonstrates a rare anatomical complexity in the mesial root of a mandibular first molar. Four independent root canal orifices were found in this root by clinical detection with the aid of a dental operating microscope. This case shows that additional canals can be located in any root undergoing endodontic treatment and clinicians should always be aware of aberrant internal anatomy. PMID- 17697251 TI - Radiographic images on orthopantomographs and periapical film. PMID- 17697252 TI - The cysteine bond in the Escherichia coli FimH adhesin is critical for adhesion under flow conditions. AB - Cysteine bonds are found near the ligand-binding sites of a wide range of microbial adhesive proteins, including the FimH adhesin of Escherichia coli. We show here that removal of the cysteine bond in the mannose-binding domain of FimH did not affect FimH-mannose binding under static or low shear conditions (< or = 0.2 dyne cm(-2)). However, the adhesion level was substantially decreased under increased fluid flow. Under intermediate shear (2 dynes cm(-2)), the ON-rate of bacterial attachment was significantly decreased for disulphide-free mutants. Molecular dynamics simulations demonstrated that the lower ON-rate of cysteine bond-free FimH could be due to destabilization of the mannose-free binding pocket of FimH. In contrast, mutant and wild-type FimH had similar conformation when bound to mannose, explaining their similar binding strength to mannose under intermediate shear. The stabilizing effect of mannose on disulphide-free FimH was also confirmed by protection of the FimH from thermal and chemical inactivation in the presence of mannose. However, this stabilizing effect could not protect the integrity of FimH structure under high shear (> 20 dynes cm(-2)), where lack of the disulphide significantly increased adhesion OFF-rates. Thus, the cysteine bonds in bacterial adhesins could be adapted to enable bacteria to bind target surfaces under increased shear conditions. PMID- 17697253 TI - The staphylococcal respiratory response regulator SrrAB induces ica gene transcription and polysaccharide intercellular adhesin expression, protecting Staphylococcus aureus from neutrophil killing under anaerobic growth conditions. AB - In anaerobic environments, Staphylococcus aureus increases the transcription of the intercellular adhesin (ica) cluster, leading to increased polysaccharide intercellular adhesin (PIA) production. The regulatory mechanisms involved in this phenotypic change are mostly unknown. Here we show that the staphylococcal respiratory response regulator, SrrAB, significantly increases icaA transcription under anaerobic growth in S. aureus. Phosphorylated SrrA preferentially bound to a 100 bp DNA sequence located upstream of ica, and dot blot assays revealed little or no PIA expression in S. aureus srrAB deletion-replacement mutants of strains Sa113 and SH1000, grown anaerobically. The biological relevance of SrrAB for S. aureus was assessed in a phagocytosis assay employing human neutrophils. Sixty-eight per cent of PIA producing wild-type cells, but only 19% of srrAB mutant cells survived under anaerobic conditions, suggesting that PIA protected S. aureus against non-oxidative killing mechanisms of the neutrophils. No protection was observed when S. aureus or S. epidermidis strains, producing PIA also under aerobic conditions, were subjected to phagocytosis under aerobic conditions. These results demonstrate that SrrAB is a major activator of ica expression and PIA production in anaerobic environments, where it contributes to the protection of S. aureus against non-oxidative defence mechanisms. PMID- 17697254 TI - Function and molecular architecture of the Yersinia injectisome tip complex. AB - By quantitative immunoblot analyses and scanning transmission electron microscopy (STEM), we determined that the needle of the Yersinia enterocolitica E40 injectisome consists of 139 +/- 19 YscF subunits and that the tip complex is formed by three to five LcrV monomers. A pentamer represented the best fit for an atomic model of this complex. The N-terminal globular domain of LcrV forms the base of the tip complex, while the central globular domain forms the head. Hybrids between LcrV and its orthologues PcrV (Pseudomonas aeruginosa) or AcrV (Aeromonas salmonicida) were engineered and recombinant Y. enterocolitica expressing the different hybrids were tested for their capacity to form the translocation pore by a haemolysis assay. There was a good correlation between haemolysis, insertion of YopB into erythrocyte membranes and interaction between YopB and the N-terminal globular domain of the tip complex subunit. Hence, the base of the tip complex appears to be critical for the functional insertion of YopB into the host cell membrane. PMID- 17697255 TI - Muralytic activity and modular structure of the endolysins of Pseudomonas aeruginosa bacteriophages phiKZ and EL. AB - Pseudomonas aeruginosa bacteriophage endolysins KZ144 (phage phiKZ) and EL188 (phage EL) are highly lytic peptidoglycan hydrolases (210 000 and 390 000 units mg(-1)), active on a broad range of outer membrane-permeabilized Gram-negative species. Site-directed mutagenesis indicates E115 (KZ144) and E155 (EL188) as their respective essential catalytic residues. Remarkably, both endolysins have a modular structure consisting of an N-terminal substrate-binding domain and a predicted C-terminal catalytic module, a property previously only demonstrated in endolysins originating from phages infecting Gram-positives and only in an inverse arrangement. Both binding domains contain conserved repeat sequences, consistent with those of some peptidoglycan hydrolases of Gram-positive bacteria. Fusions of these domains with green fluorescent protein immediately label all outer membrane-permeabilized Gram-negative bacteria tested, isolated P. aeruginosa peptidoglycan and N-acetylated Bacillus subtilis peptidoglycan, demonstrating the broad range of peptidoglycan-binding capacity by these domains. Specifically, A1 chemotype peptidoglycan and fully N-acetylated glucosamine units are essential for binding. Both KZ144 and EL188 appear to be a natural chimeric enzyme, originating from a recombination of a cell wall-binding domain encoded by a Bacillus or Clostridium species and a catalytic domain of an unknown ancestor. PMID- 17697256 TI - WaaL of Pseudomonas aeruginosa utilizes ATP in in vitro ligation of O antigen onto lipid A-core. AB - waaL has been implicated as the gene that encodes the O-antigen ligase. To date, in vitro biochemical evidence to prove that WaaL possesses ligase activity has been lacking due to the difficulty of purifying WaaL and unavailability of substrates. Here we describe the purification of WaaL, a membrane protein with 11 potential transmembrane segments from Pseudomonas aeruginosa, and the development of an in vitro O-antigen ligase assay. WaaL was expressed in a P. aeruginosa wbpL knockout strain, which is defective in its initial glycosyltransferase for O antigen biosynthesis. This approach allowed the purification of WaaL without contaminating O-antigen-undecaprenol-phosphate (Und-P) molecules. Purified WaaL resolved to a monomer (35 kDa) and a dimer (70 kDa) band in SDS-PAGE. The substrates for the O-antigen ligase assay, O-antigen-Und-P and lipid A-core were prepared from a waaL mutant. ATP at 2-4 mM is optimum for the O-ligase activity, and ATP hydrolysis by WaaL follows Michaelis-Menten kinetics. Site-directed mutagenesis analysis indicated that the periplasmic loop region of WaaL is important for ligase activity. A waaL mutant of P. aeruginosa could not be cross complemented by waaL of Escherichia coli, which suggested that each of these proteins has specificity for its cognate core oligosaccharide. PMID- 17697257 TI - The perils of organ retrieval. PMID- 17697259 TI - Valganciclovir versus IV ganciclovir for therapy of cytomegalovirus viremia: has victory been achieved? PMID- 17697261 TI - Increased urologic complications in children after kidney transplants for obstructive and reflux uropathy. AB - In the cyclosporine era, reports on pediatric kidney transplant (KTx) patients with obstructive and reflux uropathy are limited by small numbers, short follow up, and/or lack of control groups. Our single-center study evaluated long-term outcomes (patient and graft survival, urinary tract infections [UTIs], urologic complications) in a large cohort of KTx recipients (<20 years old). We matched our 117 study patients with obstructive and reflux uropathy with 117 controls whose KTx was needed for other reasons; all 234 underwent their KTx between April 25, 1984, and October 23, 2002. The mean age was 8.0 +/- 6.2 years; mean follow up, 133 +/- 67 months. The urologic complication rate was higher in study patients (43%) than in controls (11%) (p < 0.0001), as was the UTI rate (45% vs. 2%; p < 0.0001). The metabolic acidosis and UTI rates were higher in study patients who did (vs. did not) undergo bladder augmentation (p < 0.0001). We found no significant difference between study patients and controls in patient or graft survival, acute or chronic rejection, or mean estimated glomerular filtration rates. Unique to our study is the finding of higher metabolic acidosis and UTI rates in study patients who underwent bladder augmentation. PMID- 17697260 TI - ESDN is a marker of vascular remodeling and regulator of cell proliferation in graft arteriosclerosis. AB - Vascular remodeling is a common feature of many vasculopathies, including graft arteriosclerosis (GA). We investigated whether endothelial and smooth muscle cell derived neuropilin-like protein (ESDN) is a marker of vascular remodeling in GA. Immunostaining of human coronary arteries demonstrated high levels of ESDN in GA, but not in normal arteries. In a model of GA, where a segment of human coronary is transplanted into a severe combined immunodeficient mouse, followed by allogeneic human peripheral blood mononuclear cell (PBMC) reconstitution, ESDN was minimally expressed in transplanted human arteries in the absence of reconstitution. By 2 weeks following PBMC reconstitution, at a time corresponding to maximal vascular cell proliferation, high levels of ESDN were detected in the transplanted arteries. Similarly, injury-induced vascular remodeling in apoE(-/-) mice was associated with early and transient ESDN upregulation, in parallel with cell proliferation. In vascular smooth muscle cell (VSMC) cultures, ESDN expression was significantly higher in proliferating, as compared to growth arrested cells. ESDN overexpression in VSMC led to a decline in growth curves, while ESDN knock down had the opposite effect. We conclude that ESDN is a marker of vascular remodeling and regulator of VSMC proliferation. ESDN may serve as a therapeutic or diagnostic target for GA. PMID- 17697262 TI - Ischemic pre-conditioning in deceased donor liver transplantation: a prospective randomized clinical trial. AB - To assess the immediate and long-term effects of ischemic preconditioning (IPC) in deceased donor. liver transplantation (LT), we designed a prospective, randomized controlled trial involving 60 donors: control group (CTL, n = 30) or study group (IPC, n = 30). IPC was induced by 10-min hiliar clamping immediately before recovery of organs. Clinical data and blood and liver samples were obtained in the donor and in the recipient for measurements. IPC significantly improved biochemical markers of liver cell function such as uric acid, hyaluronic acid and Hypoxia-Induced Factor-1 alpha (HIF-1 alpha) levels. Moreover, the degree of apoptosis was significantly lower in the IPC group. On clinical basis, IPC significantly improved the serum aspartate aminotransferase (AST) levels and reduced the need for reoperation in the postoperative period. Moreover, the incidence of primary nonfunction (PNF) was lower in the IPC group, but did not achieve statistical significance. We conclude that 10-min IPC protects against I/R injury in deceased donor LT. PMID- 17697263 TI - Auxiliary liver transplantation for propionic acidemia: a 10-year follow-up. AB - Orthotopic liver transplantation (OLT) is an established treatment for patients with liver-based metabolic disorders that produce structural and functional impairment. Auxiliary liver transplantation (ALT) has been proposed as an alternative approach due to the potential advantage of preserving the native liver that could be used for future gene therapy and also serves as a back-up should the graft fail. The aim of our study was to determine if ALT has the long term potential to correct the underlying abnormality in propionic acidemia (PA). A retrospective analysis was performed on graft function, metabolic parameters and effects on development in a child who underwent ALT for PA at our institute. The clinical and biochemical parameters are near normal with no diet restrictions and with good graft survival. A normal growth and an acceptable neurological and psychomotor development were achieved in the child. ALT is feasible and provides adequate liver mass to prevent metabolic decompensation in PA. PMID- 17697264 TI - Veno-occlusive disease of the liver after lung transplantation. AB - Veno-occlusive disease (VOD) of the liver is mainly described after chemo irradiation conditioning regimens during haematopoietic stem cell transplantation (SCT) and has been sporadically reported after kidney and liver transplantation. In the latter cases, it is commonly attributed to azathioprine and/or tacrolimus. One case of tacrolimus-induced hepatic VOD developing after lung transplantation (LT) has been recently reported. Here we describe another case of VOD occurring after LT, but in which the causative role was played by azathioprine. PMID- 17697267 TI - Industrial epidemics, public health advocacy and the alcohol industry: lessons from other fields. PMID- 17697268 TI - Crack use in North American cities: the neglected 'epidemic'. PMID- 17697269 TI - Can LAAM, like Lazarus, come back from the dead? PMID- 17697271 TI - The need for values: science and art in alcohol harm reduction. PMID- 17697272 TI - Using neurobiology to reframe the need for alcohol policy interventions. PMID- 17697273 TI - To educate or not to educate: is that the question? PMID- 17697275 TI - Conversation with William L. White. PMID- 17697276 TI - Causes, types and severity of injury among army soldiers hospitalized with alcohol comorbidity. AB - AIM: To examine the relationship between alcohol use and the cause, type and severity of hospitalized injuries. DESIGN/SETTING: We used the Total Army Injury and Health Outcomes Database (TAIHOD) to conduct cross-sectional analyses of the association between alcohol comorbidity and the cause, type and severity of soldiers' non-combat injuries requiring hospitalization. PARTICIPANTS: Subjects were active-duty US army soldiers (n = 211 790) hospitalized with a primary diagnosis of injury between 1980 and 2002. FINDINGS: Alcohol comorbidity was positively associated with hospitalized injuries resulting from fights and falls and negatively associated with sports injuries; positively associated with hospitalized cases of head injury, open wounds and poisonings and negatively associated with musculoskeletal injury; and, overall, associated with shorter length of stay. Controlling for demographic factors did not moderate the association between alcohol and cause, type or severity of injury. CONCLUSION: Alcohol comorbidity is specifically associated with injuries related to impairment and antisocial behavior. PMID- 17697277 TI - Levo-alpha-acetylmethadol (LAAM) versus methadone maintenance: 1-year treatment retention, outcomes and status. AB - AIMS: To compare levo-alpha-acetylmethadol (LAAM) and methadone maintenance (MM) on treatment retention, drug use during treatment and at follow-up, and abstinence. DESIGN: A two-group experimental design with patients assigned randomly (2:1) to receive fully subsidized LAAM or MM for 52 weeks. SETTING: A community clinic providing maintenance treatment in Los Angeles, California. PARTICIPANTS: A total of 315 treatment-seeking patients willing to be assigned randomly to treatment condition; 289 (91.7%) were interviewed at 52 weeks. INTERVENTION: LAAM or MM, plus ancillary services available to all patients. Medication dose varied according to clinical judgement. MEASUREMENTS: Treatment retention and status at 52-week follow-up, weekly clinical urinalysis, self reported drug use and research urinalysis on samples collected at follow-up. FINDINGS: LAAM participants were more likely to complete the planned 52 weeks (57.4%) than MM participants (46.2%) and were less likely to be discharged for arrest/incarceration. LAAM produced fewer during treatment clinic opiate-positive samples (M = 48.8) than MM (M = 62.3). Further, 24.4% on LAAM compared to 11.8% on MM were able to sustain at least 12 weeks of abstinence during the last 24 weeks of treatment. Opiate use at follow-up was lowest (50.9%) among LAAM participants in maintenance treatment. No adverse events, cardiological or otherwise, were observed with LAAM administration. CONCLUSIONS: LAAM is an effective medication for the treatment of opiate dependence in community clinics with numerous behavioral and clinical advantages. LAAM is more effective than MM in promoting retention and extended reduction in and abstinence from opiate use while in treatment. PMID- 17697278 TI - Full participation in harm reduction programmes is associated with decreased risk for human immunodeficiency virus and hepatitis C virus: evidence from the Amsterdam Cohort Studies among drug users. AB - OBJECTIVES: To investigate the impact of harm-reduction programmes on HIV and hepatitis C virus (HCV) incidence among ever-injecting drug users (DU) from the Amsterdam Cohort Studies (ACS). METHODS: The association between use of harm reduction and seroconversion for human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV) was evaluated using Poisson regression. A total of 714 DU were at risk for HIV and/or HCV during follow-up. Harm reduction was measured by combining its two most important components--methadone dose and needle exchange programme (NEP) use--and looking at five categories of participation, ranging from no participation (no methadone in the past 6 months, injecting drug use in the past 6 months and no use of NEP) to full participation (> or = 60 mg methadone/day and no current injecting or > or = 60 mg methadone/day and current injecting but all needles exchanged). RESULTS: Methadone dose or NEP use alone were not associated significantly with HIV or HCV seroconversion. However, with combination of these variables and after correction for possibly confounding variables, we found that full participation in a harm reduction programme (HRP) was associated with a lower risk of HIV and HCV infection in ever-injecting drug users (DU), compared to no participation [incidence rate ratio 0.43 (95% CI 0.21 0.87) and 0.36 (95% CI 0.13-1.03), respectively]. CONCLUSIONS: In conclusion, we found that full participation in HRP was associated with a lower incidence of HCV and HIV infection in ever-injecting DU, indicating that combined prevention measures--but not the use of NEP or methadone alone--might contribute to the reduction of the spread of these infections. PMID- 17697279 TI - Who runs alcohol policy in Brazil? PMID- 17697280 TI - Rates of HIV/AIDS care and antiretroviral therapy response among active injection drug users. PMID- 17697286 TI - There is much to learn from history. PMID- 17697287 TI - Anaesthesia and amnesia. PMID- 17697288 TI - Acta Anaesthesiologica Scandinavica--the first years (from lead to electrons). AB - Acta Anaesthesiologica Scandinavia is the official scientific journal of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine. It was founded in 1957 and we are thus now celebrating its 50th anniversary. This paper relates the history behind the start of the journal and describes its development until 1993. PMID- 17697289 TI - Challenges in scientific publishing--reflections after 14 years as Editor-in Chief. PMID- 17697290 TI - Chlorpromazine and chlorcyclizine in the prevention of postoperative nausea and vomiting. Acta Anaesth. Scandinav. 1958, 2, 153-162. PMID- 17697292 TI - Effect of local anaesthetics on wound healing. An experimental study with special reference to carbocain. Acta Anaesth. Scandinav. 1957, 2, 87-99. PMID- 17697294 TI - Lidocaine for spinal anesthesia. A study of the concentration in the spinal fluid. Acta Anaesth. Scandinav. 1957, 2, 105-115. PMID- 17697296 TI - The effect of some curarizing drugs in unanaesthetized man. I. d-Tubocurarine chloride, gallamonium iodide, decamethonium iodide, succinylcholine iodide and its bis-monoethyl-substituted derivative in single or repeated doses. Acta Anaesth. Scandinav. 1957, 1, 15-39. PMID- 17697298 TI - Teaching mouth-to-mouth resuscitation in primary schools. Acta Anaesthesiol Scand Suppl. 1961;Suppl 9:63-81. PMID- 17697299 TI - The birth of the resuscitation mannequin, Resusci Anne, and the teaching of mouth to-mouth ventilation. PMID- 17697300 TI - Immediate peri-operative memory. AB - BACKGROUND: Information about anterograde and retrograde amnesias in the immediate peri-operative period is scarce. During this period, assessment of memory for real-life events is also rare. We hypothesized that there would be both anterograde and retrograde amnesias and memory for peri-operative events would be better than for verbal memory. METHODS: We studied 40 patients who underwent general anesthesia and surgery and 19 control volunteers who were matched to the patients but did not have surgery. Patients completed the state anxiety part of the Spielberger State-Trait Anxiety Inventory in the pre operative period. They were presented with three word lists in the holding area, the operating room before induction of anesthesia and the recovery room. Memory for the words was tested the next day by recall and recognition tests. Memory for events that happened on the day of surgery was tested by administering a questionnaire. The control subjects were tested similarly but did not complete the events questionnaire. Retrograde amnesia would be demonstrated by a decline in patients' memory from the holding area to the operating room which exceeded any corresponding changes in controls; anterograde amnesia would be demonstrated by memory impairment of the patients in the recovery room, relative to controls. RESULTS: Recall and recognition of words were significantly impaired in the recovery room with a decline from 12% in the holding area to zero% in the recovery room for recall and from 43% to 7% for recognition. The decline in memory from the holding area to the operating room was not significantly greater in patients than in controls, 80% vs. 56% for recall and 27% vs. 14% for recognition. There were no significant differences for recognition of events which happened in the three rooms. CONCLUSIONS: We were unable to detect retrograde amnesia. Patients' memory for neutral stimuli in the recovery room was severely impaired. The events questionnaire proved to be insensitive. PMID- 17697301 TI - Comparison of transmucosal midazolam with inhalation sedation for dental extractions in children. A randomized, cross-over, clinical trial. AB - BACKGROUND: The transmucosal route for conscious sedation in children has been reported widely in the field of medicine, but less so in dental patients. The aim of this study was to evaluate the efficacy and safety profile of midazolam (0.2 mg/kg) administered by the buccal transmucosal route, in comparison with nitrous oxide/oxygen inhalation sedation, for orthodontic extractions in 10-16-year-old dental patients. METHODS: Each patient attended for two visits and was randomly allocated to receive buccal midazolam (0.2 mg/kg) or nitrous oxide/oxygen titrated to 30%/70% at the first visit, the alternative being used at the second visit. The patients' vital signs, sedation levels and behavioural scores were recorded throughout. Post-operatively, side-effects, recall of the visit and satisfaction levels were recorded via questionnaire. RESULTS: Thirty-six patients, with a mean age of 12.9 years, completed both arms of the trial. The maximum level of sedation was achieved with buccal midazolam in a mean time of 14.42 min, compared with 7.05 min with inhalation sedation. The vital signs with both types of sedation remained within acceptable limits and the reported side effects were of no clinical significance. Buccal midazolam was found to be acceptable by 65.7%. Only 28.6% of cases preferred this technique, the main disadvantage being the taste of the solution. CONCLUSION: Buccal midazolam sedation (0.2 mg/kg) seems to be equally as safe and effective as nitrous oxide/oxygen for the extraction of premolar teeth in anxious children. However, further research is required to refine the midazolam vehicle to improve acceptability. PMID- 17697302 TI - Anaesthesiological considerations in small-incision and laparoscopic cholecystectomy in symptomatic cholecystolithiasis: implications for pulmonary function. A randomized clinical trial. AB - BACKGROUND: Upper abdominal surgery, including laparoscopic cholecystectomy (LC), is associated with post-operative pulmonary dysfunction. LC has, by consensus, become the treatment of choice for symptomatic cholecystolithiasis. Small incision cholecystectomy (SIC), a procedure that does not require a pneumoperitoneum, threatens to be lost to clinical practice, even though there is evidence of equality. We hypothesized that the SIC technique should be equal, and might even be superior, to LC when considering post-operative pulmonary function because of the short incision length. METHODS: A single-centre randomized clinical trial was performed including patients scheduled for elective cholecystectomy. Pulmonary flow-volume curves were measured pre-operatively, post operatively and at follow-up. Blood gas analyses were measured pre-operatively, in the recovery phase and on post-operative day 1. Anaesthesia, analgesics and peri-operative care were standardized by protocol. Post-operatively, patients and caregivers were blind to the procedure. RESULTS: Two hundred and fifty-seven patients were analysed. There was one pulmonary complication (pneumonia) in the LC group. In both groups, similar reductions of approximately 20% in pulmonary function parameters occurred, with complete recovery to pre-operative values. Patients in the SIC group consumed more analgesia when compared with the LC group, without any impact on blood gas analysis. Patients converted to a conventional open technique showed significant differences in six of the eight parameters in pulmonary function tests. CONCLUSION: When evaluated with strict methodology and standardization of care, no clinically relevant differences were found between SIC and LC with regard to pulmonary function. Our results suggest that the popularity of the laparoscopic technique cannot be attributed to pulmonary preservation. PMID- 17697303 TI - Norepinephrine in low to moderate doses may not increase luminal concentrations of L-lactate in the gut in patients with septic shock. AB - AIM: To investigate the effect of different doses of norepinephrine (noradrenaline) on luminal concentrations of L-lactate in the rectum and stomach in patients with fluid-resuscitated septic shock. METHODS: This was a paired cross-over study in which the dose of norepinephrine was titrated to mean arterial blood pressures (MAPs) of 65 and 85 mmHg in random sequence. It was performed in a mixed intensive care unit at a university hospital. Eight patients with fluid-resuscitated septic shock requiring norepinephrine (>0.1 microg/kg/min) were included. Patients were treated with norepinephrine to a MAP of either 65 or 85 mmHg for 2 h. After a 'washout' period of 2 h, the dose of norepinephrine was titrated to the other endpoint of MAP for another 2 h. The concentrations of L-lactate in the rectal and gastric lumen were estimated by 1-h equilibrium dialysis during the second hour of the treatment periods. RESULTS: MAP and central venous oxygen saturation were increased by increasing the dose of norepinephrine [median (range) (microg/kg/min): 0.07 (0.00-0.60) and 0.18 (0.11 1.00) at MAPs of 65 and 85 mmHg, respectively], whereas the metabolic markers were unaffected [luminal concentrations (mmol/l) of L-lactate in the rectum of 1.9 (0.8-6.4) and 1.8 (0.9-5.7) (P =0.94) and in the stomach of 1.1 (0.1-10.0) and 1.3 (0.3-9.7) (P =0.88) at MAPs of 65 and 85 mmHg, respectively]. CONCLUSION: In this small study, luminal concentrations of L-lactate in the rectum and stomach were unaffected by norepinephrine at low to moderate doses. These data suggest that norepinephrine may not increase luminal concentrations of l-lactate in the gut in patients with fluid-resuscitated septic shock. PMID- 17697304 TI - Effects of endotoxaemia on markers of permeability, metabolism and inflammation in the large bowel of healthy subjects. AB - BACKGROUND: Increased permeability and increased luminal concentrations of L lactate have previously been shown in the large bowel in septic patients. To advance these observations, a human model of colorectal barrier failure in sepsis is desirable. Therefore, we assessed the effects of endotoxaemia on markers of permeability, metabolism and inflammation in the large bowel in healthy subjects. METHODS: Twelve healthy male subjects received intravenous endotoxin (2 ng/kg body weight) or saline in a paired cross-over design. Colorectal permeability was assessed after 3, 6, 9 and 12 h by the systemic recovery of luminally instilled (99m)Tc-diethylenetriaminepentaacetate. Luminal concentrations of L-lactate were assessed by equilibrium dialysis. Mucosal biopsies from the large bowel were sampled after 6 and 12 h, and the apoptotic ratio of the epithelium was assessed by terminal deoxynucleotidyl transferase-mediated desoxyuridinetriphosphate nick end-labelling (TUNEL) assay and the expression of inducible nitric oxide synthase (iNOS) mRNA by reverse transcriptase-polymerase chain reaction. RESULTS: Systemic effects of endotoxaemia were observed, including fever, tachycardia and strongly increased plasma values of tumour necrosis factor-alpha. By contrast, the colorectal permeability, luminal lactate concentrations, mucosal infiltration of inflammatory cells, epithelial apoptotic ratio and expression of iNOS were all unaffected by endotoxin. CONCLUSIONS: No effect of a single intravenous dose of endotoxin was observed on markers of large bowel permeability, metabolism and inflammation in healthy subjects. This suggests that this part of the gut is relatively resistant to the systemic inflammation induced by experimental endotoxaemia in humans. PMID- 17697305 TI - Dexmedetomidine during coronary artery bypass grafting surgery: is it neuroprotective?--A preliminary study. AB - BACKGROUND: In the present study, we aimed to determine whether during coronary artery bypass grafting (CABG) surgery, dexmedetomidine has protective effects against cerebral ischemic injury. METHOD: Twenty-four patients, aged 50-70 years, undergoing CABG surgery were randomized into two groups of 12 patients each: those receiving dexmedetomidine (group D) and those not receiving it (group C). As basal blood samples from arterial and jugular bulb catheters were drawn, dexmedetomidine (1 microg/kg bolus and infusion at a rate of 0.7 microg/kg/h) was administered to patients in group D. Arterial and jugular venous blood gas analyses, serum S-100B protein (S-100B), neuron-specific enolase (NSE) and lactate measurements were performed after induction, 10 min after the initiation of cardiopulmonary bypass (CPB), 1 min after declamping, at the end of CPB, at the end of the operation and 24 h after surgery. Mann-Whitney U- and Wilcoxon's tests were used for statistical analyses. RESULTS: No significant between-group differences were found regarding arterial and jugular venous pH, PO(2), PCO(2) and O(2) saturations. S-100B, NSE and lactate levels were also similar between groups D and C. During the post-operative period, there were no clinically overt neurological complications in any patient. CONCLUSION: Cerebral ischemia marker (S-100B, NSE, lactate) patterns were as expected during CPB; however, there were no differences between the groups, which led us to believe that during CABG surgery dexmedetomidine has no neuroprotective effects. Future studies with larger populations are recommended to further establish the effects of this drug. PMID- 17697306 TI - Disturbances in melatonin and core body temperature circadian rhythms after minimal invasive surgery. AB - BACKGROUND: Sleep disturbances, fatigue and reduced general well-being frequently occur after minimal invasive surgery. The circadian rhythms of melatonin and core body temperature are central to the regulation of normal sleep. The aim of this study was to assess changes in these circadian rhythms after laparoscopic cholecystectomy. METHODS: Twelve women were studied before and after laparoscopic cholecystectomy. The major urinary melatonin metabolite, 6-sulphatoxymelatonin (aMT6s), and the core body temperature were measured for 1 day before and 1 day after surgery. The basal and maximum secretion of aMT6s were determined, as well as the timing and amplitude of aMT6s and the temperature rhythm. The patients' rest-activity and calculated sleep parameters were assessed by actigraphy. RESULTS: A significant delay in the timing of aMT6s rhythm was observed after surgery [median (range) peak time of aMT6s: after surgery, 05:49 h (02:57-08:23 h); before surgery, 04:32 h (02:18-06:49 h); P< or = 0.05]. The amplitude of the aMT6s rhythm was also significantly decreased after surgery [after surgery, 7.1 ng aMT6s/mg creatinine (1-15.9 ng); before surgery, 13.2 ng aMT6s/mg creatinine (2.9-22.7 ng); P< or = 0.005]. There was almost a 12-h phase delay of the core body temperature rhythm after surgery [peak time: before surgery, 17:39 h (15:17 22:06 h); after surgery, 05:14 h (03:24-21:43 h); P< or = 0.01]. CONCLUSIONS: Following laparoscopic cholecystectomy, there was a delay in the timing of the aMT6s rhythm and a decreased evening decline in the temperature rhythm. PMID- 17697307 TI - Plasma levels of endothelin-1 after a pulmonary embolism of bone marrow fat. AB - BACKGROUND: During orthopedic surgery, embolization of bone marrow fat can lead to potentially fatal, intra-operative cardiovascular deterioration. Vasoactive mediators may also be released from the bone marrow and contribute to these changes. Increased plasma levels of endothelin-1 (ET-1) have been observed after pulmonary air and thrombo-embolism. The role of ET-1 in the development of acute cardiovascular deterioration as a result of bone marrow fat embolization during vertebroplasty was therefore investigated. METHODS: Bone cement was injected into three lumbar vertebrae of six sheep in order to force bone marrow fat into the circulation. Invasive blood pressures and heart rate were recorded continuously until 60 min after the last injection. Cardiac output, arterial and mixed venous blood gas parameters and plasma ET-1 concentrations were measured at selected time points. Post-mortem, lung biopsies were taken for analysis of intravascular fat. RESULTS: Cement injections resulted in a sudden (within 1 min) and severe increase in pulmonary arterial pressure (>100%). Plasma concentrations of ET-1 started to increase after the second injection, but no significant changes were observed. Intravascular fat and bone marrow cells were present in all lung lobes. CONCLUSION: Cement injections into vertebral bodies elicited fat embolism resulting in subsequent cardiovascular changes that were characterized by an increase in pulmonary arterial pressure. Cardiovascular complications as a result of bone marrow fat embolism should thus be considered in patients undergoing vertebroplasty. No significant changes in ET-1 plasma values were observed. Thus, ET-1 did not contribute to the acute cardiovascular changes after fat embolism. PMID- 17697308 TI - Management of nerves during leg amputation--a neglected area in our understanding of the pathogenesis of phantom limb pain. AB - BACKGROUND: Chronic neuropathic pain after leg amputation is a significant problem, with a reported incidence during the first year as high as 70%. Intra operative handling of the nerves during amputation has not been discussed in the literature on post-amputation pain and, in major textbooks, it is recommended that the ischial nerve be ligated, despite the fact that the experimental literature uses nerve ligations to produce neuropathic pain. The purpose of this study was to investigate the clinical practice of nerve handling during leg amputation. METHODS: Trainees with at least 2 years of practice received a questionnaire regarding handling of the nerves during leg amputation; 128 of 149 questionnaires sent (86%) were returned. RESULTS: Ligation of the nerves was used by 31% of surgeons. CONCLUSION: There is no consistency in the management of the large nerves during lower leg amputation. The recommendations in major textbooks may not be appropriate when compared with the experimental literature on nerve ligature models to produce neuropathic pain. Future studies on post-amputation pain should consider intra-operative nerve management. PMID- 17697309 TI - Effects of thoracic epidural anaesthesia on pulmonary venous admixture and oxygenation during one-lung ventilation. AB - BACKGROUND: In this clinical randomized study, the effects of four anaesthesia techniques during one-lung ventilation [total intravenous anesthesia (TIVA) with or without thoracic epidural anaesthesia (TEA) (G-TIVA-TEA and G-TIVA), isoflurane anaesthesia with or without TEA (G-ISO-TEA and G-ISO)] on pulmonary venous admixture (Qs/Qt) and oxygenation (OLV) were investigated. METHODS: In 100 patients (four groups, 25 patients in each) undergoing thoracotomy, a thoracic epidural catheter was inserted pre-operatively. In G-TIVA-TEA and G-ISO-TEA, bupivacaine 0.1% + 0.1 mg/ml morphine was administered intra-operatively (10 ml of first bolus + 7 ml/h infusion). Propofol infusion or isoflurane concentration was adjusted to keep a bispectral index (BIS) of between 40 and 50 in all groups. FiO(2) was 0.8 during OLV and 0.5 before and after OLV. Partial arterial and central venous oxygen pressures (PaO(2) and PvO(2)), arterial and venous oxygen saturations and Qs/Qt values were recorded before, during and after OLV. RESULTS: During OLV, PaO(2) was significantly higher and Qs/QT significantly lower in G TIVA-TEA and G-TIVA compared with G-ISO-TEA and G-ISO (PaO2: 188 +/- 36; 201 +/- 39; 159 +/- 33; 173 +/- 42 mmHg, respectively; Qs/Qt: 31.2 +/- 7.4; 28.2 +/- 7; 36.7 +/- 7.1; 33.7 +/- 7.7%, respectively). No statistical changes were observed in patients with TEA compared with without TEA in any measurement. CONCLUSION: During OLV, TEA does not significantly affect the oxygenation and Qs/Qt and can be used safely regardless of whether TIVA or inhalation techniques are used. PMID- 17697310 TI - Levosimendan improves the initial outcome of cardiopulmonary resuscitation in a swine model of cardiac arrest. AB - BACKGROUND: Cardiac arrest remains the leading cause of death in Western societies. Advanced Life Support guidelines propose epinephrine (adrenaline) for its treatment. The aim of this study was to assess whether a calcium sensitizer agent, such as levosimendan, administered in combination with epinephrine during cardiopulmonary resuscitation, would improve the initial resuscitation success. METHODS: Ventricular fibrillation was induced in 20 Landrace/Large-White piglets, and left untreated for 8 min. Resuscitation was then attempted with precordial compressions, mechanical ventilation and electrical defibrillation. The animals were randomized into two groups (10 animals each): animals in Group A received saline as placebo (10 ml dilution, bolus) + epinephrine (0.02 mg/kg), and animals in Group B received levosimendan (0.012 mg/kg/10 ml dilution, bolus) + epinephrine (0.02 mg/kg) during cardiopulmonary resuscitation. Electrical defibrillation was attempted after 10 min of ventricular fibrillation. RESULTS: Four animals in Group A showed restoration of spontaneous circulation and 10 in Group B (P = 0.011). The coronary perfusion pressure, saturation of peripheral oxygenation and brain regional oxygen saturation were significantly higher during cardiopulmonary resuscitation in Group B. CONCLUSIONS: A calcium sensitizer agent, when administered during cardiopulmonary resuscitation, significantly improves initial resuscitation success and increases coronary perfusion pressure during cardiopulmonary resuscitation. PMID- 17697311 TI - Potentially life-threatening bradycardia after remifentanil infusion in a child. PMID- 17697312 TI - The use of the LMA Fastrach system as a guidance tool for inaccessible glottic lesion biopsies. PMID- 17697313 TI - Ventricular tachycardia after administration of sildenafil citrate: a case report. AB - BACKGROUND: It has not previously been reported that sildenafil citrate causes malignant arrhythmias in humans. CASE PRESENTATION: A 41-year-old man developed sustained ventricular tachycardia following sildenafil citrate administration. CONCLUSION: It cannot be dismissed that this patient experienced ventricular tachycardia as an adverse effect of sildenafil citrate administration. PMID- 17697314 TI - Ecological study of socio-economic indicators and prevalence of asthma in schoolchildren in urban Brazil. AB - BACKGROUND: There is evidence of higher prevalence of asthma in populations of lower socio-economic status in affluent societies, and the prevalence of asthma is also very high in some Latin American countries, where societies are characterized by a marked inequality in wealth. This study aimed to examine the relationship between estimates of asthma prevalence based on surveys conducted in children in Brazilian cities and health and socioeconomic indicators measured at the population level in the same cities. METHODS: We searched the literature in the medical databases and in the annals of scientific meeting, retrieving population-based surveys of asthma that were conducted in Brazil using the methodology defined by the International Study of Asthma and Allergies in Childhood. We performed separate analyses for the age groups 6-7 years and 13-14 years. We examined the association between asthma prevalence rates and eleven health and socio-economic indicators by visual inspection and using linear regression models weighed by the inverse of the variance of each survey. RESULTS: Six health and socioeconomic variables showed a clear pattern of association with asthma. The prevalence of asthma increased with poorer sanitation and with higher infant mortality at birth and at survey year, GINI index and external mortality. In contrast, asthma prevalence decreased with higher illiteracy rates. CONCLUSION: The prevalence of asthma in urban areas of Brazil, a middle income country, appears to be higher in cities with more marked poverty or inequality. PMID- 17697315 TI - Baseline verbal fluency performance as predictor of state anxiety during a live hand-grenade throwing exercise - A prospective study of Swedish military conscripts. AB - BACKGROUND: We investigated whether individual differences in baseline executive control capacity could predict state anxiety during a potentially life threatening situation. METHODS: 19 Swedish military conscripts were assessed during two measurement occasions. During a baseline measurement, data regarding performance on a letter fluency task and state anxiety were assessed. During a second measurement, performed immediately prior to participation in a live hand grenade throwing exercise, data regarding state anxiety was assessed. All participants were male, right-handed and had fulfilled 12 years of education. RESULTS: The level of state anxiety was significantly increased between the two measurement occasions (p < .01). Both the number of words produced (beta = -.37; p < .05) and the number of perseveration made (beta = .43; p < .05) on the verbal fluency task predicted, while controlling for state anxiety at baseline, the level of experienced state anxiety during the threatening situation. CONCLUSION: Although more research is needed the present finding suggests that individual differences in executive control capacity might be related to emotion regulation ability during acute stressor exposure. PMID- 17697316 TI - Mechanisms, molecular and sero-epidemiology of antimicrobial resistance in bacterial respiratory pathogens isolated from Japanese children. AB - BACKGROUND: The clinical management of community-acquired respiratory tract infections (RTIs) is complicated by the increasing worldwide prevalence of antibacterial resistance, in particular, beta-lactam and macrolide resistance, among the most common causative bacterial pathogens. This study aimed to determine the mechanisms and molecular- and sero-epidemiology of antibacterial resistance among the key paediatric respiratory pathogens in Japan. METHODS: Isolates were collected at 18 centres in Japan during 2002 and 2003 from children with RTIs as part of the PROTEKT surveillance programme. A proportion of Haemophilus influenzae isolates was subjected to sequencing analysis of the ftsI gene; phylogenetic relatedness was assessed using multilocus sequence typing. Streptococcus pneumoniae isolates were screened for macrolide-resistance genotype by polymerase chain reaction and serotyped using the capsular swelling method. Susceptibility of isolates to selected antibacterials was performed using CLSI methodology. RESULTS AND DISCUSSION: Of the 557 H. influenzae isolates collected, 30 (5.4%) were beta-lactamase-positive [BL+], 115 (20.6%) were BL-nonproducing ampicillin-resistant (BLNAR; MIC >or= 4 mg/L) and 79 (14.2%) were BL-nonproducing ampicillin-intermediate (BLNAI; MIC 2 mg/L). Dabernat Group III penicillin binding protein 3 (PBP3) amino acid substitutions in the ftsI gene were closely correlated with BLNAR status but phylogenetic analysis indicated marked clonal diversity. PBP mutations were also found among BL+ and BL-nonproducing ampicillin sensitive isolates. Of the antibacterials tested, azithromycin and telithromycin were the most active against H. influenzae (100% and 99.3% susceptibility, respectively). A large proportion (75.2%) of the 468 S. pneumoniae isolates exhibited macrolide resistance (erythromycin MIC >or= 1 mg/L); erm(B) was the most common macrolide resistance genotype (58.8%), followed by mef(A) (37.2%). The most common pneumococcal serotypes were 6B (19.7%), 19F (13.7%), 23F (13.5%) and 6A (12.8%). Telithromycin and amoxicillin-clavulanate were the most active antibacterials against S. pneumoniae (99.8% and 99.6% susceptibility, respectively). CONCLUSION: Approximately one-third of H. influenzae isolates from paediatric patients in Japan are BLNAI/BLNAR, mainly as a result of clonally diverse PBP3 mutations. Together with the continued high prevalence of pneumococcal macrolide resistance, these results may have implications for the clinical management of paediatric RTIs in Japan. PMID- 17697317 TI - Susceptibility to type 1 diabetes conferred by the PTPN22 C1858T polymorphism in the Spanish population. AB - BACKGROUND: The protein tyrosine phosphatase N22 gene (PTPN22) encodes a lymphoid specific phosphatase (LYP) which is an important downregulator of T cell activation. A PTPN22 polymorphism, C1858T, was found associated with type 1 diabetes (T1D) in different Caucasian populations. In this study, we aimed at confirming the role of this variant in T1D predisposition in the Spanish population. METHODS: A case-control was performed with 316 Spanish white T1D patients consecutively recruited and 554 healthy controls, all of them from the Madrid area. The PTPN22 C1858T SNP was genotyped in both patients and controls using a TaqMan Assay in a 7900 HT Fast Real-Time PCR System. RESULTS: We replicated for the first time in a Spanish population the association of the 1858T allele with an increased risk for developing T1D [carriers of allele T vs. CC: OR (95%) = 1.73 (1.17-2.54); p = 0.004]. Furthermore, this allele showed a significant association in female patients with diabetes onset before age 16 years [carriers of allele T vs. CC: OR (95%) = 2.95 (1.45-6.01), female patients vs female controls p = 0.0009]. No other association in specific subgroups stratified for gender, HLA susceptibility or age at onset were observed. CONCLUSION: Our results provide evidence that the PTPN22 1858T allele is a T1D susceptibility factor also in the Spanish population and it might play a different role in susceptibility to T1D according to gender in early-onset T1D patients. PMID- 17697318 TI - Health inequalities, physician citizens and professional medical associations: an Australian case study. AB - BACKGROUND: As socioeconomic health inequalities persist and widen, the health effects of adversity are a constant presence in the daily work of physicians. Gruen and colleagues suggest that, in responding to important population health issues such as this, defining those areas of professional obligation in contrast to professional aspiration should be on the basis of evidence and feasibility. Drawing this line between obligation and aspiration is a part of the work of professional medical colleges and associations, and in doing so they must respond to members as well as a range of other interest groups. Our aim was to explore the usefulness of Gruen's model of physician responsibility in defining how professional medical colleges and associations should lead the profession in responding to socioeconomic health inequalities. METHODS: We report a case study of how the Royal Australian College of General Practitioners is responding to the issue of health inequalities through its work. We undertook a consultation (80 interviews with stakeholders internal and external to the College and two focus groups with general practitioners) and program and policy review of core programs of College interest and responsibility: general practitioner training and setting of practice standards, as well as its work in public advocacy. RESULTS: Some strategies within each of these College program areas were seen as legitimate professional obligations in responding to socioeconomic health inequality. However, other strategies, while potentially professional obligations within Gruen's model, were nevertheless contested. The key difference between these lay in different moral orientations. Actions where agreement existed were based on an ethos of care and compassion. Actions that were contested were based on an ethos of justice and human rights. CONCLUSION: Colleges and professional medical associations have a role in explicitly leading a debate about values, engaging both external stakeholder and practicing member constituencies. This is an important and necessary step in defining an agreed role for the profession in addressing health inequalities. PMID- 17697319 TI - High genetic variability of HIV-1 in female sex workers from Argentina. AB - BACKGROUND: A cross-sectional study on 625 Female Sex Workers (FSWs) was conducted between 2000 and 2002 in 6 cities in Argentina. This study describes the genetic diversity and the resistance profile of the HIV-infected subjects. RESULTS: Seventeen samples from HIV positive FSWs were genotyped by env HMA, showing the presence of 9 subtype F, 6 subtype B and 2 subtype C. Sequence analysis of the protease/RT region on 16 of these showed that 10 were BF recombinants, three were subtype B, two were subtype C, and one sample presented a dual infection with subtype B and a BF recombinant. Full-length genomes of five of the protease/RT BF recombinants were also sequenced, showing that three of them were CRF12_BF. One FSW had a dual HIV-1 infection with subtype B and a BF recombinant. The B sections of the BF recombinant clustered closely with the pure B sequence isolated from the same patient. Major resistance mutations to antiretroviral drugs were found in 3 of 16 (18.8%) strains. CONCLUSION: The genetic diversity of HIV strains among FSWs in Argentina was extensive; about three-quarters of the samples were infected with diverse BF recombinants, near twenty percent had primary ART resistance and one sample presented a dual infection. Heterosexual transmission of genetically diverse, drug resistant strains among FSWs and their clients represents an important and underestimated threat, in Argentina. PMID- 17697320 TI - MOZ-TIF2 repression of nuclear receptor-mediated transcription requires multiple domains in MOZ and in the CID domain of TIF2. AB - BACKGROUND: Fusion of the MOZ and TIF2 genes by an inv (8) (p11q13) translocation has been identified in patients with acute mixed-lineage leukemia. Characterization of the molecular structure of the MOZ-TIF2 fusion protein suggested that the fusion protein would effect on nuclear receptor signaling. RESULTS: A series of deletions from the N-terminus of the MOZ-TIF2 fusion protein demonstrated that the MOZ portion is essential for nuclear localization of the fusion protein. Transient expression of MOZ-TIF2 dramatically decreased both basal and estradiol inducible reporter gene activity in an estrogen receptor element (ERE) driven luciferase reporter system and decreased androgen-inducible reporter gene activity in an androgen receptor element (ARE) luciferase reporter system. Deletions in the MOZ portion of the MOZ-TIF2 fusion protein reduced the suppression in the ER reporter system. Stable expression of MOZ-TIF2 inhibited retinoic acid (RA) inducible endogenous CD11b and C/EBPbeta gene response. The suppression of the reporter systems was released with either a CID domain deletion or with mutations of leucine-rich repeats in the TIF2 portion of MOZ TIF2. The co-expression of TIF2, but not CBP, with MOZ-TIF2 partially restored the inhibition of the reporter systems. In addition, analysis of protein interactions demonstrated MOZ-TIF2 interaction with the C-terminus of CBP through both the MOZ and TIF2 portions of the fusion protein. CONCLUSION: MOZ-TIF2 inhibited nuclear receptor-mediated gene response by aberrant recruitment of CBP and both the MOZ and TIF2 portions are required for this inhibition. PMID- 17697321 TI - An unusual presentation of adenoid cystic carcinoma of the minor salivary glands with cranial nerve palsy: a case study. AB - BACKGROUND: Adenoid Cystic Carcinoma (ACC) is a rare tumor entity and comprises about 1% of all malignant tumor of the oral and maxillofacial region. It is slow growing but a highly invasive cancer with a high recurrence rate. Intracranial ACC is even more infrequent and could be primary or secondary occurring either by direct invasion, hematogenous spread, or perineural spread. We report the first case of the 5th and 6th nerve palsy due to cavernous sinus invasion by adenoid cystic carcinoma. CASE PRESENTATION: A 49-year-old African American female presented to the emergency room complaining of severe right-sided headache, photophobia, dizziness and nausea, with diplopia. The patient had a 14 year history migraine headaches, hypertension, and mild intermittent asthma. Physical examination revealed right lateral rectus muscle palsy with esotropia. There was numbness in all three divisions of the right trigeminal nerve. Motor and sensory examination of extremities was normal. An MRI of the brain/brain stem was obtained which showed a large mass in the clivus extending to involve the nasopharynx, pterygoid plate, sphenoid and right cavernous sinuses. Biopsy showed an ACC tumor with a cribriform pattern of the minor salivary glands. The patient underwent total gross surgical resection and radiation therapy. CONCLUSION: This is a case of ACC of the minor salivary glands with intracranial invasion. The patient had long history of headaches which changed in character during the past year, and symptoms of acute 5th and 6th cranial nerve involvement. Our unique case demonstrates direct invasion of cavernous sinus and could explain the 5th and 6th cranial nerve involvement as histopathology revealed no perineural invasion. PMID- 17697322 TI - Rehabilitation needs for older adults with stroke living at home: perceptions of four populations. AB - BACKGROUND: Many people who have suffered a stroke require rehabilitation to help them resume their previous activities and roles in their own environment, but only some of them receive inpatient or even outpatient rehabilitation services. Partial and unmet rehabilitation needs may ultimately lead to a loss of functional autonomy, which increases utilization of health services, number of hospitalizations and early institutionalization, leading to a significant psychological and financial burden on the patients, their families and the health care system. The aim of this study was to explore partially met and unmet rehabilitation needs of older adults who had suffered a stroke and who live in the community. The emphasis was put on needs that act as obstacles to social participation in terms of personal factors, environmental factors and life habits, from the point of view of four target populations. METHODS: Using the focus group technique, we met four types of experts living in three geographic areas of the province of Quebec (Canada): older people with stroke, caregivers, health professionals and health care managers, for a total of 12 groups and 72 participants. The audio recordings of the meetings were transcribed and NVivo software was used to manage the data. The process of reducing, categorizing and analyzing the data was conducted using themes from the Disability Creation Process model. RESULTS: Rehabilitation needs persist for nine capabilities (e.g. related to behaviour or motor activities), nine factors related to the environment (e.g. type of teaching, adaptation and rehabilitation) and 11 life habits (e.g. nutrition, interpersonal relationships). The caregivers and health professionals identified more unmet needs and insisted on an individualized rehabilitation. Older people with stroke and the health care managers had a more global view of rehabilitation needs and emphasized the availability of resources. CONCLUSION: Better knowledge of partially met or unmet rehabilitation needs expressed by the different types of people involved should lead to increased attention being paid to education for caregivers, orientation of caregivers towards resources in the community, and follow-up of patients' needs in terms of adjustment and rehabilitation, whether for improving their skills or for carrying out their activities of daily living. PMID- 17697323 TI - A new paradigm in respiratory hygiene: modulating respiratory secretions to contain cough bioaerosol without affecting mucus clearance. AB - BACKGROUND: Several strategies and devices have been designed to protect health care providers from acquiring transmissible respiratory diseases while providing care. In modulating the physical characteristics of the respiratory secretions to minimize the aerosolization that facilitates transmission of airborne diseases, a fundamental premise is that the prototype drugs have no adverse effect on the first line of respiratory defense, clearance of mucus by ciliary action. METHODS: To assess and demonstrate the primary mechanism of our mucomodulators (XLs), we have built our evidence moving from basic laboratory studies to an ex-vivo model and then to an in-vivo large animal model. We exposed anesthetized dogs without hypersecretion to different dose concentrations of aerosolized XL "B", XL "D" and XL "S". We assessed: cardio-respiratory pattern, tracheal mucus clearance, airway patency, and mucus viscoelastic changes. RESULTS: Exposure of frog palate mucus to XLs did not affect the clearance of mucus by ciliary action. Dogs maintained normal cardio-respiratory pattern with XL administration. Tracheal mucociliary clearance in anesthetized dogs indicated a sustained 40% mean increase. Tracheal mucus showed increased filance, and there was no mucus retention in the airways. CONCLUSION: The ex-vivo frog palate and the in-vivo mammalian models used in this study, appear to be appropriate and complement each other to better assess the effects that our mucomodulators exert on the mucociliary clearance defence mechanism. The physiological function of the mucociliary apparatus was not negatively affected in any of the two epithelial models. Airway mucus crosslinked by mucomodulators is better cleared from an intact airway and normally functioning respiratory system, either due to enhanced interaction with cilia or airflow-dependent mechanisms. Data obtained in this study allow us to assure that we have complied with the fundamental requirement criteria established in the initial phase of developing the concept of mucomodulation: Can we modulate the physical characteristics of the respiratory secretions to reduce aerosolization without affecting normal mucociliary clearance function, or even better improving it? PMID- 17697324 TI - Extrapyramidal signs in normal pressure hydrocephalus: an objective assessment. AB - BACKGROUND: Beyond the classic Normal Pressure Hydrocephalus (NPH) triad of gait disturbance, incontinence, and dementia are characteristic signs of motor dysfunction in NPH patients. We used highly sensitive and objective methods to characterize upper limb extrapyramidal signs in a series of NPH subjects compared with controls. Concentrated evaluation of these profound, yet underappreciated movement disorders of NPH before and after techniques of therapeutic intervention may lead to improved diagnosis, insight into pathophysiology, and targeted treatment. METHODS: Twenty-two (22) consecutive NPH patients and 17 controls performed an upper limb motor task battery where highly sensitive and objective measures of akinesia/bradykinesia, tone, and tremor were conducted. NPH subjects performed this test battery before and more than 36 h after continuous CSF drainage via a spinal catheter over 72 h and, in those subjects undergoing permanent ventriculo-peritoneal shunt placement, at least 12 weeks later. Control subjects performed the task battery at the same dates as the NPH subjects. Statistical analyses were applied to group populations of NPH and control subjects and repeated measures for within subject performance. RESULTS: Twenty (20) NPH subjects remained in the study following CSF drainage as did 14 controls. NPH subjects demonstrated akinesia/bradykinesia (prolonged reaction and movement times) and increased resting tone compared with controls. Furthermore, the NPH group demonstrated increased difficulty with self-initiated tasks compared with stimulus-initiated tasks. Following CSF drainage, some NPH subjects demonstrated reduced movement times with greater improvement in self- versus stimulus-initiated tasks. Group reaction time was unchanged. Resting tremor present in one NPH subject resolved following shunt placement. Tone measures were consistent for all subjects throughout the study. CONCLUSION: Clinical motor signs of NPH subjects extend beyond gait deficits and include extrapyramidal manifestations of bradykinesia, akinesia, rigidity, and propensity to perform more poorly when external cues to move are absent. Objective improvement of some but not all of these features was seen following temporary or permanent CSF diversion. PMID- 17697325 TI - Detection of knockdown resistance (kdr) mutations in Anopheles gambiae: a comparison of two new high-throughput assays with existing methods. AB - BACKGROUND: Knockdown resistance (kdr) is a well-characterized mechanism of resistance to pyrethroid insecticides in many insect species and is caused by point mutations of the pyrethroid target site the para-type sodium channel. The presence of kdr mutations in Anopheles gambiae, the most important malaria vector in Africa, has been monitored using a variety of molecular techniques. However, there are few reports comparing the performance of these different assays. In this study, two new high-throughput assays were developed and compared with four established techniques. METHODS: Fluorescence-based assays based on 1) TaqMan probes and 2) high resolution melt (HRM) analysis were developed to detect kdr alleles in An. gambiae. Four previously reported techniques for kdr detection, Allele Specific Polymerase Chain Reaction (AS-PCR), Heated Oligonucleotide Ligation Assay (HOLA), Sequence Specific Oligonucleotide Probe - Enzyme-Linked ImmunoSorbent Assay (SSOP-ELISA) and PCR-Dot Blot were also optimized. The sensitivity and specificity of all six assays was then compared in a blind genotyping trial of 96 single insect samples that included a variety of kdr genotypes and African Anopheline species. The relative merits of each assay was assessed based on the performance in the genotyping trial, the length/difficulty of each protocol, cost (both capital outlay and consumable cost), and safety (requirement for hazardous chemicals). RESULTS: The real-time TaqMan assay was both the most sensitive (with the lowest number of failed reactions) and the most specific (with the lowest number of incorrect scores). Adapting the TaqMan assay to use a PCR machine and endpoint measurement with a fluorimeter showed a slight reduction in sensitivity and specificity. HRM initially gave promising results but was more sensitive to both DNA quality and quantity and consequently showed a higher rate of failure and incorrect scores. The sensitivity and specificity of AS-PCR, SSOP-ELISA, PCR Dot Blot and HOLA was fairly similar with a small number of failures and incorrect scores. CONCLUSION: The results of blind genotyping trials of each assay indicate that where maximum sensitivity and specificity are required the TaqMan real-time assay is the preferred method. However, the cost of this assay, particularly in terms of initial capital outlay, is higher than that of some of the other methods. TaqMan assays using a PCR machine and fluorimeter are nearly as sensitive as real-time assays and provide a cost saving in capital expenditure. If price is a primary factor in assay choice then the AS-PCR, SSOP ELISA, and HOLA are all reasonable alternatives with the SSOP-ELISA approach having the highest throughput. PMID- 17697326 TI - Health care utilization and costs in Saskatchewan's registered Indian population with diabetes. AB - BACKGROUND: The prevalence of diabetes in North American is recognized to be higher in Aboriginal populations. The relative magnitude of health care utilization and expenditures between Aboriginal and non-Aboriginal populations is uncertain, however. Our objective was to compare health care utilization and per capita expenditures according to Registered Indian and diabetes status in the province of Saskatchewan. METHODS: Administrative databases from Saskatchewan Health were used to identify registered Indians and the general population diabetes cases and two controls for each diabetes case. Health care resource utilization (physician visits, hospitalizations, day surgeries and dialysis) and costs for these individuals in the 2001 calendar year were determined. The odds of having used each resource category, adjusted for age and location of residence, was assessed according to Registered Indian and diabetes status. The average number of encounters for each resource category and per capita healthcare expenditures were also determined. RESULTS: Registered Indian diabetes cases were younger than general population cases (45.7 +/- 14.5 versus 58.4 +/- 16.4 years, p < 0.001) and fewer were male (42.3% versus 53.2%, p < 0.001). Registered Indians were more likely to visit a physician, be hospitalized or receive dialysis than the general population, regardless of diabetes status. Diabetes increased the probability of having used all resource categories for both Registered Indians and the general population. Per capita health care expenditures for the diabetes subgroups were more than twice that of their respective controls and were 40% to 60% higher for registered Indians than the general population, regardless of diabetes status. CONCLUSION: Relative to individuals without the disease, both registered Indians and the general population with diabetes had substantially higher health care utilization and costs. Excess hospitalization and dialysis suggested that registered Indians with and without diabetes experienced greater morbidity than the general population. PMID- 17697327 TI - Tubular adenoma with high-grade dysplasia in the ileal segment 34 years after augmentation ileocystoplasty: report of a first case. AB - Neoplasms of the urinary bladder following augmentation ileocystoplasty are rare. We present the case of a 39-year-old male with a tubular adenoma with high-grade dysplasia in the ileal segment 34 years after augmentation ileocystoplasty to enlarge a post-chemoradiation-induced shrunken bladder. He presented with gross hematuria. Cystoscopy revealed a papillary tumor at the site of ileovesical anastomosis, and transurethral resection was performed. Histologic examination revealed a tubular adenoma with high-grade dysplasia. There are only two previous reports of tubulovillous adenoma in ileal segment after ileocystoplasty, both without high-grade dysplasia. Our observation supports the hypothesis that an ileal neobladder may undergo all the morphologic and molecular changes observed in the development of gastrointestinal adenocarcinoma. Therefore, patients who had an ileal neobladder created should be closely followed. PMID- 17697328 TI - Clinical decision modeling system. AB - BACKGROUND: Decision analysis techniques can be applied in complex situations involving uncertainty and the consideration of multiple objectives. Classical decision modeling techniques require elicitation of too many parameter estimates and their conditional (joint) probabilities, and have not therefore been applied to the problem of identifying high-performance, cost-effective combinations of clinical options for diagnosis or treatments where many of the objectives are unknown or even unspecified. METHODS: We designed a Java-based software resource, the Clinical Decision Modeling System (CDMS), to implement Naive Decision Modeling, and provide a use case based on published performance evaluation measures of various strategies for breast and lung cancer detection. Because cost estimates for many of the newer methods are not yet available, we assume equal cost. Our use case reveals numerous potentially high-performance combinations of clinical options for the detection of breast and lung cancer. RESULTS: Naive Decision Modeling is a highly practical applied strategy which guides investigators through the process of establishing evidence-based integrative translational clinical research priorities. CDMS is not designed for clinical decision support. Inputs include performance evaluation measures and costs of various clinical options. The software finds trees with expected emergent performance characteristics and average cost per patient that meet stated filtering criteria. Key to the utility of the software is sophisticated graphical elements, including a tree browser, a receiver-operator characteristic surface plot, and a histogram of expected average cost per patient. The analysis pinpoints the potentially most relevant pairs of clinical options ('critical pairs') for which empirical estimates of conditional dependence may be critical. The assumption of independence can be tested with retrospective studies prior to the initiation of clinical trials designed to estimate clinical impact. High performance combinations of clinical options may exist for breast and lung cancer detection. CONCLUSION: The software could be found useful in simplifying the objective-driven planning of complex integrative clinical studies without requiring a multi-attribute utility function, and it could lead to efficient integrative translational clinical study designs that move beyond simple pair wise competitive studies. Collaborators, who traditionally might compete to prioritize their own individual clinical options, can use the software as a common framework and guide to work together to produce increased understanding on the benefits of using alternative clinical combinations to affect strategic and cost-effective clinical workflows. PMID- 17697329 TI - Adrenal involvement in the biostimulatory effect of bulls. AB - BACKGROUND: The objective was to evaluate if cortisol concentrations are associated with the resumption of luteal activity in postpartum, primiparous cows exposed to bulls. The hypotheses were that 1) interval from start of exposure to resumption of luteal activity; 2) proportions of cows that resumed luteal function during the exposure period; and 3) cortisol concentrations do not differ among cows exposed or not exposed to bulls (Exp. 1), and cows continuously exposed to bull or steer urine (Exp. 2). METHODS: In Exp. 1, 28 anovular cows were exposed (BE; n = 13) or not exposed (NE; n = 15) to bulls for 30 d at 58 d after calving. In Exp. 2, 38 anovular cows were fitted with a controlled urine delivery device at 45 d after calving and exposed continuously (24 h/d) to bull (BUE; n = 19) or steer (SUE; n = 19) urine. Length of exposure was ~64 d. Blood samples were collected from each cow on D 0 and every 3 d throughout exposure periods in both experiments and assayed for progesterone. Cortisol was assayed in samples collected on D 0, 8, 16, and 24 in Exp. 1; and, D 0, 19, 38, and 57 in Exp. 2. RESULTS: In Exp. 1, interval from the start of exposure to resumption of luteal activity was shorter (P < 0.05) for BE cows than NE cows, similarly, more (P < 0.05) BE cows than NE cows resumed luteal function during the exposure period. In Exp. 2, there was no difference in intervals from the start of exposure to resumption of luteal activity and proportions of cows that resumed luteal function during the exposure period between BUE and SUE cows. In Exp. 1, there was no difference in cortisol concentrations between BE and NE cows at the start of the experiment (D 0), however, cortisol concentrations were greater (P < 0.05) in BE cows than NE cows on D 9, 18, and 27. In Exp. 2, cortisol concentrations were higher for BUE than SUE cows on D 0 (P < 0.05), thereafter cortisol decreased (P < 0.05) but did not differ between BUE and SUE cows. CONCLUSION: We conclude that the physical presence of bulls stimulates resumption of luteal activity and is coincident with increased cortisol concentrations, and hypothesize a possible association between adrenal activation and the biostimulatory effect of bulls. PMID- 17697330 TI - Phosphorylation of Ser78 of Hsp27 correlated with HER-2/neu status and lymph node positivity in breast cancer. AB - BACKGROUND: Abnormal amplification/expression of HER-2/neu oncogene has been causally linked with tumorigenesis and metastasis in breast cancer and associated with shortened overall survival of patients. Recently, heat shock protein 27 (Hsp27) was reported to be highly expressed in HER-2/neu positive tumors and cell lines. However, putative functional links between phosphorylation of Hsp27 with HER-2/neu status and other clinicopathological features remain to be elucidated. RESULTS: Comparative phosphoproteomic studies of HER-2/neu positive and -negative breast tumors revealed that Hsp27, one of the identified phosphoproteins, was highly phosphorylated in HER-2/neu positive tumors. The extent of Hsp27 phosphorylation at its Ser15, Ser78 and Ser82 residues were further evaluated with site-specific antibodies in tumor samples by tissue lysate array- and tissue microarray-based analyses, and in the BT474 breast cancer cell line treated with heregulin alpha1 (HRG alpha1) or the p38 MAPK inhibitor, SB203580. The tissue lysate array study indicated that only the level of pSer78 in HER-2/neu positive tumors was more than 2-fold that in HER-2/neu negative tumors. Treatment of BT474 cells with HRG alpha1 and SB203580 indicated that Ser78 phosphorylation was mainly regulated by the HER-2/neu-p38 MAPK pathway. Immunohistochemical staining of sections from a tissue microarray with 97 breast tumors showed that positive staining of pSer78 significantly correlated with HER-2/neu (p = 0.004) and lymph node positivity (p = 0.026). CONCLUSION: This investigation demonstrated the significant correlation of enhanced phosphorylation of the Ser78 residue of Hsp27 with HER-2/neu and lymph node positivity in breast cancer. PMID- 17697331 TI - An evaluation of Comparative Genome Sequencing (CGS) by comparing two previously sequenced bacterial genomes. AB - BACKGROUND: With the development of new technology, it has recently become practical to resequence the genome of a bacterium after experimental manipulation. It is critical though to know the accuracy of the technique used, and to establish confidence that all of the mutations were detected. RESULTS: In order to evaluate the accuracy of genome resequencing using the microarray-based Comparative Genome Sequencing service provided by Nimblegen Systems Inc., we resequenced the E. coli strain W3110 Kohara using MG1655 as a reference, both of which have been completely sequenced using traditional sequencing methods. CGS detected 7 of 8 small sequence differences, one large deletion, and 9 of 12 IS element insertions present in W3110, but did not detect a large chromosomal inversion. In addition, we confirmed that CGS also detected 2 SNPs, one deletion and 7 IS element insertions that are not present in the genome sequence, which we attribute to changes that occurred after the creation of the W3110 lambda clone library. The false positive rate for SNPs was one per 244 Kb of genome sequence. CONCLUSION: CGS is an effective way to detect multiple mutations present in one bacterium relative to another, and while highly cost-effective, is prone to certain errors. Mutations occurring in repeated sequences or in sequences with a high degree of secondary structure may go undetected. It is also critical to follow up on regions of interest in which SNPs were not called because they often indicate deletions or IS element insertions. PMID- 17697332 TI - Factors influencing delay in the diagnosis of colorectal cancer: a study protocol. AB - BACKGROUND: Colorectal cancer (CRC) is the second most frequent tumor in developed countries. Since survival from CRC depends mostly on disease stage at the time of diagnosis, individuals with symptoms or signs suspicious of CRC should be examined without delay. Many factors, however, intervene between symptom onset and diagnosis. This study was designed to: 1) Describe the diagnostic process of CRC from the onset of first symptoms to diagnosis and treatment. 2) Establish the time interval from initial symptoms to diagnosis and treatment, globally and considering patient's and doctors' delay, with the latter due to family physician and/or hospital services. 3) Identify the factors related to defined types of delay. 4) Assess the concordance between information included in primary health care and hospital clinical records regarding onset of first symptoms. METHODS: Descriptive study, coordinated, with 5 participant groups of 5 different Spanish regions (Balearic Islands, Galicia, Catalunya, Aragon and Valencia Health Districts), with a total of 8 acute public hospitals and 140 primary care centers. Incident cases of CRC during the study period, as identified from pathology services at the involved hospitals. A sample size of 896 subjects has been estimated, 150 subjects for each participant group. Information will be collected through patient interviews and primary health care and hospital clinical records. Patient variables will include sociodemographic variables, family history of cancer, symptom perception, and confidence in the family physician; tumor variables will include tumor site, histological type, grade and stage; symptom variables will include date of onset, type and number of symptoms; health system variables will include number of patient contacts with family physician, type and content of the referral, hospital services attending the patient, diagnostic modalities and results; and delay intervals, including global delays and delays attributed to the patient, family physician and hospital. DISCUSSION: To obtain a nonrestricted sample of patients with CRC we have minimized selection risk by identifying the patients from pathology services. A greater constraint may be associated with information sources based on clinical records. Due to inherent features of coordinated studies, it is important to standardize the collection of information. PMID- 17697333 TI - The benefits of participatory methodologies to develop effective community dialogue in the context of a microbicide trial feasibility study in Mwanza, Tanzania. AB - BACKGROUND: As part of a microbicide trial feasibility study among women at high risk of HIV and sexually transmitted infections in Mwanza City, northern Tanzania we used participatory research tools to facilitate open dialogue and partnership between researchers and study participants. METHODS: A mobile community-based sexual & reproductive health service was established in ten city wards. Wards were divided into seventy-eight geographical clusters and representatives at cluster and ward level elected in a process facilitated by the projects Community Liaison Officer. A city-level Community Advisory Committee (CAC) with representatives from each ward was established. Workshops and community meetings at ward and city-level were conducted to explore project-related concerns using tools adapted from participatory learning and action techniques such as listing, scoring, ranking, chapatti diagrams and pair-wise matrices. RESULTS: Key issues identified included beliefs that blood specimens were being sold for witchcraft purposes; worries about specula not being clean; inadequacy of transport allowances; and delays in reporting laboratory test results to participants. To date, the project has responded by inviting members of the CAC to visit the laboratory to observe how blood and genital specimens are prepared; demonstrated the use of the autoclave to community representatives; raised reimbursement levels; introduced HIV rapid testing in the clinic; and streamlined laboratory reporting procedures. CONCLUSIONS: Participatory techniques were instrumental in promoting meaningful dialogue between the research team, study participants and community representatives in Mwanza, allowing researchers and community representatives to gain a shared understanding of project-related priority areas for intervention. PMID- 17697334 TI - WASP: a Web-based Allele-Specific PCR assay designing tool for detecting SNPs and mutations. AB - BACKGROUND: Allele-specific (AS) Polymerase Chain Reaction is a convenient and inexpensive method for genotyping Single Nucleotide Polymorphisms (SNPs) and mutations. It is applied in many recent studies including population genetics, molecular genetics and pharmacogenomics. Using known AS primer design tools to create primers leads to cumbersome process to inexperience users since information about SNP/mutation must be acquired from public databases prior to the design. Furthermore, most of these tools do not offer the mismatch enhancement to designed primers. The available web applications do not provide user-friendly graphical input interface and intuitive visualization of their primer results. RESULTS: This work presents a web-based AS primer design application called WASP. This tool can efficiently design AS primers for human SNPs as well as mutations. To assist scientists with collecting necessary information about target polymorphisms, this tool provides a local SNP database containing over 10 million SNPs of various populations from public domain databases, namely NCBI dbSNP, HapMap and JSNP respectively. This database is tightly integrated with the tool so that users can perform the design for existing SNPs without going off the site. To guarantee specificity of AS primers, the proposed system incorporates a primer specificity enhancement technique widely used in experiment protocol. In particular, WASP makes use of different destabilizing effects by introducing one deliberate 'mismatch' at the penultimate (second to last of the 3'-end) base of AS primers to improve the resulting AS primers. Furthermore, WASP offers graphical user interface through scalable vector graphic (SVG) draw that allow users to select SNPs and graphically visualize designed primers and their conditions. CONCLUSION: WASP offers a tool for designing AS primers for both SNPs and mutations. By integrating the database for known SNPs (using gene ID or rs number), this tool facilitates the awkward process of getting flanking sequences and other related information from public SNP databases. It takes into account the underlying destabilizing effect to ensure the effectiveness of designed primers. With user-friendly SVG interface, WASP intuitively presents resulting designed primers, which assist users to export or to make further adjustment to the design. This software can be freely accessed at http://bioinfo.biotec.or.th/WASP. PMID- 17697335 TI - Nuclear and mitochondrial data reveal different evolutionary processes in the Lake Tanganyika cichlid genus Tropheus. AB - BACKGROUND: Cichlid fishes are notorious for their wealth of intra- and interspecific colour pattern diversity. In Lake Tanganyika, the endemic genus Tropheus represents the most impressive example for geographic variation in the pattern and hue of integument colouration, but the taxonomy of the over 100 mostly allopatric colour morphs remains to a large degree unresolved. Previous studies of mitochondrial DNA sequence data revealed polyphyly of the six nominally described species and complex phylogeographic patterns influenced by lake level fluctuations and population admixture, and suggested the parallel evolution of similar colour patterns in divergent evolutionary lineages. A gene tree of a rapidly radiating group may be subject to incomplete and stochastic lineage sorting, and to overcome this problem we used multi-locus, nuclear AFLP data in comparison with mtDNA sequences to study diversification, migration and introgression in Tropheus colour morphs in Lake Tanganyika. RESULTS: Significant incongruence between phylogenetic reconstructions from mitochondrial and AFLP data suggested incomplete sorting of mitochondrial haplotypes as well as frequent introgression between differentiated lineages. In contrast to the mitochondrial phylogeny, the AFLP phenogram was largely congruent with species classifications, colour pattern similarities, and in many cases also with the current geographic distribution of populations, and did not produce evidence of convergent colour pattern evolution. Homoplasy in the AFLP data was used to identify populations that were strongly affected by introgression. CONCLUSION: Different evolutionary processes were distinguished by the combination of mitochondrial and AFLP data. Mitochondrial phylogeographic patterns retained signals of large-scale migration events triggered by historical, major lake level fluctuations, whereas AFLP data indicated genetic cohesion among local groups of populations resulting from secondary contact of adjacent populations in the course of the more frequently occurring, minor lake level fluctuations. There was no support for the parallel evolution of similar colour patterns in the AFLP data. Genetic signatures of introgression and hybridisation detected in several populations suggest that lake level fluctuations drove the stunning diversification of Tropheus morphs not only through population fragmentation, but also by promoting hybridisation between differentiated morphs in secondary contact. PMID- 17697336 TI - Corticosterone mediates electroacupuncture-produced anti-edema in a rat model of inflammation. AB - BACKGROUND: Electroacupuncture (EA) has been reported to produce anti-edema and anti-hyperalgesia effects on inflammatory disease. However, the mechanisms are not clear. The present study investigated the biochemical mechanisms of EA anti inflammation in a rat model. METHODS: Three experiments were conducted on male Sprague-Dawley rats (n = 7-8/per group). Inflammation was induced by injecting complete Freund's adjuvant (CFA) subcutaneously into the plantar surface of one hind paw. Experiment 1 measured plasma corticosterone (CORT) levels to see if EA regulates CORT secretion. Experiment 2 studied the effects of the adrenal gland on the therapeutic actions of EA using adrenalectomy (ADX) rats. Experiment 3 determined whether a prototypical glucocorticoid receptor antagonist, RU486, affects EA anti-edema. EA treatment, 10 Hz at 3 mA and 0.1 ms pulse width, was given twice, for 20 min each, once immediately after CFA administration and again 2 h post-CFA. Plasma CORT levels, paw thickness, indicative of the intensity of inflammation, and paw withdrawal latency (PWL) were measured 2 h and 5 h after the CFA injection. RESULTS: EA significantly increased plasma corticosterone levels 2 h (5 folds) and 5 h (10 folds) after CFA administration compared to sham EA control, but EA alone in naive rats and CFA alone did not induce significant increases in corticosterone. Adrenalectomy blocked EA-produced anti-edema, but not EA anti-hyperalgesia. RU486 (15 mul, 15 mug/mul), a prototypical glucocorticoid receptor antagonist, also prevented EA anti-edema. CONCLUSION: The data demonstrate that EA activates the adrenals to increase plasma corticosterone levels and suppress edema and suggest that EA effects differ in healthy subjects and in those with pathologies. PMID- 17697337 TI - Autonomic and muscular responses and recovery to one-hour laboratory mental stress in healthy subjects. AB - BACKGROUND: Stress is a risk factor for musculoskeletal pain. We wanted to explore stress related physiology in healthy subjects in order to gain insight into mechanisms of pain development which may relate to the pathophysiology of musculoskeletal pain disorders. METHODS: Continuous blood pressure, heart rate, finger skin blood flow, respiration, surface electromyography together with perception of pain, fatigue and tension were recorded on 35 healthy women and 9 healthy men before, during a 60 minute period with task-related low-grade mental stress, and in the following 30 minute rest period. RESULTS: Subjects responded physiologically to the stressful task with an increase in trapezius and frontalis muscle activity, increased blood pressure, respiration frequency and heart rate together with reduced finger skin blood flow. The blood pressure response and the finger skin blood flow response did not recover to baseline values during the 30 minute rest period, whereas respiration frequency, heart rate, and surface electromyography of the trapezius and frontalis muscles recovered to baseline within 10 minutes after the stressful task. Sixty-eight percent responded subjectively with pain development and 64% reported at least 30% increase in pain. Reduced recovery of the blood pressure was weakly correlated to fatigue development during stress, but was not correlated to pain or tension. CONCLUSION: Based on a lack of recovery of the blood pressure and the acral finger skin blood flow response to mental stress we conclude that these responses are more protracted than other physiological stress responses. PMID- 17697339 TI - Repetition priming affects guessing not familiarity. AB - BACKGROUND: The claim that recollection and familiarity based memory processes have distinct retrieval mechanisms is based partly on the observation that masked repetition and semantic priming influence estimates of familiarity derived from know responses but have no effect on estimates of recollection derived from remember responses. Close inspection of the experiments on which this claim is based reveal the effect size to be small, potentially the result of a type-2 error, and/or inflated due to participants not having the opportunity to report guesses. This paper re-evaluates these claims by attempting a partial replication of two such Experiments. METHODS: In Experiment 1 participants made remember, know, and guess responses following primed and unprimed target words. In Experiment 2 participants made sure, unsure, and guess following primed and unprimed target words. RESULTS: In Experiment 1 the repetition priming effect occurred only for guess responses and only for unstudied items. In Experiment 2 the priming effect occurred for both unsure and guess responses, but again only for unstudied items. CONCLUSION: The data are consistent with the view that remembering and knowing do not correspond to confidence ratings; and suggest that contrary to earlier findings, recollection and familiarity do not differ in retrieval mechanisms. As such the effects of repetition priming on subjective reports of remembering should not be cited as evidence for the distinction between recollection and familiarity based memory processes. PMID- 17697338 TI - Expectations and changing attitudes of bar workers before and after the implementation of smoke-free legislation in Scotland. AB - BACKGROUND: In Scotland on March 26, 2006 a comprehensive prohibition on smoking in all enclosed public places was introduced. This study examines bar workers' attitudes towards a smoke-free working environment. METHODS: An intervention study comparing bar workers' opinions before and after the implementation of the smoke-free legislation. Bars were randomly selected in three Scottish cities (Glasgow, Edinburgh & Aberdeen) and towns (Aberdeenshire & Borders). Bar workers were recruited from 72 bars that agreed to participate from 159 approached. Pre- and post-implementation attitudes towards legislation, second-hand smoke and smoke-free working environments were compared. RESULTS: Initially the majority of bar workers agreed with the proposed legislation on smoking (69%) and the need for it to protect the health of workers (80%), although almost half (49%) thought the legislation would damage business. In 266 bar workers seen at both surveys, a significant positive attitudinal change towards the legislation was seen. Post implementation, support for the legislation rose to 79%, bar workers continued to believe it was needed to protect health (81%) and concerns about the impact on business were expressed by fewer than 20%. Only the statement that the legislation would encourage smokers to quit showed reduced support, from 70% pre implementation to fewer than 60% post-implementation. Initial acceptance was greater among younger bar workers; older workers, initially more sceptical, became less so with experience of the legislation's effects. CONCLUSION: This study shows that bar workers had generally positive attitudes towards the legislation prior to implementation, which became stronger after implementation. The affirmative attitudes of these key stakeholders are likely to contribute towards the creation of 'smoke-free' as the new social norm. PMID- 17697340 TI - Nationwide trends in molecular epidemiology of methicillin-resistant Staphylococcus aureus, Finland, 1997-2004. AB - BACKGROUND: In Finland, the annual number of MRSA notifications to the National Infectious Disease Register (NIDR) has constantly increased since 1995, and molecular typing has revealed numerous outbreak isolates of MRSA. We analyzed the data on MRSA notifications of the NIDR, and MRSA isolates were identified mainly by pulsed-field gel electrophoresis (PFGE) at the National Reference Laboratory (NRL) in Finland during 1997-2004. One isolate representative of each major PFGE type was further characterized by multilocus sequence (MLST)-, staphylococcal cassette chromosome mec (SCCmec)-, and Panton-Valentine leukocidin (PVL)-typing. RESULTS: The annual number of MRSA notifications to the NIDR rose over ten-fold, from 120 in 1997 to 1458 in 2004, and the proportion of MRSA among S. aureus blood isolates tripled, from <1% during 1997-2003 to 2.8% in 2004. During the same period of time, 253 different strains among 4091 MRSA isolates were identified by PFGE: 215 were sporadic and 38 outbreak/epidemic strains, including 24 new strains. Two epidemic strains resembling internationally recognized MRSA clones accounted for most of the increase: FIN-16 (ST125:IA) from <1% in 1997 to 25% in 2004, and FIN-21 (ST228:I) from 6% in 2002 to 28% in 2004. Half of the ten most common strains carried SCCmec IV or V. CONCLUSION: The predominant MRSA strains seem to change over time, which encourages us to continue implementing active control measures with each new MRSA case. PMID- 17697341 TI - GSK-3 inhibitors induce chromosome instability. AB - BACKGROUND: Several mechanisms operate during mitosis to ensure accurate chromosome segregation. However, during tumour evolution these mechanisms go awry resulting in chromosome instability. While several lines of evidence suggest that mutations in adenomatous polyposis coli (APC) may promote chromosome instability, at least in colon cancer, the underlying mechanisms remain unclear. Here, we turn our attention to GSK-3 - a protein kinase, which in concert with APC, targets beta-catenin for proteolysis - and ask whether GSK-3 is required for accurate chromosome segregation. RESULTS: To probe the role of GSK-3 in mitosis, we inhibited GSK-3 kinase activity in cells using a panel of small molecule inhibitors, including SB-415286, AR-A014418, 1-Azakenpaullone and CHIR99021. Analysis of synchronised HeLa cells shows that GSK-3 inhibitors do not prevent G1/S progression or cell division. They do, however, significantly delay mitotic exit, largely because inhibitor-treated cells have difficulty aligning all their chromosomes. Although bipolar spindles form and the majority of chromosomes biorient, one or more chromosomes often remain mono-oriented near the spindle poles. Despite a prolonged mitotic delay, anaphase frequently initiates without the last chromosome aligning, resulting in chromosome non-disjunction. To rule out the possibility of "off-target" effects, we also used RNA interference to selectively repress GSK-3beta. Cells deficient for GSK-3beta exhibit a similar chromosome alignment defect, with chromosomes clustered near the spindle poles. GSK-3beta repression also results in cells accumulating micronuclei, a hallmark of chromosome missegregation. CONCLUSION: Thus, not only do our observations indicate a role for GSK-3 in accurate chromosome segregation, but they also raise the possibility that, if used as therapeutic agents, GSK-3 inhibitors may induce unwanted side effects by inducing chromosome instability. PMID- 17697344 TI - Mapping of a quantitative trait locus for resistance against infectious salmon anaemia in Atlantic salmon (Salmo salar): comparing survival analysis with analysis on affected/resistant data. AB - BACKGROUND: Infectious Salmon Anaemia (ISA) is a viral disease affecting farmed Atlantic salmon (Salmo salar) worldwide. The identification of Quantitative Trait Loci (QTL) affecting resistance to the disease could improve our understanding of the genetics underlying the trait and provide a means for Marker-Assisted Selection. We previously performed a genome scan on commercial Atlantic salmon families challenge tested for ISA resistance, identifying several putative QTL. In the present study, we set out to validate the strongest of these QTL in a larger family material coming from the same challenge test, and to determine the position of the QTL by interval mapping. We also wanted to explore different ways of performing QTL analysis within a survival analysis framework (i.e. using time to-event data), and to compare results using survival analysis with results from analysis on the dichotomous trait 'affected/resistant'. RESULTS: The QTL, located on Atlantic salmon linkage group 8 (following SALMAP notation), was confirmed in the new data set. Its most likely position was at a marker cluster containing markers BHMS130, BHMS170 and BHMS553. Significant segregation distortion was observed in the same region, but was shown to be unrelated to the QTL. A maximum likelihood procedure for identifying QTL, based on the Cox proportional hazard model, was developed. QTL mapping was also done using the Haley-Knott method (affected/resistant data), and within a variance-component framework (affected/resistant data and time-to-event data). In all cases, analysis using affected/resistant data gave stronger evidence for a QTL than did analysis using time-to-event data. CONCLUSION: A QTL for resistance to Infectious Salmon Anaemia in Atlantic salmon was validated in this study, and its more precise location on linkage group eight was determined. The QTL explained 6% of the phenotypic variation in resistance to the disease. The linkage group also displayed significant segregation distortion. Survival models proved in this case not to be more suitable than models based on the dichotomous trait 'affected/resistant' for analysing the data. PMID- 17697343 TI - Birth after caesarean study--planned vaginal birth or planned elective repeat caesarean for women at term with a single previous caesarean birth: protocol for a patient preference study and randomised trial. AB - BACKGROUND: For women who have a caesarean section in their preceding pregnancy, two care policies for birth are considered standard: planned vaginal birth and planned elective repeat caesarean. Currently available information about the benefits and harms of both forms of care are derived from retrospective and prospective cohort studies. There have been no randomised trials, and recognising the deficiencies in the literature, there have been calls for methodologically rigorous studies to assess maternal and infant health outcomes associated with both care policies. The aims of our study are to assess in women with a previous caesarean birth, who are eligible in the subsequent pregnancy for a vaginal birth, whether a policy of planned vaginal birth after caesarean compared with a policy of planned repeat caesarean affects the risk of serious complications for the woman and her infant. METHODS/DESIGN: DESIGN: Multicentered patient preference study and a randomised clinical trial. INCLUSION CRITERIA: Women with a single prior caesarean presenting in their next pregnancy with a single, live fetus in cephalic presentation, who have reached 37 weeks gestation, and who do not have a contraindication to a planned VBAC. Trial Entry & Randomisation: Eligible women will be given an information sheet during pregnancy, and will be recruited to the study from 37 weeks gestation after an obstetrician has confirmed eligibility for a planned vaginal birth. Written informed consent will be obtained. Women who consent to the patient preference study will be allocated their preference for either planned VBAC or planned, elective repeat caesarean. Women who consent to the randomised trial will be randomly allocated to either the planned vaginal birth after caesarean or planned elective repeat caesarean group. Treatment Groups: Women in the planned vaginal birth group will await spontaneous onset of labour whilst appropriate. Women in the elective repeat caesarean group will have this scheduled for between 38 and 40 weeks. Primary Study Outcome: Serious adverse infant outcome (death or serious morbidity). SAMPLE SIZE: 2314 women in the patient preference study to show a difference in adverse neonatal outcome from 1.6% to 3.6% (p = 0.05, 80% power). PMID- 17697345 TI - Multi-drug resistant Acinetobacter infections in critically injured Canadian forces soldiers. AB - BACKGROUND: Military members, injured in Afghanistan or Iraq, have returned home with multi-drug resistant Acinetobacter baumannii infections. The source of these infections is unknown. METHODS: Retrospective study of all Canadian soldiers who were injured in Afghanistan and who required mechanical ventilation from January 1 2006 to September 1 2006. Patients who developed A. baumannii ventilator associated pneumonia (VAP) were identified. All A. baumannii isolates were retrieved for study patients and compared with A. baumannii isolates from environmental sources from the Kandahar military hospital using pulsed-field gel electrophoresis (PFGE). RESULTS: During the study period, six Canadian Forces (CF) soldiers were injured in Afghanistan, required mechanical ventilation and were repatriated to Canadian hospitals. Four of these patients developed A. baumannii VAP. A. baumannii was also isolated from one environmental source in Kandahar - a ventilator air intake filter. Patient isolates were genetically indistinguishable from each other and from the isolates cultured from the ventilator filter. These isolates were resistant to numerous classes of antimicrobials including the carbapenems. CONCLUSION: These results suggest that the source of A. baumannii infection for these four patients was an environmental source in the military field hospital in Kandahar. A causal linkage, however, was not established with the ventilator. This study suggests that infection control efforts and further research should be focused on the military field hospital environment to prevent further multi-drug resistant A. baumannii infections in injured soldiers. PMID- 17697342 TI - A physical map of the bovine genome. AB - BACKGROUND: Cattle are important agriculturally and relevant as a model organism. Previously described genetic and radiation hybrid (RH) maps of the bovine genome have been used to identify genomic regions and genes affecting specific traits. Application of these maps to identify influential genetic polymorphisms will be enhanced by integration with each other and with bacterial artificial chromosome (BAC) libraries. The BAC libraries and clone maps are essential for the hybrid clone-by-clone/whole-genome shotgun sequencing approach taken by the bovine genome sequencing project. RESULTS: A bovine BAC map was constructed with HindIII restriction digest fragments of 290,797 BAC clones from animals of three different breeds. Comparative mapping of 422,522 BAC end sequences assisted with BAC map ordering and assembly. Genotypes and pedigree from two genetic maps and marker scores from three whole-genome RH panels were consolidated on a 17,254 marker composite map. Sequence similarity allowed integrating the BAC and composite maps with the bovine draft assembly (Btau3.1), establishing a comprehensive resource describing the bovine genome. Agreement between the marker and BAC maps and the draft assembly is high, although discrepancies exist. The composite and BAC maps are more similar than either is to the draft assembly. CONCLUSION: Further refinement of the maps and greater integration into the genome assembly process may contribute to a high quality assembly. The maps provide resources to associate phenotypic variation with underlying genomic variation, and are crucial resources for understanding the biology underpinning this important ruminant species so closely associated with humans. PMID- 17697346 TI - Subclinical sympathetic neuropathy appears early in the course of Crohn's disease. AB - BACKGROUND: We have previously demonstrated that patients with Crohn's disease (CD) of long duration have signs of autonomic neuropathy. The aim of this study was to examine whether autonomic neuropathy is an early manifestation of CD, or a sign appearing late in the course. METHODS: Twenty patients, median age 40 years, with a short duration of CD were included. Examination of autonomic reflexes included heart rate reaction to tilt (acceleration index - AI, brake index - BI) and heart rate variation to deep-breathing (expiration/inspiration index-E/I). Seven years later the same examinations were repeated, and in addition we examined the vasoconstriction response to indirect cooling by laser Doppler (vasoconstriction-index - VAC-index). The results were compared with healthy individuals. RESULTS: There was no difference in the blood pressure between controls and the patients with CD at rest, but eight minutes after tilt, the systolic blood pressure was lowered in patients compared to controls, both at the first assessment (p = 0.016) and after seven years (p = 0.042). The change in systolic blood pressure between rest and eight minutes after tilt was not significant at the first assessment, while a significant change compared to controls was observed seven years later (p = 0.028). This indicates a progressive dysfunction. There were no differences in E/I, AI, BI or VAC indexes between patients and controls. CONCLUSION: Patients with CD suffer from autonomic neuropathy early in their disease, suggesting involvement of many different organ systems in this entity. PMID- 17697347 TI - A minimal peach type II chlorophyll a/b-binding protein promoter retains tissue specificity and light regulation in tomato. AB - BACKGROUND: Promoters with tissue-specificity are desirable to drive expression of transgenes in crops to avoid accumulation of foreign proteins in edible tissues/organs. Several photosynthetic promoters have been shown to be strong regulators of expression of transgenes in light-responsive tissues and would be good candidates for leaf and immature fruit tissue-specificity, if expression in the mature fruit were minimized. RESULTS: A minimal peach chlorophyll a/b-binding protein gene (Lhcb2*Pp1) promoter (Cab19) was isolated and fused to an uidA (beta glucuronidase [GUS]) gene containing the PIV2 intron. A control vector carrying an enhanced mas35S CaMV promoter fused to uidA was also constructed. Two different orientations of the Cab19::GUS fusion relative to the left T-DNA border of the binary vector were transformed into tomato. Ten independent regenerants of each construct and an untransformed control line were assessed both qualitatively and quantitatively for GUS expression in leaves, fruit and flowers, and quantitatively in roots. CONCLUSION: The minimal CAB19 promoter conferred GUS activity primarily in leaves and green fruit, as well as in response to light. GUS activity in the leaves of both Cab19 constructs averaged about 2/3 that observed with mas35S::GUS controls. Surprisingly, GUS activity in transgenic green fruit was considerably higher than leaves for all promoter constructs; however, in red, ripe fruit activities were much lower for the Cab19 promoter constructs than the mas35S::GUS. Although GUS activity was readily detectable in flowers and roots of mas35S::GUStransgenic plants, little activity was observed in plants carrying the Cab19 promoter constructs. In addition, the light inducibility of the Cab19::GUS constructs indicated that all the requisite cis elements for light responsiveness were contained on the Cab19 fragment. The minimal Cab19 promoter retains both tissue-specificity and light regulation and can be used to drive expression of foreign genes with minimal activity in mature, edible fruit. PMID- 17697348 TI - Technology to accelerate pangenomic scanning for unknown point mutations in exonic sequences: cycling temperature capillary electrophoresis (CTCE). AB - BACKGROUND: Rapid means to discover and enumerate unknown mutations in the exons of human genes on a pangenomic scale are needed to discover the genes carrying inherited risk for common diseases or the genes in which somatic mutations are required for clonal diseases such as atherosclerosis and cancers. The method of constant denaturing capillary electrophoresis (CDCE) permitted sensitive detection and enumeration of unknown point mutations but labor-intensive optimization procedures for each exonic sequence made it impractical for application at a pangenomic scale. RESULTS: A variant denaturing capillary electrophoresis protocol, cycling temperature capillary electrophoresis (CTCE), has eliminated the need for the laboratory optimization of separation conditions for each target sequence. Here are reported the separation of wild type mutant homoduplexes from wild type/mutant heteroduplexes for 27 randomly chosen target sequences without any laboratory optimization steps. Calculation of the equilibrium melting map of each target sequence attached to a high melting domain (clamp) was sufficient to design the analyte sequence and predict the expected degree of resolution. CONCLUSION: CTCE provides practical means for economical pangenomic detection and enumeration of point mutations in large-scale human case/control cohort studies. We estimate that the combined reagent, instrumentation and labor costs for scanning the approximately 250,000 exons and splice sites of the approximately 25,000 human protein-coding genes using automated CTCE instruments in 100 case cohorts of 10,000 individuals each are now less than U.S. $500 million, less than U.S. $500 per person. PMID- 17697349 TI - Constructing gene co-expression networks and predicting functions of unknown genes by random matrix theory. AB - BACKGROUND: Large-scale sequencing of entire genomes has ushered in a new age in biology. One of the next grand challenges is to dissect the cellular networks consisting of many individual functional modules. Defining co-expression networks without ambiguity based on genome-wide microarray data is difficult and current methods are not robust and consistent with different data sets. This is particularly problematic for little understood organisms since not much existing biological knowledge can be exploited for determining the threshold to differentiate true correlation from random noise. Random matrix theory (RMT), which has been widely and successfully used in physics, is a powerful approach to distinguish system-specific, non-random properties embedded in complex systems from random noise. Here, we have hypothesized that the universal predictions of RMT are also applicable to biological systems and the correlation threshold can be determined by characterizing the correlation matrix of microarray profiles using random matrix theory. RESULTS: Application of random matrix theory to microarray data of S. oneidensis, E. coli, yeast, A. thaliana, Drosophila, mouse and human indicates that there is a sharp transition of nearest neighbour spacing distribution (NNSD) of correlation matrix after gradually removing certain elements insider the matrix. Testing on an in silico modular model has demonstrated that this transition can be used to determine the correlation threshold for revealing modular co-expression networks. The co-expression network derived from yeast cell cycling microarray data is supported by gene annotation. The topological properties of the resulting co-expression network agree well with the general properties of biological networks. Computational evaluations have showed that RMT approach is sensitive and robust. Furthermore, evaluation on sampled expression data of an in silico modular gene system has showed that under sampled expressions do not affect the recovery of gene co-expression network. Moreover, the cellular roles of 215 functionally unknown genes from yeast, E. coli and S. oneidensis are predicted by the gene co-expression networks using guilt-by-association principle, many of which are supported by existing information or our experimental verification, further demonstrating the reliability of this approach for gene function prediction. CONCLUSION: Our rigorous analysis of gene expression microarray profiles using RMT has showed that the transition of NNSD of correlation matrix of microarray profile provides a profound theoretical criterion to determine the correlation threshold for identifying gene co-expression networks. PMID- 17697350 TI - Chondroprotective effects of a proanthocyanidin rich Amazonian genonutrient reflects direct inhibition of matrix metalloproteinases and upregulation of IGF-1 production by human chondrocytes. AB - BACKGROUND: The Amazonian medicinal plant Sangre de grado (Croton palanostigma) has traditional applications for the treatment of wound healing and inflammation. We sought to characterize two extracts (progrado and zangrado) in terms of safety and oligomeric proanthocyanidin chain length. Additionally progrado was evaluated for antioxidant activity and possible chondroprotective actions. METHODS: Acute oral safety and toxicity was tested in rats according under OECD protocol number 420. The profile of proanthocyanidin oligomers was determined by HPLC and progrado's antioxidant activity quantified by the ORAC, NORAC and HORAC assays. Human cartilage explants, obtained from surgical specimens, were used to assess chondroproteciton with activity related to direct inhibitory effects on human matrix metalloproteinase (MMP, gelatinolytic) activity using synovial fluid and chondrocytes activated with IL-1beta (10 ng/ml). Additionally, progrado (2-10 mug/ml) was tested for its ability to maintain optimal IGF-1 transcription and translation in cartilage explants and cultured chondrocytes. RESULTS: Both progrado and zangrado at doses up to 2000 mg/kg (po) displayed no evidence of toxicity. Oligomeric proanthocyanidin content was high for both progrado (158 mg/kg) and zangrado (124 mg/kg), with zangrado almost entirely composed of short oligomers (<6 mer), whereas the majority of oligomers in progrado exceeded 10 mers. Progrado was a remarkably potent antioxidant in the standardized tests ORAC, NORAC and HORAC. Progrado was exceptionally effective in reducing both basal and IL-1beta induced glycosaminoglycan release from human cartilage explants at concentrations that also directly blocked the gelatinolytic activity of MMP-2 and MMP-9. Progrado prevented IL-1beta induced suppression of IGF-1 production from human cartilage explants as well as stimulating basal IGF-1 production (P < 0.05). Comparable changes in IGF-1 gene expression were noted in cultured human chondrocytes. CONCLUSION: Progrado has a promising safety profile, significant chondroprotective and antioxidant actions, directly inhibits MMP activity and promotes the production of the cartilage repair factor, IGF-1. This suggests that progrado may offer therapeutic benefits in joint health, wound healing and inflammation. PMID- 17697351 TI - Quantitative multiplex detection of plant pathogens using a novel ligation probe based system coupled with universal, high-throughput real-time PCR on OpenArrays. AB - BACKGROUND: Diagnostics and disease-management strategies require technologies to enable the simultaneous detection and quantification of a wide range of pathogenic microorganisms. Most multiplex, quantitative detection methods available suffer from compromises between the level of multiplexing, throughput and accuracy of quantification. Here, we demonstrate the efficacy of a novel, high-throughput, ligation-based assay for simultaneous quantitative detection of multiple plant pathogens. The ligation probes, designated Plant Research International-lock probes (PRI-lock probes), are long oligonucleotides with target complementary regions at their 5' and 3' ends. Upon perfect target hybridization, the PRI-lock probes are circularized via enzymatic ligation, subsequently serving as template for individual, standardized amplification via unique probe-specific primers. Adaptation to OpenArrays, which can accommodate up to 3072 33 nl PCR amplifications, allowed high-throughput real-time quantification. The assay combines the multiplex capabilities and specificity of ligation reactions with high-throughput real-time PCR in the OpenArray, resulting in a flexible, quantitative multiplex diagnostic system. RESULTS: The performance of the PRI-lock detection system was demonstrated using 13 probes targeting several significant plant pathogens at different taxonomic levels. All probes specifically detected their corresponding targets and provided perfect discrimination against non-target organisms with very similar ligation target sites. The nucleic acid targets could be reliably quantified over 5 orders of magnitude with a dynamic detection range of more than 104. Pathogen quantification was equally robust in single target versus mixed target assays. CONCLUSION: This novel assay enables very specific, high-throughput, quantitative detection of multiple pathogens over a wide range of target concentrations and should be easily adaptable for versatile diagnostic purposes. PMID- 17697352 TI - Glycosaminoglycan profiles of repair tissue formed following autologous chondrocyte implantation differ from control cartilage. AB - Currently, autologous chondrocyte implantation (ACI) is the most commonly used cell-based therapy for the treatment of isolated femoral condyle lesions of the knee. A small number of centres performing ACI have reported encouraging long term clinical results, but there is currently a lack of quantitative and qualitative biochemical data regarding the nature of the repair tissue. Glycosaminoglycan (GAG) structure influences physiological function and is likely to be important in the long-term stability of the repair tissue. The objective of this study was to use fluorophore-assisted carbohydrate electrophoresis (FACE) to both quantitatively and qualitatively analyse the GAG composition of repair tissue biopsies and compare them with age-matched cadaveric controls. We used immunohistochemistry to provide a baseline reference for comparison. Biopsies were taken from eight patients (22 to 52 years old) 1 year after ACI treatment and from four cadavers (20 to 50 years old). FACE quantitatively profiled the GAGs in as little as 5 microg of cartilage. The pattern and intensity of immunostaining were generally comparable with the data obtained with FACE. In the ACI repair tissue, there was a twofold reduction in chondroitin sulphate and keratan sulphate compared with age-matched control cartilage. By contrast, there was an increase in hyaluronan with significantly shorter chondroitin sulphate chains and less chondroitin 6-sulphate in repair tissue than control cartilage. The composition of the repair tissue thus is not identical to mature articular cartilage. PMID- 17697353 TI - Differential cytokine gene expression profiles in the three pathological forms of sheep paratuberculosis. AB - BACKGROUND: Johne's disease is a chronic inflammatory disease of the gut caused by infection with Mycobacterium avium subspecies paratuberculosis (MAP). Symptoms include wasting, diarrhoea, loss of condition and eventual death. Three forms of Johne's disease have been described in sheep - paucibacillary, multibacillary and asymptomatic. The paucibacillary form is characterized by an inflammatory, Th1 type immune response. The multibacillary form of the disease, which disseminates the infection, is characterized by macrophage infiltration mediated by a Th2-type immune response, and asymptomatic animals have no clinical symptoms or pathology but are infected with MAP. What determines these three forms of the disease is unknown. To further understand these differences, we used real-time RT-PCR to compare the expression of thirteen cytokine and cytokine-related genes in ileal tissue from sheep with the three forms of the disease. RESULTS: Three pathological forms of sheep paratuberculosis were defined on the basis of histopathology, cytochemistry (Zeihl-Neelsen) and IS900 PCR. Paucibacillary lesions have largely T cell and eosinophil infiltration and are ZN negative; multibacillary lesions have macrophage infiltration and large numbers of acid fast bacteria. The pauci- and multibacillary forms are linked to the differential expression of IFN gamma and IL-10 respectively. In addition the increased levels of the proinflammatory cytokines (IL-1 beta and TNFalpha), IL-8, IL-18 and TRAF-1 in both diseased forms is indicative of persistent inflammatory lesions. No changes were seen in IL-1 alpha in any sheep ileum tissues. Asymptomatic animals are IS900+ with normal histology but have significantly decreased levels of IL-18 and increased levels TNFalpha. CONCLUSION: We have quantified the expression levels of thirteen cytokine and cytokine related genes in three forms of ovine paratuberculosis using real-time PCR analyses and confirm that sheep pauci- and multibacillary disease are linked to type 1 and type 2 T cell responses respectively. The expression patterns of other cytokines shows that both disease forms have an inflammatory aetiology but that the central role for IL-1 alpha in bovine paratuberculosis is not seen in the sheep infection. Asymptomatic animals are infected and show no pathology but can be distinguished, in terms of cytokine expression pattern, from uninfected controls. PMID- 17697354 TI - Identification of human pathogens isolated from blood using microarray hybridisation and signal pattern recognition. AB - BACKGROUND: Pathogen identification in clinical routine is based on the cultivation of microbes with subsequent morphological and physiological characterisation lasting at least 24 hours. However, early and accurate identification is a crucial requisite for fast and optimally targeted antimicrobial treatment. Molecular biology based techniques allow fast identification, however discrimination of very closely related species remains still difficult. RESULTS: A molecular approach is presented for the rapid identification of pathogens combining PCR amplification with microarray detection. The DNA chip comprises oligonucleotide capture probes for 25 different pathogens including Gram positive cocci, the most frequently encountered genera of Enterobacteriaceae, non-fermenter and clinical relevant Candida species. The observed detection limits varied from 10 cells (e.g. E. coli) to 10(5) cells (S. aureus) per mL artificially spiked blood. Thus the current low sensitivity for some species still represents a barrier for clinical application. Successful discrimination of closely related species was achieved by a signal pattern recognition approach based on the k-nearest-neighbour method. A prototype software providing this statistical evaluation was developed, allowing correct identification in 100 % of the cases at the genus and in 96.7 % at the species level (n = 241). CONCLUSION: The newly developed molecular assay can be carried out within 6 hours in a research laboratory from pathogen isolation to species identification. From our results we conclude that DNA microarrays can be a useful tool for rapid identification of closely related pathogens particularly when the protocols are adapted to the special clinical scenarios. PMID- 17697355 TI - Activation of superior colliculi in humans during visual exploration. AB - BACKGROUND: Visual, oculomotor, and - recently - cognitive functions of the superior colliculi (SC) have been documented in detail in non-human primates in the past. Evidence for corresponding functions of the SC in humans is still rare. We examined activity changes in the human tectum and the lateral geniculate nuclei (LGN) in a visual search task using functional magnetic resonance imaging (fMRI) and anatomically defined regions of interest (ROI). Healthy subjects conducted a free visual search task and two voluntary eye movement tasks with and without irrelevant visual distracters. Blood oxygen level dependent (BOLD) signals in the SC were compared to activity in the inferior colliculi (IC) and LGN. RESULTS: Neural activity increased during free exploration only in the SC in comparison to both control tasks. Saccade frequency did not exert a significant effect on BOLD signal changes. No corresponding differences between experimental tasks were found in the IC or the LGN. However, while the IC revealed no signal increase from the baseline, BOLD signal changes at the LGN were consistently positive in all experimental conditions. CONCLUSION: Our data demonstrate the involvement of the SC in a visual search task. In contrast to the results of previous studies, signal changes could not be seen to be driven by either visual stimulation or oculomotor control on their own. Further, we can exclude the influence of any nearby neural structures (e.g. pulvinar, tegmentum) or of typical artefacts at the brainstem on the observed signal changes at the SC. Corresponding to findings in non-human primates, our data support a dependency of SC activity on functions beyond oculomotor control and visual processing. PMID- 17697356 TI - The roles of binding site arrangement and combinatorial targeting in microRNA repression of gene expression. AB - BACKGROUND: MicroRNAs (miRNAs) are small noncoding RNAs that bind mRNA target transcripts and repress gene expression. They have been implicated in multiple diseases, such as cancer, but the mechanisms of this involvement are not well understood. Given the complexity and degree of interactions between miRNAs and target genes, understanding how miRNAs achieve their specificity is important to understanding miRNA function and identifying their role in disease. RESULTS: Here we report factors that influence miRNA regulation by considering the effects of both single and multiple miRNAs targeting human genes. In the case of single miRNA targeting, we developed a metric that integrates miRNA and mRNA expression data to calculate how changes in miRNA expression affect target mRNA expression. Using the metric, our global analysis shows that the repression of a given miRNA on a target mRNA is modulated by 3' untranslated region length, the number of target sites, and the distance between a pair of binding sites. Additionally, we show that some miRNAs preferentially repress transcripts with longer CTG repeats, suggesting a possible role for miRNAs in repeat expansion disorders such as myotonic dystrophy. We also examine the large class of genes targeted by multiple miRNAs and show that specific types of genes are progressively more enriched as the number of targeting miRNAs increases. Expression microarray data further show that these highly targeted genes are downregulated relative to genes targeted by few miRNAs, which suggests that highly targeted genes are tightly regulated and that their dysregulation may lead to disease. In support of this idea, cancer genes are strongly enriched among highly targeted genes. CONCLUSION: Our data show that the rules governing miRNA targeting are complex, but that understanding the mechanisms that drive such control can uncover miRNAs' role in disease. Our study suggests that the number and arrangement of miRNA recognition sites can influence the degree and specificity of miRNA-mediated gene repression. PMID- 17697357 TI - Influence of IFN-gamma and its receptors in human breast cancer. AB - BACKGROUND: Interferons are a group of proteins that trigger multiple responses including prevention of viral replication, inhibition of cell growth, and modulation of cell differentiation. In different mammary carcinoma cell lines IFNgamma induces growth arrest at mid-G1. At the present there are no in vivo studies in human breast. The aim of this study was to investigate the expression patterns of IFNgamma and its two receptors (IFNgamma-Ralpha and IFNgamma-Rbeta) by Western blot and immunohistochemistry, in order to elucidate its role in the different types of human breast cancer (in situ and infiltrative). METHODS: Immunohistochemical and semiquantitative study of IFNgamma, its receptors types (IFNgamma-Ralpha and IFNgamma-Rbeta), cell proliferation (proliferating cell nuclear antigen, also named PCNA), and apoptosis (TUNEL method) was carried between the three breast groups (fibrocystic lesions, in situ tumors and infiltrating tumors). RESULTS: In the three groups of patients, IFNgamma and IFNgamma-Ralpha immunoreactions appeared in the cytoplasm while IFNgamma-Rbeta also was found in the nucleus. The optical density to IFNgamma was higher in in situ carcinoma than in benign and infiltrating tumors. When we observed IFNgamma Ralpha, the optical density was lower in infiltrating carcinoma than in benign and in situ tumors (the higher density). To IFNgamma-Rbeta, the optical density was similar in the three group samples. In tumor samples PCNA and TUNEL index was significantly higher; than in benign diseases. PCNA index increased with the malignance. No significant differences were found between cancer types to TUNEL. IFNgamma could be a potential therapeutic tool in breast cancer. However, tumor cells are able to escape from the control of this cytokine in the early tumor stages; this is probably due to a decreased expression of IFNgamma, or also to an alteration of either its receptors or some transduction elements. CONCLUSION: We conclude that the decrease in the % positive samples that expressed IFNgamma and IFNgamma-Ralpha together with the nuclear localization of IFNgamma-Rbeta, could be a tumoral cell response, although perhaps insufficient to inhibit the uncontrolled cell proliferation. Perhaps, IFNgamma might be unable to activate p21 to stop the cell cycle, suggesting a possible participation in breast cancer development. PMID- 17697358 TI - Evolutionary conservation of lampbrush-like loops in drosophilids. AB - BACKGROUND: Loopin-1 is an abundant, male germ line specific protein of Drosophila melanogaster. The polyclonal antibody T53-F1 specifically recognizes Loopin-1 and enables its visualization on the Y-chromosome lampbrush-like loop named kl-3 during primary spermatocyte development, as well as on sperm tails. In order to test lampbrush-like loop evolutionary conservation, extensive phase contrast microscopy and immunostaining with T53-F1 antibody was performed in other drosophilids scattered along their genealogical tree. RESULTS: In the male germ line of all species tested there are cells showing giant nuclei and intranuclear structures similar to those of Drosophila melanogaster primary spermatocytes. Moreover, the antibody T53-F1 recognizes intranuclear structures in primary spermatocytes of all drosophilids analyzed. Interestingly, the extent and conformation of the staining pattern is species-specific. In addition, the intense staining of sperm tails in all species suggests that the terminal localization of Loopin-1 and its orthologues is conserved. A comparison of these cytological data and the data coming from the literature about sperm length, amount of sperm tail entering the egg during fertilization, shape and extent of both loops and primary spermatocyte nuclei, seems to exclude direct relationships among these parameters. CONCLUSION: Taken together, the data reported strongly suggest that lampbrush-like loops are a conserved feature of primary spermatocyte nuclei in many, if not all, drosophilids. Moreover, the conserved pattern of the T53-F1 immunostaining indicates that a Loopin-1-like protein is present in all the species analyzed, whose localization on lampbrush-like loops and sperm tails during spermatogenesis is evolutionary conserved. PMID- 17697359 TI - Influence of dextran-70 on systemic inflammatory response and myocardial ischaemia-reperfusion following cardiac operations. AB - INTRODUCTION: Experimental studies have demonstrated that dextran-70 reduces the leukocyte-endothelium interaction, but clinical evidence is still lacking. Our objective was to justify the anti-inflammatory effect of dextran-70 following cardiac operations. METHODS: Forty patients undergoing coronary bypass surgery (n = 32) or aortic valve replacement (n = 8) were enrolled in this prospective, randomized, double-blind study. Two groups were formed. In group A (n = 20), dextran-70 infusion was administered at a dose of 7.5 ml/kg before the initiation of cardiopulmonary bypass and at a dose of 12.5 ml/kg after the cessation of cardiopulmonary bypass. Group B served as a control with identical amounts of gelatin infusion (n = 20). The plasma concentration of procalcitonin, C-reactive protein, IL 6, IL 6r, IL 8, IL 10, soluble endothelial leukocyte adhesion molecule-1, soluble intercellular adhesion molecule-1, cardiac troponin-I and various haemodynamic parameters were measured in the perioperative period. Multivariate methods were used for statistical analysis. RESULTS: In group A, lower peak (median) plasma levels of procalcitonin (0.2 versus 1.4, p < 0.001), IL 8 (5.6 versus 94.8, p < 0.001), IL 10 (47.2 versus 209.7, p = 0.001), endothelial leukocyte adhesion molecule-1 (88.5 versus 130.6, p = 0.033), intercellular adhesion molecule-1 (806.7 versus 1,375.7, P = 0.001) and troponin I (0.22 versus 0.66, p = 0.018) were found. There was no significant difference in IL 6, IL-6r and C-reactive protein values between groups. Higher figures of the cardiac index (p = 0.010) along with reduced systemic vascular resistance (p = 0.005) were noted in group A. CONCLUSION: Our investigation demonstrated that the use of dextran-70 reduces the systemic inflammatory response and cardiac troponin-I release following cardiac operation. TRIAL REGISTRATION NUMBER: ISRCTN38289094. PMID- 17697360 TI - Success of microvascular surgery; repair mesenteric injury and prevent short bowel syndrome: a case report. AB - BACKGROUND: Superior mesenteric injury is a rare entity but when it occurs, short bowel syndrome is one of the uninvited results of the emergency surgical procedures. CASE PRESENTATION: We present a 19-year-old boy with blunt abdominal trauma which caused serious mesenteric injury. Because ultrasound revealed free intraabdominal fluid, he underwent emergency laparotomy. Adequate vascularization of approximately 20 cm of proximal jejunal segment and approximately 20 cm of terminal ileum was observed. Nevertheless, the mesentery of the rest of the small intestine segments was ruptured completely. We performed an end-to-end anastomosis between a distal branch of the superior mesenteric artery in the mesentery of the ileal segment and a branch of the superior mesenteric artery using separate sutures of 7.0 monofilament polypropylene. The patient's gastrointestinal passage returned to normal on the postoperative day 2. He recovered without any complication and was discharged from hospital on the postoperative day seven. DISCUSSION: In this case report, we emphasize the importance of preservation of injured mesenteric artery due to abdominal trauma which could have resulted in short bowel syndrome. PMID- 17697361 TI - Taurine chloramine differentially inhibits matrix metalloproteinase 1 and 13 synthesis in interleukin-1beta stimulated fibroblast-like synoviocytes. AB - It has been suggested that taurine chloramine (TauCl) plays an important role in the downregulation of proinflammatory mediators. However, little is known about its effect on the expression of matrix metalloproteinases (MMPs). In this study, we investigated the effects of TauCl on synovial expression of MMPs. The effects of TauCl on MMP expression in IL-1beta stimulated fibroblast-like synoviocytes (FLSs) were studied using the following techniques. Real-time PCR and semi quantitative PCR were employed to analyze the mRNA expression of MMPs. ELISA was used to determine protein levels of MMPs. Western blot analyses were performed to analyze the mitogen-activated protein kinase and inhibitor of nuclear factor kappaB (IkappaB) kinase signalling pathways. Finally, electrophoretic mobility shift assay and immunohistochemistry were used to assess localization of transcription factors. IL-1beta increased the transcriptional and translational levels of MMP-1 and MMP-13 in rheumatoid arthritis FLSs, whereas the levels of MMP-2 and MMP-9 were unaffected. TauCl at a concentration of 400 to 600 micromol/l greatly inhibited the transcriptional and translational expression of MMP-13, but the expression of MMP-1 was significantly inhibited at 800 micromol/l. At a concentration of 600 micromol/l, TauCl did not significantly inhibit phosphorylation of mitogen-activated protein kinase or IkappaB degradation in IL-1beta stimulated rheumatoid arthritis FLSs. The degradation of IkappaB was significantly inhibited at a TauCl concentration of 800 micromol/l. The inhibitory effect of TauCl on IkappaB degradation was confirmed by electrophoretic mobility shift assay and immunochemical staining for localization of nuclear factor-kappaB. TauCl differentially inhibits the expression of MMP-1 and MMP-13, and inhibits expression of MMP-1 primarily through the inhibition of IkappaB degradation, whereas it inhibits expression of MMP-13 through signalling pathways other than the IkappaB pathway. PMID- 17697362 TI - Analysis of the geographic distribution of HFRS in Liaoning Province between 2000 and 2005. AB - BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) is endemic in Liaoning Province, China, and this province was the most serious area affected by HFRS during 2004 to 2005. In this study, we conducted a spatial analysis of HFRS cases with the objective to determine the distribution of HFRS cases and to identify key areas for future public health planning and resource allocation in Liaoning Province. METHODS: The annual average incidence at the county level was calculated using HFRS cases reported between 2000 and 2005 in Liaoning Province. GIS-based spatial analyses were conducted to detect spatial distribution and clustering of HFRS incidence at the county level, and the difference of relative humidity and forestation between the cluster areas and non-cluster areas was analyzed. RESULTS: Spatial distribution of HFRS cases in Liaoning Province from 2000 to 2005 was mapped at the county level to show crude incidence, excess hazard, and spatial smoothed incidence. Spatial cluster analysis suggested 16 and 41 counties were at increased risk for HFRS (p < 0.01) with the maximum spatial cluster sizes at < or = 50% and < or = 30% of the total population, respectively, and the analysis showed relative humidity and forestation in the cluster areas were significantly higher than in other areas. CONCLUSION: Some clustering of HFRS cases in Liaoning Province may be etiologically linked. There was strong evidence some HFRS cases in Liaoning Province formed clusters, but the mechanism underlying it remains unknown. In this study we found the clustering was consistent with the relative humidity and amount of forestation, and showed data indicating there may be some significant relationships. PMID- 17697363 TI - Comparison of disc diffusion, Etest and broth microdilution for testing susceptibility of carbapenem-resistant P. aeruginosa to polymyxins. AB - BACKGROUND: Considering the increasing use of polymyxins to treat infections due to multidrug resistant Gram-negative in many countries, it is important to evaluate different susceptibility testing methods to this class of antibiotic. METHODS: Susceptibility of 109 carbapenem-resistant P. aeruginosa to polymyxins was tested comparing broth microdilution (reference method), disc diffusion, and Etest using the new interpretative breakpoints of Clinical and Laboratory Standards Institute. RESULTS: Twenty-nine percent of isolates belonged to endemic clone and thus, these strains were excluded of analysis. Among 78 strains evaluated, only one isolate was resistant to polymyxin B by the reference method (MIC: 8.0 microg/mL). Very major and major error rates of 1.2% and 11.5% were detected comparing polymyxin B disc diffusion with the broth microdilution (reference method). Agreement within 1 twofold dilution between Etest and the broth microdilution were 33% for polymyxin B and 79.5% for colistin. One major error and 48.7% minor errors were found comparing polymyxin B Etest with broth microdilution and only 6.4% minor errors with colistin. The concordance between Etest and the broth microdilution (reference method) was respectively 100% for colistin and 90% for polymyxin B. CONCLUSION: Resistance to polymyxins seems to be rare among hospital carbapenem-resistant P. aeruginosa isolates over a six year period. Our results showed, using the new CLSI criteria, that the disc diffusion susceptibility does not report major errors (false-resistant results) for colistin. On the other hand, showed a high frequency of minor errors and 1 very major error for polymyxin B. Etest presented better results for colistin than polymyxin B. Until these results are reproduced with a large number of polymyxins-resistant P. aeruginosa isolates, susceptibility to polymyxins should be confirmed by a reference method. PMID- 17697364 TI - Development of a workplace intervention for sick-listed employees with stress related mental disorders: Intervention Mapping as a useful tool. AB - BACKGROUND: To date, mental health problems and mental workload have been increasingly related to long-term sick leave and disability. However, there is, as yet, no structured protocol available for the identification and application of an intervention for stress-related mental health problems at the workplace. This paper describes the structured development, implementation and planning for the evaluation of a return-to-work intervention for sick-listed employees with stress-related mental disorders (SMDs). The intervention is based on an existing successful return-to-work intervention for sick-listed employees with low back pain. METHODS: The principles of Intervention Mapping were applied to combine theory and evidence in the development, implementation and planning for the evaluation of a participatory workplace intervention, aimed at an early return-to work for sick-listed employees with SMDs. All stakeholders were involved in focus group interviews: i.e. employees recently sick-listed with SMDs, supervisors and occupational health professionals. RESULTS: The development of the participatory workplace intervention according to the Intervention Mapping principles resulted in a structured return-to-work intervention, specifically tailored to the needs of sick-listed employees with SMDs. Return-to-work was proposed as a behavioural change, and the Attitude - Social influence - self-Efficacy model was identified as a theoretical framework. Stakeholder involvement in focus group interviews served to enhance the implementation. The cost-effectiveness of the intervention will be evaluated in a randomised controlled trial. CONCLUSION: Intervention Mapping was found to be a promising method to develop interventions tailored to a specific target group in the field of occupational health. PMID- 17697365 TI - Increased interferon alpha receptor 2 mRNA levels is associated with renal cell carcinoma metastasis. AB - BACKGROUND: Interferon-alpha (IFN-alpha) is one of the central agents in immunotherapy for renal cell carcinoma (RCC) and binds to the IFN-alpha receptor (IFNAR). We investigated the role of IFNAR in RCC. METHODS: We quantified IFNAR mRNA expression in paired tumor and non-tumor samples from the surgical specimens of 103 consecutive patients with RCC using a real-time reverse transcription polymerase chain reaction (RT-PCR), and IFNAR2 protein using Western blotting. RESULTS: The absolute level of IFNAR1 and IFNAR2 mRNAs in tumor and non-tumor tissues did not correlate with the malignant and metastatic profiles. The relative yields of the PCR product from the tumor tissue to that from the corresponding non-tumor tissue (T/N) for the expression of IFNAR mRNAs were calculated. While the T/N ratio of IFNAR1 did not correlate with any factor, a high T/N ratio of IFNAR2 correlated with poor differentiation (P < 0.05), local invasion (P < 0.001), and metastasis (P < 0.0001). By multivariate analysis, a high T/N ratio of IFNAR2 predicted a shortened overall survival in all cases (P < 0.05) and a shorter disease-free survival in those without metastasis (M0; 68 cases, P < 0.05). Impressively, patients with a poorer response to IFN-alpha treatment had a higher IFNAR2 T/N ratio than those who had a good response (P < 0.05). IFNAR2c protein expression was higher in the primary tumors in patients with metastases (M1; 35 cases) compared to those without ( P < 0.0001). CONCLUSION: IFNAR2 is associated with the progression of RCC. PMID- 17697367 TI - Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH): study protocol. AB - BACKGROUND: Young women presenting with breast cancer are more likely to have a genetic predisposition to the disease than breast cancer patients in general. A genetic predisposition is known to increase the risk of new primary breast (and other) cancers. It is unclear from the literature whether genetic status should be taken into consideration when planning adjuvant treatment in a young woman presenting with a first primary breast cancer. The primary aim of the POSH study is to establish whether genetic status influences the prognosis of primary breast cancer independently of known prognostic factors. METHODS/DESIGN: The study is a prospective cohort study recruiting 3,000 women aged 40 years or younger at breast cancer diagnosis; the recruiting period covers 1st June 2001 to 31st December 2007. Written informed consent is obtained at study entry. Family history and known epidemiological risk data are collected by questionnaire. Clinical information about diagnosis, treatment and clinical course is collected and blood is stored. Follow up data are collected annually after the first year. An additional recruitment category includes women aged 41 to 50 years who are found to be BRCA1 or BRCA2 gene carriers and were diagnosed with their first breast cancer during the study recruiting period. DISCUSSION: Power estimates were based on 10% of the cohort carrying a BRCA1 gene mutation. Preliminary BRCA1 and BRCA2 mutation analysis in a pilot set of study participants confirms we should have 97% power to detect a difference of 10% in event rates between gene carriers and sporadic young onset cases. Most of the recruited patients (>80%) receive an anthracycline containing adjuvant chemotherapy regimen making planned analyses more straightforward. PMID- 17697366 TI - B cells in Sjogren's syndrome: indications for disturbed selection and differentiation in ectopic lymphoid tissue. AB - Primary Sjogren's syndrome (pSS) is an autoimmune disorder characterized by specific pathological features. A hallmark of pSS is B-cell hyperactivity as manifested by the production of autoantibodies, hypergammaglobulinemia, formation of ectopic lymphoid structures within the inflamed tissues, and enhanced risk of B-cell lymphoma. Changes in the distribution of peripheral B-cell subsets and differences in post-recombination processes of immunoglobulin variable region (IgV) gene usage are also characteristic features of pSS. Comparison of B cells from the peripheral blood and salivary glands of patients with pSS with regard to their expression of the chemokine receptors CXCR4 and CXCR5, and their migratory capacity towards the corresponding ligands, CXCL12 and CXCL13, provide a mechanism for the prominent accumulation of CXCR4+ CXCR5+ memory B cells in the inflamed glands. Glandular B cells expressing distinct features of IgV light and heavy chain rearrangements, (re)circulating B cells with increased mutations of cmu transcripts in both CD27- and CD27+ memory B-cell subsets, and enhanced frequencies of individual peripheral B cells containing IgV heavy chain transcripts of multiple isotypes indicate disordered selection and incomplete differentiation processes of B cells in the inflamed tissues in pSS. This may possibly be related to a lack of appropriate censoring mechanisms or different B cell activation pathways within the ectopic lymphoid structures of the inflamed tissues. These findings add to our understanding of the pathogenesis of this autoimmune inflammatory disorder and may result in new therapeutic approaches. PMID- 17697368 TI - Reduced tumor growth in vivo and increased c-Abl activity in PC3 prostate cancer cells overexpressing the Shb adapter protein. AB - BACKGROUND: Induction of apoptosis is one strategy for treatment of prostate cancer. The Shb adapter protein has been found to regulate apoptosis in various cell types and consequently human prostate cancer 3 (PC3) cells were transfected to obtain cells overexpressing Shb in order to increase our understanding of the mechanisms regulating PC3 cell apoptosis. METHODS: Human prostate cancer cells (PC3) were transfected with control vector or a vector containing the Shb cDNA. Clones overexpressing Shb were studied with respect to apoptosis (Dapi, M30) and c-Abl activation (Western blot for pY-245-Abl). The cells were exposed to the anti-tumor agent 2-methoxyestradiol (2-ME) and the p38 MAPK and c-Abl inhibitors SB203580 and STI-571, respectively, after which cell death was determined. In vivo tumor growth and tumor cell proliferation (Ki-67 staining) or apoptosis (active caspase 3 staining) were also determined in nude mice. RESULTS: PC3 cells overexpressing Shb exhibited increased rates of apoptosis in the presence of the anti-tumor agent 2-ME. The Shb cells displayed increased activity of the pro apoptotic kinase c-Abl. Pre-treatment with p38 MAPK (SB203580) or c-Abl (STI-571) inhibitors completely blocked 2-ME-induced apoptosis, implicating these two pathways in the response. The PC3-Shb cells displayed reduced tumor growth in vivo, an effect occurring as a consequence of increased apoptosis and reduced DNA synthesis. CONCLUSION: It is concluded that Shb promotes 2-ME-induced PC3 cell apoptosis by increased pro-apoptotic signaling via the c-Abl pathway and that this causes reduced tumor growth in vivo. PMID- 17697369 TI - An apricot story: view through a keyhole. AB - BACKGROUND: Very few cases of small bowel obstruction due to ingested fruits have been described in literature, and most of these have managed by a laparotomy. Laparoscopic assisted surgery can effectively deal with such impacted foreign bodies, thereby avoiding a formal laparotomy. CASE PRESENTATION: A 75 years old lady was admitted via the Accident and Emergency to the surgical ward with a three-day history of abdominal pain and vomiting. Investigations were suggestive of acute small bowel obstruction. On laparoscopy, there was an area of sudden change in calibre of small bowel with dilated proximal and collapsed distal segment in distal jejunum. A foreign body, dried undigested apricot, was extracted by mini-laparotomy. DISCUSSION: Small bowel obstruction is a frequent cause of emergency surgery, and aetiology may include food bolus obstruction. Diagnosis is usually confirmed intra-operatively. Foreign body impacted in small bowel can be removed by open or laparoscopic methods. CONCLUSION: Generally, laparotomy is performed for diagnosis and management in acute bowel obstruction, but with increasing expertise, laparoscopy can be equally effective with all the other advantages of minimal access approach. PMID- 17697370 TI - Management of insertional Achilles tendinopathy through a Cincinnati incision. AB - BACKGROUND: About 10% of patients not responding to 3-6 months of conservative management for insertional Achilles tendinopathy undergo surgery. Traditionally, surgery of the Achilles tendon is performed through longitudinal extensile incisions. Such surgery is prone to the complications of wound healing, wound breakdown and iatrogenic nerve injury. METHODS: We describe our current method of exposure of the Achilles tendon insertion and debridement of the peritendinous and tendon tissue with osteotomy of the calcaneum through a transverse skin incision at the level of the Achilles insertion. RESULTS: This method has been used since 2002 on over 40 patients for exposure of the Achilles tendon insertion and the distal Achilles tendon. CONCLUSION: The Cincinnati incision allows adequate exposure, has minimal risk of symptomatic iatrogenic nerve injury, and has minimal problems related to the scar. PMID- 17697371 TI - Portal vein thrombosis; risk factors, clinical presentation and treatment. AB - BACKGROUND: Portal vein thrombosis (PVT) is increasingly frequently being diagnosed, but systematic descriptions of the natural history and clinical handling of the condition are sparse. The aim of this retrospective study was to describe risk factors, clinical presentation, complications and treatment of portal vein thrombosis in a single-centre. METHODS: Sixty-seven patients were identified in the electronic records from 1992 to 2005. All data were obtained from the patient records. RESULTS: One or more risk factors (e.g. prothrombotic disorder or abdominal inflammation) were present in 87%. Symptoms were abdominalia, splenomegaly, fever, ascites, haematemesis, and weight loss. Abdominalia and fever occurred more frequently in patients with acute PVT. Frequent complications were splenomegaly, oesophageal- and gastric varices with or without bleeding, portal hypertensive gastropathy and ascites. Varices and bleeding were more frequent in patients with chronic PVT. Patients who received anticoagulant therapy more frequently achieved partial/complete recanalization. Patients with varices who were treated endoscopically in combination with beta blockade had regression of the varices. The overall mortality was 13% in one year, and was dependent on underlying causes. CONCLUSION: Most patients had a combination of local and systemic risk factors for PVT. We observed that partial/complete recanalization was more frequent in patients treated with anticoagulation therapy, and that regression of varices was more pronounced in patients who where treated with active endoscopy combined with pharmacological treatment. PMID- 17697372 TI - Microbial proteomics: a mass spectrometry primer for biologists. AB - It is now more than 10 years since the publication of the first microbial genome sequence and science is now moving towards a post genomic era with transcriptomics and proteomics offering insights into cellular processes and function. The ability to assess the entire protein network of a cell at a given spatial or temporal point will have a profound effect upon microbial science as the function of proteins is inextricably linked to phenotype. Whilst such a situation is still beyond current technologies rapid advances in mass spectrometry, bioinformatics and protein separation technologies have produced a step change in our current proteomic capabilities. Subsequently a small, but steadily growing, number of groups are taking advantage of this cutting edge technology to discover more about the physiology and metabolism of microorganisms. From this research it will be possible to move towards a systems biology understanding of a microorganism. Where upon researchers can build a comprehensive cellular map for each microorganism that links an accurately annotated genome sequence to gene expression data, at a transcriptomic and proteomic level.In order for microbiologists to embrace the potential that proteomics offers, an understanding of a variety of analytical tools is required. The aim of this review is to provide a basic overview of mass spectrometry (MS) and its application to protein identification. In addition we will describe how the protein complexity of microbial samples can be reduced by gel-based and gel free methodologies prior to analysis by MS. Finally in order to illustrate the power of microbial proteomics a case study of its current application within the Bacilliaceae is given together with a description of the emerging discipline of metaproteomics. PMID- 17697373 TI - Signatures of seaway closures and founder dispersal in the phylogeny of a circumglobally distributed seahorse lineage. AB - BACKGROUND: The importance of vicariance events on the establishment of phylogeographic patterns in the marine environment is well documented, and generally accepted as an important cause of cladogenesis. Founder dispersal (i.e. long-distance dispersal followed by founder effect speciation) is also frequently invoked as a cause of genetic divergence among lineages, but its role has long been challenged by vicariance biogeographers. Founder dispersal is likely to be common in species that colonize remote habitats by means of rafting (e.g. seahorses), as long-distance dispersal events are likely to be rare and subsequent additional recruitment from the source habitat is unlikely. In the present study, the relative importance of vicariance and founder dispersal as causes of cladogenesis in a circumglobally distributed seahorse lineage was investigated using molecular dating. A phylogeny was reconstructed using sequence data from mitochondrial and nuclear markers, and the well-documented closure of the Central American seaway was used as a primary calibration point to test whether other bifurcations in the phylogeny could also have been the result of vicariance events. The feasibility of three other vicariance events was explored: a) the closure of the Indonesian Seaway, resulting in sister lineages associated with the Indian Ocean and West Pacific, respectively; b) the closure of the Tethyan Seaway, resulting in sister lineages associated with the Indo-Pacific and Atlantic Ocean, respectively, and c) continental break-up during the Mesozoic followed by spreading of the Atlantic Ocean, resulting in pairs of lineages with amphi-Atlantic distribution patterns. RESULTS: Comparisons of pairwise genetic distances among the seahorse species hypothesized to have diverged as a result of the closure of the Central American Seaway with those of published teleost sequences having the same distribution patterns show that the seahorses were among the last to diverge. This suggests that their cladogenesis was associated with the final closure of this seaway. Although two other divergence events in the phylogeny could potentially have arisen as a result of the closures of the Indonesian and Tethyan seaways, respectively, the timing of the majority of bifurcations in the phylogeny differed significantly from the dates of vicariance events suggested in the literature. Moreover, several divergence events that resulted in the same distribution patterns of lineages at different positions in the phylogeny did not occur contemporaneously. For that reason, they cannot be the result of the same vicariance events, a result that is independent of molecular dating. CONCLUSION: Interpretations of the cladogenetic events in the seahorse phylogeny based purely on vicariance biogeographic hypotheses are problematic. We conclude that the evolution of the circumglobally distributed seahorse lineage was strongly influenced by founder dispersal, and suggest that this mode of speciation may be particularly important in marine organisms that lack a pelagic dispersal phase and instead disperse by means of rafting. PMID- 17697374 TI - Microarray amplification bias: loss of 30% differentially expressed genes due to long probe - poly(A)-tail distances. AB - BACKGROUND: Laser microdissection microscopy has become a rising tool to assess gene expression profiles of pure cell populations. Given the low yield of RNA, a second round of amplification is usually mandatory to yield sufficient amplified RNA for microarray approaches. Since amplification induces truncation of RNA molecules, we studied the impact of a second round of amplification on identification of differentially expressed genes in relation to the probe - poly(A)-tail distances. RESULTS: Disagreement was observed between gene expression profiles acquired after a second round of amplification compared to a single round. Thirty percent of the differentially expressed genes identified after one round of amplification were not detected after two rounds. These inconsistent genes have a significant longer probe - poly(A)-tail distance. qRT PCR on unamplified RNA confirmed differential expression of genes with a probe - poly(A)-tail distance >500 nucleotides appearing only after one round of amplification. CONCLUSION: Our data demonstrate a marked loss of 30% of truly differentially expressed genes after a second round of amplification. Therefore, we strongly recommend improvement of amplification procedures and importance of microarray probe design to allow detection of all differentially expressed genes in case of limited amounts of RNA. PMID- 17697375 TI - Selection of reference genes for gene expression studies in pig tissues using SYBR green qPCR. AB - BACKGROUND: Real-time quantitative PCR (qPCR) is a method for rapid and reliable quantification of mRNA transcription. Internal standards such as reference genes are used to normalise mRNA levels between different samples for an exact comparison of mRNA transcription level. Selection of high quality reference genes is of crucial importance for the interpretation of data generated by real-time qPCR. RESULTS: In this study nine commonly used reference genes were investigated in 17 different pig tissues using real-time qPCR with SYBR green. The genes included beta-actin (ACTB), beta-2-microglobulin (B2M), glyceraldehyde-3 phosphate dehydrogenase (GAPDH), hydroxymethylbilane synthase (HMBS), hypoxanthine phosphoribosyltransferase 1 (HPRT1), ribosomal protein L4 (RPL4), succinate dehydrogenase complex subunit A (SDHA), TATA box binding protein (TPB)and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta polypeptide (YWHAZ). The stability of these reference genes in different pig tissues was investigated using the geNorm application. The range of expression stability in the genes analysed was (from the most stable to the least stable): ACTB/RPL4, TBP, HPRT, HMBS, YWHAZ, SDHA, B2M and GAPDH. CONCLUSION: Expression stability varies greatly between genes. ACTB, RPL4, TPB and HPRT1 were found to have the highest stability across tissues. Based on both expression stability and expression level, our data suggest that ACTB and RPL4 are good reference genes for high abundant transcripts while TPB and HPRT1 are good reference genes for low abundant transcripts in expression studies across different pig tissues. PMID- 17697376 TI - Failure of psychiatric referrals from the pediatric emergency department. AB - BACKGROUND: Recognition of mental illness in the pediatric emergency department (PED) followed by brief, problem oriented interventions may improve health-care seeking behavior and quality of life. The objective of this study was to compare the frequency of mental health follow up after an enhanced referral compared to a simple referral in children presenting to the PED with unrecognized mental health problems. METHODS: A prospective randomized control trial comparing an enhanced referral vs. simple referral in 56 families of children who were screened for mental health symptoms was performed in a large tertiary care PED. Children presenting to the PED with stable medical problems were approached every fourth evening for enrollment. After consent/assent was obtained, children were screened for a mental health problem using both child and parent reports of the DISC Predictive Scales. Those meeting cutoffs for a mental health problem by either parent or child report were randomized to 1) simple referral (phone number for mental health evaluation by study psychiatrist) or 2) enhanced referral (short informational interview, appointment made for child, reminder 2 days before and day of interview for an evaluation by study psychiatrist). Data analysis included descriptive statistics and Chi-Square test to calculate the proportion of children with mental health problems who completed mental health follow-up with and without the enhanced referral. RESULTS: A total of 69 families were enrolled. Overall 56 (81%) children screened positive for a mental health problem as reported by either the child (self report) or mother (maternal report of child mental health problem). Of these, 33 children were randomized into the enhanced referral arm and 23 into the simple referral arm. Overall, only 6 families with children screening positive for a mental health problem completed the psychiatric follow up evaluation, 2 in the enhanced referral arm and 4 in the simple referral arm (p = .13). CONCLUSION: Children screened in the ED for unrecognized mental health problems are very unlikely to follow-up for a mental health evaluation with or without an enhanced referral. Understanding the role of ED based mental health screening and the timing of an intervention is key in developing ED based mental health interventions. PMID- 17697377 TI - Phylogenomic analyses of KCNA gene clusters in vertebrates: why do gene clusters stay intact? AB - BACKGROUND: Gene clusters are of interest for the understanding of genome evolution since they provide insight in large-scale duplications events as well as patterns of individual gene losses. Vertebrates tend to have multiple copies of gene clusters that typically are only single clusters or are not present at all in genomes of invertebrates. We investigated the genomic architecture and conserved non-coding sequences of vertebrate KCNA gene clusters. KCNA genes encode shaker-related voltage-gated potassium channels and are arranged in two three-gene clusters in tetrapods. Teleost fish are found to possess four clusters. The two tetrapod KNCA clusters are of approximately the same age as the Hox gene clusters that arose through duplications early in vertebrate evolution. For some genes, their conserved retention and arrangement in clusters are thought to be related to regulatory elements in the intergenic regions, which might prevent rearrangements and gene loss. Interestingly, this hypothesis does not appear to apply to the KCNA clusters, as too few conserved putative regulatory elements are retained. RESULTS: We obtained KCNA coding sequences from basal ray finned fishes (sturgeon, gar, bowfin) and confirmed that the duplication of these genes is specific to teleosts and therefore consistent with the fish-specific genome duplication (FSGD). Phylogenetic analyses of the genes suggest a basal position of the only intron containing KCNA gene in vertebrates (KCNA7). Sistergroup relationships of KCNA1/2 and KCNA3/6 support that a large-scale duplication gave rise to the two clusters found in the genome of tetrapods. We analyzed the intergenic regions of KCNA clusters in vertebrates and found that there are only a few conserved sequences shared between tetrapods and teleosts or between paralogous clusters. The orthologous teleost clusters, however, show sequence conservation in these regions. CONCLUSION: The lack of overall conserved sequences in intergenic regions suggests that there are either other processes than regulatory evolution leading to cluster conservation or that the ancestral regulatory relationships among genes in KCNA clusters have been changed together with their regulatory sites. PMID- 17697378 TI - One-step selection of Vaccinia virus-binding DNA aptamers by MonoLEX. AB - BACKGROUND: As a new class of therapeutic and diagnostic reagents, more than fifteen years ago RNA and DNA aptamers were identified as binding molecules to numerous small compounds, proteins and rarely even to complete pathogen particles. Most aptamers were isolated from complex libraries of synthetic nucleic acids by a process termed SELEX based on several selection and amplification steps. Here we report the application of a new one-step selection method (MonoLEX) to acquire high-affinity DNA aptamers binding Vaccinia virus used as a model organism for complex target structures. RESULTS: The selection against complete Vaccinia virus particles resulted in a 64-base DNA aptamer specifically binding to orthopoxviruses as validated by dot blot analysis, Surface Plasmon Resonance, Fluorescence Correlation Spectroscopy and real-time PCR, following an aptamer blotting assay. The same oligonucleotide showed the ability to inhibit in vitro infection of Vaccinia virus and other orthopoxviruses in a concentration-dependent manner. CONCLUSION: The MonoLEX method is a straightforward procedure as demonstrated here for the identification of a high affinity DNA aptamer binding Vaccinia virus. MonoLEX comprises a single affinity chromatography step, followed by subsequent physical segmentation of the affinity resin and a single final PCR amplification step of bound aptamers. Therefore, this procedure improves the selection of high affinity aptamers by reducing the competition between aptamers of different affinities during the PCR step, indicating an advantage for the single-round MonoLEX method. PMID- 17697379 TI - DFsn collaborates with Highwire to down-regulate the Wallenda/DLK kinase and restrain synaptic terminal growth. AB - BACKGROUND: The growth of new synapses shapes the initial formation and subsequent rearrangement of neural circuitry. Genetic studies have demonstrated that the ubiquitin ligase Highwire restrains synaptic terminal growth by down regulating the MAP kinase kinase kinase Wallenda/dual leucine zipper kinase (DLK). To investigate the mechanism of Highwire action, we have identified DFsn as a binding partner of Highwire and characterized the roles of DFsn in synapse development, synaptic transmission, and the regulation of Wallenda/DLK kinase abundance. RESULTS: We identified DFsn as an F-box protein that binds to the RING domain ubiquitin ligase Highwire and that can localize to the Drosophila neuromuscular junction. Loss-of-function mutants for DFsn have a phenotype that is very similar to highwire mutants - there is a dramatic overgrowth of synaptic termini, with a large increase in the number of synaptic boutons and branches. In addition, synaptic transmission is impaired in DFsn mutants. Genetic interactions between DFsn and highwire mutants indicate that DFsn and Highwire collaborate to restrain synaptic terminal growth. Finally, DFsn regulates the levels of the Wallenda/DLK kinase, and wallenda is necessary for DFsn-dependent synaptic terminal overgrowth. CONCLUSION: The F-box protein DFsn binds the ubiquitin ligase Highwire and is required to down-regulate the levels of the Wallenda/DLK kinase and restrain synaptic terminal growth. We propose that DFsn and Highwire participate in an evolutionarily conserved ubiquitin ligase complex whose substrates regulate the structure and function of synapses. PMID- 17697380 TI - Raman and SEM analysis of a biocolonised hot spring travertine terrace in Svalbard, Norway. AB - BACKGROUND: A profile across 8 layers from a fossil travertine terrace from a low temperature geothermal spring located in Svalbard, Norway has been studied using both Raman spectroscopy and SEM (Scanning Electron Microscopy) techniques to identify minerals and organic life signals. RESULTS: Calcite, anatase, quartz, haematite, magnetite and graphite as well as scytonemin, three different carotenoids, chlorophyll and a chlorophyll-like compound were identified as geo- and biosignatures respectively, using 785 and/or 514 nm Raman laser excitation wavelengths. No morphological biosignatures representing remnant microbial signals were detected by high-resolution imaging, although spectral analyses indicated the presence of organics. In contrast, in all layers, Raman spectra identified a series of different organic pigments indicating little to no degradation or change of the organic signatures and thus indicating the preservation of fossil biomarker compounds throughout the life time of the springs despite the lack of remnant morphological indicators. CONCLUSION: With a view towards planetary exploration we discuss the implications of the differences in Raman band intensities observed when spectra were collected with the different laser excitations. We show that these differences, as well as the different detection capability of the 785 and 514 nm laser, could lead to ambiguous compound identification. We show that the identification of bio and geosignatures, as well as fossil organic pigments, using Raman spectroscopy is possible. These results are relevant since both lasers have been considered for miniaturized Raman spectrometers for planetary exploration. PMID- 17697381 TI - Validation of rice genome sequence by optical mapping. AB - BACKGROUND: Rice feeds much of the world, and possesses the simplest genome analyzed to date within the grass family, making it an economically relevant model system for other cereal crops. Although the rice genome is sequenced, validation and gap closing efforts require purely independent means for accurate finishing of sequence build data. RESULTS: To facilitate ongoing sequencing finishing and validation efforts, we have constructed a whole-genome SwaI optical restriction map of the rice genome. The physical map consists of 14 contigs, covering 12 chromosomes, with a total genome size of 382.17 Mb; this value is about 11% smaller than original estimates. 9 of the 14 optical map contigs are without gaps, covering chromosomes 1, 2, 3, 4, 5, 7, 8 10, and 12 in their entirety - including centromeres and telomeres. Alignments between optical and in silico restriction maps constructed from IRGSP (International Rice Genome Sequencing Project) and TIGR (The Institute for Genomic Research) genome sequence sources are comprehensive and informative, evidenced by map coverage across virtually all published gaps, discovery of new ones, and characterization of sequence misassemblies; all totalling ~14 Mb. Furthermore, since optical maps are ordered restriction maps, identified discordances are pinpointed on a reliable physical scaffold providing an independent resource for closure of gaps and rectification of misassemblies. CONCLUSION: Analysis of sequence and optical mapping data effectively validates genome sequence assemblies constructed from large, repeat-rich genomes. Given this conclusion we envision new applications of such single molecule analysis that will merge advantages offered by high resolution optical maps with inexpensive, but short sequence reads generated by emerging sequencing platforms. Lastly, map construction techniques presented here points the way to new types of comparative genome analysis that would focus on discernment of structural differences revealed by optical maps constructed from a broad range of rice subspecies and varieties. PMID- 17697382 TI - Extraordinary diversity among members of the large gene family, 185/333, from the purple sea urchin, Strongylocentrotus purpuratus. AB - BACKGROUND: Recent analysis of immune-related genes within the sea urchin genome revealed a number of large gene families with vertebrate homologues, such as the Toll-like and NOD/NALP-like receptor families and C-type lectins in addition to a rudimentary complement system. Therefore, the immune response of the purple sea urchin appears to be more complex than previously believed. Another component of the sea urchin immune response is an unusual family of mRNAs, known as 185/333, which is strongly upregulated in response to pathogen challenge. The work presented here indicates that this family of transcripts is derived from an unexpectedly diverse gene family. RESULTS: The 185/333 genes are small (< 2 kb) with only two exons. Their extraordinary diversity was exemplified by 121 unique sequences identified from 171 cloned genes. Sequences from the second exons were aligned optimally by introducing large gaps, which defined blocks of sequence known as elements. Genes were defined by the presence or absence of elements. Phylogenetic analysis defined five intron types which, when combined with the exon element patterns resulted in 31 gene patterns, 14 of which were not described previously. Sequence diversity was present in all elements, and was higher in the intron than the exons. Repeats within the sequence facilitated multiple alignments, of which two were analyzed in detail. Although the two alignments differed in length, number of elements, and number of patterns, both were about equally accurate at describing the 185/333 sequences. The genes were closely linked and flanked by short repeats. The repeats within and between the genes may promote their diversification through gene conversion, recombination, and meiotic mispairing. CONCLUSION: The diversity of the 185/333 gene family represents an intriguing addition to what is known about the S. purpuratus immune response, and provides further evidence that invertebrate immune systems are neither simple nor static. PMID- 17697383 TI - Biomarker discovery for colon cancer using a 761 gene RT-PCR assay. AB - BACKGROUND: Reverse transcription PCR (RT-PCR) is widely recognized to be the gold standard method for quantifying gene expression. Studies using RT-PCR technology as a discovery tool have historically been limited to relatively small gene sets compared to other gene expression platforms such as microarrays. We have recently shown that TaqMan RT-PCR can be scaled up to profile expression for 192 genes in fixed paraffin-embedded (FPE) clinical study tumor specimens. This technology has also been used to develop and commercialize a widely used clinical test for breast cancer prognosis and prediction, the Onco typeDX assay. A similar need exists in colon cancer for a test that provides information on the likelihood of disease recurrence in colon cancer (prognosis) and the likelihood of tumor response to standard chemotherapy regimens (prediction). We have now scaled our RT-PCR assay to efficiently screen 761 biomarkers across hundreds of patient samples and applied this process to biomarker discovery in colon cancer. This screening strategy remains attractive due to the inherent advantages of maintaining platform consistency from discovery through clinical application. RESULTS: RNA was extracted from formalin fixed paraffin embedded (FPE) tissue, as old as 28 years, from 354 patients enrolled in NSABP C-01 and C-02 colon cancer studies. Multiplexed reverse transcription reactions were performed using a gene specific primer pool containing 761 unique primers. PCR was performed as independent TaqMan reactions for each candidate gene. Hierarchal clustering demonstrates that genes expected to co-express form obvious, distinct and in certain cases very tightly correlated clusters, validating the reliability of this technical approach to biomarker discovery. CONCLUSION: We have developed a high throughput, quantitatively precise multi-analyte gene expression platform for biomarker discovery that approaches low density DNA arrays in numbers of genes analyzed while maintaining the high specificity, sensitivity and reproducibility that are characteristics of RT-PCR. Biomarkers discovered using this approach can be transferred to a clinical reference laboratory setting without having to re-validate the assay on a second technology platform. PMID- 17697384 TI - Cardiovascular benefits and safety profile of acarbose therapy in prediabetes and established type 2 diabetes. AB - Dysglycaemic disease is one of the most important health issues facing the world in the 21st century. Patients with type 2 diabetes and individuals with prediabetes are at risk of developing macrovascular and microvascular complications. Long-term management strategies are therefore required that are effective at controlling dysglycaemia, well tolerated and, ideally, offer additional cardiovascular disease (CVD) risk-reduction benefits. The efficacy, safety and tolerability of the alpha-glucosidase inhibitor acarbose have been well-established in a wide range of patient populations in both clinical and community trials. In addition, acarbose has been shown to reduce cardiovascular complications in type 2 diabetes and prevent hypertension and CVD in individuals with impaired glucose tolerance (IGT). Acarbose has a very good safety profile and, owing to its straightforward, non-systemic mode of action, avoids most adverse events. The most common side-effects of acarbose are mild-to-moderate gastrointestinal complaints that subside as treatment continues. They can be minimised through the use of an appropriate stepwise dosing regimen and careful choice of diet. Acarbose is therefore a valuable option for the management of type 2 diabetes and, as the only oral antidiabetes agent approved for the treatment of prediabetes, can help to improve clinical management across the dysglycaemic disease continuum. PMID- 17697385 TI - Longitudinal increases in mitochondrial DNA levels in blood cells are associated with survival in critically ill patients. AB - BACKGROUND: Mitochondrial dysfunction may be causally related to the pathogenesis of organ failure in critically ill patients. Decreased mitochondrial DNA (mtDNA) levels have been associated with mitochondrial dysfunction and were investigated here in relation to short-term (31-day) survival. METHODS: This was a prospective longitudinal cohort study of 28 mechanically ventilated critically ill adults admitted to a single center tertiary care intensive care unit (ICU) with hypotension secondary to cardiogenic (N = 13), septic (N = 14) or hypovolemic (N = 1) disease processes. Clinical data and blood were collected at baseline and patients were followed until they expired or left the ICU. Blood was collected every Monday, Wednesday and Friday, and the buffycoat relative mtDNA/nuclear DNA (nDNA) ratio was determined. An archived pool of healthy controls was also studied. RESULTS: At baseline, the patients' mtDNA/nDNA ratio was 30% lower than a pool of 24 healthy controls (0.76 versus 1.09) and was not different between short-term survivors and non-survivors (0.74 +/- 0.05 (N = 16) versus 0.79 +/- 0.06 (N = 12), p = 0.49). By day 4, the percent mtDNA/nDNA change from baseline in survivors was significantly different from that in non-survivors (+29.5% versus -5.7%, p = 0.03). It also tended to be higher in survivors at last measurement (+38.4% versus +7.1%, p = 0.06). There was a weak correlation between within patient mtDNA/nDNA and platelet count (r = 0.20, p = 0.03) but not with Sequential Organ Failure Assessment (SOFA) scores (r = 0.12, p = 0.23). The mtDNA associations remained after adjustment for platelet. CONCLUSION: Blood mtDNA levels appeared initially low, increased over time in patients who ultimately survived, and remained low in those who did not. This is consistent with mitochondrial recovery being associated with survival and warrants further investigation as a marker of mitochondrial alterations and outcome in critical illness. PMID- 17697386 TI - Do horizontal propulsive forces influence the nonlinear structure of locomotion? AB - BACKGROUND: Several investigations have suggested that changes in the nonlinear gait dynamics are related to the neural control of locomotion. However, no investigations have provided insight on how neural control of the locomotive pattern may be directly reflected in changes in the nonlinear gait dynamics. Our simulations with a passive dynamic walking model predicted that toe-off impulses that assist the forward motion of the center of mass influence the nonlinear gait dynamics. Here we tested this prediction in humans as they walked on the treadmill while the forward progression of the center of mass was assisted by a custom built mechanical horizontal actuator. METHODS: Nineteen participants walked for two minutes on a motorized treadmill as a horizontal actuator assisted the forward translation of the center of mass during the stance phase. All subjects walked at a self-select speed that had a medium-high velocity. The actuator provided assistive forces equal to 0, 3, 6 and 9 percent of the participant's body weight. The largest Lyapunov exponent, which measures the nonlinear structure, was calculated for the hip, knee and ankle joint time series. A repeated measures one-way analysis of variance with a t-test post hoc was used to determine significant differences in the nonlinear gait dynamics. RESULTS: The magnitude of the largest Lyapunov exponent systematically increased as the percent assistance provided by the mechanical actuator was increased. CONCLUSION: These results support our model's prediction that control of the forward progression of the center of mass influences the nonlinear gait dynamics. The inability to control the forward progression of the center of mass during the stance phase may be the reason the nonlinear gait dynamics are altered in pathological populations. However, these conclusions need to be further explored at a range of walking speeds. PMID- 17697387 TI - Planning an integrated disease surveillance and response system: a matrix of skills and activities. AB - BACKGROUND: The threat of a global influenza pandemic and the adoption of the World Health Organization (WHO) International Health Regulations (2005) highlight the value of well-coordinated, functional disease surveillance systems. The resulting demand for timely information challenges public health leaders to design, develop and implement efficient, flexible and comprehensive systems that integrate staff, resources, and information systems to conduct infectious disease surveillance and response. To understand what resources an integrated disease surveillance and response system would require, we analyzed surveillance requirements for 19 priority infectious diseases targeted for an integrated disease surveillance and response strategy in the WHO African region. METHODS: We conducted a systematic task analysis to identify and standardize surveillance objectives, surveillance case definitions, action thresholds, and recommendations for 19 priority infectious diseases. We grouped the findings according to surveillance and response functions and related them to community, health facility, district, national and international levels. RESULTS: The outcome of our analysis is a matrix of generic skills and activities essential for an integrated system. We documented how planners used the matrix to assist in finding gaps in current systems, prioritizing plans of action, clarifying indicators for monitoring progress, and developing instructional goals for applied epidemiology and in-service training programs. CONCLUSION: The matrix for Integrated Disease Surveillance and Response (IDSR) in the African region made clear the linkage between public health surveillance functions and participation across all levels of national health systems. The matrix framework is adaptable to requirements for new programs and strategies. This framework makes explicit the essential tasks and activities that are required for strengthening or expanding existing surveillance systems that will be able to adapt to current and emerging public health threats. PMID- 17697388 TI - Body fat measurement by bioelectrical impedance and air displacement plethysmography: a cross-validation study to design bioelectrical impedance equations in Mexican adults. AB - BACKGROUND: The study of body composition in specific populations by techniques such as bio-impedance analysis (BIA) requires validation based on standard reference methods. The aim of this study was to develop and cross-validate a predictive equation for bioelectrical impedance using air displacement plethysmography (ADP) as standard method to measure body composition in Mexican adult men and women. METHODS: This study included 155 male and female subjects from northern Mexico, 20-50 years of age, from low, middle, and upper income levels. Body composition was measured by ADP. Body weight (BW, kg) and height (Ht, cm) were obtained by standard anthropometric techniques. Resistance, R (ohms) and reactance, Xc (ohms) were also measured. A random-split method was used to obtain two samples: one was used to derive the equation by the "all possible regressions" procedure and was cross-validated in the other sample to test predicted versus measured values of fat-free mass (FFM). RESULTS AND DISCUSSION: The final model was: FFM (kg) = 0.7374 * (Ht2 /R) + 0.1763 * (BW) - 0.1773 * (Age) + 0.1198 * (Xc) - 2.4658. R2 was 0.97; the square root of the mean square error (SRMSE) was 1.99 kg, and the pure error (PE) was 2.96. There was no difference between FFM predicted by the new equation (48.57 +/- 10.9 kg) and that measured by ADP (48.43 +/- 11.3 kg). The new equation did not differ from the line of identity, had a high R2 and a low SRMSE, and showed no significant bias (0.87 +/- 2.84 kg). CONCLUSION: The new bioelectrical impedance equation based on the two-compartment model (2C) was accurate, precise, and free of bias. This equation can be used to assess body composition and nutritional status in populations similar in anthropometric and physical characteristics to this sample. PMID- 17697389 TI - Non-pharmaceutical public health interventions for pandemic influenza: an evaluation of the evidence base. AB - BACKGROUND: In an influenza pandemic, the benefit of vaccines and antiviral medications will be constrained by limitations on supplies and effectiveness. Non pharmaceutical public health interventions will therefore be vital in curtailing disease spread. However, the most comprehensive assessments of the literature to date recognize the generally poor quality of evidence on which to base non pharmaceutical pandemic planning decisions. In light of the need to prepare for a possible pandemic despite concerns about the poor quality of the literature, combining available evidence with expert opinion about the relative merits of non pharmaceutical interventions for pandemic influenza may lead to a more informed and widely accepted set of recommendations. We evaluated the evidence base for non-pharmaceutical public health interventions. Then, based on the collective evidence, we identified a set of recommendations for and against interventions that are specific to both the setting in which an intervention may be used and the pandemic phase, and which can be used by policymakers to prepare for a pandemic until scientific evidence can definitively respond to planners' needs. METHODS: Building on reviews of past pandemics and recent historical inquiries, we evaluated the relative merits of non-pharmaceutical interventions by combining available evidence from the literature with qualitative and quantitative expert opinion. Specifically, we reviewed the recent scientific literature regarding the prevention of human-to-human transmission of pandemic influenza, convened a meeting of experts from multiple disciplines, and elicited expert recommendation about the use of non-pharmaceutical public health interventions in a variety of settings (healthcare facilities; community-based institutions; private households) and pandemic phases (no pandemic; no US pandemic; early localized US pandemic; advanced US pandemic). RESULTS: The literature contained a dearth of evidence on the efficacy or effectiveness of most non-pharmaceutical interventions for influenza. In an effort to inform decision-making in the absence of strong scientific evidence, the experts ultimately endorsed hand hygiene and respiratory etiquette, surveillance and case reporting, and rapid viral diagnosis in all settings and during all pandemic phases. They also encouraged patient and provider use of masks and other personal protective equipment as well as voluntary self-isolation of patients during all pandemic phases. Other non-pharmaceutical interventions including mask-use and other personal protective equipment for the general public, school and workplace closures early in an epidemic, and mandatory travel restrictions were rejected as likely to be ineffective, infeasible, or unacceptable to the public. CONCLUSION: The demand for scientific evidence on non-pharmaceutical public health interventions for influenza is pervasive, and present policy recommendations must rely heavily on expert judgment. In the absence of a definitive science base, our assessment of the evidence identified areas for further investigation as well as non-pharmaceutical public health interventions that experts believe are likely to be beneficial, feasible and widely acceptable in an influenza pandemic. PMID- 17697390 TI - Gene expression studies of developing bovine longissimus muscle from two different beef cattle breeds. AB - BACKGROUND: The muscle fiber number and fiber composition of muscle is largely determined during prenatal development. In order to discover genes that are involved in determining adult muscle phenotypes, we studied the gene expression profile of developing fetal bovine longissimus muscle from animals with two different genetic backgrounds using a bovine cDNA microarray. Fetal longissimus muscle was sampled at 4 stages of myogenesis and muscle maturation: primary myogenesis (d 60), secondary myogenesis (d 135), as well as beginning (d 195) and final stages (birth) of functional differentiation of muscle fibers. All fetuses and newborns (total n = 24) were from Hereford dams and crossed with either Wagyu (high intramuscular fat) or Piedmontese (GDF8 mutant) sires, genotypes that vary markedly in muscle and compositional characteristics later in postnatal life. RESULTS: We obtained expression profiles of three individuals for each time point and genotype to allow comparisons across time and between sire breeds. Quantitative reverse transcription-PCR analysis of RNA from developing longissimus muscle was able to validate the differential expression patterns observed for a selection of differentially expressed genes, with one exception. We detected large-scale changes in temporal gene expression between the four developmental stages in genes coding for extracellular matrix and for muscle fiber structural and metabolic proteins. FSTL1 and IGFBP5 were two genes implicated in growth and differentiation that showed developmentally regulated expression levels in fetal muscle. An abundantly expressed gene with no functional annotation was found to be developmentally regulated in the same manner as muscle structural proteins. We also observed differences in gene expression profiles between the two different sire breeds. Wagyu-sired calves showed higher expression of fatty acid binding protein 5 (FABP5) RNA at birth. The developing longissimus muscle of fetuses carrying the Piedmontese mutation shows an emphasis on glycolytic muscle biochemistry and a large-scale up regulation of the translational machinery at birth. We also document evidence for timing differences in differentiation events between the two breeds. CONCLUSION: Taken together, these findings provide a detailed description of molecular events accompanying skeletal muscle differentiation in the bovine, as well as gene expression differences that may underpin the phenotype differences between the two breeds. In addition, this study has highlighted a non-coding RNA, which is abundantly expressed and developmentally regulated in bovine fetal muscle. PMID- 17697392 TI - Recently published papers: delivery, volume and outcome--what is best for our patient? AB - Many studies have demonstrated that prompt appropriate treatment for the critically ill patient improves outcome. Moving patients to the best place for instituting care, however, is not always associated with improved outcome. Recent studies on delivering patients to the best place for treatment as well as further work on the effects of volume are discussed. Finally, a large retrospective cohort study comparing outcomes of patients treated with continuous venovenous haemofiltration or intermittent haemodialysis is outlined. PMID- 17697391 TI - BCoR-L1 variation and breast cancer. AB - INTRODUCTION: BRCA1 is involved in numerous essential processes in the cell, and the effects of BRCA1 dysfunction in breast cancer carcinogenesis are well described. Many of the breast cancer susceptibility genes such as BRCA2, p53, ATM, CHEK2, and BRIP1 encode proteins that interact with BRCA1. BCL6 corepressor like 1 (BCoR-L1) is a newly described BRCA1-interacting protein that displays high homology to several proteins known to be involved in the fundamental processes of DNA damage repair and transcription regulation. BCoR-L1 has been shown to play a role in transcription corepression, and expression of the X linked BCoR-L1 gene has been reported to be dysregulated in breast cancer subjects. BCoR-L1 is located on the X chromosome and is subject to X inactivation. METHODS: We performed mutation analysis of 38 BRCA1/2 mutation negative breast cancer families with male breast cancer, prostate cancer, and/or haplotype sharing around BCoR-L1 to determine whether there is a role for BCoR-L1 as a high-risk breast cancer predisposition gene. In addition, we conducted quantitative real-time PCR (qRT-PCR) on lymphoblastoid cell lines (LCLs) from the index cases from these families and a number of cancer cell lines to assess the role of BCoR-L1 dysregulation in cancer and cancer families. RESULTS: Very little variation was detected in the coding region, and qRT-PCR analysis revealed that BCoR-L1 expression is highly variable in cancer-free subjects, high-risk breast cancer patients, and cancer cell lines. We also report the investigation of a new expression control, DIDO1 (death inducer-obliterator 1), that is superior to GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and UBC (ubiquitin C) for analysis of expression in LCLs. CONCLUSION: Our results suggest that BCoR-L1 expression does not play a large role in predisposition to familial breast cancer. PMID- 17697393 TI - Visual attention and self-regulation of driving among older adults. AB - BACKGROUND: With the number of older drivers increasing, self-regulation of driving has been proposed as a viable means of balancing the autonomy of older adults against the sometimes competing demand of public safety. In this study, we investigate self-regulation of driving among a group of older adults with varying functional abilities. METHOD: Participants in the study comprised 1,543 drivers aged 75 years or older. They completed an objective measure of visual attention from which crash risk was estimated, and self-report measures of driving avoidance, driving exposure, physical functioning, general health status, and vision. Crash records were obtained from the State Department of Public Safety. RESULTS: Overall, participants were most likely to avoid driving in bad weather followed by driving at night, driving on high traffic roads, driving in unfamiliar areas, and making left-hand turns across oncoming traffic. With the exception of driving at night, drivers at higher risk of crashes generally reported greater avoidance of these driving situations than lower risk drivers. However, across all driving situations a significant proportion of higher risk drivers did not restrict their driving. In general, self-regulation of driving did not result in reduced social engagement. CONCLUSION: Some older drivers with visual attention impairments do not restrict their driving in difficult situations. There is a need for physicians and family members to discuss driving behaviors with older adults routinely to ensure their safety. The association between visual attention and driving restriction also has implications for interventions aimed at preserving mobility in the elderly. PMID- 17697394 TI - Genetic polymorphisms in the 5-hydroxytryptamine type 3B receptor gene and paroxetine-induced nausea. AB - Selective serotonin reuptake inhibitor (SSRI)-induced nausea can be severe enough to lead to early treatment discontinuation. However, it is currently not possible to predict the occurrence of nausea before the initiation of SSRI treatment. In this study, we investigated the effect of genetic polymorphisms in the 5 hydroxytryptamine type 2A, 3A, and 3B (5-HT3B) receptors, 5-HT transporter, and CYP2D6 genes on the incidence of paroxetine-induced nausea. A consecutive series of 72 Japanese patients with depressive or anxiety disorders were treated with paroxetine. Paroxetine-induced nausea was assessed by a pharmacist and was observed in 29.2% of the patients. A significant (nominal p=0.00286) association was found between the incidence of nausea and the -100_-102AAG insertion/deletion polymorphism of the 5-HT3B receptor gene. No significant associations were observed between the other genetic polymorphisms and the incidence of nausea. The -100_-102AAG deletion variant of the 5-HT3B receptor gene may affect paroxetine induced nausea. PMID- 17697395 TI - Antidepressive therapy with escitalopram improves mood, cognitive symptoms, and identity memory for angry faces in elderly depressed patients. AB - Depression is a common disorder in the elderly handicapping patients with affective and cognitive symptoms. Because of their good tolerability relative to the older tricyclic compounds, selective serotonin reuptake inhibitors (SSRIs) are increasingly used for the treatment of depression in the elderly. Little is known about their effects on cognition in elderly patients. In the present 4-wk, single-centre, randomized, open-label trial we investigated the antidepressive effects of escitalopram, an SSRI, in 18 elderly depressed patients [mean age (+/ s.e.m.) 76.2+/-1.8 yr] compared to 22 healthy age-matched controls (mean age 76.9+/-1.8 yr). Affective and cognitive symptoms were assessed using the Geriatric Depression Scale (GDS), Mini-Mental State Examination (MMSE), and a face portrait recognition test to assess memory for happy and angry faces. Depressed patients prior to treatment had markedly reduced memory performance. Treatment with escitalopram improved affective and cognitive symptoms significantly. Furthermore, escitalopram treatment improved memory for negative facial stimuli. Control subjects confirmed the well- established memory bias favouring recognition of identities acquired with happy expressions. Importantly, this bias was absent in depressed patients prior to, but also after treatment. In conclusion, escitalopram, even after a relatively short treatment period, was effective in treating depression in the elderly and may help improve cognitive performance for social stimuli. PMID- 17697397 TI - Propofol attenuates ischaemia-reperfusion injury in the rat heart in vivo. AB - BACKGROUND: We have previously demonstrated, in the isolated rat heart, that propofol attenuates hydrogen peroxide-induced damage and ischaemia-reperfusion injury, and that the beneficial effect of propofol is correlated with reduction of the lipid peroxidation. This study was designed to evaluate whether propofol has a cardioprotective effect against ischaemia-reperfusion injury in a rat model in vivo. METHODS: Adult rats were anaesthetized with pentobarbital 10 mg kg(-1) h(-1) alone (control group), pentobarbital 10 or 20 mg kg(-1) h(-1) + Intralipid as a vehicle (Pent-10, Pent-20 group), propofol 10 or 20 mg kg(-1) h(-1) (Prop 10, Prop-20 group) intravenously throughout the experiment. The left anterior descending coronary artery was occluded for 30 min followed by 120 min of reperfusion. Infarct size was determined at the end of reperfusion. The tissue concentration of malondialdehyde was measured at 30 min after reperfusion to evaluate lipid peroxidation. RESULTS: The infarct sizes (% of area at risk) were significantly smaller in the Prop-10 (54 +/- 11%; P < 0.01 vs. control) and Prop 20 (39 +/- 8%; P < 0.01 vs. control) groups than in the control (68 +/- 9%), Pent 10 (69 +/- 13%) and Pent-20 (68 +/- 14%) groups (n = 12). In the Pent-10 and Pent 20 groups, ischaemia-reperfusion produced significant increases in the values for tissue malondialdehyde (0.72 +/- 0.24 micromol mg protein-1; P < 0.05 and 0.63 +/ 0.33 micromol mg protein-1; P < 0.05 vs. 0.46 +/- 0.22 micromol mg protein-1 in non-ischaemic hearts, n = 8). However, the values of malondialdehyde in the Prop 10 and -20 groups were suppressed by 41% and 63%, respectively, compared with the Pent-10 group (P < 0.01). CONCLUSION: Our results suggest that propofol could be cardioprotective against ischaemia-reperfusion injury dose dependently in a rat model in vivo and that the beneficial action of propofol may be correlated with its antioxidant effect. PMID- 17697396 TI - Type I and type II fatty acid biosynthesis in Eimeria tenella: enoyl reductase activity and structure. AB - Apicomplexan parasites of the genus Eimeria are the major causative agent of avian coccidiosis, leading to high economic losses in the poultry industry. Recent results show that Eimeria tenella harbours an apicoplast organelle, and that a key biosynthetic enzyme, enoyl reductase, is located in this organelle. In related parasites, enoyl reductase is one component of a type II fatty acid synthase (FAS) and has proven to be an attractive target for antimicrobial compounds. We cloned and expressed the mature form of E. tenella enoyl reductase (EtENR) for biochemical and structural studies. Recombinant EtENR exhibits NADH dependent enoyl reductase activity and is inhibited by triclosan with an IC50 value of 60 nm. The crystal structure of EtENR reveals overall similarity with other ENR enzymes; however, the active site of EtENR is unoccupied, a state rarely observed in other ENR structures. Furthermore, the position of the central beta-sheet appears to block NADH binding and would require significant movement to allow NADH binding, a feature not previously seen in the ENR family. We analysed the E. tenella genomic database for orthologues of well-characterized bacterial and apicomplexan FAS enzymes and identified 6 additional genes, suggesting that E. tenella contains a type II FAS capable of synthesizing saturated, but not unsaturated, fatty acids. Interestingly, we also identified sequences that appear to encode multifunctional type I FAS enzymes, a feature also observed in Toxoplasma gondii, highlighting the similarity between these apicomplexan parasites. PMID- 17697398 TI - The effects of regular consumption of short-chain fructo-oligosaccharides on digestive comfort of subjects with minor functional bowel disorders. AB - A comparative, randomised, double-blind trial was performed in the medical departments of five hospitals to study the effects of regular consumption of short-chain fructo-oligosaccharides (sc-FOS) on the digestive comfort of subjects with minor functional bowel disorders (FBD). In step 1, 2235 subjects were questioned to assess the incidence and intensity of digestive disorders. In step 2, 105 of these patients diagnosed with minor FBD were randomised into two groups to receive either 5 g sc-FOS or 5 g placebo (sucrose and maltodextrins) per d over a 6-week period. The incidence and intensity of digestive disorders were assessed at the end of the treatment period (day 43) using the step 1 questionnaires. A quality-of-life questionnaire was also completed at the start and end of the treatment period to assess potential effects on well-being and social performance. In step 1, 44 % of the subjects questioned presented FBD, of whom 57.1 % suffered from minor FBD. In step 2, on day 43, the intensity of digestive disorders decreased by 43.6 % in the sc-FOS group v. a 13.8 % increase in the placebo group (P = 0.026). Symptoms were experienced less frequently by 75.0 % of subjects in the sc-FOS group, while 53.8 % of controls experienced no change (P = 0.064). Using the functional digestive disorders quality of life questionnaire, the discomfort item scores increased in the sc-FOS group (P = 0.031). However, expressed as change in quality of life (improvement, worsening or unchanged), daily activities were significantly improved in the sc-FOS group (P = 0.022). Regular consumption of sc-FOS may improve digestive comfort in a working population not undergoing medical treatment. PMID- 17697399 TI - Docosahexaenoic acid is associated with endosteal circumference in long bones in young males with cystic fibrosis. AB - In children, but not adults with cystic fibrosis (CF), associations between essential fatty acids (FA) and bone mass have been reported. Low bone mineral density (BMD) is common in these patients. Previously we found a normal annual increase of BMD, suggesting a potential for attaining normal bone mass. The aim of the present study was to investigate phospholipid FA pattern in relation to bone in young adult men with CF compared with healthy controls. Fourteen male patients with CF were compared with forty-two healthy controls, using dual-energy X-ray absorptiometry for total bone, lumbar spine and femur and peripheral quantitative computerised tomography for tibia and radius. A questionnaire concerning physical activity and nutrition was used. FA in serum phospholipids were measured using capillary GLC. CF patients did not differ in physical activity and anthropometry from controls. There were no differences in bone parameters between the two groups, but patients chronically colonised with Pseudomonas aeruginosa had lower BMD than non-colonised patients. The trabecular BMD in the tibia differed between patients and controls, but not after adjustment for age and weight. The endosteal circumference of the radius was significantly associated with serum phospholipid concentration of DHA and inversely with the n 6:n-3 FA ratio in CF patients but not in controls. The present study showed that young physically active adult males with classical CF obtained similar bone mass as controls, although influenced by pseudomonas colonisation. The association between DHA and long bone endosteal circumference suggested a later peak bone mass in those with CF compared with controls. PMID- 17697400 TI - Effect of 3-month treatment of children and adolescents with familial and polygenic hypercholesterolaemia with a soya-substituted diet. AB - Soya protein has well-documented beneficial effects on serum lipid levels in adults, the potential beneficial effect of a prolonged soya protein-substituted diet in children and adolescents with familial (FH) and polygenic hypercholesterolaemia (PH) being unknown. To assess the effect of 3 months' treatment of children and adolescents with FH and PH with a soya-substituted diet on serum lipids and lipoproteins, twenty-three children and adolescents were initially assigned to a standard phase 1 diet for 3 months, after which they were instructed to include soya protein (0.25-0.5 g/kg body weight) into their diet for 3 months. Sixteen patients (ten males and six females, thirteen with FH (eight males and five females), three with PH (two males and one female); mean age 8.8 (sd 4.2) years (range 4-18 years); mean BMI 16.7 (sd 2.6) kg/m2)) completed both phases. The phase 1 diet resulted in a significant reduction of total cholesterol (TC), LDL-cholesterol and apo B by 12.3, 11.8 and 10.6 %, respectively, HDL-cholesterol, TAG, apo A1 and lipoprotein(a) not being different. Dietary intake of soya protein during phase 2 resulted in a significant decrease of TC, LDL-cholesterol and apo B by 7.7, 6.4, and 12.6 %, respectively. TAG, HDL-cholesterol, apo A1, and lipoprotein(a) did not change significantly. Substitution of soya protein for animal protein in a low-fat, fat modified diet is of additional benefit in many, but not all, children and adolescents with FH and PH when aiming at lowering serum TC, LDL and apo B. It seems to be a feasible long-term dietary lifestyle intervention and may grant additive benefit in the prevention of early vascular disease. PMID- 17697401 TI - Dietary patterns of the Andean population of Puna and Quebrada of Humahuaca, Jujuy, Argentina. AB - The aim of the present study was to describe dietary patterns in a representative sample from Puna and Quebrada of Humahuaca, Jujuy, Argentina. A cross-sectional nutritional survey was carried out in a representative sample (n 1236) of individuals from these regions. For the present study, only children aged 2-9 years (n 360), adolescents aged 10-18 years (n 223) and adults aged 18 years or over (n 465) were considered. Breast-fed children, pregnant women and lactating women were excluded. Dietary data collection methods comprised one 24 h recall and a semi-quantitative FFQ. We used principal component (PC) analyses to identify prevailing dietary patterns. Multiple linear regression analyses were performed to assess the determinants of the identified dietary patterns. Two dominant PC were identified: PC1 reflected a 'Western-like' diet with an emphasis on not-autochthon foods. This pattern tended to be present in urban areas of the Quebrada region and was associated with a younger age, a higher level of development, and a worse diet quality. PC2 reflected an 'Andean-like' diet including a variety of autochthon crops. This was preferred by individuals living in rural areas from Puna with a high level of development during the post-harvest season, and was associated with a greater diet quality. These results suggest that the nutrition transition phenomenon is a reality in certain sectors of this population and might be one of the leading causes of the observed double burden of malnutrition. PMID- 17697402 TI - Disruption of lipid metabolism in the liver of the pregnant rat fed folate deficient and methyl donor-deficient diets. AB - The importance of folic acid and the methionine cycle in fetal development is well recognised even though the mechanism has not been established. Since the cycle is active in the maternal liver, poor folate status may modify hepatic metabolism. Pregnant rats were fed diets deficient in folic acid (-F) or in three key methyl donors, folic acid, choline and methionine (-FLMLC) and the maternal liver was analysed on day 21 of gestation. Two-dimensional gel electrophoresis of soluble proteins identified differentially abundant proteins, which could be allocated into nine functional groups. Five involved in metabolic processes, namely, folate/methionine cycle, tyrosine metabolism, protein metabolism, energy metabolism and lipid metabolism, and three in cellular processes, namely, endoplasmic reticulum function, bile production and antioxidant defence. The mRNA for sterol regulatory element-binding protein-1c and acetyl-CoA carboxylase-1 (fatty acid synthesis) were decreased by both -F and -FLMLC diets. The mRNA for PPARalpha and PPARgamma and carnitine palmitoyl transferase (fatty acid oxidation) were increased in the animals fed the -FLMLC diets. Changes in the abundance of proteins associated with intracellular lipid transport suggest that folate deficiency interferes with lipid export. Reduced fatty acid synthesis appeared to prevent steatosis in animals fed the -F diet. Even with increased oxidation, TAG concentrations were approximately three-fold higher in animals fed the -FLMLC diet and were associated with an increase in the relative abundance of proteins associated with oxidative stress. Fetal development may be indirectly affected by these changes in hepatic lipid metabolism. PMID- 17697403 TI - Effect of folic acid on prenatal alcohol-induced modification of brain proteome in mice. AB - Maternal alcohol consumption during pregnancy can induce central nervous system abnormalities in the fetus, and folic acid supplementation can reverse some of the effects. The objective of the present study was to investigate prenatal alcohol exposure-induced fetal brain proteome alteration and the protective effect of folic acid using proteomic techniques. Alcohol (5.0 g/kg) was given intragastrically from gestational day (GD) 6 to 15, with or without 60.0 mg folic acid/kg given intragastrically during GD 1-16 to pregnant Balb/c mice. The control group received distilled water only. Results of litter evaluation on GD 18 showed that supplementation of folic acid reversed the prevalence of microcephaly induced by alcohol. Proteomic analysis indicated that, under the dosage of the present investigation, folic acid mainly reversed the alcohol altered proteins involved in energy production, signal pathways and protein translation, which are all important for central nervous system development. PMID- 17697404 TI - Folic acid under scrutiny. PMID- 17697405 TI - Free fucose is a danger signal to human intestinal epithelial cells. AB - Fucose is present in foods, and it is a major component of human mucin glycoproteins and glycolipids. l-Fucose can also be found at the terminal position of many cell-surface oligosaccharide ligands that mediate cell recognition and adhesion-signalling pathways. Mucin fucose can be released through the hydrolytic activity of pathogens and indigenous bacteria, leading to the release of free fucose into the intestinal lumen. The immunomodulating effects of free fucose on intestinal epithelial cells (enterocyte-like Caco-2) were investigated. It was found that the presence of l-fucose up regulated genes and secretion of their encoded proteins that are involved in both the innate and adaptive immune responses, possibly via the toll-like receptor-2 signalling pathway. These include TNFSF5, TNFSF7, TNF-alpha, IL12, IL17 and IL18. Besides modulating immune reactions in differentiated Caco-2 cells, fucose induced a set of cytokine genes that are involved in the development and proliferation of immune cells. These include the bone morphogenetic proteins (BMP) BMP2, BMP4, IL5, thrombopoietin and erythropoietin. In addition, the up regulated gene expression of fibroblast growth factor-2 may help to promote epithelial cell restitution in conjunction with the enhanced expression of transforming growth factor-beta mRNA. Since the exogenous fucose was not metabolised by the differentiated Caco-2 cells as a carbon source, the reactions elicited were suggested to be a result of the direct interaction of fucose and differentiated Caco-2 cells. The presence of free fucose may signal the invasion of mucin hydrolysing microbial cells and breakage of the mucosal barrier. The intestinal epithelial cells respond by up regulation and secretion of cytokines, pre-empting the actual invasion of pathogens. PMID- 17697406 TI - Co-ingestion of leucine with protein does not further augment post-exercise muscle protein synthesis rates in elderly men. AB - Leucine has been suggested to have the potential to modulate muscle protein metabolism by increasing muscle protein synthesis. The objective of this study was to investigate the surplus value of the co-ingestion of free leucine with protein hydrolysate and carbohydrate following physical activity in elderly men. Eight elderly men (mean age 73 +/- 1 years) were randomly assigned to two cross over treatments consuming either carbohydrate and protein hydrolysate (CHO+PRO) or carbohydrate, protein hydrolysate with additional leucine (CHO+PRO+leu) after performing 30 min of standardized physical activity. Primed, continuous infusions with L-[ring-(13)C(6)]phenylalanine and L-[ring-(2)H(2)]tyrosine were applied, and blood and muscle samples were collected to assess whole-body protein turnover as well as protein fractional synthetic rate in the vastus lateralis muscle over a 6 h period. Whole-body protein breakdown and synthesis rates were not different between treatments. Phenylalanine oxidation rates were significantly lower in the CHO+PRO+leu v. CHO+PRO treatment. As a result, whole-body protein balance was significantly greater in the CHO+PRO+leu compared to the CHO+PRO treatment (23.8 (SEM 0.3) v. 23.2 (SEM 0.3) micromol/kg per h, respectively; P < 0.05). Mixed muscle fractional synthetic rate averaged 0.081 (SEM 0.003) and 0.082 (SEM 0.006) %/h in the CHO+PRO+leu and CHO+PRO treatment, respectively (NS). Co-ingestion of leucine with carbohydrate and protein following physical activity does not further elevate muscle protein fractional synthetic rate in elderly men when ample protein is ingested. PMID- 17697407 TI - fMRI detection of early neural dysfunction in preclinical Huntington's disease. AB - Neuropsychological and neuroimaging changes have been observed in individuals with the Huntington's disease (HD) gene expansion prior to the onset of manifest HD. This cross-sectional fMRI study of preclinical HD (pre-HD) individuals was conducted to determine if functional brain changes precede deficits in behavioral performance and striatal atrophy. Twenty-six pre-HD and 13 demographically matched healthy participants performed a time reproduction task while undergoing fMRI scanning. Pre-HD participants were divided into two groups (n=13 each): FAR (>12 years to estimated onset [YEO] of manifest HD) and CLOSE (<12 YEO). The CLOSE group demonstrated behavioral deficits, striatal atrophy, and reduced neural activation in the left putamen, SMA, left anterior insula and right inferior frontal gyrus. The FAR group showed reduced neural activation in the right anterior cingulate and right anterior insula. The FAR group also demonstrated increased neural activation in the left sensorimotor, left medial frontal gyrus, left precentral gyrus, bilateral superior temporal gyri and right cerebellum. The fMRI changes in the FAR group occurred in the relative absence of striatal atrophy and behavioral performance deficits. These results suggest that fMRI is sensitive to neural dysfunction occurring more than 12 years prior to the estimated onset of manifest HD. PMID- 17697408 TI - Working memory after severe traumatic brain injury. AB - The aim of the present study was to assess the functioning of the different subsystems of working memory after severe traumatic brain injury (TBI). A total of 30 patients with severe chronic TBI and 28 controls received a comprehensive assessment of working memory addressing the phonological loop (forward and backward digit span; word length and phonological similarity effects), the visuospatial sketchpad (forward and backward visual spans), and the central executive (tasks requiring simultaneous storage and processing of information, dual-task processing, working memory updating). Results showed that there were only marginal group differences regarding the functioning of the two slave systems, whereas patients with severe TBI performed significantly poorer than controls on most central executive tasks, particularly on those requiring a high level of controlled processing. These results suggest that severe TBI is associated with an impairment of executive aspects of working memory. The anatomic substrate of this impairment remains to be elucidated. It might be related to a defective activation of a distributed network, including the dorsolateral prefrontal cortex. PMID- 17697410 TI - One-year follow-up study of relapsing-remitting MS patients' cognitive performances: Paced Auditory Serial Addition Test's susceptibility to change. AB - To evaluate the progression of cognitive decline in multiple sclerosis (MS) patients and the susceptibility of the Multiple Sclerosis Functional Composite (MSFC) Paced Auditory Serial Addition Test (PASAT) to change, we conducted a 1 year follow-up with a comprehensive neuropsychological examination to 19 initially cognitively impaired and 26 cognitively intact relapsing-remitting MS patients, and to 48 healthy controls. The results indicated that the cognitive performance of MS patients remained relatively stable. Healthy controls tended to perform better on most neuropsychological measures at follow-up, the same was not observed in the MS groups. PASAT showed a significant difference between the groups: the cognitively impaired group tended to deteriorate, whereas the control group and the cognitively intact group improved. The change in PASAT could not be explained by the background variables, for example, mood, quality of life, or nervousness. Therefore, the MSFC-PASAT seems to be a sensitive measure to show clinical change in the cognitive status. PMID- 17697409 TI - Neurobehavioral effects of HIV-1 infection in China and the United States: a pilot study. AB - The HIV epidemic in China has been increasing exponentially, yet there have been no studies of the neurobehavioral effects of HIV infection in that country. Most neuroAIDS research has been conducted in Western countries using Western neuropsychological (NP) methods, and it is unclear whether these testing methods are appropriate for use in China. Twenty-eight HIV seropositive (HIV+) and twenty three HIV seronegative (HIV-) individuals with comparable gender, age, and education distributions were recruited in Beijing and the rural Anhui province in China. Thirty-nine HIV+ and thirty-one HIV- individuals were selected from a larger U.S. cohort recruited at the HIV Neurobehavioral Research Center, in San Diego, to be matched to the Chinese sample for age, disease status, and treatment variables. The NP test battery used with the U.S. and China cohorts included instruments widely used to study HIV infection in the United States. It consisted of 14 individual test measures, each assigned to one of seven ability areas thought to be especially vulnerable to effects of HIV on the brain (i.e., verbal fluency, abstraction/executive function, speed of information processing, working memory, learning, delayed recall, and motor function). To explore the cross cultural equivalence and validity of the NP measures, we compared our Chinese and U.S. samples on the individual tests, as well as mean scaled scores for the total battery and seven ability domains. On each NP test measure, the mean of the Chinese HIV+ group was worse than that of the HIV- group. A series of 2x2 analyses of variance involving HIV+ and HIV- groups from both countries revealed highly significant HIV effects on the Global and all Domain mean scaled scores. Country effects appeared on two of the individual ability areas, at least partly due to education differences between the two countries. Importantly, the absence of HIV-by-Country interactions suggests that the NP effects of HIV are similar in the two countries. The NP test battery that was chosen and adapted for use in this study of HIV in China appears to have good cross-cultural equivalence, but appropriate Chinese norms will be needed to identify disease-related impairment in individual Chinese people. To inform the development of such norms, a much larger study of demographic effects will be needed, especially considering the wide range of education in that country. PMID- 17697411 TI - The Indiana University telephone-based assessment of neuropsychological status: a new method for large scale neuropsychological assessment. AB - Sensitive measures of neuropsychological function were adapted to a telephone administration format for use in a large survey of quality of life in breast cancer survivors (BCS). Healthy controls (HC) and BCS were recruited from the community and administered the same neuropsychological test battery on two occasions separated by 1 week. Subjects were randomly assigned to conditions, stratified by diagnosis: In-person at Time-1 and In-person at Time-2 (P-P); Telephone at Time-1 and Telephone at Time-2 (T-T); T-P; and P-T. Four cognitive (Rey Auditory Verbal Learning Test, Controlled Oral Word Association, Digit Span, Symbol Digit) and two self-report measures (Squire Memory Self-Report Scale, Center for Epidemiological Studies Depression Scale) were used. The 106 subjects were randomized (54 HC and 52 BCS). Test-retest reliabilities (intraclass correlations) did not differ significantly by condition across the cognitive or self-report measures and ranged from moderate to near perfect (r's .43-.93; p's<.05). Mean scores at Time-1, practice effects (Time-1 to Time-2), and standard errors of measurement were comparable between In-person and Telephone administration formats. Results suggest that memory, attention, information processing speed, verbal fluency, and self-report of mood and memory can be measured reliably and precisely over the telephone. PMID- 17697412 TI - Neuropsychological functioning in adolescent marijuana users: subtle deficits detectable after a month of abstinence. AB - In adults, studies examining the long-lasting cognitive effects of marijuana use demonstrate subtle deficits in attention, executive function, and memory. Because neuromaturation continues through adolescence, these results cannot necessarily generalize to adolescent marijuana users. The goal of this study was to examine neuropsychological functioning in abstinent marijuana using and demographically similar control adolescents. Data were collected from 65 adolescent marijuana users (n=31, 26% females) and controls (n=34, 26% females) 16-18 years of age. Extensive exclusionary criteria included independent psychiatric, medical, and neurologic disorders. Neuropsychological assessments were conducted after>23 days of monitored abstinence. After controlling for lifetime alcohol use and depressive symptoms, adolescent marijuana users demonstrated slower psychomotor speed (p<.05), and poorer complex attention (p<.04), story memory (p<.04), and planning and sequencing ability (p<.001) compared with controls. Post hoc analysis revealed that the number of lifetime marijuana use episodes was associated with poorer cognitive function, even after controlling for lifetime alcohol use. The general pattern of results suggested that, even after a month of monitored abstinence, adolescent marijuana users demonstrate subtle neuropsychological deficits compared with nonusers. It is possible that frequent marijuana use during adolescence may negatively influence neuromaturation and cognitive development. PMID- 17697413 TI - Intelligence quotient-adjusted memory impairment is associated with abnormal single photon emission computed tomography perfusion. AB - Cognitive reserve among highly intelligent older individuals makes detection of early Alzheimer's disease (AD) difficult. We tested the hypothesis that mild memory impairment determined by IQ-adjusted norms is associated with single photon emission computed tomography (SPECT) perfusion abnormality at baseline and predictive of future decline. Twenty-three subjects with a Clinical Dementia Rating (CDR) score of 0, were reclassified after scores were adjusted for IQ into two groups, 10 as having mild memory impairments for ability (IQ-MI) and 13 as memory-normal (IQ-MN). Subjects underwent cognitive and functional assessments at baseline and annual follow-up for 3 years. Perfusion SPECT was acquired at baseline. At follow-up, the IQ-MI subjects demonstrated decline in memory, visuospatial processing, and phonemic fluency, and 6 of 10 had progressed to a CDR of 0.5, while the IQ-MN subjects did not show decline. The IQ-MI group had significantly lower perfusion than the IQ-MN group in parietal/precuneus, temporal, and opercular frontal regions. In contrast, higher perfusion was observed in IQ-MI compared with IQ-MN in the left medial frontal and rostral anterior cingulate regions. IQ-adjusted memory impairment in individuals with high cognitive reserve is associated with baseline SPECT abnormality in a pattern consistent with prodromal AD and predicts subsequent cognitive and functional decline. PMID- 17697414 TI - Visual memory errors in schizophrenic patients with auditory and visual hallucinations. AB - Hallucinations have been found associated with false detection or false recognition of acoustic/verbal material in several studies. We investigated whether they were also linked with false recognition of pictures. Furthermore, an association between hallucinations and deficits in remembering temporal context was observed in previous research on schizophrenia. We investigated whether the association extends to deficits in remembering spatial context. Forty-one patients with schizophrenia underwent a visual memory task. Sixteen mixed black and-white and colored pictures were presented at different locations. Participants had to recognize the pictures among distractors, then to recall the spatial context of the presentation of the target pictures. Results showed that auditory hallucinations were associated with poor recognition of the colored pictures. When recognition efficiency and negative symptoms were statistically controlled, auditory hallucinations were also associated with increased response bias toward false recognition of nontarget pictures, and with errors in remembering the spatial context. No associations with visual hallucinations emerged. Anhedonia was associated with response bias, in the direction opposite to that of hallucinations. In conclusion, the association between hallucinations and response bias extends across modalities to picture recognition. The association between hallucinations and temporal context impairment extends to spatial context. PMID- 17697415 TI - Assessment and quantification of head motion in neuropsychiatric functional imaging research as applied to schizophrenia. AB - Differing degrees of head motion have long been recognized as a potential confound in functional neuroimaging studies comparing neuropsychiatric populations to healthy normal volunteers, and studies often cite excessive head motion as a possible reason for the different patterns of functional activation frequently observed between groups. We empirically tested the degree of head motion in 16 patients with chronic schizophrenia and 16, age- and education matched controls during the acquisition of functional magnetic resonance imaging data. We examined the degree of motion across three different indices (total motion, relative motion, task-correlated motion) during a complex attentional task and the effect of entering the motion parameters as additional regressors in a general linear model analysis. Results indicate that individuals with schizophrenia did not exhibit more task-correlated or total motion compared with controls. Moreover, the residual error term from the general linear model analysis was similar for both groups of subjects. In conclusion, current results suggest that stable patients with schizophrenia are capable of controlling head motion compared with matched normal controls. However, a direct comparison of the motion parameters is an essential step for any quality assurance protocol to determine whether additional corrective techniques need to be implemented. PMID- 17697416 TI - Intensive language training in the rehabilitation of chronic aphasia: efficient training by laypersons. AB - Intense language training has been found to be more efficient in the rehabilitation of chronic aphasia than treatment spread across time. Intense treatment, however, challenges personnel and financial resources of the health care system. The present study examined, whether laypersons can be trained to apply standardized language training for chronic aphasia with effects comparable to training by experts. Twenty individuals with chronic aphasia participated in the training, Constraint-Induced Aphasia Therapy (CIAT), which comprises communicative language games with increasing level of difficulty in a motivating context for 3 hr/day on 10 consecutive days. Following a random-control design, training was applied either by experienced therapists (n=10) or trained laypersons (n=10). Standardized language assessments revealed significant within group improvements, however, between-group differences were not present. We conclude that a standardized training program, such as CIAT, can be efficiently accomplished by trained laypersons with results comparable to that of experienced therapists. PMID- 17697417 TI - A model of comprehension in spina bifida meningomyelocele: meaning activation, integration, and revision. AB - Spina bifida meningomyelocele (SBM) is a neurodevelopmental disorder associated with adequate development of word reading and single word comprehension, but deficient text and discourse comprehension. Studies of comprehension in children with SBM are reviewed in relation to a comprehension model in which meanings are either activated from the surface code or constructed through resource-intensive integration and revision processes to form representations of the text base and models of the situation described by the text. Two new studies probed the construction of situation models in SBM. Experiment 1 tested the ability to build spatial and affective situation models from single sentences in 86 children with SBM (8 to 18 years of age) and 37 control children (8 to 16 years of age). Experiment 2 tested the ability to integrate across sentences to build spatial situation models in 15 children with SBM and 15 age-matched controls. Compared to age peers, children with SBM did not construct situation models that required integration of information across sentences, even though they could construct such models from single sentences. The data bear on the distinctive SBM neurocognitive profile, and more generally, on the significance of integration processes for the constructive aspects of language comprehension. PMID- 17697418 TI - Neural substrates of semantic memory. AB - Semantic memory is described as the storage of knowledge, concepts, and information that is common and relatively consistent across individuals (e.g., memory of what is a cup). These memories are stored in multiple sensorimotor modalities and cognitive systems throughout the brain (e.g., how a cup is held and manipulated, the texture of a cup's surface, its shape, its function, that is related to beverages such as coffee, and so on). Our ability to engage in purposeful interactions with our environment is dependent on the ability to understand the meaning and significance of the objects and actions around us that are stored in semantic memory. Theories of the neural basis of the semantic memory of objects have produced sophisticated models that have incorporated to varying degrees the results of cognitive and neural investigations. The models are grouped into those that are (1) cognitive models, where the neural data are used to reveal dissociations in semantic memory after a brain lesion occurs; (2) models that incorporate both cognitive and neuroanatomical information; and (3) models that use cognitive, neuroanatomic, and neurophysiological data. This review highlights the advances and issues that have emerged from these models and points to future directions that provide opportunities to extend these models. The models of object memory generally describe how category and/or feature representations encode for object memory, and the semantic operations engaged in object processing. The incorporation of data derived from multiple modalities of investigation can lead to detailed neural specifications of semantic memory organization. The addition of neurophysiological data can potentially provide further elaboration of models to include semantic neural mechanisms. Future directions should incorporate available and newly developed techniques to better inform the neural underpinning of semantic memory models. PMID- 17697419 TI - Patients with Parkinson's disease can successfully remember to execute delayed intentions. AB - The present study investigated prospective memory in patients with Parkinson's disease (PD) and healthy controls. In addition, the influence of task importance on participants' performance was examined. Experimental settings required participants to focus either on the prospective or the ongoing task. The three main findings are (1) PD patients performed as well on a prospective memory task as healthy controls when the focus was laid on the prospective memory task, (2) their prospective memory performance was impaired when the ongoing activity was stressed, and (3) differences in working memory capacity were related to these differential effects. Results indicate that PD patients can perform event-based prospective memory tasks to a normal degree if the prospective task component is prioritized. Data also suggest that a reduced working memory capacity plays an important role in this process. Findings are discussed in terms of conceptual, methodological, and clinical implications. PMID- 17697420 TI - Language and crossed finger localization in patients with schizophrenia. AB - Language deficits are frequently reported in studies of patients with schizophrenia. The present study sought to test the hypothesis that such deficits are related to callosal function in this group. The FAS test of verbal fluency and Perin's Spoonerisms test of phonological processing were the tests of language. Callosal function was assessed using a Crossed Finger Localisation Test (CFLT), which is a measure of the interhemispheric transfer of somatosensory information. Patients with schizophrenia performed less well than controls on measures of language function, as well as on the CFLT. Significant positive correlations between CFLT performance and language function were present in the patient group, but not the control group. These findings extend on previous studies that report functional abnormalities of the corpus callosum in schizophrenia and are consistent with the hypothesis that language deficits in schizophrenia are related to impaired callosal functioning in this group. However, other explanations cannot be ruled out. PMID- 17697421 TI - Cognitive estimation in traumatic brain injury. AB - The present study explores the construct and ecological validity of the Biber Cognitive Estimation Test (BCET) in a traumatic brain injury (TBI) sample. Participants completed the BCET in the course of a neuropsychological evaluation at 1-15 years after injury. BCET scores correlated moderately with other standard measures of executive functioning, and contrary to our hypotheses, at least as high with neuropsychological tests with minimal demands on executive functioning. Moreover, partialing out the portion of BCET variance not attributable to executive functioning markedly attenuated the former correlations. With respect to ecological validity, BCET scores did not predict concurrent functional status, as measured by the Disability Rating Scale. By comparison, standard measures of executive functioning strongly correlated with each other, correlated less strongly with nonexecutive functioning measures, and predicted functional status. In conclusion, unlike standard measures of executive functioning, the BCET demonstrated poor construct and ecological validity in TBI patients. PMID- 17697422 TI - A maternal 'junk food' diet in pregnancy and lactation promotes an exacerbated taste for 'junk food' and a greater propensity for obesity in rat offspring. AB - Obesity is generally associated with high intake of junk foods rich in energy, fat, sugar and salt combined with a dysfunctional control of appetite and lack of exercise. There is some evidence to suggest that appetite and body mass can be influenced by maternal food intake during the fetal and suckling life of an individual. However, the influence of a maternal junk food diet during pregnancy and lactation on the feeding behaviour and weight gain of the offspring remains largely uncharacterised. In this study, six groups of rats were fed either rodent chow alone or with a junk food diet during gestation, lactation and/or post weaning. The daily food intakes and body mass were measured in forty-two pregnant and lactating mothers as well as in 216 offspring from weaning up to 10 weeks of age. Results showed that 10 week-old rats born to mothers fed the junk food diet during gestation and lactation developed an exacerbated preference for fatty, sugary and salty foods at the expense of protein-rich foods when compared with offspring fed a balanced chow diet prior to weaning or during lactation alone. Male and female offspring exposed to the junk food diet throughout the study also exhibited increased body weight and BMI compared with all other offspring. This study shows that a maternal junk food diet during pregnancy and lactation may be an important contributing factor in the development of obesity. PMID- 17697423 TI - Gabapentin action and interaction on the antinociceptive effect of morphine on visceral pain in mice. AB - BACKGROUND AND OBJECTIVE: Visceral pain is one of the most common forms of pain and for which new drugs would be welcome. The aim of this study was to investigate whether gabapentin inhibits induced abdominal contractions in mice and to examine the effect of its co-administration with morphine. METHODS: A total of 96 mice received acetic acid intraperitoneally after administration of saline or gabapentin (1, 5, 10, 50 and 100 mg kg(-1)) or morphine (0.25, 0.5, 1, 3 and 5 mg kg(-1)) or a combination of morphine and gabapentin. Other groups also received naloxone. The number of writhes were counted. RESULTS: Both gabapentin and morphine reduced writhing in a dose-dependent manner. The number of writhes was decreased significantly by gabapentin (50 and 100 mg kg(-1)) and morphine (0.5, 1, 3 and 5 mg kg(-1)) (P < 0.001). Also, the lowest dose of morphine 0.25 mg kg(-1) when combined with low doses of gabapentin significantly decreased the number of writhes (P < 0.005). The combination of a low effective dose of gabapentin (50 mg kg(-1)) with a low dose of morphine decreased the writhing by 94% as compared to the controls. The antinociceptive effect of combined administration was not reversed by naloxone. CONCLUSION: These data demonstrated the comparable efficacy of gabapentin with morphine in visceral pain. Also, the results showed that the combination of doses of gabapentin and morphine, which were ineffective alone, produced a significant analgesic effect in the writhing model of pain. This may be clinically important in the management of visceral pain. PMID- 17697424 TI - Exploration of possible correlates of nutrition awareness and the relationship with nutrition-related behaviours: results of a consumer study. AB - OBJECTIVES: To unravel the concept of nutrition awareness, as it relates to risky personal nutrition-related behaviours, and to assess the sociodemographic and psychosocial correlates of nutrition awareness. DESIGN: Data were collected in a cross-sectional study with the aid of a face-to-face interview-assisted questionnaire that was based on the Precaution Adoption Process Model and Stages of Change Model. SETTING: Dutch consumer homes. SUBJECTS: Six hundred and three Dutch adults aged 18 to 80 years, selected from a panel. RESULTS: Our model explains nutrition awareness well (explained variance 53.7%). Psychosocial correlates were involvement with nutrition, health awareness, association with healthy food, perceived relevance of eating less fat, association with necessity, perceived relevance of vitamins, and perceived attributes of independent organisations. Sociodemographic correlates were gender and age. The relationship between nutrition awareness and nutrition-related behaviours proved to be very complicated. CONCLUSIONS: The value of our study is that it unravels the concept of nutrition awareness. Understanding the correlates of nutrition awareness can contribute to a more effective application of behavioural change models. Our results support increasing involvement with nutrition through personalising and tailoring to the motivational stage. PMID- 17697425 TI - Use of sourdough lactobacilli and oat fibre to decrease the glycaemic index of white wheat bread. AB - This work was aimed at decreasing the glycaemic index (GI) of white wheat bread. Breads made with wheat flour (WF) or wholemeal flour (WMF) and fermented with baker's yeast had similar values of resistant starch (RS; 1.4-1.7 %, starch basis). Sourdough Lactobacillus plantarum P1 and Lactobacillus brevis P2 favoured the highest formation of RS (approximately 5 %) when fermented with WF and WMF. The mixture (1:1) of WF and WMF (WF/WMF) was selected. The effect of dietary fibres, chemical or sourdough acidification on the hydrolysis index (HI) of WF/WMF bread was determined. Among fibres, only the addition of oat fibre (5 %) decreased the HI to 90.84 %. Lactic acid determined the lowest HI, and the effect was related to the decrease of pH. For the same decrease of pH, breads fermented with L. plantarum P1 and L. brevis P2 (sourdough WF/WMF) showed values of HI lower than chemical acidification. The glucose response and GI of WF bread or sourdough WF/WMF bread enriched with oat fibre was determined by using fifteen healthy volunteers. Anhydrous glucose was used as reference. The area under the glucose response curve and the value of GI (72 %) of WF bread were significantly (P < 0.05) higher than sourdough WF/WMF bread enriched with oat fibre (GI = 53.7 %). The decrease of GI of the sourdough WF/WMF bread may be due to both fibre content and decreased pH. Compared to WMF bread, sourdough WF/WMF bread, enriched with oat fibre, had higher specific volume, better cell crumb structure and more appreciated acidulous smell, taste and aroma. PMID- 17697426 TI - Children's estimates of food portion size: the development and evaluation of three portion size assessment tools for use with children. AB - A number of methods have been developed to assist subjects in providing an estimate of portion size but their application in improving portion size estimation by children has not been investigated systematically. The aim was to develop portion size assessment tools for use with children and to assess the accuracy of children's estimates of portion size using the tools. The tools were food photographs, food models and an interactive portion size assessment system (IPSAS). Children (n 201), aged 4-16 years, were supplied with known quantities of food to eat, in school. Food leftovers were weighed. Children estimated the amount of each food using each tool, 24 h after consuming the food. The age specific portion sizes represented were based on portion sizes consumed by children in a national survey. Significant differences were found between the accuracy of estimates using the three tools. Children of all ages performed well using the IPSAS and food photographs. The accuracy and precision of estimates made using the food models were poor. For all tools, estimates of the amount of food served were more accurate than estimates of the amount consumed. Issues relating to reporting of foods left over which impact on estimates of the amounts of foods actually consumed require further study. The IPSAS has shown potential for assessment of dietary intake with children. Before practical application in assessment of dietary intake of children the tool would need to be expanded to cover a wider range of foods and to be validated in a 'real-life' situation. PMID- 17697427 TI - Effect of high and low glycaemic index recovery diets on intramuscular lipid oxidation during aerobic exercise. AB - Intramyocellular lipid (IMCL) and plasma NEFA are important skeletal muscle fuel sources. By raising blood insulin concentrations, carbohydrate ingestion inhibits lypolysis and reduces circulating NEFA. We hypothesised that differences in the postprandial glycaemic and insulin response to carbohydrates (i.e. glycaemic index; GI) could alter NEFA availability and IMCL use during subsequent exercise. Endurance-trained individuals (n 7) cycled for 90 min at 70 % V O2peak and then consumed either high GI (HGI) or low GI (LGI) meals over the following 12 h. The following day after an overnight fast, the 90 min cycle was repeated. IMCL content of the vastus lateralis was quantified using magnetic resonance spectroscopy before and after exercise. Blood samples were collected at 15 min intervals throughout exercise and analysed for NEFA, glycerol, glucose, insulin, and lactate. Substrate oxidation was calculated from expired air samples. The 90 min cycle resulted in >2-fold greater reduction in IMCL in the HGI trial (3.5 (sem 1.0) mm/kg wet weight) than the LGI trial (1.6 (sem 0.3) mm/kg wet weight, P < 0.05). During exercise, NEFA availability was reduced in the HGI trial compared to the LGI trial (area under curve 2.36 (sem 0.14) mEq/l per h v. 3.14 (sem 0.28) mEq/l per h, P < 0.05 respectively). No other differences were significant. The findings suggest that HGI carbohydrates reduce NEFA availability during exercise and increase reliance on IMCL as a substrate source during moderate intensity exercise. PMID- 17697428 TI - Asian plantain (Plantago asiatica) essential oils suppress 3-hydroxy-3-methyl glutaryl-co-enzyme A reductase expression in vitro and in vivo and show hypocholesterolaemic properties in mice. AB - Asian plantain (Plantago asiatica) essential oil (PAEO) contains multiple bioactive compounds, but its potential effects on lipid metabolism have not been examined. PAEO was found to be mostly composed of oxygenated monoterpenes, with linalool as the major component (82.5 %, w/w), measured using GC-MS. Incubation of 0-200 microg PAEO/ml with HepG2 cells for 24 h resulted in no significant toxicity. Incubation with 0.2 mg PAEO/ml altered the expression of LDL receptor (+83 %; P < 0.05) and 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase ( - 37 %; P < 0.05), as assessed using RT-PCR. LDL oxidation was markedly inhibited by PAEO treatment due to the prevalence of linalool compounds in PAEO. Oral administration of PAEO for 3 weeks in C57BL/6 mice significantly reduced plasma total cholesterol and TAG concentrations by 29 and 46 %, respectively. The mRNA (+58 %; P < 0.05), but not protein, levels of the LDL receptor were significantly higher, whereas both mRNA and protein levels of HMG-CoA reductase were significantly lower ( - 46 and - 11 %, respectively; P < 0.05) in the liver of PAEO-fed than of control mice. The mRNA levels of CYP7A1 were marginally reduced in HepG2 cells, but not in mouse liver after PAEO treatment. Thus, PAEO may have hypocholesterolaemic effects by altering the expression of HMG-CoA reductase. Reduced TAG and oxidised LDL may provide additional cardiovascular protective benefits. PMID- 17697429 TI - A Nori but not a Konbu, dietary supplement decreases the cholesterolaemia, liver fat infiltration and mineral bioavailability in hypercholesterolaemic growing Wistar rats. AB - The nutritional consequences of algae consumption in young populations consuming hypercholesterolaemic diets have hardly been investigated. This study tests the effect of algae supplementation of cholesterol-enriched balanced diets on growth, dietary efficiency ratio, mineral intake and absorption, organ weight and structure and cholesterolaemia in growing Wistar rats. Three groups of ten rats each were fed for 3 weeks with experimental diets containing 93 % casein-soyabean oil base with 2.4 % cholesterol-raising agent and 7 % supplement. The control group received cellulose (35 %), group 2 consumed Nori (33.8 % fibre) and group 3 consumed Konbu (36.1 % fibre). Food intake and body weight gain were not significantly affected. Algae groups presented significantly higher dietary efficiency ratio values than control rats. Apparent absorption of several minerals appeared significantly affected, mainly in Nori-fed rats, with a significant decrease in the ratio of Zn and Cu intakes and apparent absorption. Nori diet significantly decreased plasma cholesterol. Algae supplement did not significantly affect organ size and structure. Control and Konbu rats showed severe liver fat infiltration, while Nori rats exhibited a significantly lower degree of lipid-like hepatocyte vacuolization but light to moderate leukocyte infiltration. Light to moderate scaling off of the epithelium and moderate submucosa oedema was observed in all groups. Although long-term studies are needed to check the possible extrapolation of these data to human subjects, it can be concluded that a Nori, but not a Konbu, dietary supplement reverses the negative effect of dietary cholesterol intake and also appears to be related to mineral availability in growing subjects. PMID- 17697430 TI - Responses of surrogate markers of cholesterol absorption and synthesis to changes in cholesterol metabolism during various amounts of fat and cholesterol feeding among healthy men. AB - Serum ratios to cholesterol of lathosterol, and of cholestanol, campesterol and sitosterol measure respective relative cholesterol synthesis and absorption, but their clinical applicability is not known in evaluation of cholesterol metabolism under different dietary conditions. We compared relative synthesis and absorption of cholesterol to the respective absolute ones in healthy male volunteers (n 29) on four subsequent diets: baseline home (HD), low-cholesterol low-fat (LCLF), high-cholesterol low-fat (HCLF) and low-cholesterol high-fat (LCHF). Serum lipids, lipoproteins, sterols, fractional cholesterol absorption and sterol synthesis were examined. HCLF and LCHF decreased fractional cholesterol absorption by approximately 23-27 % from baseline HD (P < 0.05) and increased the levels of total and LDL-cholesterol in serum from LCLF by approximately 9-14 % (P < 0.05). On HCLF, bile acid synthesis was high (P < 0.05 for each), and absolute cholesterol synthesis tended to be higher than on HD and LCHF (NS). Relative synthesis was positively associated with absolute cholesterol synthesis, but inversely with relative absorption during each diet (P < 0.05). The relative absorption markers were interrelated in each diet, and were also associated with fractional absorption of cholesterol in each diet but HD. In conclusion, relative markers of cholesterol absorption and synthesis reflect changes in cholesterol metabolism despite the amount of dietary fat and cholesterol consumed, but their validity with this respect is strengthened by controlled diets in metabolic studies. Additions of cholesterol and fat to a diet low in fat and cholesterol cause practically equal changes in the serum lipid profiles, whereas synthesis of cholesterol (NS) and bile acids (P < 0.05) were higher with the high-cholesterol feeding. PMID- 17697431 TI - Naturally occurring iodine in humic substances in drinking water in Denmark is bioavailable and determines population iodine intake. AB - Iodine intake is important for thyroid function. Iodine content of natural waters is high in some areas and occurs bound in humic substances. Tap water is a major dietary source but bioavailability of organically bound iodine may be impaired. The objective was to assess if naturally occurring iodine bound in humic substances is bioavailable. Tap water was collected at Randers and Skagen waterworks and spot urine samples were collected from 430 long-term Randers and Skagen dwellers, who filled in a questionnaire. Tap water contained 2 microg/l elemental iodine in Randers and 140 microg/l iodine bound in humic substances in Skagen. Median (25; 75 percentile) urinary iodine excretion among Randers and Skagen dwellers not using iodine-containing supplements was 50 (37; 83) microg/24 h and 177 (137; 219) microg/24 h respectively (P < 0.001). The fraction of samples with iodine below 100 microg/24 h was 85.0 % in Randers and 6.5 % in Skagen (P < 0.001). Use of iodine-containing supplements increased urinary iodine by 60 microg/24 h (P < 0.001). This decreased the number of samples with iodine below 100 microg/24 h to 67.3 % and 5.0 % respectively, but increased the number of samples with iodine above 300 microg/24 h to 2.4 % and 16.1 %. Bioavailability of iodine in humic substances in Skagen tap water was about 85 %. Iodine in natural waters may be elemental or found in humic substances. The fraction available suggests an importance of drinking water supply for population iodine intake, although this may not be adequate to estimate population iodine intake. PMID- 17697432 TI - Reponses of sheep to a vaccination of entodinial or mixed rumen protozoal antigens to reduce rumen protozoal numbers. AB - Two rumen protozoa vaccine formulations containing either whole fixed Entodinium or mixed rumen protozoa cells were tested on Merino sheep with the aim of decreasing the number and/or activity of protozoa in the rumen. Negative control (no antigen) and positive control (Tetrahymena corlissi antigens) treatments were also included in the experiment. Blood and saliva were sampled to measure the specific immune response. Protozoal numbers in the rumen were monitored by microscopic counts. Vaccination with protozoal formulations resulted in the presence of specific IgG in plasma and saliva, but saliva titres were low. Titres after secondary vaccination were higher (P 0.05) by the vaccination and there was also no difference (P>0.05) between treatments in rumen fluid ammonia-N concentration or wool growth. In vitro studies investigated the binding ability of the antibodies and estimated the amount of antibody required to reduce cell numbers in the rumen. The studies showed that the antibodies did bind to and reduced protozoa numbers, but the amount of antibody generated by vaccination was not enough to produce results in an in vivo system. It is suggested that the vaccine could be improved if specific protozoal antigens are determined and isolated and that improved understanding of the actions of protozoa antibodies in rumen fluid and the relationships between levels of antibodies and numbers of protozoa in the rumen is needed. PMID- 17697433 TI - Graves' disease, with and without nodules, and the risk of thyroid carcinoma. AB - OBJECTIVE: Thyroid nodules are frequently present in Graves' disease. The aim of this study was to evaluate the risk of thyroid carcinoma in Graves' disease patients, with and without ultrasonographically identified nodules, who subsequently underwent surgical treatment. DESIGN: The study group included 150 consecutive patients with diagnosed Graves' disease who subsequently underwent surgery. SUBJECTS: The patients were divided into two groups according to whether the pre-operative ultrasound scan showed diffuse parenchyma (group one; n = 70) or nodules (group two; n = 80). RESULTS: Of the 150 patients, 18 (12 per cent) were found to have papillary thyroid carcinoma. Papillary carcinoma was found in seven patients (10 per cent) in group one and in 11 patients (1.7 per cent) in group two. After evaluating the overall groups, the incidence of carcinoma in the parenchyma outside a nodule was 67 per cent, whereas the incidence of carcinoma in a nodule was 33 per cent. CONCLUSION: Carcinoma can occur in Graves' disease patients without nodules, and the absence of nodules on ultrasonographic examination does not reduce the risk of malignancy. PMID- 17697434 TI - Lateral soft tissue neck X-rays: are they useful in management of upper aero digestive tract foreign bodies? AB - OBJECTIVES: To assess the value of lateral soft tissue neck X-rays in patients presenting with upper aero-digestive tract foreign bodies. DESIGN: Retrospective study. INCLUSION CRITERIA: (1) Patients referred to the ENT team, via either the accident and emergency department or their general practitioner; (2) a history of a non-aspirated, upper airway, aero-digestive tract foreign body; and (3) a lateral soft tissue neck X-ray taken on admission. RESULTS: A total of 62 patients met the inclusion criteria. Twenty-four patients (38.7 per cent) had positive findings on lateral soft tissue neck X-ray. 'Soft' signs, such as widened pre-vertebral shadow and loss of lordosis, were seen in all 24 patients, and foreign bodies were visualised in six patients. Overall, lateral soft tissue neck X-rays were helpful in the management of 32 patients (51.6 per cent). Rather worryingly, doctors in the accident and emergency and ENT departments missed 79.2 and 66.6 per cent of the positive findings, respectively. CONCLUSIONS: A lateral soft tissue neck X-ray is a helpful tool in the management of patients presenting with upper aero-digestive tract foreign bodies. Junior doctors need better radiology training. PMID- 17697435 TI - Evidence-based review of aetiopathogenic theories of congenital and acquired cholesteatoma. AB - Cholesteatoma is a non-neoplastic, keratinising lesion which has two forms: congenital and acquired. Congenital cholesteatoma develops behind a normal, intact tympanic membrane, whilst acquired cholesteatoma is associated with a defect in the tympanic membrane. The pathological substrate of cholesteatoma is keratinising stratified squamous epithelium, but the origin of this epidermal tissue in the middle ear is controversial. Here, we review the most relevant and recent evidence for the principal aetiopathogenic theories of both forms of cholesteatoma, in the light of recent otopathological findings. Congenital cholesteatoma is most plausibly explained by the persistence of fetal epidermoid formation. Conclusive 'proof' awaits the unambiguous demonstration of the metamorphosis of an epidermoid nidus into a lesion in vivo. Acquired cholesteatoma may develop by various mechanisms: immigration, basal hyperplasia, retraction pocket and/or trauma (iatrogenic or non-iatrogenic). However, squamous metaplasia of the normal cuboidal epithelium of the middle ear is a highly unlikely explanation. Chronic inflammation seems to play a fundamental role in multiple aetiopathogenic mechanisms of acquired cholesteatoma. Therefore early treatment of inflammatory conditions might reduce their sequelae, perhaps by preventing the development of hyperplastic papillary protrusions. Continued otopathological, cellular and molecular research would enhance our limited understanding of cholesteatoma and may lead to new therapeutic strategies for this erosive disease, which often defies surgical treatment. PMID- 17697436 TI - Comparison of contact endoscopy and frozen section histopathology in the intra operative diagnosis of laryngeal pathology. AB - Andrea et al. were the first to use contact endoscopy in the diagnosis of laryngeal disease, in 1995. This method enables in vivo microscopy of laryngeal mucosa. In the present study, comparison of contact endoscopy with frozen section histopathology was performed in 142 patients with various diseases of the larynx. Paraffin section histopathology diagnosed 70 benign lesions, 23 precancerous lesions and 49 malignant lesions. Frozen section histopathology showed a sensitivity of 89.8 per cent, a specificity of 98.9 per cent and an accuracy of 95.7 per cent (chi2 = 1.5; p = 0.18). Frozen histopathology diagnosed 45 malignant lesions, including one false positive and five false negative results. Contact endoscopy yielded a sensitivity of 79.59 per cent, a specificity of 100 per cent and an accuracy of 92.95 per cent (chi2 = 8.1; p = 0.002). All malignant lesions diagnosed by contact endoscopy were confirmed by histopathology; contact endoscopy failed to recognise malignant lesions in 10 patients. Contact endoscopy is preferable to frozen section histopathology as it is noninvasive, provides information on microscopic diagnosis and laryngeal lesion margins, and enables visualisation of the laryngeal mucosa microvasculature. The use of contact endoscopy along with frozen section histopathology improves diagnostic accuracy and allows for operative (or other) therapy to continue according to the results obtained. PMID- 17697437 TI - Intranasal lysine-aspirin administration decreases polyp volume in patients with aspirin-intolerant asthma. AB - INTRODUCTION: Nasal polyposis associated with aspirin-intolerant asthma tends to be difficult to control, with frequent recurrences. We examined the effect of intranasal lysine-aspirin administration on resistant nasal polyps of asthmatic, aspirin-intolerant patients, when used in addition to routine therapy. PATIENTS AND METHODS: Thirteen patients with asthma and intolerance to aspirin were recruited. All but one had undergone numerous polypectomies and were uncontrolled on standard therapy with intranasal corticosteroids, leukotriene receptor antagonists and nasal douching. Aspirin treatment involved one drop (100 microl) of 30 mg/ml lysine-aspirin solution to each nostril, initially daily, increased every two or three days up to a maximal of 18 drops (54 mg lysine-aspirin) a day. Nasal symptoms, nitric oxide level, nasal inspiratory peak flow rate, peak expiratory flow rate and nasendoscopic grading were assessed prior to therapy and three months later. We also compared the change in endoscopic polyp scores during three months of lysine-aspirin administration with the changes which had occurred during the three months prior to administration (during which time other therapies had been identical). RESULTS: Nasal blockage symptoms tended to decrease; other nasal symptoms were unchanged. Significant changes were seen in nasal inspiratory peak flow rate (103.3 +/- 18.9 and 140.0 +/- 16.7 l/min before and after aspirin, respectively; p = 0.014), but not in peak expiratory flow rate (438.7 +/- 33.4 and 440.0 +/- 28.4 l/min before and after aspirin, respectively; p = 0.700). Nasal nitric oxide levels rose significantly (in both sides, p = 0.028). Expired chest nitric oxide levels did not change. Nasal polyp scores on nasendoscopic examination were significantly reduced (right side, p = 0.027; left side, p = 0.018). Compared with the preceding three months, adding intranasal lysine-aspirin application had the effect on decreasing nasal polyp volume (right side, p = 0.031; left side, p = 0.016). CONCLUSION: This open study suggests that intranasal lysine-aspirin administration reduces nasal polyp volume in aspirin intolerant patients, without any adverse affect on concomitant asthma. This was a preliminary study and should be followed by a placebo-controlled, double-blind trial. PMID- 17697438 TI - A psychometric evaluation of a Swedish version of the Quality of Life in Late Stage Dementia (QUALID) scale. AB - BACKGROUND: The aim of the present study was to evaluate the validity, reliability and responsiveness of a Swedish translation of the Quality of Life in Late-Stage Dementia (QUALID) Scale. METHOD: A total of 169 elderly residents at 19 dementia special care units in eight long-term care facilities in the Gothenburg city region participated in the study. Assessments were made by 107 proxy informants. RESULTS: Results showed satisfactory levels of internal consistency reliability (Cronbach's alpha coefficients 0.74), acceptable inter rater reliability between informants (0.69), and high test-retest reliability (0.86). As hypothesized, QUALID scores were also associated with those from other quality-of-life (QoL) indices (criterion validity), as well as with use of psychoactive drugs, and with tests of cognitive impairment (clinical validity). The responsiveness of the questionnaire was also acceptable. CONCLUSIONS: As important clinical decisions may derive from perceived QoL effects, it is vital that the QoL data be reliable, valid and sensitive to change. Our evaluations of the psychometric properties of the Swedish QUALID indicate that it satisfactorily meets the need for an instrument to assess QoL in late-stage dementia in Sweden, in a wide range of settings and applications. PMID- 17697440 TI - Blockade of autoreceptor-mediated inhibition of norepinephrine release by atipamezole is maintained after chronic reuptake inhibition. AB - The role of alpha(2)-adrenergic autoreceptor desensitization in the delayed onset of antidepressant efficacy of selective norepinephrine (NE) reuptake inhibitors is unclear. Using the alpha(2)-antagonist yohimbine, we showed previously that chronic treatment with desipramine (DMI) did not alter autoreceptor-mediated inhibition of NE release in the cortex. However, yohimbine may have non-selective effects that could confound this interpretation. Thus, using microdialysis, we measured acute effects of the highly selective alpha(2)-antagonist atipamezole on NE release in the prefrontal cortex following chronic DMI treatment, after 0-8 d washout. Atipamezole induced a similar elevation of extracellular NE in all treatment groups, indicating no change in autoreceptor function. Further, the effect was most rapid in DMI-treated rats with 0- and 2-d washout, suggesting that autoreceptor-mediated inhibition was most prominent when NE levels were highest. This provides further evidence that autoreceptor-mediated inhibition of NE neurotransmission remains functional after chronic DMI treatment, arguing against the hypothesis that desensitization of alpha(2)-autoreceptors accounts for the delayed onset of action of selective NE reuptake inhibitors. PMID- 17697439 TI - Profiles of matrix metalloproteinases and their inhibitors in plasma of patients with dementia. AB - BACKGROUND: Matrix metalloproteinases (MMPs) are elevated in the brain tissue of patients with dementia and may play a role in the pathophysiology of dementia. MMP-9 and tissue inhibitors of MMPs (TIMPs) are elevated in postmortem brain tissue of patients with Alzheimer's disease (AD). In a previous study we showed that circulating levels of MMP-9 are elevated in AD patients. The aim of the present study was to examine circulating levels of MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 in the plasma of patients with mild cognitive impairment (MCI), AD, vascular dementia (VaD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD), to determine, whether plasma profiles of MMPs and TIMPs differ in various types of dementia. METHODS: Gelatinolytic activity (MMP-2 and MMP-9) was measured in all plasma samples by zymography. Levels of MMP-2, MMP-9, MMP-1 as well as TIMP-1 and TIMP-2 were measured by ELISA. RESULTS: We found constitutive expression of MMP-1, -2 and -9 as well as TIMP-1 and -2 in all the samples investigated. As shown previously, MMP-9 was significantly elevated in the plasma of AD patients (p = 0.004) as compared to controls and MCI patients. Plasma levels of TIMP-1 were significantly lower in VD samples as compared to all other groups. Levels of TIMP-2 were significantly lower in patients with FTD as compared to AD, VaD and MCI patients. There were no significant changes of MMP-1 and MMP-2 levels in the samples. CONCLUSION: These findings suggest that circulating levels of MMP-9, TIMP-1 and TIMP-2 and changes in the MMP/TIMP balance in plasma differ in various types of dementia. PMID- 17697441 TI - Local influence of mitochondrial calcium transport in retinal amacrine cells. AB - Ca2+-dependent synaptic transmission from retinal amacrine cells is thought to be initiated locally at dendritic processes. Hence, understanding the spatial and temporal impact of Ca2+ transport is fundamental to understanding how amacrine cells operate. Here, we provide the first examination of the local effects of mitochondrial Ca2+ transport in neuronal processes. By combining mitochondrial localization with measurements of cytosolic Ca2+, the local impacts of mitochondrial Ca2+ transport for two types of Ca2+ signals were investigated. Disruption of mitochondrial Ca2+ uptake with carbonyl cyanide 4 (trifluoromethoxy) phenylhydrazone (FCCP) produces cytosolic Ca2+ elevations. The amplitudes of these elevations decline with distance from mitochondria suggesting that they are related to mitochondrial Ca2+ transport. The time course of the FCCP-dependent Ca2+ elevations depend on the availability of ER Ca2+ and we provide evidence that Ca2+ is released primarily via nearby ryanodine receptors. These results indicate that interactions between the ER and mitochondria influence cytosolic Ca2+ in amacrine cell processes and cell bodies. We also demonstrate that the durations of glutamate-dependent Ca2+ elevations are dependent on their proximity to mitochondria in amacrine cell processes. Consistent with this observation, disruption of mitochondrial Ca2+ transport alters the duration of glutamate-dependent Ca2+ elevations near mitochondria but not at sites more than 10 microm away. These results indicate that mitochondria influence local Ca2+-dependent signaling in amacrine cell processes. PMID- 17697442 TI - The clinical and public health value of non-culture methods in the investigation of a cluster of unexplained pneumonia cases. AB - During 2003, a cluster of initially unexplained pneumonia cases (two fatal) occurred in patients aged <50 years in a British city. Routine culture tests were inconclusive, however, pneumococcal infection was suspected and the putative outbreak was investigated using non-culture methods. Clinical samples from ten patients were tested by pneumococcal polymerase chain reaction (PCR) and multi locus sequence typing (MLST), or Binax NOW pneumococcal urine antigen test and serotype-specific enzyme-linked immunosorbent assay (ELISA). Lung samples from the deceased patients were PCR positive and yielded different MLST types. Two patients in one family group were serotype 1 pneumococcal antigen positive. Two further patients were serotype 1 antigen positive, and one serotype 4 positive. Two antigen-positive cases were also serum PCR positive. Non-culture methods confirmed the disease aetiology in six cases. Serotype and MLST results showed no single outbreak, but a family cluster of cases in a high background of pneumococcal pneumonia, providing important epidemiological data that would not otherwise have been available. PMID- 17697443 TI - Trends in resistance to penicillin and erythromycin of invasive pneumococci in Portugal. AB - Antimicrobial resistance of pneumococci is influenced by serotypes, antimicrobial consumption and vaccine use. Serotyping of 697 out of 1331 pneumococcal isolates, recovered in Portugal from 1994 to 2004, showed that the theoretical rate of heptavalent conjugate vaccine coverage was 91.7% and 63.6% for penicillin and erythromycin non-susceptible strains, respectively, in children up to 1 year old. The use of amoxicillin and erythromycin decreased in the vaccine period 2001-2004 (P=0.04 and P<0.01, respectively) but azithromycin usage increased in the same period (P<0.01). By using linear regression models, we evaluated the role of antimicrobial and vaccine use in the trends of resistance to penicillin and erythromycin among the isolates. The models suggest that the use of macrolides was the main factor associated with an increase of penicillin and erythromycin non-susceptible isolates from adults (P<0.01) and erythromycin non-susceptible isolates among children (P=0.006). These models also suggest that heptavalent vaccine is failing to reduce antimicrobial resistance as expected, possibly due to the increased consumption of azithromycin (P=0.04). The efficient use of new antibiotics may reverse the present trends of antimicrobial resistance. PMID- 17697444 TI - Epidemiological characteristics and medical follow-up of 61 patients with acute hepatitis C identified through the hepatitis C surveillance system in France. AB - This study aimed to describe current epidemiological and clinical characteristics, medical follow-up and outcome in the real practice of acute hepatitis C (AHC) patients. AHC cases were retrospectively identified through the French Hepatology Reference Centres Surveillance system and additional data were collected. Sixty-one patients with AHC were identified (sex ratio: M/F 1.7/1; mean age 39 years). Forty-four (72%) had documented seroconversion within a 6 month period. Main reported risk exposures were intravenous or nasal drug use (35%), invasive medical procedures (25%) and sexual contact with a HCV-positive partner (20%). Spontaneous clearance of HCV RNA was observed in seven out of 16 patients followed without therapy. This study confirms the major role of drug use in HCV transmission and highlights the role of invasive medical procedures and occupational exposure. PMID- 17697445 TI - Real-time computed tomography image update for endoscopic skull base surgery. AB - INTRODUCTION: The development of computer-aided systems for endoscopic sinus surgery has enabled surgical navigation through diseased or surgically altered sinus anatomy with increased confidence. However, conventional computer-aided systems do not provide intra-operative updated computed tomography imaging. We describe the technical aspects of the xCAT, a new intra-operative mobile volume computed tomography scanner. TECHNICAL REPORT: A patient with a malignant melanoma unwittingly removed at another hospital underwent surgery for removal of the lateral nasal wall and directed biopsies, in an attempt to identify the site of tumour origin. The procedure was performed with the GE InstaTrak 3500 Plus computer-aided system, updated with intra-operative computed tomography images. Intra-operative, updated images were integrated successfully into the InstaTrak system, and these images were consistent with the observed endoscopic anatomy. CONCLUSION: The xCAT intra-operative mobile volume computed tomography scanner is a technological advancement that can assist the endoscopic sinus surgeon when performing complex rhinological and skull base procedures. PMID- 17697446 TI - Host-based identification is not supported by morphometrics in natural populations of Gyrodactylus salaris and G. thymalli (Platyhelminthes, Monogenea). AB - Gyrodactylus salaris is a serious pest of wild pre-smolt Atlantic salmon (Salmo salar) in Norway. The closely related G. thymalli, originally described from grayling (Thymallus thymallus), is assumed harmless to both grayling and salmon. The 2 species are difficult to distinguish using traditional, morphometric methods or molecular approaches. The aim of this study was to explore whether there is a consistent pattern of morphometrical variation between G. salaris and G. thymalli and to analyse the morphometric variation in the context of 'diagnostic realism' (in natural populations). Specimens from the type-material for the 2 species are also included. In total, 27 point-to-point measurements from the opisthaptoral hard parts were used and analysed by digital image processing and uni- and multivariate morphometry. All populations most closely resembled its respective type material, as expected from host species, with the exception of G. thymalli from the Norwegian river Trysilelva. We, therefore, did not find clear support in the morphometrical variation among G. salaris and G. thymalli for an a priori species delineation based on host. The present study also indicates an urgent need for more detailed knowledge on the influence of environmental factors on the phenotype of gyrodactylid populations. PMID- 17697447 TI - Exploring psychological mechanisms of collective action: does relevance of group identity influence how people cope with collective disadvantage? AB - Two studies examined how the relevance of group identity influences two psychological mechanisms of collective action: Emotion- and problem-focused coping with collective disadvantage. Extending Van Zomeren, Spears, Fischer, and Leach's (2004) integrative theoretical model of coping with collective disadvantage, we predicted that when group identity is more relevant to disadvantaged group members, it increases their collective action tendencies through their feelings of group-based anger about their group's disadvantage. When group identity is less relevant and hence emotion-focused coping processes are less likely, group-efficacy beliefs become more predictive of disadvantaged group members' collective action tendencies because people focus more instrumentally on whether collective action will be effective (and benefit them) or not. A field study and a follow-up experiment both showed that the relevance of group identity facilitated emotion-focused coping and moderated problem focused coping with collective disadvantage. We discuss these results in terms of two distinct psychological mechanisms of collective action. PMID- 17697448 TI - Interracial prison contact: the pros for (socially dominant) cons. AB - Individuals high in social dominance orientation (SDO; Sidanius & Pratto, 1999) endorse group hierarchies and social inequality. Surprisingly little research has addressed contextual factors associated with reduced intergroup biases among such individuals. The present investigation considers a Person x Situation approach to this question in two British prisons, exploring the contextual factors outlined in the Contact Hypothesis (Allport, 1954). White inmates scoring higher in SDO exhibited significantly less in-group bias when reporting increased contact with Black inmates (Studies 1 & 2), when perceiving that favourable contact conditions are institutionally supported (Study 1), or when experiencing more pleasant personal interactions with Black inmates (Study 2). These SDO x Contact Condition moderation effects were mediated in Study 2: among high-SDO individuals, increased empathy towards Black inmates mediated the relation between contact variables and lower in-group bias. Implications for considering individual differences and empathy in contact settings are considered. PMID- 17697449 TI - Etoricoxib versus naproxen in patients with rheumatoid arthritis: a prospective, randomized, comparator-controlled 121-week trial. AB - BACKGROUND: Etoricoxib is a cyclooxygenase-2 (COX-2) selective inhibitor effective in the treatment of rheumatoid arthritis. An initial 12-week treatment study found that etoricoxib (90 mg once daily) was more effective than naproxen (500 mg twice daily) or placebo in treating rheumatoid arthritis. The present two part extension of that study was performed to monitor tolerability and examine long-term efficacy of etoricoxib 90 mg or 120 mg compared with naproxen. METHODS: Patients completing the initial 12-week study and those discontinuing due to lack of efficacy, were eligible for the Extension Study Part I (12-52 weeks) and assigned (2:1:2 ratio) to receive etoricoxib (90 mg or 120 mg daily) or naproxen (500 mg twice daily); these patients remained on the same therapy for Extension Study Part II (52-121 weeks). Primary outcome measures included investigator and patient assessment of disease activity, and tender and swollen joint counts. RESULTS: Of 816 patients enrolled in the initial 12-week trial, 717 continued into the Extension Study Part I; 505 patients completed and 390 entered the Extension Study Part II, with 283 patients completing 121 weeks. Patients receiving etoricoxib (90 mg) or naproxen throughout the study experienced sustained efficacy in all outcomes, as did patients transitioning to etoricoxib (120 mg) following the initial 12-week trial. Patients transitioning from placebo to etoricoxib (90 mg) experienced rapid, sustained improvements in all outcome measures. CONCLUSION: In conclusion, etoricoxib provided sustained efficacy throughout the 121-week study, with efficacy comparable to naproxen. PMID- 17697450 TI - Mapping MOS Sleep Scale scores to SF-6D utility index. AB - OBJECTIVE: Deriving preference scores for the Medical Outcomes Study (MOS) Sleep Scale would enable its use in cost-utility analyses. The objective of this study was to map scores of the MOS Sleep Scale to a preference-based health-state utility index (SF-6D) scored from the SF-36 Health Survey (SF-36). RESEARCH DESIGN AND METHODS: Three datasets were used: (1) the MOS study, a 4-year observational study of chronically ill patients, (2) a 7-week open-label, non comparative clinical trial of an osmotic controlled-release oral delivery system (OROS) hydromorphone in the treatment of chronic low back pain (CLBP), and (3) a 6-week open-label randomized controlled trial of OROS hydromorphone in the treatment of pain associated with chronic osteoarthritis (OA). Various models were tested, where SF-6D was regressed onto the Sleep Problem Index-II (SLP9) in 1000 random half (developmental) samples of the MOS (n = 1413). The best fitting model was applied to the other 1000 random half (cross-validation) samples of the MOS (n = 1412), and to the two trial samples (n = 199 in the CLBP trial; n = 124 in the OA trial). RESULTS: The best fitting model in the MOS samples included a quadratic term for the SLP9 which explained 34% of the variance in SF-6D in the developmental samples. Errors in prediction were greatest at higher SLP9 scores. Addition of demographic and clinical variables to the model explained minimal incremental amounts of variance (< 5%) in SF-6D scores. These results were replicated in the cross-validation MOS samples. In both developmental and cross validation MOS samples, mean predicted and observed SF-6D scores were nearly identical. When the mapping algorithm developed in the MOS was applied to the CLBP sample, mean predicted SF-6D scores were 0.09 points higher than observed SF 6D scores at both baseline and final visits, while changes in predicted and observed SF-6D scores were identical. CONCLUSION: Results indicate that it is possible to map MOS SLP9 to SF-6D yielding useable preference-based scores essential for cost-utility analyses. A limitation concerns the interpretation of SF-6D scores estimated from SLP9 scores above 60, where the prediction errors increased considerably. PMID- 17697451 TI - Comparison of pegfilgrastim with filgrastim on febrile neutropenia, grade IV neutropenia and bone pain: a meta-analysis of randomized controlled trials. AB - BACKGROUND AND OBJECTIVE: While head-to-head clinical trials demonstrate pegfilgrastim to be as efficacious as filgrastim in reducing chemotherapy-induced neutropenia, these studies lacked the statistical power to demonstrate better outcomes with one therapy compared to the other. Our objective was to obtain a pooled estimate of the effect of pegfilgrastim compared with filgrastim on incidence of febrile neutropenia (FN), and related outcomes among patients with solid tumors and malignant lymphomas receiving myelosuppressive chemotherapy. RESEARCH DESIGN AND METHODS: We searched PubMed and EMBASE for articles published from January 1, 1990 to August 31, 2006 reporting on randomized controlled trials (RCTs) that compared the efficacy and safety of pegfilgrastim versus filgrastim. We only accepted studies in which filgrastim (5 microg/kg/day) and pegfilgrastim (100 microg/kg or a fixed dose of 6 mg) were administered at approved doses indicated on the package insert. Pooled relative risk (RR) was estimated using the conservative random effects, empirical Bayesian method of Hedges and Olkin. MAIN OUTCOME MEASURES: Rates of grade IV neutropenia and of FN, time to absolute neutrophil count (ANC) recovery, and bone pain. RESULTS: We identified five RCTs, with a total of 617 patients, evaluating the efficacy of a single dose of pegfilgrastim per cycle versus daily filgrastim injections. Although only one study had a statistically significant difference in FN reductions favoring pegfilgrastim over filgrastim (relative risk reduction of 50%; p = 0.027), the pooled RR showed a statistically significant favorable result for pegfilgrastim (RR = 0.64; 95% CI, 0.43-0.97). Grade IV neutropenia rates (for cycle 1: RR = 0.99; 95% CI, 0.91-1.08; cycle 2: RR = 0.88; 95% CI, 0.70-1.11; cycle 3: RR = 0.80; 95% CI, 0.47-1.36; cycle 4: RR = 0.90; 95% CI, 0.71-1.13), time to ANC (SMD = 0.11, 95% CI, -0.34-0.56), and incidence of bone pain (RR = 0.95; 95% CI, 0.76 1.19) were similar between the two G-CSFs. The included trials varied in the type of cancer, chemotherapy regimen and type of trial. CONCLUSION: A single dose of pegfilgrastim performed better than a median of 10-14 days of filgrastim in reducing FN rates for patients undergoing myelosuppressive chemotherapy. PMID- 17697453 TI - Modeling the economic and health consequences of managing chronic osteoarthritis pain with opioids in Germany: comparison of extended-release oxycodone and OROS hydromorphone. AB - OBJECTIVE: The Osmotic controlled-Release Oral delivery System (OROS) hydromorphone ensures continuous release of hydromorphone over 24 hours. It is anticipated that this will facilitate optimal pain relief, improve quality of sleep and compliance. This simulation compared managing chronic osteoarthritis pain with once-daily OROS hydromorphone with an equianalgesic dose of extended release (ER) oxycodone administered two or three times a day. METHODS: This discrete event simulation follows patients for a year after initiating opioid treatment. Pairs of identical patients are created; one receives OROS hydromorphone the other ER oxycodone; undergo dose adjustments and after titration can be dissatisfied or satisfied, suffer adverse events, pain recurrence, or discontinue the opioid. Each is assigned an initial sleep problems score, and an improved score from a treatment dependent distribution at the end of titration; these are translated to a utility value. Utilities are assigned pre treatment, updated until the patient reaches the optimal dose or is non-compliant or dissatisfied. The OROS hydromorphone and ER oxycodone doses are converted to equianalgesic morphine doses using the following ratios: hydromorphone to morphine ratio; 1:5, oxycodone to morphine ratio; 1:2. Sensitivity analyses explored uncertainty in the conversion ratios and other key parameters. Direct medical costs are in 2005 euros. RESULTS: Over 1 year on a mean daily morphine equivalent dose of 90 mg, 14% were estimated to be dissatisfied with each opioid. OROS hydromorphone was predicted to yield 0.017 additional quality-adjusted life years (QALYs)/patient for a small additional annual cost (E141/patient), yielding an incremental cost-effectiveness ratio (ICER) of E8343/QALY gained. Changing the assumed conversion ratio for oxycodone:morphine to 1:1.5 led to lower net costs of E68 per patient, E3979/QALY, and for hydromorphone to 1:7.5 to savings. CONCLUSION: Based on these analyses, OROS hydromorphone is expected to yield health benefits at reasonable cost in Germany. PMID- 17697454 TI - Review and analysis of hospitalization costs associated with antipsychotic nonadherence in the treatment of schizophrenia in the United States. AB - OBJECTIVE: To review the literature addressing the economic outcomes of nonadherence in the treatment of schizophrenia, and to utilize the review results to provide an update on the economic impact of hospitalizations among schizophrenia patients related to antipsychotic nonadherence. METHODS: A structured search of EMBASE, Ovid MEDLINE, PubMed and PsycINFO for years 1995 2007 was conducted to identify published English-language articles addressing the economic impact of antipsychotic nonadherence in schizophrenia. The following key words were used in the search: compliance, noncompliance, adherence, nonadherence, relapse, economic, cost, and schizophrenia. A bibliographic search of retrieved articles was performed to identify additional studies. For a study to be included, the date of publication had to be from 1/1/1995 to 6/1/2007, and the impact of nonadherence had to be measured in terms of direct healthcare costs or inpatient days. Subsequently, an estimate of incremental hospitalization costs related to antipsychotic non adherence was extrapolated at the US national level based on the reviewed studies (nonadherence rate and hospitalization rate) and the National Inpatient Sample of Healthcare Cost and Utilization Project (average daily hospitalization costs). RESULTS: Seven studies were identified and reviewed based on the study design, measurement of medication nonadherence, study setting, and cost outcome results. Despite the varied adherence measures across studies, all articles reviewed showed that antipsychotic nonadherence was related to an increase in hospitalization rate, hospital days or hospital costs. We also estimated that the national rehospitalization costs related to antipsychotic nonadherence was $1479 million, ranging from $1392 million to $1826 million in the US in 2005. LIMITATIONS: The estimate of rehospitalization costs was restricted to schizophrenia patients from the Medicaid program. Additionally, the studies we reviewed did not capture the newer antipsychotic drugs (ziprasidone, aripiprazole and paliperidone). Thus, the nonadherence rates or rehospitalization rates might have changed after these new drugs came to the market, which could limit our cost estimation. CONCLUSIONS: Poor adherence to antipsychotic medications was consistently associated with higher risk of relapse and rehospitalization and higher hospitalization costs. To reduce the cost of hospitalizations among schizophrenia patients, it seems clear that efforts to increase medication adherence should be undertaken. PMID- 17697455 TI - Clinical outcomes using a flexible regimen of GnRH-antagonists and a 'step-up' of additional gonadotropins in donor oocyte cycles. AB - OBJECTIVE: To assess the impact of serum estradiol upon oocyte donor cycle stimulation characteristics and clinical outcomes using flexible GnRH-antagonist (GnRH-ant) with additional FSH supplementation. RESEARCH DESIGN AND METHODS: A retrospective chart review of 99 oocyte donor cycles using ovarian hyperstimulation with recombinant FSH (rFSH) and GnRH-ant was analyzed. Following discontinuation of oral contraceptives, controlled ovarian hyperstimulation was begun using rFSH (150-300 IU daily). GnRH-ant (ganirelix, Organon) and an additional 75 IU of FSH/day were begun when lead follicles were 13-14 mm in greatest diameter. Cycles were analyzed based on serum estradiol response following administration of GnRH-ant (Group 1: progressive rise and Group 2: no rise or a decline). Primary endpoints were cycle stimulation characteristics based on serum estradiol following GnRH-ant, clinical pregnancy and implantation rates. RESULTS: A decline in serum estradiol was seen after GnRH-ant administration in 45% of cycles. Clinical pregnancy rates per transfer (70 vs. 72%) and implantation rates (43 vs. 56%) were similar for each group. CONCLUSION: Flexible regimens of GnRH-ant even with additional rFSH in a 'step-up' fashion frequently result in a decline in serum estradiol during ovulation induction. While our study is non-randomized, it does not appear to result in any adverse affect in clinical outcomes in donor oocyte cycles. PMID- 17697456 TI - Clinical comparison of two topical prednisolone acetate 1% formulations in reducing inflammation after cataract surgery. AB - PURPOSE: To compare the efficacy of two formulations of prednisolone acetate 1% in reducing postoperative inflammation in patients having primary phacoemulsification surgery with IOL implantation. METHODS: This multicenter study was conducted in randomized, double-masked fashion with a parallel active control group. Patients undergoing phacoemulsification surgery with IOL implantation were assigned to one of two treatment groups receiving study drug in addition to standard therapy. Study drug was administered four times daily beginning one day before surgery, postoperatively for 14 days, then twice daily until the bottle was empty. Clinical efficacy was compared for differences in corneal surface keratitis, anterior chamber cells and flare, and postoperative pain. Results were compared on day 1, 2 weeks, and 4 weeks postoperatively. RESULTS: No statistical differences in clinical efficacy or safety were seen between the two formulations tested at any time point evaluated. CONCLUSIONS: In this study of routine cataract patients, both prednisolone acetate 1% formulations are comparably effective and safe when administered for the reduction of inflammation after phacoemulsification surgery with IOL implantation. PMID- 17697459 TI - Subsurface and transcutaneous Raman spectroscopy and mapping using concentric illumination rings and collection with a circular fiber-optic array. AB - Different spatial separations between an illumination ring and a bundle of 50 collection fibers focused to collect light in the center of the ring were used to investigate the recovery of subsurface Raman spectra. The depth of Raman signal recovery and the preservation of spatial information in the recovered signal were investigated using polymer blocks stacked in different geometries. The illumination rings were then combined into a single data set to increase variation in the signal. Multivariate data analysis was used to recover the Raman spectra of the subsurface component. The Raman spectrum of a Delrin target was recoverable at depths up to 22.6 mm of overlying Teflon. Spatial information was lost at approximately 6.5 mm below the Teflon surface. The same protocols were used to recover canine bone spectra transcutaneously at depths up to 5 mm below the skin's surface. The recovered bone spectra were validated by exposed bone measurements. PMID- 17697460 TI - Discrimination of bacteria and bacteriophages by Raman spectroscopy and surface enhanced Raman spectroscopy. AB - Detection of pathogenic organisms in the environment presents several challenges due to the high cost and long times typically required for identification and quantification. Polymerase chain reaction (PCR) based methods are often hindered by the presence of polymerase inhibiting compounds and so direct methods of quantification that do not require enrichment or amplification are being sought. This work presents an analysis of pathogen detection using Raman spectroscopy to identify and quantify microorganisms without drying. Confocal Raman measurements of the bacterium Escherichia coli and of two bacteriophages, MS2 and PRD1, were analyzed for characteristic peaks and to estimate detection limits using traditional Raman and surface-enhanced Raman spectroscopy (SERS). MS2, PRD1, and E. coli produced differentiable Raman spectra with approximate detection limits for PRD1 and E. coli of 10(9) pfu/mL and 10(6) cells/mL, respectively. These high detection concentration limits are partly due to the small sampling volume of the confocal system but translate to quantification of as little as 100 bacteriophages to generate a reliable spectral signal. SERS increased signal intensity 10(3) fold and presented peaks that were visible using 2-second acquisitions; however, peak locations and intensities were variable, as typical with SERS. These results demonstrate that Raman spectroscopy and SERS have potential as a pathogen monitoring platform. PMID- 17697461 TI - Feasibility of a wide area illumination scheme for reliable Raman measurement of petroleum products. AB - A newly developed Raman collection scheme, a wide area illumination (WAI) scheme, was employed to demonstrate its utility for the analysis of petroleum products. For this purpose, the compositional analysis of simulated naphtha samples was attempted. The WAI scheme utilized a laser beam that illuminated a sample in a circular fashion with a diameter of 6 mm and a focal length of 250 mm. The reproducibility of the Raman measurement can be improved due to decreased sensitivity of the sample position as well as orientation with regard to the focal plane, as shown in a previous study. Near-infrared (NIR) spectroscopy, widely adopted in the field of petroleum refining, was also employed to compare with the prediction results obtained using the WAI scheme. Since the Raman spectral feature is more distinct and selective, the resulting calibration accuracy could be improved as long as reproducible Raman spectra could be collected. Overall prediction results using Raman spectroscopy were superior to those from NIR spectroscopy. The feasibility of the WAI scheme for reliable Raman analysis of petroleum products such as naphtha was demonstrated in this paper. PMID- 17697462 TI - Requirements for relative intensity correction of Raman spectra obtained by column-summing charge-coupled device data. AB - The relative intensity correction of Raman spectra requires the measurement of a source of known relative irradiance. Raman spectrometers that employ two dimensional charge-coupled device (CCD) array detectors may be operated in two distinct modes. One mode directly measures the counts in each CCD pixel, but more commonly for the collection of spectra, the counts in the CCD row pixels are summed for a given column. If distortions in the corrected spectral shapes are to be avoided, operation in the mode where rows are summed places restrictions on the spatial intensity profile of the source of known irradiance that is used for the relative intensity correction procedure and, in some cases, also on the spatial intensity profile of the measured Raman light. Numerical expressions are given from which these restrictions can be derived. Magnitudes of distortions that can arise when intensity-correcting spectra obtained with CCD data where rows in a column are summed are estimated by modeling different cases. Data are given showing the inherent pixel quantum efficiency variation that exists in CCDs. Spectra are given showing the effects of a local area of significant change in pixel quantum efficiency that was found to be present on one CCD detector. PMID- 17697463 TI - Developing micro-Raman mass spectrometry for measuring carbon isotopic composition of carbon dioxide. AB - We investigated the applicability of micro-Raman spectroscopy for determining carbon isotopic compositions (13C/12C) of minute CO2 fluid inclusions in minerals. This method is nondestructive and has sufficiently high spatial resolution (1 microm) to measure each fluid inclusion independently. Raman spectra of CO2 fluid have 12CO2-origin peaks at about 1285 cm(-1) and 1389 cm(-1) (V(-)([12]) and V+[12]) and a 13CO2-origin peak at about 1370 cm(-1) (V+[13]). The relationship between carbon isotopic compositions and peak intensity ratios of V+[12] and V+[13] was calibrated. Considering several factors affecting the peak intensity ratio, the error in obtained carbon isotopic composition was 2% (20%). The reproducibility of the intensity ratio under the same experimental environment was 0.5% (5%). Within these error values, we can distinguish biogenic CO2 from abiogenic CO2. PMID- 17697464 TI - A sensitive chemiluminescence procedure for the determination of carbon monoxide with myoglobin-luminol chemiluminescence system. AB - A novel chemiluminescence method combined with the flow injection technique for the determination of carbon monoxide is presented in this paper. The chemiluminescence signal based on the reaction between myoglobin and luminol in an alkaline medium was remarkably enhanced by carbon monoxide. The enhanced chemiluminescence intensity was linear with carbon monoxide concentration in the range from 0.01 to 10.0 pmol.L(-1), and the detection limit was 3x10(-3) pmol.L( 1) (3sigma). The whole process, including sampling and washing, could be completed in 0.5 min with a relative standard deviation of less than 4.0%. The proposed method was applied successfully in the assay of carbon monoxide in human serum and artificial water samples without any pretreatment procedure. PMID- 17697465 TI - Single particle fluorescence: a simple experimental approach to evaluate coincidence effects. AB - Real-time characterization of the chemical and physical properties of individual aerosol particles is an important issue in environmental studies. A well established way of accomplishing this task relies on the use of laser-induced fluorescence or laser ionization mass spectrometry. We describe here a simple approach aimed at experimentally verifying that single particles are indeed addressed. The approach has been tested with a system consisting of a series of aerodynamic lenses to form a beam of dye-doped particles aerosolized from a solution of known concentration with a medical nebulizer. Two independent spectral detection channels simultaneously measure the fluorescence signals generated in two different spectral regions by the passage of a mixture of two dye-doped particles through a focused laser beam in a vacuum chamber. Coincidence effects, arising from the simultaneous observation of both fluorescence emissions, can then be directly observed. Both dual-color fluorescence and pulse height distribution have been analyzed. As expected, the probability of single- or multiple-particle interaction strongly depends on the particle flux in the chamber, which is related to the concentration of particles in the nebulized solution. In our case, to achieve a two-particle coincidence smaller than 10%, a particle concentration lower than 1.2x10(5) particles/mL is required. Moreover, it was found that the experimental observations are in agreement with a simple mathematical model based on Poisson statistics. Although the results obtained refer to particle concentrations in solution, our approach can equally be applicable to experiments involving direct air sampling, provided that the number density of particles in air can be measured a priori, e.g., with a particle counter. PMID- 17697466 TI - Optical restriction of plasma emission light for nanometric sampling depth and depth profiling of multilayered metal samples. AB - Improvement in depth profiling capabilities of laser-induced breakdown spectrometry (LIBS) for multilayered samples has been attempted. For this purpose, in a typical LIBS experiment, an optical restriction consisting of a pinhole placed between the dichroic mirror and the collecting lenses has been used. This new optical approach allows observing only the light emission coming from the central region of the plume. The microplasma was created on the sample by a pulsed Nd:YAG laser operating at 1064 nm with a homogeneous distribution of energy across the beam. Light emitted by the microplasma was detected with an intensified charge-coupled device (iCCD) multichannel detector. The effect of pinhole diameter and the delay time influence on depth analysis have been assessed. An ablation range of only a few nanometers per pulse has been achieved. Depth profiles of various metals (Cr, Ni, Cu) from multilayered samples have been generated by LIBS and depth resolution at different delay times using various pinhole diameters have been calculated and compared. PMID- 17697467 TI - Population measurement of the 3p(5)4s configuration levels in an argon microwave plasma at atmospheric pressure. AB - Metastable atoms, due to their intrinsic properties, are very useful to characterize plasma and to control the scientific and technological applications carried out with it. This paper describes the implementation of a method to determine the densities of the argon 3p(5)4s metastable and resonant levels in a microwave plasma at atmospheric pressure. Because the method is based on the self absorption of the radiation emitted by the plasma, no external radiation source is needed. Using this method, the populations of the four levels of the 3p(5)4s argon configuration were found to be in the range 10(10)-10(12) cm(-3), in agreement with the values found in the literature. PMID- 17697468 TI - Spectral renormalization for multi-component fourier transform infrared absorbance data: importance to multivariate calibration and quantitative exploratory chemometrics studies. AB - Although infrared spectroscopy is a very common analytical tool in the chemical sciences, quantitative infrared spectroscopic studies of multi-component solutions (particularly on-line or in-line studies) have been hampered by the lack of a concise and robust numerical approach. Using an inert chemical species as internal standard, the usual absorbance ratio analysis is generalized into a mathematical form that converts typical absorbance measurement A into its renormalized absorbance A(renorm), with the latter directly relating to the absolute moles rather than the concentration of the constituents. The renormalized absorbance has a number of very important properties, including (1) insensitivity to path length changes due to variations in temperature or pressure of the Fourier transform infrared (FT-IR) cell and (2) insensitivity to solution volume changes arising from reaction, chemical transport, or thermodynamic conditions. The methodology is first applied to a simple model test system to demonstrate its utility for multivariate calibration, and then re-applied to a real problem: the calibration of the rhodium carbonyl hydride HRh(CO)4, a long sought species in organometallic chemistry and homogeneous catalysis (Angewandte Chemie Int. Ed., vol. 41, 3786 (2002)). The utility of the developed methodology for multivariate calibration and exploratory chemometric studies is demonstrated. Emphasis is placed on providing a numerical recipe for the practicing analytical chemist. PMID- 17697469 TI - Importance of prediction outlier diagnostics in determining a successful inter vendor multivariate calibration model transfer. AB - This paper reports on the transfer of calibration models between Fourier transform near-infrared (FT-NIR) instruments from four different manufacturers. The piecewise direct standardization (PDS) method is compared with the new hybrid calibration method known as prediction augmented classical least squares/partial least squares (PACLS/PLS). The success of a calibration transfer experiment is judged by prediction error and by the number of samples that are flagged as outliers that would not have been flagged as such if a complete recalibration were performed. Prediction results must be acceptable and the outlier diagnostics capabilities must be preserved for the transfer to be deemed successful. Previous studies have measured the success of a calibration transfer method by comparing only the prediction performance (e.g., the root mean square error of prediction, RMSEP). However, our study emphasizes the need to consider outlier detection performance as well. As our study illustrates, the RMSEP values for a calibration transfer can be within acceptable range; however, statistical analysis of the spectral residuals can show that differences in outlier performance can vary significantly between competing transfer methods. There was no statistically significant difference in the prediction error between the PDS and PACLS/PLS methods when the same subset sample selection method was used for both methods. However, the PACLS/PLS method was better at preserving the outlier detection capabilities and therefore was judged to have performed better than the PDS algorithm when transferring calibrations with the use of a subset of samples to define the transfer function. The method of sample subset selection was found to make a significant difference in the calibration transfer results using the PDS algorithm, while the transfer results were less sensitive to subset selection when the PACLS/PLS method was used. PMID- 17697470 TI - Thermal degradation of poly(3-hydroxybutyrate) and poly(3-hydroxybutyrate-co-3 hydroxyhexanoate) in nitrogen and oxygen studied by thermogravimetric-Fourier transform infrared spectroscopy. AB - The thermal degradation behavior of poly(3-hydroxybutyrate) (PHB) and poly(3 hydroxybutyrate-co-3-hydroxyhexanoate) (P(HB-co-HHx), HHx=12 mol%) has been studied under different environmental conditions by thermogravimetric analysis (TGA) Fourier transform infrared (FT-IR) spectroscopy. It is reported that at higher temperature (>400 degrees C) carbon dioxide and propene are formed from the decomposition product crotonic acid in a nitrogen atmosphere, whereas in an oxygen atmosphere propene oxidizes in a further step to carbon dioxide, carbon monoxide and hydrogen. It was also found that PHB and P(HB-co-HHx) have a similar thermal degradation mechanism. The analysis of the FT-IR-spectroscopic data was performed with 2D and perturbation-correlation moving-window 2D (PCMW2D) correlation spectroscopy. PMID- 17697471 TI - Structure analysis of poly(N-isopropylacrylamide) using near-infrared spectroscopy and generalized two-dimensional correlation infrared spectroscopy. AB - Based on a detailed study of the fundamental vibrations in the mid-infrared (MIR) region and supported by NH-proton deuteration results, the assignment of the overtone and combination bands in the near-infrared (NIR) spectrum of poly(N isopropylacrylamide) (PNIPAM) is presented. Variable-temperature experiments and two-dimensional correlation infrared spectroscopy are used to determine the chemical mechanism and changing sequence of groups in PNIPAM; we conclude that bonded NH groups turn into free NH groups during the heating process, while the CH groups on the side-chains change prior to those on the main chains. A heterospectral dynamical correlation between the NIR and MIR regions or H included groups in both regions was also performed. The temperature-induced dissociation of the hydrogen-bonded NH groups is found to proceed earlier than the conformational changes in the hydrocarbon chains. PMID- 17697472 TI - Spectroscopic study of the uranyl-acetohydroxamate adduct with tributyl phosphate. AB - The ultraviolet-visible (UV-Vis) and Fourier transform infrared (FT-IR) spectroscopic studies carried out for the system UO2(NO3)/AHA/TBP (uranyl acetohydroxamate-tributyl phosphate) confirmed the presence of the adduct of UO2(NO3)(AHA) 2TBP with 1:1 stoichiometry for UO2:AHA (acetohydroxamic acid). The spectrum of this complex is identical to the infrared spectrum of the organic phase formed in the uranium distribution experiments with 30% TBP/n-dodecane and AHA present in aqueous phase. Disappearance of the hydroxyl stretching band and a shift in the position of the carbonyl band in the infrared spectra revealed that both the hydroxyl and the carbonyl group of acetohydroxamic acid are involved in the chelate ring with uranium. Also, acetic acid, accrued after acidic hydrolysis of acetohydroxamic acid, was identified in the extraction organic phase. PMID- 17697473 TI - Sheath-flow cuvette for high-sensitivity laser-induced fluorescence detection in capillary electrophoresis. AB - The sheath-flow cuvette is a key component in a high-sensitivity post-column laser-induced fluorescence detector for capillary electrophoresis. Most designs are based on commercial cuvettes originally manufactured for use in a flow cytometer. In these devices, a quartz flow chamber is held in a stainless-steel fixture that is difficult to machine and subjects the cuvette to a torque when sealed, which frequently leads to damage of the flow chamber. In this report we present a design for a cuvette that may easily be constructed. This design uses compression to hold and seal the quartz flow chamber without applying torque. The system produces detection limits (3sigma) of 115 yoctomoles (70 copies) for FQ labeled carbonic anhydrase. PMID- 17697474 TI - Potential of far-ultraviolet absorption spectroscopy as a highly sensitive qualitative and quantitative analysis method for polymer films, part I: classification of commercial food wrap films. AB - The aim of the present study is to propose a totally new technique for the utilization of far-ultraviolet (UV) spectroscopy in polymer thin film analysis. Far-UV spectra in the 120-300 nm region have been measured in situ for six kinds of commercial polymer wrap films by use of a novel type of far-UV spectrometer that does not need vacuum evaporation. These films can be straightforwardly classified into three groups, polyethylene (PE) films, polyvinyl chloride (PVC) films, and polyvinylidene chloride (PVDC) films, by using the raw spectra. The differences in the wavelength of the absorption band due to the sigma-sigma* transition of the C-C bond have been used for the classification of the six kinds of films. Using this method, it was easy to distinguish the three kinds of PE films and to separate the two kinds of PVDC films. Compared with other spectroscopic methods, the advantages of this technique include nondestructive analysis, easy spectral measurement, high sensitivity, and simple spectral analysis. The present study has demonstrated that far-UV spectroscopy is a very promising technique for polymer film analysis. PMID- 17697475 TI - Noninvasive characterization of pharmaceutical solids by diode laser oxygen spectroscopy. PMID- 17697477 TI - Investigating the active ingredients of cognitive behaviour therapy and counselling for patients with chronic fatigue in primary care: developing a new process measure to assess treatment fidelity and predict outcome. AB - OBJECTIVES: To develop a brief measure of the therapy process and use it to examine which therapeutic ingredients were associated with outcome in a sample of patients from a randomized controlled trial (RCT) of cognitive behaviour therapy (CBT) versus counselling for patients with chronic fatigue in primary care. It was hypothesized that the two therapies would be clearly distinguishable and that in terms of process variables, the therapeutic alliance would be important in predicting outcome. DESIGN: The data for this study were collected alongside a RCT in primary care and included audiotaped therapy sessions. These tapes were assessed by two independent raters using a newly devised measure in order to evaluate therapy process and its relationship with outcome. METHODS: Tapes from 71 patients participating in the RCT were assessed to form the basis of the process analysis. Outcome was self-reported fatigue symptoms at 6 months follow up. Data reduction was achieved via a principal component analysis (PCA). Factors were entered into a multiple regression analysis to produce a final model of predictors of outcome. RESULTS: The process measure showed that although the treatments could be distinguished, there was some overlap between them. The key predictor of a good fatigue outcome was emotional processing, including the expression, acknowledgement and acceptance of emotional distress. CONCLUSION: A new process measure was developed successfully which now warrants further testing. It was able to assess treatment adherence and unpack, and distinguish the common factor which predicted outcome across therapy modalities. The findings lend preliminary support to the view that the specific techniques associated with particular 'brand names' of therapy are not necessarily the 'active ingredients' that help patient's change within the primary care setting. Emotional processing predicted outcome for patients with chronic fatigue and therefore future research might explore this in more depth, in order to understand better how it can be facilitated. PMID- 17697478 TI - Psychometric properties of the Depression Anxiety Stress Scales (DASS) in depressed clinical samples. AB - OBJECTIVES: The psychometric properties of the Depression Anxiety Stress Scales (DASS; Lovibond & Lovibond, 1995a) were examined in depressed psychiatric hospital samples. DESIGN AND METHODS: Three studies administered the DASS and other symptom measures at admission and discharge to consecutive adult hospital patients with a primary diagnosis of depression. Study 3 aimed to address problems with the DASS by extending the response options. RESULTS: Study 1 found that the DASS had good reliability and validity, was moderately sensitive to change, but the Depression Scale exhibited a ceiling effect. In Study 2, confirmatory factor analysis supported a three-factor structure and the DASS continued to demonstrate good psychometric properties, but the ceiling effect was replicated. Study 3 found that by extending the response scale to include an additional option, the factor structure of the instrument as a whole was maintained, the sensitivity to treatment was increased, but the ceiling effect was only marginally reduced. CONCLUSIONS: The psychometric properties of the DASS were sound in clinically depressed samples, but the Depression Scale exhibited a ceiling effect that could not be resolved with minor changes to the scale. Suggestions for revisions of the DASS are made. PMID- 17697479 TI - [A network to promote health systems based on primary health care in the Region of the Americas]. AB - OBJECTIVES: To identify the relational components of an international network of organizations that provide technical and financial assistance to promote the development of health systems based on primary health care in the countries of the Region of the Americas; to analyze the linkages that would allow the collaborating partners of the Pan American Health Organization (PAHO) to work together on health issues; and to determine the basic theoretical elements that can help to develop action strategies that support advocacy efforts by a network. METHODS: This was a qualitative and quantitative cross-sectional study based on identifying key informants and on analyzing social networks. Ethnographic and relational information from 46 international organizations was collected through a self-administered semistructured questionnaire. From 46 international health cooperation organizations, 29 decision makers from 29 organizations participated (63.0% response rate). The structure and the strength of the network was evaluated in terms of density, closeness, clustering, and centralization. The statistical analysis was done using computer programs that included UCINET, Pajek, and Microsoft Access. RESULTS: We found a structurally centralized theoretical network, whose nodes were clustered into four central subgroups linked by a shared vision. The leadership, influence, and political interests reflected the formal and technical-cooperation linkages, the formal support for health systems based on primary health care, and the flow of resources being more often technical ones than financial ones. CONCLUSIONS: The interorganizational relational components and the social-action ties that were identified could help in the development and consolidation of a thematic network for advocacy and for the management of technical and financial assistance that supports primary health care in the Americas. The linkages for joint action that were identified could advance international cooperation in developing health systems based on primary health care, once PAHO formulates clear implementation strategies and takes a leadership position in mobilizing financial resources and in creating informal and interpersonal linkages for action. PMID- 17697480 TI - Risk factors for asthma and cough among Hispanic children in the southwestern United States of America, 2003-2004. AB - OBJECTIVES: To investigate the impact of environmental tobacco smoke (ETS) exposure and mother's place of birth (Mexico vs. United States of America) on the prevalence of asthma and dry nighttime cough among children 2-12 years old residing in the southwestern United States. METHODS: Data were collected from November 2003 through March 2004 as part of a health survey of Hispanic mothers with young children who sought emergency, nutrition, or other clinical services. Information about respiratory health was obtained for one randomly selected child per United States-born (no. = 144) or Mexico-born (no. = 125) mother. Information on maternal and household sociodemographic variables, smoking, parental asthma, and child's exposure to room or automobile ETS during the previous seven days was also collected. Adjusted prevalence ratios were estimated with modified Poisson regression models. RESULTS: Most sociodemographic and ETS exposure variables differed significantly by mother's country of birth. Modeled asthma prevalence was 1.95 [95% confidence interval (CI) = 1.03-3.68] times greater in children of United States-born mothers than children of Mexico-born mothers. This difference persisted after known asthma risk factors were controlled for, including parental asthma, socioeconomic and demographic variables, and child ETS exposure. Children's recent automobile ETS exposure was associated with dry nighttime cough [adjusted prevalence ratio (PR) = 1.94, 95% CI = 1.19-3.15] and asthma (PR = 2.09; 95% CI = 0.99-4.39). CONCLUSIONS: Exposure to ETS in automobiles is an important risk factor for asthma and dry nighttime cough among Hispanic children in the southwest United States, regardless of mother's country of birth. Further research is needed to identify causes of the higher prevalence of asthma in Hispanic children of United States-born mothers. PMID- 17697481 TI - [The relationship between deaths that are avoidable with adequate health care and the implementation of the Unified Health System in Brazil]. AB - OBJECTIVE: To analyze the relationship between the occurrence of deaths that are avoidable with adequate health care and the reorganization of the Brazilian health care system between 1983 and 2002. METHOD: This ecological study analyzed avoidable mortality in 117 municipalities of Brazil. The causes of death avoidable with adequate health care were grouped into three: (1) ones avoidable through early diagnosis and treatment, (2) ones avoidable with improvements in the quality of treatment and medical care, and (3) ischemic heart disease. To evaluate the association between avoidable mortality and reorganization of the health care system, the period under study was divided into two subperiods: from 1983 through 1992 and from 1993 through 2002 (respectively, before and after approval of the operational guideline that served as the reference for the organization of the Unified Health System (Sistema Unico de Saude)). A negative binomial regression model that controlled for sex, age, geographic region, and socioeconomic conditions was used for the analysis. RESULTS: During the period analyzed, 1 854 165 individuals between 0 and 74 years old died from avoidable causes in the municipalities studied. The multivariate analysis showed that, for all three groups of avoidable causes, the risk of avoidable mortality was higher in the 1983-1992 subperiod than in the 1993-2002 subperiod. For the entire 1983 2002 period, the risk was higher for males than for females, especially with respect to ischemic heart disease. Younger populations had lower risk. Higher socioeconomic level reduced the risk of death from avoidable causes, except for ischemic heart disease. CONCLUSIONS: Our results suggest that in Brazil the decrease in avoidable mortality from the 1983-1992 subperiod to the 1993-2002 subperiod was partially due to the changes in the availability of and access to health services brought about by the reorganization of the Brazilian health care system. PMID- 17697482 TI - Sociodemographic and nutritional correlates of neurobehavioral development: a study of young children in a rural region of Ecuador. AB - OBJECTIVE: To identify and describe the sociodemographic and nutritional characteristics associated with neurobehavioral development among young children living in three communities in the northeastern Andean region of Cayambe Tabacundo, Ecuador. METHODS: Women in the study communities who had a child 3 to 61 months of age completed a questionnaire about maternal and child health and sociodemographic characteristics. The Ages and Stages Questionnaire (ASQ) was directly administered to 283 children by two trained interviewers. Growth measurements and a hemoglobin finger-prick blood test were obtained in 2003-2004. Prevalence of developmental delay was calculated, and associations between child development and maternal, child, and household characteristics were explored. RESULTS: High frequencies of developmental delay were observed. Children 3 to 23 months old displayed delay in gross motor skills (30.1%), and children 48 to 61 months old displayed delay in problem-solving skills (73.4%) and fine motor skills (28.1%). A high frequency of both anemia (60.4%) and stunting (53.4%) was observed for all age groups. Maternal educational level was positively associated with communication and problem-solving skills, and monthly household income was positively associated with communication, gross motor, and problem-solving skills. CONCLUSIONS: The results suggest a high prevalence of developmental delay and poor child health in this population. Child health status and the child's environment may contribute to developmental delay in this region of Ecuador, but sociodemographic factors affecting opportunities for stimulation may also play a role. Research is needed to identify what is causing high percentages of neurobehavioral developmental delay in this region of Ecuador. PMID- 17697483 TI - [Effectiveness of the "Five-Day Plan to Stop Smoking" in a city in Argentina]. AB - OBJECTIVES: To evaluate the effectiveness of the "Five-Day Plan to Stop Smoking" at the end of the intervention and after one year in a sample of participants in the city of Rosario, Santa Fe, Argentina. METHODS: The quasi-experimental, longitudinal, prospective cohort, comparative study was based on the evaluation of the effectiveness of the "Five-Day Plan to Stop Smoking" in Rosario, Argentina, with eight groups of participants. Each session of the five-night course included presentations on medical aspects of smoking, an emphasis on group support in quitting, and relaxation techniques. The eight groups included a total of 739 people (50.5% of them women and 49.5% men). Using a sample of 281 participants who were chosen at random, effectiveness was evaluated immediately after the end of each course and again after one year. Effectiveness was assessed in relation to the age the subjects began smoking, the average daily consumption of cigarettes, the number of years participants had smoked, their educational level, the number of previous attempts to quit smoking, and the level of nicotine dependence as measured by the Fagerstrom scale. Association among qualitative variables was determined using relative risk (RR), with 95% confidence intervals. Differences in the means of quantitative variables were determined using the t test for independent samples. The chi-square test was used to establish differences among the categorical variables studied. RESULTS: Of the 281 participants (138 men and 143 women) in the sample, 201 (71.5%) (104 men and 97 women) quit smoking by the end of the course, and 77 (27.4%) (48 men and 29 women) did not smoke after one year. There was a significant association between relapse and female gender (RR = 1.22; P = 0.005), as was there for a score > or = 7 on the Fagerstrom scale of nicotine dependence (RR = 1.17; P = 0.03). Beginning to smoke before the age of 20 was a protective factor against relapse among those attending the "Five-Day Plan to Stop Smoking" courses. The most frequent determinants of relapse were abstinence syndrome symptoms (40.3%) and stressful situations (28.2%). CONCLUSIONS: The "Five-Day Plan to Stop Smoking" is an effective tool for secondary prevention of smoking. In the study population its effectiveness was associated with male gender and with a lower level of nicotine dependence. PMID- 17697484 TI - [Non-HDL cholesterol levels in students aged 7 to 17 years in a Brazilian town]. AB - OBJECTIVE: To describe the levels of non-HDL cholesterol and correlated factors in a group of Brazilian male and female children and adolescents. METHODS: From March to October 2002 we evaluated 2,029 schoolchildren from 7 to 17 years old in the town of Maracai, Sao Paulo, Brazil. The biochemical determinations of triglycerides, total cholesterol, and high-density lipoprotein (HDL) cholesterol were carried out using enzymatic reactions and the Vitros 750 analyzer. Low density lipoprotein (LDL) cholesterol levels were calculated using the Friedewald formula: LDL cholesterol = total cholesterol-HDL cholesterol-(triglycerides/5). Non-HDL cholesterol was calculated by subtracting HDL cholesterol from total cholesterol. RESULTS: The correlation between non-HDL cholesterol levels and LDL cholesterol levels was 0.971 (P < 0.001). Non-HDL cholesterol had a stronger correlation than did LDL cholesterol with all the variables under study: total cholesterol, triglycerides, HDL cholesterol, very low-density lipoproteins, body mass index, and waist circumference. The non-HDL cutpoints identified as corresponding to the four cutpoints of LDL cholesterol (110, 130, 160, and 190 mg/dL) indicating the need to treat dyslipidemia in children and adolescents were, respectively: 127.8, 149.2, 181.2, and 213.2 mg/dL. CONCLUSIONS: Our findings contribute toward estimating non-HDL levels in Brazilian children and adolescents. The results also indicate that non-HDL cholesterol is a reliable and less costly method for researching the presence of dyslipidemias in this age group. PMID- 17697485 TI - [A validation of the MOS-HIV quality of life measure in HIV-infected patients in Mexico]. AB - OBJECTIVE: To validate the Medical Outcomes Study HIV Health Survey (MOS-HIV) quality of life instrument for its application in clinical research in Mexico. METHODS: The data for this study were collected between April, 2002, and February, 2004. An expert committee combined two Spanish-language translations of the MOS-HIV questionnaire. The new questionnaire's feasibility was assessed in a group of 32 HIV-infected persons by measuring how long they took to complete the questionnaire and the numbers of items they left unanswered. The questionnaire was then applied to a group of 120 HIV-positive patients and to a control group of 102 HIV-negative individuals. The following questionnaire characteristics were evaluated: (1) internal reliability (Cronbach alpha coefficient), (2) discriminant validity (the receiver operating characteristic (ROC) curves derived from the scores of the two groups), and (3) convergent validity (the Spearman correlation coefficients for the scores of the HIV-positive patients on the 11 MOS-HIV dimensions and their scores on the analog visual scale of the European Quality of Life 5-Dimensional format (EQ-5D) questionnaire, a list of symptoms, the viral load, and the CD4 cell count). RESULTS: The mean response time with the questionnaire was 10 minutes and 22 seconds, and the mean number of unanswered items was 0.62. With each of the 11 dimensions of the questionnaire, the Cronbach alpha coefficient was at least 0.75. The mean scores obtained by the two groups were different for 9 of the 11 dimensions, and the 95% confidence intervals of the areas under the ROC curves did not include the value of 0.5 for 8 of the dimensions. The absolute value of the Spearman correlation coefficient was less than 0.3 for the CD4 cell count and for the viral load, and it was greater than 0.3 for each dimension and the scores on the list of symptoms and on the analog visual scale of the EQ-5D questionnaire. CONCLUSIONS: The MOS-HIV measure is valid for use in clinical research among HIV-infected persons in Mexico. PMID- 17697486 TI - Gender and health inequalities among adolescents and adults in Brazil, 1998. AB - OBJECTIVES: To assess the extent of gender inequalities in health status and health services utilization among adolescents and adults in Brazil. METHODS: A representative sample of 217,248 individuals from 15 to 64 years of age was obtained from the National Household Sample Survey (Pesquisa Nacional de Amostras por Domicilios, PNAD) conducted in 1998 by the Brazilian Institute of Geography and Statistics and funded by the Ministry of Health. The study focused on three outcome variables (self-assessed health status, medical visits, and hospitalizations (except childbirth)) and five exposure variables (age, gender, ethnicity, income, and education). Unconditional logistic regression and Mantel Haenszel stratified analysis was employed. Prevalence rate ratios were calculated for each stratum. Confidence intervals were calculated using the Taylor series, with a 95% confidence interval (95% CI). RESULTS: Women were more likely to report fair or poor health than men (odds ratio (OR) = 1.33; 95% CI: 1.31-1.35). Gender disparities were significant for all ages, household income brackets, and education levels, and were always unfavorable to women (1.17 < or = OR < or = 1.44). Gender disparities for medical visits were higher for those in good health; tended to fall as age, income, and education increased; and were always favorable for women (1.12 < or = OR < or = 2.06). Gender disparities in hospitalization rates decreased with age, varied according to income and education level in each age group, and were always favorable for women (1.16 < or = OR < or = 1.66). CONCLUSIONS: The difference in self-reported health status for men and women became even greater after adjusting for socioeconomic variables, suggesting that poorer women have more pronounced, relative differences than men do. The impact of structural determinants, such as education and income, is considerably smaller than the social construct of gender, although the former are more important predictors. Women use health services more often than men do, which is consistent with their health needs. However, medical visit rates show an inverse relationship to health care needs, suggesting an inequitable access to outpatient care, mainly preventive care. PMID- 17697487 TI - What about the women? Ethical and policy aspects of egg supply for cloning research. AB - As more and more countries open their doors to human cloning and embryonic stem cell research, scientists will be confronted with one fundamental problem: where will all the eggs come from? The mass harvesting of eggs raises serious issues about women's health, status and well-being. This paper critically examines proposals for ova supply such as altruistic donation, surplus IVF eggs and commercial sale. It questions the meaningfulness of informed consent and the risk benefit ratio in a climate where powerful economic and social forces increasingly view the risks to women as the necessary trade-off for scientific advance. PMID- 17697488 TI - Minimal ovarian stimulation with clomiphene citrate: a large-scale retrospective study. AB - Enclomiphene, an isomeric component of clomiphene citrate, acts antagonistically to the oestradiol receptor at the hypothalamus level, inhibiting both negative and positive feedback, and resulting in the induction of ovarian stimulation and suppression of ovulation. The minimal ovarian stimulation protocol takes full advantage of these characteristics of clomiphene citrate. Administration of 50 mg clomiphene citrate is initiated on cycle day 3, and from day 8 patients receive 150 IU of FSH every other day. When the size of the dominant follicle and the oestradiol concentration reach the predefined values, gonadotrophin-releasing hormone agonist is administered to induce follicular maturation. Oocytes are then retrieved 32-35 h later. Because the short half-life of enclomiphene (24 h) is of critical importance in this protocol, it is necessary to continue oral administration of clomiphene citrate until the day before maturation is triggered. Of all 43,433 cycles initiated, the rates for oocyte retrieval and embryo cleavage were 83 and 64% respectively. The mean number of oocytes retrieved was 2.2. The rates for live births, miscarriages, and ectopic pregnancies, in relation to initiated cycles, including cases of frozen-thawed transfer, were 11.1, 3.4 and 0.2% respectively. PMID- 17697489 TI - Natural cycle IVF with and without terminal HCG: learning from failed cycles. AB - Natural cycle IVF, without the use of LH down-regulation, is difficult because women start spontaneous LH surges at any time of the day and on any day of the week. This is not readily compatible with delivery of a routine IVF service and so historically the natural cycle has been modified by the use of human chorionic gonadotrophin (HCG) to make the natural cycle fit convenient clinical practice. This report re-evaluates data collected some years ago and seeks to determine whether the use of HCG is ultimately beneficial. Two large series of natural cycle IVF where only LH monitoring was performed (534 cycles) or where this was combined with HCG as necessary (241 cycles) were analysed. In essence, the use of HCG introduced as many problems as it overcame: there was no net benefit with respect to the number of eggs collected or clinical pregnancies generated. In fact there was an overall deterioration in all indices. The principle difficulties with natural cycle IVF are those associated with the prediction of follicle maturity and hence timing egg collection, and the conflict between costly and intrusively frequent monitoring with simpler but far less effective approaches. PMID- 17697490 TI - Gonadotrophin therapy in combination with ICSI in men with hypogonadotrophic hypogonadism. AB - The aim of this study was to evaluate the impact of gonadotrophin therapy in combination with intracytoplasmic sperm injection (ICSI) in men with hypogonadotrophic hypogonadism (HH). Twenty-five azoospermic men were diagnosed with HH due to low FSH, LH and total testosterone concentrations. These patients were treated with human chorionic gonadotrophin for 1 month plus recombinant FSH the following month. Total testosterone concentrations were measured in the first and third months. Semen analyses were performed monthly after the third month of treatment. ICSI was performed when sperm production commenced. Total testosterone concentration and testicular volume were significantly increased after gonadotrophin therapy (P < 0.001). On average, spermatozoa were detected in the ejaculate after 10 months. Spontaneous pregnancies were achieved in four couples. Twenty-two ICSI cycles were performed in 18 couples using ejaculated or testicular spermatozoa, and 12 pregnancies (54.5% per cycle) were achieved. These results showed that HH could be treated successfully with hormonal therapy combined with ICSI using ejaculated spermatozoa. The use of ICSI made it possible to achieve pregnancy when spermatozoa appeared in the ejaculate, and shortened the duration of gonadotrophin therapy. PMID- 17697491 TI - Adding human menopausal gonadotrophin to antagonist protocols - is there a benefit? AB - The objective of this retrospective analysis was to compare the clinical outcomes of recombinant FSH (r-FSH) with combination r-FSH plus human menopausal gonadotrophin (HMG) protocols in a large private practice using a single IVF laboratory, from 2001 to 2003. Patients underwent ovarian stimulation by standard gonadotrophin-releasing hormone (GnRH) antagonist protocol using r-FSH or combination r-FSH plus HMG. When two or more follicles had attained a minimum mean diameter of 20 mm, follicular triggering was achieved with either recombinant HCG (r-HCG; Ovidrel, 250 microg s.c.) or urinary HCG (u-HCG; 10,000 IU i.m.). The main outcome measures were number of oocytes retrieved and clinical pregnancy rate. There was a lower percentage of cancelled cycles and an increased number of oocytes retrieved, mature oocytes, oocytes that fertilized, embryo that cleaved and a tendency towards higher clinical pregnancy rates in patients treated with r-FSH alone compared with those treated with r-FSH plus HMG. Patients treated with r-FSH plus HMG had lower miscarriage rates and the live birth rate was similar in both treatment groups. In conclusion, irrespective of age, using a treatment regimen consisting of a combination of HMG plus r-FSH was not beneficial compared with r-FSH alone in patients using a GnRH antagonist protocol. PMID- 17697492 TI - Effect of a sharp serum oestradiol fall before HCG administration during ovarian stimulation in donors. AB - The current study evaluated how a sudden fall in serum oestradiol during ovarian stimulation in donors affects recipient outcome. After the assessment of pregnancy rate in cases of oestradiol falls of <10 or > or =10% (57.0 versus 45.6%), <20 or > or = 20% (55.2 versus 44.9%), <25 or > or =25% (57.2 versus 41.2%), and < 30 or > or =30% (57.1 versus 32.0%; P < 0.05), a significantly lower pregnancy rate was observed when the fall was > or =30%. Therefore, the study group (n = 25) included recipients who received oocytes from donors with a fall of > or =30%, and the control group included patients (n = 197) in which the fall in oestradiol was <30% and all cases with no fall in oestradiol concentrations. Pregnancy rates in both groups were 32.0 versus 57.1%; P < 0.05. The number of morphologically normal oocytes was similar (14.2 versus 18.1%) and good quality embryos was lower (8.0 versus 21.0%; P < 0.05) for study group. This seems related to a lower capability of the embryos to implant (15.2 versus 37.4%; P < 0.001). These data indicate that a fall of > or =30% in serum oestradiol concentration during ovarian stimulation in donors negatively affects pregnancy rates and embryo quality in recipients. In these cases, cycle cancellation should be considered. PMID- 17697493 TI - Evidence-based clinical outcome of oocyte slow cooling. AB - In the last few years, there has been a significant improvement in oocyte cryopreservation techniques. To investigate the clinical significance of oocyte freezing, an assessment of the cumulative pregnancy rate per started cycle derived from the use of fresh and frozen-thawed oocytes was performed. Between 2004 and 2006, 749 cycles were carried out, in which no more than three fresh oocytes were inseminated either by standard IVF or microinjection. Supernumerary mature oocytes were cryopreserved by slow cooling. Cryopreservation of fresh embryos was performed in rare cases to prevent the risk of ovarian hyperstimulation syndrome using a standard embryo freezing protocol. Fresh embryo transfer cycles totalled 680, 257 of which resulted in pregnancy. The pregnancy rates per patient and per transfer were 34.3% and 37.8% respectively. When frozen thawed oocytes were used, following 660 thawing cycles, 590 embryo transfers were performed in 510 patients. Eighty-eight pregnancies were achieved with embryos from frozen oocytes, with a success rate of 17.2% per cycle. When fresh and frozen-thawed cycles were combined, the number of pregnancies was 355, giving a cumulative pregnancy rate of 47.4%. Oocyte cryopreservation can contribute considerably to the overall clinical success, ensuring a cumulative rate approaching that achievable with embryo storage. PMID- 17697495 TI - D-Mannose-binding sites are putative sperm determinants of human oocyte recognition and fertilization. AB - The aim of the present study was to further evaluate the participation of D mannose in the process of human sperm-egg interaction. Zona pellucida binding competitive assays in the presence of D-mannose were carried out using discarded oocytes from IVF. Spermatozoa were capacitated and D-mannose-binding site (MBS) expression, sperm viability and follicular fluidinduced acrosome reaction (AR) were evaluated. MBS were visualized using a fluorescein-neoglycoprotein probe. The capacity of free D-mannose and mannosylated albumin to induce the AR was also tested. MBS and the IVF outcome were also analysed. The involvement of D-mannose in sperm binding to the zona pellucida was verified by the inhibitory effect produced when the sugar was present during binding assays. MBS expression increased during capacitation, in parallel with the ability to undergo the induced AR. Mannosylated albumin, but not the free sugar, induced the AR. In acrosome-reacted spermatozoa, the MBS was located at the plasma membrane, as shown by confocal analysis. No significant difference in the increase in MBS expression was observed among the different IVF groups of patients. The data show that D-mannose is involved in the sperm-zona pellucida interaction, and that the expression of MBS on the sperm surface occurs during the acquisition of in-vitro sperm fertilizing ability. PMID- 17697496 TI - A phase of chromosome aggregation during meiosis in human oocytes. AB - A higher rate of chromosomal abnormality occurs in human oocytes compared with other animal oocytes. In this study, chromosome movement has been successfully observed during first and second meiosis using a time-lapse culture system and a differential interference contrast inverted microscope. In human oocytes, a specific sequence of early maturation changes was observed. Following the completion of nucleolar breakdown, chromosomes were assembled into a single aggregation that heralded the start of nuclear membrane breakdown. The chromosome aggregation phase (gere phase) persisted after germinal vesicle (GV) breakdown, lasting several hours, and a similar gere phase (chromosome gathering) occurred after the first polar body extrusion, lasting 1-4 h. In contrast, in mouse GV oocytes, nucleolar and nuclear membranes started to break down almost at the same time. A chromosome aggregation phase was not observed in mouse oocytes. The discovery of a gere phase during human oocyte maturation may provide important information related to the mechanism of abnormal chromosomal segregation, which often occurs during meiosis. PMID- 17697497 TI - Effect of polyvinylpyrrolidone on bovine oocyte maturation in vitro and subsequent fertilization and embryonic development. AB - The exact role of polyvinylpyrrolidone (PVP) in culture medium for oocyte maturation is still largely unknown. Bovine cumulus-oocyte complexes (COC) were cultured in in-vitro maturation (IVM) medium supplemented with 10% fetal bovine serum (FBS), 0.3% PVP (K-90) or 10% serum substitute supplement (SSS) respectively. The rates of oocyte maturation, fertilization and early embryonic development were evaluated. In addition, the status of DNA fragmentation in the oocytes was determined by comet assay, and the ratio of trophectoderm (TE) cells and inner cell mass (ICM) in blastocysts was determined by differential staining. Furthermore, the percentage of apoptotic cells in the blastocysts was examined by TUNEL assay. The results indicated that the effect of PVP in IVM medium was similar to FBS in terms of oocyte maturation and subsequent embryonic development. However, the addition of SSS in IVM medium retarded further embryonic development and resulted in more oocyte DNA fragmentation and a higher ratio of TE cells and ICM in the blastocysts. However, the number of apoptotic cells in blastocysts was similar among the three groups. These results suggest for the first time that the addition of PVP in oocyte maturation medium is not only a suitable substitute for serum but is also beneficial to in-vitro oocyte maturation. PMID- 17697499 TI - Relationship between sperm DNA damage, induced acrosome reaction and viability in ICSI patients. AB - The DNA damage in human spermatozoa is a relevant predictor of prognosis in male infertility, whereby increased sperm DNA damage impairs the outcomes of artificial reproduction. Theoretically, DNA damage should alter the special cellular functions of human spermatozoa, and lead to diminished acrosome reaction with reduced fertilization rates. Nevertheless, intracytoplasmic sperm injection (ICSI) has been reported to alleviate such negative outcomes due to DNA damage. This study investigated the relationship between DNA fragmentation and acrosome reaction as well as viability in ICSI patients. The study enrolled 42 men undergoing ICSI due to poor sperm parameters. The DNA fragmentation indexes (DFI) were 4-10% in 38% of the cases, and > or = 10% in 19% of the cases. The results of both acrosome reaction and viability assays showed negative correlations with DFI values in all cases and especially in cases with fertilization rates <60% (P < 0.05). However, such correlations were not found in cases with fertilization rates >60%. There were no live deliveries in patients with high DFI levels (>10%). In conclusion, negative correlations were identified between increased DNA damage, and acrosome reaction and/or viability of human spermatozoa, especially in cases with reduced fertilization rates. PMID- 17697500 TI - Induction of ovulation in idiopathic premature ovarian failure: a randomized double-blind trial. AB - In this prospective randomized study, women with idiopathic karyotypically normal premature ovarian failure (POF) were treated with gonadotrophin-releasing hormone (GnRH) agonist and gonadotrophins with and without the addition of corticosteroids in an attempt to restore ovarian function. The study comprised 58 women with idiopathic POF randomly allocated to either GnRH agonists (GnRHa) plus gonadotrophin therapy with the addition of corticosteroids (29 patients) or GnRHa plus gonadotrophin therapy with placebo (29 patients). Ovulation occurred in six cases (20.7%) in the dexamethasone group versus three cases (10.3%) in the placebo group. There were two singleton pregnancies in the dexamethasone group. There were no reported complications from the use of dexamethasone apart from a sense of sleepiness and fatigue. The combination of corticosteroids with pituitary suppression followed by ovarian stimulation with gonadotrophin appeared to be beneficial in restoring ovarian function in patients with idiopathic POF and normal karyotype. PMID- 17697501 TI - Age, oestradiol and blastocysts can predict success in natural cycle IVF-embryo transfer. AB - The aim of this study was to evaluate the influence of maternal age and oestradiol concentrations on blastocyst development and live birth rates in natural cycle IVF-embryo transfer. This observational study included 397 natural cycles with IVF embryo transfer for female infertility with embryo transfer on day 5. The cycles were divided into two groups according to the woman's age (<39 and > or = 39 years of age), and into two groups according to oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) administration (0.4-0.49 nmol/l and 0.5-1.2 nmol/l). Comparison between the cycles in younger versus older age groups showed significant differences in blastocyst development rate, live birth rate per embryo transfer and live birth rate per cycle (55 versus 29%, 23 versus 3% and 13 versus 2% respectively) (P < 0.001). Comparison between cycles with lower versus higher oestradiol concentrations showed no significant differences in blastocyst development rate, live birth rate per embryo transfer and live birth rate per cycle (47 versus 49%, 18 versus 18%, and 11 versus 10% respectively). Advanced maternal age negatively predicts the success of natural cycle IVF, while low oestradiol concentrations on the day of HCG administration (ultrasound criteria fulfilled) do not negatively predict blastocyst development and success of natural cycle IVF. PMID- 17697502 TI - Candidate epigenetic biomarkers for non-invasive prenatal diagnosis of Down syndrome. AB - This report describes the first identification and characterization of three chromosome-21-specific DNA sequences (and reference sequences from other chromosomes) that are differentially methylated between peripheral blood and placental tissue, with the aim of providing epigenetic biomarkers for quantifying cell-free fetal DNA in maternal plasma. To select sequences to be screened for differential methylation, three strategies were adopted: (i) investigating promoters of highly differentially expressed genes; (ii) choosing 'random' promoter regions; and (iii) choosing 'random' non-promoter regions. Over 200 pre selected DNA sequences were screened using a methylation-specific restriction enzyme assay. Differentially methylated sequences located at 21q22.3 (AIRE, SIM2 and ERG genes), 1q32.1 (CD48 gene and FAIM3 gene), 2p14 (ARHGAP25 gene) and 12q24 (SELPLG gene) were identified. Bisulphite conversion confirmed that CpG sites within the AIRE promoter region are highly differentially methylated, and optimized methylation-specific primers for this region that are highly specific for placental DNA were devised. Next, it was shown that the methylation status of chorionic villus sample DNA from first trimester pregnancies matched the hypermethylated state of term placenta. Thus there is no indication of a difference in methylation status between early and term pregnancy for the sequences tested. The identified sequences constitute candidate biomarkers for non-invasive prenatal diagnosis of Down syndrome. PMID- 17697504 TI - SmARTest regulation? Comparing the regulatory structures for ART in the UK and Australia. AB - Assisted reproductive technologies are regulated in both the UK and Australia, thereby curtailing both reproductive and professional autonomy. Different regulatory models have developed in each jurisdiction, despite the similar legal, scientific and cultural histories of the two jurisdictions. In the UK the regulatory structures are under review, largely in the absence of empirical research on the costs and benefits of regulation. The regulatory structures in each jurisdiction are compared and some key differences identified. The UK regulatory structure governing assisted reproductive technologies is currently simpler, more accountable and more transparent than that in Australia. On the other hand, despite administrative and legislative restrictions (particularly in Victoria), the medical scientists and clinicians in Australia generally have more control than their British counterparts over the technical aspects of their work in the provision of IVF and other treatment services, and to a lesser extent in embryo research. Recent proposals appear to move the UK regulatory structure towards a less accountable and less transparent model, but with no evident increase in reproductive or professional autonomy. It is suggested that this change is not in the interests of patients, doctors and the public, and a different model is outlined for devolution of both authority and accountability to the professions. PMID- 17697505 TI - Infertile couples, assisted reproduction and increased risks to the children. AB - Among possible causes of increased risks of health problems in babies resulting from assisted reproduction treatment, the main one is infertility itself. Epidemiological investigations aimed at assessing assisted reproduction and child health are difficult ones. Large multicentric international studies are necessary. PMID- 17697506 TI - Physical rehabilitation using telemedicine. AB - Telerehabilitation is the provision at a distance of rehabilitation services such as physiotherapy, speech pathology or occupational therapy. The primary aim is to provide equitable access to rehabilitation services. Broadly speaking, the technologies used for telemedicine-based physical rehabilitation can be classified as: (1) image-based telerehabilitation; (2) sensor-based telerehabilitation; and (3) virtual environments and virtual reality telerehabilitation. To date, much of the research has been technology focused, and has consisted of single case or small sample research designs. The next step is to demonstrate viable telerehabilitation services in real world environments using well controlled research methodologies with large patient cohorts. In addition, the broader issues of cost-benefit and cost-effectiveness require investigation. If this can be done, then the undoubted potential benefits of telerehabilitation, for both the patient and health-care systems, can be realized. PMID- 17697507 TI - The STARPAHC collection: part of an archive of the history of telemedicine. AB - An early telemedicine project involving NASA, the Papago Tribe (now the Tohono O'odham Indian Nation), the Lockheed Missile and Space Company, the Indian Health Service and the Department of Health, Education and Welfare explored the possibilities of using technology to provide improved health care to a remote population in southern Arizona. The project, called STARPAHC (Space Technology Applied to Rural Papago Advanced Health Care), took place in the 1970s and demonstrated the feasibility of a consortium of public and private partners working together to provide medical care to remote populations via telecommunication. In 2001 the Arizona Health Sciences Library acquired important archival materials documenting the STARPAHC project and in collaboration with the Arizona Telemedicine Program established the Arizona Archive of Telemedicine. The material is likely to interest those studying early attempts to use technology to deliver health care at a distance, as well as those studying the sociological ramifications of technical and scientific projects among indigenous populations. PMID- 17697508 TI - Audiology telemedicine. AB - Various real-time telemedicine applications have been investigated in audiology, including pure tone audiometry, otoacoustic emission testing, auditory brainstem response recordings, hearing aid fitting and video-otoscopy. Store-and-forward applications have usually been used to transmit basic patient data including case history information and hearing screening results, although both video nystagmography and video-otoscopy have been piloted. Remote access to computerized equipment is relevant to audiology telemedicine, although there have been few reports of the use of application sharing using computerized audiology equipment. In a pilot trial of real-time telemedicine, both pure tone and speech audiometry measures were provided remotely through application sharing. Audiology telemedicine appears promising, but it is at an early stage of development and many areas such as its cost effectiveness, patient acceptance and test efficacy require systematic investigation. PMID- 17697509 TI - A systematic review of research methodology in telemedicine studies. AB - We conducted a systematic review of 15 relevant databases for articles about telemedicine. After eliminating articles that did not meet the inclusion criteria, 1615 remained for analysis. Three raters coded the articles to assess various theoretical and methodological variables. Only 5% (n = 85) of the telemedicine articles made mention of any theory or paradigmatic approach. Studies commonly reported the objectives (96%) but rarely stated a research question or hypothesis (11%). Randomized selection of the subjects was reported in 11% of patient studies and 4% of studies where providers were the subject. There was a wide range in the number of subjects employed, although the majority of studies were based on sample sizes of less than 100. Only 26% of the studies reported a time frame. Until the telemedicine field adheres to agreed standards of reporting methodological details it will be difficult to draw firm conclusions from review studies. PMID- 17697510 TI - Development of a consultation and teaching concept for leg wound treatment in home health care. AB - We developed a consultation and teaching concept about leg wounds and their care, for use by patients and caregivers in a home health-care setting. Descriptive data were gathered through a survey distributed to three groups, comprising 21 individuals (18 nurses and 3 health administrators). These participants provided answers regarding group activities, meeting frequency, meeting notes and meeting content, as well as responses to questions regarding the Website, Web materials, film and a pamphlet. Seventeen people answered the survey (81% response rate). They made predominantly positive comments. The combined total average score was 3.6 (1=very bad to 4=very good). The concept was implemented in one municipality in a health-care region in southern Sweden using high bandwidth videophones (640 kbit/s). The results showed that elderly persons at home and nurses working in home health care were interested in using the concept and communicating via videophone. A strength of the Web-based information and communication material is its adaptability to suit both patients and care givers. PMID- 17697511 TI - Tele-assistance in intellectual disability. AB - We conducted a trial of multidisciplinary tele-assistance to support 20 families of patients with intellectual disability. Psychological, educational, social and medical support was provided by videoconferencing, email and on-line sharing of diagnostic and rehabilitation tools. The main topics dealt with were self-care, learning processes, adaptation skills, management of problem behaviours and health problems. A computer network was developed which connected workstations at the patients' houses and two main sites at the Oasi Institute. It was based on ISDN transmission. During the study, 840 videoconference sessions and 805 programme planning and case discussions took place. After one year of tele assistance, most families (84%) stated that they were satisfied with the experience, underlining, among various advantages, the availability of professional and continuous support, the reduction of inconvenient travelling to specialized centres and the increase in adaptation skills of their children. Although the present study was empirical, our experience suggests that tele assistance can satisfy some of the main needs of persons with intellectual disability and their families. PMID- 17697513 TI - An economic evaluation of a telehealth network in British Columbia. AB - We carried out an economic evaluation of the northernmost five sites of the British Columbia telehealth network. The videoconferencing network links health care facilities in 12 communities with Vancouver, for clinical consultations, administrative meetings and educational sessions. The economic evaluation was based on the netcost criterion (i.e. cost of telehealth minus travel costs avoided). Cost and utilization data were obtained from client interviews and log data compiled between September 2001 and January 2003. The results showed that the subnetwork of five sites was not only cost reducing, but also cost-effective. Travel costs for administrative meetings were reduced by $724,457/annum and were greater than the annual fixed and variable costs of all the telehealth sessions ($553,740). A sensitivity analysis was conducted on six parameters: amortization period, opportunity cost of capital, operating cost of a telehealth session (by type of session), number of telehealth sessions, travel time and the opportunity cost of travel time. The study suggests that the cost-effectiveness of telehealth to remote areas will increase over time as the cost of equipment continues to fall, as network connections become cheaper and as utilization rates rise. PMID- 17697512 TI - The other side of teledermatology: patient preferences. AB - We studied patient preferences for a real-time teledermatology consultation or a conventional dermatology consultation. Dermatology patients were given the option of being seen by a dermatologist at their outlying primary care site via telemedicine or of being examined face-to-face by the same dermatologist at the primary care site. The same dermatologist provided the teleconsultations and the conventional consultations. During a 16-month study period, 52 patients were evaluated via telemedicine and 46 patients were seen face-to-face. The demographics for both study groups were similar. Those patients who selected telemedicine were more likely to have seen a dermatologist fewer than twice during the previous year, more likely to self-describe themselves in excellent health and more likely to choose a face-to-face evaluation when presenting with a possible skin cancer or a mole. Patients aged 56 years or less tended to be more likely to be seen via telemedicine, although the association with age was not significant (P = 0.06). This information may help providers to devise strategies to direct patients to telemedicine if and when it is appropriate. PMID- 17697514 TI - An analysis of business issues in a telestroke project. AB - A telehealth network based at the Medical College of Georgia was established in 2003 to treat stroke patients in remote hospitals. In the first three years, more than 400 patients were evaluated at nine rural hospitals. A total of 65 patients (16%) were treated with tissue plasminogen activator (approximately half of them in less than 2 h). Although clinically successful, the system reached the point at which it would either further diffuse or die out. We examined the roles played by internal and external factors in the development of the system. We interviewed 25 individuals in five hospitals (the hub hospital and four rural hospitals). Important business issues were identified that would need to be addressed in order to expand the project and make it self-sustaining. The external factors were economic, legal and market issues. The internal factors were organizational, technical and educational issues. Early identification and negotiation of business issues related to project implementation are likely to be important in diffusion and sustainability. PMID- 17697517 TI - Health professionals who are disconnecting from ICT. PMID- 17697515 TI - Care coordination and telemedicine improves glycaemic control in ethnically diverse veterans with diabetes. AB - We conducted a pilot study of a care-coordination programme involving daily monitoring and education of elderly diabetic veterans from different racial/ethnic groups. A telephone-based, in-home messaging device was used for patient monitoring and education. Sixty-nine patients were enrolled in the study and HbA(1c) values were obtained both before and after the telemedicine intervention in 41 of them. The mean HbA(1c) before enrolment was 7.6% and the mean value 9 months later was 7.3% (P = 0.09). The greatest fall in HbA(1c) occurred in African-Americans (0.65%, P = 0.05). The total number of hospital admissions decreased from 31 pre-enrolment to 25 post-enrolment (P = 0.0002). Bed days of care decreased from 368 to 149 (P = 0.0002). Care coordination, facilitated by telemedicine, appeared to improve glycaemic control in veterans with diabetes from diverse ethnic backgrounds, particularly African-Americans. This may reduce health-care resource utilization. PMID- 17697519 TI - Killing effect of the herpes simplex virus thymidine kinase/ganciclovir enzyme/prodrug system on human nasopharyngeal carcinoma cells. AB - A promising new approach for the gene therapy of cancer is the introduction of the herpes simplex virus thymidine kinase (HSV tk) gene into tumour cells, where the HSV tk gene product converts the nontoxic prodrug ganciclovir (GCV) into its cytotoxic metabolite. We constructed a recombinant plasmid containing the HSV tk gene using standard molecular biology techniques in order to investigate whether the HSV tk/GCV enzyme/prodrug system could kill the human nasopharyngeal carcinoma cell line HNE-1. The recombinant plasmid pcDNA3.1(-) CMV. TK was transfected into the HNE-1 cells by electroporation. The expression of HSV tk by the transfected HNE-1/TK cells was confirmed by mRNA amplification and Western blotting. The growth of HNE-1/TK cells was inhibited by GCV in a dose-dependent manner. The HSV tk/GCV system also demonstrated a considerable bystander effect on co-cultured wild type HNE-1 cells. We conclude that the HSV tk/GCV system could be used as gene therapy for nasopharyngeal carcinoma. PMID- 17697520 TI - Non-invasive detection of acute renal allograft rejection by measurement of vascular endothelial growth factor in urine. AB - Urinary vascular endothelial growth factor (VEGF) was determined by enzyme-linked immunosorbent assay in 199 renal allograft recipients and 80 healthy controls. Urinary VEGF level did not change significantly during the first 8 weeks after transplantation in 119 patients with stable renal function and there were no abnormal histological findings (No-AR). In 67 patients with acute rejection, urinary VEGF was significantly higher (28.57 +/- 6.21 pg/micromol creatinine) than in the No-AR patients (3.05 +/- 0.45 pg/micromol creatinine) and healthy controls (2.87 +/- 0.35 pg/micromol creatinine). At a cut-off point of 3.26 pg/micromol creatinine, sensitivity and specificity for diagnosis of acute rejection were 86.6 and 71.4%, respectively. The 13 patients with subclinical rejection excreted urinary VEGF (16.14 +/- 4.09 pg/micromol creatinine) at a significantly higher level than No-AR patients (3.05 +/- 0.45 pg/micromol creatinine). At a cut-off point of 4.69 pg/micromol creatinine, sensitivity and specificity for diagnosis of subclinical rejection were 84.6 and 79.8%, respectively. In conclusion, monitoring VEGF in urine might offer a new non invasive way to detect acute and subclinical rejection in renal transplant recipients. PMID- 17697521 TI - No duplicate KRAS mutation is identified on the same allele in gastric or colorectal cancer cells with multiple KRAS mutations. AB - Codon 12 and 13 mutations in 170 colorectal cancer (CRC) and 66 gastric cancer (GC) specimens were analysed by an 'enriched' polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. All identified mutations were verified by direct sequencing of the second PCR products. Among the 170 CRC specimens, mutations were identified in 47 (28%) and 13 (7.6%) cases in codons 12 and 13, respectively. In the 66 GC specimens examined, however, mutations in codons 12 and 13 were only detected in two (3.0%) and one (1.5%) cases, respectively. Mutations in both codon 12 and 13 were found in 3/170 (1.8%) CRCs and 1/66 (1.5%) GCs. Duplicate mutations were never identified in the same allele, which was confirmed by direct sequencing of the second amplified products. The majority of colorectal and gastric cancer cells with KRAS mutations are homogeneous because they have the same KRAS mutation. A few colorectal or gastric cancers, however, showed heterogeneity, as verified by the fact that single mutations were identified in the same allele. PMID- 17697522 TI - Obstructive sleep apnoea, glucose tolerance and liver steatosis in obese women. AB - In this study of obstructive sleep apnoea (OSA), glucose tolerance and liver steatosis in females from an obesity unit, 45 patients (mean age 46.8 years, mean body mass index 39.4 kg/m(2), all non-diabetic and alcohol abstainers) underwent nocturnal polysomnography, a 2 h oral glucose tolerance test and abdominal ultrasonography. OSA, defined as an apnoea-hypopnoea index (AHI) of > or = 10 events/h, was present in 20 patients (44%). Impaired glucose tolerance (IGT) was found in eight patients (40%) with OSA and three patients (12%) without OSA; there was a positive linear relationship between AHI and post-load glucose levels. On multivariate logistic regression analysis, IGT was predicted by OSA independently of age, waist circumference, systolic blood pressure and current smoking. Liver steatosis was present in 37 women (82.2%), of whom six had grade III steatosis. Of the variables tested, IGT was the only predictor of grade III steatosis. In conclusion, OSA is an independent predictor of IGT which, in turn, is associated with severe liver steatosis in an obesity unit-based sample of women. PMID- 17697523 TI - Lesion detectability and clinical effectiveness of dual-head coincidence gamma camera imaging in comparison with dedicated PET systems in tumour patients. AB - The lesion detection capability and clinical effectiveness of dual-head coincidence gamma camera imaging (c-PET) were compared with those of dedicated positron emission tomography (d-PET) in 37 cancer patients who underwent whole body c-PET and d-PET imaging after administration of 370 - 540 MBq (18)F fluorodeoxyglucose. Eighty-nine lesions were detected on c-PET whereas 133 lesions were seen with d-PET imaging. The relative sensitivity of c-PET compared with d-PET was 62% and 73% for lesions < 15 and > or = 15 mm, respectively, and the relative concordance rate was 84% when the patients were restaged. Since the lesion detection rate of c-PET imaging was lower than that of d-PET, the detection of small lesions, therefore, requires care. The clinical effectiveness of c-PET, however, was similar to that of d-PET and, therefore, it is concluded that c-PET can be used as an alternative to d-PET, particularly considering the high cost and limited availability of d-PET cameras. PMID- 17697524 TI - Use of (99m)Tc-sulesomab for the diagnosis of prosthesis infection after total joint arthroplasty. AB - This study aimed to evaluate the diagnostic efficacy of antigranulocyte scintigraphy using the antibody fragment (99m)Tc-sulesomab (LeukoScan) for the diagnosis of prosthesis infection in patients with total hip or knee arthroplasty. The results from 19 patients with suspected total joint arthroplasty infection who had undergone a three-phase bone scan and a subsequent examination with (99m)Tc-sulesomab during a 1-year period were reviewed. Twelve patients were shown to have prosthesis infection on culture of aspirated synovial fluid or intra-operative samples. The overall sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy for (99m)Tc-sulesomab were 75%, 86%, 90%, 66% and 79%, respectively, compared with 54%, 83%, 88%, 45% and 63%, respectively, for the three-phase bone scan. This study showed that (99m)Tc-sulesomab had good diagnostic value for the detection of prosthesis infection. The combination of (99m)Tc-sulesomab with other laboratory or imaging examinations may improve diagnostic performance in prosthesis infection and should be investigated further. PMID- 17697525 TI - Telmisartan, an angiotensin II type 1 receptor blocker, inhibits advanced glycation end-product (AGE)-induced monocyte chemoattractant protein-1 expression in mesangial cells through downregulation of receptor for AGEs via peroxisome proliferator-activated receptor-gamma activation. AB - Interaction between advanced glycation end-products (AGEs) and their receptor (RAGE) plays a central role in diabetic nephropathy pathogenesis. Pathophysiological crosstalk between the AGEs-RAGE system and angiotensin II (Ang II) is also involved in this disease. This study investigated the role of proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity on inhibition of monocyte chemoattractant protein (MCP-1) expression. Telmisartan, an Ang II type 1 receptor blocker, downregulated RAGE mRNA and inhibited superoxide generation and MCP-1 gene expression in mesangial cells; these processes were blocked by GW9662, a PPAR-gamma inhibitor. Candesartan, an Ang II type 1 receptor blocker, did not suppress AGEs-induced superoxide generation. Telmisartan and the antioxidant, N-acetylcysteine, completely inhibited AGEs induced MCP-1 overproduction by mesangial cells. These results suggest that telmisartan inhibits AGEs-signalling to MCP-1 expression in mesangial cells by downregulating RAGE gene expression and subsequent oxidative stress generation via PPAR-gamma activation. This study has demonstrated a unique benefit of telmisartan in that it may function as an anti-inflammatory agent against AGEs via PPAR-gamma activation and may play a protective role in diabetic nephropathy. PMID- 17697526 TI - Inhibitory effect of triptolide on glioblastoma multiforme in vitro. AB - This study investigated the effect of triptolide, derived from the traditional Chinese herb Tripterygium wilfordii, on the growth of glioblastoma multiforme (GBM) cells. Glioma cell lines U251MG and U87MG and normal human fetal astrocytes were exposed to various concentrations of triptolide, and 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium and colony formation assays were used to measure cell growth and survival. Cell apoptosis was determined using annexin V. Levels of the oncogenic transformation-related proteins Ras-guanosine triphosphate (Ras GTP), extracellular signal-regulated kinase (ERK) and Akt were determined by Western blotting. Triptolide caused a dose-dependent decrease in proliferation and increase in apoptosis in the glioma cell lines. Since U87MG has a wildtype p53 gene while U251MG harbours a mutated p53 gene, these results indicate that triptolide induces apoptosis in GBM cells via a p53-independent pathway. Treatment of GBM cells with triptolide attenuated both the Ras/ERK and the Ras/Akt signalling pathways. This could provide a theoretical basis for triptolide treatment in GBM, but further animal studies and clinical research are necessary. PMID- 17697527 TI - Predictive models for post-operative nausea and vomiting in patients using patient-controlled analgesia. AB - This study identified predictive factors for post-operative nausea and vomiting (PONV) in patients using patient-controlled analgesia (PCA) and developed five predictive model pathways to calculate the probability of PONV using decision tree analysis. The sample consisted of 1181 patients using PCA. Data were collected using: a specifically designed check-off form to collect patient-, surgery-, anaesthesia- and post-operation-related data; the Beck Anxiety Inventory to measure pre-operative anxiety; and a visual analogue scale, to measure post-operative pain. The incidence of PONV was 27.7%. Nine factors were highly predictive of PONV in our five model pathways: gender, obesity, anxiety, history of previous PONV, history of motion sickness, inhalation of nitrous oxide during operation, use of inhalational agents, starting oral fluid/food intake after operation, and post-operative pain. With these five predictive model pathways, we can predict the probability of PONV in an individual patient according to their individual characteristics. PMID- 17697528 TI - Study of ATP-binding cassette transporter A1 (ABCA1)-mediated cellular cholesterol efflux in diabetic golden hamsters. AB - The effects of cyclic adenosine monophosphate (cAMP) and atorvastatin on macrophage adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) mediated cholesterol efflux were investigated in a diabetic animal model. Golden hamsters were fed a high-fat diet which resulted in insulin resistance. Diabetes was induced by a single intraperitoneal injection of streptozotocin (30 mg/kg). Normal golden hamsters were used as controls. Peritoneal macrophages were incubated with apolipoprotein A-1 (apoA-1), 8-bromoadenosine-3',5'-cyclic monophosphate (8-br-cAMP), and atorvastatin in vitro. Intracellular cholesterol accumulation was greater in the diabetic animals than in the insulin-resistant animals. Expression of ABCA1 mRNA in macrophages from diabetic animals was upregulated by 8-br-cAMP and atorvastatin. ApoA-1 caused a time-dependent cellular cholesterol efflux. Both atorvastatin and 8-br-cAMP significantly facilitated ABCA1-mediated cellular cholesterol efflux, with the maximal cholesterol efflux rate observed in the macrophages from diabetic animals. Accumulation of cholesterol in the macrophages of diabetic animals can be significantly alleviated by atorvastatin or 8-br-cAMP through improving ABCA1 mediated cellular cholesterol efflux. PMID- 17697529 TI - Apocynin attenuates cerebral infarction after transient focal ischaemia in rats. AB - This study investigated whether inhibition of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase attenuates cerebral infarction after transient focal ischaemia in rats. Focal ischaemia (1.5 h) was produced in male Sprague-Dawley rats (250 - 280 g) by middle cerebral artery occlusion. Some rats also received treatment with 50 mg/kg apocynin, a NADPH oxidase inhibitor, by intraperitoneal injection 30 min prior to reperfusion. Two hours after reperfusion, brains were harvested to measure NADPH oxidase activity and superoxide levels. After 24 h, the remaining brains were harvested to investigate infarct size. NADPH oxidase activity and superoxide level were all augmented 2 h after reperfusion compared with controls. Apocynin treatment significantly reduced NADPH oxidase activity and superoxide levels. Cerebral infarct size was significantly smaller in the apocynin-treated group compared with those undergoing ischaemia/reperfusion alone. These results indicate that inhibition of NADPH oxidase attenuates cerebral infarction after transient focal ischaemia in rats, suggesting that inhibition of NADPH oxidase may provide a therapeutic strategy for ischaemic stroke. PMID- 17697530 TI - Effects of simvastatin on lung injury induced by ischaemia-reperfusion of the hind limbs in rats. AB - We investigated whether simvastatin reduces lung injury caused by ischaemia reperfusion of the hind limbs in rats. The control group underwent dissection of bilateral femoral arteries; another group (I/R group) underwent ischaemia of bilateral hind limbs for 2 h followed by 3 h reperfusion; and two other groups were pretreated with 5 or 10 mg/kg per day simvastatin for 3 days and then underwent ischaemia-reperfusion. The control and I/R group rats received placebo (water) instead of simvastatin. The lungs of the I/R rats showed marked histopathological changes compared with the other groups. Lung tissue myeloperoxidase, malondialdehyde, neutrophil count and lung injury scores in both simvastatin groups were significantly lower than in the I/R group; 10 mg/kg per day simvastatin significantly reduced lung water content although 5 mg/kg per day did not. Expression of haem oxygenase-1 (HO-1) protein in lung tissue was significantly greater in the simvastatin groups than in the I/R group. Simvastatin protects against lung injury associated with lower extremity ischaemia-reperfusion by reduction of neutrophil aggregation and oxidative damage, and upregulation of HO-1 expression in the injured lung. PMID- 17697531 TI - Efficacy of atorvastatin therapy in ischaemic heart disease - effects on oxidized low-density lipoprotein and adiponectin. AB - The lipid-lowering and anti-atherosclerotic effects of atorvastatin (10 mg/day) were investigated by measuring changes in the levels of oxidized low-density lipoprotein (LDL), serum lipids (total cholesterol [TC], LDL-cholesterol [LDL-C] and triglycerides [TG]), and in the protein adiponectin. This was undertaken in 22 patients with ischaemic heart disease and serum LDL-C levels > 100 mg/dl. After 3 months of therapy, atorvastatin significantly decreased serum lipids, oxidized LDL was reduced from 457.0 +/- 148.6 to 286.9 +/- 88.5 nmol/l, and adiponectin increased from 9.7 +/- 7.4 to 13.9 +/- 9.98 microg/ml. No significant correlation was observed between adiponectin and LDL-C, TG and high-density lipoprotein cholesterol. Atorvastatin therapy was not associated with side effects, such as myalgia and gastrointestinal disorders, and did not give abnormal laboratory test results. It is concluded that atorvastatin decreases serum lipid and oxidized LDL levels, and increases adiponectin levels in patients with ischaemic heart disease. PMID- 17697532 TI - Features of stroke in Chinese diabetes patients: a hospital-based study. AB - In this study, demographic characteristics, risk factors, stroke subtypes and outcome were compared in 2532 patients with and without diabetes hospitalized for first-ever stroke. Diabetes was present in 471 (18.6%) of the patients. Patients with diabetes presented more frequently with ischaemic stroke (92.1% versus 71.3%), especially lacunar infarction (41.2% versus 35.2%), compared with non diabetics. Cerebral haemorrhage was less frequent in diabetics than non-diabetics (4.2% versus 18.1%). In-hospital mortality rates from ischaemic stroke were similar in the two groups (18.2% in diabetics and 16.9% in non-diabetics). Predictors of in-hospital mortality in diabetic patients included decreased consciousness, congestive heart failure and atrial fibrillation. In conclusion, stroke in diabetic patients was different to stroke in non-diabetic patients: in diabetics the frequency of cerebral haemorrhage was lower and the rate of lacunar infarct syndrome was higher, but in-hospital mortality from ischaemic stroke was not increased. Clinical factors evident at the onset of stroke have a major influence on in-hospital mortality and may help clinicians provide a more accurate prognosis. PMID- 17697533 TI - Detection of metastases in patients with cutaneous melanoma using FDG-PET/CT. AB - This study aimed to detect metastases in patients with stage III or IV cutaneous melanoma by (18)F-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT). Thirty-nine patients with clinically evident stage III or IV melanoma underwent whole-body FDG-PET/CT scans for metastatic disease and these results were compared with those of biopsy. Scans for 38 of the patients were evaluated; one patient's scan could not be evaluated. There were 11 true-positive, two false-positive, 24 true-negative and one false-negative scans for the detection of melanoma metastases, with sensitivity 91%, specificity 92%, accuracy 92%, and positive and negative predictive values 84% and 96%, respectively. False-positive FDG-PET/CT scans were due to sarcoidosis in the lung and infected cyst in the liver. It is concluded that FDG-PET/CT scanning has high sensitivity and specificity for detecting stage III or IV metastatic melanoma. PMID- 17697534 TI - Resistance of Haemophilus influenzae isolates in children under 5 years old with acute respiratory infections in China between 2000 and 2002. AB - This prospective, three-centre study tested for antimicrobial susceptibility in 898 isolates of Haemophilus influenzae between 2000 and 2002 in Chinese children aged under 5 years with acute upper respiratory tract infection. The average incidence of beta-lactamase production was 12.0%. Overall, 88.0% of isolates were susceptible to ampicillin, 100.0% were susceptible to amoxicillin/clavulanic acid, ceftriaxone, cefuroxime and azithromycin, and 99.0% were susceptible to ciprofloxacin. Isolates from Beijing and Shanghai had a lower susceptibility to tetracycline (57.0% and 61.0%, respectively) compared with those from Guangzhou (81.0%), while trimethoprim/sulfamethoxazole susceptibilities in Shanghai (47.0%) and Guangzhou (54.0%) were significantly higher than in Beijing (35.0%). A total of 34.5% of all the isolates were susceptible to all eight of these antimicrobial agents and 12.8% were multi-drug resistant. Ampicillin resistance increased over the duration of the study. These findings show that beta-lactamase production and ampicillin resistance among isolates from Chinese children with upper respiratory tract infection are increasing, and highlight the strong correlation between ampicillin resistance and resistance to cefaclor, chloramphenicol and tetracycline in H. influenzae isolates. PMID- 17697535 TI - A mutation in the 5' untranslated region of the BRCA1 gene in sporadic breast cancer causes downregulation of translation efficiency. AB - We screened 117 breast tumour samples in Chinese females for mutations in the breast cancer 1 (BRCA1) gene and identified a novel mutation in the 5' untranslated region (5' UTR) in two patients with grade III infiltrating ductal breast carcinoma. We examined whether this 5' UTR mutation affected the translational efficiency of BRCA1 protein. A vector was constructed containing the mutated 5' UTR up-stream of luciferase and we compared its translational efficiency with a wild-type 5' UTR. The expression of BRCA1 protein in breast tumour samples was evaluated using immunohistochemistry. The mutated 5' UTR of BRCA1 resulted in less luciferase activity compared with the wild-type 5' UTR, while there were no significant differences in luciferase mRNA levels. BRCA1 protein was much less expressed in breast tumour tissue from patients with the 5' UTR mutation than in samples from patients without the mutation. Our results show that a mutation in the 5' UTR of the BRCA1 gene downregulates translational efficiency of the protein. PMID- 17697536 TI - Enzyme replacement therapy in patients with Fabry's disease. AB - Fabry's disease, a disorder affecting the gene for the lysosomal enzyme alpha galactosidase A (alpha-GAL A), can cause accumulation of globotriaosylceramide (GL-3) in the vascular endothelial cells. Symptoms include pain, angiokeratoma, corneal clouding, and damage to the heart and kidneys. Human recombinant alpha GAL A for use as an enzyme replacement therapy was launched in Japan in April 2004. Eleven ambulatory patients with Fabry's disease were given replacement alpha-GAL A therapy. Three patients died due to factors associated with Fabry's disease. The enzyme replacement therapies in the remaining eight patients continued safely without any notable adverse events. The following were observed: a lowering of the plasma levels of GL-3 in seven cases, an improvement in the daily activities in six cases, and a reduction in corneal clouding in three cases. Although careful observation is necessary, these results suggest that replacement alpha-GAL A therapy may be a safe and effective treatment of Fabry's disease. PMID- 17697537 TI - [Interleukin-12 restores and promotes the T-cell immune function inhibited by 5 fluorouracil]. AB - BACKGROUND & OBJECTIVE: Currently, 5-fluorouracil (5-FU) is still one of the widely applied chemotherapeutic agents for tumors. Interleukin-12 (IL-12) can promote the differentiation of Th1 cells and induce the production of interferon gamma (IFN-gamma) by CD8+ T cells. This study was to investigate the suppression mechanism of 5-FU on the immune response mediated by T cells from normal human peripheral blood, and to determine the effect of IL-12 on the immune suppression induced by 5-FU. METHODS: The effects of 5-FU on the proliferation of peripheral blood mononuclear cells (PBMCs) and liver cancer cell line HepG2 were examined. PBMCs were stimulated with either anti-CD3 alone or anti-CD3 plus anti-CD28 in the presence or absence of 5-FU at different concentrations (0.20-50.00 microg/ml). The level of IFN-gamma in the culture supernatant was determined by ELISA. PBMCs were pretreated with 5-FU and stimulated with anti-CD3 and anti-CD28 for 2 days. The proportions of CD4+IFN-gamma+, CD8+IFN-gamma+, CD4+IL-2+ and CD8+IL-2+ T cells, and the expression of CD25 on CD4+ and CD8+ T cells were examined by flow cytometry (FCM). PBMCs were cultured in different combinations with anti-CD3 plus anti-CD28, IL-12 and/or 5-FU for 48 h. IFN-gamma level in the supernatant was detected by ELISA. The expression of IFN-gamma on CD4+ and CD8+ T cells were examined by FCM. RESULTS: 5-FU inhibited the proliferation of HepG2 cells and PBMCs, and suppressed INF-gamma production in PBMCs in a dose-dependent manner. The proportions of immune T cells were lower in 5-FU-pretreated PBMCs than in control PBMCs (0.7% vs. 2.1% for CD4+IFN-gamma+ T cells, 2.2% vs. 3.9% for CD8+IFN-gamma+ T cells, 0.7% vs. 2.5% for CD4+IL-2+ T cells, 0.2% vs. 0.4% for CD8+IL-2+ T cells). Both the positive rate and mean fluorescence intensity (MFI) of CD25 on CD4+ and CD8+ T cells were decreased after pretreatment of 5-FU. When stimulated by anti-CD3 and anti-CD28, the proportions of CD4+IFN-gamma+ and CD8+IFN-gamma+ T cells were 1.1% and 3.2% before adding IL-12, and 1.6% and 4.1% after treatment of IL-12. When stimulated by anti-CD3, anti-CD28, and 5-FU, the proportions of CD4+IFN-gamma+ and CD8+IFN-gamma+ T cells were 0.5% and 1.1% before adding IL-12, and 1.0% and 2.5% after treatment of IL-12. CONCLUSIONS: 5 FU could inhibit the proliferation of HepG2 cells and the immune function of PBMCs. IL-12 could restore the T-cell immune function inhibited by 5-FU. PMID- 17697538 TI - [Apoptosis of human leukemia HL-60 cells induced by rhabdastrellic acid-A and its mechanisms]. AB - BACKGROUND & OBJECTIVE: Rhabdastrellic acid-A is an isomalabaricane triterpenoid isolated from the sponge Rhabdastrella globostellata from South China Sea. Our previous study indicated that rhabdastrellic acid-A can inhibit the proliferation of many types of tumor cells with minor toxicity. This study was to investigate the apoptosis of human leukemia HL-60 cells induced by rhabdastrellic acid-A and its possible mechanisms. METHODS: Inhibitory effect of rhabdastrellic acid-A on the proliferation of HL-60 cells was evaluated by MTT assay. DNA fragmentation was analyzed by agarose electrophoresis. Cell morphology was observed under fluorescent microscope. The protein levels of Caspase-3, poly(ADP-ribose) polymerase (PARP), P73, Bcl-2 and Bax were analyzed by Western blot. The expression profile of apoptosis-related genes was analyzed by gene microarray. Reverse transcription-polymerase chain reaction (RT-PCR) was conducted to confirm some altered genes identified by gene microarray. RESULTS: Rhabdastrellic acid-A inhibited the proliferation of HL-60 cells and the 50% inhibition concentration (IC50) was (0.64+/-0.21) microg/ml. When treated with 1 microg/ml rhabdastrellic acid-A for 36 h, condensation of nuclear chromatin of HL-60 cells was observed under fluorescent microscope and DNA fragmentation was observed by agarose electrophoresis. Also, rhabdastrellic acid-A induced cleavage of PARP and Caspase 3. The mRNA levels of 44 genes, including p73, JunD, TNFAIP3 and GADD45A, were up regulated and the mRNA levels of 16 genes, including MAP2K5 and IGF2R, were down regulated. The results were further confirmed by RT-PCR. The protein level of P73 was up-regulated after rhabdastrellic acid-A treatment. CONCLUSION: Rhabdastrellic acid-A could induce the apoptosis of HL-60 cells which may be related to the up-regulation of apoptosis-related genes such as p73 and JunD, and the down-regulation of MAP2K5 and IGF2R. PMID- 17697539 TI - [Effects of mitofusin-2 gene on proliferation and chemosensitivity of human breast carcinoma cell line MCF-7]. AB - BACKGROUND & OBJECTIVE: Mitofusin-2(mfn2), a proliferation-inhibiting gene, targets to the outer membrane of mitochondria. Its overexpression suppresses the proliferation of vascular smooth muscle cells. This study was to explore the effects of mfn2 gene on the proliferation and chemosensitivity of human breast carcinoma cell line MCF-7. METHODS: Plasmid pEGFP-mfn2 containing mfn2 cDNA was constructed and transfected into MCF-7 cells by sofast. The expression of green fluorescent protein (GFP) in MCF-7 cells was detected by Western blot. Cell proliferation was measured by MTT assay and cell counting. Cell cycle and chemosensitivity of MCF-7 cells to camptothecin (CAM) was observed by flow cytometry (FCM). RESULTS: After transfection of pEGFP-mfn2, the stable expression of GFP protein was detected in MCF-7 cells, and cell cycle was arrested: the S phase proportion was significantly higher in pEGFP-mfn2-transfected cells than in pEGFP-transfected and untransfected cells [(42.7+/-1.3)% vs. (17.2+/-2.0)% and (19.6+/-1.7)%, P<0.05]. The apoptosis rate were significantly higher in pEGFP mfn2-transfected cells than in pEGFP-transfected and untransfected cells [(16.0+/ 0.3)% vs. (4.5+/-0.9)% and (3.6+/-0.6)% before treatment of CAM, P<0.05; (69.6+/ 4.3)% vs. (31.0+/-1.8)% and (23.4+/-2.8)% after 4-hour treatment of CAM, P<0.05]. CONCLUSION: mfn2 gene can inhibit the proliferation of MCF-7 cells and increase their chemosensitivity to CAM. PMID- 17697540 TI - [Effects of STAT3 antisense oligonucleotide on proliferation and apoptosis of non small cell lung cancer cell line A549]. AB - BACKGROUND & OBJECTIVE: Signal transducer and activator of transcription 3 (STAT3) is highly expressed in various human tumor tissues and tumor cell lines, and may be involved in tumor genesis and development. This study was to design effective antisense oligonucleotide targeting STAT3 mRNA, and explore its effect on the proliferation and apoptosis of human non-small cell lung cancer cell line A549. METHODS: Ten sets of antisense sequences targeting STAT3 were designed with RNAstructure4.2 software and STAT3 mRNA total sequences, and transfected respectively into A549 cells (AS group). Cell proliferation inhibition was measured by Cell Count Kit (CCK-8) assay. Cell proliferation and apoptosis were observed under inverted phase contrast microscope. Cell apoptosis was determined by flow cytometry (FCM) with Hoechst33258 staining and Annexin V/PI double staining. The expression of STAT3, p-STAT3, and Bcl-x(L) were detected by Western blot. Cell cycle was detected by FCM. RESULTS: The 10 sets of designed sequences inhibited the proliferation of A549 cells. The inhibition rate of A549 cell proliferation reached 75.46% after transfection of AS10; the higher the concentration of the antisense oligonucleotide was, the heavier the inhibitory effect was displayed (P<0.01). Apoptotic cells were increased after transfection of antisense oligonucleotide. Antisense oligonucleotide induced early apoptosis in A549 cells: the early apoptosis rate was significantly higher in AS group than in control group (11.51% vs. 5.18%, P<0.01). The expression of STAT3, p-STAT3, and Bcl-x(L) were down-regulated after transfection of antisense oligonucleotide. The G1 phase proportion of A549 cells was significantly higher in AS group than in control group (63.96% vs. 44.47%, P<0.01). CONCLUSION: The antisense oligonucleotide sequences targeting STAT3 designed with computer could inhibit the proliferation and induce the apoptosis of A549 cells. PMID- 17697541 TI - [Inhibitory effect of diallyl disulfide on proliferation of human colon cancer cell line SW480 in nude mice]. AB - BACKGROUND & OBJECTIVE: Diallyl disulfide (DADS) can inhibit the proliferation of various cancer cell lines in vitro, but little is known about its in vivo antitumor effect. This study was to investigate the inhibitory effect of DADS on the proliferation of human colon cancer cell line SW480 in nude mice. METHODS: After subcutaneous transplantation of SW480 cells in the back of nude mice, 5 mice received intraperitoneal injection of DADS (30 mg/kg), and 5 received intraperitoneal injection of normal saline as control. The body weight of nude mice and tumor growth were measured. The morphology of tumor was observed under optical microscope and electron microscope. The expression of proliferating cell nuclear antigen (PCNA) was detected by immunohistochemistry and morphometric quantitative analysis. Cell cycle distribution was analyzed by flow cytometry (FCM). RESULTS: The growth of transplanted tumor was inhibited markedly by DADS; the relative tumor growth rate (T/C%) was 49.85%. In DADS group, the cellular atypia and nucleus-cytoplasm ratio were decreased, intracytoplasm cellular organs were abundant, and retrograde alters and apoptotic bodies were manifested in some cells. The protein level of PCNA was significantly lower in DADS group than in control group (149.02+/-4.26 vs. 178.86+/-7.69, P<0.05). SW480 cells in DADS group were arrested in G2/M phase; the G2/M phase proportion was significantly higher in DADS group than in control group (38.6% vs. 18.8%, P<0.01). CONCLUSION: DADS has significant inhibitory effect on the proliferation of human colon cancer SW480 cells in nude mice and can arrest cell cycle in G2/M phase. PMID- 17697542 TI - [Effect of histamine on metastasis of melanoma B16 cell xenograft in C57BL/6 mice]. AB - BACKGROUND & OBJECTIVE: In the biotherapy for tumors, microvessel permeability is the main barrier for large molecular antibody-coupled antitumor drugs to enter the tumor mass. Histamine may enrich these drugs in the tumor matrix through enhancing microvessel permeability and tissue-fluid formation. This study was to investigate whether the increased microvessel permeability and more tissue fluid formation could increase the probability of lymphatic or hemal metastasis of tumor cells. METHODS: Cultured melanoma B16 cells were inoculated into the left armpit of C57BL/6 mice to develop melanoma. Five days after inoculation, the test group were injected subcutaneously at the dorsal part with histamine (300 mg/kg) every other day for 5 times, while the control group were given normal saline. The metastasis statuses in the lymph node, liver, lung, spleen, and brain were examined by histochemistry. Student t-test and Fisher's exact test were used respectively to analyze the effects of histamine on tumor growth and metastasis. RESULTS: All the mice developed melanoma after inoculation. At the end of the experiment, the tumor weight was significantly lighter in test group than in control group [(5.26 +/- 1.55) g vs. (6.96 +/- 1.31) g, P < 0.01]. The lymphatic and hemal metastasis rates were significantly lower in test group than in control group (33.3% vs. 75.0%, P < 0.05; 25.0% vs. 75.0%, P < 0.05). CONCLUSION: Histamine can inhibit the metastasis of melanoma B16 cells in C57BL/6 mice either through lymphatic or hemal route, and this partly because of its inhibitory effect on tumor growth. PMID- 17697543 TI - [Expression of CD16zeta in NK cells of B-cell non-Hodgkin's lymphoma patients and in vitro killing effect of rituximab combined lymphokine-activated killer cells on B-NHL cells]. AB - BACKGROUND & OBJECTIVE: Natural killer (NK) cells are the main effector of antibody-dependent cellular cytotoxicity (ADCC). The activation disorder of NK cells in cancer patients may affect the treatment effect of monoclonal antibody. Reversing the dysfunction of signal transduction of CD16zeta chain in NK cells and combining lymphokine-activated killer (LAK) cells with rituximab may give rise to synergistic effect. This study was to find out whether the activation disorder of NK cells exist in B-cell non-Hodgkin's lymphoma (B-NHL) patients, whether interleukin-2 (IL-2) can reverse the activation disorder in vitro, and whether the combination of rituximab and LAK cells can produce synergistic antitumor effect. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 69 B-NHL patients and 30 healthy donors by density gradient centrifugation method, and cultured with IL-2 (1 000 U/ml) to prepare LAK cells. The positive rate and median fluorescence intensity (MFI) of CD16zeta chain in PBMCs and LAK cells were detected by flow cytometry (FCM). The expression of CD20 on Raji cells was also detected by FCM. The apoptosis of Raji cells after treatment of rituximab was detected by FCM with Annexin V/PI staining. The cytotoxicity was assessed by lactate dehydrogenase (LDH) release experiment. RESULTS: The positive rate and MFI value of CD16zeta chain on CD56+ cells were significantly lower in B-NHL group than in control group [(63.3+/-16.4)% vs. (97.8+/-3.1)%, P<0.001; 1.3+/-1.3 vs. 3.6+/-1.7, P<0.001]. There was no significant difference in the positive rate and MFI value of CD16zeta on LAK cells between the 2 groups [(99.3+/-4.1)% vs. (99.7+/-3.9)%, P=0.145; 29.2+/-12.5 vs. 31.4+/-13.8, P=0.44]. At the concentration of 40 mug/ml, rituximab completely combined CD20 antigens on cell membrane. The obvious enhancive effect of rituximab on cell apoptosis appeared at 24 h after treatment. The killing rate of Raji cells was significantly higher in rituximab combined LAK group than in LAK group (P<0.05). While the combination of LAK cells and Herceptin (40 mug/ml) didn't make a significant increase as compared with Herceptin alone (P>0.05). There was no significant difference in killing rate of Jurket cells between rituximab combined LAK group and LAK group (P>0.05). CONCLUSIONS: The down regulation of CD16zeta chain expression widely exists in B-NHL patients, while high dose of IL-2 could enhance the expression of CD16zeta chain greatly in vitro. The combination of rituximab and LAK cells shows strong killing effect on Raji cells. PMID- 17697544 TI - [Effects of hydroxycamptothecin and teniposide on proliferation and apoptosis of gastric cancer cell line BGC-823]. AB - BACKGROUND & OBJECTIVE: Some studies have showed that topoisomerase (Topo)I and II inhibitors have synergistic effects in tumor therapy, but the combinations have seldom been used in gastric cancer. This study was to investigate the effects of Topo I inhibitor hydroxycamptothecin (HCPT) and Topo II inhibitor teniposide (VM-26) on the proliferation and apoptosis of gastric cancer cell line BGC-823. METHODS: MTT assay was used to examine the inhibitory effects of VM-26 and HCPT, used alone or in combination, on the proliferation of BGC-823 cells. Cell apoptosis was examined by flow cytometry (FCM). RESULTS: The inhibition rates of BGC-823 cell proliferation were 15.99%-80.83% when treated with 1.963 31.413 micromol/L VM-26; the apoptosis rates were 3.90%, 4.42%, 7.36%, 17.07% when exposed to 1.963 micromol/L VM-26 for 0, 12, 24, 48 h, respectively. The inhibition rates of BGC-823 cell proliferation were 7.89%-70.32% when treated with 8.577-137.227 micromol/L HCPT; the apoptosis rates were 2.80%, 8.50%, 10.50%, 13.30% when exposed to 8.577 micromol/L HCPT for 0, 12, 24, 48 h, respectively. When treated with 1.963 micromol/L VM-26 and 3.125 microg/ml HCPT for 0, 12, 24, 48 h, the inhibition rates of BGC-823 cell proliferation were 21.32%-87.74%, and the apoptosis rates were 2.80%, 15.50%, 15.70%, 20.20%, respectively. The combination index (CI) was 1.293. CONCLUSION: HCPT and VM-26 used alone could inhibit the proliferation and induce the apoptosis of BGC-823 cells, and they have antagonistic effect on gastric cancer BGC-823 cells. PMID- 17697545 TI - [Reversing multidrug resistance of epidermoid carcinoma drug-resistant cell line KB-MRP1 by tetrandrine]. AB - BACKGROUND & OBJECTIVE: Tetrandrine (Tet), a bisbenzylisoquinoline albaloid isolated from the Chinese herb "Hanfangji" (Radix Stephania Tetrandra), could effectively reverse P-glycoprotein-mediated multidrug resistance. This study was to investigate the reversal effect of tetrandrine on multidrug resistance of human epidermoid carcinoma cell line KB-MRP1. METHODS: The effects of tetrandrine on the proliferation of KB-3-1 and KB-MRP1 cells were observed by MTT assay. The inhibitory effects of cisplatin (DDP), vincristine (VCR), adriamycin (ADM) and etoposide (VP-16) used alone or in combination with tetrandrine on the proliferation of KB-3-1 and KB-MRP1 cells were evaluated by MTT assay. The effects of tetrandrine on ADM accmulation in KB-MRP1 cells and VCR-induced apoptosis were determined by flow cytometry (FCM). RESULTS: Tetrandrine at the concentration of 1.5 microg/ml and below showed no significant cytotoxicity to KB 3-1 and KB-MRP1 cells. The resistance of KB-MRP1 cells to VCR, ADM, VP-16 and DDP were 21.23, 38.39, 12.47 and 1.31 folds of that of KB-3-1 cells. When added 1 microg/ml tetrandrine, the chemosensitivity of KB-MRP1 cells to VCR, ADM and VP 16 were increased to 4.96, 5.85 and 4.24 folds, respectively; when added 1.5 microg/ml tetrandrine, the chemosensitivity of KB-MRP1 cells to VCR, ADM and VP 16 were much higher. When treated with 1.5 microg/ml tetrandrine, ADM accumulation in KB-MRP1 cells and the VCR-induced apoptosis were enhanced significantly. CONCLUSION: Tetrandrine could moderately reverse the multidrug resistance of KB-MRP1 cells through increasing the accumulation of chemo-drugs in cells and promoting apoptosis. PMID- 17697546 TI - [Correlation of cyclooxygenase-2 expression to P-glycoprotein expression in B cell non-Hodgkin's lymphoma]. AB - BACKGROUND & OBJECTIVE: The overexpression of P-glycoprotein (P-gp) plays an important role in the chemoresistance of relapsed lymphoma. It is up-regulated in a cyclooxygenase-2 (COX-2)-dependent manner. This study was to observe the expression and correlation of COX-2 and P-gp in B-cell non-Hodgkin's lymphoma (B NHL), and to investigate their correlations to clinicopathologic features of B NHL. METHODS: The expression of COX-2 and P-gp in 43 specimens of naive B-NHL and 27 specimens of relapsed B-NHL were detected by SP immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The positive rates of COX-2 and P-gp were significantly lower in naive B-NHL than in relapsed B-NHL (23.3% vs. 74.1%, 11.6% vs. 70.4%, P<0.01). COX-2 expression was positively correlated to P-gp expression in relapsed B-NHL (r=0.998, P<0.01). The positive rates of COX-2 and P-gp were significantly higher in aggressive B-NHL than in indolent B-NHL (64.3% vs. 10.7%, P=0.002; 52.4% vs. 7.1%, P=0.012). CONCLUSION: COX-2 and P-gp are highly expressed in relapsed B-NHL, and they may play a role in tumor metastasis of B-NHL. PMID- 17697547 TI - [Clinical tolerance trial on recombinant human endostatin adenovirus]. AB - BACKGROUND & OBJECTIVE: Recently, some phase I trials on endostatin has shown broad antitumor activity with low toxicity. This study was to determine the maximal tolerant dose (MTD) of recombinant human endostatin adenovirus Ad-Es for human. METHODS: For the sake of safety, 1 patient was treated with 1x10(10) VP Ad Es single intratumoral injection in advance. A total of 14 patients with malignant tumors received weekly intratumoral injection of Ad-Es in a dose escalation manner (1x10(11) VP, 5x10(11) VP, 1x10(12) VP) for 2 weeks. RESULTS: Toxicity profiles in all 15 cases were available. All patients tolerated well. No dose-limited toxicity (DLT) and serious adverse event were observed during treatment. Main adverse events were injection reaction (40.0%) and fever (53.3%). One patient with nasopharyngeal carcinoma had a minor response, 12 patients showed stable disease and 2 patients had progressive disease. CONCLUSION: Ad-Es is well tolerated up to 1x10(12) VP. The recommended dose for phase II trial is 1x10(12) VP intratumor injection for 4 consecutive weeks. PMID- 17697548 TI - [Efficacy of transcatheter arterial chemoembolization combined thalidomide on hepatocellular carcinoma: a controlled randomized trial]. AB - BACKGROUND & OBJECTIVE: Transcatheter arterial chemoembolization (TACE) is an important therapy for hepatocellular carcinoma (HCC), but the recurrence rate is still high and the long-term survival is unsatisfactory. This study was to evaluate the efficacy of TACE combined thalidomide on HCC. METHODS: From Aug. 2004 to Aug. 2006, 108 patients with unresectable primary HCC were randomized into combination (TACE plus thalidomide) group and TACE group. Combination group received oral administration of thalidomide (200 mg/d) for 1-6 months. Both groups were treated with 0.4-1.6 g gemcitabine, 100-200 mg oxaliplatin, and 0.5 1.0 g floxuridine as chemotherapeutic drugs, ethanol, glutin, and iodolipol as ambolic agent in TACE. The side effects of thalidomide and survival of the patients were observed. RESULTS: The median survival period was 18 months [95% confidence interval (CI), 12-24 months] in combination group and 13 months (95% CI, 10-16 months) in TACE group. The 6-month, 1-year, and 2-year survival rates were 92.9%, 82.7%, and 58.4% respectively in combination group, and 85.6%, 57.2%, and 32.3% respectively in TACE group. The median time to progression was significantly longer in combination group than in TACE group [181 days (95% CI, 91-271 days) vs. 97 days (95% CI, 33-161 days), P<0.05]. Excluding the patients who took thalidomide for less than 1 month, the median survival period was significantly longer in combination group than in TACE group [18 months (95% CI, 12-24 months) vs. 13 months (95% CI, 10-16 months), P<0.05]u the 6-month, 1-year, and 2-year survival rates were 96.6%, 70.8%, and 44.3% respectively in combination group, and 84.7%, 54.4%, and 14.9% respectively in TACE group. The occurrence rate of serious rashes was 11.1% and that of serious somnolency was 6.7%. Multivariate Cox analysis showed that the times of TACE was an independent prognostic factor of HCC. CONCLUSIONS: Compared with TACE alone, the combination of TACE and thalidomide can obviously postpone disease progression and prolong survival of HCC patients. The times of TACE is a prognostic factor of HCC after TACE. PMID- 17697549 TI - [Feasibility to treat pediatric cancer pain with analgesics for adults and their efficacy]. AB - BACKGROUND & OBJECTIVE: Lacking enough knowledge of pediatric cancer pain and pediatric dosage form of analgesics, current treatment of pediatric cancer pain in China is unsatisfactory. This study was to probe the efficacy and safety of treating pediatric cancer pain with analgesics for adults through summarizing the experience of diagnosis and treatment in Cancer Center of Sun Yet-sen University. METHODS: Basing on the components and the endurable dosage of each component for children, we formulated the appropriate dosage and usage of a few analgesics (including sustained release tablets of morphine, oxycodone and transdermal fantanyl) available in China, most of which were used in adults. Cancer pain of 139 children with newly diagnosed tumors were treated according to the World Health Organization (WHO) analgesic ladder, including 19 cases of mild pain, 41 cases of moderate pain and 79 cases of severe pain. Efficacy and adverse events were evaluated. RESULTS: Of the 139 patients, 104 (74.8%) were treated with analgesics of 1 WHO ladder step, 35 (25.2%) were treated with increased WHO ladder steps (ladder 1-->2 or 2-->3) or reduced WHO ladder steps (ladder 3-->2 or 2-->1). The total response rate for pain relief was 100%: 129 (92.8%) patients had complete relief, 7 (5.0%) had obvious relief, 3(2.2%) had moderate relief. The median time for pain control was 5 days (range, 1-12 days). Sustained release tablets of morphine, transdermal fantanyl, and sustained release tablets of oxycodone were used in 20, 28, and 40 patients, respectively. The median ages of the 3 groups were 10 (5-18), 6 (2.3-16), and 5 (2.5-16) years, respectively. The median of maximum dosages of the 3 single drugs were 20 (10-70) mg, 25 (12.5-50) microg/h, and 10 (5-30) mg, respectively. The median doses used in the 3 groups were 100 (20-360) mg, 5 (1.25-7.5) mg, and 60 (10-200) mg, respectively. The non steroid anti-inflammatory drug-induced adverse events were nausea and vomiting with very low frequencies. The weak opioid and strong opioid drug-induced adverse events included constipation, nausea, vomiting, and somnolence, all of which were reversible. No severe adverse events, including respiratory depression and drug addiction, happened. CONCLUSIONS: The WHO ladder approach for cancer pain is appropriate for children. Currently in China, most analgesics for adults could be used for pediatric cancer pain treatment. PMID- 17697550 TI - [Tropisetron hydrochloride in preventing and treating chemotherapy-induced nausea and vomiting: a phase II, randomized, multicenter, double-blinded, comparative clinical trial]. AB - BACKGROUND & OBJECTIVE: Tropisetron hydrochloride (Navoban), as a highly selective 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, has been widely used in preventing and treating chemotherapy-induced nausea and vomiting for many years. This study was to evaluate the efficacy and safety of homemade tropisetron hydrochloride in preventing and treating cisplatin-based chemotherapy-induced nausea and vomiting. METHODS: A randomized, double-blinded, multicenter, comparative trial was conducted in cancer patients receiving cisplatin-based chemotherapy. All patients were assigned to group A-B or B-A randomly, and took homemade tropisetron hydrochloride and Navoban (positive control agent) to treat chemotherapy-induced nausea and vomiting. RESULTS: A total of 118 patients were enrolled: 60 in group A-B and 58 in group B-A. There was no difference in the efficacy of relieving acute vomiting between homemade tropisetron hydrochloride and Navoban (P>0.05). The inhibition rates of nausea and vomiting were 28.59% and 52.61% respectively in group A-B, while 29.21% and 51.94% in group B-A (P>0.05). In addition, quality of life (QOL) showed no significant difference between the 2 groups at Days 3, 6, 10, and 21 (P>0.05). Besides, the occurrence rate of adverse events, such as constipation, abdominal distention, vertigo, headache and fatigue, was 27.97% in group A-B and 22.03% in group B-A (P>0.05). CONCLUSION: Homemade tropisetron hydrochloride injection has both reliable efficacy and safety in preventing and treating cisplatin-induced acute or chronic nausea and vomiting; it is comparable with Navoban on many aspects, such as long action time, less adverse effects and improved QOL. PMID- 17697551 TI - [Phase II clinical trial of h-R3 combined radiotherapy for locoregionally advanced nasopharyngeal carcinoma]. AB - BACKGROUND & OBJECTIVE: Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are easily to produce human anti-murine antibody response at present clinical use. This may influence therapeutic effect. This study was to evaluate the short-term and long-term efficacy and toxicity of the humanized anti-EGFR monoclonal antibody h-R3 in combination with radiotherapy for locoregionally advanced nasopharyngeal carcinoma (NPC). METHODS: Patients with newly diagnosed stage III-IVb (UICC 1997) NPC, who had moderate or strong EGFR expression, were randomized into radiotherapy alone group or radiotherapy combined h-R3 group. Similar dosage and technique of radiotherapy was administered in both groups. The combination group received weekly intravenous infusion of 100 mg h-R3 during radiotherapy. The short-term efficacy was evaluated according to WHO criteria. The survival was analyzed by Kaplan-Meier method. RESULTS: A total of 35 patients were enrolled, 17 in radiotherapy alone group and 18 in combination group. During treatment, only 1 patient withdrew from the combination group. The overall complete remission (CR) rates at the end of treatment, 5 and 17 weeks after treatment were significantly higher in combination group than in radiotherapy alone group (72.2% vs. 35.3%, 83.3% vs. 41.2%, and 83.3% vs. 47.1%, P<0.05). Median follow-up time was 31.9 months (range, 4.2-40.7 months). No significant differences in 3-year locoregional control, distant metastasis-free survival and overall survival rates between the 2 groups were found. Except for 1 patient suffered from grade 2 vomiting, no patient developed other adverse events in combination group. No significant differences in radiotherapy-related adverse events between the 2 groups were observed. CONCLUSIONS: h-R3 is a safe drug which may enhance the response of advanced NPC patients to radiotherapy. However, h-R3 seems not to significantly affect the long-term outcomes. PMID- 17697552 TI - [Comparison of efficacy of docetaxel combined cisplatin (TP regimen) and cisplatin combined 5-fluorouracil (PF regimen) on locally advanced nasopharyngeal carcinoma]. AB - BACKGROUND & OBJECTIVE: Docetaxel and cisplatin (DDP) are effective drugs for head and neck tumors. Stage II-III clinical trial of TP regimen (docetaxel combined DDP) for head and neck tumors has completed. This study was to compare the efficacy and toxicity of TP regimen and PF regimen [DDP combined 5 fluorouracil (5-FU)] in treating nasopharyngeal carcinoma (NPC), to provide a new chemotherapeutic regimen for NPC. METHODS: Twenty NPC patients treated in Cancer Center of Sun Yat-sen University between Oct. 1, 2005 and Mar. 1, 2006 were subjected to study group (TP group). Twenty patients were chosen randomly from the 45 NPC patients treated with PF regimen between May 1, 2004 and Sep. 30, 2005 as control group (PF group). Both groups received concurrent radiotherapy. The efficacy and adverse events of the 2 groups were compared. RESULTS: The mean number of chemotherapy cycles was significantly higher in TP group than in PF group (3.85 cycles vs. 2.75 cycles, P<0.001). After induction chemotherapy, in TP group, 18 achieved partial remission (PR) and 2 had stable disease (SD) for nasopharyngeal lesions, 7 achieved complete remission (CR), 11 achieved PR and 2 had SD for regional lymph nodes; in PF group, 17 achieved PR and 3 had SD for nasopharyngeal lesions, 2 achieved CR, 15 achieved PR and 1 had SD for regional lymph nodes. After concurrent chemoradiotherapy, all in TP group and 18 in PF group achieved CR for nasopharyngeal lesions, and 19 in TP group and 15 in PF group achieved CR for regional lymph nodes. There was no significant difference in efficacy between the 2 groups (P>0.05). The occurrence rates of grade 3-4 neutropenia were significantly higher in TP group than in PF group (40.5% vs. 0% after induction chemotherapy, 40.5% vs. 10.2% after concurrent radiochemotherapy, P<0.05). The occurrence rates of anemia and thrombocytopenia were significantly lower in TP group than in PF group (P<0.05). The uses of antibiotics and parenteral nutritional support in the 2 groups were similar. CONCLUSION: The efficacy of TP regimen on NPC is similar to that of PF regimen, and the adverse events are tolerable, but the long-term outcomes and toxicities need to be further investigated. PMID- 17697553 TI - [Long-term efficacy of induction chemotherapy plus concurrent radiochemotherapy on advanced nasopharyngeal carcinoma]. AB - BACKGROUND & OBJECTIVE: Induction chemotherapy plus concurrent radiochemotherapy may prolong disease-free and overall survival of advanced nasopharyngeal carcinoma (NPC) patients. This study was to compare the long-term efficacy of induction chemotherapy plus concurrent radiochemotherapy and radiotherapy alone on advanced NPC. METHODS: Clinical data of 535 advanced NPC patients, treated in Cancer Center of Sun Yat-sen University from Jan. 1997 to Dec. 1998, were analyzed. Of the 535 patients, 75 were treated with 3-5 cycles of induction and concomitant chemotherapy of PF regimen (cisplatin combined 5-fluorouracil) plus radiotherapy, 460 were treated with radiotherapy alone. The survival statuses of the 2 groups were compared. Prognostic factors were analyzed by Cox regression analysis. Cumulative survival rate was analyzed by Kaplan-Meier method. RESULTS: The 5-year overall and disease-free survival rates were significantly higher in radiochemotherapy group than in radiotherapy group (78.15% vs. 55.27%, 71.55% vs. 48.99%, P<0.05). For the patients with stage III tumors, the median overall and disease-free survival term were significantly longer in radiochemotherapy group than in radiotherapy group (94.5 months vs. 85.1 months, 89.5 months vs. 82.9 months, P<0.05). For the patients with stage IVa tumors, the same results were obtained (82.4 months vs. 44.4 months, 69.6 months vs. 40.3 months, P<0.05). Cox regression analysis showed that clinical stage and chemotherapy were dependent prognostic factors of advanced NPC. CONCLUSION: Induction chemotherapy plus concurrent radiochemotherapy could prolong the survival of patients with advanced NPC. PMID- 17697555 TI - [Meta-analysis on gemcitabine of fixed-dose rate infusion plus oxaliplatin as first-line therapy for advanced pancreatic cancer]. AB - BACKGROUND & OBJECTIVE: Recent clinical trials showed that gemcitabine (GEM) of fixed-dose rate infusion has certain effect on advanced pancreatic cancer. Some meta-analyses suggest that GEM plus cisplatin (DDP) or its analogues is better than GEM alone in treating advanced pancreatic cancer. This study was to evaluate the efficacy of GEM of fixed-dose rate infusion plus oxaliplatin (GEMOX regimen) as first-line therapy for advanced pancreatic cancer by meta-analysis. METHODS: Two reviewers performed the meta-analysis of all relative studies through searching the international literature, including MEDLINE, EMBASE, ASCO abstracts. This meta-analysis included all randomized evidences to compare GEMOX regimen with GEM alone with respect to overall survival rate and adverse events in patients with advanced pancreatic cancer. RESULTS: Two randomized controlled trials (including 869 patients) were screened from 182 reports. GEMOX regimen was better than GEM alone in terms of 6-month survival rate [risk difference (RD)=0.09, 95% confidence interval (CI)=0.03-0.16, P=0.005], 1-year survival rate (RD=0.05, 95% CI=-0.01-0.11, P=0.08), and objective remission rate (RD=0.06, 95% CI=0.02-0.10, P=0.006). WHO grade 3-4 adverse events analysis revealed that GEMOX was associated with a reduction in anemia (RD=-0.05, 95% CI=-0.08 - -0.01, P=0.01); the addition of oxaliplatin, however, significantly increased neuropathy (RD= 0.14, 95% CI=0.04-0.24, P=0.009) and nausea/vomiting (RD=0.13, 95% CI=0.08 0.18, P<0.001). The occurrence rates of neutropenia and thrombocytopenia were similar in the 2 groups. CONCLUSION: Analyses of the available evidences suggest GEMOX regimen is promising as the first-line therapy for advanced pancreatic cancer, which encourages further clinical trials. PMID- 17697554 TI - [Efficacy of gemcitabine-based chemotherapy on advanced pancreatic cancer]. AB - BACKGROUND & OBJECTIVE: Advanced pancreatic cancer has a poor prognosis. Gemcitabine (GEM) can improve the quality of life of pancreatic cancer patients. However, the efficacy of gemcitabine-based combination chemotherapy is uncertain. This study was to compare the efficacy of GEM-based combination therapy and GEM alone on advanced pancreatic cancer. METHODS: Clinical data of 40 patients with pathologically or clinically diagnosed advanced pancreatic cancer were analyzed. Of the 40 patients, 15 were treated with GEM (1,000 mg/m(2)) alone weekly for 7 weeks followed by a 2-week rest, then received cycles of 3-week administration with 1-week rest; 25 were treated with GEM (1,000 mg/m(2)) weekly for 2 weeks plus 5-fluorouracil (5-FU) (425-600 mg/m(2)) as bolus at Day 1-5 or 120-hour infusion every 21 days, or cisplatin (DDP) (30-37.5 mg/m(2)) at Day 1-2 every 21 days, or oxaliplatin (85-130 mg/m(2)) at Day 1 every 21 days, or capecitabine (1,000 mg/m(2)) twice a day at Day 1-14 every 21 days, respectively. The survival was analyzed by Kaplan-Meier method. Median time to progression (mTTP), clinical benefit response (CBR), disease control rate, median overall survival (mOS) and toxicity were assessed according to World Health Organization criteria. RESULTS: The rate of CBR was 56.0% in GEM-combination group and 46.7% in GEM alone group. There were no significant differences in disease control rate, mOS, CBR, and adverse events between the two groups (all P>0.05). However, for the patients with stage III-IV advanced pancreatic cancer, the disease control rate was higher in GEM-combination group than in GEM alone group (75.0% vs. 45.5%, P=0.13). CONCLUSION: GEM-combination regimens and GEM alone have similar efficacy, and lead to similar clinical benefit response and mOS for the patients with advanced pancreatic cancer. PMID- 17697556 TI - [Value of fused 18F-FDG PET/CT images in predicting efficacy of neoadjuvant chemotherapy on breast cancer]. AB - BACKGROUND & OBJECTIVE: Previous studies confirmed that fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging relates to clinical or pathologic responses of tumors to neoadjuvant therapy. This study was to evaluate the correlation of fused 18F-FDG PET/CT images to cell apoptosis of breast cancer after neoadjuvant chemotherapy, and explore its value in predicting the efficacy of neoadjuvant chemotherapy on breast cancer. METHODS: Forty-five patients with primary breast cancer, proven by core needle biopsy, underwent 3 cycles of neoadjuvant chemotherapy. PET/CT was performed before and after treatment, and the ratio of tumor area activity to non-tumor area activity (T/N) was calculated. The apoptosis index (AI) was determined using TUNEL technique. RESULTS: Of the 45 patients, 4(8.9%) achieved complete remission (CR), 29 (64.4%) achieved partial remission (PR), 10 (22.2%) presented stable disease (SD), and 2 (4.4%) presented progressive disease (PD) after neoadjuvant chemotherapy. The mean T/N ratio was decreased from 3.23+/-0.63 before chemotherapy to 2.31+/-0.49 after chemotherapy (P=0.006) by 6.4%-50.8%. The mean AI was increased from (2.81+/-0.76)% before chemotherapy to (17.31+/-6.85)% after chemotherapy (P<0.001) by 1.9%-41.3%. The T/N ratio reduction rate was positively correlated to AI change (r(s)=0.850, P<0.001). At a threshold of 20% decrease from baseline in T/N ratio, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PET/CT in predicting clinical response were 90.9%, 83.3%, 93.8%, 76.9%, and 92.1%, respectively. CONCLUSIONS: Neoadjuvant chemotherapy might effectively induce cell apoptosis in breast cancer and inhibit the glucose uptake. Fused PET/CT imaging is closely related to cell apoptosis status of breast cancer after neoadjuvant chemotherapy, and may be applied to predict the response of breast cancer to neoadjuvant chemotherapy. PMID- 17697557 TI - [Efficacy of CPT-11 combined 5-FU/CF (FOLFIRI) regimen on advanced colorectal cancer]. AB - BACKGROUND & OBJECTIVE: Combination therapy of irinotecan, leucovorin (LV), and 5 fluorouracil (5-FU)(FOLFIRI regimen) has certain effect on advanced colorectal cancer. However, data of this regimen as first-line chemotherapy for Chinese patients with advanced colorectal cancer is still lacking, and its efficacy and safety still needs to be defined. This study was to explore the efficacy of FOLFIRI regimen as first-line chemotherapy on advanced colorectal cancer in Chinese patients, and observe its safety. METHODS: Clinical data of 54 chemotherapy-naive patients with advanced colorectal cancer, treated with FOLFIRI regimen from Jan. 2002 to Sep. 2005 in Cancer Center of Sun Yat-sen University, were analyzed. RESULTS: Of the 54 patients, 52 were evaluable for response. The overall response rate was 42.6%, the time to progression (TTP) was 6 months, and the overall survival time was 15.2 months. The most common drug-related adverse events were neutropenia (38.9%), diarrhea (37.1%) and nausea and vomiting (50.0%). The occurrence rates of these grade 3-4 events were 5.6%, 9.3%, and 9.3%, respectively. All adverse events were tolerable. CONCLUSION: FOLFIRI regimen is effective and well-tolerated as first-line treatment for Chinese patients with advanced colorectal cancer. PMID- 17697558 TI - [Treatment outcomes and prognostic analyses of relapsed or refractory T-cell non Hodgkin's lymphoma]. AB - BACKGROUND & OBJECTIVE: The prognosis of relapsed or refractory T-cell non Hodgkin's lymphoma (T-NHL) is poor. There is no definite prognostic factors and standard regimens for these patients. This study was to explore the prognostic factors and effective regimens for relapsed or refractory T-NHL. METHODS: Clinical records of 45 patients with relapsed or refractory T-NHL, treated in Cancer Center of Sun Yat-sen University from Jan. 1997 to Mar. 2003, were analyzed in terms of response, long-term survival and prognostic factors. RESULTS: By the end of Jul. 2006, 5 patients still alive; the median follow-up time was 30 (2-70) months. The median survival time after relapse was 22 (2-62) months. Of the 45 patients, 42 (93.3%) received salvage regimen, the response rate was 61.9% (26/42); for those received second-line chemotherapy, the response rate was 52.4% (22/42). The 1-, 3-, and 5-year overall survival rates were 75.6%, 17.8%, and 4.4% for the whole group, 82.1%, 25.0%, and 5.8% for low risk group and 64.7%, 6.5%, and 6.5% for high risk group, respectively (P=0.026). Multivariate analysis showed that serum lactate dehydrogenase (LDH) level (P=0.010), second-line Ann Arbor stage (P=0.009), second-line IPI score (P=0.015), autologous stem cell transplantation (P=0.026), performance status (P=0.002), and IMVP-16 regimen (P=0.026) were independent prognostic factors of relapsed or refractory T-NHL. CONCLUSIONS: Second-line IPI score, autologous stem cell transplantation, and so on, may be independent prognostic factors for relapsed or refractory T-NHL. The prognosis of this disease is poor and the addition of intensive treatments, such as stem cell transplantation, should be considered when alleviated after chemotherapy. PMID- 17697559 TI - [Efficacy and toxicity of intravenous busulfan-based conditioning before allogeneic peripheral blood stem cell transplantation for leukemia]. AB - BACKGROUND & OBJECTIVE: Busulfan (Bu) is commonly used as a component of conditioning regimens for hematopoietic stem cell transplantation. Erratic gastrointestinal absorption as a result of oral administration of Bu not only affects the efficacy, but also increases the risk of toxicity. This study was to analyze the efficacy and toxicity of intravenous Bu and cyclophosphamide (Cy) conditioning before allogeneic peripheral blood stem cell transplantation (allo PBSCT) for leukemia. METHODS: Fifteen leukemia patients received intravenous Bu/Cy conditioning before allo-PBSCT, while 20 patients received oral Bu/Cy conditioning. The responses and adverse events of the 2 groups were assessed. RESULTS: All 15 patients in intravenous Bu/Cy group had hematopoietic engraftment. The median time of engraftment was 12 (9-15) days for neutrophils and 15 (11-24) days for platelets. Of the 15 patients, 6 (40.0%) developed acute graft-versus-host disease (aGVHD), including 4 cases of grade I-II aGVHD and 2 cases of grade III-IV aGVHD; during conditioning, 7 (46.6%) had vomiting, 1 (6.7%) had oral mucositis, 1 (6.7%) had hemorrhagic cystitis, 2 (13.3%) had hepatic damage, none developed seizure. With a median follow-up of 180 days (range, 35-420 days), 14 (93.3%) patients were alive, 1 died of severe aGVHD accompanied fungal infection of the lung and central nerve system. The occurrence rates of hepatic damage and oral mucositis were significantly lower in intravenous Bu/Cy group than in oral Bu/Cy group (13.3% vs. 60.0%, 6.7% vs. 80.0%, P<0.01). There were no significant differences in hematopoietic reconstruction, aGVHD, stomatitis, gastrointestinal reaction, and hemorrhagic cystitis between the 2 groups (P>0.05). CONCLUSION: The intravenous Bu/Cy conditioning before allo-PBSCT for leukemia has clear efficacy with low extramedullary toxicity. PMID- 17697560 TI - [Primary non-Hodgkin's lymphoma of the paranasal sinuses: a report of 14 cases]. AB - BACKGROUND & OBJECTIVE: Primary paranasal sinus lymphoma (PPSL) is a rare presentation of extranodal non-Hodgkin's lymphoma with a natural history distinct from other lymphomas. This study was to evaluate the clinical and pathologic characteristics, treatment outcomes and prognosis of PPSL. METHODS: The records of 14 PPSL patients, treated at Cancer Center of Sun Yat-sen University from 1994 to 2006, were analyzed. RESULTS: The primary involvement sites included the maxillary sinus (11 cases), ethmoid sinus (2 cases), and sphenoid sinus (1 case). All patients were at stage I-II (Ann Arbor system). According to the AJCC TNM staging system, most patients had advanced T3-T4 disease. Of the 14 patients, 12 had B-cell PPSL, 1 had T-cell PPSL, and 1 had unclassified PPSL. The most common type was diffuse large B-cell PPSL (6 cases, 42.9%). Two patients underwent total maxillectomy and 12 underwent local excision or biopsy. All patients received chemotherapy and 6 received radiotherapy after chemotherapy. Both 5-year overall and event-free survival rates were 78.6%, with a median survival of 59.5 months(range, 2-192 months). CONCLUSIONS: PPSL is an uncommon presentation of lymphoma characterized by bulky local disease. Diffuse large B-cell lymphoma is the most common histologic type and the maxillary sinus is the most common original site of PPSL. A combined-modality approach with systemic chemotherapy and local-regional radiation is recommended for PPSL patients. The prognosis of PPSL is relatively good. PMID- 17697561 TI - [Research advance on role of tumor microenvironment in mediating acquired drug resistance]. AB - The emergence of clinical drug resistance continues to be an obstacle for the successful treatment of cancer. In the past twenty years, our primary understanding of the mechanisms associated with drug resistance has been ascertained through investigating unicellular drug-resistant models. These models are critical in elucidating drug-resistant mechanism and have aided in the identification of drug targets in some cases. However, these models do not address resistance mechanisms that contribute to acquired drug resistance. Therefore, to improve the efficacy of cancer chemotherapy, seeking and identifying the mechanisms of acquired drug resistance has become a hotspot in current researches. Many researches have suggested that tumor microenvironment plays an important role in mediating acquired drug resistance and confers resistance to physiologic mediators of cell death. The specific niches within it may provide a sanctuary for subpopulations of tumor cells that affords a survival advantage following initial drug exposure and may promote acquired drug resistance. Our review focused on tumor microenvironment and its role in mediating acquired drug resistance. PMID- 17697562 TI - [1 Case of Lymphoepithelioma-like Carcinoma of Esophagus]. PMID- 17697563 TI - The effects of irregular sampling and missing data on largest Lyapunov exponents. AB - Human self-report time series data are typically marked by irregularities in sampling rates arising from the data generation process. The largest Lyapunov exponent lamda1 is an indicator of chaos in time series data. Relatively little has been published to assist the calculation of lamda1's using irregularly sampled data. We report the results of a series of computational experiments on synthetic data sets assessing techniques for handling irregular time series data in the calculation of lamda1 . Regularly sampled data sets were disrupted by data point removal using an empirically motivated data gap distribution of either uniform random or power law form. Missing data segments were patched using segment concatenation, segment filling with average data values, or local interpolation in phase space. We compared results of lamda1 calculations using complete and patched sets. The greatest proportion of missing data possible that will allow an accurate estimate of lamda1 depends on the nature of the underlying system and the patching technique used. Self-similar data patched with segment concatenation was particularly robust. Local interpolation in phase space was successful in many cases, but required potentially impractical quantities of intact data as a primer. Optimally, estimates of lamda1 can readily be recovered with 15%-20% or greater amounts of missing data. PMID- 17697564 TI - Principal difference between stability and structural stability (robustness) as used in systems biology. AB - The concepts stability and structural stability (robustness) are used often in systems biology. According to Kitano (2004) robustness is a fundamental property of evolvable complex biological systems. For that reason, the purpose of this review is to clarify: (a) how are strictly formulated concepts, such as stability and robustness of a dynamical system, used in computational systems biology; (b) what is meant by structural stability (robustness) in contemporary biology and how are stability and robustness distinguished from each other; and (c) why is it necessary to investigate whether a cell signal pathway is stable. We formulate the two concepts stability and structural stability (robustness) of a dynamical system with an arbitrary dimensionality, in the way they are known in mathematics and mechanics, and clarify the principal difference between them. We also consider how these two concepts are used in the analysis of a concrete biological system in systems biology. In the last section we formulate when, according to us, in biology (and in systems biology in particular), it should be said that a system (process) is stable, and when it is structurally stable. PMID- 17697565 TI - Nonlinear model of epidemic spreading in a complex social network. AB - The epidemic spreading in a human society is a complex process, which can be described on the basis of a nonlinear mathematical model. In such an approach the complex and hierarchical structure of social network (which has implications for the spreading of pathogens and can be treated as a complex network), can be taken into account. In our model each individual has one of the four permitted states: susceptible, infected, infective, unsusceptible or dead. This refers to the SEIR model used in epidemiology. The state of an individual changes in time, depending on the previous state and the interactions with other individuals. The description of the interpersonal contacts is based on the experimental observations of the social relations in the community. It includes spatial localization of the individuals and hierarchical structure of interpersonal interactions. Numerical simulations were performed for different types of epidemics, giving the progress of a spreading process and typical relationships (e.g. range of epidemic in time, the epidemic curve). The spreading process has a complex and spatially chaotic character. The time dependence of the number of infective individuals shows the nonlinear character of the spreading process. We investigate the influence of the preventive vaccinations on the spreading process. In particular, for a critical value of preventively vaccinated individuals the percolation threshold is observed and the epidemic is suppressed. PMID- 17697566 TI - Nonlinear dynamics and probabilistic behavior of adolescent suicidal outbreaks. AB - There is increasing evidence of suicide contagion among teenagers. This phenomenon is further exacerbated by the availability of long-range communication channels like the Internet. The aim of this work is to develop a quantitative model linking contagion to the nonlinear dynamics underlying the imitation phenomena at work; to explore different scenarios and predict trends to be expected; and to propose prevention strategies. To this end, the methods of population dynamics and epidemiology are augmented by incorporating individual variability by means of Monte Carlo simulation. It is shown that contagion may take an explosive form which is dramatically accelerated in the presence of long range interactions. Situations of undecidability can also be reached. The relevant time scales are identified and linked to two fundamental parameters. Applications in prevention in hospital, in school and in use of Internet are outlined. It is suggested that interpretations of surveys based on purely random scenarios need to be reassessed. PMID- 17697567 TI - An approach to the study of dynamics of work motivation using the diary method. AB - This study is concerned with work motivation as a dynamic process. Twenty workers kept a motivation diary over a period of several weeks. Using a PDA they recorded their level of motivation, self-efficacy beliefs and perceived instrumentality with respect to the task being carried out. The time series obtained were analyzed using common procedures in the study of dynamic systems in order to determine whether motivation followed linear or nonlinear patterns. The results revealed highly nonlinear dynamics for the different variables studied. The implications of these findings are discussed and questions are raised regarding the basic assumptions underlying current theories and models of motivation, for example, the assumptions of linearity and stability. PMID- 17697568 TI - Nonlinear models for the adoption and diffusion of innovations for industrial energy conservation. AB - Four different theoretical models for explaining the diffusion of innovation were compared for 13 energy-related innovations--the Theory of Planned Behavior, the S curve for Diffusion of Innovations, the power law distribution, and the cusp catastrophe. The substantive concern was to explore the roles of facilitative and obstructive factors in diffusing industrial and commercial innovations. Participants were 102 industrial plant and facilities managers from sites that were among the top users of electrical energy and natural gas in the United States. They completed a survey that contained measurements of positive attitudes toward innovation, organizational resistance to innovation, and the extent to which they had investigated or adopted each of the target innovations. Seven of the 13 innovations exhibited strong cusp catastrophe models (via nonlinear regression, average R2 = .91) compared to linear alternative models (average R2 = .31) for those innovations; the S-curve for diffusion was regarded as a simplified version of the cusp. One innovation was characterized best by a power law distribution (R2 = .94), and the remaining five were characterized best by a linear model that was based on the Theory of Planned Behavior (R2 = .41). Different underlying dynamics for the various innovations were implied by these results. PMID- 17697569 TI - Neural network-based computer-aided diagnosis in distinguishing malignant from benign solitary pulmonary nodules by computed tomography. AB - BACKGROUND: Computer-aided diagnosis (CAD) of lung cancer is the subject of many current researches. Statistical methods and artificial neural networks have been applied to more quantitatively characterize solitary pulmonary nodules (SPNs). In this study, we developed a CAD scheme based on an artificial neural network to distinguish malignant from benign SPNs on thin-section computed tomography (CT) images, and investigated how the CAD scheme can help radiologists with different levels of experience make diagnostic decisions. METHODS: Two hundred thin-section CT images of SPNs with proven diagnoses (135 small peripheral lung cancers and 65 benign nodules) were analyzed. Three clinical features and nine CT signs of each case were studied by radiologists, and the indices of qualitative diagnosis were quantified. One hundred and forty nodules were selected randomly to form training samples, on which the neural network model was built. The remaining 60 nodules, forming test samples, were presented to 9 radiologists with 3 - 20 years of clinical experience, accompanied by standard reference images. The radiologists were asked to determine whether a nodule was malignant or benign first without and then with CAD output. Diagnostic performance was evaluated by receiver operating characteristic (ROC) analysis. RESULTS: CAD outputs on test samples had higher agreement with pathological diagnoses (Kappa = 0.841, P < 0.001). Compared with diagnostic results without CAD output, the average area under the ROC curve with CAD output was 0.96 (P < 0.001) for junior radiologists, 0.94 (P = 0.014) for secondary radiologists and 0.96 (P = 0.221) for senior radiologists, respectively. The differences in diagnostic performance with CAD output among the three levels of radiologists were not statistically significant (P = 0.584, 0.920 and 0.707, respectively). CONCLUSIONS: This CAD scheme based on an artificial neural network could improve diagnostic performance and assist radiologists in distinguishing malignant from benign SPNs on thin-section CT images. PMID- 17697570 TI - Role of serum angiopoietin-2 level in screening for esophageal squamous cell cancer and its precursors. AB - BACKGROUND: Angiopoietin-2 (Ang-2) is one of the critical regulators of tumor angiogenesis. Studies have shown a significant correlation of Ang-2 expression to tumor invasion and metastasis in various human cancers, but little is known about the serum Ang-2 (sAng-2) levels in esophageal squamous cell cancer (ESCC) and its precursors. In this study, we aimed to investigate its role in screening for ESCC and its precursors. METHODS: We carried out a free endoscopic screening in Feicheng City, a high ESCC incidence area in Shandong Province of China. Serum samples were collected as follows: 91 from normal subjects, 44 from patients with esophagitis, 85 from patients with hyperplasia, and 13 from patients with early ESCC. In addition, 28 serum samples were obtained from patients with invasive ESCC undergoing surgery in People's Hospital of Feicheng City. All the subjects of the five groups were diagnosed by histopathology. The sAng-2 levels were tested and compared, and the diagnostic power in early or/and invasive ESCC was calculated in terms of sensitivity and other parameters. RESULTS: The sAng-2 levels were (22.0 +/- 5.5), (21.3 +/- 3.2), (20.5 +/- 3.3), (24.0+/- 5.0), and (29.8 +/- 5.0) U/ml in normal, esophagitis, hyperplasia, early ESCC, and invasive ESCC groups respectively. It was significantly higher in early ESCC than inhyperplasia group (P = 0.009). The invasive ESCC group showed the highest Ang-2 level among all groups (all P = 0.000). The sensitivities of sAng-2 to early and invasive ESCC were 23.1% and 78.6% respectively. CONCLUSION: sAng-2 level is related to carcinogenesis and progression of ESCC, but it can not be used to screen for early ESCC. PMID- 17697571 TI - Expression and immunogenicity of recombinant Mycobacterium bovis Bacillus Calmette-Guerin strains secreting the antigen ESAT-6 from Mycobacterium tuberculosis in mice. AB - BACKGROUND: Tuberculosis remains the leading cause of human death. Currently, Bacillus Calmette-Guerin (BCG) is the only available vaccine against tuberculosis but its efficacy is highly variable. Thus, developing new tuberculosis vaccines becomes an urgent task. In this study, we evaluated in BALB/c mice the humoral and cellular immune responses of recombinant BCG expressing the antigen ESAT-6 from Mycobacterium tuberculosis. METHODS: Escherichia coli-BCG shuttle plasmid named pDE22-esat-6 was constructed by inserting the BamHI/EcoRI digested esat-6 gene PCR product into the similarly digested parental plasmid pDE22. BCG cells were transformed with pDE22-esat-6, which was named recombinant BCG (rBCG). BALB/c mice were immunized subcutaneously on the back with 100 microl normal saline containing 10(6) CFU of BCG or rBCG. They were sacrificed after 4 weeks to detect their humoral and cellular responses. RESULTS: There was no any significant differences in the growth characteristics between the conventional BCG and rBCG. In immunized mice, the IgG antibody titres of rBCG group were as high as 1:8000, which was significantly higher than that in BCG group (1:1400, P < 0.05). The elicited IFN-gamma level of rBCG group was (1993 +/- 106) pg/ml, which was also significantly higher than that in BCG group ((1463 +/- 105) pg/ml, P < 0.05). The splenocyte proliferation index of rBCG group reached 4.34 +/- 0.31, which was higher than that of BCG group (3.79 +/- 0.24, P < 0.05). CONCLUSION: rBCG secreted expressing antigen ESAT-6 stimulated stronger humoral and cellular immune responses than BCG did, and, therefore may be the better vaccine against mycobacterium tuberculosis. PMID- 17697572 TI - Effect of intracoronary administration of anisodamine on slow reflow phenomenon following primary percutaneous coronary intervention in patients with acute myocardial infarction. AB - BACKGROUND: Many basic and clinical studies have proved that anisodamine can produce significant effect on relieving microvascular spasm, improving and dredging the coronary microcirculation. It may be beneficial to the improvement of slow-reflow phenomenon (SRP) following percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). So we investigated the effect of intracoronary administration of anisodamine on SRP of infarct related artery (IRA) following primary PCI in patients with ST segment elevated acute myocardial infarction (STEAMI). METHODS: Twenty-one patients with SRP from a total of 148 STEAMI patients accepted primary PCI were enrolled into this study from September 2004 to December 2005. When SRP happened, nitroglycerin (200 microg) was "bolus" injected firstly into IRA to exclude the spasm of epicardial artery and identify SRP as well as a baseline and self-control agent following PCI. Ten minutes later, 1000 microg of anisodamine was injected into IRA with SRP at 200 microg/s, while the coronary angiography (CAG) was taken before and at 1st, 3rd and 10th minute after administration of nitroglycerin or anisodamine, respectively. The corrected TIMI frame count (cTFC), TIMI myocardial perfusion grade (TMPG) and the diameter of IRA were calculated and analyzed by Gibson's TIMI frame count method using quantitative computer angiography (QCA) system to evaluate the influence of anisodamine on coronary flow and vessel lumen. In the meantime the invasive hemodynamic parameters of intracoronary and systemic artery (systolic, diastolic and mean pressure) and electrocardiogram (ECG) were measured and monitored. The changes of ventricular performance parameters and the adverse reaction were evaluated and followed-up at 1 month post-PCI. RESULTS: No significant changes in cTFCs and TMPGs were found at 1st, 3rd and 10th minute after intracoronary administration of nitroglycerin as compared with the baseline control (P > 0.05). cTFCs were decreased by 58.3%, 56.2%, and 54.6%, respectively (P < 0.001), and TMPGs were increased from 1.13 +/- 0.21 grade to 2.03 +/- 0.32, 2.65 +/- 0.45 and 2.51 +/- 0.57 grades (P < 0.05) at 1st, 3rd and 10th minute after intracoronary administration of anisodamine as compared with those after intracoronary administration of nitroglycerine, respectively. The average coronary blood flow of TIMI grade was improved from 1.76 +/- 0.43 to 2.71 +/- 0.46 (P < 0.05) while the diameter of middle segment in re-patented coronary artery was slightly increased from (3.20 +/- 0.40) mm to (3.40 +/- 0.50) mm at the 3rd minute after intracoronary administration of anisodamine (P > 0.05) as compared with those of nitroglycerine control. The systolic, diastolic and mean pressures of intracoronary artery after intracoronary administration of anisodamine increased from 115 to 123, 75 to 84, 88 to 95 mmHg (P < 0.05), respectively, along with the rise of heart rate from 68 to 84 beats per minute (P < 0.05). There were no significant changes in intervals of PR, QT and QRS (P > 0.05) and no any severe fast arrhythmia after intracoronary administration of anisodamine. The ventricular performance parameters were significantly improved and no major adverse cardiovascular events (MACE) were found during follow-up at 1 month post PCI. CONCLUSIONS: Intracoronary administration of 1000 microg anisodamine is effictive in reversing SRP following PCI in STEAMI patients, especially it is suitable for SRP patients with bradycardia or hypotension. PMID- 17697573 TI - Functional magnetic resonance imaging and immunohistochemical study of hypothalamic function following oral glucose ingestion in rats. AB - BACKGROUND: The hypothalamus plays a central role in the regulation of metabolism by sensing metabolic demands and releasing regulatory neurotransmitters. This study investigated the response of the hypothalamus to glucose ingestion in rats by blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) and immunohistochemical techniques to determine the role of the hypothalamus in glyco-regulation during disturbances in carbohydrate metabolism. METHODS: The signal intensity of the hypothalamus was monitored by fMRI for 60 minutes after oral glucose intake in 48 healthy rats (age 14 months), which included 24 normal weight rats (weighing (365 +/- 76.5) g) and 24 overweight rats (weighing (714 +/- 83.5) g). Then, 12 rats (6 normal, 6 overweight) underwent a repeat fMRI scan after consuming an equivalent amount of water without glucose on a separate day. The procedure for fMRI with water intake was the same as for glucose ingestion. fMRI data was processed using time cluster analysis and intensity averaging method. After fMRI, the expression of neuropeptide Y (NPY) and 5 hydroxytryptamine (5-HT) in the hypothalamus of all rats was determined by immunohistochemistry. Positive cells for NPY or 5-HT were counted. RESULTS: There was a transient, but significant, decrease in fMRI signal intensity in all rats (mean (3.12 +/- 0.78)%) in the hypothalamus within 19.5 - 25.5 minutes of oral glucose ingestion. In overweight rats, the decrease in signal intensity in response to the glucose ingestion was more markedly attenuated than that observed in normal weight rats ((2.2 +/- 1.5)% vs (4.2 +/- 0.7)% inhibition, t = 2.12, P < 0.05). There was no significant response in the hypothalamus after oral water ingestion. The percentage of NPY positive cells in obese rats were slightly lower than those in control group (21% vs 23%, t = 0.71, P > 0.05); but there was no significant difference between the two groups; the percentage of 5-HT positive cells in obese rats were significantly lower than those in the control group (22% vs 31%, t = 3.25, P < 0.01). CONCLUSIONS: There is a transient, but significant, decrease in BOLD signal intensity in the hypothalamus following glucose ingestion, which is similar to that observed in humans. The response of the hypothalamus to glucose ingestion was different in overweight and normal weight rats. The percentage of NPY positive cells in obese rats were lower than those in the control group, although this difference was not statistically significant. The percentage of 5-HT positive cells in obese rats was significantly lower than those in the control group. PMID- 17697574 TI - Adeno-associated virus-mediated Bcl-xL prevents aminoglycoside-induced hearing loss in mice. AB - BACKGROUND: Recent studies showed that aminoglycosides destroyed the cochlear cells and induced ototoxicity by producing reactive oxygen species, including free radicals in the mitochondria, damaging the membrane of mitochondria and resulting in apoptotic cell death. Bcl-x(L) is a well characterized anti apoptotic member of the Bcl-2 family. The aim of this study was to determine the potential cochlear protective effect of Bcl-x(L) as a therapeutic agent in the murine model of aminoglycoside ototoxicity. METHODS: Serotype 2 of adeno associated virus (AAV2) as a vector encoding the mouse Bcl-x(L) gene was injected into mice cochleae prior to injection of kanamycin. Bcl-x(L) expression in vitro and in vivo was examined with Western blotting and immunohistochemistry separately. Cochlear dissection and auditory steady state responses were checked to evaluate the cochlear structure and function. RESULTS: The animals in the AAV2 Bcl-x(L)/kanamycin group displayed better auditory steady state responses hearing thresholds and cochlear structure than those in the artificial perilymph/kanamycin or AAV2-enhanced humanized green fluorescent protein/kanamycin control group at all tested frequencies. The auditory steady state responses hearing thresholds and cochlear structure in the inoculated side were better than that in the contralateral side. CONCLUSIONS: AAV2-Bcl-x(L) afforded significant preservation of the cochlear hair cells against ototoxic insults and protected the cochlear function. AAV2-mediated Bcl-x(L) might be an approach with respect to potential therapeutic application in the cochlear degeneration. PMID- 17697575 TI - Effect of recombinant human endostatin on endometriosis in mice. AB - BACKGROUND: Direct and indirect evidences have suggested that angiogenesis is a prerequisite for the development of endometriosis. Aiming at offering experimental evidences for anti-angiogenesis therapy, we transplanted the eutopic endometrium from patient with endometriosis into the severe combined immunodeficiency disease (SCID) mice, to evaluate the effect of the endostatin on the growth and angiogenesis of the established endometriosis lesions in SCID mice model. METHODS: Eutopic endometrium of women with endometriosis was transplanted into the SCID mice. The mice were randomized into treatment (n = 10) and control groups (n = 10). Two weeks after the implantation of endometrium fragment, the treatment group was injected with recombinant human endostatin YH-16 into the peritoneal cavity (2 mgxkg(-1)xd(-1)), whereas the control group received equivalent volume of PBS (200 microl/d). The volume of endometriotic lesions in SCID mice was measured every three days, and all the treatment lasted for 14 days. Immunohistochemistry was used to determine microvessel density (MVD) and the expression of VEGF. The results were analyzed by t test and chi(2) test to value the treating effect. RESULTS: Compared with the control group, growth of endometriosis lesion was reduced in the mice treated with YH-16. Statistically significant differences in the volume and weight of the ectopic lesions were observed between the treatment and the control groups (P < 0.05). Microscopical examination showed that after being treated with YH-16, the volume of the endometrial tissues decreased, the glands depauperated, and the glandular epithelium partially degenerated. Necrotic debris was observed in the endometrial stroma. MVD and expression of VEGF in the treatment group were significantly lower than those in the control group (P < 0.05). CONCLUSIONS: Recombinant human endostatin affects the maintenance and growth of endometriotic tissues by inhibiting angiogenesis and reducing the expression of VEGF in ectopic lesion. The angiostatic agent may be promising as a therapy for endometriosis. PMID- 17697576 TI - Effect of blockage of costimulatory signal on murine abortion-prone model. AB - BACKGROUND: Inhibition of the key costimulatory signals results in T cell anergy, indicating the alloantigen-specific immunologic unresponsiveness. In this study, the effect of blockage of costimulatory signal CD(86) on murine abortion-prone model was studied. METHODS: Thirty CBA/J female mice cohabitated with DBA/2 male or BALB/c male mice were investigated. CBA/J x DBA/2 matings were used as the abortion-prone model, and CBA/J x BALB/c matings were used as the normal pregnant model. The abortion-prone models were divided into experimental and control groups, and the normal pregnant models were set as a normal group (10 mice in each group). The mice in the experimental group were treated with anti-mouse CD(86) monoclonal antibody (mAb) (100 microg) on day 4.5 of gestation, while the controls received irrelevant-isotype matched rat IgG(2b). As for the normal group, nothing was given to the mice. The mice were killed on day 13.5 of gestation, embryo resorption rate and the expression of transforming growth factor beta(1) (TGF-beta(1)), plasminogen activator inhibitor 1 (PAI-1), and matrix metalloproteinase 9 (MMP-9) were detected. Then the data were analyzed by Chi-square test and Fisher's exact test. RESULTS: The embryo resorption rate in the experimental (8.2%) and normal groups (7.7%) was significantly lower than that of the control (23.5%, P < 0.05). No significant difference was detected between the experimental and normal groups (P > 0.05). The positive expression rates of TGF-beta(1) and PAI-1 proteins in the experimental and normal groups were significantly higher than those in the control group (P < 0.05). The positive expression rate of MMP-9 protein in the experimental and normal groups was significantly lower than that in the control group (P < 0.05). No significant difference in the positive expression rates of the three proteins was detected between the experimental and normal groups (P > 0.05). CONCLUSIONS: Blockage of costimulatory signal CD(86) at early pregnancy can treat uncertain recurrent spontaneous abortion by stimulating the expression of TGF-beta(1), MMP-9 and PAI 1 and reducing the embryo resorption rate. PMID- 17697577 TI - Role of CXCL12 in metastasis of human ovarian cancer. AB - BACKGROUND: In a previous study, we have verified that CXCR4 expression is correlated with tumor aggressive progression and poor prognosis in patients with epithelial ovarian cancer. The aim of this study was to explore the effect of CXCL12-CXCR4 axis on the metastasis of human ovarian cancer. METHODS: The expressions of CXCR4 and CXCL12 mRNA and protein in human ovarian cancer cell line CAOV-3 was detected by RT-PCR and immunocytochemistry. Methythiazolyltetrazolium (MTT) was used to analyze the effect of different concentrations of CXCL12 on the proliferation of CAOV-3 cells. Transwell invasion chamber and matrigel were used to evaluate the effect of various concentrations of CXCL12 and ascites on the migration and invasion of CAOV-3 cells. The expressions of integrin beta(1) and vascular endothelial growth factor-C (VEGF-C) mRNA were detected by RT-PCR. Data were analyzed using ANOVA by SAS 6.12. RESULTS: Under serum-free suboptimal culture conditions, CXCL12 (100 ng/ml) significantly enhanced the proliferation of CAOV-3 cells compared with the control and 10 ng/ml CXCL12 groups (0.428 +/- 0.051 vs. 0.325 +/- 0.045 and 0.328 +/- 0.039, P < 0.05). This enhancing effect of CXCL12 was significantly inhibited by 10 microg/ml neutralizing CXCR4 antibody or 1 microg/ml CXCR4 antagonist AMD3100. However, 10 microg/ml neutralizing CXCR4 antibody could not inhibit cell proliferation without CXCL12. The levels of migration and invasion of the CAOV-3 cells treated with 100 ng/ml CXCL12 were significantly higher than those in the control (migration: 523.3 +/- 25.2 vs 108.0 +/- 7.2; invasion: 39.3 +/- 4.0 vs. 4.0 +/- 1.0). The enhancing effect of CXCL12 on cell migration and invasion increased with the concentration of CXCL12 (100 ng/ml vs10 ng/ml: migration, 523.3 +/- 25.2 vs 211.7 +/- 24.7; invasion, 39.3 +/- 4.0 vs 15.7 +/- 3.1, P < 0.05), and was strongly inhibited by 10 microg/ml neutralizing CXCR4 antibody or 1 microg/ml AMD3100. The number of migrated and invading cells in the CAOV-3 added with ascites was significantly higher than those in the 100 ng/ml CXCL12 group (migration: 706.6 +/- 30.6 vs 523.3 +/- 25.2, invasion: 61.7 +/- 7.6 vs 39.3 +/- 4.0, P < 0.05). The level of integrin beta(1) mRNA was greatly increased at 3 hours after being treated with CXCL12 (0.53 +/- 0.10 vs. 1.53 +/- 0.16, P < 0.05), and VEGF-C mRNA displayed significant augment at 24 hours after being treated with CXCL12 (0.52 +/- 0.09 vs 1.11 +/- 0.15, P < 0.05). CONCLUSIONS: CXCL12 and its receptor CXCR4 can promote the proliferation, migration, invasion of ovarian cancer cell line CAOV-3 and enhance its secretion of integrin beta(1) and VEGF-C. These effects can be inhibited by neutralizing CXCR4 antibody or AMD3100. CXCL12-CXCR4 axis plays an important role in ovarian cancer growth and metastasis. PMID- 17697578 TI - Advances on circulating fetal DNA in maternal plasma. PMID- 17697579 TI - Current opinion on human leukocyte antigen-G in China. PMID- 17697581 TI - Foreigners take a back seat to Chinese in organ transplants. PMID- 17697580 TI - Effects of arsenic trioxide on voltage-dependent potassium channels and on cell proliferation of human multiple myeloma cells. PMID- 17697582 TI - Retroperitoneoscopic right living donor nephrectomy. PMID- 17697584 TI - Pupillary response in patients receiving intrathecal sufentanil. PMID- 17697585 TI - Extended operation for thoracic malignancies invading superior vena cava and/or innominate vein. PMID- 17697586 TI - Prenatal diagnosis of nonmosaic tetrasomy 9p by microdissection and FISH: case report. PMID- 17697587 TI - Angiomyolipoma arising in the gluteal region. PMID- 17697588 TI - Spontaneous cerebrospinal fluid rhinorrhea in a patient with tentorial meningioma. PMID- 17697589 TI - Glomus tumor of the gastric body: helical CT findings. PMID- 17697590 TI - The chest tube inserted into the stomach after a transthoracic operation for esophageal cancer: case report. PMID- 17697591 TI - Second pregnancy of trisomy 21 in a mother with mosaicism. PMID- 17697592 TI - [Present situation and prospects of reproductive tract infections and sexually transmitted infections in Chinese women]. PMID- 17697593 TI - [Summary of national congress of the diagnosis and treatment of the infections, emergency and complications in obstetrics and gynecology]. PMID- 17697594 TI - [Relationship between blood lipid levels of pregnant women with glucose metabolism disorders and perinatal outcomes]. AB - OBJECTIVE: To study the relationship between blood lipid levels of pregnant women with glucose metabolism disorders and the perinatal outcomes. METHODS: Three hundred and fifty-eight pregnant women with glucose metabolism disorders were enrolled in this study, including 28 cases with diabetes mellitus (DM), 152 cases with gestational diabetes mellitus (GDM), 178 cases with gestational impaired glucose tolerance (GIGT). Beckman-CX9 automatic biochemical analyzer was used to measure serum levels of total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C). RESULTS: (1) The TG, TC, HDL-C and LDL-C levels in GDM group was (2.9 +/- 0.7), (6.7 +/- 1.9), (1.64 +/- 0.31), and (3.7 +/- 0.8) mmol/L, respectively, which were not significantly different from those in GIGT group [TG (2.7 +/- 0.7), TC (6.2 +/- 1.1), HDL-C (1.78 +/- 0.22), and LDL-C (3.8 +/- 0.9) mmol/L, respectively (P > 0.05)]. Maternal serum concentrations of TG and LDL-C were significantly increased in DM group [(3.6 +/- 0.9) and (4.8 +/- 0.6) mmol/L] compared with GIGT group [(2.7 +/- 0.7) and (3.8 +/- 0.9) mmol/L] and GDM group [(2.9 +/- 0.7) and (3.7 +/- 0.8) mmol/L] (P < 0.05). However, the HDL-C (1.24 +/- 0.19) mmol/L in DM group was significantly lower than that in GDM group (1.64 +/- 0.31) mmol/L and GIGT group (1.78 +/- 0.22) mmol/L (P < 0.05). (2) The incidence of pre-eclampsia and preterm labor in the DM group (35.7% and 39.3%) was higher than that in GIGT group (16.8% and 16.8%) and GDM group (14.5% and 19.7%, P < 0.05). Among the three groups, the incidence of polyhydramnios and premature rupture of membrane had no significant difference (P > 0.05). The incidence of fetal distress in the GIGT group (9.8%) was lower than that in DM group (20.2%) and GDM group (21.4%, P < 0.05). The incidence of fetal macrosomia in GDM group (11.2%) and GIGT group (14.4%) was higher than that in DM group (3.5%, P < 0.05). CONCLUSION: The blood lipid level of pregnant women with glucose metabolism disorders is one of the effective indexes to prognosticate perinatal outcomes. Reducing blood lipid level can decrease the incidence of pre-eclampsia and preterm labor significantly. PMID- 17697595 TI - [Relationship between ureaplasma urealyticum infection and ectopic pregnancy]. AB - OBJECTIVES: To explore the relationship between different subtypes of Ureaplasma Urealyticum infection and ectopic pregnancy. METHODS: Ectopic pregnancy group included 33 patients and another 40 patients undergoing salpingo-ovariectomy with ovarian cyst or uterine myoma were investigated as control group. Polymerase chain reaction technique was used to detect Uu DNA in the two groups samples from endosalpinx and secretion of cervix. At the same time, these samples were set to electron microscope for examination. RESULTS: (1) Uu was detected in 27 fallopian tubal epithelium tissues among 33 ectopic pregnancy samples (81.8%), in which biovar1 was positive in 17 samples (52%, 17/33), biovar 2 was positive in 15 (46%, 15/33) and both biovar 1 and 2 positive was 5 (15.2%). While in the control group, Uu was detected in 24 fallopian tubal epithelium tissues among 40 samples (60%), in which biovar1 was positive in 21 samples (52%, 21/40), biovar 2 was positive in 5 (12%, 5/40) and both biovar 1 and 2 positive was 2 (5%). There was no significant difference between the two groups in Uu of biovar 1 (P > 0.05). The positive rate of Uu in biovar 2 show a significant difference (P < 0.05). (2) Co-expression samples in both fallopian tubal epithelium and cervical mucus samples from ectopic pregnancy patients in biovar1 was 13 (72.2%), and in biovar 2 was 11 (71.4%). While in control group, co-expression samples in both fallopian tubal epithelium and cervical mucus samples in biovar 1 was 18 (81.8%), and in biovar 2 was 5 (71.4%). There was no significant difference between the two groups in co-expression in both fallopian tubal epithelium and cervical mucus samples (P > 0.05). (2) The fallopian tubes infected by biovar 2 have a high rate (90%) of ciliary adhesion and exuviation. While there is a low rate (10%) for biovar1 with ciliary adhesion and exuviation. There was significant difference between the two groups of Uu (P < 0.05). CONCLUSION: The infection of ureaplasma urealyticum may increase the occurrence of fallopian pregnancy. The infection of ureaplasma urealyticum may be concerned with the morphological changes and functional damage of uterine fallopian epithelium. PMID- 17697596 TI - [Vulvovaginal candidiasis in pregnant women with impaired tolerance for glucose]. AB - OBJECTIVE: To evaluate whether incidence of 50 g glucose challenge test (GCT) and 75 g oral glucose tolerance test (OGTT) is higher in pregnant women with vulvovaginal candidiasis (VVC). METHODS: A retrospective study of pregnant women with IGGT or GDM who delivered at Peking University First Hospital from Jan 1, 2004 to June 30, 2005 was conducted. The prevalence of VVC and re-infected vulvovaginal candidiasis (RVVC) were determined, and blood glucose concentrations of GGT and OGTT in VVC, RVVC and NVVC groups were compared. RESULTS: Four hundred and one pregnant women were recruited, of whom 51 had VVC, and 16 had RVVC. The prevalence of VVC was greater among GDM women than among IGGT women (P = 0.014). Glucose concentrations were higher in VVC cases than in NVVC cases at GCT [(9.6 +/- 2.0) vs (9.3 +/- 1.6) mmol/L], OGTT 0 hour [(5.4 +/- 1.1) vs (5.3 +/- 0.9) mmol/L], 1 hour [(11.1 +/- 1.7) vs (11.0 +/- 1.5) mmol/L], 2 hours [(9.4 +/- 1.8) vs (9.2 +/- 1.6) mmol/L], however, there were no statistical differences (P > 0.05). Glucose concentrations were higher in RVVC cases than in NVVC cases at GCT [(10.4 +/- 1.2) vs (9.3 +/- 1.6) mmol/L]; OGTT 0 hour [(5.3 +/- 0.6) vs (5.3 +/- 0.9) mmol/L], 1 hour [(11.4 +/- 1.0) vs (11.0 +/- 1.5) mmol/L]; 2 hours [(9.4 +/- 1.4) vs (9.2 +/- 1.6) mmol/L], but there were no statistical differences (P > 0.05). CONCLUSION: The incidence of VVC is higher in pregnant women with GDM than in pregnant women with GIGT, however, GCT, and OGTT show no statistical differences between women with VVC and those without VVC. PMID- 17697597 TI - [Maternal and fetal outcomes in pregnant women with abnormal glucose metabolism]. AB - OBJECTIVE: To understand the incidence of abnormal glucose metabolism during pregnancy and the maternal and neonatal outcomes after standard management. METHODS: A retrospective study of maternal and neonatal outcomes was conducted in 1490 pregnant women who were diagnosed and treated for abnormal glucose metabolism and delivered in the Department of Obstetrics and Gynecology of First Hospital of Peking University from Jan 1995 to Dec 2004 by reviewing the medical records. The selected cases consisted of 79 women with diabetes mellitus (DM group), 777 with gestational diabetes mellitus (GDM group), including 355 cases of A1, 316 with A2 and 106 cases unclassified, and 634 with gestational impaired glucose test (GIGT group). Maternal and fetal outcomes were analysed in comparison with the controls of 19 013 pregnant women with normal glucose metabolism who delivered during the same period. RESULTS: (1) The total incidence of gestational abnormal glucose metabolism was 7.3% and increased gradually from 1995 to 2004. The first stage, from Jan 1995 to Dec 1999, saw a slow increase in the incidence [4.3% (376/8739)]; the second stage, from Jan 2000 to Dec 2001, showed a fast increasing trend. The average incidence was 10.8% (445/4133). The incidence in the third stage kept stable at 8.9% (678/7640) from Jan 2002 to Dec 2004. (2) The incidence of macrosomia, preeclampsia and preterm birth were 12.1% (180/1490), 9.5% (141/1490) and 9.4% (140/1490), which were significantly higher than those women with normal glucose metabolism (P < 0.01). A significant difference was found in the incidence of preeclampsia, preterm birth, intrauterine infection, polyhydramnios and ketonuria among the three groups (P < 0.05), but not in the incidence of macrosomia (P > 0.05). (3) The perinatal mortality rate (PMR) of abnormal glucose metabolism group was 1.19% (18/1513) which was significantly higher in the DM group (4.93%) than GDM (1.14%) and GIGT groups (0.78%, P < 0.01), while the incidence of neonatal asphyxia, hypoglycemia, malformation and admission to NICU in the DM group were all higher than GDM and GIGT groups (P < 0.01). (4) NRDS was found in 9 cases among 1505 neonates (0.6%) and all were delivered preterm. CONCLUSIONS: (1) The incidence of gestational abnormal glucose metabolism is increasing and the screening and diagnosis of diabetes in pregnancy should be strengthened. (2) Macrosomia, preeclampsia and preterm birth remain the first three common complications even after standardized glycemic management, but the maternal and neonatal complications are reduced in the GIGT group except for macrosomia. Those women in the DM group has a higher rate of maternal and neonatal complications than those in GDM and GIGT groups, so management in these patients should be strengthened. (3) NRDS is no longer a primary neonatal complication provided proper management is performed. PMID- 17697598 TI - [Expression of Apelin in placentas of patients with hypertensive disorders complicating pregnancy]. AB - OBJECTIVE: To investigate the expression of Apelin in placenta tissue from women with hypertensive disorders complicating pregnancy. METHODS: Thirty six women with hypertensive disorders complicating pregnancy (HDCP) and 15 normal pregnant women were studied. The expression of Apelin-36 was analyzed semi-quantitatively using immunohisto-chemistry and image analysis in placenta tissue and the levels of Apelin mRNA expression were determined by real-time quantitative RT-PCR method. RESULTS: The levels of Apelin-36 and Apelin mRNA in placenta from normal pregnant women were 0.27 +/- 0.04 and 0.82 +/- 0.25, respectively. The levels of Apelin-36 and Apelin mRNA in placenta from HDCP women were 0.18 +/- 0.05 and 0.31 +/- 0.21; in gestational hypertensive women, the values were 0.24 +/- 0.02 and 0.59 +/- 0.16; in mild preeclampsia were 0.16 +/- 0.03 and 0.25 +/- 0.07, and in severe preeclampsia they were 0.14 +/- 0.02 and 0.17 +/- 0.09, respectively. The levels of Apelin-36 and Apelin mRNA in HDCP were lower than those in normal pregnant women (P < 0.01, P < 0.01), and they were decreased gradually with a significant difference between gestational hypertension, mild preeclampsia and severe preeclampsia (P < 0.01) and between mild preeclampsia and severe preeclampsia (P < 0.05). CONCLUSION: The abnormal expressions of Apelin in placenta may be related to pathogenesis of HDCP. PMID- 17697599 TI - [Expression and significance of Edg4 and Edg7 in the placentas of patients with hypertensive disorder complicating pregnancy]. AB - OBJECTIVE: To study Edg4 and Edg7 expression in placenta of women with hypertensive disorder complicating pregnancy, and to investigate the relation between the expression of lysophosphatidic acid (LPA) and hypertensive disorder complicating pregnancy. METHODS: Immunohistochemical SP method was used to measure the expressions of Edg4 and Edg7 in placenta of women with normal pregnancy, 20 women with gestational hypertension, 20 with mild preeclampsia, and with severe preeclampsia. RESULTS: (1) LOCATION: immunohistochemical staining for Edg4 and Edg7 protein were located at the membrane and endochylema of cytotrophoblast as well as decidua cells. (2) The positive expression of Edg4 protein and Edg7 protein on membrane and endochylema of cytotrophoblast was 25% and 20% (normal women), 60% and 40% (gestational hypertension), 80% and 65% (mild preeclampsia), and 83.3% and 86.7% (severe preeclampsia). The expression of Edg4 and Edg7 protein in mild preeclampsia and severe preeclampsia was significantly correlated with the degree of differentiation (P < 0.05). The expression of Edg4 and Edg7 protein showed an insignificant difference in normal pregnant women and gestational hypertension (P > 0.05). (3) The positive expression of Edg4 protein and Edg7 protein on membrane and endochylema of decidua was 20% and 25% (normal pregnancy), 55% and 50% (gestational hypertension), 70% and 55% (mild preeclampsia), and 83.3% and 73.3% (severe preeclampsia) respectively. The expression of Edg4 and Edg7 protein in mild preeclampsia and severe preeclampsia showed a significant correlation with the degree of differentiation (P < 0.05). The expression of Edg4 and Edg7 protein showed an insignificant difference in normal pregnancy and gestational hypertension (P > 0.05). CONCLUSIONS: The high expression of Edg4 and Edg7 protein in the placentas of patients with hypertensive disorder complicating pregnancy indicates that LPA combines with Edg4 and Edg7, inducing the occurrence of hypertensive disorder complicating pregnancy. PMID- 17697600 TI - [Study of the mechanism of mast cell increase in cellular leiomyoma of uterus]. AB - OBJECTIVE: To study the mechanism of mast cell increase in cellular leiomyoma of uterus. METHODS: Tissue sections from 30 cases of cellular leiomyoma of uterus, 15 cases of leiomyosarcoma and 30 cases of ordinary leiomyoma were studied using immunohistochemical double labeling techniques. The expression of mast cell tryptase and Ki-67 as well as mast cell tryptase and chemotactic factors RANTES, Eotaxin, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor beta (TGF-beta) were double immunostained. RESULTS: Ki-67 in mast cells was rarely expressed in each group. Expressions of regulate upon activation normal T cell expressed and secreted (RANTES), Eotaxin and TGF -beta in cellular leiomyoma were 78%, 89%, 91%, respectively. They were all higher than those in ordinary leiomyoma and leiomyosarcoma (P < 0.01), which were 60%, 81%, 86% and 39%, 44%, 59%, respectively. There were positive correlations between RANTES and the number of mast cells (r = 0.655, P < 0.01) as well as between Eotaxin and the number of mast cells (r = 0.543, P < 0.01). However, expression of MCP-1 was not observed in tumor cells in any group. CONCLUSIONS: Mast cell increase in cellular leiomyoma of the uterus is due to local recruitment of mast cells. RANTES and Eotaxin secreted by smooth muscle tumor cells correlates with the recruitment of mast cells, but MCP-1 and TGF-beta do not. PMID- 17697601 TI - [Clinical significance of detection of tumor suppressor genes aberrant methylation in cervical carcinoma tissue]. AB - OBJECTIVE: To investigate the change of aberrant methylation of p16, CDH, RASSF1A and TIMP3 in cervical carcinoma and their significance in cervical carcinoma. METHODS: Using the bisulfite-modification technique and methylation-specific PCR (MSP), we examined the aberrant promoter hypermethylation patterns of 4 tumor suppressor genes (p16, CDH1, RASSF1A, TIMP3) in 140 samples of cervical intraepithelial neoplasia (CINI, n = 40), CINII-III (n = 40), cervical carcinomas (CC, n = 40), and normal cervical tissue as a control group (n = 20). RESULTS: (1) Methylation was completely absent in control tissues. (2) Significant differences between CINII-III group and CINI group were detected for p16 and CDH1 (22% vs 2%, P < 0.05; 35% vs 5%, P < 0.05), while there were no significant differences between the two groups for RASSF1A and TIMP3 (12% vs 2%, P > 0.05; 15% vs 2%, P > 0.05). (3) The presence of methylation of p16 (40%), CDH1 (58%), RASSF1A (20%) and TIMP3 (35%) in CC were higher than the corresponding CINII-III group, but with no significant differences (P > 0.05). (4) Significant differences between CC and CINIfor p16, CDH1, RASSF1A and TIMP3 genes (P < 0.05) were observed. (5) Methylation for at least one gene was a frequent event. These figures in CC 90% (36/40) were significantly different from CINII-III 55% (22/40; P < 0.05). In comparison between CINI8% (3/40) and CC and CINII-III, these figures were significantly different (P < 0.05). CONCLUSIONS: Among the four genes, p16, CDH, RASSF1A and TIMP3, there is a significant trend for increased methylation with increasing degree of histopathological change. It suggests that the aberrant methylation of tumor suppressor genes plays a role during cervical cancer development. This may help identify women at increased risk for or cancer development and progression. PMID- 17697602 TI - [Inhibitory effect of breast cancer metastasis suppressor l gene on metastasis of human ovarian cancer cell in vitro and in vivo]. AB - OBJECTIVE: To study the inhibition effects of breast cancer metastasis suppressor l (BRMS1) gene on metastasis of human ovarian cancer cell in vivo and in vitro. METHODS: BRMS1 gene was transfected into human ovarian cancer cell line A2780 by liposome transfection method. The cells were divided into 3 groups: transfected group with pcDNA3-BRMS1, negative control group with empty plasmid pcDNA3, blank control group without any transfection. Proliferation, apoptosis, growth rate, capability of colony formation, gap junctional intercellular communication (GJIC), capability of adhesion, changes of surface and internal structures of cells were observed in vitro. The cells were injected into athymic mice to establish animal tumor models, and inhibition of the tumorigenicity and metastasis were observed in vivo. RESULTS: BRMS1 gene was transfected into A2780 cell line successfully. There were no significant differences in the growth rate among transfected group, negative control group and blank control group (P > 0.05). The amounts of cell clones per well were 40 +/- 4 in transfected group, 42 +/- 7 in blank control group and 39 +/- 4 in negative control group (P > 0.05 between each two groups). The ratios of S vs G(2)/M and G(0)/G(1) were not significantly different in three groups (P > 0.05). The ultramicrostructure of cells detected by electron microscope showed that GJIC function in transfected group was higher than that in the other two groups. While in migration assay, the numbers of cells in lower chamber passing through the membrane in transfected group, blank control group and negative control group were 112 +/- 23, 306 +/- 49 and 322 +/- 91, respectively; with significant differences among 3 groups (P < 0.01). CONCLUSION: BRMS1 gene could suppress metastasis of ovarian cancer in vitro and in vivo. PMID- 17697603 TI - [Effect of chemokine CXCL12 and its receptor CXCR4 on proliferation, migration and invasion of epithelial ovarian cancer cells]. AB - OBJECTIVE: To explore the effect of chemokine CXCL12 and its receptor CXCR4 on proliferation, migration and invasion of epithelial ovarian cancer cells. METHODS: CXCR4 and CXCL12 mRNA and protein expression of human ovarian cancer cell line CAOV3 was detected by RT-PCR and immunocytochemistry. Integrin beta1 and vascular endothelial growth factor-C (VEGF-C) mRNA expression were detected in CAOV3 cells stimulated by CXCL12. The CAOV3 cells were divided into 6 groups: control group (un-stimulated), experimental group 1 (stimulated by 100 ng/ml CXCL12), experimental group 2 (stimulated by 10 ng/ml CXCL12), experimental group 3 (100 ng/ml CXCL12 and 10 microg/ml neutralizing CXCR4 antibody), experimental group 4 (100 ng/ml CXCL12 and 1 microg/ml CXCR4 antagonist AMD3100), experimental group 5 (10 microg/ml neutralizing CXCR4 antibody or ascites). Methyl thiazolyl tetrazolium (MTT) was used to analyze the effects of different concentrations of CXCL12 on CAOV3 cell proliferation. Transwell invasion chamber and reconstructed basement membrane (Matrigel) were used to evaluate effect of various concentrations of CXCL12 and ascites on CAOV3 cell migration and invasion. RESULTS: CAOV3 cells expressed CXCR4 mRNA (0.70 +/- 0.10) and protein, but did not express CXCL12 mRNA or protein. Immunostaining of CXCR4 was mainly located in cytoplasm. CXCR4 mRNA was up-regulated after 100 ng/ml CXCL12 stimulation (1.24 +/- 0.14; t = -7.1088, P = 0.0021). Integrin beta1 mRNA was greatly increased at 3 hours by stimulation of 100 ng/ml CXCL12 (before and after stimulation 0.53 +/- 0.10, 1.53 +/- 0.16; P < 0.01), and VEGF-C mRNA showed significant increase at 24 hours by treatment with CXCL12 (before and after stimulation 0.52 +/- 0.09, 1.11 +/- 0.15; P < 0.05). Under serum-free sub-optimal culture conditions, experimental group 1 greatly enhanced cell proliferation in CAOV3 cells compared with control group and experimental group 2 (respectively 0.428 +/- 0.051, 0.325 +/- 0.045, 0.328 +/- 0.039; P < 0.05). Experimental group 1 was strongly inhibited compared with experimental groups 3 and 4 (the latter two groups respectively 0.356 +/- 0.031, 0.373 +/- 0.029; P < 0.05). There was no significant difference between experimental group 5 (0.349 +/- 0.038) and control group (P > 0.05). Experimental group 1 stimulated the migration and invasion of CAOV3 cells in chemotaxis assay compared with control group and experimental group 2 (number of cell migration respectively 523.3 +/- 25.2, 108.0 +/- 7.2, 211.7 +/- 24.7, number of cell invasion respectively 39.3 +/- 4.0, 4.0 +/- 1.0, 15.7 +/- 3.1; P < 0.01). This enhancing effect of experimental group 1 was strongly inhibited compared with experimental groups 4 and 5 (P < 0.05). The number of migrating and invading cells in experimental group 5 (migration: 706.6 +/- 30.6, invasion: 61.7 +/- 7.6) was significantly higher than that of experimental group 1 (P < 0.05). CONCLUSIONS: This in vitro study shows CXCL12 promote proliferation, migration, invasion of ovarian cancer cell line CAOV3, and up-regulate integrin beta1 and VEGF-C expression, and these effects are strongly inhibited by neutralizing CXCR4 antibody. It suggests CXCL12 and its receptor CXCR4 may play important roles in ovarian cancer growth and metastasis. PMID- 17697604 TI - [Overexpression of estrogen receptor-related receptor alpha can stimulate estrogen receptor negative endometrial cancer cell proliferation]. AB - OBJECTIVE: To investigate the role of human estrogen receptor-related receptor (ERR) alpha, a submember of orphan receptors, in the tumorigenesis of endometrial cancer. METHODS: Plasmid of pSG-ERRalpha was transfected into endometrial cancer cell lines HEC-1A, HEC-1B, and Ishikawa. Real-time quantitative RT-PCR and western blot were used to analyze the mRNA and protein expression of ERRalpha in endometrial cancer cell. Flow cytometry was used to analyze the cellular growth. RESULTS: Expressions of the ERRalpha were significantly increased in the endometrial cancer cells transfected with pSG-ERRalpha plasmid; expression of the ERRalpha mRNA in HEC-1A cell was 9644.4 copies/ng, HEC-1B: 9835.3 copies/ng, and Ishikawa: 8008.6 copies/ng (P < 0.01); expression of the ERRalpha protein in HEC 1A cell was 1.128, HEC-1B: 1.104, and Ishikawa: 1.008 (P < 0.05). Flow cytometry showed over-expression of ERRalpha was accompanied by increased HEC-1A and HEC-1B cells in S and G(2)/M phase (P < 0.01), while this could not be observed in the estrogen receptor (ER) positive endometrial cancer cell line Ishikawa. Furthermore, cellular growth analysis showed that over-expression of ERRalpha induced cell growth increase of the ER negative endometrial cancer cells HEC-1A and HEC-1B (P < 0.05). CONCLUSION: Over-expression of ERRalpha could stimulate ER negative endometrial cancer cell proliferation independent of estrogen-ER pathway. PMID- 17697605 TI - [Reversal effect of MDR1 and MDR3 gene silencing on resistance of A2780/taxol cells to paclitaxel]. AB - OBJECTIVE: To investigate the reversal effect of MDR1 and MDR3 gene silencing on resistance of A2780/taxol cells to paclitaxel. METHODS: shRNA plasmid vector specifically targeting MDR1 and MDR3 genes was transfected into A2780/taxol cells. The early stage cell apoptosis and the effect of intracellular rhodamine 123 (Rh123) accumulation were detected by flow cytometry (FCM). The late stage cell apoptosis rate was detected by terminal deoxynucleotidyl transferase (TdT) mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL). The 50% inhibition concentration (IC(50)) of paclitaxel on A2780/taxol cells was determined by methyl thiazolyl tetrazolium (MTT) assay. MDR1 and MDR3 mRNA were assessed by RT-PCR, and caspase-3 protein was detected by western blot. RESULTS: After treatment with MDR1 and MDR3 shRNA plasmid vector, early apoptosis rate of A2780/taxol cells was (20.21 +/- 0.56)% and (10.87 +/- 1.24)%, respectively. MDR1 and MDR3 shRNA could increase cellular Rh123 accumulation (116.6 +/- 8.1 and 98.4 +/- 3.8, respectively). The late stage apoptosis rates detected by TUNEL displayed the same tendency as FCM results did. The IC(50) for paclitaxel of A2780/taxol cells was decreased significantly. The mRNA levels of MDR1 and MDR3 in A2780/taxol cells were decreased by (73.3 +/- 0.8)% and (51.6 +/- 0.4)% of control, and the reduction of MDR1 and MDR3 mRNA was in a time-dependent manner. The expression of caspase-3 protein of MDR1 and MDR3 shRNA vector transfected group in A2780/taxol cells was significantly increased [(80.8 +/- 2.6)% and (72.0 +/- 4.7)%, respectively]. CONCLUSION: MDR1 and MDR3 gene silencing could recover sensitivity of A2780/taxol cells to paclitaxel and induce cell apoptosis, thus reversing cell resistance to paclitaxel. PMID- 17697613 TI - [Induction chemotherapy in childhood acute lymphoblastic leukemia: the association between the intensity of therapy and cure]. PMID- 17697614 TI - [Evaluation of a modified induction chemotherapy in children with acute lymphoblastic leukemia]. AB - OBJECTIVE: To improve the treatment outcome of children with acute lymphoblastic leukemia (ALL), and to evaluate the efficacy and safety of a modified induction chemotherapy between the two protocols used to treat children with ALL in Shanghai Children's Medical Center. METHODS: From Jan. 1st, 1999 to Mar. 1st, 2006, 311 patients with newly diagnosed childhood ALL, who underwent induction chemotherapy for over 10 days, were eligible for analysis. Group 99 (n = 243) patients who were admitted before May 1st, 2005, were treated with ALL-XH-99 Protocol, whereas 68 patients admitted afterwards, defined as Group 05, were treated with ALL Protocol 2005 which was based on ALL-XH-99 Protocol but the treatment intensity was reduced to decrease treatment associated mortality. Clinically, the distributions of the initial data from the patients, treatment responses, complete remission rates after therapy, and treatment-associated infections in the two groups were evaluated. RESULTS: Patients from the two groups obtained similar complete remission rate (91.8% vs. 95.6%, P = 0.29), while patients from Group 05 were benefited more from their therapy. They had lower therapy associated infection rate (23.5% vs. 54.7% in Group 99, P < 0.01), and no severe infection (0 vs. 9.1% in Group 99) and no infection related death occurred (0 vs. 3.7% in Group 99). Patients in the Group 05 also had shortened period from the beginning day of the initial therapy to complete remission (32.34 +/- 3.36 days vs. 34.18 +/- 4.96 days, P < 0.01). CONCLUSIONS: ALL Protocol 2005 had the same efficacy as ALL-XH-99 Protocol had in the induction therapy in treating children with ALL, but it was safer than ALL-XH-99. PMID- 17697615 TI - [High mobility group box 1 is increased in children with acute lymphocytic leukemia and stimulates the release of tumor necrosis factor-alpha in leukemic cell]. AB - OBJECTIVE: Cytokine mediated cell immunity is the main mode of anti-tumor immunity in organism, and the disequilibrium of cytokine network is the main cause of tumor cells escaping immunologic surveillance. High mobility group box 1 (HMGB1), a nuclear protein, has recently been identified as an important mediator of local and systemic inflammatory diseases when released into the extracellular milieu. In the present study, the investigators explored the clinical significance of alteration in the serum levels of HMGB1 in childhood acute lymphocytic leukemia (ALL) and the mechanism of HMGB1-induced tumor necrosis factor (TNF)-alpha secretion in leukemic cells. METHODS: The serum levels of HMGB1 in healthy children and childhood ALL were assayed by Western blotting. K562 leukemic cells were stimulated with recombinant HMGB1 protein in vitro, and the secretion of TNF-alpha was determined by using ELISA. The effects of HMGB1 on activation of p38, c-Jun amino-terminal kinase (JNK), and extracellular-signal regulated protein kinase (ERK) and mitogen-activated protein kinase (MAPK) in K562 cells were assayed by using Western blotting. The effects of inhibitors specific for the MAPK on HMGB1-induced TNF-alpha secretion were assayed by using ELISA. RESULTS: The serum levels of HMGB1 were significantly higher in ALL initial treatment group (n = 15, 43.78 +/- 4.62 microg/ml) than those in healthy control group (n = 15, 0.60 +/- 0.48 microg/ml, P < 0.01) and ALL complete remission group (n = 15, 0.89 +/- 0.62 microg/ml, P < 0.01). No significant difference was found between the healthy control group and ALL complete remission group in HMGB1 levels (P > 0.05). TNF-alpha started to become detectable at 2 h and was still increasing at 16 h after HMGB1 (1 microg/ml) treatment in K562 cell culture. TNF-alpha was also secreted from K562 cells in a dose-dependent manner after HMGB1 (1 ng/ml-1 microg/ml) exposure. HMGB1 induced the phosphorylation of p38, JNK and ERK in k562 cells. Inhibitors specific for the JNK (SP600125), MEK (PD98059), and p38 MAPK (SB203580), abrogated HMGB1-induced TNF-alpha secretion. CONCLUSIONS: The measurement of serum HMGB1 is helpful to evaluate the prognosis of the childhood ALL. HMGB1 stimulates leukemic cells to secrete TNF-alpha through a MAPK-dependent mechanism. PMID- 17697617 TI - [Evaluation of the P-gp pump function on leukemic cell membrane and proper application of its reversal agents with Calcein-AM and flow cytometry]. AB - OBJECTIVE: Leukemia is the most common malignancy in children. Combined chemotherapy is currently the primary treatment modality. During the past decade, very high cure rates of childhood acute lymphoblastic leukemia (ALL) have been reported both at home and abroad. However, the cure rates of children with acute myeloid leukemia (AML) remain low due to the multiple-drug resistance (MDR). P glycoprotein (P-gp) is one of the most important mechanisms of MDR for leukemia cells. However, the function of the protein, the clinical application of its reversal agents and the efficacy of the combination of the reversal agents remain to be elucidated. The present study aimed to evaluate the P-gp pump function on leukemia cell membrane and the effects of the combined administration of the reversal agents cyclosporin A (CSA) and verapamil (VER) through the observation of Calcein-AM (C-AM) metabolism in the cell line K562 and its multi-drug resistant subline K562/VCR. METHODS: The mean fluorescence intensity (MFI) of C AM inside the cytoplasm was analyzed with flow cytometry (FCM). The events of K562 and K562/VCR cells treated and untreated with CSA, VER and CSA + VER were acquired at time points 0, 30, 60, 90 and 120 minutes, respectively, and the data obtained were analyzed with CellQuest software. RESULTS: The C-AM in the K562 and K562/VCR varied more apparently in the fist 24 hours. In addition, the MFI of the C-AM in K562 was significantly higher than that in K562/VCR cells indicating that the P-gp pump molecules were functioning. The MFIs of the CSA, VER and CSA + VER groups co-cultured with K562/VCR cells were 4014 +/- 219, 3879 +/- 116 and 4158 +/- 302, respectively after 120 min of incubation, significantly higher as compared to that of control group (3251 +/- 107, P < 0.05). On the other hand, significant inhibition of the efflux from the K562/VCR cell line was also noticed after the same time period of incubation with the MFIs of 2237 +/- 155, 1932 +/- 233 and 2231 +/- 147, respectively in the three groups, which was significantly higher than that of control group (1622 +/- 191, P < 0.05). CSA, VER and CSA + VER could increase the uptake and inhibit the efflux of C-AM by K562/VCR cells, while no evident influence on those functions inside the parental cell line K562 cells was noticed. CONCLUSIONS: CSA, VER and CSA + VER could increase the uptake and reduce the efflux of C-AM by K562/VCR cells while no significant difference between the CSA + VER and CSA or VER was noticed. P-gp pump function and the effects of its reversal agents on leukemic cells can be rapidly and easily evaluated by using the C-AM and FCM. PMID- 17697618 TI - [Optimal central nervous system directed therapy in childhood acute lymphoblastic leukemia.]. PMID- 17697619 TI - [Podocyte depletion in children with hepatitis B virus-associated membranous nephropathy]. AB - OBJECTIVE: Hepatitis B virus-associated membranous nephropathy (HBV-MN) is a disease characterized by podocytopathy. Podocyte is a terminally differentiated cell with limited capability of proliferation. Thus, damage of podocyte might result in decreased cell number, and then lead to the development of marked proteinuria and glomerulosclerosis. The present study aimed to investigate the changes of glomerular podocyte number in the children with hepatitis B virus associated membranous nephropathy (HBV-MN), and their significance in the pathogenesis of HBV-MN. METHODS: Podocytes were identified through specific immunohistological staining of Wilms tumor gene protein 1 (WT1), a characteristic marker for podocyte nuclei, and podocyte numerical density (Nv), mean glomerular tuft volume (V) and the podocyte number per glomerulus (Npodo) were estimated through Weibel-Gomez method in 19 children with biopsy-proven HBV-MN and 8 children with thin basement membrane disease (control group), and analyses were made for possible correlation with clinical, serological and pathological data. RESULTS: Among the 19 cases with HBV-MN, 3 showed microvillus-like foot process of podocytes, granular degeneration of podocyte were found in 4 cases, vacuolization in 1 case and podocyte detachment in 2 cases. Nv and Npodo were significantly decreased in children with HBV-MN compared with control group (t = 12.851, P = 0.0002 and t = 6.433, P = 0.0002, respectively). Moreover, the number of podocytes decreased more significantly in patients with stronger HBsAg deposition (> ++) than those with weak HBsAg deposition (< or = ++), P = 0.004, but no significant difference was found between patients with phase III or IV of HBV-MN and those with phase Ior II in podocyte number per glomerulus (P = 0.5262) and podocyte numerical density (P = 0.3564). Podocyte numerical density decreased more significantly in patients with massive proteinuria (> or = 2 g/24 h) than those with moderate proteinuria (< 2 g/24 h), P = 0.0488. The numbers of podocyte correlated significantly with serum levels of C(3) (r = 0.548, P = 0.028), but did not correlate with serum levels of albumin (r = -0.037, P = 0.891). CONCLUSION: All patients with HBV-MN showed podocyte damage and decreased number per glomerulus, which may play an important role in the pathogenesis of HBV-MN in children. PMID- 17697620 TI - [Detection of changes in cerebral blood flow and cerebrovascular autoregulation by near-infrared spectroscopy in newborn piglets]. AB - OBJECTIVE: A large body of experimental and clinical observations indicates that disturbances in cerebral blood flow (CBF) and impaired cerebrovascular autoregulation are important in the pathogenesis of germinal matrix intraventricular hemorrhage (GMH-IVH) and periventricular leukomalacia (PVL), the 2 most important forms of brain injury in pretmature infants. Near-infrared spectroscopy (NIRS) has been used recently to estimate CBF in human newborns. The objectives of this study were to evaluate the correlation of NIRS estimations and cerebral blood flow in newborn piglets, which in turn may help provide the ideal NIRS estimation reflecting the changes of cerebral blood flow and cerebrovascular autoregulation. METHODS: Ten newborn piglets, aged 1 - 3 days, were randomly assigned to one of the following groups: normal control group (n = 6) and hypotension group (n = 4). Hypotension was induced by withdrawing blood from an arterial catheter. We NIRS was used to determine quantitative changes in cerebral concentrations of oxygenated hemoglobin (DeltaHbO(2)) and deoxygenated hemoglobin (DeltaHHb), then calculated NIRS estimations DeltatHb (DeltaHbO(2)+DeltaHHb) and DeltaHbD (DeltaHbO(2)-DeltaHHb). Cerebral blood flow (CBF) was determined by colored microspheres, and mean artery blood pressure (MABP) measured by arterial catheter pressure transducer was recorded simultaneously. Linear regression methods were used to analyze the relationships between NIRS estimations, CBF measured by micropheres, and MABP. RESULTS: The correlation of NIRS estimations and CBF was quantitated by calculating coherence scores. A coherence of 1.0 indicates perfect correlation, a coherence of 0 indicates a complete lack of correlation. In the norm group, the experimental study showed strong correlations beween DeltaHbD, DeltatHb and changes in global CBF (GCBF), cerebral cortex CBF (CBFc), coherence scores r(1a) = 0.409, r(1b) = 0.440, r(2a) = 0.394 and r(2b) = 0.400, respectively, P < 0.05. In the hypotension group, the decrease of CBF was significant when the MABP dropped to 35 mm Hg (P < 0.05). With the decreasing MABP, there was a notable increase of DeltaHHb (P < 0.01), a modest increase (P < 0.05) at the beginning and then a marked fall (P < 0.01) of DeltaHbO(2) and DeltatHb was noted when the MABP dropped to 35 mm Hg. DeltaHbD decreased in parallel with the decline in CBF determined by colored microspheres, DeltaHbD varied with CBF during hypotensive episodes. Notably, there was a very strong correlations between DeltaHbD and changes in CBF (coherence scores GCBF r(3a) = 0.890, CBFc r(3b) = 0.887, P < 0.01); Importantly, decreases in DeltatHb did not correlate significantly with decreases in CBF during hypotension (coherence scores GCBF r(4a) = 0.395, CBFc r(4b) = 0.375, P > 0.05). Concordant changes (correlation coefficient > 0.5) in DeltaHbD, CBF and MABP, consistent with impaired cerebrovascular autoregulation, were observed in newborn piglets when MABP was less than 35 mm Hg. When MABP was more than 35 mm Hg, newborn piglets with intact cerebrovascular autoregulation in which CBF are maintained constant despite alternations in MABP have shown inconsistent changes in DeltaHbD, CBF and MABP (correlation coefficient < 0.5). CONCLUSION: DeltaHbD signal is more sensitive to changes in CBF than DeltatHb signal, in terms of cerebral hemodynamic changes both in normal and hypotensive conditions, while DeltatHb in normal condition. The lower limit of CBF autoregulation in newborn piglets aged 1 - 3 days was 35 mm Hg, and correlation between NIRS estimation (DeltaHbD) and MABP could be used to identify cerebrovascular autoregulation in newborn piglets. PMID- 17697621 TI - [Neuroprotective effects of exogenous basic fibroblast growth factor on the hypoxic-ischemic brain damage of neonatal rats]. AB - OBJECTIVE: To investigate the neuroprotective effect of basic fibroblast growth factor (bFGF) on neurological function after hypoxic-ischemic brain damage (HIBD) in neonatal rats. METHODS: Ninety-six HIBD models of neonatal Wistar rats were made by shearing right arteria carotis communis and then breathing 8% O(2)+92%N(2) for two hours. The models were divided into two groups randomly: the bFGF trial group and the normal saline control group. Each group had forty-eight rats. The other forty-eight neonatal Wistar rats were taken into the sham operation group. Forty rats were taken from each group and sacrificed on the 4 th, 7 th, 10 th, 17 th and 24 th days after the operation, respectively, The pathological changes in the brain were observed by optical microscope and the expressions of nestin and growth-associated protein-43 (GAP-43) in hippocampal CA1 region were examined with immunohistochemical staining and image quantitative analysis on the 4 th, 7 th, 10 th, 17 th and 24 th days after the operation. The spatial cognitive capability of other eight rats which were taken from each group respectively was evaluated by using the Morris water maze at the age of 30 days. RESULTS: (1) No brain damage was found in the sham operation group, the neurocytes were degenerative and necrotic in the control group of normal saline. The pathological manifestation of the brain damage in the bFGF trial group was milder than that of the normal saline control group. (2) Expression of nestin: The number of nestin-positive cells in hippocampal CA1 region of control group on the 4 th, 7 th, 10 th, 17 th and 24 th days after the operation was significantly increased compared with that of the sham operation group at all time points, and the numbers of nestin-positive cells in hippocampal CA1 region of the trial group were higher than those of the sham operation group and the control group (P < 0.01). (3) The expression of GAP-43 in hippocampal CA1 region of the neonatal rats reached peak on the 10th day after the operation in all the three groups. The integral optical density (IOD) of GAP-43 in hippocampal CA1 region of the control group was higher than that of the sham-operation group at all time points, and the IOD of GAP-43 in hippocampal CA1 region of the trial group was higher than those of the sham operation group and the control group at all time points (P < 0.01 for all). (4) The latency to escape platform in control group (51.75 +/- 11.27s) was longer than that in trial group (40.32 +/- 11.48s) and the sham operation group (36.58 +/- 10.83s) (P < 0.05); the frequency of passing through the platform in control group (2.34 +/- 2.42) was less than that in trial group (5.08 +/- 3.86) and the sham operation group (7.03 +/- 3.62) (P < 0.05). There was no significant difference between the trial group and the sham operation group (P > 0.05). CONCLUSIONS: (1) The expression of nestin and GAP-43 increased in hippocampal CA1 region of neonatal rats with HIBD, it may be involved in the activation of neural stem cells and the regeneration of neurocytes after HIBD. (2) The treatment with bFGF can improve the ability of learning and memory of neonatal rats with HIBD. (3) Exogenous bFGF could enhance the expression of nestin and GAP-43 in the brain of neonatal rats with HIBD, which may play an important role in restoration of neurons damaged due to hypoxia ischemia. PMID- 17697622 TI - [An overview of the ninth Asian-Oceanian Congress of Child Neurology.]. PMID- 17697623 TI - [Early diagnostic significance and dynamic pattern of DWI compared with conventional MRI in newborns with neonatal cerebral infarction]. AB - OBJECTIVE: To evaluate the early diagnostic significance of diffusion weighted imaging (DWI) compared with conventional magnetic resonance imaging (MRI) and to find the dynamic pattern of DWI and conventional MRI in newborn infants with neonatal cerebral infarction (NCI). METHODS: The imaging studies and clinical records of six newborn infants with NCI admitted to our ward between April 2004 and October 2005 were reviewed. All examinations were performed on a 3.0-T MRI system (Philips Intera Acheva Magnetom Vision) with echo-planar imaging capability with the use of a standard protocol. The imaging protocol for all the patients contained diffuse weighted images (EPI-SE, TR = 2144 ms, TE = 56 ms), T(1)-weighted images (TR = 389 ms; TE = 15 ms; slice thickness = 4 mm) as well as T(2)-weighted images (TR = 3035 ms; TE = 100 ms; slice thickness = 4 mm). Except the magnetic resonance image examination mentioned above, the following examinations were performed in all patients: whole blood cells count, serum total calcium and ionized calcium, blood glucose, C-reactive protein (CRP), blood culture, prothrombin time and partial thromboplastin time, chest radiograph (CR), cardiac color Doppler, conventional MRI and DWI of brain. RESULTS: All the patients were full term infants. One had severe asphyxia and the other five had neither intrauterine distress nor birth asphyxia. Five of the patients had no localized neurological signs in the early course except for abnormal muscular tone to some extent, but just seizure as their major symptom. A seizure episode was the most common sign and no other positive signs of nervous system was found in the newborn with NCI. All the patients had normal white blood cells, red blood cells, blood platelet, blood glucose, serum total calcium and ionized calcium, prothrombin time and partial thromboplastin time, CRP and cardiac color Doppler. The first MRI was performed from 18 hours to 4 days after the onset of illness when four patients showed abnormal findings on routine MRI (T(1)WI hypointensity, T(2)WI hyperintensity) and the other two showed normal results while all the six showed abnormal hyperintensty on DMI. On following up, all the patients showed T(1)WI hypointensity and T(2)WI hyperintensity on routine MRI while hypointensity was shown on DWI. There were cortical and subcortical white matter damage with obvious high signal intensity on DWI in left temporal lobe and parietal-occipital lobes of 4 cases and in left frontal-parietal lobes of one patient and in left basal ganglia of another patient, but lesions of hypointensity on T(1)W and hyperintensity on T(2)W in only 3 patients between 2nd day and 3rd day after onset; two weeks later there were the lesions of hypointensity on T(1)W and on DWI and hyperintensity on T(2)W seen in all patients in the areas similar to those found before on DWI. Lesions of hypointensity on T(1)W and DWI and of hyperintensity on T(2)W remained in two patients at sixth month and in one patients at 15th month. CONCLUSION: Seizure was the most common sign of newborn infants with NCI and seizures in the neonatal period may be the single symptom of acute ischemic cerebral infarction. It was difficult to establish the diagnosis in the acute phase by the use of ultrasound, CT, and conventional MRI because of the high water content of the immature brain.. DWI seems to be a sensitive early diagnostic measure for NCI. Hyperintensity was shown on DWI at the early stage of the disease. Two weeks later, the hyperintensity turned to hypointensity and lasted long with the same signal characters and lesions on T(1)WI. The lesions of hypointensity on T(1)W and DWI and hyperintensity on T(2)W appeared at 2 weeks and remained for more than 1 year. T(2)-weighted sequences should supplement DW images to reliably detect subacute ischemic infarctions in the neonatal period. PMID- 17697624 TI - [Expression and significance of Toll-like receptors in cord blood mononuclear cells.]. AB - OBJECTIVE: To investigate the expression of TLR4/2 mRNA in neonatal cord blood mononuclear cells (MNC). METHODS: Forty-six neonates without asphyxia and 40 neonates with asphyxia were divided into groups depending on the gestational age. In the neonates without asphyxia, there were 18 full term infants (the gestational age > or = 37 weeks), 16 preterm infants whose gestational age was > or = 32 weeks but < 37 weeks, and 12 preterm infants whose gestational age was < 32 weeks. In the neonates with asphyxia, 11 were full term infants, 15 were preterm infants whose gestational age was > or = 32 weeks but < 37 weeks and 14 were preterm infants at gestational age < 32 weeks. MNCs were separated and cultured with LPS (1 microg/ml) for 3 h. Cells were collected for analysis of gene expression of TLR4/2 by RT-PCR technique. Cell supernatants were taken to measure TNF-alpha production following the ELISA protocol. Fifteen healthy adults were enrolled into the control group. In addition, the Pearson correlation analyses were carried out between the levels of TLR4, TLR2 mRNA and the levels of TNF-alpha. RESULTS: In the neonates without asphyxia, TLR4, TLR2 mRNA and TNF alpha levels were 0.75 +/- 0.12, 0.63 +/- 0.08, 2502.6 +/- 273.1 ng/L, separately, in the full term infants, 0.37 +/- 0.04, 0.32 +/- 0.03, 1218.8 +/- 145.7 ng/L, separately, in the preterm infants whose gestational ages were > or = 32 weeks but < 37 weeks, and 0.26 +/- 0.03, 0.20 +/- 0.03, 811.8 +/- 105.2 ng/L separately, in the preterm infants whose gestational ages were < 32 weeks. In the neonates with asphyxia, TLR4, TLR2 mRNA and TNF-alpha levels were 0.58 +/- 0.07, 0.50 +/- 0.06, 1946.4 +/- 244.2 ng/L, separately, in the full term infants, 0.29 +/- 0.03, 0.26 +/- 0.03, 970.0 +/- 94.3 ng/L, separately, in the preterm infants whose gestational age was > or = 32 weeks but < 37 weeks, and 0.17 +/- 0.02, 0.14 +/- 0.02, 652.6 +/- 60.3 ng/L, separately, in the preterm infants whose gestational age was < 32 weeks. The levels of TLR4, TLR2 mRNA and TNF-alpha in the adults were 2.71 +/- 0.75, 2.61 +/- 0.33, 9270.1 +/- 1098.3 ng/L, separately. In the preterm infants and full term infants, the levels of TLR4, TLR2 mRNA and TNF-alpha were lower in comparison to the adults. The lower the gestational age, the lower the levels of TLR4, TLR2 mRNA and TNF-alpha. There were significant differences between the levels of TLR4, TLR2 mRNA and TNF-alpha of the neonates without asphyxia and those of the neonates with asphyxia. In the neonates with asphyxia, the levels of TLR4, TLR2 mRNA and TNF-alpha were lower than those in the neonates without asphyxia (P < 0.01). Whether the neonates were asphyxic or not, the levels of TLR4, TLR2 were paralleled with the levels of TNF-alpha. CONCLUSIONS: The expression of TLRs in the neonates, especially in the preterm infants was lower than that in the adults, which probably contributes to the susceptibility of neonates to infections. PMID- 17697625 TI - [Effects of recombinant human insulin-like growth factor-1 on the expression of Clara cell secretory protein in lung of hyperoxia-exposed newborn rats]. AB - OBJECTIVE: The development of neonatology and the availability of pulmonary surfactant have been helpful in effective reduction of the mortality of very low birth weight infants at the expense of an increasing number of survivors with bronchopulmonary dysplasia (BPD) caused by lung immaturity. BPD is a common syndrome in newborns, especially in preterm infants, when treated with hyperoxia and mechanical ventilation. Unfortunately, there have been no effective measure for the prevention and treatment of BPD. The purpose of this study was to investigate the influence of recombinant human insulin-like growth factor-1 (rh IGF-1) on cell apoptosis and Clara cell secretory protein (CCSP) expression during the lung injury induced by hyperoxia, so as to assess its effect on the inflammatory lung injury and its developmental repair. METHODS: Eighty full term neonatal Wistar rats under the same condition were divided randomly into four groups on the second day after birth. Group I was air control, group II was exposed to hyperoxia, group III air + rh-IGF-1, and group IV was treated with hyperoxia + rh-IGF-1. The pups in the control group were kept in room air, while pups in hyperoxia group were kept in a Plexiglas chamber and exposed to over 85% oxygen. Pups in group III were under the same raising condition except for exposure to room air and treated with intraperitoneal injection of rh-IGF-1 (1 microg/Kg) everyday from the third day. Pups in group IV were treated with intraperitoneal injection of rh-IGF-1 (1 microg/Kg) everyday from the third day of exposure to hyperoxia. Lung tissue sections of the neonatal rats were stained with hematoxylin and eosin (HE) after 7 d of hyperoxia exposure, expression of CCSP was examined by immunohistochemical method, and apoptotic cell index of lung tissue was calculated by using TUNEL method. RESULTS: It was observed from immunohistochemical examination that positive staining of CCSP was distributed mainly in distal and respiratory bronchioles. The percentage of Clara cells in distal and respiratory bronchioles epithelium decreased in hyperoxia group (32.17 +/- 3.19)% compared to that in air control group (68.32 +/- 2.04)%, P < 0.01. Statistically significant differences were found in intensity of positiveness of Clara cells between hyperoxia (29.45 +/- 5.56) and air control group (42.37 +/- 3.24), P < 0.01. TUNEL assay showed that most apoptotic cells were alveolar and bronchial epithelial cells. The apoptotic index increased significantly in the hyperoxia group (55.77 +/- 6.09)% compared to the air control group (16.41 +/- 4.01)%, (P < 0.01). The positive rate (52.98 +/- 2.68)% of Clara cells and the expression (41.22 +/- 6.36) of CCSP in hyperoxia + rh-IGF-1 group increased significantly when compared with hyperoxia group, and the differences between these two group were also statistically significant (P < 0.01). The apoptotic index increased significantly in the hyperoxia + rh-IGF-1 group (27.98 +/- 3.09)% compared to the hyperoxia group (P < 0.01). CONCLUSIONS: Hyperoxia exposure can promote the pneumocyte apoptosis and inhibit the expression of CCSP. Rh-IGF-1 can remove the block of the formation of lung alveoli, increase the secretion of CCSP, mitigate inflammatory responses in airway and alleviate lung injury via pneumocyte apoptosis. Therefore, the results of this study provide a theoretic and experimental evidence for clinical application of rh-IGF-1 in prevention and treatment of BPD. PMID- 17697626 TI - [Association between serotonin 2C gene polymorphisms and attention deficit hyperactivity disorder in children with or without comorbidity of disruptive behavior disorder]. AB - OBJECTIVE: Disruptive behavior disorder (DBD) is one of the main comorbidity of attention deficit hyperactivity disorder (ADHD). Previous studies showed significantly different serotonin function between ADHD children with and without the comorbidity of DBD. Therefore, it is needed to compare these two groups in terms of serotonin receptor gene polymorphisms, which may provide further evidence for the previous studies. The current study aimed to investigate the relationship between two serotonin receptor 2C (HTR2C) gene polymorphisms, that are C-759T and G-697C polymorphisms, and ADHD with or without concomitant DBD. METHOD: Blood samples were taken from 237 trios with probands of ADHD with DBD comorbidity and 251 trios with probands of ADHD without comorbidity of DBD. All the subjects were from the ADHD clinic of Peking University Sixth Hospital. DNA was extracted and PCR was performed to amplify the fragments containing both C 759T and G-697C polymorphisms. AciI was used to detect different alleles of the two polymorphisms. Both allele-based and haplotype-based TDT analyses were used to test the association of the two polymorphisms of HTR2C gene and ADHD with or without comorbidity of DBD. RESULTS: The haplotypes -759C (chi(2) = 4.25, P = 0.04), -697G(chi(2) = 3.21, P = 0.07), as well as -759C/-697G were over transmitted (chi(2) = 4.31, P = 0.04) to the probands of ADHD without DBD. No biased transmission of any allele and haplotype were found in families with probands of ADHD with DBD. CONCLUSION: ADHD with or without the comorbidity DBD was different at the level of HTR2C gene polymorphisms of C-759T and G-697C. HTR2C is related to ADHD without DBD, while not related to ADHD with DBD. The results suggested that the two groups may have different genetic background, at least in HTR2C. PMID- 17697627 TI - [Blood pressure of children and adolescents in Beijing]. AB - OBJECTIVE: Hypertension is one of the most common disorders in adults. Although it may be already present in children and adolescents, it does not often have clinical pictures. There is a lack of data on the blood pressure in children in Beijing area. This study was conducted to investigate the present situation of blood pressure of children and adolescents in Beijing area. METHODS: Children and adolescents aged 3 to 18 years in 4 urban and 3 rural areas of Beijing were involved in the study at random. Blood pressure (BP) was measured three times with the use of mercury sphygmomanometery, and the means of the last two BP value were recorded. Systolic BP (SBP) was determined by the first Korotkoff sound, and diastolic BP (DBP) by the fourth Korotkoff sound. RESULTS: Altogether, 20 780 (99.6%) individuals with complete records were studied, including 10 582 from urban and 10 198 from rural areas; 10 398 were males and 10 382 were females. BP of boys was higher than that of girls [SBP: (106 +/- 12) mm Hg vs. (101 +/- 11) mm Hg, u = 27.14, P < 0.01; DBP: (67 +/- 9) mm Hg vs. (65 +/- 8) mm Hg, u = 14.14, P < 0.01]. BP of both boys and girls increased with age. However, SBP had a larger magnitude of increase than that of DBP. Both SBP and DBP of urban children were lower than those of rural children [SBP: (103 +/- 12) mm Hg vs. (104 +/- 12) mm Hg, u = 2.55, P < 0.05; DBP: (66 +/- 8) mm Hg vs. (67 +/- 9) mm Hg, u = 6.73, P < 0.01]. There was a positive correlation between BP and age, height, weight and BMI. SBP had a stronger relationship with each variable than DBP did. Among children aged 6 - 18 years, about 8.1% were found to have hypertension according to the criteria of blood pressure of children and adolescents by age and by gender of 1987 in Beijing. CONCLUSIONS: The present study provided with the current information and characteristics of blood pressure of children and adolescents in Beijing area. The blood pressure was correlated with sex, age, body height, body weight and BMI of children and adolescents. PMID- 17697628 TI - [Epidemiological study of Streptococcus pneumoniae in the nasopharynx of healthy children under 5 years of age in Wuhan]. AB - OBJECTIVE: To investigate the population biology of Streptococcus (S.) pneumoniae carried by healthy children under 5 years of age in Wuhan. METHODS: S. pneumoniae was isolated from nasopharyngeal swabs of healthy children under the age of 5 years (under 5) in Wuhan. The susceptibility to 12 antimicrobial agents was tested by agar dilution method. The erythromycin resistant genes were detected by using the technique of polymerase chain reaction. The quellung reaction was used for serotyping. RESULTS: The carrier rate of S. pneumoniae was 22.31% (135/605) in under 5 children in Wuhan. Among the 133 alive strains, the proportion of penicillin non-susceptible S. pneumoniae (PNSSP) was 45.9% (61/133). The susceptibility of S. pneumoniae to the first (cefalexin), the second (cefaclor) and the third (cefixime, cefpodoxime and cetriaxone) generations of cephalosporins was 6.0%, 45.1%, 54.9%, 56.4%, and 88.7%, respectively. None of the strains were found resistant to fluoroquinolones except for one strain which was resistant to ciprofloxacin at low level. The susceptibility to macrolides was low, 14.3% - 15.8%. Among totally 114 strains resistant to erythromycin, the genes ermB alone, both ermB and mefA, and mefA alone were found in 76 strains (66.7%), 46 strains (40.4%) and 2 strains (1.8%), respectively. Seventeen serotypes were involved and the prevalent serotypes were 19, 23, 6, 15 and 14. Seven strains remained nontypable for serotype. PNSSP strains were found to be distributed in serotypes 19, 23, 6 and nontypable group. CONCLUSIONS: The antibiotic resistance of S. pneumoniae was serious in Wuhan area. The ribosomal modification (ermB gene mediated) was the main mechanism of S. pneumoniae resistant to erythromycin. The major prevalent serotypes were 19, 23 and 6. PMID- 17697630 TI - [No.127: Edema, hypoproteinemia and anemia]. PMID- 17697629 TI - [Expression and activity of RhoA/Rho kinase in remodeling of high blood flow pulmonary vessels.]. AB - OBJECTIVE: High pulmonary blood flow induced pulmonary hypertension (PH) is often associated with increased vasoconstriction and deteriorating pulmonary artery remodeling, of which the exact mechanism has not been completely elucidated. The involvement of RhoA/Rho-kinase pathway has been demonstrated in the pathogenesis of hypoxia and monocrotaline induced PH. Thus the purpose of this study was to test whether RhoA/Rho-kinase pathway is involved in the process of high pulmonary flow induced pulmonary artery remodeling in rats. METHODS: Wistar rats aged 4 weeks in the shunt group underwent left common carotid artery-external jugular vein shunt operation, those in control group received sham-operation. At weeks 1, 2, 4 and 8 of the study, rats underwent right ventricular systolic pressure (RVSP) measurement; blood gases were analyzed to calculate Qp/Qs. The morphologic alterations of the pulmonary arteries were observed under optical microscope. The mean percentage of media wall thickness (%MT) was also measured to assess the extent of medial wall thickness of moderate size pulmonary arteries. Proliferating smooth muscle cells (SMCs) were evaluated by proliferating cell nuclear antigen (PCNA) immunohistochemical staining. Apoptotic SMCs were detected by TUNEL method. RhoA activity in pulmonary arteries was detected using pull down assay. Rho kinase activity was quantified by the extent of MYPT1 phosphorylation with Western blotting. The expression of RhoA and Rho kinase (ROCK2) was also detected with Western blotting. RESULTS: Carotid artery-jugular vein shunt resulted in high pulmonary blood flow, of all rats in shunted groups, the mean Qp/Qs was 2.26 +/- 0.35, which were all considered large shunts. Compared with the control group, RVSP in shunt group increased significantly at both week 1 and week 8 (t = 8.799, t = 5.332, respectively, P < 0.01). Compared with the control group, moderate pulmonary artery medial wall thickening characterized by SMCs hyper-proliferation and hypertrophy in shunted group was firstly appeared at week 4 and became more significant at week 8, as indicated by MT% (t = 9.192, t = 11.185, respectively, P < 0.01). Compared with the control group, the percentage of PCNA-positive SMCs in shunted group increased significantly at week 1 (t = 2.438, P < 0.05), and reached the maximal level at week 2 (t = 7.213, P < 0.01), then, it decreased to a level significantly lower than that of the control group at week 4 (t = 4.183, P < 0.01), and continued to decrease to so low a level that proliferative SMCs was scarcely observed at week 8 (t = 6.152, P < 0.01). The percentage of TUNEL-positive SMCs decreased significantly compared with the control group at week 2 (t = 2.418, P < 0.05), and continued to decrease to a level that apoptotic SMCs was scarcely observed at week 8 (t = 4.582, P < 0.01). Compared with the control group, the expression of RhoA and ROCK2 increased significantly at week 1 (t = 6.056, t = 8.411, respectively, P < 0.01), and reached the maximal level at week 2 (t = 9.342, t = 10.437, respectively, P < 0.01), then began to decrease at week 4, however, both of them were still significantly higher than those of the control group at week 8 (t = 4.743, t = 4.455, respectively, P < 0.01). In line with the expression of RhoA and ROCK2, both RhoA and Rho kinase activity of shunted group increased significantly compared with the control group at week 1 (t = 10.246, t = 19.110, respectively, P < 0.01), and reached the maximal level at week 4 (t = 24.984, t = 16.124, respectively, P < 0.01), then decreased, however, both of them were still higher than those of the control group at week 8 (t = 4.934, t = 10.426, respectively, P < 0.01). CONCLUSION: Activated RhoA/Rho-kinase pathway is associated with both high pulmonary blood flow induced acute pulmonary vasoconstriction and chronic pulmonary artery remodeling in rats. PMID- 17697631 TI - [Screening for systemic artery aneurysm in children with Kawasaki disease by using Doppler vascular ultrasound]. PMID- 17697632 TI - [A therapeutic window of intracerebral transplantation of rat bone marrow stromal cells after hypoxic-ischemic brain damage in neonate rats]. PMID- 17697633 TI - [Combined therapy for a case of rare Rh hemolytic disease of the newborn]. PMID- 17697634 TI - [A case with neonatal retroperitoneal rhabdomyosarcoma]. PMID- 17697637 TI - Hereditary immunologic disorders caused by pyrin and cryopyrin. AB - A new family of hereditary immunologic disorders known as the autoinflammatory diseases involves dysregulation of the innate immune system. Elucidation of the genetic basis of these disorders has resulted in improved understanding of the disease pathophysiology of systemic and tissue inflammation, and has also revealed novel nonpathologic innate immune mechanisms. These advances have also resulted in direct improvement in diagnosis and therapy for autoinflammatory disorders such as the cryopyrinopathies and familial Mediterranean fever and have implications for more common inflammatory diseases. PMID- 17697638 TI - CD23: an overlooked regulator of allergic disease. AB - Given the importance of immunoglobulin (Ig) E in mediating type I hypersensitivity, inhibiting IgE production would be a general way of controlling allergic disease. The low-affinity IgE receptor (FceRII or CD23) has long been proposed to be a natural regulator of IgE synthesis. In vivo research supporting this concept includes the observation that mice lacking CD23 have increased IgE production whereas mice overexpressing CD23 show strongly suppressed IgE responses. In addition, the finding that mice injected with monoclonal antibody directed against the coiled-coil stalk of CD23 have enhanced soluble CD23 release and increased IgE production demonstrates that full-length, trimeric CD23 is responsible for initiating an IgE inhibitory signal. The recent identification of ADAM10 (a disintegrin and metalloprotease) as the CD23 metalloprotease provides an alternative approach for designing therapies to combat allergic disease. Current data suggest that stabilizing cell-surface CD23 would be a natural means to decrease IgE synthesis and thus control type I hypersensitivity. PMID- 17697639 TI - IL-13 receptor isoforms: breaking through the complexity. AB - Interleukin (IL)-13 is an immunoregulatory cytokine secreted predominantly by activated T-helper type 2 (Th2) cells, and it has been identified as crucial in developing allergic inflammatory responses. Its diverse functions are mediated by a complex receptor system including IL-4 receptor alpha (IL-4Ralpha; CD124) and two other cognate cell surface proteins, IL-13Ralpha1 (CD213a1) and IL-13Ralpha2 (CD213a2). IL-13Ralpha1 forms a heterodimer with IL-4Ralpha that is a signaling IL-13 receptor. In contrast, IL-13Ralpha2 has been thought to be a decoy receptor due to its short cytoplasmic tail. IL-13Ralpha2 exists on the cell membrane, intracellularly, and in soluble form. Recent reports revealed that membrane IL 13Ralpha2 may have some signaling capabilities, and soluble IL-13Ralpha2 is a critical endogenous modulator for IL-13 responses. The receptor has more complicated functions than a simple decoy receptor. In this review, we describe the isoforms of IL-13Ralpha2 and discuss newly revealed functions of IL 13Ralpha2. PMID- 17697643 TI - Aspergillus and Penicillium allergens: focus on proteases. AB - Penicillium and Aspergillus species are prevalent airborne fungi. It is imperative to identify and characterize their major allergens. Alkaline and/or vacuolar serine proteases are major allergens of several prevalent Penicillium and Aspergillus species. They are also major immunoglobulin (Ig) E-reacting components of the most prevalent airborne yeast, Rhodotorula mucilaginosa, and the most prevalent Cladosporium species, C. cladosporioides. IgE cross-reactivity has been detected among these major pan-fungal serine protease allergens. In addition, the alkaline serine protease of P. chrysogenum (Pen ch 13) induces histamine release from basophils of asthmatic patients, degrades the tight junction protein occludin, and stimulates release of proinflammatory mediators from human bronchial epithelial cells. In addition to induction of IgE and inflammatory airway responses, the alkaline serine protease allergen of A. fumigatus (Asp f 13) has synergistic effects on Asp f 2-induced immune response in mice. Studies of these serine protease major allergens elucidate the diverse allergic disease mechanisms and facilitate the development of better therapeutic strategies. PMID- 17697644 TI - Effects of allergenic extracts on airway epithelium. AB - When allergen is inhaled it comes into contact with the epithelium of the respiratory tract. This contact triggers multiple events that can ultimately stimulate development of allergic asthma. Some allergens, like house dust mite, contain active proteolytic enzymes that break down tight epithelial cell junctions. Others act to enhance inflammation by stimulating epithelial cells to make proinflammatory cytokines and chemokines. Alterations in airways include mucous cell metaplasia and eosinophil recruitment. In this review, cell culture experiments as well as several animal models and human patient data are utilized to examine the mechanisms by which allergens alter the normal epithelial homeostasis. Environmental pollutants, such as ozone and environmental tobacco smoke, enhance allergen-mediated effects on epithelium. PMID- 17697645 TI - Proteases as Th2 adjuvants. AB - Several cysteine and serine protease allergens have been cloned from house dust mites, including Der p 1, Der p 3, Der p 6, and Der p 9. A significant body of evidence suggests that these allergens mimic helper T (Th) 2 cell adjuvants. Der p 1 cleaves CD23 from activated B cells and CD25 from T cells. Der p 1 proteolytically degrades tight junctions in lung epithelium and causes release of proinflammatory cytokines from bronchial epithelial cells, mast cells, and basophils. These synergistic effects of mite enzyme allergens may promote IgE synthesis and have direct inflammatory effects on lung epithelium, which could explain why mite allergens are associated with asthma. The crystal structures of the proenzyme and mature forms of Der p 1 have been determined, as have the structures of other indoor allergens that are not enzymes (eg, Der p 2, Fel d 1, and Bla g 2). Cockroach allergens are strongly associated with asthma in US inner cities, yet none of the cockroach allergens that have been cloned are proteolytic enzymes. Thus although mite proteases allergens may act as Th2 adjuvants, a paradoxical effect is that other allergens may elicit strong Th2 responses in the absence of enzyme activity. PMID- 17697646 TI - Inflammatory effect of environmental proteases on airway mucosa. AB - Proteases--both endogenous proteases from the coagulation cascade, mast cells, and respiratory epithelial trypsin, and exogenous proteases from parasites, insects, mites, molds, pollens, and other aeroallergens--stimulate a tissue response that includes attraction and activation of eosinophils and neutrophils, degranulation of eosinophils and mast cells, increased response of afferent neurons, smooth muscle contraction, angiogenesis, fibrosis, and production of immunoglobulin E. This response to exogenous proteases can be considered a form of innate immunity directed against multicellular organisms. The response of the airways to environmental proteases very closely resembles the response to airborne allergens. Although clinical research in this area is just beginning, the response to environmental proteases appears to be important in the pathogenesis of rhinitis and asthma developing from damp, water-damaged buildings, and intrinsic asthma with its associated rhinosinusitis and polyps. PMID- 17697647 TI - Early exposure to pets: good or bad? AB - Although pet exposure is known to trigger or worsen allergy symptoms and asthma in patients sensitized to pets, data from recent years has shown that pet exposure in early childhood may actually prevent the development of allergic sensitization and allergic diseases including allergic rhinitis, asthma, and atopic dermatitis. The concept of a protective pet effect remains controversial because these findings have not been duplicated in all studies. Moreover, some studies suggest that pet exposure promotes allergic disease. The protective pet effect may be influenced by multiple factors including type of pet; timing, duration, and intensity of exposure; and genetic factors. The mechanisms behind the protective pet effect remain under investigation but may include alterations in immune development, pet-specific tolerance, and exposure to innate immune stimuli. PMID- 17697648 TI - The interplay of obesity and asthma. AB - The relationships, interactions, and association between obesity and asthma are complex, and are active sources of hypotheses and research. An association between obesity and asthma has been reported in many studies, although considerable debate about the existence of the association and its meaning still exists. Potential associative relationships may result from genetics, immune system modifications, and mechanical mechanisms. The rising prevalence of asthma and obesity in children and adults, and the significant morbidity from both, make it imperative that clinicians recognize the importance of weight management in patients with and without asthma. PMID- 17697649 TI - Assessing asthma control. AB - Guidelines for the treatment of asthma have identified that the primary goal of management is achieving good asthma control, thus reducing the risk of exacerbations. Research has shown, however, that the accuracy with which clinicians can estimate the adequacy of control may not be very good. Nor are clinicians accurate in estimating change in asthma control between clinic visits. Simple questionnaires to measure asthma control are now available, and can be used to evaluate the adequacy of control and to monitor whether levels of control change between assessments. This article discusses selection of a questionnaire, interpretation of data obtained, and methods of administration. PMID- 17697650 TI - Arthroscopic treatment of osteochondral lesions of the distal tibia. AB - BACKGROUND: Osteochondral lesions of the tibia are much less frequent than those of the talus, and treatment guidelines have not been established. We hypothesized that arthroscopic treatment methods used for osteochondral lesion of the talus would also be effective for those of the distal tibia. METHODS: A review of 880 consecutive ankle arthroscopies identified 23 patients (2.6%) with osteochondral lesions of the distal tibia. Four patients were excluded because of concomitant acute ankle fractures requiring open reduction and internal fixation and two were lost to followup, leaving 17 in the study. The mean age was 38 (19 to 71) years. Six (35%) had osteochondral lesions of the tibia and talus; 11 had isolated lesions of the distal tibia. Treatment included excision, curettage, and abrasion arthroplasty in all patients. Five patients had transmalleolar drilling of the lesion, two had microfracture, and two had iliac bone grafting. At last followup, patients were evaluated with a questionnaire, physical examination, and ankle radiographs. RESULTS: Mean followup was 44 (24 to 99) months. Preoperatively, the median American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot score was 52; postoperatively, it was 87. Using the Wilcoxon signed-rank test to compare preoperative and postoperative scores, there was significant improvement in the ankle-hindfoot score postoperatively (p < 0.001). Seven patients had excellent results, seven had good results, one had a fair result, and two had poor results. CONCLUSIONS: Osteochondral lesions of the distal tibia present a challenge to the orthopedic surgeon. Arthroscopic treatment by means of debridement, curettage, abrasion arthroplasty, and, in some patients, transmalleolar drilling, microfracture, or iliac crest bone grafting, resulted in excellent and good results in 14 of 17 patients at medium-term followup. PMID- 17697651 TI - Outcome of Ilizarov ankle arthrodesis. AB - BACKGROUND: Many operative techniques have been described for ankle arthrodesis, with varying fusion rates. In revisions, the fusion rate is lower than in primary arthrodesis. Recent reports have described good results after Ilizarov ankle arthrodesis. However, descriptions were qualitative, with none using an accepted score. We describe our experience with this technique and functional outcomes in our patients. METHODS: Seventeen patients (average age 48 years) had primary or revision unilateral ankle arthrodesis using the Ilizarov technique at two centers. Diagnoses included post-traumatic arthritis and Charcot arthropathy. Three patients had talar osteonecrosis. Time in the frame averaged 15 weeks and in a cast 4 weeks. Followup averaged 6 years. Outcome was assessed using the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale. RESULTS: All ankles achieved solid fusion. The average AOFAS score was 65 out of 86 possible. Based on this, results were defined as excellent in three patients, good in eight, fair in four, and poor in two. Minor complications were common, all resolving with local treatment. No deep infection developed. One fusion malunited in 8 degrees of varus. CONCLUSIONS: The Ilizarov external fixator has numerous advantages applicable to ankle fusion, including: stable fixation, respect for soft tissues, and the possibility of postoperative alignment 'fine tuning'. Additionally, the ability to direct forces through or around skeletal elements allows varying of the load through the skeletal elements, allowing early weightbearing. The Ilizarov technique, with its high union rate, may be considered for any ankle arthrodesis but is especially useful in complex cases such as revisions, talar osteonecrosis, soft-tissue compromise, and infection. Early weightbearing is an added benefit. PMID- 17697652 TI - Physical properties, durability, and energy-dissipation function of dual-density orthotic materials used in insoles for diabetic patients. AB - BACKGROUND: Patients with neuropathic conditions may develop plantar bony deformities through neuropathic collapse, frequently placing the skin and soft tissues at risk. Orthoses have been used to accommodate and distribute plantar pressures over a large surface area, thereby minimizing peak loading pressures in small regions and reducing the risk of ulceration. METHODS: A previously described bony prominence model (Brodsky et al.) was used to test the pressure absorbing and force-transmission properties of various orthotic material combinations used in our outpatient clinic. Six materials were tested in five combinations of materials for their compressive properties: [MS]: medium plastazote (M) + soft plastazote (S); [MN]: medium plastazote (M) + nickelplast (N); [NP] nickelplast (N) + Poron (P); [MO] medium plastazote (M) + Spenco (O); and [MC] medium plastazote (M) + P-cell (C). Materials were tested for 100,000 cycles using a materials-testing system (MTS) apparatus (MTS Systems Corporation, Cary, NC) and software. Stress-strain curves comparing the measured peak pressure to the elastic deformation, or the percentage of compression a material experiences with respect to its original thickness, were plotted for each orthotic combination. RESULTS: For MS, MN, MO, and to a lesser extent, MC, a trend was noted for decreased elastic deformation with increased testing. Additionally, the peak pressures before and after testing for each 10,000 testing cycle for each of the orthotic combinations were plotted. For both MN and NP, no demonstrable difference was noted in the peak pressures in the pretesting and post-testing for the 100,000 cycles. The MO showed a trend for increased peak pressures after each testing cycle. Both the MC and MS peak pressures markedly increased with respect to pretesting value. Also, the MN, MO, and MS all showed an overall trend for increased load cell values with increasing cycles at fast loading. CONCLUSIONS: These data showed that some orthotic combinations are more effective than others at reducing peak pressures during compression testing using our bony prominence model. Further studies are needed to test the orthotic combinations for shear and combined shear and compression modes. PMID- 17697653 TI - Calcaneonavicular coalition resection with extensor digitorum brevis interposition in adults. AB - BACKGROUND: Traditionally, pediatric patients with symptomatic calcaneonavicular coalitions have been treated with resection of the coalition and interposition of the origin of the extensor digitorum brevis muscle. Despite the success of calcaneonavicular coalition resection in children, many surgeons are reluctant to perform this procedure in adults or in patients with osseous coalitions, and joint sacrificing arthrodesis often is done instead. METHODS: Seven adult patients (eight feet) had calcaneonavicular coalition resection with extensor digitorum brevis interposition. The average patient age was 41 years, and all patients displayed isolated, symptomatic calcaneonavicular coalitions without any radiographic evidence of degenerative arthritis. At followup, physical and radiographic evaluations were performed, and an American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot score was recorded. Charts were reviewed for complications and patients were questioned with regards to their overall satisfaction with the surgery. RESULTS: At a mean postoperative followup of 56.5 months, the average AOFAS score was 87. Review of most recent radiographs revealed no degenerative changes or recurrence of the coalition. All patients responded that they would have this surgery again and that they would recommend this procedure to a friend. Complications included one superficial infection and one dysesthesia involving the sural nerve. CONCLUSIONS: The results of the present study suggest that resection combined with muscular interposition can be successful in patients over the age of 18 in whom conservative management of their symptomatic coalitions has failed. This procedure offers an excellent alternative to arthrodesis and has a very low complication rate. PMID- 17697654 TI - Spherical ceramic interpositional arthroplasty for basal fourth and fifth metatarsal arthritis. AB - BACKGROUND: Arthrosis of the fourth and fifth tarsometatarsal joints is difficult to treat. Arthrodesis is both difficult to achieve as well as disabling. Tendon interpositional arthroplasty has been performed with some success. A new technique using ceramic ball interpositional arthroplasty was evaluated. METHODS: Between 2001 and 2003, 13 patients in whom nonoperative treatment had failed had resection arthroplasty of the base of the fourth or fifth metatarsals with ceramic ball interposition (Orthosphere, Wright Medical Technology, Arlington, Tennessee). Patients were evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) Midfoot Scale, a visual analogue scale, a satisfaction index, physical examination, and radiographs. RESULTS: At an average 34-months followup, 11 of the 13 patients were available for evaluation. The five men and six women had an average age of 48 years. Seven patients reported a traumatic etiology. Average postoperative AOFAS score was 53 points, an 87% improvement over preoperative values. Visual analogue scale pain improved 42%. All 11 patients were satisfied and would undergo the operation again. One of the patients demonstrated subsidence of the implant into the cuboid but continued to have improvement in symptoms. To date there have been no implant dislocations. Three of the 11 patients had differential injections before surgery. CONCLUSIONS: Lateral column tarsometatarsal interpositional arthroplasty is an effective salvage operation for lateral column midfoot arthrosis and should be considered in this patient population. The use of the ceramic ball allows a technically simple procedure and rapid recovery. PMID- 17697655 TI - The venous pump of the first metatarsophalangeal joint: clinical implications. AB - BACKGROUND: Although the anatomy and physiology of the venous circulation of the ankle and midfoot are well documented, the physiologic importance of forefoot mobility has not been reported in the literature. The question of this study was whether the first metatarsophalangeal (MTP) joint may operate, like the ankle, as a "pump" to encourage venous return. METHODS: Forty-nine cadaver foot specimens were examined using dissection, plastination, vessel infiltration, and maceration, and radiographic (including venography, MRI, and magnetic resonance angiography) techniques. The anatomy and physiology were described and compared to the ankle joint. Forty patients had biphasic Doppler flow studies. RESULTS: The major finding was the medial drainage of the plantar venous sinus, which is fibrotically bound to the joint capsule. Functional venous valves were evident distally and within fibrous vascular lumens. Mobilization of the first MTP joint led to compression and emptying of the veins. Passive mobilization of the first MTP joint led to an average flow increase of 55% +/- 7 (p < 0.0001), while active movement led to an average increase of 78% +/- 7 (p < 0.0001). CONCLUSIONS: Our described connection between the joint capsule and veins indicates a "toe-ankle pump" with a significant increase of venous blood flow during motion of the MTP joint. Possible clinical applications for an external MTP pump include anti-edema or thromboprophylactic therapy, especially in patients with foot or ankle injuries. A new toe-pump has been designed based on these results. PMID- 17697656 TI - Risk of neurovascular injuries in flexor hallucis longus tendon transfers: an anatomic cadaver study. AB - BACKGROUND: Flexor hallucis longus (FHL) tendon transfer is a frequently used treatment for both posterior tibial tendon insufficiency and chronic Achilles tendinopathy. We observed difficulties in harvesting the FHL tendon that may arise from cross-attachments with the flexor digitorum longus (FDL) tendon near the knot of Henry. The posterior tibial nerve is located nearby the decussation of these tendons. This study examined whether the difficult harvesting may be the cause of nerve injury. METHODS: A cadaver study was performed on 24 foot specimens. In all feet, we used a double-incision technique. The FHL tendon was transected in the distal medial midfoot incision and retracted through the posteromedial hindfoot incision. After harvesting the FHL tendon, we exposed the posterior tibial nerve and its lateral and medial plantar branches to identify if any lesion had occurred. RESULTS: The retraction failed at the first attempt in all specimens because of the presence of cross-attachments between the FHL and FDL tendons. A more extensive dissection of the FHL and FDL tendons was therefore required. We found lesions in 33% of all foot specimens, including two complete ruptures of the medial plantar nerve. CONCLUSIONS: Harvesting of the FHL tendon when transection is made distal to the knot of Henry may cause injuries to the medial and lateral plantar nerves. Experience in this procedure may reduce the risk of nerve injuries but even then nerve lesions remain possible. The clinical significance of these nerve lesions is not described in literature and remains to be determined. PMID- 17697657 TI - Hammer toe correction using an absorbable intramedullary pin. AB - BACKGROUND: Fixed flexion deformity of the proximal interphalangeal joint with or without hyperextension of the metatarsophalangeal joint is one of the most common foot deformities. Many operative options have been recommended. Complaints after operative procedures include a too straight toe, floating toe, painful toe recurvatum, mallet toe, pin track infection, broken hardware, and the necessity of removing hardware. A proximal interphalangeal joint arthrodesis for hammertoe deformity using a 2-mm absorbable pin for internal fixation is described. METHODS: The results of 48 toe arthrodeses in 35 patients were reviewed. Followup ranged from 16 to 58 (average 38.5) months. RESULTS: The procedure is simple and safe for the correction of painful rigid hammertoe deformities. Patient satisfaction was high, complications were minimal, and followup required no pin management or removal. CONCLUSIONS: This procedure can be used for hammer toe deformities requiring surgery when the metatarsophalangeal joint is stable, the skin is not compromised, and the intramedullary canal of the proximal phalanx is 2.0 mm or less. It also has been useful in stabilizing hammertoe correction when there are severe pre-existing metal allergies. PMID- 17697658 TI - Evaluation of periprosthetic lucency after total ankle arthroplasty: helical CT versus conventional radiography. AB - BACKGROUND: Osteolysis after total ankle arthroplasty (TAA) has become a major concern regarding long-term implant survival. The primary goal of this study was to determine whether CT was more sensitive than plain films in detecting the presence and extent of periprosthetic lucency. A secondary goal was to determine whether lack of syndesmotic fusion was associated with more extensive lucency. METHODS: Seventeen patients (19 ankles) who had TAA between 2001 and 2003 were consecutively recruited and evaluated as part of a prospective study. Plain radiographs and helical CT with metal-artifact minimization were obtained. Evidence of lucent lesions and syndesmotic fusion was compared using the different imaging techniques. RESULTS: Of the 19 ankles imaged, a total of 29 lesions were detected by CT, whereas plain radiographs detected 18 lesions. CT detected 21 lesions less than 200 mm(2), of which plain radiographs detected only 11. The mean size of the lesions detected on CT was over three times larger than the size on plain radiographs. With the small sample size used, there were no statistically significant differences between ankles with and without fusion of the syndesmosis and the extent (p = 0.84) and location (p = 0.377) of lucency. CONCLUSION: CT is a more accurate method for early detection and quantification of periprosthetic lucency than plain radiographs. Accurate evaluation of lucent lesions may identify patients at high risk for lack of syndesmotic fusion with subsequent loosening and implant failure. PMID- 17697659 TI - Morphometric dimensions of the calcaneonavicular (spring) ligament. AB - BACKGROUND: The spring ligament complex (SLC) is a static support of the head of the talus and a major anatomical contributor to the integrity of the medial longitudinal arch, particularly if the dynamic support of the posterior tibial tendon is compromised. For this reason, we sought to further elucidate the anatomical components and dimensions of this ligamentous complex. METHODS: Dissection was performed on 30 adult cadaver feet disarticulated at the ankle joint that were preserved by embalming technique. RESULTS: The superomedial ligament (SML) averages 42.51 +/- 3.93 mm and 33.44 +/- 3.34 mm at the superomedial and inferolateral borders, respectively. The width at the level of sustentaculum tali and navicular tuberosity averaged 20.00 +/- 2.35 mm and 10.26 +/- 2.05 mm, respectively. The medioplantar oblique (MPO) ligament averaged 23.56 +/- 2.15 mm and 21.20 +/- 1.42 mm at the medial and the lateral borders, respectively. The widths at the navicular and calcaneal side were 2.71 +/- 0.39 mm and 8.14 +/- 0.56 mm, respectively. The inferoplantar longitudinal (IPL) ligament measured 4.26 +/- 0.43 mm and 2.66 +/- 0.42 mm at the medial and lateral borders, respectively. The width at the calcaneal and navicular insertions measured 5.21 +/- 0.53 mm and 3.39 +/- 0.39 mm, respectively. CONCLUSIONS: The distinction between the SML and MPO components of the spring ligament complex is difficult. This study tried to clarify the dimensions and configurations of these components of the SLC. CLINICAL RELEVANCE: This effort may aid surgeons who wish to repair this ligament with more precision. PMID- 17697660 TI - Custom talar prosthesis after open talar extrusion in a pediatric patient. PMID- 17697661 TI - Nonunion of a sesamoid with tophaceous gout: a case report. PMID- 17697662 TI - Five-year followup of ankle joint distraction for post-traumatic chondrolysis in an adolescent: a case report. PMID- 17697663 TI - Technique tip: lateral soft-tissue release for correction of hallux valgus through a medial incision using a dorsal flap over the first metatarsal. PMID- 17697664 TI - Current concepts review: Charcot arthropathy of the foot and ankle. PMID- 17697666 TI - [Publication of clinical trials in scientific journals: editorial issues]. PMID- 17697667 TI - [Revista Espanola de Cardiologia 2006: activity, readership, and scientific impact]. PMID- 17697668 TI - C-terminal effect of Thermoanaerobacter tengcongensis ribosome recycling factor on its activity and conformation changes. AB - The in vivo activities and conformational changes of ribosome recycling factor from Thermoanaerobacter tengcongensis (TteRRF) with 12 successive C-terminal deletions were compared. The results showed that TteRRF mutants lacking one to four amino acid residues are inactive, those lacking five to nine are reactivated to a similar or a little higher level than wild-type TteRRF, and those lacking ten to twelve are inactivated again gradually. Conformational studies indicated that only the ANS binding fluorescence change is correlated well with the RRF in vivo activity change, while the secondary structure and local structure at the aromatic residues are not changed significantly. Trypsin cleavage site identification and protein stability measurement suggested that mutation only induced subtle conformation change and increased flexibility of the protein. Our results indicated that the ANS-detected local conformation changes of TteRRF and mutants are one verified direct reason of the in vivo inactivation and reactivation in Escherichia coli. PMID- 17697669 TI - Trimethylamine N-oxide counteracts the denaturing effects of urea or GdnHCl on protein denatured state. AB - To understand trimethylamine N-oxide (TMAO) attenuation of the denaturating effects of urea or guanidine hydrochloride (GdnHCl), we have determined the apparent transfer free energies (DeltaG(tr)(')) of cyclic dipeptides (CDs) from water to TMAO, urea or GdnHCl, and also the blends of TMAO and denaturants (urea or GdnHCl) at a 1:2 ratio as well as various denaturant concentrations in the presence of 1M TMAO, through the solubility measurements, at 25 degrees C. The CDs investigated in the present study included cyclo(Gly-Gly), cyclo(Ala-Ala) and cyclo(Val-Val). The observed DeltaG(tr)(') values indicate that TMAO can stabilize the CDs while urea or GdnHCl can destabilize the CDs. Furthermore, the DeltaG(tr)(') values of the blends of TMAO with urea or GdnHCl revealed that TMAO strongly counteracted the denaturating effects of urea on CDs in all instances, however, TMAO partially counteracted the perturbing effects of GdnHCl on CDs. TMAO counteraction ability of the deleterious effects of denaturants depended on the denaturant-CDs pair. The experimental results were further used to estimate the transfer free energies (Deltag(tr)(')) of the various functional group contributions from water to TMAO, urea or GdnHCl individually and to the combinations of TMAO and the denaturants in various ratios. PMID- 17697670 TI - Different mutation patterns of mitochondrial DNA displacement-loop in hepatocellular carcinomas induced by N-nitrosodiethylamine and a choline deficient l-amino acid-defined diet in rats. AB - Mutations of the mitochondria DNA (mtDNA) displacement loop (D-loop) were investigated to clarify different changes of exogenous and endogenous liver carcinogenesis in rats. We induced hepatocellular carcinomas (HCCs) in rats with N-nitrosodiethylamine (DEN) and a choline-deficient l-amino acid-defined (CDAA) diet. DNAs were extracted from 10 HCCs induced by DEN and 10 HCCs induced by the CDAA diet. To identify mutations in mtDNA D-loop, polymerase chain reaction (PCR) single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing, was performed. Mutations were detected in 5 out of 10 HCCs (50%) induced by DEN. Four out of 5 mutations were G/C to A/T transitions at positions 15707, 15717, 15930, and 16087, and one T/A to C/G transition at position 15559. By contrast, no mutations were found in 10 HCCs induced by the CDAA diet. These results demonstrated that mutations in mtDNA D-loop occur in rat HCCs induced by DEN but not by the CDAA diet, suggesting that mtDNA D-loop is a target of exogenous liver carcinogenesis in rats. PMID- 17697671 TI - Desaturase genes in a psychrotolerant Nostoc sp. are constitutively expressed at low temperature. AB - Antarctic psychrotolerant, Nostoc sp. (SO-36), when grown at 25 degrees C and then shifted to 10 degrees C, showed an increase in the tri-unsaturated fatty acid [C(18:3(9,12,15))] at the expense of mono- [C(18:1(9))] and di-unsaturated [C(18:2(9,12))] fatty acids. These results indicate that the activities of the enzymes DesA and DesB are up-regulated, when cultures were grown at 10 degrees C or shifted to 10 degrees C from 25 degrees C. However, RT-PCR studies indicated a constitutive expression of desA, desB, desC, and desC2 genes when cultures grown at 25 degrees C were shifted to 10 degrees C. This constitutive expression of des genes is in contrast to that observed in mesophilic cyanobacteria, in which desA and desB are transcriptionally up-regulated in response to lowering of growth temperature. PMID- 17697672 TI - A gold(I) phosphine complex selectively induces apoptosis in breast cancer cells: implications for anticancer therapeutics targeted to mitochondria. AB - Bis-chelated gold(I) phosphine complexes have shown great potential as anticancer agents, however, their efficacy has been limited by their high toxicity and lack of selectivity for cancer cells. Here, we have investigated the anticancer activity of a new bis-chelated Au(I) bidentate phosphine complex of the novel water soluble ligand 1,3-bis(di-2-pyridylphosphino)propane (d2pypp). We show that this gold complex [Au(d2pypp)(2)]Cl, at submicromolar concentrations, selectively induces apoptosis in breast cancer cells but not in normal breast cells. Apoptosis was induced via the mitochondrial pathway, which involved mitochondrial membrane potential depolarisation, depletion of the glutathione pool and caspase 3 and caspase-9 activation. The gold lipophilic complex was accumulated in mitochondria of cells, driven by the high mitochondrial membrane potential. To address the molecular basis of the observed selectivity between the two cell lines we investigated the effect of the gold complex on the thioredoxin/thioredoxin reductase system in normal and cancer breast cells. We show that [Au(d2pypp)(2)]Cl inhibits the activities of both thioredoxin and thioredoxin reductase and that this effect is more pronounced in the breast cancer cells. This difference may account for the selective cell death seen in the breast cancer cells but not in the normal cells. Our investigation has led to new insights into the mechanism of action of bis-chelated gold(I) diphosphine complexes and their future development as mitochondria targeted chemotherapeutics. PMID- 17697673 TI - The role of STAT3 in antigen-IgG inducing regulatory CD4(+)Foxp3(+)T cells. AB - Unraveling the events that control the suppressive function of regulatory T (Treg) cells is extremely important because it will enable investigators to manipulate these cells to inhibit or enhance their functions as necessary. One of the members of the Signal Transducer and Activators of Transcription (STATs) family, STAT3, has emerged as a negative regulator of inflammatory responses. Here, we study the role of STAT3 in Treg cell induction. We found that GAD-IgG transduced splenocytes induce a CD4(+)Foxp3(+)Treg cell increase in NOD mice. In parallel with the Treg cell increase, an IL-6-STAT3 signal pathway is activated. When STAT3 activation is blocked, GAD-specific tolerance disappears, the percentage of Treg cells decreases and IL-10 secretion is reduced in the splenocytes of NOD mice recipients of GAD-IgG-transduced splenocytes. Our findings indicate that transcription factor STAT3 plays an important role in immune tolerance. PMID- 17697674 TI - Infrared spectroscopy and differential scanning calorimetry studies of binary combinations of cis-6-octadecenoic acid and octadecanoic acid. AB - Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) studies are reported for combinations of cis-6-octadecenoic acid (also termed petroselinic acid, PSA) and octadecanoic acid (also termed stearic acid, SA) across a wide range of binary mole ratio combinations. The data are then used to plot the phase diagram which is found to be montotectic with the PSA reducing the melting temperature of SA at all compositions. The relevance of these experiments to stratum corneum (SC) biophysical behavior, particularly the influence and potential mechanisms of PSA on dermal permeation, is discussed. The potential role of cis-6-octadecenoic acid as a permeation enhancer is discussed in the context of these studies of its interaction with saturated fatty acids. PMID- 17697675 TI - Tic Tac Toe: effects of predictability and importance on acoustic prominence in language production. AB - Importance and predictability each have been argued to contribute to acoustic prominence. To investigate whether these factors are independent or two aspects of the same phenomenon, naive participants played a verbal variant of Tic Tac Toe. Both importance and predictability contributed independently to the acoustic prominence of a word, but in different ways. Predictable game moves were shorter in duration and had less pitch excursion than less predictable game moves, whereas intensity was higher for important game moves. These data also suggest that acoustic prominence is affected by both speaker-centered processes (speaker effort) and listener-centered processes (intent to signal important information to the listener). PMID- 17697676 TI - Factors predicting patient satisfaction following major trauma. AB - INTRODUCTION: Patient satisfaction is an intuitively important outcome measure and has been previously linked to general health status. Previous research on patient satisfaction after injury has concentrated on satisfaction with medical care. This study aims to explore possible predictors of patient satisfaction with outcome following major trauma. METHODS: A cross-sectional survey involving consecutive adult patients involved in major accidental trauma from a major metropolitan trauma centre, over a 5-year period, was performed between 1 and 6 years post-injury. The outcome used was patient satisfaction with progress since the injury. Multiple logistic regression was used to develop a model of significant predictors of patient satisfaction. RESULTS: The survey was mailed to 728 eligible patients, 56 were excluded due to death or inability to complete the survey, 93 refused to participate and 90 were not contactable. One hundred and thirty-four patients did not respond and 355 completed surveys were returned. Patient dissatisfaction was found to be significantly associated with unemployment at the time of follow up (OR, 2.38; 95% CI, 1.38-4.08; p=0.004), having one or more chronic illnesses at the time of injury (OR, 2.57; 95% CI, 1.45-4.55; p=0.001), being involved in a motor vehicle accident (OR, 1.83; 95% CI, 1.02-3.30; p=0.04) and having an unsettled compensation claim (OR, 5.19; 95% CI, 2.80-9.65; p<0.0001). Patient satisfaction was not significantly associated with any measure of injury severity. CONCLUSIONS: Having an unsettled compensation claim after major trauma is the strongest predictor of patient dissatisfaction following major trauma, allowing for other factors. PMID- 17697677 TI - Revascularisation later than 24h after popliteal artery trauma: is it worthwhile? AB - BACKGROUND: Traumatic popliteal artery injury carries heavy morbidity. Ischaemic time is an important factor affecting limb survival. In developing countries most patients present late for repair and there are no distinct guidelines in deciding for revascularisation. PATIENTS AND METHODS: Patients with popliteal artery trauma who had presented at least 24h after injury were included in the study. Individuals with dead foot were excluded; participants underwent either amputation or revascularisation. RESULTS: Among 30 patients entered in the study, 3 underwent amputation; of these, 2 had complete paralysis with partial sensory loss and 1 had complete sensory and motor loss. The rate of amputation was significantly higher among patients with motor deficit (p=0.008) but not among those with sensory deficit. CONCLUSIONS: Revascularisation can be successful for patients who retain only one foot movement. We recommend revascularisation also for cases presenting late and with complete motor deficit below the knee, but without mottling. PMID- 17697678 TI - Transforming students' views of gerontological nursing: realising the potential of 'enriched' environments of learning and care: a multi-method longitudinal study. AB - BACKGROUND: Gerontological nursing is often viewed as unchallenging and is rarely a positive career choice for student nurses. Issues of recruitment and retention in gerontological nursing are a global phenomenon and strategies are needed to encourage more students to opt for this area of work. AIMS AND OBJECTIVES: To identify the role and influence of students' learning experiences on shaping their predispositions to work with older people and to identify the characteristics of a positive learning environment that might promote a more favourable view of gerontological nursing. METHODS: The study was a 312-year longitudinal investigation using multiple methods of data collection and analysis, including an extensive review of the literature, large-scale postal surveys, focus groups and case studies of clinical placements. The design of the study was emergent and essentially constructivist, and participants, especially student nurses, were actively engaged in the on-going process of data analysis. FINDINGS: The results suggest that students do not necessarily enter nurse training with negative predispositions towards work with older adults, but that such negative views develop during their training largely as a result of clinical placements and extra-curricula paid work. Student nurses are often exposed to 'impoverished' environments of care in which they witness poor standards of care and negative attitudes towards older people. However, if they experienced 'enriched' environments they are far more likely to view gerontological nursing in a favourable light. The characteristics of an enriched environment can be understood using the Senses Framework as an analytic lens to interpret students' learning experiences. RELEVANCE TO PRACTICE: The study reinforces the vital role that the placement experience plays in helping students to identify with a particular area of practice. The promotion of an 'enriched' environment of learning and care can be used to help ensure that students have a positive experience of learning to care for older people. PMID- 17697679 TI - First molecular characterisation of hydrogenosomes in the protozoan parasite Histomonas meleagridis. AB - Histomonas meleagridis is a trichomonad species that undergoes a flagellate-to amoeba transformation during tissue invasion and causes a serious disease in gallinaceous birds (blackhead disease or histomoniasis). Living in the avian cecum, the flagellated form can be grown in vitro in the presence of an ill defined bacterial flora. Its cytoplasm harbours numerous spherical bodies which structurally resemble hydrogenosomes. To test whether these organelles may be involved in anaerobic metabolism, we undertook the identification of H. meleagridis genes encoding some potentially conserved hydrogenosomal enzymes. The strategy was based on several PCR amplification steps using primers designed from available sequences of the phylogenetically-related human parasite Trichomonas vaginalis. We first obtained a C-terminal sequence of an iron-hydrogenase homologue (Hm_HYD) with typical active site signatures (H-cluster domain). Immunoelectron microscopy with anti-Hm_HYD polyclonal antibodies showed specific gold labelling of electron-dense organelles, thus confirming their hydrogenosomal nature. The whole genes encoding a malic enzyme (Hm_ME) and the alpha-subunit of a succinyl coenzyme A synthetase (Hm_alpha-SCS) were then identified. Short N terminal presequences for hydrogenosomal targeting were predicted in both proteins. Anti-Hm_ME and anti-Hm_alpha-SCS antisera provided immunofluorescence staining patterns of H. meleagridis cytoplasmic granules similar to those observed with anti-Hm_HYD antiserum or mAb F5.2 known to react with T. vaginalis hydrogenosomes. Hm_ME, Hm_alpha-SCS and Hm_HYD were also detected as reactive bands on immunoblots of proteins from purified hydrogenosomes. Interestingly, anti-Hm_alpha-SCS staining of the cell surface in non-permeabilised parasites suggests a supplementary role for SCS in cytoadherence, as previously demonstrated in T. vaginalis. PMID- 17697680 TI - Pathogenicity of the protozoan parasite Marteilioides chungmuensis in the Pacific oyster Crassostrea gigas. AB - Marteilioides chungmuensis is an ovarian parasite that causes nodule-like structures to appear on the gonads of female Pacific oysters, Crassostrea gigas. It is known that the prevalence of infection increases in summer and decreases from autumn to spring. To investigate the decrease in prevalence of infection and pathogenicity of the parasite, a biopsy method was developed to detect infected oysters, which were then monitored to calculate the mortality rate. Mortality of infected oysters was recorded monthly and changes in reproductive development observed histologically. Compared with control groups, a significant difference in mortality was observed in infected oysters in September and October. Histological observations showed that infected oysters produced oocytes continuously, even in autumn when healthy oysters were reproductively inactive. This prolonged spawning activity of infected oysters resulted in nutritional wasting and mortality. From December onwards, however, almost all infected oysters survived, though the infection persisted. Infection intensity decreased gradually from December. Histological observations revealed that, in winter, infected oysters released infected and uninfected oocytes through the genital canal. The gonad subsequently degenerated and was replaced with connective tissue, as in normal, healthy spent oysters. The results revealed that prevalence of infection decreased from September to May. It is hypothesised that the decline in prevalence within the epizootic area in autumn occurred because infected oysters died and that the winter decrease was due to recovery from infection. PMID- 17697681 TI - Differential expression of fat body genes in Glossina morsitans morsitans following infection with Trypanosoma brucei brucei. AB - To determine which fat body genes were differentially expressed following infection of Glossina morsitans morsitans with Trypanosoma brucei brucei we generated four suppression subtractive hybridisation (SSH) libraries. We obtained 52 unique gene fragments (SSH clones) of which 30 had a known orthologue at E-05 or less. Overall the characteristics of the orthologues suggest: (i) that trypanosome infection has a considerable effect on metabolism in the tsetse fly; (ii) that self-cured flies are mounting an oxidative stress response; and (iii) that self-cured flies are displaying increased energy usage. The three most consistently differentially expressed genes were further analysed by gene knockdown (RNAi). Knockdown of Glossina transferrin transcripts, which are upregulated in self-cured flies compared with flies infected with trypanosomes, results in a significant increase in the number of trypanosome infections establishing in the fly midgut, suggesting transferrin plays a role in the protection of tsetse flies from trypanosome infection. PMID- 17697682 TI - Determination of real-time in-vivo cartilage contact deformation in the ankle joint. AB - The knowledge of real-time in-vivo cartilage deformation is important for understanding of cartilage function and biomechanical factors that may relate to cartilage degeneration. This study investigated cartilage contact area and peak contact compressive strain of four healthy human ankle joints as a function of time using a combined magnetic resonance (MR) and dual-orthogonal fluoroscopic imaging technique. Each ankle was subjected to a different constant loading (between 700 and 820 N). The cartilage contact deformation was obtained from the first second to 300 s after the load was applied. In all ankle joints studied in this paper, contact strains increased to 24-38% at first 20 s after loading. Beyond 20 s, the change of cartilage contact deformation was relatively small and varied in a rate close to zero beyond 50 s. These data indicated that the cartilage contact areas and contact strain could raise dramatically right after loading and reach a relatively stable condition within 1 min after constant loading. The history of cartilage deformation determined in this study may provide a real-time boundary condition for 3D finite element simulation of in vivo cartilage contact stress in the joint as a function of time. PMID- 17697683 TI - Influence of geometrical personalization on the simulation of clavicle fractures. AB - Finite element body models enable the evaluation of car occupant protection. In general, these models represent average males and inter-individual geometry variability is not taken into account. As the most frequent shoulder injury during car lateral accidents is a clavicle fracture, the purpose of this study is to investigate whether clavicle geometry has an influence on bone response until failure, and whether geometrical personalization of clavicle models is required. Eighteen clavicles from 9 subjects (5 males and 4 females, mean age: 76 +/- 12 years) were harvested. Six clavicles were scanned, enabling the development of subject-specific models and the quantification of geometrical features defining shape and cortical thickness. Bone mineral densities (BMD) were measured through double X-ray absorptiometry. Then, the general clavicle responses to dynamic compression until failure were studied. Simulations of the compression tests were carried out with the subject-specific models to assess the sensitivity of force deflection clavicle responses to geometrical features. Clavicle fractures occurred at an average velocity of 1.41 +/- 0.4 ms(-1), with a fracture force of 1.48 +/- 0.46 kN and a deflection of 5.4 +/- 1.1 mm. A significant difference was found between male and female clavicle force values at rupture although their BMDs were not significantly different. Simulations with subject-specific models led to the conclusion that cortical bone thickness and bone shape have large effects on bone responses until failure and on fracture location. This study highlights the need for a geometrical personalization of clavicle models in order to take into account both gender discrepancies concerning clavicle shape and aging effects affecting cortical thickness. PMID- 17697684 TI - A framework for the functional identification of joint centers using markerless motion capture, validation for the hip joint. AB - The objective of the study was to develop a framework for the accurate identification of joint centers to be used for the calculation of human body kinematics and kinetics. The present work introduces a method for the functional identification of joint centers using markerless motion capture (MMC). The MMC system used 8 color VGA cameras. An automatic segmentation-registration algorithm was developed to identify the optimal joint center in a least-square sense. The method was applied to the hip joint center with a validation study conducted in a virtual environment. The results had an accuracy (6mm mean absolute error) below the current MMC system resolution (1cm voxel resolution). Direct experimental comparison with marker-based methods was carried out showing mean absolute deviations over the three anatomical directions of 11.9 and 15.3mm if compared with either a full leg or only thigh markers protocol, respectively. Those experimental results were presented only in terms of deviations between the two systems (marker-based and markerless) as no real gold standard was available. The methods presented in this paper provide an important enabling step towards the biomechanical and clinical applications of markerless motion capture. PMID- 17697685 TI - Multi-residue determination of pesticides in water using multi-walled carbon nanotubes solid-phase extraction and gas chromatography-mass spectrometry. AB - A reliable multi-residue method which was based on solid-phase extraction (SPE) with multi-walled carbon nanotubes (MWCNTs) as adsorbent was developed for determination and quantitation of 12 pesticides (carbofuran, iprobenfos, parathion-methyl, prometryn, fenitrothion, parathion-ethyl, isocarbofos, phenthoate, methidathion, endrin, ethion, methoxychlor) in surface water by gas chromatography-mass spectrometry (GC-MS). Parameters that might influence the extraction efficiency such as the eluent volume, the sample flow rate and the sample loading volume were optimized. The experimental results showed the excellent linearity of 12 pesticides (R(2)>0.99) over the range of 0.04-4 microg L(-1), and the precisions (RSD) were 3.1-15.1% under the optimal conditions. The detection limits of proposed method could reach 0.01-0.03 microg L(-1) based on the ratio of chromatographic signal to base line noise (S/N=3). Good recoveries achieved with spiked water samples were in the range of 82.0-103.7%. The results indicated that MWCNTs have good adsorbability to the 12 pesticides tested in this study. With less cost, less analytical time and less solvent-consuming, the developed multi-residue method could be used to determine multi-class pesticides in water simultaneously. PMID- 17697686 TI - Recent advancements in comprehensive two-dimensional separations with chemometrics. AB - Comprehensive two-dimensional (2D) separations provide the analyst with a tremendous amount of complex data. In order to glean useful information from this complex data, advancements in commercially available software that implement chemometrics are currently available and continue to evolve. Future advancements will no doubt involve commercializing (or adapting) specialized, in-house chemometric techniques that are currently found only in the hands of technical experts and researchers in industry, government, and academia. In order to make timely advancements, future commercialization of novel chemometric techniques should involve collaborations among instrument software manufacturers, professional programmers, technical experts, and researchers. During the last decade, this field has seen a steady advancement from single analyte target analysis to comprehensive non-target analysis of entire multidimensional sample profiles (involving sample classification and/or data mining for discovery-based sample comparisons). The advancements in instrumentation and chemometric software tools have a tremendous impact in various applications: fuels, food, environmental, pharmaceuticals, metabolomics, etc. Most of the development has been for software to apply with gas chromatography-based instrumentation, such as comprehensive two-dimensional gas chromatography (GC x GC) and comprehensive two dimensional gas chromatography with time-of-flight mass spectrometry (GC x GC-TOF MS). More recently there have been notable advancements in liquid-phase instrumentation as well. PMID- 17697687 TI - 1-phenylethyl isocyanate is a powerful reagent for the chiral analysis of secondary alcohols and hydroxy fatty acids with remote stereogenic centres. AB - 1-phenylethyl isocyanate (1-PEIC), a chiral derivatisation reagent for the resolution of secondary alcohols is a powerful tool to determine the configuration and enantiomeric excess of medium- to long-chain secondary alcohols by capillary gas chromatography. The separation of 1-phenylethylcarbamates (1 PECs) of secondary alcohols was systematically evaluated depending on the position of the stereogenic centre in the molecule, namely in alkanols (C(15) C(18)), alkenols (C(15)-C(18)) and hydroxy fatty acids (C(14)-C(18)). The successful separation of the diastereomeric carbamates of (+/-)-heptadecan-7-ol or (+/-)-12-hydroxyoctadecanoic acid methyl ester by gas liquid chromatography demonstrates the unique separation power for 1-PECs for analytes with remote stereogenic centres. Saturated derivatives showed consistently higher resolution factors than the corresponding unsaturated derivatives. PMID- 17697688 TI - One-hit stochastic decline in a mechanochemical model of cytoskeleton-induced neuron death I: cell-fate arrival times. AB - Much experimental evidence shows that the cytoskeleton is a downstream target and effector during cell death in numerous neurodegenerative diseases, including Parkinson's, Huntington's, and Alzheimer's diseases. However, recent evidence indicates that cytoskeletal dysfunction can also trigger neuronal death, by mechanisms as yet poorly understood. This is the first of two papers in which we study a mathematical model of cytoskeleton-induced neuron death. In our model, assembly control of the neuronal cytoskeleton interacts with both cellular stress levels and cytosolic free radical concentrations to trigger neurodegeneration. This trigger mechanism is further modulated by the presence of cell interactions in the form of a diffusible toxic factor released by dying neurons. We find that, consistent with empirical observations, our model produces one-hit exponential and sigmoid patterns of cell dropout. In all cases, cell dropout is exponential tailed and described accurately by a gamma distribution. The transition between exponential and sigmoidal is gradual, and determined by a synergetic interaction between the magnitude of fluctuations in cytoskeleton assembly control and by the degree of cell coupling. We conclude that a single mechanism involving neuron interactions and fluctuations in cytoskeleton assembly control is compatible with the experimentally observed range of neuronal attrition kinetics. PMID- 17697690 TI - Disruption of implicit perceptual memory by intervening neutral stimuli. AB - After viewing directional motion, one is likely to perceive a subsequently presented directionally ambiguous motion as being in the same direction as the prior motion. The perceptual bias towards the most recent percept gradually develops as the interval between the prior stimulus and a subsequent test becomes longer. This form of positive bias, or priming, is created in an automatic fashion. It remain unclear how such perceptual bias could be eliminated by a stimulus manipulation. Here we examine whether presentation of a stimulus, which was neutral as to the competing perceptual interpretations, during the interval between prior and test stimuli, disrupts the development of the priming effect. In experiments with ambiguous motion, we used stationary gratings as the neutral stimuli, and in an experiment with binocular rivalry between orthogonal gratings, we used a plaid pattern consisting of the two rival gratings. In both cases, presenting the neutral stimuli reduced the perceptual bias. These findings show that the visual system dynamically calibrates its internal bias using a recent percept and that this internal bias can be nullified by presenting neutral stimuli. PMID- 17697689 TI - The response of the amblyopic visual system to noise. AB - Visual perception is limited by both the strength of the neural signals, and by the noise in the visual nervous system. Here we use one-dimensional white noise as input, to study the response of amblyopic visual system. We measured the thresholds for detection and discrimination of noise contrast. Using an N-pass reverse correlation technique, we derived classification images and estimated response consistency. Our results provide the first report of the sensitivity of the amblyopic visual system to white noise. We show that amblyopes have markedly reduced sensitivity for detecting noise, particularly at high spatial frequencies, and much less loss for discriminating suprathreshold noise contrast. Compensating for the detection loss almost (but not quite) equates performance of the amblyopic and normal visual system. The classification images suggest that the amblyopic visual system contains adjustable channels for noise, similar to those found in normal vision, but "tuned" to slightly lower spatial frequencies than in normal observers. Our N-pass results show that the predominant factor limiting performance in our task in both normal and amblyopic vision is internal random multiplicative noise. For the detection of white noise the raised thresholds of the amblyopic visual system can be attributed primarily to extra additive noise. However, for the discrimination of suprathreshold white noise contrast, there is surprisingly little additional deficit, after accounting for the visibility of the noise. PMID- 17697691 TI - The development of visual feature binding processes after visual deprivation in early infancy. AB - Higher visual functions were investigated in patients treated for bilateral congenital cataracts in two experiments. Participants were asked to detect either real or illusory contours (Kanizsa squares in Experiment 1 or one of four different Kanizsa contours in Experiment 2) among distractor items. Compared to normally sighted participants matched for age, gender and education, cataract patients treated after the age of 5-6 months took relatively longer to detect Kanizsa figures (Experiments 1 and 2) and they had higher miss rates (Experiment 2). The present results suggest that the ability of visual feature binding depends on early visual input and is permanently impaired if patterned vision is prevented in early infancy for 5 months or more. PMID- 17697692 TI - Attraction of flashes to moving dots. AB - Motion is known to distort visual space, producing illusory mislocalizations for flashed objects. Previously, it has been shown that when a stationary bar is flashed in the proximity of a moving stimulus, the position of the flashed bar appears to be shifted in the direction of nearby motion. A model consisting of predictive projections from the sub-system that processes motion information onto the sub-system that processes position information can explain this illusory position shift of a stationary flashed bar in the direction of motion. Based on this model of motion-position interactions, we predict that the perceived position of a flashed stimulus should also be attracted towards a nearby moving stimulus. In the first experiment, observers judged the perceived vertical position of a flash with respect to two horizontally moving dots of unequal contrast. The results of this experiment were in agreement with our prediction of attraction towards the high contrast dot. We obtained similar findings when the moving dots were replaced by drifting gratings of unequal contrast. In control experiments, we found that neither attention nor eye movements can account for this illusion. We propose that the visual system uses predictive influences from the motion processing sub-system on the position processing sub-system to overcome the temporal limitations of the position processing system. PMID- 17697693 TI - The role of interword spacing in reading Japanese: an eye movement study. AB - The present study investigated the role of interword spacing in a naturally unspaced language, Japanese. Eye movements were registered of native Japanese readers reading pure Hiragana (syllabic) and mixed Kanji-Hiragana (ideographic and syllabic) text in spaced and unspaced conditions. Interword spacing facilitated both word identification and eye guidance when reading syllabic script, but not when the script contained ideographic characters. We conclude that in reading Hiragana interword spacing serves as an effective segmentation cue. In contrast, spacing information in mixed Kanji-Hiragana text is redundant, since the visually salient Kanji characters serve as effective segmentation cues by themselves. PMID- 17697694 TI - Uranium removal from contaminated groundwater by synthetic resins. AB - Synthetic resins are shown to be effective in removing uranium from contaminated groundwater. Batch and field column tests showed that strong-base anion-exchange resins were more effective in removing uranium from both near-neutral-pH (6.5)- and high-pH (8)-low-nitrate-containing groundwaters, than metal-chelating resins, which removed more uranium from acidic-pH (5)-high-nitrate-containing groundwater from the Oak Ridge Reservation (ORR) Y-12 S-3 Ponds area in Tennessee, USA. Dowex 1-X8 and Purolite A-520E anion-exchange resins removed more uranium from high-pH (8)-low-nitrate-containing synthetic groundwater in batch tests than metal chelating resins. The Dowex 21K anion-exchange resin achieved a cumulative loading capacity of 49.8 mg g(-1) before breakthrough in a field column test using near-neutral-pH (6.5)-low-nitrate-containing groundwater. However, in an acidic-pH (5)-high-nitrate-containing groundwater, metal-chelating resins Diphonix and Chelex-100 removed more uranium than anion-exchange resins. In 15 m L of acidic-pH (5)-high-nitrate-containing groundwater spiked with 20 mg L(-1) uranium, the uranium concentrations ranged from 0.95 mg L(-1) at 1-h equilibrium to 0.08 mg L(-1) at 24-h equilibrium for Diphonix and 0.17 mg L(-1) at 1-h equilibrium to 0.03 mg L(-1) at 24-h equilibrium for Chelex-100. Chelex-100 removed more uranium in the first 10 min in the 100mL of acidic-(pH 5)-high nitrate-containing groundwater ( approximately 5 mg L(-1) uranium); however, after 10 min, Diphonix equaled or out-performed Chelex-100. This study presents an improved understanding of the selectivity and sorption kenetics of a range of ion-exchange resins that remove uranium from both low- and high-nitrate containing groundwaters with varying pHs. PMID- 17697695 TI - A comparative study of fouling-related properties of sludge from conventional and membrane enhanced biological phosphorus removal processes. AB - The physical and biochemical properties of activated sludge mixed liquor, including floc size distribution, zeta potential, relative hydrophobicity, and bound and unbound (soluble) extracellular polymeric substances (EPS), were examined in this study to evaluate their relationship to membrane fouling. Mixed liquors from a membrane enhanced biological phosphorus removal (MEBPR) process and a conventional enhanced biological phosphorus removal (CEBPR) process were compared. It was found that the floc size distribution and the amount of soluble EPS in the mixed liquor were the most important properties that significantly influenced the fouling propensity of sludge. Contrary to the literature, the content of EPS bound in activated sludge flocs was not found to be directly associated with membrane fouling, and sludge surface properties such as zeta potential and relative hydrophobicity were not closely related to the observed differences in the fouling tendencies of the two types of sludge. PMID- 17697696 TI - N-nitrosodimethylamine (NDMA) removal by reverse osmosis and UV treatment and analysis via LC-MS/MS. AB - N-nitrosodimethylamine (NDMA) is a probable human carcinogen found in ng/l concentrations in chlorinated and chloraminated water. A method was developed for the determination of ng/l levels of NDMA using liquid chromatography-tandem mass spectrometry (LC-MS/MS) preceded by sample concentration via solid-phase extraction with activated charcoal. Recoveries were greater than 90% and allowed a method reporting limit as low as 2ng/l. Using this method, the removal of NDMA was determined for the Interim Water Purification Facility (IWPF), an advanced wastewater treatment facility operated by the Orange County Water District (OCWD) in Southern California. The facility treats effluent from an activated sludge treatment plant with microfiltration (MF), reverse osmosis (RO), and an ultraviolet-hydrogen peroxide advanced oxidation process (UV-AOP). Six nitrosamines were surveyed: NDMA, N-nitrosomethylethylamine (NMEA), N nitrosodiethylamine (NDEA), N-nitrosodi-n-propylamine (NDPA), N-nitrosopiperidine (NPip), and N-nitrosopyrrolidine (NPyr). Only NDMA was detected and at all treatment steps in the IWPF, with influent concentrations ranging from 20 to 59 ng/l. Removals for RO and UV ranged from 24% to 56% and 43% to 66%, respectively. Overall, 69+/-7% of the original NDMA concentration was removed from the product water across the advanced treatment process and, in combination with blending, the final concentration did not exceed the California drinking water notification level of 10 ng/l. NDMA removal data are consistent with findings reviewed for other advanced treatment facilities and laboratory studies. PMID- 17697697 TI - Hydroponic phytoremediation of Cd, Cr, Ni, As, and Fe: can Helianthus annuus hyperaccumulate multiple heavy metals? AB - Sundance sunflowers were subjected to contaminated solutions containing 3, 4, or 5 heavy metals, with and without EDTA. The sunflowers exhibited a metal uptake preference of Cd=Cr>Ni, Cr>Cd>Ni>As and Fe>>As>Cd>Ni>Cr without EDTA and Cr>Cd>Ni, Fe>>As>Cd>Cr>Ni with EDTA. As uptake was not affected by other metals, but it decreased Cd and Ni concentration in the stems. The presence of Fe improved the translocation of the other metals regardless of whether EDTA was present. In general, EDTA served as a hindrance to metal uptake. For the experiment with all five heavy metals, EDTA decreased Cd in the roots and stems from 2.11 to 1.36 and from 2.83 to 2.3 2mg g(-1) biomass, respectively. For the same conditions, Ni in the stems decreased from 1.98 to 0.94 mg g(-1) total metal uptake decreased from 14.95 mg to 13.89 mg, and total biomass decreased from 2.38 g to 1.99 g. These results showed an overall negative effect in addition of EDTA. However it is unknown whether the negative effect was due to toxicity posed by EDTA or the breaking of phytochelatin-metal bonds. The most important finding was the ability of Sundance sunflowers to achieve hyperaccumulator status for both As and Cd under all conditions studied. Ni hyperaccumulator status was only achieved in the presence of three metals without EDTA. PMID- 17697698 TI - Mechanistics of trichloroethylene mineralization by the white-rot fungus Trametes versicolor. AB - The white-rot fungus Trametes versicolor degraded trichloroethylene (TCE), a highly oxidized chloroethene, and produced 2,2,2-trichloroethanol and carbon dioxide as the main products of degradation, based on the results obtained using [13C]-TCE as the substrate. For a range of concentrations of TCE between 2 and 20 mg l(-1), 53% of the theoretical maximum chloride expected from complete degradation of TCE was observed. Laccase was shown to be induced by TCE, but did not appear to play a role in TCE degradation. Cytochrome P-450 appears to be involved in TCE degradation, as evidenced by marked inhibition of degradation of TCE in the presence of 1-aminobenzotriazole, a known inhibitor of cytochrome P 450. Our results suggested that chloral (trichloroacetaldehyde) was an intermediate of the TCE degradation pathway. The results indicate that the TCE degradation pathway in T. versicolor appears to be similar to that previously reported in mammals and is mechanistically quite different from bacterial TCE degradation. PMID- 17697699 TI - Photodegradation of hexachlorobenzene and theoretical prediction of its degradation pathways using quantum chemical calculation. AB - Experimentally determined photodegradation pathways of hexachlorobenzene (HCB), a chlorinated aromatic compound, in hexane, 2-propanol (IPA), and methanol were compared with those predicted by quantum chemical calculation based on density functional theory (DFT), and the adequacy of the prediction method was evaluated. The experimental main degradation pathways of HCB were virtually the same for the three solvents and also agreed with the predicted main degradation pathways. In the DFT method, the main degradation product was the dechlorinated benzene at the position where the C-Cl bond was predicted to have the lowest bond dissociation energy. This result suggested that the photodechlorination pathways of chlorinated aromatic compounds could be predicted by comparing the bond dissociation energies calculated with the DFT method. PMID- 17697700 TI - Simulation of resuspended sediments resulting from dredging operations by a numerical flocculent transport model. AB - Environmental remediations such as dredging operations cause contaminated sediments from the bottom of water bodies to become suspended into the water column. These resuspended particles are significant water quality concerns and cause adverse effects to aquatic organisms. In this paper, we present a vertically integrated two-dimensional flocculent sediment transport model to better model concentration changes of resuspended bottom sediments. The flocculent transport model has been applied to the Savannah River cutterhead dredge field study involving the resuspension of bottom sediments. The results showed that the model predictions correlate reasonably well with field data. These comparisons suggest that the flocculent sediment transport model can be used to predict the concentration profiles of a plume of toxic compounds resulting from cutterhead dredge operation. PMID- 17697701 TI - The study of distribution and fate of nitrobenzene in a water/sediment microcosm. AB - In November 2005, an explosion occurred at a petrochemical plant of the Jilin Petrochemical Corporation in Jilin Province, China. A nearby water body was seriously polluted with a large spill of toxic substances made up of a mixture of benzene, aniline, and nitrobenzene (NB). To understand the long term impact of NB on public health and ecosystem around the Songhua River, it was necessary to investigate its fate in the environment. In this study, a microcosm was used to mimic the polluted water system and to study the transport and fate of NB in the river water body. The volatility and biodegradation of NB was investigated and a Markov model was applied to predict the fate of NB in the environment. The simulated results matched very well with the results obtained from the microcosm experiment. The model indicated that at room temperature and after around 500 h, there was only residual NB in the water and sediment. Most of the NB (around 82%) evaporated into the air and 18% was degraded by microorganisms. PMID- 17697702 TI - Increased permeability of blood-brain barrier on the hippocampus of a murine model of senescence. AB - SAMP8 mice show several indicative characteristics of accelerated aging and have been used to study the physiological and physiopathological processes that take place during senescence. There is some controversy about the presence of a functional blood-brain barrier (BBB) disturbance on these animals, which could be related to the oxidative stress or the amyloidosis present in their brain. In order to elucidate BBB status in the hippocampus of SAMP8 mice, in this study we have determined the extravasation from brain microvessels of endogenous IgG in SAMP8 mice aged 3, 7 and 12 months and in age-matched control SAMR1 mice. Immunohistochemistry, confocal microscopy and an imaging methodology specially designed to quantify IgG extravasation have been used. The choroid plexus was analyzed as a control for positive extravasation in SAMP8 and SAMR1 mice and, as expected, in all studied ages high IgG immunoreactivity was observed in both strains. We have found significantly higher levels of IgG extravasation in the hippocampus of 12-month-old SAMP8 mice compared to SAMR1 mice, indicating an increased permeability of BBB in aged senescence-accelerated mice. PMID- 17697703 TI - HLA-B*1502-bound peptides: implications for the pathogenesis of carbamazepine induced Stevens-Johnson syndrome. AB - BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) can involve MHC-restricted presentation of a drug or its metabolites for T-cell activation. HLA-B(*)1502 tightly associated with carbamazepine (CBZ) induced these conditions in a Han Chinese population. OBJECTIVE: We sought to identify HLA-B(*)1502-bound peptides that might be involved in CBZ-induced SJS/TEN. METHODS: Soluble HLA-B(*)1502 was used to identify bound peptides in the presence and absence of CBZ by using liquid chromatography-tandem mass spectrometry. Peptide-binding assays were performed to detect the specific interaction between the HLA molecule and the identified peptides. Mass spectra were compared to detect CBZ-modified peptides. RESULTS: We identified more than 145 peptides bound to HLA-B(*)1502. In 13 of 15 peptides examined, we functionally confirmed their specificity with binding assays. Preferable uses of these peptides at the anchoring residues P2 and P9 were similar to those observed in other HLA-B alleles in the Han Chinese population. However, the preferable use of serine residues at the nonanchoring position (P) 5, P6, P7, and P8 appeared to be unique for the B(*)1502 peptides. No specific CBZ-modified peptides were detected when we compared the mass spectra of peptides detected in the presence or absence of the drug. CONCLUSION: Noncovalent interaction between a drug and an HLA complex might contribute to cytotoxic T cell-mediated cell death in patients with SJS/TEN. CLINICAL IMPLICATIONS: An understanding of pharmacologic interaction of drugs with an HLA complex might lead to safer drugs that avoid SJS/TEN. PMID- 17697704 TI - Expression of activated Fc gamma RII discriminates between multiple granulocyte priming phenotypes in peripheral blood of allergic asthmatic subjects. AB - BACKGROUND: Allergic asthma is associated with chronic airway and systemic immune responses. Systemic responses include priming of peripheral blood eosinophils, which is enhanced after allergen challenge. In a subpopulation of asthmatic subjects, neutrophils are associated with bronchial inflammation. OBJECTIVE: We sought to monitor systemic granulocyte priming in allergic asthmatic subjects as a consequence of chronic and acute inflammatory signals initiated by allergen challenge. METHODS: Blood was taken at baseline and 6 to 24 hours after allergen challenge in asthmatic subjects with and without late asthmatic responses. Systemic granulocyte priming was studied by using expression of cellular markers, such as alpha-chain of Mac-1 (alpha m)/CD11b, L-selectin/CD62L, and an activation epitope present on Fc gamma RII/CD32 recognized by monoclonal phage antibody A17. RESULTS: Eosinophils of asthmatic subjects have a primed phenotype identified by cell-surface markers. Neutrophils of these patients were subtly primed, which was only identified after activation with N-formyl-methionyl-leucyl-phenylalanine. After allergen challenge, an acute increase in eosinophil priming characterized by enhanced expression of activated Fc gamma RII was found in patients experiencing a late asthmatic response and not in patients with a single early asthmatic response. In contrast, expression of alpha m/CD11b and L-selectin on granulocytes was not different between control and asthmatic subjects and was not affected by allergen challenge. Interestingly, expression of both adhesion molecules was positively correlated, and alpha m expression on eosinophils and neutrophils correlated positively with bronchial hyperresponsiveness. CONCLUSION: Different phases, phenotypes, or both of allergic asthma are associated with distinct priming profiles of inflammatory cells in peripheral blood. CLINICAL IMPLICATIONS: Insight in differences of systemic innate responses will lead to better definition of asthma subtypes and to better designs of new therapeutic options. PMID- 17697705 TI - Eosinophilia in cholesterol atheroembolic disease. PMID- 17697706 TI - Evaluation of sources of uncertainties in microtensile bond strength of dental adhesive system for different specimen geometries. AB - OBJECTIVE: The aim of this research is to use finite element analysis (FEA) to quantify the effect of the sample shape and the imperfections induced during the manufacturing process of samples on the bond strength and modes of failure of dental adhesive systems through microtensile test. Using the FEA prediction for individual parameters effect, estimation of expected variation and spread of the microtensile bond strength results for different sample geometries is made. METHODS: The estimated stress distributions for three different sample shapes, hourglass, stick and dumbbell predicted by FEA are used to predict the strength for different fracture modes. Parameters such as the adhesive thickness, uneven interface of the adhesive and composite and dentin, misalignment of axis of loading, the existence of flaws such as induced cracks during shaping the samples or bubbles created during application of the adhesive are considered. Microtensile experiments are performed simultaneously to measure bond strength and modes of failure. These are compared with the FEA results. RESULTS: The relative bonding strength and its standard deviation for the specimens with different geometries measured through the microtensile tests confirm the findings of the FEA. The hourglass shape samples show lower tensile bond strength and standard deviation compared to the stick and dumbbell shape samples. ANOVA analysis confirms no significant difference between dumbbell and stick geometry results, and major differences of these two geometries compared to hourglass shape measured values. Induced flaws in the adhesive and misalignment of the angle of application of load have significant effect on the microtensile bond strength. Using adhesive with higher modulus the differences between the bond strength of the three sample geometries increase. SIGNIFICANCE: The result of the research clarifies the importance of the sample geometry chosen in measuring the bond strength. It quantifies the effect of the imperfections on the bond strength for each of the sample geometries through a systematic and all embracing study. The results explain the reasons of the large spread of the microtensile test results reported by various researchers working in different labs and the need for standardization of the test method and sample shape used in evaluation of the dentin-adhesive bonding system. PMID- 17697707 TI - Fracture toughness comparison of six resin composites. AB - OBJECTIVES: This study investigated the Mode I and II fracture toughness values of resin composites used for the restorations of anterior teeth by the Brazilian disk test method. METHODS: The Brazilian disk test was performed on six commercially available dental resin composites, Venus (hybrid resin composite), Durafill (micro-filled resin composite), Gradia (micro-filled/hybrid resin composite), Point4 (hybrid resin composite), Supreme (nano-particle resin composite) and Filtek Z250 (resin composite with zirconia particles). Five resin composite disks of 25 mm in diameter and 2mm in thickness with chevron notches were prepared for each fracture mode per material. The specimens were stored in distilled water for 24h at 37 degrees C, and then tested by a Zwick testing machine under compression mode with a constant crosshead speed of 0.25 mm/min at room temperature. The stress intensity factors under combined Modes I and II fracture toughness were calculated by the formula presented by Atkinson et al. The fracture patterns of two specimens randomly selected from each test group were examined using a scanning electron microscope. A one-way analysis of variance (ANOVA) was performed for the statistical evaluations followed by the post-hoc Tukey's Student Range (HSD) test. RESULTS: The highest mean Mode I and II fracture toughness values were found in Filtek Z250 and Filtek Supreme and they were significantly higher than other materials (comparisons significant at the 0.05 level). The intermediate group consisted of Point4, Venus and Gradia ANTERIOR, whereas Durafill, statistically, had the lowest mean value for fracture toughness. SIGNIFICANCE: Fracture toughness values of hybrid and nano-particle resin composites are significantly higher than those of micro-filled resin composites. This suggests that the latter should be used for non-stress bearing areas. PMID- 17697708 TI - Decreased Staphylococcus epidermis adhesion and increased osteoblast functionality on antibiotic-loaded titania nanotubes. AB - Bacterial infection is one of the most common problems after orthopedic implant surgery. If not prevented, bacterial infection can result in serious and life threatening conditions such as osteomyelitis. Thus, in order to reduce chances of such serious complication, patients are often subjected to antibiotic drug therapy for 6-8 weeks after initial surgery. The antibiotics are systemically delivered either intravenously, intramuscularly or topically. Systemic antibiotic delivery entails certain drawbacks such as systemic toxicity and limited bioavailability. Further, in order for the drug to be effective at the site of implantation, high doses are required, which can result in undesired side effects in patients. Thus, local antibiotic therapy is the preferred way of administering drugs. To that end, we have developed titania nanotubular arrays for local delivery of antibiotics off-implant at the site of implantation. These nanotubes were fabricated on bulk titanium using anodization techniques. The fabrication strategies allow us to precisely control the nanotube length and diameter, thus enabling us to load different amounts of drugs and control the release rates. In this work we have fabricated titania nanotubes with 80 nm diameter and 400 nm length. We have loaded these tubes with 200, 400 and 600 microg of gentamicin. The gentamicin release kinetics from these nanotubes and its effect on Staphylococcus epidermis adhesion were investigated. Further, a preosteoblastic cell line called MC3T3-E1 was cultured on gentamicin-loaded nanotubes to evaluate the effect of nanoarchitecture on cell functionality. Our results indicate that we can effectively fill the nanotubes with the drug and the drug eluting nanotubes significantly reduce bacterial adhesion on the surface. Also, there is enhanced osteoblast differentiation on nanotubes filled with gentamicin. PMID- 17697709 TI - The effect of discrete calcium phosphate nanocrystals on bone-bonding to titanium surfaces. AB - We sought to address the question: Can metallic surfaces be rendered bone bonding? We employed dual acid-etched (DAE) commercially pure titanium (cpTi) and titanium alloy (Ti6Al4V) custom-made rectangular coupons (1.3 mm x 2.5 mm x 4 mm) with, or without, further modification by the discrete crystalline deposition (DCD) of calcium phosphate (CAP) nanocrystals. A total of 48 implants comprising four groups were placed bilaterally in the distal femur of male Wistar rats for 9 days. After harvesting, the bone immediately proximal and distal to the implant was removed, resulting in a test sample comprising the implant with two attached cortical arches. The latter were distracted at 30 mm/min, in an Instron machine, and the disruption force was recorded. Results showed that alloy samples exhibited greater disruption forces than cpTi, and that DCD samples had statistically significantly greater average disruption forces than non-DCD samples. The bone-bonding phenomenon was visually evident by fracture of the cortical arches and an intact bone/implant interface. Field emission scanning electron microscopy showed the bone/implant interface was occupied by a bony cement line matrix that was interlocked with the surface topographical features of the implant. We conclude that titanium implant surfaces can be rendered bone bonding by an increase in the complexity of the surface topography. PMID- 17697710 TI - Protein repellent properties of covalently attached PEG coatings on nanostructured SiO(2)-based interfaces. AB - In this study, we report the systematic comparison of different poly(ethylene glycol) (PEG) self-assembled monolayers on glass with respect to their protein adsorption and cell adhesion resistance. Combining PEGylation with micellar nanolithography allowed the formation of gold nanoparticle arrays on glass and selective coverage of the free glass area by PEG. The gold nanoparticles serve as anchor points for the attachment of individual proteins and peptides such as the cell-matrix adhesion promoting cyclic RGDfK motif or the kinesin motor protein Eg5. The capability of the motor protein to bind microtubules remained unaffected by the immobilization. It was shown that the film thickness of a water swollen PEG layer is crucial to maximize the interaction between proteins and peptides with the nanostructures. Non-specific interaction between cells or microtubules and the surface was minimized. The optimum PEG layer thickness correlated with the size of gold nanoparticles which was approximately 5 nm. PMID- 17697711 TI - Bone bonding at natural and biomaterial surfaces. AB - Bone bonding is occurring in each of us and all other terrestrial vertebrates throughout life at bony remodeling sites. The surface created by the bone resorbing osteoclast provides a three-dimensionally complex surface with which the cement line, the first matrix elaborated during de novo bone formation, interdigitates and is interlocked. The structure and composition of this interfacial bony matrix has been conserved during evolution across species; and we have known for over a decade that this interfacial matrix can be recapitulated at a biomaterial surface implanted in bone, given appropriate healing conditions. No evidence has emerged to suggest that bone bonding to artificial materials is any different from this natural biological process. Given this understanding it is now possible to explain why bone-bonding biomaterials are not restricted to the calcium-phosphate-based bioactive materials as was once thought. Indeed, in the absence of surface porosity, calcium phosphate biomaterials are not bone bonding. On the contrary, non-bonding materials can be rendered bone bonding by modifying their surface topography. This paper argues that the driving force for bone bonding is bone formation by contact osteogenesis, but that this has to occur on a sufficiently stable recipient surface which has micron-scale surface topography with undercuts in the sub-micron scale-range. PMID- 17697713 TI - IL-12/IFN-gamma/NO axis plays critical role in development of Th1-mediated experimental autoimmune encephalomyelitis. AB - The importance of the IL-12/IFN-gamma/nitric oxide (NO) axis in the pathogenesis of autoimmune diseases remains controversial. In parallel experiments, we explored the role of the IL-12/IFN-gamma/NO axis in the development of MOG 35-55 induced experimental autoimmune encephalomyelitis (EAE) in mice lacking IL-12, IFN-gamma receptor (IFN-gammaR) and inducible nitric oxide synthase (NOS2), respectively. In comparison with wide-type control mice, IL-12-/-, IFN-gammaR-/- and NOS2-/- mice displayed more severe clinical signs of EAE both in remission and at subsequent relapse. Given the relatively low IFN-gamma production in IL-12 /- mice and the lack of IFN-gamma/IFN-gammaR signaling pathway in IFN-gammaR-/- mice, IL-12-/-, IFN-gammaR-/- and NOS2-/- mice with EAE exhibited low NO production. This correlated negatively with MOG 35-55-induced T cell proliferation. Both ED1-positive macrophages and CD4-positive T cells were increased in spinal cords from IL-12-/-, IFN-gammaR-/- and NOS2-/- compared to control mice. In vitro experiments demonstrate that spleen mononuclear cells from IL-12-/-, IFN-gammaR-/- and NOS2-/-mice with EAE present stronger migration capacity when compared to control mice. These results reveal that the IL-12/IFN gamma/NO axis plays a critical role in the development of MOG 35-55-induced EAE, possibly over failing NO production. PMID- 17697712 TI - Hydrogel biomaterials: a smart future? AB - Hydrogels were the first biomaterials developed for human use. The state-of-the art and potential for the future are discussed. Recently, new designs have produced mechanically strong synthetic hydrogels. Protein-based hydrogels and hybrid hydrogels containing protein domains present a novel advance; such biomaterials may self-assemble from block or graft copolymers containing biorecognition domains. One of the domains, the coiled coil, ubiquitously found in nature, has been used as an example to demonstrate the developments in the design of smart hydrogels. The application potential of synthetic, protein based, DNA based, and hybrid hydrogels bodes well for the future of this class of biomaterials. PMID- 17697714 TI - Effects of fluoridation and disinfection agent combinations on lead leaching from leaded-brass parts. AB - This study concerns effects on water-borne lead from combinations of chlorine (CL) or chloramines (CA) with fluosilicic acid (FSA) or sodium fluoride (NaF). CL is known to corrode brass, releasing lead from plumbing devices. It is known that CA and CL in different ratios with ammonia (NH) mobilize copper from brass, which we have found also enhances elution of lead from leaded brass alloys. Phase I involved leaded-brass 1/4 in. elbows pre-conditioned in DI water and soaked in static solutions containing various combinations of CL, CA, FSA, NaF, and ammonium fluosilicate. In Phase II 20 leaded-brass alloy water meters were installed in pipe loops. After pre-conditioning the meters with 200 flushings with 1.0 ppm CL water, seven different solutions were pumped for a period of 6 weeks. Water samples were taken for lead analysis three times per week after a 16 h stagnation period. In the static testing with brass elbows, exposure to the waters with CA+50% excess NH3+FSA, with CA and ammonium fluosilicate, and with CA+FSA resulted in the highest estimated lead concentrations. In the flow-through brass meter tests, waters with CL+FSA, with CL+NaF, and with CL alone produced the highest average lead concentration for the first 3-week period. Over the last 3 weeks the highest lead concentrations were produced by CL+NaF, followed by CL alone and CA+NH3+FSA. Over the first test week (after CL flushing concentrations were increased from 1.0 to 2.0 ppm) lead concentrations nearly doubled (from about 100 to nearly 200 ppb), but when FSA was also included, lead concentrations spiked to over 900 ppb. Lead concentrations from the CL-based waters appeared to be decreasing over the study period, while for the CA+NH3+FSA combination, lead concentrations seemed to be increasing with time. PMID- 17697715 TI - Disease spectrum of cervical lymphadenitis: analysis based on ultrasound-guided core-needle gun biopsy. AB - OBJECTIVES: Despite the high frequency of cervical lymphadenopathy in the outpatient clinics, there was no published data on the disease spectrum of cervical lymphadenopathy among adult outpatients. We are evaluating the disease spectrum of cervical lymphadenitis in the outpatient setting. METHODS: As for the patients with cervical lymphadenitis, ultrasound-guided core-needle gun biopsy has been performed in Korea University Hospital. We reviewed medical records of adult outpatients with cervical lymphadenitis between January 2004 and April 2006, and compared the clinical, laboratory and radiological differences among them. RESULTS: The study included 147 patients with the mean age of 33.7 years. Histopathological diagnoses were obtained from 137 (93.2%) cases: Kikuchi's disease (34.7%), tuberculous lymphadenitis (22.4%), non-specific lymphadenitis (22.4%), lymphoma (6.1%), metastatic carcinoma (3.4%), etc. Overall, clinical manifestations were indistinguishable among tuberculous lymphadenitis, Kikuchi's disease and non-specific lymphadenitis. Leucopenia was characteristic of Kikuchi's disease, while anemia, thrombocytosis and pulmonary tuberculosis (irrespective of activity) were more common in the tuberculous lymphadenitis. CONCLUSION: Kikuchi's disease and tuberculosis were the most common and clinically important causes of cervical lymphadenitis. Complete blood count, chest X-ray and ultrasound-guided core-needle gun biopsy would be helpful in the differential diagnosis of cervical lymphadenitis, especially between Kikuchi's disease and tuberculous lymphadenitis. PMID- 17697716 TI - Improved outcomes associated with advances in therapy for invasive fungal infections in immunocompromised hosts. AB - Invasive fungal infections cause substantial morbidity and mortality in immunocompromised hosts. The response rate to therapy, in particular for invasive aspergillosis and invasive mould infections, has been poor. Recently a number of techniques to facilitate early diagnosis of these infections, in parallel with the development of a number of antifungals with increased potency and lower toxicity, have raised optimism that outcomes for invasive fungal infection can be improved upon. The availability of lipid formulations of amphotericin B, azoles with extended spectrum against filamentous fungi and the development of a new class of antifungal agents, the echinocandins, presents the clinician with a range of therapeutic choices. Recent clinical trials have provided important insights into how these agents should be used. In particular, voriconazole has demonstrated superior efficacy to amphotericin B in the management of invasive aspergillosis, posaconazole has been shown to have significant efficacy in the prophylaxis of invasive fungal infection in high-risk individuals and a role in salvage therapy of invasive aspergillosis, caspofungin has demonstrated efficacy in salvage therapy of invasive aspergillosis, and each of the echinocandins show activity without significant toxicity in invasive candidiasis. Nevertheless, many therapeutic areas of uncertainty remain, including the role of combination therapy, and will provide the focus for future studies. PMID- 17697717 TI - Multiplex real-time RT-PCR for the simultaneous detection and quantification of transmissible gastroenteritis virus and porcine epidemic diarrhea virus. AB - Transmissible gastroenteritis virus (TGEV) and porcine epidemic diarrhea virus (PEDV) are major etiological agents of diarrhea and death in piglets. Multiplex real-time reverse transcriptase (RT)-PCR was developed for simultaneous differential quantification of each virus in a single reaction tube, using Cy5- and FAM-labeled TaqMan-probes based on sequences from the TGEV and PEDV nucleocapsid genes. The copy numbers for transcripts of TGEV and PEDV were quantified using this assay over a range from 9x10(7) to 9x10(1) copies and 7x10(7) to 7x10(1) copies, respectively. The variability of the intra-assay and inter-assay were evaluated using standard solutions of each transcript, with coefficients of variation (CV) less than 3.43 and 3.33%, respectively. Piglets were experimentally infected with virulent TGEV and PEDV, and the amounts of virus from the onset of diarrhea were measured. Samples obtained from farms experiencing PED or TGE were quantified between 10(2) and 10(5) RNA copies. In conclusion, this assay provides an effective etiological diagnostic tool for detecting and quantifying viral loads. The assay may also prove useful for detecting infections, ultimately leading to better disease control on farms. PMID- 17697718 TI - Effects of social crowding on emotionality and expression of hippocampal nociceptin/orphanin FQ system transcripts in mice. AB - The novel nociceptin/orphanin FQ (N/OFQ) system was proposed to be an important component of neural circuits involved in stress-coping behaviour and fear. This study investigated whether variations between the mouse strains in vulnerability to social crowding stress might be linked to different regulation of N/OFQ system transcripts in mice. Three weeks old C57BL/6J (B6), BALB/cByJ (CBy) and 129S2/SvPas (129S2) male mice were housed individually or in crowded (7/cage) conditions and then tested as adults in a battery of anxiety tests (open field, elevated plus-maze and acoustic startle reflex tests). Both 129S2 and B6 mice displayed increased signs of anxiety under crowded housing, while CBy mice tended to show the opposite profile. Analysis of gene expression revealed a 10-fold increase of nociceptin precursor and 4-fold increase of the NOP receptor mRNAs contents in the hippocampus of CBy mice kept in crowded conditions compared to those housed individually. In B6 mice, mRNA level of the peptide precursor remained unchanged, while that of the receptor was increased by 2-fold under crowding compared to individual housing. No significant changes were detected in 129S2 mice. These findings show that social housing may be important environmental stress factor in mice depending on the strain. The possible involvement of central nociceptin mechanisms in behavioural resilience to social crowding stress is discussed. PMID- 17697719 TI - Effects of brief and long maternal separations on the HPA axis activity and the performance of rats on context and tone fear conditioning. AB - Previous studies show that early life events result in neurobehavioural alterations that may be either beneficial or detrimental to the stress response. Given the close relationship between corticosterone secretion and mnemonic processes, the purpose of the present study was to investigate the effects of brief (BMS, 15 min) and long maternal separations (LMS, 180 min) on memory tasks in adult rats, assessed by context and tone fear conditioning. At adulthood, males were evaluated for behavioural and hormonal reaction to the training environment, being tested for context fear conditioning; tone fear conditioning; and learning curve in the context fear conditioning, in which rats were daily re exposed to the context, followed by a brief footshock and in the last day of the experiment (day 5) animals were exposed to the context. Corticosterone and ACTH plasma levels were determined in naive rats (basal) or 5, 25 or 45 min after each test. Peak ACTH and corticosterone levels were similar among the groups after context fear conditioning; however, levels of CTL rats remained elevated for a longer time. In the learning curve of context fear conditioning, both BMS and LMS rats exhibited less freezing behaviour than CTL rats, without differences in hormone secretion. There was neither an association between activity of the HPA axis and performance on memory tasks nor different activational properties of the tasks on the HPA axis between BMS and LMS rats, i.e., both manipulations lead to similar performance in hippocampus-dependent and independent memory tasks. PMID- 17697721 TI - Vascular and rare liver tumors: a good indication for liver transplantation? PMID- 17697720 TI - Altered development and reproduction in mosquitofish exposed to pulp and paper mill effluent in the Fenholloway River, Florida USA. AB - Female mosquitofish exposed to pulp and paper mill effluent (PME) in the Fenholloway River, Florida, USA have masculinized secondary sex characteristics and altered aromatase enzyme activity. We and others have shown that the Fenholloway River PME contains androgenic and progestogenic substance(s). The present study was designed to test the hypothesis that the development and reproductive health of PME-exposed Fenholloway River mosquitofish are altered compared to mosquitofish living in Econfina River, which is the reference site. Fish were collected on a single day from both sites in June and August 1999 and January and June 2000. We compared standard length, anal fin length and segment number; body, liver, and gonad mass; and number of eggs and embryos from Fenholloway and Econfina River mosquitofish. The data were analyzed collectively for generalized site effect, for site effects during reproductive and nonreproductive seasons, and for repeatability of site effects between years. Mosquitofish exposed to PME in the Fenholloway River were generally smaller in length and mass, anal fin segment number was greater, and the number of embryos, but not oocytes, was significantly decreased compared to the reference site fish. Anal fin length and segment number and liver and testis masses were generally greater in Fenholloway compared to the Econfina River males. The importance of this study is that we have documented masculinized development and decreased embryo production in PME-exposed mosquitofish and that these site effects are generally consistent across seasons and between years. PMID- 17697722 TI - Cholangiocarcinoma: is transplantation an option? For whom? PMID- 17697723 TI - Neuroendocrine tumors metastatic to the liver: how to select patients for liver transplantation? PMID- 17697724 TI - Economics of chronic hepatitis B and hepatitis C. AB - Although not all patients develop progressive liver disease, chronic hepatitis B and chronic hepatitis C infections cause substantial morbidity and mortality worldwide. To address this need, many new antiviral treatments have become available over the past 10 years. While safety, efficacy, and therapeutic indications have been well established for these agents, the economics of antiviral treatment have become increasingly a focus of discussion for physicians, policymakers, and health payers. In this paper, we will elucidate some economic principles using examples from the treatment of hepatitis B and C. In particular, we will examine the considerations in estimating drug costs, methods for performing economic analyses and lastly summarize published cost effectiveness analyses for antiviral treatments of chronic hepatitis B and chronic hepatitis C. This review should help clinicians understand economic issues regarding new drugs and answer questions about whether the clinical benefit provided by a medication justifies its expense. PMID- 17697725 TI - Best practice in the treatment of chronic hepatitis B: a summary of the European Viral Hepatitis Educational Initiative (EVHEI). AB - Hepatitis B causes acute and chronic hepatitis, the latter resulting in cirrhosis and hepatocellular carcinoma. There are four phases of infection: during the phases of immune tolerance and immune control of the virus, no treatment is recommended but in the phases of immune clearance and immune escape, viraemia with biopsy evidence of significant fibrosis requires anti-viral therapy. The areas of agreement and disagreement between the various consensus statements are discussed. Health economic issues indicate that a trial of pegylated interferon should be offered in non-cirrhotic cases, particularly those that are HBe antigen positive, followed in those that do not establish a sustained viral response, by long term viral suppressive therapy with nucleoside analogues singly or in combination. The indications for treatment and methods of follow-up, as well as issues of viral resistance are discussed. PMID- 17697726 TI - A brand new mechanism for copper toxicity. PMID- 17697727 TI - Adefovir for lamivudine resistant HBV: more than meets the eye. PMID- 17697728 TI - Serum Sialyl Lewis x and cytokeratin 19 fragment as predictive factors for recurrence in patients with stage I non-small cell lung cancer. AB - This study aimed to establish the clinical significance of preoperative serum cytokeratin 19 fragment (CYFRA21-1) and Sialyl Lewis(x) (SLX) in patients with stage I non-small cell lung cancer (NSCLC). The study involved 137 patients (87 male, 50 female; median age 69 years) with completely resected stage I NSCLC. SLX, carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), and CYFRA21-1 were examined. Receiver operator characteristic (ROC) curves were constructed to determine prognostic cut-off values. Among the 137 patients, we identified 30 with recurrence within 3 years. The 5-year survival rates in patients with (n=30) and without (n=107) recurrence were 14% and 81%, respectively. The serum concentrations of SLX, CEA, and CYFRA21-1 in the recurrence group were significantly higher than those in the non-recurrence group. The areas under the ROC curve (AUC) were 0.72, 0.65, 0.53, and 0.64 for SLX, CEA, SCC, and CYFRA21-1, respectively. The prognostic cut-off values were 36U/ml, 7.8ng/ml, 1.5ng/ml, and 3.2ng/ml for SLX, CEA, SCC, and CYFRA21-1, respectively. A log-rank test revealed that age, performance status, T factor, lymphatic invasion, vascular invasion, SLX, CEA, SCC, and CYFRA21-1 were all significantly associated with survival. By multivariate analysis, age, performance status, lymphatic invasion, SLX (risk ratio, 4.11) and CYFRA21-1 (risk ratio, 3.47) were independent prognostic factors. For patients positive for both CYFRA21-1 and SLX, the relative risk was 5.32 compared with patients who were negative for both markers. The 5-year survival rates were 80% in the group negative for both markers (n=86); 52% in the group positive for one of the markers (n=43); and 13% for the group positive for both markers (n=8) (p<0.001). We concluded that serum SLX and CYFRA21-1 were prognostic markers for stage I NSCLC. Their combination should contribute to the classification of stage I NSCLC patients. There is a need to consider adjuvant and neoadjuvant therapies to improve prognosis in patients positive for both tumor markers. PMID- 17697729 TI - Boron-induced amelioration of aluminium toxicity in a monocot and a dicot species. AB - Previous research has reported inconsistent results from experiments on the influence of boron (B) on plant sensitivity to potentially toxic aluminium (Al) concentrations. Differences in B requirement and cell wall properties among species, especially between Poaceae and dicots, may account for this. This investigation reports amelioration by B of Al-induced inhibition of root elongation in Al-sensitive cucumber (Cucumis sativus), but not in Al-sensitive maize (Zea mays). Vital staining, however, also revealed a positive influence of B supply on Al tolerance in maize. In both species, adequate B supply decreased Al-induced damage of cell integrity. In cucumber, increasing B supply enhanced Al concentrations and haematoxylin staining in root tips. In maize, no differences for root Al among B treatments were observed. These results indicate that the positive effect of B on Al resistance was not due to less Al accumulation in root tips. Enhanced concentrations of reduced glutathione were found in roots of Al stressed maize plants growing with adequate B. It is concluded that adequate B supply is essential for prevention of Al toxicity in both the dicot and the monocot species. In dicot cucumber, the B-induced amelioration of root elongation, despite higher Al accumulation in root tips, indicates B-induced change in either or both Al speciation and compartmentation in the tips. The protection by an adequate B supply of roots against Al-induced cell death suggests a role for B in the defence against oxidative stress. This is supported by the observation that Al induced enhanced levels of GSH in roots of maize plants growing with adequate B supply but not in those growing with either deficient or excess B concentrations. PMID- 17697730 TI - Long-term immunogenicity of a virosomal subunit inactivated influenza vaccine in children with asthma. AB - To evaluate long-term immunogenicity of a virosomal subunit inactivated influenza vaccine in children with asthma, a prospective study was conducted during 2005 2006 influenza season in six public pediatric clinics in Milan and surroundings, Northern Italy. A single dose (0.5 ml) of a virosomal subunit inactivated influenza vaccine (Inflexal V) was injected in 106 asthmatic children aged 3-9 years. Serum hemagglutinin inhibition antibody titers were determined against the recommended influenza strains A/New Caledonia (H1N1), A/California (H3N2), and B/Shanghai (B), at pre-vaccination and 1 and 6 months after vaccination. Seroconversion rate (95% CI) against the strains A/H1N1, A/H3N2 and B was, respectively, 78% (68.6-85.7), 57% (46.7-66.9) and 66% (55.8-71.2) at 1 month. Seroprotection (titer> or =40) rate for A/H1N1, A/H3N2 and B was, respectively, 87% (77.8-92.2), 82% (72.6-89.7) and 90% (82.6-94.8) at 1 month and 74% (64.3 82.3), 77% (67.5-84.8), and 77% (67.5-84.8) at 6 months. Seroprotection rate was high and persistent (>95%) in children with pre-existing antibodies (titer> or =10) at pre-vaccination for any specific strain. In children without pre-existing antibodies, seroprotection rate for A/H1N1, A/H3N2 and B was, respectively, 67.6%, 66.7% and 74.4% at 1 month, and 35.1%, 56.2% and 41.0% at 6 months after vaccination. Vaccine was well tolerated. These results indicate that in unvaccinated children with asthma vaccination with a single dose of virosomal adjuvanted influenza vaccine is well tolerated and effective as a whole. However, while immunity response and persistence are excellently high in children with pre existing antibodies, in children naive for the antigens the immune parameters are lower at 6 months after vaccination. PMID- 17697731 TI - Role of beer as a possible protective factor in preventing Alzheimer's disease. AB - Aluminium (Al), a neurotoxin, has lately been implicated as one of the possible causal factors contributing to Alzheimer's disease. Because silicon (Si) intake can affect the bioavailability of aluminium, the object of the present study was to assess whether moderate beer consumption might, as a source of dietary Si, affect the toxicokinetics of Al and thereby limit that element's neurotoxicity. The results obtained confirmed that at moderately high levels of beer intake the Si present in the beer was able to reduce Al uptake in the digestive tract and thus was able to slow the accumulation of this metal in the body, brain tissue included. In consequence, moderate beer consumption, due to its content in bioavailability silicon, possibly affording a protective factor for preventing Alzheimer's disease, could perhaps be taken into account as a component of the dietary habits of the population. PMID- 17697732 TI - Implants for life? A critical review of implant-supported restorations. AB - AIM: This review critically appraises the literature on implant-supported restorations. METHOD: The review was conducted in March 2007 using OVID Medline with the search terms, limited to the English Language, of implant, crown, bridge, fixed and removable partial dentures and complete dentures. From a total of 5135 papers combining implants and implant-supported restorations only 131 were found, after a thorough hand search, to be relevant to the restoration of implants. RESULTS: The outcome of implant fixtures have consistently been shown to be successful over the long-term. However, the same focus of research into the restorations used to support implants has not. Where research is available to guide clinicians towards a particular technique the rigour of the research is limited. CONCLUSION: More emphasis by the research community on the outcome of restorations supported by implants is needed. PMID- 17697733 TI - Acute respiratory failure leading to emergency intubation: an unusual manifestation of Munchausen's syndrome. AB - Munchausen's syndrome is a contrived psychiatric disorder, in which patients present with an intentionally produced or feigned illness with the aim to assume the sick role and to gain medical attention. Patients may even seek the application of invasive procedures, sometimes with serious risk to life. We describe the case of a 38-year-old woman, who repeatedly presented with apparent respiratory failure leading to tracheal intubation and mechanical ventilation. In addition, we present a systematic review of the literature over respiratory and pulmonary manifestations of Munchausen's syndrome. This case report may contribute to the awareness among emergency physicians of Munchausen's syndrome as a differential diagnosis of respiratory failure. Recognition of this psychiatric disease is not only important for correct medical diagnosis and treatment, but also essential in protecting the patients from unnecessary invasive and aggressive medical procedures. PMID- 17697734 TI - Volume therapy with colloid solutions preserves intestinal microvascular perfusion in endotoxaemia. AB - Colloid solutions have been suggested to improve microvascular perfusion due to their anti-inflammatory properties. Whether this also applies for the gut, an important immunological organ vulnerable to hypoperfusion is unknown. This study investigated intestinal microcirculation of endotoxaemic rats after volume therapy with colloid solutions such as hydroxyethyl starch (HES) and gelatin or isotonic saline (NaCl). In addition intestinal oxygenation and morphology as well as mesenteric leukocyte-endothelium interaction were quantified. Rats were anaesthetised with urethane and ketamine, mechanically ventilated, and monitored haemodynamically. Normotensive endotoxaemia was induced by a continuous intravenous infusion of Escherichia coli lipopolysaccharide (LPS, 1.5 mg kg(-1) h(-1)). After 1 h of LPS infusion either 6% HES (16 ml kg(-1)), 4% gelatin (16 ml kg(-1)) or 0.9% NaCl (64 ml kg(-1)) were infused for 1 h. Using intravital microscopy, functional capillary density (FCD) and red blood cell velocity (RBCV) were measured in the mucosa of the terminal ileum at baseline and 3 h after volume therapy. In another set of animals, mesenteric leukocyte-endothelium interaction was determined 3 h after volume therapy. In all animals intestinal lactate/pyruvate ratio and intestinal morphology were assessed. Three hours after volume therapy, FCD decreased in NaCl (808 [749/843] cm(-1); median [quartiles] P<0.05 versus baseline) but not in HES (995 [945/1036] cm(-1)) and gelatin (988 [867/1193] cm(-1)) groups. RBCV, lactate/pyruvate ratio and intestinal morphology did not differ among groups. Also mesenteric leukocyte-endothelium interaction was not significantly influenced by either treatment. In conclusion, early volume therapy with HES or gelatin, but not with NaCl, preserved gut microvascular perfusion during endotoxaemia but did not have a significant effect on tissue oxygenation nor morphological appearance in this experimental model. An anti inflammatory effect of colloid solutions was not seen and fails to explain the changes in intestinal microcirculation. PMID- 17697735 TI - Cardiovascular effects of ephedrine during cardiopulmonary resuscitation. PMID- 17697736 TI - Unexpected fatal neurological deterioration after successful cardio-pulmonary resuscitation and therapeutic hypothermia. AB - A 77-year-old woman was admitted to the intensive care unit after successful cardiopulmonary resuscitation for out-of-hospital cardiac arrest due to pulseless electrical activity. She was treated with mild therapeutic hypothermia to minimise secondary anoxic brain damage. After a 24 h period of therapeutic hypothermia with a temperature of 32.5 degrees C, the patient was rewarmed and sedation discontinued. Neurological evaluation after 24 h revealed a maximum Glasgow Coma Score of E4M4Vt with spontaneous breathing. However the patient developed a fever reaching 39 degrees C for several hours that was unresponsive to conventional cooling methods. In the subsequent 24 h patient developed apnoea, hypotension and bradycardia with deterioration of the coma score. Diabetes insipidus was confirmed. Cerebral CT was performed which showed diffuse brain oedema with herniation and brainstem compression. The patient died within hours. Autopsy showed massive brain swelling and tentorial herniation. Hyperthermia possibly played a pivotal role in the development of this fatal insult to this vulnerable brain after cardiac arrest and therapeutic hypothermia treatment. The acute histopathological alterations in the brain, possibly caused by the deleterious effects of fever after cardiac arrest in human brain, may be considered a new observation. PMID- 17697737 TI - Patients with a history of diabetes have a lower survival rate after in-hospital cardiac arrest. AB - AIM: To describe the association between a history of diabetes and outcome among patients suffering an in-hospital cardiac arrest. METHOD: All patients suffering an in-hospital cardiac arrest in whom cardiopulmonary resuscitation (CPR) was attempted at Sahlgrenska University Hospital in Goteborg between 1994 and 2006 and at nine further hospitals in Sweden between 2005 and 2006. RESULTS: In all, 1810 patients were included in the survey, 395 (22%) of whom had a previous history of diabetes. Patients with a history of diabetes differed from those without such a history by having a higher prevalence of previous myocardial infarction, stroke, heart failure and renal disease. They were more frequently treated with anti-arrhythmic drugs during resuscitation. Whereas immediate survival did not differ between groups (51.7% and 53.1%, respectively), patients with diabetes were discharged alive from hospital (29.3%) less frequently compared with those without diabetes (37.6%). When correcting for dissimilarities at baseline, the adjusted odds ratio for being discharged alive (diabetes/no diabetes) was 0.57 (95% CL 0.40-0.79). CONCLUSION: Among patients suffering an in hospital cardiac arrest in Sweden in whom CPR was attempted, 22% had a history of diabetes. These patients had a lower survival rate, which cannot simply be explained by different co-morbidity. PMID- 17697738 TI - Sternal fracture and osteomyelitis: an unusual complication of a precordial thump. AB - Out of hospital cardiac arrest is generally managed by cardiopulmonary resuscitation (CPR) and defibrillation. The precordial thump can also be used in the initial management of witnessed cardiac arrest whilst awaiting direct current cardioversion. However, complications are associated with a precordial thump. We report a case of an out-of-hospital cardiac arrest due to ventricular fibrillation that was treated initially with a precordial thump, which resulted in a sternal fracture and the development of sternal osteomyelitis. PMID- 17697739 TI - On the edge of life and death: a medical student's experience of resuscitation. PMID- 17697740 TI - From agonal to output: An ECG history of a successful pre-hospital thoracotomy. AB - This case report describes the first reported successful UK pre-hospital thoracotomy performed outside the London HEMS system. Continuous ECG monitoring during the procedure has allowed presentation of sequential ECGs recorded during the procedure. PMID- 17697741 TI - Prediction of countershock success employing single features from multiple ventricular fibrillation frequency bands and feature combinations using neural networks. PMID- 17697742 TI - Valproic acid induces apoptosis in chronic lymphocytic leukemia cells through activation of the death receptor pathway and potentiates TRAIL response. AB - OBJECTIVE: Chronic lymphocytic leukemia (CLL) cells develop chemoresistance over time associated with defects in apoptosis pathway. Novel treatment strategies are required to overcome resistance of cells to commonly used agents. The effects of valproic acid (VPA), an antiepileptic drug with histone deacetylase inhibitory activity, on mononuclear cells isolated from 40 CLL patients were evaluated. METHODS: CLL cells were treated with increasing doses of VPA (0.5, 1, 2, and 5 mM). The mode of cytotoxic drug action was determined by annexin binding, DNA fragmentation, and caspase activation. RESULTS: Exposure of CLL cells to VPA resulted in dose-dependent cytotoxicity and apoptosis in the 40 CLL patients. VPA treatment induced apoptotic changes in CLL cells including phosphatidylserine externalization and DNA fragmentation. The mean apoptotic rates were similar between IgV(H) mutated and unmutated patients, the latter presenting a more aggressive clinical course. VPA induced apoptosis via the extrinsic pathway involving engagement of the caspase-8-dependent cascade. Although CLL cells are commonly resistant to death receptor-induced apoptosis, VPA significantly increased sensitivity of leukemic cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and led to downregulation of c-FLIP (L) expression. VPA caused no potentialization of TRAIL-induced apoptosis on normal B cells. In addition, VPA overcame the prosurvival effects of bone marrow stromal cells. CONCLUSION: These findings point out that the combination of TRAIL and VPA, at clinically relevant concentration, may be valuable in the treatment of CLL. PMID- 17697743 TI - Primitive and committed human hematopoietic progenitor cells interact with primary murine neural cells and are induced to undergo self-renewing cell divisions. AB - OBJECTIVE: Studies in animal models have indicated that hematopoietic progenitor cells (HPC) migrate and home to the central nervous system and might acquire neural features under specific circumstances. The interaction between HPC and the neural environment and the functional effect on hematopoiesis have not yet been defined. METHODS: CD34(+)133(+) cells from mobilized peripheral blood were cocultured with primary murine neurons or astrocytes. Chemotaxis and adhesive interactions were studied by applying beta(1)- and beta(2)-integrin function blocking anibodies. The impact of neural feeder layers on integrin expression of HPC and the presence of appropriate adhesion ligands on neural cells were determined by immunostaining and flow cytometry. The hematopoietic long-term fate was monitored by time-lapse microscopy of individual cell-division history followed by long-term culture-initiating cell (LTC-IC) and colony-forming cell (CFC) assays. Neural differentiation was assessed by immunostaining against specific neuronal and glial antigens. RESULTS: The 23.0% +/- 4.9% of HPC showed stromal cell-derived factor-1-induced migration toward neural cells, and 20.2% +/ 1.6% displayed firm beta(1)-integrin-mediated adhesion to astrocytes. The latter expressed appropriate adhesion ligands, stabilized beta(1)-integrin expression, and increased beta(2)-integrin expression of HPC. Neural differentiation of HPC could not be identified but astrocytes were able to induce limited self-renewing cell divisions of HPC and thus maintain 25.8% +/- 3.4% of the initial LTC-IC and 80.7% +/- 1.9% of the initial CFC. CONCLUSION: Human HPC are able to interact with neural cells and interaction maintains, albeit to a limited extent, the self renewal capability of HPC. PMID- 17697745 TI - Telomere length in paroxysmal nocturnal hemoglobinuria correlates with clone size. AB - OBJECTIVE: To study if telomere length can be used as a surrogate marker for the mitotic history in normal and affected hematopoietic cells from patients with paroxysmal nocturnal hemoglobinuria (PNH). METHODS: The telomere length was measured by automated multicolor flow fluorescence in situ hybridization in glycosyl-phosphatidyl-inositol anchored protein (GPI)-negative and GPI-positive peripheral blood leukocytes. Eleven patients were studied, two with predominantly hemolytic PNH and nine with PNH associated with marrow failure. RESULTS: Telomere length in GPI-negative cells was significantly shorter than in GPI-positive cells of the same patient (p < 0.01, n = 11). The difference in telomere length (telomere length in GPI-positive minus telomere length in GPI-negative cells) correlated with the percentage of GPI-negative white blood cells. CONCLUSION: Our results support the hypothesis that telomere length is correlated to the replicative history of GPI-positive and GPI-negative cells and warrant further studies of telomere length in relation to disease progression in PNH. PMID- 17697744 TI - A novel high throughput immunomagnetic cell sorting system for potential clinical scale depletion of T cells for allogeneic stem cell transplantation. AB - OBJECTIVE: To develop an immunomagnetic cell separation system for allogeneic hematopoietic stem cell (HSC) transplantations, which can achieve a high level of T-cell depletion (at least 4.0 log(10)), high level of recovery of hematopoietic stem cells (>90%), with a high throughput (>10(6) cells/second). METHODS: Peripheral blood leukocytes (PBLs) from buffy coats were spiked with CD34 expressing cells (KG1a) to mimic a leukaphoresis product containing stimulated HSCs. T cells were labeled with anti-CD3(+) Dynabeads and separated in a quadrupole magnetic cell sorter (QMS). The performance of the system with respect to T-cell depletion and recovery of non-T cells and spiked KG1a was determined using four-color, flow cytometry analysis, with the aid of Trucount cell concentration calibration beads. Limiting dilution assays were also performed to quantify the log(10) depletion of clonable T cells. RESULTS: While the general performance of the QMS system is governed by proven theoretical principles, significant system variability exist, not all of which can be explained by our current understanding. Consequently, a factorial design was employed, guided by JMP software, to optimize the labeling conditions and operation of the QMS focused on maximizing the depletion of T cell, and recovery of unlabeled cells including KG1a cells. From these studies, an optimized, no wash, immunomagnetic labeling protocol and optimized QMS operating conditions were developed. For an average initial cell concentration of 1.7 x 10(8) total cells, an average 3.96 +/ 0.33 log(10) depletion (range, 3.53-4.34) of CD3(+)CD45(+) cells with a mean 99.43% +/- 4.23% recovery of CD34(+)CD45(+) cells (range, 94.38-104.90%) was achieved at a sorting speed of 10(6) cells/s (n = 6). Limiting dilution assays on the T-cell depleted fractions, which gave a log(10) depletion of 3.51 for the clonable T cells. CONCLUSION: We suggest that this system will provide superior performance with respect to T-cell depletion and CD34(+) recovery for clinical allogeneic bone marrow transplants. Ongoing studies, on a clinical scale, are being conducted to demonstrate this claim. PMID- 17697746 TI - Sites and kinetics of donor thrombopoiesis following transplantation of whole bone marrow and progenitor subsets. AB - INTRODUCTION: Little is known about the sites and kinetics of thrombopoiesis following bone marrow transplant. The spleen is a site of hematopoiesis in a healthy mouse, and hematopoietic activity increases in response to stress. We hypothesized that the spleen is a major site of early post-transplant thrombopoiesis. METHODS: We transplanted whole bone marrow (WBM) or lineage depleted progenitor subsets fractionated based on expression of c-kit and Sca-1 from transgenic mice expressing green fluorescent protein into lethally irradiated C57BL/6 recipients. We also transplanted whole bone marrow cells into healthy and splenectomized mice. Post-transplant megakaryopoiesis was assessed by measuring circulating platelet number, percent donor-derived platelets, bone marrow cellularity, splenic weight, megakaryocyte size, and megakaryocyte concentration from hour 3 to day 28 post transplant. RESULTS: Following transplant, circulating donor-derived platelets were derived only from c-kit expressing subsets. Donor-derived platelets first appeared on post-transplant day five. Splenectomy reduced the number of these earliest circulating platelets. Splenic megakaryopoiesis increased dramatically from day 7-14 post-transplant. However, splenectomy accelerated platelet engraftment during this time frame. CONCLUSION: Overall, these results demonstrate that the first platelets are produced by c-kit expressing megakaryocyte progenitors in the bone marrow and spleen. After post-transplant day 5, the net effect of the spleen on thrombopoiesis is to slow engraftment due to immune effects or hypersplenism. PMID- 17697747 TI - Vocal cord paralysis after vagus nerve stimulator battery replacement successfully treated with medialization thyroplasty. AB - The vagus nerve stimulator (VNS) has been used effectively for partial seizure disorders, however many patients suffer from side effects of alterations in voice. This case describes a new remediable adverse effect of the VNS. A patient with medically intractable epilepsy had improvement of his seizure control with VNS therapy after titrating him to a high output and rapid cycling paradigm with essentially no side effects. After a battery replacement, he was restarted on his previous settings and subsequently developed a hoarse voice. He was found to have complete left vocal cord paralysis, an adverse effect attributed to a rapid titration to his previous high output and rapid cycling paradigm. This side effect has not been previously described in the literature. The patient subsequently had a medialization thyroplasty with resolution of his hoarse voice. PMID- 17697748 TI - Bisphosphonates in cancer therapy. AB - Bisphosphonates are the standard of care in the treatment of malignant bone diseases, because of their ability to inhibit osteoclast-mediated bone destruction. We review here preclinical evidence that bisphosphonates also exert direct antitumour effects and antiangiogenic properties. Furthermore, we describe new insights on how bisphosphonates may act synergistically in combination with antineoplastic drugs or gammadelta T cells to exhibit antitumour activity. These findings reveal new exciting possibilities to fully exploit the antitumour potential of bisphosphonates in the clinical practice. PMID- 17697749 TI - Enhancement of electrokinetic remediation of arsenic spiked soil by chemical reagents. AB - An enhanced electrokinetic remediation process for removal of arsenic, presented as As(V) form, from spiked soil has been investigated with groundwater (GW) and chemical reagents of cetylpyridinium chloride (CPC, a cationic surfactant), ethylenediaminetetraacetic acid (EDTA) and citric acid (CA) under potential gradient of 2.0-3.3V/cm for 5 days treatment. The removal efficiency of As(V) in EK-EDTA system was better than that in other two EK systems. As potential gradient increased from 2.0V/cm to 3.0V/cm, the removal efficiency of As(V) was increased from 35.4% to 44.8% in EK-EDTA system. It showed that the arsenic removal could be enhanced by selecting suitable chemical reagent and increasing potential gradient. The intensive of electroosmotic flow towards the cathode caused a significant retardation of electromigration of arsenic towards the anode. The quantity of As(V) collected in anode reservoir was 1.4-2.5 times greater than that in cathode reservoir for all EK systems. It implied that As(V) removal was directly related to the electromigration rather than electroosmosis mechanism in EK systems. A further investigation need to be conducted to achieve higher removal efficiency of As(V). PMID- 17697750 TI - Energy-loss near-edge structure (ELNES) and first-principles calculation of electronic structure of nickel silicide systems. AB - The electronic structures of nanometre-sized nickel silicide systems, Ni(2)Si and NiSi, have been studied by energy-loss near-edge structure (ELNES) and first principles band structure calculations. Experimental ELNES of Ni L(3)- and Si L(2,3)-edges could be explained well using theoretical spectra calculated for the ground state without the core hole, suggesting metallic properties for both silicides. It was shown that a slight difference in ELNES spectra of Ni(2)Si and NiSi comes from the coupling among the Ni d and Si p, d states in the unoccupied bands. The density of states and the contour plots of all the valence electron densities for Ni(2)Si, NiSi together with NiSi(2) show that Ni(2)Si has the bond with the strongest covalent character between Ni and Si atoms and the most transition metal-like character of the Ni 3d band among the three silicides. PMID- 17697752 TI - Fasciola hepatica: an assessment on the vectorial capacity of Radix labiata and R. balthica commonly found in Belgium. AB - A previous study conducted in Belgium revealed that genetic material of Fasciola sp. was present in snail species belonging to the genus Radix. Here, these snails were collected and identified by DNA-based techniques as Radix labiata and Radix balthica. These two species and Galba truncatula (the major intermediate host in Europe) were experimentally infected with Fasciola hepatica. The resulting metacercariae were fed to rats and the infection was monitored using several techniques. Microscopy revealed the presence of larval stages in 78.3, 45, and 6.25% of G. truncatula, R. labiata, and R. balthica snails, respectively. These results were confirmed by a PCR that amplifies a Fasciola sp. specific sequence. Furthermore, this PCR was found to be more sensitive than microscopic examination. R. labiata shed fewer metacercariae than G. truncatula but these were as infective to rats as those shed by G. truncatula. This study demonstrates that R. labiata may act as an incidental intermediate host for F. hepatica in Belgium. PMID- 17697751 TI - Proteolytic activity in salivary gland products of sheep bot fly (Oestrus ovis) larvae. AB - This study identified and characterized hydrolytic enzymes in salivary gland products of Oestrus ovis larvae. Third instars were collected from the heads of slaughtered goats. Salivary glands were extracted, their products obtained by centrifugation and the enzymatic profile determined. Optimum pH, temperature of maximum proteolytic activity, thermal stability, and resistance of salivary gland products were determined on collagen and subclasses of proteases were identified using protease inhibitors. Zymograms were used to determine the molecular weight of proteases. Antigenic protein bands were revealed by immunoblotting using sera obtained from experimentally infested goats. Seven positive enzymatic activities were detected in salivary gland products: acid phosphatase, naphthol-AS-BI phosphohydrolase, esterase (C4), esterase lipase (C8), leucine arylamidase, alpha glucosidase and N-acetyl-beta-glucosaminidase. Optimum pH for proteolytic activity was 8.0; proteolytic activity increased with temperature (10-50 degrees C) then drastically decreased at 60 degrees C. Proteases in O. ovis salivary gland products belong to the serine subclass. In Zymograms, bands of proteolytic activity were detected in the 20-63 kDa range; the immunoblot showed three antigenic bands, one of them related to a protease band (63 kDa). Serine proteases in O. ovis salivary gland products are most likely involved in larval nutrition and host immuno-modulation. PMID- 17697753 TI - In vitro detection of benzimidazole resistance in Haemonchus contortus: egg hatch test versus larval development test. AB - The present study was designed to compare the egg hatch test (EHT) and the larval development test (LDT) as in vitro tools for detection of benzimidazole (BZ) resistance in Haemonchus contortus, a nematode parasite of small ruminants. Comparisons were made during a course of infection and changes in both EHT and LDT were monitored to measure the correlation between resistance and susceptibility in different parasite stages (eggs and larvae). In addition, mixed doses of known numbers of susceptible and BZ-resistant H. contortus eggs were used to assess the sensitivity of LDT for the detection of low levels of resistance. The degree of resistance for each test was expressed as resistance factor (RF). The LDT showed a greater ability to distinguish between four susceptible and four resistant isolates of H. contortus with higher resistance factors compared to the EHT. For the EHT the RF by using ED(50) criterion ranged from 3.2 to 13.3 and from 7.4 to 25.2 by using LC(99). For LDT the resistant isolates were 4.3-63.1 times more tolerant than the susceptible isolates using the ED(50) criterion and 91.1-1411.0 times more tolerant using the LC(99) criterion. The LDT was also able to clearly indicate the presence of low level (4%) of resistant larvae amongst a susceptible background population. PMID- 17697754 TI - Humoral immune response in pregnant heifers inoculated with Neospora caninum tachyzoites by conjunctival route. AB - The aim of this study was to compare systemic humoral immune responses in pregnant heifers inoculated with Neospora caninum tachyzoites by conjunctival and intravenous routes. Twenty nine heifers separated in three experimental groups were studied: Group 1 (n=10 animals) and Group 2 (n=9 animals) were inoculated with 10(8) of N. caninum tachyzoites by conjunctival and intravenous routes at 5th month of gestation, respectively; Group 3 (n=10 animals) were non-inoculated control animals. An indirect fluorescent antibody test (IFAT) and western immunoblotting (IB) were used to analyze the humoral immune response. All animals from Group 1 developed N. caninum specific antibody responses after conjunctival inoculation recording the highest antibody titer (mean+/-SE: 160+/-49.9) at 6th month of gestation. There were statistical differences between humoral immune responses found in Group 1 and 2 being higher in the second one at 6.5th, 8.5th and 9th months of gestation (P<0.05). Interestingly, all heifers from Group 1 reverted to seronegative status at the end of gestation. No increase in antibody was detected in the uninfected control group. Same pattern of N. caninum antigens was recognized by sera from heifers inoculated by conjunctival route and heifers inoculated by intravenous route. Recognized antigens were 116, 92, 84, 77, 45, 40, 25-26 and 17-18 kDa. The conjunctival instillation of N. caninum tachyzoites in pregnant heifers induces specific systemic antibodies. Further work is needed in order to clarify the consequences of this novel experimental route of infection not only on the fetus but also on the dam. PMID- 17697755 TI - The human mind development as a reaction to improvements in memory: possible consequences on sleep, dreams and psychiatric disorders. PMID- 17697756 TI - Cooperative behaviour and cooperative breeding: what constitutes an explanation? PMID- 17697757 TI - Integrating cooperative breeding with general mechanisms enforcing cooperation: comments and further directions. PMID- 17697758 TI - Study on colon-specific pectin/ethylcellulose film-coated 5-fluorouracil pellets in rats. AB - The purpose of the present study is to assess the biodistribution and pharmacokinetics of pectin/ethylcellulose film-coated and uncoated pellets containing 5-fluorouracil (5-FU) in rats. Both coated and uncoated pellets were orally administered to the rats at a dosage equivalent to 15mg/kg. 5-FU concentrations in different parts of the gastrointestinal (GI) tract and plasma were quantitatively analyzed using a high-performance liquid chromatography (HPLC) assay. 5-FU released from uncoated pellets mainly distributes in the upper GI tract, however, 5-FU released from coated pellets mainly distributes in the cecum and colon. In plasma, the observed mean C(max) from the coated pellets group (3.65+/-2.3microg/mL) was lower than that of the uncoated pellets group (23.54+/-2.9microg/mL). The AUC values obtained from the uncoated pellets and the coated pellets were 49.08+/-3.1 and 9.06+/-1.2microgh/mL, respectively. The relatively high local drug concentration with prolonged exposure time provides a potential to enhance anti-tumor efficacy with low systemic toxicity for the treatment of colon cancer. PMID- 17697759 TI - Metabolic aspects of the extreme longevity. AB - Starting from young to very old subjects, aging is associated with a progressive remodeling. Such an age-dependent remodeling process mainly affects anthropometrics, endocrine and thus, also metabolic factors. Interestingly, it occurs in some individuals successfully, while in others unsuccessfully. Centenarians in good health conditions are a very selected group of subjects representing an exceptional condition. Why the centenarians reach the extreme human life span is still unknown. Thus, in this article we will review the best known causes of age-related insulin resistance, outline the main metabolic differences between aged subjects and healthy centenarians, underline the clinical relevance of insulin resistance in the elderly and finally, we will try to propose a unifying hypothesis for explaining the development of insulin resistance with aging. PMID- 17697760 TI - Quantitative analysis of iridoids, secoiridoids, xanthones and xanthone glycosides in Gentiana lutea L. roots by RP-HPLC and LC-MS. AB - The here described HPLC-method enables the determination of all major, currently known bioactive compounds in gentian roots. A separation of iridoids (loganic acid), secoiridoids (swertiamarin, gentiopicroside, amarogentin, sweroside), xanthones (gentisin, isogentisin) and two xanthone glycosides (gentiosides) was possible on RP-18 column material, using 0.025% aqueous TFA, acetonitrile and n propanol as mobile phase. The method is sensitive (LOD or = 5 cm and verbal numeric pain score > or = 6/10) were given CSE for labor analgesia with intrathecal plain bupivacaine and fentanyl 15 microg. The initial dose of bupivacaine was 1.75 mg. Doses were varied in a 0.25-mg testing interval according to a method of sequential allocation designed to cluster the dose around the ED95. Effectiveness was defined as a verbal numeric pain score < or = 1 within 10 min of intrathecal injection. RESULTS: There was a 100% response rate to the 1.75-mg dose (95% CI 84.6-100.0%) and an 85.0% response rate to 1.50 mg (95% CI 64.0-95.8%). The ED95 for intrathecal plain bupivacaine with fentanyl 15 microg in active labor was 1.66 mg (95% CI 1.50-482.5 mg). The incidence of fetal bradycardia was 7.5%. The incidence of pruritus was 55%. No patient experienced motor block. CONCLUSIONS: This is the first dose-finding study specifically designed to estimate the ED95 of intrathecal bupivacaine combined with a fixed amount of fentanyl for analgesia in active labor. The combination of bupivacaine 1.75 mg with fentanyl 15 microg rapidly and reliably alleviated pain in the active phase of labor. PMID- 17697772 TI - The removal of As(III) and As(V) from aqueous solutions by waste materials. AB - The use of different waste materials such as Atlantic Cod fish scale, chicken fat, coconut fibre and charcoal in removing arsenic [As(III) and As(V)] from aqueous solutions was investigated. Initial experimental runs, conducted for both As(III) and As(V) with the aforementioned materials, demonstrated the potential of using Atlantic Cod fish scale in removing both species of arsenic from aqueous streams. Therefore, the biosorbent fish scale was selected for further investigations and various parameters such as residence time, adsorbent dose, initial concentration of adsorbate, grain size of the adsorbent and pH of the bulk phase were studied to establish optimum conditions. The maximum adsorption capacity was observed at pH value 4.0. The equilibrium adsorption data were interpreted by using both Freundlich and Langmuir models. Rapid small-scale column tests (RSSCT) were also performed to determine the breakthrough characteristics of the arsenic species with respect to packed biosorbent columns. PMID- 17697773 TI - Continuous deodorization and bacterial community analysis of a biofilter treating nitrogen-containing gases from swine waste storage pits. AB - A biofilter inoculated with Arthrobacter sp. was applied to the simultaneous elimination of trimethylamine (TMA) and ammonia (NH3) from the exhaust air of swine waste storage pits. The results showed that the biofilter achieved average removal efficiencies of 96.8+/-2.5% and 97.2+/-2.3% for TMA and NH3, respectively. A near-neutral pH (7.3-7.4) was maintained due to the accumulation of acid metabolites and the adsorption of alkaline NH3. Low moisture demand, low pressure drop and high biofilm stability in the system were other advantages. After long-term operation, the bacterial community structure showed that at least twenty-five bands were explicitly detected by a denaturing gradient gel electrophoresis (DGGE) method. However, the inoculated Arthrobacter sp. still maintained a dominant population (>50%). Paracoccus denitrificans' presence in the biofilter could play an important role in oxidizing NH3 and reducing nitrite by heterotrophic nitrification and anaerobic denitrification. PMID- 17697774 TI - Cadmium and zinc removal from aqueous solutions by Bacillus jeotgali: pH, salinity and temperature effects. AB - Effects of pH, salinity and temperature on biosorption of Cd and Zn by bacteria Bacillus jeotgali strain U3 were evaluated in batch experiments. Traditional and Subsequent Addition Methods (SAM) were used to carry out the bioassays. Sorption of metals was higher when pH or temperature was increased, or when salinity was reduced. The Langmuir isotherm better fit the biosorption data for Cd, while the Freundlich model fitted better for Zn biosorption. A comparison with similar biosorbents suggested that Bacillus jeotgali strain U3 could be considered a good biosorbent for Cd and Zn recovery. PMID- 17697775 TI - Application of biodegradable natural polymers for flocculated sedimentation of clay slurry. AB - Tamarind seed kernel powder (TSKP) is a cheap starchy biodegradable material that has not been tested before for its flocculating properties. Sedimentation of clay slurry has been studied using this material. We have also done experiments with chemical grade starch and its blends with TSKP and compared their performance with that of potash alum for sedimentation of the clay slurry. The sedimentation phenomenon showed constant and falling rate zones. Sedimentation velocity, mass flux and concentration have been calculated at different time intervals for all the flocculants. Among the three types of natural flocculants, starch showed the highest rate constant in the constant rate zone and TSKP offers faster sedimentation in the falling rate zone. Thus TSKP, starch and their blends are potentially attractive environmentally benign flocculants. A qualitative explanation of the flocculating property of TSKP has been given. PMID- 17697776 TI - Antibacterial characteristics and activity of acid-soluble chitosan. AB - The antibacterial activity of chitosan was investigated by assessing the mortality rates of Escherichia coli and Staphylococcus aureus based on the extent of damaged or missing cell walls and the degree of leakage of enzymes and nucleotides from different cellular locations. Chitosan was found to react with both the cell wall and the cell membrane, but not simultaneously, indicating that the inactivation of E. coli by chitosan occurs via a two-step sequential mechanism: an initial separation of the cell wall from its cell membrane, followed by destruction of the cell membrane. The similarity between the antibacterial profiles and patterns of chitosan and those of two control substances, polymyxin and EDTA, verified this mechanism. The antibacterial activity of chitosan could be altered by blocking the amino functionality through coupling of the chitosan to active agarose derivatives. These results verify the status of chitosan as a natural bactericide. PMID- 17697777 TI - Coffee oil as a potential feedstock for biodiesel production. AB - A preliminary evaluation of the feasibility of producing biodiesel using oil extracted from defective coffee beans was conducted as an alternative means of utilizing these beans instead of roasting for consumption of beverage with depreciated quality. Direct transesterifications of triglycerides from refined soybean oil (reference) and from oils extracted from healthy and defective coffee beans were performed. Type of alcohol employed and time were the reaction parameters studied. Sodium methoxide was used as alkaline catalyst. There was optimal phase separation after reactions using both soybean and healthy coffee beans oils when methanol was used. This was not observed when using the oil from defective beans which required further processing to obtain purified alkyl esters. Nevertheless, coffee oil was demonstrated to be a potential feedstock for biodiesel production, both from healthy and defective beans, since the corresponding oils were successfully converted to fatty acid methyl and ethyl esters. PMID- 17697778 TI - Optimization of acetic acid production from synthesis gas by chemolithotrophic bacterium--Clostridium aceticum using statistical approach. AB - Efforts in optimizing reducing agents, cysteine-HCl.H2O and sodium sulfide in order to attain satisfactory responses during acetic acid fermentation have been carried out in this study. Cysteine-HCl.H2O each with five concentrations (0.00 0.50 g/L) was optimized one at a time and followed by sodium sulfide component (0.00-0.50 g/L). Response surface methodology (RSM) was used to determine the optimum concentrations of cysteine-HCl.H2O and sodium sulfide. The statistical analysis showed that the amount of cells produced and efficiency in CO conversion were not affected by sodium sulfide concentration. However, sodium sulfide is required as it does influence the acetic acid production. The optimum reducing agents for acetic acid fermentation was at 0.30 g/L cysteine-HCl.H2O and sodium sulfide respectively and when operated for 60 h cultivation time resulted in 1.28 g/L acetic acid production and 100% CO conversion. PMID- 17697779 TI - Controversies in the use of sentinel nodes: microinvasion, post surgery and after preoperative systemic treatment. AB - In the past 10 years, sentinel lymph node biopsy (SLNB) has become a safe and accurate method for axillary staging. Several recent publications worldwide have been progressively elucidating old controversies. The list of clinical scenarios in which SLNB was initially contraindicated seems to be dwindling as experience with this technique increases. Here we discuss the suitability of SLNB in the settings of microinvasive cancer, after breast or axillary surgery and after neoadjuvant chemotherapy. PMID- 17697780 TI - Follow-up care of patients with breast cancer. AB - In the US, over 200,000 new cases of invasive breast cancer are diagnosed each year, with an additional 60,000 cases of ductal carcinoma in situ. The majority of these women will never experience a recurrence of their disease, and most will survive more than 5 years. Follow-up care for these women is focused on addressing long-term complications of therapy, and early detection of new primary cancers and locoregional recurrences. There is no evidence that early detection of distant metastases will lead to an increase in survival, and currently routine imaging studies are not recommended. With the growing number of breast cancer survivors, further studies should be undertaken to study the cost-effectiveness of surveillance strategies. PMID- 17697781 TI - Structure-activity relationships of 3,4-dihydro-1H-quinazolin-2-one derivatives as potential CDK5 inhibitors. AB - Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that plays a critical role in the early development of the nervous system. Deregulation of CDK5 is believed to contribute to the abnormal phosphorylation of various cellular substrates associated with neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and ischemic stroke. Acyclic urea 3 was identified as a potent CDK5 inhibitor and co-crystallographic data of urea 3/CDK2 enzyme were used to design a novel series of 3,4-dihydroquinazolin 2(1H)-ones as CDK5 inhibitors. In this investigation we present our synthetic studies toward this series of compounds and discuss their biological relevance as CDK5 inhibitors. PMID- 17697782 TI - Concentration of radiocaesium 137Cs and 134Cs in sediments of the Malaysian marine environment. AB - The concentrations of 137Cs and 134Cs in Malaysian marine sediments were measured by gamma-ray spectrometry with a high-purity germanium (HPGe) detector connected to a multichannel analyzer. In general, the 137Cs concentration in Malaysian marine sediments has been found to be very low and less than 5 Bq/kg dry weight with the exception of those from a few sampling locations. The concentration of 134Cs was found to be less than the minimum detectable activity for the measuring condition used. Data reported in this paper were found to be comparable with results from within the region and thus can be used as reference data for the country. PMID- 17697783 TI - Comparative analysis of peripheral and localised cytokine secretion in glioblastoma patients. AB - BACKGROUND: Malignant gliomas are the most common primary brain tumours of both children and adults. The unique aspects of their biology and anatomic site render them refractory to conventional therapeutic strategies such as surgery and chemotherapy. Significant attention has been given, recently, to immunotherapy which, although promising in preclinical studies, has not yet enhanced the survival of patients with glioblastomas. METHODS: To further understand the immunobiology of glioblastomas in clinical settings, we examined the secretion of four main cytokines in the peripheral blood and in primary cell cultures of 33 human glioblastoma patients. An ELISPOT methodology was used for the first time to examine Th1, and Th2 cytokine secretion from both peripheral lymphocytes and glioma tumour cells. RESULTS: Th1 cytokines (tumour necrosis factor (TNF-alpha), interferon (IFN-gamma) were markedly reduced compared to control levels (P=0.01 and P<0.001, respectively), whereas in contrast, Th2 (interleukin (IL)-4 and IL 10) were strongly expressed in both peripheral lymphocytes and glioma cell cultures (P=0.05 and P<0.001, respectively). CONCLUSION: This pattern indicates an 'immunosuppressive status' in glioblastomas which is related to their origination and the evasion of glioma cells from immune surveillance and could account for the failure of immunotherapy in such tumours. Furthermore, ELISPOT methodology can be used for monitoring of cytokine secretion from tumour cells, in addition to the well-established peripheral cytokine secretion. PMID- 17697784 TI - The AviD-tag, a NeutrAvidin/avidin specific peptide affinity tag for the immobilization and purification of recombinant proteins. AB - The widespread success of affinity tags throughout the biological sciences has prompted interest in developing new and convenient labeling strategies. Affinity tags are well-established tools for recombinant protein immobilization and purification. More recently these tags have been utilized for selective biological targeting towards multiplexed protein detection in numerous imaging applications as well as for drug-delivery. Recently, we discovered a phage display selected cyclic peptide motif that was shown to bind selectively to NeutrAvidin and avidin but not to the structurally similar streptavidin. Here, we have exploited this selectivity to develop an affinity tag based on the evolved DRATPY moiety that is orthogonal to known Strep-tag technologies. As proof of principle, the divalent AviD-tag (Avidin-Di-tag) was expressed as a Green Fluorescent Protein variant conjugate and exhibited superior immobilization and elution characteristics to the first generation Strep-tag and a monovalent DRATPY GFP-fusion protein analogue. Additionally, we demonstrate the potential for a peptide based orthogonal labeling strategy involving our divalent AviD-tag in concert with existing streptavidin-based affinity reagents. We believe the AviD tag and its unique recognition properties will provide researchers with a useful new affinity reagent and tool for a variety of applications in the biological and chemical sciences. PMID- 17697785 TI - Heterologous expression of new antifungal chitinase from wheat. AB - Chitinases (EC 3.2.1.14) have been grouped into seven classes (class I-VII) on the basis of their structural properties. Chitinases expressed during plant microbe interaction are involved in defense responses of host plant against pathogens. In the present investigation, chitinase gene from wheat has been subcloned and overexpressed in Escherichia coli BL-21 (DE3). Molecular phylogeny analyses of wheat chitinase indicated that it belongs to an acidic form of class VII chitinase (glycosyl hydrolase family 19) and shows 77% identity with other wheat chitinase of class IV and low level identity to other plant chitinases. The three-dimensional structural model of wheat chitinase showed the presence of 10 alpha-helices, 3 beta-strands, 21 loop turns and the presence of 6 cysteine residues that are responsible for the formation of 3 disulphide bridges. The active site residues (Glu94 and Glu103) may be suggested for its antifungal activity. Expression of chitinase (33 kDa) was confirmed by SDS-PAGE and Western hybridization analyses. The yield of purified chitinase was 20 mg/L with chitinase activity of 1.9 U/mg. Purified chitinase exerted a broad-spectrum antifungal activity against Colletotrichum falcatum (red rot of sugarcane) Pestalotia theae (leaf spot of tea), Rhizoctonia solani (sheath blight of rice), Sarocladium oryzae (sheath rot of rice) Alternaria sp. (grain discoloration of rice) and Fusarium sp. (scab of rye). Due to its innate antifungal potential wheat chitinase can be used to enhance fungal-resistance in crop plants. PMID- 17697786 TI - Socioeconomic position and the metabolic syndrome in early, middle, and late life: evidence from NHANES 1999-2002. AB - PURPOSE: To evaluate whether there is an association between socioeconomic position (SEP) and the metabolic syndrome at various ages, including adolescent, middle-aged and older participants in gender-specific analyses. METHODS: Participants were from the 1999-2002 National Health and Nutrition Examination Survey. SEP was measured by income and years of education. Metabolic syndrome was measured in adults using the American Heart Association guidelines and in adolescents using methods based on national reference data. Cross-sectional multivariable-adjusted logistic regression analyses were performed. RESULTS: In women aged 25 to 45 and 46 to 65 years, income below the poverty line (poverty income ratio [PIR] less than one) was associated with higher odds of metabolic syndrome compared with PIR greater than 3 (odds ratio [OR] = 4.90; 95% confidence interval (CI) = 2.24, 10.71, and OR = 2.54; CI = 1.38, 4.67, for the respective age groups) after adjustment for age, race/ethnicity, and menopause. Similar findings were observed for educational attainment. In adolescents, older adults (aged >65 years), and males, income and education were not related to the metabolic syndrome. CONCLUSIONS: This report demonstrates that SEP is associated with the metabolic syndrome in females aged 25 to 65 years and is less strongly associated in males, adolescents, or older participants. These findings provide physiologic mechanistic evidence linking SEP to risk for coronary heart disease. PMID- 17697787 TI - Blunt trauma as a risk factor for group A streptococcal necrotizing fasciitis. AB - PURPOSE: Anecdotal reports suggest that blunt trauma and seemingly innocuous musculoskeletal injuries (e.g., muscle strains) are risk factors for developing necrotizing fasciitis (NF) and myositis caused by group A Streptococcus and other bacteria; however, this hypothesis has not been tested in analytic epidemiologic studies of invasive group A streptococcal (GAS) disease. We conducted two case control studies to determine whether nonpenetrating trauma is a risk factor for either NF or severe cellulitis caused by GAS. METHODS: A secondary analysis of patients who were hospitalized throughout Florida for invasive GAS disease during a 4-year period was conducted. Two case series were used. The first series comprised patients who had severe GAS cellulitis. The second were patients who had GAS NF. Case-patients were compared to a single control series composed of patients with invasive GAS disease not including either NF or cellulitis (e.g., primary bacteremia, septic arthritis). RESULTS: After we adjusted for age, race, and clindamycin usage, GAS NF cases were 5.97 times as likely as controls to have a recent history of blunt trauma (p = 0.04). Patients with severe cellulitis were not more likely than controls to have associated blunt trauma. CONCLUSIONS: Nonpenetrating trauma is significantly associated with the development of GAS NF. PMID- 17697788 TI - The feeling of fluent perception: a single experience from multiple asynchronous sources. AB - Zeki and co-workers recently proposed that perception can best be described as locally distributed, asynchronous processes that each create a kind of microconsciousness, which condense into an experienced percept. The present article is aimed at extending this theory to metacognitive feelings. We present evidence that perceptual fluency-the subjective feeling of ease during perceptual processing-is based on speed of processing at different stages of the perceptual process. Specifically, detection of briefly presented stimuli was influenced by figure-ground contrast, but not by symmetry (Experiment 1) or the font (Experiment 2) of the stimuli. Conversely, discrimination of these stimuli was influenced by whether they were symmetric (Experiment 1) and by the font they were presented in (Experiment 2), but not by figure-ground contrast. Both tasks however were related with the subjective experience of fluency (Experiments 1 and 2). We conclude that subjective fluency is the conscious phenomenal correlate of different processing stages in visual perception. PMID- 17697789 TI - Acute hepatic injury in four children with Dravet syndrome: valproic acid, topiramate or acetaminophen? AB - We describe four children with Dravet syndrome treated with the combination of valproic acid (VPA) and topiramate (TPM) who developed transient liver toxicity. The time-interval between fever, administration of acetaminophen, epileptic status and liver enzyme disturbances in our four cases suggests that accumulation of toxic acetaminophen-metabolites is possibly responsible for liver toxicity. If acetaminophen and its metabolites cause those liver problems in children treated with the combination of VPA and TPM, the advice to use acetaminophen for treating fever in children using this combination, should be changed. Only future clinical observations and research can solve this clinical dilemma. PMID- 17697790 TI - Valproate decreases EEG synchronization in a use-dependent manner in idiopathic generalized epilepsy. AB - INTRODUCTION: In order to explore the mechanism of action of valproate (VPA) in idiopathic generalized epilepsy (IGE), the effect of VPA on cortical EEG activity was investigated. HYPOTHESIS: VPA decreases EEG synchronization in the delta and theta frequency bands in a use-dependent manner in IGE patients. METHODS: First setting: EEG records of 17 untreated IGE patients (NAE group) were analyzed and compared to those of 15 healthy controls (NC group). Second setting: EEG recorded in the untreated condition (NAE) was compared to the EEG recorded in the treated condition (VPA) of the patient group. Technique and analysis: 2 min of eyes closed, waking EEG background activity (without epileptiform potentials and artifacts) were analyzed. Absolute power (AP) and mean frequency (MF) were computed for 19 electrodes and four frequency bands (delta=1.5-3.5 Hz, theta=3.5 7.5 Hz, alpha=7.5-12.5 Hz, beta=12.5-25.0 Hz). Log-transformed data entered further analysis. Group differences were computed by means of parametric statistics including correction for multiple comparisons. The VPA-related changes (APvpa-APnae) were correlated with the degree of the baseline abnormality (APnae) and the daily dose/serum levels of VPA. MAIN RESULTS: Statistically significant (p<0.05, corrected) changes in the first setting: diffuse delta, theta, alpha AP increase, mainly right hemispheric beta AP increase was found in the NAE group, as compared to the NC group. Second setting: VPA decreased delta and theta AP. Strong correlation was demonstrated between the degree of the initial AP abnormality and the VPA-related AP decrease. AP decrease did not correlate with the daily dose and the serum level of the drug. CONCLUSION: The hypothesis that VPA decreased EEG synchronization in the delta and theta frequency bands in a use dependent manner was supported. The findings contribute to the understanding of the action of VPA at the network level. PMID- 17697791 TI - Circulating insulin-like growth factors and related binding proteins are selectively altered in amyotrophic lateral sclerosis and multiple sclerosis. AB - OBJECTIVE: To provide a detailed profile of the peripheral IGF system in the neurological conditions; amyotrophic lateral sclerosis (ALS), post polio syndrome (PPS) and multiple sclerosis (MS). To determine whether subsets of patients within the disease groups could be identified in whom one or more components of the IGF regulatory system are altered compared to healthy control subjects matched for age, sex and BMI. DESIGN: Three cohorts of patients were recruited, 28 with ALS, 18 with PPS and 23 with MS. Patients were individually matched to a healthy control based on sex, age (+/-3 yr), and BMI (+/-2.5 kg m(-2)). The concentration (ng/ml) of serum IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and acid-labile subunit (microg/ml) was determined by IRMA. RESULTS: In ALS patients, there was an increase of 11% in [IGF(TOTAL)] (p=0.042) ([IGF(TOTAL)]=[IGF-I]+[IGF II]) and [IGFBP-1] was decreased by 34% (p=0.050) compared to matched controls. In "surviving" ALS patients, defined as those ALS patients with long disease duration (+2 SD from the mean survival time for Irish patients post diagnosis), there was an increase in [IGF-I] 36% (p=0.032) and a large decrease in [IGFBP-1] 58% (p=0.020) compared to controls. These differences were not evident in pre agonal ALS patients. The concentration of serum IGF-I was 38% (p=0.018), acid labile subunit 17% (p=0.044) and IGFBP-2 43% (p=0.035) higher in MS patients compared to controls. When stratified for interferon-beta (IFN-beta) use, we observed an increase in serum [IGF-I] 52% (p=0.013) and [IGF(TOTAL)] 19% (p=0.043) in MS patients undergoing IFN-beta treatment, but MS patients not undergoing IFN-beta treatment had similar IGF and IGFBP concentration to controls. Serum [IGFBP-3] 18% (p=0.033), [IGFBP-2] 86% (p=0.015) and (acid-labile subunit) 33% (p=0.012) was also higher in IFN-beta patients compared to controls. Stratified by stage of disease the most significant increase in components of the peripheral IGF system was attributed to relapsing-remitting MS patients treated with IFN-beta. All components of the peripheral IGF system in PPS patients were similar to controls. CONCLUSIONS: The increase in circulating IGF-I and a reduction in regulatory binding protein IGFBP-1 in ALS patients with a "stable" disease profile suggest a potential change in peripheral IGF bioavailability in these subjects. In MS, we report a change in a number of components of the peripheral IGF system, the observed increase in IGF-I in patients treated with IFN-beta being of most significance as a potential therapeutic biomarker. PMID- 17697792 TI - Brain death with calcium oxalate deposition in the kidney: clue to the diagnosis of ethylene glycol poisoning. AB - A young man presented to the emergency department with mental status changes, severe metabolic acidosis, and oliguria. Acute ethylene glycol intoxication was diagnosed. The patient suffered clinical brain death three days after admission despite intensive care and continuous hemodiafiltration. The patient died one month after admission. Autopsy revealed acute tubular necrosis of the kidneys with significant calcium oxalate depositions. The brain was markedly softening and with chronic meningoencephalitis and dural sinus thrombosis. We considered that the amount and the persistence of the calcium oxalate deposition in the kidney may afford a best clue to the postmortem diagnosis of ethylene glycol poisoning even in the chronic stage. PMID- 17697793 TI - Motor unit potential characterization using "pattern discovery". AB - Typically in clinical practice, electromyographers use qualitative auditory and visual analysis of electromyographic (EMG) signals to help infer if a neuromuscular disorder is present and if it is neuropathic or myopathic. Quantitative EMG methods exist that can more accurately measure feature values but require qualitative interpretation of a large number of statistics. Electrophysiological characterization of a neuromuscular system can be improved through the quantitative interpretation of EMG statistics. The aim of the present study was to compare the accuracy of pattern discovery (PD) characterization of motor unit potentials (MUPs) to other classifiers commonly used in the medical field. In addition, a demonstration of PD's transparency is provided. The transparency of PD characterization is a result of observing statistically significant events known as patterns. Using clinical MUP data from normal subjects and patients with known neuropathic disorders, PD achieved an error rate of 30.3% versus 29.8% for a Naive Bayes classifier, 30.1% for a Decision Tree and 29% for discriminant analysis. Similar results were found for simulated EMG data. PD characterization succeeded in interpreting the information extracted from MUPs and transforming it into knowledge that is consistent with the literature and that can be valuable for the capture and transparent expression of clinically useful knowledge. PMID- 17697794 TI - Inhomogeneity of tissue-level strain distributions in individual trabeculae: mathematical model studies of normal and osteoporosis cases. AB - Little is known about the distributions of mechanical strains and stresses in individual trabeculae of cancellous bone, despite evidence that tissue-level strains affect the metabolism of bone. Recently, micro-finite element (micro-FE) studies have provided the first insights into the mechanical conditions in trabeculae, and suggested that osteoporotic cancellous bone experience higher and substantially less-uniform strains with respect to healthy cancellous bone. We may therefore ask whether the inhomogeneity of bone tissue strains is predominantly a consequence of micro-architectural differences between trabeculae, or is it mostly caused by the curvatures of each individual trabecula. Accordingly, the objectives of the present study were to determine the contribution of the shape of a trabecula to the intra-trabecula strain inhomogeneity, and to determine potential differences in intra-trabecula strain inhomogeneities between normal and thinner, osteoporotic-like trabeculae. We employed our previously reported generic single-trabecula model, which is a mathematical representation of the shape of a trabecula based on statistical analyses of mammalian trabecular dimensions. The single-trabecula model was loaded axially and in bending, and strain distributions were calculated for individual trabeculae as well as for "populations" of trabeculae, formed by assigning different trabecular thickness values in the trabecular model, in order to represent the distributions of trabecular shapes in normal and osteoporotic bones. We found that when subjected to equivalent loads, thinner, osteoporotic like individual trabeculae and populations of thin trabeculae developed substantially greater strain inhomogeneities compared with normal trabeculae. We conclude that the intra-trabecula strain inhomogeneities are likely to be an important factor contributing to the overall increased strain inhomogeneity in osteoporotic cancellous bone, as previously observed in micro-FE studies. PMID- 17697795 TI - Effect of recovery intensity on peak power output and the development of heat strain during intermittent sprint exercise while under heat stress. AB - This study compared two intensities of active recovery on intermittent sprint exercise performance and the development of heat strain in hot, humid conditions. Eight male game players completed four Cycling Intermittent Sprint Protocols (CISP) consisting of twenty 2-min periods, each including 10-s passive rest, 5-s maximal sprint against a resistance of 7.5% body mass and 105-s active recovery. The CISP was performed in mean (S.D.) temperate conditions with active recovery intensities of 50% V(O)(2peak) (TEMP50) and 35% V(O)(2peak)(TEMP35) and in hot, humid [35.2 (0.4) degrees C, 80.4 (2.1)% RH] conditions with the same intensities (HOT50 and HOT35, respectively) in a randomised, counterbalanced order. Heat strain (physiological strain index (PSI)) was calculated from rectal temperature and heart rate. All subjects completed the CISP (20 sprints) in TEMP50 and TEMP35. The mean number of sprints completed for HOT50 and HOT35 was 13 (3) and 17 (2), respectively; both of which were lower than TEMP50 and TEMP35 (P<0.01) and different between hot conditions. Reductions in peak power output (PPO) occurred in the TEMP50 and HOT50 by sprint 8 (P<0.05), but in HOT35 a reduction was delayed until sprint 13 (P<0.05). The rate of PSI increase was faster in HOT50 than TEMP50 and HOT35, but peak PSI was not different. By lowering the recovery intensity, one component of the PSI (heart rate) was reduced and intermittent sprint exercise performance was maintained for longer in the heat. PMID- 17697797 TI - Somatotype, size and body composition of competitive female volleyball players. AB - The aim of this study was to describe the morphological characteristics of competitive female volleyball players. For this purpose, body weight and height, breadths and girths as well as skinfold thickness at various body sites were assessed in 163 elite female volleyball players (age: 23.8+/-4.7 years, years of playing: 11.5+/-4.2, hours of training per week: 11.9+/-2.9, means+/-S.D.). Seventy-nine of these players were from the A1 division and the rest from the A2 division of the Greek National League. Two-way ANOVA was used to compare the differences in these characteristics between competition level and playing position. Body height ranged from 161cm to 194cm, and the mean value (177.1+/ 6.5cm) was not inferior to that of international players of similar calibre. Adiposity of these players (sum of 5 skinfolds: 51.8+/-10.2mm, percent body fat: 23.4+/-2.8) was higher than that reported in other studies in which, however, different methodology was used. Volleyball athletes of this study were mainly balanced endomorphs (3.4-2.7-2.9). The A1 division players were taller and slightly leaner with greater fat-free mass than their A2 counterparts. Significant differences were found among athletes of different playing positions which are interpreted by their varying roles and physical demands during a volleyball game. The volleyball players who play as opposites were the only subgroup of players differing between divisions; the A2 opposites had more body fat than A1 opposites. These data could be added in the international literature related to the anthropometric characteristics of competitive female volleyball players. PMID- 17697796 TI - Delay of 6 weeks between aprotinin injections for tendinopathy reduces risk of allergic reaction. AB - Aprotinin is a collagenase inhibitor previously shown to be effective for treating tendinopathies but associated with systemic allergic reactions. This historical cohort study aimed to determine whether or not the injection regime used affected the risk of allergic reaction and outcome. It compared 223 tendinopathy cases (group R) generally treated with a rapid series of aprotinin injections spaced one to two weekly and 158 cases (group D) generally given a single injection or a delay in their repeat injection(s) of over 6 weeks. Side effects and outcome measures were documented by questionnaire with a response rate of 75%. Systemic allergic reactions occurred in 7% of group R cases compared with 2% in group D (NS). Injections given 2-4 weeks after a previous injection were significantly more likely to lead to allergic reactions (6%) than initial injections (0.3%) and injections given >6 weeks after a previous injection (0.9%) (P<0.05). Overall patient rated satisfaction and outcome measures were similar between groups. In summary the current published regime of multiple aprotinin injections over a period of a few weeks has a fairly high rate of systemic allergic reactions. This can be reduced by minimising repeat injections and recommending a delay of at least 6 weeks between injections. Practitioners using aprotinin must have available facilities to treat anaphylaxis. PMID- 17697798 TI - In-utero intervention for severe congenital heart disease. AB - The concept of fetal therapy is well established for many disorders diagnosed before birth but practical issues regarding its introduction into clinical practice are more difficult. Cardiac malformations are common, with major lesions affecting about 3.5 per thousand pregnancies; however, only a small proportion of these is likely to benefit from an intrauterine intervention. In addition, there are no good animal models of human cardiac disease and our knowledge of the underlying mechanisms is at best sketchy. This combination of factors has resulted in slow progress in developing effective therapies for the intrauterine management of cardiac disease. Recent research and clinical developments have included percutaneous valvuloplasty for severe aortic and pulmonary stenosis, perforation of the closed or restrictive inter-atrial septum and pacing for complete heart block. Progress in these endeavours has been variable but - overall - shows promise for treatment of the human fetus. PMID- 17697799 TI - Hand carried echocardiography screening for LV systolic dysfunction in a pulmonary function laboratory. AB - AIMS: Dyspnea is a common indication for pulmonary evaluation but also a common symptom in heart failure. Identification of dyspneic patients with significant LV systolic dysfunction is critical because of high morbidity of untreated heart failure. We sought to determine whether screening patients referred for pulmonary function testing (PFT) using a hand carried ultrasound (HCU) device could identify LV systolic dysfunction. METHODS: Forty-nine subjects were recruited from a pulmonary function lab to undergo a brief echocardiographic examination by an internist using a HCU device. All subjects also received an examination with a full-featured echocardiogram machine as a gold standard. RESULTS: All subjects with normal PFT had normal LV systolic function. Among subjects with abnormal PFT, 6 (15%) had LV systolic dysfunction and the remainder had normal LV systolic function. No subjects with LV systolic dysfunction by full-featured echocardiograms were missed by the HCU (sensitivity 100%, specificity 95%, negative predictive value 100%, positive predictive value 75%). CONCLUSIONS: LV systolic dysfunction is prevalent among patients with pulmonary disease and can be accurately screened for by a physician using a hand carried ultrasound device with subsequent confirmation with complete echocardiography. PMID- 17697800 TI - A novel mathematical model of the sagittal spine: application to pedicle subtraction osteotomy for correction of fixed sagittal deformity. AB - BACKGROUND CONTEXT: The C7 plumb line method oversimplifies the true complexity of the spine. In a previous study, we mathematically modeled the normal spine using the spline function, enabling quantification of previously undescribed measurements such as area under the curve (AUC) and average sagittal position. The spine in fixed sagittal imbalance and the results of surgical correction have not been studied in a similar manner. PURPOSE: To quantitatively evaluate changes in spinal conformation in patients who underwent pedicle subtraction osteotomy (PSO) using measures derived from the spline model and to correlate these changes with functional outcome. STUDY DESIGN: Application of a mathematical model to a cohort of patients who underwent deformity surgery. PATIENT SAMPLE: Thirty-four consecutive patients with fixed sagittal imbalance who underwent PSO from 2001 to 2003. OUTCOME MEASURES: Preoperative and postoperative 22-item Scoliosis Research Society (SRS-22) Outcomes Questionnaire scores were used for functional assessment. METHODS: Radiographs of the 34 patients who underwent thoracic or lumbar PSO with at least 2 years of follow-up were examined at three time points. The posterosuperior aspect of each vertebral body was chosen as a representative point for the spinal sagittal curve. A cubic spline function was derived from these points. From this function, the AUCs and average sagittal positions of the thoracic, lumbar, and thoracolumbar segments were calculated. RESULTS: The average sagittal position does not overlap the C7 plumb line in deformity patients, but is a much more stable measure. In the lumbar PSO cohort, the lumbar AUC and average sagittal position were not significantly different among normal, preoperative, and postoperative groups. The thoracic and thoracolumbar AUCs and average sagittal positions were dramatically more positive in the preoperative cohort compared with normals; these values significantly decreased toward neutrality after lumbar PSO, but remained abnormal. In the thoracic PSO cohort, the lumbar, thoracic, and thoracolumbar AUCs and average sagittal positions were not significantly different among normal, preoperative, and postoperative groups. The changes in thoracolumbar AUC and average sagittal position were better predictors of the SRS-22 total score than the change in C7 plumb line. CONCLUSIONS: The average sagittal position more comprehensively captures the nuances of a nonlinear spinal curve. Subcurve analysis enabled by the spline model is particularly helpful in assessing deformity and surgical correction on a segmental level. Increased sensitivity to the nuances of the spinal curve in this model results in superior correlation with clinical outcomes when compared with the C7 plumb line. We feel that a critical examination of the spinal curve will lead to improved understanding of deformity and planning for an optimal correction. PMID- 17697801 TI - Quantitative changes in the cervical neural foramen resulting from axial traction: in vivo imaging study. AB - BACKGROUND CONTEXT: Cervical traction has a long history as a method of conservative treatment for cervical spine diseases. However, information on quantitative changes in the cervical neural foramen resulting from axial traction in vivo is lacking. PURPOSE: To quantitatively evaluate the changes in the neural foramen of the cervical spine during axial traction in vivo. STUDY DESIGN: A prospective radiographic analysis of the cervical neural foramen of adult volunteers. PATIENT SAMPLE: Fifteen healthy volunteers (10 men, 5 women) without any history of cervical spine disease. OUTCOME MEASURES: The changes in cervical cross-sectional foraminal areas and heights were measured. METHODS: Cervical magnetic resonance (MR) images of the volunteers were taken at the neutral position and were reconstructed in the oblique plane perpendicular to the long axis of each neural foramen from the C2-3 to the C6-7 level. The changes in the neural foraminal dimensions at incremental axial traction forces (0, 5, 10, and 15 kg) were analyzed. RESULTS: After each 5-kg incremental increase in traction weight, there was a significant (p value less than .05) increase in area and height of the intervertebral foramen compared with the position in which no weight was applied. There was an average increase of 5.81%, 16.56%, and 18.9% in the foraminal area and an average increase of 3.75%, 8.67%, and 10.43% in foraminal height compared with the position with no weight at traction of 5, 10, and 15 kg, respectively. There was no statistically significant difference for the increase in foraminal area and height from 10 to 15 kg of traction (p value greater than .05). CONCLUSIONS: There was a significant increase in intervertebral foraminal area and height after each 5-kg increment in traction weight compared with the position in which no weight was applied. From 10 to 15 kg of traction, there was no significant change in the foraminal area and height. PMID- 17697802 TI - Acute cervical osteomyelitis and prevertebral abscess after routine tonsillectomy. AB - BACKGROUND CONTEXT: Tonsillectomy is among the most commonly performed surgical procedures. The development of severe infection after tonsillectomy is a very rare but potentially fatal complication that has not been described in the orthopedic, neurosurgical, or spine literature. PURPOSE: To present acute cervical osteomyelitis and prevertebral abscess formation as a complication of a routine tonsillectomy. STUDY DESIGN: Case report, literature review. METHODS: A case report was prepared on the clinical and radiographic data of a patient presenting with prevertebral abscess and acute cervical osteomyelitis 6 weeks after routine tonsillectomy. A review of relevant literature was additionally performed. RESULTS: The patient presented 6 weeks after tonsillectomy with evidence of a deep cervical infection. Operative debridement with anterior and posterior surgical stabilization was performed. The patient completed a 6-week course of intravenous antibiotics. At 24-month follow-up, the patient showed no signs of infection and demonstrated a stable fusion mass. CONCLUSIONS: The development of prevertebral abscess and acute cervical osteomyelitis has been discussed in a small number of otolaryngology case reports and has not been previously reported in the orthopedic, neurosurgical, or spine literature. Symptoms may be nonspecific, and so a high index of clinical suspicion is needed. Delay in treatment may lead to significant morbidity and even mortality. Successful treatment can be obtained through operative debridement and intravenous antibiotic therapy. PMID- 17697803 TI - Myelopathy in a 6-year-old girl caused by neurofibromatosis Type 1: a case report. AB - BACKGROUND CONTEXT: Even when there is radiological evidence of spinal involvement, young patients with neurofibromatosis Type 1 (NF-1) seldom have symptoms. We report the case of a child who developed rapidly progressive myelopathy. PURPOSE: To describe a technique used to prevent postoperative spinal deformity and instability, after removal of a dumbbell-shaped tumor in a 6-year old child. STUDY DESIGN: Case report. PATIENT SAMPLE: A 6-year-old female. METHODS: Retrospective case review. RESULTS: The patient underwent a resection of the cervical dumbbell tumor using an osteoplastic laminectomy technique to prevent postoperative spinal deformity. At 2-year follow-up, there was no clinical or radiographic evidence of complications or spinal kyphotic deformity. CONCLUSIONS: The case of a 6-year-old girl with cervical myelopathy caused by NF 1 was reported. The tumor was removed after osteoplastic laminectomy, which could prevent postoperative kyphotic deformity. PMID- 17697804 TI - Use of stand-up magnetic resonance imaging for evaluation of a cervicothoracic injury in a patient with ankylosing spondylitis. AB - BACKGROUND CONTEXT: Injuries at the cervicothoracic junction are common in patients with ankylosing spondylitis. These injuries present challenges for both initial and follow-up imagings. PURPOSE: To describe a case of a patient with ankylosing spondylitis who was treated with laminectomy and a cervicothoracic orthosis for a spinal epidural hematoma after a nondisplaced fracture at the cervicothoracic junction and to discuss the merits of stand-up magnetic resonance imaging (MRI) for follow-up evaluation of this type of injury. STUDY DESIGN/SETTING: Case report. METHODS: Clinical data of a patient with ankylosing spondylitis who sustained a nondisplaced C7 fracture are presented, followed by a detailed review of the literature concerning imaging techniques available for the evaluation of cervical spine trauma in this patient population. RESULTS: The patient was treated with emergent laminectomy and evacuation of the epidural hematoma, followed by definitive management in a cervicothoracic orthosis secondary to medical comorbidities. The patient was then successfully followed postoperatively with stand-up MRI because conventional imaging techniques could not adequately image the injury level in an upright position. CONCLUSIONS: Cervicothoracic injuries are common in patients with ankylosing spondylitis and may be difficult to follow with conventional imaging techniques. Stand-up MRI is a relatively new modality that may offer significant advantages over conventional imaging because of the ability to evaluate the cervicothoracic junction in a more functional position and the lack of a confining space such as that found in standard MRI units. PMID- 17697805 TI - Fast urinary screening for imipramine and desipramine using on-line solid-phase extraction and selective derivatization. AB - A continuous-flow configuration based on sequential solid-phase extraction and derivatization is proposed for the screening of urine samples for imipramine and related metabolites. For the first time, a 50/50 (v/v) methanol/nitric acid mixture is used as both eluent and derivatizing reagent. Sample aliquots are injected into the flow manifold and driven by a water stream to an RP-C(18) column where the drugs are quantitatively retained. Following clean-up step with 40/60 (v/v) methanol/water, the eluent/derivatizing reagent is injected and passed through the sorbent column, eluted drugs reacting with nitric acid to form a blue dye that is monitored at 600 nm. The global signal thus obtained for the antidepressants can be used to estimate their total concentration in the samples without the need to individually quantify the analytes. This total index can be used for timely decision-making in case of overdosage. The proposed method is sensitive and selective; thus, typical interferents such as endogenous and diet compounds have no substantial effect on the analytical signal. This allows imipramine and its metabolites to be determined at therapeutic levels in urine samples. PMID- 17697806 TI - Effectiveness of workload at the heart rate of 100 beats/min in predicting cardiovascular mortality in men aged 42, 48, 54, or 60 years at baseline. AB - The magnitude of work an individual is able to perform at the heart rate (HR) of 100 beats/min (WL(100)) is a simple, integrated measure of HR at rest, HR response to light dynamic exercise, as well as cardiorespiratory performance. Because a high HR at rest and a low cardiorespiratory performance are previously established risk factors for cardiovascular disease (CVD) mortality, it can be deduced that WL(100) is a potential predictor of CVD and coronary heart disease (CHD) mortality. The aim of the present study was to investigate whether WL(100) independently predicts CVD and CHD mortality in middle-aged men. The subjects were a representative sample of 1,314 middle-aged men who did not have CHD and did not use HR-lowering medication at baseline. The association of WL(100) with CVD and CHD mortality was examined by Cox regression models with backward stepwise selection, including numerous known risk factors for CVD death. During an average follow-up of 11.5 years, there were 51 CVD deaths, of which 35 were due to CHD. In Cox multivariable models, CVD mortality increased by 72% (95% confidence interval 27% to 138%, p = 0.001) and CHD mortality by 89% (95% confidence interval 28% to 178%, p = 0.001) with 1 SD (31 W) decrement in WL(100). WL(100) improved the predictive power of the adjusted Cox models, including other HR-derived and exercise test variables. In conclusion, WL(100) predicts CVD and CHD mortality in men without previous CHD. The association of WL(100) with CVD and CHD mortality is not explained by maximal cardiorespiratory performance. PMID- 17697807 TI - High molecular weight adiponectin as a predictor of long-term clinical outcome in patients with coronary artery disease. AB - Adiponectin is an adipocyte-specific secretory protein that is highly and specifically expressed in adipose tissue, and low plasma levels of adiponectin are associated with coronary artery disease (CAD). It has been suggested that high molecular weight (HMW) adiponectin is more important for vascular protection than total amount of adiponectin. To establish the clinical relevance of HMW adiponectin, we measured its serum levels in 149 patients with CAD. The levels were lower in vasospastic angina pectoris (3.4 +/- 2.4 microg/ml, p <0.01), stable angina pectoris (3.3 +/- 2.6 microg/ml, p <0.001), and healed myocardial infarction (3.8 +/- 2.9 microg/ml, p <0.01) than chest pain syndrome (controls) (6.6 +/- 5.4 microg/ml). The levels were also lower in multivessel CAD (3.4 +/- 2.4 microg/dl) compared with single vessel CAD (4.2 +/- 2.7 microg/ml, p <0.05) or no organic stenosis (5.1 +/- 3.5 microg/ml, p <0.01). In univariate analysis, diabetes mellitus (p = 0.03), insulin resistance (p = 0.06), high-sensitivity C reactive protein levels (p = 0.0012), and low HMW adiponectin levels (p = 0.0001) predicted cardiovascular events during 7 years of follow-up. However, multivariate analysis showed that only HMW adiponectin levels were an independent predictor of cardiovascular events (relative risk 2.79, 95% confidence interval 1.49 to 5.24, p = 0.0014). In conclusion, serum HMW adiponectin levels may serve as a predictor of future cardiovascular events in patients with CAD as well as a marker for severity of CAD. PMID- 17697808 TI - Accuracy of N-terminal pro-brain natriuretic peptide to predict mortality in various subsets of patients with coronary artery disease. AB - The ability of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) to predict mortality in various subsets of patients with coronary artery disease (CAD) is not known. The aim of present study was to investigate the ability of NT-pro-BNP to predict mortality in various subsets of patients with CAD. The study included 1,552 consecutive patients with angiographically proven CAD. Based on receiver operating characteristic curve analysis, the best NT-pro-BNP level for mortality prediction was 721 ng/L (sensitivity 71.3%, specificity 71.3%). Patients were divided into 2 groups: the group with NT-pro-BNP level < or =721 ng/L (1,034 patients) and the group with NT-pro-BNP level >721 ng/L (518 patients). The primary end point of the study was mortality. The median follow-up was 3.6 years (interquartile range 3.3 to 4.6). In total there were 171 deaths: 49 deaths in the group with NT-pro-BNP < or =721 ng/L and 122 deaths in the group with NT-pro BNP >721 ng/L (mortality estimates 6.6% vs 29.5%, odds ratio 5.2; 95% confidence intervals 3.9 to 7.0, p <0.001). In 28 subsets of patients, NT-pro-BNP level predicted mortality with odds ratio varying from 2.8 to 7.5. In conclusion, NT pro-BNP is a reliable predictive marker of mortality in all subsets of patients with CAD. PMID- 17697809 TI - Time course of hemoglobin concentrations in the intensive care unit in nonbleeding patients with acute coronary syndrome. AB - Critically ill patients commonly show a decrease in hemoglobin concentration during their stay in the intensive care unit. The purpose of the present study was to evaluate whether nonbleeding patients with acute coronary syndrome (ACS) show a similar decrease of hemoglobin, and thereby furnish reference values and analyze possible mechanisms. In this retrospective, descriptive study, the charts of all patients with ACS hospitalized between January 2004 and September 2005 were screened with regard to patient characteristics, time course of hemoglobin, as well as clinical parameters, concomitant drug therapy, and fluid balances. One hundred three nonbleeding patients with ACS were analyzed. They showed an average hemoglobin decrease of 1.27 +/- 1.00 g/dl (p <0.001). The decrease in hemoglobin level was observed during the first 12 to 24 hours; thereafter the hemoglobin concentration remained stable. We found a correlation among decrease of hemoglobin, parameters of stress, such as hypertension (p = 0.019), tachycardia (p = 0.004), pain (p = 0.043), and white blood cells (p = 0.021), as well as the intravenous administration of nitroglycerin (p = 0.004). In conclusion, during the first 24 hours in the intensive care unit the hemoglobin concentration of nonbleeding patients with ACS regularly decreases at 1.27 +/- 1.00 g/dl. Any further decrease in hemoglobin level beyond these values should entail early active search of the bleeding source. We hypothesize that this decrease is due to normalization of the previous stress-induced hemoconcentration and "internal hemodilution" by nitroglycerin. PMID- 17697810 TI - Prognostic significance of fragmented QRS complex for predicting the risk of recurrent cardiac events in patients with Q-wave myocardial infarction. AB - There are limited data regarding the prognostic value of QRS complex fragmentation, defined as changes in QRS morphology (<120 ms) with different RSR' patterns: additional R waves, notched S wave, or >1 R' wave. The purpose of our analysis was to assess the prognostic value of presence of Q waves and QRS fragmentation for predicting recurrent cardiac events, defined as cardiac death, nonfatal myocardial infarction (MI), or unstable angina, whichever occurs first, in 350 patients with first Q-wave MI. In follow-up (2 months on average) electrocardiograms (ECGs), 277 patients (79%) had persistent Q waves and 73 (21%) had resolution of Q waves. Independently of Q waves, presence of QRS complex fragmentation was found in 187 patients (53%). Resolved Q waves on 2-month ECGs was associated with worsened prognosis (adjusted hazard ratio [HR] 2.33, p = 0.007), whereas presence of any fragmented QRS did not increase risk of recurrent cardiac events (adjusted HR 0.93, p = 0.79). Among patients for whom Q waves disappeared on 2-month ECGs, patients with QRS fragmentation (n = 37) had over twofold higher risk of recurrent events (adjusted HR 2.68, p = 0.004) compared with those without fragmented QRS and persistent Q waves. In conclusion, presence of fragmented QRS independently of Q waves was not associated with increased risk of recurrent events in the general population of patients after MI. However, among patients with resolved Q waves, fragmented QRS was associated with increased risk of cardiac events. Fragmented QRS complex should not be neglected in patients with transient Q waves after myocardial infarction. PMID- 17697811 TI - Usefulness of noninvasive cardiac imaging using dual-source computed tomography in an unselected population with high prevalence of coronary artery disease. AB - The aim of the present study was to evaluate the diagnostic accuracy of a new dual-source computed tomographic scanner generation with 83-ms temporal resolution in cardiac imaging. Fifty-one unselected consecutive patients (mean age 64 +/- 10 years) scheduled for invasive coronary angiography because of suspected or known coronary artery disease (CAD) were examined with dual-source computed tomography (DSCT). All coronary segments were analyzed regarding the presence of coronary artery lesions. The findings were compared with invasive coronary angiography. During computed tomographic examination, mean heart rate was 65 +/- 14 beats/min. Thirteen of 51 patients (25%) did not have sinus rhythm. Mean Agatston score equivalent was 779 (median 358, range 0 to 3,898). Prevalence of CAD was 75%. Based on a coronary segment model, sensitivity was 96%, specificity 87%, positive predictive value 61%, and negative predictive value 99% for the detection of significant lesions (> or =50% diameter stenosis). The main reason for false-positive results was an overestimation of mild lesions by DSCT. In conclusion, our initial data indicate that DSCT allows a high accuracy to exclude relevant coronary stenosis in unselected patients with a high prevalence of CAD and a relevant number with heart rhythm irregularities. However, overestimation of stenosis, especially in cases of calcifications, is still a limitation. PMID- 17697812 TI - Peripheral-blood dendritic cells in men with coronary heart disease. AB - Accumulating evidence suggests that an imbalance in T-helper type 1 (Th1)/Th2 response with enhanced Th1 immune response has an important role in the process of coronary artery disease (CAD). Dendritic cell (DC) subsets, myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), could regulate immune reactions by polarizing naive T-helper cells into Th1 or Th2 effector cells. In this study, total peripheral blood DCs and mDC and pDC subsets were examined in patients with coronary heart disease. Thirty-two men who underwent coronary angiography for chest pain were divided into the CAD group (n = 21) and control group (normal coronary angiographic results, n = 11). Peripheral-blood DCs and DC subsets were detected using a 3-color flow cytometry technique. DCs were defined as Lin1(-)HLA-DR(+); mDCs, as Lin1(-)HLA-DR(+)CD11c(+); and pDCs, as Lin1(-)HLA-DR(+)CD123(+). The absolute number of peripheral-blood DCs was significantly higher in the CAD group compared with the control group (p = 0.04). The mDC fraction in terms of both percentage and absolute number was also significantly increased in the CAD group compared with the control group (all p <0.05), whereas the pDC fraction was similar between the 2 groups (p >0.05). The mDC/pDC ratio was significantly increased in the CAD group than in the control group (p = 0.01). In conclusion, total peripheral-blood DCs are significantly higher in patients with CAD because of an increase in mDC subset, which might contribute to enhanced Th1 response in patients with CAD. PMID- 17697813 TI - Usefulness of microvolt T-wave alternans on predicting outcome in patients with ischemic cardiomyopathy with and without defibrillators. AB - Microvolt T-wave alternans (MTWA) was proposed as an effective tool to identify high-risk patients with ischemic cardiomyopathy. However, previous studies suggested that the prognostic utility of MTWA may be limited to only patients with normal QRS duration. It therefore was assessed whether MTWA and QRS duration >120 ms independently predict mortality in patients with ischemic cardiomyopathy and whether the prognostic utility of MTWA differs by QRS duration. A total of 768 consecutive patients with ischemic cardiomyopathy (left ventricular ejection fraction < or =35%) and no history of ventricular arrhythmia were enrolled, of whom 514 (67%) screened MTWA non-negative (positive or indeterminate) and 223 (29%) had a QRS >120 ms on resting electrocardiogram. After multivariable adjustment, a non-negative MTWA test result was associated with a significantly higher risk for all-cause mortality in patients without an implantable cardioverter-defibrillator (ICD) (hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.22 to 4.24, p = 0.01) and for all-cause mortality and appropriate ICD shocks in patients with an ICD (HR 2.42, 95% CI 1.07 to 5.41, p = 0.04). In contrast, a QRS >120 ms was not associated with all-cause mortality and ICD shocks in patients without (HR 0.96, 95% CI 0.52 to 1.75, p = 0.88) or with an ICD (HR 1.25, 95% CI 0.76 to 2.08, p = 0.40). No significant interaction was found between MTWA and QRS >120 ms (non-ICD p = 0.19, ICD p = 0.73). In conclusion, MTWA, but not QRS duration, predicted mortality outcomes in patients with ischemic cardiomyopathy. Moreover, the prognostic utility of MTWA did not appear to differ by QRS duration. PMID- 17697814 TI - Comparison of the prognostic value of the stress-recovery index versus standard electrocardiographic criteria in patients with a negative exercise electrocardiogram. AB - To verify whether the stress recovery index (SRI) improves risk stratification in patients with a negative exercise electrocardiogram (ECG) using standard criteria, the SRI was derived in 708 consecutive patients with a negative exercise ECG. All-cause mortality and the combination of death or nonfatal myocardial infarction were target end points. The individual effect of clinical and exercise testing data on outcome was evaluated using Cox regression analysis with separate models for each group of variables. Model validation was performed using bootstrap adjusted by degree of optimism in estimates. Survival analysis was performed using a product-limit Kaplan-Meier method. During a 37-month follow up, 22 deaths and 40 nonfatal acute coronary syndromes occurred. After adjusting for confounding variables, age (hazard ratio 1.62, 95% confidence interval [CI] 1.14 to 2.31 for interquartile difference), hypertension (hazard ratio 1.74, 95% CI 1.04 to 2.89), and SRI (hazard ratio 0.75, 95% CI 0.65 to 0.86 for interquartile difference) were predictive of death or nonfatal myocardial infarction. Moreover, SRI increased the prognostic power of the model on top of clinical and exercise testing variables and provided significant discrimination of survival. In conclusion, the SRI may help refine the prognostic stratification of patients with a negative exercise test result using standard electrocardiographic criteria. PMID- 17697815 TI - Effects of triple antiplatelet therapy (aspirin, clopidogrel, and cilostazol) on platelet aggregation and P-selectin expression in patients undergoing coronary artery stent implantation. AB - The purpose of this study was to determine the effect of the addition of cilostazol to aspirin plus clopidogrel on platelet aggregation after intracoronary stent implantation. Twenty patients who underwent coronary stent placement were randomly assigned to therapy with aspirin plus clopidogrel (dual therapy group, n = 10) or aspirin plus clopidogrel plus cilostazol (triple therapy group, n = 10). A loading dose of clopidogrel (300 mg) and cilostazol (200 mg) was administered immediately after stent placement, and clopidogrel (75 mg/day) and cilostazol (100 mg twice daily) were given for 1 month. Platelet aggregation in response to adenosine diphosphate (ADP; 5 and 20 micromol/L) or collagen and P-selectin (CD-62P) expression was assayed at baseline, 2 hours, 24 hours, 1 week, and 1 month after stent placement. Inhibition of ADP-induced platelet aggregation was significantly higher in patients receiving triple therapy than those receiving dual therapy from 24 hours after stent placement, and inhibition of collagen-induced platelet aggregation was significantly higher in the triple-therapy group beginning 1 week after stent placement. P-Selectin expression was significantly lower in the triple-therapy than dual-therapy group at 1 week and 30 days. In conclusion, compared with dual antiplatelet therapy, triple therapy after coronary stent placement resulted in more potent inhibition of platelet aggregation induced by ADP and collagen. These findings suggest that triple therapy may be used clinically to prevent thrombotic complications after coronary stent placement. PMID- 17697816 TI - Intravascular ultrasound parameters associated with stent thrombosis after drug eluting stent deployment. AB - Drug-eluting stent (DES) thrombosis (ST) can be devastating. The study aim was to evaluate intravascular ultrasound (IVUS) predictors for DES thrombosis by comparing IVUS studies after implantation in 13 patients with 14 DES thrombosis lesions with a group of controls (30 lesions in 27 patients) matched for history of chronic renal failure and type of DES. Five patients (38%) discontinued dual antiplatelet therapy at the time of ST. There were 3 in-stent restenosis lesions (21%) treated using DESs in the ST group compared with 0 in the control group (p <0.05). Compared with the control group, IVUS studies in the ST group showed a smaller minimum stent area (4.6 +/- 1.1 vs 5.6 +/- 1.7 mm(2), p = 0.0489). In the ST group, 11 of 14 stents had a minimum stent area < or =5.0 mm(2) compared with 12 of 30 in the control group (p = 0.0392). Minimum stent area in patients who stopped clopidogrel therapy and developed ST (5.30 +/- 1.15 mm(2)) tended to be larger compared with that in patients who developed ST while using clopidogrel (4.24 +/- 0.96 mm(2), p = 0.091). Within the 5-mm-long proximal and distal reference segments analyzed, the ST group had larger proximal reference maximum plaque burdens and smaller minimum lumen areas, along with a tendency toward similar findings in the distal reference segments. In conclusion, IVUS findings at the time of DES implantation in patients who subsequently developed ST showed a smaller minimum stent area (especially in patients who developed ST while using clopidogrel) and more residual disease at the stent edges. PMID- 17697817 TI - Meta-analysis of angiographic versus intravascular ultrasound parameters of drug eluting stent efficacy (from TAXUS IV, V, and VI). AB - Both quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) are currently used to assess in-stent restenosis. This study aimed to use standardized imaging and clinical follow-up to compare QCA parameters with several IVUS parameters to evaluate their strengths and weaknesses for detecting in-stent restenosis in a drug-eluting stent population. A subset of patients from the TAXUS IV, V, and VI studies was evaluated. The subset, which included 216 TAXUS-treated patients and 191 bare-metal stent-treated patients, had complete IVUS and QCA performed at baseline and follow-up. As expected, all QCA and IVUS parameters were consistent with less intimal hyperplasia in TAXUS patients than controls. The overall incidence of QCA binary restenosis was 14.0%, which was 9.3% in TAXUS-treated patients and 19% in bare-metal stent-treated patients (p = 0.0008). Regression analysis showed that QCA late lumen loss and percentage of diameter stenosis correlated only moderately with the various IVUS measures of neointimal hyperplasia for the combined group of patients (TAXUS + bare-metal stent), as well as for the TAXUS-treated and bare-metal stent-treated patients separately. However, in general, correlations within the control (bare-metal stent) group tended to be stronger than within the TAXUS group. The strongest correlation was between QCA percentage of diameter stenosis and IVUS percentage of intimal hyperplasia in the overall group and the control group. The strongest IVUS predictor of QCA binary restenosis at 9 months was maximum percentage of intimal hyperplasia, with an overall C = 0.91 and p <0.001. In conclusion, the QCA and IVUS parameters used to evaluate drug-eluting stent efficacy showed a moderate correlation with IVUS percentage of intimal hyperplasia, reliably predicting QCA binary in-stent restenosis. PMID- 17697818 TI - Frequency of stent fracture as a cause of coronary restenosis after sirolimus eluting stent implantation. AB - Stent fracture (SF) was suggested as a cause of restenosis after sirolimus eluting stent (SES) implantation. This study was performed to evaluate the incidence and characteristics of SF to determine its contribution to restenosis in patients with in-stent restenosis (ISR) after SES implantation. From May 2003 to February 2006, SESs were used for percutaneous coronary intervention in 868 patients with 1,109 coronary narrowings. Follow-up coronary angiography was performed in 366 patients (42%), and 26 ISR lesions were observed. These patients were enrolled in this study. SF was divided into 3 types as avulsion, collapse, and partial based on the findings of fluoroscopy, coronary angiography, and intravascular ultrasound study. Of 26 patients with ISR lesions, SF was identified in 10. SF types were avulsion (5 patients), collapse (2 patients), and partial (3 patients). SF was identified at the midshaft (7 patients) and overlap sites (3 patients) of stents. SF was not observed in the 30 patients with ISR after bare-metal Bx Velocity stent implantation. Four patients with SF were treated with paclitaxel-eluting stents. In conclusion, SF is 1 of the leading causes of ISR after SES implantation. Careful fluoroscopic examination is necessary at the time of follow-up angiography to identify this problem. PMID- 17697819 TI - Usefulness of preprocedural N-terminal pro-brain natriuretic peptide in predicting angiographic no-reflow phenomenon during stent implantation in patients with ST-segment elevation acute myocardial infarction. AB - The no-reflow phenomenon after primary percutaneous coronary intervention (PCI) is associated with larger infarct size, worse functional recovery, and higher incidence of complication after acute ST-elevation myocardial infarction (STEMI). The aim of this study was to assess the relation between preprocedural N-terminal pro-brain-type natriuretic peptide (NT-pro-BNP) and angiographic no-reflow phenomenon. We measured preprocedural serum NT-pro-BNP level in 159 consecutive patients with acute STEMI (aged 63 +/- 12 years; 72% men) before PCI. Angiographic no-reflow after PCI was defined as Thrombolysis In Myocardial Infarction (TIMI) flow grade <3. Baseline characteristics, including time from chest pain onset, between the no-reflow (n = 67) and normal-reflow groups (n = 92) were similar. NT-pro-BNP was significantly higher in the no-reflow group than the normal reflow group (1,982 +/- 3,314 vs 415 +/- 632 pg/ml; p = 0.005). Also, high-sensitivity C-reactive protein, monocytes, and troponin-T were significantly higher in the no-reflow group than the normal-reflow group. In the no-reflow group, NT-pro-BNP was much higher in patients with TIMI flow grade 0 (n = 41; 2,290 +/- 3,495 pg/ml) than those with TIMI grade 1 or 2 (n = 26; 1,575 +/- 2,340 pg/ml), but without significant difference. The area under the receiver-operating characteristic curve for NT-pro-BNP was 0.78, and the optimal cut-off value identified using receiver-operating characteristic curve analysis was 500 pg/ml. At the standard cut-off value of >500 pg/ml, increased NT-pro-BNP showed a high probability of no-reflow phenomenon (odds ratio 4.42, 95% confidence interval 1.15 to 17.00, p = 0.028). In conclusion, preprocedural NT-pro-BNP may be a strong predictor of the development of no-reflow phenomenon after PCI in patients with acute STEMI. PMID- 17697820 TI - Comparison of N-terminal pro-brain natriuretic peptide versus electrophysiologic study for predicting future outcomes in patients with an implantable cardioverter defibrillator after myocardial infarction. AB - The aim of the study was to examine the predictive value of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) versus electrophysiologic study in patients with implantable cardioverter-defibrillators (ICDs) after myocardial infarction (MI). We prospectively studied 99 consecutive patients with a history of MI who underwent ICD implantation for primary or secondary prevention of sudden cardiac death. An electrophysiologic study was performed in all patients. Venous blood samples for NT-pro-BNP measurement were obtained at the beginning of the study. The primary end point was ventricular tachycardia or ventricular fibrillation (VT/VF) and the secondary end point was a composite of death, hospitalization for heart failure, or MI. On multivariate Cox regression analysis, NT-pro-BNP level at or greater than median (497 ng/L) was the only significant predictor for VT/VF occurrence (p = 0.047). Along with amiodarone use (p = 0.001), NT-pro-BNP levels higher than median were also associated with a higher risk of composite clinical events (p = 0.036). Kaplan-Meier analysis showed that patients with NT-pro-BNP level at or greater than median had a higher risk of experiencing VT/VF and composite clinical events than patients with NT-pro-BNP levels less than median (log-rank p <0.05). In conclusion, assay of NT-pro-BNP, which is easy to perform and widely available, is superior to electrophysiologic study for prediction of future outcomes in predominantly secondary prophylactic ICD recipients after MI. In the era of primary prophylactic ICD implantation without preimplantation electrophysiologic study, higher NT-pro-BNP levels might help to improve risk adjusted concomitant antiarrhythmic therapy and device selection. PMID- 17697821 TI - Predictors of aorto-saphenous vein bypass narrowing late after coronary artery bypass grafting. AB - The objective of this study was to evaluate the clinical and angiographic factors associated with significant saphenous vein graft (SVG) atherosclerosis progression at mid-term follow-up in a series of unselected coronary patients who had previously received a coronary artery bypass graft (CABG). A total of 123 SVGs from 86 patients who underwent cardiac catheterization twice, 15 +/- 12 months apart, were included in the study. None of the SVGs presented any > or =50% diameter stenosis (DS) lesion or underwent any intervention at baseline. All SVGs were divided into 3 segments and each SVG segment was scored from 0 to 3 depending on the presence of lesions, with percent DS ranging from 0% to 19% (score 0), 20% to 29% (score 1), 30% to 39% (score 2), and > or =40% (score 3). The SVG atherosclerotic burden score (ABS) was calculated by adding the score obtained for each of the 3 SVG segments. Significant progression was defined as > or =10% increase in lesion percent DS or > or =0.6 mm decrease in minimal lumen diameter between baseline and follow-up studies. Mean age of the study population was 66 +/- 9 years, and most of the patients were receiving statin therapy with mean low-density lipoprotein cholesterol of 85 +/- 26 mg/dl. Significant angiographic progression occurred in > or =1 SVG in 41 patients (48%). On multivariate analysis, the variables associated with SVG atherosclerosis progression were SVG ABS (odds ratio [OR], 1.52 for each increase of 1 point in SVG ABS; 95% confidence interval [CI] 1.1 to 2.29) and high-density lipoprotein (HDL) cholesterol (OR 1.38 for each decrease of 5 mg/dl in HDL cholesterol levels, 95% CI 1.09 to 1.85). Twenty-two patients (26%) had a cardiac event at follow-up related to SVG disease progression. The percent DS of the SVG segment at baseline was associated with SVG disease progression leading to a cardiac event (OR 3.67 for each increase of 5% in percent DS, 95% CI 2.11 to 6.38). In conclusion, simple clinical and angiographic variables such as HDL cholesterol, ABS, and lesion severity remain independent predictors of significant SVG atherosclerosis progression in mild to moderately diseased SVGs despite mean low density lipoprotein levels <90 mg/dl. PMID- 17697822 TI - Usefulness of combining complement factor H and C-reactive protein genetic profiles for predicting myocardial infarction (from the Rotterdam Study). AB - Complement factor H (CFH) is an important regulator of the complement cascade. Binding of C-reactive protein (CRP) to CFH augments the ability of CFH to downregulate the effect of complement in atherosclerotic lesions. The CFH Tyr402His polymorphism has been suggested to influence the ability of CFH to bind CRP. We hypothesized that the combined presence of unfavorable CRP and CFH genetic profiles is associated with risk of myocardial infarction (MI). The Rotterdam Study is a population-based cohort study in 7,983 men and women aged > or =55 years. The CFH Tyr402His (rs1061170) polymorphism was determined (His(402) allele 37%), and using 3 tagging polymorphisms (rs1130864, rs1205, and rs3093068), CRP haplotypes were inferred (1 = CTC, 2 = TCC, 3 = CCC, 4 = CCG; frequencies of 33%, 32%, 30%, and 6%, respectively). Participants were grouped by CFH genotype (TyrTyr [reference], TyrHis, and HisHis) and CRP haplotype (haplotype 1 homozygotes [reference], haplotype 2 carriers, haplotype 3 carriers, and haplotype 4 carriers), which resulted in a total of 12 groups. CFH His(402) homozygotes who were also CRP haplotype 3 carriers had an age- and gender adjusted hazard ratio of 5.9 (95% confidence interval 2.1 to 16.5) to develop MI compared with the reference group. In conclusion, this population-based study suggests that the combined presence of unfavorable CFH and CRP genetic profiles is associated with risk of MI. PMID- 17697823 TI - Comparison of long-term follow-up of electrocardiographic features in Brugada syndrome between the SCN5A-positive probands and the SCN5A-negative probands. AB - To investigate changes of electrocardiographic parameters with aging and their relation to the presence of SCN5A mutation in probands with Brugada syndrome (BS), we measured several electrocardiographic parameters prospectively during long-term follow-up (10 +/- 5 years) in 8 BS probands with SCN5A mutation (SCN5A positive group, all men; age 46 +/- 10 years) and 36 BS probands without SCN5A mutation (SCN5A-negative group, all men; age 46 +/- 13 years). Throughout the follow-up period, depolarization parameters, such as P-wave (lead II), QRS (leads II, V(2), V(5)), S-wave durations (leads II, V(5)), and PQ interval (leads II) were all significantly longer and S-wave amplitude (II, V(5)) was significantly deeper in the SCN5A-positive group than in the SCN5A-negative group. The SCN5A positive group showed a significantly longer corrected QT interval (lead V(2)) and higher ST amplitude (lead V(2)) than those in the SCN5A-negative group. The depolarization parameters increased with aging during the follow-up period in both groups; however, the PQ interval (lead II) and QRS duration (lead V(2)) were prolonged more prominently and the QRS axis deviated more to the left with aging in the SCN5A-positive group than in the SCN5A-negative group. In conclusion, conduction slowing was more marked and more progressively accentuated in Brugada probands with SCN5A mutation than in those without SCN5A mutation. PMID- 17697824 TI - Incidence of Brugada electrocardiographic pattern and outcomes of these patients after intentional tricyclic antidepressant ingestion. AB - Brugada syndrome is a genetic dysfunction of the myocardial sodium channel that leads to ventricular dysrhythmias. The electrocardiographic (ECG) pattern of Brugada syndrome is occasionally seen after tricyclic antidepressant (TCA) ingestion; however, the outcome and complication risk for these patients is not clear. The objective of our study was to describe the incidence of Brugada ECG pattern (BEP) and serious complications of these patients in a large case series of intentional TCA ingestions. We also compared the proportion of complications of patients with BEP versus those without BEP. We evaluated 402 TCA ingestions, of which 9 (2.3%) were associated with the development of BEP. We compared the adverse outcomes of all TCA ingestions versus TCA ingestions with BEP. A increase in the adverse outcomes in the BEP group was found: seizures (relative risk [RR] 4; 95% confidence interval [CI] 1.5 to 10.8), widened QRS (RR 4.8; 95% CI 1.8 to 12.9), and hypotension (RR 3.9; 95% CI 2.1 to 7.4). To reduce confounding ingestants, we also compared all patients with an isolated TCA ingestion versus those with BEP. A significant increase in adverse outcomes was again found with the BEP group: seizures (RR 3; 95% CI 1.1 to 8.6), widened QRS (RR 4.8; 95% CI 1.5 to 15.1), and hypotension (RR 3.4; 95% CI 1.9 to 22.3). No deaths or dysrhythmias were found in the BEP group. In conclusion, BEP after TCA ingestion is rare, and death or dysrhythmias did not occur. However, patients with BEP are likely at increased risk for TCA-induced complications. PMID- 17697825 TI - Atrial and ventricular rate response and patterns of heart rate acceleration during maternal-fetal terbutaline treatment of fetal complete heart block. AB - Terbutaline is used to treat fetal bradycardia in the setting of complete heart block (CHB); however, little is known of its effects on atrial and ventricular beat rates or patterns of heart rate (HR) acceleration. Fetal atrial and ventricular beat rates were compared before and after transplacental terbutaline treatment (10 to 30 mg/day) by fetal echocardiography in 17 fetuses with CHB caused by immune-mediated damage to a normal conduction system (isoimmune, n = 8) or a congenitally malformed conduction system associated with left atrial isomerism (LAI, n = 9). While receiving terbutaline, 9 of the 17 fetuses underwent fetal magnetocardiography (fMCG) to assess maternal HR and rhythm, patterns of fetal HR acceleration, and correlation between fetal atrial and ventricular accelerations (i.e., AV correlation). Maternal HR and fetal atrial and ventricular beat rates increased with terbutaline. However, terbutaline's effects were greater on the atrial pacemaker(s) in fetuses with isoimmune CHB and greater on the ventricular pacemaker(s) in those with LAI-associated CHB. Patterns of fetal HR acceleration also differed between isoimmune and LAI CHB. Finally, despite increasing HR, terbutaline did not restore the normal coordinated response between atrial and ventricular accelerations in isoimmune or LAI CHB. In conclusion, the pathophysiologic heterogeneity of CHB is reflected in the differing effect of terbutaline on the atrial and ventricular pacemaker(s) and varying patterns of HR acceleration. However, regardless of the cause of CHB, terbutaline augments HR but not AV correlation, suggesting that its effects are determined by the conduction system defect rather than the autonomic control of the developing heart. PMID- 17697827 TI - Quality of life within one year following presentation after transient loss of consciousness. AB - The purpose of this study was to examine (1) changes in quality of life (QoL) within 1 year after presentation with transient loss of consciousness (TLOC) and (2) which factors are predictive of these changes. This study was part of the Fainting Assessment Study (FAST), which assessed diagnostic strategies in patients with TLOC. Adult patients presenting to Academic Medical Center, Amsterdam, The Netherlands, with TLOC were included in the study. QoL was assessed with the generic Short Form 36 and the disease-specific Syncope Functional Status Questionnaire at presentation and 1 year of follow-up. Of 468 included patients, 82% completed questionnaires at presentation and 72% after 1 year follow-up. QoL improved on 7 of 8 subscales of the Short Form 36 and on all summary scales of the Syncope Functional Status Questionnaire. Older age, recurrence, higher level of co-morbidity, and a neurologic or psychogenic diagnosis were predictive of poorer QoL. In conclusion, QoL in patients with TLOC improves significantly over time. Physicians should particularly pay attention to patients who are older, have recurrent episodes, a neurologic or psychogenic diagnosis, and a higher level of co-morbidity because these patients are vulnerable to a relatively poorer QoL. PMID- 17697826 TI - Angiographic analysis of the anatomic relation of coronary arteries to mitral and tricuspid annulus and implications for radiofrequency ablation. AB - Coronary artery (CA) narrowings and/or occlusions after radiofrequency ablation (RFA) have been reported. The aim of this study was to describe the in vivo topographic anatomy of CAs and their anatomic relation to the mitral and tricuspid annulus using selective coronary angiography. Fifty consecutive patients undergoing RFA for narrow QRS complex tachycardia were included in the study. Multipolar electrode catheters were inserted into the right atrial appendage, His bundle region, distal coronary sinus (CS), and right ventricle. A mapping catheter was placed across the subeustachian isthmus (SEI). Selective coronary angiography was performed. The maximum and minimum distances between the distal CAs and the mapping catheter located along the mitral and tricuspid annulus were measured during systole and diastole and in right and left anterior oblique projections. The large (> or =1.5 mm) distal right CA was < or =5 mm from the mapping catheter in the SEI in 4 patients (8%). The large posterolateral branch of the right CA was < or =2 mm from the CS Os-middle cardiac vein in 10 patients (20%). The large left circumflex CA was < or =2 mm from the floor or ceiling of the CS in 7 patients (14%) and < or =2 mm from the CS catheter at the lateral and anterolateral mitral annulus in 12 patients (24%). RFA was canceled in 2 patients because of the close proximity (< or =2 mm) of the distal CA to the ablation site. In conclusion, large CAs are frequently located in close proximity to the common ablation sites. Coronary angiography should be considered in children and adults who may develop any signs or symptoms suggestive of acute CA occlusion until larger controlled series are available. PMID- 17697828 TI - The editor's roundtable: ablation of atrial fibrillation. PMID- 17697829 TI - Evidence for the continued safety and tolerability of fixed-dose isosorbide dinitrate/hydralazine in patients with chronic heart failure (the extension to African-American Heart Failure Trial). AB - The benefits of fixed-dose combination isosorbide dinitrate plus hydralazine (ID/H) in African-Americans with heart failure (HF) were established by the African-American Heart Failure Trial (A-HeFT), which was terminated early because of a significant survival benefit of ID/H. The Extension to A-HeFT trial (X-A HeFT), designed to make ID/H available for ethical reasons after A-HeFT termination, afforded an opportunity to further observe responsiveness and compliance with ID/H. In total 198 patients completing the A-HeFT took ID/H for an additional 209 +/- 116 days. Their age (57 +/- 13 years), cause and duration of HF, and HF medications were not different from all A-HeFT patients. New York Heart Association class at X-A-HeFT baseline was > or =III in 51% of patients versus 100% of all patients at A-HeFT baseline, remained unchanged in most patients, improved in 24%, and worsened in only 9% during X-A-HeFT. The average number of ID/H tablets taken during X-A-HeFT was 3.7 +/- 1.8 per day with compliance averaging 87 +/- 25%. The most common adverse events, headache (34%) and dizziness (16%), were less than in patients taking ID/H in A-HeFT, with only 6% discontinuations for adverse events. The 6% annualized mortality rate in X-A HeFT was the same as for ID/H in A-HeFT. There were no statistically significant differences in baseline characteristics or outcomes in X-A-HeFT patients analyzed according to their A-HeFT randomization. In conclusion, these results confirm the good compliance, tolerability, and responsiveness, with low mortality and improved symptoms, during treatment with ID/H observed in A-HeFT. PMID- 17697830 TI - Comparative effectiveness of beta-adrenergic antagonists (atenolol, metoprolol tartrate, carvedilol) on the risk of rehospitalization in adults with heart failure. AB - Placebo-controlled randomized trials have demonstrated the efficacy of selected beta blockers on outcomes in chronic heart failure (HF), but the relative effectiveness of different beta blockers in usual clinical care is poorly understood. We compared 12-month risk of rehospitalization for HF associated with receipt of different beta blockers in 7,883 adults hospitalized for HF within 2 large health plans between January 1, 2001 and December 31, 2002. Beta-blocker use was ascertained from electronic pharmacy databases and readmissions within 12 months were identified from hospital discharge databases. Extended Cox regression was used to examine the association between receipt of different beta blockers and risk of readmission for HF after adjustment for potential confounders. During follow-up, there were 3,234 person-years of exposure to beta blockers (39.3% atenolol, 42.0% metoprolol tartrate, 12.3% carvedilol, and 6.4% other). Crude 12 month rates of readmissions for HF were high overall (42.6 per 100 person-years). After adjustment for potential confounders, cumulative exposure to each beta blocker, and propensity to receive carvedilol compared with atenolol, adjusted risks of readmission were not significantly different for metoprolol tartrate (adjusted hazard ratio 0.95, 95% confidence interval 0.85 to 1.05) or for carvedilol (adjusted hazard ratio 0.92, 95% confidence interval 0.74 to 1.14). In conclusion, in a contemporary cohort of high-risk patients hospitalized with HF, we found that adjusted risks of rehospitalization for HF within 12 months were not significantly different in patients receiving atenolol, shorter-acting metoprolol tartrate, or carvedilol. PMID- 17697831 TI - Validation of the Seattle Heart Failure Model in a community-based heart failure population and enhancement by adding B-type natriuretic peptide. AB - Management of heart failure (HF) remains complex with low 5-year survival. The Seattle Heart Failure Model (SHFM) is a recently described risk score derived predominantly from clinical trial populations that may enable the prediction of survival in patients with HF. This study sought to validate the SHFM in an independent, nonclinical trial-based HF population. Patients (n = 4,077) from the hospital-based Intermountain Heart Collaborative Study registry with a diagnosis of HF were evaluated using prospectively collected data (mean +/- SD follow-up 4.4 +/- 3.1 years). The SHFM was used to calculate a risk score for each patient. Receiver-operating characteristic area under the curve provided SHFM predictive ability for a composite end point of survival free from death, transplantation, or left ventricular assist device implantation. Addition of creatinine, serum urea nitrogen, diabetes status, and B-type natriuretic peptide (BNP) to the SHFM was also evaluated. Patient age averaged 67 +/- 13 years and 61% were men. Area under the curves were 0.70 (95% confidence interval 0.66 to 0.70), 0.67 (95% confidence interval 0.66 to 0.69), 0.67 (95% confidence interval 0.065 to 0.68), and 0.66 (95% confidence interval 0.63 to 0.67) for 1-, 2-, 3-, and 5-year survivals, respectively. Area under the curves were slightly attenuated in patients >75 years of age (n = 1,339), implantable cardioverter-defibrillator recipients (n = 693), and patients with an ejection fraction >40% (n = 1,634). BNP added significantly to the model (area under the curve +0.06). BNP was found to add additional predictive ability at 1 year (area under the curve change +0.05) and nominally at 5 years (area under the curve change +0.02). In conclusion, the SHFM predicts survival in patients with HF in a hospital-based population, with areas under the curve similar to those from data on which models were initially fit. PMID- 17697832 TI - Accuracy of 64-slice computed tomography for the preoperative detection of coronary artery disease in patients with chronic aortic regurgitation. AB - We studied the diagnostic accuracy of 64-slice computed tomography for the diagnosis of significant coronary artery disease (CAD) compared with conventional coronary angiography (CA) in patients with chronic aortic regurgitation (AR) referred for elective aortic valve surgery. Fifty consecutive patients with chronic AR (38 men, mean age 54 +/- 14 years) scheduled for valve surgery underwent 64-slice computed tomographic (CT) coronary angiography and CA. Significant stenosis was defined as a luminal diameter decrease >50%. Mean heart rate during CT scanning was 65.5 +/- 7.4 beats/min. Mean Agatston score was 136 +/- 278 (range 0 to 1207); prevalence of significant CAD in the study population was 26% (13 of 50 patients). Thirteen of 742 segments (1.8%) in 3 patients were considered nondiagnostic with computed tomography because of motion artifacts (n = 9) or calcium (n = 4). In a patient-based analysis taking nonevaluative segments as falsely positive, sensitivity, specificity, and positive and negative predictive values of computed tomography were 100%, 95%, 87%, and 100%, respectively. Preoperative CA could have been avoided in 70% of patients (35 of 50), CA would have been performed to confirm the CT diagnosis in 26% (13 of 50), and unnecessary CA would have been performed in 4% (2 of 50) on the basis of false-positive CT ratings. In conclusion, 64-slice CT coronary angiography provides high diagnostic accuracy for diagnosing significant CAD in patients with chronic AR and may be used as a filter test before valve surgery to decide whether CA should be performed. PMID- 17697833 TI - Effect of primary mitral regurgitation on left ventricular synchrony. AB - Mitral regurgitation (MR) promotes left ventricular (LV) dilatation and eccentric remodeling. In the presence of LV dyssynchrony and heart failure, cardiac resynchronization therapy decreases the severity of MR. Whether primary MR can cause LV dyssynchrony is unknown. We investigated whether moderate to severe primary MR causes LV dyssynchrony in the presence of LV dilation and an ejection fraction (EF) >55%. We studied 37 normal subjects and 22 patients with moderate to severe MR and no coronary artery disease. Electrocardiographically gated cine and tagged cardiac magnetic resonance imaging was performed. Two-dimensional, maximum-circumferential shortening strain and time-to-peak strain (TTPS) were computed using harmonic-phase analysis of tagged magnetic resonance imaging. LV dyssynchrony was assessed by comparing TTPS delay of various LV quadrants and TTPS dispersion among the contralateral quadrants in patients with MR and normal subjects. Statistical comparison was done using a generalized linear model for repeated measurements. LV end-diastolic and LV end-systolic volumes were significantly larger in patients with MR versus normal subjects (207 +/- 11 vs 130 +/- 4 and 73 +/- 5 vs 47 +/- 2 ml, p <0.001). LVEF did not differ in patients with MR and normal subjects. The difference in the TTPS among various quadrants and the dispersion among the contralateral quadrants of the LV myocardium was similar between patients with MR and normal subjects. In conclusion, moderate to severe MR does not cause LV dyssynchrony in patients with LV dilatation and normal LVEF. Thus, cardiac resynchronization therapy in the absence of LV dyssynchrony may not decrease the severity of MR. PMID- 17697834 TI - Usefulness of brain natriuretic peptide levels in the clinical evaluation of patients with hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HC) is associated frequently with heart failure symptoms and diastolic dysfunction. Although the influence of brain natriuretic peptide (BNP) levels in the management of patients with systolic dysfunction is evolving, there are few data on the role of BNP in the management of patients with HC. BNP was compared with clinical and echocardiographic variables, including measures of diastolic filling, in 217 patients with HC. BNP values were correlated with New York Heart Association classification, echocardiographic estimates of diastolic filling pressure, and right ventricular systolic pressure even after adjusting for age, gender, renal function, and body habitus. However, the overlap of the BNP levels in these respective categories was notable. BNP values did not correlate with objective measures of exercise capacity, and serial BNP values did not track changes in clinical status. In conclusion, BNP levels in patients with HC are associated with similar subjective and objective measures as have been observed in patients with left ventricular systolic dysfunction, but these correlations are relatively weak and do not allow the precise characterization of clinical status. PMID- 17697835 TI - Usefulness of magnetic resonance angiography in the evaluation of complex congenital heart disease in newborns and infants. AB - This study evaluated the quality of the visualization of extracardiac thoracic vessels by magnetic resonance angiography (MRA) in young infants with congenital heart disease. Echocardiography is often sufficient in evaluating CHD in young infants. Cardiac catheterization is needed in some instances to evaluate extracardiac thoracic vessels. Extracardiac thoracic vessels can be accurately evaluated using MRA in adults and older children, but image quality in small infants may be limited. Twenty-nine magnetic resonance angiographic scans were performed at a single institution on 28 infants aged <3 months (median 6 days, range 1 to 90 days) with complex CHD in whom imaging was inconclusive by echocardiography. A blinded observer at a different institution graded (from 0 to 3) the quality of the visualization of the main, branch, lobar, and second generation pulmonary arteries; lobar pulmonary veins; aortopulmonary collaterals; vena cavae; thoracic aorta and its branches; patent ductus arteriosus; and visceral sidedness. The results of MRA were compared with those of x-ray angiography and surgical inspection, when available. The mean image quality grade was >2 for all structures except the second-generation pulmonary arterial branches, for which it was 2. The median total scan duration was 9 minutes (range 3 to 46). Findings were concordant with surgical inspection (n = 25) and cardiac catheterization (n = 8) in all subjects. There were no complications. In conclusion, MRA is excellent for the visualization of extracardiac thoracic vessels in young infants with CHD and can be used as an alternative to cardiac catheterization when echocardiography is inconclusive. PMID- 17697837 TI - Cardiac troponin I in patients with acute lower limb ischemia. AB - The presence, cause, and clinical significance of elevated cardiac troponin I in patients with acute lower limb ischemia is yet unknown. Forty-six patients (20 men [43%]; mean age 72 +/- 10 years, range 42 to 92) with acute lower limb ischemia were enrolled in this study. Serial creatine kinase (CK), CK isoenzyme MB (CK-MB), and troponin I measurements were obtained in all consecutive patients. Peak levels were evaluated for each patient. Twenty-four patients (52%) had elevated peak troponin I levels (>0.2 ng/ml) during their hospitalization. Patients were divided into 3 groups according to their peak troponin I levels: 11 patients (24%) had peak troponin I levels >1 ng/ml (the high troponin I group), 13 (28%) had levels of 0.2 to 1 ng/ml (the intermediate troponin I group), and the remaining 22 (48%) had peak troponin I levels <0.2 ng/ml (the low troponin I group). The peak CK levels were 10,263 +/- 16,513, 1,294 +/- 1,512, and 934 +/- 1,045 IU/ml (p = 0.04) in the 3 different troponin I subgroups, respectively, and the peak CK-MB levels were 143 +/- 170, 38 +/- 31, and 38 +/- 43, respectively (p = 0.04). Troponin I was positively correlated with CK (R = 0.35, p = 0.017) and CK-MB (R = 0.38, p = 0.009). The mean length of hospitalization was 8.3 +/- 6.2 days for the whole study group and did not vary among the 3 troponin I groups (10.5 +/- 10.9 vs 8.6 +/- 4.9 vs 7.2 +/- 4.0 days, p = 0.762). There were no differences in mortality during hospitalization among the 3 groups (4 of 11 vs 1 of 13 vs 4 of 22 patients, p = 0.22). In conclusion, patients with acute lower limb ischemia often have elevated cardiac troponin I levels. Elevated troponin I levels were not associated with the duration of hospitalization or with in hospital mortality in this group of patients. PMID- 17697836 TI - Influence of preparative procedures on assay of platelet function and apparent effects of antiplatelet agents. AB - Previous studies have shown that anticoagulants alter platelet reactivity and the apparent effects of antiplatelet agents. This study was conducted to identify the impact of methods of preparation of blood samples on an assay of platelet function and the effects of antiplatelet agents. The activation of platelets was identified with the use of flow cytometry in response to thrombin (1 and 10 nmol/L), adenosine diphosphate (0.2 and 1 micromol/L), platelet activating factor (1 nmol/L), and convulxin (1 and 10 ng/ml). Antiplatelet effects were assessed after the addition in vitro of tirofiban (50 ng/ml) and cangrelor (10 nmol/L). Results were compared in whole blood and platelet-rich plasma (PRP) anticoagulated with corn trypsin inhibitor (32 microg/ml, a specific inhibitor of factor XIIa). The fraction of young platelets was quantified with thiazole orange, which identifies ribonucleic acid. The activation of platelets was consistently less in PRP compared with whole blood. Activation in PRP was 23 +/- 15% that in whole blood for thrombin, 65 +/- 26% for adenosine diphosphate, 40 +/ 20% for platelet activating factor, and 49 +/- 25% for convulxin (p <0.01 for each comparison). The fraction of young platelets in PRP was 39 +/- 11% that in whole blood (p <0.001). The effects of antiplatelet agents varied with agonist and antiplatelet agent but were generally greater in PRP compared with whole blood (p <0.05). In conclusion, platelet reactivity is lower and the effects of antiplatelet agents are greater and potentially misleading in PRP compared with whole blood. The accuracy of platelet function testing may be improved by performance in whole blood. PMID- 17697838 TI - Prevalence and correlates of septal delayed contrast enhancement in patients with pulmonary hypertension. AB - Using cardiac magnetic resonance, the presence of myocardial delayed contrast enhancement (DCE) has been described in the ventricular septum at the level of the right ventricular insertion points in patients with pulmonary hypertension (PH). The aim of this study was to investigate the prevalence, extent, and correlates of this finding. Septal DCE was evaluated in 55 patients with known or suspected PH of various causes. The extent of DCE was estimated visually with an insertion enhancement score (range 0 to 4) and quantified as DCE mass. The results were correlated with cine magnetic resonance and right-sided cardiac catheterization. Predictors of DCE were investigated using multivariate analysis. PH at rest was present in 42 patients (group 1) and absent in 13 (group 2). DCE was noted in 41 patients (97%) in group 1 and 3 (23%) in group 2 (p <0.0001). The extent of DCE was higher in group 1 than group 2 (median insertion enhancement score 3 vs 0, median DCE mass 8.7 vs 0 g, respectively; p <0.0001 for both). The extent of DCE showed moderate to good univariate correlations (r = 0.5 to 0.73) with pulmonary pressures and with right ventricular volumes, mass, and ejection fractions. In multivariate analysis, systolic pulmonary pressure was the only predictor of DCE. In conclusion, the presence of septal DCE at the right ventricular insertion points is common in PH of different causes, and the level of systolic pulmonary pressure elevation appears to be the main determinant of this finding. PMID- 17697839 TI - Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome. AB - The aim of this study was to characterize cardiovascular involvement in a large number of patients with LEOPARD syndrome. Twenty-six patients (age range 0 to 63 years, median age at the time of the study evaluation 17 years) underwent clinical and genetic investigations. Familial disease was ascertained in 9 patients. Nineteen patients (73%) showed electrocardiographic abnormalities. Left ventricular (LV) hypertrophy was present in 19 patients (73%), including 9 with LV outflow tract obstructions; right ventricular hypertrophy was present in 8 patients (30%). Valve (57%) and coronary artery (15%) anomalies were also observed. Single patients showed LV apical aneurysm, LV noncompaction, isolated LV dilation, and atrioventricular canal defect. During follow-up (9.1 +/- 4.5 years), 2 patients died suddenly, and 2 patients had cardiac arrest. These patients had LV hypertrophy. Despite the limited number of subjects studied, genotype-phenotype correlations were observed in familial cases. In conclusion, most patients with LEOPARD syndrome showed LV hypertrophy, often in association with other valvular or congenital defects. A spectrum of underrecognized cardiac anomalies were also observed. Long-term prognosis was benign, but the occurrence of 4 fatal events in patients with LV hypertrophy indicates that such patients require careful risk assessment and, in some cases, consideration for prophylaxis against sudden death. PMID- 17697841 TI - Patients with advanced heart failure and the effects of levosimendan. PMID- 17697842 TI - Impact of radial artery cannulation on radial artery function. PMID- 17697843 TI - Regional myocardial performance index for diagnosis of pulmonary embolism in patients with echocardiographic signs of pulmonary hypertension. PMID- 17697844 TI - A novel method of two-dimensional echocardiographic tracking. PMID- 17697845 TI - Nesiritide in acute decompensated heart failure: to use or not to use, that is the question? PMID- 17697846 TI - The relation of patients' treatment preferences to outcome in a randomized clinical trial. AB - Randomization procedures are performed in order to maximize the internal validity of treatment outcome studies. Objections have been made that this practice undermines the external validity of these studies because it ignores patients' treatment preferences, thereby precluding the self-selection of treatment that can occur in the community. This study used data from a multisite, double-blind, randomized, placebo-controlled trial comparing antidepressant medication to cognitive therapy for moderately to severely depressed outpatients. It compared the treatment outcomes of patients who, via randomization, received their preferred treatment versus those who did not. Although the majority of patients stated a preference for one treatment over the other, there was no significant difference in the magnitude of reduction in symptoms of depression between those who received their treatment of choice versus those who did not. These results do not provide support for the claim that the external validity of randomized controlled trials suffers from this aspect of the randomization procedure. PMID- 17697847 TI - Treatment acceptability among mexican american parents. AB - There is a void in the literature with regard to Hispanic parents' views about common interventions for children with behavior problems. The purpose of this study was to examine the treatment acceptability of child management techniques in a Mexican American sample. Parents' acculturation was also examined to determine if it would account for differences in treatment acceptability. Mexican American parents found response cost, a punishment-based technique, more acceptable than positive reinforcement-based techniques (e.g., differential attention). Results suggest that Mexican American parents' acculturation has little impact on acceptability of child management interventions. No association was found between mothers' acculturation and treatment acceptability. However, more acculturated Mexican American fathers viewed token economy as more acceptable than less acculturated fathers. Results are discussed in the context of clinical work and research with Mexican Americans. PMID- 17697849 TI - Initial psychometric properties of the experiences questionnaire: validation of a self-report measure of decentering. AB - Decentering is defined as the ability to observe one's thoughts and feelings as temporary, objective events in the mind, as opposed to reflections of the self that are necessarily true. The Experiences Questionnaire (EQ) was designed to measure both decentering and rumination but has not been empirically validated. The current study investigated the factor structure of the EQ in both undergraduate and clinical populations. A single, unifactorial decentering construct emerged using 2 undergraduate samples. The convergent and discriminant validity of this decentering factor was demonstrated in negative relationships with measures of depression symptoms, depressive rumination, experiential avoidance, and emotion regulation. Finally, the factor structure of the EQ was replicated in a clinical sample of individuals in remission from depression, and the decentering factor evidenced a negative relationship to concurrent levels of depression symptoms. Findings from this series of studies offer initial support for the EQ as a measure of decentering. PMID- 17697850 TI - Discomfort intolerance: evaluation of a potential risk factor for anxiety psychopathology. AB - Discomfort intolerance, defined as an individual difference in the capacity to tolerate unpleasant bodily sensations, is a construct recently posited as a risk factor for panic and anxiety psychopathology. The present report used a biological challenge procedure to evaluate whether discomfort intolerance predicts fearful responding beyond the effects of trait anxiety and a well established psychological vulnerability factor (i.e., anxiety sensitivity). Nonclinical community participants (N=44) with no history of panic attacks or any Axis I condition completed a 35% CO(2) challenge. Results are consistent with our hypothesis suggesting that discomfort intolerance incrementally predicts increased subjective reactivity to the challenge. Moreover, there was some suggestion that discomfort intolerance interacted synergistically with anxiety sensitivity to increase anxiety-related symptoms. These findings add to a small but growing literature suggesting that discomfort intolerance may play a role in the development of anxiety problems. PMID- 17697851 TI - A laboratory-based study of the relationship between childhood abuse and experiential avoidance among inner-city substance users: the role of emotional nonacceptance. AB - Despite the theorized centrality of experiential avoidance in abuse-related psychopathology, empirical examinations of the relationship between childhood abuse and experiential avoidance remain limited. The present study adds to the extant literature on this relationship, providing a laboratory-based investigation of the relationships between childhood sexual, physical, and emotional abuse, experiential avoidance (indexed as unwillingness to persist on 2 psychologically distressing laboratory tasks), and self-reported emotional nonacceptance among a sample of 76 inner-city treatment-seeking substance users. As hypothesized, results provide evidence for heightened experiential avoidance and emotional nonacceptance among individuals with moderate-severe sexual, physical, and emotional abuse (compared to individuals reporting none-low abuse). However, although emotional nonacceptance was associated with increased risk for experiential avoidance, it mediated the relationship between childhood abuse and experiential avoidance only for emotional abuse. As such, results suggest that one mechanism through which emotional abuse in particular leads to experiential avoidance is emotional nonacceptance. Findings suggest the utility of interventions aimed at decreasing experiential avoidance and promoting emotional acceptance among abused individuals. PMID- 17697852 TI - Taxometric and factor analytic models of anxiety sensitivity among youth: exploring the latent structure of anxiety psychopathology vulnerability. AB - This study represents an effort to better understand the latent structure of anxiety sensitivity (AS), a well-established affect-sensitivity individual difference factor, among youth by employing taxometric and factor analytic approaches in an integrative manner. Taxometric analyses indicated that AS, as indexed by the Child Anxiety Sensitivity Index (CASI; Silverman, Flesig, Rabian, & Peterson, 1991), demonstrates taxonic latent class structure in a large sample of youth from North America (N=4,462; M(age)=15.6 years; SD=1.3). Subsequent confirmatory factor analyses indicated that the latent continuous, multidimensional, 4-factor model of AS among youth (Silverman, Goedhart, Barrett, & Turner, 2003) provided good fit for the CASI data among the complement class ("normative form" of AS), but not among the taxon class ("high-risk form" of AS). EFAs supported the prediction that the AS taxon demonstrates a unique, heretofore unexplored latent continuous, unidimensional factor structure among youth. Findings are discussed in relation to refining our understanding of the latent structure of AS and the clinical implications that arise from it. PMID- 17697853 TI - Delineating components of emotion and its dysregulation in anxiety and mood psychopathology. AB - Two studies sought to elucidate the components of emotion and its dysregulation and examine their role in both the overlap and distinctness of the symptoms of 3 highly comorbid anxiety and mood disorders (i.e., generalized anxiety disorder, major depression, and social anxiety disorder). In Study 1, exploratory factor analyses demonstrated that 4 factors--heightened intensity of emotions, poor understanding of emotions, negative reactivity to emotions, and maladaptive management of emotions--best reflected the structure of 4 commonly used measures of emotion function and dysregulation. In Study 2, a separate sample provided support for this 4-factor model of emotion dysregulation. Poor understanding, negative reactivity, and maladaptive management were found to relate to a latent factor of emotion dysregulation. In contrast, heightened intensity of emotions was better characterized separately, suggesting it may relate more strongly to dispositional emotion generation or emotionality. Finally, the 4 components demonstrated both common and specific relationships to self-reported symptoms of generalized anxiety disorder, major depression, and social anxiety disorder. PMID- 17697854 TI - A preliminary investigation of the relationship between emotion regulation difficulties and posttraumatic stress symptoms. AB - This study examined the relationship between posttraumatic stress (PTS) symptoms and particular aspects of emotion regulation difficulties among trauma-exposed individuals. Participants were an ethnically diverse sample of 108 undergraduates from an urban university. PTS symptom severity was found to be associated with lack of emotional acceptance, difficulty engaging in goal-directed behavior when upset, impulse-control difficulties, limited access to effective emotion regulation strategies, and lack of emotional clarity. Further, overall difficulties in emotion regulation were associated with PTS symptom severity, controlling for negative affect. Finally, individuals exhibiting PTS symptoms indicative of a PTSD diagnosis reported greater difficulties with emotion regulation than those reporting PTS symptoms at a subthreshold level. The implications of these findings for research and treatment are discussed. PMID- 17697855 TI - Does distress tolerance moderate the impact of major life events on psychosocial variables and behaviors important in the management of HIV? AB - Living with HIV involves management of multiple stressful disease-related and other life events. Distress tolerance may provide a functional, individual-based context for qualifying the established relationships between major life events and psychosocial variables important in the management of HIV. The present study provided a preliminary test of the hypothesis that distress tolerance moderates the impact of major life events on these predictors of disease progression. HIV positive patients (n=116) completed psychosocial and medical questionnaires. Results indicated that major life events interacted with distress tolerance such that lower distress tolerance and higher life events were associated with significantly higher levels of depressive symptoms, substance use coping, alcohol and cocaine use, and medication adherence. In addition, distress tolerance was directly related to self-reported HIV-related symptoms. These results suggest that low distress tolerance, particularly in the face of major life events, may present significant challenges to adaptive management of HIV. Distress tolerance assessment may help to specify targets for cognitive-behavioral and stress management treatments for people living with HIV. PMID- 17697856 TI - Measuring insulin sensitivity in postmenopausal women covering a range of glucose tolerance: comparison of indices derived from the oral glucose tolerance test with the euglycemic-hyperinsulinemic clamp. AB - This study compares indices of insulin sensitivity derived from fasting and oral glucose tolerance test (OGTT) glucose and insulin measurements, with respect to the reference measure (M/I), obtained from the euglycemic-hyperinsulinemic clamp, in postmenopausal women with varying glucose tolerance status. Fasting plasma insulin index, homeostasis model assessment index, and OGTT-derived indices (insulin 120-minute, Matsuda, metabolic clearance rate [MCR] of glucose, insulin sensitivity [ISI], and Cederholm indices) were calculated and compared with the M/I value in 112 postmenopausal women. All indices examined were significantly correlated with M/I (0.28 < or = r(2) < or = 0.56). Association studies revealed that on average, 48% of women were grouped in the same tertile of insulin sensitivity when using M/I and fasting plasma insulin index, and 54% when using M/I and insulin 120-minute index. However, concordance with M/I tertiles were 57%, 58%, 64%, 64%, and 68% for homeostasis model assessment, Matsuda, MCR, ISI, and Cederholm indices, respectively. Finally, correlation coefficients between M/I and insulin sensitivity indices were generally lower in women with normal glucose tolerance compared with women with impaired glucose tolerance or type 2 diabetes mellitus. These results suggest that in postmenopausal women, surrogate indices of insulin sensitivity obtained from OGTT data and incorporating a measurement of body weight or body mass index) (Cederholm, ISI, and MCR indices) appear to be superior to those without OGTT data or body weight-body mass index measurements and, therefore, could offer a better estimate of insulin sensitivity, allowing an improved clinical evaluation of this population at higher risk of cardiovascular disease and type 2 diabetes mellitus. PMID- 17697857 TI - Relationship between low serum endogenous androgen concentrations and arterial stiffness in men with type 2 diabetes mellitus. AB - The aim of this study was to evaluate the relationship between arterial stiffness determined by pulse wave velocity (PWV) and serum endogenous androgen concentrations as well as major cardiovascular risk factors in men with type 2 diabetes mellitus. Serum free testosterone and dehydroepiandrosterone sulfate (DHEA-S) concentrations were measured in 268 men with type 2 diabetes mellitus. Relationships between PWV and serum endogenous androgen concentrations as well as major cardiovascular risk factors, including age, blood pressure, serum lipid concentration, glycemic control (hemoglobin A(1c)), body mass index, and degree of albuminuria, were evaluated. Positive correlations were found between PWV and age (r = 0.491, P < .0001), duration of diabetes (r = 0.320, P < .0001), systolic blood pressure (r = 0.292, P < .0001), and log (urinary albumin excretion) (r = 0.269, P < .0001). Inverse correlations were found between serum free testosterone concentration and PWV (r = -0.228, P = .0003) and between serum DHEA S concentration and PWV (r = -0.252, P = .0002) in men with type 2 diabetes mellitus. Pulse wave velocity was significantly greater in patients with lower concentrations of free testosterone (<10 pg/mL) than in patients with higher concentrations of free testosterone (1864 +/- 359 vs 1736 +/- 327 cm/s; P = .0053). Pulse wave velocity also was significantly greater in patients with lower concentrations of DHEA-S (<1000 ng/mL) than in patients with higher concentrations of DHEA-S (1843 +/- 371 vs 1686 +/- 298 cm/s; P = .0008). Multiple regression analysis identified both serum free testosterone concentration (beta = -.151, P = .0150) and serum DHEA-S concentration (beta = -.200, P = .0017) as independent determinants of PWV. In conclusion, serum endogenous androgen concentrations are inversely associated with arterial stiffness determined by PWV in men with type 2 diabetes mellitus, which is true for men in general based on other works. PMID- 17697858 TI - The rs12255372(G/T) and rs7903146(C/T) polymorphisms of the TCF7L2 gene are associated with type 2 diabetes mellitus in Asian Indians. AB - One thousand thirty-eight normal glucose-tolerant and 1031 type 2 diabetic subjects selected from the Chennai Urban Rural Epidemiology Study were genotyped using polymerase chain reaction-restriction fragment length polymorphism assay to investigate the association of rs12255372(G/T) and rs7903146(C/T) polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene with type 2 diabetes mellitus in Asian Indians. The frequency of the "T" allele of both rs12255372(G/T) and rs7903146(C/T) polymorphisms was significantly higher in diabetic subjects (23% and 33%) compared to that in normal glucose-tolerant subjects (19% and 28%; P = .001 and P = .0001, respectively). Logistic regression analysis of the rs12255372(G/T) polymorphism showed that the odds ratio (adjusted for age, sex, and body mass index) was 1.56 (95% confidence interval [CI], 1.03-2.37; P = .034) for the TT genotype and 1.29 (95% CI, 1.06-1.58; P = .011) for the TG genotype when compared with the GG genotype. Adjusted odds ratios for the TT and TC genotypes of the rs7903146(C/T) polymorphism were found to be 1.50 (95% CI, 1.08 2.08; P = .013) and 1.44 (95% CI, 1.18-1.76; P = .0003), respectively, compared with the CC genotype. Normal glucose-tolerant subjects with the TT genotype of rs12255372(G/T) had significantly higher 2-hour plasma glucose levels (mean +/- SD, 6.1 +/- 1.4 mmol/L) than those with the GG genotype (5.6 +/- 1.0 mmol/L, P = .011). Normal glucose-tolerant subjects with the TT genotype of rs7903146(C/T) polymorphism had significantly higher 2-hour plasma glucose levels (mean +/- SD, 6.0 +/- 1.3 mmol/L) than those with the CC genotype (5.6 +/- 1.0 mmol/L, P = .004). In conclusion, the T allele of the rs12255372(G/T) and rs7903146(C/T) polymorphisms of TCF7L2 gene confer susceptibility to type 2 diabetes mellitus in Asian Indians. PMID- 17697859 TI - Efficacy and safety of allopurinol in patients with hypoxanthine-guanine phosphoribosyltransferase deficiency. AB - Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is a genetic disease of purine metabolism resulting in uric acid overproduction. Allopurinol, which inhibits the enzyme xanthine oxidase and reduces uric acid synthesis, is widely used for the treatment of gout and uric acid overproduction. The aim of the study was to analyze the long-term efficacy and safety of allopurinol in patients with HPRT deficiency. Nineteen patients (13 with Lesch-Nyhan syndrome and 6 with partial HPRT deficiency) were treated with allopurinol (mean dose, 6.4 mg/kg body weight per day; range, 3.7-9.7 mg/kg body weight per day) and followed up for at least 12 months (mean follow-up, 7.6 years). The efficacy of allopurinol was evaluated by serial measurement of purine metabolic parameters and renal function as well as by clinical manifestations. Safety was assessed by recording adverse events. Treatment with allopurinol normalized serum urate level in all patients and resulted in a mean reduction in serum urate of 47%. Allopurinol treatment was associated with a mean 74% reduction in urinary uric acid-to-creatinine ratio. In contrast, allopurinol treatment increased mean hypoxanthine and xanthine urinary excretion rates 5.4- and 9.5-fold, respectively, compared with baseline levels. The decrease in uric acid excretion in complete and partial HPRT-deficient patients was not accompanied by a stoichiometric substitution of hypoxanthine and xanthine excretion rates. Allopurinol-related biochemical changes were similar in patients with either complete or partial HPRT deficiency. Renal function remained stable or improved with treatment. Three patients had urolithiasis during allopurinol treatment. In 2 patients, xanthine stones were documented and they required allopurinol dose adjustments aimed at reducing excessive oxypurine excretion rates. No allopurinol hypersensitivity reactions occurred. Neurologic manifestations were not influenced by allopurinol therapy. In conclusion, allopurinol is efficacious and generally safe for the treatment of uric acid overproduction in patients with HPRT deficiencies. Xanthine lithiasis, developing as a consequence of allopurinol therapy, should be preventable by adjustment of allopurinol dose. PMID- 17697860 TI - Impact of markedly elevated serum lipoprotein(a) levels (> or = 100 mg/dL) on the risk of coronary heart disease. AB - The serum lipoprotein(a) [Lp(a)] concentration is under genetic control, and most humans have values lower than 30 mg/dL. Subjects with markedly elevated serum Lp(a) concentrations, that is, > or =100 mg/dL, are rarely encountered, and these subjects have not yet been fully characterized from the clinical point of view. In the present investigation, we studied a total of 223 subjects, comprising 123 males and 100 females, with serum Lp(a) values of more than 100 mg/dL. Many of these subjects had a variety of underlying diseases, including metabolic disorders, renal diseases, and hypertension. We focused our attention on the patients with metabolic disorders, namely, familial hypercholesterolemia (FH), primary non-FH hypercholesterolemia (HC), and type 2 diabetes mellitus (DM), and conducted a comparative study of the patients of these 3 disease groups with the corresponding disease controls with serum Lp(a) levels of less than 30 mg/dL, a presumed high normal value. The frequency of markedly elevated serum Lp(a) levels in the general population has not been reported previously. We determined the frequencies in a consecutive series of patients at our Diabetes and Lipid Outpatient Clinic; the results revealed that the frequencies were 6.4% (8/125), 2.6% (6/232), and 0.9% (3/352) in patients with FH, HC, and type 2 DM, respectively. In an attempt to further demonstrate the impact of markedly elevated serum Lp(a) concentrations on the risk of coronary heart disease (CHD), we compared the prevalence of CHD among the study subjects with that among the corresponding disease controls. The results revealed a significantly higher CHD prevalence in the study subjects of all the 3 groups as compared with that in the corresponding disease controls: the odds ratios of a markedly elevated serum Lp(a) level were 5.429 (95% confidence interval [CI], 1.353-21.782), 8.243 (95% CI, 2.793-24.327), and 5.981 (95% CI, 2.530-14.139) for FH, HC, and type 2 DM, respectively. In the present study, we examined some characteristics of this rare population of subjects with markedly elevated serum Lp(a) levels and demonstrated a very high prevalence of CHD among these patients with FH, HC, and type 2 DM, strongly suggesting the significance of Lp(a) as a risk factor for CHD. PMID- 17697861 TI - Evidence for the regulation of contraction-induced fatty acid oxidation via extracellular signal-regulated kinase 1/2 activation independent of changes in fatty acid uptake. AB - Data show that extracellular signal-regulated kinase 1/2 (ERK1/2) may be involved in the regulation of fatty acid (FA) uptake during muscle contraction via stimulation of CD36 translocation to the plasma membrane. The perfused hind limb model was used to determine (1) the importance of ERK1/2 signaling on contraction induced FA uptake and (2) the effect of ERK1/2-mediated FA uptake on contraction induced FA oxidation. We perfused rat hind limbs with 8 mmol/L glucose, 550 micromol/L palmitate, and no insulin at rest in the absence of inhibitor and during moderate-intensity electrical stimulation and dose-dependent pharmacologic inhibition of ERK1/2 using increasing concentrations of PD98059 (P1 = none, P2 = 10 micromol/L, P3 = 20 micromol/L, P4 = 50 micromol/L). Increasing PD98059 concentration resulted in a gradual decrease in contraction-induced ERK1/2 phosphorylation, and this was accompanied by a decrease in contraction-induced FA uptake (concentration required for 50% inhibition [IC(50)] = 15.8 +/- 1.6 mumol/L) and in plasma membrane CD36 content (IC(50) = 8.7 +/- 0.3 micromol/L) (P < .05). Percent FA oxidation was significantly lower in P3 and P4 compared with P1 and P2. Based on IC(50) values, FA oxidation demonstrated a greater sensitivity than FA uptake to changes in ERK1/2 phosphorylation (IC(50) = 5.4 +/- 0.3 micromol/L) (P < .05). A positive correlation was found between FA uptake and plasma membrane CD36 content (R(2) = 0.85, P < .05). Plasma membrane CD36 content, FA uptake, and FA oxidation each shared a positive correlation with ERK1/2 phosphorylation (R(2) = 0.64, 0.66, and 0.71, respectively; P < .05). These results suggest that during moderate-intensity muscle contraction, ERK1/2 phosphorylation is required for translocation of CD36 to the plasma membrane and the subsequent increase in FA uptake. In addition, these data suggest that ERK1/2 signaling may be involved in the regulation of FA oxidation independently of its effects on FA uptake. PMID- 17697862 TI - The effect of renal transplantation on adiponectin and its isoforms and receptors. AB - Insulin resistance (IR) and other proatherogenic risk factors associated with end stage kidney disease (ESKD) are improved by renal transplantation. Adiponectin is a protein with insulin-sensitizing, anti-inflammatory, and antiatherogenic properties. It exists in several isoforms, but the high molecular weight (HMW) isoform correlates best with insulin sensitivity. Paradoxically, the levels of this protein and its HMW isoform are increased in ESKD. We measured the homeostasis model assessment for insulin resistance (HOMA-IR), plasma adiponectin and its isoforms, and messenger RNA for adiponectin receptors (AdipoR1 and AdipoR2) on peripheral blood mononuclear cells in 54 stable transplant recipients, 50 patients established on hemodialysis, and 52 controls; groups were matched for body mass index and sex. HOMA-IR values were significantly higher in patients with ESKD compared with controls (P < .0005) and transplant patients (P < .05) but there was no difference between the latter 2 groups. Adiponectin levels were also higher in patients with ESKD compared with controls (P < .0005), and although levels were lower in the transplant group, they remained higher than in controls (P < .0001). However, although the absolute amount of HMW isoform in transplant patients remained higher than in controls (P < .0001), the proportion was similar, and less than in patients with ESKD (P < .005). The absolute amount of the HMW isoform correlated with superior metabolic indices in all 3 cohorts. AdipoR1 and AdipoR2 messenger RNA levels after transplantation were significantly lower than those of ESKD subjects (P < .0001, P < .01), but transplant patients had less AdipoR1 than controls, although their AdipoR2 levels were higher. AdipoR1 correlated with AdipoR2 in all 3 cohorts. We conclude that HOMA-IR was lower in the transplant group compared with the group on hemodialysis and this coincided with lower total adiponectin levels and absolute amount of the HMW isoform and AdipoR on peripheral blood mononuclear cells. Lower AdipoR after transplantation may be secondary to immunosuppression and/or an improvement in glomerular filtration rate and the uremic milieu. PMID- 17697863 TI - Adiponectin levels are reduced, independent of polymorphisms in the adiponectin gene, after supplementation with alpha-linolenic acid among healthy adults. AB - Our first aim was to determine whether an isocaloric intervention using alpha linolenic acid (ALA) in the form of flaxseed oil would alter adiponectin levels among overweight, otherwise healthy, males and females, and our second aim was to test for any potential modification of this intervention by 2 single nucleotide polymorphisms (276 and 45) in the adiponectin gene. Subjects included healthy adult males and females (approximately 81% female; average age, 38 years) with increased waist circumference (mean, 99 cm) and body mass index (mean, 30 kg/m(2)) who were free of chronic disease, not taking medications, and sedentary. Subjects met weekly with a registered dietician for 8 weeks. The control subjects (n = 27) were instructed not to alter their habitual diet and the ALA group (n = 30) was instructed to follow an enriched ALA diet by using flaxseed oil capsules (increasing ALA to 5% of total energy intake) and to lower their dietary fat consumption by a commensurate amount. Diets were analyzed using the Food Intake and Analysis System (v. 3.0, University of Texas School of Public Health, 1998). Fasting blood samples were obtained before and after the 8-week intervention. We found significant decreases (P = .02) in adiponectin (10.12 microg/mL pre, 9.23 microg/mL post) in the ALA group as compared with the control group (7.93 microg/mL pre, 8.10 microg/mL post) after the intervention. We also saw a decline in adiponectin in all genotype groups with the greatest decline among those carrying the rare T allele of single nucleotide polymorphism 276. There were no significant changes in fasting insulin, glucose, or quantitative insulin sensitivity check index values as a result of this intervention. In conclusion, this study suggests that supplementing with ALA for 8 weeks may lower adiponectin levels among healthy individuals, and this effect appears to be independent of polymorphisms in the adiponectin gene. Although the change in adiponectin in response to the omega-3 fatty acids was not accompanied by any change in glucose, insulin, or quantitative insulin sensitivity check index, long-term implications of such a decrease should be considered in future studies. PMID- 17697864 TI - The relationship between visfatin levels and anthropometric and metabolic parameters: association with cholesterol levels in women. AB - Adipose tissue has recently been identified as an endocrine organ. Visfatin is a novel adipocytokine predominantly secreted from visceral adipocytes. Visceral obesity is an important component of metabolic syndrome; however, the relationship between visfatin levels and metabolic syndrome is not clear. The purpose of this study was to explore the association between visfatin levels and anthropometry and parameters of metabolic syndrome. Anthropometric measurements included height, weight, body mass index, waist and hip circumferences, waist-to hip ratio, and blood pressure. Metabolic parameters including fasting serum visfatin, fasting serum insulin and fasting plasma glucose, lipid profiles, and uric acid levels were measured. Data of 500 subjects (244 men and 256 women) were used for the analysis. There was no significant difference in serum visfatin levels between male and female subjects. Visfatin correlated negatively with body mass index (beta = -.011, P = .025) in male subjects; however, visfatin did not correlate with any other anthropometric or any metabolic parameters in male subjects. There was no correlation between visfatin levels and any anthropometric parameters in female subjects; however, it did correlate positively with high density lipoprotein cholesterol levels (beta = .126, P = .006) and correlate negatively with low-density lipoprotein cholesterol levels (beta = -.039, P = .010) in female subjects. In conclusion, visfatin is not related to most anthropometric parameters and most parameters of metabolic syndrome. It may play a role in cholesterol homeostasis in women. PMID- 17697865 TI - Leptin and high-sensitivity C-reactive protein and their interaction in the metabolic syndrome in middle-aged subjects. AB - High-sensitivity C-reactive protein (hsCRP) and leptin, known to interact at the molecular level, have been associated with the metabolic syndrome (MS). We examined the independent and joint effects of high leptin and hsCRP levels on the development of MS in a population-based cohort of middle-aged subjects (N = 1035). Leptin and hsCRP levels increased with an increase in the number of metabolic abnormalities (P < .001). However, additional adjustment for body mass index diluted the association of leptin with MS in women. In men, the association of high leptin with insulin resistance and waist circumference (P < .001), and in women, the association of high hsCRP with insulin resistance (P = .029) and waist circumference (P = .009) persisted in the multivariate logistic regression models. High leptin in men and high hsCRP in women were significant predictors of MS in logistic regression analysis (P < .001). The highest prevalence of MS (86% in men and 71% in women) was observed in the subjects who belonged to the highest quartile in both leptin and hsCRP. MS is associated independently with high leptin in men and with hsCRP in women, whereas individuals with both of these markers belong to the highest risk of metabolic cluster. The study suggests sex specific interplay between metabolic and inflammatory markers in the pathogenesis of MS. PMID- 17697866 TI - Association between serum testosterone concentration and collagen degradation fragments in men with type 2 diabetes mellitus. AB - The aim of the present study was to evaluate relationships between serum endogenous androgens and urinary concentration of cross-linked N-telopeptides of type I collagen (NTx), a bone resorption marker, in men with type 2 diabetes mellitus because low androgen concentrations are associated with both osteoporosis and cardiovascular disease. Relationships between serum free testosterone and urinary NTx concentrations were investigated in 246 consecutive men with type 2 diabetes mellitus. In addition, relationships between urinary NTx concentration and other variables including age, duration of diabetes, blood pressure, serum lipid concentration, hemoglobin A(1c), and body mass index were evaluated. Urinary NTx concentrations were 27.8 (26.4-29.3) nmol of bone collagen equivalent per millimole of creatinine, correlating inversely with serum free testosterone (r = -0.263, P < .0001). Multiple regression analysis identified serum free testosterone (beta = -.292, P < .0001), hemoglobin A(1c) (beta = .144, P = .0404), and smoking status (beta = .143, P = .0402) as independent determinants of urinary NTx. In conclusion, serum free testosterone concentration correlated inversely with urinary NTx concentration, which may partly account for an observed link between osteoporosis and cardiovascular disease in men with type 2 diabetes mellitus. PMID- 17697867 TI - Effect of chromium on carbohydrate and lipid metabolism in a rat model of type 2 diabetes mellitus: the fat-fed, streptozotocin-treated rat. AB - Chromium supplements are widely used as an alternative remedy for type 2 diabetes mellitus (T2DM). In vitro study findings show that chromium picolinate (CrPic) may improve insulin sensitivity by enhancing intracellular insulin receptor. In this study, we evaluated the metabolic effects of CrPic in a rat model of T2DM. Male Sprague-Dawley rats (n = 45, 8 weeks old) were divided into 3 groups. The controls (group I) received a standard diet (12% of calories as fat); group II received a high-fat diet (HFD; 40% of calories as fat) for 2 weeks and then were intraperitoneally injected with streptozotocin (STZ, 40 mg/kg; HFD/STZ) on day 14; group III rats were given group II diets with the addition of 80 microg CrPic per kilogram body weight per day. The addition of CrPic in the group III treatment lowered glucose by an average of 63% (P < .001), total cholesterol by 9.7% (P < .001), and triglycerides by 6.6% (P < .001) compared with group II treatment. Compared with group II, CrPic treatment also lowered free fatty acid levels by 24% (P < .001), blood urea by 33% (P < .05), and creatinine level by 25% (P < .01), and reduced the severity of glomerular sclerosis (P < .0001). Histopathologic findings suggest that the CrPic-treated group had normal renal tubular appearance compared with the HFD/STZ-treated group. Normal appearance of hepatocytes was observed in the CrPic-treated group. These results showed that CrPic has marked beneficial effects against microvascular complications. In conclusion, HFD/STZ rats provide a novel animal model for T2DM. Further treatment with CrPic for 10 weeks significantly ameliorated changes in metabolic risk factors including favorable changes in histopathology of the liver, kidney, and pancreas, suggesting its potential role in the management of diabetes. PMID- 17697868 TI - Liver Galbeta1,4GlcNAc alpha2,6-sialyltransferase is down-regulated in human alcoholics: possible cause for the appearance of asialoconjugates. AB - Galbetal,4GlcNAc alpha2,6-sialyltransferase (ST6GalI) mediates the glycosylation of proteins and lipids to form functionally important glycoproteins and glycolipids in the Golgi compartment. Our previous work demonstrated that long term ethanol feeding in rats caused a marked 59% decrease in ST6GalI activity as well as ST6GalI messenger RNA (mRNA) level in the liver that was due to decreased stability of the mRNA. Clinical observations show that down-regulation of ST6GalI gene and consequent impaired activity of ST6GalI seems to be the major cause for the appearance of asialoconjugates in the blood of long-term alcoholics. The plasma carbohydrate-deficient transferrin (CDT) and sialic acid index of plasma apolipoprotein J were also altered in the alcoholic group compared with the nondrinkers. We have now investigated how alcohol affects the gene regulation of ST6GalI and the possible mechanism in postmortem human liver specimens taken from nondrinkers, moderate alcohol drinkers, and heavy alcohol drinkers. Real-time polymerase chain reaction analyses of the liver RNA extract showed that ST6GalI mRNA level was progressively decreased by 49% in moderate drinkers (P < .01) and by 69% in heavy drinkers (P < .01) compared with nondrinkers. Western blot analysis showed that liver ST6GalI protein level was negligibly decreased in moderate drinkers but decreased by 30% (P < .05) in heavy drinkers compared with nondrinkers. We further demonstrated a single ST6GalI mRNA-binding protein complex in the normal human liver extract, which progressively decreased in the liver extracts of moderate and heavy alcohol drinkers. Thus, it is concluded that the appearance of asialoconjugates in alcoholics is possibly due to the down regulation of ST6GalI gene expression. PMID- 17697869 TI - Mutational analysis of CYP27A1: assessment of 27-hydroxylation of cholesterol and 25-hydroxylation of vitamin D. AB - The CYP27A1 gene encodes a mitochondrial enzyme that modulates the acidic biosynthetic pathway for bile acids beginning with the 27-hydroxylation of cholesterol. CYP27A1 also 25-hydroxylates vitamin D(3). Gene mutations cause cerebrotendinous xanthomatosis (CTX), an autosomal recessive disorder, and may cause 25-hydroxyvitamin D deficiency and early-onset osteoporosis and fractures in affected patients. To examine the effects of mutations of CYP27A1 on vitamin D and cholesterol hydroxylating activity, recombinant CYP27A1 and mutant complementary DNAs produced by site-directed mutagenesis were stably expressed in either Escherichia coli or COS-1 cells. Activities of wild-type and mutant enzymes were determined with cholesterol, vitamin D(3), and 1alpha-hydroxyvitamin D(3) (1alphaOHD(3)) as substrates. Of the 15 mutants tested, 11 expressed protein and 4 expressed little or no protein. Functional heme activity, estimated by reduced CO difference spectra at 450 nm, was absent in 12 mutants. When expressed in E. coli, 3 mutants, K226R, D321G, and P408S, each known to cause clinically CTX, showed modest decreases in reduced CO spectra peak and either no change or decreases of less than 50% in hydroxylation of cholesterol, vitamin D(3), and 1alphaOHD(3) compared with wild type. When expressed transiently in COS-1 cells, each of these mutants showed 25-hydroxylation activity for 1alphaOHD(3) as well as wild type. Thus, 3 mutants, K226R, D321G, and P408S, known to occur clinically with nonfunctioning mutants, hydroxylated cholesterol, vitamin D(3), and 1alphaOHD(3). How they contribute to the pathogenesis of CTX despite being biologically active in vitro remains to be determined. PMID- 17697870 TI - Acceleration of diabetic renal injury in the superoxide dismutase knockout mouse: effects of tempol. AB - Indices of renal injury and oxidative stress were examined in mice with deficiency of cytosolic Cu(2+)/Zn(2+) superoxide dismutase (SOD1-/-, KO) and their wild-type (WT) littermates with streptozotocin-induced diabetes. After 5 weeks of diabetes, KO diabetic (D) but not WT-D mice developed marked albuminuria, increases in glomerular content of transforming growth factor beta, collagen alpha1(IV), and nitrotyrosine, and higher glomerular superoxide compared with corresponding values in nondiabetics. After 5 months of diabetes, increases in these parameters, mesangial matrix expansion, renal cortical malondialdehyde content, and severity of tubulointerstitial injury were all significantly greater, whereas cortical glutathione was lower, in KO-D than in WT-D. In contrast to WT-D, after 4 weeks of diabetes, KO-D mice did not develop the increase in inulin clearance (C(In)) characteristic of early diabetes. The nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methylester suppressed C(In) in WT-D, but had no effect on C(In) in KO-D. Treatment of KO-D with the SOD mimetic tempol for 4 weeks suppressed albuminuria, increases in glomerular transforming growth factor beta, collagen alpha1(IV), nitrotyrosine, and glomerular superoxide, and concurrently increased C(In). The latter action of tempol in KO-D was blocked by the N(omega)-nitro-l-arginine methylester. The findings provide support for a role for superoxide and its metabolism by SOD1 in the pathogenesis of renal injury in diabetes in vivo, and implicate increased interaction of superoxide with nitric oxide as a pathogenetic factor. PMID- 17697871 TI - Effects of hyperglycemia on quantitative liver functions by the galactose load test in diabetic rats. AB - Blood galactose clearance after an intravenous galactose load has been widely used as a quantitative liver function test. We have developed a novel quantitative rat liver function test, the galactose single point (GSP) method, to assess residual liver function with various injuries by measuring single time point galactose concentration in blood after an intravenous bolus injection of galactose. The goal of this study was to evaluate the influence of nonhepatic factors such as hyperglycemia on GSP and galactose elimination capacity (GEC) in rats. Four groups of animal studies were carried out, as follows: (1) normal control (NC), (2) streptozotocin-induced diabetes (DM), (3) carbon tetrachloride induced hepatotoxicity (CCl(4)), and (4) streptozotocin-induced diabetes with CCl(4)-induced hepatotoxicity (DM + CCl(4)). The serum glucose levels in the diabetic groups (DM and DM + CCl(4)) were significantly increased compared with the NC and CCl(4) groups (P < .001). A significant increase in hepatic activities of aspartate aminotransferase and alanine aminotransferase was observed in the CCl(4)-treated groups (CCl(4) and DM + CCl(4)) compared with the NC and DM groups (P < .001). In comparison with the NC group, the values of GSP and GEC in the diabetic groups (DM and DM + CCl(4)) were significantly reduced (P < .001) and increased (P < .01), respectively. Galactose single point had highly significant correlations with GEC (P < .001). These results suggest that galactose metabolism tests-as quantitative parameters of liver function-should be interpreted with caution in the condition of a significant hyperglycemia. PMID- 17697872 TI - Exercise before or after refeeding prevents refeeding-induced recovery of cell size after fasting with a different pattern of metabolic gene expressions in rat epididymal adipocytes. AB - We investigated the effect of exercise before or after refeeding on cell size and on the expression of several messenger RNAs (mRNAs) involved in lipolysis and lipogenesis in fasted rat epididymal adipocytes. Fasting for 65 hours reduced the diameter of adipocytes to 72.0 microm from 78.4 microm in fed control rats, whereas refeeding for 1 or 2 days restored adipocyte size to 74.0 or 75.8 microm, respectively. Exercise before or after refeeding blocked refeeding-induced restoration of adipocyte size and led to adipocyte size similar to that observed after fasting. Fasting dramatically reduced expression of the fatty acid synthase mRNA, although expression of this gene returned to the control level after refeeding. However, exercise after but not before refeeding inhibited recovery of the expression of fatty acid synthase mRNA resulting from refeeding. In contrast, exercise before but not after refeeding led to enhanced expression of mRNAs encoding the hormone-sensitive lipase and beta(3)-aderenoceptor. Thus, exercise before or after refeeding prevents refeeding-induced restoration of adipocyte size after fasting via different pathways. Exercise before and after refeeding enhanced the expression of lipolytic mRNAs or inhibited the expression of lipogenic mRNAs, respectively. PMID- 17697873 TI - Analysis of the SLC26A4 gene in patients with Pendred syndrome in Taiwan. AB - Pendred syndrome (PS) is an autosomal recessive disease that is characterized by congenital sensorineural hearing loss, goiter, and a partial iodine organification defect. In this study, we characterized the thyroid status and identified mutations in the SLC26A4 gene in Chinese subjects with PS. We evaluated 7 unrelated Chinese subjects who had PS. Biochemical analysis, formal audiogram, ultrasonography of the thyroid gland, perchlorate discharge test, computerized tomography scan of the vestibular aqueducts, and DNA sequence analysis of SLC26A4 were performed. Levels of thyroid hormones were essentially normal in all patients: 2 patients had goiters and/or elevated serum thyroglobulin levels, whereas 2 other patients had positive thyroid antibodies and a positive perchlorate discharge test. We identified SLC26A4 gene mutations in 6 of 7 probands and their affected relatives. The affected subjects in family I was compound heterozygous for 2 missense mutations: a mutation in exon 9 (1079C>T) that resulted in the replacement of alanine by valine at codon 360 (A360V) and a mutation in exon 19 (2168A>G) that resulted in the replacement of histidine by arginine at codon 723 (H723R). The affected subjects in families II and III all were homozygous for a mutation in intron 7. The probands IV and V were compound heterozygotes for the mutation in intron 7 and in exon 19, and the proband VI was compound heterozygous for the intron 7 mutation and a missense mutation in exon 12 (1343C>T) that resulted in the replacement of serine by leucine at codon 448 (S448L). One novel mutation was identified (A360V). We identified biallelic mutations in the SLC26A4 gene in 6 of 7 probands with PS in Taiwan, including a novel missense mutation. The mild thyroid dysfunction in these patients suggests that PS should be considered in all patients with congenital or early-onset hearing impairment. PMID- 17697874 TI - The dual peroxisome proliferator-activated receptor alpha/gamma agonist tesaglitazar further improves the lipid profile in dyslipidemic subjects treated with atorvastatin. AB - Tesaglitazar (GALIDA; AstraZeneca, Wilmington, DE) is a dual peroxisome proliferator-activated receptor alpha/gamma agonist previously in clinical development for the treatment of glucose and lipid abnormalities associated with type 2 diabetes mellitus and insulin resistance. This study compared the efficacy of tesaglitazar with that of pioglitazone as adjunctive therapy to atorvastatin in subjects with abdominal obesity and dyslipidemia. In this open-label, 3-way crossover study, 58 subjects received atorvastatin 10 mg once daily in a 6-week run-in period, followed by tesaglitazar 3 mg, pioglitazone 45 mg, or placebo, as adjunctive therapy to atorvastatin, in a randomized sequence for 6 weeks each. Serum triglycerides and other lipids, apolipoproteins, glucose, and insulin concentrations were compared between treatments. Tesaglitazar adjunctive therapy reduced serum triglycerides significantly more from baseline (-1.07 mmol/L) than pioglitazone (-0.33 mmol/L; P = .007) or placebo (-0.09 mmol/L; P < .0001). Tesaglitazar also resulted in significantly greater improvements in free fatty acids, very low-density lipoprotein cholesterol, low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio, low-density lipoprotein particle size, apolipoprotein (apo) B, apo C-III, and the apo B/apo A I ratio compared with pioglitazone or placebo. Tesaglitazar adjunctive therapy also reduced fasting plasma glucose, fasting plasma insulin, and insulin resistance (homeostasis model assessment index) significantly more than pioglitazone or placebo (P < .0001 for all comparisons). Tesaglitazar was generally well tolerated in combination with atorvastatin, but hemoglobin and absolute neutrophil count decreased and serum creatinine increased more with tesaglitazar than with pioglitazone or placebo. These effects, also shown in previous trials, led to the discontinuation of the clinical development of the drug. In conclusion, the addition of tesaglitazar to a background of atorvastatin therapy further improved the dyslipidemia associated with insulin resistance. PMID- 17697875 TI - Short- and long-term beneficial effects of a multidisciplinary therapy for the control of metabolic syndrome in obese adolescents. AB - Visceral fat is highly correlated with metabolic syndrome in obese adolescents. The aims of this study were to determine the prevalence of metabolic syndrome and to assess the effect of a long-term (1 year) intervention with multidisciplinary therapy in predicting metabolic syndrome among obese adolescents, as well as to compare short- with long-term therapy. Eighty-three postpuberty obese adolescents were recruited, including 37 boys (body mass index [BMI], 36.19 +/- 3.85 kg/m(2)) and 46 girls (BMI, 35.73 +/- 4.42 kg/m(2)). Body composition was measured by plethysmography using the BOD POD body composition system (version 1.69, Life Measurement Instruments, Concord, CA), and visceral fat was analyzed by ultrasound. Metabolic syndrome was determined according to the World Health Organization criteria. Patients were assigned to a weight loss multidisciplinary intervention consisting of nutritional, exercise, psychological, and clinical therapy. At the beginning of therapy, we found that 27.16% of the obese adolescents presented metabolic syndrome, whereas only 8.3% did so after intervention. Indeed, in boys, BMI (36.19 +/- 3.85 to 32.06 +/- 5.85 kg/m(2)), visceral fat (4.88 +/- 1.35 to 3.63 +/- 1.71 cm), homeostasis model assessment of insulin resistance (4.77 +/- 3.41 to 3.18 +/- 2.33), and percentage of body fat (38.24% +/- 6.54% to 30.02% +/- 13.43%) presented a statistically significant reduction; and their fat-free mass percentage increased (62.14% +/- 5.78% to 69.17% +/- 12.37%). In girls, after long-term therapy, BMI (35.73 +/- 4.42 to 33.62 +/- 3.78 kg/m(2)), visceral fat (3.70 +/- 1.40 to 2.75 +/- 1.01 cm), and percentage of body fat (46.10% +/- 5.66% to 39.91% +/- 5.59%) showed a statistically significant reduction; and their fat-free mass increased (53.61% +/ 5.65% to 59.82% +/- 5.78%). In conclusion, long-term multidisciplinary therapy was effective in promoting beneficial changes in some predictors and decreasing the prevalence of metabolic syndrome in obese adolescents. PMID- 17697877 TI - Quantitative measurements of integrin-mediated adhesion to extracellular matrix. AB - Integrin-mediated adhesion is based on the binding of integrins to immobilized ligands either in the extracellular matrix or on the surface of adjacent cells. The strength of adhesion is determined primarily by the number of adhesive bonds that form. Integrins have also been described as signaling receptors. Like adhesion, signals from integrins receptors can depend on the number of integrins that are bound to substrate attached ligands. The common methods for measuring cell adhesion are only capable of measuring initial interactions because the multivalent nature of adhesive bonds when the cell is considered as a unit, these assays reach plateau levels. To measure adhesive integrin-ligand bonds, a spinning disc device is described in which the mean cell detachment force is proportional to the number of adhesive bonds. Particularly as the field has moved from identification of integrins and their ligands into the analysis of adhesion and its relationship to cell signaling, it is important to shift to assays that relate the extracellular binding to the intracellular signals. Specific plans, methods, and analytic strategies are provided to apply this technology to current problems in integrin biology. At present, this is the only published approach that will provide good measures of the number of adhesive bonds that can be generally applied. PMID- 17697878 TI - Investigating integrin regulation and signaling events in three-dimensional systems. AB - There has been much recent interest in working with cells cultured in three dimensional (3D) matrices to better model the properties of the extracellular matrix environment found in vivo. However, working within 3D matrices adds several difficulties to experiments that have become routine in two-dimensional (2D) culture systems. Biochemical approaches are made difficult by the presence of milligram quantities of matrix protein, while cell biology approaches are more difficult to assess and image. Moreover, 3D imaging adds complexity to fluorescence studies, including the inherent challenge of a 3D volume as opposed to a 2D image, increased depths of field, and problems of light scatter. The purpose of this chapter is to provide a few overall strategies for working within 3D culture systems, focusing on biochemical and molecular imaging approaches. PMID- 17697879 TI - Integrins in cell migration. AB - Integrins are cell-surface adhesion receptors that play a central role in regulating cell migration by mediating interactions between the extracellular matrix and the actin cytoskeleton. Substantial progress has been made in understanding the mechanisms by which the formation and breakdown of adhesions are regulated. Here we describe general methods used to study integrin-mediated cell migration. Furthermore, we outline detailed procedures to examine focal adhesion assembly and disassembly using time-lapse fluorescent microscopy. Finally, we provide methods for the analysis of podosomes, which are highly dynamic adhesive structures that form in immune cells and invasive cancer cells. PMID- 17697880 TI - Integrin cytoskeletal interactions. AB - Integrin adhesion receptors mediate cell-cell and cell-substratum adhesion and provide a continuous link for the bidirectional transmission of mechanical force and biochemical signals across the plasma membrane. Integrin-dependent cellular activities such as adhesion, migration, proliferation, and survival rely upon the dynamic interaction of integrin cytoplasmic tails with intracellular integrin binding proteins. In this review, we describe some of the methods that we have used to identify and characterize the interactions between integrin cytoplasmic tails and cytoskeletal proteins, as well as highlight methods to decipher the regulation of integrin tail interactions with intracellular ligands. Specifically, we describe recombinant models of integrin cytoplasmic tails and their use in protein-protein interaction studies. PMID- 17697881 TI - Cell survival in a three-dimensional matrix. AB - Integrin-mediated adhesion acts as a pluripotent mediator of cell signaling, triggering many pathways that promote proliferation and permit them to resist exogenous proapototic insults. To date, most studies have focused on apoptosis among cells adherent to rigid tissue-culture plastic substrates that tends to maximize integrin survival signaling. The physiological interpretation of such studies remains unclear. Here we describe methods to study integrin-mediated cell survival using matched cell populations that differ only in integrin expression, using a three-dimensional (3D) extracellular matrix culture. The preparation of appropriate cell types as well as the use of 3D collagen and fibrin gels is described. Methods to assess apoptosis and their application in the model are detailed. These techniques will offer an opportunity to study cell survival in the context of a non-rigid 3D extracellular matrix. PMID- 17697882 TI - Platelet integrin adhesive functions and signaling. AB - Integrin-mediated cellular events affect all cell types and functions, in physiological as well as pathological settings. Blood platelets, because of their unique nature, have proven to be a powerful cell model with which to study the adhesive and signaling properties of integrins. The characterization of the structural and molecular mechanisms regulating the main platelet integrin, alphaIIbbeta3, has provided some essential clues as to how integrins are regulated in general. The present chapter details the various protocols and reagents currently in use in our laboratory to study alphaIIbbeta3 adhesive responses and signaling in both human and murine cell models. PMID- 17697883 TI - Development of monoclonal antibodies to integrin receptors. AB - Integrins are heterodimeric cell surface receptors composed of an alpha and a beta subunit. They are involved in homotopic and heterotopic cell adhesion and also function as receptors for extracellular matrix molecules such as collagen, fibronectin and laminin. The family to which an integrin belongs is defined by the presence of a particular beta subunit paired with a unique alpha subunit. In this chapter we describe methods to produce monoclonal antibodies to the family of integrin subunits characterized by beta1 and provide detailed instructions for the development of a monoclonal antibody to the alpha6 integrin receptor expressed by human prostate carcinoma cells (PC3 cells). Data are presented that correlate the functional capabilities of an antibody with its biochemical characterization. PMID- 17697884 TI - Cell adhesion, cellular tension, and cell cycle control. AB - Cooperative signaling between growth factor receptor tyrosine kinases, integrins, and the actin cytoskeleton is required for activation of the G1-phase cyclin dependent kinases and progression through G1-phase. Increasing evidence suggests that there is cell type specificity in these cooperative interactions and that the compliance of the underlying substratum can strongly affect adhesion dependent signaling to the cell cycle. This chapter reviews our current methods for studying how cell type specificity and changes in substratum compliance can contribute to G1-phase cell cycle control. We also describe several of our current analytical procedures. PMID- 17697885 TI - Analysis of integrin signaling by fluorescence resonance energy transfer. AB - Fluorescence resonance energy transfer (FRET) has been proven to be a powerful tool to visualize and quantify the signaling cascades in live cells with high spatiotemporal resolutions. Here we describe the development of the genetically encoded and FRET-based biosensors for imaging of integrin-related signaling cascades. The construction of a FRET biosensor for Src kinase, an important tyrosine kinase involved in integrin-related signaling pathways, is used as an example to illustrate the construction procedure and the pitfalls involved. The design strategies and considerations on improvements of sensitivity and specificity are also discussed. The FRET-based biosensors provide a complementary approach to traditional biochemical assays for the analysis of the functions of integrins and their associated signaling molecules. The dynamic and subcellular visualization enabled by FRET can shed new light on the molecular mechanisms regulating integrin signaling and advance our knowledge in the understanding of integrin-related pathophysiological processes. PMID- 17697886 TI - Studies on integrins in the nervous system. AB - Integrins are of interest to neuroscientists because they and many of their ligands are widely expressed in the nervous system and have been shown to have diverse roles in neural development and function (Clegg et al., 2003; Li and Pleasure, 2005; Pinkstaff et al., 1998, 1999; Reichardt and Tomaselli, 1991; Schmid et al., 2005). Integrins have also been implicated in control of pathogenesis in several neurodegenerative diseases, brain tumor pathogenesis, and the aftermath of brain and peripheral nervous system injury (Condic, 2001; Ekstrom et al., 2003; Kloss et al., 1999; Verdier and Penke, 2004; Wallquist et al., 2004). Using integrin antagonists as therapeutic agents in a variety of neurological diseases is of great interest at present (Blackmore and Letourneau, 2006; Mattern et al., 2005; Polman et al., 2006; Wang et al., 2006). In this chapter, we describe methods used in our laboratory to characterize neuronal responses to extracellular matrix proteins, and procedures for assessing integrin roles in neuronal cell attachment and differentiation. PMID- 17697887 TI - Methods for identifying novel integrin ligands. AB - Integrins are cell adhesion receptors that have many important roles in organ development and tissue integrity, functioning to mediate interactions between cells and the ECM. The entire repertoire of integrins is vast, and the specific roles of each are determined by unique integrin-ligand interactions. These interactions allow for dynamic regulation of multiple processes. Despite intense efforts to elucidate individual integrin ligands, existing methods have been limiting. In this chapter, we describe methods developed in our laboratory to identify new integrin ligands that should be useful for characterizing novel integrin functions. These methods are applicable for studies on a variety of integrins, and may be extended to other cell surface receptors as well. PMID- 17697888 TI - Analysis of integrin functions in peri-implantation embryos, hematopoietic system, and skin. AB - Integrins mediate cell adhesion, permit traction forces important for cell migration, and cross-talk with growth factor receptors to regulate cell proliferation, cell survival, and cell differentiation. The plethora of functions explains their central role for development and disease. The progress in mouse genetics and the ease with which the mouse genome can be manipulated enormously contributed to our understanding of how integrins exert their functions at the molecular level. In the present chapter, we describe tests that are routinely used in our laboratory to investigate embryos, organs, and cells (peri implantation embryos, hematopoietic system, epidermis, and hair follicles) that lack the expression of integrins or integrin-associated proteins. PMID- 17697889 TI - Identification and molecular characterization of multiple phenotypes in integrin knockout mice. AB - Each of the 24 known integrin subunits has now been inactivated in mice, and a growing number of conditional null lines are becoming available. Lines of mice expressing null mutations in integrin subunit genes have taught us a great deal about the remarkably diverse functions that integrins perform in vivo in mammals. Thorough evaluation of the phenotypes manifested by these lines has also revealed a number of previously unexpected integrin ligands and signaling partners. In this article, we review approaches that can contribute to optimal use of this valuable resource. PMID- 17697890 TI - Purification, analysis, and crystal structure of integrins. AB - Integrins are large modular cell-surface receptors that regulate almost every aspect of cellular function through bidirectional signals transmitted across the lipid bilayer. Regulation of integrin activity is accomplished by complex and still incompletely understood biochemical pathways that modify integrin ligand binding, clustering, trafficking, and signaling functions. The dynamic tertiary and quaternary changes required to channel some of these activities have hampered, until recently, the crystal structure determination of these heterodimeric receptors. In this chapter, we review the methods used to purify and characterize these proteins biophysically and functionally, and to derive their three-dimensional structures. PMID- 17697891 TI - Electron microscopy of integrins. AB - Integrins are a family of heterodimeric, cell-surface receptors that mediate interactions between the cytoskeleton and the extracellular matrix. We have used electron microscopy and single-particle image analysis combined with molecular modeling to investigate the structures of the full-length integrin alpha(IIb)beta(3) and the ectodomain of alpha(V)beta(3) in a complex with fibronectin. The full-length integrin alpha(IIb)beta(3) is purified from human platelets by ion exchange and gel filtration chromatography in buffers containing the detergent octyl-beta-D-glucopyranoside, whereas the recombinant ectodomain of alpha(V)beta(3) is soluble in aqueous buffer. Transmission electron microscopy is performed either in negative stain, where the protein is embedded in a heavy metal such as uranyl acetate, or in the frozen-hydrated state, where the sample is flash-frozen such that the buffer is vitrified and native conditions are preserved. Individual integrin particles are selected from low-dose micrographs, either by manual identification or an automated method using a cross-correlation search of the micrograph against a set of reference images. Due to the small size of integrin heterodimers (approximately 250 kDa) and the low electron dose required to minimize beam damage, the signal-to-noise level of individual particles is quite low, both by negative-stain electron microscopy and electron cryomicroscopy. Consequently, it is necessary to average many particle images with equivalent views. The particle images are subjected to reference-free alignment and classification, in which the particles are aligned to a common view and further grouped by statistical methods into classes with common orientations. Assessment of the structure from a set of two-dimensional averaged projections is often difficult, and a further three-dimensional (3D) reconstruction analysis is performed to classify each particle as belonging to a specific projection from a single 3D model. The 3D reconstruction algorithm is an iterative projection matching routine in which the classified particles are used to construct a new, 3D map for the next iteration. Docking of known high-resolution structures of individual subdomains within the molecular envelope of the 3D EM map is used to derive a pseudoatomic model of the integrin complex. This approach of 3D EM image analysis and pseudoatomic modeling is a powerful strategy for exploring the structural biology of transmembrane signaling by integrins because it is likely that multiple conformational states will be difficult to crystallize, whereas the different states should be amenable to electron cryomicroscopy. PMID- 17697892 TI - Intravital imaging and cell invasion. AB - The main cause of cancer treatment failure is the invasion of normal tissues by cancer cells that have migrated from a primary tumor. An important obstacle to understanding cancer invasion has been the inability to acquire detailed, direct observations of the process over time in a living system. Intravital imaging, and the rodent dorsal skinfold window chamber in particular, were developed several decades ago to address this need. However, it is just recently, with the advent of sophisticated new imaging systems such as confocal and multiphoton microscopy together with the development of a wide range of fluorescent cellular and intracellular markers, that intravital methods and the window chamber have acquired powerful new potential for the study of cancer cell invasion. Moreover, the interaction of various cell signaling pathways with the integrin class of cell surface receptors has increasingly been shown to play a key role in cancer invasion. The window chamber in combination with integrin-knockout rodent models, integrin-deficient tumor cell lines, and integrin antagonists, allows real-time observation of integrin-mediated cancer invasion and angiogenesis. The present review outlines the history, uses, and recent methods of the rodent dorsal skinfold window chamber. The introduction of labeled tumor cells into the chamber is described, and imaging of tumors and angiogenic vessels within chambers using standard brightfield, confocal, and multiphoton microscopy is discussed in detail, along with the presentation of sample images. PMID- 17697893 TI - Using Xenopus embryos to investigate integrin function. AB - Xenopus embryos are a useful and important system for cell biological studies of integrin adhesion and signaling. Explants prepared from gastrulating embryos undergo normal morphogenetic movements when cultured in simple salt solutions. These preparations are accessible to a variety of experimental perturbations and time-lapse imaging at high resolution, making it possible to elucidate mechanisms of integrin function in intact tissues and whole embryos. Methods used for the visualization of integrins, cadherins, extracellular matrix, and cytoskeletal linkages in both fixed and live tissues are described. We also discuss the use of a novel explant preparation suitable for following the normal deposition and assembly of fibronectin fibrils by ectoderm and mesoderm at gastrulation. PMID- 17697894 TI - Methods to study lymphatic vessel integrins. AB - The lymphatic system plays a key role in the drainage of fluids and proteins from tissues and in the trafficking of immune cells throughout the body. Comprised of a network of capillaries, collecting vessels, and lymph nodes, the lymphatic system plays a role in the metastasis of tumor cells to distant parts of the body. Tumors induce lymphangiogenesis, the growth of new lymphatic vessels, in the peritumoral space and also within tumors and lymph nodes. Tumor lymphangiogenesis has been shown to play a role in promoting tumor metastasis. As mediators of lymphatic endothelial cell adhesion, migration, and survival, integrins play key roles in the regulation of lymphangiogenesis. Recent studies indicate that select integrins promote lymphangiogenesis during development and disease and that inhibitors or loss of expression of these integrins can block lymphangiogenesis. In this report, we describe methods to isolate and culture murine and human lymphatic endothelial cells as well as methods to analyze the expression of integrins on these cells. We also show how to assess integrin mediated adhesion, migration, and tube formation in vitro. We demonstrate how to evaluate integrin function during lymphangiogenesis in a variety of animal models in vivo. Additionally, we show how to study lymphangiogenesis using intravital microscopy. PMID- 17697895 TI - Analysis of integrin signaling in genetically engineered mouse models of mammary tumor progression. AB - Cancer progression-the evolution of malignant tumors towards metastatic dissemination-is a complex, multistep process orchestrated by neoplastic cells but aided by elements of the tumor microenvironment such as macrophages, activated fibroblasts, and endothelial cells. During tumor progression, cancer cells acquire a number of traits, such as the ability to undergo unrestrained proliferation, to resist pro-apoptotic insults, and to invade through tissue boundaries. Genetic and epigenetic changes conspire to drive the emergence of these traits against the backdrop of host selection. It is becoming increasingly clear that certain integrins and integrin-signaling components amplify oncogenic signaling to promote tumor progression. Mouse models of cancer provide useful, if not necessary, experimental systems to study tumor initiation and progression in vivo and to test novel therapeutic approaches. We have utilized mouse models of mammary tumorigenesis to examine the role of integrin alpha6beta4 signaling in tumor progression in vivo. In this chapter, we describe a collection of cell biological and genetic methods that may aid in characterizing the roles of integrin signals in mammary tumorigenesis. PMID- 17697896 TI - Design and chemical synthesis of integrin ligands. AB - The design and synthesis of peptidic and nonpeptidic integrin ligands derived from the most abundant natural tripeptide sequence, RGD, are described in this article. Special emphasis is placed on the activity and selectivity of the ligands to integrin subtypes. Two approaches are described-ligand- and structure oriented design. When no structure of the complex or the target is known, one may derive suitable starting points from natural peptide sequences, which often require conformational restriction for a further optimization. A "spatial screening" procedure was used to identify highly active and selective ligands for the integrin subtypes alphavbeta3 and alphaIIbbeta3. Structure-based methods require knowledge of the binding domain of the target. Hence, the first structure of the alphavbeta3 integrin with bound cilengitide was a landmark for the structure-based approach. Meanwhile, a design using homology models of other integrin subtypes has also been successfully applied. To improve the ADME profile, nonpeptidic ligands have been developed using the information of the spatial distances and orientations of the most important pharmacophoric groups (especially the carboxyl group and the basic moiety at the other end of the molecule). Applications of the alphavbeta3 ligands as drugs in antiangiogenic tumor therapy for molecular imaging of metastases and for improvement of biocompatibility of grafts are briefly described. PMID- 17697897 TI - Evaluating integrin function in models of angiogenesis and vascular permeability. AB - All vascular biological processes are influenced to some degree by integrins expressed on endothelial cells, vascular smooth muscle cells, fibroblasts, platelets, or other circulating cells. In particular, angiogenesis requires cells to process signals from their microenvironment and respond by altering their cell cell and cell-matrix adhesion, events which allow migration and vascular remodeling over the period of days to weeks. On the other hand, endothelial cells can respond to a permeability stimulus and alter their junctional adhesion molecules or vesicular transport machinery within seconds or minutes. This chapter will discuss the current understanding of how integrins participate in these processes, and explore the in vitro and in vivo models available to study the role of integrin function during angiogenesis and vascular leak. PMID- 17697898 TI - Hypertriglyceridemia and cardiovascular risk reduction. AB - BACKGROUND: Elevated triglyceride (TG) levels are prevalent among the US population, often occurring in persons who are overweight or obese, or who have type 2 diabetes or the metabolic syndrome. There is evidence that elevated TG levels may be a significant independent risk factor for coronary heart disease (CHD), particularly in women. OBJECTIVE: This article reviews data on the epidemiology, associated risks, treatment, and prevention of hypertriglyceridemia, including recommended TG goals and available TG-lowering agents. METHODS: MEDLINE was searched for articles published from 1990 through 2006 using the terms hypertriglyceridemia, dyslipidemia, and coronary heart disease, with subheadings for risk, statins, niacin, fibrates, thiazolidinediones, and omega-3 fatty acids. The reference lists of relevant articles were examined for additional citations. Publications discussing the epidemiology of hypertriglyceridemia, CHD risk, treatment guidelines for lipid management, clinical trials involving TG-lowering drugs, and outcomes for lipid modifying therapies were selected for review. RESULTS: Concern over the increasing rate of hypertriglyceridemia and its deleterious health consequences is reflected in the most recent National Cholesterol Education Program guidelines. Several lipid-lowering agents are available, including statins, fibrates, niacin, thiazolidinediones, and prescription omega-3 fatty acids. Clinical trials of these drugs have reported lowering of TG by 7% to 50%. Along with lifestyle changes, the use of combination pharmacotherapy to reduce lipid levels (including TG) may be an effective strategy in patients with dyslipidemia. CONCLUSION: Use of strategies to manage TG levels, along with low-density lipoprotein cholesterol levels, is warranted to help reduce the risk of CHD. PMID- 17697899 TI - Cholesterol reduction yields clinical benefits: meta-analysis including recent trials. AB - BACKGROUND: Previous meta-analyses reported by Gould et al found significant decreases of 15% in the risk for coronary heart disease (CHD)-related mortality and 11 % in risk for all-cause mortality per decrease of 10% in total cholesterol (TC) level. OBJECTIVE: To evaluate the effects of reducing cholesterol on clinical events after including data from recent clinical trials. METHODS: Using a literature search (MeSH key terms, including: bezafibrate, coronary disease, efficacy, gemfibrozil, hydroxymethylglutaryl-CoA reductase inhibitors, hypercholesterolemia, niacin [nicotinic acids], randomized controlled trials, and treatment outcome; years: 1999-2005), we identified trials published in English that assessed the effects of lipid-modifying therapies on CHD end points, including CHD-related death, myocardial infarction, and angina pectoris. We also included all studies from the previously published meta-analysis. Using the same analytic approach as previously, we determined the effects of net absolute reductions (1 mmol/L [38.7 mg/dL]) in TC and low-density lipoprotein cholesterol (LDL-C) on the relative risks (RRs) for all-cause mortality, CHD-related mortality, any CHD event (mortality or nonfatal myocardial infarction), and non CHD-related mortality. RESULTS: We included 62 studies involving 216,616 patients, including 126,474 from 24 randomized controlled trials the findings of which were published since the previous meta-analysis (1998). Among all patients, for every 1-mmol/L decrease in TC, there was a 17.5 reduction in RR for all-cause mortality; 24.5 %, for CHD-related mortality; and 29.5% for any CHD event. Corresponding reductions for every 1-mmol/L decrease in LDL-C were 15.6%, 28.0%, and 26.6%, respectively. Similar relationships were observed in patients without CHD. No significant relationship was found between lipid reduction and non-CHD related mortality risk. CONCLUSIONS: The results from the present analysis support conclusions from previous meta-analyses that cholesterol lowering is clinically beneficial in patients with CHD or at elevated CHD risk. These results also support the previous finding that non-CHD-related mortality is unrelated to lipid reductions. PMID- 17697900 TI - Inhaled dry powder insulin for the treatment of diabetes mellitus. AB - BACKGROUND: Inhaled dry powder insulin (IDPI) is the first inhaled insulin approved for the treatment of type 1 and type 2 diabetes mellitus (DM). OBJECTIVE: This article reviews available information on IDPI, focusing on its clinical pharmacokinetics, comparative efficacy, tolerability, adverse events, dosage and administration, and cost. METHODS: MEDLINE (1966-July 2006) and Web of Science (1995-July 2006) were searched for original research and review articles published in English. The search terms used were inhaled insulin, inhaled human insulin, rDNA origin inhalation powder, inbaled dry powder insulin, and IDPI. All published comparative efficacy studies were included in the review, as well as selected information from the package insert for IDPI. RESULTS: IDPI is an inhaled dry powder form of regular human insulin (RHI) that is used as a premeal insulin to improve glycemic control by reducing postprandial glucose excursions. The literature search identified 5 efficacy trials comparing reductions in glycosylated hemoglobin (HbA(1c)) in a total of 582 patients with type 1 DM who received either premeal IDPI plus neutral protamine Hagedorn (NPH) or Ultralente insulin or injectable RHI plus NPH or Ultralente insulin. The search identified 5 comparative efficacy studies of IDPI monotherapy or the addition of IDPI to the current regimen in a total of 1413 patients with type 2 DM that was uncontrolled with diet and exercise, metformin, a sulfonylurea, metformin and a sulfonylurea, or a secretagogue plus an insulin sensitizer. The use of IDPI as a mealtime insulin in these studies was associated with absolute changes in HbA(1c) ranging from -0.6% to +0.1% in patients with type 1 DM and from -1.4% to -2.9% in patients with type 2 DM. HbA(1c) values <7% were achieved in 16.9% to 28.2% of patients with type 1 DM and 16.7% to 44.0% of patients with type 2 DM. The most common nonrespiratory adverse event noted during clinical trials of IDPI was hypoglycemia (type 1 DM: 8.6-9.3 episodes/subject-month; type 2 DM: 0.3-1.4 episodes/subject-month), and the most common adverse event involving the pulmonary system was cough (21.9%-29.5%). CONCLUSIONS: IDPI is the first available inhaled insulin. It provides an additional option for the achievement of HbA(1c) goals with a premeal insulin. PMID- 17697901 TI - Comparison of inhibition of cutaneous histamine reaction of ebastine fast dissolving tablet (20 mg) versus desloratadine capsule (5 mg): a randomized, double-blind, double-dummy, placebo-controlled, three-period crossover study in healthy, nonatopic adults. AB - BACKGROUND: Ebastine is a long-acting, second-generation, selective histamine H1 receptor antagonist. A fast-dissolving tablet formulation of ebastine has been developed at 10- and 20-mg doses, with the intention of facilitating administration to patients experiencing problems with swallowing, including those confined to bed and elderly people, as well as those who may need to use ebastine when they do not have easy access to water to aid swallowing a tablet. OBJECTIVES: This study was conducted to assess the pharmacodynamic effects (ie, inhibition of wheal response to cutaneous histamine challenge, and subjective assessments of itching, flare, and pain) and tolerability of the fast-dissolving 20-mg ebastine tablet formulation compared with desloratadine 5-mg capsule and placebo. Acceptability and convenience of the fast-dissolving tablet were also evaluated. METHODS: This double-blind, double-dummy, randomized, placebo controlled, 3-period crossover study was conducted at the Drug Research Centre, Department of Clinical Pharmacology, the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Healthy, nonatopic, white adults aged 18 to 40 years were randomly assigned to 1 of 6 study sequences: ABC, ACB, BAC, BCA, CBA, or CAB, where A was the ebastine fast-dissolving 20-mg tablet, B was the desloratadine 5 mg capsule, and C was placebo. All study drugs were given orally once daily (8-9 AM) on days 1 to 5 of each study period. Study periods were separated by a washout period of 7 to 10 days. Histamine skin-prick test (SPT) challenge was performed before study drug administration on day 1 of each period (baseline), and then every 20 minutes for 2 hours after administration and again after 24 hours. The final SPT was 24 hours after the day-5 dose was administered. The primary end point was inhibition o f the histamine response, defined as the percentage reduction from baseline wheal area 24 hours after 5 days of administration. Subjective symptoms (itching, flare, and pain) were assessed by subjects using visual analog scales every 20 minutes for 2 hours after administration on day 1. At study end, acceptability (taste, convenience, and overall preference) of the fast-dissolving tablet and capsule formulations were assessed using a questionnaire completed by subjects. Tolerability was assessed using physical examination, laboratory analysis, physician questioning, and spontaneous reporting. RESULTS: Thirty-six people were randomized (22 women, 14 men; mean [SD] age, 24.7 [4.1] years; mean [SD] weight, 63.2 [9.9] kg); 35 completed the study (1 subject was lost to follow-up after the second study period). Unadjusted mean (SD) wheal areas 24 hours after dose administration on day 5 were 72.9 (29.5), 115.0 (32.1), and 146.7 (32.2) mm(2), for ebastine, desloratadine, and placebo, respectively. Mean differences in reduction from baseline in wheal area were 29.0% for ebastine versus desloratadine and 43.7% for ebastine versus placebo (both, P < 0.001). Corresponding unadjusted mean (SD) wheal areas 24 hours after administration of the first dose on day 1 were 76.5 (22.5), 128.9 (24.0), and 140.5 (33.1) mm(2). Mean itching, flare, and pain ratings were not significantly different between study drugs. Results from the preference questionnaire indicated that the majority (80%) preferred the ebastine fast-dissolving tablet to the desloratadine capsule (and hypothetically also to tablets and oral solution, which were not tested in this study). Ninety-seven percent of subjects were of the opinion that compliance in the home setting would be facilitated by the fas-tdissolving tablet formulation. Fourteen adverse events (AEs) were reported in 9 (25%) volunteers; all AEs were of mild or moderate intensity. Five occurred with ebastine 20 mg (intermittent somnolence, back pain, pharyngolaryngeal pain, pyrexia, and oral pain [1 patient each]), 5 occurred with desloratadine 5 mg (asthenia [2 patients] and dry mouth, somnolence, and back pain [1 patient each]), and 4 occurred with placebo (diarrhea [2 patients] and somnolence and headache [1 patient each]). The relationship with the study drugs was considered unlikely in 6 cases and possible in the remaining 8 cases. An additional AE (back pain) occurred during a washout period. CONCLUSIONS: In this small study in healthy, nonatopic white subjects, inhibition of the response to histamine injection was significantly greater with the ebastine 20-mg fast dissolving tablet compared with desloratadine 5-mg capsule and placebo after 1 and 5 days of administration. Most participants expressed an overall preference for the fast-dissolving tablet formulation over capsules. All study drugs were well tolerated. PMID- 17697902 TI - Twelve-week, randomized, placebo-controlled, multicenter study of the efficacy and tolerability of budesonide and formoterol in one metered-dose inhaler compared with budesonide alone and formoterol alone in adolescents and adults with asthma. AB - BACKGROUND: The addition of the long-acting beta(2)-adrenergic agonist formoterol to low- to moderate-dose budesonide has shown clinical efficacy in patients with persistent asthma. Combination therapy with budesonide/formoterol in 1 pressurized metered-dose inhaler (pMDI) has been found to have greater efficacy than its monocomponents in patients with moderate to severe persistent asthma, but it has not been assessed in patients with mild to moderate persistent asthma. OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of budesonide and formoterol delivered via 1 pMDI (budesonide/formoterol pMDI), budesonide pMDI, formoterol dry powder inhaler (DPI), and placebo. METHODS: This 12-week, multicenter, double-blind, randomized, placebo-controlled, double-dummy study was conducted at 56 centers across the United States. Patients aged > or =12 years with mild to moderate persistent asthma treated with inhaled corticosteroids (ICSs) for > or =4 weeks before screening and who had a forced expiratory volume in 1 second (FEV(1)) of > or =60% to < or =90% of predicted normal at screening were eligible. After 2 weeks (current asthma therapy discontinued), patients received twice-daily budesonide/formoterol pMDI 80/4.5 microg x 2 inhalations (160/9 microg), budesonide pMDI 80 microg x 2 inhalations (160 microg), formoterol DPI 4.5 microg x 2 inhalations (9 microg), or placebo. The coprimary efficacy variables were changes from baseline in morning predose FEV(1) and 12-hour mean FEV(1) (from serial spirometry) after administration of the morning dose of study medication. Tolerability was assessed based on adverse events (AEs); routine laboratory assessments; electrocardiography; 24-hour Holter monitor assessments; and physical examinations, including vital signs (eg, systolic and diastolic blood pressure and heart rate). AEs were recorded manually by the patient in paper notebooks and reviewed at each clinic visit by the investigator and during a final follow-up phone call. RESULTS: A total of 480 patients were randomized (299 females, 181 males; mean age, 36 years; mean FEV(1), 2.4 L; budesonide/formoterol pMDI, 123 patients; budesonide pMDI, 121; formoterol DPI, 114; placebo, 122). At end of treatment, the mean increases from baseline in predose FEV(1) were greater with budesonide/formoterol pMDI versus budesonide pMDI, formoterol DPI, and placebo (0.37 vs 0.23, 0.17, and 0.03 L, respectively; all, P<0.005). 0.005). After administration of the first dose and at weeks 2 and 12, mean increases in 12-hour mean FEV(1) were significantly greater with budesonide/formoterol pMDI (0.41, 0.47, and 0.50 L, respectively) versus budesonide pMDI (0.17, 0.30, and 0.32 L) and placebo (0.15, 0.12, and 0.12 L) (all, P < 0.001). Fewer patients receiving budesonide/formoterol pMDI met criteria for (18.7%; P < 0.001) or withdrew because of (7.3%; P < or = 0.010) worsening asthma versus formoterol DPI (42.1% and 18.4%, respectively) and placebo (56.6% and 32.8%); results were similar between budesonide pMDI (21.5% and 6.6%, respectively) and budesonide/formoterol pMDI. Three patients experienced serious AEs; none was considered related to study medication. The proportions of withdrawals due to worsening asthma were not significantly different between the budesonide/formoterol pMDI and budesonide pMDI groups. CONCLUSIONS: In this population of adults and adolescents with mild to moderate persistent asthma previously treated with ICSs, twice-daily budesonide/formoterol pMDI was associated with significantly increased pulmonary function versus its monocomponents. All study drugs were generally well tolerated. PMID- 17697903 TI - Comparison of extended-release metformin in combination with a sulfonylurea (glyburide) to sulfonylurea monotherapy in adult patients with type 2 diabetes: a multicenter, double-blind, randomized, controlled, phase III study. AB - BACKGROUND: Metformin is widely used in the management of type 2 diabetes, either as monotherapy or in combination with other oral antihyperglycemic agents such as sulfonylureas and thiazolidinediones. Combination treatment with metformin and sulfonylurea in patients who failed monotherapy has been reported to be effective in maintaining glycemic control. OBJECTIVE: The purpose for this study was to compare the efficacy and tolerability of extended-release metformin (MER) administered with a sulfonylurea (glyburide) to sulfonylurea monotherapy in patients with type 2 diabetes. METHODS: This multicenter, double-blind, randomized, controlled study enrolled adult patients with type 2 diabetes who were either drug naive or previously treated with oral diabetic medications and who had not achieved glycemic control. Patients were stabilized on sulfonylurea (10 mg/d for 2 weeks, then 15 mg/d for 4 weeks) then randomly assigned at base line to receive MER (1500 mg QD, 1000 mg BID, or 2000 mg QD) plus sulfonylurea (MER+S) or sulfonylurea monotherapy for 24 weeks. Patients were evaluated every 1 to 2 weeks during sulfonylurea stabilization and initial metformin treatment, and then every 4 weeks until study end. The primary efficacy end point was glycemic control as determined by changes in glycosylated hemoglobin (HbA(1c)) from baseline to study end between those receiving combination MER+S treatment and those receiving sulfonylurea monotherapy. Adverse events (AEs) were recorded throughout the study by direct questioning, self-reporting by patients, and from the results of physical examinations and clinical laboratory tests. RESULTS: A total of 741 patients were enrolled. Of these, 134 patients were stabilization failures, 607 patients were randomized, 575 patients received treatment and were included in the intent-to-treat population, and 417 patients completed the study per protocol. There were no significant differences between treatment groups for any demographic or baseline characteristics (all patients: mean [SD] age, 53.0 [10.6] years; male sex, 54.6% [314/575]; race, white, 58.8% [338/575], Hispanic, 28.5% [164/575]; mean [SD] weight, 97.0 [22.2] kg; obese [body mass index > or =30 kg/m(2)], 69.4% [399/575] ). There were significant decreases from baseline in mean fasting plasma glucose (FPG) levels by the end of week 1 and in mean HbA(1c) levels by week 8 in each MER+S group (both, P < 0.001). The mean (95% CI) changes from baseline to study end in the combined MER+S groups (HbA(1c), -0.74% [-0.85% to -0.64%]; FPG, -12.9 [-17.1 to -8.7] mg/dL) were significantly different from the sulfonylurea monotherapy group (HbA(1c), 0.08% [-0.08% to 0.25%]; FPG, 15.5 [8.2 to 22.8] mg/dL; P < 0.001). Among patients treated with MER+S, the mean (SEM) change in HbA(1c) was -1.26% (-1.44% to -1.07%) for drugnaive patients and -0.59% (-0.46% to 0.71%) for patients previously treated with metformin. There was a significant difference between treatment groups with regard to the prevalence of hypoglycemia (MER+S groups, 11.6% vs sulfonylurea monotherapy group, 4.2%; P = 0.007), but no significant difference was observed for gastrointestinal events. The most common gastrointestinal AEs were diarrhea and nausea (8.6% and 3.9%, respectively, in the combined MER+S groups; 2.8% and 1.4%, respectively, in the sulfonylurea monotherapy group). CONCLUSIONS: The combination of QD or BID treatment with MER+S was significantly more effective in lowering HbA(1c) and glucose levels than sulfonylurea monotherapy in these adult patients with type 2 diabetes. However, a significant increase in the prevalence of hypoglycemia was observed in the MER+S treatment groups compared with the sulfonylurea monotherapy group. PMID- 17697904 TI - Prevention of pain due to injection of propofol with IV administration of lidocaine 40 mg + metoclopramide 2.5, 5, or 10 mg or saline: a randomized, double blind study in Japanese adult surgical patients. AB - BACKGROUND: Pain on injection is a recognized adverse event (AE) with propofol, an agent used to induce general anesthesia in surgical patients. Lidocame (LID) has been found efficacious in reducing pain on injection of propofol; however, this type of pain may not be completely eliminated with LID. Metoclopramide (MET) is a dopamine receptor agonist with antiemetic and prokinetic properties used for the treatment of nausea and facilitation of gastric emptying in patients with gastroparesis. MET also has local anesthetic properties similar to those of LID. OBJECTIVE: The aim of this study was to examine the effects of LID administered with 3 different doses of MET or saline on pain on injection of propofol in Japanese adults undergoing elective surgery. METHODS: This randomized, double blind study was conducted at the Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, Tsukuba, Japan. Japanese patients aged 20 to 67 years who were scheduled to undergo elective surgery were eligible for participation. Patients were randomized to receive N administration of LID 40 mg + MET 2.5, 5, or 10 mg or saline. A rubber tourniquet was used to perform 1 minute of venous occlusion before administration of the study and control drugs, and then 25% of the total calculated dose of propofol (2 mg/kg) was injected into the dorsal vein of the hand through a 20-G N cannula at a rate of 1 mL/s. During a 10-second pause before the induction of anesthesia, patients were questioned by a blinded investigator about the pain intensity on injection. Pain intensity was assessed through the use of a 4-point verbal rating scale, with scores ranging from 0 (no pain) to 3 (severe pain). Incidence and intensity of pain (as assessed by mean pain scores) were determined in each of the 4 study groups. Extrapyramidal reactions and injection-site AEs, including pain, edema, wheals, and inflammation occurring up to 24 hours after surgery were recorded by a blinded investigator. RESULTS: The study enrolled 240 patients (126 men, 114 women; mean [SD] age, 43 [13] years [range, 20-67 years]; mean [SD] height, 160 [8] cm [133-181 cm]; mean [SD] body weight, 57 [10] kg [range, 33-85 kg]). There were 60 patients randomized to each of the 4 study groups, which were comparable in distribution of demographic characteristics. Incidence of propofol-induced pain was significantly lower, but the intensity of pain was not less, in the groups that received LID/MET 40/5 or 40/10 (both, 5%) compared with those who received LID/MET 40/2.5 or LID/saline (18% and 20%, respectively) (all, P < 0.05). There were no reports of injection-site AEs or extrapyramidal reactions after injection of the control or study drugs in any of the study groups. CONCLUSION: Among these 240 Japanese patients undergoing elective surgery, N administration of LID/MET 40/5 or 40/10 was associated with lower incidence, but not lower mean pain intensity scores, of pain on injection of propofol than LID/MET 40/2.5 or LID/saline before induction of anesthesia. PMID- 17697905 TI - Assessment of comparative pain relief and tolerability of SKI306X compared with celecoxib in patients with rheumatoid arthritis: a 6-week, multicenter, randomized, double-blind, double-dummy, phase III, noninferiority clinical trial. AB - BACKGROUND: SKI306X, which consists of biologically active ingredients from Clematis mandsburica, Tricbosantbes kirilowii, and Prunella vulgaris, was developed and tested in preclinical trials in Korea. Those studies found that SKI306X was associated with an anti-inflammatory and analgesic effect, and that it can delay the destruction of cartilage in rheumatoid arthritis (RA). OBJECTIVE: The aim of this study was to compare the pain relief and tolerability of SKI306X and celecoxib in patients with RA. METHODS: This study was a 6-week, multicenter, randomized, double-blind, double-dummy, Phase III, noninferiority clinical trial. Eligible patients were aged 18 to 80 years, had a history of RA with a disease duration of > or =3 months, and were functional American College of Rheumatology (ACR) class I, II, or III before entry. After a washout period of 2 weeks, patients were randomized to SKI306X 200 mg TID or celecoxib 200 mg BID for 6 weeks. The primary end point was a change in patient assessment of pain intensity using a visual analog scale (VAS). The secondary end points were a 20% improvement in response rate as defined by the ACR (ACR20) and the frequency of rescue medication use. Results after 3 and 6 weeks of treatment were compared with baseline and between treatment groups, and all patients were assessed for adverse events (AEs), clinical laboratory data, and vital signs. AEs were identified based on spontaneous reports by patients during interviews conducted by the investigators and the study coordinator. RESULTS: Two hundred twenty-two Korean patients from 7 medical centers were assessed and 183 were enrolled and randomized to 1 of 2 treatment groups. Ninety-one patients (10 male, 81 female; mean [SD] age, 52.13 [12.64] years; mean [SD] duration of RA, 9.08 [10.23] years; no. [%] of ACR class I, II, and III, 13 [14.29], 44 [48.35] and 34 [37.36] patients, respectively) received SKI306X 200 mg TID and 92 patients (10 male, 82 female; mean [SD] age, 51.78 [10.94] years; mean [SD] duration of RA, 8.78 [7.78] years; no. [%] of ACR class I, II, and III, 14 [15.22], 44 [47.83], and 34 [36.96] patients, respectively) received celecoxib 200 mg BID. An analysis of the change in reported pain intensity as determined by VAS (mm) score between baseline and week 3 (mean [SD], 13.64 [16.62] vs 14.45 [15.89]), and between baseline and week 6 (18.4 [20.8] vs 17.9 [19.1], respectively) suggested that SKI306X was not inferior to celecoxib. The number of patients who achieved ACR20 response rate was not significantly different between the SKI306X group and the celecoxib group at week 3 (16/87 [18.4%] vs 24/87 [27.6%], respectively) and at week 6 (29/87 [33.3%] vs 29/87 [33.3%]). The frequency of rescue medication use was not significantly different between the SKI306X group and celecoxib group at week 3 (54/87 [62.1%] vs 47/87 [54.0%], respectively) or week 6 (57/87 [65.5%] vs 49/87 [56.3%]). Drug-related AEs were reported by 27 (29.7%) patients in the SKI306X group and 22 (23.9%) patients in the celecoxib group. The most frequent drug-related AEs were epigastric pain (9/91 [9.9%]) in the SKI306X group and glutamyltranferase elevation (4/92 [4.3%]) in the celecoxib group. No significant between-group differences were observed in the prevalence of drug-related clinical- or laboratory-determined AEs. CONCLUSION: The results of this study suggest that SKI306X was generally well tolerated and not inferior to celecoxib in regard to pain relief in these Korean patients with RA. PMID- 17697906 TI - Efficacy and tolerability of once-daily OROS hydromorphone and twice-daily extended-release oxycodone in patients with chronic, moderate to severe osteoarthritis pain: results of a 6-week, randomized, open-label, noninferiority analysis. AB - OBJECTIVE: This study compared the efficacy and tolerability of a once-daily controlled-release formulation of hydromorphone (OROS) hydromorphone, Janssen Cilag, Beerse, Belgium) and twice-daily extended-release (ER) oxycodone in patients with chronic, moderate to severe osteoarthritis (OA) pain. OROS hydromorphone is currently available only in Europe. METHODS: Adults who met American College of Rheumatology clinical criteria for OA of the knee or hip with moderate to severe mean daily pain intensity despite chronic use of stable doses of NSAIDs or other nonsteroidal, nonopioid therapies were eligible for participation in this randomized, open-label study. The study consisted of a 14 day dose-titration and stabilization phase and a 28-day maintenance phase. OROS hydromorphone and ER oxycodone were initiated at dosages of 8 mg QD and 10 mg BID, respectively. Patients maintained diaries in which they rated their pain (from 0 = none to 3 = severe) and pain relief (from 0 = no relief to 4 = complete relief). Other assessments completed every 14 days included patient and investigator global evaluations of treatment effectiveness (scale from 1 = poor to 5 = excellent), the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index, and the Medical Outcomes Study (MOS) Sleep Scale. Adverse events (whether observed by study personnel, identified in response to questioning, or spontaneously reported) and vital signs were monitored throughout the study. The primary efficacy measures were the mean pain relief score at end point and the time from initiation of treatment to the third day of moderate to complete pain relief, as reported in the patient diary. Noninferiority analyses were conducted on all primary and secondary efficacy variables. RESULTS: One hundred thirty-eight patients (71 OROS hydromorphone, 67 ER oxycodone) received treatment (safety population), and 83 (60.1%) completed the study. Data from 124 patients were included in the efficacy analyses; the majority of these patients were white (85.5%) and female (69.4%), with a mean age of 63.6 years. The most commonly affected joint was the knee (79.8 %). At end point, the OROS hydromorphone group had a mean pain relief score of 2.3 (median, 2.0) and the ER oxycodone group had a mean pain relief score of 2.3 (median, 2.3) (95% CI, -0.30 to infinity). The mean time to the third day of moderate to complete pain relief was 6.2 days (median, 4.0) in the OROS hydromorphone group and 5.5 days (median, 5.0) in the ER oxycodone group (95% CI, -0.31 to infinity). Mean pain intensity decreased from baseline to end point by 0.6 point in the OROS hydromorphone group and by 0.4 point in the ER oxycodone group. Mean scores on the patient global evaluation improved by a respective 1.2 and 1.0 points (median, 1 in both groups). Approximately two thirds of patients in each group (67.2% and 66.7%) rated the overall effectiveness of treatment as good to excellent at end point. There were no statistically significant differences between groups in total WOMAC scores at end point, and similar improvements from baseline in the WOMAC physical function, stiffness, and pain scales were observed in both groups. Whereas MOS sleep outcomes scores improved from baseline in both groups, OROS hydromorphone was associated with a significantly greater improvement on the MOS Sleep Problems Index I compared with ER oxycodone (P < 0.045). Adverse events were comparable in both groups; the most frequently reported adverse events were nausea (35.2% and 29.9%), constipation (29.6% and 25.4%), somnolence (25.4% and 17.9%), vomiting (16.9% and 11.9%), and dizziness (14.1% and 22.4%). Adverse events led to study discontinuation in 35.2% (25/71) of patients in the OROS hydromorphone group and 32.8% (22/67) in the ER oxycodone group. Discontinuations due to adverse events during the titration phase were numerically greater in the OROS hydromorphone group (29.6% [21/71]) than in the ER oxycodone group (19.4% [13/67]). Only 1 serious adverse event (diarrhea in a patient receiving OROS hydromorphone) was considered possibly related to study drug. CONCLUSIONS: Once-daily OROS hydromorphone and twice-daily ER oxycodone provided similar pain relief in these patients with OA of the knee or hip. The tolerability profiles of the 2 agents were similar. PMID- 17697907 TI - Empiric therapy for secondary peritonitis: a pharmacodynamic analysis of cefepime, ceftazidime, ceftriaxone, imipenem, levofloxacin, piperacillin/tazobactam, and tigecycline using Monte Carlo simulation. AB - BACKGROUND: Inappropriate antibiotic therapy (ie, the selection of an empiric agent without activity against the responsible pathogen) of secondary peritonitis may result in poor patient outcomes. The selection of an appropriate agent can be challenging because of the emerging resistance of target organisms to commonly prescribed antibiotics. OBJECTIVE: The aim of this study was to perform a pharmacodynamic analysis, using recent global surveillance data, of commonly prescribed antibiotic agents and a newer agent, tigecycline, indicated in 2005 for the treatment of complicated intra-abdominal infections, to determine their probability for achieving microbiologic success against aerobic bacteria associated with secondary peritonitis. METHODS: A 2-compartment model was constructed using pharmacokinetic data from critically ill patients and global surveillance data on MIC distributions for microorganisms encountered in secondary peritonitis. A Monte Carlo simulation of the modeled data was performed to determine drug-appropriate pharmacodynamic end points, including free-drug time above the MIC, steady-state concentration above the MIC, and AUC/MIC ratios. A cumulative fraction of response (CFR) against aerobic bacteria involved in secondary peritonitis was calculated for cefepime, ceftazidime, ceftriaxone, imipenem, levofloxacin, pip eracillin/tazobactam, and tigecycline. A CFR > or =90% was considered microbiologic success. The following treatment regimens, administered as 30-minute N infusions, were examined: cefepime 1 and 2 g q12h, ceftazidime 1 and 2 g q8h, ceftriaxone 1 and 2 g q24h, imipenem 500 mg q6h, levofloxacin 750 mg q24h, pip eracillin/tazobactam 3.375 g q6h, and tigecycline 50 mg q12h, after a loading dose of 100 mg. RESULTS: A CFR > or =90% against nonenterococcal bacteria was predicted for imipenem 500 mg q6h (96.8%), cefepime 2 and 1 g q12h (95.3% and 92.4%, respectively), ceftazidime 2 g q8h (94.2%), and piperacillin/tazobactam 3.375 g q6h (91.2%). A CFR of 84.5% was predicted for tigecycline 50 mg q12h. Ceftriaxone and levofloxacin were predicted to have a CFR <80%. When enterococci were included in the model, the predicted CFRs for imipenem, piperacillin/tazobactam, and tigecycline were 93.4%, 88.4%, and 86.7%, respectively. CONCLUSIONS: : MIC distribution and pathogen prevalence strongly influence the likelihood of microbiological success in secondary peritonitis; therefore, decisions regarding empiric therapy should consider local epidemiology. Using current global data, the following regimens are adequate choices if Enterococcus is not targeted: Combination therapy (with metronidazole) using cefepime 1 g or 2 g q12h, or ceftazidime 2 g q8h; or monotherapy with imipenem 500 mg q6h or piperacillin-tazobactam 3.375 g q6h. When Enterococcus is included in the epidemiologic mix, imipenem, piperacillin/tazobactam, and tigecycline all appear to be viable monotherapeutic choices. PMID- 17697908 TI - Influence of food on the oral bioavailability of rupatadine tablets in healthy volunteers: a single-dose, randomized, open-label, two-way crossover study. AB - BACKGROUND: Rupatadine is an oral active antihistamine for the management of diseases with allergic inflammatory conditions, such as perennial and seasonal rhinitis and chronic idiopathic urticaria. Oral rupatadine has been approved for the treatment of allergic rhinitis and chronic urticaria in adults and adolescents in several European countries. OBJECTIVE: The purpose of this study was to describe the effect of the concomitant intake of food on the pharmacokinetic profile and bioavailability of a single dose of rupatadine. METHODS: This was a single-dose, randomized, open-label, 2-way crossover study in which healthy male and female volunteers received a single, 20-mg oral dose of rupatadine under fed and fasting conditions. Blood samples were collected and plasma concentrations of rupatadine and its active metabolites desloratadine and 3-hydroxydesloratadine were determined by liquid chromatography tandem mass spectrometry. Tolerability was based on the recording of adverse events (AEs), physical examinations, electrocardiograms, and laboratory tolerability tests immediately before each treatment period and at the final visit of the study. RESULTS: Twenty-four volunteers (12 males; mean [SD] age, 25.4 [5.3] years [range, 18-34 years]; mean [SD] weight, 71.2 [4.3] kg [range, 64-77 kg]; 12 females; mean [SD] age, 26.8 [6.5] years [range, 18-38 years]; mean [SD] weight, 58.4 [6.8] kg, [range 50-69 kg]) were enrolled and randomized with equal distribution of sex. A significant increase in AUC from drug administration to the final quantifiable sample (AUC(0-t)) and AUC from drug administration to infinity (AUC(0-infinity)) values of rupatadine was seen under fed conditions without affecting C(max). The ratios (90% CI) of the mean log-transformed AUC(0 t) and AUC(0-infinity) for rupatadine revealed a significant increase in AUC(0-t) (ratio 131%; 90% CI, 111%-154%) and AUC(0-infinity) (ratio 133%; 90% CI, 113% 156%), whereas C(max) remained unaltered (ratio 97%; 90% CI, 80%-116%). Plasma concentration-time profiles of desloratadine and 3-hydroxydesloratadine were similar with and without food, and no differences were seen for AUC(0-t), AUC(0 infinity), or C(max). Seven (28%) subjects reported > or =1 AE. All AEs were mild, resolved spontaneously, and did not affect the outcome of the study. CONCLUSIONS: The results of this study indicate that concomitant intake of food with a single 20-mg oral dose of rupatadine exhibits a significant increase in rupatadine bioavailability. Despite the absence of bioequivalence, the drug was well tolerated under fed and fasting conditions, and no major changes in severity and/or prevalence of AEs were reported. PMID- 17697910 TI - Paroxetine and congenital malformations: meta-Analysis and consideration of potential confounding factors. AB - BACKGROUND: Antidepressants have been commonly used by women of childbearing age. Recent studies suggest that paroxetine, a selective serotonin reuptake inhibitor (SSRI), might specifically increase teratogenic risk. OBJECTIVES: The purpose of this study was to quantify first-trimester exposure to paroxetine and birth defects and examine potential sources of bias in the in utero or postnatal detection of more congenital malformations among women with depression. We also sought to examine whether paroxetine was used for the same indications as other SSRIs among pregnant women. METHODS: This meta-analysis was designed to quantify malformation rates associated with the use of paroxetine. A search of the literature from 1985 to 2006 (English language) found in MEDLINE, EMBASE, REPROTOX, Scopus, and Biological Abstracts was conducted using the following terms: pregnancy outcome, congenital or fetal AND anomalies, malformations, cardiac/heart defects, AND selective serotonin reuptake inhibitors, paroxetine, and Paxil. Administrative databases of medication and medical services use in the Province of Quebec, Canada, were used to calculate the rates of ultrasound and echocardiogram in pregnancy and infancy in women/infants exposed to SSRIs and to compare the indications for general SSRI use versus paroxetine use. RESULTS: Based on the studies analyzed, first-trimester paroxetine exposure was associated with a significant increase in the risk for cardiac malformation (odds ratio [OR], 1.72; 95% CI, 1.22-2.42). Women using antidepressants in pregnancy had a 30% higher rate of utilization of ultrasound in pregnancy. Infants of women who received SSRIs underwent approximately twice as many echocardiograms in the first year of life compared with children of women who used nothing. Significantly more women receiving paroxetine used the drug for anxiety or panic than women receiving other SSRIs (OR, 4.11; 95% CI, 2.39-7.08). CONCLUSIONS: Based on the results of this metaanalysis, first-trimester exposure to paroxetine appears to be associated with a significant increase in the risk for cardiac malformation. However, a detection bias cannot be ruled out as contributing to the apparent increased detection of cardiovascular malformation of children exposed in utero to paroxetine. A significantly greater number of women were using paroxetine for anxiety or panic when compared with women using other SSRIs. PMID- 17697909 TI - Prospective evaluation of patient-reported outcomes during treatment with deferasirox or deferoxamine for iron overload in patients with beta-thalassemia. AB - BACKGROUND: Iron chelation therapy (ICT) with deferoxamine (DFO), the current standard for the treatment of iron overload in patients with transfusion dependent disorders such as beta-thalassemia, requires regular subcutaneous or intravenous infusions. This can lead to reduced quality of life and poor adherence, resulting in increased morbidity and mortality in iron-overloaded patients with beta-thalassemia. Deferasirox is an orally administered iron chelator that has been approved for use in the United States, Switzerland, and other countries. OBJECTIVE: This analysis was conducted to compare patient reported outcomes (PROs) during receipt of DFO infusions or once-daily oral therapy with deferasirox (ICL670). METHODS: PROs were prospectively evaluated as part of a randomized, Phase III study comparing the efficacy and safety profile of DFO 20 to 60 mg/kg per day with those of deferasirox 5 to 30 mg/kg per day in patients (age > or =2 years) with beta-thalassemia who were receiving regular transfusions and had a liver iron concentration of > or =2 mg/g dry weight. PRO questionnaires were completed by patients or a parent or legal guardian at baseline, week 4, week 24, and end of study (EOS). Patients assessed their level of satisfaction with study treatment (very satisfied, satisfied, neutral, dissatisfied, or very dissatisfied) and rated its convenience (very convenient, convenient, neutral, inconvenient, or very inconvenient). Time lost from normal activities due to ICT in the previous 4 weeks was recorded using a single global assessment. At week 4, patients who had previous experience with DFO were asked to indicate their preference for treatment (ICT received before the study, ICT received during the study, no preference, or no response) and the reason for that preference. At EOS, all patients were asked if they would be willing to continue using the ICT they had received during the study. All study analyses were performed in all patients who received at least 1 dose of study medication. RESULTS: Five hundred eighty-six patients (304 females, 282 males; age range, 2 53 years) received treatment with DFO (n = 290) or deferasirox (n = 296). Significantly more patients treated with deferasirox reported being very satisfied or satisfied with treatment compared with those treated with DFO (week 4: 92.0% vs 50.4%, respectively; week 24: 89.6% vs 44.0%; EOS: 85.1% vs 38.7%; all, P < 0.001). At the same time points, the majority of those treated with deferasirox reported that treatment was very convenient or convenient compared with those treated with DFO (95.5% vs 21.3%, 91.7% vs 17.4%, and 92.7% vs 11.3%, respectively; all, P < 0.001). Among patients who had previously taken DFO and were randomized to receive deferasirox during the study, 96.9% reported a preference for deferasirox over DFO. At EOS, the proportion of patients indicating a willingness to continue study therapy was significantly greater in those receiving deferasirox than in those receiving DFO (85.8% vs 13.8%; P < 0.001). CONCLUSIONS: In this study, patient-reported satisfaction and convenience were significantly higher for the once-daily, oral ICT deferasirox than for DFO infusions. Among patients who had received DFO before the study, the majority indicated a preference for deferasirox over DFO. Most patients receiving deferasirox indicated that they would be willing to continue taking it. These results suggest that deferasirox had a positive impact on patients' daily lives. PMID- 17697911 TI - Comparison of the pharmacokinetic and pharmacodynamic profiles of biphasic insulin aspart 50 and 30 in patients with type 2 diabetes mellitus: a single center, randomized, double-blind, two-period, crossover trial in Japan. AB - BACKGROUND: To overcome the complicated mixing procedures required in the use of insulin formulations, premixed formulations consisting of rapid-acting and intermediate-type insulin in various mixing proportions have been developed. Biphasic insulin aspart 50 (BIAsp50) and 30 (BlAsp30) are 2 premixed formulations containing the active ingredient insulin aspart (IAsp) and consisting of a rapid acting component soluble IAsp) and intermediate-acting component (protamine crystallized protracted IAsp) in ratios of 50/50 and 30/70, respectively. These formulations are provided with the expectation that BIAsp30 and BIAsp50 will be beneficial for patients needing to improve their postprandial blood glucose control without changing their dietary habits and lifestyles. BIAsp30 has been widely used in medical practice, whereas BIAsp50 is being investigated in clinical trials. OBJECTIVE: The aim of this study was to compare the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of BIAsp50 (test) and BIAsp30 (reference) after single-dose SC injection in patients with type 2 diabetes mellitus. METHODS: This single-center, randomized, doubleblind, 2 period, crossover trial was conducted at the H.E.C. Science Clinic, Yokohama, Japan. Male and female patients aged > or = 20 years with a > or = 1 year history of type 2 diabetes were eligible. Patients were randomly assigned to 1 of 2 treatment sequences: group A received BIAsp30 in period 1 and BIAsp50 in period 2; group B received BIAsp50 in period 1 and BIAsp30 in period 2. All treatments were administered as an SC injection of a single dose (0.3 U/kg). The study periods were separated by a washout period of 4 to 21 days. For PK analysis of IAsp (maximum serum IAsp concentration [C(max,IAsp); primary end point], AUC of serum IAsp 0 to 120, 240, and 480 minutes after administration [AUC(0-120 min,IAspl), AUC(0-240 min,IAsp), and AUC(0-480 min,IAsp5) respectively], and time to (Cmax,IAsp) [T(max,IAsp)] ), blood samples were drawn immediately before (baseline) and at prespecified time points over 480 minutes after administration. The PD profiles of BIAsp50 and BIAsp30 were also examined by comparing the time course of the glucose infusion rate (GIR) using the euglycemic clamp technique. The PD end points were AUC of GIR 0 to 120 minutes after administration (AUC(0 120 min,GIR)), maximum GIR (GIR(max)), and time to GIRmax (T(max,GIR)). Tolerability was assessed using physical examination, including vital sign measurement, electrocardiography, body weight, adverse events (AEs), and clinical laboratory analysis (hematology and serum biochemistry). RESULTS: Six men and 4 women were enrolled in the study (mean age, 62.4 years; mean body weight, 58.3 kg; mean body mass index, 22.22 kg/m(2); mean duration of diabetes, 9.53 years; and mean glycosylated hemoglobin concentration, 6.07%). Mean(Cmax,IAsp) with BIAsp50 was 63% higher than that for BIAsp30 (P < 0.002). The BIAsp50/BIAsp30 ratio with AUC(0-120 min,IAsp) was 1.68 (95% CI, 1.31-2.14). The BIAsp50/BIAsp30 ratiofor AUC(0-120 min,GIR) was 1.31 (95% CI, 1.02-1.68). A total of 9 AEs were reported in 5 patients, but none of the AEs were considered related to the study drug. CONCLUSION: In this small PK/PD study in adults with type 2 diabetes in Japan, mean C(max,IAsp) was significantly higher with BIAsp50 than with BIAsp30, and AUC(0-120 min,IAsp) and AUC(0-120 min,GIR) were higher with BIAsp50 than with BIAsp30. PMID- 17697912 TI - Analyzing international prescribing patterns and medication use: an approach to assisting in the improvement of health care quality and patient outcomes. PMID- 17697913 TI - The cycle of migraine: patients' quality of life during and between migraine attacks. AB - BACKGROUND: Despite advances in therapy, the prevalence of migraine has remained constant over the past 17 years. The current diagnostic procedure for migraine does not take into account the entire cycle of migraine, which includes both the pain of the acute attack and the worry between attacks. OBJECTIVES: This review discusses the effects of migraine on health-related quality of life. The focus is on the impact of migraine between attacks and more successful clinical management of the complete cycle of migraine in both the neurology and primary care settings. METHODS: A search of MEDLINE (January 1997-January 2007) was conducted to determine the impact of migraine on quality of life and the need for and use of migraine preventive treatment. The search terms were migraine prevention, migraine prophylaxis, bead-ache and quality of life, migraine disability, and head-ache disability. The inclusion of specific studies was based on subjective, comparative evaluation and standard levels of evidence. Older publications were included to provide a historical perspective. RESULTS: Worry in expectation of the next migraine attack can have negative effects on the family and social lives and work productivity of patients with migraine. The benefits of preventive pharmacotherapy for migraine may be measured over time in terms of changes in the frequency of acute attacks, impact of acute treatment on headache recurrence within the next 24 hours, and reduction in overall functional impairment. Optimizing the acute treatment outcome and reducing the frequency of episodes may help alleviate the cycle of migraine. The clinical assessment of migraine should include multiple dimensions. Several questionnaires, such as the Migraine Disability Assessment and the 6-item Headache Impact Test, have been developed to help clinicians assess the dimensions of migraine. These questionnaires should be used in conjunction with open communication techniques that elicit any underlying worry associated with migraines. Preventive therapies that have been approved by the US Food and Drug Administration include the neurostabilizers divalproex sodium and topiramate, and the beta-blockers timolol and propranolol. Despite not being approved for this indication, the antidepressant amitriptyline has shown levels of evidence of efficacy in preventing migraine in controlled trials similar to those for the approved medications. CONCLUSION: The assessment of whether patients with migraine may benefit from preventive therapy should include the use of open communication techniques to uncover possible impairment between attacks. PMID- 17697914 TI - A disease-specific measure of health-related quality of life in adults with chronic immune thrombocytopenic purpura: psychometric testing in an open-label clinical trial. AB - BACKGROUND: The Immune Thrombocytopenic Purpura Patient Assessment Questionnaire (ITP-PAQ) was developed to assess disease-specific quality of life (QoL) in adults with ITP. It is a 44-item questionnaire that includes scales for physical health (symptoms, fatigue/sleep, bother, and activity), emotional health (psychological and fear), overall QoL, social activity, women's reproductive health, and work. A previous study reported preliminary evidence of its reliability and validity. OBJECTIVES: The present study was conducted to ascertain the responsiveness (ability to detect a clinically important treatment effect), reliability, and validity of the ITP-PAQ and to corroborate the earlier findings. The women's reproductive health scale was evaluated for psychometric evidence of the existence of separate menstrual symptoms and fertility subscales. METHODS: The ITP-PAQ was evaluated in the context of an ongoing open-label extension study assessing the tolerability and durability of increases in the platelet count with AMG 531 (a thrombopoiesis peptibody that increases platelet production by targeting the thrombopoietin receptor) administered by subcutaneous injection once weekly in adult patients with ITP It was self-administered at baseline and at weeks 4, 12, and 24. The responsiveness of the questionnaire was evaluated by calculating and comparing the change scores of patients who showed clinical improvement-categorized as platelet responders (those with a platelet count > or =50 x 10(9) cells/L and a doubling of baseline values at week 24) and durable platelet responders (those with a platelet count > or =50 x 10(9) cells/L and a doubling of baseline values on > or =6 occasions during weeks 17-24)-with the change scores of patients wh did not show clinical improvement. The reliability (internal consistency and test-retest) and validity (convergent, discriminant, and known groups) of the questionnaire were also evaluated. Validity was examined in terms of correlations between the ITP-PAQ and the 36 item Short-Form Health Survey (SF-36), a generic measure of health-related QoL. RESULTS: Thirty-four patients completed the ITP-PAQ. Most of the scales were found capable of detecting clinically important treatment effects, with the scales for symptoms, fatigue/sleep, bother, and activity being particularly responsive. All scales were found to have internal consistency reliability (Cronbach's alpha, 0.700-0.950), with the exceptions of the menstrual symptoms subscale (0.988 and 0.959 at weeks 12 and 24, respectively) and the work scale (0.691 at week 24). Test-retest reliability was acceptable (intraclass correlation coefficient, 0.725-0.867), with the exceptions of the scales for symptoms (0.677) and women's reproductive health (0.592) and the fertility subscale (0.171). Construct validity was supported by correlations between specific ITP-PAQ and SF-36 scales, with the exceptions of the menstrual symptoms and fertility subscales. Discriminant validity was reported for the symptoms, fatigue/sleep, bother, and activity scales. Durable platelet responders had significantly better scores than nonresponders on the symptoms (P = 0.022), bother (P = 0.008), psychological (P = 0.033), and overall QoL scales (P = 0.032). Compared with those who had undergone splenectomy, patients without splenectomy had significantly higher scores on the women's reproductive health scale (P = 0.03). CONCLUSIONS: The results of this analysis indicate that the ITP PAQ has acceptable responsiveness, reliability, and validity. Further study of the minimal clinically important difference in ITP-PAQ scale scores is needed. PMID- 17697915 TI - An economic assessment of losartan-based versus atenolol-based therapy in patients with hypertension and left-ventricular hypertrophy: results from the Losartan Intervention For Endpoint reduction (LIFE) study adapted to The Netherlands. AB - BACKGROUND: The Losartan Intervention For Endpoint reduction (LIFE) study was a randomized, doubleblind trial that compared the effects of losartan-based treatment with those of atenolol-based treatment on cardiovascular disease (CVD) related morbidity and mortality in 9193 patients with hypertension and left ventricular hypertrophy (LVH). Compared with atenolol, losartan reduced the combined risk for CVD-related morbidity and mortality by 13% (P = 0.021), and reduced the risk for stroke by 25% (P = 0.001), with comparable blood pressure control in both trial arms. OBJECTIVE: The aim of this study was to analyze the cost-effectiveness of losartan compared with atenolol in the treatment of stroke from the Dutch health care perspective. METHODS: Utilization of losartan and atenolol within the trial period (mean, 4.8 years) and an estimation of direct medical costs of stroke for The Netherlands were combined with estimates of reduction in life expectancy through stroke. Medication costs and stroke incidence during 5.5 years of patient follow-up were estimated separately, adjusted for the baseline degree of LVH and Framingham risk score. To estimate lifetime stroke costs, the cumulative incidence of stroke was multiplied by the lifetime direct medical costs attributable to stroke. All costs are in 2006 Dutch prices and discounted following the former (4% costs and effects) and new Dutch guideline (4% costs, 1.5% effects) for conducting pharmacoeconomic analyses. RESULTS: With 4% discounting, prevention of stroke was associated with a gain of 3.7 life-years. As a consequence, losartan treatment was associated with 0.059 life-year gained (LYG) per patient treated with losartan. Losartan reduced stroke related costs by 1,076 Euros (US $1,349) per patient. After inclusion of study medication cost, net cost per patient was 51 Euros ($64) higher for losartan than atenolol. The net cost per LYG was 864 Euros ($1083), which is below the Dutch pharmacoeconomic threshold of 20,000 Euros/LYG (~$25,000/LYG) for accepting interventions. The corresponding probability of a cost-effectiveness ratio below this Dutch threshold was 0.95. Discounting money and health following the new Dutch guideline resulted in an even more favorable cost-effectiveness for losartan. CONCLUSIONS: Results from the present analysis suggest that, in The Netherlands, treatment with losartan compared with atenolol may well be a cost effective intervention based on the reduced risk for stroke observed in the LIFE trial. PMID- 17697916 TI - Hypertension treatment in a medicare population: adherence and systolic blood pressure control. AB - BACKGROUND: Despite substantial trial evidence that demonstrates the effectiveness of pharmacologic treatment for reducing blood pressure (BP) and cardiovascular events, many patients are nonadherent to their hypertension treatment. OBJECTIVES: The purpose of this study was to examine patient adherence to hypertension medications using pharmacy data (ie, outpatient, inpatient, and mail-order prescriptions) and the association between adherence measures and systolic BP (SBP) control. METHODS: The study included Medicare + Choice beneficiaries (aged > or = 65 years) who were continuously enrolled in an integrated delivery system in 2003, and who had documented hypertension and received > or = 1 hypertension drug in 2002. This analysis used automated clinical data and the 2000 US Census. We estimated 2 measures of hypertension treatment adherence in 2003 using the supply of dispensed drugs in days (proportion of days covered > or = 80%): (1) adherence to > or = 1 hypertension drug; and (2) adherence to the full hypertension treatment regimen. We defined the regimen by the number of hypertension drugs used concurrently in 2002. We assessed adherence annually and during the 30, 60, and 90 days before an SBP measurement. Logistic regression was used to examine the association between adherence and the number of drugs in the hypertension regimen, as well as the association between adherence and elevated SBP ( > or = 140 mm Hg). We adjusted for patient sociodemographic and clinical characteristics. RESULTS: The majority (52.8%) of patients had multidrug hypertension regimens. In 2003, 87.3% of subjects were adherent to > or = 1 hypertension drug; 72.1% were adherent to their full regimen. After adjustment, we found that subjects with multidrug regimens were significantly more likely to be adherent to > or = 1 drug and significantly less likely to be adherent to their full regimen, compared with patients on a 1-drug regimen. Over one-third of subjects had elevated SBP in 2003. Both adherence measures were associated with lower odds of having elevated SBP (eg, odds ratio = 0.87 [95% CI, 0.84-0.89] for adherence to the full regimen). For subjects with multidrug regimens, partial adherence and nonadherence to the regimen were associated with higher odds of having elevated SBP. CONCLUSIONS: Adherence measures using automated pharmacy data can identify patients who are nonadherent to their drug treatment regimen and who are more likely to have inadequately controlled BP. Adherence measures that account for the number of drugs in a patients' drug regimen might help identify additional patients at risk for poor BP outcomes due to partial treatment adherence. PMID- 17697917 TI - Tattoos and piercings. PMID- 17697918 TI - Tattoos and religion. AB - Tattoos play an important role in many religions. Tattoos have been used for thousands of years as important tools in ritual and tradition. Judaism, Christianity, and Islam have been hostile to the use of tattoos, but many religions, in particular Buddhism and Hinduism, make extensive use of them. This article examines their use as tools for protection and devotion. PMID- 17697919 TI - Medical applications of tattooing. AB - Tattooing is an ancient procedure, practiced by humans from all parts of the world for a variety of reasons. However, relatively little is known by the medical audience of the numerous medical conditions where tattooing is employed as a therapeutic modality or a diagnostic method. Tattooing for cosmetic and medicinal purposes, referred to as either micropigmentation, dermatography, or medical tattooing, may ensure permanent camouflage in a wide range of dermatological diseases. It can be a valuable finishing step in several surgical procedures in the fields of craniofacial surgery, plastic and reconstructive operations, cosmetic surgery procedures, and breast reconstruction. Other fields of application of medical tattooing include radiation therapy, endoscopic surgery, and ophthalmology. PMID- 17697920 TI - Tattoos: dermatological complications. AB - From the Eskimo in Greenland to the tribes in Polynesia-the whole world knows the art of tattoo. Despite their wide popularity the relation between the skin diseases and the tattooed pictures aren't studied in depth. With the appearance of professional tattoo studios, the risk of infectious complications was reduced. Simultaneously, on a global scale there has been an increase in pseudolymphoma and allergic reactions caused by the introduction of an exogenous pigment into the dermis. The results of our clinical and therapeutic research and review of literature on the subject outline the major problems related to tattoos, i.e. clinical complications. The summarized data showed infectious diseases transmitted through the process of tattooing and many allergic reactions, granulomas and tumors as complications of a tattoo. PMID- 17697921 TI - Temporary henna tattoos. AB - Today, temporary henna tattoos drawn on the skin are very fashionable and have become more and more popular. At the same time, allergic reactions following these tattoos has increased worldwide. Actually, henna has a very low allergic potential. In most cases, allergic reactions are caused by the mixtures used by the so-called "artists" which contain not only natural henna but also many chemical coloring agents such as diaminotoluenes and diaminobenzenes. The long duration of skin contact, the high concentrations of sensitizing materials, and the lack of a neutralizing agent dramatically increases the risk of skin sensitization. We summarized 31 of our own cases with allergic contact dermatitis due to temporary henna tattoos and outlined the main characteristics for this peculiar contact dermatitis. PMID- 17697922 TI - Tattoo removal. AB - Tattoos have been a part of costume, expression, and identification in various cultures for centuries. Although tattoos have become more popular in western culture, many people regret their tattoos in later years. In this situation, it is important to be aware of the mechanisms of tattoo removal methods available, as well as their potential short- and long-term effects. Among the myriad of options available, laser tattoo removal is the current treatment of choice, given its safety and efficacy. PMID- 17697923 TI - Tattoos: surgical removal. AB - Surgical treatment of tattoos remains a useful tool for complete removal despite the availability of laser and other nonsurgical techniques. The procedures are in accordance with standard dermatosurgery used in aesthetic and oncologic therapies. Healing by primary intention or healing by secondary intention has its own indications. Skin defects can be closed by flaps, grafts, tissue extension, or tissue expansion. PMID- 17697924 TI - The hole picture: risks, decision making, purpose, regulations, and the future of body piercing. AB - Can it be said that body piercing is ubiquitous, found across all socioeconomic groups? The major concentration is among adolescents and young adults 15 to 30 years old, in some studies, 50% of the population. Commonly identified physical risks are bleeding, tissue trauma, and bacterial infections; psychosocial risks are unhappiness, low self-esteem, and disappointment. The Health Belief Model is used to explain decision making; purposes for body piercing consistently center on personal expression (self-identity) and uniqueness. The international and US body piercing regulations are discussed, leading to the need for tracking complications globally and standardization of regulations. Proactive health education for clients and health providers remains a priority. PMID- 17697925 TI - Body piercing: where and how. AB - Although earrings have been worn since time immemorial, most clinicians will have noticed more and more patients over the past 30 years who have been seen to have single or multiple piercing almost anywhere into the skin. This article will try to trace the history of body piercing, its comparatively recent popularity, where on the body piercing occurs, and the requirement for guidelines and legislation to try to ensure that the risks inherent in body piercing are lessened. PMID- 17697926 TI - Body piercing: psychosocial and dermatologic aspects. AB - Piercing, a self-provoked body modification, is the insertion of one or more objects through one or more perforating wounds on the skin or mucosa in exposed and covered areas. It is currently more and more frequent, especially in adolescents and young adults, most commonly on the ears and lips. Risks, more common in self-piercers, include infections, allergic sensitization, and traumatic lesions. Calm conversation between the individual and a physician, particularly a dermatologist with experience in medical psychology, can clarify the risks and lead to better understanding of the motivations for such behavior. PMID- 17697927 TI - Tattoos defined. AB - Tattoo definitions from general, foreign language, medical dictionaries and textbooks are reviewed. In addition to the common usage "to mark the skin with pigments," the word tattoo, used as a noun, first meant a signal on a drum or bugle to call military men to quarters. This chapter includes a variety of colorful, cultural and historical references. The increasing popularity of tattoos stimulated the American Academy of Dermatology to produce the 2004 brochure Tattoos, Body Piercing and Other Skin Adornments, which is reproduce here. When asked by patients about getting tattooed, it is wise to caution that even with the variety of modern techniques for removal available, some scarring may result. PMID- 17697928 TI - Gender-specific medicine and ageing: the endocrine impact: second world congress, Rome, Italy, March 8-11, 2007. PMID- 17697929 TI - An athlete's feet. PMID- 17697931 TI - Thioredoxin and thioredoxin-binding protein-2 in cancer and metabolic syndrome. AB - Thioredoxin (TRX), a small redox-active multifunctional protein, acts as a potent antioxidant and a redox regulator in signal transduction. TRX expression is elevated in various types of human cancer. Overexpression of TRX introduces resistance to anti-cancer drugs or radiation-induced apoptosis; however, there is no evidence that the incidence of cancer is frequent in TRX-transgenic mice or that the administration of recombinant human TRX enhances tumor growth. Plasma/serum level of TRX is a good marker for oxidative stress-induced various disorders, including metabolic syndrome. Thioredoxin-binding protein-2 (TBP-2), which was originally identified as a negative regulator of TRX, acts as a growth suppressor and a regulator in lipid metabolism. TBP-2 expression is downregulated in various types of human cancer. TBP-2 deficiency induces lipid dysfunction and a phenotype resembling Reye syndrome. Thus, TRX and TBP-2 play important roles in the pathophysiology of cancer and metabolic syndrome by direct interaction or by independent mechanisms. PMID- 17697932 TI - Redox regulation of hepatitis C in nonalcoholic and alcoholic liver. AB - Hepatitis C virus (HCV) is an RNA virus of the Flaviviridae family that is estimated to have infected 170 million people worldwide. HCV can cause serious liver disease in humans, such as cirrhosis, steatosis, and hepatocellular carcinoma. HCV induces a state of oxidative/nitrosative stress in patients through multiple mechanisms, and this redox perturbation has been recognized as a key player in HCV-induced pathogenesis. Studies have shown that alcohol synergizes with HCV in the pathogenesis of liver disease, and part of these effects may be mediated by reactive species that are generated during hepatic metabolism of alcohol. Furthermore, reactive species and alcohol may influence HCV replication and the outcome of interferon therapy. Alcohol consumption has also been associated with increased sequence heterogeneity of the HCV RNA sequences, suggesting multiple modes of interaction between alcohol and HCV. This review summarizes the current understanding of oxidative and nitrosative stress during HCV infection and possible combined effects of HCV, alcohol, and reactive species in the pathogenesis of liver disease. PMID- 17697933 TI - S-glutathionylation in protein redox regulation. AB - Protein S-glutathionylation, the reversible formation of mixed disulfides between glutathione and low-pKa cysteinyl residues, not only is a cellular response to mild oxidative/nitrosative stress, but also occurs under basal (physiological) conditions. S-glutathionylation has now emerged as a potential mechanism for dynamic, posttranslational regulation of a variety of regulatory, structural, and metabolic proteins. Moreover, substantial recent studies have implicated S glutathionylation in the regulation of signaling and metabolic pathways in intact cellular systems. The growing list of S-glutathionylated proteins, in both animal and plant cells, attests to the occurrence of S-glutathionylation in cellular response pathways. The existence of antioxidant enzymes that specifically regulate S-glutathionylation would emphasize its importance in modulating protein function, suggesting that this protein modification too might have a role in cell signaling. The continued development of proteomic and analytical methods for disulfide analysis will help us better understand the full extent of the roles these modifications play in the regulation of cell function. In this review, we describe recent breakthroughs in our understanding of the potential role of protein S-glutathionylation in the redox regulation of signal transduction. PMID- 17697934 TI - Commentary on "Copper chaperone for Cu,Zn-SOD supplement potentiates the Cu,Zn SOD function of neuroprotective effects against ischemic neuronal damage in the gerbil hippocampus". PMID- 17697935 TI - Oxidative stress biomarkers responses to physical overtraining: implications for diagnosis. AB - Overtraining syndrome is characterized by declining performance and transient inflammation following periods of severe training with major health implications for the athletes. Currently, there is no single diagnostic marker for overtraining. The present investigation examined the responses of oxidative stress biomarkers to a resistance training protocol of progressively increased and decreased volume/intensity. Twelve males (21.3+/-2.3 years) participated in a 12-week resistance training consisting of five 3-week periods (T1, 2 tones/week; T2, 8 tones/week; T3, 14 tones/week; T4, 2 tones/week), followed by a 3-week period of complete rest. Blood/urine samples were collected at baseline and 96 h following the last training session of each period. Performance (strength, power, jumping ability) increased after T2 and declined thereafter, indicating an overtraining response. Overtraining (T3) induced sustained leukocytosis, an increase of urinary isoprostanes (7-fold), TBARS (56%), protein carbonyls (73%), catalase (96%), glutathione peroxidase, and oxidized glutathione (GSSG) (25%) and a decline of reduced glutathione (GSH) (31%), GSH/GSSG (56%), and total antioxidant capacity. Isoprostanes and GSH/GSSG were highly (r=0.764-0.911) correlated with performance drop and training volume increase. In conclusion, overtraining induces a marked response of oxidative stress biomarkers which, in some cases, was proportional to training load, suggesting that they may serve as a tool for overtraining diagnosis. PMID- 17697937 TI - GM1 ganglioside induces vasodilation and increases catalase content in the brain. AB - Monosialoganglioside (GM1) is a glycosphingolipid present in most cell membranes that displays antioxidant and neuroprotective properties. GM1 increases catalase activity in cerebral cortices in vivo, but the mechanisms underlying this effect of GM1 are not known. In the current study we investigated the effect of GM1 (50 mg/kg, ip) on the content of hemoglobin and catalase activity of hippocampus, cortex, and striatum of rats. GM1 administration increased catalase activity and hemoglobin content in brain samples after 30 min, but had no effect on blood catalase activity. GM1-induced increase in catalase activity was abolished by brain perfusion with heparinized saline. Brain catalase activity in the absence of blood, estimated by regression analysis of data from perfused and nonperfused animals, was not altered by the systemic injection of GM1. Moreover, the addition of GM1 (30 or 100 microM) did not increase catalase activity in slices of cerebral cortex in situ, further suggesting that blood circulation is required for this effect. The GM1-induced vasodilation was confirmed in vivo, because the systemic injection of GM1 (50 mg/kg, ip) increased (1.2-1.6 times) the width of pial vessels. PMID- 17697938 TI - Dietary antioxidants as inhibitors of the heme-induced peroxidation of linoleic acid: mechanism of action and synergism. AB - In this work, a quantitative kinetic model for investigating the heme-induced peroxidation of linoleic acid and its inhibition by two important dietary antioxidants, quercetin and alpha-tocopherol, is developed. The main conclusions of this work are: (1) The time dependence of the lipid hydroperoxide concentration is critically dependent on the rate constant for lipid hydroperoxide cleavage, initial fraction of lipid hydroperoxides among the pool of conjugated dienes, and rate of heme degradation. (2) The lipophilic antioxidant alpha-tocopherol acts as a chain-breaking antioxidant that quickly reduces 1-2 eq of lipid peroxyl radicals (inhibition of propagation), whereas the more hydrophilic antioxidant quercetin is only marginally chain-breaking but capable of reducing 4-5 eq of iron-oxo initiator (inhibition of initiation). (3) Based on comparisons between experimental peroxidation curves and simulated curves assuming additivity, it can be concluded that combinations of alpha tocopherol and quercetin are generally synergistic. The kinetic analysis and HPLC titrations of the antioxidants both suggest that synergism mainly arises from a capacity of alpha-tocopherol to regenerate some quercetin oxidation products still endowed with a reducing activity. PMID- 17697936 TI - Effects of thioredoxin reductase-1 deletion on embryogenesis and transcriptome. AB - Thioredoxin reductases (Txnrd) maintain intracellular redox homeostasis in most organisms. Metazoan Txnrds also participate in signal transduction. Mouse embryos homozygous for a targeted null mutation of the txnrd1 gene, encoding the cytosolic thioredoxin reductase, were viable at embryonic day 8.5 (E8.5) but not at E9.5. Histology revealed that txnrd1-/- cells were capable of proliferation and differentiation; however, mutant embryos were smaller than wild-type littermates and failed to gastrulate. In situ marker gene analyses indicated that primitive streak mesoderm did not form. Microarray analyses on E7.5 txnrd-/- and txnrd+/+ littermates showed similar mRNA levels for peroxiredoxins, glutathione reductases, mitochondrial Txnrd2, and most markers of cell proliferation. Conversely, mRNAs encoding sulfiredoxin, IGF-binding protein 1, carbonyl reductase 3, glutamate cysteine ligase, glutathione S-transferases, and metallothioneins were more abundant in mutants. Many gene expression responses mirrored those in thioredoxin reductase 1-null yeast; however, mice exhibited a novel response within the peroxiredoxin catalytic cycle. Thus, whereas yeast induce peroxiredoxin mRNAs in response to thioredoxin reductase disruption, mice induced sulfiredoxin mRNA. In summary, Txnrd1 was required for correct patterning of the early embryo and progression to later development. Conserved responses to Txnrd1 disruption likely allowed proliferation and limited differentiation of the mutant embryo cells. PMID- 17697939 TI - Partial uncoupling of oxidative phosphorylation induces premature senescence in human fibroblasts and yeast mother cells. AB - The mitochondrial theory of aging predicts that functional alterations in mitochondria leading to reactive oxygen species (ROS) production contribute to the aging process in most if not all species. Using cellular senescence as a model for human aging, we have recently reported partial uncoupling of the respiratory chain in senescent human fibroblasts. In the present communication, we address a potential cause-effect relationship between impaired mitochondrial coupling and premature senescence. Chronic exposure of human fibroblasts to the chemical uncoupler carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) led to a temporary, reversible uncoupling of oxidative phosphorylation. FCCP inhibited cell proliferation in a dose-dependent manner, and a significant proportion of the cells entered premature senescence within 12 days. Unexpectedly, chronic exposure of cells to FCCP led to a significant increase in ROS production, and the inhibitory effect of FCCP on cell proliferation was eliminated by the antioxidant N-acetyl-cysteine. However, antioxidant treatment did not prevent premature senescence, suggesting that a reduction in the level of oxidative phosphorylation contributes to phenotypical changes characteristic of senescent human fibroblasts. To assess whether this mechanism might be conserved in evolution, the influence of mitochondrial uncoupling on replicative life span of yeast cells was also addressed. Similar to our findings in human fibroblasts, partial uncoupling of oxidative phsophorylation in yeast cells led to a substantial decrease in the mother-cell-specific life span and a concomitant incrase in ROS, indicating that life span shortening by mild mitochondrial uncoupling may represent a "public" mechanism of aging. PMID- 17697940 TI - Cellular prion protein protects against reactive-oxygen-species-induced DNA damage. AB - Although the cellular form of the prion protein (PrPC) is critical for the development of prion disease through its conformational conversion into the infectious form (PrPSc), the physiological role of PrPC is less clear. Using alkaline single-cell gel electrophoresis (the Comet assay), we show that expression of PrPC protects human neuroblastoma SH-SY5Y cells against DNA damage under basal conditions and following exposure to reactive oxygen species, either hydroxyl radicals following exposure to Cu2+ or Fe2+ or singlet oxygen following exposure to the photosensitizer methylene blue and white light. Cells expressing either PrPDeltaoct which lacks the octapeptide repeats or the prion-disease associated mutants A116V or PG14 had increased levels of DNA damage compared to cells expressing PrPC. In PrPSc-infected mouse ScN2a cells there was a significant increase in DNA damage over noninfected N2a cells (median tail DNA 2.87 and 7.33%, respectively). Together, these data indicate that PrPC has a critical role to play in protecting cells against reactive-oxygen-species mediated DNA damage; a function which requires the octapeptide repeats in the protein, is lost in disease-associated mutants of the protein or upon conversion to PrPSc, and thus provide further support for the neuroprotective role for PrPC. PMID- 17697941 TI - Curcumin induces apoptosis through mitochondrial hyperpolarization and mtDNA damage in human hepatoma G2 cells. AB - Curcumin, a major pigment of turmeric, is a natural antioxidant possessing a variety of pharmacological activities and therapeutic properties. But its mechanisms are unknown. In our previous study, we found that a 2-h exposure to curcumin induced DNA damage to both the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA) in HepG2 cells and that mtDNA damage was more extensive than nDNA damage. Therefore, experiments were initiated to evaluate the role of mtDNA damage in curcumin-induced apoptosis. The results demonstrated that HepG2 cells challenged with curcumin for 1 h showed a transient elevation of the mitochondrial membrane potential (DeltaPsim), followed by cytochrome c release into the cytosol and disruption of DeltaPsim after 6 h exposure to curcumin. Apoptosis was detected by Hoechst 33342 and annexin V/PI assay after 10 h treatment. Interestingly, the expression of Bcl-2 remained unchanged. A resistance to apoptosis for the corresponding rho0 counterparts confirmed a critical dependency for mitochondria during the induction of apoptosis in HepG2 cells mediated by curcumin. The effects of PEG-SOD in protecting against curcumin induced cytotoxicity suggest that curcumin-induced cytotoxicity is directly dependent on superoxide anion O2- production. These data suggest that mitochondrial hyperpolarization is a prerequisite for curcumin-induced apoptosis and that mtDNA damage is the initial event triggering a chain of events leading to apoptosis in HepG2 cells. PMID- 17697942 TI - Nox2 regulates endothelial cell cycle arrest and apoptosis via p21cip1 and p53. AB - Endothelial cells (EC) express constitutively two major isoforms (Nox2 and Nox4) of the catalytic subunit of NADPH oxidase, which is a major source of endothelial reactive oxygen species. However, the individual roles of these Noxes in endothelial function remain unclear. We have investigated the role of Nox2 in nutrient deprivation-induced cell cycle arrest and apoptosis. In proliferating human dermal microvascular EC, Nox2 mRNA expression was low relative to Nox4 (Nox2:Nox4 approximately 1:13), but was upregulated 24 h after starvation and increased to 8+/-3.5-fold at 36 h of starvation. Accompanying the upregulation of Nox2, there was a 2.28+/-0.18-fold increase in O2.- production, a dramatic induction of p21cip1 and p53, cell cycle arrest, and the onset of apoptosis (all p<0.05). All these changes were inhibited significantly by in vitro deletion of Nox2 expression and in coronary microvascular EC isolated from Nox2 knockout mice. In Nox2 knockout cells, although there was a 3.8+/-0.5-fold increase in Nox4 mRNA expression after 36 h of starvation (p<0.01), neither O2.- production nor the p21cip1 or p53 expression was increased significantly and only 0.46% of cells were apoptotic. In conclusion, Nox2-derived O2.-, through the modulation of p21cip1 and p53 expression, participates in endothelial cell cycle regulation and apoptosis. PMID- 17697943 TI - Modulation of nitric oxide formation by endothelial nitric oxide synthase gene haplotypes. AB - Nitric oxide (NO) is a major regulator of the cardiovascular system. However, the effects of endothelial nitric oxide synthase (eNOS) gene polymorphisms or haplotypes on the circulating concentrations of nitrite (a sensitive marker of NO formation) and cGMP are unknown. Here we examined the effects of eNOS polymorphisms in the promoter region (T-786C), in exon 7 (Glu298Asp), and in intron 4 (4b/4a) and eNOS haplotypes on the plasma levels of nitrite and cGMP. We hypothesized that eNOS haplotypes could have a major impact on NO formation. We genotyped 142 healthy subjects by PCR-RFLP. To assess NO formation, the plasma concentrations of nitrite and cGMP were determined using an ozone-based chemiluminescence assay and an enzyme immunoassay. Haplotypes were inferred using the PHASE 2.1 program. No significant differences were found in age, body mass index, systolic and diastolic arterial blood pressure, heart rate, total cholesterol, triglycerides, cGMP, or nitrite among the genotype groups for the three polymorphisms studied here (all p>0.05). Interestingly, the C-4b-Glu haplotype was associated with lower plasma nitrite concentrations than those found in the other haplotype groups (p<0.05), but not with different cGMP levels (p>0.05). These findings suggest that eNOS gene variants combined within a specific haplotype modulate NO formation, although individual eNOS polymorphisms probably do not have major effects. PMID- 17697945 TI - Supporting independence in hospitalized elders in acute care. AB - Planning for care of the older adult is especially important during critical illness states when recovery can be uncertain. Patients often present to the ICU with complex illness; therefore, targeting measures to prevent functional status decline is important for hospitalized elders, who are at risk for prolonged recovery from critical illness. Addressing and planning for the needs of hospitalized elders, including the integration of strategies to target independence, is a key area of focus for nursing care. This article provides a review of the literature on strategies for promoting independence during acute illness and includes recommendations for practice, education, research, and policy to promote optimal care for hospitalized elders in acute care. PMID- 17697946 TI - What critical care nurses need to know about health care access when caring for elders in acute care settings. AB - Health care system issues, in general, and access to care, in particular, are not problems typically studied by critical care nurses. Rather, initial and continuing education focuses on clinical aspects of care. This focus is necessary to assure that critical care nurses have the expertise to care for patients who need astute surveillance for complicated physical problems and their emotional sequelae, as well as in-depth knowledge and skills related to care coordination for patient stabilization and transfer. However, evidence is growing that patients benefit when critical care nurses expand their knowledge about access to care. This article provides insights regarding access to health care and how it relates to many of the admission and readmission patterns that critical care nurses observe. PMID- 17697947 TI - Cultivating responsive systems for the care of acutely and critically ill older adults. AB - This article examines the importance of creating acute care systems that are responsive to the needs of acutely and critically ill and injured older adults. Four attributes of the responsive system are examined: elasticity, enabling, ease, and equanimity. An analytic literature review provides the basis for recommended practices by responsive professionals in responsive systems. Implications for practice, research, education, and policy are provided. PMID- 17697948 TI - Hospital recovery is facilitated by prevention of pressure ulcers in older adults. AB - Pressure ulcers are areas of tissue damage caused by unrelieved pressure that results in ischemia. About 70% of pressure ulcers occur in adults who are older than 65 years of age; the most common sites are the sacrum and heels. The rate at which new ulcers develop in acute care settings varies from 0.4% to 38%, with a mean incidence of about 7%. Recovery in patients who have pressure ulcers is delayed, as demonstrated by an increased length of hospitalization and increased health care costs. This article addresses recovery in older adults who are at risk for the development of a pressure ulcer. PMID- 17697949 TI - Maximizing safety of hospitalized elders. AB - The safety of elders in acute care settings has been a long-standing nursing concern; it is well known that elders are at a higher risk for injury and adverse events during hospitalization. Common sensory changes, comorbidities, and frailty of elders may contribute to injury and poorer outcomes. Confusion, delirium, falls, or adverse drug events experienced by hospitalized elderly also may contribute to injury and adverse hospital outcomes. Nurses may use strategies to protect hospitalized elderly from injury and optimize their outcomes by establishing a culture of safety. Approaches to foster safe hospital stays for elderly patients are outlined, and recommendations for institutional management and administration, policy and nursing practice, education, and research are identified. PMID- 17697950 TI - Optimizing reserve in hospitalized elderly. AB - Aging is a multidimensional process that involves the physical, psychosocial, and spiritual domains. The reserves in each of these areas are challenged during the stressful experience of acute and critical care illness and hospitalization. It is imperative that hospital nursing staff recognize the vulnerability of the elderly and take appropriate evidence-based interventions to prevent avoidable decline and deterioration. There are opportunities for nurses to strengthen reserve in the elderly in the areas of practice, research, education, and policy. PMID- 17697951 TI - Upholding dignity in hospitalized elders. AB - Caring for the elderly in today's acute care setting can be a challenging and complex process. Regardless of whether the interventions provided by caregivers are physical or psychosocial, one of the basic tenets of caring for elderly is to uphold their dignity. The concept of dignity is defined and challenges to maintaining dignity for elderly in the acute care setting are described. Strategies and recommendations for education, practice, research, and policy development are outlined to assist nurses in ensuring that elders receive the dignified care that they deserve. PMID- 17697952 TI - Maintaining vigilance to promote best outcomes for hospitalized elders. AB - This article presents contemporary evidence regarding the promotion of a culture of caring for hospitalized older persons through nursing vigilance. A summary of the literature regarding the need for vigilance, what to be vigilant about, and how vigilance can be enhanced for hospitalized older persons is provided, as well as recommendations for practice, education, research, and policy. Evidence indicates that vigilance is enhanced by having nurses who have specialized knowledge to differentiate normal aging from abnormal pathology, and who use point-of-care information, electronic health records, patient care information systems, and computerized adverse events detection systems to monitor symptoms and outcomes and prevent errors. The use of specialized models of patient care and adequate nurse-patient staffing also have been shown to prevent errors and improve patient outcomes. PMID- 17697953 TI - Using nurse practitioners to implement best practice care for the elderly during hospitalization: the NICHE journey at the University of Virginia Medical Center. AB - The Nurses Improving Care to Health System (NICHE) program has provided a valuable framework for developing initiatives that address the needs of the elderly. Three NICHE models have been implemented within the University of Virginia Health System since 1992. These include the Geriatric Resource Nurse model, the Acute Care of the Elderly model, and, most recently, the Geriatric Consultation Service model. Nurse practitioners (NPs) with geriatric expertise have provided the leadership in implementing these initiatives to achieve the goal of improving geriatric care delivery within the health system. Each NP functions in a broad role that is tailored to meet the needs of the patients and staff and includes the role components of clinician, educator, team leader, and care coordinator. Sustainability and growth of NICHE is contingent upon demonstrating favorable outcomes that can be directly attributed to NICHE. PMID- 17697954 TI - On risks and benefits of iron supplementation recommendations for iron intake revisited. AB - Iron is an essential trace element with a high prevalence of deficiency in infants and in women of reproductive age from developing countries. Iron deficiency is frequently associated with anaemia and, thus, with reduced working capacity and impaired intellectual development. Moreover, the risk for premature delivery, stillbirth and impaired host-defence is increased in iron deficiency. Iron-absorption and -distribution are homeostatically regulated to reduce the risk for deficiency and overload. These mechanisms interact, in part, with the mechanisms of oxidative stress and inflammation and with iron availability to pathogens. In the plasma, fractions of iron may not be bound to transferrin and are hypothesised to participate in atherogenesis. Repleted iron stores and preceding high iron intakes reduce intestinal iron absorption which, however, offers no reliable protection against oral iron overload. Recommendations for dietary iron intake at different life stages are given by the US Food and Nutrition Board (FNB), by FAO/WHO and by the EU Scientific Committee, among others. They are based, on estimates for iron-losses, iron-bioavailability from the diet, and iron-requirements for metabolism and growth. Differences in choice and interpretation of these estimates lead to different recommendations by the different panels which are discussed in detail. Assessment of iron-related risks is based on reports of adverse health effects which were used in the attempts to derive an upper safe level for dietary iron intake. Iron-related harm can be due to direct intestinal damage, to oxidative stress, or to stimulated growth of pathogens. Unfortunately, it is problematic to derive a reproducible cause-effect and dose-response relationship for adverse health effects that suggest a relationship to iron-intake, be they based on mechanistic or epidemiological observations. Corresponding data and interpretations are discussed for the intestinal lumen, the vascular system and for the intracellular and interstitial space, considering interference of the mechanisms of iron homoeostasis as a likely explanation for differences in epidemiological observations. PMID- 17697955 TI - Trace element concentration in metastatic liver disease: a systematic review. AB - BACKGROUND: There are conflicting reports about the levels of trace elements in secondary liver cancers. This review summarises the evidence associating secondary liver tumours with trace elements. METHODS: MEDLINE, EMBASE and CENTRAL databases were searched for the period up to January 2006 using a formal search strategy. Various inclusion and exclusion criteria were applied to select the articles for inclusion. Data extraction was performed using a custom designed data extraction form. RESULTS: A total of 6917 references were identified. About 1359 duplicates were excluded using EndNote. About 5529 clearly irrelevant references were excluded through reading titles and abstracts. Of these 24 references were excluded by applying the exclusion criteria. Five studies including 239 patients and measuring iron content (2), copper content (4) and zinc (3) qualified for the review. Both studies on iron, three studies on copper and all the studies on zinc used quantitative methods to determine mineral content. A meta-analysis was performed using the random effects model. CONCLUSION: Copper and zinc content are lower in secondary liver cancer compared to livers from healthy patients. Iron, copper and zinc content are lower in liver secondaries compared to the normal tissues surrounding the secondaries. Reasons and implications for the trace element alterations should be further investigated. PMID- 17697956 TI - Molybdenum in human whole blood of adult residents of the Merida State (Venezuela). AB - The concentration of molybdenum was measured in whole blood samples of 418 (244 males and 174 females) apparently normal donors ranging in age from 18 to 27 years old and living in nine different locations in the Merida State (Venezuela). The geometric mean concentration of molybdenum of 418 subjects was of 2.66+/-0.66 microgL(-1) (range: 1.20-4.80 microgL(-1)). The levels of molybdenum in whole blood samples found in this work were of 2.57+/-0.52 and 2.54+/-0.51 (range: 1.20 4.80 and 1.40-4.20) microgL(-1) for males and females, respectively. The data of the content molybdenum in whole blood had no statistical correlation with age, sex or height above the sea level of the sampling sites. However, there was a tendency to decrease the levels of the element in those sampling sites located in highlands (> or = 1900 m above the sea level). This variability may be due to the source of molybdenum from the soil to the food chain that has affected its levels in donors from these areas under study. The results of this study are compared with values previously reported for subjects studied in other populations. PMID- 17697957 TI - Milk ceruloplasmin is a valuable source of nutrient copper ions for mammalian newborns. AB - This research focuses on the role of milk ceruloplasmin (Cp), the main extracellular copper-containing protein of vertebrates, as a source of copper for newborns. In the first part of the study, Cp concentration and Cp-associated copper were measured in human skimmed milk at the 1st and the 5th days postpartum. It was shown that most of the copper was associated with Cp and that the decrease in copper concentration during lactation was related to the drop of Cp levels. The following in vivo experiments demonstrated that milk [(125)I]Cp per os administered to 6-day-old rats (embryonic-type copper metabolism) was transported into their bloodstream. The electrophoretic mobility and relative molecular weight of [(125)I]Cp transferred through the cellular barrier remained unaltered. However, 22-day-old rats (adult-type copper metabolism) digested the administered milk [(125)I]Cp completely. In the final part of the study, newborn rats were fed with baby formula for 8d. It was found that these rats switched their copper metabolism from embryonic type to adult type earlier than their littermates fed by dams. Activation of Cp gene expression in the liver, increased Cp and copper concentrations in the blood, and reduced copper content of the liver were observed in the rats fed with baby formula. In the brain, no copper concentration change was observed, but Cp and copper concentrations were dramatically increased in the cerebrospinal fluid. The role of milk Cp as a source of copper adapted to embryonic-type copper metabolism is discussed. PMID- 17697958 TI - Effect of n-propylthiouracil or thyroxine on arsenic trioxide toxicity in the liver of rat. AB - Involvement of thyroid gland in the hepatotoxic manifestations of arsenic trioxide (As(III)) has been studied in rat. The effects of n-propylthiouracil (PTU) (a thyrotoxic compound) and L-thyroxine (a thyroid hormone) have been studied with reference to T(3) and T(4) values in the serum, arsenic concentration in the liver, Ca(2+) accumulation in the liver, aspartate transaminase, alanine transaminase and bilirubin values as the indicators of liver function, histopathological observations and finally the ultrastructural studies. It is concluded that hypothyroid condition protects against As(III) toxicity. Scavenging of reactive oxygen species (ROS) that significantly contribute in As(III) toxicity, by high intracellular concentration of reduced glutathione, as a consequence of PTU treatment is proposed as the plausible protective mechanism. PMID- 17697959 TI - Lithium down-regulates the expression of CXCR4 in human neutrophils. AB - The CXC chemokine receptor CXCR4 and its unique ligand SDF-1 (stromal-derived factor-1) play critical roles for the retention of hematopoietic cells within the bone marrow (BM) and for their mobilization into the circulation. Lithium often produces neutrophilia in psychiatric patients, but the mechanism of mobilization related to neutrophilia has not been fully clarified. We showed here that lithium dose-dependently reduces the levels of surface CXCR4 protein and mRNA in neutrophils, but not in lymphocytes. The chemotactic migration of neutrophils in response to SDF-1 was reduced after a pre-incubation with lithium. We provide evidence that lithium down-regulates the CXCR4 expression of neutrophils and it attenuates their responsiveness to SDF-1. Our studies support the concept that down-regulation of CXCR4 is one of the mechanisms by which causes neutrophilia. PMID- 17697961 TI - Hematopoietic cell transplantation in acute promyelocytic leukemia: a comprehensive review. AB - The past three decades have brought major therapeutic advances in the management of acute promyelocytic leukemia. The current state-of-the-art induction treatment with all-trans retinoic acid in combination with anthracycline-based chemotherapy results in long-lasting remissions and cure in up to 70% of newly diagnosed patients. Unfortunately, treatment failure still occurs in one-third of patients. When disease relapses, patients can achieve subsequent remissions with arsenic trioxide, all-trans retinoic acid with or without chemotherapy, or other therapies. Patients achieving molecular remissions after salvage therapy are generally considered candidates for high-dose chemotherapy and autologous hematopoietic cell transplantation as a postconsolidation strategy. On the other hand, patients with evidence of persistent hematologic or molecular disease after salvage therapy could be offered allogeneic hematopoietic transplantation if a suitable HLA-donor is identified and the patient's overall performance and clinical condition are permissible. We hereby provide a comprehensive review and analysis of published clinical trials that evaluate the role of hematopoietic cell transplantation across different stages of acute promyelocytic leukemia. PMID- 17697960 TI - Oxidative damage in liver after perinatal intoxication with lead and/or cadmium. AB - Lead acetate (300 mg Pb/L) and/or cadmium acetate (10mg Cd/L) in blood and liver were administrated as drinking water to pregnant Wistar rats from day 1 of pregnancy to parturition (day 0) or until weaning (day 21), to investigate the toxic effects in blood and in the liver. Both metals produced mycrocitic anaemia in the pups as well as oxidative damage in the liver, as suggested by the significant increase in TBARS production and the high catalase activity. Moreover, intense alkaline and acid phosphatase activity, used as biomarkers of liver adaptation to damaging factors, was observed. In addition, the toxikinetics are different for Pb and Cd: while Cd is a hepatotoxic from day 0, Pb is not until day 21. Finally, simultaneous perinatal administration of both metals seems to protect, at least, in the liver TBARS production against the toxicity produced by Cd or Pb separately. PMID- 17697962 TI - T cell repertoire development in XSCID dogs following nonconditioned allogeneic bone marrow transplantation. AB - Dogs with X-linked severe combined immunodeficiency (XSCID) can be successfully treated by bone marrow transplants (BMT) resulting in full immunologic reconstitution and engraftment of both donor B and T cells without the need for pretransplant conditioning. In this study, we evaluated the T cell diversity in XSCID dogs 4 months to 10.5 years following BMT. At 4 months posttransplantation, when the number of CD45RA+ (naive) T cells had peaked and plateaued, the T cells in the transplanted dogs showed the same complex, diverse repertoire as those of normal young adult dogs. A decline in T cell diversity became evident approximately 3.5 years posttransplant, but the proportion of Vbeta families showing a polyclonal Gaussian spectratype still predominated up to 7.5 years posttransplant. In 2 dogs evaluated at 7.5 and 10.5 years posttransplant, >75% of the Vbeta families consisted of a skewed or oligoclonal spectratype that was associated with a CD4/CD8 ratio of <0.5. The decline in the complexity of T cell diversity in the transplanted XSCID dogs is similar to that reported for XSCID patients following BMT. However, in contrast to transplanted XSCID boys who show a significant decline in their T cell diversity by 10 to 12 years following BMT, transplanted XSCID dogs maintain a polyclonal, diverse T cell repertoire through midlife. PMID- 17697963 TI - Use of fluid-ventilated, gas-permeable scleral lens for management of severe keratoconjunctivitis sicca secondary to chronic graft-versus-host disease. AB - Keratoconjunctivitis sicca (KCS) occurs in 40%-60% of patients with chronic graft versus-host-disease (cGVHD) after allogeneic hematopoietic cell transplantation. Although immunosuppressive therapy is the primary treatment of chronic GVHD, ocular symptoms require measures to improve ocular lubrication, decrease inflammation, and maintain mucosal integrity. The liquid corneal bandage provided by a fluid-ventilated, gas-permeable scleral lens (SL) has been effective in mitigating symptoms and resurfacing corneal erosions in patients with KCS related to causes other than cGVHD. We report outcomes in 9 consecutive patients referred for SL fitting for cGVHD-related severe KCS that was refractory to standard treatments. All patients reported improvement of ocular symptoms and reduced the use of topical lubricants after SL fitting resulting from decreased evaporation. No serious adverse events or infections attributable to the SL occurred. The median Ocular Surface Disease Index improved from 81 (75-100) to 21 (6-52) within 2 weeks after SL fitting, and was 12 (2-53) at the time of last contact, 1-23 months (median, 8.0) after SL fitting. Disability related to KCS resolved in 7 patients after SL fitting. The use of SL appears to be safe and effective in patients with severe cGVHD-related KCS refractory to conventional therapies. PMID- 17697964 TI - Host T cells affect donor T cell engraftment and graft-versus-host disease after reduced-intensity hematopoietic stem cell transplantation. AB - Mixed chimerism in the T cell compartment (MCT) after reduced-intensity stem cell transplantation (RIST) may influence immune repopulation with alloreactive donor T cells. We examined effects of host T cell numbers on donor T cell engraftment and recovery and on acute graft-versus-host disease (aGVHD) in a relatively homogeneous patient population with respect to residual host T cells through quantified immune depletion prior to RIST and to donor T cells by setting the allograft T cell dose of 1x10(5) CD3+ cells/kg. In this setting, 2 patterns of early donor T cell engraftment could be distinguished by day +42: (1) early and complete donor chimerism in the T cell compartment (FDCT) and (2) persistent MCT. FDCT was associated with lower residual host CD8+ T cell counts prior to transplant and aGVHD. With persistent MCT, subsequent development of aGVHD could be predicted by the direction of change in T cell donor chimerism after donor lymphocyte infusion, and no aGVHD occurred until FDCT was established. MCT did not affect recovery of donor T cell counts. These observations suggest that the relative number and alloreactivity of donor and host T cells are more important than the absolute allograft T cell dose in determining donor engraftment and aGVHD after RIST. PMID- 17697965 TI - Frequency and targeted detection of HLA-DPB1 T cell epitope disparities relevant in unrelated hematopoietic stem cell transplantation. AB - The majority of unrelated donor (UD) hematopoietic stem cell (HSC) transplants are performed across HLA-DP mismatches, which, if involving disparity in a host versus-graft (HVG) direction for an alloreactive T cell epitope (TCE), have been shown by our group to be associated with poor clinical outcome in 2 cohorts of patients transplanted for hematopoietic malignancies and beta-thalassemia, respectively. Using site-directed mutagenesis of DPB1*0901, we show here that the TCE is abrogated by the presence of amino acids LFQG in positions 8-11 of the DP beta-chain. Based on this and on alloreactive T cell responsiveness, we have determined the presence or absence of the TCE for 72 DPB1 alleles reported in the ethnic groups representative of the worldwide UD registries, and predict that 67% 87% (mean 77%) of UD recipient pairs will not present a DPB1 TCE disparity in the HVG direction. We developed and validated in 112 healthy Italian blood donors an innovative approach of DPB1 epitope-specific typing (EST), based on 2 PCR reactions. Our data show that DPB1 TCE disparities may hamper the clinical success of a considerable number of transplants when DPB1 matching is not included into the donor selection criteria, and that a donor without DPB1 TCE disparities in the HVG direction can be found for the majority of patients. Moreover, the study describes the first protocol of targeted epitope-specific DPB1 donor-recipient matching for unrelated HSC transplantation. This protocol will facilitate large-scale retrospective clinical studies warranted to more precisely determine the clinical relevance of DPB1 TCE disparities in different transplant conditions. PMID- 17697967 TI - Allografted recipients immunized against hepatitis B virus are at high risk of gradual surface antibody (HbsAb) disappearance post transplant, regardless of adoptive immunity transfer. AB - Immunized against hepatitis B virus (HBV) recipients are at risk of developing HBV postallogeneic stem cell transplantation because of the potential loss of their HBV immunity. The aim of the study was to evaluate: (1) the HbsAb eradication incidence posttransplant and potential risk factors, (2) the impact of donor's immunity on HbsAb loss, (3) the incidence of hepatitis B in patients with HbsAb disappearance. We studied, retrospectively, in 26 vaccinated and 56 naturally immunized recipients, the posttransplant HbsAb titers for a median period of 36 (6-132) months. The probability of HbsAb loss and HBV-related hepatitis was determined in all recipients. The impact of donor's immunity origin in the HBsAb disappearance was evaluated in the subgroup of, actively or naturally, immunized recipients/donors pairs. The 5-year probability of HbsAb disappearance was 90% for all patients with 18% probability of developing hepatitis at 12 years, for those who lost HbsAb. Marrow graft, antithymocyte globulin administration, age<30 years and chronic graft-versus-host disease were significant risk factors for HbsAb loss. In the subgroup of immunized recipients/donors, the donor's active immunization significantly affected this loss. Allotransplanted patients are at high risk of losing protection against HBV. The adoptive transfer of active HBV immunity does not seem to offer sustained protection posttransplant. PMID- 17697966 TI - Extended mycophenolate mofetil and shortened cyclosporine failed to reduce graft versus-host disease after unrelated hematopoietic cell transplantation with nonmyeloablative conditioning. AB - We previously reported data from 103 patients with hematologic malignancies (median age 54 years) who received peripheral blood stem cell (PBSC) grafts from HLA-matched unrelated donors after nonmyeloablative conditioning and were given postgrafting immunosuppression consisting of mycophenolate mofetil (MMF; administered from day 0 until day +40 with taper through day +96) and cyclosporine (CSP; given from day -3 to day +100, with taper through day 180) (historical patients). The incidences of grade II-IV acute and extensive chronic graft-versus-host disease (aGVHD, cGVHD) were 52% and 49%, respectively, and the 1-year probabilities of relapse, nonrelapse mortality (NRM), and progression-free survival (PFS) were 26%, 18%, and 56%, respectively. Here, we treated 71 patients with hematologic malignancies (median age 56 years) with unrelated PBSC grafts and investigated whether postgrafting immunosuppression with an extended course of MMF, given at full dosing until day +150 and then tapered through day +180, and a shortened course of CSP, through day +80, would promote tolerance induction and reduce the incidence of GVHD (current patients). We observed 77% grade II-IV aGVHD and 45% extensive cGVHD (P=.03, and P=.43, respectively, in current compared to historical patients). The 1-year probabilities of relapse, NRM, and PFS were 23%, 29%, and 47%, respectively (P=.89, P=.02, and P=.08 compared to the historical patients). We conclude that postgrafting immunosuppression with extended MMF and shortened CSP failed to decrease the incidence of GVHD among unrelated PBSC recipients given nonmyeloablative conditioning. PMID- 17697968 TI - Long-term survival after autologous bone marrow transplantation for follicular lymphoma in first remission. AB - The role of autologous stem cell transplantation (ASCT) in the treatment of follicular lymphoma is still being defined in the era of antibody therapy. Here we report the long-term 12-year clinical outcomes of patients treated with autologous bone marrow transplantation (ABMT) for follicular non-Hodgkin's lymphoma (NHL) in first remission. Between 1988 and 1993, advanced-stage follicular NHL patients in need of initial therapy were enrolled in 2 consecutive prospective treatment trials of either standard-dose CHOP induction (83 patients) or high-dose CHOP plus granulocyte-colony stimulating factor (G-CSF) (20 patients). Patients who achieved an adequate remission with induction therapy underwent conditioning with cyclophosphamide and total body irradiation (TBI) followed by ABMT in first remission using bone marrow (BM) purged in vitro with anti-B cell monoclonal antibodies and rabbit complement (96 patients). At 12-year follow-up, 61% of the patients are alive and 43% remain in continuing complete remission. The only predictors of decreased progression-free survival proved to be histologic BM involvement at time of harvest (hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.3-3.9, P<.004) and PCR detectable disease in the BM product after purging (HR 4.18, 95% CI 1.99-8.8, P=.0002). No significant predictors of overall survival were identified. These results at 12-year follow up suggest that a subset of follicular lymphoma patients can experience prolonged survival with ABMT in first remission. PMID- 17697969 TI - Deletion of the short arm of chromosome 1 (del 1p) is a strong predictor of poor outcome in myeloma patients undergoing an autotransplant. AB - Several chromosomal abnormalities detected by conventional cytogenetic analysis have an adverse impact on the outcome in myeloma patients. A wide spectrum of abnormalities involving chromosomes 1, 13, 14, and 17 has been described. We analyzed the outcome of 83 patients with clonal cytogenetic abnormalities, who underwent high-dose therapy and autologous stem cell transplantation for multiple myeloma at our institution. Clonal abnormalities were detected at diagnosis by conventional cytogenetic analysis in 83 patients. Patients underwent a single autologous transplant between April 2000 and May 2005. Preparative regimen was high-dose melphalan alone (73), or a combination of topotecan, melphalan, and cyclophosphamide (TMC=10). The most commonly observed chromosomal abnormalities were deletion of chromosome 13 (32%), hyperdiploidy (21%), deletion of chromosome 1p (18%), and t (11; 14) in 7% patients. Median follow-up among surviving patients was 25.5 months. Median interval from diagnosis to autotransplant was 7.7 months (range: 2.5-52). Median progression-free survival (PFS) for the entire group was 19 months and the median overall survival (OS) was 52 months. On univariate analysis, both PFS and OS were significantly shorter in patients with deletion 1p (P=.001 and <.0001, respectively). Thirty-two patients whose cytogenetic abnormalities returned to normal prior to autotransplant had longer PFS and OS than patients with persistent abnormalities (P=.02 and .08, respectively). Deletion 1p is associated with a significantly shorter remission and survival in patients undergoing high-dose therapy and a single autologous transplant for myeloma. PMID- 17697970 TI - Results of unrelated cord blood transplant in fanconi anemia patients: risk factor analysis for engraftment and survival. AB - We retrospectively analyzed results of unrelated cord blood transplantation (UCBT) in 93 Fanconi anemia (FA) patients. Median age at transplantation was 8.6 years (1-45). The units transplanted were HLA-A, -B, or -DRB1 identical in 12 cases, 1 HLA mismatch in 35 cases, and 2 or 3 HLA differences in 45 cases. The median number of nucleated cells (NC) and CD34+ cells infused of recipient weight was 4.9x10(7)/kg and 1.9x10(5)/kg, respectively. Participating centers selected the preparative regimen of their choice, in 57 patients (61%), it included Fludarabine. Graft-versus-host disease (GVHD) prophylaxis consisted mostly of cyclosporine with prednisone. Cumulative incidence (CI) of neutrophil recovery was 60+/-5% at day +60. In multivariate analysis, Fludarabine containing regimen and NC infused>or=4.9x10(7)/kg were associated with higher probability of recovery. CI of grade II-IV acute and of chronic GVHD (aGVHD, cGVHD) was 32%+/-5% and 16%+/-4%, respectively. Overall survival (OS) was 40%+/-5%. In multivariate analysis, factors associated with favorable outcome were use of Fludarabine in the conditioning regimen, number of NC infused>or=4.9x10(7)/kg, and negative cytomegalovirus (CMV) serology in the recipient. In conclusion, factors easily modifiable such as donor selection and a Fludarabine-containing regimen can considerably improve survival in FA patients given a UCBT. These data are the basis for designing prospective protocols. PMID- 17697971 TI - Allogeneic stem cell transplantation in first complete remission enhances graft versus-leukemia effect in adults with acute lymphoblastic leukemia: antileukemic activity of chronic graft-versus-host disease. AB - The aim of the present study was to identify graft-versus-leukemia effects and the factors that affect outcome in 201 adults with acute lymphobalstic leukemia who received myeloablative allogeneic stem cell transplantation from matched sibling or unrelated donors (1995-2004). One hundred seventy-eight (88.6%) of these patients had high-risk criteria, and 151 (75.1%) patients were transplanted in first complete remission (CR). All patients received unmodified stem cell grafts (185 bone marrow and 16 peripheral blood) following total- body irradiation-containing myeloablative preparations. Graft-versus-host disease (GVHD) prophylaxis was uniformly attempted by administering calcineurin inhibitor plus methotrexate. After a median follow-up of 63 months (range: 25+ to 139+ months) for surviving transplants, disease-free survival at 5 years was 47.8% for all patients and 60.3% for patients in the first CR. No difference in transplantation outcome was observed between sibling and unrelated transplants in the first CR. The most powerful predictive factor affecting transplantation outcome was disease status at transplantation (the first CR versus beyond the first CR, P<.001). Chronic GVHD (cGVHD), especially limited type, was also found to have a significant antileukemic effect. Interestingly, the influence of cGVHD on relapse risk was prominent in patients with chromosomal translocations or normal cytogenetics. PMID- 17697972 TI - Randomized comparison of four-times-daily versus once-daily intravenous busulfan in conditioning therapy for hematopoietic cell transplantation. AB - Sixty patients were randomized to receive intravenous busulfan (iBU) either as 0.8 mg/kg, over 2 hours 4 times a day (BU4 arm) or 3.2 mg/kg, over 3 hours once a day (BU1 arm) in conditioning therapy for hematopoietic cell transplantation. The complete pharmacokinetic parameters for the first busulfan dose were obtained from all patients and were comparable between the 2 arms: for the BU4 and BU1 groups, elimination half-life (mean+/-SD) was 2.75+/-0.22 versus 2.83+/-0.21 hours, estimated daily AUC was 6058.0+/-1091.9 versus 6475.5+/-1099.4 microM.min per day, and clearance was 2.05+/-0.36 versus 1.91+/-0.31 mL/min/kg, respectively. Times to engraftment after transplantation were similar between the 2 arms. No significant differences were evident in the occurrence of acute graft versus-host disease (aGVHD) and hepatic veno-occlusion disease (VOD). Moreover, other toxicities observed within 100 days after transplantation were not significantly different between the 2 arms. The cumulative incidence of nonrelapse mortality was 20.8% in BU4 arm and 13.3% in BU1 arm. In conclusion, our randomized study demonstrates that the pharmacokinetic profiles and posttransplant complications are similar for once-daily iBU and traditional 4 times-daily iBU. PMID- 17697973 TI - Cytomegalovirus infection after allogeneic transplantation: comparison of cord blood with peripheral blood and marrow graft sources. AB - Cytomegalovirus (CMV) infection is an important complication following allogeneic hematopoietic stem cell transplant (HSCT), but the natural history in the cord blood setting has not been well studied. We assessed CMV infection episodes in 753 consecutive allogeneic HSCT recipients at the University of Minnesota between January 1, 1998 and December 31, 2003. The 6-month cumulative incidence of viremia/antigenemia was 22% by day +182: 21% (95% confidence interval 16%-26%) in cord blood recipients (UCB), 24% (20%-28%) in marrow (BM), and 22% (16%-28%) using peripheral blood grafts (PBSC). CMV disease incidence was 6% (2%-10%) in UCB, 8% (5%-11%) in BM, and 9% (6%-12%) in PBSC. In multivariate analysis, CMV infection (viremia/antigenemia and disease) was significantly more likely in patients who were seropositive to CMV, in those with acute graft versus host disease, and in those receiving T cell-depleted grafts. Graft source did not independently contribute to the risk of CMV infection and did not impact survival after CMV infection. These data confirm that recipient CMV serostatus remains the dominant risk factor for CMV infection. Recipients of UCB have similar risks of CMV infection, responses to antiviral therapy, and survival following CMV infection as recipients of either marrow or PBSC. PMID- 17697974 TI - Grover's Disease after Bone Marrow Transplantation. PMID- 17697975 TI - Mantle cell lymphoma in first complete remission. PMID- 17697976 TI - Microbial manganese oxide formation and interaction with toxic metal ions. AB - Diverse bacteria and fungi oxidize Mn(II) enzymatically and produce insoluble Mn(III, IV) oxides, and these organisms are considered to be the primal agents for the occurrence of natural Mn oxide phases in most environments. Biogenic Mn oxides have a high sorption capacity for metal cations and an ability to oxidize numerous inorganic and organic compounds, owing to their structural and redox features. Thus, the microbial process is of significance in both biogeochemical and biotechnological contexts. In this article we summarize the enzymatic Mn(II) oxidation and interactions of biogenic Mn oxides with toxic metal and metalloid ions. Although Mn oxide formation by fungi has not been fully characterized yet, recent researches with ascomycetes emphasize the similarity between the bacterial and fungal Mn(II) oxidation with respect to the involved catalyst (i.e., multicopper oxidase-type enzymes) and the reaction product [i.e., layer-type Mn(IV) oxides]. Laboratory cultures of bacterial and fungal Mn oxidizers are expected to provide fundamental knowledge in their potential use for remediation of environments and effluents contaminated with toxic metal(loid) ions. PMID- 17697977 TI - Effects of lactose and glucose on production of itaconic acid and lovastatin by Aspergillus terreus ATCC 20542. AB - Fermentation products of Aspergillus terreus ATCC 20542 (a parent strain for lovastatin production) were collected, and the coexistence of itaconic acid (IA) with lovastatin was confirmed in this study. Using a lactose-based medium (LBM), lovastatin production was 873 mg/l on day 10, but IA production was only 22-28 mg/l during the cultures. When lactose in LBM was simply replaced with glucose, IA production was markedly enhanced by 20-fold (491 mg/l on day 5), which showed a growth-associated pattern. The findings indicated that the carbon source used (glucose or lactose) controlled the biosynthetic pathway. The net yield of lovastatin production when using lactose was calculated to be 25.1 mg/g (5.1 fold) in comparison with when using glucose in the cultures. Furthermore, lovastatin production was further increased by 9.2% when IA (0.5 g/l) was added to LBM. When IA was added at 5 g/l, the fermentation broth turned dark-brown, and lovastatin production was reduced by 18.0%. Hence, these two metabolites (IA and lovastatin) produced by the fungus might be related. PMID- 17697978 TI - Generation and characterization of islet cell tumor in pTet-on/pTRE-SV40Tag double-transgenic mice model. AB - A line of double-transgenic mice that develop neoplasms arising primarily in the pancreas was established. In these mice, the oncogene SV40 T antigen (Tag) was detected in the pancreas with and without the control of Tet-on system. The transgenic mice that developed pancreatic tumors as early as 20 weeks of age showed hypoglycemia on a blood glucose test. Pathological and immunohistochemical characterizations demonstrated that the tumors belonged to neuroendocrine neoplasms arising from pancreatic islets. A change in IGFs/IGF-1R signaling pathway was detected using real-time PCR analysis. A potential association between the IGFs/IGF-1R system and SV40Tag was studied to further explain the cancerogenesis of the double-transgenic mice by Western blot analysis and immunoprecipitation experiments. The results suggest that a Tag transgenic mice model could be used to study the molecular mechanism of the tumorigenesis of islets. PMID- 17697979 TI - Novel transglucosylating reaction of sucrose phosphorylase to carboxylic compounds such as benzoic acid. AB - We examined the synthesis of benzoyl glucoside using the transglucosylation reaction of sucrose phosphorylase. Sucrose phosphorylase from Streptococcus mutans showed marked transglucosylating activity, particularly under acidic conditions. On the other hand, sucrose phosphorylase from Leuconostoc mesenteroides showed very weak transglucosylating activity. Three main products were detected from the reaction mixture using benzoic acid as an acceptor molecule and sucrose as a donor molecule. These compounds were identified as 1-O benzoyl alpha-D-glucopyranoside, 2-O-benzoyl alpha-D-glucopyranose and 2-O benzoyl beta-D-glucopyranose on the basis of their isolation and the isolation of their acetylated products and subsequent analysis using 1D- and 2D-NMR analyses. From the results of the time-course analyses of the enzyme reaction and the degradation of 1-O-benzoyl alpha-D-glucopyranoside, 1-O-benzoyl alpha-D glucopyranoside was considered to be initially produced by the transglucosylation reaction of the enzyme, and 2-O-benzoyl alpha-D-glucopyranose and 2-O-benzoyl beta-D-glucopyranose were produced from 1-O-benzoyl alpha-D-glucopyranoside by intramolecular acyl migration reaction. The acceptor specificity in the glucosylation reaction of S. mutans sucrose phosphorylase was also investigated. This sucrose phosphorylase could transglucosylate toward various carboxylic compounds. Short-chain fatty acids, hydroxy acids and dicarboxylic acids were also glucosylated with this sucrose phosphorylase. PMID- 17697980 TI - Synthesis of enzymatically-gellable carboxymethylcellulose for biomedical applications. AB - We synthesized a carboxymethylcellulose with phenol moieties by covalently incorporating tyramine into carboxymethylcellulose using aqueous-phase carbodiimide activation chemistry. The resulting hydrogel was obtained from an aqueous solution of the conjugate via the horseradish peroxidase-catalyzed oxidation reaction of phenols by consuming H(2)O(2), where the gelation speed depended on the concentrations of enzyme and H(2)O(2). The viability of the mammalian cells enclosed within the hydrogel prepared from 1.5% (w/v) conjugate solution containing 5 units/ml horseradish peroxidase and 1 mM H(2)O(2), was 80% after 24 h. These results demonstrate that this carboxymethylcellulose with phenol moieties has potential for biomedical applications including tissue engineering. PMID- 17697981 TI - Development of series of gateway binary vectors, pGWBs, for realizing efficient construction of fusion genes for plant transformation. AB - We developed a new series of binary vectors useful for Gateway cloning to facilitate transgenic experiments in plant biotechnology. The new system, Gateway Binary Vectors (pGWBs) realized efficient cloning, constitutive expression using the cauliflower mosaic virus (CaMV) 35S promoter and the construction of fusion genes by simple clonase reaction with an entry clone. The reporters employable in this system are beta-glucuronidase (GUS), synthetic green fluorescent protein with S65T mutation (sGFP), luciferase (LUC), enhanced yellow fluorescent protein (EYFP), and enhanced cyan fluorescent protein (ECFP). The tags available are 6xHis, FLAG, 3xHA, 4xMyc, 10xMyc, GST, T7-epitope, and tandem affinity purification (TAP). In total, 13 kinds of reporter or tag were arranged and were almost applicable to both N- and C-fusions. The pGWBs could be used for many purposes, such as promoter::reporter analysis, observation of subcellular localization by the expression of proteins fused to a reporter or tag, and analysis of protein-protein interaction by copurification and immunodetection experiments. The pGWBs were constructed with modified pBI101 containing a CaMV35S promoter-driven hygromycin phosphotransferase (HPT) gene as the second selection marker. We also constructed pGWBs with the marker HPT driven by the nopaline synthase promoter. By using the pGWB system, the expression of tagged proteins, and the localization of GFP-fused proteins were easily analyzed. Moreover, tissue specific and inducible gene expression using a promoter was also monitored with pGWBs. It is expected that, the pGWB system will serve as a powerful tool for plasmid construction in plant research. PMID- 17697982 TI - Effects of divalent cations on Halobacterium salinarum cell aggregation. AB - Ca(2+) was found to be essential for initiating Halobacterium salinarum CCM 2090 cell aggregation. The floc formed from such aggregation could easily be dissociated without cellular lysis by sodium citrate. Cr(2+), Mn(2+), Fe(3+), Co(2+), Ni(2+), Cu(2+), and Zn(2+) could replace Ca(2+). However, Mg(2+), Sr(2+), Mo(2+), Cd(2+), Sn(2+), Hg(2+), and Pb(2+) induced no flocculation of cells of this halophilic archaeon. Mg(2+) acted antagonistically against Ca(2+)-induced aggregation. Such aggregation might be directly caused by the interaction of Ca(2+) and aggregation factors from 55 degrees C-treated cell extract. PMID- 17697983 TI - Cloning, characterization and expression analysis of calcium channel beta subunit from pearl oyster (Pinctada fucata). AB - The absorption, transport and localization of calcium underlie the basis of biomineralization, and Ca(2+) entry into epithelial cell is the primary step in shell formation. However, the related mechanism of Ca(2+) transport is poorly documented at the gene or protein level. L-type voltage-dependent calcium channels may be involved in calcium transport for biomineralization in some marine invertebrates. In this study, a full-length cDNA of a voltage-dependent calcium channel beta subunit from Pinctada fucata (PCabeta) was cloned, and its amino acid sequence was deduced. PCabeta shared 51%-67% apparently sequence identity with voltage-dependent calcium channel beta subunits from other species. However, PCabeta was much shorter than other voltage-dependent calcium channel beta subunits particularly at the carboxyl terminus, indicating that it is likely a truncated beta subunit isoform. Semi-quantitative RT-PCR analysis showed that PCabeta was expressed in all the tested tissues and that it had a higher expression level in the gill tissue and hemolymph than in other tissues, suggesting that L-type voltage-dependent calcium channels are responsible for Ca(2+) absorption in the gill and Ca(2+) entry into hemocytes. In the mantle, PCabeta mRNA was predominantly expressed in the inner and middle folds of the mantle epithelium, suggesting that L-type voltage-dependent calcium channels are involved in Ca(2+) absorption from the ambient medium in the mantle. All these results suggest that voltage-dependent calcium channels are involved in Ca(2+) uptake and transport during oyster biomineralization. PMID- 17697984 TI - Evaluation of cell wall binding domain of Staphylococcus aureus autolysin as affinity reagent for bacteria and its application to bacterial detection. AB - We evaluated the cell wall binding (CWB) domain of Staphylococcus aureus autolysin as an affinity reagent for bacteria. A fusion of CWB domain and green fluorescent protein (CWB-GFP) bound to S. aureus with a dissociation constant of 15 nM. CWB-GFP bound to a wide range of gram-positive bacteria, but not to most gram-negative bacteria. We suspected that the outer membrane of gram-negative bacteria inhibits the access of CWB-GFP to peptidoglycan layer. Indeed, CWB-GFP bound to gram-negative bacteria when they were treated with benzalkonium chloride. Because CWB-GFP bound to the bacterial peptidoglycan layer, it appeared to be an effective affinity reagent for bacteria and CWB fusion with reporter proteins could be applied to detect bacteria. We also constructed a fusion of CWB and luciferase, which can be used for the rapid detection of bacteria. PMID- 17697985 TI - Enhanced anaerobic biodegradation of polychlorinated biphenyls in burnt soil culture. AB - Anaerobic microbial degradation of polychlorinated biphenyls (PCBs) in Kanechlors 300 and -400 was enhanced significantly by adding burnt soil originally obtained from an uncontaminated paddy soil to the microbial culture. The maximum PCB degrading activity was 0.49 nmol-Cl/ml-culture/day (238 ng-total-PCBs/ml culture/day), where the degradation was observed in most of the congeners in Kanechlors-300 and -400: not only in meta- and para-substituted congeners but also ortho-substituted congeners. The degradation of PCBs occurred during the increase in the microbial population with acetate as the main electron donor. The ratio between the consumption of electron donors and the dechlorination of PCBs was revealed to be 93.9 nmol-Cl/mmol-e-donor, which is also the dechlorination efficiency over 56 d of incubation. The addition of acetate and lactate several times into the culture rejuvenated the activity. PMID- 17697986 TI - Evaluation of L929 fibroblast attachment and proliferation on Arg-Gly-Asp-Ser (RGDS)-immobilized chitosan in serum-containing/serum-free cultures. AB - In this study, chitosan membranes prepared by the solvent casting method were modified with the Arg-Gly-Asp-Ser (RGDS) sequence of fibronectin using the photochemical immobilization technique. The results obtained from attenuated total reflection-Fourier transform infrared spectra and X-ray photoelectron spectroscopy studies confirmed the successful immobilization of RGDS on chitosan membranes. The immobilized peptide concentration was determined by ninhydrin analysis on the order of 10(-7) mol/cm(2). In vitro cell culture studies were performed with L929 mouse fibroblasts to investigate the effect of biomodification on fibroblast cell behaviour in serum-free and 10% serum containing media. The results obtained from cell culture studies pointed out the specific interactions between biosignal RGDS molecules and fibroblast cells. A triggered cell attachment and proliferation were observed on RGDS-modified chitosan membranes that were more distinguishable in serum-free medium. In addition, the photochemical immobilization technique was realized in the presence of a photomask that was used to immobilize the RGDS molecules in a defined micropattern. L929 mouse fibroblasts attached on the RGDS-micropatterned areas indicating integrin-mediated interactions. PMID- 17697987 TI - Microbial conversion of glycerol into glycolipid biosurfactants, mannosylerythritol lipids, by a basidiomycete yeast, Pseudozyma antarctica JCM 10317(T). AB - Microbial conversion of glycerol into functional bio-based materials was investigated, aiming to facilitate the utilization of waste glycerol. A basidiomycete yeast, Pseudozyma antarctica JCM 10317, efficiently produced mannosylerythritol lipids (MELs) as glycolipid biosurfactants from glycerol. The amount of MEL yield reached 16.3 g l(-1) by intermittent feeding of glycerol. PMID- 17697989 TI - Gene-tagging mutagenesis in the methylotrophic yeast Candida boidinii. AB - A gene-tagging mutagenesis method by random integration of linear DNA fragments was developed and used in the methylotrophic yeast Candida boidinii to isolate mutants defective in methanol-inducible gene expression. A large number of mutants were obtained, indicating that this method is a powerful tool for random mutagenesis in C. boidinii. PMID- 17697988 TI - Hydrogen fermentation properties of undiluted cow dung. AB - Anaerobic treatment of undiluted cow dung (15% total solids), so-called dry fermentation, produced hydrogen (743 ml-H(2)/kg-cow dung) at an optimum temperature of 60 degrees C, with butyrate and acetate formation. The hydrogen production was inhibited by the addition of NH(4)(+) in a dose-dependent manner. A bacterium with similarity to Clostridium cellulosi was detected in the fermented dung by a 16S rDNA analysis. PMID- 17697990 TI - Psychosocial interventions in cardiovascular nursing. PMID- 17697991 TI - Making the right moves. AB - The structure of the nucleotide-free F(1)-ATPase from a thermoalkaliphilic bacterium presented in this issue of Structure (Stocker et al., 2007) reveals the structural interactions that prevent the enzyme from operating naturally in the hydrolytic direction. The data provide new insights into the mechanism of the F(o)F(1)-ATP synthase. PMID- 17697992 TI - Diguanylate cyclase activation: it takes two. AB - Characterization of an activated diguanylate cyclase reported in this issue of Structure by Wassmann et al. (2007) reveals how phosphorylation promotes dimerization necessary for synthesis of the second messenger c-di-GMP, establishes the catalytic mechanism, and identifies a widely conserved mode of product inhibition. PMID- 17697993 TI - Gate-crashing the nuclear pore complex. AB - As a third in a series of MD simulations investigating the binding dynamics between nuclear transport receptors and FG-repeats, Isgro and Schulten (2007b) unveil that close, physical intimacy between partners is likely to ensure a hassle-free passage through the nuclear pore complex. PMID- 17697994 TI - Folate synthesis: an old enzyme identified. AB - In this issue of Structure, Amzel, Bessman, and colleagues (Gabelli et al., 2007) present the crystal structure of a 17 kDa Nudix hydrolase from Escherichia coli previously characterized as a dATPase and provide evidence that it functions in vivo to remove pyrophosphate from the folate precursor dihydroneopterin triphosphate. PMID- 17697995 TI - An IgG-like domain in the minor pilin GBS52 of Streptococcus agalactiae mediates lung epithelial cell adhesion. AB - Streptococcus agalactiae is the leading cause of neonatal pneumonia, sepsis, and meningitis. The pathogen assembles heterotrimeric pilus structures on its surface; however, their function in pathogenesis is poorly understood. We report here the crystal structure of the pilin GBS52, which reveals two IgG-like fold domains, N1 and N2. Each domain is comprised of seven antiparallel beta strands, an arrangement similar to the fold observed in the Staphylococcus aureus adhesin Cna. Consistent with its role as an adhesin, deletion of gbs52 gene significantly reduces bacterial adherence to pulmonary epithelial cells. Moreover, latex beads linked to the GBS52 protein adhere to pulmonary but not to many other epithelial cells; binding to the former is specifically inhibited by antibodies against GBS52. Nonetheless, substantial binding is only observed with N2 domain conjugated beads. This study presents the structure of a Gram-positive pilin that utilizes a distinct IgG fold variant to mediate pathogen adherence to a specific tissue. PMID- 17697996 TI - The structural basis for unidirectional rotation of thermoalkaliphilic F1-ATPase. AB - The ATP synthase of the thermoalkaliphilic Bacillus sp. TA2.A1 operates exclusively in ATP synthesis direction. In the crystal structure of the nucleotide-free alpha(3)beta(3)gamma epsilon subcomplex (TA2F(1)) at 3.1 A resolution, all three beta subunits adopt the open beta(E) conformation. The structure shows salt bridges between the helix-turn-helix motif of the C-terminal domain of the beta(E) subunit (residues Asp372 and Asp375) and the N-terminal helix of the gamma subunit (residues Arg9 and Arg10). These electrostatic forces pull the gamma shaft out of the rotational center and impede rotation through steric interference with the beta(E) subunit. Replacement of Arg9 and Arg10 with glutamines eliminates the salt bridges and results in an activation of ATP hydrolysis activity, suggesting that these salt bridges prevent the native enzyme from rotating in ATP hydrolysis direction. A similar bending of the gamma shaft as in the TA2F(1) structure was observed by single-particle analysis of the TA2F(1)F(o) holoenzyme. PMID- 17697997 TI - Structure of BeF3- -modified response regulator PleD: implications for diguanylate cyclase activation, catalysis, and feedback inhibition. AB - Cyclic di-guanosine monophosphate (c-di-GMP) is a ubiquitous bacterial second messenger involved in the regulation of cell surface-associated traits and persistence. We have determined the crystal structure of PleD from Caulobacter crescentus, a response regulator with a diguanylate cyclase (DGC) domain, in its activated form. The BeF(3)(-) modification of its receiver domain causes rearrangement with respect to an adaptor domain, which, in turn, promotes dimer formation, allowing for the efficient encounter of two symmetric catalytic domains. The substrate analog GTPalphaS and two putative cations are bound to the active sites in a manner similar to adenylate cyclases, suggesting an analogous two-metal catalytic mechanism. An allosteric c-di-GMP-binding mode that crosslinks DGC and an adaptor domain had been identified before. Here, a second mode is observed that crosslinks the DGC domains within a PleD dimer. Both modes cause noncompetitive product inhibition by domain immobilization. PMID- 17697998 TI - NikD, an unusual amino acid oxidase essential for nikkomycin biosynthesis: structures of closed and open forms at 1.15 and 1.90 A resolution. AB - NikD is an unusual amino-acid-oxidizing enzyme that contains covalently bound FAD, catalyzes a 4-electron oxidation of piperideine-2-carboxylic acid to picolinate, and plays a critical role in the biosynthesis of nikkomycin antibiotics. Crystal structures of closed and open forms of nikD, a two-domain enzyme, have been determined to resolutions of 1.15 and 1.9 A, respectively. The two forms differ by an 11 degrees rotation of the catalytic domain with respect to the FAD-binding domain. The active site is inaccessible to solvent in the closed form; an endogenous ligand, believed to be picolinate, is bound close to and parallel with the flavin ring, an orientation compatible with redox catalysis. The active site is solvent accessible in the open form, but the picolinate ligand is approximately perpendicular to the flavin ring and a tryptophan is stacked above the flavin ring. NikD also contains a mobile cation binding loop. PMID- 17697999 TI - Ligand-induced structural transitions in ErbB receptor extracellular domains. AB - Crystallographic studies showed that epidermal growth factor (EGF) receptor activation involves major domain rearrangements. Without bound ligand, the extracellular region of the receptor (sEGFR) adopts a "tethered" configuration with its dimerization site occluded by apparently autoinhibitory intramolecular interactions. Ligand binding causes the receptor to become "extended," breaking the tether and exposing the dimerization site. Using small-angle X-ray scattering (SAXS), we confirm that the tethered and extended conformations are also adopted in solution, and we describe low-resolution molecular envelopes for an intact sEGFR dimer. We also use SAXS to monitor directly the transition from a tethered to extended configuration in the monomeric extracellular regions of ErbB3 and a dimerization-defective EGFR mutant. Finally, we show that mutating every intramolecular tether interaction in sEGFR does not greatly alter its conformation. These findings explain why tether mutants fail to activate EGF receptor and provide new insight into regulation of ErbB receptor conformation. PMID- 17698000 TI - Normal-mode refinement of anisotropic thermal parameters for potassium channel KcsA at 3.2 A crystallographic resolution. AB - We report a normal-mode method for anisotropic refinement of membrane-protein structures, based on a hypothesis that the global near-native-state disordering of membrane proteins in crystals follows low-frequency normal modes. Thus, a small set of modes is sufficient to represent the anisotropic thermal motions in X-ray crystallographic refinement. By applying the method to potassium channel KcsA at 3.2 A, we obtained a structural model with an improved fit with the diffraction data. Moreover, the improved electron density maps allowed for large structural adjustments for 12 residues in each subunit, including the rebuilding of 3 missing side chains. Overall, the anisotropic KcsA structure at 3.2 A was systematically closer to a 2.0 A KcsA structure, especially in the selectivity filter. Furthermore, the anisotropic thermal ellipsoids from the refinement revealed functionally relevant structural flexibility. We expect this method to be a valuable tool for structural refinement of many membrane proteins with moderate-resolution diffraction data. PMID- 17698001 TI - Structural studies of the Cpx pathway activator NlpE on the outer membrane of Escherichia coli. AB - NlpE, an outer membrane lipoprotein, functions during envelope stress responses in Gram-negative bacteria. In Escherichia coli, adhesion to abiotic surfaces has been reported to activate the Cpx pathway in an NlpE-dependent manner. External copper ions are also thought to activate the Cpx pathway mediated by NlpE. We determined the crystal structure of NlpE from E. coli at 2.6 A resolution. The structure showed that NlpE consists of two beta barrel domains. The N-terminal domain resembles the bacterial lipocalin Blc, and the C-terminal domain has an oligonucleotide/oligosaccharide-binding (OB) fold. From both biochemical analyses and the crystal structure, it can be deduced that the cysteine residues in the CXXC motif may be chemically active. Furthermore, two monomers in the asymmetric unit form an unusual 3D domain-swapped dimer. These findings indicate that tertiary and/or quaternary structural instability may be responsible for Cpx pathway activation. PMID- 17698002 TI - Cse1p-binding dynamics reveal a binding pattern for FG-repeat nucleoporins on transport receptors. AB - Nuclear pore proteins with phenylalanine-glycine repeats are vital to the functional transport of molecules across the nuclear pore complex. The current study investigates the binding of these FG-nucleoporins to the Cse1p:Kap60p:RanGTP nuclear export complex. Fourteen binding spots for FG nucleoporin peptides are revealed on the surface of Cse1p, and 5 are revealed on the Kap60p surface. Taken together, and along with binding data for two other transport receptors, the data suggest that the ability to bind FG-nucleoporins by itself is not enough to ensure viable nuclear transport. Rather, it is proposed that the density of binding spots on the transport receptor surface is key in determining transport viability. The number of binding spots on the transport receptor surface should be large enough to ensure multiple, simultaneous FG repeat binding, and their arrangement should be close enough to ensure multiple binding from the same FG-nucleoporin. PMID- 17698003 TI - Crystal structure of human nicotinamide riboside kinase. AB - Nicotinamide riboside kinase (NRK) has an important role in the biosynthesis of NAD(+) as well as the activation of tiazofurin and other NR analogs for anticancer therapy. NRK belongs to the deoxynucleoside kinase and nucleoside monophosphate (NMP) kinase superfamily, although the degree of sequence conservation is very low. We report here the crystal structures of human NRK1 in a binary complex with the reaction product nicotinamide mononucleotide (NMN) at 1.5 A resolution and in a ternary complex with ADP and tiazofurin at 2.7 A resolution. The active site is located in a groove between the central parallel beta sheet core and the LID and NMP-binding domains. The hydroxyl groups on the ribose of NR are recognized by Asp56 and Arg129, and Asp36 is the general base of the enzyme. Mutation of residues in the active site can abolish the catalytic activity of the enzyme, confirming the structural observations. PMID- 17698004 TI - Structure and function of the E. coli dihydroneopterin triphosphate pyrophosphatase: a Nudix enzyme involved in folate biosynthesis. AB - Nudix hydrolases are a superfamily of pyrophosphatases, most of which are involved in clearing the cell of potentially deleterious metabolites and in preventing the accumulation of metabolic intermediates. We determined that the product of the orf17 gene of Escherichia coli, a Nudix NTP hydrolase, catalyzes the hydrolytic release of pyrophosphate from dihydroneopterin triphosphate, the committed step of folate synthesis in bacteria. That this dihydroneopterin hydrolase (DHNTPase) is indeed a key enzyme in the folate pathway was confirmed in vivo: knockout of this gene in E. coli leads to a marked reduction in folate synthesis that is completely restored by a plasmid carrying the gene. We also determined the crystal structure of this enzyme using data to 1.8 A resolution and studied the kinetics of the reaction. These results provide insight into the structural bases for catalysis and substrate specificity in this enzyme and allow the definition of the dihydroneopterin triphosphate pyrophosphatase family of Nudix enzymes. PMID- 17698005 TI - Fragile X tremor/ataxia syndrome: blame the messenger! AB - rCGG repeats in premutant alleles of the fragile X gene (FMR1) cause neurodegeneration in Drosophila and are thought to cause fragile X-associated tremor/ataxia syndrome in humans. Two reports in this issue of Neuron (Jin et al. and Sofola et al.) present data indicating a disease mechanism involving disruption of RNA-binding protein function. PMID- 17698006 TI - PIP2--the master key. AB - The function of inwardly rectifying K+ (Kir) channels is highly diverse and therefore is tightly regulated by various environmental factors. In their article in this issue of Neuron, Rapedius et al. recognize a conserved structural mechanism for Kir channels gating by both pH and PIP2. In light of these findings and accumulated knowledge, PIP2 is suggested to have a common coregulatory role in the gating of Kir channels by all their soluble modulators. PMID- 17698007 TI - Use 'em and lose 'em-activity-induced removal of calcium channels from the plasma membrane. AB - Calcium influx via L-type (Cav1.2 and Cav1.3) calcium channels is tightly regulated to ensure optimal intracellular calcium levels. Although much is known about acute modulation of these channels by second messengers, the mechanisms that control their trafficking to and from the plasma membrane remain poorly understood. In this issue of Neuron, Green and colleagues demonstrate that the opening of L-type calcium channels results in negative feedback regulation due to their calcium-dependent internalization. PMID- 17698008 TI - Contributions of the amygdala to reward expectancy and choice signals in human prefrontal cortex. AB - The prefrontal cortex (PFC) receives substantial anatomical input from the amygdala, and these two structures have long been implicated in reward-related learning and decision making. Yet little is known about how these regions interact, especially in humans. We investigated the contribution of the amygdala to reward-related signals in PFC by scanning two rare subjects with focal bilateral amygdala lesions using fMRI. The subjects performed a reversal learning task in which they first had to learn which of two choices was the more rewarding, and then flexibly switch their choices when contingencies changed. Compared with healthy controls, both amygdala lesion subjects showed a profound change in ventromedial prefrontal cortex (vmPFC) activity associated with reward expectation and behavioral choice. These findings support a critical role for the human amygdala in establishing expected reward representations in PFC, which in turn may be used to guide behavioral choice. PMID- 17698010 TI - RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS. AB - Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently described neurodegenerative disorder of older adult carriers of premutation alleles (60-200 CGG repeats) in the fragile X mental retardation gene (FMR1). It has been proposed that FXTAS is an RNA-mediated neurodegenerative disease caused by the titration of RNA-binding proteins by the CGG repeats. To test this hypothesis, we utilize a transgenic Drosophila model of FXTAS that expresses a premutation length repeat (90 CGG repeats) from the 5' UTR of the human FMR1 gene and displays neuronal degeneration. Here, we show that overexpression of RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppresses the phenotype of the CGG transgenic fly. Furthermore, we show that hnRNP A2/B1 directly interacts with riboCGG repeats and that the CUGBP1 protein interacts with the riboCGG repeats via hnRNP A2/B1. PMID- 17698009 TI - Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome. AB - Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently recognized neurodegenerative disorder in fragile X premutation carriers with FMR1 alleles containing 55-200 CGG repeats. Previously, we developed a Drosophila model of FXTAS and demonstrated that transcribed premutation repeats alone are sufficient to cause neurodegeneration, suggesting that rCGG-repeat-binding proteins (RBPs) may be sequestered from their normal function by rCGG binding. Here, we identify Pur alpha and hnRNP A2/B1 as RBPs. We show that Pur alpha and rCGG repeats interact in a sequence-specific fashion that is conserved between mammals and Drosophila. Overexpression of Pur alpha in Drosophila could suppress rCGG mediated neurodegeneration in a dose-dependent manner. Furthermore, Pur alpha is also present in the inclusions of FXTAS patient brains. These findings support the disease mechanism of FXTAS of rCGG repeat sequestration of specific RBPs, leading to neuronal cell death, and implicate that Pur alpha plays an important role in the pathogenesis of FXTAS. PMID- 17698011 TI - Retrograde BMP signaling regulates trigeminal sensory neuron identities and the formation of precise face maps. AB - Somatosensory information from the face is transmitted to the brain by trigeminal sensory neurons. It was previously unknown whether neurons innervating distinct areas of the face possess molecular differences. We have identified a set of genes differentially expressed along the dorsoventral axis of the embryonic mouse trigeminal ganglion and thus can be considered trigeminal positional identity markers. Interestingly, establishing some of the spatial patterns requires signals from the developing face. We identified bone morphogenetic protein 4 (BMP4) as one of these target-derived factors and showed that spatially defined retrograde BMP signaling controls the differential gene expressions in trigeminal neurons through both Smad4-independent and Smad4-dependent pathways. Mice lacking one of the BMP4-regulated transcription factors, Onecut2 (OC2), have defects in the trigeminal central projections representing the whiskers. Our results provide molecular evidence for both spatial patterning and retrograde regulation of gene expression in sensory neurons during the development of the somatosensory map. PMID- 17698012 TI - C. elegans RPM-1 regulates axon termination and synaptogenesis through the Rab GEF GLO-4 and the Rab GTPase GLO-1. AB - C. elegans RPM-1 (for Regulator of Presynaptic Morphology) is a member of a conserved protein family that includes Drosophila Highwire and mammalian Pam and Phr1. These are large proteins recently shown to regulate synaptogenesis through E3 ubiquitin ligase activities. Here, we report the identification of an RCC1 like guanine nucleotide exchange factor, GLO-4, from mass spectrometry analysis of RPM-1-associated proteins. GLO-4 colocalizes with RPM-1 at presynaptic terminals. Loss of function in glo-4 or in its target Rab GTPase, glo-1, causes neuronal defects resembling those in rpm-1 mutants. We show that the glo pathway functions downstream of rpm-1 and acts in parallel to fsn-1, a partner of RPM-1 E3 ligase function. We find that late endosomes are specifically disorganized at the presynaptic terminals of glo-4 mutants. Our data suggest that RPM-1 positively regulates a Rab GTPase pathway to promote vesicular trafficking via late endosomes. PMID- 17698013 TI - H bonding at the helix-bundle crossing controls gating in Kir potassium channels. AB - Specific stimuli such as intracellular H+ and phosphoinositides (e.g., PIP2) gate inwardly rectifying potassium (Kir) channels by controlling the reversible transition between the closed and open states. This gating mechanism underlies many aspects of Kir channel physiology and pathophysiology; however, its structural basis is not well understood. Here, we demonstrate that H+ and PIP2 use a conserved gating mechanism defined by similar structural changes in the transmembrane (TM) helices and the selectivity filter. Our data support a model in which the gating motion of the TM helices is controlled by an intrasubunit hydrogen bond between TM1 and TM2 at the helix-bundle crossing, and we show that this defines a common gating motif in the Kir channel superfamily. Furthermore, we show that this proposed H-bonding interaction determines Kir channel pH sensitivity, pH and PIP2 gating kinetics, as well as a K+-dependent inactivation process at the selectivity filter and therefore many of the key regulatory mechanisms of Kir channel physiology. PMID- 17698014 TI - The tumor suppressor eIF3e mediates calcium-dependent internalization of the L type calcium channel CaV1.2. AB - Voltage-gated calcium channels (VGCCs) convert electrical activity into calcium (Ca2+) signals that regulate cellular excitability, differentiation, and connectivity. The magnitude and kinetics of Ca2+ signals depend on the number of VGCCs at the plasma membrane, but little is known about the regulation of VGCC surface expression. We report that electrical activity causes internalization of the L-type Ca2+ channel (LTC) CaV1.2 and that this is mediated by binding to the tumor suppressor eIF3e/Int6 (eukaryotic initiation factor 3 subunit e). Using total internal reflection microscopy, we identify a population of CaV1.2 containing endosomes whose rapid trafficking is strongly regulated by Ca2+. We define a domain in the II-III loop of CaV1.2 that binds eIF3e and is essential for the activity dependence of both channel internalization and endosomal trafficking. These findings provide a mechanism for activity-dependent internalization and trafficking of CaV1.2 and provide a tantalizing link between Ca2+ homeostasis and a mammalian oncogene. PMID- 17698015 TI - Axon initial segment Kv1 channels control axonal action potential waveform and synaptic efficacy. AB - Action potentials are binary signals that transmit information via their rate and temporal pattern. In this context, the axon is thought of as a transmission line, devoid of a role in neuronal computation. Here, we show a highly localized role of axonal Kv1 potassium channels in shaping the action potential waveform in the axon initial segment (AIS) of layer 5 pyramidal neurons independent of the soma. Cell-attached recordings revealed a 10-fold increase in Kv1 channel density over the first 50 microm of the AIS. Inactivation of AIS and proximal axonal Kv1 channels, as occurs during slow subthreshold somatodendritic depolarizations, led to a distance-dependent broadening of axonal action potentials, as well as an increase in synaptic strength at proximal axonal terminals. Thus, Kv1 channels are strategically positioned to integrate slow subthreshold signals, providing control of the presynaptic action potential waveform and synaptic coupling in local cortical circuits. PMID- 17698016 TI - Postsynaptic decoding of neural activity: eEF2 as a biochemical sensor coupling miniature synaptic transmission to local protein synthesis. AB - Activity-dependent regulation of dendritic protein synthesis is critical for enduring changes in synaptic function, but how the unique features of distinct activity patterns are decoded by the dendritic translation machinery remains poorly understood. Here, we identify eukaryotic elongation factor-2 (eEF2), which catalyzes ribosomal translocation during protein synthesis, as a biochemical sensor in dendrites that is specifically and locally tuned to the quality of neurotransmission. We show that intrinsic action potential (AP)-mediated network activity in cultured hippocampal neurons maintains eEF2 in a relatively dephosphorylated (active) state, whereas spontaneous neurotransmitter release (i.e., miniature neurotransmission) strongly promotes the phosphorylation (and inactivation) of eEF2. The regulation of eEF2 phosphorylation is responsive to bidirectional changes in miniature neurotransmission and is controlled locally in dendrites. Finally, direct spatially controlled inhibition of eEF2 phosphorylation induces local translational activation, suggesting that eEF2 is a biochemical sensor that couples miniature synaptic events to local translational suppression in neuronal dendrites. PMID- 17698017 TI - Dopamine mediates context-dependent modulation of sensory plasticity in C. elegans. AB - Dopamine has been implicated in the modulation of diverse forms of behavioral plasticity, including appetitive learning and addiction. An important challenge is to understand how dopamine's effects at the cellular level alter the properties of neural circuits to modify behavior. In the nematode C. elegans, dopamine modulates habituation of an escape reflex triggered by body touch. In the absence of food, animals habituate more rapidly than in the presence of food; this contextual information about food availability is provided by dopaminergic mechanosensory neurons that sense the presence of bacteria. We find that dopamine alters habituation kinetics by selectively modulating the touch responses of the anterior-body mechanoreceptors; this modulation involves a D1-like dopamine receptor, a Gq/PLC-beta signaling pathway, and calcium release within the touch neurons. Interestingly, the body touch mechanoreceptors can themselves excite the dopamine neurons, forming a positive feedback loop capable of integrating context and experience to modulate mechanosensory attention. PMID- 17698018 TI - Infection by Ascaris lumbricoides and bronchial hyper reactivity: an outstanding association in Venezuelan school children from endemic areas. AB - Asthma and other respiratory diseases have increased in the last years among Venezuelan children from helminthic endemic areas where the infection by Ascaris lumbricoides has been associated to bronchial airway inflammation in parasitized individuals. The aim of this work was to investigate the possible associations between the development of bronchial hyper reactivity and the immune response against A. lumbricoides in urban and rural children. We evaluated 470 school children from rural and urban communities. Pulmonary function tests were performed and >or=20% PC(20) changes were considered as a positive diagnostic of bronchial hyper reactivity. The prevalence and intensity of A. lumbricoides infection was determined by faecal examination. Specific serum IgE levels using a modified ELISA and skin prick tests against A. lumbricoides and the common allergen Dermatophagoides pteronyssinus were done. The number of circulating lymphocyte sub populations was determined by flow cytometry analysis. In rural children, bronchial hyper reactivity was associated with increased specific levels of anti-A. lumbricoides IgE (p<0.0001) and skin test positivity for A. lumbricoides (p<0.0001). The percentage of FEV1 predictive values correlated inversely (p<0.0001) with anti-A. lumbricoides IgE levels. Elevated numbers of circulating CD3+CD4+ and CD20+CD23+ cells were found in rural children with bronchial hyper reactivity compared to their asymptomatic counterparts. They correlated positively with anti-A. lumbricoides IgE levels (p<0.005 and <0.0001, respectively). In contrast, in urban children, bronchial hyper reactivity was associated with elevated anti-D. pteronyssinus IgE levels (p=0. 0089), skin hyper reactivity towards this aero allergen (p=0.003) and to an increase in the number of CD3+CD8+ (p<0.0001). Our results suggest that the IgE response against A. lumbricoides infection may be involved in the development of bronchial hyper reactivity among rural children from endemic areas and also that improved hygienic conditions in the urban environment is associated with increased responses to airborne allergens. PMID- 17698019 TI - Optical coherence tomography identification of occult choroidal neovascularization in age-related macular degeneration. AB - PURPOSE: To evaluate and describe the various optical coherence tomography (OCT) features of occult choroidal neovascularization (CNV) in age-related macular degeneration (AMD) at the time of diagnosis. DESIGN: Prospective, consecutive, observational case series. METHODS: One hundred and fifty-three eyes of 130 consecutive patients with subfoveal occult CNV diagnosed on scanning laser ophthalmoscope (SLO) fluorescein angiography (FA) and SLO indocyanine green angiography (ICGA) were evaluated with OCT. The diagnostic criteria for occult CNV on angiography were heterogeneous hyperfluorescence with late leakage in the macular region associated with pigment epithelial detachment (PED), stippled hyperfluorescent dots, and signs of deterioration. OCT findings were evaluated and described. RESULTS: A PED was observed on OCT in 98% (150 eyes) either as a limited retinal pigment epithelium (RPE) elevation (54 eyes [35.3%]) or a complete detachment (96 eyes [62.7%]). Occult CNV corresponded to zones of hyperreflectivity in contact with the RPE band and was detected in 62.7% of eyes. In fibrovascular PED (63 eyes [65.5%]), the elevated RPE was highlighted posteriorly by a moderately reflective band overlying a hyporeflective cavity. In serous PED, the cavity remained optically empty. The RPE in the detached zone showed changes such as fragmentation (137 eyes [89.5%]). OCT also showed intraretinal (122 eyes [79.7%]) and subretinal (64 eyes [41.8%]) fluid. CONCLUSIONS: Analysis of the various OCT features observed in this study confirms the polymorphic nature of occult CNV in AMD, their exudative reactions, the almost constant presence of PED, and the different changes in the RPE band. OCT examination, therefore, provides valuable data to confirm the features of subepithelial occult CNV. PMID- 17698020 TI - Microbiology of pediatric orbital cellulitis. AB - PURPOSE: To evaluate the microbiology of pediatric orbital cellulitis associated with sinusitis. DESIGN: Retrospective review of medical records of pediatric patients treated for orbital cellulitis. METHODS: All pediatric patients treated for orbital cellulitis associated with sinusitis at Texas Children's Hospital between December 1, 2001 and September 30, 2005 were reviewed. Data collected included patient age, history, microbiology results, and surgical intervention. RESULTS: Thirty-eight cases were identified. Fifteen cases required medical management, whereas 23 patients received a combination of medical and surgical intervention. Three patients had multiple surgical procedures performed. Of the procedures performed, four were sinus irrigation, 12 were sinusotomy and drainage, nine were orbitotomy with drainage of abscess, and one was craniotomy with drainage of abscess. Surgical aspirate specimens yielded a higher positive culture result rate with 9/9 of orbital abscesses and 13/16 of sinus aspirates demonstrating a positive yield. Two of the 27 blood cultures had a positive yield. Staphylococcus species was the most common organism isolated. Methicillin resistant S. aureus (MRSA) represented 73% of S. aureus isolates. Streptococcus species was the next most common pathogen. Three cultures yielded Haemophilus species with one being positive for H. influenzae. CONCLUSIONS: Organisms responsible for causing pediatric orbital cellulitis are evolving, with Staphylococcus followed by Streptococcus species being the most common pathogens. The occurrence of MRSA in pediatric orbital cellulitis is increasing, and empiric antimicrobial therapy should be directed against these organisms if they are prevalent in the community. Sinus and orbital abscess aspirates yielded the greatest number of positive cultures, though these invasive surgical procedures should be performed only when clinically indicated. PMID- 17698022 TI - Ocular nocardiosis: HSP65 gene sequencing for species identification of Nocardia spp. AB - PURPOSE: To assess hsp65 gene sequencing for detection and species identification of genus Nocardia from ocular isolates. DESIGN: A prospective study based on laboratory investigation. METHODS: Genus-specific hsp65 gene sequencing was used to identify the genus Nocardia isolated from 11 consecutive cases of ocular nocardiosis to the species level. RESULTS: Eleven eye clinical isolates belong to six species: N. arthritidis (3/11), N. neocaledoniensis (3/11), N. asiatica (2/11), N. asteroids type 4 (1/11), N. brasiliensis (1/11), and N. pseudobrasiliensis (1/11). N. arthritidis is the most important etiologic species that causes Nocardia keratitis. N. neocaledoniens is isolated in the conjunctiva, and might cause conjunctivitis. CONCLUSIONS: Genus-specific hsp65 gene sequencing can be a rapid and reliable adjunct in the diagnosis of ocular Nocardia to the genus and species level. N. arthritidis other than N. asteroids (often appeared in surveys) is the most important etiologic species in ocular nocardiasis. N. neocaledoniensis can be isolated in conjunctiva, and might be able to cause conjunctivitis. The diversity of species has important implications for the etiology, pathogenesis, and treatment (drug susceptibility). PMID- 17698021 TI - Age-related macular degeneration and the immune response: implications for therapy. AB - PURPOSE: To review the available information concerning the immune mediation of age-related macular degeneration (AMD) and to speculate on proposed mechanisms and immunotherapy. DESIGN: Interpretative essay. METHODS: Literature review and interpretation. RESULTS: An ever-growing body of evidence is gathering concerning the role of the immune system in AMD. Evidence to date suggests that the underlying mechanism leading to AMD is the decline of the ocular downregulatory immune environment. The subsequent activation of the immune system would lead to T-cell sensitization. When combined with local antiangiogenic therapy, several existing immunotherapies may be used to downregulate the immune response, potentially leading to a more efficient inhibition of choroidal neovascularization. CONCLUSIONS: The loss of the downregulatory immune environment is central to the development of AMD, permitting activation of the immune system. If so, immunotherapy could positively alter the course of the disease. PMID- 17698023 TI - Central corneal thickness: congenital cataracts and aphakia. AB - PURPOSE: To evaluate central corneal thickness (CCT) in normal children (controls) and in those with cataracts, pseudophakia, and aphakia. DESIGN: Prospective, observational case series. METHODS: CCT was measured in 369 eyes of 223 children. Subjects with glaucoma, anterior segment abnormalities, or intraocular pressure of more than 30 mm Hg were excluded. Group means were compared for controls and for eyes with pediatric cataracts, pseudophakia, and aphakia. RESULTS: The mean CCT of eyes with cataracts was more than that of controls (574 +/- 54 microm [n = 46] and 552 +/- 38 microm [n = 230], respectively; P = .001). After excluding from the cataract group those eyes with aniridia, Down syndrome, Marfan syndrome, or glaucoma surgery, the mean CCT (564 +/- 34 microm [n = 36]) was no longer greater than that of controls (P = .07). The mean CCT of pseudophakic eyes (598 +/- 56 microm [n = 29]) was greater than the mean CCT of controls (P < .001) and was similar to the mean CCT of eyes with cataracts (P = .06). The mean CCT of aphakic eyes (642 +/- 88 microm [n = 64]) was greater than the mean CCT of controls (P < .001), eyes with cataracts (P < .001), and eyes with pseudophakia (P = .003). CONCLUSIONS: In the absence of factors known to affect CCT (Down syndrome, Marfan syndrome, and aniridia), CCT is similar in eyes with pediatric cataracts and normal controls and increases after cataract surgery. PMID- 17698024 TI - Recent progress in protein subcellular location prediction. PMID- 17698025 TI - Sense or antisense? False priming reverse transcription controls are required for determining sequence orientation by reverse transcription-PCR. PMID- 17698026 TI - X-ray absorption analysis of the active site of Streptomyces antibioticus Tyrosinase upon binding of transition state analogue inhibitors. AB - The key structural features that define the reaction mechanism of the binuclear copper enzyme Tyrosinase (Ty) from Streptomyces antibioticus were investigated by X-ray absorption spectroscopy. The data for the met form, the halide bound derivative and the adduct with the competitive inhibitor and transition state analogue Kojic acid were analysed using the recently developed MXAN package. This analysis permitted the definition of structural clusters that include all atoms within 5A from the metal ions of the active site. The data obtained for the different forms provide validation of the structural models previously proposed on the basis of the magnetic properties investigated by both pulsed EPR and paramagnetic NMR spectroscopies. The structural model of the reaction center obtained in this solution study is compared with the crystallographic structures recently proposed for several derivatives of bacterial Ty to suggest that only one of these structures is relevant to solution conditions. PMID- 17698027 TI - Insulin inhibition of apolipoprotein B mRNA translation is mediated via the PI-3 kinase/mTOR signaling cascade but does not involve internal ribosomal entry site (IRES) initiation. AB - Although insulin normally activates global mRNA translation, it has a specific inhibitory effect on translation of apolipoprotein B (apoB) mRNA. This suggests that insulin induces a unique signaling cascade that leads to specific inhibition of apoB mRNA translation despite global translational stimulation. Recent studies have revealed that insulin functions to regulate apoB mRNA translation through a mechanism involving the apoB mRNA 5' untranslated region (5' UTR). Here, we further investigate the role of downstream insulin signaling molecules on apoB mRNA translation, and the mechanism of apoB mRNA translation itself. Transfection studies in HepG2 cells expressing deletion constructs of the apoB 5' UTR showed that the cis-acting region responding to insulin was localized within the first 64 nucleotides. Experiments using chimeric apoB UTR-luciferase constructs transfected into HepG2 cells followed by treatment with wortmannin, a PI-3K inhibitor, and rapamycin, an mTOR inhibitor, showed that signaling via PI-3K and mTOR pathways is necessary for insulin-mediated inhibition of chimeric 5' UTR luciferase expression. In vitro translation of chimeric cRNA confirmed that the effects observed were translational in nature. Furthermore, using RNA-EMSA we found that wortmannin pretreatment blocked insulin-mediated inhibition of the binding of RNA-binding factor(s), migrating near the 110 kDa marker, to the 5' UTR. Radiolabeling studies in HepG2 cells also showed that insulin-mediated control of the synthesis of endogenously expressed full length apoB100 is mediated via the PI-3K and mTOR pathways. Finally, using dual-cistronic luciferase constructs we demonstrate that apoB 5' UTR may have weak internal ribosomal entry (IRES) translation which is not affected by insulin stimulation, and may function to stimulate basal levels of apoB mRNA translation. PMID- 17698028 TI - Induced rumination dampens executive processes in dysphoric young adults. AB - Self-focused, analytical mental rumination constitutes a central process in depression. It has been hypothesized that such rumination depletes executive resources that are necessary for an efficient cognitive regulation of emotion and behavior. However, most of the research supporting this hypothesis is of correlational nature. The present study examined the effects of induced rumination versus distraction on executive capacities in dysphoric and nondsyphoric college students. Executive functioning was measured with the Stroop task. Results indicate that induced rumination decreases inhibition capacities in dysphoric individuals only. The flexibility facet of executive functioning was not affected by induced rumination. However, dysphoric individuals demonstrated a fundamental impairment in this latter capacity, independent of rumination induction. The implications for the facets of executive functioning affected by depression and by rumination are discussed. PMID- 17698029 TI - Repression of GLUT4 expression by the endoplasmic reticulum stress response in 3T3-L1 adipocytes. AB - Expression of GLUT4 is decreased in adipocytes in obesity and type 2 diabetes, contributing to the insulin resistance of these states. Recent investigations suggest a role for activation of the ER stress response in the pathophysiology of type 2 diabetes. We investigated activation of the ER stress response in 3T3-L1 adipocytes. We show that activation of the ER stress response decreased GLUT4 expression at the level of gene transcription. Activation of the ER stress response also increased the expression of CHOP10, an inhibitor of the activity and expression of C/EBPalpha. As expected, activation of the ER stress response decreased expression of C/EBPalpha, an activator of GLUT4 expression, providing a mechanism to account for the repression of GLUT4 by ER stress activation. Our studies identify repression of GLUT4 expression as another potential mechanism for obesity-induced activation of the ER stress response to contribute to the insulin resistance of obesity. PMID- 17698030 TI - Coexistence of mitochondrial 12S rRNA C1494T and CO1/tRNA(Ser(UCN)) G7444A mutations in two Han Chinese pedigrees with aminoglycoside-induced and non syndromic hearing loss. AB - Mutations in mitochondrial DNA are one of the important causes of hearing loss. We report here the clinical, genetic, and molecular characterization of two Han Chinese pedigrees with maternally transmitted aminoglycoside-induced and nonsyndromic bilateral hearing loss. Clinical evaluation revealed the wide range of severity, age-at-onset, and audiometric configuration of hearing impairment in matrilineal relatives in these families. The penetrances of hearing loss in these pedigrees were 20% and 18%, when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrances of hearing loss in these seven pedigrees were 10% and 15%. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the presence of the deafness associated 12S rRNA C1494T and CO1/tRNA(Ser(UCN)) G7444A mutations. Their distinct sets of mtDNA polymorphism belonged to Eastern Asian haplogroup C4a1, while other previously identified six Chinese mitochondrial genomes harboring the C1494T mutation belong to haplogroups D5a2, D, R, and F1, respectively. This suggested that the C1494T or G7444A mutation occurred sporadically and multiplied through evolution of the mitochondrial DNA (mtDNA). The absence of functionally significant mutations in tRNA and rRNAs or secondary LHON mutations in their mtDNA suggest that these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the 12S rRNA C1494T and CO1/tRNA(Ser(UCN)) G7444A mutations in those Chinese families. However, aminoglycosides and other nuclear modifier genes play a modifying role in the phenotypic manifestation of the C1494T mutation in these Chinese families. PMID- 17698031 TI - Identification and characterization of Piwi subfamily in insects. AB - As a subfamily of Argonaute proteins, Piwi is poorly understood compared with Ago subfamily until recent discovery of Piwi protein interacting with piRNA. We did a large scale screening of insect genomes to identify piwi-like genes. Full or partial cDNA sequences were obtained by EST elongation and GENSCAN. We found that the exon numbers were totally different between vertebrates and invertebrates, approximately 20 exons in mammals but only 6-9 exons in insects. This infers either intron insertion or loss occurred during evolution. Characterized PAZ, c terminal PIWI domains exist in almost all predicted Piwi-like proteins. We found six conserved motifs, which contain active catalytic triad "Asp-Asp-His/Lys" required for slicer activity. The expression of siwi1 and siwi2 in Bombyx mori were verified with RT-PCR. Phylogenetic tree inferred by Bayesian algorithm indicates invertebrate Piwi-like proteins are classified into three clades, of which Ago3 clade is closer to mammalian Piwi proteins. PMID- 17698032 TI - Visualization of beta-secretase cleavage in living cells using a genetically encoded surface-displayed [corrected] FRET probe. AB - The human beta-secretase, BACE, plays a key role in the generation of pathogenic amyloid beta-peptide (Abeta) in Alzheimer's disease and has been identified as an ideal target for therapy. Previous studies reported the monitoring of BACE activity in vitro utilizing chemical synthesized sensors. Here we describe the first genetically encoded FRET probe that can detect BACE activity in vivo. The FRET probe was constructed with the BACE substrate site (BSS) and two mutated green fluorescent proteins. In living cell, the FRET probe was directed to the secretory pathway and anchored on the cell surface to measure BACE enzymatic activity. The results show that the FRET probe can be cleaved by BACE effectively in vivo, suggesting that the probe can be used for real-time monitoring of BACE activity. This assay provides a novel platform for BACE inhibitor screening in vivo. PMID- 17698033 TI - Mahanine reverses an epigenetically silenced tumor suppressor gene RASSF1A in human prostate cancer cells. AB - It is becoming clear that frequent epigenetic silencing of tumor suppressor genes could be responsible for the development of cancer in various organs. Several recent reports suggest that suppression of RASSF1A is associated with the advanced grade and stage of prostate cancer and many other cancers. In this investigation, we demonstrated that, mahanine, a plant derived carbazole alkaloid, induced RASSF1A expression in both androgen-responsive (LNCaP) and androgen-negative (PC3) prostate cancer cells by inhibiting DNA methyltransferase (DNMT) activity. Mahanine-induced expression of RASSF1A in turn significantly reduced cyclin D1 but not other cyclins. To understand the inverse relationship between RASSF1A and cyclin D1, we observed that mahanine treatment down-regulates cyclin D1 and addition of RASSF1A siRNA prevented this inhibition. This study show for the first time that mahanine can reverse an epigenetically silenced gene, RASSF1A in prostate cancer cells by inhibiting DNMT activity that in turn down-regulates a key cell cycle regulator, cyclin D1. Mahanine therefore, promises an encouraging therapeutic choice for advanced prostatic cancer. PMID- 17698034 TI - Activation of mammalian target of rapamycin complex 1 and insulin resistance induced by palmitate in hepatocytes. AB - Excessive supply of fatty acids to the liver might be a contributing factor to hepatic insulin resistance associated with obesity and type 2 diabetes mellitus. The aim of this study was to investigate direct effects of palmitate on insulin signaling in hepatocytes. The ability of metformin to reverse changes induced by palmitate was also studied. Rat hepatocytes in primary culture exhibited a rightward shift of the insulin dose-response curve for PKB phosphorylation during culture with palmitate. The insulin-stimulated phosphorylation of GSK-3beta, a metabolic substrate of PKB, was diminished in palmitate hepatocytes. By contrast, the mTOR protein kinase was overstimulated in cells incubated with palmitate. Hepatocytes cultured with palmitate displayed hyperphosphorylation of IRS-1 at Ser residues 632/635, known to be phosphorylated by mTOR. Metformin treatment of the hepatocytes resulted in activation of the AMP-activated kinase, attenuation of the mTOR/S6K1 pathway, reduction of IRS-1 phosphorylation, and a leftward shift in the insulin dose-response curve for PKB activation. These data suggest a link between an oversupply of fatty acid to hepatocytes, a disproportionate stimulation of mTOR/S6K1, and resistance to insulin. PMID- 17698035 TI - A novel nacre protein N19 in the pearl oyster Pinctada fucata. AB - A novel 19kDa protein, which was named N19, was isolated from the nacreous layer of the pearl oyster Pinctada fucata. N19 is one of predominant proteins found in the water-insoluble fraction of the nacreous layer. MALDI-TOF/TOF analysis indicated that the three trypsin-digested peptides (791.45, 824.42, and 1118.65m/z) corresponded to the amino acid sequences predicted from a cDNA isolated from a mantle cDNA library of P. fucata. Northern blot analysis revealed that the N19 mRNA was a little more abundant in the pallial region than the edge region, in the mantle. In CaCO(3) precipitation assay, the recombinant N19 protein inhibited the crystallization of CaCO(3). These results indicate that N19 is localized in the nacre and plays a negative regulatory role in calcification in the pearl oyster. PMID- 17698036 TI - The mitochondrial Ca2+-activated K+ channel activator, NS 1619 inhibits L-type Ca2+ channels in rat ventricular myocytes. AB - We examined the effects of the mitochondrial Ca(2+)-activated K(+) (mitoBK(Ca)) channel activator NS 1619 on L-type Ca(2+) channels in rat ventricular myocytes. NS 1619 inhibited the Ca(2+) current in a dose-dependent manner. NS 1619 shifted the activation curve to more positive potentials, but did not have a significant effect on the inactivation curve. Pretreatment with inhibitors of membrane BK(Ca) channel, mitoBK(Ca) channel, protein kinase C, protein kinase A, and protein kinase G had little effect on the Ca(2+) current and did not alter the inhibitory effect of NS 1619 significantly. The application of additional NS 1619 in the presence of isoproterenol, a selective beta-adrenoreceptor agonist, reduced the Ca(2+) current to approximately the same level as a single application of NS 1619. In conclusion, our results suggest that NS 1619 inhibits the Ca(2+) current independent of the mitoBK(Ca) channel and protein kinases. Since NS 1619 is widely used to study mitoBK(Ca) channel function, it is essential to verify these unexpected effects of NS 1619 before experimental data can be interpreted accurately. PMID- 17698037 TI - Centrin controls the activity of the ciliary reversal-coupled voltage-gated Ca2+ channels Ca2+-dependently. AB - In Paramecium, ciliary reversal is coupled with voltage-gated Ca(2+) channels on the ciliary membrane. We previously isolated a P. caudatum mutant, cnrC, with a malfunction of the Ca(2+) channels and discovered that the channel activity of cnrC was restored by transfection of the P. caudatum centrin (Pccentrin1p) gene, which encodes a member of the Ca(2+)-binding EF-hand protein family. In this study, we injected various mutated Pccentrin1p genes into cnrC and investigated whether these genes restore the Ca(2+) channel activity of cnrC. A Pccentrin1p mutant gene lacking Ca(2+) sensitivity of the third and fourth EF-hands lost the ability to restore the channel function of cnrC, and mutation of the fourth EF hand caused more serious impairment than mutation of the third EF-hand. Moreover, a Pccentrin1p gene lacking the N-terminal 34-amino acid sequence also lost the ability to restore the channel activity. Native-PAGE analysis demonstrated that the N-terminal sequence is important for the Ca(2+)-dependent structural change of Pccentrin1p. These results demonstrate that Pccentrin1p Ca(2+)-dependently regulates the Ca(2+) channel activity in vivo. PMID- 17698038 TI - RAP80 interacts with the SUMO-conjugating enzyme UBC9 and is a novel target for sumoylation. AB - RAP80, a nuclear protein with two functional ubiquitin-interaction motifs (UIMs) at its N-terminus, plays a critical role in the regulation of estrogen receptor alpha and DNA damage response signaling. A yeast two-hybrid screen identified the SUMO-conjugating enzyme UBC9 as a protein interacting with RAP80. The interaction of RAP80 with UBC9 was confirmed by co-immunoprecipitation and GST pull-down analyses. The region between aa 122-204 was critical for the interaction of RAP80 with UBC9. In addition, we demonstrate that RAP80 is a target for SUMO-1 modification in intact cells. Expression of UBC9 enhanced RAP80 mono-sumoylation and also induced multi-sumoylation of RAP80. In addition to SUMO-1, RAP80 was efficiently conjugated to SUMO-3 but was only a weak substrate for SUMO-2 conjugation. These findings suggest that sumoylation plays a role in the regulation of RAP80 functions. PMID- 17698039 TI - Roles of neuropeptides in O,O,S-trimethylphosphorothioate (OOS-TMP)-induced anorexia in mice. AB - O,O,S-Trimethylphosphorothioate (OOS-TMP), an impurity present in various organophosphorus insecticides, has previously been shown to induce hypophagia. The major goal of this study was to investigate its mechanism of action. Both intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) injection transiently induced hypophagia at a dose of 5mg/kg within 6h, without causing lung injury. Hypophagia was accompanied by up-regulation of corticotropin releasing factor (CRF) (2.92+/-0.45 vs. 1.7+/-0.5, at 2h after i.c.v., 3.40+/-1.38 vs. 1.76+/-0.41 at 6h after i.p., P<0.05) in the hypothalamus. After i.c.v. injection, hypophagia recovered by 6h after dosing. At doses higher than 5mg/kg, i.c.v. injection induced continuous hypophagia from 20min to 72h after dosing, accompanied by hypothermia and lung injury. OOS-TMP was considered to induce hypophagia through enhancing expression of CRF. PMID- 17698040 TI - Neuron numbers and volume of the amygdala in subjects diagnosed with bipolar disorder or schizophrenia. AB - BACKGROUND: Growing evidence supports a pivotal role for the amygdala in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ). However, the occurrence of morphologic changes in the amygdala is currently controversial. METHODS: Total number and numeric density of neurons, neuronal somata size, and volume of the lateral (LN), basal (BN), accessory basal (ABN), and cortical (CO) nuclei of the amygdala were measured in 12 normal control, 10 BD, and 16 SZ subjects. RESULTS: In BD subjects, reductions of total numbers (41.1%; p = .01) and numeric densities of neurons (14.5%, p = .01), as well as volume (29.0%; p = .01), were detected in LN. Density of neurons was also decreased in ABN of the same subjects (20.8%; p = .0005). These changes were not related to antipsychotics or lithium salt exposure. In SZ subjects, a decrease of total numbers of neurons was detected in LN (23.6%; p = .04). This effect was no longer significant once exposure to antipsychotics was taken into account. CONCLUSIONS: These findings offer structural evidence for an involvement of the amygdala in BD. Consequent loss of amygdalar function may account for abnormalities in emotion processing typical of BD subjects. In contrast, changes in SZ were limited and may have been induced by pharmacologic treatment. PMID- 17698041 TI - The interplay of familial depression liability and adverse events in predicting the first onset of depression during a 10-year follow-up. AB - BACKGROUND: The aim of the present article is to explore interaction and correlation effects between familial depression liability and selected adverse (separation and traumatic) events in predicting the first onset of a major depressive episode (MDE) in a 10-year prospective longitudinal community survey. METHODS: Analyses are based on 1982 subjects (14 to 24 years at baseline) without baseline MDE who participated during the whole study period and for whom diagnostic information about psychopathology in both parents was available. The offspring's familial depression liability was determined by aggregating information on parental depressive symptoms obtained from family history data and direct interviews with parents. Data were assessed with the Munich-Composite International Diagnostic Interview according to its DSM-IV algorithms. RESULTS: Adverse events predicted a substantially increased incidence of MDE among respondents with familial liability but not in those without familial liability. There was a significant interaction between familial liability and traumatic events with the strongest effect for the number of severe traumatic events (risk difference = 11.3%; 95% confidence interval = 3.55-19.15). Associations with familial liability were most pronounced for separation events. CONCLUSIONS: Adverse events are particularly pathogenic in individuals with familial liability. The involvement of interactions and correlations between familial liability and adversity might depend on type, severity, and number of events. Both processes are suggested to be concomitant rather than exclusive. PMID- 17698042 TI - The genetic covariation between fear conditioning and self-report fears. AB - BACKGROUND: Fear conditioning is a traditional model for the acquisition of phobias, whereas behavioral therapies use processes underlying extinction to treat phobic and other anxiety disorders. Furthermore, fear conditioning has been proposed as an endophenotype for genetic studies of anxiety disorders. Although prior studies have demonstrated that fear conditioning and self-report fears are heritable, no studies have determined whether they share a common genetic basis. METHODS: We obtained fear conditioning data from 173 twin pairs from the Swedish Twin Registry who also provided self-report ratings of 16 common fears. With multivariate structural equation modeling, we analyzed factor-derived scores for the subjective fear ratings together with the electrophysiologic skin conductance responses during habituation, acquisition, and extinction to determine the extent of their genetic covariation. RESULTS: Phenotypic correlations between experimental and self-report fear measures were modest and, counter-intuitively, negative (i.e., subjects who reported themselves as more fearful had smaller electrophysiologic responses). Best-fit models estimated a significant (negative) genetic correlation between them, although genetic factors underlying fear conditioning accounted for only 9% of individual differences in self-report fears. CONCLUSIONS: Experimentally derived fear conditioning measures share only a small portion of the genetic factors underlying individual differences in subjective fears, cautioning against relying too heavily on the former as an endophenotype for genetic studies of phobic disorders. PMID- 17698043 TI - Consequences of parameter differences in a model of short-term persistent spiking buffers provided by pyramidal cells in entorhinal cortex. AB - In previous simulations of hippocampus-dependent and prefrontal cortex-dependent tasks, we demonstrated the use of one-shot short-term buffering with time compression that may be achieved through persistent spiking activity during theta rhythm. A biophysically plausible implementation of such a first-in first-out buffer of short sequences of spike patterns includes noise and differences between the parameter values of individual model pyramidal cells. We show that a specific set of parameters determines model buffer capacity and buffer function, and individual differences can have consequences similar to those of noise. The set of parameters includes the frequency of network theta rhythm and the strength of recurrent inhibition (affecting capacity), as well as the time constants of the characteristic after-depolarizing response and the phase of afferent input during theta rhythm (affecting buffer function). Given a sufficient number of pyramidal cells in layer II of entorhinal cortex, and in each self-selected category of pyramidal cells with similar model parameters, buffer function within a category is reliable with category-specific properties. Properties include buffering of spikes in the order of inputs or in the reversed order. Multiple property sets may enable parallel buffers with different capacities, which may underlie differences of place field sizes and may interact with grid cell firing in a separate population of layer II stellate cells in the entorhinal cortex. PMID- 17698045 TI - Behavioral alteration in the adult rats prenatally exposed to para chlorophenylalanine. AB - In the present work, effects of maternal administration of para chlorophenylalanine (PCPA), a serotonin synthesis inhibitor, on behavior of adult offspring were studied. Pregnant rats were injected intraperitoneally with PCPA (200/100/100/50 mg/kg) either on the gestational days (GD) 8-11 or 14-17, or with vehicle at the same days. Behavioral parameters, in an open field, the Porsolt forced swim test and the Morris water maze test were evaluated at the age of 3 3.5 months in the male and female offspring. The prenatal PCPA increased activity in an open field in the offspring treated on either GD 8-11 or 14-17. The highest levels of the activity were revealed in the male and female offspring treated on GD 14-17. Besides, the PCPA treatment on GD 8-11 or 14-17 facilitated the intersession habituation of activity to repeated exposures to an open field in the male offspring. Both male and female offspring treated on GD 14-17 showed an increased immobility in the Porsolt forced swim test and a significant learning impairment in the Morris water maze. Thus, it has been shown that administration of PCPA to pregnant rats might cause significant changes in the adult offspring behavior. These results provide further evidence that unfavorable influence may have more adverse effects on the behavioral development of rats when exposed during the final trimester of pregnancy than during the second trimester. PMID- 17698044 TI - An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat. AB - Paclitaxel (Taxol) is a frontline antineoplastic agent used to treat a variety of solid tumors including breast, ovarian, or lung cancer. The major dose limiting side effect of paclitaxel is a peripheral sensory neuropathy that can last days to a lifetime. To begin to understand the cellular events that contribute to this neuropathy, we examined a marker of cell injury/regeneration (activating transcription factor 3; ATF3), macrophage hyperplasia/hypertrophy; satellite cell hypertrophy in the dorsal root ganglia (DRG) and sciatic nerve as well as astrocyte and microglial activation within the spinal cord at 1, 4, 6 and 10 days following intravenous infusion of therapeutically relevant doses of paclitaxel. At day 1 post-infusion, there was an up-regulation of ATF3 in a subpopulation of large and small DRG neurons and this up-regulation was present through day 10. In contrast, hypertrophy of DRG satellite cells, hypertrophy and hyperplasia of CD68(+) macrophages in the DRG and sciatic nerve, ATF3 expression in S100beta(+) Schwann cells and increased expression of the microglial marker (CD11b) and the astrocyte marker glial fibrillary acidic protein (GFAP) in the spinal cord were not observed until day 6 post-infusion. The present results demonstrate that using the time points and markers examined, DRG neurons show the first sign of injury which is followed days later by other neuropathological changes in the DRG, peripheral nerve and dorsal horn of the spinal cord. Understanding the cellular changes that generate and maintain this neuropathy may allow the development of mechanism-based therapies to attenuate or block this frequently painful and debilitating condition. PMID- 17698046 TI - Effect of aminoguanidine on post-ischemic brain edema in transient model of focal cerebral ischemia. AB - Previous experimental studies have shown that aminoguanidine (AG) is beneficial in the late phase of cerebral ischemia. Recently, it has been reported that AG reduces cerebral edema in traumatic brain injury. However, the effects of AG on post-ischemic cerebral edema and blood-brain barrier (BBB) permeability are not clear. Under chloral hydrate anesthesia, transient focal cerebral ischemia was induced in rats by 60 min of middle cerebral artery occlusion (MCAO), followed by 23 h of reperfusion. Saline as vehicle or AG at the doses of 75, 150 and 300 mg/kg, i.p., was administered at the beginning or at 1 or 3 h after induction of ischemia. Subsequently, 24 h after MCAO brain edema, BBB permeability and infarct volume were evaluated. Administration of AG (150 mg/kg) at the beginning or at 1 or 3 h after MCAO, significantly reduced cerebral edema (P<0.001), while AG at the doses of 75 and 300 mg/kg had no effect. Moreover, treatment with AG (150 mg/kg) significantly reduces Evans Blue extravasation by 48% into ischemic brain compared to the saline group (P<0.001). Additionally, AG at the doses of 75 and 150 mg/kg significantly reduces cortical and striatal infarct volumes (P<0.001), while AG at the dose of 300 mg/kg did not change striatal infarct volumes (P>0.05). Our findings show that AG significantly reduced post-ischemic increase of brain edema with a 3-h therapeutic window in the transient model of focal cerebral ischemia. Moreover, it seems that at least part of the anti-edematous effects of AG is due to decrease of BBB disruption. PMID- 17698047 TI - The shape of the olfactory bulb influences axon targeting. AB - Each primary olfactory neuron in the mouse expresses a single type of odorant receptor. All neurons expressing the same odorant receptor gene typically project to two topographically fixed glomeruli, one each on the medial and lateral surfaces of the olfactory bulb. While topographic gradients of guidance receptors and their ligands help to establish the retinotectal projection, similar orthogonal distributions of cues have not yet been detected within the olfactory system. While odorant receptors are crucial for the final targeting of axons to glomeruli, it is unclear whether the olfactory bulb itself provides instructive cues for the establishment of the topographic map. To begin to understand the role of the olfactory bulb in the formation of the olfactory nerve pathway, we developed a model whereby the gross shape of the bulb in the P2-IRES-tau-LacZ line of mice was radically altered during postnatal development. We have shown here that the topography of axons expressing the P2 odorant receptor is dependent on the shape of the olfactory bulb. When the dorsoventral axis of the olfactory bulb was compressed during the early postnatal period, newly developing P2 axons projected to multiple inappropriate glomeruli surrounding their normal target site. These results suggest that the distribution of local guidance cues within the olfactory bulb is influenced by the shape of the olfactory bulb and that these cues contribute to the topographic positioning of glomeruli. PMID- 17698048 TI - Sensitization of rat dorsal horn neurons by NGF-induced subthreshold potentials and low-frequency activation. A study employing intracellular recordings in vivo. AB - Intramuscular injection of NGF in human subjects has been reported not to elicit pain, whereas 5% NaCl does. On the other hand, NGF injections induce a long lasting hyperalgesia. In the present study, the possible neuronal basis of these effects was studied at the spinal level. In anesthetized rats, neurons in the segment L4 were recorded intracellularly before (n=65), during (n=15), and after injections of NGF (n=50) as well as during and after 5% NaCl (during: n=12, after: n=39) into the gastrocnemius-soleus (GS) muscle. The neuronal responses to electrical and mechanical stimuli were tested and possible changes caused by the stimulants recorded. Of those neurons that responded to the NGF injections (7 out of 15), the majority exhibited subthreshold excitatory postsynaptic potentials (EPSPs). Only 3 out of 15 neurons reacted with action potentials (APs) at a low frequency. Already 5 to 30 min after NGF injection, some of these neurons showed signs of a sensitization. In comparison to NGF, hypertonic saline i.m. elicited APs at a higher frequency in a larger number of neurons (9 out of 12). One day after NGF i.m., the proportion of dorsal horn neurons responding with APs to electrical stimulation of the GS nerves had increased significantly from 4.6% to 28.0%. Despite the stronger excitatory effect of 5% NaCl, the sensitization of the dorsal horn neurons after hypertonic saline was less than that after NGF (15.3%). Behavioral experiments showed that NGF injections induced stronger mechanical allodynia and hyperalgesia than hypertonic saline i.m. The data demonstrate that low-frequency activation or even subthreshold potentials in dorsal horn neurons evoked by unmyelinated muscle afferents are an effective means of sensitizing these neurons. PMID- 17698049 TI - Fluctuations in brain concentrations of neurosteroids are not associated to changes in gephyrin levels. AB - Fluctuations in the brain concentrations of neurosteroids are accompanied by changes in the expression of GABA(A) receptor subunits in the cerebral cortex and hippocampus. Here, we investigated the expression of the postsynaptic molecule gephyrin in the cerebral cortex and hippocampus of pregnant rats, as well as in rats treated chronically with contraceptive drugs. The amounts of gephyrin mRNA and protein did not change during pregnancy and after delivery, as well as in rats treated with ethynylestradiol (EE) and levonorgestrel (LNG) for 4 weeks. Similarly, using immunofluorescence and laser scanning confocal microscopy, we did not detect significant changes in the number and size of gephyrin immunopositive clusters, which likely represent inhibitory postsynaptic sites. These findings indicate that the expression of gephyrin and the density of cortical inhibitory synapses are not influenced by endogenous neurosteroids. PMID- 17698050 TI - Insulin resistance affects the cytoprotective effect of insulin in cardiomyocytes through an impairment of MAPK phosphatase-1 expression. AB - OBJECTIVE: Insulin protects cardiomyocytes from apoptosis. Insulin resistance usually refers to a defect in the ability of insulin to stimulate glucose uptake. It is unknown, however, whether or not insulin resistance compromises the cell protective effect of the hormone. Caspases are a family of cysteine proteases that regulate apoptosis. We explored the effects of insulin resistance on hypoxia induced caspase-3 activation in cardiomyocytes. METHODS: Experiments were performed in cultured neonatal rat cardiomyocytes. Insulin resistance was induced by treating cardiac myocytes with isoproterenol, a beta-adrenergic receptor agonist. RESULTS: Twelve hours of hypoxia-induced caspase-3 cleavage, which was inhibited by treatment with insulin, while pre-treatment with isoproterenol abolished the insulin effect. Hypoxia-induced cleavage of caspase-3 was mediated by p38 mitogen-activated protein kinase (MAPK). Insulin inhibited hypoxia-induced phosphorylation of p38 through MAPK phosphatase-1 (MKP-1). Insulin-induced MKP-1 expression was mediated by extracellular signal-regulated protein kinases (ERK) 1/2, c-Jun NH2-terminal kinases (JNK) MAPK, and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Isoproterenol stimulation failed to induce expression of MKP 1; moreover, insulin resistance induced by long-term beta-adrenergic stimulation inhibited insulin-evoked expression of MKP-1 by impairing insulin-induced phosphorylation of both ERK1/2 and JNK without affecting Akt kinase activity. Furthermore, concomitant activation of Akt, ERK 1/2, and JNK was required for insulin to exert its protective effect against the hypoxia-induced cleavage of caspase-3. CONCLUSIONS: The results of this study lead to the conclusions that, in cardiac myocytes, antiapoptotic signals induced by insulin are mediated by more than one signaling pathway, and that long-term beta-adrenergic receptor stimulation impairing some of these pathways affects the cytoprotective action of insulin. PMID- 17698051 TI - Role of mitochondria in angiotensin II-induced reactive oxygen species and mitogen-activated protein kinase activation. AB - Peptide hormone Angiotensin II (Ang II) activates NAD(P)H oxidase, via AT1 receptors leading to increased generation of reactive oxygen species (ROS), such as the superoxide anion (O(2)(-)). As an important intracellular second messenger, ROS can activate many downstream signaling molecules, including mitogen-activated protein kinases (MAPK), protein tyrosine phosphatases, protein tyrosine kinases, and transcriptional factors. Activation of these signaling cascades is highly related to risk for cardiovascular diseases. Accumulating evidence reveals that membrane-bound NAD(P)H oxidase is the main source responsible for Ang II-induced ROS generation. However, recent novel findings suggest that Ang II stimulation induces opening of mitochondrial K(ATP) channels, depolarizes mitochondrial potential (DeltaPsi(M)), and further amplifies ROS generation from mitochondria, resulting in redox-sensitive activation of MAPK. In this review, we discuss the possible mechanisms of Ang II-induced cardiac pharmacological preconditioning (PC), and focus on the role of mitochondrial K(ATP) channels, mitochondrial ROS production, and MAPK activation in response to Ang II stimulation. PMID- 17698052 TI - Tachykinins and hematopoiesis. AB - Originally discovered in the 1930s, tachykinins have been a subject of renewed interest. Antagonists to the tachykinin receptors have shown potential in the treatment of a variety of maladies including neurodegenerative disorders, heart disease, pain perception and malignancies. Tachykinins have been the subject of intense studies due to their impact on hematopoiesis that has significant effects on endothelial tissue and vascular conditions. Hematopoiesis relies on a relatively small subset of bone marrow-resident hematopoietic stem cells. This review discusses the network developed by cytokines and the tachykinins to regulate hematopoiesis. An understanding of tachykinin effect on normal hematopoietic functions and their involvement in hematological disorders could lead to new treatments for bone marrow disorders such as fibrosis, leukemia and anemia. PMID- 17698053 TI - Actin, a reliable marker of internal control? AB - Beta-actin is commonly used to normalize molecular expression studies due to its high conservation as an endogenous housekeeping gene. However, recent studies have shown that beta-actin expression can change in response to biochemical stimuli, during growth and differentiation, and in disease states. As can be expected, these phenomena substantially compromise the use of beta-actin as an internal reference marker. Under these conditions, varying expression of beta actin likely indicates changed function for this maintenance molecule. Further studies exploring the function of actin in these environments will probably lead to a new integrative understanding of the roles of this housekeeping gene. PMID- 17698054 TI - Kinesin-2 controls development and patterning of the vertebrate skeleton by Hedgehog- and Gli3-dependent mechanisms. AB - Hedgehog signaling plays an essential role in patterning of the vertebrate skeleton. Here we demonstrate that conditional inactivation of the Kif3a subunit of the kinesin-2 intraflagellar transport motor in mesenchymal skeletal progenitor cells results in severe patterning defects in the craniofacial area, the formation of split sternum and the development of polydactyly. These deformities are reminiscent of those previously described in mice with deregulated hedgehog signaling. We show that in Kif3a-deficient mesenchymal tissues both the repressor function of Gli3 transcription factor and the activation of the Shh transcriptional targets Ptch and Gli1 are compromised. Quantitative analysis of gene expression demonstrates that the Gli1 transcript level is dramatically reduced, whereas Gli3 expression is not significantly affected by kinesin-2 depletion. However, the motor appears to be required for the efficient cleavage of the full-length Gli3 transcription factor into a repressor form. PMID- 17698055 TI - Mechanisms of palatal epithelial seam disintegration by transforming growth factor (TGF) beta3. AB - TGFbeta3 signaling initiates and completes sequential phases of cellular differentiation that is required for complete disintegration of the palatal medial edge seam, that progresses between 14 and 17 embryonic days in the murine system, which is necessary in establishing confluence of the palatal stroma. Understanding the cellular mechanism of palatal MES disintegration in response to TGFbeta3 signaling will result in new approaches to defining the causes of cleft palate and other facial clefts that may result from failure of seam disintegration. We have isolated MES primary cells to study the details of MES disintegration mechanism by TGFbeta3 during palate development using several biochemical and genetic approaches. Our results demonstrate a novel mechanism of MES disintegration where MES, independently yet sequentially, undergoes cell cycle arrest, cell migration and apoptosis to generate immaculate palatal confluency during palatogenesis in response to robust TGFbeta3 signaling. The results contribute to a missing fundamental element to our base knowledge of the diverse roles of TGFbeta3 in functional and morphological changes that MES undergo during palatal seam disintegration. We believe that our findings will lead to more effective treatment of facial clefting. PMID- 17698056 TI - A model for selecting bioindicators to monitor radionuclide concentrations using Amchitka Island in the Aleutians as a case study. AB - World War II and the Cold War have left the Unites States, and other Nations, with massive cleanup and remediation tasks for radioactive and other legacy hazardous wastes. While some sites can be cleaned up to acceptable residential risk levels, others will continue to hold hazardous wastes, which must be contained and monitored to protect human health and the environment. While media (soil, sediment, groundwater) monitoring is the usual norm at many radiological waste sites, for some situations (both biological and societal), biomonitoring may provide the necessary information to assure greater peace of mind for local and regional residents, and to protect ecologically valuable buffer lands or waters. In most cases, indicators are selected using scientific expertise and a literature review, but not all selected indicators will seem relevant to stakeholders. In this paper, I provide a model for the inclusion of stakeholders in the development of bioindicators for assessing radionuclide levels of biota in the marine environment around Amchitka Island, in the Aleutian Chain of Alaska. Amchitka was the site of three underground nuclear tests from 1965 to 1971. The process was stakeholder-initiated, stakeholder-driven, and included stakeholders during each phase. Phases included conceptualization, initial selection of biota and radionuclides, refinement of biota and radionuclide target lists, collection of biota, selection of biota and radionuclides for analysis, and selection of biota, tissues, and radionuclides for bioindicators. The process produced site specific information on biota availability and on radionuclide levels that led to selection of site-appropriate bioindicators. I suggest that the lengthy, iterative, stakeholder-driven process described in this paper results in selection of bioindicators that are accepted by biologists, public health personnel, public-policy makers, resource agencies, regulatory agencies, subsistence hunters/fishers, and a wide range of other stakeholders. The process is applicable to other sites with ecologically important buffer lands or waters, or where contamination issues are contentious. PMID- 17698057 TI - 5-Hydroxytryptamine directly inhibits neuronal nicotinic acetylcholine receptors in rat trigeminal ganglion neurons. AB - In the present study, whole-cell patch clamp recording technique was used to investigate the action of 5-hydroxytryptamine (5-HT) on the function of native neuronal nicotinic acetylcholine receptors expressed in the rat trigeminal ganglion neurons. Inward currents (I(nic)) caused by externally-applied nicotine were observed in majority of the examined neurons, which were mediated by alpha bungarotoxin-insensitive nicotinic acetylcholine receptors. We found that 5-HT could reversibly inhibit I(nic) in a concentration-dependent manner, and the inhibition did not involve 5-HT receptors. Other serotonergic agents, such as 2 methyl-5-HT, alpha-methyl-5-HT, sumatriptan and ICS-205,930, also had similar inhibitory effects on I(nic). 5-HT inhibited nicotinic acetylcholine receptors in a non-competitive manner, as 5-HT decreased the maximal current response to nicotine but had no effect on the threshold and EC(50). The inhibition of I(nic) by 5-HT was voltage-dependent and became stronger at hyperpolarized potentials. These results indicated that 5-HT directly inhibited nicotinic acetylcholine receptors in the trigeminal ganglion neurons. As a local modulator of the nicotinic acetylcholine receptor, 5-HT might play a role in the modulation of sensory information. PMID- 17698058 TI - Osteoblast protects osteoclast devoid of sodium-dependent vitamin C transporters from oxidative cytotoxicity of ascorbic acid. AB - The view that ascorbic acid indirectly benefits osteoclastogenesis through expression of receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) by osteoblasts is prevailing. In this study, we have examined the direct effect of ascorbic acid on osteoclastogenesis in cultured mouse osteoclasts differentiated from bone marrow precursors. The absence of alkaline phosphatase and osteoblastic marker genes validated the usefulness of isolation procedures. Sustained exposure to ascorbic acid, but not to dehydroascorbic acid, significantly reduced the number of multinucleated cells positive to tartrate resistant acid phosphatase (TRAP) staining. In cultured osteoclasts, mRNA expression was seen for glucose transporter-1 involved in membrane transport of dehydroascorbic acid, but not for sodium-dependent vitamin C transporters-1 and 2 that are both responsible for the transport of ascorbic acid. The inhibition by ascorbic acid was completely prevented by catalase, while ascorbic acid or hydrogen peroxide drastically increased the number of cells stained with propidium iodide and the generation of reactive oxygen species, in addition to inducing mitochondrial membrane depolarization in cultured osteoclasts. In pre osteoclastic cell line RAW264.7 cells, ascorbic acid similarly inhibited the formation of TRAP-positive multinucleated cells, with a significant decrease in RANKL-induced NF-kappaB transactivation. Moreover, co-culture with osteoblastic MC3T3-E1 cells significantly prevented the ascorbic acid-induced decrease in the number of TRAP-positive multinucleated cells in RAW264.7 cells. These results suggest that ascorbic acid may play a dual repulsive role in osteoclastogenesis toward bone remodeling through the direct cytotoxicity mediated by oxidative stress to osteoclasts, in addition to the indirect trophism mediated by RANKL from osteoblasts. PMID- 17698059 TI - Isoeugenol suppression of inducible nitric oxide synthase expression is mediated by down-regulation of NF-kappaB, ERK1/2, and p38 kinase. AB - Isoeugenol, which is a naturally occurring o-methoxyphenol in a variety of foods and essential oils, is known to have anti-inflammatory effects, although the mechanism is not clear. In the present study, we investigated the effect of isoeugenol on NF-kappaB signaling leading to inducible nitric oxide synthase (iNOS) expression in RAW 264.7 murine macrophages stimulated with lipopolysaccharide (LPS). Isoeugenol markedly inhibited nitric oxide (NO) production in dose- and time-dependent manners. The decrease in NO production was found to correlate with a decrease in iNOS expression, as determined by Western blot analysis and real-time RT-PCR. To characterize further the inhibitory mechanisms of isoeugenol at the transcriptional level, we examined the DNA binding and transcriptional activities of NF-kappaB. Isoeugenol inhibited NF kappaB-dependent transcriptional activity and DNA-binding activity by decreasing the nuclear translocation of p65, which is a component of NF-kappaB. In addition, isoeugenol blocked signaling upstream of NF-kappaB activation, such as degradation of I-kappaBalpha and the phosphorylation of extracellular signal regulated kinases 1 and 2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK), in LPS-stimulated RAW 264.7 cells. The isoeugenol analogues eugenol and allylbenzene also inhibited LPS-induced NF-kappaB signaling and iNOS expression, albeit with less potency than isoeugenol. These results suggest that isoeugenol and its analogues inhibit NO production and iNOS expression in LPS-stimulated RAW 264.7 cells, and that these effects are mediated, at least in part, by blocking the phosphorylation of ERK1/2 and p38 kinase, degradation of I-kappaBalpha, and activation of NF-kappaB. PMID- 17698060 TI - Effects of GABA(B) receptor antagonist, agonists and allosteric positive modulator on the cocaine-induced self-administration and drug discrimination. AB - Preclinical and clinical findings indicate that a GABA(B) receptor agonist baclofen decreases cocaine use. The present study investigated the effects of the GABA(B) receptor antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), the agonists baclofen and 3-aminopropyl(methyl)phoshinic acid (SKF 97541) and the allosteric positive modulator 3,5-bis(1,1-dimethylethyl-4-hydroxy beta,beta-dimethylbenzenepropanol (CGP 7930) in cocaine-and food-maintained responding under a fixed ratio 5 schedule of reinforcement in male Wistar rats. The effects of the GABA(B) receptor ligands on cocaine (10 mg/kg)-induced discriminative stimulus in a two-lever, water-reinforced fixed ratio 20 task and on basal locomotor activity were also assessed. Baclofen (2.5-5 mg/kg), SKF 97541 (0.1-0.3 mg/kg) and CGP 7930 (30-100 mg/kg) decreased the cocaine (0.5 mg/kg/injection)-maintained responding; SCH 50911 (3-10 mg/kg) was inactive in this respect. Baclofen (5 mg/kg) and SKF 97541 (0.3 mg/kg), but not CGP 7930 or SCH 50911 attenuated the food-maintained responding. The inhibitory effects of the GABA(B) receptor agonists and the modulator were blocked by SCH 50911. SKF 97541 (0.1 mg/kg) or CGP 9730 (30-100 mg/kg) did not produce a significant shift in the cocaine (1.25-10 mg/kg) dose-response curve in a drug discrimination procedure, while baclofen (1.5 mg/kg) or SCH 50911 (10 mg/kg) attenuated the effects of separate doses of cocaine. Baclofen (5 mg/kg) and CGP 7930 (100 mg/kg) significantly reduced basal horizontal activity. We found that pharmacological stimulation of GABA(B) receptors by direct agonists or allosteric positive modulation reduces cocaine reinforcement while this property of cocaine is not related to tonic activation of GABA(B) receptors. The GABA(B) receptor stimulation-induced reduction of cocaine reinforcement was separated from its discriminative stimulus effects. Moreover, a dissociation between effects of direct GABA(B) receptor agonists and a GABA(B) allosteric positive modulator on cocaine vs. food-maintained responding was demonstrated. PMID- 17698061 TI - Functional involvement of TMF/ARA160 in Rab6-dependent retrograde membrane traffic. AB - The small GTPase Rab6 regulates retrograde membrane traffic from endosomes to the Golgi apparatus and from the Golgi to the endoplasmic reticulum (ER). We examined the role of a Rab6-binding protein, TMF/ARA160 (TATA element modulatory factor/androgen receptor-coactivator of 160 kDa), in this process. High resolution immunofluorescence imaging revealed that TMF signal surrounded Rab6 positive Golgi structures and immunoelectron microscopy revealed that TMF is concentrated at the budding structures localized at the tips of cisternae. The knockdown of either TMF or Rab6 by RNA interference blocked retrograde transport of endocytosed Shiga toxin from early/recycling endosomes to the trans-Golgi network, causing missorting of the toxin to late endosomes/lysosomes. However, the TMF knockdown caused Rab6-dependent displacement of N acetylgalactosaminyltransferase-2 (GalNAc-T2), but not beta1,4 galactosyltransferase (GalT), from the Golgi. Analyses using chimeric proteins, in which the cytoplasmic regions of GalNAc-T2 and GalT were exchanged, revealed that the cytoplasmic region of GalNAc-T2 plays a crucial role in its TMF dependent Golgi retention. These observations suggest critical roles for TMF in two Rab6-dependent retrograde transport processes: one from endosomes to the Golgi and the other from the Golgi to the ER. PMID- 17698062 TI - PKC-induced stiffening of hyaluronan/CD44 linkage; local force measurements on glioma cells. AB - Interaction of cells with hyaluronan (HA) rich extracellular matrix involves the membrane receptor CD44. HA-CD44 interactions are particularly important in the development of glioma pathogenesis for its implication in tumor cells spreading. Highly motile states rely on the spaciotemporal regulation of HA-CD44 interactions occurring in specific cytoskeletal-supported membrane organization such as microvilli or the leading edge observed in migrating cell. We used AFM based force measurement to probe the HA-CD44 interaction at localized regions at the surface of living glioma cells expressing high level of the CD44 standard isoform. We show that unstimulated cells interact with HA over their entire surfaces and are highly deformable when force is exerted on individual HA molecules bound to membrane CD44 receptors. Conversely, in PKC-activated cells the probed interactions are concentrated at the leading edge of the cells with reduced membrane deformability. Taken together, our results show that PKC enhanced motility in glioma cells is associated with a redistribution of CD44 receptors at the leading edges concomitant with a stiffer anchoring of CD44 to the cell surface involving the actin cytoskeleton. PMID- 17698063 TI - Minocycline protects the blood-brain barrier and reduces edema following intracerebral hemorrhage in the rat. AB - Intracerebral hemorrhage (ICH) results from rupture of a blood vessel in the brain. After ICH, the blood-brain barrier (BBB) surrounding the hematoma is disrupted, leading to cerebral edema. In both animals and humans, edema coincides with inflammation, which is characterized by production of pro-inflammatory cytokines, activation of resident brain microglia and migration of peripheral immune cells into the brain. Accordingly, inflammation is an attractive target for reducing edema following ICH. In the present study, BBB damage was assessed by quantifying intact microvessels surrounding the hematoma, monitoring extravasation of IgG and measuring brain water content 3 days after ICH induced by collagenase injection into the rat striatum. In the injured brain, the water content increased in both ipsilateral and contralateral hemispheres compared with the normal brain. Quantitative real-time RT-PCR revealed an up-regulation of inflammatory genes associated with BBB damage; IL1beta, TNFalpha and most notably, MMP-12. Immunostaining showed MMP-12 in damaged microvessels and their subsequent loss from tissue surrounding the hematoma. MMP-12 was also observed for the first time in neurons. Dual-antibody labeling demonstrated that neutrophils were the predominant source of TNFalpha protein. Intraperitoneal injection of the tetracycline derivative, minocycline, beginning 6 h after ICH ameliorated the damage by reducing microvessel loss, extravasation of plasma proteins and edema; decreasing TNFalpha and MMP-12 expression; and reducing the numbers of TNFalpha-positive cells and neutrophils in the brain. Thus, minocycline, administered at a clinically relevant time, appears to target the inflammatory processes involved in edema development after ICH. PMID- 17698064 TI - Oxidative folding of nerve growth factor can be mediated by the pro-peptide of neurotrophin-3. AB - We have previously shown that the pro-peptide of human nerve growth factor (NGF) facilitates oxidative folding of the mature part. For the analysis of functional specificities of the pro-peptides of NGF and the related neurotrophin-3 (NT-3) with respect to structure formation, chimeric proteins with swapped pro-peptides were generated. Neither the structure nor the stability of the mature domains was influenced by the heterologous pro-peptides. For the pro-peptide of NT-3 fused to the mature part of NGF, stabilization of the pro-peptide moiety by the NGF part was observed. Folding kinetics and renaturation yields of this chimeric protein were comparable to those of proNGF. Our results demonstrate functional interchangeability between the pro-peptides of NGF and NT-3 with respect to their role in assisting oxidative folding of the mature part. PMID- 17698065 TI - Stimulus interval, rate and direction differentially regulate phosphorylation for mechanotransduction in neonatal cardiac myocytes. AB - The effect of interval, direction and rate of strain on mechanotransduction in neonatal rat cardiomyocytes is determined for focal adhesion kinase (Y397pFAK), extracellular signal-regulated kinase ERK1/2 (Thr(183)/Tyr(185)) and paxillin (pY31) and phosphorylation time courses to 10% strain assessed. Cells are non responsive at 5 min but recover at 15 min (P<0.03) with FAK nuclear translocation by 30 min. Cyclic biaxial strain increased phosphorylation from slower to faster rates (P<0.05). Uniaxial strain to groove-aligned myocytes increased FAK and ERK1/2 phosphorylation transversely more than longitudinally (P<0.05). Mechanotransduction may have a refractory period of 5 min and differentiate directions and rates of strain. PMID- 17698066 TI - Arabidopsis thaliana inositol 1,3,4-trisphosphate 5/6-kinase 4 (AtITPK4) is an outlier to a family of ATP-grasp fold proteins from Arabidopsis. AB - The Arabidopsis genome encodes a family of inositol 1,3,4-trisphosphate 5/6 kinases which form a subgroup of a larger group of ATP-grasp fold proteins. An analysis of the inositol 1,3,4-trisphosphate 5/6-kinase family might, ultimately, be best rewarded by detailed comparison of related enzymes in a single genome. The enzyme encoded by At2G43980, AtITPK4; is an outlier to its family. At2G43980 is expressed in male and female organs of young and mature flowers. AtITPK4 differs from other family members in that it does not display inositol 3,4,5,6 tetrakisphosphate 1-kinase activity; rather, it displays inositol 1,4,5,6 tetrakisphosphate and inositol 1,3,4,5-tetrakisphosphate isomerase activity. PMID- 17698067 TI - Five-year colon surveillance after screening colonoscopy. AB - BACKGROUND & AIMS: Outcomes of colon surveillance after colorectal cancer screening with colonoscopy are uncertain. We conducted a prospective study to measure incidence of advanced neoplasia in patients within 5.5 years of screening colonoscopy. METHODS: Three thousand one hundred twenty-one asymptomatic subjects, age 50 to 75 years, had screening colonoscopy between 1994 and 1997 in the Department of Veterans Affairs. One thousand one hundred seventy-one subjects with neoplasia and 501 neoplasia-free controls were assigned to colonoscopic surveillance over 5 years. Cohorts were defined by baseline findings. Relative risks for advanced neoplasia within 5.5 years were calculated. Advanced neoplasia was defined as tubular adenoma greater than > or =10 mm, adenoma with villous histology, adenoma with high-grade dysplasia, or invasive cancer. RESULTS: Eight hundred ninety-five (76.4%) patients with neoplasia and 298 subjects (59.5%) without neoplasia at baseline had colonoscopy within 5.5 years; 2.4% of patients with no neoplasia had interval advanced neoplasia. The relative risk in patients with baseline neoplasia was 1.92 (95% CI: 0.83-4.42) with 1 or 2 tubular adenomas <10 mm, 5.01 (95% CI: 2.10-11.96) with 3 or more tubular adenomas <10 mm, 6.40 (95% CI: 2.74-14.94) with tubular adenoma > or =10 mm, 6.05 (95% CI: 2.48-14.71) for villous adenoma, and 6.87 (95% CI: 2.61-18.07) for adenoma with high-grade dysplasia. CONCLUSIONS: There is a strong association between results of baseline screening colonoscopy and rate of serious incident lesions during 5.5 years of surveillance. Patients with 1 or 2 tubular adenomas less than 10 mm represent a low-risk group compared with other patients with colon neoplasia. PMID- 17698068 TI - Transient receptor potential vanilloid 1 mediates hyperalgesia and is up regulated in rats with chronic pancreatitis. AB - BACKGROUND & AIMS: The neurobiologic basis of pancreatic hyperalgesia in chronic pancreatitis (CP) is understood poorly and there is a need to identify novel therapeutic targets. Our aim was to study the role of the transient receptor potential vanilloid 1 (TRPV1), a key integrator of noxious stimuli, in the pathogenesis of pancreatic pain in a rat model of CP. METHODS: CP was induced in rats by intraductal injection of trinitrobenzene sulfonic acid. TRPV1 currents in pancreas-specific DRG neurons were measured using perforated patch-clamp techniques. Reverse-transcription polymerase chain reaction was used to measure mRNA expression of TRPV1 in these neurons after laser capture microdissection. Immunofluorescence and Western blot analysis, using TRPV1-specific antibodies, also were performed. Pancreatic hyperalgesia was assessed by rat's nocifensive behavior to electrical stimulation of the pancreas. RESULTS: CP was associated with a 4-fold increase in capsaicin-induced current density (P < .02), along with an increase in the proportion of pancreas-specific DRG neurons that responded to capsaicin (52.9% in controls vs 79.0% in CP; P < .05). CP also was associated with a significant increase in TRPV1 expression both at the messenger RNA and protein level in whole thoracic DRGs and pancreas-specific sensory neurons. Systemic administration of the TRPV1 antagonist SB-366791 markedly reduced both visceral pain behavior and referred somatic hyperalgesia in rats with CP, but not in control animals. CONCLUSIONS: TRPV1 up-regulation and sensitization is a specific molecular mechanism contributing to hyperalgesia in CP and represents a useful target for treating pancreatic hyperalgesia caused by inflammation. PMID- 17698069 TI - Direct tissue MALDI-FTMS profiling of individual Cancer productus sinus glands reveals that one of three distinct combinations of crustacean hyperglycemic hormone precursor-related peptide (CPRP) isoforms are present in individual crabs. AB - Over the past decade, mass spectrometry has become a prominent technique for identifying peptide hormones. In crustaceans, studies directed at characterizing the peptide complements present in neuroendocrine structures have generally involved the isolation of tissue from a large number of individuals, which are pooled, extracted, purified, and then analyzed via chromatographic techniques coupled with mass spectrometry. While this approach provides information on the peptides present in the population of animals used as the tissue source, data on the peptide complement present in any individual animal are lost. Direct tissue matrix assisted laser desorption/ionization Fourier transform mass spectrometry (MALDI-FTMS) of single tissues has the potential to identify differences in peptide expression between individuals. Here, we have used direct tissue MALDI FTMS of individual sinus glands (SGs) to show that the four isoforms of crustacean hyperglycemic hormone precursor-related peptide (CPRP) identified previously from pooled Cancer productus SGs (i.e. Fu, Q., Christie, A.E., Li, L. 2005. Mass spectrometric characterization of crustacean hyperglycemic hormone precursor-related peptides (CPRPs) from the sinus gland of the crab, Cancer productus. Peptides 26, 2137-2150.) are differentially distributed in conserved patterns among individual crabs. Of the crabs examined, approximately 61% of the individuals possessed Capr-CPRP I and II, but not III or IV, approximately 26% Capr-CPRP I, II and III, but not IV, and approximately 13% Capr-CPRP I, II and IV, but not III. Our findings set the stage for future molecular investigations on the origin(s) of this individual-specific variation in CPRP complement, as well as investigations of the function and regulation of the individual isoforms. These data also lend a cautionary note to the assumption that the peptides identified via pooled tissues reveal an accurate picture of the peptides present in any given individual. PMID- 17698070 TI - Diagnosis of medial tubercle fractures of the talar posterior process using oblique views. AB - Fracture of the medial tubercle of posterior process of talus is a very rare injury. Often, these fractures are not seen on the AP and lateral radiographs of the ankle joint resulting in them being misdiagnosed as an ankle sprain. This study examines 10 ankle specimens simulated with a posteromedial fracture in varying planes, by multiple X-ray views in varying angles of external rotation in order to increase the sensitivity of oblique views to diagnose a fracture of the posteromedial tubercle. True AP and lateral views (0 degrees and 90 degrees of external rotation) of the ankle joint were unable to detect the fracture simulated in the posteromedial tubercle of the posterior process in any specimens. The fractures in all the specimens were clearly visible when the X-ray beam was parallel to the plane of osteotomy. The fractures could still be identified when the plane of X-ray beam was within +/-10 degrees from the plane of osteotomy. Any further increase or decrease in plane of the X-ray beam could not identify the fracture. Two oblique views at 45 degrees and 70 degrees of external rotation could identify the fractures of the posteromedial tubercle at all planes. These oblique views can be used before resorting to the CT scan. PMID- 17698071 TI - Improved outcomes after polytrauma: do we know the reasons? PMID- 17698072 TI - Carotid atherosclerosis in familial combined hyperlipidemia associated with the APOB/APOA-I ratio. AB - OBJECTIVES: The effects of risk factors on carotid atherosclerosis in familial combined hyperlipidemia (FCHL) remain unclear. We assessed carotid intima-media thickness (IMT) and plaque in relation to classical risk factors and apolipoprotein A-I (apoA-I) and B (apoB) levels in patients with FCHL. METHODS AND RESULTS: We included 131 unrelated FCHL patients (27 with prior cardiovascular disease (CVD)) diagnosed by standard criteria and 190 age- and sex matched control subjects. Cardiovascular risk factors were assessed and IMT in the far wall of all carotid segments and plaque burden were determined in FCHL patients and controls. All carotid measurements were increased in FCHL patients compared to controls (P<0.001), irrespective of CVD status. For asymptomatic FCHL, the adjusted difference in mean common carotid IMT was 0.08 mm, corresponding to approximately 16 years of physiological IMT increase. By multivariate analysis in a model with all risk factors, inclusive of the metabolic syndrome, independent associations of IMT were age, the apoB/apoA-I ratio, systolic blood pressure, fasting glucose, family history of CVD and total/HDL cholesterol ratio (r(2)=0.475, P<0.001). The strongest determinant of IMT was the apoB/apoA-I ratio (beta=0.422, P<0.001). CONCLUSIONS: Patients with FCHL have increased carotid IMT that is strongly related to the apoB/apoA-I ratio, a measure of overall lipid abnormalities. The findings support the atherogenicity of the lipid phenotype in FCHL beyond associated risk factors. They also have implications for diagnosis and management of CVD risk in this condition. PMID- 17698074 TI - A microanalytical method for ammonium and short-chain primary aliphatic amines using precolumn derivatization and capillary liquid chromatography. AB - A new microscale method is presented for the determination of ammonium and primary short-chain aliphatic amines (methylamine, ethylamine, propylamine, n butylamine and n-pentylamine) in water. The assay uses precolumn derivatization with the reagent o-phthaldialdehyde (OPA) in combination with the thiol N-acetyl L-cysteine (NAC), and capillary liquid chromatography with UV detection at 330 nm. The described method is very simple and rapid as no preconcentration of the analytes is necessary, and the volume of sample required is only 0.1 mL. Under the proposed conditions good linearity has been obtained up to a concentration of the analytes of 10.0 mgL(-1), the limits of detection being of 8-50 microgL(-1). No matrix effect was found, and recoveries between 97 and 110% were obtained. The precision of the method was good, and the achieved variation coefficients were below 12%. The reliability of the proposed approach has been tested by analyzing a microsample of fogwater collected from leaf surfaces. PMID- 17698073 TI - Computational fluid dynamics can detect changes in airway resistance in asthmatics after acute bronchodilation. AB - The effect of a bronchodilator in asthmatics is only partially described by changes in spirometric values since no information on regional differences can be obtained. Imaging techniques like high-resolution computed tomography (HRCT) provide further information but lack detailed information on specific airway responses. The aim of the present study was to improve the actual imaging techniques by subsequent analysis of the imaging data using computational fluid dynamics (CFD). We studied 14 mild to moderately severe asthmatics. Ten patients underwent HRCT before and 4h after inhalation of a novel long acting beta(2) agonist (LABA) that acts shortly after inhalation. Four patients were studied for chronic effects and underwent CT scans twice after adequate wash-out of bronchodilators. In the active group, a significant bronchodilator response was seen with a forced expiratory volume in 1s (FEV1) increase of 8.78 +/- -6.27% pred vs -3.38 +/- 6.87% pred in the control group. The changes in FEV1 correlated significantly with the changes in distal airway volume (r = 0.69, p = 0.007), total airway resistance (r = -0.73, p = 0.003) and distal airway resistance (r = 0.76, p = 0.002) as calculated with the CFD method. The changes in distal R(aw) were not fully homogeneous. In some patients with normal FEV1 at baseline, CFD based changes in R(aw) were still detectable. We conclude that CFD calculations, based on airway geometries of asthmatic patients, provide additional information about changes in regional R(aw). All changes in the CFD-based calculated R(aw) significantly correlate with the observed changes in spirometric values therefore validating the CFD method for the studied application. PMID- 17698075 TI - Characterization of active phenolic components in the ethanolic extract of Ananas comosus L. leaves using high-performance liquid chromatography with diode array detection and tandem mass spectrometry. AB - HPLC-DAD-MS was utilized to investigate the phytochemical constituents in ethanolic extract of Ananas comosus L. leaves (EEACL) responsible for antidiabetic, antihyperlipidemic and antioxidative effects. Eight phenylpropane diglycerides, together with two hydroxycinnamic acids, three hydroxycinnamoyl quinic acids, four phenylpropane monoglycerides, three flavones and six phenylpropanoid glycosides were detected, and their proposed structures were elucidated based on HPLC retention time, UV and MS profiles. Meanwhile, a new HPLC-DAD-MS method was established for the identification and characterization of phenylpropane diglycerides in natural plants. PMID- 17698076 TI - Protein adsorption isotherm behavior in hydrophobic interaction chromatography. AB - The adsorption behavior of proteins in hydrophobic interaction chromatography (HIC) was evaluated by determining the isotherms of a wide range of proteins on various HIC resin systems. Parallel batch experiments were carried out with eleven proteins on three hydrophobic resins with different ligand chemistries and densities. The effects of salt concentration, resin chemistry and protein properties on the isotherms were also examined. The resulting isotherms exhibited unique patterns of adsorption behaviors. For certain protein-resin combinations, a "critical salt behavior" was observed where the amount of protein bound to the resin increased significantly above this salt concentration. Proteins that exhibited this behavior tended to be relatively large with more solvent accessible hydrophobic surface area. Further, calculations indicated that under these conditions the occupied surface area of the adsorbed protein layer could exceed the accessible surface area. The establishment of unique classes of adsorption behavior may shed light on our understanding of the behavior of proteins in HIC systems. PMID- 17698077 TI - Bioassay evidence for the transmission of WSSV by the harpacticoid copepod Nitocra sp. AB - White Spot Syndrome Virus (WSSV) is now one of the most devastating and virulent viral agents threatening the penaeid shrimp culture industry and has been responsible for serious economic losses for shrimp farms worldwide. One remarkable characteristic of WSSV is its wide reservoir range, which contributes to its wide geographical distribution. Among epizootiological surveys, there is substantial evidence for WSSV-positive copepods found in shrimp farming ponds. Therefore, copepods are suspected to be the vector of WSSV. In the present study, nested-PCR analysis showed positive results in the harpacticoid copepod Nitocra sp. exposed to WSSV by virus-phytoplankton adhesion route. Oral route and intramuscular injection were used to test the pathogenicity of WSSV isolated from the WSSV-positive Nitocra sp. For the oral route of infection, Marsupenaeus japonicus postlarvae were fed with WSSV-positive copepods. The shrimp postlarvae in the infected treatment became WSSV-positive and occurred 52.50+/-5.00% mortality which was significant higher (P <0.05) than that in the control treatment (20.00+/-0.00%) when postlarvae were fed with WSSV free copepods. In the intramuscular injection challenge, M. japonicus juveniles were injected with the copepods inoculum extracted from the WSSV-positive Nitocra sp., and showed 72.50+/-9.57% mortality which was also significant higher (P <0.05) than that in the control treatment (22.50+/-5.00%) when juveniles were received mock injection of a tissue homogenate prepared from WSSV-negative Nitocra sp. Based on these laboratory challenge studies, it was confirmed that the copepods can serve as a vector in WSSV transmission. PMID- 17698078 TI - Crystal structure of the BIR1 domain of XIAP in two crystal forms. AB - X-linked inhibitor of apoptosis (XIAP) is a potent negative regulator of apoptosis. It also plays a role in BMP signaling, TGF-beta signaling, and copper homeostasis. Previous structural studies have shown that the baculoviral IAP repeat (BIR2 and BIR3) domains of XIAP interact with the IAP-binding-motifs (IBM) in several apoptosis proteins such as Smac and caspase-9 via the conserved IBM binding groove. Here, we report the crystal structure in two crystal forms of the BIR1 domain of XIAP, which does not possess this IBM-binding groove and cannot interact with Smac or caspase-9. Instead, the BIR1 domain forms a conserved dimer through the region corresponding to the IBM-binding groove. Structural and sequence analyses suggest that this dimerization of BIR1 in XIAP may be conserved in other IAP family members such as cIAP1 and cIAP2 and may be important for the action of XIAP in TGF-beta and BMP signaling and the action of cIAP1 and cIAP2 in TNF receptor signaling. PMID- 17698079 TI - The characterization of Saccharomyces cerevisiae Mre11/Rad50/Xrs2 complex reveals that Rad50 negatively regulates Mre11 endonucleolytic but not the exonucleolytic activity. AB - The evolutionarily conserved heterotrimeric Mre11/Rad50/Xrs2 (Nbs1) (MRX/N) complex plays a central role in an array of cellular responses involving DNA damage, telomere length homeostasis, cell-cycle checkpoint control and meiotic recombination. The underlying biochemical functions of MRX/N complex, or each of its individual subunits, at telomeres and the importance of complex formation are poorly understood. Here, we show that the Saccharomyces cerevisiae MRX complex, or its subunits, display an overwhelming preference for G-quadruplex DNA than for telomeric single-stranded or double-stranded DNA implicating the possible existence of this DNA structure in vivo. Although these alternative DNA substrates failed to affect Rad50 ATPase activity, kinetic analyses revealed that interaction of Rad50 with Xrs2 and/or Mre11 led to a twofold increase in the rates of ATP hydrolysis. Significantly, we show that Mre11 displays sequence specific double-stranded DNA endonuclease activity, and Rad50, but not Xrs2, abrogated endonucleolytic but not the exonucleolytic activity. This repression was alleviated upon ATP hydrolysis by Rad50, suggesting that complex formation between Rad50 and Mre11 might be important for blocking the inappropriate cleavage of genomic DNA. Mre11 alone, or in the presence of ATP, MRX, MR or MX sub-complexes cleaved at the 5' end of an array of G residues in single-stranded DNA, at G quartets in G4 DNA, and at the center of TGTG repeats in duplex DNA. We propose that negative regulation of Mre11 endonuclease activity by Rad50 might be important for native as well as de novo telomere length homeostasis. PMID- 17698080 TI - Cognitive MR spectroscopy of anterior cingulate cortex in ADHD: elevated choline signal correlates with slowed hit reaction times. AB - The anterior cingulate cortex (ACC) plays a major role in modulating executive control of attention. Here, 15 medication-nai ve patients with attention deficit/hyperactivity disorder (ADHD) and 10 carefully matched healthy controls were studied with 2D (1)H-magnetic resonance spectroscopic imaging (MRSI) of the ACC [Brodmann areas 24b'-c' and 32']. Attentional skills were assessed using the identical pairs version of the continuous performance task (CPT-IP). Analysis of regional brain spectra revealed a significantly increased signal of choline containing compounds (Ch) in the ACC of ADHD patients (p<0.05). Across and within groups, the Ch signal showed high correlations with slowed hit reaction times on the CPT-IP. No group differences in N-acetyl-aspartate (NAA) and creatine (tCr) were detectable. The combination of performance deficits and elevated Ch levels in the ACC supports the hypothesis that subtle structural abnormalities underlie the functional alterations in ACC activation previously observed in ADHD patients. PMID- 17698081 TI - Neural correlates of associative learning and memory in veterans with posttraumatic stress disorder. AB - Impaired attention and memory are symptoms frequently associated with posttraumatic stress disorder (PTSD). Although patients with PTSD frequently report memory difficulties and empirical research provides support for a memory deficit in PTSD, as of yet, no fMRI study has adequately investigated the neural correlates of learning and memory of neutral (i.e. not trauma related) material in patients with PTSD compared to controls. Twelve male veterans with PTSD, and twelve male veterans without PTSD, were recruited, and matched for age, region and year of deployment. Encoding and retrieval of 12 word-pair associates was assessed during fMRI in both experimental groups. Compared to controls veterans with PTSD revealed underactivation of the frontal cortex, and overactivation of the temporal cortex during the encoding phase. Retrieval of the paired associates resulted in underactivation of right frontal cortex, bilateral middle temporal gyri, and the left posterior hippocampus/parahippocampal gyrus in patients with PTSD. Deficits in memory performance in PTSD appear to be related to altered activity in fronto-temporal areas during both the encoding and retrieval phase of memory processing. PMID- 17698082 TI - Intracranial incidental findings on brain MR images in a pediatric neurology practice: a retrospective study. AB - BACKGROUND AND PURPOSE: Previous studies have addressed the prevalence of incidental findings largely in healthy adult and pediatric populations. Our study aims to elucidate the prevalence of incidental findings in a pediatric neurology practice. METHODS: We reviewed the charts of 1618 patients seen at a pediatric neurology practice at a tertiary care center from September 2003 to December 2005 for clinical data and incidental intracranial findings on brain magnetic resonance imaging reports. Incidental findings were divided into two categories: normal or abnormal variants. Clinical and demographic data were assessed for associations with incidental findings. RESULTS: From 1618 charts reviewed, only 666 patients (41% of all patients) had brain MRIs ordered. One-hundred and seventy-one (171) patients (25.7% of all patients; 95% CI: 22.6, 29.0) had incidental findings. Of these, 113 (17.0%; 95% CI: 14.1, 19.8) were classified as normal-variants and 58 (8.7%; 95% CI: 6.6, 10.9) were classified as abnormal. The nature of incidental findings was not related to age group, sex or clinical diagnosis (p=0.29, p=0.31 and p=0.69 respectively). Two patients (0.3%; 95% CI: approximately 0.0, 0.7) required neurosurgical referral. CONCLUSIONS: We report a high prevalence of and a low rate of referrals for incidental findings in comparison to previous studies. The present study may help guide management decisions and discussions with patients and families. Future studies should attempt to address issues of associations between primary or secondary diagnoses and intracranial incidental findings in a controlled, prospective fashion. PMID- 17698083 TI - Double saccadic pulses and macrosaccadic oscillations from a focal brainstem lesion. AB - Double saccadic pulses (DSP) are saccadic intrusions that consist of an initial saccade away from a fixation followed immediately by a return saccade back to the fixation. DSP have been reported in patients with presumed multiple sclerosis and metabolic encephalopathy. However, DSP have not been described in a circumscribed brain lesion. We report a man who developed almost continuous DSP with intervening macrosaccadic oscillations from a circumscribed lesion in the dorsal pontine tegmentum which extended up to the midbrain level and spared the nucleus raphe interpositus where the pause cells reside. Damage to the projections from the superior colliculus to omnipause neurons and resultant dysfunction of omnipause neuron may be a mechanism of saccadic intrusions and oscillations observed in our patient with a circumscribed brainstem lesion. PMID- 17698085 TI - Age-related mitochondrial DNA point mutations in patients with mitochondrial myopathy. AB - Mutations in the control region (D-loop) of mitochondrial DNA (mtDNA) have been described in normal old individuals and it is suggested that they originated from oxidative damage. Respiratory chain defects may lead to increased free radical generation, increased susceptibility to oxidative damage and further increased accumulation of age-related mutations. The objective of this study was to verify whether patients with a mitochondrial disease are more predisposed to accumulate the A189G and T408A mutations in the D-loop and confirm their age-associated nature. We evaluated the presence and levels of heteroplasmy of these two mutations in muscle DNA of 52 individuals with different ages (21 age-matched controls and 31 patients with single or multiple mtDNA deletions). The frequency of both mutations was significantly increased with age, but no differences were observed comparing the group of patients with their age-matched controls. We could not observe correlation of levels of heteroplasmy with age. Our results confirm the age-related nature of the A189G and T408A mutations in the D-loop in controls and patients with mitochondrial disease, but do not suggest that patients are more predisposed to the development of age-related point mutations. PMID- 17698084 TI - Chlorogenic acid, a polyphenol from Prunus domestica (Mirabelle), with coupled anxiolytic and antioxidant effects. AB - BACKGROUND: Oxidative stress is linked to neurodegenerative diseases, cancer, cardiovascular diseases and to some behaviors, such as anxiety and depression. In particular, recent research observed a close relationship between oxidative stress and anxiety. METHODS: We investigated the anxiolytic effect of chlorogenic acid, a dietary antioxidant present in fruits, in mouse models of anxiety including the light/dark test, the elevated plus maze and the free exploratory test. Moreover, the antioxidative effect of chlorogenic acid on peripheral blood granulocytes was investigated. RESULTS: Chlorogenic acid (20 mg/kg) induced a decrease in anxiety-related behaviors suggesting an anxiolytic-like effect of this polyphenol. The anti-anxiety effect was blocked by flumazenil suggesting that anxiety is reduced by activation of the benzodiazepine receptor. In vitro, chlorogenic acid protected granulocytes from oxidative stress. CONCLUSIONS: Chlorogenic acid is one of the most abundant polyphenols in fruits. We demonstrated in vivo and in vitro for the first time, that chlorogenic acid has anxiolytic effects coupled with antioxidant activity. Thus, fruits such as plums (Mirabelle), apples and cherries may provide health-promoting advantages to consumers. PMID- 17698086 TI - Calculation of folding energies of single-stranded nucleic acid sequences: conceptual issues. AB - The stability of a folded single-stranded nucleic acid depends on the composition and order of its constituent bases and may be assessed by taking into account the pairing energies of its constituent dinucleotides. To assess the possible biological significance of a computed structure, Maizel and coworkers in the 1980s compared the energy of folding of a natural single-stranded RNA sequence with the energies of several versions of the same sequence produced by shuffling base order. However, in the 2000s many took as self-evident the view that shuffling at the mononucleotide level (single bases) was conceptual wrong and should be replaced by shuffling at the level of dinucleotides (retaining pairs of adjacent bases). Folding energies then became indistinguishable from those of corresponding shuffled sequences and doubt was cast on the importance of secondary structures. Nevertheless, some continued productively to employ the single base shuffling approach, the justification for which is the topic of this paper. Because dinucleotide pairing energies are needed to calculate structure, it does not follow that shuffling should not disrupt dinucleotides. Base shuffling allows determination of the relative contributions of base composition and base order to total folding energy. The potential for secondary structure arises from pressures acting at both DNA and RNA levels, and is abundant throughout genomes-with a probable primary role in recombination. Within a gene the potential can often be accommodated, and base order and composition work together (values have the same negative sign) in contributing to total folding energy. But sometimes protein-coding pressure on base order conflicts with the pressure for secondary structure and the values have opposite signs. Total folding energy can be deemed of potential biological significance when the average of several readings is significantly less than zero. PMID- 17698087 TI - Prognostic factors for renal cell carcinoma with tumor thrombus extension. AB - PURPOSE: We identified prognostic factors for renal cell carcinoma with tumor thrombus extension and assessed whether the current T3 classification could be improved. MATERIALS AND METHODS: We studied clinicopathological parameters in 321 consecutive patients who were surgically treated for renal cell carcinoma with tumor thrombus extension. Disease specific survival was evaluated with univariate and multivariate analysis. Harrell's C-index was used to assess the prognostic accuracy of prognostic models. RESULTS: Tumor thrombus extended into the renal vein in 166 patients, the inferior vena cava in 137 and the atrium in 18. Metastatic renal cell carcinoma was found in 198 patients (62%). The thrombus level had no impact on clinicopathological parameters or survival but perioperative morbidity and mortality increased with cranial extension of the thrombus. Mean followup was 49 months. Five and 10-year disease specific survival rates were 36% and 24%, respectively. On multivariate analysis Eastern Cooperative Oncology Group performance status, lymph node and distant metastases, sarcomatoid features and perinephric fat invasion were independent prognostic factors. Weight loss, anemia, collecting system invasion, incomplete surgical resection, nuclear grade and T classification were also significant prognosticators on univariate analysis. For patients with advanced disease the number of metastatic sites and the disease-free interval further predicted prognosis. The overall immunotherapy response rate was 19%, which decreased with cranial extension of the thrombus. Redefinition of the T3 classification with the incorporation of fat invasion improved prognostic accuracy, as shown by an increase in the C-index. CONCLUSIONS: Eastern Cooperative Oncology Group performance status, metastatic status, sarcomatoid features and concomitant perinephric fat invasion are the most powerful prognostic factors of survival in renal cell carcinoma with tumor thrombus extension. Our data indicate that a redefinition of the current T3 classification may improve its predictive accuracy. We propose that T3 renal cell carcinoma with fat invasion or thrombus extension alone should be classified as T3a, while that with thrombus extension plus fat invasion should be classified as T3b. PMID- 17698088 TI - Contrast medium induced nephropathy in urological practice. AB - PURPOSE: Contrast medium induced nephropathy is the third cause of in-hospital acute renal failure. The first studies in this area were done with reference to urological practice only. Although various guidelines on the management of contrast medium induced nephropathy were provided by the European Society of Urogenital Radiology, more recently many investigators have focused their attention on contrast medium use in interventional vascular radiology and cardiology. We critically reviewed the literature to clarify the impact of contrast medium induced nephropathy in urology and the possible prophylactic measures against it. MATERIALS AND METHODS: A MEDLINE/PubMed, EMBASE and Cochrane Library search for 1971 to 2006 was performed. All articles related to the use of contrast medium in urological practice and contrast medium induced nephropathy were reviewed. RESULTS: Many pathological conditions frequently seen by urologists are diagnosed by imaging requiring contrast medium. A basic understanding of the risk factors for contrast medium induced nephropathy and the strategies for its prevention are useful to prepare urological patients for these procedures. Prophylaxis includes the discontinuation of potentially nephrotoxic drugs and the use of protocols for periprocedural hydration. CONCLUSIONS: The general approach to the recognition and prevention of contrast medium induced nephropathy in patients at risk should be extended to urological clinical practice since no definitive evidence based data are available regarding contrast medium induced nephropathy management in urological patients. Moreover, these patients can frequently present with the most significant risk factor for contrast medium mediated kidney damage, that is preexisting acute or chronic renal failure. Controlled trials are needed to establish the incidence of contrast medium induced nephropathy in diagnostic or interventional procedures in uroradiology. PMID- 17698090 TI - Management of low grade papillary bladder tumors. AB - PURPOSE: We evaluated the management and treatment outcomes of low grade papillary bladder tumors. MATERIALS AND METHODS: We evaluated 215 patients diagnosed with low grade and noninvasive papillary bladder tumors, and followed them every 6 months with flexible cystoscopy for 6 to 10 or more years. Tumor recurrence was treated with transurethral resection or outpatient cystoscopic fulguration. RESULTS: Of the 215 patients 143 (67%) had at least 1 recurrence (positive cystoscopy). With a median followup of 8 years tumor recurrences averaged 6.2 (range 1 to 19) requiring 0.34 transurethral resections per year or 1 transurethral resection every 3 years, or 0.61 fulgurations or 1 fulguration approximately every 2 years. There were 17 patients (8%) who had progression in grade or stage and 1 patient (0.5%) died of bladder cancer. Patients most likely to have recurrence had multiple tumors, low grade (TaLG) carcinoma or tumor at first followup cystoscopy. CONCLUSIONS: Surveillance cystoscopy at 6-month intervals coupled with outpatient fulguration controls recurrent tumors and reduces the therapeutic burden for patients diagnosed with low grade papillary bladder tumors. PMID- 17698092 TI - The change in the dihydrotestosterone level in the prostate before and after androgen deprivation therapy in connection with prostate cancer aggressiveness using the Gleason score. AB - PURPOSE: We investigated the change in dihydrotestosterone in the prostate during androgen deprivation therapy in connection with prostate cancer aggressiveness using the Gleason score. MATERIALS AND METHODS: A total of 28 patients with clinically localized prostate cancer who were treated with androgen deprivation therapy for 6 months were enrolled in this study. Dihydrotestosterone in the prostate and serum were analyzed using liquid chromatography/electrospray ionization-mass spectrometry after polar derivatization before and after androgen deprivation therapy. RESULTS: The change in dihydrotestosterone during androgen deprivation therapy in the prostate with Gleason score 7 to 10 prostate cancer was significantly smaller than that in the prostate with Gleason score 6 or less (p = 0.016). There were no significant differences between patients with Gleason score 7 to 10 prostate cancer and patients with Gleason score 6 or less in dihydrotestosterone in the prostate, in serum androgens and in serum androgen ratios before and after androgen deprivation therapy. CONCLUSIONS: Low dihydrotestosterone in the prostate is probably sufficient to propagate the growth of aggressive prostate cancer. Furthermore, the prostate with aggressive prostate cancer can produce androgens from adrenal precursors more autonomously than the prostate with nonaggressive prostate cancer under a low testosterone environment with testicular suppression. PMID- 17698095 TI - Importance of tumor location in patients with high preoperative prostate specific antigen levels (greater than 20 ng/ml) treated with radical prostatectomy. AB - PURPOSE: We investigated the effect of tumor location (anterior vs posterior) on pathological characteristics and biochemical-free survival in patients with a preoperative prostate specific antigen level of greater than 20 ng/ml undergoing radical prostatectomy since transition zone tumors are known to present with higher prostate specific antigen levels. MATERIALS AND METHODS: We retrospectively studied the records of 265 patients treated with radical prostatectomy between 1984 and 2005 who had preoperative prostate specific antigen levels greater than 20 ng/ml. Review of pathology reports was performed and tumor location (anterior vs posterior) was defined. Differences in clinicopathological characteristics and prostate specific antigen recurrence rates were examined. RESULTS: Of 265 patients with a preoperative prostate specific antigen level of greater than 20 ng/ml who underwent radical prostatectomy 50 (19%) had anterior tumors and 215 (81%) had posterior tumors. Patients with anterior tumors had lower clinical stage and less seminal vesicle involvement than patients with posterior tumors (p = 0.006 and <0.001, respectively). Although Kaplan-Meier analysis demonstrated significantly higher rates of 5-year biochemical recurrence-free survival for patients with anterior vs posterior tumors (63% vs 40%, p = 0.020), anterior tumor location was not an independent predictor of biochemical recurrence. CONCLUSIONS: Radical prostatectomy is a feasible treatment option in patients with a preoperative prostate specific antigen level of greater than 20 ng/ml. The 5-year biochemical free survival rate was 47%. Although anterior tumor location was associated with favorable pathological features and improved biochemical-free survival, it was not an independent predictor of biochemical recurrence. Further studies are warranted to identify patients with high preoperative prostate specific antigen levels most likely to have recurrence. PMID- 17698097 TI - Renal cell cancer and nuclear receptor levels--biomarkers or functionally relevant? PMID- 17698099 TI - Application of artificial intelligence to the management of urological cancer. AB - PURPOSE: Artificial intelligence techniques, such as artificial neural networks, Bayesian belief networks and neuro-fuzzy modeling systems, are complex mathematical models based on the human neuronal structure and thinking. Such tools are capable of generating data driven models of biological systems without making assumptions based on statistical distributions. A large amount of study has been reported of the use of artificial intelligence in urology. We reviewed the basic concepts behind artificial intelligence techniques and explored the applications of this new dynamic technology in various aspects of urological cancer management. MATERIALS AND METHODS: A detailed and systematic review of the literature was performed using the MEDLINE and Inspec databases to discover reports using artificial intelligence in urological cancer. RESULTS: The characteristics of machine learning and their implementation were described and reports of artificial intelligence use in urological cancer were reviewed. While most researchers in this field were found to focus on artificial neural networks to improve the diagnosis, staging and prognostic prediction of urological cancers, some groups are exploring other techniques, such as expert systems and neuro-fuzzy modeling systems. CONCLUSIONS: Compared to traditional regression statistics artificial intelligence methods appear to be accurate and more explorative for analyzing large data cohorts. Furthermore, they allow individualized prediction of disease behavior. Each artificial intelligence method has characteristics that make it suitable for different tasks. The lack of transparency of artificial neural networks hinders global scientific community acceptance of this method but this can be overcome by neuro-fuzzy modeling systems. PMID- 17698100 TI - Computer modeling technology to assess extracapsular tissue coverage of whole mount sections after retropubic and laparoscopic radical prostatectomy. AB - PURPOSE: The introduction of new surgical approaches to radical prostatectomy requires methodologies that permit valid comparison that are more expedient than long-term outcomes of biochemical local and distant failure and survival. We used a computer modeling program to assess the percent of extracapsular tissue coverage of prostate glands removed by the open retropubic and laparoscopic approaches. MATERIALS AND METHODS: Specimens were available for 15 and 17 patients who underwent open and laparoscopic radical prostatectomy, respectively. Serial whole mount sections were taken at 5 mm intervals. A genitourinary pathologist drew the contours of the prostate capsule on each tissue section. The whole mount was scanned to produce digital images. A software program was used to create a file with capsule information and a file with extraprostatic fibroadipose tissue information. Two separate point cloud files were generated to represent the capsule and extraprostatic models, and software algorithms were used to generate differences in the point clouds to quantify the extent of extracapsular tissue coverage. RESULTS: When separated into sides dissected by a nerve or nonnerve sparing technique, the overall percent of gland surface coverage by extracapsular fibroadipose tissue was statistically greater with laparoscopic dissection than with the open approach. When a segmental analysis of gland coverage was evaluated, a statistically greater percent of fibroadipose coverage was associated with laparoscopic dissection in the apical and inferolateral segments with nonnerve sparing, and in the apical segment with nerve sparing. CONCLUSIONS: This small radical prostatectomy series, analyzed by computer reconstruction as described, provides information suggesting that overall extracapsular tissue coverage is at least equal if not superior using the laparoscopic vs the open approach. This was specifically the case in areas of inferolateral and apical dissection with nonnerve sparing procedures and in areas of the apical dissection with nerve sparing procedures. PMID- 17698101 TI - Rates of biochemical remission remain higher in black men compared to white men after radical prostatectomy despite similar trends in prostate specific antigen induced stage migration. AB - PURPOSE: We evaluated biochemical relapse-free survival after surgery for localized prostate cancer, comparing rates between black and white men in the early and late prostate specific antigen eras. Our hypothesis was that the gap in biochemical relapse-free survival between these groups would lessen in the later prostate specific antigen era due to catch-up awareness/availability of screening and treatment in the black population. MATERIALS AND METHODS: Data on 2,910 men treated with prostatectomy from 1987 to 2004 were evaluated. The primary end points were 1) rates of organ confined disease and 2) biochemical relapse-free survival after prostatectomy in the early (1987 to 1997) and late (1998 to 2004) prostate specific antigen eras. Rates of organ confined disease were compared using the chi-square test. Biochemical failure was analyzed using Kaplan-Meier estimates and Cox proportional hazards regression. RESULTS: Median followup for the early and late prostate specific antigen periods was 9.8 (range 1.2 to 18.2) and 3.3 years (range 1.0 to 7.7), respectively. Based on rates of organ confined disease in the early vs late periods black and white men had significant gains in the number presenting with favorable disease at diagnosis in the late prostate specific antigen period (54% vs 76% and 49% vs 71%, respectively, each p <0.01). Despite gains of similar magnitude in favorable features at presentation biochemical relapse-free survival for black men lagged behind white men by 11% at 5 years in the early era and by 12% in the late era. Race was a significant predictor of biochemical relapse-free survival on multivariate analysis in each era. CONCLUSIONS: Despite similar increases in the rate of organ confined disease between black and white men in the late vs early prostate specific antigen eras black men continue to show higher rates of biochemical failure after surgery. PMID- 17698103 TI - Higher frequency of familial clustering of prostate cancer in French-Canadian men. AB - PURPOSE: Prostate cancer is the second cause of cancer related death in North American men. We investigated the frequency of familial clustering in a French Canadian population of prostate cancer cases. MATERIALS AND METHODS: Between October 2004 and September 2005, 179 consecutively seen patients with localized prostate cancer identified each of their parents as being of French-Canadian descent. They were asked for their family history of cancer in first-degree relatives, age at diagnosis, whether affected relatives were alive, age and markers of tumor aggressiveness, including prostate specific antigen, Gleason and disease stage. ANOVA was used to compare the distribution of quantitative factors according to qualitative factors identified in our population. Differences between qualitative factors were assessed by the Fisher exact test. All p values were 2-sided. RESULTS: Mean age at diagnosis was 67 years. A total of 45 French Canadian patients (25.1%) had at least 1 first-degree relative with prostate cancer, including 34 (19%) with 1 first-degree relative, 9 with a father-son pair, 25 with a brother-brother pair and 11 (6.1%) with at least 2 first-degree relatives. In our series the frequency of familial clustering defined by at least 1 relative with prostate cancer was high. We found a higher percent of French Canadian men with at least 1 first-degree relative with prostate cancer than what was previously reported for an unselected population in Canada (25.1% vs 14.7%, p <0.0001). CONCLUSIONS: Those preliminary results open a new perspective to a better understanding of familial prostate cancer in the Province of Quebec. PMID- 17698104 TI - Salvage cryoablation of the prostate: followup and analysis of predictive factors for outcome. AB - PURPOSE: We assessed the efficacy of cryoablation of the prostate with an emphasis on finding predictive factors that lead to improved outcome. MATERIALS AND METHODS: A total of 187 patients with locally recurrent prostate cancer after radiotherapy underwent salvage cryoablation of the prostate, and were studied after a mean followup of 39 months. Survival analysis was performed with the Kaplan-Meier method. Several variables were tested for predictive value using the Cox regression model including serum prostate specific antigen before radiotherapy, serum prostate specific antigen at cryoablation, clinical stage before radiotherapy, Gleason score before radiotherapy, Gleason score at cryoablation, number of positive biopsy cores and use of neoadjuvant hormonal therapy before cryoablation. RESULTS: Serum prostate specific antigen at cryoablation was a predictive factor for biochemical recurrence on univariate and multivariate analysis (p <0.001). Patients with pre-cryoablation prostate specific antigen less than 4 ng/ml had a 5 and 8-year biochemical recurrence-free survival of 56% and 37%, respectively. In contrast, patients with pre cryoablation prostate specific antigen 10 ng/ml or greater had a 5 and 8-year biochemical recurrence-free survival of only 1% and 7%, respectively. Patients with pre-cryoablation prostate specific antigen from 4 to 9.99 ng/ml had intermediate survival outcomes. Of the patients 32% were started on hormonal therapy for disease progression at a mean of 31 months postoperatively. Overall 5 and 8-year survival was 97% and 92%, respectively. CONCLUSIONS: Salvage cryoablation is a viable treatment option for patients with prostate cancer in whom radiation therapy has failed. Salvage cryoablation should be performed when serum prostate specific antigen is still relatively low because in these patients the procedure may potentially be curative. Even when cryoablation fails to eradicate the disease in some patients, it allows hormonal therapy to be deferred for a significant period of time in that cohort. PMID- 17698105 TI - Survival following the diagnosis of noninvasive bladder cancer: WHO/International Society of Urological Pathology versus WHO classification systems. AB - PURPOSE: The WHO/International Society of Urological Pathology classification of bladder cancer, introduced in 1998, differs from the traditional 1973 WHO classification. Few studies have reported survival data based on the WHO/International Society of Urological Pathology classification and none has demonstrated clear superiority compared to the 1973 WHO system. In a large, nonselected population of patients with bladder cancer we rated all incident tumors using each system and compared long-term patient survival. MATERIALS AND METHODS: New Hampshire residents with bladder cancer diagnosed between 1994 and 2000 were identified through the State Cancer Registry. Slides were retrieved from more than 90% of cases and reviewed by a single pathologist. Tumors were classified according to WHO and WHO/International Society of Urological Pathology criteria. Overall patient survival was determined for the cohort of 504 patients after an average of 7 years using a national mortality database. RESULTS: For both grading systems there was a gradient of progressively lower survival times from the lowest grade to the highest grade tumors. Hazard ratios and 95% confidence intervals for the WHO/International Society of Urological Pathology system were 1.9 (1.0-3.4) for low grade papillary urothelial carcinoma and 3.0 (1.5-6.0) for high grade papillary urothelial carcinoma, compared to papillary urothelial neoplasms of low malignant potential. For the WHO (1973) system compared to grade 1 tumors the hazard ratio for grade 2 tumors was 1.8 (1.1-3.1) and for grade 3 was 2.4 (1.2-4.7). CONCLUSIONS: Advantages of the WHO/International Society of Urological Pathology bladder tumor classification include more detailed diagnostic criteria, the ability to define a lesion with minimal malignant potential and the ability to identify a larger group of patients needing closer surveillance. However, we found that the WHO/International Society of Urological Pathology tumor categories did not detect a clear overall survival advantage compared to the WHO (1973) classification system. PMID- 17698107 TI - Lead time of prostate cancer detected in population based screening for prostate cancer in Japan. AB - PURPOSE: We clarified that lead time bias in screen detected prostate cancer is important for evaluating the outcome of any individual screening system. MATERIALS AND METHODS: Between 1992 and 2001, 195 and 958 prostate cancer cases with clinical T1c/T2N0M0 and T3N0M0 disease were enrolled in the current study as screen detected and outpatient clinic detected prostate cancer, respectively. Log10 prostate specific antigen velocity was calculated using log10 prostate specific antigen at diagnosis and at the most recent screening before cancer detection. Lead time in screen detected cancer was then estimated as the year when log10 prostate specific antigen in screen detected cancer would increase to the levels of log10 prostate specific antigen in outpatient clinic detected prostate cancer. RESULTS: Median log10 prostate specific antigen was 0.87 and 1.08 ng/ml for clinical T1c/T2N0M0 disease, and 1.14 and 1.53 ng/ml for T3N0M0 disease in screen and outpatient clinic detected cancer, respectively. The 25th, 50th and 75th percentiles of log10 prostate specific antigen velocity before cancer detection in the screening population were 0.05, 0.08 and 0.14 for T1c/T2N0M0 disease, and 0.07, 0.13 and 0.21 for T3N0M0 disease, respectively. The 25th, 50th and 75th percentiles of expected lead time in screen detected cancer were 1.9, 3.3 and 5.2 years for T1c/T2N0M0 disease and 1.4, 2.2 and 4.1 years for T3N0M0 disease, respectively. CONCLUSIONS: The lead time of screen detected cancer in our screening system is not as long as previously thought. This new methodology for lead time estimation may be useful for evaluating treatment outcomes of screen detected prostate cancer in individual screening systems done in various regions worldwide. PMID- 17698111 TI - Advanced but not localized prostate cancer is associated with increased oxidative stress. AB - PURPOSE: Oxidative damage has been linked to prostate carcinogenesis but its role in disease development and progression remains elusive. We investigated associations between indexes of oxidative stress with localized and advanced prostate cancer. Specifically we assessed the susceptibility of serum lipids to copper induced peroxidation (oxidizability). MATERIALS AND METHODS: Serum oxidizability, and levels of alpha-tocopherol, malonyldialdehyde and uric acid were assessed in samples from 79 patients with prostate cancer, including 42 with localized and 37 with metastatic disease receiving androgen deprivation therapy, and 25 control subjects. Oxidizability was assayed by continuous spectroscopic monitoring of the accumulation of peroxidation products. The lag preceding oxidation, that is the delay between the induction and propagation of the reaction, served as a measure of the resistance of serum lipids to oxidation. RESULTS: Compared to control subjects patients with localized prostate cancer had no difference in oxidative stress indexes, whereas those with metastatic disease had a shorter lag preceding oxidation and increased malonyldialdehyde (p <0.05), each reflecting a state of high oxidative stress. In patients with prostate cancer the probability of disease progression from localized to advanced state increased with a shorter lag preceding oxidation (p <0.001), increased malonyldialdehyde (p <0.03) and decreased uric acid (p <0.04). Localized and metastatic disease was associated with increased rather than decreased alpha tocopherol (p <0.008 and <0.005, respectively). CONCLUSIONS: Patients with advanced prostate cancer are subject to high oxidative stress, as determined by increased susceptibility of serum lipids to peroxidation. This association was not detected in patients with localized cancer and it is not attributable to altered levels of alpha-tocopherol. PMID- 17698113 TI - Radical cystectomy and extended pelvic lymphadenectomy: survival of patients with lymph node metastasis above the bifurcation of the common iliac vessels treated with surgery only. AB - PURPOSE: We assessed the clinical outcome in patients with invasive bladder cancer and lymph node metastasis above the bifurcation of the common iliac vessels treated with radical cystectomy including extended pelvic lymph node dissection without adjunct therapy. MATERIALS AND METHODS: Between 1993 and June 2005 a total of 336 consecutive patients underwent radical cystectomy and extended pelvic lymphadenectomy without preoperative or postoperative chemotherapy by 1 surgeon. A total of 263 patients (78.3%) had orthotopic bladder reconstruction. The pelvic lymph node dissection began at the distal aorta including the common and external iliac lymph nodes, and the periaortic, presacral and obturator fossa nodes. The lymphatic tissue removed above and below the bifurcation of the common iliac vessels was submitted separately for histopathological analysis. Data were prospectively entered into a database that forms the basis of this cohort study. RESULTS: The 5-year overall and recurrence free survival rates in the entire study population of 336 patients were 68% and 69%, respectively. Overall 64 patients (19%) had lymph node metastases of whom 22 (34.4%) had lymph node involvement above the bifurcation of the common iliac vessels outside the template of the standard lymph node dissection. The median number of retrieved lymph nodes was 27 (range 7 to 78) and in those with lymph node metastases 27 (range 11 to 49) included 8 (range 0 to 17) above the bifurcation and 18 (range 8 to 41) below the bifurcation of the common iliac vessels in the true pelvis. Lymph node involvement proved a significant adverse prognostic factor with a 5-year probability of survival of 39% vs 76%. The overall 5-year survival rates was similar in patients with lymph node involvement above the bifurcation of the common iliac vessels (37%) compared to the entire population with lymph node metastasis (41%) and to those with lymphatic metastases in the true pelvis below the bifurcation of the common iliac vessels (42%). The survival rate was significantly higher in patients with 5 or less involved lymph nodes (50% vs 13%, p <0.002) and in those with a lymph node density (number of lymph nodes involved/total number of lymph nodes removed) less than 20% (25% vs 47%, p <0.05), but it did not relate to the total number of retrieved lymph nodes. CONCLUSIONS: Overall 34% of our patients with lymph node metastases had nodal involvement in the common iliac, periaortic and presacral regions after radical cystectomy for bladder cancer. Survival was similar in this group of patients with lymphatic metastasis outside the boundaries of the standard pelvic lymph node dissection template compared to the entire population with lymph node metastasis. This finding underscores the contention that extended dissection not only provides the most accurate staging but also offers the patient the best chance of survival. Following radical cystectomy patients can be stratified into risk groups according to tumor stage, lymph node involvement, number of metastatic nodes and lymph node density. Our results support the idea that the benchmark for radical cystectomy should include extensive pelvic lymph node dissection with anatomical boundaries including the common iliac and presacral nodes. PMID- 17698116 TI - Plasminogen activation inhibitor-1 improves the predictive accuracy of prostate cancer nomograms. AB - PURPOSE: We tested whether the addition of preoperative circulating plasminogen activator inhibitor type I levels improves the accuracy of standard preoperative and postoperative models for prediction of biochemical recurrence after radical prostatectomy. MATERIALS AND METHODS: Preoperative plasma levels of plasminogen activator inhibitor type I were measured in 429 consecutive patients treated with radical prostatectomy for clinically localized prostate cancer. The patients were randomly divided into a development (67%, 286) and a split sample validation cohort (33%, 143). Cox regression analysis was used to develop prognostic nomograms for prediction of biochemical recurrence. RESULTS: In standard univariate analyses categorically coded preoperative plasminogen activator inhibitor type I was significantly associated with biochemical recurrence (p <0.001). In standard preoperative and postoperative multivariate analyses preoperative plasminogen activator inhibitor type I was independently associated with biochemical recurrence (p <0.001 and p = 0.002, respectively). In the split sample validation cohort the addition of plasminogen activator inhibitor type I increased the predictive accuracy of the preoperative multivariate model by 1.2%, 7.7%, 10.3%, 6.7% and 5.4% at 1, 2, 3, 4 and 5 years, respectively (p values <0.001). Moreover, the addition of plasminogen activator inhibitor type I increased the predictive accuracy of the postoperative model by 0.5%, 1.1%, 4.0%, 2.4% and 3.6% at 1, 2, 3, 4 and 5 years, respectively (p values <0.001). CONCLUSIONS: Preoperative circulating plasminogen activator inhibitor type I is a predictor of biochemical recurrence, and it enhances the accuracy of preoperative and postoperative nomograms. After external validation these nomograms may assist clinical decision making regarding treatment choice and followup as well as identification of patients at high risk for biochemical recurrence who may benefit from neoadjuvant and/or adjuvant treatment. PMID- 17698119 TI - Methods of lithotripsy in ancient Greece and Byzantium. AB - PURPOSE: In this article we present the medical methods of lithotripsy applied by ancient Greek and Byzantine physicians, and their influence on the development of surgery after that time. MATERIALS AND METHODS: Study and analysis of the original texts of the Byzantine medical writers, written in Greek and containing the knowledge of the ancient Greek, Hellenistic and Roman periods, were performed. RESULTS: The Byzantine method of lithotripsy was the result of the eternal knowledge of the spasmolytic, analgesic and lithotriptic effect of various herbs, together with ancient surgical techniques of stone removal from Hellenistic and Roman periods. No operation was attempted for the extraction of stones from kidneys. Rather the idea was to drop the stones to the bladder or into the urethra, or dilute them into smaller pieces with various herbs. CONCLUSIONS: Ancient Greek and Byzantine physicians described conservative and surgical methods, derived from the texts of early surgeons, to which they added their own observations. PMID- 17698121 TI - Subclassification of clinical stage T1 prostate cancer: impact on biochemical recurrence following radical prostatectomy. AB - PURPOSE: We investigated biochemical outcomes following radical prostatectomy across subclassifications of clinical stage T1 prostate cancer. MATERIAL AND METHODS: Of 8,658 men who underwent radical prostatectomy for clinical stage T1 prostate cancer 85, 156 and 8,417 had clinical stage T1a, T1b and T1c disease, respectively. Age, race, prostate specific antigen, year of surgery and preoperative Gleason scores were compared across clinical stage T1 subcategories. Time to prostate specific antigen recurrence was compared among groups using Kaplan-Meier and Cox hazards modeling. RESULTS: Patients with clinical stage T1a prostate cancer had more favorable postoperative pathological features, including lower prostatectomy Gleason scores (p <0.001), rates of extraprostatic extension (p <0.001), lymph node invasion (p <0.001) and positive surgical margins (p = 0.006). Patients with T1a cancer also showed significantly lower rates of biochemical recurrence on Kaplan-Meier analysis than men with T1b and T1c disease (log rank 0.006). Cox regression analysis adjusted for known predictors of biochemical recurrence demonstrated that clinical tumor stage in the subgroup of patients with T1 disease was not an independent predictor of biochemical recurrence (p = 0.321). CONCLUSIONS: Men with clinical stage T1a prostate cancer who undergo radical prostatectomy have significantly lower biochemical recurrence rates than men with stage T1b or T1c disease. However, subclassification of tumors in this group of patients was not an independent prognostic factor for biochemical recurrence after accounting for preoperative variables, including prostate specific antigen and Gleason score. PMID- 17698122 TI - Percutaneous core biopsy for renal masses: indications, accuracy and results. AB - PURPOSE: We evaluated the results, accuracy and clinical incidence of our standard procedure of percutaneous biopsy for solid renal masses. MATERIALS AND METHODS: From March 1999 to April 2005, 119 percutaneous core biopsies of renal masses were performed. Biopsies were proposed when there was no formal evidence for a carcinoma diagnosis on computerized tomography. RESULTS: Benign lesions were diagnosed in 24 biopsies (20.1%), including oncocytoma in 13, angiomyolipoma in 5 and chronic pyelonephritis in 5. Malignancy was identified in 70 biopsies (58.8%), including 57 renal carcinomas (conventional renal cell in 41, papillary in 12 and chromophobe in 4), 4 transitional cell carcinomas, 8 metastases and 1 lymphoma. For 25 biopsies (21%) no accurate diagnosis was possible, including 12 that showed inflammatory tissue and 13 with normal or necrotic tissue. These inconclusive biopsies prompted repeat biopsy in 13 patients, in whom a total of 11 malignant lesions were diagnosed. A total of 64 nephrectomies were performed with a biopsy accuracy for histopathological tumor type and Fuhrman nuclear grade of 86% and 46%, respectively. A period of watchful waiting was proposed for 31 patients (34.2%) and no renal malignancies were found. Computerized tomography showed stabilization or disappearance of the initial renal mass. CONCLUSIONS: Percutaneous renal tumor biopsies are safe, cost-effective and often conclusive for an acute histological diagnosis. This procedure could be decisive for choosing the optimal treatment, particularly to avoid nephrectomy for benign lesions. Biopsies should not be considered a routine procedure but they could be indicated when there is a lack of radiological evidence in elective patients. PMID- 17698123 TI - Biocompatibility assessment of synthetic sling materials for female stress urinary incontinence. AB - PURPOSE: We evaluated the performance and complications of currently available synthetic sling materials with a focus on in vitro and in vivo biocompatibility, and acceptance in the human body. MATERIALS AND METHODS: We reviewed the MEDLINE database for relevant literature pertaining to various synthetic sling materials. The Food and Drug Administration regulations regarding the regulation and biocompatibility testing of synthetic meshes were also reviewed. RESULTS: Many synthetic meshes used for sling construction were introduced before rigorous Food and Drug Administration regulations were passed and, thus, some became associated with unique complications. Most meshes used in pubovaginal and mid urethral sling surgery are associated with high short-term success rates and relatively few intraoperative complications. Despite modifications and additives, slings constructed from polytetrafluoroethylene and polyethylene are poorly accepted by the human body. Flexible, macroporous, polypropylene meshes appear to integrate more completely with human tissue than other synthetic materials. However, multifilament and nonknitted polypropylene slings may integrate poorly. CONCLUSIONS: The composition, weave and pore size of each material are unique. These properties are responsible for the strength and durability of the material, as well as the ultimate acceptance and incorporation in the human body. Each material should be individually evaluated and patients should be counseled appropriately before implantation. PMID- 17698124 TI - The practice of medicine--a business or a profession? PMID- 17698125 TI - Patient identification error among prostate needle core biopsy specimens--are we ready for a DNA time-out? AB - PURPOSE: Patient identification errors in surgical pathology often involve switches of prostate or breast needle core biopsy specimens among patients. We assessed strategies for decreasing the occurrence of these uncommon and yet potentially catastrophic events. MATERIALS AND METHODS: Root cause analyses were performed following 3 cases of patient identification error involving prostate needle core biopsy specimens. RESULTS: Patient identification errors in surgical pathology result from slips and lapses of automatic human action that may occur at numerous steps during pre-laboratory, laboratory and post-laboratory work flow processes. CONCLUSIONS: Patient identification errors among prostate needle biopsies may be difficult to entirely prevent through the optimization of work flow processes. A DNA time-out, whereby DNA polymorphic microsatellite analysis is used to confirm patient identification before radiation therapy or radical surgery, may eliminate patient identification errors among needle biopsies. PMID- 17698126 TI - Shock wave lithotripsy or ureteroscopy for the management of proximal ureteral calculi: an old discussion revisited. AB - PURPOSE: The goal of treating ureteral calculi is to achieve complete stone clearance with minimal patient morbidity. Shock wave lithotripsy and ureteroscopy have become standards of care for ureteral calculi. However, the optimal choice of treatment depends on various factors, including stone size, composition and location, clinical patient factors, equipment availability and surgeon capability. Indications for and outcomes data on shock wave lithotripsy and ureteroscopy for proximal ureteral calculi were reviewed to provide recommendations on the optimal treatment choice for managing symptomatic ureteral calculi. MATERIALS AND METHODS: A systematic review was performed based on an English literature search using the MEDLINE database between 1997 and 2005. The key words used were proximal ureteral calculi, ureteroscopy and shock wave lithotripsy. RESULTS: A total of 87 articles were identified, of which 33 were selected for inclusion. Shock wave lithotripsy and ureteroscopy provided an excellent stone-free rate (86% to 90%) for stones less than 10 mm, whereas for larger stones ureteroscopy achieved better outcomes vs shock wave lithotripsy (67% vs 73%). Ureteroscopy was preferred over shock wave lithotripsy in patients with pregnancy or bleeding diathesis. CONCLUSIONS: Ureteroscopy provides optimal stone clearance in patients with proximal ureteral calculi more than 10 mm. It is also recommended in patients with contraindications for shock wave lithotripsy. In patients with smaller stones (less than 10 mm) shock wave lithotripsy may be considered a reasonable alternative with outcomes similar to those of ureteroscopy. PMID- 17698128 TI - Uroplakin III-delta4 messenger RNA as a promising marker to identify nonulcerative interstitial cystitis. AB - PURPOSE: Interstitial cystitis remains a poorly understood urological condition characterized by chronic pelvic pain and increased urinary frequency in the absence of any known etiology. Urothelial dysfunction and other abnormalities are presumed to be involved in the disease. Uroplakins that are expressed by urothelial cells are thought to have an important role as major barrier proteins on the apical surface of the urothelium. MATERIALS AND METHODS: Gene expression of uroplakin Ia, Ib, II, III and III-delta4 was quantitatively measured in bladder biopsy samples from 29 patients with interstitial cystitis and 16 control subjects using real-time reverse transcriptase-polymerase chain reaction. RESULTS: The mRNA levels of the uroplakin Ia, Ib and II genes were relatively low and uroplakin III was relatively high in interstitial cystitis bladders compared to normal controls, although not significantly. Uroplakin III-delta4, a splicing variant of uroplakin III, was significantly up-regulated in interstitial cystitis samples (p <0.001). When patients with interstitial cystitis were divided into those with and without ulcerative changes, the uroplakin III and III-delta4 genes were significantly up-regulated only in patients with nonulcerative interstitial cystitis. Even more interesting was the finding that up-regulation of uroplakin III-delta4 was much more prominent than that of uroplakin III, that is 26.5 vs 5.6-fold compared to the median values of normal subjects. CONCLUSIONS: Although the clinical implications of the over expression of uroplakin III and III-delta4 in nonulcerative interstitial cystitis bladders remains to be clarified, from the diagnostic viewpoint uroplakin III-delta4 is a potential marker for identifying nonulcerative interstitial cystitis. PMID- 17698132 TI - Bladder cancer: improving care with better classification and risk stratification. PMID- 17698131 TI - Predicting unilateral prostate cancer based on biopsy features: implications for focal ablative therapy--results from the SEARCH database. AB - PURPOSE: For men with low risk prostate cancer it was recently proposed that ablative treatment to the affected side may decrease morbidity, while maintaining good oncological outcomes. However, few studies have assessed the correlation between biopsy parameters and pathological outcome (unilateral vs bilateral disease). MATERIALS AND METHODS: Using the Shared Equal Access Regional Cancer Hospital Database of men treated with radical prostatectomy at multiple equal access medical centers we retrospectively examined the records of 261 men with clinical stage T1c or T2a prostate cancer, prostate specific antigen less than 10 ng/ml, Gleason sum 6 or less and only 1 or 2 ipsilateral positive cores on at least sextant biopsy. We compared clinical characteristics between men with pathologically unilateral disease or less (pT2b or less) and men with pathologically bilateral disease or extraprostatic extension (pT2c or greater). To determine the significant predictors of pT2c or greater disease we used a multivariate logistic regression model. RESULTS: Of the cohort of 261 men with low risk prostate cancer only 93 (35.1%) had unilateral or no evidence of disease following examination of radical prostatectomy specimens. Men with pathologically unilateral or less disease did not differ from those with bilateral or more advanced disease by age, prostate specific antigen, clinical stage, body mass index or number of positive biopsy cores (1 vs 2). On multivariate analysis no clinical feature was significantly related to pathologically unilateral or less vs bilateral or greater disease. CONCLUSIONS: The majority of men with low risk prostate cancer and 1 or 2 ipsilateral positive biopsy cores have pathologically bilateral disease. Therefore, strategies for unilateral treatment of prostate cancer are unlikely to be curative for these men. PMID- 17698133 TI - Combined inguinal hernia repair with prosthetic mesh during transperitoneal robot assisted laparoscopic radical prostatectomy: a 4-year experience. AB - PURPOSE: Inguinal hernias are detected in 20% to 30% of patients undergoing radical prostatectomy. We report our experience with concomitant transperitoneal robot assisted laparoscopic radical prostatectomy and intraperitoneal inguinal herniorrhaphy using prosthetic mesh. MATERIALS AND METHODS: A retrospective review was performed of the medical records of 533 consecutive robot assisted laparoscopic radical prostatectomies performed by 1 surgeon from June 2002 to April 2007. All cases that included combined herniorrhaphy were recorded in a prospective database, reviewed and compared against a cohort of patients matched for body mass index and age who underwent robot assisted laparoscopic radical prostatectomy alone. RESULTS: A total of 49 concurrent herniorrhaphy procedures were performed in 40 patients for 31 unilateral (left side in 30 and right side in 19) and 9 bilateral inguinal hernias. Five patients underwent prior ipsilateral inguinal herniorrhaphy, and 3 each underwent contralateral and prior bilateral repair. Preoperatively 15 of 40 patients (37.5%) had a definite inguinal hernia, 5 (12.5%) had noticeable weakness of the external ring and 20 (50%) had a completely normal physical examination. Compared with a matched cohort undergoing robot assisted laparoscopic radical prostatectomy alone there were no significant differences in smoking history, narcotic use, hospital stay or complications. Hernia repair added approximately 10 minutes of operative time. Postoperatively 1 of 49 hernias (2.0%) recurred at 4 months during a median followup of 15.3 months. There were no complications related to hernia repair. CONCLUSIONS: Concurrent repair of inguinal hernias during transperitoneal robot assisted laparoscopic radical prostatectomy using prosthetic mesh is technically feasible and effective, and without increased complications or morbidity. PMID- 17698136 TI - Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. AB - PURPOSE: We determined the testosterone castration level with clinical relevance in patients with prostate cancer on continuous androgen deprivation therapy. Secondary objectives were to analyze the role of associated bicalutamide in breakthrough increases of serum testosterone in these patients and the possible benefit of maximal androgen blockade. MATERIALS AND METHODS: Serum testosterone was determined 3 times (in 6 months) in 73 patients with nonmetastatic prostate cancer treated with medical castration, 28 (38.4%) of whom also received bicalutamide (maximal androgen blockade). During a mean followup of 51 months (range 12 to 240) 41 (67.1%) events of androgen independent progression were identified, and correlated with breakthrough testosterone increases of 50 ng/dl (classic level) and 20 ng/dl (surgical castration level). RESULTS: Testosterone was less than 20 ng/dl in all determinations in 32 patients (43.6%). Breakthrough increases between 20 and 50 ng/dl were observed in 23 patients (31.5%), and increases greater than 50 ng/dl were observed in the remaining 18 (24.7%). The lowest testosterone level with a significant impact on survival free of androgen independent progression was 32 ng/dl. Mean survival free of androgen independent progression in patients with breakthrough increases greater than 32 ng/dl was 88 months (95% CI 55-121) while it was 137 months (95% CI 104-170) in those without breakthrough increases (p <0.03). Patients on maximal androgen blockade had an incidence of testosterone increase similar to those receiving monotherapy. However, maximal androgen blockade provided a significantly longer survival free of androgen independent progression in those with breakthrough increases greater than 50 ng/dl. CONCLUSIONS: In the current report the lowest testosterone castration level with clinical relevance in medically castrated patients with prostate cancer was 32 ng/dl. Breakthrough increases greater than this threshold predicted a lower survival free of androgen independent progression. Maximal androgen blockade might benefit medically castrated cases of prostate cancer with breakthrough increases of more than 50 ng/dl. PMID- 17698141 TI - The significance of positive surgical margin in areas of capsular incision in otherwise organ confined disease at radical prostatectomy. AB - PURPOSE: The significance of capsular incision into tumor at radical prostatectomy with otherwise organ confined tumor is not well understood. MATERIALS AND METHODS: Inclusion criteria were positive margin in an area of capsular incision, no extraprostatic extension elsewhere, negative seminal vesicles and lymph nodes, entire prostate submitted for examination, and no neoadjuvant therapy. RESULTS: The postoperative progression of 135 cases of radical prostatectomy with capsular incision (1.3% of radical prostatectomies 1993 to 2004) was compared to 10,311 radical prostatectomies without capsular incision. Mean tumor length at the capsular incision site was 2.6 mm. Capsular incision was posterolateral (61.5%), posterior (18.5%), anterior (8.9%), lateral (8.1%) and apical (3%). The 5-year actuarial freedom from biochemical recurrence for tumors with capsular incision was worse (71.3%) than organ confined margin negative tumor (96.7%) (p <0.0001) and focal extraprostatic extension margin negative disease (89.7%) (p = 0.02), yet better than extensive extraprostatic extension margin positive tumors (58.5%) (p <0.0001). The risks of progression in men with capsular incision, focal extraprostatic extension margin positive and extensive extraprostatic extension margin negative disease were not significantly different. Risk of recurrence correlated with tumor length at the capsular incision site (p = 0.002). The 5-year risks of biochemical progression were 20.0% and 55% for less than 3 mm and 3 mm or greater of tumor cut across, respectively. CONCLUSIONS: Isolated capsular incision into tumor is uncommon in cases of radical prostatectomy performed by experienced urologists, typically Gleason score 6, and most common in the neurovascular bundle region. Isolated capsular incision has a higher recurrence rate than organ confined or focal extraprostatic extension margin negative disease, yet a lower recurrence rate than extensive extraprostatic extension margin positive tumor, and a worse prognosis with greater extent of capsular incision. PMID- 17698142 TI - Androgen deprivation therapy for prostate cancer. PMID- 17698144 TI - Does preoperative topical antimicrobial scrub reduce positive surgical site culture rates in men undergoing artificial urinary sphincter placement? AB - PURPOSE: We determined if the incidence of a perioperative surgical site-positive culture was reduced by a 5-day topical antimicrobial scrub before implantation of an artificial urinary sphincter. MATERIALS AND METHODS: A single surgeon prospective cohort study was conducted of 100 consecutive artificial urinary sphincter implants placed between May 2003 and November 2005. We compared 50 men who performed preoperative topical antimicrobial scrub with 4% chlorhexidine to the abdominal site and perineal site with 50 men who used their normal hygiene (soap and water). All received povidone-iodine skin disinfection before incision, and bacterial cultures of the abdominal and perineal sites were collected immediately after skin disinfection and after artificial urinary sphincter implantation. Baseline comparisons between groups were done with the Wilcoxon rank sum and Fisher exact tests. Predictors of positive culture were identified using multivariate logistic regression analysis. RESULTS: The causes of incontinence were radical prostatectomy (90), radiation therapy (8) and transurethral resection of the prostate (2). There were no baseline differences between the groups including age, diabetes or previous urethral surgery. Overall 140 of the 400 cultures were positive with only 37% of the positive cultures (52 of 140) observed with topical antimicrobial scrub. For the perineal site the only factor affecting preoperative culture status was topical antimicrobial scrub (OR 0.23, p = 0.003). A positive postoperative culture was predicted by a positive preoperative perineal (OR 4.61, p = 0.003) and abdominal culture (OR 3.80, p = 0.013). CONCLUSIONS: Preoperative topical antimicrobial scrub resulted in a 4 fold reduction in preoperative perineal colonization rate and overall reduction in positive surgical site cultures. Given the low cost, safety and efficacy, topical antimicrobial scrub should be considered before artificial urinary sphincter placement. PMID- 17698145 TI - Oncological and functional outcome of radical cystectomy in patients with bladder cancer and obstructive uropathy. AB - PURPOSE: We present our experience with the perioperative, functional and oncological outcomes of radical cystectomy in patients with bladder cancer and obstructive uremia. MATERIALS AND METHODS: From 1998 to June 2006, 58 patients with bladder cancer, and concomitant obstructive uropathy and azotemia presented to our institution. Mean +/- SD serum creatinine at presentation was 9.2 +/- 4.5 mg% (range 2.4 to 16.5). Radical cystectomy, bilateral pelvic lymphadenectomy and urinary diversion were performed after stabilizing renal function with and without percutaneous nephrostomy in 28 and 8 patients, respectively. Various preoperative variables were evaluated for predicting long-term treatment failure and renal deterioration. Mean followup was 34 months. RESULTS: Mean serum creatinine at surgery was 1.85 mg%. An ileal conduit was used in 32 patients and cutaneous ureterostomy was used in 4. One patient died of chest infection in the perioperative period. All patients had muscle invasive disease, while 15 had positive lymph nodes. At the mean followup 15 patients (41.6%) were free of disease and 21 had treatment failure. Of the factors evaluated pathological tumor stage, grade and lymph node involvement predicted the long-term oncological outcome, while serum creatinine greater than 2.5 mg% at surgery and ileal conduit diversion predicted long-term renal deterioration. CONCLUSIONS: Patients with bladder cancer who have obstructive uremia usually present with locally advanced disease. Radical cystectomy is not associated with additional morbidity, provided that patients are adequately prepared before surgery by optimizing renal function. An adequate number of these patients achieve long-term disease-free survival after radical cystectomy. As the urinary diversion of choice, an ileal conduit appears to be safe in patients with serum creatinine less than 2.5 mg% at surgery. PMID- 17698147 TI - Impact of the extent of regional lymphadenectomy on the survival of patients with urothelial carcinoma of the upper urinary tract. AB - PURPOSE: We determined the impact of the extent of regional lymphadenectomy on survival in patients with urothelial carcinoma of the upper urinary tract. MATERIALS AND METHODS: Between January 1989 and January 2006, 169 patients with nonmetastatic urothelial carcinoma of the upper urinary tract underwent curative surgery. We previously reported the primary sites of nodal metastases in urothelial carcinoma of the upper urinary tract. Nodal sites where the incidence of metastases was 30% or more were considered regional lymph nodes. When all primary sites were resected, this was considered complete lymphadenectomy. Regional lymphadenectomy without the removal of all primary sites was considered incomplete lymphadenectomy. We retrospectively analyzed the influence of the extent of lymphadenectomy on patient survival. RESULTS: A total of 45 patients (26.6%) underwent complete lymphadenectomy. Lymphadenectomy was performed in an additional 36 patients (21.3%) but it was incomplete. Lymphadenectomy was not performed in 88 patients. Cancer specific survival did not significantly differ between the groups when all patients were analyzed. However, patient survival significantly depended on the extent of lymphadenectomy when we focused on patients with T stage pT3 or higher. Patient survival was likely to improve when the number of lymph nodes removed increased. Multivariate analysis showed that complete lymphadenectomy was a significant prognostic factor for cancer specific survival (p = 0.009) as well as T stage (pT3 or less p = 0.0004) and tumor grade (G3 p = 0.0001). CONCLUSIONS: Although further investigation is required to make a definite conclusion, the extent of lymphadenectomy may significantly influence its therapeutic effect, especially for patients with advanced disease. PMID- 17698148 TI - Effects of resveratrol on glycerol-induced renal injury. AB - Glycerol-induced renal lesions can have many causes, including increased oxidative stress and inflammation. Resveratrol, a polyphenolic phytoalexin found in grapes and red wine, is an antioxidant agent with anti-inflammatory effects. In the present study, we investigated the possible protective effect of resveratrol on glycerol-induced nephrotoxicity. Male Wistar rats were injected intramuscularly with 8 ml/kg of either 50% glycerol (n=18), glycerol+resveratrol (n=22), 0.15 M saline (n=14), saline+carboxymethylcellulose (n=10) or saline+resveratrol (n=8). The rats were killed 3 days after the injections, at which time the kidneys were removed for histological and immunohistochemical studies and lipid peroxidation determination. Blood and urine samples were collected in order to quantify sodium and creatinine. The results of the histological and immunohistochemical studies were scored according to the extent of damage and immunostaining, respectively, in the cortical tubulointerstitium. Lipid peroxidation was estimated by measuring malondialdehyde in renal tissue samples collected from control rats and glycerol-injected rats. By postinjection day 3, glycerol-only treated rats presented increases in plasma creatinine levels, as well as in fractional excretion of sodium and potassium (P<0.001). These increases were less pronounced in glycerol+resveratrol-treated rats (P<0.05). Cortical expression of macrophages, lymphocytes, nuclear factor-kappa B, heme oxygenase-1 and nitrotyrosine was greater in glycerol-treated rats than in controls (P<0.001). In addition, the histological findings for glycerol treated rats were characteristic of acute tubular necrosis. Resveratrol attenuated all of these alterations (P<0.001). We conclude that resveratrol ameliorates glycerol-induced renal injury by suppressing the inflammatory process and by inhibiting lipid peroxidation. PMID- 17698149 TI - Characterisation of three pathways for osmolyte efflux in human erythroleukemia cells. AB - Cell volume decrease is a key step during differentiation of erythroid cells. This could arise from membrane transporter activation leading to a loss of cell osmolytes; however, the pathways involved are poorly understood. We have characterised Cl(-)-independent K(+) and (3)H-taurine efflux from the erythroleukemia cell line, K562. K(+) efflux (measured using (86)Rb(+)) from pre loaded cells subjected to hypo-osmotic challenge demonstrated two phases, a rapid increase in K(+) efflux followed by a smaller slower increase. Swelling-activated taurine efflux only demonstrated a single phase. Both phases of K(+) efflux were significantly (P<0.05) blocked by anion channel inhibitor 5-nitro-2-(3 phenypropylamino)-benzoic acid (NPPB). However the antiestrogen, tamoxifen, only inhibited the slow late phase. The initial rapid phase had a higher IC(50) for NPPB inhibition than the slow phase, and was insensitive to protein kinases inhibitors KN-62, wortmannin and PD98059. For the slow K(+) efflux phase, the IC(50) for NPPB inhibition and the inhibition by KN-62, wortmannin, genistein or PD98059, were very similar to those measured for the hypo-osmotically-activated taurine efflux. With NPPB (100 microM) present, the slow K(+) efflux phase was further significantly decreased by the Ca(2+) chelator BAPTA-AM or by the Ca(2+) activated K(+) channel blockers clotrimazole and charybdotoxin but not by apamin. Thus, at least 3 Cl(-)-independent pathways are involved: (a) a tamoxifen sensitive and taurine-permeable anion channel; (b) a tamoxifen-insensitive and taurine-impermeable K(+) efflux pathway; and (c) a subtype of Ca(2+)-activated K(+) channel. Any or all of these could be involved in the cell volume decrease associated with differentiation in K562 cells. PMID- 17698150 TI - The protective effect of ApolipoproteinA-I on myocardial ischemia-reperfusion injury in rats. AB - It is well established that reperfusion of heart is the optimal method for salvaging ischemic myocardium, however, the success of this therapy could be limited by reperfusion injury, which is involved in inflammatory responses. High density lipoprotein (HDL) has an anti-inflammatory function and can protect the heart from ischemia-reperfusion (I/R) injury. In this study, we investigated the cardioprotective role of apolipoprotein A-I (ApoA-I), the major apolipoprotein of HDL, in I/R injury. Using rats subjected to myocardial I/R by ligation of left anterior descending coronary artery (LAD), we found that administration of ApoA-I (20 mg/kg, iv) before the onset of reperfusion of myocardial infarction can significantly reduce serum creatine kinase (CK) levels (62.1+/-13.8%, p<0.01) and heart TNF-alpha as well as IL-6 levels, compared with saline controls (40.4+/ 14.7%, 44+/-9.8%, p<0.01 respectively). Moreover, ApoA-I treatment suppresses the expression of ICAM-1 on endothelium, thus diminishing neutrophil adherence, transendothelial migration, and the subsequent myocyte injury. We concluded that ApoA-I could effectively protect rat heart from I/R injury. PMID- 17698151 TI - Contribution of endogenous glycine and d-serine to excitotoxic and ischemic cell death in rat cerebrocortical slice cultures. AB - N-methyl-D-aspartate (NMDA) receptors, whose activation requires glycine site stimulation, play crucial roles in various physiological and pathological conditions in the brain. We investigated the regulatory roles of potential endogenous glycine site agonists, glycine and d-serine, in excitotoxic and ischemic cell death in the cerebral cortex. Cytotoxicity of NMDA on rat cerebrocortical slice cultures was potentiated by addition of glycine or d serine. In contrast, cell death induced by oxygen/glucose deprivation (OGD) was not affected by exogenous glycine or d-serine, although blockade of NMDA receptors by MK-801 abolished cell death. In addition, higher concentrations of 2,7-dichlorokynurenic acid (DCKA), a competitive glycine site antagonist, were required to suppress OGD-induced cell death than those to suppress NMDA cytotoxicity. We also found that OGD triggered a robust increase in extracellular glycine. A glycine transporter blocker ALX 5407 increased the extracellular level of glycine, and the protective effect of DCKA against NMDA cytotoxicity was diminished in the presence of ALX 5407. Sensitivity of NMDA cytotoxicity to DCKA was also diminished by l-serine that increased the extracellular level of d serine. These results indicate that both glycine and d-serine can act as endogenous ligands for NMDA receptor glycine site in the cerebral cortex, and that endogenous glycine may saturate the glycine site under ischemic conditions. The present findings are important for the interpretation of the mechanisms of NMDA and OGD cytotoxicity. PMID- 17698152 TI - Application of biotic indices and relationship with structural and functional features of macrobenthic community in the lagoon of Venice: an example over a long time series of data. AB - In the context of the application of WFD, a scientific debate is growing about the applicability of biotic indices in coastal and transitional waters. In the present work, the question about the discriminating power of different biotic indices and the relationships with the structure and functioning of the macrobenthic community in a transitional environment is discussed. A time series of samples collected during the last 70 years in the lagoon of Venice, reflecting different environmental conditions (a sort of 'pristine state' in 1935, the distrophic crisis in 1988 and subsequent modifications in 1990, the invasion by an alien species and the developing of high impacting fishery in 1999) has been used. The comparison of results obtained by applying different biotic indices, such as AMBI, Bentix and BOPA, shows differences in the discriminating power of indices and a general overestimation of environmental conditions. Discrepancies between environmental status as indicated by biotic indices and the structure and functioning of the benthic community have been highlighted. PMID- 17698153 TI - The effects of JWB1-84-1 on memory-related task performance by amyloid Abeta transgenic mice and by young and aged monkeys. AB - JWB1-84-1 is one of 50 tertiary amine analogs of choline synthesized with expectation that they would be high potency compounds for cytoprotection. As one of the more potent analogs in this regard, JWB1-84-1, a piperazine derivative, was selected for testing as a cognition-enhancing agent. The compound was evaluated for efficacy in Alzheimer's disease transgenic mice (B6C3-Tg(APPswe, PSEN1dE9)85Dbo/J). A separate cohort of mice (AD Tg) were first subjected to a behavioral test battery in which the transgenic strain was compared with the wild type strain. AD Tg mice were shown to exhibit specific deficits in the acquisition of a working memory (5-trial/session radial arm water maze, RAWM) task at a time when the animals exhibited maximal cerebral amyloid burden. JWB1 84-1 produced a dose-dependent decrease in the number of errors made by well trained AD-Tg mice the RAWM task that was maximal after the 20 microg/kg dose. Aged macaques (20-32 y) were trained to proficiency in their performance of a computer-assisted delayed matching-to-sample task. Vehicle (normal saline) or JWB1-84-1 (5-150 microg/kg, i.m.) was administered 10 min before the initiating of testing. On average, JWB1-84-1 treatment significantly improved task accuracy after all but the lowest dose. The maximal degree of improvement was attained after animals received the 100 microg/kg dose. The drug's effects were restricted primarily to Medium and Long delay trials - the most difficult portions of the task, which were improved by up to 18% above control. In young macaques JWB1-84-1 treatment also significantly reversed the decrements in task accuracy associated with the random presentation of a task distractor. Thus JWB1-84-1exhibits the potential for treating the cognitive symptoms associated with neurodegenerative diseases and attention deficit disorders. Its cytoprotective action might also work to slow the progression of Alzheimer's disease. PMID- 17698154 TI - Characterization of the folate salvage enzyme p-aminobenzoylglutamate hydrolase in plants. AB - Folates break down in vivo to give pterin and p-aminobenzoylglutamate (pABAGlu) fragments, the latter usually having a polyglutamyl tail. Pilot studies have shown that plants can hydrolyze pABAGlu and its polyglutamates to p aminobenzoate, a folate biosynthesis precursor. The enzymatic basis of this hydrolysis was further investigated. pABAGlu hydrolase activity was found in all species and organs tested; activity levels implied that the proteins responsible are very rare. The activity was located in cytosol/vacuole and mitochondrial fractions of pea (Pisum sativum L.) leaves, and column chromatography of the activity from Arabidopsis tissues indicated at least three peaks. A major activity peak from Arabidopsis roots was purified 86-fold by a three-column procedure; activity loss during purification exceeded 95%. Size exclusion chromatography gave a molecular mass of approximately 200 kDa. Partially purified preparations showed a pH optimum near 7.5, a Km value for pABAGlu of 370 microM, and activity against folic acid. Activity was relatively insensitive to thiol and serine reagents, but was strongly inhibited by 8-hydroxyquinoline-5-sulfonic acid and stimulated by Mn2+, pointing to a metalloenzyme. The Arabidopsis genome was searched for proteins similar to Pseudomonas carboxypeptidase G, which contains zinc and is the only enzyme yet confirmed to attack pABAGlu. The sole significant matches were auxin conjugate hydrolase family members and the At4g17830 protein. None was found to have significant pABAGlu hydrolase activity, suggesting that this activity resides in hitherto unrecognized enzymes. The finding that Arabidopsis has folate-hydrolyzing activity points to an enzymatic component of folate degradation in plants. PMID- 17698155 TI - Genetic characterization of porcine circovirus type 2 in Republic of Korea. AB - Porcine circovirus type 2 (PCV2) is a major causative agent of postweaning multisystemic wasting syndrome (PMWS). Sequence and phylogenetic analyses based on the ORF2 capsid protein gene fragment showed that field isolate in Republic of Korea (ROK), PCV2 YJK 0703, was closely related with the PCV2 Fh18 isolate. PCV2 YJK 0703 was genetically distinct and not related to previously reported ROK isolates. Therefore, genotypic variation exists among prevailing PCV2 in ROK. This result suggests that several PCV2 genotypes exist in Korean pig farms. PMID- 17698156 TI - Three new steroids from the roots of Serratula wolffii. AB - Investigation of the methanol extract of the roots of Serratula wolffii resulted in an ecdysone-related compound, 2beta,3beta,20R,22R,25-pentahydroxy-5beta cholest-6,8(14)-dien (1), a new ecdysteroid, 24-methylene-shidasterone (2), the known compound stachysterone B (3) and its 14,15-alpha-epoxide (4), a novel natural product. The structures of compounds 1-4 were established by spectral analysis ((1)H NMR, (13)C NMR, COSY, NOESY, HMQC, HMQC-TOCSY and HMBC). PMID- 17698157 TI - Development of a physiologically based pharmacokinetic model for bisphenol A in pregnant mice. AB - Bisphenol A (BPA) is a weakly estrogenic monomer used to produce polymers for food contact and other applications, so there is potential for oral exposure of humans to trace amounts via ingestion. To date, no physiologically based pharmacokinetic (PBPK) model has been located for BPA in pregnant mice with or without fetuses. An estimate by a mathematical model is essential since information on humans is difficult to obtain experimentally. The PBPK model was constructed based on the pharmacokinetic data of our experiment following single oral administration of BPA to pregnant mice. The risk assessment of bisphenol A (BPA) on the development of human offspring is an important issue. There have been limited data on the exposure level of human fetuses to BPA (e.g. BPA concentration in cord blood) and no information is available on the pharmacokinetics of BPA in humans with or without fetuses. In the present study, we developed a physiologically based pharmacokinetic (PBPK) model describing the pharmacokinetics of BPA in a pregnant mouse with the prospect of future extrapolation to humans. The PBPK model was constructed based on the pharmacokinetic data of an experiment we executed on pregnant mice following single oral administration of BPA. The model could describe the rapid transfer of BPA through the placenta to the fetus and the slow disappearance from fetuses. The simulated time courses after three-time repeated oral administrations of BPA by the constructed model fitted well with the experimental data, and the simulation for the 10 times lower dose was also consistent with the experiment. This suggested that the PBPK model for BPA in pregnant mice was successfully verified and is highly promising for extrapolation to humans who are expected to be exposed more chronically to lower doses. PMID- 17698158 TI - Isolation and characterization of bacteria from the copepod Pseudocaligus fugu ectoparasitic on the panther puffer Takifugu pardalis with the emphasis on TTX. AB - A total of 50 bacterial isolates was obtained from the copepod Pseudocaligus fugu, which is a common parasite, collected from the body surface of the panther puffer Takifugu pardalis. On the basis of colony characteristics, these bacterial isolates were grouped into six types, of which only two (Types-I and -II) showed a high affinity for adhesion to the carapace of the banana shrimp Penaeus merguiensis. These two types of adhesive bacteria were identified through 16S rRNA sequence analysis as Shewanella woodyi (Type-I) and Roseobacter sp. (Type II). Representative isolates of these two adhesive bacteria were examined for tetrodotoxin (TTX) production by high-performance liquid chromatography (HPLC) fluorometric system, gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). It was rather unexpectedly revealed that TTX and anhydroTTX were present in the supernatant of culture of the Type-II isolate Roseobacter sp. PMID- 17698159 TI - Arenavirus entry occurs through a cholesterol-dependent, non-caveolar, clathrin mediated endocytic mechanism. AB - Arenaviruses are important causes of viral hemorrhagic fevers in humans. Arenavirus infection of cells occurs via a pH-dependent endocytic route, but detailed studies of entry pathways have not been done. We investigated the role of cell membrane cholesterol, caveolae, and clathrin coated pits in infection by Lassa virus (LASV), which utilizes alpha-dystroglycan (alpha-DG) as a receptor, and Pichinde virus (PICV), which does not. Depletion of cellular cholesterol by treatment with methyl betacyclodextrin (MbetaCD) or nystatin/progesterone inhibited PICV replication and transfer of packaged marker gene by LASV or PICV pseudotyped retroviral particles. In cells lacking caveolae due to silencing of the caveolin-1 gene, no inhibition of PICV infection or LASV pseudotype transduction was observed. However, PICV infection and LASV and PICV pseudotype transduction was inhibited when an Eps15 dominant negative mutant was used to inhibit clathrin-mediated endocytosis. Altogether, the results indicate that diverse arenaviruses have a common requirement for cell membrane cholesterol and clathrin mediated endocytosis in establishing infection. PMID- 17698160 TI - GM-CSF DNA: an adjuvant for higher avidity IgG, rectal IgA, and increased protection against the acute phase of a SHIV-89.6P challenge by a DNA/MVA immunodeficiency virus vaccine. AB - Single intradermal or intramuscular inoculations of GM-CSF DNA with the DNA prime for a simian-human immunodeficiency virus (SHIV)-89.6 vaccine, which consists of DNA priming followed by modified vaccinia Ankara (MVA) boosting, increased protection of both the blood and intestines against the acute phase of an intrarectal SHIV-89.6P challenge. GM-CSF appeared to contribute to protection by enhancing two antibody responses: the avidity maturation of anti-Env IgG in blood (p=or<0.01) and the presence of long lasting anti-viral IgA in rectal secretions (p<0.01). The avidity of anti-Env IgG showed strong correlations with protection both pre and post challenge. Animals with the highest avidity anti-Env Ab had 1000-fold reductions in peak viremia over those with the lowest avidity anti-Env Ab. The enhanced IgA response was associated with the best protection, but did not achieve significance. PMID- 17698161 TI - Analysis of the selective advantage conferred by a C-E1 fusion protein synthesized by rubella virus DI RNAs. AB - During serial passaging of rubella virus (RUB) in cell culture, the dominant species of defective-interfering RNA (DI) generated contains an in-frame deletion between the capsid protein (C) gene and E1 glycoprotein gene resulting in production of a C-E1 fusion protein that is necessary for the maintenance of the DI [Tzeng, W.P., Frey, T.K. (2006). C-E1 fusion protein synthesized by rubella virus DI RNAs maintained during serial passage. Virology 356 198-207.]. A BHK cell line stably expressing the RUB structural proteins was established which was used to package DIs into virus particles following transfection with in vitro transcripts from DI infectious cDNA constructs. Packaging of a DI encoding an in frame C-GFP-E1 reporter fusion protein corresponding to the C-E1 fusion protein expressed in a native DI was only marginally more efficient than packaging of a DI encoding GFP, indicating that the C-E1 fusion protein did not function by enhancing packaging. However, infection with the DI encoding the C-GFP-E1 fusion protein (in the absence of wt RUB helper virus) resulted in formation of clusters of GFP-positive cells and the percentage of GFP-positive cells in the culture following infection remained relatively constant. In contrast, a DI encoding GFP did not form GFP-positive clusters and the percentage of GFP-positive cells declined by roughly half from 2 to 4 days post-infection. Cluster formation and sustaining the percentage of infected (GFP-positive) cells required the C part of the fusion protein, including the downstream but not the upstream of two arginine clusters (both of which are associated with RNA binding and association with mitochondrial p32 protein) and the E1 part through the transmembrane sequence, but not the C-terminal cytoplasmic tail. Among a collection of mutant DI constructs, cluster formation and sustaining infected cell percentage correlated with maintenance during serial passage with wt RUB. We hypothesize that cluster formation and sustaining infected cell percentage increase the likelihood of co infection by a DI and wt RUB during serial passage thus enhancing maintenance of the DI. Cluster formation and sustaining infected cell percentage were found to be due to a combination of attenuated cytopathogenicity of DIs that express the C E1 fusion protein and cell-to-cell movement of the DI. In infected cells, the C GFP-E1 fusion protein was localized to potentially novel vesicular structures that appear to originate from ER-Golgi transport vacuoles. This species of DI expressing a C-E1 fusion protein that exhibits attenuated cytopathogenicity and the ability to increase the number of infected cells through cell-to-cell movement could be the basis for development of an attractive vaccine vector. PMID- 17698162 TI - The "pressure pan" evolution of human erythrovirus B19 in the Amazon, Brazil. AB - To understand the evolutionary dynamics of human parvovirus B19, we analyzed VP1 and VP2 gene sequences of B19 sampled from Belem (Amazon), the city of Sao Paulo, Brazil and globally. Our analysis revealed a strikingly different pattern of evolutionary change for those viral lineages introduced into Belem, which exhibited a higher rate of nonsynonymous substitutions compared to those viruses sampled from other locations. We propose that difference this is due to the high prevalence of B19 in Belem (up to 85%) compared to other locations (prevalences of approximately 50%), which imposes a more intense selection pressure. Hence, those B19 lineages introduced into Belem experienced an elevated rate of amino acid change, driven by positive selection, in order to generate serial re infections in a small web of transmission, which can be thought of as an evolutionary "pressure pan". PMID- 17698163 TI - Solving da Vinci stereopsis with depth-edge-selective V2 cells. AB - We propose a new model for da Vinci stereopsis based on a coarse-to-fine disparity energy computation in V1 and disparity-boundary-selective units in V2. Unlike previous work, our model contains only binocular cells, relies on distributed representations of disparity, and has a simple V1-to-V2 feedforward structure. We demonstrate with random-dot stereograms that the V2 stage of our model is able to determine the location and the eye-of-origin of monocularly occluded regions, and improve disparity map computation. We also examine a few related issues. First, we argue that since monocular regions are binocularly defined, they cannot generally be detected by monocular cells. Second, we show that our coarse-to-fine V1 model for conventional stereopsis explains double matching in Panum's limiting case. This provides computational support to the notion that the perceived depth of a monocular bar next to a binocular rectangle may not be da Vinci stereopsis per se [Gillam, B., Cook, M., & Blackburn, S. (2003). Monocular discs in the occlusion zones of binocular surfaces do not have quantitative depth--a comparison with Panum's limiting case. Perception 32, 1009 1019.]. Third, we demonstrate that some stimuli previously deemed invalid have simple, valid geometric interpretations. Our work suggests that studies of da Vinci stereopsis should focus on stimuli more general than the bar-and-rectangle type and that disparity-boundary-selective V2 cells may provide a simple physiological mechanism for da Vinci stereopsis. PMID- 17698164 TI - Ozonation combined with electrolysis of 1,4-dioxane using a two-compartment electrolytic flow cell with solid electrolyte. AB - Ozonation combined with electrolysis (ozone-electrolysis) is a new advanced oxidation process for water treatment. The advantages of ozone-electrolysis are (1) that reagents such as hydrogen peroxide or ferrous salts are unnecessary, (2) there is less influence from chromaticity, and (3) electric power is only required for operation. However, electrolysis has a serious limitation, in that it requires electrical conductivity (EC). This research is aimed at developing an ozone-electrolysis reactor that is applicable to wastewater with low EC using a cation exchange membrane as solid electrolyte. Moreover, experimental evidence of hydroxyl radical (.OH) generation via the cathodic reduction of ozone was obtained. Competitive kinetics analysis, based on the experimental data from the ozone-electrolysis of a mixed solution of 1,4-dioxane and tert-butyl alcohol, revealed that .OH contributed to 1,4-dioxane degradation. The ozone-electrolysis reactor was successfully applicable to degradation of 1,4-dioxane in both 1,4 dioxane solution (EC: less than 0.30 microS/cm) and a landfill leachate treated by a low-pressure reverse osmosis membrane (EC: 0.06 mS/cm). The use of a solid electrolyte was also very effective in reducing the electric power required for electrolysis. PMID- 17698165 TI - Formation, release and control of dioxins in cement kilns. AB - Co-processing of hazardous wastes in cement kilns have for decades been thought to cause increased emissions of PCDD/PCDFs--a perception that has been evaluated in this study. Hundreds of PCDD/PCDF measurements conducted by the cement industry and others in the last few years, on emissions and solid materials, as well as recent test burns with hazardous wastes in developing countries do not support this perception. Newer data has been compared with older literature data and shows in particular that many emission factors have to be reconsidered. Early emission factors for cement kilns co-processing hazardous waste, which are still used in inventories, are shown to be too high compared with actual measurements. Less than 10 years ago it was believed that the cement industry was the main contributor of PCDD/PCDFs to air; data collected in this study indicates however that the industry contributes with less than 1% of total emissions to air. The Stockholm Convention on POPs presently ratified by 144 parties, classifies cement kilns co-processing hazardous waste as a source category having the potential for comparatively high formation and release of PCDD/PCDFs. This classification is based on early investigations from the 1980s and 1990s where kilns co-processing hazardous waste had higher emissions compared to those that did not burn hazardous waste. However, the testing of these kilns was often done under worst case scenario conditions known to favour PCDD/PCDF formation. More than 2000 PCDD/PCDF cement kiln measurements have been evaluated in this study, representing most production technologies and waste feeding scenarios. They generally indicate that most modern cement kilns co-processing waste today can meet an emission level of 0.1ngI-TEQ/m(3), when well managed and operated. In these cases, proper and responsible use of waste including organic hazardous waste to replace parts of the fossil fuel does not seem to increase formation of PCDD/PCDFs. Modern preheater/precalciner kilns generally seems to have lower emissions than older wet-process cement kilns. It seems that the main factors stimulating formation of PCDD/PCDFs is the availability of organics in the raw material and the temperature of the air pollution control device. Feeding of materials containing elevated concentrations of organics as part of raw-material mix should therefore be avoided and the exhaust gases should be cooled down quickly in long wet and long dry cement kilns without preheating. PCDD/PCDFs could be detected in all types of solid samples analysed: raw meal, pellets and slurry; alternative raw materials as sand, chalk and different ashes; cement kiln dust, clinker and cement. The concentrations are however generally low, similar to soil and sediment. PMID- 17698166 TI - Polyfluorinated chemicals in a spatially and temporally integrated food web in the Western Arctic. AB - This study reports on an investigation of the presence of polyfluorinated chemicals in a spatially and temporally integrated set of biological samples representing an Arctic food web. Zooplankton, Arctic cod, and seal tissues from the western Canadian Arctic were analyzed for perfluoroalkyl sulfonates [PFAS], perfluorocarboxylates [PFCAs], and other polyfluorinated acids. Perfluorooctane sulfonate [PFOS] was found in all samples [0.20-34 ng/g] and in the highest concentrations. PFCAs from nine to 12 carbons were quantified in most of the samples [0.28-6.9 ng/g]. PFCAs with carbon chain lengths of eight or less were not detected. Likewise, 8-2 fluorotelomer acid [8-2 FTA] and 8-2 fluorotelomer unsaturated acid [8-2 FTUA], products of fluorotelomer environmental transformation, were not detected. 2H,2H,3H,3H, heptadecafluoro decanoic acid [7 3 Acid], an additional metabolite from fluorotelomer biological transformation, was detected only in seal liver tissue [0.5-2.5 ng/g]. The ratios of branched to linear PFOS isomers in fish and seal tissue were not similar and did not match that of technical PFOS as manufactured. No branched PFCA isomers were detected in any samples. It is concluded that differing pharmacokinetics complicate the use of branched to linear ratios of PFCAs in attributing their presence to a specific manufacturing process. A statistical analysis of the data revealed significant correlations between PFOS and the PFCAs detected as well as among the PFCAs themselves. The 7-3 Acid was not correlated with either PFCAs or PFAS, which suggests that it may have a different exposure pathway. PMID- 17698167 TI - Photocatalytic oxidation of organic pollutants on titania-clay composites. AB - TiO2/Ca-montmorillonite composites were prepared by wet grinding in an agate mill. Positively charged TiO2 nanoparticles are bound to the surface of the negatively charged montmorillonite layers via heterocoagulation; the clay mineral is used as adsorbent and support for the photooxidation process. Aquatic solution of 0.5mM phenol was degraded by irradiation with UV-VIS light (lambda=250-440 and 540-590 nm) in suspensions of TiO2-clay composites and significant photodegradation was observed at 40-60% TiO2/Ca-montmorillonite compositions. Synergistic effect was detected at solid/liquid interface for degradation of phenol and at solid/gas interface in the recycling flow reactors for photooxidation of ethanol and toluene vapors. PMID- 17698168 TI - Developmental exposure to decabromodiphenyl ether (PBDE 209): effects on thyroid hormone and hepatic enzyme activity in male mouse offspring. AB - Decabrominated diphenyl ether (PBDE 209) is the second most used brominated flame retardant (BFRs). Many studies have shown that some of the BFRs act as endocrine disruptors via alterations in thyroid hormone homeostasis and affect development. Little is known about the effect of prenatal exposure to PBDE 209 on the development in male offspring. Using a CD-1 mouse model, we attempt to estimate the possible effect of in utero exposure to PBDE 209 on thyroid hormone and hepatic enzymes activities in male offspring. Pregnant mice were administered different doses of PBDE 209 (10, 500, and 1500 mg/kg/day) or corn oil for controls per gavage from gestational days 0-17. In adult male offspring whose mothers had been treated with 1500 mg/kg of PBD 209, hepatic enzyme activity of S9 7-ethoxyresorufin O-deethylase (EROD) was weak but significantly increased (54%). However, no significant changes were observed in S9 4-nitrophenol uridinediphosphate-glucuronosyltransferase (UDPGT) in any of the treatment groups. Serum triiodothyronine (T3) was found to have decreased significantly (ca. 21% both 10 mg/kg and 1500 mg/kg) in offspring, but not thyroxine (T4). Histopathological examination revealed that prenatal exposure of PBDE 209 might be related with cell swelling of hepatocytes in male offspring and there were mild changes in the thyroid glands in 1500 mg/kg group. These data demonstrate that PBDE 209 is likely an endocrine disrupter in male mice following exposure during development. Further studies using environmentally relevant doses are needed for hazard identification. PMID- 17698169 TI - Chemical characteristics and mutagenic activity of PM10 in Torino, a northern Italian city. AB - Epidemiological studies of particulate matter (PM) have associated PM mass, as well as certain individual components of PM such as secondary particulate with adverse human health effects. For example genotoxic effects attributed to PM may relate to the content of organic compounds but also to the oxidative DNA damage generated by transition metals like iron. However the exact physiochemical mechanism by which PM produces adverse effects is not clear. The aims of this study were to evaluate (1) concentrations of PM10, (2) amounts of bioavailable iron associated with PM10, (3) amounts of secondary particulate expressed as SO4(=) and NO3(-) and (4) the mutagenic activities of PM10 organic extracts. Sampling was carried out in a meteochemical station located in Torino, a northern Italian city with high levels of PM10. The mean PM10 concentration in the considered period was 46.1+/-28.8 microg/m3, the iron mean concentration was 0.83 microg/m3 (+/-0.65 microg/m3) and the bioavailable Fe was 5.7% (+/-4.4%). The data showed that secondary particulate matter (as sum of sulfates and nitrates) constituted about 47% of PM10 total mass. Both iron and secondary species concentrations were positively associated with PM10 levels. Seasonal variations of PM10 concentration, iron level and secondary species amount were significant. Samples were tested for mutagenicity with Salmonella typhimurium strains TA98 and TA100, with and without metabolic activation and a positive response was observed especially for TA98. There were positive statistical associations between mutagenicity and PM10, bioavailable iron, sulfates and nitrates concentrations. Therefore, these results showed the usefulness of this biological approach for monitoring PM10. PMID- 17698170 TI - Levels of PAI-1 and outcome after electrical cardioversion for atrial fibrillation. PMID- 17698171 TI - Plasma levels of P-selectin are determined by platelet turn-over and the P selectin Thr715Pro polymorphism. AB - BACKGROUND: Plasma levels of soluble P-selectin (sP-selectin) are often used to demonstrate platelet activation. METHODS: We determined sP-selectin in a variety of disorders characterized by high or low platelet counts and compared their levels with those in healthy subjects. Furthermore, we determined the Thr715Pro polymorphism in all subjects. RESULTS: Total concentrations of sP-selectin were clearly associated with levels of platelet counts. Thus, calculation of sP selectin per platelet showed that these levels in patients with thrombocytopenia due to marrow failure and in patients with increased platelet counts were similar to those in controls. Only patients with an increased platelet turn-over had elevated sP-selectin per platelet. While carriers of the Pro715 polymorphism had lower sP-selectin levels than non-carriers, this genetic disposition was over ruled in patients with increased platelet turn-over. CONCLUSION: For the demonstration of platelet activation it is preferable to define sP-selectin based on platelet counts under the consideration of the Pro715Thr polymorphism. PMID- 17698172 TI - Quantitative analysis of ciliary ultrastructure in patients with primary ciliary dyskinesia. AB - The present study was designed to investigate dynein arm and microtubule defects quantitatively in patients with respiratory disease and to establish the clinical relevance of dynein arm deficiency and microtubule abnormalities. Thirty-four patients with recurrent upper and/or lower respiratory infections were included in the study. Nasal mucosal brushings were fixed in glutaraldehyde and routine electron microscopic procedures were carried out. At least 20 cross-sectioned cilia were examined from each subject. Dynein arm and microtubular abnormalities were quantified and a statistical analysis was performed. Twenty-nine percent of the patients showed dynein arm deficiency and a further 21% had possible deficiency (PD). Microtubule defects in patients with dynein arm deficiency and PD were found to be significantly increased compared to the patients with no dynein arm deficiency. The most prominent defect in the dynein arm deficiency group was a translocation of central and/or peripheral microtubules. The high percentage of translocation defect in this group of patients suggests that these defects are primary, rather than secondary to infection. PMID- 17698173 TI - Suppression of apoptosis and oxidative stress by deprenyl and estradiol in aged rat liver. AB - Aging is accompanied by significant structural and functional transformations of all organs and systems. Age-associated increase in apoptotic behavior may cause disease. Older cells are more susceptible to endogenous oxidative damage, and oxidative stress is a potent inducer of apoptosis. Deprenyl is an irreversible monoamine-oxidase B inhibitor which has anti-oxidant, anti-apoptotic and neuroprotective effects. Estrogen is also a neuroprotective and anti-oxidant hormone. The objectives of this study were to determine whether the anti oxidative effects of deprenyl can suppress apoptotic activity, with or without estradiol, in aged female rat livers. In this study, ovariectomized female Wistar albino rats were divided into six groups as follows; young (3 months old) saline treated control, aged (24 months old) saline-treated control, aged deprenyl treated, aged estradiol treated, aged deprenyl plus estradiol treated and aged sham controls. All rats except for the sham group were treated for 21 days. Determination of oxidative stress parameters was performed spectrophotometrically. To detect apoptotic cells, TUNEL staining was performed. The results were analyzed by one-way ANOVA post hoc Bonferroni test. Deprenyl and estradiol administration, alone or in combination, decreased significantly the levels of lipid peroxidation and increased superoxide dismutase activity in the liver relative to aged control and sham rats (P<0.05). The number of TUNEL positive cells decreased significantly in deprenyl and estradiol-treated rats compared with aged control and sham rats. The results indicate that deprenyl treatment alone, or in combination with estradiol, may modulate age-related apoptotic changes in rat liver by decreasing oxidative stress. PMID- 17698174 TI - Differentiation of alpha-gustducin in taste buds of the mouse soft palate and fungiform papillae. AB - We used alpha-gustducin, a type II taste-cell-specific G protein, to investigate the onset of taste transduction and its relation to the development of the soft palate (SP) and fungiform (FF) papillae taste buds in the mouse. Paraffin wax embedded sections were prepared from the SP and anterior region of the tongue of the mouse from birth until postnatal day (PD) 63. No alpha-gustducin immunoreactive cells were observed on the day of birth. One day later, alpha gustducin was immunolocalised in taste buds with pores with a relatively higher frequency recorded in the SP as compared with the FF papillae. The immunoreactive cells were spindle shaped with elongated processes extending from the base to the pore of the taste buds. On PD 7, the number of taste buds containing alpha gustducin-immunoreactive cells in the SP was three times greater than that of FF papillae. Our results indicate that taste transduction is essentially acquired from the time of birth. Moreover, the onset of taste transduction by the SP taste buds developed earlier than that achieved by taste buds in the FF papillae. PMID- 17698175 TI - Effect of a T0 radical hysterectomy specimen on survival for early stage cervical cancer. AB - OBJECTIVE: : Radical hysterectomy with regional lymphadenectomy is the surgical procedure of choice for stage IA-IIA cervical carcinoma. The goal of this study was to evaluate the outcome of patients with no residual tumor (T0) in their hysterectomy specimens. METHODS: : An analysis of all women who underwent type II or III hysterectomy for invasive cervical cancer from 1989 to 2005 was performed. The pathologic data and clinical outcome of each patient was documented. T0 subjects were compared to the remainder of the cohort. Survival was evaluated with the Kaplan-Meier method. RESULTS: : A total of 594 patients were identified. No residual tumor was noted in the hysterectomy specimens of 171 (29%). T0 patients had earlier stage tumors than the controls (IA 32%, IB 68%) (p<0.0001). Lymphadenectomy was performed in 89% of the T0 subjects. No T0 patients had lymphatic or parametrial disease. The median node yield was similar between the T0 group and those with residual tumors (24 vs. 25) (p=0.34). Adjuvant therapy was not administered to any of the T0 subjects. There were no recurrences and no cancer-related deaths in the T0 patients. Kaplan-Meier analysis revealed an improved disease free (p<0.0001) and overall survival (p<0.0001) for the T0 subjects compared to women with residual tumors. The results were similar when the analysis was restricted to stage IB1 patients (p=0.0004 and 0.002). CONCLUSIONS: : A T0 radical hysterectomy specimen indicates a curative therapy. This subgroup of patients has a favorable prognosis with minimal risk of recurrence. Patients with T0 tumors may be candidates for less intensive, abbreviated follow-up. PMID- 17698176 TI - Expression analysis and RNA localization of PAI-RBP1 (SERBP1) in epithelial ovarian cancer: association with tumor progression. AB - OBJECTIVE: The plasminogen activator system (PA) plays an important role in invasion and metastasis of solid tumors. The PA Inhibitor type 1 (PAI-1) is the main physiologic regulator of plasminogen activation. A recently characterized protein, PAI-RBP1 (PAI-1 mRNA Binding Protein 1), appears to regulate the stability of PAI-1 mRNA. Expression of PAI-RBP1 (the new, approved gene symbol is SERBP1) has not been previously analyzed in human tumors. We present herein for the first time expression analysis of PAI-RBP1 in epithelial ovarian cancer. METHODS: PAI-RBP1 was identified as gene overexpressed in ovarian cancer by an in silico approach using EST database mining. A thorough expression analysis of PAI RBP1 and PAI-1 was performed in normal ovary (n=4), benign (n=6) and malignant (n=42) ovarian lesions using non-radioactive RNA in situ hybridization and immunohistochemistry, respectively. RESULTS: PAI-RBP1 mRNA and PAI-1 were significantly overexpressed in tumor epithelial cells as compared to benign and normal ovarian tissue. A significant correlation between PAI-RBP1 expression and advanced disease stage (FIGO) was found (p=0.042). CONCLUSION: In ovarian cancer, PAI-RBP1 is significantly overexpressed in tumor epithelial cells, suggesting a biological role in tumor invasion and metastasis. Its expression is higher in advanced disease, thus the prognostic significance of PAI-RBP1 in ovarian cancer remains to be evaluated in further studies. PMID- 17698177 TI - Modafinil restores memory performance and neural activity impaired by sleep deprivation in mice. AB - The original aims of our study have been to investigate in sleep-deprived mice, the effects of modafinil administration on spatial working memory, in parallel with the evaluation of neural activity level, as compared to non-sleep-deprived animals. For this purpose, an original sleep deprivation apparatus was developed and validated with continuous electroencephalography recording. Memory performance was evaluated using spontaneous alternation in a T-maze, whereas the neural activity level was estimated by the quantification of the c-Fos protein in various cerebral zones. This study allowed altogether: First, to evidence that a diurnal 10-h sleep deprivation period induced an impairment of spatial working memory. Second, to observe a decrease in c-Fos expression after sleep deprivation followed by a behavioural test, as compared to non-sleep-deprived mice. This impairment in neural activity was evidenced in areas involved in wake-sleep cycle regulation (anterior hypothalamus and supraoptic nucleus), but also in memory (frontal cortex and hippocampus) and emotions (amygdala). Finally, to demonstrate that modafinil 64 mg/kg is able to restore on the one hand memory performance after a 10-h sleep deprivation period, and on the other hand, the neural activity level in the very same brain areas where it was previously impaired by sleep deprivation and cognitive task. PMID- 17698178 TI - Catalpol ameliorates cognition deficits and attenuates oxidative damage in the brain of senescent mice induced by D-galactose. AB - The neuroprotective effects of catalpol, an iridoid glycoside isolated from the fresh Rehmannia roots, on the senescent mice induced by D-galactose were assessed. The mice subcutaneously injected with catalpol (5 or 10 mg/kg, 2 weeks, from fifth week) showed significantly improved learning and memory ability in Morris water maze test compared with d-galactose treated mice (150 mg/kg, 6 weeks). We further investigated the mechanism involved in the neuroprotective effects of catalpol on the mice brain tissue. The results showed that catalpol increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), decreased the malondialdehyde (MDA) level, elevated the activities of Na+ -K+ ATPase and Ca2+ -Mg2+ ATPase on the cerebral cortex and hippocampus of d galactose treated mouse. All the data suggested that catalpol had the potential to be a useful cognitive impairment treatment, and its beneficial effects may be partly mediated via enhancing endogenous antioxidant enzymatic activities and inhibiting free radical generation. PMID- 17698179 TI - Subchronic phencyclidine exposure potentiates the behavioral and c-Fos response to stressful stimuli in rats. AB - Prior exposure to subchronic phencyclidine (PCP) produces behaviors argued to model schizophrenia in rats, including alterations in the behavioral responses to stress-inducing stimuli. Prior exposure to a single injection of PCP also produces a number of schizophrenia-like behaviors in rats, suggesting that a single injection of PCP is able to model schizophrenia-like behaviors as well. We examined the effects of prior exposure to either a single injection or subchronic PCP on stress-induced behavior and c-Fos-like immunoreactivity (FLI). Twenty-four hours after a single injection of PCP (15 mg/kg) or subchronic PCP (10 mg/kg for 14 days) or saline, male rats were exposed to either novel environment, forced swim, or left in their home cages. A single injection of PCP produced only small effects on stress-induced behavior and FLI: a drugxtime interaction on the number of cage crossings in the novel environment and a drugxcondition interaction on FLI in the shell of the nucleus accumbens. However, subchronic PCP decreased cage crosses and rears in the novel environment and increased immobility in the forced swim test. The increased immobility in the forced swim test was accompanied by increased striatal FLI. These data suggest that while a single injection of PCP produces only minimal alterations in the response to stressful stimuli, subchronic PCP produces a quantitatively greater effect. In addition, the observation that PCP pretreatment increased striatal FLI induced by forced swim but not novelty suggest that PCP alters the behavioral responses to these stressors via different neurochemical mechanisms. PMID- 17698180 TI - Evaluation of the interaction between acemetacin and opioids on the hargreaves model of thermal hyperalgesia. AB - It has been shown that the association of opioids analgesic agents with non steroidal anti-inflammatory drugs (NSAIDs) can increase their antinociceptive activity, allowing the use of lower doses and thus limiting side effects. Therefore, the goal of the present study was to examine the possible pharmacological interaction between acemetacin and two opioids in the Hargreaves model of thermal hyperalgesia in the mouse. Acemetacin, codeine, nalbuphine or fixed-dose ratios acemetacin-codeine and acemetacin-nalbuphine combinations were administrated systemically to mice and the antihyperalgesic effect was evaluated using the thermal hyperalgesia test. All treatments produced a dose-dependent antihyperalgesic effect. ED40 values were estimated for all the treatments and an isobologram was constructed. The derived theoretical ED40 for the acemetacin codeine and acemetacin-nalbuphine combinations were 55.9+/-4.9 mg/kg and 40.3+/ 3.8 mg/kg, respectively, being significantly higher than the actually observed experimental ED40, 14.5+/-1.7 mg/kg and 12.7+/-2.2 mg/kg, respectively. These results correspond to synergistic interactions between acemetacin and opioids on the Hargreaves model of thermal hyperalgesia. Highest doses of the individual drugs or the combinations did not affect motor coordination in the balancing test on a rota-rod. Data suggest that low doses of the acemetacin-opioids combination can interact synergistically at systemic level and therefore this drugs association may represent a therapeutic advantage for the clinical treatment of inflammatory pain. PMID- 17698181 TI - GABAergic modulation of binge-like ethanol intake in C57BL/6J mice. AB - GABA receptor systems have long been implicated in alcoholism, and GABAergic drugs have demonstrated efficacy in altering alcohol intake in some rodent models. The present study was designed to assess the effects of baclofen, muscimol, and gaboxadol (THIP) in a variation on a new mouse model of binge-like ethanol intake. Three hours into their dark cycle, male and female C57BL/6J mice were given access to a 20% unsweetened ethanol solution for 2 h each day, for four days. On day five, mice received varying doses of baclofen, muscimol or THIP and were allowed access to 20% ethanol for 60 min. Baclofen dose-dependently increased binge-like ethanol intake, while both muscimol and THIP reduced ethanol intake. Subsequent studies testing the effect of baclofen, muscimol and THIP on water intake using the same procedure revealed that whereas baclofen had no significant effect, muscimol and THIP both reduced the measure. These results add to the growing literature suggesting a role for GABA receptor systems in the modulation of ethanol intake. However, whereas the role of GABA(B) receptor systems seems selective in the modulation of binge-like ethanol intake, the role for GABA(A) receptor systems appears to also extend to general fluid intake. PMID- 17698182 TI - Concordance of population-based estimates of mammography screening. AB - OBJECTIVE: Estimates of adherence to mammography screening guidelines vary, in part, due to lack of consensus on defining adherence. This study estimated adherence to repeat (two successive on-time screenings) and regular screening (three or more successive screenings) and evaluated the impact of varying operational definitions and evaluation periods. METHODS: The study included women aged 50-80 without a history of breast cancer who: were on a biennial screening cycle and due for a screening mammogram between 1995 and 1996; underwent screening (index date) in response to a reminder letter; and belonged to Group Health, an integrated health care delivery system in Washington State, for 6 or more years after the index date. Automated records provided information on enrollment, health care utilization, and procedures. RESULTS: Among 1336 women, 67-82% experienced a repeat screen. Adherence to regular screening over the 6 year evaluation period was 42-84%--and higher with longer allowable intervals between screenings, when definitions did not require on-schedule screenings, when intervals were reset after a diagnostic mammogram, and for shorter evaluation periods. CONCLUSION: Estimates of adherence to screening guidelines varied by the operational definition of "success" and time period of evaluation. Consensus in definitions and terminology is needed to compare evaluations. PMID- 17698183 TI - The co-occurrence of smoking and a major depressive episode among mothers 15 months after delivery. AB - OBJECTIVE: To examine the association between maternal smoking 15 months after delivery and the occurrence of a major depressive episode in the prior 12 months. METHODS: Data were obtained from the Fragile Families and Child Wellbeing Study, a birth cohort study. In 20 U.S. cities, 4898 mothers were surveyed at delivery in the years 1998 to 2000. In a survey 15 months later, 4353 (89%) of the mothers reported their smoking behavior and symptoms of a major depressive episode during the prior 12 months. RESULTS: At the follow-up survey, 26.6% of mothers reported that they were current smokers and 13.6% reported that they had symptoms of a major depressive episode during the prior 12 months. After adjusting for sociodemographic characteristics, the prevalence (95% confidence interval) of a major depressive episode was higher among smokers than nonsmokers: 17.7% (15.7%, 19.8%) vs. 12.1% (10.9%, 13.3%). Smoking was also more common among mothers with a major depressive episode than in those without one: 34.0% (30.6%, 37.4%) vs. 25.5% (24.1%, 26.8%). CONCLUSION: Smoking and depression often co-occur among mothers with infants. This suggests that these conditions should not be diagnosed or treated in isolation from each other and that the care of mothers and children should be integrated. PMID- 17698184 TI - Environment and cancer--how can the ecological study help us? PMID- 17698185 TI - Promoting transportation cycling for women: the role of bicycle infrastructure. AB - OBJECTIVE: Females are substantially less likely than males to cycle for transport in countries with low bicycle transport mode share. We investigated whether female commuter cyclists were more likely to use bicycle routes that provide separation from motor vehicle traffic. METHODS: Census of cyclists observed at 15 locations (including off-road bicycle paths, on-road lanes and roads with no bicycle facilities) within a 7.4 km radius of the central business district (CBD) of Melbourne, Australia, during peak commuting times in February 2004. RESULTS: 6589 cyclists were observed, comprising 5229 males (79.4%) and 1360 females (20.6%). After adjustment for distance of the bicycle facility from the CBD, females showed a preference for using off-road paths rather than roads with no bicycle facilities (odds ratio [OR]=1.43, 95% confidence interval [CI]: 1.12, 1.83), or roads with on-road bicycle lanes (OR=1.34, 95% CI: 1.03, 1.75). CONCLUSIONS: Consistent with gender differences in risk aversion, female commuter cyclists preferred to use routes with maximum separation from motorized traffic. Improved cycling infrastructure in the form of bicycle paths and lanes that provide a high degree of separation from motor traffic is likely to be important for increasing transportation cycling amongst under-represented population groups such as women. PMID- 17698186 TI - Do nutrition knowledge and beliefs modify the association of socio-economic factors and diet quality among US adults? AB - OBJECTIVES: We examined effects of socio-economic status (SES) factors on diet quality and fruits and vegetables intake among US adults and effect modification by nutrition knowledge and beliefs. METHODS: We used national cross-sectional data (Continuing Survey of Food Intake by Individuals) on 4356 US adults, aged 20 65 years, collected in 1994-1996. Socio-economic factors considered were education and poverty income ratio. Nutrition knowledge and belief score was measured by principal components analysis of 11 question responses. We considered three binary and two continuous outcomes related to United States Department of Agriculture recommended intake of fruits and vegetables and overall diet quality through Healthy Eating Index and alternate Mediterranean Diet Score. RESULTS: Multivariate analyses indicated that better SES independently improved likelihood of adequate fruits and vegetables intake and overall diet quality. In several cases, nutrition knowledge and beliefs acted as an effect modifier. In particular, education showed no association with diet quality among subjects in the lowest nutrition knowledge and belief tertile, while the association was consistently stronger in the highest tertile (Education x Nutrition knowledge and beliefs interaction term P<0.10 for Healthy Eating Index and both fruits and vegetables guidelines). A similar interaction was noted for poverty income ratio. CONCLUSION: For improvement in overall diet quality, socio-economic interventions must be coupled with health education programs targeting all segments of the US population. PMID- 17698187 TI - Effect of occlusal contact size on interfacial stresses and failure of a bonded ceramic: FEA and monotonic loading analyses. AB - OBJECTIVE: This study investigated whether contact area (i.e. facet size) would influence the loads necessary for subsurface radial crack formation in porcelain specimens bonded to a dentin analog material. METHODS: Dental porcelain discs (0.5 mm, 1 mm, and 1.5 mm thick) were bonded to compliant bases simulating dentin, and loaded with either a 1 mm, 2 mm, or 3 mm diameter aluminum piston until fracture. Pop-in of the subsurface radial crack from the bonded interface was detected using the acoustic emission (AE) method. Pre-test and post-test finite element analysis (FEA) was used to model the experiment and to calculate subsurface failure stresses. RESULTS: There were significant differences in loads sustained before fracture according to both the ceramic thickness and the piston diameter (p<0.05; ANOVA and post-hoc Scheffe). Failure loads were found to be proportional to the square of the porcelain thickness. For all thicknesses, significantly higher loads were sustained beneath the 3mm piston than beneath the 1mm piston. FEA calculated failure strengths for the 1 mm thick porcelain (calculated from experimental mean loads) differed significantly for loading with the 1mm piston (168 MPa) or 3 mm piston (60 MPa). CONCLUSIONS: It appears that both ceramic thickness and contact facet size may be clinically controlled to increase load-bearing ability of all-ceramic crowns. Single value strengths may not accurately model bonded dental ceramics; adjustments such as with Weibull scaling may improve accuracy. These results further suggest that small spherical indenters do not create clinically analogous contact conditions. PMID- 17698188 TI - Islet-encapsulation in ultra-thin layer-by-layer membranes of poly(vinyl alcohol) anchored to poly(ethylene glycol)-lipids in the cell membrane. AB - The microencapsulation of islets of Langerhans (islets) in a semipermeable membrane, i.e., the creation of a bioartificial pancreas, has been studied as a safe and simple technique for islet transplantation without the need for immunosuppressive therapy. The total volume of the implant tends to increase after enclosure of the islets in the semipermeable membrane, which limits transplantation sites. Thus, ultra-thin membranes are required for clinical applications. Here, we propose a novel method to encapsulate islets in an ultra thin membrane of poly(vinyl alcohol) (PVA) anchored to a poly(ethylene glycol) (PEG)-phospholipid conjugate bearing a maleimide group (Mal-PEG-lipids, PEG Mw: 5000) in the cell membranes of islets. When Mal-PEG-lipids were added to an islet suspension, they spontaneously formed a thin layer on cells of the outer layer of islets. The PEG-lipid layer on the islets was covered by a PVA monolayer, and the PVA membrane was further reinforced by using the layer-by-layer method with thiol/disulfide exchange reactions. No practical volume increase in islets was observed after microencapsulation by this method. In addition, encapsulation of the islet surface in PVA membranes did not impair insulin release in response to glucose stimulation. PMID- 17698190 TI - Temperature and nitric oxide control spontaneous calcium transients in astrocytes. AB - Transient spontaneous increases in the intracellular Ca2+ concentration have been frequently observed in astrocytes in cell culture and in acutely isolated slices from several brain regions. Recent in vivo experiments, however, reported only a low frequency of spontaneous Ca2+ events in astrocytes. Since the ex vivo experiments were usually performed at temperatures lower than physiological body temperature, we addressed the question whether temperature could influence the spontaneous Ca2+ activity in astrocytes. Indeed, comparing the frequency and spike width of spontaneous Ca2+ transients in astrocytes at temperatures between 20 and 37 degrees C in culture as well as in acute cortical slices from mouse brain, revealed that spontaneous Ca2+ responses occurred frequently at low temperature and became less frequent at higher temperature. Moreover, the single Ca2+ events had a longer duration at low temperature. We found that nitric oxide (NO) mimicked the increase in spontaneous Ca2+ activity and that an NO-synthase inhibitor attenuated the effect of lowering the temperature. Thus, temperature and NO are major determinants of spontaneous astrocytic Ca2+ signalling. PMID- 17698191 TI - A new MALDI-TOF-based assay for monitoring JAK2 V617F mutation level in patients undergoing allogeneic stem cell transplantation (allo SCT) for classic myeloproliferative disorders (MPD). AB - JAK2 V617F mutation is found in a high proportion of MPD patients. We developed a quantitative assay for the detection of the JAK2 mutation and demonstrated its clinical utility in MPD patients who underwent SCT. Sixty percent of the patients were JAK2 V617F positive prior to the SCT (mean mutation levels 74%, range 16 98%). After the procedure, the mutation levels progressively decreased and were in correlation with the donor-recipient chimerism status (r=0.97, p<0.001). At a median follow up of 16 months (range 2-58), 9/15 patients are alive and in CR. The levels of the JAK2 V617F mutation reached 0% in all surviving patients. PMID- 17698189 TI - Biomaterial-mediated retroviral gene transfer using self-assembled monolayers. AB - Biomaterial-mediated gene delivery has recently emerged as a promising alternative to conventional gene transfer technologies that focus on direct delivery of viral vectors or DNA-polymer/matrix complexes. However, biomaterial based strategies have primarily targeted transient gene expression vehicles, including plasmid DNA and adenovirus particles. This study expands on this work by characterizing biomaterial properties conducive to the surface immobilization of retroviral particles and subsequent transduction of mammalian cells at the cell-material interface. Self-assembled monolayers (SAMs) of functionally terminated alkanethiols on gold were used to establish biomaterial surfaces of defined chemical composition. Gene transfer was observed to be greater than 90% on NH(2)-terminated surfaces, approximately 50% on COOH-functionalized surfaces, and undetectable on CH(3)-terminated SAMs, similar to controls of tissue culture treated polystyrene. Gene delivery via the NH(2)-SAM was further characterized as a function of retrovirus coating time, virus concentration, and cell seeding density. Finally, SAM-mediated gene delivery was comparable to fibronectin- and poly-l-lysine-based methods for gene transfer. This work is significant to establishing safe and effective gene therapy strategies, developing efficient methods for gene delivery, and supporting recent progress in the field of biomaterial-mediated gene transfer. PMID- 17698192 TI - Rotavirus gastroenteritis: why to back up the development of new vaccines? AB - Rotaviruses (RVs) are the main aetiologic agent of severe acute diarrhoea in children under the age of 5, worldwide. Given that the currently available preventive measures to fight against the transmission of RV disease are not sufficiently effective, vaccination likely represents the only efficacious adapted response to the massive impact of this infection. Although the two current RV vaccines have shown good tolerance and significant efficacy to protect infant against severe RV disease, their development have raised key questions that are still unanswered regarding their cost, efficacy and safety. These two vaccines have in common the disadvantages related to the use of oral attenuated live viruses which limit their implementation in both developed and developing countries. In order to overcome these hurdles, it is important to support the development of new, non-replicating vaccines which will not suffer the potential disadvantages of the present vaccines. New approaches and other routes of administration are being tested in animal models and soon will be evaluated in humans. Among those are viral-like particle-based vaccines which have provided the most promising results. Finally, the epidemiology of the disease which differs in developed and developing countries can affect decisions about vaccine composition and delivery. The answer brought by the development of new RV vaccines could reside in developing several types of RV vaccines specifically designed to be used in different settings. PMID- 17698193 TI - Assessment of polychlorinated dibenzo-p-dioxins and dibenzofurans in sludges according to the European environmental policy. AB - The amount of sewage sludge generated in Europe is expected to surpass the 10 million tons/year in 2006 as a result of the waste water treatment process according to the Water Policy in European Union. Sewage sludge is what is left behind after water is cleaned in waste treatment plants and is characterized for this high content in nitrogen and phosphorous that could be of great importance in agriculture as fertilizer or soil conditioner. On the other hand, pollutants like metals and organic contaminants are usually removed from water and are accumulated in the sewage sludge, reaching the food chain if their concentrations are not below the safe limits established by the European legislation. The latter issue is of great concern nowadays and in this sense, different works alert against the use of the sewage sludge in agriculture arguing that serious illnesses, even resulting in death as well as adverse environmental impacts are associated to the application of sewage sludge. This work is a continuation of a former comprehensive survey on of priority organic pollutant in sludges for agricultural purposes carried out by our group in Catalonia and this time is focused on the polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F), one of the most toxic group of organic compounds listed in the Work Document on Sludge which is the reference tool in this field in Europe and is also included in the Stockholm Convention. Eighty eight samples were collected from the end of 2003 to April 2006 and the concentrations detected were lower than the 100 ng/kg I-TEQ limit recommended by the European legislation (EC, 2000). Thus, sewage sludges generated in Catalonia do not represent a threat to human health if they are used as fertilizers in agriculture. PMID- 17698194 TI - Granulocyte chemotactic properties of M. tuberculosis versus M. bovis-infected bovine alveolar macrophages. AB - The incidence of bovine tuberculosis (TB) continues to rise, and causes significant economic losses worldwide. The causative agent of bovine TB, Mycobacterium bovis, is closely related to the human pathogen M. tuberculosis, and yet these two organisms differ profoundly in their ability to cause disease in cattle. The innate immune system is primarily responsible for controlling disease, with the alveolar macrophage (AlvMvarphi) acting as one of the first points of contact between host and respiratory pathogens. In this study we have examined some of the differences in this component of the host immune response to M. bovis and M. tuberculosis, with the aim of improving our understanding of why M. bovis is able to cause disease in cattle whereas M. tuberculosis is efficiently controlled. Initial studies using microarray technology revealed that chemokines represented some of the most differentially expressed genes between M. tuberculosis and M. bovis-infected bovine AlvMvarphi. M. tuberculosis-infected bovine AlvMvarphi expressed significantly higher levels of the chemokines CCL3, CCL4, CCL5 and CXCL8, whereas M. bovis-infected AlvMvarphi were shown to express higher levels of CCL23. We further demonstrated the role of chemokines in bovine TB by showing that supernatants from AlvMvarphi infected with M. tuberculosis were significantly more effective than those from M. bovis-infected cells at attracting bovine granulocytes in an in vitro chemotaxis assay. These results have significant implications in vivo as they suggest that the M. bovis-infected macrophage is able to circumvent activation of the host chemotactic response and thereby evade killing by the host immune system. PMID- 17698195 TI - Season of birth, natural light, and myopia. AB - PURPOSE: To investigate the possible roles of season of birth and perinatal duration of daylight hours (photoperiod) in the development of myopia. DESIGN: Retrospective, population-based, epidemiological study. PARTICIPANTS: A total of 276 911 adolescents (157 663 male, 119 248 female) 16 to 22 years old. All were Israeli-born conscripts to the Israeli Defense Forces who were examined during the 5-year period 2000 through 2004. METHODS: Noncycloplegic refraction was determined by autorefractometer and validated by qualified optometrists. Myopia, defined on the basis of right eye spherical equivalence, was classified as mild ( 0.75 to -2.99 diopters [D]), moderate (-3.0 to -5.99 D), or severe (-6.0 D or worse). The photoperiod was recorded from astronomical tables and classified into 4 categories. Using multivariate logistic regression models, we calculated odds ratios (ORs) for several risk factors of myopia including season of birth. MAIN OUTCOME MEASURE: The OR for photoperiod categories as risk factors for myopia. RESULTS: Overall prevalences of mild, moderate, and severe myopia were 18.8%, 8.7%, and 2.4%, respectively. There were seasonal variations in moderate and severe myopia according to birth month, with prevalence highest for June/July births and lowest for December/January. On multivariate logistic regression, the ORs of photoperiod categories for moderate and severe myopia were highly significant and demonstrated a dose-response pattern. Odds ratios for severe myopia were highest for the shortest versus the longest photoperiods (1.24; 95% confidence interval, 1.15-1.33; P<0.001). Mild myopia was not associated with season of birth or perinatal light exposure. Other risk factors were gender (1.14 for female), education level (1.32 for age above 12), and father's origin (1.31 for Eastern vs. Israeli origin). CONCLUSION: Myopia in this population is associated with birth during summer months. The exact associating mechanism is not known but might be related to exposure to natural light during the early perinatal period. PMID- 17698197 TI - Electron microscopic investigation of the lens capsule and conjunctival tissues in individuals with clinically unilateral pseudoexfoliation syndrome. AB - PURPOSE: To determine the presence of pseudoexfoliative material in the unaffected eyes of patients with clinically unilateral pseudoexfoliation syndrome. DESIGN: Prospective observational case series. PARTICIPANTS: Thirty-two consecutive patients with clinically unilateral pseudoexfoliation syndrome, undergoing routine cataract surgery. METHODS: Transmission electron microscopy (TEM) was used to examine conjunctival and anterior lens capsule specimens in affected and unaffected eyes. MAIN OUTCOME MEASURE: Presence of characteristic pseudoexfoliation syndrome findings on TEM. RESULTS: Transmission electron microscopy demonstrated pseudoexfoliative material on either the anterior capsule or conjunctival sample from the clinically unaffected eye in 26 of the 32 patients with clinically unilateral pseudoexfoliation syndrome (81%; 95% confidence interval, 64%-93%). CONCLUSION: The results suggest that the seemingly uninvolved eye in a patient with clinically unilateral pseudoexfoliation syndrome has an 81% likelihood of being affected ultrastructurally. Several population studies examining conversion rates from unilateral to bilateral disease have found a similar proportion of patients with bilateral pseudoexfoliation syndrome in the later decades of life. PMID- 17698196 TI - A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. AB - OBJECTIVE: To provide data on the short-term effect of intravitreal bevacizumab for diabetic macular edema (DME). DESIGN: Randomized phase II clinical trial. PARTICIPANTS: One hundred twenty-one eyes of 121 subjects (109 eligible for analysis) with DME and Snellen acuity equivalent ranging from 20/32 to 20/320. INTERVENTIONS: Random assignment to 1 of 5 groups: (A) focal photocoagulation at baseline (n = 19), (B) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks (n = 22), (C) intravitreal injection of 2.5 mg of bevacizumab at baseline and 6 weeks (n = 24), (D) intravitreal injection of 1.25 mg of bevacizumab at baseline and sham injection at 6 weeks (n = 22), or (E) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks with photocoagulation at 3 weeks (n = 22). MAIN OUTCOME MEASURES: Central subfield thickness (CST) on optical coherence tomography and best-corrected visual acuity (VA) were measured at baseline and after 3, 6, 9, 12, 18, and 24 weeks. RESULTS: At baseline, median CST was 411 mum and median Snellen VA equivalent was 20/50. Compared with group A, groups B and C had a greater reduction in CST at 3 weeks and about 1 line better median VA over 12 weeks. There were no meaningful differences between groups B and C in CST reduction or VA improvement. A CST reduction > 11% (reliability limit) was present at 3 weeks in 36 of 84 (43%) bevacizumab-treated eyes and 5 of 18 (28%) eyes treated with laser alone, and at 6 weeks in 31 of 84 (37%) and 9 of 18 (50%) eyes, respectively. Combining focal photocoagulation with bevacizumab resulted in no apparent short-term benefit or adverse outcomes. Endophthalmitis developed in 1 eye. The following events occurred during the first 24 weeks in subjects treated with bevacizumab without attributing cause to the drug: myocardial infarction (n = 2), congestive heart failure (n = 1), elevated blood pressure (n = 3), and worsened renal function (n = 3). CONCLUSION: These results demonstrate that intravitreal bevacizumab can reduce DME in some eyes, but the study was not designed to determine whether treatment is beneficial. A phase III trial would be needed for that purpose. PMID- 17698198 TI - Awareness of incident open-angle glaucoma in a population study: the Barbados Eye Studies. AB - PURPOSE: To evaluate factors related to awareness of incident open-angle glaucoma (OAG) in the Barbados Eye Studies. DESIGN: Cohort study with 81% to 85% response rate over 9 years. PARTICIPANTS: Four thousand three hundred fourteen participants of African descent, 40 to 84 years old at baseline. METHODS: Standardized study visits included an interview on demographic, medical, health care, and other factors; various ophthalmic measurements; fundus photography; and comprehensive ophthalmologic examinations for those referred. MAIN OUTCOME MEASURES: Definite OAG was defined by both visual field and optic disc criteria after ophthalmologic confirmation, regardless of intraocular pressure (IOP). Definite incident participants without prior OAG diagnosis/treatment were considered unaware. Logistic regression analyses evaluated factors associated with OAG unawareness. Results were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Over 9 years, 125 participants newly developed definite OAG, of whom 53% were previously unaware. At baseline, the unaware group had significantly lower mean IOP (OR, 0.86; 95% CI, 0.79-0.94) and more hyperopia (OR, 2.69; 95% CI, 1.08-6.69) than those aware. Most unaware and aware participants had > or =2 medical care visits in the previous year (72.7% vs. 83.1%). However, those in the unaware group sought eye care less frequently than those aware (last visit in preceding year, 33.4% vs. 64.4%); these visits were mainly for eyeglasses (71.4% vs. 12.5%), with most having glaucoma tests only during study visits (72.7% vs. 37.3%). The unaware group reported more visits to opticians/optometrists than to private ophthalmologists (OR, 4.20; 95% CI, 1.00-17.66) and fewer visits to a public ophthalmologic clinic (OR, 0.18; 95% CI, 0.04-0.86). CONCLUSIONS: Over half of participants with incident OAG were unaware of their diagnosis. Unawareness was related to lower IOP, hyperopia, and eye care utilization patterns. Although persons in the unaware group had regular visits for medical care, visits for eye care and OAG testing were limited. Unawareness was 4 times more likely when opticians/optometrists were the regular eye care source, compared with private ophthalmologists, and about 80% less likely with a public ophthalmologic source. These findings highlight the high frequency of undiagnosed OAG and importance of comprehensive examinations in disease detection. PMID- 17698199 TI - Small choroidal melanoma with chromosome 3 monosomy on fine-needle aspiration biopsy. AB - PURPOSE: To evaluate the presence of chromosome 3 monosomy in small choroidal melanoma using fine-needle aspiration biopsy (FNAB). DESIGN: Noncomparative case series. PARTICIPANTS: Fifty-six patients with small choroidal melanoma measuring 3 mm or less in thickness who were undergoing plaque radiotherapy. METHODS: Fine needle aspiration biopsy was used at the time of plaque radiotherapy to sample tumor cells using a 27-gauge long needle via an indirect transvitreal approach into the tumor apex for postequatorial tumors or a 30-gauge short needle via a direct transscleral approach into the tumor base for preequatorial tumors. MAIN OUTCOME MEASURES: Chromosome 3 monosomy in small choroidal melanoma. RESULTS: The median tumor thickness was 2.6 mm. Monosomy 3 was found in 15 (27%) cases and disomy 3 was found in 32 (57%) cases. In 9 (16%) cases, genomic DNA yield was insufficient for genetic analysis. Fine-needle aspiration biopsy with a 27-gauge needle transvitreal approach provided quantity sufficient for genetic testing in 31 (97%) of 32 cases versus 16 (67%) of 24 cases sampled with a 30-gauge transscleral technique. Compared with disomy 3 tumors, monosomy 3 tumors were statistically more likely to occur in older patients (P = 0.040). Monosomy 3 (versus disomy 3) tumors showed thickness of more than 2 mm in 100% (vs. 84%), subretinal fluid in 87% (vs. 94%), symptoms in 40% (vs. 56%), orange pigment in 93% (vs. 81%), and margin of 3 mm or less to the optic disc in 20% (vs. 50%). There was no statistical difference between monosomy 3 and disomy 3 tumors in the presence or number of these clinical factors. However, small choroidal melanomas with monosomy 3 mutation were more likely to have had documented growth (63%) compared with those with disomy 3 (25%; P = 0.025; odds ratio, 5.00). CONCLUSIONS: Using FNAB at the time of plaque radiotherapy, monosomy 3 was found in approximately 27% of small choroidal melanomas, more often in older patients and tumors with documented growth. Transvitreal biopsy into the tumor apex provided better yield compared with transscleral biopsy into the tumor base. PMID- 17698200 TI - Nonarteritic anterior ischemic optic neuropathy: natural history of visual outcome. AB - OBJECTIVE: To investigate systematically the natural history of visual outcome in nonarteritic anterior ischemic optic neuropathy (NAION). DESIGN: Cohort study. PARTICIPANTS: Three hundred forty consecutive untreated patients (386 eyes) with NAION, first seen in our clinic from 1973 to 2000. METHODS: At first visit, all patients gave a detailed ophthalmic and medical history and underwent a comprehensive ophthalmic evaluation. Visual evaluation was done by recording visual acuity, using the Snellen visual acuity chart, and visual fields with a Goldmann perimeter. The same ophthalmic evaluation was performed at each follow up visit. MAIN OUTCOME MEASURES: Natural history of visual acuity and visual field outcome in NAION. RESULTS: Of the 386 eyes, 332 had 8 weeks or more of follow-up from the initial visit. At the initial visit, in eyes seen < or =2 weeks from onset of symptoms, 49% had visual acuity of > or =20/30 and 23% had < or =20/200; in these eyes, 38% had minimal to mild visual field defect and 43% marked to severe defect. In those who were first seen < or =2 weeks after onset with visual acuity < or =20/70, there was improvement in 41% at 6 months and in 42% at 1 year after the initial visit. Two years after the initial visit, there was deterioration in 9% of eyes with initial visual acuity of > or =20/60, and in 18% of those with initial visual acuity of < or =20/70. In those who were first seen < or =2 weeks of onset with moderate to severe visual field defect, there was improvement in 26% at 6 months and 27% at 1 year after the initial visit. Two years after the initial visit, 27% of eyes with initial minimal to mild field defects showed worsening, as did 19% of those with moderate to severe defects. CONCLUSIONS: About half of the eyes with NAION presented with almost normal visual acuity (20/15 to 20/30) at the initial visit. Thus, the presence of normal visual acuity does not rule out NAION. Visual acuity and visual fields showed improvement or further deterioration mainly up to 6 months, with no significant change after that. PMID- 17698201 TI - Incorporation of thiolate donation using 2,2'-dithiodibenzaldehyde: complexes of a pentadentate N2S3 ligand with relevance to the active site of Co nitrile hydratase. AB - The use of 2,2'-dithiodibenzaldehyde (DTDB) as a reactant for incorporating thiolate donors into the coordination sphere of a transition metal complex without the need for protecting groups is expanded to include the synthesis of complexes with pentadentate ligands. The ligand N,N'-bis(thiosalicylideneimine) 2,2'-thiobis(ethylamine) (tsaltp) is synthesized at a cobalt center by the reaction of DTDB with a Co complex of thiobis(ethylamine). The resulting Co complexes are thus coordinated by the N(2)S(3) pentadentate ligand through two imine N atoms, two thiolate S atoms, and one thioether S atom. A dimeric, bis thiolate-bridged complex (1) is isolated and converted to a monomeric CN adduct (2) by treatment with KCN. The N(2)S(3) coordination environment provided by the tsaltp ligand is similar to that provided by the protein donors at the active site of the nitrile hydratase enzymes, with 2 being the first octahedral Co complex reported with such a coordination sphere. PMID- 17698202 TI - Computational definition of a mixed valent Fe(II)Fe(I) model of the [FeFe]hydrogenase active site resting state. AB - Density-functional calculations have been used to examine the electronic structure and bonding in the recently reported complex [(PMe(3))(CO)(2)Fe(mu pdt)(mu-CO)Fe(CO)(IMes)](+) (1(+), IMes=1,3-bis(2,4,6-trimethylphenyl)-imidazol-2 ylidene). This mixed valent Fe(II)Fe(I) complex features a rotated geometry that places a carbonyl ligand in a semi-bridging position, which makes it an accurate model of the S =(1/2) resting state of the [FeFe]-hydrogenase active site. Calculations indicate that the unpaired electron in this complex lies almost entirely on the rotated iron center, implying that this iron remains in the Fe(I) oxidation state, while the unrotated iron has been oxidized to Fe(II). The frontier molecular orbitals in 1(+) are compared with those in the neutral Fe(I)Fe(I) precursor (PMe(3))(CO)(2)Fe(mu-pdt)(mu-CO)Fe(CO)(IMes) at both its optimized geometry (1) and constrained to a rotated geometry (1(rot)). These theoretical results are used to address the role of the bridging CO ligand in 1(+) and to predict reactivity patterns; they are related back to the intricate biological mechanism of [FeFe]-hydrogenase. PMID- 17698203 TI - A computational study on DNA bases interactions with dinuclear tetraacetato diaqua-dirhodium(II,II) complex. AB - In our study, we have determined the thermodynamic behavior for the replacement reaction of one and two acetyl-ligands from the diaqua-tetrakis(mu acetylato)dirhodium(II,II) complex by purine DNA bases. The complexes were optimized at the density functional theory (DFT) level with the B3LYP functional. Stuttgart-Dresden pseudopotentials were used for the description of the Rh atoms. Most of the replacement reactions are mildly exothermic, delta G is up to 12 kcal/mol for the first acetyl-ligand and up to 8 kcal/mol for the second ligand replacement. For all explored complexes, stabilization and bonding energies were computed together with selected electronic properties. Adenine base coordinates to the dirhodium complex slightly more firmly than guanine. In head-to-tail conformation the two guanines are better stabilized (by about 8 kcal/mol) than in head-to-head arrangement due to minimization of sterical repulsion of both bases. We have shown that the bonding energy of axial water ligands is very small (up to 13 kcal/mol), resembling more H-bonds than dative coordination. Despite the larger stabilization energies of adenine-containing complexes, the thermodynamic parameters of the studied replacement reactions are more favorable in case of guanine complexes. Higher exothermicity is connected with easier deprotonization of guanine N1-site in comparison with N6-site of adenine in accord with experimental data. PMID- 17698204 TI - Ethylene oligomerization using nickel dithiolene complexes Ni(S2C2R2)2 (R=Ph, CF3) and the crystal structure of Ni[S2C2(CF3)2]2. AB - Nickel bis(dithiolene) complexes have been known for over four decades, yet little is known regarding the chemistry of this important subclass of inorganic coordination complexes in olefin oligomerization or polymerization. We report here that Ni(S(2)C(2)R(2))(2) (R=Ph, CF(3)) are converted to active catalysts for ethylene oligomerization when activated with methylaluminoxane (MAO). The catalyst activity is comparable to some nickel coordination complexes with N donor ligands under similar conditions. The products are mainly butenes and hexenes, with small amounts of higher oligomers. The product distribution pattern is consistent with a nickel hydride species being the active center, where fast beta-hydride elimination limits the products to mostly butenes and hexenes. The exact nature of the active center and the reaction mechanism remain to be investigated. In addition, we determined the crystal structure for Ni[S(2)C(2)(CF(3))(2)](2). The molecule crystallizes in the P2(1)/n space group and adopts a planar geometry with expected bond lengths and angles. Comparing this structure with that for the donor-acceptor complex with perylene reveals elongation of both the Ni-S and the S-C bonds in the latter, suggesting reduction of Ni[S(2)C(2)(CF(3))(2)](2) may have occurred in the latter. PMID- 17698205 TI - EEG and MEG coherence: measures of functional connectivity at distinct spatial scales of neocortical dynamics. AB - We contrasted coherence estimates obtained with EEG, Laplacian, and MEG measures of synaptic activity using simulations with head models and simultaneous recordings of EEG and MEG. EEG coherence is often used to assess functional connectivity in human cortex. However, moderate to large EEG coherence can also arise simply by the volume conduction of current through the tissues of the head. We estimated this effect using simulated brain sources and a model of head tissues (cerebrospinal fluid (CSF), skull, and scalp) derived from MRI. We found that volume conduction can elevate EEG coherence at all frequencies for moderately separated (<10 cm) electrodes; a smaller levation is observed with widely separated (>20 cm) electrodes. This volume conduction effect was readily observed in experimental EEG at high frequencies (40-50 Hz). Cortical sources generating spontaneous EEG in this band are apparently uncorrelated. In contrast, lower frequency EEG coherence appears to result from a mixture of volume conduction effects and genuine source coherence. Surface Laplacian EEG methods minimize the effect of volume conduction on coherence estimates by emphasizing sources at smaller spatial scales than unprocessed potentials (EEG). MEG coherence estimates are inflated at all frequencies by the field spread across the large distance between sources and sensors. This effect is most apparent at sensors separated by less than 15 cm in tangential directions along a surface passing through the sensors. In comparison to long-range (>20 cm) volume conduction effects in EEG, widely spaced MEG sensors show smaller field-spread effects, which is a potentially significant advantage. However, MEG coherence estimates reflect fewer sources at a smaller scale than EEG coherence and may only partially overlap EEG coherence. EEG, Laplacian, and MEG coherence emphasize different spatial scales and orientations of sources. PMID- 17698206 TI - Association of a dopamine beta-hydroxylase gene variant with depression in elderly women possibly reflecting noradrenergic dysfunction. AB - BACKGROUND: Depression has a multifactorial etiology which involves genetic factors and comorbid diseases. METHODS: A cross-sectional sample of 1371 elderly women (mean age=69.2 years) was examined. Detailed information on their health was obtained. Cognitive functions were assessed by the Short Blessed Test and the Animal Naming Task. A 19 bp insertion/deletion polymorphism in the dopamine beta hydroxylase (DBH) gene, the apolipoprotein (APOE) epsilon2/epsilon3/epsilon4 variation and 5-HTTLPR in the serotonin transporter gene were genotyped. RESULTS: Depression was univariately associated with homozygosity for the DBH gene 19 bp deletion allele (odds ratio [OR]=1.96, 95% confidence intervals [95% CI]=1.17 3.29, p=0.01), family history of depression (OR=3.86, 95% CI=1.85-8.06, p=0.0003), a composite measure of cardiovascular diseases (OR=1.96, 95% CI=1.11 3.47, p=0.02), cognitive impairment assessed by the Short Blessed Test (OR=3.88, 95% CI=1.29-11.64, p=0.02) and performance on the Animal Naming Task (OR=0.74, 95% CI=0.59-0.93, p=0.01). The strength of the association of DBH genotype with depression essentially remained unchanged after correction for other variables in a multivariate model. This association may reflect noradrenaline dysfunction in the brain. PMID- 17698207 TI - Plasticity and heterogeneity of lymphoid organs. What are the criteria to call a lymphoid organ primary, secondary or tertiary? AB - Lymphoid organs are generally classified in a hierarchy with primary lymphoid organs such as the thymus and bone marrow for the production of receptor specific T and B lymphocytes, respectively, independent of antigens. In secondary lymphoid organs such as lymph nodes, spleen, and tonsils, the lymphocytes are expanded due to antigen exposure, producing memory T cells and effector B cells, resulting in plasma cells. Tertiary lymphoid tissues are often defined as aggregations of lymphoid cells in autoimmune diseases. It will be outlined that all these organs have a high plasticity and also the thymic medulla is included in the route of migrating mature T cells and the bone marrow, not only in the traffic of CD4+ but also of CD8+ lymphocytes. The mucosa-associated lymphoid organs depend to a much larger extent on microbial antigen and are much more diverse than often described. The role of structural elements as well as blood and lymphatic vessels as an entry and exit site of lymphocytes will be outlined. Using a precise terminology, taking account of the plasticity of these organs at different ages and considering species differences will reduce misunderstandings among immunologists. PMID- 17698208 TI - Differential ex vivo nitric oxide production by acutely isolated neonatal and adult microglia. AB - Microglia are the macrophage population residing in the parenchyma of the central nervous system (CNS), and are thought to play critical roles in CNS development, homeostasis and defense against pathogens. Microglia are capable of rapidly responding to microbial pathogens through engagement of their Toll-like receptors (TLRs). We first compared the efficiency of these responses in primary microglia acutely isolated from adult and neonatal mice. While the cytokine and chemokine responses of adult microglia were generally higher than those of neonatal cells stimulated ex vivo through TLRs, the nitric oxide response of neonatal microglia was markedly enhanced relative to the adult cells. We then went on to identify culture conditions such as exposure to M-SCF or GM-CSF that markedly enhanced the nitric oxide response of microglia, particularly those from the adult CNS. Finally, we demonstrate that the differential nitric oxide response of neonatal and adult microglia is not only limited to the mouse, but also extends to rat microglia. PMID- 17698209 TI - Procalcitonin is elevated in the cerebrospinal fluid of patients with dementia and acute neuroinflammation. AB - Procalcitonin (PCT) is an established marker for severe systemic bacterial infection and sepsis in blood. Here we measured PCT by immunoassay in CSF and matched serum/plasma samples of controls and patients with different primary dementia disorders and acute neuroinflammation. PCT in CSF was significantly increased in patients with probable Alzheimer's disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia and acute neuroinflammation (encephalitis, meningitis) compared to non-demented controls. In contrast, PCT levels in matched plasma samples were normal in dementia groups, but elevated in meningitis/encephalitis. Our results indicate a central production of PCT and suggest PCT as a valuable marker candidate for the monitoring of dementia and acute neuroinflammation. PMID- 17698210 TI - A case of laryngeal ductal cyst: antenatal diagnosis and peripartum management. AB - Laryngeal mucous cysts are rare congenital malformations of the upper aero digestive tract. We report one case of a ductal cyst developed in the supraglottic area. The diagnosis of an antenatal malformation was suspected on the basis of a hydramnios development during pregnancy. Ultrasound scan showed a cervical anechogen mass. This led to a fetal MRI which showed the cyst extension. A management of delivery had to be prepared due to the risk of air obstruction at the birth. The treatment consisted of a marsupialization of the cyst under laryngo-endoscopic surgery. Six months follow-up showed no recurrence. PMID- 17698211 TI - Three weeks of running wheel exposure improves cognitive performance in the aged Tg2576 mouse. AB - If begun early in life, exercise effectively reduces the development of cognitive deficits in transgenic mouse models of Alzheimer's disease (AD). However, the effectiveness of exercise, once the cognitive impairments are established, is not as clear. In terms of translating research in animal models to treatments involving exercise in Alzheimer's disease patients, it is critical to evaluate exercise intervention at time points that address not only prevention, but also treatment of cognitive decline. We provided exercise wheels to Tg2576 (TG) (n=12) and C57BL6 (WT) (n=17) mice at 16-18 months of age for three weeks. At this age animals have significant cognitive impairment and neuropathology consistent with AD. Age matched sedentary TG (n=13) and WT (n=12) mice were also included, as well as groups provided access to an immobile wheel (TG n=9, WT n=12). After three weeks, animals were evaluated in a radial arm water maze. Significant impairments were observed in the sedentary TG mice compared to WT in reference/long-term and working/short-term memory, as well as in probe trials. Exercised TG mice demonstrated improvements in memory, which made them indistinguishable from WT mice on all tasks. In addition, animals provided with an immobile wheel exhibited improvement in some, but not all cognitive measures. Our findings demonstrate that exercise can improve cognitive performance in a mouse model of AD even if applied after the development of pathology. PMID- 17698212 TI - Lesions of dopaminergic neurons in the substantia nigra pars compacta and in the ventral tegmental area enhance depressive-like behavior in rats. AB - Depression is the most common psychiatric complication in Parkinson's disease (PD). The pathophysiological events leading to PD-associated depression, however, remain largely unknown. The present study tested the differential implication of dopaminergic systems in depressive-like behavior in rats and its response to l Dopa and the selective serotonin reuptake inhibitor citalopram. The learned helplessness model was used as a behavioral paradigm. Rats were lesioned in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) and assigned to subgroups with respect to the stereologically verified extent of the nigral and/or VTA degeneration. Both lesions increased depressive-like behavior in rats, which was reduced by both citalopram and l-Dopa treatment. We conclude that dopaminergic lesions of either the SNc or the VTA contribute to the manifestation of depressive-like behavior in rats. The effects of citalopram administration on depressive behavior induced by lesions of dopaminergic brain regions furthermore suggest an involvement of serotonergic pathways in dopaminergic cell loss-induced depression. PMID- 17698213 TI - Food vacuole targeting and trafficking of falcipain-2, an important cysteine protease of human malaria parasite Plasmodium falciparum. AB - Malaria proteases are attractive anti-malarial targets because of their roles in parasite development and infection. Falcipain-2 (FP-2), a food vacuole cysteine protease in Plasmodium falciparum, is involved in hemoglobin degradation and cleavage of cytoskeletal elements. To understand the route of trafficking and identify the signals involved in trafficking to food vacuole, we have generated transgenic parasites expressing green fluorescent protein (GFP) fusion proteins comprising of N-terminal regions of falcipain-2 fused to GFP. Using falcipain2 GFP chimeras and anti-falcipain-2 antibody, we show that falcipain-2 is trafficked through a classical vesicle mediated secretory pathway involving endoplasmic reticulum and Golgi-like apparatus. Photobleaching and confocal microscopy techniques reveal that falcipain-2 is carried to the food vacuole in the form of cytostomal vesicles. We identify an N-terminal sequence (1-120aa) of falcipain-2, sufficient for its transport to the food vacuole. Analysis of sequences of few other food vacuole targeted proteins suggests a common mechanism for protein trafficking to food vacuole of malaria parasite. PMID- 17698214 TI - Hippocampal MMP-3 elevation is associated with passive avoidance conditioning. AB - Alterations in synaptic efficiency that underlie learning and memory consolidation appear to require an accompanying reconfiguration of the extracellular matrix (ECM). This restructuring of the ECM is carried out, in part, by a family of enzymes called, the matrix metalloproteinases, which includes matrix metalloproteinase-3 (MMP-3: stromelysin-1). The present study determined that a transient elevation in hippocampal MMP-3 expression occurred in rats following associative learning in the passive avoidance (PA) task. No change in MMP-3 was observed when rats were exposed either to the behavioral apparatus or the training stimulus alone. Furthermore, when an MMP-3 inhibitor was administered prior to PA training, dose-dependent learning deficits were observed, suggesting a causal relationship between learning-induced hippocampal MMP-3 elevation and associative memory formation. These findings suggest that increased hippocampal MMP-3 expression is an event that may play an important role in synaptic plasticity and memory consolidation. PMID- 17698215 TI - Cardiac contusion: ending myocardial confusion in this capricious syndrome. AB - Symptoms of cardiac contusion are very greatly and sometimes are non recognized or are masked by associated injury in severe chest trauma. Cardiac contusion clinically presents as a spectrum of signs and symptoms of varying severity, ranging from precordial pain, dyspnoea, and non specific ECG changes to increased serum activity of several enzymes, early severe rhythm abnormalities, severe conduction defects and death. We present a fatal case in which the definitive diagnosis of myocardial contusion has proved complex. All clinical data were suggestive of acute myocardial infarction, but the history of chest wall injury and gross and histological examination of the heart and coronary vessels led us to conclude for a cardiac contusion without myocardial infarction. In case of chest blunt trauma, the ECG should be interpreted within the context of the clinical situation, on history of chest wall injury, since a fatal myocardial contusion may occur after apparently mild injury. PMID- 17698216 TI - Left ventricular papillary muscles and trabeculae are significant determinants of cardiac MRI volumetric measurements: effects on clinical standards in patients with advanced systolic dysfunction. AB - BACKGROUND: Left ventricular (LV) mass and ejection fraction are of diagnostic and therapeutic importance in patients with systolic dysfunction. Cardiac MRI (CMR) has been proposed as a standard for these indices. Prior studies have variably included papillary muscles and trabeculae in either intracavitary or myocardial volumes. Quantitative effects and clinical implications of this methodological difference in patients with systolic dysfunction are unknown. METHODS: Fifty consecutive patients with known systolic dysfunction (EF<40%) underwent CMR. LV volumes were determined using previously established methods: Method 1 included papillary muscles and trabeculae in cavity volume, method 2 included these in myocardial volume. Both methods were used for each patient with tracings superimposed to isolate papillary/trabecular volume and insure consistency of other endocardial contours. Readers applied methods in random order blinded to clinical findings and results of the other method. RESULTS: LV mass differed substantially by method (p<0.001) with absolute difference of 16.6%. Ejection fraction differed by 3 points (p<0.001) with absolute differences of > or =5 points in 16% of patients. Mean differences in LV mass and ejection fraction were produced by consistent methodological differences on a per-patient basis. Methodology used produced differences in patients meeting established criteria for LV hypertrophy (28% vs. 60%, p<0.001) and ICD implantation (64% vs. 48%, p<0.01). CONCLUSIONS: LV mass and ejection fraction differ significantly between commonly employed CMR methods. Alternative inclusion of papillary muscles and trabeculae in either cavity or myocardial volumes produces significant differences in clinical and therapeutic indices that can affect management of patients with advanced systolic dysfunction. PMID- 17698217 TI - Correlation between omental TNF-alpha protein and plasma PAI-1 in obesity subjects. AB - BACKGROUND: The role of TNF-alpha in contributing to obesity-associated cardiovascular and metabolic risk has gained much attention. MATERIALS AND METHODS: Paired biopsies of omental and subcutaneous fat were collected from 16 lean subjects and 32 central obesity subjects. The expression of TNF-alpha in omental and subcutaneous fat was quantified by western blotting method, and correlations with plasma PAI-1, homeostasis model assessment insulin resistance (HOMA-IR), and lipid were investigated. RESULTS: In obese female, TNF-alpha expression was higher in the omental than in the subcutaneous fat tissue. There was no significant difference in the levels of TNF-alpha between subcutaneous and visceral fat in obese male. Significant positive correlations were found between omental TNF-alpha protein and plasma PAI-1 levels in obesity. In obese female subjects, omental TNF-alpha protein levels showed a close association with most of the parameters studied: fasting glucose (r=0.541, P<0.05); fasting insulin (r=0.599, P<0.01); HOMA-IR (r=0.546, P<0.05); triglycerides (r=0.469, P<0.05); HDL-cholesterol (r=-0.759, P<0.01). In obese male population, correlations between omental TNF-alpha protein levels and fasting glucose (r=0.762, P<0.01); fasting insulin (r=0.622, P<0.05); triglycerides (r=0.650, P<0.05); HDL cholesterol (r=-0.880, P<0.01) were found. CONCLUSION: Omental TNF-alpha may play a key role in contributing to cardiovascular risk in central obesity subjects. PMID- 17698218 TI - A strategy to offset the extra cost of sirolimus-eluting stent in patients undergoing intervention for acute myocardial infarction. AB - OBJECTIVE: To obtain a quantitative estimate of the overall costs and cost effectiveness ratio of sirolimus-eluting stents (SES) implantation and tirofiban infusion compared to abciximab and bare metal stent (BMS) in patients undergoing primary intervention for acute ST segment elevation myocardial infarction (STEMI). METHODS: In the attempt to make the unrestricted use of SES in STEMI patients affordable under the current European reimbursement system, between March 6, 2003, and April 23, 2004, 175 patients with STEMI were randomized to receive tirofiban infusion and SES versus abciximab and BMS as part of the STRATEGY trial. Costs and outcome were monitored for 2 years. RESULTS: The cost of the index procedure was 9345 euros +/-2573 and 9657+/-2114 for the tirofiban+SES and abciximab+BMS group, respectively (P=0.048). At follow-up, the composite of death or myocardial infarction and the costs not related to target vessel revascularisation (TVR) did not differ in the two groups while the rate of TVR and the costs related to it were lower in the tirofiban+SES group. The overall 2-year cost of treating a patient in the tirofiban+SES group was 10,971 euros +/-4185 compared to 12,066 euros +/-4636 for the abciximab+BMS group (P=0.006). Halving the cost of abciximab resulted in higher initial hospital costs for the tirofiban+SES but overall cost neutrality over a 24-month time horizon. CONCLUSIONS: Compared to abciximab+BMS, tirofiban infusion+SES implantation in STEMI patients was an economically dominant strategy, with an improved composite outcome and lower overall costs. PMID- 17698219 TI - Stepwise evaluation of syncope: a prospective population-based controlled study. AB - BACKGROUND: Evaluation of syncope remains often unstructured. The aim of the study was to assess the effectiveness of a standardized protocol designed to improve the diagnosis of syncope. METHODS: Consecutive patients with syncope presenting to the emergency departments of two primary and tertiary care hospitals over a period of 18 months underwent a two-phase evaluation including: 1) noninvasive assessment (phase I); and 2) specialized tests (phase II), if syncope remained unexplained after phase I. During phase II, the evaluation strategy was alternately left to physicians in charge of patients (control), or guided by a standardized protocol relying on cardiac status and frequency of events (intervention). The primary outcomes were the diagnostic yield of each phase, and the impact of the intervention (phase II) measured by multivariable analysis. RESULTS: Among 1725 patients with syncope, 1579 (92%) entered phase I which permitted to establish a diagnosis in 1061 (67%) of them, including mainly reflex causes and orthostatic hypotension. Five-hundred-eighteen patients (33%) were considered as having unexplained syncope and 363 (70%) entered phase II. A cause for syncope was found in 67 (38%) of 174 patients during intervention periods, compared to 18 (9%) of 189 during control (p<0.001). Compared to control periods, intervention permitted diagnosing more cardiac (8%, vs 3%, p=0.04) and reflex syncope (25% vs 6%, p<0.001), and increased the odds of identifying a cause for syncope by a factor of 4.5 (95% CI: 2.6-8.7, p<0.001). Overall, adding the diagnostic yield obtained during phase I and phase II (intervention periods) permitted establishing the cause of syncope in 76% of patients. CONCLUSION: Application of a standardized diagnostic protocol in patients with syncope improved the likelihood of identifying a cause for this symptom. Future trials should assess the efficacy of diagnosis-specific therapy. PMID- 17698220 TI - "Once apical ballooning, always apical ballooning?". AB - It is important that a cardiologist knows and recognizes the entity of takotsubo cardiomyopathy or apical ballooning, but remains aware that a subsequent similar episode is not necessarily a recurrence of this syndrome. Relapse may be caused by "classical" coronary atherosclerosis, as described in this case report. PMID- 17698221 TI - Anomalous interarterial left coronary artery: an evidence based systematic overview. AB - BACKGROUND: Isolated anomalous left main coronary artery (ALMCA) from the right aortic sinus of Valsalva (RASV) with an interarterial course between the pulmonary trunk and aorta is a rare congenital abnormality. We performed an evidence based systematic overview spanning 4 decades to assess the prevalence, clinical features and management of this anomaly. METHODS: A computerized search spanning 40 years was conducted to identify articles describing cases of ALMCA arising from the RASV with an interarterial course. The bibliographies of all relevant articles were also searched. RESULTS: The search identified 264 cases. Age ranged from 3.5 months to 87 years. Male/female ratio was 2.9/1. Forty-nine percent of the cases were diagnosed postmortem. Cardiac catheterization was the most common diagnostic tool (41.7%) followed by echocardiography, magnetic resonance imaging (MRI) and computerized assisted tomography. Fifty-seven (21.6%) cases underwent surgical procedures with no mortality and low morbidity. CONCLUSIONS: ALMCA from the RASV is associated with increased risk of sudden death, notably in young patients. Unfortunately the majority are diagnosed postmortem. More than a third present with sudden cardiac death. Echocardiography, computerized assisted tomography and cardiac MRI are valuable non-invasive diagnostic tools. Cardiac catheterization provides a definitive diagnosis in the majority. Surgical correction is the mainstay of treatment with low risk and good anatomic and functional results. PMID- 17698222 TI - The prognostic value of cardiopulmonary exercise testing with a peak respiratory exchange ratio of <1.0 in patients with chronic heart failure. AB - BACKGROUND: Peak oxygen consumption derived from a maximal cardiopulmonary exercise test (CPET) is a standard prognostic indicator in patients with chronic heart failure (CHF). Tests with a peak respiratory exchange ratio (pRER)<1.0 are often taken to be submaximal, and data from such tests are treated as less helpful. The aim of the current study was to compare the prognostic value of CPETs with a peak respiratory exchange ratio (pRER)<1.0 versus a pRER>/=1.0 in a large, representative sample of patients with CHF. METHODS AND RESULTS: 445 patients underwent a symptom-limited, treadmill-based CPET using the modified Bruce protocol, [82% males; age 72 (65-79) years]. 255 patients completed the CPET with a pRER>/=1.0. 121 patients died, and in survivors, the median follow-up period was 42 months. 42% of patients could not perform a CPET with pRER>/=1.0 using a modified Bruce protocol. Independent predictors of mortality were peak oxygen uptake, and the VE/VCO(2) ratio. 190 patients completed the CPET with a pRER<1.0. Independent predictors of mortality were age, peak oxygen pulse, and history of angina. RER group (pRER<1.0 versus pRER>/=1.0) remained an independent predictor of mortality in all patients. CONCLUSIONS: Independent predictors of mortality were different in patients with a pRER<1.0 compared to those with a pRER>/=1.0. In CHF patients with a pRER<1.0, traditional prognostic markers (VE/VCO(2) slope, peak oxygen uptake) were not independently predictive of mortality. PMID- 17698223 TI - Prolonged combination anti-platelet therapy following per-cutaneous coronary intervention (PCI) is impractical in the elderly. AB - A prolonged course of anti-platelet therapy is increasingly recommended following per-cutaneous coronary intervention based on the evidence from several clinical trials. However, the practicality and risk of such therapy in unselected patient population is as yet unclear. This study shows that such prolonged regimes of anti-platelet therapy are not practical in the elderly sub-group of patients. PMID- 17698224 TI - Diagnostic performance of mid-regional pro-adrenomedullin as an analyte for the exclusion of left ventricular dysfunction. AB - AIMS: In ambulatory patients with coronary artery disease (CAD) we aimed to evaluate the diagnostic performance of mid-regional pro-adrenomedullin (MR proADM) for the detection or exclusion of impaired left ventricular ejection fraction (LVEF). METHODS AND RESULTS: MR-proADM levels were measured in blood samples taken from 102 outpatients with CAD classified according to the New York Heart Association (NYHA) and Canadian Cardiovascular society (CCS) I-II. Increased levels of MR-proADM correlated with impaired LVEF (r=-0.21, p=0.046). The optimal threshold of MR-proADM for identification of impaired LVEF <50% was 0.54 nmol/L with an area under the ROC curve (AUC) of 0.64 (p=0.06). In univariate and multivariate calculation, MR-proADM >0.54 nmol/L remained associated with left ventricular dysfunction even after adjusting for age and gender. The negative predictive value (NPV) for MR-proADM T) is a significant risk factor for an acute myocardial infarction (AMI) and if SNPs affect the transcription of the gene that elevates the MMP-9 expression level. METHODS: A polymerase chain reaction, followed by a restriction fragment length polymorphism analysis, was performed in 173 control participants and 206 AMI patients. The serum levels of MMP-9 in the groups with or without the SNP were measured using ELISA and compared. RESULTS: There was a significantly higher incidence of th-1562C>T MMP-9 polymorphism in the AMI patients compared to the control group (27.6% vs 17.9%, p=0.04). A multiple logistic regression analysis of the risk factors for coronary artery disease and the MMP-9 polymorphism showed the MMP-9 polymorphism to be an important factor in the prediction of an AMI (odds ratio 1.67, 95% confidence interval 1.02-2.67, p=0.04). The serum level of MMP-9 was also higher in the group with the SNP than in the group without (494.8+/-3.66 ng/ml vs 309.5+/-2.19 ng/ml, p=0.04). CONCLUSION: These results suggest that the -1562C>T polymorphism in the MMP-9 promoter is strongly associated with an AMI. PMID- 17698229 TI - Enhanced concentration and isolation of Cyclospora cayetanensis oocysts from human fecal samples. AB - Cyclospora cayetanensis is the causative agent of cyclosporiasis, an emerging infectious disease. We present a new method for the purification of C. cayetanensis oocysts from feces using a modified detachment solution and Renocal sucrose gradient sedimentation. This method yields oocysts free from adherent fecal debris and amenable to processing using flow cytometry. PMID- 17698230 TI - Pictures of microbiology -- the biofilm imaging facility under Dr. David C. White. AB - This contribution honoring David C. White (DC) summarizes the five years I interacted with him on a daily basis in his laboratory. Over this time we worked on many different projects all tied together by the unifying principle now recognized as central to bacterial life in nature: biofilms. My goal is to convey some of the excitement and joy of working with DC and, from my perspective, that means telling how the Biofilm Imaging Facility at the Center for Environmental Biotechnology (CEB) came into existence and describing some of the projects on which DC and I worked. PMID- 17698231 TI - Accuracy of volume and DVH parameters determined with different brachytherapy treatment planning systems. AB - PURPOSE: To determine the uncertainties in dose volume histogram (DVH) analysis used in modern brachytherapy treatment planning systems (TPSs). MATERIALS AND METHODS: A phantom with three different volumes was scanned with CT and MRI. An inter-observer analysis was based on contouring performed by 5 persons. The volume of a standard contour set was calculated using seven different TPSs. For five systems a typical brachytherapy dose distribution was used to compare DVH determination. RESULTS: The inter-observer variability (1SD) was 13% for a small cylindrical volume, 5% for a large cylinder and 3% for a conical shape. A standardized volume for a 4mm CT scan contoured on seven different TPS varied by 7%, 2%, and 5% (1SD). Use of smaller slice thickness reduced the variations. A treatment plan with the sources between the large cylindrical shape and the cone showed variations for D(2cc) of 1% and 5% (1SD), respectively. Deviations larger than 10% were observed for a smaller source to cylinder surface distance of 5mm. CONCLUSIONS: Modern TPSs minimize the volumetric and dosimetric calculation uncertainties. These are comparable to inter-observer contouring variations. However, differences in volume result from the methods of calculation in the first and last slice of a contoured structure. For this situation and in case of high dose gradients inside analyzed volumes, high uncertainties were observed. The use of DVH parameters in clinical practice should take into account the method of calculation and the possible uncertainties. PMID- 17698232 TI - The problem of serial order in behavior: Lashley's legacy. AB - In a prescient paper Karl Lashley (1951) rejected reflex chaining accounts of the sequencing of behavior and argued instead for a more cognitive account in which behavioral sequences are typically controlled with central plans. An important feature of such plans, according to Lashley, is that they are hierarchical. Lashley offered several sources of evidence for the hierarchical organization for behavioral plans, and others afterward provided more evidence for this hypothesis. We briefly review that evidence here and then shift from a focus on the structure of plans (Lashley's point of concentration) to the processes by which plans are formed in real time. Two principles emerge from the studies we review. One is that plans are not formed from scratch for each successive movement sequence but instead are formed by making whatever changes are needed to distinguish the movement sequence to be performed next from the movement sequence that has just been performed. This plan-modification view is supported by two phenomena discovered in our laboratory: the parameter remapping effect, and the handpath priming effect. The other principle we review is that even single movements appear to be controlled with hierarchically organized plans. At the top level are the starting and goal postures. At the lower level are the intermediate states comprising the transition from the starting posture to the goal posture. The latter principle is supported by another phenomenon discovered in our lab, the end-state comfort effect, and by a computational model of motor planning which accounts for a large number of motor phenomena. Interestingly, the computational model hearkens back to a classical method of generating cartoon animations that relies on the production of keyframes first and the production of interframes (intermediate frames) second. PMID- 17698233 TI - Modeling the effect of temperature on the growth rate and lag phase of Penicillium expansum in apples. AB - The objective of the present study was to develop validated models that describe the effect of storage temperature on the growth rate and lag phase of six Penicillium expansum strains. The growth of the selected strains was therefore studied on Apple Puree Agar Medium (APAM) at 30, 25, 16, 10, 4 and 2 degrees C. Growth rates and lag phases were estimated using linear regression. Several secondary models were evaluated and for the growth rate, a modification of the extended Ratkowsky model was selected. Regarding the lag phase, the Arrhenius Davey model provided the best adjustment to the observed data. Model validation was performed in two steps. Firstly, the developed models were validated on APAM. The obtained bias factors (Bf) ranged from 0.91 to 1.14 and the accuracy factors (Af) were <1.2 for the validation performed on APAM, indicating that the models were good predictors of the true mean colony growth rate and lag phase. Afterwards, an external validation was carried out in apples. For the growth rate, Bf ranged from 0.64 to 0.81 and Af<1.39, indicating conservative predictions. On the contrary for the lag phase, a clear deviation was observed between predictions and observed values on apples (0.351.6). These results highlight that the use of simulation or synthetic media for the development of predictive models for the lag phase of moulds can lead to inadequate predictions and that a validation on the real food matrix is necessary. Application of the developed models is possible in the framework of Quantitative Risk Assessment to develop control strategies against blue mould rot in apple and enables the inclusion of strain variability. However, possible underestimation of the lag phase should be taken into account. PMID- 17698234 TI - Circumventing the heterogeneity and instability of human serum albumin-interferon alpha2b fusion protein by altering its orientation. AB - Albuferon is a novel long-acting interferon resulted from the direct genetic fusion of human albumin and interferon-alpha2b (HSA-IFN-alpha2b). Albuferon, co developed by Human Genome Sciences Inc. and Novartis, is currently in late stage development for the treatment of hepatitis C. It was unexpected that HSA-IFN alpha2b secreted from Pichia pastoris migrated as doublets on non-reducing SDS PAGE and was prone to form covalent aggregates in aqueous solution. The heterogeneity and instability of HSA-IFN-alpha2b lowered its recovery rate to about 10% and necessitated lyophilized formulation. Site-directed mutagenesis revealed that the heterogeneity and instability of HSA-IFN-alpha2b was caused by the incomplete disulfide bridge formation between Cys1 and Cys98 of IFN-alpha2b. To alleviate the structural perturbation of IFN-alpha2b by HSA, IFN-alpha2b-HSA fusion protein, in which IFN-alpha2b was located at the N-terminus, was created. IFN-alpha2b-HSA was shown to be homogeneous and stable at 37 degrees C for at least 10 days. The improved homogeneity and stability of IFN-alpha2b-HSA increased the recovery rate by 2.5-fold and made the development of stable solution formulation possible. In vitro antiviral assays showed that both fusion proteins retained the activity of IFN-alpha2b, and the EC(50) of HSA-IFN-alpha2b, and IFN-alpha2b-HSA was calculated to be 120+/-12.5, and 160+/-1 1.3ng/ml, respectively. The increased recovery rate and the possibility of solution formulation of IFN-alpha2b-HSA may compensate for its slightly decreased in vitro activity, and makes it to be a promising therapeutic agent that deserves further evaluation. PMID- 17698235 TI - A non-isotopic in vitro assay for histone acetylation. AB - We describe a simple, robust, and relatively inexpensive non-radioactive in vitro assay for measuring histone acetyl-transferase activity. The assay takes advantage of easy to purify recombinant E. coli-derived fusion proteins containing the NH(2)-terminal tails of histones H3 and H4 linked to epitope tagged maltose-binding protein (MBP), and immunoblotting with antibodies specific to acetylated H3 and H4. Here we show the specificity and dynamic range of this assay for the histone acetyl-transferases, p300 and PCAF. This assay may be adapted readily for other substrates by simply generating new fusion proteins and for other acetyl-transferases by modifying reaction conditions. PMID- 17698236 TI - Assessing the expression of chicken anemia virus proteins in plants. AB - Chicken anemia virus (CAV) is an important pathogen of chicken worldwide, causing severe anemia and immunodeficiency. Its small single-stranded DNA genome (2.3kb) encodes three proteins: VP1, the only structural protein, VP2, a protein phosphatase, and VP3, also known as apoptin, which induces apoptosis. In this study, CAV proteins were expressed in plants as an alternative for recombinant protein production in animal cells. Additionally, the effect of VP3 expression was tested to evaluate possible involvement in programmed cell death in plants. The CAV genes were cloned in binary vectors with the Green fluorescent protein (GFP) as N terminal fusion, and into a Potato virus X (PVX) and Tobacco Mosaic Virus (TMV)-based vectors. Nicotiana benthamiana plants were inoculated with Agrobacterium tumefaciens containing the binary vector constructs or the PVX and TMV constructs. Upon transient expression GFP:VP1 and GFP:VP2 were observed throughout the nucleoplasm, whereas VP3 formed compact aggregates within the nucleus, indicating functional nuclear localization signals in all three proteins. An intense fluorescence was observed for VP2 and VP3 fusions, whereas GFP:VP1 fluorescence remained faint and was only detected in a limited number of cells. Co-expression of GFP:VP1 and VP2 had a marked alteration on the distribution of GFP:VP1, forming large VP1 aggregates throughout the nucleus, indicating an interaction of the two CAV proteins. No visible alteration on GFP pattern was detected upon co-expression of GFP:VP1 and VP3, or with GFP:VP2 and VP3. Plants infected with PVX or TMV-based vectors expressing VP3 displayed strong necrosis and wilting, however, a direct association with VP3 expression and programmed cell death in plants, could not be established. Overall, our results show that all CAV proteins can be expressed in plant cells, though expression level of VP1 needs to be further optimized before testing its potential as (edible) subunit vaccine. PMID- 17698237 TI - Hepatic fat content-independent association of the serum level of gamma glutamyltransferase with visceral adiposity, but not subcutaneous adiposity. AB - We investigated the association between the serum level of gamma glutamyltransferase (GGT) and parameters of adiposity and lipid profile, including the serum triglyceride (TG), HDL-cholesterol (HDL-C) and LDL cholesterol (LDL-C) levels in Japanese patients with type 2 diabetes mellitus and non-diabetic subjects. A total of 257 Japanese subjects (169 patients with type 2 diabetes and 88 non-diabetic subjects) were enrolled in the study. To assess the hepatic fat content, the ratio of the CT attenuation value of the liver to that of the spleen (L/S ratio) was calculated. Serum GGT was significantly correlated with the waist circumference, BMI, visceral fat area (VFA), L/S ratio and TG, but not with the subcutaneous fat area (SFA). The serum GGT was still correlated with the VFA and TG, but not with the SFA, after adjustment for the four variables of age, gender, serum HbA1c and the L/S ratio. Our finding that the serum GGT is specifically associated with the VFA, but not with the SFA, suggests that the serum GGT may be useful as a convenient indicator of VFA in the clinical treatment of obesity. PMID- 17698238 TI - Is there a place for Liver Transplantation for "non HCC" tumors? PMID- 17698239 TI - Palestinian women's pregnancy intentions: analysis and critique of the Demographic and Health Survey 2004. AB - OBJECTIVES: The Palestinian DHS2004 reports on pregnancy intentions and their determinants are analyzed for the first time. Through this analysis, the survey instrument limitations are also highlighted. METHODS: Data on 15-49 years old ever married, non-pregnant women reporting on their last pregnancy were selected from a nationally representative cross sectional survey dataset. RESULTS: Older women were more likely not to desire the pregnancy at all, and younger women more likely to have desired to wait; with higher reports of not desiring the pregnancy at all or desiring to wait among those with a higher number of children; with higher reports of not desiring the pregnancy at all, or desiring to wait, among women who reported ever using family planning methods. Women who experienced prenatal and postnatal complications reported higher levels of having desired to wait or not having wanted the pregnancy at all, calling for the inclusion of process measures in pregnancy intention studies. CONCLUSIONS: While some of our findings are comparable to those cited in the international literature, the analysis was limited to the type of questions asked in the Palestinian DHS survey. There is a need to further develop the survey instrument in order to address women's needs from a public health policy perspective. We call for the inclusion of additional social measures to identify some of the contextual factors that influence pregnancy intentions. PMID- 17698240 TI - Photodynamic therapy for lung cancers based on novel photodynamic diagnosis using talaporfin sodium (NPe6) and autofluorescence bronchoscopy. AB - BACKGROUND: We had previously developed the possibility of use of a photodynamic diagnosis (PDD) system using a tumor-selective photosensitizer and laser irradiation for the early detection and photodynamic therapy (PDT) for centrally located early lung cancers. Recently, we established the autofluorescence diagnosis system integrated into a videoendoscope (SAFE-3000) as a very useful technique for the early diagnosis of lung cancer. PATIENTS AND METHODS: Twenty nine patients (38 lesions) with centrally located early lung cancer received PDD and PDT using the second-generation photosensitizer, talaporfin sodium (NPe6). Just before the PDT, we defined the tumor margin accurately using the novel PDD system SAFE-3000 with NPe6 and a diode laser (408nm). RESULTS: Red fluorescence emitted from the tumor by excitation of the photosensitizer by the diode laser (408nm) from SAFE-3000 allowed accurate determination of the tumor margin just before the PDT. The complete remission (CR) rate following NPe6-PDT in the cases with early lung cancer was 92.1% (35/38 lesions). We also confirmed the loss of red fluorescence from the tumors immediately after the PDT using SAFE-3000. We confirmed that all the NPe6 in the tumor had been excited and photobleached by the laser irradiation (664nm) and that no additional laser irradiation was needed for curative treatment. CONCLUSIONS: This novel PDD system using SAFE-3000 and NPe6 improved the quality and efficacy of PDT and avoided misjudgement of the dose of the photosensitizer or laser irradiation in PDT. PDT using NPe6 will become a standard option of treatments for centrally located early lung cancer. PMID- 17698241 TI - Combination chemotherapy with cisplatin, etoposide and irinotecan in patients with extensive small-cell lung cancer: A phase II study of the Hellenic Co operative Oncology Group. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy and toxicity of cisplatin, etoposide and irinotecan as first-line treatment in patients with extensive small-cell lung cancer (E-SCLC). PATIENTS AND METHODS: Chemo-naive adult patients with a performance status (PS) of 0-2 and adequate organ function were eligible. Patients received cisplatin 20mg/m(2) i.v. daily for three consecutive days, etoposide 75mg/m(2) i.v. daily for three consecutive days and irinotecan 120mg/m(2) i.v. on day 2, every 21 days for six to eight cycles. Administration of G-CSF was given in the presence of febrile neutropenia and as a 5-day prophylaxis around the recorded nadir day in patients who developed grades 3-4 neutropenia. RESULTS: Fifty-six patients were assessable. The median age was 62.2 years; 96.4% had PS 0-1, 33.5% had >3 metastatic sites. The overall response rate was 80.4% with 8 (14.3%) patients achieving a complete response. The median time to tumor progression was 7.8 months [95% confidence interval (CI), 7.1-8.6 months] with a median survival of 15.1 months [95% CI, 9.7-20.5 months] and 1 year survival rate of 56.5%. One patient died from toxicity. Grades 3-4 neutropenia occurred in 37.5% of patients, grades 3-4 thrombocytopenia occurred in 10.9% of patients and 11 (19.6%) patients developed febrile neutropenia. Grades 3-4 non-hematological toxicities were primarily nausea-vomiting 3.6%, diarrhea 7.1% and fatigue 3.6%. CONCLUSION: This study strongly suggests that cisplatin, etoposide and irinotecan combination is very effective for the treatment of E-SCLC with good safety profile. The triplet regimen currently seems a promising regimen and has to be further explored in phase III trials. PMID- 17698242 TI - Effect of water-table fluctuation on dissolution and biodegradation of a multi component, light nonaqueous-phase liquid. AB - Light nonaqueous-phase liquids (LNAPLs) such as gasoline and diesel fuel are among the most common causes of soil and groundwater contamination. Dissolution and subsequent advective transport of LNAPL components can negatively impact water supplies, while biodegradation is thought to be an important sink for this class of contaminants. We present a laboratory investigation of the effect of a water-table fluctuation on dissolution and biodegradation of a multi-component LNAPL (85% hexadecane, 5% toluene, 5% ethylbenzene, and 5% 2-methylnapthalene on a molar basis) in a pair of similar model aquifers (80 cm x 50 cm x 3 cm), one of which was subjected to a water-table fluctuation. Water-table fluctuation resulted in LNAPL and air entrapment below the water table, an increase in the vertical extent of the LNAPL source zone (by factor 6.7), and an increase in the volume of water passing through the source zone (by factor ~18). Effluent concentrations of dissolved LNAPL components were substantially higher and those of dissolved nitrate lower in the model aquifer where a fluctuation had been induced. Thus, water-table fluctuation led to enhanced biodegradation activity (28.3 mmol of nitrate consumed compared to 16.3 mmol in the model without fluctuation) as well as enhanced dissolution of LNAPL components. Despite the increased biodegradation, fluctuation led to increased elution of dissolved LNAPL components from the system (by factors 10-20). Hence, water-table fluctuations in LNAPL-contaminated aquifers might be expected to result in increased exposure of downgradient receptors to LNAPL components. Accordingly, water-table fluctuations in contaminated aquifers are probably undesirable unless the LNAPL is of minimal solubility or the dissolved-phase plume is not expected to reach a receptor due to distance or the presence of some form of containment. PMID- 17698243 TI - Evaluating equilibrium and non-equilibrium transport of bromide and isoproturon in disturbed and undisturbed soil columns. AB - In this study, displacement experiments of isoproturon were conducted in disturbed and undisturbed columns of a silty clay loam soil under similar rainfall intensities. Solute transport occurred under saturated conditions in the undisturbed soil and under unsaturated conditions in the sieved soil because of a greater bulk density of the compacted undisturbed soil compared to the sieved soil. The objective of this work was to determine transport characteristics of isoproturon relative to bromide tracer. Triplicate column experiments were performed with sieved (structure partially destroyed to simulate conventional tillage) and undisturbed (structure preserved) soils. Bromide experimental breakthrough curves were analyzed using convective-dispersive and dual permeability (DP) models (HYDRUS-1D). Isoproturon breakthrough curves (BTCs) were analyzed using the DP model that considered either chemical equilibrium or non equilibrium transport. The DP model described the bromide elution curves of the sieved soil columns well, whereas it overestimated the tailing of the bromide BTCs of the undisturbed soil columns. A higher degree of physical non-equilibrium was found in the undisturbed soil, where 56% of total water was contained in the slow-flow matrix, compared to 26% in the sieved soil. Isoproturon BTCs were best described in both sieved and undisturbed soil columns using the DP model combined with the chemical non-equilibrium. Higher degradation rates were obtained in the transport experiments than in batch studies, for both soils. This was likely caused by hysteresis in sorption of isoproturon. However, it cannot be ruled out that higher degradation rates were due, at least in part, to the adopted first order model. Results showed that for similar rainfall intensity, physical and chemical non-equilibrium were greater in the saturated undisturbed soil than in the unsaturated sieved soil. Results also suggested faster transport of isoproturon in the undisturbed soil due to higher preferential flow and lower fraction of equilibrium sorption sites. PMID- 17698244 TI - Interspecific root interactions and rhizosphere effects on salt ions and nutrient uptake between mixed grown peanut/maize and peanut/barley in original saline sodic-boron toxic soil. AB - Two glasshouse studies were conducted to investigate the effect of interspecific complementary and competitive root interactions and rhizosphere effects on the concentration and uptake of Na, Cl and B, and N, P, K, Ca, Mg, Fe, Zn and Mn nutrition of mixed cropped peanut with maize (Experiment I), and barley (Experiment II) grown in nutrient-poor saline-sodic and B toxic soil. Mixed cropped plants were grown in either higher density or lower density. The results of the experiment revealed that dry shoot weight decreased in peanut but increased in maize and barley with associated plant species compared to their monoculture. Shoot Na and Cl concentrations of peanut decreased significantly in both experiments, regardless of higher or lower density. The concentrations of Na also decreased in the shoots of mixed cropped maize and barley, but Cl concentrations increased slightly. The concentration of B significantly decreased in mixed cropping in all plant species regardless of higher or lower density. Rhizosphere chemistry was strongly and differentially modified by the roots of peanut, maize and barley, and mixed growing. There were significant correlations between the root-secreted acid phosphatases (S-APase), acid phosphatase in rhizosphere (RS-APase) and rhizosphere P concentration (RS-P) in the both experiments. The Fe-solubilizing activity (Fe-SA) and ferric reducing (FR) capacity of the roots were generally higher in mixed culture relative to their monoculture, which improved Fe, Zn and Mn nutrition of peanut. Further, there were also significant correlations among FR, Fe-SA and RS-Fe concentrations. Peanut facilitated P nutrition of maize and barley, while maize and barley improved K, Fe, Zn and Mn nutrition of peanut grown in nutrient-poor saline-sodic and B toxic soil. PMID- 17698245 TI - Inhibitory effect of PACAP-38 on acute neurogenic and non-neurogenic inflammatory processes in the rat. AB - Inhibitory actions of pituitary adenylate cyclase activating polypeptide (PACAP) have been described on cellular/vascular inflammatory components, but there are few data concerning its role in neurogenic inflammation. In this study we measured PACAP-like immunoreactivity with radioimmunoassay in the rat plasma and showed a two-fold elevation in response to systemic stimulation of capsaicin sensitive sensory nerves by resiniferatoxin, but not after local excitation of cutaneous afferents. Neurogenic plasma extravasation in the plantar skin induced by intraplantar capsaicin or resiniferatoxin, as well as carrageenan-induced paw edema were significantly diminished by intraperitoneal PACAP-38. In summary, these results demonstrate that PACAP is released from activated capsaicin sensitive afferents into the systemic circulation. It diminishes acute pure neurogenic and mixed-type inflammatory reactions via inhibiting pro-inflammatory mediator release and/or by acting at post-junctional targets on the vascular endothelium. PMID- 17698247 TI - Rapid identification of precursor cDNAs encoding five structural classes of antimicrobial peptides from pickerel frog (Rana palustris) skin secretion by single step "shotgun" cloning. AB - The skin secretion of the North American pickerel frog (Rana palustris) has long been known to have pronounced noxious/toxic properties and to be highly effective in defence against predators and against other sympatric amphibians. As it consists largely of a complex mixture of peptides, it has been subjected to systematic peptidomic study but there has been little focus on molecular cloning of peptide-encoding cDNAs and by deduction, the biosynthetic precursors that they encode. Here, we demonstrate that the cDNAs encoding the five major structural families of antimicrobial peptides can be elucidated by a single step "shotgun" cloning approach using a cDNA library constructed from the source material of the peptidomic studies--the defensive skin secretion itself. Using a degenerate primer pool designed to a highly conserved nucleic acid sequence 5' to the initiation codon of known antimicrobial peptide precursor transcripts, we amplified cDNA sequences representing five major classes of antimicrobial peptides, such as esculentins, brevinins, ranatuerins, palustrins and temporins. Bioinformatic comparisons of precursor open-reading frames and nucleic acid sequences revealed high degrees of structural similarities between analogous peptides of R. palustris and the Chinese bamboo odorous frog, Rana versabilis. This approach thus constitutes a robust technique that can be used either alone or ideally, in parallel with peptidomic analysis of skin secretion, to rapidly extract primary structural information on amphibian skin secretion peptides and their biosynthetic precursors. PMID- 17698246 TI - Effect of orphanin FQ/nociceptin (OFQ/N) and isoflurane on the prolactin secretory response in OFQ/N knockout mice. AB - The prolactin secretory response to subcutaneous injection of orphanin FQ/nociceptin (OFQ/N) was measured in wild-type and OFQ/N knockout mice. These injections were given with and without isoflurane anesthesia, to determine if isoflurane would affect the prolactin secretory response. OFQ/N injection significantly increased prolactin levels in males and females, regardless of genotype, with a more robust response in females. Isoflurane pretreatment did not affect prolactin levels in controls or in animals injected with OFQ/N. This is the first report that exogenously administered OFQ/N stimulates prolactin secretion in mice and that brief isoflurane exposure does not significantly affect this response. PMID- 17698248 TI - Prolyl, cystyl and pyroglutamyl peptidase activities in the hippocampus and hypothalamus of streptozotocin-induced diabetic rats. AB - Prolyl, cystyl and pyroglutamyl peptidases are emerging targets for diabetes and cognitive deficit therapies. The present study is focused on the influence of diabetes mellitus induced by streptozotocin on levels of representative hydrolytic activities of these enzymes in the rat hypothalamus and hippocampus. Streptozotocin-diabetic rats presented about 348mg glucose/dL blood, and a slightly increased hematocrit and plasma osmolality. The activities of soluble and membrane-bound dipeptidyl-peptidase IV, and soluble cystyl aminopeptidase did not differ between diabetic and control rats in both brain areas. Hippocampal soluble prolyl oligopeptidase presented similar activities between diabetic and controls. Increased activities in diabetics were observed for soluble prolyl oligopeptidase (1.78-fold) and membrane-bound cystyl aminopeptidase (2.55-fold) in the hypothalamus, and for membrane-bound cystyl aminopeptidase (5.14-fold) in the hippocampus. In both brain areas, the activities of membrane-bound and soluble pyroglutamyl aminopeptidase were slightly lower (<0.7-fold) in diabetics. All modifications (except hematocrit) observed in streptozotocin-treated rats were mitigated by the administration of insulin. Glucose and/or insulin were shown to alter in vitro the hypothalamic activities of soluble pyroglutamyl aminopeptidase and prolyl oligopeptidase, as well as membrane-bound cystyl aminopeptidase. These data provide the first evidence that diabetes mellitus generates direct and indirect effects on the activity levels of brain peptidases. The implied regional control of regulatory peptide activity by these peptidases suggests novel potential approaches to understand certain disruptions on mediator and modulatory functions in diabetes mellitus. PMID- 17698249 TI - Evidence for a C-terminal structural motif in gastrin and its bioactive fragments in membrane mimetic media. AB - The conformational preferences of human little gastrin, [Nle(15)] gastrin-17, and its short analogues, gastrin-4 and [beta-Ala(1)] gastrin-5, which include the C terminal tetrapeptide sequence Trp-Met-Asp-Phe-NH(2) crucial for gastrin bioactivity, were determined by NMR spectroscopy in aqueous solutions of zwitterionic dodecylphosphocholine micelles. Backbone HN chemical shift temperature variance, Halpha chemical shift deviations and complex non-sequential NOE patterns pointed to the C-terminal of [Nle(15)] gastrin-17 adopting an ordered conformation. Distance geometry calculations and NOE-restrained molecular dynamics simulations in membrane mimetic solvent boxes of decane and water indicated the C-terminal tetrapeptide sequence of all three peptides adopted a similar, well defined structure, with a general type IV beta-turn observed for all three peptides. The conformation of [Nle(15)] gastrin-17 consisted of two short helices between Leu(5)-Glu(9) and Ala(11)-Trp(14), with the one helix terminating in a type I beta-turn spanning Gly(13)-Asp(16). The experimental evidence and conformational characteristics of the three peptides in micellar media support a membrane-associated mechanism of receptor recognition and activation for the gastrin hormone family and furthermore point to a possible biologically relevant structural motif for gastrin activity. PMID- 17698250 TI - Isolation and cDNA cloning of cholecystokinin from the skin of Rana nigrovittata. AB - Many neuroendocrine peptides that are distributed in amphibian gastrointestinal tract and central nervous system are also found in amphibian skins, and these peptides are classified into skin-gut-brain triangle peptides, such as bombesins, gastrin-releasing peptides. Cholecystokinins (CCKs) are neuroendocrine peptides known for their production in the gastrointestinal tract and central nervous system of mammalians. Several CCKs have been identified from two amphibians, Rana catesbeiana and Xenopus laevis. These amphibian CCKs are found to be express in brain and in the gastrointestinal tract, but not in skin. In the current report, a cholecystokinin (CCK) isoform was identified from skin secretions of the frog, Rana nigrovittata. Its amino acid sequence is RVDGNSDQKAVIGAMLAKDLQTRKAGSSTGRYAVLPNR PVIDPTHRINDRDYMGWMDF, which is the same with that of CCK from R. catesbeiana. Four different cDNAs (GenBank accession nos. EF608063-6) encoding CCK precursors were cloned from the cDNA library of the skin of R. nigrovittata. The present data demonstrated that amphibian CCK could also be expressed in gastrointestinal tract, central nervous system and skin as other amphibian skin-gut-brain triangle peptides. PMID- 17698251 TI - Purification and characterization of antimicrobial peptides from the skin secretion of Rana dybowskii. AB - Six antimicrobial peptides designated dybowskins were isolated from the skin secretion of Rana dybowskii, an edible frog in Korea. Dybowskin-1 (FLIGMTHGLICLISRKC) and dybowskin-2 (FLIGMTQGLICLITRKC) were isoforms differing in only two amino acid residues at the 7th and 14th positions from the N terminus, and they showed amino acid sequence similarities with ranalexin peptides. Dybowskin-3 (GLFDVVKGVLKGVGKNVAGSLLEQLKCKLSGGC), dybowskin-4 (VWPLGLVICKALKIC), dybowskin-5 (GLFSVVTGVLKAVGKNVAKNVGGSLLEQLKCKISGGC), and dybowskin-6 (FLPLLLAGLPLKLCFLFKKC) differed in both size and sequence, and they were, in terms of amino acid sequence similarities, related to brevinin-2, japonicin-2, esculentin-2, and brevinin-1 peptides, respectively. All the peptides presented in this paper contained Rana-box, the cyclic heptapeptide domain, which is conserved in other antimicrobial peptides derived from the genus Rana. All the dybowskin peptides showed a broad spectrum of antimicrobial activity against the Gram-positive and Gram-negative bacteria (minimum inhibition concentrations (MIC), 12.5 to >100 microg/ml) and against Candida albicans (MIC, 25 to >100 microg/ml). Especially, dybowskin-4 with valine at its N-terminus was the most abundant and showed the strongest antimicrobial activity among all the dybowskin peptides. This result indicates that the dybowskin peptides from R. dybowskii, whose main habitats are mountains or forests, have evolved differently from antimicrobial peptides isolated from other Korean frogs, whose habitats are plain fields. PMID- 17698252 TI - An antimicrobial peptide with antimicrobial activity against Helicobacter pylori. AB - An antimicrobial peptide named odorranain-HP was identified from skin secretions of the diskless odorous frog, Odorrana grahami. It is composed of 23 amino acids with an amino acid sequence of GLLRASSVWGRKYYVDLAGCAKA. By BLAST search, odorranain-HP had similarity to antimicrobial peptide odorranain-W1 but it has a different GLLR N-terminus. The cDNA encoding odorranain-HP was cloned from the cDNA library of the skin of O. grahami. This peptide showed antimicrobial activities against tested microorganisms. Interestingly, odorranain-HP could exert antimicrobial capability against Helicobacter pylori, along with its antimicrobial activities similar to odorranain-W1. This is the first report of naturally occurring peptide with anti-H. pylori activity from amphibian skins. PMID- 17698253 TI - In vitro activity of the synthetic lipopeptide PAL-Lys-Lys-NH(2) alone and in combination with antifungal agents against clinical isolates of Cryptococcus neoformans. AB - The in vitro activity of the lipopeptide PAL-Lys-Lys-NH(2) (PAL), alone or combined with either fluconazole (FLU) or amphotericin B (AMB), was investigated against 14 Cryptococcus neoformans isolates. PAL MICs ranged from 1.0 to 4.0 microg/ml. Fungicidal activity was observed. Synergy, defined as a fractional inhibitory concentration (FIC) index of < or =0.5, was observed in 21.4% of PAL/AMB interactions. Antagonism (FIC index>4) was never observed. The broad antifungal activity and the positive interactions with AMB suggest that PAL can represent a promising candidate in infections due to C. neoformans. PMID- 17698254 TI - Noladin ether, a putative endocannabinoid, inhibits mu-opioid receptor activation via CB2 cannabinoid receptors. AB - We examined the occurrence of possible changes in mRNA expression and the functional activity of opioid receptors after acute in vivo and in vitro treatment with the putative endogenous cannabinoid noladin ether. While noladin ether (NE) demonstrates agonist activity at CB1 cannabinoid receptors, recent data indicate that NE acts as a full agonist at CB2 cannabinoid receptors too. Considering the functional interactions between opioids and cannabinoids, it is of interest to examine whether NE affects the opioid system. To that end, we studied the influence of NE on mu-opioid receptor (MOR) mRNA expression and MOR mediated G-protein signaling. We used real-time PCR and [35S]GTPgammaS binding assays to examine the changes of MOR mRNA levels and the capability of the mu opioid agonist peptide ([D-Ala2,(NMe)Phe4,Gly5-ol]enkephalin (DAMGO) in activating regulatory G-proteins via MORs in forebrain membrane fractions of wild type (w.t., CB1+/+) and CB1 receptor deficient transgenic mice (knockout, CB1-/ ). We found, that the expression of MOR mRNAs significantly decreased both in CB1+/+ and CB1-/- forebrain after a single injection of NE at 1 mg/kg when compared to control. Consequently, MOR-mediated signaling is attenuated after acute in vivo treatment with NE in both CB1+/+ and CB1-/- mice. Inhibition on MOR mediated activation is observed after in vitro NE administration as well. Radioligand binding competition studies showed that the noticed effect of NE on MOR signaling is not mediated through MORs. Both in vivo and in vitro attenuations of NE can be antagonized by the CB2 selective antagonist SR144528. Taken together, our data suggest that the NE caused pronounced decrease in the activity of MOR is mediated via CB2 cannabinoid receptors. PMID- 17698255 TI - Ethanol and acetaldehyde alter NTPDase and 5'-nucleotidase from zebrafish brain membranes. AB - Alcohol abuse is an acute health problem throughout the world and alcohol consumption is linked to the occurrence of several pathological conditions. Here we tested the acute effects of ethanol on NTPDases (nucleoside triphosphate diphosphohydrolases) and 5'-nucleotidase in zebrafish (Danio rerio) brain membranes. The results have shown a decrease on ATP (36.3 and 18.4%) and ADP (30 and 20%) hydrolysis after 0.5 and 1% (v/v) ethanol exposure during 60 min, respectively. In contrast, no changes on 5'-nucleotidase activity were observed in zebrafish brain membranes. Ethanol in vitro did not alter ATP and ADP hydrolysis, but AMP hydrolysis was inhibited at 0.5, and 1% (23 and 28%, respectively). Acetaldehyde in vitro, in the range 0.5-1%, inhibited ATP (40-85%) and ADP (28-65%) hydrolysis, whereas AMP hydrolysis was reduced (52, 58 and 64%) at 0.25, 0.5 and 1%, respectively. Acetate in vitro did not alter these enzyme activities. Semi-quantitative expression analysis of NTPDase and 5'-nucleotidase were performed. Ethanol treatment reduced NTPDase1 and three isoforms of NTPDase2 mRNA levels. These findings demonstrate that acute ethanol intoxication may influence the enzyme pathway involved in the degradation of ATP to adenosine, which could affect the responses mediated by adenine nucleotides and nucleosides in zebrafish central nervous system. PMID- 17698256 TI - 3D-QSAR studies of Checkpoint Kinase Weel inhibitors based on molecular docking, CoMFA and CoMSIA. AB - Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed on 97 4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione inhibitors, based on molecular docking scores obtained by using GOLD 3.1, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA). The docking results provided a reliable conformational alignment scheme for the 3D-QSAR model. Based on the docking conformations and alignments, highly predictive CoMFA and CoMSIA were obtained with cross-validated q(2) value of 0.828 and 0.796, respectively, and non-cross-validated partial least-squares (PLS) analysis with the optimum components of five showed a conventional r(2) of 0.962 and 0.949, respectively. The predictive ability was validated by compounds that were not included in the training set. Furthermore, the CoMFA and CoMSIA model plots were mapped back to the binding sites of Checkpoint Kinase Weel, to get a better understanding of vital interactions between the inhibitors and Weel kinase. As a result, we have identified some key features in the 4 phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones responsible for the Weel inhibitory activity that may be used to design more potent 4-phenylpyrrolo[3,4 c]carbazole-1,3(2H,6H)-diones and predict their activity prior to synthesis. PMID- 17698257 TI - Class II-selective histone deacetylase inhibitors. Part 2: alignment-independent GRIND 3-D QSAR, homology and docking studies. AB - (Aryloxopropenyl)pyrrolyl hydroxamates were recently reported by us as first examples of class II-selective HDAC inhibitors and can be useful tools to probe the biology of such enzymes. Molecular modelling and 3-D QSAR studies have been performed on a series of 25 (aryloxopropenyl)pyrrolyl hydroxamates to gain insights about their activity and selectivity against both maize HD1-B and HD1-A, two enzymes homologous of mammalian class I and class II HDACs, respectively. The studies have been accomplished by calculating alignment-independent descriptors (GRIND descriptors) using the ALMOND software. Highly descriptive and predictive 3-D QSAR models were obtained using either class I or class II inhibitory activity displaying r(2)/q(2) values of 0.96/0.81 and 0.98/0.85 for HD1-B and HD1 A, respectively. A deeper inspection revealed that in general a bent molecular shape structure is a prerequisite for HD1-A-selective inhibitory activity, while straight shape molecular skeleton leads to selective HD1-B compounds. The same conclusions could be achieved by molecular docking studies of the most selective inhibitors. PMID- 17698258 TI - Epimers of bicyclo[2.2.2]octan-2-ol derivatives with antiprotozoal activity. AB - (2SR,6RS,7RS)-4-Dialkylaminobicyclo[2.2.2]octan-2-ols and several of their esters have shown promising activity against the causative organisms for malaria and sleeping sickness. The base-catalyzed epimerization of the alcohols was carried out by different methods giving their (2RS,6RS,7RS)-isomers. Best results were obtained by the consecutive use of potassium tert-butoxide and sodium. The isomeric alcohols were converted to selected esters. All new compounds were tested for their activity against Trypanosoma brucei rhodesiense (STIB 900) and a multiresistant strain of Plasmodium falciparum. The antitrypanosomal activity and the cytotoxicity were in general increased. The most active antitrypanosomal agents were the benzoate 8b and the 4-chlorobenzoate 9b of the 4-pyrrolidino series. The nicotinate 10a and the isonicotinate 11a showed the highest antiplasmodial activities. PMID- 17698259 TI - Scaffolding reflective journal writing - negotiating power, play and position. AB - A three-year qualitative study based on an action-research design, framed within the critical genre and using a multi-method approach, was used to establish how a model of critical reflective practice [Van Aswegen, E.J., Brink, H.I., Steyn, P.J., 2000. A model for facilitation of critical reflective practice: Part I- Introductory discussion and explanation of the phases followed to construct the model. Part ll - Conceptual analysis within the context of constructing the model. Part III - Description of the model. Curationis 23 (4), 117-135.] could be implemented. Reflective journals were introduced as one of the educational strategies within the model to support and sustain 'deep' transformatory learning. A component of this larger study focused on how scaffolding deep learning through reflective writing is enhanced by supportive structures. These include critiquing (feedback), a mutually developed self-evaluation strategy, as well as an awareness of and sensitivity to the need for student/writer-responder negotiation. Three student groups of part-time post-basic, practicing South African nurses engaged in reflective writing over the period of an academic year. This article is based on their perceptions, mid-way through their writing, of these strategies. It reflects the story of assumptions made by educators, and challenges for change. Students find reflective writing difficult, and although they are willing to accept its value and engage in the process, they require a regular, specific and sensitive critical response from their writer-responder and follow-up supportive contact. Self-evaluation for the purposes of 'owning' their own ideas is difficult, and requires constant support and validation. Transformatory learning comes at a cost, and a revisiting of the balance of power between student and educator is in order. PMID- 17698260 TI - Hearing the voice of people with dementia in professional education. PMID- 17698262 TI - Plasmid DNA and viral vector-based vaccines for the treatment of cancer. AB - Plasmid DNA and viral vector-based cancer vaccines have many inherent features that make them promising cancer vaccine candidates. This review focuses on the use of plasmid DNA and viral vector vaccines to deliver tumour-specific antigens to induce a tumour-specific immune response. Examples of different antigen delivery systems that have been tested in recent clinical trials are summarised and advantages and disadvantages of a number of delivery systems and approaches are discussed. Finally, an outlook on how plasmid DNA and viral vectors might be developed further as cancer vaccines is provided. PMID- 17698261 TI - Lactoferrin enhanced efficacy of the BCG vaccine to generate host protective responses against challenge with virulent Mycobacterium tuberculosis. AB - Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is a disease with world wide consequences, affecting nearly a third of the world's population. The established vaccine for TB, an attenuated strain of Mycobacterium bovis Calmette Guerin (BCG), has existed since 1921. Lactoferrin, an iron-binding protein found in mucosal secretions and granules of neutrophils was hypothesized to be an ideal adjuvant to enhance the efficacy of the BCG vaccine, specifically because of previous reports of lactoferrin enhancement of IL-12 production from macrophages infected with BCG. Different vaccination protocols were investigated for generation of host protective responses against MTB infection using lactoferrin admixed to the BCG vaccine. Resulting effects demonstrate that BCG/lactoferrin increased host protection against MTB infection by decreasing organ bacterial load and reducing lung histopathology; significant reduction in tissue CFUs and pathology were observed post-challenge compared to those seen with BCG alone. Addition of lactoferrin to the vaccine led to reduced pathological damage upon subsequent infection with virulent MTB, with positive results demonstrated when admixed in oil-based vehicle (incomplete Freund's adjuvant, IFA) or when given with BCG in saline. The observed post-challenge results paralleled increasing production of IFN-gamma and IL-6, but only limited changes to proinflammatory mediators TNF-alpha or IL-1beta from BCG-stimulated splenocytes. Overall, these studies indicate that lactoferrin is a useful and effective adjuvant to improve efficacy of the BCG vaccine, with potential to reduce related tissue damage and pulmonary histopathology. PMID- 17698263 TI - Effect of influenza vaccine status on winter mortality in Spanish community dwelling elderly people during 2002-2005 influenza periods. AB - This study assessed the relationship between the reception of conventional inactivated influenza vaccine and winter mortality in a prospective cohort that included 11,240 Spanish community-dwelling elderly individuals followed from January 2002 to April 2005. Annual influenza vaccine status was a time-varying condition and primary outcome was all-cause death during study period. Multivariable Cox proportional-hazard models adjusted by age, sex and co morbidity were used to evaluate vaccine effectiveness. Influenza vaccination was associated with a significant reduction of 23% in winter mortality risk during overall influenza periods. The attributable mortality risk in non-vaccinated people was 24 deaths per 100,000 persons-week within influenza periods, the prevented fraction for the population was 14%, and one death was prevented for every 239 annual vaccinations (ranging from 144 in Winter 2005 to 1748 in Winter 2002). PMID- 17698264 TI - Plasmacytoma in the temporomandibular joint: a case report. AB - We report a case of a 64-year-old patient in whom limitation of mouth opening was the presenting symptom of plasmacytoma. Intra-oral biopsy confirmed a plasma-cell tumour, with no sign of extension on imaging. He was treated with radiotherapy (4000 cGy) and followed up. The diagnosis of solitary plasmacytoma of bone can be confirmed only when the presence of systemic disease has been excluded by clinical, biological, and radiological investigations. We think that the treatment should consist only of radiotherapy. Long-term follow-up is necessary because of the high risk of development of multiple myeloma, which may be delayed. PMID- 17698265 TI - Global fate of POPs: current and future research directions. AB - For legacy and emerging persistent organic pollutants (POPs), surprisingly little is still known in quantitative terms about their global sources and emissions. Atmospheric transport has been identified as the key global dispersal mechanism for most legacy POPs. In contrast, transport by ocean currents may prove to be the main transport route for many polar, emerging POPs. This is linked to the POPs' intrinsic physico-chemical properties, as exemplified by the different fate of hexachlorocyclohexanes in the Arctic. Similarly, our current understanding of POPs' global transport and fate remains sketchy. The importance of organic carbon and global temperature differences have been accepted as key drivers of POPs' global distribution. However, future research will need to understand the various biogeochemical and geophysical cycles under anthropogenic pressures to be able to understand and predict the global fate of POPs accurately. PMID- 17698266 TI - Isozyme markers associated with O(3) tolerance indicate shift in genetic structure of ponderosa and Jeffrey pine in Sequoia National Park, California. AB - Effects of canopy ozone (O(3)) exposure and signatures of genetic structure using isozyme markers associated with O(3) tolerance were analyzed in approximately 20 , approximately 80-, and >200-yr-old ponderosa (Pinus ponderosa Dougl. ex Laws.) and Jeffrey pine (Pinus jeffreyi Grev. & Balf.) in Sequoia National Park, California. For both species, the number of alleles and genotypes per loci was higher in parental trees relative to saplings. In ponderosa pine, the heterozygosity value increased, and the fixation index indicated reduction of homozygosity with increasing tree age class. The opposite tendencies were observed for Jeffrey pine. Utilizing canopy attributes known to be responsive to O(3) exposure, ponderosa pine was more symptomatic than Jeffrey pine, and saplings were more symptomatic than old growth trees. We suggest that these trends are related to differing sensitivity of the two species to O(3) exposure, and to higher O(3) exposures and drought stress that younger trees may have experienced during germination and establishment. PMID- 17698267 TI - Pollution level, phase distribution and health risk of polycyclic aromatic hydrocarbons in indoor air at public places of Hangzhou, China. AB - PAHs pollution survey in air of public places was conducted in Hangzhou, China. The most serious PAHs pollution was observed in indoor air of shopping centers and the slightest was in train stations. The molecular weight of chrysene (MW 228) appeared to be the dividing line for the PAHs with a larger or smaller distribution in the vapor or particulate phase. Concentrations of 15 PAHs on PM2.5 accounted for 71.3% of total particulate PAHs, and followed by PM2.5-10 fraction (17.6%) and >PM10 fraction (11.1%). In shopping centers and supermarkets, emission of 2-4 rings PAHs occurred from indoor sources, whereas 5 6 rings PAHs predominantly originated from transport of outdoor air. In temples, PAHs in indoor air mainly originated from incense burning. Health risks associated with the inhalation of PAHs were assessed, and naphthalene made the greatest contribution (62.4%) to the total health risks. PMID- 17698268 TI - Endocrine disruptors in freshwater streams of Hesse, Germany: changes in concentration levels in the time span from 2003 to 2005. AB - Four small freshwater streams in the region known as Hessisches Ried in Germany were investigated with respect to the temporal and spatial concentration variations of the endocrine disruptors bisphenol A (BPA), 4-tert-octylphenol (4 tert-OP), and the technical isomer mixture of 4-nonylphenol (tech.-4-NP). Measured concentrations of the target compounds in the river water samples ranged from <20 ng/l to 1927 ng/l, <10 ng/l to 770 ng/l, and <10 ng/l to 420 ng/l for BPA, 4-tert-OP and tech.-4-NP, respectively. BPA levels were, with the exception of two samples, below the predicted no-effect concentration (PNEC) for water organisms. Tech.-4-NP concentrations showed a significant tendency of decreasing concentrations during the sampling period. This is mainly attributed to the implementation of the European Directive 2003/53/EG, which restricts both the marketing and use of nonylphenols. Results from the analysis of additionally collected water samples from sewage treatment plant (STP) effluents indicate that the STPs cannot be the only sources for tech.-4-NP found in the river water. PMID- 17698269 TI - Low cost measurements of nitrogen and sulphur dry deposition velocities at a semi alpine site: gradient measurements and a comparison with deposition model estimates. AB - The conditional time averaged gradient method was used to measure air-surface exchange of nitrogen and sulphur compounds at a semi-alpine site in Southern Norway. Dry deposition velocities were then obtained from the bi-weekly concentration gradient measurements. Annual deposition velocities were found to be 1.4, 11.8 and 4.0 mm s(-1) for NH3, HNO3 and SO2, respectively, if all data were included, and to be 10.8, 11.8 and 13.0 mm s(-1), respectively, if only positive values were included. Measured deposition velocities were compared to two sets of values estimated from a big-leaf dry deposition module applying to two different land types (short grass and forbs, and tundra), driven by measured micrometeorological parameters. The deposition module gives reasonable values for this site throughout the year, but does not reproduce the large variability as shown in the measured data. No apparent seasonal variations were found from either measurements or module estimates due to the very low productivity of the studied area. PMID- 17698270 TI - Characteristics of organic phosphorus fractions in different trophic sediments of lakes from the middle and lower reaches of Yangtze River region and Southwestern Plateau, China. AB - In this study, the characteristics of organic phosphorus (Po) fractions in sediments of six lakes from the middle and lower reaches of Yangtze River region and Southwestern China Plateau, China were investigated using a soil Po fractionation scheme, and the relationships between Po, inorganic phosphorus (Pi) and pollution status were also discussed. The results show that the rank order of Po fractions was: residual Po>HCl-Po>fulvic acid-P>humic acid-P>NaHCO3-Po, with their average relative proportion 8.7:4.6:3.2:2.1:1.0. Po fractions, especially nonlabile Po, were significantly correlated with organic matter, Po and NaOH-Pi. Different distribution patterns of P fractions were observed in those two different regions. Po fractions in the heavily polluted sediments were higher than those in moderately and no polluted sediments, it is suggested that Po should be paid more attention in the lake eutrophication investigation. PMID- 17698271 TI - Cost-effectiveness analysis and formulary decision making in England: findings from research. AB - In a context of rapid technological advances in health care and increasing demand for expensive treatments, local formulary committees are key players in the management of scarce resources. However, little is known about the information and processes used when making decisions on the inclusion of new treatments. This paper reports research on the use of economic evaluations in technology coverage decisions in England, although the findings have a relevance to other health care systems with devolved responsibility for resource allocation. It reports a study of four local formulary committees in which both qualitative and quantitative data were collected. Our main research finding is that it is an exception for cost-effectiveness analysis to inform technology coverage decisions. Barriers to use include access and expertise levels, concerns relating to the independence of analyses and problems with implementation of study recommendations. Further barriers derive from the constraints on decision makers, a lack of clarity over functions and aims of local committees, and the challenge of disinvestment in medical technologies. The relative weakness of the research-practice dynamics in this context suggests the need for a rethinking of the role of both analysts and decision makers. Our research supports the view that in order to be useful, analysis needs to better reflect the constraints of the local decision-making environment. We also recommend that local decision-making committees and bodies in the National Health Service more clearly identify the 'problems' which they are charged with solving and how their outputs contribute to broader finance and commissioning functions. This would help to establish the ways in which the routine use of cost-effectiveness analysis might become a reality. PMID- 17698272 TI - Are urban children really healthier? Evidence from 47 developing countries. AB - On average, child health outcomes are better in urban than in rural areas of developing countries. Understanding the nature and the causes of this rural-urban disparity is essential in contemplating the health consequences of the rapid urbanization taking place throughout the developing world and in targeting resources appropriately to raise population health. Using micro-data on child health taken from the most recent Demographic and Health Surveys for 47 developing countries, the purpose of this paper is threefold. First, we document the magnitude of rural-urban disparities in child nutritional status and under-5 mortality across all 47 developing countries. Second, we adjust these disparities for differences in population characteristics across urban and rural settings. Third, we examine rural-urban differences in the degree of socioeconomic inequality in these health outcomes. The results demonstrate that there are considerable rural-urban differences in mean child health outcomes in the entire developing world. The rural-urban gap in stunting does not entirely mirror the gap in under-5 mortality. The most striking difference between the two is in the Latin American and Caribbean region, where the gap in growth stunting is more than 1.5 times higher than that in mortality. On average, the rural-urban risk ratios of stunting and under-5 mortality fall by, respectively, 53% and 59% after controlling for household wealth. Controlling thereafter for socio-demographic factors reduces the risk ratios by another 22% and 25%. We confirm earlier findings of higher socioeconomic inequality in stunting in urban areas and demonstrate that this also holds for under-5 mortality. In a considerable number of countries, the urban poor actually have higher rates of stunting and mortality than their rural counterparts. The findings imply that there is a need for programs that target the urban poor, and that this is becoming more necessary as the size of the urban population grows. PMID- 17698273 TI - Sometimes doing the right thing sucks: frame combinations and multi-fetal pregnancy reduction decision difficulty. AB - Data are analyzed for 54 women who made an appointment with a North American Center specializing in multifetal pregnancy reduction (MFPR) to be counseled and possibly have a reduction. The impact on decision difficulty of combinations of three frames through which patients may understand and consider their options and use to justify their decisions are examined: a conceptional frame marked by a belief that life begins at conception; a medical frame marked by a belief in the statistics regarding risk and risk prevention through selective reduction; and a lifestyle frame marked by a belief that a balance of children and career has normative value. All data were gathered through semi-structured interviews and observation during the visit to the center over an average 2.5h period. Decision difficulty was indicated by self-assessed decision difficulty and by residual emotional turmoil surrounding the decision. Qualitative comparative analysis was used to analyze the impact of combinations of frames on decision difficulty. Separate analyses were conducted for those reducing only to three fetuses (or deciding not to reduce) and women who chose to reduce below three fetuses. Results indicated that for those with a non-intense conceptional frame, the decision was comparatively easy no matter whether the patients had high or low values of medical and lifestyle frames. For those with an intense conceptional frame, the decision was almost uniformly difficult, with the exception of those who chose to reduce only to three fetuses. Simplifying the results to their most parsimonious scenarios oversimplifies the results and precludes an understanding of how women can feel pulled in different directions by the dictates of the frames they hold. Variations in the characterization of intense medical frames, for example, can both pull toward reduction to two fetuses and neutralize shame and guilt by seeming to remove personal responsibility for the decision. We conclude that the examination of frame combinations is an important tool for understanding the way women carrying multiple fetuses negotiate their way through multi-fetal pregnancies, and that it may have more general relevance for understanding pregnancy decisions in context. PMID- 17698274 TI - Anxiolytic-like effects of obovatol isolated from Magnolia obovata: involvement of GABA/benzodiazepine receptors complex. AB - This experiment was performed to investigate whether obovatol isolated from the leaves of Magnolia obovata has anxiolytic-like effects through GABA benzodiazepine-receptors Cl(-) channel activation. The anxiolytic-like effects of obovatol in mice were examined using the elevated plus-maze and the automatic hole-board apparatus. Oral administration of obovatol (0.2, 0.5 and 1.0 mg/kg) significantly increased the number of open arm entries and the spent time on open arm in the elevated plus-maze test, compared with those of saline. Obovatol (0.2, 0.5 and 1.0 mg/kg) also produced anxiolytic-like effects, as reflected by an increase in head-dipping behaviors. These effects were comparable to those of diazepam (1.0 mg/kg), a well known anxiolytic drug. On the other hand, the anxiolytic-like effects of obovatol and diazepam were reversed by flumazenil, a benzodiazepine receptor antagonist, suggesting that the anxiolytic-like effects of obovatol were involved in GABA-benzodiazepine receptors complex. Obovatol was muscle relaxant by rota-rod test, but its effect was weaker than diazepam. Spontaneous locomotor activity also was inhibited by obovatol. Obovatol selectively increased the GABA(A) receptors alpha(1) subunit expression in amygdala of mouse brain. Obovatol also showed to bind to benzodiazepine receptors competitively in experiments using [(3)H]flunitrazepam in the cerebral cortex of mouse brain. Moreover, obovatol (10, 20 and 50 microM) increased Cl(-) influx and the increased Cl(-) influx was inhibited by flumazenil, in primary cultured neuronal cells and IMR-32 human neuroblastoma cells. These results suggest that obovatol has anxiolytic-like effects, and these pharmacological effects may be mediated by GABA-benzodiazepine receptors-activated Cl(-) channel opening. PMID- 17698275 TI - Quetiapine as monotherapy for social anxiety disorder: a placebo-controlled study. AB - Social anxiety disorder (SAD) is one of the most common anxiety disorders. Reports have suggested an effect of the atypical antipsychotic quetiapine in anxiety disorders. Given these considerations, we conducted a controlled trial of quetiapine monotherapy in SAD. Fifteen patients were randomized to quetiapine (up to 400 mg/day) or placebo for 8 weeks. The Brief Social Phobia Scale (BSPS) and the Clinical Global Impression of Improvement Scale (CGI-I) were the primary outcome measures, while the Social Phobia Inventory (SPIN) and the Sheehan Disability Inventory (SDI) were secondary measures. There was no significant difference on the BSPS score at endpoint between the quetiapine and placebo groups. There was a significant time effect but not a significant time x treatment group interaction, indicating that both the quetiapine and placebo patients did better over the course of the trial. 20% of the quetiapine patients had a 50% or greater drop in BSPS score at the end of the trial compared to baseline, while 0% had such a drop in the placebo group. There was no significant difference in responders (CGI-I score of 1 or 2) versus non-responder (CGI-I score of 3 or more) across the groups. However, 40% of quetiapine patients and 0% of the placebo patients showed much or very much improvement on the CGI-I. The Number Needed to Treat (NNT) to be a responder on the CGI-I was 3. Significant time effects were noted for the SPIN and SDI, as well as a significant time x treatment effect in favor of quetiapine on the SPIN. Additionally, quetiapine showed a large effect size on the SPIN. PMID- 17698276 TI - A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. AB - Quercetin is a naturally-occurring flavonol (a member of the flavonoid family of compounds) that has a long history of consumption as part of the normal human diet. Because a number of biological properties of quercetin may be beneficial to human health, interest in the addition of this flavonol to various traditional food products has been increasing. Prior to the use of quercetin in food applications that would increase intake beyond that from naturally-occurring levels of the flavonol in the typical Western diet, its safety needs to be established or confirmed. This review provides a critical examination of the scientific literature associated with the safety of quercetin. Results of numerous genotoxicity and mutagenicity, short- and long-term animal, and human studies are reviewed in the context of quercetin exposure in vivo. To reconcile results of in vitro studies, which consistently demonstrated quercetin-related mutagenicity to the absence of carcinogenicity in vivo, the mechanisms that lead to the apparent in vitro mutagenicity, and those that ensure absence of quercetin toxicity in vivo are discussed. The weight of the available evidence supports the safety of quercetin for addition to food. PMID- 17698278 TI - Myocardial stunning after successful defibrillation. PMID- 17698277 TI - Plant pre-tRNA splicing enzymes are targeted to multiple cellular compartments. AB - Splicing of precursor tRNAs in plants requires the concerted action of three enzymes: an endonuclease to cleave the intron at the two splice sites, an RNA ligase for joining the resulting tRNA halves and a 2'-phosphotransferase to remove the 2'-phosphate from the splice junction. Pre-tRNA splicing has been demonstrated to occur exclusively in the nucleus of vertebrates and in the cytoplasm of budding yeast cells, respectively. We have investigated the subcellular localization of plant splicing enzymes fused to GFP by their transient expression in Allium epidermal and Vicia guard cells. Our results show that all three classes of splicing enzymes derived from Arabidopsis and Oryza are localized in the nucleus, suggesting that plant pre-tRNA splicing takes place preferentially in the nucleus. Moreover, two of the splicing enzymes, i.e., tRNA ligase and 2'-phosphotransferase, contain chloroplast transit signals at their N termini and are predominantly targeted to chloroplasts and proplastids, respectively. The putative transit sequences are effective also in the heterologous context fused directly to GFP. Chloroplast genomes do not encode intron-containing tRNA genes of the nuclear type and consequently tRNA ligase and 2'-phosphotransferase are not required for classical pre-tRNA splicing in these organelles but they may play a role in tRNA repair and/or splicing of atypical group II introns. Additionally, 2'-phosphotransferase-GFP fusion protein has been found to be associated with mitochondria, as confirmed by colocalization studies with MitoTracker Red. In vivo analyses with mutated constructs suggest that alternative initiation of translation is one way utilized by tRNA splicing enzymes for differential targeting. PMID- 17698279 TI - Withholding advanced cardiac life support in out-of-hospital cardiac arrest: a prospective study. AB - AIM OF THE STUDY: To evaluate the decision criteria leading to refrain from starting cardiopulmonary resuscitation (CPR) in the prehospital setting. MATERIALS AND METHODS: We conducted a prospective, descriptive study, in a physician-staffed emergency medical service during a 12 month period. All patients presenting with a cardiac arrest were included. Patients were allocated to two groups: immediate decision to give CPR (R group) or withholding CPR (NR group). Characteristics of patients including previous health status, time intervals, therapies and outcomes, were collected. Data were compared between the two groups, *p<0.05. RESULTS: One hundred and fourteen patients (aged 61+/-18 years) were enrolled in R group and 113 (73+/-19 years*) in NR group. Patients of NR group more frequently presented with a deterioration of functional independence (51% versus 10%*), cognitive impairment (21% versus 8%*) and higher McCabe score and Knaus class (McCabe 2: 24% versus 2%*; Knaus class D: 23% versus 3%*). Presence of a bystander (75% versus 44%*) or basic life support (BLS) started by the bystander (40% versus 12%*) were more frequent in R than NR. Age (OR, 1.1; 95% CI, 1.0-1.1), McCabe score >0 (OR, 10.5; 95% CI, 1.4-79.0), lack of bystander BLS (OR, 11.2; 95% CI, 2.2-60.7) and ineffectiveness of BLS by EMTs (OR, 12.1; 95% CI, 2.0-72.8) were independent factors of withholding CPR. The physician conducted often the discussion alone (48%). CONCLUSION: Decision criteria leading to refrain from starting CPR in the prehospital setting are age, previous health status and initial BLS. Further thought should be allowed to ensure a share in the decision-making process in this particular practice. PMID- 17698280 TI - Schizophrenia patients show impaired response switching in saccade tasks. AB - Action control deficits of schizophrenia patients result from frontostriatal brain abnormalities and presumably reflect an impairment of selective cognitive processes. This study aimed at dissociating two different levels of action control in saccades toward and away from visual stimuli (pro- and antisaccades). Results of previous studies suggested that task switch effects (between pro- and antisaccades) reflect the persistence of a task-specific production rule and refer to the level of task selection, whereas response switch effects (between leftward and rightward saccades) point to the persistence of a specific response program, referring to the level of response selection. In the present study, task switching and response switching were investigated in 20 schizophrenia patients and 20 control subjects. Groups did not differ concerning task switch effects. In contrast, response switching entailed a stronger enhancement of error rates in patients, suggesting a specific deficit on the level of response selection in schizophrenia. The deficit was associated with spatial working memory capacities, confirming and specifying existing hypotheses on a relationship between working memory and action control. PMID- 17698281 TI - The role of quantitative Schlieren assessment of physiotherapy ultrasound fields in describing variations between tissue heating rates of different transducers. AB - Differences in tissue heating rates between ultrasound transducers have been well documented; however, comparative analysis between ultrasound fields to determine why tissue heating rates may differ is lacking. We selected three transducers from the same manufacturer with similar effective radiating area, output power, effective intensity and beam nonuniformity ratio [as defined by the FDA, 21 CFR Chap. 1, part 1,050 (10)], but markedly different Schlieren images. Each transducer was utilized to heat tissue with a standardized ultrasound application to determine whether Schlieren analysis may be useful in understanding variability in tissue heating rates. Thermocouples were inserted into the left triceps surae of 12 volunteers at a depth of 1.5 cm below one half the measured skin fold thickness (estimated average depth of the thermocouple was 1.99 +/- 0.27 cm). Each subject received one treatment from each transducer in a single session (n = 3); 3 MHz at 1.2 W/cm(2) for 8 min with a 100% duty cycle. Each transducer increased the IM temperature over time (p < 0.0001). IM temperatures were not significantly different between transducers from time zero to the fourth minute of treatment. After the fourth min, transducers B and C generated significantly higher tissue temperatures (p < 0.01). Transducer A, B and C increased IM temperature from 34.9 +/- 0.5 to 41.2 +/- 1.3 degrees C, 34.9 +/- 0.6 to 42.5 +/- 1.4 degrees C and 34.9 +/- 0.5 to 42.7 +/- 1.7 degrees C, respectively. Interestingly, transducer C emitted 22% lower output power but heated 24% higher than transducer A and our Schlieren images demonstrate that transducers B and C produced a more concentrated field compared with transducer A. The data we present here supports the general contention that a more concentrated field will heat to a higher temperature than a more disperse field, however, technical challenges in estimating output power, ERA and Schlieren analysis remain an issue. PMID- 17698283 TI - Noninvasive vascular elastography: toward a complementary characterization tool of atherosclerosis in carotid arteries. AB - Only a minority of patients with carotid arterial disease have warning symptoms, because the majority of strokes are caused by previously asymptomatic lesions. Because morbidity and mortality after acute stroke are high, patients should be diagnosed and treated before symptoms develop. The hypothesis of this study is that vascular elasticity maps (or elastograms) of carotids are of predictive value for plaque characterization. The strain tensor from either cross-sectional or longitudinal ultrasound radiofrequency data were assessed by a new implementation of the Lagrangian speckle model estimator (LSME), which considers local echogenicity variations. A 26-year-old healthy male (HS1), a 40-year-old (HS2) normal female subject and two 75-year-old asymptomatic patients with severe carotid stenoses were scanned. Reproducible elastograms were obtained as a function of time over five to seven cardiac cycles. Stress-strain modulus elastograms were computed for normal subjects. Stiffening of healthy carotid walls was estimated to be 148 +/- 7 kPa and 163 +/- 30 kPa at peak-systole for HS1 and HS2, respectively. For patients with heterogeneous plaques, strain and shear elastograms revealed interesting information about plaque size, tissue composition and mechanical interaction between structures. In conclusion, the LSME provides a promising approach for strain and shear estimates to characterize vulnerable plaque. PMID- 17698282 TI - In vivo assessment of myocardial stiffness with acoustic radiation force impulse imaging. AB - Acoustic radiation force impulse (ARFI) imaging has been demonstrated to be capable of visualizing variations in local stiffness within soft tissue. Recent advances in ARFI beam sequencing and parallel imaging have shortened acquisition times and lessened transducer heating to a point where ARFI acquisitions can be executed at high frame rates on commercially available diagnostic scanners. In vivo ARFI images were acquired with a linear array placed on an exposed canine heart. The electrocardiogram (ECG) was also recorded. When coregistered with the ECG, ARFI displacement images of the heart reflect the expected myocardial stiffness changes during the cardiac cycle. A radio-frequency ablation was performed on the epicardial surface of the left ventricular free wall, creating a small lesion that did not vary in stiffness during a heartbeat, though continued to move with the rest of the heart. ARFI images showed a hemispherical, stiffer region at the ablation site whose displacement magnitude and temporal variation through the cardiac cycle were less than the surrounding untreated myocardium. Sequences with radiation force pulse amplitudes set to zero were acquired to measure potential cardiac motion artifacts within the ARFI images. The results show promise for real-time cardiac ARFI imaging. PMID- 17698284 TI - Raymond-Cestan syndrome in pontine ischemia. PMID- 17698285 TI - Urinary frequency in a case of Neuro-Behcet disease involving the brainstem - clinical, electrophysiological and urodynamic features. AB - Micturitional disturbances are reported in 5-20% of patients with Behcet disease (BD) affecting the central nervous system. However, corresponding data regarding urodynamic and electrophysiological findings are limited. A patient with known BD presented with dysarthria, diplopia and urinary frequency (36 times/day). MRI revealed an extensive lesion involving the lateral and tegmental pons, reaching the pontomedullary junction. Auditory evoked potentials indicated a left-side lesion between superior olivary nucleus and superior colliculus. Blink reflex examination indicated a location caudal to the left trigeminal root. Pudendal nerve somatosensory evoked potentials and transcranial magnetic stimulation of the perineal muscles were slightly affected. Bulbocavernosus reflex latencies were normal. EMG of the bulbocavernosus muscles showed a normal maximal voluntary contraction activity. Urodynamic studies revealed normal urine volume, maximum flow rate and residual volume. After intravenous administration of methylprednisolone diplopia and dysarthria resolved within 3 weeks. Urinary frequency remained almost unchanged for the first 8 weeks, but clearly improved during the following months. We assume that the present case of urinary frequency is the result of vasculitic lesion affecting the pontine micturition inhibitory area on the ground of Neuro-Behcet disease. PMID- 17698287 TI - Role of gastrin peptides in carcinogenesis. AB - Gastrin gene expression is upregulated in a number of pre-malignant conditions and established cancer through a variety of mechanisms. Depending on the tissue where it is expressed and the level of expression, differential processing of the polypeptide product leads to the production of different biologically active peptides. In turn, acting through the classical CCK-2R receptor, CCK-2R isoforms and alternative receptors, these peptides trigger signalling pathways which influence the expression of downstream genes that affect cell survival, angiogenesis and invasion. Here we review this network of events, highlighting the importance of cellular context for interpreting the role of gastrin peptides and a possible role for gastrin in supporting the early stage of carcinogenesis. PMID- 17698286 TI - chFRP5-ZZ-PE38, a large IgG-toxin immunoconjugate outperforms the corresponding smaller FRP5(Fv)-ETA immunotoxin in eradicating ErbB2-expressing tumor xenografts. AB - As therapeutics, antibodies can be used "un-armed" or as immunoconjugates to direct cytotoxic moieties to tumor cells. Immunoconjugates are made by attaching chemotherapy drugs, radioisotopes or toxins to the antibody. Small recombinant antibody fragments fused to cytotoxic moieties, termed recombinant immunotoxins are also being developed as an additional approach for a targeted cancer therapy. Key parameters in determining the therapeutic potential of such targeted therapies are target specificity, affinity, stability and size. With regard to treating solid tumors, tumor penetration (which is inversely proportional to size) is currently regarded as the prime factor for efficacy, while parameters such as binding affinity and residence time in the body are thought to contribute to a lesser extent. When comparing recombinant immunotoxins and antibody-toxin immunoconjugates that target ErbB2/HER2, here we found that a bivalent antibody toxin immunoconjugate (200 kDa) was superior to the corresponding recombinant monovalent immunotoxin (69 kDa) in killing ErbB2-expressing tumor cells in culture and as xenografts in nude mice, suggesting that higher avidity and longer residence time may outweigh tumor penetration. Our study suggests that the re valuation of currently neglected, large IgG-effector molecule conjugates for anti cancer therapy may be justified. PMID- 17698288 TI - Effect of distillery sludge on seed germination and growth parameters of green gram (Phaseolus mungo L.). AB - Experiments were carried out to study the effect of distillery sludge amendments with garden soil (10, 20, 40, 60, 80 and 100%) on seed germination and growth parameters of Phaseolus mungo L. Germination percentage and index values decreased with rise in sludge concentration. Soil amended with 10% (w/w) sludge showed favorable growth while >10% was inhibitory for plant growth. Soil amended with 10% (w/w) distillery sludge induced the growth in root length, shoot length, number of leaves, biomass, photosynthetic pigment, protein and starch while 20% (w/w) sludge amended soil had variable effects on the root, shoot, leaves and nodules of P. mungo L. At concentrations (>40%) reduced all the growth parameters, viz., root length, shoot length, number of leaves, biomass, photosynthetic pigment, protein and starch of P. mungo. Malondialdehyde (MDA) product of lipid peroxidation was also enhanced in both root and leaves of sludge amended soil grown P. mungo at all the sludge amendments and exposure periods. A coordinated increase in cysteine, non-protein thiol and ascorbic acid antioxidants was up to 40 days of growth. After this period a decrease was observed. The N, P, K and Mg accumulation followed the order shoot>leaf>root. Calcium accumulation was highest in the upper part of the plants (including shoot and leaves). Furthermore, heavy metals content were also increased in different parts of P. mungo grown on increasing concentration of sludge amended garden soil with time. Zinc and copper accumulation was maximum versus other heavy metals. Based on these studies, sludge having concentrations < or =10% (w/w) can be applied as a fertilizer. PMID- 17698289 TI - Comments on LNG fire hazards. PMID- 17698290 TI - A new model of severe neurogenic pulmonary edema in spinal cord injured rat. AB - We describe a new model of neurogenic pulmonary edema in spinal cord injured Wistar male rats. The pulmonary edema was elicited by an epidural thoracic balloon compression spinal cord lesion, performed under a low concentration of isoflurane (1.5 or 2%) in air. Anesthesia with 1.5% isoflurane promoted very severe interstitial and intraalveolar neurogenic pulmonary edema with a significantly increased thickness of the alveolar walls and massive pulmonary hemorrhage. In this group, 33% of animals died. Anesthesia with 2% isoflurane promoted severe interstitial and intraalveolar neurogenic pulmonary edema with less thickening of the alveolar walls and pulmonary hemorrhage. For evoking severe neurogenic pulmonary edema in spinal cord injured rats, 2% isoflurane anesthesia would be more suitable. However, if very severe neurogenic pulmonary edema needs to be evoked, spinal cord injury under 1.5% isoflurane anesthesia could be used, but one-third of the animals will be lost. PMID- 17698291 TI - Magnetic circular dichroism in EELS: towards 10 nm resolution. AB - We describe a new experimental setup for the detection of magnetic circular dichroism with fast electrons (EMCD). As compared to earlier findings the signal is an order of magnitude higher, while the probed area could be significantly reduced, allowing a spatial resolution of better than 40 nm. A simplified analysis of the experimental results is based on the decomposition of the mixed dynamic form factor S(q-->,q-->('),E) into a real part related to the scalar product and an imaginary part related to the vector product of the scattering vectors q--> and q-->('). Following the recent detection of chiral electronic transitions in the electron microscope the present experiment is a crucial demonstration of the potential of EMCD for nanoscale investigations. PMID- 17698292 TI - The oncogenic fusion protein Pax3-FKHR has a greater post-translational stability relative to Pax3 during early myogenesis. AB - The childhood solid muscle tumor Alveolar Rhabdomyosarcoma (ARMS) is characterized by the t(2;13)(q35;q14) chromosomal translocation, which results in the fusion of two transcription factors important for myogenesis, Pax3 and FKHR (FOX01a). The effects of myogenic differentiation on the stability of FKHR have been well characterized. However, similar studies have yet to be performed on Pax3 or the oncogenic fusion protein Pax3-FKHR. Therefore, we demonstrate in the physiologically relevant mouse primary myoblast system that the expression of Pax3 decreases nearly 95% during the first 24 h of myogenic differentiation. In contrast, there is an aberrant persistence of expression of Pax3-FKHR during this same time period. These differences in protein expression levels do not result from changes on the transcriptional nor the translational level since we observed no concomitant decrease in the levels of Pax3 or Pax3-FKHR mRNA or in the ability of both proteins to be translated. Instead, a pulse-chase analysis determined that Pax3-FKHR has a half-life significantly greater than? the half-life of wild type Pax3 demonstrating for the first time that Pax3-FKHR has greater post translational protein stability relative to wild type Pax3 during early myogenic differentiation. Finally, the persistence of expression of Pax3-FKHR prevents the terminal differentiation of primary myoblasts demonstrating a biological consequence of its aberrant expression. PMID- 17698293 TI - Microalbuminuria: a marker of systemic endothelial dysfunction during burn excision. AB - INTRODUCTION: Systemic endothelial dysfunction characterises both burn injury and surgery and can be monitored by serial immunoassay of urine albumin (microalbuminuria). The aim of this study was to assess microalbuminuria before and during burn excision and identify factors that may influence it. METHODS: Serial half-hourly urine albumin/creatinine ratio (ACR, normal <2.3mg/mmol) was measured in 25 adult patients during 44 burn-excision procedures, at a median of 5 days post-injury. Median total body surface area (TBSA) excised was 12%. RESULTS: Pre-operative median ACR was normal rising to 3.25mg/mmol at 1.5h of surgery (p<0.05). Per-operative ACR at 0.5, 1, 2 and 2.5h were all associated with % TBSA burn excised (p<0.04). Median intraoperative ACR at 1h was 2.3mg/mmol for surgery within 48h post-injury, 1.6 for surgery at 2-7 days and 25.5 during excisions later than 1 month after injury (p<0.05). ACR at 1h was associated with CRP at 48h post-surgery (p=0.04). Per-operative ACR was also significantly correlated with post-operative complications. CONCLUSION: Systemic endothelial dysfunction of acute thermal injury assessed by microalbuminuria recurs with surgery, is minimal at 2-7 days post-burn and affected by % TBSA burn excised and post-operative complications. PMID- 17698294 TI - The risk factors of psychosocial problems for burn patients. AB - Many burn patients experience psychosocial problems such as personality change, post-traumatic stress disorder, family trouble, and financial burden. The purpose of this study was to identify the risk factors of these psychosocial problems that prevented burn patients from developing appropriate adjustments after burn. Six hundred eighty-six adult burn inpatients were interviewed. Most of them suffered from burns less than 10% of total body surface area. They were asked to fill in a questionnaire for this study, which was a psychosocial problem checklist of 17 items. Descriptive analysis, factor analysis, Chi-square test, and multiple logistic regression analysis were used to analyze the results. Lack of family support and living expense burden were the two significant risk factors for psychosocial problems including, burn treatment problems, rehabilitation problems, and welfare information problems on both acute and chronic burn patients. Medical expense burden was the risk factor among chronic burn patients. These findings suggested that active interventions by the burn team including mental health professionals (psychologist, psychiatrist or social worker) might reduce psychosocial problems of burn patients and encourage social rehabilitation. PMID- 17698296 TI - Caspase-3 activity is reduced after spinal cord injury in mice lacking dynorphin: differential effects on glia and neurons. AB - Dynorphins are endogenous opioid peptide products of the prodynorphin gene. An extensive literature suggests that dynorphins have deleterious effects on CNS injury outcome. We thus examined whether a deficiency of dynorphin would protect against tissue damage after spinal cord injury (SCI), and if individual cell types would be specifically affected. Wild-type and prodynorphin(-/-) mice received a moderate contusion injury at 10th thoracic vertebrae (T10). Caspase-3 activity at the injury site was significantly decreased in tissue homogenates from prodynorphin(-/-) mice after 4 h. We examined frozen sections at 4 h post injury by immunostaining for active caspase-3. At 3-4 mm rostral or caudal to the injury, >90% of all neurons, astrocytes and oligodendrocytes expressed active caspase-3 in both wild-type and knockout mice. At 6-7 mm, there were fewer caspase-3(+) oligodendrocytes and astrocytes than at 3-4 mm. Importantly, caspase 3 activation was significantly lower in prodynorphin(-/-) oligodendrocytes and astrocytes, as compared with wild-type mice. In contrast, while caspase-3 expression in neurons also declined with further distance from the injury, there was no effect of genotype. Radioimmunoassay showed that dynorphin A(1-17) was regionally increased in wild-type injured versus sham-injured tissues, although levels of the prodynorphin processing product Arg(6)-Leu-enkephalin were unchanged. Our results indicate that dynorphin peptides affect the extent of post injury caspase-3 activation, and that glia are especially sensitive to these effects. By promoting caspase-3 activation, dynorphin peptides likely increase the probability of glial apoptosis after SCI. While normally beneficial, our findings suggest that prodynorphin or its peptide products become maladaptive following SCI and contribute to secondary injury. PMID- 17698297 TI - Effects of an acute stressor on blood pressure and heart rate in rats pretreated with intracerebroventricular oxytocin injections. AB - Oxytocin induces a long-lasting reduction of blood pressure in rats. The aim of the present study was to investigate the effects of an acute stressor on blood pressure and heart rate in rats previously exposed to repeated administration of intracerebroventricular (ICV) oxytocin. For this purpose oxytocin (0.3 microg, ICV) was administered to male rats once a day during 5 days. Blood pressure and heart rate were measured before and after treatment. In addition, blood pressure and heart rate were measured during 30 min after exposure to 10s of noise from an alarm clock. The oxytocin treatment reduced blood pressure significantly (systolic: 108+/-4.6 vs. 121+/-1.8, p<0.01, diastolic: 96+/-5.1 vs. 108+/-3.0, p<0.01), whereas heart rate remained unchanged. In contrast, systolic and diastolic blood pressure increased significantly after the exposure to the ringing alarm clock in the oxytocin-treated rats (p<0.05), and became equal to the blood pressure in controls. In addition, heart rate increased and stayed significantly higher in the oxytocin-treated rats compared to the controls during the 30 min observation period (ANOVA p<0.01). Twenty-four hours later, blood pressure was again significantly lower in the oxytocin-treated rats compared to controls (p<0.01). In conclusion, oxytocin decreased blood pressure without changing pulse rate. However, when the oxytocin-treated rats were subjected to the unexpected noise from a ringing alarm clock blood pressure and heart rate increased significantly. No such effect was observed in the control group. Thus repeated oxytocin treatment can, in spite of decreasing blood pressure during basal conditions, increase cardiovascular reactivity to some types of stressors. PMID- 17698298 TI - Three orthologs in rice, Arabidopsis, and Populus encoding starch branching enzymes (SBEs) are different from other SBE gene families in plants. AB - Starch branching enzymes (SBEs) play important roles in plant starch synthesis. Three orthologs encoding SBEs in rice, Arabidopsis thaliana, and Populus trichocarpa are described. Putative amino acid sequences of these three SBE genes show approximately 30% identity to those of SBEI and SBEII from plants such as maize, barley, and wheat. More interestingly, they share approximately 31% amino acid sequence identity with those of glycogen-branching enzymes from such animals as mouse, horse, and monkey. The three genes have similar genomic structures, but their structural features are quite different from those of genes of both SBEI and SBEII families in plants. Based on phylogenetic analysis and genomic structure comparison, it is proposed that the three SBE genes represent a new family of SBEs. PMID- 17698299 TI - Maternally inherited aminoglycoside-induced and nonsyndromic hearing loss is associated with the 12S rRNA C1494T mutation in three Han Chinese pedigrees. AB - We report here the clinical, genetic and molecular characterization of three Han Chinese pedigrees with maternally transmitted aminoglycoside-induced and nonsyndromic bilateral hearing loss. Clinical evaluation revealed the wide range of severity, age-at-onset and audiometric configuration of hearing impairment in matrilineal relatives in these families. The penetrances of hearing loss in these pedigrees were 28%, 20%, and 15%, with an average of 21%, when aminoglycoside induced deafness was included. When the effect of aminoglycosides was excluded, the penetrances of hearing loss in these seven pedigrees were 21%, 13% and 8%, with an average of 14%. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the presence of the deafness-associated 12S rRNA C1494T mutation, in addition to distinct sets of mtDNA polymorphism belonging to Eastern Asian haplogroups F1a1, F1a1 and D5a2, respectively. This suggested that the C1494T mutation occurred sporadically and multiplied through evolution of the mtDNA. The absence of functionally significant mutations in tRNA and rRNAs or secondary LHON mutations in their mtDNA suggests that these mtDNA haplogroup specific variants may not play an important role in the phenotypic expression of the C1494T mutation in those Chinese families. In addition, the lack of significant mutation in the GJB2 gene ruled out the possible involvement of GJB2 in the phenotypic expression of the C1494T mutation in those affected subjects. However, aminoglycosides and other nuclear modifier genes play a modifying role in the phenotypic manifestation of the C1494T mutation in these Chinese families. PMID- 17698300 TI - Multiple receptor-like kinase cDNAs from liverwort Marchantia polymorpha and two charophycean green algae, Closterium ehrenbergii and Nitella axillaris: Extensive gene duplications and gene shufflings in the early evolution of streptophytes. AB - Plant receptor-like kinases (RLKs) comprise a large family with more than several hundred members in vascular plants. The RLK family is thought to have diverged specifically in the plant kingdom, and no family member has been identified in other lineages except for animals and Plasmodium, both of which have RLK related families of small size. To know the time of divergence of RLK family members by gene duplications and domain shufflings, comprehensive isolations of RLK cDNAs were performed from a nonvascular plant, liverwort Marchantia polymorpha and two charophycean green algae, Closterium ehrenbergii, and Nitella axillaris, thought to be the closest relatives to land plants. We obtained twenty-nine, fourteen, and thirteen RLK related cDNAs from M. polymorpha, C. ehrenbergii, and N. axillaris, respectively. The amino acid sequences of these RLKs were compared with those of vascular plants, and phylogenetic trees were inferred by GAMT, a genetic algorithm-based maximum likelihood (ML) method that outputs multiple trees, together with best one. The inferred ML trees revealed ancient gene duplications generating subfamilies with different domain organizations, which occurred extensively at least before the divergence of vascular and nonvascular plants. Rather it remains possible that the extensive gene duplications occurred during the early evolution of streptophytes. Multicellular-specific somatic embryogenesis receptor kinase (SERK) involved in somatic embryogenesis was found in a unicellular alga C. ehrenbergii, suggesting the evolution of SERK by gene recruitment of a unicellular gene. PMID- 17698301 TI - A randomized controlled trial of an early intervention program in low birth weight children: outcome at 2 years. AB - BACKGROUND: Preterm infants are at increased risk of cognitive, motor and behavioral problems. Different intervention programs have been designed in an attempt to improve outcome, but the results are conflicting. OBJECTIVE: To examine the effects of an early intervention program on cognitive, motor and behavioral problems and parenting stress among low birth weight children at 2 years corrected age. METHODS: A randomized controlled trial was conducted including infants with a birth weight <2000 g treated at the University Hospital of North Norway, to examine the effects of a modified version of the Mother Infant Transaction Program on cognitive, motor and behavioral outcomes and parenting stress. The children were assessed with the Bayley Scales of Infant Development and the Child Behavior Checklist/2-3 (CBCL) and the Parenting Stress Index were administered to the parents at 2 years corrected age. RESULTS: Sixty nine children in the intervention group and 67 in the control group were assessed at 2 years. There were no differences between the groups in cognitive or motor outcomes. The intervention group scored consistently lower on all CBCL syndrome scales, but no difference was significant. The mothers in the intervention group reported significantly lower parental stress in both child and parent domain, whereas the fathers reported lower stress in child domain compared to the control group. CONCLUSION: This early intervention program does not improve cognitive, motor or behavioral outcomes at 2 years. There was a significant reduction in parenting stress reported by both mothers and fathers in the intervention group. PMID- 17698302 TI - Activities of respiratory chain complexes and pyruvate dehydrogenase in isolated muscle mitochondria in premature neonates. AB - BACKGROUND AND AIMS: Most diseases in premature neonates are secondary to immaturity of various organ systems. Also the inadequate capacity of mitochondrial energy production may play an important role in the neonatal morbidity. SUBJECTS AND METHODS: The activities and amount of respiratory chain (RC) complexes, pyruvate dehydrogenase (PDH) and citrate synthase (CS) were analysed in isolated muscle mitochondria obtained at autopsy in 19 premature neonates using spectrophotometric and radioenzymatic methods and blue-native electrophoresis and Western blotting. Two groups of children recommended for muscle biopsy at the age of 0.5-2 and 3-18 years served as controls. RESULTS: In premature neonates, the activities of RC complexes III, IV, PDH and CS were markedly lower in comparison with older children. On the contrary, the activity of complex I was higher in premature neonates than in older children. The ratios between RC complexes I, II and III and CS were significantly higher in premature neonates in comparison with older children. In addition, the protein amount of RC complexes and PDH subunits were lower in premature neonates in comparison with older children. CONCLUSION: The results of our study document the age-dependent differences in activities of PDH and respiratory chain complexes in early childhood. Lower functional capacity of mitochondrial energy-providing system in critically ill neonates may be explained by combination of various factors including the delay in maturation of PDH and respiratory chain complexes in very premature neonates and increased degradation of mitochondrial proteins in connection with sepsis, tissue hypoperfusion or hypoxemia. PMID- 17698303 TI - Preventive effect of D-psicose, one of rare ketohexoses, on di-(2-ethylhexyl) phthalate (DEHP)-induced testicular injury in rat. AB - To investigate the preventive effects of d-psicose, one of rare ketohexoses, on di-(2-ethylhexyl) phthalate (DEHP)-induced testicular injury, prepubertal male Sprague-Dawley rats were exposed to DEHP via their diet or orally, while under treatment with d-psicose. The rats given a diet-containing 1% DEHP alone for 7-14 days showed severe testicular atrophy accompanied by aspermatogenesis. On the other hand, those given the diet plus 2% but not 1% d-psicose-supplemented water for 14 days did not develop testicular atrophy, and exhibited an almost complete spermatogenesis. There was no significant difference in plasma mono-(2 ethylhexyl) phthalate (MEHP) levels between the d-psicose-free and d-psicose treated groups. The testicular malondialdehyde (MDA) level after a single oral administration of 2g/kg of DEHP showed a similar pattern of increase to the plasma MEHP level and peaked in 24h suggesting a close and dose-dependent relation between plasma MEHP and testicular reactive oxygen species (ROS) levels. Pretreatment with d-psicose at a concentration of 2% and 4% resulted in an almost complete but not absolute suppression of testicular MDA production among rats administered 2g/kg of DEHP. The microarray analysis showed the induction of oxidative stress related genes including the thioredoxin, glutathione peroxidase 1 and 2, glutaredoixn 1 after 24h of the DEHP treatment in the testis. These results show that d-psicose prevents DEHP-induced testicular injury by suppressing the generation of ROS in the rat testis. This effect may be due to the direct scavenging by d-psicose of ROS generated in the testis. PMID- 17698304 TI - Acute and chronic vitamin A supplementation at therapeutic doses induces oxidative stress in submitochondrial particles isolated from cerebral cortex and cerebellum of adult rats. AB - Vitamin A is an essential micronutrient to the normal brain function. However, there is an increasing concern regarding the use of vitamin A at high doses even therapeutically. Here, we show that acute and chronic vitamin A supplementation induces oxidative stress to submitochondrial particles (SMP) isolated from rat cerebral cortex and cerebellum. Both chronic and acute vitamin A supplementation at therapeutic (1000 IU/kg or 2500 IU/kg) or excessive (4500 IU/kg or 9000 IU/kg) doses induced lipid peroxidation, protein carbonylation, and oxidation of protein thiol groups in cerebral cortex and cerebellum SMP. Furthermore, vitamin A supplementation induced an increase in the superoxide (O(2)(-)) anion production, indicating an uncoupling in the electron transfer chain (ETC). Locomotory and exploratory activity, which are associated to cerebral cortex and cerebellum, also were affected by both acute and chronic vitamin A supplementation. Vitamin A induced a decrease in both locomotory and exploratory behavior. Together, these results show that vitamin A could be toxic at the sub cellular level, inducing mitochondrial dysfunction and altering cerebral cortex and/or cerebellum dependent behavior. PMID- 17698305 TI - Prior exposure of maiden ewes to rams enhances their behavioural interactions with rams but is not a pre-requisite to their endocrine response to the ram effect. AB - In this study, we tested whether prior experience with rams would modify the behavioural and endocrine responses of maiden ewes to rams. During mid-anoestrus, sexually naive, maiden ewes were exposed to rams for 7 days (ram experienced, RE; n=61) or isolated from rams (ram naive, RN; n=63). All ewes were subsequently isolated from rams. In Experiment 1, RE (n=55) and RN (n=57) ewes were introduced to rams during late anoestrus. RE ewes had more total and positive interactions with rams than RN ewes (P<0.001). RE ewes showed more ram seeking behaviour and spent more time in proximity of rams than RN ewes (at least; P<0.05). In Experiment 2, RE (n=6) and RN (n=6) ewes were introduced to rams midway through a frequent blood sampling regime in late anoestrus. Ram introduction stimulated an increase in LH pulse frequency and basal LH in both RE and RN ewes (at least P<0.05). RE ewes had an increase in mean LH concentrations (P<0.01) that failed to reach significance in RN ewes (P<0.1). There was no significant effect of prior experience with rams on LH pulse frequency, amplitude or whether ewes had an LH surge. In conclusion, prior experience with rams is important in developing appropriate ewe-ram interactions but is not a pre-requisite to the endocrine response to the ram effect. PMID- 17698306 TI - Anti-proliferative and mutagenic activities of aqueous and methanol extracts of leaves from Pereskia bleo (Kunth) DC (Cactaceae). AB - The anti-proliferative effects of the aqueous and methanol extracts of leaves of Pereskia bleo (Kunth) DC (Cactaceae) against a mouse mammary cancer cell line (4T1) and a normal mouse fibroblast cell line (NIH/3T3) were evaluated under an optimal (in culture medium containing 10% foetal bovine serum (FBS)) and a sub optimal (in culture medium containing 0.5% FBS) conditions. Under the optimal condition, the aqueous extract showed a significant (p<0.05) anti-proliferative effect at 200 microg/mL and 300 microg/mL in 4T1 cells and 300 microg/mL in NIH/3T3 cells, whereas the methanol extract did not show any notable anti proliferative effect in these cell lines, at any of the concentrations tested. Under the sub-optimal condition, the aqueous extract showed a significant (p<0.05) anti-proliferative effect at 200 microg/mL and 300 microg/mL in NIH/3T3 cells, whilst the methanol extract showed a significant (p<0.05) anti proliferative effect at 200 microg/mL and 300 microg/mL in both cell lines. An upward trend of apoptosis was observed in both 4T1 and NIH/3T3 cells treated with increasing concentrations of the aqueous extract. The level of apoptosis observed at all the concentrations of the aqueous extract tested was consistently higher than necrosis. There was a significant (p<0.05) increase in the level of necrosis observed in the 4T1 cells treated with 300 microg/mL of the methanol extract. Generally, the level of necrosis was noted to be higher than that of apoptosis in the methanol extract-treated cells. The mutagenicity assay performed showed that in the absence of S-9 liver metabolic activation, the extract was not mutagenic up to the concentration of 165 microg/mL . However, in the presence of S-9 liver metabolic activation, the aqueous extract was mutagenic at all the concentrations tested. This study shows that both the aqueous and methanol extracts of the leaves from Pereskia bleo (Kunth) DC (Cactaceae) do not have appreciable anti proliferative effect on the 4T1 and NIH/3T3 cells as the EC(50) values obtained are greater than 50 microg/mL when tested under optimal culture condition. Moreover, the aqueous extract may form mutagenic compound(s) upon the metabolisation by liver enzymes. PMID- 17698308 TI - [Hormone replacement therapy and vessels: what's the story in 2007?]. PMID- 17698307 TI - Potential involvement of calcium and nitric oxide in protective effects of puerarin on oxygen-glucose deprivation in cultured hippocampal neurons. AB - The aim of this study was to clarify the mechanisms underlying neuroprotection of puerarin (Pur) against cerebral hypoxia-ischemia. Primary hippocampal cultures were prepared from 2-day-old Sprague-Dawley rats. After 8 days in vitro, the cultures subjected to 3h oxygen/glucose deprivation (OGD). Flow cytometric analysis of annexin-V and propidium iodide (PI) labeling cells found that apoptosis and necrosis were significantly reduced in the cultured hippocampal neurons by addition of Pur during 3h OGD and for the following 24h. Pur (40 and 100 microM) also attenuated glutamate (Glu) induced neuronal damage, suppressing apoptosis and necrosis induced by Glu of 0.5mM. Furthermore, the changes in intracellular Ca(2+) and generation of nitric oxide (NO) were measured by confocal laser scanning microscopy with Fluo-3, a Ca(2+) probe, and diaminofluorescein diacetate (DAF DA), a NO probe, respectively. In agreement with the results from flow cytometric analysis, Pur (40 and 100 microM) markedly slowed down OGD-induced Ca(2+) influx and lowered the intracellular Ca(2+) peak. Meanwhile, NO synthesis induced by OGD was significantly inhibited by Pur. Our findings suggest that Pur can ameliorate hippocampal neuronal death induced by OGD in vitro. The protective effects of Pur are associated with inhibiting the action of glutaminergic transmitter, intracellular Ca(2+) elevation and neuronal NO synthesis. PMID- 17698309 TI - [Lyme arthritis, Lyme carditis and other presentations potentially associated to Lyme disease]. AB - Lyme disease or Lyme borreliosis is the most common tick-transmitted disease in the Northern hemisphere and is caused by Borrelia burgdorferi spirochetes. Lyme disease commonly begins with a characteristic skin lesion, erythema migrans. Weeks or months later, the patients may have neurologic, joint, or cardiac abnormalities. Some patients may still present persistent deep fatigue and various unspecific symptoms after standard courses of antibiotic treatment for Lyme disease. This constellation of symptoms has been variously referred to as "chronic Lyme disease", or "post-Lyme disease syndrome". The first French National Consensus Conference on Lyme Disease was the reason to review all aspects of articular and cardiac manifestations of Lyme disease after a synthesis of recent literature. The involvement of Borrelia species in chronic Lyme disease and other pathologies is discussed. PMID- 17698312 TI - Use of bioluminescence imaging to detect enhanced hepatic and systemic tumor growth following partial hepatectomy in mice. AB - BACKGROUND: The impact of partial hepatectomy on intra-hepatic and distant tumor growth is a matter of controversy. Utilizing a highly sensitive tumor imaging strategy, we sought to demonstrate whether this growth-acceleration occurs, and to develop an animal model with which to investigate potential therapeutic strategies. METHODS: Mice bearing constitutively-active luciferase-expressing tumor cells were subjected to either 70% partial hepatectomy (PH; n=10) or a sham operation (n=11). Mice were sacrificed 14 days later and remnant livers (or anatomic equivalents in the control group) and lungs harvested for bioluminescence detection. RESULTS: Remnant liver weights were significantly increased in PH compared to equivalent lobes in sham-operated animals (t-test; p=0.005). Tumor burden as measured by bioluminescence was significantly higher in both liver and lung specimens in the PH group (Wilcoxon's Rank Sum test; p=0.01 and 0.004, respectively). CONCLUSIONS: Following PH, enhanced metastatic growth was depicted regionally and systemically with bioluminescence imaging providing an objective measure of tumor burden. This preclinical model can help to identify adjuvant therapies that can influence both tumor growth and liver regeneration. PMID- 17698311 TI - Identity and coping experiences in Chronic Fatigue Syndrome: a synthesis of qualitative studies. AB - OBJECTIVE: To provide insight into patients' and doctors' experiences with CFS. METHODS: We compiled available qualitative studies and applied meta-ethnography to identify and translate across the studies. Analysis provided second-order interpretation of the original findings and developed third-order constructs from a line of arguments. RESULTS: Twenty qualitative studies on CFS experiences were identified. Symptom experiences and the responses from significant others could jeopardise the patients' senses of identity. They felt severely ill, yet blamed and dismissed. Patients' beliefs and causal attributions oppose the doctor's understanding of the condition. For the patient, getting a diagnosis and knowing more was necessary for recovery. Doctors were reluctant towards the diagnosis, and struggle to maintain professional authority. For patients, experience of discreditation could lead to withdrawal and behavioural disengagement. CONCLUSION: The identities of CFS patients are challenged when the legitimacy of their illness is questioned. This significant burden adds to a loss of previously established identity and makes the patient more vulnerable than just suffering from the symptoms. CFS patients work hard to cope with their condition by knowing more, keeping a distance to protect themselves and learning more about their limits. PRACTICE IMPLICATIONS: Doctors can support patients' coping by supporting the strong sides of the patients instead of casting doubt upon them. PMID- 17698313 TI - [Salmonella non typhi: an unusual cause of acute acalculous cholecystitis in adults]. PMID- 17698310 TI - Calcium metabolism and vitamin D in the extreme longevity. AB - Skeletal remodelling is a continuous process during life and is still active also in extreme senescence. In the elderly, bone resorption often prevails over bone formation, causing bone loss and fragility. Elderly subjects are exposed to the risk of fractures, and loss of self-sufficiency, if considering that the proximal femur is the most frequently involved site. Bone remodelling can maintain circulating calcium within physiological ranges, at the expense of a substantial loss of this ion from the skeleton, particularly during senescence. Calcium metabolism is regulated at cellular/molecular level by a network of cytokines, growth factors, systemic hormones that act on bone in paracrine/autocrine/systemic fashion. Among the molecules involved in bone metabolism, parathyroid hormone (PTH) and vitamin D present some peculiar aspects during senescence. The osteometabolic features in a consistent group of centenarians have been evaluated. It results that a severe hypovitaminosis D was present in 99 out of 104 centenarians (25-OH vitamin D below 5 nmol/L), and that it plays an important role as a factor inducing a vicious circle involving hypocalcemia, secondary hyperparathyroidism, together with biochemical features indicating a consistent bone loss. Serum C-terminal cross-linking telopeptide, a specific marker of bone resorption was elevated in 92% of these subjects. Moreover, it has been found that several femoral fractures had occurred after 90 years of age. These data offer a rational for the possible prevention of elevated bone turnover, bone loss and consequently the reduction of osteoporotic fractures and fractures-induced disability, in the oldest olds, through the simple supplementation with calcium and vitamin D. PMID- 17698314 TI - [Ventilator-associated pneumonia: follow the guidelines!]. AB - OBJECTIVES: To compare the clinical outcomes and the causative pathogens of early onset and late-onset ventilator-associated pneumonia (VAP) diagnosed by bronchoalveolar lavage (BAL). STUDY DESIGN: Prospective, observational, epidemiological study. PATIENTS AND METHODS: During a 7-years period, all first episodes of VAP were prospectively included. Diagnosis was confirmed by a BAL with a threshold of 10(4) cfu/ml. Late-onset pneumonia was defined if occurred after the seventh day after mechanical ventilation. RESULTS: One hundred and thirteen VAP were studied. Fifty were early-onsets and 63 late-onsets. Thirty four per cent of early-onset VAP and 73% of late-onset VAP were due to potential multiresistants pathogens. Pseudomonas aeruginosa was the most commonly isolated bacteria both in early-onset and late-onset VAP (16 and 39% respectively). Morbidity and mortality (29 vs 29%, ns) were not statically different between the two groups (early-onset and late-onset VAP). CONCLUSION: In our study, both early onset and late-onset VAP were mainly caused by potentially multiresistants bacteria, most commonly Gram negative bacilli. Even for early VAP, clinicians should be aware about all risk factors for potentially multiresistants pathogens and not only the delay of onset of the VAP episode. PMID- 17698316 TI - [Closed-loop titration of propofol guided by the bispectral index]. AB - This review analyzes the clinical studies concerning the automated perfusion, or closed-loop, of propofol guided by the bispectral index (BIS). To carry out the maintenance of general anaesthesia by a closed loop propofol-BIS is feasible as shown by studies comprising few low risk patients. We showed that induction of anaesthesia is feasible with a closed loop, haemodynamic stability being similar to a manual titration. A second study, bearing on the whole of the anaesthesia of patients ASA I to III undergoing very diverse surgical acts, showed that the closed loop propofol-BIS was more precise than a manual perfusion. This confirms that the closed loop propofol-BIS is not an esoteric research and that it represents a tool with a future for the clinician. PMID- 17698317 TI - Increased plasma malondialdehyde and fructosamine in iron deficiency anemia: effect of treatment. AB - Glycation and lipid peroxidation are spontaneous reactions that are believed to play a key role in the pathogenesis of many clinical disorders. Glycation of proteins is enhanced by elevated glucose concentrations. However, increased glycated hemoglobin levels have been documented in iron deficiency anemic patients without any history of diabetes. Collective evidences reveal that lipid peroxidation can modulate protein glycation. This study was undertaken to unravel the possible association of malondialdehyde and fructosamine in iron deficient anemic patients and to observe the possible alteration in malondialdehyde and fructosamine levels in these patients after one month supplementation with iron. Twenty non-diabetic anemic patients and 16 age-matched healthy subjects were enrolled for this study. Plasma lipid peroxides, fasting glucose, fructosamine, iron, ferritin and hemoglobin were analyzed in both the groups. Partial correlation analysis was performed to predict the independent association of malondialdehyde and fasting glucose on fructosamine. In anemic patients, while fructosamine and malondialdehyde levels were found to be significantly increased, hemoglobin, iron and ferritin levels decreased significantly when compared to before treatment. Fructosamine was found to have a significant positive correlation with malondialdehyde even after nullifying the effect of glucose. After one month supplementation with iron, both fructosamine and malondialdehyde levels decreased significantly when compared to before treatment. There was a significant increase in iron, ferritin and hemoglobin levels in anemic patients after one month of treatment. In conclusion, an increased level of fructosamine and malondialdehyde was found in anemic patients. These data suggest that fructosamine levels are closely associated with malondialdehyde concentrations in iron deficient anemic patients. PMID- 17698318 TI - Neutrophil elastase and systemic inflammatory response syndrome in the initiation and development of acute lung injury among critically ill patients. AB - Critically ill patients are commonly associated with systemic inflammatory response syndrome (SIRS) and are at a greater risk of developing acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Under these conditions, large amounts of various cytokines are produced, which either directly or indirectly induce tissue injury and finally organ dysfunctions, through the activation of neutrophils and as a result of release of cytotoxic molecules, especially neutrophil elastase (NE). In the present study, we determined plasma neutrophil elastase-alpha-1 antitrypsin complex (NE-AT) and elastase digests of cross-linked fibrin (e-XDP) in critically ill patients to elucidate the significance of NE in the initiation and progression of ALI and ARDS in the presence or absence of SIRS. We found significantly increased levels of plasma NE-AT in the patients with ARDS, especially when the definition of SIRS was met. Among ALI/ARDS groups, plasma NE-AT, but not e-XDP, correlated significantly with the decrease in PaO(2)/FIO(2) ratio and the duration of ALI/ARDS. Furthermore, NE-AT, but not e-XDP, significantly increased in subgroups whose PaO(2)/FIO(2) ratio decreased by more than 20%. Such correlations and differences between the subgroups were not observed in the non-ALI patients. From these results, we speculate that NE-AT, but not e-XDP, may be predictive of progressive lung injury in the early stage of ALI and ARDS. PMID- 17698319 TI - French maritime pine bark extract Pycnogenol reduces thromboxane generation in blood from diabetic male rats. AB - The protective effect of Pycnogenol against cardiovascular diseases was clearly demonstrated. Nevertheless, little is known about its antithrombotic effect, especially in diabetes associated with enhanced thromboxane synthesis leading to severe vascular complications. Therefore, the main purpose of our study was to evaluate the effect of long-term Pycnogenol intake on synthesis of prothrombotic thromboxane A(2) (TXA(2)) in animal model of insulin-dependent diabetes. The levels of main plasma TXA(2) metabolite, thromboxane B(2) (TXB(2)), were assessed by enzyme-linked immunosorbent assay. Diabetes was induced in Wistar male rats by single injection of streptozotocin, resulting after 8 weeks in significant body weight reduction, increased plasma glucose concentrations, and decreased plasma C peptide levels, compared to non-diabetic animals. There was no significant reduction of plasma glucose concentrations after Pycnogenol ingestion. It was found, however, that daily administration of either Pycnogenol (5mg/kg b.wt.) or acetylsalicylic acid (ASA, 10mg/kg b.wt.) significantly reduced plasma TXB(2) concentrations, and this inhibitory effect was higher in the latter case. Nonetheless, simultaneous administration of Pycnogenol and ASA did not improve effectiveness of ASA-mediated decrease in TXB(2) generation. The results of the present study suggest that Pycnogenol might have a beneficial antithrombotic effect when administered alone or as a supplementation of standard antiplatelet therapy in diabetic patients. PMID- 17698320 TI - Infant of 22 months of age with no anomalies born from a HCV- and HIV-infected mother under treatment with pegylated interferon, ribavirin and antiretroviral therapy during the first 16 weeks of pregnancy. AB - The product label of ribavirin states that it is contraindicated during pregnancy, so the risk in its administering during pregnancy is concerned. We show a case of an infant of 22 months of age with no anomalies born from an HCV- and HIV-infected mother under treatment with pegylated interferon, ribavirin and antiretroviral therapy during the first 16 weeks of pregnancy. The infant is neither HIV- nor HCV-infected. PMID- 17698322 TI - Th1-type immune responses by Toll-like receptor 4 signaling are required for the development of myocarditis in mice with BCG-induced myocarditis. AB - The immunological aspects of autoimmune myocarditis are difficult to understand because of the existence of many infectious agents and animal models suggesting different mechanisms in autoimmune myocarditis. To overcome these difficulties, two strains of mice, C3H/HeN and C3H/HeJ, showing different immune responses to mycobacteria, were immunized with myosin mixed with BCG. The C3H/HeN mice with a wild-type Toll-like receptor 4 (TLR4) showed severe myocarditis, whereas the C3H/HeJ mice with nonfunctional mutated TLR4 did not. CD4(+) cells from both strains of mice exhibited appreciable proliferative responses following myosin stimulation; however, the cytokines from these cells differed between these two strains. The C3H/HeN mice showed T helper (Th)1-type cytokine responses, whereas the expressions of mRNA in C3H/HeJ mice were Th2-type cytokine. When both of these strains of immunized mice were inoculated with a plasmid encoding cDNA of interleukin (IL)-4 or agonistic IL-4, the development of myocarditis was inhibited in C3H/HeN mice. Moreover, C3H/HeJ mice, in which development of myocarditis was not induced by immunization of myosin mixed with BCG, showed myocarditis after injection of IL-4 antagonistic mutant DNA for the induction of Th1-type immune responses. The results suggested that the induction of autoimmune myocarditis by myosin is affected by Th1-type immune responses. PMID- 17698321 TI - Cocaine disrupts pup-induced maternal behavior in juvenile and adult rats. AB - Impaired onset of maternal behavior in first generation rat dams was previously correlated with rearing by cocaine-treated dams and prenatal cocaine exposure. Pup-induced maternal behavior in non-lactating rats has not been examined with regard to cocaine exposure and rearing conditions. First generation male and female juveniles and young adult males reared by cocaine-treated or control dams and prenatally exposed to either cocaine or control conditions were tested for pup-induced maternal behavior at postnatal days 28 and 60. We now report disruptions in pup-induced maternal behavior in both 28 and 60 day old first generation offspring attributable to rearing condition and prenatal cocaine exposure. PMID- 17698323 TI - Frequency and predictive values of first rank symptoms at baseline among 362 young adult patients with first-episode schizophrenia Results from the Danish OPUS study. AB - AIM: To investigate the frequency of the Schneiderian First Rank Symptoms (FRSs) in a representative group of patients with first-episode schizophrenia and to analyse the predictive value of these symptoms in relation to psychopathology, work situation, depression, dependency and admission after 2 years of treatment. METHOD: 547 patients were included in the Danish OPUS trial. A subgroup of these, namely the 388 patients who fulfilled the diagnostic criteria for schizophrenia (ICD-10), was included in this study. Data from SCAN interviews were used to describe the frequency of the different first rank symptoms and to compare the characteristics of the patients with and without FRSs. RESULTS: FRSs were very common among these patients with first-episode schizophrenia. Only 16% reported no FRSs at all. Almost half of the patients had experienced commenting or discussing voices, and more than 40% had experienced loud thoughts. More patients with than without FRSs had some kind of substance abuse. FRSs at baseline did not predict the level of scores in the psychotic, negative or disorganized dimension after 2 years. Having FRSs at baseline was related to a significantly lower number of days of admission during the two-year period, but was not associated with antipsychotic medication or depression after 2 years. CONCLUSION: FRSs are very common among first-episode psychosis patients, but their predictive value seems to be limited with respect to outcome measures like psychopathology, work or substance abuse. However, FRSs did predict a lower mean of days of admission. PMID- 17698324 TI - Differential alterations of kainate receptor subunits in inhibitory interneurons in the anterior cingulate cortex in schizophrenia and bipolar disorder. AB - The aim of this study was to examine whether glutamatergic inputs onto GABA interneurons via the kainate receptor in the anterior cingulate cortex may be altered in schizophrenia and bipolar disorder. Hence, in a cohort of 60 post mortem human brains from schizophrenia, bipolar disorder, and normal control subjects, we simultaneously labeled the mRNA for the GluR5 or GluR6 subunit of the kainate receptor with [(35)S] and the mRNA for the 67 kD isoform of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD)(67) with digoxigenin using an immunoperoxidase method. The density of the GAD(67) mRNA-containing neurons that co-expressed GluR5 mRNA was decreased by 43% and 40% in layer 2 of the anterior cingulate cortex in schizophrenia and bipolar disorder, respectively. In contrast, the density of the GAD(67) mRNA-containing cells that expressed GluR6 mRNA was unaltered in either condition. Furthermore, the amount of GluR5 or GluR6 mRNA in the GAD(67) mRNA-expressing cells that contained a detectable level of these transcripts was also unchanged. Finally, the density of cells that did not contain GAD(67) mRNA, which presumably included all pyramidal neurons, but expressed the mRNA for the GluR5 or GluR6 subunit was not altered. Thus, glutamatergic modulation of inhibitory interneurons, but not pyramidal neurons, via kainate receptors containing the GluR5 subunit appears to be selectively altered in the anterior cingulate cortex in schizophrenia and bipolar disorder. PMID- 17698325 TI - No association between the DRD3 Ser9Gly polymorphism and schizophrenia. AB - OBJECTIVE: To investigate the association between a Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) and schizophrenia. METHODS: 408 schizophrenic patients and 172 control subjects were compared with regard to their DRD3 Ser9Gly genotypic and allelic frequencies. In addition, we carried out a family-based association study including 183 pedigrees (472 subjects) using the transmission disequilibrium test (TDT). RESULTS: No significant differences of genotype or homozygosity distribution were identified between patients and controls. When patients were stratified according to gender, response to treatment, age at onset, no significant differences were observed. Neither allele A (Ser), or G (Gly) were preferentially transmitted from parents to affected offspring. CONCLUSION: The hypothesis that the DRD3 Ser9Gly polymorphism plays a predisposing role in schizophrenia is not supported by this study. PMID- 17698326 TI - Pseudomonas aeruginosa bloodstream infections: how should we treat them? AB - Pseudomonas aeruginosa remains a major cause of bloodstream infections associated with high mortality. Adequacy of empirical therapy seems to influence outcome. Because of its high intrinsic resistance and its capacity to develop resistance during therapy, exposure to antimicrobial therapies frequently leads to subsequent P. aeruginosa bacteraemia with resistant isolates, increasing the risk of inadequate empirical therapy. Therefore empirical therapy should not include antimicrobial agents used in the last few months. Definitive combination therapy does not influence the prognosis of P. aeruginosa bacteraemia. Similarly, empirical combination therapy does not improve survival until receipt of the antibiogram. In contrast, empirical combination therapy does improve survival from the day of receipt of antibiogram to day 30. We therefore suggest that patients suspected of P. aeruginosa bacteraemia should receive empirical combination therapy until receipt of the antibiogram, followed by downgrading to an adequate monotherapy. This strategy might reduce mortality in P. aeruginosa bloodstream infections without exposing the patient to an excessive risk of adverse events. Antimicrobial therapies might select P. aeruginosa isolates with particular virulence phenotypes. The influence of specific virulence determinants on the prognosis of P. aeruginosa bacteraemia, as well as the potential benefit of virulence inhibition, deserves further investigation. PMID- 17698327 TI - In vitro activity of micafungin combined with itraconazole against Candida spp. AB - The in vitro activity of the combination micafungin + itraconazole was evaluated against 105 strains of six species of Candida. The highest percentage of synergy was obtained against Candida albicans (50%) and the lowest against Candida tropicalis (0%). PMID- 17698328 TI - CYP2D6 metabolizer status and atomoxetine dosing in children and adolescents with ADHD. AB - To determine whether physicians can adequately titrate atomoxetine without knowing genotype status for hepatic cytochrome P450 2D6, we pooled data from two open-label studies of atomoxetine in children and adolescents with attention deficit/hyperactivity disorder. Patients were assessed weekly up to 10 weeks and doses titrated for efficacy and tolerability at the discretion of investigators (max. 1.8 mg/kg/d). Mean dose was 0.1 mg/kg/d lower in poor metabolizer (PM) patients (n=87) than extensive metabolizers (EMs, n=1239). PMs demonstrated marginally better efficacy on the ADHDRS-IV-Parent:Inv and had comparable safety profiles, except for a 4.0-bpm greater increase in mean pulse rate and a 1.0-kg greater weight loss. Changes from baseline in Fridericia QTc did not differ between groups or correlate with dose in PMs. Results suggest genotyping is unnecessary during routine clinical management, because investigators were able to dose atomoxetine to comparable efficacy and safety levels in EMs and PMs without knowledge of genotype metabolizer status. PMID- 17698329 TI - Real time observation of diffusion and bioaffinity binding processes in single polyelectrolyte-coated microcapsules: a fluorescence-based approach. AB - We report on using fluorescence microscopy to study, visualize and determine the diffusion phenomena into and bioaffinity binding within single microcapsules in real time by using biotin-fluorescein as diffusive species and encapsulated avidin as binding partner. Microcapsules were constructed by entrapment of avidin within an agarose matrix and encapsulated with polyelectrolyte layers by Layer-by Layer (LbL) polyelectrolyte self assembly. A "ring" of high fluorescence intensity advancing with time towards the capsule centre was observed during incubation of capsules with fluorescent-labeled biotin. Fluorescence intensity was build up in capsule areas where binding to avidin occurred and was visualized in real time. A model for the diffusion process in microcapsules was developed and experimental data was plotted and fitted well with trends predicted by the model. The value of the diffusion coefficient for biotin-fluorescein was determined to be 3.5x10(-8)cm(2)/s, which is comparable to literature values of similar sized molecules. PMID- 17698330 TI - Increased uptake of quinine into the brain by inhibition of P-glycoprotein. AB - The impact of P-glycoprotein (P-gp) on the distribution of quinine between brain and plasma was studied experimentally in mice. Administration of quinine (20mg/kg, i.v.) to mdrla knockout mice resulted in enhanced brain concentrations of quinine as compared to the wild-type mice (7.9+/-1.4 microg/g versus 1.6+/-0.8 microg/g, respectively). Quinine concentrations and quinine-to-3-hydroxyquinine ratio in plasma were similar in normal and P-gp-deficient mice. The effect of intravenously administered drugs before quinine (20mg/kg, i.v.) was evaluated on brain uptake and biotransformation of quinine in mice. Cyclosporine A (50 mg/kg), erythromycine (40 mg/kg), verapamil (5mg/kg) or mefloquine (20 mg/kg) increased the brain-to-plasma quinine concentration ratio (by factors of 3.8-, 1.8-, 1.9- and 2.5-fold, respectively) and the quinine-to-3-hydroxyquinine ratio in plasma (by factors 2.1-, 3.7-, 1.8- and 2.0-fold, respectively). After cinchonine (40 mg/kg) and halofantrine (40 mg/kg) pre-treatment, the brain-to-plasma ratio for quinine increased by factor of 2.3 and 1.8, respectively without changes of quinine or metabolite concentrations in plasma. Doxycycline (20 mg/kg), artesunate (50 mg/kg) or artemether (50 mg/kg) did not alter quinine disposition. These results confirm in vivo that quinine is a substrate for mdr1a P-gp. Drug associations led not only to metabolic interactions but also increased quinine uptake by tissues protected by P-gp. Such interactions may have implications for the improvement of chemotherapy but should be also taken into account for potential enhancement of adverse effects. PMID- 17698331 TI - Temporal abstraction for feature extraction: a comparative case study in prediction from intensive care monitoring data. AB - OBJECTIVES: To compare two temporal abstraction procedures for the extraction of meta features from monitoring data. Feature extraction prior to predictive modeling is a common strategy in prediction from temporal data. A fundamental dilemma in this strategy, however, is the extent to which the extraction should be guided by domain knowledge, and to which extent it should be guided by the available data. The two temporal abstraction procedures compared in this case study differ in this respect. METHODS AND MATERIAL: The first temporal abstraction procedure derives symbolic descriptions from the data that are predefined using existing concepts from the medical language. In the second procedure, a large space of numerical meta features is searched through to discover relevant features from the data. These procedures were applied to a prediction problem from intensive care monitoring data. The predictive value of the resulting meta features were compared, and based on each type of features, a class probability tree model was developed. RESULTS: The numerical meta features extracted by the second procedure were found to be more informative than the symbolic meta features of the first procedure in the case study, and a superior predictive performance was observed for the associated tree model. CONCLUSION: The findings indicate that for prediction from monitoring data, induction of numerical meta features from data is preferable to extraction of symbolic meta features using existing clinical concepts. PMID- 17698332 TI - Involvement of the renin-angiotensin system in obesity: older and newer pathways. PMID- 17698333 TI - Trouble with lichen: the re-evaluation and re-interpretation of thallus form and fruit body types in the molecular era. AB - Following discussions of the definition of the terms 'lichen' and 'thallus', the role of lichenization in the evolution of asco- and basidiomycetes, and divergence and convergence in fruit body types, the morphogenetic interpretation of types of thallus form in lichens is reviewed. Attention is drawn to the various morphogenetic hypotheses proposed to explain the lichen thallus, but it is concluded that it is best interpreted as a novel phenotype with no exact homologue. Similar ascomatal and thallus types are found in lichen-forming fungi of different orders and families, as now revealed by molecular phylogenetic studies. These are interpreted as examples of convergent evolution, strategies by which unrelated fungi either display captured algae to maximize photosynthetic opportunities, or to attach themselves to a substratum. Phenotypic evolution of fruit body and thallus types in the major orders and clades is summarized, and the thallus types known in each order are tabulated. An hypothesis relating the evolution of these structures to hygroscopic movements is proposed, and the critical position of lichens in developing an integrated approach to ascomycete evolution is emphasized. PMID- 17698334 TI - Dissociation of lung function, dyspnea ratings and pulmonary extension in bronchiectasis. AB - Bronchiectasis is a heterogeneous disease in terms of its clinical and functional presentation. Some isolated parameters have been used to assess the severity of bronchiectasis or its response to treatment. A study was undertaken to evaluate whether lung function, dyspnea and extension of the disease are separate entities in the impact of bronchiectasis upon patients using factor analysis. Patients with bronchiectasis diagnosed by high-resolution computed tomography (HRCT) and airflow obstruction defined by FEV1/FVC<70% were included. Data were collected relating to clinical history, three different clinical ratings of dyspnea (Medical Research Council (MRC), Borg scale and Basal Dyspnea Index), the extent of bronchiectasis and functional variables. A total of 81 patients (mean age (SD): 69.5 (8.7)) years were included. The degree of dyspnea (MRC) was 1.9 (0.8). Mean FEV1 was 1301 ml (56.9% pred.). Four factors were found that accounted for 84.1% of the total data variance. Factor 1 (45.6% of the data variance) included the three measurements of dyspnea. Factor 2 (16% variance) comprised airflow obstruction parameters (FEV1, FEV1/FVC and PEF). Factor 3 (13.8% variance) included RV/TLC and RV (lung hyperinflation). Factor 4 (8.6% variance) included bronchiectasis extent. Dyspnea was more closely correlated with lung hyperinflation (r:0.33-0.54) than with airflow obstruction parameters (r:0.17 0.26). CONCLUSIONS: Airflow obstruction, dyspnea, lung hyperinflation and the lung extent of the bronchiectasis are four independent entities in the impact of bronchiectasis upon patients. PMID- 17698335 TI - Advances in proteomic workflows for systems biology. AB - Mass spectrometry, specifically the analysis of complex peptide mixtures by liquid chromatography and tandem mass spectrometry (shotgun proteomics) has been at the centre of proteomics research for the past decade. To overcome some of the fundamental limitations of the approach, including its limited sensitivity and high degree of redundancy, new proteomic workflows are being developed. Among these, targeting methods in which specific peptides are selectively isolated, identified and quantified are particularly promising. Here we summarize recent incremental advances in shotgun proteomic methods and outline emerging targeted workflows. The development of the target-driven approaches with their ability to detect and quantify identical, non-redundant sets of proteins in multiple repeat analyses will be crucially important for the application of proteomics to biomarker discovery and validation, and to systems biology research. PMID- 17698336 TI - The effect of anesthetic method for prophylactic cervical cerclage on plasma oxytocin: a randomized trial. AB - BACKGROUND: This study compared the changes in plasma oxytocin, intraoperative hemodynamics and postoperative uterine activity in patients who underwent elective Shirodkar cerclage for cervical incompetence with general or spinal anesthesia. METHODS: Thirty-seven singleton pregnant patients were enrolled in this prospective, randomized, controlled comparison of general (n=17) and spinal anesthesia (n=20) for elective Shirodkar suture in the second trimester. Plasma oxytocin concentration was measured before, 1 h after, and 24 h after the procedure. Uterine activity was recorded by external tocography twice daily for 30 min over a three-day period. RESULTS: Plasma oxytocin concentration did not change significantly after cerclage in either group. There were no significant differences between the two groups at any time. None of the patients reported painful contractions during study period. Two (11.8%) and four patients (20.0%) in the general and spinal groups, respectively (NS), showed increased uterine activity but these symptoms disappeared without treatment. The systolic blood pressure in the spinal group was significantly lower after anesthesia compared with the baseline and was significantly lower than in the general group during the procedure. CONCLUSIONS: Anesthetic method used for elective Shirodkar procedure did not affect the perioperative changes in plasma oxytocin nor postoperative uterine activity. PMID- 17698337 TI - The parturient with coronary heart disease. AB - Cardiac disease is one of the leading indirect causes of maternal mortality in the UK, exceeding numbers of direct deaths from thromboembolism and hypertension combined. Over one year in our unit we managed six women with coronary heart disease. In this series five women had stable coronary heart disease. Three delivered electively by caesarean section under combined spinal-epidural anaesthesia, a further two women had spontaneous vaginal deliveries, one planned under epidural analgesia, the second unplanned after a rapid labour. The sixth woman had unstable angina requiring percutaneous coronary intervention in the 28th week of pregnancy and went on to deliver by caesarean section under general anaesthesia. Regional anaesthesia was avoided in this case because of antiplatelet and anticoagulant medication. There is a lack of level-one evidence to direct the management of these women. Clinical decisions were directed by guidelines for the perioperative management of patients with cardiac disease in non-cardiac surgery and the management of all cardiac disease in the obstetric population. A multi-disciplinary approach was taken, with a collaborative plan made for each pregnancy and delivery. A thorough clinical history and examination together with transthoracic echocardiography allows risk stratification of women with coronary heart disease at risk of peripartum cardiac events. Further investigation specific to each woman's management can then be undertaken. PMID- 17698338 TI - Can we improve maternal outcome for high-risk obstetric patients? PMID- 17698339 TI - Contraindications to regional anaesthesia in obstetrics: a survey of German practice. AB - BACKGROUND: We assessed current practice regarding indications and contraindications to regional analgesia and anaesthesia for labour and delivery in Germany. METHODS: Questionnaires were mailed to the directors of 918 German departments of anaesthesiology. RESULTS: A total of 397 completed replies were received representing 41.3% of all deliveries in Germany. More than half of the respondents never perform spinal or epidural anaesthesia when the platelet count falls below 65x10(9)/L. Preeclampsia, which was not graded for severity, was considered an absolute contraindication to regional block by 15% and placenta praevia by 30% of respondents. If a woman had taken aspirin three days before, the numbers of respondents considering epidural anaesthesia contraindicated (40.2%) were nearly double those considering spinal anaesthesia contraindicated (21.7%) (P<0.001). For a platelet count of 79x10(9)/L, epidural anaesthesia was thought to be contraindicated by 37% and spinal anaesthesia by 22.2% (P=0.001). In departments with <500 deliveries/year, reluctance to use regional blockade was more pronounced than in departments with >1000 deliveries/year. CONCLUSION: Clinical practice varies considerably in Germany. Concerns regarding the use of regional blockade were more prevalent in hospitals with small delivery units. Indications and contraindications are not consistent in Germany and some recommendations or guidelines are needed. PMID- 17698342 TI - Recombinant factor VIIa should be used in massive obstetric haemorrhage. PMID- 17698343 TI - Challenges in critical care obstetrics in West Africa. PMID- 17698344 TI - Is preparation for emergency obstetric anaesthesia adequate? A maternal questionnaire survey. AB - BACKGROUND: Women are often unprepared for emergency obstetric procedures and need to receive information about anaesthesia quickly and succinctly. In the absence of previous studies, we sought feedback from women to find out how information was given, and particular areas of concern in order to define practice and improve women's experiences. METHODS: After Ethics Committee approval this prospective structured questionnaire study was conducted in a teaching and a district general hospital. Women were recruited up to 48 h after anaesthesia. RESULTS: Of 102 women studied, 55 had no prior knowledge of obstetric anaesthetic interventions and risks until told, usually by the obstetrician (n=47), just before the procedure. The most frightening aspect was anticipating the efficacy of regional anaesthesia (n=18), but 28 women were reassured by the explanation provided by the anaesthetist. All but two women expressed satisfaction with the content of information and the described attendant risks. Nevertheless, in contrast to our observed practice, 51 (50%) would have preferred having verbal information before labour preferably from an anaesthetist or midwife. CONCLUSIONS: Most women were unprepared for emergency obstetric anaesthesia. Many received information just before the event. After delivery they expressed a clear preference for earlier information. PMID- 17698345 TI - Clinical decision making in breast cancer: TAM and aromatase inhibitors for older patients -- a jungle? AB - Aromatase inhibitors and inactivators (AIs) have been/are being widely investigated as an alternative to tamoxifen in the treatment of postmenopausal breast cancer patients. In this paper we have reviewed data from phase III studies to define the role of AIs versus tamoxifen as first-line therapy in patients with metastatic breast cancer, as primary therapy for not operable or early breast cancers not suitable for conservative surgery and as adjuvant treatment for women with early breast cancer. An effort has been performed to evaluate whether specific recommendations were needed for older postmenopausal patients. AIs play a key role in the treatment of advanced breast cancer and represent the agent of choice in patients who are candidates to neoadjuvant hormone-therapy. Longer follow-up of already published trials and additional data coming from ongoing studies will better define when and how to use AIs in the adjuvant setting. PMID- 17698346 TI - Switching benchmarks in cancer of unknown primary: from autopsy to microarray. AB - INTRODUCTION: Cancer of unknown primary (CUP) is associated with unknown biology and dismal prognosis. Information on the primary site of origin is scant and has never been analysed. We systematically reviewed all published evidence on the CUP primary site identified by two different approaches, either autopsy or microarray gene expression profiling. METHODS: Published reports on identification of CUP primary site by autopsy or microarray-based multigene expression platforms were retrieved and analysed for year of publication, primary site, patient age, gender, histology, rate of primary identification, manifestations and metastatic deposits, microarray chip technology, training and validation sets, mathematical modelling, classification accuracy and number of classifying genes. RESULTS: From 1944 to 2000, a total of 884 CUP patients (66% males) underwent autopsy in 12 studies after presenting with metastatic or systemic symptoms and succumbing to their disease. A primary was identified in 644 (73%) of them, mostly in the lung (27%), pancreas (24%), hepatobiliary tree (8%), kidneys (8%), bowel, genital system and stomach, as a small focus of adenocarcinoma or poorly differentiated carcinoma. An unpredictable systemic dissemination was evident with high frequency of lung (46%), nodal (35%), bone (17%), brain (16%) and uncommon (18%) deposits. Between the 1944-1980 and the 1980-2000 series, female representation increased, 'undetermined neoplasm' diagnosis became rarer, pancreatic primaries were found less often while colonic ones were identified more frequently. Four studies using microarray technology profiled more than 500 CUP cases using classifier set of genes (ranging from 10 to 495) and reported strikingly dissimilar frequencies of assigned primary sites (lung 11.5%, pancreas 12.5%, bowel 12%, breast 15%, hepatobiliary tree 8%, kidneys 6%, genital system 9%, bladder 5%) in 75-90% of the cases. CONCLUSIONS: Evolution in medical imaging technology, diet and lifestyle habits probably account for changing epidemiology of CUP primaries in autopsies. Discrepant assignment of primary sites by microarrays may be due to the presence of 'sanctuary sites' in autopsies, molecular misclassification and the postulated presence of a pro-metastatic genetic signature. In view of the absence of patient therapeutic or prognostic benefit with primary identification, gene expression profiling should be re orientated towards unraveling the complex pathophysiology of metastases. PMID- 17698347 TI - Do pathological fractures influence survival and local recurrence rate in bony sarcomas? AB - The influence of pathological fracture on surgical management, local recurrence and survival was established in patients with high grade, localised, extremity osteosarcoma (n=484), chondrosarcoma (n=130) and Ewing's sarcoma (n=156). Limb salvage was possible in 79% of patients with a fracture compared to 84% of patients without a fracture (p=0.17). No difference in local recurrence was found between fracture and control groups. In univariate analysis, survival in the fracture group was lower than in the control group for osteosarcoma (34% versus 58%, p<0.01) and chondrosarcoma (35% versus 63%, p=0.04), but not for Ewing's sarcoma (75% versus 64%, p=0.80). In multivariate analysis, fracture remained a significant predictor of survival for osteosarcoma, but not for chondrosarcoma, where dedifferentiated subtype appeared to be decisive. Pathological fracture independently predicts worse survival in osteosarcoma, but not chondrosarcoma and Ewing's sarcoma. Limb saving surgery seems safe, if adequate resection margins are achieved. PMID- 17698348 TI - Broiler litter supplementation improves storage and feed-nutritional value of sawdust-based spent mushroom substrate. AB - A study was conducted to determine the effect of broiler poultry litter (BL) supplementation to spent mushroom substrate (SMS) on its storage and feed nutritional value improvement. In Exp. 1, the sawdust-based SMS from a king oyster mushroom (Pleurotus eryngii) farm was mixed with BL at 0%, 25%, 50%, 75% and 100% levels on a wet basis and deepstack stored for short-term (1-wk) and long-term (3-wk). At 1-wk of short-term deepstack storage, SMS with more than 50% BL levels showed favorable conservation. At 3-wk of long-term storage, all treatments except for BL 100% had a serious fungal problem. Based on chemical parameters, BL-blending to SMS practically improved the feed-nutritional value of the mixtures. Since the deepstacking method was not effective for long term storage, in Exp. 2 SMS ensiled with or without BL was attempted to improve long term (3-wk) storage. All the ensiled treatments (SMS 100%, SMS 75%+BL 25% and SMS 50%+BL 50%) had desirable fermentation. As in deepstacking, BL-blending to SMS improved the nutritive value of the ensiled mixtures. The populations of total bacteria, lactic acid bacteria and yeast were highest (P<0.05) when 75% SMS was blended with 25% BL. In conclusion, blending 50% or more BL with SMS was effective for the short-term (1-wk) deepstack storage. For long-term (3-wk) storage of SMS, an ensiling method was effective with or without the addition of BL. PMID- 17698349 TI - Effects of in situ nitrogen removal on degradation/stabilization of MSW in bioreactor landfill. AB - The effects of in situ nitrogen removal on degradation of municipal solid waste (MSW) in bioreactor landfill system were investigated. The in situ nitrogen removal bioreactor landfill (NBL) consisted of fresh-refuse filled, methanogenic and nitrifying reactors was operated. The two-phase bioreactor landfill (BL) comprised of fresh-refuse filled and methanogenic reactors was used as control. The methanogenic and nitrifying reactors were all loaded with aged refuse whose placement time was 6-7 yr. Furthermore, the nitrifying reactor was in situ aerated. The results showed that the degradation of fresh-refuse was delayed and CH4 production also was reduced in the in situ nitrogen removal bioreactor landfill. It was feasible to perform in situ ammonia nitrification in aged refuse. Moreover, the efficiency of oxygen utility was high during the in situ nitrification because of the porous characteristic of aged refuse. Supplementing only 8.5mg O2 mg(-1)Nd(-1) to aged refuse could make ammonia removed completely. However, aeration did not accelerate the further stabilization of aged refuse. PMID- 17698350 TI - Effect of Pseudomonas sp. P7014 on the growth of edible mushroom Pleurotus eryngii in bottle culture for commercial production. AB - Addition of bacterial culture strain P7014 and its supernatant to the mushroom growing media resulted in mushroom mycelia run faster. Mycelial growth rate of Pleurotus eryngii was increased up to 1.6 fold and primordial formation was induced one day earlier. Moreover, it was supposed that addition of bacteria had beneficial applications for commercial mushroom production, which appreciably reduced total number of days for cultivation of about 5+/-2 days compared with uninoculated, which took 55+/-2 days. PMID- 17698351 TI - Evaluation of waste mushroom logs as a potential biomass resource for the production of bioethanol. AB - In order to investigate the possibility of using waste mushroom logs as a biomass resource for alternative energy production, the chemical and physical characteristics of normal wood and waste mushroom logs were examined. Size reduction of normal wood (145 kW h/tone) required significantly higher energy consumption than waste mushroom logs (70 kW h/tone). The crystallinity value of waste mushroom logs was dramatically lower (33%) than normal wood (49%) after cultivation by Lentinus edodes as spawn. Lignin, an enzymatic hydrolysis inhibitor in sugar production, decreased from 21.07% to 18.78% after inoculation of L. edodes. Total sugar yields obtained by enzyme and acid hydrolysis were higher in waste mushroom logs than in normal wood. After 24h fermentation, 12 g/L ethanol was produced on waste mushroom logs, while normal wood produced 8 g/L ethanol. These results indicate that waste mushroom logs are economically suitable lignocellulosic material for the production of fermentable sugars related to bioethanol production. PMID- 17698352 TI - The effects of Fe(II) and Fe(III) concentration and initial pH on microbial leaching of low-grade sphalerite ore in a column reactor. AB - In this study the effects of initial concentration of Fe(II) and Fe(III) ions as well as initial pH on the bioleaching of a low-grade sphalerite ore in a leaching column over a period of 120 days with and without bacteria were investigated. Four different modifications of medium were used as column feed solutions to investigate the effects of initial concentration of Fe(II) and Fe(III) ions on zinc extraction. The experiments were carried out using a bench-scale, column leaching reactor, which was inoculated with mesophilic iron oxidizing bacteria, Acidithiobacillus ferrooxidans, initially isolated from the Sarcheshmeh chalcopyrite concentrate (Kerman, Iran). The effluent solutions were periodically analyzed for Zn, total Fe, Fe(II) and Fe(III) concentrations as well as pH values. Bacterial population was measured in the solution (free cells). Maximum zinc recovery in the column was achieved about 76% using medium free of initial ferrous ion and 11.4 g/L of ferric ion (medium 2) at pH 1.5. The extent of leaching of sphalerite ore with bacteria was significantly higher than that without bacteria (control) in the presence of ferrous ions. Fe(III) had a strong influence in zinc extraction, and did not adversely affect the growth of the bacteria population. PMID- 17698353 TI - Pseudomonas aeruginosa LBI production as an integrated process using the wastes from sunflower-oil refining as a substrate. AB - Pseudomonas aeruginosa LBI produced surface active rhamnolipids when cultivated on waste from the sunflower-oil process under different conditions. These biosurfactants, which reduce the superficial and interfacial tensions between fluids, offer advantages over their chemical counterparts, especially because of their ecological acceptability. These molecules can be used in fields as diverse as chemical, pharmaceutical and petrochemical industries. In this work, we present the effect of C/N ratio on growth and production yield. The best production yields (Y P/S) were achieved for C/N ratios (in g/g) of 8/1 (0.22) and 6.4/1 (0.23). The product concentration was very satisfactory (7.3g/L) at C/N ratio of 8/1, especially when considering that the substrate was basically composed of wastes that would otherwise constitute an environmental disposal problem. PMID- 17698354 TI - Batch and column studies of biosorption of heavy metals by Caulerpa lentillifera. AB - The biosorption of Cu(II), Cd(II), and Pb(II) by a dried green macroalga Caulerpa lentillifera was investigated. The sorption kinetic data could be fitted to the pseudo second order kinetic model. The governing transport mechanisms in the sorption process were both external mass transfer and intra-particle diffusion. Isotherm data followed the Sips isotherm model with the exponent of approximately unity suggesting that these biosorption could be described reasonably well with the Langmuir isotherm. The maximum sorption capacities of the various metal components on C. lentillifera biomass could be prioritized in order from high to low as: Pb(II)>Cu(II)>Cd(II). The sorption energies obtained from the Dubinin Radushkevich model for all sorption systems were in the range of 4-6 kJ mol(-1) indicating that a physical electrostatic force was potentially involved in the sorption process. Thomas model could well describe the breakthrough data from column experiments. Ca(II), Mg(II), and Mn(II) were the major ions released from the algal biomass during the sorption which revealed that ion exchange was one of the main sorption mechanisms. PMID- 17698355 TI - Preparation and characterization of polyurethane foams using a palm oil-based polyol. AB - Polyurethane (PU) foams were prepared using a palm oil-based polyol (PO-p). At the first stage, palm oil was converted to monoglycerides as a new type of polyol by glycerolysis. A yield of the product reached 70% at reaction temperature of 90 degrees C by using an alkali catalyst and a solvent. At the second stage, PU foams were prepared from mixtures of the polyol and polyethylene glycol (PEG) or diethylene glycol (DEG) and an isocyanate compound. Characterization of the foams was carried out by thermal and mechanical analyses. The analyses showed that the chain motion of polyurethane becomes more flexible at the higher PO-p content in the whole polymer, which indicates that the monoglyceride molecules work as soft segments. The study here may lead to a development of a new type of polyurethane foams using palm oil as a raw material. PMID- 17698356 TI - Adsorption of gold(III), platinum(IV) and palladium(II) onto glycine modified crosslinked chitosan resin. AB - The adsorption of Au(III), Pt(IV) and Pd(II) onto glycine modified crosslinked chitosan resin (GMCCR) has been investigated. The parameters studied include the effects of pH, contact time, ionic strength and the initial metal ion concentrations by batch method. The optimal pH for the adsorption of Au(III), Pt(IV) and Pd(II) was found to range from 1.0 to 4.0 and the maximum uptake was obtained at pH 2.0 for Au(III), Pt(IV) and Pd(II). The results obtained from equilibrium adsorption studies are fitted in various adsorption models such as Langmuir and Freundlich and the model parameters have been evaluated. The maximum adsorption capacity of GMCCR for Au(III), Pt(IV) and Pd(II) was found to be 169.98, 122.47 and 120.39mg/g, respectively. The kinetic data was tested using pseudo-first-order and pseudo-second-order kinetic models and an intraparticle diffusion model. The correlation results suggested that the pseudo-second-order model was the best choice among all the kinetic models to describe the adsorption behavior of Au(III), Pt(IV) and Pd(II) onto GMCCR. Various concentrations of HCl, thiourea and thiourea-HCl solutions were used to desorb the adsorbed precious metal ions from GMCCR. It was found that 0.7M thiourea-2M HCl solution provided effectiveness of the desorption of Au(III), Pt(IV) and Pd(II) from GMCCR. The modification of glycine on crosslinked chitosan resin (CCR) was studied by Fourier transform infrared spectrometry (FTIR) and scanning electron microscopy (SEM). PMID- 17698357 TI - The effects of heat treatment on physical properties and surface roughness of red bud maple (Acer trautvetteri Medw.) wood. AB - Heat treatment is often used to improve the dimensional stability of wood. In this study, the effects of heat treatment on physical properties and surface roughness of red-bud maple (Acer trautvetteri Medw.) wood were examined. Samples obtained from Duzce Forest Enterprises, Turkey, were subjected to heat treatment at varying temperatures and durations. The physical properties of heat-treated samples were compared against controls in order to determine their; oven-dry density, air-dry density, and swelling properties. A stylus method was employed to evaluate the surface characteristics of the samples. Roughness measurements, using the stylus method, were made in the direction perpendicular to the fiber. Three main roughness parameters; mean arithmetic deviation of profile (Ra), mean peak-to-valley height (Rz), and maximum roughness (Rmax) obtained from the surface of wood, were used to evaluate the effect of heat treatment on the surface characteristics of the specimens. Significant differences were determined (p>0.05) between surface roughness parameters (Ra, Rz, Rmax) at three different temperatures and three periods of heat treatment. The results showed that the values of density, swelling and surface roughness decreased with increasing temperature treatment and treatment times. Red-bud maple wood could be utilized successfully by applying proper heat treatment techniques without any losses in investigated parameters. This is vital in areas, such as window frames, where working stability and surface smoothness are important factors. PMID- 17698358 TI - Biosorption of a textile dye (Acid Blue 40) by cone biomass of Thuja orientalis: estimation of equilibrium, thermodynamic and kinetic parameters. AB - Biosorption of Acid Blue 40 (AB40) onto cone biomass of Thuja orientalis was studied with variation in the parameters of pH, contact time, biosorbent and dye concentration and temperature to estimate the equilibrium, thermodynamic and kinetic parameters. The AB40 biosorption was fast and the equilibrium was attained within 50 min. Equilibrium data fitted well to the Langmuir isotherm model in the studied concentration range of AB40 and at various temperatures. Maximum biosorption capacity (q(max)) for AB40 was 2.05 x 10(-4)mol g(-1) or 97.06 mg g(-1) at 20 degrees C. The changes of Gibbs free energy, enthalpy and entropy of biosorption were also evaluated for the biosorption of AB40 onto T. orientalis. The results indicate that the biosorption was spontaneous and exothermic. Kinetics of biosorption of AB40 was analyzed and rate constants were also derived and the results show that the pseudo-second-order kinetic model agrees very well with the experimental data. PMID- 17698359 TI - Results of a phase I trial of intravenous vinorelbine plus oral capecitabine as first-line chemotherapy of metastatic breast cancer. AB - The management of metastatic breast cancer becomes increasingly intricate, requiring new drugs and combinations. We present here the results of a phase I study evaluating the maximal tolerated dose of vinorelbine combined with capecitabine as first-line chemotherapy. Vinorelbine was administered intravenously on days 1 and 15, and capecitabine was given orally twice daily from day 1 to 14 (three cycles every 21 days). Three out of six patients receiving vinorelbine at 25mg/m2/day and capecitabine at 2000 mg/m2/day presented with a dose-limiting toxicity, consisting of protracted grade 3 neutropenia, hand foot syndrome and/or liver test disturbances. Despite of a dose reduction in vinorelbine (20mg/m2/day), one patient among four developed a dose-limiting febrile neutropenia. This regimen cannot be recommended as first-line treatment of metastatic breast cancer. These findings are not in agreement with previous publications of this schedule, or with promising results using both drugs orally. PMID- 17698360 TI - Rasburicase in the prevention and treatment of tumour lysis syndrome. AB - Tumour lysis syndrome (TLS) can be a life threatening complication of cancer therapy where cells undergo overwhelming lysis. The result is a pattern of metabolic abnormalities leading to acute renal failure and possible coagulopathy. Prophylactic pharmaceutical interventions can prevent this syndrome in almost all patients reducing possible admission to the intensive care unit. This article reviews the clinical efficacy, side effect profile, dosing and administration of rasburicase, an intravenous recombinant urate oxidase used in patients at risk of Tumour lysis syndrome due to a high tumour burden or where treatment is required. Rasburicase is an expensive but effective treatment option in the prevention and treatment of tumour lysis syndrome. PMID- 17698361 TI - The ecology of Ebola virus. AB - Since Ebola virus was first identified more than 30 years ago, tremendous progress has been made in understanding the molecular biology and pathogenesis of this virus. However, the means by which Ebola virus is maintained and transmitted in nature remains unclear despite dedicated efforts to answer these questions. Recent work has provided new evidence that fruit bats might have a role as a reservoir species, but it is not clear whether other species are also involved or how transmission to humans or apes takes place. Two opposing hypotheses for Ebola emergence have surfaced; one of long-term local persistence in a cryptic and infrequently contacted reservoir, versus another of a more recent introduction of the virus and directional spread through susceptible populations. Nevertheless, with the increasing frequency of human filovirus outbreaks and the tremendous impact of infection on the already threatened great ape populations, there is an urgent need to better understand the ecology of Ebola virus in nature. PMID- 17698363 TI - High-pressure polymorphic transformation of rutile to alpha-PbO2-type TiO2 at {011}R twin boundaries. AB - The presence of nano-scale lamellae of the alpha-PbO2-type polymorph of TiO2 sandwiched between twinned rutile inclusions in jadeite has been confirmed by electron diffraction and high-resolution transmission electron microscopy, backed up by image simulation techniques, from ultrahigh-pressure jadeite quartzite at Shuanghe in the Dabie Mountains, China. The crystal structure is orthorhombic with lattice parameters a=4.58 A, b=5.42 A, c=5.02 A and space group Pbcn. A three-dimensional structural model has been constructed for the rutile to alpha PbO2-type TiO2 phase transformation based on high-resolution electron microscopic images. Computer image simulation and structural model analysis reveal that rutile {011}R twin interface is a basic structural unit of alpha-PbO2-type TiO2. Nucleation of alpha-PbO2-type TiO2 lamellae 1-2 nm thick is caused by the displacement of one half of the titanium cations within the {011}R twin slab. This displacement reduces the Ti-O-Ti distance and is favored by high pressure. PMID- 17698362 TI - Identification, biological activity, and mechanism of the anti-ischemic quinolone analog. AB - The quinolone analog SQ-4004 has been identified as a potentially excellent anti ischemic agent, which exhibited highly potent efficacy in reducing infarct volume size in vivo rat MCAO model (32.1% at 0.01mg/kg) and potent cardioprotective effect at myocardial infarction in vivo model (26.6% at 0.01mg/kg) while it exhibited highly reduced anti-bacterial activity. The mechanistic study revealed that the anti-ischemic activity might exert via an anti-apoptotic pathway, which implies its therapeutic uses against the ischemic cell injuries including ischemic stroke and ischemic heart disease. PMID- 17698364 TI - Characterisation of colloidal drug delivery systems from the naked eye to Cryo FESEM. AB - Poly(ethylcyanoacrylate) nanoparticles prepared by interfacial polymerisation on the basis of microemulsions were prepared in this study and both colloidal systems, nanoparticles and microemulsions, were analysed by visual observation and several microscopic techniques. Phase boundaries for the microemulsions of the two pseudoternary systems ethyloleate, polyoxyethylene 20 sorbitan mono oleate/sorbitan monolaurate and water with and without butanol as a cosurfactant were determined by visual observation of the samples. Microemulsions containing liquid crystals were determined by polarisation light microscopy. Using freeze fracture transmission electron microscopy and Cryo-field emission scanning electron microscopy the type of microemulsion (w/o droplet, bicontinuous, solution) was characterised. Nanoparticles prepared from the different types of microemulsion were additionally observed by conventional scanning electron microscopy. The size of the nanoparticles obtained from electron microscopy was in good agreement with particle sizing techniques (photon correlation spectroscopy) from earlier studies and no morphological differences could be observed in particles prepared from the different types of microemulsions. Cryo field emission scanning electron microscopy proved to be a most valuable technique in the visualisation of the colloidal systems as samples could be observed close to their natural state. PMID- 17698365 TI - Manual stimulation of facial muscles improves functional recovery after hypoglossal-facial anastomosis and interpositional nerve grafting of the facial nerve in adult rats. AB - The facial nerve in humans is often prone to injuries requiring surgical intervention. In the best case, nerve reconstruction is achieved by a facial facial anastomosis (FFA), i.e. suture of the proximal and distal stumps of the severed facial nerve. Although a method of choice, FFA rarely leads to a satisfactory functional recovery. We have recently devised and validated, in an established experimental paradigm in rats, a novel strategy to improve the outcome of FFA by daily manual stimulation (MS) of facial muscles. This treatment results in full recovery of facial movements (whisking) and is achieved by reducing the proportion of functionally detrimental poly-innervated motor end plates. Here we asked whether MS could also be beneficial after two other commonly used surgical methods of clinical facial nerve reconstruction namely hypoglossal-facial anastomosis (HFA) and interpositional nerve grafting (IPNG) which, however, seem to have a poorer outcome compared to FFA. Compared to FFA, daily MS for 2 months after HFA and IPGN did not completely restore function but, nevertheless, significantly improved the amplitude of whisker movements by 50% compared with untreated animals. Functional improvement was associated with a reduction in the proportion of polyinnervated end-plates. MS did not reduce the extent of axonal branching at the lesion site nor the subsequent misdirected axonal regrowth to inappropriate targets. Our data show that a simple approach leading to improved quality of muscle fiber reinnervation is functionally beneficial after different types of clinically relevant surgical interventions. PMID- 17698366 TI - The management of insulin resistance in polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) has reproductive and metabolic implications. Insulin resistance (IR), secondary to genetic and lifestyle factors, is integral in the pathogenesis, metabolic, clinical features and the long-term sequelae in the majority of people with PCOS. Therapeutic strategies targeting IR in PCOS ameliorate clinical features and might reduce long-term sequelae including diabetes. The mainstay for improving IR is lifestyle change; however, feasibility and sustainability remain concerns. In PCOS, metformin reduces IR, improves ovarian function, regulates cycles, lowers androgens, improves clinical hyperandrogenism and potentially improves fertility. Metformin is also likely to delay diabetes onset and has a role in PCOS in those at high risk of diabetes; however, further research is needed to clarify specific target subgroups and clinical indications. PMID- 17698367 TI - HLA-G and cancer. PMID- 17698368 TI - Involvement of the plasminogen enzymatic cascade in the reaction to axotomy of rat sympathetic neurons. AB - Axotomy of superior cervical ganglion (SCG) neurons is characterized by peripheral regeneration of injured axons and temporary disassembly of the intraganglionic synapses, necessary for synaptic silencing. Both events require remodeling of the extracellular matrix achieved through controlled proteolysis of its components by different enzymatic systems. In this study, we investigate the involvement of the plasminogen enzymatic cascade in the response to axotomy of rat SCG neurons. All components of this proteolytic pathway, tissue plasminogen activator (tPA), plasminogen, membrane receptor annexin II and tPA inhibitor (PAI 1), are constitutively expressed in uninjured SCG and increase significantly after SCG neuron axotomy. Immunolocalization of plasminogen, the key protein converted into the enzymatically active plasmin by tPA, in both neurons and non neuronal cells indicates that all cell types are involved in the response to axotomy. The time course of activation of tPA/plasmin enzymatic pathway suggests its involvement in both intraganglionic synapse remodeling and axonal regeneration. PMID- 17698369 TI - Positioning of NORs and NOR-bearing chromosomes in relation to nucleoli. AB - It is widely accepted that chromosomes occupy more or less fixed positions in mammalian interphase nucleus. However, relation between large-scale order of chromosome positioning and gene activity remains unclear. We used the model of the human ribosomal genes to address specific aspects of this problem. Ribosomal genes are organized at particular chromosomal sites in clusters termed nucleolus organizer regions (NORs). Only some NORs, called competent are generally accepted to be transcriptionally active during interphase. Importantly in this respect, the regularities in distribution of competent, and non-competent NORs among the specific chromosomes were already established in two human-derived cell lines: transformed HeLa and primary LEP cells. In the present study, using FISH and immunocytochemistry, we found that in HeLa and LEP cells the large-scale positioning of the NOR-bearing chromosomes with regard to nucleoli is linked to the transcription activity of rDNA. Namely, the tendency of rDNA-bearing chromosomes to associate with nucleoli correlates with the number of transcriptionally competent NORs in the respective chromosome homologs. Regarding the position of NORs, we found that not only competent but also most of the non competent NORs are included in the nucleoli. Some intranucleolar NORs (supposedly non-competent) are situated on elongated chromatin protrusions connecting nucleoli with respective chromosome territories spatially distanced from nucleoli. PMID- 17698370 TI - Averaging tens to hundreds of icosahedral particle images to resolve protein secondary structure elements using a Multi-Path Simulated Annealing optimization algorithm. AB - Accurately determining a cryoEM particle's alignment parameters is crucial to high resolution single particle 3-D reconstruction. We developed Multi-Path Simulated Annealing, a Monte-Carlo type of optimization algorithm, for globally aligning the center and orientation of a particle simultaneously. A consistency criterion was developed to ensure the alignment parameters are correct and to remove some bad particles from a large pool of images of icosahedral particles. Without using any a priori model, this procedure is able to reconstruct a structure from a random initial model. Combining the procedure above with a new empirical double threshold particle selection method, we are able to pick tens of best quality particles to reconstruct a subnanometer resolution map from scratch. Using the best 62 particles of rice dwarf virus, the reconstruction reached 9.6A resolution at which four helices of the P3A subunit of RDV are resolved. Furthermore, with the 284 best particles, the reconstruction is improved to 7.9A resolution, and 21 of 22 helices and six of seven beta sheets are resolved. PMID- 17698371 TI - Imaging the changing role of feedback during learning in decision-making. AB - Learning from the outcome of decisions can be expected not only to change future decisions, but also our reaction to future outcomes. Using functional magnetic resonance imaging we investigated the neural responses of healthy subjects to feedback about choice outcomes before and after learning a response strategy which led to correct choices only. The task was designed so that losses were unavoidable even when all the choices made were correct. Subjects showed a distinct pattern of learning starting with an initial exploratory phase in which hypotheses about the correct strategy were generated and tested, followed by a phase of rapid strategy acquisition before reaching a final phase of proficiency. Neural activation was more pronounced during feedback processing in the exploratory phase than in the proficiency phase in a distributed network encompassing prefrontal and parietal areas as well as the striatum. These areas are involved in working memory processes, the management of uncertainty and the establishment of stimulus-outcome contingencies. Reduced activation during feedback processing following learning was not only observed within subjects across learning phases, but also between subjects with different learning speeds. Thus, controlled and automatic processing are characterised by differing amounts of activation in identical task-relevant areas. Furthermore, whereas the same brain regions coded for gains and losses, the activation following gains changed to a larger extent with learning than following losses. This suggests that positive prediction errors are more sensitive to increased reward predictability than are negative prediction errors. PMID- 17698372 TI - Prefrontal involvement in imitation learning of hand actions: effects of practice and expertise. AB - In this event-related fMRI study, we demonstrate the effects of a single session of practising configural hand actions (guitar chords) on cortical activations during observation, motor preparation and imitative execution. During the observation of non-practised actions, the mirror neuron system (MNS), consisting of inferior parietal and ventral premotor areas, was more strongly activated than for the practised actions. This finding indicates a strong role of the MNS in the early stages of imitation learning. In addition, the left dorsolateral prefrontal cortex (DLPFC) was selectively involved during observation and motor preparation of the non-practised chords. This finding confirms Buccino et al.'s [Buccino, G., Vogt, S., Ritzl, A., Fink, G.R., Zilles, K., Freund, H.-J., Rizzolatti, G., 2004a. Neural circuits underlying imitation learning of hand actions: an event related fMRI study. Neuron 42, 323-334] model of imitation learning: for actions that are not yet part of the observer's motor repertoire, DLPFC engages in operations of selection and combination of existing, elementary representations in the MNS. The pattern of prefrontal activations further supports Shallice's [Shallice, T., 2004. The fractionation of supervisory control. In: Gazzaniga, M.S. (Ed.), The Cognitive Neurosciences, Third edition. MIT Press, Cambridge, MA, pp. 943-956] proposal of a dominant role of the left DLPFC in modulating lower level systems and of a dominant role of the right DLPFC in monitoring operations. PMID- 17698373 TI - Characterization of adenosine receptors in bovine chondrocytes and fibroblast like synoviocytes exposed to low frequency low energy pulsed electromagnetic fields. AB - OBJECTIVE: The present study describes the presence and binding parameters of the A1, A2A, A2B and A3 adenosine receptors in bovine chondrocytes and fibroblast like synoviocytes. The effect of low frequency low energy pulsed electromagnetic fields (PEMFs) on the adenosine receptor affinity and density was studied. METHODS: Saturation, competition binding experiments and Western blotting assays in the absence and in the presence of PEMFs on the adenosine receptors in bovine chondrocytes or fibroblast-like synoviocytes were performed. Thermodynamic analysis of the A2A or A3 binding was studied to investigate the forces driving drug-receptor coupling. In the adenylyl cyclase and proliferation assays the potency of typical high-affinity A2A or A3 agonists in the absence and in the presence of PEMFs was evaluated. RESULTS: Bovine chondrocytes and fibroblast-like synoviocytes expressed all adenosine receptors. PEMFs evoked an up-regulation of A2A and A3 receptors and thermodynamic parameters indicate that adenosine binding is enthalpy and entropy driven. In PEMF-treated cells the potency of typical A2A or A3 agonists on cyclic AMP assays was significantly increased when compared with the untreated cells. PEMFs potentiated the effect of A2A or A3 agonists on cell proliferation in both cell types. CONCLUSIONS: PEMFs mediate an up regulation of A2A and A3 receptors related to an increase of their functional activities in bovine chondrocytes and fibroblast-like synoviocytes. No differences are present in adenosine affinity and in the drug-receptor interactions. Our data could be used as a trigger to future studies addressed to PEMFs and adenosine therapeutic intervention in inflammatory joint diseases. PMID- 17698374 TI - Alteration in articular cartilage of rat knee joints after spinal cord injury. AB - OBJECTIVE: Mechanical forces are crucial for the maintenance of the morphologic and functional integrity of articular cartilage. The alteration of the articular cartilage after spinal cord injury (SCI) has been described in relation to a suppression of mechanical forces, since the joint is unloaded and restricted in movement. However, the morphological and biochemical characteristics of the cartilage after SCI are still poorly understood. We identified the localization of cartilage alterations after SCI and verified the influence of mechanical forces on the articular cartilage. METHOD: A total of 32 Wistar rats were used. Sixteen animals underwent an SCI and 16 animals served as control. The articular cartilage of the knee joint was assessed, respectively, at 4, 8, 10, and 12 weeks after intervention by histochemical, histomorphometric, immunohistochemical, and biochemical analyses. RESULTS: Cartilage thickness of spinal cord-injured knees decreased at the tibial and posterior femoral (FP) regions and increased at the anterior femoral (FA) region. Spinal cord injuries decreased the number of chondrocytes at the anterior regions and decreased the cartilage matrix staining only at the tibial regions. Immunolabeling to collagen type II was noted comparably in the superficial layer but noted weakly from the middle to deep layer. Collagen type I existed excessively at the cartilage surface and the pericellular regions. CONCLUSION: Cartilage alterations after SCI would not be explained by only a suppression of mechanical forces by unloading and immobilization, but there may be influences on the cartilage in addition to the change in mechanical forces. PMID- 17698375 TI - Promoter polymorphisms of the vascular endothelial growth factor gene is associated with an osteonecrosis of the femoral head in the Korean population. AB - OBJECTIVE: Disruption of the vascular supply to the bone and subsequent hypoxia has been implicated in the pathogenesis of osteonecrosis of the femoral head (ONFH). Vascular endothelial growth factor (VEGF), a major inducer of angiogenesis, has been correlated with several pathological conditions, from inflammation to ischemic processes. A number of polymorphisms in the VEGF gene have been described as being associated with several diseases, such as diabetic retinopathy, prostate cancer and breast cancer. The aim of this study was to evaluate the association of VEGF gene polymorphisms with ONFH in a case--control study. METHODS: Three polymorphisms (-2578C>A, -634G>C and +936C>T) in VEGF were genotyped in 317 ONFH patients and 497 control subjects, using the TaqMan 5' allelic discrimination assay. We performed the association analysis of genotyped single nucleotide polymorphisms (SNPs) and haplotypes with ONFH. RESULTS: The 634G>C genotype was significantly associated with an increased risk for ONFH in dominant model with odds ratio (OR) of 1.47, 95% confidence intervals (CIs) 1.08 2.01 with P value 0.015. Further analysis stratified by sex showed that the 634G>C genotype was also significantly associated with a high risk for male patients considering the dominant model with OR of 1.60, 95% CI 1.13-2.26 with P value 0.008. Haplotype association analysis did not provide a further delineation of the risk allele. CONCLUSION: Our study is, to our knowledge, the first report that shows the -634G>C polymorphism in the VEGF promoter was associated with an increased susceptibility of ONFH in the Korean population. PMID- 17698376 TI - The natural history of cartilage defects in people with knee osteoarthritis. AB - OBJECTIVES: Cartilage defects are highly prevalent in subjects with knee osteoarthritis (OA). Although they are associated with increased cartilage loss and joint replacement, there is little data on the natural history of cartilage defects. The aim of this study was to examine the progression of cartilage defects over 2 years in people with knee OA and to identify factors associated with progression. METHODS: One hundred and seventeen subjects with OA underwent magnetic resonance imaging of their dominant knee at baseline and follow-up. Cartilage defects were scored (0-4) at four sites. Bone size of the medial and lateral tibial plateau was determined. Height, weight, body mass index and physical activity were measured by standard protocols. RESULTS: The mean cartilage defect score increased significantly over the 2-year study period in all tibiofemoral compartments (all P<0.001), except the lateral tibial compartment with age and tibial plateau bone area at baseline being predictors of progression. However, there was heterogeneity with 81% progressing at any site, 15% remaining stable and 4% decreasing. CONCLUSION: Over 2 years, cartilage defects tend to progress in people with symptomatic OA, with only a small percentage decreasing in severity. Increasing age and increased bone area are risk factors for progression. Interventions aimed at preventing cartilage defects from occurring and reducing their severity may result in a reduction in the severity of OA, by reducing loss of articular cartilage and subsequent requirement for knee joint replacement. PMID- 17698377 TI - Increased expression of human calcium-activated chloride channel 1 gene is correlated with mucus overproduction in Chinese asthmatic airway. AB - Asthma is usually complicated with mucus overproduction in airway. Recently the increased expression of the human calcium-activated chloride channel 1 (CaCC1) was found to play an important role in mucus overproduction in the asthmatic airways. To investigate the relationship of Calcium-activated chloride channel 1 (CaCC1) and mucus overproduction in Chinese asthmatic airway, the expression of CaCC1, mucin 5AC (MUC5AC) and mucus in bronchial tissues were examined. Bronchial tissues were isolated from non-cancerous areas of lungs obtained following resection for lung neoplasm in West China Hospital from April to July in 2004. Six patients were diagnosed lung neoplasm with moderate asthma, and other ten were diagnosed lung neoplasm without asthma as the control subjects. The expression of CaCC1, MUC5AC and mucin in bronchial tissues was detected by reverse transcriptase-polymerase chain reaction (RT-PCR), in situ hybridized with digoxigenin (DIG)-labeled RNA probe, immunohistochemical and Alcian blue-periodic acid Schiff (AB-PAS) staining, respectively. In RT-PCR, two expression patterns of CaCC1 mRNA were found, which were located in the 450 bp and 510 bp. With in situ hybridization, a stronger expression of CaCC1 mRNA was further detected throughout the bronchial tissues from patients with asthma than control subjects (P<0.01); Samples from asthmatics were showed a stronger staining for MUC5AC than those in control subjects (P<0.05); AB-PAS staining revealed more mucins and goblet cells in asthmatic bronchial epithelium and submucosal gland comparing to that in control subjects (P<0.05). The increased expression of CaCC1 in asthmatic airways was well correlated with the expression of MUC5AC protein, the percentage of goblet cells and the area of submucosal gland (P<0.01, P<0.01, P<0.05). These results suggest that the up-regulated gene expression of CaCC1 exists, which is complicated with mucus hyper-secretion in Chinese asthmatic airway. PMID- 17698378 TI - Pores for thought: further landmarks in the elucidation of the mechanism of secretion. PMID- 17698379 TI - Transthyretin influences spatial reference memory. AB - Transthyretin (TTR) is a plasma and cerebrospinal fluid carrier for thyroxine and retinol, described also to sequester the amyloid beta peptide. TTR levels have been described as decreased in the cerebrospinal fluid of patients with Alzheimer's disease. In order to investigate the role of TTR in learning and memory, we studied young adult and old TTR-null 129/Sv mice for cognitive performance. In the absence of TTR, 5-month-old mice display spatial reference memory impairment when compared to age-matched wild-type mice. Interestingly, while aging in wild-type mice is associated with a worsening reference memory performance, TTR-null mice show no further impairment with increasing age. As a result, no significant differences were found in this spatial reference task in old mice. Our data show that the absence of TTR seems to accelerate the poorer cognitive performance normally associated with aging. PMID- 17698380 TI - MN1, a novel player in human AML. AB - The transcriptional coactivator MN1 has been identified as a gene overexpressed in certain types of human acute myeloid leukemia. Upregulation is invariantly associated with inv(16) AML but is also found in other AML subtypes. Overexpression of this gene is also associated with a worse prognosis and a shorter survival in AML patients with a normal karyotype. In this short review, I will discuss the role of MN1 in myeloid leukemia. PMID- 17698381 TI - Avian influenza: We have the chance to make a difference. PMID- 17698382 TI - The effect of epinephrine on feeding and motion patterns in goldfish Carassius auratus (L.). AB - The effect of intraperitoneal injections of epinephrine (0.14 and 0.70 mg/kg) on some characteristics of feeding activity (ration and total time of feeding) as well as on motion patterns (time of swimming in group and separately) in juvenile goldfish has been investigated. Two-phase (short-term decrease in the first phase, increase in the second one) feeding response under both doses of epinephrine has been revealed. More pronounced effect of epinephrine at the dose of 0.14 mg/kg on the ration and time of feeding (comparing to the dose of 0.70 mg/kg and Ringer injection) was observed in the second phase. Furthermore, significant decrease of time of "separated" swimming in the first phase under both doses of the hormone is revealed. The hyperglycemic response induced by the injections of epinephrine, with synchronous reduction of the concentration of glycogen in hepatopancreas allows to suggest that glycogen-phosphorylase activating mechanism was underlying the "first-phase" change of feeding reactions of goldfish. PMID- 17698383 TI - A homozygous tyrosine hydroxylase gene promoter mutation in a patient with dopa responsive encephalopathy: clinical, biochemical and genetic analysis. AB - We report a recessive mutation in the tyrosine hydroxylase gene (TH) promoter (c.1-71C>T), present at homozygosity in a patient with dopa-responsive encephalopathy. The change lies in a cAMP response element (CRE) and alters a binding site for the CREM transcription factor. Previous studies support that the CRE in the TH gene is essential for its transcription, suggesting that mutations within this consensus motif may cause an impairment of catecholamine biosynthesis and lead to a pathogenic phenotype. PMID- 17698384 TI - Hepatitis B virus (HBV) genotype and YMDD motif mutation profile among patients infected with HBV and untreated with lamivudine. AB - OBJECTIVES: A few reports exist on hepatitis B virus (HBV) genotype distribution in Iran; however the sample sizes of these studies are insufficient. The first objective of this study was to determine the HBV genotype distribution with a large sample size (147 specimens). The second objective was to determine the incidence of the lamivudine-resistant YMDD mutant profile among HBV-infected patients not treated with lamivudine; some studies have reported that YMDD mutants are detectable even before antiviral treatment. METHODS: We used two cost effective PCR-based methods that have been developed in-house: gap-PCR and artificially created restriction site-PCR (ACRS-PCR). Also, 11 samples were randomly selected and bi-directionally sequenced and subjected to phylogenetic analysis. RESULTS: Gap-PCR results revealed genotype D of HBV in all patients, and ACRS-PCR results disclosed the absence of mutation within the YMDD motif before antiviral therapy in the study population. Phylogenetic analysis supported the former genotyping results with the segregation of all Iranian HBV isolates in the genotype D branch with a high bootstrap value (99%, 1000 replicates). CONCLUSIONS: The present study using two cost-effective methods showed that genotype D of HBV is dominant among Iranian HBV-infected subjects, and HBV lamivudine-resistant strains do not exist naturally among Iranian patients not treated with lamivudine. PMID- 17698385 TI - Risk factors for human brucellosis in Iran: a case-control study. AB - BACKGROUND: Brucellosis is a zoonotic disease of worldwide distribution. Despite its control in many countries, it remains endemic in Iran. The aim of this study was to determine the risk factors for brucellosis acquisition in the central province of Iran. METHODS: A matched case-control study was conducted in the central part of Iran. A total of 300 subjects (150 cases and 150 controls) were enrolled in the investigation. Brucellosis cases were defined on the basis of epidemiologic, clinical, and laboratory criteria. Subjects were interviewed using a questionnaire to obtain risk factor information. We used odds ratios and conditional logistic regression models to explore the association between the disease and the variables studied. RESULT: Significant risk factors for infection were related to the existence of another case of brucellosis in the home (OR=7.55, p=0.0001) and consumption of unpasteurized dairy products (OR=3.7, p=0.014). Keeping cattle and cattle vaccination were also important risk factors. CONCLUSIONS: Pasteurization of dairy products and education regarding fresh cheese must be pursued for eradication of brucellosis. A major risk factor for acquiring brucellosis is the existence of another infected family member. Therefore screening family members of an index case of brucellosis may lead to the detection of additional cases. PMID- 17698386 TI - [Pelviperineoscopy. Preliminary study of feasibility on cadavers]. AB - OBJECTIVE: The traditional access of perineum for the treatment of the pelvic organ prolapse by vaginal route is probably responsible for the risk of mesh exposure and a longer convalescence. So, endoscopic access to perinemeum needs to be evaluated. PATIENTS AND METHODS: Feasibility study on cadavers. Details of the procedure: opening of the pararectal space by digital dissection first after incision on the level of the posterior commissure. Introduction of an optical trocart to the level of the perineum incision; dissection of pararectal space with optics and CO(2); individualization of the various elements; installation of a transobturator trocart and a transgluteal trocart; dissection of the rectovaginal septum and visualization of the sacrospinous ligament and pudendal nerve. The measured variables were: operational incidents, possibility of creation of working space, dissection of the rectovaginal septum; finally, visualization of the sacrospinous ligament and pudendal pedicle. RESULTS: On the 4 studied cadavers, we could carry out a dissection of pelvirectal space in all the cases. On the 8 pararectal fosses, in all the cases we could carry out a cavity of dissection and to open the recto vaginal septum, visualization of the sacrosciatic ligament and pudendal pedicle was possible in 6 cases out of 8. There were one rectal injury, two vaginal injuries and one lesion of the pudendal pedicle. DISCUSSION AND CONCLUSION: This endoscopic access allows in the majority of cases to see the structures necessary to the realization of a vaginal sacrospinofixation or the installation of posterior mesh without a colpotomy and a traumatic exposure. The incidents are probably due to our inexperience and should disappear in time. The pelvi-perineoscopy is an endoscopic access of perineum which should be evaluated. PMID- 17698387 TI - [The new prenatal leave]. PMID- 17698388 TI - [Medical information and patients' choices. Influences on term singleton breech deliveries]. AB - OBJECTIVE: The mode of delivery of term singleton breech presentation has been argued for decades. Many elements are responsible for the current increase in the rate of elective cesarean delivery. Among these elements, the influence of medical information and patients' choices are unknown. PATIENTS AND METHODS: We studied retrospectively, between January 1996 and December 2005, the mode of term breech delivery in a French maternity. RESULTS: Medical information relates primarily to the complications of vaginal birth. Patient's request for an elective Cesarean has been in constant increase since 1996. DISCUSSION AND CONCLUSION: Medical information and patients' choices strongly influence the practice of breech delivery. PMID- 17698389 TI - DNA analysis of family members with deletion in Yp11.2 region containing amelogenin locus. AB - For personal identification of two male bodies discovered at the scene of a fire, autosomal and Y chromosomal STR of the two cadavers and of two living male relatives were genotyped. The four males were incorrectly typed as female due to the lack of the amelogenin Y homolog, whereas all loci of Y-STR except for DYS458 were successfully genotyped. Because PCR of Y-specific amelogenin (AMELY) and DYS458 loci failed to amplify target products when using additional primer sets, it was concluded that deletion in the Yp11.2 region containing the loci of AMELY and of DYS458 on the Y chromosome, rather than mutation in the annealing region of the primer sets, had occurred. Investigation using Y-specific markers showed the deletion extending approximately 2.56 Mb in the Yp11.2 region. The variety of deletion sizes and Y-STR haplotypes among AMELY negative males presented to date suggests that the mutation of the Yp11.2 region occurs independently in different ethnic groups. A study on the frequency of the AMELY deletion in the Japanese population would be helpful for future criminal investigation. PMID- 17698390 TI - Experimental pulmonary fat embolism induced by injection of triolein in rats. AB - The relationship between the volume of fat flowing in the bloodstream and the degree of pulmonary fat embolism has remained unclear. In this study, in order to examine whether the volume of fat particles in the bloodstream could be estimated from the degree of pulmonary fat embolism, 0.05, 0.1, 0.15, 0.2 and 0.25 ml of triolein were injected into male rats weighing 300-320 g, through the caudal vein. Consequently, it was noted that the severity of pulmonary fat embolism tended to gradually increase in proportion to the volume of injected triolein, with the severity of pulmonary fat embolism being significantly augmented by the injection of 0.2 and 0.25 ml of triolein, based on morphometric analysis. In application to human cases, about 60 ml of fat particles was estimated to flow into the bloodstream after the occurrence of a pelvic fracture. Moreover, the results of this study led to the hypothesis that the prognosis of pulmonary fat embolism is affected by the severity of preceding conditions which have caused fat embolism. PMID- 17698391 TI - Forensic pathological investigation of myocardial hypoxia-inducible factor-1 alpha, erythropoietin and vascular endothelial growth factor in cardiac death. AB - The present study investigated the immunohistochemical distributions and mRNA expressions of myocardial hypoxia-inducible factor (HIF)-1 alpha and its downstream factors, erythropoietin (Epo) and vascular endothelial growth factor (VEGF), in cardiac deaths. Medico-legal autopsy cases (n=114, within 48-h postmortem) of cardiac deaths (n=58) and control cases (n=56) were examined. Immunohistochemical positivities of HIF-1 alpha, Epo and VEGF were patchily observed in cardiomyocytes in the acute ischemic lesions of myocardial infarction (n=37), showing a relationship to morphological cardiomyocyte damage: the staining was intense in the regions with early ischemic changes and weak in the necrotic regions. Immunopositivities were sporadically detected in cardiomyocytes in some cases of sudden cardiac death without infarction (SCD, n=13). In chronic congestive heart disease (CHD, n=8), weak positivities were diffusely observed in the cardiomyocytes. However, there were no such findings in cases of mechanical asphyxiation (n=16) or drowning (n=18). HIF-1 alpha, Epo and VEGF mRNA expressions, as measured by real-time reverse transcription-polymerase chain reaction (RT-PCR), showed localized elevations related to acute myocardial infarction (AMI) lesions, whereas such findings were mild in recurrent myocardial infarction (RMI) and SCD cases. CHD showed significant elevations of these mRNAs irrespective of the sampling site. The mRNA expressions were significantly lower in cases of drowning. These findings suggest that focal immunopositivities and increased mRNAs of these factors are indicative of short and substantial duration of myocardial ischemia, respectively. The combined analyses may not only be useful for investigating the site, phase and severity of acute myocardial ischemia and the severity of chronic ischemic stress, but also contribute to differentiating cardiac deaths from asphyxiation and drowning or interpreting the possible contribution of cardiac disease in traumatic death. PMID- 17698392 TI - Two small linear marks on a mandible: collaborative networking between forensic experts. AB - A human male mandible was found under the eaves of a house. There were no associated items that allowed for personal identification. An anthropologist, who voluntarily joined our forensics team to give an expert opinion, found two small linear marks of 0.6 cm on the surface of the right condylar process. He thought these marks had been produced by a sharp object, and at the very least were not the result of bite marks by rodents or other animals. At first, the police did not appreciate the significance of the marks. One month later, however, other remains with similar marks were found near the scene, strongly suggesting that the case was a mutilation murder with a sharp weapon. After a vigorous search, the police obtained information that a young man in his twenties had gone missing in the area one year previously. After checking up on his relationships, a suspect was identified and arrested. The suspect subsequently confessed and was convicted as guilty of the crime. There are only a few forensic anthropologists in Japan. Consequently, almost all cases requiring bone examination have been handled by forensic pathologists, but it is hard for forensic pathologists to cover all fields comprehensively. The present case might have been solved without help from the anthropologist. However, we believe that forensic pathologists, especially less experienced ones, should seek advice from an expert in the field of forensic anthropology in order to carry a multidisciplinary forensic investigation. Given the current situation in, it is difficult in many institutes of forensics to obtain direct help from forensic anthropologists. The authors believe that collaborative networking via the Internet between forensic experts in each field cannot only obtain further information on complicated cases, but would also be helpful in training young forensic pathologists. PMID- 17698393 TI - Sexual dimorphism of the human sternum in a Maharashtrian population of India: a morphometric analysis. AB - Determination of sex from human skeletal remains is an imperative element of any medicolegal investigation. Length of manubrium, length of mesosternum, and combined length of manubrium and mesosternum were measured in 115 sternums of confirmed sex (75 male and 40 female) for sexual dimorphism. Application of "the 50 rule" for the manubrium confirmed sex in 77.3% male and 77.5% female bones, while application of "the 81 rule" for the mesosternum confirmed sex in 73.3% male and 75% female bones accurately. Application of "the 131 rule" derived from the study for combined length of manubrium and mesosternum confirmed sex in 85.3% male and 77.5% female sternums correctly. This study confined to the Maharashtra region of western India is useful to determine the sex of the sternum when it is subjected for medicolegal skeletal examination. PMID- 17698394 TI - Polymorphism of the vWA locus located in the center of the three vWA STRs in the Japanese population. AB - The structural polymorphism of the vWA locus (vWA-T) located between the two polymorphic vWA loci (vWA-K and -P) was analyzed in 100 Japanese individuals using DNA samples isolated from dental pulp. The polymorphism of this locus was based on the difference in the number of tcta repeat. New interallele 11.1 was found in two samples. All together 9 alleles and 19 genotypes were observed. In addition, one mutant allele contained tcga in the common tcta repeat structure. The value of PD was calculated to be 0.900. Inheritance of the polymorphism was confirmed in a family including 23 individuals and 6 matings. PMID- 17698395 TI - Detectability of SGM Plus profiles in heart and lungs tissue samples incubated in different environments. AB - The aim of the study was assessment of environmental effect on typeability of AmpFlSTR SGM Plus loci: D3S1358, VWA, D16S539, D2S1338, D81179, D21S11, D18S51, D19S433, TH01, FGA and gender marker amelogenin. Heart and lungs specimens collected during autopsies of five persons aged 20-30 years were incubated at 21 degrees C and 4 degrees C in different environmental conditions, fresh different water and soil conditions. DNA was extracted by organic method from tissue samples collected in 7-day intervals and subsequently typed using AmpFlSTR SGM Plus kit and ABI 310. Incubation at 21 degrees C and prevented air access, as well as in peat soil and in sand favoured faster DNA degradation reflected by decrease in typeability rate. In samples with negative genotyping results no DNA was found by fluorometric quantitation. Decomposed soft tissues are potential material for DNA typing. PMID- 17698396 TI - Ultrasound emulsification: effect of ultrasonic and physicochemical properties on dispersed phase volume and droplet size. AB - Ultrasonic emulsification of oil and water was carried out and the effect of irradiation time, irradiation power and physicochemical properties of oil on the dispersed phase volume and dispersed phase droplet size has been studied. The increase in the irradiation time increases the dispersed phase volume while decreases the dispersed phase droplets size. With an increase in the ultrasonic irradiation power, there is an increase in the fraction of volume of the dispersed phase while the droplet size of the dispersed phase decreases. The fractional volume of the dispersed phase increases for the case of groundnut oil water system while it is low for paraffin (heavy) oil-water system. The droplet size of soyabean oil dispersed in water is found to be small while that of paraffin (heavy) oil is found to be large. These variations could be explained on the basis of varying physicochemical properties of the system, i.e., viscosity of oil and the interfacial tension. During the ultrasonic emulsification, coalescence phenomenon which is only marginal, has been observed, which can be attributed to the collision of small droplets when the droplet concentration increases beyond a certain number and the acoustic streaming strength increases. PMID- 17698397 TI - Hybrid multiresolution Slantlet transform and fuzzy c-means clustering approach for normal-pathological brain MR image segregation. AB - The paper presents a new approach for automated segregation of brain MR images, using an improved orthogonal discrete wavelet transform (DWT), known as the Slantlet transform (ST), and a fuzzy c-means (FCM) clustering approach. ST has excellent time-frequency resolution characteristics and these can be achieved with shorter supports for the filter, compared to DWT employed for identical situations. FCM clustering, on the other hand, can provide efficient classification results, if it is implemented for well-processed input feature vectors. Thus, by combining both the ST and the FCM clustering approaches, a hybrid scheme has been developed that can segregate brain MR images. This automated tool when developed can infer whether the input image is that of a normal brain or a pathological brain. The proposed technique has been applied to several benchmark brain MR images and the results reveal excellent accuracy in characterizing human brain MR imaging. PMID- 17698398 TI - Cyr61/CCN1 is a tumor suppressor in human hepatocellular carcinoma and involved in DNA damage response. AB - Cyr61/CCN1 is a secreted extracellular matrix associated protein involved in diverse biological functions and plays multiple roles in tumorigenesis. Cyr61 was down-regulated in HCC tumor tissues as observed in our previous cDNA microarray study, but its potential role in hepatocarcinogenesis is still unclear. To explore the biological significance of Cyr61 in HCC development, over-expression of this gene was established in HCC cell lines and its effects on cell proliferation, adhesion, migration and invasion were analyzed in this study. Cyr61 expression was down-regulated in HCC tumors as measured by quantitative real-time PCR and its protein level was decreased in most HCC cell lines as detected by Western blot. Over-expression of Cyr61 in HCC cell lines suppressed cell proliferation in monolayer and anchorage-independent growth in soft agar, whereas down-regulation of Cyr61 by siRNA increased cell proliferation rate. Over expression of Cyr61 also significantly enhanced adhesion activities of HepG2 cells to various ECM proteins. Moreover, stably transfected HepG2-Cyr61 cells showed inhibited cell mobility (40-45%) and reduced invasiveness (30-40%) compared to HepG2-Neo controls. Furthermore, upon exposure to 5-Fluorouracil and UV irradiation, Cyr61 was rapidly induced in both p53(+/+) HepG2 and p53(-/-) Hep3B cells. However, only HepG2 cells showed increased G2/M phase arrest with concomitant up-regulation in p53 and p21 levels, suggesting that Cyr61 may play an active role in regulating HCC cell growth involving p53 as well as alternative pathways. In conclusion, we demonstrated that Cyr61 is a tumor suppressor in hepatocarcinogenesis and is involved in DNA damage response. PMID- 17698399 TI - The role of syndecans in the regulation of body weight and synaptic plasticity. AB - Body weight is tightly regulated by a feedback mechanism involving peripheral adiposity signals and multiple central nervous system neurotransmitter pathways. Despite the tight regulation of body weight there is an increase in the prevalence of obesity and overweight in Western society. Obesity and overweight are conditions of excess body weight stored as fat. Syndecan-3, a member of the syndecan family of type I transmembrane heparan sulfate proteoglycans is a novel a regulator of feeding behavior and body weight. Syndecans are extracellular matrix molecules (ECMs) that modulate cell adhesion, cell-cell interactions and ligand-receptor interactions. The finding that syndecan-3 can regulate body weight is novel and provides a unique link between the extracellular matrix and body weight regulatory mechanisms. Uniquely, hormones such as leptin previously thought only to regulate body weight by modulating neuropeptide levels, have now been demonstrated to regulate neuronal plasticity in the hypothalamus. ECMs and syndecans have long been recognized as regulators of plasticity. Therefore, this review will focus on highlighting the role of syndecans and in particular syndecan-3 in neuronal development and synaptic organization and how these processes may integrate body weight regulation. As part of this review, we will highlight how syndecan-3 can mediate the activity of adiposity signals, such as leptin, and facilitate changes in neuronal plasticity. PMID- 17698401 TI - The true story of the HD-Zip family. AB - The HD-Zip family of transcription factors is unique to the plant kingdom. These proteins exhibit the singular combination of a homeodomain with a leucine zipper acting as a dimerization motif. They can be classified into four subfamilies, according to a set of distinctive features that include DNA-binding specificities, gene structures, additional common motifs and physiological functions. Some HD-Zip proteins participate in organ and vascular development or meristem maintenance. Others mediate the action of hormones or are involved in responses to environmental conditions. Here, we review recent data for this family of transcription factors from a wide variety of plant species to unravel their crucial role in plant development. PMID- 17698400 TI - The response of mammalian cells to double-stranded RNA. AB - Double-stranded RNA (dsRNA) has long been recognized as a central component of the interferon (IFN) system. It was originally characterized as a key mediator of IFN induction in response to virus infection. Subsequently, it was identified as a prime activator of the antiviral response. In recent years the discovery of the RNA interference (RNAi) pathway in mammals has renewed interest in dsRNA-mediated cellular responses. This has coincided with the identification of key components of the IFN induction pathway. Here, we present an overview of the current knowledge of dsRNA-mediated pathways in mammalian cells and introduce a link between these pathways and application of RNAi. PMID- 17698402 TI - Plastid endosymbiosis, genome evolution and the origin of green plants. AB - Evolutionary relationships among complex, multicellular eukaryotes are generally interpreted within the framework of molecular sequence-based phylogenies that suggest green plants and animals are only distantly related on the eukaryotic tree. However, important anomalies have been reported in phylogenomic analyses, including several that relate specifically to green plant evolution. In addition, plants and animals share molecular, biochemical and genome-level features that suggest a relatively close relationship between the two groups. This article explores the impacts of plastid endosymbioses on nuclear genomes, how they can explain incongruent phylogenetic signals in molecular data sets and reconcile conflicts among different sources of comparative data. Specifically, I argue that the large influx of plastid DNA into plant and algal nuclear genomes has resulted in tree-building artifacts that obscure a relatively close evolutionary relationship between green plants and animals. PMID- 17698403 TI - Using the logarithm of odds to define a vector space on probabilistic atlases. AB - The logarithm of the odds ratio (LogOdds) is frequently used in areas such as artificial neural networks, economics, and biology, as an alternative representation of probabilities. Here, we use LogOdds to place probabilistic atlases in a linear vector space. This representation has several useful properties for medical imaging. For example, it not only encodes the shape of multiple anatomical structures but also captures some information concerning uncertainty. We demonstrate that the resulting vector space operations of addition and scalar multiplication have natural probabilistic interpretations. We discuss several examples for placing label maps into the space of LogOdds. First, we relate signed distance maps, a widely used implicit shape representation, to LogOdds and compare it to an alternative that is based on smoothing by spatial Gaussians. We find that the LogOdds approach better preserves shapes in a complex multiple object setting. In the second example, we capture the uncertainty of boundary locations by mapping multiple label maps of the same object into the LogOdds space. Third, we define a framework for non-convex interpolations among atlases that capture different time points in the aging process of a population. We evaluate the accuracy of our representation by generating a deformable shape atlas that captures the variations of anatomical shapes across a population. The deformable atlas is the result of a principal component analysis within the LogOdds space. This atlas is integrated into an existing segmentation approach for MR images. We compare the performance of the resulting implementation in segmenting 20 test cases to a similar approach that uses a more standard shape model that is based on signed distance maps. On this data set, the Bayesian classification model with our new representation outperformed the other approaches in segmenting subcortical structures. PMID- 17698404 TI - Sortal concepts, object individuation, and language. AB - Cognitive science is an interdisciplinary enterprise. This review highlights how the philosophical notion of a 'sortal'--a concept that provides principles of individuation and principles of identity - has been introduced into cognitive developmental psychology. Although the notion 'sortal' originated in metaphysics, importing it into the cognitive sciences has bridged a gap between philosophical and psychological discussions of concepts and has generated a fruitful and productive research enterprise. As I review here, the sortal concept has inspired several lines of empirical work in the past decade, including the study of object individuation; object identification; the relationship between language and acquisition of kind concepts; the representational capacities of non-human primates; object-based attention and cognitive architecture; and the relationship between kind concepts and individual concepts. PMID- 17698405 TI - How emotions inform judgment and regulate thought. AB - Being happy or sad influences the content and style of thought. One explanation is that affect serves as information about the value of whatever comes to mind. Thus, when a person makes evaluative judgments or engages in a task, positive affect can enhance evaluations and empower potential responses. Rather than affect itself, the information conveyed by affect is crucial. Tests of the hypothesis find that affective influences can be made to disappear by changing the source to which the affect is attributed. In tasks, positive affect validates and negative affect invalidates accessible cognitions, leading to relational processing and item-specific processing, respectively. Positive affect is found to promote, and negative affect to inhibit, many textbook phenomena from cognitive psychology. PMID- 17698406 TI - The linguistic benefits of musical abilities. AB - Growing evidence points to a link between musical abilities and certain phonetic and prosodic skills in language. However, the mechanisms that underlie these relations are not well understood. A recent study by Wong et al. suggests that musical training sharpens the subcortical encoding of linguistic pitch patterns. We consider the implications of their methods and findings for establishing a link between musical training and phonetic abilities more generally. PMID- 17698407 TI - The role of secreted proteins in diseases of plants caused by rust, powdery mildew and smut fungi. AB - Five unrelated avirulence (Avr) gene families have been cloned from flax rust and barley powdery mildew, fungal pathogens that make close contact with living host plant cells using specialized feeding structures called haustoria. Transgenic expression studies indicate Avr proteins are recognized by disease resistance (R) proteins within host cells, which suggests that Avr proteins are transported via an as yet unidentified route from the fungus to the host during infection. Recognition of flax rust AvrL567 proteins is by direct R-Avr protein interaction. Virulence effector functions have been demonstrated for barley powdery mildew Avr proteins Avra10 and Avrk1. Mildew resistance triggered by Avra10 in barley involves association of the cognate barley R protein Mla10 and transcriptional repressor proteins, including HvWRKY2, in the host nucleus. High amplitude defence gene expression has a dual dependence on transcriptional de-repression induced by specific R-Avr protein recognition and additionally, activation signals initiated by host perception of general pathogen molecules. PMID- 17698408 TI - Homogeneous solvation controlled photoreduction of cobalt(III) complexes in aqueous 2-methyl-2-propanol solutions linear solvation energy relationship and cyclic voltammetric analyses. AB - The effect of solvent participation on the ligand-to-metal charge transfer (LMCT, L-->Co(III)) reduction of the of Co(III)(en)(2)Br(RC(6)H(4)NH(2))(2+) where R=m OCH(3), p-F, H, m-CH(3), p-CH(3,)p-OC(2)H(5) and p-OCH(3) were examined in aqueous 2-methyl-2-propanol (Bu(t)OH) solutions. The change in the reduction behavior of Co(III) centre was also examined through cyclic voltammetric studies. The observed reduction in quantum yield due to LMCT excitation can mainly be accounted using linear solvation energy relationship (LSER) comprising model correlation equations. These consist of empirical parameters such as Grunwald Winstein's solvent ionizing power, Y, Dimroth-Richardt's solvent micro-polarity parameter, E(T)(N), Gutmann's donor number, DN(N), along with Kamlet-Taft's solvatochromic parameters (hydrogen bond acceptor acidity/basicity alpha/beta and solvent dipolarity/polarizability, pi*). The origin of solvent effect is found to be due to microscopic interaction between the solvent donor and the nitrogen bound hydrogen of the ligand. Cyclic voltammograms show an irreversible reduction of Co(III) in DMF using Glassy Carbon Electrode, GCE, the redox peaks for the aniline complexes appear at -0.20 and 0.525V. Irradiation of the complexes with UV light (lambda=254nm) in binary mixtures produce Co(II)(aq) and the concentration of this species are highly dependent on x(alc) (x(alc)=mole fraction of alcohol). The observed quantum yield (logPhi(Co(II))) is found to be linearly related to mole fraction of organic co-solvent added in the mixture, therefore, logPhi(Co(II))=26.41 x 10(-2) when x(2)=0.0094 and 43.75 x 10(-2) when x(2)=0.076 for a typical complex Co(III)(en)(2)Br(p-OCH(3)C(6)H(4)NH(2))(2+) in aqueous 2-methyl-2-propanol at 300K. Cyclic voltammetry and LSER analyses illustrate the variation of reduction property of Co(III) by the aryl ligand and homogeneous solvation of the excited state of the complex Co(III)(en)(2)Br(RC(6)H(4)NH(2))(2+) in H(2)O/Bu(t)OH mixtures. PMID- 17698409 TI - The photochemistry properties on interaction silver with tryptophan. AB - UV-vis and fluorescence spectra for interaction silver(I) ion with tryptophan (Trp) have been studied. The influence of pH of media, multicomponent concentration, including amino acids, silver(I) ion, formaldehyde, sodium dodecyl sulfate (SDS), and trihydroxymethylaminomethane (Tris) as well as temperature, illumination, time, etc. on reaction were investigated, and the mechanism of reaction has been explored. The results shown that the optimum condition for the interaction between tryptophan and silver(I) ion were found. PMID- 17698411 TI - Emergence and persistence of multiple antiviral-resistant CMV strains in a highly immunocompromised child. AB - BACKGROUND: The emergence of human cytomegalovirus (CMV) antiviral resistance plays a significant role in disease progression in immunocompromised patients who have received antiviral therapy. OBJECTIVES: To determine the pattern of antiviral-resistant CMV strains in a highly immunocompromised child. STUDY DESIGN: Retrospective specimens of blood and urine were analysed using PCR sequencing to identify antiviral-resistant CMV strains containing UL97 or UL54 mutations. RESULTS: CMV strains resistant to antiviral agents contributed to disease in a bone marrow transplant recipient with X-linked severe combined immunodeficiency (SCID) treated with ganciclovir (GCV) and foscarnet (FOS). Retrospective analyses detected GCV-resistant CMV (L595S) in a specimen taken after disease progression. This GCV-resistant CMV strain persisted for 1 year, after which time it was no longer detected even though the patient continued to receive GCV. A FOS-resistant strain (T700A) then emerged even though no FOS had been administered in the preceding year. CONCLUSION: The detection of antiviral resistant CMV did not follow the patterns found in other patients tested for antiviral resistance, including emergence of a FOS-resistant strain in the absence of antiviral-selective pressure. These findings indicate the patient's underlying immunosuppressive condition should be considered for diagnosis and management of resistant CMV. PMID- 17698410 TI - Reflections on the interpretation of heterogeneity and strain differences based on very limited PCR sequence data from Kaposi's sarcoma-associated herpesvirus genomes. AB - Ever since the original identification of fragments of KSHV DNA in Kaposi's sarcoma (KS) tissue by Chang et al. in 1994, PCR has been used successfully and extensively to detect the virus in clinical samples from the accepted etiological diseases of KS, PEL and MCD. However, a number of other clinical and epidemiological studies claiming evidence for KSHV in multiple myeloma or sarcoid and more recently in primary pulmonary hypertension, as well as claims about the biological significance of DNA sequence polymorphisms based just on small ORF26 PCR DNA fragments have not been convincing. Here, we evaluate the validity and interpretations of previous results in the context of both the observed rates and global patterns of sequence variability within an extended ORF26 locus, as well as from the perspective of the overall levels of KSHV variability found after sampling multiple loci across the complete KSHV genome. The results cast doubts on most claims for biological significance for these polymorphisms, which instead correlate with viral subtype clustering arising from geographic and ethnic divergence of the ancestral human hosts. In addition, we describe several observations that help to explain likely sources of the often either unexpectedly high or unexpectedly low levels of sporadic variability seen in the PCR DNA sequence data reported in some of those studies. PMID- 17698412 TI - Physiological and psychological responses to a 12-week BodyBalance training programme. AB - BodyBalance is a popular mind-body program practised at numerous leisure centres throughout the western world that makes many unsubstantiated claims as to the benefits of participation. This study examines physiological and psychological responses in adults, aged (mean+/-S.D.) 43.9+/-10.9 years, to a 12-week 'BodyBalance' exercise program. An exercise intervention group (n=17) undertook three 1-h classes, each week for 12 consecutive weeks while the control group (n=17) attended three 90-min 'health lectures'. ANCOVA demonstrated significant differences between the control and exercise groups in body mass, skinfold measures, total girth circumference from six sites, maximal isometric back strength, five measures of flexibility and state anxiety. Post-hoc tests on the experimental group data showed body fat decreased significantly by 1.10+/-1.02% (t=4.44; P<0.01), girth by 4.40+/-5.80cm (t=3.13; P<0.01) and back strength increased by 17.12+/-15.39kgf (t=-4.59; P<0.01). Flexibility was also significantly enhanced with performance of the modified sit-and-reach test increasing by 5.90+/-2.56cm (t=-9.50; P<0.01), hip flexion by 9.84+/-8.41 degrees (t=-4.82; P<0.01), hip extension by 7.65+/-4.48 degrees (t=-7.04; P<0.01), hip abduction by 10.00+/-4.91 degrees (t=-8.40; P<0.01) and lateral trunk flexion by 3.06+/-5.72 degrees (t=-2.21; P<0.05). Finally, state-anxiety (STAI) was significantly reduced intra-class at weeks 1, 6 and 12 by 9.24+/-9.46 (t=4.02; P<0.01), 6.59+/-6.26 (t=4.34; P<0.01) and 7.18+/-5.50 (t=5.38; P<0.01), respectively. The findings of this study suggest mind-body exercise programs like BodyBalance could significantly benefit state-anxiety as well as strength, flexibility, and anthropometry around the trunk. PMID- 17698413 TI - Incidence of injury in junior rugby league players over four competitive seasons. AB - While several studies have documented the incidence of injury in senior rugby league players, information on the injury rates of junior rugby league players is limited. In addition, all of the injury surveillance studies performed on junior rugby league players have been performed over a limited time frame (typically one season). The purpose of this study was to document the incidence of injury in junior rugby league players over four competitive seasons. Injury data were collected from 84 matches. An injury was defined as one that occurred in a match and resulted in the player missing a subsequent match. The overall incidence of injury was 56.8 (95% CI, 42.6-70.9) per 1000 playing hours. The majority of injuries were sustained to the shoulder (15.6 [95% CI, 8.2-23.0] per 1000 playing hours). Sprains were the most common type of injury (24.7 [95% CI, 15.4-34.1] per 1000 playing hours). Injuries were most commonly sustained while being tackled (19.2 [95% CI, 11.0-27.5] per 1000 playing hours) and while tackling (10.1 [95% CI, 4.1-16.0] per 1000 playing hours). While there was a tendency towards differing injury rates over the four competitive seasons (chi(2)=6.3, d.f.=3), the differences were not statistically significant (p=0.10). These findings demonstrate that the incidence of junior rugby league injuries is similar to previously reported for senior competitors. A long-term collaborative effort to reduce the incidence of injury in junior rugby league players is warranted. PMID- 17698415 TI - Diagnosis and management of fetal growth restriction: the role of fetal therapy. AB - Fetal growth restriction remains a major cause of perinatal morbidity and mortality in modern obstetric practice. Placental insufficiency is the most common association, but is often a diagnosis of exclusion. Currently, no treatment can ameliorate or reverse established growth restriction: maximising gestational age and judicious timing of steroid administration and delivery are the primary tasks for the obstetrician. Although comprehensive surveillance of the preterm fetus now includes ductus venosus Doppler studies, its effectiveness in timing delivery has yet to be confirmed in randomised controlled trials. More basic research on the regulation of fetal growth is needed before specific therapies for established growth restriction can be developed. PMID- 17698414 TI - Photoinactivation of Trypanosoma cruzi in red cell suspensions with thiopyrylium. AB - Chagas disease, endemic in rural areas of Mexico, Central and South America, is caused by the protozoan parasite, Trypanosma cruzi, which is spread by the Reduviid bug and also by transfusion or organ transplant. Transmission of the organism from asymptomatic donors to immunocompromised recipients, leads to clinically apparent disease. With recent immigration patterns, T. cruzi is now becoming an increasing problem in non-endemic areas of North America and Europe. Blood screening tests for T. cruzi are being developed, and one test is currently licensed by the United States Food and Drug Administration and has been implemented in some US blood centers. This study alternatively investigates the potential for a novel DNA-intercalating photosensitizer, thiopyrylium (TP), to inactivate T. cruzi in red cell suspensions. With complete inactivation using 6.3 microM of TP and 1.1J/cm(2) red light treatment, results suggest that the organism is highly sensitive to photoinactivation under conditions much less stringent than those that have been previously demonstrated to maintain red cell (RBC) properties during 42 day storage. PMID- 17698416 TI - Transient global amnesia after dobutamine--atropine stress echocardiography. AB - Dobutamine-atropine stress echocardiography is a useful and relatively safe test for coronary artery disease assessment. However, possible complications should be recognized. We describe a case of transient global amnesia in a woman who underwent a standard-protocol dobutamine-atropine stress echocardiogram for coronary ischaemia detection, after having complained about chest pain. The test was not positive for coronary ischaemia, but a typical picture of transient global amnesia ensued. Symptoms shortly resolved spontaneously. Neurological work up was negative for organic disease. Transient global amnesia is a neurological syndrome of unknown origin and good prognosis. Dobutamine-atropine stress echocardiography can be added to the described precipitants of transient global amnesia. This neurological syndrome should be taken into account as a possible complication of dobutamine-atropine stress echocardiography. PMID- 17698417 TI - Identification and characterisation of an androgen receptor from zebrafish Danio rerio. AB - Androgens play key roles in vertebrate sex differentiation, gonadal differentiation and sexual behaviour. The action of androgens is primarily mediated through androgen receptors (ARs). The present study describes the isolation, sequencing and initial characterisation of an androgen receptor from zebrafish Danio rerio. The predicted protein of 868 residues has an estimated calculated molecular weight of 96 kDa. The amino acid sequence of the zebrafish AR (zfRA) shows high homology with other vertebrate ARs. The highest overall similarity was 82% to ARs from fathead minnow (Pimephales promelas) and goldfish (Carassius auratus). Binding assays with zfAR demonstrated high affinity, saturable, single class binding site, with the characteristics of an androgen receptor. Saturation experiments along with subsequent Scatchard analysis determined that the Kd of the zfAR for 3H-testosterone was 2 nM. Androgen binding affinities in competition with 3H-testosterone were: 5alpha dihydrotestosterone>11-ketotestosterone>testosterone>androstenedione. The deletion of 12 amino acids (zfARd12) in the ligand binding domain of zfAR resulted in impaired binding to the receptor. Therefore, it was not possible to determine Kd for the zfARd12. The characterisation of this zfAR provides a new perspective for understanding the mechanisms underlying androgen actions in a model vertebrate species commonly used for studies investigating potential endocrine disrupters. PMID- 17698418 TI - A method for linking computed image features to histological semantics in neuropathology. AB - In medical image analysis the image content is often represented by features computed from the pixel matrix in order to support the development of improved clinical diagnosis systems. These features need to be interpreted and understood at a clinical level of understanding Many features are of abstract nature, as for instance features derived from a wavelet transform. The interpretation and analysis of such features are difficult. This lack of coincidence between computed features and their meaning for a user in a given situation is commonly referred to as the semantic gap. In this work, we propose a method for feature analysis and interpretation based on the simultaneous visualization of feature and image domain. Histopathological images of meningiomas WHO (World Health Organization) grade I are represented by features derived from color transforms and the Discrete Wavelet Transform. The wavelet-based feature space is then visualized and explored using unsupervised machine learning methods. We show how to analyze and select features according to their relevance for the description of clinically relevant characteristics. PMID- 17698419 TI - Egr-1-d2EGFP transgenic rats identify transient populations of neurons and glial cells during postnatal brain development. AB - The inducible transcription factor Egr-1 has been extensively studied in the adult brain but potential roles during development are largely unexplored. Here we describe the analysis of a new transgenic rat model (egr-1 promoter driving a destabilized GFP molecule) that has provided novel information about the postnatal roles of Egr-1. We show that Egr-1 is more widely expressed in the neonatal brain than was previously appreciated, and is not restricted to neurons; it is expressed in glial cells in the postnatal neocortex and hippocampus. This pattern of expression has been revealed due to cellular filling by GFP, permitting co-localization with glial markers. The transgene/Egr-1 is also expressed in a novel population of cells associated with Cajal-Retzius-like neurons within the marginal zone of the postnatal neocortex. Both of these cellular populations are transient, being limited to the neonatal period, before Egr-1 expression becomes established in an adult-like pattern within neocortical neurons, CA1 hippocampus, and striatum. Another transient population of transgene/Egr-1 cells in the bed nucleus of the stria terminalis is maintained until pre-adolescence. The transient phenotype of these cells involves a low relative expression of the neuronal marker NeuN, perhaps indicating a failure to achieve full neuronal differentiation. Egr-1 is therefore present in a diverse range of cell-types during postnatal development. Transgenic expression of a destabilized fluorescent marker has permitted identification of these novel cell populations and will facilitate further analysis of the transcriptional mechanisms that underlie the specific functions and fate of these cells during postnatal brain development. PMID- 17698420 TI - Protein and gene expression analysis of Phf6, the gene mutated in the Borjeson Forssman-Lehmann Syndrome of intellectual disability and obesity. AB - The Plant homeodomain finger gene 6 (PHF6) was identified as the gene mutated in patients suffering from the Borjeson-Forssman-Lehmann Syndrome (BFLS), an X linked mental retardation disorder. BFLS mental disability is evident from an early age, suggesting a developmental brain defect. The PHF6 protein contains four nuclear localisation signals and two imperfect plant homeodomain (PHD) fingers similar to the third, imperfect PHD fingers in members of the trithorax family of transcriptional regulators. The PHF6 gene is highly conserved in vertebrate species. Despite the devastating effects of mutation of the PHF6 gene, nothing is known about the cellular function of PHF6. In order to lay the base for functional studies, we identify here the cell types that express the murine Phf6 gene and protein during prenatal and postnatal development. The Phf6 gene and protein are expressed widely. However, expression levels vary from strong to barely detectable. Strongest Phf6 gene expression and nuclear localisation of Phf6 protein were observed in the developing central nervous system, the anterior pituitary gland, the primordia of facial structures and the limb buds. Expression levels of both mRNA and protein decline over the course of development. In the adult brain moderate Phf6 expression is maintained in projection neurons, such as mitral cells in the olfactory bulb, cerebrocortical pyramidal cells and cerebellar Purkinje cells. Phf6 gene expression and nuclear localisation of Phf6 protein correlate with clinical symptoms in BFLS patients, namely mental disability, pan-anterior pituitary hormonal deficiency and facial as well digit abnormalities. PMID- 17698421 TI - Expression analysis of nha-oc/NHA2: a novel gene selectively expressed in osteoclasts. AB - Bone resorption by osteoclasts is required for normal bone remodeling and reshaping of growing bones. Excessive resorption is an important pathologic feature of many diseases, including osteoporosis, arthritis, and periodontitis [Abu-Amer, Y. (2005). Advances in osteoclast differentiation and function. Curr. Drug Targets. Immune. Endocr. Metabol. Disord. 5, 347-355]. On the other hand, deficient resorption leads to osteopetrosis which is characterized by increased bone mass and may lead to bone deformities or in severe cases to death [Blair, H.C., Athanasou, N.A. 2004. Recent advances in osteoclast biology and pathological bone ddresorption. Histol. Histopathol. 19, 189-199; Del Fattore, A., Peruzzi, B., Rucci, N., Recchia, I., Cappariello, A., Longo, M., Fortunati, D., Ballanti, P., Iacobini, M., Luciani, M., Devito, R., Pinto, R., Caniglia, M., Lanino, E., Messina, C., Cesaro, S., Letizia, C., Bianchini, G., Fryssira, H., Grabowski, P., Shaw, N., Bishop, N., Hughes, D., Kapur, R.P., Datta, H.K., Taranta, A., Fornari, R., Migliaccio, S., and Teti, A. 2006. Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment. J. Med. Genet. 43, 315--325]. Recently, we identified a gene, nha oc/NHA2, which is strongly up regulated during RANKL-induced osteoclast differentiation in vitro and in vivo. nha-oc/NHA2 encodes a novel cation/proton exchanger that is strongly expressed in osteoclasts. The purpose of this work was to further validate the restricted expression of nha-oc/NHA2 in osteoclasts by in situ hybridization. Our results showed that nha-oc is expressed predominantly in bone. In the head, expression was found in the supraoccipitale bone, calvarium, mandible, and maxilla. Furthermore, nha-oc positive cells co-express the osteoclast markers TRAP and cathepsin k, confirming nha-oc/NHA2 osteoclast localization. However, only a subset of cathepsin k-expressing cells is positive for nha-oc/NHA2, suggesting that nha-oc is expressed by terminally differentiated osteoclasts. PMID- 17698422 TI - Using a climate-dependent model to predict mosquito abundance: application to Aedes (Stegomyia) africanus and Aedes (Diceromyia) furcifer (Diptera: Culicidae). AB - Mosquitoes, acting as vectors, are involved in the transmission of viruses. Thus, their abundances, which strongly depend on the weather and environment, are closely linked to major disease outbreaks. The aim of this paper is to provide a tool to predict vector abundance. In order to describe the dynamics of mosquito populations, we developed a matrix model integrating climate fluctuations. The population is structured in five stages: two egg stages (immature and mature), one larval stage and two female flying stages (nulliparous and parous). The water availability in breeding sites was considered as the main environmental factor affecting the mosquito life-cycle. Thus, the model represents the evolution of the mosquito abundance in each stage over time, in connection with water availability. The model was used to simulate the abundance trends over 3 years of two mosquito species, Aedes africanus (Theobald) and Aedes furcifer (Edwards), vectors of the yellow fever virus in Ivory Coast. As both these species breed in tree holes, the water dynamics in the tree hole was reproduced from daily rainfall data. The results we obtained showed a good match between the simulated populations and the field data over the time period considered. PMID- 17698423 TI - Mammalian mitochondrial nucleoids: organizing an independently minded genome. AB - Mitochondrial DNA is arranged in nucleoprotein complexes, or nucleoids. Nucleoid proteins include not only factors involved in replication and transcription but also structural proteins required for mitochondrial DNA maintenance. Although several nucleoid proteins have been identified and characterized in yeast over the course of the past decade, little was known of mammalian mitochondrial nucleoids until recently. Two publications in the past year have expanded considerably the pool of putative mammalian mitochondrial nucleoid proteins; and analysis of one of the candidates, ATAD3p, suggests that mitochondrial nucleoid formation and division are orchestrated, not random, events. PMID- 17698424 TI - A distinct role of formamidopyrimidine DNA glycosylase (MutM) in down-regulation of accumulation of G, C mutations and protection against oxidative stress in mycobacteria. AB - Reactive oxygen species produced as a part of cellular metabolism or environmental agent cause a multitude of damages in cell. Oxidative damages to DNA or the free nucleotide pool result in occurrence of 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA, and failure to replace it with the correct base results in a variety of mutations in the genome. Formamidopyrimidine DNA glycosylase (Fpg/MutM), a functionally conserved repair enzyme initiates the 8-oxoG repair pathway in all eubacteria. DNA in mycobacteria with G+C rich genomes is particularly vulnerable to the oxidative damage. In this study, we disrupted fpg gene in Mycobacterium smegmatis to generate an Fpg deficient strain. The strain showed an enhanced mutator phenotype and susceptibility to hydrogen peroxide. Analyses of rifampicin resistance determining region (RRDR) revealed that, in contrast to Fpg deficient Escherichia coli where C to A mutations predominate, Fpg deficient M. smegmatis shows a remarkable increase in accumulation of A to G (or T to C) mutations. Interestingly, exposure of the mutant to sub-lethal level of hydrogen peroxide results in a major shift towards C to G (or G to C) mutations. Biochemical analysis showed that mycobacterial Fpg; and MutY (which excises misincorporated A against 8-oxoG) possess substrate specificities similar to their counterparts in E. coli. However, the DNA polymerase assays with cell free extracts showed preferential incorporation of G in M. smegmatis as opposed to an A in E. coli. Our studies highlight the importance and the distinctive features of Fpg mediated DNA repair in mycobacteria. PMID- 17698425 TI - A simplified method for the measurement of urinary free cortisol using LC-MS/MS. AB - The measurement of 24 h urinary free cortisol is used in the investigation of patients with symptoms of hypercortisolism. Many different methods have been published for the measurement of cortisol, but most of these methods involve cumbersome pre-extraction of the cortisol prior to analysis. We have developed a method using in-well protein precipitation which serves to clean up the sample without requiring lengthy sample preparation. A Shimadzu SIL-HT autosampler was used to inject 50 microL of extract onto a Phenomemex Gemini C18 guard column attached to a Waters Xbridge C18 column. The eluant was introduced directly into a Waters Quattro Micro tandem mass spectrometer. The method was found to be linear up to 3448 nmol/L with a lower limit of detection of 5.3 nmol/L. Precision and accuracy were acceptable, and no interference was noted from compounds such as prednisolone or fenofibrate. This assay was compared to a previously published method, which uses solid phase extraction prior to LC-MS/MS analysis. We have developed a simplified, robust assay for the quantitation of urinary free cortisol that will increase the throughput of the assay and avoid the use of neurotoxic solvents such as dichloromethane. PMID- 17698426 TI - Lactoperoxidase folding and catalysis relies on the stabilization of the alpha helix rich core domain: a thermal unfolding study. AB - Lactoperoxidase (LPO) belongs to the mammalian peroxidase family and catalyzes the oxidation of halides, pseudo-halides and a number of aromatic substrates at the expense of hydrogen peroxide. Despite the complex physiological role of LPO and its potential involvement in carcinogenic mechanisms, cystic fibrosis and inflammatory processes, little is known on the folding and structural stability of this protein. We have undertaken an investigation of the conformational dynamics and catalytic properties of LPO during thermal unfolding, using complementary biophysical techniques (differential scanning calorimetry, electron spin resonance, optical absorption, fluorescence and circular dichroism spectroscopies) together with biological activity assays. LPO is a particularly stable protein, capable of maintaining catalysis and structural integrity up to a high temperature, undergoing irreversible unfolding at 70 degrees C. We have observed that the first stages of the thermal denaturation involve a minor conformational change occurring at 40 degrees C, possibly at the level of the protein beta-sheets, which nevertheless does not result in an unfolding transition. Only at higher temperature, the protein hydrophobic core, which is rich in alpha-helices, unfolds with concomitant disruption of the catalytic heme pocket and activity loss. Evidences concerning the stabilizing role of the disulfide bridges and the covalently bound heme cofactor are shown and discussed in the context of understanding the structural stability determinants in a relatively large protein. PMID- 17698427 TI - Differentially expressed cytosolic proteins in human leukemia and lymphoma cell lines correlate with lineages and functions. AB - Identification of cytosolic proteins differentially expressed between types of leukemia and lymphoma may provide a molecular basis for classification and understanding their cellular properties. Two-dimensional fluorescence difference gel electrophoresis (DIGE) and mass spectrometry have been used to identify proteins that are differentially expressed in cytosolic extracts from four human leukemia and lymphoma cell lines: HL-60 (acute promyelocytic leukemia), MEC1 (B cell chronic lymphocytic leukemia), CCRF-CEM (T-cell acute lymphoblastic leukemia) and Raji (B-cell Burkitt's lymphoma). A total of 247 differentially expressed proteins were identified between the four cell lines. Analysis of the data by principal component analysis identified 22 protein spots (17 different protein species) differentially expressed at more than a 95% variance level between these cell lines. Several of these proteins were differentially expressed in only one cell line: HL-60 (myeloperoxidase, phosphoprotein 32 family member A, ras related protein Rab-11B, protein disulfide-isomerase, ran-specific GTPase activating protein, nucleophosmin and S-100 calcium binding protein A4), and Raji (ezrin). Several of these proteins were differentially expressed in two cell lines: Raji and MEC1 (C-1-tetrahydrofolate synthase, elongation factor 2, alpha- and beta-tubulin, transgelin-2 and stathmin). MEC1 and CCRF-CEM (gamma-enolase), HL-60 and CCRF-CEM (ubiquitin-conjugating enzyme E2 N). The differentially expressed proteins identified in these four cell lines correlate with cellular properties and provide insights into the molecular basis of these malignancies. PMID- 17698428 TI - Is there evidence that long-term outcomes have improved with intensive care? AB - Advances in perinatal interventions over the past three decades, such as antenatal steroid therapy, ventilator techniques, surfactant therapy, and enhanced nutrition have resulted in a dramatic improvement in the survival of very low birth weight (VLBW) infants. Simultaneously, other advances in reproductive technology procedures have resulted in greater numbers of preterm and multiple births. These extremely premature births account for the vast majority of infant mortality and morbidity in the developed world. Despite the innovative interventions, VLBW infants remain at substantial risk for a wide spectrum of long-term morbidity including cerebral palsy (CP), mental retardation, developmental delay, school problems, behavioral issues, growth failure, and overall poor health status. Recently, ethical concerns have been expressed that improved survival rates for the most immature infants may result in increased rates of disability with substantial resource utilization and declining quality of life for the survivors. This chapter critically evaluates the available neurodevelopmental and health outcomes of very premature infants from the developed world in an attempt to determine if there is evidence that long-term outcomes have improved with neonatal intensive care. Studies on the rates of neurodevelopmental impairment including CP, early childhood and school age functional problems, and special health care issues are surveyed in order to evaluate changes over time and provide an assessment of the success of neonatal intensive care over the past three decades. PMID- 17698429 TI - Role of atrial remodeling in patients with atrial fibrillation. AB - Atrial fibrillation (AF) maintenance is promoted by an atrial substrate that is suitable for the initiation and continuation of the re-entering wavelets. During the first week of AF, the atrial substrate is modified by electrical remodeling, with shortening of the atrial refractoriness and slowing of the conduction velocity. Structural remodeling is the so-called "second factor" that facilitates the maintenance of AF in the following months. The ultrastructural changes result in an inhomogeneous conduction and electrical uncoupling, and the enlarged atrium is able to accommodate more circulating wave fronts that stabilize the AF. Reversal of the electrical remodeling develops within 1 week after the restoration of AF to sinus rhythm. However, reverse structural remodeling develops more slowly and may be just partially reversible. The substrate properties during AF recurrences after undergoing catheter ablation are more complex and need to be clarified in future studies. PMID- 17698430 TI - AFP-L3 in chronic liver diseases with persistent elevation of alpha-fetoprotein. AB - BACKGROUND: Alpha-fetoprotein (AFP) is an important marker for hepatocellular carcinoma (HCC). However, persistent elevation of AFP is found in patients with chronic liver diseases. The value of AFP-L3, which is more specific than AFP, was examined in such patients. METHODS: We enrolled patients without image-detectable tumor, but with transient AFP value > 900 ng/mL (group A) or with persistent AFP value > 50 ng/mL for longer than 6 months (group B). Forty-one patients with HCC and AFP value > 50 ng/mL were included as the HCC control group (group C). AFP-L3 measurement was done by lectin-affinity electrophoresis coupled with antibody affinity blotting. The study patients were followed with AFP, liver biochemistry and abdominal ultrasound at 3- to 6-month intervals. Additional studies were done when a tumor was suspected. RESULTS: One of 17 patients in group A and 13 of 39 patients in group B developed HCC within 2 years. When the cutoff value of AFP-L3 ratio was 15%, both the sensitivity and specificity were 71% for prediction of HCC during the next 2 years in all patients. Ninety percent of tumors larger than 5 cm had AFP-L3 > 15%, compared with only 60% for tumors smaller than 2 cm. Three patients in group A had AFP-L3 ratio > 17.5%. One patient developed HCC 10 months later; the other 2 patients were associated with hepatic failure. CONCLUSION: AFP L3 provides a clue in HCC detection in patients with persistent elevation of AFP. However, AFP-L3 could be highly elevated in severe hepatitis. PMID- 17698431 TI - Risk factor analysis of acute respiratory distress syndrome among hospitalized patients with Chlamydophila pneumoniae pneumonia. AB - BACKGROUND: Chlamydophila pneumoniae (C. pneumoniae) pneumonia-associated acute respiratory distress syndrome (ARDS) is rare and has been seldom reported, but the outcome is usually fatal. This study was designed to identify the risk factors for hospitalized C. pneumoniae patients developing ARDS and to describe the outcomes. METHODS: A retrospective study was performed to evaluate hospitalized patients over 18 years old diagnosed with C. pneumoniae pneumonia in a tertiary medical center. RESULTS: Eleven patients who fulfilled the diagnostic criteria were included in this study. ARDS developed in 6 of 11 patients and mostly within 7 days of admission. Five of 6 patients needed to be transferred to the intensive care unit, and all of these patients died. The patients who developed ARDS had higher initial Acute Physiology and Chronic Health Evaluation II scores and CURB-65 (confusion, urea, respiratory rate, blood pressure, age) scores. The risk factors for developing ARDS included age >or= 75 years, comorbid disease such as congestive heart failure, diabetes or liver cirrhosis, APACHE II score >or= 12, CURB-65 score >or= 2, white blood cell count > 12,000/mm3 or < 4,000/mm3, serum creatinine >or= 1.4 mg/dL, and bilateral or multilobar involvement. CONCLUSION: C. pneumoniae associated with ARDS has a higher mortality, and several risk factors, such as older age, underlying comorbidity and bilateral or multilobar involvement, should be identified earlier. PMID- 17698432 TI - Randomized trial of low-pressure carbon dioxide-elicited pneumoperitoneum versus abdominal wall lifting for laparoscopic cholecystectomy. AB - BACKGROUND: Two alternative surgical techniques for elective laparoscopic cholecystectomy (LC), low-pressure insufflation of the peritoneal cavity and abdominal wall lifting (AWL), have been developed over time to minimize the disadvantages associated with CO2-elicited pneumoperitoneum. To the best of our knowledge, the 2 methods have seldom been compared as regards their relative advantages and disadvantages. METHODS: Eighty patients scheduled for elective LC were randomized into either a low-pressure (8 mmHg) CO2 insufflation method (LPLC) group, or a gasless technique using a subcutaneous abdominal wall lifting device (GLC group). The duration of the surgical procedure, the surgical results including level of postoperative pain, and perioperative cardiopulmonary function changes experienced by the members of both groups were compared. RESULTS: Laparoscopic surgery was completed for all but 1 patient from each group due to an inadequate surgical-site exposure. There was no mortality for study participants, and no major complications were noted for members of either group. The LPLC group evidenced a shorter surgical duration as compared to the GLC group (77 +/- 28 minutes vs. 98 +/- 27 minutes, respectively; p < 0.01) and a lower incidence of postoperative shoulder pain (2/38 vs. 8/39, respectively; p < 0.05), although significant differences in intraoperative pulmonary function were noted (an increased PaCO2, Pet CO2 and peak-airway pressure and decreased arterial blood pH; p < 0.01) for the LPLC group compared to the GLC group. CONCLUSION: Both alternative methods for this type of surgery appeared feasible and safe for LC. Low-pressure CO2 pneumoperitoneum had a shorter surgical duration and less postoperative shoulder pain compared to the GLC technique, but did not feature any other advantage over the AWL technique with regard to impact on cardiopulmonary function. PMID- 17698433 TI - A randomized controlled clinical trial of auricular acupuncture in smoking cessation. AB - BACKGROUND: Tobacco smoking is responsible for human diseases of the lung, heart, circulatory system and various kinds of cancers, and is a serious public health problem worldwide. Acupuncture has been promoted as a treatment modality for smoking cessation. However, its efficacy still remains controversial. METHODS: We conducted a prospective, randomized, controlled trial using auricular acupuncture for smoking cessation in 131 adults who wanted to stop smoking. Thirteen subjects withdrew from the study and 118 subjects were included in the final analyses (mean age, 53.7 +/- 16.8 years; 100 males, 18 females). The treatment group (n = 59) received auricular acupuncture in Shen Men, Sympathetic, Mouth and Lung points for 8 weeks. The control group (n = 59) received sham acupuncture in non smoking-cessation-related auricular acupoints (Knee, Elbow, Shoulder and Eye points). The enrolled subjects were then followed monthly for 6 months after stopping the acupuncture treatment. RESULTS: Between both groups before acupuncture treatment, there was no significant difference with regard to gender, mean age, education level, and mean values for the age at which smoking started, smoking duration, daily number of cigarettes smoked and nicotine dependent score. At the end of treatment, cigarette consumption had significantly decreased in both groups, but only the treatment group showed a significant decrease in the nicotine withdrawal symptom score. Smoking cessation rate showed no significant difference between the treatment group (27.1%) and the control group (20.3%) at the end of treatment. There was also no significant difference in the smoking cessation rate between the treatment group (16.6%) and the control group (12.1%) at the end of follow-up. There were no major side effects of auricular acupuncture in both groups. CONCLUSION: Our results showed that auricular acupuncture did not have a better efficacy in smoking cessation compared to sham acupuncture. Combined acupuncture with behavior counseling or with nicotine replacement therapy should be used in further smoking cessation trials to enhance the success rate of smoking cessation. PMID- 17698434 TI - Cervical spinal stenosis and myelopathy due to atlas hypoplasia. AB - This paper describes a patient who presented at our hospital with neurologic symptoms due to congenital cervical spinal stenosis at the atlas level. Congenital atlantal stenosis is usually due to hypoplasia of the posterior arch of the atlas. It is a rare cause of spinal stenosis, and only 12 symptomatic patients with isolated atlantal stenosis have been reported. Current treatment is surgical decompression, and all reported patients receiving surgical treatment improved to some degree. PMID- 17698435 TI - Magnetic resonance imaging as a diagnostic tool in pregnancy with appendiceal abscess. AB - Abdominal pain presenting itself during pregnancy may be multifactorial, requiring immediate attention and care. In cases of intractable pain without obstetrical condition, surgical abdominal exploration is widely advised. However, we present a case where a 30-year-old, gravida 1, para 0, female complained of persistent right abdominal pain during her 25th week of pregnancy. Ultrasound revealed a right upper quadrant cystic mass and magnetic resonance imaging was arranged with compatible findings. Final impression of appendiceal abscess was determined. Broad-spectrum antibiotics were administered and the patient was discharged in stable condition after 10 days of conservative treatment. She delivered a healthy baby boy at her 40th week of gestation uneventfully. PMID- 17698436 TI - Management of anaphylactic shock during intravenous fluorescein angiography at an outpatient clinic. AB - We report the proper management of a severe adverse reaction of anaphylactic shock during intravenous fluorescein angiography at an outpatient clinic. A 72 year-old male developed the severe, life-threatening complication after intravenous injection of sodium fluorescein dye for retinal angiography. Three minutes after receiving an intravenous injection of fluorescein, the patient developed syncope, apnea and circulatory shock. Fortunately, he recovered without any neurologic sequelae after immediate intensive resuscitation with fluid and inotropic support. We highlight the occurrence of anaphylactic shock as a potentially fatal complication during intravenous fluorescein angiography. Thus, one should be alert to the possibility of this adverse event and be prepared to deal with it when fluorescein angiography is performed. When it happens, immediate intensive medical resuscitation is essential to minimize morbidity and to avoid mortality. PMID- 17698437 TI - A missing silk strip during laparoscopic radical cystectomy and bilateral nephroureterectomy. AB - Many accidents and complications may occur intraoperatively and postoperatively. Herein, we present an intraoperative accident of a missing yellowish silk strip, which was sucked out by a hook cautery and suction probe during laparoscopic radical cystectomy and bilateral nephroureterectomy. PMID- 17698438 TI - Duodenal angiosarcoma: an unusual cause of severe gastrointestinal bleeding. AB - Angiosarcoma is a rare soft-tissue neoplasm that occurs most often in the skin and the subcutaneous tissues but very rarely in the gastrointestinal tract. We report a case of primary intestinal angiosarcoma with severe gastrointestinal bleeding. This patient was referred to our institute for shock with tarry-bloody stool and severe anemia. Panendoscopy revealed multiple duodenal polypoid tumors, and initial biopsy specimen showed poorly differentiated adenocarcinoma. The tumors were treated with pancreaticoduodenectomy, but the patient died 2 weeks after the operation as a result of acute respiratory distress syndrome. The pathology was consistent with angiosarcoma of the duodenum. In our experience, this tumor may cause severe bleeding, and surgery should be performed as soon as possible to prevent complications of hypovolemic shock. PMID- 17698443 TI - Two waves of diversification in mammals and reptiles of Baja California revealed by hierarchical Bayesian analysis. AB - Many species inhabiting the Peninsular Desert of Baja California demonstrate a phylogeographic break at the mid-peninsula, and previous researchers have attributed this shared pattern to a single vicariant event, a mid-peninsular seaway. However, previous studies have not explicitly considered the inherent stochasticity associated with the gene-tree coalescence for species preceding the time of the putative mid-peninsular divergence. We use a Bayesian analysis of a hierarchical model to test for simultaneous vicariance across co-distributed sister lineages sharing a genealogical break at the mid-peninsula. This Bayesian method is advantageous over traditional phylogenetic interpretations of biogeography because it considers the genetic variance associated with the coalescent and mutational processes, as well as the among-lineage demographic differences that affect gene-tree coalescent patterns. Mitochondrial DNA data from six small mammals and six squamate reptiles do not support the perception of a shared vicariant history among lineages exhibiting a north-south divergence at the mid-peninsula, and instead support two events differentially structuring genetic diversity in this region. PMID- 17698445 TI - Evolution of Pinnipedia lactation strategies: a potential role for alpha lactalbumin? AB - Despite the considerable variation in milk composition found among mammals, a constituent common across all groups is lactose, the main sugar and osmole in most eutherians milk. Exceptions to this are the families Otariidae (fur seals and sea lions) and Odobenidae (walruses), where lactose has not been detected. We investigated the molecular basis for this by cloning alpha-lactalbumin, the modifier protein of the lactose synthase complex. A mutation was observed which, in addition to preventing lactose production, may enable otariids to maintain lactation despite the extremely long inter-suckling intervals during the mother's time at sea foraging (more than 23 days in some species). PMID- 17698446 TI - Interspecific audience effects on the alarm-calling behaviour of a kleptoparasitic bird. AB - Audience effects are increasingly recognized as an important aspect of intraspecific communication. Yet despite the common occurrence of interspecific interactions and considerable evidence that individuals respond to the calls of heterospecifics, empirical evidence for interspecific audience effects on signalling behaviour is lacking. Here we present evidence of an interspecific audience effect on the alarm-calling behaviour of the kleptoparasitic fork-tailed drongo (Dicrurus adsimilis). When foraging solitarily, drongos regularly alarm at aerial predators, but rarely alarm at terrestrial predators. In contrast, when drongos are following terrestrially foraging pied babblers (Turdoides bicolor) for kleptoparasitic opportunities, they consistently give alarm calls to both aerial and terrestrial predators. This change occurs despite no difference in the amount of time that drongos spend foraging terrestrially. Babblers respond to drongo alarm calls by fleeing to cover, providing drongos with opportunities to steal babbler food items by occasionally giving false alarm calls. This provides an example of an interspecific audience effect on alarm-calling behaviour that may be explained by the benefits received from audience response. PMID- 17698447 TI - Virgin birth, genetic variation and inbreeding. PMID- 17698448 TI - Save Isoptera: a comment on Inward et al. PMID- 17698449 TI - Species richness and abundance of forest birds in relation to radiation at Chernobyl. AB - The effects of low-level radiation on the abundance of animals are poorly known, as are the effects on ecosystems and their functioning. Recent conclusions from the UN Chernobyl forum and reports in the popular media concerning the effects of radiation from Chernobyl on animals have left the impression that the Chernobyl exclusion zone is a thriving ecosystem, filled with an increasing number of rare species. Surprisingly, there are no standardized censuses of common animals in relation to radiation, leaving the question about the ecological effects of radiation unresolved. We conducted standardized point counts of breeding birds at forest sites around Chernobyl differing in level of background radiation by over three orders of magnitude. Species richness, abundance and population density of breeding birds decreased with increasing level of radiation, even after controlling statistically for the effects of potentially confounding factors such as soil type, habitat and height of the vegetation. This effect was differential for birds eating soil invertebrates living in the most contaminated top soil layer. These results imply that the ecological effects of Chernobyl on animals are considerably greater than previously assumed. PMID- 17698450 TI - Effects of age and gender on success and death of mountaineers on Mount Everest. AB - Increasing numbers of climbers are attempting Mount Everest, the highest mountain on Earth. We compiled interview data and computed the probabilities of summiting and of dying as a function of climber age and gender (2211 climbers, spring season) for the period of 1990-2005. Men and women had similar odds of summiting and of dying. However, climbers older than 40 years have reduced odds of summiting, and those older than 60 years have increased odds of dying, especially when descending from the summit. On Mount Everest, phenotypic selection appears blind to gender but favours young mountaineers. PMID- 17698451 TI - Complexity and variation in loggerhead sea turtle life history. AB - Juvenile loggerhead sea turtles spend more than a decade in the open ocean before returning to neritic waters to mature and reproduce. It has been assumed that this transition from an oceanic to neritic existence is a discrete ontogenetic niche shift. We tested this hypothesis by tracking the movements of large juveniles collected in a neritic foraging ground in North Carolina, USA. Our work shows that the shift from the oceanic to neritic waters is both complex and reversible; some individuals move back into coastal waters and then return to the open ocean for reasons that are still unclear, sometimes for multiple years. These findings have important consequences for efforts to protect these threatened marine reptiles from mortality in both coastal and open-ocean fisheries. PMID- 17698452 TI - Absence of contagious yawning in children with autism spectrum disorder. AB - This study is the first to report the disturbance of contagious yawning in individuals with autism spectrum disorder (ASD). Twenty-four children with ASD as well as 25 age-matched typically developing (TD) children observed video clips of either yawning or control mouth movements. Yawning video clips elicited more yawns in TD children than in children with ASD, but the frequency of yawns did not differ between groups when they observed control video clips. Moreover, TD children yawned more during or after the yawn video clips than the control video clips, but the type of video clips did not affect the amount of yawning in children with ASD. Current results suggest that contagious yawning is impaired in ASD, which may relate to their impairment in empathy. It supports the claim that contagious yawning is based on the capacity for empathy. PMID- 17698453 TI - Yoga in stroke rehabilitation: a systematic review and results of a pilot study. AB - PURPOSE: This article presents a systematic review of the literature pertaining to the use of yoga in stroke rehabilitation. In addition, we present the results of a small pilot study designed to explore the hypothesis that a Kundalini yoga practice of 12 weeks would lead to an improvement in aphasia as well as in fine motor coordination in stroke patients. METHOD: The 3 participants attended yoga classes twice a week for 12 weeks, before and after which they were tested on the O'Connor Tweezer Dexterity test, a timed test where the participant places pins in a Peg-Board with tweezers, and the Boston Aphasia Exam for speech. RESULTS: All 3 participants showed improvement on both measures. CONCLUSION: The small sample size makes it impossible to draw definite conclusions, but the positive trends in this study suggest that further research should be done to examine the effects of Kundalini yoga on specific illnesses or medical conditions. PMID- 17698454 TI - Tai Chi exercise and stroke rehabilitation. AB - According to reported global estimates, 15 million people suffer from a stroke each year, resulting in 5.5 million deaths, with 5 million left permanently disabled. Typical disabilities following stroke include poor neuromuscular control, hemodynamic imbalance, and negative mood state. Tai Chi (TC) is associated with better balance, lower blood pressure, and improved mood, which are important for stroke survivors. An overview of the philosophy and principles of TC exercise is provided, followed by a literature review of reported TC studies examining balance, blood pressure, and mood. Finally, the potential application of TC exercise to stroke rehabilitation is discussed. PMID- 17698455 TI - Reaching kinematics to measure motor changes after mental practice in stroke. AB - OBJECTIVE: To examine mental practice (MP) efficacy using a new kinematics reaching model. METHOD: This was a prepost, case series conducted at an outpatient rehabilitation hospital of 5 patients who experienced stroke >1 year before study entry (3 males; mean age = 52.6 +/- 15.4 years [range, 38-76 years]; mean time since stroke = 51.2 months [range, 13-126 months]) exhibiting upper limb hemiparesis on their dominant sides. Participants received 30-minute therapy sessions emphasizing activities of daily living (ADLs) using their affected arms, which occurred 2 days/week for 6 weeks. After therapy, participants received 30 minute MP sessions requiring MP of the ADLs. The main outcome measure was 3-D Motion Analysis (kinematics), in which patients performed 2 functional reaching tasks consisting of reaching and grasping a plastic cylinder positioned at either elbow height (reach out) or shoulder height (reach up). Dependent variables included horizontal reaching distance, hand velocity, elbow range of motion, and shoulder range of motion. RESULTS: Prior to intervention, the mean horizontal reaching distance was 8.3 +/- 1.7 cm and 10.9 +/- 2.2 cm for the reach-up and reach-out tasks, respectively. Upon completion of the intervention, ability to reach up significantly improved to 9.9 +/- 1.6 cm (p <.001). Horizontal reach distance also improved during the reach-out task (11.7 +/- 2.2 cm, p = .366). No statistically significant change was observed in linear hand velocity. Patients also exhibited greater shoulder flexion and elbow extension during both the posttest reach-up and posttest reach-out tasks. DISCUSSION AND CONCLUSION: Kinematics appears to offer a precise, objective way of quantifying MP-induced motor changes during ADL performance. MP appears to improve several aspects of affected arm reaching. PMID- 17698456 TI - Adjunctive care with nutritional, herbal, and homeopathic complementary and alternative medicine modalities in stroke treatment and rehabilitation. AB - This article presents an overview of nutritional, herbal, and homeopathic treatment options from complementary and alternative medicine (CAM) as adjuncts in stroke prevention, treatment, and rehabilitation. Despite many promising leads, the evidence does not favor recommendation of most of these treatments from a public health policy perspective. However, simple preventive interventions such as use of a high-quality multivitamin/multimineral supplement in patients with undernutrition may improve outcomes with minimal long-term risk. Natural agents such as the antioxidant alphalipoic acid, certain traditional Asian herbal mixtures, and some homeopathically prepared remedies show promise for reducing infarct size and associated impairments. A number of nutrients and herbs may assist in treatment of stroke-related complications such as pressure sores, urinary tract infections, and pneumonia. Individualized homeopathy may even play a helpful adjunctive role in treatment of sepsis. However, a great deal of systematic research effort lies ahead before most of the options discussed would meet mainstream medical standards for introduction into routine treatment regimens. PMID- 17698457 TI - Does acupuncture work for stroke rehabilitation: what do recent clinical trials really show? AB - A number of randomized controlled trials of acupuncture for stroke recovery were critically reviewed, beginning with an existing systematic review and meta analysis. A number of these clinical studies suffered from methodological flaws that tended to obscure and reduce the reported effect size. These flaws included inadequate statistical analysis, failure to adequately account for differences in baseline stroke severity, and the use of an inadequate posttreatment assessment period. These three flaws, taken individually or in combination, resulted in the underreporting of acupuncture effects in 5 of the randomized controlled trials reviewed. By informally adjusting study results for these limitations, it was possible to demonstrate that acupuncture is probably much more effective in assisting stroke recovery than has generally been reported, especially when the stroke is in the moderately severe range. The negative impact of well-intended but inappropriate exclusion criteria in the meta-analysis was also illustrated. The importance of giving more attention to ancillary results, such as walking speed and mortality, was illustrated as a way to gain a deeper understanding of the true impact of a still poorly understood therapy such as acupuncture. The general conclusion of the reanalysis presented here is that there is in fact substantial evidence that acupuncture is effective as an adjunctive treatment for facilitating stroke recovery. PMID- 17698458 TI - The role of biofeedback in stroke rehabilitation: past and future directions. AB - Biofeedback has been applied to many aspects of stroke rehabilitation, with mixed results. This is largely due to the varying modalities, differences between study designs, and methods of measuring success and progress. How well biofeedback works appears to be inversely related to the direct observability of the function about which information is being provided. The more covert the function (e.g., swallowing muscle activity, attention, cortical functioning, etc.), the more helpful biofeedback is likely to be. However, biofeedback in general can have a very positive impact, even through indirect means. Improvements in self confidence, shifting of locus of control, and instantly being provided information regarding changes in one's physical functioning as a result of mental activity can be helpful in setting the tone for success in rehabilitation more generally. PMID- 17698459 TI - Preventing hip fracture after stroke. AB - Hip fracture after stroke is a frequently occurring and costly complication. The bone quality of stroke survivors is affected by decreased mobility, asymmetric weight bearing, and impaired vitamin D stores. Simultaneously, the risk of falling after stroke is often increased by various impairments. Yet, attempts to limit falls are not enough to prevent fractures. Closer attention to bone health is also needed. Bone markers, which reflect the dynamics of bone remodeling, are becoming more available. Activity is necessary for bone health, but there are no clear guidelines for the type and amount of therapeutic exercise. New metrics for studying bone mineral density and exercise are on the horizon. Finally, there appears to be a role for bisphosphonate prophylaxis in a yet-to-be-defined at risk population of stroke survivors. The purpose of this review is to discuss the setting for hip fracture after stroke and assess emerging treatments and technologies that may be used to combat the problem. PMID- 17698460 TI - When life imitates art: surrogate decision making at the end of life. AB - The privileging of the substituted judgment standard as the gold standard for surrogate decision making in law and bioethics has constrained the research agenda in end-of-life decision making. The empirical literature is inundated with a plethora of "Newlywed Game" designs, in which potential patients and potential surrogates respond to hypothetical scenarios to see how often they "get it right." The preoccupation with determining the capacity of surrogates to accurately reproduce the judgments of another makes a number of assumptions that blind scholars to the variables central to understanding how surrogates actually make medical decisions on behalf of another. These assumptions include that patient preferences are knowable, surrogates have adequate and accurate information, time stands still, patients get the surrogates they want, patients want and surrogates utilize substituted judgment criteria, and surrogates are disinterested. This article examines these assumptions and considers the challenges of designing research that makes them problematic. PMID- 17698461 TI - A whole new world. PMID- 17698463 TI - Searching chaos and coherent structures in the atmospheric turbulence above the Amazon forest. AB - In this work, the possible chaotic nature of the atmospheric turbulence above a densely forested area in the Amazon region is investigated. To this end, we use high-resolution temperature data obtained during a micrometeorological measurement campaign in the Brazilian Amazonia. Estimates of the correlation dimension (D(2)=3.50+/-0.05) and of the largest Lyapunov exponent (lambda(1)=0.050+/-0.002) suggest the existence of chaos in the atmospheric boundary layer. Our findings indicate that this low-dimensional chaotic dynamics is associated with the presence of the coherent structures within the boundary layer right above the canopy top and not with the atmospheric turbulence per se, as previously claimed. PMID- 17698464 TI - In situ monitoring of friction surfaces and their sequence pattern analysis. AB - Friction occurs between solid surfaces, and even sometimes on lubricated surfaces. To understand tribological subjects, it is important to know the changes that occur in friction surfaces. In this study, a laser strobe technique is applied to a friction surface observation. The recorded surface images were analysed using pattern-matching methods and their correlations are discussed. A test using pin-on-plate methods with carbon steels was performed using a reciprocating motion speed of 10 Hz for 4.9 N. A pulsed laser light (Nd:YAG SHG=532 nm, 5 ns per pulse) was irradiated onto the friction surface. It was induced using an optical microscope that was located just to the side of the pin. The laser pulse was synchronized with the plate motion, which was a trigger of the laser pulse. The surface image was stored for every cycle. These sequences were calculated and their correlations were analysed as a function of the surface pattern and the friction track size and shape. Analysis revealed that some groups were distinguishable as parameters of the damage size and shape. PMID- 17698465 TI - Chaos computing: ideas and implementations. AB - We review the concept of the 'chaos computing' paradigm, which exploits the controlled richness of nonlinear dynamics to obtain flexible reconfigurable hardware. We demonstrate the idea with specific schemes and verify the schemes through proof-of-principle experiments. PMID- 17698466 TI - Piecewise linear approach to an archetypal oscillator for smooth and discontinuous dynamics. AB - In a recent paper we examined a model of an arch bridge with viscous damping subjected to a sinusoidally varying central load. We showed how this yields a useful archetypal oscillator which can be used to study the transition from smooth to discontinuous dynamics as a parameter, alpha, tends to zero. Decreasing this smoothness parameter (a non-dimensional measure of the span of the arch) changes the smooth load-deflection curve associated with snap-buckling into a discontinuous sawtooth. The smooth snap-buckling curve is not amenable to closed form theoretical analysis, so we here introduce a piecewise linearization that correctly fits the sawtooth in the limit at alpha=0. Using a Hamiltonian formulation of this linearization, we derive an analytical expression for the unperturbed homoclinic orbit, and make a Melnikov analysis to detect the homoclinic tangling under the perturbation of damping and driving. Finally, a semi-analytical method is used to examine the full nonlinear dynamics of the perturbed piecewise linear system. A chaotic attractor located at alpha=0.2 compares extremely well with that exhibited by the original arch model: the topological structures are the same, and Lyapunov exponents (and dimensions) are in good agreement. PMID- 17698467 TI - Recurrence plots for dynamical analysis of non-invasive mechanical ventilation. AB - Quantifiers were introduced to convert recurrence plots into a statistical analysis of dynamical properties. It is shown that the Shannon entropy, if properly computed, increases as the chaotic regime is developed as expected. Recurrence plots and a new estimator for the Shannon entropy are then used to identify asynchronisms in non-invasive mechanical ventilation. It is thus shown that the phase coherence-easily identified using a Shannon entropy-is relevant in the quality of the mechanical ventilation. In particular, some patients with chronic respiratory diseases or healthy subjects can have a high rate of asynchronisms but a regular breathing rhythm. PMID- 17698468 TI - Low-dimensional chaos and wave turbulence in plasmas. AB - We investigated drift-wave turbulence in the plasma edge of a small tokamak by considering solutions of the Hasegawa-Mima equation involving three interacting modes in Fourier space. The resulting low-dimensional dynamics presented periodic as well as chaotic evolution of the Fourier-mode amplitudes, and we performed the control of chaotic behaviour through the application of a fourth resonant wave of small amplitude. PMID- 17698470 TI - Accumulation boundaries: codimension-two accumulation of accumulations in phase diagrams of semiconductor lasers, electric circuits, atmospheric and chemical oscillators. AB - We report high-resolution phase diagrams for several familiar dynamical systems described by sets of ordinary differential equations: semiconductor lasers; electric circuits; Lorenz-84 low-order atmospheric circulation model; and Rossler and chemical oscillators. All these systems contain chaotic phases with highly complicated and interesting accumulation boundaries, curves where networks of stable islands of regular oscillations with ever-increasing periodicities accumulate systematically. The experimental exploration of such codimension-two boundaries characterized by the presence of infinite accumulation of accumulations is feasible with existing technology for some of these systems. PMID- 17698469 TI - Fitting ordinary differential equations to short time course data. AB - Ordinary differential equations (ODEs) are widely used to model many systems in physics, chemistry, engineering and biology. Often one wants to compare such equations with observed time course data, and use this to estimate parameters. Surprisingly, practical algorithms for doing this are relatively poorly developed, particularly in comparison with the sophistication of numerical methods for solving both initial and boundary value problems for differential equations, and for locating and analysing bifurcations. A lack of good numerical fitting methods is particularly problematic in the context of systems biology where only a handful of time points may be available. In this paper, we present a survey of existing algorithms and describe the main approaches. We also introduce and evaluate a new efficient technique for estimating ODEs linear in parameters particularly suited to situations where noise levels are high and the number of data points is low. It employs a spline-based collocation scheme and alternates linear least squares minimization steps with repeated estimates of the noise-free values of the variables. This is reminiscent of expectation-maximization methods widely used for problems with nuisance parameters or missing data. PMID- 17698471 TI - Generating surrogates from recurrences. AB - In this paper, we present an approach to recover the dynamics from recurrences of a system and then generate (multivariate) twin surrogate (TS) trajectories. In contrast to other approaches, such as the linear-like surrogates, this technique produces surrogates which correspond to an independent copy of the underlying system, i.e. they induce a trajectory of the underlying system visiting the attractor in a different way. We show that these surrogates are well suited to test for complex synchronization, which makes it possible to systematically assess the reliability of synchronization analyses. We then apply the TS to study binocular fixational movements and find strong indications that the fixational movements of the left and right eye are phase synchronized. This result indicates that there might be only one centre in the brain that produces the fixational movements in both eyes or a close link between the two centres. PMID- 17698472 TI - Topological characterization of deterministic chaos: enforcing orientation preservation. AB - The determinism principle, which states that dynamical state completely determines future time evolution, is a keystone of nonlinear dynamics and chaos theory. Since it precludes that two state space trajectories intersect, it is a core ingredient of a topological analysis of chaos based on a knot-theoretic characterization of unstable periodic orbits embedded in a strange attractor. However, knot theory can be applied only to three-dimensional systems. Still, determinism applies in any dimension. We propose an alternative framework in which this principle is enforced by constructing an orientation-preserving dynamics on triangulated surfaces and find that in three dimensions our approach numerically predicts the correct topological entropies for periodic orbits of the horseshoe map. PMID- 17698473 TI - Experimental separation of chaotic signals through synchronization. AB - In this paper using a negative feedback scheme we study the problem of synchronizing two systems (each of them made of n independent chaotic circuits) through the transmission of a unique signal (i.e. a scalar variable). To find the appropriate values of the feedback gains, an approach based on the design of an asymptotic observer leading to a set of linear matrix inequalities is used for piecewise linear systems, while for systems with continuous nonlinearities a master stability function approach is adopted. Numerical results showing the suitability of the approach are reported. Furthermore, the experiment showing separation and synchronization of two pairs of chaotic circuits is discussed. Despite the presence of parameter mismatches, separation and synchronization of the two systems can be achieved. This is an experimental demonstration of the successful possibility of multiplexing two (or more) chaotic signals in the same channel. PMID- 17698474 TI - Fluctuations, correlations and transitions in granular materials: statistical mechanics for a non-conventional system. AB - In this work, we first review some general properties of dense granular materials. We are particularly concerned with a statistical description of these materials, and it is in this light that we briefly describe results from four representative studies. These are: experiment 1: determining local force statistics, vector forces, force distributions and correlations for static granular systems; experiment 2: characterizing the jamming transition, for a static two-dimensional system; experiment 3: characterizing plastic failure in dense granular materials; and experiment 4: a dynamical transition where the material 'freezes' in the presence of apparent heating for a sheared and shaken system. PMID- 17698475 TI - Wind direction modelling using multiple observation points. AB - The prediction of wind direction is a prerequisite for the intelligent and efficient operation of wind turbines. This is a complex task, due to the intermittent behaviour of wind, its non-Gaussian and nonlinear nature, and the coupling between the wind speed and direction. To provide improved wind direction forecasting, we propose a nonlinear model with augmented information from an additional measurement point. This is further enhanced by making use of both the speed and direction components of the wind field vector. The analysis and a comprehensive set of simulations demonstrate that the proposed approach achieves improved prediction performance over the standard and persistent model. The potential of the proposed approach is justified by the fact that even relatively small improvements in the forecasts result in large gains in the produced output power. PMID- 17698476 TI - Chitosan-mediated crystallization and assembly of hydroxyapatite nanoparticles into hybrid nanostructured films. AB - The synthesis and subsequent assembly of nearly spherical nano-hydroxyapatite (nHA) particles in the presence of trace amounts of the polysaccharide chitosan was carried out employing a wet chemical approach. Chitosan addition during synthesis not only modulated HA crystallization but also aided in the assembly of nHA particles onto itself. Solvent extraction from these suspensions formed iridescent films, of which the bottom few layers were rich in self-assembled nHA particle arrays. The cross-section of these hybrid films revealed compositional and hence structural grading of the two phases and exhibited a unique morphology in which assembled nHA particles gradually gave way to chitosan-rich top layers. Transmission electron microscope and selected area electron diffraction studies suggested that the basal plane of HA had interacted with chitosan, and scanning electron microscope studies of the hybrid films revealed multi-length scale hierarchical architecture composed of HA and chitosan. Phase identification was carried out by X-ray diffraction (XRD) and Rietveld analysis of digitized XRD data showed that the basic apatite structure was preserved, but chitosan inclusion induced subtle changes to the HA unit cell. The refinement of crystallite shape using the Popa method clearly indicated a distinct change in the growth direction of HA crystallites from [001] to [100] with increasing chitosan concentration. The paper also discusses the likelihood of chitosan phosphorylation during synthesis, which we believe to be a pathway, by which chitosan molecules chemically interact with calcium phosphate precursor compounds and orchestrate the crystallization of nHA particles. Additionally, the paper suggests several interesting biomedical applications for graded nHA-chitosan nanostructured films. PMID- 17698477 TI - A stochastic model for ecological systems with strong nonlinear response to environmental drivers: application to two water-borne diseases. AB - Ecological systems with threshold behaviour show drastic shifts in population abundance or species diversity in response to small variation in critical parameters. Examples of threshold behaviour arise in resource competition theory, epidemiological theory and environmentally driven population dynamics, to name a few. Although expected from theory, thresholds may be difficult to detect in real datasets due to stochasticity, finite population size and confounding effects that soften the observed shifts and introduce variability in the data. Here, we propose a modelling framework for threshold responses to environmental drivers that allows for a flexible treatment of the transition between regimes, including variation in the sharpness of the transition and the variance of the response. The model assumes two underlying stochastic processes whose mixture determines the system's response. For environmentally driven systems, the mixture is a function of an environmental covariate and the response may exhibit strong nonlinearity. When applied to two datasets for water-borne diseases, the model was able to capture the effect of rainfall on the mean number of cases as well as the variance. A quantitative description of this kind of threshold behaviour is of more general application to predict the response of ecosystems and human health to climate change. PMID- 17698478 TI - Disease dynamics over very different time-scales: foot-and-mouth disease and scrapie on the network of livestock movements in the UK. AB - We analyse the relationship between the network of livestock movements in the UK and the dynamics of two diseases: foot-and-mouth disease (FMD), which has an incubation period of days, and scrapie, which incubates over years. For FMD, the time-scale of expected epidemics is similar to the time-scale of the evolution of the network. We argue that, under appropriate conditions, a static network analysis can be an appropriate tool for gaining insights into disease dynamics even when the relevant time-scales are similar, as with FMD. We show that a subclass of 'linkage moves' maintains the network structure, and so removing these links has a dramatic effect on the number of potentially infected farms, an effect corroborated by simulations. In contrast, because scrapie has a low probability of transmission per contact and a long incubation period, a static network representation is probably appropriate; however, the signature of the network in the pattern of transmission is likely to be faint. Scrapie-notifying farms were more likely to be associated with each other via trading at markets than were control farms; however, network community structure proves to be less representative of prevalence patterns than geographical region. These contradictory indicators emphasize that appropriate observation time frames and good discrimination among types of potentially infectious contacts are vital in order for network analysis to be a valuable epidemiological tool. PMID- 17698479 TI - The thermodynamic driving force for bone growth and remodelling: a hypothesis. AB - The Eshelby stress (static energy momentum) tensor is derived for bone modelled as an inhomogeneous piezoelectric and piezomagnetic Cosserat (micropolar) medium. The divergence of this tensor is the configurational force felt by material gradients and defects in the medium. Just as in inhomogeneous elastic media, this force is identified with the thermodynamic force for phase transformations, in bone it is the thermodynamic cause of structural transformations, i.e. remodelling and growth. The thermodynamic approach shows that some terms of driving force are proportional to the stress, and some acting on material inhomogeneities are quadratic in the stress-the latter outweigh by far the former. Since inertial forces due to acceleration enter the energy-momentum tensor, it follows that the rate of loading matters and that both tension and compression stimulate growth, which is favoured at heterogeneities. PMID- 17698480 TI - Influence of macrofaunal assemblages and environmental heterogeneity on microphytobenthic production in experimental systems. AB - Despite the complexity of natural systems, heterogeneity caused by the fragmentation of habitats has seldom been considered when investigating ecosystem processes. Empirical approaches that have included the influence of heterogeneity tend to be biased towards terrestrial habitats; yet marine systems offer opportunities by virtue of their relative ease of manipulation, rapid response times and the well-understood effects of macrofauna on sediment processes. Here, the influence of heterogeneity on microphytobenthic production in synthetic estuarine assemblages is examined. Heterogeneity was created by enriching patches of sediment with detrital algae (Enteromorpha intestinalis) to provide a source of allochthonous organic matter. A gradient of species density for four numerically dominant intertidal macrofauna (Hediste diversicolor, Hydrobia ulvae, Corophium volutator, Macoma balthica) was constructed, and microphytobenthic biomass at the sediment surface was measured. Statistical analysis using generalized least squares regression indicated that heterogeneity within our system was a significant driving factor that interacted with macrofaunal density and species identity. Microphytobenthic biomass was highest in enriched patches, suggesting that nutrients were obtained locally from the sediment-water interface and not from the water column. Our findings demonstrate that organic enrichment can cause the development of heterogeneity which influences infaunal bioturbation and consequent nutrient generation, a driver of microphytobenthic production. PMID- 17698482 TI - Encountering competitors reduces clutch size and increases offspring size in a parasitoid with female-female fighting. AB - Understanding the size of clutches produced by only one parent may require a game theoretic approach: clutch size may affect offspring fitness in terms of future competitive ability. If larger clutches generate smaller offspring and larger adults are more successful in acquiring and retaining resources, clutch size optima should be reduced when the probability of future competitive encounters is higher. We test this using Goniozus nephantidis, a gregarious parasitoid wasp in which the assumption of size-dependent resource acquisition is met via female female contests for hosts. As predicted, smaller clutches are produced by mothers experiencing competition, due to fewer eggs being matured and to a reduced proportion of matured eggs being laid. As assumed, smaller clutches generate fewer but larger offspring. We believe this is the first direct evidence for pre ovipositional and game-theoretic clutch size adjustment in response to an intergenerational fitness effect when clutches are produced by a single individual. PMID- 17698483 TI - Contrasting responses of bumble bees to feeding conspecifics on their familiar and unfamiliar flowers. AB - Animals exploiting their familiar food items often avoid spatio-temporal aggregation with others by avoiding scents, less rewarding areas or visual contacts, thereby minimizing competition or interference when resources are replenished slowly in patches. When animals are searching or assessing available food sources, however, they may benefit from reducing sampling costs by following others at food sites. Therefore, animals may adjust their responses to others depending on their familiarity with foraging situations. Here, we conducted field experiments to test whether nectar-collecting bumble bees make this adjustment. We allowed free-foraging bees to choose between two inflorescences, one occupied by a conspecific bee and another unoccupied. When bees were presented with flowers of a familiar type, they avoided occupied inflorescences. In contrast, bees visited an occupied inflorescence when the flower type was unfamiliar. To our knowledge, this is the first report suggesting that animals adjust their responses to feeding conspecifics depending on their familiarity with food sources. Such behavioural flexibilities should allow foragers to both explore and exploit their environments efficiently. PMID- 17698484 TI - New sea spiders from the Jurassic La Voulte-sur-Rhone Lagerstatte. AB - The diverse and exceptionally well-preserved pycnogonids described herein from the Middle Jurassic La Voulte Lagerstatte fill a 400 Myr gap of knowledge in the evolutionary history of this enigmatic group of marine arthropods. They reveal very close morphological and functional (locomotion, feeding) similarities with present-day pycnogonids and, by contrast, marked differences with all Palaeozoic representatives of the group. This suggests a relatively recent, possibly Mesozoic origin for at least three major extant lineages of pycnogonids (Ammotheidae, Colossendeidae, Endeidae). Combined evidence from depositional environment, faunal associates and recent analogues indicate that the La Voulte pycnogonids probably lived in the upper bathyal zone (ca 200 m). Our results point to a remarkable morphological and ecological stability of this arthropod group over at least 160 Myr and suggest that the colonization of the deep sea by pycnogonids occurred before the Jurassic. PMID- 17698485 TI - Mass-dependent predation risk and lethal dolphin-porpoise interactions. AB - In small birds, mass-dependent predation risk (MDPR) is known to make the trade off between avoiding starvation and avoiding predation dependent on individual mass. This occurs because carrying increased fat reserves not only reduces starvation risk but also results in a higher predation risk due to reduced escape flight performance and/or the increased foraging exposure needed to maintain a higher body mass. In principle, the theory of MDPR could also apply to any animal capable of storing energy reserves to reduce starvation and whose escape performance decreases with increasing mass. We used a unique situation along certain parts of coastal Britain, where harbour porpoises (Phocoena phocoena) are pursued and killed but crucially not eaten by bottlenose dolphins (Tursiops truncatus), to investigate whether a MDPR effect can occur in non-avian species. We show that where high levels of dolphin 'predation' occur, porpoises carry significantly less energy reserves than would otherwise be expected and this equates to reducing by approximately 37% the length of time that a porpoise could survive without feeding. These results provide the first evidence that a mass dependent starvation-predation risk trade-off may be a general ecological principle that can apply to widely different animal types rather than, as is currently thought, only to birds. PMID- 17698486 TI - Synchrony between fruit maturation and effective dispersers' foraging activity increases seed protection against seed predators. AB - The evolution of pollination and seed dispersal mutualisms is conditioned by the spatial and temporal co-occurrence of animals and plants. In the present study we explore the timing of seed release of a myrmecochorous plant (Helleborus foetidus) and ant activity in two populations in southern Spain during 2 consecutive years. The results indicate that fruit dehiscence and seed shedding occur mostly in the morning and correspond to the period of maximum foraging activity of the most effective ant dispersers. By contrast, ant species that do not transport seeds and/or that do not abound near the plants are active either before or after H. foetidus diaspores are released. Experimental analysis of diet preference for three kinds of food shows that effective ant dispersers are mostly scavengers that readily feed on insect corpses and sugars. Artificial seed depots suggest that seeds deposited on the ground out of the natural daily time window of diaspore releasing are not removed by ants and suffer strong predation by nocturnal rodents Apodemus sylvaticus. Nevertheless, important inter-annual variations in rodent populations cast doubts on their real importance as selection agents. We argue that traits allowing synchrony between seed presentation and effective partners may constitute a crucial pre-adaptation for the evolution of plant-animal mutualisms involving numerous animal partners. PMID- 17698487 TI - Do capuchin monkeys (Cebus apella) use tokens as symbols? AB - In the absence of language, the comprehension of symbols is difficult to demonstrate. Tokens can be considered symbols since they arbitrarily stand for something else without having any iconic relation to their referent. We assessed whether capuchin monkeys (Cebus apella) can use tokens as symbols to represent and combine quantities. Our paradigm involved choices between various combinations of tokens A and B, worth one and three rewards, respectively. Pay off maximization required the assessment of the value of each offer by (i) estimating token numerousness, (ii) representing what each token stands for and (iii) making simple computations. When one token B was presented against one to five tokens A (experiment 1), four out of ten capuchins relied on a flexible strategy that allowed to maximize their pay-off, i.e. they preferred one token B against one and two tokens A, and they preferred four or five tokens A against one token B. Moreover, when two tokens B were presented against three to six tokens A (experiment 2), two out of six capuchins performed summation over representation of quantities. These findings suggest that capuchins can use tokens as symbols to flexibly combine quantities. PMID- 17698488 TI - Breeding experience and population density affect the ability of a songbird to respond to future climate variation. AB - Predicting how populations respond to climate change requires an understanding of whether individuals or cohorts within populations vary in their response to climate variation. We used mixed-effects models on a song sparrow (Melospiza melodia) population in British Columbia, Canada, to examine differences among females and cohorts in their average breeding date and breeding date plasticity in response to the El Nino Southern Oscillation. Climatic variables, age and population density were strong predictors of timing of breeding, but we also found considerable variation among individual females and cohorts. Within cohorts, females differed markedly in their breeding date and cohorts also differed in their average breeding date and breeding date plasticity. The plasticity of a cohort appeared to be due primarily to an interaction between the environmental conditions (climate and density) experienced at different ages rather than innate inter-cohort differences. Cohorts that expressed higher plasticity in breeding date experienced warmer El Nino springs in their second or third breeding season, suggesting that prior experience affects how well individuals responded to abnormal climatic conditions. Cohorts born into lower density populations also expressed higher plasticity in breeding date. Interactions between age, experience and environmental conditions have been reported previously for long-lived taxa. Our current results indicate that similar effects operate in a short-lived, temperate songbird. PMID- 17698489 TI - Sensorimotor experience enhances automatic imitation of robotic action. AB - Recent research in cognitive neuroscience has found that observation of human actions activates the 'mirror system' and provokes automatic imitation to a greater extent than observation of non-biological movements. The present study investigated whether this human bias depends primarily on phylogenetic or ontogenetic factors by examining the effects of sensorimotor experience on automatic imitation of non-biological robotic, stimuli. Automatic imitation of human and robotic action stimuli was assessed before and after training. During these test sessions, participants were required to execute a pre-specified response (e.g. to open their hand) while observing a human or robotic hand making a compatible (opening) or incompatible (closing) movement. During training, participants executed opening and closing hand actions while observing compatible (group CT) or incompatible movements (group IT) of a robotic hand. Compatible, but not incompatible, training increased automatic imitation of robotic stimuli (speed of responding on compatible trials, compared with incompatible trials) and abolished the human bias observed at pre-test. These findings suggest that the development of the mirror system depends on sensorimotor experience, and that, in our species, it is biased in favour of human action stimuli because these are more abundant than non-biological action stimuli in typical developmental environments. PMID- 17698490 TI - Parental prey selection affects risk-taking behaviour and spatial learning in avian offspring. AB - Early nutrition shapes life history. Parents should, therefore, provide a diet that will optimize the nutrient intake of their offspring. In a number of passerines, there is an often observed, but unexplained, peak in spider provisioning during chick development. We show that the proportion of spiders in the diet of nestling blue tits, Cyanistes caeruleus, varies significantly with the age of chicks but is unrelated to the timing of breeding or spider availability. Moreover, this parental prey selection supplies nestlings with high levels of taurine particularly at younger ages. This amino acid is known to be both vital and limiting for mammalian development and consequently found in high concentrations in placenta and milk. Based on the known roles of taurine in mammalian brain development and function, we then asked whether by supplying taurine-rich spiders, avian parents influence the stress responsiveness and cognitive function of their offspring. To test this, we provided wild blue tit nestlings with either a taurine supplement or control treatment once daily from the ages of 2-14 days. Then pairs of size- and sex-matched siblings were brought into captivity for behavioural testing. We found that juveniles that had received additional taurine as neonates took significantly greater risks when investigating novel objects than controls. Taurine birds were also more successful at a spatial learning task than controls. Additionally, those individuals that succeeded at a spatial learning task had shown intermediate levels of risk taking. Non-learners were generally very risk-averse controls. Early diet therefore has downstream impacts on behavioural characteristics that could affect fitness via foraging and competitive performance. Fine-scale prey selection is a mechanism by which parents can manipulate the behavioural phenotype of offspring. PMID- 17698491 TI - Improved model-based, platform-independent feature extraction for mass spectrometry. AB - MOTIVATION: Mass spectrometry (MS) is increasingly being used for biomedical research. The typical analysis of MS data consists of several steps. Feature extraction is a crucial step since subsequent analyses are performed only on the detected features. Current methodologies applied to low-resolution MS, in which features are peaks or wavelet functions, are parameter-sensitive and inaccurate in the sense that peaks and wavelet functions do not directly correspond to the underlying molecules under observation. In high-resolution MS, the model-based approach is more appealing as it can provide a better representation of the MS signals by incorporating information about peak shapes and isotopic distributions. Current model-based techniques are computationally expensive; various algorithms have been proposed to improve the computational efficiency of this paradigm. However, these methods cannot deal well with overlapping features, especially when they are merged to create one broad peak. In addition, no method has been proven to perform well across different MS platforms. RESULTS: We suggest a new model-based approach to feature extraction in which spectra are decomposed into a mixture of distributions derived from peptide models. By incorporating kernel-based smoothing and perceptual similarity for matching distributions, our statistical framework improves existing methodologies in terms of computational efficiency and the accuracy of the results. Our model is parameterized by physical properties and is therefore applicable to different MS instruments and settings. We validate our approach on simulated data, and show that the performance is higher than commonly used tools on real high- and low resolution MS, and MS/MS data sets. PMID- 17698492 TI - Expression ratio evaluation in two-colour microarray experiments is significantly improved by correcting image misalignment. AB - MOTIVATION: Two-colour microarrays are widely used to perform transcriptome analysis. In most cases, it appears that the 'red' and 'green' images resulting from the scan of a microarray slide are slightly shifted one with respect to the other. To increase the robustness of the measurement of the fluorescent emission intensities, multiple acquisitions with the same or different PMT gains can be used. In these cases, a systematic correction of image shift is required. RESULTS: To accurately detect this shift, we first developed an approach using cross-correlation. Second, we evaluated the most appropriate interpolation method to be used to derive the registered image. Then, we quantified the effects of image shifts on spot quality, using two different quality estimators. Finally, we measured the benefits associated with a systematic image registration. In this study, we demonstrate that registering the two images prior to data extraction provides a more reliable estimate of the two colours' ratio and thus increases the accuracy of measurements of variations in gene expression. AVAILABILITY: http://bioinfome.cgm.cnrs-gif.fr/. PMID- 17698493 TI - Learning string similarity measures for gene/protein name dictionary look-up using logistic regression. AB - MOTIVATION: One of the bottlenecks of biomedical data integration is variation of terms. Exact string matching often fails to associate a name with its biological concept, i.e. ID or accession number in the database, due to seemingly small differences of names. Soft string matching potentially enables us to find the relevant ID by considering the similarity between the names. However, the accuracy of soft matching highly depends on the similarity measure employed. RESULTS: We used logistic regression for learning a string similarity measure from a dictionary. Experiments using several large-scale gene/protein name dictionaries showed that the logistic regression-based similarity measure outperforms existing similarity measures in dictionary look-up tasks. AVAILABILITY: A dictionary look-up system using the similarity measures described in this article is available at http://text0.mib.man.ac.uk/software/mldic/. PMID- 17698494 TI - PhylArray: phylogenetic probe design algorithm for microarray. AB - MOTIVATION: Microbial diversity is still largely unknown in most environments, such as soils. In order to get access to this microbial 'black-box', the development of powerful tools such as microarrays are necessary. However, the reliability of this approach relies on probe efficiency, in particular sensitivity, specificity and explorative power, in order to obtain an image of the microbial communities that is close to reality. RESULTS: We propose a new probe design algorithm that is able to select microarray probes targeting SSU rRNA at any phylogenetic level. This original approach, implemented in a program called 'PhylArray', designs a combination of degenerate and non-degenerate probes for each target taxon. Comparative experimental evaluations indicate that probes designed with PhylArray yield a higher sensitivity and specificity than those designed by conventional approaches. Applying the combined PhyArray/GoArrays strategy helps to optimize the hybridization performance of short probes. Finally, hybridizations with environmental targets have shown that the use of the PhylArray strategy can draw attention to even previously unknown bacteria. PMID- 17698495 TI - pIPHULA--parallel inference of population parameters using a likelihood approach. AB - pIPHULA is the parallel program to estimate the parameters of a realistic model of population growth. PMID- 17698496 TI - PIB is a non-specific imaging marker of amyloid-beta (Abeta) peptide-related cerebral amyloidosis. AB - The in vivo imaging probe [11C]-PIB (Pittsburgh Compound B, N-methyl[11C]2-(4' methylaminophenyl-6-hydroxybenzathiazole) is under evaluation as a key imaging tool in Alzheimer's disease (AD) and to date has been assumed to bind with high affinity and specificity to the amyloid structures associated with classical plaques (CPs), one of the pathological hallmarks of the disease. However, no studies have systematically investigated PIB binding to human neuropathological brain specimens at the tracer concentrations achieved during in vivo imaging scans. Using a combination of autoradiography and histochemical techniques, we demonstrate that PIB, in addition to binding CPs clearly delineates diffuse plaques and cerebrovascular amyloid angiopathy (CAA). The interaction of PIB with CAA was not fully displaceable and this may be linked to the apolipoprotein E epsilon4 allele. PIB was also found to label neurofibrillary tangles, although the overall intensity of this binding was markedly lower than that associated with the amyloid-beta (Abeta) pathology. The data provide a molecular explanation for PIB's limited specificity in diagnosing and monitoring disease progression in AD and instead indicate that the ligand is primarily a non-specific marker of Abeta-peptide related cerebral amyloidosis. PMID- 17698497 TI - Anatomically related grey and white matter abnormalities in adolescent-onset schizophrenia. AB - Adolescent-onset schizophrenia provides an exceptional opportunity to explore the neuropathology of schizophrenia free from the potential confounds of prolonged periods of medication and disease interactions with age-related neurodegeneration. Our aim was to investigate structural grey and white matter abnormalities in adolescent-onset schizophrenia. Whole-brain voxel-wise investigation of both grey matter topography and white matter integrity (Fractional Anisotropy) were carried out on 25 adolescent-onset schizophrenic patients and 25 healthy adolescents. We employed a refined voxel-based morphometry-like approach for grey matter analysis and the recently introduced method of tract-based spatial statistics (TBSS) for white matter analysis. Both kinds of studies revealed widespread abnormalities characterized by a lower fractional anisotropy neuroanatomically associated with localized reduced grey matter in the schizophrenic group. The grey matter changes can either be interpreted as the result of a locally reduced cortical thickness or as a manifestation of different patterns of gyrification. There was a widespread reduction of anisotropy in the white matter, especially in the corpus callosum. We speculate that the anisotropy changes relate to the functional changes in brain connectivity that are thought to play a central role in the clinical expression of the disease. The distribution of grey matter changes was consistent with clinical features of the disease. For example, grey and white matter abnormalities found in the Heschl's gyrus, the parietal operculum, left Broca's area and the left arcuate fasciculus (similar to previous findings in adult-onset schizophrenia) are likely to relate to functional impairments of language and auditory perception. In addition, in contrast to earlier studies, we found striking abnormalities in the primary sensorimotor and premotor cortices and in white matter tracts susbserving motor control (mainly the pyramidal tract). This novel finding suggests a new potential marker of altered white matter maturation specific to adolescent-onset schizophrenia. Together, our observations suggest that the neuropathology of adolescent-onset schizophrenia involves larger and widespread changes than in the adult form, consistent with the greater clinical severity. PMID- 17698498 TI - Problems with causality. PMID- 17698499 TI - MeCP2 interacts with HP1 and modulates its heterochromatin association during myogenic differentiation. AB - There is increasing evidence of crosstalk between epigenetic modifications such as histone and DNA methylation, recognized by HP1 and methyl CpG-binding proteins, respectively. We have previously shown that the level of methyl CpG binding proteins increased dramatically during myogenesis leading to large-scale heterochromatin reorganization. In this work, we show that the level of HP1 isoforms did not change significantly throughout myogenic differentiation but their localization did. In particular, HP1gamma relocalization to heterochromatin correlated with MeCP2 presence. Using co-immunoprecipitation assays, we found that these heterochromatic factors interact in vivo via the chromo shadow domain of HP1 and the first 55 amino acids of MeCP2. We propose that this dynamic interaction of HP1 and MeCP2 increases their concentration at heterochromatin linking two major gene silencing pathways to stabilize transcriptional repression during differentiation. PMID- 17698500 TI - Protein p56 from the Bacillus subtilis phage phi29 inhibits DNA-binding ability of uracil-DNA glycosylase. AB - Protein p56 (56 amino acids) from the Bacillus subtilis phage 29 inactivates the host uracil-DNA glycosylase (UDG), an enzyme involved in the base excision repair pathway. At present, p56 is the only known example of a UDG inhibitor encoded by a non-uracil containing viral DNA. Using analytical ultracentrifugation methods, we found that protein p56 formed dimers at physiological concentrations. In addition, circular dichroism spectroscopic analyses revealed that protein p56 had a high content of beta-strands (around 40%). To understand the mechanism underlying UDG inhibition by p56, we carried out in vitro experiments using the Escherichia coli UDG enzyme. The highly acidic protein p56 was able to compete with DNA for binding to UDG. Moreover, the interaction between p56 and UDG blocked DNA binding by UDG. We also demonstrated that Ugi, a protein that interacts with the DNA-binding domain of UDG, was able to replace protein p56 previously bound to the UDG enzyme. These results suggest that protein p56 could be a novel naturally occurring DNA mimicry. PMID- 17698501 TI - Translational control of the interferon regulatory factor 2 mRNA by IRES element. AB - Translational control represents an important mode of regulation of gene expression under stress conditions. We have studied the translation of interferon regulatory factor 2 (IRF2) mRNA, a negative regulator of transcription of interferon-stimulated genes and demonstrated the presence of internal ribosome entry site (IRES) element in the 5'UTR of IRF2 RNA. Various control experiments ruled out the contribution of leaky scanning, cryptic promoter activity or RNA splicing in the internal initiation of IRF2 RNA. It seems IRF2-IRES function is not sensitive to eIF4G cleavage, since its activity was only marginally affected in presence of Coxsackievirus 2A protease. Interferon alpha treatment did not affect the IRF2-IRES activity or the protein level significantly. Also, in cells treated with tunicamycin [an agent causing endoplasmic reticulum (ER) stress], the IRF2-IRES activity and the protein levels were unaffected, although the cap dependent translation was severely impaired. Analysis of the cellular protein binding with the IRF2-IRES suggests certain cellular factors, which might influence its function under stress conditions. Interestingly, partial knockdown of PTB protein significantly inhibited the IRF2-IRES function. Taken together, it appears that IRF2 gene expression during stress condition is controlled by the IRES element, which in turn influences the cellular response. PMID- 17698502 TI - Autosomal-dominant distal myopathy with a myotilin S55F mutation: sorting out the phenotype. AB - OBJECTIVE: To describe the clinical phenotype of an autosomal-dominant pedigree with myotilinopathy. METHODS: Two symptomatic patients and six asymptomatic gene mutation carriers were examined. We performed serum chemistry, electrophysiological assessments, magnetic resonance imaging (MRI) of lower limb musculature, histochemical and immunohistochemical studies of a muscle biopsy and mutation analysis of the myotilin gene. RESULTS: Both symptomatic patients, aged 76 and 61 years, presented with late-onset, distal lower-limb weakness involving the ankle and toe flexo-extensor muscles extending up to the thigh muscles; there was mild weakness of the intrinsic hand musculature in the eldest patient. Electromyography revealed a myopathic pattern. Serum creatine kinase levels were slightly elevated. Muscle biopsy revealed myopathic changes with myotilin- and desmin-positive aggregates. Gene sequencing identified a myotilin S55F mutation. In both patients, MRI showed moderate to severe fatty atrophy of all four leg muscle compartments, extending up to the thigh musculature, mainly involving the biceps, femoris, semimembranosus, vasti and glutei muscles; intrinsic foot musculature was involved but to a lesser degree. In all six gene mutation carriers, aged from 21 to 63 years, clinical examinations showed no myopathic signs. MRI was normal in the youngest individual, whereas in the remaining five individuals the outstanding finding was fatty infiltration of the soleus muscles. CONCLUSIONS: Myotilin S55F mutations may cause a clinically distinct autosomal dominant late-onset and lower-limb distal myopathic syndrome involving all four leg muscle compartments. MRI helps to reliably depict the topography of fatty muscle atrophy and to detect early leg muscle changes in asymptomatic gene mutation carriers. PMID- 17698503 TI - Neurological care and risk of hospital mortality for patients with myasthenia gravis in England. AB - BACKGROUND: Myasthenia gravis (MG) is a rare neurological disorder, which can be life threatening. Although death is a rare outcome, evidence does not exist as to whether neurological care leads to any better outcome than care by other specialties. METHODS: A matched nested case control study sampled from all public sector hospital admissions in England with a primary diagnosis of MG from 1991 to 1999. Cases were defined as MG admissions which resulted in death and controls were other MG admissions, matched on sex, age (+/-2 years) and date of admission (+/-20 days) that were non-fatal. From a total of 18 251 finished consultant episodes with a mention of MG, we were able to create 196 matched sets with 196 fatal admissions and 788 control admissions. RESULTS: Admission under a neurologist was associated with a 69% reduced risk of death (OR 0.31, 95% CI 0.22 to 0.44; p<0.001). This was only slightly attenuated after adjustment for a variety of patient related and hospital covariates (OR 0.37, 95% CI 0.23 to 0.62; p<0.001). CONCLUSIONS: This is the first evidence that patients admitted with MG are far less likely to die if they are under the care of a neurologist. We cannot determine whether this is because of better management per se or because neurologists are usually based in specialist centres and may have better intensive care support, or both. Alternatively, this may be a result of "selection bias" so that neurologists select less seriously ill patients. PMID- 17698504 TI - Short duration of sleep and unintentional injuries among adolescents in China. AB - Using a population-based cross-sectional health survey, the authors investigated the association between nightly duration of sleep and unintentional injuries among high school students in Nanning, China. The survey utilized a two-stage random cluster-sampling design. In March 2005, adolescents aged 13-17 years were recruited from students attending the first 3 years of high school in Nanning. Sleep duration was measured by self-reported usual times of going to bed and rising during a normal school week. Unintentional injury was assessed via a structured personal interview. Data were analyzed using multinomial logistic regression with adjustment for the effects of cluster sampling. After adjustment for potentially confounding factors, adolescents who slept less than 7 hours per night during a normal school week were approximately two times more likely to have experienced multiple episodes of unintentional injury during the 3-month pre survey period (odds ratio = 2.2, 95% confidence interval: 1.1, 4.8) than those who slept 7 hours or more (p < 0.05). There was also a nonsignificantly (p > 0.05) increased risk of single injury for adolescents with short sleep durations (odds ratio = 1.5, 95% confidence interval: 0.9, 2.3). Findings suggest that a short nightly duration of sleep can be considered a potential risk factor for multiple unintentional injuries among adolescents. PMID- 17698505 TI - Differential dietary nutrient intake according to hormone replacement therapy use: an underestimated confounding factor in epidemiologic studies? AB - Observational studies and randomized controlled trials have produced divergent results concerning the effect of hormone replacement therapy (HRT) on cardiovascular disease and, to a lesser extent, dementia. Residual confounding (confounding that remains even after adjustment for various socioeconomic and lifestyle factors) is one explanation that has been offered for these divergent results. The authors used data collected between 1990 and 1995 from 6,697 French women aged 61-72 years participating in a prospective cohort study to explore the hypothesis that nutritional intake varies according to HRT use and thus may be a source of residual confounding. After the authors adjusted for health and lifestyle factors, HRT users, compared with never users, had significantly higher intakes of alcohol; omega3 fatty acids; vitamins B6, B12, and D; and phosphorus and a lower intake of starch. These differential nutrient intakes were related to differences in eating habits. In particular, HRT users in the studied sample, compared with nonusers, ate significantly more fish. Most of the dietary differences were seen in both early users and delayers of HRT. To limit residual confounding in observational studies, dietary factors may be important parameters to be taken into account in analyses of HRT use and health outcomes. PMID- 17698506 TI - Self-reported racial discrimination and substance use in the Coronary Artery Risk Development in Adults Study. AB - The authors investigated whether substance use and self-reported racial discrimination were associated in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Smoking status, alcohol consumption, and lifetime use of marijuana, amphetamines, and opiates were ascertained in 2000-2001, 15 years after baseline (1985-1986). Most of the 1,507 African Americans reported having experienced racial discrimination, 79.5% at year 7 and 74.6% at year 15, compared with 29.7% and 23.7% among the 1,813 Whites. Compared with African Americans experiencing no discrimination, African Americans reporting any discrimination had more education and income, while the opposite was true for Whites (all p < 0.001). African Americans experiencing racial discrimination in at least three of seven domains in both years had 1.87 (95% confidence interval (CI): 1.18, 2.96) and 2.12 (95% CI: 1.42, 3.17) higher odds of reporting current tobacco use and having any alcohol in the past year than did their counterparts experiencing no discrimination. With control for income and education, African Americans reporting discrimination in three or more domains in both years had 3.31 (95% CI: 1.90, 5.74) higher odds of using marijuana 100 or more times in their lifetime, relative to African Americans reporting no discrimination. These associations were similarly positive in Whites but not significant. Substance use may be an unhealthy coping response to perceived unfair treatment for some individuals, regardless of their race/ethnicity. PMID- 17698507 TI - The role of tumor necrosis factor alpha in lipopolysaccharide/ranitidine-induced inflammatory liver injury. AB - Exposure to a nontoxic dose of bacterial lipopolysaccharide (LPS) increases the hepatotoxicity of the histamine-2 (H2) receptor antagonist, ranitidine (RAN). Because some of the pathophysiologic effects associated with LPS are mediated through the expression and release of inflammatory mediators such as tumor necrosis factor alpha (TNF), this study was designed to gain insights into the role of TNF in LPS/RAN hepatotoxicity. To determine whether RAN affects LPS induced TNF release at a time near the onset of liver injury, male Sprague-Dawley rats were treated with 2.5 x 10(6) endotoxin units (EU)/kg LPS or its saline vehicle (iv) and 2 h later with either 30 mg/kg RAN or sterile phosphate-buffered saline vehicle (iv). LPS administration caused an increase in circulating TNF concentration. RAN cotreatment enhanced the LPS-induced TNF increase before the onset of hepatocellular injury, an effect that was not produced by famotidine, a H2-receptor antagonist without idiosyncrasy liability. Similar effects were observed for serum interleukin (IL)-1beta, IL-6, and IL-10. To determine if TNF plays a causal role in LPS/RAN-induced hepatotoxicity, rats were given either pentoxifylline (PTX; 100 mg/kg, iv) to inhibit the synthesis of TNF or etanercept (Etan; 8 mg/kg, sc) to impede the ability of TNF to reach cellular receptors, and then they were treated with LPS and RAN. Hepatocellular injury, the release of inflammatory mediators, hepatic neutrophil (PMN) accumulation, and biomarkers of coagulation and fibrinolysis were assessed. Pretreatment with either PTX or Etan resulted in the attenuation of liver injury and diminished circulating concentrations of TNF, IL-1beta, IL-6, macrophage inflammatory protein-2, and coagulation/fibrinolysis biomarkers in LPS/RAN-cotreated animals. Neither PTX nor Etan pretreatments altered hepatic PMN accumulation. These results suggest that TNF contributes to LPS/RAN-induced liver injury by enhancing inflammatory cytokine production and hemostasis. PMID- 17698508 TI - Toxicogenomics of drug-induced hemolytic anemia by analyzing gene expression profiles in the spleen. AB - Hemolytic anemia is a serious adverse effect of therapeutic drugs that is caused by increased destruction of drug-damaged erythrocytes by macrophages in the spleen and liver. We previously applied a toxicogenomic approach to the toxicity by analyzing microarray data of the liver of rats dosed with two hemolytic agents: phenylhydrazine and phenacetin. In the present study, we analyzed gene expression profiles in the spleen, the primary organ for destruction of damaged erythrocytes, of the same models in order to identify splenic gene expression alterations that could be used to predict the hematotoxicity. Microarray analyses revealed hundreds of genes commonly deregulated under all severe hemolytic conditions, which included genes related to splenic events characteristic of the hematotoxicity, such as proteolysis and iron metabolism. Eleven upregulated genes were selected as biomarker candidates, and their expression changes were validated by quantitative real-time PCR. The transcript levels of most of these genes showed strong correlation with the results of classical toxicological assays (e.g., histopathology and hematology). Furthermore, hierarchical clustering analysis suggested that altered expression patterns of the 11 genes sensitively reflected the erythrocyte damage even under a condition that caused no decrease in erythrocyte counts. Among the selected genes, heme oxygenase 1 was one of the most promising biomarker candidates, the upregulation of which on the protein level was confirmed by immunohistochemistry. These results indicate that altered splenic expression of a subset of genes may allow detection of drug induced hemolytic anemia, with better sensitivity than that of erythrocyte counts in the blood. PMID- 17698509 TI - Xenobiotic transporters: ascribing function from gene knockout and mutation studies. AB - Transporter-mediated absorption, secretion, and reabsorption of chemicals are increasingly recognized as important determinants in the biological activities of many xenobiotics. In recent years, the rapid progress in generating and characterizing mice with targeted deletion of transporters has greatly increased our knowledge of the functions of transporters in the pharmacokinetics/toxicokinetics of xenobiotics. In this introduction, we focus on functions of transporters learned from experiments on knockout mice as well as humans and rodents with natural mutations of these transporters. We limit our discussion to transporters that either directly transport xenobiotics or are important in biliary excretion or cellular defenses, namely multidrug resistance, multidrug resistance-associated proteins, breast cancer resistance protein, organic anion transporting polypeptides, organic anion transporters, organic cation transporters, nucleoside transporters, peptide transporters, bile acid transporters, cholesterol transporters, and phospholipid transporters, as well as metal transporters. Efflux transporters in intestine, liver, kidney, brain, testes, and placenta can efflux xenobiotics out of cells and serve as barriers against the entrance of xenobiotics into cells, whereas many xenobiotics enter the biological system via uptake transporters. The functional importance of a given transporter in each tissue depends on its substrate specificity, expression level, and the presence/absence of other transporters with overlapping substrate preferences. Nevertheless, a transporter may affect a tissue independent of its local expression by altering systemic metabolism. Further studies on the gene regulation and function of transporters, as well as the interrelationship between transporters and phase I/II xenobiotic-metabolizing enzymes, will provide a complete framework for developing novel strategies to protect us from xenobiotic insults. PMID- 17698510 TI - microRNAs in adult rodent liver are refractory to dioxin treatment. AB - Dioxin-like chemicals are well known for their ability to upregulate expression of numerous genes via the AH receptor (AHR). However, recent transcriptomic analyses in several laboratories indicate that dioxin-like chemicals or AHR genotype itself also can downregulate levels of mRNAs encoded by numerous genes. The mechanism responsible for such downregulation is unknown. We hypothesized that microRNAs (miRNAs), which have emerged as powerful negative regulators of mRNA levels in several systems, might be responsible for mRNA downregulation in dioxin/AHR pathways. We used two miRNA array platforms as well as quantitative reverse transcriptase-polymerase chain reaction to measure miRNA levels in wild type (WT) versus Ahr-null mice, in dioxin-sensitive Long-Evans (L-E; Turku/AB) rats versus dioxin-resistant Han/Wistar (H/W; Kuopio) rats and in rat 5L and mouse Hepa-1 hepatoma cells in culture. Treatment with 2,3,7,8-tetrachlorodibenzo p-dioxin (TCDD) in vivo caused few changes in miRNA levels in mouse or rat livers, and those changes that were statistically significant were of modest magnitude. Hepatoma cells in culture also exhibited few changes in miRNA levels in response to TCDD. AHR genotype had little effect on hepatic miRNA levels, either in constitutive expression or in response to TCDD-only a few miRNAs differed in expression between Ahr-null mice compared to mice with WT AHR or between L-E rats (that have WT AHR) compared to H/W rats (whose AHR has a large deletion in the transactivation domain). It is unlikely that mRNA downregulation by dioxins is mediated by miRNAs, nor are miRNAs likely to play a significant role in dioxin toxicity in adult rodent liver. PMID- 17698511 TI - Aging pathways for organophosphate-inhibited human butyrylcholinesterase, including novel pathways for isomalathion, resolved by mass spectrometry. AB - Some organophosphorus compounds are toxic because they inhibit acetylcholinesterase (AChE) by phosphylation of the active site serine, forming a stable conjugate: Ser-O-P(O)-(Y)-(XR) (where X can be O, N, or S and Y can be methyl, OR, or SR). The inhibited enzyme can undergo an aging process, during which the X-R moiety is dealkylated by breaking either the P-X or the X-R bond depending on the specific compound, leading to a nonreactivatable enzyme. Aging mechanisms have been studied primarily using AChE. However, some recent studies have indicated that organophosphate-inhibited butyrylcholinesterase (BChE) may age through an alternative pathway. Our work utilized matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry to study the aging mechanism of human BChE inhibited by dichlorvos, echothiophate, diisopropylfluorophosphate (DFP), isomalathion, soman, sarin, cyclohexyl sarin, VX, and VR. Inhibited BChE was aged in the presence of H2O18 to allow incorporation of (18)O, if cleavage was at the P-X bond. Tryptic-peptide organophosphate conjugates were identified through peptide mass mapping. Our results showed no aging of VX- and VR-treated BChE at 25 degrees C, pH 7.0. However, BChE inhibited by dichlorvos, echothiophate, DFP, soman, sarin, and cyclohexyl sarin aged exclusively through O-C bond cleavage, i.e., the classical X-R scission pathway. In contrast, isomalathion aged through both X-R and P-X pathways; the main aged product resulted from P-S bond cleavage and a minor product resulted from O-C and/or S-C bond cleavage. PMID- 17698512 TI - Proteomic analysis of rat striatal synaptosomes during acrylamide intoxication at a low dose rate. AB - We have hypothesized that acrylamide (ACR) intoxication causes cumulative nerve terminal damage by forming adducts with nucleophilic cysteine sulfhydryl groups on critical presynaptic proteins. To determine the cumulative effects of ACR on the cysteine-containing proteome of nerve terminal, we employed cleavable isotope coded affinity tagging (ICAT) and liquid chromatography-tandem mass spectrometry. ICAT analysis uses a sulfhydryl-specific tag to identify and quantitate cysteine containing proteins. Synaptosomes were prepared from striatum of ACR-intoxicated rats (21 mg/kg/day x 7, 14, or 21 days) and their age-matched controls. The synaptosomal proteins of each experimental group were labeled with either light (12C9--control) or heavy (13C9--ACR) ICAT reagent. Results show that ACR intoxication caused a progressive reduction in the ICAT labeling of many nerve terminal proteins. A label-free mass spectrometric approach (multidimensional protein identification) was used to show that the observed reductions in ICAT incorporation were not due to general changes in protein abundance and that ACR formed adducts with cysteine residues on peptides which also exhibited reduced ICAT incorporation. The decrease in labeling was temporally correlated to the development of neurological toxicity and confirmed previous findings that cysteine adducts of ACR accumulate as a function of exposure. The accumulation of adduct is consistent with the cumulative neurotoxicity induced by ACR and suggests that cysteine adduct formation is a necessary neuropathogenic step. Furthermore, our analyses identified specific proteins (e.g., v-ATPase, dopamine transporter, N-ethylmaleimide-sensitive factor) that were progressively and significantly adducted by ACR and might, therefore, be neurotoxicologically relevant targets. PMID- 17698513 TI - Thimerosal-induced apoptosis in human SCM1 gastric cancer cells: activation of p38 MAP kinase and caspase-3 pathways without involvement of [Ca2+]i elevation. AB - Thimerosal is a mercury-containing preservative in some vaccines. The effect of thimerosal on human gastric cancer cells is unknown. This study shows that in cultured human gastric cancer cells (SCM1), thimerosal reduced cell viability in a concentration- and time-dependent manner. Thimerosal caused apoptosis as assessed by propidium iodide-stained cells and caspase-3 activation. Although immunoblotting data revealed that thimerosal could activate the phosphorylation of extracellular signal-regulated kinase, c-Jun NH2-terminal protein kinase, and p38 mitogen-activated protein kinase (p38 MAPK), only SB203580 (a p38 MAPK inhibitor) partially prevented cells from apoptosis. Thimerosal also induced [Ca2+](i) increases via Ca2+ influx from the extracellular space. However, pretreatment with (bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetate)/AM, a Ca2+ chelator, to prevent thimerosal-induced [Ca2+](i) increases did not protect cells from death. The results suggest that in SCM1 cells, thimerosal caused Ca2+ independent apoptosis via phosphorylating p38 MAPK resulting in caspase-3 activation. PMID- 17698514 TI - Quantitative comparisons of the acute neurotoxicity of toluene in rats and humans. AB - The behavioral and neurophysiological effects of acute exposure to toluene are the most thoroughly explored of all the hydrocarbon solvents. Behavioral effects have been experimentally studied in humans and other species, for example, rats. The existence of both rat and human dosimetric data offers the opportunity to quantitatively compare the relative sensitivity to acute toluene exposure. The purpose of this study was to fit dose-effect curves to existing data and to estimate the dose-equivalence equation (DEE) between rats and humans. The DEE gives the doses that produce the same magnitude of effect in the two species. Doses were brain concentrations of toluene estimated from physiologically based pharmacokinetic models. Human experiments measuring toluene effects on choice reaction time (CRT) were meta-analyzed. Rat studies employed various dependent variables: amplitude of visual-evoked potentials (VEPs), signal detection (SIGDET) accuracy (ACCU) and reaction time (RT), and escape-avoidance (ES-AV) behaviors. Comparison of dose-effect functions showed that human and rat sensitivity was practically the same for those two task regimens that exerted the least control over the behaviors being measured (VEP in rats and CRT in humans) and the sensitivity was progressively lower for SIGDET RT, SIGDET ACCU, and ES-AV behaviors in rats. These results suggested that the sensitivity to impairment by toluene depends on the strength of control over the measured behavior rather than on the species being tested. This interpretation suggests that (1) sensitivity to toluene would be equivalent in humans and rats if both species performed behaviors that were controlled to the same extent, (2) the most sensitive tests of neurobehavioral effects would be those in which least control is exerted on the behavior being measured, and (3) effects of toluene in humans may be estimated using the DEEs from rat studies despite differences in the amount of control exerted by the experimental regimen or differences in the behaviors under investigation. PMID- 17698515 TI - High dietary inorganic phosphate affects lung through altering protein translation, cell cycle, and angiogenesis in developing mice. AB - Inorganic phosphate (Pi) plays a key role in diverse physiological functions. Several studies indicate that Pi may affect lung cell development through Na/Pi cotransporter (NPT). Several NPT subtypes have been identified in mammalian lung, and considerable progress has been made in our understanding of their function and regulation. Therefore, current study was performed to elucidate the potential effects of high dietary Pi on lungs of developing mice. Our results clearly demonstrate that high dietary Pi may affect the lung of developing mice through Akt-related cap-dependent protein translation, cell cycle regulation, and angiogenesis. Our results support the hypothesis that Pi works as a critical signal molecule for normal lung growth and suggest that careful restriction of Pi consumption may be important in maintaining a normal development. PMID- 17698516 TI - Cystic intraventricular solitary fibrous tumor. PMID- 17698517 TI - Bovine aortic arch. PMID- 17698518 TI - Noninvasive imaging of treated cerebral aneurysms, Part II: CT angiographic follow-up of surgically clipped aneurysms. AB - Although not useful for the evaluation of coiled aneurysms, CT angiography (CTA) is far superior to MR angiography (MRA) for the evaluation of aneurysms after surgical clipping. Using the latest multidetector row scanners and optimized imaging parameters, CTA can often effectively depict and follow small aneurysm remnants; demonstrate patency, stenosis, or vasospasm in the adjacent parent vessels; and provide surveillance of the entire cerebrovasculature for de novo aneurysms after surgical clipping. Despite these advances, conventional angiography remains the gold standard for the evaluation of surgically treated aneurysms and should be liberally used to resolve any cases of diagnostic uncertainty on noninvasive imaging. PMID- 17698520 TI - Cranial ultrasound in metabolic disorders presenting in the neonatal period: characteristic features and comparison with MR imaging. AB - BACKGROUND AND PURPOSE: Brain imaging is an integral part of the diagnostic work up for metabolic disorders, and the bedside availability of cranial ultrasonography (cUS) allows very early brain imaging in symptomatic neonates. Our aim was to investigate the role and range of abnormalities seen on cUS in neonates presenting with metabolic disorders. A secondary aim, when possible, was to address the question of whether brain MR imaging is more informative by comparing cUS to MR imaging findings. MATERIALS AND METHODS: Neonates with a metabolic disorder who had at least 1 cUS scan were eligible. cUS images were reviewed for anatomic and maturation features, cysts, calcium, and other abnormalities. When an MR imaging scan had been obtained, both sets of images were compared. RESULTS: Fifty-five infants (35 also had MR imaging) were studied. The most frequent findings were in oxidative phosphorylation disorders (21 cUS and 12 MR imaging): ventricular dilation (11 cUS and 6 MR imaging), germinolytic cysts (GLCs; 7 cUS and 5 MR imaging), and abnormal white matter (7 cUS and 6 MR imaging); in peroxisomal biogenesis disorders (13 cUS and 9 MR imaging): GLCs (10 cUS and 6 MR imaging), ventricular dilation (10 cUS and 5 MR imaging), abnormal cortical folding (8 cUS and 7 MR imaging), and lenticulostriate vasculopathy (8 cUS); in amino acid metabolism and urea cycle disorders (14 cUS and 11 MR imaging): abnormal cortical folding (9 cUS and 4 MR imaging), abnormal white matter (8 cUS and 8 MR imaging), and hypoplasia of the corpus callosum (7 cUS and 6 MR imaging); in organic acid disorders (4 cUS and 2 MR imaging): periventricular white matter echogenicity (2 cUS and 1 MR imaging); and in other disorders (3 cUS and 1 MR imaging): ventricular dilation (2 cUS and 1 MR imaging). cUS findings were consistent with MR imaging findings. cUS was better for visualizing GLCs and calcification. MR imaging was more sensitive for subtle tissue signal intensity changes in the white matter and abnormality in areas difficult to visualize with cUS, though abnormalities of cortical folding suggestive of polymicrogyria were seen on cUS. CONCLUSION: A wide range of abnormalities is seen using cUS in neonatal metabolic disorders. cUS is a reliable bedside tool for early detection of cysts, calcium, structural brain abnormalities, and white matter echogenicity, all suggestive of metabolic disorders. PMID- 17698519 TI - Diffusion tensor imaging in children with periventricular leukomalacia: variability of injuries to white matter tracts. AB - BACKGROUND AND PURPOSE: Conventional MR imaging shows evidence of brain injury and/or maldevelopment in 70%-90% of children with cerebral palsy (CP), though its capability to identify specific white matter tract injury is limited. The great variability of white matter lesions in CP already demonstrated by postmortem studies is thought to be one of the reasons why response to treatment is so variable. Our hypothesis is that diffusion tensor imaging (DTI) is a suitable technique to provide in vivo characterization of specific white matter tract lesions in children with CP associated with periventricular leukomalacia (PVL). MATERIALS AND METHODS: In this study, 24 children with CP associated with PVL and 35 healthy controls were evaluated with DTI. Criteria for identification of 26 white matter tracts on the basis of 2D DTI color-coded maps were established, and a qualitative scoring system, based on visual inspection of the tracts in comparison with age-matched controls, was used to grade the severity of abnormalities. An ordinal grading system (0=normal, 1=abnormal, 2=severely abnormal or absent) was used to score each white matter tract. RESULTS: There was marked variability in white matter injury pattern in patients with PVL, with the most frequent injury to the retrolenticular part of the internal capsule, posterior thalamic radiation, superior corona radiata, and commissural fibers. CONCLUSION: DTI is a suitable technique for in vivo assessment of specific white matter lesions in patients with PVL and, thus, a potentially valuable diagnostic tool. The tract-specific evaluation revealed a family of tracts that are highly susceptible in PVL, important information that can potentially be used to tailor treatment options in the future. PMID- 17698521 TI - Assessing disease severity in late infantile neuronal ceroid lipofuscinosis using quantitative MR diffusion-weighted imaging. AB - BACKGROUND AND PURPOSE: Late infantile neuronal ceroid lipofuscinosis (LINCL), a form of Batten disease, is a fatal neurodegenerative genetic disorder, diagnosed via DNA testing, that affects approximately 200 children in the United States at any one time. This study was conducted to evaluate whether quantitative data derived by diffusion-weighted MR imaging (DWI) techniques can supplement clinical disability scale information to provide a quantitative estimate of neurodegeneration, as well as disease progression and severity. MATERIALS AND METHODS: This study prospectively analyzed 32 DWI examinations from 18 patients having confirmed LINCL at various stages of disease. A whole-brain apparent diffusion coefficient (ADC) histogram was fitted with a dual Gaussian function combined with a function designed to model voxels containing a partial volume fraction of brain parenchyma versus CSF. Previously published whole-brain ADC values of age-matched control subjects were compared with those of the LINCL patients. Correlations were tested between the peak ADC of the fitted histogram and patient age, disease severity, and a CNS disability scale adapted for LINCL. RESULTS: ADC values assigned to brain parenchyma were higher than published ADC values for age-matched control subjects. ADC values between patients and control subjects began to differ at 5 years of age based on 95% confidence intervals. ADC values had a nearly equal correlation with patient age (R2=0.71) and disease duration (R2=0.68), whereas the correlation with the central nervous system disability scale (R2=0.27) was much weaker. CONCLUSION: This study indicates that brain ADC values acquired using DWI may be used as an independent measure of disease severity and duration in LINCL. PMID- 17698522 TI - Changes in T2 relaxation times associated with maturation of the human intervertebral disk. AB - BACKGROUND AND PURPOSE: By calculating T2 relaxation times for intervertebral disks, we tested the hypothesis that disk water concentration increases between the first and second decades of life. MATERIALS AND METHODS: In subjects younger than 10 years old (group 1) and subjects between 19 and 20 years old (group 2), a sagittal MR image of the lumbar spine was obtained with a modified 3D fast spin echo (FSE) multi-echo sequence. T2 relaxation times for each voxel were calculated by fitting a logarithmic regression to the signal intensity in images at 16 different echo times. T2 times were averaged for each spinal disk in each group and differences tested for statistical significance by analysis of variance (ANOVA). T2 times along the vertical axis of the disk at the midline were plotted and inspected for evidence of a central lower signal intensity region (CLSIR) in the 2 groups. We tested the differences between groups for significance with the Student t test. RESULTS: Maps of T2 relaxation times showed different patterns in groups 1 and 2. The mean T2 relaxation times in each disk level in group 1 ranged from 74-95 ms and in group 2, from 91-119 ms. Differences between the 2 groups were significant (P<.001, ANOVA, P=.0002, Student t test of means); differences between levels were not. In group 2, development of a CLSIR was significantly more common than in group 1 (P=.0001, Student t test). CONCLUSIONS: T2 increases in the intervertebral disk between the first and second decades of life. PMID- 17698523 TI - Spinal epidural hemangiomas: various types of MR imaging features with histopathologic correlation. AB - BACKGROUND AND PURPOSE: Because of the high vascularization of hemangiomas, preoperative misinterpretation may result in unexpected intraoperative hemorrhage and incomplete resection, which results in the persistence of clinical symptoms or recurrence. Our purpose was to analyze various MR imaging features of a spinal epidural hemangioma with histopathologic correlation. MATERIALS AND METHODS: After searching through the pathology data bases in 3 hospitals, we included 14 patients (9 male and 5 female; mean age, 38 years; age range, 2-62 years) with spinal epidural hemangiomas confirmed by surgical resection after MR imaging. Three radiologists reviewed the MR imaging in consensus and categorized the features into subtypes on the basis of histopathologic findings. RESULTS: We categorized the MR imaging features as follows: type A for a cystlike mass with T1 hyperintensity (2 cases, arteriovenous type with an organized hematoma), type B for a cystlike mass with T1 isointensity (3 cases, venous type), type C for a solid hypervascular mass (7 cases, cavernous type), and type D for an epidural hematoma (2 cases, cavernous type with hematoma). Types A and B had frequent single segmental involvement (4/5), whereas types C and D had multisegmental involvement in all. Regardless of MR types, lobular contour (8/14) and a rim of low T2 signal intensity (8/14) of the mass were common. T1 hyperintensity of the mass was occasionally seen (5/14). CONCLUSIONS: Spinal epidural hemangiomas can have various MR imaging features according to their different histopathologic backgrounds. In addition to common features such as solid hypervascularity, lobular contour, and a rim of low T2 signal intensity, T1 hyperintensity or multisegmental involvement may also be a clue in the differential diagnosis of a spinal epidural hemangioma. PMID- 17698524 TI - Value and limitations of contrast-enhanced MR angiography in spinal arteriovenous malformations and dural arteriovenous fistulas. AB - BACKGROUND AND PURPOSE: The purpose of this work was to study the validity of MR angiography (MRA) for identification of spinal arteriovenous (AV) abnormalities. MATERIALS AND METHODS: Thirty-four consecutive patients with suspicion of spinal vascular abnormalities underwent digital subtraction angiography (DSA) after MRA. The level and side of the suspected spinal dural arteriovenous fistula (SDAVF) and the feeding arteries in spinal arteriovenous malformations (SAVMs) were determined from the MRA and compared with DSA. RESULTS: DSA revealed SDAVF in 20 abnormalities of which 19 were spinal and 1 was tentorial with spinal drainage, as well as SAVM in 11 patients. In 3 patients, MRA and DSA were both normal. For detection of spinal arteriovenous abnormalities, neither false-positive nor false negative MRA results were obtained. The MRA-derived level of the feeding artery in SDAVF agreed with DSA in 14 of 19 cases. In 5 cases, a mismatch of 1 vertebral level (not side) was noted for the feeding artery. For the tentorial AVF, only the spinal drainage was depicted; the feeding artery was outside the MRA field of view. In intradural SAVM, the main feeding artery was identified by MRA in 10 of 11 patients. MRA could differentiate between glomerular and fistulous SAVM in 4 of 6 cases and between sacral SDAVF and filum terminale SAVM in 2 of 5 cases. CONCLUSIONS: MRA reliably detects or excludes various types of spinal AV abnormalities and localizes the (predominant) arterial feeder of most spinal AV shunts. Although classification of the subtype of SAVMs remains difficult, with MRA it greatly helps to focus subsequent DSA. PMID- 17698525 TI - Pain improvement after intradiskal lidocaine administration in provocation lumbar diskography: association with diskographic contrast leakage. AB - BACKGROUND AND PURPOSE: Our aim was to evaluate the relationship of pain reduction, after intradiskal lidocaine administration during provocation lumbar diskography, to the presence of contrast leakage on postdiskographic imaging. MATERIALS AND METHODS: Intradiskal lidocaine was injected at 182 significantly painful disk levels in 111 patients. The clinical records and imaging studies were reviewed for response to the lidocaine injection and for the presence/absence of diskographic contrast leakage on postdiskographic images and CT. Pain response was assigned the following grades: 1) complete or substantial improvement, 2) partial improvement, or 3) no significant improvement after lidocaine administration. Fluoroscopic imaging and postdiskographic CT were evaluated for the presence or absence of contrast leakage. RESULTS: Eighty-two (45%) significantly painful treated disks were contained, and 100 (55%) demonstrated contrast leakage. In leaking disks, 74 (74%) demonstrated complete or near-complete pain reduction after lidocaine administration, 15 (15%) demonstrated partial improvement, and 11 (11%) demonstrated no pain relief. In contained disks, 56 disks (69%) demonstrated no improvement after lidocaine administration, 9 (11%) demonstrating partial relief, and 17 (20%) demonstrated complete or substantial improvement. Results comparing leaking disks versus contained disks and complete versus no improvement were statistically significant (P<.001). CONCLUSION: Painful disks exhibiting diskographic leakage tend to be highly responsive to intradiskal lidocaine administration, whereas painful disks without diskographic leakage tend not to improve. This observation has implications with respect to targeting the origin of a patient's back pain and may have specific implications with respect to choice of treatment. PMID- 17698526 TI - Sacroplasty versus vertebroplasty: comparable clinical outcomes for the treatment of fracture-related pain. AB - BACKGROUND AND PURPOSE: Little is known about the long-term clinical outcomes of sacroplasty, a relatively new minimally invasive percutaneous procedure for the treatment of sacral insufficiency fractures. The first purpose of the present study, therefore, was to investigate the effects of sacroplasty on pain, mobility, and activities of daily living (ADLs). A second purpose was to compare clinical outcomes of sacroplasty with those of vertebroplasty, a similar but more established procedure. MATERIALS AND METHODS: A retrospective case series of 12 patients who had a sacroplasty and a control group of 21 patients who had undergone a vertebroplasty was conducted. A 12-item questionnaire and subsequent telephone interview requested each patient to rate the intensity of pain, as well as the ability to ambulate and perform ADLs, before sacroplasty or vertebroplasty, and at the time of the interview. RESULTS: There was a statistically significant decrease in overall self-reported pain, as well as an increase in self-reported ability to ambulate and perform ADLs after sacroplasty or vertebroplasty. These improvements were equivalent, regardless of which procedure the patient received. CONCLUSION: The present study suggests that the treatment of sacral insufficiency fractures with sacroplasty produces relatively long-lasting improvements in pain, mobility, and the ability to perform ADLs. These data also suggest that the clinical outcomes of sacroplasty are comparable with those of vertebroplasty, an accepted and more routinely performed procedure. PMID- 17698527 TI - MR diffusion tensor imaging and fiber tracking in spinal cord arteriovenous malformations: a preliminary study. AB - BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) of the spinal cord in patients harboring spinal arteriovenous malformations (AVMs) was carried out to evaluate the feasibility of this new technique to determine the displacement of the spinal cord tracts and to correlate morphologic and functional DTI data (fractional anisotropy [FA] and apparent diffusion coefficient [ADC]) with the clinical symptoms. MATERIALS AND METHODS: Nine patients with spinal cord AVMs were investigated at 1.5T using a sagittal spin-echo single-shot echo-planar generalized autocalibrating partially parallel acquisition diffusion-weighted imaging sequence. ADC and FA maps were computed in different regions of interest (both above and below the nidus), and tractography was used to visualize the course of the tracts. The data were correlated with the clinical symptoms and compared with 12 healthy control subjects. RESULTS: At the level of the nidus, tracts were normal, shifted, separated, or interrupted but not intermingled with the nidus. Interruption of the tracts was coherent with the clinical symptoms. In patients with severe neurologic deficits, FA values caudal to the nidus showed a reduced anisotropy consistent with loss of white matter tracts. CONCLUSIONS: We demonstrate that AVMs may interrupt, displace, or separate the fiber tracts and that clinical symptoms may be reflected by the quantitative FA results and the morphologic loss of fibers distant to the lesion. DTI with fiber tracking offers a novel approach to image spinal cord AVMs and may open a window to understand the complex pathophysiology of these lesions. PMID- 17698528 TI - High-resolution contrast-enhanced, susceptibility-weighted MR imaging at 3T in patients with brain tumors: correlation with positron-emission tomography and histopathologic findings. AB - BACKGROUND AND PURPOSE: The purpose of this work was to demonstrate susceptibility effects (SusE) in various types of brain tumors with 3T high resolution (HR)-contrast-enhanced (CE)-susceptibility-weighted (SW)-MR imaging and to correlate SusE with positron-emission tomography (PET) and histopathology. MATERIALS AND METHODS: Eighteen patients with brain tumors, scheduled for biopsy or tumor extirpation, underwent high-field (3T) MR imaging. In all of the patients, an axial T1-spin-echo (SE) sequence and an HR-SW imaging sequence before and after IV application of a standard dose of contrast agent (MultiHance) was obtained. Seven patients preoperatively underwent PET. The frequency and formation of intralesional SusE in all of the images were evaluated and correlated with tumor grade as determined by PET and histopathology. Direct correlation of SusE and histopathologic specimens was performed in 6 patients. Contrast enhancement of the lesions was assessed in both sequences. RESULTS: High grade lesions demonstrated either high or medium frequency of SusE in 90% of the patients. Low-grade lesions demonstrated low frequency of SusE or no SusE. Correlation between intralesional frequency of SusE and histopathologic, as well as PET, tumor grading was statistically significant. Contrast enhancement was equally visible in both SW and SE sequences. Side-to-side comparison of tumor areas with high frequency of SusE and histopathology revealed that intralesional SusE reflected conglomerates of increased tumor microvascularity. CONCLUSIONS: 3T HR-CE-SW-MR imaging shows both intratumoral SusE not visible with standard MR imaging and contrast enhancement visible with standard MR imaging. Because frequency of intratumoral SusE correlates with tumor grade as determined by PET and histopathology, this novel technique is a promising tool for noninvasive differentiation of low-grade from high-grade brain tumors and for determination of an optimal area of biopsy for accurate tumor grading. PMID- 17698529 TI - Metabolic findings on 3T 1H-MR spectroscopy in peritumoral brain edema. AB - BACKGROUND AND PURPOSE: Little is known about the metabolic properties of brain edema associated with tumors. This work was conducted on the basis of the assumption that, in the presence of intra-axial and extra-axial brain tumors, the white matter involved by the edema is a site of metabolic change that involves the structure of the myelin sheath. MATERIALS AND METHODS: Thirteen patients comprised our cohort affected by intra-axial and extra-axial cerebral tumors with a peritumoral T2-weighted MR signal hyperintensity as a result of edema, where MR spectroscopy showed no increase in choline-containing compounds. Measurements on proton MR spectroscopy (1H-MR spectroscopy) were performed with a 3T whole-body scanner with use of a point-resolved spectroscopy sequence for localization (TR, 2000 ms; TE, 35 ms), and the metabolites were quantified with the SAGE method. Peak intensities of the main metabolites were expressed as ratios of one another and were compared with values obtained in the white matter of the left frontal region in a control group of 16 healthy volunteers. RESULTS: Choline-to-creatine (Cho/Cr) and myo-inositol-to-creatine (mIns/Cr) signal intensity ratios were normal in all patients. N-acetylaspartate-to-creatine (NAA/Cr) and N acetylaspartate-to-choline (NAA/Cho) ratios decreased in 4 patients. Glutamate plus glutamine-to-creatine (Glx/Cr) was increased in 10 patients. A resonance peak at 3.44 ppm, strongly suggesting the presence of glucose, was detected in all but 1 patient. Lactate was detected in 12 patients and lipids in 5. Moreover, the resonances that pertained to the aliphatic amino acids valine, leucine, and isoleucine were present in 12 patients. CONCLUSIONS: Our findings on MR spectroscopy confirmed the hypothesis that in the edema surrounding brain tumors, an energy-linked metabolic alteration was associated with injury to the myelin sheath. PMID- 17698530 TI - Measuring elevated microvascular permeability and predicting hemorrhagic transformation in acute ischemic stroke using first-pass dynamic perfusion CT imaging. AB - BACKGROUND AND PURPOSE: Hemorrhagic transformation (HT) can be a devastating complication of acute ischemic stroke (AIS). The purpose of this study was to determine whether increased microvascular permeability (PS) of the blood-brain barrier was detected in early AIS by using first-pass dynamic perfusion CT (PCT) and whether PS was significantly higher in infarcts destined for HT. MATERIALS AND METHODS: Fifty patients with AIS less than 3 hours old and evaluated by PCT were included. PS color maps were retrospectively generated from PCT data using the Patlak model. One reader analyzed each PS map by drawing 4 circular 10-mm regions of interest on any focal abnormality. The mean of these 4 regions of interest represented the PS of the infarct (PSinfarct). The mean of 4 mirror regions of interest on the nonischemic contralateral hemisphere was also obtained (PScontrol). PSinfarct and PScontrol were compared by using an exact Wilcoxon test. PSinfarct for infarcts that developed HT on follow-up (PSHT) was compared with all of the others (PSNo-HT) using an exact Mann-Whitney test. RESULTS: Forty four infarcts (88%) showed focal PS elevation in the region of infarct. In units of milliliters per 100 milliliters per minute, PSinfarct ranged from 0 to 13 (mean: 3.5+/-3.1) versus PScontrol of 0-0.8 (mean: 0.28+/-0.27; P<.0001). Six infarcts (12%) developed HT, all of which were within the region of PS elevation. PSHT ranged from 5.2 to 13 (mean: 9.8+/-2.9) versus PSNo-HT of 0-5.9 (mean: 2.7+/ 2.0; P<.0001). Eighteen infarcts (36%) were treated with recombinant tissue plasminogen activator (rtPA). A significant difference between PSHT and PSNo-HT persisted irrespective of rtPA treatment. CONCLUSIONS: Elevated permeability was detectable in AIS by using first-pass PCT and it predicted subsequent HT. PMID- 17698531 TI - Increasing contrast agent concentration improves enhancement in first-pass CT perfusion. AB - BACKGROUND AND PURPOSE: Our aim was to evaluate whether increasing iodine concentration, at a constant total iodine dose, resulted in better brain tissue opacification in patients with acute stroke symptoms during their evaluation by first-pass CT perfusion (CTP). MATERIALS AND METHODS: One hundred two patients presenting to the emergency department within 3 hours of onset of acute stroke symptoms underwent CTP scanning. Three different concentrations of iodinated nonionic contrast material were used (300, 350, or 400 mg/mL). Total iodine dose (15 g) and injection rate (7 mL/s) were kept constant. There were 25, 53, and 19 patients in the different concentration groups, respectively; 5 patients were excluded due to uncorrectable motion artifacts. CTP scanning was performed at the level of the putamen, and data were analyzed by determining peak opacification for normal gray and white matter, arterial input, and venous output. Mean and SD values were calculated, and 3 concentration groups, stratified by region-of interest location, were compared by using a single-tailed unpaired t test. RESULTS: Monotonic increasing peak opacification was observed in all region-of interest locations. Statistically significant differences were observed between the 300 and 350 mg/mL, 300 and 400 mg/mL, as well as the 350 and 400 mg/mL groups (P<.01) in white matter, gray matter, and the arterial input. Statistical significance was seen in the venous output group between the 300 and 400 mg/mL (P<.005) and 350 and 400 mg/mL (P<.007) groups, but not between the 300 and 350 mg/mL (P=.2) groups. CONCLUSION: Increasing contrast concentration improves peak opacification of tissue, suggesting that CTP evaluation of patients with acute stroke is better performed with the highest available concentration contrast agent. PMID- 17698532 TI - Assessment of collateral supply by two-coil continuous arterial spin labeling after coil occlusion of the internal carotid artery. AB - A patient undergoing coil occlusion of a left internal carotid artery aneurysm was investigated by continuous arterial spin labeling MR imaging to evaluate perfusion territory mapping. Labeling was restricted to the left- or right-sided carotid artery by use of a separate neck coil. Before embolization, perfusion contrast was largely restricted to the labeled hemisphere. After embolization, perfusion contrast was created symmetrically in both hemispheres on labeling the right side, verifying sufficient collateral supply. PMID- 17698533 TI - Low choline concentrations in normal-appearing white matter of patients with multiple sclerosis and normal MR imaging brain scans. AB - BACKGROUND AND PURPOSE: Spectroscopic studies (1H-MR spectroscopy) of normal appearing white matter (NAWM) in patients with multiple sclerosis (MS) with MR imaging brain lesions have already been performed, but our intention was to investigate NAWM in MS patients who lack brain lesions to elucidate whether the same pathologic changes could be identified. MATERIALS AND METHODS: We checked 350 medical files of patients with MS who are registered in our institution. Fourteen patients (11 women and 3 men; mean age, 48.6 years; handicap score, Expanded Disability Status Scale [EDSS] 2.9; range, 1-6.5) with clinically definite MS and a normal MR imaging of the brain were included. 1H-MR spectroscopy was performed in 4 voxels (size approximately 17x17x17 mm3) using absolute quantification of metabolite concentrations. Fourteen healthy control subjects (11 women and 3 men; mean age, 43.3 years) were analyzed in the same way. RESULTS: Significant differences in absolute metabolite concentrations were observed, with the patients with MS showing a lower total concentration of N acetyl compounds (tNA), including N-acetylaspartate and N-acetyl aspartylglutamate (13.5 mmol/L versus 14.6 mmol/L; P=.002) compared with the healthy control subjects. Unexpectedly, patients with MS presented significantly lower choline-containing compounds (Cho) compared with healthy control subjects (2.2 mmol/L versus 2.4 mmol/L; P<.001). The EDSS showed a positive correlation to myo-inositol concentrations (0.14 mmol/L per EDSS; r2=0.06) and a negative correlation to tNA concentrations (-0.41 mmol/L per EDSS; r2=0.22). CONCLUSION: The unexpected finding of lower Cho concentrations has not been reported previously. We suggest that patients with MS who lack lesions in the brain constitute a separate entity and may have increased protective or healing abilities. PMID- 17698534 TI - Whole-brain histogram and voxel-based analyses of diffusion tensor imaging in patients with leukoaraiosis: correlation with motor and cognitive impairment. AB - BACKGROUND AND PURPOSE: Cerebral white matter changes, termed leukoaraiosis (LA), appearing as areas of increased signal intensity in T2-weighted MR images, are common in elderly subjects, but the possible correlation of LA with cognitive or motor deficit has not been established. We hypothesized that histogram and voxel based analyses of whole-brain mean diffusivity (MD) and fractional anisotropy (FA) maps calculated from diffusion tensor imaging (DTI) could be more sensitive tools than visual scales to investigate the clinical correlates of LA. MATERIALS AND METHODS: Thirty-six patients of the Leukoaraiosis and Disability Study were evaluated with fluid-attenuated inversion recovery for LA extension, T1-weighted images for volume, and DTI for MD and FA. The extent of LA was rated visually. The normalized total, gray, and white matter brain volumes were computed, as well as the 25th percentile, 50th percentile, kurtosis, and skewness of the MD and FA maps of the whole brain. Finally, voxel-based analysis on the maps of gray and white matter volume, MD, and FA was performed with SPM2 software. Correlation analyses between visual or computerized data and motor or neuropsychologic scale scores were performed using the Spearman rank test and the SPM2 software. RESULTS: The visual score correlated with some MD and FA histogram metrics (P<.01). However, only the 25th and 50th percentiles, kurtosis, and skewness of the MD and FA histograms correlated with motor or neuropsychologic deficits. Voxel-based analysis revealed a correlation (P<.05 corrected for multiple comparisons) between a large cluster of increased MD in the corpus callosum and pericallosal white matter and motor deficit. CONCLUSIONS: These results are consistent with the hypothesis that histogram and voxel-based analyses of the whole-brain MD and FA maps are more sensitive tools than the visual evaluation for clinical correlation in patients with LA. PMID- 17698535 TI - Distinct imaging patterns and lesion distribution in posterior reversible encephalopathy syndrome. AB - BACKGROUND AND PURPOSE: Although the term posterior reversible encephalopathy syndrome (PRES) was popularized because of the typical presence of vasogenic edema in the parietal and occipital lobes, other regions of the brain are also frequently affected. We evaluated lesion distribution with CT and MR in a large cohort of patients who experienced PRES to comprehensively assess the imaging patterns identified. MATERIALS AND METHODS: The locations of the PRES lesion at toxicity were comprehensively identified and tabulated in 136 patients by CT (22 patients) and MR (114 patients) imaging including the hemispheric, basal ganglial, and infratentorial locations. Clinical associations along with presentation at toxicity including blood pressure were assessed. RESULTS: Vasogenic edema was consistently present in the parietal or occipital regions (98%), but other locations were common including the frontal lobes (68%), inferior temporal lobes (40%), and cerebellar hemispheres (30%). Involvement of the basal ganglia (14%), brain stem (13%), and deep white matter (18%) including the splenium (10%) was not rare. Three major patterns of PRES were noted: the holohemispheric watershed (23%), superior frontal sulcal (27%), and dominant parietal-occipital (22%), with additional common partial or asymmetric expression of these primary PRES patterns (28%). CONCLUSION: Involvement of the frontal lobe, temporal lobe, and cerebellar hemispheres is common in PRES, along with the occasional presence of lesions in the brain stem, basal ganglia, deep white matter, and splenium. Three primary PRES patterns are noted in the cerebral hemispheres, along with frequent partial or asymmetric expression of these PRES patterns. Awareness of these patterns and variations is important to recognize PRES neurotoxicity more accurately when present. PMID- 17698536 TI - Wernicke encephalopathy: MR findings at clinical presentation in twenty-six alcoholic and nonalcoholic patients. AB - BACKGROUND AND PURPOSE: Wernicke encephalopathy is a severe neurologic disorder that results from a dietary vitamin B1 deficiency. It is characterized by changes in consciousness, ocular abnormalities, and ataxia. This study was undertaken to analyze and compare findings on MR imaging and neurologic symptoms at clinical presentations of patients with Wernicke encephalopathy with and without a history of alcohol abuse. MATERIALS AND METHODS: A multicenter study group retrospectively reviewed MR brain imaging findings, clinical histories, and presentations of 26 patients (14 female, 12 male) diagnosed between 1999 and 2006 with Wernicke encephalopathy. The age range was 6-81 years (mean age, 46 .6+/-19 years). RESULTS: Fifty percent of the patients had a history of alcohol abuse, and 50% had no history of alcohol abuse. Eighty percent showed changes in consciousness, 77% had ocular symptoms, and 54% had ataxia. Only 38% of the patients showed the classic triad of the disease at clinical presentation. At MR examination, 85% of the patients showed symmetric lesions in the medial thalami and the periventricular region of the third ventricle, 65% in the periaqueductal area, 58% in the mamillary bodies, 38% in the tectal plate, and 8% in the dorsal medulla. Contrast enhancement of the mamillary bodies was statistically positively correlated with the alcohol abuse group. CONCLUSIONS: Our study confirms the usefulness of MR in reaching a prompt diagnosis of Wernicke encephalopathy to avoid irreversible damage to brain tissue. Contrast enhancement in the mamillary bodies is a typical finding of the disease in the alcoholic population. PMID- 17698537 TI - Comparative evaluation of fungal, tubercular, and pyogenic brain abscesses with conventional and diffusion MR imaging and proton MR spectroscopy. AB - BACKGROUND AND PURPOSE: It is difficult to differentiate the cause of brain abscesses with the use of CT and MR imaging. We did a comparative evaluation of pyogenic, tubercular, and fungal brain abscesses by using conventional, diffusion weighted imaging (DWI), and proton MR spectroscopy (PMRS) with an aim to define the unique features that may differentiate among the pyogenic, tubercular, and fungal brain abscesses. MATERIALS AND METHODS: We performed a retrospective analysis on 110 patients with surgically proved brain abscesses. Imaging studies included T2, T1, postcontrast T1, DWI, and PMRS. Apparent diffusion coefficient (ADC) of the wall and cavity of the abscesses were quantified. The morphologic, physiologic, and metabolite features of pyogenic (n=91), tubercular (n=11), and fungal (n=8) abscesses were compared. RESULTS: The pyogenic abscesses had smooth (55/91) and lobulated (36/91) walls, whereas the tubercular abscesses had smooth (4/11), lobulated (6/11), or crenated walls (1/11) with no intracavitary projections. The fungal abscesses showed irregular walls (lobulated 4/8, crenated 4/8) with intracavitary projections (8/8). The wall as well as the cavity showed low ADC in the pyogenic and tubercular abscesses. In the fungal abscesses, the wall and projections showed low ADC (8/8); however, the cavity itself showed high ADC (8/8). PMRS showed cytosolic amino acids (89/91), acetate (25/91), and succinate (18/91) in the pyogenic abscesses, whereas lipid/lactate (11/11) was seen in the tubercular abscesses. The fungal abscesses showed lipid (4/8), lactate (7/8), amino acids (4/8), and multiple peaks between 3.6 and 3.8 ppm assigned to trehalose (5/8). CONCLUSION: Based on the morphologic, ADC, and metabolite information, it may be possible to differentiate among the pyogenic, tubercular, and fungal brain abscesses. PMID- 17698538 TI - Hippocampal shape analysis of Alzheimer disease based on machine learning methods. AB - BACKGROUND AND PURPOSE: Alzheimer disease (AD) is a neurodegenerative disease characterized by progressive dementia. The hippocampus is particularly vulnerable to damage at the very earliest stages of AD. This article seeks to evaluate critical AD-associated regional changes in the hippocampus using machine learning methods. MATERIALS AND METHODS: High-resolution MR images were acquired from 19 patients with AD and 20 age- and sex-matched healthy control subjects. Regional changes of bilateral hippocampi were characterized using computational anatomic mapping methods. A feature selection method for support vector machine and leave 1-out cross-validation was introduced to determine regional shape differences that minimized the error rate in the datasets. RESULTS: Patients with AD showed significant deformations in the CA1 region of bilateral hippocampi, as well as the subiculum of the left hippocampus. There were also some changes in the CA2-4 subregions of the left hippocampus among patients with AD. Moreover, the left hippocampal surface showed greater variations than the right compared with those in healthy control subjects. The accuracies of leave-1-out cross-validation and 3 fold cross-validation experiments for assessing the reliability of these subregions were more than 80% in bilateral hippocampi. CONCLUSION: Subtle and spatially complex deformation patterns of hippocampus between patients with AD and healthy control subjects can be detected by machine learning methods. PMID- 17698539 TI - Reproducibility of activations in Broca area with two language tasks: a functional MR imaging study. AB - BACKGROUND AND PURPOSE: Functional MR imaging (fMRI) is rapidly evolving and claims to complement or even substitute intraoperative mapping (IOM) of language functions. However, little is known about the reproducibility of imaging data in the language domain. The aim of our study was to assess the reproducibility of activations for 2 widely used paradigms: naming and word generation. Individual analysis was focused on the Broca area and the left insula. MATERIALS AND METHODS: We examined 13 healthy right-handed subjects in 3 sessions with fMRI. Two conditions were assessed: overt naming and overt naming plus noun generation. The same stimuli were used in all of the sessions. A random-effects analysis was performed to analyze whole-brain activation on a group level. For the regions of interest, the number of voxels classified as active were counted for each subject, and individual reproducibility coefficients were calculated over sessions. RESULTS: For the naming condition, the random-effects analysis did not reveal significant activations in the specified regions; small individual activations were not reproducible. For the combined task, all of the subjects showed activations in the Broca area that were more extensive and reproducible than in the naming task. Activations in the insula were only poorly reproducible. CONCLUSION: Naming is an approved task in IOM but does not identify the Broca area with fMRI in a reproducible way. Priming may have affected our results, but the use of a combined task, in which naming is paired with noun generation, improves the reproducibility of activations and is also suitable for IOM. PMID- 17698540 TI - Incorporating functional MR imaging into diffusion tensor tractography in the preoperative assessment of the corticospinal tract in patients with brain tumors. AB - BACKGROUND AND PURPOSE: Our goal was to improve the preoperative assessment of the corticospinal tract (CST) in patients with brain tumors. We investigated whether the integration of functional MR imaging (fMRI) data and diffusion tensor (DT) tractography can be used to evaluate the spatial relationship between the hand and foot fibers of the CST and tumor borders. MATERIALS AND METHODS: We imaged 10 subjects: 1 healthy volunteer and 9 patients. Imaging consisted of a 3D T1-weighted sequence, a gradient-echo echo-planar imaging (EPI) sequence for fMRI, and a diffusion-weighted EPI sequence for DT tractography. DT tractography was initiated from a seed region of interest in the white matter area subjacent to the maximal fMRI activity in the precentral cortex. The target region of interest was placed in the cerebral peduncle. RESULTS: In the healthy volunteer, we successfully tracked hand, foot, and lip fibers bilaterally by using fMRI based DT tractography. In all patients, we could track the hand fibers of the CST bilaterally. In 4 patients who also performed foot tapping, we could clearly distinguish hand and foot fibers. We were able to depict the displacement of hand and foot fibers by tumor and the course of fibers through areas of altered signal intensity. CONCLUSION: Incorporating fMRI into DT tractography in the preoperative assessment of patients with brain tumors may provide additional information on the course of important white matter tracts and their relationship to the tumor. Only this approach allows a distinction between the CST components, while visualization of the CST is improved when fiber tracking is hampered by tumor (infiltration) or perifocal edema. PMID- 17698541 TI - Bone-subtraction CT angiography: evaluation of two different fully automated image-registration procedures for interscan motion compensation. AB - BACKGROUND AND PURPOSE: Bone-subtraction techniques have been shown to enhance CT angiography (CTA) interpretation, but motion can lead to incomplete bone removal. The aim of this study was to evaluate 2 novel registration techniques to compensate for patient motion. MATERIALS AND METHODS: Fifty-four patients underwent bone-subtraction CTA (BSCTA) for the evaluation of the neck vessels with 64-section CT. We tested 3 different registration procedures: pure rigid registration (BSCTA), slab-based registration (SB-BSCTA), and a partially rigid registration (PR-BSCTA) approach. Subtraction quality for the assessment of different vascular segments was evaluated by 2 examiners in a blinded fashion. The Cohen kappa test was applied for interobserver variability, and the Wilcoxon signed rank test, for differences between the procedures. Motion between the corresponding datasets was measured and plotted against image-quality scores. RESULTS: Algorithms with motion compensation revealed higher image-quality scores (SB-BSCTA, mean 4.31; PR-BSCTA, mean 4.43) than pure rigid registration (BSCTA, mean 3.88). PR-BSCTA was rated superior to SB-BSCTA for the evaluation of the cervical internal and external carotid arteries (P<.001), whereas there was no significant difference for the other vessels (P=.157-.655). Both algorithms were clearly superior to pure rigid registration for all vessels except the basilar and ophthalmic artery. Interobserver agreement was high (kappa=0.46-0.98). CONCLUSION: Bone-subtraction algorithms with motion compensation provided higher image-quality scores than pure rigid registration methods, especially in cases with complex motion. PR-BSCTA was rated superior to SB-BSCTA in the visualization of the internal and external carotid arteries. PMID- 17698542 TI - Combined pituitary hormone deficiency and PROP-1 mutation in two siblings: a distinct MR imaging pattern of pituitary enlargement. AB - Mutations of the PROP-1 gene are the most frequent genetic defect in patients with combined pituitary hormone insufficiency. We present the cases of 2 siblings with PROP-1 mutations whom we observed longitudinally. Their initial pituitary MR imaging examinations showed identical findings: an enlarged adenohypophysis, with striking hypointensity on T2-weighted images and slight hyperintensity on T1 weighted images. In one of the children, the follow-up MR imaging obtained 3 years after hormonal replacement revealed a decrease in the size of the anterior pituitary lobe. PMID- 17698543 TI - False-positive positron-emission tomography-CT of a Teflon granuloma in the parapharyngeal space occurring after treatment for a patulous eustachian tube. AB - This report presents a 55-year-old woman who underwent 2 Teflon injections in 1971 for a patulous eustachian tube. The patient returned in 2006 with a bloody left otorrhea. A positron-emission tomography-CT scan demonstrated a 2-cm hypermetabolic parapharyngeal mass, initially interpreted as a skull base tumor. Repeat neck CT confirmed a 2-cm hyperattenuated left parapharyngeal granulomatous mass. This is the first reported case of a Teflon granuloma presenting as a false positive parapharyngeal mass. PMID- 17698544 TI - Leiomyosarcoma in the nasopharynx: MR imaging findings. AB - The MR imaging findings of a leiomyosarcoma arising from the nasopharynx are presented. To our knowledge, this is the first MR imaging description of this entity. PMID- 17698545 TI - Expansile organized maxillary sinus hematoma: MR and CT findings and review of literature. AB - An organized hematoma is a chronic state of fibrotic tissue surrounding a hemorrhage. A mass lesion resulting from hematoma in the maxillary sinus was first reported in 1917, and the term, "blood boil," was clinically coined from such features as encapsulated blood and locally aggressive behavior. Subsequently, others have reported lesions with a similar appearance and clinical course, and now, in Japan, blood boil is used as a clinical term for such lesions. Factors that may predispose a patient to hematoma formation vary, and the pathogenesis of the mass is still uncertain. The lesions are mainly composed of an organized hematoma, regardless of their origin. We present 2 cases of organized maxillary sinus hematomas that have unusual radiologic findings and correlate these findings with the histopathologic findings. PMID- 17698546 TI - Carotid stenting without use of balloon angioplasty and distal protection devices: preliminary experience in 100 cases. AB - BACKGROUND AND PURPOSE: A major concern during carotid artery stent placement is the potential for cerebral embolism. Diminishing the number of device manipulations across the lesion might reduce procedural stroke risk. For this purpose, we report our initial experience with carotid stent placement without the use of either balloon angioplasty or distal protection devices. MATERIALS AND METHODS: Eighty-seven consecutive patients with 100 carotid stenoses compose this series. Ninety four of the 100 hundred stented carotid arteries were either symptomatic (58 [58%]) or had a greater than 70% stenosis (36 [36%]). Six percent of them were asymptomatic and had stenosis between 50% and 70%. Patients underwent neurologic evaluation before the procedure and during follow-up at 1, 3, 6, and 12 months and annually thereafter. Carotid sonography and plain films of the neck were performed immediately after the procedure and then at the same time intervals. RESULTS: Primary stent placement was successful in 98 of 100 case subjects. In 2 case subjects, predilation was necessary before stent deployment. Neurologic periprocedural complications included 1 nondisabling and 1 disabling stroke and 5 transient ischemic attacks. The mean duration of follow-up was 23 months (range: 10-36 months). During the follow-up period, there were 5 deaths, all unrelated to the carotid disease, and no major stroke. The degree of stenosis decreased from a mean of 78.85% before the procedure to a mean of 21.23% immediately after. CONCLUSIONS: In this series, carotid stent placement without the use of either balloon angioplasty or distal protection devices was safe and effective with a low incidence of periprocedural complications. PMID- 17698547 TI - Packing performance of helical Guglielmi detachable coil (GDC) 18 in intracranial aneurysms: a comparison with helical GDC 10 coils and complex Trufill/Orbit coils. AB - BACKGROUND AND PURPOSE: The purpose of this study was to retrospectively compare the packing performance of helical Guglielmi detachable coil (GDC) 18 (thickness, 0.0135-0.015 inch) with the packing performance of both helical GDC 10 (thickness, 0.010 inch) and complex Trufill/Orbit coils (thickness, 0.012 inch). MATERIALS AND METHODS: From our data base, we selected aneurysms that were exclusively coiled with GDC 18 coils. For every aneurysm treated with GDC 18 coils, we tried to identify a volume-matched control aneurysm treated with exclusively GDC 10 coils or exclusively Trufill/Orbit coils. This process resulted in 32 aneurysm pairs treated with either GDC 18 or GDC 10 coils and 35 aneurysm pairs treated with either GDC 18 or Trufill/Orbit coils. RESULTS: The mean packing of 24.2% of aneurysms treated with GDC 18 was significantly higher than the mean packing of 18.3% of aneurysms treated with GDC 10 (P<.0001). The mean packing of 23.1% of GDC 18 coils was not different from the mean packing of 25.1% of Trufill/Orbit coils (P=.15). CONCLUSION: In aneurysms of 4 mm or larger, packing performance of helical GDC 18 coils is superior to that of helical GDC 10 coils and equal to that of complex Trufill/Orbit coils. PMID- 17698548 TI - HyperForm balloon-assisted endovascular neck bypass technique to perform balloon or stent-assisted treatment of cerebral aneurysms. AB - We describe a technique to bypass aneurysm neck using the HyperForm balloon to perform balloon- or stent-assisted endovascular treatment of complex large or giant aneurysms with very wide neck in which other methods would fail to obtain an access distal to the aneurysm. PMID- 17698549 TI - Factors predicting hemorrhagic complications after multimodal reperfusion therapy for acute ischemic stroke. AB - BACKGROUND AND PURPOSE: We sought to find predictors for hemorrhagic complications in patients with acute ischemic stroke treated with multimodal endovascular therapy. MATERIALS AND METHODS: We retrospectively reviewed patients with acute ischemic stroke treated with multimodal endovascular therapy from May 1999 to March 2006. We reviewed clinical and angiographic data, admission CT Alberta Stroke Programme Early CT Score (ASPECTS), and the therapeutic endovascular interventions used. Posttreatment CT scans were reviewed for the presence of a parenchymal hematoma or hemorrhagic infarction based on defined criteria. Predictors for these types of hemorrhages were determined by logistic regression analysis. RESULTS: We identified 185 patients with a mean age of 65+/ 13 years and mean National Institutes of Health Stroke Scale score of 17+/-4. Sixty-nine patients (37%) developed postprocedural hemorrhages: 24 (13%) parenchymal hematomas and 45 (24%) hemorrhagic infarctions. Patients with tandem occlusions (odds ratio [OR] 4.6 [1.4-6.5], P<.016), hyperglycemia (OR 2.8 [1.1 7.7], P<.043), or treated concomitantly with intravenous (IV) tissue plasminogen activator (tPA) and intra-arterial (IA) urokinase (OR 5.1 [1.1-25.0], P<.041) were at a significant risk for a parenchymal hematoma. Hemorrhagic infarction occurred significantly more in patients presenting with an ASPECTS15 mm) and giant basilar tip aneurysms. MATERIALS AND METHODS: Between January 1995 and October 2005, 44 very large and giant basilar tip aneurysms in 44 patients were coiled. There were 13 men (30%) and 31 women (70%) with a mean age of 51.4 years (median, 51 years; range, 34-72 years). Mean aneurysm size was 19.6 mm (range, 15-30 mm). Of 44 aneurysms, 33 (75%) had ruptured. Of 11 unruptured basilar tip aneurysms, 7 were incidentally discovered, 1 was additional to another ruptured aneurysm, and 3 were symptomatic by mass effect. RESULTS: Procedural mortality was 2/44 (4.6%, 95% confidence interval (CI), 0.4%-16%) and morbidity 1/44 (2.3%, 95% CI, 0.01% 13%). Of 33 patients with ruptured aneurysms, mean clinical follow-up was 5.2 years (range, 0.5-11.5 years). Two patients had a rebleeding from the coiled basilar tip aneurysm leading to death in 1 patient and to dependency in the other patient (annual rebleeding rate, 1.1%) One other patient died 2 years later of progressive brain stem compression. Mean angiographic follow-up in 41 of 42 surviving patients was 3.1 years. Nineteen aneurysms reopened and were coiled for a second time. Of these, 9 repeatedly reopened with time and were repeatedly coiled up to 6 times. Additional treatments were without complications. CONCLUSION: Coiling of very large and giant basilar tip aneurysms is associated with reasonably low morbidity. Although additional treatment during follow-up is frequently necessary, rebleeding is uncommon. PMID- 17698554 TI - Embolization of high-flow craniofacial vascular malformations with onyx. AB - BACKGROUND AND PURPOSE: Various techniques and materials have been used for the endovascular treatment of craniofacial high-flow arteriovenous vascular malformations, because their rarity precludes standardization of their treatment. The aim of this retrospective review is to assess Onyx as the primary embolic agent in the treatment of these vascular malformations. MATERIALS AND METHODS: Six patients with arteriovenous fistulas and 3 with arteriovenous malformations (AVMs) of the head and neck region were treated with intra-arterial (IA)/direct percutaneous injections of Onyx. Adjunctive maneuvers used during embolization included external compression of the arterial feeders or venous outflow (6 patients), balloon assist (4 patients), and direct embolization of the draining vein remote to the fistula site (1 patient). n-butyl-2-cyanoacrylate (n-BCA) was used in addition to Onyx for rapid induction of thrombosis in a large venous pouch (1 patient) and for cost containment purposes (1 patient). Four patients were treated surgically after the embolization. RESULTS: There were no neurologic complications secondary to the embolization procedure. The arteriovenous shunt was eliminated in all of the fistulous lesions and 2 of the 3 AVMs. The embolization was incomplete in 1 patient with a large AVM who declined further endovascular or surgical procedures. Untoward events included 2 instances of catheter entrapment (of 9 IA injections), blackish skin discoloration necessitating surgical revision in 1 patient, and difficulty of balloon deflation/wire withdrawal during a balloon-assisted embolization. CONCLUSION: Onyx appears to be a safe and effective liquid embolic agent for use in the treatment of craniofacial high-flow vascular malformations with distinct advantages and disadvantages compared with n-BCA. PMID- 17698555 TI - Transorbital puncture for the treatment of cavernous sinus dural arteriovenous fistulas. AB - This report describes a series of patients for whom dural arteriovenous fistulae (DAVFs) of the cavernous sinus were successfully embolized using a percutaneous, transorbital technique to directly cannulate the cavernous sinus. A vascular access needle and catheter are percutaneously advanced along the inferolateral aspect of the orbit to access the cavernous sinus via the superior orbital fissure. Safe and effective embolization is achieved without the need for a surgical cut-down. PMID- 17698556 TI - Sudden coronary death, fatal acute myocardial infarction and widespread coronary and myocardial inflammation. AB - BACKGROUND: T-lymphocyte activation within atherosclerotic plaque, and widespread to the myocardium, has been shown in patients with acute coronary syndromes. OBJECTIVE: To investigate the presence of T-lymphocyte infiltrate at different stages of acute coronary syndromes by studying patients with sudden coronary death, acute myocardial infarction (AMI) and healed infarction, in comparison with patients with myocarditis and patients with non-ischaemic heart failure. METHODS: 72 cases were studied at autopsy: 12 dying of sudden coronary death (group 1), 12 dying <4 weeks (group 2) and 12 dying >4 months after AMI (group 3), 12 with active lymphocytic myocarditis (group 4), 12 with hypertensive heart disease (group 5), and 12 control subjects (group 6). Light microscopy was performed to measure the number of activated T-lymphocytes (CD3+/DR+) in the myocardium and coronary artery wall, and intercellular adhesion molecule-1 (ICAM 1) expression in the myocardium. RESULTS: Activated T-lymphocyte infiltrates and ICAM-1 myocardial expression in both remote and peri-infarction regions and activated T-lymphocytes within the epicardial coronary artery wall of both the infarct- and non-infarct-related arteries were found in groups 1, 2 and 3, whereas myocardial, but not coronary, infiltrates were found in groups 4 (p<0.001 vs groups 1, 2 and 3 for coronary infiltrates). Groups 5 and 6 had no evidence of myocardial or coronary inflammation (p<0.001 vs groups 1, 2 and 3). CONCLUSIONS: The study shows the presence of a lymphocytic infiltrate in both coronary arteries and myocardium and a proinflammatory phenotype shift in the myocardium associated with acute coronary thrombosis in patients dying suddenly, shortly, or even late after coronary thrombosis. PMID- 17698558 TI - Responsiveness to change: a quality indicator for assessment of knowledge translation systems. PMID- 17698557 TI - Role of the C-344T aldosterone synthase gene variant in left ventricular mass and left ventricular structure-related phenotypes. AB - AIM: We performed a systematic review of the literature by means of a meta analysis to evaluate the influence of the aldosterone synthase gene (CYP11B2) C 344T polymorphism on left ventricular mass (LVM) and related phenotypes. DESIGN: From 485 reports, we included 14 studies about the association between the C-344T variant and left ventricular mass and left ventricular structure-related phenotypes, from which information about number of subjects in each category, outcomes data and genotyping performed with a validated molecular method could be extracted. Fixed and random effect models were used to pool data from individual studies, and the results in the abstract show the extreme genotype comparison, homozygous TT vs homozygous CC. RESULTS: From a total of 2157 subjects, we found no significant association between LVM and the C-344T variant (D: 0.049, 95% CI: 0.091 to 0.179, p = 0.462). Similarly, no significant association was found for interventricular septal-wall thickness (D: 0.027, 95% CI: -0.090 to 0.143, p = 0.654, n: 2105). However, homozygous TT hypertensive subjects had increased LVM (D: 0.251, 95% CI: 0.020 to 0.481, p = 0.04, n: 332). Lastly, in 10 homogeneous studies posterior wall thickness (PWT) was lower in homozygous CC individuals (D: 0.142, 95% CI: 0.016 to 0.268, p = 0.028, n = 1994). CONCLUSION: Independently of hypertension, homozygous individuals for the -344T allele may have 2.4% higher PWT compared to homozygous subjects for the C-344 allele. Besides, homozygous hypertensive TT subjects show a 6.9% increase in LVM compared to CC homozygous subjects. PMID- 17698559 TI - Human CD4+ central and effector memory T cells produce IL-21: effect on cytokine driven proliferation of CD4+ T cell subsets. AB - IL-21 regulates certain functions of T cells, B cells, NK cells and dendritic cells. Although activated CD4(+) T cells produce IL-21, data identifying the specific CD4(+) T cell subsets that produce IL-21 are conflicting. In a previous study, mouse IL-21 message was detected in T(H)2, whereas human IL-21 (hIL-21) message was found in both T(H)1 and follicular helper T cells. To identify the IL 21-secreting cell populations in human, we established a hybridoma cell line producing an anti-hIL-21 mAb. Intracellular hIL-21-staining experiments showed that hIL-21 was mainly expressed in activated CD4(+) central memory T cells and in activated CD4(+) effector memory T cells, but not in activated CD4(+) naive T cells. Moreover, IL-21 was produced upon activation by some IFN-gamma-producing T(H)1-polarized cells and some IL-17-producing T(H)17-polarized cells, but not by IL-4-producing T(H)2-polarized cells. These results suggest that specific CD4(+) T cell populations produce IL-21. In the functional analysis, we found that IL-21 significantly enhanced the cytokine-driven proliferation of CD4(+) helper T cells synergistically with IL-7 and IL-15 without T cell activation stimuli. Taken together, IL-21 produced from CD4(+) memory T cells may have a supportive role in the maintenance of CD4(+) T cell subsets. PMID- 17698560 TI - Two genetic loci independently confer susceptibility to autoimmune gastritis. AB - Autoimmune gastritis is a CD4+ T cell-mediated disease induced in genetically susceptible mice by thymectomy on the third day after birth. Previous linkage analysis indicated that Gasa1 and Gasa2, the major susceptibility loci for gastritis, are located on mouse chromosome 4. Here we verified these linkage data by showing that BALB.B6 congenic mice, in which the distal approximately 40 Mb of chromosome 4 was replaced by C57BL/6 DNA, were resistant to autoimmune gastritis. Analysis of further BALB.B6 congenic strains demonstrated that Gasa1 and Gasa2 can act independently to cause full expression of susceptibility to autoimmune disease. Gasa1 and Gasa2 are located between D4Mit352-D4Mit204 and D4Mit343 telomere, respectively. Numerical differences in Foxp3+ regulatory T cells were apparent between the BALB/c and congenic strains, but it is unlikely that this phenotype accounted for differences in autoimmune susceptibility. The positions of Gasa1 and Gasa2 correspond closely to the positions of Idd11 and Idd9, two autoimmune diabetes susceptibility loci in nonobese diabetic (NOD), mice and this prompted us to examine autoimmune gastritis in NOD mice. After neonatal thymectomy, NOD mice developed autoimmune gastritis, albeit at a slightly lower incidence and severity of disease than in BALB/c mice. Diabetes-resistant congenic NOD.B6 mice, harbouring a B6-derived interval encompassing the Gasa1/2 Idd9/11 loci, demonstrated a slight reduction in the incidence of autoimmune gastritis. This reduction was not significant compared with the reduction observed in BALB.B6 congenic mice, suggesting a difference in the genetic aetiology of autoimmune gastritis in NOD and BALB mice. PMID- 17698561 TI - Anti-thymocyte globulin (ATG) prevents autoimmune encephalomyelitis by expanding myelin antigen-specific Foxp3+ regulatory T cells. AB - The T cell-depleting polyclonal antibody, anti-thymocyte globulin (ATG) has long been used in organ transplantation to treat acute rejection episodes. More recently, it is also being used as part of an induction regimen to protect allografts. It has been proposed that ATG might deplete effector T cells (T-effs) while sparing regulatory T cells (T-regs). In order to test whether ATG is effective in autoimmune disease, we used Foxp3gfp 'knock-in' mice in combination with a myelin oligodendrocyte glycoprotein (MOG)(35-55)/IA(b) tetramer to study more closely the effect of ATG treatment on antigen-specific T cell responses in vivo during MOG-induced experimental autoimmune encephalomyelitis (EAE), an animal model for Multiple Sclerosis. ATG treatment enhanced the expansion of MOG specific T-regs (CD4(+)Foxp3(+)) in MOG-immunized mice. T-effs were depleted, but on a single-cell basis, the effector function of residual T-effs was not compromised by ATG. Thus, ATG tipped the balance of T-effs and T-regs and skewed an auto-antigen-specific immune reaction from a pathogenic T cell response to a potentially protective T-reg response. In both acute and relapsing remitting disease models, ATG treatment resulted in the attenuation from EAE, both in a preventive and early therapeutic setting. We conclude that ATG treatment enforces the development of a dominant immunoregulatory environment which may be advantageous for the treatment of T cell-driven autoimmune diseases. PMID- 17698562 TI - Regional IFNgamma expression is insufficient for efficacious control of food borne bacterial pathogens at the gut epithelial barrier. AB - IFNgamma is critical for host defence against various food-borne pathogens including Salmonella enterica and Listeria monocytogenes, the causative agents of salmonellosis and listeriosis, respectively. We investigated the impact of regional IFNgamma expression at the intestinal epithelial barrier on host invasion by salmonellae and listeriae following oral challenge. Transgenic mice (IFNgamma-gut), generated on an IFNgamma knock-out (KO) background, selectively expressed IFNgamma in the gut driven by the modified liver fatty acid-binding protein (Fabpl(4x at -132)) promoter. Infections with attenuated S. enterica Typhimurium or with L. monocytogenes did not differ significantly in IFNgamma-KO, IFNgamma-gut and wild-type mice. Further, Listeria-specific CD4+ and CD8+ T cells were not altered in IFNgamma-gut mice. Thus, this model indicates that local IFNgamma expression by non-immunological cells in the distal part of the small intestine, caecum and colon is insufficient for prevention of gut penetration by S. enterica Typhimurium and L. monocytogenes. PMID- 17698563 TI - Amelioration of hepatic fibrosis via beta-glucosylceramide-mediated immune modulation is associated with altered CD8 and NKT lymphocyte distribution. AB - BACKGROUND: While CD8 lymphocytes possess pro-fibrogenic properties and NK (non T) cells are anti-fibrogenic, the role of NKT lymphocytes in liver fibrosis is still unclear. Beta-glucosylceramide (GC), a naturally occurring glycolipid, exerts modulatory effects on these cells. AIM: To explore the role of NKT cells in hepatic fibrosis via GC. METHODS: Hepatic fibrosis was induced by biweekly intra-peritoneal (IP) carbon tetrachloride (CCl(4)) administrations for 7 weeks in 5 groups (A-E) of male C57Bl/6 mice. Mice were treated with daily IP GC injections in groups A and C, or daily oral doses in groups B and D. GC was administered either for the duration of the study period (in groups A and B), or for the last 3 weeks of CCl(4) induction (groups C and D). GC-treated mice were compared with non-treated fibrotic controls (group E) and naive rodents (group F). Liver fibrosis, injury parameters and FACS analysis of lymphocytes were assessed. RESULTS: Marked amelioration (P < 0.0001) of hepatic fibrosis observed in all GC-treated mice without altering reactive oxygen species production. As determined by Sirius red-stained liver tissue sections and measured by Bioquant morphometry; all CCl(4)-administered groups significantly (P < 0.0001) increased the relative fibrosis area compared with naive animals. The increases were 14.4 +/- 1.03-fold in group A, 7.9 +/- 0.37-fold in group B, 5.2 +/- 0.2-fold in group C, 10.3 +/- 0.4-fold in group D and 23.8 +/- 1.9-fold in group E. Western blot analysis for alpha smooth muscle actin from liver extracts followed a similar pattern, increasing in groups A-E. A significant decrease in liver damage was observed in all GC-treated groups, as noted by a decrease in transaminase serum levels (P < 0.005). The beneficial effect of GC was associated with a significant decrease in the intra-hepatic NKT and CD8 lymphocytes as well as their attenuation of both T(h)1 and T(h)2 cytokines. CONCLUSIONS: Administration of GC had a significant anti-fibrotic effect following CCl(4) administration. This effect was associated with an altered NKT and CD8 lymphocyte distribution and a cytokine shift. Immune modulation using GC may have a role in the treatment of fibrosis and other immune-mediated disorders. PMID- 17698564 TI - Dose dependence of oral tolerance to nickel. AB - The dose dependence of oral nickel tolerance was analyzed by comparing three different subsets of C57BL/6 mice: Ni(very low) mice were reared in a nickel reduced environment, Ni(low) and Ni(high) mice were reared in a stainless steel containing environment and the latter received oral NiCl(2) (10 mM). In spleen and feces, Ni(very low) mice exhibit significantly lower nickel concentrations than Ni(low) and Ni(high) mice. In contrast to Ni(very low) mice that can be sensitized with a single intradermal administration of NiCl(2) alone, Ni(low) mice can only be sensitized in the presence of an adjuvant and Ni(high) mice cannot be sensitized at all. This dose-dependent resistance to nickel sensitization (i.e. Ni(high) > Ni(low) > Ni(very low)) correlates with differences in the number and type of nickel-specific T regulatory (Treg) cells. Adoptive transfer studies into Ni(very low) recipients showed that Ni(very low) mice completely lack specific Treg cells whereas Ni(low) and Ni(high) mice harbor them, albeit their numbers and/or suppressive strength are much higher in Ni(high) than Ni(low) mice. The principal Treg subset in Ni(low) mice consists of CD4(+)CD25(+) cells, among which CD4(+)CD25(+)alpha(E)beta(7)(+) cells are the most effective. In Ni(high) mice, CD4(+)CD25(+) Treg cells co-exist with an ensemble of CD8(+) Treg and CD4(+)CD25(-) suppressor-inducer cells. PMID- 17698565 TI - Expression and function of mixed lineage kinases in dendritic cells. AB - Dendritic cells (DCs) sense the presence of conserved microbial structures in their local microenvironment via specific pattern recognition receptors (PRRs). This leads to a programme of changes, which include migration and activation, and enables them to induce adaptive T cell immunity. Mitogen-activated protein kinases (MAPKs) are implicated in this response, but the pathways leading from PRR ligation to MAPK activation, and hence DC activation, are not fully understood. Recent studies in the nervous system have suggested that the mixed lineage kinase (MLK) family of MAPK kinase kinase proteins may be involved as an intermediary step between PRRs and MAPKs. Therefore, in this study, we have used a well-established DC model to explore the role of MLKs in these cells. Messenger RNA for MLKs 2, 3, 4 and DLK and protein for MLKs 2, 3 and DLK are found in DC. DC activation in response to model PRR ligands, such as LPS or poly (I:C), is accompanied by phosphorylation of MLK3. In contrast, another known PRR ligand, zymosan, induces little MLK3 phosphorylation. Inhibition of MLK activity using a pharmacological inhibitor, CEP11004, blocks p38 and Jun N-terminal kinase (JNK) MAPK activation in response to LPS and poly (I:C), but not zymosan. The inhibition is associated with a block in DC activation as measured by cell surface marker expression and cytokine secretion. Thus, MLKs are expressed in DC, and are implicated in DC activation, and the involvement of MLKs appears to be selective, depending on the nature of the DC stimulus. PMID- 17698566 TI - The O antigen enables Bordetella parapertussis to avoid Bordetella pertussis induced immunity. AB - Bordetella pertussis and Bordetella parapertussis are closely related endemic human pathogens which cause whooping cough, a disease that is reemerging in human populations. Despite how closely related these pathogens are, their coexistence and the limited efficacy of B. pertussis vaccines against B. parapertussis suggest a lack of cross-protective immunity between the two. We sought to address the ability of infection-induced immunity against one of these pathogens to protect against subsequent infection by the other using a mouse model of infection. Immunity induced by B. parapertussis infection protected against subsequent infections by either species. However, immunity induced by B. pertussis infection prevented subsequent B. pertussis infections but did not protect against B. parapertussis infections. The O antigen of B. parapertussis inhibited binding of antibodies to the bacterial surface and was required for B. parapertussis to colonize mice convalescent from B. pertussis infection. Thus, the O antigen of B. parapertussis confers asymmetrical cross-immunity between the causative agents of whooping cough. We propose that these findings warrant investigation of the relative role of B. parapertussis in the resurgence of whooping cough. PMID- 17698567 TI - Six genes are preferentially transcribed by the circulating and sequestered forms of Plasmodium falciparum parasites that infect pregnant women. AB - In areas of stable malaria transmission, susceptibility to Plasmodium falciparum malaria increases during first pregnancy. Women become resistant to pregnancy malaria over successive pregnancies as they acquire antibodies against the parasite forms that sequester in the placenta, suggesting that a vaccine is feasible. Placental parasites are antigenically distinct and bind receptors, like chondroitin sulfate A (CSA), that are not commonly bound by other parasites. We used whole-genome-expression analysis to find transcripts that distinguish parasites of pregnant women from other parasites and employed a novel approach to define and adjust for cell cycle timing of parasites. Transcription of six genes was substantially higher in both placental parasites and peripheral parasites from pregnant women, and each gene encodes a protein with a putative export sequence and/or transmembrane domain. This cohort of genes includes var2csa, a member of the variant PfEMP1 gene family previously implicated in pregnancy malaria, as well as five conserved genes of unknown functions. Women in East Africa acquire antibodies over successive pregnancies against a protein encoded by one of these genes, PFD1140w, and this protein shows seroreactivity similar to that of VAR2CSA domains. These findings suggest that a suite of genes may be important for the genesis of the placental binding phenotype of P. falciparum and may provide novel targets for therapeutic intervention. PMID- 17698568 TI - Monomeric expression of bovine beta2-integrin subunits reveals their role in Mannheimia haemolytica leukotoxin-induced biological effects. AB - The ruminant-specific leukotoxin (Lkt) of Mannheimia haemolytica is the key virulence factor contributing to the pathogenesis of lung injury in bovine pneumonic pasteurellosis. Previous studies by us and others indicate that M. haemolytica Lkt binds to CD18, the beta subunit of bovine beta(2)-integrins on leukocytes, and that the species specificity of Lkt-induced effects is resident in the beta subunit CD18 and not in the alpha subunit CD11. However, Lkt also binds to the CD11a subunit of LFA-1. Furthermore, antibodies specific for CD18 or CD11a inhibit signaling events leading to elevation of intracellular [Ca(2+)], tyrosine phosphorylation of the cytosolic domain of CD18, and cytolysis of bovine leukocytes. These observations underscore the need for further investigation to identify the precise subunit of bovine LFA-1 utilized by M. haemolytica Lkt as the functional receptor. For this purpose, monomeric bovine CD18 and CD11a and heterodimeric LFA-1 were expressed in the HEK-293 cell line by transfection, and the resulting transfectants were tested for susceptibility to Lkt-induced effects. All three transfectants effectively bound Lkt. However, Lkt-induced cytolysis was observed only with transfectants expressing monomeric bovine CD18 or LFA-1. Furthermore, intracellular [Ca(2+)] elevation following exposure to Lkt, which is a marker for postbinding signaling leading to cellular activation, was seen only with transfectants expressing monomeric bovine CD18 or LFA-1. These results clearly indicate that the bovine CD18 subunit of beta(2)-integrins is the functional receptor for M. haemolytica Lkt. PMID- 17698569 TI - Lipopolysaccharide from Salmonella enterica activates NF-kappaB through both classical and alternative pathways in primary B Lymphocytes. AB - Lipopolysaccharides (LPS) are potent polyclonal B-lymphocyte activators. Recently, we have shown that LPS inhibits both spontaneous and drug-induced apoptosis in mature B lymphocytes, through cytosolic retention of Bax, a proapoptotic protein of the Bcl-2 family, by preventing its translocation to mitochondria. Research within the last few years has revealed that members of the NF-kappaB transcription factor regulate cell viability by activating genes involved in mitochondrion-dependent apoptosis. In this report, we examined the effect of sustained LPS stimulation on cytosolic and nuclear proteins of the IkappaB/NF-kappaB family to determine which NF-kappaB pathway, canonical (classical) or noncanonical (alternative), is activated by this agent in mature B cells. Immunoblotting analyses showed that LPS induced a time-dependent degradation of the NF-kappaB inhibitors IkappaBbeta and IkappaBepsilon (preferentially to isoform IkappaBalpha), via IkappaB kinase beta. In addition, we observed that LPS triggered the processing of NF-kappaB p105 to p50 and that of NF-kappaB p100 to p52 in parallel with nuclear translocation of active p50 and p52, as NF-kappaBp50/RelA and NF-kappaBp52/RelB heterodimers, respectively. These results suggest that sustained stimulation with LPS can activate NF-kappaB through both classical and alternative pathways. PMID- 17698570 TI - Antibody-independent, CD4+ T-cell-dependent protection against pneumococcal colonization elicited by intranasal immunization with purified pneumococcal proteins. AB - Immunity to pneumococcal colonization in mice by exposure to live or killed pneumococci has been shown to be antibody independent but dependent on CD4+ T cells. Here we show that intranasal immunization with pneumococcal proteins (pneumococcal surface protein C, adhesin A, and a pneumolysoid) can elicit a similar mechanism of protection. Colonization could be significantly reduced in mice congenitally deficient in immunoglobulins after intranasal immunization with this mixture of proteins; conversely, the depletion of CD4+ T cells in immunized wild-type mice at the time of challenge eliminated the protection afforded by immunization. Overall, our results show that intranasal immunization with a mixture of pneumococcal proteins protects against colonization in an antibody independent, CD4+ T-cell-dependent manner. PMID- 17698571 TI - Prolonged colonization of mice by Vibrio cholerae El Tor O1 depends on accessory toxins. AB - Cholera epidemics caused by Vibrio cholerae El Tor O1 strains are typified by a large number of asymptomatic carriers who excrete vibrios but do not develop diarrhea. This carriage state was important for the spread of the seventh cholera pandemic as the bacterium was mobilized geographically, allowing the global dispersion of this less virulent strain. Virulence factors associated with the development of the carriage state have not been previously identified. We have developed an animal model of cholera in adult C57BL/6 mice wherein V. cholerae colonizes the mucus layer and forms microcolonies in the crypts of the distal small bowel. Colonization occurred 1 to 3 h after oral inoculation and peaked at 10 to 12 h, when bacterial loads exceeded the inoculum by 10- to 200-fold, indicating bacterial growth within the small intestine. After a clearance phase, the number of bacteria within the small intestine, but not those in the cecum or colon, stabilized and persisted for at least 72 h. The ability of V. cholerae to prevent clearance and establish this prolonged colonization was associated with the accessory toxins hemolysin, the multifunctional autoprocessing RTX toxin, and hemagglutinin/protease and did not require cholera toxin or toxin-coregulated pili. The defect in colonization attributed to the loss of the accessory toxins may be extracellularly complemented by inoculation of the defective strain with an isogenic colonization-proficient V. cholerae strain. This work thus demonstrates that secreted accessory toxins modify the host environment to enable prolonged colonization of the small intestine in the absence of overt disease symptoms and thereby contribute to disease dissemination via asymptomatic carriers. PMID- 17698572 TI - Respiration of Escherichia coli in the mouse intestine. AB - Mammals are aerobes that harbor an intestinal ecosystem dominated by large numbers of anaerobic microorganisms. However, the role of oxygen in the intestinal ecosystem is largely unexplored. We used systematic mutational analysis to determine the role of respiratory metabolism in the streptomycin treated mouse model of intestinal colonization. Here we provide evidence that aerobic respiration is required for commensal and pathogenic Escherichia coli to colonize mice. Our results showed that mutants lacking ATP synthase, which is required for all respiratory energy-conserving metabolism, were eliminated by competition with respiratory-competent wild-type strains. Mutants lacking the high-affinity cytochrome bd oxidase, which is used when oxygen tensions are low, also failed to colonize. However, the low-affinity cytochrome bo(3) oxidase, which is used when oxygen tension is high, was found not to be necessary for colonization. Mutants lacking either nitrate reductase or fumarate reductase also had major colonization defects. The results showed that the entire E. coli population was dependent on both microaerobic and anaerobic respiration, consistent with the hypothesis that the E. coli niche is alternately microaerobic and anaerobic, rather than static. The results indicate that success of the facultative anaerobes in the intestine depends on their respiratory flexibility. Despite competition for relatively scarce carbon sources, the energy efficiency provided by respiration may contribute to the widespread distribution (i.e., success) of E. coli strains as commensal inhabitants of the mammalian intestine. PMID- 17698573 TI - Hemolysin and the multifunctional autoprocessing RTX toxin are virulence factors during intestinal infection of mice with Vibrio cholerae El Tor O1 strains. AB - The seventh cholera pandemic that started in 1961 was caused by Vibrio cholerae O1 strains of the El Tor biotype. These strains produce the pore-forming toxin hemolysin, a characteristic used clinically to distinguish classical and El Tor biotypes. Even though extensive in vitro data on the cytolytic activities of hemolysin exist, the connection of hemolysin to virulence in vivo is not well characterized. To study the contribution of hemolysin and other accessory toxins to pathogenesis, we utilized the model of intestinal infection in adult mice sensitive to the actions of accessory toxins. In this study, we showed that 4- to 6-week-old streptomycin-fed C57BL/6 mice were susceptible to intestinal infection with El Tor strains, which caused rapid death at high doses. Hemolysin had the predominant role in lethality, with a secondary contribution by the multifunctional autoprocessing RTX (MARTX) toxin. Cholera toxin and hemagglutinin/protease did not contribute to lethality in this model. Rapid death was not caused by increased dissemination due to a damaged epithelium since the numbers of CFU recovered from spleens and livers 6 h after infection did not differ between mice inoculated with hemolysin-expressing strains and those infected with non-hemolysin-expressing strains. Although accessory toxins were linked to virulence, a strain defective in the production of accessory toxins was still immunogenic since mice immunized with a multitoxin-deficient strain were protected from a subsequent lethal challenge with the wild type. These data suggest that hemolysin and MARTX toxin contribute to vaccine reactogenicity but that the genes for these toxins can be deleted from vaccine strains without affecting vaccine efficacy. PMID- 17698574 TI - Constitutive acid sphingomyelinase enhances early and late macrophage killing of Salmonella enterica serovar Typhimurium. AB - We have identified acid sphingomyelinase (ASM) as an important player in the early and late anti-Salmonella activity of macrophages. A functional ASM participated in the killing activity of macrophages against wild-type Salmonella enterica serovar Typhimurium. The role of ASM in early macrophage killing of Salmonella appears to be linked to an active NADPH phagocyte oxidase enzymatic complex, since the flavoprotein inhibitor diphenyleneiodonium not only blocked a productive respiratory burst but also abrogated the survival advantage of Salmonella in macrophages lacking ASM. Lack of ASM activity also increased the intracellular survival of an isogenic DeltaspiC::FRT Salmonella strain deficient in a translocator and effector of the Salmonella pathogenicity island 2 (SPI2) type III secretion system, suggesting that the antimicrobial activity associated with ASM is manifested regardless of the SPI2 status of the bacteria. Constitutively expressed ASM is responsible for the role that this lipid metabolizing hydrolase plays in the innate host defense of macrophages against Salmonella. Accordingly, the ASM activity and intracellular concentration and composition of ceramide, gangliosides, and neutral sphingolipids did not increase upon Salmonella infection. Salmonella triggered, nonetheless, a significant increase in the secreted fraction of ASM. Collectively, these findings have elucidated a novel role for constitutive ASM in the anti-Salmonella activity of murine macrophages. PMID- 17698575 TI - Taenia solium oncosphere adhesion to intestinal epithelial and Chinese hamster ovary cells in vitro. AB - The specific mechanisms underlying Taenia solium oncosphere adherence and penetration in the host have not been studied previously. We developed an in vitro adhesion model assay to evaluate the mechanisms of T. solium oncosphere adherence to the host cells. The following substrates were used: porcine intestinal mucosal scrapings (PIMS), porcine small intestinal mucosal explants (PSIME), Chinese hamster ovary cells (CHO cells), epithelial cells from ileocecal colorectal adenocarcinoma (HCT-8 cells), and epithelial cells from colorectal adenocarcinoma (Caco-2 cells). CHO cells were used to compare oncosphere adherence to fixed and viable cells, to determine the optimum time of oncosphere incubation, to determine the role of sera and monolayer cell maturation, and to determine the effect of temperature on oncosphere adherence. Light microscopy, scanning microscopy, and transmission microscopy were used to observe morphological characteristics of adhered oncospheres. This study showed in vitro adherence of activated T. solium oncospheres to PIMS, PSIME, monolayer CHO cells, Caco-2 cells, and HCT-8 cells. The reproducibility of T. solium oncosphere adherence was most easily measured with CHO cells. Adherence was enhanced by serum-binding medium with >5% fetal bovine serum, which resulted in a significantly greater number of oncospheres adhering than the number adhering when serum at a concentration less than 2.5% was used (P < 0.05). Oncosphere adherence decreased with incubation of cells at 4 degrees C compared with the adherence at 37 degrees C. Our studies also demonstrated that T. solium oncospheres attach to cells with elongated microvillus processes and that the oncospheres expel external secretory vesicles that have the same oncosphere processes. PMID- 17698576 TI - CD4 T-cell epitopes associated with protective immunity induced following vaccination of mice with an ehrlichial variable outer membrane protein. AB - The ehrlichiae express variable outer membrane proteins (OMPs) that play important roles in both pathogenesis and host defense. Previous studies revealed that OMPs are immunodominant B-cell antigens and that passive transfer of anti OMP antibodies can protect SCID mice from fatal ehrlichial infection. In this study, we used a model of fatal monocytotropic ehrlichiosis caused by Ehrlichia bacteria from Ixodes ovatus (IOE) to determine whether OMP immunization could generate protective immunity in immunocompetent mice. Immunization of C57BL/6 mice with a purified recombinant OMP expressed by IOE omp19 generated protection from fatal IOE infection and elicited robust humoral and CD4 T-cell responses. To identify CD4 T-cell epitopes within OMPs, we performed enzyme-linked immunospot analyses for gamma interferon (IFN-gamma) production using a panel of overlapping 16-mer peptides from IOE OMP-19. Five immunoreactive peptides comprising residues 30 to 45, 77 to 92, 107 to 122, 197 to 212, and 247 to 264 were identified; the strongest response was generated against OMP-19(107-122). Most of the peptides are conserved between E. muris and E. chaffeensis OMP-19, and they elicited IFN gamma production in CD4 T cells from E. muris-infected mice, indicating that T cell epitope cross-reactivity likely contributes to heterologous immunity. Accordingly, CD4 T-cell responses to both OMP-19 and OMP-19(107-122) were of greater magnitude following high-dose IOE challenge of mice that had been immunized by prior infection with E. muris. Our studies cumulatively identify B- and T-cell epitopes that are associated with protective homologous and heterologous immunity during ehrlichial infection. PMID- 17698577 TI - Trivalent live attenuated intranasal influenza vaccine administered during the 2003-2004 influenza type A (H3N2) outbreak provided immediate, direct, and indirect protection in children. AB - OBJECTIVE: Live attenuated influenza vaccine may protect against wild-type influenza illness shortly after vaccine administration by innate immunity. The 2003-2004 influenza A (H3N2) outbreak arrived early, and the circulating strain was antigenically distinct from the vaccine strain. The objective of this study was to determine the effectiveness of influenza vaccines for healthy school-aged children when administered during the influenza outbreak. DESIGN/METHODS: An open labeled, nonrandomized, community-based influenza vaccine trial was conducted in children 5 to 18 years old. Age-eligible healthy children received trivalent live attenuated influenza vaccine. Trivalent inactivated influenza vaccine was given to children with underlying health conditions. Influenza-positive illness was compared between vaccinated and nonvaccinated children. Medically attended acute respiratory illness and pneumonia and influenza rates for Scott and White Health Plan vaccinees were compared with age-eligible Scott and White Health Plan nonparticipants in the intervention communities. Herd protection was assessed by comparing age-specific medically attended acute respiratory illness rates in Scott and White Health Plan members in the intervention and comparison communities. RESULTS: We administered 1 dose of trivalent live attenuated influenza vaccine or trivalent inactivated influenza vaccine to 6569 and 1040 children, respectively (31.5% vaccination coverage), from October 10 to December 30, 2003. The influenza outbreak occurred from October 12 to December 20, 2003. Significant protection against influenza-positive illness (37.3%) and pneumonia and influenza events (50%) was detected in children who received trivalent live attenuated influenza vaccine but not trivalent inactivated influenza vaccine. Trivalent live attenuated influenza vaccine recipients had similar protection against influenza-positive illness within 14 days compared with >14 days (10 of 25 vs 9 of 30) after vaccination. Indirect effectiveness against medically attended acute respiratory illness was detected in children 5 to 11 and adults 35 to 44 years of age. CONCLUSION: One dose of trivalent live attenuated influenza vaccine was efficacious in children even when administered during an influenza outbreak and when the dominant circulating influenza virus was antigenically distinct from the vaccine strain. We hypothesize that trivalent live attenuated influenza vaccine provides protection against influenza by both innate and adaptive immune mechanisms. PMID- 17698578 TI - Impact of interview mode on accuracy of child and parent report of adherence with asthma-controller medication. AB - OBJECTIVES: Parents and children often overreport adherence to treatment regimens, which in turn complicates interpretation and application of clinical trial findings. The objective of this investigation was to test the effect of reporting mode on accuracy of inhaled corticosteroid-adherence reporting in children with asthma and their parents under conditions similar to those of an asthma clinical trial. PATIENTS AND METHODS: Participants included 104 children who were being treated with an inhaled corticosteroid delivered by a metered-dose inhaler for asthma diagnosed by their health care provider. Each parent and child dyad was randomly assigned to 1 of 3 self-report adherence-assessment modes: (1) audio computer-assisted self-interviewing; (2) face-to-face interview with study staff; or (3) self-administered paper-and-pencil questionnaire. At the 4 monthly visits, the parent and child were interviewed separately and asked questions about adherence on the previous day and in the past week. Electronic devices were attached to the each participant's metered-dose inhaler to provide an objective record of actual daily medication activations. RESULTS: Both children and parents greatly overreported their inhaled corticosteroid adherence when queried about either time frame (1 day or 1 week) in any of the 3 interview modes. One of 3 responses reported full adherence when no medication had been taken. Inconsistent with the study hypothesis, discrepancy between self-report and objectively measured adherence was greatest in the computer-interview condition. In the optimal circumstance where children were interviewed by study staff about their adherence within the previous 24 hours, reported adherence was within the +/-25% accuracy range for only half of the participants. Larger discrepancy scores were observed for both parents and children when reporting by computer or questionnaire. CONCLUSIONS: Under the best of conditions in this study, accuracy of self-report was insufficient to provide a stand-alone measure of adherence. Verification of treatment adherence by objective measures remains necessary. PMID- 17698579 TI - Diagnostic tests for children who are referred for the investigation of Cushing syndrome. AB - OBJECTIVE: Endogenous Cushing syndrome in children is a rare disorder that is most frequently caused by pituitary or adrenocortical tumors. Diagnostic criteria have generally been derived from studies of adult patients despite significant differences in both the physiology of the hypothalamic-pituitary-adrenal axis and the epidemiology of Cushing syndrome in childhood. The purpose of this study was to identify the tests that most reliably and efficiently diagnose pituitary or adrenal tumors in a large cohort of pediatric patients with Cushing syndrome. METHODS: A retrospective review of clinical data of children who were referred to a tertiary care center for evaluation for Cushing syndrome during the years 1997 to 2005 was conducted. A total of 125 consecutive children were studied retrospectively; 105 were found to have Cushing syndrome, which was confirmed histologically; and 20 children who did not have Cushing syndrome or any other endocrinopathy served as the control group. The following tests were performed in all children: midnight and morning cortisol, corticotropin hormone, urinary free cortisol and 17-hydroxycorticosteroid levels, ovine corticotropin-releasing hormone stimulation test, and overnight high-dosage dexamethasone suppression test. Imaging of the pituitary and adrenal glands was also obtained. The main outcome measure was the sensitivity of these parameters for the diagnosis and differential diagnosis of Cushing syndrome at 100% specificity. RESULTS: A midnight cortisol value of > or = 4.4 microg/dL confirmed the diagnosis of Cushing syndrome in almost all children, with a sensitivity of 99% and a specificity of 100%. Suppression of morning cortisol levels > 20% in response to an overnight, high-dosage dexamethasone test excluded all patients with adrenal tumors and identified almost all patients with pituitary tumors (sensitivity: 97.5%; specificity: 100%). CONCLUSIONS: Our study suggests that among children who were referred for the evaluation of possible Cushing syndrome, a single cortisol value at midnight followed by overnight high-dosage dexamethasone test led to rapid and accurate confirmation and diagnostic differentiation, respectively, of hypercortisolemia caused by pituitary and adrenal tumors. PMID- 17698580 TI - A role for yeast and human translesion synthesis DNA polymerases in promoting replication through 3-methyl adenine. AB - 3-Methyl adenine (3meA), a minor-groove DNA lesion, presents a strong block to synthesis by replicative DNA polymerases (Pols). To elucidate the means by which replication through this DNA lesion is mediated in eukaryotic cells, here we carry out genetic studies in the yeast Saccharomyces cerevisiae treated with the alkylating agent methyl methanesulfonate. From the studies presented here, we infer that replication through the 3meA lesion in yeast cells can be mediated by the action of three Rad6-Rad18-dependent pathways that include translesion synthesis (TLS) by Pol(eta) or -zeta and an Mms2-Ubc13-Rad5-dependent pathway which presumably operates via template switching. We also express human Pols iota and kappa in yeast cells and show that they too can mediate replication through the 3meA lesion in yeast cells, indicating a high degree of evolutionary conservation of the mechanisms that control TLS in yeast and human cells. We discuss these results in the context of previous observations that have been made for the roles of Pols eta, iota, and kappa in promoting replication through the minor-groove N2-dG adducts. PMID- 17698581 TI - TOR signaling is a determinant of cell survival in response to DNA damage. AB - The conserved TOR (target of rapamycin) kinase is part of a TORC1 complex that regulates cellular responses to environmental stress, such as amino acid starvation and hypoxia. Dysregulation of Akt-TOR signaling has also been linked to the genesis of cancer, and thus, this pathway presents potential targets for cancer chemotherapeutics. Here we report that rapamycin-sensitive TORC1 signaling is required for the S-phase progression and viability of yeast cells in response to genotoxic stress. In the presence of the DNA-damaging agent methyl methanesulfonate (MMS), TOR-dependent cell survival required a functional S-phase checkpoint. Rapamycin inhibition of TORC1 signaling suppressed the Rad53 checkpoint-mediated induction of ribonucleotide reductase subunits Rnr1 and Rnr3, thereby abrogating MMS-induced mutagenesis and enhancing cell lethality. Moreover, cells deleted for RNR3 were hypersensitive to rapamycin plus MMS, providing the first demonstration that Rnr3 contributes to the survival of cells exposed to DNA damage. Our findings support a model whereby TORC1 acts as a survival pathway in response to genotoxic stress by maintaining the deoxynucleoside triphosphate pools necessary for error-prone translesion DNA polymerases. Thus, TOR-dependent cell survival in response to DNA-damaging agents coincides with increased mutation rates, which may contribute to the acquisition of chemotherapeutic drug resistance. PMID- 17698582 TI - Cyclin D3/CDK11p58 complex is involved in the repression of androgen receptor. AB - Androgen receptor (AR) is essential for the maintenance of the male reproductive systems and is critical for the carcinogenesis of human prostate cancers (PCas). D-type cyclins are closely related to the repression of AR function. It has been well documented that cyclin D1 inhibits AR function through multiple mechanisms, but the mechanism of how cyclin D3 exerts its repressive role in the AR signaling pathway remains to be identified. In the present investigation, we demonstrate that cyclin D3 and the 58-kDa isoform of cyclin-dependent kinase 11 (CDK11p58) repressed AR transcriptional activity as measured by reporter assays of transformed cells and prostate-specific antigen expression in PCa cells. AR, cyclin D3, and CDK11p58 formed a ternary complex in cells and were colocalized in the luminal epithelial layer of the prostate. AR activity is controlled by phosphorylation at specific sites. We found that AR was phosphorylated at Ser-308 by cyclin D3/CDK11p58 in vitro and in vivo, leading to the repressed activity of AR transcriptional activation unit 1 (TAU1). Furthermore, androgen-dependent proliferation of PCa cells was inhibited by cyclin D3/CDK11p58 through AR repression. These data suggest that cyclin D3/CDK11p58 signaling is involved in the negative regulation of AR function. PMID- 17698583 TI - Species selectivity of mixed-lineage leukemia/trithorax and HCF proteolytic maturation pathways. AB - Site-specific proteolytic processing plays important roles in the regulation of cellular activities. The histone modification activity of the human trithorax group mixed-lineage leukemia (MLL) protein and the cell cycle regulatory activity of the cell proliferation factor herpes simplex virus host cell factor 1 (HCF-1) are stimulated by cleavage of precursors that generates stable heterodimeric complexes. MLL is processed by a protease called taspase 1, whereas the precise mechanisms of HCF-1 maturation are unclear, although they are known to depend on a series of sequence repeats called HCF-1(PRO) repeats. We demonstrate here that the Drosophila homologs of MLL and HCF-1, called Trithorax and dHCF, are both cleaved by Drosophila taspase 1. Although highly related, the human and Drosophila taspase 1 proteins display cognate species specificity. Thus, human taspase 1 preferentially cleaves MLL and Drosophila taspase 1 preferentially cleaves Trithorax, consistent with coevolution of taspase 1 and MLL/Trithorax proteins. HCF proteins display even greater species-specific divergence in processing: whereas dHCF is cleaved by the Drosophila taspase 1, human and mouse HCF-1 maturation is taspase 1 independent. Instead, human and Xenopus HCF-1PRO repeats are cleaved in vitro by a human proteolytic activity with novel properties. Thus, from insects to humans, HCF proteins have conserved proteolytic maturation but evolved different mechanisms. PMID- 17698584 TI - Regulation of the extrinsic apoptotic pathway by the extracellular matrix glycoprotein EMILIN2. AB - Elastin microfibril interface-located proteins (EMILINs) constitute a family of extracellular matrix (ECM) glycoproteins characterized by the presence of an EMI domain at the N terminus and a gC1q domain at the C terminus. EMILIN1, the archetype molecule of the family, is involved in elastogenesis and hypertension etiology, whereas the function of EMILIN2 has not been resolved. Here, we provide evidence that the expression of EMILIN2 triggers the apoptosis of different cell lines. Cell death depends on the activation of the extrinsic apoptotic pathway following EMILIN2 binding to the TRAIL receptors DR4 and, to a lesser extent, DR5. Binding is followed by receptor clustering, colocalization with lipid rafts, death-inducing signaling complex assembly, and caspase activation. The direct activation of death receptors by an ECM molecule that mimics the activity of the known death receptor ligands is novel. The knockdown of EMILIN2 increases transformed cell survival, and overexpression impairs clonogenicity in soft agar and three-dimensional growth in natural matrices due to massive apoptosis. These data demonstrate an unexpected direct and functional interaction of an ECM constituent with death receptors and discloses an additional mechanism by which ECM cues can negatively affect cell survival. PMID- 17698585 TI - Human Cdc34 employs distinct sites to coordinate attachment of ubiquitin to a substrate and assembly of polyubiquitin chains. AB - The Cdc34 E2 ubiquitin (Ub) conjugating enzyme catalyzes polyubiquitination of a substrate recruited by the Skp1-Cullin 1-F-box protein-ROC1 E3 Ub ligase. Using mutagenesis studies, we now show that human Cdc34 employs distinct sites to coordinate the transfer of Ub to a substrate and the assembly of polyubiquitin chains. Mutational disruption of the conserved charged stretch (residues 143 to 153) or the acidic loop residues D102 and D103 led to accumulation of monoubiquitinated IkappaBalpha while failing to yield polyubiquitin chains, due to a catalytic defect in Ub-Ub ligation. These results suggest an ability of human Cdc34 to position the attacking Ub for assembly of polyubiquitin chains. Analysis of Cdc34N85Q and Cdc34S138A revealed severe defects of these mutants in both poly- and monoubiquitination of IkappaBalpha, supporting a role for N85 in stabilizing the oxyanion and in coordinating, along with S138, the attacking lysine for catalysis. Finally, Cdc34S95D and Cdc34(E108A/E112A) abolished both poly- and monoubiquitination of IkappaBalpha. Unexpectedly, the catalytic defects of these mutants in di-Ub synthesis can be rescued by fusion of a glutathione S transferase moiety at E2's N terminus. These findings support the hypothesis that human Cdc34 S95 and E108/E112 are required to position the donor Ub optimally for catalysis, in a manner that might depend on E2 dimerization. PMID- 17698586 TI - Reelin signals through phosphatidylinositol 3-kinase and Akt to control cortical development and through mTor to regulate dendritic growth. AB - Reelin is an extracellular matrix protein with various functions during development and in the mature brain. It activates different signaling cascades in target cells, one of which is the phosphatidylinositol 3-kinase (PI3K) pathway, which we investigated further using pathway inhibitors and in vitro brain slice and neuronal cultures. We show that the mTor (mammalian target of rapamycin)-S6K1 (S6 kinase 1) pathway is activated by Reelin and that this depends on Dab1 (Disabled-1) phosphorylation and activation of PI3K and Akt (protein kinase B). PI3K and Akt are required for the effects of Reelin on the organization of the cortical plate, but their downstream partners mTor and glycogen synthase kinase 3beta (GSK3beta) are not. On the other hand, mTor, but not GSK3beta, mediates the effects of Reelin on the growth and branching of dendrites of hippocampal neurons. In addition, PI3K fosters radial migration of cortical neurons through the intermediate zone, an effect that is independent of Reelin and Akt. PMID- 17698587 TI - Analysis of endogenous LRP6 function reveals a novel feedback mechanism by which Wnt negatively regulates its receptor. AB - The canonical Wnt pathway plays a crucial role in embryonic development, and its deregulation is involved in human diseases. The LRP6 single-span transmembrane coreceptor is essential for transmission of canonical Wnt signaling. However, due to the lack of immunological reagents, our understanding of LRP6 structure and function has relied on studies involving its overexpression, and regulation of the endogenous receptor by the Wnt ligand has remained unexplored. Using a highly sensitive and specific antibody to LRP6, we demonstrate that the endogenous receptor is modified by N-glycosylation and is phosphorylated in response to Wnt stimulation in a sustained yet ligand-dependent manner. Moreover, following triggering by Wnt, endogenous LRP6 is internalized and recycled back to the cellular membrane within hours of the initial stimulus. Finally, we have identified a novel feedback mechanism by which Wnt, acting through beta-catenin, negatively regulates LRP6 at the mRNA level. Together, these findings contribute significantly to our understanding of LRP6 function and uncover a new level of regulation of Wnt signaling. In light of the direct role that the Wnt pathway plays in human bone diseases and malignancies, our findings may support the development of novel therapeutic approaches that target Wnt signaling through LRP6. PMID- 17698588 TI - New markers for murine memory B cells that define mutated and unmutated subsets. AB - The study of murine memory B cells has been limited by small cell numbers and the lack of a definitive marker. We have addressed some of these difficulties with hapten-specific transgenic (Tg) mouse models that yield relatively large numbers of antigen-specific memory B cells upon immunization. Using these models, along with a 5-bromo-2'-deoxyuridine (BrdU) pulse-label strategy, we compared memory cells to their naive precursors in a comprehensive flow cytometric survey, thus revealing several new murine memory B cell markers. Most interestingly, memory cells were phenotypically heterogeneous. Particularly surprising was the finding of an unmutated memory B cell subset identified by the expression of CD80 and CD35. We confirmed these findings in an analogous V region knock-in mouse and/or in non-Tg mice. There also was anatomic heterogeneity, with BrdU(+) memory cells residing not just in the marginal zone, as had been thought, but also in splenic follicles. These studies impact the current understanding of murine memory B cells by identifying new phenotypes and by challenging assumptions about the location and V region mutation status of memory cells. The apparent heterogeneity in the memory compartment implies either different origins and/or different functions, which we discuss. PMID- 17698589 TI - Memory CD8+ T cells mediate antibacterial immunity via CCL3 activation of TNF/ROI+ phagocytes. AB - Cytolysis, interferon gamma and tumor necrosis factor (TNF) alpha secretion are major effector mechanisms of memory CD8+ T cells that are believed to be required for immunological protection in vivo. By using mutants of the intracellular bacterium Listeria monocytogenes, we found that none of these effector activities is sufficient to protect against secondary infection with wild-type (WT) bacteria. We demonstrated that CCL3 derived from reactivated memory CD8+ T cells is required for efficient killing of WT bacteria. CCL3 induces a rapid TNF-alpha secretion by innate inflammatory mononuclear phagocytic cells (MPCs), which further promotes the production of radical oxygen intermediates (ROIs) by both MPCs and neutrophils. ROI generation is the final bactericidal mechanism involved in L. monocytogenes clearance. These results therefore uncover two levels of regulation of the antibacterial secondary protective response: (a) an antigen dependent phase in which memory CD8+ T cells are reactivated and control the activation of the innate immune system, and (b) an antigen-independent phase in which the MPCs coordinate innate immunity and promote the bactericidal effector activities. In this context, CCL3-secreting memory CD8+ T cells are able to mediate "bystander" killing of an unrelated pathogen upon antigen-specific reactivation, a mechanism that may be important for the design of therapeutic vaccines. PMID- 17698590 TI - Presenilins regulate alphabeta T cell development by modulating TCR signaling. AB - TCRalphabeta signaling is crucial for the maturation of CD4 and CD8 T cells, but the role of the Notch signaling pathway in this process is poorly understood. Genes encoding Presenilin (PS) 1/2 were deleted to prevent activation of the multiple Notch receptors expressed by developing thymocytes. PS1/2 knockout thymocyte precursors inefficiently generate CD4 T cells, a phenotype that is most pronounced when thymocytes bear a single major histocompatibility complex (MHC) class II-restricted T cell receptor (TCR). Diminished T cell production correlated with evidence of impaired TCR signaling, and could be rescued by manipulations that enhance MHC recognition. Although Notch appears to directly regulate binary fate decisions in many systems, these findings suggest a model in which PS-dependent Notch signaling influences positive selection and the development of alphabeta T cells by modifying TCR signal transduction. PMID- 17698591 TI - Requirement for T-bet in the aberrant differentiation of unhelped memory CD8+ T cells. AB - Immunity to intracellular pathogens requires dynamic balance between terminal differentiation of short-lived, cytotoxic effector CD8+ T cells and self-renewal of central-memory CD8+ T cells. We now show that T-bet represses transcription of IL-7Ralpha and drives differentiation of effector and effector-memory CD8+ T cells at the expense of central-memory cells. We also found T-bet to be overexpressed in CD8+ T cells that differentiated in the absence of CD4+ T cell help, a condition that is associated with defective central-memory formation. Finally, deletion of T-bet corrected the abnormal phenotypic and functional properties of "unhelped" memory CD8+ T cells. T-bet, thus, appears to function as a molecular switch between central- and effector-memory cell differentiation. Antagonism of T-bet may, therefore, represent a novel strategy to offset dysfunctional programming of memory CD8+ T cells. PMID- 17698592 TI - Enzyme replacement in Fabry disease: pharmacokinetics and pharmacodynamics of agalsidase alpha in children and adolescents. AB - This multicenter, open-label study evaluated pharmacokinetics, pharmacodynamics, and safety of agalsidase alpha in pediatric compared with adult patients with Fabry disease. The pharmacokinetic parameters of pediatric patients (19 boys, 5 girls, 6-18 years old; mean age, 11.8 years) were compared to those of adult male and female patients who participated in other clinical studies. All patients received agalsidase alpha at a dose of 0.2 mg/kg infused over 40 minutes every other week. Agalsidase alpha exhibited a biphasic serum elimination profile with a maximum serum concentration at the end of the 40-minute infusion; <1% of the maximum concentration was detected 8 hours after dosing. In children, serum clearance was 2.0 to 9.4 mL/min/kg and tended to decrease with increasing age. The average clearance in children, 3.7 +/- 1.5 mL/min/kg (mean +/- SD), was significantly greater than that measured in 33 adults (2.3 +/- 0.7 mL/min/kg, P < .0001). Mean terminal elimination half-life of agalsidase alpha was prolonged in week 25 compared with baseline (150 vs 66 minutes) in 8 of 19 male children. The magnitude of the reduction of plasma globotriaosylceremide was similar in all age groups and was independent of area under the curve and other pharmacokinetic parameters. Except for clearance in younger patients, agalsidase alpha appears to have comparable pharmacokinetic and pharmacodynamic profiles in pediatric and adult Fabry patients of both genders. PMID- 17698593 TI - Estimation of the glomerular filtration rate from serum creatinine and cystatin C with regard to therapeutic digoxin monitoring. PMID- 17698594 TI - beta-Scorpion toxin modifies gating transitions in all four voltage sensors of the sodium channel. AB - Several naturally occurring polypeptide neurotoxins target specific sites on the voltage-gated sodium channels. Of these, the gating modifier toxins alter the behavior of the sodium channels by stabilizing transient intermediate states in the channel gating pathway. Here we have used an integrated approach that combines electrophysiological and spectroscopic measurements to determine the structural rearrangements modified by the beta-scorpion toxin Ts1. Our data indicate that toxin binding to the channel is restricted to a single binding site on domain II voltage sensor. Analysis of Cole-Moore shifts suggests that the number of closed states in the activation sequence prior to channel opening is reduced in the presence of toxin. Measurements of charge-voltage relationships show that a fraction of the gating charge is immobilized in Ts1-modified channels. Interestingly, the charge-voltage relationship also shows an additional component at hyperpolarized potentials. Site-specific fluorescence measurements indicate that in presence of the toxin the voltage sensor of domain II remains trapped in the activated state. Furthermore, the binding of the toxin potentiates the activation of the other three voltage sensors of the sodium channel to more hyperpolarized potentials. These findings reveal how the binding of beta-scorpion toxin modifies channel function and provides insight into early gating transitions of sodium channels. PMID- 17698595 TI - Control of inward rectifier K channel activity by lipid tethering of cytoplasmic domains. AB - Interactions between nontransmembrane domains and the lipid membrane are proposed to modulate activity of many ion channels. In Kir channels, the so-called "slide helix" is proposed to interact with the lipid headgroups and control channel gating. We examined this possibility directly in a cell-free system consisting of KirBac1.1 reconstituted into pure lipid vesicles. Cysteine substitution of positively charged slide-helix residues (R49C and K57C) leads to loss of channel activity that is rescued by in situ restoration of charge following modification by MTSET(+) or MTSEA(+), but not MTSES(-) or neutral MMTS. Strikingly, activity is also rescued by modification with long-chain alkyl-MTS reagents. Such reagents are expected to partition into, and hence tether the side chain to, the membrane. Systematic scanning reveals additional slide-helix residues that are activated or inhibited following alkyl-MTS modification. A pattern emerges whereby lipid tethering of the N terminus, or C terminus, of the slide-helix, respectively inhibits, or activates, channel activity. This study establishes a critical role of the slide-helix in Kir channel gating, and directly demonstrates that physical interaction of soluble domains with the membrane can control ion channel activity. PMID- 17698596 TI - KCNE1 and KCNE3 stabilize and/or slow voltage sensing S4 segment of KCNQ1 channel. AB - KCNQ1 is a voltage-dependent K(+) channel whose gating properties are dramatically altered by association with auxiliary KCNE proteins. For example, KCNE1, which is mainly expressed in heart and inner ear, markedly slows the activation kinetics of KCNQ1. Whether the voltage-sensing S4 segment moves differently in the presence of KCNE1 is not yet known, however. To address that question, we systematically introduced cysteine mutations, one at a time, into the first half of the S4 segment of human KCNQ1. A226C was found out as the most suited mutant for a methanethiosulfonate (MTS) accessibility analysis because it is located at the N-terminal end of S4 segment and its current was stable with repetitive stimuli in the absence of MTS reagent. MTS accessibility analysis revealed that the apparent second order rate constant for modification of the A226C mutant was state dependent, with faster modification during depolarization, and was 13 times slower in the presence of KCNE1 than in its absence. In the presence of KCNE3, on the other hand, the second order rate constant for modification was not state dependent, indicating that the C226 residue was always exposed to the extracellular milieu, even at the resting membrane potential. Taken together, these results suggest that KCNE1 stabilizes the S4 segment in the resting state and slows the rate of transition to the active state, while KCNE3 stabilizes the S4 segment in the active state. These results offer new insight into the mechanism of KCNQ1 channel modulation by KCNE1 and KCNE3. PMID- 17698597 TI - A switch from prohormone convertase (PC)-2 to PC1/3 expression in transplanted alpha-cells is accompanied by differential processing of proglucagon and improved glucose homeostasis in mice. AB - OBJECTIVE: Glucagon, which raises blood glucose levels by stimulating hepatic glucose production, is produced in alpha-cells via cleavage of proglucagon by prohormone convertase (PC)-2. In the enteroendocrine L-cell, proglucagon is differentially processed by the alternate enzyme PC1/3 to yield glucagon-like peptide (GLP)-1, GLP-2, and oxyntomodulin, which have blood glucose-lowering effects. We hypothesized that alteration of PC expression in alpha-cells might convert the alpha-cell from a hyperglycemia-promoting cell to one that would improve glucose homeostasis. RESEARCH DESIGN AND METHODS: We compared the effect of transplanting encapsulated PC2-expressing alpha TC-1 cells with PC1/3 expressing alpha TCDeltaPC2 cells in normal mice and low-dose streptozotocin (STZ)-treated mice. RESULTS: Transplantation of PC2-expressing alpha-cells increased plasma glucagon levels and caused mild fasting hyperglycemia, impaired glucose tolerance, and alpha-cell hypoplasia. In contrast, PC1/3-expressing alpha cells increased plasma GLP-1/GLP-2 levels, improved glucose tolerance, and promoted beta-cell proliferation. In GLP-1R(-/-) mice, the ability of PC1/3 expressing alpha-cells to improve glucose tolerance was attenuated. Transplantation of PC1/3-expressing alpha-cells prevented STZ-induced hyperglycemia by preserving beta-cell area and islet morphology, possibly via stimulating beta-cell replication. However, PC2-expressing alpha-cells neither prevented STZ-induced hyperglycemia nor increased beta-cell proliferation. Transplantation of alpha TCDeltaPC2, but not alpha TC-1 cells, also increased intestinal epithelial proliferation. CONCLUSIONS: Expression of PC1/3 rather than PC2 in alpha-cells induces GLP-1 and GLP-2 production and converts the alpha-cell from a hyperglycemia-promoting cell to one that lowers blood glucose levels and promotes islet survival. This suggests that alteration of proglucagon processing in the alpha-cell may be therapeutically useful in the context of diabetes. PMID- 17698598 TI - Low birth weight and zygosity status is associated with defective muscle glycogen and glycogen synthase regulation in elderly twins. AB - OBJECTIVE: An adverse intrauterine environment indicated by both low birth weight and monozygosity is associated with an age- or time-dependent reduction in glucose disposal and nonoxidative glucose metabolism in twins, suggesting impaired regulation of muscle glycogen synthesis. RESEARCH DESIGN AND METHODS: We measured the activities of glycogen synthase (GS), GS kinase (GSK)3 alpha, GS phosphorylation, and glycogen levels in muscle biopsies obtained from 184 young and elderly twins before and after a euglycemic-hyperinsulinemic clamp. RESULTS: Elderly monozygotic twins had significantly lower fractional GS activity amidst higher glycogen and GS protein levels compared with dizygotic twins. In addition, we demonstrated strong nongenetic associations between birth weight and defect muscle glycogen metabolism in elderly--but not in younger--twins. Thus, for every 100 g increase in birth weight within pairs, GS fractional activity, GS protein level, and glycogen content was increased by 4.2, 8.7, and 4.5%, respectively, in elderly twins. Similarly, for every 100 g increase in birth weight, GSK3 alpha activity and GS phosphorylation at the sites 2, 2+2a, and 3a+3b were decreased by 3.1, 9.0, 10.1, and 9.5%, respectively. CONCLUSIONS: The age- or time-dependent nongenetic impact of birth weight on insulin action in twins may partly be explained by reduced insulin activation of muscle GS, mediated through increased GSK3 alpha activity and GS phosphorylation. Reduced GS activity and negative feedback inhibition of glycogen metabolism by glycogen per se may contribute to the insulin resistance in elderly monozygotic compared with dizygotic twins. PMID- 17698599 TI - Frequency of the G/G genotype of resistin single nucleotide polymorphism at -420 appears to be increased in younger-onset type 2 diabetes. AB - OBJECTIVE: Resistin is an adipocyte-secreted cytokine associated with insulin resistance in mice. We previously reported that the G/G genotype of a resistin single nucleotide polymorphism (SNP) at -420 increases type 2 diabetes susceptibility by enhancing its promoter activity. The aim of the present study was to determine the relevance of SNP -120 in a large number of subjects. RESEARCH DESIGN AND METHODS: We examined 2,610 type 2 diabetic case and 2,502 control subjects. The relation between SNP -420 and the age of type 2 diabetes onset was further analyzed by adding 237 type 2 diabetic subjects with age of onset or=40 years (G/G vs. C/C, P = 0.003). In a total of 2,430 type 2 diabetic subjects with age of onset <60 years, the trend test showed that the G/G genotype had an increasing linear trend as the age grade of type 2 diabetes onset became younger (P = 0.0379). In control subjects, the frequency of C/G genotype showed an increasing linear trend with increasing age (P = 0.010). CONCLUSIONS: The G/G genotype frequency of resistin SNP -420 appears to be increased in younger-onset type 2 diabetic subjects. PMID- 17698601 TI - Predictors of incident depression after hip fracture surgery. AB - OBJECTIVE: Depression after hip fracture surgery is prevalent and associated with increased mortality rates and impaired functional recovery. The incidence of new onset depressive symptoms in patients initially not depressed after hip fracture surgery and their relationship with functional recovery is unknown. METHODS: A cohort of 139 nondepressed elderly patients (>60 years) hospitalized for hip fracture surgery were followed up for six months. Clinically significant depressive symptoms were defined as a score of 7 or more on the 15-item Geriatric Depression Scale. RESULTS: The authors found a cumulative incidence rate of 20.5% adjusted for dropouts. Multiple Cox-regression analyses yielded the presence of subthreshold symptoms of depression, anxiety, pain, and cognitive impairment at baseline, the premorbid level of mobility, and a history of (treated) depression as risk factors for incident depression (p <0.05). A forward, conditional procedure identified postoperative pain (hazard ratio [HR] = 1.32, 95% confidence interval [CI]: 1.14-1.53, Wald chi(2) = 13.57, df = 1, p <0.001) and baseline anxiety (HR = 1.25, 95% CI: 1.08-1.44, Wald chi(2) = 8.86, df = 1, p = 0.003) as the strongest independent risk factors. Incident depression was associated with a less favorable outcome at 3 months follow-up. CONCLUSION: This exploratory study identified two treatable baseline characteristics that predicted incident depression in nondepressed patients after hip-fracture surgery. PMID- 17698600 TI - Genotype by diabetes interaction effects on the detection of linkage of glomerular filtration rate to a region on chromosome 2q in Mexican Americans. AB - OBJECTIVE: Glomerular filtration rate (GFR) is used to assess the progression of renal disease. We performed linkage analysis to localize genes that influence GFR using estimated GFR data from the San Antonio Family Diabetes/Gallbladder Study. We also examined the effect of genotype by diabetes interaction (G x DM) on the detection of linkage to address whether genetic effects on GFR differ in diabetic and nondiabetic subjects. RESEARCH DESIGN AND METHODS: GFR (N = 453) was estimated using the recently recalculated Cockcroft-Gault (GFR-CGc) and the simplified Modification of Diet in Renal Disease (GFR-4VMDRD) formulae. Both estimates of GFR exhibited significant heritabilities, but only GFR-CGc showed significant G x DM interaction. We therefore performed multipoint linkage analyses on both GFR measures using models that did not include G x DM interaction effects (Model 1) and that included G x DM interaction effects (Model 2, in the case of GFR-CGc). RESULTS: The strongest evidence for linkage (Model 1) of both GFR-CGc (logarithm of odds [LOD] 2.9) and GFR-4VMDRD (LOD 2.6) occurred between markers D9S922 and D9S1120 on chromosome 9q. However, using Model 2, the strongest evidence for linkage of GFR-CGc on chromosome 2q was found near marker D2S427 (corrected LOD score [LOD(C)] 3.3) compared with the LOD score of 2.7 based on Model 1. Potential linkages (LOD or LOD(C) >or=1.2) were found only for GFR-CGc on chromosomes 3p, 3q, 4p, 8q, 11q, and 14q. CONCLUSIONS: We found a major locus on chromosome 2q that differentially influences GFR in diabetic and nondiabetic environments in the Mexican-American population. PMID- 17698602 TI - Depression morbidity in later life: prevalence and correlates in a developing country. AB - OBJECTIVE: To investigate the one-month prevalence of depression morbidity and its association with sociodemographic characteristics, health and functional status, and use of health services in community residents aged 60 years and over in Brazil. METHODS: This study used a cross-sectional design of face-to-face interviews (N = 7,040) in Rio Grande do Sul State, Brazil. Participants were household residents aged 60 years and older. Measurements included the Short Psychiatric Evaluation Schedule (six-item version) and questionnaire that assessed sociodemographic characteristics, self-reported health status, systemic illnesses, activities of daily living (ADL), use of medical services, and social support. RESULTS: The overall prevalence of depression morbidity was 22% (men: 18%, women: 25.2%). In controlled analyses, younger age, low income, rural origin, never or no longer married, poor self-rated health, presence of systemic illnesses, visual, hearing, or ADL impairments, hospitalization in the past 12 months, and lack of exercise or employment were significantly associated with depression morbidity, whereas living alone was nearly so associated. Gender, education, minority race, or outpatient visits in the previous six months were not associated with depression morbidity. CONCLUSION: The overall prevalence of depression morbidity was among the highest previously reported for older persons. In controlled analyses, prevalence declined as age increased, and rates were higher for those with lower income and poorer social, health, and functional status, but did not differ significantly by gender, education, or race/ethnicity. Increased attention should be paid to identifying depression morbidity in those with adverse circumstances and to identifying ameliorating interventions. PMID- 17698603 TI - Terry Lechler: the cytoskeleton is skin deep. Interview by Nicole LeBrasseur. AB - If form is function, Terry Lechler thinks scientists should know more about how cells acquire their form. That's one reason he studies the cytoskeleton. PMID- 17698604 TI - A seamless trespass: germ cell migration across the seminiferous epithelium during spermatogenesis. AB - During spermatogenesis, preleptotene spermatocytes traverse the blood-testis barrier (BTB) in the seminiferous epithelium, which is reminiscent of viral pathogens breaking through the tight junctions of host epithelial cells. The process also closely resembles the migration of leukocytes across endothelial tight junctions to reach inflammation sites. Cell adhesion molecules of the immunoglobulin superfamily (e.g., JAM/CAR/nectin) participate in germ cell migration by conferring transient adhesion between Sertoli and germ cells through homophilic and heterophilic interactions. The same molecules also comprise the junctional complexes at the BTB. Interestingly, JAM/CAR/nectin molecules mediate virus uptake and leukocyte transmigration in strikingly similar manners. It is likely that the strategy used by viruses and leukocytes to break through junctional barriers is used by germ cells to open up the inter-Sertoli cell junctions. In associating these diverse cellular events, we highlight the "guiding" role of JAM/CAR/nectin molecules for germ cell passage. Knowledge on viral invasion and leukocyte transmigration has also shed insights into germ cell movement during spermatogenesis. PMID- 17698605 TI - An in vitro nuclear disassembly system reveals a role for the RanGTPase system and microtubule-dependent steps in nuclear envelope breakdown. AB - During prophase, vertebrate cells disassemble their nuclear envelope (NE) in the process of NE breakdown (NEBD). We have established an in vitro assay that uses mitotic Xenopus laevis egg extracts and semipermeabilized somatic cells bearing a green fluorescent protein-tagged NE marker to study the molecular requirements underlying the dynamic changes of the NE during NEBD by live microscopy. We applied our in vitro system to analyze the role of the Ran guanosine triphosphatase (GTPase) system in NEBD. Our study shows that high levels of RanGTP affect the dynamics of late steps of NEBD in vitro. Also, inhibition of RanGTP production by RanT24N blocks the dynamic rupture of nuclei, suggesting that the local generation of RanGTP around chromatin may serve as a spatial cue in NEBD. Furthermore, the microtubule-depolymerizing drug nocodazole interferes with late steps of nuclear disassembly in vitro. High resolution live cell imaging reveals that microtubules are involved in the completion of NEBD in vivo by facilitating the efficient removal of membranes from chromatin. PMID- 17698606 TI - SCAPER, a novel cyclin A-interacting protein that regulates cell cycle progression. AB - Cyclin A/Cdk2 plays an important role during S and G2/M phases of the eukaryotic cell cycle, but the mechanisms by which it regulates cell cycle events are not fully understood. We have biochemically purified and identified SCAPER, a novel protein that specifically interacts with cyclin A/Cdk2 in vivo. Its expression is cell cycle independent, and it associates with cyclin A/Cdk2 at multiple phases of the cell cycle. SCAPER localizes primarily to the endoplasmic reticulum. Ectopic expression of SCAPER sequesters cyclin A from the nucleus and results specifically in an accumulation of cells in M phase of the cell cycle. RNAi mediated depletion of SCAPER decreases the cytoplasmic pool of cyclin A and delays the G1/S phase transition upon cell cycle re-entry from quiescence. We propose that SCAPER represents a novel cyclin A/Cdk2 regulatory protein that transiently maintains this kinase in the cytoplasm. SCAPER could play a role in distinguishing S phase- from M phase-specific functions of cyclin A/Cdk2. PMID- 17698607 TI - Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium. AB - The HMG-box transcription factor Sox9 is expressed in the intestinal epithelium, specifically, in stem/progenitor cells and in Paneth cells. Sox9 expression requires an active beta-catenin-Tcf complex, the transcriptional effector of the Wnt pathway. This pathway is critical for numerous aspects of the intestinal epithelium physiopathology, but processes that specify the cell response to such multipotential signals still remain to be identified. We inactivated the Sox9 gene in the intestinal epithelium to analyze its physiological function. Sox9 inactivation affected differentiation throughout the intestinal epithelium, with a disappearance of Paneth cells and a decrease of the goblet cell lineage. Additionally, the morphology of the colon epithelium was severely altered. We detected general hyperplasia and local crypt dysplasia in the intestine, and Wnt pathway target genes were up-regulated. These results highlight the central position of Sox9 as both a transcriptional target and a regulator of the Wnt pathway in the regulation of intestinal epithelium homeostasis. PMID- 17698608 TI - Cells that express MyoD mRNA in the epiblast are stably committed to the skeletal muscle lineage. AB - The epiblast of the chick embryo contains cells that express MyoD mRNA but not MyoD protein. We investigated whether MyoD-positive (MyoDpos) epiblast cells are stably committed to the skeletal muscle lineage or whether their fate can be altered in different environments. A small number of MyoDpos epiblast cells were tracked into the heart and nervous system. In these locations, they expressed MyoD mRNA and some synthesized MyoD protein. No MyoDpos epiblast cells differentiated into cardiac muscle or neurons. Similar results were obtained when MyoDpos cells were isolated from the epiblast and microinjected into the precardiac mesoderm or neural plate. In contrast, epiblast cells lacking MyoD differentiated according to their environment. These results demonstrate that the epiblast contains both multipotent cells and a subpopulation of cells that are stably committed to the skeletal muscle lineage before the onset of gastrulation. Stable programming in the epiblast may ensure that MyoDpos cells express similar signaling molecules in a variety of environments. PMID- 17698609 TI - Barrier to autointegration factor blocks premature cell fusion and maintains adult muscle integrity in C. elegans. AB - Barrier to autointegration factor (BAF) binds double-stranded DNA, selected histones, transcription regulators, lamins, and LAP2-emerin-MAN1 (LEM) domain proteins. During early Caenorhabditis elegans embryogenesis, BAF-1 is required to organize chromatin, capture segregated chromosomes within the nascent nuclear envelope, and assemble lamin and LEM domain proteins in reforming nuclei. In this study, we used C. elegans with a homozygous deletion of the baf-1 gene, which survives embryogenesis and larval stages, to report that BAF-1 regulates maturation and survival of the germline, cell migration, vulva formation, and the timing of seam cell fusion. In the seam cells, BAF-1 represses the expression of the EFF-1 fusogen protein, but fusion still occurs in C. elegans lacking both baf 1 and eff-1. This suggests the existence of an eff-1-independent mechanism for cell fusion. BAF-1 is also required to maintain the integrity of specific body wall muscles in adult animals, directly implicating BAF in the mechanism of human muscular dystrophies (laminopathies) caused by mutations in the BAF-binding proteins emerin and lamin A. PMID- 17698610 TI - Src kinase activity and SH2 domain regulate the dynamics of Src association with lipid and protein targets. AB - Src functions depend on its association with the plasma membrane and with specific membrane-associated assemblies. Many aspects of these interactions are unclear. We investigated the functions of kinase, SH2, and SH3 domains in Src membrane interactions. We used FRAP beam-size analysis in live cells expressing a series of c-Src-GFP proteins with targeted mutations in specific domains together with biochemical experiments to determine whether the mutants can generate and bind to phosphotyrosyl proteins. Wild-type Src displays lipid-like membrane association, whereas constitutively active Src-Y527F interacts transiently with slower-diffusing membrane-associated proteins. These interactions require Src kinase activity and SH2 binding, but not SH3 binding. Furthermore, overexpression of paxillin, an Src substrate with a high cytoplasmic population, competes with membrane phosphotyrosyl protein targets for binding to activated Src. Our observations indicate that the interactions of Src with lipid and protein targets are dynamic and that the kinase and SH2 domain cooperate in the membrane targeting of Src. PMID- 17698611 TI - Lactation after normal pregnancy is not associated with blood glucose fluctuations. PMID- 17698612 TI - Cognitive function and army rejection rate in young adult male offspring of women with diabetes: a Danish population-based cohort study. AB - OBJECTIVE: While maternal diabetes is a known risk factor for perinatal complications, there is little data on long-term intellectual outcome in offspring. We compare the rejection rate and cognitive functioning of military conscripts according to maternal diabetes status during pregnancy. RESEARCH DESIGN AND METHODS: We identified a cohort of Danish male offspring of diabetic mothers born between 1976 and 1984 and followed this cohort together with population-based control subjects to military conscription. The main outcome was army rejection rate and cognitive function measured with a validated intelligence test. RESULTS: The army rejection rate was 52.5% among 282 men whose mothers had diabetes during pregnancy and 45.4% among 870 control subjects (risk difference 7.3 [95% CI 0.6-14.0]). Mean cognitive scores were 41.4 units (95% CI 40.2-42.6) in diabetes-exposed conscripts and 42.7 units (42.0-43.4) in control subjects. Stratification by gestational age, Apgar score, and White's class (A-F) did not change the associations. In a subgroup analysis using available data on A1C levels during pregnancy, this variable was inversely associated with cognitive functioning. In men with maternal A1C <7%, cognitive scores were identical to those in control subjects. CONCLUSIONS: The slightly higher army rejection rate in men with maternal diabetes indicates higher morbidity. The identical cognitive functioning in cases of well-controlled maternal diabetes compared with that in control subjects is reassuring, but the negative association between A1C and cognitive score highlights the importance of striving for optimal metabolic control in diabetic women who are or plan to become pregnant. PMID- 17698613 TI - Five-year prevalence and persistence of disturbed eating behavior and eating disorders in girls with type 1 diabetes. PMID- 17698614 TI - Cost-effectiveness of screening for pre-diabetes among overweight and obese U.S. adults. AB - OBJECTIVE: To estimate the cost-effectiveness of screening overweight and obese individuals for pre-diabetes and then modifying their lifestyle based on the Diabetes Prevention Program (DPP). RESEARCH DESIGN AND METHODS: A Markov simulation model was used to estimate disease progression, costs, and quality of life. Cost-effectiveness was evaluated from a health care system perspective. We considered two screening/treatment strategies for pre-diabetes. Strategy 1 included screening overweight subjects and giving them the lifestyle intervention included in the DPP if they were diagnosed with both impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). Strategy 2 included screening followed by lifestyle intervention for subjects diagnosed with either IGT or IFG or both. Each strategy was compared with a program of no screening. RESULTS: Screening for pre-diabetes and treating those identified as having both IGT and IFG with the DPP lifestyle intervention had a cost-effectiveness ratio of $8,181 per quality adjusted life-year (QALY) relative to no screening. If treatment was also provided to subjects with only IGT or only IFG (strategy 2), the cost effectiveness ratio increased to $9,511 per QALY. Changes in screening-related parameters had small effects on the cost-effectiveness ratios; the results were more sensitive to changes in intervention-related parameters. CONCLUSIONS: Screening for pre-diabetes in the overweight and obese U.S. population followed by the DPP lifestyle intervention has a relatively attractive cost-effectiveness ratio. PMID- 17698615 TI - Pramlintide improved glycemic control and reduced weight in patients with type 2 diabetes using basal insulin. AB - OBJECTIVE: To assess the efficacy and safety of pramlintide in patients with type 2 diabetes suboptimally controlled with basal insulin. RESEARCH DESIGN AND METHODS: In a 16-week, double-blind, placebo-controlled study, 212 patients using insulin glargine with or without oral antidiabetes agents (OAs) were randomized to addition of pramlintide (60 or 120 microg b.i.d./t.i.d.) or placebo. Insulin glargine was adjusted to target a fasting plasma glucose concentration of 70-100 mg/dl. One coprimary end point was the change in A1C at week 16. The other coprimary end point was a composite measure of overall diabetes control comprising A1C < or = 7.0% or reduction > or = 0.5%, mean daily postprandial glucose (PPG) increments < or = 40 mg/dl, no increase in body weight, and no severe hypoglycemia. Patients meeting all four conditions at week 16 achieved this end point. RESULTS: More pramlintide- than placebo-treated patients achieved the composite end point (25 vs. 7%; P < 0.001). Reductions (means +/- SE) in A1C (-0.70 +/- 0.11% vs. -0.36 +/- 0.08%; P < 0.05) and PPG increments (-24.4 +/- 3.6 mg/dl vs. -0.4 +/- 3.0 mg/dl; P < 0.0001) were greater in pramlintide- versus placebo-treated patients, respectively. Glycemic improvements were accompanied by progressive weight loss with pramlintide and weight gain with placebo (-1.6 +/- 0.3 kg vs. +0.7 +/- 0.3 kg; P < 0.0001). No treatment-related severe hypoglycemia occurred. CONCLUSIONS: Pramlintide improved multiple glycemic parameters and reduced weight with no increase in hypoglycemia in patients with type 2 diabetes who were not achieving glycemic targets with basal insulin with or without OAs. PMID- 17698616 TI - Comparison of accuracy measures of two screening tests for gestational diabetes mellitus. AB - OBJECTIVE: To compare the accuracy measures of the random glucose test and the 50 g glucose challenge test as screening tests for gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: In this prospective cohort study, pregnant women without preexisting diabetes in two perinatal centers in the Netherlands underwent a random glucose test and a 50-g glucose challenge test between 24 and 28 weeks of gestation. If one of the screening tests exceeded predefined threshold values, the 75-g oral glucose tolerance test (OGTT) was performed within 1 week. Furthermore, the OGTT was performed in a random sample of women in whom both screening tests were normal. GDM was considered present when the OGTT (reference test) exceeded predefined threshold values. Receiver operating characteristic (ROC) analysis was used to evaluate the performance of the two screening tests. The results were corrected for verification bias. RESULTS: We included 1,301 women. The OGTT was performed in 322 women. After correction for verification bias, the random glucose test showed an area under the ROC curve of 0.69 (95% CI 0.61-0.78), whereas the glucose challenge test had an area under the curve of 0.88 (0.83-0.93). There was a significant difference in area under the curve of the two tests of 0.19 (0.11-0.27) in favor of the 50-g glucose challenge test. CONCLUSIONS: In screening for GDM, the 50-g glucose challenge test is more useful than the random glucose test. PMID- 17698617 TI - A novel role for protein kinase Cdelta-mediated phosphorylation of acid sphingomyelinase in UV light-induced mitochondrial injury. AB - Multiple studies have addressed the mechanisms by which ultraviolet (UV) light induces cell death, and a few have focused on stress mediators such as acid sphingomyelinase (ASMase) or protein kinase Cdelta (PKCdelta). Based on a recent study that identified a novel mechanism of activation of ASMase through phosphorylation, the current study was undertaken to determine the upstream mechanisms regulating ASMase in response to UV and to investigate the role of ASMase and its phosphorylation at S508 as an integral event during UV light induced cell death. Exposure of MCF-7 breast cancer cells to UV light type C (UVC) transiently activated ASMase with maximal activity detected at 10 min postirradiation. A significant increase in C16-ceramide was detected concomitant with a decrease in C16-sphingomyelin. In marked contrast, cells overexpressing the ASMase(S508A) mutant, which could not be phosphorylated, had no change in either ASMase activity or ceramide levels post-UV radiation. Loss of PKCdelta by RNA interference or its inhibition by rottlerin blocked ASMase phosphorylation and membrane targeting, thus implicating PKCdelta upstream of ASMase activation by UV light. Further investigations revealed that UV radiation altered mitochondrial morphology from elongated tubules to fragmented perinuclear organelles, consistent with the onset of the apoptotic cascade. Importantly, cells overexpressing ASMase(S508A) were protected (>50%) from UV light-induced mitochondrial fragmentation. Mechanistically, the results showed that ASMase(S508A) cells had 50% less active Bax than ASMase(WT) cells. These molecular differences culminated in resistance of ASMase(S508) cells to UVC induced cell death (25%) as compared to ASMase(WT) cells (46%). Taken together, this study provides key molecular insights into activation of ASMase in response to UV light, the role of PKCdelta in this activation, and the role of ASMase in mediating apoptotic responses. PMID- 17698618 TI - Artemisinin-resistant mutants of Toxoplasma gondii have altered calcium homeostasis. AB - Artemisinin is a plant sesquiterpene lactone that has become an important drug for combating malaria, especially in regions where resistance to other drugs is widespread. While the mechanism of action is debated, artemisinin has been reported to inhibit the sarcoplasmic endoplasmic reticulum Ca(2+) ATPase (SERCA) in the malaria parasite. Artemisinin is also effective against Toxoplasma in vitro and in vivo, although it is less potent and, hence, is generally not used therapeutically to treat toxoplasmosis. To explore the mechanism of action, we generated chemically derived mutants of Toxoplasma gondii that were resistant to growth inhibition by this compound in vitro. Three artemisinin-resistant (ART(r)) mutant clones that differed in their sensitivities in vitro by three- to fivefold compared with that of the wild-type parasites were obtained. ART(r) mutants were cross-resistant to other derivatives of artemisinin, the most potent of which was artemisone. Resistance was not due to molecular alterations or differences in the expression of SERCA or other putative targets, such as proteins that code for multidrug resistance or translationally controlled tumor protein. ART(r) mutants were resistant to the induction of protein secretion from micronemes, a calcium dependent process that is triggered by artemisinin. ART(r) mutants were not cross resistant to secretion induced by thapsigargin but were more sensitive and were unable to regulate cytoslic calcium following treatment with this compound. These studies implicate calcium homeostasis in the mechanism of action of artemisinins against apicomplexan parasites. PMID- 17698619 TI - Galanin message-associated peptide suppresses growth and the budded-to-hyphal form transition of Candida albicans. AB - The expression of the mRNA encoding galanin message-associated peptide (GMAP) in human keratinocytes is upregulated by lipopolysaccharides and exposure to Candida albicans. GMAP has growth-inhibiting activity against C. albicans and inhibits the budded-to-hyphal-form transition, establishing GMAP as a possible new component of the innate immune system. PMID- 17698620 TI - Targeting of the Brucella suis virulence factor histidinol dehydrogenase by histidinol analogues results in inhibition of intramacrophagic multiplication of the pathogen. AB - Brucella suis histidinol dehydrogenase (HDH) can be efficiently targeted by substrate analogues. The growth of this pathogen in minimal medium was inhibited and the multiplication in human macrophages was totally abolished in the presence of the drugs. These effects have been shown to be correlated with the previously described inhibition of Brucella HDH activity. PMID- 17698621 TI - Adenosine kinase of Trypanosoma brucei and its role in susceptibility to adenosine antimetabolites. AB - Trypanosoma brucei cannot synthesize purines de novo and relies on purine salvage from its hosts to build nucleic acids. With adenosine being a preferred purine source of bloodstream-form trypanosomes, adenosine kinase (AK; EC 2.7.1.20) is likely to be a key player in purine salvage. Adenosine kinase is also of high pharmacological interest, since for many adenosine antimetabolites, phosphorylation is a prerequisite for activity. Here, we cloned and functionally characterized adenosine kinase from T. brucei (TbAK). TbAK is a tandem gene, expressed in both procyclic- and bloodstream-form trypanosomes, whose product localized to the cytosol of the parasites. The RNA interference-mediated silencing of TbAK suggested that the gene is nonessential under standard growth conditions. Inhibition or downregulation of TbAK rendered the trypanosomes resistant to cordycepin (3'-deoxyadenosine), demonstrating a role for TbAK in the activation of adenosine antimetabolites. The expression of TbAK in Saccharomyces cerevisiae complemented a null mutation in the adenosine kinase gene ado1. The concomitant expression of TbAK with the T. brucei adenosine transporter gene TbAT1 allowed S. cerevisiae ado1 ade2 double mutants to grow on adenosine as the sole purine source and, at the same time, sensitized them to adenosine antimetabolites. The coexpression of TbAK and TbAT1 in S. cerevisiae ado1 ade2 double mutants proved to be a convenient tool for testing nucleoside analogues for uptake and activation by T. brucei adenosine salvage enzymes. PMID- 17698623 TI - The antifungal polyketide ambruticin targets the HOG pathway. AB - The polyketide ambruticin is an attractive candidate for drug development as an antifungal agent, but its mechanism of action has not yet been elucidated. Here we present evidence that ambruticin exerts its effect by targeting HOG, the osmotic stress control pathway, through Hik1, a group III histidine kinase. PMID- 17698622 TI - 2,N6-disubstituted adenosine analogs with antitrypanosomal and antimalarial activities. AB - A library of 2,N(6)-disubstituted adenosine analogs was synthesized and the analogs were tested for their antiprotozoal activities. It was found that 2 methoxy and 2-histamino and N(6)-m-iodobenzyl substitutions generally produced analogs with low levels of antiprotozoal activity. The best antiplasmodial activity was achieved with large aromatic substitutions, such as N(6)-2,2 diphenylethyl and naphthylmethyl, which could indicate a mechanism of action through aromatic stacking with heme in the digestive vacuole of Plasmodium spp. The activities against Trypanosoma cruzi trypomastigotes and Leishmania donovani amastigotes were generally low; but several analogs, particularly those with cyclopentylamino substitutions, displayed potent activities against Trypanosoma brucei rhodesiense and T. b. brucei bloodstream forms in vitro. The most active were 2-cyclopentylamino-N(6)-cyclopentyladenosine (compound NA42) and 2 cyclopentylamino-N(6)-cyclopentyladenine (compound NA134), with the nucleobase an order of magnitude more potent than the nucleoside, at 26 +/- 4 nM. It was determined that the mode of action of these purines was trypanostatic, with the compounds becoming trypanocidal only at much higher concentrations. Those 2,N(6) disubstituted purines tested for their effects on purine transport in T. b. brucei displayed at best a moderate affinity for the transporters. It is highly probable that the large hydrophobic substitutions, which bestow high calculated octanol-water coefficient values on the analogs, allow them to diffuse across the membrane. Consistent with this view, the analogs were as effective against a T. b. brucei strain lacking the P2 nucleoside transporter as they were against the parental strain. As the analogs were not toxic to human cell lines, the purine analogs are likely to act on a trypanosome-specific target. PMID- 17698624 TI - Cellular effects of reversed amidines on Trypanosoma cruzi. AB - Aromatic diamidines represent a class of DNA minor groove-binding ligands that exhibit high levels of antiparasitic activity. Since the chemotherapy for Chagas' disease is still an unsolved problem and previous reports on diamidines and related analogues show that they have high levels of activity against Trypanosoma cruzi infection both in vitro and in vivo, our present aim was to evaluate the cellular effects in vitro of three reversed amidines (DB889, DB702, and DB786) and one diguanidine (DB711) against both amastigotes and bloodstream trypomastigotes of T. cruzi, the etiological agent of Chagas' disease. Our data show that the reversed amidines have higher levels of activity than the diguanidine, with the order of trypanocidal activities being as follows: DB889 > DB702 > DB786 > DB711. Transmission electron microscopy analysis showed that the reversed amidines induced many alterations in the nuclear morphology, swelling of the endoplasmic reticulum and Golgi structures, and consistent damage in the mitochondria and kinetoplasts of the parasites. Interestingly, in trypomastigotes treated with the reversed amidine DB889, multiple axoneme structures (flagellar microtubules) were noted. Flow cytometry analysis confirmed that the treated parasites presented an important loss of the mitochondrial membrane potential, as revealed by a decrease in rhodamine 123 fluorescence. Our results show that the reversed amidines have promising activities against the relevant mammalian forms of T. cruzi and display high trypanocidal effects at very low doses. This is especially the case for DB889, which merits further in vivo evaluation. PMID- 17698625 TI - A cysteine protease inhibitor cures Chagas' disease in an immunodeficient-mouse model of infection. AB - Chagas' disease, caused by the parasite Trypanosoma cruzi, remains the leading cause of cardiopathy in Latin America with about 12 million people infected. Classic clinical manifestations derive from infection of muscle cells leading to progressive cardiomyopathy, while some patients develop megacolon or megaesophagus. A very aggressive clinical course including fulminant meningoencephalitis has been reported in patients who contract Chagas' disease in the background of immunodeficiency. This includes patients with human immunodeficiency virus infection as well as patients receiving immunosuppressive therapy for organ transplant. Currently, only two drugs are approved for the treatment of Chagas' disease, nifurtimox and benznidazole. Both have significant limitations due to common and serious side effects as well as limited availability. A promising group of new drug leads for Chagas' disease is cysteine protease inhibitors targeting cruzain, the major protease of T. cruzi. The inhibitor N-methyl-Pip-F-homoF-vinyl sulfonyl phenyl (N-methyl-Pip-F-hF-VS phi) is in late-stage preclinical development. Therefore, the question arose as to whether protease inhibitors targeting cruzain would have efficacy in Chagas' disease occurring in the background of immunodeficiency. To address this question, we studied the course of infection in recombinase-deficient (Rag1(-/-)) and normal mice infected with T. cruzi. Infections localized to heart and skeletal muscle in untreated normal animals, while untreated Rag1(-/-) mice showed severe infection in all organs and predominantly in liver and spleen. Treatment with the dipeptide N-methyl-Pip-F-hF-VS phi rescued immunodeficient animals from lethal Chagas' infection. The majority (60 to 100%) of inhibitor treated Rag1(-/-) mice had increased survival, negative PCR, and normal tissues by histopathological examination. PMID- 17698626 TI - Complete nucleotide sequence of the pCTX-M3 plasmid and its involvement in spread of the extended-spectrum beta-lactamase gene blaCTX-M-3. AB - Here we report the nucleotide sequence of pCTX-M3, a highly conjugative plasmid that is responsible for the extensive spread of the gene coding for the CTX-M-3 extended-spectrum beta-lactamase in clinical populations of the family Enterobacteriaceae in Poland. The plasmid belongs to the IncL/M incompatibility group, is 89,468 bp in size, and carries 103 putative genes. Besides bla(CTX-M 3), it also bears the bla(TEM-1), aacC2, and armA genes, as well as integronic aadA2, dfrA12, and sul1, which altogether confer resistance to the majority of beta-lactams and aminoglycosides and to trimethoprim-sulfamethoxazole. The conjugal transfer genes are organized in two blocks, tra and trb, separated by a spacer sequence where almost all antibiotic resistance genes and multiple mobile genetic elements are located. Only bla(CTX-M-3), accompanied by an ISEcp1 element, is placed separately, in a DNA fragment previously identified as a fragment of the Kluyvera ascorbata chromosome. On the basis of sequence analysis, we speculate that pCTX-M3 might have arisen from plasmid pEL60 from plant pathogen Erwinia amylovora by acquiring mobile elements with resistance genes. This suggests that plasmids of environmental bacterial strains could be the source of those plasmids now observed in bacteria pathogenic for humans. PMID- 17698627 TI - Comparative analysis of IncHI2 plasmids carrying blaCTX-M-2 or blaCTX-M-9 from Escherichia coli and Salmonella enterica strains isolated from poultry and humans. AB - Salmonella enterica bla(CTX-M-2) and bla(CTX-M-9) plasmid backbones from isolates from Belgium and France were analyzed. The bla(CTX-M-2-)plasmids from both human and poultry isolates were related to the IncHI2 pAPEC-O1-R plasmid, previously identified in the United States in avian Escherichia coli strains; the bla(CTX-M 9) plasmids were closely related to the IncHI2 R478 plasmid. PMID- 17698628 TI - Trioxaquines and heme-artemisinin adducts inhibit the in vitro formation of hemozoin better than chloroquine. AB - Trioxaquines, potential antimalarial agents, and heme-artemisinin adducts, resulting from the alkylation of heme by artemisinin, were evaluated as inhibitors of beta-hematin formation in 10 M acetate medium at pH 5. PMID- 17698629 TI - Fatty acid synthesis is essential for survival of Cryptococcus neoformans and a potential fungicidal target. AB - Fatty acid synthase in the yeast Cryptococcus neoformans is composed of two subunits encoded by FAS1 and FAS2 genes. We inserted a copper-regulated promoter (P(CTR4-2)) to regulate FAS1 and FAS2 expression in Cryptococcus neoformans (strains P(CTR4-2)/FAS1 and P(CTR4-2)/FAS2, respectively). Both mutants showed growth rates similar to those of the wild type in a low-copper medium in which FAS1 and FAS2 were expressed, but even in the presence of exogenous fatty acids, strains were suppressed in growth under high-copper conditions. The treatment of C. neoformans with fluconazole was shown to have an increased inhibitory activity and even became fungicidal when either FAS1 or FAS2 expression was suppressed. Furthermore, a subinhibitory dose of fluconazole showed anticryptococcal activity in vitro in the presence of cerulenin, a fatty acid synthase inhibitor. In a murine model of pulmonary cryptococcosis, a tissue census of yeast cells in P(CTR4-2)/FAS2 strain at day 7 of infection was significantly lower than that in mice treated with tetrathiomolybdate, a copper chelator (P < 0.05), and a yeast census of P(CTR4-2)/FAS1 strain at day 14 of infection in the brain was lower in the presence of more copper. In fact, no positive cultures from the brain were detected in mice (with or without tetrathiomolybdate treatment) infected with the P(CTR4-2)/FAS2 strain, which implies that this mutant did not reach the brain in mice. We conclude that both FAS1 and FAS2 in C. neoformans are essential for in vitro and in vivo growth in conditions with and without exogenous fatty acids and that FAS1 and FAS2 can potentially be fungicidal targets for C. neoformans with a potential for synergistic behavior with azoles. PMID- 17698630 TI - Multiple antibiotics exert delayed effects against the Plasmodium falciparum apicoplast. AB - Several classes of antibiotics exert antimalarial activity. The mechanisms of action of antibiotics against malaria parasites have been unclear, and prior studies have led to conflicting results, in part because they studied antibiotics at suprapharmacological concentrations. We examined the antimalarial effects of azithromycin, ciprofloxacin, clindamycin, doxycycline, and rifampin against chloroquine-resistant (W2) and chloroquine-sensitive (3D7) Plasmodium falciparum strains. At clinically relevant concentrations, rifampin killed parasites quickly, preventing them from initiating cell division. In contrast, pharmacological concentrations of azithromycin, ciprofloxacin, clindamycin, and doxycycline were relatively inactive against parasites initially but exerted a delayed death effect, in which the progeny of treated parasites failed to complete erythrocytic development. The drugs that caused delayed death did not alter the distribution of apicoplasts into developing progeny. However, the apicoplasts inherited by the progeny of treated parasites were abnormal. The loss of apicoplast function became apparent as the progeny of antibiotic-treated parasites initiated cell division, with the failure of schizonts to fully mature or for erythrocyte rupture to take place. These findings explain the slow antimalarial action of multiple antibiotics. PMID- 17698631 TI - Genetic characteristics and clonal dissemination of beta-lactamase-negative ampicillin-resistant Haemophilus influenzae strains isolated from the upper respiratory tract of patients in Japan. AB - We evaluated the recent prevalence of antimicrobial-resistant Haemophilus influenzae isolated from the upper respiratory tracts (URT) of patients in Japan. Mutations in the ftsI gene, which encodes penicillin binding protein 3 (PBP3), and the clonal dissemination of the resistant strains were also investigated. A total of 264 H. influenzae isolates were collected from patients with URT infections. According to the criteria of the Clinical and Laboratory Standards Institute for the susceptibility of H. influenzae to ampicillin (AMP), the isolates were distributed as follows: 161 (61.0%) susceptible strains (MIC < or = 1 microg/ml), 37 (14.0%) intermediately resistant strains (MIC = 2 microg/ml), and 66 (25.0%) resistant strains (MIC > or = 4 microg/ml). According to PCR-based genotyping, 172 (65.1%) of the isolates had mutations in the ftsI gene and were negative for the beta-lactamase (bla) gene. These 172 isolates were thus defined as genetically beta-lactamase-negative ampicillin-resistant (gBLNAR) strains. The ftsI mutant group included 98 (37.1%) strains with group I/II mutations in the variable mutated region (group I/II gBLNAR) and 74 (28.0%) strains with group III mutations in the highly mutated region (group III gBLNAR). Eighty-seven (33.0%) of the isolates were genetically beta-lactamase-negative ampicillin-susceptible (gBLNAS) strains. The group III gBLNAR strains showed resistance to beta-lactams. Only five strains (1.9%) were positive for a bla gene encoding TEM-type beta lactamase. The three clusters consisting of 16 strains found among the 61 BLNAR strains (MIC > or = 4 microg/ml and without the bla gene) showed identical or closely related DNA restriction fragment patterns. Those isolates were frequently identified among strains with a MIC to AMP of 16 microg/ml. The current study demonstrates the apparent dissemination and spread of a resistant clone of H. influenzae among medical centers in Japan. The gBLNAR strains show a remarkable prevalence among H. influenzae isolates, with the prevalence increasing with time. This fact should be taken into account when treating URT infections. PMID- 17698632 TI - Homocysteine inhibits endothelial cell growth via DNA hypomethylation of the cyclin A gene. AB - We reported previously that homocysteine (Hcy) inhibits endothelial cell (EC) growth by transcriptional inhibition of the cyclin A gene via a hypomethylation related mechanism. In this study, we examined the effect of Hcy on epigenetic modification of the cyclin A gene and its biologic role in human ECs. Cyclin A mRNA levels were significantly suppressed by Hcy and a DNA methyltransferase inhibitor. The cyclin A promoter contains a CpG island spanning a 477-bp region ( 277/200). Bisulfite sequencing followed by polymerase chain reaction (PCR) amplification of the cyclin A promoter (-267/37) showed that Hcy eliminated methylation at 2 CpG sites in the cyclin A promoter, one of which is located on the cycle-dependent element (CDE). Mutation of CG sequence on the CDE leads to a 6-fold increase in promoter activity. Hcy inhibited DNA methyltransferase 1 (DNMT1) activity by 30%, and reduced the binding of methyl CpG binding protein 2 (MeCP2) and increased the bindings of acetylated histone H3 and H4 in the cyclin A promoter. Finally, adenovirus-transduced DNMT1 gene expression reversed the inhibitory effect of Hcy on cyclin A expression and EC growth inhibition. In conclusion, Hcy inhibits cyclin A transcription and cell growth by inhibiting DNA methylation through suppression of DNMT1 in ECs. PMID- 17698633 TI - Activity of TKI258 against primary cells and cell lines with FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome. AB - The 8p11 myeloproliferative syndrome (EMS) is an aggressive, atypical stem cell myeloproliferative disorder associated with chromosome translocations that disrupt and constitutively activate FGFR1 by fusion to diverse partner genes. To explore the possibility of targeted therapy for EMS, we have investigated the use of TKI258, a multitargeted receptor tyrosine kinase inhibitor with activity against FGFR, VEGFR, PDGFR, FLT3, and KIT that is currently being assessed for the treatment of a variety of malignancies in phase 1 clinical studies. The viability of Ba/F3 cells transformed to IL3 independence by ZNF198-FGFR1 or BCR FGFR1 was specifically inhibited by TKI258 with IC(50) values of 150 nM and 90 nM, respectively. Inhibition was accompanied by dose-dependent inhibition of phosphorylation of each fusion gene, ERK, and STAT5. TKI258 also specifically inhibited proliferation and survival of the FGFR1OP2-FGFR1-positive KG1 and KG1A cell lines, resulting in increased levels of apoptosis. Primary cells from EMS patients showed significant, dose-dependent responses in liquid culture and in methylcellulose colony assays compared with controls. This work provides evidence that targeted therapy may be beneficial for patients with EMS. PMID- 17698634 TI - Multiagent induction and maintenance therapy for patients with refractory immune thrombocytopenic purpura (ITP). AB - Patients with severe immune thrombocytopenic purpura (ITP) may require an acute increase in the platelet count for surgery or ongoing hemorrhage as well as long term maintenance treatment. Certain of these patients may be refractory to steroids, intravenous anti-D, intravenous immunoglobulin (IVIG), and splenectomy. Therefore, acute platelet increases were studied in 35 patients completely unresponsive to IVIG or high-dose steroid treatment. Because of their lack of response to either or both single agents, these patients were administered a 3- or 4-drug combination including IVIG 1 g/kg, intravenous methylprednisolone 30 mg/kg, Vinca alkaloids (VCR 0.03 mg/kg), and/or intravenous anti-D (50-75 microg/kg). Subsequent maintenance therapy with the oral combination of danazol (10-15 mg/kg) and azathioprine (2 mg/kg) was given to 18 of the 35 patients. Seventy-one percent of the patients responded to the intravenous combination treatment with acute platelet increases of at least 20 x 10(9)/L to a level greater than 30 x 10(9)/L. Two thirds of the patients given maintenance therapy achieved stable platelet counts greater than 50 x 10(9)/L without other treatments. One patient developed an ileus, but otherwise there was little toxicity of combination treatment. Combination chemotherapy is a useful approach for patients with ITP refractory to conventional treatments both for acute induction and for long-term maintenance therapy. PMID- 17698635 TI - NOTCH1 pathway activation is an early hallmark of SCL T leukemogenesis. AB - The acquired activation of stem cell leukemia (SCL) during T lymphopoiesis is a common event in T-cell acute lymphoblastic leukemia (T-ALL). Here, we generated tamoxifen (TAM)-inducible transgenic mice (lck-ER(T2)-SCL) to study the consequences of acquired SCL activation during T-cell development. Aberrant activation of SCL in thymocytes resulted in the accumulation of immature CD4(+)CD8(+) (double-positive, DP) cells by preventing normal surface expression of the T-cell receptor alphabeta (TCRalphabeta) complex. SCL-induced immature DP cells were further characterized by up-regulated NOTCH1 and generated noncycling polyclonal CD8(+)TCRbeta(low) cells. The prevalence of these cells was SCL dependent because TAM withdrawal resulted in their disappearance. Furthermore, we observed that SCL activation led to a dramatic up-regulation of NOTCH1 target genes (Hes-1, Deltex1, and CD25) in thymocytes. Strikingly, NOTCH1 target gene up regulation was already observed after short-term SCL induction, implying that enhanced NOTCH signaling is mediated by SCL and is not dependent on secondary genetic events. These data represent the basis for a novel pathway of SCL-induced leukemogenesis and provide a functional link between SCL and NOTCH1 during this process. PMID- 17698636 TI - hDectin-1 is involved in uptake and cross-presentation of cellular antigens. AB - Human Dectin-1 (hDectin-1) is a member of the C-type lectin-like receptor family that was shown to be the major receptor for fungal beta-glucans and to play an important role in the cellular responses mediated by these carbohydrates. In this study, we demonstrate that hDectin-1 is involved in the uptake and cross presentation of cellular antigens. Furthermore, activation of monocyte-derived dendritic cells (MDCs) with toll-like receptor 3 (TLR3) ligand but not with TLR2 ligand or TLR7 ligand resulted in down-regulation of hDectin-1 expression and reduced phagocytosis of apoptotic tumor cells as well as presentation of pp65 derived T-cell epitopes upon engulfment of cytomegalovirus (CMV)-infected human foreskin fibroblasts. PMID- 17698637 TI - Improved amber and opal suppressor tRNAs for incorporation of unnatural amino acids in vivo. Part 2: evaluating suppression efficiency. AB - The incorporation of unnatural amino acids into proteins is a valuable tool for addition of biophysical probes, bio-orthogonal functionalities, and photoreactive cross-linking agents, although these approaches often require quantities of protein that are difficult to access with chemically aminoacylated tRNAs. THG73 is an amber suppressor tRNA that has been used extensively, incorporating over 100 residues in 20 proteins. In vitro studies have shown that the Escherichia coli Asn amber suppressor (ENAS) suppresses better than THG73. However, we report here that ENAS suppresses with <26% of the efficiency of THG73 in Xenopus oocytes. We then tested the newly developed Tetrahymena thermophila Gln amber suppressor (TQAS) tRNA library, which contains mutations in the second to fourth positions of the acceptor stem. The acceptor stem mutations have no adverse effect on suppression efficiency and, in fact, can increase the suppression efficiency. Combining mutations causes an averaging of suppression efficiency, and increased suppression efficiency does not correlate with increased DeltaG of the acceptor stem. We created a T. thermophila opal suppressor, TQOpS', which shows approximately 50% suppression efficiency relative to THG73. The TQAS tRNA library, composed of functional suppressor tRNAs, has been created and will allow for screening in eukaryotic cells, where rapid analysis of large libraries is not feasible. PMID- 17698638 TI - Improved amber and opal suppressor tRNAs for incorporation of unnatural amino acids in vivo. Part 1: minimizing misacylation. AB - The incorporation of unnatural amino acids site-specifically is a valuable technique for structure-function studies, incorporation of biophysical probes, and determining protein-protein interactions. THG73 is an amber suppressor tRNA used extensively for the incorporation of >100 different residues in over 20 proteins, but under certain conditions THG73 is aminoacylated in vivo by endogenous aminoacyl-tRNA synthetase. Similar aminoacylation is seen with the Escherichia coli Asn amber suppressor tRNA, which has also been used to incorporate UAAs in many studies. We now find that the natural amino acid placed on THG73 is Gln. Since the E. coli GlnRS recognizes positions in the acceptor stem, we made several acceptor stem mutations in the second to fourth positions on THG73. All mutations reduce aminoacylation in vivo and allow for the selection of highly orthogonal tRNAs. To show the generality of these mutations, we created opal suppressor tRNAs that show less aminoacylation in Xenopus oocytes relative to THG73. We have created a library of Tetrahymena thermophila Gln amber suppressor tRNAs that will be useful for determining optimal suppressor tRNAs for use in other eukaryotic cells. PMID- 17698639 TI - Systematic analysis of microRNA expression of RNA extracted from fresh frozen and formalin-fixed paraffin-embedded samples. AB - microRNAs (miRNAs) are noncoding small RNAs that regulate gene expression at the translational level by mainly interacting with 3' UTRs of their target mRNAs. Archived formalin-fixed paraffin-embedded (FFPE) specimens represent excellent resources for biomarker discovery. Currently there is a lack of systematic analysis on the stability of miRNAs and optimized conditions for expression analysis using FFPE samples. In this study, the expression of miRNAs from FFPE samples was analyzed using high-throughput locked nucleic acid-based miRNA arrays. The effect of formalin fixation on the stability of miRNAs was also investigated using miRNA real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. The stability of miRNAs of archived colorectal cancer FFPE specimens was characterized with samples dating back up to 10 yr. Our results showed that the expression profiles of miRNAs were in good correlation between 1 mug of fresh frozen and 1-5 mug of FFPE samples (correlation coefficient R (2) = 0.86-0.89). Different formalin fixation times did not change the stability of miRNAs based on real-time qRT-PCR analysis. There are no significant differences of representative miRNA expression among 40 colorectal cancer FFPE specimens. This study provides a foundation for miRNA investigation using FFPE samples in cancer and other types of diseases. PMID- 17698640 TI - Cloning and expression profiling of testis-expressed piRNA-like RNAs. AB - Using a novel small RNA cloning method, we identified 630 piRNA-like RNAs (pilRNAs) from the mouse testis, and 498 of them are novel. These pilRNA genes were mapped to all chromosomes as 71 clusters, and the majority of them ( approximately 84%) are derived from intergenic, intronic, and exonic sequences. One of the structural characteristics for pilRNAs is that a single locus can encode numerous homologous pilRNAs with overlapping sequences. Hundreds or even thousands of pilRNAs from a single pilRNA gene cluster are all produced from a single long transcript. Expression profiling for 64 pilRNAs revealed that approximately 14% of all the pilRNAs analyzed displayed a ubiquitous expression pattern, although the majority of ( approximately 86%) pilRNAs were preferentially or exclusively expressed in meiotic and haploid male germ cells of the testis. Our semiquantitative analyses also suggest that the testis is the organ with the highest expression of pilRNAs both in number and in abundance. The large number, high abundance, unique genomic locations, and biogenesis all suggest that pilRNAs have important regulatory roles not only in spermatogenesis but also in other biological processes. PMID- 17698641 TI - A functional interaction of SmpB with tmRNA for determination of the resuming point of trans-translation. AB - In trans-translation, transfer-messenger RNA (tmRNA), possessing a dual function as a tRNA and an mRNA, relieves a stalled translation on the ribosome with the help of SmpB. Here, we established an in vitro system using Escherichia coli translation and trans-translation factors to evaluate two steps of trans translation, peptidyl transfer from peptidyl-tRNA to alanyl-tmRNA and translation of the resume codon on tmRNA. Using this system, the effects of several mutations upstream of the tag-encoding region on tmRNA were examined. These mutations affected translation of the resume codon rather than peptidyl transfer, and one of them, A84U/U85G, caused a shift of the resume codon by -1. We also found that U(85) is protected from chemical modification by SmpB. In the A84U/U85G mutant, the base of protection was shifted from 85 to 84. Another mutation, A86U, which caused a shift of the resume codon by +1, shifted the base of protection from 85 to 86. The protection at 85 was suppressed by a mutation in the tRNA-like domain critical to SmpB binding. These results suggest that SmpB serves to bridge two separate domains of tmRNA to determine the initial codon for tag-translation. A mutant SmpB with a truncation of the unstructured C-terminal tail failed to promote peptidyl transfer, although it still protected U(85) from chemical modification. PMID- 17698642 TI - Defining the optimal parameters for hairpin-based knockdown constructs. AB - Induction of gene silencing using intracellularly expressed silencing triggers has been explored for large-scale loss-of-function screening, creation of knockdown cell lines or knockdown animals, and disease intervention. In all of these applications, the use of highly potent silencing constructs can maximize the possibility of obtaining target knockdown and thereby is intrinsically important for the chance of success. Several attempts have been made to improve the potency of a silencing construct. Results published in high profile journals such as Nature Biotechnology and Nature Genetics suggest that shRNAs with a 29 nucleotide (nt) stem is much more potent than shRNAs with a 19-nt stem, and miR30 based silencing constructs are much more potent than shRNA-based constructs. In this study, we systematically investigated several parameters, including the use of shRNA- or miR30-based scaffolds, the length of shRNA, and the selection of shRNA sequences for their impact on the knockdown efficiency of a silencing construct. Our studies revealed that the optimal configurations for a potent silencing trigger could be an shRNA with a 19-nt stem and a 9-nt loop. By comparing properties that favor the functional shRNAs and siRNAs using a set of 190 shRNAs against 19 targets and 360 siRNAs against four targets, we found that the functional shRNAs and siRNAs displayed similar but not identical nucleotide preferences. Based on the characteristic nucleotide preferences in the functional versus the nonfunctional shRNAs, we developed a computer program that outperforms an advanced siRNA selection algorithm for the enrichment of highly functional shRNAs. PMID- 17698643 TI - Instrumentation and metrology for single RNA counting in biological complexes or nanoparticles by a single-molecule dual-view system. AB - Limited by the spatial resolution of optical microscopy, direct detection or counting of single components in biological complexes or nanoparticles is challenging, especially for RNA, which is conformationally versatile and structurally flexible. We report here the assembly of a customized single molecule dual-viewing total internal reflection fluorescence imaging system for direct counting of RNA building blocks. The RNA molecules were labeled with a single fluorophore by in vitro transcription in the presence of a fluorescent AMP. Precise calculation of identical or mixed pRNA building blocks of one, two, three, or six copies within the bacteriophage phi29 DNA packaging motor or other complexes was demonstrated by applying a photobleaching assay and evaluated by binomial distribution. The dual-viewing system for excitation and recording at different wavelengths simultaneously will enable the differentiation of different complexes with different labels or relative motion of each labeled component in motion machines. PMID- 17698644 TI - Alternative splicing of the ADAR1 transcript in a region that functions either as a 5'-UTR or an ORF. AB - The ADAR enzymes mediate the hydrolytic deamination of adenosines in specific RNA substrates and thereby diversify both the transcriptome and the proteome in metazoan species. Three promoters drive the transcription from the ADAR1 gene yielding the ADAR1-A, -B, and -C transcripts, which, in turn, lead to the production of two protein isoforms, namely, iADAR1 and cADAR1. In this study, we establish the presence of a previously unidentified alternative intron within the 5'-end of the common second exon of mRNAs encoding ADAR1 in primate species-a region that can function either as a 5'-UTR or an ORF. In addition, it is shown that the relative expression of the three promoter-specific ADAR1 transcripts is tissue specific and that the novel intron is excised from all transcripts, but at different relative levels indicating a specific regulation of the alternative splicing. Finally, possible functional consequences of the splicing are investigated. From these studies, we conclude that the alternatively spliced ADAR1-A transcript is immune to nonsense-mediated decay although it is a potential substrate. Moreover, this transcript is associated with translating ribosomes, which suggests that a truncated version of iADAR1 is expressed. PMID- 17698645 TI - Changing patterns of chikungunya virus: re-emergence of a zoonotic arbovirus. PMID- 17698646 TI - Reduction of vector gene expression increases foreign antigen-specific CD8+ T cell priming. AB - Viral vectors have been shown to induce protective CD8(+) T-cell populations in animal models, but significant obstacles remain to their widespread use for human vaccination. One such obstacle is immunodominance, where the CD8(+) T-cell response to a vector can suppress the desired CD8(+) T-cell response to a recombinantly encoded antigen. To overcome this hurdle, we broadly reduced vector specific gene expression. We treated a recombinant vaccinia virus, encoding antigen as a minimal peptide determinant (8-10 aa), with psoralen and short-wave UV light. The resulting virus induced 66 % fewer vector-specific immunodominant CD8(+) T cells, allowing the in vivo induction of an increased number of CD8(+) T cells specific for the recombinant antigen. PMID- 17698647 TI - Mapping to completeness and transplantation of a group-specific, discontinuous, neutralizing epitope in the envelope protein of dengue virus. AB - Dengue is caused by a taxonomic group of four viruses, dengue virus types 1-4 (DENV1-DENV4). A molecular understanding of the antibody-mediated protection against this disease is critical to design safe vaccines and therapeutics. Here, the energetic epitope of antibody mAb4E11, which neutralizes the four serotypes of DENV but no other flavivirus, and binds domain 3 (ED3) of their envelope glycoprotein, was characterized. Alanine-scanning mutagenesis of the ED3 domain from serotype DENV1 was performed and the affinities between the mutant domains and the Fab fragment of mAb4E11 were measured. The epitope residues (307-312, 387, 389 and 391) were at the edges of two distinct beta-sheets. Four residues constituted hot spots of binding energy. They were aliphatic and contributed to form a hydrophobic pocket (Leu308, Leu389), or were positively charged (Lys307, Lys310). They may bind the diversity residues of mAb4E11, H-Trp96-Glu97. Remarkably, cyclic residues occupy and block the hydrophobic pocket in all unrelated flaviviruses. Transplanting the epitope from the ED3 domain of DENV into those of other flaviviruses restored affinity. The epitope straddles residues of ED3 that are involved in virulence, e.g. Asn/Asp390. These results define the epitope of mAb4E11 as an antigenic signature of the DENV group and suggest mechanisms for its neutralization potency. PMID- 17698648 TI - Adaptation of two flaviviruses results in differences in genetic heterogeneity and virus adaptability. AB - West Nile virus (WNV) is a mosquito-borne flavivirus that was first introduced into the USA in the New York City area in 1999. Since its introduction, WNV has steadily increased both its host and geographical ranges. Outbreaks of the closely related flavivirus, St. Louis encephalitis virus (SLEV), occur in the USA periodically, but levels of activity and host range are more restricted than those of WNV. Understanding the selective pressures that drive arbovirus adaptation and evolution in their disparate mosquito and avian hosts is crucial to predicting their ability to persist and re-emerge. Here, we evaluated the in vivo phenotypes of mosquito cell-adapted WNV and SLEV. Results indicated that in vitro adaptations did not translate to in vivo adaptations for either virus, yet SLEV displayed attenuated growth in both mosquitoes and chickens, while WNV generally did not. In vitro growth analyses also indicated that WNV adaptations could be generalized to cell cultures derived from other mosquito species, while SLEV could not. Analysis of genetic diversity for passaged SLEV revealed a highly homogeneous population that differed significantly from previous results of high levels of diversity in WNV. We hypothesize that this difference in genetic diversity is directly related to the viruses' success in new and changing environments in the laboratory and that differences in a viruses' ability to produce and maintain heterogeneous populations in nature may in some instances explain the variable levels of success seen among arboviruses. PMID- 17698649 TI - Structure of the C-terminal head domain of the fowl adenovirus type 1 long fiber. AB - Avian adenovirus CELO (chicken embryo lethal orphan virus, fowl adenovirus type 1) incorporates two different homotrimeric fiber proteins extending from the same penton base: a long fiber (designated fiber 1) and a short fiber (designated fiber 2). The short fibers extend straight outwards from the viral vertices, whilst the long fibers emerge at an angle. In contrast to the short fiber, which binds an unknown avian receptor and has been shown to be essential to the invasiveness of this virus, the long fiber appears to be unnecessary for infection in birds. Both fibers contain a short N-terminal virus-binding peptide, a slender shaft domain and a globular C-terminal head domain; the head domain, by analogy with human adenoviruses, is likely to be involved mainly in receptor binding. This study reports the high-resolution crystal structure of the head domain of the long fiber, solved using single isomorphous replacement (using anomalous signal) and refined against data at 1.6 A (0.16 nm) resolution. The C terminal globular head domain had an anti-parallel beta-sandwich fold formed by two four-stranded beta-sheets with the same overall topology as human adenovirus fiber heads. The presence in the sequence of characteristic repeats N-terminal to the head domain suggests that the shaft domain contains a triple beta-spiral structure. Implications of the structure for the function and stability of the avian adenovirus long fiber protein are discussed; notably, the structure suggests a different mode of binding to the coxsackievirus and adenovirus receptor from that proposed for the human adenovirus fiber heads. PMID- 17698650 TI - The CD4+ T-cell response to adenovirus is focused against conserved residues within the hexon protein. AB - Adenovirus is a significant pathogen in immunocompromised patients and is widely utilized as a gene delivery vector, so a detailed understanding of the human immune response to adenovirus infection is critical. This study characterized the adenovirus-specific CD4(+) T-cell response of healthy donors by incubation with whole virus or with individual hexon and fiber proteins. Adenovirus-specific CD4(+) T cells averaged 0.26 % of the CD4(+) T-cell pool and were detectable in all donors. T cells recognizing the highly conserved hexon protein accounted for 0.09 %, whereas no response was observed against the fiber protein. A panel of hexon-specific CD4(+) T-cell clones was generated and shown to lyse targets infected with adenovirus from different serotypes and species. Three CD4 T-cell epitopes are described, which map to highly conserved regions of the hexon protein. PMID- 17698651 TI - Systematic analysis of longitudinal serological responses of pigs infected experimentally with African swine fever virus. AB - The protective immune response to African swine fever virus (ASFV) includes both cellular and serological components. In this study, the role of antibodies in the pathogenicity and diagnosis of African swine fever (ASF) was explored. Accordingly, total and Ig isotype antibody responses against the 12 viral proteins previously demonstrated to be the main targets of serological immunity were evaluated in longitudinally collected sera from pigs infected experimentally with the non-pathogenic ASFV/NH/P68 isolate. Strong total IgG antibody responses were observed against viral proteins E183L/p54, K205R/'unassigned', A104R/histone like and B602L/'unassigned'; therefore, IgM, IgG1 and IgG2 responses to these proteins were also determined. One protein stimulating IgM (K205R) may have practical potential for the detection of recently infected animals. There was a clear trend towards an IgG1 response to all of the proteins. This may reflect a dominant Th2-controlled immune response. In order to identify possible correlations between these serological responses and the pathogenesis of ASF, total IgG responses to the 12 recombinant proteins were compared in asymptomatic and chronically infected animals. For the proteins NP419L/DNA ligase, CP312R, B646L/p73, K196R/thymidine kinase and K205R, the antibody titres were significantly higher in animals developing lesions. One exception was the antibody response to the A104R/histone-like protein, which was higher in asymptomatic than in chronically infected pigs, suggesting that antibodies against this protein might be an indicator of an effective immune response or that this response is somehow involved in protection. PMID- 17698652 TI - An activation-defective mutant of the human cytomegalovirus IE2p86 protein inhibits NF-kappaB-mediated stimulation of the human interleukin-6 promoter. AB - The IE2p86 protein of human cytomegalovirus is an essential activator of early- and late-phase viral gene expression. Whilst IE2p86 activates expression of a number of cellular genes, it also represses certain cellular genes, particularly those activated by nuclear factor kappaB (NF-kappaB). As the interleukin-6 (IL-6) promoter can be activated by both NF-kappaB and IE2p86, it was examined whether there is competition between these two factors. Here, it is reported that both wild-type and mutant IE2p86 can block activation of the IL-6 promoter in response to interleukin-1beta. By using an artificial activator in which the activation domain of NF-kappaB is directed to the promoter by the GAL4 DNA-binding domain, it is shown that the mutant form of IE2p86 can inhibit NF-kappaB-mediated activation at a step subsequent to promoter recruitment. These data therefore suggest a novel mechanism for inhibition of NF-kappaB by IE2p86. PMID- 17698653 TI - Anti-IE1 CD4+ T-cell clones kill peptide-pulsed, but not human cytomegalovirus infected, target cells. AB - Cellular immunity plays a major role in the control of human cytomegalovirus (HCMV) infection. CD4(+) T lymphocytes have been shown to contribute to this function but their precise role is a matter of debate. Although CD4(+) T cells have been shown to kill target cells through the perforin/granzyme pathway, whether HCMV-specific CD4(+) T cells are capable of killing HCMV-infected targets has not yet been documented. In the present paper, we have taken advantage of well established cellular reagents to address this issue. Human CD4(+) T-cell clones specific for the major immediate-early protein IE1 were shown to perform perforin-based cytotoxicity against peptide-pulsed targets. However, when tested on infected anitgen presenting cell targets, cytotoxicity was not detectable, although gamma interferon (IFN-gamma) production was significant. Furthermore, cytotoxicity against peptide-pulsed targets was inhibited by HCMV infection, whereas IFN-gamma production was not modified, suggesting that antigen processing was not altered. Remarkably, degranulation of CD4(+) T cells in the presence of infected targets was significant. Together, our data suggest that impaired cytotoxicity is not due to failure to recognize infected targets but rather to a mechanism specifically related to cytotoxicity. PMID- 17698654 TI - Sequence analysis of the equid herpesvirus 2 chemokine receptor homologues E1, ORF74 and E6 demonstrates high sequence divergence between field isolates. AB - Equid herpesvirus 2 (EHV-2), in common with other members of the subfamily Gammaherpesvirinae, encodes homologues of cellular seven-transmembrane receptors (7TMR), namely open reading frames (ORFs) E1, 74 and E6, which each show some similarity to cellular chemokine receptors. Whereas ORF74 and E6 are members of gammaherpesvirus-conserved 7TMR gene families, E1 is currently unique to EHV-2. To investigate their genetic variability, EHV-2 7TMRs from a panel of equine gammaherpesvirus isolates were sequenced. A region of gB was sequenced to provide comparative sequence data. Phylogenetic analysis revealed six 'genogroups' for E1 and four for ORF74, which exhibited approximately 10-38 and 11-27 % amino acid difference between groups, respectively. In contrast, E6 was highly conserved, with two genogroups identified. The greatest variation was observed within the N terminal domains and other extracellular regions. Nevertheless, analysis of the number of non-synonymous (d(N)) and synonymous (d(S)) substitutions per site generally supported the hypothesis that the 7TMRs are under negative selective pressure to retain functionally important residues, although some site-specific positive selection (d(N)>d(S)) was also observed. Collectively, these data are consistent with transmembrane and cytoplasmic domains being less tolerant of mutations with adverse effects upon function. Finally, there was no evidence for genetic linkage between the different gB, E1, ORF74 and E6 genotypes, suggesting frequent intergenic recombination between different EHV-2 strains. PMID- 17698655 TI - A comprehensive library of mutations of Epstein Barr virus. AB - A mutant library of 249 mutants with mutations that span the entire Epstein-Barr virus (EBV) genome was generated by transposition with EZ : : TN and insertion with an apramycin resistance gene by a PCR-targeting method. This study also demonstrates the feasibility of generating deletions and site-specific mutations in the BRLF1 promoter on the EBV genome to determine the regions in the promoter that are crucial to transcription. Analysing BZLF1 and BRLF1 mutants by microarray analysis revealed that these two genes regulate the transcription of EBV lytic genes differently. A BZLF1 mutation affects global expression of EBV lytic genes; almost no lytic gene is expressed by the mutant after lytic induction. However, although a BRLF1 mutant still transcribes most lytic genes, the expression of these lytic genes is inefficient. Furthermore, this study shows that the proximal Zta-response element in the BRLF1 promoter is crucial to BRLF1 transcription from the EBV genome, despite the fact that another work demonstrated that this site was unimportant in transient transfection analysis. Furthermore, mutants with a mutation in BDLF1 and BORF1 cannot assemble viral capsids. Results of this study demonstrate the usefulness of a comprehensive mutant library in genetic analyses of EBV. PMID- 17698656 TI - Virus distribution of the attenuated MVA and NYVAC poxvirus strains in mice. AB - Recombinant vaccinia viruses based on the attenuated NYVAC and MVA strains are promising vaccine candidates against a broad spectrum of diseases. Whilst these vectors are safe and immunogenic in animals and humans, little is known about their comparative behaviour in vivo. In this investigation, a head-to-head analysis was carried out of virus dissemination in mice inoculated by the mucosal or systemic route with replication-competent (WRluc) and attenuated recombinant (MVAluc and NYVACluc) viruses expressing the luciferase gene. Bioluminescence imaging showed that, in contrast to WRluc, the attenuated recombinants expressed the reporter gene transiently, with MVAluc expression limited to the first 24 h and NYVACluc giving a longer signal, up to 72 h post-infection, for most of the routes assayed. Moreover, luciferase levels in MVAluc-infected tissues peaked earlier than those in tissues infected by NYVACluc. These findings may be of immunological relevance when these vectors are used as recombinant vaccines. PMID- 17698657 TI - Reprogramming the chiA expression profile of Autographa californica multiple nucleopolyhedrovirus. AB - Expression of chiA and v-cath RNA and enzyme activity in wild-type Autographa californica multiple nucleopolyhedrovirus (AcMNPV) was compared with that of recombinant AcMNPV viruses reprogrammed for expression of the endogenous chiA. To establish a baseline for our recombinant AcMNPV studies, we compared, for the first time, the temporal expression profiles of both AcMNPV chiA transcription and translation simultaneously. The rate of intracellular chitinase accumulation during AcMNPV infection followed the same pattern observed for chiA transcription but was delayed by about 6 h. Replacement of 21 nucleotides containing the native late chiA and v-cath promoters with a selectable polh-EGFP cassette was sufficient to eliminate expression of both chiA and v-cath. Viruses were generated that express chiA from either the late p6.9 or very late polh promoters of AcMNPV, replacing the native chiA promoter. There was a marked difference in the temporal chiA transcription profiles from the native, p6.9 and polh promoters, resulting in respective specific activities of chitinase at 48 h p.i. of 62, 160 and 219 mU (mg lysate total protein)(-1). Based on temporal analysis of v-cath transcription by Northern blot, AcMNPV v-cath was transcribed from 9 h p.i. in Sf21 cells. However, expression of v-cath RNA or enzyme from a reconstructed v-cath promoter in the chiA-reprogrammed viruses was not detected at 48 h of virus replication. Reprogramming for increased chitinase (and putatively cathepsin) expression with native baculovirus promoters might provide a means for designing environmentally benign biological insecticides. PMID- 17698658 TI - The Chilo iridescent virus DNA polymerase promoter contains an essential AAAAT motif. AB - The delayed-early DNA polymerase promoter of Chilo iridescent virus (CIV), officially known as Invertebrate iridescent virus, was fine mapped by constructing a series of increasing deletions and by introducing point mutations. The effects of these mutations were examined in a luciferase reporter gene system using Bombyx mori cells transfected with promoter constructs and infected with CIV. When the size of the upstream element was reduced from position -19 to -15, relative to the transcriptional start site, the luciferase activity was reduced to almost zero. Point mutations showed that each of the 5 nt (AAAAT) located between -19 and -15 were equally essential for promoter activity. Mutations at individual bases around the transcription initiation site showed that the promoter extended until position -2 upstream of the transcription start site. South-Western analysis showed that a protein of approximately 100 kDa interacted with the -19 nt promoter fragment in CIV-infected cells. This binding did not occur with a point mutant that lacked promoter activity. The AAAAT motif was also found in the DNA polymerase promoter region of other iridoviruses and in other putative CIV delayed-early genes. PMID- 17698659 TI - Robust production of infectious viral particles in Huh-7 cells by introducing mutations in hepatitis C virus structural proteins. AB - Recently, the characterization of a cell culture system allowing the amplification of an authentic virus, named hepatitis C virus cell culture (HCVcc), has been reported by several groups. To obtain higher HCV particle productions, we investigated the potential effect of some amino acid changes on the infectivity of the JFH-1 isolate. As a first approach, successive infections of naive Huh-7 cells were performed until high viral titres were obtained, and mutations that appeared during this selection were identified by sequencing. Only one major modification, N534K, located in the E2 glycoprotein sequence was found. Interestingly, this mutation prevented core glycosylation of E2 site 6. In addition, JFH-1 generated with this modification facilitated the infection of Huh 7 cells. In a second approach to identify mutations favouring HCVcc infectivity, we exploited the observation that a chimeric virus containing the genotype 1a core protein in the context of JFH-1 background was more infectious than wild type JFH-1 isolate. Sequence alignment between JFH-1 and our chimera, led us to identify two major positions, 172 and 173, which were not occupied by similar amino acids in these two viruses. Importantly, higher viral titres were obtained by introducing these residues in the context of wild-type JFH-1. Altogether, our data indicate that a more robust production of HCVcc particles can be obtained by introducing a few specific mutations in JFH-1 structural proteins. PMID- 17698660 TI - Efficient infection of tree shrew (Tupaia belangeri) with hepatitis C virus grown in cell culture or from patient plasma. AB - The generation of a new, cost-effective, non-primate, small-animal model would greatly facilitate research into hepatitis C virus (HCV) pathogenesis and the development of novel therapeutic and preventative technologies to control the increasing HCV threat to public health. Native HCV from patient plasma and HCV grown in cell culture (HCVcc) were used to inoculate adult tree shrews. Each animal was inoculated with one HCV genotype. Alanine aminotransferase (ALT) levels, HCV RNA and viral load were determined in the animals before and after inoculation. For native HCV, 16/18 inoculated tree shrews (89 %) became infected; 12/16 (75 %) of these animals became chronically infected, whilst infection was resolved in the remaining four (25 %). For HCVcc, infection occurred in 10/12 inoculated tree shrews (83 %) and chronic infection was observed in two of these animals. HCVcc from Huh7 cells showed a higher infectivity than that from HeLa cells. The animals inoculated with inadequate amounts of HCV were not infected in either native HCV or HCVcc experiments. Peak viral loads reached 10(3)-10(5) international units ml(-1) in chronically infected animals. ALT level changes reflected the normal fluctuation range in most animals. Thus, tree shrews without immunosuppression can be infected efficiently by native HCV and HCVcc when the animal is inoculated with an adequate amount of single-genotype HCV. PMID- 17698662 TI - Enterovirus surveillance reveals proposed new serotypes and provides new insight into enterovirus 5'-untranslated region evolution. AB - Human enteroviruses are currently grouped into five species Human enterovirus A (HEV-A), HEV-B, HEV-C, HEV-D and Poliovirus. During surveillance for enteroviruses serologically non-typable enterovirus strains were found from acute flaccid paralysis patients and healthy individuals. In this study, we report isolates of recently described enterovirus types EV76 and EV90 of HEV-A species and characterize two new enterovirus type candidates, EV96 and EV97, to species HEV-C and HEV-B, respectively. Analysis of partial 3D regions of EV96 strains revealed sequence divergence consistent with several recombination events between EV96, other HEV-C viruses and polioviruses. Phylogenetic analysis of all available 5'-untranslated region sequences of human entero- and rhinovirus prototype strains and 10 simian enterovirus strains suggested interspecies recombination involving this region. PMID- 17698661 TI - Increasing genetic diversity of hepatitis C virus in haemophiliacs with human immunodeficiency virus coinfection. AB - Patients with inherited bleeding disorders who received clotting factor concentrates before 1987 have high rates of hepatitis C virus (HCV) or HCV/human immunodeficiency virus (HIV) infection. To determine whether the persistent nature of HIV affects the genetic diversity of HCV by less selective pressure through the immunosuppression of HIV/HCV-coinfected patients, both the change of genetic diversity and selective pressure were examined in the HCV envelope genes (E1 and E2) of 325 genotype 1a subclones from eight HIV-positive and five HIV negative patients with two time points (more than 6 years apart). To infer the genetic diversity of HCV in each patient, we used two approaches. One method was to estimate the difference of total evolutionary distances in the phylogenetic tree between the two time points, and another was to estimate the changes of genetic diversity along the time based on the coalescence theory. The two results indicate that the HIV-positive group has significantly more diverse population structure than the HIV-negative group. A comparative analysis of the synonymous and non-synonymous substitutions found that the HIV-positive group was subject to less selective pressure than the HIV-negative group. In conclusion, HIV-positive patients would have a more diversified HCV population than HIV-negative patients due to less selective pressure from the immune system. PMID- 17698663 TI - Attachment and internalization of feline infectious peritonitis virus in feline blood monocytes and Crandell feline kidney cells. AB - In this study, kinetics of attachment and internalization of feline infectious peritonitis virus (FIPV) serotype I strain Black and serotype II strain 79-1146 were determined in feline monocytes from two cats and in Crandell feline kidney (CrFK) cells. Attached FIPV I (Black) particles were observed on almost all monocytes. Within 1 h, 17 particles were bound per cell and, within 1 min, 89 % of the bound particles were internalized. For FIPV II (79-1146), attachment was observed on 66 and 95 % of all monocytes from the two cats. After 1 h, respectively five and 20 particles were bound per cell (all cells considered). Within 1 min, 60 % of the bound particles were internalized. Internalization in monocytes was efficient and proceeded via endocytosis. In CrFK cells, attachment and internalization were less efficient, especially for FIPV I (Black), so this cell line is not suitable for studying FIPV entry. PMID- 17698664 TI - Functional consequences of attenuating mutations in the haemagglutinin neuraminidase, fusion and polymerase proteins of a wild-type mumps virus strain. AB - Wild-type mumps viruses (MuVs) are highly neurotropic and, prior to widespread vaccination programmes, were a major cause of viral meningitis and encephalitis in most developed countries. At present, there are no markers for virus attenuation, apart from the failure of a passaged isolate to produce clinical symptoms in vaccinees. Indeed, some MuV vaccines have retained residual neurovirulence properties and have caused aseptic meningitis in vaccinees. Three amino acid changes associated with the neuroattenuation of a wild-type MuV strain were identified previously. This study evaluated the impact of these changes on the function of the respective proteins. The data demonstrated that the Ser-->Asp amino acid substitution at position 466 in the haemagglutinin-neuraminidase protein resulted in decreased receptor binding and neuraminidase activity, the Ala/Thr-->Thr selection in the fusion protein resulted in decreased fusion activity, and the Ile-->Val substitution in the polymerase resulted in increased replicative/transcriptional activity. These data suggest a polygenic component (i.e. specific and inter-related roles of these amino acid changes) to MuV neuroattenuation. PMID- 17698665 TI - Cis-acting elements in the antigenomic promoter of Nipah virus. AB - Genome synthesis in paramyxoviruses, including Nipah virus (NiV), is controlled by sequence elements that reside in the non-coding nucleotides at the 5'-trailer (3'-antigenomic) end that make up the antigenomic promoter (AGP). Using a chloramphenicol acetyl transferase-based plasmid-driven minigenome system, the terminal 96 nt of NiV AGP were first mutagenized in blocks of three hexamers to enable broad mapping of the minigenome functional regions. This was followed by further dissection of these functional regions to define the cis-acting elements contained therein. Results based on RNA analysis and reporter gene activity identified a bipartite promoter structure similar to that seen in related viruses, but with some distinct differences: in NiV, each of the two discrete replication control elements was bimodal, characterized by a critical conserved region (nt 1-12 and 79-91) and a contiguous non-conserved region (nt 13-36 and 73 78), which appeared less important. The regulatory role of these less critical regions was underscored by the use of a two-step mutation strategy, which revealed the additive detrimental effect of substitutions in this part of the terminal element. The structure and sequence characteristics of the internal control element was also different: it involved four contiguous hexamers, and the region encompassing three of these (nt 79-96, corresponding to hexamers 14, 15 and 16), although analogous in position to the equivalent element in the Sendai virus AGP, was characterized by the distinct 5'-(GNNNUG)(14-15)(GNNNNN)(16) motif. PMID- 17698666 TI - Local immune response to respiratory syncytial virus infection is diminished in senescence-accelerated mice. AB - The effect of ageing on the local defence system against respiratory syncytial virus (RSV) infection was investigated using an aged mouse model of the senescence-accelerated mouse (SAM) strain P1. Following intranasal infection with RSV, SAM-P1 mice showed a marked loss in weight, with elevated virus growth in the lungs and prolonged virus shedding. The increased susceptibility to RSV infection was associated mainly with diminished cellular immunity by local virus specific cytotoxic T lymphocytes and natural killer cells. The deficiency in cellular immune responses was due to a lack of clonal expansion of CD4(+) and CD8(+) T lymphocytes, together with an imbalance of T-helper type 1 (Th1)/Th2 cytokine production in the respiratory tract, including the lungs. Furthermore, the production of virus-specific local IgA antibody was restrained. Prolonged virus loading in the lungs of SAM-P1 mice caused a massive infiltration of CD16(+)/32(+) inflammatory cells, which was one factor responsible for severe pneumonia. The adoptive transfer of immune-competent spleen cells achieved an appreciable protection for SAM-P1 mice against RSV challenge infection. These results suggested that age-related immune dysfunction, especially defects in cellular immune responses, accounts for the increased morbidity and mortality in RSV infection of the elderly. PMID- 17698667 TI - Modifications of the PSAP region of the matrix protein lead to attenuation of vesicular stomatitis virus in vitro and in vivo. AB - The matrix (M) protein of vesicular stomatitis virus (VSV) is a multi-functional protein involved in virus assembly, budding and pathogenesis. The (24)PPPY(27) late (L) domain of the M protein plays a key role in virus budding, whereas amino acids downstream of the PPPY motif contribute to host protein shut-off and pathogenesis. Using a panel of (37)PSAP(40) recombinant viruses, it has been demonstrated previously that the PSAP region of M does not possess L-domain activity similar to that of PPPY in BHK-21 cells. This study reports the unanticipated finding that these PSAP recombinants were attenuated in cell culture and in mice compared with control viruses. Indeed, PSAP recombinant viruses exhibited a small-plaque phenotype, reduced CPE, reduced levels of activated caspase-3, enhanced production of IFN-beta and reduced titres in the lungs and brains of infected mice. In particular, recombinant virus M6PY>A4-R34E was the most severely attenuated, exhibiting little or no CPE in cell culture and undetectable titres in the lungs and brains of infected mice. These findings indicate an important role for the PSAP region (aa 33-44) of the M protein in the pathology of VSV infection and may have implications for the development of VSV as a vaccine and/or oncolytic vector. PMID- 17698668 TI - Virus-associated host CD62L increases attachment of human immunodeficiency virus type 1 to endothelial cells and enhances trans infection of CD4+ T lymphocytes. AB - Previous studies have identified several host-derived cell-surface proteins incorporated within emerging human immunodeficiency virus type 1 (HIV-1) particles. Some of these molecules play a role in different steps of the virus life cycle and are often advantageous for the virus. We report here that the leukocyte L-selectin (also called CD62L) remains functional when inserted within the envelope of HIV-1. Indeed, we demonstrate that adsorption of virions to endothelial cells is enhanced upon acquisition of host-derived CD62L. The more important binding of CD62L-bearing HIV-1 particles resulted in a more efficient virus transmission to CD4(+) T lymphocytes. Capture and eventual transfer of such CD62L-bearing virions by the endothelium could play a role in the pathogenesis of HIV-1 infection. PMID- 17698669 TI - Effects of feline immunodeficiency virus on feline monocyte-derived dendritic cells infected by spinoculation. AB - During type 1 human immunodeficiency virus infection, not only can dendritic cells (DCs) prime T cells against the virus, but they can also infect them in trans. Feline AIDS is caused by feline immunodeficiency virus (FIV) and is considered a model for the human illness because the two diseases have many features in common. Little is known about the interaction of feline DCs with FIV; therefore, this study attempts to tackle such an issue. Infection of feline monocyte-derived DCs (MDDCs) was attempted by spinoculation with FIV strains Petaluma (FIV-Pet) and M2. FIV-Pet was released rapidly in the supernatants of both infected MDDCs and activated T cells after spinoculation. It is shown that FIV-Pet was produced by MDDCs by monitoring viral content in the supernatants of infected MDDCs, by intracellular staining for p25 and by showing its cytopathic effect. Although activated T cells were better substrates for FIV replication, leading to prolonged viral shedding, both immature MDDCs and MDDCs matured with lipopolysaccharide supported virus production, mostly during the first 2 days after infection. At later times, FIV induced syncytium formation by MDDCs. Concerning the FIV receptors, MDDCs were shown to be CD134-negative and CXCR4 positive, a phenotype compatible with permissiveness to FIV-Pet. These results also suggest that maturation is not hampered by FIV infection and that virus exposure itself does not induce MDDC maturation. It is also shown that infected MDDCs can infect activated PBMCs efficiently in trans. It is concluded that MDDCs can be infected by FIV, although infection does not appear to influence their functionality. PMID- 17698670 TI - Establishment of productively infected walleye dermal sarcoma explant cells. AB - Walleye dermal sarcoma virus (WDSV) is a complex retrovirus associated with dermal sarcomas in walleye fish. Virus expression is tightly regulated and limited to accessory gene transcripts throughout tumour development. During tumour regression, this regulation is lost and the replication of virus is greatly enhanced. Cultured walleye fibroblasts infected in vitro do not produce significant quantities of infectious virus. Tissue culture cells established by explantation of tumour cells were found to harbour WDSV provirus and to express accessory and structural proteins. The sequence of the provirus showed little variation from a previous WDSV isolate. Retroviral particles were isolated from supernatants from these cells and were able to transfer infection to uninfected walleye fibroblasts. In addition to the virus present in supernatants, much of the virus was cell associated and liberated only by sonication. This virus was found at internal cellular membranes, including mitochondria, and was infectious. PMID- 17698671 TI - A novel virus isolated from the aphid Brevicoryne brassicae with similarity to Hymenoptera picorna-like viruses. AB - A novel virus, Brevicoryne brassicae virus (BrBV), has been identified in the cabbage aphid using a method based on the random amplification of encapsidated RNA. The complete sequence of the RNA genome of BrBV has been determined. The positive-strand genomic RNA is 10 161 nt, excluding the 3' poly(A) tail, and contains a single open reading frame (positions 793-9744) encoding a putative polyprotein of 2983 aa. The N-terminal part of the polyprotein shows similarity with the structural proteins of iflaviruses. The C-terminal part possesses consensus sequences of the helicase, cysteine protease and RNA-dependent RNA polymerase similar to those of iflaviruses and other picorna-like viruses. The highest sequence similarity observed was with iflaviruses from honeybee and an endoparasitic wasp. Replication and transmission of BrBV was not dependent on endoparasitic wasp infestation of the aphids. PMID- 17698672 TI - 2b ORFs encoded by subgroup IB strains of cucumber mosaic virus induce differential virulence on Nicotiana species. AB - Cucumber mosaic virus (CMV)-encoded 2b protein from subgroup IA or subgroup II was shown to be a determinant of virulence in many solanaceous hosts. In this study, the virulence of 2b proteins from subgroup IB strains was analysed using four intraspecies hybrid viruses, which were generated by precise replacement of the 2b open reading frame (ORF) in subgroup IA strain Fny-CMV with the 2b ORFs of four subgroup IB strains, Cb7-CMV, PGs-CMV, Rad35-CMV and Na-CMV, generating FCb7(2b)-CMV, FPGs(2b)-CMV, FRad35(2b)-CMV and FNa(2b)-CMV, respectively. FCb7(2b)-CMV was more virulent than Fny-CMV, and was similar in phenotype to its parental virus Cb7-CMV on the three Nicotiana species tested. FNa(2b)-CMV also was virulent on these host species, equivalent to Fny-CMV or Na-CMV. However, FRad35(2b)-CMV only caused mild mosaic or undetectable symptoms on all the host species tested, and was less virulent than Fny-CMV or Rad35-CMV. FPGs(2b)-CMV infected all the host species systemically, and induced either mosaic or barely visible symptoms, demonstrating that the inability of PGs-CMV to infect these three Nicotiana species was not due to its 2b protein. The diverse virulence was shown to be mediated by the 2b proteins rather than the C-terminal overlapping parts of the 2a proteins, and was associated with the level of viral progeny RNA accumulation in systemically infected leaves, but not with the rate of long distance viral movement in host plants. Through analysis of encapsidation of viral RNAs, there was an apparent correlation between the virulence and the high level of encapsidated RNA 2 in virions of Fny-CMV, FCb7(2b)-CMV and FNa(2b)-CMV. PMID- 17698673 TI - Analysis of the serological variability of Lettuce mosaic virus using monoclonal antibodies and surface plasmon resonance technology. AB - A panel of 19 monoclonal antibodies (mAbs) was used to study the immunological variability of Lettuce mosaic virus (LMV), a member of the genus Potyvirus, and to perform a first epitope characterization of this virus. Based on their specificity of recognition against a panel of 15 LMV isolates, the mAbs could be clustered in seven reactivity groups. Surface plasmon resonance analysis indicated the presence, on the LMV particles, of at least five independent recognition/binding regions, correlating with the seven mAbs reactivity groups. The results demonstrate that LMV shows significant serological variability and shed light on the LMV epitope structure. The various mAbs should prove a new and efficient tool for LMV diagnostic and field epidemiology studies. PMID- 17698674 TI - Combinations of two amino acids (Ala40 and Phe75 or Ser40 and Tyr75) in the coat protein of apple chlorotic leaf spot virus are crucial for infectivity. AB - Amino acid sequences of apple chlorotic leaf spot virus (ACLSV) coat protein (CP) were compared between 12 isolates from apple, plum and cherry, and 109 cDNA clones that were amplified directly from infected apple tissues. Phylogenetic analysis based on the amino acid sequences of CP showed that the isolates and cDNA clones were separated into two major clusters in which the combinations of the five amino acids at positions 40, 59, 75, 130 and 184 (Ala(40)-Val(59) Phe(75)-Ser(130)-Met(184) or Ser(40)-Leu(59)-Tyr(75)-Thr(130)-Leu(184)) were highly conserved within each cluster. Site-directed mutagenesis using an infectious cDNA clone of ACLSV indicated that the combinations of two amino acids (Ala(40) and Phe(75) or Ser(40) and Tyr(75)) are necessary for infectivity to Chenopodium quinoa plants by mechanical inoculation. Moreover, an agroinoculation assay indicated that the substitution of a single amino acid (Ala(40) to Ser(40) or Phe(75) to Tyr(75)) resulted in extreme reduction in the accumulation of viral genomic RNA, double-stranded RNAs and viral proteins (movement protein and CP) in infiltrated tissues, suggesting that the combinations of the two amino acids at positions 40 and 75 are important for effective replication in host plant cells. PMID- 17698675 TI - Amyloid-specific fluorophores for the rapid, sensitive in situ detection of prion contamination on surgical instruments. AB - Prion diseases or transmissible spongiform encephalopathies (TSEs) are a group of rare, transmissible and fatal neurodegenerative diseases associated with the protein agent (PrP(Sc)). As such, the sensitive and rapid detection of prion PrP(Sc) amyloid on the surface of suspect surgical instruments is of great importance and may even allow remedial action to be taken prior to any further operative intervention and possible iatrogenic transmission. However, conventional PrP(Sc) detection methodologies tend to rely on the inefficient and unreliable removal of suspect material from a surface using swabs or wipes prior to antibody analysis. Here we show how the combination of an advanced light microscope technique, episcopic differential interference contrast/epifluorescence (EDIC/EF) microscopy, and the application of beta amyloid fluorescent thiazole markers (thioflavin T, thioflavin S) can be used to detect, in situ, submicron (attomole) levels of prion protein amyloid contamination in brain and spleen sections, smears and homogenate on surgical stainless steel surfaces and surgical instruments. This technique, although not specific to an amyloid type, can be used to verify that surgical instruments are substantially free from prion amyloid protein soiling and hence reduce the risk of iatrogenic transmission. PMID- 17698676 TI - Prognostic factors in heat wave related deaths: a meta-analysis. AB - BACKGROUND: Although identifying individuals who are at increased risk of dying during heat waves and instituting protective measures represent an established strategy, the evidence supporting the components of this strategy and their strengths has yet to be evaluated. We conducted a meta-analysis of observational studies on risk and protective factors in heat wave-related deaths. METHODS: Using the OVID interface, we searched Medline (1966-2006) and CINHAL (1982-2006) databases. The Web sites of the World Health Organization, Institut National de Veille Sanitaire, and Centers for Disease Control and Prevention were also visited. The search terms included heat wave, heat stroke, heatstroke, sunstroke, and heat stress disorders. Eligible studies were case-control or cohort studies. Odds ratios (ORs) and information on study quality were abstracted by 2 investigators independently. Six case-control studies involving 1065 heat wave related deaths were identified. RESULTS: Being confined to bed (OR, 6.44; 95% confidence interval [CI], 4.5-9.2), not leaving home daily (OR, 3.35; 95% CI, 1.6 6.9), and being unable to care for oneself (OR, 2.97; 95% CI, 1.8-4.8) were associated with the highest risk of death during heat waves. Preexisting psychiatric illness (OR, 3.61; 95% CI, 1.3-9.8) tripled the risk of death, followed by cardiovascular (OR, 2.48; 95% CI, 1.3-4.8) and pulmonary (OR, 1.61; 95% CI, 1.2-2.1) illness. Working home air-conditioning (OR, 0.23; 95% CI, 0.1 0.6), visiting cool environments (OR, 0.34; 95% CI, 0.2-0.5), and increasing social contact (OR, 0.40; 95% CI, 0.2-0.8) were strongly associated with better outcomes. Taking extra showers or baths (OR, 0.32; 95% CI, 0.1-1.1) and using fans (OR, 0.60; 95% CI, 0.4-1.1) were associated with a trend toward lower risk of death. CONCLUSION: The present study identified several prognostic factors that could help to detect those individuals who are at highest risk during heat waves and to provide a basis for potential risk-reducing interventions in the setting of heat waves. PMID- 17698677 TI - Short- and long-term outcomes of heatstroke following the 2003 heat wave in Lyon, France. AB - BACKGROUND: During August 2003, Europe sustained a severe heat wave that resulted in 14 800 heat-related deaths in France. Most of these excess deaths occurred in urban areas, where maximal temperatures broke all records. Heatstroke is the most severe form of heat-related illness. The clinical course of heatstroke in urban areas of temperate countries is poorly documented. METHODS: During the French heat wave (August 1-20, 2003), we conducted a prospective study in a university hospital located in Lyon, one of the largest metropolitan areas in France. We evaluated survival and functional outcome for 2 years and looked for factors influencing the prognosis. RESULTS: A total of 83 patients presented with heatstroke. The 28-day and 2-year mortality rates were 58% and 71%, respectively. Mortality was influenced as early as admission by the level of fever and the number of organ dysfunctions. Multivariate analysis revealed an independent contribution to mortality if patients came from an institution (hazard ratio [HR], 1.98; 95% confidence interval [CI], 1.05-3.71), used long-term antihypertensive medication (HR, 2.17; 95% CI, 1.17-4.05), or presented at admission with anuria (HR, 5.24; 95% CI, 2.29-12.03), coma (HR, 2.95; 95% CI, 1.26-6.91), or cardiovascular failure (HR, 2.43; 95% CI, 1.14-5.17). Most surviving patients exhibited a dramatic alteration of their functional status at 1 and 2 years. CONCLUSIONS: Heatstroke is associated with poor outcomes in temperate urban areas. This could be explained at least in part by our lack of experience. Western temperate countries need to be more prepared for future heat waves. PMID- 17698678 TI - Behavioral factors, bias, and practice guidelines in the decision to use percutaneous coronary interventions for stable coronary artery disease. PMID- 17698679 TI - Institutional review boards should require clinical trial registration. PMID- 17698680 TI - Prevention of sports injuries: systematic review of randomized controlled trials. AB - Increased participation in sports has led to more sports injuries. Evidence-based methods to prevent sports injuries are needed. A systematic review was conducted of the effects of randomized controlled interventions to prevent sports injuries. A systematic search was performed of various databases and the reference lists of articles and reviews. Two reviewers independently extracted the data and assessed the methodological quality of the included trials. Thirty-two trials (24,931 participants) met the inclusion criteria. We found evidence of the preventive effect of 3 types of injury prevention interventions. In 5 trials including 6 different comparisons (2446 participants), custom-made or prefabricated insoles reduced lower limb injuries compared with no insoles in military recruits (risk reduction > or =50% in 4 comparisons). All 7 studies investigating external joint supports (10,300 participants) showed a tendency to prevent ankle, wrist, or knee injuries (risk reduction > or =50% in 5 studies). All 6 multi-intervention training programs (2809 participants) were effective in preventing sports injuries (risk reduction > or =50% in 5 studies). Various interventions may prevent sports injuries. A decreased risk of sports injuries was associated with the use of insoles, external joint supports, and multi-intervention training programs. More high-quality randomized controlled trials in different sports and populations are needed. PMID- 17698681 TI - Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. AB - BACKGROUND: The risk of recurrence of cardiovascular events among patients using aspirin (acetylsalicylic acid) for secondary prevention of such events remains high. Persistent platelet reactivity despite aspirin therapy, a laboratory defined phenomenon called aspirin resistance (hereinafter, laboratory aspirin resistance), might explain this in part, but its actual contribution to the risk remains unclear. The objective of this study was to systematically review all available evidence on whether laboratory aspirin resistance is related to a higher risk of cardiovascular recurrent events. METHODS: Using a predefined search strategy, we searched electronic databases. To be included in our analysis, articles had to report on patients who used aspirin for secondary cardiovascular prevention, had to contain a clear description of a method to establish the effects of aspirin on platelet reactivity, and had to report recurrence rates of cardiovascular events. Odds ratios of cardiovascular outcome of eligible studies were pooled in a random-effects model. RESULTS: We included 15 full-text articles and 1 meeting abstract. Fifteen of these studies revealed an adverse association between laboratory aspirin resistance and occurrence of cardiovascular events. The pooled odds ratio of all cardiovascular outcomes was 3.8 (95% confidence interval, 2.3-6.1) for laboratory aspirin resistance. CONCLUSION: This systematic review and meta-analysis shows that patients biochemically identified as having laboratory aspirin resistance are more likely to also have "clinical resistance" to aspirin because they exhibit significantly higher risks of recurrent cardiovascular events compared with patients who are identified as (laboratory) aspirin sensitive. PMID- 17698682 TI - Cardiologists' use of percutaneous coronary interventions for stable coronary artery disease. AB - BACKGROUND: Percutaneous coronary intervention (PCI) is commonly performed in patients with stable coronary artery disease, despite current evidence suggesting that such patients derive minimal benefit from the procedure. We sought to determine the influences on cardiologists' decision to perform elective PCI in patients with stable coronary artery disease. METHODS: We conducted a qualitative study using 3 focus groups of interventional and noninterventional cardiologists in California. Participants discussed issues surrounding the decision to perform PCI using hypothetical case scenarios. We analyzed the data according to the principles of grounded theory. RESULTS: Despite acknowledging data showing that PCI offers no reduction in the risk of death or myocardial infarction in patients with stable coronary artery disease, cardiologists generally believed that PCI would benefit such patients. Reasons given for performing PCI included belief in the benefits of treating ischemia and the open artery hypothesis, especially with drug-eluting stents; potential regret for not intervening if a cardiac event could be averted; alleviation of patient anxiety; and medicolegal considerations. Participants believed that, in patients undergoing coronary angiography, an "oculostenotic reflex" prevailed and all significant amenable stenoses would receive intervention, even in asymptomatic patients. CONCLUSIONS: The widespread application of PCI in stable coronary artery disease for indications unsupported by evidence may reflect discordance between cardiologists' clinical knowledge and their beliefs about the benefits of PCI. Nonclinical factors appear to have substantial influence on physician decision making. Future studies should focus on the development of methods to help providers more fully incorporate clinical evidence into their medical decision making. PMID- 17698683 TI - A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study. AB - BACKGROUND: Randomized trials have largely failed to support an effect of antioxidant vitamins on the risk of cardiovascular disease (CVD). Few trials have examined interactions among antioxidants, and, to our knowledge, no previous trial has examined the individual effect of ascorbic acid (vitamin C) on CVD. METHODS: The Women's Antioxidant Cardiovascular Study tested the effects of ascorbic acid (500 mg/d), vitamin E (600 IU every other day), and beta carotene (50 mg every other day) on the combined outcome of myocardial infarction, stroke, coronary revascularization, or CVD death among 8171 female health professionals at increased risk in a 2 x 2 x 2 factorial design. Participants were 40 years or older with a history of CVD or 3 or more CVD risk factors and were followed up for a mean duration of 9.4 years, from 1995-1996 to 2005. RESULTS: A total of 1450 women experienced 1 or more CVD outcomes. There was no overall effect of ascorbic acid (relative risk [RR], 1.02; 95% CI, 0.92-1.13 [P = .71]), vitamin E (RR, 0.94; 95% CI, 0.85-1.04 [P = .23]), or beta carotene (RR, 1.02; 95% CI, 0.92 1.13 [P = .71]) on the primary combined end point or on the individual secondary outcomes of myocardial infarction, stroke, coronary revascularization, or CVD death. A marginally significant reduction in the primary outcome with active vitamin E was observed among the prespecified subgroup of women with prior CVD (RR, 0.89; 95% CI, 0.79-1.00 [P = .04]; P value for interaction, .07). There were no significant interactions between agents for the primary end point, but those randomized to both active ascorbic acid and vitamin E experienced fewer strokes (P value for interaction, .03). CONCLUSION: There were no overall effects of ascorbic acid, vitamin E, or beta carotene on cardiovascular events among women at high risk for CVD. PMID- 17698684 TI - Association of troponin status with guideline-based management of acute myocardial infarction in older persons. AB - BACKGROUND: Over the past decade, a large body of evidence has emerged demonstrating the prognostic significance of troponin as well as its use in tailoring therapeutic interventions. Little is known, however, regarding the association of troponin status with guideline-based therapies in older patients with acute myocardial infarction (AMI). METHODS: A nationwide sample of eligible Medicare beneficiaries 65 years or older, who were hospitalized with a primary discharge diagnosis of AMI from April 1998 to March 1999 or from July 2000 to June 2001, was evaluated. The analysis was restricted to patients with clinically confirmed AMI who underwent testing for both creatine kinase-myocardial band (CK MB) and troponin. Results were assessed in 3 groups of patients based on biomarker status: those whose findings were positive for troponin only (hereinafter, troponin-only patients), those whose findings were positive for CK MB only (hereinafter, CK-MB-only patients), and those whose findings were positive for both troponin and CK-MB (hereinafter, troponin/CK-MB patients). Then, the use of guideline-recommended care was compared for patients without contraindications to treatment across the 3 groups. RESULTS: The final study sample included 33 096 patients (mean age, 77.6 years [range, 65-105 years]). The crude in-hospital mortality rate was highest for troponin-only patients (14%) and lowest for CK-MB-only patients (10%, P<.001). After adjusting for demographics, physician specialty, and hospital characteristics, CK-MB-only patients were more likely to receive aspirin (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.28-1.65) and beta-blocker (OR, 1.21; 95% CI, 1.08-1.34) within 24 hours of hospital arrival and aspirin on discharge (OR, 1.27; 95% CI, 1.08-1.49) compared with troponin-only patients. In addition, troponin/CK-MB patients were more likely to receive aspirin (OR, 1.55; 95% CI, 1.42-1.69) and beta-blocker (OR, 1.22; 95% CI, 1.12-1.31) within 24 hours of arrival and on discharge compared with troponin-only patients (ORs, 1.31 [95% CI, 1.17-1.46] and 1.33 [95% CI, 1.15 1.52] for aspirin and beta-blocker, respectively) . CONCLUSIONS: Despite the known poor prognosis associated with troponin elevations in AMI, we demonstrate that guideline-based therapies are underused in older patients with AMI. Therefore, national efforts should focus on the unique characteristics of this high-risk patient population to improve the quality of care for older patients with AMI. PMID- 17698685 TI - Characteristics associated with delirium in older patients in a medical intensive care unit. AB - BACKGROUND: Delirium is a highly prevalent disorder among older patients in the intensive care unit. METHODS: We performed a prospective cohort study of 304 patients 60 years or older admitted from September 5, 2002, through September 30, 2004, to a 14-bed ICU in an urban university teaching hospital. The main outcome measure was ICU delirium that developed within 48 hours of ICU admission. Patients were assessed for delirium with the Confusion Assessment Method for the ICU and medical record review. Risk factors for delirium were assessed on ICU admission by interview with proxies and medical record review. A model was developed using multivariate logistic regression and internally validated with bootstrapping methods. RESULTS: Delirium occurred in 214 study participants (70.4%) within the first 48 hours of ICU admission. In a multivariate regression model, 4 admission risk factors for delirium were identified. These risk factors included dementia (odds ratio [OR], 6.3; 95% confidence interval [CI], 2.9-13.8), receipt of benzodiazepines before ICU admission (OR, 3.4; 95% CI, 1.6-7.0), elevated creatinine level (OR, 2.1; 95% CI, 1.1-4.0), and low arterial pH (OR, 2.1; 95% CI, 1.1-3.9). The C statistic was 0.78. CONCLUSIONS: Delirium is frequent among older ICU patients. Admission characteristics can be important markers for delirium in these patients. Knowledge of these admission risk factors can prompt early correction of metabolic abnormalities and may subsequently reduce delirium duration. PMID- 17698686 TI - Defining the population-based burden of nosocomial pneumococcal bacteremia. AB - BACKGROUND: The characteristics, risk factors, and outcome of patients with nosocomial pneumococcal bacteremia (NPB) have not been described in large, population-based studies. METHODS: All episodes of invasive pneumococcal infections reported by Finnish clinical microbiology laboratories (positive blood or cerebrospinal fluid culture) from January 1, 1995, through December 31, 2002, were linked to data in national health care registries and vital statistics to obtain information on the patient's preceding hospitalizations, comorbidities, and outcome of illness. Pneumococcal bacteremia was defined as nosocomial if the first positive blood culture was obtained more than 2 days after hospital admission, or if the patient had been hospitalized for more than 2 days within 7 days of the first positive blood culture. RESULTS: Information on hospital admission was available for 4217 of 4357 persons (96.8%) with invasive pneumococcal infections. We identified 387 NPBs (9.7%) among 3973 pneumococcal bacteremias. Patients with NPB were older (median age, 67 years vs 52 years; P < .001) and were more likely to have at least 1 high-risk condition (other than age > or = 65 years), for which 23-valent pneumococcal polysaccharide vaccine is recommended (59.2% vs 34.6%; P < .001), compared with patients who had community associated pneumococcal bacteremias. The case fatality proportion at 28 days was higher in patients with NPB than in those with community-associated pneumococcal bacteremias (23.8% vs 10.8%; P < .001). Pneumococcal serotypes included in 23 valent polysaccharide vaccine and 7-valent conjugate vaccine caused 71.5% and 46.1% of NPBs, respectively. CONCLUSIONS: A substantial proportion of pneumococcal bacteremias are health care associated. The high prevalence of conditions for which pneumococcal polysaccharide vaccine is recommended provides opportunities for strengthening prevention efforts in these patients at high risk of illness and death. PMID- 17698687 TI - Single-site vs multisite bone density measurement for fracture prediction. AB - BACKGROUND: Bone density measurement with dual-energy x-ray absorptiometry is widely used for fracture risk assessment. Discordance between measurement sites is common, but it is unclear how this affects fracture prediction. METHODS: We performed a historical cohort study among 16 505 women 50 years or older at the time of baseline dual-energy x-ray absorptiometry of the spine and hip (mean +/- SD observation period, 3.2 +/- 1.5 years). The study population was drawn from a database that contains all clinical dual-energy x-ray absorptiometry test results for the province of Manitoba, Canada. Each subject's longitudinal health service record was assessed for the presence of fracture codes after bone density testing. The likelihood ratio test was used to assess the improvement in fracture prediction from Cox proportional hazards models using bone density covariates from a single site or from combined sites. RESULTS: Age-adjusted hazard ratios (HRs) per standard deviation for osteoporotic fracture ranged from 1.61 (95% confidence interval [CI], 1.39-1.87) for the lumbar spine to 1.85 (95% CI, 1.70 2.01) for the total hip, with intermediate values for the femur neck (HR, 1.76 [95% CI, 1.62-1.92]) and trochanter (HR, 1.77 [95% CI, 1.63-1.92]). For fracture prediction, use of the minimum bone density measurement was no better than use of a hip measurement alone. When the total hip measurement was included in a fracture prediction model for the overall population, none of the other measurements added substantial information. The spine was the most useful site for the prediction of spine fractures alone. CONCLUSIONS: Proximal femur bone density measurements consistently outperformed lumbar spine measurements for global fracture prediction. In this cohort, the total hip was the best site for overall fracture assessment. PMID- 17698688 TI - Sex differences in the relationship between amiodarone use and the need for permanent pacing in patients with atrial fibrillation. AB - BACKGROUND: Amiodarone use was associated with an increased need for pacemaker insertion in a retrospective study of patients with atrial fibrillation (AF) and prior myocardial infarction. The aims of this study were to determine prospectively whether amiodarone increases the need for pacemakers in a general population of patients with AF and whether this effect is modified by sex. METHODS: The study included 1005 patients with new-onset AF who were enrolled in the Fibrillation Registry Assessing Costs, Therapies, Adverse events, and Lifestyle (FRACTAL). Multivariable Cox regression models, including time dependent covariates accounting for medication exposure, were used to evaluate the risk of pacemaker insertion associated with amiodarone use. RESULTS: Amiodarone use was associated with an increased risk of pacemaker insertion (hazard ratio [HR], 2.01; 95% confidence interval [CI], 1.08-3.76) after adjustment for age, sex, atrial flutter, coronary artery disease, heart failure, and hypertension. The effect of amiodarone use was modified by sex, with a significant risk in women but not in men (HR, 4.69; 95% CI, 1.99-11.05 vs HR, 1.05; 95% CI, 0.42-2.58 [P = .02]). This interaction remained significant after adjustment for weight, body mass index, weight-adjusted amiodarone dose, and use of other antiarrhythmic or rate control drugs. CONCLUSION: The risk of bradyarrhythmia requiring pacemaker insertion associated with amiodarone use for AF is significantly greater in women than in men, independent of weight or body mass index. PMID- 17698689 TI - Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. AB - BACKGROUND: Severe sepsis is common and frequently fatal, and community-acquired pneumonia (CAP) is the leading cause. Although severe sepsis is often attributed to uncontrolled and unbalanced inflammation, evidence from humans with infection syndromes across the breadth of disease is lacking. In this study we describe the systemic cytokine response to pneumonia and determine if specific patterns, including the balance of proinflammatory and anti-inflammatory markers, are associated with severe sepsis and death. METHODS: This is a cohort study of 1886 subjects hospitalized with CAP through the emergency departments in 28 US academic and community hospitals. We defined severe sepsis as CAP complicated by new-onset organ dysfunction, following international consensus conference criteria. We measured plasma tumor necrosis factor, IL-6 (interleukin 6), and IL 10 levels daily for the first week and weekly thereafter. Our main outcome measures were severe sepsis and 90-day mortality. RESULTS: A total of 583 patients developed severe sepsis (31%), of whom 149 died (26%). Systemic cytokine level elevation occurred in 82% of all subjects with CAP. Mean cytokine concentrations were highest at presentation, declined rapidly over the first few days, but remained elevated throughout the first week, beyond resolution of clinical signs of infection. Cytokine levels were highest in fatal severe sepsis and lowest in CAP with no severe sepsis. Unbalanced (high/low) cytokine patterns were unusual (4.6%) and not associated with decreased survival. Highest risk of death was with combined high levels of the proinflammatory IL-6 and anti inflammatory IL-10 cytokine activity (hazard ratio, 20.5; 95% confidence interval, 10.8-39.0) (P<.001). CONCLUSIONS: The circulating cytokine response to pneumonia is heterogeneous and continues for more than a week after presentation, with considerable overlap between those who do and do not develop severe sepsis. Unbalanced activation is uncommon, and mortality is highest when both proinflammatory and anti-inflammatory cytokine levels are high. PMID- 17698690 TI - The impact of standardized order sets and intensive clinical case management on outcomes in community-acquired pneumonia. AB - BACKGROUND: Community-acquired pneumonia is a frequent cause for hospital admission that results in significant costs to the health care system. The length of hospital stay (LOS) affects costs as well as risk for nosocomial medical complications. The purpose of this study was to test whether the addition of intensive clinical case management to clinical guidelines could lead to a reduction in LOS that was not achievable by guidelines alone, while maintaining quality of care. METHODS: Patients were studied in 3 sequential blocks at a single hospital from November 2002 to February 2005. Block 1 patients (n = 110) were given conventional treatment. For block 2 (n = 119), guidelines and/or standardized order sets (SOSs) were used supported by intensive clinical case management (ICCM) (full variance tracking with concurrent feedback and reminders). The ICCM interventions were conducted by resident physicians. For block 3 (n = 115), all orders were written with guidelines and/or SOSs but without ICCM. RESULTS: The mean +/- SD time to clinical stability was not significantly different between the groups (block 1, 3.3 +/- 1.4 days; block 2, 3.2 +/- 1.2 days; and block 3, 3.4 +/- 1.3 days). The mean LOS was significantly lower in block 2 (5.3 +/- 3.5 days) than in blocks 1 (8.8 +/- 4.4 days) (P<.001) and 3 (7.3 +/- 3.9 days) (P<.01) and significantly lower in block 3 than in block 1 (P = .05). Time to change to oral antibiotics was earlier in block 2 (3.7 +/- 0.9 days) than in blocks 1 and 3 (5.7 +/- 2.4 and 5.0 +/- 1.9 days, respectively) (P<.001). The mean time from clinical stability to hospital discharge was significantly shorter for block 2 (2.1 +/- 2.2 days) than for blocks 1 (5.3 +/- 4.4 days) (P<.001) and 3 (4.9 +/- 4.2 days) (P<.001). Patients in block 2 had a greater proportion with progressive ambulation (P<.001), pneumococcal (P<.001) or influenza vaccination (P<.01), deep-venous thrombosis prophylaxis (P = .01), and smoking cessation counseling (P = .01). There was no significant difference between the blocks in mortality or hospital readmission rate. CONCLUSIONS: The combined intervention of SOS plus ICCM led to a substantial reduction in LOS while maintaining quality of care. The main effect occurred by reducing the time from clinical stability to discharge, which appeared to be the key "modifiable" process of care adding to a prolonged LOS. PMID- 17698691 TI - Obesity, waist circumference, weight change, and the risk of psoriasis in women: Nurses' Health Study II. AB - BACKGROUND: Psoriasis is a common, chronic, inflammatory skin disorder. Higher adiposity may increase the risk of psoriasis, but, to our knowledge, no prospective data are available on this relationship. METHODS: We prospectively examined the relationships between body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), weight change, waist circumference, hip circumference, waist-hip ratio, and incident psoriasis in 78 626 women over a 14-year period (1991-2005) in the Nurses' Health Study II. The primary outcome was incident, self-reported, physician-diagnosed psoriasis. RESULTS: During the 14 years of follow-up, there were 892 self-reported incident cases of psoriasis. There was a graded positive association between BMI measured at multiple time points and the risk of incident psoriasis. When we analyzed BMI updated every 2 years, compared with a BMI of 21.0 through 22.9, the multivariate relative risks of psoriasis were 1.40 (95% confidence interval [CI], 1.13-1.73) for a BMI of 25.0 through 29.9; 1.48 (95% CI, 1.15-1.91) for a BMI of 30.0 through 34.9; and 2.69 (95% CI, 2.12-3.40) for a BMI of 35.0 or greater (P for trend, < .001). For BMI at the age of 18 years, the multivariate relative risk for the top BMI category (> or = 30.0) was 1.73 (95% CI, 1.24-2.41) and that for a lower BMI category (< 21.0) was 0.76 (95% CI, 0.65-0.90) (P for trend, < .001). Weight gain from the age of 18 years, higher waist circumference, hip circumference, and waist-hip ratio were all associated with a higher risk of incident psoriasis (all P values for trend, < .001). CONCLUSION: This large prospective study indicates that increased adiposity and weight gain are strong risk factors for incident psoriasis in women. PMID- 17698692 TI - A prospective study of inflammatory cytokines and diabetes mellitus in a multiethnic cohort of postmenopausal women. AB - BACKGROUND: Inflammatory cytokines, including tumor necrosis factor alpha, IL-6 (interleukin 6), and high-sensitivity C-reactive protein (hsCRP), have been related to both insulin resistance and type 2 diabetes mellitus. However, prospective studies that comprehensively assess their roles in the development of type 2 diabetes are few, especially in minority populations. METHODS: Among 82,069 postmenopausal women aged 50 to 79 years without cardiovascular disease or diabetes mellitus who participated in the Women's Health Initiative Observational Study, we prospectively examined the relationships of plasma levels of tumor necrosis factor alpha receptor 2, IL-6, and hsCRP to diabetes risk. During a median follow-up period of 5.9 years, 1584 women who had clinical diabetes were matched by age, ethnicity, clinical center, time of blood draw, and duration of follow-up to 2198 study participants who were free of the disease. RESULTS: After adjustment for matching factors and known diabetes risk factors, all 3 markers were significantly associated with increased diabetes risk; the estimated relative risks comparing the highest with the lowest quartiles were 1.47 (95% confidence interval [CI], 1.10-1.97) for tumor necrosis factor alpha receptor 2, 3.08 (95% CI, 2.25-4.23) for IL-6, and 3.46 (95% CI, 2.50-4.80) for hsCRP (P for trend, <.01 for all biomarkers). When mutually adjusted, IL-6 and hsCRP remained significant in each ethnic group. While no statistically significant interactions were observed between ethnicity and these biomarkers on diabetes risk, there were consistent trends for the associations of hsCRP and IL-6 with increased diabetes risk in all ethnic groups. CONCLUSION: These prospective data showed that elevated levels of IL-6 and hsCRP were consistently and significantly associated with an increased risk of clinical diabetes in postmenopausal women. PMID- 17698693 TI - Midterm prognosis of patients with suspected coronary artery disease and normal multislice computed tomographic findings: a prospective management outcome study. AB - BACKGROUND: The gold standard test for the diagnosis of coronary artery disease (CAD) is conventional coronary angiography (C-CAG). Lately, multislice computed tomographic coronary angiography (MSCT-CAG) demonstrated a high sensitivity and a negative predictive value for a CAD primary diagnosis when compared with C-CAG. The aim of our study is to prospectively assess the safety of ruling out CAD based solely on a normal MSCT-CAG result. METHODS: From June 15, 2004, to January 20, 2006, consecutive patients initially scheduled for C-CAG for a primary diagnosis of CAD underwent MSCT-CAG instead. Patients with a highly calcified coronary network or with an abnormal or a noninterpretable MSCT-CAG result underwent secondary C-CAG and were excluded from the study. We included patients whose diagnosis of CAD was ruled out by a normal MSCT-CAG result; in those patients, C-CAG was not performed. All patients underwent further follow-up with clinical end points (death, subsequent C-CAG, and myocardial infarction). RESULTS: In 141 patients, MSCT-CAG results were considered normal. During the follow-up period (mean, 14.7 months), those patients experienced 0% mortality, a 3.5% rate of subsequent C-CAG, and a 0.7% rate of myocardial infarction. The risks of subsequent death, new referral for C-CAG, or coronary events compare favorably with those following normal C-CAG, which were 0.4%, 4.3%, and 0.6%, respectively. CONCLUSIONS: Multislice computed tomographic CAG safely rules out CAD in patients with suspected disease and allows patients to be managed less invasively, by reducing the number in whom C-CAG has to be performed. PMID- 17698694 TI - The number needed to be exposed: a potential use for quantifying the strength of an individual risk factor including a protective factor in a cohort study. PMID- 17698695 TI - Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial. AB - OBJECTIVE: To assess safety and immune modulation by BHT-3009, a tolerizing DNA vaccine encoding full-length human myelin basic protein, in patients with multiple sclerosis (MS). DESIGN: The study was a randomized, double-blind, placebo-controlled trial. Subjects receiving placebo were crossed over into an active arm after treatment unblinding. SETTING: The trial was conducted at 4 academic institutions within North America. Patients Thirty patients with relapsing-remitting or secondary progressive MS who were not taking any other disease-modifying drugs were enrolled in the trial. Further, the patients were required to have either 1 to 5 gadolinium-enhancing lesions on screening brain magnetic resonance imaging (MRI), a relapse in the previous 2 years, or disease worsening in the previous 2 years. INTERVENTIONS: BHT-3009 was administered as intramuscular injections at weeks 1, 3, 5, and 9 after randomization into the trial, with or without 80 mg of daily oral atorvastatin calcium in combination. Three dose levels of BHT-3009 were tested (0.5 mg, 1.5 mg, and 3 mg). MAIN OUTCOME MEASURES: The primary outcome measures were safety and tolerability of BHT-3009. Secondary outcome measures included the number and volume of gadolinium enhanced lesions on MRI, relapses, and analysis of antigen-specific immune responses. RESULTS: BHT-3009 was safe and well tolerated, provided favorable trends on brain MRI, and produced beneficial antigen-specific immune changes. These immune changes consisted of a marked decrease in proliferation of interferon-gamma-producing, myelin-reactive CD4+ T cells from peripheral blood and a reduction in titers of myelin-specific autoantibodies from cerebral spinal fluid as assessed by protein microarrays. We did not observe a substantial benefit of the atorvastatin combination compared with BHT-3009 alone. CONCLUSION: In patients with MS, BHT-3009 is safe and induces antigen-specific immune tolerance with concordant reduction of inflammatory lesions on brain MRI. PMID- 17698696 TI - Transient ischemic attack with abnormal diffusion-weighted imaging results: what's in a name? PMID- 17698697 TI - Treatment options in the modern management of Parkinson disease. PMID- 17698698 TI - Medication-related impulse control and repetitive behaviors in Parkinson disease. AB - A range of behaviors presumed to be related to aberrant or excessive dopaminergic medications are being increasingly recognized in Parkinson disease. These behaviors are linked by their incentive- or reward-based and repetitive natures and include pathological gambling, hypersexuality, compulsive shopping, compulsive eating, hobbyism, and compulsive medication use. Such behaviors can have potentially devastating psychosocial consequences and are often hidden. Whether these behaviors are simply related to dopaminergic medications interacting with an underlying individual vulnerability or whether the primary pathological features of Parkinson disease play a role is not known. We reviewed the literature on these behaviors in Parkinson disease, including definitions, epidemiological and potential pathophysiological features, and management. The study of these behaviors allows not only improved clinical management but also greater insight into a biologically mediated complex behavioral model. PMID- 17698699 TI - Using functional magnetic resonance imaging to detect covert awareness in the vegetative state. AB - The assessment of patients with disorders of consciousness, including the vegetative state, is difficult and depends frequently on subjective interpretations of the observed spontaneous and volitional behavior. For those patients who retain peripheral motor function, rigorous behavioral assessment supported by structural imaging and electrophysiological findings is usually sufficient to establish a patient's level of wakefulness and awareness. However, it is becoming increasingly apparent that in some patients damage to the peripheral motor system may prevent overt responses to command although the cognitive ability to perceive and understand such commands may remain intact. Recent advances in functional neuroimaging suggest a novel solution to this problem; in several cases, so-called activation studies have been used to identify residual cognitive function and conscious awareness in patients who are assumed to be in a vegetative state yet retain cognitive abilities that have evaded detection using standard clinical methods. PMID- 17698700 TI - Impact of abnormal diffusion-weighted imaging results on short-term outcome following transient ischemic attack. AB - OBJECTIVE: To characterize short-term prognoses among patients with transient ischemic attack (TIA) and normal diffusion-weighted imaging (DWI) results, TIA patients with abnormal DWI results (transient symptoms associated with infarction [TSI]), and patients with completed ischemic stroke (IS). DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: We reviewed patient medical records between January 2003 and December 2004 with International Classification of Diseases, Ninth Revision codes for TIA at admission, resolution of neurological symptoms within 24 hours, magnetic resonance imaging within 48 hours, and a discharge diagnosis of TIA or IS. A random sample of 50 IS patients was selected from all IS admissions and discharges by International Classification of Diseases, Ninth Revision codes. Demographic, clinical, radiographic, and in-hospital outcome data were recorded. Three diagnostic categories were created: TIA with normal DWI results, TSI, and IS. Multivariate logistic regression was used to estimate the association between diagnostic category and rate of in-hospital stroke or recurrent TIA among the 3 groups. RESULTS: We identified 146 classic TIA (25% with TSI) and 50 IS cases. There were 4 recurrent TIAs and 6 strokes among patients with TSI (27.0%); 3 recurrent TIAs and no strokes among patients with normal DWI results (2.8%); and 1 recurrent stroke and no TIAs among IS patients (2.0%). Transient symptoms associated with infarction was independently associated with in-hospital recurrent TIA or stroke (adjusted odds ratio, 11.2; P < .01). CONCLUSIONS: Transient symptoms associated with infarction is associated with a greater rate of early recurrent TIA and stroke than both IS and TIA with normal DWI results. These data suggest that TSI may be a separate clinical entity with unique prognostic implications. PMID- 17698701 TI - Central nervous system manifestations of cardiac myxoma. AB - BACKGROUND: Neurologic complications can be the initial manifestation of atrial myxoma. Prompt diagnosis is of paramount significance to prevent recurrent complications. OBJECTIVE: To identify patients with neurologic complications attributed to atrial myxoma. DESIGN, SETTING, AND PATIENTS: With institutional review board approval, we retrospectively reviewed the medical records of 74 consecutive patients with pathologically confirmed cardiac myxoma at the Mayo Clinic from January 1, 1993, through December 31, 2004. MAIN OUTCOME MEASURES: Discharge and follow-up modified Rankin score. RESULTS: Nine of the 74 patients with cardiac myxoma (12%) presented with neurologic manifestations in the setting of atrial myxoma. Mean age was 48.5 years (range, 17-70 years). There were 6 females and 3 males. Among patients with myxoma and neurologic symptoms, ischemic cerebral infarct was the most common neurologic manifestation (8 patients [89%]). No patients had concomitant cardiac symptoms. The size of the atrial myxoma was variable, with a mean diameter of 2.7 (range, 0.4-6.5) cm. Most of the atrial myxomas causing neurologic symptoms demonstrated a mobile component on transesophageal echocardiography (8 patients [89%]). Two patients (22%) had pathologic evidence of systemic myxomatous emboli. One patient with intracerebral hemorrhage had pathologically confirmed intracranial metastatic myxoma and myxoma induced aneurysmal dilatation. CONCLUSIONS: Neurologic complications are associated with cardiac myxoma in some patients with myxoma and, when they occur, frequently present with cerebral infarction. The mobility, not the size, of the myxoma appears to be related to embolic potential. Potential delayed neurologic complications relevant to patients with tumor embolization include myxoma-induced cerebral aneurysm and myxomatous metastasis, which can mimic the clinical picture of central nervous system vasculitis or infective endocarditis. PMID- 17698702 TI - Classification of myasthenia gravis based on autoantibody status. AB - OBJECTIVES: To investigate the autoantibody status of patients with myasthenia gravis (MG) and to evaluate its usefulness for disease classification. DESIGN: Retrospective cohort study of patients with MG, who have autoantibodies to receptors and ion channels expressed at neuromuscular junctions and in muscles that impair neuromuscular transmission. One of the autoantibodies studied was a recently identified, novel, MG-specific autoantibody to a voltage-gated potassium (Kv) channel, Kv1.4. SETTING: Keio University Hospital, Tokyo, and Iwate Medical University Hospital, Morioka. PATIENTS: Two hundred nine patients with MG. MAIN OUTCOME MEASURES: Anti-Kv1.4 antibody was measured by an immunoprecipitation assay with sulfur 35-labeled extract from rhabdomyosarcoma cells. Antititin antibody was detected with a commercially available enzyme-linked immunosorbent assay. RESULTS: Anti-acetylcholine receptor, anti-Kv1.4, and antititin antibodies were detected in 150 (72%), 26 (12%), and 50 (24%) of the 209 patients with MG, respectively. All of the patients who were positive for anti-Kv1.4 or antititin antibody were seropositive for the anti-acetylcholine receptor antibody. They were classified into 4 groups based on their status in regard to 3 MG-related autoantibodies: anti-Kv1.4, antititin, and anti-acetylcholine receptor. Clinical associations were found between anti-Kv1.4 and bulbar involvement, myasthenic crisis, thymoma, and concomitant myocarditis and/or myositis; between antititin and older-onset MG; between anti-acetylcholine receptor alone and younger-onset MG; and between seronegativity and ocular MG. In addition, patients with MG in the anti-Kv1.4 group had more severe manifestations of disease than those in the other 3 groups. CONCLUSION: Classification of patients with MG based on autoantibody status may be useful in defining clinical subsets. PMID- 17698703 TI - Patterns of atrophy differ among specific subtypes of mild cognitive impairment. AB - BACKGROUND: In most patients, mild cognitive impairment (MCI) represents the clinically evident prodromal phase of dementia. This is most well established in amnestic MCI, which is most commonly a precursor to Alzheimer disease (AD). It follows, however, that subjects with MCI who have impairment in nonmemory domains may progress to non-AD degenerative dementias. OBJECTIVE: To investigate patterns of cerebral atrophy associated with specific subtypes of MCI. DESIGN: Case control study. SETTING: Community-based sample at a tertiary referral center. PATIENTS: One hundred forty-five subjects with MCI and 145 age- and sex-matched cognitively normal control subjects. Mild cognitive impairment was classified as amnestic, single cognitive domain; amnestic, multiple domain; nonamnestic, single domain; and nonamnestic, multiple domain. Subjects with nonamnestic single-domain MCI were classified into language, attention/executive, and visuospatial subgroups on the basis of specific cognitive impairment. MAIN OUTCOME MEASURE: Patterns of gray matter loss in the MCI groups compared with control subjects, assessed using voxel-based morphometry. RESULTS: Subjects in the amnestic single- and multiple-domain groups showed loss in the medial and inferior temporal lobes compared with control subjects, and those in the multiple-domain group also had involvement of the posterior temporal lobe, parietal association cortex, and posterior cingulate. Subjects in the nonamnestic single-domain group with language impairment showed loss in the left anterior inferior temporal lobe. The group with attention/executive deficits showed loss in the basal forebrain and hypothalamus. No coherent patterns of loss were observed in the other subgroups. CONCLUSIONS: The pattern of atrophy in the amnestic MCI groups is consistent with the concept that MCI in most of these subjects represents prodromal AD. However, the varying patterns in the language and attention/executive subgroups suggest that these subjects may have a different underlying disorder. PMID- 17698704 TI - Evaluating atypical dementia syndromes using positron emission tomography with carbon 11 labeled Pittsburgh Compound B. AB - CONTEXT: A progressive decline in episodic memory affecting activities of daily living is the usual clinical presentation of Alzheimer disease. However, patients presenting with atypical or focal clinical symptoms such as language or visuospatial dysfunction often pose a diagnostic challenge. OBJECTIVE: To explore the presence and topography of beta amyloid (Abeta) as measured by carbon 11 labeled Pittsburgh Compound B ((11)C-PiB) in patients with atypical presentations of dementia. DESIGN, SETTING, AND PARTICIPANTS: At a tertiary referral center for memory disorders, 15 healthy controls, 10 patients with Alzheimer disease, a patient with primary progressive aphasia (PPA), and a patient with posterior cortical atrophy (PCA) underwent (11)C-PiB positron emission tomographic studies. Retention of (11)C-PiB was compared between different groups using statistical parametric mapping. MAIN OUTCOME MEASURE: The topography of cortical (11)C-PiB binding in atypical vs typical Alzheimer disease. RESULTS: Cortical (11)C-PiB binding was higher in the group with Alzheimer disease and in the patients with PPA and PCA than the controls (P < .001). Both patients with atypical dementia had a similar (11)C-PiB binding pattern to Alzheimer disease although (11)C-PiB retention was higher on the left cerebral hemisphere in the patient with PPA (P < .01) and higher in the occipital cortex in the patient with PCA (P < .01). CONCLUSIONS: The presence of distinctive focal (11)C-PiB retention patterns was demonstrated in 2 patients with atypical onset of dementia. Pittsburgh Compound B has the potential to facilitate differential diagnosis of dementia and identify patients who could benefit from specific therapeutic strategies aimed at beta amyloid reduction. PMID- 17698705 TI - Clinical, genetic, and pathologic characteristics of patients with frontotemporal dementia and progranulin mutations. AB - BACKGROUND: Patients with frontotemporal dementia due to mutation of progranulin may have a distinct phenotype. OBJECTIVE: To identify distinct clinical and pathologic features of patients with frontotemporal dementia who have mutations of progranulin (GRN). DESIGN: Retrospective clinical-pathologic study. SETTING: Academic medical center. PATIENTS: Twenty-eight patients with frontotemporal dementia, including 9 with GRN mutations (4 autopsy cases and 5 with only clinical information) and 19 with the identical pathologic diagnosis- frontotemporal lobar degeneration with ubiquitin-positive and tau-negative inclusions (FTLD-U)--and no GRN mutations. MAIN OUTCOME MEASURES: Demographic, symptom, neuropsychological, and autopsy characteristics. RESULTS: Patients with and without a GRN mutation have similar demographic features, although family history is significantly more common in patients with frontotemporal dementia and a GRN mutation. Both patient groups have frequent social and personality complaints. Neuropsychological evaluation reveals a significant recognition memory deficit in patients with a GRN mutation but a significant language deficit only in patients without a GRN mutation. At autopsy, the semiquantitative burden of ubiquitin abnormality is relatively modest in both groups of patients. CONCLUSION: Patients with a GRN mutation differ clinically from those with the same pathologic diagnosis but no GRN mutation. PMID- 17698706 TI - Association of neocortical volume changes with cognitive deterioration in relapsing-remitting multiple sclerosis. AB - BACKGROUND: We previously reported selective decreases of neocortical volumes in patients with early relapsing-remitting (RR) multiple sclerosis (MS) with mild cognitive impairment, with a good correlation between cortical volumes and cognitive measures. OBJECTIVE: To assess the relevance of gray matter changes over time to changes in cognition in RRMS. DESIGN: A longitudinal survey after 2.5 years. Each patient underwent a magnetic resonance imaging (MRI) protocol identical to that performed at baseline; cognitive performance was reassessed with the Rao Brief Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis. SETTING: Two university MS clinics. PATIENTS: Of 41 patients with RRMS who participated in the original cross-sectional study, 28 were available for the follow-up evaluation (18 women; mean +/- SD age, 37.1 +/- 8.9 years; mean +/- SD MS duration, 7.3 +/- 2.9 years; mean +/- SD Expanded Disability Status Scale score, 1.8 +/- 1.5). MAIN OUTCOME MEASURES: We measured the percentage of brain volume changes, normalized cortical volume (NCV) changes, and normalized deep gray matter volume changes on conventional T1-weighted MRIs and changes in lesion load on T2-weighted MRIs. The number of tests failed on the Rao Brief Repeatable Battery were used to classify the patients as cognitively deteriorating or stable or improving. RESULTS: We identified 12 of 28 cognitively deteriorating and 16 of 28 stable or improving patients. These subgroups did not differ in the mean +/- SD percentage of brain volume changes (-2.1% +/- 1.2% vs -1.3% +/- 1.3%; P = .11), normalized deep gray matter volume changes (-2.1 +/- 2.8 mL vs -0.6 +/- 3.1 mL; P = .60), and changes in lesion load on T2-weighted MRIs (1.9 +/- 2.6 mL vs 1.6 +/- 2.3 mL; P = .73). However, NCV changes were significantly higher in deteriorating than in stable or improving patients (-43.0 +/- 18.9 mL vs -17.8 +/ 26.6 mL; P = .007). In deteriorating patients, NCV changes were correlated with performance in a verbal fluency test (r = 0.73; P < .001). In a regression model, only NCV changes were significantly associated with deteriorating cognitive performance (odds ratio, 0.8; 95% confidence interval, 0.7-0.9). CONCLUSION: Progressive neocortical gray matter loss is relevant to MS-associated cognitive impairment and may represent a sensitive marker of deteriorating cognitive performance in RRMS. PMID- 17698707 TI - Determinants of disability in multiple sclerosis at various disease stages: a multiparametric magnetic resonance study. AB - OBJECTIVE: To investigate whether diffusion-tensor magnetic resonance imaging and whole brain N-acetylaspartate (WBNAA) proton magnetic resonance spectroscopy can provide complementary pieces of information to achieve a better understanding of the factors associated with disability in multiple sclerosis (MS). DESIGN: Cross sectional survey. SETTING: Referral hospital-based MS center. PATIENTS: Ten healthy control subjects, 27 patients with a clinically isolated neurological syndrome, 21 patients with relapsing-remitting MS, and 29 patients with secondary progressive MS. MAIN OUTCOME MEASURES: Conventional and diffusion-tensor magnetic resonance imaging, as well as WBNAA proton magnetic resonance spectroscopy, of the brain was performed. T2-hyperintense lesion volumes were measured. The mean values of mean diffusivity (MD) and fractional anisotropy of T2-visible lesions were computed. Histograms of MD and fractional anisotropy values were produced for normal-appearing white matter and gray matter (GM). RESULTS: Patients with a clinically isolated neurological syndrome had a significantly (P=.002) lower WBNAA concentration than control subjects. Patients with relapsing-remitting MS had significantly higher T2 lesion volume (P=.007), mean lesion MD (P=.003), normal-appearing white matter fractional anisotropy peak height (P=.03), and a lower WBNAA concentration (P<.001) than patients with a clinically isolated neurological syndrome. Patients with secondary progressive MS had significantly higher T2 lesion volume (P=.01), lower mean normal-appearing white matter fractional anisotropy (P=.003), higher mean GM MD (P=.004), and lower GM MD peak height (P=.01) than patients with relapsing-remitting MS. Disease duration, GM MD peak height, and WBNAA concentration entered a multivariate model, explaining nearly 70% of the disability variance. CONCLUSIONS: The accumulation of macroscopic lesions and normal-appearing white matter damage seems to occur mainly during the earliest clinical phases of MS, whereas pathological features of GM may be a hallmark of the late progressive stage of the disease. This supports the notion of MS as a "2-stage" disease. PMID- 17698708 TI - White matter volume as a major predictor of cognitive function in Sturge-Weber syndrome. AB - OBJECTIVE: To assess the role of gray and white matter volume loss vs seizures in cognitive impairment of children with Sturge-Weber syndrome with unilateral involvement. DESIGN: Patients were enrolled in this prospective cohort during a period of 3 years. SETTING: Pediatric neurology clinic with national referral through the Sturge-Weber Foundation. PARTICIPANTS: Twenty-one children (age range, 1 year 6 months to 10 years 4 months) with unilateral Sturge-Weber syndrome. MAIN OUTCOME MEASURES: Cortical gray matter and hemispheric white matter volumes were measured on segmented volumetric magnetic resonance imaging and correlated with the age of the participants. Global intellectual function (IQ) was correlated with magnetic resonance imaging and seizure variables in both univariate and multivariate analyses. RESULTS: Both gray and white matter volumes showed an age-related linear increase. Tissue volumes on the side of the angioma showed a positive correlation with IQ after controlling for age in univariate regression analyses (white matter, r = 0.71, P < .001; gray matter, r = 0.48, P = .03), while seizure variables did not correlate with IQ (P > .1). A multivariate regression showed that hemispheric white matter volume ipsilateral to the angioma was an independent predictor of IQ (R = 61, P = .006), which also showed a negative correlation with age (R = - 0.52, P = .022) but no correlation with gray matter volumes. CONCLUSIONS: Early hemispheric white matter loss may play a major role in cognitive impairment in children with Sturge-Weber syndrome. Future therapeutic approaches should aim at preserving white matter integrity in addition to seizure control to improve cognitive outcome. PMID- 17698709 TI - Phenotypic study in 40 patients with dysferlin gene mutations: high frequency of atypical phenotypes. AB - OBJECTIVE: To describe the phenotypic spectrum of dysferlin (DYSF) gene mutations (which cause dysferlinopathies, autosomal recessive muscular dystrophies) in patients with a dysferlin protein deficiency. DESIGN: Clinical, biological, and pathological data from 40 patients were reviewed. The diagnosis of dysferlinopathy was based on the absence or strong reduction of dysferlin in muscle, and confirmed by mutational screening of the DYSF gene. SETTING: Two French neuromuscular diseases centers (in Paris and Marseilles). RESULTS: Two main dysferlinopathy phenotypes are well recognized: Miyoshi myopathy and limb girdle muscular dystrophy type 2B. Typical Miyoshi myopathy and limb-girdle muscular dystrophy type 2B were found in 20 (50%) patients only. Unusual phenotypes included a mixed phenotype, referred to as "proximodistal," combining distal and proximal onset in 14 (35%) patients, pseudometabolic myopathy in 4 (10%), and asymptomatic hyperCKemia (an increased serum creatine kinase level) in 2 (5%). The disease may worsen rapidly, and 10 (25%) patients were initially misdiagnosed as having polymyositis. We suggest a relationship between proximodistal phenotype, inflammation, and severity. CONCLUSION: In addition to typical Miyoshi myopathy and limb-girdle muscular dystrophy type 2B, dysferlinopathies are a clinically heterogeneous group of disorders ranging from asymptomatism to severe functional disability. PMID- 17698710 TI - A pianist's recovery from stroke. AB - OBJECTIVE: To determine alternative neural pathways for restitution of piano playing after right hemispheric infarction causing left arm and hand paralysis. DESIGN: Case report testing coordinated bimanual skills using structured motor skills tests and neuroimaging. SETTING: A professional pianist sustained a lacunar infarction in the posterior limb of his right internal capsule, which resulted in left hemiparesis with immobilized left-hand and -finger movements persisting for 13 weeks. After 6 months, he had recovered bimanual coordinated piano skills by "ignoring" his left hand while concentrating or discussing subjects other than music while playing. PATIENT: A 63-year-old, male professional pianist. INTERVENTION: Detailed neurological examination including computed cranial tomography, functional magnetic resonance imaging, and positron emission tomography. RESULTS: Functional magnetic resonance imaging activation patterns correlated with rapid movements of fingers in each hand separately and together demonstrating that subcortical and cerebellar pathways were activated during skilled motor function of his left hand. Contralateral cerebral and cerebellar activation occurred with both left- and right-hand movements. During tapping of the left fingers, there was bilateral cerebellar, parietal, and left premotor strip and left thalamic activation. CONCLUSION: Patterns of activation relate to task performance and they are not similar to subjects engaged in simpler tasks such as finger opposition. PMID- 17698711 TI - Neuromyelitis optica in a mother and daughter. AB - BACKGROUND: Neuromyelitis optica (NMO) is a rare demyelinating disease of the central nervous system that most often results in selective involvement of the optic nerves and spinal cord. Although most cases are sporadic, several familial cases have been reported. All of those patients have been siblings who experienced disease onset at similar ages. To our knowledge, there has not been a documented case between a mother-daughter pair, nor has there been a reported case in which family members developed the disease at different stages of life. OBJECTIVES: To illustrate the clinical courses of NMO in a white mother-daughter pair, which supports a hereditary predisposition to this disorder, as well as to reinforce that onset of disease can occur at different ends of the age spectrum even within the same family. Design, Setting, and Patients Case report of a mother-daughter pair with NMO treated at the University of Michigan Medical Center. RESULTS: After multiple occurrences of optic neuritis and transverse myelitis as well as extensive workups, both mother and daughter were eventually diagnosed with NMO but with different ages at onset, at ages 62 and 29 years, respectively. CONCLUSIONS: Development of NMO is in part genetically influenced. Our familial cases show that NMO may differ clinically within a family. While current diagnostic criteria include an extensive spinal cord lesion, the second case (mother) illustrates that milder cases of NMO might not fulfill that requirement, in which case NMO-IgG antibody seropositivity may confirm the diagnosis. PMID- 17698712 TI - Dissociation of neuropathologic findings and cognition: case report of an apolipoprotein E epsilon2/epsilon2 genotype. AB - BACKGROUND: The apolipoprotein E (APOE) epsilon2 allele has been suggested as having a protective effect and delaying the age at onset of Alzheimer disease. OBJECTIVE: To describe a dissociation between neuropathologic findings with normal cognition in a woman with severe Alzheimer disease with the APOE epsilon2/epsilon2 genotype. DESIGN: Case report from a community-based prospective study of persons 90 years or older (The 90+ Study). PARTICIPANT: A 92 year-old woman without dementia with the APOE epsilon2/epsilon2 genotype who lived independently without significant cognitive or functional loss and was a participant in The 90+ Study. She died in December 2004, and postmortem examination of her brain was performed. INTERVENTION: Neurologic examination and a battery of neuropsychological tests were performed 6 months and 1 month before death. Neuropathologic examination included Braak and Braak staging for senile plaques and neurofibrillary tangles. RESULTS: Neuropathologic examination of the brain revealed advanced senile plaque and neurofibrillary tangle disease consistent with a high likelihood of Alzheimer disease. At clinical evaluation, the participant demonstrated no dementia and only mild cognitive deficits. CONCLUSIONS: The APOE genotype may have contributed to maintenance of cognition despite advanced neuropathologic findings of Alzheimer disease. This case suggests that the APOE epsilon2 isoform may have a protective effect against cognitive decline in Alzheimer disease that may be independent from senile plaques and neurofibrillary tangles. PMID- 17698713 TI - Massive sellar and parasellar schwannoma. PMID- 17698714 TI - Magnetic resonance imaging of biceps femoris muscles in benign acute childhood myositis. PMID- 17698715 TI - Scale for distinguishing sleep disorders from seizures. PMID- 17698716 TI - Babinski, pseudo-Babinski, and dystonia. PMID- 17698717 TI - Progression to dementia in probable and possible mild cognitive impairment. PMID- 17698718 TI - Vascular remodeling, retinal arteries, and hypertension. PMID- 17698719 TI - Effect of ovariectomy on renal estrogen receptor-alpha and estrogen receptor-beta in young salt-sensitive and -resistant rats. AB - This study evaluated the effect of ovariectomy on renal estrogen receptor (ER) alpha and ERbeta expression in young female Dahl salt-sensitive and salt resistant rats. Our hypothesis was that estrogen depletion results in an imbalance in ERalpha and ERbeta expression in salt-sensitive rats. Rats were subjected to sham surgery (intact), ovariectomy, and ovariectomy with estrogen replacement. Kidneys were harvested 8 weeks later. Western blot was used to measure ERalpha and ERbeta expression in the cortex and medulla. In intact rats, ERalpha was 2.7- and 4.3-fold higher in salt-sensitive compared with salt resistant rats in the renal cortex and medulla, respectively. In salt-sensitive rats, ovariectomy caused 42% and 52% decreases in ERalpha and 107% and 314% increases in ERbeta in renal cortex and medulla, respectively. In salt-resistant rats, ovariectomy caused 33% and 150% increases in ERalpha and 107% and 100% increases in ERbeta in renal cortex and medulla, respectively. Estrogen replacement did not alter ERalpha but restored ERbeta expression levels similar to levels in intact rats in both salt-sensitive and salt-resistant rats. Thus, estrogen loss had opposite effects on ERalpha in salt-sensitive (downregulation) and salt-resistant rats (upregulation). We propose that the decrease in ERalpha expression in salt-sensitive rats after estrogen loss alters the balance of renal ERs and may play a role in accelerating the development of hypertension and renal damage. PMID- 17698720 TI - The continuing saga of neuronal oxidative stress in hypertension: Nox, Nox who's there, and where? PMID- 17698721 TI - Aortic distensibility and retinal arteriolar narrowing: the multi-ethnic study of atherosclerosis. AB - Increased aortic stiffness and retinal arteriolar narrowing are subclinical vascular effects of chronic hypertension and predict future cardiovascular events. The relationship between these 2 vascular measures is uncertain and is examined in the Multi-Ethnic Study of Atherosclerosis. This cross-sectional analysis involves 3425 participants (aged 45 to 85 years) free of clinical cardiovascular disease. Retinal vascular caliber was quantified from digital retinal photographs using standardized protocols. Aortic distensibility was determined from chest MRI. After controlling for age, squared age, gender, race, study center, height, weight, heart rate, cigarette smoking, past and current systolic blood pressure, use of antihypertensive medications, diabetes, fasting glucose, lipid profile, and C-reactive protein, reduced aortic distensibility (first versus fourth distensibility quartile) was associated with increased odds of retinal arteriolar narrowing (odds ratio: 1.72; 95% CI: 1.15 to 2.58, comparing lowest to highest quartile of arteriolar caliber). Further adjustments for atherosclerotic measures (carotid intima-media thickness, coronary calcium score, and ankle brachial index) had minimal impact on this association (odds ratio: 1.70; 95% CI: 1.13 to 2.55). Reduced aortic distensibility was not associated with retinal venular caliber. We conclude that increased aortic stiffness is associated with retinal arteriolar narrowing, independent of measured blood pressure levels and vascular risk factors. These data suggest that changes in the microvasculature may play a role linking aortic stiffness with clinical cardiovascular events. PMID- 17698722 TI - Increased wall:lumen ratio of retinal arterioles in male patients with a history of a cerebrovascular event. AB - Arterial hypertension is a major risk factor for stroke, and retinal vessels can be regarded as a mirror of the cerebral vasculature. Whether vascular remodeling of retinal arterioles with ageing and hypertension plays a role in cerebrovascular risk stratification has not yet been adequately addressed. In study 1, retinal arteriolar structure was assessed in 182 normotensive volunteers and 117 patients with essential hypertension. In study 2, we compared retinal arteriolar structure among 74 normotensive volunteers, 47 patients with treated essential hypertension, and 18 subjects with a history of a cerebrovascular event. Retinal arteriolar structure was assessed using scanning laser Doppler flowmetry and automatic full-field perfusion imaging analysis. In study 1, wall:lumen ratio of retinal arterioles revealed a significant correlation with age (r=0.198; P=0.001). In study 2, wall:lumen ratio was highest in patients with a history of a cerebrovascular event compared with treated hypertensive and normotensive subjects (0.46+/-0.08, 0.36+/-0.14, and 0.35+/-0.12; P=0.007). When the treated group with hypertension was divided into 2 subgroups according to the quality of blood pressure control, patients with poor blood pressure control showed higher wall:lumen ratio than subjects with good blood pressure control (0.40+/-0.13 versus 0.31+/-0.13; P=0.025). Thus, assessment of wall:lumen ratio of retinal arterioles emerged as an attractive tool to identify treated patients with hypertension with increased cerebrovascular risk. PMID- 17698723 TI - Differential regulation of NADPH oxidase in sympathetic and sensory Ganglia in deoxycorticosterone acetate salt hypertension. AB - We demonstrated recently that superoxide anion levels are elevated in prevertebral sympathetic ganglia of deoxycorticosterone acetate-salt hypertensive rats and that this superoxide anion is generated by reduced nicotinamide-adenine dinucleotide phosphate oxidase. In this study we compared the reduced nicotinamide-adenine dinucleotide phosphate oxidase enzyme system of dorsal root ganglion (DRG) and sympathetic celiac ganglion (CG) and its regulation in hypertension. The reduced nicotinamide-adenine dinucleotide phosphate oxidase activity of ganglion extracts was measured using fluorescence spectrometry of dihydroethidine; the activity in hypertensive dorsal root ganglion was 34% lower than in normotensive DRG. In contrast, activity was 79% higher in hypertensive CG than normotensive CG. mRNA for the oxidase subunits NOX1, NOX2, NOX4, p47(phox), and p22(phox) were present in both CG and DRG; mRNA for NOX4 was significantly higher in CG than in DRG. The levels of mRNA and protein expression of the membrane-bound catalytic subunit p22(phox) and of the regulatory subunits p47(phox) and Rac-1 were measured in CG and DRG in normotensive and hypertensive rats. p22(phox) mRNA and protein expression was greater in CG of hypertensive rats but not in DRG. Compared with normotensive controls, p47(phox) mRNA and protein, as well as Rac-1 protein, were significantly decreased in hypertensive DRG but not in CG. Immunohistochemical staining of p47(phox) showed translocation from cytoplasm to membrane in hypertensive CG but not in hypertensive DRG. This suggests that reduced nicotinamide-adenine dinucleotide phosphate oxidase activation in sympathetic neurons and sensory neurons is regulated in opposite directions in hypertension. This differential regulation may contribute to unbalanced vasomotor control and enhanced vasoconstriction in the splanchnic circulation. PMID- 17698724 TI - Effects of PREMIER lifestyle modifications on participants with and without the metabolic syndrome. AB - Lifestyle modification can reduce blood pressure and lower cardiovascular risk. Established recommendations include weight loss, sodium reduction, and increased physical activity. PREMIER studied the effects of lifestyle interventions based on established recommendations alone and with the addition of the Dietary Approaches to Stop Hypertension (DASH) dietary pattern. This analysis aimed to assess the interventions' impact on cardiometabolic variables in participants with, compared with those without, metabolic syndrome. The primary outcome was 6 month change in systolic blood pressure. Participants with prehypertension or stage-1 hypertension were randomly assigned to an advice only control group, a 6 month intensive behavioral intervention group of established recommendations (EST), or an established recommendations plus DASH group (EST+DASH). Metabolic syndrome was defined per National Cholesterol and Education Program Adult Treatment Panel III. We used general linear models to test intervention effects on change in blood pressure, lipids, and insulin resistance (homeostasis model assessment), in subgroups defined by the presence or absence of metabolic syndrome. Of 796 participants, 399 had metabolic syndrome. Both EST and EST+DASH reduced the primary outcome variable, systolic blood pressure. Within the EST+DASH group, those with and without metabolic syndrome responded similarly (P=0.231). However, within EST, those with metabolic syndrome had a poorer response, with a decrease in systolic blood pressure of 8.4 mm Hg versus 12.0 mm Hg in those without metabolic syndrome (P=0.002). Thus, metabolic syndrome attenuated the systolic blood pressure reduction of EST, but this attenuation was overcome in EST+DASH. Finally, diastolic blood pressure, lipids, and homeostasis model assessment responded similarly to both interventions regardless of metabolic syndrome status. Our data suggest that strategies for lowering BP in individuals with metabolic syndrome may be enhanced by recommendations to adopt the DASH dietary pattern. PMID- 17698725 TI - Selective genotyping reveals association between the epithelial sodium channel gamma-subunit and systolic blood pressure. AB - Systolic blood pressure is determined in large part by genes. Six independent studies have reported evidence of linkage between systolic pressure and chromosome 16p12 that incorporates SCNN1G, the gene encoding the gamma-subunit of the epithelial sodium channel. We undertook the first comprehensive association analysis of SCNN1G and systolic pressure. To achieve genetic contrast, we sampled unrelated subjects within the upper (mean: 166 mm Hg; n=96) and lower (mean: 98 mm Hg; n=94) 10% of the systolic pressure distribution of 2911 subjects from the Victorian Family Heart Study. We examined genotypes and haplotypes related to 26 single nucleotide polymorphisms across SCNN1G and its promoter. Each of 3 single nucleotide polymorphisms (rs13331086, rs11074553, and rs4299163) in introns 5 and 6 showed evidence of association with systolic pressure in logistic regression analyses adjusted for age, sex, and body mass index. Considered as a haplotype block, these single nucleotide polymorphisms were significantly associated with systolic pressure (haplo.score global: P=0.0001). In permutation analyses to account for multiple testing, a result such as this was observed only once in 10,000 permutations. The estimated frequency of 1 haplotype (TGC) was substantially greater in high (13.3%) than low (0.6%) systolic pressure subjects (P=0.0001). Three other haplotypes (TGG, TAC, and GGC) showed associations with high or low systolic pressure consistent with the observed associations of their composite alleles. These findings identify relatively common polymorphisms in the SCNN1G gene that are associated with high systolic blood pressure in the general Australian white population. PMID- 17698726 TI - Multimarker approach to evaluate the incidence of the metabolic syndrome and longitudinal changes in metabolic risk factors: the Framingham Offspring Study. AB - BACKGROUND: The metabolic syndrome (MetS) is associated with increased cardiovascular risk. We evaluated the relative contributions of circulating biomarkers representing distinct biological pathways to the incidence of MetS and to longitudinal changes of its constituent risk factors. METHODS AND RESULTS: We measured 8 circulating biomarkers reflecting inflammation (C-reactive protein), hemostasis (plasminogen activator inhibitor-1, fibrinogen), neurohormonal activity (aldosterone, renin, B-type natriuretic peptide, N-terminal proatrial natriuretic peptide), and endothelial dysfunction (homocysteine) in 2292 Framingham Offspring Study participants (mean age, 57 years; 56% women). We related the biomarker panel to incidence of MetS on follow-up initially and then related biomarkers associated with incident MetS to longitudinal change in its components. On follow-up (mean, 2.9 years), 282 participants (of 1473 participants without prevalent MetS at baseline) developed MetS. After adjustment for clinical risk factors, the biomarker panel was associated with incident MetS (P=0.008). On backward elimination, plasminogen activator inhibitor-1 and aldosterone remained associated with incident MetS (multivariable-adjusted odds ratio per 1-SD increment log marker, 1.31 [P=0.004] and 1.21 [P=0.015], respectively). In multivariable analyses evaluating longitudinal change in MetS components (analyzed as continuous variables), plasminogen activator inhibitor-1 was significantly and positively associated with changes in fasting glucose, systolic blood pressure, and triglycerides (all P<0.05). Serum aldosterone was associated positively with change in systolic blood pressure (P=0.023) and inversely with change in high-density lipoprotein cholesterol (P=0.001). CONCLUSIONS: Higher circulating plasminogen activator inhibitor-1 and aldosterone levels are associated with the development of MetS and with longitudinal change of its components, suggesting that these biomarkers and related pathways play a key role in mediating metabolic risk. PMID- 17698727 TI - Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients. AB - BACKGROUND: Mexiletine (Mex) has been proposed as a gene-specific therapy for patients with long-QT syndrome type 3 (LQT3) caused by mutations in the cardiac sodium channel gene (SCN5A). The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations. We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations. METHODS AND RESULTS: We identified 4 SCN5A mutations in 5 symptomatic LQT3 patients with different responses to Mex (6 to 8 mg . kg(-1) . d(-1)). We classified the mutations as sensitive to Mex (P1332L, R1626P; >/=10% of QTc shortening and QTc <500 ms or no arrhythmias) or insensitive to Mex (S941N, M1652R; negligible or no QTc shortening and sudden death). We measured Na(+) current from HEK 293 cells transfected with wild-type (WT) or mutant Nav1.5. All mutations showed impaired inactivation of Na(+) current, but the mutations identified in patient responders to Mex (P1332L, R1626P) showed a hyperpolarizing shift of V(1/2) of steady-state inactivation. Furthermore, Mex produced use-dependent block with the order R1626P=P1332L>S941N=WT>M1652R, suggesting that Mex-sensitive mutants present prolonged recovery from Mex block. CONCLUSIONS: We propose that voltage dependence of channel availability and shifts of V(1/2) of steady-state inactivation correlate with the clinical response observed in LQT3 patients. This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3. PMID- 17698728 TI - Independent impact of gout on mortality and risk for coronary heart disease. AB - BACKGROUND: Although gout and hyperuricemia are related to several conditions that are associated with reduced survival, no prospective data are available on the independent impact of gout on mortality. Furthermore, although many studies have suggested that hyperuricemia is associated with cardiovascular disease (CVD), limited data are available on the impact of gout on CVD. METHODS AND RESULTS: Over a 12-year period, we prospectively examined the relation between a history of gout and the risk of death and myocardial infarction in 51,297 male participants of the Health Professionals Follow-Up Study. During the 12 years of follow-up, we documented 5825 deaths from all causes, which included 2132 deaths from CVD and 1576 deaths from coronary heart disease (CHD). Compared with men without history of gout and CHD at baseline, the multivariate relative risks among men with history of gout were 1.28 (95% confidence interval [CI], 1.15 to 1.41) for total mortality, 1.38 (95% CI, 1.15 to 1.66) for CVD deaths, and 1.55 (95% CI, 1.24 to 1.93) for fatal CHD. The corresponding relative risks among men with preexisting CHD were 1.25 (95% CI, 1.09 to 1.45), 1.26 (95% CI, 1.07 to 1.50), and 1.24 (95% CI, 1.04 to 1.49), respectively. In addition, men with gout had a higher risk of nonfatal myocardial infarction than men without gout (multivariate relative risk, 1.59; 95% CI, 1.04 to 2.41). CONCLUSIONS: These prospective data indicate that men with gout have a higher risk of death from all causes. Among men without preexisting CHD, the increased mortality risk is primarily a result of an elevated risk of CVD death, particularly from CHD. PMID- 17698729 TI - Impact of repeated dietary counseling between infancy and 14 years of age on dietary intakes and serum lipids and lipoproteins: the STRIP study. AB - BACKGROUND: Atherosclerosis development might be delayed or prevented by dietary measures. The aims of the present study were to evaluate the effect of low saturated-fat, low-cholesterol dietary counseling on fat intakes, growth, serum cholesterol values, and pubertal development in children and adolescents. METHODS AND RESULTS: In the randomized prospective Special Turku Coronary Risk Factor Intervention Project (STRIP), a low-saturated-fat, low-cholesterol diet was introduced to intervention infants (n=540) at 7 months of age, and control children (n=522) received an unrestricted diet. Dietary intakes, serum cholesterol values, somatic growth, and development were followed up throughout childhood and adolescence. Saturated fat intakes, serum total cholesterol, and low-density lipoprotein cholesterol values were lower (P<0.001) in the intervention than in control children during the 14 years, whereas high-density lipoprotein cholesterol values in the 2 study groups showed no difference. Boys had lower total and low-density lipoprotein cholesterol concentrations than girls throughout childhood (P<0.001), and the intervention effect on serum cholesterol concentration was larger in boys than girls. The 2 study groups showed no difference in growth, body mass index, pubertal development, or age at menarche (median, 13.0 and 12.8 years in the intervention and control girls, respectively; P=0.52). The cholesterol values decreased as puberty progressed. Mean concentrations of total and high-density lipoprotein cholesterol decreased from approximately 4.5 and approximately 1.4 mmol/L, respectively, in Tanner stage 1 (prepubertal) boys to approximately 3.9 and approximately 1.1 mmol/L in Tanner stage 4 (late pubertal) boys. CONCLUSIONS: Repeated dietary counseling remains effective in decreasing saturated fat and cholesterol intake and serum cholesterol values at least until 14 years of age. Puberty markedly influences serum cholesterol concentrations. PMID- 17698730 TI - Activation patterns of Purkinje fibers during long-duration ventricular fibrillation in an isolated canine heart model. AB - BACKGROUND: The roles of Purkinje fibers (PFs) and focal wave fronts, if any, in the maintenance of ventricular fibrillation (VF) are unknown. If PFs are involved in VF maintenance, it should be possible to map wave fronts propagating from PFs into the working ventricular myocardium during VF. If wave fronts ever arise focally during VF, it should be possible to map them appearing de novo. METHODS AND RESULTS: Six canine hearts were isolated, and the left main coronary artery was cannulated and perfused. The left ventricular cavity was exposed, which allowed direct endocardial mapping of the anterior papillary muscle insertion. Nonperfused VF was induced, and 6 segments of data, each 5 seconds long, were analyzed during 10 minutes of VF. During 36 segments of data that were analyzed, 1018 PF or focal wave fronts of activation were identified. In 534 wave fronts, activation was mapped propagating from working ventricular myocardium to PF. In 142 wave fronts, activation was mapped propagating from PF to working ventricular myocardium. In 342 wave fronts, activation was mapped arising focally. More than 1 of these 3 patterns could occur in the same wave front. CONCLUSIONS: PFs are highly active throughout the first 10 minutes of VF. In addition to retrograde propagation from the working ventricular myocardium to PFs, antegrade propagation occurs from PFs to working ventricular myocardium, which suggests PFs are important in VF maintenance. Prior plunge needle recordings in dogs indicate activation propagates from the endocardium toward the epicardium after 1 minute of VF, which suggests that focal sites on the endocardium may represent foci and not breakthrough. If so, in addition to reentry, abnormal automaticity or triggered activity may also occur during VF. PMID- 17698731 TI - Epinephrine is required for normal cardiovascular responses to stress in the phenylethanolamine N-methyltransferase knockout mouse. AB - BACKGROUND: Epinephrine (EPI) is an important neurotransmitter and hormone. Its role in regulating cardiovascular function at rest and with stress is unclear, however. METHODS AND RESULTS: An epinephrine-deficient mouse model was generated in which the epinephrine-synthesizing enzyme phenylethanolamine N methyltransferase was knocked out (KO). Blood pressure and heart rate were monitored by telemetry at rest and during graded treadmill exercise. Cardiac structure and function were evaluated by echocardiography in mice under 1 of 2 conditions: unstressed and lightly anesthetized or restrained and awake. In KO mice, resting cardiovascular function, including blood pressure, heart rate, and cardiac output, was the same as that in wild-type mice, and the basal norepinephrine plasma level was normal. However, inhibition of sympathetic innervation with the ganglion blocker hexamethonium caused a 54% smaller decrease in blood pressure in KO mice, and treadmill exercise caused an 11% higher increase in blood pressure, both suggesting impaired vasodilation in KO mice. Interestingly, phenylethanolamine N-methyltransferase KO did not change the heart rate response to ganglionic blockade and exercise. By echocardiography, KO mice had an increased ratio of left ventricular posterior wall thickness to internal dimensions but did not have cardiac hypertrophy, suggesting concentric remodeling in the KO heart. Finally, in restrained, awake KO mice, heart rate and ejection fraction remained normal, but cardiac output was significantly reduced because of diminished end-diastolic volume. CONCLUSION: Our data suggest that epinephrine is required for normal blood pressure and cardiac filling responses to stress but is not required for tachycardia during stress or normal cardiovascular function at rest. PMID- 17698732 TI - Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis: discovery of common human genetic variants governing transcription, autonomic activity, and blood pressure in vivo. AB - BACKGROUND: Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. Does common genetic variation at human TH alter autonomic activity and predispose to cardiovascular disease? We undertook systematic polymorphism discovery at the TH locus and then tested variants for contributions to sympathetic function and blood pressure. METHODS AND RESULTS: We resequenced 80 ethnically diverse individuals across the TH locus. One hundred seventy-two twin pairs were evaluated for sympathetic traits, including catecholamine production, reflex control of the circulation, and environmental (cold) stress responses. To evaluate hypertension, we genotyped subjects selected from the most extreme diastolic blood pressure percentiles in the population. Human TH promoter haplotype/reporter plasmids were transfected into chromaffin cells. Forty-nine single-nucleotide polymorphisms were discovered, but coding region polymorphism did not account for common phenotypic variation. A block of linkage disequilibrium spanned 4 common variants in the proximal promoter. Catecholamine secretory traits were significantly heritable (h2), as were stress induced blood pressure changes. In the TH promoter, significant associations were found for urinary catecholamine excretion and for blood pressure response to stress. TH promoter haplotype 2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. Coalescent simulations suggest that TH haplotype 2 likely arose approximately 380,000 years ago. In hypertension, 2 independent case-control studies (1266 subjects with 53% women and 927 subjects with 24% women) replicated the effect of C-824T in the determination of blood pressure. CONCLUSIONS: We conclude that human catecholamine secretory traits are heritable, displaying joint genetic determination (pleiotropy) with autonomic activity and finally with blood pressure in the population. Catecholamine secretion is influenced by genetic variation in the adrenergic pathway encoding catecholamine synthesis, especially at the classically rate-limiting step, TH. The results suggest novel pathophysiological links between a key adrenergic locus, catecholamine metabolism, and blood pressure and suggest new strategies to approach the mechanism, diagnosis, and treatment of systemic hypertension. PMID- 17698733 TI - Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure. AB - BACKGROUND: Circulating cardiac troponin T, a marker of cardiomyocyte injury, predicts adverse outcome in patients with heart failure (HF) but is detectable in only a small fraction of those with chronic stable HF. We assessed the prognostic value of circulating cardiac troponin T in patients with stable chronic HF with a traditional (cTnT) and a new precommercial highly sensitive assay (hsTnT). METHODS AND RESULTS: Plasma troponin T was measured in 4053 patients with chronic HF enrolled in the Valsartan Heart Failure Trial (Val-HeFT). Troponin T was detectable in 10.4% of the population with the cTnT assay (detection limit < or = 0.01 ng/mL) compared with 92.0% with the new hsTnT assay (< or = 0.001 ng/mL). Patients with cTnT elevation or with hsTnT above the median (0.012 ng/mL) had more severe HF and worse outcome. In Cox proportional hazards models adjusting for clinical risk factors, cTnT was associated with death (780 events; hazard ratio=2.08; 95% confidence interval, 1.72 to 2.52; P<0.0001) and first hospitalization for HF (655 events; hazard ratio=1.55; 95% confidence interval, 1.25 to 1.93; P<0.0001). HsTnT was associated with the risk of death in unadjusted analysis for deciles of concentrations and in multivariable models (hazard ratio=1.05; 95% confidence interval, 1.04 to 1.07 for increments of 0.01 ng/mL; P<0.0001). Addition of hsTnT to well-calibrated models adjusted for clinical risk factors, with or without brain natriuretic peptide, significantly improved prognostic discrimination (C-index, P<0.0001 for both outcomes). CONCLUSIONS: In this large population of patients with HF, detectable cTnT predicts adverse outcomes in chronic HF. By the highly sensitive assay, troponin T retains a prognostic value at previously undetectable concentrations. PMID- 17698734 TI - Bone marrow derived cells are involved in the pathogenesis of cardiac hypertrophy in response to pressure overload. AB - BACKGROUND: Bone marrow (BM) cells possess broad differentiation potential and can form various cell lineages in response to pathophysiological cues. The present study investigated whether BM-derived cells contribute to the pathogenesis of cardiac hypertrophy, as well as the possible cellular mechanisms involved in such a role. METHODS AND RESULTS: Lethally irradiated wild-type mice were transplanted with BM cells from enhanced green fluorescent protein transgenic mice. The chimeric mice were subjected to either prolonged hypoxia or transverse aortic constriction. BM-derived enhanced green fluorescent protein expressing cardiomyocytes increased in number over time, emerging predominantly in the pressure-overloaded ventricular myocardium, although they constituted <0.01% of recipient cardiomyocytes. To determine whether BM-derived cardiomyocytes were derived from cell fusion or transdifferentiation at the single-cell level, lethally irradiated Cre mice were transplanted with BM cells from the double-conditional Cre reporter mouse line Z/EG. BM-derived cardiomyocytes were shown to arise from both cell fusion and transdifferentiation. Interestingly, BM-derived myofibroblasts expressing both vimentin and alpha-smooth muscle actin were concentrated in the perivascular fibrotic area. These cells initially expressed MAC-1/CD14 but lost expression of these markers during the chronic phase, which suggests that they were derived from monocytes. A similar phenomenon occurred in cultured human monocytes, most of which ultimately expressed vimentin and alpha-smooth muscle actin. CONCLUSIONS: We found that BM-derived cells were involved in the pathogenesis of cardiac hypertrophy via the dual mechanisms of cell fusion and transdifferentiation. Moreover, the present results suggest that BM-derived monocytes accumulating in the perivascular space might play an important role in the formation of perivascular fibrosis via direct differentiation into myofibroblasts. PMID- 17698735 TI - Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. AB - BACKGROUND: The risk of heart failure in type 2 diabetes mellitus is greater than can be accounted for by hypertension and coronary artery disease. Rodent studies indicate that in obesity and type 2 diabetes mellitus, lipid overstorage in cardiac myocytes produces lipotoxic intermediates that cause apoptosis, which leads to heart failure. In humans with diabetes mellitus, cardiac steatosis previously has been demonstrated in explanted hearts of patients with end-stage nonischemic cardiomyopathy. Whether cardiac steatosis precedes the onset of cardiomyopathy in individuals with impaired glucose tolerance or in patients with type 2 diabetes mellitus is unknown. METHODS AND RESULTS: To represent the progressive stages in the natural history of type 2 diabetes mellitus, we stratified 134 individuals (age 45+/-12 years) into 1 of 4 groups: (1) lean normoglycemic (lean), (2) overweight and obese normoglycemic (obese), (3) impaired glucose tolerance, and (4) type 2 diabetes mellitus. Localized (1)H magnetic resonance spectroscopy and cardiac magnetic resonance imaging were used to quantify myocardial triglyceride content and left ventricular function, respectively. Compared with lean subjects, myocardial triglyceride content was 2.3-fold higher in those with impaired glucose tolerance and 2.1-fold higher in those with type 2 diabetes mellitus (P<0.05). Left ventricular ejection fraction was normal and comparable across all groups. CONCLUSIONS: In humans, impaired glucose tolerance is accompanied by cardiac steatosis, which precedes the onset of type 2 diabetes mellitus and left ventricular systolic dysfunction. Thus, lipid overstorage in human cardiac myocytes is an early manifestation in the pathogenesis of type 2 diabetes mellitus and is evident in the absence of heart failure. PMID- 17698736 TI - Central role of calcium-dependent tyrosine kinase PYK2 in endothelial nitric oxide synthase-mediated angiogenic response and vascular function. AB - BACKGROUND: The involvement of Ca2+-dependent tyrosine kinase PYK2 in the Akt/endothelial NO synthase pathway remains to be determined. METHODS AND RESULTS: Blood flow recovery and neovessel formation after hind-limb ischemia were impaired in PYK2-/- mice with reduced mobilization of endothelial progenitors. Vascular endothelial growth factor (VEGF)-mediated cytoplasmic Ca2+ mobilization and Ca2+-independent Akt activation were markedly decreased in the PYK2-deficient aortic endothelial cells, whereas the Ca2+-independent AMP activated protein kinase/protein kinase-A pathway that phosphorylates endothelial NO synthase was not impaired. Acetylcholine-mediated aortic vasorelaxation and cGMP production were significantly decreased. Vascular endothelial growth factor dependent migration, tube formation, and actin cytoskeletal reorganization associated with Rac1 activation were inhibited in PYK2-deficient endothelial cells. PI3-kinase is associated with vascular endothelial growth factor-induced PYK2/Src complex, and inhibition of Src blocked Akt activation. The vascular endothelial growth factor-mediated Src association with PLCgamma1 and phosphorylation of 783Tyr-PLCgamma1 also were abolished by PYK2 deficiency. CONCLUSION: These findings demonstrate that PYK2 is closely involved in receptor- or ischemia-activated signaling events via Src/PLCgamma1 and Src/PI3-kinase/Akt pathways, leading to endothelial NO synthase phosphorylation, and thus modulates endothelial NO synthase-mediated vasoactive function and angiogenic response. PMID- 17698737 TI - Spotlight: Dennis Michael Krikler, MD, FESC. PMID- 17698738 TI - Images in cardiovascular medicine. Asymptomatic huge popliteal pseudoaneurysm with 2 internal solid thrombi. PMID- 17698739 TI - Images in cardiovascular medicine. Large free-floating intra-aortic thrombus. PMID- 17698740 TI - Letter regarding article by Gammie et al, "influence of hospital procedural volume on care process and mortality for patients undergoing elective surgery for mitral regurgitation". PMID- 17698741 TI - Short QT: when does it matter? PMID- 17698742 TI - Patients' persistence of evidence-based treatment of chronic heart failure: a treatment paradox. PMID- 17698743 TI - Drug-eluting stents: dual antiplatelet therapy for every survivor? PMID- 17698744 TI - Genes and atrial fibrillation: a new look at an old problem. PMID- 17698745 TI - Sepsis and the heart. AB - Sepsis is generally viewed as a disease aggravated by an inappropriate immune response encountered in the afflicted individual. As an important organ system frequently compromised by sepsis and always affected by septic shock, the cardiovascular system and its dysfunction during sepsis have been studied in clinical and basic research for more than 5 decades. Although a number of mediators and pathways have been shown to be associated with myocardial depression in sepsis, the precise cause remains unclear to date. There is currently no evidence supporting global ischemia as an underlying cause of myocardial dysfunction in sepsis; however, in septic patients with coexistent and possibly undiagnosed coronary artery disease, regional myocardial ischemia or infarction secondary to coronary artery disease may certainly occur. A circulating myocardial depressant factor in septic shock has long been proposed, and potential candidates for a myocardial depressant factor include cytokines, prostanoids, and nitric oxide, among others. Endothelial activation and induction of the coagulatory system also contribute to the pathophysiology in sepsis. Prompt and adequate antibiotic therapy accompanied by surgical removal of the infectious focus, if indicated and feasible, is the mainstay and also the only strictly causal line of therapy. In the presence of severe sepsis and septic shock, supportive treatment in addition to causal therapy is mandatory. The purpose of this review is to delineate some characteristics of septic myocardial dysfunction, to assess the most commonly cited and reported underlying mechanisms of cardiac dysfunction in sepsis, and to briefly outline current therapeutic strategies and possible future approaches. PMID- 17698746 TI - Long-term intraocular pressure fluctuation and progressive visual field deterioration in patients with glaucoma and low intraocular pressures after a triple procedure. AB - OBJECTIVE: To evaluate the association of long-term intraocular pressure (IOP) fluctuation and visual field (VF) progression in patients with glaucoma and low IOP. METHODS: Four hundred eight eyes with IOPs below 18 mm Hg after a triple procedure (phacoemulsification, posterior chamber intraocular lens implantation, and trabeculectomy) were included in this study. Measurements of IOP and VF were taken for at least 3 years after surgery. Based on the SD in postoperative IOPs, the sample was split into 2 groups (group 1: SD2). Change in VF at each test location was defined as a change in threshold sensitivity of 1 dB per year or higher, with P 0.2 s), at 240 to 960 mg/day, with one requiring a permanent pacemaker. Four patients had junctional rhythm, and one had second-degree heart block. Four patients had right bundle branch block. There was bradycardia (HR < 60 bpm) in 39 patients (36%), but verapamil was stopped in only 4 patients. In eight patients the PR interval was lengthened, but not to >0.2 s. The incidence of arrhythmias on verapamil in this patient group is 19%, and bradycardia 36%. CONCLUSION: We therefore strongly recommend EKG monitoring in all patients with cluster headache on verapamil, to observe for the potential development of atrioventricular block and symptomatic bradycardia. PMID- 17698789 TI - Minimum incidence of primary cervical dystonia in a multiethnic health care population. AB - BACKGROUND: The two existing estimates of the incidence of primary cervical dystonia were based on observations in relatively ethnically homogeneous populations of European descent. OBJECTIVE: To estimate the minimum incidence of primary cervical dystonia in the multiethnic membership of a health maintenance organization in Northern California. METHODS: Using a combination of electronic medical records followed by medical chart reviews, we identified incident cases of cervical dystonia first diagnosed between 1997 and 1999. RESULTS: We identified 66 incident cases of cervical dystonia from 8.2 million person-years of observation. The minimum estimate of the incidence of cervical dystonia in this population is 0.80 per 100,000 person-years. Ethnicity-specific incidence rates were calculated for individuals over age 30. Incidence was higher in white individuals (1.23 per 100,000 person-years) than in persons of other races (0.15 per 100,000 person-years, p < 0.0001). The minimum estimated incidence was 2.5 times higher in women than in men (1.14 vs 0.45 per 100,000 person-years, p = 0.0005). The average age at diagnosis was higher in women (56 years) than in men (45 years, p = 0.0004). There was no significant difference in reported symptom duration prior to diagnosis between women and men (3.9 vs 5.3 years). CONCLUSION: The estimated incidence of diagnosed cervical dystonia among white individuals in this Northern Californian population is similar to previous estimates in more ethnically homogeneous populations of largely European descent. The incidence in other races, including Hispanic, Asian, and black appears to be significantly lower. The incidence is also higher in women than in men. PMID- 17698790 TI - Sixty hertz pallidal deep brain stimulation for primary torsion dystonia. AB - OBJECTIVE: To evaluate the safety and efficacy of 60 Hz deep brain stimulation (DBS) of the globus pallidus internus (GPi) in 15 consecutive patients with primary dystonia. METHODS: We conducted a retrospective analysis of clinic charts relative to 15 consecutive patients with medically refractory primary dystonia who underwent stereotactic implantation of DBS leads within the GPi. Twelve had the DYT1 gene mutation. Frame-based MRI and intraoperative microelectrode recording were employed for targeting. All patients were treated exclusively with stimulation at 60 Hz from therapy outset. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) served as the primary measure of symptom severity at baseline and 1, 3, 6, and 12 months after treatment. RESULTS: All patients tolerated DBS treatment well and showed a progressive median improvement of their BFMDRS motor subscores from 38% at 1 month to 89% at 1 year (p < 0.001, Wilcoxon rank sum test). The disability subscores were similarly improved. The clinical response to DBS allowed seven patients to completely discontinue their medications; six additional patients had reduced their medications by at least 50%. Surgical complications were limited to two superficial infections, which were treated successfully. CONCLUSIONS: Stimulation of the internal globus pallidus at 60 Hz is safe and effective for treating medically refractory primary dystonia. PMID- 17698791 TI - Isolated diaphragmatic tremor: is there a spectrum in "respiratory myoclonus"? AB - BACKGROUND: Respiratory myoclonus or diaphragmatic flutter is an unusual movement disorder with abnormal diaphragmatic activity, which may be associated with respiratory symptoms. The effects of distracting maneuvers on diaphragmatic activity have not been investigated. METHODS: Two patients with nondisabling abdominal movements of suspected diaphragmatic origin were studied with surface and needle electromyography (EMG). RESULTS: The abdominal movements resulted from isolated, rhythmic diaphragmatic contractions with variable EMG burst duration, suppressibility with breath-holding and distracting maneuvers, and other attributes of volitional control. CONCLUSION: "Respiratory myoclonus" may be a heterogeneous disorder ranging from synchronous movements of the diaphragm and other respiratory muscles associated with respiratory compromise, to diaphragmatic movements under at least some volitional control with no respiratory or functional disability. The latter group could be designated phenomenologically as "isolated diaphragmatic tremor." PMID- 17698792 TI - Diagnostic pitfalls in sporadic transthyretin familial amyloid polyneuropathy (TTR-FAP). AB - Transthyretin familial amyloid polyneuropathies (TTR-FAPs) are autosomal dominant neuropathies of fatal outcome within 10 years after inaugural symptoms. Late diagnosis in patients who present as nonfamilial cases delays adequate management and genetic counseling. Clinical data of the 90 patients who presented as nonfamilial cases of the 300 patients of our cohort of patients with TTR-FAP were reviewed. They were 21 women and 69 men with a mean age at onset of 61 (extremes: 38 to 78 years) and 17 different mutations of the TTR gene including Val30Met (38 cases), Ser77Tyr (16 cases), Ile107Val (15 cases), and Ser77Phe (5 cases). Initial manifestations included mainly limb paresthesias (49 patients) or pain (17 patients). Walking difficulty and weakness (five patients) and cardiac or gastrointestinal manifestations (five patients), were less common at onset. Mean interval to diagnosis was 4 years (range 1 to 10 years); 18 cases were mistaken for chronic inflammatory demyelinating polyneuropathy, which was the most common diagnostic error. At referral a length-dependent sensory loss affected the lower limbs in 2, all four limbs in 20, and four limbs and anterior trunk in 77 patients. All sensations were affected in 60 patients (67%), while small fiber dysfunction predominated in the others. Severe dysautonomia affected 80 patients (90%), with postural hypotension in 52, gastrointestinal dysfunction in 50, impotence in 58 of 69 men, and sphincter disturbance in 31. Twelve patients required a cardiac pacemaker. Nerve biopsy was diagnostic in 54 of 65 patients and salivary gland biopsy in 20 of 30. Decreased nerve conduction velocity, increased CSF protein, negative biopsy findings, and false immunolabeling of amyloid deposits were the main causes of diagnostic errors. We conclude that DNA testing, which is the most reliable test for TTR-FAP, should be performed in patients with a progressive length-dependent small fiber polyneuropathy of unknown origin, especially when associated with autonomic dysfunction. PMID- 17698793 TI - Treatment of human myasthenia gravis with oral antisense suppression of acetylcholinesterase. PMID- 17698794 TI - Precipitating factors of spontaneous spinal CSF leaks and intracranial hypotension. PMID- 17698795 TI - Adult-onset primary lateral sclerosis is not associated with mutations in the ALS2 gene. PMID- 17698796 TI - Progressive multifocal leukoencephalopathy after rituximab in a case of non Hodgkin lymphoma. PMID- 17698797 TI - Painful neuropathy due to intraneural leukemic spread in a patient with acute myeloid leukemia. PMID- 17698798 TI - Cerebral response to patient's own name in the vegetative and minimally conscious states. PMID- 17698799 TI - Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis. PMID- 17698800 TI - The progression of Parkinson disease: a hypothesis. PMID- 17698801 TI - Ethnic variation in the incidence of ALS: a systematic review. PMID- 17698802 TI - Ovarian cancer: is dose intensity dead? PMID- 17698803 TI - How do you distinguish a malignant pelvic mass from a benign pelvic mass? Imaging, biomarkers, or none of the above. PMID- 17698804 TI - Phase III trial of high-dose sequential chemotherapy with peripheral blood stem cell support compared with standard dose chemotherapy for first-line treatment of advanced ovarian cancer: intergroup trial of the AGO-Ovar/AIO and EBMT. AB - PURPOSE: Although ovarian cancer is one of the most chemotherapy-sensitive solid tumors, cure after radical surgery and chemotherapy is uncommon. A randomized trial comparing high-dose sequential chemotherapy with peripheral blood stem cell (PBSC) support with platinum-based combination chemotherapy was conducted to investigate whether dose-intensification improves outcome. PATIENTS AND METHODS: One hundred forty-nine patients with untreated ovarian cancer were randomly assigned after debulking surgery to receive standard combination chemotherapy or sequential high-dose (HD) treatment with two cycles of cyclophosphamide and paclitaxel followed by three cycles of HD carboplatin and paclitaxel with PBSC support. HD melphalan was added to the final cycle. The median age was 50 years (range, 20 to 65 years) and International Federation of Gynecology and Obstetrics stage was IIb/IIc in 4%, III in 78%, and IV in 17%. RESULTS: Seventy-six percent of patients received all five cycles in the HD arm and the main toxicities were neuro-/ototoxicity, gastrointestinal toxicity, and infection and one death from hemorrhagic shock. After a median follow-up of 38 months, the progression-free survival was 20.5 months in the standard arm and 29.6 months in the HD arm (hazard ratio [HR], 0.84; 95% CI, 0.56 to 1.26; P, .40). Median overall survival (OS) was 62.8 months in the standard arm and 54.4 months in the HD arm (HR, 1.17; 95% CI, 0.71 to 1.94; P, .54). CONCLUSION: This is the first randomized trial comparing sequential HD versus standard dose chemotherapy in first-line treatment of patients with advanced ovarian cancer. We observed no statistically significant difference in progression-free survival or OS and conclude that HD chemotherapy does not appear to be superior to conventional dose chemotherapy. PMID- 17698805 TI - Inclusion of CA-125 does not improve mathematical models developed to distinguish between benign and malignant adnexal tumors. AB - PURPOSE: To test the value of serum CA-125 measurements alone or as part of a multimodal strategy to distinguish between malignant and benign ovarian tumors before surgery based on a large prospective multicenter study (International Ovarian Tumor Analysis). PATIENTS AND METHODS: Patients with at least one persistent ovarian mass preoperatively underwent transvaginal ultrasonography using gray scale imaging to assess tumor morphology and color Doppler imaging to obtain indices of blood flow. RESULTS: Data from 809 patients recruited from nine centers were included in the analysis; 567 patients (70%) had benign tumors and 242 (30%) had malignant tumors-of these 152 were primary invasive (62.8%), 52 were borderline malignant (21.5%), and 38 were metastatic (15.7%). A logistic regression model including CA-125 (M2) resulted in an area under the receiver operating characteristic curve (AUC) of 0.934 and did not outperform a published (M1) without serum CA-125 information (AUC, 0.936). Specifically designed new models including CA-125 for premenopausal women (M3) and for postmenopausal women (M4) did not perform significantly better than the model without CA-125 (M1; AUC, 0.891 v AUC, 0.911 and AUC, 0.975 v AUC, 0.949, respectively). In postmenopausal patients, serum CA-125 alone (AUC, 0.920) and the risk of malignancy index (AUC, 0.924) performed very well. Results were very similar when the models were prospectively tested on a group of 345 new patients with adnexal masses of whom 126 had malignant tumors (37%). CONCLUSION: Adding information on CA-125 to clinical information and ultrasound information does not improve discrimination of mathematical models between benign and malignant adnexal masses. PMID- 17698806 TI - Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. AB - The structures of F(1)-ATPase from bovine heart mitochondria inhibited with the dietary phytopolyphenol, resveratrol, and with the related polyphenols quercetin and piceatannol have been determined at 2.3-, 2.4- and 2.7-A resolution, respectively. The inhibitors bind to a common site in the inside surface of an annulus made from loops in the three alpha- and three beta-subunits beneath the "crown" of beta-strands in their N-terminal domains. This region of F(1)-ATPase forms a bearing to allow the rotation of the tip of the gamma-subunit inside the annulus during catalysis. The binding site is a hydrophobic pocket between the C terminal tip of the gamma-subunit and the beta(TP) subunit, and the inhibitors are bound via H-bonds mostly to their hydroxyl moieties mediated by bound water molecules and by hydrophobic interactions. There are no equivalent sites between the gamma-subunit and either the beta(DP) or the beta(E) subunit. The inhibitors probably prevent both the synthetic and hydrolytic activities of the enzyme by blocking both senses of rotation of the gamma-subunit. The beneficial effects of dietary resveratrol may derive in part by preventing mitochondrial ATP synthesis in tumor cells, thereby inducing apoptosis. PMID- 17698807 TI - Structural basis for the acyl chain selectivity and mechanism of UDP-N acetylglucosamine acyltransferase. AB - UDP-N-acetylglucosamine (UDP-GlcNAc) acyltransferase (LpxA) catalyzes the first step of lipid A biosynthesis, the reversible transfer of the R-3-hydroxyacyl chain from R-3-hydroxyacyl acyl carrier protein to the glucosamine 3-OH group of UDP-GlcNAc. Escherichia coli LpxA is highly selective for R-3-hydroxymyristate. The crystal structure of the E. coli LpxA homotrimer, determined previously in the absence of lipid substrates or products, revealed that LpxA contains an unusual, left-handed parallel beta-helix fold. We have now solved the crystal structures of E. coli LpxA with the bound product UDP-3-O-(R-3-hydroxymyristoyl) GlcNAc at a resolution of 1.74 A and with bound UDP-3-O-(R-3-hydroxydecanoyl) GlcNAc at 1.85 A. The structures of these complexes are consistent with the catalytic mechanism deduced by mutagenesis and with a recent 3.0-A structure of LpxA with bound UDP-GlcNAc. Our structures show how LpxA selects for 14-carbon R 3-hydroxyacyl chains and reveal two modes of UDP binding. PMID- 17698808 TI - Allene formation by gold catalyzed cross-coupling of masked carbenes and vinylidenes. AB - Addition of a sterically demanding cyclic (alkyl)(amino)carbene (CAAC) to AuCl(SMe(2)) followed by treatment with [Et(3)Si(Tol)](+)[B(C(6)F(5))(4)](-) in toluene affords the isolable [(CAAC)Au(eta(2)-toluene)](+)[B(C(6)F(5))(4)](-) complex. This cationic Au(I) complex efficiently mediates the catalytic coupling of enamines and terminal alkynes to yield allenes and not propargyl amines as observed with other catalysts. Mono-, di-, and tri-substituted enamines can be used, as well as aryl-, alkyl-, and trimethylsilyl-substituted terminal alkynes. The reaction tolerates sterically hindered substrates and is diastereoselective. This general catalytic protocol directly couples two unsaturated carbon centers to form the three-carbon allenic core. The reaction most probably proceeds through an unprecedented "carbene/vinylidene cross-coupling." PMID- 17698809 TI - von Hippel Lindau binding protein 1-mediated degradation of integrase affects HIV 1 gene expression at a postintegration step. AB - HIV-1 integrase, the viral enzyme responsible for provirus integration into the host genome, can be actively degraded by the ubiquitin-proteasome pathway. Here, we identify von Hippel-Lindau binding protein 1(VBP1), a subunit of the prefoldin chaperone, as an integrase cellular binding protein that bridges interaction between integrase and the cullin2 (Cul2)-based von Hippel-Lindau (VHL) ubiquitin ligase. We demonstrate that VBP1 and Cul2/VHL are required for proper HIV-1 expression at a step between integrase-dependent proviral integration into the host genome and transcription of viral genes. Using both an siRNA approach and Cul2/VHL mutant cells, we show that VBP1 and the Cul2/VHL ligase cooperate in the efficient polyubiquitylation of integrase and its subsequent proteasome-mediated degradation. Results presented here support a role for integrase degradation by the prefoldin-VHL-proteasome pathway in the integration-transcription transition of the viral replication cycle. PMID- 17698810 TI - Evolution in the hypervariable environment of Madagascar. AB - We show that the diverse ecoregions of Madagascar share one distinctive climatic feature: unpredictable intra- or interannual precipitation compared with other regions with comparable rainfall. Climatic unpredictability is associated with unpredictable patterns of fruiting and flowering. It is argued that these features have shaped the evolution of distinctive characteristics in the mammalian fauna of the island. Endemic Herpestidae and Tenrecidae and members of five endemic primate families differ from closely related species elsewhere, exhibiting extremes of "fastness" and "slowness" in their life histories. Climatic features may also account for the dearth of frugivorous birds and mammals in Madagascar, and for the evolutionary prevalence of species with large body mass. PMID- 17698811 TI - Copb1-facilitated axonal transport and translation of kappa opioid-receptor mRNA. AB - mRNA of kappa opioid receptor (KOR) can be transported to nerve fibers, including axons of dorsal root ganglia (DRG), and can be locally translated. Yeast three hybrid screening identifies Copb1 as a kor mRNA-associated protein that form complexes with endogenous kor mRNA, which are colocalized in the soma and axons of DRG neurons. Axonal transport of kor mRNA is demonstrated, directly, by observing mobilization of biotin-labeled kor mRNA in Campenot chambers. Efficient transport of kor mRNA into the side chamber requires Copb1 and can be blocked by a drug that disrupts microtubules. The requirement for Copb1 in mobilizing kor mRNA is confirmed by using the MS2-GFP mRNA-tagging system. Furthermore, Copb1 also facilitates the translation of kor mRNA in the soma and axons. This study provides evidence for a microtubule-dependent, active axonal kor mRNA-transport process that involves Copb1 and can stimulate localized translation and suggests coupling of transport and translation of mRNAs destined to the remote areas such as axons. PMID- 17698812 TI - Metabolite essentiality elucidates robustness of Escherichia coli metabolism. AB - Complex biological systems are very robust to genetic and environmental changes at all levels of organization. Many biological functions of Escherichia coli metabolism can be sustained against single-gene or even multiple-gene mutations by using redundant or alternative pathways. Thus, only a limited number of genes have been identified to be lethal to the cell. In this regard, the reaction centric gene deletion study has a limitation in understanding the metabolic robustness. Here, we report the use of flux-sum, which is the summation of all incoming or outgoing fluxes around a particular metabolite under pseudo-steady state conditions, as a good conserved property for elucidating such robustness of E. coli from the metabolite point of view. The functional behavior, as well as the structural and evolutionary properties of metabolites essential to the cell survival, was investigated by means of a constraints-based flux analysis under perturbed conditions. The essential metabolites are capable of maintaining a steady flux-sum even against severe perturbation by actively redistributing the relevant fluxes. Disrupting the flux-sum maintenance was found to suppress cell growth. This approach of analyzing metabolite essentiality provides insight into cellular robustness and concomitant fragility, which can be used for several applications, including the development of new drugs for treating pathogens. PMID- 17698813 TI - Jordan's Principle, governments' paralysis. PMID- 17698814 TI - American Medical Association boards implantable chip wagon. PMID- 17698815 TI - A conversation with Dr. Day: the joys of notoriety. PMID- 17698816 TI - C. difficile outbreaks in Gatineau, Sault Ste. Marie. PMID- 17698817 TI - Ontario overhauls medical audit regime. PMID- 17698818 TI - From the medical front: treadmills. PMID- 17698819 TI - Acquired hemophilia A presenting post partum. PMID- 17698820 TI - Acquired hemophilia A presenting in an elderly man. PMID- 17698821 TI - A tourist with tungiasis. PMID- 17698822 TI - Drug drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. AB - BACKGROUND: Anticoagulants and antiplatelet drugs (e.g., warfarin, clopidogrel and acetylsalicylic acid) are key therapeutic agents in the treatment of cardiovascular diseases. However, drug-drug interactions may lead to a greatly increased risk of gastrointestinal bleeding when these drugs are combined. We assessed whether antithrombotic drug combinations increased the risk of such bleeding in a general practice population. METHODS: We conducted a population based, retrospective case-control study using records in the United Kingdom General Practice Research Database from 2000 through 2005. Cases were identified as patients over 18 years of age with a first-ever diagnosis of gastrointestinal bleeding. They were matched with controls by physician practice, patient age and index date (date of diagnosis of bleeding). All eligible patients had to have at least 3 years of follow-up data in the database. Drug exposure was considered to be any prescription issued in the 90 days before the index date. RESULTS: There were 4028 cases with a diagnosis of gastrointestinal bleeding and 40 171 matched controls. The prescribing of acetylsalicylic acid with either clopidogrel (adjusted rate ratio [RR] 3.90, 95% confidence interval [CI] 2.78-5.47) or warfarin (adjusted RR 6.48, 95% CI 4.25-9.87) was associated with a greater risk of gastrointestinal bleeding than that observed with each drug alone. The same was true when a nonsteroidal anti-inflammatory drug was combined with either clopidogrel (adjusted RR 2.93, 95% CI 1.74-4.93) or warfarin (RR 4.60, 95% CI 2.77-7.64). INTERPRETATION: Drug combinations involving antiplatelets and anticoagulants are associated with a high risk of gastrointestinal bleeding beyond that associated with each drug used alone. Physicians should be aware of these risks to better assess their patients' therapeutic risk-benefit profiles. PMID- 17698823 TI - Comparison of obstetric outcomes between on-call and patients' own obstetricians. AB - BACKGROUND: The question "will you be delivering my baby?" is one that pregnant women frequently ask their physicians. We sought to determine whether obstetric outcomes differed between women whose babies were delivered by their own obstetrician (regular-care obstetrician) and those attended by an on-call obstetrician who did not provide antenatal care. METHODS: We performed a cohort study of all live singleton term births between 1991 and 2001 at the Royal Victoria Hospital in Montreal. We excluded breech deliveries, elective cesarean sections and deliveries with placenta previa or prolapse of the umbilical cord. Logistic regression analysis was used to compare obstetric outcomes (e.g., cesarean delivery, instrumental vaginal delivery and episiotomy) between the regular-care and on-call obstetricians after adjustment for potential confounders. RESULTS: A total of 28,332 eligible deliveries were attended by 26 obstetricians: 21,779 (76.9%) by the patient's own obstetrician and 6553 (23.1%) by the on-call obstetrician. Compared with women attended by their regular-care obstetrician, those attended by an on-call obstetrician had higher rates of cesarean delivery (11.9% v. 11.4%, adjusted odds ratio [OR] 1.13, 95% confidence interval [CI] 1.03-1.24, p < 0.01) and of third-or fourth-degree tears (7.9% v. 6.4%, adjusted OR 1.21, 95% CI 1.07-1.36, p < 0.01) but lower rates of episiotomy (38.5% v. 42.9%, OR 0.77, 95% CI 0.72-0.82, p < 0.001). No differences were observed between the groups in the rate of instrumental vaginal delivery. The increase in the overall rate of cesarean delivery among women attended by an on call obstetrician was due mainly to an increase in cesarean deliveries during the first stage of labour because of nonreassuring fetal heart tracing (2.9% v. 1.7%, adjusted OR 1.79, 95% CI 1.49-2.15, p < 0.001). The time of day of delivery did not modify the observed effects. INTERPRETATION: The type of attending obstetrician (regular care v. on call) had a minor effect on obstetric outcomes. PMID- 17698824 TI - Interaction between lopinavir/ritonavir and warfarin. AB - Drug interactions involving protease inhibitors are common. Protease inhibitors are well known inhibitors of the 3A4 isozyme of cytochrome P450. Select protease inhibitors, including co-formulated lopinavir/ritonavir, may induce glucuronidation or the activity of other CYP450 isozymes. We describe the case of a patient taking warfarin who experienced a significantly decreased international normalized ratio after the initiation of antiretroviral therapy that included lopinavir/ritonavir. We review the possible mechanisms of this interaction and the reported interactions between warfarin and other protease inhibitors. PMID- 17698825 TI - Urine proteomics: the present and future of measuring urinary protein components in disease. AB - For centuries, physicians have attempted to use the urine for noninvasive assessment of disease. Today, urinalysis, in particular the measurement of proteinuria, underpins the routine assessment of patients with renal disease. More sophisticated methods for assessing specific urinary protein losses have emerged; however, albumin is still the principal urinary protein measured. Changes in the pattern of urinary protein excretion are not necessarily restricted to nephrourological disease; for instance, the appearance of beta human chorionic gonadotropin in the urine of pregnant women is the basis for all commercially available pregnancy kits. Similarly, microalbuminuria is a clinically important marker not only of early diabetic nephropathy but also of concomitant cardiovascular disease. With the emergence of newer technologies, in particular mass spectrometry, it has become possible to study urinary protein excretion in even more detail. A variety of techniques have been used both to characterize the normal complement of urinary proteins and also to identify proteins and peptides that may facilitate earlier detection of disease, improve assessment of prognosis and allow closer monitoring of response to therapy. Such proteomics-based approaches hold great promise as the basis for new diagnostic tests and as the means to better understand disease pathogenesis. In this review, we summarize the currently available methods for urinary protein analysis and describe the newer approaches being taken to identify urinary biomarkers. PMID- 17698826 TI - Drug interactions with warfarin: what clinicians need to know. PMID- 17698827 TI - "You're not my obstetrician" (and it may not matter). PMID- 17698828 TI - Canada's approach to conflict- of-interest oversight. PMID- 17698829 TI - Ethical funds for physicians. PMID- 17698830 TI - Enhancing research integrity. PMID- 17698831 TI - Sleepy older drivers. PMID- 17698832 TI - Is primary care a lost cause? PMID- 17698833 TI - Genetic analysis to prevent warfarin complications. PMID- 17698834 TI - New thinking about postoperative delirium. PMID- 17698835 TI - Antitumor activity of the combination of synthetic retinoid ST1926 and cisplatin in ovarian carcinoma models. AB - BACKGROUND: The novel adamantyl retinoid ST1926 is a potent inducer of apoptosis in ovarian carcinoma cells. Since the pro-apoptotic effect is associated with activation of p53, in this study we have investigated the efficacy of combination of ST1926 with cisplatin, a DNA-damaging agent that is known to induce p53 dependent apoptosis. MATERIALS AND METHODS: The efficacy of ST1926 and its combination with cisplatin was evaluated in human ovarian carcinoma models, including resistant tumors. RESULTS: Oral treatment with ST1926 alone caused a marginal tumor growth inhibition (<50%), but the combination with cisplatin resulted in an improved efficacy, most evident in terms of tumor growth delay without a substantial increase of toxicity. The combination therapy achieved the best effects against the HOC18 ovarian carcinoma tumor, resulting in an appreciable number of animals without evidence of disease at the end of the experiment. In contrast to the marginal effect of ST1926 alone against the subcutaneous-growing tumors, loco-regional (intraperitoneal) treatment achieved a marked increase of survival of animals with ascitic IGROV-1 tumor. CONCLUSIONS: The present results document the efficacy of the combination of cisplatin with ST1926 and provide a rational basis for the design of novel, well-tolerated platinum-based treatment approaches in human ovarian carcinoma. PMID- 17698836 TI - Timely disclosure of progress in childhood cancer survival by 'period' analysis in the Automated Childhood Cancer Information System. AB - BACKGROUND: A few years ago, a new method of survival analysis, denoted 'period' analysis, was introduced to provide more up-to-date survival estimates of cancer patients. PATIENTS AND METHODS: We evaluated the period survival method using the large database of the Automated Childhood Cancer Information System (ACCIS). Our evaluation is based on data from 35 191 children diagnosed with cancer in 13 European countries between 1975 and 1989 and followed for vital status until around 1999. RESULTS: Using the follow-up data available in 1989, 10-year survival for all children with cancer calculated by the period method for the 1985-89 period was 58%, while it was 43% when calculated by traditional 'cohort' life-table analysis (based on children diagnosed in 1975-79). The period method provided a better estimate of the true 10-year survival of 62%, observed 10 years later in the cohort of patients diagnosed in 1985-89. Similar results were observed for each of the common groups of childhood cancer. CONCLUSION: Period analysis is especially useful for monitoring childhood cancer survival, because at a given point in time it provides more timely estimates of long-term survival expectations than the cohort life-table method. Using the ACCIS database, up-to date estimates of period survival for childhood cancer are derived in subsequent papers in this journal. PMID- 17698837 TI - Quality of life and/or symptom control in randomized clinical trials for patients with advanced cancer. AB - BACKGROUND: Measures reflecting quality of life (QoL) or symptom control should be included as major endpoints in most phase III trials for patients with advanced cancer. Here we review the use of such endpoints. METHODS: We evaluated methodological aspects relating to QoL or symptom control in randomized controlled trials (RCTs) that included >or=150 patients, published from 1994 to 2004, using a 10-point checklist. RESULTS: Of 112 RCTs that met our criteria, few were rated as high quality: 22% defined QoL or symptom control as a primary endpoint; 19% established an a priori hypothesis relevant to palliation and 21% defined minimal differences in QoL or symptom scores that were clinically meaningful. Most trials (81%) analyzed differences between mean or median scores across groups and only 21% defined the proportion of individual patients who met criteria for palliative response. Only 15% of the studies met more than 5/10 criteria from our checklist. There was improvement over time in methodology and reporting. CONCLUSIONS: Current standards for analyzing QoL and symptom control in RCTs are poor. Definition of a palliative endpoint, with an a priori hypothesis, is essential; defining the proportion of patients with palliative response is preferred. The proposed checklist could raise standards of reporting in future RCTs. PMID- 17698838 TI - Implementation of the hepatitis C guidelines in UK health care workers. AB - BACKGROUND: The UK Health Department circular HSC 2002/010 requires health care employers to test certain groups of health care workers (HCWs) for hepatitis C, without additional funding. Little is known about the consistency of implementation of such guidelines. AIM: This study audited the process, completeness and problems of implementation of circular HSC 2002/010 in acute and ambulance trusts in London and the Southeast of England. METHOD: Telephone questionnaire survey of 51 National Health Service trusts between July and October 2005. RESULTS: The response rate was 92% (47/51). Eighty-five per cent (40/47) of the trusts reported partial or full implementation of the guidance. All compliant trusts reported testing HCWs entering exposure prone procedure specialities, although 40% (16/40) were testing more staff than specified in the guidance. CONCLUSION: Most trusts (85%) in this audit reported having implemented the guidance 3 years after publication and 90% claimed not to have needed additional funding. Implementation may be improved by greater clarity about which staff should be tested, frequency of testing and by raising HCWs awareness about hepatitis C infection and treatment. Newly published health clearance guidance addresses some of these points. PMID- 17698839 TI - Work-related bilateral osteoarthritis of the first carpometacarpal joints. AB - BACKGROUND: A 44-year-old industrial worker produced panels for folding doors for 9 years. During this period, he developed osteoarthritis (OA) of both first carpometacarpal joints. Surgery was performed without improvement. METHODS: Clinical examination, demonstration and recording of work conditions, with photos and videos. The literature concerning first carpometacarpal OA was reviewed using PubMed. RESULTS: The observation of work conditions demonstrated unusual forceful and repetitive ulnar flexion of both first fingers. No competing causes of OA could be identified. CONCLUSION: This patient had specific and intense work related strain of both first carpometacarpal joints. A good temporal relation between work exposure and disease development was demonstrated and it appears likely that the OA was caused by work. However, there is very limited epidemiological evidence relating first carpometacarpal OA to work exposure. PMID- 17698840 TI - Mcl-1 as a buffer for proapoptotic Bcl-2 family members during TRAIL-induced apoptosis: a mechanistic basis for sorafenib (Bay 43-9006)-induced TRAIL sensitization. AB - Previous studies have suggested that Mcl-1, an antiapoptotic Bcl-2 homolog that does not exhibit appreciable affinity for the caspase 8-generated C-terminal Bid fragment (tBid), diminishes sensitivity to tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL). This study was performed to determine the mechanism by which Mcl-1 confers TRAIL resistance and to evaluate methods for overcoming this resistance. Affinity purification/immunoblotting assays using K562 human leukemia cells, which contain Mcl-1 and Bcl-x(L) as the predominant antiapoptotic Bcl-2 homologs, demonstrated that TRAIL treatment resulted in binding of tBid to Bcl-x(L) but not Mcl-1. In contrast, TRAIL caused increased binding between Mcl-1 and Bak that was diminished by treatment with the caspase 8 inhibitor N-(N(alpha)-acetylisoleucylglutamylthreonyl) aspartic acid (O-methyl ester)-fluoromethyl ketone (IETD(OMe)-fmk) or the c-Jun N-terminal kinase inhibitor SP600125. In addition, TRAIL caused increased binding of Bim and Puma to Mcl-1 that was inhibited by IETD(OMe)-fmk but not SP600125. Further experiments demonstrated that down-regulation of Mcl-1 by short hairpin RNA or the kinase inhibitor sorafenib increased TRAIL-induced Bak activation and death ligand-induced apoptosis in a wide variety of neoplastic cell lines as well as clinical acute myelogenous leukemia specimens. Collectively, these observations not only suggest a model in which Mcl-1 confers TRAIL resistance by serving as a buffer for Bak, Bim, and Puma, but also identify sorafenib as a potential modulator of TRAIL sensitivity. PMID- 17698841 TI - Stabilization of p53 in human cytomegalovirus-initiated cells is associated with sequestration of HDM2 and decreased p53 ubiquitination. AB - Human cytomegalovirus (HCMV) induces serum- or density-arrested human lung (LU) cells to traverse the cell cycle, providing it with a strategy to replicate in post-mitotic cells that are its cellular substrate in vivo. HCMV infection also induces high cellular levels of p53, seemingly in contradiction to the observed cell cycle progression. This study was undertaken to examine the mechanism(s) of the increased p53 abundance. HCMV infection caused a 4-fold increase in p53 that preceded a substantial increase in p53 transcripts by more than 24 h. p53 was stabilized in HCMV-infected cells (from a half-life of less than 30 min to about 8 h) and was less sensitive to proteasome-mediated degradation. Ubiquitination of p53 in mock-infected LU cells was sensitive to inhibition by trans-4-iodo, 4' boranyl-chalcone, consistent with HDM2-catalyzing ubiquitination of p53. In HCMV infected cells, ubiquitination of p53 was essentially undetectable. Although HDM2 had a nuclear distribution in mock-infected LU cells, in HCMV-infected cells HDM2 was translocated to the cytoplasm beginning at 12 h and demonstrated decreased cellular abundance thereafter. HDM2 was stabilized in the HCMV-infected cells by MG132, indicating a shift from p53 to HDM2 ubiquitination. p53 demonstrated a predominantly nuclear distribution in HCMV-infected cells through 48 h, resulting in p53 and HDM2 in distinct subcellular compartments. The principal mechanism responsible for increased p53 stabilization was nuclear export and degradation of HDM2. Thus, HCMV uses a shift from p53 to HDM2 ubiquitination and destabilization to obtain protracted high levels of p53, while promoting cell cycle traverse. PMID- 17698842 TI - Characterization of the metabolic activation of hepatitis C virus nucleoside inhibitor beta-D-2'-Deoxy-2'-fluoro-2'-C-methylcytidine (PSI-6130) and identification of a novel active 5'-triphosphate species. AB - beta-D-2'-Deoxy-2'-fluoro-2'-C-methylcytidine (PSI-6130) is a potent inhibitor of hepatitis C virus (HCV) replication in the subgenomic HCV replicon system, and its corresponding 5'-triphosphate is a potent inhibitor of the HCV RNA polymerase in vitro. In this study the formation of PSI-6130-triphosphate was characterized in primary human hepatocytes. PSI-6130 and its 5'-phosphorylated derivatives were identified, and the intracellular concentrations were determined. In addition, the deaminated derivative of PSI-6130, beta-d-2'-deoxy-2'-fluoro-2'-C methyluridine (RO2433, PSI-6026) and its corresponding phosphorylated metabolites were identified in human hepatocytes after incubation with PSI-6130. The formation of the 5'-triphosphate (TP) of PSI-6130 (PSI-6130-TP) and RO2433 (RO2433-TP) increased with time and reached steady state levels at 48 h. The formation of both PSI-6130-TP and RO2433-TP demonstrated a linear relationship with the extracellular concentrations of PSI-6130 up to 100 mum, suggesting a high capacity of human hepatocytes to generate the two triphosphates. The mean half-lives of PSI-6130-TP and RO2433-TP were 4.7 and 38 h, respectively. RO2433 TP also inhibited RNA synthesis by the native HCV replicase isolated from HCV replicon cells and the recombinant HCV polymerase NS5B with potencies comparable with those of PSI-6130-TP. Incorporation of RO2433-5'-monophosphate (MP) into nascent RNA by NS5B led to chain termination similar to that of PSI-6130-MP. These results demonstrate that PSI-6130 is metabolized to two pharmacologically active species in primary human hepatocytes. PMID- 17698843 TI - Mode of growth hormone action in osteoblasts. AB - Growth hormone (GH) affects bone size and mass in part through stimulating insulin-like growth factor type 1 (IGF-1) production in liver and bone. Whether GH acts independent of IGF-1 in bone remains unclear. To define the mode of GH action in bone, we have used a Cre/loxP system in which the type 1 IGF-1 receptor (Igf1r) has been disrupted specifically in osteoblasts in vitro and in vivo. Calvarial osteoblasts from mice homozygous for the floxed IGF-1R allele (IGF 1R(flox/flox)) were infected with adenoviral vectors expressing Cre. Disruption of IGF-1R mRNA (>90%) was accompanied by near elimination of IGF-1R protein but retention of GHR protein. GH-induced STAT5 activation was consistently greater in osteoblasts with an intact IGF-1R. Osteoblasts lacking IGF-1R retained GH-induced ERK and Akt phosphorylation and GH-stimulated IGF-1 and IGFBP-3 mRNA expression. GH-induced osteoblast proliferation was abolished by Cre-mediated disruption of the IGF-1R or co-incubation of cells with an IGF-1-neutralizing antibody. By contrast, GH inhibited apoptosis in osteoblasts lacking the IGF-1R. To examine the effects of GH on osteoblasts in vivo, mice wild type for the IGF-1R treated with GH subcutaneously for 7 days showed a doubling in the number of osteoblasts lining trabecular bone, whereas osteoblast numbers in similarly treated mice lacking the IGF-1R in osteoblasts were not significantly affected. These results indicate that although direct IGF-1R-independent actions of GH on osteoblast apoptosis can be demonstrated in vitro, IGF-1R is required for anabolic effects of GH in osteoblasts in vivo. PMID- 17698844 TI - Human collagen Krox up-regulates type I collagen expression in normal and scleroderma fibroblasts through interaction with Sp1 and Sp3 transcription factors. AB - Despite several investigations, the transcriptional mechanisms that regulate the expression of both type I collagen genes (COL1A1 and COL1A2) in either physiological or pathological situations, such as scleroderma, are not completely known. We have investigated the role of hc-Krox transcription factor on type I collagen expression by human dermal fibroblasts. hc-Krox exerted a stimulating effect on type I collagen protein synthesis and enhanced the corresponding mRNA steady-state levels of COL1A1 and COL1A2 in foreskin fibroblasts (FF), adult normal fibroblasts (ANF), and scleroderma fibroblasts (SF). Forced hc-Krox expression was found to up-regulate COL1A1 transcription through a -112/-61-bp sequence in FF, ANF, and SF. Knockdown of hc-Krox by short interfering RNA and decoy strategies confirmed the transactivating effect of hc-Krox and decreased substantially COL1A1 transcription levels in all fibro-blast types. The -112/-61 bp sequence bound specifically hc-Krox but also Sp1 and CBF. Attempts to elucidate the potential interactions between hc-Krox, Sp1, and Sp3 revealed that all of them co-immunoprecipitate from FF cellular extracts when a c-Krox antibody was used and bind to the COL1A1 promoter in chromatin immunoprecipitation assays. Moreover, hc-Krox DNA binding activity to its COL1A1-responsive element is increased in SF, cells producing higher amounts of type I collagen compared with ANF and FF. These data suggest that the regulation of COL1A1 gene transcription in human dermal fibroblasts involves a complex machinery that implicates at least three transcription proteins, hc-Krox, Sp1, and Sp3, which could act in concert to up-regulate COL1A1 transcriptional activity and provide evidence for a pro fibrotic role of hc-Krox. PMID- 17698845 TI - An asparaginyl endopeptidase mediates in vivo protein backbone cyclization. AB - Proteases can catalyze both peptide bond cleavage and formation, yet the hydrolysis reaction dominates in nature. This presents an interesting challenge for the biosynthesis of backbone cyclized (circular) proteins, which are encoded as part of precursor proteins and require post-translational peptide bond formation to reach their mature form. The largest family of circular proteins are the plant-produced cyclotides; extremely stable proteins with applications as bioengineering scaffolds. Little is known about the mechanism by which they are cyclized in vivo but a highly conserved Asn (occasionally Asp) residue at the C terminus of the cyclotide domain suggests that an enzyme with specificity for Asn (asparaginyl endopeptidase; AEP) is involved in the process. Nicotiana benthamiana does not endogenously produce circular proteins but when cDNA encoding the precursor of the cyclotide kalata B1 was transiently expressed in the plants they produced the cyclotide, together with linear forms not commonly observed in cyclotide-containing plants. Observation of these species over time showed that in vivo asparaginyl bond hydrolysis is necessary for cyclization. When AEP activity was suppressed, either by decreasing AEP gene expression or using a specific inhibitor, the amount of cyclic cyclotide in the plants was reduced compared with controls and was accompanied by the accumulation of extended linear species. These results suggest that an AEP is responsible for catalyzing both peptide bond cleavage and ligation of cyclotides in a single processing event. PMID- 17698846 TI - Oxygen metabolism by endothelial nitric-oxide synthase. AB - Nitric-oxide synthase (NOS) catalyzes both coupled and uncoupled reactions that generate nitric oxide and reactive oxygen species. Oxygen is often the overlooked substrate, and the oxygen metabolism catalyzed by NOS has been poorly defined. In this paper we focus on the oxygen stoichiometry and effects of substrate/cofactor binding on the endothelial NOS isoform (eNOS). In the presence of both L-arginine and tetrahydrobiopterin, eNOS is highly coupled (>90%), and the measured stoichiometry of O(2)/NADPH is very close to the theoretical value. We report for the first time that the presence of L-arginine stimulates oxygen uptake by eNOS. The fact that nonhydrolyzable L-arginine analogs are not stimulatory indicates that the occurrence of the coupled reaction, rather than the accelerated uncoupled reaction, is responsible for the L-arginine-dependent stimulation. The presence of 5,6,7,8-tetrahydrobiopterin quenched the uncoupled reactions and resulted in much less reactive oxygen species formation, whereas the presence of redox-incompetent 7,8-dihydrobiopterin demonstrates little quenching effect. These results reveal different mechanisms for oxygen metabolism for eNOS as opposed to nNOS and, perhaps, partially explain their functional differences. PMID- 17698847 TI - The site of action of the antiterminator protein N from the lambdoid phage H-19B. AB - Transcription antitermination by N proteins of lambdoid phages involves specific interactions of the C-terminal domain of N with the elongation complex (EC). The interacting surface of N on the EC is unknown, knowledge of which is essential to understand the mechanism of antitermination. Specific cleavage patterns were generated near the active site Mg2+ of the RNA polymerase of an N-modified stalled EC using iron-(S)-1-(p-bromoacetamidobenzyl)ethylenediaminetetraacetate conjugated to the only cysteine residue in the C-terminal domain of N from a lambdoid phage H-19B. Modification of EC by N also induced conformational changes around the same region as revealed from the limited trypsin digestion and in situ Fe-dithiothreitol cleavage pattern of the same EC. These data, together with the previously obtained H-19B N-specific mutations in RNA polymerase, beta (G1045D), and beta' (P251S, P254L, G336S, and R270C) subunits, suggest that the active center cleft of the EC could be the site of action of this antiterminator. H-19B N induced altered interactions in this region of EC, prevented the backtracking of the stalled EC at the ops pause site and destabilized RNA hairpin-beta subunit flap domain interactions at the his pause site. We propose that the physical proximity of the C-terminal domain of H-19B N to the active center cleft of the EC is required for the process of transcription antitermination and that it involves both stabilization of the weak RNA-DNA hybrid at a terminator and destabilization of the interactions of terminator hairpin in the RNA exit channel. PMID- 17698848 TI - Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter. AB - Ibogaine, a hallucinogenic alkaloid with purported anti-addiction properties, inhibited serotonin transporter (SERT) noncompetitively by decreasing V(max) with little change in the K(m) for serotonin (5-HT). Ibogaine also inhibited binding to SERT of the cocaine analog 2beta-2-carbomethoxy-3-(4 [(125)I]iodophenyl)tropane. However, inhibition of binding was competitive, increasing the apparent K(D) without much change in B(max). Ibogaine increased the reactivity of cysteine residues positioned in the proposed cytoplasmic permeation pathway of SERT but not at nearby positions out of that pathway. In contrast, cysteines placed at positions in the extracellular permeation pathway reacted at slower rates in the presence of ibogaine. These results are consistent with the proposal that ibogaine binds to and stabilizes the state of SERT from which 5-HT dissociates to the cytoplasm, in contrast with cocaine, which stabilizes the state that binds extracellular 5-HT. PMID- 17698849 TI - Characterization of a mutation in the Phox homology domain of the NADPH oxidase component p40phox identifies a mechanism for negative regulation of superoxide production. AB - The phagocyte oxidase (Phox) protein p40(phox) contains a Phox homology (PX) domain which, when expressed alone, interacts with phosphatidylinositol 3 phosphate (PtdIns (3)P). The functions of the PX domain in p40(phox) localization, association with the cytoskeleton, and superoxide production were examined in transgenic COS-7 cells expressing gp91(phox), p22(phox), p67(phox), and p47(phox) (COS(phox) cells). Full-length p40(phox) exhibited a cytoplasmic localization pattern in resting cells. Upon stimulation with phorbol 12-myristate 13-acetate or fMet-Leu-Phe, p40(phox) translocated to plasma membrane in a p67(phox)- and p47(phox)-dependent manner. Heterologous expression of p40(phox) markedly enhanced superoxide production in phorbol 12-myristate 13-acetate - and fMet-Leu-Phe-stimulated COS(phox) cells. Unexpectedly, mutation of Arg-57 in the PX domain to Gln, which abrogated PtdIns (3)P binding, produced a dominant inhibitory effect on agonist-induced superoxide production and membrane translocation of p47(phox) and p67(phox). The mutant p40(phox) (p40R57Q) displayed increased association with actin and moesin and was found enriched in the Triton X-100-insoluble fraction along with p67(phox) and p47(phox). The enhanced cytoskeleton association of p67(phox) and p47(phox) and the dominant inhibitory effect produced by the p40R57Q were alleviated when a second mutation at Asp-289, which eliminated p40(phox) interaction with p67(phox), was introduced. Likewise, cytochalasin B treatment abolished the dominant inhibitory effect of p40R57Q on superoxide production. These findings suggest a dual regulatory mechanism through the PX domain of p40(phox); its interaction with the actin cytoskeleton may stabilize NADPH oxidase in resting cells, and its binding of PtdIns (3)P potentiates superoxide production upon agonist stimulation. Both functions require the association of p40(phox) with p67(phox). PMID- 17698850 TI - Human T-cell leukemia virus type 1 Tax oncoprotein prevents DNA damage-induced chromatin egress of hyperphosphorylated Chk2. AB - De novo expression of human T-cell leukemia virus type 1 Tax results in cellular genomic instability. We demonstrated previously that Tax associates with the cell cycle check point regulator Chk2 and proposed that the inappropriate activation of Chk2 provides a model for Tax-induced loss of genetic integrity (Haoudi, A., Daniels, R. C., Wong, E., Kupfer, G., and Semmes, O. J. (2003) J. Biol. Chem. 278, 37736-37744). Here we provide an explanation for how Tax induces some Chk2 activities but represses others. We show that Tax interaction with Chk2 generates two activation signals in Chk2, oligomerization and autophosphorylation. However, egress of Chk2 from chromatin, normally observed in response to ionizing radiation, was repressed in Tax-expressing cells. Analysis of chromatin-bound Chk2 from Tax-expressing cells revealed phosphorylation at Thr(378), Ser(379), Thr(383), Thr(387), and Thr(389). In contrast, chromatin-bound Chk2 in the absence of Tax was phosphorylated at Thr(383) and Thr(387) in response to ionizing radiation. We further establish that Tax binds to the kinase domain of Chk2. Confocal microscopy revealed a redistribution of Chk2 to colocalize with Tax in Tax speckled structures, which we have shown previously to coincide with interchromatin granules. We propose that Tax binding via the Chk2 kinase domain sequesters phosphorylated Chk2 within chromatin, thus hindering chromatin egress and appropriate response to DNA damage. PMID- 17698851 TI - Phospholemman transmembrane structure reveals potential interactions with Na+/K+ ATPase. AB - Phospholemman (PLM) is a 72-residue bitopic cardiac transmembrane protein, which acts as a modulator of the Na(+)/K(+)-ATPase and the Na(+)/Ca(2+) exchanger and possibly forms taurine channels in nonheart tissue. This work presents a high resolution structural model obtained from a combination of site-specific infrared spectroscopy and experimentally constrained high throughput molecular dynamics (MD) simulations. Altogether, 37 experimental constraints, including nine long range orientational constraints, have been used during MD simulations in an explicit lipid bilayer/water system. The resulting tetrameric alpha-helical bundle has an average helix tilt of 7.3 degrees and a crossing angle close to 0 degrees . It does not reveal a hydrophilic pore, but instead strong interactions between various residues occlude any pore. The helix-helix packing is unusual, with Gly(19) and Gly(20) pointing to the outside of the helical bundle, facilitating potential interaction with other transmembrane proteins, thus providing a structural basis for the modulatory effect of PLM on the Na(+)/K(+) ATPase. A two-stage model of interaction between PLM and the Na(+)/K(+)-ATPase is discussed involving PLM-ATPase interaction and subsequent formation of an unstable PLM trimer, which readily interacts with surrounding ATPase molecules. Further unconstrained MD simulations identified other packing models of PLM, one of which could potentially undergo a conformational transition to an open pore. PMID- 17698852 TI - Selective cysteine protease inhibition contributes to blood-feeding success of the tick Ixodes scapularis. AB - Ixodes scapularis is the main vector of Lyme disease in the eastern and central United States. Tick salivary secretion has been shown as important for both blood meal completion and pathogen transmission. Here we report a duplication event of cystatin genes in its genome that results in a transcription-regulated boost of saliva inhibitory activity against a conserved and relatively limited number of vertebrate papain-like cysteine proteases during blood feeding. We further show that the polypeptide products of the two genes differ in their binding affinity for some enzyme targets, and they display different antigenicity. Moreover, our reverse genetic approach employing RNA interference uncovered a crucial mediation in tick-feeding success. Given the role of the targeted enzymes in vertebrate immunity, we also show that host immunomodulation is implicated in the deleterious phenotype of silenced ticks making I. scapularis cystatins attractive targets for development of anti-tick vaccines. PMID- 17698853 TI - Dynamic processing of recombinant dentin sialoprotein-phosphophoryn protein. AB - Dentin sialoprotein (DSP) and phosphophoryn (PP) are the two noncollagenous proteins classically linked to dentin but more recently found in bone, kidney, and salivary glands. These two proteins are derived from a single copy DSP-PP gene. Although this suggests that the DSP-PP gene is first transcribed into DSP PP mRNAs, which later undergo processing to yield the DSP and PP proteins, this mechanism has not yet been demonstrated because of the inability to identify a DSP-PP precursor protein from any cell or tissue sample. To study this problem, we utilized a baculovirus expression system to produce recombinant DSP-PP precursor proteins from a DSP-PP(240) cDNA, which represents one of several endogenous DSP-PP transcripts that influence various tooth mineralization phases. Our in vitro results demonstrate that DSP-PP(240) precursor proteins are produced by this system and are capable of self-processing to yield both DSP and PP proteins. We further demonstrated that purified recombinant DSP-PP(240), purified recombinant PP(240), and the native highly phosphorylated protein (equivalent to the PP(523) isoform) have proteolytic activity. These newly identified tissue proteases may play key roles in tissue modeling during organogenesis. PMID- 17698854 TI - Membrane translocation of P-Rex1 is mediated by G protein betagamma subunits and phosphoinositide 3-kinase. AB - P-Rex1 is a guanine-nucleotide exchange factor (GEF) for the small GTPase Rac that is directly activated by the betagamma subunits of heterotrimeric G proteins and by the lipid second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP(3)), which is generated by phosphoinositide 3-kinase (PI3K). Gbetagamma subunits and PIP(3) are membrane-bound, whereas the intracellular localization of P-Rex1 in basal cells is cytosolic. Activation of PI3K alone is not sufficient to promote significant membrane translocation of P-Rex1. Here we investigated the subcellular localization of P-Rex1 by fractionation of Sf9 cells co-expressing P Rex1 with Gbetagamma and/or PI3K. In basal, serum-starved cells, P-Rex1 was mainly cytosolic, but 7% of the total was present in the 117,000 x g membrane fraction. Co-expression of P-Rex1 with either Gbetagamma or PI3K caused only an insignificant increase in P-Rex1 membrane localization, whereas Gbetagamma and PI3K together synergistically caused a robust increase in membrane-localized P Rex1 to 23% of the total. PI3K-driven P-Rex1 membrane recruitment was wortmannin sensitive. The use of P-Rex1 mutants showed that the isolated Dbl homology/pleckstrin homology domain tandem of P-Rex1 is sufficient for synergistic Gbetagamma- and PI3K-driven membrane localization; that the enzymatic GEF activity of P-Rex1 is not required for membrane translocation; and that the other domains of P-Rex1 (DEP, PDZ, and IP4P) contribute to keeping the enzyme localized in the cytosol of basal cells. In vitro Rac2-GEF activity assays showed that membrane-derived purified P-Rex1 has a higher basal activity than cytosol derived P-Rex1, but both can be further activated by PIP(3) and Gbetagamma subunits. PMID- 17698855 TI - HDL serves as a S1P signaling platform mediating a multitude of cardiovascular effects. AB - The lysosphingolipid sphingosine 1-phosphate (S1P) is a component of HDL. Findings from a growing number of studies indicate that S1P is a mediator of many of the cardiovascular effects of HDL, including the ability to promote vasodilation, vasoconstriction, and angiogenesis, protect against ischemia/reperfusion injury, and inhibit/reverse atherosclerosis. These latter cardioprotective effects are being shown to involve the S1P-mediated suppression of inflammatory processes, including reduction of the endothelial expression of monocyte and lymphocyte adhesion molecules, decreased recruitment of polymorphonuclear cells to sites of infarction, and blocking of cardiomyocyte apoptosis after myocardial infarction. This review article summarizes the evidence that S1P as a component of HDL serves to regulate vascular cell and lymphocyte behaviors associated with cardiovascular (patho)physiology. PMID- 17698856 TI - Apolipoprotein B and non-high density lipoprotein cholesterol and the risk of coronary heart disease in Chinese. AB - The aim of our study was to compare apolipoprotein B (apoB), non-high density lipoprotein cholesterol (nonHDL-C), low density lipoprotein cholesterol (LDL-C), and other lipid markers as predictors of coronary heart disease (CHD) in Chinese. Overall, 122 individuals developed CHD during a median 13.6 years of follow-up in 3,568 adult participants from a community-based cohort. The multivariate relative risk of CHD in the highest quintile compared with the lowest quintile was 2.74 [95% confidence interval (CI), 1.45-5.19] for apoB, 1.98 (95% CI, 1.00-3.92) for nonHDL-C, and 1.86 (95% CI, 1.00-3.49) for LDL-C (all tests for trend, P < 0.05). ApoB also had the highest receiver operator characteristic curve area (0.63; 95% CI, 0.58-0.68) in predicting CHD. When apoB and nonHDL-C were mutually adjusted, only apoB was predictive; the relative risk was 2.80 (95% CI, 1.31-5.96; P = 0.001) compared with 1.09 (95% CI, 0.49-2.40; P = 0.75) for nonHDL-C. Compared with the lowest risk, participants with the highest apoB and total cholesterol/HDL-C had a 3-fold increased risk of developing CHD (relative risk = 3.21; 95% CI, 1.45-7.14). These data provide strong evidence that apoB concentration was a better predictor of CHD than other lipid markers in Chinese. PMID- 17698857 TI - Rescuing yeast mutants with human genes. AB - The fission yeast Schizosaccharomyces pombe and the budding yeast Saccharomyces cerevisiae have, in addition to being extensively studied themselves, both been utilized for the last quarter century as experimental systems for the isolation of genes from other organisms. Mutations conferring growth defects in either of the two yeast strains have frequently been complemented by expression of cDNA libraries from heterologous species, often human. Many successful experiments have utilized available yeast mutations to allow successful complementation by a human gene, which can thus be deduced to have the same, or an overlapping function as the mutated yeast gene. However complementation in yeast has also been used with success to study two fields, apoptosis and steroid receptor signalling, which, at first glance, seem to be foreign to the yeast life cycle. PMID- 17698858 TI - Mining complex genotypic features for predicting HIV-1 drug resistance. AB - MOTIVATION: Human immunodeficiency virus type 1 (HIV-1) evolves in human body, and its exposure to a drug often causes mutations that enhance the resistance against the drug. To design an effective pharmacotherapy for an individual patient, it is important to accurately predict the drug resistance based on genotype data. Notably, the resistance is not just the simple sum of the effects of all mutations. Structural biological studies suggest that the association of mutations is crucial: even if mutations A or B alone do not affect the resistance, a significant change might happen when the two mutations occur together. Linear regression methods cannot take the associations into account, while decision tree methods can reveal only limited associations. Kernel methods and neural networks implicitly use all possible associations for prediction, but cannot select salient associations explicitly. RESULTS: Our method, itemset boosting, performs linear regression in the complete space of power sets of mutations. It implements a forward feature selection procedure where, in each iteration, one mutation combination is found by an efficient branch-and-bound search. This method uses all possible combinations, and salient associations are explicitly shown. In experiments, our method worked particularly well for predicting the resistance of nucleotide reverse transcriptase inhibitors (NRTIs). Furthermore, it successfully recovered many mutation associations known in biological literature. AVAILABILITY: http://www.kyb.mpg.de/bs/people/hiroto/iboost/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 17698859 TI - Steroid responsive aortitis. PMID- 17698860 TI - Epidemiological trends of pre-malignant gastric lesions: a long-term nationwide study in the Netherlands. AB - BACKGROUND: The pre-malignant gastric lesions atrophic gastritis (AG), intestinal metaplasia (IM) and dysplasia (DYS) have long been identified as principal risk factors for gastric cancer. OBJECTIVE: To evaluate epidemiological time trends of pre-malignant gastric lesions in the Netherlands. METHODS: Patients with a first diagnosis of AG, IM or DYS between 1991 and 2005 were identified in the Dutch nationwide histopathology registry. The number of new diagnoses per year were evaluated relative to the total number of patients with a first gastric biopsy. Time trends were evaluated with age-period-cohort models using logistic regression analysis. RESULTS: In total, 23 278 patients were newly diagnosed with AG, 65 937 patients with IM, and 8517 patients with DYS. The incidence of AG declined similarly in men and women with 8.2% per year [95% CI 7.9% to 8.6%], and DYS with 8.1% per year [95% CI 7.5% to 8.6%]. The proportional number of new IM cases declined with 2.9% per year [95% CI 2.7% to 3.1%] in men and 2.4% [95% CI 2.2% to 2.6%] in women. With age-period-cohort models a cohort phenomenon was demonstrated for all categories of pre-malignant gastric lesions in men and in women with IM and DYS. Period phenomena with a larger decline in number of diagnoses after 1996 were also demonstrated for AG and IM. CONCLUSIONS: The incidence of pre-malignant gastric lesions is declining. Period and cohort phenomena were demonstrated for diagnoses of AG and IM. These findings imply that a further decrease of at least 24% in the incidence of gastric cancer in the coming decade may be anticipated in Western countries without specific intervention. PMID- 17698861 TI - Sensitivity and specificity of bispectral index for classification of overt hepatic encephalopathy: a multicentre, observer blinded, validation study. AB - BACKGROUND: The severity of hepatic encephalopathy is currently graded clinically using West Haven criteria and psychometric tests. OBJECTIVE: To assess the discriminative power of the bispectral index (BIS) monitor to classify the degree and progression of hepatic encephalopathy. DESIGN: A consecutive, multicentre, observer blinded validation study. SETTING: Medical University of Graz (Graz, Austria), Zhejiang University First Affiliated Hospital (Hang Zhou, China), and Cairo University (Cairo, Egypt). PATIENTS: 28 consecutive patients with hepatic encephalopathy were first enrolled at Medical University of Graz as a test set. The estimated BIS cut off values were subsequently tested in a validation set of 31 patients at Zhejiang University First Affiliated Hospital and 26 patients at Cairo University; 18 patients were reassessed later in a longitudinal study. Fifteen of 85 patients (18%) were excluded from the final analysis (11 became too agitated with high electromyographic activity; four fell asleep during the recording). RESULTS: Applying the Austrian BIS cut off values of 85, 70, and 55 for discriminating West Haven grades 1 to 4 yielded agreement between BIS classification and West Haven grades in 40 of the 46 validation patients (87%), and in 16 of the 18 follow up patients (89%). Mean (SD) BIS values differed significantly between patients with West Haven grade 1 (90.2 (2.5)), grade 2 (78.4 (6.6)), grade 3 (63.2 (4.8)), and grade 4 (45.4 (5.0)). CONCLUSIONS: BIS is a useful measure for grading and monitoring the degree of involvement of the central nervous system in patients with chronic liver disease. PMID- 17698862 TI - Risks and benefits of combining immunosuppressives and biological agents in inflammatory bowel disease: is the synergy worth the risk? AB - Since the introduction of infliximab to treat Crohn's disease, combination therapy with immunosuppressants has reduced immunogenicity, without impacting efficacy. The availability of novel anti-TNF agents and potential combined toxicities question the risk/benefit of combination therapies. PMID- 17698863 TI - The classics in perspective. PMID- 17698864 TI - Fatty liver in chronic hepatitis C infection: unravelling the mechanisms. PMID- 17698865 TI - Chronic pancreatitis: diagnosis and management of complications. PMID- 17698866 TI - Editor's quiz: Acute liver failure in a patient with lung cancer. PMID- 17698867 TI - Editor's quiz: Oesophagogastric fistula: a post-operative complication. PMID- 17698868 TI - Editor's quiz: Sigmoid stricture in a 39-year-old female. PMID- 17698869 TI - Association of BclI polymorphism of the glucocorticoid receptor gene locus with response to glucocorticoids in inflammatory bowel disease. PMID- 17698870 TI - Iron deficiency anaemia: further education regarding the British Society of Gastroenterology guidelines is required. PMID- 17698871 TI - MYO9B polymorphisms in patients with inflammatory bowel disease. PMID- 17698872 TI - Cathepsin B gene polymorphism Val26 is not associated with idiopathic chronic pancreatitis in European patients. PMID- 17698873 TI - Familial association of benign pancreatic hyperenzymaemia and pancreatic cancer. PMID- 17698874 TI - Safe endoscopic polypectomy of jejunal polyps with a detachable snare during double balloon enteroscopy. PMID- 17698875 TI - Is there an association between coeliac disease and irritable bowel syndrome? PMID- 17698876 TI - Risk of pancreatic cancer in patients with cystic fibrosis. PMID- 17698877 TI - Glucocorticoid receptor isoform expression does not predict steroid treatment response in IBD. PMID- 17698878 TI - A non-invasive screen for infectivity in transmissible spongiform encephalopathies. PMID- 17698879 TI - Inflammation in the genesis of hypertension and its complications--the role of angiotensin II. PMID- 17698880 TI - Adaptive style in children with cancer: implications for a positive psychology approach. AB - OBJECTIVE: To describe the adaptive style paradigm as a heuristic model for understanding the very positive psychosocial adjustment that has been observed in children with cancer, and to integrate findings regarding repressive adaptive style into a broader positive psychology framework. METHOD: A selective review of the literature on adaptive style, and its' relevance to outcomes of depressive symptoms, posttraumatic stress symptoms, somatic distress, and health-related quality of life in children with cancer. RESULTS: Studies have found children with cancer report low levels of psychological distress. Adaptive style is a much stronger predictor of psychosocial outcomes than is health history. CONCLUSION: Children with cancer represent a flourishing population. A repressive adaptive style is one pathway to resilience in this population. Additional constructs from the domain of positive psychology are reviewed, and a positive psychology model is suggested as a framework for guiding future research in this area. PMID- 17698881 TI - Redox regulation of chloroplast enzymes in Galdieria sulphuraria in view of eukaryotic evolution. AB - Redox modulation is a general mechanism for enzyme regulation, particularly for the post-translational regulation of the Calvin cycle in chloroplasts of green plants. Although red algae and photosynthetic protists that harbor plastids of red algal origin contribute greatly to global carbon fixation, relatively little is known about post-translational regulation of chloroplast enzymes in this important group of photosynthetic eukaryotes. To address this question, we used biochemistry, phylogenetics and analysis of recently completed genome sequences. We studied the functionality of the chloroplast enzymes phosphoribulokinase (PRK, EC 2.7.1.19), NADP-dependent glyceraldehyde 3-phosphate dehydrogenase (NADP GAPDH, GapA, EC 1.2.1.13), fructose 1,6-bisphosphatase (FBPase, EC 3.1.3.11) and glucose 6-phosphate dehydrogenase (G6PDH, EC 1.1.1.49), as well as NADP-malate dehydrogenase (NADP-MDH, EC 1.1.1.37) in the unicellular red alga Galdieria sulphuraria (Galdieri) Merola. Despite high sequence similarity of G. sulphuraria proteins to those of other photosynthetic organisms, we found a number of distinct differences. Both PRK and GAPDH co-eluted with CP12 in a high molecular weight complex in the presence of oxidized glutathione, although Galdieria CP12 lacks the two cysteines essential for the formation of the N-terminal peptide loop present in higher plants. However, PRK inactivation upon complex formation turned out to be incomplete. G6PDH was redox modulated, but remained in its tetrameric form; FBPase was poorly redox regulated, despite conservation of the two redox-active cysteines. No indication for the presence of plastidic NADP-MDH (and other components of the malate valve) was found. PMID- 17698882 TI - Endogenous phosphotyrosine signaling in zebrafish embryos. AB - In the developing embryo, cell growth, differentiation, and migration are strictly regulated by complex signaling pathways. One of the most important cell signaling mechanisms is protein phosphorylation on tyrosine residues, which is tightly controlled by protein-tyrosine kinases and protein-tyrosine phosphatases. Here we investigated endogenous phosphotyrosine signaling in developing zebrafish embryos. Tyrosine phosphorylated proteins were immunoaffinity-purified from zebrafish embryos at 3 and 5 days postfertilization and identified by multidimensional LC-MS. Among the identified proteins were tyrosine kinases, including Src family kinases, Eph receptor kinases, and focal adhesion kinases, as well as the adaptor proteins paxillin, p130Cas, and Crk. We identified several known and some unknown in vivo tyrosine phosphorylation sites in these proteins. Whereas most immunoaffinity-purified proteins were detected at both developmental stages, significant differences in abundance and/or phosphorylation state were also observed. In addition, multiplex in vitro kinase assays were performed by incubating a microarray of peptide substrates with the lysates of the two developmental stages. Many of the in vivo observations were confirmed by this on chip in vitro kinase assay. Our experiments are the first to show that global tyrosine phosphorylation-mediated signaling can be studied at endogenous levels in complex multicellular organisms. PMID- 17698883 TI - Commentary: Smokeless tobacco: seeing the whole picture. PMID- 17698884 TI - House-level risk factors for triatomine infestation in Colombia. AB - BACKGROUND: Chagas disease, transmitted domestically by triatomine bugs, is the most important vector-borne disease in Latin America. The association between triatomine infestation and housing characteristics was investigated based on a standardized survey in 41 971 houses in 15 Departments in Colombia. METHODS: Multivariate logistic regression was used to test for associations of two highly correlated infestation measures of infestation (householders reporting having seen triatomines inside the house, and sending triatomines to the survey team), with 15 household-level risk factors. Risks were measured relative to a reference category of houses with up to three inhabitants, area up to 50 m(2), unplastered adobe walls, thatch roof and no outbuildings or domestic animals. RESULTS: The probability of seeing triatomines was highest for households with over seven inhabitants (OR = 1.24, 95% CI 1.11-1.39), overhead storage space (OR = 1.16, 95% CI 1.03-1.32), grain shed (OR = 1.25, 95% CI 1.02-1.52), cats (OR = 1.27, 95% CI 1.14-1.42) and pigs (OR = 1.16, 95% CI 1.03-1.30). Lowest risks were in houses with wooden walls (OR = 0.46, 95% CI 0.34-0.61), fully plastered walls (OR = 0.78, 95% CI 0.68-0.88), roofs made of tiles (OR = 0.51, 95% CI 0.33-0.78) and flagstone floors (OR = 0.57, 95% CI 0.42-0.76). Results for householders returning triatomines support this set of risk factors, but with wider confidence intervals. CONCLUSIONS: Surveillance of a few easily assessed household characteristics provides an accurate, rapid assessment of house-level variation in risk. Measured effect sizes for specific structural characteristics could be used to maximize the cost-effectiveness of programmes to reduce vector infestation and interrupt Chagas disease transmission by improving house quality. PMID- 17698885 TI - SCHIP reconsidered. AB - The reauthorization of the State Children's Health Insurance Program (SCHIP) in Congress offers an opportunity to assess the legislation in light of recent developments in Medicaid and states' health coverage reform efforts. Fundamental child health goals can be achieved while still affording states additional flexibility to invest in populations of all ages. PMID- 17698886 TI - Validation of a clinical score for the diagnosis of late onset neonatal septicemia in babies weighing 1000-2500 g. AB - There is paucity of data about the predictive values and likelihood ratios of clinical signs of late onset nosocomial sepsis in neonates. A clinical score comprising of seven items had been derived from analysis of individual signs and had been published by this group in the Journal of Tropical Pediatrics in 2003. The current study was done to validate the score in a fresh validation cohort, to evaluate the score at 0 and 24 h after onset of clinical signs of sepsis and to evaluate the sepsis screen in combination with the clinical score. The seven clinical signs in the clinical score included grunting, abdominal distension, increased prefeed aspirates, tachycardia, hyperthermia, chest retractions and lethargy. A total of 220 episodes of sepsis among 208 babies were evaluated. The clinical score was calculated at 0 h and 24 h. A sepsis screen (micro erythrocyte sedimentation rate, C reactive protein, absolute neutrophil count and immature/total neutrophil ratio) and blood culture were performed in all subjects at enrollment. Sepsis screen was considered 'positive' if any two parameters were positive. The outcome of interest was 'definite sepsis', defined as blood culture positive. The 0-h clinical score had sensitivity, specificity, PPV, NPV, LR(+) and LR(-) of 90, 22.5, 30.3, 85.7, 1.16 and 0.44%, respectively. The 24-h score had higher specificity (60.6%) but lower sensitivity than the 0-h score. Sepsis screen per se had a sensitivity and NPV of 48.3 and 78.3% but when combined with the 0-h clinical score, the sensitivity and NPV rose to 95 and 90.6%, respectively. The 'clinical score' in combination with sepsis screen result can be used by clinicians to rule out sepsis. PMID- 17698887 TI - Relationship between trachoma and chronic and acute malnutrition in children in rural Ethiopia. AB - Trachoma is the leading infectious cause of blindness in the world. Areas where it is most prevalent also have some of the highest rates of childhood malnutrition. We examined the relationship between both acute and chronic malnutrition and clinical trachoma. We also explored whether malnutrition alters the clinical manifestations of the disease. Children with chronic malnutrition, but not acute malnutrition, were more likely to have clinical trachoma. Stunted children are 1.96 times more likely to have clinical trachoma than nonstunted children (95% CI: 1.12-3.43), even after controlling for age, gender and infection status of other household members. Host factors including malnutrition may play a role in determining disease manifestations. PMID- 17698888 TI - Development of a proxy wealth index for women utilizing emergency obstetric care in Bangladesh. AB - There are increasing concerns regarding inequities in access to health care, and hence calls for routine data collection to improve monitoring. For many developing countries, such as Bangladesh, increasing the availability and uptake of emergency obstetric care (EmOC) is vital in improving maternal health. It is crucial, however, that women of all socio-economic status benefit from this. This paper describes the development and validation of a proxy wealth index for assessing women's socio-economic status in Bangladesh as they are admitted to hospital. Existing poverty assessment tools are unsuitable for use in this context as they are too lengthy or need to be administered at household or community level. We sought to develop a tool with a limited number of indicators to allow quick administration and avoid interference with treatment. We also aimed to develop a pragmatic tool to be able to calculate a score in the field. The steps, involving selecting and weighting indicators, assigning a proxy wealth score and validating the score, are outlined. Indicators were selected from the Bangladeshi Demographic and Health Survey (DHS) data, which allowed comparison of socio-economic status between women using EmOC and those in the wider population. The tool proved quick and easy to use and was acceptable to women and their families. The validity of the tool was established by means of factor analysis. Our comparison with DHS data suggested that women using EmOC were significantly wealthier than women in the wider population. The implications of this, as well as the strengths and limitations of the proxy wealth index, are discussed. The proxy wealth index offers potential as a pragmatic and quick means of assessing poverty status in a busy hospital setting. Such a tool may enable monitoring of equity in access to treatment and identification of those least able to afford treatment, to enable any mechanisms in place to pay for care to be applied in a timely fashion, so avoiding delays in treating life-threatening complications. PMID- 17698890 TI - 10 best resources on... health equity. PMID- 17698889 TI - Gender differences in delays in diagnosis and treatment of tuberculosis. AB - OBJECTIVE: To assess the gender variations in delay from symptom onset to help seeking, diagnosis and treatment of tuberculosis (TB) using DOTS at community level, in 10 subdistricts of Bangladesh with 2.5 million people under a non governmental organization's (Building Resources Across Communities, or BRAC) DOTS programme for TB control. DESIGN: A cross-sectional survey of 1000 newly diagnosed pulmonary TB patients (500 women and 500 men). FINDINGS: Women, in comparison with men, had significantly longer mean and median delays in total delay (63.2 and 61.0 days vs. 60.3 and 53 days, respectively), total diagnostic delay (61.2, 60.0 vs. 58.5, 52.0 days), patient's delay (51.9, 50.0 vs. 48.7, 42.0 days) and treatment delay (2.0, 1.0 vs. 1.9, 1.0 day). Patient's mean and median delays were longer than the health system delay. However, patient gender showed strong association with total delay, total diagnostic delay and patient's delay. Older age of women was significantly associated with longer patient and treatment delay categories, respectively. CONCLUSION: Compared with men, women experienced longer delays at various stages of the clinical process of help seeking for TB. This warrants appropriate measures to improve the situation. PMID- 17698891 TI - Analysis of flavonoid phytoestrogens in botanical and ephedra-containing dietary supplements. AB - BACKGROUND: Plant-derived botanical and dietary supplements are widely self prescribed in the US and considered natural, safe, and beneficial. However, because they are not strictly regulated by the Food and Drug Administration (FDA), their ingredients are not always known and they may contain unexpected agents. Among the myriad plant-produced molecules are flavonoids, which reportedly have various human health effects, including anticancer, antioxidant, and estrogenic properties. Several flavonoids (eg, isoflavones) are known as phytoestrogens, based on their ability to mimic estrogen in mammals. Because botanical and dietary supplements are plant products and need not be processed or purified due to their FDA classification as foods, they may contain unexpected phytoestrogens, such as flavonoids. OBJECTIVE: To analyze 8 botanical and 11 ephedra-containing dietary supplements for the presence and concentration of 5 flavonoids (biochanin A, daidzein, formononetin, genistein, quercetin), which may deliver unexpected estrogenic activity. METHOD: Randomly selected tablets from single bottles of 19 botanical and dietary supplements purchased locally were pooled. Flavonoids were extracted into ethanolic solution and analyzed by high performance liquid chromatography. RESULTS: Flavonoids were detected in all supplements tested, with the largest number (4) found in Kava Kava. Almost all supplements contained measurable amounts of genistein and/or daidzein, known estrogenic agents, at up to 22 mg/day of isoflavone, per recommended daily dosage of supplement. CONCLUSIONS: These results suggest that single-component botanical and multi-ingredient dietary supplements could contain unexpected estrogenic agents, which may impact the health of consumers. PMID- 17698892 TI - Update on the pharmacotherapy of obesity. 1998. PMID- 17698893 TI - Alzheimer's disease: clinical features, pathogenesis, and treatment. 1984. PMID- 17698894 TI - Intraosseous drug administration in children and adults during cardiopulmonary resuscitation. AB - OBJECTIVE: To review and assess the available literature on the use of intraosseous (IO) drug administration during cardiopulmonary resuscitation, addressing the benefits and risks of using this method of drug delivery in children and adults. DATA SOURCES: The MEDLINE (1950-July 2007) database was searched for pertinent abstracts, using the key term intraosseous infusions. Additional references were obtained from the bibliographies of the articles reviewed. Manufacturer Web sites were used to obtain information about IO insertion devices. STUDY SELECTION AND DATA EXTRACTION: All available English language clinical trials, retrospective studies, and review articles describing IO drug administration were reviewed. Studies conducted in animal models to evaluate the effectiveness and safety of IO drug administration were also included. DATA SYNTHESIS: IO access uses the highly vascularized bone marrow to deliver fluids and medications during cardiopulmonary resuscitation. This route, developed in the 1940s, has been revived in the past decade as a means of achieving rapid vascular access when intravenous access cannot be obtained. The primary advantage of IO access is the high success rate (approximately 80%). Most trained providers can place an IO line within 1-2 minutes. A number of small scale studies and retrospective reviews have established the usefulness of this route for the delivery of many commonly used resuscitation drugs. In addition, animal models have demonstrated rapid drug delivery to the systemic circulation. While all resuscitation drugs can be given by the IO route, administration of ceftriaxone, chloramphenicol, phenytoin, tobramycin, and vancomycin may result in lower peak serum concentrations. The most common adverse effect seen with IO use, extravasation, has been reported in 12% of patients. Compartment syndrome, osteomyelitis, and tibial fracture are rare, but have also been reported. CONCLUSIONS: IO administration is a safe and effective method for delivering drugs during cardiopulmonary resuscitation. It should be considered whenever intravenous access cannot be rapidly obtained. PMID- 17698895 TI - Successful treatment of previously uncontrolled adult asthma with budesonide inhalation suspension: five-year case histories. AB - OBJECTIVE: To determine whether nebulized budesonide inhalation suspension (BIS) is effective in treating adults with asthma that has been uncontrolled by inhaled therapies. CASE SUMMARIES: Three adults with severe persistent asthma were switched to BIS after poor outcomes with other controller medications, including inhaled corticosteroids (ICSs). BIS dosages were initiated with 1 mg twice daily. Based on physician discretion as symptoms improved, dosages were decreased to 0.5 mg twice daily (2 pts.) or once daily (1 pt.). Patients were instructed to self manage their asthma, increasing their dosages during periods of asthma worsening. Peak expiratory flow (PEF) was assessed before and after the initiation of BIS. The number of healthcare visits and oral corticosteroid courses recorded in patient medical records during the 3 years before and 5 years after initiation of BIS therapy were compared. In all 3 cases, BIS improved asthma control. BIS consistently increased PEF and reduced the number of urgent care visits and oral corticosteroid courses. All patients reported satisfaction with BIS therapy. DISCUSSION: Despite proven effectiveness of ICSs for persistent asthma, some patients fail to respond optimally to treatment administered via an inhaler. These 3 case reports suggest that BIS is effective in treating adults with severe persistent asthma who fail to respond optimally to treatment with other ICS preparations. Failure to use inhalers properly, previous poor adherence in 1 case, or patient preference for the nebulizer might explain why nebulized BIS was more effective than other inhaler therapies. CONCLUSIONS: Switching adults with uncontrolled asthma to BIS therapy may be a valuable treatment option for those who are unable to achieve optimal asthma control, despite asthma education and training on inhaler technique. PMID- 17698896 TI - An update on the diagnosis of adrenal insufficiency and the use of corticotherapy in critical illness. AB - OBJECTIVE: To examine recent literature regarding corticotherapy in critically ill patients suffering from sepsis, acute respiratory distress syndrome (ARDS), and severe community-acquired pneumonia (SCAP). DATA SOURCES: Literature was identified through MEDLINE (1966-April 2007) using combinations of the key words hydrocortisone, adrenal insufficiency, acute respiratory distress syndrome, pneumonia, sepsis, and cortisol. Bibliographies of relevant articles were reviewed for additional citations. Presentations at recent critical care meetings were also incorporated. STUDY SELECTION AND DATA EXTRACTION: Articles were chosen based upon their relevance to the topics covered. DATA SYNTHESIS: Earlier studies using high-dose corticotherapy in the intensive care unit have shown treatment to be ineffective. Recent studies using extended courses of low-to-moderate doses of steroids have found favorable results; however, these results must be interpreted with caution due to limitations in the data. One trial of steroids in septic shock found a survival benefit in patients who failed to increase their baseline cortisol by greater than 9 microg/dL in response to adrenocorticotropic hormone, but these results were not reproduced in a subsequent Phase 3 trial. Recently, inaccuracies in measuring cortisol have been identified, making interpretation of cortisol concentrations difficult. A large-scale study failed to confirm a previously reported mortality benefit of corticotherapy in late ARDS, but preliminary data suggest a role for steroid treatment in early ARDS. Finally, a pilot study has found that hydrocortisone lowers morbidity and mortality in SCAP. CONCLUSIONS: Corticotherapy may be beneficial to some patients with sepsis. The decision to administer steroids in sepsis cannot be based on biochemical markers of adrenal function; rather, treatment should be considered in septic patients with vasopressor refractory hypotension. Although preliminary evidence suggests a role for steroids in early ARDS and SCAP, there are not enough data to suggest routine administration of steroids in these conditions. Additional studies are needed to assess corticotherapy in the critically ill. PMID- 17698897 TI - Anti-immunoglobulin E therapy with omalizumab for asthma. AB - OBJECTIVE: To evaluate data on anti-immunoglobulin E (anti-IgE) therapy for asthma. DATA SOURCES: Information was selected from PubMed from 1989 to May 2007 using the search term omalizumab and included randomized, controlled trials. These studies evaluated asthma treatment with omalizumab and focused on its efficacy, tolerability, and cost-effectiveness in this population. STUDY SELECTION AND DATA EXTRACTION: All randomized clinical trials were reviewed (23 were identified and 19 were included; 3 were not relevant and 1 contained duplicative data). Other articles using the search words anti-IgE therapy and cost-effectiveness were evaluated; relevant information was extracted. DATA SYNTHESIS: IgE-dependent mechanisms play an important role in the development and maintenance of airway inflammation in asthma. Omalizumab is a subcutaneously administered monoclonal anti-IgE antibody that reduces unbound IgE concentrations and promotes down-regulation of IgE receptors. Results from clinical trials in adults, adolescents, and children with poorly controlled IgE-mediated asthma have shown that omalizumab improves symptom control and allows patients to be managed with lower doses of inhaled corticosteroids (ICS). It has been well tolerated in clinical trials lasting as long as 52 weeks, but injection-site reactions are common (45% in omalizumab group vs 43% in placebo group) and anaphylaxis has occurred in 0.2% of patients. A consensus expert panel has recommended that omalizumab should be considered for patients 12 years of age or older with allergic asthma who are inadequately controlled on guideline-based therapy and require maintenance therapy with systemic corticosteroids or high-dose ICSs, or who have poor adherence to ICS therapy. CONCLUSIONS: Anti-IgE therapy provides an effective and generally safe approach to the treatment of patients with IgE mediated asthma who are not adequately controlled by conventional guideline-based medications. However, the potential benefit must be weighed against the cost and inconvenience of this new therapy. PMID- 17698898 TI - Impact of a protocol for prevention of ventilator-associated pneumonia. AB - BACKGROUND: Several interventions have been shown to be effective in reducing the incidence of ventilator-associated pneumonia (VAP), but their implementation in clinical practice has not gained widespread acceptance. OBJECTIVE: To determine the impact of a protocol that incorporates evidence-based interventions shown to reduce the frequency of VAP on the overall rate of VAP, early-onset VAP, and late onset VAP in the intensive care unit (ICU) of a tertiary care adult teaching hospital. METHODS: This pre- and postintervention observational study included mechanically ventilated patients admitted to the Montreal General Hospital ICU between November 2003 and May 2004 (preintervention) and between November 2004 and May 2005 (postintervention). A multidisciplinary prevention protocol was developed, implemented, and reinforced. Rates of VAP per 1000 ventilator-days were calculated pre- and postprotocol implementation for all patients, for patients with early-onset VAP, and for those with late-onset VAP. RESULTS: In the pre- and postintervention groups, 349 and 360 patients, respectively, were mechanically ventilated. Twenty-three VAP episodes occurred in 925 ventilator days (crude incidence rate 25 per 1000) in the preintervention period. Following implementation, the VAP rate decreased to 22 episodes in 988 ventilator-days (crude incidence rate 22.3 per 1000), corresponding to a relative reduction in rate of 10.8% (p < 0.001). The incidence of early-onset VAP decreased from 31.0 to 18.5 VAP per 1000 ventilator-days (p < 0.001), while the incidence of late onset VAP increased from 21.9 to 24.1 VAP per 1000 ventilator-days (p < 0.001). However, when all covariates were adjusted, the impact of the prevention protocol was not statistically significant. CONCLUSIONS: Implementation of a VAP prevention protocol incorporating evidence-based interventions reduced the crude incidence of VAP, early-onset VAP, and late-onset VAP. However, when covariates were adjusted, the beneficial effect was no longer observed. Further research is needed to assess the impact of such measures on VAP, early-onset VAP, and late onset VAP. PMID- 17698899 TI - Features of natural and gonadotropin-releasing hormone antagonist-induced corpus luteum regression and effects of in vivo human chorionic gonadotropin. AB - CONTEXT: The natural process of luteolysis and luteal regression is induced by withdrawal of gonadotropin support. OBJECTIVE: The objectives of this study were: 1) to compare the functional changes and apoptotic features of natural human luteal regression and induced luteal regression; 2) to define the ultrastructural characteristics of the corpus luteum at the time of natural luteal regression and induced luteal regression; and 3) to examine the effect of human chorionic gonadotropin (hCG) on the steroidogenic response and apoptotic markers within the regressing corpus luteum. DESIGN: Twenty-three women with normal menstrual cycles undergoing tubal ligation donated corpus luteum at specific stages in the luteal phase. Some women received a GnRH antagonist prior to collection of corpus luteum, others received an injection of hCG with or without prior treatment with a GnRH antagonist. MAIN OUTCOME MEASURE: Main outcome measures were plasma hormone levels and analysis of excised luteal tissue for markers of apoptosis, histology, and ultrastructure. RESULTS: The progesterone and estradiol levels, corpus luteum DNA, and protein contents in induced luteal regression resembled those of natural luteal regression. hCG treatment raised progesterone and estradiol in both natural luteal regression and induced luteal regression. The increase in apoptosis detected in induced luteal regression by cytochrome c in the cytosol, activated caspase-3, and nuclear DNA fragmentation, was similar to that observed in natural luteal regression. The antiapoptotic protein Bcl-2 was significantly lower during natural luteal regression. The proapoptotic proteins Bax and Bak were at a constant level. Apoptotic and nonapoptotic death of luteal cells was observed in natural luteal regression and induced luteal regression at the ultrastructural level. hCG prevented apoptotic cell death, but not autophagy. CONCLUSION: The low number of apoptotic cells disclosed and the frequent autophagocytic suggest that multiple mechanisms are involved in cell death at luteal regression. hCG restores steroidogenic function and restrains the apoptotic process, but not autophagy. PMID- 17698900 TI - The dipeptidyl peptidase 4 inhibitor vildagliptin does not accentuate glibenclamide-induced hypoglycemia but reduces glucose-induced glucagon-like peptide 1 and gastric inhibitory polypeptide secretion. AB - BACKGROUND/AIMS: Inhibition of dipeptidyl peptidase 4 by vildagliptin enhances the concentrations of the active form of the incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). The present study asked whether vildagliptin accentuates glibenclamide-induced hypoglycemia or affects endogenous secretion of GLP-1 and GIP after an oral glucose tolerance test. METHODS: There were 16 healthy male subjects studied on four occasions after an overnight fast in a double-blind, four-way crossover study. In random order, vildagliptin (100 mg) or placebo, with and without glibenclamide (5 mg), was administered 30 min before 75 g oral glucose. Blood was sampled to measure glucose, and total (sum of active and inactive) GLP-1 and GIP. Statistical evaluation was done using repeated-measures ANOVA. RESULTS: Glibenclamide provoked hypoglycemia (or= 0.22; P < 0.05), with the HMW isoform also positively correlated with high-density lipoprotein cholesterol (r = 0.19; P = 0.036). In contrast, hexameric and trimeric adiponectin were significantly associated with only body mass index (r = -0.23; P = 0.0102) and mid-upper arm circumference (r = 0.21; P = 0.039), respectively. On separate forward stepwise multiple linear regression analyses, fasting glucose and ALT emerged as independent, negative covariates of both total and HMW adiponectin, whereas no independent covariates of hexameric and trimeric adiponectin were identified. Furthermore, after adjustment for age, gender, and diabetes, mean ALT was highest in subjects in the lowest tertile of HMW adiponectin, followed in turn by the middle and highest tertiles, respectively (trend P = 0.028). CONCLUSIONS: HMW adiponectin, but not hexameric or trimeric, tracks with the metabolic correlates of total adiponectin. Furthermore, an independent inverse association exists between ALT and HMW adiponectin. PMID- 17698904 TI - Changes in serum anti-mullerian hormone level during low-dose recombinant follicular-stimulating hormone therapy for anovulation in polycystic ovary syndrome. AB - CONTEXT: We previously hypothesized that the excess of anti-mullerian hormone (AMH) at the level of selectable follicles could be involved in the follicular arrest of polycystic ovary syndrome (PCOS), mainly through inhibition of FSH effect on aromatase expression. OBJECTIVE: In this study, we investigated whether a decrease in the serum AMH level was concomitant to the appearance of a dominant follicle induced by administration of mild amounts of exogenous FSH in women with PCOS. DESIGN: A total of 30 women with PCOS in whom anovulation was resistant to clomiphene citrate received recombinant FSH using the low-dose step-up protocol during only one cycle. Serum levels of estradiol, AMH, LH, FSH, inhibin B, and ultrasound parameters were assessed twice a week until 3 d after the appearance of one or more dominant follicle(s). RESULTS: The day of dominance (d 0) was defined by the appearance of at least one follicle more than 10 mm growing 2 mm/d. From d -14 before dominance to d +3, the mean serum AMH level and the 2- to 5-mm follicle number at ultrasound declined steadily, although not significantly by ANOVA. Mean AMH relative values (100% being the value at d 0) declined significantly (P = 0.04), from 125 +/- 32% at d -14 to 105 +/- 15% at d -4. Within the same time lag, the mean FSH relative values increased from 91 +/- 17% to 107 +/- 19% (P = 0.013). In the 87 samples obtained from d -14 to -4, absolute values of AMH were positively and negatively associated with those of LH and FSH, respectively, in an independent manner (P = 0.009 and P = 0.03, respectively). In the 55 samples collected at d 0 and +3, they were negatively correlated to those of estradiol (r = -0.272; P < 0.05). CONCLUSIONS: These data suggest that in anovulatory women with PCOS, gently increasing the serum FSH level reduces the AMH excess, thus relieving the inhibition from the latter on aromatase expression by selectable follicles and allowing the emergence of a dominant follicle. PMID- 17698905 TI - Exercise alone reduces insulin resistance in obese children independently of changes in body composition. AB - CONTEXT: The number of obese children with insulin resistance and type 2 diabetes is increasing, but the best management strategy is not clear. OBJECTIVE: The objective of this study was to assess the effect of a structured 8-wk exercise training program on insulin resistance and changes in body composition in obese children. DESIGN: The study was 8 wk of structured supervised exercise intervention with outcome measures before and after the exercise period. SUBJECTS: Fourteen obese children (12.70 +/- 2.32 yr; eight male, six female) with high fasting insulin levels were enrolled into the study. INTERVENTION: INTERVENTION consisted of 8 wk of supervised circuit-based exercise training, composed of three fully supervised 1-h sessions per week. OUTCOME MEASURES: Outcome measures were assessed pretraining program and posttraining program and included insulin sensitivity (euglycemic-hyperinsulinemic clamp studies), fasting insulin and glucose levels, body composition using dual energy x-ray absorptiometry scan, lipid profile, and liver function tests. RESULTS: Insulin sensitivity improved significantly after 8 wk of training (M(lbm) 8.20 +/- 3.44 to 10.03 +/- 4.33 mg/kg.min, P < 0.05). Submaximal exercise heart rate responses were significantly lower following the training (P < 0.05), indicating an improvement in cardiorespiratory fitness. Dual energy x-ray absorptiometry scans revealed no differences in lean body mass or abdominal fat mass. CONCLUSION: An 8 wk exercise training program increases insulin sensitivity in obese children, and this improvement occurred in the presence of increased cardiorespiratory fitness but is independent of measurable changes in body composition. PMID- 17698906 TI - Abnormal preantral folliculogenesis in polycystic ovaries is associated with increased granulosa cell division. AB - CONTEXT: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women, but its etiology remains obscure. Recent data suggest that an intrinsic abnormality of early follicle development in the ovary is key to the pathogenesis of PCOS. We have recently found that in PCOS the proportion of primordial follicles is decreased with a reciprocal increase in the proportion of primary follicles. OBJECTIVE: Our aim was to examine whether the accelerated transition of follicles from primordial to primary stages in polycystic ovaries (PCO) is due to increased granulosa cell (GC) division. DESIGN: This study is a comparison of expression of minichromosome maintenance protein 2 (MCM2) (present in the nuclei of cells that are licensed to divide) in archive tissue from normal and PCO. SETTING: This is a laboratory-based study. PATIENTS: There were 16 women with regular cycles (six with normal and 10 with PCO) and five anovulatory women with PCO, classified histologically, with reference to menstrual history and ultrasound. MAIN OUTCOME MEASURES: The presence of MCM2 expression in the GCs of 1,371 follicles was determined. RESULTS: GC proliferation was increased in anovulatory PCO compared with both normal and ovulatory PCO, with an increased proportion of preantral follicles with MCM2-positive GCs (P 4) (67.0%; P = 0.003). The A76A at risk T allele was also associated with overeating during meals (P = 0.02) in an additional group of 102 nonobese children. None of the MCHR2 variants, including the A76A SNP, showed association with adult severe obesity, although a trend for association of the T allele of this variant with food disinhibition (P = 0.06) and higher hunger (P = 0.09) was found. This variant was not associated with childhood obesity in an independent case-control study, including 1,573 subjects (P = 0.98). Moreover, the A76A SNP did not explain the linkage on the 6q locus. CONCLUSION: Our results altogether suggest that MCHR2 is not a major contributor to polygenic obesity and support a modest effect of the A76A SNP on food intake abnormalities in childhood. PMID- 17698914 TI - CCR7 mediates the migration of Foxp3+ regulatory T cells to the paracortical areas of peripheral lymph nodes through high endothelial venules. AB - Thymus-derived forkhead box p3(+) naturally occurring regulatory T cells (nTreg) are thought to circulate throughout the body to maintain peripheral immunological self-tolerance through interactions with dendritic cells (DCs), resulting in regulation of conventional T cells. However, the chemokine receptors, which are putatively involved in the in vivo migration of nTreg, have not been fully established. Here, we demonstrated that lymph node nTreg preferentially migrated to the paracortical area of lymph nodes after adoptive transfer, where they were observed to make contact frequently with CD8alpha(+) DCs and CD8alpha(-) CD11b(-) DCs. This migration of nTreg to the paracortical areas was impaired severely when cells were prepared from CCR7-deficient mice. However, to some extent, CCR7 independent migration of nTreg in such CCR7-deficient mice was also observed, but this occurred mainly in the medullary high endothelial venules. Taken together, these data provide the evidence that CCR7 mediates nTreg migration to the paracortical areas of lymph nodes under steady-state conditions; however, CCR7 independent migration also takes place in the medulla. PMID- 17698915 TI - Prostaglandin E2 is a key factor for monocyte-derived dendritic cell maturation: enhanced T cell stimulatory capacity despite IDO. AB - The exclusive ability of dendritic cells (DCs) to stimulate primary and secondary immune responses favors the use of antigen-loaded human monocyte-derived DCs (MoDCs) in vaccinations against tumors. Previous studies demonstrated that PGE(2) is fundamental during MoDC maturation to facilitate migration toward lymph node derived chemokines. A recent study challenged the use of PGE(2), as PGE(2) induced IDO in mature MoDCs. In MoDCs compatible for clinical use, we now demonstrate that PGE(2) is responsible for IDO induction if matured by soluble CD40 ligand, LPS, or cytokines. In contrast, IDO expression in MoDCs matured by TLR3 triggering occurs independently of PGE(2). It is surprising that despite active IDO protein, MoDCs matured with PGE(2) display a greater potential to stimulate naive CD4(+) and CD8(+) T cell proliferation, which is not increased further by IDO inhibition. Moreover, we found elevated levels of tryptophanyl tRNA-synthetase (TTS) in T cells cultured with PGE(2)-matured MoDCs. Our data demonstrate that PGE(2) induces IDO in MoDCs but that T cell-stimulating capacities of PGE(2)-matured MoDCs overcome IDO activity, probably through TTS induction. As PGE(2) is critical for DC migration and enhances the capability of MoDCs to induce T cell proliferation, we highly recommend supplementing DC maturation stimuli with PGE(2) for use in clinical trials. PMID- 17698916 TI - Mycoplasma contaminants present in exosome preparations induce polyclonal B cell responses. AB - Exosome fractions of dendritic cells (DC) produced in long-term cultures (LTC) were found to contain Mycoplasma contaminants. In this study, Mycoplasma infected, -uninfected, and -reinfected cultures of DC and control cell lines have been compared for their capacity to activate lymphocytes. Using differential centrifugation, size fractionation, and inhibition assays, it has been possible to map Mycoplasma to the exosome or vesicle fraction purified from culture supernatant (CSN). Mycoplasma fractions were shown to induce proliferation of B and not T cells. The B cell response was sensitive to mitomycin C and primaquine, both known antibiotics, but resistant to protease and DNase, suggesting a role for lipoproteins. Mycoplasma-contaminated exosome fractions of LTC-DC were potent mitogens for naive B cells and promoted Ig secretion. In contrast to the polyclonal B cell mitogen LPS, they were unable to promote Ig isotype switching. They induced polyclonal activation of all B cell subsets, including naive B cells, the T1 and T2 subsets of transitional B cells, marginal zone (MZ), and follicular (FO) B cells. The B cell proliferative response was not antigen specific and occurred independently of T cell help. Implications for autoimmune sequelae associated with Mycoplasma infection are discussed along with the possibility that primaquine could be an effective treatment for Mycoplasma infection in humans. This study highlights the close association between exosomes and infectious agents like Mycoplasma and cautions about purification procedures for preparation of exosomes for studies on immunity. PMID- 17698917 TI - Securinine, a GABAA receptor antagonist, enhances macrophage clearance of phase II C. burnetii: comparison with TLR agonists. AB - Innate immune cell stimulation represents a complementary approach to vaccines and antimicrobial drugs to counter infectious disease. We have used assays of macrophage activation and in vitro and in vivo phase II Coxiella burnetii infection models to compare and contrast the activity of a novel innate immune cell agonist, securinine, with known TLR agonists. As expected, TLR agonists, such as LPS (TLR4) and fibroblast-stimulating lipopeptide-1 (FSL-1; TLR2), induced macrophage activation and increased macrophage killing of phase II C. burnetii in vitro. FSL-1 also induced accelerated killing of C. burnetii in vivo. Securinine, a gamma-aminobutyric acid type A receptor antagonist, was found to induce TLR-independent macrophage activation in vitro, leading to IL-8 secretion, L-selectin down-regulation, and CD11b and MHC Class II antigen up-regulation. As seen with the TLR agonists, securinine also induced accelerated macrophage killing of C. burnetii in vitro and in vivo. In summary, as predicted by the literature, TLR agonists enhance macrophage killing of phase II C. burnetii in vitro, and at least for TLR2 agonists, this activity occurs in vivo as well. Securinine represents a novel macrophage agonist, which has similar effects as TLR agonists in this model yet apparently, does not act through known TLRs. Securinine has minimal toxicity in vivo, suggesting it or structurally similar compounds may represent novel, therapeutic adjuvants, which increase resistance to intracellular pathogens. PMID- 17698918 TI - Ninein is released from the centrosome and moves bi-directionally along microtubules. AB - Cell-to-cell contact and polarisation of epithelial cells involve a major reorganisation of the microtubules and centrosomal components. The radial microtubule organisation is lost and an apico-basal array develops that is no longer anchored at the centrosome. This involves not only the relocation of microtubules but also of centrosomal anchoring proteins to apical non-centrosomal sites. The relocation of microtubule minus-end-anchoring proteins such as ninein to the apical sites is likely to be essential for the assembly and stabilisation of the apico-basal arrays in polarised epithelial cells. In this study, we establish that ninein is highly dynamic and that, in epithelial cells, it is present not only at the centrosome but also in the cytoplasm as distinct speckles. Live-cell imaging reveals that GFP-ninein speckles are released from the centrosome and move in a microtubule-dependent manner within the cytoplasm and thus establishes that epithelial cells possess the mechanical means for relocation of ninein to non-centrosomal anchoring sites. We also provide evidence for the deployment of ninein speckles to apical anchoring sites during epithelial differentiation in both an in situ tissue and an in vitro culture system. In addition, the findings suggest that the non-centrosomal microtubule anchoring sites associate with adherens junctions in polarised epithelial cells. PMID- 17698919 TI - Rab27a and MyoVa are the primary Mlph interactors regulating melanosome transport in melanocytes. AB - Melanosome transport in melanocytes is a model system for the study of cytoskeletal regulation of intracellular transport. Melanophilin (Mlph) is a Rab27a- and myosin Va (MyoVa)-binding protein that regulates this process. Using yeast two-hybrid screening, we identified MT plus-end binding protein (EB1) as a melanocyte-expressed Mlph-interacting protein. To address the role of EB1 versus Rab27a and MyoVa interactions in Mlph targeting and function, we used siRNA and Mlph mutations to specifically disrupt each interaction in cultured melanocytes. Using the Mlph R35W mutant that blocks Mlph-Rab27a interaction and Rab27a siRNA we show this interaction is required for melanosome targeting and stability of Mlph. Mutants and siRNA that affect Mlph-MyoVa and Mlph-EB1 interactions reveal that while neither MyoVa nor EB1 affect Mlph targeting to melanosomes, MyoVa but not EB1 interaction is required for transport of melanosomes to peripheral dendrites. We propose that Mlph is targeted to and/or stabilised on melanosomes by Rab27a, and then recruits MyoVa, which provides additional stability to the complex and allows melanosomes to transfer from MT to actin-based transport and achieve peripheral distribution. EB1 appears to be non-essential to this process in cultured melanocytes, which suggests that it plays a redundant role and/or is required for melanocyte/keratinocyte contacts and melanosome transfer. PMID- 17698920 TI - Regulation of meiotic cohesion and chromosome core morphogenesis during pachytene in Drosophila oocytes. AB - During meiosis, cohesion between sister chromatids is required for normal levels of homologous recombination, maintenance of chiasmata and accurate chromosome segregation during both divisions. In Drosophila, null mutations in the ord gene abolish meiotic cohesion, although how ORD protein promotes cohesion has remained elusive. We show that SMC subunits of the cohesin complex colocalize with ORD at centromeres of ovarian germ-line cells. In addition, cohesin SMCs and ORD are visible along the length of meiotic chromosomes during pachytene and remain associated with chromosome cores following DNase I digestion. In flies lacking ORD activity, cohesin SMCs fail to accumulate at oocyte centromeres. Although SMC1 and SMC3 localization along chromosome cores appears normal during early pachytene in ord mutant oocytes, the cores disassemble as meiosis progresses. These data suggest that cohesin loading and/or accumulation at centromeres versus arms is under differential control during Drosophila meiosis. Our experiments also reveal that the alpha-kleisin C(2)M is required for the assembly of chromosome cores during pachytene but is not involved in recruitment of cohesin SMCs to the centromeres. We present a model for how chromosome cores are assembled during Drosophila meiosis and the role of ORD in meiotic cohesion, chromosome core maintenance and homologous recombination. PMID- 17698921 TI - Differential targeting of secretory lysosomes and recycling endosomes in mast cells revealed by patterned antigen arrays. AB - Polarized response towards a contact interface is a common theme in intercellular signaling. To visualize spatial regulation of stimulated secretion within a contact region, we exposed IgE-sensitized rat basophilic leukemia (RBL) mast cells to a surface that was patterned on the microm scale with hapten-containing lipid bilayers to activate cell surface IgE-receptor complexes. We find that, within 10 minutes of stimulation, fusion of individual secretory lysosomes is targeted towards the cell-substrate interface, but is spatially segregated from the patterned bilayers and receptor signaling complexes. By contrast, stimulated outward trafficking of recycling endosomes is preferentially targeted towards the patterned bilayers. High spatial resolution of both antigen presentation in these arrays and detection of exocytotic events provides direct evidence for the heterogeneity of polarized responses. PMID- 17698922 TI - The distinct roles of Ras and Rac in PI 3-kinase-dependent protrusion during EGF stimulated cell migration. AB - Cell migration involves the localized extension of actin-rich protrusions, a process that requires Class I phosphoinositide 3-kinases (PI 3-kinases). Both Rac and Ras have been shown to regulate actin polymerization and activate PI 3 kinase. However, the coordination of Rac, Ras and PI 3-kinase activation during epidermal growth factor (EGF)-stimulated protrusion has not been analyzed. We examined PI 3-kinase-dependent protrusion in MTLn3 rat adenocarcinoma cells. EGF stimulated phosphatidyl-inositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P(3)] levels showed a rapid and persistent response, as PI 3-kinase activity remained elevated up to 3 minutes. The activation kinetics of Ras, but not Rac, coincided with those of leading-edge PtdIns(3,4,5)P(3) production. Small interfering RNA (siRNA) knockdown of K-Ras but not Rac1 abolished PtdIns(3,4,5)P(3) production at the leading edge and inhibited EGF-stimulated protrusion. However, Rac1 knockdown did inhibit cell migration, because of the inhibition of focal adhesion formation in Rac1 siRNA-treated cells. Our data show that in EGF-stimulated MTLn3 carcinoma cells, Ras is required for both PtdIns(3,4,5)P(3) production and lamellipod extension, whereas Rac1 is required for formation of adhesive structures. These data suggest an unappreciated role for Ras during protrusion, and a crucial role for Rac in the stabilization of protrusions required for cell motility. PMID- 17698923 TI - The Drosophila homolog of the Exo84 exocyst subunit promotes apical epithelial identity. AB - The polarized architecture of epithelial tissues involves a dynamic balance between apical and basolateral membrane domains. Here we show that epithelial polarity in the Drosophila embryo requires the exocyst complex subunit homolog Exo84. Exo84 activity is essential for the apical localization of the Crumbs transmembrane protein, a key determinant of epithelial apical identity. Adherens junction proteins become mislocalized at the cell surface in Exo84 mutants in a pattern characteristic of defects in apical, but not basolateral, components. Loss of Crumbs from the cell surface precedes the disruption of Bazooka and Armadillo localization in Exo84 mutants. Moreover, Exo84 mutants display defects in apical cuticle secretion that are similar to crumbs mutants and are suppressed by a reduction in the basolateral proteins Dlg and Lgl. In Exo84 mutants at advanced stages of epithelial degeneration, apical and adherens junction proteins accumulate in an expanded recycling endosome compartment. These results suggest that epithelial polarity in the Drosophila embryo is actively maintained by exocyst-dependent apical localization of the Crumbs transmembrane protein. PMID- 17698924 TI - Macromolecule biosynthesis: a key function of sleep. AB - The function(s) of sleep remains a major unanswered question in biology. We assessed changes in gene expression in the mouse cerebral cortex and hypothalamus following different durations of sleep and periods of sleep deprivation. There were significant differences in gene expression between behavioral states; we identified 3,988 genes in the cerebral cortex and 823 genes in the hypothalamus with altered expression patterns between sleep and sleep deprivation. Changes in the steady-state level of transcripts for various genes are remarkably common during sleep, as 2,090 genes in the cerebral cortex and 409 genes in the hypothalamus were defined as sleep specific and changed (increased or decreased) their expression during sleep. The largest categories of overrepresented genes increasing expression with sleep were those involved in biosynthesis and transport. In both the cerebral cortex and hypothalamus, during sleep there was upregulation of multiple genes encoding various enzymes involved in cholesterol synthesis, as well as proteins for lipid transport. There was also upregulation during sleep of genes involved in synthesis of proteins, heme, and maintenance of vesicle pools, as well as antioxidant enzymes and genes encoding proteins of energy-regulating pathways. We postulate that during sleep there is a rebuilding of multiple key cellular components in preparation for subsequent wakefulness. PMID- 17698925 TI - Recombinant inbred strain panels: a tool for systems genetics. PMID- 17698926 TI - Quantitative trait locus for seizure susceptibility on mouse chromosome 5 confirmed with reciprocal congenic strains. AB - Multiple quantitative trait locus (QTL) mapping studies designed to localize seizure susceptibility genes in C57BL/6 (B6, seizure resistant) and DBA/2 (D2, seizure susceptible) mice have detected a significant effect originating from midchromosome 5. To confirm the presence and refine the position of the chromosome 5 QTL for maximal electroshock seizure threshold (MEST), reciprocal congenic strains between B6 and D2 mice were created by a DNA marker-assisted backcross breeding strategy and studied with respect to changes in MEST. A genomic interval delimited by marker D5Mit75 (proximal to the acromere) and D5Mit403 (distal to the acromere) was introgressed for 10 generations. A set of chromosome 5 congenic strains produced by an independent laboratory was also studied. Comparison of MEST between congenic and control (parental genetic background) mice indicates that genes influencing this trait were captured in all strains. Thus, mice from strains having D2 alleles from chromosome 5 on a B6 genetic background exhibit significantly lower MEST compared with control littermates, whereas congenic mice harboring B6 chromosome 5 alleles on a D2 genetic background exhibit significantly higher MEST compared with control littermates. Combining data from all congenic strains, we conclude that the gene(s) underlying the chromosome 5 QTL for MEST resides in the interval between D5Mit108 (26 cM) and D5Mit278 (61 cM). Generation of interval-specific congenic strains from the primary congenic strains described here may be used to achieve high-resolution mapping of the chromosome 5 gene(s) that contributes to the large difference in seizure susceptibility between B6 and D2 mice. PMID- 17698927 TI - Circulating chemokines accurately identify individuals with clinically significant atherosclerotic heart disease. AB - Serum inflammatory markers correlate with outcome and response to therapy in subjects with cardiovascular disease. However, current individual markers lack specificity for the diagnosis of coronary artery disease (CAD). We hypothesize that a multimarker proteomic approach measuring serum levels of vascular derived inflammatory biomarkers could reveal a "signature of disease" that can serve as a highly accurate method to assess for the presence of coronary atherosclerosis. We simultaneously measured serum levels of seven chemokines [CXCL10 (IP-10), CCL11 (eotaxin), CCL3 (MIP1 alpha), CCL2 (MCP1), CCL8 (MCP2), CCL7 (MCP3), and CCL13 (MCP4)] in 48 subjects with clinically significant CAD ("cases") and 44 controls from the ADVANCE Study. We applied three classification algorithms to identify the combination of variables that would best predict case-control status and assessed the diagnostic performance of these models with receiver operating characteristic (ROC) curves. The serum levels of six chemokines were significantly higher in cases compared with controls (P < 0.05). All three classification algorithms entered three chemokines in their final model, and only logistic regression selected clinical variables. Logistic regression produced the highest ROC of the three algorithms (AUC = 0.95; SE = 0.03), which was markedly better than the AUC for the logistic regression model of traditional risk factors of CAD without (AUC = 0.67; SE = 0.06) or with CRP (AUC = 0.68; SE = 0.06). A combination of serum levels of multiple chemokines identifies subjects with clinically significant atherosclerotic heart disease with a very high degree of accuracy. These results need to be replicated in larger cross-sectional studies and their prognostic value explored. PMID- 17698928 TI - A new efficient statistical test for detecting variability in the gene expression data. AB - DNA microarray technology allows researchers to monitor the expressions of thousands of genes under different conditions. The detection of differential gene expression under two different conditions is very important in microarray studies. Microarray experiments are multi-step procedures and each step is a potential source of variance. This makes the measurement of variability difficult because approach based on gene-by-gene estimation of variance will have few degrees of freedom. It is highly possible that the assumption of equal variance for all the expression levels may not hold. Also, the assumption of normality of gene expressions may not hold. Thus it is essential to have a statistical procedure which is not based on the normality assumption and also it can detect genes with differential variance efficiently. The detection of differential gene expression variance will allow us to identify experimental variables that affect different biological processes and accuracy of DNA microarray measurements.In this article, a new nonparametric test for scale is developed based on the arctangent of the ratio of two expression levels. Most of the tests available in literature require the assumption of normal distribution, which makes them inapplicable in many situations, and it is also hard to verify the suitability of the normal distribution assumption for the given data set. The proposed test does not require the assumption of the distribution for the underlying population and hence makes it more practical and widely applicable. The asymptotic relative efficiency is calculated under different distributions, which show that the proposed test is very powerful when the assumption of normality breaks down. Monte Carlo simulation studies are performed to compare the power of the proposed test with some of the existing procedures. It is found that the proposed test is more powerful than commonly used tests under almost all the distributions considered in the study. A microarray data is used to illustrate the working of the proposed test. Results indicate that the proposed test is very powerful in detecting the smallest change in differential expression variance with high degree of confidence than some of its competitors. PMID- 17698929 TI - A statistical modelling approach for the analysis of TMD chronic pain data. AB - This paper presents a discrete mixture model as a suitable approach for the analysis of chronic pain data, when they are expressed by means of ordered scores (ratings). The model is developed to allow for covariates effects; parameters estimation by maximum likelihood (using an E-M algorithm) and related inferential issues are discussed. A case-study concerning the assessment of pain (for a given pathology) and the effect of patients' covariates (e.g., gender, depression state) is illustrated. Besides, the same covariates are considered also for explaining the disruption in everyday lifestyle due to the chronic pain condition. PMID- 17698930 TI - Evaluation of change in CD4+ cell counts in AIDS clinical trials. AB - To evaluate the antiretroviral activity of antiretroviral agents and to compare the effects of two different antiretroviral agents, we propose a non-parametric mixed-effects model to investigate change of CD4+ counts. The proposed model and methods are applied to analyse the data from PACTG345 study. Population and individual patterns of change of CD4+ counts and a reference band are obtained. Our results indicate that treatment with high-dose ritonavir is significantly superior compared with low-dose ritonavir. PMID- 17698931 TI - Ensemble clustering method based on the resampling similarity measure for gene expression data. AB - The rapid development of microarray technologies enabled the monitoring of expression levels of thousands of genes simultaneously. Microarray technology has great potential for creating an enormous amount of data in a short time, and now becomes a new tool for studying such broad problems as classification of tumors in biology and medical science. Many statistical methods are available for analysing and systematizing these complex data into meaningful information, and one of the main goals in analysing gene expression data is the detection of samples or genes with similar expression patterns. In this paper, we developed a new clustering method of class discovery in a dataset. The performances of the new and existing methods were compared using both simulated data and real gene expression data. The proposed method was generally found to give more accurate cluster numbers and cluster assignments for individual objects than the three well-known general clustering methods such as agglomerative and divisive hierarchical clustering (HC) and self-organizing map (SOM). It also gave better results than the three consensus clustering methods based on agglomerative and divisive HC and SOM. PMID- 17698932 TI - Spatio-temporal modeling of perimetric test data. AB - This work describes the application of a spatio-temporal modeling to the study of glaucoma, a very serious ocular illness. The aim of this modeling is to solve various significant medical problems, namely the forecasting of future observations, the classification of observations as normal or defective, and the simulation of new longitudinal data sets. In order to ascertain whether a patient suffers from glaucoma, a perimetry is performed. The output of a perimetry is called a visual field and consists of a map with 52 numerical values plotted on a regular grid. In this work, a data set of healthy patients' visual fields is used. The work begins with an exploratory spatial data analysis. A semi parametric approach is used to model the mean, and the variogram is fitted using a Matern function. Once the spatial structure has been analysed, the spatial mean is subtracted from all the observations in the data set and the spatio-temporal correlation of the residuals is explored. All this information is used to build a space-time model, the parameters of which are estimated by maximum likelihood. Different methods are used to check the goodness of fit. PMID- 17698933 TI - Efficacy studies of malaria treatments in Africa: efficient estimation with missing indicators of failure. AB - The effect of missing data in causal inference problems is widely recognized. In malaria drug efficacy studies, it is often difficult to distinguish between new and old infections after treatment, resulting in indeterminate outcomes. Methods that adjust for possible bias from missing data include a variety of imputation procedures (extreme case analysis, hot-deck, single and multiple imputation), weighting methods, and likelihood based methods (data augmentation, EM procedures and their extensions). In this article, we focus our discussion on multiple imputation and two weighting procedures (the inverse probability weighted and the doubly robust (DR) extension), comparing the methods' applicability to the efficient estimation of malaria treatment effects. Simulation studies indicate that DR estimators are generally preferable because they offer protection to misspecification of either the outcome model or the missingness model. We apply the methods to analyze malaria efficacy studies from Uganda. PMID- 17698934 TI - A general approach to evaluating agreement between two observers or methods of measurement from quantitative data with replicated measurements. AB - We present a general approach to the definition and estimation of coefficients for evaluating agreement between two fixed methods of measurements or human observers. The measured variable is assumed to be continuous with a finite second moment. No other distributional assumptions are made. We introduce the term ;disagreement function' for the function of the observations that is used to quantify the extent of disagreement between the two measurements made on the same subject. The proposed inter-methods agreement coefficients compare the disagreement between measurements made by different methods on the same subject to the corresponding disagreement between replicated measurements made by the same method. Therefore, the new coefficients require data with replications readings. We propose inter-methods agreement coefficients for two practical situations involving two methods that have a measurement error: 1) comparison of a new method to a gold standard (or a reference method), and 2) comparison of two methods where neither method is considered a gold standard. We consider three disagreement functions based on the differences between two measurements: 1) the mean squared difference, 2) the mean absolute difference and 3) the mean relative difference. We then derive non-parametric estimates for the various agreement coefficients. Our approach is illustrated using data from a study comparing systolic blood pressure measurements by a human observer and an automatic monitor. The performance of the new estimates is assessed via stochastic simulations. PMID- 17698935 TI - Modeling influenza incidence for the purpose of on-line monitoring. AB - We describe and discuss statistical models of Swedish influenza data, with special focus on aspects which are important in on-line monitoring. Earlier suggested statistical models are reviewed and the possibility of using them to describe the variation in influenza-like illness (ILI) and laboratory diagnoses (LDI) is discussed. Exponential functions were found to work better than earlier suggested models for describing the influenza incidence. However, the parameters of the estimated functions varied considerably between years. For monitoring purposes we need models which focus on stable indicators of the change at the outbreak and at the peak.For outbreak detection we focus on ILI data. Instead of a parametric estimate of the baseline (which could be very uncertain), we suggest a model utilizing the monotonicity property of a rise in the incidence. For ILI data at the outbreak, Poisson distributions can be used as a first approximation.To confirm that the peak has occurred and the decline has started, we focus on LDI data. A Gaussian distribution is a reasonable approximation near the peak. In view of the variability of the shape of the peak, we suggest that a detection system use the monotonicity properties of a peak. PMID- 17698936 TI - A review of modern multiple hypothesis testing, with particular attention to the false discovery proportion. AB - In the last decade a growing amount of statistical research has been devoted to multiple testing, motivated by a variety of applications in medicine, bioinformatics, genomics, brain imaging, etc. Research in this area is focused on developing powerful procedures even when the number of tests is very large. This paper attempts to review research in modern multiple hypothesis testing with particular attention to the false discovery proportion, loosely defined as the number of false rejections divided by the number of rejections. We review the main ideas, stepwise and augmentation procedures; and resampling based testing. We also discuss the problem of dependence among the test statistics. Simulations make a comparison between the procedures and with Bayesian methods. We illustrate the procedures in applications in DNA microarray data analysis. Finally, few possibilities for further research are highlighted. PMID- 17698937 TI - The zero-inflated negative binomial regression model with correction for misclassification: an example in caries research. AB - Zero-inflated models for count data are becoming quite popular nowadays and are found in many application areas, such as medicine, economics, biology, sociology and so on. However, in practice these counts are often prone to measurement error which in this case boils down to misclassification. Methods to deal with misclassification of counts have been suggested recently, but only for the binomial model and the Poisson model. Here we look at a more complex model, that is, the zero-inflated negative binomial, and illustrate how correction for misclassification can be achieved. Our approach is illustrated on the dmft-index which is a popular measure for caries experience in caries research. An extra problem was the fact that several dental examiners were involved in scoring caries experience. Using our example, we illustrate how a non-differential misclassification process for each examiner can lead to differential misclassification overall. PMID- 17698938 TI - A Bayesian approach to assess interaction between known risk factors: the risk of lung cancer from exposure to asbestos and smoking. AB - We review the literature on the combined effect of asbestos exposure and smoking on lung cancer, and explore a Bayesian approach to assess evidence of interaction. Previous approaches have focussed on separate tests for an additive or multiplicative relation. We extend these approaches by exploring the strength of evidence for either relation using approaches which allow the data to choose between both models. We then compare the different approaches. PMID- 17698939 TI - Optimal designs for clinical trials with second-order polynomial treatment effects. AB - The effect of adding intermediate measures on the efficiency of treatment effect estimation is considered for a second-order polynomial treatment effect, equidistant time-points, different covariance structures and two optimality criteria, assuming either a fixed sample size or a fixed budget. The benefit of adding intermediate measures (at the expense of subjects) depends strongly on the assumed covariance structure and is hardly affected by the two used optimality criteria (Ds or c). For a fixed sample size, the increase in efficiency by adding intermediate measures is large for a compound symmetric structure and small for a first-order auto-regressive structure. For a first-order auto-regressive structure with measurement error, the results depend on the covariance parameter values. For a fixed budget and linear cost function, the design with only three measures per subject is often highly efficient. If the structure resembles compound symmetry and the cost per subject is eight or more times larger than the cost per repeated measure, however, more than three measures are required to obtain highly efficient treatment effect estimators. If the covariance structure is unknown, the optimal design based on a first-order auto-regressive structure with measurement error is preferable in terms of robustness against misspecification of the covariance structure. Given a design with three repeated measures and a second-order polynomial treatment effect, equidistant time-points are either optimal (Ds-) or highly efficient (c-optimality criterion). The results are illustrated by a practical example. PMID- 17698940 TI - Relative efficiency of unequal cluster sizes for variance component estimation in cluster randomized and multicentre trials. AB - Cluster randomized and multicentre trials evaluate the effect of a treatment on persons nested within clusters, for instance patients within clinics or pupils within schools. Although equal sample sizes per cluster are generally optimal for parameter estimation, they are rarely feasible. This paper addresses the relative efficiency (RE) of unequal versus equal cluster sizes for estimating variance components in cluster randomized trials and in multicentre trials with person randomization within centres, assuming a quantitative outcome. Starting from maximum likelihood estimation, the RE is investigated numerically for a range of cluster size distributions. An approximate formula is presented for computing the RE as a function of the mean and variance of cluster sizes and the intraclass correlation. The accuracy of this approximation is checked and found to be good. It is concluded that the loss of efficiency for variance component estimation due to variation of cluster sizes rarely exceeds 20% and can be compensated by sampling 25% more clusters. PMID- 17698941 TI - Hyperamylasemia and acute pancreatitis following anticholinesterase poisoning. AB - A prospective study was undertaken to find the incidence of hyperamylasemia and acute pancreatitis in patients with anticholinesterase poisoning. This was done by serial estimation of total serum amylase and pancreatic imaging by ultrasonography and confirmed, if necessary, by computerized tomography. Anticholinesterase poisoning was caused by either ingestion or accidental exposure to organophosphates or carbamates; it was diagnosed when patients presented with features of cholinergic crisis, depressed serum butyrylcholinesterase activity of >50% and showed improvement following administration of atropine alone or atropine and 2-PAM. All the patients admitted with anticholinesterase poisoning between July 2001 and June 2005 were prospectively studied for elevated serum amylase. The serum amylase levels were estimated daily up to 10 days in survivors and in nonsurvivors till they survived. Ultrasonography of the abdomen was carried out in all to find swelling of the pancreas. Computerized tomography was undertaken in those who had a swollen pancreas or whose serum amylase levels were elevated significantly (> or =800 S.U). Of the 86 patients enrolled, 79 were taken up for analysis as data were incomplete in 7. Of the 79 patients, serum amylase was found to be elevated that is, >200 S.U. in 37 patients (46.95%). In three patients it was 800 S.U. One of them showed swollen pancreas on ultrasonography, which was confirmed by computerized tomography. This patient had ingested propoxyfur. In the other two patients, evidence of acute pancreatitis was not observed (on autopsy in one who died and on imaging in the other who survived). They had ingested chlorpyrifos. There was no significant correlation between the nature of the compounds (organophosphate or carbamates), inhibition of serum BUChE at admission, duration and severity of cholinergic syndrome and increase and time course of increase in serum amylase. Except for fenthion, significant persistent increase in serum amylase was not observed with individual compounds. The other associated abnormalities were polymorphonuclear leukocytosis (TLC >11,000/cumm) in all 37 patients who had elevated amylase, hyperglycemia (6/37) and, elevated transaminases (6/37). Mild elevation of serum amylase is common in patients with anticholinesterase poisoning. However, acute pancreatitis is rare. PMID- 17698942 TI - Escitalopram ingestions reported to Texas poison control centers, 2002-2005. AB - Limited information exists on potentially adverse escitalopram ingestions reported to poison control centers. Using isolated escitalopram ingestions reported to Texas poison control centers during 2002-2005, the proportion of cases involving serious medical outcomes was determined for selected variables and evaluated for statistical significance by calculating the rate ratio (RR) and 95% confidence interval (CI). Of 1179 cases identified, 234 (20%) involved serious outcomes. Serious outcomes were significantly more likely to occur with a maximum dose of >100 mg (RR 4.69, CI 2.52-9.29) or >5 tablets (RR 4.96, CI 2.94 8.93), where the circumstances of the exposures involved self-harm or malicious intent (RR 3.21, CI 2.42-4.29), or when the patient was already at or en route to a health care facility when the poison control center was contacted (RR 7.88, CI 4.31-15.79) or referred to a health care facility by the poison control center (RR 15.91, CI 8.78-31.64). The severity of the outcome associated with isolated escitalopram ingestions depended on the dose and the circumstances of the ingestion. The management of patients with serious outcomes were more likely to involve health care facilities. Such information is useful for creating triage guidelines for the management of escitalopram ingestions. PMID- 17698943 TI - Adult lisinopril ingestions reported to Texas poison control centers, 1998 2005. AB - There is limited information on potentially adverse lisinopril ingestions reported to poison control centers. Using adult lisinopril ingestions reported to Texas poison control centers during 1998-2005, the proportion of cases involving serious outcomes was determined for selected variables and evaluated for statistical significance by calculating the rate ratio (RR) and 95% confidence interval (CI). Of 468 cases identified, 43 (9%) involved serious outcomes. The severity of the outcome associated with adult lisinopril ingestions depended on the dose and the circumstances of the ingestion. Thus, serious outcomes were significantly more likely to occur with a maximum dose >80 mg (RR 5.69, CI 2.43 13.33) or, if the dose was unknown, > or =3 tablets (RR 9.57, CI 2.39-54.97), where the circumstances of the exposures involved self-harm or malicious intent (RR 6.96, CI 3.65-13.31), or the patient was already at or en route to a health care facility when the poison control center was contacted (RR 7.33, CI 3.09 17.85) or referred to a health care facility by the poison control center (RR 23.76, CI 10.62-55.67). The management of patients with severe outcomes was more likely to involve health care facilities. Such information is useful for creating of triage guidelines for the management of adult lisinopril ingestions. PMID- 17698944 TI - Ovarian toxicity in rats caused by methidathion and ameliorating effect of vitamins E and C. AB - We have investigated the effect of subchronic administration of methidathion (MD) on ovary evaluated ameliorating effects of vitamins E and C against MD toxicity. Experimental groups were as follows: control group; a group treated with 5 mg/kg body weight MD (MD group); and a group treated with 5 mg/kg body weight MD plus vitamin E and vitamin C (MD + Vit group). MD and MD + Vit groups were given MD by gavage five days a week for four weeks at a dose level of 5 mg/kg/day by using corn oil as the vehicle. Serum malondialdehyde (MDA: an indicator of lipid peroxidation) concentration, serum activity of cholinesterase (ChE), and ovary histopathology were studied. The level of MDA increased significantly in the MD group compared with the control (P < 0.005). Serum MDA decreased significantly in the MD + Vit group compared with the MD group (P < 0.05). The activities of ChE decreased significantly both in the MD and MD + Vit groups compared with the controls ( P < 0.05). However, the decrease in the MD + Vit groups was less than in the MD group; the ChE activity in the MD + Vit group was significantly higher compared with MD group (P < 0.05). Number of ovarian follicles were significantly lower in the MD group compared to the controls (P < 0.05). Number of atretic follicles were significantly higher in the MD group than in the controls (P < 0.05). Follicle counts in MD + Vit group showed that all types of ovarian follicles were significantly higher, and a significant decrease in the number of atretic follicles compared with the MD group (P < 0.05). In conclusion, subchronic MD administration caused an ovarian damage, in addition, LPO may be one of the molecular mechanisms involved in MD-induced toxicity. Treatment with vitamins E and C after the administration of MD reduced LPO and ovarian damage. PMID- 17698945 TI - Lead exposure effect on angiotensin II renal vasoconstriction. AB - Low levels of chronic lead exposure can produce hypertension and endothelial dysfunction, which could be associated with oxidative stress, changes in vascular tone and an imbalance of endothelial-derived vasoconstriction and vasodilator factors. The aim was to investigate the effect of chronic lead-exposure on angiotensin II-induced vasoconstriction in isolated perfused kidney and microvessels. Male Wistar rats (230-250 g) were treated for 12 weeks with lead acetate (100 ppm, Pbgroup) or pure water (control group). We evaluated the vascular reactivity in the kidneys and renal microvessels in the presence and absence of N(omega)-nitro-L-arginine methyl ester (L-NAME) in both groups. The nitrite concentration in renal perfusate was measured as an index of NO released, renal abundance of 3-nitrotyrosine was measured as well as endothelial NO synthase (eNOS) expression. Oxidative stress was measured by using the oxidative fluorescence dye dihydroethidium (DHE) to evaluate in situ production of superoxide and identified by confocal microscopy. Lead-exposure significantly increased blood pressure, eNOS protein expression, oxidative stress and vascular reactivity to angiotensin II. L-NAME potentiated vascular response to angiotensin II in control group but had no effect on the Pb-group. Nitrites released from the kidney of lead-group was lower compared to the control group while 3 nitrotyrosine was higher. This data suggest that lead-induced hypertension could be caused partially by an altered NOsystem. PMID- 17698946 TI - Nephrotoxicity and its prevention by taurine in tamoxifen induced oxidative stress in mice. AB - Tamoxifen (TAM) is an anti-neoplastic drug used for the treatment of breast cancer. It decreases the hexose monophosphate shunt and thereby increasing the incidence of oxidative stress in cells leading to tissue injury. The present study was undertaken to investigate modulatory effects of taurine on the nephrotoxicity of TAM with special reference to protection against disruption of nonenzymatic and enzymatic antioxidants. Oxidative stress was measured by renal lipid peroxidation (LPO) level, protein carbonyl (PC) content, reduced glutathione (GSH), activities of phase I and II drug metabolizing and antioxidant enzymes. TAM treatment resulted in a significant (P < 0.001) increase in LPO in kidney tissues as compared to control, while taurine pretreatment showed a significant decrease (P < 0.01) in the LPO in kidneys when compared with the TAM treated group. Taurine + TAM group animals showed restoration in the level of cytochrome P450 content, activities of glutathione metabolizing enzymes viz., glutathione-S-transferase, glutathione peroxidase, glutathione reductase, glucose 6-phosphate dehydrogenase. Pretreatment of animals with taurine markedly attenuated, PC content, restored the depleted nonenzymatic and enzymatic antioxidants. These results clearly demonstrate the role of oxidative stress, and suggest a protective effect of taurine on TAM-induced nephrotoxicity in mice. PMID- 17698947 TI - Protective effect of N-acetylcysteine, caffeic acid and vitamin E on doxorubicin hepatotoxicity. AB - The aim of this study was to compare the possible protective effects of N acetylcysteine (NAC), caffeic acid (CAPE) and vitamin E (Vit-E) on doxorubicin induced hepatotoxicity. Thirty-two male Wistar albino rats, weighing between 250 and 350 g were supplied and randomly divided into five groups. Animals in study groups were pretreated with a single dose of doxorubicin (Dox), which was administered intraperitoneally (i.p.). Control group (Group I) was treated with intraperitoneal saline injection. Group II did not received any antioxidant agent after the injection. Group III and Group IV were given CAPE and intraperitoneal vitamin E injection for eight days, respectively. Group V received NAC for eight days. The study was finished after 10 days. Tissue samples were collected from all animals and histopathological examination was performed. There was statistically significant difference between the experiment groups and controls by means of mononuclear cell infiltration and diameters of hepatic sinusoid, terminal hepatic venule (central vein) and portal area (portal canal). Changes related with hepatocellular damage were more prominent, whereas there was no significant difference between Dox and NAC given groups histopathologically. It was observed that structural changes were regressed after CAPE administration. However, this recovery was more prominent in vitamin E given group. These findings suggest that Dox induced liver damage could be efficiently reversed by vitamin E administration. It has been found that CAPE, but not NAC has protective effects on Dox-induced hepatocellular damage. PMID- 17698948 TI - Effects of diallyl tetrasulfide on cadmium-induced oxidative damage in the liver of rats. AB - The protective efficacy of diallyl tetrasulfide (DTS) from garlic on liver injury induced by cadmium (Cd) was investigated. In this study, Cd (3 mg/kg body weight) was administered subcutaneously for 3 weeks to induce toxicity. DTS was administered orally (10, 20 and 40 mg/kg body weight) for 3 weeks with subcutaneous (sc) injection of Cd. Cd-induced liver damage was evidenced from increased activities of serum hepatic enzymes, namely aspartate transaminase, alanine transaminase, alkaline phosphatase and lactate dehydrogenase, with significant elevation of lipid peroxidation indices (thiobarbituric acid reactive substances and hydroperoxides) and protein carbonyl groups in the liver. Rats subjected to Cd toxicity also showed a decline in the levels of total thiols, reduced glutathione (GSH), vitamin C and vitamin E, accompanied by an increased accumulation of Cd, and significantly decreased activities of superoxide dismutase, catalase (CAT), glutathione peroxidase, glutathione-S-transferase (GST), glutathione reductase, and glucose-6-phosphate dehydrogenase in the liver. Administration of DTS at 40 mg/kg body weight significantly normalised the activities of hepatic marker enzymes, compared to other doses of DTS (10 and 20 mg/kg body weight). In addition, DTS (40 mg/kg body weight) significantly reduced the accumulation of Cd and the level of lipid peroxidation, and restored the level of antioxidant defense in the liver. Histological studies also showed that administration of DTS to Cd-treated rats resulted in a marked improvement of hepatocytes morphology with mild portal inflammation. Our results suggest that DTS might play a vital role in protecting Cd-induced oxidative damage in the liver. PMID- 17698949 TI - Assessment of prenatal tobacco smoke exposure by determining nicotine and its metabolites in meconium. AB - Meconium samples collected from 115 neonates were analysed for nicotine, cotinine and trans -3-hydroxycotinine (OH-cotinine) by means of high-performance liquid chromatography (HPLC) to identify prenatal smoke exposure. The self-reported maternal smoking status during pregnancy was determined by means of a questionnaire and verified by measurements in urine prior to childbirth. The total sum of nicotine and its metabolites (Sum(tot)) of the first passed meconium samples was 1560 +/- 1024 pmol/g in newborns of smoking mothers. Smoking of less than five cigarettes was clearly detected. Sum(tot) remained constant in all meconium samples passed by a neonate in succession. However, the proportion of nicotine decreased with the time of passage after birth and the OH-cotinine proportion increased, whereas cotinine hardly changed. Nicotine or its metabolites were not detectable in meconium (detection limit < 20 pmol/g), when the mothers were only exposed to environmental tobacco smoke (ETS) using the HPLC method. The hypothesis that the content of nicotine metabolites in meconium reflects long-term smoke exposure could not be confirmed in newborns whose mothers had quit smoking during the latter half of pregnancy. Determining Sum(tot) enables the intensity of continuous smoking during pregnancy to be estimated in all meconium samples passed by a newborn. PMID- 17698950 TI - Declines in invasive breast cancer and use of postmenopausal hormone therapy in a screening mammography population. AB - Whether a recent large decline in use of postmenopausal hormone therapy after the release of the Women's Health Initiative findings in July 2002 and/or a decline in screening mammography use is related to a recently reported decline in breast cancer incidence in the United States is controversial. We prospectively collected data from four screening mammography registries from January 1997 through December 2003 for 603411 screening mammography examinations performed on women aged 50-69 years. Of these women, 3238 were diagnosed with breast cancer within 12 months of a screening examination. We calculated quarterly rates of self-reported current postmenopausal hormone therapy use and of invasive breast cancer, ductal carcinoma in situ (DCIS), and estrogen receptor (ER)-positive invasive breast cancer adjusted for age, registry, and time between screening examinations. All statistical tests were two-sided. Between 2000 and 2002 and between 2002 and 2003, annual rates of postmenopausal hormone therapy use declined by 7% and 34%, respectively (P(trend) < .001 for both). Between 2000 and 2003, annual rates of invasive cancer declined by 5% (P(trend) = .003). Between 2001 and 2003, annual rates of ER-positive invasive breast cancer declined by 13% (P(trend) = .002). Rates of DCIS were stable during the study period. Our finding of a statistically significant decline in the rate of ER-positive invasive breast cancer in a screening mammography population after the start of a concomitant substantial decline in postmenopausal hormone therapy use suggests that a decline in screening mammography rates is unlikely to account for the recent decline in US breast cancer incidence. PMID- 17698951 TI - Increased incidence of squamous cell carcinoma of eye after kidney transplantation. AB - Squamous cell carcinoma (SCC) of the eye occurs at substantially increased rates in individuals with human immunodeficiency virus (HIV) infection, but it has not been reported in individuals with iatrogenic or congenital immune deficiency. In a national, population-based cohort of 10,180 renal transplantation patients from Australia with 86,898 person-years of follow-up, we ascertained primary incident cancers diagnosed in 1982-2003 by record linkage between the Australia and New Zealand Dialysis and Transplant Registry and the Australian National Cancer Statistics Clearing House. Standardized incidence ratios (SIRs) of cancer were calculated using age-, sex-, calendar year-, and state/territory-specific population cancer incidence rates. Statistical tests were two-sided. Five patients were diagnosed with ocular SCC after kidney transplantation (0.26 were expected), and the incidence was increased 20-fold (SIR = 19.5, 95% confidence interval [CI] = 6.3 to 45.5). Compared with the entire cohort, the five patients with ocular SCC after transplantation were more likely to have resided in the subtropical state of Queensland (60% versus 17%, P = .04), to have had end-stage kidney disease as a result of glomerulonephritis (100% versus 46%, P = .02), and to have a history of cutaneous SCC (100% versus 29%, P = .002). The increased incidence of ocular SCC after kidney transplantation and after HIV infection strongly suggests that this neoplasm is an immune deficiency-associated cancer. Our data also support an interaction between immune suppression and sun exposure in the development of ocular SCC after kidney transplantation. PMID- 17698952 TI - Involvement of the 90-kDa heat shock protein (Hsp-90) in CB2 cannabinoid receptor mediated cell migration: a new role of Hsp-90 in migration signaling of a G protein-coupled receptor. AB - The endocannabinoid 2-arachidonoylglycerol (2-AG) enhances cell migration through the CB2 cannabinoid receptor. In this study, using an immunoprecipitation and mass spectrometry-based proteomic approach, we first identified the 90-kDa heat shock protein (Hsp90), a chaperone protein with novel signaling functions, as a CB2-interacting protein. The CB2/Hsp90 interaction was confirmed in human embryonic kidney 293 cells expressing transfected CB2 and in differentiated HL-60 cells expressing endogenous CB2, by coimmunoprecipitation and Western blot experiments, as well as by treatment with geldanamycin (GA), a specific Hsp90 inhibitor. Disruption of the CB2/Hsp90 interaction by treatment with GA or reducing Hsp90 levels with specific short interfering RNAs markedly inhibited 2 AG-induced cell migration, demonstrating that Hsp90 is crucial for 2-AG-induced cell migration. 2-AG treatment resulted in a CB2-mediated stimulation of Rac1 activity, and treatment with GA blocked 2AG-induced activation of Rac1. It is noteworthy that expression of the dominant-negative form of Rac1 reduced 2-AG induced cell migration. These data demonstrate that 2-AG-induced activation of Rac1 is essential for 2-AG-induced cell migration, and the CB2/Hsp90 interaction is needed for 2-AG-induced activation of Rac1. Furthermore, 2-AG-induced Rac1 activation was sensitive to pertussis toxin treatment, hence involving G(i) proteins. In addition, treatment with GA significantly inhibited the CB2/Galpha(i2) interaction. As a whole, our data indicate that Hsp90 may serve as scaffold to keep the CB2 receptor and its signaling components, including Galpha(i2), in proximity, thus facilitating CB2-mediated signaling to cell migration through the G(i)-Rac1 pathway. By demonstrating that Hsp90 is essential for CB2-mediated signaling to cell migration, this study reveals a novel role of Hsp90 in the signaling events mediated by a G protein-coupled receptor. PMID- 17698953 TI - Expression of a functional g protein-coupled receptor 54-kisspeptin autoregulatory system in hypothalamic gonadotropin-releasing hormone neurons. AB - The G protein-coupled receptor 54 (GPR54) and its endogenous ligand, kisspeptin, are essential for activation and regulation of the hypothalamic-pituitary-gonadal axis. Analysis of RNA extracts from individually identified hypothalamic GnRH neurons with primers for GnRH, kisspeptin-1, and GPR54 revealed expression of all three gene products. Also, constitutive and GnRH agonist-induced bioluminescence resonance energy transfer between Renilla luciferase-tagged GnRH receptor and GPR54 tagged with green fluorescent protein, expressed in human embryonic kidney 293 cells, revealed heterooligomerization of the two receptors. Whole cell patch clamp recordings from identified GnRH neurons showed initial depolarizing effects of kisspeptin on membrane potential, followed by increased action potential firing. In perifusion studies, treatment of GT1-7 neuronal cells with kisspeptin 10 increased GnRH peak amplitude and duration. The production and secretion of kisspeptin in cultured hypothalamic neurons and GT1-7 cells were detected by a specific RIA and was significantly reduced by treatment with GnRH. The expression of kisspeptin and GPR54 mRNAs in identified hypothalamic GnRH neurons, as well as kisspeptin secretion, indicate that kisspeptins may act as paracrine and/or autocrine regulators of the GnRH neuron. Stimulation of GnRH secretion by kisspeptin and the opposing effects of GnRH on kisspeptin secretion indicate that GnRH receptor/GnRH and GPR54/kisspeptin autoregulatory systems are integrated by negative feedback to regulate GnRH and kisspeptin secretion from GnRH neurons. PMID- 17698954 TI - Transcriptional regulation of pituitary POMC is conserved at the vertebrate extremes despite great promoter sequence divergence. AB - The stress response involves complex physiological mechanisms that maximize behavioral efficacy during attack or defense and is highly conserved in all vertebrates. Key mediators of the stress response are pituitary hormones encoded by the proopiomelanocortin gene (POMC). Despite conservation of physiological function and expression pattern of POMC in all vertebrates, phylogenetic footprinting analyses at the POMC locus across vertebrates failed to detect conserved noncoding sequences with potential regulatory function. To investigate whether ortholog POMC promoters from extremely distant vertebrates are functionally conserved, we used 5'-flanking sequences of the teleost fish Tetraodon nigroviridis POMCalpha gene to produce transgenic mice. Tetraodon POMCalpha promoter targeted reporter gene expression exclusively to mouse pituitary cells that normally express Pomc. Importantly, transgenic expression in mouse corticotrophs was increased after adrenalectomy. To understand how conservation of precise gene expression mechanisms coexists with great sequence divergence, we investigated whether very short elements are still conserved in all vertebrate POMC promoters. Multiple local sequence alignments that consider phylogenetic relationships of ortholog regions identified a unique 10-bp motif GTGCTAA(T/G)CC that is usually present in two copies in POMC 5'-flanking sequences of all vertebrates. Underlined nucleotides represent totally conserved sequences. Deletion of these paired motifs from Tetraodon POMCalpha promoter markedly reduced its transcriptional activity in a mouse corticotropic cell line and in pituitary POMC cells of transgenic mice. In mammals, the conserved motifs correspond to reported binding sites for pituitary-specific nuclear proteins that participate in POMC transcriptional regulation. Together, these results demonstrate that mechanisms that participate in pituitary-specific and hormonally regulated expression of POMC have been preserved since mammals and teleosts diverged from a common ancestor 450 million years ago despite great promoter sequence divergence. PMID- 17698955 TI - Brain activity associated with stimulation therapy of the visual borderzone in hemianopic stroke patients. AB - BACKGROUND AND OBJECTIVE: Visual restoration therapy is a home-based treatment program intended to expand visual fields of hemianopic patients through repetitive stimulation of the borderzone adjacent to the blind field. We hypothesized that the training itself would induce visual field location-specific changes in the brain's response to stimuli, a phenomenon demonstrated in animal experiments but never in humans with brain injury. METHODS: Six chronic right hemianopic patients underwent functional magnetic resonance imaging (fMRI)- responding to stimuli in the trained visual borderzone versus the nontrained seeing field before and after 1 month of visual restoration therapy. Spatially normalized fMRI time-series data were analyzed in a fixed-effects group analysis comparing blood oxygen level dependent (BOLD) activity in the borderzone versus seeing location at baseline and at 1 month. Percent BOLD change was measured to determine each condition's contribution to the time-by-condition interaction. RESULTS: There was a significant time by condition interaction manifested as increased BOLD activity for borderzone detection relative to seeing detection after the first month of therapy, which correlated with a relative improvement in response times in the borderzone location out-of-scanner. The right inferior and lateral temporal, right dorsolateral frontal, bilateral anterior cingulate, and bilateral basal ganglia showed the greatest response. CONCLUSION: Visual restoration therapy appears to induce an alteration in brain activity associated with a shift of attention from the nontrained seeing field to the trained borderzone. The effect appears to be mediated by the anterior cingulate and dorsolateral frontal cortex in conjunction with other higher order visual areas in the occipitotemporal and middle temporal regions. Demonstration of a visual field-specific training effect on brain activity provides an important starting point for understanding the potential for visual therapy in hemianopia. PMID- 17698956 TI - One at a time, live tracking of NGF axonal transport using quantum dots. AB - Retrograde axonal transport of nerve growth factor (NGF) signals is critical for the survival, differentiation, and maintenance of peripheral sympathetic and sensory neurons and basal forebrain cholinergic neurons. However, the mechanisms by which the NGF signal is propagated from the axon terminal to the cell body are yet to be fully elucidated. To gain insight into the mechanisms, we used quantum dot-labeled NGF (QD-NGF) to track the movement of NGF in real time in compartmentalized culture of rat dorsal root ganglion (DRG) neurons. Our studies showed that active transport of NGF within the axons was characterized by rapid, unidirectional movements interrupted by frequent pauses. Almost all movements were retrograde, but short-distance anterograde movements were occasionally observed. Surprisingly, quantitative analysis at the single molecule level demonstrated that the majority of NGF-containing endosomes contained only a single NGF dimer. Electron microscopic analysis of axonal vesicles carrying QD NGF confirmed this finding. The majority of QD-NGF was found to localize in vesicles 50-150 nm in diameter with a single lumen and no visible intralumenal membranous components. Our findings point to the possibility that a single NGF dimer is sufficient to sustain signaling during retrograde axonal transport to the cell body. PMID- 17698957 TI - Stabilized immune modulatory RNA compounds as agonists of Toll-like receptors 7 and 8. AB - Viral and synthetic single-stranded RNAs are the ligands for Toll-like receptor (TLR)7 and TLR8. However, single-stranded RNA is rapidly degraded by ubiquitous RNases, and the studies reported to date have used RNA with lipid carriers. To overcome nuclease susceptibility of RNA, we have synthesized several RNAs incorporating a range of chemical modifications. The present study describes one pool of RNA compounds, referred to as stabilized immune modulatory RNA (SIMRA) compounds, in which two RNA segments are attached through their 3' ends. SIMRA compounds showed greater stability in human serum compared with linear RNA and activated human TLR8, but not TLR7, in HEK293 cells without using lipid carriers. Interestingly, another set of SIMRA compounds containing 7-deazaguanosine substituted for natural guanosine activated human TLR7 and TLR8. Additionally, TLR7- and TLR8-activating compounds, but not the compounds that activated only TLR8, stimulated mouse immune cells in vitro and in vivo and produced dose dependent T helper 1-type cytokines. Both types of compounds activated human peripheral blood mononuclear cells, but only TLR7- and TLR8-activating compounds activated plasmacytoid dendritic cells and produced high levels of IFN-alpha. In monkeys, s.c. administration of both types of SIMRA compounds induced transient changes in peripheral blood monocytes and neutrophils, and activated T lymphocytes, monocytes, and NK cells. Both types of compounds induced IFN-gamma inducible protein 10, but only the 7-deazaguanosine-containing compound that activated both TLR7 and TLR8 induced IFN-alpha in monkeys. This is a comprehensive study of RNA-based compounds containing structures and synthetic stimulatory motifs in mouse, monkey, and human systems without using lipid carriers. PMID- 17698958 TI - Anomalous compression behavior in lanthanum/cerium-based metallic glass under high pressure. AB - In situ high-pressure x-ray diffraction, low-temperature resistivity, and magnetization experiments were performed on a La(32)Ce(32)Al(16)Ni(5)Cu(15) bulk metallic glass (BMG). A sudden change in compressibility at approximately 14 GPa and a rapid increase of resistivity at approximately 12 K were detected, whereas magnetic phase transformation and magnetic field dependence of the low temperature resistivity do not occur at temperatures down to 4.2 K. An interaction between conduction electrons and the two-level systems is suggested to explain the temperature and field dependences of resistivity of the BMG alloy. Although the cause of the unusual change in compressibility at approximately 14 GPa is not clear, we believe that it could be linked with the unique electron structure of cerium in the amorphous matrix. An electronic phase transition in BMG alloys, most likely a second-order amorphous-to-amorphous phase transition, is suggested. PMID- 17698959 TI - ErpA, an iron sulfur (Fe S) protein of the A-type essential for respiratory metabolism in Escherichia coli. AB - Understanding the biogenesis of iron-sulfur (Fe-S) proteins is relevant to many fields, including bioenergetics, gene regulation, and cancer research. Several multiprotein complexes assisting Fe-S assembly have been identified in both prokaryotes and eukaryotes. Here, we identify in Escherichia coli an A-type Fe-S protein that we named ErpA. Remarkably, erpA was found essential for growth of E. coli in the presence of oxygen or alternative electron acceptors. It was concluded that isoprenoid biosynthesis was impaired by the erpA mutation. First, the eukaryotic mevalonate-dependent pathway for biosynthesis of isopentenyl diphosphate restored the respiratory defects of an erpA mutant. Second, the erpA mutant contained a greatly reduced amount of ubiquinone and menaquinone. Third, ErpA bound Fe-S clusters and transferred them to apo-IspG, a protein catalyzing isopentenyl diphosphate biosynthesis in E. coli. Surprisingly, the erpA gene maps at a distance from any other Fe-S biogenesis-related gene. ErpA is an A-type Fe-S protein that is characterized by an essential role in cellular metabolism. PMID- 17698960 TI - Yeast aconitase binds and provides metabolically coupled protection to mitochondrial DNA. AB - Aconitase (Aco1p) is a multifunctional protein: It is an enzyme of the tricarboxylic acid cycle. In animal cells, Aco1p also is a cytosolic protein binding to mRNAs to regulate iron metabolism. In yeast, Aco1p was identified as a component of mtDNA nucleoids. Here we show that yeast Aco1p protects mtDNA from excessive accumulation of point mutations and ssDNA breaks and suppresses reductive recombination of mtDNA. Aconitase binds to both ds- and ssDNA, with a preference for GC-containing sequences. Therefore, mitochondria are opportunistic organelles that seize proteins, such as metabolic enzymes, for construction of the nucleoid, an mtDNA maintenance/segregation apparatus. PMID- 17698961 TI - Genetics of microenvironmental canalization in Arabidopsis thaliana. AB - Canalization is a fundamental feature of many developmental systems, yet the genetic basis for this property remains elusive. We examine the genetic basis of microenvironmental canalization in the model plant Arabidopsis thaliana, focusing on differential developmental stability between genotypes in one fitness and four quantitative morphological traits. We measured developmental stability in genetically identical replicates of two populations of recombinant inbred (RI) lines and one population of geographically widespread accessions of A. thaliana grown in two different photoperiod-controlled environments. We were able to map quantitative trait loci associated with developmental stability. We also identified a candidate gene, ERECTA, that may contribute to microenvironmental canalization in rosette leaf number under long-day photoperiods, and analysis of mutant lines indicates that the er-105 allele results in increased canalization for this trait. ERECTA, which encodes a signaling protein, appears to act as an ecological amplifier by transducing developmental noise (e.g., microenvironmental variation) into phenotypic differentiation. We also measured genotypic selection on four plant architecture traits and find evidence for selection for both increased and decreased canalization at various traits. PMID- 17698962 TI - Nucleosome hopping and sliding kinetics determined from dynamics of single chromatin fibers in Xenopus egg extracts. AB - Chromatin function in vivo is intimately connected with changes in its structure: a prime example is occlusion or exposure of regulatory sequences via repositioning of nucleosomes. Cell extracts used in concert with single-DNA micromanipulation can control and monitor these dynamics under in vivo-like conditions. We analyze a theory of the assembly-disassembly dynamics of chromatin fiber in such experiments, including effects of lateral nucleosome diffusion ("sliding") and sequence positioning. Experimental data determine the force dependent on- and off-rates as well as the nucleosome sliding diffusion rate. The resulting theory simply explains the very different nucleosome displacement kinetics observed in constant-force and constant-pulling velocity experiments. We also show that few-piconewton tensions comparable to those generated by polymerases and helicases drastically affect nucleosome positions in a sequence dependent manner and that there is a long-lived structural "memory" of force driven nucleosome rearrangement events. PMID- 17698963 TI - Empirical evidence for a recent slowdown in irrigation-induced cooling. AB - Understanding the influence of past land use changes on climate is needed to improve regional projections of future climate change and inform debates about the tradeoffs associated with land use decisions. The effects of rapid expansion of irrigated area in the 20th century has remained unclear relative to other land use changes, such as urbanization, that affected a similar total land area. Using spatial and temporal variations in temperature and irrigation extent observed in California, we show that irrigation expansion has had a large cooling effect on summertime average daily daytime temperatures (-0.14 degrees C to -0.25 degrees C per decade), which corresponds to an estimated cooling of -1.8 degrees C to -3.2 degrees C since the introduction of irrigation practices. Irrigation has negligible effects on nighttime temperatures, leading to a net cooling effect of irrigation on climate (-0.06 degrees C to -0.19 degrees C per decade). Stabilization of irrigated area has occurred in California since 1980 and is expected in the near future for many irrigated regions. The suppression of past human-induced greenhouse warming by increased irrigation is therefore likely to slow in the future, and a potential decrease in irrigation may even contribute to a more rapid warming. Changes in irrigation alone are not expected to influence broad-scale temperatures, but they may introduce large uncertainties in climate projections for irrigated agricultural regions, which provide approximately 40% of global food production. PMID- 17698964 TI - Varying environments can speed up evolution. AB - Simulations of biological evolution, in which computers are used to evolve systems toward a goal, often require many generations to achieve even simple goals. It is therefore of interest to look for generic ways, compatible with natural conditions, in which evolution in simulations can be speeded. Here, we study the impact of temporally varying goals on the speed of evolution, defined as the number of generations needed for an initially random population to achieve a given goal. Using computer simulations, we find that evolution toward goals that change over time can, in certain cases, dramatically speed up evolution compared with evolution toward a fixed goal. The highest speedup is found under modularly varying goals, in which goals change over time such that each new goal shares some of the subproblems with the previous goal. The speedup increases with the complexity of the goal: the harder the problem, the larger the speedup. Modularly varying goals seem to push populations away from local fitness maxima, and guide them toward evolvable and modular solutions. This study suggests that varying environments might significantly contribute to the speed of natural evolution. In addition, it suggests a way to accelerate optimization algorithms and improve evolutionary approaches in engineering. PMID- 17698965 TI - Nature and causes of trends in male diabetes prevalence, undiagnosed diabetes, and the socioeconomic status health gradient. AB - This paper investigates levels in diabetes prevalence patterns across key socioeconomic status indicators and how they changed over time. The investigation spans both the conventional concept of diagnosed diabetes and a more comprehensive measure that includes those whose diabetes is undiagnosed. By doing so, I separate the distinct impact of covariates on trends over time in disease onset and the probability of disease diagnosis. The principal force leading to higher diabetes prevalence over time is excessive weight and obesity, which was only partially offset by improvements in the education of the population over time. Undiagnosed diabetes remains an important health problem, but much less so than 25 years ago. Although race and ethnic differentials in undiagnosed diabetes were eliminated over the last 25 years, the disparities became larger across other measures of disadvantage, such as education. PMID- 17698966 TI - Relationship between white matter apparent diffusion coefficients in preterm infants at term-equivalent age and developmental outcome at 2 years. AB - OBJECTIVE: The aim of this study was to develop a simple reproducible method for the measurement of apparent diffusion coefficient values in the white matter of preterm infants using diffusion-weighted imaging to test the hypothesis that elevated mean apparent diffusion coefficient values are associated with lower developmental quotient scores at 2 years' corrected age. METHODS: We obtained diffusion-weighted imaging in 38 preterm infants at term-equivalent age who had no evidence of overt cerebral pathology on conventional MRI. Mean apparent diffusion coefficient values at the level of the centrum semiovale were determined. The children were assessed using a standardized neurologic examination, and the Griffiths Mental Development Scales were administered to obtain a developmental quotient at 2 years' corrected age. The relationship between mean apparent diffusion coefficient values and developmental quotient was examined. Clinical data relating to postnatal sepsis, antenatal steroid exposure, supplemental oxygen, gender, patent ductus arteriosus, and inotrope requirement were collected, and the mean apparent diffusion coefficient values for each group were compared. RESULTS: The mean (+/-SD) apparent diffusion coefficient value in the white matter was 1.385 +/- 0.07 x 10(-3) mm2/second, and the mean developmental quotient was 108.9 +/- 11.5. None of the children had a significant neurologic problem. There was a significant negative correlation between mean apparent diffusion coefficient and developmental quotient. CONCLUSION: These findings suggest that higher white matter apparent diffusion coefficient values at term-equivalent age in preterm infants without overt lesions are associated with poorer developmental performance in later childhood. Consequently, apparent diffusion coefficient values at term may be of prognostic value for neurodevelopmental outcome in infants who are born preterm and who have no other imaging indicators of abnormality. PMID- 17698967 TI - Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single-center retrospective report of 38 patients. AB - OBJECTIVES: Familial hemophagocytic lymphohistiocytosis is a genetically determined condition that is characterized by unremitting CD8 T lymphocyte and macrophage activation and leads to death in the absence of therapy. On the basis of the immunologic pathophysiology of familial hemophagocytic lymphohistiocytosis, we propose a therapy with a combination of antithymocyte globulins with corticosteroids, cyclosporin A, and intrathecal injections of methotrexate. METHODS: We retrospectively analyzed the outcome of antithymocyte globulin-based therapy that was performed in 38 consecutive patients who had familial hemophagocytic lymphohistiocytosis and were treated in a single center between 1991 and 2005. Overall, they received 45 courses of antithymocyte globulin (5-10 mg/kg per day for 5 days). RESULTS: This regimen was associated with infections after 10 of 45 courses of antithymocyte globulin. There were 6 events after 11 antithymocyte globulin courses given as second-line therapy against 4 after 34 antithymocyte globulin courses in patients who were treated primarily with antithymocyte globulin. Antithymocyte globulin administration led to rapid and complete response of familial hemophagocytic lymphohistiocytosis in 73% of cases, partial response in 24%, and no response only once. When hematopoietic stem cell transplantation was performed early after complete or partial response induction, it led to a high rate of cure, in 16 of 19 cases. Overall survival was 21 of 38 with 4 toxic deaths. CONCLUSION: Antithymocyte globulin based immunotherapy of familial hemophagocytic lymphohistiocytosis is efficient and carries an acceptable toxicity when used as a first treatment of familial hemophagocytic lymphohistiocytosis. PMID- 17698968 TI - Comparison of propofol with pentobarbital/midazolam/fentanyl sedation for magnetic resonance imaging of the brain in children. AB - OBJECTIVE: Propofol and pentobarbital, alone or combined with other agents, are frequently used to induce deep sedation in children for MRI. However, we are unaware of a previous comparison of these 2 agents as part of a randomized, controlled trial. We compared the recovery time of children after deep sedation with single-agent propofol with a pentobarbital-based regimen for MRI and considered additional variables of safety and efficacy. METHODS: This prospective, randomized trial at a tertiary children's hospital enrolled 60 patients 1 to 17 years old who required intravenous sedation for elective cranial MRI. Patients were assigned randomly to receive a loading dose of propofol followed by continuous intravenous infusion of propofol or to receive sequential doses of midazolam, pentobarbital, and fentanyl until a modified Ramsay score of >4 was attained. A nurse who was blind to group assignment assessed discharge readiness (Aldrete score > 8) and administered a follow-up questionnaire. We compared recovery time, time to induction of sedation, total sedation time, quality of imaging, number of repeat-image sequences, adverse events, caregiver satisfaction, and time to return to presedation functional status. RESULTS: The groups were similar in age, gender, race, American Society of Anesthesiology physical status class, and frequency of cognitive impairment. No sedation failure or significant adverse events were observed. Propofol offered significantly shorter sedation induction time, recovery time, total sedation time, and time to return to baseline functional status. Caregiver satisfaction scores were also significantly higher in the patients in the propofol group. CONCLUSIONS: Propofol permits faster onset and recovery than, and comparable efficacy to, a pentobarbital/midazolam/fentanyl regimen for sedation of children for MRI. PMID- 17698969 TI - Interactions between MYC and transforming growth factor alpha alter the growth and tumorigenicity of liver progenitor cells. AB - The MYC oncogene induces both cell proliferation and apoptosis. The apoptotic function of MYC is thought to inhibit carcinogenesis; thus, when disrupted, tumorigenic potential is increased. Both MYC and transforming growth factor alpha (TGFalpha) are commonly over-expressed in hepatocellular carcinomas, and transgenic mice expressing these genes rapidly develop tumors via the suppression of MYC-induced apoptosis by the growth factor. However, the nature of the interactions between MYC and TGFalpha are not well understood. Specifically, it is unclear whether TGFalpha acts only as an anti-apoptotic factor in its interactions with MYC or whether it has substantial effects on cell growth. We investigated whether TGFalpha can provide additional mitogenic signals if it is not required to act as an anti-apoptotic factor. We demonstrate that expression of MYC and TGFalpha in liver progenitor cells (known as oval cells) results in enhanced cell proliferation in culture and the generation of poorly differentiated tumors after inoculation into nude mice. We further demonstrate that while the apoptosis-deficient T58A and S71F alleles of MYC retain their ability to promote oval cell proliferation, they have opposite growth interactions with TGFalpha. The T58A allele has a stimulatory effect on both proliferation and tumorigenicity. In contrast, co-expression of the S71F allele reduces proliferation and slows tumor development. We conclude that the tumorigenic growth effects of MYC in TGFalpha-expressing liver progenitor cells are not solely dependent on its apoptotic activity. PMID- 17698970 TI - Critical role of oxidative stress and sustained JNK activation in aloe-emodin mediated apoptotic cell death in human hepatoma cells. AB - Aloe-emodin (AE), one of the main bioactive anthraquinones of Rheum palmatum, possesses potent antitumor properties. Our previous proteomic study revealed that AE-induced apoptosis was associated with oxidative stress and oxidation of many redox-sensitive proteins. In this study, we aimed to further dissect the cell death-signaling pathways in AE-induced apoptosis. AE was found to cause redox imbalance and deplete the intracellular-reduced glutathione (GSH). Manipulation of the intracellular GSH with buthionine-L-sulfoximine (a GSH synthesis inhibitor) sensitized, and with glutathione monomethyl ester (a GSH donor) protected the AE-induced apoptosis, respectively. More importantly, AE treatment led to evident and sustained activation of c-Jun N-terminal kinase (JNK), an important stress-responsive mitogen-activated protein kinase (MAPK). Over expression of antioxidant gene sod1 significantly reduced AE-induced JNK activation and cell death, suggesting that oxidative stress-mediated JNK is the effector molecule in AE-induced apoptosis. Such a notion was clearly supported by subsequent studies in which JNK activation was inhibited by JNK inhibitor, JNK small interfering RNA knockdown or over-expression of dominant-negative JNK. In addition, we provided evidence demonstrating the critical role of apoptosis signal-regulating kinase 1, a well-established MAPK kinase kinase, in AE-induced JNK activation and apoptotic cell death. Finally, we showed that dissociation of inactive JNK-Glutathione S-transferase pi (GST-pi) complex was also involved in JNK activation through GST-pi oxidation. Taken together, these results suggest that AE-induced apoptotic cell death is mediated via oxidative stress and sustained JNK activation. PMID- 17698972 TI - Re: "From menarche to menopause: trends among US women born from 1912 to 1969". PMID- 17698971 TI - Duplicate VegfA genes and orthologues of the KDR receptor tyrosine kinase family mediate vascular development in the zebrafish. AB - Vascular endothelial growth factor A (VEGFA) and the type III receptor tyrosine kinase receptors (RTKs) are both required for the differentiation of endothelial cells (vasculogenesis) and for the sprouting of new capillaries (angiogenesis). We have isolated a duplicated zebrafish VegfA locus, termed VegfAb, and a duplicate RTK locus with homology to KDR/FLK1 (named Kdrb). Morpholino-disrupted VegfAb embryos develop a normal circulatory system until approximately 2 to 3 days after fertilization (dpf), when defects in angiogenesis permit blood to extravasate into many tissues. Unlike the VegfAa(121) and VegfAa(165) isoforms, the VegfAb isoforms VegfAb(171) and VegfAb(210) are not normally secreted when expressed in mammalian tissue culture cells. The Kdrb locus encodes a 1361-amino acid transmembrane receptor with strong homology to mammalian KDR. Combined knockdown of both RTKs leads to defects in vascular development, suggesting that they cooperate in mediating the vascular effects of VegfA in zebrafish development. Both VegfAa and VegfAb can individually bind and promote phosphorylation of both Flk1 (Kdra) and Kdrb proteins in vitro. Taken together, our data support a model in the zebrafish, in which duplicated VegfA and multiple type III RTKs mediate vascular development. PMID- 17698973 TI - Nonsteroidal antiinflammatory drugs and breast cancer risk: the multiethnic cohort. AB - Previous studies on nonsteroidal antiinflammatory drugs (NSAIDs) and breast cancer have produced mixed results. Incident invasive cases of breast cancer from the Multiethnic Cohort (African Americans, Caucasians, Japanese Americans, Latinas, and Native Hawaiians from Hawaii and California) were identified from 1993 to 2002. Data on aspirin, acetaminophen, and other NSAID (ibuprofen, naproxen, indomethacin) use were based on a self-administered questionnaire at baseline (1993-1996). Multivariate Cox proportional hazards models provided estimates of hazard rate ratios and 95% confidence intervals. The authors observed no associations between breast cancer risk and duration of aspirin use for current or past users (hazard rate ratio = 1.05, 95% confidence interval: 0.88, 1.25 and hazard rate ratio = 1.04, 95% confidence interval: 0.84, 1.27 for > or =6 years of use, respectively) compared with nonusers. However, duration of current other NSAID use was protective (hazard rate ratio = 0.70, 95% confidence interval: 0.51, 0.95 for > or =6 years of use; p(trend) = 0.01) against the risk of breast cancer, while past use was not (hazard rate ratio = 0.90, 95% confidence interval: 0.62, 1.30 for > or =6 years of use). Analyses by ethnicity and hormone receptor status showed that the protective effect of current other NSAID use was limited to Caucasians and African Americans and to women with at least one positive hormone receptor. This study found duration of current other NSAID use to be protective against breast cancer risk. PMID- 17698974 TI - Human renal cortical and medullary UDP-glucuronosyltransferases (UGTs): immunohistochemical localization of UGT2B7 and UGT1A enzymes and kinetic characterization of S-naproxen glucuronidation. AB - There is currently little information regarding the localization of UDP glucuronosyltransferases (UGTs) in human renal cortex and medulla, and the functional contribution of renal UGTs to drug glucuronidation remains poorly defined. Using human kidney sections and human kidney cortical microsomes (HKCM) and human kidney medullary microsomes (HKMM), we combined immunohistochemistry to investigate UGT1A and UGT2B7 expression with in vitro microsomal studies to determine the kinetics of S-naproxen acyl glucuronidation. With the exception of the glomerulus, Bowman's capsule, and renal vasculature, UGT1A proteins and UGT2B7 were expressed throughout the proximal and distal convoluted tubules, the loops of Henle, and the collecting ducts. Additionally, UGT1A and UGT2B7 expression was demonstrated in the macula densa, supporting a potential role of UGTs in regulating aldosterone. Consistent with the immunohistochemical data, S naproxen acyl glucuronidation was catalyzed by HKCM and HKMM. Kinetic data were well described by the two-enzyme Michaelis-Menten equation. K(m) values for the high-affinity components were 34 +/- 14 microM (HKCM) and 45 +/- 14 microM (HKMM). Fluconazole inhibited the high-affinity component establishing UGT2B7 as the enzyme responsible for S-naproxen glucuronidation in cortex and medulla. The low-affinity component was relatively unaffected by fluconazole (<15% inhibition), supporting the presence of other UGTs with S-naproxen glucuronidation capacity (e.g., UGT1A6 and UGT1A9) in cortex and medulla. We postulate that the ubiquitous distribution of UGTs in mammalian kidney may buffer physiological responses to endogenous mediators, but at the same time competitive xenobiotic-endobiotic interactions may provide an explanation for the adverse renal effects of drugs, including nonsteroidal anti-inflammatory drugs. PMID- 17698975 TI - Mu-opioid receptor up-regulation and functional supersensitivity are independent of antagonist efficacy. AB - Chronic opioid antagonist treatment up-regulates opioid receptors and produces functional supersensitivity. Although opioid antagonists vary from neutral to inverse, the role of antagonist efficacy in mediating the chronic effects of opioid antagonists is not known. In this study, the effects of two putative inverse agonists (naltrexone, naloxone) and a putative neutral antagonist (6beta naltrexol) were examined. Initially, peak effect (40 min, naltrexone and naloxone; 70 min, 6beta-naltrexol) and relative potency to antagonize morphine analgesia were determined (relative potencies = 1, 2, and 16, 6beta-naltrexol, naloxone, and naltrexone, respectively). Next, mice were infused for 7 days with naloxone (0.1-10 mg/kg/day), naltrexone (10 or 15 mg s.c. pellet), or 6beta naltrexol (0.2-20 mg/kg/day), and spinal micro-opioid receptor density was examined, or morphine analgesia dose-response studies were conducted. All antagonists up-regulated mu-opioid receptors (60-122%) and induced supersensitivity (1.8-2.0-fold increase in morphine potency). There were no differences in antagonist potency to produce up-regulation or supersensitivity. These data suggest that opioid antagonist-induced mu-opioid receptor up regulation and supersensitivity require occupancy of the receptor and that antagonist efficacy is not critical. Finally, the ED(50) to precipitate withdrawal jumping was examined in morphine-dependent mice. Naltrexone, naloxone, and 6beta-naltrexol produced withdrawal jumping, although potencies relative to 6beta-naltrexol were 211, 96, and 1, respectively. Thus, antagonist potency to precipitate opioid withdrawal was related to inverse agonist efficacy. Overall, the estimated relative potency of the opioid antagonists was a function of the outcome measured, and inverse agonist activity was not required for mu-opioid receptor up-regulation and supersensitivity. PMID- 17698976 TI - Phase II, open-label study of PTK787/ZK222584 for the treatment of metastatic gastrointestinal stromal tumors resistant to imatinib mesylate. AB - BACKGROUND: We evaluated safety and efficacy of PTK787/ZK222584 (PTK/ZK), a novel tyrosine kinase inhibitor of KIT, platelet-derived growth factor receptors and vascular endothelial cell growth factor receptors (VEGFRs), in patients with imatinib-resistant gastrointestinal stromal tumor (GIST). This is the first study of PTK/ZK in this population. PATIENTS AND METHODS: Patients with metastatic GIST that had progressed after >/= 4-week treatment with imatinib mesylate were eligible. Prior VEGFR-2 inhibitor therapy was not permitted. PTK/ZK 1250 mg orally once-daily was administered to 15 patients (accrued as a two-stage procedure), most of whom (n = 11) had been unsuccessfully treated with imatinib 800 mg daily, until treatment failure. Patients were monitored at 4- to 8-week intervals. RESULTS: All 15 patients enrolled were eligible; two (13%) achieved partial response (PR), eight (53%) had stable disease (SD) >/=3 months, and five (33%) progressed. The clinical benefit rate (PR + SD) was 67% (95% CI 38% to 86%). Median time to progression was 8.5 months (range 0.9-24.8+ months). Three patients had not progressed at the time of analysis, including one PR at 24.8 months and two SDs at 16.6 and 18.6 months on treatment. PTK/ZK was generally well tolerated. CONCLUSION: PTK/ZK 1250 mg p.o. once daily is active and well tolerated in patients with imatinib-resistant GIST. PMID- 17698977 TI - Clinical multimorbidity and physical function in older adults: a record and health status linkage study in general practice. AB - BACKGROUND: Multiple chronic conditions occurring in the same individual are associated with adverse health outcomes. In family practice, individuals are seen who, over time, may experience many different symptoms, illnesses and chronic diseases. Measures for defining multimorbidity, which incorporate the diverse range of health problems seen in population-based family practice, remain to be developed. We have investigated whether routinely collected consultation data could be used as the basis for a simple classification of multimorbidity that reflects an individual's overall health status. METHODS: Morbidity consultation data for 9,439 English patients aged 50 years and over in an 18-month time period were linked to their self-reported physical health status measured by Short-Form 12 at the end point. Associations between physical function and all-cause multimorbidity counts were estimated relative to single morbidity only, and between physical function and morbidity severity (185 morbidities categorized on four ordinal scales of severity) relative to persons who had not consulted about any of the 185. RESULTS: In the 18-month period, 19% had consulted for a single morbidity and 23% for six or more (a high multimorbidity count). An estimated 24% of poor physical function in the family practice consulting population may be attributable to high multimorbidity. There was an increasing strength of association between poor physical function and increasing severity of multimorbidity on all four severity scales. Estimated associations (adjusted odds ratios) of the most severe morbidity categories with poor physical function were, for each of the four scales, respectively, 5.6 for chronicity [95% confidence interval (CI) 4.4-7.1], 7.0 for time course (4.5-10.6) and 3.6 for health care use (2.0-6.6) and for patient impact (6.7; 5.2-8.8). CONCLUSIONS: Multimorbidity defined by using routinely collected family practice consultation data and classified by count and by severity was associated with poorer physical function. This approach offers the potential for systematic use of routine records to classify multimorbidity and to identify groups with high likelihood of poor physical status for needs assessment and targeted intervention. PMID- 17698978 TI - Treatment of menopausal symptoms by qualified herbal practitioners: a prospective, randomized controlled trial. AB - OBJECTIVES: To assess the effectiveness of professional herbal practice in the treatment of menopausal symptoms. To generate pilot data for future sample size calculations. METHODS: A pilot prospective, randomized, waiting list controlled trial was conducted in primary care at one urban UK GP practice. Participants were 45 women aged 46-59, experiencing self-defined menopausal symptoms and no menstrual bleeding for 3 months. Exclusion criteria included use of hormone replacement therapy. Participants were block randomized into a treatment group (n = 15) who received a course of individualized treatment from one of three herbal practitioners, and control group (n = 30) offered treatment after waiting 4 months. Treatment was six consultations over 5 months including discussion of nutrition, lifestyle and individualized herbal prescription. Change in menopausal symptoms was measured in both groups using the validated Greene Climacteric Scale. Measure Yourself Medical Outcome Profile recorded changes in self-defined most troublesome symptoms. RESULTS: Forty-four participants completed the study. The treatment group demonstrated a statistically and clinically significant reduction in menopausal symptoms compared to the control group. Total scores for menopausal symptoms reduced for both groups. Reduction for the treated group was 9.05 points greater than that for the control group, CI 5.08-13.03, as were changes in vasomotor scores (mean 1.81, CI 1.00-2.62). Libido increased (mean 0.69, CI 0.38-0.99) in the group receiving herbal treatment. CONCLUSION: The treatment package from herbal practitioners improved menopausal symptoms, particularly hot flushes and low libido. This offers evidence to support herbal medicine as a treatment choice during the menopause. PMID- 17698979 TI - GPs' experiences of primary care mental health research: a qualitative study of the barriers to recruitment. AB - OBJECTIVE: To investigate the perceived barriers among GPs towards introducing participation in randomized controlled trials (RCTs) to patients presenting with depression during consultations. METHODS: Qualitative study using semi-structured interviews. Interviews were recorded using a digital voice recorder, transcribed verbatim and analysed using the Framework Approach. The participants were 41 GPs from five primary care trusts in the South West who were collaborating with the University of Bristol on an RCT recruiting patients with depression. RESULTS: Three themes were identified: (i) concern about protecting the vulnerable patient and the impact on the doctor-patient relationship; (ii) the perceived lack of skill and confidence of GPs to introduce a request for research participation within a potentially sensitive consultation; and (iii) the priority given to clinical and administrative issues over research participation. These themes were underpinned by GPs' observations that consultations with people about depression differed in content, style and perceived difficulty compared to other types of consultations. CONCLUSION: Depressed patients were often viewed as vulnerable and in need of protection and it was seen as difficult and intrusive to introduce research. Patients were not always given the choice to participate in research in the same way that they are encouraged to participate in treatment decision making. A lack of skills in introducing research could be addressed with training through the new Primary Care Research Network. A more radical change in clinician attitudes and policy may be needed in order to give research a higher priority within primary care. PMID- 17698980 TI - Imaging CD8+ T cell dynamics in vivo using a transgenic luciferase reporter. AB - After activation, populations of antigen-specific T cells flow between sites of antigen expression, local lymphoid structures and other lymphoid and non-lymphoid organs. In this study, we documented the in vivo dynamics of a CD8(+) T cell response to antigen delivered using herpes simplex virus amplicon vectors and revealed several unexpected features. First, the T cells localized to the site of vector injection, as well as the draining lymph node within 24-48 h. Second, the major site to which T cells later redistributed were intra-abdominal lymphoid organs, including milky spots, mesenteric and lumbar lymph nodes. We determined the relationship between bioluminescent signal and antigen-specific T cell numbers in various lymphoid organs, and concluded that bioluminescent signal is a valid surrogate measure of T cell abundance in superficial lymph nodes, but not in deeper structures such as the spleen. PMID- 17698981 TI - Forced expression of Id2 in fetal thymic T cell progenitors allows some of their progeny to adopt NK cell fate. AB - The E proteins are indispensable for early T cell development. On the other hand, we previously demonstrated that their inhibitor Id2 is essential for NK lineage commitment from bipotent progenitors generating both T and NK cells (p-T/NK). To shed more light on the role of E proteins and Id2 in the development of early intrathymic progenitors, we performed a clonal analysis: individual fetal thymic CD4(-)CD8(-)CD44(+)CD25(-)CD122(-) (DN1CD122(-)) cells were retrovirally transduced with an Id2-internal ribosomal entry site (IRES)-green fluorescent protein (GFP) (Id2-GFP) gene or a control IRES-GFP (GFP) gene, and cultured in a modified fetal thymus organ culture able to support T and NK cell development. After the culture, both T and NK cells, T cells and no NK cells, NK cells and no T cells, or completely no cells were generated from single cells in each lobe. Hence, the seeded cells were regarded as p-T/NK, unipotent progenitors generating T cells (p-T), unipotent NK progenitors, or cells without progenitor activity, respectively. With Id2-GFP transduction, p-T disappeared and more p-T/NK emerged than with GFP transduction. This increase corresponded to the number of p-T that was counted when the vector-transduced-DN1CD122(-) cells of the same number were examined. Additionally, a fraction of GFP(-) NK cells obtained after Id2-GFP transduction underwent TCRbeta D-J rearrangement. Our data strongly suggest that forced expression of Id2 allows some progeny of p-T to adopt an NK cell fate, and that p-T retain a program for NK lineage development that can be implemented by inhibiting the function of E proteins. PMID- 17698982 TI - Impaired LPS-induced signaling in microglia overexpressing the Wiskott-Aldrich syndrome protein N-terminal domain. AB - Wiskott-Aldrich syndrome protein (WASP) plays important roles in TCR signaling, but its roles in signal transduction in innate immune cells have not been well characterized. As microglia are the primary immune effector cells in the brain, WASP may possibly have important roles in microglial activation, such as production of inflammatory and anti-inflammatory cytokines and neurotoxic factors. Here, we established a microglial cell line from WASP dominant-negative transgenic (Tg) mice overexpressing the N-terminal enabled/vasodilator-stimulated phosphoprotein homology 1 (EVH1) domain. WASP Tg microglia were impaired in production of inflammatory cytokines such as tumor necrosis factor-alpha, IL-6 and IL-1beta upon LPS stimulation, whereas anti-inflammatory IL-10 production was significantly enhanced. Also, LPS-induced phosphorylation of nuclear factor kappaB was reduced in WASP Tg microglia. Furthermore, WASP Tg microglia exhibited less cytotoxicity against co-cultured neurons after stimulation by LPS and IFN gamma, with a concordant decrease in nitric oxide production. These results strongly suggest that WASP may have pivotal roles through the EVH1 domain in the LPS signaling cascade, either directly or indirectly, and modulates inflammatory immune responses in microglia. PMID- 17698983 TI - Lipoprotein receptor expression during luteinization of the ovarian follicle. AB - Ovarian follicles luteinize after ovulation, requiring structural and molecular remodeling along with exponential increases in steroidogenesis. Cholesterol substrates for luteal steroidogenesis are imported via scavenger receptor-BI (SR BI) and the low-density lipoprotein (LDL) receptor from circulating high-density lipoproteins and LDL. SR-BI mRNA is expressed in pig ovaries at all stages of folliculogenesis and in the corpus luteum (CL). An 82-kDa form of SR-BI predominates throughout, is weakly present in granulosa cells, and is robustly expressed in the CL, along with the less abundant 57-kDa form. Digestion of N linked carbohydrates substantially reduced the SR-BI mass in luteal cells, indicating that differences between forms is attributable to glycosylation. Immunohistochemistry revealed SR-BI to be concentrated in the cytoplasm of follicular granulosa cells, although found mostly at the periphery of luteal cells. To examine receptor dynamics during gonadotropin-induced luteinization, pigs were treated with an ovulatory stimulus, and ovaries were collected at intervals to ovulation. SR-BI in granulosa cell cytoplasm increased through the periovulatory period, with migration to the cell periphery as the CL matured. In vitro culture of follicles with human chorionic gonadotropin induced time dependent upregulation of 82-kDa SR-BI in granulosa cells. SR-BI and LDL receptor were reciprocally expressed, with the latter highest in follicular granulosa cells, declining precipitously with CL formation. We conclude that luteinization causes upregulation of SR-BI expression, its posttranslational maturation by glycosylation, and insertion into luteal cell membranes. Expression of the LDL receptor is extinguished during luteinization, indicating dynamic regulation of cholesterol importation to maintain elevated steroid output by the CL. PMID- 17698984 TI - Insulin at physiological concentrations increases microvascular perfusion in human myocardium. AB - Vascular endothelium regulates vascular tone and tissue perfusion in response to various physiological and pathological stimuli. Insulin and meal feeding increase microvascular perfusion and thus oxygen, nutrient, and hormone delivery to human skeletal muscle. Meal feeding also increases cardiac microvascular perfusion in healthy humans. To examine whether insulin at physiological concentrations increases microvascular perfusion in human myocardium, we studied 13 healthy, overnight-fasted, lean, young human volunteers by using myocardial contrast echocardiography (MCE) and insulin-clamp techniques. We measured cardiac microvascular blood volume (MBV), microvascular flow velocity (MFV), and microvascular blood flow (MBF) at baseline, 60 min, and 120 min after initiating insulin infusion at 1 mU.kg(-1).min(-1). MBF is the product of MBV and MFV and represents microvascular perfusion. Insulin increased myocardial MBV by 23% at 60 min (P < 0.01) and by 41% at 120 min (P = 0.001) without changing MFV. As a result, insulin-mediated myocardial MBF increased significantly at both 60 min (P < 0.01) and 120 min (P < 0.0005). Insulin also significantly increased brachial artery diameter, flow velocity, and total blood flow at 60 and 120 min (P < 0.05 for all). The changes in cardiac MBV correlated positively with quantitative insulin sensitivity check index (QUICKI) and negatively with body mass index but not with the steady-state glucose-infusion rates or the changes in brachial artery parameters. We conclude that insulin, at physiologically relevant concentrations, increases microvascular perfusion in human heart muscle by increasing cardiac MBV in healthy, insulin-sensitive adults. This insulin mediated cardiac microvascular perfusion may play an important role in normal human myocardial oxygen and substrate physiology. PMID- 17698985 TI - Effects of prior or concurrent food restriction on amylin-induced changes in body weight and body composition in high-fat-fed female rats. AB - Amylin infusion reduces food intake and slows body weight gain in rodents. In obese male rats, amylin (but not pair feeding) caused a preferential reduction of fat mass with protein preservation despite equal body weight loss in amylin treated (fed ad libitum) and pair-fed rats. In the present study, the effect of prior or concurrent food restriction on the ability of amylin to cause weight loss was evaluated. Retired female breeder rats were maintained on a high-fat diet (40% fat) for 9 wk. Prior to drug treatment, rats were either fed ad libitum or food restricted for 10 days to lose 5% of their starting body weight. They were then subdivided into treatment groups that received either vehicle or amylin (100 microgxkg(-1)xday(-1) via subcutaneous minipump) and placed under either a restricted or ad libitum feeding schedule (for a total of 8 treatment arms). Amylin 1) significantly reduced body weight compared with vehicle under all treatment conditions, except in always restricted animals, 2) significantly decreased percent body fat in all groups, and 3) preserved lean mass in all groups. These results indicate that amylin's anorexigenic and fat-specific weight loss properties can be extended to a variety of nutritive states in female rats. PMID- 17698986 TI - A Thr94Ala mutation in human liver fatty acid-binding protein contributes to reduced hepatic glycogenolysis and blunted elevation of plasma glucose levels in lipid-exposed subjects. AB - Liver fatty acid-binding protein (L-FABP) is a highly conserved key factor in lipid metabolism. Amino acid replacements in L-FABP might alter its function and thereby affect glucose metabolism in lipid-exposed subjects, as indicated by studies in L-FABP knockout mice. Amino acid replacements in L-FABP were investigated in a cohort of 1,453 Caucasian subjects. Endogenous glucose production (EGP), gluconeogenesis, and glycogenolysis were measured in healthy carriers of the only common Thr(94)-to-Ala amino acid replacement (Ala/Ala(94)) vs. age-, sex-, and BMI-matched wild-type (Thr/Thr(94)) controls at baseline and after 320-min lipid/heparin-somatostatin-insulin-glucagon clamps (n = 18). Whole body glucose disposal was further investigated (subset; n = 13) using euglycemic hyperinsulinemic clamps without and with lipid/heparin infusion. In the entire cohort, the only common Ala/Ala(94) mutation was significantly associated with reduced body weight, which is in agreement with a previous report. In lipid exposed, individually matched subjects there was a genotype vs. lipid-treatment interaction for EGP (P = 0.009) driven mainly by reduced glycogenolysis in Ala/Ala(94) carriers (0.46 +/- 0.05 vs. 0.59 +/- 0.05 mgxkg(-1)xmin(-1), P = 0.013). The lipid-induced elevation of plasma glucose levels was smaller in Ala/Ala(94) carriers compared with wild types (P < 0.0001). Whole body glucose disposal was not different between lipid-exposed L-FABP genotypes. In summary, the Ala/Ala(94)-mutation contributed significantly to reduced glycogenolysis and less severe hyperglycemia in lipid-exposed humans and was further associated with reduced body weight in a large cohort. Data clearly show that investigation of L FABP phenotypes in the basal overnight-fasted state yielded incomplete information, and a challenge test was essential to detect phenotypical differences in glucose metabolism between L-FABP genotypes. PMID- 17698987 TI - Adenine nucleotide translocator promotes oxidative phosphorylation and mild uncoupling in mitochondria after dexamethasone treatment. AB - The composition of the mitochondrial inner membrane and uncoupling protein [such as adenine nucleotide translocator (ANT)] contents are the main factors involved in the energy-wasting proton leak. This leak is increased by glucocorticoid treatment under nonphosphorylating conditions. The aim of this study was to investigate mechanisms involved in glucocorticoid-induced proton leak and to evaluate the consequences in more physiological conditions (between states 4 and 3). Isolated liver mitochondria, obtained from dexamethasone-treated rats (1.5 mg.kg(-1).day(-1)), were studied by polarography, Western blotting, and high performance thin-layer chromatography. We confirmed that dexamethasone treatment in rats induces a proton leak in state 4 that is associated with an increased ANT content, although without any change in membrane surface or lipid composition. Between states 4 and 3, dexamethasone stimulates ATP synthesis by increasing both the mitochondrial ANT and F1-F0 ATP synthase content. In conclusion, dexamethasone increases mitochondrial capacity to generate ATP by modifying ANT and ATP synthase. The side effect is an increased leak in nonphosphorylating conditions. PMID- 17698989 TI - The contribution of the medial prefrontal cortex, orbitofrontal cortex, and dorsomedial striatum to behavioral flexibility. AB - Behavioral flexibility refers to the ability to shift strategies or response patterns with a change in environmental contingencies. The frontal lobe and basal ganglia are two brain regions implicated in various components for successfully adapting to changed environmental contingencies. This paper discusses a series of experiments that investigate the contributions of the rat prelimbic area, infralimbic area, orbitofrontal cortex, and dorsomedial striatum to behavioral flexibility. Orbitofrontal cortex inactivation did not impair initial learning of discrimination tests, but it impaired reversal learning due to perseverance in the previously learned choice pattern. Inactivation of the prelimbic area did not affect acquisition or reversal learning of different discrimination tests, but it selectively impaired learning when rats had to inhibit one strategy and shift to using a new strategy. However, comparable to orbitofrontal cortex inactivation, strategy-switching deficits following prelimbic inactivation resulted from a perseverance of the previously relevant strategy. Fewer studies have examined the infralimbic region, but there is some evidence suggesting that this region supports reversal learning by maintaining the reliable execution of a new choice pattern. Dorsomedial striatal inactivation impaired both reversal learning and strategy switching. The behavioral flexibility deficits following dorsomedial striatal inactivation resulted from the inability to maintain a new choice pattern once selected. Taken together, the results suggest that orbitofrontal and prelimbic subregions differentially contribute to behavioral flexibility, but they are both critical for the initial inhibition of a previously learned strategy, while the dorsomedial striatum plays a broader role in behavioral flexibility and supports a process that allows the reliable execution of a new strategy once selected. PMID- 17698988 TI - Reconciling the roles of orbitofrontal cortex in reversal learning and the encoding of outcome expectancies. AB - Damage to orbitofrontal cortex (OFC) has long been associated with decision making deficits. Such deficits are epitomized by impairments in reversal learning. Historically, reversal learning deficits have been linked to a response inhibition function or to the rapid reversal of associative encoding in OFC neurons. However here we will suggest that OFC supports reversal learning not because its encoding is particularly flexible-indeed it actually is not-but rather because output from OFC is critical for flexible associative encoding downstream in basolateral amygdala (ABL). Consistent with this argument, we will show that reversal performance is actually inversely related to the flexibility of associative encoding in OFC (i.e., the better the reversal performance, the less flexible the encoding). Further, we will demonstrate that associative correlates in ABL are more flexible during reversal learning than in OFC, become less flexible after damage to OFC, and are required for the expression of the reversal deficit caused by OFC lesions. We will propose that OFC facilitates associative flexibility in downstream regions, such as ABL, for the same reason that it is critical for outcome-guided behavior in a variety of setting-namely that processing in OFC signals the value of expected outcomes. In addition to their role in guiding behavior, these outcome expectancies permit the rapid recognition of unexpected outcomes, thereby driving new learning. PMID- 17698990 TI - Orbital versus dorsolateral prefrontal cortex: anatomical insights into content versus process differentiation models of the prefrontal cortex. AB - Content differentiation models posit that different areas of the prefrontal cortex perform similar operations but differ in terms of the content that is operated on. For example, it has been suggested that the orbitofrontal cortex (OFC) and the dorsolateral prefrontal cortex (DLPFC) perform similar working memory or inhibitory operations, but on different types of content (e.g., reward versus spatial or feature-based versus abstract). In contrast to the above models, process differentiation models posit that different areas of the prefrontal cortex perform fundamentally different operations. Surprisingly, discussions of these dueling models rarely incorporate information about anatomy. The only exception is that advocates of content differentiation models appropriately note that different parts of the prefrontal cortex receive different afferents. Yet, an examination of the anatomy of the OFC and the DLPFC reveal numerous differences in cortical structure and interneuron composition. These structural differences necessitate that the OFC and the DLPFC will have strikingly different computational features. Given such computational differences, strong versions of content differentiation models are untenable. While overarching themes may help explain the operations in both the OFC and the DLPFC, the specific operations performed in the two regions are likely to be both quantitatively and qualitatively different in nature. PMID- 17698991 TI - Difficulty overcoming learned non-reward during reversal learning in rats with ibotenic acid lesions of orbital prefrontal cortex. AB - Behavioral flexibility is a concept often invoked when describing the function of the prefrontal cortex. However, the psychological substrate of behavioral flexibility is complex. Its key components are allocation of attention, goal directedness, planning, working memory, and response selection. Furthermore, there is evidence that different regions of the prefrontal cortex might be implicated in these different components. In rule-switching tasks, a distinction is made between errors that are perseverative (difficulty switching from a previously rewarded strategy) and errors due to learned-irrelevance (difficulty switching to a strategy previously uncorrelated with reward). A similar distinction might be made for reversal learning, which involves inhibition of a previously rewarded response and activation of a previously unrewarded response. Damage to the orbital prefrontal cortex (OPFC) results in a deficit in reversal learning. The present study was designed to examine whether one or both of either perseveration or learned non-reward might account for the deficit. Rats with bilateral ibotenic acid-induced lesions of the OPFC were not impaired in acquisition of discriminations. They were impaired, relative to controls, only when they had to overcome learned non-reward. They did not show enhanced perseveration. We conclude that an inability to overcome learned non-reward significantly contributes to OPFC lesion-induced deficits in behavioral flexibility. PMID- 17698992 TI - Orbitofrontal cortex and the computation of economic value. AB - Economic choice is the behavior observed when individuals select one of many available options solely based on subjective preferences. Behavioral evidence suggests that economic choice entails two mental processes: values are first assigned to the available options, and a decision is subsequently made between these values. Numerous reports show that lesions to the orbitofrontal cortex (OFC) lead to choice deficits in various domains, and imaging studies indicate that the OFC activates when people make choices. In this chapter, we review evidence from single cell recordings linking the OFC more specifically to valuation. Individual neurons in the OFC encode the value that monkeys assign to different beverages when they choose between them. These neurons encode economic value as a subjective quantity. Most importantly, neurons in the OFC encode economic value per se, not as a modulation of sensory or motor processes. This trait distinguishes the value representation in the OFC from that observed in other brain areas. That OFC neurons encode economic value independently of visuomotor contingencies suggests that economic choice is fundamentally a choice between goods (good-based model) rather than a choice between actions (action based model). PMID- 17698993 TI - Orbitofrontal cortex and cognitive-motivational impairments in psychostimulant addiction: evidence from experiments in the non-human primate. AB - Addiction is characterized by compulsive drug use despite adverse consequences. The precise psychobiological changes that underlie the progression from casual use to loss of control over drug-seeking and drug-taking behavior are not well understood. Here we report that short-term cocaine exposure in monkeys is sufficient to produce both selective deficits in cognitive functions dependent on the orbitofrontal cortex (OFC) concurrent with enhancements in motivational processes involving limbic-striatal regions. Additional findings from behavioral studies and analyses of the synaptic proteome provide new behavioral and biochemical evidence that cocaine-induced neuroadaptations in cortical and subcortical brain regions result in dysfunctional decision-making abilities and loss of impulse control that in combination with enhancements of incentive motivation may contribute to the development of compulsive behavior in addiction. PMID- 17698994 TI - Taste in the medial orbitofrontal cortex of the macaque. AB - Taste activates about 6% of the neurons in the anterior insula (primary taste cortex) of the macaque. The anterior insula has many direct and indirect projections to the orbitofrontal cortex (OFC), including the caudolateral OFC (clOFC), where only 2% of the neurons respond to taste. We have identified a 12 mm(2) region in the medial OFC (mOFC) where taste represents 7-28% of the population. This rich trove of taste cells has functional characteristics typical of both the insular cortex that projects to it and the clOFC to which it projects. Mean spontaneous rate was 3.1 spikes/s, nearly identical to that in the insula, but double that of the clOFC. In the mOFC, 19% of the taste cells also responded to other modalities, most commonly olfaction and touch, slightly less than the 27% in the clOFC. The distribution of best stimulus neurons was almost even across the four prototypical stimuli in the mOFC, as in insula, but discrepant from the clOFC, where sugar responsiveness dominated. The broadly tuned taste neurons in the mOFC were similar to those in the insula and strikingly different from the more specialized cells of the clOFC. Whereas the responsiveness to the taste of a satiating stimulus declines among the narrowly tuned clOFC cells, satiety has much less impact on the responsiveness of mOFC neurons. The mOFC is a robust area worthy of exploration for its involvement in gustatory coding, the amalgamation of sensory inputs to create flavor, and the hedonics that guide feeding. PMID- 17698995 TI - Dysfunctions of medial and lateral orbitofrontal cortex in psychopathy. AB - Psychopathy is a developmental disorder marked by emotional hypo-responsiveness and an increased risk for instrumental and reactive aggression. In this paper, it will be argued that the developmental origins of psychopathy do not lie in orbitofrontal cortex (OFC) dysfunction. This is because the key functional impairments seen in psychopathy are associated with amygdala damage, not with OFC damage. However, it will be argued that the role played by the integrated functioning of the amygdala and medial OFC in stimulus-reinforcement learning and decision making is disrupted in psychopathy. Impaired learning of stimulus reinforcement associations and representation of reinforcement expectations are thought to underlie the impairments in socialization and appropriate decision making seen in psychopathy. It is suggested that the impairment in the role of medial OFC in prediction error signaling and the detection of contingency change may underlie the impairments in flexible behavioral change seen in psychopathy. PMID- 17698996 TI - Specialized elements of orbitofrontal cortex in primates. AB - The orbitofrontal cortex is associated with encoding the significance of stimuli within an emotional context, and its connections can be understood in this light. This large cortical region is architectonically heterogeneous, but its connections and functions can be summarized by a broad grouping of areas by cortical type into posterior and anterior sectors. The posterior (limbic) orbitofrontal region is composed of agranular and dysgranular-type cortices and has unique connections with primary olfactory areas and rich connections with high-order sensory association cortices. Posterior orbitofrontal areas are further distinguished by dense and distinct patterns of connections with the amygdala and memory-related anterior temporal lobe structures that may convey signals about emotional import and their memory. The special sets of connections suggest that the posterior orbitofrontal cortex is the primary region for the perception of emotions. In contrast to orbitofrontal areas, posterior medial prefrontal areas in the anterior cingulate are not multi-modal, but have strong connections with auditory association cortices, brain stem vocalization, and autonomic structures, in pathways that may mediate emotional communication and autonomic activation in emotional arousal. Posterior orbitofrontal areas communicate with anterior orbitofrontal areas and, through feedback projections, with lateral prefrontal and other cortices, suggesting a sequence of information processing for emotions. Pathology in orbitofrontal cortex may remove feedback input to sensory cortices, dissociating emotional context from sensory content and impairing the ability to interpret events. PMID- 17698997 TI - Synergistic and regulatory effects of orbitofrontal cortex on amygdala-dependent appetitive behavior. AB - This paper will review two avenues of our research in marmosets that have focused on the role of the orbitofrontal cortex (OFC) in amygdala-dependent appetitive behavior. The first demonstrates the important contribution of both the OFC and the amygdala to conditioned reinforcement (CRF). The second reveals the regulatory effects of the OFC on amygdala-dependent autonomic and behavioral arousal in appetitive conditioning. The process of CRF is one way in which an environmental cue can guide emotional behavior. As a consequence of its previous relationship with reward, a cue can take on affective value and reinforce behavior. Lesion studies in marmosets are described that show that CRF is dependent upon both the amygdala and OFC. The synergistic interactions between these structures that have been shown to underlie other aspects of reward processing are then considered with respect to CRF. The results are contrasted with those that show the importance of the OFC in suppressing positive affective responses elicited by the amygdala in response to a conditioned stimulus (CS). Specifically, it will be shown that the OFC is involved in the rapid suppression of conditioned autonomic arousal upon CS withdrawal and in the co-ordination of conditioned autonomic and behavioral responses when adapting to changing reward contingencies. It will be argued that, overall, the OFC plays a critical role in the context-dependent regulation of positive affective responding governed by external cues, in keeping with a role in executive control. PMID- 17698998 TI - The role of the orbitofrontal cortex in anxiety disorders. AB - Advances in neuroimaging techniques over the past two decades have allowed scientists to investigate the neurocircuitry of anxiety disorders. Such research has implicated the orbitofrontal cortex (OFC). Characterizing the role of OFC in anxiety disorders, however, is principally complicated by two factors-differences in underlying pathophysiology across the anxiety disorders and heterogeneity in function across different OFC sub-territories. Contemporary neurocircuitry models of anxiety disorders have primarily focused on amygdalo-cortical interactions. The amygdala is implicated in generating fear responses, whereas cortical regions, specifically the medial OFC (mOFC) and the ventromedial prefrontal cortex (vmPFC), are implicated in fear extinction. In contrast to mOFC, anterolateral OFC (lOFC) has been associated with negative affects and obsessions and thus dysfunctional lOFC may underlie different aspects of certain anxiety disorders. Herein, we aim to review the above-mentioned theories and provide a heuristic model for conceptualizing the respective roles of mOFC and lOFC in the pathophysiology and treatment of anxiety disorders. We will also review the role of the OFC in fear extinction and the implications of this role to the pathophysiology of anxiety disorders. PMID- 17698999 TI - Definition of the orbital cortex in relation to specific connections with limbic and visceral structures and other cortical regions. AB - The orbitofrontal cortex is often defined topographically as the cortex on the ventral surface of the frontal lobe. Unfortunately, this definition is not consistently used, and it obscures distinct connectional and functional systems within the orbital cortex. It is difficult to interpret data on the orbital cortex that do not take these different systems into account. Analysis of cortico cortical connections between areas in the orbital and medial prefrontal cortex indicate two distinct networks in this region. One system, called the orbital network, involves most of the areas in the central orbital cortex. The other system, has been called the medial prefrontal network, though it is actually more complex, since it includes areas on the medial wall, in the medial orbital cortex, and in the posterolateral orbital cortex. Some areas in the medial orbital cortex are involved in both networks. Connections to other brain areas support the distinction between the networks. The orbital network receives several sensory inputs, from olfactory cortex, taste cortex, somatic sensory association cortex, and visual association cortex, and is connected with multisensory areas in the ventrolateral prefrontal cortex and perirhinal cortex. The medial network has outputs to the hypothalamus and brain stem and connects to a cortical circuit that includes the rostral part of the superior temporal gyrus and dorsal bank of the superior temporal sulcus, the cingulate and retrosplenial cortex, the entorhinal and posterior parahippocampal cortex, and the dorsomedial prefrontal cortex. PMID- 17699000 TI - The cover. The canal at Saint-Mammes. PMID- 17699001 TI - A piece of my mind. The other side. PMID- 17699002 TI - Experts look for ways to lessen impact of drug shortages and discontinuations. PMID- 17699003 TI - New tactics help curb adolescent substance abuse and dependence. PMID- 17699004 TI - Predictive index for renal replacement therapy. PMID- 17699005 TI - Obesity and the right brain. PMID- 17699006 TI - Cardiovascular response to a modern roller coaster ride. PMID- 17699007 TI - Access and diversity in academic mentoring. PMID- 17699008 TI - Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. AB - CONTEXT: Viruslike particle human papillomavirus (HPV) vaccines were designed to prevent HPV infection and development of cervical precancers and cancer. Women with oncogenic HPV infections might consider vaccination as therapy. OBJECTIVE: To determine whether vaccination against HPV types 16 and 18 increases the rate of viral clearance in women already infected with HPV. DESIGN AND SETTING: Phase 3, masked, community-based randomized trial conducted in 2 provinces of Costa Rica. PARTICIPANTS: A total of 2189 women aged 18 to 25 years who were recruited between June 2004 and December 2005. Participants were positive for HPV DNA at enrollment, had at least 6 months of follow-up, and had follow-up HPV DNA results. INTERVENTION: Participants were randomly assigned to receive 3 doses of a bivalent HPV-16/18 L1 protein viruslike particle AS04 candidate vaccine (n = 1088) or a control hepatitis A vaccine (n = 1101) over 6 months. MAIN OUTCOME MEASURES: Presence of HPV DNA was determined in cervical specimins by a molecular hybridization assay using chemiluminescence with HPV RNA probes and by polymerase chain reaction using SPF10 primers and a line probe assay detection system before vaccination and by polymerase chain reaction after vaccination. We compared rates of type-specific viral clearance using generalized estimating equations methods at the 6-month visit (after 2 doses) and 12-month visit (after 3 doses) in the 2 study groups. RESULTS: There was no evidence of increased viral clearance at 6 or 12 months in the group who received HPV vaccine compared with the control group. Clearance rates for HPV-16/18 infections at 6 months were 33.4% (82/248) in the HPV vaccine group and 31.6% (95/298) in the control group (vaccine efficacy for viral clearance, 2.5%; 95% confidence interval, -9.8% to 13.5%). Human papillomavirus 16/18 clearance rates at 12 months were 48.8% (86/177) in the HPV vaccine group and 49.8% (110/220) in the control group (vaccine efficacy for viral clearance, -2.0%; 95% confidence interval, -24.3% to 16.3%). There was no evidence of a therapeutic effect for other oncogenic or nononcogenic HPV categories, among women receiving all vaccine doses, among women with single infections, or among women stratified by the following entry variables: HPV-16/18 serology, cytologic results, HPV DNA viral load, time since sexual debut, Chlamydia trachomatis or Neisseria gonorrhoeae infection, hormonal contraceptive use, or smoking. CONCLUSION: In women positive for HPV DNA, HPV-16/18 vaccination does not accelerate clearance of the virus and should not be used to treat prevalent infections. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00128661. PMID- 17699009 TI - Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer. AB - CONTEXT: Dietary factors have been associated with the risk of developing colon cancer but the influence of diet on patients with established disease is unknown. OBJECTIVE: To determine the association of dietary patterns with cancer recurrences and mortality of colon cancer survivors. DESIGN, SETTING, AND PATIENTS: Prospective observational study of 1009 patients with stage III colon cancer who were enrolled in a randomized adjuvant chemotherapy trial (CALGB 89803) between April 1999 and May 2001. Patients reported on dietary intake using a semiquantitative food frequency questionnaire during and 6 months after adjuvant chemotherapy. We identified 2 major dietary patterns, prudent and Western, by factor analysis. The prudent pattern was characterized by high intakes of fruits and vegetables, poultry, and fish; the Western pattern was characterized by high intakes of meat, fat, refined grains, and dessert. Patients were followed up for cancer recurrence or death. MAIN OUTCOME MEASURES: Disease free survival, recurrence-free survival, and overall survival by dietary pattern. RESULTS: During a median follow-up of 5.3 years for the overall cohort, 324 patients had cancer recurrence, 223 patients died with cancer recurrence, and 28 died without documented cancer recurrence. A higher intake of a Western dietary pattern after cancer diagnosis was associated with a significantly worse disease free survival (colon cancer recurrences or death). Compared with patients in the lowest quintile of Western dietary pattern, those in the highest quintile experienced an adjusted hazard ratio (AHR) for disease-free survival of 3.25 (95% confidence interval [CI], 2.04-5.19; P for trend <.001). The Western dietary pattern was associated with a similar detriment in recurrence-free survival (AHR, 2.85; 95% CI, 1.75-4.63) and overall survival (AHR, 2.32; 95% CI, 1.36-3.96]), comparing highest to lowest quintiles (both with P for trend <.001). The reduction in disease-free survival with a Western dietary pattern was not significantly modified by sex, age, nodal stage, body mass index, physical activity level, baseline performance status, or treatment group. In contrast, the prudent dietary pattern was not significantly associated with cancer recurrence or mortality. CONCLUSIONS: Higher intake of a Western dietary pattern may be associated with a higher risk of recurrence and mortality among patients with stage III colon cancer treated with surgery and adjuvant chemotherapy. Further studies are needed to delineate which components of such a diet show the strongest association. PMID- 17699010 TI - Diabetes and mortality following acute coronary syndromes. AB - CONTEXT: The worldwide epidemic of diabetes mellitus is increasing the burden of cardiovascular disease, the leading cause of death among persons with diabetes. The independent effect of diabetes on mortality following acute coronary syndromes (ACS) is uncertain. OBJECTIVE: To evaluate the influence of diabetes on mortality following ACS using a large database spanning the full spectrum of ACS. DESIGN, SETTING, AND PATIENTS: A subgroup analysis of patients with diabetes enrolled in randomized clinical trials that evaluated ACS therapies. Patients with ACS in 11 independent Thrombolysis in Myocardial Infarction (TIMI) Study Group clinical trials from 1997 to 2006 were pooled, including 62,036 patients (46,577 with ST-segment elevation myocardial infarction [STEMI] and 15,459 with unstable angina/non-STEMI [UA/NSTEMI]), of whom 10 613 (17.1%) had diabetes. A multivariable model was constructed to adjust for baseline characteristics, aspects of ACS presentation, and treatments for the ACS event. MAIN OUTCOME MEASURES: Mortality at 30 days and 1 year following ACS among patients with diabetes vs patients without diabetes. RESULTS: Mortality at 30 days was significantly higher among patients with diabetes than without diabetes presenting with UA/NSTEMI (2.1% vs 1.1%, P < .001) and STEMI (8.5% vs 5.4%, P < .001). After adjusting for baseline characteristics and features and management of the ACS event, diabetes was independently associated with higher 30-day mortality after UA/NSTEMI (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.24-2.56) or STEMI (OR, 1.40; 95% CI, 1.24-1.57). Diabetes at presentation with ACS was associated with significantly higher mortality 1 year after UA/NSTEMI (hazard ratio [HR], 1.65; 95% CI, 1.30-2.10) or STEMI (HR, 1.22; 95% CI, 1.08 1.38). By 1 year following ACS, patients with diabetes presenting with UA/NSTEMI had a risk of death that approached patients without diabetes presenting with STEMI (7.2% vs 8.1%). CONCLUSION: Despite modern therapies for ACS, diabetes confers a significant adverse prognosis, which highlights the importance of aggressive strategies to manage this high-risk population with unstable ischemic heart disease. PMID- 17699011 TI - Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. AB - CONTEXT: Evidence is conflicting regarding the performance of apolipoproteins vs traditional lipids for predicting coronary heart disease (CHD) risk. OBJECTIVES: To compare performance of different lipid measures for CHD prediction using discrimination and calibration characteristics and reclassification of risk categories; to assess incremental utility of apolipoproteins over traditional lipids for CHD prediction. DESIGN, SETTING, AND PARTICIPANTS: Population-based, prospective cohort from, Framingham, Massachusetts. We evaluated serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, apolipoprotein (apo) A-I and apo B, and 3 lipid ratios (total cholesterol:HDL-C, LDL-C:HDL-C, and apo B:apo A-I) in 3322 middle-aged white participants who attended the fourth offspring examination cycle (1987-1991) and were without cardiovascular disease. Fifty-three percent of the participants were women. MAIN OUTCOME MEASURE: Incidence of first CHD event (recognized or unrecognized myocardial infarction, angina pectoris, coronary insufficiency, or coronary heart disease death). RESULTS: After a median follow up of 15.0 years, 291 participants, 198 of whom were men, developed CHD. In multivariate models adjusting for nonlipid risk factors, the apo B:apo A-I ratio predicted CHD (hazard ratio [HR] per SD increment, 1.39; 95% confidence interval [CI], 1.23-1.58 in men and HR, 1.40; 95% CI, 1.16-1.67 in women), but risk ratios were similar for total cholesterol:HDL-C (HR, 1.39; 95% CI, 1.22-1.58 in men and HR, 1.39; 95% CI, 1.17-1.66 in women) and for LDL-C:HDL-C (HR, 1.35; 95% CI, 1.18 1.54 in men and HR, 1.36; 95% CI 1.14-1.63 in women). In both sexes, models using the apo B:apo A-I ratio demonstrated performance characteristics comparable with but not better than that for other lipid ratios. The apo B:apo A-I ratio did not predict CHD risk in a model containing all components of the Framingham risk score including total cholesterol:HDL-C (P = .12 in men; P = .58 in women). CONCLUSIONS: In this large, population-based cohort, the overall performance of apo B:apo A-I ratio for prediction of CHD was comparable with that of traditional lipid ratios but did not offer incremental utility over total cholesterol:HDL-C. These data do not support measurement of apo B or apo A-I in clinical practice when total cholesterol and HDL-C measurements are available. PMID- 17699012 TI - High-density lipoprotein as a therapeutic target: a systematic review. AB - CONTEXT: High-density lipoprotein cholesterol (HDL-C) is a cardiovascular risk factor that is gaining substantial interest as a therapeutic target. OBJECTIVES: To review the current and emerging strategies that modify high-density lipoproteins (HDLs). DATA SOURCES: Systematic search of English-language literature (1965-May 2007) in MEDLINE and the Cochrane database, using the key words HDL-C and apolipoprotein A-I and the subheadings reverse cholesterol transport, CVD [cardiovascular disease] prevention and control, drug therapy, and therapy; review of presentations made at major cardiovascular meetings from 2003 2007; and review of ongoing trials from ClinicalTrials.gov and current guidelines from major cardiovascular societies. STUDY SELECTION AND DATA EXTRACTION: Study selection was prioritized to identify randomized controlled trials over meta analyses over mechanistic studies; identified studies also included proof-of concept studies and key phase 1 through 3 trials of novel agents. Study eligibility was assessed by 2 authors; disagreements were resolved by consensus with the third. DATA SYNTHESIS: Of 754 studies identified, 31 randomized controlled trials met the inclusion criteria. Currently available therapeutic and lifestyle strategies, when optimized, increase HDL-C levels by 20% to 30%. While basic and small pilot studies have shown promise, proof that increasing HDL-C levels confers a reduction in major cardiovascular outcomes independent of changes in levels of low-density lipoprotein cholesterol or triglycerides has been more elusive. Some novel therapeutic agents in human studies appear to effectively increase HDL-C levels, whereas other novel strategies that target HDL metabolism or function may have minimal effect on HDL-C levels. CONCLUSIONS: At present there is modest evidence to support aggressively increasing HDL-C levels in addition to what is achieved by lifestyle modification alone. Ongoing clinical trials that target specific pathways in HDL metabolism may help expand cardiovascular treatment options. PMID- 17699013 TI - How to run a successful academic practice plan. PMID- 17699014 TI - Mortality as a measure of quality: implications for palliative and end-of-life care. PMID- 17699015 TI - HPV vaccines prophylactic, not therapeutic. PMID- 17699016 TI - JAMA patient page. Acute coronary syndromes. PMID- 17699017 TI - Invited review: Advances in starter cultures and cultured foods. AB - With 2005 retail sales close to $4.8 million, cultured dairy products are driving the growth of dairy foods consumption. Starter cultures are of great industrial significance in that they play a vital role in the manufacturing, flavor, and texture development of fermented dairy foods. Furthermore, additional interest in starter bacteria has been generated because of the data accumulating on the potential health benefits of these organisms. Today, starter cultures for fermented foods are developed mainly by design rather than by the traditional screening methods and trial and error. Advances in genetics and molecular biology have provided opportunities for genomic studies of these economically significant organisms and engineering of cultures that focuses on rational improvement of the industrially useful strain. Furthermore, much research has been published on the health benefits associated with ingesting cultured dairy foods and probiotics, particularly their role in modulating immune function. The aim of this review is to describe some of the major scientific advances made in starter and non-starter lactic acid bacteria during the past 10 yr, including genomic studies on dairy starter cultures, engineering of culture attributes, advances in phage control, developments in methods to enumerate lactic acid bacteria and probiotics in dairy foods, and the potential role of cultured dairy foods in modulation of immune function. PMID- 17699018 TI - Invited review: New perspectives on the roles of nutrition and metabolic priorities in the subfertility of high-producing dairy cows. AB - Management, nutrition, production, and genetics are the main reasons for the decline in fertility in the modern dairy cow. Selection for the single trait of milk production with little consideration for traits associated with reproduction in the modern dairy cow has produced an antagonistic relationship between milk yield and reproductive performance. The outcome is a multi-factorial syndrome of subfertility during lactation; thus, to achieve a better understanding and derive a solution, it is necessary to integrate a range of disciplines, including genetics, nutrition, immunology, molecular biology, endocrinology, metabolic and reproductive physiology, and animal welfare. The common theme underlying the process is a link between nutritional and metabolic inputs that support complex interactions between the gonadotropic and somatotropic axes. Multiple hormonal and metabolic signals from the liver, pancreas, muscle, and adipose tissues act on brain centers regulating feed intake, energy balance, and metabolism. Among these signals, glucose, fatty acids, insulin-like growth factor-I, insulin, growth hormone, ghrelin, leptin, and perhaps myostatin appear to play key roles. Many of these factors are affected by changes in the somatotropic axis that are a consequence of, or are needed to support, high milk production. Ovarian tissues also respond directly to metabolic inputs, with consequences for folliculogenesis, steroidogenesis, and the development of the oocyte and embryo. Little doubt exists that appropriate nutritional management before and after calving is essential for successful reproduction. Changes in body composition are related to the processes that lead to ovulation, estrus, and conception. However, better indicators of body composition and measures of critical metabolites are required to form precise nutritional management guidelines to optimize reproductive outcomes. The eventual solution to the reduction in fertility will be a new strategic direction for genetic selection that includes fertility related traits. However, this will take time to be effective, so, in the short term, we need to gain a greater understanding of the interactions between nutrition and fertility to better manage the issue. A greater understanding of the phenomenon will also provide markers for more targeted genetic selection. This review highlights many fruitful directions for research, aimed at the development of strategies for nutritional management of reproduction in the high producing subfertile dairy cow. PMID- 17699019 TI - Enzymatic hydrolysis of heated whey: iron-binding ability of peptides and antigenic protein fractions. AB - This study evaluated the influence of various enzymes on the hydrolysis of whey protein concentrate (WPC) to reduce its antigenic fractions and to quantify the peptides having iron-binding ability in its hydrolysates. Heated (for 10 min at 100 degrees C) WPC (2% protein solution) was incubated with 2% each of Alcalase, Flavourzyme, papain, and trypsin for 30, 60, 90, 120, 150, 180, and 240 min at 50 degrees C. The highest hydrolysis of WPC was observed after 240 min of incubation with Alcalase (12.4%), followed by Flavourzyme (12.0%), trypsin (10.4%), and papain (8.53%). The nonprotein nitrogen contents of WPC hydrolysate followed the hydrolytic pattern of whey. The major antigenic fractions (beta-lactoglobulin) in WPC were degraded within 60 min of its incubation with Alcalase, Flavourzyme, or papain. Chromatograms of enzymatic hydrolysates of heated WPC also indicated complete degradation of beta-lactoglobulin, alpha-lactalbumin, and BSA. The highest iron solubility was noticed in hydrolysates derived with Alcalase (95%), followed by those produced with trypsin (90%), papain (87%), and Flavourzyme (81%). Eluted fraction 1 (F-1) and fraction 2 (F-2) were the respective peaks for the 0.25 and 0.5 M NaCl chromatographic step gradient for analysis of hydrolysates. Iron-binding ability was noticeably higher in F-1 than in F-2 of all hydrolysates of WPC. The highest iron contents in F-1 were observed in WPC hydrolysates derived with Alcalase (0.2 mg/kg), followed by hydrolysates derived with Flavourzyme (0.14 mg/kg), trypsin (0.14 mg/kg), and papain (0.08 mg/kg). Iron concentrations in the F-2 fraction of all enzymatic hydrolysates of WPC were low and ranged from 0.03 to 0.05 mg/kg. Fraction 1 may describe a new class of iron chelates based on the reaction of FeSO4 x 7 H2O with a mixture of peptides obtained by the enzymatic hydrolysis of WPC. The chromatogram of Alcalase F-1 indicated numerous small peaks of shorter wavelengths, which probably indicated a variety of new peptides with greater ability to bind with iron. Alcalase F-1 had higher Ala (18.38%), Lys (17.97%), and Phe (16.58%) concentrations, whereas the presence of Pro, Gly, and Tyr was not detected. Alcalase was more effective than other enzymes at producing a hydrolysate for the separation of iron-binding peptides derived from WPC. PMID- 17699020 TI - Peptic and tryptic hydrolysis of native and heated whey protein to reduce its antigenicity. AB - This study examined the effects of enzymes on the production and antigenicity of native and heated whey protein concentrate (WPC) hydrolysates. Native and heated (10 min at 100 degrees C) WPC (2% protein solution) were incubated at 50 degrees C for 30, 60, 90, and 120 min with 0.1, 0.5, and 1% pepsin and then with 0.1, 0.5, and 1% trypsin on a protein-equivalent basis. A greater degree of hydrolysis was achieved and greater nonprotein nitrogen concentrations were obtained in heated WPC than in native WPC at all incubation times. Hydrolysis of WPC was increased with an increasing level of enzymes and higher incubation times. The highest hydrolysis (25.23%) was observed in heated WPC incubated with 1% pepsin and then with 1% trypsin for 120 min. High molecular weight bands, such as BSA, were completely eliminated from sodium dodecyl sulfate-PAGE of both native and heated WPC hydrolysates produced with pepsin for the 30-min incubation. The alpha lactalbumin in native WPC was slightly degraded when incubated with 0.1% pepsin and then with 0.1% trypsin; however, it was almost completely hydrolyzed within 60 min of incubation with 0.5% pepsin and then with 0.5% trypsin. Incubation of native WPC with 1% pepsin and then with 1% trypsin for 30 min completely removed the BSA and alpha-lactalbumin. The beta-lactoglobulin in native WPC was not affected by the pepsin and trypsin treatments. The beta-lactoglobulin in heated WPC was partially hydrolyzed by the 0.1 and 0.5% pepsin and trypsin treatments and was completely degraded by the 1% pepsin and trypsin treatment. Antigenicity reversibly mimicked the hydrolysis of WPC and the removal of beta-lactoglobulin from hydrolysates. Antigenicity in heated and native WPC was reduced with an increasing level of enzymes. A low antigenic response was observed in heated WPC compared with native WPC. The lowest antigenicity was observed when heated WPC was incubated with 1% pepsin and then with 1% trypsin. These results suggested that incubation of heated WPC with 1% pepsin and then with 1% trypsin was the most effective for producing low-antigenic hydrolysates by WPC hydrolysis and obtaining low molecular weight small peptides. Further research is warranted to identify the low molecular weight small peptides in the WPC hydrolysates produced by pepsin and trypsin, which may enhance the use of whey. PMID- 17699021 TI - Galactose metabolism and capsule formation in a recombinant strain of Streptococcus thermophilus with a galactose-fermenting phenotype. AB - The capsule-producing, galactose-negative Streptococcus thermophilus MR-1C strain was first transformed with a low-copy plasmid containing a functional galK gene from Streptococcus salivarius to generate a recombinant galactose-fermenting Strep. thermophilus strain named MR-AAC. Then, we compared the functional properties of Strep. thermophilus MR-AAC with those of the parent MR-1C strain when used as starter for fermented products and cheese. In lactose-supplemented laboratory medium, MR-AAC metabolized galactose, but only when the amount of lactose was less than 0.1% (wt/vol). After 7 h of fermentation, the medium was almost depleted of galactose. The parent strain, MR-1C, showed the same pattern, except that the concentration of galactose decreased by only 25% during the same period. It was found that, during milk fermentation and Mozzarella cheese production, the galactose-fermenting phenotype was not expressed by MR-AAC and this strain expelled galactose into the medium at a level similar to the parent MR-1C strain. In milk and in lactose-supplemented medium, capsular exopolysaccharide production occurred mainly during the late exponential phase and the stationary growth phase with similar kinetics between MR-1C and MR-AAC. PMID- 17699022 TI - Texture of low-fat Iranian White cheese as influenced by gum tragacanth as a fat replacer. AB - The effect of different concentrations of gum tragacanth on the textural characteristics of low-fat Iranian White cheese was studied during ripening. A batch of full-fat and 5 batches of low-fat Iranian White cheeses with different gum tragacanth concentrations (without gum or with 0.25, 0.5, 0.75, or 1 g of gum/kg of milk) were produced to study the effects of fat content reduction and gum concentration on the textural and functional properties of the product during ripening. Cheese samples were analyzed with respect to chemical, color, and sensory characteristics, rheological parameters (uniaxial compression and small amplitude oscillatory shear), and microstructure. Reducing the fat content had an adverse effect on cheese yield, sensory characteristics, and the texture of Iranian White cheese, and it increased the instrumental hardness parameters (i.e., fracture stress, elastic modulus, storage modulus, and complex modulus). However, increasing the gum tragacanth concentration reduced the values of instrumental hardness parameters and increased the whiteness of cheese. Although when the gum concentration was increased, the low-fat cheese somewhat resembled its full-fat counterpart, the interaction of the gum concentration with ripening time caused visible undesirable effects on cheese characteristics by the sixth week of ripening. Cheeses with a high gum tragacanth concentration became very soft and their solid texture declined somewhat. PMID- 17699023 TI - Preliminary study of ultrasonic structural quality control of Swiss-type cheese. AB - There is demand for a new nondestructive cheese-structure analysis method for Swiss-type cheese. Such a method would provide the cheese-making industry the means to enhance process control and quality assurance. This paper presents a feasibility study on ultrasonic monitoring of the structural quality of Swiss cheese by using a single-transducer 2-MHz longitudinal mode pulse-echo setup. A volumetric ultrasonic image of a cheese sample featuring gas holes (cheese-eyes) and defects (cracks) in the scan area is presented. The image is compared with an optical reference image constructed from dissection images of the same sample. The results show that the ultrasonic method is capable of monitoring the gas solid structure of the cheese during the ripening process. Moreover, the method can be used to detect and to characterize cheese-eyes and cracks in ripened cheese. Industrial application demands were taken into account when conducting the measurements. PMID- 17699024 TI - Quantitative measurement of tetrahydromenaquinone-9 in cheese fermented by propionibacteria. AB - Propionibacteria produce tetrahydromenaquinone-9 [MK-9 (4H)] as a major menaquinone (vitamin K2). This study aimed to determine the MK-9 (4H) concentration in commercial propionibacteria-fermented cheese. The MK-9 (4H) concentration was quantified using an HPLC instrument with a fluorescence detector after postcolumn reduction. Among the various cheese samples, the MK-9 (4H) concentration was highest in Norwegian Jarlsberg cheese, followed by Swiss Emmental cheese. In contrast, the MK-9 (4H) concentrations in Appenzeller or Gruyere cheeses were extremely low or undetected. Likewise, the concentrations in Comte and Raclette cheeses were lower than those in Jarlsberg and Emmental cheeses. In the present study, the MK- 9 (4H) concentration in cheese showed a correlation with the viable propionibacterial cell count and propionate concentration. This implies that the increase in propionibacteria contributed to the generation of MK-9 (4H) in cheese. We presumed, based on these results, that Swiss Emmental and Norwegian Jarlsberg cheeses contain a meaningful amount of vitamin K because of their high MK-9 (4H) concentrations (200 to 650 ng/g). PMID- 17699025 TI - Use of human lysozyme transgenic goat milk in cheese making: effects on lactic acid bacteria performance. AB - Genetically engineered goats expressing elevated levels of the antimicrobial enzyme lysozyme in their milk were developed to improve udder health, product shelf life, and consumer well-being. The purpose of this study was to evaluate the effect of lysozyme on the development of lactic acid bacteria (LAB) throughout the cheese-making process. Raw and pasteurized milk from 7 lysozyme transgenic goats and 7 breed-, age-, and parity-matched nontransgenic controls was transformed into cheeses by using industry methods, and their microbiological load was evaluated. The numbers of colony-forming units of LAB were determined for raw and pasteurized goat milk, whey, and curd at d 2 and at d 6 or 7 of production. Selective plating media were used to enumerate lactococcal species separately from total LAB. Although differences in the mean number of colony forming units between transgenic and control samples in raw milk, whey, and cheese curd were non-significant for both total LAB and lactococcal species from d 2 of production, a significant decrease was observed in both types of LAB among d 6 transgenic raw milk cheese samples. In pasteurized milk trials, a significant decrease in LAB was observed only in the raw milk of transgenic animals. These results indicate that lysozyme transgenic goat milk is not detrimental to LAB growth during the cheese-making process. PMID- 17699026 TI - Bovine kappa-casein gene promoter haplotypes with potential implications for milk protein expression. AB - Genetic analysis of the kappa-casein gene (CSN3) promoter regions of 42 cattle representing 9 different breeds revealed that 2 distinct haplotypes (A and B) exist at this locus, differing from each other by single base changes at positions -514 (T/G), -426 (T/C), and -384 (T/C), where haplotype A has bases T, T, and T and haplotype B has bases G, C, and C. The AA and AB haplotypes were found to occur at a higher frequency in the animals tested, with 69.0 and 21.4% being homozygous and heterozygous, respectively. The sequences that include these polymorphisms are potentially important in transcriptional regulation of the kappa-casein gene, because they contain putative sites for binding of many transcription factors. Linkage disequilibrium between the kappa-casein promoter haplotype and either one of the 2 major kappa-casein coding sequence haplotypes was not evident. The A allele is dominant in all groups (dairy, beef, and dual purpose) with an allele frequency of 80% and is higher among high-yielding dairy animals (88.9%) than among beef animals (75%). The AB haplo-type is comparatively rare in the dairy cattle (11.1%) compared with both beef and dual-purpose animals. The BB haplotype, though rare overall (9.5%), is much higher in dual purpose animals (18.8%) than dairy (5.6%) animals. In contrast, the B allele is much more representative of the kappa-casein promoters from other ruminants. PMID- 17699027 TI - Rapid and effective method for separation of Staphylococcus aureus from somatic cells in mastitis milk. AB - Quantitative PCR can be an effective method for identifying the bacteria causing mastitis. However, PCR detection is hampered by the presence of inflammatory somatic cells. To eliminate this problem, we attempted to establish methods that allow the effective separation of bacterial cells from somatic cells in mastitis milk with amino-silica. Somatic cells and Staphylococcus aureus cells have different sizes, surface structures, and overall electrical charges; therefore, their adsorption and desorption behavior on amino-silica was also different. We found that although amino-silica could efficiently adsorb both somatic cells and Staph. aureus, somatic cells were adsorbed much more strongly than bacterial cells. We identified conditions under which most of the somatic cells adsorbed and only Staph. aureus desorbed from amino-silica upon addition of a desorption solution. We demonstrated that this procedure effectively eliminated somatic cells in heavily contaminated milk samples, which resulted in improved clarity of the PCR band. These results indicate that pretreatment of the samples with amino silica made the PCR-based strategy for identifying and quantifying disease causing bacteria applicable for all milk samples. PMID- 17699028 TI - A survey of bovine colostrum composition and colostrum management practices on Pennsylvania dairy farms. AB - Colostrum composition and management were surveyed via sample and data collection from 55 dairy farms in Pennsylvania. Colostrum samples were analyzed for fat, protein, lactose, total solids, ash, Ig, lactoferrin, water- and fat-soluble vitamins, and minerals. Mean percentages of fat, protein, and lactose in colostrum were 6.7, 14.9, and 2.5, respectively. Concentrations of IgG1, IgG2, IgA, IgM, and lactoferrin were 35.0, 6.0, 1.7, 4.3, and 0.8 mg/mL, respectively. Mean concentrations of fat-soluble vitamins, including retinol, tocopherol, and beta-carotene, were 4.9, 2.9, and 0.7 microg/g, respectively. Mean concentrations of water-soluble vitamins were 0.34, 0.90, 4.55, 0.60, 0.15, 0.21, and 0.04 microg/mL for niacin, thiamine, riboflavin, vitamin B12, pyridoxal, pyridoxamine, and pyridoxine, respectively. Mean concentrations (mg/kg) of selected minerals in colostrum were also determined (Ca 4,716; P 4,452; Mg 733; Na 1,058; K 2,845; Zn 38; Fe 5.3; Cu 0.3; S 2,595; and Mn 0.1). The findings of this study revealed that the mean concentrations of most nutrients in colostrum have increased when compared with values previously reported. Results also showed that management practices have improved over time, particularly with regard to colostrum storage and feeding. Additionally, we observed that herd size influenced colostrum management and quality. It can be inferred, based on these findings, that although improvements have been made with regard to colostrum management and quality, there is still a need to educate producers on issues related to storage and timely feeding of colostrum to increase passive transfer and decrease the rate of calf morbidity and mortality. PMID- 17699029 TI - Increasing selenium concentration in milk: effects of amount of selenium from yeast and cereal grain supplements. AB - Two experiments were conducted to establish responses in milk Se concentrations in grazing dairy cows to different amounts of dietary Se yeast, and to determine the effects of the Se concentration of the basal diet. The hypothesis tested was that the response in milk, blood, and tissue Se concentrations to supplemental Se would not be affected by whether the Se was from the basal diet or from Se yeast. In addition, by conducting a similar experiment in either early (spring; experiment 1) or late (autumn; experiment 2) lactation, we hypothesized that different Se input-output relationships would result. Both 6-wk experiments involved 60 multiparous Holstein-Friesian cows, all of which had calved in spring. They were allocated to 1 of 10 dietary Se treatments that included 2 types of crushed triticale grain (low Se, approximately 165 microg of Se/kg of DM; or high Se, approximately 580 microg/kg of DM) fed at 4 kg of DM/d, and 1 kg of DM/d of pellets formulated to carry 5 quantities of Se yeast (0, 4, 8, 12, or 16 mg of Se). Daily total Se intakes ranged from <2 to >18 mg/cow in both experiments. Milk Se concentrations plateaued after 15 and 7 d of supplementation in experiments 1 and 2, respectively, and then remained at plateau concentrations. Average milk Se concentrations for the plateau period increased as the amount of Se yeast increased, and low- and high-Se grain treatments were different at all quantities of Se yeast, although there was a tendency for this difference to diminish at the greatest concentrations of yeast. There were significant positive, linear relationships between Se intake and the concentrations of Se in milk, which were not affected by the source of Se, and the relationships were similar for both experiments. Therefore, the output of Se in milk in experiment 1 was greater than that in experiment 2 because the milk yield of the cows in early lactation was greater. The estimated proportions of Se partitioned to destinations other than milk and feces increased with the amount of Se in the diet and were greater in experiment 2 than in experiment 1, a result that was supported by Se concentrations in whole blood and plasma and in semitendinosus muscle tissue. If high-Se products are to be produced for human nutrition, it is important to be able to develop feeding systems that produce milk with consistent and predictable Se concentrations so that products can consistently meet specifications. The results indicate that this objective is achievable. PMID- 17699030 TI - Extraction and quantitative analysis of stearoyl-coenzyme A desaturase mRNA from dairy cow milk somatic cells. AB - Study of stearoyl-coenzyme A desaturase (SCD) gene expression in the bovine mammary gland is limited by restricted availability of mammary tissue samples from biopsy or postmortem sampling of cows during temporal experiments. A technique was developed to isolate total RNA from somatic cells in bovine milk and to analyze SCD mRNA expression by quantitative reverse-transcription PCR. Total RNA yield was lower than in a previous goat study and was related to numbers of viable somatic cells. To obtain sufficient total RNA, 1-L milk samples were taken and stored for up to 24 h at 4 degrees C. Complementary DNA prepared from somatic cells showed a 99% match with the published sequence for SCD mRNA in bovine adipose tissue. Stearoyl-CoA desaturase mRNA abundance relative to beta actin mRNA for 12 cows sampled across 4 time points varied (mean +/- SE) from 0.88 +/- 0.17 to 4.40 +/- 0.50. Fifty-five percent of variation was due to individual cows and 42% was due to daily variation within cows. Relative abundance of SCD mRNA was not related to the number of viable somatic cells or total RNA extracted from samples, but it was related to mammary desaturase activity, as indicated by changes in milk C14 fatty acid concentrations. We concluded that somatic cells provide a noninvasive and repeatable alternative to mammary tissue samples obtained by biopsy or postmortem. PMID- 17699031 TI - Effect of herd characteristics, management practices, and season on different categories of the herd somatic cell count. AB - In this study, the contribution of management practices, herd characteristics, and seasonal variables to the herd somatic cell count (SCC) was quantified in herds with low (<150,000 cells/mL), medium (150,000-200,000 cells/mL), and high (>200,000 cells/mL) herd SCC (HSCC). Selection of the variables was performed using a linear mixed effect model; HSCC was calculated as the arithmetic mean of the individual cow's SCC. The data concerning management practices were derived from 3 questionnaires on mastitis prevention and management practices on 246 Dutch dairy farms. The monthly Dairy Herd Improvement test data of these 246 farms were used to calculate the herd characteristics and seasonal effects. None of the management practices were associated with HSCC in all 3 HSCC categories. Some variables only had a significant association with HSCC in one HSCC category, such as dry premilking treatment (-9,100 cells/mL in the low HSCC category) or feeding calves with high SCC milk (11,100 cells/ mL in the medium HSCC category). Others had an opposite effect on HSCC in different HSCC categories, such as average parity (-6,400 and 11,000 cells/mL in the low and medium HSCC category, respectively) and feeding calves with fresh milk (10,300 and -9,700 cells/ mL in the low and high HSCC category, respectively). We conclude that, given the individual Dairy Herd Improvement data and information on management practices of an individual farm, it is possible to provide quantitative insight into the contribution of these different variables to the HSCC of an individual farm. Being able to provide such insight is a prerequisite for interpretation, prediction, and control of HSCC on individual dairy farms. PMID- 17699032 TI - Short communication: Comparison of bulk milk, yield-corrected, and average somatic cell counts as parameters to summarize the subclinical mastitis situation in a dairy herd. AB - In this study, the correlation was determined between the prevalence of high cow level somatic cell count (SCC >250,000 cells/mL), a summary of the subclinical mastitis situation in a dairy herd, and 3 average herd SCC parameters: bulk milk SCC (BMSCC), yield-corrected test-day SCC (CHSCC), and the arithmetic average test-day SCC (HSCC) of the lactating herd. The herd prevalence of cows with an SCC of >250,000 cells/mL was calculated by using Dairy Herd Improvement data. Herds were included if BMSCC was sampled within 2 d of the Dairy Herd Improvement test day and if the BMSCC did not exceed 400,000 cells/mL. The interval between sampling, 0, 1, or 2 d, did not significantly influence the correlation between BMSCC and the prevalence of high SCC. The correlations between the prevalence of high SCC and BMSCC, yield-corrected test-day SCC, and HSCC, examined by using a linear regression model, were 0.64, 0.78, and 0.89, respectively. Therefore, it can be concluded that, based on the highest correlation, HSCC is a more appropriate parameter than BMSCC to summarize the average herd subclinical mastitis situation in a dairy herd. PMID- 17699033 TI - Effect of supplementation with calcium salts of fish oil on n-3 fatty acids in milk fat. AB - Enrichment of milk fat with n-3 fatty acids, in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may be advantageous because of their beneficial effects on human health. In addition, these fatty acids play an important role in reproductive processes in dairy cows. Our objective was to evaluate the protection of EPA and DHA against rumen biohydrogenation provided by Ca salts of fish oil. Four Holstein cows were assigned in a Latin square design to the following treatments: 1) ruminal infusion of Ca salts of fish oil and palm fatty acid distillate low dose (CaFO-1), 2) ruminal infusion of Ca salts of fish oil and palm fatty acid distillate high dose (CaFO-2), 3) ruminal infusion of fish oil high dose (RFO), and 4) abomasal infusion of fish oil high dose (AFO). The high dose of fish oil provided approximately 16 and approximately 21 g/d of EPA and DHA, respectively, whereas the low dose (CaFO-1) provided 50% of these amounts. A 10-d pretreatment period was used as a baseline, followed by 9-d treatment periods with interceding intervals of 10 d. Supplements were infused every 6 h, milk samples were taken the last 3 d, and plasma samples were collected the last day of baseline and treatment periods. Milk fat content of EPA and DHA were 5 to 6 times greater with AFO, but did not differ among other treatments. Milk and milk protein yield were unaffected by treatment, but milk fat yield and DM intake were reduced by 20 and 15%, respectively, by RFO. Overall, results indicate rumen biohydrogenation of long chain n-3 fatty acids was extensive, averaging >85% for EPA and >75% for DHA for the Ca salts and unprotected fish oil supplements. Thus, Ca salts of fish oil offered no protection against the biohydrogenation of EPA and DHA beyond that observed with unprotected fish oil; however, the Ca salts did provide rumen inertness by preventing the negative effects on DM intake and milk fat yield observed with unprotected fish oil. PMID- 17699034 TI - Epidemiology of mastitis in pasture-grazed peripartum dairy heifers and its effects on productivity. AB - An observational field study was conducted on 708 heifers in 30 spring-calving dairy herds in the Waikato region of New Zealand. The aim of the study was to describe patterns and effects of intramammary infection (IMI) and clinical mastitis (CM) in the peripartum period. Mammary secretion samples for bacteriological testing were taken from all quarters approximately 3 wk before the planned start of the calving period and within 5 d following calving, in addition to quarters diagnosed with CM within 14 d of calving. Precalving IMI was diagnosed in 18.5% of quarters, and of these, coagulase-negative staphylococci were the predominant isolate (13.5% of quarters). Streptococcus uberis prevalence increased 4-fold to 10.0% of quarters on the day of calving compared with the precalving period. Prevalence of all pathogens decreased rapidly following calving. Clinical mastitis cases were predominantly associated with Strep. uberis (64%). The daily hazard of diagnosis was higher in heifers than in cows (0.06 vs. 0.02/d on d 1 postcalving, respectively), but was not different by d 5 (0.005 vs. 0.002, respectively) of lactation. Intramammary infection with a major pathogen was associated with an increased risk of removal from the herd (15 vs. 10% for infected and noninfected heifers, respectively) and somatic cell count >200,000 cells/mL at subsequent herd tests (15 vs. 8%), but neither CM nor IMI were associated with reduced milk yield or milk solids production. Results suggest that bacterial species involved and the pattern of IMI prevalence in pasture grazed peripartum heifers differ from those in other production systems. Further, mastitis control programs need to target major environmental pathogens causing precalving IMI, because new infections are likely before the onset of lactation, whereas existing detection and control measures are generally implemented after calving. Novel control programs that reduce new infections due to Strep. uberis immediately before calving are required to reduce the incidence of CM in pasture grazed dairy heifers. PMID- 17699035 TI - Risk factors for peripartum mastitis in pasture-grazed dairy heifers. AB - A longitudinal observational field study was conducted using 708 heifers in 30 spring-calving dairy herds in the Waikato region of New Zealand. The aim of the study was to investigate risk factors for subclinical and clinical mastitis (CM) in the peripartum period using path analysis methods and to find the factors most important at the population level as a basis for potential control programs. Body condition and udder hygiene scores, blood samples, and quarter mammary secretion samples for bacteriology were collected approximately 3 wk before the planned start of the seasonal calving period and again within 5 d following calving. Additionally, milk samples were collected from quarters diagnosed with CM within 14 d of calving. Significant risk factors for subclinical mastitis postcalving were precalving subclinical mastitis (3.32 incidence risk ratio; IRR), low minimum teat height above the ground (1.32 IRR), and unhygienic udder postcalving (1.32 IRR). Significant risk factors for clinical mastitis postcalving were precalving subclinical mastitis (2.14 IRR), Friesian breed (1.94 IRR), low minimum teat height above the ground (2.05 IRR), udder edema (1.81 IRR), and low postcalving nonesterified fatty acid serum concentration (1.55 IRR). Control of precalving subclinical mastitis and udder edema by producers, and enhancement of breed immunity by geneticists were important factors at a population level, and hence, are likely the most rewarding areas to target in any heifer mastitis management program. PMID- 17699036 TI - Effect of isoflupredone acetate with or without insulin on energy metabolism, reproduction, milk production, and health in dairy cows in early lactation. AB - Glucocorticoids are commonly used to treat cows with clinical ketosis and fatty liver disease, but their use is controversial. The objectives of the present study were to investigate the effects of isoflupredone acetate alone or with insulin on the energy metabolism of dairy cows in early lactation in a large double-blind, randomized clinical trial. A total of 1,162 Holstein cows and first lactation heifers were randomly assigned to receive 1 of 3 treatments between the day of parturition and 8 DIM: group A, 20-mg i.m. injection of isoflupredone and 100 units of insulin; group B, 20-mg i.m. injection of isoflupredone; group C (control group), 10-mL i.m. injection of sterile water. Treatments were randomized across 24 dairy farms located near Guelph, Ontario, Canada. Serum samples obtained at the time of treatment and at wk 1 and 2 following treatment were analyzed for beta-hydroxybutyrate, nonesterified fatty acids, glucose, calcium, potassium, sodium, and chloride. Cows were assigned a body condition score at the time of enrollment. Data were analyzed using a repeated-measures mixed model that accounted for the effects of parity and body condition score, and the random effects of cow and farm. Cows that received isoflupredone with insulin and isoflupredone alone had higher beta-hydroxybutyrate and nonesterified fatty acid concentrations 1 wk after treatment compared with control cows. Cows that received isoflupredone acetate plus insulin had lower glucose concentrations at 1 wk after treatment. Calcium concentrations 1 wk after treatment were lower for cows that received isoflupredone and insulin or isoflupredone only compared with control cows. Serum sodium, potassium, and chloride concentrations were not influenced by treatment. The effect of treatment on the proportion of cows with subclinical ketosis was evaluated with a logistic regression model. Over the 2 wk following treatment, a significant increase in the prevalence of subclinical ketosis was observed in the isoflupredone plus insulin group relative to the control group. Among 972 cows that were not ketotic at enrollment, cows that received isoflupredone acetate plus insulin or isoflupredone acetate only were, respectively, 1.72 and 1.59 times more likely than control cows to develop subclinical ketosis 1 wk after treatment. There were no treatment effects on test day milk production, milk fat and protein percentages, or the intervals from calving to first insemination or pregnancy. PMID- 17699037 TI - Behavior of dairy cows in an alternative bedded-pack housing system. AB - The objectives of this study were to measure lying behavior and social interactions of lactating cows housed in an alternative bedded-pack system, commonly referred to as a compost dairy barn, and to investigate the association between the temperature-humidity index and lying behavior of these cows. The study was conducted in 12 compost dairy barns in Minnesota between late June 2005 and September 2005. Lying, standing, and walking behavior of 147 focal cows was measured by automatic activity monitors. The daily lying time was 9.34 +/- 1.94 h. The number of daily lying bouts was 11.0 +/- 3.2 and the lying bout length was 50.8 +/- 35.6 min. As days in milk increased, the total number of lying bouts increased, corresponding to an increase in total daily lying time. Cows in the compost barns lay down for less time, took more steps, and reduced the length of lying bouts as the temperature-humidity index increased. Social interactions and lying positions of all cows in the bedded-pack area (total of 886 cows in the 12 dairies) were recorded using visual observations during two 4-h periods on 2 separate days. A total of 43.3% of the cows were lying down at any time. All 4 natural lying positions (head back, head up, flat on the side, and head on the ground) were observed in 9 of the bedded packs during the direct visual observation periods. The majority (84.6%) of the cows observed lying down assumed the head-up position. Of all observed lying events, the head-back lying position was assumed 8.8% of the time, the head on the ground 5.4% of the time, and flat on the side 0.8% of the time. Observations of social interactions on the bedded pack area showed that 0.94 +/- 1.5 incidents of chasing away, 0.94 +/- 1.8 of pushing, 1.4 +/- 1.6 of head butting, and 2.3 +/- 2.9 of allogrooming (social licking) occurred per hour. Observations of lying behavior, social interactions, and natural lying positions indicated that compost dairy barns can be an adequate housing system for dairy cows. PMID- 17699038 TI - Body condition score and body weight effects on dystocia and stillbirths and consequent effects on postcalving performance. AB - The objective of this study was to quantify the effect of periparturient body condition score (BCS) and body weight (BW) related traits on the incidence of calving dystocia and stillbirths, and to determine any consequent effect of dystocia and stillbirths on BCS, BW, milk production, udder health, and fertility in grazing Holstein-Friesian dairy cows. Up to 2,384 lactation records with data on calving dystocia or stillbirths were available from one research herd across 15 yr. Mixed models and generalized estimating equations were used to quantify all effects. Body condition score or BW 8 wk precalving or at calving, or change precalving did not significantly affect the odds of a difficult calving or stillbirth. Cows that experienced dystocia lost, on average, more BCS and BW between calving and nadir and had significantly reduced nadir BCS and BW. Incidence of stillbirths did not affect BCS in early lactation, although BW loss postpartum was greater following a stillbirth. A dystocia or stillbirth event was associated with reduced 60-d milk yield (42 and 52 kg less milk produced following a difficult calving or a stillbirth, respectively). The effect of stillbirth on milk yield was independent of dystocia. Cows that experienced dystocia had reduced milk concentration of fat, protein, and lactose, whereas average somatic cell score (natural logarithm of somatic cell count) in the first 60-d postpartum was elevated. There was no significant effect of dystocia or stillbirth on clinical mastitis, but pregnancy rates to first service and throughout the 12-wk breeding season were compromised in cows that had experienced difficulty at calving. The significance of the effects of stillbirth on somatic cell score and reduced fertility were mediated through its association with dystocia. In conclusion, periparturient BCS and BW within the range observed in the current study did not significantly affect incidence of dystocia and stillbirth, but these events negatively affected cow performance in early lactation. PMID- 17699039 TI - Reducing the interval from presynchronization to initiation of timed artificial insemination improves fertility in dairy cows. AB - The objective was to determine if reducing the interval from presynchronization to the first GnRH injection (G1) of a timed artificial insemination (AI) protocol improves pregnancy per AI. One thousand two hundred fourteen Holstein cows, at 37 +/- 3 d in milk (DIM), were stratified by parity, DIM, and milk yield in the first month postpartum and randomly assigned to control (n = 412), 2 injections of PGF2alpha at 37 +/- 3 and 51 +/- 3 DIM, then enrolled in a timed AI protocol 14 d later; PShort (n = 410), 2 injections of PGF2alpha at 40 +/- 3 and 54 +/- 3 DIM, then enrolled in a timed AI protocol 11 d later; or PShortG (n = 392), same as PShort, but with an injection of GnRH 7 d before G1. All cows received the same timed AI protocol (d 65, G1; d 72, PGF2alpha; d 73, 1 mg of estradiol cypionate; d 75, AI). A subset of 1,000 cows had their ovaries examined by ultrasonography at G1 and 7 d later when PGF2alpha of the timed AI was given to determine presence of corpus luteum (CL) and ovulation to G1. Pregnancy was diagnosed on d 38 after timed AI, and pregnant cows were reevaluated for pregnancy 4 wk later. Altering the interval between presynchronization and G1 did not affect the proportion of cows with a CL at G1, but GnRH 7 d before G1 increased the proportion of cows with a CL. Ovulation to G1 was greater for 11 compared with the 14 d interval, but GnRH did not improve ovulation. The increased ovulation to G1 when the interval was reduced from 14 to 11 d was observed only in cows with a CL at G1, but treatment did not affect ovulation in cows without a CL at G1. Treatment affected the pregnancy per AI on d 38 and 66 after insemination, and they were greater for the 11 compared with 14-d interval, but addition of GnRH did not improve pregnancy per AI. Cows ovulating to G1 had greater pregnancy per AI regardless of whether or not they had a CL at G1. Reducing the interval from presynchronization to initiation of the timed AI protocol from 14 to 11 d increased ovulation to G1 and pregnancy per AI in lactating dairy cows. PMID- 17699040 TI - Pharmacokinetics and milk penetration of orbifloxacin after intravenous, subcutaneous, and intramuscular administration to lactating goats. AB - The single-dose disposition kinetics of orbifloxacin were determined in clinically normal lactating goats (n = 6) after intravenous, subcutaneous, and intramuscular administration of 2.5 mg of orbifloxacin/kg of body weight. Orbifloxacin concentrations were determined by HPLC with fluorescence detection. The concentration-time data were analyzed by compartmental and noncompartmental kinetic methods. Steady-state volume of distribution and clearance of orbifloxacin after intravenous administration were 1.13 +/- 0.08 L/kg and 0.40 +/ 0.11 L/h x kg, respectively. Following subcutaneous and intramuscular administration, orbifloxacin achieved maximum plasma concentrations of 1.85 +/- 0.20 and 1.66 +/- 0.14 mg/L at 1.25 +/- 0.22 and 0.87 +/- 0.38 h, respectively. The absolute bioavailabilities after subcutaneous and intramuscular routes were 108.96 +/- 17.61% and 105.01 +/- 15.61%, respectively. Orbifloxacin penetration from the blood into the milk was rapid and showed high levels of concentrations in milk secretion. From this data, orbifloxacin could have success against susceptible mastitis pathogens in goats. PMID- 17699041 TI - In vitro growth of enterococci of bovine origin in bovine mammary secretions from various stages of lactation. AB - In vitro growth responses of Enterococcus faecium and Enterococcus faecalis were tested in cell-free, fat-free bovine mammary secretions. Mammary secretions were collected during the dry period, and during early, late, and extended lactation. Sixty-three enterococcal isolates from aseptically collected bovine quarter milk samples and bedding samples from a commercial dairy herd were tested. Isolates from bovine quarter milk samples originated from mammary glands with clinical mastitis, cows with composite somatic cell score >4, postpartum milk samples, or from routine milk samples submitted to a mastitis diagnostic laboratory. Source of enterococcal isolates and the species significantly contribute to the ability of organisms to multiply in mammary secretions from various stages of lactation. Isolates collected from milk samples of the commercial herd and isolates from milk submitted to a mastitis diagnostic lab did not display enhanced growth in mammary secretions compared with isolates from bedding. Growth responses of E. faecalis were greater than those for E. faecium in secretions collected during the dry period, late lactation, and extended lactation. Bacterial growth did not differ between enterococcal species in mammary secretion collected from cows in early lactation. Differences in bacterial growth between E. faecalis and E. faecium in mammary secretions may indicate differences between species in susceptibility of mammary glands during the lactation cycle. PMID- 17699042 TI - Effects of a concentrated lidocaine solution on the acute phase stress response to dehorning in dairy calves. AB - The objective of this study was to more fully define the surgical stress response to dehorning by heat cauterization in dairy calves by measuring behavioral, hormonal, inflammatory, and immunological markers of stress and to determine whether a nerve block of the surgical site with a concentrated solution of lidocaine (5%) reduces the degree of stress. Thirty-two 10- to 12-wk-old female Holstein calves were randomly allotted to 1 of 4 treatments: 5% lidocaine followed by dehorning, 2% lidocaine followed by dehorning, saline followed by dehorning, or 5% lidocaine followed by sham dehorning. Plasma cortisol concentration was measured in blood samples collected via a jugular catheter at 0.5, 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 9, 12, 24, 48, and 72 h. Various other blood constituents were measured in samples collected at -0.5, 12, 24, 48, and 72 h. Feeding, drinking, scratching, grooming, rubbing, licking, and inactivity behaviors were observed in the standing and recumbent positions using a 10-min scan sampling method analyzed on a time period and daily basis for 72 h following the dehorning procedure. The frequency of vocalization, kicking, and lying in the chute during the dehorning procedure were also assessed. The overall plasma cortisol concentrations were higher in calves subjected to dehorning than in control calves. Compared with the control group, the saline-treated calves had a higher cortisol concentration at 30 and 60 min postdehorning. Plasma cortisol concentrations were higher in all groups at 30 min postdehorning than at other sampling times. The percentage of circulating neutrophils and the neutrophil:lymphocyte ratio were increased in the saline and 2% lidocaine group. Total plasma protein, fibrinogen, and alpha1-acid glycoprotein concentrations were similar among treatments. The behavioral response to dehorning, as manifested by kicking while in the chute, was greater in the saline and 2% lidocaine group than in the control or 5% lidocaine treatment groups. In the postdehorning period, the percentage of time calves spent performing various maintenance behaviors did not differ among treatments. Thus, injection of 5% lidocaine may not provide any added comfort after the dehorning but may decrease the overall stress response during the procedure. PMID- 17699043 TI - Evaluation of methods of resynchronization for insemination in cows of unknown pregnancy status. AB - The objectives of this study were to evaluate the effect of 3 methods of resynchronization of estrus and ovulation for lactating dairy cows of unknown pregnancy status on conception rate and time to pregnancy. Holstein cows (n = 495) were randomly assigned to 1 of 3 treatments: 1) control (n = 167), resynchronization with a timed AI protocol upon diagnosis of nonpregnancy on d 31 after preenrollment AI (PAI); 2) CIDR-G (n = 159), use of an intravaginal progesterone insert from d 14 to 21 after AI, with AI at estrus from d 21 to 24 and initiation of a timed AI protocol on d 24 after AI in cows not reinseminated; 3) CIDR-G + ECP (n = 169), the same treatment as CIDR-G but with an injection of 1 mg of estradiol cypionate at the time of progesterone insert removal. Cows were continuously reenrolled in the same treatment until diagnosed as pregnant, which resulted in a total of 1,148 AI (495 PAI and 653 resynchronized AI; RAI). Blood was collected from 1,001 cows on d 14, 21, and 24 after each AI for analysis of progesterone, and ovaries were scanned on d 21, 24, and 31 after AI. The presence of an active corpus luteum was presumed based on progesterone > or = 1 ng/mL. Pregnancy was diagnosed by ultrasonography on d 31 and 61 after AI. The presence of an active corpus luteum and the incidence of luteolysis were similar for all treatments from d 14 to 24; however, luteolysis increased in the CIDR-G + ECP treatment from d 21 to 24. Conception rates for the PAI and all AI were similar on d 31 and 61 after insemination. Conception rates at 31 and 61 d after the RAI were also similar among treatments. Overall pregnancy loss for the PAI, RAI, and all AI were similar for all treatments. The accuracy of estrous detection, based on progesterone concentration within 2 d of detection of estrus, was similar for all treatments for the RAI and averaged 95.3%. The estrus-detection rate (EDR) decreased for the CIDR-G and CIDR-G + ECP treatments from d 14 to 21, but increased from d 21 to 24 compared with control cows; however, the EDR was smaller for cows in the CIDR-G treatment during the entire resynchronization period compared with those in the CIDR-G + ECP and control groups. The reinsemination interval was reduced in cows receiving the CIDR-G + ECP treatment compared with control cows because of increased EDR after removal of the intravaginal insert; however, the interval from study enrollment to pregnancy was not different among treatments. These results indicate that the reproductive performance of dairy cows did not differ among the 3 resynchronization treatments evaluated. PMID- 17699045 TI - Comparison of functional aspects in two automatic milking systems and auto-tandem milking parlors. AB - Milk yield, milking frequency, intermilking interval, teat-cup attachment success rate, and length of the milking procedure are important functional aspects of automatic milking systems (AMS). In this study, these variables were compared for 2 different models of AMS (AMS-1, with free cow traffic, and AMS-2, with selectively guided cow traffic) and auto-tandem milking parlors (ATM) on 4 farms each. Data on milking-stall visits and milkings of 20 cows were recorded on 3 successive days by means of video observations. Data were evaluated with mixed effects models. Milk yield did not differ among the 3 milking systems. Milking frequency in the AMS was 2.47/d [95% confidence interval (CI) = (2.38, 2.56)], and was significantly higher than the 2 milkings/d in ATM. Milking frequency was lower for cows with a higher number of days in milk (DIM) in AMS-1 [change of 0.057/10 DIM, CI = (-0.070, -0.044)], but remained constant for cows with varying DIM in AMS-2 [change of -0.003/10 DIM, CI = (-0.034, 0.027)]. As a consequence, milking frequency was higher in early lactation [by 0.603, CI = (0.102, 1.103)] and lower in late lactation in AMS-1 than in AMS-2 [by -0.397, CI = (-0.785, 0.008)]. The intermilking interval showed the opposite pattern. Teat-cup attachment was more successful in AMS-1 than in AMS-2 (98.4 vs. 94.3% of the milkings), with some variation among farms (range: AMS-1 96.2 to 99.5%; AMS-2 91.5 to 96.1%). The length of the entire milking process did not differ among the milking systems [454 s, CI = (430, 478)], although the preparation phase was longer [changes in comparison with ATM: in AMS-1 by a factor of 2.90, CI = (2.30, 3.65), and in AMS-2 by 5.15, CI = (4.09, 6.48)] and the actual milking phase was shorter in both AMS-1 and AMS-2 than in ATM [changes in comparison with ATM: in AMS-1 by a factor of 0.76, CI = (0.62, 0.94), and in AMS-2 by 0.75, CI = (0.60, 0.93)]. The admission [changes in comparison with ATM: in AMS-1 by a factor of 2.56, CI = (1.55, 4.22), and in AMS-2 by 3.07, CI = (1.86, 5.08)] and preparation phases lasted longer in AMS-2 than in AMS-1, whereas the time required by the cows to leave the milking stall did not differ among the systems [changes in comparison with ATM: in AMS-1 by a factor of 0.89, CI = (0.55, 1.44), and in AMS 2 by 1.02, CI = (0.63, 1.66)]. In conclusion, different technical approaches to automatic milking led to differences in teat-cup attachment success rates, in the duration of several phases of the milking process, and in milking frequency. The capacity of an AMS could be further improved by shortening the preparation phase and reducing the proportion of failed milkings. PMID- 17699044 TI - Evaluation of the mechanism of action of conjugated linoleic acid isomers on reproduction in dairy cows. AB - The objective of this study was to evaluate the mechanism of action through which conjugated linoleic acid (CLA) beneficially affects reproduction. Lactating Holstein cows (n = 45, 20 +/- 1 DIM) were assigned to 1 of 3 treatments: 70 g/d of Ca salts of tallow (control); 63 g/d of lipid-encapsulated CLA providing 7.1 g/d of cis-9, trans-11 CLA and 2.4 g/d of trans-10, cis-12 CLA (CLA 75:25); or 76 g/d of lipid-encapsulated CLA providing 7.1 g/d each of cis-9, trans-11 and trans 10, cis-12 CLA (CLA 50:50). Supplements were top-dressed for 37 d, milk production and DMI were recorded daily, and blood samples were taken 3 times per week. At 30 +/- 3 DIM, ovulation was synchronized in all cows with a modified Ovsynch protocol, and on d 15 of the cycle cows received an oxytocin injection; blood samples were obtained frequently to measure 13,14 dihydro, 15-keto PGF2alpha. On d 16 of the cycle cows received a PGF2alpha injection and ovarian follicular aspiration was performed 54 h later. Follicular fluid was analyzed for fatty acids, progesterone, and estradiol. Endometrial biopsies were taken before and again near the end of the supplementation period for fatty acid analysis. The CLA resulted in decreased milk fat content of 14.1 and 6.1% at wk 5 of treatment of CLA 50:50 and CLA 75:25, respectively. There were no differences in energy balance or plasma nonesterified fatty acids; however, plasma IGF-I was greater in cows supplemented with CLA 50:50. The CLA isomers were not detectable in endometrial tissue, but cis-9, trans-11 CLA tended to be greater in follicular fluid of supplemented cows. Response to the oxytocin challenge was not different among treatments. Progesterone during the early luteal phase and the estradiol:progesterone ratio in follicular fluid tended to be greater in cows supplemented with CLA 50:50. Overall, these results indicate that short periods of CLA supplementation do not alter uterine secretion of PGF2alpha. The mechanism through which CLA affects reproduction may involve improved ovarian follicular steroidogenesis and increased circulating concentrations of IGF-I. PMID- 17699046 TI - Comparison of two management strategies for retained fetal membranes on small dairy farms in Germany. AB - The objective of this study was to compare 2 strategies for the management of dairy cows having retained fetal membranes (RFM) with regard to clinical traits, milk yield, and reproductive performance. In contrast to recent studies evaluating optimal strategies for the management of cows with RFM, this trial was conducted on small dairy farms with 26 to 166 cows per herd. In the systemic (SYS) group (n = 116), cows having RFM and a rectal temperature > or = 39.5 degrees C were treated with 1 mg/kg of body weight of ceftiofur on 3 to 5 consecutive days. The RFM cows without fever remained untreated. In the intrauterine (IUT) group (n = 115), all RFM cows received an intrauterine treatment with 6 g of tetracycline on 3 consecutive days combined with an attempt to remove the fetal membranes manually. The IUT cows with a fever received an additional systemic treatment with 10 mg/kg of body weight of amoxicillin on 3 to 5 consecutive days. Body temperature, daily milk yield, prevalence of vaginal discharge 28 to 35 d in milk (DIM), and reproductive performance traits within 200 DIM were monitored. The proportion of cows experiencing fever within 5 d after enrollment was greater in SYS compared with IUT. The proportion of cows with mucopurulent or purulent vaginal discharge 28 to 34 DIM did not differ between the groups. Furthermore, no significant differences between groups were found in daily milk yield in the first 10 d after enrollment, or in reproductive performance or proportion of cows culled. Significant differences in the proportion of cows with a fever in SYS and IUT have not been reported in studies with similar study designs conducted on large dairy farms. Further results on milk yield and reproductive performance, however, support findings that a management strategy for RFM based on a selective systemic treatment of feverish cows is at least as efficacious as a strategy based on intrauterine treatments of all cows and a systemic antibiotic treatment of feverish cows. PMID- 17699047 TI - Comparison of J5 vaccinates and controls for incidence, etiologic agent, clinical severity, and survival in the herd following naturally occurring cases of clinical mastitis. AB - Holstein dairy cattle in 3 commercial herds were randomly allocated to J5 vaccination (n = 251) or untreated control (n = 306) groups. There were 221 new cases of clinical mastitis (CM) affecting 120 cows. Coliform mastitis cases had a higher percentage of severe quarter swelling or signs of systemic illness among control cows but not among J5 vaccinates, in comparison to noncoliform cases. Culling or death from CM affected 13 controls (4.3%) and 4 vaccinates (1.6%), with losses occurring earlier in lactation among controls, a higher hazard (probability of a cow dying on each day of lactation) for controls than vaccinates. The J5 vaccination was significantly associated with protection from culling for mastitis among the 15 Klebsiella cases; 2 out of 10 (20%) Klebsiella infected controls were culled and 0 out of 5 vaccinates were culled. Cows in second lactation were at reduced hazard of culling for mastitis compared with older animals, even when adjusting for effects of J5 vaccination. When all CM cases (including subsequent new cases during the same lactation and multiple quarters or pathogens within the same cow on the same day) were evaluated, for the 221 cases of CM, the rate was significantly higher among vaccinates than controls (0.10 and 0.07 cases/30 d in milk, respectively). This was because J5 vaccinates had more subsequent new cases of CM in the same cow than controls. Pathogens isolated, which included mainly environmental bacteria, were not different among J5 vaccinates and controls. Immunization with J5 was associated with protection against severe clinical coliform mastitis signs, culling, and death loss from CM but not with any reduction in overall CM. PMID- 17699048 TI - Hepatocyte growth factor exerts multiple biological functions on bovine mammary epithelial cells. AB - The met proto-oncogene product Met is a member of the family of tyrosine kinase growth factor receptors, and hepatocyte growth factor/scatter factor (HGF/SF) has been identified as its only ligand. Bovine Met and HGF/SF have been recently cloned and their expression has been characterized in the mammary gland, but no data regarding the biological effects of this ligand/receptor couple in bovine mammary cells are yet available. We examined the role of HGF/SF and its receptor in a bovine mammary epithelial cell line (BME-UV). Expression of Met at the mRNA level in BME-UV mammary epithelial cells evaluated by real-time PCR was similar to the expression in MDCK cells, a widely used model for Met biology. Met expression in BME-UV at the protein level was confirmed by western blot. The analysis of some signal transductional pathways downstream from the Met receptor revealed that HGF/SF addition to BME-UV cells induced activation of the extracellular signal-regulated kinase 1/2 proliferative pathway and the Akt antiapoptotic pathway. The BME-UV cells treated with HGF responded with increased proliferation, cell scatter, and motility. Met activation by HGF induced degradation of the extracellular matrix and migration through matrigel coated transwells. Moreover, BME-UV cells included in a 3-dimensional matrix of collagen and treated with HGF developed tubular structures, reminiscent of the mammary gland ducts. These data indicate that HGF and Met might be important regulators of mammary gland growth, morphogenesis, and development in the bovine. PMID- 17699049 TI - Early in vitro fertilization improves development of bovine ova heat stressed during in vitro maturation. AB - The objectives were to examine the development of embryos derived from control (38.5 degrees C) or heat-stressed ova [41.0 degrees C during the first 12 h of in vitro maturation (hIVM)] when in vitro fertilization (IVF) was performed at 16, 18, 20, 24, or 30 hIVM. Effects of heat stress in compromising ovum development depended on when IVF was performed (in vitro maturation temperature x IVF time interaction). When IVF was performed at 24 or 30 hIVM, fewer heat-stressed ova developed to the blastocyst stage compared with the respective controls. In contrast, when IVF was performed at 16, 18, or 20 hIVM, more heat-stressed ova developed to the blastocyst stage compared with the respective controls. Performing IVF earlier than usual was beneficial, because the ability of heat stressed ova to develop to the blastocyst stage was improved when IVF was performed at 18 or 20 vs. 24 hIVM. Blastocyst stage and quality were equivalent to non-heat-stressed controls regardless of IVF time. Control ova undergoing IVF at 20, 24, 30, or 32 hIVM and heat-stressed ova undergoing IVF at 16, 18, 20, or 24 hIVM were compared for blastocyst development by multisource regression. Although linear and quadratic slopes were similar, heat stress reduced the peak and shifted the developmental response of ova by 7.3 h. In other words, obtaining optimal blastocyst development from heat-stressed ova would depend on performing IVF at 19.5 hIVM compared with 26.7 hIVM for non-heat-stressed controls. Heat induced reductions in peak blastocyst development significantly reduced the window of time available to perform IVF and obtain > or = 20% blastocyst development. In summary, results support an effect of heat stress to hasten developmentally important events during oocyte maturation. The inability of earlier IVF to fully restore the development of heat-stressed ova to that of non heat-stressed controls highlights the importance of further study. PMID- 17699050 TI - Effects of pasture feeding during the periparturient period on postpartum anovulation in grazed dairy cows. AB - Extended postpartum anovulatory intervals (PPAI) are a major contributor to infertility in seasonal dairy systems constrained to 365-d calving intervals. This study was conducted to evaluate the effects of pasture-based dietary energy intakes during the transitional calving period on PPAI. Sixty-eight multiparous Holstein-Friesian cows were assigned to high [11.9 kg of dry matter (DM)/d] or low (4.8 kg of DM/d) pasture intakes for 29 +/- 7.7 d prepartum. After calving, cows within each prepartum diet were assigned to either a high (13.5 kg of DM/d) or low (8.6 kg of DM/d) pasture intake for 35 d in a 2 x 2 factorial arrangement. Progesterone concentrations were measured in milk samples collected twice weekly to determine PPAI, which was defined as the day on which progesterone level was elevated to > or = 3 ng/mL with subsequent concentrations being consistent with an ovulatory cycle. Blood samples were collected before initiation of treatments, and at d -21, -14, -7, 0 (day of calving), 1, 2, 3, 4, 7, 14, 21, 28, and 35 in all cows. The PPAI was associated with body condition score, concentrations of plasma insulin and insulin-like growth factor-I, and growth hormone. Postpartum intake did not affect these metabolic hormones or PPAI, but yield of FCM during the first 35 d was reduced by 23% among cows on a restricted intake. No relationships were found between PPAI and milk production characteristics. These data demonstrate that when pasture is the sole dietary source during the calving transition period, PPAI may be influenced by prepartum intake levels, whereas postpartum intake influences milk yield, but not PPAI. The underlying mechanism(s) that associates the prepartum period to PPAI may involve the sensitivity of the growth hormone-insulin-like growth factor axis to dietary intake levels. Nonetheless, PPAI in grazing multiparous dairy cows appears largely unresponsive to intake levels during the calving transition period. PMID- 17699051 TI - Short communication: Effect of increasing levels of corn bran on milk yield and composition. AB - Thirty-nine lactating Holstein cows (23 multiparous and 16 primiparous) were randomly assigned to 1 of 3 dietary treatments in a crossover design. Dietary treatments differed by the proportion of corn bran [10, 17.5, and 25% dry matter (DM); designated as low, medium, and high] replacing corn silage and alfalfa. The corn bran coproduct contained 8.2% moisture and 12.9% crude protein, 30.4% neutral detergent fiber (NDF), and 45.0% nonfiber carbohydrate, 9.9% ether extract, and 0.70% P (DM basis). The low treatment consisted of 15.8% NDF from forage (fNDF) and 33.1% total NDF; the medium treatment consisted of 12.9% fNDF and 32.5% total NDF; and the high diet contained 9.9% fNDF and 31.8% total NDF. Dry matter intake was not affected by treatment. The percent milk fat decreased by 0.26% with the inclusion of corn bran from 10 to 25% of the diet DM, but total milk fat yield was not affected. In comparison, corn bran increased yield of milk protein 0.12 kg/d when bran increased from 10 to 25% of the diet DM. Total milk yield tended to increase when bran increased from 10 to 25% of the diet DM, but no differences were observed on 3.5% fat-corrected milk. Lastly, feed conversion significantly improved with increasing inclusion: 1.39, 1.39, and 1.55 +/- 0.05 kg of milk/kg of DMI for low, medium, and high, respectively. Observed effects were likely due to the increase in energy intake associated with increasing levels of corn bran. PMID- 17699052 TI - Comparison of feeding management and body condition of dairy cows in herds with low and high mastitis rates. AB - Feeding practices, ration composition, and body condition scores (BCS) were assessed in an observational case-contrast study of Norwegian dairy herds with low (n = 98) and high (n = 94) mastitis infection rates. Differences between the 2 groups of herds were associated with feeding practices and amount of roughage. More herds in the low-infection group were fed a reduced amount of roughage at drying off, and reduced rations during the dry period resulted in lower BCS at calving. Cows in the low-infection herds had significantly lower BCS in the last month before calving and the first month of lactation than cows in the high infection herds. The significant associations between mastitis infection rates and BCS, frequency of concentrate feeding, and amount of roughage at drying off and during the dry period indicated that feeding practices may have an important influence on the risk of mastitis in Norwegian dairy cows. PMID- 17699053 TI - Effect of glutamine supplementation on splanchnic metabolism in lactating dairy cows. AB - The suggestion that glutamine (Gln) might become conditionally essential postpartum in dairy cows has been examined through increased postruminal supply of Gln. Net nutrient flux through the splanchnic tissues and mammary gland was measured in 7 multiparous Holstein cows receiving abomasal infusions of water or 300 g/d of Gln for 21 d in a crossover design. Milk yield increased significantly (by 3%) in response to Gln supplementation, but the 2.4% increase in milk protein yield was not statistically significant. Glutamine treatment had no effect on portal or hepatic venous blood flows. Net portal appearance of Gln and Glu was increased by Gln supplementation, accounting for 83% of the infused dose with, therefore, only limited amounts available to provide additional energy to fuel metabolism of the portal-drained viscera. The extra net portal appearance of Gln was offset, however, by a corresponding increase in hepatic removal such that net Gln splanchnic release was not different between treatments. Nonetheless, the Gln treatment resulted in a 43% increase in plasma Gln concentration. Infusions of Gln did not affect splanchnic flux of other nonessential amino acids or of essential amino acids. Glutamine supplementation increased plasma urea-N concentration and tended to increase net hepatic urea flux, with a numerical increase in liver hepatic O2 consumption. There were no effects on glucose in terms of plasma concentration, net portal appearance, net liver release, or postliver supply, suggesting that Gln supplementation had no sparing effect on glucose metabolism. Furthermore, mammary uptake of glucose and amino acids, including Gln, was not affected by Gln supplementation. In conclusion, this study did not support the hypothesis that supplemental Gln would reduce glucose utilization across the gut or increase liver gluconeogenesis or mammary glutamine uptake to increase milk protein synthesis. PMID- 17699054 TI - A milk diet partly containing soy protein does not change growth but regulates jejunal proteins in young goats. AB - Soy protein is known to alter intestinal function and structure. We determined in young goats whether a diet partly containing soy protein differently affects intestinal morphology and the jejunal and hepatic proteome as compared with a milk diet. Fourteen male 2-wk-old White German dairy goat kids were fed comparable diets based on whole cow's milk in which 35% of the crude protein was casein (milk protein group; MP) or soy protein supplemented by indispensable AA (SPAA) for 34 d (n = 7/group). Body weight gain and food efficiency were not different. Jejunal and hepatic tissue was collected to determine intestinal morphology by microscopy and protein repertoire by 2-dimensional gel electrophoresis and mass spectrometry. Jejunal crypt depth was reduced and villus height to crypt depth ratio was higher in SPAA than in milk protein. Out of 131 proteins identified, 32 proteins were found to be differently expressed in both groups. In SPAA, down-regulated jejunal proteins were involved in processes related to cytoskeleton generation, protein, lipid, and energy metabolism. Downregulated hepatic proteins were related to glycolysis and Krebs cycle. Thirteen proteins were upregulated in SPAA. Among these, 2 hepatic proteins were related to carbohydrate breakdown. The other 11 jejunal proteins were involved in cytoskeleton assembly, proteolysis, and carbohydrate breakdown. In addition, glutathione-S-transferase was found to be upregulated in the medial jejunum. In conclusion, a SPAA diet as compared with a milk diet was related to changes in jejunal morphology and jejunal proteins relevant for protein turnover, energy metabolism, and cytoskeleton assembly with no apparent impact on animal BW gain. PMID- 17699055 TI - Effect of milk allowance on concentrate intake, ruminal environment, and ruminal development in milk-fed Holstein calves. AB - The aim of the present experiment was to test the hypothesis that a barley-based concentrate would induce an acidic ruminal environment in young calves and that increased milk allowance would alleviate this condition. Eight Holstein calves ruminally cannulated at d 7 +/- 1 of age were used to study the effect of variation in barley-based starter concentrate intake induced by 4 different milk allowances (3.10, 4.84, 6.60, and 8.34 kg of milk replacer/d; 123 g of dry matter/kg of milk) on the ruminal environment, blood variables, and fore-stomach development from wk 2 to 5 of age. Twelve ruminal fluid samples were collected during a weekly 24-h sampling in 4 consecutive weeks. Blood samples were collected by venipuncture between 1200 and 1300 h on ruminal sampling days. Rumen papillae development and visceral organ mass were recorded at slaughter. A linear treatment x week effect was observed for concentrate intake, with the calves fed the lowest milk allowance having the fastest increase in concentrate intake whereby these calves reached the same ME intake in wk 5 compared with calves with the highest milk allowance. Effects on ruminal variables were dominated by week of sampling, with minor differences among treatments. Ruminal pH was below 5.5 for 5 to 13 h/d and all calves with concentrate intake above 20 g of dry matter/d were observed to have a daily ruminal pH minimum at pH 5.5 or lower. The ruminal concentration of total volatile fatty acids (VFA) increased from 71 to 133 +/- 9 mmol/L in wk 2 to 5 and was characterized by a relatively high molar proportion of propionate, increasing from 34 to 40 mol/100 mol of VFA in wk 2 to 5. In addition, the presence of ethanol and propanol as well as numerous VFA esters points to a ruminal environment with a relatively high hydrogen pressure. Plasma glucose and insulin responded to the highest milk allowance in wk 2 to 4. Plasma VFA and ketone bodies increased with the lowest milk allowance in wk 4 to 5. At slaughter, empty wet weights of the rumen + reticulum and omasum as well as mass of digesta in these compartments were found to decrease linearly and perirenal fat was found to increase linearly with milk allowance, indicating that the milk allowance changed the body composition of the calves. Lengths of ruminal papillae in the atrium and ventral ruminal sac were not affected by treatment. We concluded that the ruminal environment of young calves fed a barley-based starter concentrate was characterized by a low ruminal pH and high VFA concentration regardless of the milk allowance. PMID- 17699056 TI - Manure nutrient excretion by lactating cows fed exogenous phytase and cellulase. AB - The effect of an exogenous phytase and cellulase-containing enzyme formulation on nutrient digestibility and excretion was evaluated in 24 Holstein cows. Cows were fed corn silage- and alfalfa silage-based diets with or without a cellulase phytase blend for 31 d in a continuous random design. Treatment groups were balanced for parity, days in milk, and mature-equivalent projected milk yield. Diets contained 37% forage, 18.3% crude protein, 35.4% neutral detergent fiber, 18% acid detergent fiber, and 0.42% P (no supplemental P). Cows were fed once daily in Calan doors and milked 2 times daily. Body weight and milk yield were recorded at each milking. Milk samples were collected on d 28 to 31 at 8 consecutive milkings. On d 28 to 31, fecal grab samples were collected every 8 h, with sampling times advanced by 2 h each day. Feces samples were pooled by cow. Feed and feces samples were analyzed for acid detergent lignin (used as an internal marker) and for N, P, neutral detergent fiber, and acid detergent fiber. Days in milk were similar between treatments, and body weight and milk yield were unaffected by treatment. Cows fed the enzyme formulation had reduced fecal dry matter, neutral detergent fiber, and acid detergent fiber excretion and reduced fecal excretion of N and P. Apparent digestibility of dry matter, acid detergent fiber, neutral detergent fiber, and N tended to increase with the enzyme formulation. Addition of an exogenous phytase and cellulase enzyme formulation to diets for lactating cows reduced fecal nutrient excretion. PMID- 17699057 TI - Effects of feeding oxidized fat with or without dietary antioxidants on nutrient digestibility, microbial nitrogen, and fatty acid metabolism. AB - A dual-effluent continuous culture system was used to investigate, in a 2 x 2 factorial design, the effect of feeding a fresh (FF) or oxidized (OF) blend of unsaturated fats (33% fish oil, 33% corn oil, 26% soybean oil, and 7% inedible tallow) when supplemented with a blend of antioxidants (AO; Agrado Plus, Novus International Inc.; Agrado Plus is a trademark of Novus International Inc. and is registered in the United States and other countries) on nutrient digestibility, bacterial protein synthesis, and fatty acid metabolism. Twice a day for 10 d, 12 fermenters were fed a diet that consisted of 52% forage and 48% grain mixture that contained 3% (dry matter basis) FF or OF, with or without AO. The OF contained a higher concentration of peroxides (215 vs. 3.5 mEq/kg), and a lower concentration of unsaturated fatty acids than the FF. Feeding OF reduced nitrogen digestibility, microbial nitrogen yield, and efficiency (expressed as kilograms of dry matter digested) and increased the outflow of saturated fatty acids in the effluent when compared with feeding FF. Adding AO improved total carbohydrate, neutral, and acid detergent fiber digestibilities and the amount of digested feed nitrogen converted to microbial nitrogen across the types of fats. From this study, we concluded that feeding OF reduced microbial nitrogen and increased the outflow of saturated fatty acids. Feeding AO improved fiber digestibility by rumen microorganisms, regardless of the type of fat. PMID- 17699058 TI - Effects of patterns of suboptimal pH on rumen fermentation in a dual-flow continuous culture system. AB - Low ruminal pH affects rumen fermentation, with the effects being larger as the time at suboptimal pH increases. Eight 1,325-mL dual-flow continuous culture fermenters were used to examine the hypothesis that the negative effects of a single cycle of 12 h (experiment 1) or 8 h (experiment 2) at pH 5.5 can be reduced by splitting it into several cycles. Temperature (39 degrees C), diet (97 g/d of a 60:40 forage:concentrate diet), and solid (5%/h) and liquid (10%/h) dilution rates were kept constant. In experiment 1, treatments were a constant pH 6.4 (H); 1 cycle of 12 h at pH 5.5 (L12); 2 cycles of 6 h at pH 5.5; and 3 cycles of 4 h at pH 5.5. In experiment 2, treatments were a constant pH 6.4 (H); 1 cycle of 4 h at pH 5.5 (L4); 1 cycle of 8 h at pH 5.5 (L8); or 2 cycles of 4 h at pH 5.5. During the rest of the day, pH was maintained at 6.4. Each experiment consisted of 2 replicated periods of 8 d (5 d for adaptation and 3 d for sampling). Within period, treatments were randomly assigned to fermenters. Data were analyzed as a randomized complete block using PROC MIXED of SAS and differences declared at P < 0.05 using the Tukey's test. In experiment 1, L12 reduced neutral detergent fiber (NDF) digestion, acetate proportion, and the acetate:propionate ratio, increased propionate proportion, and tended to reduce ammonia N concentration, compared with H, but had no effect on the flow of dietary or microbial N, crude protein degradation, efficiency of microbial protein synthesis, or the flow of total, essential, and individual amino acids. Dividing the 12 h at suboptimal pH into 2 or 3 cycles reduced true organic matter (OM) degradation compared with H, and did not alleviate the negative effects on NDF digestion and volatile fatty acid profile observed in L12. In experiment 2, L4 tended to reduce true OM digestion, ammonia N concentration, and bacterial N flow, reduced CP degradation, and increased dietary N flow. Treatment L8 reduced OM and NDF digestion, and ammonia N concentration, compared with H. Treatments L4 and L8 also reduced acetate proportion and the acetate:propionate ratio, and increased propionate proportion and the flow of total, essential, and most individual amino acids, but had no effect on efficiency of microbial protein synthesis compared with the H treatment. When the 8 h at suboptimal pH was divided into 2 cycles of 4 h the effects were not different from L8. Results suggest that the effects of low pH are dependent on the total amount of time that pH is suboptimal and are not reduced by splitting it into various cycles. PMID- 17699059 TI - Describing the body condition score change between successive calvings: a novel strategy generalizable to diverse cohorts. AB - The objective of this study was to explore the derivation of a mathematical model that adequately describes the intercalving body condition score (BCS) profile in dairy cows and is robust and applicable to different animal cohorts. The data used to generate the function were 75,352 daily BCS records across 3,209 lactations in 1,172 cows from a research herd in New Zealand. Mean daily BCS (scale 1 to 10) across all data were plotted and 4 distinct phases were observed. The functional form used to describe the pattern and quantify its features comprised the sum of the 4 phase functions created from intercepts, rates of change, approximate timing of phase transition points, and the sharpness of these transition points in the BCS profile. The generality and applicability of the described model were tested across substrata of BCS at calving and parity. A second data set consisting of a multiyear study comparing cows fed a total mixed ration (TMR) or grazing fresh pasture was compiled from a different research farm. This data set consisted of 4,112 BCS records from 211 lactations on 95 cows. The third data set was a collation of data from another multiyear experiment comparing animal performance under different stocking rates. The data set consisted of 12,414 BCS test-day records on 564 lactations from 287 cows. The presented model is robust and applicable to different animal cohorts, explaining between 29 and 79% of variation depending on the cohort studied. A notable second period of negative energy balance was evident in all grazing cows during midlactation, irrespective of calving BCS, parity, or stocking rate, but did not appear in cows fed TMR. The amount of BCS lost postcalving and nadir BCS were positively correlated with calving BCS, with fatter cows at calving losing more BCS postcalving but remaining at a greater BCS at nadir. Primiparous cows calved at a greater BCS than multiparous cows, as dictated by management protocols, but they failed to regain BCS postnadir as effectively as their multiparous counterparts. Results may highlight the need for preferential feeding of younger cows during late lactation, at least in grazing systems, to ensure that they achieve the required calving BCS at second calving. Cows receiving TMR lost BCS at a slower rate than cows on pasture but for a longer period; the amount of BCS lost between calving and nadir did not differ between the different feeding treatments. Calving BCS declined with increasing stocking rate, and the rates of both loss and gain were negatively affected by stocking rate. The presented model accurately identified biological attributes of the intercalving BCS profile of different groups of cows. PMID- 17699060 TI - Effects of rumen or duodenal glucose infusions on intake in dairy cows fed fresh perennial ryegrass indoors. AB - The aim of this study was to determine whether the intake of fresh highly digestible ryegrass could be limited by the total amount of energy absorbed. Moreover, it investigated whether the limitation was more specific to energy absorbed as volatile fatty acids in the rumen compared with energy absorbed in the lower gastrointestinal tract. Four treatments were compared: infusion of 1.25 kg of glucose into the rumen (R1.25), infusion of 2.5 kg of glucose into the rumen (R2.5), infusion of 1.5 kg of glucose into the duodenum (D1.5), and a control treatment consisting of water and salts. Treatments R2.5 and D1.5 were assumed to supply about 16.5 MJ of net energy for lactation. All treatments consisted of 2 infusions, one into the rumen and the other into the duodenum, with one of these infusions being a control. All infused solutions were isoosmotic with osmolarities around 340 and 330 mmol/L for rumen and duodenum, respectively. Treatments were compared using 4 dairy cows in mid lactation according to a 4 x 4 Latin square design replicated twice during 8 periods of 7 d each. Cows were housed in tie stalls and fed ad libitum with fresh perennial ryegrass cut every morning during the spring at 28 d of regrowth. Intake and feeding behavior were measured, as well as concentrations of ruminal fermentation products and some blood metabolites. The pepsin-cellulase organic matter digestibility of the offered herbage averaged 0.76 +/- 0.011. The average dry matter intake of herbage was 15.5 +/- 0.52 kg/d. The glucose infusions decreased dry matter intake by 0.95 kg/d compared with the control, but had the same satiating effect regardless of site or dose of infusion. The average concentration of volatile fatty acids in rumen fluid was 97.9 +/- 2.03 mmol/L and the molar proportion of propionate was 21.6 +/- 0.19 mmol/100 mmol. Glucose infusions into the rumen led to a decrease in the molar proportions of acetate from 64.4 on the control treatment to 60.9 mmol/100 mmol on R2.5 and increased the molar proportions of butyrate from 10.2 (control) to 13.5 mmol/100 mmol on R2.5, and minor acids (valerate and caproate), from 1.27 (control) to 2.54 mmol/100 mmol on R2.5, proportionally to the dose infused. These results suggested that energy nutrients can limit intake in dairy cows fed high digestibility ryegrass and that butyrate and minor acids would have a limited satiating effect compared with propionate. PMID- 17699061 TI - Inbreeding effects on milk production, calving performance, fertility, and conformation in Irish Holstein-Friesians. AB - The objective of this study was to determine the effect of inbreeding on milk production, somatic cell count, fertility, survival, calving performance, and cow conformation in Irish Holstein-Friesian pluriparous dairy cows. Inbreeding was included in a linear mixed model as either a class variable or a continuous variable, where higher order polynomials of the latter were also tested in the model as an indicator of nonlinear inbreeding depression. The effects of dam inbreeding and calf inbreeding on calving-related traits were analyzed separately. Inbreeding had a deleterious effect on most of the traits analyzed, although inbreeding depression was sometimes nonlinear or differed significantly across parities. A primiparous animal, 12.5% inbred (i.e., following the mating of noninbred half-sibs), had milk, fat, and protein yields reduced by 61.8, 5.3, and 1.2 kg, respectively; fat and protein concentrations reduced by 0.05 and 0.01%, respectively; and somatic cell scores (i.e., natural log of somatic cell count divided by 1,000) increased by 0.03. The 12.5% inbred animal was also expected to have a 2% greater incidence of dystocia, a 1% greater incidence of stillbirth, a 0.7% greater incidence of male calves, an increase in calving interval of 8.8 d, an increase in age at first calving of 2.5 d, and a reduced survival to second lactation of 4 percentage units. Inbred animals were also taller, narrower, and more angular. Although the effects of inbreeding were statistically significant, they were small and are unlikely to cause great financial loss on Irish dairy farms. PMID- 17699062 TI - Technical note: Bovine oviduct and endometrium array version 1: a tailored tool for studying bovine endometrium biology and pathophysiology. AB - Fertility problems are the main reason for slaughter of high-performance milk cows, because elongated calving intervals result in financial losses for the farmer and retard genetic progress. Genetic improvement of fertility would be of great benefit, but functional traits for effective selection are missing. Recent advances in functional genomics tools like DNA microarrays could be the key to identify gene expression patterns in the endometrium that correlate with maternal fertility. Therefore, a first version of a bovine oviduct and endometrium cDNA array was established that contains a set of 1,440 cDNA clones and long oligonucleotides representing 950 different genes. The major part of these genes has been identified in a series of differential gene expression studies in endometrium (different stages of the estrous cycle, d 18 pregnant vs. nonpregnant) and in oviduct epithelial cells (different stages of the estrous cycle) using a combination of subtracted cDNA libraries and cDNA array hybridization. Furthermore, cDNA clones of genes, which showed no changes in their mRNA levels in the analyzed tissues, were added as controls. Reproducibility of the array hybridization, a comparison with the Affymetrix bovine genome array, and confirmation of differential gene expression with reverse transcription-quantitative PCR is shown. Potential future applications include systematic studies of interactions between metabolic status and functionality of the endometrium to identify genes that could be used for differential diagnosis of fertility problems. Further, endometrium transcriptome profiles may serve as novel traits to improve fertility by genetic selection. PMID- 17699063 TI - Phenotypic relationships of common health disorders in dairy cows to lactation persistency estimated from daily milk weights. AB - The objective of this study was to investigate the phenotypic relationship between common health disorders in dairy cows and lactation persistency, uncorrelated with 305-d yield. The relationships with peak yield and days in milk (DIM) at peak were also studied. Daily milk weights and treatment incidence records of 991 Holstein lactations from experimental dairy herds at Virginia Tech and Pennsylvania State University were used. Persistency was calculated as a function of daily yield deviations from standard lactation curves, developed separately for first (FL) and later lactations (LL), and deviations of DIM around reference dates: 128 for FL and 125 for LL. Days in milk at peak and peak yield were computed for each lactation by using Wood's function. The disease traits studied were mastitis (MAST) only during the first 100 d (MAST1), only after 100 DIM (MAST2), both before and after 100 DIM (MAST12), and at any stage of lactation (MAST1/2), as well as metritis, displaced abomasums, lameness, and metabolic diseases. Each disease was defined as a binary trait, distinguishing between lactations with at least one incidence (1) and lactations with no incidences (0). The relationships of diseases to persistency, DIM at peak, and peak yield were investigated separately for FL and LL for all disease traits except MAST12, which was investigated across parities. The relationships of persistency to probability of the diseases in the same lactation and in the next lactation were examined using odds ratios from a logistic regression model. Metritis and displaced abomasums in FL and LL were associated with significantly higher persistencies. Metabolic diseases and MAST1 in LL were significantly related to higher persistencies. The relationships of MAST2 in both FL and LL, and MAST12 across parities were significant but negative. Cows affected by MAST tended to have less persistent lactations. Most of the diseases had a significant impact on DIM at peak in LL. In LL, metritis, metabolic diseases, and displaced abomasums tended to significantly delay DIM at peak. Mastitis only after 100 DIM was associated with significantly earlier DIM at peak in LL. Increasing persistency was associated with low MAST2 and MAST1/2 in primiparous cows. None of the diseases studied was significantly related to persistency of the previous lactation. PMID- 17699064 TI - Estimation of heritability and genetic correlations for the major fatty acids in bovine milk. AB - The current cattle selection program for dairy cattle in the Walloon region of Belgium does not consider the relative content of the different fatty acids (FA) in milk. However, interest by the local dairy industry in differentiated milk products is increasing. Therefore, farmers may be interested in selecting their animals based on the fat composition. The aim of this study was to evaluate the feasibility of genetic selection to improve the nutritional quality of bovine milk fat. The heritabilities and correlations among milk yield, fat, protein, and major FA contents in milk were estimated. Heritabilities for FA in milk and fat ranged from 5 to 38%. The genetic correlations estimated among FA reflected the common origin of several groups of FA. Given these results, an index including FA contents with the similar metabolic process of production in the mammary gland could be used, for example, to increase the monounsaturated and conjugated fatty acids in milk. Moreover, the genetic correlations between the percentage of fat and the content of C14:0, C12:0, C16:0, and C18:0 in fat were -0.06, 0.55, 0.60, and 0.84, respectively. This result demonstrates that an increase in fat content is not directly correlated with undesirable changes in FA profile in milk for human health. Based on the obtained genetic parameters, a future selection program to improve the FA composition of milk fat could be initiated. PMID- 17699065 TI - Genetic variability of lactoferrin content estimated by mid-infrared spectrometry in bovine milk. AB - The effects of lactoferrin (LF) on the immune system have already been shown by many studies. Unfortunately, the current methods used to measure LF levels in milk do not permit the study of the genetic variability of lactoferrin or the performance of routine genetic evaluations. The first aim of this research was to derive a calibration equation permitting the prediction of LF in milk by mid infrared spectrometry (MIR). The calibration with partial least squares on 69 samples showed a ratio of standard error of cross-validation to standard deviation equal to 1.98. Based on this value, the calibration equation was used to establish an LF indicator trait (predicted LF; pLF) on a large number of milk samples (n = 7,690). A subsequent study of its variability was conducted, which confirmed that stage of lactation and lactation number influence the overall pLF level. Small differences in mean pLF among 7 dairy breeds were also observed. The pLF content of Jersey milk was significantly higher than that in Holstein milk. Therefore, the choice of breed could change the expected LF level. Heritability estimated for pLF was 19.7%. The genetic and phenotypic correlations between somatic cell score and pLF were 0.04 and 0.26, respectively. As somatic cell score increases in presence of mastitis, this observation seems to indicate that pLF, or a function of observed pLF, compared with expected LF might have potential as an indicator of mastitis. The negative genetic correlation (-0.36) between milk yield and pLF could indicate an undesirable effect of selection for high milk production on the overall LF level. PMID- 17699066 TI - Impact of calving ease on functional longevity and herd amortization costs in Basque Holsteins using survival analysis. AB - The aim of this study was to analyze the impact of calving ease (CE) on functional longevity of Basque Holsteins, using a Weibull proportional hazards model. The data considered for the analysis were 53,353 calving records from 25,810 Holstein cows distributed across 781 herds and sired by 746 bulls. The effects included in the statistical model were age at first calving, stage of lactation, interaction between year and season of calving, 305-d adjusted milk yield, CE, herd, and sire. Calving ease was considered as a time-dependent covariate and, as was the case for the rest of covariates included in the model, had a significant effect on functional longevity. Calvings needing assistance or surgery increased culling risk by 18%, when compared with unassisted calvings. The effect of CE on length of productive life in primiparous and multiparous cows was also investigated. A second analysis was performed replacing the CE effect with the interaction between parity and CE to evaluate the effect of CE in primiparous and multiparous cows. An increase in calving difficulty had a greater impact on culling during first lactations than in subsequent ones. Therefore, difficult calvings, mainly at first parities, had a high impact on herd amortization costs, increasing them by 10% in relation to easy calvings. Therefore, calving difficulty should be avoided as much as possible, especially in primiparous cows, to avoid reduction of profitability. PMID- 17699067 TI - Stearoyl-coenzyme A desaturase gene polymorphism and milk fatty acid composition in Italian Holsteins. AB - Milk fatty acid composition is a parameter of great interest for evaluation of nutritional quality of milk. Stearoyl-CoA desaturase (SCD) is a key enzyme in mammary lipid metabolism because it is able to add a double bond in the cis delta9-position in a large spectrum of medium- and long-chain fatty acids. A polymorphism with 2 alleles (A and V) in the fifth exon of the SCD gene has been reported. The effect of SCD genotype on individual milk fatty acid composition and on cis-9 unsaturated/saturated fatty acid ratios of 297 Holstein Italian Friesian cows was investigated in this paper. The SCD genotypes were determined by using a single strand conformation polymorphism method. Relative frequencies of SCD genotypes were 27, 60, and 13% for AA, AV, and VV, respectively. Milk of AA cows had a greater content of cis-9 C18:1 and total monounsaturated fatty acids and a higher C14:1/C14 ratio than did milk of VV cows. The relative contribution of SCD genotype to variation of monounsaturated fatty acids, cis-9 C18:1, and cis-9 C14:1 was 5, 4, and 7.7%, respectively. No significant differences were detected between SCD genotypes in the milk content of cis-9, trans-11 C18:2. Results of the present work provide some indication of an association between SCD locus and the fatty acid profile in the examined sample of Italian Holsteins, thus suggesting a possible role of this gene in the genetic variation of milk nutritional properties. PMID- 17699068 TI - Motivation of dairy farmers to improve mastitis management. AB - The aims of this study were 1) to explore different motivating factors and to quantify their importance in decisions of farmers on improving mastitis management, 2) to evaluate different quality payment schemes as extra incentive mechanisms for farmers, and 3) to link the motivating factors to farmer characteristics. Data on characteristics of farmers were obtained through a traditional paper-based questionnaire (n = 100). Data on the factors motivating farmers to improve mastitis management were collected in a computer-interactive mode. Adaptive conjoint analysis was used to investigate perceptions of farmers of the importance of factors. Factors that are internal to the farm performance and the individual farmer provided more motivation than external factors implying esteem and awareness of the whole dairy sector performance. Internal nonmonetary factors relating to internal esteem and taking pleasure in healthy animals on the farm were equally motivating as monetary factors affecting farm economic performance. The identified difference in perceptions of farmers of importance of extra financial incentive based on bulk milk somatic cell count (BMSCC) depending on whether farmers think in terms of quality premium or penalty for a lower and a higher BMSCC, respectively, suggested that farmers are expected to be more motivated by a price decrease for milk with a greater BMSCC than by a price increase for milk with a lower BMSCC. In this respect, quality penalties were found to be more effective in motivating farmers than quality premiums. Two-stage cluster analysis of individual perceptions resulted in 3 distinct clusters according to motivation of farmers: premium- or penalty-oriented motivation, motivation to have an efficient (well-organized) farm that easily complies with regulatory requirements, and basic economic motivation. The obtained results highlight possible areas of improvement in incentive and educational programs aimed at improving mastitis management. PMID- 17699069 TI - Detection of low frequency external electronic identification devices using commercial panel readers. AB - The ability of a commercially available panel reader system to read International Standards Organization-compliant electronic identification devices under commercial dairy conditions was examined. Full duplex (FDX-B) and half-duplex (HDX) low frequency radio-frequency identification external ear tags were utilized. The study involved 498 Holstein cows in the final 6 wk of gestation. There were 516 total electronic identification devices (n = 334 HDX and n = 182 FDX-B). Eighteen FDX-B were replaced with HDX during the study due to repeated detection failure. There were 6,679 HDX and 3,401 FDX-B device detection attempts. There were 220 (2.2%) unsuccessful and 9,860 (97.8%) successful identification detection attempts. There were 9 unsuccessful detection attempts for HDX (6,670/6,679 = 99.9% successful detection attempts) and 211 unsuccessful detection attempts for FDX-B (3,190/3,401 = 93.8% successful detection attempts). These results demonstrate that this panel system can achieve high detection rates of HDX devices and meet the needs of the most demanding management applications. The FDX-B detection rate was not sufficient for the most demanding applications, requiring a high degree of detection by panel readers. The lower FDX-B rate may not be inherent in the device technology itself, but could be due to other factors, including the particular panel reader utilized or the tuning of the panel reader. PMID- 17699070 TI - Results and evaluation of thirty years of health recordings in the Norwegian dairy cattle population. AB - The results are based on the Norwegian Cattle Health Recording System, which has been in place for the entire country since 1975. The dairy breeds in Norway consist of 94% Norwegian Red and 4% crossbreeds with Norwegian Red. No other breed consists of more than 0.5% of the total population. During the past 30 yr, there have been 11,563,692 dairy cows within the recording system, corresponding to 8,633,532 cow-years and 8,632,516 calvings. This population consisted of 3,038,675 first-calving cows. Altogether, 8,435,704 different diagnoses were recorded from 4,444,485 different cows each year. The general trend for all recordings was an increase in the incidence rate of all cases from 0.74 per 365 d at risk (cow-year) in 1976 to 1.36 in 1990, and then a decrease to 0.62 in 2002. The corresponding figures for cows treated per cow-year were 0.44 up to a maximum of 0.82, and then a decrease to 0.46 per cow-year in 2002. The most common diseases were acute (severe to moderate) clinical mastitis, chronic (mild) clinical mastitis, ketosis, milk fever, teat injuries, retained placenta, silent heat or anestrous, indigestion, cystic ovaries, and metritis. Clinical mastitis increased from 0.15 cows treated per cow-year in 1975 to 0.44 in 1994, and then decreased to 0.23 in 2002. Ketosis began at 0.10 in 1975, increased to 0.24 in 1985, and then decreased to 0.05 in 2005. For several of the most common diseases, there was a reduction of more than 50% from the 1990s to the years after 2000. Validation processes confirmed that this fluctuation reflected the general trend in the population. The disease recording system also reflected the known outbreaks of bovine respiratory syncytial virus during 1976, 1989 to 1990, and 1995. A marked increase in malformation diagnoses could be seen in 1986 and in 1989 and 1990. These could be related to the Chernobyl nuclear power plant accident in April 1986. The diagnosis that showed the most stability throughout these 30 yr was retained placenta. The 3 main reasons for the large fluctuation for many of the diseases could be the following: a breeding effect, an effect of preventive work, and an effect of changing the therapeutic attitude. Many of the actions taken to bring about improvements would not have been possible without a functioning and practical recording system. Our experience is that an organ related diagnosis system with up to 60 or 70 different diagnoses will meet the needs of the dairy industry. PMID- 17699071 TI - An outbreak of type C botulism in herring gulls (Larus argentatus) in southeastern Sweden. AB - From 2000 to 2004, over 10,000 seabirds, primarily Herring Gulls (Larus argentatus), died from an undetermined cause in the Blekinge archipelago in southeastern Sweden. In June 2004, 24 affected Herring Gulls were examined clinically, killed humanely, and 23 were examined by necropsy. Seven and 10 unaffected Herring Gulls collected from a local landfill site and from Iceland, respectively, served as controls. All affected birds showed similar neurologic signs, ranging from mild incoordination and weakness to severe flaccid paralysis of legs and wings, but generally were alert and responsive. All affected gulls were in normal nutritional condition, but were dehydrated and had empty stomachs. No gross or microscopic lesions, and no bacterial or viral pathogens were identified. Type C botulinum toxin was detected in the sera of 11 of 16 (69%) affected gulls by mouse inoculation. Type C botulism was the proximate cause of disease in 2004. Sera from 31% of birds tested from outbreaks in 2000 to 2003 also had detectable type C botulinum toxin by mouse inoculation. No large-scale botulism outbreak has been documented previously in this area. The source of toxin, initiating conditions, and thus, the ultimate cause of this outbreak are not known. This epidemic might signal environmental change in the Baltic Sea. PMID- 17699072 TI - Investigation of the link between avian vacuolar myelinopathy and a novel species of cyanobacteria through laboratory feeding trials. AB - Avian vacuolar myelinopathy (AVM) is a neurologic disease affecting Bald Eagles (Haliaeetus leucocephalus), American Coots (Fulica americana), and other birds in the southeastern United States. The cause of the disease has not yet been determined, although it is generally thought to be a natural toxin. Previous studies have linked AVM to aquatic vegetation, and the current working hypothesis is that a species of cyanobacteria growing epiphytically on that vegetation is producing a toxin that causes AVM. Surveys of epiphytic communities have identified a novel species of cyanobacteria in the order Stigonematales as the most likely suspect. The purpose of this study was to further examine the relationship between the suspect Stigonematales species and induction of AVM, by using animal feeding trials. Adult Mallards and domestic chickens were fed aquatic vegetation from two study sites containing the suspect cyanobacterial epiphyte, as well as a control site that did not contain the Stigonematales species. Two trials were conducted. The first trial used vegetation collected during mid-October 2003, and the second trial used vegetation collected during November and December 2003. Neither treatment nor control birds in the first trial developed AVM lesions. Ten of 12 treatment Mallards in the second trial were diagnosed with AVM, and control birds were not affected. This study provides further evidence that the novel Stigonematales species may be involved with AVM induction, or at the least it is a good predictor of AVM toxin presence in a system. The results also demonstrate the seasonal nature of AVM events. PMID- 17699073 TI - Identification of a novel Mannheimia granulomatis lineage from lesions in roe deer (Capreolus capreolus). AB - Eight atypical Mannheimia isolates were isolated from lesions in roe deer (Capreolus capreolus). Traditional classification based on morphologic and physiologic traits showed that they belong to a distinct biogroup (taxon) within genus Mannheimia. Extensive phenotypic characterization suggested that the isolates should be classified as M. granulomatis, although the presence of distinct traits justified their classification into a separate biogroup within this species. Phylogenetic analyses based on 16S rRNA sequences from two roe deer isolates and 41 other Mannheimia strains supported that the roe deer isolates form a monophyletic group within M. granulomatis. The lktA genotype was present in all roe deer isolates based on Southern blot analysis, whereas the corresponding beta-hemolytic phenotype was absent in one of these isolates. PMID- 17699074 TI - Experimental inoculation of meadow voles (Microtus pennsylvanicus), house mice (Mus musculus), and Norway rats (Rattus norvegicus) with Mycobacterium bovis. AB - Mycobacterium bovis has a wide host range that includes several wildlife species, and this can hamper attempts to eradicate bovine tuberculosis from livestock. The purpose of this study was to determine if common rodent species, namely meadow voles (Microtus pennsylvanicus), house mice (Mus musculus), and Norway rats (Rattus norvegicus), that inhabit the bovine tuberculosis endemic area of Michigan, can be experimentally infected with M. bovis. The objectives of the study were: 1) to determine if these rodent species can be infected, and if so, to document attendant pathologic processes/pathogenesis; 2) to detect any fecal shedding of M. bovis; and 3) to evaluate the relative susceptibility of the three species to M. bovis infection. For each species (n=36) there were two treatment (n=12/group) and one or two control groups depending on species (n=6-12/group); the maximum study duration was 60 days. The meadow vole treatments consisted of high dose inocula that were given by oral or intranasal routes, whereas the house mice and Norway rats were given only oral inocula at either a high or low dose. Of the three species, meadow voles were most susceptible to M. bovis infection. Upon intranasal inoculation, all 12 voles were infected as determined by gross and microscopic lesions and culture of M. bovis from tissue and feces. Seven of the 12 meadow voles inoculated orally were infected. House mice also were susceptible; M. bovis was isolated from 14 of 24 animals. Only one Norway rat in the high dose treatment group was positive by culture and this was the only animal from which minimal attendant lesions were observed. Results of this study indicate that meadow voles and house mice can be infected with M. bovis and might serve as spillover hosts. Concerted efforts should, therefore, be made to reduce or eliminate these rodents on premises where M. bovis-infected livestock are present. PMID- 17699075 TI - Parasites of forage fishes in the vicinity of Steller sea lion (Eumetopias jubatus) habitat in Alaska. AB - Fish serve as intermediate hosts for a number of larval parasites that have the potential of maturing in marine mammals such as Steller sea lions (Eumetopias jubatus). We examined the prevalence of parasites from 229 fish collected between March and July 2002 near two islands used by Steller sea lions in Southeast Alaska and island habitats in the Aleutian Islands. Sea lion populations have remained steady in Southeast Alaska but have been declining over the last 30 yr in the Aleutian Islands. Even though the fish samples near the Southeast Alaska haul-outs were composed of numerous small species of fish and the Aleutian Islands catch was dominated by juveniles of commercially harvested species, the parasite fauna was similar at all locations. Eleven of the 20 parasite taxa identified were in their larval stage in the fish hosts, several of which have been described from mammalian final hosts. Four species of parasite were more prevalent in Southeast Alaska fish samples, and seven parasite species, including several larval forms capable of infecting marine mammals, were more prevalent in fish from the Aleutian Islands. Nevertheless, parasites available to Steller sea lions from common fish prey are not likely to be a major factor in the decline of this marine mammal species. PMID- 17699076 TI - Transmission of Ehrlichia chaffeensis from lone star ticks (Amblyomma americanum) to white-tailed deer (Odocoileus virginianus). AB - Amblyomma americanum is an aggressive ixodid tick that has been implicated as a vector for several bacterial agents. Among these is Ehrlichia chaffeensis, which causes human monocytic (or monocytotropic) ehrlichiosis. In this study, experimental tick transmission of E. chaffeensis from infected lone star ticks to deer was revisited, and the question of whether it would be possible to re isolate the organism from deer was asked, because this had not been done previously. Here, we were able to transmit a wild strain of E. chaffeensis from acquisition-fed lone star ticks to white-tailed deer. Ehrlichia chaffeensis was re-isolated from one white-tailed deer on multiple days during the infection and from another deer on one day during the infection. Peak rickettsemias for E. chaffeensis-infected deer were 17 DPI with acquisition-fed ticks and 14 DPI with needle-inoculated deer. This study supports the role of the lone star tick and white-tailed deer as vector and reservoir host for E. chaffeensis, demonstrating culture re-isolation of E. chaffeensis in deer infected by experimental tick transmission for the first time. PMID- 17699078 TI - Trichomonas gallinae in Mauritian columbids: implications for an endangered endemic. AB - Although well known as a widespread parasitic disease of columbids and birds of prey, there have been few studies of trichomonosis in populations of wild birds. In Mauritius, trichomonosis has been highlighted as a major threat to an endangered endemic, the Pink Pigeon (Neosoenas [Columba] mayeri). In this study, we examined the role that populations of other columbids in Mauritius might be playing as infectious reservoirs of the causal flagellate protozoan, Trichomonas gallinae. We screened 296 wild individuals of three columbid species (Madagascan Turtle Dove [Streptopelia picturata], Spotted Dove [Streptopelia chinensis], and Zebra Dove [Geopelia striata]) between September 2002 and April 2004. Prevalence varied significantly among species (ranging from 19% in S. chinensis to 59% in G. striata) and between S. picturata sampled from upland and coastal sites; S. picturata from upland sites (>500 m) were significantly less likely to be infected with T. gallinae than those from lowland sites (<50 m; 62% and 27% prevalence, respectively). There was no significant difference in the prevalence of T. gallinae at sites where Pink Pigeons were also present compared to those sampled at sites without Pink Pigeons. We show that T. gallinae infection prevalence is higher at sites and times of warmer temperatures and lower rainfall. PMID- 17699077 TI - Prevalence and diversity of avian hematozoan parasites in Asia: a regional survey. AB - Tissue samples from 699 birds from three regions of Asia (Myanmar, India, and South Korea) were screened for evidence of infection by avian parasites in the genera Plasmodium and Haemoproteus. Samples were collected from November 1994 to October 2004. We identified 241 infected birds (34.0%). Base-on-sequence data for the cytochrome b gene from 221 positive samples, 34 distinct lineages of Plasmodium, and 41 of Haemoproteus were detected. Parasite diversity was highest in Myanmar followed by India and South Korea. Parasite prevalence differed among regions but not among host families. There were four lineages of Plasmodium and one of Haemoproteus shared between Myanmar and India and only one lineage of Plasmodium shared between Myanmar and South Korea. No lineages were shared between India and South Korea, although an equal number of distinct lineages were recovered from each region. Migratory birds in South Korea and India originate from two different migratory flyways; therefore cross-transmission of parasite lineages may be less likely. India and Myanmar shared more host species and habitat types compared to South Korea. Comparison between low-elevation habitat in India and Myanmar showed a difference in prevalence of haematozoans. PMID- 17699079 TI - Modeling plague persistence in host-vector communities in California. AB - Plague is an enzootic disease in the western United States, even though long-term persistent infections do not seem to occur. Enzootic persistence may occur as a function of dynamic interactions between flea vectors and transiently infected hosts, but the specific levels of vector competence, host competence, and transmission and recovery rates that would promote persistence and emergence among wild hosts and vectors are not known. We developed a mathematical model of enzootic plague in the western United States and implemented the model with the following objectives: 1) to use matrix manipulation within a classic susceptible- >infective-->resistant-->susceptible (SIRS) model framework to describe transmission of the plague bacterium Yersinia pestis among rodents and fleas in California, 2) to perform sensitivity analysis with model parameters and variables to indicate which values tended to dominate model output, and 3) to determine whether enzootic maintenance would be predicted with realistic parameter values obtained from the literature for Y. pestis in California rodents and fleas. The model PlagueSIRS was implemented in discrete time as a computer simulation incorporating environmental stochasticity and seasonality, by using matrix functions in the computer language R, allowing any number of rodent and flea species to interact through parasitism and disease transmission. Sensitivity analysis indicated that the model was sensitive to flea attack rate, host recovery rate, and rodent host carrying capacity but relatively insensitive to changes in the duration of latent infection in the flea, host and vector competence, flea recovery from infection, and host mortality attributable to plague. Realistic parameters and variable values did allow for the model to predict enzootic plague in some combinations, specifically when rodent species that were susceptible to infection but resistant to morbidity were parasitized by multiple poorly competent flea species, including some that were present year round. This model could be extended to similar vectorborne disease systems and could be used iteratively with data collection in sylvatic plague studies to better understand plague persistence and emergence in nature. PMID- 17699080 TI - The potential role of swift foxes (Vulpes velox) and their fleas in plague outbreaks in prairie dogs. AB - Swift foxes (Vulpes velox) have been proposed as potential carriers of fleas infected with the bacterium Yersinia pestis between areas of epizootics in black tailed prairie dogs (Cynomys ludovicianus). We examined antibody prevalence rates of a population of swift foxes in Colorado, USA, and used polymerase chain reaction (PCR) assays to examine their flea biota for evidence of Y. pestis. Fifteen of 61 (24%) captured foxes were seropositive, and antibody prevalence was spatially correlated with epizootic plague activity in prairie dog colonies in the year of, and previous to, the study. Foxes commonly harbored the flea Pulex simulans, though none of the fleas was positive for Y. pestis. PMID- 17699081 TI - Feasibility of using coyotes (Canis latrans) as sentinels for bovine mycobacteriosis (Mycobacterium bovis) infection in wild cervids in and around Riding Mountain National Park, Manitoba, Canada. AB - Elk (Cervus elaphus manitobensis) and white-tailed deer (Odocoileus virginianus) in the Riding Mountain National Park (RMNP) region of southwestern Manitoba have been identified as a likely wildlife reservoir of Mycobacterium bovis, the causative agent of bovine mycobacteriosis in livestock. The feasibility of using coyotes (Canis latrans) collected from trappers as a sentinel species was investigated. Retropharyngeal, mesenteric, and colonic lymph nodes and tonsils collected at necropsy from 82 coyotes were examined by bacterial culture, polymerase chain reaction (PCR), and acid-fast histopathology. Mycobacterium bovis was not identified in any animal by culture or PCR although Mycobacterium avium species were isolated. A single acid-fast organism was identified on histopathologic examination of one animal. Based on the methods used in this study, trapper-caught coyotes do not appear to be a sensitive sentinel species of M. bovis infection in cervids in and around RMNP. PMID- 17699082 TI - Comparison of immune responses of brown-headed cowbird and related blackbirds to west Nile and other mosquito-borne encephalitis viruses. AB - The rapid geographic spread of West Nile virus (family Flaviviridae, genus Flavivirus, WNV) across the United States has stimulated interest in comparative host infection studies to delineate competent avian hosts critical for viral amplification. We compared the host competence of four taxonomically related blackbird species (Icteridae) after experimental infection with WNV and with two endemic, mosquito-borne encephalitis viruses, western equine encephalomyelitis virus (family Togaviridae, genus Alphavirus, WEEV), and St. Louis encephalitis virus (family Flaviviridae, genus Flavivirus, SLEV). We predicted differences in disease resistance among the blackbird species based on differences in life history, because they differ in geographic range and life history traits that include mating and breeding systems. Differences were observed among the response of these hosts to all three viruses. Red-winged Blackbirds were more susceptible to SLEV than Brewer's Blackbirds, whereas Brewer's Blackbirds were more susceptible to WEEV than Red-winged Blackbirds. In response to WNV infection, cowbirds showed the lowest mean viremias, cleared their infections faster, and showed lower antibody levels than concurrently infected species. Brown-headed Cowbirds also exhibited significantly lower viremia responses after infection with SLEV and WEEV as well as coinfection with WEEV and WNV than concurrently infected icterids. We concluded that cowbirds may be more resistant to infection to both native and introduced viruses because they experience heightened exposure to a variety of pathogens of parenting birds during the course of their parasitic life style. PMID- 17699083 TI - Prevalence of Batrachochytrium dendrobatidis in American bullfrog and southern leopard frog larvae from wetlands on the Savannah River Site, South Carolina. AB - Batrachochytrium dendrobatidis, an aquatic fungus, has been linked to recent amphibian population declines. Few surveys have assessed B. dendrobatidis infections in areas where the disease is suggested to be less virulent and population declines have not been observed, such as southeastern North America. Although adult Rana catesbeiana and Rana sphenocephala from the Savannah River Site, South Carolina collected in 1979 and 1982 were identified as having B. dendrobatidis, it is unknown whether the fungus is currently present at the site or if susceptibility to infection varies among species or wetlands with different histories of environmental contamination. From 15 May through 15 August 2004, we collected R. catesbeiana and R. sphenocephala tadpoles from three wetlands with differing contamination histories on the Savannah River Site, South Carolina. We found B. dendrobatidis in only one of the wetlands we surveyed. Batrachochytrium dendrobatidis infection was identified in 64% of the R. catesbeiana tadpoles sampled and histologically assessed (n=50) from a wetland contaminated with mercury, copper, and zinc. No R. sphenocephala tadpoles from this site (n=50) were infected. In combination with a recently published report, our data suggest that B. dendrobatidis has been present at the Savannah River Site for over 25 yr but has not caused any apparent population declines. This time period is similar to the known presence of 30 yr of B. dendrobatidis in northeastern North America. Our data suggest that R. sphenocephala larvae might be resistant to infection, even when occupying the same wetland as the infected R. catesbeiana. Our survey did not clarify the effects of environmental contamination on infection severity, but our study stresses the importance of additional field surveys to document how this pathogen is affecting amphibians globally. PMID- 17699084 TI - Neonatal mortality in New Zealand sea lions (Phocarctos hookeri) at Sandy Bay, Enderby Island, Auckland Islands from 1998 to 2005. AB - As part of a health survey of New Zealand sea lions (Phocarctos hookeri) on Enderby Island, Auckland Islands (50 degrees 30'S, 166 degrees 17'E), neonatal mortality was closely monitored at the Sandy Bay colony for seven consecutive years. Throughout the breeding seasons 1998-99 to 2004-05, more than 400 postmortem examinations were performed on pups found dead at this site. The primary causes of death were categorized as trauma (35%), bacterial infections (24%), hookworm infection (13%), starvation (13%), and stillbirth (4%). For most pups, more than one diagnosis was recorded. Every year, two distinct peaks of trauma were observed: the first associated with mature bulls fighting within the harem and the second with subadult males abducting pups. In 2001-02 and 2002-03, epidemics caused by Klebsiella pneumoniae increased mortality by three times the mean in nonepidemic years (10.2%). The increased mortality was attributed directly to acute suppurative infection due to the bacterium and also to an increase in traumatic deaths of debilitated pups. Parasitic infection with the hookworm Uncinaria spp. was a common finding in all pups older than three weeks of age and debilitation by the parasite may have contributed to increased susceptibility to other pathogens such as Klebsiella sp. or Salmonella sp. This study provides valuable quantitative data on the natural causes of neonatal mortality in New Zealand sea lions that can be used in demographic models for management of threatened species. PMID- 17699085 TI - Are pikas exposed to and affected by selenium deficiency? AB - Regional extirpations of pikas (Ochatona princeps) within the last few decades have been attributed to global warming. Other recent global alterations such as increased nitrogen (N) deposition and associated selenium (Se) deficiency may further stress pika populations. In 2003 and 2004, we live-trapped pikas from three populations in Wyoming and measured Se values in their hair. We also sampled hair and liver from museum specimens collected throughout the Northern Rocky Mountains in 1987 and 1988. Our results suggest that liver and hair values were related, and that pika hair reflected the Se concentrations of the geologic parent materials. We determined that animals residing in several remote areas in the Rocky Mountain region could be Se deficient and that increase in N deposition correlated with an increase rather than a decrease in Se values in pika hair. In addition, we found no relation between Se contents in hair and body condition index, suggesting that low Se levels may not have negative effects on individual pikas. Whether Se levels influence reproductive success of pikas is unknown and should be the focus of future studies. PMID- 17699086 TI - Species-specific visitation and removal of baits for delivery of pharmaceuticals to feral swine. AB - Within the domestic swine industry there is growing trepidation about the role feral swine (Sus scrofa) play in the maintenance and transmission of important swine diseases. Innovative disease management tools for feral swine are needed. We used field trials conducted in southern Texas from February to March 2006 to compare species-specific visitation and removal rates of fish-flavored and vegetable-flavored baits with and without commercially available raccoon (Procyon lotor) repellent (trial 1) and removal rates of baits deployed in a systematic and cluster arrangement (trial 2). During trial 1, 1) cumulative bait removal rates after four nights ranged from 93% to 98%; 2) bait removal rates by feral swine, raccoons, and collared peccaries (Pecari tajacu) did not differ by treatment; and 3) coyotes (Canis latrans) removed more fish-flavored baits without raccoon repellent and white-tailed deer removed more vegetable-flavored baits without raccoon repellent than expected. During trial 2, feral swine removed fish-flavored baits distributed in a cluster arrangement (eight baits within 5 m2) at a rate greater than expected. Our observed bait removal rates illustrate bait attractiveness to feral swine. However, the diverse assemblage of omnivores in the United States compared with Australia where the baits were manufactured adds complexity to the development of a feral swine-specific baiting system for pharmaceutical delivery. PMID- 17699087 TI - Leptospirosis serology in the common brushtail possum (Trichosurus vulpecula) from urban Sydney, Australia. AB - The common brushtail possum (Trichosurus vulpecula) is indeed a common marsupial in major cities of Australia. This species is known to be susceptible to leptospirosis and often lives in close contact with humans, raising concerns about the potential for transmission of this disease in urban areas. A total of 192 brushtail possum blood samples were collected from 136 individuals in suburban areas of metropolitan Sydney from November 2002 to November 2004. Sera were screened against a reference panel of 21 Leptospira spp. using the microscopic agglutination test. Leptospiral antibodies were detected in 9.6% (13/136) of tested brushtail possums and represented two serovars; antibodies to Leptospira interrogans serovar Hardjo were most frequently identified (11/136). A representative of the exotic sero-group Ballum, most likely serovar Arborea, was found in two of 136 brushtail possums. Exposure to leptospirosis seemed to be associated with age, as older animals had a higher incidence, but there was no distinction in relation to gender. Antibody prevalence varied between the different sampling sites and seropositive animals were clustered and restricted to a few sites. These data support the possible role of brushtail possums as a maintenance host for Leptospira spp. in urban environments and also identified them as a previously unknown and potential source of serovar Arborea. PMID- 17699088 TI - Paresis and death in elk (Cervus elaphus) due to lichen intoxication in Wyoming. AB - During February-April 2004, an estimated 400-500 free-ranging elk (Cervus elaphus) developed paresis, became recumbent, and died or were euthanized in the Red Rim Wildlife Habitat Management Area (RRWHMA), Wyoming, USA. Elk were found in sternal recumbency, alert and responsive, but unable to rise. Their condition progressed to lateral recumbency followed by dehydration, obtundation, and death. Gross lesions were limited to degenerative myopathy, with pallor and streaking in skeletal muscles. Microscopically, affected muscles had degenerative lesions of varying duration, severity, and distribution, some with early mineralization and attempts at regeneration. Diagnostic testing ruled out common infectious, inflammatory, toxic, and traumatic causes. Tumbleweed shield lichen (Xanthoparmelia chlorochroa) was found in the area and in the rumen of several elk. This lichen was collected and fed to three captive elk. Two of these elk exhibited signs of ataxia, which rapidly progressed to weakness and recumbency after 7 and 10 days on this diet, respectively, and a degenerative myopathy, consistent with lesions observed in the elk affected at RRWHMA, was observed. All remaining elk migrated from the RRWHMA during the spring and no subsequent losses have been documented. PMID- 17699089 TI - Immunologic and molecular identification of Babesia bovis and Babesia bigemina in free-ranging white-tailed deer in northern Mexico. AB - The suitability of white-tailed deer (Odocoileus virginianus) as hosts for the cattle ticks Rhipicephalus (Boophilus) microplus and Rhipicephalus (Boophilus) annulatus, has been well documented. These ticks have a wide host range, and both transmit Babesia bovis and Babesia bigemina, the agents responsible for bovine babesiosis. Although this disease and its vectors have been eradicated from the United States and some states in northern Mexico, it still is a problem in other Mexican states. It is not known if wild cervids like white-tailed deer can act as reservoirs for bovine babesiosis. The purpose of this study was to determine if B. bovis and B. bigemina or antibodies against them occur in white-tailed deer in the states of Nuevo Leon and Tamaulipas, Mexico. Twenty blood samples from white tailed deer from two ranches were collected and tested with a nested polymerase chain reaction (nested PCR) and indirect immunofluorescence antibody test (IFAT) for B. bovis and B. bigemina. Eleven samples were positive for B. bigemina and four for B. bovis by nested PCR; amplicon sequences were identical to those reported in GenBank for B. bovis (Rap 1) and B. bigemina. Results of the IFA test showed the presence of specific antibodies in serum samples. This is the first report of the presence of B. bovis and B. bigemina in white-tailed deer using these techniques and underscores the importance of cervids as possible reservoirs for bovine babesiosis. PMID- 17699090 TI - First report of Thelazia callipaeda (Spirurida, Thelaziidae) in wolves in Italy. AB - Thelazia callipaeda (Spirurida, Thelaziidae) infects the eyes of humans and rabbits as well of domestic and wild carnivores (i.e., dogs, cats, and foxes). The first three cases of infection by T. callipaeda eyeworms in wolves (Canis lupus) are here described with up to 96 nematodes collected from a single animal. The host competence of wolf was demonstrated by the retrieval of adult worms in the eyes of all examined animals. All nematodes collected were evaluated by morphologic and molecular techniques. Sequence analysis of the partial mitochondrial cytochrome c oxidase subunit 1 gene (cox1) confirmed that only one haplotype of T. callipaeda was present. The competence of wolves as a definitive host for T. callipaeda is discussed in view of the relevance of wild fauna in maintaining and spreading eyeworm infection in humans and domestic animals. PMID- 17699091 TI - Fatal Sarcoptes scabiei infection of blue sheep (Pseudois nayaur) in Pakistan. AB - Sarcoptes scabiei was detected for the first time in skin scrapings, hair pluckings, and histologic sections from a blue sheep (Pseudois nayaur) from the Shimshali Pamir in the Karakorum range of the western Himalaya in Pakistan (36 degrees 28'N, 75 degrees 36'E). Local reports suggest many hundred animals have been affected by a severe skin disease over a 10-yr period, but the shy nature of this species and the extreme climate that they inhabit meant only a single affected animal was available for detailed evaluation. The severe skin lesions were confined to the forelegs and brisket, and many Sarcoptes scabiei mites were present in all the samples examined. Histologic preparations of the skin showed hyperkeratotic and parakeratotic hyperkeratosis of the epidermis with a severe exudative dermatosis with many polymorphonuclear neutrophils and gram-positive cocci, yet no eosinophils. These findings might suggest the lack of an appropriate immune response to the parasite or other coping strategies because there has been no abatement of the clinical signs in affected animals over several years. Treatment options are limited due to the behavior of the species and its habitat. The blue sheep is a primary source of prey for the endangered snow leopard (Panthera uncia) and continued depletion could have serious consequences for the survival of the latter. PMID- 17699092 TI - Presence of Leishmania infantum in red foxes (Vulpes vulpes) in southern Italy. AB - Skin, lymph node (popliteal), and bone marrow samples were collected from 50 red foxes (Vulpes vulpes) from May 2004 to May 2005 in southern Italy. Samples were tested for Leishmania infantum by polymerase chain reaction (PCR). The parasite was detected by PCR from 20 of 50 (40%) fox carcasses. All 20 positive cases were PCR-positive from lymph node and bone marrow samples, whereas 17 of 20 positive cases were PCR-positive from skin samples. Infection status was not related to age or sex. This is the first report of leishmaniasis in red foxes in Italy based on PCR results, and these results reinforce the assumption that this wild canid can serve as a reservoir for Leishmania. PMID- 17699093 TI - Chytrid fungus in frogs from an equatorial African montane forest in western Uganda. AB - Batrachochytrium dendrobatidis, the causative agent of chytridiomycosis, was found in 24 of 109 (22%) frogs from Kibale National Park, western Uganda, in January and June 2006, representing the first account of the fungus in six species and in Uganda. The presence of B. dendrobatidis in an equatorial African montane forest raises conservation concerns, considering the high amphibian diversity and endemism characteristic of such areas and their ecological similarity to other regions of the world experiencing anuran declines linked to chytridiomycosis. PMID- 17699094 TI - Sensitivity of a diagnostic test for amphibian Ranavirus varies with sampling protocol. AB - Field samples are commonly used to estimate disease prevalence in wild populations. Our confidence in these estimates requires understanding the sensitivity and specificity of the diagnostic tests. We assessed the sensitivity of the most commonly used diagnostic tests for amphibian Ranavirus by infecting salamanders (Ambystoma tigrinum; Amphibia, Caudata) with Ambystoma tigrinum virus (ATV) and then sampling euthanized animals (whole animal) and noneuthanized animals (tail clip) at five time intervals after exposure. We used a standard polymerase chain reaction (PCR) protocol to screen for ATV. Agreement between test results from whole-animal and tail-clip samples increased with time postexposure. This indicates that the ability to identify infected animals increases following exposure, leading to a more accurate estimate of prevalence in a population. Our results indicate that tail-clip sampling can underestimate the true prevalence of ATV in wild amphibian populations. PMID- 17699095 TI - Malignant catarrhal fever associated with ovine herpesvirus-2 in free-ranging mule deer in Colorado. AB - Malignant catarrhal fever (MCF) was diagnosed in four free-ranging mule deer (Odocoileus hemionus) in January and February of 2003. Diagnosis was based on typical histologic lesions of lymphocytic vasculitis and PCR identification of ovine herpesvirus-2 (OHV-2) viral genetic sequences in formalin-fixed tissues. The animals were from the Uncompahgre Plateau of southwestern Colorado. Deer from these herds occasionally resided in close proximity to domestic sheep (Ovis aries), the reservoir host of OHV-2, in agricultural valleys adjacent to their winter range. These cases indicate that fatal OHV-2 associated MCF can occur in free-ranging mule deer exposed to domestic sheep that overlap their range. PMID- 17699096 TI - Prevalence of west Nile virus antibodies in a breeding population of American Kestrels (Falco sparverius) in Pennsylvania. AB - West Nile virus (WNV) has been identified in nearly 300 species of wild birds, including raptors, in North America since its introduction in New York City in 1999. American Kestrels (Falco sparverius) are susceptible to WNV infection, and the numbers of these birds have declined along the Atlantic coast in recent years. We examined the population biology and WNV exposure of kestrels breeding in the area surrounding Hawk Mountain Sanctuary in Kempton, Pennsylvania, USA. The reproductive biology of kestrels in this area was studied from 1992 until 2004. The number of kestrels breeding in nestboxes in 2004 was only 44% of the 6 yr mean observed prior to 1999. During the 2004 nesting season (study period: 8 June through 22 July 2004), adult kestrels were trapped near the site of their nestboxes. Blood samples were obtained, and serum antibodies specific to WNV were quantified using a plaque reduction neutralization test. Of 22 birds tested, 21 exhibited serum antibodies to WNV, suggesting that most (95%) of the adult kestrels in the population had been exposed to WNV. PMID- 17699097 TI - A case of chondrosarcoma in a free-flying Great Egret. AB - A free-flying Great Egret (Ardea alba) captured in Gifu, central Japan, in May 2006 had a large mass on the right carpal joint. The tumor was diagnosed as chondrosarcoma by histopathologic examination. PMID- 17699098 TI - An observation of Clostridium perfringens in Greater Sage-Grouse. AB - Mortality due to infectious diseases is seldom reported in the Greater Sage Grouse (Centrocercus urophasianus). A case of necrotic enteritis associated with Clostridium perfringens type A is described in a free-ranging adult male sage grouse in eastern Oregon. Clostridial enteritis is known to cause outbreaks of mortality in various domestic and wild birds, and should be considered as a potential cause of mortality in sage-grouse populations. PMID- 17699099 TI - Presence of antibotulinum neurotoxin antibodies in selected wild canids in Israel. AB - Serum samples from 35 golden jackals (Canis aureus syriacus), eight wolves (Canis lupus), and four red foxes (Vulpes vulpes) from various regions of Israel were collected during the years 2001-04 and tested for antibodies to Clostridium botulinum neurotoxin (BoNT) types C and D. Antibodies against BoNT types C and D were detected in 10 (29%) and in 3 (9%) of 35 golden jackals, respectively, using enzyme-linked immunosorbent assay. This report describes detection of anti BoNT antibodies in wild canids other than coyotes (Canis latrans) for the first time and demonstrates that C. botulinum type C is prevalent in Israel. PMID- 17699100 TI - Serosurvey of small carnivores in the Bolivian Chaco. AB - Five species of Bolivian carnivores, including nine Geoffroy's cats (Oncifelis geoffroyi), ten ocelots (Leopardus pardalis), one jaguarundi (Herpailurus yaguarondi), nine pampas foxes (Pseudalopex gymnocercus), and five crab-eating foxes (Cerdocyon thous) were sampled between March 2001 and April 2005 and tested for antibodies to common pathogens of domestic carnivores. Carnivores were trapped in three areas: a village, the region between human settlements and a protected area, and within Kaa-Iya National Park, Bolivia. Antibodies to canine distemper virus were detected in ocelots and pampas foxes. Antibodies to canine parvovirus were detected in pampas foxes and crab-eating foxes. Geoffroy's cats and all of the ocelots tested positive for antibodies to feline calicivirus (FCV), while fewer than half of Geoffroy's cats and no ocelots had antibodies to feline panleukopenia (FPV). These results confirm that these species of Bolivian carnivores are not naive to common pathogens of domestic carnivores, and seropositive animals were found in villages as well as in the national park. PMID- 17699101 TI - Tgf-Beta signaling in development. AB - The transforming growth factor-beta (TGF-beta) superfamily comprises nearly 30 growth and differentiation factors that include TGF-betas, activins, inhibins, and bone morphogenetic proteins (BMPs). Multiple members of the TGF-beta superfamily serve key roles in stem cell fate commitment. The various members of the family can exhibit disparate roles in regulating the biology of embryonic stem (ES) cells and tumor suppression. For example, TGF-beta inhibits proliferation of multipotent hematopoietic progenitors, promotes lineage commitment of neural precursors, and suppresses epithelial tumors. BMPs block neural differentiation of mouse and human ES cells, contribute to self-renewal of mouse ES cells, and also suppress tumorigenesis. ES cells and tumors may be exposed to multiple TGF-beta members, and it is likely that the combination of growth factors and cross-talk among the intracellular signaling pathways is what precisely defines stem cell fate commitment. This Connections Map Pathway in the Database of Cell Signaling integrates signaling not only from TGF-beta and BMP but also from the ligands nodal and activin, and describes the role of the signaling pathways activated by these ligands in mammalian development. Much of the evidence for the connections shown comes from studies on mouse and human ES cells or mouse knockouts. This pathway is important for understanding not only stem cell biology, but also the molecular effectors of TGF-beta and BMP signaling that may contribute to cancer suppression or progression and thus are potential targets for therapeutic intervention. PMID- 17699102 TI - Nicotine and synaptic plasticity in prefrontal cortex. AB - Nicotinic receptor activation enhances working memory and attention. The prefrontal cortex is a key brain area involved in working memory, and plasticity of excitatory synaptic transmission within the cortex is likely an important cellular mechanism of memory. A recent study has explored the cellular and synaptic basis of nicotine's effects on excitability within the prefrontal cortex. The findings suggest that nicotine enhances inhibitory synaptic inputs to layer V pyramidal cells, which suppresses induction of long-term potentiation (LTP). This inhibitory effect can be overcome by stimulating the pyramidal cells in bursts, which suggests a modification in the signal-to-noise ratio for synaptic input. Thus, the impact of strong stimuli on working memory would be enhanced when combined with nicotinic receptor activity. These findings may lead to novel and more effective treatments for memory disorders. PMID- 17699103 TI - Modulation of bcl-xL in tumor cells regulates angiogenesis through CXCL8 expression. AB - In this paper, we investigated whether bcl-xL can be involved in the modulation of the angiogenic phenotype of human tumor cells. Using the ADF human glioblastoma and the M14 melanoma lines, and their derivative bcl-xL overexpressing clones, we showed that the conditioned medium of bcl-xL transfectants increased in vitro endothelial cell functions, such as proliferation and morphogenesis, and in vivo vessel formation in Matrigel plugs, compared with the conditioned medium of control cells. Moreover, the overexpression of bcl-xL induced an increased expression of the proangiogenic interleukin-8 (CXCL8), both at the protein and mRNA levels, and an enhanced CXCL8 promoter activity. The role of CXCL8 on bcl-xL-induced angiogenesis was validated using CXCL8-neutralizing antibodies, whereas down-regulation of bcl-xL through antisense oligonucleotide or RNA interference strategies confirmed the involvement of bcl-xL on CXCL8 expression. Transient overexpression of bcl-xL led to extend this observation to other tumor cell lines with different origin, such as colon and prostate carcinoma. In conclusion, our results showed that CXCL8 modulation by bcl-xL regulates tumor angiogenesis, and they point to elucidate an additional function of bcl-xL protein. PMID- 17699104 TI - Ribotoxic stress sensitizes glioblastoma cells to death receptor induced apoptosis: requirements for c-Jun NH2-terminal kinase and Bim. AB - A prominent feature of glioblastoma is its resistance to death receptor-mediated apoptosis. In this study, we explored the possibility of modulating death receptor-induced cell death with the c-Jun-NH2-terminal kinase (JNK) activator anisomycin. Anisomycin activates JNK by inactivating the ribosome and inducing "ribotoxic stress." We found that anisomycin and death receptor ligand anti-Fas antibody CH-11 or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induce apoptosis in multiple human glioblastoma cell lines. For example, in U87 cells, anisomycin reduced the IC50 of CH-11 by more than 20-fold (from 500 to 25 ng/mL). Cell viability in response to anisomycin, CH-11, and their combination was 79%, 91%, and 28% (P<0.001), respectively. Anisomycin and TRAIL were found to be similarly synergistic in glioblastoma cells maintained as tumor xenografts. The potentiation of death receptor-dependent cell death by anisomycin was specific because emetine, another ribosome inhibitor that does not induce ribotoxic stress or activate JNK, did not have a similar effect. Synergistic cell death was predominantly apoptotic involving both extrinsic and intrinsic pathways. Expression of Fas, FasL, FLIP, and Fas-associated death domain (FADD) was not changed following treatment with anisomycin+CH-11. JNK was activated 10- to 22-fold by anisomycin+CH-11 in U87 cells. Inhibiting JNK activation with pharmacologic inhibitors of JNKK and JNK or with dominant negative mitogen-activated protein kinase (MAPK) kinase kinase 2 (MEKK2) significantly prevented cell death induced by the combination of anisomycin+CH 11. We further found that anisomycin+CH-11 up-regulated the proapoptotic protein Bim by approximately 14-fold. Simultaneously inhibiting Bim expression and JNK activation additively desensitized U87 cells to anisomycin+CH-11. These findings show that anisomycin-induced ribotoxic stress sensitizes glioblastoma cells to death receptor-induced apoptosis via a specific mechanism requiring both JNK activation and Bim induction. PMID- 17699105 TI - The opposing effect of hypoxia-inducible factor-2alpha on expression of telomerase reverse transcriptase. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) has been implicated in the transcriptional regulation of the telomerase reverse transcriptase (hTERT) gene expression and telomerase activity, essential elements for cellular immortalization and transformation. However, controversial results were obtained in different studies. Moreover, it is totally unclear whether HIF-2alpha, the paralog of HIF-1alpha, plays a role in regulating hTERT expression. In the present study, we found that hypoxic treatment enhanced hTERT mRNA expression and telomerase activity in three renal cell carcinoma (RCC) cell lines with different genetic backgrounds. Both HIF-1alpha and HIF-2alpha were capable of significantly increasing the hTERT promoter activity in these cells. Moreover, depleting HIF 2alpha led to a down-regulation of hTERT mRNA level in RCC A498 cells expressing constitutive HIF-2alpha. It was found that HIF-2alpha bound to the hTERT proximal promoter and enhanced the recruitment of the histone acetyltransferase p300 and histone H3 acetylation locally in A498 cells treated with hypoxia. Increased levels of hTERT mRNA were observed in two of three hypoxia-treated malignant glioma cell lines. However, HIF-1alpha stimulated whereas HIF-2alpha inhibited the hTERT promoter activity in these glioma cell lines. Ectopic expression of HIF 2alpha resulted in diminished hTERT expression in glioma cells. Collectively, HIF 1alpha activates hTERT and telomerase expression in both RCC and glioma cells, and HIF-2alpha enhances hTERT expression in RCC cells, whereas it represses the hTERT transcription in glioma cells. These findings reveal a complex relationship between HIF-1alpha/2alpha and hTERT/telomerase expression in malignant cells, which may have both biological and clinical implications. PMID- 17699106 TI - (Dihydro)ceramide synthase 1 regulated sensitivity to cisplatin is associated with the activation of p38 mitogen-activated protein kinase and is abrogated by sphingosine kinase 1. AB - Resistance to chemotherapeutic drugs often limits their clinical efficacy. Previous studies have implicated the bioactive sphingolipid sphingosine-1 phosphate (S-1-P) in regulating sensitivity to cisplatin [cis diamminedichloroplatinum(II)] and showed that modulating the S-1-P lyase can alter cisplatin sensitivity. Here, we show that the members of the sphingosine kinase (SphK1 and SphK2) and dihydroceramide synthase (LASS1/CerS1, LASS4/CerS4, and LASS5/CerS5) enzyme families each have a unique role in regulating sensitivity to cisplatin and other drugs. Thus, expression of SphK1 decreases sensitivity to cisplatin, carboplatin, doxorubicin, and vincristine, whereas expression of SphK2 increases sensitivity. Expression of LASS1/CerS1 increases the sensitivity to all the drugs tested, whereas LASS5/CerS5 only increases sensitivity to doxorubicin and vincristine. LASS4/CerS4 expression has no effect on the sensitivity to any drug tested. Reflecting this, we show that the activation of the p38 mitogen-activated protein (MAP) kinase is increased only by LASS1/CerS1, and not by LASS4/CerS4 or LASS5/CerS5. Cisplatin was shown to cause a specific translocation of LASS1/CerS1, but not LASS4/CerS4 or LASS5/CerS5, from the endoplasmic reticulum (ER) to the Golgi apparatus. Supporting the hypothesis that this translocation is mechanistically involved in the response to cisplatin, we showed that expression of SphK1, but not SphK2, abrogates both the increased cisplatin sensitivity in cells stably expressing LASS1/CerS and the translocation of the LASS1/CerS1. The data suggest that the enzymes of the sphingolipid metabolic pathway can be manipulated to improve sensitivity to the widely used drug cisplatin. PMID- 17699107 TI - Ataxia telangiectasia-mutated dependent DNA damage checkpoint functions regulate gene expression in human fibroblasts. AB - The relationships between profiles of global gene expression and DNA damage checkpoint functions were studied in cells from patients with ataxia telangiectasia (AT). Three telomerase-expressing AT fibroblast lines displayed the expected hypersensitivity to ionizing radiation (IR) and defects in DNA damage checkpoints. Profiles of global gene expression in AT cells were determined at 2, 6, and 24 h after treatment with 1.5-Gy IR or sham treatment and were compared with those previously recognized in normal human fibroblasts. Under basal conditions, 160 genes or expressed sequence tags were differentially expressed in AT and normal fibroblasts, and these were associated by gene ontology with insulin-like growth factor binding and regulation of cell growth. On DNA damage, 1,091 gene mRNAs were changed in at least two of the three AT cell lines. When compared with the 1,811 genes changed in normal human fibroblasts after the same treatment, 715 were found in both AT and normal fibroblasts, including most genes categorized by gene ontology into cell cycle, cell growth, and DNA damage response pathways. However, the IR-induced changes in these 715 genes in AT cells usually were delayed or attenuated in comparison with normal cells. The reduced change in DNA damage response genes and the attenuated repression of cell cycle-regulated genes may account for the defects in cell cycle checkpoint function in AT cells. PMID- 17699108 TI - Activated signal transducers and activators of transcription 3 signaling induces CD46 expression and protects human cancer cells from complement-dependent cytotoxicity. AB - CD46 is one of the complement-regulatory proteins expressed on the surface of normal and tumor cells for protection against complement-dependent cytotoxicity. Cancer cells need to access the blood circulation for continued growth and metastasis, thus exposing themselves to destruction by complement system components. Previous studies have established that the signal transducers and activators of transcription 3 (STAT3) transcription factor is persistently activated in a wide variety of human cancer cells and primary tumor tissues compared with their normal counterparts. Using microarray gene expression profiling, we identified the CD46 gene as a target for activated STAT3 signaling in human breast and prostate cancer cells. The CD46 promoter contains two binding sites for activated STAT3 and mutations introduced into the major site abolished STAT3 binding. Chromatin immunoprecipitation confirms binding of STAT3 to the CD46 promoter. CD46 promoter activity is induced by activation of STAT3 and blocked by a dominant-negative form of STAT3 in luciferase reporter assays. CD46 mRNA expression is induced by interleukin-6 and by transient transfection of normal human epithelial cells with a persistently active mutant construct of STAT3, STAT3C. Furthermore, we show that inhibition of STAT3-mediated CD46 cell surface expression sensitizes DU145 prostate cancer cells to cytotoxicity in an in vitro complement lysis assay using rabbit anti-DU145 antiserum and rabbit complement. These results show that activated STAT3 signaling induces the CD46 promoter and protects human cancer cells from complement-dependent cytotoxicity, suggesting a potential mechanism whereby oncogenic signaling contributes to tumor cell evasion of antibody-mediated immunity. PMID- 17699109 TI - c-Src/histone deacetylase 3 interaction is crucial for hepatocyte growth factor dependent decrease of CXCR4 expression in highly invasive breast tumor cells. AB - Hepatocyte growth factor (HGF), a cytokine of tumor microenvironment, exerts opposite effects on CXCR4 expression in MCF-7 (low invasive) and MDA-MB231 (highly invasive) breast carcinoma cells, and here, we show that completely different molecular mechanisms downstream of c-Src activation were involved. As experimental models, we used cells transfected with two CXCR4 promoter constructs and treated with HGF or cotransfected with c-Src wild-type (Srcwt) expression vector; phospho-c-Src formation was enhanced in both cell lines. In MCF-7 cells, consistent with activations of CXCR4Luc constructs after HGF treatment and Srcwt expression, Ets1 and nuclear factor-kappaB (NF-kappaB) transcription factors were activated. In contrast, in MDA-MB231 cells, CXCR4Luc construct, Ets1 and NF kappaB activities decreased. The divergence point seemed to be downstream of HGF/c-Src and consisted in the interaction between c-Src and the substrate histone deacetylase 3 (HDAC3). Only in MDA-MB231 cells, HDAC3 level was enhanced in membranes and nuclei 30 min after HGF and colocalized/coimmunoprecipitated with phospho-c-Src and phosphotyrosine. Thus, the CXCR4 induction by HGF in MCF-7 cells required NF-kappaB and Ets1 activations, downstream of phosphoinositide-3 kinase/Akt, whereas in HGF-treated MDA-MB231 cells, HDAC3 activation via c-Src probably caused a reduction of transcription factor activities, such as that of NF-kappaB. These results indicate possible roles of HGF in invasive growth of breast carcinomas. By enhancing CXCR4 in low invasive tumor cells, HGF probably favors their homing to secondary sites, whereas by suppressing CXCR4 in highly invasive cells, HGF might participate to retain them in the metastatic sites. PMID- 17699110 TI - Stimulated PI3K-AKT signaling mediated through ligand or radiation-induced EGFR depends indirectly, but not directly, on constitutive K-Ras activity. AB - Previous results showed an inducible radiation sensitivity selectively observable for K-RAS-mutated cell lines as a function of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor blockade of phosphatidylinositol 3-kinase (PI3K) AKT signaling. Therefore, the role of K-Ras activity for a direct (i.e., through activation of PI3K by K-Ras) or an indirect stimulation of PI3K-AKT signaling (through K-Ras activity-dependent EGFR ligand production) was investigated by means of small interfering RNA and inhibitor approaches as well as ELISA measurements of EGFR ligand production. K-RASmt tumor cells presented a constitutively activated extracellular signal-regulated kinase-1/2 signaling, resulting in enhanced production and secretion of the EGFR ligand amphiregulin (AREG). Medium supernatants conditioned by K-RASmt tumor cells equally efficiently stimulated EGFR signaling into the PI3K-AKT and mitogen-activated protein kinase pathways. Knocking down K-Ras expression by specific small interfering RNA markedly affected autocrine production of AREG, but not PI3K-AKT signaling, after treatment of K-RAS-mutated or wild-type cells with EGFR ligands or exposure to ionizing radiation. These results indicate that PI3K-mediated activation of AKT in K-RASmt human tumor cells as a function of EGFR ligand or radiation stimulus is independent of a direct function of K-Ras enzyme activity but depends on a K-Ras-mediated enhanced production of EGFR ligands (i.e., most likely AREG) through up-regulated extracellular signal-regulated kinase-1/2 signaling. The data provide new differential insight into the importance of K-RAS mutation in the context of PI3K-AKT-mediated radioresistance of EGFR overexpressing or EGFR-mutated tumors. PMID- 17699111 TI - An evaluation of the coping patterns of rape victims: integration with a schema based information-processing model. AB - The current study sought to provide an expansion of Resick and Schnicke's information-processing model of interpersonal violence response. Their model posits that interpersonal violence threatens victims' schematic beliefs and that victims can resolve this threat through assimilation, accommodation, or overaccommodation. In addition, it is hypothesized that how victims resolve schematic threat affects their coping strategies. To test this hypothesis, a cluster analysis of rape victims' coping patterns was conducted. Victims' coping patterns were related to distress, self-worth, and rape label in ways consistent with predictions. Thus, future research should focus on the implications of how victims integrate trauma with schemas. PMID- 17699112 TI - Patterns of injuries: accident or abuse. AB - This study uses two types of independent variables, age and the location of the physical wound, to develop a model of injury patterning that identifies violent behavior without direct observation of the assault. In this research, domestic violence injuries are compared to accidental injuries. The results indicate that there are specific and predictable injury patterns that separate abuse from other kinds of wounds. A logistic regression model was developed to identify the regions of the body most susceptible to injury from domestic assault. Using the age of the victim and the injury regions, probabilities were calculated to determine which wounds were caused by abuse. PMID- 17699113 TI - An integrative feminist model: the evolving feminist perspective on intimate partner violence. AB - The feminist perspective on intimate partner violence is a predominant model in the field, although not immune to criticism. In this research, frontline workers in the violence against women movement responded to critiques of the feminist model. The project used a focus group and a modified grounded theory analysis. Participants agreed with some criticisms, including an overreliance on a punitive criminal justice system, but reported skepticism toward proposed alternatives. Findings led to the development of the Integrative Feminist Model, which expands the feminist perspective in response to critiques, new research, and alternative theories while retaining a gendered analysis of violence. PMID- 17699114 TI - Intimate partner violence, technology, and stalking. AB - This research note describes the use of a broad range of technologies in intimate partner stalking, including cordless and cellular telephones, fax machines, e mail, Internet-based harassment, global positioning systems, spy ware, video cameras, and online databases. The concept of "stalking with technology" is reviewed, and the need for an expanded definition of cyberstalking is presented. Legal issues and advocacy-centered responses, including training, legal remedies, public policy issues, and technology industry practices, are discussed. PMID- 17699115 TI - Negotiating state and NGO politics in Bangladesh: women mobilize against acid violence. AB - This note showcases the story of Nurun Nahar, a survivor of acid violence in Bangladesh, to demonstrate that, despite protective measures, state, medical, and legal institutions continually fail to adequately respond to violence against women systematically and deny women rights to state protection, which are affirmatively embodied in law. The failure of state institutions to ensure appropriate care has been somewhat mitigated by nongovernmental organizations (NGOs), particularly women's groups, which are albeit heavily constrained because of the volume of demand yet scarcity of expertise, infrastructure, and funds. In addition, this note offers some thoughts on how nonstate actors, namely, women's NGOs, have created alternative strategies and visions for victimized women's recovery and empowerment. PMID- 17699116 TI - Understanding the complexities of feminist perspectives on woman abuse: a commentary on Donald G. Dutton's Rethinking Domestic Violence. PMID- 17699117 TI - Acceptance and commitment therapy for generalized social anxiety disorder: a pilot study. AB - Despite the demonstrated efficacy of cognitive-behavior therapy (CBT) for social anxiety disorder (SAD), many individuals do not respond to treatment or demonstrate residual symptoms and impairment posttreatment. Preliminary evidence indicates that acceptance-based approaches (e.g., acceptance and commitment therapy; ACT) can be helpful for a variety of disorders and emphasize exposure based strategies and processes. Nineteen individuals diagnosed with SAD participated in a 12-week program integrating exposure therapy and ACT. Results revealed no changes across a 4-week baseline control period. From pretreatment to follow-up, significant improvements occurred in social anxiety symptoms and quality of life, yielding large effect size gains. Significant changes also were found in ACT-consistent process measures, and earlier changes in experiential avoidance predicted later changes in symptom severity. Results suggest the acceptability and potential efficacy of ACT for SAD and highlight the need for future research examining both the efficacy and mechanisms of change of acceptance-based programs for SAD. PMID- 17699118 TI - Spontaneous recovery of previously extinguished behavior as an alternative explanation for extinction-related side effects. AB - Extinction is accepted as a viable intervention for behaviors that are hypothesized to be maintained by contingent attentional reinforcement. However, it is frequently acknowledged that extinction has potential numerous side effects, including the generation of aggressive behavior. This explanation does not provide a behavioral conceptualization of such side effects. This article offers that spontaneous recovery of previously extinguished behavior as a behavioral explanation of side effects sometimes observed during the extinction process. PMID- 17699119 TI - Behavioral treatment of drooling: a methodological critique of the literature with clinical guidelines and suggestions for future research. AB - Many children with mental retardation and developmental disabilities suffer from the consequences of chronic drooling. Behavioral treatment for drooling should be considered before other, more intrusive treatments such as medication and surgery are implemented. However, empirical studies on behavioral procedures are scarce. This article reviews 19 behavioral studies published since 1970. Treatment procedures are (a) instruction, prompting, and positive reinforcement; (b) negative social reinforcement and declarative procedures; (c) cueing techniques; and (d) self-management procedures. Although these procedures yield positive results, critical examination of experimental methodology of the studies reveals several methodological shortcomings. Guidelines for clinical use of behavioral treatment for drooling are presented, and recommendations are given for future research in this area. PMID- 17699120 TI - Two-day, intensive cognitive-behavioral therapy for panic disorder: a case study. AB - Cognitive-behavioral therapy (CBT) is a highly effective treatment for panic disorder. However, few patients have access to this treatment, particularly those living in rural areas. In a pilot study, the author previously described the efficacy of a 2-day, intensive, exposure-based CBT intervention that was developed for the purpose of delivering CBT to a largely rural patient population that must travel long distances to find a treatment provider. The present study describes the successful implementation of this treatment with a 38-year-old woman with panic disorder and agoraphobia whose clinical presentation was complicated by recurrent fainting episodes during her panic attacks. Technical and theoretical issues in the conduct of this treatment are discussed, along with more general strategies to increase the efficiency and efficacy of CBT for panic disorder. PMID- 17699121 TI - Efficacy of cognitive-behavioral therapy for comorbid panic disorder with agoraphobia and generalized anxiety disorder. AB - The goal of this study was to evaluate the efficacy of cognitive-behavioral therapy for comorbid panic disorder with agoraphobia (PDA) and generalized anxiety disorder (GAD) by combining treatment strategies for both disorders. A single-case, multiple-baseline design across participants was used. Three participants with primary PDA and secondary GAD took part in the study. The efficacy of the treatment was assessed by means of a structured interview, self administered questionnaires, and daily self-monitoring measures. After treatment, 2 of the 3 participants achieved high end-state functioning and maintained this level of functioning at 3-, 6-, and 12-month follow-ups. The third participant also improved but only reached high end-state functioning at 6-month follow-up. It therefore appears that the combined treatment is relatively effective for PDA GAD comorbidity. Possible avenues for improving the treatment are suggested. PMID- 17699122 TI - Longitudinal retention of families in the assessment of a prevention program targeting adolescent alcohol and tobacco use: the utility of an ecological systems framework. AB - This study examined the association between ecological context (extrafamilial, familial, child factors) at baseline and longitudinal retention of families in the 36-month assessment of an adolescent alcohol and tobacco use prevention program that was conducted within a pediatric primary care setting. A total of 1,780 families were enrolled at baseline when the youth were in the fifth and sixth grades, and 1,220 of these families participated in the 36-month assessment. Findings indicated that familial and child, but not extrafamilial, factors were associated with the participation of families in the 36-month assessment. Clinical implications and future research directions are discussed. PMID- 17699123 TI - Using video modeling for generalizing toy play in children with autism. AB - The present study examined effects of video modeling on generalized independent toy play of two boys with autism. Appropriate and repetitive verbal and motor play were measured, and intermeasure relationships were examined. Two single participant experiments with multiple baselines and withdrawals across toy play were used. One boy was presented with three physically unrelated toys, whereas the other was presented with three related toys. Video modeling produced increases in appropriate play and decreases in repetitive play, but generalized play was observed only with the related toys. Generalization may have resulted from variables including the toys' common physical characteristics and natural reinforcing properties and the increased correspondence between verbal and motor play. PMID- 17699124 TI - Social-skills treatments for children with autism spectrum disorders: an overview. AB - Marked advances in the treatment of children with autism spectrum disorders (ASDs) has occurred in the past few decades, primarily using applied behavior analysis. However, reviews of trends in social skills treatment for children with ASDs have been scant, despite a robust and growing empirical literature on the topic. In this selective review of 79 treatment studies, the authors note that the research has been particularly marked by fragmented development, using a range of intervention approaches and definitions of the construct. Modeling and reinforcement treatments have been the most popular model from the outset, with most studies conducted in school settings by teachers or psychologists. Investigators have been particularly attentive to issues of generalization and follow-up. However, large-scale group studies and comparisons of different training strategies are almost nonexistent. These trends and their implications for future research aimed at filling gaps in the existing literature are discussed. PMID- 17699125 TI - Percutaneous mechanical thrombectomy for acute pulmonary embolism: a double-edged sword. PMID- 17699126 TI - Pulmonary hypertension: from an orphan disease to a public health problem. PMID- 17699127 TI - Finding signals amidst the noise in pulmonary function testing. PMID- 17699128 TI - Spirometry for COPD is both underutilized and overutilized. PMID- 17699129 TI - Containing conflicts of interest. PMID- 17699130 TI - Diuretics in obstructive sleep apnea with diastolic heart failure. AB - BACKGROUND: Upper airway edema might contribute to pharyngeal collapsibility and account for the high prevalence of obstructive sleep apnea (OSA) in patients with heart disease. The aim of this study was to evaluate if intensive unloading with diuretics improves sleep-disordered breathing and increases pharyngeal caliber in patients with severe OSA and diastolic heart failure. METHODS: Fifteen patients with severe OSA, hypertension, and diastolic heart failure were hospitalized to receive IV furosemide, 20 mg, and spironolactone, 100 mg, bid for 3 days. Polysomnography was performed for assessment of apnea-hypopnea index (AHI), acoustic pharyngometry was performed for assessment of the oropharyngeal junction (OPJ) area, and forced midinspiratory flow (FIF(50)), forced midexpiratory flow (FEF(50))/FIF(50) percentage, and exhaled nitric oxide (FeNO) were measured before and after diuretic treatment. RESULTS: Diuretic treatment produced a significant decrease in body weight, BP, and AHI (from 74.89 +/- 6.95 to 57.17 +/ 5.40/h, p < 0.001), associated with an improvement in OPJ area (from 1.33 +/- 0.10 to 1.78 +/- 0.16 cm(2), p = 0.007), FIF(50) (from 3.16 +/- 0.4 to 3.94 +/- 0.4 L/s, p = 0.006), and FEF(50)/FIF(50) percentage (from 117.9 +/- 11.8 to 93.15 +/- 10.1%, p = 0.002). Weight loss was significantly related to the decrease of AHI (R = 0.602; p = 0.018), to the increase of FIF(50) (R = 0.68; p = 0.005), and to the decrease of FEF(50)/FIF(50) (R = 0.635; p = 0.011). CONCLUSIONS: These findings suggest that pharyngeal edema contributes to sleep-disordered breathing in obese patients with severe OSA, hypertension, and diastolic heart failure. Upper airway edema may contribute to the frequent occurrence of OSA in patients with heart disease. PMID- 17699131 TI - Experimental severe Pseudomonas aeruginosa pneumonia and antibiotic therapy in piglets receiving mechanical ventilation. AB - BACKGROUND: Little is known about the general and local consequences of severe pneumonia under mechanical ventilation (SPMV) and how these are resolved with antibiotic therapy (ABT). OBJECTIVES: To investigate the physiologic, biological, microbiological, and pathologic changes produced by experimental SPMV in a porcine model, and to evaluate the effect of ABT. METHODS: Pseudomonas aeruginosa was inoculated in 12 large white-Landrace piglets receiving mechanical that were killed after 72 h if death did not occur before. Vital signs, serum and BAL cytokines, serum C-reactive protein (CRP), and graded postmortem lung pathology and cultures (blood and quantitative BAL and lung) were evaluated. Six piglets received inappropriate ABT (no ABT or ceftriaxone), and six piglets received appropriate ABT (ciprofloxacin). MEASUREMENTS AND MAIN RESULTS: Pathologic and microbiological evidence of infection were present in all the animals in both groups. SPMV produced significant oxygenation and lung compliance worsening, increased serum CRP, and reduced BAL fluid tumor necrosis factor (TNF)-alpha. Arterial thrombosis in lung pathology was associated with higher temperature, hypoxemia and low lung compliance, higher initial serum CRP and TNF-alpha concentrations, and increased serum interleukin (IL)-6 and BAL IL-6 and TNF alpha. Reduced ABT reduced body temperature and culture positivity. CONCLUSIONS: This model resembles VAP and has been used for studying pulmonary infection and inflammation related to mechanical ventilation. ABT reduced fever and bacterial burden in SPMV but had no effect on cytokine or CRP concentrations, oxygenation, or lung mechanics. Pulmonary artery thrombosis was associated with worse response to infection. PMID- 17699132 TI - Different bacteriology and prognosis of thoracic empyemas between patients with chronic and end-stage renal disease. AB - BACKGROUND: Bacterial infections are a well-documented complication in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). However, there are no previous studies of the empyemas that can develop in these patients. METHODS: This retrospective study investigated the bacteriology and outcomes of empyema in stage 4 CKD (predialysis) and ESRD patients receiving long-term dialysis and treated in a tertiary university hospital from January 2001 to March 2006. RESULTS: Eighty-four stage 4 CKD patients and 40 ESRD patients had empyemas. Most empyemas (n = 77, 62%) were secondary to pneumonia. Empyema culture findings were positive in 102 patients (82%): 87 microorganism were isolated in pleural fluid from 67 stage 4 CKD patients, and 39 microorganisms were isolated in pleural fluid from 35 ESRD patients. Aerobic Gram-negative organisms (n = 58, 67%), especially Klebsiella pneumoniae (n = 20, 34%), were the predominant pathogens in stage 4 CKD patients; aerobic Gram-positive organisms (n = 21, 54%), especially Staphylococcus aureus (n = 14, 67%), were the main pathogens in ESRD patients. Compared to stage 4 CKD patients, ESRD patients had a significantly higher percentage of catheter infections (p = 0.002) and aerobic Gram-positive organism bacteremia (p = 0.001), as well as a lower aerobic Gram negative organism infection rate (p < 0.001) and a lower infection-related mortality rate (p = 0.022). CONCLUSION: Stage 4 CKD patients and ESRD patients with empyema have different causative pathogens and outcomes. In ESRD patients, the dialysis catheter or the dialysis process appear to alter the microbiological flora responsible for empyema. This finding has clinical implications that clinicians need to consider. PMID- 17699134 TI - The importance of diagnosing and managing ICU delirium. AB - ICU delirium represents a form of brain dysfunction that in many cohorts has been diagnosed in 60 to 85% of patients receiving mechanical ventilation. This organ dysfunction is grossly underrecognized because a majority of patients have hypoactive or "quiet" delirium characterized by "negative" symptoms (eg, inattention and a flat affect) not alarming the treating team. Hyperactive delirium, formerly called ICU psychosis, stands out because of symptoms such as agitation that may cause harm to self or staff, but is actually rare relative to hypoactive delirium and associated with a better prognosis. Delirium is often incorrectly thought to be transient and of little consequence. After adjusting for numerous covariates, delirium is a strong, independent predictor of prolonged length of stay, reintubation, higher mortality, and cost of care. Expanded work on patient safety and recommendations by professional societies have established the importance of delirium monitoring and recommended it as standard practice in ICUs all over the world. This evidence-based review for physicians, nurses, respiratory therapists, and pharmacists will outline why it is imperative that patients be routinely monitored for delirium. This review will discuss modifiable risk factors for delirium, such as metabolic disturbances or potent sedative and analgesic medications. Attention to mitigating risk factors, along with recommended pharmacologic approaches such as antipsychotic medications, may provide resolution of delirium in some patients, while others will persist with refractory brain dysfunction and long-term cognitive impairment following critical illness. PMID- 17699133 TI - Airway stabilization with silicone stents for treating adult tracheobronchomalacia: a prospective observational study. AB - RATIONALE: It is postulated that in patients with severe tracheobronchomalacia (TBM), airway stabilization with stents may relieve symptoms. OBJECTIVES: To evaluate the effect of silicone stents (tracheal, mainstem bronchus, or both) on symptoms, quality of life, lung function, and exercise capacity in these patients. METHODS: A prospective observational study in which baseline measurements were compared to those obtained 10 to 14 days after stent placement. MEASUREMENTS AND MAIN RESULTS: Of 75 referred patients, 58 had severe disease and underwent therapeutic rigid bronchoscopy with stent placement. Mean age was 69 years (range, 39 to 91 years), 34 were men, 33 had COPD, and 13 had asthma. Almost all patients (n = 57) had dyspnea as a sole symptom or in combination with cough and recurrent infections; four patients required mechanical ventilation for respiratory failure. In 45 of 58 patients, there was reported symptomatic improvement; quality of life scores improved in 19 of 27 patients (p = 0.002); dyspnea scores improved in 22 of 24 patients (p = 0.001); functional status scores improved in 18 of 26 patients (p = 0.002); and mean exercise capacity improved from baseline, although not significantly. The 49 complications included mainly 21 partial stent obstructions, 14 infections, and 10 stent migrations. Most patients with concomitant COPD also improved on most measures. CONCLUSIONS: In the short term, airway stabilization with silicone stents in patients with severe TBM can improve respiratory symptoms, quality of life, and functional status. Coexisting COPD is not an absolute contraindication to a stenting trial in this population. Stenting is associated with a high number of short-term and long-term but generally reversible complications. PMID- 17699136 TI - Lung development and adult lung diseases. AB - Adult respiratory diseases are caused by many factors, including genetic environmental interaction. Genetic abnormalities can impact early fetal lung development, postnatal lung maturation, as well as adult lung injury and repair. Studies suggest that abnormally developed lung structure and function may contribute as a susceptibility factor for several adult lung diseases. This review focuses on the relationship between lung development and pathogenesis of several lung diseases including COPD, cystic fibrosis (CF), and asthma. COPD with emphysema has been considered to be an accelerated involutional disease of aging smokers. However, since only a proportion (approximately 15%) of smokers get COPD with emphysema, clearly genetic susceptibility must play a significant part in determining both the age of onset and the rapidity of decline in lung function. In mice, interference with key genes either by null mutation, hypomorphism, or gain or loss of function results in phenotypes comprising either neonatal lethal respiratory distress if the structural effect is severe, or reduced alveolarization and/or early onset emphysema if the effect is milder. Reported susceptibility candidate genes are therefore discussed in some detail, including elastin, lysyl oxidase, fibrillin, the transforming growth factor-beta-Smad3 pathway, as well as extracellular matrix proteases. In the case of CF, the Cftr gene has been shown to regulate fetal lung epithelial cell differentiation and maturation. Subtle abnormalities of lung structure and function are found in clinically asymptomatic CF infants. Finally, airway remodeling due to chronic inflammation is important in infants who later acquire asthma. PMID- 17699135 TI - Recent advances in idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) remains the most common of the idiopathic interstitial pneumonias and portends a poor prognosis. Significant strides have been made in the approach to diagnosis and in the ability to predict outcome in the last few years. Advances in high-resolution CT (HRCT) scanning have allowed an accurate diagnosis obviating the need for surgical biopsy in many patients. Furthermore, HRCT scanning may aid in determining prognosis and identifying disease progression. The appropriate use of the HRCT scan requires a multidisciplinary iterative approach incorporating all available data to reach a final diagnosis. However, there remains great heterogeneity in disease progression. Pulmonary hypertension and acute exacerbations of IPF negatively influence prognosis and are increasingly a target of therapy. There has been an increase in the number of well-designed clinical trials of IPF that have focused on more specific targets. While no cure has yet been found, each trial expands our understanding regarding the natural course of the disease and the impact of targeted therapy. In the interim, lung transplantation, which appears to improve survival in a subset of IPF patients, remains the only intervention. The objective of this article is to review advances in the understanding of IPF and the evidence for the findings outlined above. PMID- 17699137 TI - Catheter embolectomy for acute pulmonary embolism. AB - Massive pulmonary embolism (PE) is a life-threatening condition with a high early mortality rate due to acute right ventricular failure and cardiogenic shock. As soon as the diagnosis is suspected, an IV bolus of unfractionated heparin should be administered. In addition to anticoagulation, rapid initiation of systemic thrombolysis is potentially life-saving and therefore is standard therapy. Many patients with massive PE cannot receive thrombolysis because of an increased bleeding risk, such as prior surgery, trauma, or cancer. In these patients, catheter or surgical embolectomy are helpful for rapidly reversing right ventricular failure. Catheter thrombectomy appears to be particularly useful if surgical embolectomy is not available or the patient has contraindications to surgery. Although no controlled clinical trials are available, data from cohort studies indicate that the clinical outcomes after surgical and catheter embolectomy may be comparable. PMID- 17699138 TI - Conflict of interest in clinical practice. AB - Conflicts of interest, ubiquitous in medicine, occur when the interests of clinicians do not align with the interests of their patients. When systemic and institutionalized, such conflicts become particularly problematic, not only creating risks for individual patients but also undermining the integrity of the medical profession. Financial conflicts of interest arise when the reimbursement of clinicians appears to encourage decisions and actions that are unlikely to be in the best interest of individual patients. More insidiously, the influence of the pharmaceutical and medical device industry on clinicians, whether through gift giving, support of continuing medical education, or guideline development, creates conflicts of interest that may go unrecognized. Recognition and acknowledgment are the first steps in ameliorating conflicts of interest, which can then be disclosed and potentially eliminated. PMID- 17699139 TI - Current issues in home mechanical ventilation. AB - As modern health care continues to evolve, we expect and are seeing that more sophisticated medical care will be provided outside the traditional acute care environments. Advances in home medical technology, economic pressures, health care consumerism, and societal changes are all factors playing a role in this evolution. Medically fragile and technology-dependent individuals who were once limited to care in acute and subacute institutional settings are now frequently cared for at home, most often by their immediate family members. Mechanical ventilation has found its way into the patient's home such that physicians and other providers must be prepared for the challenges associated with managing the conditions of complex, ventilator-dependent individuals outside of the walls, controls, and safety of the institutional setting. With little published science and recognized standards of practice, there are fewer rules to guide clinicians through this process. Experience has shown, however, that successful home management of ventilator-dependent individuals can be traced to a smooth and collaborative discharge from the hospital to home. Reimbursement and coverage issues must also be well understood to avoid the aggravation of denials and challenges for necessary equipment and assistance. Once home, a streamlined, patient-centered process supported by effective communication between all care providers can result in a safe and appropriate long-term home ventilation success story. PMID- 17699140 TI - Paradoxical worsening of shock after the use of a percutaneous mechanical thrombectomy device in a postpartum patient with a massive pulmonary embolism. PMID- 17699141 TI - Nonfatal systemic air embolism complicating percutaneous CT-guided transthoracic needle biopsy: four cases from a single institution. AB - BACKGROUND: Systemic air embolism is recognized as a potentially fatal but extremely rare complication following percutaneous transthoracic needle biopsy. However, its incidence might be underestimated by missing systemic air in patients without cardiac or cerebral symptoms. METHODS: This study was based on four cases (one man and three women; age range, 54 to 75 years) of systemic air embolism complicating CT scan-guided transthoracic needle biopsy, which were encountered among 1,010 procedures performed at our institution from April 1999 to December 2006. The target lesion was a lung tumor in three patients, and a mediastinal tumor in one patient. The procedure was performed percutaneously under CT scan-fluoroscopic guidance by using a coaxial biopsy needle system. RESULTS: In all four patients, a specimen was successfully obtained from the lesions. During or immediately after the procedure, all patients experienced paroxysms of coughing. In three patients without cardiac or cerebral symptoms, the presence of systemic air was confirmed on postprocedural CT scan images; it was resolved without causing morbidity after the immediate therapy. The presence of systemic air was missed in one initially asymptomatic patient, resulting in a subsequent neurologic deficit. CONCLUSIONS: Systemic air embolism following CT scan-guided transthoracic needle biopsy was encountered more frequently than would be expected. The considerable attention we gave to this complication enabled us to recognize it in patients without cardiac or cerebral symptoms. No sequelae were observed in the three patients in whom systemic air embolism was detected, and the therapy was initiated immediately, whereas missing systemic air led to cerebral embolism in one patient in our four cases. PMID- 17699142 TI - Seat belt-induced chylothorax: a cause of idiopathic chylothorax? AB - Chylothoraces are associated with multiple etiologies including non-Hodgkin lymphoma and surgical trauma, representing 50% and 25% of all chylothoraces, respectively. Intrathoracic operations such as repair of coarctation of the aorta and esophagectomy are commonly associated with surgical trauma. Idiopathic chylothoraces may account for up to 15% of all chylothoraces. When a thorough evaluation finding is negative, further history to identify possible blunt, nonpenetrating trauma to the chest is warranted. PMID- 17699143 TI - Dental appliance treatment for obstructive sleep apnea. AB - Oral appliances for the treatment of obstructive sleep apnea (OSA) are worn during sleep to maintain the patency of the upper airway by increasing its dimensions and reducing its collapsibility. Oral appliances are a simpler alternative to continuous positive airway pressure (CPAP). Over the last decade, there has been a significant expansion of the evidence base to support the use of oral appliances, with robust studies demonstrating their efficacy. This work has been underpinned by the recognition of the importance of upper airway anatomy in the pathophysiology of OSA. The updated practice parameters of the American Academy of Sleep Medicine now recommend their use for mild-to-moderate OSA, or for patients with severe OSA who are unable to tolerate CPAP or refuse treatment with CPAP. Oral appliances have been shown to have a beneficial impact on a number of important clinical end points, including the polysomnographic indexes of OSA, subjective and objective measures of sleepiness, BP, aspects of neuropsychological functioning, and quality of life. Elucidation of the mechanism of action of oral appliances has provided insight into the factors that predict treatment response and may improve the selection of patients for this treatment modality. Longitudinal studies to characterize the long-term adverse effects of oral appliance use are now beginning to emerge. Although less efficacious than CPAP for improving the polysomnographic indexes of OSA, oral appliances are generally preferred by patients. This has the potential to translate to better patient adherence and may provide an equivalent health outcome. PMID- 17699144 TI - Cough, dyspnea, and reticulonodular opacities in a 58-year-old smoker. PMID- 17699145 TI - A 46-year-old man with dyspnea and hemoptysis 3 years following mitral valve repair. PMID- 17699146 TI - A 60-year-old woman with cough, fever, and upper-lobe cavitary consolidation. PMID- 17699147 TI - Noninvasive ventilation for critical care. AB - Noninvasive ventilation (NIV), the provision of ventilatory assistance without an artificial airway, has emerged as an important ventilatory modality in critical care. This has been fueled by evidence demonstrating improved outcomes in patients with respiratory failure due to COPD exacerbations, acute cardiogenic pulmonary edema, or immunocompromised states, and when NIV is used to facilitate extubation in COPD patients with failed spontaneous breathing trials. Numerous other applications are supported by weaker evidence. A trial of NIV is justified in patients with acute respiratory failure due to asthma exacerbations and postoperative states, extubation failure, hypoxemic respiratory failure, or a do not-intubate status. Patients must be carefully selected according to available guidelines and clinical judgment, taking into account risk factors for NIV failure. Patients begun on NIV should be monitored closely in an ICU or other suitable setting until adequately stabilized, paying attention not only to vital signs and gas exchange, but also to comfort and tolerance. Patients not having a favorable initial response to NIV should be considered for intubation without delay. NIV is currently used in only a select minority of patients with acute respiratory failure, but with technical advances and new evidence on its proper application, this role is likely to further expand. PMID- 17699148 TI - A 31-year-old man with chronic cough and hemoptysis. PMID- 17699149 TI - Cough and persistent wheeze in a patient with long-standing asthma. PMID- 17699150 TI - Seeking funding from foundations. PMID- 17699151 TI - Patient-focused care. PMID- 17699152 TI - Risk indexes for exacerbations due to COPD: need to validate using broader criteria. PMID- 17699153 TI - Hepatitis C virus infection and isoniazid hepatotoxicity. PMID- 17699155 TI - Bis-methionine ligation to heme iron in the streptococcal cell surface protein Shp facilitates rapid hemin transfer to HtsA of the HtsABC transporter. AB - The surface protein Shp of Streptococcus pyogenes rapidly transfers its hemin to HtsA, the lipoprotein component of the HtsABC transporter, in a concerted two step process with one kinetic phase. The structural basis and molecular mechanism of this hemin transfer have been explored by mutagenesis and truncation of Shp. The heme-binding domain of Shp is in the amino-terminal region and is functionally active by itself, although inclusion of the COOH-terminal domain speeds up the process approximately 10-fold. Single alanine replacements of the axial methionine 66 and 153 ligands (Shp(M66A) and Shp(M153A)) cause formation of pentacoordinate hemin-Met complexes. The association equilibrium constants for hemin binding to wild-type, M66A, and M153A Shp are 5,300, 22,000, and 38 microM( 1), respectively, showing that the Met(153)-Fe bond is critical for high affinity binding and that Met(66) destabilizes hemin binding to facilitate its rapid transfer. Shp(M66A) and Shp(M153A) rapidly bind to hemin-free HtsA (apoHtsA), forming stable transfer intermediates. These intermediates appear to be Shp-hemin HtsA complexes with one axial ligand from each protein and decay to the products with rate constants of 0.4-3 s(-1). Thus, the M66A and M153A replacements alter the kinetic mechanism and unexpectedly slow down hemin transfer by stabilizing the intermediates. These results, in combination with the structure of the Shp heme-binding domain, allow us to propose a "plug-in" mechanism in which side chains from apoHtsA are inserted into the axial positions of hemin in Shp to extract it from the surface protein and pull it into the transporter active site. PMID- 17699156 TI - Activation of the integrated stress response regulates lovastatin-induced apoptosis. AB - Lovastatin, a potent inhibitor of mevalonate synthesis, can readily induce apoptosis in a subset of human tumor types including head and neck squamous cell carcinomas (HNSCC). We recently identified activation of transcription factor (ATF) 4 as a lovastatin induced gene in HNSCC cells. ATF4 plays a significant role in regulating cellular responses to a wide variety of stress inducers known as the integrated stress response (ISR). These cell stresses lead to the phosphorylation of eukaryotic initiation factor (eIF) 2alpha shutting down global protein translation. However, the translation of ATF4 is enhanced. In this study, lovastatin treatment induced eIF2alpha phosphorylation and inhibited global protein translation. ATF4 expression was induced followed by increased ATF3 and CHOP expression, targets of ATF4 activity, in SCC25 HNSCC cells. In CHOP(-/-) murine embryonic fibroblasts (MEFs), lovastatin-induced apoptosis was attenuated indicating a role for CHOP in this response. Furthermore, the eIF2alpha kinase GCN2 mediates lovastatin induction of ATF4 and lovastatin-induced apoptosis was also attenuated in GCN2(-/-) MEFs. The pro-drug version of lovastatin has potential proteasome inhibitory activity and recently a variety of well established proteasome inhibitors were shown to activate the ISR. In this study, neither the pro-drug nor the active forms of lovastatin had any significant effect on proteasome activity. Therefore, lovastatin, by targeting mevalonate synthesis, is a potent inducer of the ISR through a novel and as yet unrecognized mechanism. PMID- 17699157 TI - The structure of the Haemophilus influenzae HMW1 pro-piece reveals a structural domain essential for bacterial two-partner secretion. AB - In pathogenic Gram-negative bacteria, many virulence factors are secreted via the two-partner secretion pathway, which consists of an exoprotein called TpsA and a cognate outer membrane translocator called TpsB. The HMW1 and HMW2 adhesins are major virulence factors in nontypeable Haemophilus influenzae and are prototype two-partner secretion pathway exoproteins. A key step in the delivery of HMW1 and HMW2 to the bacterial surface involves targeting to the HMW1B and HMW2B outer membrane translocators by an N-terminal region called the secretion domain. Here we present the crystal structure at 1.92 A of the HMW1 pro-piece (HMW1-PP), a region that contains the HMW1 secretion domain and is cleaved and released during HMW1 secretion. Structural analysis of HMW1-PP revealed a right-handed beta-helix fold containing 12 complete parallel coils and one large extra-helical domain. Comparison of HMW1-PP and the Bordetella pertussis FHA secretion domain (Fha30) reveals limited amino acid homology but shared structural features, suggesting that diverse TpsA proteins have a common structural domain required for targeting to cognate TpsB proteins. Further comparison of HMW1-PP and Fha30 structures may provide insights into the keen specificity of TpsA-TpsB interactions. PMID- 17699158 TI - Comparative biophysical characterization of p53 with the pro-apoptotic BAK and the anti-apoptotic BCL-xL. AB - The p53 transcription-independent apoptosis in mitochondria, mediated by its interaction with the pro-apoptotic and the anti-apoptotic members of the Bcl2 family of proteins, has been described in vivo, especially in radiosensitive tissues. We have characterized the interaction of p53 with both the pro-apoptotic Bak and the anti-apoptotic Bcl-x(L) proteins, comparing their affinity and their interaction surfaces, using biophysical techniques such as fluorescence anisotropy, analytical ultracentrifugation, and NMR. We have shown that both proteins interact with only the p53 core domain and not with its N- and C terminal regions. Further, p53 has a higher affinity for Bcl-x(L) than for Bak, which is consistent with the previously described sequential binding of Bcl-x(L) and Bak by p53. Interestingly, although the interaction with both proteins is electrostatic in character, they have different binding sites. Using NMR spectroscopy, we have determined that Bcl-x(L) interacts with the DNA binding site of p53, but Bak does not interact with this site. A new potential interaction surface for Bak is proposed. PMID- 17699159 TI - The RAS-dependent ERF control of cell proliferation and differentiation is mediated by c-Myc repression. AB - The ERF transcriptional repressor is a downstream effector of the RAS/ERK pathway that interacts with and is directly phosphorylated by ERKs in vivo and in vitro. This phosphorylation results in its cytoplasmic export and inactivation, although lack of ERK activity allows its immediate nuclear accumulation and repressor function. Nuclear ERFs arrest cell cycle progression in G(1) and can suppress ras dependent tumorigenicity. Here we provide evidence that ERF function is mediated by its ability to repress transcription of c-Myc. Promoter reporter assays indicate a DNA binding-dependent and repressor domain-dependent Myc transcriptional repression. Chromatin immunoprecipitations in primary cells suggest that ERF specifically binds on the c-Myc promoter in an E2F4/5-dependent manner and only under conditions that the physiological c-Myc transcription is stopped. Cellular systems overexpressing nuclear ERF exhibit reduced c-Myc mRNA and tumorigenic potential. Elimination of Erf in animal models results in increased c-Myc expression, whereas Erf(-)(/)(-) primary fibroblasts fail to down regulate Myc in response to growth factor withdrawal. Finally, elimination of c Myc in primary mouse embryo fibroblasts negates the ability of nuclear ERF to suppress proliferation. Thus Erf provides a direct link between the RAS/ERK signaling and the transcriptional regulation of c-Myc and suggests that RAS/ERK attenuation actively regulates cell fate. PMID- 17699160 TI - Structural insight into the dual ligand specificity and mode of high density lipoprotein association of apolipoprotein D. AB - Human apolipoprotein D (ApoD) occurs in plasma associated with high density lipoprotein. Apart from the involvement in lipid metabolism, its binding activity for progesterone and arachidonic acid plays a role in cancer development and neurological diseases. The crystal structures of free ApoD and its complex with progesterone were determined at 1.8A resolution and reveal a lipocalin fold. The narrow, mainly uncharged pocket within the typical beta-barrel accommodates progesterone with its acetyl side chain oriented toward the bottom. The cavity adopts essentially the same shape in the absence of progesterone and allows complexation of arachidonic acid as another cognate ligand. Three of the four extended loops at the open end of the beta-barrel expose hydrophobic side chains, which is an unusual feature for lipocalins and probably effects association with the high density lipoprotein particle by mediating insertion into the lipid phase. This mechanism is in line with an unpaired Cys residue in the same surface region that can form a disulfide cross-link with apolipoprotein A-II. PMID- 17699161 TI - Adipose tissue integrity as a prerequisite for systemic energy balance: a critical role for peroxisome proliferator-activated receptor gamma. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is an essential regulator of adipocyte differentiation, maintenance, and survival. Deregulations of its functions are associated with metabolic diseases. We show here that deletion of one PPARgamma allele not only affected lipid storage but, more surprisingly, also the expression of genes involved in glucose uptake and utilization, the pentose phosphate pathway, fatty acid synthesis, lipolysis, and glycerol export as well as in IR/IGF-1 signaling. These deregulations led to reduced circulating adiponectin levels and an energy crisis in the WAT, reflected in a decrease to nearly half of its intracellular ATP content. In addition, there was a decrease in the metabolic rate and physical activity of the PPARgamma(+/-) mice, which was abolished by thiazolidinedione treatment, thereby linking regulation of the metabolic rate and physical activity to PPARgamma. It is likely that the PPARgamma(+/-) phenotype was due to the observed WAT dysfunction, since the gene expression profiles associated with metabolic pathways were not affected either in the liver or the skeletal muscle. These findings highlight novel roles of PPARgamma in the adipose tissue and underscore the multifaceted action of this receptor in the functional fine tuning of a tissue that is crucial for maintaining the organism in good health. PMID- 17699162 TI - The active protein-conducting channel of Escherichia coli contains an apolar patch. AB - Protein translocation across the cytoplasmic membrane of Escherichia coli is mediated by translocase, a complex of a protein-conducting channel, SecYEG, and a peripheral motor domain, SecA. SecYEG has been proposed to constitute an aqueous path for proteins to pass the membrane in an unfolded state. To probe the solvation state of the active channel, the polarity sensitive fluorophore N-((2 (iodoacetoxy)ethyl)-N-methyl) amino-7-nitrobenz-2-oxa-1,3-diazole was introduced at specific positions in the C-terminal region of the secretory protein proOmpA. Fluorescence measurements with defined proOmpA-DHFR translocation intermediates indicate mostly a water-exposed environment with a hydrophobic region in the center of the channel. PMID- 17699163 TI - A novel role of the interferon-inducible protein IFI16 as inducer of proinflammatory molecules in endothelial cells. AB - The human IFI16 gene is an interferon-inducible gene implicated in the regulation of endothelial cell proliferation and tube morphogenesis. Immunohistochemical analysis has demonstrated that this gene is highly expressed in endothelial cells in addition to hematopoietic tissues. In this study, gene array analysis of human umbilical vein endothelial cells overexpressing IFI16 revealed an increased expression of genes involved in immunomodulation, cell growth, and apoptosis. Consistent with these observations, IFI16 triggered expression of adhesion molecules such as ICAM-1 and E-selectin or chemokines such as interleukin-8 or MCP-1. Treatment of cells with short hairpin RNA targeting IFI16 significantly inhibited ICAM-1 induction by interferon (IFN)-gamma demonstrating that IFI16 is required for proinflammatory gene stimulation. Moreover, functional analysis of the ICAM-1 promoter by deletion- or site-specific mutation demonstrated that NF kappaB is the main mediator of IFI16-driven gene induction. NF-kappaB activation appears to be triggered by IFI16 through a novel mechanism involving suppression of IkappaBalpha mRNA and protein expression. Support for this finding comes from the observation that IFI16 targeting with specific short hairpin RNA down regulates NF-kappaB binding activity to its cognate DNA and inhibits ICAM-1 expression induced by IFN-gamma. Using transient transfection and luciferase assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation, we demonstrate indeed that activation of the NF-kappaB response is mediated by IFI16-induced block of Sp1-like factor recruitment to the promoter of the IkappaBalpha gene, encoding the main NF-kappaB inhibitor. Activation of NF-kappaB accompanied by induction of proinflammatory molecules was also observed when IkappaBalpha expression was down-regulated by specific small interfering RNA, resulting in an outcome similar to that observed with IFI16 overexpression. Taken together, these data implicate IFI16 as a novel regulator of endothelial proinflammatory activity and provide new insights into the physiological functions of the IFN-inducible gene IFI16. PMID- 17699164 TI - More about the "ARB MI paradox". AB - "Logic dictates that angiotensin converting enzyme inhibitors should remain the preferred drug across the entire spectrum of cardiometabolic disease" PMID- 17699165 TI - Common origin of all three major coronary vessels from the aorta through a single ostium. PMID- 17699166 TI - ACE inhibitors: back to prime time? PMID- 17699167 TI - New guidelines for cardiac resynchronisation therapy: simplicity or complexity for the doctor? PMID- 17699168 TI - Late adverse ventricular remodelling as a consequence of acute left main coronary artery occlusion. PMID- 17699169 TI - Endothelial progenitor cells, endothelial cell dysfunction and much more: observations from cardiac syndrome X. PMID- 17699170 TI - Influence of tooth loss on cardiovascular mortality. PMID- 17699171 TI - Consent bias in research: how to avoid it. PMID- 17699172 TI - Four-valve endocarditis caused by group G Streptoccocci. PMID- 17699173 TI - Determinants of implantable defibrillator discharges in high-risk patients with hypertrophic cardiomyopathy. AB - OBJECTIVES: To identify the determinants of appropriate and inappropriate implantable cardioverter-defibrillator (ICD) discharges in patients with hypertrophic cardiomyopathy (HCM). DESIGN: Retrospective cohort study. SETTING: ICD clinic at an academic hospital. PATIENTS: 61 patients with HCM who received ICDs for the primary or secondary prevention of sudden cardiac death (SCD). OUTCOME MEASURES: (a) Analysis of appropriate and inappropriate ICD discharges; (b) predictors of ICD discharges. RESULTS: Mean (SD) age at ICD insertion was 46 (18) years (range 10-79). Follow-up time was 40 (27) months (range 7-151). Eight patients experienced an appropriate discharge, occurring 24.5 (13.6) months after ICD insertion. Appropriate ICD intervention was more common in the secondary (36%) than the primary (8%) prevention group (p = 0.02). Inappropriate ICD discharges occurred in 20 (33%) patients. Multivariate Cox regression analysis identified two significant predictors of inappropriate ICD discharges: (a) age <30 years at the time of ICD insertion (hazard ratio (HR) = 3.0 (95% CI 1.1 to 8.0; p = 0.03) and (b) history of atrial fibrillation (HR = 3.1 (95% CI 1.2 to 8.1; p = 0.02). CONCLUSIONS: ICDs are effective in the prevention of SCD in HCM. However, there is a high incidence of inappropriate ICD discharges. PMID- 17699174 TI - Diagnosing chest pain: characteristic ECG changes in acute pericarditis. PMID- 17699175 TI - Intracardiac echocardiography in the diagnosis of prosthetic valve endocarditis. PMID- 17699176 TI - Acute myocardial infarction occurring at pre-existing mild stenosis, on the image obtained 3 days before the onset of acute myocardial infarction. PMID- 17699177 TI - Cardiac resynchronisation therapy for the treatment of heart failure: NICE technology appraisal guidance. AB - This NICE technology appraisal guidance on cardiac resynchronisation therapy provides additional treatment options for some of the groups of people covered in the earlier guidance on implantable cardioverter defibrillators. PMID- 17699178 TI - "Dynamic imaging" (systolic compression) of myocardial bridge visualised by electronic beam computed tomography. PMID- 17699179 TI - Implications of publishing surgical results. PMID- 17699180 TI - Clinical epidemiology of heart failure. AB - The aim of this paper is to review the clinical epidemiology of heart failure. The last paper comprehensively addressing the epidemiology of heart failure in Heart appeared in 2000. Despite an increase in manuscripts describing epidemiological aspects of heart failure since the 1990s, additional information is still needed, as indicated by various editorials. PMID- 17699181 TI - Carotid stenting for atherothrombosis. AB - Cerebrovascular accident (CVA) is the third leading cause of death in North America and Europe, accounting for approximately 10-12% of all deaths.w1 CVA may have several aetiologies but is generally characterised as being either thrombotic or haemorrhagic in origin. The thrombotic causes of CVA are multiple and can be divided into large vessel occlusion, small vessel occlusion, and embolisation. Large vessel occlusion from atherothrombosis of the carotid system is responsible for approximately 25% of those afflicted by a CVA. The treatment of carotid atherothrombosis is evolving and involves risk factor management and in selected patients may warrant either surgical carotid endarterectomy or percutaneous carotid stenting. This is a review of the current understanding of carotid atherothrombosis and data regarding percutaneous approaches for those with this condition. PMID- 17699182 TI - Chronic thromboembolic pulmonary hypertension (CTEPH). PMID- 17699184 TI - Opening words for CJASN. PMID- 17699185 TI - Epidemiology of acute renal failure: the tip of the iceberg. PMID- 17699186 TI - Kidney-heart interactions: epidemiology, pathogenesis, and treatment. PMID- 17699187 TI - Acute kidney injury associated with cardiac surgery. AB - Acute renal failure (ARF) occurs in up to 30% of patients who undergo cardiac surgery, with dialysis being required in approximately 1% of all patients. The development of ARF is associated with substantial morbidity and mortality independent of all other factors. The pathogenesis of ARF involves multiple pathways. Hemodynamic, inflammatory, and nephrotoxic factors are involved and overlap each other in leading to kidney injury. Clinical studies have identified risk factors for ARF that can be used to determine effectively the risk for ARF in patients who undergo bypass surgery. These high-risk patients then can be targeted for renal protective strategies. Thus far, no single strategy has demonstrated conclusively its ability to prevent renal injury after bypass surgery. Several compounds such as atrial natriuretic peptide and N acetylcysteine have shown promise, but large-scale trials are needed. PMID- 17699188 TI - Daily hemodialysis: a systematic review. AB - Several studies have reported improved outcomes with daily hemodialysis (DHD), but the strength of this evidence has not been evaluated. The published evidence on DHD was synthesized and its quality rated to inform need and sample size calculations for a randomized trial. Citations were identified in MEDLINE and EMBASE using validated search strategies. Dialysis journals that were not indexed and bibliographies of relevant articles were hand-searched. Two authors reviewed all citations. Articles that reported original data on five or more adults who were receiving DHD (1.5 to 3 h, 5 to 7 d/wk) for > or = 3 mo were included. Twenty-five articles reporting 14 unique populations with 268 patients (five to 72 per study) met inclusion criteria. Of the 14 cohorts, 13 were studied with an observational design, 10 were studied prospectively, and four had parallel control groups. Mean age ranged form 41 to 64 yr, mean time on dialysis was 2 to 11 yr, 0 to 28% of patients had diabetes, > 90% had arteriovenous fistulae, and > 50% were dialyzed at home. Most data were described at < or = 12 mo of follow-up. Outcomes included quality of life, cardiovascular disease, erythropoiesis, nutritional status, hospitalizations, and vascular access failures. Reporting was too heterogeneous to allow pooling of data. Ten of 11 studies suggested improvements in blood pressure; findings for other outcomes varied. Discontinuation of DHD occurred in 0 to 57% in-center and 0 to 15% home patients. Studies of DHD are limited by small sample size, nonideal control groups, selection and dropout biases, and paucity of data on potential risks. Randomized trials with adequate statistical power are required to establish the efficacy and the safety of DHD. PMID- 17699189 TI - Epidemiology and outcomes of acute renal failure in hospitalized patients: a national survey. AB - The aim of this study was to provide a broad characterization of the epidemiology of acute renal failure (ARF) in the United States using national administrative data and describe its impact on hospital length of stay (LOS), patient disposition, and adverse outcomes. Using the 2001 National Hospital Discharge Survey, a nationally representative sample of discharges from nonfederal acute care hospitals in the United States, new cases of ARF were obtained from hospital discharge records coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Multivariate regression analyses were used to explore the relation of ARF to hospital LOS and mortality as well as discharge disposition. Review of discharge data on a projected total of 29,039,599 hospitalizations identified 558,032 cases of ARF, with a frequency of 19.2 per 1000 hospitalizations. ARF was more commonly coded for in older patients; men; black individuals; and the setting of chronic kidney disease, congestive heart failure, chronic lung disease, sepsis, and cardiac surgery. ARF was associated with an adjusted prolongation of hospital LOS by 2 d (P < 0.001) and an adjusted odds ratio of 4.1 for hospital mortality and of 2.0 for discharge to short- or long-term care facilities. In a US representative sample of hospitalized patients, the presence of an ICD-9-CM code for ARF in discharge records is associated with prolonged LOS, increased mortality, and, among survivors, a greater requirement for posthospitalization care. These findings suggest that in the United States, ARF is associated with increased in hospital and post-hospitalization resource utilization. PMID- 17699190 TI - Effect of dietary protein intake on serum total CO2 concentration in chronic kidney disease: Modification of Diet in Renal Disease study findings. AB - Metabolic acidosis is a feature of chronic kidney disease (CKD), but whether serum bicarbonate concentration is influenced by variations in dietary protein intake is unknown. For assessing the effect of diet, data that were collected in the Modification of Diet in Renal Disease study were used. In this study, patients with CKD were enrolled into a baseline period, then randomly assigned to follow either a low- or a usual-protein diet (study A, entry GFR 25 to 55 ml/min) or a low- or very low-protein diet, the latter supplemented with ketoanalogs of amino acids (study B, entry GFR 13 to 24 ml/min). Serum [total CO2] and estimated protein intake (EPI) were assessed at entry (n = 1676) and again at 1 yr after randomization, controlling for changes in GFR and other key covariates (n = 723). At entry, serum [total CO2] was inversely related to EPI (1.0 mEq/L lower mean serum [total CO2]/g per kg body wt increase in protein intake/d; P = 0.009). In an intention-to-treat analysis, the reduction in mean EPI in the low-protein group as compared with the usual-protein group (0.41 g/kg body wt per d) was independently associated with a 0.9-mEq/L increase in serum [total CO2], after adjustment for covariates (P < 0.001). No such effect was evident in study B, in which the very low-protein diet group received dietary supplements. Serum [total CO2] is inversely correlated with dietary protein intake in patients with CKD. A reduction in protein intake results in an increase in serum [total CO2]. PMID- 17699191 TI - Quality of care among Aboriginal hemodialysis patients. AB - Registry data report racial differences in hemodialysis (HD) care, with ethnic minorities at a disadvantage. However, little information is available regarding Aboriginal HD patients specifically. This study sought to compare the quality of HD care between Aboriginal and non-Aboriginal patients in Canada. All adults who were established on HD for > or = 6 mo in a single Canadian province were included. Clinical information was obtained by patient interview and chart review, with race determined by self-report. Quality of HD care was assessed by small solute clearance, BP control, mineral metabolism, and anemia management. Of the 835 patients, 95 (11.4%) were Aboriginal. Aboriginal patients were significantly younger, were more likely to have diabetes as the cause of ESRD, and had a higher degree of comorbidity than non-Aboriginal patients. There were no differences between Aboriginal and non-Aboriginal patients for small solute clearance, anemia management, or use of permanent vascular access. Aboriginal patients, however, were less likely to achieve a target predialysis systolic BP of < 140 mmHg (29.5 versus 44.9%; P = 0.004), a target phosphate level of < 1.8 mmol/L (40.0 versus 67.3%; P < 0.0001), and a calcium-phosphate product < 4.4 mmol2/L2 (52.6 versus 72.7%; P < 0.001). Quality of care was found to be similar for Aboriginal compared with non-Aboriginal HD patients except for differences in predialysis systolic BP and mineral metabolism, which may be influenced by individual and cultural factors. Explanations for these differences and their impact on morbidity and mortality warrant further investigation. PMID- 17699192 TI - Magnetic resonance imaging evaluation of hepatic cysts in early autosomal dominant polycystic kidney disease: the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort. AB - The objective of this study was to investigate the prevalence of hepatic cysts by age and gender in patients with early autosomal-dominant polycystic kidney disease (ADPKD) and to determine whether hepatic cyst volume is related to renal and renal cyst volumes by using magnetic resonance imaging (MRI). A total of 230 patients with ADPKD (94 men and 136 women) who were aged 15 to 46 yr and had relatively preserved renal function were studied. MRI images of the kidney and liver were obtained to measure renal, renal cyst, and hepatic cyst volumes. These volume measurements and hepatic cyst prevalence were compared in all patients and in subgroups on the basis of gender and age (15 to 24, 25 to 34, and 35 to 46 yr). The overall prevalence of hepatic cysts was 83%; the prevalence was 58, 85, and 94% in the sequential age groups and 85% in women and 79% in men. The prevalence was related directly to renal volume (chi2 = 4.30, P = 0.04) and to renal cyst volume (chi2 = 5.59, P = 0.02). The total hepatic cyst volume was significantly greater in women than in men (a logarithmic transformation mean of 5.27 versus 1.94 ml; P = 0.003). The average hepatic cyst volume was 0.25, 5.75, and 22.78 ml in sequential age groups. Hepatic cysts are evident in 94% of patients who are older than 35 yr and in 55% of individuals who are younger than 25 yr. Hepatic cysts are more prevalent and larger in total cyst volume in women than in men. Hepatic cyst prevalence and aggregate total hepatic cyst volume increased with age. PMID- 17699193 TI - Association between serum bicarbonate and death in hemodialysis patients: is it better to be acidotic or alkalotic? AB - The optimal acid-base status for survival in maintenance hemodialysis (MHD) patients remains controversial. According to recent reports, acidosis is associated with improved survival in MHD patients. It was hypothesized that this inverse association is due to a confounding effect of the malnutrition inflammation complex syndrome (MICS). Associations between baseline (first 3 mo averaged) predialysis serum bicarbonate (HCO3(-)) and 2-yr mortality were examined in 56,385 MHD patients who were treated in virtually all DaVita dialysis clinics across the United States. The range of HCO3(-) was divided into 12 categories (< 17, > or = 27, and 10 groups in between). Three sets of Cox regression models were evaluated to estimate hazard ratios of all-cause and cardiovascular death in both incident and prevalent patients: (1) Unadjusted, (2) multivariate case mix adjusted (which also included dialysate HCO3(-) and Kt/V), and (3) adjusted for case mix and nine markers of MICS (body mass index; erythropoietin dose; protein intake; serum albumin; creatinine; phosphorus; calcium; ferritin and total iron binding capacity; and blood hemoglobin, WBC, and lymphocytes). There were significant inverse associations between serum HCO3(-) and serum phosphorus and estimated protein intake. The lowest unadjusted mortality was associated with predialysis HCO3(-) in the 17- to 23-mEq/L range, whereas values > or = 23 mEq/L were associated with progressively higher all cause and cardiovascular death rates. This association, however, reversed after case-mix and MICS multivariate adjustment, so that HCO3(-) values >22 mEq/L had lower death risk. Although previous epidemiologic studies indicated an association between high serum HCO3(-) and increased mortality in MHD patients, this effect seems to be due substantially to the effect of MICS on survival. PMID- 17699194 TI - A practical citrate anticoagulation continuous venovenous hemodiafiltration protocol for metabolic control and high solute clearance. AB - Obstacles to the widespread use of continuous renal replacement therapy (CRRT) include the need for anticoagulation, customized solutions, and complex protocols that carry an attendant risk for error, raise cost, and increase pharmacy and nursing workload. However, high solute clearance using CRRT with an effluent rate of 35 ml/kg per h has also recently been associated with improved survival in critically ill patients with acute renal failure. No published CRRT protocols using dilute regional citrate anticoagulation have achieved adequate metabolic control, effective anticoagulation, and high solute clearance in a practical, user-friendly, and economical manner. The safety and the efficacy of continuous venovenous hemodiafiltration at effluent rates of 35 ml/kg per h in critically ill acute renal failure patients were evaluated prospectively using a standardized bicarbonate-based dialysate; a systemic calcium infusion; and two separate trisodium citrate replacement solutions, a 0.67% solution and a 0.5% solution. All patients achieved adequate metabolic control, the desired effluent rate of 35 ml/kg per h, and high solute clearance. Use of the 0.67% citrate replacement solution resulted in mild alkalosis, whereas the 0.5% solution maintained appropriate acid-base balance. There was no difference in dialyzer survival between the 0.67 and 0.5% citrate groups (80 versus 82%; P = 0.60, Kaplan-Meier analysis). Dilute regional citrate as part of a CRRT protocol with a standard 25-mmol/L bicarbonate dialysate provides adequate metabolic control, high diffusive and convective clearance, and excellent dialyzer patency in a practical and cost-effective manner. PMID- 17699195 TI - Outcome of renal transplantation in patients with non-Shiga toxin-associated hemolytic uremic syndrome: prognostic significance of genetic background. AB - More than 50% of patients with non-Shiga toxin-associated hemolytic uremic syndrome (non-Stx-HUS) progress to ESRD. Kidney transplant failure for disease recurrence is common; hence, whether renal transplantation is appropriate in this clinical setting remains a debated issue. The aim of this study was to identify possible prognostic factors for renal transplant outcome by focusing on specific genetic abnormalities associated with the disease. All articles in literature that describe renal transplant outcome in patients with ESRD secondary to non-Stx HUS, genotyped for CFH, MCP, and IF mutations, were reviewed, and data of patients who were referred to the International Registry of Recurrent and Familial HUS/TTP and data from the Newcastle cohort were examined. This study confirmed that the overall outcome of kidney transplantation in patients with non Stx-HUS is poor, with disease recurring in 60% of patients, 91.6% of whom developed graft failure. No clinical prognostic factor that could identify patients who were at high risk for graft failure was found. The presence of a factor H (CFH) mutation was associated with a high incidence of graft failure (77.8 versus 54.9% in patients without CFH mutation). Similar results were seen in patients with a factor I (IF) mutation. In contrast, graft outcome was favorable in all patients who carried a membrane co-factor protein (MCP) mutation. Patients with non-Stx-HUS should undergo genotyping before renal transplantation to help predict the risk for graft failure. It is debatable whether a kidney transplant should be recommended for patients with CFH or IF mutation. Reasonably, patients with an MCP mutation can undergo a kidney transplant without risk for recurrence. PMID- 17699196 TI - Should an oral glucose tolerance test be performed routinely in all renal transplant recipients? AB - Posttransplantation diabetes (PTD) contributes to cardiovascular disease and graft loss in renal transplant recipients (RTR). Current recommendations advise fasting blood glucose (FBG) as the screening and diagnostic test of choice for PTD. This study sought to determine (1) the predictive power of FBG with respect to 2-h blood glucose (2HBG) and (2) the prevalence of PTD using FBG and 2HBG compared with that using FBG alone, in prevalent RTR. A total of 200 RTR (mean age 52 yr; 59% male; median transplant duration 6.6 yr) who were > 6 mo posttransplantation and had no known history of diabetes were studied. Patients with FBG < 126 mg/dl (7.0 mmol/L; n = 188) underwent an oral glucose tolerance test (OGTT). Receiver operating characteristic analyses evaluated the optimal level of FBG predictive of PTD (2HBG > or = 200 mg/dl [11.1 mmol/L]) and impaired glucose tolerance (IGT; 2HBG 140 to 200 mg/dl [7.8 to 11.0 mmol/L]). An abnormal OGTT was reported in 79 (42%) nondiabetic RTR: PTD (n = 22) and IGT (n = 57). The optimal FBG that was predictive of PTD was 101 mg/dl (5.6 mmol/L; area under the curve 0.70; sensitivity 64%, specificity 67%, positive predictive value 20%, negative predictive value 93%). The optimal FBG that was predictive of IGT was less well defined (area under the curve 0.54). The prevalence of PTD was higher by OGTT than by FBG alone (17 versus 6%; P < 0.001). FBG may not be the optimal screening or diagnostic tool for PTD or IGT in RTR. Consideration should be given to introducing the OGTT as a routine posttransplantation investigation, although the implications of a pathologic OGTT are still to be determined in this population. PMID- 17699198 TI - Highly active antiretroviral therapy and the kidney: an update on antiretroviral medications for nephrologists. AB - Highly active antiretroviral therapy has dramatically altered the treatment and life expectancy of individuals who are infected with HIV. More than 20 antiretroviral drugs and drug combinations now are available in the United States. Nephrologists need to have an understanding of the pharmacokinetics of antiretroviral medications and the proper dosing of these medications in patients with impaired kidney function. It is also important for nephrologists to be aware of drug-drug interactions that can occur between antiretroviral medications and other medications that they may prescribe, including immunosuppressive medications that are used for renal transplantation, as this becomes more common in HIV-infected patients. Adverse reactions that affect the kidneys and cause fluid-electrolyte complications occur with certain antiretroviral agents, although most are relatively free of nephrotoxicity. This article reviews the clinical pharmacology and dosing modifications of the newer antiretroviral medications in patients with reduced kidney function; important drug-drug interactions involving these medications, particularly with other medications that are likely to be prescribed by nephrologists; and renal toxicities of antiretroviral agents. PMID- 17699197 TI - A prospective, open-label trial of sirolimus in the treatment of focal segmental glomerulosclerosis. AB - Calcineurin inhibitors are effective therapy for steroid-resistant focal segmental glomerulosclerosis (FSGS) but are associated with significant morbidity and nephrotoxicity. Sirolimus is a novel immunosuppressive agent that is structurally related to tacrolimus but demonstrates no long-term nephrotoxicity. For determination of the efficacy of sirolimus in reducing proteinuria, a prospective, open-label trial was conducted of 21 patients with idiopathic, steroid-resistant FSGS. A complete response was defined as <300 mg protein/24 h after 6 mo, whereas a partial response was defined as a 50% reduction in baseline proteinuria. After 6 mo of therapy, sirolimus induced complete remission in four (19%) of 21 patients and partial remissions in eight (38%). Among sirolimus responsive patients, 6 mo of therapy decreased proteinuria from a mean of 8.8 +/- 1.7 to 2.1 +/- 0.5 g/24 h (P = 0.0003). In responsive patients, GFR was maintained (45 +/- 6 versus 47 +/- 7 ml/min per 1.73 m2 at 6 mo) throughout the study, whereas nonresponders tended to decrease (31 +/- 4 versus 28 +/- 5 ml/min per 1.73 m2). Using dextran sieving analysis, complete or partial response was associated with an increase in the glomerular ultrafiltration coefficient (K(f), 7 +/- 1. versus 8 +/- 0.9 units at 6 mo; P < 0.05). Glomerular permselectivity and K(f) tended to decrease in nonresponders (8.2 +/- 1.9 versus 6.2 +/- 1.3 units at 6 mo; P = 0.07). Patients with complete remission had a higher GFR (45 +/- 6 versus 31 +/- 4 ml/min per 1.73 m2) at the end of 6 mo compared with nonresponders. In patients with steroid-resistant FSGS, sirolimus reduced proteinuria and glomerular pore size and increased K(f) in patients with steroid resistant FSGS. PMID- 17699199 TI - Protocol transplant biopsies: are they really needed? AB - Studies suggest that surveillance or protocol biopsies that are performed during the first year after kidney transplantation may be clinically useful in identifying early acute rejection or chronic allograft nephropathy at a point when they may be amenable to treatment. Although the benefit of this approach has yet to be evaluated in large, multicenter, prospective trials, numerous studies suggest that implementation of protocol biopsies may improve long-term graft function. In particular, a number of reports suggest that detection of chronic allograft nephropathy in early protocol biopsies is predictive of subsequent graft function and loss and that early treatment may have a dramatic effect on the outcome of the graft. Protocol biopsies also have the potential to be of great value in high-risk patients, such as those with delayed graft function, by allowing for early intervention for acute rejection. Furthermore, the procedure seems to be relatively straightforward and safe. Nevertheless, paucity of data has meant that clear proof of a benefit of early treatment of subclinical rejection and chronic allograft nephropathy detected by protocol biopsy is lacking. Moreover, the optimal timing of protocol biopsies and reliable methods to quantify the histologic changes observed in biopsy specimens have yet to be determined. This review discusses the pros and cons of protocol biopsies and considers the place of this procedure in the routine treatment of kidney transplant patients. PMID- 17699200 TI - Protocol transplant biopsies: an underutilized tool in kidney transplantation. PMID- 17699201 TI - Protocol transplant biopsies in kidney allografts: why and when are they indicated? PMID- 17699202 TI - Volume progression in autosomal dominant polycystic kidney disease: the major factor determining clinical outcomes. AB - Autosomal dominant polycystic kidney disease (PKD) is a hereditary condition characterized by the progressive enlargement of innumerable renal cysts that contribute to life-altering morbidity early in the course of the disease. Evidence indicates that the rate of increase in kidney volume can be reliably measured by magnetic resonance or computed tomography imaging, thus providing objective means to judge the effectiveness of therapies that are targeted to the aberrant growth of renal tubules. It is now possible, therefore, to monitor the effectiveness of potential therapies on the signature abnormality in autosomal dominant PKD before irreversible damage has been done by the cysts. Evidence accumulated from human cross-sectional and longitudinal studies and longitudinal studies of PKD models in animals provide strong support for the view that reducing the rate of kidney volume enlargement will ameliorate the late-stage development of renal insufficiency. PMID- 17699203 TI - A case of acute renal failure. PMID- 17699204 TI - Peritoneal inflammation and high transport status. PMID- 17699205 TI - Calcium, calcimimetics and clinical outcomes. PMID- 17699206 TI - Diagnosis and management of ischemic nephropathy. PMID- 17699207 TI - Review of the effects of omega-3 supplementation in dialysis patients. AB - Chronic dialysis patients experience a host of conditions that limit quality and length of life, and recent therapeutic strategies have had only modest success in ameliorating many of these problems. By mediating cell membrane function and structure and the synthesis of lipid mediators such as eicosanoids, omega-3 fatty acids may offer dialysis patients a host of therapeutic benefits. Omega-3 fatty acids are derived primarily from dietary sources, and cold-water fish is the main source of eicosapentanoic and docosahexanoic acids, the two major bioactive omega 3 fatty acids. Studies of omega-3 supplementation in dialysis patients describe salutary effects on triglyceride levels, dialysis access patency, and perhaps uremic pruritus and oxidative stress. In contrast, the putative hematologic, antihypertensive, anti-inflammatory, and antiarrhythmic effects are not as well documented. Adverse effects generally have been limited to gastrointestinal complaints. Unfortunately, the preponderance of published studies are characterized by suboptimal study design, small sample sizes, supraphysiologic omega-3 doses that may be difficult to consume for extended periods, little long term follow-up, and a lack of confirmation of compliance. Not surprising, the 2005 National Kidney Foundation Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines for Cardiovascular Disease in Dialysis Patients recommend further research in this field. In summary, although preliminary data suggest that omega-3 fatty acids may have clinical benefits, formal recommendations encouraging omega-3 supplementation of dialysis patients are premature until long-term and adverse effects are better defined. PMID- 17699208 TI - Heart failure and nephropathy: catastrophic and interrelated complications of diabetes. AB - Heart failure (HF) is a major contributor to poor quality of life, a leading cause of hospitalization, and cause of premature death. Both kidney disease and diabetes are major and independent risk factors for the development of heart failure, such that individuals with diabetic nephropathy are at especially high risk. Such patients not only are likely to have coronary artery disease and hypertension but also are likely to have diabetic cardiomyopathy, a distinct pathologic entity that is more closely associated with the microvascular than the macrovascular complications of diabetes. In addition to a better understanding of the epidemiology of HF, advances in noninvasive imaging have highlighted the importance of early cardiac dysfunction in diabetes and the high prevalence of HF with preserved left ventricular systolic function. Although significant renal dysfunction is usually an exclusion criterion in HF trials, diabetes is often a prespecified subgroup so that subanalyses of large multicenter clinical trials do provide some guidance in therapeutic decision-making. However, further therapies for both HF and nephropathy in diabetes clearly are needed, and a number of new therapeutic strategies that target both disorders have already entered the clinical arena. PMID- 17699209 TI - Coronary revascularization in diabetic chronic kidney disease/end-stage renal disease: a nephrologist's perspective. PMID- 17699210 TI - Direct renin inhibition with aliskiren in hypertension and target organ damage. AB - The Joint National Committee and the World Health Organization are in agreement that hypertension in most patients who are treated is controlled inadequately and that rates of cardiovascular morbidity remain high. Additional pharmacologic treatments could ameliorate this situation. The renin-angiotensin-aldosterone system has been a highly successful pharmacologic target, as the system is strongly implicated in the development of hypertension-related target organ damage. However, compensatory increases in plasma renin levels that lead to adjustments in angiotensin production and conversion present limitations for existing renin-angiotensin-aldosterone system inhibitors. A once-daily, orally effective, small-molecule renin inhibitor, aliskiren, is now available to address angiotensin production directly at its rate-limiting step. Studies in humans attest to an effective BP-lowering effect, a side effect profile no different from AT1 receptor blockers, and the option of combination therapies. A novel animal model of high human renin hypertension in the rat attest to target organ protection. Because angiotensin receptor blockade, angiotensin-converting enzyme inhibition, calcium channel blockade, and diuretic therapy all lead to sharp increases in plasma renin activity, aliskiren offers a novel circumvention. PMID- 17699211 TI - Lessons learned from recent hypertension trials about kidney disease. PMID- 17699212 TI - Update on cyclooxygenase-2 inhibitors. AB - Nonsteroidal anti-inflammatory drugs represent the most commonly used medications for the treatment of pain and inflammation, but numerous well-described side effects can limit their use. Cyclooxygenase-2 (COX-2) inhibitors were initially touted as a therapeutic strategy to avoid not only the gastrointestinal but also the renal and cardiovascular side effects of nonspecific nonsteroidal anti inflammatory drugs. However, in the kidney, COX-2 is constitutively expressed and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in mediation of renin release, regulation of sodium excretion, and maintenance of renal blood flow. This review summarizes the current state of knowledge about both renal and cardiovascular side effects that are attributed to COX-2 selective inhibitors. PMID- 17699213 TI - Improving outcomes for dialysis patients in the international Dialysis Outcomes and Practice Patterns Study. AB - The international Dialysis Outcomes and Practice Patterns Study (DOPPS) is well suited to evaluate levels of deviation from emerging and established guidelines to clinical practice of hemodialysis, over time and by country. The DOPPS can also evaluate whether the target levels that are chosen in the guidelines are in agreement with outcomes such as elevated risk for mortality, hospitalization, and vascular access failure. At a special DOPPS symposium during the 2004 congress of the American Society of Nephrology, the authors presented such findings; key points from that symposium are presented in this article, focusing on vascular access, mineral metabolism, dialysis dose, and anemia management. Although an observational study cannot prove causality, DOPPS suggests large opportunities to improve care and outcomes of dialysis patients. The international perspective of DOPPS assists in the new efforts for international guidelines. Some encouraging trends in recent years are documented in these areas. PMID- 17699214 TI - Double-blind, placebo-controlled study on the effect of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long-term angiotensin-converting enzyme inhibitor therapy, with or without an angiotensin II receptor blocker. AB - Studies have shown that dual therapy with angiotensin-converting enzyme inhibitors (ACEI) and either angiotensin II receptor blockers or aldosterone receptor antagonists is more effective in reducing proteinuria than either agent used alone. The questions that remain are as follows: (1) Which of these agents should be used as dual therapy with the ACEI? (2) Does a higher level of blockade of the renin-angiotensin-aldosterone system with triple therapy offer an advantage over dual blockade? A 3-mo randomized, double-blind, placebo-controlled study was performed in 41 patients with proteinuria >1.5 g/d. Four treatment groups were compared: (1) Ramipril + spironolactone placebo + irbesartan placebo, (2) ramipril + irbesartan + spironolactone placebo, (3) ramipril + irbesartan placebo + spironolactone, and (4) ramipril + irbesartan + spironolactone. The percentage change in protein excretion differed according to treatment arm (ANOVA: F(3,35) = 8.6, P < 0.001). Pair-wise comparison showed that greater reduction in protein excretion occurred in treatment regimens that incorporated spironolactone. The reduction in proteinuria at 3 mo was as follows: Group 1, 1.4%; group 2, 15.7%; group 3, 42.0%; and group 4, 48.2%. The reduction in proteinuria among patients who were taking spironolactone-containing regimens was sustained at 6 and 12 mo. This study suggests that aldosterone receptor blockade offers a valuable adjuvant treatment when used with ACEI therapy for the reduction of proteinuria. Results suggest no advantage of triple blockade over dual blockade of the renin-angiotensin-aldosterone system to reduce proteinuria. PMID- 17699215 TI - Stimulation of urinary TGF-beta and isoprostanes in response to hyperglycemia in humans. AB - TGF-beta and oxidant stress have been considered to play key roles in the pathogenesis of diabetic vascular complications; however, the stimulus for these factors in humans is not clear. The purpose of this in vivo study was to determine whether transient hyperglycemia in humans is sufficient to increase renal production of TGF-beta1 and urinary isoprostanes in normal humans. A hyperglycemic clamp procedure was performed on 13 healthy volunteers. An infusion of glucose was delivered to maintain the plasma glucose between 200 and 250 mg/dl for 120 min. Timed urine samples, collected on an overnight period before the study, at each void on completion of the procedure, and the following overnight, were assayed for TGF-beta1, F2-isoprostanes, and creatinine. Plasma samples were assayed for TGF-beta1 before and at timed intervals throughout hyperglycemia. Mean baseline TGF-beta1 in plasma was 4.57 +/- 0.22 ng/ml, and no change in plasma TGF-beta1 levels was detected throughout the hyperglycemia period. Baseline urine TGF-beta1 was 4.14 +/- 1.16 pg/mg creatinine. The fractional urine samples showed a sharp increase in TGF-beta1 excretion in the 12-h period after exposure to hyperglycemia, with a mean peak TGF-beta1 of 30.43 +/- 8.05 pg/mg (P = 0.002). TGF-beta1 excretion in the subsequent overnight urine sample was not different from baseline (4.62 +/- 1.21 pg/mg). Urinary isoprostanes increased from a baseline of 4.92 +/- 0.74 to 13.8 +/- 3.37 ng/mg creatinine. It is concluded that 120 min of hyperglycemia in normal humans is sufficient to induce an increase in renal TGF-beta1 and isoprostane production. PMID- 17699216 TI - The personal dialysis capacity test is superior to the peritoneal equilibration test to discriminate inflammation as the cause of fast transport status in peritoneal dialysis patients. AB - This study evaluated the potential of the Personal Dialysis Capacity (PDC) test to discriminate fast transport status (FTS) as a consequence of inflammation versus FTS because of other causes. This distinction is important because new therapeutic options such as icodextrin and automated peritoneal dialysis can abolish the negative impact on outcome of FTS if fast transport is not caused by inflammation. A PDC test and a Peritoneal Equilibration Test (PET) were performed in 135 incident PD patients. Membrane characteristics were related with baseline biochemical parameters and C-reactive protein. After correction for other covariates, only large pore flux (J(v)L) but not surface area over diffusion distance (A0/dX) or dialysate over plasma concentration was related to C-reactive protein. Using the PDC test for detection of inflammation, positive and negative predictive values were 16/36 and 80/99, respectively, whereas with PET, positive predictive value was 5/20 and negative predictive value 92/115 (chi2 = 0.009). In a Cox regression for patient survival with correction for age, a J(v)L higher than expected by the surface area over diffusion distance, predicted outcome (P = 0.04). Patients with inflammation had a higher J(v)L (0.21 +/- 0.12 versus 0.17 +/- 0.09; P = 0.06) and a lower ultrafiltration (89 +/- 631 versus 386 +/- 601 ml/d; P = 0.06) and urine output (878.45 +/- 533.55 versus 1322 +/- 822 ml/d; P = 0.023) than patients without inflammation. There was no difference for surface area over diffusion distance (A0/dX) or dialysate over plasma concentration. A PDC test yields far more information about the peritoneal membrane characteristics than a PET. A J(v)L higher than expected by the A0/dX is an indicator of inflammation and is related to an increased mortality. The PET is not able to discriminate between FTS because of inflammation versus because of anatomic reasons, whereas the PDC test does. PMID- 17699217 TI - Endovascular treatment of the "failing to mature" arteriovenous fistula. AB - In recent literature, surgically created hemodialysis (HD) arteriovenous fistulas (AVF) have high rates of primary failure. Endovascular treatment holds promise to salvage these fistulae. The outcomes of 119 patients who had a "failing to mature" AVF and presented for endovascular management were evaluated prospectively. All patients underwent a fistulogram. Stenotic lesions underwent balloon angioplasty, and accessory veins underwent obliteration. Technical success was determined immediately after the procedure. AVF salvage was determined by successful use during HD. Patients were followed up for 1 yr, during which primary and secondary AVF patency rates were measured. The distribution of stenoses was as follows: Artery, 6 (5.1%); arterial anastomosis, 56 (47.1%); juxta-arterial anastomosis, 76 (63.9%); peripheral vein, 70 (58.8%); and central vein, 10 (8.4%). Significant accessory veins were present in 35 (29.4%). Mixed lesions were found in 85 (71.4%). The technique was successful in 107 (89.9%), and the AVF was salvaged in 99 (83.2%). Follow-up of salvaged fistulae showed a total event rate of 0.38/access-year, thrombosis rate of 0.12/access-year, and loss rate of 0.04/access-year. Endovascular treatment of "failing to mature AVF" is safe and effective when performed in a dedicated center. PMID- 17699218 TI - Statin treatment and diabetes affect myeloperoxidase activity in maintenance hemodialysis patients. AB - Myeloperoxidase (MPO), which is secreted during activation of neutrophils, may serve as one mechanistic link among persistent inflammation, oxidative stress, and cardiovascular disease. This study related MPO activity to inflammatory and oxidative stress biomarkers, comorbidity, and ongoing medication in prevalent hemodialysis (HD) patients. In a cross-sectional evaluation of 115 prevalent (vintage 25 mo) HD patients (62 men; 63 +/- 1 yr), data on comorbidity (Davies score), diabetes, medication (statins and antihypertensive drugs), nutritional status (subjective global assessment), blood lipids (cholesterol, HDL cholesterol, and triglycerides), inflammatory biomarkers (serum albumin, C reactive protein, TNF-alpha, and IL-6), oxidative stress biomarkers (pentosidine, 8-hydroxydeoxyguanosine, and MPO activity) were recorded. Patients with MPO activity greater than the median had significantly (P < 0.05) lower serum albumin levels (33.2 +/- 0.7 versus 35.0 +/- 0.5 g/L), higher 8-hydroxydeoxyguanosine levels (1.26 +/- 0.08 versus 1.05 +/- 0.06 ng/ml), and a lower prevalence of statin treatment (18 versus 36%). Therefore, the median MPO activity was significantly (P < 0.05) lower (17.7 versus 26.6 deltaOD630/min per mg protein) in the subgroup of 31 HD patients with ongoing statin treatment. In a multiple regression model, correction for the impact of age, gender, vintage, serum cholesterol, serum albumin, comorbidity, diabetes, and statin use, only diabetes (P < 0.01) and statin use (P < 0.01) were significantly associated to MPO activity. Fourteen patients who had diabetes and were receiving statin treatment had markedly (P = 0.001) lower median (19.9 versus 41.2 deltaOD630/min per mg protein) MPO activity compared with 18 who had diabetes and were not taking statins. This cross-sectional study suggests that both diabetes and statin treatment affect MPO activity in prevalent HD patients. PMID- 17699219 TI - Incidence, predictors, and associated outcomes of atrial fibrillation after kidney transplantation. AB - The risk for and predictors of atrial fibrillation (AF) after kidney transplantation are not well described. Registry data that were collected by the United States Renal Data System were used to investigate retrospectively new onset AF among adult first renal allograft recipients and transplant candidates who received a transplant or were wait-listed in 1995 to 2001 with Medicare as the primary payer. AF events were ascertained from billing records, and participants were followed until loss of Medicare coverage or December 31, 2001. Cox hazards analysis was used to identify independent correlates of posttransplantation AF (adjusted hazard ratio [AHR]; 95% confidence interval [CI]) and to examine AF as an outcomes predictor. Among 31,136 eligible transplant recipients, the cumulative incidence of new-onset AF was 3.6% (95% CI 3.4 to 3.8%) and 7.3% (95% CI 7.0 to 7.6%) at 12 and 36 mo and declined below the demographics-adjusted cumulative incidence on the waiting list by approximately 17 mo. Risk factors for posttransplantation AF included older recipient age, male gender, white race, renal failure from hypertension, and coronary artery disease. Extended pretransplantation dialysis duration, posttransplantation diabetes, and graft failure were identified as potentially modifiable correlates of AF. In separate analyses, AF independently predicted death (AHR 3.2; 95% CI 2.9 to 3.6) and death-censored graft loss (AHR 1.9; 95% CI 1.6 to 2.3). As the population of renal transplant recipients grows older, the incidence and prevalence of AF among these patients will likely increase. Appropriate risk stratification may identify transplant recipients who are in need of close monitoring for and management of this adverse cardiovascular event. PMID- 17699220 TI - Renal insufficiency and use of revascularization among a national cohort of men with advanced lower extremity peripheral arterial disease. AB - Although peripheral arterial disease is prevalent in patients with renal insufficiency, little is known about how the disease is managed in this patient group. The management of advanced limb ischemia was examined in a large cohort of male veterans (n = 6227). Patients were classified according to whether they underwent lower extremity revascularization, amputation, or no procedure within the first 6 mo after their first diagnosis of critical limb ischemia, defined as ischemic rest pain, ulceration, or gangrene. The association of renal insufficiency with revascularization and the association of management strategy with mortality within 1 yr of cohort entry were measured. Within 6 mo of initial diagnosis of critical limb ischemia, 39% of patients underwent lower extremity revascularization, 27% underwent major amputation, and 34% did not undergo either procedure. Patients with an estimated GFR 30 to 59 (adjusted odds ratio [OR] 0.84; 95% confidence interval [CI] 0.72 to 0.96), 15 to 29 ml/min per 1.73 m2 (OR 0.47; 95% CI 0.35 to 0.65), 15 ml/min per 1.73 m2 not on dialysis (OR 0.32; 95% CI 0.16 to 0.62), and dialysis patients (OR 0.62; 95% CI 0.47 to 0.84) were less likely to undergo revascularization than those with an estimated GFR > or = 60 ml/min per 1.73 m2. At all levels of renal function, mortality risk was lowest for patients who underwent revascularization. Patients with critical limb ischemia and concomitant renal insufficiency are less likely to be treated with revascularization. However, among patients with renal insufficiency, mortality is lowest for patients who receive a revascularization. Further studies are needed to determine the optimal care for this high-risk patient group. PMID- 17699221 TI - Cinacalcet hydrochloride (Sensipar) in hemodialysis patients on active vitamin D derivatives with controlled PTH and elevated calcium x phosphate. AB - Active vitamin D derivatives attenuate the severity of secondary hyperparathyroidism but often increase serum calcium (Ca) and phosphorus (P) as a result of enhanced intestinal absorption. The calcimimetic cinacalcet HCl lowers parathyroid hormone (PTH) and tends to decrease Ca x P. A 16-wk, open-label clinical trial was conducted in adult hemodialysis patients who had controlled PTH (biointact PTH [biPTH] 80 to 160 pg/ml) and elevated Ca x P (> 55 mg2/dl2) and were receiving paricalcitol > 6 microg/wk (or an equipotent dose of an alternative active vitamin D derivative). At the start of the study, active vitamin D derivatives were decreased to a mean equivalent dose of paricalcitol 6 microg/wk, and cinacalcet was titrated from 30 mg/d to a maximum possible dose of 180 mg/d. Of the 72 study patients, 53 (74%) completed 8 wk of dose titration with cinacalcet. In response to cinacalcet, the following mean percentage changes were observed: biPTH, -1.8%; Ca, -9.7% (P < 0.0001), phosphorus, -11.1% (P < 0.0001), and Ca x P, -20.1% (P < 0.0001). At the end of the study, approximate Kidney Disease Outcomes Quality Initiative targets for biPTH (< or = 160 pg/ml) were achieved in 85% (45 of 53) of patients and for Ca x P (< or = 55 mg2/dl2) in 72% (38 of 53) of patients. Concurrent achievement of both targets occurred in 47% (25 of 53) of patients. In this open-label clinical trial, hemodialysis patients who had controlled PTH but elevated Ca x P and were taking moderate- to high-dose active vitamin D derivatives achieved improved control of mineral metabolism with a combination of low-dose active vitamin D derivatives and cinacalcet. The long-term effects of this treatment regimen on clinical outcomes should be tested prospectively. PMID- 17699223 TI - Improvement in hypercalcemia with cinacalcet after kidney transplantation. AB - Cinacalcet, a calcimimetic, was evaluated in persistent hyperparathyroidism after kidney transplantation (Tx). Ten kidney transplant recipients and one kidney pancreas recipient with persistent post-Tx hypercalcemia (serum calcium [SCa] > 10.2 mg/dl), stable graft function, and intact parathyroid hormone (iPTH) > or = 2 times normal received 30 mg/d cinacalcet between 2 mo and 5 yr after Tx. SCa, serum phosphorus (SP), and iPTH were measured before and after cinacalcet. Mean pre-cinacalcet SCa was 10.9 mg/dl (8.6 to 11.9 mg/dl). Average pre-cinacalcet SP was 2.9 mg/dl (1.8 to 4.0 mg/dl). Mean pre-cinacalcet iPTH was 267.0 pg/ml (99 to 723 pg/ml). After cinacalcet, SCa decreased on average by 1.6 mg/dl (95% confidence interval 1.2 to 2.1; P < 0.0001). Post-cinacalcet SP increased on average 0.45 mg/dl (P = 0.046). Post-cinacalcet iPTH averaged 156.9 mg/dl (P = 0.10). Graft function remained stable. Cinacalcet lowers SCa and raises SP in the short term in patients with persistent post-Tx hyperparathyroidism; long-term bone effects and persistent hyperparathyroidism merit further study. PMID- 17699222 TI - Role of socioeconomic status in kidney transplant outcome. AB - There is controversy regarding the influence of genetic versus environmental factors on kidney transplant outcome in minority groups. The goal of this project was to evaluate the role of certain socioeconomic factors in allograft and recipient survival. Graft and recipient survival data from the United States Renal Data System were analyzed using Cox modeling with primary variables of interest, including recipient education level, citizenship, and primary source of pay for medical service. College (hazard ratio [HR] 0.93, P < 0.005) and postcollege education (HR 0.85, P < 0.005) improved graft outcome in the whole group and in patients of white race. Similar trends were observed for recipient survival (HR 0.9, P < 0.005 for college; HR 0.88, P = 0.09 for postcollege education) in the whole population and in white patients. Resident aliens had a significantly better graft outcome in the entire patient population (HR 0.81, P < 0.001) and in white patients in subgroup analysis (HR 0.823, P < 0.001) compared with US citizens. A similar effect was observed for recipient survival. Using Medicare as a reference group, there is a statistically significant benefit to graft survival from having private insurance in the whole group (HR 0.87, P < 0.001) and in the black (HR 0.8, P < 0.001) and the white (HR 0.89, P < 0.001) subgroups; a similar effect of private insurance is observed on recipient survival in the entire group of patients and across racial groups. Recipients with higher education level, resident aliens, and patients with private insurance have an advantage in the graft and recipient outcomes independent of racial differences. PMID- 17699224 TI - Urinary tract infections in patients with chronic renal insufficiency. AB - Despite an increasing population of patients with chronic renal insufficiency, the literature on the management of urinary tract infections (UTI) in these patients is sparse. Patients with underlying diabetes are a specific population at risk. Antimicrobial treatment of UTI requires adequate serum, renal, parenchymal, and urine concentrations of drugs with antibacterial activity versus the etiologic organism. Sulfamethoxazole and nitrofurantoin are examples of drugs with low and likely inadequate urine concentrations in patients with creatinine clearances of <50 ml/min. Urine concentrations of ciprofloxacin and levofloxacin remain sufficient as renal function fails, whereas the concentrations of gemifloxacin and moxifloxacin are too low to predict efficacy. More investigative work is needed in the management of UTI in patients with poor renal function. PMID- 17699225 TI - Early arteriovenous fistula failure: a logical proposal for when and how to intervene. AB - A significant number of arteriovenous fistulae (28 to 53%) never mature to support dialysis. Often, renal physicians and surgeons wait for up to 6 months and even longer hoping that the arteriovenous fistula (AVF) will eventually grow to support dialysis before declaring that the AVF has failed. In the interim, if dialysis is needed, then a tunneled catheter is inserted, exposing the patient to the morbidity and mortality associated with the use of this device. In general, a blood flow of 500 ml/min and a diameter of at least 4 mm are needed for an AVF to be adequate to support dialysis therapy. In most successful fistulae, these parameters are met within 4 to 6 wk. Most important, commonly encountered problems (stenosis and accessory veins) that result in early AVF failure can be diagnosed easily with skillful physical examination. Recent studies have indicated that a great majority of fistulae that have failed to mature adequately can be salvaged by percutaneous interventions and become available for dialysis. Early intervention regarding identification and salvage of a nonmaturing AVF is critical for several reasons. First, an AVF is the best available type of access regarding complications, costs, morbidity, and mortality. Second, this approach minimizes catheter use and its associated complications. Finally, access stenosis is a progressive process and eventually culminates in complete occlusion, leading to access thrombosis. In this context, the opportunity to salvage the AVF that fails early may be lost. This report reviews the process of AVF maturation and suggests a strategy for when and how to intervene to identify and salvage AVF with early failure. PMID- 17699226 TI - Strategies for successful patient oriented research: why did I (not) get funded? AB - Writing grants that are subsequently funded is an integral part of the process of patient-oriented research. A catalogue of common deficiencies that are identified in the grant review process can yield valuable insights into the process of grant writing. This article provides the authors' opinion on the common pitfalls in the current patient-oriented research applications that if identified before submission can lead to a stronger application. The authors participated in the review of clinical research grants to the National Kidney Foundation and catalogued the weaknesses of the grants that were reviewed and discussed. The top five reasons identified with grants were problems with study design (76%); statistical issues (34%); general issues such as ownership of the work, mentor, and environment (29%); weak hypothesis (24%); and problems with the research question, such as novelty or lack of creation of new data (24%). Patient-oriented research grants that have strong mentoring, are hypothesis driven, and have a strong study design that addresses sample size, analysis, and confounding factors have an increased chance of yielding high-quality research and, therefore, successful funding. PMID- 17699227 TI - My doctor said I should drink a lot! Recommendations for fluid intake in patients with chronic kidney disease. PMID- 17699228 TI - To treat or not to treat IgA nephropathy? That is the question! PMID- 17699229 TI - Depression in patients with end-stage renal disease treated with dialysis: has the time to treat arrived? PMID- 17699230 TI - Intravenous iron therapy in peritoneal dialysis patients: short-term efficacy and long-term issues. PMID- 17699231 TI - Induction therapy: are we picking our battles? PMID- 17699232 TI - Beyond histology: novel tools to diagnose allograft dysfunction. AB - Kidney biopsy is the gold standard procedure for the assessment of allograft dysfunction. The differential diagnosis for both acute and chronic dysfunction can encompass a number of different causes, and a biopsy frequently can suggest a specific cause. However, many of these causes are difficult to distinguish on morphologic basis alone, and the information that is obtained from a biopsy is limited with regard to functional and prognostic importance. Additional methods therefore are needed to guide the diagnosis and the treatment of allograft dysfunction, and numerous methods have been studied. Potential markers include protein and gene expression profiles in the peripheral blood, the urine, and the graft itself, all compartments that are relevant to the alloimmune response. Recent comprehensive sequencing of the human genome has led to an unprecedented opportunity to develop these genetic and proteomic techniques, and ongoing evaluations of potential tests have led to an improved understanding of the complexity of immune responses. The future challenge for promising tests is validation in larger patient populations to facilitate their addition to the diagnostic armamentarium. PMID- 17699233 TI - Can hyperparathyroid bone disease be arrested or reversed? AB - Parathyroid hyperplasia, oversecretion of parathyroid hormone (PTH), and hyperparathyroid bone disease are characteristic features of chronic uremia; they develop early in the course of uremia and often in a progressive way. This review focuses on the potential for arrest or regression of hyperparathyroid-induced bone disease. For this purpose, the review addresses investigations that have used bone histology and not investigations that indirectly attempted to demonstrate changes in the skeleton by measurements of bone mineral density or laboratory indices of bone turnover, other than PTH. A prerequisite for inducing regression of the hyperparathyroid bone disease is a significant suppression of PTH secretion or reversal of hyperparathyroidism and uremia. It is concluded, on the basis of paired bone biopsy studies in patients with established hyperparathyroid bone disease, that bone histology can be improved or normalized after treatment that diminishes PTH levels. Oversuppression of PTH levels, however, might lead to adynamic bone disease. PMID- 17699234 TI - Histologic versus molecular diagnosis of BK polyomavirus-associated nephropathy: a shifting paradigm? AB - Although discovered in 1970 the BK virus infections had no significant clinical impact until the emergence of BK virus-associated allograft nephropathy (BKPVAN). Escalating clinical challenges required better diagnostic tools and delineation of uniform criteria for diagnosis. In recent years, the widespread use of real time PCR for measuring viral loads has confirmed that BK viruria and viremia are consistently identified before the development of overt nephritis. The identification of this viruria-viremia-nephritis sequence has provided tools for screening renal transplant patients and the possibility of earlier intervention with improved outcomes. Analysis of current clinical trends indicates that despite the fact that a positive renal biopsy is the "gold standard" for the diagnosis of BKPVAN, clinical interventions often are based on the surrogate markers of the disease rather than on tissue diagnosis. This is conceptually supported by the fact that early BKPVAN is focal and liable to tissue sampling errors. Strong arguments remain, however, in favor of retaining the requirement for tissue evaluation in patients who are suspected of having BKPVAN. BKPVAN selectively affects the graft and is likely to occur in a background of immune and/or nonimmune renal injury. A renal biopsy is necessary to exclude other pathologic processes (e.g., acute rejection) that could coexist with BKPVAN or be the main cause of allograft dysfunction. Evaluation of a renal biopsy for the purpose of staging is important for prognosis and is also of paramount importance for the rational assessment of therapeutic success. PMID- 17699235 TI - Dose of dialysis in acute renal failure. PMID- 17699236 TI - Pre- and postdialysis blood pressures are imprecise estimates of interdialytic ambulatory blood pressure. AB - BP readings that are obtained in the dialysis unit are commonly used to make therapeutic decisions by clinicians and to predict morbidity and mortality by epidemiologists. Dialysis unit BP are also incorporated in the recent guidelines to target BP control. The magnitude of the difference, overestimation or underestimation, and agreement between dialysis unit BP and ambulatory BP (ABP) are unknown. Articles were selected from Medline to identify those that reported both ABP and dialysis unit BP in hemodialysis patients. Bias was calculated as the difference between dialysis unit and the corresponding ABP. Agreement limits between the BP measurement techniques were assessed by pooled SD of the difference using Bland-Altman methods. Predialysis systolic BP generally overestimated ABP by a variable amount. The heterogeneity between BP measurements did not allow for pooling of the estimates. The agreement limits between the two BP was 41.7 to -25.2 mmHg. Predialysis diastolic BP also generally overestimated the ABP with wide agreement limits (23.7 to -18.9 mmHg). In contrast, postdialysis BP underestimated average ABP with wide agreement limits for both postdialysis systolic BP (33.1 to -36.3 mmHg) and diastolic BP (19.3 to -23.9 mmHg). Dialysis unit BP measurements are imprecise estimates of ABP. Better methods are needed for the assessment of BP in hemodialysis patients for clinical decision making. PMID- 17699237 TI - Antibodies come back to the forefront in transplantation. PMID- 17699238 TI - Antibody mediated rejection: update 2006. PMID- 17699239 TI - Mechanisms and role of HLA and non-HLA alloantibodies. AB - The role of alloantibodies against HLA and non-HLA targets is becoming increasingly recognized as critical in the pathogenesis of acute and chronic renal allograft outcomes. This review discusses the antigenic targets, the mechanisms of T and B cell activation that result in the production of antibody, the complement cascade, methods of antibody detection, and the evidence that alloantibody-mediated mechanisms are active in acute and chronic rejection. PMID- 17699240 TI - Antibody-mediated rejection in renal allografts: lessons from pathology. AB - The past 15 years have seen major advances in the understanding of the effects of anti-donor antibodies on renal allografts at various stages after transplantation. These advances have been due in large part to pathologic examination of both early and late renal allograft biopsies, including both routine histologic evaluation and immunohistology to detect complement split products. As pathologists have become increasingly adept at diagnosing antibody mediated rejection (AMR) on allograft biopsies, substantial progress has been made in the treatment of AMR and in successful renal transplantation in recipients with pre-existing antibodies against donor blood group (ABO) and/or major histocompatibility (HLA) antigens. This article reviews the pathologic features of hyperacute, acute, and chronic AMR, including some newer findings impacting diagnosis and outcomes, and differences in the implications of similar pathologic findings in ABO- versus HLA-incompatible renal allografts. PMID- 17699241 TI - Presensitization: the problem and its management. AB - Much attention has been placed recently on transplantation in highly HLA sensitized patients. In attempts to remove these antibodies and enable successful transplantation, several novel approaches have been developed. These include intravenous Ig (IVIg), mycophenolate mofetil, sirolimus, alemtuzumab, protein A immunoabsorption, and rituximab. IVIg has emerged as a very effective agent when used alone in high dose or when used in low dose and combined with plasmapheresis. Although alemtuzumab has been used to eliminated B cells, it fails to prevent antibody-mediated rejection and therefore probably is not suitable for desensitization. Rituximab, a B cell-specific antibody, seems to be safe and to have some efficacy as a sole agent in elimination of alloantibodies but most likely will require combination therapy with IVIg or other agents. Newer agents, such as humanized anti-CD20, are being developed. Despite the great interest in the problem of allosensitization, with one notable exception, there is a major deficiency in controlled clinical trials, the conduct of which should be a focus for the near future. PMID- 17699242 TI - Sensitization after kidney transplantation. AB - Kidney transplant recipients may develop de novo anti-HLA and non-HLA antibodies after transplantation. Although these antibodies may be donor-specific or non donor-specific, their presence may increase the risk for acute and chronic rejection, thereby decreasing allograft survival. The introduction of more sensitive and specific methods to detect anti-HLA antibodies, such as Flow Specific Beads and FlowPRA, both before and after transplantation, will help to define immunologically high-risk kidney transplant recipients. Thus, posttransplantation monitoring of anti-HLA antibody production will allow the identification of kidney transplant recipients who might be at increased risk for late allograft failure. Moreover, knowledge of alloantibody status after transplantation may help to guide the appropriate use of immunomodulatory agents to downregulate anti-HLA antibody production. PMID- 17699243 TI - Increased anion gap metabolic acidosis as a result of 5-oxoproline (pyroglutamic acid): a role for acetaminophen. AB - The endogenous organic acid metabolic acidoses that occur commonly in adults include lactic acidosis; ketoacidosis; acidosis that results from the ingestion of toxic substances such as methanol, ethylene glycol, or paraldehyde; and a component of the acidosis of kidney failure. Another rare but underdiagnosed cause of severe, high anion gap metabolic acidosis in adults is that due to accumulation of 5-oxoproline (pyroglutamic acid). Reported are four patients with this syndrome, and reviewed are 18 adult patients who were reported previously in the literature. Twenty-one patients had major exposure to acetaminophen (one only acute exposure). Eighteen (82%) of the 22 patients were women. Most of the patients were malnourished as a result of multiple medical comorbidities, and most had some degree of kidney dysfunction or overt failure. The chronic ingestion of acetaminophen, especially by malnourished women, may generate high anion gap metabolic acidosis. This undoubtedly is an underdiagnosed condition because measurements of serum and/or urinary 5-oxoproline levels are not readily available. PMID- 17699244 TI - Endovascular versus surgical preemptive repair of forearm arteriovenous fistula juxta-anastomotic stenosis: analysis of data collected prospectively from 1999 to 2004. AB - Surgery is the traditional treatment for juxta-anastomotic stenoses in forearm arteriovenous fistulas (AVF), but percutaneous transluminal angioplasty (PTA) is a suitable alternative. No prospective comparative trials between the two have been reported to date, however. A retrospective analysis of prospectively, concurrently collected data was performed to compare the outcome and cost of surgery and PTA in the preemptive repair of juxta-anastomotic stenosis in lower forearm AVF. Sixty-four AVF with >50% venous juxta-anastomotic stenosis were considered: 21 were treated surgically (11 proximal neo-anastomosis and 10 polytetrafluoroethylene interposition graft) and 43 by PTA. After treatment, AVF were monitored by quarterly ultrasound dilution access blood flow measurement. End points were restenosis and procedure failure rate (re-intervention by another technique or access loss), and determinants were analyzed using Cox hazard model. Initial procedural success was 100% for surgery and 95% for PTA (P = 0.539). Restenosis rate was 0.168 and 0.519 events/AVF-year for surgery and PTA, respectively (P = 0.009). The type of procedure was the only variable that was significantly associated with restenosis, the adjusted relative risk being 2.77 fold higher (95% confidence interval 1.07 to 7.17; P = 0.036) after PTA than surgery. The procedure failure rate was 0.110 and 0.097 events/AVF-year for surgery and PTA, respectively (P = 0.736). The cost profile also was similar for the two procedures. This prospective comparative study confirms a higher restenosis rate after PTA than surgery, but with strict surveillance for restenosis, the two procedures show similar assisted primary patency and cost, suggesting that they should be considered equally valid, complementary alternatives in the preemptive treatment of juxta-anastomotic stenosis in forearm AVF. PMID- 17699245 TI - Associations between demographic factors and provider structures on cost and length of stay for hemodialysis patients with vascular access failure. AB - Vascular access failure (VAF) is a major determinant of morbidity and cost for hemodialysis patients, but little is known about the care patterns and cost implications that are associated with VAF. A total of 952 episodes of VAF in 348 patients were identified using specific procedure codes. Demographic and care pattern characteristics were available as were detailed costs for each episode. The determinants of several important performance measures were evaluated: Cost per episode, inpatient versus outpatient treatment, and length of stay (LOS). Over 5 yr of study, the proportion of VAF episodes that were treated on an outpatient basis increased from 31 to 63%. Average costs of outpatient versus inpatient episodes were $1491 and $8265, respectively. Men were more likely to be treated as outpatients (odds ratio [OR] 1.56; 95% confidence interval [CI] 1.17 to 2.08), but once admitted, their LOS was longer (difference LOS +1.3; 95% CI +0.32 to +2.28) and more costly (delta$ +2603; 95% CI +632 to +4573). Nonblack, nonwhite patients were more likely to be treated as outpatients than were white patients (OR 2.07; 95% CI 1.27 to 3.36) and had shorter LOS once admitted (deltaLOS -2.37; 95% CI -4.23 to -0.49). Compared with Medicare, non-Medicare case-managed insurance was associated with a higher likelihood of outpatient treatment (OR 1.40; 95% CI 1.01 to 1.94) for VAF and shorter LOS (deltaLOS -1.36; 95% CI -2.48 to -0.24) and lower costs (delta$ -2742; 95% CI -5012 to -472) for inpatient treatment. It is concluded that gender and racial factors may influence VAF care. Over time, more VAF episodes are being treated in outpatient settings. Case management may lead to more outpatient treatment and shorter inpatient treatment of VAF. PMID- 17699246 TI - Large within-day variation in cyclosporine absorption: circadian variation or food effect? AB - With the recent focus of monitoring cyclosporine (CsA) therapy using measures of CsA absorption, it is important to understand published reports of diurnal variation in CsA exposure. In 10 renal transplant patients, CsA concentrations were measured 0, 1, 2, 3, and 4 h after both the morning and the evening doses and in a repeat session at least 1 wk later. Both area under the curve for the final 4 h after cyclosporine dose and cyclosporine concentrate 2 h after the cyclosporine dose were more than two-fold higher after the morning dose in both sessions. Because the morning levels were collected in a fasted condition and the evening ones in a fed condition, the study was extended to collect evening levels after fasting. The area under the curve for the final 4 h after cyclosporine dose and cyclosporine concentrate 2 h after the cyclosporine dose values observed now were comparable to the morning fasted values. That the large diurnal variation was due to variation in food consumption, as opposed to a biologic circadian rhythm affecting CsA absorption, has significant implications for therapeutic drug monitoring. PMID- 17699247 TI - Clinical trial to evaluate omega-3 fatty acids and alternate day prednisone in patients with IgA nephropathy: report from the Southwest Pediatric Nephrology Study Group. AB - This randomized, placebo-controlled, double-blind trial evaluated the role of prednisone and omega 3 fatty acids (O3FA) in patients with IgA nephropathy. Entry criteria were (1) biopsy-proven IgA nephropathy, (2) estimated GFR > or = 50 ml/min per 1.73 m2, and (3) moderate to severe proteinuria. Thirty-three patients were randomly assigned to receive prednisone 60 mg/m2 every other day for 3 mo, then 40 mg/m2 every other day for 9 mo, then 30 mg/m2 every other day for 12 mo (prednisone group); 32 were randomly assigned to receive O3FA 4 g/d for 2 yr (1.88 g eicosapentaenoic acid, 1.48 g docosahexaenoic acid; O3FA group); and 31 were randomly assigned to receive placebo (placebo group). Most (73%) patients completed 2 yr of treatment. Randomly assigned patients who were hypertensive were given enalapril 2.5 to 40 mg/d. The primary end point was time to failure, defined as estimated GFR <60% of baseline. An overall significance level of 0.10 was used. The three groups were comparable at baseline except that the O3FA group had higher urine protein to creatinine (UP/C) ratios than the placebo group (P = 0.003). Neither treatment group showed benefit over the placebo group with respect to time to failure, with 14 patient failures overall (two in the prednisone group, eight in the O3FA group, and four in the placebo group). The primary factor associated with time to failure was higher baseline UP/C ratios (P = 0.009). Superiority of prednisone or O3FA over placebo in slowing progression of renal disease was not demonstrated in this study. However, the relatively short follow-up period, inequality of baseline UP/C ratios, and small numbers of patients precludes definitive conclusions. PMID- 17699248 TI - Effect of intravenous iron sucrose in peritoneal dialysis patients who receive erythropoiesis-stimulating agents for anemia: a randomized, controlled trial. AB - Although iron therapy is essential to optimize use of erythropoiesis-stimulating agents (ESA), randomized, controlled trials have heretofore been unavailable to evaluate reliably the efficacy of intravenous iron as an adjuvant to ESA treatment in peritoneal dialysis (PD) patients. In a multicenter trial, patients who had anemia, PD-dependent chronic kidney disease, stable ESA therapy, and a broad range of iron status (ferritin < or = 500 ng/ml, transferrin saturation < or = 25%) were randomly assigned to receive either 1 g of iron sucrose intravenously in three divided doses (300 mg over 1.5 h on days 1 and 15, 400 mg over 2.5 h on day 29) or no supplemental iron. No serious adverse drug events occurred after intravenous iron administration. The primary end point, peak hemoglobin increase, was higher (1.3 +/- 1.1 versus 0.7 +/- 1.1, mean +/- SD; P = 0.0028), and anemia intervention (transfusion, increase in ESA dose, or intravenous iron therapy not called for in protocol) occurred later (P = 0.0137) and less often in intravenous iron-treated patients compared with untreated control subjects (one of 66 [1.3%] versus five of 30 [16.7%]). Among patients who did not require intervention, iron-treated patients showed a calculated net ESA dose decrease compared with untreated control subjects. Baseline iron status did not predict responsiveness to intravenous iron therapy. Intravenous iron sucrose is an effective adjunct to ESA therapy in anemic patients with PD-dependent chronic kidney disease and is administered safely as 300 mg over 1.5 h or 400 mg over 2.5 h. Evidence of iron deficiency at baseline is not required to demonstrate intravenous iron efficacy. PMID- 17699249 TI - Changing incidence of glomerular disease in Olmsted County, Minnesota: a 30-year renal biopsy study. AB - Membranous nephropathy (MN) is considered the most common cause of nephrotic syndrome in white adults, but recent studies have shown an increasing incidence of focal segmental glomerulosclerosis (FSGS). These studies are difficult to interpret because the majority of cases came from urban tertiary referral centers. For validating these findings in the general population, trends in the incidence of various forms of glomerular disease (glomerulonephritis [GN]) among the residents of Olmsted County, MN were studied. Biopsy data of local patients who had a diagnosis of a nondiabetic glomerular disease from 1974 through 2003 were reviewed. Biopsies were categorized as (1) FSGS, (2) MN, (3) minimal change, (4) lupus nephritis, (5) membranoproliferative GN (MPGN), (6) IgA nephropathy (IgAN), (7) crescentic/necrotizing GN, and (8) other. Time trends in the annual age- and gender-adjusted (2000 US population) incidence rate per 100,000 Olmsted County population were estimated. A total of 195 biopsies were analyzed. Overall, IgAN was present in 22%, FSGS was present in 17%, and MN was present in 10%. Between 1974 to 1983 and 1994 to 2003, the incidence of any type of GN among Olmsted County residents increased more than two-fold (P < 0.001), FSGS by 13 fold (P < 0.001), and IgAN by three-fold (P = 0.002). Increases in MN were nonsignificant (2.5-fold; P = 0.13). Currently (1994 to 2003), the most frequent type of GN is IgAN (25%), followed by FSGS (20%) and MN (11%), with annual incidence rates of 2.1, 1.8, and 1.0 per 100,000/yr, respectively. This study confirms that the incidence of GN is growing overall, particularly for FSGS, which is the leading cause of nephrotic syndrome in white adults. PMID- 17699250 TI - Exercise performance falls over time in patients with chronic kidney disease despite maintenance of hemoglobin concentration. AB - Physical function is limited in patients with kidney disease, although previous studies have been confounded by anemia. What is not clear is how physical performance changes over time as renal function deteriorates. A cohort of 12 patients (10 male, two female; mean +/- SD age 49 +/- 11 yr) who had stages 3 to 4 chronic kidney disease without previous anemia were examined, and nine were followed for a 2-yr period. Assessments were made of peak oxygen consumption (VO2peak) by cycle ergometry, leg extension strength, and fatigue on an isokinetic dynamometer and thigh muscle cross-sectional area (TMCSA) by computed tomography. At baseline, creatinine clearance was 31 +/- 13 ml/min and hemoglobin concentration ([Hb]) was 129 +/- 9 g/L. VO2peak was low (1.88 L/min, 82% of predicted), and maximal isometric voluntary contraction was 188 +/- 42 Nm, with a TMCSA of 144 +/- 27 cm2. VO2peak correlated with creatinine clearance corrected for body surface area (r = 0.613, P = 0.034) but not to [Hb]. VO2peak adjusted for patient weight correlated with leg fatigue (r = -0.693, P = 0.012). For those with follow-up tests, there were falls in renal function by 28% (P = 0.007) and VO2peak by 9% (P = 0.03), whereas [Hb] did not change. Leg strength fell across a range of isokinetic speeds (P = 0.04), whereas no change in TMCSA was observed. In conclusion, exercise performance as measured by aerobic (VO2peak) and leg strength tests were reduced in patients with stages 3 to 4 chronic kidney disease. As renal function declined over time, there was a corresponding decline in exercise performance even when [Hb] was maintained. PMID- 17699251 TI - Temporal relation among depression symptoms, cardiovascular disease events, and mortality in end-stage renal disease: contribution of reverse causality. AB - Temporal relationships among depression, medical comorbidity, and death or cardiovascular disease (CVD) events are complex. Clarifying temporal relationships may enhance current insight regarding the nature of the association of depression with poor outcomes. The temporal relation of depression symptoms (DS; score < or = 52 on five-item Mental Health Index) assessed at 6-mo intervals for 2 yr to CVD event, all-cause death, cardiovascular disease deaths, and non cardiovascular disease deaths was studied in 917 incident dialysis patients. Cox regression models were used to assess whether the proximity of DS measurement and DS duration would change observed associations between DS and events. Whether increasing medical comorbidity was associated with worsening DS also was assessed. In time-varying models, DS were strongly associated with all-cause deaths, cardiovascular disease deaths, and CVD events (adjusted relative hazard [95% confidence interval]: 2.22 [1.36 to 3.60], 3.27 [1.57 to 6.81], and 1.68 [1.05 to 2.69], respectively). Persistent and current DS were associated with greater risks for all-cause death. Incorporating a 6-mo time lag between DS and outcomes attenuated risks for all-cause death, non-cardiovascular disease deaths, and CVD events. In a subgroup analysis, patients with worsening medical comorbidity (n = 32) during the first year of follow-up experienced a 2.42-point greater decline in mental health scores at 2 yr of follow-up compared with patients with no worsening in medical comorbidity (n = 123), but findings were not statistically significant. DS are strongly related to death and CVD events, with persistent/current DS most strongly associated with poor outcomes. Attenuated risks from time-lag analyses indicate a partial role for reverse causality, suggesting that medical comorbidity may precede DS. PMID- 17699252 TI - Septicemia in patients with ESRD is associated with decreased hematocrit and increased use of erythropoietin. AB - Septicemia, a common complication in chronic dialysis patients, may be an important factor in erythropoietin (EPO) hyporesponsiveness, because it is a form of inflammation. The quantitative impact of septicemia on EPO requirements has not been studied. The purpose of this study was to analyze patterns of EPO use and levels of anemia among patients who had ESRD and were hospitalized with septicemia. Using United States Renal Data System data, septicemia admissions were identified in patients with first ESRD service from 1996 to 2001. Mean EPO dosage and hematocrit (Hct) level were analyzed from 2 mo before until 3 mo after admission and compared with patients who were hospitalized with acute myocardial infarction (AMI) and patients with no hospitalizations. A total of 4640 hospitalized patients were included in the analysis: 3975 for septicemia and 665 for AMI. In both groups, mean Hct declined significantly in the month of admission and increased in the second month after admission. At all time points, both groups had significantly lower Hct levels compared with the nonhospitalized group. Mean EPO dosage increased, most rapidly in the month after admission. EPO use was highest in the septicemia group. Hospitalization with septicemia is associated with worsening anemia and increasing EPO use. This also was observed for patients who were hospitalized with AMI, suggesting that acute intercurrent illness plays an important role in EPO hyporesponsiveness. Strategies to prevent septicemia are important not only to decrease clinical morbidity but also to conserve EPO usage and thus contain the costs of care for this complex patient population. PMID- 17699253 TI - Steroid treatment for severe childhood IgA nephropathy: a randomized, controlled trial. AB - A previous trial showed that treatment of children with severe IgA nephropathy (IgAN) using prednisolone, azathioprine, heparin-warfarin, and dipyridamole for 2 yr early in the course of disease reduced the severity of immunologic renal injury and prevented any increase in the percentage of sclerosed glomeruli. This study compared the effects of prednisolone, azathioprine, warfarin, and dipyridamole (combination) with those of prednisolone alone in 80 children with newly diagnosed IgAN that showed diffuse mesangial proliferation. Patients were randomly assigned to receive either the combination or prednisolone alone for 2 yr. The primary end point was the disappearance of proteinuria, defined as urinary protein excretion <0.1 g/m2 per d, and the secondary end points were urinary protein excretion at the end of treatment, the change in the percentage of sclerosed glomeruli during the trial, and adverse effects. The two study groups were similar in terms of baseline characteristics. Thirty-nine of the 40 patients who received the combination and 39 of the 40 who received prednisolone completed the trial. Thirty-six (92.3%) of the 39 patients who received the combination and 29 (74.4%) of the 39 who received prednisolone reached the primary end point by the 2-yr follow-up point (P = 0.007 log-rank). The percentage of sclerosed glomeruli was unchanged in the patients who received the combination but increased from 3.1 +/- 4.8 to 14.6 +/- 15.2% in the prednisolone group (P = 0.0003). The frequency of adverse effects was similar in the two groups. It is concluded that combination treatment may be better for severe IgAN than treatment with prednisolone alone. PMID- 17699254 TI - Relationship between clinical outcomes and vascular access type among hemodialysis patients with Staphylococcus aureus bacteremia. AB - The association between hemodialysis vascular access type, costs, and outcome of Staphylococcus aureus bacteremia (SAB) among patients with ESRD remains incompletely characterized. This study was undertaken to compare resource utilization, costs, and clinical outcomes among SAB-infected patients with ESRD by hemodialysis access type. Adjusted comparisons of costs and outcomes were based on multivariable linear regression and multivariable logistic regression models, respectively. A total of 143 hospitalized hemodialysis-dependent patients had SAB at Duke University Medical Center between July 1996 and August 2001. A total of 111 (77.6%) patients were hospitalized as a result of suspected bacteremia; 32 (22.4%) were hospitalized for other reasons. Of the 111 patients, 59.5% (n = 66) had catheters as their primary access type, 36% (n = 40) had arteriovenous (AV) grafts, and 4.5% (n = 5) had AV fistulas. Patients with fistulas were excluded from analyses because of small numbers. Patients with catheters were more likely to be white, had shorter dialysis vintage, and had higher Acute Physiology and Chronic Health Evaluation II scores compared with patients with grafts. Unadjusted 12-wk mortality did not significantly differ between patients with catheters compared with patients with grafts (22.7 versus 10.0%; P = 0.098); neither did 12-wk costs differ by access type ($22,944 +/- 18,278 versus $23,969 +/- 13,731, catheter versus graft; P > 0.05). In adjusted analyses, there was no difference in 12-wk mortality (odds ratio 1.63; 95% confidence interval 0.29 to 9.02; catheter versus graft) or 12-wk costs (means ratio 0.84; 95% confidence interval 0.60 to 1.17; catheter versus graft) among SAB-infected patients with ESRD on the basis of hemodialysis access type. Twelve week mortality and costs that are associated with an episode of SAB are high in hemodialysis patients, regardless of vascular access type. Efforts should focus on the prevention of SAB in this high-risk group. PMID- 17699255 TI - Overproduction and secretion of a novel amino-terminal form of parathyroid hormone from a severe type of parathyroid hyperplasia in uremia. AB - Measurement of bioactive parathyroid hormone (PTH) is essential for optimal management of bone abnormalities in dialysis patients. This can be accomplished by PTH measurements using third-generation PTH assays, which detect more or less of the first six amino acids of the PTH structure. Such assays do not detect non (1-84) PTH fragments, such as human PTH (7-84), which are recognized by the second-generation PTH assays that use a detection antibody that recognizes an epitope within the 13-34 region of the PTH structure. Therefore, third-generation PTH results are expected to be lower than those that are obtained with second generation PTH assays. Rare exceptions to this rule have been reported for patients with severe primary hyperparathyroidism or parathyroid cancer. Sera and gland extracts were analyzed from a dialysis patient with high bone turnover disease and with surprising higher PTH levels by a third-generation assay than by a second-generation assay. This finding normalized after the surgical removal of an enlarged gland with a single nodule, an advanced type of nodular hyperplasia. HPLC fractionation of sera and gland extracts revealed the overproduction and secretion of a PTH molecule with an intact amino-terminus structure distinct from (1-84) PTH. This form of PTH was readily detectable by third-generation PTH assays but was poorly reactive in second-generation PTH assays. Therefore, parathyroid glands with advanced uremic nodular hyperplasia may overproduce and secrete a novel, biologically active form of PTH with an intact 1-6 region but a presumably modified 12-18 region required for the detection in second-generation PTH assays. PMID- 17699256 TI - Which renal transplant candidates should accept marginal kidneys in exchange for a shorter waiting time on dialysis? AB - Renal transplantation has been established as a life-saving procedure for patients with ESRD. Deceased donor kidneys convey variable life expectancies for recipients. However, limited information is available to guide patients and patient advocates concerning the appropriateness to list for expanded criteria donations (ECD). Half-lives for wait-listed transplant candidates were estimated from the time of ESRD onset on the basis of recipient age, primary diagnosis, and organ quality using survival models. In addition, we evaluated the likelihood of candidates' receiving a transplant on the basis of age and other characteristics by duration of waiting time. Older patients (65+) had longer life expectancy when they accepted an ECD within 2 yr of ESRD onset (5.6 yr) compared with waiting for a standard kidney (5.3 yr) or a living donation (5.5 yr) after 4 yr of dialysis. Conversely, younger recipients (18 to 39 yr) had longer life expectancy with a living donation (27.6 yr) or standard kidney (26.4 yr) after 4 yr on dialysis compared with an ECD after 2 yr of dialysis (17.6 yr). Increased candidate age was associated with the likelihood of not receiving a transplant during the period on the waiting list as a result of mortality and separately related to morbidity and delisting. Older and frailer transplant candidates benefit from accepting lower quality organs early after ESRD, whereas younger and healthier patients benefit from receiving higher quality organs even with longer dialysis exposure. These findings are important for transplant candidates and advocates decision-making and for potential further implementation in allocation policy. PMID- 17699257 TI - Immunophenotypic analysis of cellular infiltrate of renal allograft biopsies in patients with acute rejection after induction with alemtuzumab (Campath-1H). AB - Alemtuzumab is a humanized anti-CD52 mAb that has emerged as a safe and effective lymphocyte-depleting agent for induction therapy in renal transplantation. Recent reports have suggested that acute cellular rejection (ACR) of renal allografts in patients who receive alemtuzumab induction may be mediated by an atypical population of monocytes and not through "classical" T cell-dependent pathways of allorecognition. However, more recently, T cells with memory phenotype have been described in renal biopsies that were taken from alemtuzumab-treated patients who were experiencing ACR. This study investigated the cellular basis of ACR after alemtuzumab induction as compared with ACR that was associated with nondepleting therapy. Twelve biopsies from patients who were treated with a single dose of alemtuzumab at the time of transplantation and subsequently developed ACR were stained for the following cell markers: CD3 (T cells), CD68 (monocytes), CD20 (B cells), and CD45RO and CD45RA (memory and naive T cells). ACR biopsies from six patients who received no induction therapy were used as controls. In alemtuzumab treated patients, ACR occurred despite profound lymphopenia. A consistent number of CD3+ T cells was found in all ACR biopsies, and the majority of infiltrating CD3+ T cells displayed a memory phenotype (CD45RO+, CD45RA-). The number of infiltrating CD3+ T cells and B cells (CD20+) was similar in the two groups of patients, whereas a higher number of monocytes (CD68+) were found in the alemtuzumab than in the control group. Despite profound peripheral T cell depletion by alemtuzumab, ACR occurs and is associated with T and B cell and monocyte infiltration of the kidney. Specifically, T cells express on their surface the memory phenotype, suggesting that memory T cells may have eluded the depleting agent. PMID- 17699258 TI - Basiliximab combined with low-dose rabbit anti-human thymocyte globulin: a possible further step toward effective and minimally toxic T cell-targeted therapy in kidney transplantation. AB - In high-risk kidney transplant recipients, induction therapy with rabbit anti human thymocyte globulin (RATG) reduces the risk for acute rejection but is associated with significant toxicity, opportunistic infections, and cancer. Using reduced doses of RATG combined with anti-IL-2 antibodies may achieve the same antirejection activity of standard-dose RATG but with a better safety profile. This randomized, open-label study compared the efficacy, tolerability, and costs of low-dose RATG (0.5 mg/kg per d) plus basiliximab (20 mg 4 d apart) versus standard-dose RATG (2 mg/kg per d) in 33 consecutive high-risk renal transplant recipients (living-related transplant recipients, sensitized patients or patients who received another transplant, and patients with delayed graft function) over 6 mo of follow-up. All patients received concomitant therapy with steroids, cyclosporin A, and azathioprine or mycophenolate mofetil. Seventeen patients received low-dose RATG plus basiliximab, and 16 received standard-dose RATG. Patient (100 versus 100%) and graft (94 versus 100%) survival were comparable in the two groups, but the incidence of fever (17.6 versus 56.5%; P = 0.01), leukopenia (23.5 versus 56.3%; P < 0.05), anemia (29.4 versus 62.5%; P < 0.05), cytomegalovirus reactivations (17.6 versus 56.5%; P = 0.01), the number of transfused units (0.5 +/- 0.9 versus 2.0 +/- 2.4; P < 0.001), and treatment costs (3652 +/- 704 versus 5400 +/- 1960 euro; P = 0.001) were lower with low-dose RATG plus basiliximab than with standard-dose RATG. There was one episode of biopsy proven acute rejection on low-dose RATG plus basiliximab, and there were two on standard-dose RATG. In renal transplantation, induction therapy with basiliximab plus low-dose RATG effectively prevents acute rejection and is safer and more cost-effective than induction with standard-dose RATG. PMID- 17699259 TI - Coronary artery and other vascular calcifications in patients with cystinosis after kidney transplantation. AB - Cystinosis, an autosomal recessive disorder of lysosomal cystine accumulation, results from mutations in the CTNS gene that encodes the lysosomal cystine transporter, cystinosin. Renal tubular Fanconi syndrome occurs in infancy, followed by rickets, growth retardation, photophobia, and renal failure, which requires renal transplantation at approximately 10 yr of age. Treatment with cysteamine decreases cellular cystine levels, retards renal deterioration, and allows for normal growth. Patients with a history of inadequate cystine depletion therapy may survive, after renal transplantation, into the third to fifth decades but will experience other, extrarenal complications of the disease. Routine chest and head computed tomography scans of 41 posttransplantation patients with cystinosis were reviewed for vascular calcification. The radiologic procedures had been performed to examine lung and brain parenchyma, so there was little ascertainment bias. Thirteen of the 41 patients had vascular calcification, including 11 with coronary artery calcification. One 25-yr-old man required three vessel coronary artery bypass graft surgery. There were no significant differences between the 13 patients with calcification and the 28 without calcification in the following parameters: Time on dialysis, frequency of transplantation, hypertension, hypercholesterolemia, homozygosity for the 57-kb deletion in CTNS, serum creatinine, and calcium-phosphate product. However, the finding of vascular calcification correlated directly with duration of life without cysteamine therapy and inversely with duration of life under good cystine depleting therapy. The accumulation of intracellular cystine itself maybe a risk factor for vascular calcifications, and older patients with cystinosis should be screened for this complication. PMID- 17699260 TI - Role of maintenance immunosuppressive regimen in kidney transplant outcome. AB - Data of long-term immunosuppressive protocol comparison are lacking. The goal of this study was to compare kidney transplant outcome using three common immunosuppressive protocols. A retrospective study was performed of the graft and recipient survival using US Renal Data System data (n = 31,012) between January 1, 1995, and December 31, 1999, with the follow-up through December 31, 2000, on prednisone + cyclosporine + mycophenolate mofetil (PCM; n = 17,108), prednisone + tacrolimus + mycophenolate mofetil (PTM; n = 7225), or prednisone + cyclosporine + azathioprine (PCA; n = 6679). Compared with PCM, there is an increased risk for allograft failure associated with PTM (hazard ratio [HR] 1.09; P < 0.05) and PCA (HR 1.15; P < 0.001). Similar associations were demonstrated in the following subgroups: Early (before 1997) and late (in or after 1997) transplant periods, in living-donor transplants, and in adult and kidney-only recipients. This association also was found between PCA regimen and graft survival in the entire patient population (HR 1.15; P < 0.001) and in the studied subgroups. PCA (HR 1.15; P < 0.005), but not PTM (HR 1.01; P = 0.816), regimen was associated with increased recipient mortality in the entire patient population and in patient subgroups. Secondary outcomes (serum creatinine values at given time points, acute rejection rate, and posttransplantation malignancies) are also discussed. These data suggest that a PCM regimen is associated with lower risk for graft failure compared with a PTM regimen and with lower risk for graft failure and recipient death compared with a PCA regimen. PMID- 17699261 TI - Hypoadiponectinemia is associated with insulin resistance and glucose intolerance after renal transplantation: impact of immunosuppressive and antihypertensive drug therapy. AB - The objectives of this analysis were (1) to assess whether low serum adiponectin concentrations are associated with insulin resistance, metabolic syndrome, and new-onset posttransplantation diabetes mellitus (PTDM) and (2) to examine the possible effects of immunosuppressive and antihypertensive therapies on circulating adiponectin levels after renal transplantation. A total of 172 consecutive previously nondiabetic renal transplant recipients were examined 3 mo after transplantation, the majority (n = 167) with an oral glucose tolerance test. Serum adiponectin was measured by an in-house time-resolved immunofluorometric assay. Insulin secretion and insulin sensitivity were estimated by previously validated oral glucose tolerance test-derived indexes. One- and 6-yr follow-up data were available in subgroups of patients. Lower adiponectin levels were significantly associated with insulin resistance but not with insulinopenia. Patients with low adiponectin levels (first quartile) had significantly higher odds of PTDM (odds ratio [OR] 3.6; 95% confidence interval [CI] 1.1 to 12.7; P = 0.049) and metabolic syndrome (OR 3.9; 95% CI 1.6 to 9.5; P = 0.003) than patients in the upper (fourth) quartile. The increased risk for PTDM in patients with low adiponectin levels remained significant after adjustment for age, steroid dose, and family history of diabetes. Treatment with beta blockers was independently associated with lower serum adiponectin levels, and total steroid dose was associated with higher serum adiponectin levels. Low baseline adiponectin levels were also associated with significantly higher odds of PTDM at 6 yr (OR 6.9; 95% CI = 1.1 to 41.8; P = 0.037). Serum adiponectin levels correlate with posttransplantation insulin sensitivity and glucose tolerance. Glucocorticoids and beta blockers seem to have opposite effects on circulating adiponectin levels. PMID- 17699262 TI - Comparison of C4d immunostaining methods in renal allograft biopsies. AB - Immunostaining of renal allograft biopsies for C4d deposition has become an important diagnostic tool in the recognition of humoral-mediated graft rejection. The majority of studies have been performed on frozen tissue sections with one of several commercially available antibody reagents. However, only a single small series that compared reagents or methods, including staining of formalin-fixed, paraffin-embedded tissue, has been published. Two different staining methods in 138 renal allograft biopsies were compared directly: A mAb (Quidel, San Diego, CA) on frozen tissue sections with indirect immunofluorescence (IF) and a polyclonal antibody (Biomedica Gruppe, distributed by ALPCO, Windham, NH) applied to formalin-fixed, paraffin-embedded tissue with immunohistochemical (IHC) detection. An initial data set of 107 consecutive cases showed complete agreement between staining methods in 104 (97%) cases. Overall, nine of 107 cases were positive with one or both methods, representing 8.4% of all allograft biopsies tested, 15% of clinically indicated biopsies, and 24% of biopsies with a histologic diagnosis of acute cellular rejection. A second set of 31 cases included 17 cases that were positive by either method, with concordance in 29 of 31 cases. Combining the two data sets, the overall specificity of the IHC method compared with IF was 98%, and sensitivity was 87.5%. Direct comparison demonstrates that IHC staining of formalin-fixed, paraffin-embedded tissue with anti-C4d polyclonal antibody has acceptable sensitivity and specificity, as compared with IF staining of frozen tissue with the Quidel mAb. PMID- 17699263 TI - The nephrology quiz and questionnaire: 2005. PMID- 17699264 TI - Is mycophenolate mofetil a new treatment option in acute interstitial nephritis? PMID- 17699265 TI - More work to do on renin-angiotensin system blockade. PMID- 17699266 TI - Use of recommended medications after myocardial infarction--is kidney function really the problem? PMID- 17699267 TI - Spectrum of renal diseases associated with extreme forms of insulin resistance. AB - Diabetic nephropathy is the leading cause of ESRD in the United States. Why the pathogenic mechanisms lead to nephropathy in certain patients with type 1 and 2 diabetes and spare others is unclear, but it is clear that hyperglycemia and glomerular hyperfiltration are important factors. In patients with syndromes of extreme insulin resistance, proteinuric forms of renal disease are common, but it is surprising to find that the renal pathology usually is not diabetic nephropathy. For instance, in the lipodystrophy syndromes, membranoproliferative glomerulonephritis type 1 and type 2, focal segmental glomerulosclerosis, and also diabetic nephropathy are seen. In the syndromes of autoantibodies to the insulin receptor, the various forms of lupus glomerulonephritis are seen. Even in patients with type 2 diabetes, the renal pathology may not be diabetic nephropathy. Therefore, in patients with syndromic forms of insulin resistance and type 2 diabetes, renal biopsy has an important role in defining the pathology that leads to proteinuric nephropathy and in formulating a therapeutic approach. It is the purpose of this article to review these unusual aspects of proteinuric nephropathy in patients with diabetes. PMID- 17699268 TI - Medical care of kidney transplant recipients after the first posttransplant year. AB - Kidney transplantation is the treatment of choice for patients with ESRD. Despite improvements in short-term patient and graft outcomes, there has been no major improvement in long-term outcomes. The use of kidney allografts from expanded criteria donors, polyoma virus nephropathy, underimmunosuppression, and incomplete functional recovery after rejection episodes may play a role in the lack of improvement in long-term outcomes. Other factors, including cardiovascular disease, infections, and malignancies, also shorten patient survival and therefore reduce the functional life of an allograft. There is a need for interventions that improve long-term outcomes in kidney transplant recipients. These patients are a unique subset of patients with chronic kidney disease. Therefore, interventions need to address disease progression, comorbid conditions, and patient mortality through a multifaceted approach. The Kidney Disease Outcomes Quality Initiative from the National Kidney Foundation, the European Best Practice Guidelines, and the forthcoming Kidney Disease: Improving Global Outcomes clinical practice guidelines can serve as a cornerstone of this approach. The unique aspects of chronic kidney disease in the transplant recipient require the integration of specific transplant-oriented problems into this care schema and a concrete partnership among transplant centers, community nephrologists, and primary care physicians. This article reviews the contemporary aspects of care for these patients. PMID- 17699269 TI - Milk alkali syndrome and the dynamics of calcium homeostasis. PMID- 17699270 TI - Chronic nephropathies of cocaine and heroin abuse: a critical review. AB - Renal disease in cocaine and heroin users is associated with the nephrotic syndrome, acute glomerulonephritis, amyloidosis, interstitial nephritis, and rhabdomyolysis. The pathophysiologic basis of cocaine-related renal injury involves renal hemodynamic changes, glomerular matrix synthesis and degradation, and oxidative stress and induction of renal atherogenesis. Heroin is the most commonly abused opiate in the United States. Previous studies identified a spectrum of renal diseases in heroin users. The predominant renal lesion in black heroin users is focal segmental glomerulosclerosis and in white heroin users is membranoproliferative glomerulonephritis. Although the prevalence of heroin use in the United States has increased, the incidence of "heroin nephropathy" has declined. Because reports of heroin nephropathy predated the surveillance of hepatitis C virus and HIV, the varied findings might be related to the spectrum of viral illnesses that are encountered in injection drug users. Socioeconomic conditions, cultural and behavioral practices, or differences in genetic susceptibilities may be more associated with the development of nephropathy in heroin users than the drug's pharmacologic properties. Administration of cocaine in animal models results in nonspecific glomerular, interstitial, and tubular cell lesions, but there is no animal model of heroin-associated renal disease. The heterogeneity of responses that are associated with heroin is not consistent with a single or simple notion of nephropathogenesis. There are no well-designed, prospective, epidemiologic studies to assess the incidence and the prevalence of renal disease in populations of opiate users and to establish the validity of a syndrome such as heroin nephropathy. It is concluded although there is a paucity of evidence to support a heroin-associated nephropathy, the evidence from in vitro cellular and animal studies to support the existence of cocaine-induced renal changes is more convincing. PMID- 17699271 TI - Aldosterone antagonism in chronic kidney disease. PMID- 17699272 TI - Do we know the correct hemoglobin target for anemic patients with chronic kidney disease? AB - The major objectives of this article are to review hemoglobin outcome studies, focusing on the utility of purely observational approaches; the design limitations of hemoglobin target randomized trials; what is known from the trials that have been performed to date; and whether confident recommendations for target ranges can be made. The commonly observed association among lower hemoglobin levels, left ventricular hypertrophy, and higher mortality also has been seen within randomized trials when assigned hemoglobin targets were ignored; critically, however, corresponding relationships were absent when intention-to treat principles were used, strongly suggesting noncausal associations and the need for randomized designs. This being said, hemoglobin typical target trials often have undesirable features, including inadequate blinding and the use of imbalanced, nonstandardized, nonblinded co-interventions. The trials published to date, spanning hemoglobin levels of approximately 7 to 13 g/dl, suggest that higher treatment targets enhance quality of life but at the price of higher BP, thrombotic events, and reduced dialysis adequacy in hemodialysis patients. To date, there is no convincing evidence that targets that approach the physiologic range (versus intermediate targets) have an effect on left ventricular size or survival. Therefore, depending on the outcome examined, higher hemoglobin levels may have beneficial effects, harmful effects, or no effect, leading to the unsatisfactory situation of having to make opinion-based tradeoff decisions. Whereas the available evidence suggests that 11 g/dl is a reasonable lower bound for the hemoglobin target range, the upper bound remains to be defined and targets above 13 g/dl cannot be routinely recommended. PMID- 17699273 TI - Nephrotic syndrome after hematopoietic cell transplantation: do glomerular lesions represent renal graft-versus-host disease? AB - Glomerular disease associated with nephrotic syndrome has rarely been recognized as a distinct complication of allogeneic hematopoietic cell transplantation. Case reports in the English and Japanese literature since 1988 have described variable glomerular histology, comprising mainly membranous glomerulonephritis (MGN) in almost two thirds and minimal change disease (MCD) in nearly one quarter of patients. Review of the literature reveals a close temporal relationship between the development of nephrotic syndrome shortly after cessation of immunosuppression and the diagnosis of chronic graft-versus-host disease (GVHD). An association of glomerular disease with simultaneous GVHD was seen in 47% of patients overall. Nephrotic syndrome followed GVHD within 5 months in 60% of the combined MCD and MGN reports. A decrease in immunosuppressive medication use was linked to nephrotic syndrome occurrence within 9 months in 63% of patients with MCD and MGN. MCD occurred earlier after hematopoietic cell transplantation, was diagnosed sooner after medication change, and exhibited a better prognosis in comparison with MGN. Glomerular lesions after hematopoietic cell transplantation may therefore represent the renal manifestation of GVHD. Further studies are warranted to delineate the pathogenesis of this complication. PMID- 17699274 TI - Phosphate binders: hold the calcium? PMID- 17699275 TI - The case against calcium-based phosphate binders. AB - Disturbances of mineral metabolism are associated with significant morbidity and mortality in patients with chronic kidney disease. Unfortunately, some of the treatments for these disturbances also have been found to be associated with morbidity. More recently, there is increasing evidence in the form of prospective, randomized trials that the use of calcium-based phosphate binders contributes to progressive coronary artery and aorta calcification compared with the non-calcium-containing binder sevelamer. Moreover, there is compelling biologic plausibility that hyperphosphatemia and excess exogenous calcium administration can accelerate vascular calcification. Unfortunately, there is no bedside test that can determine whether there is a dose of calcium salts (either as maintenance or as cumulative dose) that can be administered safely, and, unfortunately, the serum calcium concentration does not reflect calcium balance. Therefore, calcium-based phosphate binders should be avoided in many, if not most, patients who are undergoing dialysis. PMID- 17699276 TI - Calcium-based phosphate binders are appropriate in chronic renal failure. AB - Many nephrologists feel threatened by the allegation that, in patients with chronic renal failure, treatment with calcium-based phosphate binders (calcium acetate and calcium carbonate) may induce coronary artery and cardiac calcification, thereby imposing a greater risk for death compared with sevelamer, a non-calcium-based binder. Acknowledging that drug manufacturers are not unaware of the marketing advantage to their product consequent to destabilizing demand for competing drugs, the case for and against abandoning calcium-based phosphate binders in favor of sevelamer is reviewed in this study. The case for continuing prescription of calcium-based phosphate binders stands on the following: (1) flawed clinical trials that favor sevelamer as a replacement; (2) weak evidence that oral calcium intake modulates vascular and/or cardiac calcification; (3) clinical trials that reinforce the safety and efficacy of calcium-based phosphate binders; and (4) the inordinate relative cost of sevelamer. Recognizing that established as well as novel phosphate binders are currently undergoing clinical evaluation, an open mind and an awareness of developing literature are necessary when deciding how to manage hyperphosphatemia in renal failure. PMID- 17699277 TI - Incident renal events and risk factors in autosomal dominant polycystic kidney disease: a population and family-based cohort followed for 22 years. AB - For determination of the incidence of renal events in autosomal dominant polycystic kidney disease (ADPKD) all patients who had ADPKD and attended nephrology/urology clinics in Newfoundland in 1981 were identified, and members of 18 families who were at 50% risk for inheriting ADPKD were followed prospectively for 22 yr, including research clinics at 6-yr intervals. Time to hypertension treatment, stage 3 chronic kidney disease (CKD), ESRD, and death was measured, and the impact of genotype, gender, gender of parent who transmitted PKD, family, family history of essential hypertension, parity, and oral contraceptive pill was assessed. Nine (50%) families had PKD1, four (22%) had PKD2, and one had both PKD1 and PKD2. The number of family members with PKD1 was 136 and with PKD2 was 60. In PKD1 median age to hypertension treatment was 46 yr, to CKD stage 3 was 50 yr, to ESRD was 53 yr, and to death was 67 yr. In PKD2, median age to hypertension treatment was 51 yr, to CKD stage 3 was 66 yr, to death was 71 yr, and ESRD was infrequent. Although the incidence of CKD was later and ESRD occurred infrequently in PKD2 compared with PKD1, early onset of hypertension occurred and life expectancy was compromised. Genotype, family, and proteinuria were identified as risk factors for incident renal events. Gender, gender of parent who transmitted PKD, family history of essential hypertension, multiparity, and use of the oral contraceptive pill were not identified as risk factors for renal events in ADPKD. PMID- 17699278 TI - Mycophenolate mofetil for the treatment of interstitial nephritis. AB - Acute interstitial nephritis (AIN) is a clinicopathologic entity that is characterized by acute renal failure and renal biopsy findings of interstitial inflammation and tubulitis. There are multiple causes of AIN, the majority of which appear to respond to immunosuppressive therapy. Corticosteroids are the mainstay of treatment for AIN, but many patients are refractory to or intolerant of treatment or are unable to discontinue therapy without clinical relapse. Herein are reported eight cases of steroid-resistant, biopsy-proven AIN that were treated successfully with mycophenolate mofetil (MMF) at one institution. Patients had a mean decline in serum creatinine from 2.3 to 1.6 mg/dl over a mean of 24.3 mo of treatment. Six of the eight patients had a decline in serum creatinine of at least 0.3 mg/dl, and the remaining two patients had stable renal function during the treatment period. At most recent follow-up, five of the eight patients successfully have discontinued treatment with MMF for a mean of 6.4 mo. MMF was well tolerated by all patients. It is concluded that MMF is a useful therapeutic option for steroid-resistant AIN and may be considered as potential first-line therapy in select populations. PMID- 17699279 TI - Segmental membranous glomerulonephritis in children: comparison with global membranous glomerulonephritis. AB - Generally, idiopathic membranous glomerulonephritis (MGN) is a global glomerular disease that affects the whole of the glomerulus. However, idiopathic segmental MGN (SMGN) that shows IgG deposits in a portion of the glomerulus is encountered often. For clarification of whether SMGN is the same entity as idiopathic global MGN (GMGN), the two diseases were compared. From 1978 to 2004, 38 children (11 with SMGN and 27 with GMGN) received a diagnosis of idiopathic MGN. Immunofluorescence microscopy showed segmental granular IgG staining along the capillary loops in SMGN, whereas GMGN showed global staining. On light microscopy, SMGN showed segmental thickening of the glomerular basement membrane, with spike formation, whereas GMGN showed global lesions. The frequency of C1q deposits in SMGN was significantly higher than that in GMGN (91 versus 41%; P < 0.01). On electron microscopy, mesangial electron-dense deposits were detected in 10 (91%) cases of SMGN and also were found in the subepithelial and intramembranous area, whereas only six (22%) cases of GMGN had mesangial electron dense deposits (P < 0.001). There were no significant differences in clinical features between the groups. Two children with SMGN underwent a repeat biopsy 3 yr after the first biopsy, and both patients again showed SMGN. At the final observation (mean observation time 7.5 yr in SMGN and 12.4 yr in GMGN), all children of both groups had a good outcome. In conclusion, these findings as a whole suggest that SMGN may be another glomerular disease entity with child predominance that is distinctive from GMGN. PMID- 17699280 TI - Add-on angiotensin receptor blocker in patients who have proteinuric chronic kidney diseases and are treated with angiotensin-converting enzyme inhibitors. AB - The benefit of the add-on angiotensin II receptor blocker candesartan to angiotensin-converting enzyme (ACE) inhibitors in inhibition of progression of nephropathy in hypertensive patient with nondiabetic renal disease compared with monotherapy with ACE inhibitors remains controversial. All patients were previously treated with ACE inhibitors. Urinary protein excretion of patients exceeded 1.0 g/d despite treatment with ACE inhibitors. Ninety hypertensive patients with chronic renal insufficiency were randomly assigned to one of two groups. One group received ACE inhibitor plus candesartan (2 to 12 mg/d), and a control group received only ACE inhibitor. The target BP was < or = 130/80 mmHg. The primary outcome was the changes in serum creatinine and the reduction of proteinuria. The mean duration of follow-up was 3.1 +/- 0.4 yr. At years 2 and 3, systolic and diastolic BP were reduced from 140 +/- 3/84 +/- 2 to 129 +/- 1/78 +/ 2 mmHg (candesartan group) and from 135 +/- 2/85 +/- 2 to 130 +/- 2/80 +/- 2 mmHg (ACE inhibitors group). In both groups, both systolic and diastolic BP decreased significantly from the beginning to the end of the study (P < 0.01). The serum creatinine concentration increased from 3.02 +/- 0.27 to 3.38 +/- 0.49 mg/dl (candesartan plus ACE inhibitor group) versus 3.00 +/- 0.37 to 4.48 +/- 0.57 mg/dl (ACE inhibitor group; P < 0.01) at year 3. Although the level of proteinuria significantly declined in each group (P < 0.05), the degree of reductions in proteinuria was greater in the candesartan group than in the ACE inhibitors group (P < 0.01). In the patients who were treated with candesartan and ACE inhibitor or ACE inhibitor alone, pretreatment proteinuria correlated significantly with decline of renal function, whereas reduction of proteinuria negatively correlated with decline in renal function in the patients who were treated with candesartan. Candesartan with an ACE inhibitor is effective in slowing the progression of renal insufficiency in hypertensive patients with nondiabetic renal disease through reduction of proteinuria. PMID- 17699281 TI - Rituximab for idiopathic membranous nephropathy: who can benefit? AB - Rituximab effectively reduces proteinuria in patients with idiopathic membranous nephropathy (IMN), but response to treatment may vary from patient to patient. The association between baseline clinical, laboratory, and histology covariates and proteinuria reduction was evaluated retrospectively by multiple linear regression analysis at 3 mo after rituximab therapy in 14 patients with IMN with proteinuria > 3.5 g/24 h while on angiotensin-converting enzyme inhibition for at least 6 mo and no previous remissions. The association strength was expressed by standardized beta coefficients (SbetaC). Glomerular (SbetaC = 0.48, P = 0.049) and tubulointerstitial (TI) scores (SbetaC = 0.61, P = 0.003) predicted the outcome. Among glomerular and TI score components, tubular atrophy (SbetaC = 0.59, P = 0.003) and interstitial fibrosis (SbetaC = 0.60, P = 0.001) were significantly associated with 3-mo proteinuria. Urinary protein excretion decreased from 9.1 +/- 4.0 to 4.6 +/- 3.5 g/24 h (P < 0.001) in eight patients with TI score 1.7 but did not change in six with a score > or = 1.7. Nine additional patients with IMN then were allocated prospectively to rituximab treatment on the basis of a TI score < 1.7. Three-month proteinuria decreased in all patients from 8.9 +/- 5.3 to 4.9 +/- 3.9 g/24 h (P < 0.001) and serum albumin increased from 2.2 +/- 0.6 to 2.8 +/- 0.5 mg/dl (P < 0.01). Changes in serum albumin and cholesterol were inversely correlated (P < 0.02, r = -0.44). Rituximab achieved CD20 and CD19 depletion in all patients. In patients with IMN and nephrotic proteinuria despite angiotensin-converting enzyme inhibition therapy, renal biopsy findings may help in predicting response to rituximab and defining selection criteria for randomized trials that aim to assess the risk/benefit profile of B cell target therapy as compared with aspecific immunosuppressants and/or conservative therapy alone. PMID- 17699282 TI - Handcarried ultrasound measurement of the inferior vena cava for assessment of intravascular volume status in the outpatient hemodialysis clinic. AB - Accurate intravascular volume assessment is critical in the treatment of patients who receive chronic hemodialysis (HD) therapy. Clinically assessed dry weight is a poor surrogate of intravascular volume; however, ultrasound assessment of the inferior vena cava (IVC) is an effective tool for volume management. This study sought to determine the feasibility of using operators with limited ultrasound experience to assess IVC dimensions using hand-carried ultrasounds (HCU) in the outpatient clinical setting. The IVC was assessed in 89 consecutive patients at two outpatient clinics before and after HD. Intradialytic IVC was recorded during episodes of hypotension, chest pain, or cramping. High-quality IVC images were obtained in 79 of 89 patients. Despite that 89% of patients presented at or above dry weight, 39% of these patients were hypovolemic by HCU. Of the 75% of patients who left HD at or below goal weight, 10% were still hypervolemic by HCU standards. Hypovolemic patients had more episodes of chest pain and cramping (33 versus 14%, P = 0.06) and more episodes of hypotension (22 versus 3%, P = 0.02). The clinic with a higher prevalence of predialysis hypovolemia had significantly more intradialytic adverse events (58 versus 27%; P = 0.01). HCU measurement of the IVC is a feasible option for rapid assessment of intravascular volume status in an outpatient dialysis setting by operators with limited formal training in echocardiography. There is a poor relationship between dry weight goals and IVC collapsibility. Practice variation in the maintenance of volume status is correlated with significant differences in intradialysis adverse events. PMID- 17699283 TI - Computed tomography evaluation of autosomal dominant polycystic kidney disease progression: a progress report. AB - At the moment, there are no effective therapies to prevent or slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Radiologic evaluations are used to monitor volume of renal cysts and parenchyma during disease evolution. Volumetric quantifications based on computed tomography were used to investigate the relation between structural and functional changes in patients with advanced-stage ADPKD. By use of image-processing techniques, volume of kidneys, renal cysts, fully enhanced parenchyma, and faintly contrast-enhanced parenchyma, referred to as intermediate, was estimated. GFR measurements and computed tomography evaluations were repeated 6 mo later. No statistically significant correlations were found between volumes of cysts and parenchyma and intermediate volume and GFR. However, the ratio of intermediate over parenchymal volume strongly correlated with GFR (r = -0.81, P < 0.001). In addition, there were significant correlations between percentage changes in intermediate volume (absolute or relative to parenchyma) and GFR changes during the observation period (r = -0.70 and r = -0.75, P < 0.01). These data support the hypothesis of a significant relation between radiologic appearance of renal structure and functional changes and suggest new ways that renal dysfunction in ADPKD may be predicted. Further work is necessary to determine the nature of faintly contrast enhanced parenchyma and its role in renal functional loss. PMID- 17699284 TI - Risk scores for predicting outcomes in patients with type 2 diabetes and nephropathy: the RENAAL study. AB - Diabetic nephropathy is the most important cause of ESRD. The aim of this study was to develop a risk score from risk predictors for ESRD, with and without death, in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study and to compare ability of the ESRD risk score and its components to predict ESRD. The risk score was developed from coefficients of independent risk factors from multivariate analysis of baseline variables and equals (1.96 x log [urinary albumin:creatinine ratio]) - (0.78 serum albumin [g/dl]) + (1.28 x serum creatinine [mg/dl]) - (0.11 x hemoglobin [g/dl]). It was robust with respect to severity of nephropathy, gender, race, and treatment group. The risk score for ESRD or death was comparable. The four risk predictors for progression of kidney disease were independent of therapy. For combined treatment groups, the hazard ratio between the fourth and first quartiles of the ESRD risk score was 49.0, as compared with the corresponding hazard ratios for each component: 14.7 for urinary albumin:creatinine ratio, 9.2 for serum creatinine, 5.5 for hemoglobin, and 10.2 for serum albumin. The RENAAL risk scores for ESRD with or without death emphasize the importance of identification of level of albuminuria, serum albumin, serum creatinine, and hemoglobin to predict development of ESRD in patients with type 2 diabetes and nephropathy. Although albuminuria is a strong risk factor for ESRD, the contribution of serum albumin, serum creatinine, and hemoglobin level further enhances prediction of ESRD. Future trials with a similar patient population and outcomes measures should consider adjusting analyses for baseline risk factors. PMID- 17699285 TI - Predictive value of dialysate cell counts in peritonitis complicating peritoneal dialysis. AB - Early prediction of outcomes has major potential implications regarding the management of dialysis-related peritonitis. The outcomes of 565 consecutive episodes of peritonitis complicating peritoneal dialysis between August 2001 and July 2005 were evaluated in relation to the dialysate cell counts. Discriminatory power, based on the area under the receiver-operating characteristic (ROC) curves, of the cell counts was assessed. The findings then were validated externally in a cohort of 217 peritonitis episodes from another dialysis unit. During the study period, 565 episodes of peritonitis were included for analysis, 465 of which had treatment success defined as complete resolution of peritonitis without the need for Tenckhoff catheter removal. Of the remaining 100 episodes (treatment failure), 70 required Tenckhoff catheter removal and 30 had peritonitis-related death. The peritoneal dialysate total white blood cell count on day 3 of peritonitis predicted treatment failure independent of standard risk factors, and it had a higher area under the ROC curve than the dialysate white cell count on day 1 (0.80 versus 0.58; P < 0.0001). Using a peritoneal dialysate white count cut point > or = 1090/mm3 on day 3, the sensitivity was 75% and the specificity was 74% for the prediction of treatment failure (defined as catheter loss or peritonitis-related death). In multiple logistic regression analyses, peritoneal dialysate white count > or = 1090/mm3 on day 3 was an independent prognostic marker for treatment failure after adjustment for conventional risk factors (hazard ratio 9.03; 95% confidence interval 4.40 to 18.6; P < 0.0001). Number of years on peritoneal dialysis; diabetes; gram-negative organisms; and Pseudomonas, fungal, or Mycobacterium species were other independent risk factors that were predictive of treatment failure. Findings from an independent validation set of peritonitis (217 episodes after exclusion of Mycobacterium and fungal causes) also favored the peritoneal dialysate white count on day 3, as compared with day 1 and day 2, to predict treatment failure. Area under the ROC curve for the white counts on day 3 was 0.98 (95% confidence interval 0.95 to 0.99) in the validation set. This study demonstrated and cross-validated the superiority of peritoneal dialysate white cell count on day 3 to predict outcomes of dialysis-related peritonitis. These results call attention to the value of validating prognostic factors of peritonitis complicating peritoneal dialysis. PMID- 17699286 TI - Mortality by dialysis modality among patients who have end-stage renal disease and are awaiting renal transplantation. AB - Comparing outcomes related to dialysis modality is complicated by selection bias introduced by patients and physicians. To address the impact of selection bias, this study compared mortality by initial dialysis modality among patients who had ESRD and were placed on the transplant waiting list. This study was a historical prospective cohort of 12,568 patients in the United States who initiated dialysis between May 1, 1995, and October 31, 1998, and were placed on the transplant waiting list before dialysis initiation. Two-year mortality was compared using Kaplan-Meier curves and Cox proportional hazards models that analyzed patients primarily using an intention-to-treat approach and separately censored patients on a modality switch. At 2 yr, the unadjusted mortality rate was 6.6% among peritoneal dialysis (PD) patients compared with 6.9% among hemodialysis (HD) patients (hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.82 to 1.23). After controlling for differences in baseline characteristics, comorbidities, and laboratory variables, the selection of PD versus HD remained associated with a similar 2-yr mortality risk (HR 1.03; 95% CI 0.83 to 1.28). In separate models, 2 yr mortality associated with PD versus HD was significant among patients with body mass index (BMI) > or = 26 kg/m2 (HR 1.37; 95% CI 1.01 to 1.83) but not among patients with BMI < 26 kg/m2 (HR 0.81; 95% CI 0.61 to 1.07). Results were similar after censoring on a modality switch. In conclusion, although choice of initial dialysis modality seems to be associated with equivalent outcomes among patients who have ESRD and are placed on the transplant waiting list, patients with BMI > or = 26 kg/m2 have increased 2-yr mortality associated with the selection of PD versus HD. Because the interpretation of observational data is highly affected by residual confounding and selection bias, further efforts should focus on the formation and testing of hypotheses to improve dialysis delivery. PMID- 17699287 TI - N-3 fatty acids as secondary prevention against cardiovascular events in patients who undergo chronic hemodialysis: a randomized, placebo-controlled intervention trial. AB - Patients who are treated with chronic hemodialysis (HD) experience premature cardiovascular disease and an increased mortality. N-3 polyunsaturated fatty acids (PUFA) may be effective in the secondary prevention of cardiovascular disease, but the effects of n-3 PUFA has not previously been examined in HD patients. It was hypothesized that secondary prevention with n-3 PUFA would reduce the number of cardiovascular events and death in patients who are treated with chronic HD. A randomized, double-blind, placebo-controlled intervention trial compared the effect of n-3 PUFA and a control treatment as secondary prevention of cardiovascular events in HD patients. The primary outcome was a composite of total cardiovascular events and death. A total of 206 patients were randomly assigned to treatment with n-3 PUFA or control treatment and followed for 2 yr or until reaching a predefined end point. During the trial, 121 (59%) of 206 patients reached a primary end point. N-3 PUFA had no significant effect on the primary composite end point of cardiovascular events and death (62 versus 59; NS). In the n-3 PUFA group, a significant reduction was seen in the number of myocardial infarctions (four versus 13; P = 0.036). This trial was limited by a relatively small number of patients and a large number of withdrawals. However, it is concluded that treatment with n-3 PUFA did not reduce the total number of cardiovascular events and death in this high-risk population. N-3 PUFA significantly reduced the number of myocardial infarctions as a secondary outcome, a finding that might be of clinical interest. PMID- 17699288 TI - Evaluation of GFR estimating equations in the general community: implications for screening. AB - The Kidney Disease Outcomes Quality Initiative has recommended the use of GFR estimating equations to detect silent chronic kidney disease (CKD) in the community. The benefit of general reporting of CKD must be balanced with the harm of mislabeling people who do not have CKD. The popular Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) GFR estimating equations were compared with the recently devised Rule equation in a representative community population sample (2166) divided into subsamples with (385) and without (1781) previous renal impairment. The prevalence of CKD was CG > MDRD >> Rule estimates. The magnitude of difference in prevalence of CKD as detected by the MDRD and CG versus the Rule equation increases markedly when the subsamples with (30.8 and 29.7 versus 17.5%) and without (12 and 11.3 versus 3.0%) previous kidney impairment are compared. General demographic and potential or known risk factors were used in a logistic regression model to assess the association with CKD. The MDRD estimates note female gender (odds ratio 2.19; 95% confidence interval 1.63 to 2.95) and both MDRD and the Rule equations identify hypertension and diabetes as significant CKD risk factors. All estimating equations identify age to be associated with CKD. The annualized serial decline in GFR was CG > MDRD > Rule estimates. Only the Rule GFR estimates detected a greater decline in renal impaired versus unimpaired populations. The calibrated Rule equation seems to perform better than CG and MDRD (CKD 3 versus 11.3 to 12%) but lacks validation against gold standards for community-based screening. PMID- 17699289 TI - Kidney function and use of recommended medications after myocardial infarction in elderly patients. AB - Several studies have found reduced use of recommended medications after myocardial infarction (MI) in patients with impaired kidney function. However, the reasons for such undertreatment are not well understood. A total of 1380 Medicare patients who survived at least 90 d after MI and had prescription drug coverage through Pennsylvania's medication assistance program for the elderly were studied. Filled prescriptions were used to assess use of angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), beta blockers, and statins within 90 d of MI. Patients' demographics, comorbidities, and health care utilization before MI also were ascertained. We used logistic regression to test the association between kidney function and postdischarge use of each medication. Overall, 619 (45%) patients filled a prescription for a beta blocker, 675 (49%) received an ACEI or ARB, and 406 (29%) received a statin after discharge but within 90 d after their admission for MI. Reduced kidney function was associated with both lower beta blocker and statin use (P = 0.01 and P = 0.002, respectively), but after multivariate adjustment, these associations disappeared (P = 0.23 and P = 0.62, respectively). Use of ACEI or ARB was nearly half in patients with estimated GFR <30 ml/min compared with patients with better kidney function in univariate and multivariate analyses (P < 0.001). Analyses using serum creatinine measurements rather than estimations of GFR yielded similar results. Differences in other characteristics such as age, rather than kidney function, may be responsible for much or all the reported reduction in use of preventive medications after MI seen in patients with chronic kidney disease. PMID- 17699290 TI - Sleep quality and its correlates in the first year of dialysis. AB - Although sleep problems are thought to be prevalent among patients who undergo dialysis, there is only limited information on the determinants of sleep quality and the change in sleep quality during the first year of dialysis treatment. This report uses data from a national cohort study of incident hemodialysis and peritoneal dialysis patients to identify the correlates of sleep quality and to determine the extent to which sleep quality is related to patients' health related quality of life and survival. This report includes 909 incident dialysis patients who responded to questions about sleep quality. Three quarters of incident dialysis patients reported impaired sleep, and 14% had a decline in sleep quality in the first year of treatment. Poor sleep quality was significantly related to black race, higher serum phosphate, current smoking, benzodiazepine prescription, and complaints of severe restless legs. Poor baseline sleep quality was associated with lower SF-36 physical and mental component summary scores, vitality scores, and bodily pain scores (all P < 0.001). Younger age, current smoking, and benzodiazepine prescription were associated with decreases in sleep quality at 1 yr. There was no association between baseline sleep quality and survival; however, a decline in sleep quality during the first year on dialysis was associated with shorter survival (hazard ratio 1.44; 95% confidence interval 1.13 to 1.83; P = 0.003). Future work should examine the link between sleep quality and daytime functioning in the kidney failure population and the extent to which improving sleep quality will improve dialysis patient outcomes. PMID- 17699291 TI - Clinical outcome of thrombotic microangiopathy after living-donor liver transplantation treated with plasma exchange therapy. AB - Thrombotic microangiopathy (TMA) is a well-documented but severe complication that occurs after solid-organ transplant. Administration of calcineurin inhibitors is considered a major cause of this fatal complication; prompt initiation of plasma exchange therapy after reduction or conversion of calcineurin inhibitors has been recommended. Nevertheless, little is known about clinical evidence of this strategy against TMA after solid-organ, especially non renal-organ, transplantation. Medical records of 63 patients who were hospitalized at Artificial Organ and Transplantation Division in Tokyo University Hospital and underwent blood purification therapy between January 1999 and May 2005 were reviewed. Twenty-eight living-donor liver transplantation (LDLT) recipients who received plasma exchange therapy were identified, and 18 of them were found retrospectively to receive a diagnosis of having TMA. Of the 18 patients, 10 (56%) responded to this therapy and survived after the treatment was stopped, whereas eight (44%) patients died before improvement. Subsequent follow up of patients clarified that 1-yr survival rate of post-LDLT TMA was approximately 30%. Multivariate Cox proportional-hazards regression analysis demonstrated that the interval between transplant surgery and onset of TMA (hazard ratio 1.35 per 30 d; 95% confidence interval 1.07 to 1.71; P = 0.021) and pretreatment blood urea nitrogen level (hazard ratio 1.39 per 10 mg/dl; 95% confidence interval 1.02 to 1.90; P = 0.037) predicted mortality. Analyses identified post-LDLT recipients with TMA as being at high risk for poor prognosis. Effective strategies are needed for late-onset TMA after LDLT to improve treatment response and survival. PMID- 17699292 TI - Appropriateness of antihypertensive drug therapy in hemodialysis patients. AB - The prevalence and treatment of hypertension in hemodialysis (HD) patients exceeds 85% in the United States. Because of uncertainties in the evaluation of BP, it is unclear whether the HD patients who are being treated with medications are truly hypertensive. For ascertainment of the appropriateness of antihypertensive therapy, a prospective study in which antihypertensive drugs were discontinued in HD patients and 44-h interdialytic ambulatory BP monitoring was performed and left ventricular mass and inferior vena cava were measured by echocardiography was conducted. Home BP was monitored weekly during washout. An average of 2.3 medications were tapered and discontinued in 41 black participants (age 56 yr, 46% men, 54% diabetes, duration of dialysis 5.3 yr). Thirty-three (80%) of 41 patients became hypertensive, but eight (20%) remained normotensive at 3 to 5 wk. Patients who remained normotensive had a higher body mass index (31 versus 25.7 kg/m2) and diabetes (78 versus 45%), were less likely to smoke (13 versus 52%), had lower home BP at baseline (135/76 versus 147/85 mmHg), and had a lower left ventricular mass index (115 versus 146 g/m2). The rate of rise of home BP was more rapid in patients who became hypertensive. None of the normotensive patients were volume overloaded in contrast to 12% of the hypertensive patients. It is concluded that a majority of the treated black hypertensive patients are appropriately receiving therapy for hypertension. Those who have well-controlled home BP and no left ventricular hypertrophy may have a cautious withdrawal of their antihypertensive drugs. PMID- 17699293 TI - Association of disorders in mineral metabolism with progression of chronic kidney disease. AB - Abnormalities of mineral metabolism are associated with increased mortality in patients with ESRD, but their effects in predialysis chronic kidney disease (CKD) are less well characterized. In this study, the associations between levels of serum phosphorus, calcium, and calcium-phosphorus product and progression of CKD were examined. Historical data were collected on 985 male US veterans (age 67.4 +/- 10.9; 23.9% black) with CKD stages 1 through 5. Unadjusted and multivariable adjusted relative risks for progressive CKD (defined as the composite of ESRD or doubling of serum creatinine) were calculated for categories of serum phosphorus, calcium, and calcium-phosphorus product using Cox proportional hazards models. Higher phosphorus was associated with a higher risk for the composite end point (adjusted hazard ratio [HR] [95% confidence interval (CI)] for phosphorus levels 3.3 to 3.8, 3.81 to 4.3, and >4.3 versus <3.3 mg/dl 0.83 [0.54 to 1.27], 1.24 [0.82 to 1.88], and 1.60 [1.06 to 2.41]; P = 0.001 for trend). A 1-mg/dl higher phosphorus level was associated with an adjusted HR (95% CI) of 1.29 (1.12 to 1.48; P < 0.001). Higher calcium-phosphorus product also was associated with higher risk for progressive CKD (adjusted HR [95% CI] for calcium-phosphorus products 30 to 35, 36 to 40, and >40 versus <30 mg2/dl2 0.58 [0.36 to 0.94], 0.87 [0.57 to 1.34], and 1.37 [0.91 to 2.07]; P = 0.002 for trend). A 10-mg2/dl2 higher calcium-phosphorus product was associated with an adjusted HR (95% CI) of 1.29 (1.11 to 1.51; P = 0.001). Lower serum calcium showed a trend toward higher risk for progressive CKD but without statistical significance. Higher serum phosphorus and higher calcium-phosphorus product are associated with progression of CKD. PMID- 17699294 TI - Increasing referral for renal transplant evaluation in recipients of nonrenal solid-organ transplants: a single-center experience. AB - The use of cyclosporine and tacrolimus therapy in nonrenal (heart, heart/lung, lung, and liver) transplantation has resulted in improved patient and graft survival. Nephrotoxicity is one of the major side effects of tacrolimus and cyclosporine therapy and may lead to ESRD. The trend of referral of nonrenal solid-organ transplant recipients for kidney transplant evaluation at a large multiorgan transplant center was examined. Records of all patients who were referred for renal transplantation at the University of Alabama between January 1, 1993, and June 30, 2004, were reviewed. Eighty (0.96%) of 8318 individuals had previously undergone a nonrenal solid-organ transplant and were included in the study. The majority (72%) of patients had their nonrenal transplants performed at the University of Alabama. Twenty-two patients had their nonrenal transplant performed elsewhere and had fewer data available for analysis. From the period 1993-1996 to 2001-2004, an 11-fold increase in the absolute number of referrals of patients with nonrenal transplants was noted. Of patients who were referred for transplant evaluation, 25 became recipients of kidney transplants with a predominance of living-donor transplants. Referral for kidney transplant evaluation among nonrenal solid-organ transplant recipients is increasing and will exacerbate the existing shortage of deceased-donor kidneys that are available for transplantation. There was a trend for liver transplant recipients compared with other solid-organ recipients to develop ESRD at a greater rate. PMID- 17699295 TI - Pretransplant physical functioning and kidney patients' risk for posttransplantation hospitalization/death: evidence from a national cohort. AB - Patient physical functioning level is an indicator of medical fitness that may predict outcomes after kidney transplantation. A small study of patients at a single center found a correlation between patient-rated physical functioning pretransplantation and the number of emergency hospital visits posttransplantation. In a national multicenter cohort, the association of incident dialysis patients' physical functioning scores with their risk for posttransplantation all-cause hospitalization/death was investigated using Cox proportional hazards analysis. The study cohort included patients who participated in the Dialysis Morbidity and Mortality Study (DMMS) Wave 2 and received a first transplant no more than 24 mo after treatment start. Updated patient information was available in the 2004 United States Renal Data System Standard Analysis Files. Higher pretransplantation physical functioning score was found to be a significant predictor of transplant recipients' reduced risk for hospitalization/death. Patients in the Cox model who were aged 55+ had increased risk for hospitalization/death. Gender, race, diabetic ESRD, and cardiovascular comorbidity were NS predictors. A potential explanation for the ability of the Medical Outcomes Study Short-Form 36 physical functioning measure to predict risk for posttransplantation morbidity/mortality is that physical activity/exercise behavior is likely to be closely associated with an individual's physical functioning level, and pretransplantation activity levels may be indicative of lifestyle habits that continue to influence patient behavior posttransplantation. More research investigating patients' pre- and posttransplantation physical functioning levels in relation to transplant outcomes would be valuable. PMID- 17699296 TI - Safety and adverse events profiles of intravenous gammaglobulin products used for immunomodulation: a single-center experience. AB - Intravenous Ig (IVIg) products are used in various medical conditions. Differences in excipients account for most adverse events (AE). Reports of complications including acute myocardial infarction (AMI) and acute renal failure (ARF) have emerged. Herein is described one institution's experience with IVIg related complications. This study is a retrospective analysis of infusion-related AE that are associated with various IVIg products. Infusion-related AE were monitored during and after the administration of three IVIg products: Gamimune-N 10% (n = 76), Polygam (n = 105), and Carimune (n = 98). AE segregated to specific IVIg products. No patients who received Gamimune-N experienced AMI or ARF. Five (4.7%) patients (P < 0.01) in the Polygam group experienced AMI. Eight (8.2%) patients (P < 0.0001) in the Carimune group developed ARF. IVIg was safe to give on hemodialysis. IVIg products differ in osmolality, pH, and sugar and sodium content; this results in specific AE. Polygam resulted in no ARF but an increase in AMI. Carimune products at 9% concentration resulted in an increase in ARF. Gamimune-N 10% and other IVIg products were frequently associated with headaches. Administration of IVIg to patients who are on hemodialysis seems to be safe and effective. PMID- 17699297 TI - Upregulation of renal inducible nitric oxide synthase during human endotoxemia and sepsis is associated with proximal tubule injury. AB - The incidence and the mortality of septic acute kidney injury are high, partly because the pathogenesis of sepsis-induced renal dysfunction is not clear. The objective of this study was to investigate the upregulation of renal inducible nitric oxide synthase (iNOS) in human endotoxemia and sepsis and the effect of NO on tubular integrity. Septic patients and endotoxemia that was induced by a bolus injection of 2 ng/kg Escherichia coli LPS in human volunteers were studied. In addition, the effect of co-administration of the selective iNOS inhibitor aminoguanidine was evaluated. The urinary excretion of the cytosolic glutathione S-transferase-A1 (GSTA1-1) and GSTP1-1, markers for proximal and distal tubule damage, respectively, was determined. In septic patients, an almost 40-fold induction of iNOS mRNA in cells that were isolated from urine was found accompanied by a significant increase in NO metabolites in blood. The mRNA expression of iNOS was induced 34-fold after endotoxin administration. LPS treated healthy volunteers showed a higher urinary excretion of NO metabolites compared with control subjects. Urinary NO metabolite excretion correlated with urinary GSTA1-1 excretion, indicating proximal tubule damage, whereas no distal tubular damage was observed. Co-administration of aminoguanidine reduced the upregulation of iNOS mRNA, urinary NO metabolite, and GSTA1-1 excretion, indicating that upregulation of iNOS and subsequent NO production may be responsible for renal proximal tubule damage observed. PMID- 17699298 TI - New therapies for lupus nephritis. PMID- 17699299 TI - Evolving practices in critical care and potential implications for management of acute kidney injury. PMID- 17699300 TI - Surrogate end points for clinical trials of kidney disease progression. PMID- 17699301 TI - Medical risks in living kidney donors: absence of proof is not proof of absence. AB - Living-kidney donation has become increasingly widespread, yet there has been little critical analysis of existing studies of long-term medical outcomes in living donors. This review analyzes issues in study design that affect the quality of the evidence and summarizes possible risk factors in living donors. Virtually all studies of long-term outcomes in donors are retrospective, many with large losses to follow-up, and therefore are subject to selection bias. Most studies have small sample sizes and are underpowered to detect clinically meaningful differences between donors and comparison groups. Many studies compare donors with the general population, but donors are screened to be healthier than the general population and this may not be a valid comparison group. Difficulties in measurement of BP and renal function may underestimate the impact of donation on these outcomes. Several studies have identified possible risk factors for development of hypertension, proteinuria, and ESRD, but potential vulnerability factors in donors have not been well explored and there is a paucity of data on cardiovascular risk factors in donors. Prospective registration of living kidney donors and prospective studies of diverse populations of donors are essential to protect living donors and preserve living-kidney donation. PMID- 17699302 TI - Dialysis at a crossroads: reverse engineering renal replacement therapy. PMID- 17699303 TI - Can we rely on blood urea nitrogen as a biomarker to determine when to initiate dialysis? PMID- 17699304 TI - Reverse race and ethnic disparities in survival increase with severity of chronic kidney disease: what does this mean? PMID- 17699305 TI - Corticosteroids and kidney transplantation. PMID- 17699306 TI - Age-related increase in plasma urea level and decrease in fractional urea excretion: clinical application in the syndrome of inappropriate secretion of antidiuretic hormone. AB - This study confirms in humans an age-related increase in plasma urea levels (r = 0.62; P < 0.001; y = 0.229x + 18.26) and no correlation between plasma creatinine and age (r = 0.06; NS). Fractional urea excretion (FE urea) decreases with age (r = -0.41; P < 0.001; y = -0.226x + 55). Comparing urea and creatinine clearances, measured in 19 young and in 15 old women, a larger decrease of urea clearance ( 56%) compared with the creatinine clearance (-43%) was observed as expected, explaining the lower FE urea in the elderly. In old women, the daily urea excretion was 27% and the daily creatinine excretion was 42% lower than in young women. An age-related decrease of same magnitude in both creatinine production and creatinine clearance explains why plasma creatinine remains stable with increasing age. The observation of a more important decrease in urea clearance (56%) than in urea production (27%) in older women led to an expected increase in plasma urea of 29%. These observations incited a comparison of biochemical profiles from younger and older patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Young patients with SIADH present lower mean plasma urea (18 +/- 8 mg/dl) and higher mean FE urea (58 +/- 14%), compared with both young control subjects (mean plasma urea 27 +/- 7 mg/dl; mean FE urea 46 +/- 10%) and old patients with SIADH (mean plasma urea 29 +/- 8 mg/dl; mean FE urea 44 +/- 15%). Physicians must realize that frankly low plasma urea values and high FE urea values can be expected only in young patients with SIADH, whereas old patients with SIADH will present values of plasma urea and FE urea in the same range than young control subjects. However, old patients with SIADH show still lower mean plasma urea values and higher mean FE urea values, compared with old control subjects (mean plasma urea 39 +/- 8 mg/dl; mean FE urea 36 +/- 9%), in whom plasma urea values between 40 and 50 mg/dl must be considered as usual. PMID- 17699307 TI - Timing of initiation of dialysis in critically ill patients with acute kidney injury. AB - Among critically ill patients, acute kidney injury (AKI) is a relatively common complication that is associated with an increased risk for death and other complications. To date, no treatment has been developed to prevent or attenuate established AKI. Dialysis often is required, but the optimal timing of initiation of dialysis is unknown. Data from the Program to Improve Care in Acute Renal Disease (PICARD), a multicenter observational study of AKI, were analyzed. Among 243 patients who did not have chronic kidney disease and who required dialysis for severe AKI, we examined the risk for death within 60 d from the diagnosis of AKI by the blood urea nitrogen (BUN) concentration at the start of dialysis (BUN < or = 76 mg/dl in the low degree of azotemia group [n = 122] versus BUN > 76 mg/dl in the high degree of azotemia group [n = 121]). Standard Kaplan-Meier product limit estimates, proportional hazards (Cox) regression methods, and a propensity score approach were used to account for selection effects. Crude survival rates were slightly lower for patients who started dialysis at higher BUN concentrations, despite a lesser burden of organ system failure. Adjusted for age, hepatic failure, sepsis, thrombocytopenia, and serum creatinine and stratified by site and initial dialysis modality, the relative risk for death that was associated with initiation of dialysis at a higher BUN was 1.85 (95% confidence interval 1.16 to 2.96). Further adjustment for the propensity score did not materially alter the association (relative risk 1.97; 95% confidence interval 1.21 to 3.20). Among critically ill patients with AKI, initiation of dialysis at higher BUN concentrations was associated with an increased risk for death. Although the results could reflect residual confounding by severity of illness, they provide a rationale for prospective testing of alternative dialysis initiation strategies in critically ill patients with severe AKI. PMID- 17699308 TI - Giant cell tubulitis with tubular basement membrane immune deposits: a report of two cases after cardiac valve replacement surgery. AB - This paper presents two elderly patients who had normal baseline renal function and had stenotic valvular lesions secondary to rheumatic fever and underwent aortic valve replacements with mechanical valves. Both patients developed acute renal failure after cardiac valve replacement procedures. The renal biopsies revealed acute granulomatous tubulointerstitial nephritis. The unique histologic features were tubular basement membrane (TBM) immune complex deposition detected by both immunofluorescence and electron microscopy and prominent multinucleated giant cells surrounding intact TBM. The temporal relationship to the surgical procedure and the subsequent recovery of the patients' renal functions upon therapy suggested that the renal failure may have been due to an allergic drug reaction from the perioperative exposure to unknown agents, such as prophylactic antibiotics and furosemide. The literature on TBM immune complex deposition was reviewed, and the pathophysiologic mechanisms that may account for the similarities between the clinicopathologic features of these two cases were examined. These two cases expand the histopathologic spectrum of previously described cases of putative drug-induced acute tubulointerstitial nephritis. PMID- 17699309 TI - A randomized pilot trial comparing cyclosporine and azathioprine for maintenance therapy in diffuse lupus nephritis over four years. AB - There is not agreement about the best maintenance treatment for patients with diffuse lupus nephritis. This multicenter, randomized trial compared the safety and efficacy of cyclosporine and azathioprine. Seventy-five patients with diffuse proliferative lupus were given three intravenous methylprednisolone pulses followed by prednisone and oral cyclophosphamide for a median of 90 d. Subsequently, patients were randomly assigned either to cyclosporine or to azathioprine for 2 yr (core study). Treatment continued for up to 4 yr (follow-up study). The primary outcome measure was the incidence of disease flares. Secondary end points were proteinuria per day, creatinine clearance, and adverse effects. Seven flares occurred in the cyclosporine group, and eight occurred in the azathioprine group. At the end of the core study, mean proteinuria decreased from 2.8 +/- 3.57 to 0.4 +/- 0.85 g/d (P < 0.0001) in the cyclosporine group and from 2.2 +/- 1.94 to 0.5 +/- 0.78 g/d (P < 0.0002) in the azathioprine group. After 4 yr, mean proteinuria was 0.2 +/- 0.24 and 0.3 +/- 0.33 g/d, respectively. At the core study end and at the follow-up completion, creatinine clearance and BP levels did not change significantly from baseline in either group. Five of 36 patients who were receiving cyclosporine and four of the 33 who were receiving azathioprine stopped the treatment because of adverse effects. For patients with diffuse proliferative lupus nephritis, azathioprine or cyclosporine combined with corticosteroids demonstrated equal efficacy in the prevention of flares. PMID- 17699310 TI - Is body size a biomarker for optimizing dosing of omega-3 polyunsaturated fatty acids in the treatment of patients with IgA nephropathy? AB - Re-analysis of the North American IgA Nephropathy Study suggested that efficacy of omega-3 polyunsaturated fatty acids (omega-3 PUFA) was dosage-dependent on the basis of body size and plasma omega-3/omega-6 and eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratios. The objective of this study was to confirm these assertions. Data from a previously reported randomized 2-yr clinical trial in which two dosages of an ethyl ester omega-3 PUFA (Omacor) were given to 73 high-risk patients with IgA nephropathy were reviewed. Omacor also was used in the North American IgA Nephropathy Study. Parameters included body weight; body mass index (BMI); plasma phospholipid AA, EPA, and docosahexanoic acid (DHA) levels and serum creatinine and 24-h urine protein (UP) levels during the 2-yr trial; and time to ESRD after 6.4 yr. Plasma phospholipid levels of EPA, DHA, and EPA/AA ratios were significantly inversely correlated with increasing body weight and BMI in the Omacor 4-g dosage group but not in the Omacor 8-g dosage group. Conversely, increasing levels of lipid parameters were observed with increasing dosages of Omacor (EPA+DHA) in grams per kilogram of body weight at 6 wk of treatment. None of the plasma omega-3 PUFA levels, EPA/AA ratios, or Omacor dosage per kilogram was significantly associated with reciprocal serum creatinine or UP slopes during the 2-yr trial or with ESRD. This post hoc analysis of body weight and BMI, plasma omega-3 PUFA status, and renal outcome did not find that treatment efficacy of omega-3 PUFA was dosage dependent on the basis of body size. PMID- 17699311 TI - Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. AB - Previous studies have shown that the selective aldosterone blocker eplerenone, in doses of up to 200 mg/d, reduces albuminuria in patients with type 2 diabetes. This study was conducted to ascertain whether lower doses of eplerenone (50 or 100 mg/d) co-administered with the angiotensin-converting enzyme (ACE) inhibitor enalapril would produce a similar antialbuminuric effect while obviating the hyperkalemia observed previously. After open-label run-in with enalapril 20 mg/d, patients with diabetes and a urinary albumin:creatinine ratio (UACR) > or = 50 mg/g were randomly assigned to receive enalapril plus one of three double-blind daily treatments for 12 wk: placebo, eplerenone 50 mg (EPL50), or eplerenone 100 mg (EPL100). After week 4, amlodipine 2.5 to 10 mg/d was allowed for BP control (systolic/diastolic BP < or = 130/80 mmHg). The primary study end points were the percentage change from baseline at week 12 in UACR and the incidence of hyperkalemia. Secondary end points included percentage changes from baseline in UACR at weeks 4 and 8 and changes from baseline in systolic and diastolic BP. Treatment with EPL50 or EPL100 but not placebo significantly reduced albuminuria from baseline. By week 12, UACR was reduced by 7.4% in the placebo group, by 41.0% in the EPL50 group, and by 48.4% in the EPL100 group (both eplerenone groups, P < 0.001 versus placebo). The incidences of sustained and severe hyperkalemia were not significantly different in any of the three treatment arms and did not differ on the basis of quartile of estimated GFR (all NS). For the secondary end points, both eplerenone treatment groups significantly reduced albuminuria from baseline as early as week 4 (P < 0.001), whereas placebo treatment (including enalapril) did not result in any significant decreases in UACR. Systolic BP decreased significantly in all treatment groups at all time points, but, generally, all treatment groups experienced similar decreases in BP. Co-administration of EPL50 or EPL100 with an ACE inhibitor as compared with an ACE inhibitor alone significantly reduces albuminuria in patients with diabetes without producing significant increases in hyperkalemia. PMID- 17699312 TI - Minutes to recovery after a hemodialysis session: a simple health-related quality of life question that is reliable, valid, and sensitive to change. AB - Patients who have end-stage renal failure and are treated by hemodialysis (HD) face a stressful chronic illness with a demanding treatment regimen that affects quality of life. Quality-of-life domains can be measured by assessment questionnaires that are easy to complete, reliable, valid, and sensitive to change. There is current interest in HD regimens that provide more frequent treatments (e.g., daily) than the conventional thrice weekly. Improvement in quality of life by these regimens has been reported. A published prospective, cohort, controlled study (London Daily/Nocturnal Hemodialysis Study) included the results of a number of quality-of-life indicators that were applied to the study patients. In general, the indicators used were well established and of proven validity. Included was one single question that was added intuitively and had not received previous validation: "How long does it take you to recover from a dialysis session?" The responses to this question allow the validation of this simple question as a tool to be used in HD clinical research. Twenty-three patients who were treated by frequent HD (5 to 7 d or nights) and 22 control subjects who were treated by thrice-weekly dialysis were studied during an 18-mo period. The "time to recovery" question was administered along with a battery of renal disease-specific questionnaires and the Generic Medical Outcomes Survey 36 Item-Short Form (SF-36) plus the global Health Utilities Index. Missing data rates, reliability over time, construct validity, and sensitivity to change were assessed from the "time to recovery" responses by standard methods. The question was administered on a total of 314 occasions and answered successfully on 313. The test-retest correlation over 3-mo intervals was highly significant (r = 0.962, P = 0.000; n = 100). Convergent construct validity was established by significant correlations between time to recovery and fatigue (r = 0.38, P = 0.000; n = 313), dialysis stress (r = 0.348, P = 0.000), disease stress (r = 0.374, P = 0.000), SF-36 subscales especially vitality (r = -0.356 P = 0.000), and the Health Utilities Index (r = -0.232, P = 0.000). These scales captured mainly physical or physiologic domains. Divergent construct validity was established by lack of correlations between "time to recovery" and a number of subscales that captured mainly emotional or psychosocial domains, e.g., SF-36 subscale for "role emotional" (r = -0.102, NS) and dialysis stressors such as access problems (r = -0.015, NS) or equipment malfunction (r = 0.032, NS). Test sensitivity was established when the conventionally dialyzed group showed no significant difference in time to recovery between baseline and other time periods, whereas the daily/nocturnal group had a significant reduction between baseline (while on conventional dialysis) and the result at each other time period (minimum P = 0.05). There also was a significant difference between the control and experimental groups over time (ANOVA P = 0.000). The response to the question, "How long does it take you to recover from a dialysis session?" is interpreted easily, is easy to which to respond, shows stability over time by test-retest, shows both convergent and divergent validity, and is sensitive to change. As such, it should be considered as a standard question in HD-related studies in which a health-related quality-of-life outcome is examined. PMID- 17699313 TI - Hemodialysis blood access flow rates can be estimated accurately from on-line dialysate urea measurements and the knowledge of effective dialyzer urea clearance. AB - Measurement of blood flow rate (Qa) is used to monitor arteriovenous fistulas and grafts that are used for hemodialysis blood access. Most Qa measurements use indicator dilution techniques to measure the recirculation that is induced by the reversal of hemodialysis blood lines. R plus the dialysis circuit flow (Qb) allows the calculation of Qa. The principle of needle reversal also can be used with a dialysate urea monitor (e.g., DQM 200 [Gambro]) without injection of diluent; the effect of the reversal on urea concentration is observed. Access blood water flow rate (Qaw) in relation to the effective clearance (K) is found from the urea concentrations in the dialysate with needles in the normal (Cn) and reverse (Cr) positions: K/Qaw = (Cn - Cr)/Cr. Qa is calculated by adjusting Qaw for hematocrit and protein. For testing of this theoretical relationship, 20 patients who were dialyzed on Integra (Hospal) and Centrysystem 3 (Cobe) machines that were fitted with DQM 200 were studied. During each treatment, lines were reversed and Qa was measured by ultrasound velocity dilution (Transonic HD01 monitor); at the same time, Cn and Cr were measured by DQM 200 and K was calculated. K1 was determined from a predialysis blood urea concentration (Cb), initial dialysate urea concentration (Cd), dialysate flow rate (Qd), and the relationship K x Cb = Qd x Cd (K1). K was determined separately from a conductivity step method using Diascan (Hospal) attached to Integra machines only (K2). With the use of K1, 127 comparisons were made; a correlation existed (r = 0.916), although Bland-Altman analysis showed that the dialysate urea method gave a mean value 5.3% +/- 15.3 (+/-SD) higher than that of Transonic (P < 0.001). With the use of K2, there also was a correlation of (r = 0.944; n = 63), and Bland-Altman testing showed an NS difference of +3.5% between the dialysate urea and Transonic methods. Qa can be estimated from on-line dialysate urea measurements that are taken before and after line reversal together with knowledge of K. PMID- 17699314 TI - Relationship between blood flow in central venous catheters and hemodialysis adequacy. AB - Central venous catheter dysfunction is a frequent problem and often is defined as a blood flow <300 ml/min. This prospective, cross-sectional study included 259 patients and examined the relationship between catheter blood flow and dialysis adequacy as measured by urea reduction ratio (URR), single pool urea kinetics, and online effective ionic dialysance clearance. Dialysis adequacy at blood flow rates of <300, <275, and <250 ml/min; sensitivity; specificity; and positive and negative predictive values were calculated. Mean blood flow was 352 ml/min (SD +/ 48.8). Mean blood flow <300 ml/min occurred in 10.5% of the patients, and only 26% had a URR of <65%. Maximum blood flows <300 ml/min occurred in 6.9% of patients, and only 22.2% had URR <65%. The positive predictive value of mean blood flow of <300 and <275 ml/min to predict a URR <65% was 22 and 40%, respectively. Using receiver operator characteristic curves, the area under the curve was not significantly different for blood flows of 300, 275, or 250 ml/min. This study indicates that mean blood flows <300 ml/min are not commonly associated with dialysis inadequacy. Setting a single blood flow cut point of <300 ml/min to define the need for intervention will result in a significant number of unnecessary interventions. There is a need to reexamine the definition of catheter dysfunction and expand the definition beyond blood flow rates. PMID- 17699315 TI - Influence of luminal diameters on flow surveillance of hemodialysis grafts: insights from a mathematical model. AB - Randomized controlled trials have not shown that surveillance of graft blood flow (Q) prolongs graft life. Because luminal diameters affect flow resistance, this study examined whether the influence of diameters on Q can explain the limitations of surveillance. Inflow artery and outflow vein diameters were determined from duplex ultrasound studies of 94 patients. These diameters were applied to a mathematical model for determination of how they affect the relation between Q and stenosis. Also determined was the correlation between Q (by ultrasound dilution) and diameters, stenosis, and mean arterial pressure in 88 patients. Artery and vein diameters varied widely between patients, but arteries generally were narrower than veins. The model predicts that the relation between Q and stenosis is sigmoid: as stenosis progresses, Q initially remains unchanged but then rapidly decreases. A narrower artery increases flow resistance, causing a longer delay followed by a more rapid reduction in Q. In a multiple regression analysis of data from patients, Q correlated with artery and vein diameters, sum of largest stenoses from each circuit segment, and mean arterial pressure (R = 0.689, P < 0.001). This study helps to explain why Q surveillance predicts thrombosis in some patients but not others. Luminal diameters control the relation between Q and stenosis, and these diameters vary widely. During progressive stenosis, the delay and then rapid reduction in Q may impair recognition of low Q before thrombosis occurs. Surveillance outcomes might be improved by taking frequent measurements so that there is no delay in discovering that Q has decreased. PMID- 17699316 TI - Pro- and anti-inflammatory cytokines in chronic pediatric dialysis patients: effect of aspirin. AB - Dialysis provides effective and safe treatment of ESRD in children, but patients who are maintained on chronic dialysis are at risk for cardiovascular disease. One major risk factor for cardiovascular disease in adult patients with ESRD is chronic inflammation. The effect of anti-inflammatory therapy with aspirin on serum cytokine concentration was studied in seven children who were receiving hemodialysis (HD) and seven who were receiving continuous cycling peritoneal dialysis (CCPD or PD). Dialysis vintage was 4.3 +/- 4.6 yr; single-pool Kt/V was 1.46 +/- 1.4, mean equilibrated Kt/V was 1.27 +/- 0.16, and PD weekly Kt/V was 2.45 +/- 0.30. Baseline proinflammatory cytokine IL-1beta, IL-6, IL-8, and TNF alpha serum concentrations were significantly elevated, whereas serum anti inflammatory cytokine IL-4 and IL-10 concentrations were normal. The patterns of cytokine elevation were similar for patients who were receiving HD versus PD. IL 4 and IL-6 concentrations demonstrated strong positive correlation with dialysis vintage (IL-4, P < 0.03; IL-6, P < 0.0001). Pre-aspirin serum cytokine concentrations did not vary with single-pool Kt/V or equilibrated Kt/V for HD patients or with weekly Kt/V for PD patients. Serum IL-8 and TNF-alpha concentrations were significantly reduced by aspirin treatment at 4 mo (P = 0.04 and P = 0.007, respectively). Serum IL-6 concentration decreased with aspirin treatment but not significantly (P = 0.1). Serum IL-1beta concentration remained unchanged, and IL-4 and IL-10 concentrations remained stable throughout aspirin treatment. The effect of aspirin treatment on serum cytokine concentrations was similar for HD and PD patients. In HD patients, IL-6, IL-8, and TNF-alpha remained suppressed 1 mo after discontinuation of aspirin. It is concluded that proinflammatory cytokines are elevated in pediatric HD and PD patients without counterbalance from anti-inflammatory cytokines, and aspirin therapy attenuates inflammation. PMID- 17699317 TI - Clinical course associated with vascular access type in a national cohort of adolescents who receive hemodialysis: findings from the Clinical Performance Measures and US Renal Data System projects. AB - Limited research has described clinical outcomes that are associated with the type of vascular access in pediatric patients who receive maintenance hemodialysis. This retrospective cohort study examined prevalent pediatric patients who were aged 12 to <18 yr and identified in the 2000 ESRD Clinical Performance Measures Project as receiving in-center hemodialysis. Vascular access type as of December 31, 1999, was identified. These patients were linked with 1 yr of data (January 1, 2000, through December 31, 2000) from US Renal Data System standard analytic files that allow for the comparison of rates of hospitalizations and access complications by access type. Of the 418 patients who met inclusion criteria, the mean age was 15.6 yr, 53% were male, 49% were white, the mean time on dialysis was 22 mo, and 42% had a structural/urologic cause of ESRD; 42% of patients had an arteriovenous graft or fistula, and 58% had a vascular catheter. Patients with a vascular catheter as compared with those with a graft or fistula had the following adjusted relative risks (95% confidence interval): 1.84 (1.38 to 2.44) for hospitalization for any cause, 4.74 (2.02 to 11.14) for hospitalization as a result of infection, and 2.72 (2.00 to 3.69) for a complication of vascular access. Vascular catheters are the predominant access type in adolescent patients who receive maintenance hemodialysis and are associated with significantly more hospitalizations and complications. PMID- 17699318 TI - Survival advantage of black patients with kidney disease after acute myocardial infarction. AB - Black individuals have a disproportionate incidence of ESRD when compared with white individuals, and among patients with ESRD, black patients experience better survival. The aim of this analysis is to assess, in a nationally representative sample of patients with cardiovascular disease, ethnic differences in survival among predialysis patients with kidney disease. A retrospective cohort analysis was conducted of Cooperative Cardiovascular Project data of Medicare patients who were aged > 65 yr and admitted for incident acute myocardial infarction and had 3 yr of mortality follow-up. Cox regression models and Kaplan Meier estimates were performed to examine differences in survival between black and white patients stratified by severity of kidney disease. Of 57,942 patients, 7.3% were black. Black patients were younger and more likely to be female and were less likely to have decreased kidney function. A significant interaction between race and kidney function existed with respect to mortality among patients who survived to discharge. The adjusted hazard ratios for death, black compared with white patients, were 1.00 (95% confidence interval 0.90 to 1.11) among patients with a GFR > or = 60 ml/min per 1.73 m2 and decreased monotonically among patients with lower GFR to 0.79 (95% confidence interval 0.61 to 0.97) among patients with a GFR 15 to 29 ml/min per 1.73 m2. Among patients with incident acute myocardial infarction, black patients with more severe kidney disease, when compared with their white counterparts, experience better survival. Further investigation into the reasons for ethnic differences in survival and progression of kidney disease is warranted. PMID- 17699319 TI - Dementia as a predictor of mortality in dialysis patients. AB - The life expectancy of patients who have dementia and are initiated on dialysis in the United States has not been described in the medical literature. A retrospective cohort study was conducted of 272,024 Medicare/Medicaid primary patients in the US Renal Data System who were started on ESRD therapy between April 1, 1995, and December 31, 1999, and followed through December 31, 2001. Cox regression was used to calculate adjusted hazard ratios for risk for death after initiation of dialysis for patients whose dementia was diagnosed before the initiation of dialysis as shown by Medicare claims. The average time to death for patients with dementia was 1.09 versus 2.7 yr (P < 0.001) with an adjusted hazard ratio of 1.87 (95% confidence interval 1.77 to 1.98). The 2-yr survival for patients with dementia was 24 versus 66% for patients without dementia (P < 0.001 via log rank test). Dementia that is diagnosed before initiation on dialysis is an independent risk factor for subsequent death. Such patients should be considered for time-limited trials of dialysis and careful discussion in choosing whether to pursue initiation of dialysis or palliative care. PMID- 17699320 TI - Design and methods of the Chronic Kidney Disease in Children (CKiD) prospective cohort study. AB - An estimated 650,000 Americans will have ESRD by 2010. Young adults with kidney failure often develop progressive chronic kidney disease (CKD) in childhood and adolescence. The Chronic Kidney Disease in Children (CKiD) prospective cohort study of 540 children aged 1 to 16 yr and have estimated GFR between 30 and 75 ml/min per 1.73 m2 was established to identify novel risk factors for CKD progression; the impact of kidney function decline on growth, cognition, and behavior; and the evolution of cardiovascular disease risk factors. Annually, a physical examination documenting height, weight, Tanner stage, and standardized BP is conducted, and cognitive function, quality of life, nutritional, and behavioral questionnaires are completed by the parent or the child. Samples of serum, plasma, urine, hair, and fingernail clippings are stored in biosamples and genetics repositories. GFR is measured annually for 2 yr, then every other year using iohexol, HPLC creatinine, and cystatin C. Using age, gender, and serial measurements of Tanner stage, height, and creatinine, compared with iohexol GFR, a formula to estimate GFR that will improve on traditional pediatric GFR estimating equations when applied longitudinally is expected to be developed. Every other year, echocardiography and ambulatory BP monitoring will assess risk for cardiovascular disease. The primary outcome is the rate of decline of GFR. The CKiD study will be the largest North American multicenter study of pediatric CKD. PMID- 17699321 TI - Incidence of ANCA-associated primary renal vasculitis in the Miyazaki Prefecture: the first population-based, retrospective, epidemiologic survey in Japan. AB - Clinicoepidemiological manifestations of the vasculitides differ geographically. According to a nationwide, hospital-based survey in Japan, the prevalence of microscopic polyangiitis (MPA) and/or renal-limited vasculitis (RLV) is much higher than that of Wegener's granulomatosis (WG). However, little is known about the incidence of antineutrophil cytoplasmic autoantibodies (ANCA)-associated primary renal vasculitis (PRV) in Japan. The incidence of PRV was retrospectively determined by a population-based method in Miyazaki Prefecture in Japan between 2000 and 2004. PRV was defined according to the following criteria from the European Systemic Vasculitis Study Group: (1) new patients with WG, MPA, Churg Strauss syndrome (CSS), or RLV, (2) renal involvement attributable to active vasculitis, and (3) ANCA considered positive if the disease was not histologically confirmed. The numbers of patients with PRV in the years 2000, 2001, 2002, 2003, and 2004 were 9, 9, 9, 16, and 13, respectively. The male to female ratio was 24:32 and the average age was 70.4 +/- 10.9 (mean +/- SD) yr. The estimated annual incidence of PRV was 14.8 (95% confidence interval [CI] 10.8 to 18.9) and 44.8 (95% CI 33.2 to 56.3) per million adults (>15 yr old) and seniors (>65 yr old), respectively. Ninety-one percent of the patients were myeloperoxidase (MPO)-ANCA positive, but none were positive for proteinase 3 (PR3)-ANCA. There were no WG or CSS patients. The incidence of PRV did not differ between Japan and Europe, but WG was not widespread in Japan. Furthermore, the ratio of serum MPO to PR3-ANCA among Japanese with PRV was much higher than that found among European and US patients. PMID- 17699322 TI - Facilitating advance care planning for patients with end-stage renal disease: the patient perspective. AB - Comprehensive care of patients with ESRD requires expertise in advance care planning (ACP), including attention to ethical, psychosocial, and spiritual issues related to starting, continuing, withholding, and stopping dialysis. However, there are no standards of care regarding when to initiate or how to facilitate ACP. The purpose of this study was to determine the perspectives of patients with ESRD of the salient elements of ACP discussions. An ethnographic, qualitative, in-depth interview study was conducted of outpatients of a university-affiliated nephrology program. Twenty-four patients with ESRD were purposively selected from the renal insufficiency, hemodialysis, and peritoneal dialysis clinics. Establishing patient "buy-in" by identifying perceived benefits of ACP along with acknowledging patients' sense of personal empowerment were critical both for the effective framing of facilitated ACP and for determining patients' ability to participate in facilitated ACP. Patients required more information and earlier initiation of ACP discussions. Information needed to focus more on the individual and how his or her illness and interventions would affect his or her life and relationships and what he or she values most. Empathetic listening also was viewed as an integral component of facilitated ACP. Physicians clearly were seen as having the responsibility for initiating and guiding ACP. The role of patients and family within ACP is complex and varies significantly between patients. For most, family was an integral component of ACP, and many relied extensively on family to make end-of-life decisions. These findings identify a precarious tension between patients' preferences in terms of facilitated ACP and current clinical practice. PMID- 17699323 TI - Effect of prednisone versus no prednisone as part of maintenance immunosuppression on long-term renal transplant function. AB - Corticosteroids have been a component of maintenance immunosuppression for renal transplant since the 1960s and have helped to reduce the rate of acute rejection. Corticosteroids, however, have many adverse effects, and with the development of new immunosuppressive medications, many transplant centers have adopted protocols that eliminate or completely avoid the use of corticosteroids. Despite promising short-term results, the impact of corticosteroid elimination on long-term kidney function still is unclear. This single-center, retrospective, sequential study analyzed 212 renal transplant patients with a median follow-up of 5 yr. All patients received induction with IL-2 receptor antagonist and maintenance immunosuppression with mycophenolate mofetil and tacrolimus. Ninety-six patients were maintained on chronic prednisone, and 116 were maintained without chronic prednisone (rapid steroid elimination). Kaplan-Meier patient and graft survival at 7 yr after transplantation were not statistically different between the two groups. Rate and severity of acute cellular rejection were similar. Furthermore, the slope of GFR decline per month at 5 yr after transplantation was not statistically different between the two groups. Prednisone-treated patients had a significantly higher incidence of hyperlipidemia and posttransplantation diabetes when compared with patients with rapid steroid elimination. It was concluded that with the current immunosuppressive medications, the use of chronic prednisone to maintain long-term kidney function and prevent acute cellular rejection is not justified. PMID- 17699324 TI - Aldosteronism and hypertension. AB - A growing body of evidence suggests that hyperaldosteronism contributes significantly to the development and the severity of hypertension as well as to resistance to antihypertensive treatment. In cross-sectional analyses, plasma aldosterone levels have been shown to relate to BP levels, particularly in obese individuals. In these same individuals, BP was not related to plasma renin activity, suggesting an effect of aldosterone on BP independent of renin angiotensin II. In a recent prospective analysis from the Framingham investigators, baseline serum aldosterone was strongly associated with development of hypertension during a 4-yr follow-up. PMID- 17699325 TI - Renin angiotensin system blockade and nephropathy: why is it being called into question, and should it be? PMID- 17699326 TI - Properties permitting the renal cortex to be the oxygen sensor for the release of erythropoietin: clinical implications. AB - The PO2 at this site where erythropoietin release is regulated should vary only when the hemoglobin concentration changes in capillary blood. The kidney cortex is an ideal location for this O2 sensor for four reasons. First, it extracts a small proportion of the oxygen that is delivered in each liter of blood; this makes the PO2 signal easier to recognize. Second, there is a constant ratio of the work performed (consumption of O2) to the renal blood flow rate (delivery of O2). Third, the high renal blood flow rate improves diffusion of O2 from capillaries to this O2 receptor. Fourth, a high renal cortical PCO2 prevents an additional shift of the O2:hemoglobin dissociation curve by other factors from being a confounding variable. This suggests that the GFR and the renal blood flow rate should be examined in patients with unexplained anemia or erythrocytosis. PMID- 17699327 TI - Progression of renal disease: renoprotective specificity of renin-angiotensin system blockade. AB - Recent guidelines for management of patients with chronic kidney disease recommend both lower optimal BP targets and agents that block the renin angiotensin system (RAS) for specific additional BP-independent renoprotection. Although there are other compelling rationales to use RAS blockade in patients with chronic kidney disease, including its antihypertensive effectiveness and ability to counteract the adverse effects of diuretics, a critical review of the available scientific evidence suggests that the specificity of renoprotection that is provided by RAS blockade has been greatly overemphasized. Little evidence of truly BP-independent renoprotection is observed in experimental animal models when ambient BP is assessed adequately by chronic continuous BP radiotelemetry. Although the clinical trial evidence is somewhat stronger, nevertheless, even when interpreted favorably, the absolute magnitude of the BP-independent component of the renoprotection that is observed with RAS blockade is much smaller than what is due to its antihypertensive effects. PMID- 17699328 TI - Hepatorenal syndrome: pathophysiology and management. PMID- 17699329 TI - Steroid sparing in kidney transplantation: changing paradigms, improving outcomes, and remaining questions. AB - The widely known adverse effects of long-term therapy with corticosteroids have motivated increasing interest in steroid-free immunosuppression for kidney transplant recipients. Results from recent trials that used newer immunosuppressants to facilitate elimination of steroids suggest better short term results than were achieved in an earlier era. However, the best results have been reported in uncontrolled trials of low-risk patients or in randomized trials with relatively short periods of follow-up. Increasingly, the therapeutic paradigm has shifted from late withdrawal of steroids to very early withdrawal after transplantation or even complete avoidance. Induction antibody therapy has been used routinely in the most successful trials that involved early steroid withdrawal or avoidance. Although the outcomes of kidney transplant recipients who are treated with steroid-free immunosuppression are improving steadily, there still is room for concern in recommending this strategy as a standard of practice. PMID- 17699330 TI - Management of dyslipidemias in patients with diabetes and chronic kidney disease. AB - Cardiovascular disease (CVD) is the leading cause of death in patients with stage 5 chronic kidney disease (CKD), and the mortality rate in stage 5 CKD is even higher in patients with diabetes. CVD risk reduction includes control of hyperglycemia, dyslipidemia, and BP. An LDL cholesterol goal of 70 mg/dl has been suggested for such high-risk patients. Most studies that have showed CVD risk reduction with statins have been in patients without CKD. However, some studies have had sufficient numbers of patients with CKD stages 2 to 3 to permit analysis, and these generally have shown CVD benefits similar to those found in patients without CKD. Studies that have shown benefit in patients who were on dialysis or after transplantation have been mixed, in part because CVD in such patients is far advanced and may not respond as well to intervention. As GFR falls, the dosages of many of the drugs that are used for the treatment of dyslipidemias need to be modified. In general, however, atorvastatin and fluvastatin dosages do not have to be modified. Drug interactions with cyclosporine also occur. In general, combinations of statins and fibrates should be avoided, and fenofibrate should be avoided in all patients with decreased GFR levels. Overall, on the basis of the very high risk for CVD in patients with diabetes and CKD, aggressive management of dyslipidemias is warranted, with an LDL goal of 70 mg/dl. PMID- 17699331 TI - TNF-alpha bioactivity-inhibiting therapy in ANCA-associated vasculitis: clinical and experimental considerations. AB - Wegener's granulomatosis, microscopic polyangiitis, idiopathic necrotizing crescentic glomerulonephritis, and Churg-Strauss syndrome are associated with the presence of ANCA with specificity for myeloperoxidase or proteinase 3. Current therapy consists mainly of corticosteroids and cyclophosphamide, but because this treatment regimen is associated with considerable morbidity, other treatment modalities remain desirable. There is compelling evidence that TNF-alpha plays an important role in the pathogenesis of ANCA-associated vasculitis. Consequently, inhibition of TNF-alpha bioactivity potentially results in attenuation of disease. This review discusses whether TNF-alpha bioactivity-inhibiting drugs are useful in the treatment of ANCA-associated vasculitis. The results of in vitro and in vivo experiments, as well as clinical studies, are evaluated. Although the importance of TNF-alpha during lesion development is evident, clinical trials that use TNF-alpha blockers in patients with ANCA-associated vasculitis give mixed results. Importantly, in a large-scale, randomized trial, treatment with etanercept was found not to be effective and resulted in an excess of treatment related morbidity. It remains to be investigated whether inhibition of TNF-alpha bioactivity is effective in a subgroup of patients. PMID- 17699332 TI - Diagnostic approach in autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most common Mendelian disorder of the kidney and affects all racial groups worldwide. It is characterized by focal development of renal and extrarenal cysts in an age dependent manner. Typically, only a few renal cysts are detected in most affected individuals before 30 yr of age. However, by the fifth decade of life, hundreds to thousands of renal cysts will be found in the majority of patients. ADPKD is genetically heterogeneous. Mutations of two genes, PKD1 and PKD2, account for approximately 85 and 15% of cases, respectively. Although the clinical manifestations of these two genotypes overlap completely, patients with PKD1 have much more severe renal disease compared with those with PKD2, as evidenced by their ESRD occurring approximately 15 yr earlier. Renal ultrasonography commonly is used for the assessment of ADPKD, and age-dependent ultrasound diagnostic criteria with high sensitivity and specificity have been established for individuals who are born with 50% risk for PKD1. Although these diagnostic criteria are used widely for genetic counseling and for the evaluation of at-risk individuals as living-related kidney donors to their affected relatives, their application to individuals who are at risk for PKD2 or have undefined genotype needs to be refined further. Molecular genetic testing is available for ADPKD and may be useful for evaluation of at-risk individuals with equivocal imaging results, younger at-risk individuals as a living-related kidney donor, and individuals with atypical or de novo renal cystic disease. PMID- 17699334 TI - Cohort studies: marching forward. PMID- 17699335 TI - Studying the prevention of acute kidney injury: lessons from an 18th-century mathematician. PMID- 17699336 TI - Why we should develop a regulated system of kidney sales: a call for action! PMID- 17699337 TI - Kidney vending: the "Trojan horse" of organ transplantation. PMID- 17699338 TI - Iranian model of paid and regulated living-unrelated kidney donation. AB - Since the 1980s, many countries have passed legislation prohibiting monetary compensation for organ donation. Organ donation for transplantation has become altruistic worldwide. During the past two decades, advances in immunosuppressive therapy has led to greater success in transplantation and to increased numbers of patients on transplant waiting lists. Unfortunately, the altruistic supply of organs has been less than adequate, and severe organ shortage has resulted in many patient deaths. A number of transplant experts have been convinced that providing financial incentives to organ sources as an alternative to altruistic organ donation needs careful reconsideration. In 1988, a compensated and regulated living-unrelated donor renal transplant program was adopted in Iran. As a result, the number of renal transplants performed substantially increased such that in 1999, the renal transplant waiting list was completely eliminated. By the end of 2005, a total of 19,609 renal transplants were performed (3421 from living related, 15,356 from living-unrelated and 823 from deceased donors). In this program, many ethical problems that are associated with paid kidney donation also were prevented. Currently, Iran has no renal transplant waiting lists, and >50% of patients with ESRD in the country are living with a functioning graft. In developed countries, the severe shortage of transplantable kidneys has forced the transplant community to adopt new strategies to expand the kidney donor pool. However, compared with the Iranian model, none of these approaches has the potential to eliminate or even alleviate steadily worsening renal transplant waiting lists. PMID- 17699339 TI - Payment for kidneys: a government-regulated system is not ethically achievable. PMID- 17699340 TI - Creating a medical, ethical, and legal framework for complex living kidney donors. PMID- 17699341 TI - Successful long-term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion with satavaptan (SR121463B), an orally active nonpeptide vasopressin V2-receptor antagonist. AB - The effects of satavaptan (SR121463B), a novel long-acting orally active vasopressin V(2)-receptor antagonist, were investigated in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In the first part of this randomized, double-blind study, 34 patients first were treated with satavaptan (versus placebo) for up to 5 d and then during 23 d of open-label dosage-adjustment period. In the second part of the study, long-term efficacy and safety of satavaptan was assessed in an open-label trial during at least 12 mo. Mean (+/-SD) serum sodium (SNa) levels before treatment were 127 +/- 2 mmol/L (placebo, n = 8), 125 +/- 6 mmol/L (25 mg, n = 14), and 127 +/- 5 mmol/L (50 mg, n = 12). Responders (patients SNa levels normalized or increased by at least 5 mmol/L from baseline during the double-blind period) were 79% in the 25-mg group (SNa 136 +/- 3 mmol/L; P = 0.006), 83% in the 50-mg group (SNa 140 +/- 6 mmol/L; P = 0.005), and 13% in the placebo group (SNa 130 +/- 5 mmol/L). No drug-related serious adverse events were recorded. During the long-term treatment, 15 of 18 enrolled patients achieved 6 mo and 10 achieved 12 mo of treatment. The SNa response was maintained during this time with a good tolerance. The new oral vasopressin V(2)-receptor antagonist satavaptan adequately corrects mild or moderate hyponatremia in patients with SIADH and has a good safety profile. PMID- 17699342 TI - Sodium thiosulfate treatment for calcific uremic arteriolopathy in children and young adults. AB - In adult patients with ESRD, calcific uremic arteriolopathy (CUA) is an uncommon but life-threatening complication. No effective therapy exists, although anecdotal case reports highlight the use of sodium thiosulfate (STS), a calcium chelating agent with antioxidant properties. CUA is rare in children, and STS use has not been reported. The objective of this study was to determine the influence of STS treatment on three patients with CUA in a pediatric chronic dialysis unit. The patients were between 12 and 21 yr of age; two were male; and primary diagnoses were obstructive uropathy, renal dysplasia, and calcineurin nephrotoxicity. Time from ESRD to CUA diagnosis was 1, 9, and 20 yr. Diagnosis was made by tissue biopsy and three-phase bone scan. Pain was the presenting symptom. Initial treatment included discontinuation of calcitriol and use of non calcium-based phosphate binders and low-calcium dialysate concentration. STS dosage was 25 g/1.73 m(2) per dose intravenously after each hemodialysis session. For optimization of removal of calcium deposits, patient three received a combination of STS and continuous venovenous hemofiltration for the first 10 d. All patients demonstrated rapid pain relief. Within weeks, skin induration and joint mobility of the extremities improved. Radiographic evidence of reduction in the calcium deposits occurred within 3 mo of initiation of STS. The only complication was prolonged QT interval in one patient as a result of hypocalcemia, who was resolved by use of a higher dialysate calcium concentration. STS seems well tolerated in children and young adults with CUA and has mild adverse effects. For determination of its efficacy, optimum dosage, duration of therapy, and dialysis modality, controlled trials are needed. PMID- 17699343 TI - Efficacy of omega-3 fatty acids in children and adults with IgA nephropathy is dosage- and size-dependent. AB - Previous studies that have evaluated fish oil preparations in patients with IgA nephropathy (IgAN) have produced a wide range of conclusions. Proposed explanations for these discordant results have not provided a unifying hypothesis. Results from two clinical trials were analyzed to examine whether there is a dosage-dependent effect of Omacor, a purified preparation of omega-3 fatty acids, in patients with IgAN. Whether changes in the level of proteinuria and plasma phospholipid fatty acid profiles were dependent on the dose of Omacor factored by body size was determined. In a post hoc analysis of the first trial results, correlations were found between (1) phospholipid eicosapentaenoic acid (EPA)/arachidonic acid (AA) and docosahexaenoic acid (DHA)/AA ratios and the dosage of Omacor, expressed as milligrams per kilogram of body weight (r = 0.78, P < 0.001 for EPA/AA; r = 0.86, P < 0.001 for DHA/AA), (2) phospholipid EPA/AA and DHA/AA levels and percentage change in urine protein/creatinine ratio after 21 to 24 mo of therapy (r = -0.50, P = 0.02 for EPA/AA; r = -0.52, P = 0.01 for DHA/AA), and (3) dosage of Omacor per kilogram of body weight and change in proteinuria after 21 to 24 mo (r = -0.50, P = 0.02). A similar relationship was observed between urine protein/creatinine ratio and dosage of Omacor per kilogram of body weight in trial 2 (r = -0.38, P < 0.001). It is concluded from these data that the effect of Omacor on proteinuria in patients with IgAN is dosage dependent and is associated with a dosage-dependent effect of Omacor on plasma phospholipid EPA and DHA levels. PMID- 17699344 TI - Mycophenolate mofetil in children with frequently relapsing nephrotic syndrome: a report from the Southwest Pediatric Nephrology Study Group. AB - Children with frequently relapsing nephrotic syndrome (FRNS) often develop adverse effects from prednisone. Attempts to induce long-term remission in such patients have had varying levels of success. In this multicenter, prospective, open-label study, 14 centers enrolled 33 patients with FRNS, all of whom were in remission at the time of entry. Six of the patients were steroid dependent. The patients received mycophenolate mofetil (MMF) 600 mg/m(2) twice daily (maximum 1 g twice daily) for 6 mo. A tapering dosage of alternate-day prednisone was given to each patient during the first 16 wk of MMF therapy. Patients were monitored for relapses of NS during and after MMF therapy. Treatment failure was defined as a relapse of NS. The patients had the following features at study entry: Age 6.8 +/- 2.7 yr (range 2 to 15 yr); 56% male, 44% female; and 50% white; 25% black, and 25% other. Estimated GFR at entry was 138 +/- 42 ml/min per 1.73 m(2). Twenty four (75%) of 32 patients stayed in remission throughout the 6 mo of MMF therapy. The relapse rate in these patients improved from one episode every 2 mo before MMF to one every 14.7 mo after MMF. Eight patients stayed in remission during the post-MMF period, for periods of 18 to 30 mo, whereas 16 relapsed after stopping MMF. Eight (25%) of 32 patients relapsed while taking MMF. It is concluded that MMF is effective for maintaining remission in patients who have FRNS and receive treatment for at least 6 mo and is associated with a low incidence of adverse events. PMID- 17699345 TI - Staphylococcus infection-associated glomerulonephritis mimicking IgA nephropathy. AB - The association of methicillin-resistant Staphylococcus aureus (MRSA) infection with glomerulonephritis (GN) has been well documented in Japan but not in North America. Recently, eight renal biopsies with IgA-predominant or -codominant GN from eight patients with underlying staphylococcal infection, but without endocarditis, were observed at a single institution in a 12-mo period. Renal biopsies were worked up by routinely used methodologies. Eight cases of primary IgA nephropathy were used as controls. Five patients had MRSA infection, one had methicillin-resistant S. epidermidis (MRSE) infection, and two had methicillin sensitive S. aureus infection. Four patients became infected after surgery; two patients were diabetic and had infected leg ulcers. All patients developed acute renal failure, with active urine sediment and severe proteinuria. Most renal biopsies showed only mild glomerular hypercellularity. Two biopsies had prominent mesangial and intracapillary hypercellularity; one of them (the MRSE-associated case) had large glomerular hyalin thrombi. This patient also had a positive cryoglobulin test. Rare glomerular hyalin thrombi were noted in two other cases. Immunofluorescence showed IgA pre- or codominance in all biopsies. Electron microscopy revealed mesangial deposits in all cases. Five biopsies had rare glomerular capillary deposits as well. In the MRSE-associated GN, large subendothelial electron-dense deposits were present. These cases demonstrate that staphylococcal (especially MRSA) infection-associated GN occurs in the US as well, and a rising incidence is possible. It is important to differentiate a Staphylococcus infection-associated GN from primary IgA nephropathy to avoid erroneous treatment with immunosuppressive medications. PMID- 17699346 TI - Relationship between urinary albumin excretion and left ventricular mass with mortality in patients with type 2 diabetes. AB - Increased urinary albumin excretion (UAE) has been shown to be associated with increased cardiovascular mortality in patients with type 2 diabetes. This study evaluated whether the association between UAE and cardiovascular mortality in 880 patients with type 2 diabetes was related to an increase in left ventricular mass (LVM). LVM was estimated by electrocardiographic index, namely adjusted Cornell voltage. LVM was significantly different between the stages of albuminuria (8.17 +/- 0.12 in normoalbuminuric, 9.05 +/- 0.21 in microalbuminuric, and 10.30 +/- 0.30 in overt albuminuric patients; P < 0.001). There also was a positive correlation between log UAE and LVM independent of BP. During 5 yr of follow-up, survivors had significantly lower LVM (8.62 +/- 0.11 versus 9.88 +/- 0.45; P = 0.0140) and lower UAE (154.60 +/- 16.53 versus 446.62 +/- 114.11; P = 0.0003) than nonsurvivors. The results indicate that patients with type 2 diabetes and increased UAE should be evaluated for increased LVM as an important and potentially reversible cardiovascular risk factor. PMID- 17699347 TI - Hemodialysis and peritoneal dialysis: patients' assessment of their satisfaction with therapy and the impact of the therapy on their lives. AB - This study was undertaken to examine patient satisfaction with peritoneal dialysis (PD) and hemodialysis (HD) therapies, focusing attention on the positive and negative impact of the therapies on patients' lives. Patients were recruited from a free-standing PD unit and two free-standing HD units. A total of 94% (n = 62) of eligible PD and 84% (n = 84) of eligible HD patients participated. HD patients were significantly older and had higher Charlson Comorbidity Index scores than the PD patients, but there were no differences in duration of dialysis treatment, prevalence of diabetes, educational backgrounds, or home situations. Patients were asked to rate their overall satisfaction with and the overall impact of their dialysis therapy on their lives, using a 1 to 10 Likert scale. In addition, patients were asked to rate the impact of their therapy on 15 domains that had been cited previously as being important for patients' quality of life. The mean satisfaction score for PD patients (8.02 +/- 1.41) was higher than for HD patients (7.4 +/- 1.4; P = 0.15). PD patients indicated that there was less impact of the dialysis treatment on their lives globally (7.25 +/- 2.12 versus 6.19 +/- 2.83; P = 0.019). In addition, PD patients noted less impact of the therapy in 14 of the 15 domains examined. With the use of a proportional odds model analysis, the only significant predictor of overall satisfaction and impact of therapy was dialysis modality (P = 0.037 and P = 0.021, respectively). Patients also were asked to comment freely on the positive and negative effects of the dialysis treatments on their lives, and a taxonomy of patient perceptions and concerns was developed. This study suggests that PD patients in general are more satisfied with their overall care and believe that their treatment has less impact on their lives than HD patients. PMID- 17699348 TI - Falls and fall-related injuries in older dialysis patients. AB - Dialysis patients are increasingly older and more disabled. In community-dwelling seniors without kidney disease, falls commonly predict hospitalization, the onset of frailty, and the need for institutional care. Effective fall prevention strategies are available. On the basis of retrospective data, it was hypothesized that the fall rates of older (> or =65 yr) chronic outpatient hemodialysis (HD) patients would be higher than published rates for community-dwelling seniors (0.6 to 0.8 falls/patient-year). It also was hypothesized that risk factors for falls in dialysis outpatients would include polypharmacy, dialysis-related hypotension, cognitive impairment, and decreased functional status. Using a prospective cohort study design, HD patients who were > or =65 yr of age at a large academic dialysis unit were recruited. All study participants underwent baseline screening for fall risk factors. Patients were followed prospectively for a minimum of 1 yr. Falls were identified through biweekly patient interviews in the HD unit. A total of 162 patients (mean age 74.7 yr) were recruited; 57% were male. A total of 305 falls occurred in 76 (47%) patients over 190.5 person-years of follow-up (fall-incidence 1.60 falls/person-year). Injuries occurred in 19% of falls; 41 patients had multiple falls. Associated risk factors included age, comorbidity, mean predialysis systolic BP, and a history of falls. In the HD population, the fall risk is higher than in the general community, and fall-related morbidity is high. Better identification of HD patients who are at risk for falls and targeted fall intervention strategies are required. PMID- 17699349 TI - Hemoglobin level variability: associations with comorbidity, intercurrent events, and hospitalizations. AB - National payment policies target a hemoglobin range of 11 to 12.5 g/dl for patients with ESRD. However, clinical complications and provider practices may contribute to wide fluctuations over time. This study evaluated the frequency with which patients maintain stable hemoglobin levels below, within, and above the Centers for Medicare & Medicaid Services target range and assessed patterns of hemoglobin level change that resulted in large fluctuations across the target range during a 6-mo period. All hemodialysis patients who survived the first 6 mo of 2003, had Medicare as primary payer, and had Medicare outpatient erythropoietin claims in each of the first 6 mo of 2003 (n = 152,846) were studied. Six patient groups were defined on the basis of patterns of hemoglobin level fluctuation: Consistently low (<11 g/dl), consistently target range (11 to 12.5 g/dl), consistently high (> or =12.5 g/dl), low-amplitude fluctuation with low hemoglobin levels, low-amplitude fluctuation with high hemoglobin levels, and high-amplitude fluctuation. Only 10.3% of patients maintained stable hemoglobin levels during the 6 mo and only 6.5% in the target range. The consistently low group had the highest percentage of hospitalizations and the highest number of comorbid conditions. High-amplitude fluctuation was the most common pattern (39.5%), with hemoglobin levels falling below and rising above the target range during the 6-mo period. Hemoglobin levels in almost 90% of patients are in some degree of flux at any point in time, and the fluctuation is highly associated with clinical complications and provider practices. PMID- 17699350 TI - Pharmacokinetics and pharmacodynamics of intravenous and subcutaneous continuous erythropoietin receptor activator (C.E.R.A.) in patients with chronic kidney disease. AB - Continuous Erythropoietin Receptor Activator (C.E.R.A.) is a new agent that is in development for the treatment of anemia with extended administration intervals in patients who have chronic kidney disease (CKD), both those on and those not on dialysis. This was an open-label, randomized, multicenter, two-period, crossover study in erythropoiesis-stimulating agentnaive patients who had CKD and anemia and were receiving peritoneal dialysis. After a 1-wk run-in period, 16 patients were randomly assigned to receive a single administration of intravenous C.E.R.A. 0.4 microg/kg (n = 8) or subcutaneous C.E.R.A. 0.8 microg/kg (n = 8). Six weeks after the first administration of C.E.R.A. (4-wk assessment, 2-wk washout), the route of administration was switched so that all patients received single administrations of both intravenous C.E.R.A. 0.4 microg/kg and subcutaneous C.E.R.A. 0.8 microg/kg. C.E.R.A. had a prolonged and comparable half-life after intravenous (mean 134 h) and subcutaneous (mean 139 h) administration. Reticulocyte counts peaked at a median of 8 d after intravenous and subcutaneous administration with no difference in the time course between administration routes. This resulted in similar mean values for the area under the reticulocyte count-time curve (1191 x 10(9) and 1193 x 10(9).d per L, respectively) and the maximum absolute increase in reticulocyte counts (36 x 10(9) and 41 x 10(9)/L, respectively). C.E.R.A. has a prolonged and comparable half-life after intravenous or subcutaneous injection, suggesting that extended administration intervals may be feasible in patients with CKD. PMID- 17699351 TI - Dialysis-induced regional left ventricular dysfunction is ameliorated by cooling the dialysate. AB - Dialysis patients who develop cardiac failure have a poor prognosis. Recurrent subclinical myocardial ischemia is important in the genesis of heart failure in nondialysis patients. It has previously been demonstrated that subclinical ischemia occurs during hemodialysis; therefore, this study examined whether the improved stability of cool-temperature dialysis lessens this phenomenon. Ten patients who were prone to intradialytic hypotension entered a randomized, crossover study to compare the development of dialysis-induced left ventricular (LV) regional wall motion abnormalities (RWMA) at dialysate temperatures of 37 and 35 degrees C. Serial echocardiography with quantitative analysis was used to assess ejection fraction and regional systolic LV function. BP and hemodynamic variables were measured using continuous pulse wave analysis. The severity of thermal symptoms was scored using a simple questionnaire. Forty-nine new RWMA developed in nine patients during hemodialysis with dialysate at 37 degrees C (HD(37)), compared with thirteen RWMA that developed in four patients during HD(35) (odds ratio 3.8; 95% confidence interval 2.1 to 6.9). The majority of RWMA displayed improved function by 30 min after dialysis. Overall, regional systolic LV function was significantly more impaired during HD(37) (P < 0.001). BP was higher during HD(35), with fewer episodes of hypotension as a result of a higher peripheral resistance and no difference in stroke volume. The development of thermal symptoms was heterogeneous, with most patients tolerating HD(35) well. This study confirms previous findings of reversible LV RWMA that develop during hemodialysis. It also shows that this phenomenon can be ameliorated by reducing dialysate temperature, a simple intervention with no cost implications. PMID- 17699352 TI - Comparison of infectious complications between incident hemodialysis and peritoneal dialysis patients. AB - The impact of dialysis modality on infection, especially early in the course of dialysis, has not been well studied. This study compared infection between hemodialysis (HD) and peritoneal dialysis (PD) from the start of dialysis and evaluated factors that have an impact on infection risk. In this observational cohort study, all incident dialysis patients (n = 181; HD 119 and PD 62) at a single center from 1999 to 2005 had data collected prospectively beginning day 1 of dialysis. Excluded were those with any previous ESRD therapy. Infection rates were evaluated using multivariate Poisson regression. Overall infection rates were similar (HD 0.77 versus PD 0.86/yr; P = 0.24). Only HD patients had bacteremia (0.16/yr), and only PD patients had peritonitis (0.24/yr). Bacteremia that occurred < or =90 d after start of HD was 0.44/yr, increased compared with overall rate of 0.16/yr (P < 0.004). HD catheters, used in 67% of patients who started HD, were associated with a strikingly increased rate of bacteremia. Peritonitis < or =90 d was 0.22/yr, no different from the overall rate. Modality was not an independent predictor of overall infections (PD versus HD: relative risk 1.30; 95% confidence interval 0.93 to 1.8; P = 0.12) using multivariate analysis. PD and HD patients had similar infection rates overall, but type of infection and risk over time varied. HD patients had an especially high risk for bacteremia in the first 90 d, whereas the risk for peritonitis for the PD cohort was not different over time. These results support the placement of permanent accesses (fistula or PD catheter) before the start of dialysis to avoid use of HD catheters. PMID- 17699353 TI - Hospital resource utilization that occurs with, rather than because of, kidney failure in patients with end-stage renal disease. AB - More than $18 billion annually is attributed to care of patients with ESRD, with the perception of high renal costs for a relatively small population. It was proposed that accounting methods exaggerate resource utilization that often occurs with rather than because of kidney failure. The dialysis patients in this study had nearly all of their care at university facilities with one financial database. For 1 yr, 112 chronic hemodialysis patients were studied using demographic, insurance, and hospital facility (diagnoses, length of stay, charges, costs, and net income) variables. Substantial inpatient costs and hospitalizations were for nonrenal primary diagnoses, including malignancies, substance abuse, trauma, HIV, and psychiatric diseases: 37% of admissions, 36% of inpatient days, and 32% of charges. Dialysis patients were healthier than indicated by averaged length of stay and cost data, because results were very skewed: Mean 17.3 inpatient days but median only 2.4 d; 43% of patients had 0 to 1 inpatient days (1.3% of charges), 23% had 2 to 7 d (charges 7.6%), 18% had 8 to 30 d (charges 26%), and 16% had >30 d (charges 66%). Lengthy hospitalizations had disproportionately high operating room and respiratory care costs. The large group of relatively healthy outpatients did not avoid hospitalization by high use of facility resources. The true costs for medical care that results from ESRD are not as high as publicized, as a result of misclassification of inpatient expenses from nonrenal comorbidities. When not confounded by analyses that use data means, it is clear that substantial numbers of hemodialysis patients have very brief hospitalizations with low resource utilization. PMID- 17699354 TI - Outcome and prognosis factors in HIV-infected hemodialysis patients. AB - HIV-infected patients who are on hemodialysis have a worse prognosis than noninfected patients who are on hemodialysis. Their outcome in the highly active antiretroviral therapy (HAART) era remains unclear. Outcomes in patients who were enrolled in the French Dialysis in HIV/AIDS (DIVA) cohort were determined in a 2 yr prospective follow-up. All HIV-infected patients who were on hemodialysis in France on January 1, 2002, were included and followed prospectively until January 1, 2004. Patients' survival was examined by Kaplan-Meier method, and mortality risk factors were examined using uni- and multicovariate analyses. Survival was compared with that of 584 hemodialysis patients who did not have HIV or diabetes and were enrolled in the French Dialysis Outcomes and Practice Patterns Study II (DOPPS II) in the same period (after standardization for the average age, gender, and ethnicity of the DIVA cohort). A total of 27,577 patients were receiving hemodialysis in France at the beginning of the study; 164 (0.59%) were infected with HIV, 72% were male, mean age was 44.8 +/- 10.9 yr, and 65% were black. The 2 yr survival rate was 89 +/- 2% and statistically indistinguishable from the survival of the French cohort extracted from the DOPPS II study. Significant mortality risk factors were low CD4 cell count (hazard ratio [HR] 1.4/100 CD4 cells per mm(3) lower), high viral load (HR 2.5/1 Log per ml), absence of HAART (HR 2.7), and a history of opportunistic infection (HR 3.7), the last two being independent (HR 2.6 and 3.6, respectively). Survival of HIV-infected patients who are hemodialysis has greatly improved. A prospective cohort of paired hemodialysis patients with and without HIV is required to compare better their mortality in the HAART era. PMID- 17699355 TI - Use of hospice in the United States dialysis population. AB - Hospice is recognized for providing excellent end-of-life care but may be underused by dialysis patients. Hospice use and related outcomes were measured among dialysis patients, and factors that were associated with hospice use were identified. The 2-yr US Renal Data System dialysis patients who died between January 1, 2001, and December 31, 2002, and hospice claims from the Centers for Medicare & Medicaid Services were examined to measure prevalence, factors, and costs that were associated with dialysis withdrawal and hospice use. Of the 115,239 deceased patients, 21.8% withdrew from dialysis and 13.5% used hospice. Of those who withdrew, 41.9% used hospice. Failure to thrive was the most common reason for dialysis withdrawal (42.9%). On multivariable logistic regression analysis, factors that were significantly associated with hospice referral among patients who withdrew from dialysis were age, race, reason for withdrawal, ability to walk or transfer at dialysis initiation, and state of residence. Among patients who withdrew from dialysis and used hospice, median cost of per-patient care during the last week of life was $1858, compared with $4878 for nonhospice patients (P < 0.001); hospitalization costs accounted for most of that difference. Only 22.9% of dialysis hospice patients died in the hospital, compared with 69.0% of nonhospice patients (P < 0.001). A minority of dialysis patients use hospice, even among patients who withdrew from dialysis, whose death usually is certain. Increased hospice use may enable more dialysis patients to die at home, with substantial cost savings. Research regarding additional benefits of hospice care for dialysis patients is needed. PMID- 17699356 TI - Nephrologists' reported preparedness for end-of-life decision-making. AB - Nephrologists commonly engage in end-of-life decision-making with patients with ESRD and their families. The purpose of this study was to determine the perceived preparedness of nephrologists to make end-of-life decisions and to determine factors that are associated with the highest level of perceived preparedness. The nephrologist members of the Renal Physicians Association (RPA) and the Canadian Society of Nephrology were invited to participate in an online survey of their end-of-life decision-making practices. A total of 39% of 360 respondents perceived themselves as very well prepared to make end-of-life decisions. Age >46 yr, six or more patients withdrawn from dialysis in the preceding year, and awareness of the RPA/American Society of Nephrology (ASN) guideline on dialysis decision-making were independently associated with the highest level of self reported preparedness. Nephrologists who reported being very well prepared were more likely to use time-limited trials of dialysis and stop dialysis of a patient with permanent and severe dementia. Compared with Americans, Canadian nephrologists reported being equally prepared to make end-of-life decisions, stopped dialysis of a higher number of patients, referred fewer to hospice, and were more likely to stop dialysis of a patient with severe dementia. Nephrologists who have been in practice longer and are knowledgeable of the RPA/ASN guideline report greater preparedness to make end-of-life decisions and report doing so more often in accordance with guideline recommendations. To improve nephrologists' comfort with end-of-life decision-making, fellowship programs should teach the recommendations in the RPA/ASN guideline and position statement. PMID- 17699357 TI - Pharmacokinetics of moxifloxacin and levofloxacin in intensive care unit patients who have acute renal failure and undergo extended daily dialysis. AB - Extended daily dialysis (EDD) is increasingly popular in the treatment of acute renal failure (ARF). EDD could remove drugs to a much different degree compared with intermittent standard hemodialysis or continuous renal replacement therapies; however, there are only scarce data on how EDD influences the pharmacokinetics of frequently used drugs. The aim of this study was to determine the pharmacokinetics of two quinolone antibiotics in patients who had anuric ARF and were being treated with EDD. Adult patients who were in the intensive care unit at a tertiary care university hospital and receiving moxifloxacin (n = 10) or levofloxacin (n = 5) therapy were included. The antibiotics were administered intravenously 8 h (400 mg of moxifloxacin) or 12 h (500 mg of levofloxacin) before EDD to study pharmacokinetics off and on EDD. Treatment lasted 8 h; blood and dialysate flow rates were 160 ml/min. In addition to standard pharmacokinetic parameters, the total dialysate concentration of both drugs was measured using a technically simple single-pass batch dialysis system for EDD. Moxifloxacin pharmacokinetics in critically ill patients who had ARF and were undergoing EDD were similar to those in healthy subjects without renal impairment. Levofloxacin, although removed by EDD, had a lower total clearance compared with healthy subjects. According to these findings, anuric critically ill patients who are undergoing EDD should be treated with the standard dosage of moxifloxacin (400 mg/d intravenously). The levofloxacin dosage, however, should be reduced according to the intensity of renal replacement therapy. PMID- 17699358 TI - Comparative value of orange juice versus lemonade in reducing stone-forming risk. AB - Foods that are high in citrate content generally are assumed to deliver alkali load when consumed irrespective of the accompanying cation. The object of this randomized, crossover study was to compare the effects of orange juice with those of lemonade on acid-base profile and urinary stone risks under controlled metabolic conditions. Thirteen volunteers (nine healthy subjects and four stone formers) sequentially received distilled water, orange juice, or lemonade while on constant metabolic diet. Twenty-four-hour urine samples were collected for acid-base parameters and stone risk analysis. Orange juice but not lemonade provided alkali as evidenced by higher net gastrointestinal alkali absorption and higher urinary pH and citrate compared with control. Urinary calcium was not significantly different, but urinary oxalate was higher during the orange juice phase. The calculated supersaturation of calcium oxalate was lower in the orange juice phase compared with control. Calculated undissociated uric acid was lower in the orange juice phase compared with both control and lemonade phases. The calculated supersaturation of brushite was significantly higher in the orange juice phase compared with both control and lemonade phases. Despite comparable citrate content, this study showed that orange juice has greater alkalinizing and citraturic effects than lemonade. Consumption of orange juice was associated with lower calculated calcium oxalate supersaturation and lower calculated undissociated uric acid. This short-term study suggests that orange juice consumption could result in biochemical modification of stone risk factors; however, additional studies are needed to evaluate its role in long-term prevention of recurrent nephrolithiasis. PMID- 17699359 TI - Cardiorespiratory fitness is related to physical inactivity, metabolic risk factors, and atherosclerotic burden in glucose-intolerant renal transplant recipients. AB - The mechanisms of reduced cardiorespiratory fitness (CF) in renal transplant recipients (RTR) have not been studied closely. This study evaluated the relationships between CF and specific cardiovascular risk factors (metabolic syndrome [MS], physical inactivity, myocardial ischemia, and atherosclerotic burden) in glucose-intolerant RTR. Data were recorded on 71 glucose-intolerant RTR (mean age 55 yr; 55% male; median transplant duration 5.7 yr). MS was defined using National Cholesterol Education Programme Adult Treatment Panel III criteria. Resting and exercise stress echocardiography were performed, and myocardial ischemia was identified by new or worsening wall motion abnormalities. Cardiorespiratory fitness was determined using peak oxygen uptake (VO(2)) by expired gas analysis. Atherosclerotic burden was assessed by carotid intima-media thickness (IMT). Mean peak VO(2) was 19 +/- 7 ml/kg per min and was significantly lower than predicted peak VO(2) (29 +/- 6 ml/kg per min; P < 0.001). Patients with MS (63%) had reduced CF (17 +/- 6 versus 22 +/- 8 ml/kg per min; P = 0.001) and were more likely to be physically inactive (76 versus 48%; P = 0.02). CF was reduced in 14 patients with myocardial ischemia (15 +/- 3 versus 20 +/- 7 ml/kg per min; P = 0.05). CF was positively correlated with male gender, height, and physical activity and inversely correlated with number of MS risk factors and IMT (adjusted R(2) = 0.66). Carotid IMT added incremental value to clinical variables in determining VO(2) (adjusted R(2) = 0.65 versus 0.63; P = 0.04). Reduced CF is associated with physical inactivity, MS, and atherosclerotic burden in glucose intolerant RTR. Further studies should address whether increasing exercise and modifying MS risk factors improve CF in RTR. PMID- 17699360 TI - Risk factors for cardiovascular disease in children and young adults after renal transplantation. AB - Despite good outcomes in pediatric renal transplantation, life expectancy is reduced, mostly as a result of accelerated atherosclerosis. A comprehensive evaluation of cardiac status and risk factors for cardiovascular disease was performed in 60 patients after renal transplantation (age 3 to 29 yr; mean 15.8). Posttransplantation diabetes was diagnosed in 7%. Half of the patients did not engage in any physical activity, and this was associated with increased body mass index. Uncontrolled hypertension was found in 13% of patient, and 53% were on antihypertensive medications. BP index was associated with left ventricular mass index (LVMI). Dyslipidemia was relatively uncommon, with hypercholesterolemia found in 15% and elevated LDL cholesterol found in 10% of patients. Hyperhomocysteinemia was frequent (58%); in most patients, it was not due to folate or B(12) deficiency. Lipid and homocysteine abnormalities were associated with cyclosporine therapy. Echocardiography demonstrated normal LVMI in 93% of patients, although LVMI was higher than in healthy control subjects. Cardiac troponin I was normal in all patients, but N-terminal pro-brain natriuretic peptide was elevated in 35% and was associated with LVMI and renal function. Although present cardiac status is relatively normal in pediatric renal transplantation patients, cardiac risk factors are common, and strategies to prevent cardiovascular disease need to be developed. PMID- 17699361 TI - Advanced glycation end products and nephrotoxicity of high-protein diets. AB - The popularity of high-protein diets has surged recently as obesity has become more and more common in the United States and other developed nations. In view of the high prevalence of type 2 diabetes and chronic kidney disease among obese people, it is important to understand potential effects of high-protein diets on the kidney. The hypothesis that high-protein diets are nephrotoxic because of their excessive dietary advanced glycation end product (AGE) content and an increased amino acid load that enhances AGE formation in situ was explored. This review discusses the following evidence: (1) High-protein diets are deleterious to the kidney; (2) AGE are metabolic mediators of kidney damage; (3) dietary protein-derived AGE contribute to proinflammatory and pro-oxidative processes in diabetes and kidney disease; and (4) dietary protein-derived AGE produce functional and structural abnormalities that are involved in kidney damage. Future research should consider dietary AGE as a potential therapeutic target for kidney disease in obesity, diabetes, and perhaps other causes of chronic kidney disease. PMID- 17699362 TI - Bone disease after renal transplantation. AB - It has been well established that a rapid decrease in bone mineral density (BMD) occurs in the first 6 to 12 mo after a successful renal transplantation and persists, albeit at a lower rate, for many years. This rapid BMD loss significantly increases the fracture risk of these patients to levels that are even higher than those of patients who have chronic kidney disease stage 5 and are on dialysis. The presence of low BMD in renal transplant patients as a predictor of risk fracture is controversial. Indeed, as has been suggested also for patients with postmenopausal osteoporosis, there is not a compelling correlation between the decline in BMD and skeletal fractures. However, bone disease after renal transplantation probably represents a unique bone disorder that must encompass underlying renal osteodystrophy. In fact, this syndrome results from multiple factors that include pretransplantation bone status, use of glucocorticoids and other immunosuppressive drugs, hypophosphatemia, and alterations of the calcium-vitamin D axis. Recent studies have demonstrated decreased osteoblast number, reduced bone formation rate, delayed mineralization, and increased osteoblast and osteocyte apoptosis. Bisphosphonates and vitamin D metabolites may be valuable in preventing or diminishing early bone loss. However, clinicians should be careful with the use of bisphosphonates and oversuppression of bone, especially in patients with low bone turnover. New prospective, controlled trials are required to confirm the real efficacy of these drugs, particularly in long-term renal transplant patients. PMID- 17699363 TI - Defining acute renal failure: RIFLE and beyond. AB - The introduction of the RIFLE classification has increased the conceptual understanding of the acute kidney injury (AKI) syndrome, and this classification has been successfully tested in a number of clinical studies. This review discusses the strengths and weaknesses of the RIFLE classification and suggests additional parameters to broaden future definitions of AKI. These definitions should not only focus on kidney function alone, but also include parameters describing the origin of the patient, the most important causal factors responsible for AKI and information on the pre-existing kidney function. This more complete definition should lead to a decrease in the variability of the results of epidemiological studies and of future clinical trials in AKI populations. PMID- 17699364 TI - Light chains, casts, sheets and fibrils: monoclonal immunoglobulin diseases and immunotactoid/fibrillary glomerulopathy. PMID- 17699365 TI - Multiple myeloma. AB - Multiple myeloma is a malignant disease characterized by plasmacytosis, paraprotein production, bone lesions, hypercalcemia, susceptibility to infections, and renal impairment. The underlying pathophysiologic phenomena of the clinical features include suppression of humoral- and cell-mediated immunity, elevation of IL-6, abnormalities of the bone marrow microenvironment, and increased osteoclastic activity. Overwhelming predictors of prognosis include albumin, beta2-microglobulin, and chromosomal karyotype. With modern, intensive therapy including autologous hematopoietic stem cell transplantation, the median survival is approximately 5 yr. The disease is incurable and eventually relapses; requiring salvage therapy. The development of newer agents such as thalidomide, bortezomib, and lenalidomide--drugs that interfere with several of the complex pathophysiologic steps--has improved the outlook of relapsed disease significantly. Current studies are directed at exploring the use of these novel agents earlier in the course of therapy, development of newer targeted therapies, and the use of gene expression profiling to individualize therapy. PMID- 17699366 TI - Light-chain (AL) amyloidosis: diagnosis and treatment. AB - Light-chain (AL) amyloidosis is the most common form of systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. The disease often is difficult to recognize because of its broad range of manifestations and what often are vague symptoms. The clinical syndromes at presentation include nephrotic-range proteinuria with or without renal dysfunction, hepatomegaly, congestive heart failure, and autonomic or sensory neuropathy. Recent diagnostic and prognostic advances include the serum free light-chain assay, cardiac magnetic resonance imaging, and serologic cardiac biomarkers. Treatment strategies that have evolved during the past decade are prolonging survival and preserving organ function in patients with this disease. This review outlines approaches to diagnosis, assessment of disease severity, and treatment of AL amyloidosis. PMID- 17699368 TI - Immuotactoid glomerulopathy (fibrillary glomerulonephritis). PMID- 17699367 TI - Immunoglobulin light (heavy)-chain deposition disease: from molecular medicine to pathophysiology-driven therapy. AB - Light-, light- and heavy-, and heavy-chain deposition diseases belong to a family of diseases that include light-chain (AL)-amyloid, nonamyloid fibrillary and immunotactoid glomerulonephritis, and cryoglobulinemic glomerulonephritis, in which monoclonal Ig or their subunits become deposited in kidney. In clinical and pathologic terms, light-, light- and heavy-, and heavy-chain deposition diseases essentially are similar and are characterized by prominent renal involvement with severe renal failure; extrarenal manifestations; diabetes-like nodular glomerulosclerosis; marked thickening of tubular basement membranes; and monotypic deposits of light chain, mostly kappa, and/or heavy chain that feature a nonorganized granular, electron-dense appearance by electron microscopy. The most common cause is myeloma. Recent progress has been made in the understanding of the molecular pathomechanisms of Ig-chain deposition and extracellular matrix accumulation, which opens up new therapeutic avenues in addition to eradication of the Ig-secreting plasma cell clone. Because these diseases represent a model of glomerular and interstitial fibrosis that is induced by a single molecule species, a better understanding of their pathomechanisms may help to unravel the pathophysiology of kidney fibrosis and renal disease progression. PMID- 17699369 TI - Should dialysis patients ever receive warfarin and for what reasons? PMID- 17699370 TI - A primer on the design, conduct, and interpretation of clinical trials. AB - Clinical trials are an especially powerful study design that often guides health care policy and clinical practice. Indeed, well-designed and rigorously conducted trials can establish the etiologic relevance of modifiable risk factors and the benefits (and risks) of candidate therapies. Contemporary schema that classify evidence place results from randomized trials at the pinnacle of evidence. The primary objective of this article is to provide an overview of the design, conduct, and interpretation of trials with an emphasis on aspects that are relevant to nephrology. PMID- 17699371 TI - More than a decade of experience and still no consensus: controversies in iron therapy. PMID- 17699372 TI - Acute injury with intravenous iron and concerns regarding long-term safety. AB - Intravenous iron is widely used to maintain adequate iron stores and prevent iron deficiency anemia in patients with chronic kidney disease, yet concerns remain about its long-term safety with respect to oxidative stress, kidney injury, and accelerated atherosclerosis, which are the subjects of this review. Three parenteral iron formulations are available for use in the United States: Iron dextran, iron gluconate, and iron sucrose. Iron dextran, especially the high molecular form, has been linked with anaphylactoid and anaphylactic reactions, and its use has been declining. A portion of intravenous iron preparations is redox-active, labile iron available for direct donation to transferrin. In vitro tests show that commonly available intravenous iron formulations have differing capacities to saturate transferrin directly: Iron gluconate > iron sucrose > iron dextran. Intravenous iron treatment produces oxidative stress, as demonstrated by increases in plasma levels of lipid peroxidation products (malondialdehyde), at a point that is much earlier than the time to peak concentration of catalytically active iron, suggesting a direct effect of iron sucrose on oxidative stress. Furthermore, iron sucrose infusion produces endothelial dysfunction that seems to peak earlier than the serum level of free iron. Intravenous iron sucrose infusion also has been shown to produce acute renal injury and inflammation as demonstrated by increased urinary albumin, enzyme (N-acetyl-beta glucosaminidase), and cytokine (chemokine monocyte chemoattractant protein-1) excretions. Although the long-term dangers of intravenous iron are unproved, these data call for examination of effects of intravenous iron on the potential for long-term harm in patients with chronic kidney disease. PMID- 17699373 TI - Parenteral iron compounds: potent oxidants but mainstays of anemia management in chronic renal disease. AB - Ferric iron (Fe)-carbohydrate complexes are widely used for treating Fe deficiency in patients who are unable to meet their Fe requirements with oral supplements. Intravenous Fe generally is well tolerated and effective in correcting Fe-deficient states. However, the complexing of Fe to carbohydrate polymers does not block its potent pro-oxidant effects; systemic free radical generation and, possibly, tissue damage may result. The purpose of this review is to (1) underscore the capacity of currently used parenteral Fe formulations to induce oxidative stress, (2) compare the severity of these oxidant reactions with those that result from unshielded Fe salts and with each other, and (3) speculate as to the potential of these agents to induce acute renal cell injury and augment systemic inflammatory responses. The experimental data that are reviewed should not be extrapolated to the clinical setting or be used for clinical decision making. Rather, it is hoped that the information provided herein may have utility for clinical hypothesis generation and, hence, future clinical studies. By so doing, a better understanding of Fe's potential protean effects on patients with renal disease may result. PMID- 17699374 TI - Assessing iron status: beyond serum ferritin and transferrin saturation. AB - The increasing prevalence of multiple comorbidities among anemic patients with chronic kidney disease has made the use of serum ferritin and transferrin saturation more challenging in diagnosing iron deficiency. Because serum ferritin is an acute-phase reactant and because the inflammatory state may inhibit the mobilization of iron from reticuloendothelial stores, the scenario of patients with serum ferritin >800 ng/ml, suggesting iron overload, and transferrin saturation <20%, suggesting iron deficiency, has become more common. This article revisits the basis for the Kidney Disease Outcomes Quality Initiative recommendations regarding the use of serum ferritin and transferrin saturation in guiding iron therapy, then explores some of the newer alternative markers for iron status that may be useful when serum ferritin and transferrin saturation are insufficient. These newer tests include reticulocyte hemoglobin content, percentage of hypochromic red cells, and soluble transferrin receptor, all of which have shown some promise in limited studies. Finally, the role of hepcidin, a hepatic polypeptide, in the pathophysiology of iron mobilization is reviewed briefly. PMID- 17699375 TI - The fascinating but deceptive ferritin: to measure it or not to measure it in chronic kidney disease? AB - Although the emergence of erythropoiesis-stimulating agents has revolutionized the anemia management of chronic kidney disease (CKD) in the past two decades, strategies to assess iron (Fe) status and to provide Fe supplementation have remained indistinct. The reported cases of hemochromatosis in dialysis patients from the pre-erythropoiesis-stimulating agent era along with the possible associations of Fe with infection and oxidative stress have fueled the "iron apprehension." To date, no reliable marker of Fe stores in CKD has been agreed on. Serum ferritin continues to be the focus of attention. Almost half of all maintenance hemodialysis patients have a serum ferritin >500 ng/ml. In this ferritin range, Fe supplementation currently is not encouraged, although most reported hemochromatosis cases had a serum ferritin >2000 ng/ml. The moderate range hyperferritinemia (500 to 2000 ng/ml) seems to be due mostly to non-Fe related conditions, including inflammation, malnutrition, liver disease, infection, and malignancy. Recent epidemiologic studies have shown that a low, rather than a high, serum Fe is associated with a poor survival in maintenance hemodialysis patients. In multivariate adjusted models that mitigate the confounding effect of malnutrition-inflammation, serum ferritin <1200 ng/ml and Fe saturation ratio in 30 to 50% range are associated with the greatest survival in maintenance hemodialysis patients. Although ferritin is a fascinating molecule, moderate hyperferritinemia is a misleading marker of Fe stores in patients with CKD. It may be time to revisit the utility of serum ferritin in CKD and ask ourselves whether its measurement has helped us or has caused more confusion and controversy. PMID- 17699376 TI - Patient care guidelines: problems and solutions. AB - This month's CJASN Controversies section presents two discussions of interactions between industry and the KDOQI patient care guidelines for the treatment of anemia in chronic kidney disease and ESRD. In subsequent issues we will present invited commentaries from other authorities in this area and invite our general readership to express their opinions. PMID- 17699377 TI - Influence of industry on renal guideline development. PMID- 17699378 TI - Appraisal of evidence and control of bias in the kidney disease outcomes quality initiative guideline development process. PMID- 17699379 TI - Practice recommendations based on low, very low, and missing evidence. PMID- 17699382 TI - Could uric acid have a role in acute renal failure? AB - Acute renal failure (ARF), induced by either toxins or ischemia, is associated with significant morbidity. The pathogenesis of ARF is complex and is characterized by renal vasoconstriction and oxidative stress in association with tubular and microvascular injury and interstitial inflammation. In many situations, ARF is associated with a rise in serum uric acid as a result of both increased generation and decreased excretion. Although it is widely recognized that markedly elevated levels of uric acid can cause ARF via supersaturation within the tubules with crystallization and intrarenal obstruction ("acute urate nephropathy"), the possibility that uric acid may affect renal outcomes at concentrations that do not lead to tubular obstruction have not been considered. This article reviews both the salutary and the adverse effects of uric acid on biologic processes and presents the hypothesis that hyperuricemia, particularly if chronic and marked, likely represents a true risk factor for ARF. Hyperuricemia also may account for the paradoxic lack of benefit of diuretics in the management of ARF. It is suggested that studies are needed to investigate the role of chronic hyperuricemia on renal outcomes after acute tubular injury. PMID- 17699383 TI - Elevated plasma concentrations of IL-6 and elevated APACHE II score predict acute kidney injury in patients with severe sepsis. AB - Acute kidney injury (AKI) is common in critically ill patients with severe sepsis (SS), and the predictors of AKI in this population have not been well characterized. The study group was the placebo group of the Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) data set. PROWESS is a prospective, randomized, controlled study of the use of drotrecogin alpha (activated) for the treatment of SS. Placebo patients who had an admission renal sepsis organ failure score of 2 or more were excluded. AKI was defined as an increase in serum creatinine of 25% or 0.3 mg/dl during the first week postbaseline. The incidence of relevant parameters was then compared in patients with and without AKI. Half of the patients were randomly assigned to a model-building data set, and multivariable Cox regression was used to determine risk factors. Factors that remained significant in the remaining "model validation" data set were considered significant. Of the 840 patients in the placebo group, 547 met inclusion criteria. Of the 547 patients, 127 (23.2%) patients met criteria for AKI. The mean age of the 547 patients was 59.8 +/- 17.0, and 43.3% of the cohort were female. The ethnicity breakdown was as follows: White 83.2%, black 5.9%, and other 11%. Univariate analyses indicated that patients with AKI had a higher incidence of a dependence on the basis of activity of daily living scale (38.6 versus 26.7%; P = 0.01), a lower baseline platelet count (193,000 versus 222,000; P = 0.02), a higher baseline respiratory Sepsis Organ Failure Assessment score (2.9 versus 2.7; P = 0.02), higher preinfusion Acute Physiology and Chronic Health Evaluation II (APACHE II) score (24.8 versus 22.0; P = 0.0002), older age (63.7 versus 58.7 yr; P = 0.008), and higher log IL-6 (6.6 versus 5.8; P = 0.0006). In a multivariable Cox regression, the predictors of AKI were log IL-6 (P < 0.0001) and APACHE II (P = 0.0008). Increased log IL-6 and APACHE II score are significant risk factors of AKI in patients with SS. IL-6 data and the absence of correlation with measures of hypotension (e.g., mean arterial pressure, dosage of vasopressors) support the notion that inflammation is a significant component of AKI in SS. PMID- 17699384 TI - Recessive NPHS2 (Podocin) mutations are rare in adult-onset idiopathic focal segmental glomerulosclerosis. AB - Recessive NPHS2 (podocin) mutations account for up to approximately 30% of steroid-resistant idiopathic FSGS in children and are associated with a reduced risk for disease recurrence after renal transplantation. R229Q, a missense variant that is present in 3.6% of the white population, has been implicated as a common disease-causing mutation. Given these clinical implications, we examined the role of NPHS2 mutations in a cohort of patients with adult-onset FSGS. We used denaturing HPLC to screen for heterozygous and homozygous gene variants in PCR-amplified DNA fragments that contained all exons and splice junctions of NPHS2. Bidirectional sequencing was performed to define all of the gene variants detected. With the use of the denaturing HPLC in a single-blind pilot study, 40 of 43 known NPHS2 mutations were detected from 22 pediatric patients with FSGS to establish a test sensitivity of 93%. This screen then was applied to 87 adult patients with idiopathic FSGS (15 steroid-sensitive, 63 steroid-resistant, and nine familial cases). In this latter cohort, compound heterozygous mutations were detected only in one patient with steroid-sensitive FSGS (R229Q and Q285fsX302) and no homozygous mutations. Overall, R229Q accounted for eight (80%) of ten of the putative mutant alleles that were detected in the study cohort. Contrary to the pediatric experience, recessive NPHS2 mutations are rare in this study population, suggesting that the pathogenesis of FSGS in adults may differ from that in children. These data do not support R229Q as a disease-causing mutation for steroid-resistant FSGS. PMID- 17699385 TI - Normal values for renal length and volume as measured by magnetic resonance imaging. AB - The objective of this magnetic resonance imaging (MRI) study was to (1) test the validity of the ellipsoid formula for estimating kidney volume using ex vivo and in vivo models and (2) establish a normal range of values for kidney length and volume in patients with no known history of renal disease. The volumes of five excised porcine kidneys were measured by (1) disc-summation method, (2) ellipsoid formula, and (3) water displacement method. In a retrospective, consecutive group of clinically referred patients (n = 150; 300 kidneys), individual kidney volume and length were calculated by the disc-summation method and by multiplanar reformation of MRI data, respectively. For comparison, kidney volumes also were calculated using the ellipsoid formula in all patients. Renal volume that was obtained by MRI using the disc-summation method was within 5% of the volume that was determined by the water displacement method, independent of the spatial resolution of the MRI technique used. Data from both the in vivo and the ex vivo models revealed that the ellipsoid formula that commonly is used in ultrasonography underestimates renal volume by 17 to 29% compared with the disc summation method (P < 0.05). As measured by MRI (mean +/- SD), kidney lengths were 12.4 +/- 0.9 cm for men and 11.6 +/- 1.1 cm for women, and kidney volumes were 202 +/- 36 ml for men and 154 +/- 33 ml for women. The results from the ex vivo MRI study show that the kidney volume that was obtained using the disc summation method is within 5% of the true kidney volume as measured by the water displacement method. The ellipsoid formula consistently and significantly underestimates the true kidney volume. The length and the volume of kidneys that are obtained by MRI in patients with no known history of intrinsic renal disease are greater than the commonly quoted reference values that are obtained by ultrasonography. PMID- 17699386 TI - Adiponectin in children with chronic kidney disease: role of adiposity and kidney dysfunction. AB - Low serum adiponectin is a known cardiovascular risk in adult chronic kidney disease (CKD). However, adiponectin concentrations and their relation with other cardiovascular risks have not been studied in children with preterminal CKD. Forty-four children and adolescents who were aged 6 to 21 yr and had stages 2 to 4 CKD had serum adipocytes, lipoproteins, markers of inflammation, homocysteine, and insulin levels determined cross-sectionally. There were 29 lean (body mass index [BMI] <85th percentile) and 15 nonlean (BMI > or =85th percentile) patients. Mean serum adiponectin level was 30.6 +/- 14.1 microg/ml (range 7.1 to 67.8 microg/ml). A total of 83% of patients had elevated adiponectin level. Despite similar kidney function, lean patients had significantly higher adiponectin levels than nonlean patients (34.1 +/- 13.4 microg/ml versus 23.6 +/- 13.3 microg/ml; P = 0.02). In univariate analysis, serum adiponectin negatively correlated with age (r = -0.34, P = 0.02), BMI (r = -0.47, P = 0.001), leptin (r = -0.41, P = 0.006), GFR (r = -0.39, P = 0.02), and insulin (r = -0.36, P = 0.01) and positively correlated with ApoA2 (r = 0.30, P = 0.04); no significant associations were found with markers of inflammation or homocysteine. Multivariate stepwise analysis showed that GFR (beta = -0.008, P = 0.001), BMI (beta = -0.16, P = 0.015), and age (beta = -0.04, P = 0.018) independently predicted serum adiponectin levels. Separate analysis of lean patients showed no significant relations with age or BMI; only GFR independently predicted serum adiponectin level (beta = -0.01, P = 0.0008). It is concluded that serum adiponectin is elevated in children and adolescents with stages 2 to 4 CKD and that decreased kidney function is a major determinant of elevated adiponectin concentrations. Despite overall elevated adiponectin, overweight patients display lower serum adiponectin levels and might be at risk for future cardiovascular complications. PMID- 17699387 TI - Factors that determine an incomplete recovery of renal function in macrohematuria induced acute renal failure of IgA nephropathy. AB - Acute renal failure that is associated with macroscopic hematuria (ARF-MH) is a widely known complication of IgA nephropathy (IgAN). Although spontaneous recovery of renal function after cessation of MH has been described, no long-term outcome studies have been performed. The outcome of patients who had biopsy proven IgAN and presented an ARF-MH episode in the period 1975 through 2005 was studied. Thirty-six episodes of ARF-MH that occurred in 32 patients were identified. A complete recovery of baseline renal function after cessation of MH was observed in 27 (group 1); in the remaining nine episodes (25%; group 2), estimated GFR (eGFR) did not reach the baseline value. Final eGFR was 89 +/- 28 ml/min per 1.73 m(2) in group 1 patients and 38 +/- 12 ml/min per 1.73 m(2) in group 2 patients (P = 0.0005). The duration of MH was significantly longer in group 2 patients: 33.7 +/- 25.3 versus 15.4 +/- 18.4 d (P = 0008). A high proportion of tubules that were filled by red blood cell casts and had signs of acute tubular necrosis were the most striking histologic abnormalities. In conclusion, a significant proportion (25%) of ARF-MH in IgAN did not recover the baseline renal function after the disappearance of MH. Duration of MH longer than 10 d, age >50 yr, decreased baseline eGFR, absence of previous episodes of MH, and the severity of tubular necrosis were significant risk factors for an incomplete recovery of renal function. PMID- 17699388 TI - Proteinuria-lowering effect of heparin therapy in diabetic nephropathy without affecting the renin-angiotensin-aldosterone system. AB - Angiotensin-converting enzyme inhibitors and angiotensin II (AngII) type 1 receptor blockers lower proteinuria and preserve renal function in diabetic nephropathy (DN). The antiproteinuric effects are greater than their blood pressure reduction, involving the sieving properties of the glomerular filter. In DN, glomerular staining for heparan sulfate proteoglycans is decreased. AngII inhibits heparan sulfate synthesis. Also, heparins modulate AngII signaling in glomerular cells, inhibiting aldosterone synthesis and lowering proteinuria in DN. Is the antiproteinuric effect of heparins due to its interference with the renin-angiotensin-aldosterone system? Ten volunteers each with DN and glomerulonephritis and control subjects were examined before and after low-dosage enoxaparin. Renal hemodynamics were determined with (99m)Tc-DTPA and (131)I hippurate clearance. Glomerular filtration rate (GFR), effective renal plasma flow, mean arterial pressure, and heart rate were measured at baseline and during AngII infusion before and after enoxaparin while on normal salt and salt restriction. Enoxaparin did not lower aldosterone levels. GFR remained stable in all groups. AngII caused a significant decrease in effective renal plasma flow, whereas mean arterial pressure and heart rate increased significantly. Enoxaparin did not influence the AngII-induced changes of renal hemodynamics during normal salt intake or salt restriction. All groups showed identical responses to AngII before and after enoxaparin. In patients with diabetes, enoxaparin caused a significant decrease in proteinuria. It is concluded that the antiproteinuric effect of heparins in DN cannot be explained via interaction with the renin angiotensin-aldosterone system. The absence of hemodynamic changes combined with reduced proteinuria point to intrinsic alterations in the glomerular filter. The effects were seen only in DN, not in glomerulonephritis. PMID- 17699389 TI - Detecting latent tuberculosis infection in hemodialysis patients: a head-to-head comparison of the T-SPOT.TB test, tuberculin skin test, and an expert physician panel. AB - Current guidelines advocate screening hemodialysis patients for latent tuberculosis infection; however, the tuberculin skin test (TST) is believed to be insensitive in this population. This study compared the diagnostic utility of the TST with that of an IFN-gamma assay (T-SPOT.TB) and the clinical consensus of an expert physician panel. A total of 203 patients with ESRD were evaluated for latent tuberculosis infection with the TST, T-SPOT.TB test, and an expert physician panel. Test results were compared with respect to their association with established tuberculosis risk factors. Tuberculosis infection, as estimated by the tuberculin test, T-SPOT.TB test, and expert physician panel, was detected in 12.8%, 35.5, and 26.1 of patients respectively. Among patients with a history of active tuberculosis and radiographic markers of previous infection, 78.6 and 72.7% had positive T.SPOT.TB results, compared with 21.4 and 18.2% who had positive tuberculin tests. The physician panel unanimously declared infection in these two groups. On multivariate analysis, a positive T-SPOT.TB test was associated with a history of active tuberculosis, radiographic markers of previous infection, and birth in an endemic country, whereas a physician panel diagnosis also was associated with a history of previous tuberculosis contact. The TST is insensitive in hemodialysis patients and is not recommended to be used in isolation to diagnose latent tuberculosis infection. It is suggested that a combination of T-SPOT.TB testing and medical assessment may be the most accurate screening method. PMID- 17699390 TI - Peritoneal dialysis with solutions containing amino acids plus glucose promotes protein synthesis during oral feeding. AB - Inadequate food intake plays an important role in the development of malnutrition. Recently, an increased rate of protein anabolism was shown in fasting state in patients who were on automated peritoneal dialysis with combined amino acids (AA) and glucose (G) dialysate serving as a source of both proteins and calories. This study investigated the effects of such a dialysis procedure in the daytime in the fed state in patients who were on continuous ambulatory peritoneal dialysis (CAPD). A crossover study was performed in 12 CAPD patients to compare, at 7-d intervals, a mixture of AA (Nutrineal 1.1%) plus G (Physioneal l.36 to 3.86%) versus G only as control dialysate. Whole-body protein turnover was studied by primed constant intravenous infusion of (13)C-leucine during the 9 h dialysis. For meeting steady-state conditions during whole-body protein turnover, frequent exchanges with a mixture of AA plus G were done using an automated cycler. Fed-state conditions were created by identical liquid hourly meals. Using AA plus G dialysate, as compared with the control, rates of protein synthesis increased significantly (2.02 +/- 0.08 versus 1.94 +/- 0.07 mumol leucine/kg per min [mean +/- SEM]; P = 0.039). Rates of protein breakdown and net protein balance did not differ significantly between AA plus G and G. In conclusion, dialysate that contains AA plus G also improves protein synthesis in fed CAPD patients. The use of such a mixture may contribute to long-term improvement of the nutritional status in malnourished CAPD patients with deficient food intake. PMID- 17699391 TI - Exploring secular trends in the likelihood of receiving treatment for end-stage renal disease. AB - There is a limited understanding of the forces that drive the steady rise in the number of patients who receive treatment for ESRD. It was hypothesized that this is not simply due to increasing prevalence of chronic kidney disease (CKD) or changes in renal failure risk factors in the population from which ESRD cases develop. A noncurrent cohort study was conducted to quantify the change over time (per year) in the likelihood of receiving ESRD therapy in a cohort of 320,252 individuals who volunteered for health check-ups between 1964 and 1985. Initiation of ESRD treatment was ascertained using the US Renal Data System registry through 2000. A total of 1471 cases of ESRD were observed during 8,347,955 person-years of observation, with ESRD cases developing between 1973 and 2000. In unadjusted Cox proportional hazards analysis, individuals who were examined later in time had an 8% per year higher risk for progressing to receive treatment for ESRD (relative risk 1.08; 95% confidence interval 1.05 to 1.11). This temporal trend in risk for future ESRD associated with year of cohort entry (baseline examination) was not explained by increases over time in the prevalence of CKD or risk factors for renal failure. After adjustment for age, gender, race, diabetes, BP, body mass index, education level, smoking status, history of myocardial infarction, serum cholesterol, proteinuria, hematuria, and serum creatinine level, there remained an 8% per year increase in risk (relative risk 1.08; 95% confidence interval 1.06 to 1.11). Among individuals who were examined from the 1960s through the 1980s, those who were examined later were more likely to receive treatment for ESRD. This trend was not accounted for by increasing prevalence of baseline CKD or risk factors for renal failure. These findings should spur further research into other forces that drive the rise in treated ESRD. PMID- 17699392 TI - Predictors of early mortality among incident US hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS). AB - Mortality risk among hemodialysis (HD) patients may be highest soon after initiation of HD. A period of elevated mortality risk was identified among US incident HD patients, and which patient characteristics predict death during this period and throughout the first year was examined using data from the Dialysis Outcomes and Practice Patterns Study (DOPPS; 1996 through 2004). A retrospective cohort study design was used to identify mortality risk factors. All patient information was collected at enrollment. Life-table analyses and discrete logistic regression were used to identify a period of elevated mortality risk. Cox regression was used to estimate adjusted hazard ratios (HR) measuring associations between patient characteristics and mortality and to examine whether these associations changed during the first year of HD. Among 4802 incident patients, risk for death was elevated during the first 120 d compared with 121 to 365 d (27.5 versus 21.9 deaths per 100 person-years; P = 0.002). Cause-specific mortality rates were higher in the first 120 d than in the subsequent 121 to 365 d for nearly all causes, with the greatest difference being for cardiovascular related deaths. In addition, 20% of all deaths in the first 120 d occurred subsequent to withdrawal from dialysis. Most covariates were found to have consistent effects during the first year of HD: Older age, catheter vascular access, albumin <3.5, phosphorus <3.5, cancer, and congestive heart failure all were associated with elevated mortality. Pre-ESRD nephrology care was associated with a significantly lower risk for death before 120 d (HR 0.65; 95% confidence interval 0.51 to 0.83) but not in the subsequent 121- to 365-d period (HR 1.03; 95% confidence interval 0.83 to 1.27). This care was related to approximately 50% lower rates of both cardiac deaths and withdrawal from dialysis during the first 120 d. Mortality risk was highest in the first 120 d after HD initiation. Inadequate predialysis nephrology care was strongly associated with mortality during this period, highlighting the potential benefits of contact with a nephrologist at least 1 mo before HD initiation. PMID- 17699393 TI - Effects of urinary tract infection on outcomes after renal transplantation in children. AB - Urinary tract infection (UTI) is the most common infection after kidney transplantation. A previous analysis showed that late (>6 mo after transplantation) UTI is associated with earlier graft loss in adults. It was hypothesized that children who are younger than 18 yr would be at higher risk to develop UTI and develop graft loss after both early and late UTI. The US Renal Data System database was analyzed from 1996 to 2000 for Medicare claims (composite of inpatient and outpatient) for UTI up to 36 mo after transplantation. SPSS software and Cox regression models were used to determine association of UTI and age after adjustment for covariates. Early UTI was defined as occurring <6 mo after transplantation, and late UTI was defined as occurring > or =6 mo after transplantation. The risk for graft loss after early UTI was elevated in all children (adjusted hazard ratio [AHR] 5.47; 95% confidence interval [CI] 1.93 to 15.4; P < 0.001) but not after late UTI (AHR 2.09; 95% CI 0.56 to 7.80; P = 0.27). Risk for posttransplantation death was not increased significantly after either early UTI (AHR 1.23; 95% CI 0.37 to 4.08) or late UTI (relative risk 2.22; 95% CI 0.90 to 5.44). Boys aged 2 to 5 (versus age 13 to <18 years) were at significantly higher risk for UTI. In girls, only those in the youngest age category (0 to 1) had higher risk for UTI. Children are at greater risk for graft loss after early but not necessarily late UTI. UTI was not an independent predictor of death in this population. PMID- 17699394 TI - Nephrologists' changing practices in reported end-of-life decision-making. AB - Because the dialysis patient population is increasingly composed of older patients with high symptom burden, shortened life expectancy, and multiple comorbid conditions, nephrologists often engage in end-of-life decision-making with their patients. In the 1990s, reported practices of nephrologists' end-of life decision-making showed much variability. In part as a reaction to that variability, the Renal Physicians Association (RPA) and the American Society of Nephrology (ASN) developed a clinical practice guideline on end-of-life decision making. To determine whether nephrologists' attitudes and reported practices had changed over time, survey responses from 296 nephrologists completing an online survey in 2005 were compared with 318 nephrologists who completed a similar mailed survey in 1990. In 2005, less variability was noted in reported practices to withhold dialysis from a permanently unconscious patient (90% would withhold in 2005 versus 83% who would withhold in 1990, P < 0.001) and to stop dialysis in a severely demented patient (53% in 2005 would stop versus 39% in 1990, P < 0.00001). In 2005, significantly more dialysis units were reported to have written policies on cardiopulmonary resuscitation (86% in 2005 versus 31% in 1990, P < 0.0001) and withdrawal of dialysis (30% in 2005 versus 15% in 1990, P < 0.0002); nephrologists were also more likely to honor a dialysis patient's do-not resuscitate order (83% in 2005 versus 66%, P < 0.0002) and to consider consulting a Network ethics committee (52% in 2005 versus 39%, P < 0.001). Nephrologists' reported practices in end-of-life care have changed significantly over the 15 years separating the two surveys, suggesting that the development of the clinical practice guideline was worthwhile. PMID- 17699395 TI - Magnetic resonance measurements of renal blood flow and disease progression in autosomal dominant polycystic kidney disease. AB - Whether changes in renal blood flow (RBF) are associated with and possibly contribute to cystic disease progression in autosomal dominant polycystic kidney disease (ADPKD) has not been ascertained. The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) was created to develop imaging techniques and analyses to evaluate progression. A total of 131 participants with early ADPKD had measurements of RBF and total kidney (TKV) and cyst (TCV) volumes by magnetic resonance and of GFR by iothalamate clearance at baseline and 1, 2, and 3 yr. The effects of age, gender, body mass index, hypertension status, mean arterial pressure (MAP), TKV, TCV, RBF, renal vascular resistance (RVR), GFR, serum uric acid, HDL and LDL cholesterol, 24-h urine volume, sodium (UNaE) and albumin (UAE) excretions, and estimated protein intake were examined at baseline on TKV, TCV, and GFR slopes. TKV and TCV increased, RBF decreased, and GFR remained stable. TKV, TCV, RVR, serum uric acid, UAE, UNaE, age, body mass index, MAP, and estimated protein intake were positively and RBF and GFR negatively correlated with TKV and TCV slopes. TKV, RBF, UNaE, and UAE were independent predictors of TKV and TCV slopes (structural disease progression). TKV, TCV, RVR, and MAP were negatively and RBF positively correlated with GFR slopes. Regression to the mean confounded the analysis of GFR slopes. TKV and RBF were independent predictors of GFR decline (functional disease progression). In ADPKD, RBF reduction (1) parallels TKV increase, (2) precedes GFR decline, and (3) predicts structural and functional disease progression. PMID- 17699396 TI - Calcification of coronary intima and media: immunohistochemistry, backscatter imaging, and x-ray analysis in renal and nonrenal patients. AB - Coronary calcification is a potent predictor of cardiac events. In patients with chronic renal disease, both prevalence and intensity of coronary calcification are increased. It has remained uncertain whether it is the intima of the coronaries or the media that is calcified and whether the morphologic details of calcified plaques differ between renal and nonrenal patients. Autopsy samples of coronaries were obtained from standard sites in 23 renal and 23 age- and gender matched nonuremic patients. Specimens were examined using light and electron microscopy, immunohistochemistry, backscatter imaging, and x-ray analysis. In coronaries, calcified plaques occupied a similar proportion of the intima area in renal versus nonrenal patients (17.3 +/- 11.9 versus 18.1 +/- 11.9%) but occupied a significantly higher proportion of the media (16.6 +/- 10.6 versus 3.8 +/- 2.31%). Expression of the proteins osteocalcin, C-reactive protein, TGF-beta, and collagen IV was significantly more intensive around coronary plaques of renal compared with nonrenal patients. The non-plaque-bearing intima of renal patients showed minimal staining for fetuin, but fetuin staining was seen surrounding calcified plaques. In addition, more pronounced deposition of C5b-9 was found around coronary plaques of renal patients, and glycophorin deposition pointed to more past intraplaque hemorrhage in renal patients. Calcification by electron backscatter analysis is more intense in the coronary media, but not if the intima is more intense in renal compared with nonrenal patients. A more marked inflammatory response in renal patients is suggested by more frequent presence and greater intensity of markers of inflammation. PMID- 17699397 TI - A novel, semiquantitative, clinically correlated calcineurin inhibitor toxicity score for renal allograft biopsies. AB - Calcineurin inhibitor toxicity (CNIT) is an important cause of chronic allograft nephropathy (CAN), but clinically relevant, diagnostic pathologic criteria remain to be defined. A semiquantitative, clinically correlative CNIT scoring system was developed and validated by pathologic analyses of 254 renal transplant biopsies that were obtained from 50 consecutive pediatric renal transplant recipients. Differentially weighted pathologic criteria (glomerulosclerosis, tubular atrophy, arteriolar medial hyaline, and tubular isometric vacuolization) contributed to the composite CNIT model score. Unlike other established pathology chronicity scores, such as the chronic allograft damage index, Banff, and modified Banff, the CNIT score was highly correlated with future graft function. The 3-mo CNIT score correlated significantly with 12 mo (P = 0.021) and 24 mo (P = 0.03) calculated creatinine clearance. Arteriolar medial hyalinosis seems to be the most important factor contributing to the clinical impact of the CNIT score. PMID- 17699398 TI - Predialysis nephrology care improves dialysis outcomes: now what? Or chapter two. PMID- 17699399 TI - Kidney failure stabilizes after a two-decade increase: impact on global (renal and cardiovascular) health. PMID- 17699400 TI - Exercise-associated hyponatremia. AB - Exercise-associated hyponatremia has been described after sustained physical exertion during marathons, triathlons, and other endurance athletic events. As these events have become more popular, the incidence of serious hyponatremia has increased and associated fatalities have occurred. The pathogenesis of this condition remains incompletely understood but largely depends on excessive water intake. Furthermore, hormonal (especially abnormalities in arginine vasopressin secretion) and renal abnormalities in water handling that predispose individuals to the development of severe, life-threatening hyponatremia may be present. This review focuses on the epidemiology, pathogenesis, and therapy of exercise associated hyponatremia. PMID- 17699401 TI - Serum anion gap: its uses and limitations in clinical medicine. AB - The serum anion gap, calculated from the electrolytes measured in the chemical laboratory, is defined as the sum of serum chloride and bicarbonate concentrations subtracted from the serum sodium concentration. This entity is used in the detection and analysis of acid-base disorders, assessment of quality control in the chemical laboratory, and detection of such disorders as multiple myeloma, bromide intoxication, and lithium intoxication. The normal value can vary widely, reflecting both differences in the methods that are used to measure its constituents and substantial interindividual variability. Low values most commonly indicate laboratory error or hypoalbuminemia but can denote the presence of a paraproteinemia or intoxication with lithium, bromide, or iodide. Elevated values most commonly indicate metabolic acidosis but can reflect laboratory error, metabolic alkalosis, hyperphosphatemia, or paraproteinemia. Metabolic acidosis can be divided into high anion and normal anion gap varieties, which can be present alone or concurrently. A presumed 1:1 stoichiometry between change in the serum anion gap (DeltaAG) and change in the serum bicarbonate concentration (DeltaHCO(3)(-)) has been used to uncover the concurrence of mixed metabolic acid base disorders in patients with high anion gap acidosis. However, recent studies indicate variability in the DeltaAG/DeltaHCO(3)(-) in this disorder. This observation undercuts the ability to use this ratio alone to detect complex acid base disorders, thus emphasizing the need to consider additional information to obtain the appropriate diagnosis. Despite these caveats, calculation of the serum anion gap remains an inexpensive and effective tool that aids detection of various acid-base disorders, hematologic malignancies, and intoxications. PMID- 17699402 TI - Arteriovenous access and hand pain: the distal hypoperfusion ischemic syndrome. AB - An ischemic hand in a hemodialysis patient is a serious condition. It causes significant pain and discomfort but also can lead to tissue necrosis and the eventual loss of digits and even the entire hand. Although stealing of blood away from the high-resistance forearm arteries into the low-resistance arteriovenous access generally is assumed to be the cause, a great majority of both wrist and elbow accesses demonstrate retrograde flow without any evidence of hand pain or ischemia. Consequently, demonstration of retrograde flow alone does not predict or indicate the existence of distal ischemia. In this context, the term "arterial steal syndrome" is a misnomer to indicate the presence of peripheral ischemia. Recent studies have shown that, in many cases, arterial stenotic lesions cause distal hypoperfusion and result in hand ischemia. In other cases, distal arteriopathy as a result of generalized vascular calcification and diabetes is the culprit. Because any or a combination of the three mechanisms (retrograde flow, stenotic lesions, and distal arteriopathy) can lead to peripheral ischemia, distal hypoperfusion ischemic syndrome is a more appropriate term to denote hand ischemia. Treatment should start with a detailed history and physical examination to help rule out other (nonischemic) causes of hand pain. A complete arteriogram to evaluate the circulation of the extremity from the aortic arch to the palmar arch is essential. The choice of treatment modality and procedure to apply should be based on this evaluation. This report reviews the pathophysiology and presents current strategies to ameliorate distal hypoperfusion ischemic syndrome. PMID- 17699403 TI - Therapeutic monitoring of mycophenolate mofetil. PMID- 17699404 TI - Handing out grades for care in chronic kidney disease: nephrologists versus non nephrologists. PMID- 17699405 TI - Vasopressin, urine concentration, and hypertension: a new perspective on an old story. PMID- 17699406 TI - Sirolimus: defining nephrotoxicity in the renal transplant recipient. PMID- 17699407 TI - Nephrogenic systemic fibrosis, kidney disease, and gadolinium: is there a link? PMID- 17699408 TI - Living organ donation: always ethically complex. PMID- 17699409 TI - Influence of industry on renal guideline development commentary: keeping our eye on the ball and improving chronic kidney disease patient outcomes. PMID- 17699410 TI - Development of clinical practice guidelines: are we defining the issues too narrowly? PMID- 17699411 TI - Comments on the guideline debate. PMID- 17699412 TI - Translating guidelines into policy. PMID- 17699413 TI - Commentary on "Influence of industry on renal guideline development". PMID- 17699414 TI - Stacking the deck. PMID- 17699415 TI - Anemia of kidney disease and clinical practice guidelines: quo vadis? PMID- 17699416 TI - Epoetin alfa once every 2 weeks is effective for initiation of treatment of anemia of chronic kidney disease. AB - There are limited data suggesting that initiation of epoetin alfa at extended dosing intervals of every 2, 3, or 4 wk may be efficacious for treating anemia in patients who have chronic kidney disease and are not on dialysis (CKD-NOD). This open-label, multicenter, single-arm study investigated the efficacy of administration of 20,000 IU of epoetin alfa once every 2 wk as initiation therapy in these patients. Adults with CKD-NOD were eligible when they had hemoglobin (Hb) <11 g/dl, GFR of 10 to 60 ml/min per 1.73 m2, and stable serum creatinine for the past 6 mo. Patients received 20,000 IU of epoetin alfa subcutaneously every 2 wk for up to 27 wk, with dosage adjustments permitted after 4 wk of treatment. The primary efficacy end point was the proportion of patients with Hb response, defined as achievement of the target Hb range of 11 to 12 g/dl for at least two consecutive visits. Sixty-seven patients were enrolled; >88% (59 of 67) of patients achieved an Hb response. Mean Hb increased to the targeted range by week 6 and remained in the range through week 28. Hb increases of 1 and 2 g/dl were observed in 91 and 78% of patients, respectively. Epoetin Alfa was well tolerated; most adverse events were mild or moderate in nature and typical of the CKD patient population. In this study, results demonstrated that epoetin alfa can be initiated safely and effectively at an extended dosing interval of 20,000 IU every 2 wk in patients with CKD-NOD. PMID- 17699417 TI - Granulomatous interstitial nephritis. AB - Granulomatous interstitial nephritis (GIN) is a rare histologic diagnosis. This series reports the presenting features, associated conditions, treatment, and outcome of patients with a diagnosis of GIN in Glasgow during a 15-yr period and compares this with the available literature. Eighteen cases were identified: Five cases were associated with sarcoidosis, two were associated with tubulointerstitial nephritis and uveitis, two were associated with medication, and nine were idiopathic. Patients presented with advanced renal failure (median estimated creatinine clearance 21 ml/min) and minimal proteinuria (urine albumin to-creatinine ratio 9.9 mg/mmol). Sixteen patients were treated with prednisolone for a mean of 25 mo. Six patients relapsed with reduction in prednisolone dosage, and four patients required steroid-sparing agents. During the mean follow-up of 45 mo, renal function improved or stabilized in 17 patients; the rate of improvement in renal function was most marked in the first year after diagnosis with a gain in function of +1.9 ml/min per mo. The median estimated creatinine clearance at final visit was 56 ml/min. One patient required renal replacement therapy at diagnosis but recovered renal function with treatment. No patient required long-term renal replacement therapy. There was no correlation between the degree of fibrosis or inflammation on biopsy and renal outcome, and the features on biopsy did not help to determine the cause of GIN. GIN is a treatable cause of renal failure that highlights the value of renal biopsy in patients who present with renal failure even when there is minimal proteinuria. The rarity of GIN demonstrates the need for systematic data collection. PMID- 17699418 TI - Cumulative excretion of urinary podocytes reflects disease progression in IgA nephropathy and Schonlein-Henoch purpura nephritis. AB - Recent studies have revealed that podocytopenia leads to glomerular scarring and that the loss of podocytes into the urine may be a cause of podocytopenia. The purpose of this study was to examine whether serial examinations of urinary podocytes (u-podo) could be a useful predictor of disease progression in children with glomerulonephritis. Urine samples and renal biopsy specimens from 20 patients (10 males and 10 females; mean age 11.8 yr; range 4 to 24 yr) with IgA nephropathy (n = 17) and Henoch-Schonlein purpura nephritis (n = 3) were analyzed. Forty-four renal biopsies were performed on 20 patients. Proteinuria (g/d per 1.73 m2), hematuria (score), and u-podo (cells/ml) were examined twice a month in 24 intervals between two biopsies (mean 16.7 mo; range 4 to 58 mo) and average and cumulative values were determined for the intervals. Renal histologic changes were scored on the basis of acute intracapillary, acute extracapillary, acute tubulointerstitial, chronic intracapillary, chronic extracapillary, and chronic tubulointerstitial lesions, as well as glomerulosclerosis. It was found that hematuria, proteinuria, u-podo, and acute lesion scores decreased during the intervals examined, whereas chronic lesion scores increased. Changes in acute histology scores correlated well with hematuria, proteinuria, and u-podo excretion, whereas chronic histology scores and glomerulosclerosis both correlated well with cumulative u-podo excretion. Patients with severe histologic progression of disease also had persistent u-podo excretion. These findings provide additional data to support a potential causative role for prolonged urinary loss of podocytes in disease progression in children with IgA nephropathy and Henoch-Schonlein purpura nephritis. PMID- 17699419 TI - Severe periodontitis is associated with low serum albumin among patients on maintenance hemodialysis therapy. AB - The relationship between periodontitis and two measures of systemic inflammation, serum albumin and C-reactive protein (CRP), were examined among patients who were receiving chronic outpatient hemodialysis. Adult patients at two locations, North Carolina and New York City, were evaluated by dentist examiners. Six sites per tooth (up to 32 teeth per patient) were examined. A periodontitis case was defined as > or = 60% of sites with attachment level > or = 4 mm. Multivariable logistic regression was used to determine the association of periodontitis with low serum albumin, defined as < 3.5 mg/dl, and with high CRP, defined as > 3.0 mg/dl. A total of 154 patients completed the study. The mean age was 54.6 yr (SD 13.3), and average duration of dialysis was 4.0 yr (3 mo to 16 yr). Eighty-six (54.6%) were men, and 89 (58.2%) were black. Common causes of end-stage kidney disease were hypertension (12.3%), diabetes (22.1%), glomerulonephritis (7.1%), and other (58.4%). The average number of teeth was 20.3 (SD 8.4). Thirty-five (23%) patients were periodontitis cases. Severe periodontitis was associated with low serum albumin (odds ratio 8.20; 95% confidence interval 1.61 to 41.82; P = 0.01) compared with individuals without severe periodontitis disease after adjustment for age, gender, race, diabetes, hypertension, body mass index, smoking, study site, total cholesterol, serum calcium, serum phosphorus, and normalized protein catabolic rate. There was no observed association of severe periodontitis with CRP. Investigation of the potential contribution of periodontitis to serum albumin and possibly to morbidity and mortality among patients with end-stage kidney disease seems warranted. PMID- 17699420 TI - Staphylococcus aureus peritonitis complicates peritoneal dialysis: review of 245 consecutive cases. AB - Peritonitis that is caused by Staphylococcus aureus is a serious complication in peritoneal dialysis (PD), but the clinical course of PD-related S. aureus peritonitis remains unclear. All of the S. aureus peritonitis in a dialysis unit from 1994 to 2005 were reviewed. During this period, 2065 episodes of peritonitis were recorded; 245 (11.9%) episodes in 152 patients were caused by S. aureus and 45 (18.4%) episodes were caused by methicillin-resistant S. aureus (MRSA). Patients with a history of recent hospitalization had a higher risk for isolation of MRSA than the others (30.6 versus 14.2%; P = 0.004). The overall primary response rate was 87.8%; the complete cure rate was 74.3%. However, 21 (8.6%) episodes developed relapse and 59 (24.1%) developed repeat S. aureus peritonitis. Episodes that were caused by MRSA had a lower primary response rate (64.4 versus 93.0%; P < 0.001) and complete cure rate (60.0 versus 77.5%; P = 0.023) than the others. Episodes that were treated initially with vancomycin had better primary response rate than those that were treated with cefazolin (98.0 versus 85.2%; P = 0.001), but the complete cure rate was similar. Adjuvant rifampicin treatment was associated with a significantly lower risk for relapse or repeat S. aureus peritonitis than was treatment without rifampicin (21.4 versus 42.8%; P = 0.004). In contrast, initial antibiotic regimen (cefazolin versus vancomycin) and concomitant exit-site infection did not have any effect on the risk for relapse or repeat peritonitis. S. aureus peritonitis is a serious complication of PD. Recent hospitalization is a major risk factor of methicillin resistance in the bacterial isolate. Rifampicin is a valuable adjunct in preventing relapse and repeat S. aureus peritonitis after the index episode. PMID- 17699421 TI - A standard, noninvasive monitoring of hematocrit algorithm improves blood pressure control in pediatric hemodialysis patients. AB - Accurate dry weight assessment is difficult in pediatric hemodialysis patients but is essential to prevent chronic fluid overload, hypertension, and cardiovascular morbidity. A noninvasive monitoring (NIVM) of hematocrit-guided ultrafiltration algorithm was studied prospectively in 20 pediatric hemodialysis patients. The algorithm targeted the first 50% of total goal ultrafiltration to be removed during the first hour of dialysis with a maximum blood volume change of 8 to 12% per hour. The second 50% was removed during the remaining treatment time with a maximum blood volume change of 5% per hour. Data that were collected at baseline and 6 mo included weight, BP, number of antihypertensive medications, 24-h ambulatory BP monitoring (ABPM), echocardiogram, and ultrafiltration associated symptoms. Sixteen of 20 enrolled patients completed the study. No difference was seen between baseline and 6-mo weight, predialysis casual BP, nighttime ABPM, or left ventricular mass index. There was a decrease in postdialysis casual systolic BP, daytime ABPM, number of antihypertensive medications prescribed, and rate of intradialytic events related to ultrafiltration (all P < or = 0.05). Adoption of a standardized NIVM-guided algorithm led to (1) improved ABPM profiles, (2) decreased antihypertensive medication burden, and (3) decreased ultrafiltration-associated symptoms. Wider use of NIVM-guided ultrafiltration may decrease cardiovascular morbidity in pediatric hemodialysis patients. PMID- 17699422 TI - Nephrogenic systemic fibrosis: a mysterious disease in patients with renal failure--role of gadolinium-based contrast media in causation and the beneficial effect of intravenous sodium thiosulfate. AB - Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis (NSF) is an emerging scleromyxedema-like cutaneous disorder of unknown cause that is seen in patients with renal failure, and the number of reported cases has grown significantly since its first recognition. Recent case reports associated the use of gadolinium (Gd3+)-based contrast agents with the development of NSF. Herein is reported an additional patient who had NSF and had multiple previous exposures to Gd3+-based magnetic resonance imaging studies and had marked improvement in pain and skin changes after a trial of intravenous sodium thiosulfate. Discussed are the possible association of Gd3+-based contrast media with the development of NSF and potential for the use of sodium thiosulfate in the treatment of NSF. PMID- 17699423 TI - Nephrogenic systemic fibrosis: a population study examining the relationship of disease development to gadolinium exposure. AB - Nephrogenic systemic fibrosis (NSF) is a devastating complication of severe renal failure. Recent reports suggest that exposure to gadolinium-containing contrast agents (GCCA) is associated with the occurrence of NSF. The population of patients with ESRD in and around Bridgeport, CT, was studied during an 18-mo period. The incidence of NSF was 4.3 cases per 1000 patient-years. Each radiologic study using gadolinium presented a 2.4% risk for NSF. The association between gadolinium exposure and NSF was highly significant (P < or = 0.001). It is concluded that GCCA exposure is a major risk factor for NSF in the ESRD population. Because of the significant morbidity and mortality with NSF, it is believed that gadolinium exposure should be avoided in patients with ESRD. In the event that exposure cannot be avoided, careful consideration of the potential consequences, including a thorough discussion of the risks and benefits of GCCA, is advised. PMID- 17699424 TI - Increasing the use of arteriovenous fistula in hemodialysis: economic benefits and economic barriers. AB - The Fistula First Initiative set a goal of 66% arteriovenous (AV) fistula-based access among US hemodialysis patients. This study modeled the impact of achieving the target AV fistula placement rate on Medicare expenditures and on dialysis patient survival and also reviewed economic disincentives for providers that will inhibit achieving this target. The model projects lifetime costs and survival in the US 2003 incident hemodialysis population. Annual treatment costs were estimated from previous analyses of Medicare expenditures by access modality. Patient survival by mode of access was derived from the Dialysis Morbidity and Mortality Study (DMMS). These parameters were applied to a cohort of patients who meet the 66% AV fistula target and an identical cohort with the current vascular access case mix. Comparison of outcomes yields estimates of differential total expenditures and total patient life-years. If prevalence AV fistula-based access in the 2003 incident hemodialysis cohort were 66% rather than the observed 35%, then the Center for Medicare and Medicaid Services would save $840 million in access-attributed expenditures over the expected lifetime of these patients. However, population survival would increase by 35,000 additional life-years, increasing total lifetime expenditures by a net of $1.4 billion. Relative to the current mix of access modality, the shift to 66% AV fistula would be achieved at a net incremental cost of $40,000 per year of life gained. Economic barriers to reaching this goal include financial disincentives to providing adequate predialysis care, performing AV fistula surgical procedures, and monitoring vascular access flow. Achievement of the 66% AV fistula target is cost-effective. Financial incentives in the form of higher reimbursement to encourage wider use of AV fistula placement also could be cost-effective. PMID- 17699425 TI - Advanced chronic kidney disease practice patterns among nephrologists and non nephrologists: a database analysis. AB - Chronic kidney disease (CKD) outcomes, including progression to end stage, is influenced by patient treatment and is known to be suboptimal. A commercial database was analyzed to assess practice patterns and conformance to clinical practice guidelines among nephrologists and non-nephrologists who care for patients with advanced CKD (estimated GFR [eGFR] < or = 30 ml/min per 1.73 m2). Data from 1933 adults with advanced CKD on the basis of prestipulated inclusion criteria were analyzed. Individuals were designated as in a nephrologist or non nephrologist group depending on whether a nephrologist was involved in their care. With the use of published guidelines, conformance to 10 recommendations was assessed for all patients and separately for the nephrologist and non nephrologist groups. The average eGFR of included individuals was 23.6 ml/min per 1.73 m2. A majority were female and older than 65 yr. Non-nephrologists treated approximately half of all patients and a greater number of women and patients who were older than 65 yr. Nephrologists treated patients with a lower eGFR, equal numbers of men and women, and an equal number of individuals younger and older than 65 yr. Nephrologist conformance to guidelines was systematically better than that of non-nephrologists. These analyses reveal that a large number of patients with advanced CKD are being treated solely by non-nephrologists and that nephrologists treat patients with more advanced disease. Management of advanced CKD is suboptimal for all patients but is particularly poor for patients who are treated solely by non-nephrologists. PMID- 17699426 TI - Association of sleep difficulty with Kidney Disease Quality of Life cognitive function score reported by patients who recently started dialysis. AB - Sleep disorders are associated with impaired cognition in the general population, but little attention has been given to the potential association between sleep and cognitive function in the dialysis population. This study investigated reported sleep difficulty and cognitive function scores in a national cohort of patients who initiated maintenance hemodialysis and peritoneal dialysis. The cognitive function scale of the Kidney Disease Quality of Life instrument (KDQOL CF), which measures aspects of cognitive ability that are important for daily functioning (perceived reaction time, ability to concentrate, and tendency to become confused), was used. The study population included 2286 patients who responded to a questionnaire at baseline in the US Renal Data System Dialysis Morbidity and Mortality Study Wave 2. Reported sleep difficulty was associated in a univariate manner with lower KDQOL-CF score. In a multivariable regression analysis that controlled for age, gender, race, education, diabetic ESRD, cardiovascular comorbidity, smoking, hemoglobin, serum albumin, prescribed sleep medications, dialysis modality, pre-ESRD care, bodily pain, and depressed mood, the association of sleep difficulty with KDQOL-CF score remained significant (P < 0.0001); the association also was significant in a multivariable analysis that was restricted to hemodialysis patients and included adjustment for Kt/V (P = 0.001). Depressed mood and sleep medication prescription predicted a lower KDQOL CF score, and higher educational level and less bodily pain predicted a higher KDQOL-CF score. Increased understanding of links among sleep difficulty, management of sleep difficulty, and cognitive function could benefit multiple dimensions of dialysis patients' quality of life and daily functioning. PMID- 17699427 TI - Association of silica exposure with anti-neutrophil cytoplasmic autoantibody small-vessel vasculitis: a population-based, case-control study. AB - Anti-neutrophil cytoplasmic autoantibodies (ANCA) are associated with a category of small-vessel vasculitis (SVV) with frequent glomerulonephritis. The goal of this study was to evaluate the association of lifetime silica exposure with development of ANCA-SVV, with particular attention to exposure dosage, intensity, and time since last exposure. A southeastern United States, population-based, case-control study was conducted. Case patients had ANCA-SVV with pauci-immune crescentic glomerulonephritis. Population-based control subjects were frequency matched to case patients by age, gender, and state. Jobs were assessed in a telephone interview. Silica exposure scores incorporated exposure duration, intensity, and probability for each job and then were categorized as none, low/medium, or high lifetime exposure. Logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Silica exposure was found in 78 (60%) of 129 case patients and in 49 (45%) of 109 control subjects. There was no increased risk for disease from low/medium exposure relative to no exposure (OR 1.0; 95% CI 0.4 to 2.2) but increased risk with high exposure (OR 1.9; 95% CI 1.0 to 3.5; P = 0.05). Crop harvesting was associated with elevated risk (OR 2.5; 95% CI 1.1 to 5.4; P = 0.03). However, both agricultural and traditional occupational sources contributed to the cumulative silica exposure scores; therefore, the overall effect could not be attributed to agricultural exposures alone. There was no evidence of decreasing by duration of time since last exposure. High lifetime silica exposure was associated with ANCA-SVV. Exposure to silica from specific farming tasks related to harvesting may be of particular importance in the southeastern United States. Interval of time since last exposure did not influence development of ANCA-SVV. PMID- 17699428 TI - Routine recovery of cadaveric organs for transplantation: consistent, fair, and life-saving. AB - Many families deny organ recovery from recently deceased relatives. As a result, valuable organs and some of the lives they could save are lost. Several plans designed to rectify this tragic situation have been proposed, including organ sales. We suggest another approach that we believe to be superior and that is rarely discussed: routine recovery of all transplantable cadaveric organs without consent. Here we show that this plan is ethically acceptable, more equitable than our current opting-in approach, consistent with other mandatory social programs, and life-saving. Based on these considerations, we believe that it is time to eliminate entirely the consent requirement for recovery of transplantable cadaveric organs. PMID- 17699429 TI - Ethnic differences in urine concentration: possible relationship to blood pressure. AB - The mechanisms that account for the susceptibility of black individuals to hypertension and their reduced ability to excrete sodium are poorly understood. Vasopressin administration has been shown in healthy humans to delay sodium excretion along with its antidiuretic action. Black individuals have been reported to have higher vasopressin levels than white individuals. Therefore, this study investigated retrospectively 24-h urine volume (V) and urine concentration index (urine-to-plasma ratio of creatinine concentration), as well as their possible relationships with BP, in a cohort of 141 healthy young black and white individuals (18 to 40 y). Black individuals were found to have a significantly lower V and higher urine concentration than white individuals, especially during daytime. In addition, they exhibited a blunted nocturnal fall in fluid and electrolyte excretion and a higher pulse pressure than white individuals. Higher urine concentration and lower V were associated significantly with higher PP (but not with systolic or diastolic BP) in men. These relations remained significant after adjustment for age, body mass index, and sodium and potassium excretion. These results suggest that an enhanced tendency to concentrate urine may delay the excretion of the daily ingested fluid and sodium and may increase pulse pressure in young normotensive individuals. The higher urine concentration that is observed in black individuals (which could represent an adaptation to better water conservation) may participate in their enhanced susceptibility to hypertension. If these results are confirmed in further studies, then vasopressin V2 receptor antagonists might offer a novel antihypertensive strategy, especially in the black population. PMID- 17699430 TI - Resuscitative hyperkalemia in noncrush trauma: a prospective, observational study. AB - The trauma patient is exposed to physiologic processes and life-saving interventions that predispose to hyperkalemia. Severe elevations in potassium levels subject this compromised patient to additional cardiac risks in the periresuscitative period. Recent advances in the care of the massively traumatized patient may or may not increase the risk for hyperkalemia. This prospective, observational study was undertaken to define the period prevalence of hyperkalemia (plasma potassium level > or = 5.5 mmol/L) in a noncrush trauma population during the initial resuscitative period and to identify potential risk factors for the development of hyperkalemia. A total of 131 patients were studied during the initial 12 h after admission for noncrush trauma. The period prevalence of hyperkalemia was 29.0%. Hyperkalemic patients had dramatic shifts in plasma potassium levels compared with nonhyperkalemic patients. Five patients, all from the hyperkalemic group, died. By multivariate logistic regression analysis, independent risk factors for hyperkalemia were an emergency department plasma potassium level of 4.0 mmol/L or higher (relative risk 3.40; 95% confidence interval 1.17 to 9.84; P = 0.024 versus baseline potassium level < 4.0 mmol/L) and transfusion of cell- or plasma-based products (relative risk 10.56; 95% confidence interval 3.62 to 30.78; P < 0.001 per log-transformed unit). The prevalence of hyperkalemia during trauma resuscitation was not reported previously. Given the arrhythmic risks of hyperkalemia, particular caution is necessary with trauma patients who present with plasma potassium levels > 4.0 mmol/L and require aggressive transfusion support. PMID- 17699431 TI - Partial human genetic deficiency in tissue kallikrein activity and renal calcium handling. AB - A loss-of-function polymorphism of the human tissue kallikrein (TK) gene (R53H) induces a major decrease in enzyme activity. Inactivation of the TK gene in mice causes a defect in tubular calcium (Ca) reabsorption. Therefore, this study investigated the Ca phenotype of carriers of the 53H allele. In a crossover study, 30 R53R homozygous and 10 R53H heterozygous young white male individuals were randomly assigned to two 7-d low-Ca diets (10 mmol/d) associated with either a low-sodium (Na)/high-potassium (K) diet or a high-Na/low-K diet to modulate TK synthesis. On the seventh day of each diet, the participants were studied before and during a 2-h infusion of furosemide that functionally excludes the thick ascending limb and increases Ca delivery to distal tubular segments. Urinary kallikrein activity was 50 to 60% lower in R53H participants than in R53R participants. Adaptation of urinary Ca excretion to the contrasted Na/K diets was unaffected in R53H participants. By contrast, R53H participants after furosemide infusion had significantly lower serum ionized Ca concentrations than did R53R participants (P < 0.0001) and tendency toward nonsignificantly higher urinary Ca excretions than did R53R participants (P = 0.14). These effects were more marked under low-Na/high-K diet. Despite nonsignificant differences in urinary Ca excretions between the two groups, these results suggest in R53H individuals an increase in Ca reabsorption in the thick ascending limb under baseline conditions that counteracts a distal tubular defect that is revealed by furosemide infusion. In humans as in mice, TK thus may act as an intrarenal modulator of Ca reabsorption. PMID- 17699432 TI - High sirolimus levels may induce focal segmental glomerulosclerosis de novo. AB - Sirolimus has been associated with high-range proteinuria when used in replacement of calcineurin inhibitors in renal transplant recipients with chronic allograft nephropathy (CAN). Primary FSGS was demonstrated previously in some such patients, but the coexistence of CAN lesions made the interpretation uneasy. However, nephrotic syndrome and FSGS were observed recently in three patients who received sirolimus de novo, without medical history of primary FSGS or CAN. Markers of podocyte differentiation were studied in kidney biopsies of the three patients who received sirolimus de novo and of five patients who switched to sirolimus. All patients developed FSGS lesions of classic type (not otherwise specified), but only switched patients exhibited advanced sclerotic lesions. Immunohistochemistry showed that some podocytes in FSGS lesions had absent or diminished expression of the podocyte-specific epitopes synaptopodin and p57, reflecting dedifferentiation, and had acquired expression of cytokeratin and PAX2, reflecting a immature fetal phenotype. Such a pattern of epitope expression provides evidence for podocyte dysregulation. Moreover, a decrease in vascular endothelial growth factor expression was observed in some glomeruli. In conclusion, sirolimus induces FSGS that is responsible for proteinuria in some transplant patients. PMID- 17699433 TI - Fetal programming of adult kidney disease: cellular and molecular mechanisms. PMID- 17699434 TI - Transplant-associated hyperglycemia: a new look at an old problem. AB - New-onset diabetes has long been recognized as a common complication of kidney transplantation, promoting cardiovascular disease, death, and graft failure. Studies in recent years have begun to highlight the very high posttransplantation prevalence of the prediabetic states of impaired fasting glucose and impaired glucose tolerance and the significant repercussions of these states on cardiovascular health. Therefore, the overall burden of transplant-associated hyperglycemia (TAH), which encompasses new-onset diabetes and the prediabetic states, is far greater than previously appreciated. The kidney transplant population is predisposed to insulin resistance and to additional insults of hypertension and hyperlipidemia that, together with hyperglycemia, compose the metabolic syndrome and promote atherosclerosis. When recipients with an underlying, frequently nonmodifiable predisposition to glucose dysregulation encounter transplant-specific, often modifiable, diabetogenic exposures, TAH manifests. Aggressive screening will effectively detect TAH, whereas risk factor modification, lifestyle intervention, and, when appropriate, drug therapy may decrease its impact. Topics of future investigation should include the use of emerging diabetes therapies and avenues for the prevention and reversal of TAH. PMID- 17699435 TI - Pharmacologic treatment of acute kidney injury: why drugs haven't worked and what is on the horizon. AB - Current strategies to limit the extent of injury in acute renal failure are based on extensive studies that identified cellular and molecular mechanisms of acute kidney injury. Despite successes in various animal models, translation to human studies has failed or studies are inconclusive. This review describes past failures and barriers to successful clinical trials. It also focuses on promising preclinical studies using novel compounds that currently are in or close to human investigation. Implementation of previous or novel compounds in well-designed clinical trials provides hope for the successful treatment of this devastating disorder. PMID- 17699436 TI - Hypomagnesemia in patients with type 2 diabetes. AB - Hypomagnesemia has been reported to occur at an increased frequency among patients with type 2 diabetes compared with their counterparts without diabetes. Despite numerous reports linking hypomagnesemia to chronic diabetic complications, attention to this issue is poor among clinicians. This article reviews the literature on the metabolism of magnesium, incidence of hypomagnesemia in patients with type 2 diabetes, implicated contributing factors, and associated complications. Hypomagnesemia occurs at an incidence of 13.5 to 47.7% among patients with type 2 diabetes. Poor dietary intake, autonomic dysfunction, altered insulin metabolism, glomerular hyperfiltration, osmotic diuresis, recurrent metabolic acidosis, hypophosphatemia, and hypokalemia may be contributory. Hypomagnesemia has been linked to poor glycemic control, coronary artery diseases, hypertension, diabetic retinopathy, nephropathy, neuropathy, and foot ulcerations. The increased incidence of hypomagnesemia among patients with type 2 diabetes presumably is multifactorial. Because current data suggest adverse outcomes in association with hypomagnesemia, it is prudent to monitor magnesium routinely in this patient population and treat the condition whenever possible. PMID- 17699437 TI - Therapeutic monitoring of calcineurin inhibitors for the nephrologist. AB - The calcineurin inhibitors (CNI) cyclosporine and tacrolimus remain the backbone of immunosuppression for most kidney transplant recipients. Despite many years of experience, protocols that optimize efficacy with minimal toxicity remain a subject of debate. Nevertheless, studies of the pharmacokinetic properties of the CNI, particularly cyclosporine, have led to improved dosing strategies. The purpose of this article is to review the current understanding of CNI pharmacokinetics and its relevance to proper dosing and monitoring of these medications. This article also reviews the trials that have helped to define the optimal dosages and discusses the effect of adjunctive immunosuppressive agents on CNI pharmacokinetics and dosing. PMID- 17699438 TI - Continuous renal replacement therapy in the treatment of acute renal failure: critical assessment is required. AB - A continuous approach to renal replacement therapy (CRRT) for critically ill patients was introduced in 1977 and was hailed almost immediately as an improved alternative to intermittent hemodialysis (IHD). Now that CRRT has been in clinical practice for three decades, it is fair to ask whether research-based evidence (rather than expert opinion) supports the use of this complex technology in comparison to IHD. Several randomized clinical trials have compared the outcomes of CRRT and IHD. In one trial, patients assigned to CRRT had a significantly higher intensive-care mortality rate. In other recent trials, there has been no significant difference in outcome. A meta-analysis of observational studies similarly shows no benefit of CRRT versus IHD, with recent trends actually favoring IHD. While considerable attention has been focused on perceived benefits of CRRT compared to IHD, comparatively less attention has been focused on the potential for increased risks. When examining the totality of evidence from recent observational studies and clinical trials, there is no convincing evidence to support superiority of CRRT over IHD in the treatment of critically ill patients with ARF. PMID- 17699439 TI - High-frequency hemodialysis: rationale for randomized clinical trials. PMID- 17699440 TI - Report of the first World Transplant Congress. AB - During the past 20 yr, new immunosuppressant medications that reduced the rate of acute rejection became available for transplantation. Long-term survival of transplanted organs, however, did not improve to the extent predicted. Chronic immunosuppression is associated with cardiovascular, metabolic, and renal toxicities that negatively affect patient and graft survival. Therefore, there is a pressing need for new approaches to immunosuppression that might better prevent acute rejection with a safety profile that is superior to current regimens. Moreover, the performance of currently available agents should be largely ameliorated by optimizing drug combinations and dosages. The latter goal can be achieved only through the development of specific immune markers of over- and underimmunosuppression to help tailor the immunosuppressive regimen for individual patients and even to allow safe withdrawal of immunosuppression in selected patients. Recent research has resulted in the discovery of new pathways of alloimmune reactivity, thereby offering novel immunologic targets for more specific and minimally toxic antirejection therapies. Finally, recent achievements pushed transplant medicine forward toward its ultimate goal of achieving a condition of tolerance for allogeneic antigens that prevents acute rejection without maintenance immunosuppression. All of these topics were addressed in the more than 3000 abstracts that were presented at the World Transplant Congress, held in Boston July 22 through 27, 2006. PMID- 17699441 TI - Chronic kidney disease: common, harmful, and treatable--World Kidney Day 2007. PMID- 17699442 TI - Treating diabetic nephropathy: unfinished success is not failure. PMID- 17699443 TI - Can we prevent sudden cardiac death in dialysis patients? PMID- 17699444 TI - Comparing dialysis modalities for critically ill patients: are we barking up the wrong tree? PMID- 17699445 TI - Through the looking glass: anemia guidelines, vested interests, and distortions. PMID- 17699446 TI - North East Italian Prospective Hospital Renal Outcome Survey on Acute Kidney Injury (NEiPHROS-AKI): targeting the problem with the RIFLE Criteria. AB - Acute kidney injury (AKI) in the intensive care unit (ICU) is associated with an enhanced mortality. The Acute Dialysis Quality Initiative group has proposed the RIFLE (Risk-Injury-Failure-Loss-ESRD) classification to standardize the approach to AKI. This study was performed to estimate the AKI incidence in ICU patients in northeastern Italy and describe clinical characteristics and outcomes of patients with AKI on the basis of their RIFLE class. A prospective multicenter observational study was performed of patients who fulfilled AKI criteria in 19 ICU in northeastern Italy. Data were analyzed using multivariate logistic regression and survival curve analysis. Of 2164 ICU patients who were admitted during the study period, 234 (10.8%; 95% confidence interval 9.5 to 12.1%) developed AKI; 19% were classified as risk (R), 35% as injury (I), and 46% as failure (F). Preexisting kidney disease was present in 36.8%. The most common causes of AKI were prerenal causes (38.9%) and sepsis (25.6%). At diagnosis of AKI, median serum creatinine and urine output were 2.0 mg/dl and 1100 ml/d, respectively. ICU mortality was 49.5% in class F, 29.3% in I, and 20% in R. Independent risk factors for mortality included RIFLE class, sepsis, and need for renal replacement therapy, whereas a postsurgical cause of AKI, exposure to nephrotoxins, higher serum creatinine, and urine output were associated with lower mortality risk. In this study, AKI incidence in the ICU was between 9 and 12%, with 3.3% of ICU patients requiring renal replacement therapy. Sepsis was a significant contributing factor. Overall mortality was between 30 and 42%, and was highest among those in RIFLE class F. PMID- 17699447 TI - Acute kidney injury after gastric bypass surgery. AB - Gastric bypass surgery is a common treatment for morbid obesity. The presence of comorbid conditions and drugs that are used to treat them can adversely influence kidney function. Risk factors and outcomes of acute kidney injury (AKI) after gastric bypass surgery are not well understood, however. A total of 504 patients underwent gastric bypass between January 2003 and 2005. Primary outcome was AKI, defined as a > or =50% increase in serum creatinine relative to baseline or requirement of dialysis. Secondary outcomes were duration of hospitalization, all cause hospital mortality, and readmissions within 30 d after surgery. Demographic, comorbid, and laboratory variables and preoperative medication use were examined as potential risk factors for AKI. A total of 42 (8.5%) patients developed postoperative AKI. Hyperlipidemia, preoperative use of angiotensin converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB), intraoperative hypotension, and higher body mass index were associated with increased frequency of AKI. By multivariable analyses, the independent risk factors for AKI were body mass index (odds ratio [OR] 1.03; 95% confidence interval [CI] 1.00 to 1.06), hyperlipidemia (OR 2.53; 95% CI 1.21 to 5.28), and preoperative use of ACE-I or ARB (OR 2.06; 95% CI 1.05 to 4.04). The postoperative mortality was 0.45% (n = 2), both of whom had AKI. Duration of hospitalization was greater in patients with AKI versus no AKI (4.0 versus 2.7 d; P = 0.0003). Postoperative AKI is not infrequent after gastric bypass surgery. Certain comorbid conditions and their commonly prescribed treatments, ACE-I or ARB, are independently associated with increased risk for postoperative AKI. PMID- 17699448 TI - Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. AB - Sepsis is the most common cause of acute kidney injury (AKI) in critical illness, but there is limited information on septic AKI. A prospective, observational study of critically ill patients with septic and nonseptic AKI was performed from September 2000 to December 2001 at 54 hospitals in 23 countries. A total of 1753 patients were enrolled. Sepsis was considered the cause in 833 (47.5%); the predominant sources of sepsis were chest and abdominal (54.3%). Septic AKI was associated with greater aberrations in hemodynamics and laboratory parameters, greater severity of illness, and higher need for mechanical ventilation and vasoactive therapy. There was no difference in enrollment kidney function or in the proportion who received renal replacement therapy (RRT; 72 versus 71%; P = 0.83). Oliguria was more common in septic AKI (67 versus 57%; P < 0.001). Septic AKI had a higher in-hospital case-fatality rate compared with nonseptic AKI (70.2 versus 51.8%; P < 0.001). After adjustment for covariates, septic AKI remained associated with higher odds for death (1.48; 95% confidence interval 1.17 to 1.89; P = 0.001). Median (IQR) duration of hospital stay for survivors (37 [19 to 59] versus 21 [12 to 42] d; P < 0.0001) was longer for septic AKI. There was a trend to lower serum creatinine (106 [73 to 158] versus 121 [88 to 184] mumol/L; P = 0.01) and RRT dependence (9 versus 14%; P = 0.052) at hospital discharge for septic AKI. Patients with septic AKI were sicker and had a higher burden of illness and greater abnormalities in acute physiology. Patients with septic AKI had an increased risk for death and longer duration of hospitalization yet showed trends toward greater renal recovery and independence from RRT. PMID- 17699449 TI - Severity of baseline proteinuria predicts renal response in immunoglobulin light chain-associated amyloidosis after autologous stem cell transplantation. AB - Ig light chain-associated amyloidosis is a fatal plasma cell proliferative disorder that is characterized by fibril deposition in various organs. High-dose melphalan followed by autologous stem cell transplantation has been shown to improve organ dysfunction and survival. This study was undertaken to investigate factors that influence renal response. Patients who had AL amyloidosis with > or =1 g/d proteinuria and a minimum follow-up of 12 mo were recruited. Renal response was defined by >50% reduction in proteinuria with <25% decline in renal function. Hematologic response was defined as a 50% reduction in serum monoclonal protein or free light chains. Baseline characteristics were examined for relationship to renal response. Thirteen of the 135 patients were excluded for various reasons. Median follow-up was 45.4 mo. Hematologic and renal response was noted in 73 and 43.4% of the patients, respectively. Median response time for the kidney was 10 mo (1 to 40 mo). In univariate analysis, low cardiac troponin T (cTnT), higher albumin, lower proteinuria, and hematologic response were associated with renal response. In multivariate analysis, cTnT and proteinuria were predictive of renal response. Renal response was associated with a longer survival than hematologic response alone. This study showed that severe proteinuria and high cTnT negatively affected renal response after autologous stem cell transplantation. Achievement of renal response was associated with improved survival. These results suggest that early intervention with aggressive therapy is not only justified but recommended to achieve optimal response. PMID- 17699450 TI - Adult minimal-change disease: clinical characteristics, treatment, and outcomes. AB - Minimal-change disease (MCD) counts for 10 to 15% of cases of primary nephrotic syndrome in adults. Few series have examined this disease in adults. A retrospective review was performed of 95 adults who had MCD and were seen at a single referral center. Examined were presenting features, response to daily versus alternate-day steroids, response to second-line agents, relapse patterns, complications of the disease and therapy, presence of acute renal failure (ARF), and outcome data. Sixty-five patients received daily and 23 received alternate day steroids initially. There were no differences in remissions, time to remission, relapse rate, or time to relapse between daily- and alternate-day treated patients. More than one quarter of patients were steroid resistant. At least one relapse occurred in 73% of patients; 28% were frequently relapsing. A significant proportion of frequently relapsing patients became steroid dependent. Second-line agents were used for steroid dependence, steroid resistance, or frequent relapses. No single agent proved superior. There were more remissions with second-line agents in steroid-dependent patients compared with steroid resistant patients, and remissions were more likely to be complete in steroid dependent patients. ARF occurred in 24 patients; they tended to be older and hypertensive with lower serum albumin and more proteinuria than those without ARF. At follow up, patients with an episode of ARF had higher serum creatinine than those without ARF. Four patients progressed to ESRD. These patients were less likely to have responded to steroids and more likely to have FSGS on repeat renal biopsy. In this referral MCD population, response to daily and alternate day steroids is similar. Second-line agents give greater response in patients who are steroid dependent. ARF occurs in a significant number of adult MCD patients and may leave residual renal dysfunction. Few patients progress to ESRD. PMID- 17699451 TI - A thiazide test for the diagnosis of renal tubular hypokalemic disorders. AB - Although the diagnosis of Gitelman syndrome (GS) and Bartter syndrome (BS) is now feasible by genetic analysis, implementation of genetic testing for these disorders is still hampered by several difficulties, including large gene dimensions, lack of hot-spot mutations, heavy workup time, and costs. This study evaluated in a cohort of patients with genetically proven GS or BS diagnostic sensibility and specificity of a diuretic test with oral hydrochlorothiazide (HCT test). Forty-one patients with GS (22 adults, aged 25 to 57; 19 children adolescents, aged 7 to 17) and seven patients with BS (five type I, two type III) were studied; three patients with "pseudo-BS" from surreptitious diuretic intake (two patients) or vomiting (one patient) were also included. HCT test consisted of the administration of 50 mg of HCT orally (1 mg/kg in children-adolescents) and measurement of the maximal diuretic-induced increase over basal in the subsequent 3 h of chloride fractional clearance. All but three patients with GS but no patients with BS and pseudo-BS showed blunted (<2.3%) response to HCT; patients with BS and the two patients with pseudo-BS from diuretic intake had increased response to HCT. No overlap existed between patients with GS and both patients with BS and pseudo-BS. The response to HCT test is blunted in patients with GS but not in patients with BS or nongenetic hypokalemia. In patients with the highly selected phenotype of normotensive hypokalemic alkalosis, abnormal HCT test allows prediction with a very high sensitivity and specificity of the Gitelman genotype and may avoid genotyping. PMID- 17699452 TI - Determinants of progression from microalbuminuria to proteinuria in patients who have type 1 diabetes and are treated with angiotensin-converting enzyme inhibitors. AB - The aims of this study were to assess the frequency and determinants of (1) treatment with angiotensin-converting enzyme inhibitors (ACE-I) and (2) progression to proteinuria in the presence of ACE-I treatment in patients with type 1 diabetes and microalbuminuria. A clinic-based cohort study of patients with type 1 diabetes was begun in 1991. The patients who were included in this study (n = 373) are the cohort members who received a diagnosis of microalbuminuria during a 2-yr baseline observation and were followed for 10 yr with frequent assessments of urinary albumin excretion and biennial examinations. Progression to proteinuria occurred when the median urinary albumin excretion during a 2-yr interval exceeded 299 mug/min. During the decade-long study, the proportion of patients who had a history of microalbuminuria and were treated with ACE-I rose from 17 to 67%. Patients who started this treatment had (on average) higher BP, higher urinary albumin excretion, and longer diabetes duration than those who did not. Microalbuminuria often progressed to proteinuria (6.3/100 person-years) in those who were treated. Poor glycemic control and elevated serum cholesterol were the major determinants/predictors of this progression. Although treatment with ACE-I increased during the past decade, it was not completely effective, because microalbuminuria progressed to proteinuria in many treated patients. Poor glycemic control and elevated serum cholesterol were the major determinants/predictors for progression while on ACE-I treatment. The mechanisms that are responsible for the frequent failure of ACE-I to prevent progression of microalbuminuria to proteinuria in a clinical setting are not clear. PMID- 17699453 TI - Hemofiltration of recombinant hirudin by different hemodialyzer membranes: implications for clinical use. AB - Recombinant hirudin (lepirudin) is a potent direct thrombin inhibitor that is used particularly for treatment of immune-mediated heparin-induced thrombocytopenia. Because hirudin is almost exclusively eliminated by the kidneys, its half-life is markedly prolonged in patients with severe renal insufficiency. Therefore, these patients are at risk for bleeding, particularly because no antidote is available. To use hirudin safely in patients who are on renal replacement therapy, knowledge of hirudin-sieving characteristics of different hemodialyzers is required. Data on this issue are sparse and in part contradictory. Eight different conventional low-flux and high-flux hemodialyzers were tested in an in vitro circuit with ultrafiltrate reinfusion. In each experiment, lepirudin concentration was repetitively measured during 3 h in the prefilter, the postfilter, and the filtration line using a chromogenic assay. On the basis of these data, sieving coefficients were calculated. All high-flux hemodialyzers tested allowed filtration of hirudin yet with marked differences in steady-state sieving (sieving coefficients in whole blood: polysulfone [PS] 0.97 +/- 0.03; polymethylmethacrylate [PMMA] 0.75 +/- 0.02; polyarylethersulfone 0.73 +/- 0.02; polyamide 0.49 +/- 0.02). None of the low-flux hemodialyzer membranes tested (cuprophane, hemophane, PS, and PMMA) showed significant hirudin filtration. Owing to marked differences in hirudin-sieving characteristics, choice of the appropriate hemodialyzer membrane is an important determinant of bleeding risk in dialysis-dependent patients who are treated with hirudin. In case of overdosage or bleeding complications, hemofiltration via PS membranes is recommended to reduce plasma hirudin concentration. Hirudin dosage should be adapted not only to the clinical situation but also to the hirudin-sieving characteristics of the assigned dialyzer. PMID- 17699454 TI - Estimating preference scores in conventional and home nocturnal hemodialysis patients. AB - Previous studies have reported higher quality of life in patients who receive home nocturnal hemodialysis (HNHD) than conventional in-center hemodialysis (IHD). The optimal method for eliciting preferences from dialysis patients remains undefined, and there may be unique methodologic concerns in this population. Patients' preferences for IHD (n = 20) and HNHD (n = 24) were studied using the standard gamble (SG), time trade-off (TTO), and modified willingness to pay (WTP) methods. This report describes experience with operationalizing these three techniques in this population. A higher preference for HNHD was found with all measures, with significant differences observed with the SG (HNHD: median 0.79 [interquartile range (IQR) 0.67 to 0.95]; IHD: median 0.60 [IQR 0.20 to 0.82]; P = 0.031) and WTP (HNHD: median 0.50 [IQR 0.40 to 0.68]; IHD: median 0.20 [IQR 0.20 to 0.38]; P < 0.001). SG and TTO scores were moderately correlated but not with WTP. In addition, qualitative issues arose during TTO and WTP interviews that seemed to influence the interpretation of these preference scores. In the TTO, time willing to trade became oriented toward the next pivotal life event, with a failure of the requirement for a constant proportional time trade-off. WTP preferences were oriented toward the smallest survival stipend. These issues represent range restriction biases. No significant issues arose during the SG interviews. HNHD patients expressed a greater preference for current health than IHD patients. The operational performance of SG was good in this study, whereas biases and methodologic concerns were identified with the TTO and WTP in this population. PMID- 17699455 TI - Depression and anxiety in urban hemodialysis patients. AB - Depression is well established as a prevalent mental health problem for people with ESRD and is associated with morbidity and mortality. However, depression in this population remains difficult to assess and is undertreated. Current estimates suggest a 20 to 30% prevalence of depression that meets diagnostic criteria in this population. The extent of other psychopathology in patients with ESRD is largely unknown. The aim of this study was to expand the research on psychiatric complications of ESRD and examine the prevalence of a broad range of psychopathology in an urban hemodialysis center and their impact on quality of life. With the use of a clinician-administered semistructured interview in this randomly selected sample of 70 predominately black patients, >70% were found to have a psychiatric diagnosis. Twenty-nine percent had a current depressive disorder: 20% had major depression, and 9% had a diagnosis of dysthymia or depression not otherwise specified. Twenty-seven percent had a current major anxiety disorder. A current substance abuse diagnosis was found in 19%, and 10% had a psychotic disorder. The mean Beck Depression Inventory score was 12.1 +/- 9.8. Only 13% reported being in current treatment by a mental health provider, and only 5% reported being prescribed psychiatric medication by their physician. A total of 7.1% had compound depression or depression coexistent with another psychiatric disorder. The construct of depression was also disentangled from the somatic effects of poor medical health by demonstrating a unique relationship between depressive affect and depression diagnosis, independent of health status. This study also suggests the utility of cognitive variables as a meaningful way of understanding the differences between patients who have ESRD with clinical depression or other diagnoses and those who have no psychiatric comorbidity. The findings of both concurrent and isolated anxiety suggest that the prevalence of psychopathology in patients with ESRD might be higher than previously expected, and the disorders may need to be treated independently. In addition, the data suggest that cognitive behavioral therapeutic techniques may be especially advantageous in this population of patients who are treated with many medications. PMID- 17699456 TI - Predictors of survival after cardiac arrest in outpatient hemodialysis clinics. AB - Cardiac arrest (CA) is the most common cause of death in hemodialysis patients, and factors that improve survival after arrest are unknown. This study sought to identify modifiable factors that are associated with survival after CA in hemodialysis clinics. Patients who experienced in-center CA in the Gambro Healthcare System in the United States from 2002 to 2005 were identified. Patient characteristics at the time of arrest were compared between survivors and nonsurvivors at 24 h and 6 mo after CA. A total of 729 patients sustained in clinic CA; 310 (42.5%) patients survived 24 h, and 80 (11%) patients survived 6 mo. Traditional risk factors, including cardiovascular comorbidities, diabetes, hemoglobin, and dialysis adequacy, did not predict survival at either time point. After adjustment for case-mix factors, presence of indwelling catheter, and concomitant medications, only use of beta blockers (BBL), calcium-channel blockers (CCB), and angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) remained significantly associated with survival (BBL odds ratio [OR] 0.32 [95% confidence interval (CI) 0.17 to 0.61]; CCB OR 0.42 [95% CI 0.23 to 0.76]; ACEI/ARB OR 0.51 [95% CI 0.28 to 0.95]). The beneficial effect of ACEI/ARB and BBL on survival increased sequentially with higher medication dosages. Prescription of BBL at the time of the event was the only predictive variable of survival at 24 h. Therefore, traditional cardiovascular risk factors were not associated with survival after CA in this hemodialysis cohort. The benefits that are associated with BBL, CCB, and ACEI/ARB suggest that these medications may improve the chances of survival after CA. PMID- 17699457 TI - Kidney function, electrocardiographic findings, and cardiovascular events among older adults. AB - Chronic kidney disease (CKD) is associated with cardiovascular (CV) disease and mortality. It is not known whether cardiac rhythm disturbances are more prevalent among individuals with CKD or whether resting electrocardiogram findings predict future CV events in the CKD setting. Data were obtained from the Cardiovascular Health Study, a community-based study of adults aged >/=65 yr. After exclusions for prevalent heart disease, atrial fibrillation, implantable pacemaker, or antiarrhythmic medication use, 3238 participants were analyzed. CKD was defined by an estimated GFR <60 ml/min per 1.73 m(2). Outcomes were adjudicated incident heart failure (HF), incident coronary heart disease (CHD), and mortality. Participants with CKD had longer PR and corrected QT intervals compared with those without CKD; however, differences in electrocardiographic markers were explained by traditional CV risk factors and CV medication use. After adjustment for known risk factors, each 10-ms increase in the QRS interval was associated with a 15% greater risk for incident HF (95% confidence interval [CI] 1.04 to 1.27), a 13% greater risk for CHD (95% CI 1.04 to 1.24), and a 17% greater risk for mortality (95% CI 1.09, 1.25) among CKD participants. Each 5% increase in QTI was associated with a 42% (95% CI 1.23 to 1.65), 22% (95% CI 1.07 to 1.40), and 10% (95% CI 0.98 to 1.22) greater risk for HF, CHD, and mortality, respectively. Associations seemed stronger for participants with CKD; however, no significant interactions were detected. Resting electrocardiographic abnormalities are common in CKD and independently predict future clinical CV events in this setting. PMID- 17699458 TI - The burden of chronic kidney disease among the Zuni Indians: the Zuni Kidney Project. AB - The Zuni Indians of New Mexico are experiencing an epidemic of chronic kidney disease (CKD). The Zuni Pueblo created the Zuni Kidney Project (ZKP) to decrease the burden of CKD in the community. The aim of this study was to estimate the prevalence of CKD among Zuni Indians using National Kidney Foundation Kidney Disease Outcomes Quality Initiative criteria. The ZKP conducted a population based, cross-sectional survey to estimate the prevalence of CKD and related risk factors among Zuni Indians aged > or =20 yr (n = 1113). GFR was estimated using equations based on serum creatinine, and urine albumin:creatinine ratio was calculated in a single spot urine sample. ESRD counts were obtained from health care providers. The age- and sex-adjusted prevalence of CKD among the Zuni Indians was >2.5-fold higher than that among the US composite population. The estimated prevalence of CKD stages 1 and 2 combined was three- to four-fold higher than that of CKD stages 3 and 4 combined. This ratio was significantly higher than that in the US composite population (1.4-fold). The prevalence of CKD stage 5 was eight-fold higher among the Zuni Indians than among the composite US population. The Zuni Indians have an expanded pool of CKD that contributes to the high burden of ESRD. The high prevalence of CKD stages 1 and 2 provides a unique opportunity to develop innovative treatment programs to reduce the burden of CKD in Zuni Pueblo. PMID- 17699459 TI - Influence of early posttransplantation prednisone and calcineurin inhibitor dosages on the incidence of new-onset diabetes. AB - Risk for new-onset diabetes (NOD) after renal transplantation is higher with tacrolimus (Tac) than with cyclosporine (CsA), but the extent to which the diabetogenic effect of Tac is dosage dependent or steroid dependent remains uncertain. Patients who received a transplant between 1995 and 2002 were drawn from the United Network for Organ Sharing registry and prescription records and NOD diagnoses from Medicare claims, both provided by the United States Renal Data System. Patients were divided into six groups of steroid and Tac doses at 30 d after transplantation and referenced against CsA. Relative hazards of NOD with Cox proportional hazards regression were estimated incorporating propensity scores for Tac and nonimmunosuppressive factors related to NOD. A total of 8839 patients with valid immunosuppression records and without pretransplantation evidence of diabetes were included in the study. Unadjusted, cumulative, NOD incidence 1 yr after transplantation was 14.6% with CsA and 22.2% with Tac and at 3 yr after transplantation was 23.4% with CsA and 32.9% with Tac (P < 0.0001). Neither higher CsA nor higher steroid dosages were associated with NOD in CsA treated patients. However, NOD hazard was significantly higher with Tac than with CsA in all six steroid/Tac dosing groups, including the cohort with the lowest dosages of Tac (dosage thresholds at 30 d after transplantation <0.12 mg/kg per d [mean 0.07 mg/kg per d] and steroids (<0.75 mg/kg per d; hazard ratio 1.28; 95% confidence interval 1.10 to 1.48; P = 0.0012). Whereas the incidence of NOD is greatest with high Tac dosages, the increased risk versus CsA is sustained with lower Tac dosages. Higher steroid dosages increase the early diabetogenic effect of Tac but not of CsA. PMID- 17699460 TI - Racial differences in graft survival: a report from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS). AB - Multiple studies have documented racial differences in graft survival in kidney transplant recipients. Although several studies in adult kidney transplant recipients have evaluated risk factors that might predispose to these differences, studies in pediatric patients are lacking. This study retrospectively analyzed data from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) to identify racial differences in kidney transplant outcomes and evaluate factors that might contribute to those differences. The study was restricted to the first NAPRTCS registry-reported kidney transplant for pediatric patients (age < or =21 yr) whose race was reported as either black or white. Univariate graft survival analyses were performed using the log rank statistic. Relative hazard rates for the effect of race on graft failure were determined using proportional hazards models. Multivariate analyses were restricted to patients with >30 d of graft survival and were adjusted for initial diagnosis, donor source, presence of delayed graft function, era of transplantation, estimated GFR at 30 d after transplantation, and number of days hospitalized in the first month after transplantation. Graft survival was significantly lower in black transplant recipients at 3 yr (70.9 versus 83.3%) and 5 yr (59.9 versus 77.7%). After controlling for confounding factors, black recipients continued to have a higher risk for graft failure than white recipients (adjusted hazard rate 1.65; 95% confidence interval 1.46 to 1.86). Significant racial differences in kidney transplant outcomes exist among pediatric patients even after controlling for confounding factors. PMID- 17699461 TI - A proposed taxonomy for the podocytopathies: a reassessment of the primary nephrotic diseases. AB - A spectrum of proteinuric glomerular diseases results from podocyte abnormalities. The understanding of these podocytopathies has greatly expanded in recent years, particularly with the discovery of more than a dozen genetic mutations that are associated with loss of podocyte functional integrity. It is apparent that classification of the podocytopathies on the basis of morphology alone is inadequate to capture fully the complexity of these disorders. Herein is proposed a taxonomy for the podocytopathies that classifies along two dimensions: Histopathology, including podocyte phenotype and glomerular morphology (minimal change nephropathy, focal segmental glomerulosclerosis, diffuse mesangial sclerosis, and collapsing glomerulopathy), and etiology (idiopathic, genetic, and reactive forms). A more complete understanding of the similarities and differences among podocyte diseases will help the renal pathologist and the nephrologist communicate more effectively about the diagnosis; this in turn will help the nephrologist provide more accurate prognostic information and select the optimal therapy for these often problematic diseases. It is proposed that final diagnosis of the podocytopathies should result from close collaboration between renal pathologists and nephrologists and should whenever possible include three elements: Morphologic entity, etiologic form, and specific pathogenic mechanism or association. PMID- 17699462 TI - Pathophysiology of the clinical manifestations of preeclampsia. PMID- 17699463 TI - Obesity and obesity-initiated metabolic syndrome: mechanistic links to chronic kidney disease. AB - There is an epidemic of obesity and the metabolic syndrome in the United States and across the world. Both entities are associated with high mortality, mainly as a result of cardiovascular disease. The epidemic of obesity has been paralleled by an increase in the incidence of chronic kidney disease (CKD). Several recent epidemiologic studies have shown that obesity and the metabolic syndrome are independent predictors of CKD. In addition to diabetes and hypertension, several other mechanisms have been postulated to initiate and maintain kidney injury in patients with obesity and the metabolic syndrome. This article reviews the recent epidemiologic data linking obesity and the metabolic syndrome to CKD and summarizes the potential mechanisms of renal injury in this setting, with a focus on the role of inflammation, lipotoxicity, and hemodynamic factors. Potential preventive and therapeutic modalities based on the limited evidence available are discussed. PMID- 17699464 TI - The kidney transplant recipient with hepatitis C infection: pre- and posttransplantation treatment. AB - Liver disease secondary to chronic hepatitis C virus (HCV) infection is an important cause of morbidity and mortality in dialysis patients and kidney transplant recipients. Evaluation of patients with chronic HCV infection is warranted to determine stage of disease and the need for HCV therapy. Although combination therapy with interferon (IFN) plus ribavirin is the standard of care for chronic HCV infection, IFN monotherapy is recommended in dialysis patients because ribavirin is contraindicated in the presence of renal failure. The goals of pretransplantation HCV therapy are to decrease the risk for progression of HCV associated liver disease, stabilize renal function in patients with HCV-related glomerulopathy, and prevent development of HCV-associated renal disease after transplantation. Posttransplantation HCV therapy is generally not recommended because of concerns regarding risk for precipitating acute rejection; however, antiviral therapy may be indicated to treat HCV-related glomerulopathy or prevent progression of chronic hepatitis C in patients with more advanced stages of fibrosis. When treatment is required, restored renal function allows use of combination therapy with IFN and ribavirin. Limitations of current HCV therapy include lack of tolerability and suboptimal response rates. New antiviral agents that can be used in dialysis patients (e.g., ribavirin alternatives) and in the posttransplantation setting (e.g., IFN alternatives) are needed to improve outcomes in these populations. PMID- 17699465 TI - New technologies in peritoneal dialysis. AB - In recent years, there have been some interesting advances in the science and practice of peritoneal dialysis (PD). This review focuses on selected technological advances and the impact that these changes may have on this modality. New, so-called "biocompatible" fluids have more physiologic pH and reduced glucose degradation products. These new fluids may reduce the deleterious effects of chronic exposure to the peritoneal membrane. However, enthusiasm for these new fluids is outstripping rigorous evidence that they change patient outcome. Continuous-flow PD offers a way to increase dramatically small solute clearance. However, there are significant technological barriers to the implementation of this kind of dialysis. Furthermore, there is little evidence that augmented small solute clearance will improve survival in PD patients. Finally, new catheter insertion techniques provide perhaps the most practical advances in allowing successful commencement of this excellent home dialysis modality. PMID- 17699466 TI - Microalbuminuria and cardiovascular disease. AB - To reduce the burden of cardiovascular disease (CVD), management strategies are increasingly focusing on preventive measures following early detection of markers of atherosclerosis. This review focuses on microalbuminuria, which is gaining recognition as a simple marker of an atherogenic milieu. Prospective and epidemiologic studies have found that microalbuminuria is predictive, independently of traditional risk factors, of all-cause and cardiovascular mortality and CVD events within groups of patients with diabetes or hypertension, and in the general population. The pathophysiologic mechanism underlying the association between albumin excretion and CVD is not fully defined. One hypothesis is that microalbuminuria may be a marker of CVD risk because it reflects subclinical vascular damage in the kidneys and other vascular beds. It may also signify systemic endothelial dysfunction that predisposes to future cardiovascular events. Based on this theory, periodic screening for microalbuminuria could allow early identification of vascular disease and help stratify overall cardiovascular risk, especially in patients with risk factors such as hypertension or diabetes. A positive test for urinary albumin excretion could signify the need for an intensive multifactorial intervention strategy, including behavior modification and targeted pharmacotherapy, aimed at preventing further renal deterioration and improving the overall CVD risk factor profile. Data from intervention studies suggest that treatment with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, statins, and/or strict glycemic control (in diabetics) offer significant reductions in cardiovascular and/or renal morbidity in patients with albuminuria. Use of this (old) marker may allow improved use of medications and strategies for secondary prevention. PMID- 17699467 TI - Screening for complement system abnormalities in patients with atypical hemolytic uremic syndrome. PMID- 17699468 TI - Dialysis in intensive care unit patients with acute kidney injury: continuous therapy is superior. PMID- 17699469 TI - What is the nephrologist's role as a primary care provider? We all have different answers. PMID- 17699470 TI - Screening, diagnosis, and treatment of cancer in long-term dialysis patients. AB - Some have suggested that the American Cancer Society guidelines for cancer screening be applied to patients who are on long-term dialysis and have used cancer screening as a means of assessing delivered preventive health care to patients with ESRD. However, cancer screening is effective only when it leads to survival benefit (usually expressed as days of life saved) without incurring high financial costs. Certain cancers such as human papillomavirus-associated cervical and tongue cancer and urologic malignancies are more common among dialysis patients, yet because the expected remaining lifetime of most dialysis patients is shorter than the time lived to develop malignancy, cancer screening in dialysis patients as applied to the general population is ineffective from the perspective of both cost and survival benefit. Cancer screening in dialysis patients is therefore best provided in an individual patient-focused manner. The occurrence, diagnosis, and treatment of cancer as well as issues related to cancer screening in dialysis patients are discussed. PMID- 17699471 TI - Coronary artery disease. AB - Coronary heart disease is the most common cause of death in the general population and in patients with ESRD. The principles of cardiovascular risk assessment and management apply to both populations. Advances in noninvasive coronary artery imaging have improved early detection of subclinical disease. The goals of medical management of coronary disease are to modify the natural history of disease and to improve the symptoms of angina. Coronary revascularization poses a different risk and benefit equation in the ESRD population. In stable ESRD with multivessel coronary artery disease, coronary bypass surgery, despite the upfront risks of stroke, myocardial infarction, and chest wound infection, seems to be a favored approach. In patients with ESRD and acute coronary syndromes, percutaneous coronary intervention on the target vessel has been associated with the most favorable outcomes. This article explores the clinical issues with respect to coronary artery disease in patients with ESRD. PMID- 17699472 TI - Protein kinase C-beta inhibition: a promise not yet fulfilled. PMID- 17699473 TI - Acquired cystic kidney disease and renal cell cancer after transplantation: time to rethink screening? PMID- 17699474 TI - Management of renal replacement therapy in acute kidney injury: a survey of practitioner prescribing practices. AB - BACKGROUND: Data on current practices for management of renal replacement therapy (RRT) in acute kidney injury (AKI) are limited, particularly with regard to the dosing of therapy. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: A survey was conducted of practitioners at the 27 study sites that participate in the Veterans Affairs/National Institutes of Health Acute Renal Trial Network (ATN) Study before initiation of patient enrollment for ascertainment of the local prevailing practices for management of RRT in critically ill patients with AKI. Surveys were returned from 130 practitioners at 26 of 27 study sites; the remaining study site provided aggregate data. RESULTS: Intermittent hemodialysis and continuous RRT were the most commonly used modalities of RRT, with sustained low-efficiency dialysis and other "hybrid" treatments used in fewer than 10% of patients. Intermittent hemodialysis was most commonly provided on a thrice-weekly or every other-day schedule, with only infrequent assessment of the delivered dosage of therapy. Most practitioners reported that they did not dose continuous RRT on the basis of patient weight. The average prescribed dosage of therapy corresponded to a weight-based dosage of no more than 20 to 25 ml/kg per h. CONCLUSIONS: These results provide insight into clinical management of RRT and provide normative data for evaluation of the design of ongoing clinical trials. PMID- 17699475 TI - Kidney outcomes in long-term studies of ruboxistaurin for diabetic eye disease. AB - BACKGROUND: A pilot study showed that ruboxistaurin (RBX), a protein kinase C beta inhibitor, significantly decreased albuminuria and stabilized kidney function over 1 yr in patients who had diabetic nephropathy and persistent macroalbuminuria despite receiving the current standard of care, including renin angiotensin system inhibition. In contrast, in a trial of patients with diabetic retinopathy, investigators reported the adverse event "diabetic nephropathy" more frequently in patients who received RBX. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: The purpose of this study was to evaluate long-term effects of RBX on kidney outcomes among patients with diabetic eye disease in three diabetic retinopathy trials (n = 1157). Baseline-to-study end changes in estimated GFR (eGFR) were calculated. Kidney outcomes included doubling of serum creatinine, development of advanced chronic kidney disease (stages 4 to 5), and death. RESULTS: Baseline eGFR was 81.6 +/- 26.0 ml/min per 1.73 m(2). In the combined placebo and RBX treatment groups, eGFR decreased by 11.0 +/- 19.6 ml/min per 1.73 m(2) during median follow-up of 33 to 39 mo. At least one kidney outcome occurred in 11.3% of patients. Frequency of doubling of serum creatinine was 6.0%, progression to advanced chronic kidney disease was 4.1%, and death was 4.1%. Kidney outcome rates did not differ by treatment assignment. CONCLUSIONS: Long term kidney outcomes in patients with diabetic eye disease were similar in placebo and RBX groups. In conclusion, large-scale, prospective trials in patients with diabetic nephropathy are needed to confirm safety and potential benefits of RBX on clinical outcomes. PMID- 17699476 TI - Once-monthly subcutaneous C.E.R.A. maintains stable hemoglobin control in patients with chronic kidney disease on dialysis and converted directly from epoetin one to three times weekly. AB - BACKGROUND: C.E.R.A., a continuous erythropoietin receptor activator, is in development to provide anemia correction and stable maintenance of hemoglobin (Hb) levels at extended administration intervals in patients with chronic kidney disease (CKD). This study examined its efficacy and safety when administered up to once monthly in patients who have CKD and are on dialysis and randomly convert directly from epoetin alpha or beta one to three times weekly. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: In this three-arm, comparator-controlled, open label, randomized, parallel-group, Phase III study, 572 dialysis patients (> or =18 yr) who were receiving stable subcutaneous epoetin one to three times weekly were randomly assigned (1:1:1) to continue epoetin or to receive subcutaneous C.E.R.A. once monthly or twice monthly for 52 wk. Dosage was adjusted to maintain Hb +/-1.0 g/dl of baseline level. Primary end point was mean change in Hb level between baseline and the evaluation period (weeks 29 to 36). RESULTS: Mean Hb levels during the evaluation period were similar between groups (once-monthly C.E.R.A. 11.5 g/dl; twice-monthly C.E.R.A. 11.7 g/dl; epoetin 11.5 g/dl). The difference between C.E.R.A. and epoetin in mean change (97.5% confidence interval) in Hb concentration between baseline and evaluation was -0.022 g/dl ( 0.262 to 0.217) for once monthly and 0.141 g/dl (-0.098 to 0.380) for twice monthly. Analysis demonstrated that C.E.R.A. was as effective as epoetin in maintaining Hb and was well tolerated. CONCLUSIONS: Subcutaneous C.E.R.A. once or twice monthly successfully maintained tight and stable Hb levels in patients who were on dialysis and randomly converted directly from epoetin one to three times weekly. PMID- 17699477 TI - Influence of peritoneal dialysis training nurses' experience on peritonitis rates. AB - BACKGROUND: This study examined the clinical impact of peritoneal dialysis (PD) training nurses regarding Gram-positive peritonitis among incident dialysis patients. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This study included 200 consecutive inception PD patients in a single center from September 1999 through April 2003. Effects of PD nurse trainers on the clinical outcomes of Gram positive peritonitis were evaluated. RESULTS: A total of 81 patients of 200 incident PD patients (mean age 56.9 yr) developed Gram-positive peritonitis. Mean Gram-positive peritonitis-free time for patients who were trained by nurses with years of experience in the lowest tertile was 58.8 mo, as compared with 47.0 mo in those who were trained by nurses within the intermediate tertile of experience (log-rank test, P = 0.044). After adjustment for diabetes and relevant coexisting medical factors, PD trainers' having > or =3 yr of experience, body mass index, and baseline serum albumin were the only independent risk factors for the time to a first Gram-positive peritonitis. Training nurses with > or =3 yr of experience was associated with more than two-fold increased likelihood of subsequent Gram positive peritonitis, with an adjusted hazard ratio of 2.24 (95% confidence interval [CI] 1.14 to 4.41; P = 0.020). When the lowest tertile group of trainers was used as the reference group in the Cox proportional hazards regression model, the hazard ratio was 1.94 (95% CI 1.04 to 3.61) for the intermediate tertile and 2.13 (95% CI 1.12 to 4.06) for the highest tertile. Experience of the PD trainers was not predictive of Gram-negative peritonitis. CONCLUSIONS: The finding of negative association between the trainers' length of time in practice and peritonitis incidence reminds us that active continued learning and applying principles of adult learning might be the answers for the nurses to teach the patients. PMID- 17699478 TI - Mortality predictors after 10 years of dialysis: a prospective study of Japanese hemodialysis patients. AB - BACKGROUND: This work aimed to examine the predictive value for death of various clinical variables after long-term hemodialysis (HD). DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: A total of 947 patients (597 men and 350 women, aged 21 to 93 yr) who were undergoing maintenance HD in Niigata, Japan, were stratified into two cohorts: Those with >10 yr of prior HD at study enrollment (n = 391) and those with < or =10 yr of previous therapy (n = 556). The survival of patients was examined for up to 40 mo (1999 to 2003) with the Cox proportional hazards model. Baseline clinical and dialysis data and serum biochemistries were used as independent variables. For adjustment for bias in patient selection, patient survival in either cohort was analyzed separately. RESULTS: In patients with >10 yr of HD, high pulse pressure, cerebrovascular disease, low serum creatinine, and low Kt/V values were the mortality risk predictors, whereas for those with < or =10 yr of HD, age and cerebrovascular disease were independent risk predictors for death. Diabetes, coronary artery disease, serum albumin, and C-reactive protein were NS predictors in those with long-term HD. CONCLUSIONS: Providing adequate dosage of dialysis and achieving a better control of pulse pressure may further improve survival in selected patients who had undergone HD for >10 yr. PMID- 17699479 TI - Impact of hemocontrol on hypertension, nursing interventions, and quality of life: a randomized, controlled trial. AB - BACKGROUND: Volume overload contributes to the pathogenesis of hypertension in hemodialysis (HD) patients. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: The Hemocontrol (HC) system (Gambro), which automatically adjusts ultrafiltration rate and dialysate conductivity during dialysis, has been suggested to improve hemodynamic tolerance and thereby facilitate fluid removal. A 6-mo randomized, controlled trial was performed to test the hypothesis that the addition of the HC system to a systematic BP management protocol may lower home BP in comparison with standard HD as primary end point. Secondary end points were the number of nursing interventions during dialysis and health-related quality of life. RESULTS: Complete BP data were available for 36 of the 44 patients who completed the trial. There was a statistically significant overall decrease in systolic BP during the study period (P = 0.005). However, the difference between the HC group and the standard HD group was NS (HC: from 147.8 +/- 21.7 to 139.8 +/- 16.2 mmHg; standard HD: from 141.9 +/- 19.2 to 135.2 +/- 9.9 mmHg). The number of HD sessions that required nursing interventions decreased in the HC group, whereas it increased in the standard HD group (HC: 42.9% reduction; standard HD: 35.7% increase; P = 0.04). There was also a significant improvement in health-related quality of life in the HC group but not in the standard HD group. CONCLUSIONS: These results suggest that the addition of the HC system to a systematic BP management protocol provides no additional benefit with regard to BP reduction. However, the HC system may improve the patient tolerability to dialysis. PMID- 17699480 TI - Relative blood volume changes underestimate total blood volume changes during hemodialysis. AB - BACKGROUND: Measurements of relative blood volume changes (DeltaRBV) during hemodialysis (HD) are based on hemoconcentration and assume uniform mixing of erythrocytes and plasma throughout the circulation. However, whole-body hematocrit (Ht) is lower than systemic Ht. During HD, a change in the ratio between whole-body to systemic Ht (F cell ratio) is likely to occur as a result of a net shift of low Ht blood from the microcirculation to the macrocirculation. Hence, DeltaRBV may differ significantly from total blood volume changes (DeltaTBV). Therefore, this study compared DeltaRBV and DeltaTBV during HD. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Plasma and erythrocyte volumes were measured using (125)I- and (123)I-radioiodinated albumin and (51)Cr-labeled erythrocytes, respectively. After validation of the standardized method in two patients on a nondialysis day, seven patients completed the protocol during HD. (125)I-albumin and (51)Cr-labeled erythrocytes were administered 20 min before the start of HD. (123)I-albumin was administered at 160 min into the HD session to quantify and correct for (125)I-albumin leakage. DeltaRBV was measured continuously throughout HD. The F cell ratio was derived from whole-body and systemic Ht. RESULTS: Total ultrafiltration volume was 2450 +/- 770 ml. TBV declined from 5905 +/- 824 to 4877 +/- 722 ml during HD. Thus, TBV declined 17.3 +/- 4.4%, whereas the RBV decline was only 8.2 +/- 3.7% (P = 0.001). The F cell ratio increased from 0.896 +/- 0.036 to 0.993 +/- 0.049 during HD (P = 0.002). CONCLUSIONS: DeltaRBV significantly underestimates DeltaTBV during HD. The rise in F cell ratio strongly suggests that during HD, blood translocates from the microcirculation to the macrocirculation, probably as a cardiovascular compensatory mechanism in response to hypovolemia. PMID- 17699481 TI - Development and validation of bioimpedance analysis prediction equations for dry weight in hemodialysis patients. AB - BACKGROUND: Accurate assessment of hydration status and specification of dry weight (DW) are major problems in the clinical treatment of hemodialysis (HD) patients. Bioelectrical impedance analysis (BIA) has been recognized as a noninvasive and simple technique for the determination of DW in HD patients. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This study was designed to develop and validate BIA prediction equations for DW in HD patients. It included white adults (1540 disease-free adults with normal body mass index [BMI] and 456 prevalent and 27 incident HD patients). All participants underwent at least one single-frequency BIA measurement (800 muA and 50 kHz alternating sinusoidal current with a standard tetrapolar technique). The BIA variable measured was resistance (R). Data of 1463 (95% of the cohort) disease-free individuals with normal BMI (prediction sample) were used to establish best-fitting BIA prediction equations of body weight. The latter were cross-validated in the residual 5% subset (77 individuals) of the same cohort (validation sample). RESULTS: Multiple regression analysis showed a significant relationship among body weight, R, age, and height in 739 men (R(2) = 0.82, P < 0.0001) and among body weight, R, and height in 724 women (R(2) = 0.68, P < 0.0001) in the prediction sample. The Bland Altman analysis showed a mean difference between predicted and measured body weight of 0.3 +/- 1.0 kg (95% confidence interval +/- 2.0 kg) in the validation sample. The BIA prediction equations that were obtained in disease-free individuals with normal BMI were applied to a cohort of 456 prevalent HD patients: The mean difference between achieved and estimated DW was 0.1 +/- 1.0 kg (P = 0.53) in men and -0.3 +/- 1.0 (P = 0.76) in women. Finally, BIA prediction equations were tested in a cohort of 27 incident HD patients. The mean difference between predicted and achieved DW was -0.6 +/- 1.0 kg (P = 0.76) in men and 0.6 +/- 1.0 (P = 0.50) in women. CONCLUSIONS: This study was able to develop and validate BIA prediction equations for DW in HD patients. They seem to be a promising tool; however, they still need external validation. PMID- 17699482 TI - Mathematical model demonstrates influence of luminal diameters on venous pressure surveillance. AB - BACKGROUND: The reliability of dialysis venous pressure (VP) in detecting stenosis is controversial. A mathematical model may help to resolve the controversy by providing insight into the factors that influence static VP. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This study used inflow artery and outflow vein luminal diameters from duplex ultrasound studies of 94 patients. These diameters were applied to a mathematical model, and how they affect the relation among VP, mean arterial pressure (MAP), blood flow, and stenosis was determined. Whether VP/MAP is a valid adjustment for the influence of MAP on VP, and whether the standard VP/MAP referral threshold of 0.50 is valid, were also determined. RESULTS: It was found that there is an approximate one-to-one relation between MAP and VP, so VP/MAP is a valid adjustment. Also, the 0.50 threshold successfully identifies most grafts with stenosis of 65% or more. However, the ratio of artery/vein diameters varied widely between patients, and the ratio independently influences VP/MAP. When the inflow artery is relatively narrow, the VP/MAP increase is delayed followed by a more rapid increase as critical stenosis is reached. CONCLUSIONS: VP/MAP is a valid adjustment for the influence of MAP on VP, and the standard VP/MAP threshold of 0.50 warns of the transition to critical stenosis. However, relatively narrow arteries cause a delay followed by a rapid increase in VP/MAP that may not be detected before thrombosis unless measurements are very frequent. Clinical trials that emphasize trend analysis with frequent measurements are needed to evaluate the efficacy of VP surveillance. PMID- 17699483 TI - Role of oral iron in the management of long-term hemodialysis patients. AB - BACKGROUND: The literature contends that oral iron supplementation is relatively ineffective in patients who are on long-term hemodialysis (HD), and intravenous iron is the superior form of supplementation. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Data were prospectively abstracted from a cross-sectional cohort of all patients in the long-term in-center HD program at St. Michael's Hospital (SMH) from April 1, 2003, to April 1, 2004. Laboratory data were measured monthly. SMH data were compared with those in eight other centers in the Toronto Region Dialysis Registry. RESULTS: A total of 93% of the 151 patients tolerated oral iron. Eighty-eight (58%) patients received oral iron exclusively, and 60 (40%) patients received intravenous iron with or without oral iron. Of the patients who received oral iron exclusively, 73% maintained a hemoglobin of > or =110 g/L and 93% maintained a hemoglobin of > or =100 g/L. A total of 74% had an iron saturation > or =20%, and 36% had a ferritin level >100 g/L. Among the patients who were on oral iron alone and had hemoglobin of > or =110 g/L, the same amount of erythropoietin was used regardless of ferritin levels (P = 0.17), but less erythropoietin was used when they reached the target for either iron saturation or both iron indices (P = 0.02 and 0.03, respectively). Among the centers in the Toronto Region Dialysis Registry, hemoglobin levels and erythropoietin dosages did not differ among the three centers that predominantly used oral iron versus the six centers that predominantly use intravenous iron (P = 0.46 and 0.95, respectively). CONCLUSIONS: Oral iron is a well-tolerated and effective form of iron supplementation in long-term HD patients. PMID- 17699484 TI - Administration of tobramycin in the beginning of the hemodialysis session: a novel intradialytic dosing regimen. AB - BACKGROUND: Aminoglycoside antibiotic efficacy is related to peak concentration (C(max)) and postantibiotic effect, whereas toxicity is directly related to body exposure as measured by area under the serum concentration versus time curve (AUC). On the basis of pharmacokinetic simulation models, tobramycin administration during the first 30 min of high-flux hemodialysis achieves similar C(max) but significantly lower AUC and prehemodialysis concentrations compared with conventional dosing in the last 30 min of hemodialysis. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: To test this hypothesis, a pilot study in which five adult chronic hemodialysis patients who were undergoing high-flux dialysis received one dose of tobramycin 1.5 mg/kg intravenously during the first or last 30 min of hemodialysis was conducted. After a 1-mo washout period, patients crossed over to the other treatment schedule. Tobramycin serum concentrations were measured to determine C(max), interdialytic and intradialytic elimination rate constants and half-lives, AUC, and clearance. RESULTS: Tobramycin administration during the first and last 30 min of hemodialysis resulted in similar C(max) of 5.63 +/- 0.49 and 5.83 +/- 0.67 mg/L (P > 0.05) but significantly lower prehemodialysis concentrations of 0.16 +/- 0.09 and 2.44 +/- 0.43 mg/L (P < 0.001) and AUC of 21.06 and 179.23 +/- 25.84 mg/h per L (P < 0.001), respectively. CONCLUSIONS: Tobramycin administration during the first 30 min of hemodialysis results in similar C(max) but lower AUC to conventional dosing, which may translate into comparable efficacy but lower toxicity. PMID- 17699485 TI - Presenting features and short-term outcome according to pathologic variant in childhood primary focal segmental glomerulosclerosis. AB - BACKGROUND: This was a retrospective analysis of children in one center who had primary (idiopathic) FSGS. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: There were 41 patients: 34.1% female, 65.9% male, 80.5% black, and 19.5% white. At presentation, the mean age was 10.9 +/- 0.9 yr. The mean time of follow-up was 3.9 +/- 0.5 yr. RESULTS: During the observation period, the systolic BP (SBP) and diastolic BP (DBP) remained stable, serum albumin rose slightly, and the GFR was stable. Among those who received corticosteroids at presentation, 21.2% were steroid sensitive. At last follow-up among all patients, 71% were in remission, 78% had stage 1 or 2 chronic kidney disease, and 4.9% had reached ESRD. At last follow-up, the GFR was significantly higher (P = 0.01) in patients who were initially steroid sensitive. Ethnicity had no effect on clinical data or response to therapy. The pathologic variants were as follows: Cellular, 32%; collapsing, 24%; and not otherwise specified (NOS), 44%. The chronicity scores were as follows: Cellular, 4.3; collapsing 6.4; and NOS, 4.0 (significantly higher, P = 0.02, in collapsing versus NOS). At presentation, SBP (P = 0.03) and DBP (P = 0.03) were significantly higher and GFR was lower (P = 0.03) in patients with the collapsing compared with NOS variant. Remission after the initial course of corticosteroids was less common with the collapsing variant. At last follow-up, SBP (P = 0.02) and DBP (P = 0.04) were significantly higher in patients with the collapsing versus NOS variant. CONCLUSIONS: The short-term outcome in pediatric primary FSGS is generally favorable, but a more guarded prognosis exists for patients with collapsing FSGS. PMID- 17699486 TI - Association of initial hemodialysis vascular access with patient-reported health status and quality of life. AB - BACKGROUND: Although the arteriovenous fistula (AVF) is the recommended form of vascular access for patients with ESRD, its impact on patient perception of health status, quality of life (QOL), or satisfaction is unknown. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This study compared patient-reported health status and QOL scores and vascular access type among a national random sample of 1563 patients at dialysis initiation and day 60 of ESRD during 1996 to 1997. Patients were stratified into five categories: AVF at first dialysis and day 60 of ESRD, arteriovenous graft (AVG) at first dialysis and day 60, central venous catheter (CVC) at first dialysis and AVF at day 60, CVC at first dialysis and AVG at day 60, and CVC at first dialysis and day 60. RESULTS: Ten percent (n = 154) of patients had an AVF, 21% (n = 326) had an AVG, and 69% (n = 1083) had a CVC at dialysis initiation; those who were most likely to use an AVF were white and male. After statistical adjustment, patients with persistent AVF use reported greater physical activity and energy, better emotional and social well-being, fewer symptoms, less effect of dialysis and burden of kidney disease, and better sleep compared with patients with persistent CVC use, whereas measures such as cognitive and sexual function did not differ by access type. CONCLUSIONS: Compared with persistent CVC use, early persistent AVF use is associated with the perception of improved health status and QOL among patients with ESRD. Future longitudinal studies may help to clarify further the association between QOL and vascular access. PMID- 17699487 TI - Hepatitis C virus infection and the prevalence of renal insufficiency. AB - BACKGROUND: Hepatitis C virus (HCV) is associated with pathologic changes in the kidney. However, the association between HCV and renal dysfunction is not well defined. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This study estimated the prevalence of renal insufficiency among veterans who received care through the Veterans Affairs Puget Sound Health Care System. The study population consisted of veterans who underwent HCV antibody testing between January 1, 1999, and December 31, 2004, and had at least one primary care or medical subspecialty visit and at least one outpatient creatinine measurement within the 18 mo before antibody testing. Veterans were excluded when they had a history of chronic dialysis, creatinine >5 mg/dl, or renal transplantation. Study data were extracted from the electronic medical record. Renal insufficiency was defined as a creatinine level > or =1.5 mg/dl. Multivariate logistic regression was performed to estimate the risk for renal insufficiency associated with HCV. Among 25,782 eligible veterans, 1928 were HCV antibody positive and 23,854 were HCV antibody negative. RESULTS: Although the proportion with renal insufficiency was lower for antibody-positive versus -negative veterans (4.8 versus 6.0%), after adjustment for age, race, gender, diabetes, and hypertension, HCV-positive veterans had a 40% higher odds for renal insufficiency (odds ratio 1.40; 95% confidence interval 1.11 to 1.76) as compared with HCV-negative veterans. CONCLUSIONS: HCV was associated with an increased prevalence of renal insufficiency. PMID- 17699488 TI - Relationships of plasma renin levels with renal function in patients with primary aldosteronism. AB - BACKGROUND: The renal damage that is present in primary aldosteronism might reflect functional and potentially reversible abnormalities that are initiated by glomerular hyperfiltration. The aim of this study was to investigate the relationships of plasma renin and aldosterone concentrations with renal outcomes after treatment of primary aldosteronism. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Fifty-six consecutive patients who had primary aldosteronism and were recruited in a university center were studied. Patients were prospectively followed after either surgical or medical treatment for a mean of 6.2 yr, during which they received antihypertensive drugs to reach a target BP of <140/90 mmHg. RESULTS: At baseline, patients with primary aldosteronism had higher creatinine clearance and albuminuria than 323 patients with essential hypertension and 113 normotensive individuals. In patients with primary aldosteronism, plasma active renin levels that were higher than the lower limit of detection (2.5 pg/ml) were associated with higher BP, plasma potassium, and albuminuria and lower creatinine clearance. Plasma aldosterone concentrations that were higher than the median value (225 pg/ml) were associated with lower plasma potassium and higher creatinine clearance. Creatinine clearance was correlated directly with plasma aldosterone and inversely with renin. During follow-up, patients with higher baseline plasma renin required use of more antihypertensive drugs to obtain BP control and had a smaller early decline in albuminuria than did patients with suppressed renin. CONCLUSIONS: Escape of renin from suppression by excess aldosterone is associated with evidence of more severe renal damage in patients with primary aldosteronism and predicts less favorable outcomes after treatment. PMID- 17699490 TI - Door-to-dialysis time and daily hemodialysis in patients with leptospirosis: impact on mortality. AB - BACKGROUND: Leptospirosis is a public health problem, the severe form of which (Weil's disease) includes acute respiratory distress syndrome, typically accompanied by acute kidney injury (AKI), and is associated with high mortality rates. Recent evidence suggests that dialysis dosage affects outcomes in critically ill patients with sepsis-induced AKI. However, this population varies widely in terms of age, gender, and concomitant conditions, making it difficult to determine the appropriate timing (door-to-dialysis time) and dialysis dosage. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: It is logical to assume that increasing the dialysis dosage would minimize uremic complications and improve outcomes in such patients. Patients with Weil's disease constitute a homogeneous population and are typically free of comorbidities, therefore presenting an ideal model in which to test this assumption. RESULTS: The effects of dialysis dosage were evaluated in this population, with the use of either classic or slow low efficiency hemodialysis, and two periods/treatment plans were compared: 2002 to 2003/delayed, alternate-day dialysis (DAdD group; n = 15) and 2004 to 2005/prompt and daily dialysis (PaDD group; n = 18). Age, gender, AKI severity, APACHE score, serum urea, and time to recovery of renal function were assessed. All patients received vasoactive drugs (because of hemodynamic instability) and were on mechanical ventilation (because of acute respiratory distress syndrome). Mean serum urea during the dialysis period was significantly lower in the PaDD group than in the DAdD group. Of the PaDD group patients, three (16.7%) died, compared with 10 (66.7%) of the DAdD group patients. CONCLUSIONS: On the basis of this result, it is believed that alternate-day hemodialysis is no longer appropriate for critically ill patients with Weil's disease. PMID- 17699489 TI - Demographic characteristics of pediatric continuous renal replacement therapy: a report of the prospective pediatric continuous renal replacement therapy registry. AB - BACKGROUND: This article reports demographic characteristics and intensive care unit survival for 344 patients from the Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry, a voluntary multicenter observational network. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Ages were newborn to 25 yr, 58% were male, and weights were 1.3 to 160 kg. Patients spent a median of 2 d in the intensive care unit before CRRT (range 0 to 135). At CRRT initiation, 48% received diuretics and 66% received vasoactive drugs. Mean blood flow was 97.9 ml/min (range 10 to 350 ml/min; median 100 ml/min); mean blood flow per body weight was 5 ml/min per kg (range 0.6 to 53.6 ml/min per kg; median 4.1 ml/min per kg). Days on CRRT were <1 to 83 (mean 9.1; median 6). A total of 56% of circuits had citrate anticoagulation, 37% had heparin, and 7% had no anticoagulation. RESULTS: Overall survival was 58%; survival differed across participating centers. Survival was lowest (51%) when CRRT was started for combined fluid overload and electrolyte imbalance. There was better survival in patients with principal diagnoses of drug intoxication (100%), renal disease (84%), tumor lysis syndrome (83%), and inborn errors of metabolism (73%); survival was lowest in liver disease/transplant (31%), pulmonary disease/transplant (45%), and bone marrow transplant (45%). Overall survival was better for children who weighed >10 kg (63 versus 43%; P = 0.001) and for those who were older than 1 yr (62 versus 44%; P = 0.007). CONCLUSIONS: CRRT can be used successfully for a wide range of critically ill children. Survival is best for those who have acute, specific abnormalities and lack multiple organ involvement; sicker patients with selected diagnoses may have lower survival. Center differences might suggest opportunities to define best practices with future study. PMID- 17699491 TI - A randomized, controlled trial of lactic acid bacteria for idiopathic hyperoxaluria. AB - BACKGROUND: Urinary oxalate excretion is an important contributor to calcium oxalate stone formation. Methods of reducing oxalate excretion are not wholly satisfactory, and no controlled trials using them have been performed to prevent stone recurrence. Some lactic acid bacteria can degrade oxalate in vitro. This study sought to reduce urinary oxalate excretion in calcium stone formers with idiopathic hyperoxaluria. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: A randomized, double-blind, placebo-controlled trial was performed of Oxadrop, a mix of four lactic acid bacterium species. This preparation previously reduced oxalate excretion in stone formers with idiopathic and enteric hyperoxaluria. Patients were selected from two stone prevention clinics. Twenty people with calcium stones and idiopathic hyperoxaluria (>40 mg/d) were enrolled and randomly assigned 1:1 in placebo and active preparation arms. Both groups took 3.6 g of granulate each day: Either placebo or the experimental preparation. Participants performed two consecutive 24-h urine collections at baseline, at 28 d of therapy, and at 56 d, after being off the preparation for 4 wk. Diet was replicated at each point. RESULTS: There was no effect of the study preparation: Mean 24-h urinary oxalate excretion in placebo-treated patients was 73.9 mg at baseline and 72.7 mg after treatment, whereas the Oxadrop-treated patients had 59.1 mg at baseline and 55.4 mg after treatment. The preparation was well tolerated; three participants on active treatment experienced mild constipation. CONCLUSIONS: In this randomized, placebo-controlled trial, Oxadrop did not reduce urinary oxalate excretion in participants with idiopathic hyperoxaluria. PMID- 17699492 TI - Renal cell carcinoma in transplant recipients with acquired cystic kidney disease. AB - BACKGROUND: Acquired cystic kidney disease (ACKD) is a widely known renal cell carcinoma risk factor. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: An ultrasound screening of the native kidneys in all renal transplant patients of a renal outpatient clinic who received a transplant between 1970 and 1998 and presented between 1997 and 2003 (n = 916) was initiated prospectively. A total of 561 patients were screened. RESULTS: A total of 129 (23%) patients had ACKD; 46 (8.2%) patients had complex renal cysts (Bosniak classification, category IIF to III); and eight (1.5%) patients had newly diagnosed renal cell carcinoma, seven of which were associated with ACKD (category IV). One patient had renal cell carcinoma in the transplanted kidney. Together with 19 patients of the cohort with formerly diagnosed renal cell carcinoma (18 of them associated with ACKD), the prevalence of renal cell carcinoma among all patients was 4.8%; among the patients with ACKD, it was 19.4% (without ACKD 0.5%; P = 0.0001); and among the patients with complex renal cysts (category IIF to III), it was 54.4%. The patients with ACKD were older (54 +/- 13 versus 51 +/- 14 yr; P = 0.048), more often male (65 versus 54%; P = 0.03), more often had heart disease (44 versus 29%; P = 0.001), had larger kidneys (6.9 and 6.8 cm versus 6.0 and 5.9 cm; P < 0.001), and had more calcifications (29 versus 15%; P = 0.002). Renal cell carcinoma was bilateral in 26% of cases. Tumor histology was clear cell carcinoma in 58% and papillary carcinoma in 42% of cases; one patient had both. Only one patient had a lung metastasis, and no patient died. CONCLUSIONS: Renal cell carcinoma occurs often after renal transplantation and that especially patients with ACKD should routinely be screened. Because ACKD after renal transplantation seems to be less frequent (23%) than during dialysis treatment (30 to 90%), renal transplantation may inhibit renal cell carcinoma. PMID- 17699493 TI - A review of dietary supplement-induced renal dysfunction. AB - Complementary and alternative medicine (CAM) is a multibillion-dollar industry. Almost half of the American population uses some form of CAM, with many using them in addition to prescription medications. Most patients fail to inform their health care providers of their CAM use, and physicians rarely inquire. Annually, thousands of dietary supplement-induced adverse events are reported to Poison Control Centers nationwide. CAM manufacturers are not responsible for proving safety and efficacy, because the Food and Drug Administration does not regulate them. However, concern exists surrounding the safety of CAM. A literature search using MEDLINE and EMBASE was undertaken to explore the impact of CAM on renal function. English-language studies and case reports were selected for inclusion but were limited to those that consisted of human subjects, both adult and pediatric. This review provides details on dietary supplements that have been associated with renal dysfunction and focuses on 17 dietary supplements that have been associated with direct renal injury, CAM-induced immune-mediated nephrotoxicity, nephrolithiasis, rhabdomyolysis with acute renal injury, and hepatorenal syndrome. It is concluded that it is imperative that use of dietary supplements be monitored closely in all patients. Health care practitioners must take an active role in identifying patients who are using CAM and provide appropriate patient education. PMID- 17699494 TI - The unique character of cardiovascular disease in chronic kidney disease and its implications for treatment with lipid-lowering drugs. AB - Although the risk for cardiovascular disease (CVD) is high in individuals with chronic kidney disease (CKD), there are very limited data to guide the use of lipid-lowering drugs (LLDs) in this population because the major trials of LLDs in the general population have included very few individuals with CKD. The pathophysiologic and epidemiologic differences of CVD in the CKD population suggest that the study findings derived in the general population may not be directly applicable to those with CKD, and the few trials that have been directed at patients with kidney disease have not shown clear clinical benefits of LLDs. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) Work Group has provided consensus-based guidelines for managing dyslipidemias in individuals with CKD and after renal transplantation. Since the publication of these statements, further data have emerged and multiple studies are ongoing to define better the role of LLDs in patients with CKD. In this article, the data that are pertinent to the CKD population are reviewed, and updated recommendations for use of LLD in the CKD population are provided. PMID- 17699495 TI - Current management of vascular access. AB - Optimizing vascular access outcomes remains an ongoing challenge for clinical nephrologists. All other things being equal, fistulas are preferred over grafts, and grafts are preferred over catheters. Mature fistulas have better longevity and require fewer interventions, as compared with mature grafts. The major hurdle to increasing fistula use is the high rate of failure to mature of newly created fistulas. There is a desperate need for enhanced understanding of the mechanisms of failure to mature and the optimal type and timing of interventions to promote maturity. Grafts are prone to frequent stenosis and thrombosis. Surveillance for graft stenosis with preemptive angioplasty may reduce graft thrombosis, but recent randomized clinical trials have questioned the efficacy of this approach. Graft stenosis results from aggressive neointimal hyperplasia, and pharmacologic approaches to slowing this process are being investigated in clinical trials. Catheters are prone to frequent thrombosis and infection. The optimal management of catheter-related bacteremia is a subject of ongoing debate. Prophylaxis of catheter-related bacteremia continues to generate important clinical research. Close collaboration among nephrologists, surgeons, radiologists, and the dialysis staff is required to optimize vascular access outcomes and can be expedited by having a dedicated access coordinator to streamline the process. The goal of this review is to provide an update on the current status of vascular access management. PMID- 17699496 TI - Chronic kidney disease and disasters: what may the societies do? PMID- 17699497 TI - Nephrology in earthquakes: sharing experiences and information. AB - Earthquakes are the most unpredictable natural disasters and often result in many deaths and casualties as a result in part of the collapse of buildings. To restore medical facilities and activities after a large earthquake, nephrologists play critical roles not only in the restoration of dialysis facilities for regular renal replacement therapy but also in the prevention and treatment of acute kidney injury and hyperkalemia, mainly as a result of crush syndrome. For these purposes, sufficient education and establishment of functional networks among medical facilities are certainly needed. Recently, the contribution of international task forces has become more significant, especially for large-scale natural disasters. Organized detailed action plans should be prepared among regional governments and armies considering the differences in cultures and social systems. PMID- 17699498 TI - Emergency preparedness concepts for dialysis facilities: reawakened after Hurricane Katrina. PMID- 17699499 TI - Kidney patient care in disasters: lessons from the hurricanes and earthquake of 2005. AB - The active 2005 hurricane season alerted Americans to the pressing need for a more effective response to mass casualty incidents. The kidney patient community was particularly affected. Ninety-four dialysis facilities in the Gulf Coast states closed for at least 1 wk in the aftermath of Hurricane Katrina, and additional units were affected by evacuation of dialysis patients. Dialysis units along the Gulf Coast were also affected by Hurricanes Rita and Wilma. Existing emergency response plans were inadequate in providing continuity of care for kidney patients. The Kashmir, South Asia, earthquake of October 2005 killed 97,000 individuals. Building collapse was associated with widespread crush injury, and many patients required temporary hemodialysis. Several regions of the United States have the potential for catastrophic earthquakes. The Kidney Community Emergency Response Coalition has recently issued recommendations for patients, dialysis facilities, and providers, with a goal to improve care of kidney patients in future domestic disasters. With suitable planning, the nephrology community can do much to ensure the continuity of medical care for kidney patients in the face of a wide range of possible natural and human-made disasters. PMID- 17699500 TI - Kidney patient care in disasters: emergency planning for patients and dialysis facilities. AB - The catastrophic 2005 hurricane season alerted Americans to the need for a more effective response to mass casualty incidents. To address the needs of the nephrology community, the Kidney Community Emergency Response Coalition (KCERC) was formed, with representatives from more than 50 governmental agencies and private organizations. After completing phase 1 of its work, the KCERC issued recommendations for patients, dialysis units, and providers. During phase 2, the KCERC will promote implementation of those recommendations. During a disaster, the KCERC will host a daily conference call on which dialysis facilities, the End Stage Renal Disease Networks, and emergency response officials will coordinate disaster response. Predisaster preparation for kidney patients should stress identification of alternative dialysis facilities, education about the renal emergency diet, and plans for early evacuation from the disaster area and for evacuating with medical documents and medications. Dialysis facilities are required to have a disaster plan; regular revision and rehearsal are essential. Critical issues for dialysis facilities include identification of partner facilities, a robust communications plan that takes into account the limitations of telephones and broadband access, staff shortages in the face of a possible influx of new patients, the delivery of service in the face of compromised utilities (water, power), and the recovery of a dialysis facility that experiences flooding or structural damage. A timeline to safety for dialysis patients can be visualized; if specific tasks are accomplished at each disaster stage, then it is likely that the health of these vulnerable patients can be protected. PMID- 17699501 TI - Peripheral arterial disease: a guide for nephrologists. AB - Cardiovascular disease is a major source of morbidity and mortality for patients with chronic kidney disease (CKD). Peripheral arterial disease (PAD) is a strong predictor of coronary artery disease and a risk factor for mortality in the general population. This is of particular interest to nephrologists because the risk for PAD is increased in CKD. Often, PAD is overlooked as a source of morbidity and as a cardiovascular risk factor in this population. This review serves as an overview of the epidemiology, screening, diagnosis, and treatment of PAD with an emphasis on CKD. PMID- 17699502 TI - Selected primary care issues and comorbidities in children who are on maintenance dialysis: a review for the pediatric nephrologist. AB - Ten-year survival of all children who initiate dialysis at any age now approaches 70%, and in the older child this number is closer to 80%. These children will live with chronic kidney disease and its myriad of associated comorbidities during and throughout their childhood. Their care is complex and requires both teamwork and careful attention paid to maintaining lines of communication among patient, family, and both the facility-based nephrology team and caregivers who are outside the hospital setting. Irrespective of their need for dialysis, children with ESRD deserve and require developmentally appropriate care and anticipatory guidance with respect to primary care issues of childhood. The child who is on dialysis often is cared for solely or in large part by a nephrology service, therefore this review discusses issues that are particularly important to pediatric nephrologists in relation to selected primary care issues and comorbidities for the child who is on dialysis, with an emphasis on medical and psychosocial issues, and with particular weight placed on issues that are pertinent to the adolescent dialysis patient. PMID- 17699503 TI - A case of atypical light chain deposition disease--diagnosis and treatment. PMID- 17699504 TI - Viruses and diseases of the kidneys. PMID- 17699506 TI - Virus-induced cellular immune mechanisms of injury to the kidney. AB - Cellular immune systems play an important role in determining renal outcomes in virus-induced kidney diseases. Highlighted briefly are five different locations along the development of adaptive immune responses to viral infection that may promote injury to the renal parenchyma and the loss of renal function. This may occur because adaptive immune cells directly target infected renal parenchymal cells or because the kidney becomes a bystander organ of adaptive immune cell mediated injury. Examples from recent studies are provided to illustrate how this may lead to clinically relevant renal disease. PMID- 17699505 TI - Viral subversion mechanisms in chronic kidney disease pathogenesis. AB - Viruses cannot autonomously replicate but must rely on the host cellular machinery to support their life cycle. Through natural selection, viruses have evolved strategies to co-opt the host organism to be a better site for their propagation. Some of these strategies are directed at the cellular machinery and involve complicated and ingenious solutions to optimize infection, replication, viral gene expression, and new virion assembly and shedding. Other strategies are directed at the host's innate and adaptive immune systems that permit the virus to evade clearance mechanisms. The more common pathogenic viral infections in nephrology-cytomegalovirus, HIV-1, hepatitis C virus, polyomavirus BK, and parvovirus B19-all have acquired subversion strategies that benefit the virus but because they interfere with normal cellular and immune processes also have become pathogenic to the host. In addition, the highly prevalent viruses cytomegalovirus, BK, and B19 cause severe disease only in the setting of immunosuppression, revealing the very delicate balance that some viruses have achieved with their host's immune system. Thus, selective pressure for survival drives both the evolution of more sophisticated viruses and the host immune system as it evolves to combat the environment of adapting and emerging infectious agents. Understanding the molecular mechanisms of these viral subversion strategies may reveal new targets for the development of highly specific antiviral therapies and also aid vaccine development. PMID- 17699507 TI - HIV-1 and HIV-Associated Nephropathy 25 Years Later. AB - Twenty-five years after the first published description of AIDS, HIV-associated nephropathy (HIVAN) remains an important cause of kidney disease in HIV-infected patients. The pathogenesis of HIVAN involves direct HIV infection of the kidney, with both viral and host genetic factors playing an important role. The widespread use of antiretroviral therapy has influenced the epidemiology of HIV related kidney disease, and the nephrology community should support efforts to improve access to therapy and limit HIV transmission in susceptible minority populations. This article reviews the history of HIV and HIVAN, focusing on advances in the understanding of pathogenesis, epidemiology, and treatment. PMID- 17699508 TI - Genetic susceptibility, HIV infection, and the kidney. AB - In recent years, the sequencing of mammalian and microbial genomes has provided the opportunity to study how genetic variation in the host and pathogen influence the course of infectious disease. In the case of HIV-1 infection, such studies have led to identification of key viral proteins that determine pathogenicity, immune evasion, or drug resistance. In addition, candidate gene association studies have uncovered a large number of host genetic variants that influence the outcome of infection and some organ-specific complications. HIV-associated nephropathy (HIVAN) is a pathologically distinct complication of HIV infection. Interindividual variability in incidence, skewed ethnic distribution, and familial aggregation of HIVAN with other forms of ESRD have suggested genetic susceptibility as a major contributing factor. This article reviews the host genetic factors that influence the course of HIV-1 infection and discusses murine models that have increased the understanding of HIVAN pathogenesis and demonstrated the role of genetic background on determination of disease. PMID- 17699509 TI - BK virus nephropathy and kidney transplantation. AB - Nephropathy from BK virus (BKV) infection is an evolving challenge in kidney transplant recipients. It is the consequence of modern potent immunosuppression aimed at reducing acute rejection and improving allograft survival. Untreated BKV infections lead to kidney allograft dysfunction or loss. Decreased immunosuppression is the principle treatment but predisposes to acute and chronic rejection. Screening protocols for early detection and prevention of symptomatic BKV nephropathy have improved outcomes. Although no approved antiviral drug is available, leflunomide, cidofovir, quinolones, and intravenous Ig have been used. Retransplantation after BKV nephropathy has been successful. PMID- 17699510 TI - Parvovirus B19 and the kidney. AB - Infection with parvovirus B19 causes several clinical syndromes (fifth disease, transient aplastic crisis, pure red cell aplasia, and hydrops fetalis) and may contribute to other illnesses. B19 has been linked to renal disease in three settings: As a cause of acute glomerulopathy and as a cause of anemia in ESRD and kidney transplantation. Case reports implicate parvovirus in the pathogenesis of proliferative glomerulonephritis and collapsing glomerulopathy, but a causal relationship has not been established. A proposed role for B19 infection is based on the temporal association of renal findings with viral infection, positive serology, and identification of the viral genome in the glomerulus. Mechanisms may include cytopathic effects on glomerular epithelial cells and/or endothelial cells and glomerular deposition of immune complexes. Patients who require dialysis may have increased susceptibility to acute and chronic anemia after parvoviral infection. Factors that predispose this population to complications of B19 infection include impaired immune response, deficient erythropoietin production, and possibly decreased erythrocyte survival. The clinical burden of parvovirus B19 infection in renal transplant recipients may be underestimated; these individuals may develop persistent viremia as a result of a dysfunctional immune response. Chronic anemia and pure red blood cell aplasia are the most common complications of parvovirus infection in this population; the diagnosis should be considered in transplant recipients with unexplained anemia or pancytopenia. Allograft rejection and dysfunction have been reported in association with infection, but a cause-effect relationship has not been proved. Further investigation of the relationship between B19 and kidney disease is warranted. PMID- 17699511 TI - Emerging paradigms in the renal pathology of viral diseases. AB - This review considers recent information that illuminates pathogenetic mechanisms that involve three of the major viral infections that cause renal injury in the form of HIV-associated nephropathy, polyoma virus nephropathy, and hepatitis C virus-associated glomerulonephritis. PMID- 17699512 TI - Binding between the integrin alphaXbeta2 (CD11c/CD18) and heparin. AB - The interactions between cell surface receptors and sulfated glucosamineglycans serve ubiquitous roles in cell adhesion and receptor signaling. Heparin, a highly sulfated polymer of uronic acids and glucosamine, binds strongly to the integrin receptor alphaXbeta2 (p150,95, CD11c/CD18). Here, we analyze the structural motifs within heparin that constitute high affinity binding sites for the I domain of integrin alphaXbeta2. Heparin oligomers with chain lengths of 10 saccharide residues or higher provide strong inhibition of the binding by the alphaX I domain to the complement fragment iC3b. By contrast, smaller oligomers or the synthetic heparinoid fondaparinux were not able to block the binding. Semipurified heparin oligomers with 12 saccharide residues identified the fully sulfated species as the most potent antagonist of iC3b, with a 1.3 microM affinity for the alphaX I domain. In studies of direct binding by the alphaX I domain to immobilized heparin, we found that the interaction is conformationally regulated and requires Mg2+. Furthermore, the fully sulfated heparin fragment induced conformational change in the ectodomain of the alphaXbeta2 receptor, also demonstrating allosteric linkage between heparin binding and integrin conformation. PMID- 17699513 TI - TM14 is a new member of the fibulin family (fibulin-7) that interacts with extracellular matrix molecules and is active for cell binding. AB - We identified a new extracellular protein, TM14, by differential hybridization using mouse tooth germ cDNA microarrays. TM14 cDNA encodes 440 amino acids containing a signal peptide. The protein contains 3 EGF modules at the center, a C-terminal domain homologous to the fibulin module, and a unique Sushi domain at the N terminus. In situ hybridization revealed that TM14 mRNA was expressed by preodontoblasts and odontoblasts in developing teeth. TM14 mRNA was also expressed in cartilage, hair follicles, and extraembryonic tissues of the placenta. Immunostaining revealed that TM14 was localized at the apical pericellular regions of preodontoblasts. When the dentin matrix was fully formed and dentin mineralization occurred, TM14 was present in the predentin matrix and along the dentinal tubules. We found that the recombinant TM14 protein was glycosylated with N-linked oligosaccharides and interacted with heparin, fibronectin, fibulin-1, and dentin sialophosphoprotein. We also found that TM14 preferentially bound dental mesenchyme cells and odontoblasts but not dental epithelial cells or nondental cells such as HeLa, COS7, or NIH3T3 cells. Heparin, EDTA, and anti-integrin beta1 antibody inhibited TM14 binding to dental mesenchyme cells, suggesting that both a heparan sulfate-containing cell surface receptor and an integrin are involved in TM14 cell binding. Our findings indicate that TM14 is a cell adhesion molecule that interacts with extracellular matrix molecules in teeth and suggest that TM14 plays important roles in both the differentiation and maintenance of odontoblasts as well as in dentin formation. Because of its protein characteristics, TM14 can be classified as a new member of the fibulin family: fibulin-7. PMID- 17699514 TI - Regulation of heterotypic claudin compatibility. AB - Tissue barrier function is directly mediated by tight junction transmembrane proteins known as claudins. Cells that form tight junctions typically express multiple claudin isoforms which suggests that heterotypic (head-to-head) binding between different claudin isoforms may play a role in regulating paracellular permeability. However, little is known about motifs that control heterotypic claudin compatibility. We found that although claudin-3 and claudin-4 were heteromerically compatible when expressed in the same cell, they did not heterotypically interact despite having extracellular loop (EL) domains that are highly conserved at the amino acid level. Claudin-1 and -5, which were heterotypically compatible with claudin-3, did not heterotypically bind to claudin-4. In contrast, claudin-4 chimeras containing either the first EL domain or the second EL domain of claudin-3 were able to heterotypically bind to claudin 1, claudin-3, and claudin-5. Moreover, a single point mutation in the first extracellular loop domain of claudin-3 to convert Asn(44) to the corresponding amino acid in claudin-4 (Thr) produced a claudin capable of heterotypic binding to claudin-4 while still retaining the ability to bind to claudin-1 and -5. Thus, control of heterotypic claudin-claudin interactions is sensitive to small changes in the EL domains. PMID- 17699515 TI - WITHDRAWN: PUBLISHED IN ERROR BY PUBLISHER: Lumican core protein increases melanoma cell adhesion through a beta 1-type integrin receptor. AB - Ahead of Print article withdrawn by publisher PMID- 17699516 TI - The transmembrane domain is sufficient for Sbh1p function, its association with the Sec61 complex, and interaction with Rtn1p. AB - The Sec61 protein translocation complex in the endoplasmic reticulum (ER) membrane is composed of three subunits. The alpha-subunit, called Sec61p in yeast, is a multispanning membrane protein that forms the protein conducting channel. The functions of the smaller, carboxyl-terminally tail-anchored beta subunit Sbh1p, its close homologue Sbh2p, and the gamma subunit Sss1p are not well understood. Here we show that co-translational protein translocation into the ER is reduced in sbh1Delta sbh2Delta cells, whereas there is a limited reduction of post-translational translocation and no effect on export of a mutant form of alpha-factor precursor for ER-associated degradation in the cytosol. The translocation defect and the temperature-sensitive growth phenotype of sbh1Delta sbh2Delta cells were rescued by expression of the transmembrane domain of Sbh1p alone, and the Sbh1p transmembrane domain was sufficient for coimmunoprecipitation with Sec61p and Sss1p. Furthermore, we show that Sbh1p co precipitates with the ER transmembrane protein Rtn1p. Sbh1p-Rtn1p complexes do not appear to contain Sss1p and Sec61p. Our results define the transmembrane domain as the minimal functional domain of the Sec61beta homologue Sbh1p in ER translocation, identify a novel interaction partner for Shb1p, and imply that Sbh1p has additional functions that are not directly linked to protein translocation in association with the Sec61 complex. PMID- 17699517 TI - A novel Ca(V)1.2 N terminus expressed in smooth muscle cells of resistance size arteries modifies channel regulation by auxiliary subunits. AB - Voltage-dependent L-type Ca(2+) (Ca(V)1.2) channels are the principal Ca(2+) entry pathway in arterial myocytes. Ca(V)1.2 channels regulate multiple vascular functions and are implicated in the pathogenesis of human disease, including hypertension. However, the molecular identity of Ca(V)1.2 channels expressed in myocytes of myogenic arteries that regulate vascular pressure and blood flow is unknown. Here, we cloned Ca(V)1.2 subunits from resistance size cerebral arteries and demonstrate that myocytes contain a novel, cysteine rich N terminus that is derived from exon 1 (termed "exon 1c"), which is located within CACNA1C, the Ca(V)1.2 gene. Quantitative PCR revealed that exon 1c was predominant in arterial myocytes, but rare in cardiac myocytes, where exon 1a prevailed. When co expressed with alpha(2)delta subunits, Ca(V)1.2 channels containing the novel exon 1c-derived N terminus exhibited: 1) smaller whole cell current density, 2) more negative voltages of half activation (V(1/2,act)) and half-inactivation (V(1/2,inact)), and 3) reduced plasma membrane insertion, when compared with channels containing exon 1b. beta(1b) and beta(2a) subunits caused negative shifts in the V(1/2,act) and V(1/2,inact) of exon 1b-containing Ca(V)1.2alpha(1)/alpha(2)delta currents that were larger than those in exon 1c containing Ca(V)1.2alpha(1)/alpha(2)delta currents. In contrast, beta(3) similarly shifted V(1/2,act) and V(1/2,inact) of currents generated by exon 1b- and exon 1c-containing channels. beta subunits isoform-dependent differences in current inactivation rates were also detected between N-terminal variants. Data indicate that through novel alternative splicing at exon 1, the Ca(V)1.2 N terminus modifies regulation by auxiliary subunits. The novel exon 1c should generate distinct voltage-dependent Ca(2+) entry in arterial myocytes, resulting in tissue-specific Ca(2+) signaling. PMID- 17699518 TI - Structural and functional studies of the abundant tegument protein ORF52 from murine gammaherpesvirus 68. AB - The tegument is a layer of proteins between the nucleocapsid and the envelope of herpesviruses. The functions of most tegument proteins are still poorly understood. In murine gammaherpesvirus 68, ORF52 is an abundant tegument protein of 135 residues that is required for the assembly and release of infectious virus particles. To help understand the molecular basis for the function of this protein, we have determined its crystal structure at 2.1 A resolution. The structure reveals a dimeric association of this protein. Interestingly, an N terminal alpha-helix that assumes different conformation in the two monomers of the dimer mediates the formation of an asymmetrical tetramer and contains many highly conserved residues. Structural and sequence analyses suggest that this helix is more likely involved in interactions with other components of the tegument or nucleocapsid of the virus and that ORF52 functions as a symmetrical dimer. The asymmetrical tetramer of ORF52 may be a "latent" form of the protein, when it is not involved in virion assembly. The self-association of ORF52 has been confirmed by co-immunoprecipitation and fluorescence resonance energy transfer experiments. Deletion of the N-terminal alpha-helix, as well as mutation of the conserved Arg(95) residue, abolished the function of ORF52. The results of the functional studies are fully consistent with the structural observations and indicate that the N-terminal alpha-helix is a crucial site of interaction for ORF52. PMID- 17699519 TI - Identification of residues important for agonist recognition and activation in GPR40. AB - GPR40 was formerly an orphan G protein-coupled receptor whose endogenous ligands have recently been identified as free fatty acids (FFAs). The receptor, now named FFA receptor 1, has been implicated in the pathophysiology of type 2 diabetes and is a drug target because of its role in FFA-mediated enhancement of glucose stimulated insulin release. Guided by molecular modeling, we investigated the molecular determinants contributing to binding of linoleic acid, a C18 polyunsaturated FFA, and GW9508, a synthetic small molecule agonist. Twelve residues within the putative GPR40-binding pocket including hydrophilic/positively charged, aromatic, and hydrophobic residues were identified and were subjected to site-directed mutagenesis. Our results suggest that linoleic acid and GW9508 are anchored on their carboxylate groups by Arg(183), Asn(244), and Arg(258). Moreover, His(86), Tyr(91), and His(137) may contribute to aromatic and/or hydrophobic interactions with GW9508 that are not present, or relatively weak, with linoleic acid. The anchor residues, as well as the residues Tyr(12), Tyr(91), His(137), and Leu(186), appear to be important for receptor activation also. Interestingly, His(137) and particularly His(86) may interact with GW9508 in a manner dependent on its protonation status. The greater number of putative interactions between GPR40 and GW9508 compared with linoleic acid may explain the higher potency of GW9508. PMID- 17699520 TI - Uridylate-specific 3' 5'-exoribonucleases involved in uridylate-deletion RNA editing in trypanosomatid mitochondria. AB - In kinetoplastid protists, maturation of mitochondrial pre-mRNAs involves the insertion and deletion of uridylates (Us) within coding regions, as specified by mitochondrial DNA-encoded guide RNAs. U-deletion editing involves endonucleolytic cleavage of the pre-mRNA at the editing site followed by U-specific 3'-5' exonucleolytic removal of nonbase-paired Us prior to ligation of the two mRNA cleavage fragments. We showed previously that an exonuclease/endonuclease/phosphatase (EEP) motif protein from Leishmania major, designated RNA editing exonuclease 1 (REX1) (Kang, X., Rogers, K., Gao, G., Falick, A. M., Zhou, S.-L., and Simpson, L. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 1017-1022), exhibits 3'-5'-exonuclease activity. Two EEP motif proteins have also been identified in the Trypanosoma brucei editing complex. TbREX1 is a homologue of LmREX1, and TbREX2 shows homology to another editing protein in L. major, which lacks the EEP motif (LmREX2*). Here we have expressed the T. brucei EEP motif proteins in insect cells and purified them to homogeneity. We showed that these are U-specific 3'-5'-exonucleases that are inhibited by base pairing of 3' Us. The recombinant EEP motif alone also showed 3'-5' U-specific exonuclease activity, and mutations of the REX EEP motifs greatly reduced exonuclease activity. The absence of enzymatic activity in LmREX2* was confirmed with a purified recombinant protein. We showed that pre-cleaved U-deletion editing could be reconstituted with either TbREX1 or TbREX2 in combination with either RNA ligase, LmREL1, or LmREL2. Down-regulation of TbREX2 expression by conditional RNA interference had little effect on parasite viability or sedimentation of the L-complex, suggesting either that TbREX2 is inactive in vivo or that TbREX1 can compensate for the loss of TbREX2 function in down-regulated cells. PMID- 17699521 TI - C4b-binding protein and factor H compensate for the loss of membrane-bound complement inhibitors to protect apoptotic cells against excessive complement attack. AB - Apoptotic cells have been reported to down-regulate membrane-bound complement regulatory proteins (m-C-Reg) and to activate complement. Nonetheless, most apoptotic cells do not undergo complement-mediated lysis. Therefore, we hypothesized that fluid phase complement inhibitors would bind to apoptotic cells and compensate functionally for the loss of m-C-Reg. We observed that m-C-Reg are down-regulated rapidly upon apoptosis but that complement activation follows only after a gap of several hours. Coinciding with, but independent from, complement activation, fluid phase complement inhibitors C4b-binding protein (C4BP) and factor H (fH) bind to the cells. C4BP and fH do not entirely prevent complement activation but strongly limit C3 and C9 deposition. Late apoptotic cells, present in blood of healthy controls and systemic lupus erythematosus patients, are also positive for C4BP and fH. Upon culture, the percentage of late apoptotic cells increases, paralleled by increased C4BP binding. C4BP binds to dead cells mainly via phosphatidylserine, whereas fH binds via multiple interactions with CRP playing no major role for binding of C4BP or fH. In conclusion, during late apoptosis, cells acquire fluid phase complement inhibitors that compensate for the down-regulation of m-C-Reg and protect against excessive complement activation and lysis. PMID- 17699522 TI - Characterization of Ehp, a secreted complement inhibitory protein from Staphylococcus aureus. AB - We report here the discovery and characterization of Ehp, a new secreted Staphylococcus aureus protein that potently inhibits the alternative complement activation pathway. Ehp was identified through a genomic scan as an uncharacterized secreted protein from S. aureus, and immunoblotting of conditioned S. aureus culture medium revealed that the Ehp protein was secreted at the highest levels during log-phase bacterial growth. The mature Ehp polypeptide is composed of 80 residues and is 44% identical to the complement inhibitory domain of S. aureus Efb (extracellular fibrinogen-binding protein). We observed preferential binding by Ehp to native and hydrolyzed C3 relative to fully active C3b and found that Ehp formed a subnanomolar affinity complex with these various forms of C3 by binding to its thioester-containing C3d domain. Site directed mutagenesis demonstrated that Arg(75) and Asn(82) are important in forming the Ehp.C3d complex, but loss of these side chains did not completely disrupt Ehp/C3d binding. This suggested the presence of a second C3d-binding site in Ehp, which was mapped to the proximity of Ehp Asn(63). Further molecular level details of the Ehp/C3d interaction were revealed by solving the 2.7-A crystal structure of an Ehp.C3d complex in which the low affinity site had been mutationally inactivated. Ehp potently inhibited C3b deposition onto sensitized surfaces by the alternative complement activation pathway. This inhibition was directly related to Ehp/C3d binding and was more potent than that seen for Efb-C. An altered conformation in Ehp-bound C3 was detected by monoclonal antibody C3-9, which is specific for a neoantigen exposed in activated forms of C3. Our results suggest that increased inhibitory potency of Ehp relative to Efb-C is derived from the second C3-binding site in this new protein. PMID- 17699523 TI - The membrane topology of RTN3 and its effect on binding of RTN3 to BACE1. AB - Reticulon 3 (RTN3) has recently been shown to modulate Alzheimer BACE1 activity and to play a role in the formation of dystrophic neurites present in Alzheimer brains. Despite the functional importance of this protein in Alzheimer disease pathogenesis, the functional correlation to the structural domain of RTN3 remained unclear. RTN3 has two long transmembrane domains, but its membrane topology was not known. We report here that the first transmembrane domain dictates membrane integration and its membrane topology. RTN3 adopts a omega shape structure with two ends facing the cytosolic side. Subtle changes in RTN3 membrane topology can disrupt its binding to BACE1 and its inhibitory effects on BACE1 activity. Thus, the determination of RTN3 membrane topology may provide an important structural basis for our understanding of its cellular functions. PMID- 17699524 TI - Polysialylated neuropilin-2 is expressed on the surface of human dendritic cells and modulates dendritic cell-T lymphocyte interactions. AB - Polysialic acid (PSA) is a unique linear homopolymer of alpha2,8-linked sialic acid that has been identified as a posttranslational modification on only five mammalian proteins. Studied predominantly on neural cell adhesion molecule (NCAM) during development of the vertebrate nervous system, PSA modulates cell interactions mediated by NCAM and other adhesion molecules. An isoform of NCAM (CD56) on natural killer (NK) cells is the only protein known to be polysialylated in cells of the immune system, yet the function of PSA in NK cells remains unclear. We show here that neuropilin-2 (NRP-2), a receptor for the semaphorin and vascular endothelial growth factor families in neurons and endothelial cells, respectively, is expressed on the surface of human dendritic cells and is polysialylated. Expression of NRP-2 is up-regulated during dendritic cell maturation, coincident with increased expression of ST8Sia IV, one of the key enzymes of PSA biosynthesis, and with the appearance of PSA on the cell surface. PSA on NRP-2 is resistant to digestion with peptide N-glycosidase F but is sensitive to release under alkaline conditions, suggesting that PSA chains are added to O-linked glycans of NRP-2. Removal of polysialic acid from the surface of dendritic cells or binding of NRP-2 with specific IgG promoted dendritic cell induced activation and proliferation of T lymphocytes. Thus, this newly recognized polysialylated protein on the surface of dendritic cells influences dendritic cell-T lymphocyte interactions through one or more of its distinct extracellular domains. PMID- 17699525 TI - "The public health call". PMID- 17699526 TI - Assessing the social meaning, value and implications of research in genomics. PMID- 17699527 TI - Genetic and molecular epidemiology. AB - Genetic and molecular epidemiology covers a vast area of research. Given the rapid changes in this field, discussing a research agenda is a precarious and ambitious task. A representative set of high-priority concepts will be presented here, each of which alone could be the topic of a long series of essays. The wish list includes issues of full transparency and integration of information, dealing efficiently with complex multidimensional biology, juxtaposing the genome and environmental exposures, and using robust randomised trials to advance our knowledge and its application in this field. PMID- 17699528 TI - Equality and difference: persisting historical themes in health and alcohol policies affecting Indigenous Australians. AB - Disseminating national health and alcohol policies to Aboriginal and Torres Strait Islander people in Australia has been a challenging task for governments and public servants. This has been for a number of reasons, including the enduring (negative) legacy of past "Aboriginal affairs" policies, the fact that Indigenous health programmes and alcohol programmes have been treated separately since the 1970s, and a more recent context in which the recognition of cultural difference was privileged. Confronted with the politics of difference, health departments were slow to examine avenues through which best practice advice emanating from WHO, and alcohol policies such as harm minimisation and early identification and treatment in primary health care, could be communicated in culturally recognisable ways to independent Indigenous services. In addition, there was hostility towards harm minimisation policies from Indigenous service providers, and Indigenous treatment programmes remained largely committed to abstinence-oriented modalities and the disease model of alcoholism, despite moves away from these approaches in the mainstream. However, genuinely innovative acute interventions and environmental controls over alcohol have been developed by Indigenous community-based organisations, approaches that are reinforced by international policy research evidence. PMID- 17699529 TI - Violence: a priority for public health? (part 2). AB - Violence continues to grow as a priority for public health practitioners, particularly as its causes and consequences become better understood and the potential roles for public health are better articulated. This article provides the context to "Violence: a glossary (part 1)" published in the last issue of this journal, and updates some of the data, concepts and population approaches presented in the 2002 World report on violence and health. The paper addresses the following questions: What is the magnitude and global burden of injury from violence? What causes violence? Is resilience important? What is the role for public health? What are the key challenges and opportunities? We aim to engage the general reader and to increase understanding of violence as a potentially preventable issue. PMID- 17699530 TI - The Watcombe Housing Study: the short term effect of improving housing conditions on the health of residents. AB - OBJECTIVE: To assess the short term health effects of improving housing. DESIGN: Randomised to waiting list. SETTING: 119 council owned houses in south Devon, UK. PARTICIPANTS: About 480 residents of these houses. INTERVENTION: Upgrading houses (including central heating, ventilation, rewiring, insulation, and re-roofing) in two phases a year apart. MAIN OUTCOME MEASURES: All residents completed an annual health questionnaire: SF36 and GHQ12 (adults). Residents reporting respiratory illness or arthritis were interviewed using condition-specific questionnaires, the former also completing peak flow and symptom diaries (children) or spirometry (adults). Data on health service use and time lost from school were collected. RESULTS: Interventions improved energy efficiency. For those living in intervention houses, non-asthma-related chest problems (Mann-Whitney test, p = 0.005) and the combined asthma symptom score for adults (Mann-Whitney test, z = 2.7, p = 0.007) diminished significantly compared with control houses. No difference between intervention and control houses was seen for SF36 or GHQ12. CONCLUSIONS: Rigorous study designs for the evaluation of complex public health and community based interventions are possible. Quantitatively measured health benefits are small, but as health benefits were measured over a short time scale, there may have been insufficient time for measurable improvements in general and disease-specific health to become apparent. PMID- 17699531 TI - Randomised controlled trial of home-based walking programmes at and below current recommended levels of exercise in sedentary adults. AB - OBJECTIVES: To determine, using unsupervised walking programmes, the effects of exercise at a level lower than currently recommended to improve cardiovascular risk factors and functional capacity. DESIGN: 12 week randomised controlled trial. SETTING: Northern Ireland Civil Service; home-based walking. PARTICIPANTS: 106 healthy, sedentary 40 to 61 year old adults of both sexes. INTERVENTIONS: Participants were randomly allocated to a walking programme (30 minutes brisk walking three days a week (n = 44) or five days a week (n = 42)) or a control group (n = 20). Participants could choose to walk in bouts of at least 10 minutes. They used pedometers to record numbers of steps taken. Intention to treat analysis of changes within groups was done using paired t tests; extent of change (baseline to 12 week measurements) was compared between groups using analysis of variance and Gabriel's post hoc test. MAIN OUTCOME MEASURES: Blood pressure, serum lipids, body mass index, waist:hip ratio, and functional capacity (using a 10 m shuttle walk test). MAIN RESULTS: 89% (93/106) completed the study. Systolic blood pressure and waist and hip circumferences fell significantly both in the three day group (5 mm Hg, 2.6 cm, and 2.4 cm, respectively) and in the five day group (6 mm Hg, 2.5 cm, and 2.2 cm) (p<0.05). Functional capacity increased in both groups (15%; 11%). Diastolic blood pressure fell in the five day group (3.4 mm Hg, p<0.05). No changes occurred in the control group. CONCLUSIONS: This study provides evidence of benefit from exercising at a level below that currently recommended in healthy sedentary adults. Further studies are needed of potential longer term health benefits for a wider community from low levels of exercise. PMID- 17699532 TI - Factors associated with the activities of safety representatives in Spanish workplaces. AB - OBJECTIVE: To describe the activities of safety representatives in workplaces in Spain. METHODS: A specific questionnaire was applied to a representative sample of safety representatives. Activities developed during the past year, presented in a closed ended list, were categorised into three groups: information and advising; participation in occupational health management; and pressure on or negotiation with employers. Personal phone interviews were conducted from September to December 2004. A sample of 1201 interviews was attained. Crude and multivariate analyses were carried out. RESULTS: Spanish safety representatives were mostly men (76%), aged 26 to 45 years (62%), with fixed contracts (94%), and more than 10 years in their company (57%). On a comparable 0-10 scale, the mean (95% confidence interval (CI)) number of activities relating to information, management, and negotiation developed during the previous year were, respectively, 6.8 (6.7 to 6.9), 4.5 (4.4 to 4.7), and 4.0 (3.8 to 4.1). In multivariate analysis, workplace size (>30 workers), industrial sector, training, and support from the labour inspectorate were the factors most consistently associated with safety representatives' activity. Additionally, support from the employer was associated with participation in occupational health management (odds ratio = 2.38 (95% CI, 1.73 to 3.29)). CONCLUSIONS: Safety representatives in Spain have a variety of activities, mostly in the category of information and advising. These are necessary but not sufficient for real participation of workers in decisions concerning their health and safety. More participation of safety representatives in occupational health management at workplaces seems to be needed, and factors associated with this participation reinforced. PMID- 17699533 TI - Measuring the performance of urban healthcare services: results of an international experience. AB - The objective of this paper is to apply a framework for country-level performance assessment to the cities of Montreal, Canada, and Barcelona, Spain, and to use this framework to explore and understand the differences in their health systems. The UK National Health Service Performance Assessment Framework was chosen. Its indicators went through a process of selection, adaptation and prioritisation. Most of them were calculated for the period 2001-3, with data obtained from epidemiological, activity and economic registries. Montreal has a higher number of old people living alone and with limitations on performing one or more activities of daily life, as well as longer hospital stays for several conditions, especially in the case of elderly patients. This highlights a lack of mid-term, long-term and home care services. Diabetes-avoidable hospitalisation rates are also significant in Montreal, and are likely to improve following reforms in primary care. Efficient health policies such as generic drug prescription and major ambulatory surgery are lower in Barcelona. Rates of caesarean deliveries are higher in Barcelona, owing to demographics and clinical practice. Waiting times for knee arthroplasty are longer in Barcelona, which has triggered a plan to reduce them. In both cities, avoidable mortality and the prevalence of smoking have been identified as areas for improvement through preventive services. In conclusion, performance assessment fits perfectly in an urban context, as it has been shown to be a useful tool in designing and monitoring the accomplishment of programmes in both cities, to assess the performance of the services delivered, and for use in policy development. PMID- 17699534 TI - Ethnicity as a correlate of the uptake of the first dose of mumps, measles and rubella vaccine. AB - The aim of this study was to investigate whether a relationship exists between ethnicity and uptake of the first dose of mumps, measles and rubella (MMR1) vaccination, and to study important factors influencing the parental decision about vaccination. Examination of routine data on uptake of MMR1 vaccine among children living in the London borough of Brent, North West London, for associations with ethnicity was carried out. Six focus group interviews were held and a questionnaire on factors related to immunisation by convenience samples of mothers from Asian, Afro-Caribbean and White backgrounds was completed. The routine data reported MMR1 vaccine status for 6444 children living in Brent who were aged between 18 months and 3 years on 1 December 2003. A total of 37 mothers took part in the 6 focus group sessions. Significantly higher coverage by MMR1 vaccine in the Asian population (87.1%) compared with Afro-Caribbeans (74.7%) and the White group (57.5%) was noticed. The qualitative data revealed clear differences between the ethnic groups with respect to awareness of the controversy surrounding MMR vaccination (related to use of English-language media) and influence of grandparents and health professionals in decisions about immunisation. A multiple logistic regression model showed that although coverage of MMR vaccination increased with increasing socioeconomic status, there was no evidence of a statistically significant interaction between socioeconomic status and ethnicity. An important association between ethnicity and uptake of MMR1 vaccine is observed. This has implications for efforts to improve the currently inadequate levels of MMR vaccination across the population as a whole. PMID- 17699535 TI - Bringing chronic disease epidemiology and infectious disease epidemiology back together. PMID- 17699537 TI - High consumptions of grain, fish, dairy products and combinations of these are associated with a low prevalence of metabolic syndrome. AB - OBJECTIVE: To analyse the relation between various food groups and the frequency of insulin resistance syndrome (IRS). DESIGN: A sample of 912 men aged 45-64 years was randomly selected. Questionnaires on risk factors and a three consecutive day food diary were completed. Height, weight, waist circumference, and blood pressure were measured. A fasting blood sample was analysed for lipid and glucose measurements. The NCEP-ATP-III definition was used to assess IRS. Data were analysed according to quintiles of food groups and medians of dairy products, fish, or cereal grains. RESULTS: The prevalence of IRS was 23.5%. It reached 29.0%, 28.1% and 28.1% when the intake was below the median for fish, dairy products, and grain, respectively. When consumptions of all three types of food were higher than the median, the prevalence reached 13.1%, and when they were lower, the prevalence was 37.9% (p<0.001). In logistic regression adjusted for confounders (centre, age, physical activities, education level, smoking, dieting, alcohol intake, treatments for hypertension and dyslipidaemia, energy intake, and diet quality index) the odds ratios for IRS (above median value v below) were 0.51 (95% confidence interval, 0.36 to 0.71) for fish, 0.67 (0.47 to 0.94) for dairy products, and 0.69 (0.47 to 1.01) for grain. When intakes of all three kinds of food were high, the OR was 0.22 (0.10 to 0.44). CONCLUSIONS: A high consumption of dairy products, fish, or cereal grains is associated with a lower probability of IRS. The probability decreases when intakes of all three types of food were high. PMID- 17699536 TI - Income inequality and the double burden of under- and overnutrition in India. AB - OBJECTIVES: Developing countries are increasingly characterised by the simultaneous occurrence of under- and overnutrition. This study examined the association between contextual income inequality and the double burden of under- and overnutrition in India. DESIGN: A population-based multilevel study of 77,220 ever married women, aged 15-49 years, from 26 Indian states, derived from the 1998-99 Indian National Family Health Survey data. The World Health Organization recommended categories of body mass index constituted the outcome, and the exposure was contextual measure of state income inequality based on the Gini coefficient of per capita consumption expenditure. Covariates included a range of individual demographic, socioeconomic, behavioural and morbidity measures and state-level economic development. RESULTS: In adjusted models, for each standard deviation increase in income inequality, the odds ratio for being underweight increased by 19% (p = 0.02) and the odds ratio for being obese increased by 21% (p<0.0001). Income inequality had a similar effect on the risk of being overweight as it did on the risk of obesity (p = 0.01), and state income inequality increased the risk of being pre-overweight by 9% (p = 0.01). While average levels of state economic development were strongly associated with degrees of overnutrition, no association was found with the risk of being underweight. CONCLUSIONS: Rapidly developing economies, besides experiencing paradoxical health patterns, are typically characterised by increased levels of income inequality. This study suggests that the twin burden of undernutrition and overnutrition in India is more likely to occur in high-inequality states. Focusing on economic equity via redistribution policies may have a substantial impact in reducing the prevalence of both undernutrition and overnutrition. PMID- 17699538 TI - Promoting walking to school: results of a quasi-experimental trial. AB - STUDY OBJECTIVE: To assess the impact of a combined intervention on children's travel behaviour, stage of behavioural change and motivations for and barriers to actively commuting to school. DESIGN: A quasi-experimental trial involving pre- and post-intervention mapping of routes to school by active and inactive mode of travel and surveys of "stage of behaviour change" and motivations for and barriers to actively commuting to school. INTERVENTION: The intervention school participated in a school-based active travel project for one school term. Active travel was integrated into the curriculum and participants used interactive travel-planning resources at home. The control school participated in before and after measurements but did not receive the intervention. SETTING: Two primary schools in Scotland with similar socioeconomic and demographic profiles. PARTICIPANTS: Two classes of primary 5 children and their families and teachers. MAIN RESULTS: Post intervention, the mean distance travelled to school by walking by intervention children increased significantly from baseline, from 198 to 772 m (389% increase). In the control group mean distance walked increased from 242 to 285 m (17% increase). The difference between the schools was significant (t (38) = -4.679, p<0.001 (95% confidence interval -315 to -795 m)). Post intervention, the mean distance travelled to school by car by intervention children reduced significantly from baseline, from 2018 to 933 m (57.5% reduction). The mean distance travelled to school by car by control children increased from baseline, from 933 to 947 m (1.5% increase). The difference in the change between schools was significant (t (32) = 4.282, p<0.001 (95% confidence interval 445 to 1255 m)). CONCLUSIONS: Intervention was effective in achieving an increase in the mean distance travelled by active mode and a reduction in the mean distance travelled by inactive mode on school journey. PMID- 17699540 TI - Does consideration of either psychological or material disadvantage improve coronary risk prediction? Prospective observational study of Scottish men. AB - OBJECTIVE: To assess the value of psychosocial risk factors in discriminating between individuals at higher and lower risk of coronary heart disease, using risk prediction equations. DESIGN: Prospective observational study. SETTING: Scotland. PARTICIPANTS: 5191 employed men aged 35 to 64 years and free of coronary heart disease at study enrollment MAIN OUTCOME MEASURES: Area under receiver operating characteristic (ROC) curves for risk prediction equations including different risk factors for coronary heart disease. RESULTS: During the first 10 years of follow up, 203 men died of coronary heart disease and a further 200 were admitted to hospital with this diagnosis. Area under the ROC curve for the standard Framingham coronary risk factors was 74.5%. Addition of "vital exhaustion" and psychological stress led to areas under the ROC curve of 74.5% and 74.6%, respectively. Addition of current social class and lifetime social class to the standard Framingham equation gave areas under the ROC curve of 74.6% and 74.9%, respectively. In no case was there strong evidence for improved discrimination of the model containing the novel risk factor over the standard model. CONCLUSIONS: Consideration of psychosocial risk factors, including those that are strong independent predictors of heart disease, does not substantially influence the ability of risk prediction tools to discriminate between individuals at higher and lower risk of coronary heart disease. PMID- 17699541 TI - Response to findings on association between temperature and dose response coefficient of inhalable particles (PM10). PMID- 17699542 TI - A primary angiosarcoma in the aorta. AB - A 60-year-old woman after aortic valve replacement had an acute abdominal pain. Computed tomography demonstrated a tumor in the aorta, which originated from the distal portion of the thoracic aorta and extended to the aortic bifurcation. At autopsy, the orifices of celiac, superior and inferior mesenteric, right and left renal arteries were consistently occluded by incursion of the tumor. We present herein a huge primary sarcoma in the abdominal aorta, which has been reported as extremely rare. PMID- 17699539 TI - A systematic review of the association between circulating concentrations of C reactive protein and cancer. AB - The objective of this study was to review and summarise the published evidence for an association between circulating concentrations of C reactive protein (CRP) and cancer through a systematic review. 90 discrete studies were identified. 81 (90%) were prevalent case-control or cross-sectional studies, and only 9 studies had a prospective design. In most prevalent studies, CRP concentrations were found to be higher in patients with cancer than in healthy controls or controls with benign conditions. Of the nine large prospective studies identified in this review, four reported no relationship between circulating CRP levels and breast, prostate or colorectal cancers, and five studies found that CRP was associated with colorectal or lung cancers. Most of the studies evaluating CRP as a diagnostic marker of cancer did not present relevant statistical analyses. Furthermore, any association reported in the prevalent studies might reflect reverse causation, survival bias or confounding. The prospective studies provided no strong evidence for a causal role of CRP in cancer. Instead of further prevalent studies, more large prospective studies and CRP gene-cancer association studies would be valuable in investigating the role of CRP in cancer. PMID- 17699543 TI - Thoracoscopic microwave ablation of atrial fibrillation. AB - The aim of the study was to assess the safety and efficacy of thoracoscopic microwave ablation in treating atrial fibrillation (AF). AF predisposes to embolic complications and may cause heart failure. The treatment of AF is still challenging in spite of the promising results of endocardial radiofrequency approach. The present study is a follow-up study of 22 patients (mean age 45 years, range 21-59) with disabling paroxysmal (n=10) or persistent (n=12) AF who underwent a thoracoscopic microwave isolation of pulmonary veins. The patients had a lone AF. All the patients had suffered from severely disabling AF for >1 year (range 1-16 years) without any response to antiarrhythmic medication. The patients have been followed-up on an average of 11 months (range 3-22 months). During the follow-up, 13 (60%) patients have become asymptomatic without any documentation of AF since at least two months, six (27%) patients with anti arrhythmic medication have clinically improved. Because of major intrathoracic bleeding and because of liver damage the thoracoscopy wound had to be expanded to open thoracotomy in two patients. Thoracoscopic AF microwave ablation seems to be a promising alternative to endocardial ablation in the treatment of highly symptomatic paroxysmal and persistent AF. PMID- 17699544 TI - Patients and complication with off-pump vs. on-pump cardiac surgery - a single surgeon experience. AB - BACKGROUND: Off-pump operations (OPCAB) are growingly used for patients with coronary artery disease (CAD) and may be associated with improved outcomes when compared with coronary artery bypass grafting (CABG) using extracorporeal circulation (ECC), especially in patients with comorbidities. The aim of this study is to compare the intra- and postoperative results of OPCAB complete arterial myocardial revascularization with standard on-pump CABG under respect of comorbidities. METHODS: We report about the implementing of the off-pump technique in our institution from November 2004 to May 2006. Sixty-two patients with CABG in off-pump technique were compared to a control group of 129 patients with CABG using ECC. The off-pump technique was mostly used in patients with vascular and pulmonary diseases. All operations were performed by the same surgeon. All off-pumps were performed using both internal thoracic arteries (ITA) or left ITA and radial artery (RA) in T-graft technique, while in the on-pump group only the LITA and saphenous vein were used. The conversion rate from OPCAB to conventional CABG was 3.2% (two patients). RESULTS: Peripheral vascular disease (PVD) and chronic obstructive pulmonary disease (COPD) were significant more often in the off-pump group. Other preoperative risk factors were comparable between the groups. Operation time was significantly longer in the off-pump group. Postoperative symptomatic transient psychotic syndromes were more often in the on-pump group. Outcome was similar, despite significant longer operation time in off-pump group. CONCLUSION: Off-pump coronary artery surgery can be performed in patients with comorbidities with similar outcome compared to on-pump surgery. PMID- 17699545 TI - Abstracts of the 21st European Association for Cardio-Thoracic Surgery (EACTS) Meeting Techno-College, September 2007. PMID- 17699546 TI - Acupuncture as an adjunct to exercise based physiotherapy for osteoarthritis of the knee: randomised controlled trial. AB - OBJECTIVE: To investigate the benefit of adding acupuncture to a course of advice and exercise delivered by physiotherapists for pain reduction in patients with osteoarthritis of the knee. DESIGN: Multicentre, randomised controlled trial. SETTING: 37 physiotherapy centres accepting primary care patients referred from general practitioners in the Midlands, United Kingdom. PARTICIPANTS: 352 adults aged 50 or more with a clinical diagnosis of knee osteoarthritis. INTERVENTIONS: Advice and exercise (n=116), advice and exercise plus true acupuncture (n=117), and advice and exercise plus non-penetrating acupuncture (n=119). MAIN OUTCOME MEASURES: The primary outcome was change in scores on the Western Ontario and McMaster Universities osteoarthritis index pain subscale at six months. Secondary outcomes included function, pain intensity, and unpleasantness of pain at two weeks, six weeks, six months, and 12 months. RESULTS: Follow-up rate at six months was 94%. The mean (SD) baseline pain score was 9.2 (3.8). At six months mean reductions in pain were 2.28 (3.8) for advice and exercise, 2.32 (3.6) for advice and exercise plus true acupuncture, and 2.53 (4.2) for advice and exercise plus non-penetrating acupuncture. Mean differences in change scores between advice and exercise alone and each acupuncture group were 0.08 (95% confidence interval -1.0 to 0.9) for advice and exercise plus true acupuncture and 0.25 ( 0.8 to 1.3) for advice and exercise plus non-penetrating acupuncture. Similar non significant differences were seen at other follow-up points. Compared with advice and exercise alone there were small, statistically significant improvements in pain intensity and unpleasantness at two and six weeks for true acupuncture and at all follow-up points for non-penetrating acupuncture. CONCLUSION: The addition of acupuncture to a course of advice and exercise for osteoarthritis of the knee delivered by physiotherapists provided no additional improvement in pain scores. Small benefits in pain intensity and unpleasantness were observed in both acupuncture groups, making it unlikely that this was due to acupuncture needling effects. TRIAL REGISTRATION: Current Controlled Trials ISRCTN88597683 [controlled trials.com] . PMID- 17699547 TI - Inhalable beta(1->3)glucans as a non-allergenic exposure factor in Dutch bakeries. AB - OBJECTIVES: To obtain an overview of inhalable beta(1-->3)glucans levels in Dutch industrial bakeries and explore possible associations with reported respiratory health effects in bakery workers. METHODS: beta(1-->3)glucan levels were analysed in 186 personal inhalable dust measurements obtained from a random population of bakery workers. Association between respiratory health effects and exposure to beta(1-->3)glucan was explored in a population of industrial bakery workers participating in a Health Surveillance System for flour processing sectors. Based on their job, bakery workers were assigned to low or high exposure categories given the average job exposure estimates obtained from the measurement study. RESULTS: Bread bakers and dough makers had the highest exposures to beta(1- >3)glucans (GM 1.48 mug/m3 and 1.37 mug/m3 respectively). Strong correlations were found between airborne levels of inhalable dust and beta(1-->3)glucans, and between beta(1-->3)glucans and wheat allergens (Pearson correlation coefficients were 0.74 and 0.68 respectively). No significant associations could be identified between beta(1-->3)glucan exposure and work-related respiratory symptoms. CONCLUSION: This study has shown that bakery workers are exposed to inhalable beta(1-->3)glucan levels comparable with exposure levels found in other occupational settings. More refined exposure assessment is necessary to fully understand the role of beta(1-->3)glucan exposure on respiratory health in bakery workers. PMID- 17699548 TI - Plasma polychlorobiphenyl and organochlorine pesticide level and risk of major lymphoma subtypes. AB - BACKGROUND: There is conflicting epidemiological evidence concerning an increase in risk of non-Hodgkin's lymphoma (NHL) associated with elevated blood levels of persistent organochlorine (OC) pesticides and polychlorobiphenyls (PCBs). METHODS: We measured the concentration of 17 OC pesticides, including hexachlorobenzene (HCB), four lindane isomers (alpha-, beta-, gamma- and delta hexachlorocyclohexane (HCH)), two chlordane species (heptachlor and oxy chlordane), four cyclodiene insecticides (aldrin, dieldrin, endrin and mirex), six dichloro-diphenyl-trichloroethane (DDT) isomers and nine PCB congeners (PCBs 28, 52, 101, 118, 138, 153, 170, 180 and 194) in plasma samples of 377 subjects, including 174 NHL cases and 203 controls from France, Germany and Spain. The risk of NHL and its major subtypes associated with increasing blood levels of OC pesticides and PCBs was calculated using unconditional logistic regression. RESULTS: Risk of NHL, diffuse large B cell lymphoma (DLBCL) and chronic lymphatic leukaemia (CLL) did not increase with plasma levels of HCB, beta-HCH, p,p' dichloro-diphenyl-dichloroethylene (DDE), or total and individual PCBs or their functional groups, in the overall study population. Substantial heterogeneity in DLBCL risk associated with immunotoxic PCBs (p = 0.03) existed between the Spanish subgroup (odds ratio (OR) for immunotoxic PCB plasma level above the median vs below the median was 0.7, 95% CI 0.3 to 1.6) and the French and German subgroups combined (OR 3.2, 95% CI 0.9 to 11.5). CONCLUSION: We did not find evidence of an association between NHL risk and plasma level of OC pesticides and PCBs. PMID- 17699549 TI - Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1alpha-hydroxylase expression in vitro. AB - Fibroblast growth factor-23 (FGF-23) is critical to the pathogenesis of a distinct group of renal phosphate wasting disorders: tumor-induced osteomalacia, X-linked hypophosphatemia, and autosomal dominant and autosomal recessive hypophosphatemic rickets. Excess circulating FGF-23 is responsible for their major phenotypic features which include hypophosphatemia due to renal phosphate wasting and inappropriately low serum 1,25(OH)2D concentrations. To characterize the effects of FGF-23 on renal sodium-phosphate (Na/P(i)) cotransport and vitamin D metabolism, we administered FGF-23(R176Q) to normal mice. A single injection (0.33 microg/g body wt) induced significant hypophosphatemia, 20 and 29% decreases (P < 0.001) in brush-border membrane (BBM) Na/Pi cotransport at 5 and 17 h after injection, respectively, and comparable decreases in the abundance of type IIa Na/P(i) cotransporter protein in BBM. Multiple injections (6, 12, and 24 mug/day for 4 days) induced dose-dependent decreases (38, 63, and 75%, respectively) in renal abundance of 1alpha-hydroxylase mRNA (P < 0.05). To determine whether FGF-23(R176Q) exerts a direct action on 1alpha-hydroxylase gene expression, we examined its effects in cultured human (HKC-8) and mouse (MCT) renal proximal tubule cells. FGF-23(R176Q) (1 to 10 ng/ml) induced a dose dependent decrease in 1alpha-hydroxylase mRNA with a maximum suppression of 37% (P < 0.05). Suppression was detectable after 6 h of exposure and maximal after 21 h. In MCT cells, FGF-23(R176Q) suppressed 1alpha-hydroxylase mRNA and activated the ERK1/2 signaling pathway. The MAPK inhibitor PD98059 effectively abolished FGF-23-induced suppression of 1alpha-hydroxylase mRNA by blocking signal transduction via ERK1/2. These novel findings provide evidence that FGF-23 directly regulates renal 1alpha-hydroxylase gene expression via activation of the ERK1/2 signaling pathway. PMID- 17699550 TI - Dual role of the TRPV4 channel as a sensor of flow and osmolality in renal epithelial cells. AB - Gain/loss of function studies were utilized to assess the potential role of the endogenous vanilloid receptor TRPV4 as a sensor of flow and osmolality in M-1 collecting duct cells (CCD). TRPV4 mRNA and protein were detectable in M-1 cells and stably transfected HEK-293 cells, where the protein occurred as a glycosylated doublet on Western blots. Immunofluorescence imaging demonstrated expression of TRPV4 at the cell membranes of TRPV4-transfected HEK and M-1 cells and at the luminal membrane of mouse kidney CCD. By using intracellular calcium imaging techniques, calcium influx was monitored in cells grown on coverslips. Application of known activators of TRPV4, including 4alpha-PDD and hypotonic medium, induced strong calcium influx in M-1 cells and TRPV4-transfected HEK-293 cells but not in nontransfected cells. Applying increased flow/shear stress in a parallel plate chamber induced calcium influx in both M-1 and TRPV4-transfected HEK cells but not in nontransfected HEK cells. Furthermore, in loss-of-function studies employing small interference (si)RNA knockdown techniques, transfection of both M-1 and TRPV4-transfected HEK cells with siRNA specific for TRPV4, but not an inappropriate siRNA, led to a time-dependent decrease in TRPV4 expression that was accompanied by a loss of stimuli-induced calcium influx to flow and hypotonicity. It is concluded that TRPV4 displays a mechanosensitive nature with activation properties consistent with a molecular sensor of both fluid flow (or shear stress) and osmolality, or a component of a sensor complex, in flow sensitive renal CCD. PMID- 17699551 TI - Gentamicin suppresses endotoxin-driven TNF-alpha production in human and mouse proximal tubule cells. AB - Gentamicin is a mainstay in treating gram-negative sepsis. However, it also may potentiate endotoxin (LPS)-driven plasma TNF-alpha increases. Because gentamicin accumulates in renal tubules, this study addressed whether gentamicin directly alters LPS-driven tubular cell TNF-alpha production. HK-2 proximal tubular cells were incubated for 18 h with gentamicin (10-2,000 microg/ml). Subsequent LPS mediated TNF-alpha increases (at 3 or 24 h; protein/mRNA) were determined. Gentamicin effects on overall protein synthesis ([(35)S]methionine incorporation), monocyte chemoattractant protein-1 (MCP-1) levels, and LPS stimulated TNF-alpha generation by isolated mouse proximal tubules also were assessed. Finally, because gentamicin undergoes partial biliary excretion, its potential influence on gut TNF-alpha/MCP-1 mRNAs was probed. Gentamicin caused striking, dose-dependent inhibition of LPS-driven TNF-alpha production (up to 80% in HK-2 cells/isolated tubules). Surprisingly, this occurred despite increased TNF-alpha mRNA accumulation. Comparable changes in MCP-1 were observed. These changes were observed at clinically relevant gentamicin concentrations and despite essentially normal overall protein synthetic rates. Streptomycin also suppressed LPS-driven TNF-alpha increases, suggesting an aminoglycoside drug class effect. Gentamicin doubled basal TNF-alpha mRNA in cecum and in small intestine after LPS. Gentamicin can suppress LPS-driven TNF-alpha production in proximal tubule cells, likely by inhibiting its translation. Overall preservation of protein synthesis and comparable MCP-1 suppression suggest a semiselective blockade within the LPS inflammatory mediator cascade. These results, coupled with increases in gut TNF-alpha/MCP-1 mRNAs, imply that gentamicin may exert protean, countervailing actions on systemic cytokine/chemokine production during gram-negative sepsis. PMID- 17699552 TI - Size and charge selectivity of the glomerular filter in early experimental diabetes in rats. AB - Microalbuminuria is an early sign of diabetic nephropathy. The aim of the present study was to investigate whether the changes of the glomerular filtration barrier in early experimental diabetes are due to size- or charge-selective alterations. Wistar rats, made diabetic by streptozotocin (STZ) and having their blood glucose maintained at approximately 20 mM for 3 or 9 wk, were compared with age-matched controls. Glomerular clearances of native albumin (Cl-HSA) and neutralized albumin (Cl-nHSA) were assessed using a renal uptake technique. Glomerular filtration rate and renal plasma flow were assessed using (51)Cr-EDTA and [125I]iodohippurate, respectively. In a separate set of animals, diabetic for 9 wk, and in controls, glomerular sieving coefficients (theta) for neutral FITC Ficoll (molecular radius: 15-90 A) were assessed using size exclusion chromatography. At 3 wk of diabetes, Cl-HSA and Cl-nHSA remained unchanged, indicating no alteration in either size or charge selectivity. By contrast, at 9 wk of diabetes, there was a twofold increase of Cl-HSA, whereas Cl-nHSA remained largely unchanged, at first suggesting a glomerular charge defect. However, according to a two-pore model, the number of large pores, assessed from both Ficoll and Cl-HSA, increased twofold. In addition, a small reduction in proximal tubular reabsorption was observed at 3 wk, which was further reduced at 9 wk. In conclusion, no functional changes were observed in the glomerular filtration barrier at 3 wk of STZ-induced diabetes, whereas at 9 wk there was a decrease in size selectivity due to an increased number of large glomerular pores. PMID- 17699553 TI - Expression of CCN1 (CYR61) in developing, normal, and diseased human kidney. AB - CCN1 (cysteine-rich protein 61; Cyr61) is an extracellular matrix-associated signaling molecule that functions in cell migration, adhesion, and differentiation. We previously reported that CCN1 is induced at podocytes in rat anti-Thy-1 glomerulonephritis, a well-known model of reversible glomerular injury, but its expression and significance in the human kidney remain totally unknown (Sawai K, Mori K, Mukoyama M, Sugawara A, Suganami T, Koshikawa M, Yahata K, Makino H, Nagae T, Fujinaga Y, Yokoi H, Yoshioka T, Yoshimoto A, Tanaka I, Nakao K. J Am Soc Nephrol 14: 1154-1163, 2003). Here we report that, in the human kidney, CCN1 expression was confined to podocytes in normal adult and embryonic glomeruli from the capillary loop stage. Podocyte CCN1 expression was decreased in IgA nephropathy, diabetic nephropathy, and membranous nephropathy, whereas it remained unchanged in minimal change disease and focal segmental glomerulosclerosis. Downregulation of CCN1 was significantly greater in diseased kidneys with severe mesangial expansion. CCN1 protein was also localized in the thick ascending limb of Henle's loop, distal and proximal tubules, and collecting ducts, which was not altered in diseased kidneys. In vitro, recombinant CCN1 protein enhanced endothelial cell adhesion, whereas it prominently inhibited mesangial cell adhesion. CCN1 also completely suppressed mesangial cell migration, suggesting its role as a mesangial-repellent factor. In cultured podocytes, CCN1 markedly induced the expression of cyclin-dependent kinase inhibitor p27(Kip1) as well as synaptopodin in a dose-dependent manner and suppressed podocyte migration. These data indicate that CCN1 is expressed in podocytes, can act on glomerular cells to modulate glomerular remodeling, and is downregulated in diseased kidneys, suggesting that impairment of CCN1 expression in podocytes may contribute to the progression of glomerular disease with mesangial expansion. PMID- 17699554 TI - Vasopressin-induced membrane trafficking of TRPC3 and AQP2 channels in cells of the rat renal collecting duct. AB - The canonical transient receptor potential channels TRPC3 and TRPC6 are abundantly expressed along with the water channel aquaporin-2 (AQP2) in principal cells of the cortical and medullary collecting duct. Although TRPC3 is selectively localized to the apical membrane and TRPC6 is found in both the apical and basolateral domains, immunofluorescence is often observed in the cytoplasm, suggesting that TRPC3 and TRPC6 may exist in intracellular vesicles and may shuttle to and from the membrane in response to receptor stimulation. To test this hypothesis, the effect of arginine-vasopressin (AVP) on the subcellular distribution of TRPC3, TRPC6, and AQP2 was examined in the rat kidney and in cultured cell lines from the cortical (M1) and inner medullary (IMCD-3) collecting duct. Immunofluorescence analysis revealed that TRPC3, but not TRPC6, colocalized with AQP2 in intracellular vesicles. AVP caused the insertion and accumulation of TRPC3 and AQP2 in the apical membrane but had no effect on the subcellular distribution of TRPC6. TRPC3, but not TRPC6, coimmunoprecipitated with AQP2 from both medulla and M1 and IMCD-3 cell lysates. Apical-to-basolateral transepithelial 45Ca2+ flux in polarized IMCD-3 cell monolayers was stimulated by diacylglycerol analogs or by the purinergic receptor agonist ATP but not by thapsigargin. Stimulated 45Ca2+ flux was increased by overexpression of TRPC3 and attenuated by a dominant-negative TRPC3 construct. Furthermore, 45Ca2+ flux was greatly reduced by the pyrazole-derivative BTP2, a known inhibitor of TRPC3 channels. These results demonstrate that 1) TRPC3 and TRPC6 exist in different vesicle populations, 2) TRPC3 physically associates with APQ2 and shuttles to the apical membrane in response to AVP, and 3) TRPC3 is responsible for transepithelial Ca2+ flux in principal cells of the renal collecting duct. PMID- 17699555 TI - Downregulation of TRPC6 protein expression by high glucose, a possible mechanism for the impaired Ca2+ signaling in glomerular mesangial cells in diabetes. AB - The present study was performed to investigate whether transient receptor potential (TRPC)6 participated in Ca(2+) signaling of glomerular mesangial cells (MCs) and expression of this protein was altered in diabetes. Western blots and real-time PCR were used to evaluate the expression level of TRPC6 protein and mRNA, respectively. Cell-attached patch-clamp and fura-2 fluorescence measurements were utilized to assess angiotensin II (ANG II)-stimulated membrane currents and Ca(2+) responses in MCs. In cultured human MCs, high glucose significantly reduced expression of TRPC6 protein, but there was no effect on either TRPC1 or TRPC3. The high glucose-induced effect on TRPC6 was time and dose dependent with the maximum effect observed on day 7 and at 30 mM glucose, respectively. In glomeruli isolated from streptozotocin-induced diabetic rats, TRPC6, but not TRPC1, was markedly reduced compared with the glomeruli of control rats. Furthermore, TRPC6 mRNA in MCs was also significantly decreased by high glucose as early as 1 day after treatment with maximal reduction on day 4. Patch clamp experiments showed that ANG II-stimulated membrane currents in MCs were significantly attenuated or enhanced by knockdown or overexpression of TRPC6, respectively. Fura-2 fluorescence measurements revealed that the ANG II-induced Ca(2+) influxes were markedly inhibited in MCs with TRPC6 knockdown, reminiscent of the impaired Ca(2+) entry in response to ANG II in high glucose-treated MCs. These results suggest that the TRPC6 protein expression in MCs was downregulated by high glucose and the deficiency of TRPC6 protein might contribute to the impaired Ca(2+) signaling of MCs seen in diabetes. PMID- 17699556 TI - Hydrogen peroxide stimulates chloride secretion in primary inner medullary collecting duct cells via mPGES-1-derived PGE2. AB - We investigated the role and mechanism of H2O2 in regulation of NaCl transport in primary inner medullary collecting duct (IMCD) cells. IMCD cells were isolated from wild-type mice and grown onto semipermeable membranes, and short-circuit current (Isc) was determined by Ussing chamber. Exposure of IMCD cells to H2O2 at a range of 100-300 microM caused a rapid increase in Isc in a time- and dose dependent manner. This increase was almost abolished by the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel inhibitors diphenylamine 2-carboxylic acid (DPC) and CFTR inhibitor-172. In contrast, the magnitude of stimulation was unaffected by the epithelial Na+ channel (ENaC) inhibitor amiloride. The H2O2-induced Cl(-) secretion was significantly inhibited by indomethacin, as well as by microsomal PGE synthase-1 (mPGES-1) deficiency. Like H2O2, PGE2 treatment induced a twofold increase in Isc that was reduced by the protein kinase A (PKA) inhibitors H-89 and KT5720. These data suggest that H2O2 stimulates CFTR Cl(-) channel-mediated Cl(-) secretion through cyclooxygenase- and mPGES-1-dependent release of PGE2 and subsequent activation of PKA. PMID- 17699557 TI - Proinflammatory and proliferative responses of human proximal tubule cells to PAR 2 activation. AB - Despite the abundant expression of protease-activated receptor (PAR)-2 in the kidney, its relevance to renal physiology is not well understood. A role for this receptor in inflammation and cell proliferation has recently been suggested in nonrenal tissues. The aims of this study were to demonstrate that human proximal tubule cells (PTC) express functional PAR-2 and to investigate whether its activation can mediate proinflammatory and proliferative responses in these cells. Primary human PTC were cultured under serum-free conditions with or without the PAR-2-activating peptide SLIGKV-NH2 (up to 800 microM), a control peptide, VKGILS-NH2 (200 microM), or trypsin (0.01-100 nM). PAR-2 expression (RT PCR), intracellular Ca2+ mobilization (fura-2 fluorimetry), DNA synthesis (thymidine incorporation), fibronectin production (ELISA, Western blotting), and monocyte chemotactic protein (MCP)-1 secretion (ELISA) were measured. Trypsinogen expression in kidney and PTC cultures was determined by immunohistochemistry and Western blotting. In the kidney PTC were the predominant cell type expressing PAR 2. SLIGKV-NH2, but not VKGILS-NH2, stimulated a rapid concentration-dependent mobilization of intracellular Ca2+ and ERK1/2 phosphorylation and, by 24 h, increases in DNA synthesis, fibronectin secretion, and MCP-1 secretion. These delayed responses appeared to be independent of ERK1/2. Trypsin produced similar rapid but not delayed responses. Trypsinogen was weakly expressed by PTC in the kidney and in culture. In summary, PTC are the main site of PAR-2 expression in the human kidney. In PTC cultures SLIGKV-NH2 initiates proinflammatory and proliferative responses. Trypsinogen expressed within the kidney has the potential to contribute to PAR-2 activation in certain circumstances. PMID- 17699558 TI - Rapid screening of glomerular slit diaphragm integrity in larval zebrafish. AB - Gene array-type experiments have identified large numbers of genes thought to be important for the integrity of the glomerular slit diaphragm. Confirmation of individual proteins has been limited by the expenses and time involved in generating transgenic or knockout mice for each candidate. We present a functional screening assay based on the clearance of a 70-kDa fluorescent dextran in another vertebrate system that is rapid and low in cost. In the pronephric glomerulus of larval zebrafish, we have demonstrated quantifiable loss of slit diaphragm integrity in a zebrafish model of puromycin aminonucleoside (PA) toxicity. In addition, after knockdown of CD2-associated protein (CD2AP) and podocin, two well-characterized genetic contributors to podocyte differentiation in mammals, we observed glomerular loss of serum macromolecules similar to that seen in mammalian kidneys with inborn mutations in these genes. Increased filtration of 70-kDa FITC-labeled dextran correlates with effacement of podocyte foot processes in ultrastructural analysis. These findings document the value of the zebrafish model in genomics and pharmacological screening applications. PMID- 17699559 TI - Experiences of condom fit and feel among African-American men who have sex with men. AB - OBJECTIVE: To offer an empirical understanding of characteristics associated with the fit and feel of condoms among African-American men who have sex with men (MSM), a particularly high-risk group for HIV and other sexually transmitted infections (STI) in the United States. METHODS: Survey data were collected from 178 adult African-American MSM attending a community event in Atlanta, Georgia. RESULTS: Although the majority of participants reported that condoms generally fit properly and felt comfortable, a substantial number of men reported a variety of problems with the fit and feel of condoms. Specifically, 21% reported that condoms felt too tight, 18% reported that condoms felt too short, 10% reported that condoms felt too loose, and 7% reported that condoms felt too long. There were significant associations between men's reports of condom breakage and slippage, and their perceptions of condom fit and feel. Perceptions of condom fit and feel were also related to men's reports of seeking condoms for their size specific properties. CONCLUSIONS: The fit and feel issues that men in this sample identified may be among those that contribute to their likelihood of using, or not using, condoms consistently and correctly. A better understanding of these factors will be beneficial to both condom manufacturers and sexual health professionals who share a common goal of increasing consistent and correct condom use and reducing the incidence of HIV and other STI among this and other communities. PMID- 17699561 TI - Sex and sex hormones influence the development of albuminuria and renal macrophage infiltration in spontaneously hypertensive rats. AB - There is a sex difference in hypertensive renal injury, with men experiencing greater severity and a more rapid progression of renal disease than women; however, the molecular mechanisms protecting against renal injury in women are unknown. The goal of this study was to determine whether sex hormones modulate blood pressure and the progression of albuminuria during the developmental phase of hypertension in male and female spontaneously hypertensive rats (SHR). Studies were also performed to examine how sex and sex hormones influence two major risk factors for albuminuria, overactivation of the renin-angiotensin system and oxidative stress. Blood pressure was measured by telemetry in gonad-intact and gonadectomized male and female SHR. Microalbumin excretion, measured over time, and macrophage infiltration were used to assess renal health. Male SHR had significantly higher blood pressures than female SHR, and gonadectomy decreased blood pressures in males with no effect in females. Male SHR displayed a gonad sensitive increase in albuminuria over time, and female SHR had a gonad-sensitive suppression in macrophage infiltration. Female SHR had greater plasma ANG II levels and similar levels of renal cortical ANG II vs. levels shown in males but less AT(1)-receptor protein expression in the renal cortex. Female SHR also had a gonad-sensitive decrease in renal oxidative stress. Therefore, the renal protection afforded to female SHR is associated with lower blood pressure, decreased macrophage infiltration, and decreased levels of oxidative stress. PMID- 17699560 TI - New sexually transmitted infections among adolescent girls infected with HIV. AB - OBJECTIVES: Although the prevalence of sexually transmitted infections (STIs) among girls infected with HIV has been reported, the incidence of STI diagnoses has not been well documented. The objectives of this study were to examine (1) incident STI diagnoses and (2) the association between viral load (VL) and incident STI diagnosis among HIV-infected adolescent girls in care. METHODS: This was a prospective longitudinal 18-month study of girls enrolled in the Adolescent HIV trials network. Cox proportional hazard modelling was performed to evaluate the incidence of STI by baseline viral load. RESULTS: The mean (SD) age of participants was 20.6 (2.0) years, viral load of participants was 66,917 (165,942) copies/ml and median viral load was 7,096 copies/ml. The incidence of STIs for the entire cohort was 1.4 per 100 person-months. During the 18-month follow-up period, there were no significant differences in the STI incidence between the high and low viral load groups (hazard ratio (HR) = 0.86, 95% CI 0.37 to 1.95) There was also no significant association between STI incidence and log transformed viral load (HR = 1.10, 95% CI 0.92 to 1.3). CONCLUSIONS: Adolescent girls with HIV infection continue to acquire sexually transmitted infections after diagnosis. This analysis does not suggest that VL is a critical factor in STI acquisition over time. Additional work exploring the role of other contextual factors on STI acquisition among HIV-infected adolescent girls is warranted. PMID- 17699562 TI - Temporal extracellular matrix adaptations in ligament during wound healing and hindlimb unloading. AB - Previous data from spaceflight studies indicate that injured muscle and bone heal slowly and abnormally compared with ground controls, strongly suggesting that ligaments or tendons may not repair optimally as well. Thus the objective of this study was to investigate the biochemical and molecular gene expression of the collagen extracellular matrix in response to medial collateral ligament (MCL) injury repair in hindlimb unloaded (HLU) rodents. Male rats were assigned to 3- and 7-wk treatment groups with three subgroups each: sham control, ambulatory healing (Amb-healing), and HLU-healing groups. Amb- and HLU-healing animals underwent bilateral surgical transection of their MCLs, whereas control animals were subjected to sham surgeries. All surgeries were performed under isoflurane anesthesia. After 3 wk or 7 wk of HLU, rats were euthanized and MCLs were surgically isolated and prepared for molecular or biochemical analyses. Hydroxyproline concentration and hydroxylysylpyridinoline collagen cross-link contents were measured by HPLC and showed a substantial decrement in surgical groups. MCL tissue cellularity, quantified by DNA content, remained significantly elevated in all HLU-healing groups vs. Amb-healing groups. MCL gene expression of collagen type I, collagen type III, collagen type V, fibronectin, decorin, biglycan, lysyl oxidase, matrix metalloproteinase-2, and tissue inhibitor of matrix metalloproteinase-1, measured by real-time quantitative PCR, demonstrated differential expression in the HLU-healing groups compared with Amb-healing groups at both the 3- and 7-wk time points. Together, these data suggest that HLU affects dense fibrous connective tissue wound healing and confirms previous morphological and biomechanical data that HLU inhibits the ligament repair processes. PMID- 17699563 TI - Aquaporin-2 water channel in developing quail kidney: possible role in programming adult fluid homeostasis. AB - Avian kidneys have loopless and looped nephrons; a countercurrent multiplier mechanism operates in the latter by NaCl recycling. We identified an aquaporin-2 (AQP2) homolog in apical/subapical regions of cortical and medullary collecting duct (CD) cells in kidneys of Japanese quail (q), Coturnix japonica. We investigated whether undernutrition during the embryonic/maturation period retards kidney and AQP2 development in quail and programs impaired volume regulation in adults. Protocols included 1) time course and 2) effects of 5-10% egg white withdrawal (EwW) or 48-h post-hatch food deprivation (FD) on nephron growth and qAQP2 mRNA expression, and 3) effects of EwW and FD on qAQP2 mRNA responses to 72-h water deprivation in adults. In metanephric kidneys, qAQP2 mRNA is expressed in medullary CDs at embryonic day 10; distribution and intensity increase during maturation. The number and size of glomeruli continue to increase after birth, whereas nephrogenic zones decrease. In EwW embryos, qAQP2 mRNA expression is initially delayed, then restored; birth weight and hatching rate are lower than in controls. Adults from EwW embryos and FD chicks have fewer (P < 0.01) glomeruli. Water deprivation reduces body weight more in EwW birds than in controls. The results suggest that qAQP2 evolved in metanephric kidneys and that undernutrition may retard nephrogenesis, leading to impaired adult water homeostasis. PMID- 17699564 TI - Integrin-mediated mechanotransduction in renal vascular smooth muscle cells: activation of calcium sparks. AB - Integrins are transmembrane heterodimeric proteins that link extracellular matrix (ECM) to cytoskeleton and have been shown to function as mechanotransducers in nonmuscle cells. Synthetic integrin-binding peptide triggers Ca(2+) mobilization and contraction in vascular smooth muscle cells (VSMCs) of rat afferent arteriole, indicating that interactions between the ECM and integrins modulate vascular tone. To examine whether integrins transduce extracellular mechanical stress into intracellular Ca(2+) signaling events in VSMCs, unidirectional mechanical force was applied to freshly isolated renal VSMCs through paramagnetic beads coated with fibronectin (natural ligand of alpha(5)beta(1)-integrin in VSMCs). Pulling of fibronectin-coated beads with an electromagnet triggered Ca(2+) sparks, followed by global Ca(2+) mobilization. Paramagnetic beads coated with low-density lipoprotein, whose receptors are not linked to cytoskeleton, were minimally effective in triggering Ca(2+) sparks and global Ca(2+) mobilization. Preincubation with ryanodine, cytochalasin-D, or colchicine substantially reduced the occurrence of Ca(2+) sparks triggered by fibronectin coated beads. Binding of VSMCs with antibodies specific to the extracellular domains of alpha(5-) and beta(1)-integrins triggered Ca(2+) sparks simulating the effects of fibronectin-coated beads. Preincubation of microperfused afferent arterioles with ryanodine or integrin-specific binding peptide inhibited pressure induced myogenic constriction. In conclusion, integrins transduce mechanical force into intracellular Ca(2+) signaling events in renal VSMCs. Integrin mediated mechanotransduction is probably involved in myogenic response of afferent arterioles. PMID- 17699565 TI - Renal sympathetic nerve activity modulates afferent renal nerve activity by PGE2 dependent activation of alpha1- and alpha2-adrenoceptors on renal sensory nerve fibers. AB - Increasing efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA). To test whether the ERSNA-induced increases in ARNA involved norepinephrine activating alpha-adrenoceptors on the renal sensory nerves, we examined the effects of renal pelvic administration of the alpha(1)- and alpha(2)-adrenoceptor antagonists prazosin and rauwolscine on the ARNA responses to reflex increases in ERSNA (placing the rat's tail in 49 degrees C water) and renal pelvic perfusion with norepinephrine in anesthetized rats. Hot tail increased ERSNA and ARNA, 6,930 +/- 900 and 4,870 +/- 670%.s (area under the curve ARNA vs. time). Renal pelvic perfusion with norepinephrine increased ARNA 1,870 +/- 210%.s. Immunohistochemical studies showed that the sympathetic and sensory nerves were closely related in the pelvic wall. Renal pelvic perfusion with prazosin blocked and rauwolscine enhanced the ARNA responses to reflex increases in ERSNA and norepinephrine. Studies in a denervated renal pelvic wall preparation showed that norepinephrine increased substance P release, from 8 +/- 1 to 16 +/- 1 pg/min, and PGE(2) release, from 77 +/- 11 to 161 +/- 23 pg/min, suggesting a role for PGE(2) in the norepinephrine-induced activation of renal sensory nerves. Prazosin and indomethacin reduced and rauwolscine enhanced the norepinephrine-induced increases in substance P and PGE(2). PGE(2) enhanced the norepinephrine-induced activation of renal sensory nerves by stimulation of EP4 receptors. Interaction between ERSNA and ARNA is modulated by norepinephrine, which increases and decreases the activation of the renal sensory nerves by stimulating alpha(1)- and alpha(2)-adrenoceptors, respectively, on the renal pelvic sensory nerve fibers. Norepinephrine-induced activation of the sensory nerves is dependent on renal pelvic synthesis/release of PGE(2). PMID- 17699566 TI - Long-term hypoxia modulates expression of key genes regulating adrenomedullary function in the late gestation ovine fetus. AB - We previously communicated that long-term hypoxia (LTH) resulted in a selective reduction in plasma epinephrine following acute stress in fetal sheep. The present study tested the hypothesis that LTH selectively reduces adrenomedullary expression of phenylethanolamine-N-methyltransferase (PNMT), the rate-limiting enzyme for epinephrine synthesis. We also examined the effect of LTH on adrenomedullary nicotinic, muscarinic, and glucocorticoid receptor (GR) expression. Ewes were maintained at high altitude (3,820 m) from 30 to 138 days gestation (dGA); adrenomedullary tissue was collected from LTH and age-matched, normoxic control fetuses at 139-141 dGA. Contrary to our hypothesis, in addition to PNMT, adrenomedullary expression (mRNA, protein) of tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) were reduced in the LTH fetus. Immunocytochemistry indicated that TH and DBH expression was lower throughout the medulla, while PNMT appeared to reflect a reduction in PNMT-expressing cells. Nicotinic receptor alpha 1, 2, 3, 5, 6, 7, beta 1, 2, and 4 subunits were expressed in the medulla of LTH and control fetuses. Messenger RNA for alpha 1 and 7 and beta 1 and 2 subunits was lower in LTH fetuses. Muscarinic receptors M1, M2, and M3 as well as the GR were also expressed, and no differences were noted between groups. In summary, LTH in fetal sheep has a profound effect on expression of key enzymes mediating adrenomedullary catecholamine synthesis. Further, LTH impacts nicotinic receptor subunit expression potentially altering cholinergic neurotransmission within the medulla. These findings have important implications regarding fetal cardiovascular and metabolic responses to stress in the LTH fetus. PMID- 17699567 TI - Early antibodies specific for the neutralizing epitope on the receptor binding subunit of the lymphocytic choriomeningitis virus glycoprotein fail to neutralize the virus. AB - Lymphocytic choriomeningitis virus (LCMV) is a murine arenavirus whose glycoprotein consists of a transmembrane subunit (GP-2) and a receptor-binding subunit (GP-1). LCMV-neutralizing antibodies (nAbs) are directed against a single site on GP-1 and occur 1 month after the infection of cytotoxic-T-lymphocyte (CTL) deficient mice. In wild-type mice, however, CTLs control early infection, and weak nAb titers emerge very late (after 70 to 150 days) if at all. Production of recombinant GP-1 in native conformation enabled us to study the emergence of GP-1-binding antibodies directed against the neutralizing epitope. By combining binding and neutralization assays, we correlated the development of binding antibodies versus nAbs in wild-type and CTL-deficient mice after infection with different LCMV doses. We found that wild-type mice developed GP-1-specific antibodies already by day 8 after exposure to high but not low doses, demonstrating that naive GP-1-specific B cells were infrequent. Furthermore, the induced antibodies bound to the neutralizing GP-1 epitope but failed to neutralize the virus and therefore were of low affinity. In CTL-deficient mice, where massive viremia quickly levels initial differences in viral load, low and high doses induced low-affinity non-neutralizing GP-1-binding antibodies with kinetics similar to high-dose-infected wild-type mice. Only in CTL-deficient mice, however, the GP-1-specific antibodies developed into nAbs within 1 month. We conclude that LCMV uses a dual strategy to evade nAb responses in wild-type mice. First, LCMV exploits a "hole" in the murine B-cell repertoire, which provides only a small and narrow initial pool of low-affinity GP-1-specific B cells. Second, affinity maturation of the available low-affinity non-neutralizing antibodies is impaired. PMID- 17699568 TI - Viral sequence evolution in acute hepatitis C virus infection. AB - CD8(+)-T-cell responses play an important role in the containment and clearance of hepatitis C virus (HCV) infection, and an association between viral persistence and development of viral escape mutations has been postulated. While escape from CD8+ -T-cell responses has been identified as a major driving force for the evolution of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), a broader characterization of this relationship is needed in HCV infection. To determine the extent, kinetics, and driving forces of HCV sequence evolution, we sequenced the entire HCV genome longitudinally in four subjects monitored for up to 30 months after acute infection. For two subjects the transmission sources were also available. Of 53 total non-envelope amino acid substitutions detected, a majority represented forward mutations away from the consensus sequence. In contrast to studies in HIV and SIV, however, only 11% of these were associated with detectable CD8+ T-cell responses. Interestingly, 19% of non-envelope mutations represented changes toward the consensus sequence, suggesting reversion in the absence of immune pressure upon transmission. Notably, the rate of evolution of forward and reverse mutations correlated with the conservation of each residue, which is indicative of structural constraints influencing the kinetics of viral evolution. Finally, the rate of sequence evolution was observed to decline over the course of infection, possibly reflective of diminishing selection pressure by dysfunctional CD8+ T cells. Taken together, these data provide insight into the extent to which HCV is capable of evading early CD8+ T-cell responses and support the hypothesis that dysfunction of CD8+ T cells may be associated with failure to resolve HCV infections. PMID- 17699570 TI - The topology of hepatitis B virus pregenomic RNA promotes its replication. AB - Previous analysis of hepatitis B virus (HBV) indicated base pairing between two cis-acting sequences, the 5' half of the upper stem of epsilon and phi, contributes to the synthesis of minus-strand DNA. Our goal was to identify other cis-acting sequences on the pregenomic RNA (pgRNA) involved in the synthesis of minus-strand DNA. We found that large portions of the pgRNA could be deleted or substituted without an appreciable decrease in the level of minus-strand DNA synthesized, indicating that most of the pgRNA is dispensable and that a specific size of the pgRNA is not required for this process. Our results indicated that the cis-acting sequences for the synthesis of minus-strand DNA are present near the 5' and 3' ends of the pgRNA. In addition, we found that the first-strand template switch could be directed to a new location when a 72-nucleotide (nt) fragment, which contained the cis-acting sequences present near the 3' end of the pgRNA, was introduced at that location. Within this 72-nt region, we uncovered two new cis-acting sequences, which flank the acceptor site. We show that one of these sequences, named omega and located 3' of the acceptor site, base pairs with phi to contribute to the synthesis of minus-strand DNA. Thus, base pairing between three cis-acting elements (5' half of the upper stem of epsilon, phi, and omega) are necessary for the synthesis of HBV minus-strand DNA. We propose that this topology of pgRNA facilitates first-strand template switch and/or the initiation of synthesis of minus-strand DNA. PMID- 17699569 TI - Astrovirus increases epithelial barrier permeability independently of viral replication. AB - Astrovirus infection in a variety of species results in an age-dependent diarrhea; however, the means by which astroviruses cause diarrhea remain unknown. Studies of astrovirus-infected humans and turkeys have demonstrated few histological changes and little inflammation during infection, suggesting that intestinal damage or an overzealous immune response is not the primary mediator of astrovirus diarrhea. An alternative contributor to diarrhea is increased intestinal barrier permeability. Here, we demonstrate that astrovirus increases barrier permeability in a Caco-2 cell culture model system following apical infection. Increased permeability correlated with disruption of the tight junction protein occludin and decreased the number of actin stress fibers in the absence of cell death. Additionally, permeability was increased when monolayers were treated with UV-inactivated virus or purified recombinant human astrovirus serotype 1 capsid in the form of virus-like particles. Together, these results demonstrate that astrovirus-induced permeability occurs independently of viral replication and is modulated by the capsid protein, a property apparently unique to astroviruses. Based on these data, we propose that the capsid contributes to diarrhea in vivo. PMID- 17699571 TI - ORF73-null murine gammaherpesvirus 68 reveals roles for mLANA and p53 in virus replication. AB - Gammaherpesviruses establish lifelong, latent infections in host lymphocytes, during which a limited subset of viral gene products facilitates maintenance of the viral episome. Among the gamma-2-herpesvirus (rhadinovirus) subfamily, this includes expression of the conserved ORF73-encoded LANA proteins. We previously demonstrated by loss-of-function mutagenesis that the murine gammaherpesvirus 68 (MHV68) ORF73 gene product, mLANA, is required for the establishment of latency following intranasal inoculation of mice (N. J. Moorman, D. O. Willer, and S. H. Speck, J. Virol. 77:10295-10303, 2003). mLANA-deficient viruses also exhibited a defect in acute virus replication in the lungs of infected mice. The latter observation led us to examine the role of mLANA in productive viral replication. We assessed the capacity of mLANA-deficient virus (73.Stop) to replicate in cell culture at low multiplicities of infection (MOIs) and found that 73.Stop growth was impaired in murine fibroblasts but not in Vero cells. A recombinant virus expressing an mLANA-green fluorescent protein (GFP) fusion revealed that mLANA is expressed throughout the virus replication cycle. In addition, 73.Stop infection of murine fibroblasts at high MOIs was substantially more cytotoxic than infection with a genetically repaired marker rescue virus (73.MR), a phenotype that correlated with enhanced kinetics of viral gene expression and increased activation of p53. Notably, augmented cell death, viral gene expression, and p53 induction were independent of viral DNA replication. Expression of a mLANA-GFP fusion protein in fibroblasts correlated with both reduced p53 stabilization and reduced cell death following treatment with p53-inducing agonists. In agreement, accentuated cell death associated with 73.Stop infection was reduced in p53 deficient murine embryonic fibroblasts. Additionally, replication of 73.Stop in p53-deficient cells was restored to levels comparable to those of 73.MR. More remarkably, the absence of p53 led to an overall delay in replication for both 73.Stop and 73.MR viruses, which correlated with delayed viral gene expression, indicating a role for p53 in MHV68 replication. Consistent with these findings, the expression of replication-promoting viral genes was positively influenced by p53 overexpression or treatment with the p53 agonist etoposide. Overall, these data demonstrate the importance of mLANA in MHV68 replication and suggest that LANA proteins limit the induction of cellular stress responses to regulate the viral gene expression cascade and limit host cell injury. PMID- 17699572 TI - Estimating the effectiveness of simian immunodeficiency virus-specific CD8+ T cells from the dynamics of viral immune escape. AB - Antiviral CD8(+) T cells are thought to play a significant role in limiting the viremia of human and simian immunodeficiency virus (HIV and SIV, respectively) infections. However, it has not been possible to measure the in vivo effectiveness of cytotoxic T cells (CTLs), and hence their contribution to the death rate of CD4(+) T cells is unknown. Here, we estimated the ability of a prototypic antigen-specific CTL response against a well-characterized epitope to recognize and kill infected target cells by monitoring the immunodominant Mamu A*01-restricted Tat SL8 epitope for escape from Tat-specific CTLs in SIVmac239 infected macaques. Fitting a mathematical model that incorporates the temporal kinetics of specific CTLs to the frequency of Tat SL8 escape mutants during acute SIV infection allowed us to estimate the in vivo killing rate constant per Tat SL8-specific CTL. Using this unique data set, we show that at least during acute SIV infection, certain antiviral CD8(+) T cells can have a significant impact on shortening the longevity of infected CD4(+) T cells and hence on suppressing virus replication. Unfortunately, due to viral escape from immune pressure and a dependency of the effectiveness of antiviral CD8(+) T-cell responses on the availability of sufficient CD4(+) T cells, the impressive early potency of the CTL response may wane in the transition to the chronic stage of the infection. PMID- 17699573 TI - The formation of viroplasm-like structures by the rotavirus NSP5 protein is calcium regulated and directed by a C-terminal helical domain. AB - The rotavirus NSP5 protein directs the formation of viroplasm-like structures (VLS) and is required for viroplasm formation within infected cells. In this report, we have defined signals within the C-terminal 21 amino acids of NSP5 that are required for VLS formation and that direct the insolubility and hyperphosphorylation of NSP5. Deleting C-terminal residues of NSP5 dramatically increased the solubility of N-terminally tagged NSP5 and prevented NSP5 hyperphosphorylation. Computer modeling and analysis of the NSP5 C terminus revealed the presence of an amphipathic alpha-helix spanning 21 C-terminal residues that is conserved among rotaviruses. Proline-scanning mutagenesis of the predicted helix revealed that single-amino-acid substitutions abolish NSP5 insolubility and hyperphosphorylation. Helix-disrupting NSP5 mutations also abolished localization of green fluorescent protein (GFP)-NSP5 fusions into VLS and directly correlate VLS formation with NSP5 insolubility. All mutations introduced into the hydrophobic face of the predicted NSP5 alpha-helix disrupted VLS formation, NSP5 insolubility, and the accumulation of hyperphosphorylated NSP5 isoforms. Some NSP5 mutants were highly soluble but still were hyperphosphorylated, indicating that NSP5 insolubility was not required for hyperphosphorylation. Expression of GFP containing the last 68 residues of NSP5 at its C terminus resulted in the formation of punctate VLS within cells. Interestingly, GFP-NSP5-C68 was diffusely dispersed in the cytoplasm when calcium was depleted from the medium, and after calcium resupplementation GFP-NSP5-C68 rapidly accumulated into punctate VLS. A potential calcium switch, formed by two tandem pseudo-EF-hand motifs (DxDxD), is present just upstream of the predicted alpha-helix. Mutagenesis of either DxDxD motif abolished the regulatory effect of calcium on VLS formation and resulted in the constitutive assembly of GFP-NSP5 C68 into punctate VLS. These results reveal specific residues within the NSP5 C terminal domain that direct NSP5 hyperphosphorylation, insolubility, and VLS formation in addition to defining residues that constitute a calcium-dependent trigger of VLS formation. These studies identify functional determinants within the C terminus of NSP5 that regulate VLS formation and provide a target for inhibiting NSP5-directed VLS functions during rotavirus replication. PMID- 17699574 TI - Cross-priming of cytotoxic T cells dictates antigen requisites for modified vaccinia virus Ankara vector vaccines. AB - Recombinant vaccines based on modified vaccinia virus Ankara (MVA) have an excellent record concerning safety and immunogenicity and are currently being evaluated in numerous clinical studies for immunotherapy of infectious diseases and cancer. However, knowledge about the biological properties of target antigens to efficiently induce MVA vaccine-mediated immunity in vivo is sparse. Here, we examined distinct antigen presentation pathways and different antigen formulations contained in MVA vaccines for their capability to induce cytotoxic CD8(+) T-cell (CTL) responses. Strikingly, we found that CTL responses against MVA-produced antigens were dominated by cross-priming in vivo, despite the ability of the virus to efficiently infect professional antigen-presenting cells such as dendritic cells. Moreover, stable mature protein was preferred to preprocessed antigen as the substrate for cross-priming. Our data are essential for improved MVA vaccine design, as they demonstrate the need for optimal adjustment of the target antigen properties to the intrinsic requirements of the delivering vector system. PMID- 17699575 TI - Protein kinase CK2 phosphorylation of EB2 regulates its function in the production of Epstein-Barr virus infectious viral particles. AB - The Epstein-Barr Virus (EBV) early protein EB2 (also called BMLF1, Mta, or SM) promotes the nuclear export of a subset of early and late viral mRNAs and is essential for the production of infectious virions. We show here that in vitro, protein kinase CK2alpha and -beta subunits bind both individually and, more efficiently, as a complex to the EB2 N terminus and that the CK2beta regulatory subunit also interacts with the EB2 C terminus. Immunoprecipitated EB2 has CK2 activity that phosphorylates several sites within the 80 N-terminal amino acids of EB2, including Ser-55, -56, and -57, which are localized next to the nuclear export signal. EB2S3E, the phosphorylation-mimicking mutant of EB2 at these three serines, but not the phosphorylation ablation mutant EB2S3A, efficiently rescued the production of infectious EBV particles by HEK293(BMLF1-KO) cells harboring an EB2-defective EBV genome. The defect of EB2S3A in transcomplementing 293(BMLF1 KO) cells was not due to impaired nucleocytoplasmic shuttling of the mutated protein but was associated with a decrease in the cytoplasmic accumulation of several late viral mRNAs. Thus, EB2-mediated production of infectious EBV virions is regulated by CK2 phosphorylation at one or more of the serine residues Ser-55, -56, and -57. PMID- 17699576 TI - Role for amino acids 212KLR214 of Ebola virus VP40 in assembly and budding. AB - Ebola virus VP40 is able to produce virus-like particles (VLPs) in the absence of other viral proteins. At least three domains within VP40 are thought to be required for efficient VLP release: the late domain (L-domain), membrane association domain (M-domain), and self-interaction domain (I-domain). While the L-domain of Ebola VP40 has been well characterized, the exact mechanism by which VP40 mediates budding through the M- and I-domains remains unclear. To identify additional domains important for VP40 assembly/budding, amino acids (212)KLR(214) were targeted for mutagenesis based on the published crystal structure of VP40. These residues are part of a loop connecting two beta sheets in the C-terminal region and thus are potentially important for overall structure and/or oligomerization of VP40. A series of alanine substitutions were generated in the KLR region of VP40, and these mutants were examined for VLP budding, intracellular localization, and oligomerization. Our results indicated that (i) (212)KLR(214) residues of VP40 are important for efficient release of VP40 VLPs, with Leu213 being the most critical; (ii) VP40 KLR mutants displayed altered patterns of cellular localization compared to that of wild-type VP40 (VP40-WT); and (iii) self-assembly of VP40 KLR mutants into oligomers was altered compared to that of VP40-WT. These results suggest that (12)KLR(214) residues of VP40 are important for proper assembly/oligomerization of VP40 which subsequently leads to efficient budding of VLPs. PMID- 17699578 TI - Identification of amino acid residues in BK virus VP1 that are critical for viability and growth. AB - BK virus (BKV) is a ubiquitous pathogen that establishes a persistent infection in the urinary tract of 80% of the human population. Like other polyomaviruses, the major capsid protein of BKV, virion protein 1 (VP1), is critical for host cell receptor recognition and for proper virion assembly. BKV uses a carbohydrate complex containing alpha(2,3)-linked sialic acid attached to glycoprotein and glycolipid motifs as a cellular receptor. To determine the amino acids important for BKV binding to the sialic acid portion of the complex, we generated a series of 17 point mutations in VP1 and scored them for viral growth. The first set of mutants behaved identically to wild-type virus, suggesting that these amino acids were not critical for virus propagation. Another group of VP1 mutants rendered the virus nonviable. These mutations failed to protect viral DNA from DNase I digestion, indicating a role for these domains in capsid assembly and/or packaging of DNA. A third group of VP1 mutations packaged DNA similarly to the wild type but failed to propagate. The initial burst size of these mutations was similar to that of the wild type, indicating that there is no defect in the lytic release of the mutated virions. Binding experiments revealed that a subset of the BKV mutants were unable to attach to their host cells. These motifs are likely important for sialic acid recognition. We next mapped these mutations onto a model of BKV VP1 to provide atomic insight into the role of these sites in the binding of sialic acid to VP1. PMID- 17699577 TI - Disease duration determines canine distemper virus neurovirulence. AB - The Morbillivirus hemagglutinin (H) protein mediates attachment to the target cell. To evaluate its contribution to canine distemper virus neurovirulence, we exchanged the H proteins of the wild-type strains 5804P and A75 and assessed the pathogenesis of the chimeric viruses in ferrets. Both strains are lethal to ferrets; however, 5804P causes a 2-week disease without neurological signs, whereas A75 is associated with a longer disease course and neurological involvement. We observed that both H proteins supported neuroinvasion and the subsequent development of clinical neurological signs if given enough time, demonstrating that disease duration is the main neurovirulence determinant. PMID- 17699579 TI - Ribavirin reveals a lethal threshold of allowable mutation frequency for Hantaan virus. AB - The broad spectrum of antiviral activity of ribavirin (RBV) lies in its ability to inhibit IMP dehydrogenase, which lowers cellular GTP. However, RBV can act as a potent mutagen for some RNA viruses. Previously we have shown a lack of correlation between antiviral activity and GTP repression for Hantaan virus (HTNV) and evidence for RBV's ability to promote error-prone replication. To further explore the mechanism of RBV, GTP levels, specific infectivity, and/or mutation frequency was measured in the presence of RBV, mycophenolic acid (MPA), selenazofurin, or tiazofurin. While all four drugs resulted in a decrease in the GTP levels and infectious virus, only RBV increased the mutation frequency of viral RNA (vRNA). MPA, however, could enhance RBV's mutagenic effect, which suggests distinct mechanisms of action for each. Therefore, a simple drop in GTP levels does not drive the observed error-prone replication. To further explore RBV's mechanism of action, we made a comprehensive analysis of the mutation frequency over several RBV concentrations. Of importance, we observed that the viral population reached a threshold after which mutation frequency did not correlate with a dose-dependent decrease in the level of vRNA, PFU, or [RTP]/[GTP] (where RTP is ribavirin-5'-triphosphate) over these same concentrations of RBV. Modeling of the relationship of mutation frequency and drug concentration showed an asymptotic relationship at this point. After this threshold, approximately 57% of the viral cDNA population was identical to the wild type. These studies revealed a lethal threshold, after which we did not observe a complete loss of the quasispecies structure of the wild-type genome, although we observed extinction of HTNV. PMID- 17699580 TI - Pol-specific CD8+ T cells recognize simian immunodeficiency virus-infected cells prior to Nef-mediated major histocompatibility complex class I downregulation. AB - Effective, vaccine-induced CD8+ T-cell responses should recognize infected cells early enough to prevent production of progeny virions. We have recently shown that Gag-specific CD8+ T cells recognize simian immunodeficiency virus-infected cells at 2 h postinfection, whereas Env-specific CD8+ T cells do not recognize infected cells until much later in infection. However, it remains unknown when other proteins present in the viral particle are presented to CD8+ T cells after infection. To address this issue, we explored CD8+ T-cell recognition of epitopes derived from two other relatively large virion proteins, Pol and Nef. Surprisingly, infected cells efficiently presented CD8+ T-cell epitopes from virion-derived Pol proteins within 2 h of infection. In contrast, Nef-specific CD8+ T cells did not recognize infected cells until 12 h postinfection. Additionally, we show that SIVmac239 Nef downregulated surface major histocompatibility complex class I (MHC-I) molecules beginning at 12 h postinfection, concomitant with presentation of Nef-derived CD8+ T-cell epitopes. Finally, Pol-specific CD8+ T cells eliminated infected cells as early as 6 h postinfection, well before MHC-I downregulation, suggesting a previously underappreciated antiviral role for Pol-specific CD8+ T cells. PMID- 17699581 TI - Novel adeno-associated virus serotypes efficiently transduce murine photoreceptors. AB - Severe inherited retinal diseases, such as retinitis pigmentosa and Leber congenital amaurosis, are caused by mutations in genes preferentially expressed in photoreceptors. While adeno-associated virus (AAV)-mediated gene transfer can correct retinal pigment epithelium (RPE) defects in animal models, approaches for the correction of photoreceptor-specific diseases are less efficient. We evaluated the ability of novel AAV serotypes (AAV2/7, AAV2/8, AAV2/9, AAV2rh.43, AAV2rh.64R1, and AAV2hu.29R) in combination with constitutive or photoreceptor specific promoters to improve photoreceptor transduction, a limiting step in photoreceptor rescue. Based on a qualitative analysis, all AAV serotypes tested efficiently transduce the RPE as well as rod and cone photoreceptors after subretinal administration in mice. Interestingly, AAV2/9 efficiently transduces Muller cells. To compare photoreceptor transduction from different AAVs and promoters in both a qualitative and quantitative manner, we designed a strategy based on the use of a bicistronic construct expressing both enhanced green fluorescent protein and luciferase. We found that AAV2/8 and AAV2/7 mediate six- to eightfold higher levels of in vivo photoreceptor transduction than AAV2/5, considered so far the most efficient AAV serotype for photoreceptor targeting. In addition, following subretinal administration of AAV, the rhodopsin promoter allows significantly higher levels of photoreceptor expression than the other ubiquitous or photoreceptor-specific promoters tested. Finally, we show that AAV2/7, AAV2/8, and AAV2/9 outperform AAV2/5 following ex vivo transduction of retinal progenitor cells differentiated into photoreceptors. We conclude that AAV2/7 or AAV2/8 and the rhodopsin promoter provide the highest levels of photoreceptor transduction both in and ex vivo and that this may overcome the limitation to therapeutic success observed so far in models of inherited severe photoreceptor diseases. PMID- 17699582 TI - Mechanisms of late restriction induced by an endogenous retrovirus. AB - The host has developed during evolution a variety of "restriction factors" to fight retroviral infections. We investigated the mechanisms of a unique viral block acting at late stages of the retrovirus replication cycle. The sheep genome is colonized by several copies of endogenous retroviruses, known as enJSRVs, which are highly related to the oncogenic jaagsiekte sheep retrovirus (JSRV). enJS56A1, one of the enJSRV proviruses, can act as a restriction factor by blocking viral particles release of the exogenous JSRV. We show that in the absence of enJS56A1 expression, the JSRV Gag (the retroviral internal structural polyprotein) targets initially the pericentriolar region, in a dynein and microtubule-dependent fashion, and then colocalizes with the recycling endosomes. Indeed, by inhibiting the endocytosis and trafficking of recycling endosomes we hampered JSRV exit from the cell. Using a variety of approaches, we show that enJS56A1 and JSRV Gag interact soon after synthesis and before pericentriolar/recycling endosome targeting of the latter. The transdominant enJS56A1 induces intracellular Gag accumulation in microaggregates that colocalize with the aggresome marker GFP-250 but develop into bona fide aggresomes only when the proteasomal machinery is inhibited. The data argue that dominant-negative proteins can modify the overall structure of Gag multimers/viral particles hampering the interaction of the latter with the cellular trafficking machinery. PMID- 17699583 TI - Hepatitis B virus replication is associated with an HBx-dependent mitochondrion regulated increase in cytosolic calcium levels. AB - The nonstructural hepatitis B virus (HBV) protein HBx has an important role in HBV replication and in HBV-associated liver disease. Many activities have been linked to HBx expression; however, the molecular mechanisms underlying many of these activities are unknown. One proposed HBx function is the regulation of cytosolic calcium. We analyzed calcium levels in HepG2 cells that expressed HBx or replicating HBV, and we demonstrated that HBx, expressed in the absence of other HBV proteins or in the context of HBV replication, elevates cytosolic calcium. We linked this elevation of cytosolic calcium to the association of HBx with the mitochondrial permeability transition pore. PMID- 17699584 TI - Cyclodextrins inhibit replication of scrapie prion protein in cell culture. AB - Prion diseases are fatal neurodegenerative disorders that are caused by the conversion of a normal host-encoded protein, PrP(C), to an abnormal, disease causing form, PrP(Sc). This paper reports that cyclodextrins have the ability to reduce the pathogenic isoform of the prion protein PrP(Sc) to undetectable levels in scrapie-infected neuroblastoma cells. Beta-cyclodextrin removed PrP(Sc) from the cells at a concentration of 500 microM following 2 weeks of treatment. Structure activity studies revealed that antiprion activity was dependent on the size of the cyclodextrin. The half-maximal inhibitory concentration (IC(50)) for beta-cyclodextrin was 75 microM, whereas alpha-cyclodextrin, which possessed less antiprion activity, had an IC(50) of 750 microM. This report presents cyclodextrins as a new class of antiprion compound. For decades, the pharmaceutical industry has successfully used cyclodextrins for their complex forming ability; this ability is due to the structural orientation of the glucopyranose units, which generate a hydrophobic cavity that can facilitate the encapsulation of hydrophobic moieties. Consequently, cyclodextrins could be ideal candidates for the treatment of prion diseases. PMID- 17699585 TI - Regulation of ubiquitin-proteasome system mediated degradation by cytosolic stress. AB - ER-associated, ubiquitin-proteasome system (UPS)-mediated degradation of the wild type (WT) gap junction protein connexin32 (Cx32) is inhibited by mild forms of cytosolic stress at a step before its dislocation into the cytosol. We show that the same conditions (a 30-min, 42 degrees C heat shock or oxidative stress induced by arsenite) also reduce the endoplasmic reticulum (ER)-associated turnover of disease-causing mutants of Cx32 and the cystic fibrosis transmembrane conductance regulator (CFTR), as well as that of WT CFTR and unassembled Ig light chain. Stress-stabilized WT Cx32 and CFTR, but not the mutant/unassembled proteins examined, could traverse the secretory pathway. Heat shock also slowed the otherwise rapid UPS-mediated turnover of the cytosolic proteins myoD and GFPu, but not the degradation of an ubiquitination-independent construct (GFP ODC) closely related to the latter. Analysis of mutant Cx32 from cells exposed to proteasome inhibitors and/or cytosolic stress indicated that stress reduces degradation at the level of substrate polyubiquitination. These findings reveal a new link between the cytosolic stress-induced heat shock response, ER-associated degradation, and polyubiquitination. Stress-denatured proteins may titer a limiting component of the ubiquitination machinery away from pre-existing UPS substrates, thereby sparing the latter from degradation. PMID- 17699586 TI - Protein kinase A and Sch9 cooperatively regulate induction of autophagy in Saccharomyces cerevisiae. AB - Autophagy is a highly conserved, degradative process in eukaryotic cells. The rapamycin-sensitive Tor kinase complex 1 (TORC1) has a major role in regulating induction of autophagy; however, the regulatory mechanisms are not fully understood. Here, we find that the protein kinase A (PKA) and Sch9 signaling pathways regulate autophagy cooperatively in yeast. Autophagy is induced in cells when PKA and Sch9 are simultaneously inactivated. Mutant alleles of these kinases bearing a mutation that confers sensitivity to the ATP-analogue inhibitor C3-1' naphthyl-methyl PP1 revealed that autophagy was induced independently of effects on Tor kinase. The PKA-Sch9-mediated autophagy depends on the autophagy-related 1 kinase complex, which is also essential for TORC1-regulated autophagy, the transcription factors Msn2/4, and the Rim15 kinase. The present results suggest that autophagy is controlled by the signals from at least three partly separate nutrient-sensing pathways that include PKA, Sch9, and TORC1. PMID- 17699587 TI - Neurabin-I is phosphorylated by Cdk5: implications for neuronal morphogenesis and cortical migration. AB - The correct morphology and migration of neurons, which is essential for the normal development of the nervous system, is enabled by the regulation of their cytoskeletal elements. We reveal that Neurabin-I, a neuronal-specific F-actin binding protein, has an essential function in the developing forebrain. We show that gain and loss of Neurabin-I expression affect neuronal morphology, neurite outgrowth, and radial migration of differentiating cortical and hippocampal neurons, suggesting that tight regulation of Neurabin-I function is required for normal forebrain development. Importantly, loss of Neurabin-I prevents pyramidal neurons from migrating into the cerebral cortex, indicating its essential role during early stages of corticogenesis. We demonstrate that in neurons Rac1 activation is affected by the expression levels of Neurabin-I. Furthermore, the Cdk5 kinase, a key regulator of neuronal migration and morphology, directly phosphorylates Neurabin-I and controls its association with F-actin. Mutation of the Cdk5 phosphorylation site reduces the phenotypic consequences of Neurabin-I overexpression both in vitro and in vivo, suggesting that Neurabin-I function depends, at least in part, on its phosphorylation status. Together our findings provide new insight into the signaling pathways responsible for controlled changes of the F-actin cytoskeleton that are required for normal development of the forebrain. PMID- 17699588 TI - The chromosomal passenger complex controls spindle checkpoint function independent from its role in correcting microtubule kinetochore interactions. AB - The chromosomal passenger complex (CPC) is a critical regulator of chromosome segregation during mitosis by correcting nonbipolar microtubule-kinetochore interactions. By severing these interactions, the CPC is thought to create unattached kinetochores that are subsequently sensed by the spindle assembly checkpoint (SAC) to prevent premature mitotic exit. We now show that spindle checkpoint function of the CPC and its role in eliminating nonbipolar attachments can be uncoupled. Replacing the chromosomal passenger protein INCENP with a mutant allele that lacks its coiled-coil domain results in an overt defect in a SAC-mediated mitotic arrest in response to taxol treatment, indicating that this domain is critical for CPC function in spindle checkpoint control. Surprisingly, this mutant could restore alignment and cytokinesis during unperturbed cell divisions and was capable of resolving syntelic attachments. Also, Aurora-B kinase was localized and activated normally on centromeres in these cells, ruling out a role for the coiled-coil domain in general Aurora-B activation. Thus, mere microtubule destabilization of nonbipolar attachments by the CPC is insufficient to install a checkpoint-dependent mitotic arrest, and additional, microtubule destabilization-independent CPC signaling toward the spindle assembly checkpoint is required for this arrest, potentially through amplification of the unattached kinetochore-derived checkpoint signal. PMID- 17699589 TI - Parallels between global transcriptional programs of polarizing Caco-2 intestinal epithelial cells in vitro and gene expression programs in normal colon and colon cancer. AB - Posttranslational mechanisms are implicated in the development of epithelial cell polarity, but little is known about the patterns of gene expression and transcriptional regulation during this process. We characterized temporal patterns of gene expression during cell-cell adhesion-initiated polarization of cultured human Caco-2 cells, which develop structural and functional polarity resembling enterocytes in vivo. A distinctive switch in gene expression patterns occurred upon formation of cell-cell contacts. Comparison to gene expression patterns in normal human colon and colon tumors revealed that the pattern in proliferating, nonpolarized Caco-2 cells paralleled patterns seen in human colon cancer in vivo, including expression of genes involved in cell proliferation. The pattern switched in polarized Caco-2 cells to one more closely resembling that in normal colon tissue, indicating that regulation of transcription underlying Caco 2 cell polarization is similar to that during enterocyte differentiation in vivo. Surprisingly, the temporal program of gene expression in polarizing Caco-2 cells involved changes in signaling pathways (e.g., Wnt, Hh, BMP, FGF) in patterns similar to those during migration and differentiation of intestinal epithelial cells in vivo, despite the absence of morphogen gradients and interactions with stromal cells characteristic of enterocyte differentiation in situ. The full data set is available at http://microarray-pubs.stanford.edu/CACO2. PMID- 17699590 TI - Transcriptional modulation of genes encoding structural characteristics of differentiating enterocytes during development of a polarized epithelium in vitro. AB - Although there is considerable evidence implicating posttranslational mechanisms in the development of epithelial cell polarity, little is known about the patterns of gene expression and transcriptional regulation during this process. We characterized the temporal program of gene expression during cell-cell adhesion-initiated polarization of human Caco-2 cells in tissue culture, which develop structural and functional polarity similar to that of enterocytes in vivo. A distinctive switch in gene expression patterns occurred upon formation of cell-cell contacts between neighboring cells. Expression of genes involved in cell proliferation was down-regulated concomitant with induction of genes necessary for functional specialization of polarized epithelial cells. Transcriptional up-regulation of these latter genes correlated with formation of important structural and functional features in enterocyte differentiation and establishment of structural and functional cell polarity; components of the apical microvilli were induced as the brush border formed during polarization; as barrier function was established, expression of tight junction transmembrane proteins peaked; transcripts encoding components of the apical, but not the basal lateral trafficking machinery were increased during polarization. Coordinated expression of genes encoding components of functional cell structures were often observed indicating temporal control of expression and assembly of multiprotein complexes. PMID- 17699591 TI - Atg18 regulates organelle morphology and Fab1 kinase activity independent of its membrane recruitment by phosphatidylinositol 3,5-bisphosphate. AB - The lipid kinase Fab1 governs yeast vacuole homeostasis by generating PtdIns(3,5)P(2) on the vacuolar membrane. Recruitment of effector proteins by the phospholipid ensures precise regulation of vacuole morphology and function. Cells lacking the effector Atg18p have enlarged vacuoles and high PtdIns(3,5)P(2) levels. Although Atg18 colocalizes with Fab1p, it likely does not directly interact with Fab1p, as deletion of either kinase activator-VAC7 or VAC14-is epistatic to atg18Delta: atg18Deltavac7Delta cells have no detectable PtdIns(3,5)P(2). Moreover, a 2xAtg18 (tandem fusion) construct localizes to the vacuole membrane in the absence of PtdIns(3,5)P(2), but requires Vac7p for recruitment. Like the endosomal PtdIns(3)P effector EEA1, Atg18 membrane binding may require a protein component. When the lipid requirement is bypassed by fusing Atg18 to ALP, a vacuolar transmembrane protein, vac14Delta vacuoles regain normal morphology. Rescue is independent of PtdIns(3,5)P(2), as mutation of the phospholipid-binding site in Atg18 does not prevent vacuole fission and properly regulates Fab1p activity. Finally, the vacuole-specific type-V myosin adapter Vac17p interacts with Atg18p, perhaps mediating cytoskeletal attachment during retrograde transport. Atg18p is likely a PtdIns(3,5)P(2)"sensor," acting as an effector to remodel membranes as well as regulating its synthesis via feedback that might involve Vac7p. PMID- 17699592 TI - Canonical heterotrimeric G proteins regulating mating and virulence of Cryptococcus neoformans. AB - Perturbation of pheromone signaling modulates not only mating but also virulence in Cryptococcus neoformans, an opportunistic human pathogen known to encode three Galpha, one Gbeta, and two Ggamma subunit proteins. We have found that Galphas Gpa2 and Gpa3 exhibit shared and distinct roles in regulating pheromone responses and mating. Gpa2 interacted with the pheromone receptor homolog Ste3alpha, Gbeta subunit Gpb1, and RGS protein Crg1. Crg1 also exhibited in vitro GAP activity toward Gpa2. These findings suggest that Gpa2 regulates mating through a conserved signaling mechanism. Moreover, we found that Ggammas Gpg1 and Gpg2 both regulate pheromone responses and mating. gpg1 mutants were attenuated in mating, and gpg2 mutants were sterile. Finally, although gpa2, gpa3, gpg1, gpg2, and gpg1 gpg2 mutants were fully virulent, gpa2 gpa3 mutants were attenuated for virulence in a murine model. Our study reveals a conserved but distinct signaling mechanism by two Galpha, one Gbeta, and two Ggamma proteins for pheromone responses, mating, and virulence in Cryptococcus neoformans, and it also reiterates that the link between mating and virulence is not due to mating per se but rather to certain mating-pathway components that encode additional functions promoting virulence. PMID- 17699593 TI - Rabaptin-5-independent membrane targeting and Rab5 activation by Rabex-5 in the cell. AB - Rabex-5 is a guanine nucleotide exchange factor (GEF) for Rab5. Here, we report the identification of a novel functional domain of Rabex-5 that is essential for its membrane targeting and Rab5 GEF activity in vivo. The data show that full length Rabex-5 efficiently activates Rab5 in the cell. However, the GEF domain itself (residues 135-399) is inactive in this respect, despite its activity in vitro. Generation and characterization of a series of Rabex-5 constructs reveal that the GEF domain is unable to target to early endosomes and that a sequence N terminal to the GEF domain can restore its early endosomal targeting and its ability to activate Rab5 in the cell. This region (residues 81-135) is termed membrane-binding motif, which together with the downstream helical bundle domain (residues 135-230) forms an early endosomal targeting (EET) domain necessary and sufficient for association with early endosomes. Furthermore, several active Rabex-5 constructs do not contain the Rabaptin-5-binding domain in the C-terminal region. Thus, Rabex-5 can target to early endosomes via the EET domain and activate Rab5 in a Rabaptin-5-independent manner in vivo. We discuss a model to reconcile these in vivo data with previous in vitro results on Rabex-5 function and its interaction with Rabaptin-5. PMID- 17699594 TI - FGF-2 release from the lens capsule by MMP-2 maintains lens epithelial cell viability. AB - The lens is an avascular tissue, separated from the aqueous and vitreous humors by its own extracellular matrix, the lens capsule. Here we demonstrate that the lens capsule is a source of essential survival factors for lens epithelial cells. Primary and immortalized lens epithelial cells survive in low levels of serum and are resistant to staurosporine-induced apoptosis when they remain in contact with the lens capsule. Physical contact with the capsule is required for maximal resistance to stress. The lens capsule is also a source of soluble factors including fibroblast growth factor 2 (FGF-2) and perlecan, an extracellular matrix component that enhances FGF-2 activity. Matrix metalloproteinase 2 (MMP-2) inhibition as well as MMP-2 pretreatment of lens capsules greatly reduced the protective effect of the lens capsule, although this could be largely reversed by the addition of either conditioned medium or recombinant FGF-2. These data suggest that FGF-2 release from the lens capsule by MMP-2 is essential to lens epithelial cell viability and survival. PMID- 17699595 TI - Regulation of the formin for3p by cdc42p and bud6p. AB - Formins are conserved actin nucleators responsible for the assembly of diverse actin structures. Many formins are controlled through an autoinhibitory mechanism involving the interaction of a C-terminal DAD sequence with an N-terminal DID sequence. Here, we show that the fission yeast formin for3p, which mediates actin cable assembly and polarized cell growth, is regulated by a similar autoinhibitory mechanism in vivo. Multiple sites govern for3p localization to cell tips. The localization and activity of for3p are inhibited by an intramolecular interaction of divergent DAD and DID-like sequences. A for3p DAD mutant expressed at endogenous levels produces more robust actin cables, which appear to have normal organization and dynamics. We identify cdc42p as the primary Rho GTPase involved in actin cable assembly and for3p regulation. Both cdc42p, which binds at the N terminus of for3p, and bud6p, which binds near the C terminal DAD-like sequence, are needed for for3p localization and full activity, but a mutation in the for3p DAD restores for3p localization and other phenotypes of cdc42 and bud6 mutants. In particular, the for3p DAD mutation suppresses the bipolar growth (NETO) defect of bud6Delta cells. These findings suggest that cdc42p and bud6p activate for3p by relieving autoinhibition. PMID- 17699596 TI - Rab6 regulates both ZW10/RINT-1 and conserved oligomeric Golgi complex-dependent Golgi trafficking and homeostasis. AB - We used multiple approaches to investigate the role of Rab6 relative to Zeste White 10 (ZW10), a mitotic checkpoint protein implicated in Golgi/endoplasmic reticulum (ER) trafficking/transport, and conserved oligomeric Golgi (COG) complex, a putative tether in retrograde, intra-Golgi trafficking. ZW10 depletion resulted in a central, disconnected cluster of Golgi elements and inhibition of ERGIC53 and Golgi enzyme recycling to ER. Small interfering RNA (siRNA) against RINT-1, a protein linker between ZW10 and the ER soluble N-ethylmaleimide sensitive factor attachment protein receptor, syntaxin 18, produced similar Golgi disruption. COG3 depletion fragmented the Golgi and produced vesicles; vesicle formation was unaffected by codepletion of ZW10 along with COG, suggesting ZW10 and COG act separately. Rab6 depletion did not significantly affect Golgi ribbon organization. Epistatic depletion of Rab6 inhibited the Golgi-disruptive effects of ZW10/RINT-1 siRNA or COG inactivation by siRNA or antibodies. Dominant negative expression of guanosine diphosphate-Rab6 suppressed ZW10 knockdown induced-Golgi disruption. No cross-talk was observed between Rab6 and endosomal Rab5, and Rab6 depletion failed to suppress p115 (anterograde tether) knockdown induced Golgi disruption. Dominant-negative expression of a C-terminal fragment of Bicaudal D, a linker between Rab6 and dynactin/dynein, suppressed ZW10, but not COG, knockdown-induced Golgi disruption. We conclude that Rab6 regulates distinct Golgi trafficking pathways involving two separate protein complexes: ZW10/RINT-1 and COG. PMID- 17699597 TI - Human Mcm10 regulates the catalytic subunit of DNA polymerase-alpha and prevents DNA damage during replication. AB - In Saccharomyces cerevisiae, minichromosome maintenance protein (Mcm) 10 interacts with DNA polymerase (pol)-alpha and functions as a nuclear chaperone for the catalytic subunit, which is rapidly degraded in the absence of Mcm10. We report here that the interaction between Mcm10 and pol-alpha is conserved in human cells. We used a small interfering RNA-based approach to deplete Mcm10 in HeLa cells, and we observed that the catalytic subunit of pol-alpha, p180, was degraded with similar kinetics as Mcm10, whereas the regulatory pol-alpha subunit, p68, remained unaffected. Simultaneous loss of Mcm10 and p180 inhibited S phase entry and led to an accumulation of already replicating cells in late S/G2 as a result of DNA damage, which triggered apoptosis in a subpopulation of cells. These phenotypes differed considerably from analogous studies in Drosophila embryo cells that did not exhibit a similar arrest. To further dissect the roles of Mcm10 and p180 in human cells, we depleted p180 alone and observed a significant delay in S phase entry and fork progression but little effect on cell viability. These results argue that cells can tolerate low levels of p180 as long as Mcm10 is present to "recycle" it. Thus, human Mcm10 regulates both replication initiation and elongation and maintains genome integrity. PMID- 17699598 TI - Regulation of cell cycle and stress responses to hydrostatic pressure in fission yeast. AB - We have investigated the cellular responses to hydrostatic pressure by using the fission yeast Schizosaccharomyces pombe as a model system. Exposure to sublethal levels of hydrostatic pressure resulted in G2 cell cycle delay. This delay resulted from Cdc2 tyrosine-15 (Y-15) phosphorylation, and it was abrogated by simultaneous disruption of the Cdc2 kinase regulators Cdc25 and Wee1. However, cell cycle delay was independent of the DNA damage, cytokinesis, and cell size checkpoints, suggesting a novel mechanism of Cdc2-Y15 phosphorylation in response to hydrostatic pressure. Spc1/Sty1 mitogen-activated protein (MAP) kinase, a conserved member of the eukaryotic stress-activated p38, mitogen-activated protein (MAP) kinase family, was rapidly activated after pressure stress, and it was required for cell cycle recovery under these conditions, in part through promoting polo kinase (Plo1) phosphorylation on serine 402. Moreover, the Spc1 MAP kinase pathway played a key role in maintaining cell viability under hydrostatic pressure stress through the bZip transcription factor, Atf1. Further analysis revealed that prestressing cells with heat increased barotolerance, suggesting adaptational cross-talk between these stress responses. These findings provide new insight into eukaryotic homeostasis after exposure to pressure stress. PMID- 17699599 TI - Isoprenylcysteine carboxy methylation is essential for development in Dictyostelium discoideum. AB - Members of the Ras superfamily of small GTPases and the heterotrimeric G protein gamma subunit are methylated on their carboxy-terminal cysteine residues by isoprenylcysteine methyltransferase. In Dictyostelium discoideum, small GTPase methylation occurs seconds after stimulation of starving cells by cAMP and returns quickly to basal levels, suggesting an important role in cAMP-dependent signaling. Deleting the isoprenylcysteine methyltransferase-encoding gene causes dramatic defects. Starving mutant cells do not propagate cAMP waves in a sustained manner, and they do not aggregate. Motility is rescued when cells are pulsed with exogenous cAMP, or coplated with wild-type cells, but the rescued cells exhibit altered polarity. cAMP-pulsed methyltransferase-deficient cells that have aggregated fail to differentiate, but mutant cells plated in a wild type background are able to do so. Localization of and signaling by RasG is altered in the mutant. Localization of the heterotrimeric Ggamma protein subunit was normal, but signaling was altered in mutant cells. These data indicate that isoprenylcysteine methylation is required for intercellular signaling and development in Dictyostelium. PMID- 17699600 TI - Multiple myosins are required to coordinate actin assembly with coat compression during compensatory endocytosis. AB - Actin is involved in endocytosis in organisms ranging from yeast to mammals. In activated Xenopus eggs, exocytosing cortical granules (CGs) are surrounded by actin "coats," which compress the exocytosing compartments, resulting in compensatory endocytosis. Here, we examined the roles of two myosins in actin coat compression. Myosin-2 is recruited to exocytosing CGs late in coat compression. Inhibition of myosin-2 slows coat compression without affecting actin assembly. This differs from phenotype induced by inhibition of actin assembly, where exocytosing CGs are trapped at the plasma membrane (PM) completely. Thus, coat compression is likely driven in part by actin assembly itself, but it requires myosin-2 for efficient completion. In contrast to myosin 2, the long-tailed myosin-1e is recruited to exocytosing CGs immediately after egg activation. Perturbation of myosin-1e results in partial actin coat assembly and induces CG collapse into the PM. Intriguingly, simultaneous inhibition of actin assembly and myosin-1e prevents CG collapse. Together, the results show that myosin-1e and myosin-2 are part of an intricate machinery that coordinates coat compression at exocytosing CGs. PMID- 17699603 TI - Analysis of zebrafish sidetracked mutants reveals a novel role for Plexin A3 in intraspinal motor axon guidance. AB - One of the earliest guidance decisions for spinal cord motoneurons occurs when pools of motoneurons orient their growth cones towards a common, segmental exit point. In contrast to later events, remarkably little is known about the molecular mechanisms underlying intraspinal motor axon guidance. In zebrafish sidetracked (set) mutants, motor axons exit from the spinal cord at ectopic positions. By single-cell labeling and time-lapse analysis we show that motoneurons with cell bodies adjacent to the segmental exit point properly exit from the spinal cord, whereas those farther away display pathfinding errors. Misguided growth cones either orient away from the endogenous exit point, extend towards the endogenous exit point but bypass it or exit at non-segmental, ectopic locations. Furthermore, we show that sidetracked acts cell autonomously in motoneurons. Positional cloning reveals that sidetracked encodes Plexin A3, a semaphorin guidance receptor for repulsive guidance. Finally, we show that sidetracked (plexin A3) plays an additional role in motor axonal morphogenesis. Together, our data genetically identify the first guidance receptor required for intraspinal migration of pioneering motor axons and implicate the well-described semaphorin/plexin signaling pathway in this poorly understood process. We propose that axonal repulsion via Plexin A3 is a major driving force for intraspinal motor growth cone guidance. PMID- 17699601 TI - Dual Role of alpha6beta4 integrin in epidermal tumor growth: tumor-suppressive versus tumor-promoting function. AB - An increased expression of the integrin alpha6beta4 is correlated with a poor prognosis in patients with squamous cell carcinomas. However, little is known about the role of alpha6beta4 in the early stages of tumor development. We have isolated cells from mouse skin (mouse tumor-initiating cells [mTICs]) that are deficient in both p53 and Smad4 and carry conditional alleles of the beta4 gene (Itgb4). The mTICs display many features of multipotent epidermal stem cells and produce well-differentiated tumors after subcutaneous injection into nude mice. Deletion of Itgb4 led to enhanced tumor growth, indicating that alpha6beta4 mediates a tumor-suppressive effect. Reconstitution experiments with beta4 chimeras showed that this effect is not dependent on ligation of alpha6beta4 to laminin-5, but on the recruitment by this integrin of the cytoskeletal linker protein plectin to the plasma membrane. Depletion of plectin, like that of beta4, led to increased tumor growth. In contrast, when mTICs had been further transformed with oncogenic Ras, alpha6beta4 stimulated tumor growth, as previously observed in human squamous neoplasms. Expression of different effector loop mutants of Ras(V12) suggests that this effect depends on a strong activation of the Erk pathway. Together, these data show that depending on the mutations involved, alpha6beta4 can either mediate an adhesion-independent tumor suppressive effect or act as a tumor promotor. PMID- 17699602 TI - Nuclear localization of the ERK MAP kinase mediated by Drosophila alphaPS2betaPS integrin and importin-7. AB - The control of gene expression by the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (ERK) requires its translocation into the nucleus. In Drosophila S2 cells nuclear accumulation of diphospho-ERK (dpERK) is greatly reduced by interfering double-stranded RNA against Drosophila importin-7 (DIM-7) or by the expression of integrin mutants, either during active cell spreading or after stimulation by insulin. In both cases, total ERK phosphorylation (on Westerns) is not significantly affected, and ERK accumulates in a perinuclear ring. Tyrosine phosphorylation of DIM-7 is reduced in cells expressing integrin mutants, indicating a mechanistic link between these components. DIM-7 and integrins localize to the same actin-containing peripheral regions in spreading cells, but DIM-7 is not concentrated in paxillin-positive focal contacts or stable focal adhesions. The Corkscrew (SHP-2) tyrosine phosphatase binds DIM-7, and Corkscrew is required for the cortical localization of DIM-7. These data suggest a model in which ERK phosphorylation must be spatially coupled to integrin-mediated DIM-7 activation to make a complex that can be imported efficiently. Moreover, dpERK nuclear import can be restored in DIM-7-deficient cells by Xenopus Importin-7, demonstrating that ERK import is an evolutionarily conserved function of this protein. PMID- 17699604 TI - BMP signalling inhibits premature neural differentiation in the mouse embryo. AB - The specification of a subset of epiblast cells to acquire a neural fate constitutes the first step in the generation of the nervous system. Little is known about the signals required for neural induction in the mouse. We have analysed the role of BMP signalling in this process. We demonstrate that prior to gastrulation, Bmp2/4 signalling via Bmpr1a maintains epiblast pluripotency and prevents precocious neural differentiation of this tissue, at least in part by maintaining Nodal signalling. We find that during gastrulation, BMPs of the 60A subgroup cooperate with Bmp2/4 to maintain pluripotency. The inhibition of neural fate by BMPs is independent of FGF signalling, as inhibition of FGF signalling between 5.5 and 7.5 days post-coitum does not block neural differentiation in the mouse embryo. Together, our results demonstrate that inhibition of BMP signalling has a central role during neural induction in mammals and suggest that FGFs do not act as neural inducers in the post-implantation mouse embryo. PMID- 17699605 TI - Vesicular traffic at the cell membrane regulates oocyte meiotic arrest. AB - Vertebrate oocytes are maintained in meiotic arrest for prolonged periods of time before undergoing oocyte maturation in preparation for fertilization. Cyclic AMP (cAMP) signaling plays a crucial role in maintaining meiotic arrest, which is released by a species-specific hormonal signal. Evidence in both frog and mouse argues that meiotic arrest is maintained by a constitutively active G-protein coupled receptor (GPCR) leading to high cAMP levels. Because activated GPCRs are typically targeted for endocytosis as part of the signal desensitization pathway, we were interested in determining the role of trafficking at the cell membrane in maintaining meiotic arrest. Here we show that blocking exocytosis, using a dominant-negative SNAP25 mutant in Xenopus oocytes, releases meiotic arrest independently of progesterone. Oocyte maturation in response to the exocytic block induces the MAPK and Cdc25C signaling cascades, leading to MPF activation, germinal vesicle breakdown and arrest at metaphase of meiosis II with a normal bipolar spindle. It thus replicates all tested aspects of physiological maturation. Furthermore, inhibiting clathrin-mediated endocytosis hinders the effectiveness of progesterone in releasing meiotic arrest. These data show that vesicular traffic at the cell membrane is crucial in maintaining meiotic arrest in vertebrates, and support the argument for active recycling of a constitutively active GPCR at the cell membrane. PMID- 17699607 TI - Wnt signaling mediates regional specification in the vertebrate face. AB - At early stages of development, the faces of vertebrate embryos look remarkably similar, yet within a very short timeframe they adopt species-specific facial characteristics. What are the mechanisms underlying this regional specification of the vertebrate face? Using transgenic Wnt reporter embryos we found a highly conserved pattern of Wnt responsiveness in the developing mouse face that later corresponded to derivatives of the frontonasal and maxillary prominences. We explored the consequences of disrupting Wnt signaling, first using a genetic approach. Mice carrying compound null mutations in the nuclear mediators Lef1 and Tcf4 exhibited radically altered facial features that culminated in a hyperteloric appearance and a foreshortened midface. We also used a biochemical approach to perturb Wnt signaling and found that in utero delivery of a Wnt antagonist, Dkk1, produced similar midfacial malformations. We tested the hypothesis that Wnt signaling is an evolutionarily conserved mechanism controlling facial morphogenesis by determining the pattern of Wnt responsiveness in avian faces, and then by evaluating the consequences of Wnt inhibition in the chick face. Collectively, these data elucidate a new role for Wnt signaling in regional specification of the vertebrate face, and suggest possible mechanisms whereby species-specific facial features are generated. PMID- 17699606 TI - GLH-1, the C. elegans P granule protein, is controlled by the JNK KGB-1 and by the COP9 subunit CSN-5. AB - The GLHs (germline RNA helicases) are constitutive components of the germline specific P granules in the nematode Caenorhabditis elegans and are essential for fertility, yet how GLH proteins are regulated remains unknown. KGB-1 and CSN-5 are both GLH binding partners, previously identified by two-hybrid interactions. KGB-1 is a MAP kinase in the Jun N-terminal kinase (JNK) subfamily, whereas CSN-5 is a subunit of the COP9 signalosome. Intriguingly, although loss of either KGB-1 or CSN-5 results in sterility, their phenotypes are strikingly different. Whereas csn-5 RNA interference (RNAi) results in under-proliferated germlines, similar to glh-1/glh-4(RNAi), the kgb-1(um3) loss-of-function mutant exhibits germline over proliferation. When kgb-1(um3) mutants are compared with wild-type C. elegans, GLH-1 protein levels are as much as 6-fold elevated and the organization of GLH-1 in P granules is grossly disrupted. A series of additional in vivo and in vitro tests indicates that KGB-1 and CSN-5 regulate GLH-1 levels, with GLH-1 targeted for proteosomal degradation by KGB-1 and stabilized by CSN-5. We propose the ;good cop: bad cop' team of CSN-5 and KGB-1 imposes a balance on GLH-1 levels, resulting in germline homeostasis. In addition, both KGB-1 and CSN-5 bind Vasa, a Drosophila germ granule component; therefore, similar regulatory mechanisms might be conserved from worms to flies. PMID- 17699608 TI - Novel mutations affecting axon guidance in zebrafish and a role for plexin signalling in the guidance of trigeminal and facial nerve axons. AB - In zebrafish embryos, the axons of the posterior trigeminal (Vp) and facial (VII) motoneurons project stereotypically to a small number of target muscles derived from the first and second branchial arches (BA1, BA2). Use of the Islet1 (Isl1) GFP transgenic line enabled precise real-time observations of the growth cone behaviour of the Vp and VII motoneurons within BA1 and BA2. Screening for N-ethyl N-nitrosourea-induced mutants identified seven distinct mutations affecting different steps in the axonal pathfinding of these motoneurons. The class 1 mutations caused severe defasciculation and abnormal pathfinding in both Vp and VII motor axons before they reached their target muscles in BA1. The class 2 mutations caused impaired axonal outgrowth of the Vp motoneurons at the BA1-BA2 boundary. The class 3 mutation caused impaired axonal outgrowth of the Vp motoneurons within the target muscles derived from BA1 and BA2. The class 4 mutation caused retraction of the Vp motor axons in BA1 and abnormal invasion of the VII motor axons in BA1 beyond the BA1-BA2 boundary. Time-lapse observations of the class 1 mutant, vermicelli (vmc), which has a defect in the plexin A3 (plxna3) gene, revealed that Plxna3 acts with its ligand Sema3a1 for fasciculation and correct target selection of the Vp and VII motor axons after separation from the common pathways shared with the sensory axons in BA1 and BA2, and for the proper exit and outgrowth of the axons of the primary motoneurons from the spinal cord. PMID- 17699609 TI - Pbx homeodomain proteins direct Myod activity to promote fast-muscle differentiation. AB - The basic helix-loop-helix (bHLH) transcription factor Myod directly regulates gene expression throughout the program of skeletal muscle differentiation. It is not known how a Myod-driven myogenic program is modulated to achieve muscle fiber type-specific gene expression. Pbx homeodomain proteins mark promoters of a subset of Myod target genes, including myogenin (Myog); thus, Pbx proteins might modulate the program of myogenesis driven by Myod. By inhibiting Pbx function in zebrafish embryos, we show that Pbx proteins are required in order for Myod to induce the expression of a subset of muscle genes in the somites. In the absence of Pbx function, expression of myog and of fast-muscle genes is inhibited, whereas slow-muscle gene expression appears normal. By knocking down Pbx or Myod function in combination with another bHLH myogenic factor, Myf5, we show that Pbx is required for Myod to regulate fast-muscle, but not slow-muscle, development. Furthermore, we show that Sonic hedgehog requires Myod in order to induce both fast- and slow-muscle markers but requires Pbx only to induce fast-muscle markers. Our results reveal that Pbx proteins modulate Myod activity to drive fast-muscle gene expression, thus showing that homeodomain proteins can direct bHLH proteins to establish a specific cell-type identity. PMID- 17699610 TI - Hypomorphic Sox10 alleles reveal novel protein functions and unravel developmental differences in glial lineages. AB - The transcription factor Sox10 regulates early neural crest development, specification of neural crest-derived lineages and terminal differentiation of oligodendrocytes in the central nervous system. Here, we generated two novel hypomorphic Sox10 alleles in the mouse. Mutant mice either expressed a Sox10 protein with a triple alanine substitution in the dimerization domain, or a Sox10 protein with a deletion in the central portion that we define as a cell-specific transactivation domain. Phenotypic analysis revealed important roles for a functional dimerization domain and the newly defined novel transactivation domain in melanocyte and enteric nervous system development, whereas early neural crest development and oligodendrocyte differentiation were surprisingly little disturbed in both mutants. Unique requirements were additionally detected for the novel transactivation domain in satellite glia differentiation and during Schwann cell myelination, whereas DNA-dependent dimerization was needed for immature Schwann cells to enter the promyelinating stage. These two hypomorphic alleles thus uncover novel functions of Sox10 in satellite glia and Schwann cells during late developmental stages and reveal important developmental differences between these two types of peripheral glia and oligodendrocytes regarding their reliance on Sox10. PMID- 17699611 TI - Prolyl 4-hydroxylase-1 mediates O2 signaling during development of Dictyostelium. AB - Development in multicellular organisms is subject to both environmental and internal signals. In Dictyostelium, starvation induces amoebae to form migratory slugs that translocate from subterranean areas to exposed sites, where they culminate to form sessile fruiting bodies. Culmination, thought to be regulated by anterior tip cells, is selectively suppressed by mild hypoxia by a mechanism that can be partially overridden by another environmental signal, overhead light, or genetic activation of protein kinase A. Dictyostelium expresses, in all cells, an O2-dependent prolyl 4-hydroxylase (P4H1) required for O-glycosylation of Skp1, a subunit of E3SCF-Ub-ligases. P4H1-null cells differentiate the basic pre-stalk and pre-spore cell types but exhibit a selectively increased O2 requirement for culmination, from approximately 12% to near or above ambient (21%) levels. Overexpression of P4H1 reduces the O2 requirement to <5%. The requirement for P4H1 can be met by forced expression of the active enzyme in either pre-stalk (anterior) or pre-spore (posterior) cells, or replaced by protein kinase A activation or addition of small numbers of wild-type cells. P4H1-expressing cells accumulate at the anterior end, suggesting that P4H1 enables transcellular signaling by the tip. The evidence provides novel genetic support for the animal derived O2-sensor model of prolyl 4-hydroxylase function, in an organism that lacks the canonical HIFalpha transcriptional factor subunit substrate target that is a feature of animal hypoxic signaling. PMID- 17699612 TI - XCL1 (lymphotactin) chemokine produced by activated CD8 T cells during the chronic stage of infection with Mycobacterium tuberculosis negatively affects production of IFN-gamma by CD4 T cells and participates in granuloma stability. AB - CD8 T cell immune responses are known not to be essential during the initial stages of infection with Mycobacterium tuberculosis (Mtb), but their presence becomes important as the chronic infection ensues. The basis of this is still not clear. In previous studies, we showed that CD8 T cells have a distinctive positioning in the architecture of the granuloma lesion, with further changes throughout the course of the chronic infection. We have also hypothesized that further movement of lymphocytes once they are within the lung lesions could be associated with the levels of expression of the chemokine XCL1 (lymphotactin). XCL1 is produced mainly by activated CD8 T cells, and its chemotactic activity seems primarily controlling movement of CD4 and CD8 T cells. In this study, using a murine low-dose aerosol infection model coupled with antibody depletion of T cell subsets, we investigated the role of CD8 T cells in the control of the bacterial growth and in the pathogenesis of the disease in mice at early, mid, or late stages of the chronic disease state. Additionally, we also describe for the first time that during Mtb infection, activated CD8 T cells in the lungs produce XCL1 and that this chemokine is capable of controlling IFN-gamma production by CD4 T cells. PMID- 17699613 TI - Molecular basis for the impaired function of the natural F112L sorcin mutant: X ray crystal structure, calcium affinity, and interaction with annexin VII and the ryanodine receptor. AB - The penta-EF hand protein sorcin participates in the modulation of Ca2+-induced calcium-release in the heart through the interaction with several Ca2+ channels such as the ryanodine receptor. The modulating activity is impaired in the recently described natural F112L mutant. The F112 residue is located at the end of the D helix next to Asp113, one of the calcium ligands in the EF3 hand endowed with the highest affinity for the metal. The F112L-sorcin X-ray crystal structure at 2.5 A resolution displays marked alterations in the EF3 hand, where the hydrogen bonding network established by Phe112 is disrupted, and in the EF1 region, which is tilted in both monomers that give rise to the dimer, the stable form of the molecule. In turn, the observed tilt is indicative of an increased flexibility of the N-terminal part of the molecule. The structural alterations result in a 6-fold decrease in calcium affinity with respect to the wild-type protein and to an even larger impairment of the interaction with annexin VII and of the ability of sorcin to interact with and inhibit ryanodine receptors. These results provide a plausible structural and functional framework that helps elucidate the phenotypic alterations of mice overexpressing F112L-sorcin. PMID- 17699614 TI - Excess vacuolar SNAREs drive lysis and Rab bypass fusion. AB - Although concentrated soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) drive liposome fusion and lysis, the fusion of intracellular membranes also requires Rab GTPases, Rab effectors, SM proteins, and specific regulatory lipids and is accompanied by little or no lysis. To rationalize these findings, we generated yeast strains that overexpress all four vacuolar SNAREs (4SNARE(++)). Although vacuoles with physiological levels of Rab, Rab effector/SM complex, and SNAREs support rapid fusion without Rab- and SNARE dependent lysis, vacuoles from 4SNARE(++) strains show extensive lysis and a reduced need for the Rab Ypt7p or regulatory lipids for fusion. SNARE overexpression and the addition of pure homotypic fusion and vacuole protein sorting complex (HOPS), which bears the vacuolar SM protein, enables ypt7Delta vacuoles to fuse, allowing direct comparison of Rab-dependent and Rab-independent fusion. Because 3- to 40-fold more of each of the five components that form the SNARE/HOPS fusion complex are required for vacuoles from ypt7Delta strains to fuse at the same rate as vacuoles from wild-type strains, the apparent forward rate constant of 4SNARE/HOPS complex assembly is enhanced many thousand-fold by Ypt7p. Rabs function in normal membrane fusion by concentrating SNAREs, other proteins (e.g., SM), and key lipids at a fusion site and activating them for fusion without lysis. PMID- 17699615 TI - Experimental validation of Haldane's hypothesis on the role of infection as an evolutionary force for Metazoans. AB - A common drawback in evolutionary science is the fact that the evolution of organisms occurs in geological timing, completely out of the time scale of laboratory experimental work. For this reason, some relevant hypotheses on evolution of Metazoans are based on correlations more than on experimental data obtained for testing the robustness of those hypotheses. In the current work, we implement an experimental methodology to analyze the role of infections as a driving force in the evolution of Metazoans (Haldane's hypothesis). To that goal, we have used simple models of virulence with short reproduction times, large populations, and that are easily testable in the laboratory. Using the bacteriovirus nematode Caenorhabditis elegans as a model organism under evolution and their infection by the environmental opportunistic bacterial pathogen Pseudomonas aeruginosa as the selective force, we have demonstrated that bacterial infection selects an evolved nematode lineage resistant to infection, with changes in its respiration and capability of consuming novel food resources. Using an experimental approach, we show that infection is a selective force in the evolution of Metazoans as proposed earlier by Haldane. PMID- 17699616 TI - On the importance of a funneled energy landscape for the assembly and regulation of multidomain Src tyrosine kinases. AB - Regulation of signaling pathways in the cell often involves multidomain allosteric enzymes that are able to adopt alternate active or inactive conformations in response to specific stimuli. It is therefore of great interest to elucidate the energetic and structural determinants that govern the conformational plasticity of these proteins. In this study, free-energy computations have been used to address this fundamental question, focusing on one important family of signaling enzymes, the Src tyrosine kinases. Inactivation of these enzymes depends on the formation of an assembly comprising a tandem of SH3 and SH2 modules alongside a catalytic domain. Activation results from the release of the SH3 and SH2 domains, which are then believed to be structurally uncoupled by virtue of a flexible peptide link. In contrast to this view, this analysis shows that inactivation depends critically on the intrinsic propensity of the SH3 SH2 tandem to adopt conformations that are conducive to the assembled inactive state, even when no interactions with the rest of the kinase are possible. This funneling of the available conformational space is encoded within the SH3-SH2 connector, which appears to have evolved to modulate the flexibility of the tandem in solution. To further substantiate this notion, we show how constitutively activating mutations in the SH3-SH2 connector shift the assembly equilibrium toward the disassembled, active state. Based on a similar analysis of several constructs of the kinase complex, we propose that assembly is characterized by the progressive optimization of the protein's conformational energy, with little or no energetic frustration. PMID- 17699617 TI - Dissociation of the insulin receptor and caveolin-1 complex by ganglioside GM3 in the state of insulin resistance. AB - Membrane microdomains (lipid rafts) are now recognized as critical for proper compartmentalization of insulin signaling. We previously demonstrated that, in adipocytes in a state of TNFalpha-induced insulin resistance, the inhibition of insulin metabolic signaling and the elimination of insulin receptors (IR) from the caveolae microdomains were associated with an accumulation of the ganglioside GM3. To gain insight into molecular mechanisms behind interactions of IR, caveolin-1 (Cav1), and GM3 in adipocytes, we have performed immunoprecipitations, cross-linking studies of IR and GM3, and live cell studies using total internal reflection fluorescence microscopy and fluorescence recovery after photobleaching techniques. We found that (i) IR form complexes with Cav1 and GM3 independently; (ii) in GM3-enriched membranes the mobility of IR is increased by dissociation of the IR-Cav1 interaction; and (iii) the lysine residue localized just above the transmembrane domain of the IR beta-subunit is essential for the interaction of IR with GM3. Because insulin metabolic signal transduction in adipocytes is known to be critically dependent on caveolae, we propose a pathological feature of insulin resistance in adipocytes caused by dissociation of the IR-Cav1 complex by the interactions of IR with GM3 in microdomains. PMID- 17699618 TI - An inhibitor of viral RNA replication is encoded by a plant resistance gene. AB - The tomato Tm-1 gene confers resistance to tomato mosaic virus (ToMV). Here, we report that the extracts of Tm-1 tomato cells (GCR237) have properties that inhibit the in vitro RNA replication of WT ToMV more strongly than that of the Tm 1-resistance-breaking mutant of ToMV, LT1. We purified this inhibitory activity and identified a polypeptide of approximately 80 kDa (p80(GCR237)) using LC tandem MS. The amino acid sequence of p80(GCR237) had no similarity to any characterized proteins. The p80(GCR237) gene cosegregated with Tm-1; transgenic expression of p80(GCR237) conferred resistance to ToMV within tomato plants; and the knockdown of p80(GCR237) sensitized Tm-1 tomato plants to ToMV, indicating that Tm-1 encodes p80(GCR237) itself. We further show that in vitro-synthesized Tm-1 (p80(GCR237)) protein binds to the replication proteins of WT ToMV and inhibits their function at a step before, but not after, the viral replication complex is formed on the membrane surfaces. Such binding was not observed for the replication proteins of LT1. These results suggest that Tm-1 (p80(GCR237)) inhibits the replication of WT ToMV RNA through binding to the replication proteins. PMID- 17699619 TI - Propagation of large concentration changes in reversible protein-binding networks. AB - We study how the dynamic equilibrium of the reversible protein-protein-binding network in yeast Saccharomyces cerevisiae responds to large changes in abundances of individual proteins. The magnitude of shifts between free and bound concentrations of their immediate and more distant neighbors in the network is influenced by such factors as the network topology, the distribution of protein concentrations among its nodes, and the average binding strength. Our primary conclusion is that, on average, the effects of a perturbation are strongly localized and exponentially decay with the network distance away from the perturbed node, which explains why, despite globally connected topology, individual functional modules in such networks are able to operate fairly independently. We also found that under specific favorable conditions, realized in a significant number of paths in the yeast network, concentration perturbations can selectively propagate over considerable network distances (up to four steps). Such "action-at-a-distance" requires high concentrations of heterodimers along the path as well as low free (unbound) concentration of intermediate proteins. PMID- 17699620 TI - 8-Oxo-deoxyguanosine: reduce, reuse, recycle? PMID- 17699622 TI - Flexible energy storage devices based on nanocomposite paper. AB - There is strong recent interest in ultrathin, flexible, safe energy storage devices to meet the various design and power needs of modern gadgets. To build such fully flexible and robust electrochemical devices, multiple components with specific electrochemical and interfacial properties need to be integrated into single units. Here we show that these basic components, the electrode, separator, and electrolyte, can all be integrated into single contiguous nanocomposite units that can serve as building blocks for a variety of thin mechanically flexible energy storage devices. Nanoporous cellulose paper embedded with aligned carbon nanotube electrode and electrolyte constitutes the basic unit. The units are used to build various flexible supercapacitor, battery, hybrid, and dual-storage battery-in-supercapacitor devices. The thin freestanding nanocomposite paper devices offer complete mechanical flexibility during operation. The supercapacitors operate with electrolytes including aqueous solvents, room temperature ionic liquids, and bioelectrolytes and over record temperature ranges. These easy-to-assemble integrated nanocomposite energy-storage systems could provide unprecedented design ingenuity for a variety of devices operating over a wide range of temperature and environmental conditions. PMID- 17699623 TI - Functions of OsBZR1 and 14-3-3 proteins in brassinosteroid signaling in rice. AB - Brassinosteroids (BR) are essential growth hormones found throughout the plant kingdom. BR bind to the receptor kinase BRI1 on the cell surface to activate a signal transduction pathway that regulates nuclear gene expression and plant growth. To understand the downstream BR signaling mechanism in rice, we studied the function of OsBZR1 using reverse genetic approaches and identified OsBZR1 interacting proteins. Suppressing OsBZR1 expression by RNAi resulted in dwarfism, erect leaves, reduced BR sensitivity, and altered BR-responsive gene expression in transgenic rice plants, demonstrating an essential role of OsBZR1 in BR responses in rice. Moreover, a yeast two-hybrid screen identified 14-3-3 proteins as OsBZR1-interacting proteins. Mutation of a putative 14-3-3-binding site of OsBZR1 abolished its interaction with the 14-3-3 proteins in yeast and in vivo. Such mutant OsBZR1 proteins suppressed the phenotypes of the Arabidopsis bri1-5 mutant and showed an increased nuclear distribution compared with the wild-type protein, suggesting that 14-3-3 proteins directly inhibit OsBZR1 function at least in part by reducing its nuclear localization. These results demonstrate a conserved function of OsBZR1 and an important role of 14-3-3 proteins in brassinosteroid signal transduction in rice. PMID- 17699624 TI - Selective involvement of the mid-dorsolateral prefrontal cortex in the coding of the serial order of visual stimuli in working memory. AB - There is evidence that the primate prefrontal cortex is involved in the monitoring of the order in which stimuli occur. The prefrontal cortical areas, however, involved in the capacity of the human brain to encode and hold "in mind" the precise order of occurrence of a limited number of visual stimuli after a single exposure are not known. Changes in regional cerebral activity were measured with functional magnetic resonance imaging while subjects were coding the precise order of a short sequence of abstract visual stimuli. The results demonstrate the involvement of areas 46 and 9/46, within the mid-dorsolateral subdivision of the prefrontal cortex, in the coding of the precise order of a short sequence of visual stimuli in working memory, consistent with earlier results from monkey lesion studies. The availability of such detailed serial order information in working memory allows high-level cognitive planning and mental manipulation, functions that depend on prefrontal cortex. PMID- 17699625 TI - Membrane fusion as a team effort. PMID- 17699621 TI - Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. AB - The two primary human inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC), are idiopathic relapsing disorders characterized by chronic inflammation of the intestinal tract. Although several lines of reasoning suggest that gastrointestinal (GI) microbes influence inflammatory bowel disease (IBD) pathogenesis, the types of microbes involved have not been adequately described. Here we report the results of a culture-independent rRNA sequence analysis of GI tissue samples obtained from CD and UC patients, as well as non IBD controls. Specimens were obtained through surgery from a variety of intestinal sites and included both pathologically normal and abnormal states. Our results provide comprehensive molecular-based analysis of the microbiota of the human small intestine. Comparison of clone libraries reveals statistically significant differences between the microbiotas of CD and UC patients and those of non-IBD controls. Significantly, our results indicate that a subset of CD and UC samples contained abnormal GI microbiotas, characterized by depletion of commensal bacteria, notably members of the phyla Firmicutes and Bacteroidetes. Patient stratification by GI microbiota provides further evidence that CD represents a spectrum of disease states and suggests that treatment of some forms of IBD may be facilitated by redress of the detected microbiological imbalances. PMID- 17699626 TI - Chimps don't just get mad, they get even. PMID- 17699627 TI - Memory flies sooner from flies that learn faster. PMID- 17699628 TI - Unified model of tectonics and heat transport in a frigid Enceladus. AB - Recent data from the Cassini spacecraft have revealed that Enceladus, the 500-km diameter moon of Saturn, has a southern hemisphere with a distinct arrangement of tectonic features, intense heat flux, and geyser-like plumes. How did the tectonic features form? How is the heat transported from depth? To address these questions, we formulate a simple model that couples the mechanics and thermodynamics of Enceladus and gives a unified explanation of the salient tectonic features, the plumes, and the transport of heat from a source at a depth of tens of kilometers to the surface. Our findings imply that tiny, icy moons can develop complex surficial geomorphologies, high heat fluxes, and geyser-like activity even if they do not have hot, liquid, and/or convecting interiors. PMID- 17699629 TI - The role of fluctuations in tRNA selection by the ribosome. AB - The detailed mechanism of how the ribosome decodes protein sequence information with an abnormally high accuracy, after 40 years of study, remains elusive. A critical element in selecting correct transfer RNA (tRNA) transferring correct amino acid is "induced fit" between the ribosome and tRNA. By using single molecule methods, the induced fit mechanism is shown to position favorably the correct tRNA after initial codon recognition. We provide evidence that this difference in positioning and thermal fluctuations constitutes the primary mechanism for the initial selection of tRNA. This work demonstrates thermal fluctuations playing a critical role in the substrate selection by an enzyme. PMID- 17699630 TI - Encroaching forests decouple alpine butterfly population dynamics. AB - Over the past 50 years, the rising tree line along Jumpingpound Ridge in the Rocky Mountains of Alberta, Canada, has reduced the area of alpine meadows and isolated populations that reside within them. By analyzing an 11-year data set of butterfly population sizes for 17 subpopulations along the ridge, we show that forest habitat separating alpine meadows decouples the dynamics of populations of the alpine butterfly Parnassius smintheus. Although the distance between populations is often negatively correlated with synchrony of dynamics, here we show that distance through forest, not Euclidean distance, determines the degree of synchrony. This effect is consistent with previous results demonstrating that encroaching forest reduces dispersal among populations and reduces gene flow. Decoupling dynamics produces more smaller independent populations, each with greater risk of local extinction, but decoupling may produce a lower risk of regional extinction in this capricious environment. PMID- 17699631 TI - Role of purine-rich exonic splicing enhancers in nuclear retention of pre-mRNAs. AB - Intron-containing pre-mRNAs are normally retained in the nucleus until they are spliced to produce mature mRNAs that are exported to the cytoplasm. Although the detailed mechanism is not well understood, the formation of splicing-related complexes on pre-mRNAs is thought to be responsible for the nuclear retention. Therefore, pre-mRNAs containing suboptimal splice sites should tend to leak out to the cytoplasm. Such pre-mRNAs often contain purine-rich exonic splicing enhancers (ESEs) that stimulate splicing of the adjacent intron. Here, we show that ESEs per se possess an activity to retain RNAs in the nucleus through a saturable nuclear retention factor. Cross-competition experiments revealed that intron-containing pre-mRNAs (without ESEs) used the same saturable nuclear retention factor as ESEs. Interestingly, although intronless mRNAs containing ESEs were also poorly exported, spliced mRNAs produced from ESE-containing pre mRNAs were efficiently exported to the cytoplasm. Thus, the splicing reaction can reset the nuclear retention state caused by ESEs, allowing nuclear export of mature mRNAs. Our results reveal a novel aspect of ESE activity that should contribute to gene expression and RNA quality control. PMID- 17699632 TI - Lack of CD47 on nonhematopoietic cells induces split macrophage tolerance to CD47null cells. AB - Macrophages recognize CD47 as a marker of "self" and phagocytose CD47(null) hematopoietic cells. Using CD47 chimera models, here, we show that the phagocytic activity of macrophages against CD47(null) hematopoietic cells is conferred by CD47 expression on nonhematopoietic cells, and this "education" process is hematopoietic cell-independent. Macrophages in the chimeras where nonhematopoietic cells express CD47 phagocytose CD47(null) cells, whereas those in the chimeras lacking CD47 on nonhematopoietic cells are tolerant to CD47(null) cells. However, macrophages in the latter chimeras retain phagocytic activity against CD47(null) RBCs, demonstrating a split macrophage tolerance to CD47(null) hematopoietic cells. The findings highlight the potential importance of nonhematopoietic cells in the regulation of macrophage function, and suggest a previously uncharacterized mechanism of macrophage tolerance. PMID- 17699633 TI - Polaron melting and ordering as key mechanisms for colossal resistance effects in manganites. AB - Polarons, the combined motion of electrons in a cloth of their lattice distortions, are a key transport feature in doped manganites. To develop a profound understanding of the colossal resistance effects induced by external fields, the study of polaron correlations and the resulting collective polaron behavior, i.e., polaron ordering and transition from polaronic transport to metallic transport is essential. We show that static long-range ordering of Jahn Teller polarons forms a polaron solid which represents a new type of charge and orbital ordered state. The related noncentrosymmetric lattice distortions establish a connection between colossal resistance effects and multiferroic properties, i.e., the coexistence of ferroelectric and antiferromagnetic ordering. Colossal resistance effects due to an electrically induced polaron solid-liquid transition are directly observed in a transmission electron microscope with local electric stimulus applied in situ using a piezo-controlled tip. Our results shed light onto the colossal resistance effects in magnetic field and have a strong impact on the development of correlated electron-device applications such as resistive random access memory (RRAM). PMID- 17699634 TI - The crystal structure of the third signal-recognition particle GTPase FlhF reveals a homodimer with bound GTP. AB - Flagella are well characterized as the organelles of locomotion and allow bacteria to react to environmental changes. The assembly of flagella is a multistep process and relies on a complex type III export machinery located in the cytoplasmic membrane. The FlhF protein is essential for the placement and assembly of polar flagella and has been classified as a signal-recognition particle (SRP)-type GTPase. SRP GTPases appeared early in evolution and form a unique subfamily within the guanine nucleotide binding proteins with only three members: the signal sequence-binding protein SRP54, the SRP receptor FtsY, and FlhF. We report the crystal structures of FlhF from Bacillus subtilis in complex with GTP and GMPPNP. FlhF shares SRP GTPase-specific features such as the presence of an N-terminal alpha-helical domain and the I-box insertion. It forms a symmetric homodimer sequestering a composite active site that contains two head to-tail arranged nucleotides similar to the heterodimeric SRP-targeting complex. However, significant differences to the GTPases of SRP and the SRP receptor include the formation of a stable homodimer with GTP as well as severe modifications and even the absence of motifs involved in regulation of the other two SRP GTPases. Our results provide insights into SRP GTPases and their roles in two fundamentally different protein-targeting routes that both rely on efficient protein delivery to a secretion channel. PMID- 17699635 TI - A novel method using fluorescence microscopy for real-time assessment of ATP release from individual cells. AB - Many cell types release ATP in response to mechanical or biochemical stimulation. The mechanisms responsible for this release, however, are not well understood and may differ among different cell types. In addition, there are numerous difficulties associated with studying the dynamics of ATP release immediately outside the cell membrane. Here, we report a new method that allows the visualization and quantification of ATP release by fluorescence microscopy. Our method utilizes a two-enzyme system that generates NADPH when ATP is present. NADPH is a fluorescent molecule that can be visualized by fluorescence microscopy using an excitation wavelength of 340 nm and an emission wavelength of 450 nm. The method is capable of detecting ATP concentrations <1 microM and has a dynamic range of up to 100 microM. Using this method, we visualized and quantified ATP release from human polymorphonuclear leukocytes and Jurkat T cells. We show that upon cell stimulation, the concentrations of ATP can reach levels of up to 80 microM immediately outside of the cell membrane. This new method should prove useful for the study of the mechanisms of release and functional role of ATP in various cell systems, including individual cells. PMID- 17699636 TI - Functional ion channels in mouse bone marrow mesenchymal stem cells. AB - Bone marrow mesenchymal stem cells (MSCs) are used as a cell source for cardiomyoplasty; however, the cellular electrophysiological properties are not fully understood. The present study was to investigate the functional ionic channels in undifferentiated mouse bone marrow MSCs using whole cell patch voltage clamp technique, RT-PCR, and Western immunoblotting analysis. We found that three types of ionic currents were present in mouse MSCs, including a Ca(2+) activated K(+) current (I(KCa)), an inwardly rectifying K(+) current (I(Kir)), and a chloride current (I(Cl)). I(Kir) was inhibited by Ba(2+), and I(KCa) was activated by the Ca(2+) ionophore A-23187 and inhibited by the intermediate conductance I(KCa) channel blocker clotrimazole. I(Cl) was activated by hyposmotic (0.8 T) conditions and inhibited by the chloride channel blockers DIDS and NPPB. The corresponding ion channel genes and proteins, KCa3.1 for I(KCa), Kir2.1 for I(Kir), and Clcn3 for I(Cl), were confirmed by RT-PCR and Western immunoblotting analysis in mouse MSCs. These results demonstrate that three types of functional ion channel currents (i.e., I(Kir), I(KCa), and I(Cl)) are present in mouse bone marrow MSCs. PMID- 17699637 TI - Transepithelial bioelectrical properties of rabbit acinar cell monolayers on polyester membrane scaffolds. AB - In our quest to develop a tissue-engineered tear secretory system, we have tried to demonstrate active transepithelial ion fluxes across rabbit lacrimal acinar cell monolayers on polyester membrane scaffolds to evaluate the bioelectrical properties of the cultured cells. Purified lacrimal gland acinar cells were seeded onto polyester membrane inserts and cultured to confluency. Morphological properties of the cell monolayers were evaluated by transmission electron microscopy and immunofluorescence staining for Na(+),K(+)-ATPase and the tight junction-associated protein occludin. Sections revealed cell monolayers with well maintained epithelial cell polarity, i.e., presence of apical (AP) secretory granules, microvilli, and junctional complexes. Na(+),K(+)-ATPase was localized on both the basal-lateral and apical plasma membranes. The presence of tight cell junctions was demonstrated by a positive circumferential stain for occludin. Bioelectrical properties of the cell monolayers were studied in Ussing chambers under short-circuit conditions. Active ion fluxes were evaluated by inhibiting the short-circuit current (I(sc)) with a Na(+),K(+)-ATPase inhibitor, ouabain (100 microM; basal-lateral, BL), and under Cl(-)-free buffer conditions after carbachol stimulation (CCh; 100 microM). The directional apical secretion of Cl( ) was demonstrated through pharmacological analysis, using amiloride (1 mM; BL) and bumetanide (0.1 mM; BL), respectively. Regulated protein secretion was evaluated by measuring the beta-hexosaminidase catalytic activity in the AP culture medium in response to 100 microM basal CCh. In summary, rabbit lacrimal acinar cell monolayers generate a Cl(-)-dependent, ouabain-sensitive AP --> BL I(sc) in response to CCh, consistent with current models for Na(+)-dependent Cl( ) secretion. PMID- 17699638 TI - Differential effects of volatile and intravenous anesthetics on the activity of human TASK-1. AB - Volatile anesthetics have been shown to activate various two-pore (2P) domain K(+) (K(2P)) channels such as TASK-1 and TREK-1 (TWIK-related acid-sensitive K(+) channel), and mice deficient in these channels are resistant to halothane-induced anesthesia. Here, we investigated whether K(2P) channels were also potentially important targets of intravenous anesthetics. Whole cell patch-clamp techniques were used to determine the effects of the commonly used intravenous anesthetics etomidate and propofol on the acid-sensitive K(+) current in rat ventricular myocytes (which strongly express TASK-1) and selected human K(2P) channels expressed in Xenopus laevis oocytes. In myocytes, etomidate decreased both inward rectifier K(+) (K(ir)) current (I(K1)) and acid-sensitive outward K(+) current at positive potentials, suggesting that this drug may inhibit TASK channels. Indeed, in addition to inhibiting guinea pig Kir2.1 expressed in oocytes, etomidate inhibited human TASK-1 (and TASK-3) in a concentration-dependent fashion. Propofol had no effect on human TASK-1 (or TASK-3) expressed in oocytes. Moreover, we showed that, similar to the known effect of halothane, sevoflurane and the purified R-(-)- and S-(+)-enantiomers of isoflurane, without stereoselectivity, activated human TASK-1. We conclude that intravenous and volatile anesthetics have dissimilar effects on K(2P) channels. Human TASK-1 (and TASK-3) are insensitive to propofol but are inhibited by supraclinical concentrations of etomidate. In contrast, stimulatory effects of sevoflurane and enantiomeric isoflurane on human TASK-1 can be observed at clinically relevant concentrations. PMID- 17699639 TI - Seroepidemiology of human bocavirus in Hokkaido prefecture, Japan. AB - A new human virus, provisionally named human bocavirus (HBoV), was discovered by Swedish researchers in 2005. A new immunofluorescence assay using Trichoplusia ni insect cells infected with a recombinant baculovirus expressing the VP1 protein of HBoV was developed, and the levels of immunoglobulin G antibody to the VP1 protein of HBoV in serum samples were measured. The overall seroprevalence rate of antibodies against the VP1 protein of HBoV in a Japanese population aged from 0 months to 41 years was 71.1% (145 of 204). The seropositive rate was lowest in the age group of 6 to 8 months and gradually increased with age. All of the children had been exposed to HBoV by the age of 6 years. A rise in titers of antibody against the VP1 protein of HBoV during the convalescent phase was observed for four patients with lower respiratory tract infections, and HBoV DNA was detected in nasopharyngeal swab and serum samples from all four patients. These results suggest that HBoV is a ubiquitous virus acquired early in life and that HBoV might play a role in the course of lower respiratory tract infections. PMID- 17699640 TI - Presence of region of difference 1 among clinical isolates of Mycobacterium tuberculosis from India. PMID- 17699641 TI - Analysis of group B streptococcal isolates from infants and pregnant women in Portugal revealing two lineages with enhanced invasiveness. AB - The populations of group B streptococcus (GBS) associated with vaginal carriage in pregnant women and invasive neonatal infections in Portugal were compared. GBS isolates were characterized by serotyping, pulsed-field gel electrophoresis (PFGE) profiling, and multilocus sequence typing (MLST). Serotypes III and V accounted for 44% of all colonization isolates (n = 269), whereas serotypes III and Ia amounted to 69% of all invasive isolates (n = 64). Whereas serotype Ia was associated with early-onset disease (EOD), serotype III was associated with late onset disease (LOD). Characterization by PFGE and MLST identified very diverse populations in carriage and invasive disease. Serotype Ia was represented mainly by a single PFGE cluster defined by sequence type 23 (ST23) and the infrequent ST24. In contrast, serotype III was found in a large number of PFGE clusters and STs, but a single PFGE cluster defined by ST17 was found to be associated with invasive disease. Although serotype III was associated only with LOD, ST17 showed an enhanced capacity to cause both EOD and LOD. Our data reinforce the evidence for enhanced invasiveness of ST17 and identify a lineage expressing serotype Ia capsule and represented by ST23 and ST24 as having enhanced potential to cause EOD. PMID- 17699642 TI - Capsule gene analysis of invasive Haemophilus influenzae: accuracy of serotyping and prevalence of IS1016 among nontypeable isolates. AB - We evaluated the accuracy of serologic capsule typing by analyzing capsule genes and related markers among invasive Haemophilus influenzae isolates before and after the introduction of H. influenzae serotype b (Hib) conjugate vaccines. Three hundred and sixty invasive H. influenzae isolates were collected as part of Active Bacterial Core surveillance within the Georgia Emerging Infections Program between 1 January 1989 and 31 July 1998. All isolates were biotyped, serotyped by slide agglutination serotyping (SAST), and evaluated using PCR capsule typing. Nontypeable H. influenzae (NTHi) isolates were probed with Hib cap-gene containing plasmid pUO38 and with IS1016; a subset was examined with phosphoglucose isomerase (pgi) genotyping and pulsed-field gel electrophoresis (PFGE). Discrepancies between SAST and PCR capsule typing were found for 64/360 (17.5%) of the isolates; 48 encapsulated by SAST were NTHi by PCR, 8 NTHi by SAST were encapsulated by PCR, 6 encapsulated by SAST were a different capsule type by PCR, and 2 encapsulated by SAST were capsule-deficient Hib variants (Hib-minus). None of the PCR-confirmed NTHi isolates demonstrated homology with residual capsule gene sequences; 19/201 (9.5%) had evidence of IS1016, an insertion element associated with division I H. influenzae capsule serotypes. The majority of IS1016-positive NTHi were biotypes I and V and showed some genetic relatedness by PFGE. In conclusion, PCR capsule typing was more accurate than SAST and Hib minus variants were rare. IS1016 was present in 9.5% of NTHi isolates, suggesting that this subset may be more closely related to encapsulated organisms. A better understanding of NTHi may contribute to vaccine development. PMID- 17699643 TI - Large sequence polymorphisms classify Mycobacterium tuberculosis strains with ancestral spoligotyping patterns. AB - Genomic deletion analysis revealed that strains of Mycobacterium tuberculosis exhibiting spoligotyping patterns with almost all spacers present belong either to a strain lineage that includes the W-Beijing strain family or to the ancestral strain lineage of M. tuberculosis. PMID- 17699644 TI - Human papillomavirus (HPV) genotyping using paired exfoliated cervicovaginal cells and paraffin-embedded tissues to highlight difficulties in attributing HPV types to specific lesions. AB - Defining type-specific human papillomavirus (HPV) infections within cervical tissues is important for understanding the pathogenesis of cervical neoplasia and assessing the effectiveness of prophylactic vaccines with limited type-specific spectra. We compared HPV DNA-testing results from 146 matched exfoliated-cell and formalin-fixed-tissue specimens collected by cervicovaginal lavage (CVL) within 90 days of each other from women with histologically confirmed cervical intraepithelial lesions (CIN). The CVL specimens were HPV typed using a MY09/11 L1 consensus primer PCR method followed by dot blot hybridization. The tissue specimens were HPV typed using an SPF(10) line probe assay HPV detection system. Of the 146 specimen pairs with evidence of CIN in the tissue, 91.8% were positive for one or more HPV types in both the tissue and cellular specimens. Tissue sections were more likely to be HPV negative (P < 0.01). Typing directly from tissue sections resolved multiple infections detected in exfoliated cells to a single HPV type in only 46.9% of cases. Combined use of both specimen types to attribute lesions to HPV type 16 (HPV-16) and/or -18 led to 43.1% attributed to HPV-16 and/or -18 by both specimen types and 19.9% attributed to HPV-16 and/or 18 by one, but not both, specimen types. Unambiguous attribution of cervical lesions to a single, specific HPV type remains a difficult proposition. Use of multiple specimen types or the development of highly sensitive and robust in situ hybridization HPV-testing methods to evaluate the certainty of attribution of lesions to HPV types might provide insights in future efforts, including HPV vaccine trials. PMID- 17699645 TI - Validation of nasopharyngeal sampling and culture techniques for detection of Streptococcus pneumoniae in children in Kenya. AB - We compared nasopharyngeal swabs against nasal wash cultures for detecting colonizing pneumococci and examined the effect of frozen storage in skim milk tryptone-glucose-glycerin on culture. Among the 55 children with positive nasal wash cultures, swab cultures were positive for 47 (85%). Of the 96 swabs positive on direct plating, 94 (98%) were positive when recultured after freezing. PMID- 17699647 TI - Peritonitis due to Blastobotrys proliferans in a patient undergoing continuous ambulatory peritoneal dialysis. AB - Blastobotrys proliferans is an ascomycetous yeast never previously reported as a human pathogen. Here we report a case of peritonitis due to Blastobotrys proliferans in a 46-year-old man undergoing peritoneal dialysis. PMID- 17699646 TI - Bordetella pertussis strains circulating in Europe in 1999 to 2004 as determined by pulsed-field gel electrophoresis. AB - Clinical isolates of Bordetella pertussis collected during the year 2004 (n = 153) in eight European countries, Denmark, Finland, France, Germany, The Netherlands, Poland, Sweden, and United Kingdom, were analyzed by pulsed-field gel electrophoresis (PFGE), and their PFGE profiles were compared with those of isolates collected in 1999 (n = 102). The 255 isolates produced 59 distinct PFGE profiles. Among the 153 isolates from 2004, 36 profiles were found, while within the 102 isolates from 1999, 33 profiles were detected. One PFGE profile, BpSR11, was dominant (30% to 50%) in all countries except Denmark (10%) and Poland (0%). In comparison with 1999, there was an increase in BpSR11 prevalence in Finland in 2004 from 5% to 40%, coinciding with a major incidence peak. Some other PFGE profiles seemed to be associated with limited dissemination. Poland was the only country in which the most common actual European PFGE profiles were not found. In a dendrogram analysis, all common PFGE profiles were identified within PFGE group IV, and BpSR11 clustered together with PFGE subgroup IVbeta. Compared to the 1999 isolates, PFGE group V representative for pertactin variant prn3 strains had disappeared, and a new cluster was seen. In conclusion, some PFGE profiles, such as BpSR11, evidently have a higher capacity to spread, suggesting increased fitness to the present immunological environment. It is therefore of major interest to continue with surveillance programs of B. pertussis isolates, as both waning vaccine-derived immunity and strain variation may play a role in the persistence of pertussis. PMID- 17699649 TI - Bacteremia due to clonally derived methicillin-resistant, gentamicin-susceptible isolates and methicillin-susceptible, gentamicin-resistant isolates of Staphylococcus aureus. AB - We report recurrent bacteremia due to mixed infection with two clonally derived isolates of Staphylococcus aureus in a patient with Sezary syndrome. The two isolates, one gentamicin resistant and methicillin susceptible and the other gentamicin susceptible and methicillin resistant, developed by the deletion of the mecA, ant(4')Ia, and aacA-aphD genes from a common gentamicin-resistant and methicillin-susceptible ancestor. PMID- 17699648 TI - Case of keratitis caused by Aspergillus tamarii. AB - We report a case of Aspergillus tamarii keratitis. Ocular injury was known to be a predisposing factor. Topical natamycin and econazole treatment and subsequent systemic ketoconazole treatment proved effective. The isolate was identified by morphological characteristics and sequence analysis as A. tamarii, a member of Aspergillus section Flavi not hitherto reported from keratomycosis. PMID- 17699650 TI - Large-scale human immunodeficiency virus rapid test evaluation in a low prevalence ugandan blood bank population. AB - The use of rapid tests for human immunodeficiency virus (HIV) has become standard in HIV testing algorithms employed in resource-limited settings. We report an extensive HIV rapid test validation study conducted among Ugandan blood bank donors at low risk for HIV infection. The operational characteristics of four readily available commercial HIV rapid test kits were first determined with 940 donor samples and were used to select a serial testing algorithm. Uni-Gold Recombigen HIV was used as the screening test, followed by HIV-1/2 STAT-PAK for reactive samples. OraQuick HIV-1 testing was performed if the first two test results were discordant. This algorithm was then tested with 5,252 blood donor samples, and the results were compared to those of enzyme immunoassays (EIAs) and Western blotting. The unadjusted algorithm sensitivity and specificity were 98.6 and 99.9%, respectively. The adjusted sensitivity and specificity were 100 and 99.96%, respectively. This HIV testing algorithm is a suitable alternative to EIAs and Western blotting for Ugandan blood donors. PMID- 17699651 TI - Evaluation of the BD ProbeTec ET system for direct detection of Mycobacterium bovis in veterinary specimens. AB - We describe the application of the BD ProbeTec ET direct tuberculosis system for the detection of Mycobacterium bovis in bovine and cervine lymph node tissues. Compared to traditional culture, the overall sensitivity, specificity, and positive and negative predictive values of the BD ProbeTec were 87, 100, 100, and 87%, respectively. PMID- 17699652 TI - Clinical evaluation of the microscopic observation drug susceptibility assay for detection of Mycobacterium tuberculosis resistance to isoniazid or rifampin. AB - This prospective study evaluated the performance of the microscopic observation drug susceptibility (MODS) assay for the direct detection of Mycobacterium tuberculosis drug resistance. MODS assay sensitivity, specificity, and positive and negative predictive values were 96.7% (95% confidence interval [95% CI], 92.1 to 98.8%), 78.4% (95% CI, 73.5 to 80.6%), 82.4% (95% CI, 78.4 to 84.2%), and 95.8% (95% CI, 89.9 to 98.5%), respectively, for isoniazid resistance and 96.0% (95% CI, 90.3 to 98.6%), 82.9% (95% CI, 78.8 to 84.7%), 80.0% (95% CI, 75.2 to 82.1%), and 96.7% (95% CI, 91.9 to 98.8%), respectively, for rifampin resistance. For both rifampin and isoniazid testing, the likelihood ratio for a negative test was < or =0.05, indicating that the MODS assay may be useful for ruling out drug resistance. PMID- 17699653 TI - Strategic approach to produce low-cost, efficient, and stable competitive internal controls for detection of RNA viruses by use of reverse transcription PCR. AB - Molecular diagnostics based on reverse transcription (RT)-PCR are routinely complicated by the lack of stable internal controls, leading to falsely negative results. We describe a strategy to produce a stable competitive internal control (CIC) based on a Qbeta phage derivative (recombinant Qbeta [rQbeta]) bearing primers KY78 and KY80, which are widely used in the detection of hepatitis C virus (HCV). rQbeta was RNase resistant and stable at 4 degrees C for 452 days in SM medium (0.1 M NaCl, 8 mM MgSO(4).7H(2)O, 50 mM Tris HCl [pH 7.5], 2% gelatin) and for 125 days after lyophilization and reconstitution. rQbeta performance as a CIC was evaluated. rQbeta was added to HCV-positive samples, followed by RNA extraction and a CIC-HCV RT-PCR assay. This method combines RT-PCR, liquid hybridization with nonradioactive probes, and enzyme immunoanalysis. No influence of the CIC on qualitative HCV detection was observed independently of viral load, and results had high concordance with those of commercial kits. In conclusion, we describe a versatile, low-cost alternative strategy to armored RNA technology that can be adapted for detection or real-time applications of any RNA target. Moreover, the CIC reported here is an essential reagent for HCV screening in blood banks in resource-limited settings. PMID- 17699654 TI - Multiple-locus variable-number tandem-repeat analysis for longitudinal survey of sources of Pseudomonas aeruginosa infection in cystic fibrosis patients. AB - In order to identify the source of infection by Pseudomonas aeruginosa in patients with cystic fibrosis (CF), systematic genotyping of isolates is necessary. Multiple-locus variable-number tandem-repeat (VNTR) analysis (MLVA) was used to survey the sources of P. aeruginosa infections in a French (Paris, France) pediatric CF center. Between January 2004 and December 2006, 108 patients ages 2 to 21 years who were regularly monitored at the center provided sputum for culture. P. aeruginosa was detected in 46 children, 17 of whom had primary colonization. A total of 163 isolates were recovered. MLVA was improved from a previously published method by the addition of new, informative, and easily typeable markers. Upon genotyping with 15 VNTRs, a total of 39 lineages composed of indistinguishable or closely related isolates, were observed. One of them corresponds to "clone C," which is widely distributed in Europe, and another corresponds to reference strain PA14. Six patients were colonized with two different strains, and the remaining 40 patients were colonized with a single strain. Strains from seven lineages were shared by at least two and up to four patients among a total of 20 patients. The study demonstrates that MLVA is an efficient, easy, and rapid molecular method for epidemiological surveillance for P. aeruginosa infection. The resulting data and strain genetic profiles can be queried on http://bacterial-genotyping.igmors.u-psud.fr. PMID- 17699655 TI - Pichia farinosa bloodstream infection in a lymphoma patient. AB - We describe a case of Pichia farinosa bloodstream infection in a lymphoma patient. Phenotypic methods failed to identify the isolate, which was identified by sequence-based methods. This case highlights the importance of implementing molecular methods for the identification of rare fungal pathogens. PMID- 17699656 TI - Evaluation of pan-dermatophyte nested PCR in diagnosis of onychomycosis. AB - In this study, nested PCR using novel primers targeting the pan-dermatophyte specific sequence of the chitin synthase 1 gene (CHS1) was compared with KOH microscopy, culture isolation, and single-round PCR for diagnosis of 152 patients with clinically suspected onychomycosis. Results indicate that nested PCR may be considered the gold standard for the diagnosis of cases of onychomycosis for which the etiological agents are dermatophytes. PMID- 17699657 TI - Calcineurin in reactive astrocytes plays a key role in the interplay between proinflammatory and anti-inflammatory signals. AB - Maladaptive inflammation is a major suspect in progressive neurodegeneration, but the underlying mechanisms are difficult to envisage in part because reactive glial cells at lesion sites secrete both proinflammatory and anti-inflammatory mediators. We now report that astrocytes modulate neuronal resilience to inflammatory insults through the phosphatase calcineurin. In quiescent astrocytes, inflammatory mediators such as tumor necrosis factor-alpha (TNF alpha) recruits calcineurin to stimulate a canonical inflammatory pathway involving the transcription factors nuclear factor kappaB (NFkappaB) and nuclear factor of activated T-cells (NFAT). However, in reactive astrocytes, local anti inflammatory mediators such as insulin-like growth factor I also recruit calcineurin but, in this case, to inhibit NFkappaB/NFAT. Proof of concept experiments in vitro showed that expression of constitutively active calcineurin in astrocytes abrogated the inflammatory response after TNF-alpha or endotoxins and markedly enhanced neuronal survival. Furthermore, regulated expression of constitutively active calcineurin in astrocytes markedly reduced inflammatory injury in transgenic mice, in a calcineurin-dependent manner. These results suggest that calcineurin forms part of a molecular pathway whereby reactive astrocytes determine the outcome of the neuroinflammatory process by directing it toward either its resolution or its progression. PMID- 17699658 TI - The sources of variability in saccadic eye movements. AB - Our movements are variable, but the origin of this variability is poorly understood. We examined the sources of variability in human saccadic eye movements. In two experiments, we measured the spatiotemporal variability in saccade trajectories as a function of movement direction and amplitude. One of our new observations is that the variability in movement direction is smaller for purely horizontal and vertical saccades than for saccades in oblique directions. We also found that saccade amplitude, duration, and peak velocity are all correlated with one another. To determine the origin of the observed variability, we estimated the noise in motor commands from the observed spatiotemporal variability, while taking into account the variability resulting from uncertainty in localization of the target. This analysis revealed that uncertainty in target localization is the major source of variability in saccade endpoints, whereas noise in the magnitude of the motor commands explains a slightly smaller fraction. In addition, there is temporal variability such that saccades with a longer than average duration have a smaller than average peak velocity. This noise model has a large generality because it correctly predicts the variability in other data sets, which contain saccades starting from very different initial locations. Because the temporal noise most likely originates in movement planning, and the motor command noise in movement execution, we conclude that uncertainty in sensory signals and noise in movement planning and execution all contribute to the variability in saccade trajectories. These results are important for understanding how the brain controls movement. PMID- 17699659 TI - Enhanced nicotinic receptor function and drug abuse vulnerability. AB - In animals and humans, vulnerability to drug abuse varies among individuals. Animals that display high activity levels in a novel environment are more likely to self-administer psychostimulant drugs, including nicotine, cocaine, amphetamine, and morphine. Recent reports from behavioral studies indicate that nicotinic acetylcholine receptor (nAChR) activity contributes to the rewarding effects of several different addictive drugs. Thus, we hypothesized that differences in nAChR activity may contribute to the predisposition to drug self administration. After screening of adult rats (>60 d postnatal) for the behavioral response to a novel environment, electrophysiological measures of nAChR function were conducted in brain slices that included the mesoaccumbens dopamine neurons of the ventral tegmental area (VTA). We found a positive correlation between the response to novelty and nAChR function in each assay conducted, including nAChR modulation of glutamatergic and GABAergic synaptic inputs to VTA dopamine neurons, as well as somatic nAChR responses of VTA neurons. The response to novelty and sensitivity to addictive drugs are positively correlated with the hormonal response to stress. Consistent with this observation, we found enhanced nAChR responses in vitro after a 48 h corticosterone treatment and in vivo after 48 h of repeated stress. Each of these effects was inhibited by RU486 (11beta-[p-(dimethylamino)phenyl]-17beta-hydroxy 17-(1-propynyl)estra-4,9-dien-3-one) pretreatment, suggesting a steroid hormone receptor-dependent process. These findings suggest that differences in nAChR function within the mesoaccumbens dopamine system may contribute to individual differences in drug abuse vulnerability and that these are likely attributable to differences in stress hormone levels. PMID- 17699660 TI - Progressive motor neuronopathy: a critical role of the tubulin chaperone TBCE in axonal tubulin routing from the Golgi apparatus. AB - Axonal degeneration represents one of the earliest pathological features in motor neuron diseases. We here studied the underlying molecular mechanisms in progressive motor neuronopathy (pmn) mice mutated in the tubulin-specific chaperone TBCE. We demonstrate that TBCE is a peripheral membrane-associated protein that accumulates at the Golgi apparatus. In pmn mice, TBCE is destabilized and disappears from the Golgi apparatus of motor neurons, and microtubules are lost in distal axons. The axonal microtubule loss proceeds retrogradely in parallel with the axonal dying back process. These degenerative changes are inhibited in a dose-dependent manner by transgenic TBCE complementation that restores TBCE expression at the Golgi apparatus. In cultured motor neurons, the pmn mutation, interference RNA-mediated TBCE depletion, and brefeldin A-mediated Golgi disruption all compromise axonal tubulin routing. We conclude that motor axons critically depend on axonal tubulin routing from the Golgi apparatus, a process that involves TBCE and possibly other tubulin chaperones. PMID- 17699661 TI - Neuronal diversity in GABAergic long-range projections from the hippocampus. AB - The formation and recall of sensory, motor, and cognitive representations require coordinated fast communication among multiple cortical areas. Interareal projections are mainly mediated by glutamatergic pyramidal cell projections; only few long-range GABAergic connections have been reported. Using in vivo recording and labeling of single cells and retrograde axonal tracing, we demonstrate novel long-range GABAergic projection neurons in the rat hippocampus: (1) somatostatin- and predominantly mGluR1alpha-positive neurons in stratum oriens project to the subiculum, other cortical areas, and the medial septum; (2) neurons in stratum oriens, including somatostatin-negative ones; and (3) trilaminar cells project to the subiculum and/or other cortical areas but not the septum. These three populations strongly increase their firing during sharp wave-associated ripple oscillations, communicating this network state to the septotemporal system. Finally, a large population of somatostatin-negative GABAergic cells in stratum radiatum project to the molecular layers of the subiculum, presubiculum, retrosplenial cortex, and indusium griseum and fire rhythmically at high rates during theta oscillations but do not increase their firing during ripples. The GABAergic projection axons have a larger diameter and thicker myelin sheet than those of CA1 pyramidal cells. Therefore, rhythmic IPSCs are likely to precede the arrival of excitation in cortical areas (e.g., subiculum) that receive both glutamatergic and GABAergic projections from the CA1 area. Other areas, including the retrosplenial cortex, receive only rhythmic GABAergic CA1 input. We conclude that direct GABAergic projections from the hippocampus to other cortical areas and the septum contribute to coordinating oscillatory timing across structures. PMID- 17699662 TI - Constitutive excitation by Gly90Asp rhodopsin rescues rods from degeneration caused by elevated production of cGMP in the dark. AB - Previous experiments indicate that congenital human retinal degeneration caused by genetic mutations that change the Ca(2+) sensitivity of retinal guanylyl cyclase (retGC) can result from an increase in concentration of free intracellular cGMP and Ca(2+) in the photoreceptors. To rescue degeneration in transgenic mouse models having either the Y99C or E155G mutations of the retGC modulator guanylyl cyclase-activating protein 1 (GCAP-1), which produce elevated cGMP synthesis in the dark, we used the G90D rhodopsin mutation, which produces constitutive stimulation of cGMP hydrolysis. The effects of the G90D transgene were evaluated by measuring retGC activity biochemically, by recording single rod and electroretinogram (ERG) responses, by intracellular free Ca(2+) measurement, and by retinal morphological analysis. Although the G90D rhodopsin did not alter the abnormal Ca(2+) sensitivity of retGC in the double-mutant animals, the intracellular free cGMP and Ca(2+) concentrations returned close to normal levels, consistent with constitutive activation of the phosphodiesterase PDE6 cascade in darkness. G90D decreased the light sensitivity of rods but spared them from severe retinal degeneration in Y99C and E155G GCAP-1 mice. More than half of the photoreceptors remained alive, appeared morphologically normal, and produced electrical responses, at the time when their siblings lacking the G90D rhodopsin transgene lost the entire retinal outer nuclear layer and no longer responded to illumination. These experiments indicate that mutations that lead to increases in cGMP and Ca(2+) can trigger photoreceptor degeneration but that constitutive activation of the transduction cascade in these animals can greatly enhance cell survival. PMID- 17699663 TI - Long-term consequences of methamphetamine exposure in young adults are exacerbated in glial cell line-derived neurotrophic factor heterozygous mice. AB - Methamphetamine abuse in young adults has long-term deleterious effects on brain function that are associated with damage to monoaminergic neurons. Administration of glial cell line-derived neurotrophic factor (GDNF) protects dopamine neurons from the toxic effects of methamphetamine in animal models. Therefore, we hypothesized that a partial GDNF gene deletion would increase the susceptibility of mice to methamphetamine neurotoxicity during young adulthood and possibly increase age-related deterioration of behavior and dopamine function. Two weeks after a methamphetamine binge (4 x 10 mg/kg, i.p., at 2 h intervals), GDNF(+/-) mice had a significantly greater reduction of tyrosine hydroxylase immunoreactivity in the medial striatum, a proportionally greater depletion of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the striatum, and a greater increase in activated microglia in the substantia nigra than wild-type mice. At 12 months of age, methamphetamine-treated GDNF(+/-) mice exhibited less motor activity and lower levels of tyrosine hydroxylase-immunoreactivity, dopamine, DOPAC, and serotonin than wild-type mice. Greater striatal dopamine transporter activity in GDNF(+/-) mice may underlie their differential response to methamphetamine. These data suggest the possibility that methamphetamine use in young adults, when combined with lower levels of GDNF throughout life, may precipitate the appearance of parkinsonian-like behaviors during aging. PMID- 17699664 TI - The kisspeptin receptor GPR54 is required for sexual differentiation of the brain and behavior. AB - GPR54 is a G-protein-coupled receptor, which binds kisspeptins and is widely expressed throughout the brain. Kisspeptin-GPR54 signaling has been implicated in the regulation of pubertal and adulthood gonadotropin-releasing hormone (GnRH) secretion, and mutations or deletions of GPR54 cause hypogonadotropic hypogonadism in humans and mice. Other reproductive roles for kisspeptin-GPR54 signaling, including the regulation of developmental GnRH secretion or sexual behavior in adults, have not yet been explored. Using adult wild-type (WT) and GPR54 knock-out (KO) mice, we first tested whether kisspeptin-GPR54 signaling is necessary for male and female sexual behaviors. We found that hormone-replaced gonadectomized GPR54 KO males and females displayed appropriate gender-specific adult sexual behaviors. Next, we examined whether GPR54 signaling is required for proper display of olfactory-mediated partner preference behavior. Testosterone treated WT males preferred stimulus females rather than males, whereas similarly treated WT females and GPR54 KO males showed no preference for either sex. Because olfactory preference is sexually dimorphic and organized during development by androgens, we assessed whether GPR54 signaling is essential for sexual differentiation of other sexually dimorphic traits. Interestingly, adult testosterone-treated GPR54 KO males displayed "female-like" numbers of tyrosine hydroxylase-immunoreactive and Kiss1 mRNA-containing neurons in the anteroventral periventricular nucleus and likewise possessed fewer motoneurons in the spino bulbocavernosus nucleus than did WT males. Our findings indicate that kisspeptin GPR54 signaling is not required for male or female copulatory behavior, provided there is appropriate adulthood hormone replacement. However, GPR54 is necessary for proper male-like development of several sexually dimorphic traits, likely by regulating GnRH-mediated androgen secretion during "critical windows" in perinatal development. PMID- 17699665 TI - Overexpressing the glucocorticoid receptor in forebrain causes an aging-like neuroendocrine phenotype and mild cognitive dysfunction. AB - Repeated stress enhances vulnerability to neural dysfunction that is cumulative over the course of the lifespan. This dysfunction contributes to cognitive deficits observed during aging. In addition, aging is associated with dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis, leading to a delayed termination of the stress response. This delay, in turn, increases exposure to glucocorticoids and exacerbates the likelihood of neural damage. Here we asked whether similar effects could emerge at an early age as a result of genetic variations in the level or function of the brain glucocorticoid receptor (GR). We investigated the effect of forebrain-specific overexpression of GR on LHPA axis activity. Transgenic mice with GR overexpression in forebrain (GRov) display normal basal circulating adrenocorticotropic hormone and corticosterone levels. However, young GRov mice exhibit a number of LHPA alterations, including a blunted initial response to acute restraint stress followed by a delayed turn off of the stress response. This deficit in negative feedback is paradoxical in the face of elevated GR levels, resembles the stress response in aged animals, and continues to worsen as GRov mice age. The neuroendocrine dysregulation in young GRov mice is coupled with a mild cognitive deficit, also consistent with the accelerated aging hypothesis. The molecular basis of this phenotype was examined using microarray analysis of the hippocampus, which revealed a broad downregulation of glutamate receptor signaling in GRov mice. Thus, even in the absence of chronic stress, elevation of GR gene expression can lead to an increased allostatic load and result in an "aging-like" phenotype in young animals. PMID- 17699666 TI - TrpC3/C7 and Slo2.1 are molecular targets for metabotropic glutamate receptor signaling in rat striatal cholinergic interneurons. AB - Large aspiny cholinergic interneurons provide the sole source of striatal acetylcholine, a neurotransmitter critical for basal ganglia function; these tonically active interneurons receive excitatory inputs from corticostriatal glutamatergic afferents that act, in part, via metabotropic glutamate receptors (mGluRs). We combined electrophysiological recordings in brain slices with molecular neuroanatomy to identify distinct ion channel targets for mGluR1/5 receptors in striatal cholinergic interneurons: transient receptor potential channel 3/7 (TrpC3/C7) and Slo2.1. In recordings obtained with methanesulfonate based internal solutions, we found an mGluR-activated current with voltage dependent and pharmacological properties reminiscent of TrpC3 and TrpC7; expression of these TrpC subunits in cholinergic interneurons was verified by combined immunohistochemistry and in situ hybridization, and modulation of both TrpC channels was reconstituted in HEK293 (human embryonic kidney 293) cells cotransfected with mGluR1 or mGluR5. With a chloride-based internal solution, mGluR agonists did not activate interneuron TrpC-like currents. Instead, a time dependent, outwardly rectifying K(+) current developed after whole-cell access, and this Cl(-)-activated K(+) current was strongly inhibited by volatile anesthetics and mGluR activation. This modulation was recapitulated in cells transfected with Slo2.1, a Na(+)- and Cl(-)-activated K(+) channel, and Slo2.1 expression was confirmed histochemically in striatal cholinergic interneurons. By using gramicidin perforated-patch recordings, we established that the predominant agonist-activated current was TrpC-like when ambient intracellular chloride was preserved, although a small K(+) current contribution was observed in some cells. Together, our data indicate that mGluR1/5-mediated glutamatergic excitation of cholinergic interneurons is primarily a result of activation of TrpC3/TrpC7-like cationic channels; under conditions when intracellular NaCl is elevated, a Slo2.1 background K(+) channel may also contribute. PMID- 17699667 TI - Social stress enhances sympathetic innervation of primate lymph nodes: mechanisms and implications for viral pathogenesis. AB - Behavioral processes regulate immune system function in part via direct sympathetic innervation of lymphoid organs, but little is known about the factors that regulate the architecture of neural fibers in lymphoid tissues. In the present study, we find that experimentally imposed social stress can enhance the density of catecholaminergic neural fibers within axillary lymph nodes from adult rhesus macaques. This effect is linked to increased transcription of the key sympathetic neurotrophin nerve growth factor and occurs predominately in extrafollicular regions of the paracortex that contain T-lymphocytes and macrophages. Functional consequences of stress-induced increases in innervation density include reduced type I interferon response to viral infection and increased replication of the simian immunodeficiency virus. These data reveal a surprising degree of behaviorally induced plasticity in the structure of lymphoid innervation and define a novel pathway by which social factors can modulate immune response and viral pathogenesis. PMID- 17699668 TI - Interaction between telencephalin and ERM family proteins mediates dendritic filopodia formation. AB - Dendritic filopodia are long, thin, actin-rich, and dynamic protrusions that are thought to play a critical role as a precursor of spines during neural development. We reported previously that a telencephalon-specific cell adhesion molecule, telencephalin (TLCN) [intercellular adhesion molecule-5 (ICAM-5)], is highly expressed in dendritic filopodia, facilitates the filopodia formation, and slows spine maturation. Here we demonstrate that TLCN cytoplasmic region binds ERM (ezrin/radixin/moesin) family proteins that link membrane proteins to actin cytoskeleton. In cultured hippocampal neurons, phosphorylated active forms of ERM proteins are colocalized with TLCN in dendritic filopodia, whereas alpha-actinin, another binding partner of TLCN, is colocalized with TLCN at surface membranes of soma and dendritic shafts. Expression of constitutively active ezrin induces dendritic filopodia formation, whereas small interference RNA-mediated knockdown of ERM proteins decreases filopodia density and accelerates spine maturation. These results indicate the important role of TLCN-ERM interaction in the formation of dendritic filopodia, which leads to subsequent synaptogenesis and establishment of functional neural circuitry in the developing brain. PMID- 17699669 TI - Failure to regulate: counterproductive recruitment of top-down prefrontal subcortical circuitry in major depression. AB - Although depressed mood is a normal occurrence in response to adversity in all individuals, what distinguishes those who are vulnerable to major depressive disorder (MDD) is their inability to effectively regulate negative mood when it arises. Investigating the neural underpinnings of adaptive emotion regulation and the extent to which such processes are compromised in MDD may be helpful in understanding the pathophysiology of depression. We report results from a functional magnetic resonance imaging study demonstrating left-lateralized activation in the prefrontal cortex (PFC) when downregulating negative affect in nondepressed individuals, whereas depressed individuals showed bilateral PFC activation. Furthermore, during an effortful affective reappraisal task, nondepressed individuals showed an inverse relationship between activation in left ventrolateral PFC and the amygdala that is mediated by the ventromedial PFC (VMPFC). No such relationship was found for depressed individuals, who instead show a positive association between VMPFC and amygdala. Pupil dilation data suggest that those depressed patients who expend more effort to reappraise negative stimuli are characterized by accentuated activation in the amygdala, insula, and thalamus, whereas nondepressed individuals exhibit the opposite pattern. These findings indicate that a key feature underlying the pathophysiology of major depression is the counterproductive engagement of right prefrontal cortex and the lack of engagement of left lateral-ventromedial prefrontal circuitry important for the downregulation of amygdala responses to negative stimuli. PMID- 17699670 TI - The brain cytoplasmic RNA BC1 regulates dopamine D2 receptor-mediated transmission in the striatum. AB - Dopamine D(2) receptor (D(2)DR)-mediated transmission in the striatum is remarkably flexible, and changes in its efficacy have been heavily implicated in a variety of physiological and pathological conditions. Although receptor associated proteins are clearly involved in specific forms of synaptic plasticity, the molecular mechanisms regulating the sensitivity of D(2) receptors in this brain area are essentially obscure. We have studied the physiological responses of the D(2)DR stimulations in mice lacking the brain cytoplasmic RNA BC1, a small noncoding dendritically localized RNA that is supposed to play a role in mRNA translation. We show that the efficiency of D(2)-mediated transmission regulating striatal GABA synapses is under the control of BC1 RNA, through a negative influence on D(2) receptor protein level affecting the functional pool of receptors. Ablation of the BC1 gene did not result in widespread dysregulation of synaptic transmission, because the sensitivity of cannabinoid CB(1) receptors was intact in the striatum of BC1 knock-out (KO) mice despite D(2) and CB(1) receptors mediated similar electrophysiological actions. Interestingly, the fragile X mental retardation protein FMRP, one of the multiple BC1 partners, is not involved in the BC1 effects on the D(2)-mediated transmission. Because D(2)DR mRNA is apparently equally translated in the BC1-KO and wild-type mice, whereas the protein level is higher in BC1-KO mice, we suggest that BC1 RNA controls D(2)DR indirectly, probably regulating translation of molecules involved in D(2)DR turnover and/or stability. PMID- 17699671 TI - Modulation of thalamic nociceptive processing after spinal cord injury through remote activation of thalamic microglia by cysteine cysteine chemokine ligand 21. AB - Spinal cord injury (SCI) results in the generation and amplification of pain caused in part by injury-induced changes in neuronal excitability at multiple levels along the sensory neuraxis. We have previously shown that activated microglia, through an ERK (extracellular signal-regulated kinase)-regulated PGE(2) (prostaglandin E(2)) signaling mechanism, maintain neuronal hyperexcitability in the lumbar dorsal horn. Here, we examined whether microglial cells in the thalamus contribute to the modulation of chronic pain after SCI, and whether microglial activation is governed by spinally mediated increases in the microglial activator cysteine-cysteine chemokine ligand 21 (CCL21). We report that CCL21 is upregulated in dorsal horn neurons, that tissue levels are increased in the dorsal horn and ventral posterolateral (VPL) nucleus of the thalamus 4 weeks after SCI, and that the increase can be differentially reduced by spinal blockade at T1 or L1. In intact animals, electrical stimulation of the spinothalamic tract induces increases in thalamic CCL21 levels. Recombinant CCL21 injected into the VPL of intact animals transiently activates microglia and induces pain-related behaviors, effects that could be blocked with minocycline. After SCI, intra-VPL antibody-mediated neutralization of CCL21 decreases microglial activation and evoked hyperexcitability of VPL neurons, and restores nociceptive thresholds to near-normal levels. These data identify a novel pathway by which SCI triggers upregulation of the neuroimmune modulator CCL21 in the thalamus, which induces microglial activation in association with pain phenomena. PMID- 17699672 TI - NAC1 regulates the recruitment of the proteasome complex into dendritic spines. AB - Coordinated proteolysis of synaptic proteins is required for synaptic plasticity, but a mechanism for recruiting the ubiquitin-proteasome system (UPS) into dendritic spines is not known. NAC1 is a cocaine-regulated transcriptional protein that was found to complex with proteins in the UPS, including cullins and Mov34. NAC1 and the proteasome were cotranslocated from the nucleus into dendritic spines in cortical neurons in response to proteasome inhibition or disinhibiting synaptic activity with bicuculline. Bicuculline also produced a progressive accumulation of the proteasome and NAC1 in the postsynaptic density. Recruitment of the proteasome into dendrites and postsynaptic density by bicuculline was prevented in neurons from mice harboring an NAC1 gene deletion or in neurons transfected with mutated NAC1 lacking the proteasome binding domain. These experiments show that NAC1 modulates the translocation of the UPS from the nucleus into dendritic spines, thereby suggesting a potential missing link in the recruitment of necessary proteolysis machinery for synaptic remodeling. PMID- 17699673 TI - Inositol triphosphate-mediated Ca2+ signals direct purinergic P2Y receptor regulation of neuronal ion channels. AB - Purinergic P2Y receptors are one of four types of G(q/11)-coupled receptors in rat superior cervical ganglia (SCG) sympathetic neurons. In cultured SCG neurons, purinergic and bradykinin suppression of I(M) were similar in magnitude and somewhat less than that by muscarinic agonists. The effects of the P2Y receptor agonist UTP on neuronal excitability and discharge properties were studied. Under current clamp, UTP increased action potential (AP) firing in response to depolarizing current steps, depolarized the resting potential, decreased the threshold current required to fire an AP, and decreased spike-frequency adaptation. These effects were very similar to those resulting from bradykinin stimulation and not as profound as from muscarinic stimulation or full M-current blockade. We then examined the P2Y mechanism of action. Like bradykinin, but unlike muscarinic, purinergic stimulation induced rises in intracellular [Ca(2+)](i). Tests using expression of IP(3)"sponge" or IP(3) phosphatase constructs implicated IP(3) accumulation as necessary for purinergic suppression of I(M). Overexpression of wild-type or dominant-negative calmodulin (CaM) implicated Ca(2+)/CaM in the purinergic action. Both sets of results were similar to bradykinin, and opposite to muscarinic, suppression. We also examined modulation of Ca(2+) channels. As for bradykinin, purinergic stimulation did not suppress I(Ca), unless neuronal calcium sensor-1 (NCS-1) activity was blocked by a dominant-negative NCS-1 construct. Our results indicate that P2Y receptors modulate M-type channels in SCG cells via IP(3)-mediated [Ca(2+)](i) signals in concert with CaM and not by depletion of phosphatidylinositol-4, 5-biphosphate. We group purinergic P2Y and bradykinin B(2) receptors together as having a common mode of action. PMID- 17699674 TI - Protein kinase C regulates local synthesis and secretion of a neuropeptide required for activity-dependent long-term synaptic plasticity. AB - Long-term facilitation (LTF) of sensory neuron synapses in Aplysia is produced by either nonassociative or associative stimuli. Nonassociative LTF can be produced by five spaced applications of serotonin (5-HT) and requires a phosphoinosotide 3 kinase (PI3K)-dependent and rapamycin-sensitive increase in the local synthesis of the sensory neuron neuropeptide sensorin and a protein kinase A (PKA) dependent increase in the secretion of the newly synthesized sensorin. We report here that associative LTF produced by a single pairing of a brief tetanus with one application of 5-HT requires a rapid protein kinase C (PKC)-dependent and rapamycin-sensitive increase in local sensorin synthesis. This rapid increase in sensorin synthesis does not require PI3K activity or the presence of the sensory neuron cell body but does require the presence of the motor neuron. The secretion of newly synthesized sensorin by 2 h after stimulation requires both PKA and PKC activities to produce associative LTF because incubation with exogenous anti sensorin antibody or the kinase inhibitors after tetanus plus 5-HT blocked LTF. The secreted sensorin leads to phosphorylation and translocation of p42/44 mitogen-activated protein kinase (MAPK) into the nuclei of the sensory neurons. Thus, different stimuli activating different signaling pathways converge by regulating the synthesis and release of a neuropeptide to produce long-term synaptic plasticity. PMID- 17699675 TI - Dominant-negative inhibition of M-like potassium conductances in hair cells of the mouse inner ear. AB - Sensory hair cells of the inner ear express multiple physiologically defined conductances, including mechanotransduction, Ca(2+), Na(+), and several distinct K(+) conductances, all of which are critical for normal hearing and balance function. Yet, the molecular underpinnings and their specific contributions to sensory signaling in the inner ear remain obscure. We sought to identify hair cell conductances mediated by KCNQ4, which, when mutated, causes the dominant progressive hearing loss DFNA2. We used the dominant-negative pore mutation G285S and packaged the coding sequence of KCNQ4 into adenoviral vectors. We transfected auditory and vestibular hair cells of organotypic cultures generated from the postnatal mouse inner ear. Cochlear outer hair cells and vestibular type I cells that expressed the transfection marker, green fluorescent protein, and the dominant-negative KCNQ4 construct lacked the M-like conductances that typify nontransfected control hair cells. As such, we conclude that the M-like conductances in mouse auditory and vestibular hair cells can include KCNQ4 subunits and may also include KCNQ4 coassembly partners. To examine the function of M-like conductances in hair cells, we recorded from cells transfected with mutant KCNQ4 and injected transduction current waveforms in current-clamp mode. Because the M-like conductances were active at rest, they contributed to the very low potassium-selective input resistance, which in turn hyperpolarized the resting potential and significantly attenuated the amplitude of the receptor potential. Modulation of M-like conductances may allow hair cells the ability to control the amplitude of their response to sensory stimuli. PMID- 17699676 TI - Processing of abstract ordinal knowledge in the horizontal segment of the intraparietal sulcus. AB - The anterior intraparietal sulcus, and more specifically its horizontal segment (hIPS), is known to play a crucial role in the cognitive representation of numerical quantity. Whether the involvement of hIPS is restricted to the processing of numerical information or generalizes to non-numerical ordinal dimensions remains an open question. Using functional magnetic resonance imaging during comparison tasks, we demonstrate that the hIPS is equally responsive to numbers and letters, indicating that hIPS is also involved in the representation and processing of non-numerical ordinal series. This extends the numerical processing function of IPS into the realm of abstract knowledge processing. PMID- 17699677 TI - Regulation of neurite growth by spontaneous Ca2+ oscillations in astrocytes. AB - Astrocytes play a pivotal role in the regulation of neurite growth, but the intracellular signaling mechanism in astrocytes that mediates this regulation remains unclarified. We studied the relationship between spontaneous Ca(2+) oscillations in astrocytes and the astrocyte-mediated neurite growth. We generated Ca(2+) signal-deficient astrocytes in which spontaneous Ca(2+) oscillations were abolished by a chronic inhibition of IP(3) signaling. When hippocampal neurons were cultured on a monolayer of Ca(2+) signal-deficient astrocytes, the growth of dendrites and axons was inhibited. Time-lapse imaging of the advancement of axonal growth cones indicated the involvement of membrane bound molecules for this inhibition. Among six candidate membrane-bound molecules that may modulate neuronal growth, N-cadherin was downregulated in Ca(2+) signal deficient astrocytes. Although a blocking antibody to N-cadherin suppressed the axonal growth on control astrocytes, extrinsic N-cadherin expression rescued the suppressed axonal growth on Ca(2+) signal-deficient astrocytes. These findings suggest that spontaneous Ca(2+) oscillations regulate the astrocytic function to promote neurite growth by maintaining the expression of specific growth-enhancing proteins on their surface, and that N-cadherin is one of such molecules. PMID- 17699678 TI - Timing and location of synaptic inputs determine modes of subthreshold integration in striatal medium spiny neurons. AB - Medium spiny neurons (MSNs) are the principal cells of the striatum and perform a central role in sensorimotor processing. MSNs must integrate many excitatory inputs located across their dendrites to fire action potentials and enable striatal function. However, the dependence of synaptic responses on the temporal and spatial distribution of these inputs remains unknown. Here, we use whole-cell recordings, two-photon microscopy, and two-photon glutamate uncaging to examine subthreshold synaptic integration in MSNs from acute rat brain slices. We find that synaptic responses can summate sublinearly, linearly, or supralinearly depending on the spatiotemporal pattern of activity. Repetitive activity at single inputs leads to sublinear summation, reflecting long-lived AMPA receptor desensitization. In contrast, asynchronous activity at multiple inputs generates linear summation, with synapses on neighboring spines functioning independently. Finally, synchronous activity at multiple inputs triggers supralinear summation at depolarized potentials, reflecting activation of NMDA receptors and L-type calcium channels. Thus, the properties of subthreshold integration in MSNs are determined by the distribution of synaptic inputs and the differential activation of multiple postsynaptic conductances. PMID- 17699679 TI - 2-Methoxyestradiol: a potential treatment for multiple proliferative disorders. PMID- 17699680 TI - V1b receptors: new probes for therapy. PMID- 17699681 TI - A suckling feast: not so hot after all. PMID- 17699682 TI - Atriopeptins: protection from myocardial hypertrophy and heart failure. PMID- 17699683 TI - Talk to me: the embryo dictates gene expression by the endometrium. PMID- 17699685 TI - Role of protein kinase Czeta and its adaptor protein p62 in voltage-gated potassium channel modulation in pulmonary arteries. AB - Voltage-gated potassium (K(V)) channels play an essential role in regulating pulmonary artery function, and they underpin the phenomenon of hypoxic pulmonary vasoconstriction. Pulmonary hypertension is characterized by inappropriate vasoconstriction, vascular remodeling, and dysfunctional K(V) channels. In the current study, we aimed to elucidate the role of PKCzeta and its adaptor protein p62 in the modulation of K(V) channels. We report that the thromboxane A(2) analog 9,11-dideoxy-11alpha,9alpha-epoxymethano-prostaglandin F(2alpha) methyl acetate (U46619) inhibited K(V) currents in isolated mice pulmonary artery myocytes and the K(V) current carried by human cloned K(V)1.5 channels expressed in Ltk(-) cells. Using protein kinase C (PKC)zeta(-/-) and p62(-/-) mice, we demonstrate that these two proteins are involved in the K(V) channel inhibition. PKCzeta coimmunoprecipitated with K(V)1.5, and this interaction was markedly reduced in p62(-/-) mice. Pulmonary arteries from PKCzeta(-/-) mice also showed a diminished [Ca(2+)](i) and contractile response, whereas genetic inactivation of p62(-/-) resulted in an absent [Ca(2+)](i) response, but it preserved contractile response to U46619. These data demonstrate that PKCzeta and its adaptor protein p62 play a key role in the modulation of K(V) channel function in pulmonary arteries. These observations identify PKCzeta and/or p62 as potential therapeutic targets for the treatment of pulmonary hypertension. PMID- 17699686 TI - Regulation of D1 dopamine receptor trafficking and signaling by caveolin-1. AB - There is accumulating evidence that G protein-coupled receptor signaling is regulated by localization in lipid raft microdomains. In this report, we determined that the D1 dopamine receptor (D1R) is localized in caveolae, a subset of lipid rafts, by sucrose gradient fractionation and confocal microscopy. Through coimmunoprecipitation and bioluminescence resonance energy transfer assays, we demonstrated that this localization was mediated by an interaction between caveolin-1 and D1R in COS-7 cells and an isoform-selective interaction between D1R and caveolin-1alpha in rat brain. We determined that the D1R interaction with caveolin-1 required a putative caveolin binding motif identified in transmembrane domain 7. Agonist stimulation of D1R caused translocation of D1R into caveolin-1-enriched sucrose fractions, which was determined to be a result of D1R endocytosis through caveolae. This was found to be protein kinase A independent and a kinetically slower process than clathrin-mediated endocytosis. Site-directed mutagenesis of the caveolin binding motif at amino acids Phe313 and Trp318 significantly attenuated caveolar endocytosis of D1R. We also found that these caveolin binding mutants had a diminished capacity to stimulate cAMP production, which was determined to be due to constitutive desensitization of these receptors. In contrast, we found that D1Rs had an enhanced ability to maximally generate cAMP in chemically induced caveolae-disrupted cells. Taken together, these data suggest that caveolae has an important role in regulating D1R turnover and signaling in brain. PMID- 17699687 TI - Control of sensorimotor variability by consequences. AB - Studies of reaction-time distributions provide a useful quantitative approach to understand decision processes at the neural level and at the behavioral level. A strong relationship between the spread of latencies and the median is generally accepted even though there has been no attempt to disentangle experimentally these two parameters. Here we test the ability to independently control the median and the variability in reaction times. Reaction times were measured in human subjects instructed to make a discrimination between a target and a distractor in a 2AFC task. In a first experiment, saccadic latencies were measured. In a second experiment, we used manual response reaction times. Subjects were trained to produce four different reaction-time distributions. A reinforcing feedback was given depending on both the variability and the median of the latency distributions. When low variability was reinforced, the standard deviation (SD) of reaction-time distributions were reduced by a factor of two and when high variability was reinforced, the SD returned to baseline level. Our procedure independently affected the spread and the median of the distribution patterns. By fitting the latency distributions using the Reddi and Carpenter LATER model, we found that these effects could be simulated by changing the distribution of the noise affecting the decision process. Our results demonstrate that learned contingencies can affect reaction time variability and support the view that the so-called noise level in decision processes can undergo long-term changes. PMID- 17699688 TI - Withdrawal from intermittent ethanol exposure increases probability of burst firing in VTA neurons in vitro. AB - Changing the activity of ventral tegmental area (VTA) dopamine neurons from pacemaker to burst firing is hypothesized to increase the salience of stimuli, such as an unexpected reward, and likely contributes to withdrawal-associated drug-seeking behavior. Accordingly, pharmacological, behavioral, and electrophysiological data suggest an important role of the VTA in mediating alcohol-dependent behaviors. However, the effects of repeated ethanol exposure on VTA dopamine neuron ion channel function are poorly understood. Here, we repeatedly exposed rats to ethanol (2 g/kg ethanol, ip, twice per day for 5 days), then examined the firing patterns of VTA dopamine neurons in vitro after 7 days withdrawal. Compared with saline-treated animals, the function of the small conductance calcium-dependent potassium channel (SK) was reduced in ethanol treated animals. Consistent with a role for SK in regulation of burst firing, NMDA applied during firing facilitated the transition to bursting in ethanol treated but not saline-treated animals; NMDA consistently induced bursting only in saline-treated animals when SK was inhibited. Also, enhanced bursting in ethanol-treated animals was not a result of differences in NMDA-induced depolarization. Further, I(h) was also reduced in ethanol-treated animals, which delayed recovery from hyperpolarization, but did not account for the increased NMDA-induced bursting in ethanol-treated animals. Finally, repeated ethanol exposure and withdrawal also enhanced the acute locomotor-activating effect of cocaine (15 mg/kg, ip). Thus withdrawal after repeated ethanol exposure produced several alterations in the physiological properties of VTA dopamine neurons, which could ultimately increase the ability of VTA neurons to produce burst firing and thus might contribute to addiction-related behaviors. PMID- 17699690 TI - Phase-locked responses to pure tones in the auditory thalamus. AB - Accurate temporal coding of low-frequency tones by spikes that are locked to a particular phase of the sine wave (phase-locking), occurs among certain groups of neurons at various processing levels in the brain. Phase-locked responses have previously been studied in the inferior colliculus and neocortex of the guinea pig and we now describe the responses in the auditory thalamus. Recordings were made from 241 single units, 32 (13%) of which showed phase-locked responses. Units with phase-locked responses were mainly (82%) located in the ventral division of the medial geniculate body (MGB), and also the medial division (18%), but were not found in the dorsal or shell divisions. The upper limiting frequency of phase-locking varied greatly between units (60-1,100 Hz) and between anatomical divisions. The upper limit in the ventral division was 520 Hz and in the medial was 1,100 Hz. The range of steady-state delays calculated from phase plots also varied: ventral division, 8.6-14 ms (mean 11.1 ms; SD 1.56); medial division, 7.5-11 ms (mean 9.3 ms; SD 1.5). Taken together, these measurements are consistent with the medial division receiving a phase-locked input directly from the brain stem, without an obligatory relay in the inferior colliculus. Cells in both the ventral and medial divisions of the MGB showed a response that phase locked to the fundamental frequency of a guinea pig purr and may be involved in analyzing communication calls. PMID- 17699689 TI - BDNF induces calcium elevations associated with IBDNF, a nonselective cationic current mediated by TRPC channels. AB - Brain-derived neurotrophic factor (BDNF) has potent actions on hippocampal neurons, but the mechanisms that initiate its effects are poorly understood. We report here that localized BDNF application to apical dendrites of CA1 pyramidal neurons evoked transient elevations in intracellular Ca(2+) concentration, which are independent of membrane depolarization and activation of N-methyl-d-aspartate receptors (NMDAR). These Ca(2+) signals were always associated with I(BDNF), a slow and sustained nonselective cationic current mediated by transient receptor potential canonical (TRPC3) channels. BDNF-induced Ca(2+) elevations required functional Trk and inositol-tris-phosphate (IP(3)) receptors, full intracellular Ca(2+) stores as well as extracellular Ca(2+), suggesting the involvement of TRPC channels. Indeed, the TRPC channel inhibitor SKF-96365 prevented BDNF-induced Ca(2+) elevations and the associated I(BDNF). Thus TRPC channels emerge as novel mediators of BDNF-induced intracellular Ca(2+) elevations associated with sustained cationic membrane currents in hippocampal pyramidal neurons. PMID- 17699691 TI - Adaptive changes in cortical receptive fields induced by attention to complex sounds. AB - Receptive fields in primary auditory cortex (A1) can be rapidly and adaptively reshaped to enhance responses to salient frequency cues when using single tones as targets. To explore receptive field changes to more complex spectral patterns, we trained ferrets to detect variable, multitone targets in the context of background, rippled noise. Recordings from A1 of behaving ferrets showed a consistent pattern of plasticity, at both the single-neuron level and the population level, with enhancement for each component tone frequency and suppression for intertone frequencies. Plasticity was strongest near neuronal best frequency, rapid in onset, and slow to fade. Although attention may trigger cortical plasticity, the receptive field changes persisted after the behavioral task was completed. The observed comb filter plasticity is an example of an adaptive contrast matched filter, which may generally improve discriminability between foreground and background sounds and, we conjecture, may predict A1 cortical plasticity for any complex spectral target. PMID- 17699692 TI - An olfacto-hippocampal network is dynamically involved in odor-discrimination learning. AB - Several studies have shown that memory consolidation relies partly on interactions between sensory and limbic areas. The functional loop formed by the olfactory system and the hippocampus represents an experimentally tractable model that can provide insight into this question. It had been shown previously that odor-learning associated beta band oscillations (15-30 Hz) of the local field potential in the rat olfactory system are enhanced with criterion performance, but it was unknown if these involve networks beyond the olfactory system. We recorded local field potentials from the olfactory bulb (OB) and dorsal and ventral hippocampus during acquisition of odor discriminations in a go/no-go task. These regions showed increased beta oscillation power during odor sampling, accompanied by a coherence increase in this frequency band between the OB and both hippocampal subfields. This coherence between the OB and the hippocampus increased with the onset of the first rule transfer to a new odor set and remained high for all learning phases and subsequent odor sets. However, coherence between the two hippocampal fields reset to baseline levels with each new odor set and increased again with criterion performance. These data support hippocampal involvement in the network underlying odor-discrimination learning and also suggest that cooperation between the dorsal and ventral hippocampus varies with learning progress. Oscillatory activity in the beta range may thus provide a mechanism by which these areas are linked during memory consolidation, similar to proposed roles of beta oscillations in other systems with long-range connections. PMID- 17699693 TI - Nicotinic receptor activation occludes purinergic control of central cardiorespiratory network responses to hypoxia/hypercapnia. AB - Prenatal nicotine exposure alters the cardiorespiratory network responses to hypoxia/hypercapnia; however the mechanism(s) responsible for these cardiorespiratory network responses and their alteration by prenatal nicotine exposure are unknown. We used an in vitro medullary slice that allows simultaneous examination of rhythmic respiratory-related activity and excitatory synaptic neurotransmission to cardioinhibitory vagal neurons (CVNs). Respiratory related increases in glutamatergic neurotransmission only occurred on recovery from hypoxia/hypercapnia in unexposed animals. These responses were not altered by nicotinic antagonists but were mediated in part by activation of P2 purinergic receptors. Prenatal nicotine exposure transformed central cardiorespiratory responses to hypoxia/hypercapnia; CVNs received a respiratory related glutamatergic neurotransmission during periods of hypoxia and hypercapnia, whereas increases in glutamatergic neurotransmission during recovery were absent. The excitatory neurotransmission to CVNs during hypoxia/hypercapnia in prenatal nicotine-exposed animals were wholly dependent on nicotinic receptor activation. In the presence of nicotinic antagonists, the responses in prenatal nicotine animals reverted to the pattern of responses in unexposed animals in which an increase in glutamatergic neurotransmission occurred not during but only on recovery from hypoxia/hypercapnia, and this recruited excitatory pathway was blocked by P2 receptor antagonists. These data identify a new functional role for purinergic receptors in the cardiorespiratory responses to hypoxia/hypercapnia and their role in occluding nicotinic receptor activation with prenatal nicotine exposure. PMID- 17699694 TI - Computational model predicts a role for ERG current in repolarizing plateau potentials in dopamine neurons: implications for modulation of neuronal activity. AB - Blocking the small-conductance (SK) calcium-activated potassium channel promotes burst firing in dopamine neurons both in vivo and in vitro. In vitro, the bursting is unusual in that spiking persists during the hyperpolarized trough and frequently terminates by depolarization block during the plateau. We focus on the underlying plateau potential oscillation generated in the presence of both apamin and TTX, so that action potentials are not considered. We find that although the plateau potentials are mediated by a voltage-gated Ca(2+) current, they do not depend on the accumulation of cytosolic Ca(2+), then use a computational model to test the hypothesis that the slowly voltage-activated ether-a-go-go-related gene (ERG) potassium current repolarizes the plateaus. The model, which includes a material balance on calcium, is able to reproduce the time course of both membrane potential and somatic calcium concentration, and can also mimic the induction of plateau potentials by the calcium chelator BAPTA. The principle of separation of timescales was used to gain insight into the mechanisms of oscillation and its modulation using nullclines in the phase space. The model predicts that the plateau will be elongated and ultimately result in a persistent depolarization as the ERG current is reduced. This study suggests that the ERG current may play a role in burst termination and the relief of depolarization block in vivo. PMID- 17699695 TI - Frequency-modulation encoding in the primary auditory cortex of the awake owl monkey. AB - Many communication sounds, such as New World monkey twitter calls, contain frequency-modulated (FM) sweeps. To determine how this prominent vocalization element is represented in the auditory cortex we examined neural responses to logarithmic FM sweep stimuli in the primary auditory cortex (AI) of two awake owl monkeys. Using an implanted array of microelectrodes we quantitatively characterized neuronal responses to FM sweeps and to random tone-pip stimuli. Tone-pip responses were used to construct spectrotemporal receptive fields (STRFs). Classification of FM sweep responses revealed few neurons with high direction and speed selectivity. Most neurons responded to sweeps in both directions and over a broad range of sweep speeds. Characteristic frequency estimates from FM responses were highly correlated with estimates from STRFs, although spectral receptive field bandwidth was consistently underestimated by FM stimuli. Predictions of FM direction selectivity and best speed from STRFs were significantly correlated with observed FM responses, although some systematic discrepancies existed. Last, the population distributions of FM responses in the awake owl monkey were similar to, although of longer temporal duration than, those in the anesthetized squirrel monkeys. PMID- 17699696 TI - TMS pulses on the frontal eye fields break coupling between visuospatial attention and eye movements. AB - While preparing a saccadic eye movement, visual processing of the saccade goal is prioritized. Here, we provide evidence that the frontal eye fields (FEFs) are responsible for this coupling between eye movements and shifts of visuospatial attention. Functional magnetic resonance imaging (fMRI)-guided transcranial magnetic stimulation (TMS) was applied to the FEFs 30 ms before a discrimination target was presented at or next to the target of a saccade in preparation. Results showed that the well-known enhancement of discrimination performance on locations to which eye movements are being prepared was diminished by TMS contralateral to eye movement direction. Based on the present and other reports, we propose that saccade preparatory processes in the FEF affect selective visual processing within the visual cortex through feedback projections, in that way coupling saccade preparation and visuospatial attention. PMID- 17699697 TI - Spectral composition of concurrent noise affects neuronal sensitivity to interaural time differences of tones in the dorsal nucleus of the lateral lemniscus. AB - We are regularly exposed to several concurrent sounds, producing a mixture of binaural cues. The neuronal mechanisms underlying the localization of concurrent sounds are not well understood. The major binaural cues for localizing low frequency sounds in the horizontal plane are interaural time differences (ITDs). Auditory brain stem neurons encode ITDs by firing maximally in response to "favorable" ITDs and weakly or not at all in response to "unfavorable" ITDs. We recorded from ITD-sensitive neurons in the dorsal nucleus of the lateral lemniscus (DNLL) while presenting pure tones at different ITDs embedded in noise. We found that increasing levels of concurrent white noise suppressed the maximal response rate to tones with favorable ITDs and slightly enhanced the response rate to tones with unfavorable ITDs. Nevertheless, most of the neurons maintained ITD sensitivity to tones even for noise intensities equal to that of the tone. Using concurrent noise with a spectral composition in which the neuron's excitatory frequencies are omitted reduced the maximal response similar to that obtained with concurrent white noise. This finding indicates that the decrease of the maximal rate is mediated by suppressive cross-frequency interactions, which we also observed during monaural stimulation with additional white noise. In contrast, the enhancement of the firing rate to tones at unfavorable ITD might be due to early binaural interactions (e.g., at the level of the superior olive). A simple simulation corroborates this interpretation. Taken together, these findings suggest that the spectral composition of a concurrent sound strongly influences the spatial processing of ITD-sensitive DNLL neurons. PMID- 17699698 TI - Lack of spike-count and spike-time correlations in the substantia nigra reticulata despite overlap of neural responses. AB - Previous studies of single neurons in the substantia nigra reticulata (SNr) have shown that many of them respond to similar events. These results, as well as anatomical studies, suggest that SNr neurons share inputs and thus may have correlated activity. Different types of correlation can exist between pairs of neurons. These are traditionally classified as either spike-count ("signal" and "noise") or spike-timing (spike-to-spike and joint peristimulus time histograms) correlations. These measures of neuronal correlation are partially independent and have different implications. Our purpose was to probe the computational characteristics of the basal ganglia output nuclei through an analysis of these different types of correlation in the SNr. We carried out simultaneous multiple electrode single-unit recordings in the SNr of two monkeys performing a probabilistic delayed visuomotor response task. A total of 113 neurons (yielding 355 simultaneously recorded pairs) were studied. Most SNr neurons responded to one or more task-related events, with instruction cue (69%) and reward (63%) predominating. Response-match analysis, comparing peristimulus time histograms, revealed a significant overlap between response vectors. However, no measure of average correlation differed significantly from zero. The lack of significant SNr spike-count population correlations appears to be an exceptional phenomenon in the brain, perhaps indicating unique event-related processing by basal ganglia output neurons to achieve better information transfer. The lack of spike-timing correlations suggests that the basal high-frequency discharge of SNr neurons is not driven by the common inputs and is probably intrinsic. PMID- 17699699 TI - Zn(2+) slows down Ca(V)3.3 gating kinetics: implications for thalamocortical activity. AB - We employed whole cell patch-clamp recordings to establish the effect of Zn(2+) on the gating the brain specific, T-type channel isoform Ca(V)3.3 expressed in HEK-293 cells. Zn(2+) (300 microM) modified the gating kinetics of this channel without influencing its steady-state properties. When inward Ca(2+) currents were elicited by step depolarizations at voltages above the threshold for channel opening, current inactivation was significantly slowed down while current activation was moderately affected. In addition, Zn(2+) slowed down channel deactivation but channel recovery from inactivation was only modestly changed. Zn(2+) also decreased whole cell Ca(2+) permeability to 45% of control values. In the presence of Zn(2+), Ca(2+) currents evoked by mock action potentials were more persistent than in its absence. Furthermore, computer simulation of action potential generation in thalamic reticular cells performed to model the gating effect of Zn(2+) on T-type channels (while leaving the kinetic parameters of voltage-gated Na(+) and K(+) unchanged) revealed that Zn(2+) increased the frequency and the duration of burst firing, which is known to depend on T-type channel activity. In line with this finding, we discovered that chelation of endogenous Zn(2+) decreased the frequency of occurrence of ictal-like epileptiform discharges in rat thalamocortical slices perfused with medium containing the convulsant 4-aminopyridine (50 microM). These data demonstrate that Zn(2+) modulates Ca(V)3.3 channel gating thus leading to increased neuronal excitability. We also propose that endogenous Zn(2+) may have a role in controlling thalamocortical oscillations. PMID- 17699700 TI - The flaws in tooth root resorption assessment algorithms: the role of source position. AB - OBJECTIVES: The purpose of this project was to analyse the effects of X-ray source location on mathematical compensations used in the clinical assessment of external apical root resorption (EARR). METHODS: Using geometric constructions, governing equations were derived to express the relationships between actual tooth, root and crown lengths, and their image sizes on "before" and "after" radiographs. RESULTS: Good agreement was found between calculated and published experimental results. More importantly, errors associated with the assessment methods are demonstrated. CONCLUSION: It is established that root resorption assessment algorithms cannot reliably compensate for the inherent distortions in radiographic evaluations of EARR, even in the best-case scenario of an idealized, precisely characterized, linear tooth. PMID- 17699701 TI - Large scan field, high spatial resolution flat-panel detector based volumetric CT of the whole human skull base and for maxillofacial imaging. AB - OBJECTIVES: To assess the feasibility of flat-panel detector based volumetric CT (fpVCT) scanning of the whole human skull base and maxillofacial region, which has thus far only been demonstrated on small, excised specimens. Flat-panel detectors offer more favourable imaging properties than image intensifiers. It is therefore likely that they will replace them in cone-beam CT scanners that are currently used to scan parts of the skull base and maxillofacial region. Furthermore, the resolution of current CT imaging limits diagnosis, surgical planning and intraoperative navigation within these regions. fpVCT might overcome these limitations because it offers higher resolution of high contrast structures than current CT. METHODS: Three embalmed cadaver heads were scanned in two scanners: an experimental fpVCT that offers a scan field large enough for a whole human head, and in a current multislice CT (MSCT). 28 structures were compared. RESULTS: Both scanners produced bone images of diagnostic quality. Small high contrast structures such as parts of the ossicular chain and thin bony laminas were better delineated in fpVCT than in MSCT. fpVCT of maxillofacial region and skull base was rated superior to MSCT (P=0.002) as found in this limited, experimental study. CONCLUSIONS: High spatial resolution fpVCT scanning of both regions in a whole human head is feasible and might be slightly superior to MSCT. fpVCT could improve diagnostic accuracy in selected cases, as well as surgical planning and intraoperative navigation accuracy. PMID- 17699702 TI - Content-based access to oral and maxillofacial radiographs. AB - OBJECTIVES: Content-based access (CBA) to medical image archives, i.e. data retrieval by means of image-based numerical features computed automatically, has capabilities to improve diagnostics, research and education. In this study, the applicability of CBA methods in dentomaxillofacial radiology is evaluated. METHODS: Recent research has discovered numerical features that were successfully applied for an automatic categorization of radiographs. In our experiments, oral and maxillofacial radiographs were obtained from the day-to-day routine of a university hospital and labelled by an experienced dental radiologist regarding the technique and direction of imaging, as well as the displayed anatomy and biosystem. In total, 2000 radiographs of 71 classes with at least 10 samples per class were analysed. A combination of co-occurrence-based texture features and correlation-based similarity measures was used in leaving-one-out experiments for automatic classification. The impact of automatic detection and separation of multi-field images and automatic separability of biosystems were analysed. RESULTS: Automatic categorization yielded error rates of 23.20%, 7.95% and 4.40% with respect to a correct match within the first, fifth and tenth best returns. These figures improved to 23.05%, 7.00%, 4.20%, and 20.05%, 5.65% and 3.25% if automatic decomposition was applied and the classifier was optimized to the dentomaxillofacial imagery, respectively. The dentulous and implant systems were difficult to distinguish. Experiments on non-dental radiographs (10,000 images of 57 classes) yielded 12.6%, 5.6% and 3.6%. CONCLUSION: Using the same numerical features as in medical radiology, oral and maxillofacial radiographs can be reliably indexed by global texture features for CBA and data mining. PMID- 17699703 TI - Evaluation of temporomandibular joint in stress-free patients. AB - OBJECTIVES: The aetiology of temporomandibular disorders (TMD) is presently considered to be multifactorial, and stress has been regarded as an important factor in their onset. Many studies have evaluated the importance of stress in TMD; however, only patients with TMD and stress have been assessed. This study aimed at evaluating signs and symptoms of TMD in stress-free patients. METHODS: The temporomandibular joints (TMJs) of 40 stress-free patients were evaluated during clinical examination and in MRI. RESULTS: The individuals lived in an area without electric power supply or telephone services. They worked in agriculture and fishery. 77.5% of the patients presented normal mandibular function; 70% presented normal mandibular trajectory; 61.25% did not present sounds in TMJ and 93.75% did not present joint pain during palpation. Image screening showed that 70% of TMJ presented normal disc position. Only one patient (1.25%) presented TMD. CONCLUSIONS: The absence of stress is a strong factor for the non development of TMD. PMID- 17699704 TI - An approach for three-dimensional visualization using high-resolution MRI of the temporomandibular joint. AB - OBJECTIVES: To visualize the temporomandibular joint (TMJ) and the surrounding tissues in detail utilizing high-resolution MR images for the diagnosis of soft- and hard-tissue abnormalities. Clinically routine MR slices are processed by tissue segmentation and three-dimensional (3D) reconstruction and viewed with visualization software. MATERIALS AND METHODS: A 1.5 T MRI system was used. The double-echo procedure for taking oblique sagittal images was applied to obtain both proton density-weighted (PDW) and T2 weighted (T2W) images simultaneously, with separate examinations in both open and closed mouth positions. Diagnosis of the abnormality in the placement and morphology of articular discs and the joint effusion status is usually performed using multiple MRI slices. Clinically routine continuous MR slices were processed by segmentation, reconstruction and visualization algorithms, and the mandibular condyle, fossa, articular disc and other intra-articular tissues were visualized on the 3D and two-dimensional (2D) 3D fusion images. RESULTS: In a clinical case, the anterior disc displacement without reduction, with mouth open and closed, was clearly depicted in the 3D images. Also 2D-3D superposed images with changeable tissue transparency successfully depicted the stereoscopic TMJ morphology in three dimensions. DISCUSSION AND CONCLUSION: High-resolution PDW- and T2W MR images could be processed by tissue segmentation and 3D-reconstruction procedures, and the resultant images showed the anatomical details in an easily recognizable way. By the simultaneous visualization of both bony surfaces and soft tissues, disc displacement and deformity can be recognized in a 3D context. The additional superposition of the 3D visualization with the original 2D MR slices allows for a combination with conventional diagnostics. PMID- 17699705 TI - A web-based instruction module for interpretation of craniofacial cone beam CT anatomy. AB - OBJECTIVES: To develop a web-based module for learner instruction in the interpretation and recognition of osseous anatomy on craniofacial cone-beam CT (CBCT) images. METHODS: Volumetric datasets from three CBCT systems were acquired (i-CAT, NewTom 3G and AccuiTomo FPD) for various subjects using equipment specific scanning protocols. The datasets were processed using multiple software to provide two-dimensional (2D) multiplanar reformatted (MPR) images (e.g. sagittal, coronal and axial) and three-dimensional (3D) visual representations (e.g. maximum intensity projection, minimum intensity projection, ray sum, surface and volume rendering). Distinct didactic modules which illustrate the principles of CBCT systems, guided navigation of the volumetric dataset, and anatomic correlation of 3D models and 2D MPR graphics were developed using a hybrid combination of web authoring and image analysis techniques. Interactive web multimedia instruction was facilitated by the use of dynamic highlighting and labelling, and rendered video illustrations, supplemented with didactic textual material. HTML coding and Java scripting were heavily implemented for the blending of the educational modules. RESULTS: An interactive, multimedia educational tool for visualizing the morphology and interrelationships of osseous craniofacial anatomy, as depicted on CBCT MPR and 3D images, was designed and implemented. CONCLUSIONS: The present design of a web-based instruction module may assist radiologists and clinicians in learning how to recognize and interpret the craniofacial anatomy of CBCT based images more efficiently. PMID- 17699706 TI - Evaluation of the inclination in posterior dentoalveolar structures after rapid maxillary expansion: a new method. AB - OBJECTIVES: In order to compare the skeletal and dental effects of rapid maxillary expansion, orthodontists need an assessment of buccal dentoalveolar inclination. The aim of the present paper is to introduce a new technique for the evaluation of buccal inclinations in dentoalveolar structures. METHODS: Using barium sulphate solution with a paintbrush, a thin line was drawn on and between the first molars of the maxillary stone casts. Then, radiographic images of the stone casts were obtained. Buccal tipping of molar crowns and alveolar processes were evaluated on these images by means of a computerized imaging software program. CONCLUSIONS: This new evaluation technique is inexpensive, simple and reliable for the assessment of dentoalveolar inclination. In addition, the changes in dentoalveolar structures may also be visualized by superimposing the pre- and post-treatment images. PMID- 17699707 TI - Primary hyperparathyroidism presenting as an exophytic mandibular mass. AB - A 36-year-old female patient presented with a massive painless swelling in the left mandible. The patient's medical history was unremarkable. The initial clinical and radiological evaluation indicated an aggressive odontogenic neoplasm or a metastasis from an unknown primary; the suspicion of a systemic metabolic or endocrine disorder lay low on the list of differential diagnoses. Further investigations revealed gross skeletal changes and a hypoechoic right parathyroid mass. The total serum parathyroid hormone levels and ultrasound-guided fine needle aspiration cytology (FNAC) of the mandibular and parathyroid lesions provided the diagnosis of primary hyperparathyroidism presenting as a mandibular brown tumour. This case thus highlights the importance of a thorough diagnostic work-up for all lesions in the maxillofacial region and also serves to add another facet to the myriad of presentations associated with primary hyperparathyroidism. PMID- 17699708 TI - Benign cementoblastoma in a primary lower molar, a rarity. AB - An asymptomatic radiopacity surrounded by a radiolucent line was observed from a panoramic radiograph of an 11-year-old girl. The lesion was associated with the mesial root of the lower right second primary molar. The radiographic appearance of the lesion suggested a benign cementoblastoma. Histological diagnosis after surgical excision of the tumour and extraction of the tooth confirmed the radiographic diagnosis. Benign cementoblastomas associated with primary teeth are extremely rare lesions. To our knowledge, only eight cases have been reported in the literature. PMID- 17699709 TI - Apnoea-hypopnoea and mandibular retrusion as uncommon findings associated with Proteus syndrome. AB - The aetiology of Proteus syndrome (PS) is yet unclear. This disease includes partial gigantism of the hands and/or feet, nevi, hemihypertrophy due to overgrowth of long bones, subcutaneous tumours, macrocephaly, cranial hyperostosis, and pulmonary and renal abnormalities. This case report is about a 17-year-old boy with two uncommon findings associated with PS: apnoea-hypopnoea and mandibular retrusion. A multidisciplinary team was important to provide professional care for this patient. Dentists and physicians proposed an adjusted treatment plan. Maxillary disjunction was achieved with a combination of orthodontic treatment and surgical procedure. This represented the initial care for malocclusion treatment and also the preparation for orthognathic surgery. The oral maxillofacial surgeon and the otorhinolaryngologist proposed this approach in an attempt to improve pharynx airflow. The patient has been followed for almost 3 years. PMID- 17699710 TI - Importance of localization of impacted teeth. PMID- 17699713 TI - Targeting the AKT protein kinase for cancer chemoprevention. AB - The AKT protein kinase transduces signals from growth factors and oncogenes to downstream targets that control crucial elements in tumor development. The AKT pathway is one of the most frequently hyperactivated signaling pathways in human cancers. Available data are reviewed herein to support targeting the AKT kinase for cancer prevention. This review will present data to show that AKT is up regulated in preneoplastic lesions across a broad range of target tissues, briefly describe drug development efforts in this area, and present evidence that down-regulation of AKT signaling may be a viable strategy to prevent cancer. PMID- 17699714 TI - Bevacizumab plus 5-fluorouracil induce growth suppression in the CWR-22 and CWR 22R prostate cancer xenografts. AB - Prostate cancer is the most common malignancy in men. Although patients with metastatic prostate cancer can benefit from androgen ablation, most of them will die of prostate cancer progression to an androgen-refractory state. In the present study, the effects of docetaxel, bevacizumab, 5-fluorouracil (5-FU), bevacizumab plus docetaxel, and bevacizumab plus 5-FU on the growth of human CWR 22 (androgen-dependent) and CWR-22R (androgen-independent) prostate carcinoma xenografts were investigated. We report that i.p. administration of 10 mg/kg docetaxel at 1-week interval, 5 mg/kg/ bevacizumab once every 2 weeks, or 12.5 mg/kg 5-FU, bevacizumab/docetaxel, or bevacizumab/5-FU weekly to severe combined immunodeficient mice bearing prostate cancer xenografts (12 mice per treatment group) for 21 days resulted in 22.5 +/- 8%, 23 +/- 7%, 31 +/- 8%, 22 +/- 6%, and 81 +/- 5% growth inhibition, respectively. Greatest growth suppression was observed in bevacizumab/5-FU treatment. Bevacizumab/5-FU-induced growth suppression was associated with reduction in microvessel density, inhibition of cell proliferation; up-regulation of phosphatase and tensin homologue, p21(Cip1/Waf1), p16(INK4a), and p27(Kip1); hypophosphorylation of retinoblastoma protein; and inhibition of Akt/mammalian target of rapamycin pathway. Our data indicate that bevacizumab/5-FU effectively inhibits angiogenesis and cell cycle progression and suggest that bevacizumab/5-FU may represent an alternative treatment for patients with prostate cancer. PMID- 17699715 TI - Selective cell death of oncogenic Akt-transduced brain cancer cells by etoposide through reactive oxygen species mediated damage. AB - We have established several glioma-relevant oncogene-engineered cancer cells to reevaluate the oncogene-selective cytotoxicity of previously well-characterized anticancer drugs, such as etoposide, doxorubicin, staurosporine, and carmustine. Among several glioma-relevant oncogenes (activated epidermal growth factor receptor, Ras, and Akt, as well as Bcl-2 and p53DD used in the present study), the activated epidermal growth factor receptor, Ras, and Akt exerted oncogenic transformation of Ink4a/Arf(-/-) murine astrocyte cells. We identified that etoposide, a topoisomerase II inhibitor, caused selective killing of myristylated Akt (Akt-myr)-transduced Ink4a/Arf(-/-) astrocytes and U87MG cells in a dose- and time-dependent manner. Etoposide-selective cytotoxicity in the Akt-myr-transduced cells was shown to be caused by nonapoptotic cell death and occurred in a p53 independent manner. Etoposide caused severe reactive oxygen species (ROS) accumulation preferentially in the Akt-myr-transduced cells, and elevated ROS rendered these cells highly sensitive to cell death. The etoposide-selective cell death of Akt-myr-transduced cells was attenuated by pepstatin A, a lysosomal protease inhibitor. In the present study, we show that etoposide might possess a novel therapeutic activity for oncogenic Akt-transduced cancer cells to kill preferentially through ROS-mediated damage. PMID- 17699716 TI - Rapamycin inhibits multiple stages of c-Neu/ErbB2 induced tumor progression in a transgenic mouse model of HER2-positive breast cancer. AB - Amplification of the HER2 (ErbB2, c-Neu) proto-oncogene in breast cancer is associated with poor prognosis and high relapse rates. HER2/ErbB2, in conjunction with ErbB3, signals through the Akt/phosphatidylinositol 3-kinase pathway and leads to the activation of mammalian target of rapamycin (mTOR), a critical mRNA translation regulator that controls cell growth. Gene expression analysis of mammary tumors collected from mouse mammary tumor virus-c-Neu transgenic mice revealed that mRNA levels of several mTOR pathway members were either up regulated (p85/phosphatidylinositol 3-kinase and p70S6 kinase) or down-regulated (eIF-4E-BP1) in a manner expected to enhance signaling through this pathway. Treatment of these mice with the mTOR inhibitor rapamycin caused growth arrest and regression of primary tumors with no evidence of weight loss or generalized toxicity. The treatment effects were due to decreased proliferation, associated with reduced cyclin D1 expression, and increased cell death in primary tumors. Whereas many of the dead epithelial cells had the histopathologic characteristics of ischemic necrosis, rapamycin treatment was not associated with changes in microvascular density or apoptosis. Rapamycin also inhibited cellular proliferation in lung metastases. In summary, data from this preclinical model of ErbB2/Neu-induced breast cancer show that inhibition of the mTOR pathway with rapamycin blocks multiple stages of ErbB2/Neu-induced tumorigenic progression. PMID- 17699717 TI - Acute pharmacodynamic and antivascular effects of the vascular endothelial growth factor signaling inhibitor AZD2171 in Calu-6 human lung tumor xenografts. AB - The vascular endothelial growth factor-A (VEGF-A) signaling pathway, a key stimulant of solid tumor vascularization, is primarily dependent on the activation of the endothelial cell surface receptor VEGF receptor-2 (VEGFR-2). AZD2171 is an oral, highly potent small-molecule inhibitor of VEGFR tyrosine kinase activity that inhibits angiogenesis and the growth of human tumor xenografts in vivo. Here, we show pharmacodynamic changes in VEGFR-2 phosphorylation induced by AZD2171. In mouse lung tissue, a single dose of AZD2171 at 6 mg/kg inhibited VEGF-A-stimulated VEGFR-2 phosphorylation by 87% at 2 h with significant inhibition (>or=60%) maintained to 24 h. To examine inhibition of VEGFR-2 phosphorylation in tumor vasculature by immunohistochemistry, a comprehensive assessment of antibodies to various phosphorylation sites on the receptor was undertaken. Antibodies to the phosphotyrosine epitopes pY1175/1173 and pY1214/1212 were found suitable for this application. Calu-6 human lung tumor xenografts, from mice receiving AZD2171 or vehicle treatment (p.o., once daily), were examined by immunohistochemistry. A significant reduction in tumor vessel staining of phosphorylated VEGFR-2 (pVEGFR 2) was evident within 28 h of AZD2171 treatment (6 mg/kg). This effect preceded a significant reduction in tumor microvessel density, which was detectable following 52 h of AZD2171 treatment. These data show that AZD2171 is a potent inhibitor of VEGFR-2 activation in vivo and suggest that AZD2171 delivers therapeutic benefit in Calu-6 tumors by targeting vessels dependent on VEGFR-2 signaling for survival. In addition, this work highlights the utility of measuring either pY1175/1173 or pY1214/1212 on VEGFR-2 as a pharmacodynamic marker of VEGFR-2 activation. PMID- 17699718 TI - AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. AB - Constitutive activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway in human cancers is often associated with mutational activation of BRAF or RAS. MAPK/ERK kinase 1/2 kinases lie downstream of RAS and BRAF and are the only acknowledged activators of ERK1/2, making them attractive targets for therapeutic intervention. AZD6244 (ARRY-142886) is a potent, selective, and ATP-uncompetitive inhibitor of MAPK/ERK kinase 1/2. In vitro cell viability inhibition screening of a tumor cell line panel found that lines harboring BRAF or RAS mutations were more likely to be sensitive to AZD6244. The in vivo mechanisms by which AZD6244 inhibits tumor growth were investigated. Chronic dosing with 25 mg/kg AZD6244 bd resulted in suppression of growth of Colo-205, Calu-6, and SW-620 xenografts, whereas an acute dose resulted in significant inhibition of ERK1/2 phosphorylation. Increased cleaved caspase-3, a marker of apoptosis, was detected in Colo-205 and Calu-6 but not in SW-620 tumors where a significant decrease in cell proliferation was detected. Chronic dosing of AZD6244 induced a morphologic change in SW-620 tumors to a more differentiated phenotype. The potential of AZD6244 in combination with cytotoxic drugs was evaluated in mice bearing SW-620 xenografts. Treatment with tolerated doses of AZD6244 and either irinotecan or docetaxel resulted in significantly enhanced antitumor efficacy relative to that of either agent alone. These results indicate that AZD6244 has potential to inhibit proliferation and induce apoptosis and differentiation, but the response varies between different xenografts. Moreover, enhanced antitumor efficacy can be obtained by combining AZD6244 with the cytotoxic drugs irinotecan or docetaxel. PMID- 17699719 TI - Context-dependent roles of mutant B-Raf signaling in melanoma and colorectal carcinoma cell growth. AB - Mutational activation of Ras and a key downstream effector of Ras, the B-Raf serine/threonine kinase, has been observed in melanomas and colorectal carcinomas. These observations suggest that inhibition of B-Raf activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK) and the extracellular signal-regulated kinase MAPK cascade may be an effective approach for the treatment of RAS and B-RAF mutation-positive melanomas and colon carcinomas. Although recent studies with interfering RNA (RNAi) and pharmacologic inhibitors support a critical role for B-Raf signaling in melanoma growth, whether mutant B-Raf has an equivalent role in promoting colorectal carcinoma growth has not been determined. In the present study, we used both RNAi and pharmacologic approaches to further assess the role of B-Raf activation in the growth of human melanomas and additionally determined if a similar role for mutant B-Raf is seen for colorectal carcinoma cell lines. We observed that RNAi suppression of mutant B-Raf(V600E) expression strongly suppressed the anchorage dependent growth of B-RAF mutation-positive melanoma, but not colorectal carcinoma, cells. However, the anchorage-independent and tumorigenic growth of B RAF mutation-positive colorectal carcinomas was dependent on mutant B-Raf function. Finally, pharmacologic inhibition of MEK and Raf was highly effective at inhibiting the growth of B-RAF mutation-positive melanomas and colorectal carcinoma cells, whereas inhibitors of other protein kinases activated by Ras (AKT, c-Jun NH(2)-terminal kinase, and p38 MAPK) were less effective. Our observations suggest that Raf and MEK inhibitors may be effective for the treatment of B-RAF mutation-positive colorectal carcinomas as well as melanomas. PMID- 17699720 TI - Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo. AB - Chemopreventive agents in colorectal cancer possess either antiproliferative or anti-inflammatory actions. Nonsteroidal anti-inflammatory drugs (NSAID) and cyclooxygenase-2 inhibitors have shown promise, but are compromised by side effects. Nitric oxide donor NSAIDs are organic nitrates conjugated via a labile linker to an NSAID, originally designed for use in pain relief, that have shown efficacy in colorectal cancer chemoprevention. The NO chimera, GT-094, is a novel nitrate containing an NSAID and disulfide pharmacophores, a lead compound for the design of agents specifically for colorectal cancer. GT-094 is the first nitrate reported to reduce aberrant crypt foci (by 45%) when administered after carcinogen in the standard azoxymethane rat model of colorectal cancer. Analysis of proximal and distal colon tissue from 8- and 28-week rat/azoxymethane studies showed that GT-094 treatment reduced colon crypt proliferation by 30% to 69%, reduced inducible NO synthase (iNOS) levels by 33% to 67%, reduced poly(ADP ribose)polymerase-1 expression and cleavage 2- to 4-fold, and elevated levels of p27 in the distal colon 3-fold. Studies in cancer cell cultures recapitulated actions of GT-094: antiproliferative activity and transient G(2)-M phase cell cycle block were measured in Caco-2 cells; apoptotic activity was examined but not observed; anti-inflammatory activity was seen in the inhibition of up regulation of iNOS and endogenous NO production in lipopolysaccharide (LPS) induced RAW 264.7 cells. In summary, antiproliferative, anti-inflammatory, and cytoprotective activity observed in vivo and in vitro support GT-094 as a lead compound for the design of NO chimeras for colorectal cancer chemoprevention. PMID- 17699721 TI - Therapeutic targeting of nuclear receptor corepressor misfolding in acute promyelocytic leukemia cells with genistein. AB - We have recently reported that PML-RAR-induced misfolding of the N-CoR protein could be reversed by retinoic acid (RA), a therapeutic agent that promotes differentiation of acute promyelocytic leukemia (APL) cells. This finding suggests a role of misfolded N-CoR in the differentiation arrest of APL cells and highlights its significance as a potential molecular target in protein conformation-based therapy for APL. Based on this hypothesis, we investigated the therapeutic potential of several protein conformation modifiers on APL-derived cell lines NB4 and NB4-R1. Through a small-scale screening of these selected compounds, we identified genistein as a potent inhibitor of growth of both RA sensitive and RA-resistant APL cells. Genistein inhibited the growth of NB4 cells through its collective regulatory effects on cell cycle progression, differentiation, and apoptosis. Genistein-induced apoptosis of NB4 cells was mediated by activation of caspase-9 and caspase-3 and was associated with a decrease in mitochondrial transmembrane potential and cytosolic release of cytochrome c. Genistein promoted differentiation of both RA-sensitive and RA resistant NB4 cells and induced cell cycle arrest by blocking the G(2)-M transition. Genistein up-regulated the expression of PML and N-CoR proteins, promoted degradation of PML-RAR, and reorganized the microspeckled distribution of PML oncogenic domains to a normal dot-like pattern in NB4 cells. Moreover, genistein significantly reversed the PML-RAR-induced misfolding of N-CoR protein by possibly inhibiting the selective phosphorylation-dependent binding of N-CoR to PML-RAR. These findings identify genistein as a potent modifier of N-CoR protein conformation and highlights its therapeutic potential in both RA sensitive and RA-resistant APL cells. PMID- 17699722 TI - CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling. AB - Lysophosphatidic acid receptors stimulate a Galpha(12/13)/RhoA-dependent gene transcription program involving the serum response factor (SRF) and its coactivator and oncogene, megakaryoblastic leukemia 1 (MKL1). Inhibitors of this pathway could serve as useful biological probes and potential cancer therapeutic agents. Through a transcription-based high-throughput serum response element luciferase screening assay, we identified two small-molecule inhibitors of this pathway. Mechanistic studies on the more potent CCG-1423 show that it acts downstream of Rho because it blocks SRE.L-driven transcription stimulated by Galpha(12)Q231L, Galpha(13)Q226L, RhoA-G14V, and RhoC-G14V. The ability of CCG 1423 to block transcription activated by MKL1, but not that induced by SRF-VP16 or GAL4-VP16, suggests a mechanism targeting MKL/SRF-dependent transcriptional activation that does not involve alterations in DNA binding. Consistent with its role as a Rho/SRF pathway inhibitor, CCG-1423 displays activity in several in vitro cancer cell functional assays. CCG-1423 potently (<1 mumol/L) inhibits lysophosphatidic acid-induced DNA synthesis in PC-3 prostate cancer cells, and whereas it inhibits the growth of RhoC-overexpressing melanoma lines (A375M2 and SK-Mel-147) at nanomolar concentrations, it is less active on related lines (A375 and SK-Mel-28) that express lower levels of Rho. Similarly, CCG-1423 selectively stimulates apoptosis of the metastasis-prone, RhoC-overexpressing melanoma cell line (A375M2) compared with the parental cell line (A375). CCG-1423 inhibited Rho dependent invasion by PC-3 prostate cancer cells, whereas it did not affect the Galpha(i)-dependent invasion by the SKOV-3 ovarian cancer cell line. Thus, based on its profile, CCG-1423 is a promising lead compound for the development of novel pharmacologic tools to disrupt transcriptional responses of the Rho pathway in cancer. PMID- 17699723 TI - Anticancer medicines in development: assessment of bioactivity profiles within the National Cancer Institute anticancer screening data. AB - We present an analysis of current anticancer compounds that are in phase I, II, or III clinical trials and their structural analogues that have been screened in the National Cancer Institute (NCI) anticancer screening program. Bioactivity profiles, measured across the NCI 60 cell lines, were examined for a correspondence between the type of cancer proposed for clinical testing and selective sensitivity to appropriately matched tumor subpanels in the NCI screen. These results find strongest support for using the NCI anticancer screen to select analogue compounds with selective sensitivity to the leukemia, colon, central nervous system, melanoma, and ovarian panels, but not for renal, prostate, and breast panels. These results are extended to applications of two dimensional structural features to further refine compound selections based on tumor panel sensitivity obtained from tumor screening results. PMID- 17699724 TI - The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity. AB - The effect of the potent and selective poly(ADP-ribose) (PAR) polymerase-1 [and PAR polymerase-2] inhibitor CEP-8983 on the ability to sensitize chemoresistant glioblastoma (RG2), rhabdomyosarcoma (RH18), neuroblastoma (NB1691), and colon carcinoma (HT29) tumor cells to temozolomide- and camptothecin-induced cytotoxicity, DNA damage, and G(2)-M arrest and on the potentiation of chemotherapy-induced myelotoxicity was evaluated using in vitro assays. In addition, the effect of the prodrug CEP-9722 in combination with temozolomide and/or irinotecan on PAR accumulation and tumor growth was also determined using glioblastoma and/or colon carcinoma xenografts relative to chemotherapy alone. CEP-8983 sensitized carcinoma cells to the growth-inhibitory effects of temozolomide and/or SN38 increased the fraction of and/or lengthened duration of time tumor cells accumulated in chemotherapy-induced G(2)-M arrest and sensitized tumor cells to chemotherapy-induced DNA damage and apoptosis. A granulocyte macrophage colony-forming unit colony formation assay showed that coincubation of CEP-8983 with temozolomide or topotecan did not potentiate chemotherapy associated myelotoxicity. CEP-9722 (136 mg/kg) administered with temozolomide (68 mg/kg for 5 days) or irinotecan (10 mg/kg for 5 days) inhibited significantly the growth of RG2 tumors (60%) or HT29 tumors (80%) compared with temozolomide or irinotecan monotherapy, respectively. In addition, CEP-9722 showed "stand alone" antitumor efficacy in these preclinical xenografts. In vivo biochemical efficacy studies showed that CEP-9722 attenuated PAR accumulation in glioma xenografts in a dose- and time-related manner. These data indicate that CEP-8983 and its prodrug are effective chemosensitizing agents when administered in combination with select chemotherapeutic agents against chemoresistant tumors. PMID- 17699725 TI - The antipsychotic drug trifluoperazine inhibits DNA repair and sensitizes non small cell lung carcinoma cells to DNA double-strand break induced cell death. AB - Trifluoperazine (TFP), a member of the phenothiazine class of antipsychotic drugs, has been shown to augment the cytotoxicity of the DNA-damaging agent bleomycin. In the present study, we investigated the effect of trifluoperazine on (a) survival of bleomycin-treated human non-small cell lung carcinoma U1810 cells, (b) induction and repair of bleomycin-induced DNA strand breaks, and (c) nonhomologous end-joining (NHEJ), the major DNA double-strand break (DSB) repair pathway in mammalian cells. By using a clonogenic survival assay, we show here that concomitant administration of trifluoperazine at a subtoxic concentration enhances the cytotoxicity of bleomycin. Moreover, trifluoperazine also increases the longevity of bleomycin-induced DNA strand breaks in U1810 cells, as shown by both comet assay and fraction of activity released (FAR)-assay. This action seems to be related to suppression of cellular DNA DSB repair activities because NHEJ mediated rejoining of DSBs occurs with significantly lower efficiency in the presence of trifluoperazine. We propose that TFP might be capable of inhibiting one or more elements of the DNA DSB repair machinery, thereby increasing the cytotoxicity of bleomycin in lung cancer cells. PMID- 17699726 TI - Alteration of dihydropyrimidine dehydrogenase expression by IFN-alpha affects the antiproliferative effects of 5-fluorouracil in human hepatocellular carcinoma cells. AB - Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU) and its activity is closely associated with cellular sensitivity to 5-FU. This study examines the role of DPD in the antiproliferative effects of 5-FU combined with IFN-alpha on hepatocellular carcinoma (HCC) cells in culture and asks whether IFN-alpha could affect DPD expression. The combined action of IFN-alpha and 5-FU on three HCC lines was quantified by a combination index method. Coadministration of IFN-alpha and 5-FU showed synergistic effects against HAK-1A and KYN-2 but antagonistic effects against KYN-3. The cellular expression levels of DPD mRNA and protein were markedly up-regulated in KYN-3 cells by IFN-alpha but were down-regulated in HAK 1A and KYN-2. The expression of thymidylate synthase mRNA and protein was down regulated by IFN-alpha in all three cell lines. Coadministration of a selective DPD inhibitor, 5-chloro-2,4-dihydroxypyridine (CDHP), enhanced the antiproliferative effect of 5-FU and IFN-alpha on KYN-3 approximately 4-fold. However, the synergistic effects of 5-FU and IFN-alpha on HAK-1A and KYN-2 were not affected by CDHP. The antiproliferative effect of 5-FU could thus be modulated by IFN-alpha, possibly through DPD expression, in HCC cells. Inhibition of DPD activity by CDHP may enhance the efficacy of IFN-alpha and 5-FU combination therapy in patients with HCC showing resistance to this therapy. PMID- 17699727 TI - A novel animal model to investigate fractionated radiotherapy-induced alimentary mucositis: the role of apoptosis, p53, nuclear factor-kappaB, COX-1, and COX-2. AB - Radiation-induced mucositis is a common and serious side effect of radiotherapy. Molecular mechanisms of mucosal injury, however, are still poorly understood and extremely difficult to study in humans. A novel Dark Agouti rat model using fractionated radiotherapy to induce mucositis has been developed to investigate the occurrence of alimentary mucosal injury. Twenty-four Dark Agouti rats were randomly assigned to receive either fractionated radiotherapy or no radiotherapy. The irradiated rats received a fractionated course of abdominal radiotherapy at 45 Gy/18 fractions/6 weeks treating thrice weekly (i.e., at a radiation dose of 2.5 Gy per fraction). After each week of radiation, a group of irradiated rats was killed. Histomorphology and mucin distribution in the alimentary tract was investigated. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was used to examine apoptosis in the colon and jejunum, and intestinal morphometry was used to assess villus length, crypt length, and mitotic crypt count. Immunohistochemistry of p53, nuclear factor-kappaB, cyclooxygenase (COX)-1, and COX-2 was also done. The fractionated radiotherapy course induced alimentary mucositis from week 1, with more severe injury seen in the small intestine. The hallmark appearance of apoptosis was present in the crypts of the small and large intestine. In the jejunum and colon, goblet cell disorganization and degeneration was obvious and crypt mitotic counts were severely depleted throughout the treatment. Expression of p53, nuclear factor kappaB, COX-1, and COX-2 was increased in the irradiated intestinal sections. Fractionated radiation-induced alimentary mucositis has been effectively documented in the Dark Agouti rat for the first time. Further studies investigating the molecular mechanisms underlying radiation-induced mucositis are planned to ultimately achieve anti-mucotoxic-targeted therapies. PMID- 17699728 TI - A bifunctional colchicinoid that binds to the androgen receptor. AB - Castrate-resistant prostate cancer (CRPC) continues to be dependent on the androgen receptor (AR) for disease progression. We have synthesized and evaluated a novel compound that is a conjugate of colchicine and an AR antagonist (cyanonilutamide) designed to inhibit AR function in CRPC. A problem in multifunctional AR-binding compounds is steric hindrance of binding to the embedded hydrophobic AR ligand-binding pocket. Despite the bulky side chain projecting off of the AR-binding moiety, this novel conjugate of colchicine and cyanonilutamide binds to AR with a K(i) of 449 nmol/L. Structural modeling of this compound in the AR ligand-binding domain using a combination of rational docking, molecular dynamics, and steered molecular dynamics simulations reveals a basis for how this compound, which has a rigid alkyne linker, is able to bind to AR. Surprisingly, we found that this compound also binds to tubulin and inhibits tubulin function to a greater degree than colchicine itself. The tubulin inhibiting activity of this compound increases cytoplasmic AR levels in prostate cancer cells. Finally, we found that this compound has greater toxicity against androgen-independent prostate cancer cells than the combination of colchicine and nilutamide. Together, these data point to several ways of inhibiting AR function in CRPC. PMID- 17699729 TI - A new class of anticancer alkylphospholipids uses lipid rafts as membrane gateways to induce apoptosis in lymphoma cells. AB - Single-chain alkylphospholipids, unlike conventional chemotherapeutic drugs, act on cell membranes to induce apoptosis in tumor cells. We tested four different alkylphospholipids, i.e., edelfosine, perifosine, erucylphosphocholine, and compound D-21805, as inducers of apoptosis in the mouse lymphoma cell line S49. We compared their mechanism of cellular entry and their potency to induce apoptosis through inhibition of de novo biosynthesis of phosphatidylcholine at the endoplasmic reticulum. Alkylphospholipid potency closely correlated with the degree of phosphatidylcholine synthesis inhibition in the order edelfosine > D 21805 > erucylphosphocholine > perifosine. In all cases, exogenous lysophosphatidylcholine, an alternative source for cellular phosphatidylcholine production, could partly rescue cells from alkylphospholipid-induced apoptosis, suggesting that phosphatidylcholine biosynthesis is a direct target for apoptosis induction. Cellular uptake of each alkylphospholipid was dependent on lipid rafts because pretreatment of cells with the raft-disrupting agents, methyl-beta cyclodextrin, filipin, or bacterial sphingomyelinase, reduced alkylphospholipid uptake and/or apoptosis induction and alleviated the inhibition of phosphatidylcholine synthesis. Uptake of all alkylphospholipids was inhibited by small interfering RNA (siRNA)-mediated blockage of sphingomyelin synthase (SMS1), which was previously shown to block raft-dependent endocytosis. Similar to edelfosine, perifosine accumulated in (isolated) lipid rafts independent on raft sphingomyelin content per se. However, perifosine was more susceptible than edelfosine to back-extraction by fatty acid-free serum albumin, suggesting a more peripheral location in the cell due to less effective internalization. Overall, our results suggest that lipid rafts are critical membrane portals for cellular entry of alkylphospholipids depending on SMS1 activity and, therefore, are potential targets for alkylphospholipid anticancer therapy. PMID- 17699730 TI - 213Bi-induced death of HSC45-M2 gastric cancer cells is characterized by G2 arrest and up-regulation of genes known to prevent apoptosis but induce necrosis and mitotic catastrophe. AB - Tumor cells are efficiently killed after incubation with alpha-emitter immunoconjugates targeting tumor-specific antigens. Therefore, application of alpha-emitter immunoconjugates is a promising therapeutic option for treatment of carcinomas that are characterized by dissemination of single tumor cells in the peritoneum like ovarian cancer or gastric cancer. In diffuse-type gastric cancer, 10% of patients express mutant d9-E-cadherin on the surface of tumor cells that is targeted by the monoclonal antibody d9MAb. Coupling of the alpha-emitter (213)Bi to d9MAb provides an efficient tool to eliminate HSC45-M2 gastric cancer cells expressing d9-E-cadherin in vitro and in vivo. Elucidation of the molecular mechanisms triggered by alpha-emitters in tumor cells could help to improve strategies of alpha-emitter radioimmunotherapy. For that purpose, gene expression of (213)Bi-treated tumor cells was quantified using a real time quantitative-PCR low-density array covering 380 genes in combination with analysis of cell proliferation and the mode of cell death. We could show that (213)Bi-induced cell death was initiated by G(2) arrest; up-regulation of tumor necrosis factor (TNF), SPHK1, STAT5A, p21, MYT1, and SSTR3; and down-regulation of SPP1, CDC25 phosphatases, and of genes involved in chromosome segregation. Together with morphologic changes, these results suggest that (213)Bi activates death cascades different from apoptosis. Furthermore, (213)Bi-triggered up-regulation of SSTR3 could be exploited for improvement of the therapeutic regimen. PMID- 17699731 TI - Development of a fluorescence-based assay to screen antiviral drugs against Kaposi's sarcoma associated herpesvirus. AB - Tumors associated with Kaposi's sarcoma-associated herpesvirus infection include Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Virtually all of the tumor cells in these cancers are latently infected and dependent on the virus for survival. Latent viral proteins maintain the viral genome and are required for tumorigenesis. Current prevention and treatment strategies are limited because they fail to specifically target the latent form of the virus, which can persist for the lifetime of the host. Thus, targeting latent viral proteins may prove to be an important therapeutic modality for existing tumors as well as in tumor prevention by reducing latent virus load. Here, we describe a novel fluorescence-based screening assay to monitor the maintenance of the Kaposi's sarcoma-associated herpesvirus genome in B lymphocyte cell lines and to identify compounds that induce its loss, resulting in tumor cell death. PMID- 17699732 TI - Therapeutic ultrasound facilitates antiangiogenic gene delivery and inhibits prostate tumor growth. AB - Gene therapy clinical trials are limited due to several hurdles concerning the type of vector used, particularly, the viral vectors, and transfection efficacy when non-viral vectors are used. Therapeutic ultrasound is a promising non-viral technology that can be used in the clinical setting. Here, for the first time, we show the efficacy of therapeutic ultrasound to deliver genes encoding for hemopexin-like domain fragment (PEX), an inhibitor of angiogenesis, to prostate tumors in vivo. Moreover, the addition of an ultrasound contrast agent (Optison) to the transfection process was evaluated. Prostate cancer cells and endothelial cells (EC) were transfected in vitro with cDNA-PEX using therapeutic ultrasound alone (TUS + pPEX) or with Optison (TUS + pPEX + Optison). The biological activity of the expressed PEX was assessed using proliferation, migration, and apoptosis assays done on EC and prostate cancer cells. TUS + pPEX + Optison led to the inhibition of EC and prostate cancer cell proliferation (<65%), migration (<50%), and an increase in apoptosis. In vivo, C57/black mice were inoculated s.c. with prostate cancer cells. The tumors were treated with TUS + pPEX and TUS + pPEX + Optison either once or repeatedly. Tumor growth was evaluated, after which histology and immunohistochemistry analyses were done. A single treatment of TUS + pPEX led to a 35% inhibition in tumor growth. Using TUS + PEX + Optison led to an inhibition of 50%. Repeated treatments of TUS + pPEX + Optison were found to significantly (P < 0.001) inhibit prostate tumor growth by 80%, along with the angiogenic indices, with no toxicity to the surrounding tissues. These results depict the efficacy of therapeutic ultrasound as a non-viral technology to efficiently deliver genes to tumors in general, and to deliver angiogenic inhibitors to prostate cancer in particular. PMID- 17699733 TI - Thematic review series: Adipocyte Biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease. AB - In the context of obesity and its related maladies, the adipocyte plays a central role in the balance, or imbalance, of metabolic homeostasis. An obese, hypertrophic adipocyte is challenged by many insults, including surplus energy, inflammation, insulin resistance, and considerable stress to various organelles. The endoplasmic reticulum (ER) is one such vital organelle that demonstrates significant signs of stress and dysfunction in obesity and insulin resistance. Under normal conditions, the ER must function in the unique and trying environment of the adipocyte, adapting to meet the demands of increased protein synthesis and secretion, energy storage in the form of triglyceride droplet formation, and nutrient sensing that are particular to the differentiated fat cell. When nutrients are in pathological excess, the ER is overwhelmed and the unfolded protein response (UPR) is activated. Remarkably, the consequences of UPR activation have been causally linked to the development of insulin resistance through a multitude of possible mechanisms, including c-jun N-terminal kinase activation, inflammation, and oxidative stress. This review will focus on the function of the ER under normal conditions in the adipocyte and the pathological effects of a stressed ER contributing to adipocyte dysfunction and a thwarted metabolic homeostasis. PMID- 17699734 TI - Luteinizing hormone beta promoter stimulation by adenylyl cyclase and cooperation with gonadotropin-releasing hormone 1 in transgenic mice and LBetaT2 Cells. AB - Rat luteinizing hormone beta (Lhb) gene transcription is stimulated by hypothalamic gonadotropin-releasing hormone 1 (GnRH1), and this response may be modulated by other signaling pathways such as cAMP. Here we characterize the ability of cAMP, alone or with GnRH1, to stimulate Lhb gene transcription in mouse pituitary and clonal gonadotroph cells. Both cAMP and pituitary adenylyl cyclase-activating peptide increase GnRH1 stimulation of luciferase activity in pituitaries of mice expressing the rat Lhb-luciferase transgene, suggesting cAMP and GnRH1 pathways interact in vivo. cAMP stimulation of the Lhb-luciferase transgene was similar between females in metestrus and proestrus, but GnRH1 stimulation was greater at proestrus. Additive effects with combined treatments were observed at metestrus and proestrus. Elevated intracellular cAMP stimulated Lhb promoter activity in LbetaT2 clonal gonadotroph cells, alone and with GnRH1. In LbetaT2 cells, cAMP stimulation of the Lhb promoter was eliminated by inhibition of protein kinase A (PKA); GnRH1 stimulation was partially suppressed by either PKA or protein kinase C inhibitors. Only the proximal GnRH1-responsive region of the promoter was required for cAMP stimulation, and mutation of the 3' NR5A1 site diminished the response. Regulation of primary mRNA transcripts from the endogenous Lhb gene by cAMP and GnRH1 correlated with results from the Lhb luciferase transgene or transfected promoter. Occupancy of the endogenous promoter by EGR1 was increased by GnRH1 with or without forskolin, but forskolin alone had little effect. Thus, cAMP stimulation of Lhb promoter activity, and enhancement of GnRH1 stimulation, occurs in multiple physiological states independent of steroid status, via a PKA-dependent mechanism. PMID- 17699735 TI - A heterozygous mutation disrupting the SPAG16 gene results in biochemical instability of central apparatus components of the human sperm axoneme. AB - The SPAG16 gene encodes two major transcripts, one for the 71-kDa SPAG16L, which is the orthologue of the Chlamydomonas rheinhardtii central apparatus protein PF20, and a smaller transcript, which codes for the 35-kDa SPAG16S nuclear protein that represents the C-terminus (exons 11-16) of SPAG16L. We have previously reported that a targeted mutation in exon 11 of the Spag16 gene impairs spermatogenesis and prevents transmission of the mutant allele in chimeric mice. In the present report, we describe a heterozygous mutation in exon 13 of the SPAG16 gene, which causes a frame shift and premature stop codon, affording the opportunity to compare mutations with similar impacts on SPAG16L and SPAG16S for male reproductive function in mice and men. We studied two male heterozygotes for the SPAG16 mutation, both of which were fertile. Freezing boiling of isolated sperm from both affected males resulted in the loss of the SPAG16L protein, SPAG6, another central apparatus protein that interacts with SPAG16L, and the 28-kDa fragment of SPAG17, which associates with SPAG6. These proteins were also lost after freezing-boiling cycles of sperm extracts from mice that were heterozygous for an inactivating mutation (exons 2 and 3) in Spag16. Our findings suggest that a heterozygous mutation that affects both SPAG16L and SPAG16S does not cause male infertility in man, but is associated with reduced stability of the interacting proteins of the central apparatus in response to a thermal challenge, a phenotype shared by the sperm of mice heterozygous for a mutation that affects SPAG16L. PMID- 17699736 TI - Impaired reproduction in three-spined sticklebacks exposed to ethinyl estradiol as juveniles. AB - To investigate the population-level effects of exposure to environmental endocrine disrupters, a mesocosm-scale study was carried out in which the reproductive performance of groups of free-spawning three-spined sticklebacks, Gasterosteus aculeatus, exposed as juveniles to a model estrogen, was assessed. Juvenile sticklebacks were exposed to ethinyl estradiol (EE(2)) at measured concentrations of (mean +/- SEM) 1.75 +/- 0.37 ng L(-1) and 27.7 +/- 1.08 ng L( 1) for 4 wk posthatch and then reared thereafter in pristine lake water until they reached adulthood. Exposure to the higher EE(2) concentration resulted in the occurrence of ovotestis among males, whereas no gonadal abnormalities were evident among males exposed to the lower concentration of EE(2). In addition, when spawning was allowed in the mesocosm environment, fewer nests were built per male, and fewer eggs were deposited per nest, in the group exposed to 27.7 ng L( 1). Males from this group also exhibited a less intense nuptial coloration than control males. In the group exposed to 1.75 ng L(-1) EE(2) posthatch, significantly fewer nests were built than in the control group. These results demonstrate that the timing of exposure to estrogenic contaminants, in developmental terms, is critically important. Short-term exposure to estrogens as juveniles can clearly influence reproductive performance as adults, despite all growth and development subsequent to the exposure period taking place in an estrogen-free environment. In addition, these results suggest that reproductive dysfunction can occur even in fish with no gross abnormalities in gonadal structure. This suggests that the absence of gonadal intersex is not a reliable indicator of the reproductive potential, or estrogen-exposure history, of fish populations or the only important factor involved in compromising the reproduction of estrogen-exposed fish. PMID- 17699737 TI - Catechol-o-methyltransferase and methoxyestradiols participate in the intraoviductal nongenomic pathway through which estradiol accelerates egg transport in cycling rats. AB - Estradiol (E(2)) accelerates oviductal egg transport through intraoviductal nongenomic pathways in cyclic rats and through genomic pathways in pregnant rats. This shift in pathways, which we have provisionally designated as intracellular path shifting (IPS), is caused by mating-associated signals and represents a novel and hitherto unrecognized phenomenon. The mechanism underlying IPS is currently under investigation. Using microarray analysis, we identified several genes the expression levels of which changed in the rat oviduct within 6 hours of mating. Among these genes, the mRNA level for the enzyme catechol-O methyltransferase (COMT), which produces methoxyestradiols from hydroxyestradiols, decreased 6-fold, as confirmed by real-time PCR. O-methylation of 2-hydroxyestradiol was up to 4-fold higher in oviductal protein extracts from cyclic rats than from pregnant rats and was blocked by OR486, which is a selective inhibitor of COMT. The levels in the rat oviduct of mRNA and protein for cytochrome P450 isoforms 1A1 and 1B1, which form hydroxyestradiols, were detected by RT-PCR and Western blotting. We explored whether methoxyestradiols participate in the pathways involved in E(2)-accelerated egg transport. Intrabursal application of OR486 prevented E(2) from accelerating egg transport in cyclic rats but not in pregnant rats, whereas 2-methoxyestradiol (2ME) and 4 methoxyestradiol mimicked the effect of E(2) on egg transport in cyclic rats but not in pregnant rats. The effect of 2ME on egg transport was blocked by intrabursal administration of the protein kinase inhibitor H-89 or the antiestrogen ICI 182780, but not by actinomycin D or OR486. We conclude that in the absence of mating, COMT-mediated formation of methoxyestradiols in the oviduct is essential for the nongenomic pathway through which E(2) accelerates egg transport in the rat oviduct. Yet unidentified mating-associated signals, which act directly on oviductal cells, shut down the E(2) nongenomic signaling pathway upstream and downstream of methoxyestradiols. These findings highlight a physiological role for methoxyestradiols in the female genital tract, thereby confirming the occurrence of and providing a partial explanation for the mechanism underlying IPS. PMID- 17699738 TI - Assessment of the long-term and transgenerational consequences of perturbing preimplantation embryo development in mice. AB - Perturbations of the development of preimplantation embryos may have long-term consequences for the health of progeny. There are no standardized methods for assessing such risks. The OECD/OCDE 416 Guideline for Testing of Chemicals (Two Generation Reproduction Toxicity Study) is a standardized assay for detecting potential toxic effects of chemicals. The present study assessed the utility of this guideline for identifying long-term consequences of perturbing preimplantation development. Extended culturing of mammalian zygotes commonly results in retarded preimplantation development. Mouse zygotes were cultured in vitro for 96 h until the blastocyst stage (cultured blastocysts) or blastocysts were collected from the Day-3.5 uterus (in vivo blastocysts). The resulting blastocysts were transferred to the uteri of pseudopregnant recipients (P generation). Progeny from both treatments were mated for a further two generations (F1 and F2 generations). There was no effect of treatment group on gross fertility across the generations tested. Progeny of the cultured blastocysts had lower body weights to the time of weaning compared to in vivo blastocysts in the P and F1 generations, but not in the F2 generation. At maturity, there was no effect of treatment group on body weight, although thyroid weight was higher in the in vivo blastocyst group in the P generation, while the brain, pituitary, and kidneys were larger in the progeny of the cultured blastocysts of the F1 generation. The OECD/OCDE 416 assessment may have a role as a standardized test for the assessment of the biological consequences of perturbing the growth environment of the preimplantation embryo. Embryo culture influenced the somatometric parameters of the resulting progeny, some of which were maintained across a generation. PMID- 17699739 TI - B-9972 (D-Arg-[Hyp3,Igl5,Oic7,Igl8]-bradykinin) is an inactivation-resistant agonist of the bradykinin B2 receptor derived from the peptide antagonist B-9430 (D-Arg-[Hyp3,Igl5,D-Igl7,Oic8]-bradykinin): pharmacologic profile and effective induction of receptor degradation. AB - The bradykinin B(2) receptor is a heptahelical receptor regulated by a cycle of phosphorylation, endocytosis, and extensive recycling at the cell surface following agonist stimulation. B-9430 (d-Arg-[Hyp(3),Igl(5),D-Igl(7),Oic(8)] bradykinin) is a second generation peptide antagonist found to be competitive at the human B(2) receptor and insurmountable at the rabbit B(2) receptor (contractility assays, isolated human umbilical and rabbit jugular veins). Two isomers of this peptide were prepared: B-10344 (D-Arg-[Hyp(3),Igl(5),Oic(7),D Igl(8)]-bradykinin; inverted sequence Oic(7), D-Igl(8)) and B-9972 (D-Arg [Hyp(3),Igl(5),Oic(7),Igl(8)]-bradykinin); they are low- and high-potency agonists, respectively, in vascular preparations. The potency gap between bradykinin and B-9972 is narrow in contractility assays, despite the fact that B 9972 affinity is 7-fold inferior at the rabbit B(2) receptor (radioligand binding competition assay). The effects of agonists on receptors were compared using two chimerical constructions based on rabbit B(2) receptors: conjugate of the B(2) receptor with green fluorescent protein (B(2)R-GFP) and the N-terminally tagged conjugate of the myc epitope with the B(2) receptor. Imaging and immunoblotting showed that B-9972 induced a persistent endocytosis of cell surface B(2) receptors in human embryonic kidney 293 cells with slow receptor degradation (weak after 3 h of treatment, important at 12 h) and B(2)R-GFP desensitization ([(3)H]bradykinin endocytosis and extracellular signal-regulated kinase 1/2 phosphorylation assays). Bradykinin was not active in this respect but when combined with captopril, induced some degradation. B-9430 reduced the endocytosis and degradation of B(2) receptors by the agonists. The results illustrate the agonist-antagonist transition in B(2) receptor peptide ligands with a constrained C-terminal structure, the importance of species in their pharmacological profile, and the possibility of selectively degrading receptors using a peptidase resistant agonist. PMID- 17699740 TI - The transcriptional coactivator Maml1 is required for Notch2-mediated marginal zone B-cell development. AB - Signaling mediated by various Notch receptors and their ligands regulates diverse biological processes, including lymphoid cell fate decisions. Notch1 is required during T-cell development, while Notch2 and the Notch ligand Delta-like1 control marginal zone B (MZB) cell development. We previously determined that Mastermind like (MAML) transcriptional coactivators are required for Notchinduced transcription by forming ternary nuclear complexes with Notch and the transcription factor CSL. The 3 MAML family members (MAML1-MAML3) are collectively essential for Notch activity in vivo, but whether individual MAMLs contribute to the specificity of Notch functions is unknown. Here, we addressed this question by studying lymphopoiesis in the absence of the Maml1 gene. Since Maml1(-/-) mice suffered perinatal lethality, hematopoietic chimeras were generated with Maml1(-/-), Maml1(+/-), or wild-type fetal liver progenitors. Maml1 deficiency minimally affected T-cell development, but was required for the development of MZB cells, similar to the phenotype of Notch2 deficiency. Moreover, the number of MZB cells correlated with Maml1 gene dosage. Since all 3 Maml genes were expressed in MZB cells and their precursors, these results suggest that Maml1 is specifically required for Notch2 signaling in MZB cells. PMID- 17699741 TI - Galphai2 is required for chemokine-induced neutrophil arrest. AB - Chemokines, including CXCL1, participate in neutrophil recruitment by triggering the activation of integrins, which leads to arrest from rolling. The downstream signaling pathways which lead to integrin activation and neutophil arrest following G-protein-coupled receptor engagement are incompletely understood. To test whether Galpha(i2) is involved, mouse neutrophils in their native whole blood were investigated in mouse cremaster postcapillary venules and in flow chambers coated with P-selectin, ICAM-1, and CXCL1. Gnai2(-/-) neutrophils showed significantly reduced CXCL1-induced arrest in vitro and in vivo. Similar results were obtained with leukotriene B(4) (LTB(4)). Lethally irradiated mice reconstituted with Gnai2(-/-) bone marrow showed a similar defect in chemoattractant-induced arrest as that of Gnai2(-/-) mice. In thioglycollate induced peritonitis and lipopolysaccaride (LPS)-induced lung inflammation, chimeric mice lacking Galpha(i2) in hematopoietic cells showed about 50% reduced neutrophil recruitment similar to that seen in Gnai2(-/-) mice. These data show that neutrophil Galpha(i2) is necessary for chemokine-induced arrest, which is relevant for neutrophil recruitment to sites of acute inflammation. PMID- 17699742 TI - CD38 and ZAP-70 are functionally linked and mark CLL cells with high migratory potential. AB - Our interest in chronic lymphocytic leukemia (CLL) derives primarily from the exploitation of human diseases as strategic models for defining the in vivo biological roles of CD38. Using this model, we showed that CD38 triggers robust proliferation/survival signals modulated through the interactions with the CD31 ligand expressed by nurse-like cells and by the stromal/endothelial components. By analyzing a cohort of 56 patients with clinically and molecularly characterized CLL, we show that (1) patients with CD38(+)/ZAP-70(+) are characterized by enhanced migration toward Stromal derived factor-1alpha (SDF 1alpha)/CXCL12; (2) CD38 ligation leads to tyrosine phosphorylation of ZAP-70, showing that these markers are functionally linked; (3) ZAP-70 represents a limiting factor for the CD38 pathway in the CLL context, as shown by studying CD38-mediated signal transduction in 26 molecularly characterized patients; and (4) the CLL subgroup of patients defined on the basis of migratory potential is marked by a specific genetic signature, with a significant number of differentially expressed genes being involved in cell-cell interactions and movement. Altogether, the results of this work provide biological evidence for why the combined analysis of CD38 and ZAP-70 expression as determined in several clinical trials results in more dependable identification of patients with CLL who have aggressive disease. PMID- 17699743 TI - Friend retrovirus infection of myeloid dendritic cells impairs maturation, prolongs contact to naive T cells, and favors expansion of regulatory T cells. AB - Retroviruses have developed immunmodulatory mechanisms to avoid being attacked by the immune system. The mechanisms of this retrovirus-associated immune suppression are far from clarified. Dendritic cells (DCs) have been attributed a decisive role in these pathogenic processes. We have used the Friend retrovirus (FV) mouse model in order to acquire further knowledge about the role of infection of DCs in virus-induced immunosuppression. About 20% of the myeloid DCs that were generated from the bone marrow of FV-infected mice carried FV proteins. The infection was productive, and infected DCs transmitted the virus in cell culture and in vivo. FV infection of DCs led to a defect in DC maturation, as infected cells expressed very little costimulatory molecules. Live imaging analysis of the cell contact between DCs and T cells revealed prolonged contacts of T cells with infected DCs compared with uninfected DCs. Although naive T cells were still activated by FV-infected DCs, this activation did not result in antigen-specific T-cell proliferation. Interestingly, infected DCs expanded a population of Foxp3(+) regulatory T cells with immunosuppressive potential, suggesting that the contact between naive T cells and retrovirus-infected DCs results in tolerance rather than immunity. Thus, retroviral infection of DCs leads to an expansion of regulatory T cells, which might serve as an immune escape mechanism of the virus. PMID- 17699745 TI - Involvement of E-selectin in recruitment of endothelial progenitor cells and angiogenesis in ischemic muscle. AB - E-selectin plays critical roles in tethering leukocytes to endothelial cells (ECs). We studied the role of E-selectin in endothelial progenitor cell (EPC) homing and vasculogenesis. After ischemia, the expression of E-selectin on ECs peaked 6 to 12 hours and returned to baseline at 24 hours, whereas the level of soluble E-selectin (sE-selectin) in serum increased over 24 hours and remained high at day 7. Mouse bone marrow-derived EPCs expressed not only E-selectin but also its ligand. Homing of circulating EPCs to ischemic limb was significantly impaired in E-selectin knock-out mice, as well as wild-type mice pretreated with blocking antibody against E-selectin, which was rescued by local sE-selectin injection. Mechanism for this is that sE-selectin stimulated not only ECs to express ICAM-1, but also EPCs to secrete interleukin-8 (IL-8), leading to enhanced migration and incorporation to ECs capillary formation. In therapeutic aspect, local treatment with sE-selectin enhanced efficacy of EPC transplantation for vasculogenesis and salvage of ischemic limb. Conversely, when E-selectin was knocked down by E-selectin small interfering RNA, blood flow recovery after EPC transplantation was significantly impaired. But this impaired vasculogenesis was rescued by sE-selectin. In conclusion, these data demonstrate E-selectin is a pivotal molecule for EPCs' homing to ischemic limb and vasculogenesis. PMID- 17699744 TI - Dendritic cells are specialized accessory cells along with TGF- for the differentiation of Foxp3+ CD4+ regulatory T cells from peripheral Foxp3 precursors. AB - Foxp3(+)CD25(+)CD4(+) regulatory T cells are produced in the thymus (natural T regs) but can also differentiate from peripheral Foxp3(-)CD4(+) precursors (induced or adaptive T regs). We assessed antigen presenting cell (APC) requirements for the latter differentiation. With added transforming growth factor (TGF)-beta, both immature and mature populations of dendritic cells (DCs) induced antigen-specific Foxp3(+) T regs from Foxp3(-) precursors. Using endogenous TGF-beta, DCs from gut-associated mesenteric lymph nodes were capable of differentiating Foxp3(+)T regs. Spleen DCs were 100-fold more potent than DC depleted APCs for the induction of T regs and required 10-fold lower doses of peptide antigen. Interleukin-2 (IL-2) was essential, but could be provided endogenously by T cells stimulated by DCs, but not other APCs. The required IL-2 was induced by DCs that expressed CD80/CD86 costimulatory molecules. The DC induced Foxp3(+)T regs divided up to 6 times in 6 days and were comprised of CD62L and CD103 positive and negative forms. The induced Foxp3(+)T regs exerted suppression in vitro and blocked tumor immunity in vivo. These results indicate that DCs are specialized to differentiate functional peripheral Foxp3(+)T regs and help set the stage to use DCs to actively suppress the immune response in an antigen-specific manner. PMID- 17699746 TI - MicroRNAs repress translation of m7Gppp-capped target mRNAs in vitro by inhibiting initiation and promoting deadenylation. PMID- 17699747 TI - Life beyond cleavage: the case of Ago2 and hematopoiesis. PMID- 17699748 TI - Targeting oncogenic Ras. PMID- 17699749 TI - Cell- and gene-specific regulation of primary target genes by the androgen receptor. AB - The androgen receptor (AR) mediates the physiologic and pathophysiologic effects of androgens including sexual differentiation, prostate development, and cancer progression by binding to genomic androgen response elements (AREs), which influence transcription of AR target genes. The composition and context of AREs differ between genes, thus enabling AR to confer multiple regulatory functions within a single nucleus. We used expression profiling of an immortalized human prostate epithelial cell line to identify 205 androgen-responsive genes (ARGs), most of them novel. In addition, we performed chromatin immunoprecipitation to identify 524 AR binding regions and validated in reporter assays the ARE activities of several such regions. Interestingly, 67% of our AREs resided within approximately 50 kb of the transcription start sites of 84% of our ARGs. Indeed, most ARGs were associated with two or more AREs, and ARGs were sometimes themselves linked in gene clusters containing up to 13 AREs and 12 ARGs. AREs appeared typically to be composite elements, containing AR binding sequences adjacent to binding motifs for other transcriptional regulators. Functionally, ARGs were commonly involved in prostate cell proliferation, communication, differentiation, and possibly cancer progression. Our results provide new insights into cell- and gene-specific mechanisms of transcriptional regulation of androgen-responsive gene networks. PMID- 17699750 TI - Cotranscriptional recruitment of the dosage compensation complex to X-linked target genes. AB - Dosage compensation is a process required to balance the expression of X-linked genes between males and females. In Drosophila this is achieved by targeting the dosage compensation complex or the male-specific lethal (MSL) complex to the male X chromosome. In order to study the mechanism of targeting, we have studied two X chromosomal genes, mof and CG3016, using chromatin immunoprecipitation as well as immuno-FISH analysis on transgenic flies. We show that MSL complex recruitment requires the genes to be in a transcriptionally active state. MSL complex recruitment is reversible because blocking transcription severely reduces MSL binding to its target genes. Furthermore, targeting cues are found toward the 3' end of the gene and depend on the passage of the transcription machinery through the gene, whereby the type of promoter and the direction of transcription are dispensable. We propose a model of dynamic MSL complex binding to active genes based on exposed DNA target elements. PMID- 17699751 TI - Recruitment of factors linking transcription and processing of pre-rRNA to NOR chromatin is UBF-dependent and occurs independent of transcription in human cells. AB - Efficient ribosome biogenesis requires coordination of a highly complex series of events. Early events include pre-RNA transcription, processing, and modification. Analysis in yeast has demonstrated that t-UTPs, components of the U3 snoRNA containing pre-rRNA processing complex, are required for efficient transcription of ribosomal genes (rDNA) by RNA polymerase I (pol I). Here, we characterize human t-UTPs and establish that their ability to link transcription and pre-rRNA processing is evolutionarily conserved. The pol I transcription factor UBF binds extensively across rDNA throughout the cell cycle, resulting in a specialized form of chromatin that is the hallmark of active nucleolar organizer regions (NORs). Transcriptionally silent pseudo-NORs are ectopic, chromosomally integrated, artificial arrays that mimic this specialized chromatin structure. Pseudo-NORs sequester t-UTPs and factors linking transcription with pre-rRNA modification (Nopp140 and Treacle). Recruitment is independent of transcription, the underlying DNA sequence, and location within the nucleolus. Previously, we have demonstrated that pseudo-NORs sequester every component of the pol I transcription machinery. Taken together, these results highlight the importance of the specialized chromatin structure at active NORs in coordinating early events in ribosome biogenesis and nucleolar formation. PMID- 17699752 TI - Angiomotin regulates endothelial cell migration during embryonic angiogenesis. AB - The development of the embryonic vascular system into a highly ordered network requires precise control over the migration and branching of endothelial cells (ECs). We have previously identified angiomotin (Amot) as a receptor for the angiogenesis inhibitor angiostatin. Furthermore, DNA vaccination targeting Amot inhibits angiogenesis and tumor growth. However, little is known regarding the role of Amot in physiological angiogenesis. We therefore investigated the role of Amot in embryonic neovascularization during zebrafish and mouse embryogenesis. Here we report that knockdown of Amot in zebrafish reduced the number of filopodia of endothelial tip cells and severely impaired the migration of intersegmental vessels. We further show that 75% of Amot knockout mice die between embryonic day 11 (E11) and E11.5 and exhibit severe vascular insufficiency in the intersomitic region as well as dilated vessels in the brain. Furthermore, using ECs differentiated from embryonic stem (ES) cells, we demonstrate that Amot-deficient cells have intact response to vascular endothelial growth factor (VEGF) in regard to differentiation and proliferation. However, the chemotactic response to VEGF was abolished in Amot-deficient cells. We provide evidence that Amot is important for endothelial polarization during migration and that Amot controls Rac1 activity in endothelial and epithelial cells. Our data demonstrate a critical role for Amot during vascular patterning and endothelial polarization. PMID- 17699753 TI - Feedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells. AB - The ATF2 transcription factor is phosphorylated by the stress-activated mitogen activated protein kinases (MAPKs) JNK and p38. We show that this phosphorylation is essential for ATF2 function in vivo, since a mouse carrying mutations in the critical phosphorylation sites has a strong phenotype identical to that seen upon deletion of the DNA-binding domain. In addition, combining this mutant with a knockout of the ATF2 homolog, ATF7, results in embryonic lethality with severe abnormalities in the developing liver and heart. The mutant fetal liver is characterized by high levels of apoptosis in developing hepatocytes and haematopoietic cells. Furthermore, we observe a significant increase in active p38 due to loss of a negative feedback loop involving the ATF2-dependent transcriptional activation of MAPK phosphatases. In embryonic liver cells, this increase drives apoptosis, since it can be suppressed by chemical inhibition of p38. Our findings demonstrate the importance of finely regulating the activities of MAPKs during development. PMID- 17699754 TI - The interaction of DiaA and DnaA regulates the replication cycle in E. coli by directly promoting ATP DnaA-specific initiation complexes. AB - Escherichia coli DiaA is a DnaA-binding protein that is required for the timely initiation of chromosomal replication during the cell cycle. In this study, we determined the crystal structure of DiaA at 1.8 A resolution. DiaA forms a homotetramer consisting of a symmetrical pair of homodimers. Mutational analysis revealed that the DnaA-binding activity and formation of homotetramers are required for the stimulation of initiation by DiaA. DiaA tetramers can bind multiple DnaA molecules simultaneously. DiaA stimulated the assembly of multiple DnaA molecules on oriC, conformational changes in ATP-DnaA-specific initiation complexes, and unwinding of oriC duplex DNA. The mutant DiaA proteins are defective in these stimulations. DiaA associated also with ADP-DnaA, and stimulated the assembly of inactive ADP-DnaA-oriC complexes. Specific residues in the putative phosphosugar-binding motif of DiaA were required for the stimulation of initiation and formation of ATP-DnaA-specific-oriC complexes. Our data indicate that DiaA regulates initiation by a novel mechanism, in which DiaA tetramers most likely bind to multiple DnaA molecules and stimulate the assembly of specific ATP-DnaA-oriC complexes. These results suggest an essential role for DiaA in the promotion of replication initiation in a cell cycle coordinated manner. PMID- 17699755 TI - Independent and interdependent functions of LAF1 and HFR1 in phytochrome A signaling. AB - Several positive regulators of phytochrome A signaling--e.g., LAF1, HFR1, and HY5 -operate downstream from the photoreceptor, but their relative sites of action in the transduction pathway are unknown. Here, we show that HFR1RNAi/laf1 or hfr1 201/LAF1RNAi generated by RNA interference (RNAi) has an additive phenotype under FR light compared with the single mutants, hfr1-201 or laf1. This result indicates that LAF1 and HFR1 function in largely independent pathways. LAF1, an R2R3-MYB factor, interacts with HFR1, a basic helix-loop-helix (bHLH) factor, and this interaction is abolished by the R97A mutation in the LAF1 R2R3 domain. Polyubiquitinations of LAF1 and HFR1 by the COP1 E3 ligase in vitro are inhibited by LAF1/HFR1 association. Consistent with this result, endogenous HFR1 is less stable in laf1 compared with wild type, and similarly, LAF1-3HA expressed from a transgene is also less stable in hfr1-201 than wild type. In transgenic plants, HFR1 levels are significantly elevated upon induced expression of LAF1 but not LAF1(R97A). Moreover, induced expression of LAF1 but not LAF1(R97A) delays post translational HFR1 degradation in FR light. Constitutive coexpression of HFR1 and LAF1 but not HFR1 and LAF1 (R97A) confers FR hypersensitivity in double transgenic plants. Our results show that in addition to their independent functions in phyA signaling, LAF1 and HFR1 also cooperate post-translationally to stabilize each other through inhibition of ubiquitination by COP1, thereby enhancing phyA photoresponses. PMID- 17699756 TI - Retinoblastoma: from the two-hit hypothesis to targeted chemotherapy. AB - Studies on retinoblastoma have been at the heart of many of the landmark discoveries in cancer genetics over the past 35 years. However, these advances in the laboratory have had little effect on the treatment of children with retinoblastoma. One of the reasons for this has been the lack of preclinical models that recapitulated the genetic and histopathologic features of human retinoblastoma. In the past three years, a series of new animal models of retinoblastoma has been developed and characterized from several different laboratories using a variety of experimental approaches. It is encouraging that there is broad agreement about the consequences of inactivation of the Rb family in retinal development from these studies. More importantly, these new mouse models of retinoblastoma have contributed to clinical trials and novel therapeutic approaches for treating this debilitating childhood cancer. PMID- 17699757 TI - 4E-binding protein 1: a key molecular "funnel factor" in human cancer with clinical implications. AB - In an attempt to identify molecules that clearly reflect the oncogenic role of cell signaling pathways in human tumors, we propose a concept we term "funnel factor", a factor where several oncogenic signals converge and drive the proliferative signal downstream. In studies done in various tumor types, the expression of key cell signaling factors, including Her1 and Her2 growth factor receptors, as well as the RAS-RAF-mitogen-activated protein kinase and the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathways was correlated with the associated clinicopathologic characteristics of these tumors. The downstream factors p70, S6, 4E-binding protein 1 (4E-BP1), and eukaryotic translation initiation factor 4E, which play a critical role in the control of protein synthesis, survival, and cell growth, were also analyzed. We found that phosphorylated 4E-BP1 (p-4E-BP1) expression in breast, ovary, and prostate tumors is associated with malignant progression and an adverse prognosis regardless of the upstream oncogenic alterations. Thus, p-4E-BP1 seems to act as a funnel factor for an essential oncogenic capability of tumor cells, self-sufficiency in growth signals, and could be a highly relevant molecular marker of malignant potential. Further investigation into this concept may identify additional funnel factors in the oncogenic pathways and provide potential therapeutic targets. PMID- 17699758 TI - Nitric oxide boosts chemoimmunotherapy via inhibition of acid sphingomyelinase in a mouse model of melanoma. AB - Cisplatin is one of the most effective anticancer drugs, but its severe toxic effects, including depletion of immune-competent cells, limit its efficacy. We combined the systemic treatment with cisplatin with intratumor delivery of dendritic cells (DC) previously treated ex vivo with a pulse of nitric oxide (NO) released by the NO donors (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]-diazen 1-ium-1,2-diolate or isosorbide dinitrate. We found that this chemoimmunotherapy, tested in the B16 mouse model of melanoma, was significantly more efficacious than cisplatin alone, leading to tumor regression and animal survival at low doses of cisplatin that alone had no effect. Tumor cure was not observed when combining cisplatin with DCs not exposed to NO donors, indicating the key role of the pretreatment with NO. We investigated the mechanisms responsible for the synergic effect of NO-treated DCs and cisplatin and found that NO-treated DCs were protected both in vitro and in vivo from cisplatin-induced cytotoxicity. Cisplatin triggered DC apoptosis through increased expression and activation of acid sphingomyelinase; pretreatment of DCs with NO donors prevented such activation and inhibited activation of the downstream proapoptotic events, including generation of ceramide, activation of caspases 3 and 9, and mitochondrial depolarization. The effects of NO were mediated through generation of its physiologic messenger, cyclic GMP. We conclude that NO and NO generating drugs represent promising tools to increase the efficacy of chemoimmunotherapies in vivo, promoting the survival and increasing the function of injected cells by targeting a key pathway in cisplatin-induced cytotoxicity. PMID- 17699759 TI - Myeloproliferative defects following targeting of the Drf1 gene encoding the mammalian diaphanous related formin mDia1. AB - Rho GTPase-effector mammalian diaphanous (mDia)-related formins assemble nonbranched actin filaments as part of cellular processes, including cell division, filopodia assembly, and intracellular trafficking. Whereas recent efforts have led to thorough characterization of formins in cytoskeletal remodeling and actin assembly in vitro, little is known about the role of mDia proteins in vivo. To fill this knowledge gap, the Drf1 gene, which encodes the canonical formin mDia1, was targeted by homologous recombination. Upon birth, Drf1+/- and Drf1-/- mice were developmentally and morphologically indistinguishable from their wild-type littermates. However, both Drf1+/- and Drf1-/- developed age-dependent myeloproliferative defects. The phenotype included splenomegaly, fibrotic and hypercellular bone marrow, extramedullary hematopoiesis in both spleen and liver, and the presence of immature myeloid progenitor cells with high nucleus-to-cytoplasm ratios. Analysis of cell surface markers showed an age-dependent increase in the percentage of CD11b+-activated and CD14+-activated monocytes/macrophages in both spleen and bone marrow in Drf1+/- and Drf1-/- animals. Analysis of the erythroid compartment showed a significant increase in the proportion of splenic cells in S phase and an expansion of erythroid precursors (TER-119+ and CD71+) in Drf1-targeted mice. Overall, knocking out mDia1 expression in mice leads to a phenotype similar to human myeloproliferative syndrome (MPS) and myelodysplastic syndromes (MDS). These observations suggest that defective DRF1 expression or mDia1 function may contribute to myeloid malignancies and point to mDia1 as an attractive therapeutic target in MDS and MPS. PMID- 17699760 TI - Involvement of RNA helicases p68 and p72 in colon cancer. AB - The homologous proteins p68 and p72 are members of the DEAD box family of RNA helicases. Here, we show that expression of both of these helicases strongly increases during the polyp-->adenoma-->adenocarcinoma transition in the colon. Furthermore, p68 and p72 form complexes with beta-catenin and promote the ability of beta-catenin to activate gene transcription. Conversely, simultaneous knockdown of p68 and p72 leads to reduced expression of the beta-catenin regulated genes, c-Myc, cyclin D1, c-jun, and fra-1, all of which are proto oncogenes. Moreover, transcription of the cell cycle inhibitor p21(WAF1/CIP1), whose expression is suppressed by c-Myc, is enhanced on p68/p72 knockdown. Thus, p68/p72 may contribute to colon cancer formation by directly up-regulating proto oncogenes and indirectly by down-regulating the growth suppressor p21(WAF1/CIP1). Accordingly, knockdown of p68 and p72 in colon cancer cells inhibits their proliferation and diminishes their ability to form tumors in vivo. Altogether, these results suggest that p68/p72 overexpression is not only a potential marker of colon cancer but is also causally linked to this disease. Therefore, p68 and p72 may be novel targets in the combat against colon cancer. PMID- 17699761 TI - Distinct ErbB-2 coupled signaling pathways promote mammary tumors with unique pathologic and transcriptional profiles. AB - ErbB-2 overexpression and amplification occurs in 15% to 30% of human invasive breast carcinomas associated with poor clinical prognosis. Previously, we have shown that four ErbB-2/Neu tyrosine-autophosphorylation sites within the cytoplasmic tail of the receptor recruit distinct adaptor proteins and are sufficient to mediate transforming signals in vitro. Two of these sites, representing the growth factor receptor binding protein 2 (Grb2; Neu-YB) and the Src homology and collagen (Shc; Neu-YD) binding sites, can induce mammary tumorigenesis and metastasis. Here, we show that transgenic mice bearing the two other ErbB-2 autophosphorylation sites (Neu-YC and Neu-YE) develop metastatic mammary tumors. A detailed comparison of biological profiles among all Neu mutant mouse models revealed that Neu-YC, Neu-YD, and Neu-YE mammary tumors shared similar pathologic and transcriptional features. By contrast, the Neu-YB mouse model displayed a unique pathology with a high metastatic potential that correlates with a distinct transcriptional profile, including genes that promote malignant tumor progression such as metalloproteinases and chemokines. Furthermore, Neu-YB tumor epithelial cells showed abundant intracellular protein level of the chemokine CXCL12/SDF-1alpha, which may reflect the aggressive nature of this Neu mutant mouse model. Taken together, these findings indicate that activation of distinct Neu-coupled signaling pathways has an important impact on the biological behavior of Neu-induced tumors. PMID- 17699763 TI - Zonal heterogeneity for gene expression in human pancreatic carcinoma. AB - Using Affymetrix HG-U133 Plus 2.0 array and laser capture microdissection techniques, we determined whether different zones of the same pancreatic tumor exhibited differential expression of genes. Human L3.6pl pancreatic cancer cells were implanted into the pancreas of nude mice. Three weeks later when tumors were 7 to 9 mm in diameter, gene expression patterns in tumor cells within the central and peripheral zones were compared, and 1,222 genes showed statistically significant differences. Bioinformatic functional analysis revealed that 346 up regulated genes in the peripheral zone were related to cytoskeleton organization and biogenesis, cell cycle, cell adhesion, cell motility, DNA replication, localization, integrin-mediated signaling pathway, development, morphogenesis, and IkappaB kinase/nuclear factor-kappaB cascade; 876 up-regulated genes in the central zone were related to regulation of cell proliferation, regulation of transcription, transmembrane receptor protein tyrosine kinase signaling pathways, response to stress, small GTPase-mediated signal transduction, hexose metabolism, cell death, response to external stimulus, carbohydrate metabolism, and response to wounding. The reliability of the microarray results were confirmed by in situ hybridization analysis of the expression of two genes. Collectively, the data showed zonal heterogeneity for gene expression profiles in tumors and suggest that characterization of zonal gene expression profiles is essential if microarray analyses of genetic profiles are to produce reproducible data, predict disease prognosis, and allow design of specific therapeutics. PMID- 17699762 TI - Loss of p53 and Ink4a/Arf cooperate in a cell autonomous fashion to induce metastasis of hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. HCC patients frequently present with disease that has metastasized to other regions of the liver, the portal vein, lymph nodes, or lungs, leading to poor prognoses. Therefore, model systems that allow exploration of the molecular mechanisms underlying metastasis in this disease are greatly needed. We describe here a metastatic HCC model generated after the somatic introduction of the mouse polyoma virus middle T antigen to mice with liver-specific deletion of the Trp53 tumor suppressor locus and show the cell autonomous effect of p53 loss of function on HCC metastasis. We additionally find that cholangiocarcinoma also develops in these mice, and some tumors display features of both HCC and cholangiocarcinoma, suggestive of origin from liver progenitor cells. Concomitant loss of the Ink4a/Arf tumor suppressor locus accelerates tumor formation and metastasis, suggesting potential roles for the p16 and p19 tumor suppressors in this process. Significantly, tumor cell lines isolated from tumors lacking both Trp53 and Ink4a/Arf display enhanced invasion activity in vitro relative to those lacking Trp53 alone. Thus, our data illustrate a new model system amenable for the analysis of HCC metastasis. PMID- 17699764 TI - Bin1 ablation increases susceptibility to cancer during aging, particularly lung cancer. AB - Age is the major risk factor for cancer, but few genetic pathways that modify cancer incidence during aging have been described. Bin1 is a prototypic member of the BAR adapter gene family that functions in vesicle dynamics and nuclear processes. Bin1 limits oncogenesis and is often attenuated in human cancers, but its role in cancer suppression has yet to be evaluated fully in vivo. In the mouse, homozygous deletion of Bin1 causes developmental lethality, so to assess this role, we examined cancer incidence in mosaic null mice generated by a modified Cre-lox technology. During study of these animals, one notable phenotype was an extended period of female fecundity during aging, with mosaic null animals retaining reproductive capability until the age of 17.3 +/- 1.1 months. Through 1 year of age, cancer incidence was unaffected by Bin1 ablation; however, by 18 to 20 months of age, approximately 50% of mosaic mice presented with lung adenocarcinoma and approximately 10% with hepatocarcinoma. Aging mosaic mice also displayed a higher incidence of inflammation and/or premalignant lesions, especially in the heart and prostate. In mice where colon tumors were initiated by a ras-activating carcinogen, Bin1 ablation facilitated progression to more aggressive invasive status. In cases of human lung and colon cancers, immunohistochemical analyses evidenced frequent attenuation of Bin1 expression, paralleling observations in other solid tumors. Taken together, our findings highlight an important role for Bin1 as a negative modifier of inflammation and cancer susceptibility during aging. PMID- 17699765 TI - The LxCxE pRb interaction domain of cyclin D1 is dispensable for murine development. AB - Cyclin D1 is a multifunctional, tumor-associated protein that interacts with pRb via a conserved LxCxE motif, activates a kinase partner, directs the phosphorylation of pRb, activates cyclin E-cyclin-dependent kinase 2 (cdk2) by titrating Cip/Kip cdk inhibitors, and modulates the activity of a variety of transcription factors. It is thought that some of the proproliferative function of cyclin D1 is exerted by LxCxE-dependent binding to the pRb pocket domain, which might interfere with the ability of pRb to repress transcription by recruiting cellular chromatin remodeling proteins to E2F-dependent promoters. To test the importance of the LxCxE domain in vivo, we have generated a "knock-in" mouse by replacing the wild-type cyclin D1 gene with a mutant allele precisely lacking the nucleotides encoding the LxCxE domain. Analysis of this mouse has shown that the LxCxE protein is biochemically similar to wild-type cyclin D1 in all tested respects. Moreover, we were unable to detect abnormalities in growth, retinal development, mammary gland development, or tumorigenesis, all of which are affected by deleting cyclin D1. Although we cannot exclude the presence of subtle defects, these results suggest that the LxCxE domain of cyclin D1 is not necessary for function despite the absolute conservation of this motif in the D type cyclins from plants and vertebrates. PMID- 17699766 TI - The early response to DNA damage can lead to activation of alternative splicing activity resulting in CD44 splice pattern changes. AB - Expression of the human papillomavirus 16 E6 oncogene interferes with several vital cellular processes, including the p53-dependent response to DNA damage. To assess the influence of E6 on the early response to DNA damage, we analyzed gene expression following mitomycin C-induced genotoxic stress in human E6-expressing U2OS cells (U2OSE64b) as well as in p53-expressing control cells (U2OSE6AS) by comparative global expression profiling. As expected, genes involved in p53 dependent pathways were activated in p53-expressing cells. In the U2OSE64b cells, however, a largely nonoverlapping group of genes was identified, including two splicing factors of the SR family. Immunoblot analysis revealed increased expression of several SR proteins during the early response to DNA damage, which was accompanied by activation of alternative splicing activity. Disruption of splicing activity by treatment with small interfering RNA directed against splicing factor SRp55 resulted in the increased viability of p53-deficient cells following DNA damage. To determine whether the transient activation of splicing activity was due to E6-mediated degradation of p53, or was due to some other activity of E6, we compared the early response of the p53 wild-type and p53-/- isogenic HCT116 cell lines, and found that the increase in splicing activity was observed only in the absence of p53. Finally, both the U2OSE64b and the p53-/- cells showed altered splicing patterns for the CD44 receptor. Together, these data show that cells lacking p53 can activate alternative splicing following DNA damage. PMID- 17699767 TI - Cells with defective p53-p21-pRb pathway are susceptible to apoptosis induced by p84N5 via caspase-6. AB - Adeno-associated virus (AAV) infection triggers a DNA damage response in the cell. This response is not induced by viral proteins but by virtue of the structure of AAV ssDNA being recognized by the cell as damaged DNA. The consequence of this is the killing of cells lacking p53 activity. We have observed that cells that lack p21 or pRb activity are also sensitive to AAV induced cell death. We report that cells respond to AAV infection by activating two DNA damage signaling cascades. The first activates the p84N5 protein, which in turn activates caspase-6, leading to cell death. The second cascade activates the p53-21-pRb pathway, which inhibits activation of the p84N5 protein and thus prevents cell death. The result of the antagonistic interaction between these two pathways is that cells that do not exhibit functional p53-p21-pRb signaling undergo apoptosis as a consequence of AAV infection. Cells with a functional p53 21-pRb pathway are refractory to AAV-induced cell death. These results show that p53, although a proapoptotic protein, together with pRb and p21 proteins, is a member of an antiapoptotic cellular mechanism. As such, these experiments reveal features that may be exploited to specifically kill cells that lack the p53-p21 pRb pathway, such as cancer cells. The use of AAV to expose these subtle characteristics of intracellular signaling further highlights the advantages of using viruses as precision tools with which to address questions of cell biology. PMID- 17699768 TI - Serial in vivo spectroscopic nuclear magnetic resonance imaging of lactate and extracellular pH in rat gliomas shows redistribution of protons away from sites of glycolysis. AB - The acidity of the tumor microenvironment aids tumor growth, and mechanisms causing it are targets for potential therapies. We have imaged extracellular pH (pHe) in C6 cell gliomas in rat brain using 1H magnetic resonance spectroscopy in vivo. We used a new probe molecule, ISUCA [(+/-)2-(imidazol-1-yl)succinic acid], and fast imaging techniques, with spiral acquisition in k-space. We obtained a map of metabolites [136 ms echo time (TE)] and then infused ISUCA in a femoral vein (25 mmol/kg body weight over 110 min) and obtained two consecutive images of pHe within the tumor (40 ms TE, each acquisition taking 25 min). pHe (where ISUCA was present) ranged from 6.5 to 7.5 in voxels of 0.75 microL and did not change detectably when [ISUCA] increased. Infusion of glucose (0.2 mmol/kg.min) decreased tumor pHe by, on average, 0.150 (SE, 0.007; P < 0.0001, 524 voxels in four rats) and increased the mean area of measurable lactate peaks by 54.4 +/- 3.4% (P < 0.0001, 287 voxels). However, voxel-by-voxel analysis showed that, both before and during glucose infusion, the distributions of lactate and extracellular acidity were very different. In tumor voxels where both could be measured, the glucose-induced increase in lactate showed no spatial correlation with the decrease in pHe. We suggest that, although glycolysis is the main source of protons, distributed sites of proton influx and efflux cause pHe to be acidic at sites remote from lactate production. PMID- 17699769 TI - Visualization of hypoxia in microscopic tumors by immunofluorescent microscopy. AB - Tumor hypoxia is commonly observed in primary solid malignancies but the hypoxic status of subclinical micrometastatic disease is largely unknown. The distribution of hypoxia in microscopic tumors was studied in animal models of disseminated peritoneal disease and intradermal (i.d.) growing tumors. Tumors derived from human colorectal adenocarcinoma cell lines HT29 and HCT-8 ranged in size from a few hundred microns to several millimeters in diameter. Hypoxia was detected by immunofluorescent visualization of pimonidazole and the hypoxia regulated protein carbonic anhydrase 9. Tumor blood perfusion, cellular proliferation, and vascularity were visualized using Hoechst 33342, bromodeoxyuridine, and CD31 staining, respectively. In general, tumors of <1 mm diameter were intensely hypoxic, poorly perfused, and possessed little to no vasculature. Larger tumors (approximately 1-4 mm diameter) were well perfused with widespread vasculature and were not significantly hypoxic. Patterns of hypoxia in disseminated peritoneal tumors and i.d. tumors were similar. Levels of hypoxia in microscopic peritoneal tumors were reduced by carbogen breathing. Peritoneal and i.d. tumor models are suitable for studying hypoxia in microscopic tumors. If the patterns of tumor hypoxia in human patients are similar to those observed in these animal experiments, then the efficacy of systemic treatments of micrometastatic disease may be compromised by hypoxic resistance. PMID- 17699770 TI - Sequential down-regulation of E-cadherin with squamous cell carcinoma progression: loss of E-cadherin via a prostaglandin E2-EP2 dependent posttranslational mechanism. AB - The incidence of skin cancer is on the rise, with over 1 million new cases yearly. Although it is known that squamous cell cancers (SCC) are caused by UV light, the mechanism(s) involved remains poorly understood. In vitro studies with epithelial cells or reports examining malignant skin lesions suggest that loss of E-cadherin-mediated cell-cell contacts may contribute to SCCs. Other studies show a pivotal role for cyclooxygenase-dependent prostaglandin E2 (PGE2) synthesis in this process. Using chronically UV-irradiated SKH-1 mice, we show a sequential loss of E-cadherin-mediated cell-cell contacts as lesions progress from dysplasia to SCCs. This E-cadherin down-regulation was also evident after acute UV exposure in vivo. In both chronic and acute UV injury, E-cadherin levels declined at a time when epidermal PGE2 synthesis was enhanced. Inhibition of PGE2 synthesis by indomethacin in vitro, targeted deletion of EP2 in primary mouse keratinocyte (PMK) cultures or deletion of the EP2 receptor in vivo abrogated this UV-induced E-cadherin down-regulation. In contrast, addition of PGE2 or the EP2 receptor agonist butaprost to PMK produced a dose- and time-dependent decrease in E cadherin. We also show that UV irradiation, via the PGE2-EP2 signaling pathway, may initiate tumorigenesis in keratinocytes by down-regulating E-cadherin mediated cell-cell contacts through its mobilization away from the cell membrane, internalization into the cytoplasm, and shuttling through the lysosome and proteasome degradation pathways. Further understanding of how UV-PGE2-EP2 down regulates E-cadherin may lead to novel chemopreventative strategies for the treatment of skin and other epithelial cancers. PMID- 17699771 TI - Caveolin-1 reduces osteosarcoma metastases by inhibiting c-Src activity and met signaling. AB - Caveolin-1 (Cav-1) is highly expressed in normal osteoblasts. This article reports that Cav-1 down-regulation is part of osteoblast transformation and osteosarcoma progression and validates its role as oncosuppressor in human osteosarcoma. A survey of 6-year follow-up indicates a better overall survival for osteosarcoma expressing a level of Cav-1 similar to osteoblasts. However, the majority of primary osteosarcoma shows significantly lower levels of Cav-1 than normal osteoblasts. Accordingly, Met-induced osteoblast transformation is associated with Cav-1 down-regulation. In vitro, osteosarcoma cell lines forced to overexpress Cav-1 show reduced malignancy with inhibited anchorage-independent growth, migration, and invasion. In vivo, Cav-1 overexpression abrogates the metastatic ability of osteosarcoma cells. c-Src and c-Met tyrosine kinases, which are activated in osteosarcoma, colocalize with Cav-1 and are inhibited on Cav-1 overexpression. Thus, Cav-1 behaves as an oncosuppressor in osteosarcoma. Altogether, data suggest that Cav-1 down-modulation might function as a permissive mechanism, which, by unleashing c-Src and Met signaling, enables osteosarcoma cells to invade neighboring tissues. These data strengthen the rationale to target c-Src family kinases and/or Met receptor to improve the extremely poor prognosis of metastatic osteosarcoma. PMID- 17699772 TI - Mitotic cell death by chromosome fragmentation. AB - Cell death plays a key role for both cancer progression and treatment. In this report, we characterize chromosome fragmentation, a new type of cell death that takes place during metaphase where condensed chromosomes are progressively degraded. It occurs spontaneously without any treatment in instances such as inherited status of genomic instability, or it can be induced by treatment with chemotherapeutics. It is observed within cell lines, tumors, and lymphocytes of cancer patients. The process of chromosome fragmentation results in loss of viability, but is apparently nonapoptotic and further differs from cellular death defined by mitotic catastrophe. Chromosome fragmentation represents an efficient means of induced cell death and is a clinically relevant biomarker of mitotic cell death. Chromosome fragmentation serves as a method to eliminate genomically unstable cells. Paradoxically, this process could result in genome aberrations common in cancer. The characterization of chromosome fragmentation may also shine light on the mechanism of chromosomal pulverization. PMID- 17699773 TI - Epidermal growth factor receptors with tyrosine kinase domain mutations exhibit reduced Cbl association, poor ubiquitylation, and down-regulation but are efficiently internalized. AB - Some non-small cell lung cancers (NSCLC) with epidermal growth factor receptor (EGFR) tyrosine kinase domain mutations require altered signaling through the EGFR for cell survival and are exquisitely sensitive to tyrosine kinase inhibitors. EGFR down-regulation was impaired in two NSCLCs with EGFR tyrosine kinase domain mutations. The mutant receptors were poorly ubiquitylated and exhibited decreased association with the ubiquitin ligase Cbl. Overexpression of Cbl increased the degradation of EGFR. Treatment with geldanamycin, an inhibitor of the chaperone heat shock protein 90, also increased both wild-type and mutant EGFR degradation without affecting internalization. The down-regulation of the mutant EGFRs was still impaired when they were stably expressed in normal human bronchial epithelial cells. Thus, the mutations that altered signaling also decreased the interaction of EGFRs with the mechanisms responsible for endosomal sorting. PMID- 17699774 TI - Expression of L1-CAM and ADAM10 in human colon cancer cells induces metastasis. AB - L1-CAM, a neuronal cell adhesion receptor, is also expressed in a variety of cancer cells. Recent studies identified L1-CAM as a target gene of beta-catenin-T cell factor (TCF) signaling expressed at the invasive front of human colon cancer tissue. We found that L1-CAM expression in colon cancer cells lacking L1-CAM confers metastatic capacity, and mice injected in their spleen with such cells form liver metastases. We identified ADAM10, a metalloproteinase that cleaves the L1-CAM extracellular domain, as a novel target gene of beta-catenin-TCF signaling. ADAM10 overexpression in colon cancer cells displaying endogenous L1 CAM enhanced L1-CAM cleavage and induced liver metastasis, and ADAM10 also enhanced metastasis in colon cancer cells stably transfected with L1-CAM. DNA microarray analysis of genes induced by L1-CAM in colon cancer cells identified a cluster of genes also elevated in a large set of human colon carcinoma tissue samples. Expression of these genes in normal colon epithelium was low. These results indicate that there is a gene program induced by L1-CAM in colon cancer cells that is also present in colorectal cancer tissue and suggest that L1-CAM can serve as target for colon cancer therapy. PMID- 17699775 TI - The let-7 microRNA represses cell proliferation pathways in human cells. AB - MicroRNAs play important roles in animal development, cell differentiation, and metabolism and have been implicated in human cancer. The let-7 microRNA controls the timing of cell cycle exit and terminal differentiation in Caenorhabditis elegans and is poorly expressed or deleted in human lung tumors. Here, we show that let-7 is highly expressed in normal lung tissue, and that inhibiting let-7 function leads to increased cell division in A549 lung cancer cells. Overexpression of let-7 in cancer cell lines alters cell cycle progression and reduces cell division, providing evidence that let-7 functions as a tumor suppressor in lung cells. let-7 was previously shown to regulate the expression of the RAS lung cancer oncogenes, and our work now shows that multiple genes involved in cell cycle and cell division functions are also directly or indirectly repressed by let-7. This work reveals the let-7 microRNA to be a master regulator of cell proliferation pathways. PMID- 17699776 TI - p73 loss triggers conversion to squamous cell carcinoma reversible upon reconstitution with TAp73alpha. AB - The expression level of the p53 family member, p73, is frequently deregulated in human epithelial cancers, correlating with tumor invasiveness, therapeutic resistance, and poor patient prognosis. However, the question remains whether p73 contributes directly to the process of malignant conversion or whether aberrant p73 expression represents a later selective event to maintain tumor viability. We explored the role of p73 in malignant conversion in a clonal model of epidermal carcinogenesis. Whether sporadic or small interfering RNA (siRNA) induced, loss of p73 in initiated p53+/+ keratinocytes leads to loss of cellular responsiveness to DNA damage by ionizing radiation (IR) and conversion to squamous cell carcinoma (SCC). Reconstitution of TAp73alpha but not DeltaNp73alpha reduced tumorigenicity in vivo, but did not restore cellular sensitivity to IR, uncoupling p73-mediated DNA damage response from its tumor-suppressive role. These studies provide direct evidence that loss of p73 can contribute to malignant conversion and support a role for TAp73alpha in tumor suppression of SCC. The results support the activation of TAp73alpha as a rational mechanism for cancer therapy in solid tumors of the epithelium. PMID- 17699777 TI - Epigenetic modulation of estrogen receptor-alpha by pRb family proteins: a novel mechanism in breast cancer. AB - Estrogen receptor-alpha (ER-alpha) plays a crucial role in normal breast development and has also been linked to mammary carcinogenesis and clinical outcome in breast cancer patients. However, ER-alpha gene expression can change during the course of disease and, consequently, therapy resistance can occur. The molecular mechanism governing ER-alpha transcriptional activity and/or silencing is still unclear. Here, we showed that the presence of a specific pRb2/p130 multimolecular complex on the ER-alpha promoter strongly correlates with the methylation status of this gene. Furthermore, we suggested that pRb2/p130 could cooperate with ICBP90 (inverted CCAAT box binding protein of 90 kDa) and DNA methyltransferases in maintaining a specific methylation pattern of ER-alpha gene. The sequence of epigenetic events for establishing and maintaining the silenced state of ER-alpha gene can be locus- or pathway- specific, and the local remodeling of ER-alpha chromatin structure by pRb2/p130 multimolecular complexes may influence its susceptibility to specific DNA methylation. Our novel hypothesis could provide a basis for understanding how the complex pattern of ER alpha methylation and transcriptional silencing is generated and for understanding the relationship between this pattern and its function during the neoplastic process. PMID- 17699778 TI - Tumor suppressor functions of ARLTS1 in lung cancers. AB - ARLTS1 is a newly characterized tumor suppressor gene located at chromosome 13q14.3 and involved in the pathogenesis of various types of tumors: two single nucleotide polymorphisms, one of them responsible for protein truncation, were found statistically associated with familial malignancies, whereas DNA hypermethylation and genomic deletions have been identified as a mechanism of ARLTS1 down-regulation in sporadic cancers. We found that in a large portion of lung carcinomas (37%) and in all analyzed lung cancer cell lines, ARLTS1 is strongly down-regulated due to DNA methylation in its promoter region. After its restoration by adenoviral transduction, ARLTS1-negative A549 and H1299 cells underwent apoptosis and inhibition of cell growth. Furthermore, ARLTS1 reexpression significantly reduced the ability of A549 and H1299 to form tumors in nude mice. Finally, we identified approximately 650 transcripts differentially expressed after restoration of ARLTS1 expression in A549 cells, suggesting that various pathways involved in cell survival, proliferation, signaling, and development mediate the effects of wild-type ARLTS1 in a lung cancer system. PMID- 17699779 TI - Estrogen receptor alpha inhibits p53-mediated transcriptional repression: implications for the regulation of apoptosis. AB - Estrogen receptor alpha (ERalpha) and tumor suppressor protein p53 exert opposing effects on cellular proliferation. As a transcriptional regulator, p53 is capable of activating or repressing various target genes. We have previously reported that ERalpha binds directly to p53, leading to down-regulation of transcriptional activation by p53. In addition to transcriptional activation, transcriptional repression of a subset of target genes by p53 plays important roles in diverse biological processes, such as apoptosis. Here, we report that ERalpha inhibits p53-mediated transcriptional repression. Chromatin immunoprecipitation assays reveal that ERalpha interacts in vivo with p53 bound to promoters of Survivin and multidrug resistance gene 1, both targets for transcriptional repression by p53. ERalpha binding to p53 leads to inhibition of p53-mediated transcriptional regulation of these genes in human cancer cells. Transcriptional derepression of Survivin by ERalpha is dependent on the p53-binding site on the Survivin promoter, consistent with our observation that p53 is necessary for ERalpha to access the promoters. Importantly, mutagenic conversion of this site to an activation element enabled ERalpha to repress p53-mediated transcriptional activation. Further, RNA interference-mediated knockdown of ERalpha resulted in reduced Survivin expression and enhanced the propensity of MCF-7 cells to undergo apoptosis in response to staurosporine treatment, an effect that was blocked by exogenous expression of Survivin. These results unravel a novel mechanism by which ERalpha opposes p53-mediated apoptosis in breast cancer cells. The findings could have translational implications in developing new therapeutic and prevention strategies against breast cancer. PMID- 17699780 TI - The role of glycogen synthase kinase 3beta in the transformation of epidermal cells. AB - Glycogen synthase kinase 3beta (GSK3beta) is a multifunctional serine/threonine kinase. We showed that the expression of GSK3beta was drastically down-regulated in human cutaneous squamous cell carcinomas and basal cell carcinomas. Due to its negative regulation of many oncogenic proteins, we hypothesized that GSK3beta may function as a tumor suppressor during the neoplastic transformation of epidermal cells. We tested this hypothesis using an in vitro model system, JB6 mouse epidermal cells. In response to epidermal growth factor (EGF) or 12-O tetradecanoylphorbol-13-acetate (TPA), the promotion-sensitive JB6 P+ cells initiate neoplastic transformation, whereas the promotion-resistant JB6 P- cells do not. JB6 P- cells expressed much higher levels of GSK3beta than JB6 P+ cells; JB7 cells, the transformed derivatives of JB6, had the least amount of GSK3beta. The activity of GSK3beta is negatively regulated by its phosphorylation at Ser9. EGF and TPA induced strong Ser9 phoshorylation in JB6 P+ cells, but phosphorylation was seen at a much lesser extent in JB6 P- cells. EGF and TPA stimulated Ser9 phosphorylation was mediated by phosphoinositide-3-kinase (PI3K)/Akt and protein kinase C (PKC) pathways. Inhibition of GSK3beta activation significantly stimulated activator protein-1 (AP-1) activity. Overexpression of wild-type (WT) and S9A mutant GSK3beta in JB6 P+ cells suppressed EGF and TPA mediated anchorage-independent growth in soft agar and tumorigenicity in nude mice. Overexpression of a kinase-deficient (K85R) GSK3beta, in contrast, potentiated anchorage-independent growth and drastically enhanced in vivo tumorigenicity. Together, these results indicate that GSK3beta plays an important role in skin tumorigenesis. PMID- 17699781 TI - Platelet-derived growth factor receptor regulates myeloid and monocytic differentiation of HL-60 cells. AB - Here, we show that the platelet-derived growth factor receptor (PDGFR) regulates myeloid and monocytic differentiation of HL-60 myeloblastic leukemia cells in response to retinoic acid (RA) and vitamin D3 (D3), respectively. Both RA and D3 decreased the expression of PDGFR-alpha and PDGFR-beta throughout differentiation. When cells were treated with the PDGFR inhibitor AG1296 in addition to RA or D3, signs of terminal differentiation such as inducible oxidative metabolism and cell substrate adhesion were enhanced. These changes were accompanied by an increased extracellular signal-regulated kinase 1/2 activation. AG1296 also resulted in elevated expression of differentiation markers CD11b and CD66c when administered with RA or D3. Interestingly, other markers did not follow the same pattern. Cells receiving AG1296 in addition to RA or D3 showed decreased G1-G0 arrest and CD14, CD38, and CD89 expression. We thus provide evidence that certain sets of differentiation markers can be enhanced, whereas others can be inhibited by the PDGFR pathway. In addition, we found calcium levels to be decreased by RA and D3 but increased when AG1296 was given in addition to RA or D3, suggesting that calcium levels decrease during myeloid or monocytic differentiation, and elevated calcium levels can disturb the expression of certain differentiation markers. PMID- 17699782 TI - Regulation of PTEN expression in intestinal epithelial cells by c-Jun NH2 terminal kinase activation and nuclear factor-kappaB inhibition. AB - The tumor suppressor protein phosphatase and tensin homologue deleted on chromosome ten (PTEN) plays an important role in intestinal cell proliferation and differentiation and tumor suppression by antagonizing phosphatidylinositol 3 kinase. Despite its importance, the molecular mechanisms regulating PTEN expression are largely undefined. Here, we show that treatment of the colon cancer cell line HT29 with the differentiating agent sodium butyrate (NaBT) increased PTEN protein and mRNA expression and induced c-Jun NH2-terminal kinase (JNK) activation. Inhibition of JNK by chemical or genetic methods attenuated NaBT-induced PTEN expression. In addition, our findings showed a cross-talk between nuclear factor kappaB (NF-kappaB) and JNK with respect to PTEN regulation. Overexpression of the NF-kappaB superrepressor increased PTEN expression and JNK activity, whereas overexpression of the p65 NF-kappaB subunit reduced both basal and NaBT-mediated JNK activation and PTEN expression. Moreover, we showed that overexpression of PTEN or treatment with NaBT increased expression of the cyclin-dependent kinase inhibitor p27(kip1) in HT29 cells; this induction was attenuated by inhibition of PTEN or JNK expression or overexpression of p65. Finally, we show a role for PTEN in NaBT-mediated cell death and differentiation. Our findings suggest that the JNK/PTEN and NF kappaB/PTEN pathways play a critical role in normal intestinal homeostasis and colon carcinogenesis. PMID- 17699783 TI - Androgen receptor and E2F-1 targeted thymoquinone therapy for hormone-refractory prostate cancer. AB - Relapse of prostate cancer after androgen ablation therapy is hormone-refractory, with continued tumor growth being dependent on the androgen receptor (AR). E2F-1, a regulator of cell proliferation and viability, reportedly plays a role in the development of hormone-refractory prostate cancer. Thymoquinone is a component of Nigella sativa, an herb used for thousands of years for culinary and medicinal purposes in Asian and Middle Eastern countries and has been reported to have an antineoplastic effect both in vitro and in vivo. We observed that thymoquinone inhibited DNA synthesis, proliferation, and viability of cancerous (LNCaP, C4-B, DU145, and PC-3) but not noncancerous (BPH-1) prostate epithelial cells by down regulating AR and E2F-1. In LNCaP cells, this was associated with a dramatic increase in p21(Cip1), p27(Kip1), and Bax. Thymoquinone blunted progression of synchronized LNCaP cells from G1 to S phase, with a concomitant decrease in AR and E2F-1 as well as the E2F-1-regulated proteins necessary for cell cycle progression. In a xenograft prostate tumor model, thymoquinone inhibited growth of C4-2B-derived tumors in nude mice. This in vivo suppression of tumor growth, as with C4-2B cell growth in culture, was associated with a dramatic decrease in AR, E2F-1, and cyclin A as determined by Western blot of tissue extracts. Tissue immunohistochemical staining confirmed a marked reduction in E2F-1 and showed induction of apoptosis on terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay. These findings show that thymoquinone suppresses the expression of AR and E2F-1 necessary for proliferation and viability of androgen sensitive as well as androgen-independent prostate cancer cells both in vitro and in vivo and, moreover, produced no noticeable side effects in mice. We conclude that thymoquinone, a naturally occurring herbal product, may prove to be effective in treating hormone-sensitive as well as hormone-refractory prostate cancer. Furthermore, because of its selective effect on cancer cells, we believe that thymoquinone can also be used safely to help prevent the development of prostate cancer. PMID- 17699784 TI - Hypoxia enhances metastatic efficiency in HT1080 fibrosarcoma cells by increasing cell survival in lungs, not cell adhesion and invasion. AB - This study examined possible mechanisms for hypoxia-increased metastasis in a green fluorescent protein-labeled human fibrosarcoma cell line (HT1080). The efficiency of the lung arrest of tumor cells, which can be dependent on the adhesive potential of the tumor cells, was assessed by measuring the level of integrin alpha3beta1 protein and by adhesion assays, whereas the extravasation potential was examined by an invasion assay. These properties were not changed by exposure to hypoxia, indicating that lung arrest and extravasation are unlikely to play a major role in the effect of hypoxia on metastasis in this model. The main effect of hypoxic exposure was found to be increased survival after lung arrest as determined by clonogenic assay of tumor cells recovered from mouse lungs after i.v. injection. Concomitantly, apoptosis was identified as responsible for the death of lung-arrested cells, suggesting the involvement of an altered apoptotic response following hypoxic exposure of these cells. Consistent with this finding, we found that the effect of hypoxia on both increased metastasis and survival of arrested cells was inhibited by treatment with farnesylthiosalicylic acid. However, this effect was not due to down regulation of hypoxia-inducible factor-1alpha, a mechanism of action of this drug reported by previous studies. Further detailed studies of the mechanisms of action of the drug are needed. PMID- 17699785 TI - Localized hyperthermia combined with intratumoral dendritic cells induces systemic antitumor immunity. AB - Prostate adenocarcinoma, treated with localized tumor hyperthermia (LTH), can potentially serve as a source of tumor antigen, where dying apoptotic/necrotic cells release tumor peptides slowly over time. In addition, LTH-treated cells can release heat shock proteins that can chaperone antigenic peptides to antigen presenting cells, such as dendritic cells. We attempted to discern whether sequential LTH and intratumoral dendritic cell and/or systemic granulocyte macrophage colony-stimulating factor (GM-CSF) would activate antitumor immune response in a syngeneic murine model of prostate cancer (RM-1). Palpable RM-1 tumors, grown in the distal appendage of C57BL/6 male mice, were subjected to LTH (43.7 degrees C for 1 h) x 2, separated by 5 days. Following the second LTH treatment, animals received either PBS or dendritic cells (2 x 10(6)) intratumorally (every 3 days for three injections). Separate cohorts also received i.v. injection of recombinant adenovirus-expressing murine GM-CSF (AdGMCSF), 1 day after LTH. Control animals received AdenoLacZ or AdenoGFP. Intratumoral dendritic cell injection induced tumor-specific T-helper cell activity (IFNgamma ELISPOTS) and CTL activity, which was further augmented by AdGMCSF, indicating amplification of tumor-specific TH1 immunity. The combination of LTH, AdGMCSF, and intratumoral dendritic cell injection resulted in significant tumor growth delays when compared with animal cohorts that received LTH alone. These results support an in situ autovaccination strategy where systemic administration of GM-CSF and/or intratumoral injection of autologous dendritic cells, when combined with LTH, could be an effective treatment for local and systemic recurrence of prostate cancer. PMID- 17699786 TI - Emergence of epidermal growth factor receptor T790M mutation during chronic exposure to gefitinib in a non small cell lung cancer cell line. AB - The epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitor gefitinib may provide dramatic clinical responses in some patients with pulmonary adenocarcinoma carrying activating mutations of the EGFR. However, prolonged administration of gefitinib may eventually induce acquired resistance in such patients. To gain insight into the mechanisms of this phenomenon, we placed PC-9, a cell line derived from pulmonary adenocarcinoma that has a 15-bp deletion in EGFR exon 19, under the continuous selective pressure of low levels of gefitinib without any mutagen, and established a subline that was able to grow in the presence of 2 micromol/L of gefitinib (designated RPC-9). In this cell line, about half of the reverse transcription-PCR products from mutated EGFR also carried an additional mutation (T790M). In keeping with the proposed role of T790M in abrogating gefitinib binding with EGFR, gefitinib-treated RPC-9 hardly displayed any decrease in the constitutive phosphorylation of EGFR, Akt, or Erk1/2 unlike in PC-9 cells. Interestingly, transfection of the EGFR carrying only a 15-bp deletion reversed the resistance to gefitinib in RPC-9 cells. Thus, the balance of expression levels between gefitinib-sensitive or gefitinib resistant EGFR may govern the response to gefitinib in lung cancer. PMID- 17699787 TI - A potent indole-3-carbinol derived antitumor agent with pleiotropic effects on multiple signaling pathways in prostate cancer cells. AB - Indole-3-carbinol has emerged as a promising chemopreventive agent due to its in vivo efficacy in various animal models. However, indole-3-carbinol exhibits weak antiproliferative potency and is unstable in acidic milieu. Thus, this study was aimed at exploiting indole-3-carbinol to develop potent antitumor agents with improved chemical stability. This effort culminated in OSU-A9 {[1-(4-chloro-3 nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol}, which is resistant to acid catalyzed condensation, and exhibits 100-fold higher apoptosis-inducing activity than the parent compound. Relative to indole-3-carbinol, OSU-A9 displays a striking qualitative similarity in its effects on the phosphorylation or expression of multiple signaling targets, including Akt, mitogen-activated protein kinases, Bcl-2 family members, survivin, nuclear factor-kappaB, cyclin D1, p21, and p27. The ability of OSU-A9 to concurrently modulate this broad range of signaling targets underscores its in vitro and in vivo efficacy in prostate cancer cells. Nevertheless, despite this complex mode of mechanism, normal prostate epithelial cells were less susceptible to the antiproliferative effect of OSU-A9 than PC-3 and LNCaP prostate cancer cells. Treatment of athymic nude mice bearing established s.c. PC-3 xenograft tumors with OSU-A9 at 10 and 25 mg/kg i.p. for 42 days resulted in a 65% and 85%, respectively, suppression of tumor growth. Western blot analysis of representative biomarkers in tumor lysates revealed significant reductions in the intratumoral levels of phosphorylated (p-) Akt, Bcl-xL, and RelA, accompanied by robust increases in p-p38 levels. In conclusion, the ability of OSU-A9 to target multiple aspects of cancer cell survival with high potency suggests its clinical value in prostate cancer therapy. PMID- 17699788 TI - Determination of the role of target tissue metabolism in lung carcinogenesis using conditional cytochrome P450 reductase-null mice. AB - Critical to mechanisms of chemical carcinogenesis and the design of chemopreventive strategies is whether procarcinogen bioactivation in an extrahepatic target tissue (e.g., the lung) is essential for tumor formation. This study aims to develop a mouse model capable of revealing the role of pulmonary microsomal cytochrome P450 (P450)-mediated metabolic activation in xenobiotic-induced lung cancer. A novel triple transgenic mouse model, with the NADPH-P450 reductase (Cpr) gene deleted in a lung-specific and doxycycline inducible fashion (lung-Cpr-null), was generated. CPR, the obligate electron donor for microsomal P450 enzymes, is essential for the bioactivation of many procarcinogens. The lung-Cpr-null mouse was studied to resolve whether pulmonary P450 plays a major role in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induced lung cancer by producing carcinogenic metabolites in the target tissue. A liver-Cpr-null mouse was also studied to test whether hepatic P450 contributes predominantly to systemic clearance of NNK, thereby decreasing NNK-induced lung cancer. The numbers of NNK-induced lung tumors were reduced in the lung-Cpr-null mice but were increased in the liver-Cpr-null mice, relative to wild-type control mice. Decreased lung tumor multiplicity in the lung-Cpr-null mice correlated with reduced lung O6-methylguanine adduct levels, without decreases in NNK bioavailability, consistent with decreased NNK bioactivation in the lung. Moreover, lung tumors in lung-Cpr-null mice were positive for CPR expression, indicating that the tumors did not originate from Cpr-null cells. Thus, we have confirmed the essential role of pulmonary P450-mediated metabolic activation in NNK-induced lung cancer, and our mouse models should be applicable to studies on other procarcinogens that require P450-mediated metabolic activation. PMID- 17699789 TI - Use of a peptide derived from foot-and-mouth disease virus for the noninvasive imaging of human cancer: generation and evaluation of 4-[18F]fluorobenzoyl A20FMDV2 for in vivo imaging of integrin alphavbeta6 expression with positron emission tomography. AB - Expression of the epithelial-specific integrin alphavbeta6 is low or undetectable in most adult tissues but may be increased during wound healing and inflammation and is up-regulated dramatically by many different carcinomas, making alphavbeta6 a promising target for the in vivo detection of cancer using noninvasive imaging. In addition, alphavbeta6 is recognized as promoting invasion and correlates with aggressive behavior of human cancers and thus agents that recognize alphavbeta6 specifically in vivo will be an essential tool for the future management of alphavbeta6-positive cancers. Recently, we identified the peptide NAVPNLRGDLQVLAQKVART (A20FMDV2), derived from foot-and-mouth disease virus, as a potent inhibitor of alphavbeta6. Using flow cytometry and ELISA, we show that this peptide is highly selective, inhibiting alphavbeta6-ligand binding with a IC50 of 3 nmol/L, an activity 1,000-fold more selective for alphavbeta6 than for other RGD-directed integrins (alphavbeta3, alphavbeta5, and alpha5beta1). A20FMDV2 was radiolabeled on solid-phase using 4-[18F]fluorobenzoic acid, injected into mice bearing both alphavbeta6-negative and alphavbeta6-positive (DX3puro/DX3purobeta6 cell lines) xenografts and imaged using a small animal positron emission tomography (PET) scanner. Rapid uptake (<30 min) and selective retention (>5 h) of radioactivity in the alphavbeta6-positive versus the alphavbeta6-negative tumor, together with fast renal elimination of nonspecifically bound activity, resulted in specific imaging of the alphavbeta6 positive neoplasm. These data suggest that PET imaging of alphavbeta6-positive tumors is feasible and will provide an important new tool for early detection and improved management of many types of cancers. PMID- 17699790 TI - Involvement of disulfide bond formation in the activation of heparanase. AB - Heparanase is overexpressed in many solid tumor cells and is capable of specifically cleaving heparan sulfate, and this activity is associated with the metastatic potential of tumor cells; however, the activation mechanism of heparanase has remained unknown. In this study, we investigated the link between disulfide bond formation and the activation of heparanase in human tumor cells. Mass spectrometry analysis of heparanase purified from a conditioned medium of human fibrosarcoma cells revealed two disulfide bonds, Cys127-Cys179 and Cys437 Cys542, and one S-cysteinylation at the Cys211 residue. It was shown that, although the formation of the Cys127-Cys179 bond and S-cysteinylation at Cys211 have little effect on heparanase function, the disulfide bond between Cys437 and Cys542 is necessary for the secretion and activation of heparanase. Thus, the present findings will provide a basis for the further refinement of heparanase structural studies and for the development of novel heparanase inhibitors. PMID- 17699791 TI - Coadministration of a herpes simplex virus-2 based oncolytic virus and cyclophosphamide produces a synergistic antitumor effect and enhances tumor specific immune responses. AB - Despite their unique property of selective replication and propagation in tumor tissues, oncolytic viruses have had only limited antitumor effects in cancer patients. One of the major reasons is probably the host's immune defense mechanisms, which can restrict the ability of the virus to replicate and spread within tumors. The innate immune system, which can be rapidly activated during virus infection, likely plays a more pivotal antiviral role than does acquired immunity, as the antitumor effect of an oncolytic virus is mainly generated during the acute phase of virus replication. To exploit the potential of cyclophosphamide, a cancer chemotherapeutic drug that also inhibits innate immune responses, to enhance the activity of oncolytic viruses, we evaluated the effect of coadministration of this drug with a herpes simplex virus-2-based oncolytic virus (FusOn-H2) against Lewis lung carcinoma, which is only semipermissive to infection with FusOn-H2. This strategy synergistically enhanced the antitumor effect against lung carcinoma growing in mice. It also potentiated the ability of FusOn-H2 to induce tumor-specific immune responses. Together, our results suggest that coadministration of FusOn-H2 with cyclophosphamide would be a feasible way to enhance the antitumor effects of this oncolytic virus in future clinical trials. PMID- 17699792 TI - Ethacrynic acid butyl-ester induces apoptosis in leukemia cells through a hydrogen peroxide mediated pathway independent of glutathione S-transferase P1-1 inhibition. AB - Ethacrynic acid (EA), a glutathione S-transferase inhibitor and diuretic agent, inhibits cell growth and induces apoptosis in cancer cells. To improve the activities, the structure of EA has been modified, and it has been shown that EA esters had an increased cell growth inhibitory ability compared with nonesterified analogue. EA butyl-ester (EABE) was synthesized, and its apoptosis induction ability was studied. The efficacy of EABE was compared with that of EA, and the mechanisms of action were studied in HL-60 leukemia cells. EABE exhibited greater cell growth inhibitory and apoptosis induction abilities than did EA. EABE-induced apoptosis in HL-60 cells correlated with increased levels of reactive oxygen species, the death receptor 5 (DR5), and caspase activation and decreased levels of the mitochondrial membrane potential. Pretreatment with antioxidants, either N-acetylcysteine or catalase, completely blocked EABE induced apoptosis, H2O2 accumulation, and up-regulation of DR5 levels. RG19, a subclone of Raji cells stably transfected with a GSTpi expression vector, and K562 cells with high endogenous GSTP1-1 activity were less sensitive to EABE induced apoptosis. EABE was more rapidly taken up than EA by HL-60 cells as determined by high-performance liquid chromatography (HPLC) measurements of intracellular concentrations. These results suggest that (a) H2O2 production is a mediator of EABE and EA-induced apoptosis; (b) GSTP1-1 plays a negative role in EABE and EA-induced apoptosis; and (c) the activity of EABE is greater than EA due to its more rapid entry into cells. PMID- 17699793 TI - Cisplatin-induced apoptosis involves membrane fluidification via inhibition of NHE1 in human colon cancer cells. AB - We have previously shown that cisplatin triggers an early acid sphingomyelinase (aSMase)-dependent ceramide generation concomitantly with an increase in membrane fluidity and induces apoptosis in HT29 cells. The present study further explores the role and origin of membrane fluidification in cisplatin-induced apoptosis. The rapid increase in membrane fluidity following cisplatin treatment was inhibited by membrane-stabilizing agents such as cholesterol or monosialoganglioside-1. In HT29 cells, these compounds prevented the early aggregation of Fas death receptor and of membrane lipid rafts on cell surface and significantly inhibited cisplatin-induced apoptosis without altering drug intracellular uptake or cisplatin DNA adducts formation. Early after cisplatin treatment, Na+/H+ membrane exchanger-1 (NHE1) was inhibited leading to intracellular acidification, aSMase was activated, and ceramide was detected at the cell membrane. Treatment of HT29 cells with Staphylococcus aureus sphingomyelinase increased membrane fluidity. Moreover, pretreatment with cariporide, a specific inhibitor of NHE1, inhibited cisplatin-induced intracellular acidification, aSMase activation, ceramide membrane generation, membrane fluidification, and apoptosis. Finally, NHE1-expressing PS120 cells were more sensitive to cisplatin than NHE1-deficient PS120 cells. Altogether, these findings suggest that the apoptotic pathway triggered by cisplatin involves a very early NHE1-dependent intracellular acidification leading to aSMase activation and increase in membrane fluidity. These events are independent of cisplatin-induced DNA adducts formation. The membrane exchanger NHE1 may be another potential target of cisplatin, increasing cell sensitivity to this compound. PMID- 17699794 TI - Mouse dendritic-endothelial cell hybrids and 4-1BB costimulation elicit antitumor effects mediated by broad antiangiogenic immunity. AB - Antiangiogenic immunotherapy, which targets molecules critical to tumor angiogenesis, is expected to counteract the negative effect of tumor cell genetic instability on the outcome of immunotherapy targeting tumor antigens. Previously, targeting of individual angiogenic molecules has been shown to inhibit tumor angiogenesis and limit tumor growth. Nevertheless, this approach may be bypassed by redundant angiogenic pathways. To overcome this limitation, we have developed an immunization strategy targeting multiple molecules critical to angiogenesis. To this end, hybrids of dendritic cells (DC) and syngeneic endothelial cells (EC) were used as immunogens, because (a) whole EC express multiple molecules involved in angiogenesis and (b) DC tumor cell hybrids are effective in generating self antigen-specific immune responses. The immunization strategy included the administration of an agonist 4-1BB-specific monoclonal antibody (mAb), because it augments self-antigen-specific immune responses elicited by DC hybrids. Immunization of mice with DC-EC hybrids and 4-1BB-specific mAb inhibited the growth of B16.F10 melanoma and MC38 colon adenocarcinoma tumors. This effect is mediated by EC-specific CD4+ and CD8+ T-cell responses, which markedly inhibited tumor angiogenesis. No therapy-related side effects, except minor and transient hematologic changes, were observed. Our findings represent a useful background for the design of antiangiogenic immunotherapeutic strategies to control tumor growth in a clinical setting. PMID- 17699795 TI - Molecular profiling of matched samples identifies biomarkers of papillary thyroid carcinoma lymph node metastasis. AB - Biomarkers of papillary thyroid carcinoma (PTC) metastasis can accurately identify metastatic cells and aggressive tumor behavior. To find new markers, serial analysis of gene expression (SAGE) was done on three samples from the same patient: normal thyroid tissue, primary PTC, and a PTC lymph node metastasis. This genomewide expression analysis identified 31 genes expressed in lymph node metastasis, but not in the primary tumor. Eleven genes were evaluated by quantitative real-time reverse transcription-PCR (qPCR) on independent sets of matched samples to find genes that were consistently different between the tumor and metastatic samples. LIMD2 and PTPRC (CD45) showed a statistically significant difference in expression between tumor and metastatic samples (P < 0.0045), and an additional gene (LTB) had borderline significance. PTPRC and LTB were tested by immunohistochemistry in an independent set of paired samples, with both markers showing a difference in protein expression. All 20 metastases from 6 patients showed expression in both markers, with little or no expression in primary tumor. Some of these markers could provide an improved means to detect metastatic PTC cells during initial staging of a newly diagnosed carcinoma and/or to rule out recurrence. The functional role of these genes may also provide insight into mechanisms of thyroid cancer metastasis. PMID- 17699796 TI - Up-regulation of 14-3-3zeta in lung cancer and its implication as prognostic and therapeutic target. AB - A functional genomic approach integrating microarray and proteomic analyses done in our laboratory has identified 14-3-3zeta as a putative oncogene whose activation was common and driven by its genomic amplification in lung adenocarcinomas. 14-3-3zeta is believed to function in cell signaling, cycle control, and apoptotic death. Following our initial finding, here, we analyzed its expression in lung tumor tissues obtained from 205 patients with various histologic and stage non-small cell lung cancers (NSCLC) using immunohistochemistry and then explored the effects of specific suppression of the gene in vitro and in a xenograft model using small interfering RNA. The increased 14-3-3zeta expression was positively correlated with a more advanced pathologic stage and grade of NSCLCs (P = 0.001 and P = 0.006, respectively) and was associated with overall and cancer-specific survival rates of the patients (P = 0.022 and P = 0.018, respectively). Down-regulation of 14-3-3zeta in lung cancer cells led to a dose-dependent increased sensitivity to cisplatin-induced cell death, which was associated with the inhibition of cell proliferation and increased G2-M arrest and apoptosis. The result was further confirmed in the animal model, which showed that the A549 lung cancer cells with reduced 14-3 3zeta grew significantly slower than the wild-type A549 cells after cisplatin treatment (P = 0.008). Our results suggest that 14-3-3zeta is a potential target for developing a prognostic biomarker and therapeutics that can enhance the antitumor activity of cisplatin for NSCLC. PMID- 17699797 TI - Syk tyrosine kinase is linked to cell motility and progression in squamous cell carcinomas of the head and neck. AB - Syk, a non-receptor tyrosine kinase, is an important component of immunoreceptor signaling in hematopoietic cells. It has been implicated in key regulatory pathways including phosphoinositide 3-kinase and phospholipase Cgamma (PLCgamma) activation in B cells and integrin signaling in platelets and bronchial epithelial cells. Recently, potential roles in cancer have been reported. In breast cancers, reduced Syk expression was associated with invasion, and its overexpression in cell lines was shown to inhibit cell motility. In contrast, Syk has been shown to mediate chemomigration in nasopharyngeal carcinoma cells. Its role in squamous cell carcinomas of the head and neck (SCCHN) has not yet been investigated. Syk mRNA and protein expression was detected in 6 of 10 SCCHN cell lines. When Syk was transfected into Syk-negative cells (SIHN-011A), chemomigration was enhanced in vitro and this was associated with activation of PLCgamma1. Conversely, abrogation of Syk activity by pharmacologic inhibition or small interfering RNA in HN6 cells with high levels of endogenous expression inhibited migration, haptotaxis, and engagement with matrix proteins; this was accompanied by decreased levels of phosphorylated AKT. Similar effects were seen in Syk-positive CAL 27 cells but not in Syk-negative SIHN-011A cells. Immunoprecipitation suggested co-association of Syk with epidermal growth factor receptor and GRB-2. Syk expression in SCCHN patient tissues was examined by semiquantitative real-time PCR (n = 45) and immunohistochemistry (n = 38) in two independent cohorts. Higher levels of Syk expression were observed in tumors and lymph node metastases relative to normal tissues. High Syk expression significantly correlated with worse survival and may be of prognostic value in SCCHN due to its potential role in cell migration and invasion. PMID- 17699798 TI - Regulation of genes of the circadian clock in human colon cancer: reduced period 1 and dihydropyrimidine dehydrogenase transcription correlates in high-grade tumors. AB - Expression of dihydropyrimidine dehydrogenase (DPD) displays a regular daily oscillation in nonmalignant cells. In colorectal cancer cells, the expression of this 5-fluorouracil-metabolizing enzyme is decreased, but the reason remains unclear. In this study, we analyzed by real-time reverse transcription-PCR (RT PCR) the expression of DPD and of members of the cellular oscillation machinery, period 1 (Per1), period 2 (Per2), and CLOCK, in primary colorectal tumors and normal colon mucosa derived from the same patients. Analysis of tumors according to differentiation grade revealed a 0.46-fold (P = 0.005) decrease for DPD mRNA and a 0.49-fold (P = 0.004) decrease for Per1 mRNA in undifferentiated (G3) tumors compared with paired normal mucosa. In this tumor cohort, the correlation between DPD and Per1 levels was r = 0.64, P < 0.01. In moderately differentiated (G2) colon carcinomas, reduction of DPD and Per1 mRNA levels did not reach significance, but a significant correlation between the respective mRNA levels was detectable (r = 0.54; P < 0.05). The decrease and correlation of DPD and Per1 mRNA levels were even more pronounced in female (G3) patients (DPD: female, 0.35 fold, P < 0.001 versus male, 0.58-fold, P < 0.05; and Per1: female, 0.47-fold, P < 0.01 versus male, 0.52-fold, P < 0.01). The highly significant correlation of DPD mRNA with Per1 mRNA expression suggests control of DPD transcription by the endogenous cellular clock, which is more pronounced in women. Our results also revealed a disturbed transcription of Per1 during tumor progression, which might be the cause for disrupted daily oscillation of DPD in undifferentiated colon carcinoma cells. PMID- 17699799 TI - Circulating insulin-like growth factor binding protein-1 and the risk of pancreatic cancer. AB - Insulin-like growth factor (IGF)-I has growth-promoting effects on pancreatic cancer cells, and elevated fasting serum insulin has been linked to pancreatic cancer risk. IGF binding protein-1 (IGFBP-1) is a downstream target of insulin and inhibits IGF-I activity. To investigate whether prediagnostic plasma levels of IGFBP-1 are associated with pancreatic cancer risk, we did a prospective, case control study nested within the Health Professionals Follow-up Study, the Nurses' Health Study, the Physicians' Health Study, and the Women's Health Initiative. We assayed circulating IGFBP-1 among 144 pancreatic cancer cases that occurred >or=4 years after plasma collection and in 429 controls, matched for date of birth, prospective cohort, smoking status, and fasting status. When compared with participants in the three highest quartiles of plasma IGFBP-1, those in the lowest quartile experienced a relative risk (RR) for pancreatic cancer of 2.07 [95% confidence intervals (95% CI), 1.26-3.39], after adjusting for other risk factors, including circulating IGF-I, IGF binding protein-3, and C-peptide. Only participants in the lowest quartile of plasma IGFBP-1 showed an elevated risk of pancreatic cancer. The influence of low plasma IGFBP-1 became progressively stronger with time; among cases diagnosed >or=8 years after blood collection, the adjusted RR was 3.47 (95% CI, 1.48-8.14), comparing the bottom versus the top three quartiles. The influence of plasma IGFBP-1 was most marked among participants who never smoked cigarettes (RR, 3.30; 95% CI, 1.48-7.35). Among participants in four U.S. prospective cohort studies, low plasma IGFBP-1 levels significantly predicted an increased risk of pancreatic cancer. PMID- 17699800 TI - Farnesol-induced apoptosis in human lung carcinoma cells is coupled to the endoplasmic reticulum stress response. AB - Farnesol (FOH) and other isoprenoid alcohols induce apoptosis in various carcinoma cells and inhibit tumorigenesis in several in vivo models. However, the mechanisms by which they mediate their effects are not yet fully understood. In this study, we show that FOH is an effective inducer of apoptosis in several lung carcinoma cells, including H460. This induction is associated with activation of several caspases and cleavage of poly(ADP-ribose) polymerase (PARP). To obtain insight into the mechanism involved in FOH-induced apoptosis, we compared the gene expression profiles of FOH-treated and control H460 cells by microarray analysis. This analysis revealed that many genes implicated in endoplasmic reticulum (ER) stress signaling, including ATF3, DDIT3, HERPUD1, HSPA5, XBP1, PDIA4, and PHLDA1, were highly up-regulated within 4 h of FOH treatment, suggesting that FOH-induced apoptosis involves an ER stress response. This was supported by observations showing that treatment with FOH induces splicing of XBP1 mRNA and phosphorylation of eIF2alpha. FOH induces activation of several mitogen-activated protein kinase (MAPK) pathways, including p38, MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK, and c-jun NH2 terminal kinase (JNK). Inhibition of MEK1/2 by U0126 inhibited the induction of ER stress response genes. In addition, knockdown of the MEK1/2 and JNK1/2 expression by short interfering RNA (siRNA) effectively inhibited the cleavage of caspase-3 and PARP and apoptosis induced by FOH. However, only MEK1/2 siRNAs inhibited the induction of ER stress-related genes, XBP1 mRNA splicing, and eIF2alpha phosphorylation. Our results show that FOH-induced apoptosis is coupled to ER stress and that activation of MEK1/2 is an early upstream event in the FOH induced ER stress signaling cascade. PMID- 17699801 TI - Are Parkinson disease patients protected from some but not all cancers? AB - There is substantial evidence based on well designed epidemiologic studies for low cancer rates in patients with Parkinson disease (PD). This risk reduction cannot be attributed to the recognized low life-long incidence of smoking in patients with PD, as not only smoking-related cancers but also non-smoking related ones are less common in PD. Whereas the risk for most cancers appears to be relatively low in patients with PD, breast cancer and melanomas occur more frequently in the PD population as compared with controls. The relationship between this peculiar pattern of cancer rates and PD might be related to the involvement of common genes in both diseases. Mutations in parkin gene, for example, have been reported in several types of cancer. Furthermore, genes involved in familial forms of PD appear to be abnormally expressed in cancers. Thus, parkin and PINK1 might be tumor suppressor genes, whereas DJ-1 is an oncogene. Cell survival signals may differ owing to mutated genes and represent two opposite extremes such as cell proliferation in cancer and cell death due to apoptosis in PD. Unraveling the link between PD and cancer may open a therapeutic window for both diseases. PMID- 17699802 TI - How effective are disease-modifying drugs in delaying progression in relapsing onset MS? AB - OBJECTIVE: Our objective was to estimate the effectiveness of disease-modifying drugs (DMDs) in delaying multiple sclerosis (MS) disability progression in relapsing-onset (R-onset) definite MS patients under "real-world" conditions. METHODS: Treatment effect size, for DMDs as a class, was estimated in absolute terms and relative to MS natural history. A basic model estimated annual Expanded Disability Status Scale (EDSS) change before and after treatment. An expanded model estimated annual EDSS change in pretreatment years, treatment years on first drug, treatment years after drugs were switched, and in years after treatment stopped. Models were populated with 1980 through 2004 clinical data, including 1988 through 2004 data for all Nova Scotians treated with DMDs. Estimates were made for relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and R-onset groups. RESULTS: Estimated pretreatment annual EDSS increases were approximately 0.10 of one EDSS point for the RRMS group, 0.31 for the SPMS group, and 0.16 for the R-onset group. Estimates of EDSS increase avoided per treatment year on the first drug were significant for the RRMS group (-0.103, 0.000), the SPMS group (-0.065, 0.011), and the R-onset group (-0.162, 0.000); relative effect size estimates were 112%, 21%, and 105%. Estimated EDSS progression was faster in years after drug switches and treatment stops. CONCLUSIONS: Our estimates of disease-modifying drug (DMD) relative treatment effect size, in the context of "real-world" clinical practice, are similar to DMD treatment efficacy estimates in pivotal trials, though our findings attained statistical significance. DMDs, as a class, are effective in delaying Expanded Disability Status Scale progression in patients with relapsing-onset definite multiple sclerosis (MS) (90%), although effectiveness is much better for relapsing-remitting MS than for secondary progressive MS groups. PMID- 17699803 TI - Atorvastatin but not elocalcitol increases sildenafil responsiveness in spontaneously hypertensive rats by regulating the RhoA/ROCK pathway. AB - Spontaneously hypertensive rats (SHR) are characterized by impaired erectile function and overactivity of the procontractile RhoA/Rho-associated, coiled-coil containing protein kinase (RhoA/ROCK) pathway, as compared with their normotensive counterpart, Wistar-Kyoto rats. By measuring the intracavernous pressure:mean arterial pressure (ICP:MAP) ratio after electrostimulation of the cavernous nerve, we confirmed these findings and showed that responsiveness to sildenafil (25 mg/kg by oral gavage) also is hampered in SHR. A 2-week treatment with atorvastatin (5 and 30 mg/kg) improved the sildenafil-induced ICP:MAP increase and normalized RhoA and ROCK2 overexpression in SHR corpora cavernosa (CC). Conversely, other genes, neuronal nitric oxide synthase (NOS), endothelial NOS, and phosphodiesterase 5, were unaffected. In human fetal smooth muscle cells derived from CC (hfPSMC), atorvastatin inhibited RhoA membrane translocation and ROCK activity, as well as RhoA-dependent biologic functions like cell migration and cell proliferation. Atorvastatin's effect on migration was rescued in a dose dependent manner by geranylgeranyl pyrophosphate, suggesting the involvement of RhoA geranylgeranylation. In hfPSMC, atorvastatin decreased the expression of RhoA-dependent genes such as ROCK2, desmin, alpha-smooth muscle actin, SM22alpha, and myocardin. In contrast to atorvastatin, elocalcitol, a vitamin D analog that also interferes with RhoA activation in SHR bladder, was unable to restore penile responsiveness to sildenafil. In conclusion, atorvastatin, but not elocalcitol, ameliorates sildenafil-induced penile erections in SHR, likely by interfering with RhoA/ROCK signaling within the penis. PMID- 17699804 TI - A unique association of clinical "persistent mullerian duct syndrome" and syringoid carcinoma of the perineal-scrotal skin: a consequence of urologic surgery? PMID- 17699805 TI - Public health considerations in knowledge translation in the emergency department. AB - Effective preventive and screening interventions have not been widely adopted in emergency departments (EDs). Barriers to knowledge translation of these initiatives include lack of knowledge of current evidence, perceived lack of efficacy, and resource availability. To address this challenge, the Academic Emergency Medicine 2007 Consensus Conference, "Knowledge Translation in Emergency Medicine: Establishing a Research Agenda and Guide Map for Evidence Uptake," convened a public health focus group. The question this group addressed was "What are the unique contextual elements that need to be addressed to bring proven preventive and other public health initiatives into the ED setting?" Public health experts communicated via the Internet beforehand and at a breakout session during the conference to reach consensus on this topic, using published evidence and expert opinion. Recommendations include 1) to integrate proven public health interventions into the emergency medicine core curriculum, 2) to configure clinical information systems to facilitate public health interventions, and 3) to use ancillary ED personnel to enhance delivery of public health interventions and to obtain successful funding for these initiatives. Because additional research in this area is needed, a research agenda for this important topic was also developed. The ED provides medical care to a unique population, many with increased needs for preventive care. Because these individuals may have limited access to screening and preventive interventions, wider adoption of these initiatives may improve the health of this vulnerable population. PMID- 17699806 TI - Barriers to metered-dose inhaler/spacer use in Canadian pediatric emergency departments: a national survey. AB - BACKGROUND: Metered-dose inhalers and spacers (MDI+S) are at least as effective as nebulizers for treating children with mild to moderate asthma exacerbations. Despite advantages in terms of efficacy, side effects, and ease of use, MDI+S are not used in many North American pediatric emergency departments (PEDs). OBJECTIVES: To survey emergency physicians, emergency nurses, and respirologists in Canadian pediatric teaching hospitals regarding their practices, beliefs, and barriers to change with respect to bronchodilator delivery. METHODS: This was a cross-sectional, mailed survey of all emergency physicians, all respirologists, and a random sample of emergency nurses at ten Canadian PEDs. RESULTS: A total of 291 of 349 health care professionals (83%) responded. Twenty-one percent of emergency physicians use MDI+S in the PED (largely concentrated at two "user sites"). A majority at nonuser sites, and virtually all professionals at user sites, responded that MDI+S are at least as effective as nebulizers, switching to MDI+S is justified by existing research, patient outcomes would be equal or better, and they have the required knowledge and skills to use MDI+S in the emergency department. The largest perceived barriers to MDI+S implementation include concerns regarding safety and costs, related to feasibility of providing and sterilizing spacers, and parental expectations for nebulizers. Other barriers included staff beliefs regarding the effectiveness of MDI+S, changes in nursing workload, and lack of a physician champion for change. CONCLUSIONS: MDI+S are infrequently used to treat patients with acute asthma in Canadian PEDs, despite the fact that most emergency staff believe they are effective. Important barriers to using MDI+S have been identified in this study and should be used to guide future implementation strategies. PMID- 17699807 TI - Fabry nephropathy and the case for adjunctive renal therapy. PMID- 17699808 TI - The continuing story of renal repair with stem cells. PMID- 17699809 TI - Laminin compensation in collagen alpha3(IV) knockout (Alport) glomeruli contributes to permeability defects. AB - Alport disease is caused by mutations in genes encoding the alpha3, alpha4, or alpha5 chains of type IV collagen, which form the collagenous network of mature glomerular basement membrane (GBM). In the absence of alpha3, alpha4, alpha5 (IV) collagen, alpha1, alpha2 (IV) collagen persists, which ordinarily is found only in GBM of developing kidney. In addition to dysregulation of collagen IV, Alport GBM contains aberrant laminins, which may contribute to the progressive GBM thickening and splitting, proteinuria, and renal failure seen in this disorder. This study sought to characterize further the laminin dysregulation in collagen alpha3(IV) knockout mice, a model of Alport disease. With the use of confocal microscopy, laminin alpha1 and alpha5 abundance was quantified, and it was found that they co-distributed in significantly large amounts in areas of GBM thickening. In addition, labeling of entire glomeruli for laminin alpha5 was significantly greater in Alport mice than in wild-type siblings. Reverse transcriptase-PCR from isolated glomeruli demonstrated significantly more laminin alpha5 mRNA in Alport mice than in wild-type controls, indicating upregulated transcription of Lama5. For testing glomerular barrier function, ferritin was injected into 2-wk-old Alport and control mice, and GBM was examined by electron microscopy. Highest ferritin levels were seen in Alport GBM thickenings beneath effaced podocyte foot processes, but morphologically normal GBM was significantly permeable as well. We concluded that (1) ultrastructurally normal Alport GBM residing beneath differentiated podocyte foot processes is inherently and abnormally permeable, and (2) upregulation of Lama5 transcription and concentration of laminin alpha1 and alpha5 within Alport GBM thickenings contribute to abnormal permeabilities. PMID- 17699810 TI - Antiphospholipid syndrome in systemic lupus erythematosus. AB - Renal biopsies occasionally show a combination of thrombotic microangiopathy as a result of antiphospholipid syndrome and lupus nephritis. The thrombosis in this case preceded the onset of lupus probably by approximately 8 yr, consisting of repeated fetal loss and venous thrombosis. More severe disease may have both arterial and venous thrombotic manifestations, including pulmonary emboli and cerebrovascular lesions. The antiphospholipid syndrome bears no relationship to the class of lupus nephritis but is accompanied by more frequent and greater hypertension and greater azotemia and interstitial fibrosis, and is associated with worse outcomes than lupus nephritis without antiphospholipid syndrome. PMID- 17699811 TI - Anti endothelial cell autoantibodies selectively activate SAPK/JNK signalling in Wegener's granulomatosis. AB - The pathogenic role of anti-endothelial cell antibodies (AECA) in vascular injury is debated. It was previously shown that many patients with Wegener's granulomatosis (WG) have AECA that react with human kidney microvascular endothelial cells (EC). In addition, during active disease, renal endothelium strongly expresses the inflammatory molecules vascular adhesion protein-1 (VAP-1) and MHC class I-related antigen A (MICA). This study sought to determine whether AECA mediates this upregulation of VAP-1 and MICA and to define better the signaling pathways that are activated by these autoantibodies upon binding to EC in the kidney. Stimulation of human kidney microvascular EC with AECA IgG upregulated surface expression of MICA and VAP-1, elicited a rapid Ca2+ flux, induced high levels of the chemokines monocyte chemoattractant protein-1 and granulocyte chemotactic protein-2, induced specific phosphorylation of stress activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) and the transcription factors c-Jun and activating transcription factor-2, and activated NF-kappaB. Specific inhibitors of SAPK/JNK significantly reduced AECA-induced chemokine production and phosphorylation of c-Jun and activating transcription factor-2 and abrogated protein expression of MICA but not VAP-1. In kidney sections from patients with WG, infiltrating cells that expressed the ligand for MICA (NKG2D+) were identified, as were CD8+ and 32 gamma delta+ T cells. In conclusion, AECA may be involved in the pathogenesis of WG, and the SAPK/JNK pathway and the endothelial inflammatory protein VAP-1 may be novel therapeutic targets for vasculitis. PMID- 17699812 TI - Images in clinical medicine. Endometriosis. PMID- 17699813 TI - Keeping science on top in drug evaluation. PMID- 17699814 TI - Medical abortion and the risk of subsequent adverse pregnancy outcomes. AB - BACKGROUND: The long-term safety of surgical abortion in the first trimester is well established. Despite the increasing use of medical abortion (abortion by means of medication), limited information is available regarding the effects of this procedure on subsequent pregnancies. METHODS: We identified all women living in Denmark who had undergone an abortion for nonmedical reasons between 1999 and 2004 and obtained information regarding subsequent pregnancies from national registries. Risks of ectopic pregnancy, spontaneous abortion, preterm birth (at <37 weeks of gestation), and low birth weight (<2500 g) in the first subsequent pregnancy in women who had had a first-trimester medical abortion were compared with risks in women who had had a first-trimester surgical abortion. RESULTS: Among 11,814 pregnancies in women who had had a previous first-trimester medical abortion (2710 women) or surgical abortion (9104 women), there were 274 ectopic pregnancies (respective incidence rates, 2.4% and 2.3%), 1426 spontaneous abortions (12.2% and 12.7%), 552 preterm births (5.4% and 6.7%), and 478 births with low birth weight (4.0% and 5.1%). After adjustment for maternal age, interval between pregnancies, gestational age at abortion, parity, cohabitation status, and urban or nonurban residence, medical abortion was not associated with a significantly increased risk of ectopic pregnancy (relative risk, 1.04; 95% confidence interval [CI], 0.76 to 1.41), spontaneous abortion (relative risk, 0.87; 95% CI, 0.72 to 1.05), preterm birth (relative risk, 0.88; 95% CI, 0.66 to 1.18), or low birth weight (relative risk, 0.82; 95% CI, 0.61 to 1.11). Gestational age at medical abortion was not significantly associated with any of these adverse outcomes. CONCLUSIONS: We found no evidence that a previous medical abortion, as compared with a previous surgical abortion, increases the risk of spontaneous abortion, ectopic pregnancy, preterm birth, or low birth weight. PMID- 17699815 TI - Sonication of removed hip and knee prostheses for diagnosis of infection. AB - BACKGROUND: Culturing of samples of periprosthetic tissue is the standard method used for the microbiologic diagnosis of prosthetic-joint infection, but this method is neither sensitive nor specific. In prosthetic-joint infection, microorganisms are typically present in a biofilm on the surface of the prosthesis. We hypothesized that culturing of samples obtained from the prosthesis would improve the microbiologic diagnosis of prosthetic-joint infection. METHODS: We performed a prospective trial comparing culture of samples obtained by sonication of explanted hip and knee prostheses to dislodge adherent bacteria from the prosthesis with conventional culture of periprosthetic tissue for the microbiologic diagnosis of prosthetic-joint infection among patients undergoing hip or knee revision or resection arthroplasty. RESULTS: We studied 331 patients with total knee prostheses (207 patients) or hip prostheses (124 patients); 252 patients had aseptic failure, and 79 had prosthetic-joint infection. With the use of standardized nonmicrobiologic criteria to define prosthetic-joint infection, the sensitivities of periprosthetic-tissue and sonicate-fluid cultures were 60.8% and 78.5% (P<0.001), respectively, and the specificities were 99.2% and 98.8%, respectively. Fourteen cases of prosthetic joint infection were detected by sonicate-fluid culture but not by prosthetic tissue culture. In patients receiving antimicrobial therapy within 14 days before surgery, the sensitivities of periprosthetic tissue and sonicate-fluid culture were 45.0% and 75.0% (P<0.001), respectively. CONCLUSIONS: In this study, culture of samples obtained by sonication of prostheses was more sensitive than conventional periprosthetic-tissue culture for the microbiologic diagnosis of prosthetic hip and knee infection, especially in patients who had received antimicrobial therapy within 14 days before surgery. PMID- 17699816 TI - Prophylactic cranial irradiation in extensive small-cell lung cancer. AB - BACKGROUND: We conducted a randomized trial of prophylactic cranial irradiation in patients with extensive small-cell lung cancer who had had a response to chemotherapy. METHODS: Patients between the ages of 18 and 75 years with extensive small-cell lung cancer were randomly assigned to undergo prophylactic cranial irradiation (irradiation group) or receive no further therapy (control group). The primary end point was the time to symptomatic brain metastases. Computed tomography or magnetic resonance imaging of the brain was performed when any predefined key symptom suggestive of brain metastases was present. RESULTS: The two groups (each with 143 patients) were well balanced regarding baseline characteristics. Patients in the irradiation group had a lower risk of symptomatic brain metastases (hazard ratio, 0.27; 95% confidence interval [CI], 0.16 to 0.44; P<0.001). The cumulative risk of brain metastases within 1 year was 14.6% in the irradiation group (95% CI, 8.3 to 20.9) and 40.4% in the control group (95% CI, 32.1 to 48.6). Irradiation was associated with an increase in median disease-free survival from 12.0 weeks to 14.7 weeks and in median overall survival from 5.4 months to 6.7 months after randomization. The 1-year survival rate was 27.1% (95% CI, 19.4 to 35.5) in the irradiation group and 13.3% (95% CI, 8.1 to 19.9) in the control group. Irradiation had side effects but did not have a clinically significant effect on global health status. CONCLUSIONS: Prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolongs disease-free and overall survival. (ClinicalTrials.gov number, NCT00016211 [ClinicalTrials.gov].). PMID- 17699817 TI - A decade of direct-to-consumer advertising of prescription drugs. AB - BACKGROUND: Evidence suggests that direct-to-consumer advertising of prescription drugs increases pharmaceutical sales and both helps to avert underuse of medicines and leads to potential overuse. Concern about such advertising has increased recently owing to the withdrawal from the market of heavily advertised drugs found to carry serious risks. Moreover, the Food and Drug Administration (FDA) has been criticized for its weak enforcement of laws regulating such advertising. METHODS: We examined industry-wide trends in spending by pharmaceutical companies on direct-to-consumer advertising and promotion to physicians during the past decade. We characterized the drugs for which such advertising is used and assessed the timing of advertising after a drug is introduced. Finally, we examined trends in the FDA's regulation of drug advertising. RESULTS: Total spending on pharmaceutical promotion grew from $11.4 billion in 1996 to $29.9 billion in 2005. Although during that time spending on direct-to-consumer advertising increased by 330%, it made up only 14% of total promotional expenditures in 2005. Direct-to-consumer campaigns generally begin within a year after the approval of a product by the FDA. In the context of regulatory changes requiring legal review before issuing letters, the number of letters sent by the FDA to pharmaceutical manufacturers regarding violations of drug-advertising regulations fell from 142 in 1997 to only 21 in 2006. CONCLUSIONS: Spending on direct-to-consumer advertising has continued to increase in recent years in spite of the criticisms leveled against it. Our findings suggest that calls for a moratorium on such advertising for new drugs would represent a dramatic departure from current practices. PMID- 17699818 TI - Psoralen and ultraviolet a light therapy for psoriasis. PMID- 17699819 TI - Images in clinical medicine. Pearly penile papules. PMID- 17699820 TI - Case records of the Massachusetts General Hospital. Case 25-2007. A 60-year-old man with fever, odynophagia, weight loss, and rash. PMID- 17699821 TI - Ultrasound--now also for microbiologists? PMID- 17699823 TI - Bugging of the intestinal mucosa. PMID- 17699824 TI - Yearly zoledronic acid in postmenopausal osteoporosis. PMID- 17699825 TI - Antiretroviral drugs and the risk of myocardial infarction. PMID- 17699826 TI - A medical mystery: high blood pressure--the answer. PMID- 17699827 TI - Eisenmenger's syndrome and pulmonary-artery dissection. PMID- 17699828 TI - Wine-induced anaphylaxis and sensitization to hymenoptera venom. PMID- 17699829 TI - Nephrogenic systemic fibrosis, gadolinium, and iron mobilization. PMID- 17699830 TI - Thunderstorms and iPods--two reports of the same case. PMID- 17699831 TI - Toll-like receptor 4 polymorphism associated with the response to whole-cell pertussis vaccination in children from the KOALA study. AB - We examined the association between haplotype tagging single-nucleotide polymorphisms in TLR4 and the pertussis toxin-specific immunoglobulin G response after whole-cell pertussis (wP) vaccination in 515 1-year-old children from the KOALA study. A lower titer was associated with the minor allele of rs2770150, supporting a role for Toll-like receptor 4 in the antibody response to wP vaccination. PMID- 17699832 TI - Development and validation of an ovine progressive pneumonia virus quantitative PCR. AB - Ovine progressive pneumonia virus (OPPV) infects at least one sheep in 81% of U.S. sheep flocks, as determined by serology, and can cause viral mastitis, arthritis, dyspnea, and cachexia. Diagnostic tests that quantify OPPV proviral load in peripheral blood leukocytes (PBL) provide an additional method for identification of infected sheep and may help to further understanding of the pathogenesis of OPPV-induced disease. In this study, we compared a new OPPV real time quantitative PCR (qPCR) assay specific for the transmembrane region of the envelope gene (tm) with a competitive inhibition enzyme-linked immunosorbent assay (cELISA) using 396 PBL samples and sera from Idaho sheep. The OPPV qPCR had a positive concordance of 96.2% +/- 2.3% and a negative concordance of 97.7% +/- 2.5% compared to the cELISA, with a kappa value of 0.93, indicating excellent agreement between the two tests. In addition, the presence of tm in the three OPPV qPCR-positive and cELISA-negative sheep and in 15 sheep with different OPPV proviral loads was confirmed by cloning and sequencing. These data indicate that the OPPV qPCR may be used as a supplemental diagnostic tool for OPPV infection and for measurement of viral load in PBLs of infected sheep. PMID- 17699833 TI - Serum immunoglobulin G antibodies to the GOR autoepitope are present in patients with occult hepatitis C virus (HCV) infection despite lack of HCV-specific antibodies. AB - Antibody responses to the GOR autoepitope are frequently detected among anti hepatitis C virus (anti-HCV)-positive patients with chronic hepatitis. Sera from 110 anti-HCV-negative patients with occult HCV infection, as diagnosed by detection of HCV RNA in hepatic tissue, were investigated for GOR antibody reactivity. A positive test for anti-GOR immunoglobulin G (IgG) was found for 22 (20%) of them. The frequency and titers of anti-GOR IgG were significantly lower than those in chronic hepatitis C patients (70/110, 63.6%; P < 0.001). Anti-GOR IgG was not detected in any of the 120 patients with HCV-unrelated liver disease. The anti-GOR IgG assay showed specificity and sensitivity values of 100% and 20%, respectively, among the sera from patients with occult HCV infection; the positive and negative predictive values were 100% and 44.3%, respectively. None of the clinical, laboratory, or histological characteristics of the patients with occult HCV infection were different according to GOR antibody status, except that the percentage of HCV RNA-positive hepatocytes was significantly greater (P = 0.042) in patients with occult HCV infection who tested positive for anti-GOR IgG. In conclusion, serum anti-GOR IgG is present in patients with occult HCV infection, despite a lack of detectable HCV-specific antibodies as determined by commercial tests. Testing for anti-GOR IgG in patients in whom HCV RNA is not detected in their sera may help with the identification of a subset of patients with occult HCV infection without the need to perform a liver biopsy. PMID- 17699834 TI - Persistence of antibodies induced by measles-mumps-rubella vaccine in children in India. AB - Antibody levels in 41 Indian girls were measured 6 years after measles-mumps rubella (MMR) vaccination. Rates of seropositivity were 88% (measles antibodies), 95% (mumps antibodies), and 100% (rubella antibodies). The MMR vaccine induces long-term immunity in a majority of vaccinees; however, due to the observation of some seronegative vaccinees, the policy of administering a second dose of the MMR vaccine seems appropriate. PMID- 17699835 TI - Immunogenicity of a fourth dose of Haemophilus influenzae type b (Hib) conjugate vaccine and antibody persistence in young children from the United Kingdom who were primed with acellular or whole-cell pertussis component-containing Hib combinations in infancy. AB - In response to the rising incidence of Haemophilus influenzae type b (Hib) disease in the United Kingdom, a national campaign to give a booster dose of single-antigen Hib conjugate vaccine to children aged 6 months to 4 years was undertaken in 2003. Children (n = 386) eligible for Hib vaccine in the campaign were recruited. Hib antibody concentrations were measured before boost and at 1 month, 6 months, 1 year, and 2 years after boost and were analyzed according to children's ages at booster dose and whether a Hib combination vaccine containing acellular pertussis (aP) or whole-cell pertussis (wP) components was given in infancy. The geometric mean antibody concentrations (GMCs) before the booster declined as the time since primary immunization increased (P < 0.001), and GMCs were threefold higher in recipients of wP-Hib than aP-Hib combination vaccines (P < 0.001). GMCs 1 month after the booster increased with age (P < 0.001) as follows: 6 to 11 months; 30 microg/ml (95% confidence interval [CI], 22 to 40); 12 to 17 months, 68 microg/ml (95% CI, 38 to 124); and 2 to 4 years, 182 microg/ml (151 to 220), with no difference according to the type of priming vaccine received. Antibody levels declined after the booster, but 2 years later, GMCs were more than 1.0 microg/ml for all age groups. By extrapolating data for the decline in antibody levels, we found the GMCs 4 years after boosting were predicted to be 0.6, 1.4, and 2.6 microg/ml for those boosted at 6 to 11 months, 12 to 17 months, and 2 to 4 years, respectively, with levels of at least 0.15 microg/ml in about 90% of individuals. A booster dose of Hib vaccine given after the first year of life should provide long-lasting protection. PMID- 17699836 TI - Quality of the Haemophilus influenzae type b (Hib) antibody response induced by diphtheria-tetanus-acellular pertussis/Hib combination vaccines. AB - It has been repeatedly observed that mixing Haemophilus influenzae type b (Hib) conjugate vaccines with acellular pertussis-containing vaccines (diphtheria tetanus-acellular pertussis [DTPa]) resulted in a reduced magnitude of the anti polyriboseribitolphosphate antibody response compared to that obtained when Hib vaccines were administered separately and not mixed. Nevertheless, the quality and functionality of the immune responses have been shown to be the same. With the purpose of investigating the quality of the anti-Hib immune responses that are elicited under different vaccination regimens, we report here four primary and booster-based pediatric clinical trials in which Hib vaccine was either mixed with DTPa or diphtheria-tetanus-whole-cell pertussis (DTPw)-based vaccines or was coadministered. Our results show that avidity maturation of the antibodies was lower when primary vaccination involved DTPa mixed with Hib compared to when DTPa and Hib were coadministered. No such difference was observed between mixed and separately administered Hib when associated with DTPa-hepatitis B virus inactivated poliovirus or DTPw-based vaccines. All different combinations and regimens elicited the same opsonophagocytic and bactericidal activity as well as the same ability to protect in a passive infant rat protection assay. The functional activity of mixed DTPa-based and Hib vaccines was similar to that of mixed DTPw-based/Hib combinations. In conclusion, in vitro and in vivo data as well as postmarketing vaccine effectiveness data attest to the ability of DTPa based/Hib combination vaccines to effectively prevent Hib-induced disease in children. PMID- 17699838 TI - Antigenic polymorphism and naturally acquired antibodies to Plasmodium vivax merozoite surface protein 1 in rural Amazonians. AB - Merozoite surface protein 1 of Plasmodium vivax (PvMSP-1), a major target for malaria vaccine development, contains six highly polymorphic domains interspersed with conserved sequences. Although there is evidence that the sequence divergence in PvMSP-1 has been maintained over 5 million years by balanced selection exerted by the host's acquired immunity, the variant specificity of naturally acquired antibodies to PvMSP-1 remains poorly investigated. Here, we show that 15 recombinant proteins corresponding to PvMSP-1 variants commonly found in local parasites were poorly recognized by 376 noninfected subjects aged 5 to 90 years exposed to malaria in rural Amazonia; less than one-third of them had detectable immunoglobulin G (IgG) antibodies to at least one variant of blocks 2, 6, and 10 that were expressed, although 54.3% recognized the invariant 19-kDa C-terminal domain PvMSP-1(19). Although the proportion of responders to PvMSP-1 variants increased substantially during subsequent acute P. vivax infections, the specificity of IgG antibodies did not necessarily match the PvMSP-1 variant(s) found in infecting parasites. We discuss the relative contribution of antigenic polymorphism, poor immunogenicity, and original antigenic sin (the skew in the specificity of antibodies elicited by exposure to new antigenic variants due to preexisting variant-specific responses) to the observed patterns of antibody recognition of PvMSP-1. We suggest that antibody responses to the repertoire of variable domains of PvMSP-1 to which subjects are continuously exposed are elicited only after several repeated infections and may require frequent boosting, with clear implications for the development of PvMSP-1-based subunit vaccines. PMID- 17699837 TI - Pulsed-field gel electrophoresis, pertactin, pertussis toxin S1 subunit polymorphisms, and surfaceome analysis of vaccine and clinical Bordetella pertussis strains. AB - To add new insight to our previous work on the molecular epidemiology of Bordetella pertussis in Argentina, the prn and ptxS1 gene sequences and pulsed field gel electrophoresis (PFGE) profiles of 57 clinical isolates obtained during two periods, 1969 to 1989 and 1997 to 2006, were analyzed. Non-vaccine-type ptxS1A was detected in isolates obtained since 1969. From 1989 on, a shift of predominance from the vaccine prn1 type to the nonvaccine prn2 type was observed. This was also reflected in a transition of PFGE group IV to group VI. These results show that nonvaccine B. pertussis strains are currently circulating. To analyze whether the observed genomic divergences between vaccine strains and clinical isolates have functional implications, protection assays using the intranasal mouse challenge model were performed. For such experiments, the clinical isolate B. pertussis 106 was selected as representative of circulating bacteria, since it came from the major group of the PFGE dendrogram (PFGE group VI). Groups of mice were immunized either with diphtheria-tetanus-whole-cell pertussis vaccine (ptxS1B prn1) or a vaccine prepared by us containing B. pertussis 106. Immunized mice were then challenged with a B. pertussis vaccine strain (Tohama, harboring ptxS1B and prn1) or the clinical isolate B. pertussis 106 (ptxS1A prn2). An adequate bacterial-elimination rate was observed only when mice were immunized and challenged with the same kind of strain. For further characterization, comparative proteomic profiling of enriched membrane proteins was done using three vaccine strains and the selected B. pertussis 106 clinical isolate. By matrix-assisted laser desorption ionization-time of flight mass spectrometry analysis, a total of 54 proteins were identified. This methodology allowed us to detect differing proteins among the four strains studied and, in particular, to distinguish the three vaccine strains from each other, as well as the vaccine strains from the clinical isolate. The differing proteins observed have cellular roles associated with amino acid and carbohydrate transport and metabolism. Some of them have been proposed as novel vaccine candidate proteins for other pathogens. Overall, the global strategy described here is presented as a good tool for the development of next-generation acellular vaccines. PMID- 17699839 TI - Is there a future for ductal lavage? PMID- 17699840 TI - ErbB-dependent signaling as a determinant of trastuzumab resistance. PMID- 17699841 TI - Loss of secreted frizzled-related protein-1 expression in renal cell carcinoma reveals a critical tumor suppressor function. PMID- 17699842 TI - Panitumumab, a monoclonal anti epidermal growth factor receptor antibody in colorectal cancer: another one or the one? PMID- 17699843 TI - Pseudohypoxic pathways in renal cell carcinoma. AB - Mutations of the von Hippel-Lindau (VHL) or fumarate hydratase (FH) genes lead to morphologically different renal cell carcinomas with distinct clinical courses and outcomes. The VHL protein is a part of an ubiquitin ligase complex that targets proteins for proteosomal degradation. FH is one of the mitochondrial enzymes of the Kreb's cycle. Despite two different functionalities and cellular locations, loss of either VHL or FH products has been shown to alter expression levels of hypoxia-inducible factors (HIF-1alpha and HIF-2alpha) and their downstream targets. HIF proteins are key regulators of oxygen homeostasis. Tight regulation of HIF allows for cell survival and growth at the time of hypoxic stress. HIF acts via transcriptional regulation of vascular endothelial growth factor, platelet derived growth factor, endothelial growth factor receptor, glucose transporter protein 1, erythropoietin, and transforming growth factor alpha. Loss of VHL or FH is thought to result in a pseudohypoxic state so that cellular response pathways mediated by HIF are activated despite normal oxygen conditions. Understanding of these pseudohypoxic pathways has provided a better appreciation of the molecular mechanisms of carcinogenesis in addition to providing a rationale for targeted therapeutic approaches. PMID- 17699844 TI - Membrane-associated estrogen receptor signaling pathways in human cancers. PMID- 17699845 TI - Interleukin-12: biological properties and clinical application. AB - Interleukin-12 (IL-12) is a heterodimeric protein, first recovered from EBV transformed B cell lines. It is a multifunctional cytokine, the properties of which bridge innate and adaptive immunity, acting as a key regulator of cell mediated immune responses through the induction of T helper 1 differentiation. By promoting IFN-gamma production, proliferation, and cytolytic activity of natural killer and T cells, IL-12 induces cellular immunity. In addition, IL-12 induces an antiangiogenic program mediated by IFN-gamma-inducible genes and by lymphocyte endothelial cell cross-talk. The immunomodulating and antiangiogenic functions of IL-12 have provided the rationale for exploiting this cytokine as an anticancer agent. In contrast with the significant antitumor and antimetastatic activity of IL-12, documented in several preclinical studies, clinical trials with IL-12, used as a single agent, or as a vaccine adjuvant, have shown limited efficacy in most instances. More effective application of this cytokine, and of newly identified IL-12 family members (IL-23 and IL-27), should be evaluated as therapeutic agents with considerable potential in cancer patients. PMID- 17699846 TI - Nicotine induces hypoxia-inducible factor-1alpha expression in human lung cancer cells via nicotinic acetylcholine receptor-mediated signaling pathways. AB - PURPOSE: Nicotine, the major component in cigarette smoke, can promote tumor growth and angiogenesis in various cancers, including lung cancer. Hypoxia inducible factor-1alpha (HIF-1alpha) is overexpressed in human lung cancers, particularly in non-small cell lung cancers (NSCLC), and is closely associated with an advanced tumor grade, increased angiogenesis, and resistance to chemotherapy and radiotherapy. The purpose of this study was to investigate the effects of nicotine on the expression of HIF-1alpha and its downstream target gene, vascular endothelial growth factor (VEGF), in human lung cancer cells. EXPERIMENTAL DESIGN: Human NSCLC cell lines A549 and H157 were treated with nicotine and examined for expression of HIF-1alpha and VEGF using Western blot or ELISA. Loss of HIF-1alpha function using specific small interfering RNA was used to determine whether HIF-1alpha is directly involved in nicotine-induced tumor angiogenic activities, including VEGF expression, cancer cell migration, and invasion. RESULTS: Nicotine increased HIF-1alpha and VEGF expression in NSCLC cells. Pharmacologically blocking nicotinic acetylcholine receptor-mediated signaling cascades, including the Ca2+/calmodulin, c-Src, protein kinase C, phosphatidylinositol 3-kinase, mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2, and the mammalian target of rapamycin pathways, significantly attenuated nicotine-induced up-regulation of HIF-1alpha protein. Functionally, nicotine potently stimulated in vitro tumor angiogenesis by promoting tumor cell migration and invasion. These proangiogenic and invasive effects were partially abrogated by treatment with small interfering RNA specific for HIF-1alpha. CONCLUSION: These findings identify novel mechanisms by which nicotine promotes tumor angiogenesis and metastasis and provide further evidences that HIF-1alpha is a potential anticancer target in nicotine-associated lung cancer. PMID- 17699847 TI - The development and characterization of a human midgut carcinoid cell line. AB - PURPOSE: Gastrointestinal neuroendocrine tumors (NET) are rare heterogeneous tumors that hypersecrete neuropeptides. The scarcity of good gastrointestinal NET models has limited the ability to study potential therapeutic agents. We describe and characterize the establishment of a human midgut carcinoid tumor cell line carcinoid tumor 2 (CNDT2). EXPERIMENTAL DESIGN: Tumor cells (CNDT2) were isolated from a liver metastasis from a patient with a primary ileal carcinoid. After 9 weeks in culture, the cells were plated in soft agar, and cells from a single colony were put back in culture (CNDT2.1). Those CNDT2.1 cells were injected s.c. into nude mice. Cells were isolated from a single resultant tumor (CNDT2.5), cultured, and characterized by electron microscopy, reverse transcription-PCR, serotonin enzyme immunoassay, Western blotting, and immunohistochemical analysis for NET markers and potential therapeutic targets. RESULTS: CNDT2 cells grew in monolayers in vitro, formed colonies in soft agar, and formed tumors in mice. Electron microscopy revealed round, pleomorphic, electron-dense neurosecretory granules characteristic of NETs. Tumor xenografts exhibited the appearance of NETs with small "salt-and-pepper" nuclei on H&E staining and chromogranin A, synaptophysin, and CD56 on immunohistochemical staining. CNDT2.5 cells produced serotonin and expressed insulin-like growth factor receptor-I, platelet-derived growth factor receptor-beta, vascular endothelial growth factor receptor-1, cMET, epidermal growth factor receptor, neuropilin-1, and somatostatin receptors 1 to 5. Cytogenetic analysis revealed the presence of deletions at 2p and 6q and numerous translocations. CONCLUSION: The establishment of this human midgut carcinoid tumor cell line may serve as a useful model system for studying cell biology and novel targeted agents in preclinical models. PMID- 17699848 TI - The cancer/testis antigen melanoma-associated antigen-A3/A6 is a novel target of fibroblast growth factor receptor 2-IIIb through histone H3 modifications in thyroid cancer. AB - PURPOSE: Fibroblast growth factor (FGF) signals play fundamental roles in development and tumorigenesis. Thyroid cancer is an example of a tumor with nonoverlapping genetic mutations that up-regulate mitogen-activated protein kinase. We reported recently that FGF receptor 2 (FGFR2) is down-regulated through extensive DNA promoter methylation in thyroid cancer. Reexpression of the FGFR2-IIIb isoform impedes signaling upstream of the BRAF/mitogen-activated protein kinase pathway to interrupt tumor progression. In this analysis, we examined a novel target of FGFR2-IIIb signaling, melanoma-associated antigen-A3 and A6 (MAGE-A3/6). EXPERIMENTAL DESIGN: cDNA microarray analysis was done on human WRO thyroid cancer cells transfected with FGFR2-IIIb or empty vector. Identified gene target was confirmed by reverse transcription-PCR and Western blotting. Gene regulation was examined by treatment of WRO cells with the methylation inhibitor 5'-azacytidine followed by methylation-specific PCR and reverse transcription-PCR and by chromatin immunoprecipitation. RESULTS: Gene expression profiling identified the cancer/testis antigen MAGE-A3/6 as a novel target of FGFR2-IIIb signaling. MAGE-A3/6 regulation was mediated through DNA methylation and chromatin modifications. In particular, FGF7/FGFR2-IIIb activation resulted in histone 3 methylation and deacetylation associated with the MAGE-A3/6 promoter to down-regulate gene expression. CONCLUSIONS: These data unmask a complex repertoire of epigenetically controlled signals that govern FGFR2-IIIb and MAGE-A3/6 expression. Our findings provide insights into the interrelationship between novel tumor markers that may also represent overlapping therapeutic targets. PMID- 17699849 TI - INI1 induces interferon signaling and spindle checkpoint in rhabdoid tumors. AB - PURPOSE: Rhabdoid tumors are rare but aggressive pediatric malignancies characterized by biallelic loss of INI1/hSNF5. Reintroduction of INI1 causes cell arrest and senescence in rhabdoid cells. Our purpose was to identify INI1 downstream genes and to determine their functional and therapeutic significance for rhabdoid tumors. EXPERIMENTAL DESIGN: INI1 downstream targets in rhabdoid cells were identified using a cDNA microarray analysis and the expression of selected INI1 targets was confirmed by quantitative reverse transcription-PCR, Western analysis, and/or immunohistochemical analysis of rhabdoid cells and primary rhabdoid tumors. To determine the functional significance of downstream targets, activated targets of INI1 were induced and repressed targets of INI1 were knocked down (by using RNA interference) in rhabdoid cells, in the absence of INI1. Consequence of altered expression of INI1 downstream targets for rhabdoid cell survival, cell cycle, and apoptosis was assessed. RESULTS: Microarray studies indicated that INI1 activated IFN-stimulated genes at early time points and senescence markers at late time points and repressed mitotic genes such as Polo like kinase 1 (PLK1), selectively in rhabdoid cells. Treatment of rhabdoid cells with recombinant IFNs resulted in induction of IFN-stimulated genes, G1 arrest, and flat cell formation. PLK1 was overexpressed in primary human and mouse rhabdoid tumors. RNA interference-mediated knock down of PLK1 in rhabdoid cells resulted in mitotic arrest, aberrant nuclear division, decreased survival, and induction of apoptosis. CONCLUSIONS: Targeting downstream effectors of INI1 such as IFN pathway and mitotic genes leads to antiproliferative effects in rhabdoid cells. IFN treatment and down-modulation of PLK1 constitute potential novel therapeutic strategies for rhabdoid tumors. PMID- 17699850 TI - High-resolution single nucleotide polymorphism array analysis of epithelial ovarian cancer reveals numerous microdeletions and amplifications. AB - PURPOSE: Genetic changes in sporadic ovarian cancer are relatively poorly characterized compared with other tumor types. We have evaluated the use of high resolution whole genome arrays for the genetic profiling of epithelial ovarian cancer. EXPERIMENTAL DESIGN: We have evaluated 31 primary ovarian cancers and matched normal DNA for loss of heterozygosity and copy number alterations using 500 K single nucleotide polymorphism arrays. RESULTS: In addition to identifying the expected large-scale genomic copy number changes, >380 small regions of copy number gain or loss (<500 kb) were identified among the 31 tumors, including 33 regions of high-level gain (>5 copies) and 27 homozygous deletions. The existence of such a high frequency of small regions exhibiting copy number alterations had not been previously suspected because earlier genomic array platforms lacked comparable resolution. Interestingly, many of these regions harbor known cancer genes. For example, one tumor harbored a 350-kb high-level amplification centered on FGFR1 and three tumors showed regions of homozygous loss 109 to 216 kb in size involving the RB1 tumor suppressor gene only. CONCLUSIONS: These data suggest that novel cancer genes may be located within the other identified small regions of copy number alteration. Analysis of the number of copy number breakpoints and the distribution of the small regions of copy number change indicate high levels of structural chromosomal genetic instability in ovarian cancer. PMID- 17699851 TI - Secreted frizzled-related protein 1 loss contributes to tumor phenotype of clear cell renal cell carcinoma. AB - PURPOSE: Incidence and mortality rates for renal cell carcinoma (RCC) have been rising for decades. Unfortunately, the molecular events that support RCC carcinogenesis remain poorly understood. In an effort to gain a better understanding of signaling events in clear cell RCC (cRCC), we investigated the antitumor activity of secreted frizzled-related protein 1 (sFRP1), a negative regulator of Wnt signaling. EXPERIMENTAL DESIGN: Genomic profiling of cRCC tumors and patient-matched normal tissues was done and confirmed using quantitative PCR and immunohistochemistry. Methylation-specific PCR was done on patient samples to evaluate the mechanism responsible for sFRP1 loss. sFRP1 expression was restored in cRCC cells and the effects on tumor phenotype were characterized. RESULTS: Genomic profiling, quantitative PCR, and immunohistochemistry indicated that loss of sFRP1 occurred in cRCC and papillary RCC patient tissues. Twelve Wnt-regulated genes were up-regulated in cRCC tissues, including c-myc and cyclin D1, potentiators of cell proliferation and survival. Methylation of the sFRP1 gene was one mechanism identified for attenuation of sFRP1 mRNA. Stable reexpression of sFRP1 in cRCC cells resulted in decreased expression of Wnt target genes, decreased growth in cell culture, inhibition of anchorage-independent growth, and decreased tumor growth in athymic nude mice. CONCLUSIONS: To our knowledge, this is the first report to show that stable restoration of sFRP1 expression in cRCC cells attenuates the cRCC tumor phenotype. Our data support a role for sFRP1 as a tumor suppressor in cRCC and that perhaps loss of sFRP1 is an early, aberrant molecular event in renal cell carcinogenesis. PMID- 17699852 TI - OSU-03012, a novel celecoxib derivative, is cytotoxic to myeloma cells and acts through multiple mechanisms. AB - PURPOSE: OSU-03012 is a novel celecoxib derivative, without cyclooxygenase-2 inhibitory activity, capable of inducing apoptosis in various cancer cells types, and is being developed as an anticancer drug. We investigated the in vitro activity of OSU-03012 in multiple myeloma (MM) cells. EXPERIMENTAL DESIGN: U266, ARH-77, IM-9, and RPMI-8226, and primary myeloma cells were exposed to OSU-03012 for 6, 24, or 72 h. Cytotoxicity, caspase activation, apoptosis, and effects on intracellular signaling pathways were assessed. RESULTS: OSU-03012 was cytotoxic to MM cells with mean LC50 3.69 +/- 0.23 and 6.25 +/- 0.86 micromol/L and at 24 h for primary MM cells and cell lines, respectively. As a known PDK-1 inhibitor, OSU-03012 inhibited the PI3K/Akt pathway with downstream effects on BAD, GSK 3beta, FoxO1a, p70S6K, and MDM-2. However, transfection of MM cells with constitutively active Akt failed to protect against cell death, indicating activity against other pathways is important. Phospho (p)-signal transducers and activators of transcription 3 and p-MAP/ERK kinase 1/2 were down-regulated, suggesting that OSU-03012 also inhibited the Janus-activated kinase 2/signal transducer and activator of transcription 3 and mitogen-activated protein kinase pathways. Although expression of Bcl-2 proteins was unchanged, OSU-03012 also down-regulated survivin and X-linked inhibitor of apoptosis (XIAP), and also induced G2 cell cycle arrest with associated reductions in cyclins A and B. Finally, although OSU-03012 induced cleavage of caspases 3, 8 and 9, caspase inhibition did not prevent cell death. CONCLUSIONS: We conclude that OSU-03012 has potent activity against MM cells and acts via different mechanisms in addition to phosphoinositide-3-kinase/Akt pathway inhibition. These studies provide rationale for the clinical investigation of OSU-03012 in MM. PMID- 17699853 TI - Targeting neuropilin 1 as an antitumor strategy in lung cancer. AB - PURPOSE: Neuropilin 1 (NRP1) is a mediator of lung branching and angiogenesis in embryonic development and angiogenesis in cancer. The role of NRP1 in cancer progression is not fully elucidated. We investigated the role of NRP1 in cancer invasion and tumor angiogenesis, its signaling pathways, prognostic significance, and therapeutic implications. EXPERIMENTAL DESIGN: Sixty patients with non-small cell lung cancer (NSCLC) were studied. NRP1 mRNA expression was measured using real-time quantitative reverse-transcription PCR. NRP1 and cancer cell invasion, angiogenesis, and signaling pathways were studied using NRP1 stimulation by vascular endothelial growth factor 165 (VEGF(165)) and NRP1 inhibition by small interfering RNAs (siRNA), soluble NRP1 (sNRP1), and NRP1-inhibition peptides. The NRP1-inhibition peptides were identified using a phage display peptide library. RESULTS: NSCLC patients with high expression of NRP1 had shorter disease-free (P = 0.0162) and overall survival (P = 0.0164; log-rank test). Multivariate analyses showed NRP1 is an independent prognostic factor in overall (HR, 2.37, 95% CI = 1.15 to 4.9, P = 0.0196) and disease-free survival [hazard ratio (HR), 2.38; 95% confidence interval (95% CI), 1.15-4.91; P = 0.0195] of NSCLC patients. Knockdown of NRP1 suppressed cancer cell migration, invasion, filopodia formation, tumorigenesis, angiogenesis, and in vivo metastasis. NRP1 signaling pathways involved VEGF receptor 2 and phosphoinositide-3-kinase (PI3K) and Akt activation. Two potent synthetic anti-NRP1 peptides, DG1 and DG2, which block NRP1 signaling pathways and suppress tumorigenesis, cancer invasion, and angiogenesis, were identified. CONCLUSIONS: NRP1 is a cancer invasion and angiogenesis enhancer. NRP1 expression is an independent predictor of cancer relapse and poor survival in NSCLC patients. NRP1 plays a critical role in tumorigenesis, cancer invasion, and angiogenesis through VEGF, PI3K, and Akt pathways. NRP1 may have potential as a new therapeutic target in NSCLC. PMID- 17699854 TI - Epithelial to mesenchymal transition: expression of the regulators snail, slug, and twist in pancreatic cancer. AB - PURPOSE: Epithelial to mesenchymal transitions are vital for tumor growth and metastasis. Several inducers of epithelial to mesenchymal transition are transcription factors that repress E-cadherin expression, such as Snail, Slug, and Twist. In this study, we aimed to examine the expression of these transcription factors in pancreatic cancer. EXPERIMENTAL DESIGN: The expression of Snail, Slug, and Twist was detected by immunohistochemistry in tissue samples from patients with pancreatic ductal adenocarcinoma. Five human pancreatic cancer cell lines (AsPC-1, Capan-1, HPAF-2, MiaPaCa-2, and Panc-1) were analyzed by reverse transcription-PCR, real-time PCR, and Western blotting. An orthotopic nude mouse model of pancreatic cancer was applied for in vivo experiments. RESULTS: Seventy-eight percent of human pancreatic cancer tissues showed an expression of Snail, and 50% of the patients displayed positive expression of Slug. Twist showed no or only weak expression. Snail expression was higher in undifferentiated cancer cell lines (MiaPaCa-2 and Panc-1) than in more differentiated cell lines (Capan-1, HPAF-2, AsPC-1). Expression of Slug was detected in all cell lines with different intensities. Twist was not expressed. After exposure to hypoxia, the Twist gene was activated in all five pancreatic cancer cell lines. CONCLUSIONS: The transcription factors Snail and Slug are expressed in pancreatic cancer but not in normal tissue, suggesting a role in the progression of human pancreatic tumors. Twist, activated by hypoxia, may play an important role in the invasive behavior of pancreatic tumors. PMID- 17699855 TI - Comprehensive analysis of copy number and allele status identifies multiple chromosome defects underlying follicular lymphoma pathogenesis. AB - PURPOSE: Follicular lymphoma (FL) constitutes the second most common non Hodgkin's lymphoma in the Western world. The clinical course is variable and only in part explained by known tumor-intrinsic or -extrinsic factors. FL carries the hallmark chromosomal translocation t(14;18), deregulating the expression of Bcl 2, but this is not sufficient to explain either FL biology or clinical behavior. EXPERIMENTAL DESIGN: We have employed high-density genomic profiling technology using the Affymetrix 50K-XbaI oligonucleotide single nucleotide polymorphism-chip platform to interrogate the genomes of 58 fluorescence-activated cell-sorted (FACS) FL specimens for chromosomal copy number changes and 46 specimens for loss of heterozygosity (LOH). RESULTS: We report (a) previously unknown high-frequency copy-neutral LOH (uniparental disomy) in FL on chromosomes 1p (approximately 50%) and 6p (approximately 30%); (b) that del6q is complex, as reported, with at least two regions of minimal common loss at 6q13-15 and 6q23-24, and that in addition, approximately 8% of FL specimens contain a homozygous deletion at 6q23.3-24.1 that spans the negative NFkappaB regulator A20 and the p53 apoptosis effector PERP; (c) that combined analysis of chromosome 17p for LOH, copy number, and p53 mutations shows that most p53 mutations in FL do not involve del17p. Finally, we map high-frequency LOH with and without copy loss on chromosomes 9p, 10q, and 16p and genomic gains on 2p15-16 and 8q24.22-24.3. CONCLUSIONS: This comprehensive description of the pathologic anatomy of the FL genome uncovers novel genetic lesions and should aid with identification of genes relevant to FL biology and clinical behavior. PMID- 17699856 TI - PRDM5 identified as a target of epigenetic silencing in colorectal and gastric cancer. AB - PURPOSE: PR (PRDI-BF1 and RIZ) domain proteins (PRDM) are a subfamily of the kruppel-like zinc finger gene products that play key roles during cell differentiation and malignant transformation. The aim of the present study was to begin to examine the involvement of epigenetic alteration of PRDM expression in gastric and colorectal cancer. EXPERIMENTAL DESIGN: We used real-time PCR to assess expression of PRDM1-17. In addition, we used bisulfite PCR to assess DNA methylation and chromatin immunoprecipitation to assess histone modification in colorectal and gastric cancer cell lines lacking PRDM5 expression. RESULTS: Among the 17 PRDM family genes tested, we found that PRDM5 is the most frequently silenced in colorectal and gastric cancer cell lines. Silencing of PRDM5 was mediated by either DNA methylation or trimethylation of Lys(27) of histone H3. Introduction of PRDM5 into cancer cells suppressed cell growth, suggesting that it acts as a tumor suppressor in gastrointestinal cancers. Methylation of PRDM5 was detected in 6.6% (4 of 61) of primary colorectal and 50.0% (39 of 78) of primary gastric cancers but not in noncancerous tissue samples collected from areas adjacent to the tumors. CONCLUSIONS: Our data suggest that epigenetic alteration of PRDM5 (e.g., methylation of its 5'-CpG island or trimethylation of Lys(27) of histone H3) likely plays a key role in the progression of gastrointestinal cancers and may be a useful molecular marker. PMID- 17699857 TI - Activated mammalian target of rapamycin is an adverse prognostic factor in patients with biliary tract adenocarcinoma. AB - PURPOSE: The mammalian target of rapamycin (mTOR) is a protein kinase that plays a key role in cellular growth and homeostasis. Because its regulation is frequently altered in tumors, mTOR is currently under investigation as a potential target for anticancer therapy. The purpose of our study was to determine the prognostic value of activated mTOR (p-mTOR) in patients with biliary tract adenocarcinoma (BTA), in order to strengthen the rationale for targeted therapy of BTA using mTOR inhibitors. EXPERIMENTAL DESIGN: We determined expression of p-mTOR in paraffin-embedded surgical specimens of BTA by immunohistochemistry with a monoclonal antibody to phosphorylated mTOR. Overall survival was analyzed with a Cox model adjusted for clinical and pathologic factors. RESULTS: Immunostaining for p-mTOR was positive in 56 of 88 (64%) tumors. Activated mTOR was not associated with any of the clinical or pathologic variables of the patients but predicted overall survival of the patients. Overall survival was significantly shorter in patients with p-mTOR-positive tumors as compared with patients with p-mTOR-negative tumors (hazard ratio for death 2.57; 95% confidence interval, 1.35-4.89; P = 0.004). Multivariate Cox proportional hazards regression analyses identified p-mTOR to be an independent prognostic factor for death (adjusted hazard ratio for death, 2.44; 95% confidence interval, 1.24-4.80; P = 0.01). CONCLUSIONS: Patients with BTA and p-mTOR-positive tumors have a significantly shorter overall survival than patients with p-mTOR-negative tumors and may benefit from targeted therapy with mTOR inhibitors in the future. PMID- 17699858 TI - Cyclin E-associated kinase activity predicts response to platinum-based chemotherapy. AB - PURPOSE: The role of cyclin E as a predictive marker of response to chemotherapy remains unknown. We have previously shown that deregulation of cyclin E in an ovarian tumor cell line model enhances cyclin E-associated kinase activity and sensitizes tumor cells to cisplatinum. We hypothesized that cyclin E deregulation would predict for responsiveness to platinum-based regimens in ovarian cancer patients. EXPERIMENTAL DESIGN: Patients who met the following criteria were retrospectively identified from the institutional tumor bank records: (a) high grade ovarian epithelial malignancy, (b) stage III/stage IV disease, (c) optimally debulked, (d) completed platinum-based therapy. Tumor samples were analyzed for cyclin E, p21, and p27 by Western blot analysis and assessed for cyclin E-associated kinase activity. RESULTS: Seventy-five patients, who met the study criteria, were identified. Cyclin E protein levels did not correlate with cyclin E-cdk2 kinase activity (Spearman's rho, 0.07; P = 0.58). Cyclin E associated kinase activity was the only significant predictive marker for response to platinum-based therapy, with higher response rates seen in patients with higher levels of activity (P = 0.045). Cyclin E protein levels did not predict for platinum sensitivity (P = 0.20). In contrast, cyclin E protein levels, but not cyclin E-associated kinase activity, was a significant predictor for freedom from recurrence (P = 0.01 and P = 0.25, respectively). CONCLUSIONS: Cyclin E overexpression and cyclin E-associated kinase activity have distinct roles in predicting for response to chemotherapy and outcome in ovarian cancer patients. These results suggest a compartmentalization of cyclin E functions in the oncogenic process. PMID- 17699859 TI - One-step nucleic acid amplification for intraoperative detection of lymph node metastasis in breast cancer patients. AB - PURPOSE: Detection of sentinel lymph node (SLN) metastasis in breast cancer patients has conventionally been determined by intraoperative histopathologic examination of frozen sections followed by definitive postoperative examination of permanent sections. The purpose of this study is to develop a more efficient method for intraoperative detection of lymph node metastasis. EXPERIMENTAL DESIGN: Cutoff values to distinguish macrometastasis, micrometastasis, and nonmetastasis were determined by measuring cytokeratin 19 (CK19) mRNA in histopathologically positive and negative lymph nodes using one-step nucleic acid amplification (OSNA). In an intraoperative clinical study involving six facilities, 325 lymph nodes (101 patients), including 81 SLNs, were divided into four blocks. Alternate blocks were used for the OSNA assay with CK19 mRNA, and the remaining blocks were used for H&E and CK19 immunohistochemistry-based three level histopathologic examination. The results from the two methods were then compared. RESULTS: We established CK19 mRNA cutoff values of 2.5 x 10(2) and 5 x 10(3) copies/muL. In the clinical study, an overall concordance rate between the OSNA assay and the three-level histopathology was 98.2%. Similar results were obtained with 81 SLNs. The OSNA assay discriminated macrometastasis from micrometastasis. No false positive was observed in the OSNA assay of 144 histopathologically negative lymph nodes from pN0 patients, indicating an extremely low false positive for the OSNA assay. CONCLUSION: The OSNA assay of half of a lymph node provided results similar to those of three-level histopathology. Clinical results indicate that the OSNA assay provides a useful intraoperative detection method of lymph node metastasis in breast cancer patients. PMID- 17699860 TI - Decreased expression of retinoid receptors in melanoma: entailment in tumorigenesis and prognosis. AB - PURPOSE: Retinoids inhibit proliferation and induce differentiation in melanoma cells. Retinoic acid receptors (RAR) and retinoid X receptors (RXR) mediate the various modulatory effects of retinoids in cells. We have studied the in situ expression of each RAR and RXR protein (alpha, beta, gamma) in a large series of melanocytic lesions and correlated the expression with clinicopathologic features and prognosis of the patients. EXPERIMENTAL DESIGN: Tissue microarray blocks of 226 melanocytic lesions were semiquantitatively evaluated by immunohistochemistry for the cytoplasmic and nuclear expression of RAR and RXR protein (alpha, beta, gamma). RESULTS: A significant decrease of RARbeta protein (P < 0.0001), nuclear expression of RARgamma (P < 0.0001), and RXRalpha (P < 0.0001) was found in primary and metastatic melanomas as compared with nevi. Loss of nuclear immunoreactivity for RARgamma (P = 0.048) and RXRalpha (P = 0.001) was observed in the lesions showing vertical growth pattern. In addition, in patients with concomitant loss of cytoplasmic staining for RARalpha and RXRalpha, the probability of overall survival (log-rank test, P = 0.002) and disease-specific survival (log-rank test, P = 0.014) was significantly lower. CONCLUSIONS: Aberrant expression of retinoid receptors seems to be a frequent event in melanoma and suggests an impairment of the retinoid pathway in this cancer. Our data indicate the loss of retinoid receptor expression with melanoma progression and suggest a possible prognostic significance of the analysis of retinoid receptors in melanoma. PMID- 17699861 TI - Erythropoietin and erythropoietin receptor coexpression is associated with poor survival in stage I non-small cell lung cancer. AB - PURPOSE: This study was designed to evaluate the prognostic effect of erythropoietin (EPO) and EPO receptor (EPO-R) expression in stage I non-small cell lung cancer (NSCLC) patients. EXPERIMENTAL DESIGN: EPO and EPO-R expression in 158 tumor samples from resected stage I NSCLC was evaluated using immunohistochemistry and tissue array technology. RESULTS: EPO-R and EPO were highly expressed in 20.9% and 35.4% of tumors, respectively. High EPO-R expression compared with negative or low-level expression was associated with a poor 5-year disease-specific survival (60.6% versus 80.8%; P = 0.01, log-rank test). High EPO expression compared with negative and low-level expression was associated with a trend toward a poor 5-year disease-specific survival (69.6% versus 80.4%; P = 0.13, log-rank test). A high level of EPO-R and EPO coexpression was associated with a poor 5-year disease-specific survival compared with other groups of patients (50.0% versus 80.0% survival at the end of follow up; P = 0.005, log-rank test). In multivariate analysis for disease-specific survival, high-level EPO-R and EPO coexpression was an independent prognostic factor for disease-specific survival (hazard ratio, 2.214; 95% confidence interval, 1.012-4.848; P = 0.046). CONCLUSION: These results establish the pejorative prognostic value of EPO and EPO-R expression in early-stage resected NSCLC and suggest a potential paracrine and/or autocrine role of endogenous EPO in NSCLC aggressiveness. PMID- 17699862 TI - Oxaliplatin pharmacokinetics and pharmacodynamics in adult cancer patients with impaired renal function. AB - PURPOSE: To characterize the pharmacokinetics and pharmacodynamics of oxaliplatin in cancer patients with impaired renal function. EXPERIMENTAL DESIGN: Thirty-four patients were stratified by 24-h urinary creatinine clearance (CrCL) into four renal dysfunction groups: group A (control, CrCL, >or=60 mL/min), B (mild, CrCL, 40-59 mL/min), C (moderate, CrCL, 20-39 mL/min), and D (severe, CrCL, <20 mL/min). Patients were treated with 60 to 130 mg/m2 oxaliplatin infused over 2 h every 3 weeks. Pharmacokinetic monitoring of platinum in plasma, plasma ultrafiltrates, and urine was done during cycles 1 and 2. RESULTS: Plasma ultrafiltrate platinum clearance strongly correlated with CrCL (r2 = 0.712). Platinum elimination from plasma was triphasic, and maximal platinum concentrations (Cmax) were consistent across all renal impairment groups. However, only the beta-half-life was significantly prolonged by renal impairment, with values of 14.0 +/- 4.3, 20.3 +/- 17.7, 29.2 +/- 29.6, and 68.1 h in groups A, B, C, and D, respectively (P = 0.002). At a dose level of 130 mg/m2, the area under the concentration time curve increased in with the degree of renal impairment, with values of 16.4 +/- 5.03, 39.7 +/- 11.5, and 44.6 +/- 14.6 mug.h/mL, in groups A, B, and C, respectively. However, there was no increase in pharmacodynamic drug-related toxicities. Estimated CrCL using the Cockcroft-Gault method approximated the measured 24-h urinary CrCL (mean prediction error, -5.0 mL/min). CONCLUSIONS: Oxaliplatin pharmacokinetics are altered in patients with renal impairment, but a corresponding increase in oxaliplatin-related toxicities is not observed. PMID- 17699863 TI - Vascular endothelial growth factor-trap overcomes defects in dendritic cell differentiation but does not improve antigen-specific immune responses. AB - PURPOSE: Induction of antitumor immune responses requires adequate function of dendritic cells. Dendritic cell defects in cancer patients have been implicated in tumor escape and the limited efficacy of cancer vaccines. Previous studies have shown that vascular endothelial growth factor (VEGF) plays a major role in abnormal dendritic cell differentiation and function in cancer. It has been proposed that inhibition of VEGF may result in improved immune responses. The goal of this study was to test this hypothesis. EXPERIMENTAL DESIGN: Fifteen patients with refractory solid tumors were enrolled into a phase I clinical trial of VEGF-Trap. Phenotype and function of different subsets of mononuclear cells were measured before and at different time points after the start of treatment. RESULTS: VEGF-Trap treatment did not affect the total population of dendritic cells, their myeloid or plasmacytoid subsets, myeloid-derived suppressor cells (MDSC), or regulatory T cells. It significantly increased the proportion of mature dendritic cells. However, that improvement was not associated with an overall increase in immune responses to various antigens and mitogens. A subset analysis revealed significant improvement in immune responses in patients who had no increase in the proportion of MDSC. An improvement in immune responses was absent in patients with an increase in the proportion of MDSC. CONCLUSIONS: Inhibition of VEGF signaling may improve differentiation of dendritic cells in cancer patients. However, it was not sufficient to improve immune responses. This shows multifaceted nature of immune deficiency and points out to the need for complex approach to modulation of immune reactivity in cancer. PMID- 17699864 TI - Phase I targeted combination trial of sorafenib and erlotinib in patients with advanced solid tumors. AB - PURPOSE: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, the combination of these drugs is of considerable interest in solid malignancies. This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities. EXPERIMENTAL DESIGN: Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed. RESULTS: Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100%) followed by diarrhea (15 patients; 88%), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response. CONCLUSIONS: Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies. PMID- 17699865 TI - Phase I and pharmacokinetic study of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin. AB - PURPOSE: The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that shows superior antitumor efficacy in murine tumor models and a favorable toxicity profile in mice, rats, and dogs compared with doxorubicin. The purpose of the phase I study was to characterize the toxicity profile of DOXO-EMCH, establish a recommended dose for phase II studies, and assess potential anticancer activity. EXPERIMENTAL DESIGN: A starting dose of 20 mg/m2 doxorubicin equivalents was chosen. Forty-one patients with advanced cancer disease were treated with an i.v. infusion of DOXO-EMCH once every 3 weeks at a dose level of 20 to 340 mg/m2 doxorubicin equivalents. RESULTS: Treatment with DOXO-EMCH was well tolerated up to 200 mg/m2 without manifestation of drug-related side effects. Myelosuppression (grade 1-2) and mucositis (grade 1-2) were the predominant adverse effects at dose levels of 260 mg/m2 and myelosuppression (grade 1-3) as well as mucositis (grade 1-3) were dose limiting at 340 mg/m2. No cardiac toxicity was observed. Of 30 of 41 evaluable patients, 12 patients (40%) had progressive disease, 15 patients (57%) had stable disease, and 3 patients (10%) had a partial remission. CONCLUSIONS: DOXO-EMCH showed a good safety profile and was able to induce tumor regressions in tumor types known to be anthracycline-sensitive tumors, such as breast cancer, small cell lung cancer, and sarcoma. The recommended doxorubicin equivalent dose for phase II studies is 260 mg/m2. PMID- 17699866 TI - Suppression of Ewing's sarcoma tumor growth, tumor vessel formation, and vasculogenesis following anti vascular endothelial growth factor receptor-2 therapy. AB - PURPOSE: We previously showed that bone marrow cells participate in new tumor vessel formation in Ewing's sarcoma, and that vascular endothelial growth factor 165 (VEGF(165)) is critical to this process. The purpose of this study was to determine whether blocking VEGF receptor 2 (VEGFR-2) with DC101 antibody suppresses tumor growth, reduces tumor vessel formation, and inhibits the migration of bone marrow cells into the tumor. EXPERIMENTAL DESIGN: An H-2 MHC mismatched bone marrow transplant Ewing's sarcoma mouse model was used. Bone marrow cells from CB6F1 (MHC H-2(b/d)) mice were injected into irradiated BALB/cAnN mice (MHC H-2(d)). TC71 Ewing's sarcoma cells were s.c. injected 4 weeks after the bone marrow transplantation. Mice were then treated i.p. with DC101 antibody or immunoglobulin G (control) twice a week for 3 weeks starting 3 days after tumor cell injection. RESULTS: DC101 antibody therapy significantly reduced tumor growth and tumor mean vessel density (P < 0.05) and increased tumor cell apoptosis. Decreased bone marrow cell migration into the tumor was also shown after DC101 therapy as assessed by the colocalization of H-2K(b) and CD31 using immunohistochemistry. DC101 inhibited the migration of both human and mouse vessel endothelial cells in vitro. CONCLUSION: These results indicated that blocking VEGFR-2 with DC101 antibodies may be a useful therapeutic approach for treating patients with Ewing's sarcoma. PMID- 17699867 TI - Sorafenib inhibits the imatinib-resistant KITT670I gatekeeper mutation in gastrointestinal stromal tumor. AB - PURPOSE: Resistance is commonly acquired in patients with metastatic gastrointestinal stromal tumor who are treated with imatinib mesylate, often due to the development of secondary mutations in the KIT kinase domain. We sought to investigate the efficacy of second-line tyrosine kinase inhibitors, such as sorafenib, dasatinib, and nilotinib, against the commonly observed imatinib resistant KIT mutations (KIT(V654A), KIT(T670I), KIT(D820Y), and KIT(N822K)) expressed in the Ba/F3 cellular system. EXPERIMENTAL DESIGN: In vitro drug screening of stable Ba/F3 KIT mutants recapitulating the genotype of imatinib resistant patients harboring primary and secondary KIT mutations was investigated. Comparison was made to imatinib-sensitive Ba/F3 KIT mutant cells as well as Ba/F3 cells expressing only secondary KIT mutations. The efficacy of drug treatment was evaluated by proliferation and apoptosis assays, in addition to biochemical inhibition of KIT activation. RESULTS: Sorafenib was potent against all imatinib-resistant Ba/F3 KIT double mutants tested, including the gatekeeper secondary mutation KIT(WK557-8del/T670I), which was resistant to other kinase inhibitors. Although all three drugs tested decreased cell proliferation and inhibited KIT activation against exon 13 (KIT(V560del/V654A)) and exon 17 (KIT(V559D/D820Y)) double mutants, nilotinib did so at lower concentrations. CONCLUSIONS: Our results emphasize the need for tailored salvage therapy in imatinib-refractory gastrointestinal stromal tumors according to individual molecular mechanisms of resistance. The Ba/F3 KIT(WK557-8del/T670I) cells were sensitive only to sorafenib inhibition, whereas nilotinib was more potent on imatinib-resistant KIT(V560del/V654A) and KIT(V559D/D820Y) mutant cells than dasatinib and sorafenib. PMID- 17699868 TI - Hydroxamic acid analogue histone deacetylase inhibitors attenuate estrogen receptor-alpha levels and transcriptional activity: a result of hyperacetylation and inhibition of chaperone function of heat shock protein 90. AB - PURPOSE: The molecular chaperone heat shock protein (hsp)-90 maintains estrogen receptor (ER)-alpha in an active conformation, allowing it to bind 17beta estradiol (E2) and transactivate genes, including progesterone receptor (PR)-beta and the class IIB histone deacetylase HDAC6. By inhibiting HDAC6, the hydroxamic acid analogue pan-HDAC inhibitors (HA-HDI; e.g., LAQ824, LBH589, and vorinostat) induce hyperacetylation of the HDAC6 substrates alpha-tubulin and hsp90. Hyperacetylation of hsp90 inhibits its chaperone function, thereby depleting hsp90 client proteins. Here, we determined the effect of HA-HDIs on the levels and activity of ERalpha, as well as on the survival of ERalpha-expressing, estrogen-responsive human breast cancer MCF-7 and BT-474 cells. EXPERIMENTAL DESIGN: Following exposure to HA-HDIs, hsp90 binding, polyubiquitylation levels, and transcriptional activity of ERalpha, as well as apoptosis and loss of survival, were determined in MCF-7 and BT-474 cells. RESULTS: Treatment with HA HDI induced hsp90 hyperacetylation, decreased its binding to ERalpha, and increased polyubiquitylation and depletion of ERalpha levels. HA-HDI treatment abrogated E2-induced estrogen response element-luciferase expression and attenuated PRbeta and HDAC6 levels. Exposure to HA-HDI also depleted p-Akt, Akt, c-Raf, and phospho-extracellular signal-regulated kinase-1/2 levels, inhibited growth, and sensitized ERalpha-positive breast cancer cells to tamoxifen. CONCLUSIONS: These findings show that treatment with HA-HDI abrogates ERalpha levels and activity and could sensitize ERalpha-positive breast cancers to E2 depletion or ERalpha antagonists. PMID- 17699869 TI - Enhanced antitumor effect of combined triptolide and ionizing radiation. AB - PURPOSE: The lack of effective treatment for pancreatic cancer results in a very low survival rate. This study explores the enhancement of the therapeutic effect on human pancreatic cancer via the combination of triptolide and ionizing radiation (IR). EXPERIMENTAL DESIGN: In vitro AsPC-1 human pancreatic cancer cells were treated with triptolide alone, IR alone, or triptolide plus IR. Cell proliferation was analyzed with sulforhodamine B (SRB) method and clonogenic survival; comparison of apoptosis induced by the above treatment was analyzed by annexin V-propidium iodide (PI) staining. Furthermore, the expression of apoptotic pathway intermediates was measured by the assay of caspase activity and Western blot. Mitochondrial transmembrane potential was determined by JC-1 assay. In vivo, AsPC-1 xenografts were treated with 0.25 mg/kg triptolide, 10 Gy IR, or triptolide plus IR. The tumors were measured for volume and weight at the end of the experiment. Tumor tissues were tested for terminal nucleotidyl transferase mediated nick end labeling (TUNEL) and immunohistochemistry. RESULTS: The combination of triptolide plus IR reduced cell survival to 21% and enhanced apoptosis, compared with single treatment. In vivo, tumor growth of AsPC-1 xenografts was reduced further in the group treated with triptolide plus IR compared with single treatment. TUNEL and immunohistochemistry of caspase-3 cleavage in tumor tissues indicated that the combination of triptolide plus IR resulted in significantly enhanced apoptosis compared with single treatments. CONCLUSIONS: Triptolide in combination with ionizing radiation produced synergistic antitumor effects on pancreatic cancer both in vitro and in vivo and seems promising in the combined modality therapy of pancreatic cancer. PMID- 17699870 TI - p53 aerosol formulation with low toxicity and high efficiency for early lung cancer treatment. AB - PURPOSE: To develop an optimal nonviral aerosol formulation for locoregional treatment of early lung cancer. EXPERIMENTAL DESIGN: The formulation was made of polylysine/protamine combination (AND) as the carrier and p53 gene (p53sm) as therapeutic agent. To estimate the aerosol deposition, the aerodynamic size of the AND-p53sm was measured with extrusion-precipitation method. To accurately determine the dose, the aerosol efficiency in mice was measured with a fluorescent dye. The transfection efficiency and DNA protection function of the aerosolized formulation in cultured cells and mouse lungs were detected with reporter gene assays and/or reverse transcription-PCR. The preclinical safety and efficacy of AND-p53sm were studied in healthy mice and mice bearing orthotopic human non-small-cell lung cancer (NSCLC) xenograft. RESULTS: After aerosolization, AND is 3- to 17-fold more effective than commonly used PEI or cationic lipid formulations in transfecting the NSCLC cells (relative light units, 1,494 versus 534 and 86; P < 0.003). Aerodynamic size of AND-p53sm ranged 0.2 to 3 mum is the optimal aerosol droplets for deposition in the entire human respiratory tract. Significant gene expression was detected in the lungs of mice given aerosolized AND-p53sm and AND-luciferase. Aerosolized AND-p53sm significantly prolonged the life of mice bearing orthotopic human NSCLC xenografts, and it was more effective than an optimal i.v. cisplatin chemotherapy (increased life span, 93% versus 25%; P = 0.014). Inhalation of AND produced low and reversible pulmonary toxicity and no systemic toxicity. CONCLUSIONS: This optimal formulation is suitable for delivering biological materials to human lung with aerosol administration. This therapeutic strategy is an option for patients with early lung cancer and bronchoalveolar carcinoma. PMID- 17699871 TI - Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. AB - PURPOSE: We have investigated mechanisms of acquired resistance to the HER2 antibody trastuzumab in BT-474 human breast cancer cells. EXPERIMENTAL DESIGN: BT 474 xenografts established in athymic nude mice were eliminated by trastuzumab. Continuous cell lines (HR for Herceptin resistant) were generated from tumors that recurred in the presence of continuous antibody therapy. RESULTS: The isolated cells behaved resistant to trastuzumab in culture as well as when reinjected into nude mice. They retained HER2 gene amplification and trastuzumab binding and were exquisitely sensitive to peripheral blood mononuclear cells ex vivo in the presence of the antibody. The HR cells exhibited higher levels of phosphorylated epidermal growth factor receptor (EGFR) and EGFR/HER2 heterodimers. Phosphorylation of HER2 in HR cells was inhibited by the EGFR tyrosine kinase inhibitors erlotinib and gefitinib. Gefitinib also inhibited the basal association of p85 with phosphorylated HER3 in HR cells. Both inhibitors as well as the dual EGFR/HER2 inhibitor, lapatinib, induced apoptosis of the HR cells in culture. Growth of established HR5 xenografts was inhibited by erlotinib in vivo. In addition, the HR cells overexpressed EGFR, transforming growth factor alpha, heparin-binding EGF, and heregulin RNAs compared with the parental trastuzumab-sensitive cells. CONCLUSIONS: These results are consistent with the inability of trastuzumab to block the heterodimerization of HER2 and suggest that amplification of ligand-induced activation of ErbB receptors is a plausible mechanism of acquired resistance to trastuzumab that should be investigated in primary mammary cancers. PMID- 17699873 TI - Differential radiation protection of salivary glands versus tumor by Tempol with accompanying tissue assessment of Tempol by magnetic resonance imaging. AB - PURPOSE: The nitroxide free radical, Tempol, was evaluated for potential differential radiation protection of salivary glands and tumor using fractionated radiation. Mechanistic information was explored by monitoring the presence and bioreduction of Tempol in both tissues noninvasively by magnetic resonance imaging (MRI). EXPERIMENTAL DESIGN: Female C3H mice were immobilized using custom made Lucite jigs for localized irradiation (five daily fractions) either to the oral cavity or tumor-bearing leg. Tempol (275 mg/kg) was administered (i.p.) 10 min before each radiation fraction. Salivary gland damage was assessed 8 weeks after radiation by measuring pilocarpine-mediated saliva output. Tumor growth was assessed by standard radiation regrowth methods. Dynamic T1-weighted magnetic resonance scans were acquired before and after Tempol injection using a 4.7T animal MRI instrument. RESULTS: Tempol treatment was found to protect salivary glands significantly against radiation damage (approximately 60% improvement); whereas no tumor protection was observed. Intracellular reduction of Tempol to the nonradioprotective hydroxylamine as assessed by MRI was 2-fold faster in tumor compared with salivary glands or muscle. CONCLUSIONS: Tempol provided salivary gland radioprotection and did not protect tumor, consistent with the hypothesis that differential radioprotection by Tempol resides in faster reduction to the nonradioprotective hydroxylamine in tumor compared with normal tissues. The unique paramagnetic properties of Tempol afforded noninvasive MRI monitoring of dynamic changes of Tempol levels in tissue to support the finding. These data support further development and consideration of Tempol for human clinical trials as a selective protector against radiation-induced salivary gland damage. PMID- 17699872 TI - Phosphodiesterase 4 inhibitors augment levels of glucocorticoid receptor in B cell chronic lymphocytic leukemia but not in normal circulating hematopoietic cells. AB - Type 4 cyclic AMP (cAMP) phosphodiesterase (PDE4) inhibitors, a class of compounds in clinical development that activate cAMP-mediated signaling by inhibiting cAMP catabolism, offer a feasible means by which to potentiate glucocorticoid-mediated apoptosis in lymphoid malignancies such as B-cell chronic lymphocytic leukemia (B-CLL). In this study, we show that PDE4 inhibitors up regulate glucocorticoid receptor (GRalpha) transcript levels in B-CLL cells but not T-CLL cells or Sezary cells or normal circulating T cells, B cells, monocytes, or neutrophils. Because GRalpha transcript half-life does not vary in CLL cells treated with the prototypic PDE4 inhibitor rolipram, the 4-fold increase in GRalpha mRNA levels observed within 4 h of rolipram treatment seems to result from an increase in GRalpha transcription. Rolipram treatment increases levels of transcripts derived from the 1A3 promoter to a greater extent than the 1B promoter. Treatment of B-CLL cells with two other PDE4 inhibitors currently in clinical development also augments GR transcript levels and glucocorticoid mediated apoptosis. Washout studies show that simultaneous treatment with both drug classes irreversibly augments apoptosis over the same time frame that GR up regulation occurs. Although treatment of B-CLL cells with glucocorticoids reduces basal GRalpha transcript levels in a dose-related manner, cotreatment with rolipram maintained GRalpha transcript levels above baseline. Our results suggest that as a result of their unusual sensitivity to PDE4 inhibitor-mediated up regulation of GRalpha expression, treatment of B-CLL patients with combined PDE4 inhibitor/glucocorticoid therapy may be of therapeutic benefit in this disease. PMID- 17699874 TI - Comparison of ductal lavage and random periareolar fine needle aspiration as tissue acquisition methods in early breast cancer prevention trials. AB - PURPOSE: Short-term phase I and phase II breast cancer prevention trials require tissue acquisition at baseline and after intervention to evaluate modulation of potential biomarkers. Currently used tissue acquisition methods include ductal lavage (DL), random periareolar fine needle aspiration (RPFNA), and core needle biopsy. The optimum method to retrieve adequate samples and the most accepted method by study participants is not known. EXPERIMENTAL DESIGN: We compared RPFNA and DL as breast tissue acquisition methods for short-term breast cancer prevention trials by evaluating sample adequacy and tolerability in subjects who participated in two prospective phase II breast cancer prevention trials. Eighty six women at increased risk for breast cancer were included in this study and underwent baseline DL and RPFNA. High risk was defined as having a 5-year Gail score of >1.67% or a history of atypical hyperplasia (AH), lobular carcinoma, or breast cancer. RESULTS: Median age was 54.5 years (range, 39-75 years); 75% of the women were postmenopausal. About 51% of the women yielded nipple aspiration fluid, and breast fluid samples via DL were retrieved in 73% of these subjects. Of these samples, 71% were adequate samples (greater than 10 epithelial cells). However, when the entire cohort was considered, only 31% of the subjects had adequate samples. RPFNA was also attempted in all subjects, and sample retrieval rate was 100%. Out of these, 96% of the subjects had adequate samples. In DL samples, AH rate was 3.7% was and hyperplasia (H) rate was 11.1%. In RPFNA samples, AH rate was 12.9%, and H rate was 24.7%. Cytology findings in RPFNA samples correlated with age, menopausal status, and breast cancer risk category (previous history of lobular carcinoma in situ). Both procedures were well tolerated, and no complications occurred among participants. CONCLUSIONS: Considering that the main end point for short-term prevention trials is the modulation of biomarkers, it is important to optimize adequate sample acquisition; therefore, RPFNA is a more practical option for future phase I and II breast cancer prevention trials compared with DL. PMID- 17699875 TI - The world community of Physiology... on our third anniversary. PMID- 17699876 TI - Facilitated hexose transporters: new perspectives on form and function. AB - The recent sequencing of the human genome has resulted in the addition of nine new hGLUT isoforms to the SLC2A family, many of which have widely varying substrate specificity, kinetic behavior, and tissue distribution. This review examines some new hypotheses related to the structure and function of these proteins. PMID- 17699877 TI - Brain glucose sensing, counterregulation, and energy homeostasis. AB - Neuronal circuits in the central nervous system play a critical role in orchestrating the control of glucose and energy homeostasis. Glucose, beside being a nutrient, is also a signal detected by several glucose-sensing units that are located at different anatomical sites and converge to the hypothalamus to cooperate with leptin and insulin in controlling the melanocortin pathway. PMID- 17699878 TI - Microvascular dysfunction in obesity: a potential mechanism in the pathogenesis of obesity-associated insulin resistance and hypertension. AB - Obesity is an important risk factor for insulin resistance and hypertension and plays a central role in the metabolic syndrome. Insight into the pathophysiology of this syndrome may lead to new treatments. This paper has reviewed the evidence for an important role for the microcirculation as a possible link between obesity, insulin resistance and hypertension. PMID- 17699879 TI - ER-mitochondria communication. How privileged? AB - Mitochondria have a low affinity for Ca(2+), but they take up these ions during normal cell activity because they are in close proximity to the sites of calcium entry into the cell and of internal Ca(2+) release. This gives mitochondria privileged access to cytoplasmic Ca(2+) without requiring a direct communication with the endoplasmic reticulum. PMID- 17699880 TI - Activity-dependent signaling pathways controlling muscle diversity and plasticity. AB - A variety of fiber types with different contractile and metabolic properties is present in mammalian skeletal muscle. The fiber-type profile is controlled by nerve activity via specific signaling pathways, whose identification may provide potential therapeutic targets for the prevention and treatment of metabolic and neuromuscular diseases. PMID- 17699881 TI - Optimization of single-photon response transmission at the rod-to-rod bipolar synapse. AB - Our ability to see in dim light is limited by the statistics of light absorption in rod photoreceptors and the faithful transmission of the light-evoked signals through the retina. This article reviews the physiological mechanisms at the synapse between rods and rod bipolar cells, the first relay in a pathway that mediates vision near absolute threshold. PMID- 17699882 TI - Keeping an "ear" to the ground: seismic communication in elephants. AB - This review explores the mechanisms that elephants may use to send and receive seismic signals from a physical, anatomical, behavioral, and physiological perspective. The implications of the use of the vibration sense as a multimodal signal will be discussed in light of the elephant's overall fitness and survival. PMID- 17699883 TI - The effect of tibial rotation on the presence of instability in the anterior cruciate ligament deficient knee. AB - CONTEXT: The effects of tibial rotation after ACL injury have not yet been well determined. OBJECTIVE: To show whether clinical outcomes such as the amount of tibial rotation can affect functional outcomes in normal and ACL deficient knees. DESIGN: Case control study. SETTING: Research laboratory. PARTICIPANTS: Twenty normal subjects (Control) and 20 subjects with ACL deficient knees (ACL). MAIN OUTCOME MEASURES: Tibial rotation at 30 and 90 degrees of knee flexion was measured using an inclinometer. One-legged hop, crossover hop, figure-of-eight running and 10-m running tests were used and determined the effect(s) of tibial rotation on the outcome of the functional tests. RESULTS: There were significant between-group differences in internal and external rotation. The relationship between external tibial rotation and the figure-of-eight index was significantly negatively correlated. CONCLUSIONS: The amount of tibial rotation is greater in ACL ruptured knees than in uninjured knees, and these greater amounts of tibial rotation affected the figure-of-eight running index. PMID- 17699884 TI - Duration of maintained hamstring ROM following termination of three stretching protocols. AB - CONTEXT: Literature supports habitual stretching for increasing an individual's flexibility; however, immediate gains in range of motion have received limited investigation. OBJECTIVE: The purpose of this study was to determine the retention of active knee extension range of motion (AKE ROM) after a single bout of stretching. DESIGN: Subjects participated in three experimental stretching groups: contract-relax, agonist contract (CRAC); static stretch; and active control stretch. AKE ROM was measured by an analog inclinometer fixed to a modified Orthotron II for pretreatment and posttreatment measurements at 0, 3, 7, 12, 18, and 25 minutes. PARTICIPANTS: 32 active male and female college age students. RESULTS: Analysis suggested that stretching as a combined treatment effect demonstrated an increase in AKE ROM that lasted for 25 minutes; however, no specific method of stretching was found to be more beneficial. CONCLUSION: Stretching utilizing CRAC, static, or active control techniques lend support to their use for the purpose of increasing and retaining ROM prior to physical activity. PMID- 17699885 TI - Fauls stretching routine produces acute gains in throwing shoulder mobility in collegiate baseball players. AB - CONTEXT: Stretching prior to activity or as a rehabilitative intervention may promote increased throwing shoulder range of motion (ROM) in baseball pitchers. OBJECTIVE: To evaluate the acute effects of Fauls modified passive stretching routine on throwing shoulder mobility in collegiate baseball players. DESIGN: Repeated measures. SETTING: Laboratory. PARTICIPANTS: Thirty collegiate baseball players with unimpaired shoulders. INTERVENTIONS: Fauls modified passive stretching routine was performed on the throwing shoulder of each subject. OUTCOME MEASURES: Shoulder complex and passive isolated glenohumeral internal and external rotation ROM were measured with a goniometer, and posterior shoulder tightness was assessed with the Tyler's test method using a carpenter's square. Measurements were made bilaterally. RESULTS: The dominant shoulder displayed significant increases in glenohumeral and shoulder complex internal and external rotation ROM and significantly decreased posterior shoulder tightness following the stretching routine. CONCLUSION: Application of the Fauls modified passive shoulder stretching routine results in acute gains in throwing shoulder mobility of collegiate baseball players. PMID- 17699886 TI - Effect of posterior capsule tightness on glenohumeral translation in the late cocking phase of pitching. AB - CONTEXT: Throwing injuries. OBJECTIVE: To study the effects of posterior capsule tightness on humeral head position in late cocking simulation. DESIGN: Eight fresh frozen shoulders were placed in position of "late cocking," 90 degrees abduction, and 10 degrees adduction and maximal external rotation. 3D measurements of humeral head relationship to the glenoid were taken with an infrared motion sensor, both before and after suture plication of the posterior capsule. Plications of 20% posterior/inferior capsule and 20% entire posterior capsule were performed, followed by plications of 40% of the posterior/inferior capsule and 40% entire posterior capsule. SETTING: Cadaver Lab. INTERVENTION: Posterior capsular placation. MAIN OUTCOME MEASURES: Humeral head position. RESULTS: 40%, but not 20%, posterior/inferior and posterior plications demonstrated a trend to increased posterior-superior humeral head translation relative to controls. CONCLUSION: Surgically created posterior capsular tightness of the glenohumeral joint demonstrated a nonsignificant trend to increased posterior/superior humeral head translation in the late cocking position of throwing. PMID- 17699887 TI - Scapular stabilizer activity during Bodyblade, cuff weights, and Thera-Band use. AB - CONTEXT: There are numerous ways to overload the scapular stabilizers. OBJECTIVES: To assess scapular stabilizer activity using the Bodyblade and other traditional training devices. DESIGN: Repeated measures analysis of surface EMG data collected from the upper trapezius (UT), lower trapezius (LT), and serratus anterior (SA) during shoulder flexion and abduction using Bodyblade, cuff weight, and Thera-Band resistance. SETTING: Laboratory. PARTICIPANTS: Thirty collegiate athletes (20.0 +/- 1.7 years). INTERVENTION: Participants performed 10 repetitions of shoulder flexion and abduction. MAIN OUTCOME MEASURES: For each movement, normalized root mean square values (NrmsEMG) were computed for each muscle during each repetition under each training condition. Data were analyzed using 3 (condition) 3 10 (repetition) repeated measures ANOVAs. RESULTS: During shoulder flexion and abduction, the NrmsEMG of the UT, LT, and SA were significantly greater when using the Bodyblade than the Thera-Band or cuff weight. CONCLUSION: The Bodyblade produces greater scapular activity than traditional resistance techniques. PMID- 17699888 TI - Recombinant factor VIIa: a universal haemostatic agent? PMID- 17699889 TI - Hospitals and management--why the anaesthesiologist should care. PMID- 17699890 TI - Desmopressin for haemostasis in cardiac surgery: when to use? AB - Bleeding after cardiac surgery increases morbidity and exposes patients to the risks associated with blood transfusion. Desmopressin acetate, a synthetic vasopressin analogue, has been used in patients undergoing cardiac operations to reduce postoperative blood loss and transfusion requirements, although a benefit has not been demonstrated in large randomized controlled trials. Therefore, the routine use of desmopressin in uncomplicated cardiac operations is not recommended. This review article discusses the pharmacology of desmopressin as a haemostatic agent and evaluates available clinical evidence to determine current indications for desmopressin as a haemostatic agent in cardiac surgery. PMID- 17699891 TI - Perioperative transoesophageal echocardiography in noncardiac surgery. AB - Transoesophageal echocardiography (TOE) is a semi invasive technique that allows a real time evaluation of cardiac anatomy, regional and global function. Its use is becoming an irreplaceable tool for the assessment and therapeutic management of critical patients in the Perioperative setting. A systematic search for reports describing indications for intraoperative TOE monitoring was carried out. Search terms were Perioperative TEE/TOE, intraoperative monitoring, TEE/TOE and vascular surgery, neurosurgery, orthopaedic surgery, transplant surgery. In several surgical specialties, including vascular surgery, neurosurgery, laparoscopic, orthopaedic, and transplant surgery, the intraoperative TOE monitoring found specific indications. The early recognition of haemodynamic changes, pulmonary and paradoxical embolism and ischaemic events, often not diagnosed through standard monitoring such as electrocardiography and pulmonary artery catheterization, allows a prompt therapeutic intervention and a reduction in mortality and morbidity in patients with a failing cardiac function. This paper is a review of the current uses of TOE in noncardiac surgery such as vascular surgery, neurosurgery, laparoscopic, orthopaedic, and transplant surgery. In these situations, significant haemodynamic instabilities are known to occur, which require rapid identification and solutions. TOE may have prominent role in perioperative monitoring in several noncardiac surgical procedures. PMID- 17699892 TI - Clinical predictors for mortality in adults undergoing thoracic aortic surgery requiring deep hypothermic circulatory arrest. AB - This retrospective, observational study was performed on adult patients undergoing thoracic aortic surgery (ATAS) requiring standardized deep hypothermic circulatory arrest (DHCA) with following aims. (1). To determine the mortality rate after ATAS-DHCA (2). To determine univariate predictors for mortality after ATAS-DHCA (3). To determine multivariate predictors for mortality after ATAS-DHCA A total of 144 patients operated during 2000/2001 were included. The mortality rate was 11.1%. Univariate predictors for mortality after ATAS-DHCA were preoperative ejection fraction less than 40%, stroke, packed red blood cell transfusion within first 24 hours, sepsis, mediastinal re-exploration for bleeding within first 24 hours, and renal dysfunction. Multivariate predictors for mortality after ATAS-DHCA were sepsis (odds ratio 21.3:1; confidence interval 3.8-12.1; p=0.001), postoperative stroke (odds ratio 7.4:1; confidence interval 1.9-28.7; p=0.004) and mediastinal re-exploration within first 24 hours (odds ratio 7.7:1; confidence interval 1.3-45.1; p = 0.02) We conclude that mortality after ATAS-DHCA remains high. The identified multivariate predictors merit further hypothesis-driven intervention. PMID- 17699893 TI - Pulmonary artery catheter placement in high-risk coronary artery bypass grafting: should it be done before or after induction of anaesthesia? AB - Pulmonary artery catheter (PAC) is generally inserted after induction of general anaesthesia (GA). However, in high-risk coronary artery disease patients (left main disease / ejection fraction (35%), it may be desirable to insert it before the induction of GA. Thirty patients with left main coronary artery disease and / or left ventricular ejection fraction < 35% undergoing coronary artery bypass grafting (CABG) surgery were prospectively randomized into 2 groups of 15 each. In group A, pulmonary artery catheter was inserted before induction and in group B, after induction of GA. Haemodynamic parameters like heart rate (HR), mean arterial pressure (MAP), cardiac index (CI) and other derived parameters were obtained serially up to 10 min after tracheal intubation in group A and the haemodynamic management was based on these parameters. In group B, the haemodynamic management was based on HR and MAP. The demographic data was similar in both the groups. The time required for insertion of PAC was also similar in the two groups (7.6 +/- 1.8 and 6.2 +/- 1.3 min, p > 0.05). The number of interventions in the form of infusions of volume, nitroglycerin or dopamine were significantly more in group A before tracheal intubation. The patients in group A maintained better haemodynamics at 10 min after tracheal intubation as compared with group B (CI 2.8 +/- 0.67 vs 2.1 +/- 0.49, p < 0.05; stroke volume 54 +/- 18 vs 51 +/- 0.65, p < 0.05; systemic vascular resistance 1431 +/- 409 vs 1724 +/- 430, p < 0.05; pulmonary vascular resistance 109 +/- 34 vs 181 +/- 110, p < 0.05). Insertion of PAC before induction of GA provides informative data and can be utilized to treat haemodynamic alterations in high-risk patients undergoing CABG. PMID- 17699894 TI - Effects of propofol and methohexital on neutrophil function in cardiac surgical patients. AB - The aim of the study was to compare the effects of propofol and methohexital on neutrophil leukocyte oxidative burst in cardiac surgical patients. Forty-six patients after weaning from cardiopulmonary bypass either received propofol (n=29) or methohexital (n=17). Oxidative burst was measured before induction of anaesthesia, on admission to intensive care unit (ICU), 6 hours after ICU admission and 24 hours after start of anaesthesia. Neutrophil leukocyte oxidative burst at start of anaesthesia and on ICU admission was 93 +/- 4% and 95 +/- 4% (methohexital) and 95 +/- 5% and 96 +/- 4% (propofol). Oxidative burst decreased at 6 hours of ICU stay and 24 hours after start of anaesthesia in propofol group (79 +/- 16 and 72 +/- 19%, p < 0.05) and methohexital group (83 +/- 14% and 82 +/ 15%, P < 0.05). However, at 24 hours after start of anaesthesia oxidative burst was significantly higher for methohexital (82 +/- 15%) than propofol (72 +/- 19%) (p < 0.05). Neutrophil leukocyte oxidative burst is depressed more by propofol than methohexital 24 hours after induction of anaesthesia. However, there were no differences in the clinical outcome in terms of serum creatinine, serum bilirubin, duration of ventilation, pneumonia and length of ICU stay in the two groups. PMID- 17699895 TI - Recombinant factor VII-A as a rescue therapy for intractable haemorrhage after third time cardiac surgery--a case report. PMID- 17699896 TI - Hybrid cardiac surgical procedure: technique and anaesthetic management. PMID- 17699897 TI - Absent right superior vena cava in visceroatrial situs solitus: surgical and anaesthetic implications. PMID- 17699898 TI - Intraoperative cardiac arrest--successful resuscitation with open chest cardiac compression. PMID- 17699899 TI - Giant left anterior descending artery aneurysm. PMID- 17699900 TI - Utility of intraoperative autotransfusor in OPCAB surgery. PMID- 17699901 TI - Assessment of left ventricular global systolic function by transoesophageal echocardiography. PMID- 17699902 TI - A perspective. PMID- 17699903 TI - Impact of off-pump coronary artery bypass surgery on post-operative pulmonary dysfunction: current best available evidence. AB - Pulmonary dysfunction is a well-recognized complication associated with cardiopulmonary bypass (CPB) and a major cause of morbidity and mortality in cardiac surgery. Off-pump coronary artery bypass (OPCAB) surgery has been gaining in popularity in the last few years. Resurgence of interest in OPCAB is associated with the expectation that avoiding deleterious effects of the CPB pump leads to better outcomes and possibly decreased costs and resource utilization. This review article attempts to evaluate the current best available evidence from randomized controlled trials on the impact of OPCAB on postoperative pulmonary dysfunction. PMID- 17699904 TI - Evaluation of efficacy of intranasal midazolam, ketamine and their mixture as premedication and its relation with bispectral index in children with tetralogy of fallot undergoing intracardiac repair. AB - We compared the efficacy of intranasal midazolam, ketamine and their mixture as premedication in children with tetralogy of Fallot (TOF) using bispectral index (BIS), sedation score and separation score at the time of separation from parent. Sedation score at the time of intravenous cannulation was also measured. Children with TOF physiology were randomly divided into three equal groups of 20 each. Group-A received intranasal ketamine (10 mg/Kg), Group-B received intranasal midazolam (0.2 mg/Kg), while Group-C received a mixture of ketamine (7.5 mg/Kg) and midazolam (0.1 mg/Kg) intranasally. After 30 minutes of premedication, sedation and separation score were noted. BIS values were recorded at 5 minutes intervals. A 4-point scale for sedation, separation and acceptance of intravenous cannulation was used. Sedation was good in midazolam group (group B-3.25 +/- 0.44), but the separation and acceptance of intravenous catheter was poor (2.9 +/ 0.31 and 2.85 +/- 0.37 respectively). Sedation scores in group A and C were excellent (3.75 +/- 0.44 and 3.80 +/- 0.41 respectively). Separation from parent was excellent in group A (ketamine) and group C (mixture) (group A- 3.90 +/- 0.28 and group C- 3.83 +/- 0.35 respectively). Children of both these groups allowed easy placement of intravenous cannula. At BIS values < 90, the sedation achieved was good. BIS values decreased with increase in sedation scores in groups who received intranasal midazolam and mixture containing ketamine and midazolam (group B and C respectively), while it remained high in children who received ketamine. We conclude that intranasal ketamine is better than intranasal midazolam. The combination of two is better than midazolam alone but provides no benefit as compared with ketamine alone. PMID- 17699905 TI - Predictors of prolonged mechanical ventilation after on-pump coronary artery bypass grafting. AB - The predictors of prolonged mechanical ventilation and subsequent morbidity after cardiac surgery are ill defined. Our aim was to evaluate them. Four hundred and seventy consecutive patients undergoing coronary artery bypass grafting on cardiopulmonary bypass (CPB) between January and June 2002 were retrospectively analysed for preoperative predictors of prolonged ventilation, which included age, gender, ejection fraction (EF), renal function, diabetes, angina status, severity of the disease (New York Heart Association class), number of vessels diseased and chronic lung disease. Intraoperative variables such as prolonged CPB, aortic cross clamp time, intra-aortic balloon pump (IABP) usage, inotropes and postoperative variables like temperature on arrival at intensive care unit(ICU), IABP usage, organ dysfunction, inotropes and reintervention (reintubation and re-exploration) were also analysed. Prolonged ventilation was defined as > or = 24 hours and these patients were included in group I (n=22). Patients requiring less than 24 hours ventilation (n=448) were included in group II. Stepwise logistic regression analysis was performed. The average age of patients was 56.9 +/- 8.8 years with male predominance (88.4%). The overall perioperative mortality was 2.1% (10 patients) with Group I showing mortality rate of 36.3% (8 patients). In multivariate analysis, predictors of prolonged ventilation were found to be EF <40% (odds ratio, (OR) 13.38), preoperative renal dysfunction [OR 4.06 (serum creatinine > 1.2 mg%)], prolonged CPB, > 120 min (OR 9.6) and reintervention in the form of re-exploration or reintubation in the ICU (OR 13.8). Identification of perioperative variables, which may lead to prolonged ventilation may allow the development of strategies to optimize the patient's condition and ICU management. PMID- 17699906 TI - Effect of muscle relaxants on heart rate, arterial pressure, intubation conditions and onset of neuromuscular block in patients undergoing valve surgery. AB - Sixty six patients undergoing elective valve surgery were randomized to receive rocuronium bromide 0.6 mg/Kg (Group R, n=22), pancuronium bromide 0.1 mg/Kg (Group P, n= 22) and vecuronium bromide 0.1 mg/Kg (Group V, n=22), Measurements of heart rate and arterial pressure (systolic, diastolic and mean) were noted at the following stages: 1) baseline when haemodynamics were stable for 2 minutes after induction of anaesthesia (2) one, (3) three, (4) five minutes after administration of muscle relaxants, (5) One, (6) three, and (7) five minutes after intubation. In group R, the heart rate decreased 5 min after injection of muscle relaxant from 93.9 +/- 21.3 to 82.4 +/- 20.7 beats/min (p<0.001). However, it increased to 128.3 +/- 25.8 beats/min (p<0.001) following intubation and returned to baseline at 5 min after intubation. In group P, heart rate increased from 98.8 +/- 32.6 to 109.6 +/- 32.7 beats/min (p<0.001), 1 min after injection of pancuronium and this increase persisted throughout the study period. In group V, heart rate decreased from 99.9 +/- 22.3 to 83.8 +/-19.6 beats/min (p<0.001) at 5 min after injection of the drug. It increased to 118.6 +/- 22.4 beats/min (p<0.001), 1 min after intubation and returned to baseline at 5 min after intubation. The decrease in heart rate in group R and V was accompanied by a significant decrease in systolic, diastolic and mean arterial pressure. In group P, only the systolic pressure decreased significantly at 5 min after injection of the drug. Intubation was accompanied by a significant increased in systolic, diastolic and mean arterial pressure in all the groups. Excellent intubation conditions (intubation score 3-4) were observed with all the three drugs, however, there were number of patients in group P who showed diaphragmatic movement during intubation. Onset of action of muscle relaxant, was fastest with rocuronium (group R=132.7 +/- 0.3 sec, P=182.6 +/- 68.5 sec, V= 144.8 +/- 46.1 sec, Group P vs Group R). To conclude, pancuronium causes significant increase in heart rate and should be preferred in patients with regurgitant lesions having slower baseline heart rate. Vecuronium and rocuronium decrease the heart rate and should be preferred in patient with faster baseline heart rate. In terms of intubating conditions rocuronium and vecuronium provide best conditions, but onset is faster with rocuronium. PMID- 17699907 TI - Comparison of cardiac output in OPCAB: bolus thermodilution technique versus pulse contour analysis. AB - The study was designed to evaluate the clinical agreement between intermittent bolus thermodilution technique and pulse contour analysis technique. Sixty patients with normal left ventricular function undergoing elective off-pump coronary bypass surgery were included in this prospective study. In addition to routine monitoring, a 7.5F pulmonary artery thermodilution catheter via right internal jugular vein and a 4F arterial thermodilution catheter into femoral artery were also placed. Cardiac output measurements were compared before induction, after induction, after sternotomy, during the various anastomoses, post-protamine and post-sternal closure. Statistical analysis was performed using analysis of agreement to assure bias distribution of differences between the two methods by using Bland and Altman analysis. The cardiac output values obtained at preinduction, post-induction, and post-sternal closure time points showed good agreement, whereas the values obtained during the various anastomoses showed significant differences (p <0.05). Therefore it was concluded that pulse contour analysis cannot be relied upon completely whenever there is a change in the position of heart or alteration in systemic vascular resistance. But the trends in cardiac output were in complete agreement during the entire procedure. PMID- 17699908 TI - Perioperative management of cor triatriatum with congenitally corrected transposition of great arteries. PMID- 17699909 TI - Anaesthetic management of bronchial artery embolisation using double lumen endobronchial tube. PMID- 17699911 TI - Severe bradycardia in a myasthenic patient undergoing percutaneous nephrolithotomy in prone position under general anaesthesia. PMID- 17699910 TI - An unusual case of dense and extensive calcification of aorta. PMID- 17699912 TI - Anaesthetic management of unusual thoracic trauma. PMID- 17699913 TI - Accidental administration of norepinephrine due to breech in a closed infusion system. PMID- 17699914 TI - Improved needle manoeuverability on removal of flange may help in epidural catheter placement in an obese patient. PMID- 17699915 TI - Anaesthesia for the elderly cardiac patient. PMID- 17699916 TI - Facial action unit recognition by exploiting their dynamic and semantic relationships. AB - A system that could automatically analyze the facial actions in real time has applications in a wide range of different fields. However, developing such a system is always challenging due to the richness, ambiguity, and the dynamic nature of facial actions. Although a number of research groups attempt to recognize facial action units (AUs) by either improving facial feature extraction techniques, or the AU classification techniques, these methods often recognize AUs or certain AU combinations individually and statically, ignoring the semantic relationships among AUs and the dynamics of AUs. Hence, these approaches cannot always recognize AUs reliably, robustly, and consistently. In this paper, we propose a novel approach that systematically accounts for the relationships among AUs and their temporal evolutions for AU recognition. Specifically, we use a dynamic Bayesian network (DBN) to model the relationships among different AUs. The DBN provides a coherent and unified hierarchical probabilistic framework to represent probabilistic relationships among various AUs and to account for the temporal changes in facial action development. Within our system, robust computer vision techniques are used to obtain AU measurements. And such AU measurements are then applied as evidence to the DBN for inferring various AUs. The experiments show that the integration of AU relationships and AU dynamics with AU measurements yields significant improvement of AU recognition, especially for spontaneous facial expressions and under more realistic environment including illumination variation, face pose variation, and occlusion. PMID- 17699917 TI - General tensor discriminant analysis and gabor features for gait recognition. AB - The traditional image representations are not suited to conventional classification methods, such as the linear discriminant analysis (LDA), because of the under sample problem (USP): the dimensionality of the feature space is much higher than the number of training samples. Motivated by the successes of the two dimensional LDA (2DLDA) for face recognition, we develop a general tensor discriminant analysis (GTDA) as a preprocessing step for LDA. The benefits of GTDA compared with existing preprocessing methods, e.g., principal component analysis (PCA) and 2DLDA, include 1) the USP is reduced in subsequent classification by, for example, LDA; 2) the discriminative information in the training tensors is preserved; and 3) GTDA provides stable recognition rates because the alternating projection optimization algorithm to obtain a solution of GTDA converges, while that of 2DLDA does not. We use human gait recognition to validate the proposed GTDA. The averaged gait images are utilized for gait representation. Given the popularity of Gabor function based image decompositions for image understanding and object recognition, we develop three different Gabor function based image representations: 1) the GaborD representation is the sum of Gabor filter responses over directions, 2) GaborS is the sum of Gabor filter responses over scales, and 3) GaborSD is the sum of Gabor filter responses over scales and directions. The GaborD, GaborS and GaborSD representations are applied to the problem of recognizing people from their averaged gait images.A large number of experiments were carried out to evaluate the effectiveness (recognition rate) of gait recognition based on first obtaining a Gabor, GaborD, GaborS or GaborSD image representation, then using GDTA to extract features and finally using LDA for classification. The proposed methods achieved good performance for gait recognition based on image sequences from the USF HumanID Database. Experimental comparisons are made with nine state of the art classification methods in gait recognition. PMID- 17699918 TI - High-dimensional unsupervised selection and estimation of a finite generalized Dirichlet mixture model based on minimum message length. AB - We consider the problem of determining the structure of high-dimensional data, without prior knowledge of the number of clusters. Data are represented by a finite mixture model based on the generalized Dirichlet distribution. The generalized Dirichlet distribution has a more general covariance structure than the Dirichlet distribution and offers high flexibility and ease of use for the approximation of both symmetric and asymmetric distributions. This makes the generalized Dirichlet distribution more practical and useful. An important problem in mixture modeling is the determination of the number of clusters. Indeed, a mixture with too many or too few components may not be appropriate to approximate the true model. Here, we consider the application of the minimum message length (MML) principle to determine the number of clusters. The MML is derived so as to choose the number of clusters in the mixture model which best describes the data. A comparison with other selection criteria is performed. The validation involves synthetic data, real data clustering, and two interesting real applications: classification of web pages, and texture database summarization for efficient retrieval. PMID- 17699919 TI - Discriminant subspace analysis: a Fukunaga-Koontz approach. AB - The Fisher Linear Discriminant (FLD) is commonly used in pattern recognition. It finds a linear subspace that maximally separates class patterns according to the Fisher Criterion. Several methods of computing the FLD have been proposed in the literature, most of which require the calculation of the so-called scatter matrices. In this paper, we bring a fresh perspective to FLD via the Fukunaga Koontz Transform (FKT). We do this by decomposing the whole data space into four subspaces with different discriminability, as measured by eigenvalue ratios. By connecting the eigenvalue ratio with the generalized eigenvalue, we show where the Fisher Criterion is maximally satisfied. We prove the relationship between FLD and FKT analytically, and propose a unified framework to understanding some existing work. Furthermore, we extend our our theory to Multiple Discriminant Analysis (MDA). This is done by transforming the data into intra- and extra-class spaces, followed by maximizing the Bhattacharyya distance. Based on our FKT analysis, we identify the discriminant subspaces of MDA/FKT, and propose an efficient algorithm, which works even when the scatter matrices are singular, or too large to be formed. Our method is general and may be applied to different pattern recognition problems. We validate our method by experimenting on synthetic and real data. PMID- 17699920 TI - Condensed nearest neighbor data domain description. AB - A simple yet effective unsupervised classification rule to discriminate between normal and abnormal data is based on accepting test objects whose nearest neighbors distances in a reference data set, assumed to model normal behavior, lie within a certain threshold. This work investigates the effect of using a subset of the original data set as the reference set of the classifier. With this aim, the concept of a reference consistent subset is introduced and it is shown that finding the minimum cardinality reference consistent subset is intractable. Then, the CNNDD algorithm is described, which computes a reference consistent subset with only two reference set passes. Experimental results revealed the advantages of condensing the data set and confirmed the effectiveness of the proposed approach. A thorough comparison with related methods was accomplished, pointing out the strengths and weaknesses of one-class nearest-neighbor-based training set consistent condensation. PMID- 17699921 TI - Learning to transform time series with a few examples. AB - We describe a semi-supervised regression algorithm that learns to transform one time series into another time series given examples of the transformation. This algorithm is applied to tracking, where a time series of observations from sensors is transformed to a time series describing the pose of a target. Instead of defining and implementing such transformations for each tracking task separately, our algorithm learns a memoryless transformation of time series from a few example input-output mappings. The algorithm searches for a smooth function that fits the training examples and, when applied to the input time series, produces a time series that evolves according to assumed dynamics. The learning procedure is fast and lends itself to a closed-form solution. It is closely related to nonlinear system identification and manifold learning techniques. We demonstrate our algorithm on the tasks of tracking RFID tags from signal strength measurements, recovering the pose of rigid objects, deformable bodies, and articulated bodies from video sequences. For these tasks, this algorithm requires significantly fewer examples compared to fully-supervised regression algorithms or semi-supervised learning algorithms that do not take the dynamics of the output time series into account. PMID- 17699922 TI - Epipolar geometry of opti-acoustic stereo imaging. AB - Optical and acoustic cameras are suitable imaging systems to inspect underwater structures, both in regular maintenance and security operations. Despite high resolution, optical systems have limited visibility range when deployed in turbid waters. In contrast, the new generation of high-frequency (MHz) acoustic cameras can provide images with enhanced target details in highly turbid waters, though their range is reduced by one to two orders of magnitude compared to traditional low-/midfrequency (10s-100s KHz) sonar systems. It is conceivable that an effective inspection strategy is the deployment of both optical and acoustic cameras on a submersible platform, to enable target imaging in a range of turbidity conditions. Under this scenario and where visibility allows, registration of the images from both cameras arranged in binocular stereo configuration provides valuable scene information that cannot be readily recovered from each sensor alone. We explore and derive the constraint equations for the epipolar geometry and stereo triangulation in utilizing these two sensing modalities with different projection models. Theoretical results supported by computer simulations show that an opti-acoustic stereo imaging system outperforms a traditional binocular vision with optical cameras, particularly for increasing target distance and (or) turbidity. PMID- 17699923 TI - Dynamosaicing: mosaicing of dynamic scenes. AB - This paper explores the manipulation of time in video editing, enabling to control the chronological time of events. These time manipulations include slowing down (or postponing) some dynamic events while speeding up (or advancing) others. When a video camera scans a scene, aligning all the events to a single time interval will result in a panoramic movie. Time manipulations are obtained by first constructing an aligned space-time volume from the input video, and then sweeping a continuous 2D slice (time front) through that volume, generating a new sequence of images. For dynamic scenes, aligning the input video frames poses an important challenge. We propose to align dynamic scenes using a new notion of "dynamics constancy", which is more appropriate for this task than the traditional assumption of "brightness constancy". Another challenge is to avoid visual seams inside moving objects and other visual artifacts resulting from sweeping the space-time volumes with time fronts of arbitrary geometry. To avoid such artifacts, we formulate the problem of finding optimal time front geometry as one of finding a minimal cut in a 4D graph, and solve it using max-flow methods. PMID- 17699924 TI - Modeling semantic aspects for cross-media image indexing. AB - To go beyond the query-by-example paradigm in image retrieval, there is a need for semantic indexing of large image collections for intuitive text-based image search. Different models have been proposed to learn the dependencies between the visual content of an image set and the associated text captions, then allowing for the automatic creation of semantic indices for unannotated images. The task, however, remains unsolved. In this paper, we present three alternatives to learn a Probabilistic Latent Semantic Analysis model (PLSA) for annotated images, and evaluate their respective performance for automatic image indexing. Under the PLSA assumptions, an image is modeled as a mixture of latent aspects that generates both image features and text captions, and we investigate three ways to learn the mixture of aspects. We also propose a more discriminative image representation than the traditional Blob histogram, concatenating quantized local color information and quantized local texture descriptors. The first learning procedure of a PLSA model for annotated images is a standard EM algorithm, which implicitly assumes that the visual and the textual modalities can be treated equivalently. The other two models are based on an asymmetric PLSA learning, allowing to constrain the definition of the latent space on the visual or on the textual modality. We demonstrate that the textual modality is more appropriate to learn a semantically meaningful latent space, which translates into improved annotation performance. A comparison of our learning algorithms with respect to recent methods on a standard dataset is presented, and a detailed evaluation of the performance shows the validity of our framework. PMID- 17699925 TI - Context-based object-class recognition and retrieval by generalized correlograms. AB - We present a novel approach for retrieval of object categories based on a novel type of image representation: the Generalized Correlogram (GC). In our image representation, the object is described as a constellation of GCs where each one encodes information about some local part and the spatial relations from this part to others (i.e., the part's context). We show how such a representation can be used with fast procedures that learn the object category with weak supervision and efficiently match the model of the object against large collections of images. In the learning stage, we show that by integrating our representation with Boosting the system is able to obtain a compact model that is represented by very few features, where each feature conveys key properties about the object's parts and their spatial arrangement. In the matching step, we propose direct procedures that exploit our representation for efficiently considering spatial coherence between the matching of local parts. Combined with an appropriate data organization such as Inverted Files, we show that thousands of images can be evaluated efficiently. The framework has been applied to different standard databases and we show that our results are favorably compared against state-of the-art methods in both computational cost and accuracy. PMID- 17699926 TI - Quasiconvex optimization for robust geometric reconstruction. AB - Geometric reconstruction problems in computer vision are often solved by minimizing a cost function that combines the reprojection errors in the 2D images. In this paper, we show that, for various geometric reconstruction problems, their reprojection error functions share a common and quasiconvex formulation. Based on the quasiconvexity, we present a novel quasiconvex optimization framework in which the geometric reconstruction problems are formulated as a small number of small-scale convex programs that are ready to solve. Our final reconstruction algorithm is simple and has intuitive geometric interpretation. In contrast to existing local minimization approaches, our algorithm is deterministic and guarantees a predefined accuracy of the minimization result. The quasiconvexity also provides an intuitive method to handle directional uncertainties and outliers in measurements. When there are outliers in the measurements, our method provides a mechanism to locate the global minimum of a robust error function. For large scale problems and when computational resources are constrained, we provide an efficient approximation that gives a good upper bound (but not global minimum) on the reconstruction error. We demonstrate the effectiveness of our algorithm by experiments on both synthetic and real data. PMID- 17699927 TI - Hidden conditional random fields. AB - We present a discriminative latent variable model for classification problems in structured domains where inputs can be represented by a graph of local observations. A hidden-state Conditional Random Field framework learns a set of latent variables conditioned on local features. Observations need not be independent and may overlap in space and time. PMID- 17699928 TI - 2D affine-invariant contour matching using B-spline model. AB - This paper presents a new affine-invariant matching algorithm based on B-Spline modeling, which solves the problem of the non-uniqueness of B-Spline in curve matching. This method first smoothes the B-Spline curve by increasing the degree of the curve. It is followed by a reduction of the curve degree using the Least Square Error (LSE) approach to construct the Curvature Scale Space (CSS) image. CSS matching is then carried out. Our method combines the advantages of B-Spline that are continuous curve representation and the robustness of CSS matching with respect to noise and affine transformation. It avoids the need for other matching algorithms that have to use the re-sampled points on the curve. Thus, the curve matching error is reduced. The proposed algorithm has been tested by matching similar shapes from a prototype database. The experimental results showed the robustness and accuracy of the proposed method in B-Spline curve matching. PMID- 17699929 TI - Extreme compression and modeling of bidirectional texture function. AB - The recent advanced representation for realistic real-world materials in virtual reality applications is the Bidirectional Texture Function (BTF) which describes rough texture appearance for varying illumination and viewing conditions. Such a function can be represented by thousands of measurements (images) per material sample. The resulting BTF size excludes its direct rendering in graphical applications and some compression of these huge BTF data spaces is obviously inevitable. In this paper we present a novel, fast probabilistic model-based algorithm for realistic BTF modeling allowing an extreme compression with the possibility of a fast hardware implementation. Its ultimate aim is to create a visual impression of the same material without a pixel-wise correspondence to the original measurements. The analytical step of the algorithm starts with a BTF space segmentation and a range map estimation by photometric stereo of the BTF surface, followed by the spectral and spatial factorization of selected sub-space color texture images. Single mono-spectral band-limited factors are independently modeled by their dedicated spatial probabilistic model. During rendering, the sub space images of arbitrary size are synthesized and both color (possibly multi spectral) and range information is combined in a bump-mapping filter according to the view and illumination directions. The presented model offers a huge BTF compression ratio unattainable by any alternative sampling-based BTF synthesis method. Simultaneously this model can be used to reconstruct missing parts of the BTF measurement space. PMID- 17699930 TI - On the relationship between dependence tree classification error and Bayes error rate. AB - Wong and Poon [1] showed that Chow and Liu's tree dependence approximation can be derived by minimizing an upper bound of the Bayes error rate. Wong and Poon's result was obtained by expanding the conditional entropy H(w|X). We derive the correct expansion of H(w|X) and present its implication. PMID- 17699931 TI - Comments on the CASIA version 1.0 iris data set. AB - We note that the images in the CASIA version 1.0 iris dataset have been edited so that the pupil area is replaced by a circular region of uniform intensity. We recommend that this dataset is no longer used in iris biometrics research, unless there this a compelling reason that takes into account the nature of the images. In addition, based on our experience with the Iris Challenge Evaluation (ICE) 2005 technology development project, we make recommendations for reporting results of iris recognition experiments. PMID- 17699932 TI - Correlation between serum vitamin D (25(OH)D) concentration and quadriceps femoris muscle strength in Indonesian elderly women living in three nursing homes. AB - AIM: to investigate the correlation between serum vitamin D (25(OH)D) concentration and quadriceps femoris muscle strength. METHODS: this was a cross sectional correlative study, conducted at three nursing homes in Jakarta and one nursing home in Bekasi in January 2005. The subjects were women aged 60 years or above. Those selected study subjects underwent quadriceps femoris muscle strength examination with Cybex dynamometer with 150 degrees/second speed, twice (three repetitions with 30 second rest time). The 25 (OH)D concentration was measured by ELISA. RESULTS: out of 67 subjects who met the required criteria for this study, five subjects withdrew from the study during muscle strength examination. The mean age was 71.1 (SD 7.2) years old while the mean serum vitamin D concentration was 68.2 (SD 21.6) nmol/l. Vitamin D deficiency (or= 60 years old staying at the Internal Medicine Ward. Appropriateness of drug administration was evaluated based on the support from literature. The supporting references being used were guidelines at the Internal Medicine Department, reference textbooks, and drug brochures for newly approved drugs but had not been listed in references nor guidelines. RESULTS: from 347 drug administrations in 43 patients, 228 of the drug administrations (67.71%) were considered appropriate for indication, 15.85% slightly inappropriate for indication, and 18.44% with inappropriate indication. From 228 drug administrations, 206 (90.35%) were administered with adequate dosage, 2.63% subtherapeutic dosage, 3.95% overdosage, and 3.07% undefined dosage. From 126 drug administration evaluated for duration of therapy, there were 77.78% administered with appropriate duration of therapy, 18.25% with inappropriate duration, and 3.97% undefined duration. Out of 347 drug administration there were 2 possibilities of adverse drug events, 5 drugs were actually contraindicated and 25 potential drug interaction. CONCLUSION: there were 67% of drugs appropriately administered for indication. From this number, 90% were using accurate dosage, of all drug administration there were 2 possibilities of adverse drug events, 5 drugs were contraindicated and 25 potentially interacted drugs. From 126 drugs evaluated for duration of therapy, 77.78% received the right duration of therapy. PMID- 17699935 TI - Responsive treatment of pleural effusion due to probable tuberculosis infection. AB - Early diagnosis of Mycobacterium tuberculosis disease is crucial for initiating treatment and interrupting disease transmission. In keeping with the pathophysiology of disease, bacteriological evidence in extra-pulmonary tuberculosis proves to be difficult. Clinical judgment and radiographic findings are important to establish diagnosis and to evaluate treatment response. A case of 27 year-old-male with shortness of breath and associated TB symptoms is reported. The tuberculin test was highly positive and chest X-ray showed massive right-lung pleural effusion. Pleural analysis showed exudates with high mononuclear cells (98%), protein level of 5.0 g/dL, glucose level of 87 mg/dL, and high LDH level (1240 IU/L). The acid-fast bacilli (AFB) tests were negative for pleural fluid and sputum. Cultures of fluid and sputum were also negative. After being treated adequately with non-specific treatment, which showed no improvement and having undergone pleural puncture for his treatment and diagnosis, the patient started to have antituberculosis treatment. His condition was improved significantly as shown by a serial of chest X-ray follow-up. PMID- 17699936 TI - Vitamin D and autoimmune disease. AB - Vitamin D as a part of the endocrine system is an important component in the interaction between the kidney, bone, parathyroid hormone, and the intestine, which maintains extracellular calcium level within normal limits, in order to keep the vital physiologic process and skeletal integrity. Vitamin D is also associated with hypertension, muscular function, immunity, and ability to encounter infection, autoimmune disease, and cancer. The role of vitamin D in immunity is a feedback reaction of paracrine to eliminate inflammation or to influence CD4 T-cell differentiation and or to increase the function of T suppressor cell or combination between both. The active form of vitamin D produces and maintains self immunologic tolerance, some studies show that 1,25(OH)2D inhibits induction of disease in autoimmune encephalomyelitis, thyroiditis, type-1 diabetes mellitus, inflammatory bowel disease (IBD), systemic lupus erythematosus, and collagen-induced arthritis and Lyme arthritis. PMID- 17699937 TI - Neurilemmoma of the abdomen. PMID- 17699938 TI - Research by small private establishments. PMID- 17699939 TI - Retinopathy of prematurity screening in the Indian population: it's time to set our own guidelines! PMID- 17699940 TI - Retinopathy of prematurity in Asian Indian babies weighing greater than 1250 grams at birth: ten year data from a tertiary care center in a developing country. AB - BACKGROUND: Retinopathy of prematurity (ROP) is an important cause of childhood blindness in developing countries. AIM: To report the spectrum of ROP and associated risk factors in babies weighing > 1250 g at birth in a developing country. SETTING AND DESIGN: Institutional, retrospective, non-randomized, observational clinical case series. MATERIALS AND METHODS: Retrospective analysis (10 years) of 275 eyes (138 babies) with ROP. STATISTICAL ANALYSIS: Qualitative data with the Chi-square test. Quantitative data using the unpaired t test or the ANOVA and further tested using multivariate logistic regression. RESULTS: The mean birth weight was 1533.9 g (range 1251 to 2750 g) and the mean period of gestation was 30.9 weeks (range 26 to 35). One hundred and twenty-four of 275 eyes (45.1%) had threshold or worse ROP. Risk factors for threshold or worse disease were, 'outborn babies' ( P P = 0.007) and exchange transfusion ( P = 0.003). The sensitivity of the American and British screening guidelines to pick up threshold or worse ROP in our study group was 82.4% and 77.4% respectively. CONCLUSIONS: Severe ROP is often encountered in babies weighing greater than 1250 g at birth in developing countries. Western screening guidelines may require modifications before application in developing countries. PMID- 17699941 TI - Primary 25-gauge transconjunctival sutureless vitrectomy in pseudophakic retinal detachment. AB - AIMS: There are few reports on 25-gauge transconjunctival sutureless vitrectomy (TSV) in cases of pseudophakic retinal detachment. We conducted this study to report the anatomic and functional outcomes of 25-gauge TSV in the treatment of primary pseudophakic retinal detachment (RD). DESIGN: Prospective, interventional case series. MATERIALS AND METHODS: Fifteen eyes of 15 patients with RD after cataract surgery with phacoemulsification were evaluated. Primary pseudophakic RDs with macular detachment and proliferative vitreoretinopathy Stage B or less were included in the study. Pars plana vitrectomy with the 25-gauge TSV system, perfluorocarbon liquid injection followed by air exchange, endolaser photocoagulation and sulfur hexafluoride gas (20%) injection were applied to all eyes. RESULTS: Mean follow-up time was 9.2 months (range, six to 12 months). Retinal reattachment with a single operation was achieved in 93% of eyes and with additional surgery, the retina was reattached in 100% of eyes. Preoperative visual acuity was less than 20/200 in all eyes (range, hand motions to 20/400). Postoperative visual acuity was 20/40 or better in eight eyes (53%) and between 20/50 and 20/200 in seven eyes (47%). No severe hypotony was encountered and no sutures were required to close the scleral and conjunctival openings. Postoperative complications were macular pucker in one eye (7%) and cystoid macular edema in another eye (7%). CONCLUSIONS: Primary 25-gauge TSV system appears to be an effective and safe procedure in the treatment of uncomplicated pseudophakic RD. PMID- 17699942 TI - Repeatability of corneal parameters with Pentacam after laser in situ keratomileusis. AB - AIM: To investigate the coefficient of repeatability (CR) for corneal parameters evaluated with Pentacam after laser in situ keratomileusis (LASIK) in myopic eyes. DESIGN AND SETTING: Prospective, non-interventional, non-comparative study in an institutional setup. MATERIALS AND METHODS: Forty eyes of 40 consecutive subjects who had undergone LASIK for myopia were assessed with the Scheimpflug system (Pentacam 70700: Oculus, Wetzlar Germany). The mean of five consecutive measurements of all the corneal parameters was recorded and CR was calculated as standard deviation of the difference from the mean of these repeat measurements divided by the mean response. The statistical significance of the CR was calculated for these parameters at 5% significance level. RESULTS: The best CR was observed for the periphery of the anterior corneal curvature (0.18%) and the least for the horizontal meridian of the posterior corneal curvature (1.29%). Despite being significantly different ( P < 0.001), both the measurements were highly repeatable in post-LASIK eyes. The central, apical and minimal corneal thickness had a CR of 1%, 0.78% and 0.77% respectively. These were equally repeatable ( P> 0.323). The CR of the mean radius of curvature of the anterior cornea (0.29%) was significantly better ( P < 0.001) than the posterior corneal curvature (0.57%). CONCLUSION: The CR for the post-LASIK cornea with Pentacam was the best for the anterior corneal curvature. Significantly, Pentacam has a high degree of repeatability for the posterior corneal curvature, which has a potential for early detection of keratectasia in these eyes. Post-LASIK pachymetry with Pentacam also showed excellent repeatability. PMID- 17699943 TI - Role of concanavalin A lectin in recognition of pterygium remnant after surgical excision: preliminary results of a prospective study. AB - BACKGROUND: Pterygium is one of the most common conjunctival diseases among ophthalmic pathologies. The frequency of recurrences is high, either after surgical treatment or after treatment combined with mitomycin C or beta-radiation therapy. AIMS: The purpose of this study was to determine whether concanavalin A (ConA) lectin bound to the pterygial surface can be used to detect recurrence or remnants of pterygium after surgical excision. MATERIALS AND METHODS: This was a prospective study on 20 patients with pterygium, divided in five stages, pre surgery, early post-surgery (24h), late post-surgery (seven days), very late post surgery (four weeks) and two months after the procedure. A drop of fluorescein marked Con A (35 microg/mL) was instilled in the lower conjunctival eyelid sac and the eye was exposed to the light of a Wood's lamp for an average of five seconds. RESULTS: Out of the 20 patients, eight patients were found to have fluorescent stretch marks over the scar corresponding to residual pterygial tissue at four weeks; two months after the procedure of re-surgery we observed no fluorescent remnants. All residual pterygia were confirmed through histochemistry studies. CONCLUSION: It was possible to detect remnants of pterygium in postoperative patients and recurrences in early pre-clinical stages through the visualization of fluorescent ConA bound to the pterygial surface. PMID- 17699944 TI - Comparative evaluation of megadose methylprednisolone with dexamethasone for treatment of primary typical optic neuritis. AB - AIM: To compare the efficacy of intravenous methylprednisolone and intravenous dexamethasone on visual recovery and evaluate their side-effects for the treatment of optic neuritis. MATERIALS AND METHODS: Prospective, randomized case controlled study including 21 patients of acute optic neuritis presenting within eight days of onset and with visual acuity less then 20/60 in the affected eye who were randomly divided into two groups. Group I received intravenous dexamethasone 200 mg once daily for three days and Group II received intravenous methylprednisolone 250 mg/six-hourly for three days followed by oral prednisolone for 11 days. Parameters tested were pupillary reactions, visual acuity, fundus findings, color vision, contrast sensitivity, Goldmann visual fields and biochemical investigations for all patients at presentation and follow-up. RESULTS: Both groups were age and sex-matched. LOGMAR visual acuity at presentation was 1.10 +/- 0.52 in Group I and 1.52 +/- 0.43 in Group II. On day 90 of steroid therapy, visual acuity improved to 0.28 +/- 0.33 in Group I and 0.36 +/- 0.41 in Group II ( P =0.59). At three months there was no statistically significant difference in the color vision, contrast sensitivity, stereoacuity, Goldman fields and the amplitude and latency of visually evoked response between the two groups. The concentration of vitamin C, glucose, sodium, potassium, urea and creatinine were within the reported normal limits. CONCLUSION: Intravenous dexamethasone is an effective treatment for optic neuritis. However, larger studies are required to establish it as a safe, inexpensive and effective modality for the treatment of optic neuritis. PMID- 17699945 TI - Immunohistochemical localization of human papilloma virus in conjunctival neoplasias: a retrospective study. AB - BACKGROUND: The extent of association of human papilloma virus (HPV) in human conjunctival neoplasias has been debated in studies originating from different parts of the world, but no substantial evidence has been generated on Indian subjects. This prompted us to carry out a retrospective study on conjunctival neoplasias diagnosed over the past 12 years. MATERIALS AND METHODS: Histopathological and immunohistochemical analysis of 65 specimens of ocular neoplasias and 30 normal controls diagnosed between 1991 and 2002 at a tertiary eye care hospital, was undertaken. Formalin-fixed, paraffin-embedded tissues were reviewed for confirming histopathological diagnosis, presence of koilocytosis and changes related to actinic keratosis. Immunohistochemical analysis was done using HPV-specific monoclonal antibodies. Clinicopathological correlation and the association of HPV antigen with the histopathological features were performed. RESULTS: Out of the 65 cases analyzed, 35 were papillomas and 30 were ocular surface squamous neoplasias (OSSN). The mean age was 48 years with a male preponderance. Histologically, koilocytosis was observed in 17.1% of papillomas and 36.6% of OSSN. Actinic keratosis was present in 33% of OSSN. Immunohistochemically 17.1% conjunctival papillomas stained positive for HPV antigen, all cases of OSSN were negative for HPV. There was no correlation between koilocytosis or actinic keratosis and the detection of HPV antigen. CONCLUSIONS: The association between HPV and conjunctival neoplasias is variable in different geographical areas and also depends on the methods of detection used. This study warrants the need for applying more advanced techniques at a molecular level to determine the possible etiology of HPV in conjunctival neoplasias among Asian-Indians. PMID- 17699946 TI - Barriers to accessing eye care services among visually impaired populations in rural Andhra Pradesh, South India. AB - PURPOSE: To understand the reasons why people in rural south India with visual impairment arising from various ocular diseases do not seek eye care. MATERIALS AND METHODS: A total of 5,573 persons above the age of 15 were interviewed and examined in the South Indian state of Andhra Pradesh covering the districts of Adilabad, West Godavari and Mahaboobnagar. A pre-tested structured questionnaire on barriers to eye care was administered by trained field investigators. RESULTS: Of the eligible subjects, 1234 (22.1%, N=5573)) presented with distant visual acuity < 20/60 or equivalent visual field loss in the better eye. Of these, 898 (72.7%, N=1234) subjects had not sought treatment despite noticing a decrease in vision citing personal, economic and social reasons. The analysis also showed that the odds of seeking treatment was significantly higher for literates [odds ratio (OR) 1.91, 95% confidence interval (CI) 1.38 to 2.65], for those who would be defined as blind by visual acuity category (OR 1.35, 95% CI 0.96 to 1.90) and for those with cataract and other causes of visual impairment (OR 1.50, 95% CI 1.11 to 2.03). Barriers to seeking treatment among those who had not sought treatment despite noticing a decrease in vision over the past five years were personal in 52% of the respondents, economic in 37% and social in 21%. CONCLUSION: Routine planning for eye care services in rural areas of India must address the barriers to eye care perceived by communities to increase the utilization of services. PMID- 17699947 TI - Bilateral periorbital necrotizing fasciitis following exposure to Holi colors: a case report. AB - Holi festival is celebrated in India traditionally by applying colors on one another. Various ocular adverse effects of these colors have been reported including conjunctivitis and corneal abrasion. We report a case of bilateral periorbital necrotizing fasciitis, following exposure to Holi colors. General physicians might encounter more such cases after exposure to Holi colors. In India, these colors are prepared on a small scale and lack any quality checks. Use of such toxic colors should be discouraged, and all doctors should caution people against using synthetic dyes. This case report highlights the need to put manufacturing of Holi colors under guidelines of the Food and Drug Cosmetic Act and the Bureau of Indian Standards. PMID- 17699948 TI - Bilateral Pseudomonas aeruginosa endophthalmitis following bilateral simultaneous cataract surgery. AB - A bilateral simultaneous cataract surgery (BSCS) was performed on a 67-year-old man. The surgeon had not changed the surgical settings in between the two procedures for the two eyes. The patient developed fulminant bilateral endophthalmitis a day following the BSCS. Intravitreal culture grew Pseudomonas aeruginosa . The source of infection was not found. Immediate bilateral vitrectomy and intravitreal, subconjunctival, topical and systemic antibiotic did not save the eyes. Patient ended up with bilateral visual loss. PMID- 17699949 TI - In vivo confocal microscopy in different types of posterior polymorphous dystrophy. AB - Posterior polymorphous dystrophy is a rare corneal dystrophy, usually detected by chance. This case series describes the morphologic features in the three different types of posterior polymorphous dystrophy using confocal microscopy. PMID- 17699950 TI - Ocular features of hantavirus infection. AB - Hantavirus infections are an emerging infectious disease that is beginning to be recognized both worldwide and in India as a cause of hemorrhagic fever that may present as a pulmonary syndrome or as a renal syndrome. Reports of ocular involvement are rare and include transient myopia, low intraocular pressure, conjunctival hemorrhages and changes of intraocular dimensions. Eleven patients (10 males, one female, mean age 37.6 years) were admitted to the intensive care unit for pyrexia of unknown origin or hemorrhagic fever following exposure to flood waters. Five male patients (mean age 31.6 years) were identified as suffering from hantavirus infection. In one patient, dot and blot intraretinal hemorrhages were seen in the macula of one eye and streak hemorrhages of the disc in the other. In the remaining four, no fundus abnormalities were seen. Ophthalmologists should be aware of these features. PMID- 17699951 TI - Clinicopathologic correlations in eyes enucleated after uveal melanoma resection with positive surgical margins. AB - We identified three eyes that had undergone enucleation after transscleral resection of uveal melanoma. Two enucleated eyes with microscopically positive margins of resection exhibited no evidence of residual melanoma and these patients were alive without metastasis with at least four years' follow-up. One eye with a transected melanoma contained residual melanoma and that patient died with metastatic melanoma to the liver three years after enucleation. There appear to be at least two general types of positive surgical margins of resection of uveal melanoma: microscopically positive margins and macroscopically positive (transected) margins of resection. PMID- 17699952 TI - Pterygium-induced corneal refractive changes. AB - To study the effect of pterygium on corneal topography, a retrospective analysis of 151 eyes with primary pterygia was done. All cases underwent videokeratography preoperatively and one month postoperatively. Statistical analysis of average corneal power (ACP), corneal astigmatism, surface regularity index (SRI) and surface asymmetry index (SAI) was done before and one month after surgery. Topographic indices were compared statistically for various grades of pterygia. Increase in the grade of pterygia had a significant effect on topographic indices. Corneal astigmatism reduced from 4.40+/-3.64 diopter (D) to 1.55+/-1.63D ( P value < 0.001) following surgery. The regularity of corneal surface improved and asymmetry of the cornea reduced one month after surgery. Pterygium leads to significant changes in corneal refractive status, which increase with the increase in the grade of pterygia and improve following pterygium excision. PMID- 17699953 TI - Drug-induced acute myopia following chlorthalidone treatment. AB - We report a case of sudden loss of vision due to the development of acute myopia after the intake of chlorthalidone used for treating systemic hypertension. Clinically this was associated with ciliary spasm, shallow peripheral choroidal effusion and retinal striae at the macula with increase in macular thickness seen on optical coherence tomography. All these findings were reversed completely once the drug was discontinued. Development of acute myopia should be kept in mind as an adverse effect of a commonly used antihypertensive drug, namely chlorthalidone. PMID- 17699954 TI - Bilateral inverse globe retraction (Duane's) syndrome. AB - A case of true inverse Duane's retraction syndrome, bilateral inverse globe retraction syndrome apparently due to abnormal innervation, is the subject of this clinical report. PMID- 17699955 TI - Ophthalmoscopy in the early diagnosis of opportunistic tuberculosis following renal transplant. AB - Chronic renal failure is a common sequel of renal inflammatory disease or diabetes mellitus. As a result of the immunosuppression that is induced by uremia, hemodialysis or posttransplant immunosuppressive medication, these patients are at a higher risk of opportunistic infections. Various viral, bacterial and mycobacterial infections have been reported. Tuberculosis is a common systemic opportunistic infection but reports of ocular involvement with pulmonary or disseminated tuberculosis are rare. We report the systemic and ocular findings in two postrenal-transplant patients with pulmonary or disseminated tuberculosis in whom detection of choroidal tubercles led to confirmation of the diagnosis in both patients and was the only specific premortem finding in one. Fundoscopy in this group of patients may help in the diagnosis of opportunistic tuberculosis, its earlier treatment and the consequent reduction of morbidity and mortality. PMID- 17699956 TI - Combined aniridic intraocular lens implantation and vitreoretinal surgery. AB - A 45-year-old man presented with post-traumatic aniridia. We describe the combined surgery done to treat both aniridia and epiretinal membrane simultaneously. A combined aniridia intraocular lens and vitreoretinal surgery was done. The case report highlights the advantage of combined surgery in terms of cost factor and surgical time. PMID- 17699957 TI - Intraoperative floppy iris syndrome associated with terazosin. PMID- 17699958 TI - Spontaneous subcutaneous orbital emphysema following forceful nose blowing: treatment options. PMID- 17699959 TI - Intraoperative cracking of the AMO Phacoflex-II Silicone (SI-40NB) intraocular lens while implanting with the Unfolder silver series system using hydroxypropylmethylcellulose. PMID- 17699960 TI - Unilateral hemorrhagic keratouveitis as the initial presentation of Takayasu's arteritis. PMID- 17699961 TI - Ocular defects in children with cerebral palsy. PMID- 17699962 TI - Congenital or acquired Horner's? PMID- 17699963 TI - Bilateral acute keratouveitis in leptospirosis: a new entity. PMID- 17699964 TI - Ophthalmic artery occlusion: a cause of unilateral visual loss following spine surgery. PMID- 17699965 TI - Marin-Amat syndrome: a rare facial synkinesis. PMID- 17699966 TI - Evaluation of impression smears in the diagnosis of fungal keratitis. PMID- 17699967 TI - Obesity amongst affluent adolescent girls. AB - OBJECTIVE: To assess the prevalence and type of obesity in affluent schoolgirls aged 16 and 17 yr. METHODS: A cross-sectional study was conducted in 2002, in 4 randomly selected public schools of Delhi. All girls from randomly chosen classes were included. Weight, height and waist and hip circumferences were measured for all 414 schoolgirls and their socio-demographic profile was recorded. Body mass index [BMI] and waist hip ratio [WHR] were calculated for all the girls. BMI > 30 (i.e.--95th percentile) denotes obesity and BMI > 25 (i.e.--85th percentile) denotes overweight as according to International Obesity Task Force (IOTF) criteria. WC > 80 cm or WHR > 0.85 denote central obesity. RESULTS: Prevalence of obesity and overweight amongst the study subjects was 5.3% and 15.2% respectively (IOTF). Out of the 22 obese girls central obesity was present in 21 girls (95.4%) [WC > 80 cm] and 12 girls (54.5%) [WHR > 0.85]. CONCLUSION: There is significant prevalence of obesity in affluent schoolgirls in Delhi and more than half of them have central obesity. PMID- 17699968 TI - Effect of pregnancy induced hypertension on mothers and their babies. AB - OBJECTIVE: To study the hematological profile of mothers with pregnancy induced hypertension and their infants. METHODS: The effects of maternal hypertension on the hematological profile of neonates were studied in 50 cases comparing the values with that of infants born to normotensive mothers. RESULTS: There was higher number of preterm, Intra-Uterine Growth Restriction (IUGR) and Small for Gestational Age (SGA) babies among the infants of hypertensive mothers. There was a significantly higher incidence of thrombocytopenia and nucleated RBCs seen in these babies. Significant neutropenia was not documented and there was no increased incidence of bleeding when compared to controls. CONCLUSION: Although there were significant changes in the hematological profile of infants born to hypertensive mothers, there was no significant increase in neonatal morbidity as a result of these changes. PMID- 17699969 TI - Extended spectrum beta lactamase producing Klebsiella pneumoniae in neonatal intensive care unit. AB - OBJECTIVE: As infections due to Extended Spectrun beta Lactamase (ESbetaL) producing Klebsiella pneumoniae were increasing in the NICU at Karnataka Institute of Medical Sciences Hospital, Hubli, India, the present study was carried out to identify any environmental sources and the mode of transmission. METHODS: Environmental samples from various sites were collected monthly for a period of six months. RESULTS: ESbetaL producing K. pneumoniae were isolated from all the sites except room air at least on one occasion. ESbetaL producing K. pneumoniae was always isolated from one of the incubators, medicine trolley and sink; while at least one of the health care workers carried it in the hands four out of six times tested. ESbeta L producing K. pneumoniae with similar antibiogram were also isolated from the clinical samples obtained from the neonates. CONCLUSION: Widespread use of third generation cephalosporins as a pre emptive antibiotic for suspected cases of septicaemia may have contributed to emergence of ESbetaL producing K. pneumoniae in addition to other risk factors. ESbetaL producing K. pneumoniae have extensively colonised the environment of the NICU. Transmission of these pathogens to the neonates has probably occurred through the healthcare workers. Efforts to improve hand hygiene among the healthcare workers and mothers are urgently needed. PMID- 17699970 TI - Randomized trial of spacers in asthma. AB - OBJECTIVE: To compare the efficacy of all types of spacers commonly available to children in India. METHODS: 150 children 5-14 yr of age with persistent asthma presenting with peak expiratory flow (PEF) < 70% of personal best were randomized to receive 200 mg salbutamol through one of five spacers: A) 750 ml spacer with valve, B) 165 ml spacer with valve, C) 250 ml spacer without valve, D) 1000 ml indigenously made spacer without valve and E) 500 ml indigenously made spacer without valve. PEF measurement was repeated 15 minutes later. Children> 8 yr old performed spirometry in addition to PEF. Absolute change and percentage improvement of PEF and FEV1 were compared among the groups. RESULTS: Subjects in all groups had comparable baseline demographic characteristics and PEF. All showed significant improvement in PEF and FEV1 over baseline values. The change in PEF and percentage improvement were comparable among all five groups (p=0.780 and p=0.955 respectively). Likewise change in FEV1 and percentage improvement were also comparable. The five groups showed no difference in efficacy, irrespective of severity of baseline airway obstruction. CONCLUSION: The five spacers were equally efficacious for the delivery of bronchodilator in children with moderate persistent asthma presenting with airway obstruction. PMID- 17699971 TI - Interstitial lung disease in infancy. AB - OBJECTIVE: To describe the clinical profile of interstitial lung disease in infancy. METHODS: A retrospective analysis of cases diagnosed to have ILD was carried out in Kanchi Kamakoti CHILDS Trust hospital over a period of 2 yr. Infants aged 1 month to 1 yr of age were included if they had (1) respiratory symptoms (Cough, tachypnea or crepitations) for at least 1 month (2) diffuse infiltrates on chest radiography (3) Hypoxemia as defined by oxygen saturation less than 90% by pulse oximetry and (4) High Resolution Computed Tomography (HRCT) of the chest revealing findings of interstitial infiltrates or ground glass pattern. Their case records were analyzed for clinical data, treatment and follow up details. RESULTS: Of the 9 children, who were diagnosed to have ILD, 5 were boys and 4 were girls. The male: female ratio was 1.25: 1. The median age of onset of symptoms was 5 month. The common clinical features observed were tachypnea associated with chest indrawing (100%), cough (100%), hypoxia (100%), failure to thrive and fever (55%) each. The following radiographic patterns were observed in the chest skiagrams: reticulo-nodular pattern in 6(67%) and ground glass pattern in 3(33%). HRCT showed interstitial infiltrates in 6 (67%) and ground glass pattern in 3(33%). Evidence for cyto megalo virus (CMV) infection was detected in 5(56%), Adenovirus in 1 (11%) and Pneumocystis carinii (PCP) in 1(11%) infant. Open lung biopsy was performed in 2 infants, which detected CMV in 1 and PCP in the other. All children received oxygen therapy and systemic corticosteroids (oral/IV) in addition to specific therapy for infection and 3 of these infants succumbed to respiratory failure. CONCLUSION: CMV Infection was the commonest cause of ILD in infancy in our study. However, the consequences on long term follow up in these infants need to be ascertained. PMID- 17699972 TI - Qualitative evaluation of tuberculin test responses in childhood tuberculosis. AB - OBJECTIVE: To study if different forms of clinical presentation of tuberculosis in children are associated with a different type of tuberculin reaction. METHODS: This cross sectional study, describing Tuberculin skin testing (TST) responses in 268 children (134 cases and 134 controls) less than 12 yr of age was carried out over a period of 18 months at JIPMER, a tertiary care referral hospital in Pondicherry, India. The qualitative and quantitative TST responses in various clinical forms of Tuberculosis were analysed. RESULTS: Koch's and Listeria variants were more common in children with TB Lymphadenitis and Pulmonary TB respectively. 10% of the study children with TB meningitis were tuberculin negative. CONCLUSION: Qualitative TST responses are non-homogeneous among the various clinical types of childhood tuberculosis. They are not a correlate of protective immunity with little or no prognostic significance. PMID- 17699973 TI - PCR and in-situ hybridization for diagnosis of leprosy. AB - OBJECTIVE: To assess the diagnostic value of Polymerase Chain Reaction (PCR) and in situ hybridization. METHODS: This prospective study was carried out in 22 patients RESULTS: The histopathological examination confirmed the clinical diagnosis in 27.2% cases only. In situ hybridization showed a positivity of 42.8% in early (I/BT) and 46.7% in BB/BL group. In situ hybridization thus enhanced the diagnosis by 18.1%. PCR targeting 36 kDa gene of M. leprae was performed on 15 cases. In these 15 cases, histopathology confirmed the diagnosis in 4 cases (26.6%) and PCR confirmed the diagnosis in 10 cases (66.6%), thus enhancing the diagnosis by 40%. CONCLUSION: 36 kDa PCR and in situ hybridization enhance the diagnosis of leprosy when compared to routine histopathology. They are important diagnostic tools for definitive diagnosis in early and doubtful cases of leprosy. PMID- 17699974 TI - Laboratory studies in coagulation disorders. AB - It is important to go in a stepwise approach to diagnose spectrum of bleeding disorders, so that minimum tests are undertaken to make a definitive diagnosis and to avoid unnecessary tests and laboratory load. Depending on the abnormalities observed in the short screening, extended screening tests can be performed followed by specialized diagnostic tests. Bleeding time is prolonged in thrombocytopenia and platelet function disorders (PFD). If platelet count is normal, extended screening tests such as RVVT, PF3 availability and clot retraction can be performed. Russel viper venom directly activates FX, in presence of PF3, is an indicator of common pathway of coagulation. However, if there is deficiency of PF3 as obtained in PFD and APTT PT are normal, its prolongation indicates PFD. These can be tested invitro by performing RVVT with and without inosithin it is highly suggestive of underlying PFD. In such cases, diagnostic tests for PFD such as platelet aggregation with ADP, ADR, AA, Collagen and Ristocetin can be performed followed by electron microscopy if possible. Few of the interesting cases also have been discussed in the text. PMID- 17699975 TI - HPLC studies in hemoglobinopathies. AB - An accurate diagnosis of beta -thalassemia carriers, homozygous patients and identification of different structural hemoglobin variants is important for epidemiological studies as well as for management and prevention of the major hemoglobin disorders. There are many electrophoretic and chromatographic approaches for estimation of HbA2 and Hb F but cation exchange HPLC (CE HPLC)using automated dedicated machines like the Variant Hb testing system have become the method of choice for these investigations. CE-HPLC also helps in the presumptive identification of many abnormal hemoglobin variants and has been useful for both neonatal screening of sickle cell disease as well as second trimester prenatal diagnosis of thalassemia by fetal blood analysis. Other applications of HPLC in hemoglobinopathies include separation of globin chains, measuring the ratio of gamma globin chains (Ggamma/Agamma) and the recently described denaturing HPLC for detecting mutations in both alpha and beta globin genes. PMID- 17699976 TI - Liver function tests and their interpretation. AB - Liver function tests (LFT) are a helpful screening tool, which are an effective modality to detect hepatic dysfunction. Since the liver performs a variety of functions so no single test is sufficient to provide complete estimate of function of liver. Often clinicians are faced with reports that do not tally with the clinical condition of the patient and they face difficulty in interpreting the LFT. An attempt is being made to study and understand the LFT and simplify their interpretation with algorithms. PMID- 17699977 TI - Newer diagnostic tests for bacterial diseases. AB - In diagnosing bacterial infections, the rapid identification of bacteremia at an early stage of the disease is critical for a favorable outcome. Furthermore, it is important that exact information be obtained on the stage of the disease rapidly in order to choose and initiate the appropriate therapy. In recent years many new techniques have been added in the diagnostic tools. During the past decade, there has been unprecedented progress in molecular biology as well as in the application of nucleic acid technology to the study of the epidemiology of human infection. Highly sensitive molecular techniques are found to be capable of detecting minute amounts of specific microbial DNA sequences and their complex genetic variations. Moreover, altered levels of biomarkers such as procalcitonin, C-reactive protein, tumor necrosis factor alpha and several interleukins are also found to be promising to define systemic inflammatory response syndrome as indirect evidences of bacterial infections. Lastly, many rapid culture methods are coming up to achieve faster bacterial diagnosis. In this review we will focus on these three newer methods for the early diagnosis of bacterial infections. These approaches will help to expedite the diagnosis of especially early infections and might be a further step towards the improvement of therapeutic methods. PMID- 17699978 TI - Evaluation of renal tubular acidosis. AB - Renal tubular acidoses (RTA) comprises of a group of disorders characterized by a low capacity for net acid excretion and persistent hyperchloremic, metabolic acidosis. The RTAs are classified into chiefly three types (types 1,2 and 4) based on clinical and laboratory characteristics. Correct diagnosis involves careful evaluation, including exclusion of other entities causing acidosis. A variety of tests are required to be administered in a stepwise fashion for the diagnosis and characterization of RTA. PMID- 17699979 TI - Congenital imperforate submandibular duct in a newborn. AB - Varried conditions such as ranula, epidermal/dermal inclusion cyst, lymphatic cyst, thyroglossal cyst, sialolithiasis, branchial cleft cyst are known to produce swelling in the floor of mouth. Rarely imperforate or duplication anomaly of submandiblar duct may produce cystic lesion in the floor of mouth. We present a case of congenital imperforate submandibular duct with cyst formation in a newborn. We also review the literature regarding management. PMID- 17699980 TI - Exchange transfusion as an alternative therapy for recurrent severe Guillain Barre syndrome. AB - Recurrent Guillain-Barre Syndrome is a rare condition. IVIg and plasmapheresis are costly therapies and may not be affordable. We report a 6-yr-old boy in whom two severe episodes of Guillain-Barre Syndrome were successfully treated by exchange transfusion. Possible explanation for its effectiveness is discussed with respect to available literature. PMID- 17699981 TI - Central line retrieval in a neonate. AB - Peripherally inserted central lines are important for management of newborns in intensive care. 1% of PICC lines can migrate. Here we describe a preterm baby with a migrated PICC line enmeshed on the pulmonary valve. This was retrieved by snare from the pulmonary valve. The technique is described as also the challenges related to doing this in a small baby. PMID- 17699982 TI - Oligohydrosis underestimated side effect with topiramate treatment. PMID- 17699983 TI - Comprehensive approach to neonatal cholestasis. PMID- 17699984 TI - Intrathecal tetanus immunoglobulin. PMID- 17699986 TI - Laparoscopic cholecystectomy accompanied by simultaneous umbilical hernia repair. PMID- 17699985 TI - Sedation, spinal anesthesia and older patients. PMID- 17699987 TI - Thyroid cancer in toxic and non-toxic multinodular goiter. AB - BACKGROUND: Many authors have claimed that hyperthyroidism protects against thyroid cancer and believed that the incidence of malignancy is lower in patients with toxic multinodular goiter (TMG) than in those with non-toxic multinodular goiter. But in recent studies, it was reported that the incidence of malignancy with TMG is not as low as previously thought. AIM: To compare the thyroid cancer incidence in patients with toxic and non-toxic multinodular goiter. SETTINGS AND DESIGN: Histology reports of patients treated surgically with a preoperative diagnosis of toxic and non-toxic multinodular goiter were reviewed to identify the thyroid cancer incidence. Patients having a history of neck irradiation or radioactive iodine therapy were excluded from the study. MATERIALS AND METHODS: We reviewed 294 patients operated between 2001-2005 from toxic and non-toxic multinodular goiter. One hundred and twenty-four of them were toxic and 170 were non-toxic. Hyperthyroidism was diagnosed by elevated tri-iodothyroinine / thyroxine ratios and low thyroid-stimulating hormone with clinical signs and symptoms. All patients were evaluated with ultrasonography and scintigraphy and fine needle aspiration biopsy. STATISTICAL ANALYSIS USED: Significance of the various parameters was calculated by using ANOVA test. RESULTS: The incidence of malignancy was 9% in the toxic and 10.58% in the non-toxic multinodular goiter group. Any significant difference in the incidence of cancer and tumor size between the two groups could not be detected. CONCLUSIONS: The incidence of malignancy in toxic multinodular goiter is not very low as thought earlier and is nearly the same in non-toxic multinodular goiter. PMID- 17699988 TI - Neostigmine does not prolong the duration of analgesia produced by caudal bupivacaine in children undergoing urethroplasty. AB - CONTEXT: Neostigmine extends the duration of analgesia produced by caudal bupivacaine in children. AIMS: To study the effect of different doses of caudal neostigmine on the duration of postoperative analgesia. SETTINGS AND DESIGN: A randomized, double-blind study was conducted in 120 boys aged 1-12 years undergoing urethroplasty under combined general and caudal anesthesia. MATERIALS AND METHODS: Children were administered 1.875 mg/kg bupivacaine alone (Group B) or with 2, 3 or 4 microg/kg of neostigmine (groups BN 2, BN 3 or BN 4 respectively) as caudal drug (0.75 ml/kg). Children with a pain score of 4 or more (OPS and NRS) postoperatively were administered rescue analgesic. Time to first analgesic and the number of analgesic doses administered in the 24h were recorded. STATISTICAL ANALYSIS: Parametric data were analyzed using ANOVA. Kaplan Meier survival curves for the time to first analgesic administration were plotted and compared using log rank analysis. Chi-square test was used to analyze the incidence data. RESULTS: The median [IQR] time to first analgesic in Group B (540 [240-1441] min) was similar to that in Groups BN 2 (450 [240-720]), BN 3 (600 [360-1020]) and BN 4 (990 [420-1441]). Significantly more patients in Groups B (9 [34.6%]) and BN 4 (13 [44.8%]) required no supplemental analgesic for 24h than those in Groups BN 2 and BN 3 (4 [13.8%] and 4 [13.3%]). The number of analgesic doses required in 24h in the four groups was similar. CONCLUSION: Addition of neostigmine to 1.875 mg/kg of caudal bupivacaine did not prolong the analgesia following urethroplasty in children. PMID- 17699989 TI - Anti-Saccharomyces cerevisiae antibody is not useful to differentiate between Crohn's disease and intestinal tuberculosis in India. AB - CONTEXT: Clinical, endoscopic, radiological and histological parameters of intestinal tuberculosis (IT) and Crohn's disease (CD) are so similar that differentiation between these two diseases, which require different treatment, is difficult. Anti- Saccharomyces cerevisiae antibody (ASCA), which is often present in the sera of patients with CD, may be potentially useful to differentiate CD from IT. AIM: To evaluate the role of enzyme-linked immunosorbent assay test for ASCA in serum in differentiating CD from intestinal tuberculosis. SETTINGS AND DESIGN: Prospective case-control study. MATERIALS AND METHODS: Sixteen patients with IT, 16 CD, 36 UC diagnosed using standard parameters and 12 controls (11 healthy subjects and one with colonic carcinoma) were tested for IgG ASCA in serum. STATISTICAL ANALYSIS USED: Categorical variables were analyzed using Chi square test with Yates' correction, as applicable. Continuous variables were analyzed using Mann-Whitney U test. RESULTS: Eight of 16 (50%) patients with IT, 10 of 16 with CD (62%), nine of 35 with UC (26%) and one of 12 controls tested positive for ASCA in serum. Though the frequency of ASCA in serum was comparable among patients with IT and CD (8/16 vs. 10/16, P = ns), IT and UC (8/16 vs. 9/35, P =ns), CD and UC (10/16 vs. 9/35, P =ns), its frequency in CD or IT but not in UC was higher than healthy controls (P Conclusions: Serum ASCA is unlikely to be useful to differentiate between CD and IT in India. PMID- 17699990 TI - Sedation in patients above 60 years of age undergoing urological surgery under spinal anesthesia: comparison of propofol and midazolam infusions. AB - CONTEXT: Propofol and midazolam are commonly used sedatives during regional anesthesia in adults. Smaller doses of these drugs are required in older age due to altered pharmacokinetics and pharmacodynamics. AIMS: To study the sedation, side-effects and the costs involved with smaller doses of propofol and midazolam in patients aged above 60 years during spinal anesthesia. SETTINGS AND DESIGN: A randomized single-blind study was conducted in 60 ASA I-II patients aged > or = 60 years undergoing urological surgery under spinal anesthesia. MATERIALS AND METHODS: Sedation was administered after spinal anesthesia using propofol (bolus 0.4 mg.kg -1; infusion 3 mg/kg/hr) or midazolam (bolus 0.02 mg/kg; infusion 0.06 mg.kg -1.h -1) and titrated to achieve a sedation score of 3 on the modified Observer's Assessment of Alertness/Sedation Scale. Perioperative sedation, hemodynamics and respiratory events were monitored. STATISTICAL ANALYSIS: The analysis for parametric data was done using Student's unpaired t test and the incidence data using Chi-square test. RESULTS: The onset (13.0+/-4.2 vs. 18.8+/ 4.2 min, P < 0.001) and offset (8.9+/-2.8 vs. 12.5+/-3.5 min, P < 0.001) of sedation were faster and the duration of adequate sedation longer (44.7+/-12.5 vs. 29.8+/-12.9% of total infusion time, P < 0.001) with propofol than midazolam. More patients receiving propofol compared to midazolam had hypotension (16 [50%] vs.4 [14.3%], P= 0.003). Airway obstruction occurred frequently in both the groups. Sedation was significantly more expensive with propofol than midazolam (US$ 9.83 +/- 2.80 vs. US$ 0.33 +/- 0.06, P 0.001). CONCLUSIONS: Propofol provided better titration and adequacy of sedation than midazolam in patients above 60 years of age, but caused hypotension. Lighter sedation is recommended in this age group. PMID- 17699991 TI - Laparoscopic cholecystectomy accompanied by simultaneous umbilical hernia repair: a retrospective study. AB - BACKGROUND: Umbilical defects may cause technical problems for general surgeons in patients during laparoscopic cholecystectomy (LC) operations and may increase the incidence of incisional hernia. AIM: The objectives of this study were to determine the optimal repair method for umbilical hernias that already exist or are encountered incidentally and to present data regarding potential problems that may occur during LC. SETTINGS AND DESIGN: Medical records of patients who had received simultaneous umbilical hernia repair (UHR) with LC were investigated retrospectively. MATERIALS AND METHODS: Cholelithiasis was accompanied by umbilical hernia in 64 (8.6%) out of 745 patients who underwent LC and UHR simultaneously in our hospital between 2000 and 2004. STATISTICAL ANALYSIS USED: The Mann-Whitney U, Chi-square, One-Way Anova, Kaplan-Meier survival analysis, the log-rank test and t test were used for statistical analyses. RESULTS: LC was followed by UHR using primary suture (Group 1), Mayo repair (Group 2) and flat mesh-based repair (Group 3) in 32 (50%), 18 (28.1%) and 14 (21.9%) patients, respectively. Mean body mass indexes (BMI) of patients were 26.6 kg/m 2, 29.2 kg/m 2 and 39.9 kg/m 2 in Groups 1, 2 and 3, respectively. Recurrence rates were 9.4%, 5.6% and none (0%) in Groups 1, 2 and 3, respectively. Recurrence was observed in three (7.0%) out of 43(67.2%) patients with BMI > or = 30 kg/m 2 while umbilical hernia recurred in one (4.8%) out of 21 (32.8%) patients with BMI < 30 kg/m 2. Overall morbidity and mortality rates were 14.1% and 0%, respectively. CONCLUSIONS: The outcomes of the UHR with mesh after laparoscopic surgeries appear to be better for either obese or non-obese patients than primary suture techniques in recurrence rates. PMID- 17699993 TI - Central retinal vein occlusion associated with thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome: complete resolution is possible. AB - We aim to describe a case of central retinal vein occlusion associated with this is a case report of a 45-year-old patient who was admitted for management of thrombotic thrombocytopenic purpura (TTP). He developed left central retinal vein occlusion three months later. The retinal vein occlusion resolved gradually as his TTP started to respond to medical treatment but significant macular edema persisted. Focal argon laser treatment resulted in complete resolution of the macular edema. PMID- 17699992 TI - Paraphenylene diamine ingestion: an uncommon cause of acute renal failure. AB - Paraphenylene diamine (PPD) is a major component of hair dyes. The aim is to study the renal manifestations and outcome of PPD consumption. During a four-year period from 2002 to February 2006, 10 persons were admitted to our Institute after consuming a hair dye in a suicidal bid. The percentage of ARF due to PPD at our Institute was 0.95%. Seven patients out of 10 (70%) who consumed PPD developed ARF. All 10 patients, including the patients who had normal renal function had features of rhabdomyolysis. Two patients required ventilator support for respiratory distress and two more required tracheostomy due to upper airway tract edema. One patient has expired after two sessions of dialysis. Renal biopsy in two patients (one, postmortem) showed acute tubular necrosis along with presence of casts in tubules due to myoglobin. PMID- 17699994 TI - Familial hypercholesterolemia with coarctation of aorta. PMID- 17699995 TI - Pseudosarcoma: a diagnostic and treatment dilemma. PMID- 17699996 TI - Calcifying fibrous pseudotumor of peritoneum. PMID- 17699997 TI - Utility of multislice computed tomography in the diagnosis of a right coronary artery fistula to the right atrium. PMID- 17699998 TI - Present status of understanding on the G6PD deficiency and natural selection. AB - G6PD deficiency is a common hemolytic genetic disorder, particularly in the areas endemic to malaria. Individuals are generally asymptomatic and hemolytic anemia occurs when some anti-malarial drugs or other oxidizing chemicals are administered. It has been proposed that G6PD deficiency provides protection against malaria. Maintaining of G6PD deficient alleles at polymorphic proportions is complicated because of the X-linked nature of G6PD deficiency. A comprehensive review of the literature on the hypothesis of malarial protection and the nature of the selection is being presented. Most of the epidemiological, in vitro and in vivo studies report selection for G6PD deficiency. Analysis of the G6PD gene also reveals that G6PD-deficient alleles show some signatures of selection. However, the question of how this polymorphism is being maintained remains unresolved because the selection/fitness coefficients for the different genotypes in the two sexes have not been established. Prevalence of G6PD deficiency in Indian caste and tribal populations and the different variants reported has also been reviewed. PMID- 17699999 TI - The rumination syndrome in adults: a review of the pathophysiology, diagnosis and treatment. AB - Rumination in adults is considered to be the effortless regurgitation of recently ingested food into the mouth, followed by either rechewing and reswallowing or expulsion of the regurgitate. On the basis of the definition of rumination as a unique category of functional gastroduodenal disorders, according to the newly established Rome III classification, a review of the pathophysiology, diagnosis and treatment of the rumination syndrome in adults is presented after systematic and critical approach of all articles that could be retrieved through PubMed using the term "rumination". PMID- 17700000 TI - The oxidative hypothesis of senescence. AB - The oxidative hypothesis of senescence, since its origin in 1956, has garnered significant evidence and growing support among scientists for the notion that free radicals play an important role in ageing, either as "damaging" molecules or as signaling molecules. Age-increasing oxidative injuries induced by free radicals, higher susceptibility to oxidative stress in short-lived organisms, genetic manipulations that alter both oxidative resistance and longevity and the anti-ageing effect of caloric restriction and intermittent fasting are a few examples of accepted scientific facts that support the oxidative theory of senescence. Though not completely understood due to the complex "network" of redox regulatory systems, the implication of oxidative stress in the ageing process is now well documented. Moreover, it is compatible with other current ageing theories (e.g, those implicating the mitochondrial damage/mitochondrial lysosomal axis, stress-induced premature senescence, biological "garbage" accumulation, etc). This review is intended to summarize and critically discuss the redox mechanisms involved during the ageing process: sources of oxidant agents in ageing (mitochondrial -electron transport chain, nitric oxide synthase reaction- and non-mitochondrial- Fenton reaction, microsomal cytochrome P450 enzymes, peroxisomal beta -oxidation and respiratory burst of phagocytic cells), antioxidant changes in ageing (enzymatic- superoxide dismutase, glutathione reductase, glutathion peroxidase, catalase- and non-enzymatic glutathione, ascorbate, urate, bilirubine, melatonin, tocopherols, carotenoids, ubiquinol), alteration of oxidative damage repairing mechanisms and the role of free radicals as signaling molecules in ageing. PMID- 17700001 TI - A case of Marfans syndrome with aminoaciduria. PMID- 17700002 TI - Ultradian pattern bipolar affective disorder and chronic antidepressant use. PMID- 17700003 TI - Vitamin D deficiency rickets with Lamellar ichthyosis. PMID- 17700004 TI - Does penis radiological shadow indicate the side of hip fracture? PMID- 17700005 TI - Worsening of tardive dyskinesia due to clozapine therapy. PMID- 17700012 TI - GPR54 polymorphisms in Chinese girls with central precocious puberty. AB - AIMS: The GPR54 gene has been proved to be important in the process of puberty onset, yet no association study has been performed to evaluate the effect of polymorphisms in the gene on central precocious puberty (CPP). This study was designed to scan for polymorphisms in the GPR54 gene and to investigate the relationships between the genotypes of GPR54 and the disease. METHODS: 272 Chinese Han girls diagnosed to be CPP patients were recruited as the case group and 288 unrelated normal Chinese Han girls as the control group. The whole GPR54 gene was directly sequenced in randomly selected case samples, and the polymorphisms identified were genotyped by ligase detection reaction in both groups. Distributions of the polymorphisms and haplotypes were calculated for statistical evaluation. RESULTS: Totally 6 polymorphisms were found in sequencing, one of which is a nonsynonymous mutation, while genotyping declared that another SNP located in the promoter region was statistically related to the disease (p = 0.037). CONCLUSION: One polymorphism in GPR54 gene might be correlated with some cases of CPP, likely by changes in expression of the receptor, but the moderate p value and the lack of functional data make it hard to confirm the correlation. Further studies on the polymorphisms are needed for the exact mechanism. PMID- 17700013 TI - An evaluation of cyclooxygenase-2 as a prognostic biomarker in mid-gut carcinoid tumours. AB - BACKGROUND/AIMS: Mid-gut carcinoids (MGC) are the most common of the gastrointestinal carcinoid tumours. There is a lack of reliable prognostic indicators for MGC. Cox-2 and Bcl-2 were evaluated as prognostic biomarkers in a cohort of well-characterised non-appendiceal MGC. METHODS: Tissue from the primary MGC tumours of 37 patients was subjected to immunohistochemical detection of Cox-2 and Bcl-2. In 9 cases, tissue from secondary lesions was also examined. The study assessed whether tumour-associated Cox-2 and Bcl-2 expression were related to patient survival. RESULTS: Cox-2 expression was demonstrated in 30/36 primary tumours. When all tumours were analysed, Cox regression analysis indicated a trend towards worsening survival with increasing Cox-2 histoscore (intensity x proportion; hazard ratio 1.53, 95% CI 0.93, 2.52; p = 0.09). Analysis of Cox-2-positive tumours revealed a highly significant association between increasing histoscore and decreased survival (hazard ratio 3.03, 95% CI 1.33, 6.91; p = 0.008). Tumour-associated Bcl-2 expression had no effect on patient survival (hazard ratio 1.12, 95% CI 0.42, 2.99; p = 0.82). There was no significant association between Cox-2 and Bcl-2 expression (chi(2) p = 0.16), or Cox-2 histoscore and Bcl-2 expression (MWU p = 0.59). Analysis of the Cox-2 histoscores of primary tumours and their corresponding secondary lesions revealed a statistically significant trend towards increasing histoscore in the latter (Wilcoxon p = 0.04). CONCLUSIONS: This study has provided evidence that Cox-2 expression in primary MGC may be associated with a more negative prognostic outlook. PMID- 17700014 TI - ACE inhibitor-based, directly observed therapy for hypertension in hemodialysis patients. AB - BACKGROUND: Hypertension is present in nearly 80% of dialysis patients yet adequately controlled in less than half. We designed a stepped antihypertensive regimen using long-acting antihypertensives (trandolapril, atenolol and amlodipine) administered thrice a week (TIW) after each hemodialysis, and compared blood pressure (BP) control, medication cost and pill burden to each patient's prior daily antihypertensive prescriptions. METHODS: Patients were continued on their daily medications, pre-dialysis sitting BP was measured and a 44-hour interdialytic ambulatory BP monitoring (ABPM) was obtained. Then, their medications were stopped and replaced with trandolapril (2 mg TIW). Atenolol and/or amlodipine were also given TIW if the patients had any member of these classes of drugs as part of their daily regimen. Medications were titrated every 2 weeks to achieve a pre-dialysis mean arterial pressure (MAP) of <107 mm Hg. After 2 consecutive weeks with a pre-dialysis MAP of <107 mm Hg, a second 44-hour ABPM was obtained. RESULTS: Ten patients completed the study. A persistent MAP of <107 was maintained in all 10 patients after conversion to TIW dosing. The systolic BP decreased from 122.2 +/- 7.1 to 116.4 +/- 11.6, and the diastolic BP decreased from 75.3 +/- 10.4 to 70.4 +/- 11.4 mm Hg. Pill burden and cost of medications were also significantly less. CONCLUSIONS: This pilot study found that ACE inhibitor-based, directly observed TIW therapy to be effective in hemodialysis patients with mild to moderate hypertension. Larger trials of directly observed therapy for hypertension in dialysis patients are warranted. PMID- 17700015 TI - Continuous venovenous hemofiltration with or without predilution regional citrate anticoagulation: a prospective study. AB - BACKGROUND/AIMS: Continuous venovenous hemofiltration (CVVH) requires anticoagulation to prevent circuit clotting and its use is contraindicated in patients with high bleeding risk. The aim of this study was to compare CVVH with and without regional citrate anticoagulation (RCA) with respect to filter life, azotemic control and cost. METHODS: This was a prospective sequential cohort study. The first cohort of patients with a high bleeding risk and acute renal failure was treated by anticoagulant-free predilution CVVH (n = 31). In the second cohort, CVVH was applied with RCA (n = 20). RESULTS: The median filter life was 41 h (interquartile range 20-62) with RCA and 12 h (8-28) without RCA (p = 0.001). The azotemic control was better in the group with RCA. The hourly cost was comparable between the two groups. CONCLUSION: Regional anticoagulation with citrate-based replacement solution improved filter life compared to anticoagulant free predilution CVVH. This regimen appeared safe, feasible and without metabolic complications or increased costs. PMID- 17700016 TI - Non-cardiovascular mortality, low-density lipoprotein cholesterol and statins: a meta-regression analysis. AB - BACKGROUND: As of today, the effect of statins on non-cardiovascular mortality is still being debated. Single studies have not been able to provide definite answers. We performed a meta-regression analysis on randomized statin trials in order to provide evidence that non-cardiovascular mortality is related to statin treatment and low-density lipoprotein (LDL) cholesterol plasma level. METHODS: We selected 29 randomized controlled trials of statins versus placebo, a total of 90,480 patients, with a follow-up of >12 months. Baseline and follow-up LDL levels and all-cause, cardiovascular and non-cardiovascular mortality were recorded. Weighted linear regression analysis was carried out separately for placebo and treatment groups. RESULTS: LDL level was inversely related to overall mortality (p = 0.0105) and non-cardiovascular mortality (p = 0.0171) in the treatment group. By contrast, in the placebo group only non-cardiovascular mortality was inversely correlated to LDL (p = 0.0032). The regression lines have similar slopes and run almost parallel to each other, with the treatment line lying below the placebo line. To identify the threshold of risk for starting statin therapy, we analysed the relationship between baseline cardiovascular risk and overall mortality in the two groups. Both correlations are highly significant and regression lines intersect at a risk of 0.29% per year. This implies that the effects of statins are favourable when the baseline cardiovascular risk exceeds approximately 3% in 10 years. CONCLUSIONS: A trend of increased non cardiovascular mortality with decreased LDL exists both in placebo and treatment groups. However, at each given LDL cholesterol level, non-cardiovascular mortality is lower in treated patients. Therefore, statin therapy may improve the biological impact of LDL on non-cardiovascular mortality. PMID- 17700017 TI - Aortic elastic properties are related to left ventricular diastolic function in patients with type 1 diabetes mellitus. AB - OBJECTIVE: The aim of the study was to evaluate left ventricular diastolic function and its relation to aortic wall stiffness in patients with type 1 diabetes mellitus without coronary artery disease or hypertension. PATIENTS: Sixty-six patients with type 1 diabetes mellitus were examined by echocardiography and divided into two groups according to the diastolic filling pattern determined by mitral annulus tissue Doppler velocities. Group A patients (n = 21) presented diastolic dysfunction with a peak early diastolic mitral annular velocity (Em)/peak late diastolic mitral annular velocity (Am) ratio <1 whereas in group B patients (n = 45) the Em/Am ratio was >1. Coronary artery disease was excluded based on normal thallium scintigraphy. Aortic stiffness index was calculated from aortic diameters measured by echocardiography, using accepted criteria. RESULTS: Aortic stiffness index differed significantly among the two groups. Significant correlations were found between parameters of left ventricular diastolic function (Em/Am, isovolumic relaxation time, deceleration time) and aortic stiffness index. Multiple stepwise linear regression analysis revealed aortic stiffness index (beta = -0.39, p = 0.001) and isovolumic relaxation time (beta = -0.46, p < 0.001) as the main predictors of Em/Am ratio. CONCLUSIONS: Aortic stiffness is increased in type 1 diabetic patients with left ventricular diastolic dysfunction. This impairment in aortic elastic properties seems to be related to parameters of diastolic function. PMID- 17700018 TI - Fertility, pregnancy and delivery in women after biventricular repair for double outlet right ventricle. AB - OBJECTIVES: To investigate outcome of pregnancy and fertility in women with double outlet right ventricle (DORV). METHODS: Using 2 congenital heart disease registries, 21 female patients with DORV (aged 18-39 years) were retrospectively identified. Detailed recordings of each patient and their completed (>20 weeks gestation) pregnancies were recorded. RESULTS: Overall, 10 patients had 19 pregnancies, including 3 spontaneous miscarriages (16%). During the 16 live birth pregnancies, primarily (serious) noncardiac complications were observed, e.g. premature labor/delivery (n = 7 and n = 3, respectively), small for gestational age (n = 4), preeclampsia (n = 2) and recurrence of congenital heart disease (n = 2). Except for postpartum endocarditis and deterioration of subpulmonary obstruction, only mild cardiac complication pregnancies were recorded. Two women with children reported secondary female infertility. Several menstrual cycle disorders were reported: secondary amenorrhea (n = 4), primary amenorrhea (n = 3) and oligomenorrhea (n = 2). CONCLUSION: Successful pregnancy in women with DORV is possible. Primarily noncardiac complications were observed and only few (minor) cardiac complications. Infertility and menstrual cycle disorders appear to be more prevalent. PMID- 17700019 TI - Age-dependent differences in human brain activity using a face- and location matching task: an FMRI study. AB - PURPOSE: To evaluate the differences of cortical activation patterns in young and elderly healthy subjects for object and spatial visual processing using a face- and location-matching task. MATERIALS AND METHODS: We performed a face- and a location-matching task in 15 young (mean age: 28 +/- 9 years) and 19 elderly (mean age: 71 +/- 6 years) subjects. Each experiment consisted of 7 blocks alternating between activation and control condition. For face matching, the subjects had to indicate whether two displayed faces were identical or different. For location matching, the subjects had to press a button whenever two objects had an identical position. For control condition, we used a perception task with abstract images. Functional imaging was performed on a 1.5-tesla scanner using an EPI sequence. RESULTS: In the face-matching task, the young subjects showed bilateral (right > left) activation in the occipito-temporal pathway (occipital gyrus, inferior and middle temporal gyrus). Predominantly right hemispheric activations were found in the fusiform gyrus, the right dorsolateral prefrontal cortex (inferior and middle frontal gyrus) and the superior parietal gyrus. In the elderly subjects, the activated areas in the right fronto-lateral cortex increased. An additional activated area could be found in the medial frontal gyrus (right > left). In the location-matching task, young subjects presented increased bilateral (right > left) activation in the superior parietal lobe and precuneus compared with face matching. The activations in the occipito-temporal pathway, in the right fronto-lateral cortex and the fusiform gyrus were similar to the activations found in the face-matching task. In the elderly subjects, we detected similar activation patterns compared to the young subjects with additional activations in the medial frontal gyrus. CONCLUSION: Activation patterns for object-based and spatial visual processing were established in the young and elderly healthy subjects. Differences between the elderly and young subjects could be evaluated, especially by using a face-matching task. PMID- 17700020 TI - Reduction of phosphorylated tau during memantine treatment of Alzheimer's disease. AB - BACKGROUND: Memantine is a moderate affinity N-methyl-D-aspartate receptor antagonist approved for treatment of Alzheimer's disease (AD). In AD, tau is abnormally hyperphosphorylated. However, no significant changes of phosphorylated tau levels in CSF are found at follow-up in studies with AD patients. It has been shown in vitro that memantine reverse induced abnormal hyperphosphorylation of tau in hippocampal neurons of rats. METHODS: Eleven AD patients were examined with cognitive tests and interviews of relatives. CSF analyses were performed before starting treatment with memantine as well as after 1 year. RESULTS: A statistically significant reduction of CSF phosphorylated tau at the 1-year follow-up was seen, from median 126 (interquartile range 107-153) to 108 (88-133) ng/l (p = 0.018). No statistically significant differences of total tau or Abeta42 were found. CONCLUSION: The results may reflect effects of memantine on a key pathological feature in AD in line with previous in vitro findings. PMID- 17700021 TI - Neuropsychiatric symptoms are associated with progression from mild cognitive impairment to Alzheimer's disease. AB - BACKGROUND: Neuropsychiatric disturbances are common in mild cognitive impairment (MCI). Depression and apathy may identify a subset of MCI subjects at higher risk of progression to Alzheimer's disease (AD). However, it remains uncertain whether a broader spectrum of psychopathology is associated with progression to AD. METHODS: Fifty-one MCI subjects were assessed for neuropsychiatric symptoms using the Neuropsychiatric Inventory. Subjects were followed for an average of 2 years. Twelve subjects (23.5%) progressed from MCI to possible/probable AD and 39 subjects (76.5%) remained stable or improved. Baseline Neuropsychiatric Inventory indices were compared between groups. RESULTS: Subjects progressing to AD had a significantly higher prevalence of psychopathology than subjects who remained stable or improved (100 vs. 59%). Depression (67 vs. 31%) and apathy (50 vs. 18%) were more common in subjects who were later diagnosed with AD. After statistical adjustments for other baseline demographic variables, these specific symptoms were less robust predictors of progression to AD than the presence of any psychopathology. CONCLUSIONS: These findings suggest that neuropsychiatric symptoms in MCI are a predictor of progression to AD. Depression and apathy appear to be most useful for identifying MCI subjects at highest risk of developing dementia. PMID- 17700022 TI - Physiological falls risk assessment in older people with Alzheimer's disease. AB - BACKGROUND: Falls are common in people with Alzheimer's disease (AD). There is some evidence that deficits in vision, peripheral sensation, strength, reaction time and balance may be partly responsible for this increased risk. AIMS: To determine the feasibility and test-retest reliability of a physiological test battery designed to assess falls risk [the Physiological Profile Assessment (PPA)] in people with AD, and to compare their PPA scores to age- and sex-matched controls. METHODS: Twenty-one community-dwelling people with probable, mild to moderate AD aged 63-91 years, and 21 age- and sex-matched controls underwent the PPA tests and the Mini-Mental State Examination. All tests were then repeated in the AD group to determine test-retest reliability. RESULTS: Most of the PPA tests could be successfully administered to participants with AD. The AD group had a significantly higher overall falls risk score (t(40) = -2.41, p < 0.02), slower hand (t(40) = -4.86, p < 0.01) and foot reaction time (t(40) = -2.26, p < 0.05) and worse coordinated stability (t(40) = -2.40, p < 0.05) than the controls. CONCLUSION: Physiological falls risk assessment is feasible in older people with mild to moderate AD. Older people with AD demonstrate significant impairments in several physiological domains, particularly reaction time, compared to controls. PMID- 17700023 TI - The combined effect of age, education, and stroke on dementia and cognitive impairment no dementia in the elderly. AB - BACKGROUND: This study aims to detect the impact of stroke on the occurrence of dementia and cognitive impairment/no dementia (CIND) in different age, sex, and education groups. METHODS: Persons with dementia (DSM-III-R) or CIND were identified by a two-phase study design among 7,930 persons from the population based Faenza Community Aging Study. RESULTS: Subjects with a history of stroke had increased risk of both dementia [risk ratio (RR) = 3.7; 95% confidence interval (CI) = 3.1-4.4] and CIND (RR = 1.7, 95% CI = 1.4-2.2). These associations were stronger in the younger-old (61-74 years) than in the older-old (75+ years), and among higher-educated (4+ years) than lower-educated (0-3 years of schooling) persons. Dementia and CIND prevalence among stroke subjects was similar to the prevalence detected among subjects 10 years older but without a history of stroke. In stroke subjects, dementia prevalence became higher than CIND prevalence 10 years earlier than in non-stroke subjects. A combined effect for dementia due to a history of stroke, increasing age, and decreasing years of schooling was detected. CONCLUSIONS: Stroke is a strong risk factor for dementia among younger-old and higher-educated subjects; in the presence of a stroke, dementia onset might occur about 10 years earlier, possibly by accelerating the progression from CIND to dementia. PMID- 17700024 TI - Long-term re-infection rate after Helicobacter pylori eradication in Bangladeshi adults. AB - BACKGROUND AND AIM: Bangladesh is a developing country with a very high prevalence of Helicobacter pylori infection, which has been ascribed to overcrowding and poor sanitary conditions. It has generally been accepted that the re-infection rate is higher in countries with a high prevalence of H. pylori infection. Short-term follow-up studies support this assumption but no long-term studies are available to confirm or refute this assertion. The present study was aimed to define the long-term H. pylori re-infection rate (6 years after successful eradication) in duodenal ulcer patients. METHODS: In a previous study, 90 patients were successfully eradicated for H. pylori and followed-up for 24 months. 17/90 were found to be re-infected (18% re-infection rate per year in the first 12 months) [Gastroenterology 2001;792-798]. The remaining 73 patients were targeted for long-term follow-up. 26/73 were lost to follow-up; 6 symptomatic patients were tested H. pylori positive in the period between 24 and 60 months post-eradication. The remaining 41 patients were evaluated 72 months after successful eradication. The evaluation included clinical history taking, a (13)C urea breath test (UBT), and endoscopy. RESULTS: Of the 41 H. pylori-eradicated patients analyzed after 72 months, 16 were H. pylori-positive. If the 6 patients, who were tested positive between 24 and 60 months, are added, the total re infection cases amount to 22 subjects in the period between 24 and 72 months. Therefore, an overall annual re-infection rate 6 years after eradication of 5.02% can be calculated. Six of the 23 symptomatic patients had duodenal ulcer relapse, 5/6 were H. pylori re-infected and one was H. pylori-negative at 72 months post treatment. CONCLUSION: The long-term annual H. pylori re-infection rate in Bangladeshi adults is markedly higher than in Western countries but lower than anticipated. In this study, duodenal ulcer relapse is clearly related to H. pylori re-infection. PMID- 17700025 TI - Everolimus and mycophenolate mofetil sensitize human pancreatic cancer cells to gemcitabine in vitro: a novel adjunct to standard chemotherapy? AB - BACKGROUND/AIMS: Gemcitabine improves survival in pancreatic adenocarcinoma. A variety of drugs have been tested to potentiate gemcitabine treatment for pancreatic cancer cells. Two major immunosuppressive drugs, mycophenolate mofetil (MMF) and everolimus (RAD001) have been shown to exert an anti-tumoral effect, but their ability to sensitize human pancreatic cell lines during gemcitabine treatment remains unclear. We examined the effects of everolimus and MMF on gemcitabine-treated MiaPaCa and Panc-1 cell lines. METHODS: MiaPaCa and Panc-1 human pancreatic tumor cell lines were subjected to everolimus (0.001-1 microg/ml) or MMF (0.1-100 microg/ml) treatment in combination with gemcitabine (1-10(6) nM). Western blot analysis was performed for Panc-1 cells in the presence or absence of TGF-beta1 and different treatments: 0.1-100 muicro/ml MMF and 0.1-100 microg/ml everolimus. The antiproliferative effect of the treatment was assessed by BrdU test. The results were evaluated by two-way analysis of variance followed by post-hoc tests, and nonlinear regression analysis for dose response rates. RESULTS: As expected, standard treatment doses of gemcitabine decreased proliferation dose-dependently. Everolimus increased the actual EC(50) response to gemcitabine treatment (1-10(3) nM) to as much as 83.1 and 82.1% in MiaPaCa and Panc-1 cell lines, respectively. Likewise, concomitant administration with MMF altered the EC(50) of gemcitabine treatment in MiaPaCa cell lines to values between 76.8 and 85.2% for doses of >or=1 microg/ml. Even the minor dose of MMF (0.1 microg/ml) increased the antiproliferative effect of gemcitabine by 43.5% for MiaPaCa and 42.4% for Panc-1 cells. In addition, treatment of Panc-1 cells with MMF (0.1-100 microg/ml) dose-dependently inhibited TGF-beta1-induced collagen expression. CONCLUSION: We found an overadditive antiproliferative effect of both MMF and everolimus in gemcitabine-treated MiaPaCa and Panc-1 cells in vitro, and an additional inhibitory effect of MMF on TGF-beta1-induced collagen type I expression. Interestingly, both the sensitizing effect of pancreatic cancer cells to gemcitabine treatment and the inhibition of collagen type I expression could be achieved by clinically feasible doses of everolimus and MMF. The use of these drugs is promising as a novel adjunct to standard chemotherapy. PMID- 17700026 TI - Attained parental age and children's survival at mid-life ages in a large population. AB - OBJECTIVE: Long-lived persons tend to share a survival advantage with their parents and siblings; however, there is limited information on benefit beyond the extremes of longevity. We evaluated a survival benefit associated with age of parents. METHODS: A population-based study of adults 43-86 years of age in a Midwestern town was performed (n = 4,926). Extensive exam and questionnaire information including current age or age at death of parents of study participants was obtained. RESULTS: While adjusting for age and gender, those with at least one parent surviving to 100 years of age had the best survival (92% survive to age 70 and 54% to age 90). There appeared to be a survival benefit for each decade of maximal parental age. A trend persists when additional risk factors are included in the model. DISCUSSION: There is a survival benefit to offspring of increasing parental age that is apparent as early as 80 years of parental age. PMID- 17700027 TI - Associated factors and health impact of sarcopenia in older chinese men and women: a cross-sectional study. AB - BACKGROUND: Sarcopenia is increasingly being recognized as a feature of frailty in old age and is associated with unfavorable health outcomes in Western populations. Little is known about sarcopenia among Asian elderly populations. OBJECTIVES: The study was undertaken to study the association between sarcopenia and common chronic illnesses, lifestyle factors, psychosocial well-being and physical performance. METHODS: 4,000 community-dwelling Chinese elderly >/=65 years were recruited. Medical illnesses, cigarette smoking, alcohol consumption, physical activity level and psychosocial well-being scores were recorded. Physical performance measured included grip strength, timed chair-stands, stride length and a timed 6-meter walk. Muscle mass was measured using dual-energy X-ray absorptiometry. Relationships between appendicular skeletal muscle mass (ASM/ht(2)) and multiple variables were analyzed using uni- and multivariate analyses. RESULTS: Mean ASM/ht(2) was 7.19 and 6.05 kg/m(2) in men and women respectively. Older age, cigarette smoking, chronic lung disease, atherosclerosis, underweight, and physical inactivity were associated with low adjusted ASM, which was in turn associated with poorer physical well-being in men. After adjustment to age, lower appendicular muscle mass was associated with weaker grip strength in both sexes. In men, lower limb tests (chair-stands, walking speed and step length) were not related to ASM, while in women, lower muscle mass was not associated with poorer lower limb muscle performance. CONCLUSIONS: Sarcopenia in community-dwelling older Chinese men and women was associated with cigarette smoking, chronic illnesses, underweight, physical inactivity, poorer well-being and upper limb physical performance. PMID- 17700028 TI - Immune response induced by a different combined immunization of HBsAg vaccine. AB - AIMS: To evaluate the immune responses induced by different combined immunizations of HBsAg protein vaccine (P), recombinant vaccinia virus vaccine (V) and DNA vaccine (D). METHODS: Balb/c mice were primed by one of the three HBsAg vaccines P, V or D and boosted by the same or another, thus nine immune combinations were constructed. Titers of anti-HBsAg IgG and their sub-isotypes were determined by ELISA. Specific cellular immune responses were determined by calcein-release assay. RESULTS: V could induce the quickest humoral immune response with the geometrical mean titer of 1:10(1.6) at week 2 after prime immunization. The antibody titer primed by P (including PP, PV, PD) mounted up to the highest after the first boost. Antibody induced by PP was more polarized to Th2 while the other groups induced balanced Th1/Th2 response. Among all the groups, VD and DV induced the strongest CTL response. After the fourth boost, the specific lysis ratio was 64 and 71% separately at an E:T ratio of 1:1. CONCLUSIONS: P was the most potent for inducing humoral immune response while the weakest for CTL response. D was a poor immunogen to induce specific antibody production. Among all the immune combinations, DV and VD induced the strongest CTL response in Balb/c mice. PMID- 17700029 TI - Hepatitis C virus F protein up-regulates c-myc and down-regulates p53 in human hepatoma HepG2 cells. AB - OBJECTIVES: Hepatitis C virus (HCV) F protein is a newly identified protein encoded by an alternative open reading frame that +1 overlaps core-encoding gene. It has been found that regulation of c-myc and p53 genes by HCV core protein is involved in liver cancer genesis. We wondered whether HCV F protein exerts similar or adverse regulatory effects on the transcription of c-myc and p53 genes. METHODS: HCV F gene-containing, plasmid pcDNA3.1-F and HCV core gene containing pcDNA3.1-C were constructed and transiently transfected into HepG(2) cells. Real-time quantitative PCR or Western blotting was used to determine the changes at transcription or translation levels of c-myc and p53 genes. RESULTS: The transcription level of c-myc was much higher in pcDNA3.1-F transfected cells than those without plasmid transfected. Whereas the level of p53 transcription in pcDNA3.1-F transfected cells was lower than those in the parental cells. Moreover, levels of c-myc expression were up-regulated and those of p53 expression were down-regulated by HCV F protein. CONCLUSIONS: HCV F protein is of regulatory properties in cellular oncogene c-myc and anti-oncogene p53, which may be implicated in the formation of hepatocellular carcinoma. PMID- 17700031 TI - No evidence for advanced glycation endproducts in cancer. Comment on Sebekova et al: genomic damage and malignancy in end-stage renal failure: do advanced glycation end products contribute? (Kidney Blood Press Res 2007;30:56-66). PMID- 17700030 TI - Evidence of vertical transmission of dengue virus in two endemic localities in the state of Oaxaca, Mexico. AB - BACKGROUND: Dengue virus is spread in tropical areas of the world and is the causative agent of dengue fever and dengue hemorrhagic fever. It is horizontally transmitted to humans by infected Aedes mosquitoes, but it is also able to be vertically or transovarially transmitted to insect progeny. OBJECTIVE: In this work, we analyzed the vertical transmission of dengue virus in Aedes aegypti mosquitoes collected in two endemic localities in the state of Oaxaca, Mexico. METHODS: The collected larvae were grown in the laboratory and transovarial transmission of dengue virus, either in larvae or newly emerged mosquitoes, was investigated using a semi-nested reverse transcription-polymerase chain reaction method. RESULTS: Although the presence of dengue virus in larvae could not be demonstrated, the viral genome was amplified in 4 out of 43 pools of in-cage born mosquitoes: DEN 2, 3 and 4 serotypes were detected in 2 pools from Tuxtepec and two from Juchitan. CONCLUSION: The results presented here strongly suggest that dengue virus can be vertically transmitted in mosquitoes from Oaxaca, but more studies will be necessary to analyze the epidemiological impact of this mechanism of transmission. PMID- 17700033 TI - Gene expression profiles of adult peripheral and cord blood mononuclear cells altered by lipopolysaccharide. AB - BACKGROUND: Neonatal Gram-negative sepsis is often characterized by a fulminant clinical course, compared to adults, resulting in higher morbidity and mortality. Genome-wide gene expression analysis can provide insights into the molecular alterations in sepsis. OBJECTIVES: To evaluate in vitro activation of the neonatal and adult immune system, gene expression patterns were compared in mononuclear cells from cord (CBMNC) and adult peripheral blood (APBMNC). METHODS: To better understand the influence of early molecular signals on the effects of sepsis, Affymetrix gene profiling (8,475 genes) was done on RNA isolated from CBMNC and APBMNC without and after incubation with 100 ng/ml lipopolysaccharide (LPS). RESULTS: We demonstrated significant alterations in the expression of 108 CBMNC and APBMNC genes compared with basal levels, 188 significant changes in CBMNC and 97 in APBMNC, including cytokines, chemokines and immunoregulatory genes. Furthermore, we found 5 genes showing a significant interaction effect between cell type and LPS stimulation, including tumor necrosis factor receptor superfamily, member 6 (FAS), absent in melanoma 2, malic enzyme 1, hemoglobin epsilon 1, and trans-prenyltransferase. CONCLUSIONS: These results provide further support for a marked difference in the pathogenesis of neonatal and adult sepsis and may stimulate additional studies to investigate some of the altered genes as potential new targets for diagnostic tools and therapeutic strategies. PMID- 17700034 TI - Stress-induced downregulation of macrophage phagocytic function is attenuated by exercise training in rats. AB - BACKGROUND/AIMS: Acute restraint stress may induce impaired macrophage phagocytic function. Moderate physical training is associated with beneficial effects on immunological functions. We investigated the effects of moderate physical training on phagocytic function of alveolar macrophages in rats submitted to acute restraint stress. METHODS: Thirty male Wistar rats weighing 210-226 g were randomly divided into 4 groups: nontrained rats (n = 7), nontrained rats submitted to stress (n = 8), trained rats (n = 7) and trained rats submitted to stress (n = 8). Trained rats were submitted to a program of moderate running training over a period of 8 weeks. Rats subjected to restraint stress were kept immobilized in glass cylinders (8 cm in diameter and 24 cm long) during 60 min. Phagocytosis capacity of macrophages was evaluated by either Escherichia coli orzymosan stimuli. RESULTS: Restraint stress induced a decrease in phagocytosis of E. coli and zymosan particle stimulation by macrophages. Neither of these alterations was observed in trained animals submitted to acute restraint stress. CONCLUSIONS: Our data confirm that acute restraint stress is associated with impaired function of macrophages. Moreover, moderate physical training attenuates the effects of acute stress by a mechanism that involves an increase in tolerance of macrophages. PMID- 17700035 TI - Serotonin, 5-HT1A serotonin receptors and proliferation of lymphocytes in major depression patients. AB - Serotonin receptors are present in lymphocytes and might be related to the functionality of these cells in health and in pathology. The serotonergic system is affected in the brain and in peripheral immune cells of depressed patients. The objectives of this work were to evaluate the basal proliferation of lymphocytes, the response to the mitogen concanavalin A, and the role of serotonin 5-HT(1A) receptors. Twenty-nine patients, 19-52 years old, were diagnosed for a major depression episode with the Statistical and Diagnostic Manual-IV of the American Psychiatric Association, approved by ethic committees and gave written consent. The Hamilton depression score was 30.60 +/- 2.65. An apparently healthy group without a family history of psychiatric illness was included. Blood peripheral lymphocytes were isolated by density gradients with Ficoll/Hypaque and differential adhesion to plastic, cultured in 96-well plaques with RPMI-1640 medium with or without 4 mug/ml of concanavalin A. 8-Hydroxy-2-(di n-propylamino)tetralin (5-40 nM) and WAY-100,478 (0.1-100 microM), agonist and antagonist of 5-HT(1A) receptors, serotonin (12.5-100 nM) or imipramine (0.1-100 microM) were also added. Proliferation was evaluated at 72 h with 3-[4,5 dimethythiazol-2-yl]-2,5-diphenyltetrazolium bromide, and the optical density was 570 nm. Basal proliferation was three times higher in depressed patients than in controls, whereas no response to mitogen was obtained, and 5-HT(1A) receptors significantly reacted to the agonist, with increases of about 31-54% at 10, 20 and 40 nM of the specific agonist, indicating initial activation probably in relation to autoimmunity and overreactivity of these receptors in depression. The antagonist reduced proliferation in mitogen-stimulated lymphocytes, 50% in controls and 70% in depressed patients, with a differential concentration dependency; probably, these receptors are more sensitive in depression due to increased 5-HT(1A) receptor transduction. The antagonist also reduced the stimulation produced by the 5-HT(1A) agonist. Imipramine caused biphasic effects according to concentrations, showing a possible dual role for serotonin, although all values were significantly higher in depressed subjects. The described alterations might be of relevance in the pathophysiology of depression. PMID- 17700036 TI - Acute morphine administration reduces white blood cells' capability to induce innate resistance against HSV-1 infection in BALB/c mice. AB - OBJECTIVE: It has been reported that acute morphine administration modulates innate immune response to herpes simplex virus 1 (HSV-1) infection. In this study, the effect of acute morphine on innate resistance and its probable mechanisms in increasing the mortality rate during HSV-1 infection were investigated. METHODS: Mice were infected with HSV-1 24 h prior to different doses of morphine or saline administration and the mortality rate was recorded. Spleen cells were obtained from morphine- or saline-treated mice, then natural killer (NK) cell activity and interferon-gamma (IFN-gamma) production were evaluated. The effect of morphine on white blood cells' capacity to induce protection against HSV-1 infection was evaluated by adoptive transfer of spleen cells to cyclophosphamide-treated mice that were previously infected with HSV-1. Furthermore, in a separate experiment, a different group of mice received corticosterone 24 h after HSV-1 infection. RESULTS: Mortality rate in high-dose acute morphine-treated mice increased significantly compared to saline-treated mice (p = 0.035). NK cell cytotoxicity and IFN-gamma mRNA levels also showed a significant reduction compared to those of control groups (p < 0.001 and p = 0.014, respectively). Corticosterone administration reduces innate resistance against HSV-1 infection compared to saline-treated mice (p = 0.044). Furthermore, adoptive transfer of normal but not morphine-treated spleen cells induces resistance against HSV infection in cyclophosphamide-injected mice (p = 0.009). CONCLUSIONS: The current study shows that acute morphine administration reduces white blood cells' capability to induce protection against HSV-1 infection via suppression of IFN-gamma production and NK cells activity. This may be due to the increase in corticosteroids. Further studies are needed to test the effect of acute morphine on other immune cells. PMID- 17700038 TI - Nitric oxide and TNFalpha effects in experimental autoimmune encephalomyelitis demyelination. AB - The involvement of inducible nitric oxide synthase (iNOS), which plays various roles in the progression of autoimmune diseases, was studied in iNOS knockout (KO) mice and wild-type (WT) controls with respect to experimental autoimmune encephalomyelitis (EAE). The iNOS (KO) mice presented a less severe form of the disease than the WT control mice. Although the levels of TNFalpha decreased in the periphery in both groups, an increase in the number of TNFalpha-positive cells was detected in the central nervous system during the acute phase of EAE in the WT mice, but not in the KO mice. These findings suggest that NO and TNFalpha contribute to the pathogenesis of acute EAE. PMID- 17700037 TI - Use of electroacupuncture at ST36 to inhibit anaphylactic and inflammatory reaction in mice. AB - OBJECTIVE: Electroacupuncture (EA) has been used to treat myalgia, allergy and gastroenteropathy in Korea. To determine whether EA can treat anaphylactic and inflammatory reactions, the effect of EA was investigated in a murine model. METHODS: EA stimulation of the ST36 acupoint was performed for 10 min. Using a passive cutaneous anaphylaxis (PCA) model, the antianaphylactic effects of EA were examined. Interleukin-6 and tumor necrosis factor-alpha were measured using the ELISA method. The level of nuclear factor (NF)-kappaB/RelA protein and NF kappaB DNA-binding activity was determined using the Western blot analysis and the transcription factor enzyme-linked immunoassay method. RESULTS: EA inhibits PCA and beta-hexosaminidase release, IL-6 secretion on the PCA, and in addition, EA reduces NF-kappaB DNA-binding activity. CONCLUSION: These results indicate that EA may possess antianaphylactic and antiinflammatory properties. PMID- 17700040 TI - Differential expression of extracellular matrix and adhesion molecule genes in the brain of juvenile versus adult mice in responses to intracerebroventricular administration of IL-1. AB - OBJECTIVE: Intracerebroventricular (ICV) injection of interleukin-1 (IL-1) stimulates the recruitment of leukocytes into the central nervous system at different time points in juvenile versus adult mice. Our results showed that leukocytes entered brain parenchyma at 8 and 16 h after injection in juvenile and adult mice, respectively. This study compares the differential gene expression patterns of extracellular matrix and adhesion molecules in the brain of juvenile and adult mice. METHODS: We analyzed these gene expressions in mice brains by microarray and real-time PCR at 2 and 8 h after ICV IL-1. RESULTS: After ICV IL 1, the following genes were significantly upregulated in both juvenile and adult mice: LAMbeta1-1, MMP17, TGFbeta, THBS3 and VCAM1 were upregulated at 2 h after injection; LAMbeta1-1 and TGFbeta were upregulated at 8 h. Additional changes were found in adult mice only: CNTN1, ECM1, ICAM1 and LAMalpha4 were upregulated at 2 h after injection; COL4alpha1, MMP3 and VCAM1 were upregulated at 8 h; TIMP4 was downregulated. Comparing juvenile and adult mice, real-time PCR analysis showed that there was more induction of TGFbeta at 8 h and a stronger downregulation of TIMP4 at 2 h after injection in juvenile mice. Higher expression of MMP17 was found in juvenile mice, compared to adult mice, at both 2 and 8 h after injection. CONCLUSIONS: These data show distinct expression patterns of molecules related to the extracellular matrix and adhesion molecules in juvenile versus adult mice, and suggest that increased expression of MMP17 and TGFbeta and decreased expression of TIMP4 may contribute to the accelerated recruitment of leukocytes into the central nervous system in juvenile animals. PMID- 17700039 TI - Mechanisms of interferon-beta-induced survival in fetal and neonatal primary astrocytes. AB - BACKGROUND: We have previously shown that interferon-beta (IFN-beta) is a potent promoter of astrocyte survival. Although the mechanism(s) by which IFN-beta promotes astrocyte survival have not been completely elucidated, it has been shown that IFN-beta directly stimulates survival signaling pathways. In the present report, we took advantage of the differences in the susceptibility of fetal and neonatal astrocytes to apoptosis to further investigate the mechanism(s) underlying the antiapoptotic effect of IFN-beta. METHODS: Primary monolayer cultures of cortical astrocytes were established from neonatal (3- to 6 day-old) or fetal (embryonic days: E15 or E17) Sprague-Dawley rat cerebral cortices. Apoptotic cell death was determined by fluorescent-microscopic analysis of staining patterns of cell DNA with Hoechst 33258, and determination of annexin V binding.Akt phosphorylation was detected by Western blottingusing a commercial kit that allows specific recognition of both non-phosphorylated and serine phosphorylated Akt. RESULTS: In the present work, we have found that primary astrocytes obtained from neonatal rats are resistant to apoptosis induced by serum starvation, though cell death may be induced by combining serum starvation with sodium butyrate treatment. This effect is counteracted by IFN-beta treatment through a mechanism that involves phosphatidylinositol 3-kinase stimulation. CONCLUSIONS: IFN-beta can be considered as a neuroprotective agent and, therefore, part of its beneficial effects in multiple sclerosis (MS) treatment may depend on its capacity to protect astrocytes against the apoptotic cell death that occurs in the course of the MS lesions. PMID- 17700042 TI - Psychotropic profile of S 17092, a prolyl endopeptidase inhibitor, using quantitative EEG in young healthy volunteers. AB - The central activity of S 17092, a prolyl endopeptidase (PEP) inhibitor, was investigated by quantitative electroencephalography (qEEG) in 48 young healthy men participating in a double-blind, randomized, placebo-controlled, cross-over study. S 17092 (100, 200, 400 or 600 mg) and placebo were administered once daily for 10 days in a rising multiple-dose scheme. EEG recordings were performed before and repeatedly from 0.5 to 24 h after dose on day 1 and day 10. PEP activity in plasma was also measured for the same periods. S 17092 appeared as a potent inhibitor of PEP activity at all doses, after both single and repeated administrations. EEG changes after acute doses were slight and of short duration, mainly characterized by increased relative alpha 1 power, suggesting a vigilance promoting EEG profile. After repeated doses and more strikingly after a superimposed dose, increases in relative alpha 1 power were still present with additional increase in relative delta power and decreases in absolute fast alpha, fast beta, theta powers and total power at all doses. These EEG findings suggest that S 17092 might possess some mood-stabilizing potential in addition to its cognition-enhancing properties. PMID- 17700041 TI - Elevated inflammation markers in pheochromocytoma compared to other forms of hypertension. AB - OBJECTIVE: To investigate the effect of long-term catecholamine excess in pheochromocytoma on leukocyte and platelet count and on proteins of acute-phase response. METHODS: Fifteen subjects with pheochromocytoma, 16 with primary aldosteronism, 18 with essential hypertension and 17 healthy controls were studied. Sixteen subjects with pheochromocytoma were investigated after tumor removal. Leukocyte, neutrophil and platelet count, as well as C-reactive protein were measured in all subjects, while fibrinogen, alpha(1)-antitrypsin, alpha(2) macroglobulin, orosomucoid, transferrin and prealbumin were only measured in subjects with pheochromocytoma, primary aldosteronism and essential hypertension. RESULTS: Subjects with pheochromocytoma showed significantly higher leukocyte [7.5 +/- 0.9 10(9)/l, p < 0.001 vs. primary aldosteronism (5.4 +/- 0.9 10(9)/l) and healthy controls (5 +/- 0.9 10(9)/l), p = 0.04 vs. essential hypertension (6.3 +/- 1.6 10(9)/l)], neutrophil (p < 0.001 vs. primary aldosteronism and healthy subjects) and platelet counts (p < 0.001 vs. primary aldosteronism; p = 0.01 vs. essential hypertension) compared to the other groups of subjects. Similar results were obtained for positive proteins of acute-phase response in subjects with pheochromocytoma [C-reactive protein: 0.62 +/- 0.52 mg/dl, p < 0.001 vs. healthy subjects (0.08 +/- 0.08 mg/dl), p = 0.001 vs. primary aldosteronism (0.17 +/- 0.19 mg/dl), p = 0.04 vs. essential hypertension (0.31 +/ 0.26 mg/dl); fibrinogen: p = 0.02 vs. primary aldosteronism; orosomucoid: p = 0.005 vs. primary aldosteronism; alpha(2)-macroglobulin: p = 0.009 vs. primary aldosteronism]. No significant differences were found in plasma levels of alpha(1)-antitrypsin, transferrin and prealbumin. Tumor removal led to a significant decrease in leukocyte (p = 0.004), neutrophil (p = 0.007) and platelet count (p = 0.003) and also to a significant decrease in acute-phase proteins (C-reactive protein: p = 0.03, fibrinogen: p = 0.008, alpha(1) antitrypsin: p = 0.003, orosomucoid: p = 0.04). CONCLUSIONS: Chronic catecholamine excess in pheochromocytoma is accompanied by an increase in inflammation markers which was reversed by the tumor removal. PMID- 17700043 TI - Effects of a mandibular repositioning appliance on sleep structure, morning behavior and clinical symptomatology in patients with snoring and sleep disordered breathing. AB - BACKGROUND: Mandibular repositioning appliances (MRAs) have become an established treatment for snoring and sleep-disordered breathing - though most studies only focused on the evaluation of respiratory variables. METHODS: This single-blind, placebo-controlled case-series study investigated the effects of an individually adjustable MRA on psychopathology, macro-/microstructure of sleep, periodic leg movements, morning performance, mood/affect and psychophysiology. Fifty patients (37 males) aged 59.7 +/- 10.3 years, suffering from primary snoring (7), mild (22), moderate (15) and severe apnea (6), spent 4 nights in the sleep laboratory (adaptation, placebo, drug and MRA night). The drug night is not subject of the present paper. RESULTS: Confirmatory statistics showed an improvement of the snoring index by 72%. Descriptively, the apnea index and the apnea-hypopnea index normalized. A clinical improvement was seen in the Pittsburgh Sleep Quality Index, the Zung Anxiety/Depression Scales and the Epworth Sleepiness Scale. The restless legs syndrome also improved. Polysomnographically, sleep stages REM and 4 as well as REM latency increased, stage 3, movement time, stage shifts and periodic leg movements decreased, as did all arousal measures. Subjectively, morning well-being, drive, affectivity and wakefulness improved. Objectively, attention, motor and reaction time performance, critical flicker frequency as well as muscular strength increased, diastolic blood pressure and the pulse rate decreased. CONCLUSION: Apart from its good therapeutic effects on snoring and respiratory variables (snoring showed complete or partial response in 68%, the apnea-hypopnea index in 67% of the apnea patients), the MRA also improved psychopathology, objective and subjective sleep and awakening quality. PMID- 17700044 TI - Are we able to differentiate between true mental disorders and homeostatic reactions to adverse life events? PMID- 17700045 TI - The road to recovery from depression--don't drive today with yesterday's map. AB - The issue of recovery is getting increasing attention in depression research, particularly after the publication of the STAR*D results. The paper analyzes some issues which may hinder effective treatment of major depressive disorders: the inadequacies of a cross-sectional DSM assessment without clinical differentiation of the extent, development and seriousness of the disturbances (staging); over emphasis on and prolongation of drug treatment, without paying attention to problems related to tolerance; neglect of the active role of the patient in achieving recovery, with the integration of psychotherapeutic strategies in a sequential model. If we are able to remove the conceptual obstacles which obstruct our view of depression and silence the sound of propaganda, we may then become aware of a different scenario in mood disorders and be able to develop therapeutic strategies of enduring quality. PMID- 17700046 TI - Antidepressant dose reduction and the risk of relapse in major depressive disorder. AB - BACKGROUND: Whether the dose of antidepressants can be reduced following clinical improvement without subsequently increasing the likelihood of depressive relapse has not been established. Thus, the aim of this work was to compare relapse rates among patients with major depressive disorder (MDD) randomized to either continue receiving the full versus a reduced dose of antidepressants following partial or full improvement of symptoms. METHODS: Five double-blind, randomized clinical trials involving 1,009 patients with MDD randomized to either continue receiving the full versus a reduced dose of antidepressants following partial or full improvement of symptoms were pooled using a random-effect meta-analysis model. RESULTS: Patients randomized to continue treatment with lower doses of antidepressants were more likely to experience a depressive relapse than patients who continued treatment with the full dose (risk ratio 1.62, 95% confidence interval: 1.52-2.80, p = 0.001). Pooled relapse rates were 25.3 and 15.1% for the two treatment groups. CONCLUSIONS: Decreasing the antidepressant dose following partial or full symptom improvement is associated with an increased risk of relapse in MDD. PMID- 17700047 TI - The treatment of psychotic major depression: is there a role for adjunctive psychotherapy? AB - BACKGROUND: Psychotic depression is a relatively prevalent mood disorder associated with greater symptom severity, a poorer course of illness and higher levels of functional impairment compared with nonpsychotic depression. Separate lines of investigation suggest that various forms of cognitive-behavioral therapy are efficacious for treating severe forms of nonpsychotic depression as well as primary psychotic disorders. However, there currently are no empirically supported psychotherapies specifically designed for treating psychotic depression. METHOD: We review the efficacy of current somatic treatments for the disorder and discuss the limited data to date on potentially useful psychotherapeutic approaches. In particular, we describe the clinical improvement observed in a subgroup of hospitalized patients with psychotic depression treated with Acceptance and Commitment Therapy as part of a larger clinical trial. RESULTS: Pilot results demonstrated that Acceptance and Commitment Therapy was associated with clinically significant reductions in acute symptom severity and impairment compared with treatment as usual. CONCLUSION: The findings suggest that patients with psychotic depression can benefit from psychotherapy. Clinical and research recommendations in this area are presented. PMID- 17700048 TI - Sudden glory revisited: cognitive contents of hypomania. AB - INTRODUCTION: Cognitive aspects of hypomania have been historically neglected. Although they do not have an etiological role, they may be essential to understand factors underlying the hypomanic ascent in bipolar disorders and constitute key modulators of the course of illness. METHODS: We have performed a critical review of the existing literature on the role of cognition during hypomania, considering outputs coming from very different fields of knowledge. RESULTS: There is a nuclear cognitive change occurring in most hypomanic phases that we have defined as 'anastrophic' thinking. This key cognitive procedure has several implications--going from social sciences and philosophy to basic sciences. CONCLUSIONS: Hypomania has received certain attention from cognitive theorists. Unfortunately, this attention has not been translated into a cognitive model that is as robust as the one seen in depression. The inclusion of certain psychological aspects in models of hypomania should give rise, as occurred with depression, to an increased emphasis on psychoeducation and cognitive modification of behavioral patterns in the management of this disorder with combined psychological and pharmacological tools. PMID- 17700049 TI - Combination treatment for acute depression is superior only when psychotherapy is added to medication. AB - BACKGROUND: Although several forms of effective therapy exist for outpatients suffering from major depressive disorder, many patients do not profit from treatment. Combining psychotherapy and medication may be an effective strategy. However, earlier studies have rarely found a clear advantage for the combination. Where an advantage was found, a possible placebo effect of adding 2 types of treatment could not be ruled out as cause for the superior effect of the combination. METHODS: A total of 353 patients were screened, of whom 193 were randomized over 4 conditions: nefazodone plus clinical management, interpersonal psychotherapy (IPT), the combination of the two or the combination of IPT and pill-placebo. All patients suffered from major depressive disorder and had a score of at least 14 on the 17-item Hamilton Rating Scale (HAMD). The patients were treated for 12-16 weeks. At baseline, at 6 weeks and on completion of treatment, ratings were performed by independent raters. The primary outcome measure was the HAMD, and the Montgomery-Asberg Depression Rating Scale (MADRS) the secondary outcome measure. RESULTS: Of the 193 patients included, 138 completed the trial. All treatments were effective. Using a random regression model, no differences between treatments were found on the HAMD. On the MADRS, however, the combination of medication with psychotherapy was more effective in reducing depressive symptoms compared to medication alone, but not to psychotherapy alone or IPT with pill-placebo. CONCLUSIONS: The results of this study yield support for the use of combining medication with psychotherapy instead of using medication only in the treatment of depressed outpatients. Combination treatment does not have an advantage over psychotherapy alone in the present study. PMID- 17700050 TI - Combined brief dynamic therapy and pharmacotherapy in the treatment of major depressive disorder: a pilot study. AB - BACKGROUND: The relative efficacy of supplemental psychotherapy in the treatment of depression is still a matter of debate. Moreover, the superiority of brief dynamic therapy (BDT) over supportive psychotherapies is not well established. The aim of this study is to compare the efficacy of BDT added to medication with that of brief supportive psychotherapy (BSP) added to medication in the treatment of major depressive disorder. METHOD: A 12-month randomized clinical trial compared BDT (n = 18) with BSP (n = 17) combined with antidepressants in outpatients with major depressive disorder. Both psychotherapies were added during the first 6 months of the trial; all patients continued to be treated with only pharmacotherapy (paroxetine or citalopram) in the following 6-month continuation phase. Efficacy was assessed using the 17-item Hamilton Rating Scale for Depression (HAM-D), the Hamilton Rating Scale for Anxiety and the Clinical Global Impression (CGI). The data analysis was conducted on two samples: the per protocol (PP) sample and the observed-cases (OC) sample. RESULTS: Thirty-two patients completed the study. Although at the end of the combined therapies (T2) no differences emerged between the two treatment approaches, the group of patients treated with BDT showed a further clinical improvement at the end of the study (T3): a significant reduction in symptomatology emerged on the HAM-D (PP sample: F = 75.154, p = 0.03; OC sample: F = 67.149, p = 0.022) and on the CGI total scores (PP sample: F = 78.527, p = 0.016; OC sample: F = 74.104, p = 0.007). The difference in remission rates on the HAM-D (75 vs. 12.5% at T3) is statistically significant favoring BDT. CONCLUSIONS: BDT combined with antidepressants is preferable to supportive psychotherapy combined with medication in the treatment of outpatients with major depression. PMID- 17700051 TI - Psychiatrist attitudes toward self-treatment of their own depression. AB - BACKGROUND: Self-treatment and treatments of friends or relatives is a controversial issue, tolerated by some and discouraged by others, including professionals. The author studied the attitudes toward self-treatment of depression among psychiatrists in Michigan. METHOD: A questionnaire asking whether the psychiatrist would or did self-treat for depression was mailed to 830 members of the Michigan Psychiatric Society. RESULTS: The response rate was 68.3% (567 psychiatrists). Almost 43% of responders would consider self-medication or would self-medicate if afflicted with mild/moderate depression. Seven percent would self-medicate or consider self-medication for severe depression or if suicidal ideation became a component of one's depression. In the past, 15.7% responders treated themselves for depression. CONCLUSION: These results suggest that a considerable number of psychiatrists would treat themselves for depression, possibly because of fear of stigma or fear of a permanent record, or other reasons. PMID- 17700052 TI - The combination of buspirone and bupropion in the treatment of depression. PMID- 17700053 TI - Long-term alexithymic features indicate poor recovery from depression and psychopathology. A six-year follow-up. PMID- 17700054 TI - Alexithymic depression: evidence for a depression subtype? PMID- 17700055 TI - Brain MRI findings in infants with primary congenital glaucoma. AB - BACKGROUND: Congenital glaucoma appears in the first months of life, eventually at birth. Isolated congenital glaucoma is characterized by minor malformations of the irido-corneal angle of the anterior chamber of the eye. Clinical manifestations include tearing, photophobia and enlargement of the globe appearing in the first months of life. Imaging technology such as optical coherence tomography and measurement of central corneal thickness may play an important role in the assessment of children with suspected or known glaucoma. However, no MRI findings of the CNS in patients with primary congenital glaucoma (PCG) were reported in the literature. The purpose of this study was to investigate MRI findings of the brain in infants with PCG. METHODS: We reviewed the radiological, histopathological and clinical characteristics of infants with primary congenital glaucoma. The records of 17 patients with PCG were reviewed and the MRIs of the brain and associated manifestations were analyzed. RESULTS: Three patients with PCG had abnormal MRI findings suggesting agenesis of the corpus callosum. Two infants had delayed myelinization of the brain. DISCUSSION: Significant abnormal optic nerve excavation and increased corneal diameters in 2 patients with delayed myelinization may suggest that intraocular pressure can be more striking and more severe, revealing a close relationship with PCG and abnormal myelinization in the white matter. Studies with more patients are needed to confirm these results. PMID- 17700056 TI - Overexpression of autophagy-related genes inhibits yeast filamentous growth. AB - Under conditions of nitrogen stress, the budding yeast S. cerevisiae initiates a cellular response involving the activation of autophagy, an intracellular catabolic process for the degradation and recycling of proteins and organelles. In certain strains of yeast, nitrogen stress also drives a striking developmental transition to a filamentous form of growth, in which cells remain physically connected after cytokinesis. We recently identified an interrelationship between these processes, with the inhibition of autophagy resulting in exaggerated filamentous growth. Our results suggest a model wherein autophagy mitigates nutrient stress, and filamentous growth is responsive to the degree of this stress. Here, we extended these studies to encompass a phenotypic analysis of filamentous growth upon overexpression of autophagy-related (ATG) genes. Specifically, overexpression of ATG1, ATG3, ATG7, ATG17, ATG19, ATG23, ATG24 and ATG29 inhibited filamentous growth. From our understanding of autophagy in yeast, overexpression of these genes does not markedly affect the activity of the pathway; thus, we do not expect that this filamentous growth phenotype is due strictly to diminished nitrogen stress in ATG overexpression mutants. Rather, these results highlight an additional undefined regulatory mechanism linking autophagy and filamentous growth, possibly independent of the upstream nitrogen sensing machinery feeding into both processes. PMID- 17700057 TI - Coronavirus replication does not require the autophagy gene ATG5. AB - Macroautophagy (herein autophagy) is a cellular process, requiring ATG5, by which cells deliver double membrane-bound packets containing cytoplasm or cytoplasmic organelles to the lysosome. This process has been reported in some cases to be antiviral, while in other cases it has been reported to be required for efficient viral replication or release. A role for autophagy in RNA virus replication has been an attractive hypothesis because of the association of RNA virus replication with complex membrane rearrangements in the cytoplasm that can generate opposed double membranes. In this study we demonstrate that ATG5 is not required for murine hepatitis virus (MHV) replication n either bone marrow derived macrophages (BMMphi) lacking ATG5 by virtue of Crerecombinase ediated gene deletion or primary low passage murine ATG5(-/-) embryonic ibroblasts (pMEFs). We conclude that neither ATG5 nor an intact autophagic pathway re required for MHV replication or release. PMID- 17700058 TI - Superiority of extended neoadjuvant chemotherapy with gemcitabine in pancreatic cancer: a comparative analysis in a clinically adapted orthotopic xenotransplantation model in SCID beige mice. AB - BACKGROUND: Intensive efforts are being made to develop new approaches for adjuvant or neoadjuvant treatment in pancreas carcinoma. Recently, we established an animal model simulating an adjuvant therapeutic treatment setting. In order to additionally mimic a neoadjuvant treatment regime, we further developed the preclinical testing system. METHODS: Subtotal pancreatectomy was performed in mice after orthotopic inoculation of human pancreatic cancer cells (PancTu1). Four different settings were investigated: control without chemotherapy, adjuvant, neoadjuvant and extended neoadjuvant treatment protocols employing gemcitabine. All animals were autopsied 28 days after tumor resection. RESULTS: 28 of 32 animals survived the treatment setting. The largest pancreatic tumor masses were seen in animals without any chemotherapy, and the different chemotherapy protocols resulted in a stepwise reduction of the tumor mass. The mean weight of locally recurrent tumors was 553.1 +/- 133.2 mg (control) and 44 +/- 21.8 mg (adjuvant treatment group). Animals in the neoadjuvant treatment group developed larger tumor masses (215 +/- 191.3 mg) but fewer organ metastases. An extended neoadjuvant treatment setting proved to be most effective, resulting in the smallest tumor masses (25.6 +/- 8.8 mg) and the fewest organ metastases. CONCLUSION: Murine orthotopic tumor resection is an excellent simulation of the clinical situation and therefore provides a relevant option for preclinical comparative testing of new therapeutic strategies. To our knowledge, this is the first model described, in which all different therapeutic regimes for pancreatic carcinoma were systematically compared with each other in a standardized manner. The extended neoadjuvant regime proved to be superior. PMID- 17700059 TI - Inhibiting survivin expression enhances TRAIL-induced tumoricidal activity in human hepatocellular carcinoma via cell cycle arrest. AB - Human Hepatocellular carcinoma (HCC) cell types exhibit a major resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death, and the key determinants of mechanisms accounting for TRAIL susceptibility, still remain controversial. Our previous studies showed that overexpression of survivin reduced sensitivity of HCC cells to TRAIL. The aim of this study is to investigate how tumor cells escape TRAIL-mediated surveillance through survivin expression and how to reverse the resistance of TRAIL-inducing apoptosis. Seven tumor cell lines were treated with or without TRAIL protein and antisense oligodeoxynucleotides (ODNs) against survivin in culture. HepG(2) and SMMC7721 cells were treated with mimosine, thymidine or nocodazole to synchronize their cell cycle phases and then used to test their sensitivity to TRAIL. In vivo effects of TRAIL plasmid alone or in combination with survivin antisense ODNs on tumor growth were evaluated in a nude mouse hepatoma model of HepG(2) cell grafts. Varied levels of survivin mRNA in various cell lines were evaluated and negatively correlated to TRAIL-induced apoptosis. Hepatoma HepG(2) and SMMC7721 cells in G (1) or S phase are more sensitive to TRAIL than those in G(2) phase. Treatment with survivin antisense ODNscaused S phase arrest and significantly enhanced TRAIL-induced apoptosis. TRAIL protein caused G(2)/M arrest and resulted in an increase of survivin in HepG(2) cells. Combined TRAIL plasmid and survivin antisense ODNs significantly supressed the growth of tumor xenografts as compared to TRAIL plamid or antisense ODNs alone during four weeks of observation. The findings indicate that survivin may play a role in tumor cell resistance to TRAIL induced apoptosis, at least in part, through cell cycle regulation. Manipulation of survivin expression levels may sensitizes tumor cells to TRAIL-induced apoptosis. PMID- 17700060 TI - Indoleamine 2,3-dioxygenase (IDO) expression in lung cancer. AB - BACKGROUND: The expression of indoleamine 2,3-dioxygenase (IDO) by tumor cells has been considered as a major tumor immune escape mechanism. The aim of this study was to investigate the expression of IDO in lung cancer cell lines as well as in surgically resected lung cancer specimens comparing the latter, to the expression in autologous samples from the corresponding non malignant lung tissue. Correlations of IDO expression with clinicopathological parameters of the disease were performed. METHODS: Nine human lung cancer cell lines and 28 patients with various types of primary lung cancer were enrolled in the study. IDO expression was determined by quantitative real-time PCR using a sample of lung hamartoma as reference. RESULTS: IDO expression was detected in all but three patients' tumor samples, in all but four autologous non malignant lung tissues and in three out of the nine cell lines that were examined. The relative expression of IDO in lung cancer cell lines (4.7 +/- 11.1) was significantly lower than that of all patients' tumor samples (p = 0.006) as well as than that of the autologous non affected lung tissues (p = 0.027). No statistically significant differences were noted between ADC and SCC regarding either the tumor samples or the autologous non affected samples. No significant correlations between IDO expression and clinicopathological parameters were found. CONCLUSION: Direct evidence is provided demonstrating that IDO mRNA can be constitutively expressed by lung cancer cells. The higher IDO expression observed in patients' samples can be attributed to the production of the enzyme by other cells recruited in the tumor microenvironment and the peri-tumoral lung area and/or to its induction by soluble factors of tumor origin. PMID- 17700061 TI - Enhancement of anti-melanoma activity of a plasmid expressing HIV-1 Vpr delivered through in vivo electroporation. AB - The development of novel treatment strategies for the effective delivery of new therapies directed against solid tumors, particularly metastatic melanoma, are required. A novel therapeutic property has previously been discovered for the HIV 1 accessory protein viral protein R (Vpr), based on the ability of this protein to induce G(2) cell cycle arrest as well as apoptosis in various tumor cell lines. Likewise, in vivo electroporation has been utilized as an effective delivery platform for DNA plasmids expressing potentially therapeutic proteins and has been targeted to normal tissues as well as tumors. Our previous findings demonstrated that delivery of a Vpr expression plasmid (pVpr) to established subcutaneous B16.F10 melanoma tumors by in vivo electroporation yielded long-term complete tumor regression in a small percentage of mice. In this study, we modified the electroporation regimen for pVpr with the goal of enhancing the anti tumor activity of Vpr. pVpr was injected intratumorally, on days 0, 2 and 4, into established subcutaneous B16.F10 melanoma tumors followed by in vivo electroporation. Treatment with 100 mg of pVpr plus electroporation on the modified treatment days resulted in 50% of the mice undergoing complete tumor regressions coupled with long-term survival (i.e., greater than 100 days post treatment). Additional investigations established the intratumoral expression of Vpr and induction of apoptosis for a period of at least seven days after the modified pVpr treatment regimen. This report demonstrates that the anti-tumor activity of a pVpr plus electroporation regimen against established subcutaneous B16.F10 melanoma tumors can be significantly enhanced by a modified treatment schedule. In addition, it appeared that this enhanced anti-tumor effect was correlated with prolonged Vpr expression and the associated induction of intratumoral apoptosis. PMID- 17700062 TI - P-TEFb is a crucial co-factor for Myc transactivation. AB - Myc forms an heterodimer with Max and operates as a transcription factor upon binding to specific DNA sites in cellular chromatin. In addition to recruit histone acetylation activity, Myc binds to the positive transcription elongation factor b (P-TEFb) which consists of the cyclin-dependent kinase CKD9 and its regulatory subunit cyclin T. P-TEFb phosphorylates the carboxyl-terminal-domain (CTD) of the larger subunit of RNA polymerase II as well as negative elongation factors allowing efficient transcription elongation. Here, we report that Myc binds, as heterodimer with Max, exclusively the core active P-TEFb complex, and it recruits P-TEFb at Myc targets in vivo. Pharmacological inhibition of P-TEFb by 5.6-di-chloro-1-b-D-ribofuranosyl-bensimidazole (DRB) specifically inhibits expression of Myc-responsive CAD and NUC genes, and impairs the Myc-induced S phase and apoptosis of quiescent cells grown in low serum. Chromatin immunoprecipitation assays (ChIP) demonstrated co-occupancy of Myc and P-TEFb to CAD and NUC E-boxes, and DRB treatment diminished the density of Pol II phosphorylated on Ser-2 of its CTD. These results indicate that P-TEFb is recruited in vivo to Myc-target promoters and CDK9 activity is an important step for Myc-dependent stimulation of responsive genes. PMID- 17700063 TI - Toxicity of influenza A virus matrix protein 2 for mammalian cells is associated with its intrinsic proton-channeling activity. AB - Molecules of influenza matrix protein 2 (M2) are organized in tetramers that constitute a well-conserved virion component and also form proton channels in the plasma membrane of infected cells. In this report we demonstrate that influenza M2 protein is cytopathic in vitro for mammalian cells. An M2 point-mutant (M2pm) protein was constructed that contained amino acid changes designed to block the proton channel via introduction of large hydrophobic residues. This mutant was significantly less toxic upon transient transfection in vitro than the wild-type M2 (M2wt). To assess the possible correlation between M2 cytotoxicity and its proton channel activity, we monitored changes in mitochondria membrane potential induced by M2wt and M2pm. M2wt rapidly decreased mitochondria membrane potential reflecting the transmembrane proton gradient, while M2pm was markedly less efficient. Thus, M2 is cytotoxic for mammalian cells, likely via its proton channel activity and may therefore contribute to influenza pathogenesis through this previously unknown mechanism. PMID- 17700064 TI - Estrogen-induced rat breast carcinogenesis is characterized by alterations in DNA methylation, histone modifications and aberrant microRNA expression. AB - Breast cancer is the most common malignancy in women continuing to rise worldwide. Breast cancer emerges through a multi-step process, encompassing progressive changes from a normal cell to hyperplasia (with and without atypia), carcinoma in situ, invasive carcinoma, and metastasis. In the current study, we analyzed the morphological changes and alterations of DNA methylation, histone methylation and microRNA expression during estradiol-17beta (E(2))-induced mammary carcinogenesis in female August Copenhagen Irish (ACI) rats. E(2)-induced breast carcinogenesis in ACI rats provides a physiologically relevant and genetically defined animal model for studying human sporadic breast cancer. The pattern of morphological changes in mammary glands during E(2)-induced carcinogenesis was characterized by transition from normal appearing alveolar and ductular hyperplasia to focal hyperplastic areas of atypical glands and ducts accompanied by a rapid and sustained loss of global DNA methylation, LINE-1 hypomethylation, loss of histone H3 lysine 9 and histone H4 lysine 20 trimethylation, and altered microRNAs expression. More importantly, these alterations in the mammary tissue occurred after six weeks of E(2)-treatment, whereas the atypical hyperplasia, which represents a putative precursor lesion to mammary carcinoma in this model, was detected only after twelve weeks of exposure, demonstrating clearly that these events are directly associated with the effects of E(2) and are not a consequence of the preexisting preneoplastic lesions. The results of this study show that deregulation of cellular epigenetic processes plays a crucial role in the mechanism of E(2)-induced mammary carcinogenesis in ACI rats, especially in the tumor initiation process. PMID- 17700065 TI - The transcription stress response. AB - The RNA polymerase II transcription machinery acts as a molecular motor that traverses large parts of the genome on a regular basis. It has been suggested that the transcription machinery may play an important role in sensing DNA damage and activating DNA repair and stress response pathways when stalled at blocking lesions. We have collectively termed the activation of these different pathways as the transcription stress response. Recently, it was shown that the ATR kinase and the single-strand DNA-binding protein RPA mediate the phosphorylation of p53 following blockage of transcription elongation. This ATR-mediated phosphorylation occurs even when transcription elongation is blocked in the absence of DNA damage, suggesting that ATR and RPA senses the consequences of blocked transcription elongation rather than sensing DNA lesions directly. It is proposed that the transcription stress response activated by blockage of transcription may play an important role in safeguarding the genome from DNA damage and thus act to suppress tumorigenesis. PMID- 17700066 TI - DNA damage response as an anti-cancer barrier: damage threshold and the concept of 'conditional haploinsufficiency'. AB - DNA damage response (DDR) emerges as a biological tumorigenesis barrier in early stages of cancer development, and a selective pressure that favors outgrowth of malignant clones with defects in the genome maintenance machinery, such as mutations of p53 and other DDR components. Recent studies indicate that the DDR barrier is not alarmed universally among early noninvasive lesions, but rather responds to high-risk tumorigenic threats that occur in high-grade, pre-malignant lesions that are generally more likely to develop into bona fide malignancies. In addition, while the DDR barrier appears to operate in major types of cancer, such as carcinomas of the lung, breast and colon, DDR activation is rare at any stage of progression among testicular germ-cell tumors. Together with observations that several, but not all oncogenic insults are capable of activating the DDR machinery, these new results point to existence of a critical threshold of such oncogene-induced DNA damage. It seems that only cells and lesions that experience DNA replication stress and DNA damage above such threshold activate the cellular senescence or cell death pathways within the DDR machinery. The higher load of DNA damage may also contribute to cancer predisposition in families with inherited heterozygous defects in the DDR barrier, such as in ATM, BRCA1, BRCA2, p53 and other genes. We propose that carriers of such DDR defects may be more prone to malignancy due to 'conditional haploinsufficiency': such partial defects may be asymptomatic in normal tissues, yet they may become manifest under conditions of supra-threshold endogenous DNA damage in oncogene-driven pre malignant lesions. PMID- 17700067 TI - DNA repair deficiency and neurodegeneration. AB - Defects in the response to DNA single-strand or double-strand breaks underpin many human diseases associated with disorders of the nervous system. During nervous system development endogenous DNA damage often results in apoptosis, although cell replacement can occur from germinal zones within this rapidly proliferating tissue. However, if this damage surveillance is faulty, cells with genomic damage may inappropriately become incorporated into the nervous system, and the subsequent demise of these cells may result in neurodegeneration. Ataxia telangiectasia results from defective DNA double strand break signaling, and during development a failure to eliminate damaged neural precursor cells may cause the neurodegeneration present in this disease. In contrast, postmitotic neurons in the mature brain are faced with a less facile option, and in this situation DNA breaks may interfere with transcription required for cellular survival. This scenario may reflect neurodegeneration that occurs in spinocerebellar ataxia with axonal neuropathy, in which single strand break repair is defective. Therefore, the response to DNA damage in the nervous system occurs in a distinct spatiotemporal manner utilizing different DNA repair pathways to ensure genomic stability and to prevent disease. PMID- 17700068 TI - p18(Hamlet) mediates different p53-dependent responses to DNA-damage inducing agents. AB - Cells organize appropriate responses to environmental cues by activating specific signaling networks. Two proteins that play key roles in coordinating stress responses are the kinase p38alpha (MAPK14) and the transcription factor p53 (TP53). Depending on the nature and the extent of the stress-induced damage, cells may respond by arresting the cell cycle or by undergoing cell death, and these responses are usually associated with the phosphorylation of particular substrates by p38alpha as well as the activation of specific target genes by p53. We recently characterized a new p38alpha substrate, named p18(Hamlet) (ZNHIT1), which mediates p53-dependent responses to different genotoxic stresses. Thus, cisplatin or UV light induce stabilization of the p18(Hamlet) protein, which then enhances the ability of p53 to bind to and activate the promoters of pro apoptotic genes such as NOXA and PUMA leading to apoptosis induction. In a similar way, we report here that p18(Hamlet) can also mediate the cell cycle arrest induced in response to gamma-irradiation, by participating in the p53 dependent upregulation of the cell cycle inhibitor p21(Cip1) (CDKN1A). PMID- 17700069 TI - Cell cycle-and proteasome-dependent formation of etoposide-induced replication protein A (RPA) or Mre11/Rad50/Nbs1 (MRN) complex repair foci. AB - In response to DNA damage, cells activate a complex protein network designed to sustain genomic integrity. Many of the proteins involved in the network form discrete repair foci, the composition of which is determined by the specific type of damage. Replication protein A (RPA) and the Mre11/Rad50/Nbs1 (MRN) complex both participate in foci and co-localize at certain types of lesions. Following etoposide (ETOP) treatment, cells form foci containing either RPA or the MRN complex, but not both. To investigate this preferential foci formation, we used cell cycle synchronization experimentation. We demonstrate that cells in S phase contain RPA foci but lack phospho-Nbs1 foci. This is consistent with RPA's role in homologous recombination repair of DNA double-strand breaks (DSBs), the predominant form of repair during S phase. Cells synchronized at G0/G1 phase contain phospho-Nbs1 foci, consistent with the MRN complex involvement in non homologous end joining, the predominant form of repair in G1 phase. Treatment of cells with the proteasome inhibitor MG132 dramatically reduced the percentage of cells forming phospho-Nbs1 foci but did not alter the percentage of cells containing RPA or phospho-RPA foci. ETOP induced similar amounts of damage in all phases of the cell cycle as measured by the comet assay. These data suggest that in response to DNA DSBs, cell cycle-preferred repair pathways differentially engage RPA and the MRN complex in repair foci. PMID- 17700070 TI - Replication protein A is required for etoposide-induced assembly of MRE11/RAD50/NBS1 complex repair foci. AB - The presence of DNA damage activates a specific response cascade culminating in DNA repair activity and cell cycle checkpoints. Although the type of lesion dictates what proteins are involved in the response, replication protein A (RPA) and the Mre11/ Rad50/Nbs1 complex (MRN) respond to most types of lesions. To examine the relationship of RPA and the MRN complex in DNA damage responses, we used siRNA-mediated protein depletion of RPA-p70 and Mre11. Depletion of RPA-p70 decreased the ability of cells to form phospho-Nbs1 foci and increased levels of DNA double-strand breaks (DSBs) following treatment with etoposide (ETOP). In contrast, depletion of Mre11 led to increased levels of RPA-p34 foci formation, but abrogated phospho-RPA-p34 foci formation. These data support a role for RPA as an initial signal/sensor for DNA damage that facilitates recruitment of MRN and ATM/ATR to sites of damage, where they then work together to fully activate the DNA damage response. PMID- 17700071 TI - Hematopoietic stem cell quiescence attenuates DNA damage response and permits DNA damage accumulation during aging. AB - The aging of tissue-specific stem and progenitor cells is believed to be central to the pathophysiological conditions arising in aged individuals. While the mechanisms driving stem cell aging are poorly understood, mounting evidence points to age-dependent DNA damage accrual as an important contributing factor. While it has been postulated that DNA damage may deplete stem cell numbers with age, recent studies indicate that murine hematopoietic stem cell (HSC) reserves are in fact maintained despite the accrual of genomic damage with age. Evidence suggests this to be a result of the quiescent (G0) cell cycle status of HSC, which results in an attenuation of checkpoint control and DNA damage responses for repair or apoptosis. When aged stem cells that have acquired damage are called into cycle under conditions of stress or tissue regeneration however, their functional capacity was shown to be severely impaired. These data suggest that age-dependent DNA damage accumulation may underlie the diminished capacity of aged stem cells to mediate a return to homeostasis after acute stress or injury. Moreover, the cytoprotection afforded by stem cell quiescence in stress free, steady-state conditions suggests a mechanism through which potentially dangerous lesions can accumulate in the stem cell pool with age. PMID- 17700072 TI - Mx1 gene protects mice against the highly lethal human H5N1 influenza virus. AB - We investigated the importance of the host Mx1 gene in protection against highly pathogenic H5N1 avian influenza virus. Mice expressing the Mx1 gene survived infection with the lethal human H5N1 isolate A/Vietnam/1203/04 and with reassortants combining its genes with those of the non-lethal virus A/chicken/Vietnam/C58/04, while all Mx1-/- mice succumbed. Mx1-expressing mice showed lower organ virus titers, fewer lesions, and less pulmonary inflammation. Our data support the hypothesis that Mx1 expression protects mice against the high pathogenicity of H5N1 virus through inhibition of viral polymerase activity ultimately resulting in reduced viral growth and spread. Drugs that mimic this mechanism may be protective in humans. PMID- 17700073 TI - Mitochondrial protein phosphatase 2A regulates cell death induced by simulated ischemia in kidney NRK-52E cells. AB - Acute renal failure can occur after an ischemic injury and results in significant mortality. The stress-signaling pathways that are activated during renal ischemia are unknown. PP2A has emerged as an important regulator of cell death. To study the role of PP2A in ischemia-induced cell death, we used an in vitro model of simulated ischemia. In the present study, simulated ischemia in rat renal tubule epithelial NRK-52E cells (A) results in cell death that involves both necrosis and apoptosis, (B) activates PP2A, and (C) up-regulates the PP2A B56 alpha regulatory subunit. Previous data have shown that PKC alpha negatively regulates B56 alpha protein expression. Consistent with this finding, simulated ischemia suppressed PKC alpha and up-regulated B56 alpha. Treatment of NRK-52E cells with ceramide suppressed PKC alpha and activated PP2A in a manner that mimicked simulated ischemia. A role for PP2A in simulated ischemia-induced cell death is likely since inhibition of PP2A protected NRK-52E cells. In addition, overexpression of exogenous B56 alpha but not B55 in NRK-52E cells enhanced simulated ischemia-induced cell death. These findings suggest that activation of a PP2A isoform that contains the B56 alpha regulatory subunit is required for ischemia-induced cell death in kidney epithelial proximal tubule cells. PMID- 17700074 TI - Probing ATR activation with model DNA templates. AB - The ATR kinase is a critical upstream component of a checkpoint pathway that responds to many forms of damaged and incompletely replicated DNA. Cellular processes such as DNA replication and repair are thought to convert these DNA lesions into a common DNA intermediate that activates this signaling pathway. Indeed, numerous studies have shown that two DNA structures formed during these processes--single-stranded DNA (ssDNA) and junctions between double-stranded DNA (dsDNA) and ssDNA--are important components of the ATR-activating structure. However, an unanswered question is whether primed ssDNA is sufficient for activation of the ATR response. We recently demonstrated that primed ssDNA is sufficient to induce a bona fide checkpoint response in Xenopus egg extracts. This is the first well-defined DNA structure capable of eliciting ATR activation. Using this structure, we examined the contribution of ds/ssDNA junctions and ssDNA to checkpoint activation. Our results indicate the context in which the checkpoint-activating structure is generated may contribute significantly to its signaling properties. Here we discuss the implications of our findings, in the context of other recent work in the field, on our understanding of checkpoint signaling. PMID- 17700075 TI - Chromosomal instability in cancer: causality and interdependence. AB - Aberrations in the number and structure of chromosomes are a common feature of cells from solid tumours. In this brief review, I summarize the evidence that there is a causal relationship between chromosomal instability and the initiation or progression of cancer, and argue that the co-existence of both forms of instability in many solid tumours reflects mechanistic and functional interdependencies that remain poorly investigated. PMID- 17700077 TI - Smallpox vaccination: comparison of self-reported and electronic vaccine records in the millennium cohort study. AB - In December 2002, the US Government implemented policy to immunize health workers, first responders, and military personnel against smallpox in preparation for a possible bioterrorist attack. Self-reported vaccination data are commonly used in epidemiologic research and may be used to determine vaccination status in a public health emergency. To establish a measure of reliability, the agreement between self-reported smallpox vaccination and electronic vaccination records was examined using data from the Millennium Cohort Study. Descriptive measures and a kappa statistic were calculated for data from 54,066 Millennium Cohort Study participants. Multivariable modeling adjusting for potential confounders was used to investigate vaccination agreement status and health metrics, as measured by the Short Form 36-Item Health Survey for Veterans (SF-36V) and hospitalization data. Substantial agreement (kappa =0.62) was found between self-report and electronic recording of smallpox vaccination. Of all participants with an electronic record of smallpox vaccination, 90% self-reported being vaccinated; and of all participants with no electronic record of vaccination, 82% self reported not receiving a vaccination. There was no significant difference in hospitalization experience prior to questionnaire completion between vaccinated and unvaccinated participants. While overall scores on the SF-36V suggested a healthy population, participants whose self-reported vaccination status did not match electronic records had slightly lower adjusted mean scores for some scales. These results indicate strong reliability in self-reported smallpox vaccination and also suggest that discordant reporting of smallpox vaccination is not associated with substantial differences in health among Millennium Cohort participants. PMID- 17700078 TI - Long-term school outcomes for children with attention-deficit/hyperactivity disorder: a population-based perspective. AB - OBJECTIVE: The purpose of this study was to compare long-term school outcomes (academic achievement in reading, absenteeism, grade retention, and school dropout) for children with attention-deficit/hyperactivity disorder (AD/HD) versus those without AD/HD. METHODS: Subjects included 370 children with research identified AD/HD from a 1976-1982 population-based birth cohort (N = 5718) and 740 non-AD/HD control subjects from the same birth cohort, matched by gender and age. All subjects were retrospectively followed from birth until a median age of 18.4 years (AD/HD cases) or 18.3 years (non-AD/HD controls). The complete school record for each subject was reviewed to obtain information on reading achievement (last available California Achievement Test reading score), absenteeism (number/percentage of school days absent at each grade level), grade retention (having to repeat an entire grade in the subsequent school year), and school dropout (failure to graduate from high school). RESULTS: Median reading achievement scores at age 12.8 years (expressed as a national percentile) were significantly different for AD/HD cases and non-AD/HD controls (45 vs 73). Results were similar for both boys and girls with AD/HD. Median percentage of days absent was statistically significantly higher for children with AD/HD versus those without AD/HD, although the difference was relatively small in absolute number of days absent. Subjects with AD/HD were three times more likely to be retained a grade. Similarly, subjects with AD/HD were 2.7 times more likely to drop out before high school graduation (22.9%) than non-AD/HD controls (10.0%). CONCLUSIONS: The results of this population-based study clearly demonstrate the association between AD/HD and poor long-term school outcomes. PMID- 17700079 TI - Modifiers of long-term school outcomes for children with attention deficit/hyperactivity disorder: does treatment with stimulant medication make a difference? Results from a population-based study. AB - OBJECTIVE: The purpose of this study was to describe the significance of potential modifiers of long-term school outcomes among children with attention deficit/hyperactivity disorder (AD/HD), including treatment with stimulant medication. METHODS: Subjects included 370 children with research-identified AD/HD from a 1976-1982 population-based birth cohort (N = 5718). In a companion study, the complete school record for each subject was reviewed to obtain information on reading achievement, absenteeism, grade retention, and school dropout. Data on type of stimulant, dose, age at initiation of treatment, and start/stop dates were collected from medical and school records, available for all subjects. RESULTS: Treatment with stimulants was associated with decreased rates of absenteeism; longer duration of treatment was also associated with decreased absenteeism rates. There was a modest positive correlation (r = .15, p = .012) between average daily stimulant dose and last reading score. Cases treated with stimulants were 1.8 times less likely to subsequently be retained a grade (95% confidence interval: 1.01-3.2; p = .047). The proportion of school dropout was similar between treated and not treated cases (22.2% vs 25.8%, p = .54). Other potential modifiers of school outcomes (sociodemographic risk factors, presence of comorbid learning or psychiatric disorders, and receipt of special educational services) were also examined and found to be associated with poorer outcomes. CONCLUSIONS: In this birth cohort, stimulant treatment of children with AD/HD was associated with improved reading achievement, decreased school absenteeism, and decreased grade retention. This study provides support for efforts to ensure that children with AD/HD receive appropriate long-term medical treatment. PMID- 17700080 TI - Age-related incidence of publicly reported shaken baby syndrome cases: is crying a trigger for shaking? AB - OBJECTIVE: : This study aims to determine whether the age-specific incidences (1) of publicly reported cases of shaken baby syndrome (SBS) and (2) of publicly reported cases of SBS with crying as the stimulus have similar properties to the previously reported normal crying curve. METHODS: : The study reports cases of SBS by age of the child at the time of the inflicted trauma from the data set of the National Center on Shaken Baby Syndrome using cases entered between January 1, 2003 and August 31, 2004. RESULTS: : There were 591 cases of infants up to 1.5 years of age who had been reported to have been shaken or shaken and physically abused. Of these, crying was reported as the stimulus in 166 cases. In both samples, the curves of age-specific incidence started at 2-3 weeks, reached a clear peak at about 9-12 weeks of age, and declined to lower more stable levels by about 29-32 weeks of age, similar to the normal crying curve. These curves have similar onsets and shapes and a slightly later peak compared to the normal crying curve. CONCLUSIONS: : The findings provide convergent indirect evidence that crying, especially in the first 4 months of age, is an important stimulus for SBS. PMID- 17700081 TI - Behavior and self-perception in children with a surgically corrected congenital heart disease. AB - OBJECTIVE: We sought to combine parental and child reports in order to describe the behavior, self-perception, and emotional profile of children with a surgically corrected congenital heart disease (CHD). METHODS: Forty-three children with a surgically corrected CHD were selected and compared to an age- and sex-matched healthy group. The parents of the CHD children completed a behavior rating scale, the Child Behavior Checklist. Children 8 years and older (n = 23) completed a self-report questionnaire concerning perceived competence, their anxiety level, and feelings of depression. RESULTS: Compared to parents of healthy children, those of CHD children report significantly lower school results (p < .01), more school problems in general (p < .01), and a higher percentage of their children repeated a school year (p < .01). They also reported more social (p < .01) and attention problems (p < .01) and more aggressive behavior (p < .05). On self-perception and state anxiety questionnaires, no significant differences were found between the patient group and the healthy group. On a depression scale, however, children with a surgically corrected CHD reported more depressive feelings than healthy controls (p < .01). CONCLUSION: Parents of children with CHD rate their child's school competence to be weaker than healthy peers, they report more attention and social problems and more aggressive behavior. Children themselves did not report differences on perceived competence or anxiety but they do indicate more depressive symptoms than healthy peers. PMID- 17700082 TI - Are girls with ADHD at risk for eating disorders? Results from a controlled, five year prospective study. AB - OBJECTIVE: To evaluate the association between attention-deficit/hyperactivity disorder (ADHD) and eating disorders in a large adolescent population of girls with and without ADHD. METHOD: We estimated the incidence of lifetime eating disorders (either anorexia or bulimia nervosa) using Cox proportional hazard survival models. Comparisons between ADHD girls with and without eating disorders were then made on measures of comorbidity, course of ADHD, and growth and puberty. RESULTS: ADHD girls were 3.6 times more likely to meet criteria for an eating disorder throughout the follow-up period compared to control females. Girls with eating disorders had significantly higher rates of major depression, anxiety disorders, and disruptive behavior disorder compared to ADHD girls without eating disorders. Girls with ADHD and eating disorders had a significantly earlier mean age at menarche than other ADHD girls. No other differences in correlates of ADHD were detected between ADHD girls with and without eating disorders. CONCLUSIONS: ADHD significantly increases the risk of eating disorders. The presence of an eating disorder in girls with ADHD heightens the risk of additional morbidity and dysfunction. PMID- 17700083 TI - A randomized, controlled trial of a home-based intervention program for children with autism and developmental delay. AB - OBJECTIVE: This study aimed to (1) investigate whether provision of a home-based program in addition to a center-based program improves development in young children with disabilities and coping abilities of their families and (2) describe the characteristics of children and families who benefit most from the intervention. METHODS: Fifty-nine children, aged 3-5 years, with no cerebral palsy, participated in the study. Half of the group was randomized to receive an additional program in their homes. A special education teacher provided 40 visits over 12 months working with the families to help generalize skills to the home environment and assist with their concerns. All children were assessed before and after the intervention, and families completed questionnaires assessing family stress, support, and empowerment on both occasions. Differences in change over time and between the intervention and control group were analyzed by repeated measures and the association between characteristics of children and families with improved outcome by multivariate analysis of variance. RESULTS: Change in cognitive development and behavior (in the centers) over time favored the children who received the extra intervention (p = .007 and p = .007, respectively). The groups did not differ on any of the family measures of change. Multivariate analysis of variance revealed more improvement for children in the intervention group from higher than lower stressed families. CONCLUSIONS: Results suggest the need for daily reinforcement of skills learned at the center-based program and the importance of involving families, especially those with few resources and relatively high stress. PMID- 17700084 TI - Parental protection of extremely low birth weight children at age 8 years. AB - OBJECTIVE: To examine parent protection and its correlates among 8-year-old ELBW children compared with normal birth weight (NBW) controls. METHODS: The population included 217 eight-year-old ELBW children born 1992-1995 (92% of the surviving birth cohort; mean birth weight, 811 g; mean gestational age, 26.4 weeks) and 176 NBW controls. The primary outcome measure, the Parent Protection Scale (PPS), included a total score and four domains including Supervision, Separation, Dependence, and Control. Multivariate analyses were performed to examine the predictors of parental protection and overprotection. RESULTS: After adjusting for socioeconomic status (SES), race, sex, and age of the child, parents of ELBW children reported significantly higher mean total Parent Protection Scale scores (31.1 vs 29.7, p = .03) than parents of NBW children and higher scores on the subscale of Parent Control (8.0 vs 7.5, p = .04). These differences were not significant when the 36 children with neurosensory impairments were excluded. Parents of ELBW children also reported higher rates of overprotection than controls (10% vs 2%, p = .001), findings that remained significant even after excluding children with neurosensory impairments (8% vs 2%, p = .011). Multivariate analyses revealed lower SES to be associated with higher total Parent Protection Scale scores in both the ELBW (p < .001) and NBW (p < .05) groups. Additional correlates included neurosensory impairment (p < .05) and functional limitations (p < .001) in the ELBW group and black race (p < .05) and maternal depression (p < .01) in the NBW group. Lower child IQ was significantly associated with higher PPS scores only in the neurosensory impaired subgroup of ELBW children. CONCLUSIONS: Longer term follow-up will be necessary to examine the effects of the increased parent protection on the development of autonomy and interpersonal relationships as the children enter adolescence. PMID- 17700085 TI - The use of cluster analytic techniques in developmental and behavioral pediatric research. PMID- 17700086 TI - Epilepsy surgery in an 8-year-old boy with intractable seizures. AB - CASE: Mark is an 8-year-old boy with a history of intractable epilepsy. Mark's seizures started when he was five years old, lasting less than a minute, with 7 10 episodes occurring in succession. Daytime seizures were described by his parents a "staring events where he does not respond, he will pick at clothes and speak gibberish." He was often disorientated for the remainder of the day. Nighttime seizures were described as "sitting up straight in bed, staring at the ceiling, and being unresponsive." An increase in his seizure frequency after multiple anticonvulsant medications prompted a surgical evaluation. A magnetic resonance (MR) brain scan indicated mild encephalomacia in the left hemisphere. A video electroencephalogram (EEG) demonstrated that the seizures initiated from the left hemisphere in association with multiple subclinical seizures. A PET scan showed decreased uptake in the left frontal lobe compared to the right. At 7 years of age Mark underwent a left frontal temporal-parietal resection. He had a post-surgical infection, but no other medical sequelae. After surgery, there was a significant decrease in seizures with only one seizure in the 2 month post operative period. Mark had neuropsychological testing prior to and following surgery. Pre-surgical results indicated that his IQ was within the low-average range. Visual-perceptual abilities, motor tasks and attention domains indicated difficulties. Post-surgical neuropsychological evaluation revealed a positive outcome. IQ remained in the low average range and there was a mild improvement in visual-perceptual/visual-constructional areas. Academic skills were unchanged with the exception of a slight decline in reading ability. Attention scores improved although redirection was required to sustain his attention during tasks. An increase in non-compliant behavior and emotional liability was noted by his parents.At the time of referral, when Mark was 8-years 3-months old, parental concerns included inattention, anger and emotional lability. The referral question posed was: "Does Mark's inattention represent an attention deficit/hyperactivity disorder, anxiety, or other psychological problems and what is the relationship of his current behaviors to his epilepsy?" PMID- 17700087 TI - Plasticity of growth in height, weight, and head circumference: meta-analytic evidence of massive catch-up after international adoption. AB - Are serious growth delays caused by malnutrition and neglect permanent or reversible? The effects of institutionalization and international adoption on children's physical growth are estimated with meta-analysis. Studies with sufficient data to compute differences between adoptees and the reference population (33 papers with 122 study outcomes) were collected through Web of Science, ERIC (Education Resource Information Center), PsycINFO (Psychological Literature), and Medline (U.S. National Library of Medicine) (1956-2006). The influence of pre- and postadoption care on height, weight, and head circumference was tested. Effect sizes (d) and confidence intervals (CIs) around the point estimate for the growth lag indices were computed. The more time spent in institutional care, the more the children lagged behind in physical growth (d = 1.71, 95% CI: 0.82-2.60, n = 893). At adoptive placement, the children showed large delays in height, weight, and head circumference (d = -2.39 to -2.60; n = 1331-3753). Although after adoption, they showed almost complete catch-up of height (d = -0.57, 95% CI: -0.87 to -0.27, n = 3437 adoptees) and weight (d = 0.72, 95% CI: -1.04 to -0,39, n = 3259 adoptees), catch-up of head circumference seemed slower and remained incomplete (d = -1.56, 95% CI: -2.27 to -0.85, n = 527). Later age at arrival was related to less complete catch-up of height and weight. International adoption leads to substantial catch-up of height and weight but not of head circumference, demonstrating differential plasticity of children's physical growth. PMID- 17700090 TI - Breast-feeding: a unique time for nursing support. PMID- 17700091 TI - Breast-feeding success for the high-risk infant and family: nursing attitudes and beliefs. PMID- 17700092 TI - Best practices in perinatal nursing: "speaking up"--a positive approach to improving outcomes when obstetrical emergencies arise. PMID- 17700093 TI - Breast-feeding Internet Resources. PMID- 17700094 TI - Breast-feeding: good starts, good outcomes. AB - Meeting national breast-feeding objectives and mothers' personal breast-feeding goals depends on a number of factors, including the provision of current, consistent, and timely help with breast-feeding. Nurses are in a prime position to guide mothers during their hospital stay and provide community follow-up postdischarge. Mothers and infants need to acquire a set of breast-feeding skills prior to hospital discharge so that a mother goes home confident that she can adequately nourish her infant, initiate and maintain an abundant milk supply, avoid problems, and address them if they occur. This article describes strategies for optimizing breast-feeding during the first 48 hours and delineates what mothers need to know before they leave the hospital. PMID- 17700096 TI - Breast-feeding increases sleep duration of new parents. AB - OBJECTIVES: This study describes sleep patterns for mothers and fathers after the birth of their first child and compares exclusive breast-feeding families with parents who used supplementation during the evening or night at 3 months postpartum. METHODS: As part of a randomized clinical trial, the study utilized infant feeding and sleep data at 3 months postpartum from 133 new mothers and fathers. Infant feeding type (breast milk or formula) was determined from parent diaries. Sleep was measured objectively using wrist actigraphy and subjectively using diaries. Lee's General Sleep Disturbance Scale was used to estimate perceived sleep disturbance. RESULTS: Parents of infants who were breastfed in the evening and/or at night slept an average of 40-45 minutes more than parents of infants given formula. Parents of infants given formula at night also self reported more sleep disturbance than parents of infants who were exclusively breast-fed at night. CONCLUSIONS: Parents who supplement their infant feeding with formula under the impression that they will get more sleep should be encouraged to continue breast-feeding because sleep loss of more than 30 minutes each night can begin to affect daytime functioning, particularly in those parents who return to work. PMID- 17700097 TI - Exploring breast-feeding self-efficacy. AB - PURPOSE: The purpose of this descriptive study was to explore the influence of efficacy-enhancing experiences on breast-feeding self-efficacy. METHODS: Using the Breastfeeding Self-Efficacy Scale-Short Form, the influences of enactive mastery and various forms of experiences (vicarious, verbal persuasory, and physiological) on breast-feeding self-efficacy were assessed at 48 hours and 4 weeks postpartum among a convenience sample of 63 mothers. RESULTS: Those women who observed breast-feeding role models through videotapes or received praise from their partners or their own mothers had significantly higher levels of breast-feeding self-efficacy than mothers who did not. In addition, mothers who experienced physical pain or received professional assistance with breast-feeding difficulties had significantly lower levels of breast-feeding self-efficacy than those who did not. CONCLUSION: This study provides preliminary evidence that specific efficacy-enhancing strategies may significantly influence breast-feeding self-efficacy. Further research is warranted. PMID- 17700098 TI - Predicting breast-feeding attrition: adapting the breast-feeding attrition prediction tool. AB - CONTEXT: Current breast-feeding rates fall short of the recommendations set forth in Health People 2010. The Breast-feeding Attrition Prediction Tool (BAPT), administered in the postpartum period, has been useful in predicting breast feeding attrition. However, assessing a woman's intention to breast-feed prior to birth would identify women at risk for breast-feeding attrition. PURPOSE: The purpose of this study was to describe a revised BAPT, administered antepartally that measures intention to breast-feed. METHODS: The BAPT, comprising 94 items on a 6-point Likert-type scale, was translated into Spanish and back-translated for accuracy. The BAPT was then revised by reducing the number of items to 35 (32 were used for analysis) and contracting the 6-point scale to 3 categories. A Bayesian item response model provided the psychometric properties of the revised BAPT. RESULTS: The revised BAPT was completed by 143 Mexican American pregnant women. Items, some reverse scored, were recoded as "agree" versus "disagree." Item analyses indicated a wide range of item discriminabilities, with most items being useful measures of intention to breast-feed. Person analyses provided scores for intention to breast-feed. A simpler scoring system was devised for applications. CONCLUSIONS: The revised BAPT shows promise as a measure of intention to breast-feed. The scoring system also indicates which women may need additional interventions to promote breast-feeding. PMID- 17700099 TI - Breast-feeding after breast cancer in childbearing women. AB - According to the American Cancer Society in 2007, about 178,000 women are diagnosed with breast cancer each year in the United States. Of these, 25% have tumors in their childbearing years and may desire future opportunities for pregnancy and lactation. Although there is a multitude of options related to preserving fertility, little is known about the residual effects of breast cancer treatment and the ability to breast-feed afterward. This article describes the epidemiological relationship between breast cancer and pregnancy and lactation. Basic types of treatment for breast cancer including surgery, chemotherapy, and radiation are reviewed. Practical information on how to support breast-feeding after breast cancer is included. PMID- 17700100 TI - The 3 M's of breast-feeding the preterm infant. AB - Mother's own milk is considered best for preterm infants. Given the often protracted period between birth and breast-feeding for most preterm newborns, a number of challenges exist for mothers and neonatal intensive care unit nurses in establishing lactation, providing mother's own milk, and achieving breast feeding. This article conceptualizes breast-feeding the preterm infant in the context of the neonatal intensive care unit as a 3-phase process, the 3 M's of breast-feeding: medication, mother's milk feedings, and the mechanics of breast feeding. PMID- 17700102 TI - Breast-fed low-birth-weight premature neonates: developmental assessment and nutritional intake in the first 6 months of life. AB - A secondary analysis of a randomized clinical trial in which the control group received routine breast-feeding care, consisted of women planning to breast-feed their low-birth-weight (LBW) premature infants, was conducted. The purpose of this secondary analysis was to examine the nutrition of healthy premature LBW infants and its impact on their development. A longitudinal prospective descriptive design was implemented measuring the same group of 50 healthy breast feeding LBW premature infants from birth to 6 months corrected age. Developmental screening was performed at 6 months corrected age using the Bayley Scales of Infant Development to assess development in Mental scale, Motor scale, and Infant Behavioral record. Repeated measures analyses of variance were performed between the 3 gestational age groups and between the breast-fed and non-breast-fed groups. Bayley Scales of Infant Development Mental and Motor scales showed significant differences between the breast-fed and non-breast-fed groups at 6 months corrected age (P < .014 and P < .013, respectively). The nutrition of healthy premature LBW infants over time was recorded and described. Nutritional assessment indicated that human milk intake in some quantity decreased from 40 weeks corrected age to 6 months corrected age: 70% to 26%. These findings can be utilized in anticipatory guidance when caring for neonates and mothers in the neonatal intensive care unit to encourage mothers to provide their own milk and strive to breast-feed. PMID- 17700103 TI - Predictors of term infant feeding at week 12 postpartum. AB - As part of a large nonexperimental, prospective, longitudinal study, 97 breast feeding mothers of healthy term singleton infants were queried via telephone at weeks 8-12 postpartum about their infant feeding method. At week 12, 71.1% of them provided mother's milk (MM), 16.5% provided artificial milk (AM) and MM, and 12.4% provided AM only. Logistic regression analysis identified the following predictors for risk of supplemental feedings with AM at week 12 postpartum: supplementation with AM at week 6, inadequate milk supply at week 6, frequency of breast stimulation less than 7.8 times daily at week 6. Milk output during weeks 1-6 was predictive of feeding type at week 12. Mothers who reported perceived inadequate milk supply (PIMS) at week 8 were more likely to provide AM at week 12 than mothers who did not report PIMS. Further research is needed to assist mothers of healthy term infants with sustaining their milk supply and assisting them with PIMS. PMID- 17700105 TI - The problem with nursing as a job... PMID- 17700104 TI - Prediction of initiation and duration of breast-feeding for neonates admitted to the neonatal intensive care unit. AB - Women who desire to breast-feed their sick newborns often encounter obstacles, including insufficient support and education as well as unsupportive hospital practices. The purpose of this study was to describe maternal, neonatal, and outside influences associated with the intention, initiation, and duration of breast-feeding for women whose newborns were admitted to the neonatal intensive care unit. One hundred mothers were interviewed. Most mothers (67%) intended to breast-feed exclusively and this was significantly related to maternal characteristics such as age, education, parity, smoking and marital status, pre breast-feeding experience, and the influences of the neonate's father and prenatal education. Seventy-eight mothers initiated pumping. Initiation was significantly related to maternal education, smoking, parity, previous breast feeding experience, the neonate's physician, the neonate's father, and postpartum breast-feeding education. Fifty-four mothers were followed up by telephone after discharge until weaning. Thirty percent were exclusively breast-feeding at 2 weeks after discharge, and 15% were breast-feeding at 1 year. Duration of breast feeding was significantly associated with education, marital status, ethnicity, income, assistance from nurses and lactation consultants, and feeding method along with milk type and milk volume at discharge. Increased family support, timely breast-feeding information, and a supportive neonatal intensive care unit environment are needed for women to succeed in breast-feeding their hospitalized newborns. PMID- 17700106 TI - Dupuytren's disease: history, diagnosis, and treatment. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Describe the clinical features of the disease. 2. Describe the pathoanatomical structures in Dupuytren's disease. 3. Outline the various factors associated with Dupuytren's disease. 4. Describe the modalities for surgical and nonsurgical treatment of the condition. 5. Outline recent biomolecular knowledge about the basis of Dupuytren's disease. SUMMARY: Dupuytren's disease is characterized by nodule formation and contracture of the palmar fascia, resulting in flexion deformity of the fingers and loss of hand function. The authors review the historical background, clinical features, and current therapy of Dupuytren's disease; preview treatment innovations; and present molecular data related to Dupuytren's disease. These new findings may improve screening for Dupuytren's disease and provide a better understanding of the disease's pathogenesis. PMID- 17700107 TI - The infected breast prosthesis after mastectomy reconstruction: successful salvage of nine implants in eight consecutive patients. AB - BACKGROUND: The use of tissue expanders and permanent implants has an established role in breast reconstruction after mastectomy. Periprosthetic infection, however, represents a known complication. The most conservative approach to severe or recalcitrant prosthetic infection remains removal of the device. However, removal makes subsequent reinsertion and reexpansion more difficult, with less predictable cosmetic results. The authors believe that timely surgical intervention directed toward salvage of infected breast prostheses can be successful, without demonstrating increased capsular contracture. METHODS: The authors present nine consecutive cases of infected breast implants (nine implants in eight patients). All patients had previously undergone mastectomy for malignancy and immediate expander/implant reconstruction. Six patients had localized infections that failed to respond to oral antibiotics and two women initially presented with systemic infection. All patients were placed on intravenous antibiotics followed by drainage of fluid, manual debridement and curettage of the infected pocket, device exchange, and postoperative antibiotics. RESULTS: All nine infected breast prostheses responded to this approach and currently remain intact and without recurrent infection. Mean time to follow-up for all patients was 14.6 months (range, 10 to 25 months). CONCLUSIONS: In patients with severely infected breast prostheses, timely operative intervention can salvage the previously "unsalvageable" implant; in addition, the surgically replaced implants did not develop severe capsular contractures. Surgical salvage of severely infected breast prostheses after mastectomy is a treatment option that should be considered when dealing with severe or recalcitrant infection in a suitable patient. PMID- 17700108 TI - Investigation of the expansion properties of osmotic expanders with and without silicone shell in animals. AB - BACKGROUND: Particularly in clinical studies, it has been found that rapid swelling of tissue expanders leads to high-pressure peaks that can cause hypoxia in the tissue and thus also skin damage. For this reason, the present study in animals investigated whether an osmotic expander with silicone shell is capable of expanding in tissue and bringing about useful tissue expansion without complications. It was also examined whether and what quantitative and qualitative differences there are between conventional osmotic expanders and the new expanders with silicone shell. METHODS: The expansion of osmotic expanders with silicone shell was compared with that of osmotic expanders without silicone shell in four mini pigs. The expander type used was an M1 rectangle with an initial volume of 6 ml. Five expanders were implanted in each pig, meaning that 20 expanders were measured. The volume of the expanders was measured directly after explantation. Indirect volume determination was performed by producing plaster casts for subsequent laser optical measurement. RESULTS: Comparison of the two curve profiles showed a much flatter profile for the expanders with silicone shell. The absolute values for the volumes of the expanders with silicone shell were likewise substantially lower. CONCLUSIONS: Controlled skin expansion is a technique of providing localized donor tissue for reconstructive surgery. The new expanders could be in a position to lower the rate of complications in tissue expansion. PMID- 17700109 TI - Lowering the postoperative high-riding nipple. PMID- 17700110 TI - Tensional forces influence gene expression and sutural state of rat calvariae in vitro. AB - BACKGROUND: Theories regarding the cause of craniosynostosis that are more than 15 years old cite the role that tensional forces play in the normal and abnormal development of the cranial suture. These theories highlight the effect of stress bands originating from the skull base to the vertex, guiding sutural development. METHODS: In this study, the normally fusing posterior intrafrontal suture of the rat was subjected to 3 mN of tensional force for 30 minutes per day. The suture was then assessed for patency, proliferation, apoptosis, and transforming growth factor (TGF)-beta signaling components. RESULTS: Sutures that were subjected to tensional force were histologically patent at the end of 14 days. This was in contrast to sutures that were maintained without force. Proliferative and apoptotic activity was increased also in sutures maintained open artificially. Interestingly, levels of active TGF-beta-signaling components were also increased in force-maintained sutures. CONCLUSIONS: Sutural maintenance by mechanical force is concurrent with modulation of cellular activity and protein expression reminiscent of the open suture. This study demonstrates the dynamic reciprocity existing between biochemical activity and morphologic state. Although it is known that changes in TGF-betas and fibroblast growth factors can cause sutural fusion, this is the first study to demonstrate that abrogation of sutural closure is responsible for growth factor signaling modulation. PMID- 17700112 TI - Differential effects of TGF-beta isoforms on murine fetal dural cells and calvarial osteoblasts. AB - BACKGROUND: Proteins within the transforming growth factor (TGF)-beta family play a central role in both normal and pathologic calvarial morphogenesis. Previous work has suggested differential functions of the TGF-beta isoforms in these processes. Little is known, however, about effects of TGF-betas on the underlying dura. Furthermore, studies on the effects of TGF-beta isoforms on osteoblasts have been conflicting. The purpose of this study was to determine the effect of TGF-beta isoforms, specifically TGF-beta1 and TGF-beta3, on fetal calvarial osteoblast and dural cell differentiation, proliferation, and apoptosis. METHODS: Primary cultures of fetal calvarial osteoblasts and dural cells were established from embryonic day-18 CD-1 mice. Cells were treated for 48 hours with TGF-beta1 or TGF-beta3. Northern blot analysis, cell counts, and apoptosis assays were performed. RESULTS: In dural cells, TGF-beta1 stimulated the expression of early osteodifferentiation genes and resulted in a slight decrease in cell number and no effect on apoptosis. Similar results were observed in osteoblasts. TGF-beta3 had little or no effect on the genes studied in both cell types but resulted in increased apoptosis and concomitant decreases in cell number in both cell types. CONCLUSIONS: This study demonstrates that dural cells respond to TGF-beta and that this response is isoform-specific. TGF-beta1 stimulates osteodifferentiation of previously uncommitted cells in the dura. It also stimulates early events in bone matrix deposition and has little effect on late markers of bone differentiation in osteoblasts and dural cells. Both isoforms result in decreases in cell number. TGF-beta3 results in greater decreases in cell number and isoform specific stimulation of apoptosis in both dural cells and calvarial osteoblasts. PMID- 17700113 TI - Biological differences between fibroblasts derived from peripheral and central areas of keloid tissues. AB - BACKGROUND: Clinical observations indicate that the bulging and reddish peripheral areas of keloids are more elevated than their central areas. Moreover, the peripheral areas of keloids undergo aggressive growth and invasion into normal skin, beyond the boundaries of the initial wound. The aim of this study was to investigate the biological differences between peripheral and central keloid areas. METHODS: Six patients suffering from keloids on the anterior chest were selected for this study. Fibroblasts were harvested from both central and peripheral keloid areas. Cell cycle distribution and apoptosis induction were analyzed by flow cytometry and with an antibody to Fas. The expression of apoptosis-related proteins (Fas, Bcl-2, and p53) was measured by flow cytometry. RESULTS: Fibroblasts derived from both central and peripheral parts of keloids displayed significant resistance to Fas-mediated apoptosis. Analysis of cell cycle distribution indicated that approximately 60 percent of fibroblasts derived from the peripheral parts of keloids were in the proliferative periods of the cell cycle (G2 and S phase). However, the majority of fibroblasts derived from keloid centers were in G0 or G1 phase. Fas and Bcl-2 expression did not differ significantly between the two groups, but p53 expression was much higher in fibroblasts derived from central parts than from peripheral parts. CONCLUSION: It is suggested that differences in cell cycle distribution and p53 protein expression may account for the different growth characteristics of keloid peripheries and centers. PMID- 17700114 TI - Frontal reconstruction with frontal musculocutaneous V-Y island flap. AB - BACKGROUND: Defects of the frontal region are mostly caused by the ablation of tumors. When the treatment of such a defect cannot be achieved by the approximation of its margins, some of the solutions may alter the form or the continuity of the frontal aesthetic unit. METHODS: With the intent of reconstructing frontal defects with proper skin, a musculocutaneous island flap of the frontal belly of the occipitofrontalis muscle based on the supratrochlearis or the supraorbitalis vessels was planned for a V-Y application in a single procedure. It was used in 31 patients. RESULTS: The treated frontal defects ranged from 1.5 per 1.5 cm to 4.5 per 5.5 cm and, depending on the depth of the resection, exposed periosteum, bone, or dura mater. All the vessels were identified and preserved and the flaps were viable and sufficient for the defects. Three cases presented 1 cm of superficial skin necrosis with spontaneous healing that caused hypochromic scars. In eight patients the extirpation of the tumor compromised the rami temporales of the nervus facialis and caused postoperative asymmetry of the facial mimicking. All the followed patients presented normal sensitivity to touch stimuli on the flap skin and presented loss of sensitivity on the scalp distally to the flap and to the donor site. CONCLUSION: The frontal musculocutaneous island V-Y flap based on the supratrochlearis or the supraorbitalis vessels is safe and permits frontal reconstruction in a single procedure with proper maintenance of the aesthetic unit. PMID- 17700115 TI - The use of artificial dermis in the reconstruction of oncologic surgical defects. AB - BACKGROUND: Integra dermal substitute has been used in burn reconstruction with great success. Its use in general reconstruction is currently being reported. The authors set out to evaluate the utility of Integra in the reconstruction and resurfacing of defects created by tumor excision. METHODS: Since 2003, 17 patients with soft-tissue tumors involving the head and neck, lower extremity, and anterior chest wall underwent tumor resection and reconstruction with Integra dermal substitute. These patients were followed and clinical outcomes were assessed. RESULTS: Seventeen patients with a mean age of 54 +/- 21 years underwent tumor resection and reconstruction with Integra dermal substitute. Twelve patients (71 percent) were male and five (29 percent) were female. Twelve cases (71 percent) involved recurrent tumor resection. The 17 cases involved 10 different tumor types at six different anatomical locations. The mean defect size was 172 +/- 260 cm (range, 20 to 1080 cm). The second stage of the reconstruction occurred on postoperative day 23 +/- 6. The mean follow-up was 12.3 +/- 7.2 months (range, 3 to 26 months). Clinically, 16 patients had 100 percent take of skin grafts and one patient had approximately 97 percent take of his graft. All patients experienced excellent defect contouring and cosmesis. CONCLUSIONS: Artificial bilaminate acellular dermis is an excellent option for reconstructing defects created by tumor resection and can be used in a wide variety of locations. It is especially useful in large defects that usually require flaps for coverage. Patients experience minimal donor-site morbidity and have outstanding cosmetic and functional results. PMID- 17700116 TI - A standardized digital photography system with computerized eyelid measurement analysis. AB - BACKGROUND: The authors have developed a slit-lamp mounted digital photography system. This ensures that the patient's head is consistently positioned in the same plane in relation to the camera and generates standardized images of the eyelids, which are then analyzed using commercially available computer measurement software. The aim of this study was to assess the repeatability and reproducibility of this system compared with traditional methods of eyelid measurement. METHODS: Both eyes of 10 patients were photographed and then measured by three clinicians using a handheld ruler for five eyelid parameters (i.e., palpebral aperture, superior marginal reflex distance, inferior scleral show, levator function, and upper eyelid skin crease height). The photographs were then assessed using computer software by the same clinicians (twice by a consultant and once by a clinical fellow and a specialist registrar). At all times, each observer was masked to their colleagues' results. Data were analyzed using Bland-Altman plots. RESULTS: There was a good level of agreement between measurements obtained by computer analysis of digital photographs and measurements obtained by traditional methods. A higher level of reproducibility (interobserver variability) was demonstrated in all digital measurements compared with those obtained by handheld ruler. Repeatability (intraobserver variability) with the digital photograph technique was also high and consistent for each of the five eyelid parameters. CONCLUSIONS: These results suggest that a digital photography system with computer analysis is comparable to, and offers advantages over, traditional methods of measurement. This system offers a simple, standardized, and rapid method of patient assessment with important applications in electronic patient records, audit, and research. PMID- 17700117 TI - Risk assessment of immunosuppressive therapy in facial transplantation. AB - BACKGROUND: Immunosuppression-related risks are foremost among ethical concerns regarding facial transplantation. However, previous risk estimates are inaccurate and misleading, because they are based on data from studies using different immunosuppression regimens, health status of the transplant recipients, tissue composition, and antigenicity. This review provides a comprehensive risk assessment for facial transplantation based on comparable data of immunosuppression, recipient health status, and composition and antigenicity of the transplanted tissue. METHODS: The risk estimates for face transplantation presented here are based on data reported in clinical kidney (10-year experience) and hand transplantation (5-year experience) studies using tacrolimus/mycophenolate mofetil/corticosteroid therapy. Mitigating factors including ease of rejection diagnosis, rejection reversibility, infection prophylaxis, patient selection, and viral serologic status are taken into account. RESULTS: Estimated risks include acute rejection (10 to 70 percent incidence), acute rejection reversibility (approximating 100 percent with corticosteroid therapy alone), chronic rejection (<10 percent over 5 years), cytomegalovirus disease (1 to 15 percent), diabetes (5 to 15 percent), hypertension (5 to 10 percent), and renal failure (<5 percent). CONCLUSIONS: A review of these data indicates that previously reported estimates of immunosuppression-related risks are outdated and therefore should no longer be used. These updated risk estimates should be used by facial transplant teams, institutional review boards, and potential recipients when considering the immunologic risks associated with facial transplantation. PMID- 17700118 TI - Abdominal wall reconstruction following severe loss of domain: the R Adams Cowley Shock Trauma Center algorithm. AB - BACKGROUND: Large, complex, posttraumatic and recurrent abdominal hernias present a reconstructive challenge. Multiple techniques have been described to restore the integrity of the abdominal wall, although the indications and applications can be difficult to navigate. The authors propose an algorithm that facilitates the assessment and treatment of secondary large ventral defects. METHODS: The algorithm described involves a systematic approach to abdominal wall reconstruction and was applied to 23 consecutive patients at the R Adams Cowley Shock Trauma Center. Data collected from the chart review included age, body mass index, mechanism of injury, placement of skin graft and use of resorbable mesh before definitive reconstruction, size of defect, number of tissue expanders placed, length of follow-up, and complications. RESULTS: There were six female patients and 17 male patients, with an average age of 36 years. The average follow-up was 7 months. Seventeen patients had posttraumatic laparotomies, five patients had aggressive abdominal wall debridement following necrotizing fasciitis, and one patient developed a large abdominal wall hernia following complications from gastric bypass surgery. All patients underwent delayed abdominal wall reconstruction, with an average time to initial reconstruction of 19.5 months. Sixteen patients had no postoperative complications. Seven patients had complications, including one with an enterocutaneous fistula, one with a partial small bowel obstruction, two with seromas, one with a superficial wound infection, and two with recurrent abdominal wall laxity. CONCLUSIONS: The reconstructive ladder for large, complex abdominal hernias is poorly defined. The proposed algorithm provides a systematic staged approach that incorporates available techniques used for delayed reconstruction of the abdominal wall. PMID- 17700119 TI - Dorsal intercostal artery perforator flap: anatomical study and clinical applications. AB - BACKGROUND: The posterior intercostal arteries form the largest angiosome in the torso by means of their many perforators to the skin, the arteries of which are proposed to be the vascular pedicle of an island flap. Using these perforators, the authors developed a new flap, the dorsal intercostal artery perforator flap, harvested in the back. METHODS: An anatomical study was conducted on five fresh human cadavers injected with a lead oxide-gelatin mixture as a radiopaque agent. The study consisted of the cadaver dissection and the angiographic studies to map the dorsal intercostal artery perforators in detail. RESULTS: Each of the fourth to twelfth posterior intercostal arteries consistently supplied the dorsal perforators. Those derived from the fourth, fifth, sixth, tenth, and eleventh posterior intercostal arteries were the dominant direct cutaneous perforators. They were located within 5 cm of the spinous processes of the vertebrae and were clinically detectable by Doppler probe preoperatively. Eleven dorsal intercostal artery perforator flaps were applied in 10 cases. In nine cases, the muscles of the latissimus dorsi, the trapezius, or the scapular circumflex artery had been sacrificed in previous operations. The maximum flap dimension was 31 x 13 cm. All flaps showed stable postoperative blood circulation and survived completely, except for marginal necrosis in the largest flap. No functional loss attributable to flap harvest was recognized. CONCLUSION: Flap extendibility and less invasiveness without sacrifice of the underlying muscles have proved that the dorsal intercostal artery perforator flap is a new reconstructive option in the back, where suitable flaps are often proposed. PMID- 17700120 TI - The clinical importance of the relationship between the deep peroneal nerve and the dorsalis pedis artery on the dorsum of the foot. AB - BACKGROUND: The aim of this study was to describe the relationship between the deep peroneal nerve and the dorsalis pedis artery to help ensure a safer surgical approach in flap surgery. METHODS: The dissection of 36 cadaver lower limbs was undertaken to describe the relationship of the deep peroneal nerve to the dorsalis pedis artery in the anterior tarsal tunnel and on the dorsum of the foot. RESULTS: Four distinct relationships of the deep peroneal nerve to the dorsalis pedis artery were determined. In type 1 (36.1 percent), the artery was medial to the deep peroneal nerve in the tunnel and medial to the medial terminal branch below the tunnel on the dorsum of the foot. In type 2 (25.0 percent), the artery was medial to the deep peroneal nerve in the tunnel and lateral to the medial terminal branch below the tunnel on the dorsum of the foot. In type 3 (30.6 percent), the deep peroneal nerve and the artery were crossing over each other at multiple levels. In type 4 (8.3 percent), no medial terminal branch was observed. The artery was medial to the lateral terminal branch. CONCLUSIONS: The dorsalis pedis neurovascular island flap contains both the dorsalis pedis artery and the deep peroneal nerve. Because the design of a neurovascular free flap requires detailed knowledge of the nerve and vascular supply, the data presented here will help surgeons during the surgical approaches to the foot and ankle. PMID- 17700122 TI - Subacute nerve compressions after trauma and surgery of the hand. AB - BACKGROUND: It is accepted that major injuries of the upper limb may require not only fasciotomies but also nerve decompressions. That nerve compression(s) may occur after less dramatic injuries and "routine" surgery distal to the elbow is less well documented in the literature but well known to experienced clinicians. The aim of this study was to identify a possible link between injuries or elective surgery to the distal upper limb and "subacute nerve compressions." METHODS: Over a 5-year period, data of patients who developed clinical symptoms of nerve compressions distal to the elbow within 6 months after trauma or elective surgery to the same upper limb that affected postoperative management were collected prospectively. RESULTS: This study identified 91 patients (49 after trauma and 42 after elective surgery). Compression of the median nerve in the carpal tunnel was the most common syndrome (73 cases). Fasciectomy for Dupuytren's disease was the most frequent operation involved (23 cases). The average time from injury or surgery to diagnosis of nerve compression(s) was 8 weeks (range, 1 to 24 weeks). Surgical decompression of the involved nerves was performed in 43 patients (47.2 percent), with an average time from diagnosis to surgery of 30.4 weeks (range, 28 to 44 weeks). In the carpal tunnel syndrome group (47 men and 26 women), mean age was 49 years (men, 48 years; women, 50 years) and the male-to-female ratio was 1.8:1. CONCLUSION: Subacute nerve compressions should be considered as a complication during the recovery period after injury and surgery of the upper limb. PMID- 17700121 TI - Lateral retromalleolar perforator-based flap: anatomical study and preliminary clinical report for heel coverage. AB - BACKGROUND: Repair of heel soft-tissue defects remains a challenging problem in reconstructive surgery. The distally based sural neurofasciocutaneous flap is among the flaps of choice for coverage of this difficult region. The authors describe a modified lateral retromalleolar perforator-based neurocutaneous flap with a lower pivot point. METHODS: This study was divided into two parts: anatomical study and clinical application. In the anatomical study, 12 cadavers were injected with red gelatin, and all fasciocutaneous perforators between the lateral malleolus and Achilles tendon (called the lateral retromalleolar space) were identified. Clinically, based on the anatomical study, five cases of heel soft-tissue defects were reconstructed with the modified lateral retromalleolar perforator-based sural neurofasciocutaneous flap. RESULTS: The anatomical study showed that there are usually two to three retromalleolar cutaneous perforators arising from the terminal part of the peroneal artery in the lateral retromalleolar space. Their outer diameters range from 0.1 to 0.8 mm. A direct venous communicator, usually accompanied by the larger perforator, connected the superficial lesser saphenous vein and the deep peroneal venae comitantes. Five patients with heel soft-tissue defects were treated with flaps ranging from 3 x 6 cm to 5 x 12 cm. The distal pivot point was designed at 1 to 3 cm above the tip of the lateral malleolus. All flaps survived without complications. CONCLUSIONS: The lateral retromalleolar perforator is predictable and reliable for the design of a lower pivot point, distally based sural neurocutaneous flap. The procedures are simple and rapid, and the flap can be rotated easily without dog-ear deformity. This flap should be considered among the preferred flaps for heel reconstruction. PMID- 17700123 TI - Anatomical relationships among the median nerve thenar branch, superficial palmar arch, and transverse carpal ligament. AB - BACKGROUND: A possible complication of open, limited incision or endoscopic carpal tunnel release is transection of the thenar branch of the median nerve or the superficial palmar arch. Knowledge of the anatomy of these structures in relationship to the transverse carpal ligament is critical in preventing these complications. The authors investigated these anatomical relationships using cadaveric dissections. METHODS: Forty-eight fresh cadaver hands were analyzed. The distance between the distal transverse carpal ligament and the superficial palmar arch, the distance between the distal transverse carpal ligament and the origin of the thenar branch of the median nerve, and the length of the transverse carpal ligament were measured. RESULTS: In the 48 specimens, the thenar branch of the median nerve was extraligamentous in 44 (92 percent), subligamentous zero (0 percent), and transligamentous in four (8 percent). The thenar branch of the median nerve contained one branch in 28 (58 percent) and multiple branches in 20 specimens (42 percent). The average distance from the distal transverse carpal ligament to the superficial palmar arch was 18.8 +/- 0.6 mm (95 percent CI, 17.6 to 20.1 mm) and that to the thenar branch of the median nerve was 6.9 +/- 0.4 mm (95 percent CI, 6.0 to 7.8 mm) (p < 0.0001). The average length of the transverse carpal ligament was 28.5 +/- 0.8 mm (95 percent CI, 26.9 to 30.1 mm). CONCLUSIONS: The anatomical relationships among the superficial palmar arch, thenar branch of the median nerve, and distal transverse carpal ligament were found to be consistent. This will assist the hand surgeon in preventing specific complications regardless of the method of carpal tunnel release chosen. PMID- 17700124 TI - Reconstruction of ablative skull base defects in the pediatric population. AB - BACKGROUND: Neoplasms of the skull base are rare in children and require a multidisciplinary approach. Surgical defects are often large and cause significant functional, aesthetic, and psychological issues. The authors present their experience with reconstruction of the anterior and lateral skull base in the pediatric population. METHODS: The authors conducted a retrospective review at a comprehensive cancer center. RESULTS: Between January of 1993 and February of 2005, 10 children and adolescents underwent surgical resection of a skull base tumor followed by reconstruction of the skull base. Patients ranged in age from 6.4 to 17.9 years (median, 11.8 years). Four patients had rhabdomyosarcoma, and one each had spindle cell sarcoma, chondrosarcoma, liposarcoma, malignant fibrous histiocytoma, mucoepidermoid carcinoma, and neurofibromatosis. Surgical defects involved the anterior skull base in three patients, the infratemporal fossa in three patients, both the anterior and middle cranial fossae in three patients, and the temporal bone in one patient. Fourteen flap procedures were performed in these patients-11 after tumor resection and three in a delayed fashion to promote improved functional and aesthetic outcomes. Complications occurred in three patients, and there was one case of flap loss. CONCLUSIONS: Skull base reconstruction may be reliably and successfully accomplished in children and adolescents using soft-tissue free flaps or regional flaps. Full rehabilitation, including bony reconstruction and prosthetic rehabilitation, may be accomplished as craniofacial development plateaus in adolescence. PMID- 17700125 TI - Repair of transverse facial cleft in hemifacial microsomia: long-term anthropometric evaluation of commissural symmetry. AB - BACKGROUND: Cleft of the oral commissure is an uncommon malformation that results from incomplete mesenchymal merging of the mandibular and maxillary prominences of the first pharyngeal arch. Many operative techniques have been proposed to repair this cutaneous and muscular defect. Most authors recommend cutaneous closure by Z-plasty or W-plasty, but these geometric techniques cause additional cutaneous scarring; furthermore, the risk of commissural migration after repair of a transverse facial cleft is poorly documented. METHODS: Anthropometry was used to evaluate the operative outcome in 13 patients with hemifacial microsomia who underwent repair of a transverse facial cleft by the senior author between 1980 and 2001. The procedure included (1) apposition of the orbicularis oris muscle; (2) linear cutaneous closure; and (3) construction of the commissure using an inferiorly based, rectangular vermilion-mucosal flap. RESULTS: The average age at repair was 11 months, and the mean follow-up was 10.3 years. Comparing the cleft and noncleft sides, the position of the commissure was within 1 mm in all patients, whereas the melolabial fold was asymmetric in six patients. The average length of the scar was 17 mm, and the scar extended lateral to the melolabial fold in all but one patient. No patients were found to have had lateral commissural migration. CONCLUSIONS: The authors conclude that Z-plasty or W-plasty is unnecessary in repair of a transverse facial cleft. Closure of the orbicularis oris muscular ring is the critical step in the procedure to provide oral continence and a counterforce to the contraction of the cutaneous scar. There is no lateral creep of the commissure or hypertrophic scarring after straight-line cutaneous closure. PMID- 17700126 TI - Experience with presurgical nasal molding in infants with cleft lip and nose deformity. AB - BACKGROUND: Nasal deformity in infants with nasolabial clefts persists if it is not actively corrected. Some surgeons repair the nose simultaneously with the lip. Nonsurgical nasal molding with mechanical support performed in the early neonatal period has proved to be an effective alternative to surgical correction. METHODS: At the author's institution, for the past 4 years, infants with nasal asymmetry have been treated by presurgical nasal molding performed with a stent fixed to a conventional passive orthopedic plate. The efficiency of this method was evaluated retrospectively using photographs obtained at least 1 year after lip repair. Sixteen pairs of children were studied. One child of each pair had received the treatment with the stent, and the other one had been treated using the classic method of presurgical orthopedics with no stent; the diagnosis and remaining therapy were the same for both children. Nine maxillofacial surgeons and 22 students of dental medicine were asked to decide which nose of each pair was more symmetrical. RESULTS: Seventy-five percent of students and 70 percent of surgeons found that the nasal stent nose was more symmetrical than its classically treated counterpart. Statistical analysis of the results revealed highly significant agreement between the two groups of evaluators. CONCLUSIONS: Children who underwent presurgical treatment with a nasal stent had more symmetrical noses several years after lip repair than children treated by the classic method of preoperative orthopedics. Use of the modified appliance did not present major problems for the parents, but their cooperation is necessary. Treatment should start as soon as possible after birth, regardless of the width of the cleft. PMID- 17700127 TI - Intraocular pressure variations during zygomatic fracture reduction and fixation: a clinical study. AB - BACKGROUND: The reduction of midface fractures has been associated with the rare but devastating complication of blindness. An increase in intraocular pressure is important in the mechanism of blindness in this setting. In this study, the authors assessed the intraocular pressure in patients who underwent zygomatic fracture reduction (with or without fixation). METHODS: Using applanation tonometry, 29 patients underwent intraocular pressure measurements before, during, and after fracture fixation. The contralateral pressures were measured and used as the control. RESULTS: There were 29 patients with a mean age of 35 years, and the mean time to surgery was 5 days. Preoperatively, all patients had normal intraocular pressures and normal visual acuity. All patients underwent a Gillies lift and 18 patients required open reduction and fixation of the frontozygomatic suture (n = 4) or the infraorbital margin (n = 2), and the remainder (n = 12) required fixation of both points. There was no statistically significant increase in the intraocular pressures following the reduction of uncomplicated zygomatic fractures. Statistically significant pressure reductions were noted immediately after reduction and fixation. CONCLUSIONS: The surgical reduction of uncomplicated zygomatic fractures has no adverse effect on the intraocular pressure. It is the authors' opinion that adjunctive measures to reduce the pressures are unnecessary. PMID- 17700128 TI - Enlargement of nasal vault diameter with closed septoturbinotomy. AB - BACKGROUND: Septal deviation and inferior turbinate hypertrophy are important contributors to nasal airflow obstruction. In recent years, a closed septoturbinotomy, whereby a speculum is inserted into the nose and the blades are spread, has been shown to centralize the bony septum and outfracture the turbinates in most cases. It is a minimally invasive procedure that frequently corrects bony septal deviation and reduces enlarged inferior turbinates. However, the extent of vault enlargement by that method has not been quantified. The purpose of this study was to demonstrate and quantify the extent to which a closed septoturbinotomy enlarges the maximal diameter of the nasal vault. METHODS: Measurements and silicone molds of the nasal vault were obtained before and immediately after performing closed septoturbinotomy in nine human cadavers. Measurements were taken with standardized graduated rubber tubing. Molds were obtained with commercially available sealant. RESULTS: All cadaver noses demonstrated enlargement of maximal internal diameter of the obstructed side on both calibrated tubing and silicone mold measurements (p < 0.05). The mean postosteotomy-to-preosteotomy vault diameter ratio was 1.64 (range, 1.25 to 2.3) for the obstructed side and 1.16 (range, 1.0 to 1.4) for the unobstructed side. This 64 percent increase in radius permits a theoretical 7-fold increase in flow by Poiseuille's law. CONCLUSIONS: Closed septoturbinotomy is a minimally invasive technique that enlarges the nasal vault in the overwhelming majority of cases. A clinical trial with rhinomanometry is needed to verify the extent of functional improvement. PMID- 17700129 TI - Chin surgery V: treatment of the long, nonprojecting chin. AB - BACKGROUND: Correction of the long, nonprojecting chin requires both vertical reduction and sagittal augmentation. Wedge excision-based therapy reduces chin height and allows for advancement of the distal segment, but it is associated with at least a 10 percent incidence of mental nerve injury. The authors propose two innovative ways to correct the long, nonprojecting chin. METHODS: There are two approaches, intraoral and extraoral. With the intraoral approach, following a gingivobuccal incision, a single horizontally oblique osteotomy is made at least 6 mm beneath the mental nerve foramina. The vertically long genial segment is freed and the posterior edge is contoured with a side-cutting burr. The contoured jumping genial segment is secured to the mandible with countersunk screws and contoured in situ to preserve the lower 8 to 10 mm. With the extraoral approach, following a submental incision, the anterior and posterior surfaces of the symphysis are cleared (a double-armed suture is placed through the posterior musculature). A reciprocating saw is used to remove the lower border of the symphysis to reduce the vertical excess. The tagged musculature is resuspended, and a tapered, textured implant is secured to the new symphysis. RESULTS: Aesthetic outcomes using these two techniques were good and there were no complications. Representative patients, operated on by the senior author, illustrate these techniques. CONCLUSIONS: Both the intraoral one-cut in situ contoured jumping genioplasty and the extraoral vertical reduction/sagittal augmentation genioplasty reduce excess chin height, control sagittal advancement, provide pogonion projection, and avoid the risks of a standard wedge. Both techniques provide custom projection at the lower pole of the new symphysis. PMID- 17700130 TI - Electrophysiologic change and facial contour following botulinum toxin A injection in square faces. AB - BACKGROUND: This study was proposed to evaluate the facial contour and electrophysiologic changes of the masseter and temporalis muscles before and after botulinum toxin A injection in the wide lower face (square face). METHODS: The botulinum toxin A injections were performed on 10 patients for the treatment of square face with masseter hypertrophy. To obtain an objective evaluation of the change in the facial contour, physical measurements, cephalometry, and clinical photographs were taken; and for evaluation of the function of the masseter and temporalis muscles, electromyographic studies were performed before and 1, 3, 5, 7, 9, and 12 months after treatment. RESULTS: By physical measurements and cephalometry, the maximal reduction in lower facial contour (mean reduction, 6.6 mm by physical measurements and 7.5 mm by cephalometry) was observed 3 months after the injection, and increased slowly until 12 months after treatment. The maximal amplitude of the right and left masseter muscles decreased to the lowest value 1 month after treatment, with continuous increase being observed thereafter. There were statistically significant differences at all of the follow-up time points in reduction of lower facial contour by physical measurements and in electromyographic studies of the left masseter muscles. There was no hypertrophy of the temporalis muscle to compensate for the atrophy of the masseter muscles. CONCLUSIONS: In this study, there was a 2-month interval between the lowest value of the maximal amplitude of the surface electromyography and the maximal clinical effects following botulinum toxin A injection, and there was similarity between the recovery of the masseter function and the diminution of the clinical effect. The clinical effect of botulinum toxin A persisted for 12 months after treatment on physical measurements, and the authors felt that this long-lasting effect of botulinum toxin A beyond expectation could be explained by incomplete recovery of muscle function. PMID- 17700131 TI - Noninvasive body contouring by focused ultrasound: safety and efficacy of the Contour I device in a multicenter, controlled, clinical study. AB - BACKGROUND: The removal of unwanted body fat using a noninvasive technique is desirable to patients and physicians. The authors describe a controlled, multicenter, clinical trial assessing the safety and efficacy of a focused therapeutic ultrasound device for noninvasive body contouring. METHODS: Eligible healthy adult subjects were enrolled to the experimental group or the control group at five sites. The experimental group received one treatment with the Contour I device (UltraShape Ltd., Tel Aviv, Israel) in the abdomen, thighs, or flanks and were evaluated over a 12-week period. Efficacy outcomes were reduction of circumference and fat thickness. Circumference reduction was compared with the untreated group and with an untreated area (thigh) within the treated group. Safety monitoring included laboratory testing (including serum lipids), pulse oximetry, and liver ultrasound. RESULTS: One hundred sixty-four subjects participated in the study (137 subjects in the experimental group and 27 in the control, untreated group). A single Contour I treatment was safe and well tolerated and produced a mean reduction of approximately 2 cm in treatment area circumference and approximately 2.9 mm in skin fat thickness. The majority of the effect was achieved within 2 weeks and was sustained at 12 weeks. No clinically significant changes in the measured safety parameters were recorded. Seven adverse events were reported, all of which were anticipated, mild, and resolved within the study period. CONCLUSION: The Contour I device provides a safe and effective noninvasive technology for body contouring. PMID- 17700133 TI - Assessing surgical skill using bench station models. AB - BACKGROUND: The acquisition of surgical skill is one of the essentials of good surgical practice. The training of plastic surgeons is presently unstructured, with few objective measures of surgical skill. The trainee's time to acquire skills may be inadequate because of the shortened time for training with the Calman system. There is also increasing pressure from the government to introduce testing of surgical competency for all surgeons. The authors introduce a series of tasks that allow assessment of technical skill among plastic surgical trainees. METHODS: A range of surgeons with differing surgical skill were tested. They performed three tasks designed to assess their ability to suture skin, take a medium-thickness skin graft, and repair a tendon. The candidates were videotaped during the procedures and scored by four independent observers using the Objective Structured Assessment of Technical Skill scoring system. Each candidate was then given an overall competence score. RESULTS: Sixty-five candidates were tested with an experience range from consultant to junior senior health officer. Results showed significant differences down the grades, with consultants performing the tasks with greater competency than their juniors (p = 0.004). CONCLUSIONS: The authors have demonstrated a valid and reliable method of objectively measuring the surgical skill of plastic surgical trainees. The authors have shown that consultants perform better than the juniors and that the tasks are easily reproduced. This has implications for future assessment in that these tests may be used as formal assessment programs for testing and teaching trainees throughout their careers. PMID- 17700135 TI - Facing up is an act of dignity: lessons in elegance addressed to the polemicists of the first human face transplant. PMID- 17700138 TI - Nitrous oxide administered by the plastic surgeon for repair of facial lacerations in children in the emergency room. PMID- 17700139 TI - Platelet gel sealant use in rhytidectomy. PMID- 17700140 TI - Application of the endoscope to transaxillary subpectoral augmentation mammaplasty. PMID- 17700143 TI - Comparison of techniques for long-term storage of fat grafts. PMID- 17700144 TI - Are keloids and hypertrophic scars caused by fungal infection? PMID- 17700146 TI - When can a hand surgeon return to work after undergoing carpal tunnel repair? PMID- 17700145 TI - Keeping extra skin for nipple-areola reconstruction during mastectomy. PMID- 17700147 TI - Nearly [corrected] fatal outcome of meningococcal septicemia and meningitis, notwithstanding severe sequelae: an alert for clinical practitioners and a challenge for plastic surgery. PMID- 17700148 TI - A triad of technical tips to make microvascular repair simple and quick. PMID- 17700149 TI - Fat planer: a new needle for liposuction. PMID- 17700150 TI - Immunosuppression of the elderly kidney transplant recipient. AB - The growing number of elderly patients with end-stage kidney disease awaiting transplantation has resulted in a corresponding rise in the number of elderly transplant recipients. In this paper, we review existing literature on age related changes, transplant outcomes, and complications in the elderly in an attempt to propose a tailored approach to immunosuppression management in this group of patients. Despite the fact that the benefit of transplantation in the elderly is well established, clinical trials evaluating the safety and efficacy of immunosuppression regimens are lacking. Until such data exists, immunosuppression of the elderly transplant recipient should be based on the traditional principles which guide all transplant protocols and consideration of factors that are unique to the elderly. There are limited data regarding age related changes in immune function and metabolism of immunosuppression agents in this population. Results of registry data analyses suggest that the risk of acute rejection decreases with age; however, the impact of acute rejection on long-term allograft function is greater in this population. There is also an increased risk of infection and adverse events posttransplantation among these patients. Elderly patients are more likely to receive organs from extended criteria donors and the impact of donor factors on transplant outcomes must therefore be considered. Taking these factors into consideration, we propose an approach to immunosuppression in the elderly based on individual risk stratification of treatment failure and the potential for adverse events. PMID- 17700151 TI - The Transplantation Society's policy on interactions with China. AB - The Transplantation Society has for many years taken a stand against the use of organs from executed prisoners in the People's Republic of China. Recently, increasing contact between Chinese transplant programs and the international transplant community has created a need for more specific guidelines. This article presents The Transplantation Society's policy on interactions with China and also summarizes some recent positive developments. PMID- 17700152 TI - The financial burden of transplantation: a single-center survey of liver and kidney transplant recipients. AB - Little is known about the financial impact of transplantation on patients and families. We interviewed 333 liver transplant (LT) and 318 kidney transplant (KT) recipients who were at least 1 year posttransplant. Patients were asked whether transplantation caused financial problems, whether income had changed since transplantation, what resources they used to pay for transplant-related expenses, and what their out-of-pocket monthly expenses were. Descriptive and comparative statistics, measures of association, and logistic regression analyses were calculated. Many patients reported financial problems secondary to transplantation (40.6%) and less monthly income now than in the year preceding transplantation (46.5%). Average monthly out-of-pocket expense was $476.60. LT recipients had higher out-of-pocket expenses than KT recipients (t=2.46, P=0.015). Patients used personal savings (53.9%) and credit cards (25.0%) to help offset these expenses, among other strategies. For both LT and KT recipients, older age, nonworking status before transplantation, and current nonworking status predicted greater financial impact, whereas younger age and current nonworking status predicted higher monthly out-of-pocket expenses. These findings highlight the potential financial impact of transplantation on patients and families, and they have implications for assisting patients in managing out-of pocket expenses after transplantation. PMID- 17700153 TI - Immunomodulation by adenoviral-mediated SCD40-Ig gene therapy for mouse allogeneic islet transplantation. AB - BACKGROUND: The success of pancreatic islet transplantation is limited because of immune rejection of allogeneic transplanted tissue and potential adverse side effects of nonspecific immunosuppression. Local expression of an immunosuppressive agent at the site of islet transplant could promote long-term engraftment without associated systemic side effects. METHODS: We have examined the ability of adenoviral vector mediated local production of sCD40 immunoglobulin (Ig), blocking the CD40-CD40 ligand (CD40L) costimulatory pathway, from genetically modified allogeneic islets to facilitate long-term engraftment in fully allogeneic mouse model. RESULTS: Transplantation of islets infected with an adenoviral vector expressing sCD40-Ig resulted in allograft survival longer than 120 days in five of the nine recipient mice (56%). However, mice that received mock infected (n=5) or control adenoviral vector (Ad.eGFP; n=6) rejected the allograft with a median survival of 15 and 16 days, respectively. Histopathology demonstrated that the grafts of the long-term surviving animals preserved islets with minimal mononuclear cell infiltration. CONCLUSION: These results demonstrate that local inhibition of the CD40-CD40L pathway by adenoviral gene transfer of sCD40-Ig to the islets prior to transplant significantly prolonged islet allograft acceptance. This approach could be used clinically to facilitate islet transplantation. PMID- 17700154 TI - Interference with tissue factor prolongs intrahepatic islet allograft survival in a nonhuman primate marginal mass model. AB - BACKGROUND: Tissue factor (TF) expression on islets can result in an instant blood-mediated inflammatory reaction (IBMIR) that contributes to early islet loss. We tested whether peritransplant protection of islets from IBMIR with a monoclonal anti-TF antibody (CNTO859) would enhance engraftment in our nonhuman primate marginal mass model. METHODS: Each of six pairs of cynomolgus monkeys (CM) with streptozotocin-induced diabetes was closely matched for metabolic control and was transplanted with 5,000 IEQ/kg allogeneic, ABO-compatible islets from the same donor under the cover of steroid-free immunosuppression. For each pair, experimental animals received islets cultured with 20 microg/mL anti-TF and were dosed with 6 mg/kg anti-TF intravenously, 10-25 min before islet infusion; control monkeys received an equal number of islets from the same preparation cultured without anti-TF and no in vivo treatment. RESULTS: Early fasting C peptide (CP) values were different between (P<0.01), but not within, pairs and correlated with in vitro functional capacity of islets as assessed by perifusion (r=0.60; P=0.022). Compared to their matched controls, experimental animals had decreased posttransplant markers of coagulation, higher fasting CP levels (1 month posttransplant and end of study) and prolonged graft function. CONCLUSIONS: These data suggest that pretreatment of islets and the recipient with anti-TF may limit the effects of IBMIR, thereby enhancing islet engraftment and survival. PMID- 17700155 TI - Tacrolimus as prophylaxis for acute graft-versus-host disease in reduced intensity cord blood transplantation for adult patients with advanced hematologic diseases. AB - BACKGROUND: Myeloablative cord blood transplantation (CBT) for adult patients offers a 90% chance of engraftment with a 50% rate of transplant-related mortality, mostly attributable to infection. We have demonstrated the feasibility of reduced-intensity CBT (RI-CBT) for adult patients, in which cyclosporine was used for acute graft-versus-host disease (GVHD) prophylaxis. Transplantation related mortality (TRM) was 27% within 100 days. Therefore our objective was to evaluate the feasibility of RI-CBT with tacrolimus as GVHD prophylaxis for adult patients with hematologic malignancies. METHODS: Thirty-four patients with a median age of 56.5 years (range; 22-68) with hematologic diseases underwent RI CBT at Toranomon Hospital between November 2003 and September 2004. Preparative regimen comprised fludarabine 25 mg/m2 on days -7 to -3, melphalan 80 mg/m2 on day -2, and 4 Gy total body irradiation on day -1. GVHD prophylaxis was continuous intravenous infusion of tacrolimus 0.03 mg/kg, starting on day -1. RESULTS: Thirty-one patients achieved neutrophil engraftment at a median of day 20. Median infused total cell dose was 2.4 x 10E7/kg (range; 1.6-4.8). Thirty-two patients achieved complete donor chimerism at day 60. Grade II-IV acute GVHD occurred in 45% of patients, with a median onset of day 26. Primary disease recurred in five patients, and TRM within 100 days was 12%. Estimated 1-year overall survival was 70%. CONCLUSION: This study demonstrated the possible improvement in transplant-related mortality by tacrolimus as GVHD prophylaxis in adult RI-CBT recipients. PMID- 17700156 TI - Polyomavirus BK versus JC replication and nephropathy in renal transplant recipients: a prospective evaluation. AB - BACKGROUND: JC virus (JCV) viruria is more common than BK virus (BKV) viruria in healthy individuals but in kidney transplants (KT), polyomavirus nephropathy (PVAN) is primarily caused by BKV. Few cases of PVAN have been attributed to JCV. Systematic studies on JCV replication in KT are lacking. METHODS: Out of a cohort of KT patients screened with urine cytology, patients shedding decoy cells were studied (n=103). Molecular studies demonstrated BKV, JCV, or BKV+JCV shedding in 58 (56.3%), 28 (27.2%), and 17 (16.5%), respectively. Biopsy was performed when decoy cells persisted 2 months or serum creatinine increased >20%. RESULTS: BKV viruria was strongly associated with BKV viremia (93%), PVAN (48%, P=0.01) and graft loss (P=0.03). Higher BKV viremia correlated with graft dysfunction (P=0.01), more advanced histological pattern of PVAN (P<0.0001), and more infected cells in biopsy (P=0.0001). BKV viremia of > or =10,000 copies/mL was significantly associated with histologically confirmed PVAN (P=0.0001). Reduction of immunosuppression lead to disappearance of decoy cells in patients shedding BK (>93%). JCV viruria, was more often asymptomatic (P=0.002) and affected older patients (P=0.02). JCV PVAN was less common (21.4%) and was characterized by sparse cytopathic changes but significant inflammation and fibrosis. JCV viremia was rare (14.2%), transient, and low (mean 2.0E+03/mL). After reduction of immunosuppression decoy cells persisted in >50% of patients with JCV (P=0.0001), but no graft loss occurred. During the period of the current study, the incidence of BKV-PVAN was 5.5% and the incidence of JCV-PVAN was 0.9%. CONCLUSIONS: The data point to significant differences of BKV and JCV biology regarding replication and disease in KT patients, with important implications for screening and management. PMID- 17700157 TI - Older donor livers show early severe histological activity, fibrosis, and graft failure after liver transplantation for hepatitis C. AB - BACKGROUND: In hepatitis C virus (HCV)-positive liver transplant recipients, infection of the allograft and recurrent liver disease are important problems. Increased donor age has emerged as an important variable affecting patient and graft survival; however, specific age cutoffs and risk ratios for poor histologic outcomes and graft survival are not clear. METHODS: A longitudinal database of all HCV-positive patients transplanted at our center during an 11-year period was used to identify 111 patients who received 124 liver transplants. Graft survival and histological endpoints (severe activity and fibrosis) of HCV infection in the allografts were compared as a function of donor age at transplantation. RESULTS: By Kaplan-Meier analyses, older allografts showed earlier failure and decreased time to severe histological activity and fibrosis as compared with allografts from younger donors. By Cox proportional hazards analysis, older allografts were at greater risk for all severe histologic features and decreased graft survival as compared with younger allografts (P< or =0.02 for all outcomes). Analysis of donor age as a dichotomous variable showed that donors greater than 60 yr were at high risk for deleterious histologic outcomes and graft failure. An age cutoff of 60 yr showed a sensitivity of 94% and specificity of 67% for worse graft survival by receiver operating characteristics curve. CONCLUSIONS: Advanced donor age is associated with more aggressive recurrent HCV and early allograft failure in HCV positive liver transplant recipients. Consideration of donor age is important for decisions regarding patient selection, antiviral therapy, and organ allocation. PMID- 17700158 TI - Polyomavirus polymerase chain reaction as a surrogate marker of polyomavirus associated nephropathy. AB - BACKGROUND: Polyomavirus-associated nephropathy (PVAN) is a significant cause of allograft loss after renal transplantation. A noninvasive assay that can guide the evaluation of PVAN would be of clinical value. We compared the utility of BK virus (BKV) polymerase chain reaction (PCR) and urine cytology in screening for concurrent PVAN. METHODS: We used PCR to test urine and plasma samples from renal recipients simultaneously for BKV DNA. Additionally, we tested urine samples for decoy cells. Sample results were correlated with biopsy-proven PVAN. Receiver operator characteristic curves were used to determine viral load thresholds associated with concurrent PVAN. RESULTS: In this cross-sectional study, BKV viruria, viremia, and urinary decoy cells were detected in 24%, 9%, and 13% of renal recipients, respectively. Among 114 patients who had renal allograft biopsy, four (3.5%) were diagnosed with PVAN. Using pathology as gold standard for the diagnosis of PVAN, BKV viremia threshold of >1.6E+04 copies/mL had 100% sensitivity, 96% specificity, 50% positive predictive value, and 100% negative predictive value. A BKV viruria threshold of >2.5E+07 copies/mL had 100% sensitivity, 92% specificity, 31% positive predictive value, and 100% negative predictive value. In contrast, urine decoy cells had 25% sensitivity, 84% specificity, 5% positive predictive value, and 97% negative predictive value for the diagnosis of concurrent PVAN. CONCLUSION: BKV PCR may be a clinically useful noninvasive test to identify renal recipients with concurrent PVAN. BKV DNA >1.6E+04 copies/mL of plasma and >2.5E+07 copies/mL of urine were highly associated with concurrent PVAN whereas a negative PCR test makes the diagnosis of PVAN highly unlikely. PMID- 17700159 TI - Metabolic, coagulative, and hemodynamic changes during intestinal transplant: good predictors of postoperative damage? AB - BACKGROUND: Analysis of intraoperative changes of metabolic, hemodynamic, and coagulative parameters is useful to detect early ischemia-reperfusion damage after intestinal transplant. METHODS: The objective of our study is to correlate the histological damage at the end of transplant in relation to the intraoperative changes after reperfusion. The histological aspect was graded according to Park's classification at the end of the surgical procedure with biopsies of the graft. Patients were divided into two groups according to the presence or absence of histological damage of the small bowel wall: group A (normal mucosa/minimal damage: Park's grades 0-1) and group B (mucosal damage: Park's grades 2-8). RESULTS: Significant hemodynamic, metabolic, and coagulative disorders were observed in group B. Consequently, these disorders are thought to be early indicators of graft damage. CONCLUSIONS: Actual monitoring procedures used for postoperative graft surveillance remain paramount in detecting postoperative intestinal dysfunction, but the indicators described in this paper could represent a further help in intraoperative and postoperative management. PMID- 17700160 TI - Late recurrent urinary tract infections may produce renal allograft scarring even in the absence of symptoms or vesicoureteric reflux. AB - BACKGROUND: The significance of late urinary tract infections (UTIs) after renal transplantation and their association with scarring and graft dysfunction remains controversial. We sought to define the prevalence of renal scarring in allograft recipients with a history of late recurrent UTIs, to determine whether the presence of vesicoureteric reflux (VUR) confers an increased risk of scarring and to establish whether scarring correlates with graft dysfunction. METHODS: Among 307 renal allograft recipients, we identified 56 (18%) with late recurrent UTIs (> or =3/year). A total of 32 patients had undergone further investigation by both 2,3 dimercapto-succinic acid single-photon emission computed tomography (99mTc-DMSA SPECT) scan and micturating cystourethrogram (MCUG). RESULTS: Of the 32 patients, 24 (75%) had scars on 99mTc-DMSA SPECT and 15 (47%) had reflux on MCUG. Thirteen of these 15 patients with reflux (87%) had scars, although there was no significant correlation between number of scars and degree of reflux. Eleven of 17 patients (65%) with UTIs but without VUR had scars, as did 12 of 14 (86%) with previous graft pyelonephritis. The pattern of scarring (typically multiple focal cortical defects) suggested infection as the cause. This pattern was not seen in a contemporary cohort with vascular occlusions and was rarely seen in patients with chronic allograft nephropathy. Scarring was not associated with inferior graft survival (median follow-up, 15 years). CONCLUSIONS: In patients with late UTIs, renal scarring is a frequent finding. Scarring may occur even in asymptomatic patients without VUR. The lack of an effect on graft survival may reflect successful intervention with prophylactic antibiotics and surveillance urine cultures. Late recurrent UTIs may be damaging to renal allografts, even in the absence of reflux. PMID- 17700161 TI - Risk factors for mortality in diabetic nephropathy patients accepted for transplantation. AB - BACKGROUND: There is a high incidence of silent coronary artery disease (CAD) in patients with diabetes. We wanted to investigate risk factors for mortality, and especially CAD, in a well-defined cohort of diabetic nephropathy transplant candidates accepted for transplantation. METHODS: From 1999 through 2004, 155 patients underwent work up for living or deceased kidney (KA) or simultaneous pancreas-kidney (SPK) transplantation. The work up included coronary angiography for all patients and 136 were accepted. Mean (SD) age was 50 (12) years, 62% had type 1 diabetes, 73% were males, and 34% were on dialysis. Mean follow-up from time of acceptance for transplantation was 3.6 (1.9) years. RESULTS: Survival of KA transplanted patients was 97% at 1 year, 89% at 3 years, and 76% at 5 years, whereas in SPK patients 100%, 94%, and 90%, respectively (P=0.065). One- and 3- year survival was only 57% and 20% in those remaining wait-listed (P<0.001). In univariate analysis mortality was associated with KA transplantation (hazard ratio [HR]=0.30, P=0.011) and SPK transplantation (HR=0.10, P=0.001), and age (HR=1.04, P=0.014). In multivariable analysis, KA transplantation (HR=0.28, P=0.006), SPK transplantation (HR=0.09, P=0.001), age (HR=1.06, P=0.002), type 2 diabetes (HR=0.14, P=0.003), and duration of diabetes (HR=0.94, P=0.019) were parameters associated with mortality. CONCLUSIONS: The only modifiable risk factor was transplantation with risk reduction up to 90%. CAD was not a risk factor for mortality when medically treated and revascularized according to standard guidelines. PMID- 17700162 TI - The impact of renal allograft function on exposure and elimination of mycophenolic acid (MPA) and its metabolite MPA 7-O-glucuronide. AB - BACKGROUND: Previous studies have shown that total-body clearance of mycophenolic acid (MPA) is increased and total MPA exposure decreased in renal allograft recipients with severe renal dysfunction. In contrast to these studies, other studies have associated renal impairment with higher MPA exposure. The reason for these inconsistencies is not clear. METHODS: In 120 renal allograft recipients with stable graft function and treated with a combination of mycophenolate mofetil, tacrolimus, and corticosteroids, clinical determinants of exposure to total MPA and its glucuronide metabolite MPA 7-O-glucuronide (MPAG) were investigated in a multivariate regression model at 3 (n=118) and 12 (n=63) months after transplantation. RESULTS: Almost 50% of total MPA exposure could be explained by the final model, in which proteinuria, glomerular filtration rate, diabetes mellitus, and the mycophenolate mofetil dose were independent determinants of total MPA exposure. Lower glomerular filtration rate (GFR) was independently associated with higher MPA exposure both at 3 and 12 months after transplantation. GFR, alanine aminotransferase, and serum albumin levels and mycophenolate mofetil dose explained 69% of total MPAG exposure variability. CONCLUSION: In stable renal recipients, total MPA exposure negatively associates with renal function, through accumulation of both MPA and MPAG in patients with moderately reduced renal allograft function. This is in contrast to severe graft dysfunction, where MPA clearance is higher due to increased free fraction of MPA, as shown in previous studies. The duality in the effect of graft function on MPA pharmacokinetics is of clinical importance, adjusting mycophenolate mofetil dose according to renal function might help to avoid side effects and improve efficacy. PMID- 17700163 TI - Ultrasmall iron oxide particle contrast agent and MRI can be used to monitor the effect of anti-rejection treatment. AB - BACKGROUND: The purpose of the study was to investigate the feasibility of monitoring anti-rejection treatment using a blood pool contrast agent and magnetic resonance (MR) imaging. METHODS: Allogeneic heterotopic heart transplantations in rats were performed. In one group (treated group), a mild acute rejection was developed and subsequently treated and MR imaging was performed before and after anti-rejection treatment. In the other group (nontreated group), a mild acute rejection was developed and allowed to progress without treatment and MR examinations were performed before and after the advance of the acute rejection. After injecting ultrasmall superparamagnetic contrast agent, the relative change of signal intensity (SI) over time was measured. The SI difference between both radiological investigations for every animal was calculated; hence, every animal served as its own control. RESULTS: In both treated and nontreated groups, a significant difference over time was found between the two MR examinations seen as a decrease in the treated group and an increase in the nontreatment group. CONCLUSION: It is concluded that the effect of anti-rejection treatment can be detected using a blood pool agent and MR imaging, as a change in SI corresponding to changes in the vascular permeability. PMID- 17700164 TI - Improved poststorage cardiac function by poly (ADP-ribose) polymerase inhibition: role of phosphatidylinositol 3-kinase Akt pathway. AB - BACKGROUND: Inhibition of poly(ADP-ribose) polymerase 1 (PARP) has been shown to be effective in minimizing cardiac ischemia reperfusion injury. We investigated the cardioprotective effect of the PARP inhibitor, INO-1153, in isolated working rat hearts after 6 hr of hypothermic storage in Celsior. METHODS: Hearts were treated with 1 muM INO-1153 before hypothermic storage, at cardioplegia and storage or after hypothermic storage. Hearts not exposed to INO-1153 served as controls. Another group was pretreated with the phosphatidylinositol 3-kinase inhibitor Wortmannin (0.1 muM) before storage in INO-1153-supplemented Celsior. After baseline measurement of aortic flow, heart rate, coronary flow, and cardiac output were obtained, hearts were arrested and stored in Celsior at 2-3 degrees C for 6 hr. After storage, hearts were reperfused for 15 min before performing work for a further 30 min, at which time poststorage indices of cardiac function were remeasured then heart tissue was stored at -80 degrees C for Western blot analysis. RESULTS: The presence of INO-1153 during prestorage perfusion or during cardioplegia and storage significantly improved poststorage cardiac function. Functional improvements produced by INO-1153 were completely abolished by Wortmnanin pretreatment. Western blots showed a significant increase in phospho Akt in presence of INO-1153, which was inhibited by Wortmannin. CONCLUSION: Activation of the prosurvival phosphatidylinositol 3-kinase-Akt pathway was involved in the protective action of PARP inhibition in this model of donor heart procurement and hypothermic storage. Importantly for the logistics of clinical organ procurement, maximum protection is observed when the PARP inhibitor is included in the cardioplegic storage solution. PMID- 17700165 TI - Evidence for genetic susceptibility towards development of posttransplant lymphoproliferative disorder in solid organ recipients. AB - BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a life threatening complication after organ transplantation. The identification of risk factors for PTLD development is important for disease management. It has been shown that cytokine gene polymorphisms are associated with lymphoma and Epstein Barr virus (EBV)-associated diseases in nonimmunosuppressed patients. In the present case-control study, we analyzed the impact of -1082 interleukin (IL)-10, 308 tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1 (codon 10, 25), and +874 interferon (IFN)-gamma gene single-nucleotide polymorphisms on the late onset EBV-associated PTLD. METHODS: Out of 1,765 solid organ recipients, 38 patients with late-onset EBV-associated PTLD and 408 matched solid organ recipients were selected and enrolled in the study. Single nucleotide polymorphisms (SNPs) for -1082IL-10, -308TNF-alpha, TGF-beta1 (codon 10, 25), and +874IFN-gamma genes were analyzed by a sequence specific primer polymerase chain reaction and were related to the PTLD development, and the disease course and outcome. RESULTS: The TGF-beta1 (codon 25) GG genotype was detected more frequently in controls than in PTLD patients (odds ratio=0.34, 95% confidence interval: 0.17-0.69, P=0.0022). The frequency of -1082 IL-10 GG genotype was also significantly higher in controls than in PTLD patients (odds ratio=0.5, 95% confidence interval: 0.25-1.0, P=0.044). There were no associations between 308TNF-alpha, TGF-beta1 codon 10, and +874IFN-gamma SNPs and PTLD. Disease course and outcome were not associated with any cytokine SNPs. CONCLUSIONS: Polymorphisms in two key anti-inflammatory cytokines, IL-10 and TGF-beta, are associated with susceptibility to EBV-associated PTLD, suggesting that a shift in pro-/anti-inflammatory response is involved in the pathogenesis of PTLD. PMID- 17700166 TI - Dependency of the trans vivo delayed type hypersensitivity response on the action of regulatory T cells: implications for monitoring transplant tolerance. AB - BACKGROUND: The trans vivo delayed-type hypersensitivity (DTH) assay has been used for monitoring the immune status of clinical transplant recipients. Here we tested the hypothesis that the assay can reveal control of allograft rejection by CD25CD4 regulatory T cells (Treg). METHODS: CBA.Ca (H2) recipients of heterotopic C57BL/10 (H2, B10) heart transplants were untreated or pretreated with anti-CD4 antibody and donor-specific blood. This protocol has been shown previously to induce operational tolerance to alloantigens that is dependent on CD25CD4 Treg. Four weeks after transplantation leukocytes were harvested and used for the trans vivo DTH assay. Cells were stimulated with irradiated B10 leukocytes or subcellular antigen and injected into ear pinnae of immune deficient CB17.SCID.beige hosts. RESULTS: Stimulation of leukocytes from recipients rejecting B10 cardiac allografts with recall alloantigen caused a "strong" swelling response, whereas similar stimulation of leukocytes from operationally tolerant mice resulted in significantly less swelling (n=17; P=0.003). When CD25 T cells were depleted from "tolerant" leukocytes, the swelling response triggered was similar to that obtained using cells from rejecting animals (P<0.001), while coinjection of purified CD25CD4 cells from tolerant recipients with rejecting cells suppressed the swelling response (P=0.007) to the level observed with cells from tolerant mice. Both the effector and the regulatory response were triggered by indirect allorecognition and blocking experiments showed that the regulation observed was dependent on cytoxic T lymphocyte antigen (CTLA) 4. CONCLUSION: The trans vivo DTH assay can be used to reveal regulation mediated by CD25CD4 T cells and is CTLA4 dependent. PMID- 17700167 TI - Inactivation of T-cell receptor-mediated integrin activation prolongs allograft survival in ADAP-deficient mice. AB - BACKGROUND: Signaling through the T cell receptor (TCR) leads to profound changes in the function and properties of T cells, including integrin activation. Adhesion and degranulation promoting adapter protein (ADAP) is an adapter protein linking T cell receptor stimulation to integrin activation. We aim to clarify how disruption of TCR-mediated integrin activation affects alloreactive immune responses. METHODS: In vitro T cell proliferation and the cytokine production was determined. In vivo cytotoxic T lymphocyte (CTL) activity was measured as well. Allogenic skin and heart transplantation was used to test the in vivo role of ADAP in alloimmune responses. Histology and flow cytometry was applied to analyze the graft infiltrating lymphocytes. RESULTS: Upon stimulation with allogenic dendritic cells ADAP-deficient T cells displayed impaired proliferative responses compared to wild type (WT) T cells. This was accompanied by significantly decreased production of the cytokine interleukin-2. In contrast, the in vivo CTL activity in ADAP-deficient mice was comparable to that of WT mice. Consistently, we observed a prolongation of fully major histocompatibility complex (MHC) mismatched heart transplants in ADAP deficient mice. Protection of allogenic heart grafts in ADAP-deficient mice was accompanied by a decrease in the infiltration, proliferation and activation of T cells in the allograft. However, no effect was observed after fully MHC-mismatched skin transplantation. CONCLUSIONS: We have shown that although ADAP is dispensable for the rejection of allografts, ADAP function plays an important role for the efficacy of graft rejection. ADAP's main function appears to affect the induction phase of the immune response. PMID- 17700168 TI - A novel chemical compound, NK026680, targets dendritic cells to prolong recipient survival after rat liver grafting. AB - BACKGROUND: There is great interest in the recently developed immunosuppressant NK026680, which is a derivative of triazolopyrimidine. Its unique chemical structure and action mechanism are completely different from those of conventional immunosuppressants. METHODS: The present study was designed to investigate the effects of NK026680 on rat bone-marrow-derived dendritic cell (BMDC) differentiation and maturation in an in vitro culture system and its applicability in liver transplantation. RESULTS: NK026680 inhibited T-cell proliferation stimulated by alloantigen in a dose-dependent manner, but did not inhibit concanavalin A. The populations of OX6+CD161a cells and CD86+CD161a cells were suppressed in NK026680-treated dendritic cells (DCs). Exposure of DCs to NK026680 downregulated the interleukin (IL)-12 (p40, p35), interferon-gamma mRNA expression and upregulated IL-10, transforming growth factor-beta, in which impaired the ability of DC to stimulate T cell proliferation. Furthermore, oral administration of NK026680 for 14 days significantly prolonged liver allograft survival and limitation of T-cell responses and polarization toward a Th2 cytokine profile. CONCLUSIONS: These results demonstrate that NK026680 may have therapeutic potential for preventing allo-rejection in organ transplantation, acting at the step of immune response through inhibiting BMDC differentiation and maturation into potent antigen-presenting cells. PMID- 17700169 TI - Nitrosative stress and corneal transplant endothelial cell death during acute graft rejection. AB - BACKGROUND: Nitrosative stress takes place in endothelial cells (EC) during corneal acute graft rejection. The purpose of this study was to evaluate the potential role of peroxynitrite on corneal EC death. METHODS: The effect of peroxynitrite was evaluated in vivo. Fifty, 250, and 500 microM in 1.5 microL of the natural or denatured peroxynitrite in 50 microM NaOH, 50 microM NaOH alone, or balanced salt solution were injected into the anterior chamber of rat eyes (n=3/group). Corneal toxic signs after injection were assessed by slit-lamp, in vivo confocal imaging, pachymetry, and EC count. The effect of peroxynitrite was also evaluated on nitrotyrosine and leucocyte elastase inhibitor/LDNase II immunohistochemistry. Human corneas were incubated with peroxynitrite and the effect on EC viability was evaluated. A specific inducible nitric oxide synthase inhibitor (iNOS) was administered systemically in rats undergoing allogeneic corneal graft rejection and the effect on EC was evaluated by EC count. RESULTS: Rat eyes receiving as little as 50 microM peroxynitrite showed a specific dose dependent toxicity on EC. We observed an intense nitrotyrosine staining of human and rat EC exposed to peroxynitrite associated with leucocyte elastase inhibitor nuclear translocation, a noncaspase dependent apoptosis reaction. Specific inhibition of iNOS generation prevented EC death and enhanced EC survival of the grafted corneas. However, inhibition of iNOS did not have a significant influence on the incidence of graft rejection. CONCLUSION: Nitrosative stress during acute corneal graft rejection in rat eyes induces a noncaspase dependent apoptotic death in EC. Inhibition of nitric oxide production during the corneal graft rejection has protective effects on the corneal EC survival. PMID- 17700170 TI - Control of cyclosporine A-induced tumor progression using 15-deoxyspergualin for rat cardiac transplantation. AB - Immunosuppressive therapy increases the risk of recurrence of initial cancers in organ transplant patients, and compelling therapeutic protocols are needed to suppress the malignancy and protect the allograft. We examined the potential use of 15-deoxyspergualin (DSG) in relation to organ transplantation and cancer. The effect of DSG on established liver metastatic tumors in recipient rats bearing a heart allograft was evaluated using an in vivo luminescent technique with luciferase-expressing RCN-H4 rat colon cancer cells. The inhibition of cell growth by DSG was correlated with NF-kappa B activity and caspase-3/7 activity in vitro. In the cyclosporine A (CsA)-induced cancer progression model of rats, DSG treatment (3 mg/kg) blocked the increase in tumor-derived luciferase activity, while CsA (15 mg/kg) facilitated luciferase activity up to around day 20 after cardiac transplantation. Our data suggest that DSG may be a therapeutic candidate for the control of tumor growth in transplant patients. PMID- 17700171 TI - Sequential quadruple immunosuppression including sirolimus in extended criteria and nonheartbeating donor kidney transplantation. AB - The aim was to evaluate feasibility and safety of calcineurin inhibitor-free immunosuppression in high-risk donor kidney transplantation with sequential sirolimus introduction. Kidney transplant patients (n=76) with a donor aged >60 years, donor with acute renal failure, or a nonheartbeating donor were included. Immunosuppression consisted of antithymocyte globulin or basiliximab, mycophenolate mofetil, prednisone, and sequential introduction of sirolimus. One year patient survival was 96.2% and 95.8%; graft survival was 94.2% and 91.7%; acute rejection rates were 21.2% and 12.4%; delayed graft function was 21.2% and 66.7%; and creatinine clearance was 58+/-20 mL/min and 56+/-21 mL/min for the brain-dead donor group and the nonheartbeating donor group, respectively. Most adverse events were infections, but also three lymphoceles, three urinary fistulas, three wound seromas. Sequential sirolimus introduction in high-risk donor kidney transplantation was found to lead to good patient and graft survival and incidence of acute rejection and delayed graft function. PMID- 17700172 TI - Ureteral stents: a novel risk factor for polyomavirus nephropathy. AB - Polyomavirus virus nephropathy (PVN) is an important cause of renal allograft dysfunction. The risk factors for the development of PVN have not been completely elucidated. We investigated the hypothesis that ureteral trauma caused by placement of indwelling stents is an independent risk factor for PVN. Twenty cases of PVN were compared with 46 controls. Logistic regression was used to calculate odds ratios and to construct multivariate models. A total of 75% of cases and 35% of controls had stents placed during renal transplantation. In both univariate and multivariate logistic regression analyses adjusting for age, gender, deceased donor transplant, delayed graft function, tacrolimus and exposure to antibodies, the placement of a ureteral stent at the time of kidney transplantation was found to have a statistically significant association with developing PVN. Our findings reveal that the presence of a ureteral stent is associated with an increase in the risk of PVN. PMID- 17700173 TI - Seven-year prospective study of nonmelanoma skin cancer incidence in U.K. renal transplant recipients. AB - Nonmelanoma skin cancer (NMSC) causes significant morbidity and mortality posttransplantation. We examined the annual incidence of NMSC in U.K. renal transplant recipients (RTRs). A total of 269 (95% of potential population) RTRs of skin type I-IV were recruited into a prospective study of NMSC incidence between 1998 and 2006. A total of 244 (91% enrolled) RTRs were screened on at least one occasion. The mean incidence per year of NMSC was 7.82% (SD: 1.84), comprising a mean (SD) incidence per year of squamous cell carcinoma 3.45% (1.36), basal cell carcinoma 3.58% (1.17), and Bowen's disease 2.52% (0.91). The risk of developing NMSC increased with duration posttransplantation: the mean incidence per year of NMSC was 3.27% (0.53) in RTRs <5 years posttransplantation, 5.86% (3.1) in RTRs 5-10 years posttransplant, and 11.1% (1.85) in those >10 years posttransplant. Relatively low NMSC incidence rates within the first 5 years posttransplantation suggests that duration posttransplantation may determine the optimum frequency of surveillance of RTRs in the United Kingdom. PMID- 17700174 TI - Fluorine-18-fluorodeoxyglucose positron emission tomography as a novel noninvasive diagnostic tool for gastrointestinal graft-versus-host disease. PMID- 17700175 TI - Effects of a mycophenolate mofetil-based immunosuppressive regimen in Chagas' heart transplant recipients. PMID- 17700176 TI - Chemokines and chronic heart allograft rejection. PMID- 17700181 TI - SAFE discharge for infants with high-risk home environments. PMID- 17700183 TI - SAFE discharge for infants with high-risk home environments. PMID- 17700190 TI - Guide to capillary heelstick blood sampling in infants. AB - Capillary blood sampling is an essential method of blood collection performed by nurses of all skill levels to obtain samples for routine laboratory tests in neonates. Accuracy of results depends on proper heelstick and sample collection technique. Recent advances including development of devices designed specifically for heelstick capillary blood sampling and research into expanded safe heel capillary sampling sites are discussed. A step-by-step guide to capillary blood sampling is outlined along with evidence-based practice incorporating neonatal appropriate disinfection and nonpharmacological analgesia that contribute to improved infant safety and comfort during and after the procedure. PMID- 17700191 TI - Peritoneal dialysis in the neonatal intensive care unit. Management of acute renal failure after a severe subgaleal hemorrhage. AB - Acute renal failure is common in the neonatal intensive care unit but is often not recognized in its early phases, when it is potentially reversible. The typical patient with acute renal failure is premature, but many term infants are also at risk. One such group is those with severe bleeding, such as a subgaleal hemorrhage. In these cases, hypovolemia can quickly progress to ischemia, which affects many organs but has profound effects on the kidney. In term infants, acute renal failure is most commonly diagnosed in those with perinatal depression. This article presents a unique case of an infant with subgaleal and intracranial bleeding that resulted in acute renal failure requiring peritoneal dialysis in the hopes of the eventual restoration of kidney function. PMID- 17700192 TI - A matter of size: Part 2. Evaluating the large-for-gestational-age neonate. AB - Large for gestational age (LGA) is another designation used to assess and monitor growth throughout the pregnancy and after delivery. Large for gestational age is an abnormal growth descriptor that assists in anticipating neonatal needs pre-and postnatally. Careful monitoring for abnormal growth trends in the fetus is imperative prenatally. The relative size of a neonate affects many aspects of prenatal and postnatal surveillance. Nursing care is guided by the maternal history and the delivery room complications that may occur. Anticipating complications in the delivery room is vital to the survival of LGA neonates. Nursing care for LGA neonates requires knowledge based on these potential complications. A thorough physical assessment with appropriate glucose monitoring and parental education is required. Size matters when it comes to the health and welfare of all sizes of neonates. Anticipatory guidance with prenatal monitoring and education can improve outcomes in the neonate at risk for LGA complications at birth. PMID- 17700194 TI - Perinatal loss and parental distress after the birth of a healthy infant. AB - PURPOSE: Determine whether levels of depressive symptoms and current stress related to prior perinatal loss differ from similar prenatal evaluations after the birth of a subsequent healthy full-term infant and investigate differences in depressive symptoms in the postpartum period among parents with and without a history of perinatal loss. PARTICIPANTS: Seventy-four of the original 206 parents who participated in an earlier prenatal study agreed to participate at follow-up and were divided into 2 groups (38 parents with a history of perinatal loss and 36 parents with no prior losses). METHODS AND DESIGN: A 2-wave, 2-group comparative design was used. Both mothers and fathers were recruited for this study. Surveys were completed via telephone interviews. Data were analyzed using descriptive statistics, chi-square tests, t tests and Pearson correlations. MAIN OUTCOME MEASURES: The Impact of the Event Scale (IES) is broadly used to evaluate the continuing influence of a past stressful life event. In the current study, the items were anchored to the traumatic event of perinatal loss. The IES contains 2 subscales: Intrusion and Avoidance. Cronbach's alphas for the current study were .80 (total scale), .85 (Intrusion subscale), and .69 (Avoidance subscale). The Center for Epidemiologic Studies-Depression Scale (CES-D) is used to identify the duration and frequency of depressive symptoms experienced by the respondent during the previous week. The Cronbach's alpha for the current study was .92. PRINCIPLE RESULTS: There was a significant overall decrease in depressive symptoms after the birth of a healthy infant for fathers but not for mothers with prior perinatal losses. Nevertheless, approximately one third of the mothers with a history of loss continued to report CES-D scores that placed them at high risk for depression. There also was a significant decrease in stress related to the prior loss for both mother and fathers. The greater the stress associated with the prior loss, the greater were parents' depressive symptoms after birth. In contrast to the prenatal assessment, there were no significant differences in levels of depressive symptoms between the loss and nonloss groups at the postnatal assessment. CONCLUSIONS: The stress associated with perinatal loss, although diminished after the subsequent birth of a healthy infant compared with that during pregnancy, remained high for many parents, especially mothers. Neonatal nurses need to continue to evaluate parents with a history of perinatal loss for ongoing psychological distress after the birth of a subsequent healthy infant. PMID- 17700195 TI - Is meconium screening appropriate for universal use? Science and ethics say no. AB - Researchers have been actively looking to biomarker development as a way to improve diagnosis in conditions such as fetal alcohol syndrome (FAS) that have typically been difficult to identify at an early stage. Meconium testing is considered a potentially useful newborn screening method. Screening for alcohol (and other drug) use is unique from all other types of newborn screening in that there is a greater element of social risk for parents, particularly mothers (public exposure of substance use with potential for child welfare involvement). There are many factors related to the science and ethics of the meconium screening process to consider before implementing universal or targeted screening. As care providers who participate in the screening and counseling process and as advocates for infants and their families, neonatal nurses should be active participants in discussions surrounding the ethical and clinical appropriateness of meconium screening program development and expansion. The science behind meconium screening at present is not strong enough to warrant widespread implementation of screening; neonatal nurses are cautioned to approach screening carefully because of the critical social implications for mother and baby. PMID- 17700196 TI - Death within 48 hours of admission to the emergency department: the value of autopsy. AB - OBJECTIVE: To identify factors that contribute to patient death within 48 hours of admission to the emergency department. MATERIALS AND METHODS: A retrospective study of the patients who died within 48 hours of admission to the emergency department, from the years 2000 to 2003. The antemortem diagnosis and postmortem diagnosis were compared. RESULTS: A total of 189 autopsies were performed. The mean age at death for men (41.4 years) was lower than that for women (48.6) (p = 0.02). In both men and women, cardiac system involvement was the leading cause of death (27.5%), with myocardial infarction at 21.2%. The other common causes of death for both genders were blunt trauma (20.1%), intoxication with alcohol and/or other drugs (13.8%), penetrating trauma (gunshot or stab injuries) (13.2%), pulmonary thromboembolism (7.9%), and death caused by other respiratory causes (7.4%). Death caused by pulmonary thromboembolism was more common in women, whereas death caused by strokes, burns, and penetrating trauma were seen almost exclusively in men. CONCLUSIONS: Our study found a considerable concordance between the presumed antemortem cause of death and the postmortem findings. Although the mean age of death caused by myocardial infarction in our study was 52.45 years, MI caused a significant number of deaths among adults younger than 40 years of age. PMID- 17700197 TI - Fever of unknown origin: analysis of 71 consecutive cases. AB - BACKGROUND: Fever of unknown origin (FUO) is still an important problem in clinical practice. Evaluation of patient characteristics may clarify the utility of diagnostic tests and etiologies of FUO. METHODS: Fever of unknown origin in 71 patients was investigated at Ankara Numune Education and Research Hospital in Turkey between February 2001 and December 2004. RESULTS: Mean hospital stay and fever duration was 20.5 days and 44 days, respectively. Etiologies of FUO were as follows: infections 32 (45.1%), collagen vascular disease 19 (26.8%), neoplasm 10 (14.1%), and miscellaneous diseases 4 (5.6%). Diagnosis remained obscure in 6 patients (8.5 %). Tuberculosis was found to be 40% of the infectious causes of FUO. Mean hospital stay and fever duration were prolonged in infectious cases. Female predominance was observed in collagen vascular diseases (P = 0.047). Splenomegaly and lymphadenopathy were common in the neoplasm group (P = 0.017, P = 0.017, respectively). Erythrocyte sedimentation rate, aspartate aminotransferase, alanine aminotransferase and lactate hydrogenase levels were elevated in patients with collagen vascular diseases. Nine (12.7%) patients died during the follow-up period. CONCLUSIONS: Hospital stay and fever duration were prolonged in the infectious group of FUO patients. Infectious diseases, particularly tuberculosis, were the most important cause of FUO in our series. Tuberculosis should be kept in mind as an important etiology of FUO countries where tuberculosis is endemic. PMID- 17700198 TI - Comparison of Escherichia coli and Klebsiella pneumoniae liver abscesses. AB - BACKGROUND: Escherichia coli and Klebsiella pneumoniae are the most common causative pathogens of pyogenic liver abscesses. The objective of this study was to compare outcome between patients with liver abscesses due to E coli and those with liver abscesses caused by K pneumoniae; we also aimed to identify separately the predictors of mortality in the 2 groups. METHODS: We conducted a retrospective study of 202 patients who presented with pyogenic liver abscesses caused by either E coli or K pneumoniae from July 2000 to June 2005. Outcome of the patients was analyzed by exact logistic regression with adjustment for baseline and clinical covariates. Significant predictors of mortality in the E coli and the K pneumoniae groups were investigated by multivariate analysis of demographic and clinical variables in each group. RESULTS: Of the 202 patients (128 men and 74 women; age range, 19 to 89 years), pyogenic liver abscess was due to E coli infection in 55 patients and K pneumoniae in 147 patients. In contrast to patients with K pneumoniae, patients with E coli liver abscess were more likely to be older and female, have a biliary abnormality or malignancy, pleural effusion, polymicrobial infection with anaerobic or multi-drug-resistant organisms, a higher APACHE II score, and to have been treated initially with ineffective antibiotics; they were also less likely to have diabetes mellitus. The cause of K pneumoniae liver abscess was often cryptogenic. The sensitivity, specificity, positive predictive value, and likelihood ratio of the presence of biliary disorders and coexisting malignancy as a predictive parameter of E coli liver abscess were 25%, 96%, 67%, and 5.45/1, respectively. The sensitivity, specificity, positive predictive value, and likelihood ratio of the presence of diabetes mellitus with an abscess of cryptogenic origin as a predictive parameter of K pneumoniae liver abscess were 39%, 84%, 81%, and 2.36/1, respectively. There was no significant difference in mortality between patients with E coli and those with K pneumoniae infections (26% vs 4%; adjusted OR, 4.2; 95% CI, 0.63 to 27; P = 0.105). However, for patients with liver abscess caused by E coli, the APACHE II score at admission (OR, 1.7; 95% CI, 1.1 to 2.6; P = 0.021), malignancy (OR, 26; 95% CI, 1.8 to 370; P = 0.016), and right-lobe abscess (OR, 0.0029; 95% CI, 0.00010 to 0.15; P = 0.004) were significant predictors of death, whereas uremia (OR, 52; 95% CI, 3.5 to 750; P = 0.004) and multi-drug-resistant isolates (OR, 26; 95% CI, 2.3 to 290; P = 0.009) were significant predictors of death in the K pneumoniae group. CONCLUSIONS: A higher APACHE II score at admission and a higher frequency of coexisting malignancy may have contributed to the higher, although not significant, mortality rate in patients with liver abscess caused by E coli infection. Clinicians should begin with broad antibiotic coverage such as a second-generation cephalosporin and an aminoglycoside with metronidazole when treating liver abscesses with E coli as the likely pathogen due to the high frequency of multi-drug-resistant isolates among E coli isolates. PMID- 17700199 TI - Clinical features and outcome of tuberculosis in solid organ transplant recipients. AB - BACKGROUND: : Taiwan is an area with moderate to high incidence of Mycobacterium tuberculosis infection. The risk of M tuberculosis infection in transplantation recipients is considered to be significant. Our aim in this study was to investigate the clinical spectrums of M tuberculosis-infected transplantation recipients in a southeast Asian country, Taiwan. METHODS: : We retrospectively analyzed the demographic data, clinical features, treatment, and outcome of M tuberculosis infection in kidney, heart, and liver transplant recipients from May 1996 to April 2005 at the National Taiwan University Hospital. RESULTS: : Fifteen patients who had received solid organ transplantation developed tuberculosis (kidney = 6, heart = 7, liver = 2). The median duration from transplantation to diagnosis of tuberculosis was 31 months. The cumulative incidence of post transplantation tuberculosis was 2.0% (15/760), ie, approximately 3 times that of the general population. Ten patients (66.7%) had pulmonary tuberculosis, 1 (6.7%) had extrapulmonary tuberculosis, and 4 (26.7%) had disseminated tuberculosis. Nine patients completed the anti-tuberculosis treatment; the median treatment duration was 12 months (pulmonary: 9 months; extrapulmonary: 13.5 months). No treatment failure was noted in patients receiving the complete treatment course. The graft failure and mortality rates of post-transplantation tuberculosis were 13.3% each (2/15). The tuberculosis-associated mortality rate was 6.7% (1/15). CONCLUSIONS: : Cumulative incidence of tuberculosis was slightly higher in transplant recipients than in the general population in Taiwan. Conventional 4 combined anti-tuberculosis regimen for 12 months can treat the potentially fatal infection successfully in post-transplantation tuberculosis patients without recurrence. PMID- 17700200 TI - Association between cytomegalovirus infection and venous thromboembolism. AB - It has been suggested that cytomegalovirus (CMV) infection may be associated with thrombosis in immunocompromised patients. In addition, an association between CMV infection and thrombotic events in immunocompetent hosts has been sporadically reported. We report on 1 immunocompromised and 8 immunocompetent adults who were admitted to a tertiary medical center and experienced a venous thromboembolic event during CMV infection. None reported previous thromboembolic events. All patients were diagnosed as suffering from acute CMV infection. Seven of the patients had vein thromboses. Significant additional thrombophilia was identified in 5 patients; 1 had 15.3 U/mL anti-cardiolipin IgM antibodies (elevated >7), 2 others were not evaluated for genetic procoagulant tendency. The exact nature of the procoagulant effect of CMV has not yet been clarified. Even though these mechanistic studies are incomplete, we suggest that from the clinical perspective, the presence of CMV infection should be considered a possible risk factor for thrombophilia, justifying a high index of suspicion for possible thrombotic events and subsequent decisions regarding prophylactic anticoagulation. PMID- 17700201 TI - Cisplatin nephrotoxicity: a review. AB - BACKGROUND: Cisplatin is a major antineoplastic drug for the treatment of solid tumors, but it has dose-dependent renal toxicity. METHODS: We reviewed clinical and experimental literature on cisplatin nephrotoxicity to identify new information on the mechanism of injury and potential approaches to prevention and/or treatment. RESULTS: Unbound cisplatin is freely filtered at the glomerulus and taken up into renal tubular cells mainly by a transport-mediated process. The drug is at least partially metabolized into toxic species. Cisplatin has multiple intracellular effects, including regulating genes, causing direct cytotoxicity with reactive oxygen species, activating mitogen-activated protein kinases, inducing apoptosis, and stimulating inflammation and fibrogenesis. These events cause tubular damage and tubular dysfunction with sodium, potassium, and magnesium wasting. Most patients have a reversible decrease in glomerular filtration, but some have an irreversible decrease in glomerular filtration. Volume expansion and saline diuresis remain the most effective preventive strategies. CONCLUSIONS: Understanding the mechanisms of injury has led to multiple approaches to prevention. Furthermore, the experimental approaches in these studies with cisplatin are potentially applicable to other drugs causing renal dysfunction. PMID- 17700202 TI - Fusobacterium necrophorum endocarditis in a previously healthy young adult. AB - Infective endocarditis with Fusobacterium necrophorum (F necrophorum) as the sole pathogen has been reported only once previously in an infant. We describe herein a case of F necrophorum endocarditis in a 20-year-old, previously healthy man. This is the first reported case of monomicrobial F necrophorum endocarditis in an adult. PMID- 17700203 TI - Pulmonary alveolar microlithiasis in a patient with rheumatic valvular heart disease. AB - Pulmonary alveolar microlithiasis is a rare disease characterized by widespread intra-alveolar calcification of both lungs that is asymptomatic in the early stages. The disease typically follows a protracted course, and death can occur in 5 to 41 years after the initial diagnosis. Rheumatic fever is a multisystemic inflammatory disease that afflicts the child and juvenile population, and it is still very common in developing countries. Valve failure is the condition most linked to increased morbidity and mortality rates in this population and is the most severe complication of rheumatic fever, with consequent onset of chronic heart valve disease. We present a case of a female patient with a potential diagnosis of pulmonary alveolar microlithiasis with concurrent rheumatic valvular disease. PMID- 17700204 TI - Hypereosinophilia as the presentation of metastatic medullary thyroid carcinoma: a remarkable event. AB - Hypereosinophilic syndrome is a rare disorder characterized by persistent eosinophilia combined with organ system dysfunction. This report is of a 37-year old man who had eosinophilia, periodic fever, weight loss, and generalized bone pain. A small nodule in left lobe of thyroid was detected in his physical examination. The patient underwent surgery and histopathological study, which confirmed that the patient had medullary carcinoma of thyroid. The patient died 6 months after the surgery. Eosinophilia is more commonly seen with benign conditions. However, less frequent but malignant etiologies always should be contemplated. PMID- 17700205 TI - Thrombotic thrombocytopenic purpura and Graves disease. AB - Patients with an autoimmune disease have a propensity for development of a second autoimmune disease. We report the first instance of a patient with both idiopathic thrombotic thrombocytopenic purpura (TTP) and Graves disease. The TTP remitted with a combination of plasmapheresis and prednisone. Methimazole led to sustained remission of the hyperthyroid state within 6 weeks. Although hyperthyroidism may induce immune imbalance causing autoimmunity, it is unclear if this influenced the development of TTP in our patient and if treatment of hyperthyroidism alone could have resulted in the cure of both diseases. PMID- 17700206 TI - Myeloid sarcoma presenting with acute renal failure and bilateral ureteral obstruction: a case report and review of the literature. AB - Myeloid sarcoma (MS) is a very rare disease that either presents with acute myeloid leukemia or as relapse of acute myeloid leukemia. The common sites include the small intestine, skin, bone, and lymph nodes. We present an unusual case of MS presenting with acute renal failure (ARF) and bilateral ureteral obstruction. Ultrasonography showed bilateral hydronephrosis and a large pelvic mass displacing the uterus. Pelvic mass biopsy showed fibroadipose tissue with diffuse neoplastic cell infiltration and immunostaining was positive for leukocyte common antigen (LCA) and myeloperoxidase consistent with myeloid sarcoma. Bone marrow biopsy revealed 63% myeloblasts. The patient died the 17th day of induction therapy. We came across only four MS cases in English literature that presented with ARF. To our knowledge, this case is the first description of myeloid sarcoma presenting with ARF and bilateral ureteral obstruction not originating from urogenital system. Physicians should consider possible hematological malignancies in patients with similar presentation. PMID- 17700207 TI - Diagnostic dilemma in an adolescent boy: hemophagocytic syndrome in association with kala azar. AB - Leishmaniasis is caused by infection with the hemoparasite Leishmania. The disease is a major public health problem in at least 88 countries, including Turkey. Prolonged fever with anorexia and loss of appetite are the major presenting features of visceral leishmaniasis. It is rarely defined as an etiological cause of hemophagocytic syndrome. The clinical course triggered by leishmania infection and hemophagocytosis may coincide, and this may lead to considerable diagnostic difficulty, especially in young children. In this report, we describe an adolescent boy with visceral leishmaniasis as a rare cause of the hemophagocytic syndrome. This is the first reported association between hemophagocytosis and visceral leishmaniasis in an adolescent. PMID- 17700208 TI - A painful thorn in the foot: a case of eumycetoma. AB - Madura foot or mycetoma is endemic in many developing countries. It is occasionally seen within the United States due to increasing international travel but it may sometimes be acquired within US soil. Herein, we present a case of a patient with a diagnosis of mycetoma acquired through trauma to the foot. In addition, we discuss the epidemiology, etiological agents, clinical presentation, diagnosis, and treatment of mycetomas. Clinicians need to recognize mycetoma early and institute treatment promptly to reduce the substantial morbidity associated with this devastating infection. PMID- 17700209 TI - Exercise-induced asystole with syncope in a healthy young man. AB - Exercise-related syncope is frequently an ominous symptom associated with advanced cardiovascular disease. Asystole during or after exercise is a rare occurrence in persons with structural heart disease and is an even rarer cause of syncope in healthy persons. Herein we report on a healthy 40-year-old man who was hospitalized after a syncopal episode that followed playing basketball. He recalled several near-syncopal episodes after strenuous exercise over the past 6 months, during which time he used marijuana. A loss of sinoatrial activity and appearance of ventricular asystole occurred immediately after monitored exercise to suggest parasympathetic dominance, which could be related to long-term cannabinoid use. PMID- 17700210 TI - Genetic polymorphism in the pregnancy-associated plasma protein-A associated with acute myocardial infarction. AB - BACKGROUND: Pregnancy-associated plasma protein-A (PAPP-A) is a high-molecular weight, zinc-binding matrix metalloproteinase that is known to be abundantly expressed in ruptured plaques. Previous studies have shown PAPP-A to be a significant marker of plaque instability and cardiovascular events in patients with acute coronary syndromes. Because the activity of PAPP-A may be modulated by genetic variants in the PAPP-A genes, we tried to determine the association of PAPP-A gene with acute myocardial infarction (AMI). METHODS: We analyzed four single nucleotide polymorphisms (SNPs) of PAPP-A gene variants and seven other polymorphisms of cytokine genes that have been reported to have functional significance (RANTES G-403A, MCP1 G-2518A, CRP A2147G, CRP G-717A, AGER G557A, LTA T26A, IL-6 G-572C) for possible association with AMI in 170 unrelated AMI patients and unrelated age-matched controls, respectively. RESULTS: The average age of the study population was 62.2+/-11.4 years in AMI patients and 62.6+/-10.4 years in healthy controls. Multiple logistic regression analysis with risk factors such as age, male sex, smoking, hypertension, diabetes mellitus, and dyslipidemia revealed the PAPP-A IVS6+95 C allele to be associated with an increased risk of AMI (dominancy: odds ratio, 2.13; 95% confidence interval, 1.12 4.07; P=0.022; codominancy: odds ratio, 1.89; 95% confidence interval, 1.14-3.16; P=0.015). CONCLUSIONS: We found, for the first time, that PAPP-A IVS6+95 C allele is an independent risk factor for AMI even after adjustment for traditional risk factors. The determination of such genotype contributing to AMI could provide a new tool for identifying high-risk individuals. PMID- 17700211 TI - In-vivo comparison of coronary plaque characteristics using optical coherence tomography in women vs. men with acute coronary syndrome. AB - OBJECTIVE: Women with acute coronary syndromes (ACS) have worse outcomes than men. Data on sex differences of culprit plaque characteristics are lacking. Intravascular optical coherence tomography (OCT) is a high-resolution imaging technique capable of in-vivo plaque characterization. The aim of this study was to compare culprit plaque characteristics in women and men presenting with ACS. METHODS: Patients undergoing coronary angiography after ACS were enrolled. We performed OCT imaging on the culprit lesions. Previously validated criteria for OCT plaque characterization were used: lipid was quantified on cross-sectional image and lipid-rich plaque was defined as > or = 2 involved quadrants; fibrous cap thickness was measured at the thinnest point and thin-cap fibroatheroma was defined as lipid-rich plaque with fibrous cap thickness less than 65 microm. RESULTS: Forty-two patients (33 men and nine women) were included. No significant sex differences were found in baseline characteristics. Lipid-rich plaques were identified in majority of patients. No significant difference, however, was seen in the frequency of lipid-rich plaques, thin-cap fibroatheroma or minimum fibrous cap thickness (79 vs. 89%; 45 vs. 67%; 53.8 vs. 45.4 microm, respectively; P=NS) between men and women. Incidence of calcification, thrombus and plaque disruption were also similar. CONCLUSIONS: No significant sex difference was seen in culprit plaque characteristics determined by OCT imaging in patients who presented with ACS. PMID- 17700212 TI - Myocardial infarction in the young: a sex-based comparison. AB - A relative paucity of information concerns the natural history, clinical features and coronary anatomy in young patients with acute myocardial infarction. In particular, there is a dearth of data relating to sex differences in young patients. The objective was to evaluate whether or not there are correlations between the clinical characteristics and the extent and localization of coronary artery lesions in young men compared with young women. The study population consisted of 1646 young patients (87% men, 13% women; mean age 39+/-5 years) with a first acute myocardial infarction admitted to one of the 125 coronary care units of Italy in a period of 3 years. Clinical data were collected. All patients underwent coronary angiography during hospitalization. Smoking, hypercholesterolemia and obesity were significantly more prevalent in men than in women; physical inactivity was significantly more prevalent among women. Hemodynamically significant coronary stenosis occurred in 82% of patients and were more frequent in men than in women (P<0.05). Women more frequently had single-vessel disease and no coronary lesions at all (58 vs. 47% and 24 vs. 9% women vs. men respectively, both P<0.05). Men more frequently had multivessel disease (38 vs. 13%, P<0.05). Significant stenosis mainly affected the left anterior descending artery (52%) with no gender-related difference; men more likely had lesions of the left circumflex or right coronary artery (P<0.05). In conclusion, young patients with a first acute myocardial infarction risk factors profile and extent of coronary artery lesions were significantly different between sexes. PMID- 17700213 TI - Association between nonalcoholic fatty liver disease and coronary artery disease. AB - AIMS: To demonstrate whether there is a relationship between the presence of nonalcoholic fatty liver disease (NAFLD) and the presence and extent of coronary artery disease (CAD). PATIENTS AND METHODS: Ninety-two consecutive patients who planned to undergo coronary angiographies (CAG) without known CAD, other than findings of acute coronary syndrome, were enrolled in this study. Abdominal ultrasonography was performed before the CAG to detect NAFLD. CAD was defined as a stenosis of at least 50% in at least one major coronary artery. The extent of CAD was measured according to the number of major coronary artery/arteries affected by CAD. All the risk factors for CAD were included in a binary logistic regression model. Forward, backward, or step-wise selections were not used. P<0.05 was accepted as being significant. RESULTS: Sixty-five of the 92 patients (70.7%) were detected, by abdominal ultrasonography, to have fatty liver and 43 patients out of 92 (46.7%) were detected, by CAG, to have significant CAD. According to the results of logistic regression analysis, the presence of NAFLD independently increased the risk for CAD, as seen in CAG [odds ratio (OR), 95% confidence interval (CI): 6.73 (1.14-39.61); P=0.035]; this was despite factoring in the other risk factors for CAD and the components of metabolic syndrome. NAFLD was more commonly found in patients as the extent of CAD increased (P=0.001). CONCLUSION: The presence of NAFLD is independently associated with the presence and extent of CAD. Future studies are needed to explain the mechanisms of this relationship. PMID- 17700214 TI - C-reactive protein levels increase after exercise testing in patients with increased platelet reactivity. AB - Aspirin has the potential to influence C-reactive protein (CRP) levels, an inflammatory marker, by its anti-inflammatory activity. Persistently increased platelet reactivity, however, can be detected with different laboratory methods despite aspirin therapy in some patients. The aim of this study was to investigate the effects of increased platelet reactivity on CRP levels at rest and after exercise in patients with documented or suspected coronary artery disease. Blood samples were collected from 100 patients (age, 58.1+/-8.5 years; 63.0% men) who were treated with 100 or 300 mg/day enteric-coated aspirin for at least 7 days, before and immediately after treadmill test for CRP analyses. Platelet reactivity was measured by the standardized platelet function analyzer 100, and increased platelet reactivity was defined as a normal collagen/epinephrine closure time (<165 s). Of the 100 patients, 82 had normal platelet reactivity (group A) and 18 had increased platelet reactivity (group B). The CRP levels increase was statistically significant after exercise in patients with increased platelet reactivity [group A: 2.3 (1.4-4.3) to 2.8 (1.6-4.9) mg/l, P=0.09; group B: 3.3 (2.0-4.5) to 4.7 (2.9-8.5) mg/l, P=0.02]. Detecting increased platelet reactivity is associated with an increase in CRP levels. The clinical significance of this finding needs to be further investigated. PMID- 17700215 TI - Predictors and clinical significance of angiographically detected distal embolization after primary percutaneous coronary interventions. AB - OBJECTIVES: The aim of this study was to investigate clinical, angiographic and procedural predictors of distal embolization (DE) on angiography after primary percutaneous coronary intervention (PCI). The impact of DE on outcome in the first 30 days was also assessed. METHODS: Between January 2004 and April 2006, primary PCI was performed in 212 consecutive patients with acute myocardial infarction (AMI) of < or = 12-h duration. RESULTS: Distal embolization was present in 27 patients (12.7%) and more often observed in female sex (27.5 vs. 10.4%, P=0.01), in patients with right coronary artery involvement (52 vs. 28%, P=0.02), prerevascularization thrombolysis in myocardial infarction flow < or = 1 (89 vs. 69%, P=0.03), in the presence of high thrombus burden (92.6 vs. 39.5%, P=0.0009), and a long target lesion in the infarct-related artery (>14.5 mm, 74 vs. 29%, P<0.0001). By multiple stepwise logistic regression analysis, only the presence of high thrombus burden before the PCI procedure [odds ratio (OR)=5.2, 95% confidence interval (CI)=1.09-24.97, P=0.03)] and target lesion length (>14.5 mm, OR=3.9, 95% CI=1.45-10.60, P=0.007) were found independent predictors of DE. Patients with DE had an increased risk of target vessel revascularization (26 vs. 5%, P=0.001) and short-term mortality (29.6 vs. 7.5%, P=0.002) when compared with patients without angiographic signs of embolization. CONCLUSIONS: In patients who undergo primary PCI, high thrombus burden on angiography before PCI and/or a long target lesion in the infarct-related artery increase the risk of DE and subsequent short-term mortality. PMID- 17700216 TI - Increased platelet activity in patients with isolated coronary artery ectasia. AB - BACKGROUND: The common coexistence with coronary artery disease has led to the suggestion that coronary artery ectasia (CAE) is a variant of coronary artery disease. The mechanisms, however, responsible for CAE formation during the atherosclerotic process and the exact clinical significance are not well known. In this study, we aimed to investigate platelet activity in patients with isolated CAE by using specific markers of platelet activation as P-selectin, beta thromboglobulin (beta-TG) and platelet factor 4 (PF4). METHODS: Thirty-two patients with isolated CAE without significant stenosis and 30 control participants with angiographically normal coronary arteries were included in this study. According to the angiographic definition used in the Coronary Artery Surgery Study, a vessel is considered to be ectasic when its diameter is > or = 1.5 times that of the adjacent normal segment in segmental ectasia. Plasma P selectin, beta-TG and PF4 levels were measured in all patients and control participants using enzyme-linked immunosorbent assay method. RESULTS: Patients with isolated CAE were detected to have significantly higher levels of plasma P selectin, beta-TG and PF4 in comparison with control participants with angiographically normal coronary arteries (P-selectin: 248+/-46 vs. 154+/-32 ng/ml, respectively, P<0.001; beta-TG: 51+/-19 vs. 21+/-9 ng/ml, respectively, P<0.001; PF4: 58+/-23 vs. 33+/-11 ng/ml, respectively, P<0.001). CONCLUSION: In conclusion, we have shown for the first time that patients with isolated CAE have raised levels of plasma P-selectin, beta-TG and PF4 compared with control participants with angiographically normal coronary arteries, suggesting increased platelet activation in patients with CAE. PMID- 17700217 TI - 'Warm-up' phenomenon in diabetic patients with stable angina treated with diet or sulfonylureas. AB - BACKGROUND: Classic sulfonyloureas (SUs) are known to attenuate ischaemic preconditioning. Gliclazide is an SU agent believed to be more protective. We assessed the effects of diet, glibenclamide, or gliclazide on the warm-up effect in type 2 diabetic patients with stable angina. METHODS: The study group consisted of 64 men, aged 54+/-5 years: 17 patients without diabetes (G I) and 47 diabetic patients: 16 patients treated with glibenclamide (G II), 16 with gliclazide (G III) and 15 patients treated with diet (G IV). After the baseline positive exercise test (ET1), all patients reexercised after 30-min rest (ET2). We analysed exercise duration (ED, s), time to 1 mm ST depression (T-STD, s), max STD (mm), heart rate-systolic blood pressure product at 1 mm STD, or ischaemic threshold (mmHg/min x 100) and the total ischaemic time (s). RESULTS: In G I, all analysed variables improved significantly during ET2 relative to ET1. Glibenclamide (G II) completely abolished the protective effect of exercise induced ischaemia because only ED increased during ET2 (431 vs. 451, P<0.05). In G III, however, ED (486 vs. 537, P<0.001), T-STD (364 vs. 388, P<0.05) and max STD (2.5 vs. 2.0, P<0.05) improved significantly during ET2, whereas ischaemic threshold and total ischaemic time did not (PNS). In G IV, similar to G I, all variables improved significantly during ET2 relative to ET1. CONCLUSION: Warm-up effect is preserved in diabetic patients with stable angina treated with diet, partially preserved in gliclazide-treated and abolished in glibenclamide-treated patients. PMID- 17700218 TI - Renal dysfunction is the most important predictor of the extent and severity of coronary artery disease in patients with diabetes mellitus. AB - OBJECTIVES: Diabetic patients tend to have more extensive and diffuse coronary artery disease (CAD) that may contribute to the less favorable outcomes in them. The aim of this study was to elucidate the predictors of the angiographic severity and extent of CAD in patients with diabetes. METHODS: A total of 203 diabetic patients (116 men; mean age, 61.9+/-10.8) who were referred for a first coronary angiogram were included. The extent and severity of CAD was assessed in several ways. The first was a simple classification in one-vessel, two-vessel, and three-vessel disease scoring system. The total numbers of segments with > or = 20 and > or = 50% stenosis were calculated as CASS 20 and CASS 50 scores, respectively. Hamsten and Gensini scores were also calculated. RESULTS: Of the 203 patients included in the study, 175 (86.2%) had CAD. Multivariate ordinal logistic regression analysis showed that age (Wald 5.741, P=0.017), glomerular filtration rate (Wald 5.032, P=0.025), previous myocardial infarction (Wald 10.955, P=0.001), and family history of CAD (Wald 7.236, P=0.007) were independent predictors of the severity of CAD, as assessed by the clinical zero vessel to three-vessel disease scoring system. On stepwise multiple linear regression analysis, glomerular filtration rate was an independent predictor of the CASS 20 (r=-0.221, P=0.004), CASS 50 (r=-0.239, P=0.005), Gensini (r=-0.328, P<0.001), and Hamsten (r=-0.320, P<0.001) scores. Previous myocardial infarction was an independent predictor of the CASS 50 (r=0.355, P<0.001), Gensini (r=0.350, P<0.001), and Hamsten (0.256, P<0.001) scores. Age and sex were independent predictors for the CASS 50 (r=0.174, P=0.039; r=0.172, P=0.016, respectively) and Hamsten (r=0.212, P=0.011; r=0.244, P=0.001, respectively) scores. CONCLUSION: Renal function is one of the most important factors associated with the extent and severity of coronary atherosclerosis, whereas classical coronary risk factors and the degree of metabolic control were not associated with the severity of coronary atherosclerosis in diabetic patients. PMID- 17700219 TI - Presence of asymmetric dimethylarginine gradients across high-grade lesions in patients with coronary artery disease. AB - BACKGROUND: Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is a systemic marker of endothelial dysfunction. Although experimental evidence indicates that asymmetric dimethylarginine may play an important role in atherogenesis, local asymmetric dimethylarginine levels have not been measured in vivo. OBJECTIVES: We sought to determine whether: (i) asymmetric dimethylarginine is elevated locally at sites of coronary lesions, (ii) systemic asymmetric dimethylarginine concentrations correlate with local levels, and (iii) percutaneous coronary intervention produces immediate local asymmetric dimethylarginine elevation. METHODS: In patients undergoing percutaneous coronary intervention (n=15), blood samples were obtained from a peripheral venous site, the coronary ostium proximal to the lesion and the coronary vessel distal to the lesion, before percutaneous coronary intervention. Samples were also obtained distal to the coronary lesion immediately after percutaneous coronary intervention and from the peripheral venous line 24 h after percutaneous coronary intervention. RESULTS: Asymmetric dimethylarginine gradients were present across the coronary bed: local asymmetric dimethylarginine (micromol/l) was significantly higher distal to coronary lesions compared with proximally (2.39+/ 1.27 vs. 1.52+/-0.68, P=0.005), and to systemic venous levels (2.39+/-1.27 vs. 1.17+/-0.72, P=0.001). Local asymmetric dimethylarginine did not increase immediately after percutaneous coronary intervention (1.88+/-0.89 vs. 2.39+/ 1.27, P=0.11). Peripheral venous percutaneous coronary intervention levels 24 h after percutaneous coronary intervention were similar to baseline values (1.17+/ 1.2 vs. 1.17+/-0.72, P=0.98). CONCLUSION: Asymmetric dimethylarginine gradients exist across coronary lesions, suggesting asymmetric dimethylarginine release at the plaque site. Local asymmetric dimethylarginine accumulation may contribute to the endothelial dysfunction associated with high-grade coronary lesions. Peripheral asymmetric dimethylarginine is a marker of generalized endothelial dysfunction, but our findings highlight its limitation in detecting focal injury. PMID- 17700220 TI - Dimensions and anatomic variations of left main coronary artery in normal population: multidetector computed tomography assessment. AB - OBJECTIVES: The aim of our study was to determine the dimensions, morphology and anatomic variations of the left main coronary artery (LMCA) in normal participants, on multidetector computed tomography. BACKGROUND: Accurate imaging of LMCA dimensions and configuration is crucial to avoid misdiagnosis of LMCA disease. MATERIALS AND METHODS: Seventy morphologically normal LMCAs of 70 participants were carefully selected from among 600 consecutive coronary computed tomography angiography studies performed in our institute. LMCA cross-sectional diameters and areas were obtained at three points of each vessel: ostium, midvessel and distal. The length, cross-sectional shape, three-dimensional (3D) morphology and position of origin were studied. Influences of age, body weight, height and body surface area (BSA) on LMCA dimensions were evaluated. RESULTS: Different dimensions in each measured point of the LMCA were detected. Cross sectional elliptic shape at ostium, mid-LMCA and distal LMCA was found in 66/70 (94%), 51/70 (73%) and 54/70 (77%) of the participants, respectively. On the basis of the 3D presentation, four types of LMCA were identified: biconcave-shape appearance (type 1), tapering morphology (type 2), combined morphology (type 3) and funnel-shape appearance (type 4). Fifty-two of the 70 participants had an LMCA orifice originating in the middle third of the aortic sinus, 15/70 in the posterior third and 3/70 in the anterior third. In men, significant correlation was found between LMCA cross-sectional area and body weight, height and BSA. In women, no correlation was found regarding body weight, height and BSA. CONCLUSION: LMCA is not a simple straight tube but usually has various anatomical configurations, variable dimensions and cross-sectional shapes. Ostial angulation is a normal variant usually associated with the posterior position of the LMCA orifice of origin in the aortic sinus. PMID- 17700221 TI - Carotid artery stenting versus endarterectomy in relation to perioperative myocardial ischemia, troponin T release and major cardiac events. AB - BACKGROUND: Carotid artery stenting (CAS) is less invasive than endarterectomy. This study examined differences in perioperative myocardial ischemia, troponin T release and clinical cardiac events in patients undergoing CAS compared with endarterectomy. METHODS: In an observational study, CAS was performed in 24 and carotid endarterectomy in 44 patients. Before surgery, clinical risk factors were noted and dobutamine stress echocardiography was performed for cardiac risk assessment. Perioperative continuous 72-h 12-lead electrocardiographic monitoring was used for myocardial ischemia detection. Troponin T (>0.03 ng/ml) was measured on postoperative days 1, 3, 7 or before discharge. Cardiac events (cardiac death or Q-wave myocardial infarction) were noted during hospital stay and during follow-up (mean: 1.2 years). RESULTS: No significant differences were observed between patients with CAS and endarterectomy in terms of baseline clinical characteristics, dobutamine stress echocardiography results and cardiovascular medication. Perioperative myocardial ischemia was detected in nine patients (13%), perioperative troponin T release in seven patients (10%), early cardiac events in one patient (1%) and late cardiac events in three patients (4%). Significantly less perioperative myocardial ischemia was observed in patients with CAS compared with endarterectomy (0 versus 21%, P=0.02). Troponin T release was also significantly lower in CAS, compared with endarterectomy (0 versus 16%, P=0.04). Early (0 versus 2%, P=0.5) and late (0 versus 7%, P=0.2) cardiac events were lower after CAS, compared with endarterectomy, although these differences were not significant. CONCLUSION: CAS is associated with a lower incidence of perioperative myocardial ischemia and troponin T release, compared with endarterectomy. PMID- 17700222 TI - Fluvastatin blunts the effect of a high-fat meal on plasma triglyceride and high sensitivity C-reactive protein concentrations in patients at high risk for cardiovascular events. AB - BACKGROUND: The postprandial state is critical in atherogenesis. The aims of this study were to study the postprandial change of plasma high-sensitivity C-reactive protein (hsCRP) concentrations in patients at high risk for cardiovascular events, and to explore the influence of fluvastatin on hsCRP concentration. METHODS: Forty-three patients at high risk for cardiovascular events and 15 healthy controls participated in this study. All participants received an oral high-fat meal (800 calories; 50 g fat) at baseline. Blood samples were drawn at 0 and 4 h to measure the plasma concentrations of triglyceride, total cholesterol, low-density and high-density lipoprotein cholesterol and hsCRP. Then patients at high risk were randomly divided into two groups to accept fluvastatin (40 mg/day) (fluvastatin group, n=22) or placebo (placebo group, n=21). One week later, the high-fat meals were repeated and plasma samples were collected again. RESULTS: The postprandial plasma triglyceride concentrations increased in all participants, whereas the postprandial plasma hsCRP concentrations increased significantly only in patients at high risk (P<0.05), but not in healthy controls. After 1 week, the fasting or postprandial plasma lipid levels and hsCRP concentrations did not significantly change in the placebo group compared with the levels at baseline, whereas the postprandial plasma triglyceride and hsCRP concentrations significantly decreased in the fluvastatin group. The reduction of plasma hsCRP concentration was not related to the change of plasma triglyceride concentration. CONCLUSION: Fluvastatin effectively reduced postprandial plasma hsCRP concentrations in patients at high risk for cardiovascular events in a very short period of time. PMID- 17700223 TI - Drug-eluting stents for the percutaneous treatment of the anastomosis of the left internal mammary graft to left anterior descending artery. AB - BACKGROUND: Data on the treatment of left internal mammary to left anterior descending artery (LIMA-to-LAD) anastomotic disease are scarce and not homogeneous. Both surgery and percutaneous interventions (PCI) have been attempted, but the most effective treatment has not yet been established. In particular, should PCI be performed, the role of stenting seems to be limited by less favorable results than in other subsets of lesions. OBJECTIVE: To assess the clinical impact of drug-eluting stent (DES) use in this particular subset of lesions. METHODS: We describe a cohort of patients treated with PCI on LIMA-to LAD anastomoses, reporting acute 1-year clinical and angiographic outcomes. The clinical impact of DES use was evaluated as the requirement for target lesion revascularizations (TLR). RESULTS: Fifty-six consecutive patients were evaluated. Acute procedural success was achieved in 52 patients (92.8%). Plain balloon angioplasty allowed acute procedural success in 15 patients (28.8%), whereas stenting was required in 37 patients (71.2%) with suboptimal results or to treat complications. Bare-metal stents (BMS) were used in 17 and DES in 20 patients, without differences in acute results. One-year clinical follow-up was available in 96.1% of patients. TLR were needed in 17.3% of patients. No significant differences were detected in TLR rates after treatment with BMS and DES (26.6% vs. 25%; P=0.99). Two late stent thromboses were observed after DES deployment. CONCLUSION: PCI of the stenoses of LIMA-to-LAD anastomoses with DES did not provide any clinical improvement over BMS use in long-term outcomes; DES use was associated with some cases of late thrombosis. PMID- 17700224 TI - Bibliography - current world literature. PMID- 17700226 TI - Conjunctival tumors in children. AB - PURPOSE OF REVIEW: Numerous conjunctival tumors can occur in children, originating from tissues of choristomatous, epithelial, melanocytic, vascular, fibrous, xanthomatous and lymphoid. Overall, 97% prove to be benign and only 3% are malignant. RECENT FINDINGS: The most common malignancies include conjunctival lymphoma and melanoma. In our experience, the most common conjunctival tumors in children include nevus (64%), dermolipoma (5%), lymphangioma (3%) and capillary hemangioma (3%). Conjunctival nevi can manifest as a darkly pigmented (65%), lightly pigmented (19%) and completely nonpigmented (16%) mass. Most nevi occurred at the nasal or temporal limbus, without involvement of the cornea. Occasionally, they are located in the caruncle, but rarely are nevi found in the fornix or tarsal conjunctival surface. Intralesional cysts are visible in 65% of nevi. Change in nevus color over time has been noted in 5% of cases and change in nevus size has been documented in 7%. Evolution of conjunctival nevus into malignant melanoma is extremely low (<1%). SUMMARY: Conjunctival nevus is the most common conjunctival tumor in children and fewer than 1% evolve into melanoma over time. PMID- 17700227 TI - Strabismus associated with thyroid eye disease. AB - PURPOSE OF REVIEW: We discuss the evaluation and treatment of strabismus related to thyroid eye disease with special attention to the literature published in 2006. RECENT FINDINGS: The etiology of thyroid eye disease is complex, although a recent review article evaluated the causative relationship between smoking and thyroid eye disease. The treatment of thyroid eye disease is also complex and involves a multidisciplinary approach including endocrinology and ophthalmology. Several recent articles have evaluated the role of medications in the treatment of thyroid eye disease. We discuss the current surgical strategies for the treatment of strabismus related to thyroid eye disease, including the use of adjustable suture techniques. New techniques in nonadjustable surgery are also examined. SUMMARY: Strabismus related to thyroid eye disease presents many challenges to the ophthalmologist. Successful treatment of strabismus is rewarding however, and has a significant impact on improving a patient's quality of life. PMID- 17700229 TI - Diagnosis and management of third nerve palsy. AB - PURPOSE OF REVIEW: To provide clinically relevant information regarding the diagnosis, etiology, work-up and treatment of third cranial nerve palsies, while incorporating information from current publications and providing our opinions on these studies. RECENT FINDINGS: In the past year, an important study focused on the confirmation of current neuro-imaging guidelines for third cranial nerve palsies. Recent case reports have highlighted etiologies such as giant cell arteritis, trauma, neuro-syphilis and demyelination secondary to infliximab and multiple sclerosis. Surgically, newer studies have focused on globe-tethering procedures for correcting strabismus and the use of frontalis suspension for correcting ptosis. Improved imaging technology with high-resolution magnetic resonance imaging (hr-MRI) allows for direct visualization of the entire nerve path and the affected muscles. SUMMARY: Management of a third nerve palsy depends upon localization of the causative lesion and determination of the underlying etiology. Once these issues are addressed, strabismus surgery can be both challenging and rewarding in these complex patients. PMID- 17700228 TI - Systematic approach to pediatric ocular trauma. AB - PURPOSE OF REVIEW: The aim of this article is to evaluate and review the scientific literature on pediatric ocular trauma from the past several years. Recent advancements have recognized mechanisms of injury that may be unique to children, require different treatment course than adults, and raise multiple public health concerns. RECENT FINDINGS: Epidemiologic studies have shown that ocular trauma is a major cause of monocular blindness and potential disability in children worldwide. The mechanisms of injury are quite variable and often found under mundane circumstances. Orbital fractures in children are more likely to cause entrapment of orbital contents due to the structure of orbital bones at an early age and require earlier surgical repair. The management of traumatic hyphema responds well to outpatient care and topical aminocaproic acid. The management of traumatic cataracts has been enhanced with new iris-fixated lens implants. Endophthalmitis after ocular trauma carries a significantly worse prognosis, which may be reduced by early referral and intervention. SUMMARY: This review broadens our understanding of the mechanisms, treatment, and prognostic indicators in pediatric ocular trauma. This will allow improved clinical care of these injuries. PMID- 17700230 TI - Diagnosis and treatment of refractive errors in the pediatric population. AB - PURPOSE OF REVIEW: The diagnosis and successful treatment of visually significant refractive errors in children are a subject of continued study and debate. RECENT FINDINGS: Treatment of significant refractive errors is widely accepted to reduce lifelong vision loss from amblyopia. Children aged 3-5 years may be screened for unexplained vision loss, refractive errors and amblyogenic factors using traditional eye charts as well as newer modalities such as autorefractors and photoscreeners. The accuracy of various screening methods is variable throughout the literature. Debate remains as to who is best suited to administer vision screening tests. Compliance with follow-up with an eye-care professional once a child is identified with an amblyogenic factor remains suboptimal. Treatment of significant refractive errors in certain populations of pediatric patients with refractive surgery shows promise but requires further study. SUMMARY: The timely diagnosis of significant refractive errors in children remains a significant challenge, especially for ages 3-5 years, but treatment may provide significant improvement of visual acuity and quality of life. PMID- 17700231 TI - Application of new ophthalmic technology in the pediatric patient. AB - PURPOSE OF REVIEW: The present review will summarize briefly the recent advances in diagnostic tools, surgical techniques, and ophthalmic medications as they relate to the pediatric patient. The review will highlight results from studies that have investigated these new technologies and techniques. RECENT FINDINGS: In the past several years there has been a plethora of literature on the application of new technologies and surgical techniques in children. New tools have been used for everything from gathering normative data about the pediatric eye to using the technologies to study diseases such as glaucoma and ocular tumors. Results of surgical techniques such as small-incision cataract surgery, sutureless vitrectomy, and refractive surgery are now reported with regularity in the pediatric ophthalmology literature. SUMMARY: In the past 10 years pediatric ophthalmology has made significant advances. Technology has enabled us to qualify and quantify disease states more efficiently, and to explore new surgical techniques for disease processes that were formerly considered relatively untreatable. PMID- 17700232 TI - Update on shaken baby syndrome: ophthalmology. AB - PURPOSE OF REVIEW: Shaken baby syndrome is a common problem with a high morbidity and mortality. Ophthalmologists help manage this condition and therefore must keep abreast of current advances. RECENT FINDINGS: Clinical updates include the discovery that retinal folds and traumatic retinoschisis can very rarely occur after crush head injury, but remain specific for shaken baby syndrome in other scenarios. Pathology updates include new studies on orbital histology and woodpecker anatomy that suggest the retinal and optic nerve hemorrhages in shaken baby syndrome are caused by shaking itself rather than secondary to intracranial pathology. Regarding this shaking injury, some primary prevention strategies have proven surprisingly effective. In the near future, serum biomarkers may be used as a screening tool for inflicted neurotrauma. Animal models such as the neonatal pig and computer models using finite element analysis are promising experimental techniques for studying shaken baby syndrome. Finally, child abuse recently became an accredited subspecialty of pediatrics, which will lead to further advances in patient care, education, research and prevention. SUMMARY: Ophthalmologists play a key role in the diagnosis of shaken baby syndrome. In addition, they are in a unique position to study ophthalmic aspects of the syndrome, which in turn furthers the overall understanding of this devastating condition. PMID- 17700233 TI - Lymphoproliferative disease of the orbit. AB - PURPOSE OF REVIEW: Malignant lymphoma of the ocular adnexa has been reported on for many years, but many steps forward have been recently made. This paper highlights the staging strategies and treatment options based on a review of the most updated and relevant bibliography. RECENT FINDINGS: A relevant improvement in the management of ocular adnexal lymphoma is represented by PET, which improves the diagnosis and the staging of the disease. Acquisitions have been made in the treatment: low-dose radiotherapy is confirmed for primary orbital mucosa-associated lymphoid tissue lymphoma; oral chlorambucil is proposed as an alternative; immunotherapy is proposed for the treatment of systemic disease. Interestingly, the role of Chlamydia psittaci as the possible cause of mucosa associated lymphoid tissue lymphomas and the efficacy of doxycycline for the treatment of ocular adnexal lymphomas have been investigated with promising results. A large series of natural killer/T-cell lymphoma has been described and its lethality despite aggressive conventional chemotherapy has been confirmed. SUMMARY: Orbital lymphoma is the most common malignant tumor of the orbit and its incidence is increasing proportionally with the rise of the average survival rate of the general population. The combined efforts of orbital surgeons, hematologists, oncologists and radiotherapists have lately produced a mass of new information that can effectively improve the management of orbital lymphoma. PMID- 17700234 TI - A review of sclerosing idiopathic orbital inflammation. AB - PURPOSE OF REVIEW: Sclerosing idiopathic orbital inflammation is a rare, distinct subset of orbital inflammation. No consistent therapeutic regimen has been described and the majority of reports on this disease are case reports or small case series. This review looks at historical and current treatment modalities in an attempt to define the most current, effective management strategy for this disease. RECENT FINDINGS: Recently, the largest review to date of these patients was published, detailing clinical findings and responses to the various interventions. Two other case reports of patients who responded completely to therapy appeared in the literature. SUMMARY: Sclerosing idiopathic orbital inflammation is a rare disease with an unknown pathogenesis and poor prognosis. Current treatments are disappointing and often have little beneficial effect. There are anecdotal reports of success using combinations of immunosuppression, radiotherapy, and surgery, but a consistent, effective treatment course is lacking. Younger patients and those with a shorter duration of disease seem to have the best prognosis. Further research into the immunologic basis of the disease and a large, controlled study comparing the various sclerosing idiopathic orbital inflammation treatments are needed to determine the most effective treatment regimen. PMID- 17700235 TI - Metastatic tumors of the orbit and ocular adnexa. AB - PURPOSE OF REVIEW: The management of cancer metastatic to the orbit and ocular adnexa (eyelid and periocular structures) has changed in recent decades. The purpose of this article is to review the incidence, presentation, and clinical features of metastatic tumors of the orbit and ocular adnexa and discuss their multidisciplinary care. RECENT FINDINGS: The improved survival of patients with common cancers such as breast cancer and prostate cancer, together with aging of the population has led to a higher incidence of patients living with metastatic disease in unusual sites such as the orbit and ocular adnexa. Furthermore, vigilant surveillance and advances in diagnostics have led to increased detection of orbital metastases. Treatment of metastatic lesions in the orbit and ocular adnexa is usually palliative and may include radiotherapy, chemotherapy, hormonal therapy, surgery, or a combination of these modalities. SUMMARY: Breast carcinoma continues to account for the majority of metastatic lesions of the orbit and ocular adnexa. Although the overall prognosis for patients with such lesions remains poor, the longer survival time for patients with breast carcinoma, the availability of novel targeted treatment options and new investigational agents, and advances in radiotherapy techniques may lead to better quality of life and preservation of ocular function for patients with metastatic orbital tumors. PMID- 17700236 TI - Periocular infection. AB - PURPOSE OF REVIEW: The aim of this article is to acquaint the clinician with advances in the diagnosis and management of periocular cellulitis and to alert physicians to emerging pathogens. RECENT FINDINGS: The most important, recent infectious disease entity to consider is community-acquired methicillin-resistant Staphylococcus aureus, which is emerging as a significant problem across the country. The potential devastation caused by necrotizing fasciitis is also reviewed, since this diagnosis is easily missed early in its course. A variety of less common and frankly atypical pathogens is presented to remind the clinician that, on occasion, the hoofbeats are indeed a zebra's. SUMMARY: Periocular cellulitis remains an important and common entity in ophthalmology. The emergence of new pathogens and the resistance to conventional treatment by others are a cause for concern and require an understanding of management strategies. PMID- 17700237 TI - What is new in the era of focal dystonia treatment? Botulinum injections and more. AB - PURPOSE OF REVIEW: The treatment options for the management of dystonias continue to evolve and improve. Clinical outcomes, however, are not predictably consistent using a single treatment regimen in all patients. RECENT FINDINGS: Botulinum toxin is still considered the best treatment option for the treatment of focal dystonias: blepharospasm, hemifacial spasm, and apraxia of eyelid opening. New findings indicate that physicians may be a little more aggressive with the dosage when the disease progresses. A new formulation of botulinum toxin has been produced that includes no proteins and may address the immunoresistance that can occur with prolonged use. Additional systemic medications may be helpful as adjuncts only in selected cases. Improved surgical techniques are now more successful and cause fewer complications. Therefore, many refractory cases are now offered a surgical approach alone or in combination with botulinum toxin. SUMMARY: There have been recent therapeutic developments in the treatment of ocular dystonias. PMID- 17700239 TI - Bibliography. Current world literature. Pediatrics and strabismus. PMID- 17700238 TI - Floppy eyelid syndrome. AB - PURPOSE OF REVIEW: Although floppy eyelid syndrome causes significant ocular symptoms and morbidity, the condition is often underdiagnosed. This review will highlight diagnostic features of the condition, emphasizing recent advances in the understanding of its pathophysiology. Current therapeutic strategies and surgical techniques are discussed. RECENT FINDINGS: Current concepts regarding the underlying pathophysiology of floppy eyelid syndrome revolve around upregulation of elastin degrading enzymes and mechanical factors. Together, these forces cause instability of the eyelid scaffold, resulting in eyelid malposition and ocular symptoms. Newer surgical treatments aim to preserve tarsus to improve eyelid stability and position. SUMMARY: Floppy eyelid syndrome--an underdiagnosed condition--produces significant ocular morbidity. Symptoms range from occasional redness and irritation to corneal ulcer. Diagnosis is based on ocular signs, including easy or spontaneous eversion of the upper eyelids in conjunction with conjunctivitis and keratitis. The condition, associated with body mass index and obstructive sleep apnea, should be suspected in any obese patient with a chronic red and tearing eye. Treatment consists of supportive measures such as ocular lubrication, eyelid taping or a shield, and surgery to address horizontal laxity and redundant eyelid tissues. PMID- 17700240 TI - A polygon-based locally-weighted-average method for smoothing disease rates of small units. AB - BACKGROUND: Disease rates for geographic areas with small populations may be unstable. Therefore, accurate nonparametric methods for smoothing or stabilizing rates are needed. METHODS: We propose an innovative locally-weighted-average method as an easy tool for disease surveillance. Our approach has several important advantages over existing locally-weighted-average methods. One advantage is that the buffer zone is created based on a polygon rather than centroid. Second, the buffer distance is determined by a user-specified population threshold. Third, a weighting factor that accounts for variability in the rate is used in the smoothing process. We further propose a variance-driven procedure to reduce arbitrariness in selecting the population threshold, and a binary search technique to quickly and precisely find the buffer distance according to the specified population threshold. Lastly, we develop a software tool using ArcObjects (ESRI, Redland, CA) to implement this method. RESULTS: Our method was applied to town-level lung cancer incidence rates for New Hampshire. A comparison with a traditional point-based method indicated that our method produced less under- and over-smoothing. CONCLUSION: Our method and the software tool are suitable for researchers and public health workers who want to apply geographic information systems to map smoothed disease rates for exploratory purposes. PMID- 17700242 TI - Four types of effect modification: a classification based on directed acyclic graphs. AB - It is possible to classify the types of causal relationships that can give rise to effect modification on the risk difference scale by expressing the conditional causal risk-difference as a sum of products of stratum-specific risk differences and conditional probabilities. Directed acyclic graphs clarify the causal relationships necessary for a particular variable to serve as an effect modifier for the causal risk difference involving 2 other variables. The directed acyclic graph causal framework thereby gives rise to a 4-fold classification for effect modification: direct effect modification, indirect effect modification, effect modification by proxy and effect modification by a common cause. We briefly discuss the case of multiple effect modification relationships and multiple effect modifiers as well as measures of effect other than that of the causal risk difference. PMID- 17700241 TI - Estimating the effects of time-varying treatments: incidence of fractures among postmenopausal Japanese women. AB - BACKGROUND: In the absence of unmeasured confounding, standard methods for estimating the effects of time-varying treatments on an event are biased when a time-dependent risk factor for the event also predicts subsequent treatments and when past treatment history predicts subsequent risk factor levels. In contrast, structural models provide unbiased estimates of effects when unmeasured confounding is absent. METHODS: We describe a multiplicative structural mean model and use it to estimate the effects of time-varying osteoporosis treatments on incidence of fractures among 1328 postmenopausal women over 40 years of age in a hospital-based cohort study in Japan. The parameters of the structural mean model are estimated by g-estimation. RESULTS: The number of vertebral fractures and bone mineral density levels predicted the selection of subsequent treatments and were affected by the previous treatments. Incidence rate ratios of bisphosphonates, active vitamin D3, and conjugated estrogen compared with no drug therapy were 0.58 (95% confidence interval = 0.44-0.77), 0.82 (0.48-1.38), and 0.60 (0.47-0.76), respectively, after adjusting time-dependent confounders. For initial treatments estimated by the standard Poisson-GEE, incidence rate ratios were 1.61 (1.23-2.10), 1.16 (0.96-1.40), and 0.73 (0.52-1.02), respectively. CONCLUSIONS: Our analysis using the structural mean model showed that bisphosphonates, active vitamin D3, and conjugated estrogen all had preventive effects on the incidence of fractures by appropriate adjustments for time dependent confounders. The results from standard Poisson-GEE analysis were the opposite of these results and of evidence from randomized trials. We consider our methods useful to estimate time-varying treatments within observational data. PMID- 17700243 TI - Can DAGs clarify effect modification? AB - The system proposed by VanderWeele and Robins for categorization of effect modifiers that are causal nodes in a directed acyclic graph (DAG) was not intended to empower DAGs to fully represent complex interactions among causes. However, once one has algebraically identified effect modifiers, the DAG implies a role for them. The limitations of epidemiologic definitions of "effect modification" are discussed, along with the implications of scale dependency for assessing interactions, where the scale can be either absolute risk, relative risk, or odds. My view is that probabilistic independence leads to the log complement as a natural scale for interaction, but even that scale does not necessarily admit unambiguous inference. Any 2 direct causes of D are effect modifiers for each other on at least 2 scales, which can make a reasonable person question the utility of the concept. Still, etiologic models for joint effects are important, because most diseases arise through pathways involving multiple factors. I suggest an enhancement in construction of DAGs in epidemiology that includes arrow-on-arrow representations for effect modification. Examples are given, some of which depend on scale and some of which do not. An example illustrates possible biologic implications for such an effect modification DAG. PMID- 17700244 TI - Are girls more susceptible to the effects of prenatal exposure to tobacco smoke on asthma? AB - BACKGROUND: Prenatal exposure to tobacco smoke through mother's smoking increases the risk of developing asthma later in life. A recent study suggested that this effect is present only in girls. We explored potential differences in susceptibility between boys and girls. METHODS: We followed all 58,841 Finnish singleton babies born in 1987 through 5 nationwide registries for 7 years and identified all cases of doctor-diagnosed asthma (ICD-9 code 493). The birth registry provided categorical information on the mother's smoking during pregnancy: no smoking (reference), low exposure (<10 cigarettes per day), and high exposure (>10 cigarettes per day). RESULTS: In girls the cumulative incidence of asthma was 0.0245 in the reference group, 0.0310 in the low maternal smoking group (risk difference = 0.0065; 95% CI = 0.0053-0.0076), and 0.0360 in the high maternal smoking group (0.0115; 0.0096-0.0133). The corresponding cumulative incidences for boys were 0.0405, 0.0501 (0.0096; 0.0089-0.0103), and 0.0522 (0.0117; 0.0091-0.0142). In logistic regression analysis adjusting for confounding, the combined effect of male sex and high maternal smoking (compared with female sex and no smoking) was 112% excess risk. This corresponded closely to what would be expected from the additive independent effects of male sex (67% excess risk) and high maternal smoking (44% excess risk). CONCLUSIONS: Effects of maternal smoking during pregnancy on the risk of developing asthma are similar in boys and girls, with no interaction on an additive scale. PMID- 17700245 TI - Prenatal ultrasound scanning and the risk of schizophrenia and other psychoses. AB - BACKGROUND: Prenatal ultrasound exposure has been associated with increased prevalence of left-hand or mixed-hand preference, and has been suggested to affect the normal lateralization of the fetal brain. Atypical lateralization is more common in patients with schizophrenia. We evaluated possible associations of prenatal ultrasound with schizophrenia and other psychoses. METHODS: We identified a cohort of individuals born in Sweden 1973-1978. During this period, one Swedish hospital (Malmo University Hospital) performed prenatal ultrasound on a routine basis, and all individuals born at that hospital were considered exposed to ultrasound. Children born at hospitals where ultrasound was not used routinely or selectively were considered unexposed. We used Poisson regression analysis to estimate the effect of ultrasound exposure on the incidence of schizophrenia and other psychoses. RESULTS: In all, 370,945 individuals were included in the study, of whom 13,212 were exposed to ultrasound. The exposed group demonstrated a tendency toward a higher risk of schizophrenia (among men, crude incidence rate ratio = 1.58 [95% confidence interval = 0.99-2.51]; among women, 1.26 [0.62-2.55]). However, men and women born in several of the 7 tertiary level hospitals without ultrasound scanning also had higher risks of schizophrenia compared with those born in other hospitals. For other psychoses there were no differences between groups. CONCLUSIONS: No clear associations between prenatal ultrasound exposure and schizophrenia or other psychoses were found. Other factors related to place of birth might have influenced the results. PMID- 17700246 TI - Belated concerns and latent effects: the example of schizophrenia. AB - In this issue of Epidemiology, Stalberg and colleagues report the lack of an association between prenatal ultrasound and risk of schizophrenia in adulthood. These findings contribute to the search for unintended effects of an intervention designed to improve prenatal care. Although no adverse effect of ultrasound was reported, other gestational exposures have been associated with increased risk of schizophrenia. By extending the causal time frame to include long-term latent effects we are confronted with a potential paradox: interventions beneficial in early life may have undetected adverse consequences in adulthood. PMID- 17700247 TI - Ambient air pollution and cardiac arrhythmias in patients with implantable defibrillators. AB - BACKGROUND: Previous studies of ambient air pollution and ventricular tachyarrhythmias in patients with implantable cardioverter defibrillators have yielded mixed results. METHODS: We examined this relationship in a study of 518 patients with 6287 tachyarrhythmic event-days over a 10-year period in Atlanta, Georgia. The air quality data included daily measurements of PM10, ozone, nitrogen dioxide, carbon monoxide, and sulfur dioxide for the entire study period, as well as speciated measurements of PM2.5 mass and oxygenated hydrocarbons for the final 4 years of the study. Our primary analyses utilized generalized estimating equations, controlling for long-term time trends and meteorologic conditions as well as residual correlation within subjects. RESULTS: Our primary modeling approach found no association; additional sensitivity analyses and alternative analytic approaches supported those findings. The most suggestive positive findings were for coarse particles. CONCLUSIONS: The present study constitutes the largest study to date of ambient air pollution and tachyarrhythmic events in patients with implantable cardioverter defibrillators. Other than the suggestive findings for coarse particles, the study provides little evidence of an association between ambient air quality levels and tachyarrhythmic events. PMID- 17700248 TI - Short-term effects of particulate air pollution on male smokers and never smokers. AB - BACKGROUND: Numerous studies have shown that ambient air pollution and smoking are both associated with increased mortality, but until now there has been little evidence as to whether the effects of these 2 factors combined are greater than the sum of their individual effects. We assessed whether smokers are subject to additional mortality risk from air pollution relative to never-smokers. METHODS: This study included 10,833 Chinese men in Hong Kong who died at the age of 30 or above during the period 1 January to 31 December 1998. Relatives who registered for deceased persons were interviewed about the deceased's smoking history and other personal lifestyle factors about 10 years before death. Poisson regression for daily number of deaths was fitted to estimate excess risks per 10 microg/m increase in particulate matter with aerodynamic diameter <10 microm (PM10) in male smokers and never-smokers in stratified data, and additional excess risk for smokers relative to never-smokers in combined data. RESULTS: In smokers there was a significant excess risk associated with PM10 for all natural causes and cardio respiratory diseases for men age 30 years or older and men 65 or older. For all natural causes, greater excess risk associated with PM10 was observed for smokers relative to never-smokers: 1.9% (95% confidence interval = 0.3% to 3.6%) in men age 30 and older and 2.3% (0.4% to 4.3%) in those age 65 and older. CONCLUSIONS: Ambient particulate air pollution is associated with greater excess mortality in male smokers compared with never-smokers. PMID- 17700249 TI - Body mass index in adolescence and number of children in adulthood. AB - BACKGROUND: Body weight is associated with reproduction and related behaviors, but it is unknown whether it has significance for fertility differences in the general population. We examined whether adolescent body mass index (BMI; kg/m) predicted the number of children in adulthood 21 years later. METHODS: The participants were 1298 Finnish women and men (ages 12, 15, and 18 years at baseline) followed in a prospective population-based cohort study (the Cardiovascular Risk in Young Finns) from year 1980 to 2001. RESULTS: There was an inverted J-shaped association between BMI and the number of children, such that underweight adolescents had 10-16% fewer children in adulthood, overweight adolescents 4-8% fewer, and obese adolescents 32-38% fewer than individuals with normal adolescent weight. This association was similar in women and men, and independent of age, education, urbanicity of residence, and timing of menarche (in women). Adolescents with low or high BMI were less likely to have lived with a partner in adulthood, which partly accounted for their decreased number of children. The influence of adolescent BMI was independent of adulthood BMI in women but not in men. Age at menarche also predicted the number of children, such that women with early or late menarche had more children than those with average age at menarche. CONCLUSION: Underweight and especially obesity may have a negative impact on fertility in the general population. The increasing prevalence of obesity in children and adolescents may represent a concern for future reproductive health. PMID- 17700250 TI - Pet ownership and blood pressure in old age. AB - BACKGROUND: It has been proposed that pet ownership improves cardiovascular health. This study examines the relation of pet ownership with systolic and diastolic blood pressure, pulse pressure, mean arterial pressure, and hypertension in a large sample of older men and women. METHODS: Participants were 1179 community-dwelling men (n = 498) and women (n = 681) age 50-95 years. Participants responded to a 1991-1992 mailed questionnaire ascertaining pet ownership, and they attended a 1992-1996 clinic visit at which systolic (SBP) and diastolic (DBP) blood pressures were measured and use of antihypertensive medication was validated. Pulse pressure was calculated as SBP minus DBP. Mean arterial pressure was calculated as (SBP+DBP)/2. Body mass index, waist-hip ratio, and information on other potential confounders were obtained. RESULTS: Average age of participants was 70.4 +/- 10.8 years; 30.0% reported current pet ownership. Mean SBP was 137.5 +/- 21.4 mm Hg, and DBP was 76.1 +/- 9.3 mm Hg; 55.6% were hypertensive (SBP >or= 140, DBP >or= 90 or taking hypertension medication). Pet owners were younger and slightly more overweight and they exercised less than nonowners; owners were somewhat more likely to have diabetes and to use beta-blockers. In unadjusted analyses, pet owners had lower SBP, pulse pressure, and mean arterial pressure, and a reduced risk of hypertension (odds ratio = 0.62; 95% confidence interval = 0.49-0.80). However, after adjustment for age and other confounders, pet ownership was not associated with systolic or diastolic blood pressure, pulse pressure, mean arterial pressure or risk of hypertension. CONCLUSIONS: Results suggest that pet ownership is not independently associated with blood pressure, vascular reactivity, or hypertension. PMID- 17700251 TI - How much would closing schools reduce transmission during an influenza pandemic? AB - BACKGROUND: When deciding whether to close schools during an influenza pandemic, authorities must weigh the likely benefits against the expected social disruption. Although schools have been closed to slow the spread of influenza, there is limited evidence as to the impact on transmission of disease. METHODS: To assess the benefits of closing schools for various pandemic scenarios, we used a stochastic mathematical model of disease transmission fitted to attack rates from past influenza pandemics. We compared these benefits with those achieved by other interventions targeted at children. RESULTS: Closing schools can reduce transmission among children considerably, but has only a moderate impact on average transmission rates among all individuals (both adults and children) under most scenarios. Much of the benefit of closing schools can be achieved if schools are closed by the time that 2% of children are infected; if the intervention is delayed until 20% of children are infected, there is little benefit. Immunization of all school children provides only a slight improvement over closing schools, indicating that schools are an important venue for transmission between children. Relative attack rates in adults and children provide a good indication of the likely benefit of closing schools, with the greatest impact seen for infections with high attack rates in children. CONCLUSIONS: Closing schools is effective at reducing transmission between children but has only a moderate effect on average transmission rates in the wider population unless children are disproportionately affected. PMID- 17700252 TI - Cigarette smoking and risk of breast carcinoma in situ. AB - BACKGROUND: Although the associations with cigarette smoking have been explored extensively for invasive breast cancer, the relation to in situ cancer has not previously been examined in depth. METHODS: We analyzed data from a population based case-control study of women living in Wisconsin, Massachusetts, and New Hampshire. Eligible cases of incident breast carcinoma in situ were reported to statewide registries in 1997-2001 (n = 1878); similarly aged controls (n = 8041) were randomly selected from population lists. Smoking history and other risk factor information were collected through structured telephone interviews. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated from logistic regression models adjusting for potential confounders. RESULTS: In multivariate models, the OR for breast carcinoma in situ among current smokers was 0.8, compared with never-smokers (95% CI = 0.7-1.0). Risk estimates increased towards the null with greater time since smoking cessation. Odds ratios were also less than 1.0 among women who initiated smoking in adolescence (OR = 0.8) or after a full-term birth (OR = 0.7), relative to women who never smoked. The reduced odds ratios associated with current smoking were strongest among women with annual screening mammograms (OR = 0.7; 95% CI = 0.6-0.9). Odds ratios were not less than 1.0 among current smokers without a recent screening mammogram (1.3; 0.9-2.0). CONCLUSIONS: Our findings suggest an inverse association between current smoking and risk of breast carcinoma in situ among women undergoing breast cancer screening. PMID- 17700253 TI - Cigarette smoking and lung cancer: modeling effect modification of total exposure and intensity. AB - BACKGROUND: A recent analysis indicates that the excess odds ratio for lung cancer by smoking is described by a function that is linear in pack-years and exponential in the logarithm of smoking intensity and its square (Cancer Epidemiol Biomarkers Prev. 2006;15:517-523). The model suggests that below 15-20 cigarettes per day there is a "direct exposure rate" effect, ie, the excess odds ratio per pack-year for higher intensity (and shorter duration) smokers is greater than for lower-intensity (and longer duration) smokers. Above 20 cigarettes per day, there is an "inverse-exposure-rate" effect, ie, the excess odds ratio per pack-year for higher intensity smokers is smaller than for lower intensity smokers. METHODS: Using pooled data from 2 large case-control studies of lung cancer (the European Smoking and Health Study and the German Radon Study), we evaluated effect modification of the association between smoking and lung cancer. RESULTS: Interaction effects are very specific. Variations in risk of lung cancer with years since cessation of smoking, age, method of inhalation, and type of cigarette result from interactions with smoking intensity, and not total pack-years. In contrast, risk variations by sex result from the interaction with total pack-years, while intensity effects are homogeneous. Risk variations by age at which smoking started result from interactions with both total pack years and intensity. All intensity interactions are homogeneous across studies. CONCLUSIONS: The specificity of the interactions may provide clues for the molecular basis of the smoking and lung cancer relationship. PMID- 17700254 TI - Models of smoking and lung cancer risk: a means to an end. AB - This commentary provides some historical context to the analysis of smoking and lung cancer risk by Lubin and colleagues in this issue of epidemiology. It also considers the potential utility of ongoing efforts to apply complex mathematical models to epidemiologic data on smoking and lung cancer risk. We conclude that the work of Lubin and colleagues adds to the models already developed and points to some potential complexities that models should incorporate. PMID- 17700257 TI - The cost-effectiveness of the new protocol reflecting rapid virologic response to peginterferon alpha-2b and ribavirin for chronic hepatitis C. AB - OBJECTIVE: Recent studies have reported the effectiveness of shorter courses of treatment with peginterferon alpha-2b plus ribavirin for patients with chronic hepatitis C, who achieved a rapid virologic response (RVR), defined as undetectable hepatitis C virus (HCV-) RNA at week 4. The aim of this study was to evaluate the cost-effectiveness of the new protocol for treatment, from the perspective of RVR. METHODS: A cost-effectiveness analysis based on the rate of sustained virologic response was performed. A Markov cohort model of hepatitis C was constructed to demonstrate the clinical states on the basis of the assigned transition probabilities over 30 years. The treatment strategies were classified into five subgroups taking into consideration the viral genotypes, viral load, and RVR. The lifetime costs and quality-adjusted life years (QALYs) were compared between the new and standard protocols for treatment. RESULTS: Genotype 1 infected patients in the new protocol for treatment compared with the standard one could prolong QALYs by 0.33 and reduce lifetime cost by euro 5993. Genotype 2 or 3-infected patients in the new protocol for treatment compared with the standard one could prolong QALYs by 0.02 and reduce lifetime cost by euro2851. CONCLUSION: Treatment strategies that consider viral load and RVR for patients with a low viral load infected with genotype 1 and those infected with genotype 2 or 3 are more cost-effective compared with the standard protocol for treatment. PMID- 17700258 TI - Adherence to hepatitis C treatment in recovering heroin users maintained on methadone. AB - OBJECTIVES: Injection drug users are often denied hepatitis C (HCV) treatment due to concerns about adherence, despite limited data about the impact of such common issues as psychiatric illness and intercurrent drug use. We sought to define the impact of these and other potential adherence barriers in a real-world sample of recovering drug users. METHODS: We conducted a prospective observational study of 71 methadone-maintained patients who received interferon and ribavirin combination therapy in a community-based clinic with expertise in treating addictive disorders. Adherence measures were conducted with monthly interview, medication counts, and urine toxicology testing. RESULTS: Overall, 48 (68%) were adherent, and adherent patients were significantly more likely to achieve a sustained virologic response (42 vs. 4% in nonadherent patients). Patients with and without a prior psychiatric history were similarly adherent (64 vs. 72%, respectively, P>0.5), and the initiation of new psychiatric medications during HCV treatment was associated with improved adherence overall (P=0.02) and in patients that did not report a preexisting psychiatric diagnosis (P=0.04). Trend towards reduced adherence in patients without a period of abstinence was seen before initiating HCV treatment, 46 vs. 72% of those who had been abstinent for at least 1 month (P=0.10). Although occasional drug users were similarly adherent to those who were completely abstinent, patients who relapsed to regular drug use showed a significantly lower level of adherence (P=0.03). CONCLUSIONS: We conclude that the majority of methadone-maintained drug users can adhere to HCV treatment, even those with psychiatric illness and relatively limited pretreatment drug abstinence. Lack of pre-HCV treatment drug abstinence and regular drug use during HCV treatment may be relative barriers to medication adherence, but the initiation of psychiatric medications during HCV treatment may be a helpful intervention. This report provides further evidence for an individualized approach to HCV treatment that does not categorically exclude patients with potential barriers such as mental illness and limited drug abstinence. PMID- 17700259 TI - Cell cycle and apoptosis alteration of human hepatocarcinoma cells by subclinical dose 12C6+-beam irradiation. AB - OBJECTIVE: The purpose of this study is to investigate the effect of subclinical dose C-beam irradiation on cell cycle and cell apoptosis in hepatocarcinoma cells. MATERIALS AND METHODS: The HepG2 cells were exposed to 0-2.0 Gy of either the C beam or a gamma-ray. Cell survival was detected by clonogenic assay. Cell cycle was determined by flow-cytometry analysis. The apoptosis was monitored by fluorescence microscope with DAPI staining. p53 and p21 expression were detected by Western blot. RESULTS: The G0/G1 cells in the irradiated groups were significantly more than those in the control (P<0.05). The C-ion irradiation had a greater effect on the cell cycle of HepG2 cells (including promoting G1-phase and G2-phase arrest) than gamma-ray irradiation. The apoptotic cells induced by C beam were significantly more numerous than those induced by gamma-ray (P<0.05). The carbon ions had a stronger effect on p53 and p21 expression than the gamma ray irradiation. The survival fractions for cells irradiated by C beam were significantly smaller than those irradiated by gamma-ray (P<0.05). CONCLUSION: The subclinical-dose C-beam irradiation significantly suppresses HepG2 cells through cell-cycle arrests and cell apoptosis in contrast to same-dose gamma-ray irradiation. PMID- 17700260 TI - Elevation of endoglin (CD105) concentrations in serum of patients with liver cirrhosis and carcinoma. AB - OBJECTIVE: Liver cirrhosis is considered as a premalignant state, as about 80% of hepatocellular carcinoma (HCC) is associated with liver cirrhosis. Although alpha fetoprotein (AFP) has a high negative predictive value, its sensitivity for detecting HCC is poor. The aim of this study was to evaluate circulating endoglin (CD105) in the serum of patients with liver cirrhosis and at high risk for HCC. METHODS: CD105 and AFP serum concentrations were measured in 70 healthy and 94 nonliver-diseased controls and 130 patients with chronic liver diseases and HCC, respectively. RESULTS: Fifty-seven liver cirrhotic patients, 45 patients with liver cirrhosis plus HCC, 19 liver fibrosis patients and nine patients with HCC only were studied. Serum CD105 is significantly elevated in liver cirrhotic patients compared with healthy (P<0.0001) and nonliver-diseased controls (P<0.0001). Patients with liver cirrhosis and HCC show the highest CD105 concentrations being significantly elevated in comparison to liver cirrhosis (P=0.0006) and HCC only (P=0.0134). A stronger positive correlation exists between CD105 and AFP in the patient group suffering from liver cirrhosis and HCC (r=0.479, P=0.0015) than the obtained correlation between both markers in the group of patients diagnosed with liver cirrhosis alone (r=0.358, P=0.0073). The logistic regression model identified CD105 as an independent marker (P=0.0077, odds ratio 1.3). CONCLUSION: CD105 has the potential to be a novel complementary biomarker that has some important bearing on the risk assessment for development of HCC in cirrhotic patients. PMID- 17700261 TI - Hospital admissions in Italy for liver and gastrointestinal diseases in the period 1999-2002: an epidemiological study. AB - AIM: The aim of this study is to assess the total number of admissions and the rates of hospitalization in Italy for liver and gastrointestinal diseases in the period 1999-2002, and to indirectly highlight the peculiar epidemiological features of the diseases causing these admissions. METHODS: The data bank of the Italian Ministry of Health has been consulted. The total number of admissions for liver and gastrointestinal diseases as coded by the International Classification of Diseases Manual - Ninth Edition - Clinical Modification, and their relevant admission rates in the considered period have been calculated. Age, sex, and regional rates for these admissions have also been calculated. RESULTS: In Italy, during the years 1999-2002, a total number of 7,294,792 patients (4,034,195 males and 3,260,597 females) were admitted with liver and gastrointestinal diseases. The total number of admissions relevant to the pathologies being considered has been quite steady in the study period. The calculated mean national rate of admission for these diseases was 3.19/100 (highest rate of 3.27/100 recorded in 1999 and lowest rate of 3.14/100 recorded in 2002). The highest rates of admission for the considered diseases were recorded in the two age ranges '<1 year' and '75 years and more', during the entire periods (highest rates of admission of 12.23/100 and 6.56/100, respectively, recorded in 1999). In the age range '15-24 years', the lowest rates of admission have been calculated (lowest rate of admission of 1.66/100 recorded in 2002). The Italian regions where the highest and lowest admission rates for these pathologies have been recorded are the Umbria region in 1999 (admission rate of 4.02/100) and the Friuli Venezia Giulia region in 2002 (admission rate of 2.54/100), respectively. CONCLUSION: The study shows that in Italy a great percentage of hospital admissions is due to liver and gastrointestinal diseases; it might indirectly suggest that liver and gastrointestinal diseases are related to sex, age, and geographical factors. It, furthermore, indicates that the Italian hospital-assistance system is inadequate with respect to the number of hospitalizations for these diseases. PMID- 17700262 TI - N-acetyl cysteine inhibits human signet ring cell gastric cancer cell line (SJ 89) cell growth by inducing apoptosis and DNA synthesis arrest. AB - BACKGROUND AND AIMS: In this study, we investigated the inhibitory effects of N acetyl cysteine (NAC) on the growth of the human signet ring cell from the gastric-cancer cell line SJ-89 , via the induction of apoptosis and the arrest of DNA synthesis. MATERIALS AND METHODS: SJ-89 cells were regularly incubated in the presence of NAC at 5, 10 and 20 mmol/l, and with IMDM as untreated control. Trypan blue-dye exclusion analysis and 3-(4,5-dimethylthiazol-2yl)-2,5 diphenyltetrazolium bromide assay were applied to detect cell proliferation. Apoptotic morphology was observed by electron microscopy. Flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) assay were performed to detect NAC-triggered apoptosis. RESULTS: NAC could inhibit proliferation of human gastric cancer SJ-89 cells in a dose-dependent and time-dependent manner. The growth curve showed suppression by 15.8, 37.6 and 66.3% following 72 h of NAC treatment at 5, 10 and 20 mmol/l, respectively, similar to the findings of 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide assay. DNA synthesis was evidently reduced by 25, 39 and 91% after 24 h NAC treated at 20 mmol/l and 5 days at 10 and 20 mmol/l, respectively. Cell growth was inhibited by 100% with the treatment of 20 mmol/l NAC on day 6. NAC treated SJ-89 cells were characterized by typical apoptotic alterations, including morphological changes by electron microscopy, typical apoptotic sub-G1 peaking observed by flow cytometry and increase of apoptotic cells with the elevation of the concentration of NAC in a clearly dose-dependent manner by TUNEL assay. Electrophoresis analysis showed typical 'DNA ladder'. CONCLUSION: The data above implicated that NAC inhibits human gastric-cancer SJ-89 cell growth by inducing apoptosis and DNA synthesis arrest. Although the exact mechanisms involved in NAC-induced apoptosis have not been known up to now, the ability to induce apoptosis in a tumor-cell population within 48 h is worth noting. It is also noteworthy that NAC can selectively inhibit the growth of tumor cells. Further studies are needed to elucidate the mechanisms. PMID- 17700263 TI - Altered endothelin receptor subtypes in colorectal cancer. AB - BACKGROUND: The vasoactive peptide endothelin-1 (ET-1) acts via two endothelin receptor subtypes, ETA (ETAR) and ETB (ETBR). ET-1 and ETAR are overexpressed in colorectal cancer tissues. In vitro, ET-1 acting via ETAR, is a mitogen for colorectal cancer cells. To identify other potential stimulatory loops, we investigated the distribution and cell-specific localization of both ETAR and ETBR in tissue sections from patients with colorectal cancer. METHODS: Frozen sections from specimens of colorectal cancer (n=9) and normal colon (n=9) were cut and subjected to either (i) autoradiography or (ii) a combination of cell type-specific immunohistochemistry, using antibodies against fibroblasts (AS02), endothelial cells (CD31) or nerve fibres (NF200) and in-vitro receptor microautoradiography, using ETAR-specific and ETBR-specific radioligands. RESULTS: ETARs were upregulated in all cell types, apart from nerve, in cancer compared with normal colon (1:1.59 normal to cancer). Specifically, ETAR binding was highest in cancer-associated blood vessels and fibroblasts and to a lesser extent in epithelial cancer cells. In contrast, ETBRs were the predominant receptors in normal colon (1:0.59 normal to cancer) and were markedly down regulated in cancer-associated blood vessels, fibroblasts and to a lesser extent in epithelial cells. Nerve colocalization was demonstrated, but remained unchanged for all tissues. CONCLUSION: The shift in ET receptor binding observed in epithelial cancer cells and cancer-associated fibroblasts and endothelial cells may favour ET-1 signals contributing to colorectal cancer growth and neovascularization via ETAR. This may provide the basis for therapeutic use of specific ETAR antagonists as adjuvant treatment of colorectal cancer. PMID- 17700264 TI - Is ineffective oesophageal motility associated with reflux oesophagitis? AB - OBJECTIVE: To evaluate the association between ineffective oesophageal motility and reflux oesophagitis controlling for hiatal hernia, hypotensive lower oesophageal sphincter and male sex in patients with gastro-oesophageal reflux disease. METHODS: A total of 387 patients with reflux disease (mean age, 46 years, 42% men) were consecutively selected from a database. All patients underwent upper endoscopy, oesophageal manometry and 24 h oesophageal pH-metry in accordance with a standardized protocol. Reflux disease was confirmed either by endoscopy (oesophagitis grade I-IV according to Savary-Miller) or by pH-metry (increased acid exposure). Hiatal hernia was diagnosed endoscopically, whereas ineffective oesophageal motility and hypotensive lower oesophageal sphincter were characterized during manometry testing. The association between ineffective oesophageal motility and reflux oesophagitis was assessed by logistic regression analysis. RESULTS: A total of 166 patients with oesophagitis (mean age 45 years, 49% men) and 221 without oesophagitis (mean age 46 years, 37% men) were present. Prevalences of ineffective oesophageal motility, hiatal hernia, hypotensive lower oesophageal sphincter and male sex were significantly higher in patients with oesophagitis compared with those without oesophagitis (P<0.05). Ineffective oesophageal motility was independently associated with oesophagitis after multivariate logistic regression analysis (odds ratio=1.68; 95% confidence interval=1.04-2.70). CONCLUSION: Ineffective oesophageal motility is associated with reflux oesophagitis, independently of hiatal hernia, hypotensive lower oesophageal sphincter and male sex. PMID- 17700265 TI - The effect of infliximab on circulating levels of leptin, adiponectin and resistin in patients with inflammatory bowel disease. AB - BACKGROUND: Tumour necrosis factor alpha is a critical mediator of inflammation related altered metabolism in inflammatory bowel disease (IBD), possibly through its interaction with adipokines, which play an important role in IBD. Infliximab is a well established antitumour necrosis factor alpha treatment in IBD. AIM AND METHODS: We studied serum levels of leptin, adiponectin and resistin in 20 IBD patients before and after infliximab treatment using commercially available enzyme-linked immunosorbent assays. The results were correlated with alterations of disease activity, BMI and C-reactive protein. RESULTS: Infliximab induced clinical response or remission in 18 out of 20 treated IBD patients. Mean serum leptin levels were 4.6+/-0.5 and 5.1+/-0.5 ng/ml (P=0.41), mean serum-adiponectin levels were 10513.9+/-1216.9 and 9653.5+/-1031.5 ng/ml (P=0.36) and mean serum resistin levels were 26.3+/-4.1 and 13.9+/-1.4 ng/ml (P=0.004), before and after infliximab treatment, respectively. No significant correlation between the changes of BMI, C-reactive protein or the clinical indices of activity and alterations of the examined adipokines was found. CONCLUSIONS: Serum levels of leptin and adiponectin had no significant alterations, whereas serum-resistin levels are significantly decreased after infliximab therapy in IBD patients, suggesting a possible proinflammatory status for resistin in IBD and a role as a marker of successful therapy. PMID- 17700266 TI - Irritable bowel syndrome among patients attending General Outpatients' clinics in Jos, Nigeria. AB - Irritable bowel syndrome (IBS) is a common disorder in the Western world. Its prevalence is yet to be fully determined in the African setting. This was a cross sectional study of patients attending three General Outpatient clinics in Jos, Nigeria. Four hundred and eighteen randomly selected patients were interviewed using a structured questionnaire based on the Rome II diagnostic criteria for IBS. Excluded from the study were patients with established organic disease, memory problems, and pregnant women. Eighteen patients were excluded based on these criteria and 400 were analysed using Epi Info 2000 (Atlanta, Georgia, USA) statistical computer software. One hundred and thirty-two (33%) out of the 400 patients fulfilled the criteria for the diagnosis of IBS, the female to male ratio being 1.13 : 1. IBS was significantly associated with increasing age (P=0.03) and depression (P<0.001). The prevalence of IBS is high among patients attending primary care in the African setting with depression being the likely reason for seeking care. PMID- 17700267 TI - The simultaneous occurrence of mucinous cystadenomas in liver and pancreas. AB - The occurrence of mucinous cystadenomas localized to the liver and pancreas simultaneously and treated with a single surgical procedure has been described for the first time in this report. A 47-year-old woman attended the outpatient clinic complaining of abdominal pain and the appearance of an abdominal mass. On clinical examination, hepatomegaly was found. An abdominal computed tomography scan showed a large cystic lesion of the left lobe of the liver, thus causing the hepatomegaly. Moreover, the computed tomography scan showed a cystic lesion of the pancreas. Both lesions had thick walls and septa. Magnetic resonance imaging of the liver and pancreas confirmed the presence of septa within the cysts. Surgery was performed owing to the suspected malignancy. It should be emphasized that the patient had preoperatively received prophylactic treatment for hydatosis. A hepatic pericystectomy and enucleation of the pancreatic lesion were performed during the surgery. Pathology showed a mucinous cystadenoma without sign of malignancy. At the 4-year follow-up, no recurrence was found. This case is of interest for several reasons: the unusual double presentation, the treatment, and the follow-up. This case report confirms the common origin of mucinous cystic tumours of liver and pancreas. PMID- 17700268 TI - Acute pancreatitis as a possible consequence of metronidazole during a relapse of ulcerative colitis. AB - We present the first case of metronidazole-related acute pancreatitis during a relapse of ulcerative colitis. A 31-year-old male patient, with inflammatory bowel disease on mesalamine treatment for the last 5 months, suffered from a 48-h abdominal pain and nausea. He was also administered metronidazole during a relapse 5 days before. Laboratory and imaging investigation revealed acute pancreatitis. Conservative measures and metronidazole as well as mesalamine withdrawal resulted in complete recovery. Clinical remission of ulcerative colitis was obtained by prednisolone administration. Mesalamine was reintroduced and no recurrence was noticed for a year. Acute pancreatitis was mainly attributed to metronidazole owing to the absence of recurrence after mesalamine readministration, the time of onset after the initiation of metronidazole and the lower typical range between its onset and mesalamine exposure. Identifying acute pancreatitis as a possible consequence of a certain medication in inflammatory bowel disease patients may be particularly important to determine further treatment of their disease. PMID- 17700269 TI - Multiple primary liver lipomas in a patient with chronic hepatitis B: a case report. AB - True liver lipomas are extremely rare. We present a case of a female patient with a history of chronic hepatitis B and multiple liver lipomas. The patient was completely asymptomatic. Liver ultrasound was suggestive of lipomas, whereas the diagnosis was confirmed by computed tomography and magnetic resonance imaging. To our knowledge, this is the first report of multiple liver lipomas in the literature. PMID- 17700270 TI - Pyoderma gangrenosum and exacerbation of psoriasis resulting from pegylated interferon alpha and ribavirin treatment of chronic hepatitis C. AB - Interferon therapy is the cornerstone of chronic hepatitis C treatment. Side effects of interferon include possible triggering or exacerbation of immune diseases in consequence of immunomodulatory effects. We describe the unique case, in which pyoderma gangrenosum and exacerbation of psoriasis were developed 8 weeks after pegylated interferon alpha 2a and ribavirin therapy in a 45-year-old woman. The therapy had to be stopped on account of pyoderma gangrenosum and exacerbation of psoriasis in spite of a biochemical response to the therapy for hepatitis C. The evolution was favorable after stopping treatment. Therefore, we propose this would suggest a possible autoimmune mechanism for the development of pyoderma gangrenosum and exacerbation of psoriasis with pegylated interferon therapy. A susceptible patient, who has an autoimmune disease before interferon therapy, had to be informed that interferons may induce de novo or exacerbate existing immune diseases by immunomodulatory actions. To the best of our knowledge, this is the first case report of pyoderma gangrenosum and psoriasis that resulted from pegylated interferon alpha 2a and ribavirin treatment of chronic hepatitis C. PMID- 17700271 TI - Reversible alopecia universalis secondary to PEG-interferon alpha-2b and ribavirin combination therapy in a patient with chronic hepatitis C virus infection. AB - Combined treatment with pegylated interferon (PEG-IFN) and ribavirin is currently recommended for the treatment of chronic hepatitis C virus (HCV) infection. Many side effects including hair disorders have, however, been reported related to this treatment. Alopecia universalis is a severe form of hair disorder. Three cases of alopecia universalis during PEG-IFN and ribavirin combination therapy have been reported in the literature. Herein is reported a case of reversible alopecia universalis, with complete hair loss extending to the whole body, secondary to PEG-IFN alpha-2b and ribavirin combination therapy for chronic HCV infection. Hair regrowth began within 3 months of the completion of combined therapy. In case the liver disease is advanced, and virologic response occurs, treatment can still be completed, as it appears that these side effects are reversible. PMID- 17700273 TI - Prevalence of gluten-sensitive enteropathy and coeliac disease in Iran. PMID- 17700272 TI - The good and evil of flare: flares in hepatitis B virus chronic hepatitis. AB - Treatment of HBeAg-positive chronic hepatitis B with pegylated interferon achieves HBeAg seroconversion in about 30% of patients and retreatment of nonresponders is followed by a low rate of sustained response. Alanine aminotransferase flares occurring after the introduction of interferon are considered a positive predictor of response. Here we described a young patient with active chronic hepatitis B who underwent four different treatment courses developing lamivudine resistance and showing three elevated flares of different origin and with diverse outcome. We discuss the meaning of each flare and their role in treatment response or virus reactivation. PMID- 17700274 TI - Coffee ground vomit is difficult to identify. PMID- 17700275 TI - Tumor detection by diffusion-weighted MRI and ADC-mapping--initial clinical experiences in comparison to PET-CT. AB - OBJECTIVE: To evaluate the clinical potential of diffusion-weighted-imaging (DWI) with apparent diffusion coefficient (ADC)-mapping for tumor detection. MATERIALS AND METHODS: A single-shot echo-planar-imaging DWI sequence with fat suppression and ability for navigator-based respiratory triggering was implemented. Nineteen patients (11 melanoma, 4 prostate cancer, 1 non-Hodgkin lymphoma, and 3 lung cancer) were examined by positron emission tomography (PET) with an integrated computed tomography scanner (PET-CT) and DWI. Images at b = 0, 400, and 1000 s/mm2 were acquired and ADC maps were generated. PET examinations were used as a reference for tumor detection. Four hundred twenty-four regions of interest were used for DWI and 73 for PET data evaluation. RESULTS: DWI and ADC maps were of diagnostic quality. Metastases with increased tracer uptake were clearly visualized at b = 1000 s/mm2 with the exception of mediastinal lymph node metastases in cases of lung cancer. ADC mapping did not improve detection rates. CONCLUSIONS: DWI is a feasible clinical technique, improving the assessment of metastatic spread in routine magnetic resonance imaging examinations. PMID- 17700276 TI - High-resolution three-dimensional aortic magnetic resonance angiography and quantitative vessel wall characterization of different atherosclerotic stages in a rabbit model. AB - PURPOSE: Atherosclerosis results in a considerable medical and socioeconomic impact on society. We sought to evaluate novel magnetic resonance imaging (MRI) angiography and vessel wall sequences to visualize and quantify different morphologic stages of atherosclerosis in a Watanabe hereditary hyperlipidemic (WHHL) rabbit model. MATERIAL AND METHODS: Aortic 3D steady-state free precession angiography and subrenal aortic 3D black-blood fast spin-echo vessel wall imaging pre- and post-Gadolinium (Gd) was performed in 14 WHHL rabbits (3 normal, 6 high cholesterol diet, and 5 high-cholesterol diet plus endothelial denudation) on a commercial 1.5 T MR system. Angiographic lumen diameter, vessel wall thickness, signal-/contrast-to-noise analysis, total vessel area, lumen area, and vessel wall area were analyzed semiautomatically. RESULTS: Pre-Gd, both lumen and wall dimensions (total vessel area, lumen area, vessel wall area) of group 2 + 3 were significantly increased when compared with those of group 1 (all P < 0.01). Group 3 animals had significantly thicker vessel walls than groups 1 and 2 (P < 0.01), whereas angiographic lumen diameter was comparable among all groups. Post-Gd, only diseased animals of groups 2 + 3 showed a significant (>100%) signal-to noise ratio and contrast-to-noise increase. CONCLUSIONS: A combination of novel 3D magnetic resonance angiography and high-resolution 3D vessel wall MRI enabled quantitative characterization of various atherosclerotic stages including positive arterial remodeling and Gd uptake in a WHHL rabbit model using a commercially available 1.5 T MRI system. PMID- 17700277 TI - Contrast-enhanced magnetic resonance angiography: P792 blood pool agent versus Gd DOTA in rabbits at 3.0 T versus 1.5 T. AB - PURPOSE: To assess the gadolinium-based macromolecular intravascular contrast agent P792 for magnetic resonance angiography (MRA) at magnetic field strengths of 3.0 T, in comparison to 1.5 T, in rabbits. MATERIALS AND METHODS: Eleven female New Zealand rabbits of the same age served as the animal model. Dose relationship testing was performed with 2 doses (13 and 25 micromol/kg; n = 4 per group) of P792 as compared with a single dose (100 micromol/kg; n = 3) of gadoterate meglumine (Gd-DOTA). All animals underwent contrast-enhanced MRA of the abdominal aorta and its branches on 2 occasions separated by 72 hours. The particular doses were administered in random order. Contrast-enhanced MRA was performed on 3.0 and 1.5 T whole-body MR systems, using a fast 3D spoiled gradient recalled echo sequence. Data acquisition was performed before and up to 10 minutes after administration of intravenous contrast material. Image quality was judged on a 4-point-Likert scale. Signal-to-noise and contrast-to-noise measurements were performed; statistical differences (P < 0.05) between the groups were determined. RESULTS: P792 and Gd-DOTA yielded high-quality MR angiograms in rabbits in all cases. Although image quality within the first 3 minutes after contrast material administration was equal for both agents, P792 at a dose of 25 micromol/kg was considered superior to Gd-DOTA at the later time points. Signal-to-noise and contrast-to-noise values of the higher dose of P792 were statistically significantly higher than those of Gd-DOTA in the post-bolus phase. CONCLUSIONS: P792 seems to be well suited for high-quality early phase and equilibrium phase MRA in rabbits at a field strength of 3.0 T, on the basis of this initial evaluation in an animal model. PMID- 17700278 TI - Assessment of the vascularity of uterine leiomyomas using double-echo dynamic perfusion-weighted MRI with the first-pass pharmacokinetic model: correlation with histopathology. AB - OBJECTIVES: To retrospectively evaluate the feasibility of perfusion-weighted MRI (PWI) in uterine leiomyomas. MATERIALS AND METHODS: : Eighteen uterine leiomyomas in 15 patients were evaluated. PWI was performed using a double-echo T2*-weighted spoiled gradient-recalled acquisition sequence, and the first-pass pharmacokinetic model was applied to calculate relative blood volume (rBV). Histopathologic analysis was performed to measure vascular area (VA). RESULTS: PWI was successful in 13 of 15 patients. On quantitative analysis, mean (+/-SD) rBV calculated from PWI was 0.17 +/- 0.13 (range, 0.06-0.55), whereas mean VA was 3.3% +/- 1.6% (range, 1.7-8.5%). A significant correlation was identified between rBV and VA (r = 0.87, P < 0.001). CONCLUSIONS: The rBV determined at PWI correlates with histologic vascular area in uterine leiomyomas. PMID- 17700279 TI - MR-relaxometry of myocardial tissue: significant elevation of T1 and T2 relaxation times in cardiac amyloidosis. AB - OBJECTIVE: This study evaluates if MR-relaxometry of myocardial tissue reveals significant differences in cardiac amyloidosis (CA) compared with patients with systemic amyloidosis but without cardiac involvement (NCA) and a healthy control group. Therefore, we measured T1 and T2 relaxation times (RT) of the left ventricular myocardium with magnetic resonance imaging at 1.5 T. MATERIAL AND METHODS: Nineteen consecutive patients (14 males, 5 females; mean age, 59 +/- 6.1 years) with histologically proven CA were evaluated. T1-RT and T2-RT were measured by using a saturation-recovery TurboFLASH sequence and a HASTE sequence, respectively. Additionally, morphologic and functional data were acquired. Results were compared with patients with systemic amyloidosis but without cardiac involvement (NCA; 5 males, 4 females, 48.9 +/- 15.4 years) and 10 healthy, age matched control subjects (5 males, 5 females, 60.4 +/- 6.4 years). RESULTS: MR relaxometry revealed a significant elevation of T1-RT of the left ventricular myocardium in CA-patients compared with that in NCA-patients and the age-matched control group [mean +/- SD (95% CI) 1340 +/- 81 (1303-1376) msec, 1213 +/- 79 (1160-1266) msec, 1146 +/- 71 (1096-1196) msec, respectively; CA vs. control, P < 0.0001; CA vs. NCA:, P < 0.0003; NCA vs. control, P = 0.07]. T2-RT showed a marginal but significant increase in CA-patients compared with NCA-patients and the control group [mean +/- SD (95% CI) 81 +/- 12 (76-86) msec, 71 +/- 11 (64-79) msec, 72 +/- 9 (65-79) msec, respectively; CA vs. control, P = 0.04; CA vs. NCA, P = 0.04; NCA vs. control, P = 0.91]. T1-RT was best suited to discriminate between the groups as shown by logistic regression. A cut-off value of >or=1273 milliseconds for T1-RT was defined using receiver-operator characteristics analysis to establish the diagnosis of CA with a high sensitivity (84%) and specificity (>89%). CONCLUSIONS: Measurement of T1 and T2 RT is a novel approach for noninvasive evaluation of CA. MR-relaxometry might improve diagnostic reliability of magnetic resonance imaging for evaluation of cardiac involvement in systemic amyloidosis. PMID- 17700280 TI - Mechanism of hepatic parenchyma-specific contrast of microbubble-based contrast agent for ultrasonography: microscopic studies in rat liver. AB - OBJECTIVE: The objective of this study was to elucidate the mechanism of hepatic parenchyma-specific contrast of Sonazoid (microbubble contrast agent) using microscopic techniques. MATERIALS AND METHODS: Sonazoid was intravenously injected into rats to investigate the microbubble dynamics and distribution within hepatic microcirculation in exteriorized liver using intravital microscopy and to observe dose dependency of ultrasound hepatic contrast effect. In vitro and in vivo uptake of microbubbles by Kupffer cells was examined using confocal laser scanning microscopy. RESULTS: Intravital observation demonstrated freely flowing microbubbles in the sinusoid and some microbubbles co-localized with Kupffer cells. The microbubbles internalized in Kupffer cells were identified with reflected light by confocal laser scanning microscopy. The percentage of Kupffer cells taking up microbubbles was about 1% at clinical dose at which the homogeneous hepatic contrast was observed. CONCLUSIONS: The hepatic parenchyma specific contrast by Sonazoid is due to distribution of the microbubbles in Kupffer cells. PMID- 17700281 TI - Improved visualization of vessels and hepatic tumors by micro-computed tomography (CT) using iodinated liposomes. AB - OBJECTIVE: The goal of this study was to determine whether iodinated liposomes are a suitable tracer for mice microvessel and liver imaging by preclinical computed tomography (CT). MATERIALS AND METHODS: Iodinated liposomes were evaluated for vessel and liver imaging. A first group of nude mice was imaged by micro-CT after i.v. injection of liposomes at 1 or 2 gI/kg body weight (b.w.) for intervals up to 24 hours. A second group of mice bearing liver micrometastases was imaged after injection of liposomes at 2 gI/kg b.w. for intervals up to 24 hours. RESULTS: Vascular enhancements of 120 +/- 8 and 322 +/- 20 Hounsfield unit (HU) were obtained after injection of liposomes at 1 or 2 gI/kg b.w., respectively. This enhancement decreased with a blood half-life of 135 +/- 10 and 86 +/- 9 minutes, respectively. Liver enhancement of 157 +/- 5 and 235 +/- 23 HU were obtained after injection of iodinated liposomes at 1 and 2 gI/kg b.w., respectively. Liver micrometastases (250 microm) were detectable after injection of iodinated liposomes at 2 gI/kg b.w. CONCLUSIONS: Iodinated liposomes are a suitable contrast agent for vessels and liver imaging by micro-CT allowing clear vascular enhancement and detection of small liver metastases. PMID- 17700282 TI - First-pass whole-body magnetic resonance angiography (MRA) using the blood-pool contrast medium gadofosveset trisodium: comparison to gadopentetate dimeglumine. AB - OBJECTIVES: To evaluate gadofosveset trisodium for first-pass magnetic resonance angiography (MRA) in the setting of whole-body MRA (WB-MRA). MATERIALS AND METHODS: Forty patients were examined using either 10 mL gadofosveset trisodium (n = 20) or 30 mL gadopentetate dimeglumine (n = 20), followed by arterial-phase imaging of 4 consecutive anatomic regions. Signal intensity was measured in 2 vessels per region. Relative contrast values (RC) were calculated. Arterial contrast, venous overlay, and image quality were rated by 2 radiologists. The Mann-Whitney U test was used to test for significance. RESULTS: Compared with gadopentetate dimeglumine, gadofosveset trisodium enhanced imaging revealed higher RC values in 2 vessel regions, with the differences being significant in 3 of 4 vessel segments. Gadofosveset trisodium revealed lower RC values in 2 regions with significant differences in 2 segments. Qualitative evaluation revealed higher ratings for gadofosveset trisodium regarding all 3 criteria with significant differences in 2 regions. CONCLUSIONS: Gadofosveset trisodium serves well for first-pass imaging in WB-MRA. PMID- 17700283 TI - Aqueous humor sCD44 concentration and visual field loss in primary open-angle glaucoma. AB - PURPOSE: To correlate aqueous humor soluble CD44 (sCD44) concentration, visual field loss, and glaucoma risk factors in primary open-angle glaucoma (POAG) patients. METHODS: Aqueous samples were obtained by paracentesis from normal and glaucoma patients who were undergoing elective surgery and analyzed for sCD44 concentration by enzyme-linked immunosorbent assay. RESULTS: In normal aqueous (n=124) the sCD44 concentration was 5.88+/-0.27 ng/mL, whereas in POAG aqueous (n=90) the sCD44 concentration was 12.76+/-0.66 ng/mL, a 2.2-fold increase (P<0.000001). In POAG patients with prior successful filtration surgery (n=13), the sCD44 concentration was decreased by 43% to 7.32+/-1.44 (P=0.001) in comparison with POAG patients without filtration surgery; however, the sCD44 concentration in the prior successful filtration subgroup with no medications and normal intraocular pressure was 12.62+/-3.81 (P=0.05) compared with normal. The sCD44 concentration of normal pressure glaucoma patients was 9.19+/-1.75 ng/mL, a 1.6-fold increase compared with normal (P=0.02). Race and intraocular pressure pulse amplitude were significant POAG risk factors in this cohort of patients. In both normal and POAG patients with mild and moderate visual field loss, sCD44 concentration was greater in African Americans than in whites (P=0.04). CONCLUSIONS: sCD44 concentration in the aqueous of POAG patients correlated with the severity of visual field loss in all stages in white patients and in mild to moderate stages in African American patients. sCD44 concentration in aqueous is a possible protein biomarker of visual field loss in POAG. PMID- 17700284 TI - Quantification of neuroretinal rim loss using digital planimetry in long-term follow-up of normals and patients with ocular hypertension. AB - PURPOSE: The purpose of this study was to investigate if digital planimetry is appropriate for quantification of neuroretinal rim loss in patients with ocular hypertension (OHT) and if there is an age-related neuroretinal rim loss in normals. PATIENTS AND METHODS: Fifty-six patients with OHT without optic disc change, 13 patients with OHT and conversion to early glaucoma during follow-up and 42 age-matched controls were recruited from the Erlangen Glaucoma Registry. Annually, all patients underwent complete ophthalmologic examination including detailed diagnostic testing concerning glaucoma. Gold standard for morphologic evaluation of the optic nerve head was the semiquantitative 2-dimensional-method described by Jonas. Optic disc images from baseline and after 5 or 10 years follow-up were used for digital planimetry. Optic disc area and cup area were measured using commercial software: Soft Imaging System analysis. The investigator was masked for diagnosis and time point of examination. RESULTS: Mean neuroretinal rim loss was 0.36% per year in controls, 0.54% per year in patients with OHT without progressive disease, and 0.95% per year in OHT and conversion. CONCLUSIONS: Neuroretinal rim loss was highest in the group of OHT with conversion to early glaucoma during follow-up. In the control group we detected a very low mean neuroretinal rim loss during 10-year follow-up. In ocular hypertensive patients without progressive disease mean neuroretinal rim loss was approximately twice compared with normals. PMID- 17700285 TI - Intravitreal bevacizumab (Avastin) injection for neovascular glaucoma. AB - Neovascular glaucoma is a secondary glaucoma with grave prognosis which follows ischemic retinal disorders in the majority of cases. Mediators that induce new vessel formation such as the vascular endothelial growth factor-A seem to play a key role in the pathophysiology of this condition. Herein, we report 2 cases with neovascular glaucoma secondary to ischemic central retinal vein occlusion who received treatment with intravitreal bevacizumab (Avastin) a nonselective antibody against vascular endothelial growth factor-A. Both patients demonstrated dramatic short-term response in terms of intraocular pressure reduction and regression of neovascularization. PMID- 17700286 TI - Infrared imaging technique may help demonstrate iris transillumination defects in blacks who show other pigment dispersion syndrome clinical signs. AB - PURPOSE: Pigment dispersion syndrome (PDS) is considered to be rare among blacks, although the inability to detect iris transillumination defects (ITDs) among very darkly pigmented irides could diminish the clinician's commitment toward the PDS diagnosis due to uncertainty brought on by the lack of this clinical sign. The goal of this study was to investigate the potential utility of a new infrared (IR) imaging technique to demonstrate ITDs among a group of blacks whose initial PDS diagnosis had to be based on pigment dispersal signs other than iris transillumination. METHODS: A previously described digital camera system, modified to detect visible and IR light, was used to image the irides of 10 blacks (20 eyes, 8 females, 2 males; age range=51 to 67 y) considered to have PDS on the basis of the clinical signs not including the presence of ITDs as detected with traditional slit lamp examination. Only 1 eye of 2 different subjects had ITDs that were detected with slit lamp examination, but these consisted of a very small, isolated ITD of questionable importance in each of the eyes. Normal control eyes that were matched according to age, race, sex, and refractive error were also photographed, and 2 glaucoma specialists independently reviewed PDS/control eye pairs in a masked fashion. They were instructed to select the eye more likely to be the PDS eye without the benefit of clinical information other than the digital transillumination characteristics. RESULTS: Observer no. 1 correctly selected the PDS eye among 19 of 20 (95%) PDS-normal eye pairs, and observer no. 2 correctly selected the PDS eye among 15 of 20 (75%) matched pairs. On the basis of these results, it was unlikely that observer no. 1 (Fisher exact test, P<0.0001) or observer no. 2 (P=0.06) selected the PDS eye IR image due to chance alone. It was also unlikely that selection agreement between the 2 observers was due to chance alone (kappa coefficient=0.58). CONCLUSIONS: Digital IR iris photography may help demonstrate abnormal ITDs among the darkly pigmented irides of blacks who have signs of pigment dispersal but who do not have detectable ITDs with traditional slit lamp examination. Infrared iris examination with newer methods should be studied further relative to blacks and others because useful clinical and/or research oriented information could be gained. PMID- 17700287 TI - Long-term reproducibility of screening for glaucoma with FDT-perimetry. AB - PURPOSE: Aim of this study was to evaluate the long-term reproducibility of frequency doubling technology (FDT) screening procedures. METHODS: Longitudinal data of 433 eyes of 294 patients with no progression of glaucomatous optic disc atrophy were retrospectively analyzed: 62 control eyes, 184 ocular hypertensive eyes, 104 preperimetric, and 83 perimetric open-angle glaucoma eyes. All subjects had annual tests with the FDT perimeter and a standardized ophthalmologic examination (ie, conventional perimetry, optic disc inspection, tonometry, lens opacity measurement for exclusion of cataract). The present analysis used a published overall screening score with case-wise recalculation of missed localized probability levels. We analyzed long-term variability by correlation analysis, sign tests, and limits of agreement (LoA) as introduced by Altman and Bland. All subjects had at least 2 annual tests. Three hundred twenty-six eyes had 2 annual tests with the C-20 procedure and at least 1 test with the N-30 protocol another year later. One hundred thirty-five eyes had 1 C-20 and 2 annual tests with the N-30 protocol. RESULTS: Analyses of repeated measurements revealed a significant learning effect (P<0.001, LoA: -4, 17) between the first and second examination but no significant difference between the second and following tests with the C-20 protocol (P>0.6, LoA: +/-9). In addition, there was no significant difference between second C-20 and N-30 tests (P>0.5, LoA: -12, 6). CONCLUSIONS: The study demonstrates the variability of FDT tests over several years. Longitudinal FDT-results in a clinical study showed a higher reproducibility if the first test was discarded. Reproducibility of screening with the N-30 protocol is comparable to the C-20 procedure if an overall score is considered. PMID- 17700288 TI - Surgical revision of failed filtration surgery with mitomycin C augmentation. AB - AIM: The aim of the study was to assess the outcomes of surgical revision with reopening of the scleral flap in eyes with failed glaucoma surgery and adjunctive mitomycin C (MMC). METHODS: Retrospective, noncomparative, interventional case series. Fifty-four eyes of 54 consecutive patients with previously failed trabeculectomy or deep sclerectomy who underwent formal surgical revision (23 with concurrent phacoemulsification) were included. MMC, 0.2 mg/mL for 2 to 3 minutes, was applied under a fornix-based conjunctival flap. The preexisting scleral flap was dissected open to reestablish filtration. RESULTS: Mean follow up was 39.5+/-10 months. Kaplan-Meier survival analysis showed that the probability (with 95% confidence intervals) of maintaining an intraocular pressure (IOP) between 5 and 18 mm Hg and 20% decrease from preoperative IOP was 64% (47% to 76%) with medications and/or needle revision and 38% (26% to 53%) without, 3 years after surgery. Mean IOP before surgery was 23.6+/-7.2 mm Hg and 14.4+/-6.0 three years after surgery (last IOP before further glaucoma procedure carried forward). Needle revision for bleb failure or high IOP was carried out in 23 eyes (42.5%) and further glaucoma surgery in 5 eyes (9.3%). Patients were on an average of 2+/-1.1 glaucoma medications before surgery. At last follow-up, the number of medications had decreased to 0.8+/-1.2 (P<0.000), with 23 eyes (42.5%) requiring medications to control IOP. Significant complications included delayed suprachoroidal hemorrhage (3 eyes, 5.6%), delayed bleb leaks (5 eyes, 9.3%), hypotony (2 eyes, 3.7%), and blebitis (2 eyes, 3.7%). CONCLUSIONS: There is a progressive increase in IOP with time after surgical revision of failed glaucoma surgery with adjunctive MMC. A significant proportion of eyes will eventually require a needle revision procedure and/or glaucoma medications to further lower IOP. Also, there is a significant incidence of complications associated with this procedure. PMID- 17700289 TI - Accuracy of combined GDx-VCC and matrix FDT in a glaucoma screening trial. AB - PURPOSE: To assess the advantage in glaucoma screening of the use of scanning laser polarimetry with customized cornea compensation (GDx-VCC) combined with Matrix Frequency Doubling Technology (M-FDT) testing. METHODS: In a nonpopulation based prepublicized trial, self-recruited white participants were screened for glaucoma with GDx-VCC, with M-FDT, and by independent clinical examination. Cases with possible glaucoma as found with any of the screening methods underwent a detailed clinical investigation to verify or exclude glaucoma. Sensitivity, specificity, accuracy, likelihood ratios, and predictive values were calculated using different threshold criteria for GDx-VCC alone, M-FDT alone, and for various combinations. RESULTS: Of the 233 attendees, 181 participants (345 eyes) successfully underwent the GDx-VCC and M-FDT measurements. Thirty-nine eyes of 24 participants had glaucoma (11.3% prevalence among eyes tested successfully). All but 2 of the glaucomatous eyes had only early damage. Evaluated separately, the criterion GDx-VCC NFI (normal threshold < or =30) performed best, with 97.0% specificity, 88.8% accuracy, and 25.6% sensitivity; but with only 8.5 positive likelihood ratio (PLR). For paired criteria, the best combination of GDx-VCC screening test with M-FDT-screening test provided 99.6% specificity, 91.3% accuracy, and 28.6 PLR. For NFI combined with GDx-VCC nerve fiber bundle defect criterion, specificity was 99.0%, accuracy 89.6%, and PLR 18.0. However, the sensitivities in the 2 cases fell to 12.0% and 18.0%. For a triple combination of M-FDT-screening test with the latter pair of criteria, sensitivity increased to 41.7% and PLR (13.6) still remained clinically useful. CONCLUSIONS: In a self recruited white population with relatively high risk for mild glaucomatous damage, a combination of GDx-VCC together with M-FDT could usefully be employed for mass glaucoma screening. PMID- 17700291 TI - The effect of ICG on mitomycin C cytotoxicity in human tenon fibroblasts. AB - PURPOSE: To examine the effects of indocyanine green (ICG) with and without mitomycin C (MMC) on proliferation of cultured human Tenon fibroblasts. METHOD: Fibroblast monolayers were exposed to either MMC [0.4 mg/mL in phosphate buffered saline (PBS)] or PBS containing ICG (0.0625%, 0.125%, 0.25%, and 0.5% in 200 microL PBS) or a combination of MMC (0.4 mg/mL in PBS) and ICG (0.25% and 0.5%) for 5 minutes. Controls were exposed for 5 minutes to MMC, PBS, or culture medium containing no ICG. After treatment, the monolayers were washed and incubated in culture medium for 24, 48, 72 hours, and 1 week periods after which the number of viable cells was quantified. RESULTS: The presence of ICG alone, at concentrations ranging from 0.0625% to 0.5%, had no effect on the rate of fibroblast proliferation measured at any of the incubation periods. As expected, MMC treatment resulted in a significant reduction in viable fibroblast number (8.4+/-0.13x10(3)). ICG in combination with MMC did not significantly alter fibroblast numbers (8.5+/-0.05x10(3)) up to 1 week compared with MMC alone (8.4+/ 0.12x10(3)). CONCLUSIONS: ICG at concentrations of 0.5% and below do not reduce proliferation of Tenon capsule fibroblasts. ICG did not potentiate or diminish the effect of MMC on Tenon capsule fibroblast proliferation. PMID- 17700290 TI - Glaucoma in the United States and europe: predicting costs and surgical rates based upon stage of disease. AB - PURPOSE: Primary open-angle glaucoma is a significant health-economic burden in both the United States and Europe that is likely to increase. This study compared treatment patterns and cost among patients with primary open-angle glaucoma in these locations. METHODS: Retrospective medical chart reviews were conducted in the United States (1990 to 2002) and Europe (1995 to 2003). A total sample of 151 US charts and 194 European charts was studied, and patients were assigned a baseline intraocular pressure (IOP) and baseline stage, using a 6-stage visual functional glaucoma staging algorithm. Resource utilization and direct costs were assessed by stage of disease using publicly available United States and European costs. Cox Proportional Hazards modeling were used to examine covariates predicting glaucoma surgery. Total cost was predicted, adjusting for covariates using Generalized Linear Models, with baseline stage as the independent variable. RESULTS: Glaucoma surgery requirement was highly associated with baseline disease stage and IOP increase before surgery in the United States and somewhat associated with these factors in Europe. Within both locations, baseline IOP was highly associated with glaucoma surgery requirement. Controlling for covariates, patients at higher baseline stages incurred greater costs in the United States (P=0.0017) and Europe (P=0.0715). Surgery and medication were also highly predictive of increased cost (P<0.0001). Cost of care differed greatly between the European countries, with costs lowest in Italy. CONCLUSIONS: Increases in annual cost were related to higher baseline IOP, higher baseline stage, medication, and surgery. Thus, significant potential savings and reductions in annual healthcare burden are possible if patients are diagnosed and treated at earlier stages of glaucoma. PMID- 17700292 TI - Rodent models for glaucoma retinopathy and optic neuropathy. AB - Animal models are useful to elucidate the etiology and pathology of glaucoma and to develop novel and more effective therapies for the disease. Because of the substantial similarities between the rodent and primate eyes, and the advances of relevant study techniques, rat and mouse models of glaucoma have recently become popular as research tools. This review surveys research techniques used in the measurement of rodent intraocular pressure, and also the evaluation of pertinent morphologic, biochemical, and functional changes in the retina, optic nerve head, and optic nerve. This review further describes in detail the individual rodent models, some of which serve as surrogate models and do not entail ocular hypertension, whereas others involve transient or chronic increases of intraocular pressure. The technical considerations and theoretical concerns of these models, their advantages, and limitations, are also discussed. PMID- 17700293 TI - Optic nerve restoration: new perspectives. AB - Neural regeneration and repair in the central nervous system are currently hot topics in neuroscience. For many years there has been a hope that neurodegenerative diseases which are resistant to current therapies may be treated by the selective replacement of cells. Yet it is only recently that we have started to acquire the knowledge, tools, and techniques that may translate such optimism into new therapies. In this article, we will consider the potential to restore function to the damaged optic nerve. We will consider the technical issues involved and suggest a strategy for research progress. PMID- 17700294 TI - Personality characteristics and attachment in first episode psychosis: impact on social functioning. AB - Research has suggested those with chronic schizophrenia are impaired in social functioning, and that those early in the illness also exhibit these impairments. However, the factors underlying and contributing to social dysfunction have not yet been well delineated, particularly within a first episode sample. The current study sought to investigate the role of attachment style and personality characteristics in the social dysfunction of those diagnosed with a first episode of psychosis. Ninety-six participants experiencing a first episode of psychosis were compared with control participants from 2 different samples on attachment and personality variables. Results suggested that those with a first episode of psychosis may experience more problematic attachment in peer relationships compared with nonclinical controls, and that the type and amount of differences observed may vary by gender. In addition, those experiencing a first episode of psychosis report different levels of the "big five" personality traits when compared with nonclinical controls. Finally, within the first episode sample, both personality and attachment appear to contribute variance to 3 domains of social functioning: social and individual living skills, inappropriate community behavior, and quality of life. These findings have implications for the functional significance of these psychological constructs. PMID- 17700295 TI - Schreber's "bellowing miracle": a new content analysis of Daniel Paul Schreber's memoirs of my nervous illness. AB - Daniel Paul Schreber's Memoirs of My Nervous Illness has, in the 100 years since its publication, generated a substantial hermeneutic literature in psychiatry. It is 30 years since the first major content analysis was performed and published in the Journal of Nervous and Mental Disease. This study, using a simple frequency count approach to the Memoirs, has revealed that the term "bellowing miracle" (das Brullwunder) is the most frequently mentioned of all of Schreber's celebrated neologisms. The prevalence of the "bellowing miracle" in the text of the Memoirs, psychiatric charts, and court reports warrants closer examination and attempts at explanation. It is clear that the manifest symptoms of the bellowing miracle had a significant influence on Schreber's treatment and struggle to secure his release from the asylum. It is suggested that adult tic disorder may explain the symptoms of the bellowing miracle. PMID- 17700296 TI - The patient experience of depression and remission: focus group results. AB - Few depression measures were developed with the patient perspective. To obtain patient views on depression and early symptom resolution, 4 focus groups (N=31) were conducted. Patients also completed the Quick Inventory of Depressive Symptomology (Self-Report), SF-36, and a rating of the bothersomeness and significance of 12 symptoms of depression. Transcripts were reviewed for major themes. Irritability was a key symptom and it remitted earlier than others. Important to participants were low mood, low energy, lack of motivation, lack of focus/concentration, feelings of guilt, self-critical thoughts, feeling overwhelmed, lack of enjoyment, hypersomnia, restlessness, anger, and irritability. Gender differences emerged; most men reported irritability as one of the first symptoms to remit; for women, motivation level and energy commonly remitted first. Results suggest that new measures of treatment outcome should encompass irritability, anger, and ability to cope with life stressors. PMID- 17700297 TI - Severity of combat-related posttraumatic stress disorder versus noncombat-related posttraumatic stress disorder: a community-based study in American Indian and Hispanic veterans. AB - The goal of the study was to compare severity of combat-related posttraumatic stress disorder (PTSD) versus noncombat-related PTSD in a group known to have high rates of combat-related PTSD. Sample consisted of 255 male American Indian and Hispanic veterans with lifetime PTSD who were contacted in communities in 2 regions of the country. Measures of PTSD severity included current posttraumatic symptoms, remission from lifetime PTSD, lifetime severity of alcohol-drug related problems, and mental health treatment history. Our findings revealed that veterans with combat-related PTSD had more severe posttraumatic symptoms, were less apt to have remitted from PTSD during the last year, and-contrary to expectation-were less apt to have sought mental health treatment since military duty. In conclusion, combat-related PTSD was more severe, as compared with noncombat-related PTSD, in this group, on 2 out of 5 measures. A low rate of mental health treatment since military duty may have contributed to increased symptoms and a lower remission rate. PMID- 17700298 TI - Cognitive-behavioral stress management for individuals with substance use disorders: a pilot study. AB - Stress-induced craving and stress reactivity may influence risk for substance use or relapse to use. Interventions designed to attenuate stress-induced craving and stress reactivity may serve as excellent adjuncts to more comprehensive treatment programs. The purpose of this study was to (1) tailor an existing, manualized, cognitive-behavioral stress management (CBSM) intervention for use in individuals with substance use disorders and (2) preliminarily evaluate the effects of the intervention using an experimental stress-induction paradigm. Twenty individuals were interviewed and then completed a psychological stress task, the Mental Arithmetic Task (MAT). After this, participants were assigned to either the CBSM intervention group or a nontreatment comparison group. Approximately 3 weeks later, participants completed a second MAT. In contrast to the comparison group, the CBSM group demonstrated significantly less stress-induced craving (p<.04) and stress (p<.02), and reported greater ability to resist urges to use (p<.02) after the second MAT. These findings are among the first to report on the use of an intervention to attenuate craving and stress reactivity among individuals with substance use disorders. Although preliminary, the findings suggest that systematic investigation of interventions specifically targeting stress management in individuals with substance use disorders should be undertaken. PMID- 17700299 TI - Aggression levels in treatment seeking inpatients with alcohol-related problems compared to levels in the general population in Hungary. AB - Association between aggression and heavy alcohol use is documented in the literature in various disparate samples and settings. Comparison of trait aggression levels using a uniform methodology across different samples is almost entirely lacking. This study compared trait aggression levels of treated inpatients with severe alcohol-related problems with those of a nationally representative sample of the general adult population using the same methodology. Results indicated that in the patient population the trait aggression levels were substantially higher than in the general population. Because several studies have demonstrated that aggressive personality traits are closely linked with violence after drinking alcohol, our results further highlight the importance of treatment programs in this at-risk population. From a methodological perspective, the higher trait aggression level of inpatients with alcohol-related problems compared with the general population supports the assumption that the underrepresentation of alcoholics in the population surveys may restrict the range in the severity of alcohol use and dependence, and may therefore produce severely biased results in such studies. PMID- 17700301 TI - The relationship between spirituality and depressive symptoms: testing psychosocial mechanisms. AB - Although many studies suggest lower rates of depressive symptoms in those who report greater spirituality, few have investigated the mechanisms by which spirituality might relate to depressive symptoms. The current study aimed to elucidate potential psychosocial mechanisms that link these 2 variables. Data were drawn from a community-dwelling stratified sample of 630 racially diverse adults in rural North Carolina. Spirituality was assessed by 6 items of the Daily Spiritual Experiences Scale. Depressive symptoms were measured using 4 subscales from the Center for Epidemiological Studies-Depression. Hypothesized mediators were optimism, volunteering, and perceived social support. Structural equation modeling was used to test whether proposed mediators explain a link between spirituality and depressive symptoms. The model demonstrated a satisfactory fit. Spirituality was indirectly related to depressive symptoms. More specifically, spirituality was significantly associated with optimism and volunteering but not with social support, and optimism, volunteering and perceived social support were significantly associated with depressive symptoms. The link between spirituality and depressive symptoms is indirect. The relationship is mediated by optimism, volunteering, and social support. Findings present research and practice implications. PMID- 17700300 TI - Spiritual well-being and health. AB - Data on empirical associations between religious variables and health outcomes are needed to clarify the complex interplay between religion and mental health. The aim of this study was to determine whether associations with health variables are primarily attributable to explicitly religious aspects of spiritual well being (SWB) or to "existential" aspects that primarily reflect a sense of satisfaction or purpose in life. Three hundred forty-five pairs of twins from the Vietnam Era Twin Registry completed a diagnostic interview and questionnaires containing the 2-factor SWB Scale and general health items. Observed associations between SWB and health outcomes were uniquely explained by the SWB subscale of existential well-being, with much less of a unique explanatory contribution from religious well-being or "spiritual involvement." We concluded that studies of SWB and health should continue to distinguish between explicitly religious variables and others that more closely approximate the psychological construct of personal well-being. PMID- 17700302 TI - Home-recorded sleep architecture as a function of handedness II: Consistent right versus consistent left-handers. AB - Examination of individual differences in sleep architecture may help elucidate the mechanisms involved in sleep-related pathologies and cerebral processes involved in sleep. We (Propper et al., Brain Cogn. 2004;54:186-197) previously reported that degree or strength (i.e., inconsistent vs. consistent) of hand preference was more important than direction (i.e., left vs. right) of hand preference in examining sleep architecture-hand preference relationships. However, that study confounded direction and degree of hand preference; only 1 consistently left-handed individual was included in the consistently handed group. Here, we describe a comparison of the sleep of consistently left- versus consistently right-handed individuals. The basic pattern of results here and in previous work suggests that individual differences in sleep architecture are influenced by both degree and direction of handedness. Handedness differences in sleep architecture may reflect individual differences in cerebral organization on one hand and sleep stage mediated differences in cerebral interaction on the other. PMID- 17700303 TI - Depersonalization, mindfulness, and childhood trauma. AB - Depersonalization (DP), i.e., feelings of being detached from one's own mental processes or body, can be considered as a form of mental escape from the full experience of reality. This mental escape is thought to be etiologically linked with maltreatment during childhood. The detached state of consciousness in DP contrasts with certain aspects of mindfulness, a state of consciousness characterized by being in touch with the present moment. Against this background, the present article investigates potential connections between DP severity, mindfulness, and childhood trauma in a mixed sample of nonpatients and chronic nonmalignant pain patients. We found a strong inverse correlation between DP severity and mindfulness in both samples, which persisted after partialing out general psychological distress. In the nonpatient sample, we additionally found significant correlations between emotional maltreatment on the one hand and DP severity (positive) and mindfulness (negative) on the other. We conclude that the results first argue for an antithetical relationship between DP and certain aspects of mindfulness and thus encourage future studies on mindfulness-based interventions for DP and second throw light on potential developmental factors contributing to mindfulness. PMID- 17700304 TI - The role of experiential avoidance in psychological functioning after war-related stress in Kosovar civilians. AB - The current study examined the relationship between experiential avoidance and psychological distress after war-related traumatic experiences among 152 Kosovar civilian war survivors. Results showed significant correlations between experiential avoidance and psychological distress. Participants who scored high on experiential avoidance reported more impaired psychological functioning and lower subjective quality of life than those who scored low on experiential avoidance. Results of this study indicate that experiential avoidance may be a significant factor in understanding war-related psychological distress. PMID- 17700305 TI - Does posttraumatic stress disorder (PTSD) affect performance? AB - Research has increasingly identified alarming levels of traumatic stress symptoms in individuals working in emergency services and other high stress jobs. This study examined the effects of prior critical incident exposure and current posttraumatic symptoms on the performance of a nonpatient population, police recruits, during an acutely stressful event. A stressful policing situation was created through the use of a video simulator room that was responsive to actions of participants. The performance of participants to the simulated emergency was evaluated by 3 independent blinded raters. Prior exposure to critical incidents was measured using the Critical Incident History Questionnaire and current level of traumatic stress symptoms was measured using the Impact of Events Scale Revised. Neither previous exposure to critical incidents nor trauma symptoms correlated with performance level. Recruits with high or severe levels of trauma symptoms did not demonstrate impairments in judgment, communication, or situation control compared with their colleagues with lesser or no trauma symptoms. On the basis of these findings, there is no reason to believe that police recruits with PTSD are prone to making errors of communication or judgment that would place them or others at increased risk. PMID- 17700306 TI - Israeli psychiatric inpatients go to the polls. AB - In 1996, mobile polls were introduced in Israel, enabling physically and emotionally ill inpatients to vote. We surveyed the rate of participation of inpatients at Lev-Hasharon Mental Health Center in parliamentary elections, their feelings regarding voting, and the nature of their vote, compared with the general population. One hundred eighteen of 306 (38.6%) patients voted compared with 63.8% of the general population. Forty-nine more patients (16%) wanted to vote but were unable to for technical reasons. More patients voted in the open than the closed wards (chi=14.5; df=1; p=.001). Most patients reported positive subjective feelings, a sense of responsibility (39%), belonging to the general community (28%), and pride (22%) after voting. Psychiatric inpatients voted similarly to the general population, though their percentage of voters was significantly lower. This discrepancy can be accounted for by lack of concern and ineligibility due to lack of identification documents that may reflect fundamental illness-related problems. PMID- 17700312 TI - Department motto: be a fountain, not a drain. PMID- 17700313 TI - Do you know what constitutes patient abandonment? PMID- 17700315 TI - Turn theory into reality. PMID- 17700316 TI - Inactive nurses: making a comeback. PMID- 17700317 TI - From Pong to PHRs: advances in electronic record keeping. PMID- 17700318 TI - Best-practice protocols: reducing harm from MRSA. PMID- 17700320 TI - Better pain management. PMID- 17700322 TI - When hospitals merge: are you up to it? PMID- 17700323 TI - Maximize your impact with leadership domains. PMID- 17700325 TI - An interval-scaled scoring algorithm for visual function questionnaires. AB - PURPOSE: The primary purpose of the study is to present and test a simple algorithm for scoring visual function questionnaires (VFQs) that approximates person measure estimates from Rasch analysis, does not introduce nonlinearities at extreme scores, and is insensitive to missing data. A secondary purpose is to test the hypothesis that all VFQs measure the same visual ability variable and can be calibrated to a common measurement scale. METHODS: Each of 407 consecutively recruited low vision patients were administered two of four visual function questionnaires: Activities of Daily Living Scale (ADVS), National Eye Institute Visual Functioning Questionnaire (NEI VFQ), 14-item Visual Functioning Index (VF-14), Visual Activities Questionnaire (VAQ). Separate Rasch analyses, using the Andrich rating scale model, were performed on responses to each of the four VFQs and again on the merged data of all instruments. An approximation of visual ability, based on average functional reserve and an inverse hyperbolic tangent transformation, is presented and tested by comparing visual ability estimates from the Rasch analyses to corresponding estimates from the approximations. RESULTS: Relative to person measure estimates from Rasch analysis, the approximations were observed to be linear and highly reliable (intraclass correlations ranged from 0.97 to 0.997). The measurement scale of each of the four instruments was observed to be a linear transformation of the measurement scale estimated from the merged responses of all four instruments. The approximation algorithm transforms rating scale responses for each instrument to a common measurement scale. By randomly censuring item responses for each subject, it was demonstrated that the approximation algorithm is robust and insensitive to missing data. CONCLUSIONS: A simple scoring algorithm based on an inverse hyperbolic tangent transformation of average functional reserve produces highly reliable approximations of visual ability estimated from Rasch analysis for the ADVS, NEI VFQ, VAQ, and VF-14. All four instruments measure the same visual ability variable in units that can be calibrated to a common measurement scale. PMID- 17700326 TI - Content development of the Optometric Patient Anxiety Scale. AB - PURPOSE: Patient anxiety has been shown to be detrimental to many aspects of healthcare outcomes. To date, there is no method of evaluating anxiety in optometric practice. Therefore, the purpose of this study was the content development of a questionnaire to measure optometric patient anxiety. Such a tool will have both clinical and research application; allowing the identification of anxious patients in practice and as a method to establish the success of anxiety reducing interventions. METHODS: Selection of initial items was based on patient interviews, literature review, and focus group feedback. The initial 30-item Optometric Patient Anxiety Scale was piloted on 148 patients in optometric practice. Rasch analysis was used to analyze response category operation and to facilitate item removal to ensure a valid and unidimensional scale. Test-retest reliability (test-retest time, 2 weeks) was measured on 59 young adults to test the stability of the measure with time. RESULTS: Rasch analysis identified disordering of category thresholds and underutilization of the end-response category. Therefore, categories were merged to a three response solution. Item reduction was principally driven by infit and outfit statistics. The items in the final 10-item scale all had good infit and outfit values (infit: 0.80-1.20, outfit: 0.7-1.3), good person separation (>2) and high person and item reliability coefficients, 0.84 and 0.88, respectively. Test-retest reliability also demonstrated good stability of the measure with time (intraclass correlation; ICC = 0.85). CONCLUSIONS: The Optometric Patient Anxiety Scale is the first questionnaire to measure patient anxiety specific to optometric practice. The scale was developed using Rasch analysis to ensure that all the items work together to form a valid unidimensional interval scale. PMID- 17700327 TI - Computer use, symptoms, and quality of life. AB - PURPOSE: To model the effects of computer use on reported visual and physical symptoms and to measure the effects upon quality of life measures. METHODS: A survey of 1000 university employees (70.5% adjusted response rate) assessed visual and physical symptoms, job, physical and mental demands, ability to control/influence work, amount of work at a computer, computer work environment, relations with others at work, life and job satisfaction, and quality of life. Data were analyzed to determine whether self-reported eye symptoms are associated with perceived quality of life. The study also explored the factors that are associated with eye symptoms. Structural equation modeling and multiple regression analyses were used to assess the hypotheses. RESULTS: Seventy percent of the employees used some form of vision correction during computer use, 2.9% used glasses specifically prescribed for computer use, and 8% had had refractive surgery. Employees spent an average of 6 h per day at the computer. In a multiple regression framework, the latent variable eye symptoms was significantly associated with a composite quality of life variable (p = 0.02) after adjusting for job quality, job satisfaction, supervisor relations, co-worker relations, mental and physical load of the job, and job demand. Age and gender were not significantly associated with symptoms. After adjusting for age, gender, ergonomics, hours at the computer, and exercise, eye symptoms were significantly associated with physical symptoms (p < 0.001) accounting for 48% of the variance. CONCLUSIONS: Environmental variability at work was associated with eye symptoms and eye symptoms demonstrated a significant impact on quality of life and physical symptoms. PMID- 17700329 TI - Vision-related quality of life. PMID- 17700330 TI - World renowned medical scientist presents 2007 Prentice Medical Lecture. PMID- 17700331 TI - The development, assessment, and selection of questionnaires. AB - Patient-reported outcome measurement has become accepted as an important component of comprehensive outcomes research. Researchers wishing to use a patient-reported measure must either develop their own questionnaire (called an instrument in the research literature) or choose from the myriad of instruments previously reported. This article summarizes how previously developed instruments are best assessed using a systematic process and we propose a system of quality assessment so that clinicians and researchers can determine whether there exists an appropriately developed and validated instrument that matches their particular needs. These quality assessment criteria may also be useful to guide new instrument development and refinement. We welcome debate over the appropriateness of these criteria as this will lead to the evolution of better quality assessment criteria and in turn better assessment of patient-reported outcomes. PMID- 17700332 TI - Why measurement matters for measuring patient vision outcomes. AB - Optometrists, by definition, care deeply about measurement. This brief review article considers the essential features of measurement that make many optometric instruments so useful and how patient-centered survey instruments such as vision related quality of life questionnaires, can be analyzed using contemporary psychometric methods, so that they also conform to these essential features of measurement. These features include unidimensionality, hierarchical order, and equal interval scaling. Optometrists demand these features because they need to make meaningful comparisons both between patients and over time. Questionnaires about visual function or health-related quality of life, typically involve a series of rating scale type items that are added up to produce a total raw score. Yet total raw scores, which are ordinal, do not exhibit the essential properties of measurement. The Rasch Model, developed by Georg Rasch in 1956, converts ordinal-level raw score data into interval measures that demonstrate the essential features of measurement. Under the Rasch model any obtained score (response) is conceptualized as the difference between the amount of a trait reflected in an item, i.e., how "hard" the item is, and the ability of the person responding to the item. The Rasch model estimates the log odds probability (logit) for any response by any person. Logits are equal interval, representing equal amounts of the construct being measured across the entire range of the construct. Logits define the hierarchical order of items, how hard or easy items are, and the Rasch model specifies that this order of items must be invariant for all persons, that is, must be unidimensional. There are numerous software packages available for applying the Rasch model, all provide methods for evaluating how well data demonstrate unidimensionality, hierarchical order, and equal interval scaling. These can be used in the development, assessment or revision of questionnaires to optimize measurement. PMID- 17700333 TI - Impact of cataract surgery on quality of life in patients with early age-related macular degeneration. AB - PURPOSE: To investigate if cataract surgery improves overall and specific areas of quality of life (QoL) in patients with early age-related macular degeneration (AMD) using the impact of vision impairment (IVI) questionnaire. METHODS: Patients with visually significant cataract and early AMD, who were being considered for cataract surgery in the study eye, were recruited. Eligible patients were randomized to either "early surgery" or "standard surgery" (standard cataract surgery waiting time of 6 months) groups. The IVI, sociodemographic, and clinical data were collected. Rasch analysis was used to estimate QoL person measures at baseline and follow-up. The data were analyzed using repeated measures ANOVA. Effect sizes were calculated using Cohen's d coefficient. RESULTS: Fifty six patients (mean age = 78.5 years and visual acuity = 6/15) had one eye randomly allocated to either the early surgery (n = 29) or standard surgery (n = 27) groups. At follow-up, significant interaction effects were found for the overall IVI score [F(1,54) = 17.7; p < 0.001], the emotional well-being [F(1,54) = 13.4; p = 0.001], mobility and independence [F(1,54) = 13.4; p = 0.001], and reading and accessing information subscales [F(1,54) = 13.1; p = 0.001]. The standard surgery group systematically recorded worse scores at 6 months on all QoL measures whereas the early surgery group recorded significant gains (p < 0.001; Cohen's d = 0.66 to 0.91) on all of them. Visual acuity in the study eye significantly improved in the early surgery group only (Cohen's d = 1.1; p < 0.05) and improvement in log MAR lines read was identified as the single independent predictor of enhanced QoL explaining between 26 and 34% of the variance in the IVI scores. CONCLUSIONS: Cataract surgery is justified in patients with early AMD. It brings significant improvements in visual acuity, aspects of daily living, and overall QoL. PMID- 17700334 TI - Using the VA LV VFQ-48 and LV VFQ-20 in low vision rehabilitation. AB - PURPOSE: This study was conducted to demonstrate use of a simple scoring algorithm for the 48-item Veterans Affairs Low Vision Visual Functioning Questionnaire (VA LV VFQ-48) that approximates the measure of persons' visual ability that would be calculated with Rasch analysis and to provide a short form version of the questionnaire for clinical practice and outcomes research. METHODS: Items were eliminated from the VA LV VFQ-48 to reduce redundancy and shorten the instrument. The approximation of persons' visual ability calculated with the scoring algorithm for vision function questionnaires developed by Massof was compared with the person measure estimated from Rasch analysis for a sample of 126 subjects entering a low vision rehabilitation program. RESULTS: The approximation captures 98% of the variability in the Rasch measure estimate of persons' visual ability and 97% of the variability in the change score estimate. The relationship does not hold in circumstances where patients with high visual ability find most items to be easy. A 20-item short form of the instrument was constructed for use in low vision service delivery. CONCLUSIONS: The scoring algorithm can be used with the VA LV VFQ-48 or short form versions of the questionnaire. Clinicians can use the algorithm to score the VA LV VFQ from examination of individual patients or as an outcome measure for their low vision rehabilitation programs. Research investigators can use the scoring algorithm with small samples when Rasch analysis is not reliable or in studies where Rasch analysis is not practical. Rasch analysis is still recommended for research studies that require more accurate assessments. PMID- 17700335 TI - Applying multilevel item response theory to vision-related quality of life in Dutch visually impaired elderly. AB - PURPOSE: Instead of applying the usual longitudinal methods to assess the outcome of low-vision rehabilitation services in terms of vision-related quality of life, a three-level Item Response Theory (IRT) method was proposed. METHODS: The translated Vision-Related Quality of Life Core Measure (VCM1) and Low Vision Quality Of Life (LVQOL) questionnaires were used in a nonrandomized follow-up study among elderly patients (n = 296) referred to two different low-vision rehabilitation services in the Netherlands. Factor analysis was performed on the matrix of polychoric correlations to investigate (uni-)dimensionality and to prepare both questionnaires for the multilevel IRT analyses. A statistical model, which was characterized by a graded response model for rating scales, was developed. Threshold and item difficulty parameters and group by time-specific mean fixed effects were estimated. Random individual effects were predicted. Measurement invariance across occasions was tested. RESULTS: The VCM1 and the LVQOL "reading and fine work" dimension showed item parameter drift. In the multidisciplinary rehabilitation center patients, deterioration was found on the "mobility" dimension after 1 year and improvement was found on "adjustment" and "visual (motor) skills" after 5 months (p < 0.05). Patients in both low-vision services showed improvement on the "reading small print" subscale at both follow up time points (p < 0.05). CONCLUSIONS: Except for improvement in "reading small print," low-vision rehabilitation services did not seem to contribute substantially to any other dimensions of vision-related quality of life. The results showed a change in only a limited number of individual patients. However, with regard to the field of low-vision rehabilitation, the proposed IRT method seemed to be successful in the follow-up of individuals. IRT specific software was unnecessary. The data did not have to be complete and the use of cumulative logits made the proposed IRT method an economical and efficient approach. Because of item parameter drift, the VCM1 was difficult to interpret. The use of multilevel IRT models with longitudinal data and dependent observations is recommended. PMID- 17700337 TI - Measuring visual discomfort in college students. AB - PURPOSE: The purpose of this study was to measure the distribution visual discomfort symptoms in a group of college students using a survey developed by Conlon et al. and to analyze the type and frequency of symptoms in the subjects who display moderate to high amounts of visual discomfort to ascertain if this condition occurs along a single dimension or consists of different subtypes. METHODS: Members of the research team administered a survey of visual discomfort developed by Conlon et al. (Conlon et al., Vis Cogn 1999;6:637-666) to 571 college students at the Claremont Colleges University over a 2-year period. The survey for measuring visual discomfort developed by Conlon consists of 23 items with a four-point scale (0 to 3) (see below). Scores on the survey can range from 0 to 69. RESULTS: A Rasch analysis of the survey results showed that a single symptom dimension accounted for 73.5% of the variance. A principle component analysis of the residual variance from the Rasch analysis yielded three factors: factor 1 was associated with text movement and fading; factor 2 was associated with headache and soreness; and factor 3 was associated primarily with blur and diplopia. CONCLUSIONS: The survey developed by Conlon is an appropriate measure of visual discomfort. In addition to the single dimension reported by Conlon, we found that some subjects with moderate to high amounts of visual discomfort tended to report particular types of symptoms. These results suggest that there may be multiple etiologies of visual discomfort. PMID- 17700336 TI - Respondent impact on functional ability outcome measures in vision rehabilitation. AB - PURPOSE: To assess the relative importance of several measurement facets including respondent (patient or clinicians), item (functional domains), and administration (pre- and postrehabilitation) on assessing perceived functional outcomes in vision rehabilitation. METHODS: A convenience sample of VA veterans were assessed with a self-report and clinician rated perceived functional ability instrument before and after rehabilitation services. The items were analyzed using a Rasch model to ensure that both versions fit the restrictive model well enough to be directly compared. A second analysis using a generalizability theory model assessed the relative importance of each measurement facet. RESULTS: The Rasch model supported the equivalence of the two different versions of the outcome instrument. The generalizability theory model showed that administration accounted for the majority of the variance and that respondents and items contributed very little to perceived functional assessment. CONCLUSIONS: The results support the conclusion that both clinical ratings and patient self reported perceived functional ability ratings provide relative equivalent values in blind and low-vision rehabilitation settings. The relative importance of administration time in predicting scores may support the general conclusion that rehabilitation produces the largest relative changes in perceived functional ability and ought to shift researchers' focus away from the subtleties of instrument development and more toward assessing program and individual outcomes. Finally, these findings suggest that there is little promise in modeling individual differences to account for perceived functional ability changes because of rehabilitation. PMID- 17700338 TI - The Eye Sensation Scale: an ophthalmic pain severity measure. AB - PURPOSE: The aim was to develop a single-item, categorical ophthalmic pain severity scale. METHODS: Focus groups were held with people who had experienced ophthalmic pain. Participants described their ophthalmic pain experiences with reference to level of severity, and commented on proposed pain scale designs. Thematic analysis of transcripts, and participants' category choices and scale preferences, were used to determine the number of response categories and labels chosen for the instrument. The final instrument was evaluated using a mail-out questionnaire. RESULTS: Five ophthalmic pain domains were identified: intensity; nature (including subdomains: physical sensation, temporal patterning, simile/metaphor); physical effects; emotional effects; and behavioral effects. The most frequent descriptors were physical sensation (n = 160), behavioral effects (n = 87), and physical effects (n = 68). Participants preferred a five category scale. The higher frequency severity descriptors used by the participants formed the basis for the category labels for the instrument ("extreme," "severe," "moderate," "mild," "none"). Notably, many participants rejected the word "pain" in favor of "discomfort" or "light sensitivity." Participants commonly linked severity and nature descriptors; however, the same nature descriptor (e.g., "ache" or "scratching") did not confer the same pain severity between participants. CONCLUSIONS: A five-category scale was chosen for assessing the severity of ophthalmic sensations: the Eye Sensation Scale. The scale involves rating the severity of the ophthalmic sensation that is most important to the patient and provides the opportunity to describe other attributes or effects of the sensation. Evaluation indicated the adequacy of the final instrument. PMID- 17700339 TI - The Activity Inventory: an adaptive visual function questionnaire. AB - PURPOSE: The Activity Inventory (AI) is an adaptive visual function questionnaire that consists of 459 Tasks nested under 50 Goals that in turn are nested under three Objectives. Visually impaired patients are asked to rate the importance of each Goal, the difficulty of Goals that have at least some importance, and the difficulty of Tasks that serve Goals that have both some importance and some difficulty. Consequently, each patient responds to an individually tailored set of questions that provides both a functional history and the data needed to estimate the patient's visual ability. The purpose of the present article is to test the hypothesis that all combinations of items in the AI, and by extension all visual function questionnaires, measure the same visual ability variable. METHODS: The AI was administered to 1880 consecutively-recruited low vision patients before their first visit to the low vision rehabilitation service. Of this group, 407 were also administered two other visual function questionnaires randomly chosen from among the Activities of Daily Living Scale (ADVS), National Eye Institute Visual Functioning Questionnaire (NEI VFQ), 14-item Visual Functioning Index (VF-14), and Visual Activities Questionnaire (VAQ). Rasch analyses were performed on the responses to each VFQ, on all responses to the AI, and on responses to various subsets of items from the AI. RESULTS: The pattern of fit statistics for AI item and person measures suggested that the estimated visual ability variable is not unidimensional. Reading-related and other items requiring high visual resolution had smaller residual errors than expected and mobility-related items had larger residual errors than expected. The pattern of person measure residual errors could not be explained by the disorder diagnosis. When items were grouped into subsets representing four visual function domains (reading, mobility, visual motor, visual information), and separate person measures were estimated for each domain as well as for all items combined, visual ability was observed to be equivalent to the first principal component and accounted for 79% of the variance. However, confirmatory factor analysis showed that visual ability is a composite variable with at least two factors: one upon which mobility loads most heavily and the other upon which reading loads most heavily. These two factors can account for the pattern of residual errors. High product moment and intraclass correlations were observed when comparing different subsets of items within the AI and when comparing different VFQs. CONCLUSIONS: Visual ability is a composite variable with two factors; one most heavily influences reading function and the other most heavily influences mobility function. Subsets of items within the AI and different VFQs all measure the same visual ability variable. PMID- 17700340 TI - Visual Functioning Questionnaire: reevaluation of psychometric properties for a group of working-age adults. AB - PURPOSE: The Visual Functioning Questionnaire (VFQ-25) is one of the most widely used measures of vision-related quality of life. However, the questionnaire does not meet some psychometric quality criteria. The objectives of this study were first to obtain the factor structure of the VFQ-25, and second, to obtain interval scales by Rasch analysis. METHODS: The questionnaire was administered to 129 visually impaired adults (mean age 42.1 years; range 21 to 67 years). First, the items of the VFQ-25 were subjected to an exploratory factor analysis with Promax rotation. Next, we performed a separate Rasch analysis on each factor. We examined step thresholds and goodness of fit statistics of the items. Finally, we examined differential item functioning. RESULTS: Factor analysis indicated four factors: Near Activities, Distance Activities and Mobility, Mental Health and Dependency, and Pain and Discomfort. They accounted for 46.37% of the total variance. Most items showed some degree of disordering. After collapsing response categories, all items showed ordered thresholds. The Near Activities domain showed excellent fit, whereas the Distance Activities and Mobility domain, the Mental Health and Dependency domain, and the Pain and Discomfort domain had an unsatisfactory fit. There were two items showing uniform differential item functioning. CONCLUSIONS: The four-factor structure of the VFQ-25 largely confirms the structure of the questionnaire. However, the results of this study suggest that modifications of the original VFQ-25 structure are necessary. PMID- 17700341 TI - Predicting perceived quality of life scores from the National Eye Institute 25 item Visual Function Questionnaire. AB - PURPOSE: This study set out to determine the degree to which the composite score of the National Eye Institute 25-item Visual Function Questionnaire (VFQ-25) predicted perceived quality of life (PQoL) as measured by a single-item global measure of quality of life (QoL) and therefore, the extent to which the two were measuring the same construct. METHODS: Hierarchical multiple regression was used to determine the ability of VFQ-25 to predict PQoL, while controlling for other variables significantly correlated with PQoL. The latter were entered as independent variables in the first step of this analysis and VFQ-25 in the second. This model determines the degree to which VFQ-25 predicted PQoL when all other variables were controlled for. RESULTS: Of the other variables assessed, only general health and group affiliation were found to be significantly correlated with PQoL. These variables, entered in step 1 of the analysis, explained 24.3% of the variance (adjusted r = 0.243) in PQoL. When VFQ-25 was entered in step 2, the model then explained 29.3% (adjusted r = 29.3) of the variance or an additional 5% when the effects of the other two variables were controlled for (r change = 0.050, p = 0.001). In other words, VFQ-25 only predicted 5% of the variance found in PQoL. Therefore, 95% of the variance was not explained by this measure. CONCLUSIONS: It is clear from the results of this study that VFQ and PQoL were not measuring the same construct. It is also apparent that the single-item global measure of QoL did indeed ask participants to rate their PQoL. Thus, we may conclude that the measure of vision-related QoL used in this study did not measure PQoL. Further research is required to determine the extent to which this finding may apply to other measures of vision related QoL. PMID- 17700342 TI - Are standard instruments valid for the assessment of quality of life and symptoms in glaucoma? AB - PURPOSE: To determine if the impact of Visual Impairment Instrument (IVI) and Glaucoma Symptom Scale (GSS) are valid instruments to assess participation in daily living and ophthalmic complaints, respectively, in a glaucoma population. METHODS: Patients with glaucoma were recruited from private and public clinics and completed the IVI and GSS questionnaires. The two scales were assessed for fit to the Rasch model. Unidimensionality, individual item and person fit to the model, response category performance (how respondents differentiate between the response options), differential item functioning (how subgroups, despite equal levels of the underlying trait, respond differently to an individual item), and targeting of items to patients (good spread of items across the full range of patients' scores) were assessed. RESULTS: One hundred seventy-five participants (mean age = 71 year) were recruited. The majority (65%) had primary open angle glaucoma and good presenting visual acuity >or=6/9 in the better eye (87%). Only one-third of the participants had severe visual field loss in both eyes. Disordered thresholds were evident across all GSS items, indicating that the categories were difficult to discriminate and required category collapsing (5 to 3 categories). There was no evidence of person and item misfit, differential item functioning, and multidimensionality. However, both scales displayed ineffective person-item targeting as a large number of participants demonstrated little difficulty with the most difficult items. CONCLUSIONS: Because of unsatisfactory targeting, The IVI and GSS are suboptimal scales to assess patients with glaucoma but relatively good vision. It is likely that items could be added to optimize the performance of both instruments. There may however be a need to develop a glaucoma-specific instrument to assess Quality of Life in this population. PMID- 17700343 TI - Developing a preference-based Glaucoma Utility Index using a discrete choice experiment. AB - PURPOSE: To estimate a utility-based glaucoma health outcome measure, known as the Glaucoma Utility Index. METHODS: Based on focus group studies, involving people with glaucoma, existing profile measures relevant to glaucoma were modified and a six-dimensional profile instrument was developed. Dimensions were: central and near vision; lighting and glare; mobility; activities of daily living; eye discomfort and other effects. Each dimension was assigned four levels (no difficulty; some difficulty; quite a lot of difficulty; and severe difficulty). The discrete choice experiment (DCE) approach was employed to move from this profile instrument to a preference-based utility measure. Experimental design techniques were used to derive a sample of health states for which preferences were elicited using the DCE. Four hundred and seventy-three people with glaucoma received the choice questionnaire. RESULTS: The regression analysis was based on 286 consistent responses to the DCE. The regression coefficients for three of the dimensions ("central and near vision," "mobility," and "activities of daily living") moved as expected. Moving from "no difficulty" to "severe difficulty" for central and near vision resulted in the most loss of utility, followed by activities of daily living and mobility. Systemic ("other effects") and local side effects were considered the least important. Utility weights were related to self-reported glaucoma state. Utility estimates moved in line with generic measures of health outcome. CONCLUSIONS: This study developed a preference-based utility measure (Glaucoma Utility Index) using the DCE approach. The index, estimated on the basis of 286 respondents, demonstrated both theoretical and convergent validity with other generic health outcome measures and measures of glaucoma severity. Further research investigating preferences by clinically defined glaucoma health status is indicated. Methodological research should focus on alternative methods of scaling for use within a generic Quality Adjusted Life Year framework. PMID- 17700344 TI - Preference-based quality of life measures in people with visual impairment. AB - The use of preference-based measures of quality of life represents the application of principles of decision theory and welfare economics to the measurement of health-related concepts. In this Perspective, we present the theoretical basis of preference-based measures in the assessment of the impact of vision-related disease on quality of life and their role in cost-effectiveness analysis. We discuss the use of the standard gamble and time trade-off in eliciting utilities and the limitations of both methods. Scaling issues related to utility are discussed, in particular the reasons for use of the "policy scale" (i.e., a scale where utilities are anchored at 1.0 for perfect health and 0 as death). This is contrasted with the use of the "vision-truncated scale" (i.e., a scale with 1.0 representing perfect vision and 0 being death), which is commonly used in assessment of vision-related utilities. We discuss problematic aspects of using the truncated scale in conducting cost-effectiveness research for vision related disease, and provide a theoretical and empirical discussion of these limitations. In particular, we point out how these results raise questions concerning the conceptual relationship between vision- and health-related quality of life. Finally, we present the results of previous cross-cultural and trans national studies of vision-related quality of life to demonstrate how utility studies might provide insight into the meaning of disease across cultures. PMID- 17700346 TI - Variability in mobility of children with cerebral palsy. AB - PURPOSE: To examine the variability in mobility of children with cerebral palsy (CP) within classification levels. METHODS: The subjects were 183 children with CP, ages six to 12 years, at Gross Motor Function Classification System (GMFCS) levels II to IV. Parents reported their child's mobility methods in the home, school, and outdoors/community. Mobility methods were ranked using empirical data and reflect trunk and lower extremity motor control requirements. These ranks were used for Friedman analysis of variance and post-hoc analyses for each GMFCS level. RESULTS: Children within the same GMFCS level exhibited varying degrees of independence in mobility methods, which differed across setting. Children usually performed higher-ranked mobility methods (requiring the most gross motor control) at home, lower-ranked mobility methods at school, and the lowest ranked mobility methods in the outdoors/community. CONCLUSIONS: Contextual, environmental, and personal factors may explain these findings. Therapists are encouraged to examine contextual features in everyday settings when planning interventions to improve functional mobility. PMID- 17700347 TI - Anticipatory postural adjustments in children with cerebral palsy and children with typical development. AB - PURPOSE: We sought to examine whether children with cerebral palsy (CP) demonstrate anticipatory postural adjustments (APAs) similar to those observed in children with typical development (TD). METHODS: A sample of convenience of 14 children, seven with CP and seven with TD, participated in this study. The center of pressure (COP) was calculated from ground reaction force data collected from the AMTI (OR-6) force platform as the child reached forward while standing. RESULTS: Posterior COP shift frequently was observed in both groups of children before arm movement. However, the children with CP showed greater variability and significantly shorter amplitude of the APA COP excursion as compared with those with TD. CONCLUSIONS: The control of APAs is problematic for some children with CP and, therefore, intervention designed to facilitate APAs may be beneficial for those children. PMID- 17700348 TI - Parents' perceived benefits of physical therapists' direct intervention compared with parental instruction in early intervention. AB - PURPOSE: This study compared parents' perceptions of benefits of a therapist's direct intervention with intervention designed to teach parents to promote their children's motor development. METHODS: Twenty-two mothers and one father of children with disabilities watched four videotapes. Two videotapes showed a physical therapist helping a child learn to sit or walk while the mother watched; two showed a therapist instructing a mother while the mother interacted with the child. Parents then responded to a 12-item questionnaire. RESULTS: Overall, participants rated the parent instruction approach as more beneficial, but more stressful, than direct intervention. CONCLUSIONS: Most results were inconsistent with previous reports that parents believed direct intervention was more beneficial than other approaches. The parents' belief that direct intervention could be less stressful is consistent with previous studies. Research is needed to identify the most effective model that parents prefer to promote children's motor development. PMID- 17700349 TI - Physical activity, health, and dietary patterns of middle school children. AB - PURPOSE: We sought to characterize the physical activity, health, and dietary patterns of middle school children and examine associations between these factors. Parent-child relationships also were examined. METHODS: Thirty-eight children and parents participated and completed a three-day physical activity recall and 24-hour dietary recall. The Child Health Questionnaire was used to assess child health. Percentage overweight was determined for each participant. RESULTS: Forty-four percent of children did not meet the current recommendation for physical activity. Fat and sodium consumption exceeded recommendations, and intake of key nutrients was inadequate. Youth who spent more time in sedentary activity had poorer general health. There were positive associations between parent and child percentage overweight and physical activity. Parent physical activity explained an additional 46.2% of the variance in child physical activity. CONCLUSIONS: Increasing physical activity and reducing sedentary behaviors through strategies that incorporate parents is an important component of a physical therapy program for school children. PMID- 17700350 TI - Weighing in on the issues of type 2 diabetes in children: a review. AB - PURPOSE: The purpose of this review is to present the clinical issues, including risk, etiology, screening and identification, complications, management, and prevention of type 2 diabetes mellitus (T2DM) in children and to discuss the role of the pediatric physical therapist in effectively managing children with T2DM. SUMMARY OF KEY POINTS: In studies done worldwide, T2DM is being diagnosed in children at rates much greater than that of type 1 diabetes. Sedentary lifestyle and the high prevalence of obesity are the primary problems, setting the stage for a lifetime of health complications for many of today's youth. RECOMMENDATIONS: Health care providers must understand this disease to ensure proper management. A multidisciplinary approach is advocated for those children who are at risk for and diagnosed with T2DM to help prevent the disabling and often incapacitating complications associated with T2DM. PMID- 17700351 TI - Clinical characteristics of hypotonia: a survey of pediatric physical and occupational therapists. AB - PURPOSE: This study extended previous work on defining characteristics of children with hypotonia. METHODS: A survey regarding previously identified characteristics of hypotonia, examination tools, interventions, and prognosis was sent to a random sample of 500 physical therapists and 500 occupational therapists. RESULTS: A total of 268 surveys were returned, for a response rate of 26.8%. Characteristics most frequently observed in children with hypotonia included decreased strength, hypermobile joints, and increased flexibility. Observation was the most commonly cited assessment tool and 85% of those surveyed believe that characteristics of hypotonia improve with therapy. CONCLUSIONS: Despite agreement among physical and occupational therapists on characteristics of hypotonia and potential for improvement, clear clinical guidelines for the diagnosis and quantification of hypotonia have yet to be determined. Research is needed to develop an operational definition of hypotonia, develop valid tests and assess effectiveness of intervention. PMID- 17700353 TI - Normative values for active lumbar range of motion in children. AB - PURPOSE: The purpose of this study was to establish normative values for active lumbar movement in children five, seven, nine, and 11 years of age. METHODS: End range active flexion, extension, and right- and left-side bending and rotation of the lumbar spine were measured for 225 normally developing children (116 girls, 109 boys) using the Back Range of Motion (BROM II) device. Means were determined for each motion by age and sex. Group relationships were explored. RESULTS: Normative values for lumbar spine cardinal plane movements were identified. Reduced lumbar movement was found in the 11-year-old group compared with the five year-old group in active lumbar flexion in girls and in active lumbar side bending and rotation in both girls and boys. CONCLUSION: Normative data for cardinal plane movements of the lumbar spine provide therapists with a baseline for assessing spinal mobility of children of these ages. PMID- 17700352 TI - Outcomes of infants with idiopathic hypotonia. AB - PURPOSE: To describe the outcomes of children diagnosed before the age of two with idiopathic hypotonia. METHODS: A total of 105 parents of children who were diagnosed with hypotonia returned a questionnaire. Medical records were reviewed. RESULTS: A transient impairment group (10.5%) reported no problems. A minimal impairment group (32.4%) had mild problems such as learning disability or language delay but no major developmental diagnosis. A globally impaired group (40.9%) had mental retardation or a recognizable genetic/developmental diagnosis. More than 50% of the minimal impairment group had poor coordination, language delay, and learning difficulties. The mean walking age (minimal group) was 22 months. Initial fine motor and cognitive, but not gross motor, developmental quotients were significantly greater in the minimal compared with global impairment group. CONCLUSION: Deficits in motor coordination, language, and learning difficulties were common problems that persisted in the minimal and global impairment groups. PMID- 17700354 TI - Lightweight and ultralight wheelchairs: propulsion and preferences of two young children with spina bifida. AB - PURPOSE: This study compared the influence of two wheelchair styles, an ultralight rigid frame and a lightweight folding frame, on preference and propulsion in young children with spina bifida. PROCEDURE: Speed, distance, energy expenditure, and perceived exertion of two girls were studied in an A-B-A single subject design. Questionnaires were used after the three phases to obtain parent and child preference. RESULTS: Visual inspection of the data favored the ultralight wheelchair for all variables, except the first child's speed with classmates and perceived exertion. Parents and children indicated preference for the ultralight wheelchair on all questions but one by Child 1. Using two standard deviation band width (2SDBW) analyses, 12 of 16 comparisons between the phases differed significantly. 2SDBW comparison was not used in the other four phase comparisons because of autocorrelations. CONCLUSION: This study presents initial evidence supporting the use of ultralight rigid-framed wheelchairs by young children. PMID- 17700355 TI - The clinical decision-making process of prescribing power mobility for a child with cerebral palsy. AB - PURPOSE: Powered mobility has been shown to be an effective method for children with disabilities to achieve independent mobility. The purpose of this case report is to describe the physical therapist's clinical decision making related to power mobility for a child with multiple disabilities. CASE DESCRIPTION: Power wheelchair evaluation for a nine-year-old child was conducted using Furumasu's tasks for wheelchair readiness moving through a doorway, maneuvering through three cones, and driving in a hallway. Ongoing team assessment with family consultation informed clinical decision-making. OUTCOMES: A mid-wheel-drive chair afforded improved performance on Furumasu's tasks compared with a rear-wheel drive chair. SUMMARY: This case describes the clinician's role in prescribing power wheelchairs to affect the user's functional skills, as well as how, in the absence of evidence, clinical experience and patients' needs can guide clinical decision-making. PMID- 17700357 TI - Expression of three naturally occurring genetic variants (G75R, E90D, I99M) of the BCHE gene of human butyrylcholinesterase. AB - The present paper examined the effects of three non synonymous BCHE mutations (G75R, E90D and /99M) on enzyme kinetic parameters obtained after the expression of the respective recombinant BChEs. The respective nucleotide substitution that characterizes each of the three variants was introduced into BCHE cDNA by site directed mutagenesis and transfected into human embryonic kidney 293 T cells and Chinese hamster ovary cells (for E90D). BChE catalysed hydrolysis of butyrylthiocoline (BTC) was measured by Ellman method. The expression results showed that: (1) the activity of the G75R enzyme represents approximately 45% of the wild-type activity, whereas that of the I99M enzyme does not differ from the wild-type; (2) the E90D enzyme presents a silent phenotype; disruption of the salt bridge between E90 and R42 may cause the enzyme to be rapidly degraded inside the cells. In homozygous form the E90D enzyme may confer increased susceptibility to succinylcholine, but may delay cognitive impairment in aged individuals. BChE genotyping may become important for estimating prognosis, and the knowledge of the genetic variants of BChE in a particular population may be useful for carrying out the genotyping assays. PMID- 17700358 TI - Genetic variability of human diamine oxidase: occurrence of three nonsynonymous polymorphisms and study of their effect on serum enzyme activity. AB - OBJECTIVE: To analyze the occurrence and the functional effects of nonsynonymous single nucleotide polymorphisms in the human diamine oxidase (ABP1) gene. METHODS: Genomic DNA from 134 healthy Caucasian individuals was analyzed for three nonsynonymous single nucleotide polymorphisms in the ABP1 gene. Serum diamine oxidase activity was studied in 37 individuals with known ABP1 genotype. RESULTS: Variant ABP1 alleles leading to the amino-acid substitutions Thr16Met, Ser332Phe and His645Asp were identified with frequencies of 25.4, 6.3 and 30.6%, respectively. Over 70% of the population (95% confidence interval, 62.4-77.9%) carry at least one amino-acid substitution. Each amino-acid substitution was at Hardy-Weinberg's equilibrium, but linkage disequilibrium between variant alleles was observed. The percentage of individuals carrying simultaneously the three amino-acid substitutions in heterozygosity or homozygosity (9%, 95% confidence interval, 4.2-13.8%) was over three times that expected from a random association (P<0.05). Individuals carrying the 645Asp amino acid displayed lower serum diamine oxidase activity as compared with noncarriers (P<0.001) with a significant gene-dose effect (P<0.05). This was due to an increase in the Michaelis-Menten constant. Individuals heterozygous for 645Asp show Vmax/Km values of 66% and homozygous 51% as compared with noncarriers. The effect of the 16Met variant allele was lower and that of the rarest allele 332Phe was negligible. CONCLUSION: Nonsynonymous ABP1 gene polymorphisms are common in humans; they cause relevant functional effects and can be considered as major determinants of variability for human diamine oxidase activity. PMID- 17700359 TI - CYP2D6*4 polymorphism is associated with statin-induced muscle effects. AB - Statin use is associated with a variety of overtly related muscle symptoms including muscle pain, myalgia, creatine kinase elevations without pain with myolysis and myositis (rhabdomyolysis), a potentially fatal side effect that led to the withdrawal of cerivastatin in 2001. Unintended drug response phenotypes have an impact on patient compliance and sometimes patient health and the assessment of risk on an individual basis could enhance therapeutic benefit. We therefore investigated whether common single nucleotide polymorphisms were associated with the expression of broadly grouped atorvastatin-induced muscle events in a case-control study (n=263 samples, n=388 SNPs). Of a number of associations identified in a discovery sample (51 atorvastatin-induced muscle and 55 normal) only those corresponding to the CYP2D6*4 allele were significantly associated in the sample (24 atorvastatin-induced muscle and 133 normal) (Discovery P=0.004, odds ratio=3.6; Validation P=0.036, odds ratio=2.7; total P=0.001, odds ratio=2.5). The frequency of the CYP2D6*4 allele was about 50% in atorvastatin-induced muscle patients but only 28% in controls, similar to that of other patient types (28.5%). The association was independent of various demographic variables and not explained by gross demographic, clinical or population-structure differences among cases and controls. Surprisingly, the CYP2D6*4 allele appeared similarly distributed among controls and patients expressing simvastatin-induced muscle events (n=169, frequency in case participants=49.2%, P=0.067, odds ratio=1.7). Our results suggest that the CYP2D6*4 allele is associated with broadly related muscle events caused by at least two structurally dissimilar HMG-CoA reductase inhibitors, and as such, may have implications for a better understanding of this statin-wide phenomena. PMID- 17700360 TI - Polymorphisms in genes encoding drug metabolizing enzymes and their influence on the outcome of children with neuroblastoma. AB - BACKGROUND: Although several studies have shown that drug metabolizing enzyme gene polymorphisms may influence the impact of therapy in childhood leukemia, no comprehensive investigations have been carried out in children with neuroblastoma. The aim of this study was to identify polymorphisms in the genes encoding phase I and II drug metabolizing enzymes associated with the risk of relapse or death in a cohort of 209 children with neuroblastoma. METHODS: Real time PCR allelic discrimination was used to characterize the presence of polymorphisms in DNA from children with neuroblastoma. Three broad gene categories were examined: cytochrome P450, glutathione-S-transferase and N acetyltransferase. Cumulative event-free survival was computed by the Kaplan Meier method. The influence of selected factors on event-free survival was tested using the Cox proportional hazards model. RESULTS: As previously reported, amplification of MYCN (hazards ratio=4.25, 95% confidence interval=2.76-6.56, P<0.001), unfavorable stage (hazard ratio=4.14, 95% confidence interval=2.3-7.47, P<0.001) or age more than 1 year at diagnosis (hazard ratio=1.86, 95% confidence interval=1.19-2.92, P=0.007) were all associated with an increased risk of relapse or death. Carriers of a NAT1*11 allele variant were significantly less likely to relapse or die compared with those with NAT1*10 or other NAT1 allele variants (P<0.001). In multivariate analysis, children who were GSTM1 null were more likely to relapse or die during follow-up after adjusting for MYCN amplification, stage and age at diagnosis (hazard ratio=1.6, 95% confidence interval=1.02-2.9, P=0.04). CONCLUSIONS: These observations suggest that the NAT1*11 variant and the GSTM1 wild-type genotype contribute to a more favorable outcome in patients treated for neuroblastoma and are the first to demonstrate a relationship between NAT1 and GSTM1 genotypes in childhood neuroblastoma. PMID- 17700361 TI - KCNMB1 genotype influences response to verapamil SR and adverse outcomes in the INternational VErapamil SR/Trandolapril STudy (INVEST). AB - OBJECTIVES: We sought to determine whether polymorphisms in the large-conductance calcium and voltage-dependent potassium (BK) channel beta1 subunit gene, KCNMB1, are associated with blood pressure response to verapamil SR or adverse outcomes in the GENEtic substudy of the INternational VErapamil SR/trandolapril STudy (INVEST-GENES). BACKGROUND: KCNMB1 is involved in calcium sensitivity and hypertension. The association between variability in KCNMB1 and calcium antagonist response, however, has not been assessed. METHODS: Genetic samples were collected from 5979 patients in INVEST. Blood pressure response to verapamil SR and time to achieve blood pressure control was assessed in relation to Glu65Lys and Val110Leu genotypes. The primary outcome (all cause mortality, nonfatal myocardial infarction or nonfatal stroke) was compared between genotype groups, and interaction with verapamil SR therapy was assessed. RESULTS: Systolic blood pressure response to verapamil SR did not differ by KCNMB1 genotype. Lys65 variant carriers, however, achieved blood pressure control earlier than Glu65Glu individuals [1.47 (interquartile ratio 2.77) versus 2.83 (interquartile ratio 4.17) months, P=0.01] and were less likely to require multiple drugs at the time of blood pressure control (adjusted odds ratio 0.43, 95% confidence interval 0.19 0.95). Leu110 variant carriers had a reduced risk of primary outcome (hazard ratio 0.68, 95% confidence interval 0.47-0.998). Subgroup analysis revealed this finding to be more pronounced in verapamil SR-assigned patients (hazard ratio 0.587, 95% confidence interval 0.33-1.04) compared with atenolol-assigned patients (hazard ratio 0.946, 95% confidence interval 0.56-1.59). No difference was seen in the occurrence of the primary outcome compared by codon 65 genotype. CONCLUSIONS: Our findings suggest that KCNMB1 genotype influences responsiveness to verapamil SR and risk of adverse cardiovascular outcomes. PMID- 17700362 TI - Reverse transcriptase-PCR quantification of mRNA levels from cytochrome (CYP)1, CYP2 and CYP3 families in 22 different human tissues. AB - OBJECTIVE: The aim of this work was to study simultaneously the expression profile of the 23 CYP mRNAs of CYP1, CTP2 and CYP3 families in 22 different human tissues namely adrenal gland, bladder, bone marrow, colon, fetal liver, heart, kidney, liver, lung, mammary gland, ovary, placenta, prostate, salivary gland, skeletal muscle, small intestine, spleen, testis, thymus, thyroid, trachea and uterus. METHODS: Analysis of the mRNA levels of each of these CYP isoforms was performed on total RNA from pooled specimens of human organs using reverse transcriptase-PCR-based CYP mRNA assays previously validated for their sensitivity and their specificity. RESULTS: Our results confirmed previously reported data in the literature concerning isoforms expression in the most currently studied tissues. Moreover, they provided a great deal of new information, mainly about the expression of mRNA of little-known CYP isoforms. Among the 23 CYP isoforms studied, 12 were mainly hepatic (CYP1A2, 2A6, 2A7, 2A13, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4 and 3A43). Two CYP mRNAs were predominantly expressed in several extrahepatic tissues: CYP1B1 mRNA was the predominant CYP in seven extrahepatic tissues (bone marrow, kidney, mammary gland, prostate, spleen, thyroid and uterus) and CYP2J2 in four extrahepatic tissues (heart, placenta, salivary gland and skeletal muscle). Finally, some CYPs were nearly exclusively expressed in only one extrahepatic tissue. CYP2R1 was found in testis, CYP2U1 in the thymus and CYP2F1 in the respiratory tract (lung and trachea). CONCLUSION: This description will broaden the understanding of the physiological functions of these CYPs. PMID- 17700363 TI - The L84F polymorphism in the O6-Methylguanine-DNA-Methyltransferase (MGMT) gene is associated with increased hypoxanthine phosphoribosyltransferase (HPRT) mutant frequency in lymphocytes of tobacco smokers. AB - OBJECTIVES: O-methylguanine-DNA-methyltransferase (MGMT) is a crucial DNA repair protein that removes DNA adducts formed by alkylating mutagens. Several coding single nucleotide polymorphisms (cSNPs) in the MGMT gene have been reported. Their biological significance, however, is not known. METHODS: We used a newly modified cloning HPRT mutant lymphocyte assay to test the hypothesis that inheritance of the L84F and I143V coding single nucleotide polymorphism in the MGMT gene is associated with increases in HPRT mutant frequency in lymphocytes of individuals exposed to alkylating agents. In addition, we expanded and sequenced 109 mutant clones to test the hypothesis that the mutation spectrum would shift to a larger percentage of base substitutions and G-->A transition mutations in cells with L84F and I143 V coding single nucleotide polymorphisms. RESULTS: We observed no significant effect for the I143 V coding single nucleotide polymorphism on mutant frequency. In contrast, we observed a significant increase in mutant frequency (P<0.01) in lymphocytes from smokers with the 84F coding single nucleotide polymorphism compared with smokers homozygous for the referent L84 wild-type allele. A multiple regression analysis indicated that the mutant frequency increased significantly as a function of the 84F coding single nucleotide polymorphism and smoking, according to the model; mutant frequency (x10)=0.90+0.618 (84F polymorphism)+0.46 (smoking) with R=0.22. Mutation spectra analysis revealed an apparent increase, which was short of statistical significance (P=0.08), in base substitutions in cells with the 84F polymorphism. CONCLUSIONS: These new data suggest that the 84F coding single nucleotide polymorphism may alter the phenotype of the MGMT protein, resulting in suboptimal repair of O-methylguanine lesions after exposure to alkylating agents. PMID- 17700364 TI - Contribution of 20 single nucleotide polymorphisms of 13 genes to dyslipidemia associated with antiretroviral therapy. AB - BACKGROUND: HIV-1 infected individuals have an increased cardiovascular risk which is partially mediated by dyslipidemia. Single nucleotide polymorphisms in multiple genes involved in lipid transport and metabolism are presumed to modulate the risk of dyslipidemia in response to antiretroviral therapy. METHODS: The contribution to dyslipidemia of 20 selected single nucleotide polymorphisms of 13 genes reported in the literature to be associated with plasma lipid levels (ABCA1, ADRB2, APOA5, APOC3, APOE, CETP, LIPC, LIPG, LPL, MDR1, MTP, SCARB1, and TNF) was assessed by longitudinally modeling more than 4400 plasma lipid determinations in 438 antiretroviral therapy-treated participants during a median period of 4.8 years. An exploratory genetic score was tested that takes into account the cumulative contribution of multiple gene variants to plasma lipids. RESULTS: Variants of ABCA1, APOA5, APOC3, APOE, and CETP contributed to plasma triglyceride levels, particularly in the setting of ritonavir-containing antiretroviral therapy. Variants of APOA5 and CETP contributed to high-density lipoprotein-cholesterol levels. Variants of CETP and LIPG contributed to non-high density lipoprotein-cholesterol levels, a finding not reported previously. Sustained hypertriglyceridemia and low high-density lipoprotein-cholesterol during the study period was significantly associated with the genetic score. CONCLUSIONS: Single nucleotide polymorphisms of ABCA1, APOA5, APOC3, APOE, and CETP contribute to plasma triglyceride and high-density lipoprotein-cholesterol levels during antiretroviral therapy exposure. Genetic profiling may contribute to the identification of patients at risk for antiretroviral therapy-related dyslipidemia. PMID- 17700365 TI - Self-reported skin color, genomic ancestry and the distribution of GST polymorphisms. AB - BACKGROUND AND OBJECTIVE: Skin color and self-reported ethnicity have systematically been used in the pharmacogenetic/-genomic literature as phenotypic proxies for geographical ancestry. Population admixture, however, challenges the appropriateness of this approach. We compared the effectiveness of color-based and marker-based biogeographical ancestry classifications in typing polymorphisms in GSTM1, GSTM3 and GSTT1 in the heterogeneous Brazilian population. METHODS: Individual DNA from 335 healthy Brazilians was typed for a set of insertion/deletion polymorphisms, previously validated as ancestry informative markers. GSTM1-null and GSTT1-null polymorphisms were detected by multiplex PCR and the GSTM3*B polymorphism by restriction-fragment length polymorphism. Nonlinear logistic regression modeling was developed to describe the association between the GST polymorphisms and ancestry estimated by the ancestry informative markers. RESULTS: Analysis of the ancestry informative markers data with the Structure software revealed the existence of only two significant clusters, one of which was inferred to be an estimate of the African component of ancestry. Nonlinear logistic regression showed that the odds of having the GSTM1-null genotype decreases (P<0.0004, Wald statistics), whereas the odds of having the GSTM3*B allele increases (P<0.0001) with the increase of the African component of ancestry, throughout the range (0.13-0.95) observed in the population sample. The African component of ancestry proportion was not associated with GSTT1-null frequency. Within the self-reported Black and Intermediate groups, there were significant differences in ancestry informative markers between GSTM1-null and non-null individuals, and between carriers and noncarriers of the GSTM3*B allele. CONCLUSIONS: Interethnic admixture is a source of cryptic population structure that may lead to spurious genotype-phenotype associations in pharmacogenetic/ genomic studies. Logistic regression modeling of GST polymorphisms shows that admixture must be dealt with as a continuous variable, rather than proportioned in arbitrary subcategories for the convenience of data quantification and analysis. PMID- 17700366 TI - Functional effects of protein sequence polymorphisms in the organic cation/ergothioneine transporter OCTN1 (SLC22A4). AB - BACKGROUND: OCTN1 is a multispecific transporter of organic cations and zwitterions, including several clinically important drugs as well as the antioxidant ergothioneine. OCTN1 is highly expressed in the kidney, where it is thought to aid in active secretion of organic cations, and may facilitate the active reabsorption of ergothioneine. Genetic variation in OCTN1 may help to explain interindividual variability in the pharmacokinetics of many cationic or zwitterionic drugs. METHODS: We screened for human genetic variants in the OCTN1 coding region by direct sequencing in a large sample (n=270) of ethnically diverse healthy volunteers. RESULTS: Six protein sequence-altering variants were identified, including five-amino-acid substitutions and one nonsense mutation. Two of the variants, T306I and L503F, were polymorphic, occurring at frequencies of 37 and 19%, respectively, in the total sample. Allele frequencies are varied by ethnicity. In biochemical assays, two of the variants (D165G and R282X) resulted in complete loss of transport function, and one variant (M205I) caused a reduction in activity to approximately 50% of the reference sequence protein. One variant, L503F, showed altered substrate specificity; this variant occurred at particularly high allele frequency (42%) in the European-American participants in our sample. Subcellular localization and ergothioneine inhibition kinetics were similar among the common amino-acid sequence variants of OCTN1. CONCLUSIONS: The common OCTN1-L503F variant may explain a significant amount of population variation in the pharmacokinetics of OCTN1 substrate drugs. The rare loss-of function variants provide a rational tool for studying the importance of ergothioneine in humans in vivo. PMID- 17700367 TI - Identification and functional analysis of variants in the human concentrative nucleoside transporter 2, hCNT2 (SLC28A2) in Chinese, Malays and Indians. AB - The human concentrative nucleoside transporter (hCNT2), also known as SLC28A2, plays an important role in the cellular uptake across intestinal membrane of some naturally occurring nucleosides and nucleoside analogs. This study aims to determine the genetic variability of hCNT2 (SLC28A2) in three major Asian ethnic groups residing in Singapore: Chinese, Malay and Indian, and functionally characterize the variants of hCNT2. Healthy participants (n=96) from each group were screened for genetic variations in the exons of hCNT2 (SLC28A2) using denaturing high performance liquid chromatography and sequencing analyses. A total of 23 polymorphisms were identified in the exonic and flanking intronic regions, and ethnic differences in single nucleotide polymorphism frequencies were evident. Five novel nonsynonymous variants (L12R, R142H, E172D, E385K, M612T) were constructed by mutagenesis and functionally characterized in U-251 cells. Expression of these variants in U-251 cells revealed that all except E385K can uptake various substrates of hCNT2: inosine, ribavirin and uridine. PMID- 17700369 TI - Overview of procurement, processing, and sterilization of soft tissue allografts for sports medicine. AB - Musculoskeletal allografts are commonly used in orthopedic surgery and have become increasingly popular. Their indications have widened as an alternatives to autografts. A tissue processing industry has secondarily evolved. An increasing number of accredited tissue banks are providing donor screening, procurement, processing, storage, and distribution of tissue. Multiple factors play a role for a graft to be successfully implanted: sterility, reduction of antigenicity, and preservation of its biologic and biomechanical properties. A rare but catastrophic complication that has raised concern is disease transmission. Controversies exist on which is the best way to produce a strong, disease-free graft. There is no current standard, but as allograft technology evolves, surgeons need to be aware of the regulations and policies surrounding allograft tissue procurement and processing to provide the best outcomes in transplanted patients. PMID- 17700370 TI - Meniscal allografts: biomechanics and techniques. AB - Arthroscopic partial meniscectomy is one of the most common orthopedic surgical procedures performed. Numerous clinical and biomechanical studies have shown the long-term consequences of the meniscus-deficient knee, which includes increased loading of the cartilage. This leads to chondromalacia, and ultimately pain and dysfunction. Few treatment options are available for the young patient with pain in the tibiofemoral compartment secondary to meniscus deficiency. Meniscal allograft transplantation is a viable treatment option in this group of patients as short-term results have shown pain relief and functional improvement. Biomechanical studies have shown that the allograft meniscal transplant functions most like a native, intact meniscus when specific surgical principles are followed. Surgical techniques for meniscal allograft transplantation have advanced along with instrumentation. An improvement in function and pain relief can be expected when strict criteria are followed in patient selection and surgical technique. PMID- 17700371 TI - Meniscal allografts: indications and outcomes. AB - Meniscal allograft transplantation was introduced into clinical practice now over 20 years ago for the treatment of the symptomatic postmeniscectomy patient who has not yet developed osteoarthritis. Over the years, the indications have been fine-tuned and certain risk factors for failure have been identified. As the number of publications increases steadily, we now know that meniscal allografting significantly reduces pain and improves function. Recent data also suggest a potential chondroprotective effect in a subpopulation of patients. However, the major drawback in all meniscus allograft studies is the general lack of a control population. To improve our knowledge, future prospective studies should include objective outcome tools to evaluate the status of the allograft in addition to the clinical scoring systems. Future research should focus to elucidate the biologic and cellular processes involved in graft repopulation and remodelation. PMID- 17700372 TI - Osteochondral allografts in the treatment of articular cartilage injuries of the knee. AB - Osteochondral allografts have demonstrated encouraging clinical and scientific success in the treatment of full-thickness articular cartilage defects in multiple anatomic locations including the knee. The use of fresh grafts has shown the greatest potential for clinical success. There has been growing interest in cryopreservation techniques and the use of cryopreserved grafts owing to the delay in obtaining grafts secondary to regulatory testing, encouraging laboratory data surrounding their use, and the potential for more effective tissue banking. This article reviews the indications, operative technique, and clinical outcomes using osteochondral allografts for full-thickness articular cartilage defects in the knee. PMID- 17700373 TI - Allografts in the treatment of anterior cruciate ligament injuries. AB - Symptomatic knee instability is a common complaint among athletic individuals after a torn anterior cruciate ligament (ACL) of the knee. Allograft ACL reconstruction has gained popularity for primary and revision reconstructions. This graft choice has become popular with good intermediate term results combined with decreased operative times, hospital costs, and improved immediate postoperative pain and function. Intermediate follow-up has demonstrated similar results with autograft reconstructions, without the addition of donor site morbidity. Multiple allograft options exist for ACL reconstruction. The most commonly selected grafts include patellar tendon, Achilles tendon, and tibialis allografts. The use of a tibialis allograft provides a stout graft for reconstruction, while minimizing bone tunnel size. Bone-patella-bone allografts provide bone to bone fixation options with flexibility in tunnel selection sizing. PMID- 17700374 TI - Allograft use in the treatment of the multiple ligament injured knee. AB - The multiple ligament injured knee is a complex problem in orthopedic surgery. These injuries may or may not present as acute knee dislocations, and careful assessment of the extremity vascular status is essential because of the possibility of arterial and/or venous compromise. These complex injuries require a systematic approach to evaluation and treatment. Physical examination and imaging studies enable the surgeon to make a correct diagnosis and formulate a treatment plan. Multiple ligament injured knee reconstruction using allograft tissue is a reproducible procedure. Knee stability is improved postoperatively when evaluated with knee ligament rating scales, arthrometer testing, and stress radiographic analysis. Surgical timing depends upon the injured ligaments, vascular status of the extremity, reduction stability, and the overall health of the patient. The use of allograft tissue is preferred because of the strength of these large grafts, and the absence of donar site morbidity. PMID- 17700375 TI - Allografts in the treatment of athletic injuries of the shoulder. AB - As allogeneic musculoskeletal tissue is readily available, has minimal limitation in size or shape, and carries no donor site morbidity, it has become attractive for use in reconstructive shoulder surgery. Allograft is a viable option for treating osseous defects associated with glenohumeral instability and has been shown to achieve a stable shoulder with good clinical outcomes. Although there are mixed results on the use of allograft as rotator cuff augments or substitutes, new commercially processed materials such as GraftJacket are being tested to address the high failure rates associated with massive rotator cuff repair. Interposition arthroplasty as a treatment for glenohumeral arthritis in the young and active patient is a novel concept in which the arthritic glenoid is biologically resurfaced. Satisfactory results have been described using lateral meniscus and Achilles tendon allograft. Despite the promising reports on the use of allograft in reconstructive shoulder surgery, most of the published literature exists as retrospective, case reports. Additional large, controlled research is needed to prove the efficacy and safety of allograft tissue in the treatment of athletic injuries of the shoulder. PMID- 17700376 TI - Bone graft substitutes in sports medicine. AB - Bone graft substitutes are used commonly in orthopedic surgery as an alternative to autograft bone. Autograft bone has the advantages of being osteoconductive, osteoinductive, and osteogenic. However, the quantity of autograft bone available is limited in a given patient and the harvest of autograft bone has been associated with significant morbidity. Bone graft substitutes have become available in an attempt to address these issues and have found widespread use in many areas of orthopedic surgery including sports medicine. The various categories of bone graft substitutes are reviewed here, with an examination of their biologic mechanism of action. Clinical evidence to support their use is also reviewed, with a focus on sports medicine applications. PMID- 17700377 TI - Increasing chlamydia positivity in women screened in family planning clinics: do we know why? AB - OBJECTIVE: Following a 9-year 60% decline, chlamydia positivity increased 46% from 1997 through 2004 among young sexually active women screened in Region X family planning clinics. The objective of this analysis was to systematically examine the influences of risk factors, changing laboratory test methods, and interclinic variability on chlamydia positivity during this period. STUDY DESIGN: We analyzed data from 520,512 chlamydia tests from women aged 15 to 24 years screened in 125 family planning clinics. Multivariate logistic regression modeling was used to adjust the annual risk of chlamydia for the demographic, clinical, and sexual risk behavior characteristics associated with infection and for the increasing use of more sensitive laboratory test methods. A generalized linear mixed model was used to adjust for interclinic variability. RESULTS: We found a significant 5% annual increase in the risk of chlamydia even after adjusting for risk factors including laboratory test characteristics (odds ratio 1.05, 95% confidence interval: 1.04, 1.06). Variability among the clinics where screening occurred did not account for the increase. CONCLUSIONS: Based on a review of all available data, we concluded that there was a true increase in chlamydia positivity over the 8-year period. PMID- 17700380 TI - Valvular aortic stenosis in the elderly. AB - Elderly patients with valvular aortic stenosis have an increased prevalence of coronary risk factors, of coronary artery disease, and evidence of other atherosclerotic vascular diseases. Statins may reduce the progression of aortic stenosis (AS). Angina pectoris, syncope or near syncope, and congestive heart failure are the 3 classic manifestations of severe AS. Prolonged duration and late peaking of an aortic systolic ejection murmur best differentiate severe AS from mild AS on physical examination. Doppler echocardiography is used to diagnose the prevalence and severity of AS. The indications for cardiac catheterization and the medical management of AS are discussed. Once symptoms develop, aortic valve replacement (AVR) should be performed in patients with severe or moderate AS. Other indications for AVR are discussed. Warfarin should be administered indefinitely after AVR in patients with a mechanical aortic valve and in patients with a bioprosthetic aortic valve who have either atrial fibrillation, prior thromboembolism, left ventricular systolic dysfunction, or a hypercoagulable condition. Patients with a bioprosthetic aortic valve without any of these 4 risk factors should be treated with aspirin 75-100 mg daily. PMID- 17700381 TI - Ultrafiltration in heart failure. AB - Managing volume overload is essential for the treatment of symptomatic heart failure. Traditionally, it is achieved with oral and intravenous diuretics. Alternatively, the excess fluid can be removed via ultrafiltration. Modern technology has made this latter option more feasible than before for routine clinical practice. In this article we review the existing literature on the use of ultrafiltration for treating volume overload states in patients with heart failure. PMID- 17700382 TI - The changing face of postoperative atrial fibrillation prevention: a review of current medical therapy. AB - Atrial fibrillation is the most common postoperative arrhythmia with significant consequences on patient health. Postoperative atrial fibrillation (POAF) complicates up to 8% of all noncardiac surgeries, between 3% and 30% of noncardiac thoracic surgeries, and between 16% and 46% of cardiac surgeries. POAF has been associated with increased morbidity, mortality, and longer, more costly hospital stays. The risk of POAF after cardiac and noncardiac surgery may be affected by several epidemiologic and intraoperative factors, as well as by the presence of preexisting cardiovascular and pulmonary disorders. POAF is typically a transient, reversible phenomenon that may develop in patients who possess an electrophysiologic substrate for the arrhythmia that is present before or as a result of surgery. Numerous studies support the efficacy of beta-blockers in POAF prevention; they are currently the most common medication used in POAF prophylaxis. Perioperative amiodarone, sotalol, nondihydropyridine calcium channel blockers, and magnesium sulfate have been associated with a reduction in the occurrence of POAF. Biatrial pacing is a nonpharmacologic method that has been associated with a reduced risk of POAF. Additionally, recent studies have demonstrated that hydroxymethylglutaryl-CoA reductase inhibitors may decrease the risk of POAF. Finally, based on recent evidence that angiotensin converting enzyme inhibitors and angiotensin receptor blockers reduce the risk of permanent atrial fibrillation, these medications may also hold promise in POAF prophylaxis. However, there is a need for further large-scale investigations that incorporate standard methodologies and diagnostic criteria, which have been lacking in past trials. PMID- 17700383 TI - Direct inhibition of renin as a cardiovascular pharmacotherapy: focus on aliskiren. AB - The important role of renin-angiotensin-aldosterone system blockade in the treatment of systemic hypertension, heart failure, diabetic kidney disease, and atherogenesis has been clearly established. The theoretical therapeutic advantages for inhibiting the detrimental effects of the renin-angiotensin system at its most upstream point have served as the impetus for the development of renin inhibitors. The advent of aliskiren, the first in a novel class of orally active, nonpeptide, highly specific, human renin inhibitors, provides a new modality in the armamentarium of renin-angiotensin system antagonists. Studies in marmosets and rats demonstrated that aliskiren reduced blood pressure in a dose dependent manner and is highly efficacious in blocking plasma renin activity with parallel reductions in the levels of the other downstream constituents of the renin-angiotensin system. Clinical trials in hypertensive patients have confirmed these benefits with aliskiren whose blood pressure-lowering efficacy is similar to or better than those of standard therapeutic doses of enalapril, losartan, irbesartan, and hydrochlorothiazide. Aliskiren is well tolerated, with few reported adverse effects even at the highest doses tested. Given the established beneficial effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the treatment of cardiovascular and renovascular diseases, future studies may further elucidate a similar protective role for aliskiren both as a monotherapy and as part of a combination therapy. PMID- 17700384 TI - Importance of medication adherence in cardiovascular disease and the value of once-daily treatment regimens. AB - An estimated 71 million individuals in the United States are currently diagnosed with cardiovascular disease (CVD). If untreated, CVD conditions such as systemic hypertension, coronary artery disease, and heart failure will have potentially serious and often fatal outcomes. Numerous clinical trials have established a variety of evidence-based medications that are efficacious in the treatment of CVD. These drugs will be ineffective, however, if patients have trouble adhering to their prescribed regimens. In patients with hypertension or heart failure, or in those who have suffered a myocardial infarction, poor adherence to therapies has been linked to a variety of problems, including poor blood pressure control, rehospitalization, and increased healthcare resource utilization. Both the asymptomatic nature of some forms of CVD and the high pill burden associated with certain therapies have been linked to poor adherence. Reducing pill burden through the use of once-daily formulations has proven valuable in improving adherence to evidence-based therapies. This review will discuss the impact of adherence to prescribed therapies for CVD, outline common barriers to adherence, and demonstrate the value of once-daily dosing regimens for improved patient adherence. PMID- 17700385 TI - Sitagliptin: a novel drug for the treatment of type 2 diabetes. AB - Type 2 diabetes mellitus is a common chronic disease that causes significant morbidity and mortality worldwide. The primary goal of treatment is to target glycemic control by maintaining the glycosylated hemoglobin level near 6-7% without predisposing patients to hypoglycemia. Diabetes results from a combination of increased hepatic glucose production, decreased insulin secretion from beta cells, and insulin resistance in the peripheral tissues. Currently available antidiabetic agents work by different mechanisms to lower blood glucose levels. Unfortunately, each of them has its tolerability and safety concerns that limit its use and dose titration. Sitagliptin is the first antidiabetic agent from the class of dipeptidyl peptidase-4 enzyme inhibitors. It increases the amount of circulating incretins, which stimulate insulin secretion and inhibit glucose production. Sitagliptin was approved by the US Food and Drug Administration (FDA) for use with diet and exercise to improve glycemic control in adult patients with type 2 diabetes. It can be used alone or in combination with metformin or a thiazolidinedione (pioglitazone or rosiglitazone) when treatment with either drug alone provides inadequate glucose control. The usual adult dose is 100 mg once daily. A dose of 25-50 mg once daily is recommended for patients with moderate-to-severe renal impairment. In randomized, placebo controlled trials that lasted for up to 6 months, sitagliptin lowered glycosylated hemoglobin levels by 0.5-0.8%. In a 52-week clinical trial, sitagliptin was shown to be noninferior to glipizide as an add-on agent in patients inadequately controlled on metformin alone. Sitagliptin was well tolerated with the most common side effects being gastrointestinal complaints (up to 16%), including abdominal pain, nausea and diarrhea; hypoglycemia and body weight gain occurred at similar rates compared with placebo. Overall, sitagliptin provides a treatment option for patients with type 2 diabetes as a monotherapy, or as an adjunct to metformin or a thiazolidinedione when patients achieve inadequate glycemic control while on either of the agents. It is also an alternative therapy for those patients who have contraindications or intolerability to other antidiabetic agents. PMID- 17700387 TI - Public health genomics knowledge and attitudes: a survey of public health educators in the United States. AB - PURPOSE: This study assessed U.S. public health educators' attitudes toward genomic competencies, their awareness of efforts in the health promotion field to promote/incorporate genomics, and their basic & applied genomic knowledge. METHODS: A total of 1607 public health educators, nationwide, responded to a web based survey. RESULTS: The sample comprised predominantly white (76.8%) female (83.9%) participants, with an average age of 40.1 years and 11.2 years of practice in public health education/promotion. Generally, participants had negative attitudes toward genomic competencies, low awareness, and deficient genomic knowledge. Although various socioeconomic characteristics (e.g., ethnicity, gender, and educational level) correlated with participants' attitudes, awareness, and genomic knowledge, training in genetics/genomics or public health genomics also exhibited a positive association. After we controlled for socioeconomic factors, awareness, training, and genomic knowledge remained significantly associated with respondents' attitudes toward genomic competencies. CONCLUSION: Although this sample of public health educators had unfavorable attitudes and limited genomic knowledge, training seems to affect these variables. Thus, relevant training for this group of health professionals should be developed and advocated. Continuing education tools, focusing on public health genomics content, might be a venue for delivery of information and the development of favorable professional attitudes. PMID- 17700386 TI - Randomized comparison of phone versus in-person BRCA1/2 predisposition genetic test result disclosure counseling. AB - PURPOSE: This study evaluated whether phone results were equivalent to in-person result disclosure for individuals undergoing BRCA1/2 predisposition genetic testing. METHODS: A total of 111 of 136 subjects undergoing education and counseling for BRCA1/2 predisposition genetic testing agreed to randomization to phone or in-person result disclosure. Content and format for both sessions were standardized. Data from the State-Trait Anxiety Inventory and the Psychological General Well-Being index were collected at baseline and then again at 1 week and 3 months after disclosure of test results. Baseline measures were administered after the following had occurred: counseling/education session had been conducted, informed consent had been obtained, and decision to be tested had been made. Satisfaction and cost assessments were administered after the result session. At 1 week, participants were asked their preferred method of result disclosure. RESULTS: There were no differences in anxiety and general well-being measures between 50 phone and 52 in-person results disclosure. Both groups reported similar rates of satisfaction with services. Among those with a preference, 77% preferred the notification method assigned. There was a statistically significant preference for phone results among the 23% who did not prefer the method assigned. Greater costs were associated with in-person result disclosure. CONCLUSIONS: These data suggest that phone results are a reasonable alternative to traditional in-person BRCA1/2 genetic test disclosure without any negative psychologic outcomes or compromise in knowledge. However, further study is needed in a more clinically representative population to confirm these findings. PMID- 17700388 TI - The pharmacology of multiple regimens of agalsidase alfa enzyme replacement therapy for Fabry disease. AB - PURPOSE: This 10-week study was conducted to determine the pharmacokinetics of varying doses of agalsidase alfa and evaluate the effect of dose and dosing frequency on plasma Gb3 levels. METHODS: Eighteen adult male Fabry patients, naive to enzyme replacement therapy, were randomized to one of five regimens: 0.1, 0.2, or 0.4 mg/kg weekly; 0.2 mg/kg every other week (the approved dose); or 0.4 mg/kg every other week. Intravenous infusion rate was 0.1 mg/kg per 20 minutes. Plasma Gb3 levels were assessed at baseline and periodically during the study. RESULTS: The mean half-life was 56-76 minutes, and the mean volume of distribution at steady state was 17%-18% of body weight, with no significant association between dose and half-life, clearance, or volume of distribution at steady state. The area under the curve was linearly proportional to the dose from 0.1 to 0.4 mg/kg. Baseline average plasma Gb3 was 9.12 +/- 2.61 nmol/mL and after 10 weeks of treatment was significantly reduced by about 50% in each group with no statistically significant differences between groups. CONCLUSIONS: Reduction of plasma Gb3 levels was independent of dose or dose frequency in the range tested. These observations, coupled with the clinical trial experience of both agalsidase alfa and agalsidase beta, indicate that the standard dose of agalsidase alfa is sufficient to maximally reduce plasma Gb3. However, because plasma Gb3 is not a validated surrogate of disease severity in Fabry disease, further clinical study will be required to determine the optimal dosing regimen for providing maximal clinical benefit. PMID- 17700389 TI - Awareness and use of direct-to-consumer nutrigenomic tests, United States, 2006. AB - PURPOSE: Direct-to-consumer genetic tests are increasingly available and may improve confidentiality, convenience, and accessibility. Amid ethical concerns and an uncertain regulatory landscape, the future of this mode of delivery is unclear. One class of products, nutrigenomic tests, is used to analyze DNA and lifestyle habits to assess health risks. Little information is available regarding awareness or use of such tests among consumers or physicians. METHODS: We assessed consumers' awareness and use of nutrigenomic tests in the 2006 HealthStyles national survey (5250 respondents) and awareness among physicians in the 2006 DocStyles national survey (1250 respondents). RESULTS: In the HealthStyles survey, 14% of respondents were aware of nutrigenomic tests, and 0.6% overall had used these tests. Respondents who were aware of nutrigenomic tests tended to be young and educated with a high income. Many physicians (44%) were aware of nutrigenomic tests, although 41% of these physicians had never had a patient ask about such tests, and most (74%) had never discussed the results of a nutrigenomic test with a patient. CONCLUSIONS: These results provide insight into current trends in public demand and interest in nutrigenomic tests and will aid in assessing the impact of policies, efforts at public or provider education, and the evolution of the availability and demand for such tests. PMID- 17700390 TI - Assuring clinical genetic services for newborns identified through U.S. newborn screening programs. AB - PURPOSE: The study purpose was to determine whether U.S. newborn screening and/or genetics programs systematically document whether newborns and their families, identified with genetic disorders through newborn dried blood spot screening, receive clinical genetic services. METHODS: Nineteen state genetic plans were reviewed and a 30-question survey was administered to 53 respondents, including state newborn screening program coordinators and state genetics program coordinators in 36 states and principal investigators of 5 Health Resources and Services Administration-designated regional genetic and newborn screening collaboratives. RESULTS: Survey findings indicate that none of the state newborn screening and/or state genetics programs routinely tracked patient-level data on clinical genetic services for newborns identified with all of the genetic and congenital conditions for which their programs screened. Few programs could provide information systematically on whether patients were referred for, or received, genetic counseling. CONCLUSIONS: Systematic tracking of clinical genetic services for newborns identified by newborn screening programs is desirable and manageable. Recent national guidelines recommend tracking genetic counseling in newborn screening follow-up. The communications processes that state programs currently use to obtain follow-up reports from subspecialists could be augmented with clinical genetic service questions. Programs should be encouraged and supported in the efforts to track genetic services for the benefit of newborns and their families. PMID- 17700391 TI - The impact of genotype frequencies on the clinical validity of genomic profiling for predicting common chronic diseases. AB - PURPOSE: Single genetic variants in multifactorial disorders typically have small effects, so major increases in disease risk are expected only from the simultaneous exposure to multiple risk genotypes. We investigated the impact of genotype frequencies on the clinical discriminative accuracy for the simultaneous testing of 40 independent susceptibility genetic variants. METHODS: In separate simulation scenarios, we varied the genotype frequency from 1% to 50% and the odds ratio for each genetic variant from 1.1 to 2.0. Population size was 1 million and the population disease risk was 10%. Discriminative accuracy was quantified as the area under the receiver-operating characteristic curve. Using an example of genomic profiling for type 2 diabetes, we evaluated the area under the receiver-operating characteristic curve when the odds ratios and genotype frequencies varied between five postulated genetic variants. RESULTS: When the genotype frequency was 1%, none of the subjects carried more than six of 40 risk genotypes, and when risk genotypes were frequent (> or =30%), all carried at least six. The area under the receiver-operating characteristic curve did not increase above 0.70 when the odds ratios were modest (1.1 or 1.25), but higher genotype frequency increased the area under the receiver-operating characteristic curve from 0.57 to 0.82 and from 0.63 to 0.93 when odds ratios were 1.5 or 2.0. The example of type 2 diabetes showed that the area under the receiver-operating characteristic curve did not change when differences in the odds ratios were ignored. CONCLUSIONS: Given that the effects of susceptibility genes in complex diseases are small, the feasibility of future genomic profiling for predicting common diseases will depend substantially on the frequencies of the risk genotypes. PMID- 17700392 TI - Sylvian fissure morphology in Prader-Willi syndrome and early-onset morbid obesity. AB - PURPOSE: Prader-Willi syndrome is a well-defined genetic cause of childhood-onset obesity that can serve as a model for investigating early-onset childhood obesity. Individuals with Prader-Willi syndrome have speech and language impairments, suggesting possible involvement of the perisylvian region of the brain. Clinical observations suggest that many individuals with early-onset morbid obesity have similar speech/language deficits, indicating possible perisylvian involvement in these children as well. We hypothesized that similar perisylvian abnormalities may exist in both disorders. METHODS: Participants included individuals with Prader-Willi syndrome (n = 27), their siblings (n = 16), individuals with early-onset morbid obesity (n = 13), and their siblings (n = 10). Quantitative and qualitative assessments of sylvian fissure conformation, insula closure, and planum temporale length were performed blind to hemisphere and diagnosis. RESULTS: Quantitative measurements verified incomplete closure of the insula in individuals with Prader-Willi syndrome. Planar asymmetry showed its normal bias toward leftward asymmetry in all groups except those with Prader Willi syndrome maternal uniparental disomy. Individuals with Prader-Willi syndrome and siblings had a normal distribution of sylvian fissure types in both hemispheres, while individuals with early-onset morbid obesity and their siblings had a high proportion of rare sylvian fissures in the right hemisphere. CONCLUSIONS: The contrast between the anatomic findings in individuals with Prader-Willi syndrome and early-onset morbid obesity suggests that the language problems displayed by children with these two conditions may be associated with different neurodevelopmental processes. PMID- 17700393 TI - An autosomal recessive form of Alagille-like syndrome that is not linked to JAG1. AB - PURPOSE: Alagille syndrome is an autosomal dominant condition characterized by a paucity of interlobular bile ducts and chronic cholestasis, cardiac disease, skeletal abnormalities, ocular abnormalities, and characteristic facies. Most cases harbor a mutation in JAG1. We describe a large consanguineous family with five individuals affected with an Alagille-like syndrome that appears to be autosomal recessive. Our objective was to characterize the disorder clinically and determine whether affected individuals had inherited a mutation in JAG1. METHODS: Clinical data were obtained through questioning and patient chart review. Linkage analysis using microsatellite markers was used to assess the possibility of a JAG1 mutation. RESULTS: The clinical phenotype of patients was not entirely consistent with classic Alagille syndrome. All affected individuals had neonatal cholestasis with intrahepatic bile duct paucity, with three having pulmonary stenosis, but the presentation was unusually uniform and severe in childhood. There was no evidence of posterior embryotoxon or vertebral anomalies. Cardiac abnormalities were inconsistent between patients. Most significantly, the pedigree suggested an autosomal recessive form of inheritance. Linkage analysis excluded a mutation in JAG1. CONCLUSIONS: We have identified a kindred with an Alagille-like syndrome with an autosomal recessive form of inheritance not caused by a mutation in JAG1. PMID- 17700394 TI - Measurements of mechanical asynchrony in patients with heart failure: is the puzzle completed? AB - Numerous randomized clinical trials demonstrated the beneficial effects of cardiac resynchronization therapy (CRT) in the treatment of moderate to severe heart failure. Despite careful patient selection, there is still a percentage of non-responders, that is as high as 30-50%. Patients are selected mainly on electrocardiogram criteria. Recent studies have observed that the severity of mechanical systolic asynchrony is a much better predictor of a response after CRT. Echocardiography allows a non-invasive evaluation atrioventricular and inter and intraventricular synchrony; furthermore, recent advances have provided direct evidence of wall motion resynchronization in patients receiving CRT. Nevertheless, although many authors tried to search for the best echocardiographic index to identify systolic asynchrony, and consequently responders to CRT before the procedure, this issue is still a matter of debate. Our aim was to make an updated review of the more recent studies on this topic. PMID- 17700395 TI - Asymptomatic Wolff-Parkinson-White: what to do. Extensive ablation or not? PMID- 17700396 TI - Safety and efficacy of carvedilol in very elderly diabetic patients with heart failure. AB - OBJECTIVE: Beta-blockers are often cautiously prescribed to older heart failure diabetics because of the paucity of published data and their perceived unfavourable effects on glucose metabolism, in spite of the evidence of their effectiveness and safety in middle-aged diabetic patients. The aim of this study was to compare the safety, tolerability and efficacy of long-term administration of carvedilol in a group of elderly patients with chronic heart failure, with and without concomitant diabetes. METHODS: Two hundred and fifty-two patients aged > or =70 years with heart failure and left ventricular ejection fraction < or =40% were followed in specialised heart failure clinics. Diabetes was present in 29.7%. Carvedilol was associated with conventional optimised treatment in 64% of diabetics and 65% of non-diabetics (P = NS). RESULTS: At baseline, diabetics presented with a longer duration of symptoms, higher Charlson comorbidity index, more frequent renal dysfunction and smaller left ventricular volumes than non diabetics. New York Heart Association functional class and ejection fraction were similar in the two groups. At 1-year follow-up, tolerability (93.7 vs. 92.2%) and mean daily dose (24 +/- 17 vs. 23 +/- 14 mg/day) of carvedilol were similar in diabetics and non-diabetics. No worsening of fasting glucose, glycosylated haemoglobin and creatinine levels as well as the incidence of deaths and hospitalisations was observed in diabetics treated with carvedilol. Similar improvements in New York Heart Association class and mitral regurgitation severity were observed in diabetic and non-diabetic patients taking carvedilol. Ejection fraction showed a significant improvement, more pronounced in non diabetics than in diabetics (+10 vs. +7 points; improvement of at least 10 points: 15 vs. 36%, P = 0.03). CONCLUSIONS: Similarly to younger ones, also in older patients, diabetes does not negatively influence the safety, tolerability and efficacy of carvedilol. However, diabetes remains a strong prognostic factor limiting the reversibility of left ventricular systolic dysfunction and the effect of treatment on subsequent outcome. PMID- 17700398 TI - Cardiac magnetic resonance of healthy children and young adults with frequent premature ventricular complexes. AB - OBJECTIVE: To assess whether magnetic resonance imaging could detect any cardiac morphological or functional myocardial alterations in healthy children and young adults with ventricular arrhythmias. METHODS: Twenty-three subjects (14 male, mean age 15.6 +/- 6.5 years) with frequent (> or =30/h) premature ventricular complexes (PVCs) on Holter monitoring and normal echocardiographic and electrocardiographic findings underwent cardiac magnetic resonance (CMR) on a 1.5T scanner and an exercise stress test. Subjects were also followed up for a period of 71 +/- 24 months. RESULTS: CMR showed no evidence of structural cardiac abnormalities, but functional assessment revealed significant impairment in 17 subjects (74%): mild to moderate right ventricular enlargement was found in all of these subjects associated with a mild reduction of ventricular function in five cases (22%) and mild free wall and/or apex contraction abnormalities in eight subjects (35%). PVCs persisted during stress test in three subjects (13%) and disappeared in 19 (83%). No serious cardiac event was observed during the follow-up. CONCLUSIONS: Our study shows that subjects with PVCs without detectable electrocardiographic and echocardiographic abnormalities frequently exhibit functional impairment of the right ventricle at CMR, potentially responsible for ventricular arrhythmias. Although the causes of these abnormalities remain to be elucidated, the long-term outcome of these subjects is excellent. PMID- 17700397 TI - Baseline characteristics of patients recruited in the AREA IN-CHF study (Antiremodelling Effect of Aldosterone Receptors Blockade with Canrenone in Mild Chronic Heart Failure). AB - OBJECTIVE: Excess aldosterone activity contributes to the pathogenesis and progression of heart failure (HF). Aldosterone antagonists improve clinical outcome in patients with severe HF or left ventricular (LV) dysfunction after myocardial infarction, but knowledge of their impact in mild chronic HF is sparse. AREA IN-CHF was planned to investigate the effects of canrenone on progression of LV remodelling in mild HF. METHODS: AREA IN-CHF is a multicentre, randomised, double-blind, parallel group comparison of canrenone (up to 50 mg/day) versus placebo in mild stable HF. The primary endpoint is change in echocardiographic LV end-diastolic volume over 12 months. Patients had New York Heart Association class II HF, LV ejection fraction < or =45%, stable standard therapy, creatinine < or =2.5 mg/dl, potassium < or =5.0 mmol/l. Follow-up examinations were scheduled monthly for the first 3 months and every 3 months thereafter. Aldosterone was measured at baseline, brain natriuretic peptide and procollagen type III amino-terminal peptide (PIIINP) at baseline and at 6 months. Echocardiography was performed at baseline, at 6 and 12 months. RESULTS: Among 467 patients, median age 64 years (interquartile range (IQR) 56-70 years), 84% were men, 52% had ischaemic HF, 96% were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 79% beta-blockers. Brain natriuretic peptide, aldosterone and PIIINP were 88 pg/ml (IQR 35-185 pg/ml), 118 pg/ml (IQR 75-177 pg/ml), and 5.38 microg/l (IQR 3.98-7.14 microg/l), respectively. LV end diastolic volume was 79 ml/m (IQR 64-105 ml/m) and LV ejection fraction was 40% (IQR 33-45%). CONCLUSIONS: The role of aldosterone blockade in patients with mild HF remains to be established. AREA IN-CHF is addressing this issue in a large population on optimal medical therapy. PMID- 17700399 TI - Use of sirolimus-eluting stents for treatment of in-stent restenosis: long-term follow-up. AB - OBJECTIVES: The aims of this study were to assess (i) the feasibility, safety and efficacy of sirolimus-eluting stents (SESs) in treating in-stent restenosis (ISR), (ii) the risk factors for recurrent ISR, and (iii) the long-term major adverse cardiac events (MACE). METHODS: Between May 2002 and April 2004, 100 consecutive patients with evidence of myocardial ischaemia and 112 ISRs in native coronary arteries were treated using SESs. We evaluated the rate of procedural and clinical success, the incidence of in-hospital and long-term MACE, the recurrence rate of ISR after 6-8 months, and the risk factors for recurrent ISR and follow-up MACE. RESULTS: Forty-five percent of the lesions were directly stented. After stent implantation, the minimal lumen diameter increased from 0.51 +/- 0.32 to 2.50 +/- 0.32 mm in the stents and to 2.30 +/- 0.35 mm in the lesions (acute gain 1.99 +/- 0.37 mm). The procedural success rate was 99%. The clinical success rate was 88%. MACE occurred in 2.0% of patients during hospitalisation and in 12.8% after a median follow-up of 15.1 months (interquartile range 8.4 19.7). The recurrence rate of ISR was 11.8% after a median follow-up of 7.7 months (interquartile range 7.4-8.4). The risk for recurrent ISR was significantly higher in patients with diabetes or hypertension, in those aged more than 65 years and in female patients, as well as in the lesions with a small minimal lumen diameter. Three-vessel disease and age were risk factors for MACE. CONCLUSIONS: This study confirms the feasibility, safety and effectiveness of using SESs to treat ISR, and identifies a risk profile for recurrent ISR and MACE. PMID- 17700400 TI - Prevalence of conduction delay of the right atrium in patients with SSS: implications for pacing site selection. AB - OBJECTIVES: To evaluate the prevalence of severe right atrial conduction delay in patients with sinus node dysfunction (SND) and atrial fibrillation (AF) and the effects of pacing in the right atrial appendage (RAA) and in the inter-atrial septum (IAS). METHODS: Forty-two patients (15 male, 72 +/- 7 years) underwent electrophysiologic study to measure the difference between the conduction time from RAA to coronary sinus ostium during stimulation at 600 ms and after extrastimulus (DeltaCTos). Patients were classified as group A if DeltaCTos > 60 ms and group B if < 60 ms. Each Group was randomized to RAA/IAS pacing and algorithms ON/OFF. RESULTS: Fifteen patients (36%, group A) had DeltaCTos = 76 +/ 11 ms and 27 patients (64%, group B) had DeltaCTos = 36 +/- 20 ms. Twenty-two patients were paced at the RAA and 20 at the IAS. During the study, no AF recurrences were reported in 11 of 42 (26%) patients, independently of RAA or IAS pacing. Patients from group A and RAA pacing had 0.79 +/- 0.81 episodes of AF/day during DDD, which increased to 1.52 +/- 1.41 episodes of AF/day during DDDR + Alg (P = 0.046). Those with IAS pacing had 0.5 +/- 0.24 episodes of AF/day during DDD, which decreased to 0.06 +/- 0.08 episodes of AF/day during DDDR + Alg (P = 0.06). In group B, no differences were reported between pacing sites and pacing modes. CONCLUSIONS: Severe right atrial conduction delay is present in one-third of patients with SND and AF: continuous pacing at the IAS is superior to RAA for AF recurrences. In patients without severe conduction delay, no differences between pacing site or mode were observed. PMID- 17700401 TI - The obesity paradox and myocardial infarct size. AB - OBJECTIVE: Obese subjects have a risk of death from cardiovascular disease higher than those with normal body weight. Obese patients, however, have a better outcome when undergoing coronary revascularisation, and when suffering from heart failure or chronic kidney disease. The term 'obesity paradox' underlines the divergence between increased risk and better outcome in sick obese patients. We tested the hypothesis that the obesity paradox could also occur in myocardial infarction. METHODS: A group of 89 patients (mean age 62 +/- 11 years) with previous myocardial infarction (Q-wave in 72 patients) underwent contrast enhanced MRI. RESULTS: Areas of delayed contrast enhancement (which reflects myocardial necrosis) were present in 15 +/- 9% of left ventricular myocardium. Infarct size was not influenced by patient age, gender, history of arterial hypertension, hypercholesterolaemia, hypertriglyceridaemia nor tobacco smoking. Infarct size, however, was larger in insulin-dependent diabetic patients (P = 0.06) and in those with a family history of premature coronary artery disease (P = 0.06). Surprisingly, infarct size was smaller in obese patients (11 +/- 4% of left ventricular myocardium) than in those with normal body weight (16 +/- 9% of left ventricular myocardium, P = 0.03). Insulin-dependent diabetes mellitus, obesity and family history of coronary artery disease were the only independent predictors of infarct size at multiple linear regression analysis. CONCLUSIONS: Owing to its limitations (small sample size and exclusion of extremely obese patients), this study generates a working hypothesis, which should be tested in larger prospective studies, that the obesity paradox could also occur in myocardial infarction. PMID- 17700402 TI - Radiofrequency catheter ablation to cure atrial fibrillation: may be a wrong target. PMID- 17700403 TI - Left ventricular noncompaction or papillary muscle? PMID- 17700404 TI - Differential diagnoses and extracardiac manifestations in left ventricular noncompaction. PMID- 17700405 TI - Precordial murmur originating from pulmonary artero-venous malformation with and without pulmonary sequestration. AB - We report two cases of young patients in whom a continuous murmur was the only abnormal physical finding. The diagnosis was artero-venous malformation (AVM) in the context of pulmonary sequestration in the first patient and AVM alone in the second. The aim is to stress the perennial role of physical examination, the role of Doppler echocardiography and the importance of a multidisciplinary approach in the study of a pathological process involving the pulmonary vascular system. PMID- 17700406 TI - Large, unruptured, non-coronary sinus of Valsalva aneurysm. AB - We report the case of a 73-year-old previously fit man who presented with a 10 month history of worsening dyspnoea on exertion. Transthoracic echocardiography showed a mass in the right ventricle. The diagnosis of non-coronary sinus of Valsalva aneurysm was confirmed by cardiac magnetic resonance imaging. The patient underwent surgical removal of the aneurysm with uneventful recovery. Since this rare anomaly may arise from different aetiological backgrounds, it is important to consider this condition in the differential diagnosis and diagnostic process in order to deliver prompt, and potentially life-saving, treatment. PMID- 17700407 TI - Sine-wave pattern on the electrocardiogram and hyperkalaemia. AB - Hyperkalaemia is an electrolyte disturbance that can have effects on myocardial conduction causing electrocardiographic changes. Several factors may predispose to and promote potassium serum level increase leading to typical electrocardiographic abnormalities. We describe the case of a patient who presented with hyperkalaemia and an electrocardiographic aspect consistent with a sine-wave pattern. PMID- 17700408 TI - Catheter ablation of isolated premature ventricular contractions arising from the sinus of Valsalva. AB - Monomorphic premature ventricular contractions (PVCs) are a benign phenomenon in patients without structural heart disease. The focal source is usually localised in the right ventricular outflow tract and more rarely in the left ventricular outflow tract. We report two cases of frequent isolated PVCs treated with radiofrequency catheter ablation. Ventricular dysfunction was documented in one patient and the potential contribution of arrhythmia to ventricular dysfunction was suspected. In both patients electroanatomic mapping of the right and left ventricular outflow tracts was performed, which allowed identification of the earliest ventricular activation during PVCs. The site of the earliest ventricular activation was documented in both cases at the left coronary cusp of the aortic valve. Aortography was performed to disclose the relationship between the ablation catheter and the anatomic structure of the aortic root. PVCs were successfully eliminated with radiofrequency application in both patients. PMID- 17700409 TI - Acute myocardial infarction due to spontaneous coronary artery dissection treated with primary coronary angioplasty: a case report. AB - We report the case of a young woman referred to our hospital for anterior ST elevation myocardial infarction to be treated with primary coronary angioplasty. Angiography showed total dissection of the left anterior descending coronary artery, which was successfully treated with primary coronary angioplasty and multiple coronary stent implantation. Spontaneous coronary artery dissection is an unusual cause of acute coronary syndrome, which occurs more frequently in women with many pregnancies (our patient had eight sons before hospital admission for acute myocardial infarction). Although technically challenging, primary coronary angioplasty is a good strategy for treating coronary artery dissection. PMID- 17700410 TI - Intraoperative hypothermia increased defibrillation energy requirements. AB - We describe two patients with newly implanted automatic implantable cardioverter defibrillators that had excessive defibrillation thresholds associated with hypothermia at intraoperative defibrillation threshold testing. Normal defibrillation threshold levels were obtained during postoperative non-invasive electrophysiology testing in an electrophysiology laboratory when the patients were normothermic. We hypothesize that inadvertent intraoperative hypothermia during device implantation may increase the defibrillation threshold. PMID- 17700411 TI - Treatment of restenosis after bare-metal and drug-eluting stenting of an aorto ostial lesion: challenges associated with excessive stent overhang. AB - Percutaneous coronary interventions of ostial right coronary artery stenoses are associated with increased procedural complications as well as with higher rates of angiographic and clinical restenosis. Ideally, the ostium is treated by positioning the stent with a slight degree of overhang in the aorta to ensure coverage of the aorto-ostial junction. This can potentially complicate further intervention should restenosis occur. We report a case in which in-stent restenosis of an overhanging stent had been treated with an also overhanging sirolimus-coated Cypher stent (Cordis Corporation, Roden, The Netherlands). Late repeat restenosis was treated with a third (Taxus, Boston Scientific, Maple Grove, Minnesota, USA) stent that was deployed through the previously implanted stent struts. PMID- 17700413 TI - Relative adrenal insufficiency in severe congestive heart failure with preserved systolic function: a case report. AB - Relative adrenal insufficiency in critically ill patients is an important syndrome in septic shock. The insufficient stress response of the hypothalamic pituitary-adrenal axis in acute illness contributes to hemodynamic instability. Treatment of this state in septic shock improves patient outcomes. In this report, we describe the case of a patient with severe diastolic dysfunction who presented in cardiogenic shock associated with relative adrenal insufficiency and had a complete recovery with corticosteroid replacement. Alteration of the hypothalamic-pituitary-adrenal axis may be more prevalent than suspected in end stage heart failure, and the diagnosis and treatment of this syndrome may ultimately improve outcomes in a subgroup of heart failure patients. PMID- 17700412 TI - Treatment of refractory recurrent pericarditis. AB - We report a difficult case of a 45-year-old woman with refractory recurrent pericarditis, who was treated with several different medical therapies, pericardial window, and pericardiectomy. This case suggests that more invasive diagnostic and therapeutic choices, such as pericardial window and pericardiectomy, should be carefully considered for possible side-effects and the risk of promoting further recurrences. Non-steroidal anti-inflammatory drugs and colchicine are first-choice drugs, whereas corticosteroids should be considered only in patients with a frequent crisis unresponsive to non-steroidal anti inflammatory drugs, and by using proper dosage and a careful slow tapering. Patience and appropriate medical therapy are the keys to successful management. In true refractory cases, combination therapy with two or three drugs such as non steroidal anti-inflammatory drugs, colchicine and corticosteroid may be considered before applying other more complex and less safe treatments. Immunosuppressive drugs and steroid sparing agents might be used, but it should be acknowledged that only weak evidence-based data support their use. PMID- 17700414 TI - Diagnosis of idiopathic restrictive cardiomyopathy at a glance. PMID- 17700415 TI - A coronary right fistula canalized in a small accessory right atrial chamber. AB - The coronary artery fistulas are rare congenital anomalies with a very low incidence. These can be symptomatic or asymptomatic because the hemodynamic consequences of the fistula vary and depend on the shunt dimensions. Discordant opinions instead are present in the literature for the defect closing in asymptomatic patients. Here, we describe a patient affected by a coronary right fistula canalized in a small accessory right atrial chamber. During follow-up, we observed a progressive dilatation of the right coronary artery (maximum diameter 10.3 mm) with hemodynamic overload of the right sections. PMID- 17700416 TI - Pseudo-double aortic valve imaging caused by type A aortic dissection. PMID- 17700417 TI - Reply to 'Differential diagnoses and extracardiac manifestations in left ventricular noncompaction'. PMID- 17700418 TI - Reply to 'Left ventricular noncompaction or papillary muscle?'. PMID- 17700419 TI - Where have all the Helicobacters gone? PMID- 17700420 TI - Screening for hepatocellular carcinoma in clinical practice: miles to go before we sleep. PMID- 17700421 TI - Diet, gender, and colorectal neoplasia. AB - The association between diet and colorectal cancer has been studied in depth for many decades, with equivocal results. It has been hypothesized that cancers arising in the distal and proximal colon have different pathologies, and therefore different risk factors. As such, it is possible that diet-related factors might influence colorectal neoplasia differently depending on the subsite. Recent evidence indicates that women may be more likely to develop proximal cancers than men. Additionally, the link between certain dietary factors and colorectal neoplasia in women seems to vary by menopausal status. Given these observations, women may be affected differently than men by diet-related factors. The objective of this article was therefore to review the data for diet and colorectal adenomas and cancer, and then attempt to address the potential differences in the association of diet-related factors and colorectal neoplasia in men and women. For total energy intake, selenium, and fiber, it seems that there may be slightly stronger effects in men as compared with women, whereas calcium and folate seem to affect both sexes similarly. With regard to vitamin D and colorectal cancer, women may exhibit stronger associations than men. Perhaps the most evidence for a sex-specific effect is observed for obesity, where more substantial direct relationships between body size and colorectal neoplasia have been reported for men than for women. However, this observation may be influenced by the differential effects in women by menopausal status. Further research on sex-specific dietary effects is warranted. PMID- 17700422 TI - High Helicobacter pylori resistance rate to clarithromycin in Turkey. AB - GOALS: To assess the resistance of Helicobacter pylori to clarithromycin in Turkey. BACKGROUND: Recent studies have emphasized the remarkable reduction in H. pylori eradication rates. Resistance to clarithromycin is the most important factor affecting the success of H. pylori eradication therapies. STUDY: The study involved 110 consecutive adult dyspeptic patients infected with H. pylori. Resistance to clarithromycin was studied by real-time polymerase chain reaction method on gastric biopsy specimens. RESULTS: Of the 110 patients, 56 (50.9%) were male and mean age (+/-SD) was 45.1+/-13.1 years. Overall, 53 (48.2%) patients were found to be resistant to clarithromycin. Resistance to clarithromycin was not statistically associated with age, sex, previous macrolide use, residence (urban/rural), education status, and presence of peptic ulcer. CONCLUSIONS: The rate of resistance to clarithromycin was found to be markedly high. This result may explain the recently reported low success rates of H. pylori eradication therapies with clarithromycin. PMID- 17700423 TI - Detection rate of Helicobacter pylori against a background of atrophic gastritis and/or intestinal metaplasia. AB - BACKGROUND: To evaluate the detection rate of the CLOtest, Giemsa stain, and culture for the diagnosis of Helicobacter pylori organisms in patients with or without atrophic gastritis (AG) and/or intestinal metaplasia (IM). METHODS: We used either the CLOtest, Giemsa staining, or culture to determine the presence of H. pylori in 430 participants who were documented to be infected with H. pylori from September 2003 to June 2006. The detection rates of the methods were evaluated according to the presence of AG and IM in antrum and body, which were classified using the updated Sydney system classification. RESULTS: Positivity by the CLOtest markedly reduced depending on the degree of AG and IM in both antrum and body (P<0.05), and the positivity of Giemsa staining was markedly reduced as the degree of IM increased (P<0.01), but was not affected by the degree of AG (P=0.08) in antrum or body. When the results of these tests were evaluated in terms of combinations of AG and IM, the positivity of CLOtest was found to be lower in AG with IM than in AG without IM, (50.0% vs. 80.0% in antrum, 47.5% vs. 78.0% in body, respectively, P<0.01). In addition, the positivity of Giemsa stain was less frequent in AG with IM than in AG without IM in antrum (65.1% vs. 100%, respectively, P<0.01). However, the positivity of Giemsa stain in the body showed no statistical difference between AG without IM and AG with IM (97.6% vs. 91.7%, respectively). CONCLUSIONS: Invasive H. pylori tests, especially the CLOtest, had a lower detection rate for H. pylori in the presence of mucosal atrophy and IM, and this became more prominent in the presence of higher levels of IM and AG. PMID- 17700424 TI - Effect of Lactobacillus rhamnosus GG in persistent diarrhea in Indian children: a randomized controlled trial. AB - AIM: To evaluate the role of Lactobacillus rhamnosus GG (LGG) as probiotic in persistent diarrhea (PD) in children of North Bengal, India. SETTING: Hospital based study. DESIGN: Randomized, double-blind controlled trial. PATIENTS AND METHODS: All patients of PD admitted over a period of 2 years were included in the study as per predefined inclusion criteria. They were randomized to receive oral rehydration solution (ORS) alone, or ORS plus LGG powder containing 60 million cells, twice daily for a minimum period of 7 days or till diarrhea has stopped along with correction of dehydration with ORS and/or intravenous fluids as per WHO protocol and antibiotics in culture positive patients. The duration and frequency of purge and vomiting were studied. Data were analyzed by SPSS-10 software. Statistical significance was calculated by Student t test and chi2 test. RESULTS: The study comprised of 235 patients randomized into 2 groups, cases (117) and controls (118). Both the groups were similar with respect to age, number of breastfed infants, presentation with dehydration, degree of protein energy malnutrition, and distribution of infections. Stool culture was positive in 90 (38.3%) patients, Escherichia coli being the commonest organism followed by Shigella spp. and Clostridium difficile. The mean duration of diarrhea was significantly lower in the cases than in controls (5.3 vs. 9.2 d). The average duration of hospital stay was also significantly lesser in cases. No complication was observed from the dose of LGG used. CONCLUSIONS: LGG (dose of 60 million cells) could decrease the frequency and duration of diarrhea and vomiting and reduced hospital stay in patients of PD. PMID- 17700425 TI - Mechanisms of synergy between alcohol and hepatitis C virus. AB - BACKGROUND: Since the discovery of the hepatitis C virus (HCV), extensive literature has emerged on alcohol and HCV interaction. GOAL: To understand the impact of alcohol and HCV infection on the severity of liver disease and the mechanisms of interaction between the two. STUDY: Of 1269 articles (1991 to 2006) searched through MEDLINE and cited cross references, 133 were thoroughly reviewed to assess: (a) prevalence of combined alcohol use and HCV, (b) severity of liver disease (c) treatment response, and (d) mechanisms of interaction between HCV and alcohol. Data on study design, patient demographics, diagnostic tests used, and study outcomes were extracted for critical analysis. RESULTS: Prevalence of HCV is 3-fold to 30-fold higher in alcoholics compared with the general population. Patients with HCV infection and alcohol abuse develop more severe fibrosis with higher rate of cirrhosis and hepatocellular cancer compared with nondrinkers. Increased oxidative stress seems to be the dominant mechanism for this synergism between alcohol and the HCV. Abstinence is the key to the management of liver disease due to HCV and alcohol. Data have shown that lower response rates to interferon in alcoholics with HCV infection are likely due to noncompliance. CONCLUSIONS: Alcoholics with HCV infection have more severe liver disease compared with nondrinkers. Patients should be encouraged to enroll in rehabilitation programs so as to improve treatment adherence and response. PMID- 17700426 TI - Health-related quality of life, somatization, and abuse in Sphincter of Oddi dysfunction. AB - BACKGROUND: Most of the focus on patients with Sphincter of Oddi dysfunction (SOD) has centered on endoscopic management, and thus little is known about quality of life in these patients. AIMS: We sought to determine what health related quality of life components are troublesome to patients with SOD and compare to patients with recurrent pancreatitis. METHODS: Using the Brief Symptom Inventory and the SF-12 version 1, as well as proprietary questionnaires, we measured health-related quality of life in patients with biliary SOD and patients with recurrent idiopathic pancreatitis who underwent sphincter of Oddi manometry. RESULTS: Both groups had significantly worse quality of life than nonpatients and both groups somatized. Abuse histories were surprisingly common and similar between both groups. CONCLUSIONS: Health-related quality of life is impaired and abuse histories are common in SOD patients, and similar to patients with recurrent idiopathic pancreatitis. Whether these characteristics are predictors of healthcare seeking remains to be determined. PMID- 17700427 TI - Utilization of screening for hepatocellular carcinoma in the United States. AB - BACKGROUND: Screening for hepatocellular carcinoma (HCC) has been recommended for patients at high-risk of developing HCC. Yet, the utilization and determinants of screening remain unclear. METHODS: All patients diagnosed with HCC at 3 medical centers during 1998 to 2003 were identified. Information regarding receipt of HCC screening, demographics, risk factors, liver disease severity, number of HCC lesions, therapy, and date of death was abstracted from medical records. Multivariable logistic regression models were conducted to evaluate determinants of HCC screening and therapy. Cox proportional hazards models were developed to assess the effect of screening on risk of mortality. RESULTS: We identified 157 patients diagnosed with HCC. The majority of patients were <65 years (62%), white (59%), had a single mass (42%), and a Child-Pugh-Turcotte score B (41%). Approximately, 28% (n=44) received at least one possible screening test (36% alpha-fetoprotein only, 23% abdominal ultrasound only, 7% computed tomography only; 34% had more than one test). Screened patients were younger [odds ratio (OR)=2.70; 95% confidence interval (CI): 1.22-5.99) and were more likely to have underlying HCV (OR=2.91; 95% CI: 1.36-6.23), or alcoholic liver disease (OR=4.20; 95% CI: 1.89-9.35). The only predictors of receipt of therapy were presentation at tumor board conference (OR=2.85; 95% CI: 1.42-5.72) and documented referral to oncology (OR=2.33; 95% CI: 1.10-4.94). CONCLUSIONS: Less than one-third of patients who were diagnosed with HCC received screening before their diagnosis, and of those a large proportion received an alpha-fetoprotein test only. In this study, the use of screening was too suboptimal to be expected to affect outcomes. PMID- 17700428 TI - Detecting carcinoma cells in peripheral blood of patients with hepatocellular carcinoma by immunomagnetic beads and rt-PCR. AB - BACKGROUND: Increasing the sensitivity and specificity of detecting circulating carcinoma cells of patients with hepatocellular carcinoma (HCC) is very important for monitoring recurrence. GOAL: To establish a novel method of detecting circulating carcinoma cells. STUDY: For method development, 3 sets of controls using HCC cell line HepG2 cells were used. (A): Serial dilutions of HepG2 cells were directly used to extract total RNA for nested reverse transcription polymerase chain reaction (RT-PCR). (B): Five milliliter of healthy blood was spiked with a serial dilution of HepG2 cells and was used for Ficoll density gradient centrifugation to recover cells. The cells were used to extract total RNA for RT-PCR. (C): After cell recovery with the same procedure as B, the cells were sorted sequentially by CD45 and Ber-EP4 immunomagnetic beads and used for RNA extraction and RT-PCR. For clinical samples, 44 patients with HCC and 7 healthy subjects were included. The alpha-fetoprotein mRNA was amplified using nested RT-PCR technique. RESULTS: The spiking experiments using HepG2 cells showed that 10 cells in 5 mL blood could be detected by method C and an excellent dose-response to the number of spiked cells. Whereas, method B lacked any dose response and would yield high false-positive rates. In clinical samples, the improved method led to a positive detection rate of 52.9%, 76.9%, and 92.9% in Child-Plug class A, B, and C, respectively. There was significant difference between class A and class C (P<0.05). The total positive detection rate was 72.7%. CONCLUSIONS: Combining negative and positive immunomagnetic beads with RT PCR technique may improve the sensitivity and specificity of detecting circulating HCC cells. PMID- 17700429 TI - Detection of hepatic metastases from colorectal carcinoma: comparison of histopathologic features of anatomically resected liver with results of preoperative imaging. AB - GOALS: The specificity and sensitivity of intravenous-enhanced multidetector row computed tomography (MDCT), superparamagnetic iron oxide-enhanced magnetic resonance imaging (SPIO-MRI), multidetector row computed tomography with arterioportography combined with multidetector row computed tomography with hepatic arteriography (CTAP/CTHA), and intraoperative ultrasonography (IOUS) for detecting hepatic metastases from colorectal carcinoma were evaluated based on histopathologic examination of resected livers. STUDY: MDCT, SPIO-MRI, CTAP/CTHA, and IOUS were performed routinely to determine surgical indications and methods in patients with hepatic metastases from colorectal carcinoma. The resected liver specimens were then cut serially into sections 3 to 5 mm thick for routine histologic examination. RESULTS: Fifty metastatic lesions were detected by histopathologic study of a large amount of anatomically resected liver from 8 patients with colorectal liver metastasis. The tumors ranged in size from 3 to 53 mm (mean 13.8 mm) and 26 lesions (52%) were less than 10 mm in diameter. Histopathologic examination of the resected liver specimens showed that CTAP/CTHA was the most sensitive imaging modality, followed in order by IOUS, SPIO-MRI, and MDCT. Among all the tumors detected by CTAP/CTHA, SPIO-MRI overlooked 5, but all of the tumors detected by SPIO-MRI were also detected by CTAP/CTHA. The number of metastatic liver tumors detected differed significantly among MDCT, SPIO-MRI, and histopathologic examination. One false-positive lesion was detected by IOUS. CONCLUSIONS: CTAP/CTHA is a useful preoperative imaging modality for detecting small hepatic metastases from colorectal carcinoma. PMID- 17700430 TI - Effect of bone density on vertebral strength and stiffness after percutaneous vertebroplasty. AB - STUDY DESIGN: An ex vivo biomechanical study using cadaveric vertebral bodies. OBJECTIVE: To determine how bone mineral density (BMD) affects mechanical strength and stiffness of the vertebral body after vertebroplasty, and to determine how the association between mechanical properties and BMD varies with amount of cement injected. SUMMARY OF BACKGROUND DATA: Adverse events associated with vertebroplasty include cement leakage and adjacent fractures. Understanding effects of bone density and cement volume on mechanical properties may be important clinically to identify the minimum cement volume that will benefit the patient while minimizing risks of adverse events. METHODS: The bone mineral density of 13 vertebral columns from adult white female cadavers was measured with DEXA. Vertebral bodies (n = 126) were assigned to 5 groups based on cement treatment: intact, untreated, 4% fill, 12% fill, and 24% fill. Treated specimens were first loaded asymmetrically to simulate a wedge compression fracture before injection with polymethylmethacrylate cement. Strength and stiffness were measured in axial compression. RESULTS: Only the highest cement dose used (24% fill, 7 mL on average) had an effect on mechanical stiffness or strength. Within this group, stiffness was improved relative to untreated fractures but not restored to prefracture levels, and strength was enhanced beyond intact values. These improvements in stiffness and strength depended significantly on bone density, with highly osteoporotic samples benefitting the least. CONCLUSION: Results suggest that highly osteoporotic patients may receive the least amount of improvement in mechanical properties after vertebroplasty. It is recommended, therefore, that cement volume be restricted to the amount needed for fracture reduction only because there may be a limit to the mechanical benefits that additional cement can offer, depending on patient bone density. Understanding these limitations can potentially minimize risks of adverse events. PMID- 17700431 TI - Sprengel's deformity in Klippel-Feil syndrome. AB - STUDY DESIGN: A retrospective study. OBJECTIVES: To address the role of congenitally fused cervical segments, the degree of cervical scoliosis, and other risk factors on the presence of Sprengel's deformity (SD) in young patients with Klippel-Feil syndrome (KFS). SUMMARY OF BACKGROUND DATA: Numerous abnormalities are associated with KFS, one of the most common being SD. It has been postulated that more severe forms of KFS may be more associated with extraspinal manifestations, such as SD. METHODS: Thirty KFS patients from a single institution were reviewed. Cervical neutral lateral/dynamic/anteroposterior and thoracic anteroposterior plain radiographs were assessed. Radiographically, occipitalization (O-C1), number of congenitally fused segments (C1-T1), classification type (Types I-III), degree of cervical scoliosis, and the presence of SD was assessed. Clinical chart review entailed patient demographics and evidence of the clinical assessment of SD. The threshold for statistical significance was P < 0.05. RESULTS: There were 11 males (36.7%) and 19 females (63.3%) with a mean age of 13.5 years (range, 2.7-26.3 years). Occipitalization was present in 10 (33.3%) individuals and C2-C3 was the most common level fused (70.0%). The mean number of congenitally fused segments was 3.3 (range, 1-6 levels). The mean degree of cervical scoliosis was 17.3 degrees (range, 0 degrees 67 degrees). There were 6 (20%) Type I, 15 Type II (50.0%), and 9 Type III (30%) patients. SD was noted in 5 (16.7%) of the patients. Four patients had unilateral, whereas 1 patient had bilateral SD. There was 4.0 and 3.1 mean number of congenitally fused segments in patients with or without SD, respectively. SD did not occur in Type I patients (single fused block). The presence of SD was found to be nonsignificant regarding sex type (P = 0.327), presence of occipitalization (P = 0.300), number of congenitally fused segments (P = 0.246), specific congenitally fused segments (P > 0.05), classification type (P > 0.05), and scoliosis (P = 0.702). CONCLUSION: SD occurred in 16.7% of KFS patients. Sex type, number of congenitally fused segments, specific fused patterns, occipitalization, classification type, and the degree of cervical scoliosis did not seem to be significantly associated with the presence of SD in KFS patients in our series. Thorough examination for the presence and degree of SD in KFS is necessary, irrespective of the extent of cervical abnormalities. Alternatively, the treating physician should not dismiss a thorough cervical spine examination in patients with SD, evaluating factors that may predispose the KFS patient to an increased risk of neurologic injury. PMID- 17700432 TI - The use of multiple anchors for the treatment of idiopathic scoliosis. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: The purpose of this study was to determine the effectiveness of concave collar-button wires used as anchors to correct and maintain spinal alignment in adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Correction of idiopathic scoliotic deformity has been reported with various systems. We have added concave collar-button wires to a multihook, dual-rod system as an adjunct to translation and stabilization of the spine during correction of AIS. METHODS: Sixty-seven patients failing brace treatment or with curve patterns >45 degrees underwent spinal correction. Evaluation was obtained with preoperative standing posteroanterior, lateral, and recumbent right and left bending radiographs using the Cobb method. The initial postoperative films and latest radiographs were measured also. A dual-rod multihook construct with a derotation maneuver was used in all cases. Collar button wire implants were placed from the convex side of the deformity toward the concave rod through the base of the spinous processes within the construct to achieve and augment correction and stability. Twenty-four patients underwent prior anterior release and fusion by video assisted thoracoscopic surgery. RESULTS: Sixty-seven patients in total underwent this procedure. We achieved a 72.2% mean correction of thoracic curves and 63.2% mean correction of lumbar curves. There was a mean loss of correction of 2 degrees in the thoracic area and 2.2 degrees in the lumbar area after 2 years. Sagittal curve was unchanged after surgery. All patients demonstrated a solid fusion with no evidence of pseudarthrosis or junctional deformities. There were no cases of clinically significant wire breakage or hook pullout. Three delayed infections were noted. CONCLUSION: The use of multiple concave collar-button wires as anchors is a safe, easy, and reliable method of spinal stabilization in the coronal and sagittal planes. There is minimal loss of correction at long-term follow-up. PMID- 17700433 TI - Myelography using flat panel volumetric computed tomography: a comparative study in patients with lumbar spinal stenosis. AB - STUDY DESIGN: The technical feasibility of flat panel volumetric computed tomography (FPVCT) for lumbar myelographic imaging was evaluated in 20 patients and compared with multislice computed tomography (MSCT). OBJECTIVE: The purpose of this study was to determine the feasibility and sensitivity of FPVCT for myelographic imaging in lumbar spinal stenosis. SUMMARY AND BACKGROUND DATA: In the diagnosis of spinal stenosis, myelography and myelo-computed tomography (PCT) have been performed routinely for nearly 30 years. Rotational angiography is a new technique initially developed to visualize vessels but also allowing multiplanar reconstructed (MPR) CT images. The spatial resolution of FPCVT is even higher than in current MSCT. To date, this technique has not been evaluated for use in myelography. METHODS: In 20 patients referred for CT for evaluation of low back pain, lumbar myelography was performed on a biplane angiography system equipped with flat panel detectors. FPVCT was provided from a volume data set out of a rotational acquisition and compared with MSCT performed on a 4-slice CT scanner. Hereby, for a total of 100 disc levels (range from L1-L2 to L5-S1), the narrowest dural cross-sectional diameter (D-CSD) and the dural cross-sectional area (D-CSA) referred to MSCT and FPVCT were calculated. RESULTS: Mean D-CSD and C-CSA for all disc levels as measured by MSCT was 9.26 +/- 3.0 mm and 63.2 +/- 10.8 mm, respectively. Compared with D-CSD and C-CSA measured by FPVCT, there was no statistically significant difference (9.48 +/- 2.9 mm and 64.7 +/- 11.2 mm, respectively; P > 0.89). The most pronounced lumbar spinal stenosis was seen on L4/5 level with D-CSD of 6.6 +/- 3.6 mm and 6.8 +/- 3.2 mm and D-CSA of 53.7 +/- 14.7 mm and 55.0 +/- 14.3 mm, respectively. CONCLUSION: In all patients, the diagnostic quality of the reconstructed FPVCT slice images is comparable to those acquired by MSCT. Using FPVCT, radiographic myelography and postmyelographic computed tomography can be performed with less radiation in a single session at the same imaging system. PMID- 17700434 TI - Coeliac axis thrombosis after surgical correction of spinal deformity in type VI Ehlers-Danlos syndrome: a case report and review of the literature. AB - STUDY DESIGN: An unusual case of postoperative thrombosis of celiac artery in a patient of Type VI Ehlers-Danlos syndrome (EDS) with severe kyphotic deformity is reported. OBJECTIVE: To describe an unusual complication of celiac artery thrombosis following surgical correction of kyphotic deformity in Type VI EDS. SUMMARY OF BACKGROUND DATA: Neurologic deficit following surgical correction for kyphoscoliotic deformities in patients with Type VI has been reported in 4 cases previously. There has been no previous report of combined celiac artery thrombosis leading to infarction of major abdominal organs along with quadriparesis below C7-C8. METHODS: Case report and literature review. RESULTS: Subsequent to a 2-stage surgical correction with posterior instrumentation and fusion of spine, this patient with Type VI EDS developed celiac artery thrombosis leading to infarction of major abdominal organs. At laparotomy, he required hemihepatectomy, splenectomy, cholecystectomy, and a repair of gastric perforation. Following his abdominal catastrophe, he developed quadriparesis possibly due to anterior spinal artery ischemia. CONCLUSION: Spine surgeons treating Type VI EDS with progressive kyphoscoliosis should be aware of such an unusual complication of celiac artery occlusion in late postoperative period. Preoperative antithrombotic medication should be monitored carefully to avoid such catastrophic complication. The prognosis remains poor following anterior spinal artery ischemia due to infarction or thrombosis. PMID- 17700435 TI - Usefulness of 3-dimensional full-scale modeling for preoperative simulation of surgery in a patient with old unilateral cervical fracture-dislocation. AB - STUDY DESIGN: Case report. OBJECTIVE: We describe the usefulness of 3-dimensional full-scale modeling for preoperative simulation of surgery in a patient with old cervical fracture-dislocation. SUMMARY OF BACKGROUND DATA: Many different surgical procedures have been used in the treatment of unilateral cervical fracture-dislocation. However, consistent protocols and procedures for the surgical correction of old fracture-dislocations associated with nerve root lesions have not been established. METHODS: Two months after an automobile accident, a 50-year-old man developed symptoms of left C5 palsy. Four months after the accident, he was diagnosed with a fracture-dislocation at left C4-C5 facet with impingement of the left C5 root at the neural foramen. In addition, his left vertebral artery was completely occluded. Spontaneous bony fusion had progressed around the left facet and the anterior aspect of the vertebrae at C4 C5. Before surgery, a 3-dimensional full-scale model in the patient's cervical spine was made in order to simulate the planned surgical reconstruction. RESULTS: Through this simulation, we were able to accurately evaluate the deformed bony structures around the fractured C4-C5 facet. During the actual surgery, all the planned procedures were successfully achieved, including anterior release, insertion of pedicle screws at left C4 and C5, unroofing of the left C5 root, reduction of the displaced facet with the pedicle screw-rod system, and spinal fusion at C4-C5. After surgery, the patient's left C5 palsy was dramatically relieved and the spinal fusion went on to successful healing. CONCLUSION: The surgical simulation made possible by the 3-dimensional full-scale model appeared to simplify the surgical procedure and may enhance the safety of the complex spinal reconstruction. PMID- 17700437 TI - The ProDisc-C prosthesis: clinical and radiological experience 1 year after surgery. AB - STUDY DESIGN: This is a prospective randomized and controlled study, approved by the local ethical committee of Saarland (Germany). OBJECTIVE: The aim of the current study was to analyze segmental motion following artificial disc replacement using disc prosthesis over 1 year. A second aim was to compare both segmental motion as well as clinical result to the current gold standard (anterior cervical discectomy and fusion [ACDF]). SUMMARY OF BACKGROUND DATA: ACDF may be considered to be the gold standard for treatment of symptomatic degenerative disc disease within the cervical spine. However, fusion may result in progressive degeneration of the adjacent segments. Therefore, disc arthroplasty has been introduced. Among these, artificial disc replacement seems to be promising. However, segmental motion should be preserved. This, again, is very difficult to judge and has not yet been proven. METHODS: A total of 49 patients with cervical disc herniation were enrolled and assigned to either study group (receiving a disc prosthesis) or control group (receiving ACDF, using a cage with bone graft and an anterior plate). Roentgen stereometric analysis (RSA) was used to quantify intervertebral motion immediately as well as 3, 6, 12, 24, and 52 weeks after surgery. Also, clinical results were judged using visual analog scale and neuro-examination at even RSA follow-up. RESULTS: Cervical spine segmental motion decreased over time in the presence of disc prosthesis or fusion device. However, the loss segmental motion is significantly higher in the fusion group, when looked at 3, 6, 12, 24, and 52 weeks after surgery. We observed significant pain reduction in neck and arm after surgery, without significant difference between both groups. CONCLUSION: Cervical spine disc prosthesis remains cervical spine segmental motion within the first 1 year after surgery. The clinical results are the same when compared with the early results following ACDF. PMID- 17700438 TI - Cost-effectiveness of physical therapy and general practitioner care for sciatica. AB - STUDY DESIGN: An economic evaluation alongside a randomized clinical trial in primary care. A total of 135 patients were randomly allocated to physical therapy added to general practitioners' care (n = 67) or to general practitioners' care alone (n = 68). OBJECTIVE: To evaluate the cost-effectiveness of physical therapy and general practitioner care for patients with an acute lumbosacral radicular syndrome (LRS, also called sciatica) compared with general practitioner care only. SUMMARY OF BACKGROUND DATA: There is a lack of knowledge concerning the cost-effectiveness of physical therapy in patients with sciatica. METHODS: The clinical outcomes were global perceived effect and quality of life. The direct and indirect costs were measured by means of questionnaires. The follow-up period was 1 year. The Incremental Cost-effectiveness Ratio (ICER) between both study arms was constructed. Confidence intervals for the ICER were calculated using Fieller's method and using bootstrapping. RESULTS: There was a significant difference on perceived recovery at 1-year follow-up in favor of the physical therapy group. The additional physical therapy did not have an incremental effect on quality of life. At 1-year follow-up, the ICER for the total costs was 6224 euros (95% confidence interval, -10,419, 27,551) per improved patient gained. For direct costs only, the ICER was 837 euros (95% confidence interval, -731, 3186). CONCLUSION: The treatment of patients with LRS with physical therapy and general practitioners'care is not more cost-effective than general practitioners'care alone. PMID- 17700439 TI - Reduction of pain-related disability in working populations: a randomized intervention study of the effects of an educational booklet addressing psychosocial risk factors and screening workplaces for physical health hazards. AB - STUDY DESIGN: Cluster randomized controlled trial with 6 and 8 quarters of follow up. OBJECTIVE: To test the effects of giving evidence-based information addressing psychosocial risk factors for pain-related disability and of screening workplaces for physical health hazards at work on reducing new episodes and duration of pain-related and general absence taking. SUMMARY OF BACKGROUND DATA: The "flag strategy" for handling low back pain problems is recommended in many Western countries but, so far, randomized intervention studies addressing psychosocial risk factors for disability related to low back pain show mixed results. METHODS: We followed employees from 39 different work sites in western Denmark, who had received interventions consisting of either a carefully prepared booklet providing evidence-based information on common musculoskeletal pain problems alone or in combination with systematic workplace screening for physical work hazards. Absence due to pain for at least 7 days and the cumulative numbers of absence days were the main outcome measures. General absence taking was analyzed, too. Company registrations of sickness absence in combination with self report on the cause of a given absence spell was used to inform absence spells. RESULTS: A total of 3808 of 4006 eligible employees provided information. Among 1063 participants in the control arm, 1458 in the information arm, and 1287 in the information and workplace screening arm, 4.6%, 6.9%, and 4.6%, respectively, experienced pain-related absence, and 27.8%, 27.2%, and 24.0%, respectively, experienced general absence taking during follow-up. No positive effect on the risk of the 2 measures of absence or on the cumulative duration of absence among cases was seen. CONCLUSION: Results did not support population-based interventions addressing psychosocial risk factors for pain-related disability alone or in combination with workplace screening as effective in reducing the risk of pain-related absence taking or the duration of absence. PMID- 17700440 TI - Real-time direct measurement of spinal cord blood flow at the site of compression: relationship between blood flow recovery and motor deficiency in spinal cord injury. AB - STUDY DESIGN: An in vivo study to measure rat spinal cord blood flow in real-time at the site of compression using a newly developed device. OBJECTIVES: To evaluate the change in thoracic spinal cord blood flow by compression force and to clarify the association between blood flow recovery and motor deficiency after a spinal cord compression injury. SUMMARY OF BACKGROUND DATA: Until now, no real time measurement of spinal cord blood flow at the site of compression has been conducted. In addition, it has not been clearly determined whether blood flow recovery is related to motor function after a spinal cord injury. METHODS: Our blood flow measurement system was a combination of a noncontact type laser Doppler system and a spinal cord compression device. The rat thoracic spinal cord was exposed at the 11th vertebra and spinal cord blood flow at the site of compression was continuously measured before, during, and after the compression. The functioning of the animal's hind-limbs was evaluated by the Basso, Beattie and Bresnahan scoring scale and the frequency of voluntary standing. Histologic changes such as permeability of blood-spinal cord barrier, microglia proliferation, and apoptotic cell death were examined in compressed spinal cord tissue. RESULTS: The spinal blood flow decreased on each increase in the compression force. After applying a 5-g weight, the blood flow decreased to <40% of the precompression level. Complete ischemia was reached using a 20-g weight. After decompression, the blood flow level in the 20-minute complete ischemia group was significantly higher than that in the 40-minute complete ischemia group. The hind-limb motor function in the 40-minute complete ischemia group was significantly less than that in the sham group (without compression), while no significant difference was observed between the 20-minute ischemia group and the sham group. In the 20-minute ischemia group, the rats whose spinal cord blood flow recovery was incomplete showed significant motor function loss compared with rats that completely recovered blood flow. Extensive breakdown of blood-spinal cord barrier integrity and the following microglia proliferation and apoptotic cell death were detected in the 40-minute complete ischemia group. CONCLUSION: Duration of ischemia/compression and blood flow recovery of the spinal cord are important factors in the recovery of motor function after a spinal cord injury. PMID- 17700441 TI - Metal ion levels in patients with stainless steel spinal instrumentation. AB - STUDY DESIGN: Case-control study. OBJECTIVES: To determine whether metal ion concentrations are elevated in patients with spinal instrumentation. SUMMARY OF BACKGROUND DATA: Studies have shown that serum and urinary levels of component metal ions are abnormally elevated in patients with total joint arthroplasties. Little is known of metal ion release and concentrations in patients with spinal instrumentation. METHODS: The study group consisted of patients who had undergone spinal instrumentation for various spinal disorders with a variety of stainless steel implants, 5 to 25 years previously. A group of volunteers without metal implants were controls. All subjects were tested for serum nickel, blood chromium, and random urine chromium/creatinine ratio estimation. RESULTS: The study group consisted of 32 patients with retained implants and 12 patients whose implants had been removed. There were 26 unmatched controls. There was no difference in serum nickel and blood chromium levels between all 3 groups. The mean urinary chromium/creatinine ratio for patients with implants and those with implants removed was significantly greater than controls (P < 0.001). The difference between study subgroups was not significant (P = 0.16). Of several patient and instrumentation variables, only the number of couplings approached significance for correlation with the urine chromium excretion (P = 0.07). CONCLUSION: Spinal implants do not raise the levels of serum nickel and blood chromium. There is evidence that metal ions are released from spinal implants and excreted in urine. The excretion of chromium in patients with spinal implants was significantly greater than normal controls although lower where the implants have been removed. The findings are consistent with low-grade release of ions from implants with rapid clearance, thus maintaining normal serum levels. Levels of metal ions in the body fluids probably do not reach a level that causes late side effect; hence, routine removal of the implants cannot be recommended. PMID- 17700442 TI - Overexpressions of nerve growth factor and its tropomyosin-related kinase A receptor on chordoma cells. AB - STUDY DESIGN: Immunohistochemistry and in situ apoptosis detection assay were performed on chordoma and notochordal cells. OBJECTIVES: To investigate the expression levels of nerve growth factor (NGF) and its 2 receptors, tropomyosin related kinase A (TrkA) and p75, as well as proliferation potential and apoptosis indexes in chordoma and notochordal cells. SUMMARY OF BACKGROUND DATA: Chordomas arise from primitive notochordal remnants. Why these notochordal remnants undergo malignant transformation to chordoma remains unknown. The binding of NGF to the TrkA receptor promotes cell survival, while its binding to the p75 receptor triggers apoptosis. If there is simultaneous expression of both receptors, the effect of TrkA supersedes and the cells survive. METHODS: We examined 10 surgically obtained sacral chordoma tissue samples to determine the expressions of NGF and TrkA and p75 receptors as well as markers of cellular proliferation and apoptosis. As controls, we used notochordal cells of L4-L5 discs obtained from ten 1-month old rats. We quantified the expressions of NGF and TrkA and p75 receptors as well as markers of cellular proliferation and apoptosis for both groups, respectively. RESULTS: Chordoma and notochordal cells both expressed NGF as well as TrkA and p75 receptors. While the mean percentage of p75 receptor expression was very similar between chordoma and notochordal cells (P = 0.394), the mean percentages of TrkA and NGF expressions were significantly higher in chordoma cells than in notochordal cells (both P = 0.002). The mean proliferation potential index of chordoma cells was significantly higher than in notochordal cells (P < 0.01). Conversely, the mean apoptosis index of chordoma cells was significantly lower compared with that of notochordal cells (P = 0.03). CONCLUSION: The current results suggest that increased expressions of NGF and TrkA receptor in chordoma cells might be a possible mechanism of malignant transformation of notochordal remnants to chordoma by negating apoptotic signal of p75 receptor. PMID- 17700443 TI - Different effects of static versus cyclic compressive loading on rat intervertebral disc height and water loss in vitro. AB - STUDY DESIGN: In vitro biomechanical study on rat caudal motion segments to evaluate association between compressive loading and water content under static and cyclic conditions. OBJECTIVE: To test hypotheses: 1) there is no difference in height loss and fluid (volume) loss of discs loaded in compression under cyclic (0.15-1.0 MPa) and static conditions with the same root-mean-square (RMS) magnitudes (0.575 MPa); and 2) after initial disc bulge, tissue water loss is directly proportional to height loss under static loading. SUMMARY OF BACKGROUND DATA: Disc degeneration affects water content, elastic and viscoelastic behaviors. There is limited understanding of the association between transient water loss and viscoelastic creep in a controlled in vitro environment where inferences may be made regarding mechanisms of viscoelasticity. METHODS: A total of 126 caudal motion segments from 21 Wistar rats were tested in compression using 1 of 6 protocols: Static loading at 1.0 MPa for 9, 90, and 900 minutes, Cyclic loading at 0.15 to 1.0 MPa/1 Hz for 90 minutes, Mid-Static loading at 0.575 MPa for 90 minutes, and control. Water content was then measured in anulus and nucleus regions. RESULTS: Percent water loss was significantly greater in nucleus than anulus regions, suggesting some water redistribution, with average values under 1 MPa static loading of 23.0% and 14.9% after 90 minutes and 26.9% and 17.6% after 900 minutes, respectively. Cyclic loading resulted in significantly greater height loss (0.506 +/- 0.108 mm) than static loading with the same RMS value (0.402 +/- 0.096 mm), but not significantly less than static loading at peak value (0.539 +/- 0.122 mm). Significant and strong correlations were found between percent water loss and disc height loss, suggesting water was lost through volume decrease. CONCLUSION: Peak magnitude of cyclic compression and not RMS value was most important in determining height change and water loss, likely due to differences between disc creep and recovery rates. Water redistribution from nucleus to anulus occurred under loading consistent with an initial elastic compression (and associated disc bulge) followed by a reduction in disc volume over time. PMID- 17700444 TI - Laminoplasty and skip laminectomy for cervical compressive myelopathy: range of motion, postoperative neck pain, and surgical outcomes in a randomized prospective study. AB - STUDY DESIGN: A prospective randomized clinical trial in surgical treatment for cervical compressive myelopathy. OBJECTIVE: We prospectively compared modified laminoplasty and skip laminectomy in terms of surgical invasiveness, postoperative range of cervical motion, axial pain, and surgical outcomes. SUMMARY OF BACKGROUND DATA: Laminoplasty is an established procedure for the decompression of multisegmental cervical compressive myelopathy. However, it often induces postoperative problems, such as axial pain, restriction of neck motion, and loss of lordotic alignment. Skip laminectomy was recently developed as a minimally invasive procedure. METHODS: Forty-one patients with cervical spondylotic myelopathy (CSM), excluding developmental stenosis, were randomized to modified double-door laminoplasty (Lamino group; n = 21) or skip laminectomy (Skip group; n = 20), and followed for more than 1 year (average, 28.1 months). Of these patients, radiographs were taken in neutral, extension, and flexion positions before surgery and after surgery. The cervical alignment of C2-C7 curvature and range of motion (ROM) were calculated. After surgery patients were asked to rate their neck pain, using the visual analogue scale (VAS) periodically. Clinical outcomes were estimated with the Japanese Orthopedic Association scoring system (JOA score). RESULTS: There was no significant difference about operative time and blood loss between Lamino and Skip groups. The C2-C7 lordosis of neutral position in both groups was decreased by a few degrees at final follow-up. The final ROMs were 77.4/88.6% of preoperative ROM, respectively. At all collection times, no significant difference in VAS score of axial pain was seen in either group. There was no significant difference in JOA score between both groups before and after surgery. CONCLUSION: No significant differences were seen between Lamino and Skip groups, in terms of operative invasiveness, axial neck pain, cervical alignment, and ROM, and clinical results in the patients of CSM without developmental stenosis. PMID- 17700445 TI - Modified techniques to prevent sagittal imbalance after cervical arthroplasty. AB - STUDY DESIGN: Retrospective study of radiographic outcomes in patients undergoing single level cervical arthroplasty with the Bryan cervical disc (Medtronic Sofamor Danek, Memphis, TN). OBJECTIVE: This study was designed to determine whether modification of disc insertion angle and insertion depth are effective in preventing segmental or whole cervical kyphosis after arthroplasty. SUMMARY OF BACKGROUND DATA: Preservation of segmental motion and aggravation of kyphosis are known challenges after arthroplasty. However, there are currently no proven preventative factors for kyphosis. Change in disc insertion angle was only reported effective for avoiding endplate kyphosis. Additionally, it was difficult to predict the effect of insertion angle on overall sagittal alignment. There have been no studies regarding the correlation between insertion depth and sagittal alignment. METHODS: A total of 41 patients with single-level arthroplasty were evaluated. Radiologic assessment using neutral cervical radiographs at the long-term was performed. Linear regression analysis between insertion angle, insertion depth, postoperative sagittal alignment, functional spinal unit angle, and shell angle were performed. RESULTS: Disc insertion angle and insertion depth demonstrated significant negative correlation with the postoperative shell angle. Lordotic insertion angle and an anteriorly located disc led to lordosis in the shell angle. Overall sagittal alignment showed a tendency to correlate with insertion angle. By the result of effect of insertion angle ranging from 3.5 degrees to 7.5 degrees on the sagittal alignment and shell angle, we can hypothesize paradoxical biomechanical stress on the other segments. CONCLUSION: Arthroplasty using the Bryan disc provided a favorable clinical and radiologic outcome thus far; however, we should not underestimate emergent adverse outcomes. To prevent postoperative sagittal imbalance after cervical arthroplasty, intentional modification in disc insertion angle and depth would be helpful. Unexpected compensatory biomechanical loads should be elucidated in future studies. PMID- 17700446 TI - A minimum 10-year follow-up of posterior dynamic stabilization using Graf artificial ligament. AB - STUDY DESIGN: A retrospective long-term follow-up study. OBJECTIVES: To report minimum 10-year follow-up results of posterior dynamic stabilization using Graf artificial ligament and to evaluate the role and limitations of this procedure in the treatment of degenerative lumbar disorders. SUMMARY OF BACKGROUND: Motion preserving surgeries, including artificial disc replacement and ligamentoplasty, are increasingly gaining interest to avoid adverse effects of spinal fusion, but literature addressing long-term results is sparse. METHODS: A total of 56 consecutive patients who underwent Graf ligamentoplasty were reviewed at a minimum 10-year follow-up. Forty-three patients in the original cohort had sufficient clinical and radiographic follow-up for analysis. The pathologies included degenerative spondylolisthesis in 23 patients, disc herniation with flexion instability in 13 patients, spinal stenosis with flexion instability in 4 patients, and degenerative scoliosis in 3 patients. Single-level procedures were performed in 36 patients; multilevel procedures were performed in 7 patients. Radiographic and clinical assessments were performed before surgery and at the final follow-up. RESULTS: Disability due to low back pain and/or sciatic symptoms was significantly improved in the patients with degenerative spondylolisthesis or flexion instability. However, degenerative scoliosis and/or laterolisthesis were associated with poor clinical improvement. In radiographic assessment, segmental lordosis was maintained in 10.9 degrees, and flexion-extension motion was averaged 3.6 degrees at the final follow-up. Facet arthrodesis eventually occurred in 14 patients (32.6%) at an average of 82 months after surgery. Additional surgeries were required in 3 patients (7.0%) for adjacent segment pathologies. CONCLUSION: The long-term results showed that Graf ligamentoplasty is an effective treatment option for low-grade degenerative spondylolisthesis and flexion instability. However, this procedure has limitations to correct spinal deformity, and is not advocated for the treatment of degenerative scoliosis and laterolisthesis. PMID- 17700448 TI - Retrospective study on the development of spinal deformities following sternotomy for congenital heart disease. AB - STUDY DESIGN: Retrospective review with a minimum of 3 years of follow-up. OBJECTIVE: We hypothesize that following median sternotomy there may be an increase incidence of both sagittal and coronal spinal deformity. We also think that heart size and a cyanotic cardiac condition are also risk factors for development of spinal deformity. The purpose of this study was to determine the incidence and characteristics of spinal deformity in patients following sternotomy for congenital heart disease. SUMMARY OF BACKGROUND DATA: Patients with congenital heart disease are at an increased risk to develop scoliosis. METHODS: A total of 108 patients underwent a median sternotomy for the treatment of congenital heart disease and met inclusion criteria. The medical record was reviewed to gather demographic data and medical and surgical history. Serial chest and spine radiographs were reviewed. RESULTS: Scoliosis developed in 28% of the patients (10 males, 20 females). The mean follow-up was 13 years (range, 3-26 years). The mean coronal Cobb angle was 25 degrees (range, 11 degrees-88 degrees). Of these, 7 patients presented with curves of > or = 30 degrees. The mean age at diagnosis of scoliosis was 14 years (range, 2-33 years). A kyphotic deformity developed in 22% (24 patients). In patients with scoliosis, the mean sagittal kyphosis was 34 degrees (range, 2 degrees-73 degrees). Patients with a cyanotic cardiac condition had a trend toward severe scoliosis. There was no correlation between the development of scoliosis or kyphosis and the age at time of procedures, number of surgeries, gender, or heart size. CONCLUSION: The risk of developing scoliosis in children with congenital heart disease is more than 10 times that of idiopathic scoliosis. Spinal deformities, including scoliosis and/or kyphosis, were found in 34% of the patients. The sagittal alignment in scoliosis patients tends toward kyphosis. PMID- 17700449 TI - Back pain in the German adult population: prevalence, severity, and sociodemographic correlates in a multiregional survey. AB - STUDY DESIGN: A population-based cross-sectional multiregion postal survey. OBJECTIVE: To provide a descriptive epidemiology of the prevalence and severity of back pain in German adults and to analyze sociodemographic correlates for disabling back pain within and across regions. SUMMARY OF BACKGROUND DATA: Back pain is a leading health problem in Germany. However, comprehensive population based evidence on the severity of back pain is still fragmentary for this country. Despite earlier findings concerning large prevalence differences across regions, systematic explanations remain to be ascertained. METHODS: Questionnaire data were collected for 9263 subjects in 5 German cities and regions (population based random samples, postal questionnaire). Point, 1-year, and lifetime prevalence were assessed using direct questions, and graded back pain was determined using the Graded Chronic Pain Scale. Poststratification was applied to adjust for cross-regional sociodemographic differences. RESULTS: Point-prevalence was 37.1%, 1-year prevalence 76.0%, and lifetime prevalence 85.5%. A substantial minority had severe (Grade II, 8.0%) or disabling back pain (Grade III-IV, 11.2%). Subjects with a low educational level reported substantially more disabling back pain. This variable was an important predictor for large cross regional differences in the burden of back pain. CONCLUSION: Back pain is a highly prevalent condition in Germany. Disabling back pain in this country may be regarded as part of a social disadvantage syndrome. Educational level should receive greater attention in future cross-regional comparisons of back pain. PMID- 17700450 TI - Association of back pain frequency with mortality, coronary heart events, mobility, and quality of life in elderly women. AB - STUDY DESIGN: A 5-year observational cohort design using data from a randomized controlled trial of calcium intervention. OBJECTIVE: To describe the epidemiology of back pain and determine the association of back pain frequency to mortality, coronary heart events, mobility, and quality of life in elderly women. SUMMARY OF BACKGROUND DATA: Although back pain is a common physical symptom in the elderly, little is known of its effects and long-term outcomes. METHODS: The study subjects were 1484 community dwelling Australian women 70 to 85 years of age. At baseline and 5 years, back pain frequency was assessed by self-report, mobility by the Timed Up and Go Test (TUAG) and Quality of Life by the SF-36 questionnaire. The all cause of death data were ascertained from death certificates available for all deaths over 5 years, and incident clinical coronary heart disease (CHD) data were adjudicated from patient diaries verified by primary care physician and medication records. RESULTS: At baseline and 5 years, 21.7% and 26.9% subjects experienced daily back pain (> or = 1/day) and 27.6% and 24.4% subjects experienced frequent back pain (1/mo to 1/day), respectively. Compared with those with infrequent (< 1/mo) back pain, subjects with daily back pain had significantly lower quality of life physical component score and mobility as assessed by TUAG at both baseline and 5 years. Daily back was associated with greater overall mortality risk (hazards ratio = 2.03; 95% confidence interval, 1.14-3.60) and greater risk of CHD mortality and new CHD diagnosis (hazards ratio = 2.13; 95% CI, 1.35-3.34) after adjusted for baseline age. The effects remained significant after further adjustment for cardiovascular risk factors and physical activity level. CONCLUSION: Daily back pain is associated with reduced quality of life, mobility and longevity and increased risk of coronary heart events. The adverse health effects of chronic back pain deserve greater recognition. PMID- 17700452 TI - Significantly improved lumbar arthroplasty placement using image guidance: technical note. AB - STUDY DESIGN: Technical report. OBJECTIVE: To compare the accuracy of lumbar total disc arthroplasty placement using an image-guidance system (IGS) with conventional fluoroscopy. SUMMARY OF BACKGROUND DATA: Most disc arthroplasties are inserted and analyzed using fluoroscopy. One previous cadaveric study demonstrated beneficial, but insignificant, effects of IGS on total disc arthroplasty placement compared with conventional fluoroscopy. METHODS: Patients were considered for lumbar total disc arthroplasty who had chronic discogenic low back pain unresponsive to nonoperative management for at least 6 months. Total disc arthroplasty was performed in n = 6 with IGS and in n = 14 without IGS. Implant placement was analyzed after surgery using computer software on high resolution CT with respect to 3 parameters: 1) off-center mal-placement, 2) axial rotational mal-placement, and 3) coronal tilt. RESULTS: Arthroplasties inserted with IGS were positioned with significantly greater accuracy than non-IGS arthroplasties with respect to all 3 parameters measured (off-center: 1.1 +/- 0.3 vs. 2.3 +/- 0.3 mm, P = 0.031; rotation: 88.8 degrees +/- 0.2 degrees vs. 87.1 degrees +/- 0.4 degrees; P = 0.0084; and tilt: 1.0 degrees +/- 0.5 degrees vs. 2.6 degrees +/- 0.3 degrees, P = 0.01). There was no significant difference in operating time between non-IGS controls (123 +/- 5 minutes) and IGS (139 +/- 10 minutes) groups (P = 0.129). CONCLUSION: This is the first clinical study to demonstrate significantly improved accuracy of lumbar total disc arthroplasty placement on CT using IGS compared with conventional fluoroscopy. IGS should be considered for routine use with lumbar total disc arthroplasty insertion. PMID- 17700451 TI - What is different about workers' compensation patients? Socioeconomic predictors of baseline disability status among patients with lumbar radiculopathy. AB - STUDY DESIGN: Combined analysis of 2 prospective clinical studies. OBJECTIVE: To identify socioeconomic characteristics associated with workers' compensation in patients with an intervertebral disc herniation (IDH) or spinal stenosis (SpS). SUMMARY OF BACKGROUND DATA: Few studies have compared socioeconomic differences between those receiving or not receiving workers' compensation with the same underlying clinical conditions. METHODS: Patients were identified from the Spine Patient Outcomes Research Trial (SPORT) and the National Spine Network (NSN) practice-based outcomes study. Patients with IDH and SpS within NSN were identified satisfying SPORT eligibility criteria. Information on disability and work status at baseline evaluation was used to categorize patients into 3 groups: workers' compensation, other disability compensation, or work-eligible controls. Enrollment rates of patients with disability in a clinical efficacy trial (SPORT) and practice-based network (NSN) were compared. Independent socioeconomic predictors of baseline workers' compensation status were identified in multivariate logistic regression models controlling for clinical condition, study cohort, and initial treatment designation. RESULTS: Among 3759 eligible patients (1480 in SPORT and 2279 in NSN), 564 (15%) were receiving workers' compensation, 317 (8%) were receiving other disability compensation, and 2878 (77%) were controls. Patients receiving workers' compensation were less common in SPORT than NSN (9.2% vs. 18.8%, P < 0.001), but patients receiving other disability compensation were similarly represented (8.9% vs. 7.7%, P = 0.19). In univariate analyses, many socioeconomic characteristics significantly differed according to baseline workers' compensation status. In multiple logistic regression analyses, gender, educational level, work characteristics, legal action, and expectations about ability to work without surgery were independently associated with receiving workers' compensation. CONCLUSION: Clinical trials involving conditions commonly seen in patients with workers' compensation may need special efforts to ensure adequate representation. Socioeconomic characteristics markedly differed between patients receiving and not receiving workers' compensation. Identifying the independent effects of workers' compensation on outcomes will require controlling for these baseline characteristics and other clinical features associated with disability status. PMID- 17700453 TI - A review of 1985 Volvo Award winner in clinical science: objective assessment of spine function following industrial injury: a prospective study with comparison group and 1-year follow-up. AB - It is now 2 decades since Mayer et al published their Volvo Award-winning paper entitled "Objective assessment of spine function following industrial injury: a prospective study with comparison group and one-year follow-up." Their landmark paper reported that return to work rates of patients that underwent a "functional restoration" treatment program were double that of a comparative group of patients that were denied treatment by their insurers. These results were considered extraordinary and inspired both debate and enthusiasm. Our goal is to review this landmark study, report on its strengths and weaknesses, and review the studies that have attempted to replicate this work in other settings. We also highlight its contribution to our current knowledge about the treatment of back pain and disability. The major weaknesses of the paper of Mayer et al are the possibility of selection bias in the development of their cohort of patients and the lack of a true randomized controlled study design. These factors may have inflated the rates of return to work. Regardless, their reported results were robust, and cannot be easily dismissed. During the last 20 years, this treatment model has received considerable study worldwide, and it is generally agreed that it is superior to standard care for reducing work absence in patients with chronic low back pain. Additionally, the concepts underlying functional restoration have been found to be highly relevant to patients with chronic low back pain, medical providers, and disability systems and continue to gain acceptance and integration into the care of patients throughout the industrialized world. PMID- 17700454 TI - Re: Kolstad F, Nygaard OP, Leivseth G. Segmental motion adjacent to anterior cervical arthrodesis: a prospective study. Spine 2007;32:512-7. PMID- 17700455 TI - Re: Kolstad F, Nygaard OP, Leivseth G. Segmental motion adjacent to anterior cervical arthrodesis: a prospective study. Spine 2007;32:512-7. PMID- 17700456 TI - Re: Gazzeri R, Galarza M, Neroni M, et al. Fulminating septicemia secondary to oxygen-ozone therapy for lumbar disc herniation: case report. Spine 2007;32:E121 3. PMID- 17700457 TI - Re: Gazzeri R, Galarza M, Neroni M, et al. Fulminating septicemia secondary to oxygen-ozone therapy for lumbar disc herniation: case report. Spine 2007;32:E121 3. PMID- 17700504 TI - Endometrial cancer. Recognizing signs, understanding risks. PMID- 17700502 TI - Cutaneous and hemodynamic responses during hot flashes in symptomatic postmenopausal women. AB - OBJECTIVE: The aim of this study was to test the hypothesis that the postmenopausal hot flash is accompanied by rapid decreases in arterial blood pressure and increases in cutaneous vascular conductance (CVC), as evaluated by continuous measurements of these variables in symptomatic women. DESIGN: Twelve healthy, normotensive, postmenopausal women rested in a temperature-controlled laboratory (26 degrees C) for approximately 90 minutes. The onset of a hot flash was objectively identified as a transient and pronounced elevation of sternal sweat rate (capacitance hygrometry). RESULTS: Twenty-three hot flashes were recorded during the experimental sessions (3.4 +/- 1.4 min; range, 1.3-6.5 min). Mean arterial blood pressure decreased 13 +/- 2 mm Hg during 11 hot flashes in five participants. Data from these participants, categorized as responders, were analyzed separately from data for those participants whose blood pressure did not change during their hot flashes (n = 7, 12 hot flashes). Heart rate (obtained from an electrocardiogram) significantly increased during the hot flashes, but there was no difference between the responder and nonresponder groups (9 +/- 2 vs 10 +/- 1 beats/min, respectively; P > 0.05). The increase in CVC was not different between groups at either the forearm (15% +/- 3% vs 12% +/- 3% maximal CVC, P > 0.05) or sternum (24% +/- 5% vs 21% +/- 3% maximal CVC, P > 0.05). CONCLUSIONS: These data demonstrate that in a subset of participants, the hot flash is accompanied by a significant reduction in blood pressure, but there is no difference in CVC between these women and women with no drop in blood pressure. PMID- 17700505 TI - Study stirs debate about treatment of stable angina. PMID- 17700506 TI - Community screenings. Know their limitations. PMID- 17700507 TI - Mayo Clinic office visit. LASIK eye surgery. An interview with Leo Maguire, M.D. PMID- 17700508 TI - Put on your dancing shoes. Get fit and have fun. PMID- 17700510 TI - My friend says I should get a CA 125 test to check for ovarian cancer. Should I have this test done? PMID- 17700509 TI - How often should I have my bone density tested? PMID- 17700511 TI - Dexamethasone modulates interleukin-12 production by inducing monocyte chemoattractant protein-1 in human dendritic cells. AB - Glucocorticoids have long been used as first-line immunosuppressants, although their precise mechanism of action has not been fully elucidated yet. This study evaluated the gene and protein expression of monocyte chemoattractant protein-1 (MCP-1), and its relationship with interleukin-12 and interleukin-10 synthesis, in human monocyte-derived dendritic cells exposed to dexamethasone. Dendritic cells were differentiated in the presence or in the absence of dexamethasone and then activated by IFN-gamma+soluble CD40 ligand; the gene and protein expression of target cytokines was measured by real-time PCR and ELISA, respectively. Our results showed that dexamethasone-primed mature dendritic cells expressed low levels of interleukin-12, and, at the opposite, high levels of interleukin-10 and MCP-1. Transfection experiments confirmed the ability of dexamethasone to activate MCP-1 gene promoter. Dexamethasone increased also MCP-2, but not MCP-3 synthesis, and the gene expression of CC chemokine receptor-2 by mature dendritic cells. The addition of anti-MCP-1 blocking antibody depressed MCP-1 release, and increased interleukin-12 production in dexamethasone-treated dendritic cells, thus demonstrating that interleukin-12 downregulation is largely dependent on MCP 1 overexpression. Our findings suggest that the induction of MCP expression in human dendritic cells by dexamethasone, and the amplification of cell response via the upregulation of the chemokine cognate receptor, may be critical to inhibit type 1 T-helper-biased immune response and, possibly, to favor type 2 T helper-skewed response. PMID- 17700512 TI - 'Brain death': should it be reconsidered? AB - OBJECTIVE: To evaluate whether current clinical criteria and confirmatory tests for the diagnosis of 'brain death' satisfy the requirements for the irreversible cessation of all functions of the entire brain including the brainstem. DATA SOURCES: Medical, philosophical and legal literature on the subject of 'brain death'. DATA EXTRACTION/SYNTHESIS: We present four arguments to support the view that patients who meet the current operational criteria of 'brain death' do not necessarily have the irreversible loss of all brain (or brainstem) functions. First, many clinically 'brain-dead' patients maintain residual vegetative functions that are mediated or coordinated by the brain or the brainstem. Second, it is impossible to test for any cerebral function by clinical bedside exam, because the tracts of passage to and from the cerebrum through the brainstem are destroyed or nonfunctional. Furthermore, since there are limitations of clinical assessment of internal awareness in patients who otherwise lack the motor function to show their awareness, the diagnosis of 'brain death' is based on an unproved hypothesis. Third, many patients maintain several stereotyped movements (the so-called complex spinal cord responses and automatisms) which may originate in the brainstem. Fourth, not one of the current confirmatory tests has the necessary positive predictive value for the reliable pronouncement of human death. CONCLUSION: According to the above arguments, the assumption that all functions of the entire brain (or those of the brainstem) in 'brain-dead' patients have ceased, is invalidated. Reconsideration of the current concept of 'brain death' is perhaps inevitable. PMID- 17700513 TI - A novel technique to achieve cutaneous continent urinary diversion in spinal cord injured patients unable to catheterize through native urethra. AB - STUDY DESIGN: Description of a technique and prospective follow-up study. OBJECTIVES: To present and assess a perioperative strategy associated with a single-procedure surgical technique for continent cutaneous diversion in spinal cord injury (SCI) patients requiring self-catheterization and unable to do it through the native urethra. SETTING: University hospital, Paris, France. METHODS: We considered SCI patients suffering from urinary incontinence related to neurogenic detrusor overactivity and/or poor bladder emptying for more than 1 year and inability to perform self-catheterization through the native urethra. These patients including quadriplegics underwent selection for surgery by occupational therapists and neurorehabs to assess the ability to self catheterize through an abdominal stoma and to determine the optimal site to place the stoma. The surgical technique included a single procedure: aponevrotic sling in women requiring stress continence reinforcement, supratrigonal cystectomy, preserved detrusor wall flap (original description), enterocystoplasty, a catheterizable tube using either the Mitrofanoff or Young-Monti principle and Politano Leadbetter anti-reflux technique. A prospective follow-up study of consecutive patients reviewed initial condition, indication, surgical technique, complications, continence, catheterizing difficulties, functional bladder capacity and serum creatinine. RESULTS: Thirteen consecutive patients were selected for surgery. Median follow-up was 44 months. Stoma location was variable from one patient to another. All patients had a catheterizable continent stoma at last follow-up. Kidney function was preserved. CONCLUSION: Given these results, a multidisciplinary approach including neuro-rehabilitation practitioners and urologists performing appropriate technical solutions in highly selected SCI patients unable to catheterize native urethra provides upper urinary tract protection and continence after a single procedure. PMID- 17700515 TI - Vagus nerve stimulation, depression, and inflammation. PMID- 17700514 TI - An animal model of functional electrical stimulation: evidence that the central nervous system modulates the consequences of training. AB - STUDY DESIGN: Review of how spinal neurons can modulate the consequences of functional electrical stimulation (FES) in an animal model. METHODS: Spinal effects of FES are examined in male Sprague-Dawley rats transected at the second thoracic vertebra. The rats are exposed to FES training 24-48 h after surgery. Experimental manipulations of stimulation parameters, combined with physiological and pharmacological procedures, are used to examine the potential role of spinal neurons. RESULTS: The isolated spinal cord is inherently capable of learning the response-outcome relations imposed in FES training contingencies. Adaptive behavioral modifications are observed when an outcome (electrical stimulation) is contingent on a behavioral response. In contrast, a lack of correlation between the response and outcome in training produces a learning deficit in the spinal cord, rendering it incapable of adaptive learning for up to 48 h. The N-methyl-D aspartic acid receptor appears to mediate both the adaptive plasticity and loss of plasticity, seen in this spinal model. CONCLUSION: The behavioral effects observed with FES therapies are not simply due to the direct (motor) consequences of stimulation elicited by the activation of efferent motor neurons and/or selected muscles. FES training has the capacity to shape inherent spinal circuits and to produce a long-lasting behavioral modification. Further understanding of the spinal mechanisms underlying adaptive behavioral modification will be integral for establishing functional neural connections in a regenerating spinal system. PMID- 17700517 TI - G1 to S phase transition protein 1 induces apoptosis signal-regulating kinase 1 activation by dissociating 14-3-3 from ASK1. AB - Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase kinase kinase family, plays a critical role in mediating apoptosis signals initiated by a variety of death stimuli such as hydrogen peroxide and tumor necrosis factor-alpha. Owing to its critical role in inducing apoptosis, the activity of ASK1 is tightly regulated by various mechanisms such as post translational modifications and protein-protein interactions. Here we describe the identification of G(1) to S phase transition protein 1 (GSPT1), which is associated with protein translation, as a regulator of ASK1. GSPT1 interacts with ASK1 and enhances ASK1-induced apoptotic activity through the activation of caspase-3. In vitro kinase assay data show that GSPT1 enhances ASK1 autophosphorylation and its kinase activity. Cell cycle-dependent GSPT1 induction and small interfering RNA analyses show that ASK1 autophosphorylation is dependent on the expression level of endogenous GSPT1 in cells. GSPT1 inhibits the binding of ASK1 to the 14-3-3 protein, an ASK1 inhibitor, while GSPT1 has no effect on the interaction between ASK1 and TRAF2, a C-terminal-binding activator of ASK1. Thus, our results reveal a novel role of GSPT1 in the regulation of ASK1 mediated apoptosis. PMID- 17700518 TI - The PEA-15/PED protein protects glioblastoma cells from glucose deprivation induced apoptosis via the ERK/MAP kinase pathway. AB - PEA-15 (phosphoprotein enriched in astrocytes 15 kDa) is a death effector domain containing protein, which is involved in the regulation of apoptotic cell death. Since PEA-15 is highly expressed in cells of glial origin, we studied the role of PEA-15 in human malignant brain tumors. Immunohistochemical analysis of PEA-15 expression shows strong immunoreactivity in astrocytomas and glioblastomas. Phosphorylation of PEA-15 at Ser(116) is found in vivo in perinecrotic areas in glioblastomas and in vitro after glucose deprivation of glioblastoma cells. Overexpression of PEA-15 induces a marked resistance against glucose deprivation induced apoptosis, whereas small interfering RNA (siRNA)-mediated downregulation of endogenous PEA-15 results in the sensitization to glucose withdrawal-mediated cell death. This antiapoptotic activity of PEA-15 under low glucose conditions depends on its phosphorylation at Ser(116). Moreover, siRNA-mediated knockdown of PEA-15 abolishes the tumorigenicity of U87MG glioblastoma cells in vivo. PEA-15 regulates the level of phosphorylated extracellular-regulated kinase (ERK)1/2 in glioblastoma cells and the PEA-15-dependent protection from glucose deprivation induced cell death requires ERK1/2 signaling. PEA-15 transcriptionally upregulates the Glucose Transporter 3, which is abrogated by the inhibition of ERK1/2 phosphorylation. Taken together, our findings suggest that Ser(116) phosphorylated PEA-15 renders glioma cells resistant to glucose deprivation mediated cell death as encountered in poor microenvironments, for example in perinecrotic areas of glioblastomas. PMID- 17700519 TI - A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D. AB - The PPM1D gene is aberrantly amplified in a range of common cancers and encodes a protein phosphatase that is a potential therapeutic target. However, the issue of whether inhibition of PPM1D in human tumour cells that overexpress this protein compromises their viability has not yet been fully addressed. We show here, using an RNA interference (RNAi) approach, that inhibition of PPM1D can indeed reduce the viability of human tumour cells and that this effect is selective; tumour cell lines that overexpress PPM1D are sensitive to PPM1D inhibition whereas cell lines with normal levels are not. Loss of viability associated with PPM1D RNAi in human tumour cells occurs via the activation of the kinase P38. To identify chemical inhibitors of PPM1D, a high-throughput screening of a library of small molecules was performed. This strategy successfully identified a compound that selectively reduces viability of human tumour cell lines that overexpress PPM1D. As expected of a specific inhibitor, the toxicity to PPM1D overexpressing cell lines after inhibitor treatment is P38 dependent. These results further validate PPM1D as a therapeutic target and identify a proof-of-principle small molecule inhibitor. PMID- 17700520 TI - ATF-2 controls transcription of Maspin and GADD45 alpha genes independently from p53 to suppress mammary tumors. AB - The activating transcription factor, ATF-2, is a target of p38 and JNK that are involved in stress-induced apoptosis. Heterozygous Atf-2 mutant (Atf-2+/-) mice are highly prone to mammary tumors. The apoptosis-regulated gene GADD45alpha and the breast cancer suppressor gene Maspin, both of which are known to be p53 target genes, are downregulated in the mammary tumors arisen in Atf-2+/- mice. Here, we have analysed how ATF-2 controls the transcription of GADD45alpha and Maspin. ATF-2 and p53 independently activate the GADD45alpha transcription. ATF-2 does not directly bind to the GADD45alpha promoter; instead, it is recruited via Oct-1 and NF-I. ATF-2 simultaneously binds to Oct-1, NF-I and breast cancer suppressor BRCA1 to activate transcription. With regard to Maspin, ATF-2 and p53 directly bind to different sites in the Maspin promoter to independently activate its transcription. Consistent with the observation that ATF-2 and p53 independently activate the transcription of Maspin and GADD45alpha is that the loss of one copy of p53 shortened the period required for mammary tumor development in Atf-2+/- mice. These studies suggest the functional link between the ATF-2 and the two tumor suppressors BRCA1 and p53. PMID- 17700521 TI - Forced expression of a constitutively active form of Stat3 in mouse epidermis enhances malignant progression of skin tumors induced by two-stage carcinogenesis. AB - Recently, our laboratory demonstrated that Stat3 is required for the de novo development of chemically-induced skin tumors. We have further investigated the role of Stat3 in epithelial carcinogenesis using mice in which the expression of a constitutively active/dimerized form of Stat3 (Stat3C) is targeted to the proliferative compartment of epidermis (referred to as K5.Stat3C transgenic mice). Keratinocytes from K5.Stat3C mice showed increased survival following exposure to 7,12-dimethylbenz[a]anthracene (DMBA) and enhanced proliferation following exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA). In two-stage chemical carcinogenesis experiments using DMBA as the tumor initiator and TPA as the promoter, K5.Stat3C mice developed skin tumors with a shorter latency and in much greater number compared to non-transgenic littermates. Remarkably, 100% of the skin tumors that developed in K5.Stat3C transgenic mice bypassed the premalignant stage and were initially diagnosed as carcinoma in situ which rapidly progressed to squamous cell carcinoma (SCC). These tumors were highly vascularized, poorly differentiated and invasive and loss of expression of K10, filaggrin and E-cadherin was observed by 20 weeks. Finally, overexpression of Stat3C in a papilloma cell line led to enhanced cell migration and enhanced invasion through Matrigel in both the absence and presence of growth factors. In addition to its critical role in early stages of epithelial carcinogenesis, the current study reveals a novel role for Stat3 in driving malignant progression of skin tumors in vivo. PMID- 17700522 TI - Oncogenic pathways impinging on the G2-restriction point. AB - In the absence of mitogenic stimuli, cells normally arrest in G(1/0), because they fail to pass the G1-restriction point. However, abrogation of the G1 restriction point (by loss of the retinoblastoma gene family) reveals a second restriction point that arrests cells in G2. Serum-starvation-induced G2 arrest is effectuated through inhibitory interactions of p27(KIP1) and p21(CIP1) with cyclins A and B1 and can be reversed through mitogen re-addition. In this study, we have investigated the pathways that allow cell cycle re-entry from this G2 arrest. We provide evidence that recovery from G2 arrest depends on the rat sarcoma viral oncogene (RAS) and phosphatidylinositol-3 kinase pathways and show that oncogenic hits, such as overexpression of c-MYC or mutational activation of RAS can abrogate the G2-restriction point. Together, our results provide new mechanistic insight into multistep carcinogenesis. PMID- 17700523 TI - Regulation of BAG-1 IRES-mediated translation following chemotoxic stress. AB - There are three major isoforms of BAG-1 in mammalian cells, termed BAG-1L (p50), BAG-1M (p46) and BAG-1S (p36) that function as pro-survival proteins and are associated with tumorigenesis and chemoresistance. Initiation of BAG-1 protein synthesis can occur by both cap-dependent and cap-independent mechanisms and it has been shown that synthesis of BAG-1S is dependent upon the presence of an internal ribosome entry segment (IRES) in the 5'-UTR of BAG-1 mRNA. We have shown previously that BAG-1 IRES-meditated initiation of translation requires two trans acting factors poly (rC) binding protein 1 (PCBP1) and polypyrimidine tract binding protein (PTB) for function. The former protein allows BAG-1 IRES RNA to attain a structure that permits binding of the ribosome, while the latter protein appears to be involved in ribosome recruitment. Here, we show that the BAG-1 IRES maintains synthesis of BAG-1 protein following exposure of cells to the chemotoxic drug vincristine but not to cisplatin and that this is brought about, in part, by the relocalization of PTB and PCBP1 from the nucleus to the cytoplasm. PMID- 17700524 TI - ATM-dependent nuclear accumulation of IKK-alpha plays an important role in the regulation of p73-mediated apoptosis in response to cisplatin. AB - I kappa B kinase (IKK) complex plays an important role in the regulation of signaling pathway that activates nuclear factor-kappa-B (NF-kappaB). Recently, we reported that cisplatin (CDDP) treatment causes a remarkable nuclear accumulation of IKK-alpha in association with stabilization and activation of p73. However, underlying mechanisms of CDDP-induced nuclear accumulation of IKK-alpha are elusive. Here, we found that ataxia-telangiectasia mutated (ATM) is one of upstream mediators of IKK-alpha during CDDP-induced apoptosis. In response to CDDP, ATM was phosphorylated at Ser-1981, which was accompanied with nuclear accumulation of IKK-alpha in HepG2 cells, whereas CDDP treatment had undetectable effects on IKK-alpha in ATM-deficient cells. Indirect immunofluorescence experiments demonstrated that phosphorylated form of ATM colocalizes with nuclear IKK-alpha in response to CDDP. In vitro kinase assay indicated that ATM phosphorylates IKK-alpha at Ser-473. Moreover, IKK-alpha-deficient MEFs displayed CDDP-resistant phenotype as compared with wild-type MEFs. Taken together, our present results suggest that ATM-mediated phosphorylation of nuclear IKK-alpha, which stabilizes p73, is one of the main apoptotic pathways in response to CDDP. PMID- 17700525 TI - Defective TGF-beta signaling sensitizes human cancer cells to rapamycin. AB - mTOR, the mammalian target of rapamycin, is a critical target of survival signals in many human cancers. In the absence of serum, rapamycin induces apoptosis in MDA-MB-231 human breast cancer cells. However, in the presence of serum, rapamycin induces G(1) cell cycle arrest-indicating that a factor(s) in serum suppresses rapamycin-induced apoptosis. We report here that transforming growth factor-beta (TGF-beta) suppresses rapamycin-induced apoptosis in serum-deprived MDA-MB-231 cells in a protein kinase Cdelta (PKCdelta)-dependent manner. Importantly, if TGF-beta signaling or PKCdelta was suppressed, rapamycin induced apoptosis rather than G(1) arrest in the presence of serum. And, if cells were allowed to progress into S phase, rapamycin induced apoptosis in the presence of serum. BT-549 and MDA-MB-468 breast, and SW-480 colon cancer cells have defects in TGF-beta signaling and rapamycin induced apoptosis in these cells in the presence of either serum or TGF-beta. Thus, in the absence of TGF-beta signaling, rapamycin becomes cytotoxic rather than cytostatic. Importantly, this study provides evidence indicating that tumors with defective TGF-beta signaling- common in colon and pancreatic cancers--will be selectively sensitive to rapamycin or other strategies that target mTOR. PMID- 17700526 TI - Stromal inactivation of BMPRII leads to colorectal epithelial overgrowth and polyp formation. AB - Stromal-epithelial interactions play a central role in development and tumorigenesis. Bone morphogenetic protein (BMP) signaling in the intestine is involved in both of these processes. Inactivation of BMP pathway genes in the epithelium is known to cause intestinal polyposis. However, the role of the intestinal stroma in polyp initiation is incompletely understood. We observed that conditional inactivation of the BMP type II receptor (BMPRII) in the stroma leads to epithelial hyperplasia throughout the colon with increased epithelial cell proliferation. Mutant mice developed rectal bleeding and hamartomatous polyps in the colorectum. The polyps demonstrated increased proliferation of epithelial and mesenchymal cells in the mucosa with an expansion of the myofibroblast cell population. These results demonstrate that genetic mutations altering the BMP signaling pathway in the stromal microenvironment can lead to epithelial tumors in the colon. PMID- 17700527 TI - Diacylglycerol kinase-alpha phosphorylation by Src on Y335 is required for activation, membrane recruitment and Hgf-induced cell motility. AB - Diacylglycerol (DAG) kinases (Dgk), which phosphorylate DAG to generate phosphatidic acid, act as either positive or negative key regulators of cell signaling. We previously showed that Src mediates growth factors-induced activation of Dgk-alpha, whose activity is required for cell motility, proliferation and angiogenesis. Here, we demonstrate that both hepatocytes growth factor (HGF) stimulation and v-Src transformation induce tyrosine phosphorylation of Dgk-alpha on Y335, through a mechanism requiring its proline-rich C-terminal sequence. Moreover, we show that both proline-rich sequence and phosphorylation of Y335 of Dgk-alpha mediate: (i) its enzymatic activation, (ii) its ability to interact respectively with SH3 and SH2 domains of Src, (iii) its recruitment to the membrane. In addition, we show that phosphorylation of Dgk-alpha on Y335 is required for HGF-induced motility, while its constitutive recruitment at the membrane by myristylation is sufficient to trigger spontaneous motility in absence of HGF. Providing the first evidence that tyrosine phosphorylation of Dgk alpha is required for growth-factors-induced activation and membrane recruitment, these findings underscore its relevance as a rheostat, whose activation is a threshold to elicit growth factors-induced migratory signaling. PMID- 17700528 TI - Aggressive breast cancer cells are dependent on activated Abl kinases for proliferation, anchorage-independent growth and survival. AB - Mutant Abl kinases (such as BCR-Abl) drive the development of leukemia; however little is known regarding whether Abl kinases contribute to the development or progression of solid tumors. We recently demonstrated that endogenous Abl kinases (c-Abl, Arg) are activated by deregulated ErbB receptors and Src kinases, and drive invasion of aggressive breast cancer cells. In this study, we examined whether activation of endogenous Abl kinases affects transformation, proliferation and survival, which are major contributors to breast cancer development and metastatic progression. Using a pharmacological inhibitor and RNAi, we demonstrate that activation of endogenous Abl kinases dramatically promotes breast cancer cell proliferation and anchorage-independent growth in serum, as well as survival following nutrient deprivation. Activation of Abl kinases mediates phosphorylation of STAT3, and promotes proliferation by accelerating G(1) --> S progression. Moreover, we identify IGF-1R as a novel upstream activator of endogenous Abl kinases, and demonstrate that Abl kinase activation is required for IGF-1-stimulated cell cycle progression in breast cancer cells. Since activation of Abl kinases affects multiple steps of breast cancer development and progression, Abl kinase inhibitors are likely to be effective agents for the treatment of breast cancers containing highly active Abl kinases. PMID- 17700529 TI - A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells. AB - Transcriptional effects of estrogen result from its activation of two estrogen receptor (ER) isoforms; ERalpha that drives proliferation and ERbeta that is antiproliferative. Expression of ERbeta in xenograft tumors from the T47D breast cancer cell line reduces tumor growth and angiogenesis. If ERbeta can halt tumor growth, its introduction into cancers may be a novel therapeutic approach to the treatment of estrogen-responsive cancers. To assess the complete impact of ERbeta on transcription, we have made a full transcriptome analysis of ERalpha- and ERbeta-mediated gene regulation in T47D cell line with Tet-Off regulated ERbeta expression. Of the 35 000 genes and transcripts analysed, 4.1% (1434) were altered by ERalpha activation. Tet withdrawal and subsequent ERbeta expression inhibited the ERalpha regulation of 998 genes and, in addition, altered expression of 152 non-ERalpha-regulated genes. ERalpha-induced and ERbeta repressed genes were involved in proliferation, steroid/xenobiotic metabolism and ion transport. The ERbeta repressive effect was further confirmed by proliferation assays, where ERbeta was shown to completely oppose the ERalpha-E2 induced proliferation. Additional analysis of ERbeta with a mutated DNA-binding domain revealed that this mutant, at least for a quantity of genes, antagonizes ERalpha even more strongly than ERbeta wt. From an examination of the genes regulated by ERalpha and ERbeta, we suggest that introduction of ERbeta may be an alternative therapeutic approach to the treatment of certain cancers. PMID- 17700530 TI - A role for iron in Wnt signalling. AB - There is an emerging body of evidence implicating iron in carcinogenesis and in particular colorectal cancer, but whether this involves Wnt signalling, a major oncogenic signalling pathway has not been studied. We aimed to determine the effect of iron loading on Wnt signalling using mutant APC (Caco-2 and SW480) and wild-type APC (HEK-293 and human primary fibroblasts) containing cell lines. Elevating cellular iron levels in Caco-2 and SW480 cells caused increased Wnt signalling as indicated by increased TOPFLASH reporter activity, increased mRNA expression of two known targets, c-myc and Nkd1, and increased cellular proliferation. In contrast wild-type APC and beta-catenin-containing lines, HEK 293 and human primary fibroblasts were not responsive to iron loading. This was verified in SW480 cells that no longer induced iron-mediated Wnt signalling when transfected with wild-type APC. The cell line LS174T, wild type for APC but mutant for beta-catenin, was also responsive suggesting that the role of iron is to regulate beta-catenin. Furthermore, we show that E-cadherin status has no influence on iron-mediated Wnt signalling. We thus speculate that excess iron could exacerbate tumorigenesis in the background of APC loss, a common finding in cancers. PMID- 17700531 TI - Collagen matrix assembly is driven by the interaction of von Hippel-Lindau tumor suppressor protein with hydroxylated collagen IV alpha 2. AB - Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene predisposes to vascular tumor formation in several organs. VHL regulates two evolutionary conserved pathways: the targeting of hydroxylated hypoxia-inducible factor-alpha (HIF-alpha) for proteasomal degradation and the remodeling of extracellular matrix (ECM). The biochemical mechanisms of the ECM assembly pathway remain poorly defined. Here, we provide evidence supporting a biochemical role for VHL in ECM assembly. We show that VHL directly binds to the collagen IV alpha 2 (COL4A2) chain and that this interaction is necessary for its assembly into the ECM. The VHL-COL4A2 interaction is dependent on endoplasmic reticulum (ER) mediated COL4A2 hydroxylation and independent of cytosolic, hypoxia regulated HIF alpha-modifying enzymes. We find that the N-terminal tail of COL4A2 protrudes from the ER lumen into the cytosol where it is bound by VHL. Failure of VHL to interact with COL4A2 correlates with loss of collagen IV network formation in vitro and collagen IV remodeling in vivo. Our data suggest a HIF-alpha independent role for the VHL-COL4A2 interaction in suppression of angiogenic tumor formation through collagen IV network assembly. PMID- 17700532 TI - Atm is a negative regulator of intestinal neoplasia. AB - The ataxia telangiectasia-mutated (ATM) gene has been implicated as an early barrier to the growth and progression of incipient solid tumors. Here, we show that germ-line nullizygosity for the mouse Atm gene significantly increases the proliferative index, net growth rate and multiplicity of intestinal adenomas in two distinct models of familial colon cancer: Apc(Min/+) and Apc(1638N/+). These effects of Atm deficiency are quantitatively different from deficiency for either of the genomic stability genes Bloom's syndrome helicase or DNA ligase 4, and the effect of Atm loss on tumor multiplicity is largely independent of the effect of ionizing radiation. Furthermore, the loss of heterozygosity rates at the adenomatous polyposis coli (Apc) locus are unaffected by Atm loss. Taken together, these data implicate the Atm gene product as a barrier to dysplastic growth in the early stages of intestinal tumor progression, independent of its effects on genomic stability. PMID- 17700533 TI - HDM2 antagonist Nutlin-3 disrupts p73-HDM2 binding and enhances p73 function. AB - Nutlin-3, a small molecule inhibitor, activates p53 by disrupting p53-HDM2 association. In this study, we found that Nutlin-3 suppressed cell growth and induced apoptosis in the absence of wild-type p53, suggesting a p53-independent mechanism for Nutlin-3-induced cell death. Like p53, its homolog p73 transactivates proapoptotic genes and induces cell death. Since HDM2, a key negative regulator of p53, also binds to and inhibits p73, we asked whether p73 could mediate Nutlin-3-induced apoptosis. We demonstrate that Nutlin-3 inhibits endogenous binding between the proapoptotic p73 isoform TAp73alpha and HDM2 in p53-null cells. Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis. p73 knockdown by siRNA results in rescue of Nutlin-3-treated cells, indicating that Nutlin-3-induced apoptosis is, at least in part, p73 dependent. In addition, Nutlin-3 treatment increases TAp73alpha protein levels with prolongation of p73 half-life. These results provide the first evidence that Nutlin-3 disrupts endogenous p73-HDM2 interaction and enhances the stability and proapoptotic activities of p73 and thus, provides a rationale for the use of Nutlin-3 in the large number of human tumors in which p53 is inactivated. PMID- 17700534 TI - The sensitivity of the Ewing's sarcoma family of tumours to fenretinide-induced cell death is increased by EWS-Fli1-dependent modulation of p38(MAPK) activity. AB - The Ewing's sarcoma family of tumours (ESFT) are small round cell tumours characterized by the non-random EWS-ETS gene rearrangements. We have previously demonstrated that ESFT are highly sensitive to fenretinide-induced death, effected in part through a reactive oxygen species (ROS)-dependent pathway. Here, we demonstrate for the first time that the sensitivity of ESFT cells to fenretinide-induced cell death is decreased following downregulation of the oncogenic fusion protein EWS-Fli1; siRNA targeting EWS-Fli1 attenuated fenretinide-induced cell death in cell lines expressing EWS-Fli1, but not EWS ERG. This decrease in cell death was independent of the level of ROS produced following exposure to fenretinide, but was effected through EWS-Fli1-dependent modulation of p38(MAPK) activity. Furthermore, inhibition of p38(MAPK) activity and knockdown of EWS-Fli1 reduced fenretinide-induced mitochondrial permeabilization, cytochrome c release, caspase and PARP cleavage, consistent with the hypothesis that p38(MAPK) is critical for activation of the death cascade by fenretinide in ESFT cells. These data demonstrate that expression of EWS-Fli1 enhances fenretinide-induced cell death in ESFT and that this is effected at least in part through modulation of p38(MAPK) activity. PMID- 17700535 TI - The ubiquitin ligase APC(Cdh1) is required to maintain genome integrity in primary human cells. AB - Ensuring precise DNA replication and chromosome segregation is essential during cell division in order to provide genomic stability and avoid malignant growth. Proteolytic control of cell cycle regulators by the anaphase-promoting complex, activated by Cdh1 (APC(Cdh1)), is responsible for a stable G1 phase after mitotic exit allowing accurate preparation for DNA replication in the following S phase. APC(Cdh1) target proteins are frequently upregulated in tumor cells and the inactivation of human Cdh1 might interfere with genome integrity by target stabilization. Here we show that APC(Cdh1) is required for maintaining genomic integrity in primary human cells. Lentiviral-delivered strong and stable suppression of Cdh1 by RNA interference (RNAi) causes aberrant accumulation of several APC(Cdh1) target proteins, such as cyclin A, B, Aurora A or Plk1, which control accurate and equal distribution of the genetic information to daughter cells. This induces a premature and prolonged S phase, mitotic-entry delay and defects in chromosome separation and cytokinesis. Cell cycle deregulation by stable knockdown of Cdh1 leads to activation of p53/p21 and genomic instability, which is further increased by codepletion of p53. Thus, stabilization of APC(Cdh1) targets may initiate aberrant DNA replication and chromosome separation, and trigger a p53 response by deregulating G1 in primary human cells. PMID- 17700536 TI - Ectopic Tbx2 expression results in polyploidy and cisplatin resistance. AB - T-box factors play critical roles in embryonic development and have been implicated in cell cycle regulation and cancer. For example, Tbx2 can suppress senescence through a mechanism involving the repression of the cyclin-dependent kinase inhibitors, p19(ARF) and p21(WAF1/CIP1/SDII), and the Tbx2 gene is deregulated in melanoma, breast and pancreatic cancers. In this study, several transformed human lung fibroblast cell lines were shown to downregulate Tbx2. To further investigate the role of Tbx2 in oncogenesis we therefore stably reexpressed Tbx2 in one such cell line. Compared to their parental cells, the resulting Tbx2-expressing cells are larger, with binucleate and lobular nuclei containing double the number of chromosomes. Moreover, these cells had an increase in frequency of several features of genomic instability such as chromosome missegregation, chromosomal rearrangements and polyploidy. While grossly abnormal, these cells still divide and give rise to cells that are resistant to the chemotherapeutic drug cisplatin. Furthermore, this is shown to be neither species nor cell type dependent, as ectopically expressing Tbx2 in a murine melanoma cell line also induce mitotic defects and polyploidy. These results have important implications for our understanding of the role of Tbx2 in tumorigenesis because polyploidy frequently precedes aneuploidy, which is associated with high malignancy and poor prognosis. PMID- 17700537 TI - Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone. AB - The tendency of prostate cancer to produce osteoblastic bone metastases suggests that cancer cells and osteoblasts interact in ways that contribute to cancer progression. To identify factors that mediate these interactions, we compared gene expression patterns between two bone-derived prostate cancer cell lines that produce osteoblastic (MDA PCa 2b) or osteolytic lesions (PC-3). Both cell lines expressed Wnt ligands, including WNT7b, a canonical Wnt implicated in osteogenesis. PC-3 cells expressed 50 times more Dickkopf-1 (DKK1), an inhibitor of Wnt pathways, than did MDA PCa 2b cells. Evaluation of the functional role of these factors (in cocultures of prostate cancer cells with primary mouse osteoblasts (PMOs) or in bone organ cultures) showed that MDA PCa 2b cells activated Wnt canonical signaling in PMOs and that DKK1 blocked osteoblast proliferation and new bone formation induced by MDA PCa 2b cells. MDA PCa 2b cells did not induce bone formation in calvaria from mice lacking the Wnt co receptor Lrp5. In human specimens, WNT7b was not expressed in normal prostate but was expressed in areas of high-grade prostate intraepithelial neoplasia, in three of nine primary prostate tumor specimens and in 16 of 38 samples of bone metastases from prostate cancer. DKK1 was not expressed in normal or cancerous tissue but was expressed in two of three specimens of osteolytic bone metastases (P=0.0119). We conclude that MDA PCa 2b induces new bone formation through Wnt canonical signaling, that LRP5 mediates this effect, and that DKK1 is involved in the balance between bone formation and resorption that determines lesion phenotype. PMID- 17700538 TI - Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. AB - The accumulation of Ca2+ in the mitochondrial matrix can stimulate oxidative phosphorylation, but can also, at high Ca2+ concentrations, transmit and amplify an apoptotic signal. Here, we characterized the capacity of physiological stimuli (for example, histamine and inositol-1,4,5-triphosphate) and inducers of endoplasmic reticulum (ER) stress (for example, A23187, thapsigargin and tunicamycin) to release Ca2+ from ER stores, induce mitochondrial Ca2+ accumulation, and trigger cell death in human cervix and colon carcinoma cell lines. Sustained Ca2+ accumulation in the mitochondrial matrix induced by ER stress triggered signs of proapoptotic mitochondrial alteration, namely permeability transition, dissipation of the electrochemical potential, matrix swelling, relocalization of Bax to mitochondria and the release of cytochrome c and apoptosis-inducing factor from mitochondria. In contrast, rapid and transient accumulation of Ca2+ induced by physiological stimuli failed to promote mitochondrial permeability transition and to affect cell viability. The specificity of this apoptosis pathway was validated in cells using a panel of pharmacological agents that chelate Ca2+ (BAPTA-AM) or inhibit inositol-1,4,5 trisphosphate receptor (IP(3)R; 2-aminoethoxydiphenyl borate), voltage-dependent anion channel (VDAC) (4,4'-diisothiocyanatostilbene-2,2'-disulfonate, NADH), the permeability transition pore (cyclosporin A and bongkrekic acid), caspases (z-VAD fmk) and protein synthesis (cycloheximide). Finally, we designed an original cell free system in which we confronted purified mitochondria and ER vesicles, and identified IP(3)R, VDAC and the permeability transition pore as key proteins in the ER-triggered proapoptotic mitochondrial membrane permeabilization process. PMID- 17700539 TI - Nuclear insulin receptor substrate-1 activates promoters of cell cycle progression genes. AB - The insulin receptor substrate-1 (IRS-1) is a docking protein of the insulin-like growth factor-1 (IGF-1) receptor and of the insulin receptor. IRS-1 sends a strong mitogenic, anti-apoptotic signal and plays an important role in cell transformation and cancer. IRS-1 translocates to nuclei of cells, where it increases the activity of the rDNA, c-myc and cyclin D1 promoters. We show, by chromatin immunoprecipitation, occupancy by IRS-1 of the same promoters. Both promoter activation and promoter occupancy are IGF-1-dependent. In cells that respond to IGF-1 but in which IRS-1 does not translocate to nuclei, promoter occupancy is absent and promoter activation is absent or much reduced. Transcriptional activation of c-myc and cyclin D1 promoters by nuclear IRS-1 does not occur with a mutant, inactive IRS-1 protein (deletion of the phosphotyrosine binding domain, PTB) and does not require PI3-kinase activity. Taken together, these results indicate a novel mechanism by which nuclear IRS-1 activates cell cycle genes. PMID- 17700540 TI - Construction of consecutive deletions of the Escherichia coli chromosome. AB - The minimal set of genetic information necessary and sufficient to sustain a functioning cell contains not only trans-acting genes, but also cis-acting chromosomal regions that cannot be complemented by plasmids carrying these regions. In Escherichia coli (E. coli), only one chromosomal region, the origin of replication has been identified to be cis-acting. We constructed a series of mutants with long-range deletions, and the chromosomal regions containing trans acting essential genes were deleted in the presence of plasmids complementing the deleted genes. The deleted regions cover all regions of the chromosome except for the origin and terminus of replication. The terminus affects cell growth, but is not essential. Our results indicate that the origin of DNA replication is the only vital, unique cis-acting DNA sequence in the E. coli chromosome necessary for survival. PMID- 17700541 TI - Environmental signal integration by a modular AND gate. AB - Microorganisms use genetic circuits to integrate environmental information. We have constructed a synthetic AND gate in the bacterium Escherichia coli that integrates information from two promoters as inputs and activates a promoter output only when both input promoters are transcriptionally active. The integration occurs via an interaction between an mRNA and tRNA. The first promoter controls the transcription of a T7 RNA polymerase gene with two internal amber stop codons blocking translation. The second promoter controls the amber suppressor tRNA supD. When both components are transcribed, T7 RNA polymerase is synthesized and this in turn activates a T7 promoter. Because inputs and outputs are promoters, the design is modular; that is, it can be reconnected to integrate different input signals and the output can be used to drive different cellular responses. We demonstrate this modularity by wiring the gate to integrate natural promoters (responding to Mg(2+) and AI-1) and using it to implement a phenotypic output (invasion of mammalian cells). A mathematical model of the transfer function is derived and parameterized using experimental data. PMID- 17700542 TI - Immunization by application of DNA vaccine onto a skin area wherein the hair follicles have been induced into anagen-onset stage. AB - An attractive approach to immunization is to apply DNA vaccine topically onto the skin. However, it is important to ensure that a strong immune response is induced without disrupting the skin stratum corneum. The hair follicles have been shown to be the major portal of entry for DNA applied onto the skin, and it has been reported that the transfection of hair follicle cells occurs mainly at the onset of a new growing stage of the hair cycle. Using an anthrax protective antigen (PA) protein-encoding plasmid in mice, we demonstrated that the anti-PA immune responses were significantly stronger when the hair follicles in the application area were induced into anagen-onset stage than when in telogen stage. The anti-PA antibodies enabled the immunized mice to survive a lethal dose of anthrax lethal toxin challenge. The enhanced immune responses can be partially attributed to the enhanced antigen gene expression and plasmid DNA uptake in the skin area wherein the hair follicles were induced into anagen-onset stage. Moreover, the moderate dermal inflammation associated with the anagen induction may also have contributed to the enhancement of the resultant immune response. This represents a novel approach to enhancing the immune response induced by a topically applied DNA vaccine. PMID- 17700543 TI - In vivo reprogramming of hTERT by trans-splicing ribozyme to target tumor cells. AB - We have developed and validated a new tumor-targeting gene therapy strategy based upon the targeting and replacement of human telomerase reverse transcriptase (hTERT) RNA, using a trans-splicing ribozyme. By constructing novel adenoviral vectors harboring the hTERT-targeting trans-splicing ribozymes with the downstream reporter gene (Ad-Ribo-LacZ) or suicide gene (Ad-Ribo-HSVtk) driven by the cytomegalovirus (CMV) promoter, we demonstrated that this viral system selectively marks tumor cells expressing hTERT or sensitizes tumor cells to prodrug treatments. We confirmed that Ad-Ribo-LacZ successfully and selectively delivered a ribozyme that performed a highly specific trans-splicing reaction into hTERT-expressing cancer cells, both in vitro and in a peritoneal carcinomatosis nude mouse model. We also determined that the hTERT-specific expression of the suicide gene in the Ad-Ribo-HSVtk, and treatment with the corresponding prodrug, reduced tumor progression with almost the same efficacy as the strong constitutive CMV promoter-driven adenovirus, both in cancer cell lines and in nude mouse HT-29 xenografts. These observations provide the basis for a novel approach to cancer gene therapy, and demonstrate that trans-splicing ribozymes can be employed as targeting anti-cancer agents which recognize cancer specific transcripts and reprogram them, thereby combating cancerous cells. PMID- 17700544 TI - Stable gene transfer to muscle using non-integrating lentiviral vectors. AB - Human immunodeficiency virus (HIV)-based lentiviral vectors (LVs) hold immense promise for gene delivery applications because of their relatively large packaging capacity and their ability to infect a range of cell types. The genome of HIV non-specifically integrates into the host genome, and this promotes efficient, stable transgene expression in dividing cells. However, integration can also be problematic because of variations in gene expression among cells, possible gene silencing and, most importantly, insertional mutagenesis which can lead to undesirable effects such as malignant transformation. In order to alleviate these problems, we have developed a range of non-integrating LVs (NILVs) by introducing point mutations into the catalytic site, chromosome binding site, and viral DNA binding site of the viral integrase (IN). In addition, we have mutated the IN attachment (att) sites within the HIV long terminal repeats (LTRs). All of the vectors produced show efficient reverse transcription and transgene expression in dividing cells and prolonged expression in non-dividing myotubes. Finally, we show that NILV can be used for achieving highly effective gene transfer and expression in muscle in vivo. PMID- 17700545 TI - Gene transfer of an engineered zinc finger protein enhances the anti-angiogenic defense system. AB - Zinc finger protein transcription factors (ZFP TFs) have been shown to positively or negatively regulate the expression of endogenous genes involved in a number of different disease processes. In this study we investigated whether gene transfer of an engineered ZFP TF designed to up-regulate expression of the chromosomal pigment epithelium-derived factor (Pedf) gene could suppress experimentally induced choroidal neovascularization (CNV). Transient transfection with engineered ZFP TFs significantly increased both Pedf messenger RNA (mRNA) and secreted PEDF protein levels in cell culture. Six weeks after intravitreous or subretinal injection of an adeno-associated viral (AAV) vector expressing the PEDF-activating ZFP TF in mice, we observed increased retinal Pedf mRNA, and a significant reduction in the size of CNV at Bruch's membrane rupture sites, assessed in vivo by fluorescein angiography or by postmortem measurements on choroidal flat mounts. Importantly, the anti-angiogenic activity persisted at 3 months after intravitreous injection. These data suggest that ZFP TF-driven enhancement of the endogenous anti-angiogenic defense system may provide a new approach for prophylaxis and treatment of neovascular diseases of the eye. PMID- 17700546 TI - Does treatment with eicosapentaenoic acid prevent major coronary events in patients with hypercholesterolemia? PMID- 17700547 TI - Can percutaneous coronary intervention be performed safely as an outpatient procedure? PMID- 17700548 TI - The GRAIDS Trial: a cluster randomised controlled trial of computer decision support for the management of familial cancer risk in primary care. AB - The objective was to evaluate the effect of an assessment strategy using the computer decision support system (the GRAIDS software), on the management of familial cancer risk in British general practice in comparison with best current practice. The design included cluster randomised controlled trial, and involved forty-five general practice teams in East Anglia, UK. Randomised to GRAIDS (Genetic Risk Assessment on the Internet with Decision Support) support (intervention n=23) or comparison (n=22). Training in the new assessment strategy and access to the GRAIDS software (GRAIDS arm) was conducted, compared with an educational session and guidelines about managing familial breast and colorectal cancer risk (comparison) were mailed. Outcomes were measured at practice, practitioner and patient levels. The primary outcome measure, at practice level, was the proportion of referrals made to the Regional Genetics Clinic for familial breast or colorectal cancer that were consistent with referral guidelines. Other measures included practitioner confidence in managing familial cancer (GRAIDS arm only) and, in patients: cancer worry, risk perception and knowledge about familial cancer. There were more referrals to the Regional Genetics Clinic from GRAIDS than comparison practices (mean 6.2 and 3.2 referrals per 10 000 registered patients per year; mean difference 3.0 referrals; 95% confidence interval (CI) 1.2-4.8; P=0.001); referrals from GRAIDS practices were more likely to be consistent with referral guidelines (odds ratio (OR)=5.2; 95% CI 1.7-15.8, P=0.006). Patients referred from GRAIDS practices had lower cancer worry scores at the point of referral (mean difference -1.44 95% CI -2.64 to -0.23, P=0.02). There were no differences in patient knowledge about familial cancer. The intervention increased GPs' confidence in managing familial cancer. Compared with education and mailed guidelines, assessment including computer decision support increased the number and quality of referrals to the Regional Genetics Clinic for familial cancer risk, improved practitioner confidence and had no adverse psychological effects in patients. Trials are registered under N0181144343 in the UK National Research Register. PMID- 17700549 TI - Does continued alendronate therapy improve bone mineral density and reduce fracture risk in postmenopausal women? PMID- 17700550 TI - An evaluation of serum thyroglobulin assays for the detection of recurrent differentiated thyroid carcinoma. PMID- 17700551 TI - Is there a simpler and more equitable way of using HLA data to allocate deceased donor kidneys? PMID- 17700552 TI - Fluvastatin for reduction of cardiovascular risk in patients with moderate to severe renal insufficiency. PMID- 17700553 TI - Can renal tubular hypokalemic disorders be accurately diagnosed on the basis of the diuretic response to thiazide? PMID- 17700554 TI - Changes in plasma levetiracetam concentrations in pregnant women and their breastfed infants. PMID- 17700555 TI - Does a prompt list help patients and caregivers to ask questions about cancer prognosis and care? PMID- 17700556 TI - Does atovaquone provide effective prophylaxis for Pneumocystis pneumonia in children with leukemia? PMID- 17700557 TI - Should all patients with systemic lupus erythematosus receive cardioprotection with statins? PMID- 17700558 TI - How common is PSA screening in elderly men with limited life expectancies? PMID- 17700559 TI - Is the number of lymph nodes removed during PLND related to the prevalence of lymph node invasion? PMID- 17700560 TI - Is tension-free vaginal tape more effective than laparoscopic colposuspension for stress incontinence? PMID- 17700561 TI - Experimental approaches to the study of cancer-stroma interactions: recent findings suggest a pivotal role for stroma in carcinogenesis. AB - An increasing body of research indicates that stroma surrounding cancer cells plays an important role in the development and subsequent behavior of the tumor. Studies using a wide range of techniques, including stromal cell isolation, modification of stromal-specific gene expression, and recreation of specific microenvironment conditions in culture, have demonstrated that stroma can promote cancer and that the expression patterns within the stroma can influence clinical outcome. Major hurdles in the study of the cancer stroma revolve around the cellular complexity of the tumor microenvironment, both in modeling the microenvironment and discovering/isolating pure populations of stromal cell types. PMID- 17700562 TI - Quantitative nuclease protection assay in paraffin-embedded tissue replicates prognostic microarray gene expression in diffuse large-B-cell lymphoma. AB - Gene expression profiling (GEP) has identified genes whose expression levels predict patient survival in diffuse large-B-cell lymphoma (DLBCL). Such discovery techniques generally require frozen samples unavailable for most patients. We developed a quantitative nuclease protection assay to measure expression levels of prognostic DLBCL genes using formalin-fixed, paraffin-embedded (FFPE) tissue. FFPE tissue was sectioned, permeabilized, denatured in the presence of specific probes, and hybridized to mRNA in situ. Nuclease subsequently destroyed non hybridized probe. Alkaline hydrolysis freed mRNA-bound probes from tissue, which were transferred to ArrayPlates for probe capture and chemiluminescent quantification. We validated assay performance using frozen, fresh, and FFPE DLBCL samples, then used 39 archived DLBCL, previously microarray analyzed, to correlate GEP and ArrayPlate results. We compared old (>18 years) with new (<2 months) paraffin blocks made from previously frozen tissue from the original biopsy. ArrayPlate gene expression results were confirmed with immunohistochemistry for BCL2, BCL6, and HLA-DR, showing agreement between mRNA species and the proteins they encode. Assay performance was linear to approximately 1 mg sample/well. RNase and DNase treatments demonstrated assay specificity for RNA detection, both fixed and soluble RNA detection. Comparisons were excellent for lysate vs snap-frozen vs FFPE (R(2)>0.98 for all comparisons). Coefficients of variation for quadruplicates on FFPE were generally <20%. Correlation between new and old paraffin blocks from the same biopsy was good (R(2)=0.71). Comparison of ArrayPlate to Affymetrix and cDNA microarrays showed reasonable correlations. Insufficient power from small sample size prevented successfully correlating results with patient survival, although hazard ratios trended the expected directions. We developed an assay to quantify expression levels of survival prediction genes in DLBCL using FFPE, fresh, or frozen tissue. While this technique cannot replace GEP for discovery, it indicates that expression differences identified by GEP can be replicated on a platform applicable to archived FFPE samples. PMID- 17700563 TI - MS-MLPA: an attractive alternative laboratory assay for robust, reliable, and semiquantitative detection of MGMT promoter hypermethylation in gliomas. AB - Expression of the DNA repair protein O6-alkylguanine-DNA-alkyltransferase (AGT), encoded by the O6-methylguanine (O6-mG) -DNA-methyltransferase (MGMT) DNA repair gene, results in resistance to alkylating agents, and hypermethylation of the MGMT promoter is associated with chemosensitivity as it prevents AGT expression. As the interpretation of the results of immunohistochemistry to evaluate AGT expression proved to be difficult, the aim of our present study is to establish a feasible, reliable, and robust method for MGMT promoter hypermethylation testing that can be easily implemented in a diagnostic setting and is applicable to routinely processed tissue. MGMT hypermethylation analysis using methylation specific (MS-) multiplex ligation-dependent probe amplification (MLPA) was performed on 62 glioma samples of 55 individual tumors (including 12 cell lines) and compared to the more conventionally used, but improved, MS-polymerase chain reaction (PCR). In contrast to MS-PCR, MS-MLPA (i) is not based on bisulfite conversion of unmethylated cytosines (a somewhat troublesome step in MS-PCR), (ii) provided methylation status of all samples, (iii) proved to be semiquantitative, (iv) can be used to evaluate methylation status of multiple sequences (CpG dinucleotides) simultaneously, and (v) allows for a combined copy number detection and methylation specific analysis. The potential therapeutic value of MGMT hypermethylation evaluation using MS-MLPA was shown in a group of 20 glioblastoma patients receiving temozolomide chemotherapy. We conclude that MS MLPA is a robust and reliable method that can be easily applied to differently processed tissues, including those fixed in formalin and embedded in paraffin. The semiquantitative aspect of MS-MLPA may prove to be of great value, especially in predicting response to alkylating agents, not only for gliomas as evaluated in this study but also for tumors in general. PMID- 17700564 TI - IL-33 can promote survival, adhesion and cytokine production in human mast cells. AB - IL-33 is a recently identified member of the IL-1 family of molecules, which also includes IL-1 and IL-18. IL-33 binds to the receptor, T1/ST2/IL-1R4, and can promote cytokine secretion by Th2 cells and NF-kappaB phosphorylation in mouse mast cells. However, the effects of these molecules, especially IL-33, in human mast cells are poorly understood. Expression of the receptors for IL-1 family molecules, specifically, IL-1R1, IL-18R and T1/ST2, was detectable intracellularly in human umbilical cord blood-derived mast cells (HUCBMCs) by flow cytometry, but was scarcely detectable on the cells' surface. However, IL 1beta, IL-18 or IL-33 induced phosphorylation of Erk, p38 and JNK in naive HUCBMCs, and IL-33 or IL-1beta, but not IL-18, enhanced the survival of naive HUCBMCs and promoted their adhesion to fibronectin. IL-33 or IL-1beta also induced IL-8 and IL-13 production in naive HUCBMCs, and enhanced production of these cytokines in IgE/anti-IgE-stimulated HUCBMCs, without enhancing secretion of either PGD(2) or histamine. Moreover, IL-33-mediated IL-8 production by HUCBMCs was markedly reduced by the p38 MAPK inhibitor, SB203580. In contrast to findings with mouse mast cells, IL-18 neither induced nor enhanced secretion of the mediators PGD(2) or histamine by HUCBMCs. Our findings identify previously unknown functions of IL-33 in human mast cells. One of these is that IL-33, like IL-1beta, can induce cytokine production in human mast cells even in the absence of stimuli of FcepsilonRI aggregation. Our findings thus support the hypothesis that IL-33 may enhance mast cell function in allergic disorders and other settings, either in the presence or absence of co-stimulation of mast cells via IgE/antigen-FcepsilonRI signals. PMID- 17700566 TI - Forkhead box P3-positive regulatory T cells in immune surveillance and cancer. PMID- 17700567 TI - Inhibitory effects of pharmacological doses of melatonin on aromatase activity and expression in rat glioma cells. AB - Melatonin exerts oncostatic effects on different kinds of neoplasias, especially on oestrogen-dependent tumours. Recently, it has been described that melatonin, on the basis of its antioxidant properties, inhibits the growth of glioma cells. Glioma cells express oestrogen receptors and have the ability to synthesise oestrogens from androgens. In the present study, we demonstrate that pharmacological concentrations of melatonin decreases the growth of C6 glioma cells and reduces the local biosynthesis of oestrogens, through the inhibition of aromatase, the enzyme that catalyses the conversion of androgens into oestrogens. These results are supported by three types of evidence. Firstly, melatonin counteracts the growth stimulatory effects of testosterone on glioma cells, which is dependent on the local synthesis of oestrogens from testosterone. Secondly, we found that melatonin reduces the aromatase activity of C6 cells, measured by the tritiated water release assay. Finally, by (RT)-PCR, we found that melatonin downregulates aromatase mRNA steady-state levels in these glioma cells. We conclude that melatonin inhibits the local production of oestrogens decreasing aromatase activity and expression. By analogy to the implications of aromatase in other forms of oestrogen-sensitive tumours, it is conceivable that the modulation of the aromatase by pharmacological melatonin may play a role in the growth of glioblastomas. PMID- 17700568 TI - Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. AB - Cohort studies of excess body weight and risk of liver cancer were identified for a meta-analysis by searching MEDLINE and EMBASE databases from 1966 to June 2007 and the reference lists of retrieved articles. Results from individual studies were combined using a random-effects model. We identified 11 cohort studies, of which seven on overweight (with a total of 5037 cases) and 10 on obesity (with 6042 cases) were suitable for meta-analysis. Compared with persons of normal weight, the summary relative risks of liver cancer were 1.17 (95% confidence interval (CI): 1.02-1.34) for those who were overweight and 1.89 (95% CI: 1.51 2.36) for those who were obese. This meta-analysis finds that excess body weight is associated with an increased risk of liver cancer. PMID- 17700569 TI - Molar pregnancy and childhood cancer: a population-based linkage study from Denmark. AB - We observed a relative risk of 1.40 (95% confidence interval; 0.86-2.16) for cancers diagnosed under the age 20 in 6192 offspring of 3431 mothers with a molar pregnancy, indicating it is not a major determinant of childhood cancer. PMID- 17700570 TI - Rare germline mutations in the BRCA2 gene are associated with early-onset prostate cancer. AB - Studies of families who segregate BRCA2 mutations have found that men who carry disease-associated mutations have an increased risk of prostate cancer, particularly early-onset disease. A study of sporadic prostate cancer in the UK reported a prevalence of 2.3% for protein-truncating BRCA2 mutations among patients diagnosed at ages < or =55 years, highlighting the potential importance of this gene in prostate cancer susceptibility. To examine the role of protein truncating BRCA2 mutations in relation to early-onset prostate cancer in a US population, 290 population-based patients from King County, Washington, diagnosed at ages <55 years were screened for germline BRCA2 mutations. The coding regions, intron-exon boundaries, and potential regulatory elements of the BRCA2 gene were sequenced. Two distinct protein-truncating BRCA2 mutations were identified in exon 11 in two patients. Both cases were Caucasian, yielding a mutation prevalence of 0.78% (95% confidence interval (95%CI) 0.09-2.81%) and a relative risk (RR) of 7.8 (95%CI 1.8-9.4) for early-onset prostate cancer in white men carrying a protein-truncating BRCA2 mutation. Results suggest that protein truncating BRCA2 mutations confer an elevated RR of early-onset prostate cancer. However, we estimate that <1% of early-onset prostate cancers in the general US Caucasian population can be attributed to these rare disease-associated BRCA2 mutations. PMID- 17700571 TI - FISH analysis of 107 prostate cancers shows that PTEN genomic deletion is associated with poor clinical outcome. AB - This study examines the clinical impact of PTEN genomic deletions using fluorescence in situ hybridisation (FISH) analysis of 107 prostate cancers, with follow-up information covering a period of up to 10 years. Tissue microarray analysis using interphase FISH indicated that hemizygous PTEN losses were present in 42/107 (39%) of prostatic adenocarcinomas, with a homozygous PTEN deletion observed in 5/107 (5%) tumours. FISH analysis using closely linked probes centromeric and telomeric to the PTEN indicated that subband microdeletions accounted for approximately 70% genomic losses. Kaplan-Meier survival analysis of PTEN genomic losses (hemizygous and homozygous deletion vs not deleted) identified subgroups with different prognosis based on their time to biochemical relapse after surgery, and demonstrated significant association between PTEN deletion and an earlier onset of disease recurrence (as determined by prostate specific antigen levels). Homozygous PTEN deletion was associated with a much earlier onset of biochemical recurrence (P=0.002). Furthermore, PTEN loss at the time of prostatectomy correlated with clinical parameters of more advanced disease, such as extraprostatic extension and seminal vesicle invasion. Collectively, our data indicates that haploinsufficiency or PTEN genomic loss is an indicator of more advanced disease at surgery, and is predictive of a shorter time to biochemical recurrence of disease. PMID- 17700572 TI - NF-kappaB activation in inflammatory breast cancer is associated with oestrogen receptor downregulation, secondary to EGFR and/or ErbB2 overexpression and MAPK hyperactivation. AB - Activation of NF-kappaB in inflammatory breast cancer (IBC) is associated with loss of estrogen receptor (ER) expression, indicating a potential crosstalk between NF-kappaB and ER. In this study, we examined the activation of NF-kappaB in IBC and non-IBC with respect to ER and EGFR and/or ErbB2 expression and MAPK hyperactivation. A qRT-PCR based ER signature was evaluated in tumours with and without transcriptionally active NF-kappaB, as well as correlated with the expression of eight NF-kappaB target genes. Using a combined ER/NF-kappaB signature, hierarchical clustering was executed. Hyperactivation of MAPK was investigated using a recently described MAPK signature (Creighton et al, 2006), and was linked to tumour phenotype, ER and EGFR and/or ErbB2 overexpression. The expression of most ER-modulated genes was significantly elevated in breast tumours without transcriptionally active NF-kappaB. In addition, the expression of most ER-modulated genes was significantly anticorrelated with the expression of most NF-kappaB target genes, indicating an inverse correlation between ER and NF-kappaB activation. Clustering using the combined ER and NF-kappaB signature revealed one cluster mainly characterised by low NF-kappaB target gene expression and a second one with elevated NF-kappaB target gene expression. The first cluster was mainly characterised by non-IBC specimens and IHC ER+ breast tumours (13 out of 18 and 15 out of 18 respectively), whereas the second cluster was mainly characterised by IBC specimens and IHC ER- breast tumours (12 out of 19 and 15 out of 19 respectively) (Pearson chi(2), P<0.0001 and P<0.0001 respectively). Hyperactivation of MAPK was associated with both ER status and tumour phenotype by unsupervised hierarchical clustering using the MAPK signature and was significantly reflected by overexpression of EGFR and/or ErbB2. NF-kappaB activation is linked to loss of ER expression and activation in IBC and in breast cancer in general. The inverse correlation between NF-kappaB activation and ER activation is due to EGFR and/or ErbB2 overexpression, resulting in NF-kappaB activation and ER downregulation. PMID- 17700573 TI - The effects of preoperative chemotherapy on isolated tumour cells in the blood and bone marrow of gastric cancer patients. AB - Recent studies in breast cancer suggest that monitoring the isolated tumour cells (ITC) may be used as a surrogate marker to evaluate the efficacy of systemic chemotherapy. In the present study, we have investigated the effects of preoperative chemotherapy on ITC in the blood and bone marrow of patients with potentially resectable gastric cancer. After sorting out the CD45-positive cells, the presence of ITC defined as cytokeratin-positive cells was examined before and after preoperative chemotherapy. The patients received two courses of preoperative chemotherapy with cisplatin (100 mg m(-2), day 1) and 5-fluorouracil (1000 mg m(-2), days 1-5), administered every 28 days. Fourteen of 32 (44%) patients initially diagnosed with ITC in blood and/or bone marrow were found to be negative (responders) after preoperative chemotherapy (P<0.01). The incidence of ITC in bone marrow was also significantly (P<0.01) reduced from 97 (31 of 32) to 53% (17 of 32). The difference between patients positive for ITC in the blood before (n=7, 22%) and after (n=5, 16%) chemotherapy was statistically insignificant. The overall 3-year survival rates were 32 and 49% in the responders and non-responders, respectively (P=0.683). These data indicate that preoperative chemotherapy can reduce the incidence of ITC in patients with gastric cancer. PMID- 17700574 TI - Is it time to reassess the BDNF hypothesis of depression? AB - The brain-derived neurotrophic factor (BDNF) hypothesis of depression postulates that a loss of BDNF is directly involved in the pathophysiology of depression, and that its restoration may underlie the therapeutic efficacy of antidepressant treatment. While this theory has received considerable experimental support, an increasing number of studies have generated evidence which is not only inconsistent, but also directly contradicts the hypothesis. This article provides a critical review of the clinical and preclinical studies which have been responsible for this controversy, outlining pharmacological, behavioural and genetic evidence which demonstrates the contrasting role of BDNF in regulating mood and antidepressant effects throughout the brain. I will also review key studies, both human and animal, which have investigated the association of a BDNF single-nucleotide polymorphism (Val66Met) with depression pathogenesis, and detail the number of inconsistencies which also afflict this novel area of BDNF research. The article will conclude by discussing why now is a critical time to reassess the original BDNF hypothesis of depression, and look towards the formation of new models that can provide a more valid account of the complex relationships between growth factors, mood disorders and their treatment. PMID- 17700575 TI - The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis. AB - Gene-environmental interaction (G x E) between a common functional polymorphism in the promoter region of the serotonin transporter gene (5-HTT) and environmental adversity on the onset of depression in humans has been found in fifteen independent studies. It is supported by evidence from animal experiments, pharmacological challenge and neuroimaging investigations. However, negative findings have been reported in two large samples. We explore reasons for the inconsistencies and suggest means to their resolution. Sample age and gender composition emerge as important factors. While the G x E has been consistently detected in young adult samples, there are contradictory findings in adolescent boys and elderly people. The method of assessment of environmental adversity is also important with detailed interview-based approaches being associated with positive G x E findings. Unresolved issues in the definition of the genotype include the dominance of alleles and influence of other polymorphisms, both in 5 HTT and other genes. Assessment of multiple adverse outcomes, including depression, substance use and self-destructive behaviour is needed to clarify the generalisability of the G x E pathogenic mechanisms. Biological and behavioural intermediate phenotypes are yet to be exploited to understand the mechanisms underlying the G x E. PMID- 17700577 TI - Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. AB - Several lines of evidence implicate the pro-inflammatory cytokine interleukin-1 (IL-1) in the etiology and pathophysiology of major depression. To explore the role of IL-1 in chronic stress-induced depression and some of its underlying biological mechanisms, we used the chronic mild stress (CMS) model of depression. Mice subjected to CMS for 5 weeks exhibited depressive-like symptoms, including decreased sucrose preference, reduced social exploration and adrenocortical activation, concomitantly with increased IL-1 beta levels in the hippocampus. In contrast, mice with deletion of the IL-1 receptor type I (IL-1rKO) or mice with transgenic, brain-restricted overexpression of IL-1 receptor antagonist did not display CMS-induced behavioral or neuroendocrine changes. Similarly, whereas in wild-type (WT) mice CMS significantly reduced hippocampal neurogenesis, measured by incorporation of bromodeoxyuridine (BrdU) and by doublecortin immunohistochemistry, no such decrease was observed IL-1rKO mice. The blunting of the adrenocortical activation in IL-1rKO mice may play a causal role in their resistance to depression, because removal of endogenous glucocorticoids by adrenalectomy also abolished the depressive-like effects of CMS, whereas chronic administration of corticosterone for 4 weeks produced depressive symptoms and reduced neurogenesis in both WT and IL-1rKO mice. The effects of CMS on both behavioral depression and neurogenesis could be mimicked by exogenous subcutaneous administration of IL-1 beta via osmotic minipumps for 4 weeks. These findings indicate that elevation in brain IL-1 levels, which characterizes many medical conditions, is both necessary and sufficient for producing the high incidence of depression found in these conditions. Thus, procedures aimed at reducing brain IL-1 levels may have potent antidepressive actions. PMID- 17700576 TI - Linkage on chromosome 14 in a genome-wide linkage study of a broad anxiety phenotype. AB - Several linkage studies on anxiety have been carried out in samples ascertained through probands with panic disorder. The results indicated that using a broad anxiety phenotype instead of a DSM-IV anxiety disorder diagnosis might enhance the chance of finding a linkage signal. In the current study, a genome-wide linkage analysis was performed on anxiety measured with a self-report questionnaire whose scores are highly correlated with DSM-IV anxiety disorders. The self-report questionnaire was included in five surveys of a longitudinal study of the Netherlands Twin Register. Genotype and phenotype data were available for 1602 twins and siblings. To estimate identity by descent , additional genotype data for 564 parents and 22 siblings were used. Linkage analyses were carried out using MERLIN-regress on the average anxiety scores across time. A linkage signal (logarithm of odds score 3.4, empirical P-value 0.07) was obtained at chromosome 14 for marker D14S65 at 105 cM (90% confidence interval, 99-115 cM bounded by markers D14S1434 and D14S985). This finding replicates a linkage finding for a broad anxiety phenotype in a clinically based sample, indicating that the region might harbor a quantitative trait locus associated with the whole spectrum of general anxiety, that is from the normal to the clinical range. Moreover, genome-wide linkage and association studies on emotionality in mice obtained significant results in a syntenic region on mouse chromosome 12. Two homolog genes lie in this region -Dlk1 (delta-like 1 homolog, Drosophila) and Rtl1 (retrotransposon-like 1). Future association studies of these genes are warranted. PMID- 17700578 TI - A comparison of short-term appetite and energy intakes in normal weight and obese boys following glucose and whey-protein drinks. AB - OBJECTIVE: To compare the effect of glucose and whey-protein preloads on satiety and food intake (FI) as affected by time to the next meal and body composition in normal weight (NW) and obese (OB) boys. DESIGN: Cross-sectional clinical intervention study of the effect of caloric preloads on FI control in boys. SUBJECTS: Seventeen NW (body mass index (BMI)=18.9+/-0.5 kg/m(2); age=12.2+/-0.3 years) and 17 OB boys (BMI=25.8+/-0.9 kg/m(2); age=11.4+/-0.3 years) (Experiment 1) and 12 NW boys (BMI=18.6+/-0.6 kg/m(2); age=12.1+/-0.3 years) (Experiment 2). MEASUREMENTS: On three separate mornings and in random order each of the boys consumed a noncaloric sweetened preload, glucose (837 kJ) or whey protein (837 kJ) (Experiment 1) or noncaloric preload, glucose (1.0 g/kg) or whey protein (1.0 g/kg) (Experiment 2) made up to 250 ml with water 2 h after the consumption of a fixed breakfast. Food intake from a pizza meal was measured 30 min (Experiment 1) or 60 min (Experiment 2) later. RESULTS: In Experiment 1, glucose suppressed FI (mean kJ+/-s.e.m.) in NW (3126+/-304) and OB boys (3116+/-286) compared with the control (NW, 4015+/-337 and OB, 3791+/-255). Whey protein suppressed FI in NW, but not in OB boys. Body weight, fat-mass and fat-free mass were positively associated with FI after all treatments in NW, but was not related to FI in OB boys. In Experiment 2, FI was suppressed by whey protein (2683+/-367) more than by glucose (3107+/-294) or the control (3585+/-361). CONCLUSION: NW and OB boys respond differently to whey-protein preloads, with time to next meal a factor in the response to both glucose and protein preloads. PMID- 17700579 TI - A randomized clinical trial of a standard versus vegetarian diet for weight loss: the impact of treatment preference. AB - BACKGROUND: With obesity rampant, methods to achieve sustained weight loss remain elusive. OBJECTIVE: To compare the long-term weight-loss efficacy of 2 cal and fat-restricted diets, standard (omnivorous) versus lacto-ovo-vegetarian, and to determine the effect of a chosen diet versus an assigned diet. DESIGN, SUBJECTS: A randomized clinical trial was conducted with 176 adults who were sedentary and overweight (mean body mass index, 34.0 kg/m(2)). Participants were first randomly assigned to either receive their preferred diet or be assigned to a diet group and second, were given their diet of preference or randomly assigned to a standard weight-loss diet or a lacto-ovo-vegetarian diet. Participants underwent a university-based weight-control program consisting of daily dietary and exercise goals plus 12 months of behavioral counseling followed by a 6-month maintenance phase. MEASUREMENTS: Percentage change in body weight, body mass index, waist circumference, low- and high-density lipoprotein, glucose, insulin and macronutrient intake. RESULTS: The program was completed by 132 (75%) of the participants. At 18 months, mean percentage weight loss was greater (P=0.01) in the two groups that were assigned a diet (standard, 8.0% (s.d., 7.8%); vegetarian, 7.9% (s.d., 8.1%)) than in those provided the diet of their choice (standard, 3.9% (s.d., 6.1%); vegetarian, 5.3% (s.d., 6.2%)). No difference was observed in weight loss between the two types of diet. Over the 18-month program, all groups showed significant weight loss. CONCLUSIONS: Participants assigned to their dietary preference did not have enhanced treatment outcomes. However, all groups lost weight with losses ranging from 4 to 8% at 18 months. PMID- 17700580 TI - BMI-based body size guides for women and men: development and validation of a novel pictorial method to assess weight-related concepts. AB - OBJECTIVES: To develop and evaluate two BMI-based instruments to determine perceptions of weight status, particularly perceptions of overweight and obesity, using pictorial images of women and men. METHODS: Pictures of adults with known BMI values were used to construct gender-specific body size guides (BSGs) containing 10 bodies that ranged from underweight to class III obesity. Figures were standardized and a composite face was added to each. The BSGs were administered to 400 adults to assess the psychometric properties of the instruments and weight perceptions. RESULTS: High correlations between the BMIs of respondents and the BMIs of the current body selected by respondents provided strong support for the criterion-related validity of the BSGs, and the logical pattern of responses to items assessing perception of weight categories supported construct validity for the scales. Test-retest reliability, assessed by correlations for both current and ideal body, was also high, despite the lengthy 6-month testing interval. Respondents' perceptions of the bodies within specific weight categories indicated that a majority failed to recognize the overweight female as overweight and perceived the overweight male as normal weight. Obese bodies were generally unrecognized as such until the bodies reached the higher levels of obesity (that is, BMI values >39). Perception of weight was influenced by the respondents' weight status and gender. CONCLUSIONS: Psychometric analyses indicated the BSGs are valid and reliable instruments. These results, coupled with the face validity of the scales and the relationship between the bodies and BMI values, indicate the BSGs offer advantages over existing instruments for researchers of weight perception and body image. Administration of the scales to an adult sample confirmed that overweight and obesity are under-recognized. Increased efforts to improve public understanding of these terms are needed and the BSGs may provide useful tools for this purpose. PMID- 17700581 TI - Association between small for gestational age and paternally inherited 5' insulin haplotypes. AB - OBJECTIVE: To test the association between small for gestational age and polymorphisms in the insulin gene in newborns and their mothers, as well as the effect of the parental transmission of haplotypes. SUBJECTS: Pairs of healthy African-American full-term newborns (N=207) and mothers were recruited from Memphis TN and Jackson MS with birth weights ranging from 2210 to 4735 g. METHODS: Six single nucleotide polymorphisms (SNPs) located in the insulin (INS) and insulin-like growth factor 2 (IGF2) genes were genotyped in mothers and newborns. Haplotypes composed of three SNPs in the 5' region of the INS-IGF2 locus were computationally inferred. Odds ratios for risk of small for gestational age (SGA) birth were calculated for individual SNPs and inferred haplotypes in the newborns and in the mothers using logistic regression. For 162 mother--newborn pairs the parental transmission of the haplotypes could be inferred, and the risks for SGA birth were calculated for the three common haplotypes in this sample. RESULTS: Three INS SNPs exhibited significant association with risk for SGA birth. The SNP alleles associated with increased risk for SGA were opposite in the maternal and newborn genomes, implying opposing influences on the rate of fetal growth. Consistent with these results, haplotypes composed of complementary nucleotide sequences (CAC at rs3842738, rs689 and rs3842748, respectively, in the newborn versus GTG in the mother) were significantly associated with risk for SGA birth. In analyses of haplotypes according to parental transmission, the same trend in risk for SGA was observed for both maternally and paternally transmitted haplotypes, although a significant difference in risk was observed only for paternally transmitted haplotypes. CONCLUSION: Polymorphisms near the 5' end of the INS-IGF2 locus are significantly associated with risk for SGA birth with a major effect due to the paternally transmitted haplotype, which is preferentially expressed due to imprinting. PMID- 17700587 TI - Fragmentation: when pulling apart all comes together. AB - It is easy to think of a journal as a firm entity, but the modus vivendi of a highly read journal such as CPT is quite the opposite. The launch of CPT Nature Network adds another dimension. PMID- 17700588 TI - "Stemness" does not explain the repair of many tissues by mesenchymal stem/multipotent stromal cells (MSCs). AB - There has recently been an explosion of interest in adult stem/progenitor cells that have the potential to repair tissues, with over 3,000 citations to publications (PubMed) and numerous announcements of clinical trials in which the cells are used to treat individuals with a broad range of diseases. At the same time, the data present a paradox-the cells originally attracted attention because of their stem-cell-like properties, but the cells frequently repair injured tissues without much evidence of either engraftment or differentiation. PMID- 17700582 TI - Quantitative comparison and evaluation of software packages for assessment of abdominal adipose tissue distribution by magnetic resonance imaging. AB - OBJECTIVE: To examine five available software packages for the assessment of abdominal adipose tissue with magnetic resonance imaging, compare their features and assess the reliability of measurement results. DESIGN: Feature evaluation and test-retest reliability of softwares (NIHImage, SliceOmatic, Analyze, HippoFat and EasyVision) used in manual, semi-automated or automated segmentation of abdominal adipose tissue. SUBJECTS: A random sample of 15 obese adults with type 2 diabetes. MEASUREMENTS: Axial T1-weighted spin echo images centered at vertebral bodies of L2-L3 were acquired at 1.5 T. Five software packages were evaluated (NIHImage, SliceOmatic, Analyze, HippoFat and EasyVision), comparing manual, semi-automated and automated segmentation approaches. Images were segmented into cross-sectional area (CSA), and the areas of visceral (VAT) and subcutaneous adipose tissue (SAT). Ease of learning and use and the design of the graphical user interface (GUI) were rated. Intra-observer accuracy and agreement between the software packages were calculated using intra-class correlation. Intra-class correlation coefficient was used to obtain test-retest reliability. RESULTS: Three of the five evaluated programs offered a semi-automated technique to segment the images based on histogram values or a user-defined threshold. One software package allowed manual delineation only. One fully automated program demonstrated the drawbacks of uncritical automated processing. The semi-automated approaches reduced variability and measurement error, and improved reproducibility. There was no significant difference in the intra-observer agreement in SAT and CSA. The VAT measurements showed significantly lower test retest reliability. There were some differences between the software packages in qualitative aspects, such as user friendliness. CONCLUSION: Four out of five packages provided essentially the same results with respect to the inter- and intra-rater reproducibility. Our results using SliceOmatic, Analyze or NIHImage were comparable and could be used interchangeably. Newly developed fully automated approaches should be compared to one of the examined software packages. PMID- 17700589 TI - The star-allele nomenclature: retooling for translational genomics. AB - The star-allele nomenclature is the result of efforts to standardize genetic polymorphism annotation for the cytochrome P450 genes. As clinical pharmacogenetic testing becomes widespread, it is important that this system effectively communicate a patient's genotype and predicted clinical phenotype. As genomics research expands, it is equally important that the system remain a valuable tool for the wider community of genetic researchers to exploit our ever improving ability to catalog variability in the human genome. PMID- 17700590 TI - Protease inhibitors as immunomodulatory drugs for HIV infection. AB - More than 20 drugs from four therapeutic drug classes are widely available for the management of human immunodeficiency virus (HIV) infection, with promising drugs from two new drug classes expected to be approved by the US Food and Drug Administration (FDA) in mid-to-late 2007 (Table 1). When used in combination, these drugs can lead to durable and perhaps indefinite suppression of viral replication. PMID- 17700591 TI - Nicotine intake and steady-state cotinine when smoking cigarettes of different yields. PMID- 17700593 TI - The influence of fluorouracil outcome parameters on tolerance and efficacy in patients with advanced colorectal cancer. AB - The purpose of this study was to determine simple genetic factors helpful to tailor 5-FU administration and determine strategy in first-line chemotherapy of advanced colorectal cancer. In 76 patients initially treated by 5-FU, thymidylate synthase, dihydropyrimidine dehydrogenase and methylene tetrahydrofolate reductase germinal polymorphisms, dihydrouracil/uracil plasma ratio and 5-FU plasma clearance were investigated and correlated for tolerance (10.5% grade 3 and 4 toxicity) and efficacy (32.9% objective response rate and 20 months median overall survival time). Toxicity was linked to performance status >2 (P=0.004), low UH2/U ratio, 2846 A>T, IVS 14+1G>A for DPD (P=0.031), and homozygoty C/C for MTHFR 1298 A>C (P=0.0018). The overall survival of the patients with a 3R/3R TS genotype associated with C/C for 677 C>T or A/A for 1298 A>C was statistically shorter (log-rank test P=0.0065). Genetic factors permit the tailoring of 5-FU treatment. They should occupy center stage in future clinical trials for specifically designing treatment for patients with a given biologic feature. PMID- 17700594 TI - Influence of UGT1A9 intronic I399C>T polymorphism on SN-38 glucuronidation in Asian cancer patients. AB - Genetic polymorphisms in hepatically expressed UGT1A1 and UGT1A9 contribute to the interindividual variability i-n irinotecan disposition and toxicity. We screened UGT1A1 (UGT1A1*60, g.-3140G>A, UGT1A1*28 and UGT1A1*6) and UGT1A9 (g. 118(T)(9>10) and I399C>T) genes for polymorphic variants in the promoter and coding regions, and the genotypic effect of UGT1A9 I399C>T polymorphism on irinotecan disposition in Asian cancer patients was investigated. Blood samples were collected from 45 patients after administration of irinotecan as a 90 min intravenous infusion of 375 mg/m(2) once in every 3 weeks. Genotypic-phenotypic correlates showed that cancer patients heterozygous or homozygous for the I399C>T allele had approximately 2-fold lower systemic exposure to SN-38 (P<0.05) and a trend towards a higher relative extent of glucuronidation (REG) of SN-38 (P>0.05). UGT1A1-1A9 diplotype analysis showed that patients harbouring the H1/H2 (TG6GT(10)T/GG6GT(9)C) diplotype had 2.4-fold lower systemic exposure to SN-38 glucuronide (SN-38G) compared with patients harbouring the H1/H5 (TG6GT(10)T/GG6GT(10)C) diplotype (P=0.025). In conclusion, this in vivo study supports the in vitro findings of Girard et al. and suggests that the UGT1A9 I399C>T variant may be an important glucuronidating allele affecting the pharmacokinetics of SN-38 and SN-38G in Asian cancer patients receiving irinotecan chemotherapy. PMID- 17700595 TI - Pharmacogenomic associations in ABCB1 and CYP3A5 with acute kidney injury and chronic kidney disease after myeloablative hematopoietic cell transplantation. AB - Renal disease is a major complication in patients following myeloablative allogeneic hematopoietic cell transplantation (HCT). Post-HCT patients receive immunosuppressive regimens containing calcineurin inhibitor (CNIs), cyclosporine or tacrolimus, for graft-versus-host disease prophylaxis. In this retrospective trial, we investigated pharmacogenomic associations in the multidrug resistance (ABCB1) and cytochrome P450 3A5 (CYP3A5) genes and acute kidney injury (AKI) and chronic kidney disease (CKD) in a cohort of 121 patients. ABCB1 and CYP3A5 are responsible for the renal disposition of CNIs, which are known to be nephrotoxic. AKI was defined as doubling of baseline serum creatinine during the first 100 days post-HCT, and CKD as at least one glomerular filtration rate <60 ml/min/m2 between 6 and 18 months post-HCT. Patients were genotyped for CYP3A5*1>*3 and ABCB1 single nucleotide polymorphisms (SNPs) (1199G>A, 1236C>T, 2677G>T/A and 3435C>T). Odds ratios were calculated using logistic regression. Haplotype estimation and univariate association analyses were performed because of strong ABCB1 linkage disequilibrium (LD). AKI occurred in 48 of 121 patients (39.7%) and CKD in 16 of 66 patients (24.2%). No pharmacogenomic associations were found between ABCB1 and CYP3A5 SNPs and the incidences of AKI or CKD. The degree of LD(r2) between ABCB1 SNPs was estimated as follows: 2677G>T/3435C>T (0.44), 1236C>T/3435C>T (0.42) and 1236C>T/2677G>T (0.72). ABCB1 1199G>A showed no LD to other SNPs (<0.05). No associations were found between the most common ABCB1 haplotypes and AKI or CKD. Since no significant pharmacogenomic associations were observed, tailoring CNIs dosing based on these genotypes is unlikely to lower significantly the risk of renal injury following myeloablative HCT. PMID- 17700596 TI - Catechol-O-methyltransferase (COMT) polymorphisms predict treatment response in electroconvulsive therapy. AB - Several lines of evidence suggest that catechol-O-methyltransferase (COMT) may be associated with treatment response in depression. We conducted a study on 119 patients with treatment-refractory depression admitted consecutively for electroconvulsive therapy (ECT). The COMT high/high genotype leads to a higher enzyme activity and thus lowers dopaminergic activity in the prefrontal cortex. In the present sample, those homozygous to high-active allele of COMT responded significantly more frequently to ECT. PMID- 17700597 TI - High incidence of secondary failure of platelet recovery after autologous and syngeneic peripheral blood stem cell transplantation in acute promyelocytic leukemia. AB - Secondary failure of platelet recovery (SFPR), which is a delayed decline in platelet count after primary recovery following myeloablative hematopoietic SCT, is a significant problem in allogeneic SCT. However, its clinical characteristics have not been well described in autologous SCT for acute myeloid leukemia. We reviewed 11 consecutive patients who had received autologous or syngeneic SCT for acute promyelocytic leukemia. Seven of 11 patients (64%) had SFPR, which is defined as a decline in the platelet count to less than 30,000/microl for more than 7 days. The median onset of SFPR was day 36 (range, 25-51 days) and the median duration of thrombocytopenia was 13 days (range, 4-25 days). Of nine patients who received busulfan-containing preparative regimens, seven (78%) had SFPR and one had delayed primary platelet count recovery. Neither patient who received cyclophosphamide and total body irradiation as preparative regimens had SFPR. The clinical courses of SFPR were transient and self-limited. SFPR was not associated with relapse of underlying diseases, graft failure or other fatal morbidities. The unexpectedly high prevalence and the characteristics of SFPR may provide additional information on management following autologous SCT for acute myeloid leukemia. PMID- 17700598 TI - Prolonged anorexia and elevated plasma cytokine levels following myeloablative allogeneic hematopoietic cell transplant. AB - Myeloablative conditioning regimens commonly lead to prolonged anorexia and poor oral intake. In a prospective study of 147 patients receiving CY, total body irradiation and allogeneic hematopoietic cells, we determined the extent of decline in oral intake and assessed plasma cytokine levels and development of acute GVHD as explanations for protracted anorexia. For each patient, daily oral caloric intake was expressed as a percent of estimated basal requirements, calculated as basal energy expenditure, through day 20. Oral caloric intake was significantly reduced in 92% of patients and remained low. The nadir in oral intake occurred at days 10-12, when median oral caloric intake was 3% of basal energy requirements. Plasma cytokines known to affect appetite (IL2, IL6, tumor necrosis factor-alpha) were significantly elevated above normal following conditioning therapy (P<0.001 for each cytokine). Acute GVHD did not appear to affect oral intake to transplant day 20 in this cohort of patients; however, plasma levels of IL6 rose steeply before the clinical onset of GVHD. Persistent fever occurred with the greatest frequency in patients with most profound reduction in oral intake. We conclude that prolonged alterations in oral intake following this myeloablative regimen may be related to circulating cytokines known to alter eating behavior. PMID- 17700599 TI - Ethnicity, equity and public benefit: a critical evaluation of public umbilical cord blood banking in Australia. AB - Over the past decade umbilical cord blood (UCB) has been increasingly used as a source of haematopoietic stem cells (HSCs) for patients who require a HSC transplant but do not have an HLA-matched donor. It was anticipated that using UCB as an alternative source of HSCs would increase the chance of finding a donor, particularly for the otherwise underrepresented ethnic minority groups. To evaluate the effectiveness of the Australian public UCB banks to increase the ethnic diversity of available HSC donations, this paper analyses the ethnic diversity of the Sydney Cord Blood Bank (SCBB), comparing this diversity to that of the Australian Bone Marrow Donor Registry (ABMDR). It also examines the ethnic diversity of those patients who, after requesting a haematopoietic stem cell transplantation in the 2-year period between 2003 and 2005, managed to find a suitably matched bone marrow or UCB donor. We show that the ethnic mix of donors to the SCBB has remained generally broad in source, is comparative to the Australian population, and is more diverse than the ABMDR. This, however, may still not be sufficient to substantially increase the likelihood of finding a donor for some ethnic minority groups. PMID- 17700600 TI - Elevated lactate dehydrogenase is an adverse predictor of outcome in HLA-matched sibling bone marrow transplant for acute myelogenous leukemia. AB - Prognostic factors for survival following allogeneic BMT for AML include age, disease status and cytogenetic risk classification. Lactate dehydrogenase (LDH) levels have not been studied as a potential risk factor. We reviewed our experience with BMT for AML and included LDH at the time of admission in an analysis of prognostic factors for survival. We found that LDH >330 U/l (1.5 times the upper limit of normal at our institution), older age, active disease, peripheral stem cell graft and male-to-male transplant were significant adverse predictors of survival. After accounting for LDH, other factors such as disease status and cytogenetics were not significantly associated with the outcome of BMT. All but one patient with an LDH >330 U/l had active disease. However, when patients in CR were excluded, LDH >330 U/l remained a significant adverse predictor of overall survival (hazard ratio 2.70, 95% confidence interval 1.41 5.16, P=0.003). We conclude that LDH is an important adverse risk factor for survival and should be included in future studies of risk performed on larger patient cohorts. PMID- 17700601 TI - Distribution of the minor histocompatibility antigens in Korean population and disparities in unrelated hematopoietic SCT. AB - Minor histocompatibility antigens (mHags) are polymorphic peptides presented to T lymphocytes restricted by the MHC molecule. It has been reported that disparities of mHags are a potential risk factor for GVHD after hematopoietic SCT (HSCT). Here we observed allelic frequencies of HA-1, -2 and -8 in 139 Korean healthy individuals using PCR-sequence-specific primers, and analyzed the correlation between disparity of these mHags and acute GVHD (aGVHD) in 54 patients who underwent HSCT from unrelated HLA-identical donors. The allelic frequencies in Korean healthy individuals were 39.6 and 60.4% for HA-1(H) and HA-1(R), 92.4 and 7.6% for HA-2(M) and HA-2(V), 36.7 and 63.3% for HA-8(R) and HA-8(P), respectively. The frequencies of mHags incompatibility known to be associated with aGVHD were 16.7% in HA-1, 0% in HA-2 and 25.9% in HA-8. However, the statistically significant association of aGVHD with these mHags incompatibility was not found between healthy donors and leukemia patients after unrelated HSCT. This first report about mHags in Koreans may be helpful in further defining the clinical impact of mHags disparities in HSCT and in comparing with other populations. PMID- 17700602 TI - Time to first flare-up episode of GVHD can stratify patients according to their prognosis during clinical course of progressive- or quiescent-type chronic GVHD. AB - GVHD-specific survival (GSS) has been investigated as a potential study end point to describe the clinical course and outcome of chronic GVHD (cGVHD). However, reaching this end point requires a long observation time. We hypothesized that the time to the first flare-up (FFU) of cGVHD (TTF) can be an alternative statistical end point to GSS. This retrospective study included 96 patients with a diagnosis of cGVHD from a cohort of 119 patients with a prior history of acute GVHD. The median TTF was 73 days after the diagnosis of cGVHD. The 2-year cumulative incidences of first, second and third episodes of flare-up (FU) during courses of cGVHD were estimated as 69.5, 46.4 and 22.1%. Those patients who did not have an episode of FU of cGVHD had 96.0% of 2-years GSS rate, while those with 1 and > or =2 episodes had 50.8 and 46.8%, respectively (P=0.001). Shorter TTF was associated with poor GSS and decreased overall survival. The shorter TTF during the course of cGVHD was significantly associated with extensive cGVHD (P=0.002), Hopkins' risk category (P=0.022) and progressive-type cGVHD (P<0.001) in multivariate analysis. We propose that TTF can be an alternative end point to GSS in cGVHD trials. PMID- 17700608 TI - Hand eczema prognosis. PMID- 17700603 TI - Multiple cycles of PBPC-supported high-dose carboplatin and paclitaxel following mobilization with epirubicin and cisplatin are feasible but ineffective in treating patients with advanced non-small cell lung cancer. AB - We verified the feasibility of a multi-cycle peripheral blood progenitor cell (PBPC)-supported high-dose chemotherapy (HDC) regimen in patients with non-small cell lung cancer (NSCLC). The HDC regimen consisted of a single course of high dose epirubicin given in combination with cisplatin plus filgrastim, followed by three courses of high doses of carboplatin and paclitaxel with PBPC reinfusion and filgrastim. Of the 16 enrolled patients, 13 provided an adequate number of PBPCs by a single leukapheresis, while in the three needed two procedures, with a median number of CD34+, CD34+/CD33- and CD34+/CD38- cells collected per patient was 13.5 x 10(6), 10.9 x 10(6) and 0.9 x 10(6)/kg, respectively. No toxic death occurred, and the collected PBPCs supported a rapid hematopoietic reconstitution after HDC; however, seven patients early interrupted the treatment early due to early progressive disease (n=4) or prolonged grade 3 peripheral neurotoxicity (n=3). Despite an overall response rate of 42%, the median survival for stage IV patients has been 5 months (range: 1-25+). Of two patients with stage IIIB NSCLC, one is continuously disease-free at 71+ months, while of 14 with stage IV disease, one is currently alive with disease at 25+ months. In conclusion, the combination of high-dose epirubicin with cisplatin plus filgrastim is an effective regimen in releasing large amounts of PBPCs, which can then be safely employed to support multiple courses of HDC. Multiple cycles of PBPC-supported high-dose carboplatin and paclitaxel are ineffective in treating patients with advanced NSCLC. PMID- 17700610 TI - Aaron B. Lerner, 1920-2007. PMID- 17700611 TI - The early days at Yale. PMID- 17700612 TI - Aaron Lerner's Legacy at Yale University. PMID- 17700613 TI - Current understanding and future implications of the circadian uses of melatonin, a neurohormone discovered by Aaron B. Lerner. PMID- 17700614 TI - Aaron Lerner: perspectives and lessons learned from the melatonin days. PMID- 17700616 TI - Aaron Lerner: a mentor and friend. PMID- 17700617 TI - Aaron Lerner remembered. PMID- 17700615 TI - Aaron B. Lerner, MD, PhD: a personal remembrance. PMID- 17700618 TI - Training with Aaron Lerner. PMID- 17700619 TI - Aaron Lerner: the quiet promoter. PMID- 17700620 TI - Defining hair follicles in the age of stem cell bioengineering. AB - One challenge faced by stem cell biologists is the bioengineering of an organ. Ehama et al. (2007, this issue) used cells derived from human and rodent epidermis and dermal papilla to reconstitute hair-follicle mini-organs. Some result in hair follicles; others are hair follicle-like. The challenge calls for the development of a set of criteria to define a hair follicle so that bioengineered products in the future can be evaluated. PMID- 17700621 TI - Merkel cell carcinoma: more deaths but still no pathway to blame. AB - Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer with a rising incidence (1500 U.S. cases per year) that now exceeds that of cutaneous T-cell lymphoma and a mortality (33%) exceeding that of melanoma. Despite this impact, little is known about its biology. Recent studies have shown that Ras/MAP kinase activity is absent and possibly detrimental to this cancer. This makes MCC distinct from other UV--induced skin cancers and highlights the question of what drives this malignancy. PMID- 17700622 TI - How different wavelengths of the ultraviolet spectrum contribute to skin carcinogenesis: the role of cellular damage responses. AB - The carcinogenic properties of ultraviolet (UV) light are mediated by its ability to generate DNA damage. Cellular responses to UV-induced DNA damage profoundly modulate the carcinogenic effects of UV exposures, and these responses are wavelength dependent. However, the exact contributions of different wavelengths of UV light to DNA damage, cellular damage responses, mutation, and skin carcinogenesis are incompletely understood. Given that UV-induced apoptosis is a protective cellular response to UV that prevents survival of damaged cells, inhibition of UVB-induced apoptosis by adding UVA, as reported by Ibuki et al. in this issue, may be a mechanism by which UVA augments UVB-mediated mutation and skin cancer formation. PMID- 17700624 TI - Remembering the past to imagine the future: the prospective brain. AB - A rapidly growing number of recent studies show that imagining the future depends on much of the same neural machinery that is needed for remembering the past. These findings have led to the concept of the prospective brain; an idea that a crucial function of the brain is to use stored information to imagine, simulate and predict possible future events. We suggest that processes such as memory can be productively re-conceptualized in light of this idea. PMID- 17700625 TI - Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals? AB - The reactive oxygen species that are generated by mitochondrial respiration, including hydrogen peroxide (H2O2), are potent inducers of oxidative damage and mediators of ageing. It is not clear, however, whether oxidative stress is the result of a genetic programme or the by-product of physiological processes. Recent findings demonstrate that a fraction of mitochondrial H2O2, produced by a specialized enzyme as a signalling molecule in the pathway of apoptosis, induces intracellular oxidative stress and accelerates ageing. We propose that genes that control H2O2 production are selected determinants of lifespan. PMID- 17700626 TI - The role of nuclear architecture in genomic instability and ageing. AB - Eukaryotes come in many shapes and sizes, yet one thing that they all seem to share is a decline in vitality and health over time--a process known as ageing. If there are conserved causes of ageing, they may be traced back to common biological structures that are inherently difficult to maintain throughout life. One such structure is chromatin, the DNA-protein complex that stabilizes the genome and dictates gene expression. Studies in the budding yeast Saccharomyces cerevisiae have pointed to chromatin reorganization as a main contributor to ageing in that species, which raises the possibility that similar processes underlie ageing in more complex organisms. PMID- 17700627 TI - Japanese and North American/European patients with Beckwith-Wiedemann syndrome have different frequencies of some epigenetic and genetic alterations. AB - Beckwith-Wiedemann syndrome (BWS) is an imprinting-related human disease. The frequencies of causative alterations such as loss of methylation (LOM) of KvDMR1, hypermethylation of H19-DMR, paternal uniparental disomy, CDKN1C gene mutation, and chromosome abnormality have been described for North American and European patients, but the corresponding frequencies in Japanese patients have not been measured to date. Analysis of 47 Japanese cases of BWS revealed a significantly lower frequency of H19-DMR hypermethylation and a higher frequency of chromosome abnormality than in North American and European patients. These results suggest that susceptibility to epigenetic and genetic alterations differs between the two groups. PMID- 17700628 TI - A simulation-based analysis of chromosome segment sharing among a group of arbitrarily related individuals. AB - A fundamental set of issues in human genetics research concerns the statistical properties of the DNA sequence or chromosomal segments that are shared between related individuals. Although well-established mathematical formulations exist that consider such sharing via measures such as the kinship coefficient, many of these formulations are derived for entire genomes, individual sequence variations, or small stretches of DNA, and hence, do not consider either the actual size or the number of the genome-wide chromosomal segments that are shared between two or more arbitrarily related individuals. In this paper, we employ a flexible gene-dropping simulation-based approach for estimating the distribution of the size and the number of chromosomal segments shared by any number of arbitrarily related individuals. The approach takes advantage of chromosome- and sex-specific recombination rates adopted from integrated genetic and physical maps, and considers the genome as a whole, rather than specific genomic regions or loci. In addition, our analysis considers the effects of linkage disequilibrium and crossover interference on segment sharing. Our proposed analysis and computational strategy can be used to provide compelling answers to questions concerning variation in the kinship coefficient as well as the distribution of chromosomal sharing over individual chromosomes. We present results that showcase possible application of assessing genomic sharing in gene mapping and apply our analysis to data available from published gene mapping studies. PMID- 17700629 TI - Genome-wide linkage scan for exercise participation in Dutch sibling pairs. AB - This study was aimed at identifying the genomic loci linked to exercise participation in males and females. Cross-sectional exercise data of twins and siblings (18-50 years) were used from the Netherlands Twin Registry. The sample consisted of 1432 genotyped sibling pairs from 622 families (1120 sibling pairs were genotyped on all chromosomes). Exercise participation (no/yes, based on a cutoff criterion of four metabolic equivalents and 60 min weekly) was assessed by survey. Genotyping was based on 361 markers and an average marker density of 10.6 cM. Identical by descent status was estimated for a 1 cM grid. A variance components-based sex-limited linkage scan was carried out for exercise participation. The heritability of exercise participation in males was 68.5% and in females 46.3%. The genetic overlap was estimated at 0.32, indicating that partly different genes affect exercise in the two sexes. Suggestive linkage was found in all subjects on chromosome 19p13.3 (LOD=2.18). Although sex differences in linkage effect were not significant, mainly females contributed to the suggestive linkage. The 19p13.3-13.2 region harbors a number of genes related to muscle performance and muscle blood flow, which might affect exercise behavior through exercise ability. Most likely, a large number of genes with each small effects affect exercise participation in males and females. Large collaborative samples are needed to detect these effects. PMID- 17700630 TI - Co-introgression of Y-chromosome haplogroups and the sickle cell gene across Africa's Sahel. AB - The Sahel that extends from the Atlantic Ocean to the Ethiopian highland is a historical reservoir of Africa's cultures and grandest populations and a known arena of ancient and recent migrations. We are interested in the issue whether such migrations were also carriers of genetic traits and whether this introgression could be associated with population genetic markers. Based on analysis of Y-chromosome haplogroups, we present evidence that the sickle gene, one of the major protective polymorphisms known in malaria, has in fact found its way only recently to the gene pool of the populations in eastern Sahel. We discuss the possible dynamics of the process and give estimates of the age of the introduction of the S allele into eastern Sahel. PMID- 17700631 TI - Early beneficial effect of matrix metalloproteinase inhibition on blood-brain barrier permeability as measured by magnetic resonance imaging countered by impaired long-term recovery after stroke in rat brain. AB - Proteolytic disruption of the extracellular matrix with opening of the blood brain barrier (BBB) because of matrix metalloproteinases (MMPs) occurs in reperfusion injury after stroke. Matrix metalloproteinase inhibition blocks the early disruption of the BBB, but the long-term consequences of short-term MMP inhibition are not known. Recently, a method to quantify BBB permeability by graphical methods was described, which provides a way to study both early disruption of the BBB and long-term effects on recovery in the same animal. We used a broad-spectrum MMP inhibitor, BB1101, to determine both the usefulness of the Magnetic resonance imaging (MRI) method for treatment studies and the long term effects on recovery. Magnetic resonance imaging studies were performed in control (N=6) and drug-treated (N=8) groups on a dedicated 4.7-T MRI scanner. Adult Wistar-Kyoto underwent a 2-h middle cerebral artery occlusion followed by an MRI study after 3 h of reperfusion, which consisted of T2- and diffusion weighted techniques. Additionally, a rapid T1 mapping protocol was also implemented to acquire one pre-gadolinium-diethylenetriaminepentaacetic acid baseline data set followed by postinjection data sets at 3-min intervals for 45 mins. The same animal was imaged again at 48 h for lesion size estimation. Data was postprocessed pixel-wise to generate apparent diffusion coefficient and permeability coefficient maps. Treatment with BB-1101 significantly reduced BBB permeability at 3 h, but failed to reduce lesion size at 48 h. Behavioral studies showed impairment in recovery in treated rats. Magnetic resonance imaging allowed for the monitoring of multiple parameters in the same animal. Our studies showed that BB-1101 was an excellent inhibitor of the BBB damage. However, results show that BB-1101 may be responsible for significant deterioration in neurologic status of treated animals. Although these preliminary results suggest that BB 1101 is useful in reducing early BBB leakage owing to reperfusion injury in stroke, further studies will be needed to determine whether the later detrimental effects can be eliminated by shorter time course of drug delivery. PMID- 17700632 TI - Noninvasive study of neurovascular coupling during graded neuronal suppression. AB - In this study, the neurovascular coupling relationship was noninvasively studied in the human visual cortex. Graded neuronal/hemodynamic suppression conditions were generated using a paired-stimulus paradigm. Visual evoked potential was measured to quantify neuronal activity. Hemodynamic activities were measured and quantified by perfusion and blood oxygenation level-dependent changes. All quantification was normalized to the same activation condition induced by a single stimulus paradigm within each experimental session. This experiment design eliminated the confounding factors such as anesthesia and inconsistent neurovascular coupling patterns within and/or among tasks. The results reveal that (i) there is a tight neurovascular coupling at graded neuronal suppression conditions; (ii) the neurovascular coupling relationship contains a subtle, but significant, nonlinear component; and (iii) the linear model, nevertheless, is still a good approximation reflecting the neurovascular coupling relationship. This study extends the range of the neurovascular coupling relationship from graded neuronal excitation conditions to graded neuronal suppression conditions. PMID- 17700633 TI - Environment-dependent trade-offs between ectoparasite resistance and larval competitive ability in the Drosophila-Macrocheles system. AB - Costs of resistance are expected to contribute to the maintenance of genetic variation for resistance in natural host populations. In the present study, we experimentally test for genetic trade-offs between parasite resistance and larval competitive ability expressed under varying levels of crowding and temperature. Artificial selection for increased behavioral resistance was applied against an ectoparasitic mite (Macrocheles subbadius) in replicate lines of the fruit fly Drosophila nigrospiracula. We then measured correlated responses to selection in larval competitive ability by contrasting replicate selected and control (unselected) lines in the absence of parasitism. Experiments were conducted under variable environmental conditions: two temperatures and three levels of larval density. Our results reveal a negative genetic correlation between resistance and larval-adult survival under conditions of moderate and severe intra-specific competition. At both low and high temperature, percent emergence was significantly higher among control lines than selected lines. This divergence in larval competitive ability was magnified under high levels of competition, but only at low temperature. Hence, the interaction between selection treatment and larval density was modified by temperature. As predicted, larvae experiencing medium and high levels of competition exhibited an overall reduction in female body size compared to larvae at low levels of competition. Female flies emerging from selected lines were significantly smaller than those females from control lines, but this effect was only significant under conditions of moderate to severe competition. These results provide evidence of environment-dependent trade offs between ectoparasite resistance and larval competitive ability, a potential mechanism maintaining genetic polymorphism for resistance. PMID- 17700634 TI - Genetic structure of European sheep breeds. AB - Large-scale evaluations of genetic diversity in domestic livestock populations are necessary so that region-specific conservation measures can be implemented. We performed the first such survey in European sheep by analysing 820 individuals from 29 geographically and phenotypically diverse breeds and a closely related wild species at 23 microsatellite loci. In contrast to most other domestic species, we found evidence of widespread heterozygote deficit within breeds, even after removing loci with potentially high frequency of null alleles. This is most likely due to subdivision among flocks (Wahlund effect) and use of a small number of rams for breeding. Levels of heterozygosity were slightly higher in southern than in northern breeds, consistent with declining diversity with distance from the Near Eastern centre of domestication. Our results highlight the importance of isolation in terms of both geography and management in augmenting genetic differentiation through genetic drift, with isolated northern European breeds showing the greatest divergence and hence being obvious targets for conservation. Finally, using a Bayesian cluster analysis, we uncovered evidence of admixture between breeds, which has important implications for breed management. PMID- 17700635 TI - Preferential segregation of metacentric chromosomes in simple Robertsonian heterozygotes of Sorex araneus. AB - One of the hypotheses explaining preferential transmission of metacentrics among simple Robertsonian (Rb) heterozygotes of the common shrew (Sorex araneus L.) invokes the existence of meiotic drive. Thus far, evidence that metacentrics are favoured at meiosis has been obtained indirectly, on the basis of crosses made under controlled conditions. The aim of the present work was to test the hypothesis in a direct study. We analysed products of chromosome segregation among 12 simple heterozygote male subjects from a wild population, with regard to jl, io, nr and mn Rb fusions. We were able to demonstrate significant segregation distortion in favour of all four metacentrics. The level of preferential segregation was independent either of the composition of chromosome arms or the dimensions of metacentrics. We also found that X chromosomes were favoured over Y1Y2 chromosomes during segregation. We discuss the role of meiotic drive in the evolutionary success of metacentric chromosomes in S. araneus, as well as in the emergence of post-hybridization modifications in the zones of contact between races. PMID- 17700636 TI - Studies of self-incompatibility in wild tomatoes: I. S-allele diversity in Solanum chilense (Dun.) Reiche [corrected] (Solanaceae). AB - We characterized the molecular allelic variation of RNases at the self incompatibility (SI) locus of Solanum chilense Dun. We recovered 30 S-RNase allele sequences from 34 plants representing a broad geographic sample. This yielded a species-wide estimate of 35 (95% likelihood interval 31-40) S-alleles. We performed crosses to confirm the association with SI function of 10 of the putative S-RNase allele sequences. Results in all cases were consistent with the expectation that these sequences represent functional alleles under single-locus gametophytic SI. We used the allele sequences to conduct an analysis of selection, as measured by the excess of nonsynonymous changes per site, and found evidence for adaptive changes both within the traditionally defined hypervariable regions and downstream, near the 3'-end of the molecule. PMID- 17700637 TI - Applying new inter-individual approaches to assess fine-scale population genetic diversity in a neotropical frog, Eleutherodactylus ockendeni. AB - We assess patterns of genetic diversity of a neotropical leaflitter frog, Eleutherodactylus ockendeni, in the upper Amazon of Ecuador without a priori delineation of biological populations and with sufficiently intensive sampling to assess inter-individual patterns. We mapped the location of each collected frog across a 5.4 x 1 km landscape at the Jatun Sacha Biological Station, genotyped 185 individuals using five species-specific DNA microsatellite loci, and sequenced a fragment of mitochondrial cytochrome b for a subset of 51 individuals. The microsatellites were characterized by high allelic diversity and homozygote excess across all loci, suggesting that when pooled the sample is not a panmictic population. We conclude that the lack of panmixia is not attributable to the influence of null alleles or biased sampling of consanguineous family groups. Multiple methods of population cluster analysis, using both Bayesian and maximum likelihood approaches, failed to identify discrete genetic clusters across the sampled area. Using multivariate spatial autocorrelation, kinship coefficients and relatedness coefficients, we identify a continuous isolation by distance population structure, with a first patch size of ca. 260 m and apparently large population sizes. Analysis of mtDNA corroborates the observation of high genetic diversity at fine scales: there are multiple haplotypes, they are non-randomly distributed and a binary haplotype correlogram shows significant spatial genetic autocorrelation. We demonstrate the utility of inter-individual genetic methods and caution against making a priori assumptions about population genetic structure based simply on arbitrary or convenient patterns of sampling. PMID- 17700638 TI - Application of proteomics to ecology and population biology. AB - Proteomics is a relatively new scientific discipline that merges protein biochemistry, genome biology and bioinformatics to determine the spatial and temporal expression of proteins in cells, tissues and whole organisms. There has been very little application of proteomics to the fields of behavioral genetics, evolution, ecology and population dynamics, and has only recently been effectively applied to the closely allied fields of molecular evolution and genetics. However, there exists considerable potential for proteomics to impact in areas related to functional ecology; this review will introduce the general concepts and methodologies that define the field of proteomics and compare and contrast the advantages and disadvantages with other methods. Examples of how proteomics can aid, complement and indeed extend the study of functional ecology will be discussed including the main tool of ecological studies, population genetics with an emphasis on metapopulation structure analysis. Because proteomic analyses provide a direct measure of gene expression, it obviates some of the limitations associated with other genomic approaches, such as microarray and EST analyses. Likewise, in conjunction with associated bioinformatics and molecular evolutionary tools, proteomics can provide the foundation of a systems-level integration approach that can enhance ecological studies. It can be envisioned that proteomics will provide important new information on issues specific to metapopulation biology and adaptive processes in nature. A specific example of the application of proteomics to sperm ageing is provided to illustrate the potential utility of the approach. PMID- 17700639 TI - The management of CKD: a look into the future. AB - The increasing global prevalence of chronic kidney disease (CKD) and end-stage renal disease with the associated spiraling cost has profound public health and economic implications. This has made slowing the progression of CKD, a major health-care priority. CKD is invariably characterized by progressive kidney fibrosis and at present, treatment aiming to slow the progression of CKD is limited to aggressive blood pressure control, with few therapies targeting the fibrotic process itself. In this review, we explore the potential of experimental therapeutic strategies, based on preventing or reversing the pathophysiologic steps of kidney remodeling that lead to fibrosis. PMID- 17700640 TI - CD24 is a marker of exosomes secreted into urine and amniotic fluid. AB - Exosomes are small membrane vesicles that are secreted from a variety of cell types into various body fluids including the blood and urine. These vesicles are thought to play a role in cell-cell interactions. CD24 is a small but extensively glycosylated protein linked to the cell surface by means of a glycosyl phosphatidylinositol anchor. In this study we found that CD24 is present in membrane vesicles characterized as exosomes that were isolated from the urine of normal individuals. CD24 was expressed by both tubule cells and podocytes and treatment of the latter with a cholesterol-extracting agent, but not with a calcium ionophore, caused the release of CD24-containing exosomes. Using CD24 as a marker, we found exosomes in the urine of newborn infants and in the amniotic fluid of pregnant women with similar findings made in mice. Interestingly, studies with CD24 knockout mice showed that the exosomes are released from the fetus but not from the mother; however, exosome release was similar from both the knockout and the wild-type mice. This indicates that CD24 is not essential for exosome formation or release but may be a convenient exosome marker. Our studies suggest that exosomal secretion from the embryonic kidney could play a biological role at the fetal-maternal interphase. PMID- 17700641 TI - Polyuria of thyrotoxicosis: downregulation of aquaporin water channels and increased solute excretion. AB - Thyrotoxicosis is a common disorder causing cardiovascular and renal irregularities. In this study, thyrotoxicosis was produced in rats by 14 days of daily thyroxine injection. This was associated with an increase in cardiac index, mean arterial pressure, and renal blood flow compared with euthyroid controls. Food and water intake along with urine output were significantly increased in the thyrotoxic rats compared with control animals associated with a significant increase in solute excretion. Polyuria and increased solute excretion still occurred even when food and water intake was equivalent. These renal responses were associated with significant decreases in AQP1 and AQP2 water channel expression in both the ad lib and paired intake studies in the cortex and inner medulla. The downregulation of AQP2 protein occurred in spite of equivalent plasma arginine vasopressin (AVP) in the ad lib and increased AVP in the paired feeding studies. Solute-free water reabsorption was greater in both the ad lib and paired thyrotoxic than euthyroid rats and was associated with increased Na-K 2Cl cotransporter expression. We propose that the AVP-independent downregulation of AQP2, the observed increase in renal arterial pressure, and decrease in filtration fraction contribute to polyuria the increased solute excretion in spite of enhanced ion transporters in thyrotoxicosis. PMID- 17700642 TI - The use of consensus guidelines for management of cytomegalovirus infection in renal transplantation. AB - Cytomegalovirus (CMV) infection imposes a significant economic burden on susceptible patients after renal transplantation. Our study was conducted to determine the prediction, probability, consequences, and treatment costs of CMV infection under Canadian consensus guidelines in 270 sequential transplant patients. Transplant patients from donors positive (D(+)) for CMV into recipients negative (R(-)) for CMV received antiviral prophylaxis for 14 weeks and all but donor negative (D(-))/R(-) patients were monitored weekly for the CMVpp65 marker expression. Marker-positive patients and patients with CMV infection or disease received antiviral treatment. Within the first 6 months, 27% of the 270 patients tested had incidences of asymptomatic CMV infection, while 9% had CMV syndrome or disease. Only 1% of patients had infection after 6 months. The CMVpp65 marker levels were significantly greater in patients with syndrome or disease; but post test probabilities and predictive value of the marker assay were low. Mean direct costs for care were $2256 and ranged from $927 for D(-)/R(-) patients to $7069 in the D(+)/R(-) patients. Extension of antiviral prophylaxis to D(+) or D(+)/R(+) patients significantly increased the estimated mean costs for an absolute reduction to 4% in CMV syndrome or disease. Our studies show that current guidelines for treatment enable effective control of CMV infection; however, alternative strategies have different economic impact. PMID- 17700643 TI - The economic burden of end-stage renal disease in Canada. AB - End-stage renal disease (ESRD) is a serious illness with significant health consequences and high-cost treatment options. This study estimates direct and indirect cost associated with ESRD from a societal perspective. A prevalence based approach was used to estimate direct health-care costs and productivity losses from short- and long-term disability. An incident-based human capital approach was used to estimate mortality costs as the sum of the discounted present value of current and future productivity losses from premature deaths. Less than 0.1% of Canadians have ESRD; however, the disease generated direct health-care costs of $1.3 billion in the year 2000. The amount of direct spending per person with ESRD is much more than the average spending per person for all health-care conditions. Adding indirect morbidity and mortality cost brings the total burden associated with ESRD to $1.9 billion. This economic impact is higher than that for skin or infectious diseases, about the same as for genitourinary or endocrine diseases, but lower than that for conditions such as cancer or stroke. This economic weight is borne by a relatively small number of individuals. With the rapid increase in the incidence of ESRD, these findings may be useful in setting priorities for research, prevention programs, and in the planning of treatments. A better understanding of the scope and magnitude of the total economic burden of ESRD would help to inform those making policy decisions. PMID- 17700645 TI - Acute injections of the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a fear conditioning test. AB - Individuals with Down syndrome (DS) and Ts65Dn mice (a major animal model of DS) carry an extra copy of the DSCR1 (Down Syndrome Critical Region 1) gene, which encodes for a protein that inhibits calcineurin. Calcineurin itself has been shown to modulate N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation kinetics by decreasing channel mean open time and opening probability. We hypothesize that the overexpression of DSCR1 in persons with DS and Ts65Dn mice would inhibit normal calcineurin activity and produce pathological increases in NMDAR mean open time and opening probability. These kinetic changes should in turn produce an increase in inhibition of NMDAR-mediated currents by open channel blockers. To test this hypothesis, we investigated the locomotor-stimulating effects of MK-801 on Ts65Dn mice and have found that these mice display an increased sensitivity to this compound. Furthermore, we have found that acute injections (5 mg/kg, i.p.) of the uncompetitive NMDAR antagonist memantine rescue performance deficits of Ts65Dn mice on a fear conditioning test. Because the actions of memantine on NMDAR kinetics had been shown by others to mimic somewhat the actions of calcineurin, we attributed this positive effect of memantine on Ts65Dn mice to a drug-mediated 'normalization' of NMDAR function. To our knowledge, this is the first instance in which the acute injection of a pharmacological agent has improved the behavioral performance of Ts65Dn mice in a test of learning and memory. These results are very promising from a potential therapeutic perspective, given memantine's current status as a Food and Drug Administration (FDA)-approved drug. PMID- 17700644 TI - Anxiogenic-like behavioral phenotype of mice deficient in phosphodiesterase 4B (PDE4B). AB - Phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP and plays a critical role in controlling its intracellular concentration, has been implicated in depression- and anxiety-like behaviors. However, the functions of the four PDE4 subfamilies (PDE4A, PDE4B, PDE4C, and PDE4D) remain largely unknown. In animal tests sensitive to anxiolytics, antidepressants, memory enhancers, or analgesics, we examined the behavioral phenotype of mice deficient in PDE4B (PDE4B-/-). Immunoblot analysis revealed loss of PDE4B expression in the cerebral cortex and amygdala of PDE4B-/- mice. The reduction of PDE4B expression was accompanied by decreases in PDE4 activity in the brain regions of PDE4B-/- mice. Compared to PDE4B+/+ littermates, PDE4B-/- mice displayed anxiogenic-like behavior, as evidenced by decreased head-dips and time spent in head-dipping in the holeboard test, reduced transitions and time on the light side in the light dark transition test, and decreased initial exploration and rears in the open field test. Consistent with anxiogenic-like behavior, PDE4B-/- mice displayed increased levels of plasma corticosterone. In addition, these mice also showed a modest increase in the proliferation of neuronal cells in the hippocampal dentate gyrus. In the forced-swim test, PDE4B-/- mice exhibited decreased immobility; however, this was not supported by the results from the tail-suspension test. PDE4B-/- mice did not display changes in memory, locomotor activity, or nociceptive responses. Taken together, these results suggest that the PDE4B subfamily is involved in signaling pathways that contribute to anxiogenic-like effects on behavior. PMID- 17700646 TI - Estrogen administration negatively alters mood following monoaminergic depletion and psychosocial stress in postmenopausal women. AB - Differences in the rates of affective disorders between women and men may relate to gender differences in gonadal steroid levels such as estrogen that have effects on brain monoamines important to mood regulation. Changes in estrogen secretion patterns during the perimenopause and menopause may be relevant to the increased risk for affective symptoms at that time. This study examined whether 17beta-estradiol (E2) administration can modify the mood effects of experimental psychosocial stress following acute monoamine depletion in postmenopausal women. Subjects consisted of 15 normal postmenopausal women (PMW) (ages 67.1+/-11.2 years) blindly placed on either oral placebo or E2 (1 mg/day for 1 month, then 2 mg/day for 2 months). At the end of the 3-month treatment phase, subjects participated in three blinded depletion challenges in which they ingested each of three amino-acid mixtures: deficient in tryptophan, deficient in phenylalanine/tyrosine, or nutritionally balanced. After 5 h, subjects performed the Trier Social Stress Test (TSST), followed by mood and anxiety ratings. E2 treated subjects exhibited a significant increase in negative mood and anxiety after the TSST compared to placebo-treated women. These effects were independent of monoamine depletion and were not manifest before the TSST or at baseline. Exogenous estrogen administration in PMW may alter or modulate emotional reactivity to stressful events and may alter the sensitivity of emotional regulation. This modulation appears to be independent of alterations in monoaminergic neurotransmission. The dose of estrogen used after menopause may be important in determining the effects of gonadal steroids on emotional regulation. PMID- 17700647 TI - Repeated unpredictable stress and antidepressants differentially regulate expression of the bcl-2 family of apoptotic genes in rat cortical, hippocampal, and limbic brain structures. AB - Apoptosis has been proposed as a contributing cellular mechanism to the structural alterations that have been observed in stress-related mood disorders. Antidepressants, on the other hand, are hypothesized to exert trophic and/or neuroprotective actions. The present study examined the regulation of the major antiapoptotic (Bcl-2, Bcl-xl) and proapoptotic (Bax) genes by repeated unpredictable stress (an animal model of depression) and antidepressant treatments (ADT). In adult rats, exposure to unpredictable stress reduced Bcl-2 mRNA levels in the central nucleus of the amygdala (CeA), cingulate (Cg), and frontal (Fr) cortices. Bcl-xl mRNA was significantly decreased in hippocampal subfields. In contrast, chronic administration of clinically effective antidepressants from four different classes, ie fluoxetine, reboxetine, tranylcypromine, and electroconvulsive seizures (ECS) upregulated Bcl-2 mRNA expression in the Cg, Fr, and CeA. Reboxetine, tranylcypromine, and ECS selectively increased Bcl-xl, but not Bcl-2 mRNA expression in the hippocampus. Chemical ADT but not ECS, robustly enhanced Bcl-2 expression in the medial amygdaloid nucleus and ventromedial hypothalamus. Fluoxetine did not influence Bcl-xl expression in the hippocampus, but it was the only ADT that decreased Bax expression in this region. In the CeA, again in direct contrast to the stress effects, exposure to all classes of ADTs significantly increased Bcl-2 mRNA. The selective regulation of Bcl-xl and Bax in hippocampal subfields and of Bcl-2 in the Cg cortex, amygdala, and hypothalamus suggests that these cellular adaptations contribute to the long-term neural plastic adaptations to stress and ADTs in cortical, hypothalamic, and limbic brain structures. PMID- 17700648 TI - The Pro12Ala polymorphism of the PPAR-gamma2 gene affects associations of fish intake and marine n-3 fatty acids with glucose metabolism. AB - BACKGROUND/OBJECTIVES: Data on associations between marine n-3 fatty acids and glucose metabolism are inconsistent. Therefore, we explored effects of the Pro12Ala polymorphism in peroxisome proliferator-activated receptor (PPAR)-gamma2 gene on associations of fish intake and dietary and plasma eicosapentaenoic and docosahexaenoic acid with glucose metabolism. The design comprises of the cross sectional analysis. SUBJECTS/METHODS: The Pro12Ala variant in the PPAR-gamma2 (PPARG) gene was genotyped in 571 non-diabetic relatives of subjects with type II diabetes. The dietary intake was measured by a 3-day food record, and the plasma cholesterol ester fatty acid composition was analysed with gas chromatography. Associations of dietary and plasma variables with insulin resistance and fasting and 2-h glucose and free fatty acid concentrations were analysed with multiple linear regression analysis. RESULTS: In men, there was a significant interaction between PPARG polymorphism and plasma docosahexaenoic acid on fasting free fatty acid concentration (P=0.036), and genotype-stratified models showed an inverse association in Pro homozygotes only (P=0.028). In women, the proportion of plasma eicosapentaenoic acid was higher in Ala-allele carriers compared to Pro homozygotes (1.67 vs 1.44% respectively, P=0.006). A significant interaction between PPARG polymorphism and fish intake on 2-h glucose was found in women (P=0.021), and genotype-stratified models suggested an inverse association in Ala allele carriers only (P=0.039). CONCLUSIONS: The findings suggest that PPARG polymorphism might affect the plasma proportion of eicosapentaenoic acid and modulate the associations of fish intake and marine n-3 fatty acids with glucose metabolism and fasting free fatty acids. PMID- 17700649 TI - Should snacks be recommended in obesity treatment? A 1-year randomized clinical trial. AB - OBJECTIVE: To study the effect to recommend no snacks vs three snacks per day on 1-year weight loss. The hypothesis was that it is easier to control energy intake and lose weight if snacks in between meals are omitted. SUBJECTS/METHOD: In total 140 patients (36 men, 104 women), aged 18-60 years and body mass index>30 kg/m(2) were randomized and 93 patients (27 men, 66 women) completed the study. A 1-year randomized intervention trial was conducted with two treatment arms with different eating frequencies; 3 meals/day (3M) or 3 meals and 3 snacks/day (3+3M). The patients received regular and individualized counseling by dieticians. Information on eating patterns, dietary intake, weight and metabolic variables was collected at baseline and after 1 year. RESULTS: Over 1 year the 3M group reported a decrease in the number of snacks whereas the 3+3M group reported an increase (-1.1 vs +0.4 snacks/day, respectively, P<0.0001). Both groups decreased energy intake and E% (energy percent) fat and increased E% protein and fiber intake but there was no differences between the groups. Both groups lost weight, but there was no significant difference in weight loss after 1 year of treatment (3M vs 3+3M=-4.1+/-6.1 vs -5.9+/-9.4 kg; P=0.31). Changes in metabolic variables did not differ between the groups, except for high-density lipoprotein that increased in the 3M group but not in 3+3M group (P<0.033 for group difference). CONCLUSION: Recommending snacks or not between meals does not influence 1-year weight loss. PMID- 17700650 TI - Nutritional intervention to reduce the n-6/n-3 fatty acid ratio increases adiponectin concentration and fatty acid oxidation in healthy subjects. AB - BACKGROUND/OBJECTIVES: Consumption of n-3 polyunsaturated fatty acids (PUFA) has a favourable impact on inflammation and cardiovascular disease. However, the Western diet is characterized by a low n-3 PUFA intake and an imbalance in the n 6/n-3 PUFA ratio. Study the effect 10-week of diet modification to decrease the n 6/n-3 PUFA ratio on cardiovascular risk factors and resting energy expenditure. SUBJECTS AND METHODS: Ten-week dietary intervention in 17 healthy subjects. Dietary intake, euglycemic hyperinsulinemic clamp, indirect calorimetry, lipid profile, hormones, inflammatory markers and erythrocyte membrane fatty acid composition were recorded before and at the end of the intervention. Comparisons are between baseline and post-treatment levels. RESULTS: Dietary records of the linoleic acid/alpha-linolenic acid ratio (baseline: 32.2 (s.d. 3.7) vs post intervention: 2.2 (s.d. 0.1), P<0.0001) and erythrocyte membrane fatty acid composition reflected good compliance. Dietary intervention was associated with significant reductions in TNF-alpha (baseline: 2.2 (s.d. 0.3), post-intervention: 1.5 (s.d. 0.3) pg/ml, P=0.01) and low-density lipoprotein-cholesterol (baseline: 2.5 (s.d. 0.2), post-intervention: 2.3 (s.d. 0.1) mmol/l, P=0.03) and increased adiponectin (baseline: 6.5 (s.d. 0.7), post-intervention: 7.6 (s.d. 0.6) microg/ml, P=0.02). Fasting lipid oxidation was increased (baseline: 0.7 (s.d. 0.1), post-intervention: 0.9 (s.d. 0.1) mg/kg x min, P=0.01), whereas glucose oxidation decreased in both fasting (baseline: 1.6 (s.d. 0.1), post-intervention: 1.3 (s.d. 0.1) mg/kg x min, P=0.02) and hyperinsulinaemic conditions (baseline: 3.6 (s.d. 0.1), post-intervention: 3.3 (s.d. 0.1) mg/kg x min, P=0.04). Insulin sensitivity was not affected by the intervention. CONCLUSION: A decreased n-6/n-3 PUFA ratio can be achieved with simple dietary counselling, resulting in multiple, potentially favourable effects on the metabolic and inflammatory profiles. PMID- 17700651 TI - A dietary survey to determine if patients with coeliac disease are meeting current healthy eating guidelines and how their diet compares to that of the British general population. AB - OBJECTIVES: To assess the dietary intake of people with coeliac disease (CD) and to determine if they are meeting the current dietary reference values (DRVs). To compare dietary intakes of people with CD to the dietary intake of the general population. The nutritional contribution of gluten-free products (GFPs) and current purchasing trends was also evaluated. SUBJECTS/METHODS: 106 patients were invited to participate via post. Three-day food diary to assess intake and a short simple questionnaire that looked at purchasing trends of GFP. RESULTS: Forty-nine patients returned the food diary and 48 returned the questionnaire. Patients were found to have a low intake of energy, non-starch polysaccharides (NSPs), vitamin D and calcium. They were obtaining a significantly lower proportion of energy from fat and a significantly higher proportion of energy from protein than the DRVs (P<0.05). Intake was comparable to the general population for most nutrients, except they had a significantly greater intake of protein, a lower intake of fat and a significantly lower intake of vitamin D (P<0.05). Specialist GFP, especially those obtained on prescription, were an important source of energy, carbohydrate, NSP, calcium and iron. CONCLUSIONS: Patients with CD are at risk of having an inadequate intake of calcium, NSP and vitamin D. Specialist GFP, which were obtained on prescription, helped patients get a balanced diet and without these patients would be at an increased risk of many deficiencies. PMID- 17700652 TI - Nutrition in clinical practice-the refeeding syndrome: illustrative cases and guidelines for prevention and treatment. AB - The refeeding syndrome is a potentially lethal complication of refeeding in patients who are severely malnourished from whatever cause. Too rapid refeeding, particularly with carbohydrate may precipitate a number of metabolic and pathophysiological complications, which may adversely affect the cardiac, respiratory, haematological, hepatic and neuromuscular systems leading to clinical complications and even death. We aimed to review the development of the refeeding syndrome in a variety of situations and, from this and the literature, devise guidelines to prevent and treat the condition. We report seven cases illustrating different aspects of the refeeding syndrome and the measures used to treat it. The specific complications encountered, their physiological mechanisms, identification of patients at risk, and prevention and treatment are discussed. Each case developed one or more of the features of the refeeding syndrome including deficiencies and low plasma levels of potassium, phosphate, magnesium and thiamine combined with salt and water retention. These responded to specific interventions. In most cases, these abnormalities could have been anticipated and prevented. The main features of the refeeding syndrome are described with a protocol to anticipate, prevent and treat the condition in adults. PMID- 17700653 TI - Assessment of body composition in Sri Lankan children: validation of a bioelectrical impedance prediction equation. AB - OBJECTIVE: To develop bioelectrical impedance analysis (BIA) equations to predict total body water (TBW) and fat-free mass (FFM) of Sri Lankan children. SUBJECTS/METHODS: Data were collected from 5- to 15-year-old healthy children. They were randomly assigned to validation (M/F: 105/83) and cross-validation (M/F: 53/41) groups. Height, weight and BIA were measured. TBW was assessed using isotope dilution method (D(2)O). Multiple regression analysis was used to develop preliminary equations and cross-validated on an independent group. Final prediction equation was constructed combining the two groups and validated by PRESS (prediction of sum of squares) statistics. Impedance index (height(2)/impedance; cm(2)/Omega), weight and sex code (male=1; female=0) were used as variables. RESULTS: Independent variables of the final prediction equation for TBW were able to predict 86.3% of variance with root means-squared error (RMSE) of 2.1 l. PRESS statistics was 2.1 l with press residuals of 1.2 l. Independent variables were able to predict 86.9% of variance of FFM with RMSE of 2.7 kg. PRESS statistics was 2.8 kg with press residuals of 1.4 kg. Bland Altman technique showed that the majority of the residuals were within mean bias+/-1.96 s.d. CONCLUSIONS: Results of this study provide BIA equation for the prediction of TBW and FFM in Sri Lankan children. To the best of our knowledge there are no published BIA prediction equations validated on South Asian populations. Results of this study need to be affirmed by more studies on other closely related populations by using multi-component body composition assessment. PMID- 17700657 TI - Division of labour. PMID- 17700658 TI - Mbeki's mistake. PMID- 17700663 TI - Not so secure after all. PMID- 17700664 TI - Dengue fever climbs the social ladder. PMID- 17700665 TI - Geneticist trades plants for politics. Nina Fedoroff interviewed by Emma Marris. PMID- 17700666 TI - Achievement index climbs the ranks. PMID- 17700667 TI - Transparency urged over research payments. PMID- 17700671 TI - Powerful incentives. PMID- 17700668 TI - Snapshot: trouble in paradise. PMID- 17700672 TI - Space exploration: secrets of the martian soil. PMID- 17700673 TI - Materials chemistry: space invaders. PMID- 17700674 TI - International research may leave women adrift. PMID- 17700675 TI - Chemical reaction to the many-worlds hypothesis. PMID- 17700677 TI - Scientific bodies must take own action on emissions. PMID- 17700676 TI - Bush has not obstructed environmental protection. PMID- 17700681 TI - Biological chemistry: enzymes line up for assembly. PMID- 17700682 TI - Seismology: talc at fault. PMID- 17700684 TI - Materials science: metal turned to glass. PMID- 17700683 TI - Biochemistry: designer enzymes. PMID- 17700685 TI - Parkinson's disease: pro-survival effects of PINK1. PMID- 17700686 TI - Astrophysics: photons from a hotter hell. PMID- 17700688 TI - Computational biochemistry: models of transition. PMID- 17700690 TI - Earth science: coastal catastrophe in Phoenicia. PMID- 17700691 TI - Obituary: Anne McLaren (1927-2007). PMID- 17700692 TI - Obituary: Donald Michie (1923-2007). PMID- 17700693 TI - The common biology of cancer and ageing. AB - At first glance, cancer and ageing would seem to be unlikely bedfellows. Yet the origins for this improbable union can actually be traced back to a sequence of tragic--and some say unethical--events that unfolded more than half a century ago. Here we review the series of key observations that has led to a complex but growing convergence between our understanding of the biology of ageing and the mechanisms that underlie cancer. PMID- 17700694 TI - A turbulent wake as a tracer of 30,000 years of Mira's mass loss history. AB - Mira is one of the first variable stars ever discovered and it is the prototype (and also the nearest example) of a class of low-to-intermediate-mass stars in the late stages of stellar evolution. These stars are relatively common and they return a large fraction of their original mass to the interstellar medium (ISM) (ref. 2) through a processed, dusty, molecular wind. Thus stars in Mira's stage of evolution have a direct impact on subsequent star and planet formation in their host galaxy. Previously, the only direct observation of the interaction between Mira-type stellar winds and the ISM was in the infrared. Here we report the discovery of an ultraviolet-emitting bow shock and turbulent wake extending over 2 degrees on the sky, arising from Mira's large space velocity and the interaction between its wind and the ISM. The wake is visible only in the far ultraviolet and is consistent with an unusual emission mechanism whereby molecular hydrogen is excited by turbulent mixing of cool molecular gas and shock heated gas. This wind wake is a tracer of the past 30,000 years of Mira's mass loss history and provides an excellent laboratory for studying turbulent stellar wind-ISM interactions. PMID- 17700695 TI - Generation of optical 'Schrodinger cats' from photon number states. AB - Schrodinger's cat is a Gedankenexperiment in quantum physics, in which an atomic decay triggers the death of the cat. Because quantum physics allow atoms to remain in superpositions of states, the classical cat would then be simultaneously dead and alive. By analogy, a 'cat' state of freely propagating light can be defined as a quantum superposition of well separated quasi-classical states-it is a classical light wave that simultaneously possesses two opposite phases. Such states play an important role in fundamental tests of quantum theory and in many quantum information processing tasks, including quantum computation, quantum teleportation and precision measurements. Recently, optical Schrodinger 'kittens' were prepared; however, they are too small for most of the aforementioned applications and increasing their size is experimentally challenging. Here we demonstrate, theoretically and experimentally, a protocol that allows the generation of arbitrarily large squeezed Schrodinger cat states, using homodyne detection and photon number states as resources. We implemented this protocol with light pulses containing two photons, producing a squeezed Schrodinger cat state with a negative Wigner function. This state clearly exhibits several quantum phase-space interference fringes between the 'dead' and 'alive' components, and is large enough to become useful for quantum information processing and experimental tests of quantum theory. PMID- 17700696 TI - Vitrification of a monatomic metallic liquid. AB - Although the majority of glasses in use in technology are complex mixtures of oxides or chalcogenides, there are numerous examples of pure substances 'glassformers'-that also fail to crystallize during cooling. Most glassformers are organic molecular systems, but there are important inorganic examples too, such as silicon dioxide and elemental selenium (the latter being polymeric). Bulk metallic glasses can now be made; but, with the exception of Zr50Cu50 (ref. 4), they require multiple components to avoid crystallization during normal liquid cooling. Two-component 'metglasses' can often be achieved by hyperquenching, but this has not hitherto been achieved with a single-component system. Glasses form when crystal nucleation rates are slow, although the factors that create the slow nucleation conditions are not well understood. Here we apply the insights gained in a recent molecular dynamics simulation study to create conditions for successful vitrification of metallic liquid germanium. Our results also provide micrographic evidence for a rare polyamorphic transition preceding crystallization of the diamond cubic phase. PMID- 17700697 TI - Talc-bearing serpentinite and the creeping section of the San Andreas fault. AB - The section of the San Andreas fault located between Cholame Valley and San Juan Bautista in central California creeps at a rate as high as 28 mm yr(-1) (ref. 1), and it is also the segment that yields the best evidence for being a weak fault embedded in a strong crust. Serpentinized ultramafic rocks have been associated with creeping faults in central and northern California, and serpentinite is commonly invoked as the cause of the creep and the low strength of this section of the San Andreas fault. However, the frictional strengths of serpentine minerals are too high to satisfy the limitations on fault strength, and these minerals also have the potential for unstable slip under some conditions. Here we report the discovery of talc in cuttings of serpentinite collected from the probable active trace of the San Andreas fault that was intersected during drilling of the San Andreas Fault Observatory at Depth (SAFOD) main hole in 2005. We infer that the talc is forming as a result of the reaction of serpentine minerals with silica-saturated hydrothermal fluids that migrate up the fault zone, and the talc commonly occurs in sheared serpentinite. This discovery is significant, as the frictional strength of talc at elevated temperatures is sufficiently low to meet the constraints on the shear strength of the fault, and its inherently stable sliding behaviour is consistent with fault creep. Talc may therefore provide the connection between serpentinite and creep in the San Andreas fault, if shear at depth can become localized along a talc-rich principal slip surface within serpentinite entrained in the fault zone. PMID- 17700698 TI - Female mate-choice drives the evolution of male-biased dispersal in a social mammal. AB - Dispersal has a significant impact on lifetime reproductive success, and is often more prevalent in one sex than the other. In group-living mammals, dispersal is normally male-biased and in theory this sexual bias could be a response by males to female mate preferences, competition for access to females or resources, or the result of males avoiding inbreeding. There is a lack of studies on social mammals that simultaneously assess these factors and measure the fitness consequences of male dispersal decisions. Here we show that male-biased dispersal in the spotted hyaena (Crocuta crocuta) most probably results from an adaptive response by males to simple female mate-choice rules that have evolved to avoid inbreeding. Microsatellite profiling revealed that females preferred sires that were born into or immigrated into the female's group after the female was born. Furthermore, young females preferred short-tenured sires and older females preferred longer-tenured sires. Males responded to these female mate preferences by initiating their reproductive careers in groups containing the highest number of young females. As a consequence, 11% of males started their reproductive career in their natal group and 89% of males dispersed. Males that started reproduction in groups containing the highest number of young females had a higher long-term reproductive success than males that did not. The female mate choice rules ensured that females effectively avoided inbreeding without the need to discriminate directly against close kin or males born in their own group, or to favour immigrant males. The extent of male dispersal as a response to such female mate preferences depends on the demographic structure of breeding groups, rather than the genetic relatedness between females and males. PMID- 17700699 TI - Correlation between neural spike trains increases with firing rate. AB - Populations of neurons in the retina, olfactory system, visual and somatosensory thalamus, and several cortical regions show temporal correlation between the discharge times of their action potentials (spike trains). Correlated firing has been linked to stimulus encoding, attention, stimulus discrimination, and motor behaviour. Nevertheless, the mechanisms underlying correlated spiking are poorly understood, and its coding implications are still debated. It is not clear, for instance, whether correlations between the discharges of two neurons are determined solely by the correlation between their afferent currents, or whether they also depend on the mean and variance of the input. We addressed this question by computing the spike train correlation coefficient of unconnected pairs of in vitro cortical neurons receiving correlated inputs. Notably, even when the input correlation remained fixed, the spike train output correlation increased with the firing rate, but was largely independent of spike train variability. With a combination of analytical techniques and numerical simulations using 'integrate-and-fire' neuron models we show that this relationship between output correlation and firing rate is robust to input heterogeneities. Finally, this overlooked relationship is replicated by a standard threshold-linear model, demonstrating the universality of the result. This connection between the rate and correlation of spiking activity links two fundamental features of the neural code. PMID- 17700700 TI - Cdk1 is sufficient to drive the mammalian cell cycle. AB - Unicellular organisms such as yeasts require a single cyclin-dependent kinase, Cdk1, to drive cell division. In contrast, mammalian cells are thought to require the sequential activation of at least four different cyclin-dependent kinases, Cdk2, Cdk3, Cdk4 and Cdk6, to drive cells through interphase, as well as Cdk1 to proceed through mitosis. This model has been challenged by recent genetic evidence that mice survive in the absence of individual interphase Cdks. Moreover, most mouse cell types proliferate in the absence of two or even three interphase Cdks. Similar results have been obtained on ablation of some of the activating subunits of Cdks, such as the D-type and E-type cyclins. Here we show that mouse embryos lacking all interphase Cdks (Cdk2, Cdk3, Cdk4 and Cdk6) undergo organogenesis and develop to midgestation. In these embryos, Cdk1 binds to all cyclins, resulting in the phosphorylation of the retinoblastoma protein pRb and the expression of genes that are regulated by E2F transcription factors. Mouse embryonic fibroblasts derived from these embryos proliferate in vitro, albeit with an extended cell cycle due to inefficient inactivation of Rb proteins. However, they become immortal on continuous passage. We also report that embryos fail to develop to the morula and blastocyst stages in the absence of Cdk1. These results indicate that Cdk1 is the only essential cell cycle Cdk. Moreover, they show that in the absence of interphase Cdks, Cdk1 can execute all the events that are required to drive cell division. PMID- 17700701 TI - Selection and evolution of enzymes from a partially randomized non-catalytic scaffold. AB - Enzymes are exceptional catalysts that facilitate a wide variety of reactions under mild conditions, achieving high rate-enhancements with excellent chemo-, regio- and stereoselectivities. There is considerable interest in developing new enzymes for the synthesis of chemicals and pharmaceuticals and as tools for molecular biology. Methods have been developed for modifying and improving existing enzymes through screening, selection and directed evolution. However, the design and evolution of truly novel enzymes has relied on extensive knowledge of the mechanism of the reaction. Here we show that genuinely new enzymatic activities can be created de novo without the need for prior mechanistic information by selection from a naive protein library of very high diversity, with product formation as the sole selection criterion. We used messenger RNA display, in which proteins are covalently linked to their encoding mRNA, to select for functional proteins from an in vitro translated protein library of >10(12 )independent sequences without the constraints imposed by any in vivo step. This technique has been used to evolve new peptides and proteins that can bind a specific ligand, from both random-sequence libraries and libraries based on a known protein fold. We now describe the isolation of novel RNA ligases from a library that is based on a zinc finger scaffold, followed by in vitro directed evolution to further optimize these enzymes. The resulting ligases exhibit multiple turnover with rate enhancements of more than two-million-fold. PMID- 17700703 TI - Crystal structure of the MgtE Mg2+ transporter. AB - The magnesium ion Mg2+ is a vital element involved in numerous physiological processes. Mg2+ has the largest hydrated radius among all cations, whereas its ionic radius is the smallest. It remains obscure how Mg2+ transporters selectively recognize and dehydrate the large, fully hydrated Mg2+ cation for transport. Recently the crystal structures of the CorA Mg2+ transporter were reported. The MgtE family of Mg2+ transporters is ubiquitously distributed in all phylogenetic domains, and human homologues have been functionally characterized and suggested to be involved in magnesium homeostasis. However, the MgtE transporters have not been thoroughly characterized. Here we determine the crystal structures of the full-length Thermus thermophilus MgtE at 3.5 A resolution, and of the cytosolic domain in the presence and absence of Mg2+ at 2.3 A and 3.9 A resolutions, respectively. The transporter adopts a homodimeric architecture, consisting of the carboxy-terminal five transmembrane domains and the amino-terminal cytosolic domains, which are composed of the superhelical N domain and tandemly repeated cystathionine-beta-synthase domains. A solvent accessible pore nearly traverses the transmembrane domains, with one potential Mg2+ bound to the conserved Asp 432 within the pore. The transmembrane (TM)5 helices from both subunits close the pore through interactions with the 'connecting helices', which connect the cystathionine-beta-synthase and transmembrane domains. Four putative Mg2+ ions are bound at the interface between the connecting helices and the other domains, and this may lock the closed conformation of the pore. A structural comparison of the two states of the cytosolic domains showed the Mg2+-dependent movement of the connecting helices, which might reorganize the transmembrane helices to open the pore. These findings suggest a homeostasis mechanism, in which Mg2+ bound between cytosolic domains regulates Mg2+ flux by sensing the intracellular Mg2+ concentration. Whether this presumed regulation controls gating of an ion channel or opening of a secondary active transporter remains to be determined. PMID- 17700704 TI - Are oncoantigens suitable targets for anti-tumour therapy? AB - When a vaccine-elicited immune response is directed against oncoantigens- proteins required for the neoplastic process--the chance that the tumour will evade the vaccine should be reduced. But how can these causal oncoantigens be identified? One approach is to find tumour-associated and microenvironment associated oncoantigens required for progression from one tumour stage to the next by comparing gene signatures isolated from the different stages of tumour progression in cancer-prone transgenic mice. Mouse oncoantigens subsequently shown to be involved in human cancer can then be validated in mouse vaccination experiments. This provides the groundwork for the rational design of cancer vaccines for clinical trials. PMID- 17700705 TI - Direct selection of targeted adenovirus vectors by random peptide display on the fiber knob. AB - Targeting of gene transfer at the level of cell entry is one of the most attractive challenges in vector development. However, attempts to redirect adenovirus vectors to alternative receptors by engineering the capsid-coding region have shown limited success because proper targeting ligand-receptor systems on the cells of interest are generally unknown. Systematic approaches to generate adenovirus vectors targeting any given cell type need to be developed to achieve this goal. Here, we constructed an adenovirus library that was generated by a Cre-lox-mediated in vitro recombination between an adenoviral fiber-modified plasmid library and genomic DNA to display random peptides on a fiber knob. As proof of concept, we screened the adenovirus display library on a glioma cell line and observed selection of several particular peptide sequences. The targeted vector carrying the most frequently isolated peptide significantly enhanced gene transduction in the glioma cell line but not in many other cell lines. Because the insertion of a pre-selected peptide into a fiber knob often fails to generate an adenovirus vector, the selection of targeting peptides is highly useful in the context of the adenoviral capsid. This vector-screening system can facilitate the development of a targeted adenovirus vector for a variety of applications in medicine. PMID- 17700707 TI - Directing human embryonic stem cells to generate vascular progenitor cells. AB - Pluripotent human embryonic stem cells (hESCs) differentiate into most of the cell types of the adult human body, including vascular cells. Vascular cells, such as endothelial cells and vascular smooth muscle cells (SMCs) are significant contributors to tissue repair and regeneration. In addition to their potential applications for treatment of vascular diseases and stimulation of ischemic tissue growth, it is also possible that endothelial cells and SMCs derived from hESCs can be used to engineer artificial vessels to repair damaged vessels and form vessel networks in engineered tissues. Here we review the current status of directing hESCs to differentiate to vascular cells. PMID- 17700706 TI - Gene delivery by the hSP-B promoter to lung alveolar type II epithelial cells in LAL-knockout mice through bone marrow mesenchymal stem cells. AB - Tissue damage and inflammation promote bone marrow stem cells (BMSCs) to differentiate into a variety of cell types in residing tissues. BMSCs can stably maintain their plasticity and are an ideal cell population for delivery of therapeutic genes to non-hematopoietic tissues. Using lacZ as a reporter gene, we demonstrated that the lung-specific human surfactant protein B (hSP-B) 1.5-kb promoter is able to deliver the lacZ gene into the lung of lysosomal acid lipase (LAL) gene-knockout (lal-/-) mice by beta-galactosidase staining, flow cytometry and double immunofluorescence staining. Around 10-18% alveolar type II epithelial cells (AT II cells) exhibited positive lacZ gene expression after 8 weeks of BMSC injection in recipient lal-/- mice. The wild-type mice exhibited no expression after the same treatment. BMSCs from hSP-B 1.5-kb lacZ transgenic mice entered and repopulated in lal-/- bone marrow. The study supports a concept that pulmonary inflammation caused by LAL deficiency can trigger BMSC residing in lal /- bone marrow, migrating into the lung and converting into residential AT II cells. The hSP-B 1.5 kb promoter is an ideal tool to deliver therapeutic genes into AT II cells through BMSCs to cure pulmonary inflammation-triggered diseases. PMID- 17700708 TI - Gene therapy approaches for stem cell protection. AB - Cytotoxic exposure of bone marrow and other non-hematopoietic organs containing self-renewing stem cell populations is associated with damage to the supportive microenvironment. Recent evidence indicates that radical oxygen species resulting from the initial oxidative stress persist for months after ionizing irradiation exposure of tissues including oral cavity, esophagus, lung and bone marrow. Antioxidant gene therapy using manganese superoxide dismutase plasmid liposomes has provided organ-specific radiation protection associated with delay or prevention of acute and late toxicity. Recent evidence has suggested that manganese superoxide dismutase transgene expression in cells of the organ microenvironment contributes significantly to the mechanism of protection. Incorporating this knowledge into designs of novel approaches for stem cell protection is addressed in the present review. PMID- 17700709 TI - In vivo splenic CD11c cells downregulate CD4 T-cell response thereby decreasing systemic immunity to gene-modified tumour cell vaccine. AB - One of the factors influencing the efficacy of tumour cell vaccines is the site of immunization. We have shown previously that gene-modified vaccines delivered directly inside the spleen induced antigen cross-presentation by splenic antigen presenting cells (not B cells). Here, we examined the interaction between splenic CD11c(+) cells and antigen-specific CD4(+) T cells. We used tumour cells expressing ovalbumin (OVA), a situation where CD4(+) T-cell help is required for the generation of a cytotoxic T lymphocyte response. Using in vivo bioluminescence imaging of luciferase-expressing EL4-OVA cells, we could demonstrate that tumour cells were located exclusively inside the spleen following intrasplenic injection. We showed that after intrasplenic immunization with T/SA-OVA cells, splenic class I(+) class II(+) CD11c(+) cells engulfed and presented in vivo the OVA class I-restricted peptide SIINFEKL. However, in vivo previously adoptively transferred 5,6-carboxy-succinimidyl-fluorescein-ester labelled transgenic CD4(+)KJI-26(+) cells specific for the class II OVA(323-339) peptide underwent abortive proliferation in the spleen. These CD4(+)KJI-26(+) cells were only transiently activated and produced IL-10 and IL-4 and not IFN gamma. It appears that splenic CD11c(+) cells can downregulate splenic specific CD4(+) T-cell response thereby leading to a decrease in antitumour systemic immunity. PMID- 17700713 TI - Characterization of atypical antipsychotic drugs by a late decrease of striatal alpha1 spectral power in the electropharmacogram of freely moving rats. AB - BACKGROUND AND PURPOSE: Drug administration modifies the balance of neurotransmitter-controlled ion channel activity and consequently the firing pattern of local neuronal populations and intracerebral field potentials. Fast Fourier Transformation of these field potentials provides an electropharmacogram depicting drug-induced changes within defined frequency ranges. The present investigation was undertaken to investigate the difference between atypical and typical antipsychotic drugs. EXPERIMENTAL APPROACH: Adult Fisher rats were implanted with 4 bipolar concentric steel electrodes using a stereotactic surgical procedure. Field potentials from four selected brain areas in freely moving rats were used to analyse the frequency content of the electropharmacogram after administration of 4 clinically used atypical antipsychotic drugs. KEY RESULTS: Atypical antipsychotics exerted effects similar to those reported for typical antipsychotics, on the electropharmacogram during the first hour after administration, whereas clear differences emerged during the second and third hour after dosing. During the latter period, only atypical antipsychotic drugs produced a statistically significant decrease in alpha1 and beta1 spectral power, especially within the striatum, somewhat less in the cortex. CONCLUSIONS AND IMPLICATIONS: Previous studies have attributed alpha1 frequency changes to the influence of 5-hydroxytryptamine (5-HT) and the present data are consistent with additional binding of atypical drugs to 5-HT receptors. This implies that a change in the balance between dopaminergic and 5-hydroxytryptaminergic neurotransmission (activation of both) is likely to underlie the relative lack of extrapyramidal side effects characteristic of atypical antipsychotics and also for their higher efficacy in the treatment of mood and cognition deficits in schizophrenics. PMID- 17700714 TI - Nitric oxide selectively depletes macrophages in atherosclerotic plaques via induction of endoplasmic reticulum stress. AB - BACKGROUND AND PURPOSE: Macrophages in atherosclerotic plaques have a tremendous impact on atherogenesis and plaque destabilization. We previously demonstrated that treatment of plaques in cholesterol-fed rabbits with the nitric oxide (NO) donor molsidomine preferentially eliminates macrophages, thereby favouring features of plaque stability. In this study, we investigated the underlying mechanism. EXPERIMENTAL APPROACH: Macrophages and smooth muscle cells (SMCs) were treated in vitro with the NO donors, spermine NONOate or S-nitroso-N acetylpenicillamine (SNAP) as well as with the well-known endoplasmic reticulum (ER) stress inducers thapsigargin, tunicamycin, dithiothreitol or brefeldin A. Cell viability was analysed by Neutral Red viability assays. Cleavage of caspase 3, DNA fragmentation and ultrastructural changes were examined to characterize the type of macrophage death. Induction of ER stress was evaluated by measuring C/EBP homologous protein (CHOP) expression, phosphorylation of eukaryotic initiation factor 2 alpha (eIF2a), splicing of X-box binding protein 1 (XBP1) and inhibition of protein synthesis. KEY RESULTS: Macrophages and SMCs treated with spermine NONOate or SNAP showed several signs of ER stress, including upregulation of CHOP expression, hyperphosphorylation of eIF2 alpha, inhibition of de novo protein synthesis and splicing of XBP1 mRNA. These effects were similar in macrophages and SMCs, yet only macrophages underwent apoptosis. Plaques from molsidomine-treated atherosclerotic rabbits showed a 2.7-fold increase in CHOP expression as compared to placebo. Beside NO, selective induction of macrophage death could be initiated with thapsigargin and tunicamycin. CONCLUSIONS AND IMPLICATIONS: Induction of ER stress explains selective depletion of macrophages in atherosclerotic plaques by a NO donor, probably via inhibition of protein synthesis. PMID- 17700715 TI - The inhibition of monoacylglycerol lipase by URB602 showed an anti-inflammatory and anti-nociceptive effect in a murine model of acute inflammation. AB - BACKGROUND AND PURPOSE: 2-arachidonoylglycerol (2-AG) is an endocannabinoid whose hydrolysis is predominantly catalysed by the enzyme monoacylglycerol lipase (MAGL). The development of MAGL inhibitors could offer an opportunity to investigate the anti-inflammatory and anti-nociceptive role of 2-AG, which have not yet been elucidated. On these bases, URB602, a MAGL inhibitor, was tested in a murine model of inflammation/inflammatory pain. EXPERIMENTAL APPROACH: Acute inflammation was induced by intraplantar injection of lambda-carrageenan into mice. The highest dose to be employed has been selected performing the tetrad assays for cannabimimetic activity in mice. URB602 anti-inflammatory and anti nociceptive efficacy (assessed by plethysmometer and plantar test, respectively) was evaluated both in a preventive regimen (drug administered 30 min before carrageenan) and in a therapeutic regimen (URB602 administered 30 min after carrageenan). To elucidate the cannabinoid receptor involvement, rimonabant and SR144528, CB1 and CB2 selective antagonists, respectively, were given 15 min before URB602. KEY RESULTS: Systemic administration of URB602 elicited a dose dependent anti-oedemigen and anti-nociceptive effect that was reversed exclusively by the CB2 receptor antagonist. The efficacy of URB602 persisted also when the compound was administered in a therapeutic regimen, suggesting the ability of URB602 to improve established disease. CONCLUSIONS AND IMPLICATIONS: The present report highlighted the ability of the selective MAGL inhibitor, URB602, to prevent and treat an acute inflammatory disease without producing adverse psychoactive effects. The data presented herein also contributed to clarify the physiological role of 2-AG in respect to inflammatory reactions, suggesting its protective role in the body. PMID- 17700716 TI - Purinergic P2X receptor activation induces emetic responses in ferrets and Suncus murinus (house musk shrews). AB - BACKGROUND AND PURPOSE: Despite the rapid progress made in understanding the significant role played by signalling via extracellular ATP in physiology and pathology, there has been no clear information generated on its involvement in the emetic response. EXPERIMENTAL APPROACH: In the present study, the emetogenic potential of extracellular ATP signalling in mammalian species was examined using ferrets and Suncus murinus (house musk shrews). A slowly degradable ATP analogue, alpha,beta-methyleneATP (alpha,beta-meATP), was used to activate the P2X receptors, and either the non-selective P2 receptor antagonist, pyridoxal phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), or the specific P2X(3) homomer and P2X(2/3) heteromer antagonist, A-317491, were tested against the agonist-induced response. KEY RESULTS: Intraperitoneal injection of alpha,beta meATP produced significant emetic responses in ferrets (1 - 30 mg kg(-1)) and in Suncus murinus (5 - 50 mg kg(-1)). The responses occurred frequently within the first 10 min after administration, much less frequently from 11 to 60 min and no responses occurred later than 60 min. The emetic responses were completely inhibited by intraperitoneal pre-treatment with PPADS (100 mg kg(-1)) or A-317491 (100 mg kg(-1)). Abdominal surgical vagotomy did not reduce the emetic response in Suncus murinus significantly. CONCLUSIONS AND IMPLICATIONS: These results for the first time indicate that the activation of P2X receptors evokes emetic responses in mammalian species. The P2X(3) homomer and.or P2X(2/3) heteromer in the area postrema could be responsible for the emetic response. This finding contributes to the elucidation of the roles played by extracellular ATP signalling in various emetic symptoms. PMID- 17700717 TI - Agonist potency at P2X7 receptors is modulated by structurally diverse lipids. AB - BACKGROUND AND PURPOSE: The P2X(7) receptor exhibits a high degree of plasticity with agonist potency increasing after prolonged receptor activation. In this study we investigated the ability of lipids to modulate agonist potency at P2X(7) receptors. EXPERIMENTAL APPROACH: A variety of lipids, including lysophosphatidylcholine, sphingosylphosphorylcholine and hexadecylphosphorylcholine were studied for their effect on P2X(7) receptor stimulated ethidium bromide accumulation in cells expressing human recombinant P2X(7) receptors and on P2X(7) receptor-stimulated interleukin-1 beta (IL1 beta) release from THP-1 cells. The effects of the lipids were also assessed in radioligand binding studies on human P2X(7) receptors. KEY RESULTS: At concentrations (3-30 microM) below the threshold to cause cell lysis, the lipids increased agonist potency and/or maximal effects at P2X(7) receptors in both ethidium accumulation and IL1 beta release studies. There was little structure activity relationship (SAR) for this effect and sub-lytic concentrations of Triton X-100 partially mimicked the effects of the lipids. The lipids caused cell lysis and increased intracellular calcium at higher concentrations (30-100 microM) which complicated interpretation of their effects in functional studies. However, the lipids (3-100 microM) also increased agonist potency 30-100 fold in radioligand binding studies. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that a diverse range of lipids increase agonist potency at the P2X(7) receptor in functional and binding studies. The broad SAR, including the effect of Triton X-100, suggests this may reflect changes in membrane properties rather than a direct effect on the P2X(7) receptor. Since many of the lipids studied accumulate in disease states they may enhance P2X(7) receptor function under pathophysiological conditions. PMID- 17700718 TI - Roscovitine, a cyclin-dependent kinase inhibitor, affects several gating mechanisms to inhibit cardiac L-type (Ca(V)1.2) calcium channels. AB - BACKGROUND AND PURPOSE: L-type calcium channels (Ca((V))1.2) play an important role in cardiac contraction. Roscovitine, a cyclin-dependent kinase inhibitor and promising anticancer drug, has been shown to affect Ca((V))1.2 by inhibiting current amplitude and slowing activation. This research investigates the mechanism by which roscovitine inhibits Ca((V))1.2 channels. EXPERIMENTAL APPROACH: Ca((V))1.2 channels were transfected into HEK 293 cells, using the calcium phosphate precipitation method, and currents were measured using the whole-cell patch clamp technique. KEY RESULTS: Roscovitine slows activation at all voltages, which precludes one previously proposed mechanism. In addition, roscovitine enhances voltage-dependent, but not calcium-dependent inactivation. This enhancement resulted from both an acceleration of inactivation and a slowing of the recovery from inactivation. Internally applied roscovitine failed to affect Ca((V))1.2 currents, which supports a kinase-independent mechanism and extracellular binding site. Unlike the dihydropyridines, closed state inactivation was not affected by roscovitine. Inactivation was enhanced in a dose dependent manner with an IC(50)=29.5+/-12 microM, which is close to that for slow activation and inhibition. CONCLUSIONS AND IMPLICATIONS: We conclude that roscovitine binds to an extracellular site on Ca((V))1.2 channels to inhibit current by both slowing activation and enhancing inactivation. Purine-based drugs could become a new option for treatment of diseases that benefit from L-channel inhibition such as cardiac arrhythmias and hypertension. PMID- 17700719 TI - Transient allodynia pain models in mice for early assessment of analgesic activity. AB - BACKGROUND AND PURPOSE: The most common preclinical models of neuropathic pain involve surgical ligation of sensory nerves, which is especially difficult in mice. Transient models of chemically sensitized allodynia are potentially useful for rapidly characterizing the analgesic profile of compounds and conducting mechanistic studies. EXPERIMENTAL APPROACH: Increasing doses of NMDA, sulprostone (an EP1/EP3 prostaglandin receptor agonist) or phenylephrine (an alpha (1) adrenoceptor agonist) were injected intrathecally (i.t.) or i.p., and animals were subsequently assessed for allodynia. The effects of receptor antagonists and analgesic compounds on allodynia were also assessed. KEY RESULTS: A comparison of total body doses that cause allodynia following spinal or systemic administration indicated that NMDA induces allodynia in the spinal cord while sulprostone and phenylephrine act through a peripheral mechanism. Inhibition of the allodynia with receptor antagonists indicated that each agent induces allodynia by a distinct mechanism. The three models were benchmarked using compounds known to be active in neuropathic pain patients and nerve injury animal models, including gabapentin, amitriptyline and clonidine. CONCLUSIONS AND IMPLICATIONS: These transient allodynia models are a useful addition to the toolbox of preclinical pain models. They are simple, rapid and reproducible, and will be especially useful for characterizing the pain phenotype of knockout mice. PMID- 17700720 TI - Chronic exposure of sensory neurones to increased levels of nerve growth factor modulates CB1/TRPV1 receptor crosstalk. AB - BACKGROUND: Anandamide (AEA) activates both cannabinoid CB(1) and TRPV1 receptors, which are expressed on cultured dorsal root ganglion neurones. Increased levels of nerve growth factor (NGF) are associated with chronic pain states. EXPERIMENTAL APPROACH: The aim of this study was to compare of the effects of AEA on CB(1) receptor signalling and TRPV1-CB(1) crosstalk in low and high concentrations of NGF, using voltage-clamp electrophysiology and Fura-2 calcium imaging. KEY RESULTS: Chronic exposure to high NGF (200 ng ml(-1)) as compared to low NGF (20 ng ml(-1)) increases the proportion of neurones that exhibit an inward current in response to AEA (1 microM), from 7 to 29%. In contrast, inhibition of voltage-gated calcium currents by AEA is not significantly different in low NGF (33+/-9%, compared to high NGF 28+/-6%). Crosstalk between CB and TRPV1 receptors is modulated by exposure to high NGF. In low NGF, exposure to the CB(1) receptor antagonist, SR141716A, (100 nM) increases the percentage of neurones in which AEA elicits an increase in [Ca(2+)](i), from 10 to 23%. In high NGF, the antagonist does not alter the percentage of responders (33 to 30%). In low NGF, exposure to the CB receptor agonist, WIN55 (1 microM) reduces capsaicin-mediated increases in [Ca(2+)](i) to 28+/-8% of control as compared to an enhancement to 172+/-26% of control observed in high NGF. CONCLUSIONS AND IMPLICATIONS: We conclude that cannabinoid-mediated modulation of TRPV1 receptor activation is altered after exposure to high NGF. PMID- 17700721 TI - Cardiovascular effects of cannabinoids in conscious spontaneously hypertensive rats. AB - BACKGROUND AND PURPOSE: In anaesthetized spontaneously hypertensive rats (SHR), there is evidence for up-regulation of cannabinoid (CB1) receptors: antagonism of CB1 receptors causes a rise in blood pressure, and administration of the endocannabinoid, anandamide, or inhibition of anandamide degradation causes hypotension. These findings have led to the suggestion that the endocannabinoid system may be a therapeutic target in hypertension. However, since the cardiovascular responses to cannabinoids are substantially influenced by anaesthesia, the purpose of this study was to assess regional haemodynamic responses to cannabinoid receptor stimulation and inhibition in conscious SHR. EXPERIMENTAL APPROACH: Cardiovascular responses to i.v. administration of anandamide, the cannabinoid receptor agonist, WIN 55212-2, and the CB(1) receptor antagonist, AM 251, were measured in male SHR, Wistar Kyoto rats and outbred Wistar rats, chronically instrumented for recording renal, mesenteric and hindquarters haemodynamics in the conscious, freely-moving state. KEY RESULTS: Hypotensive responses to anandamide and WIN 55212-2 only occurred in SHR, but these were relatively modest and not associated with CB1 receptor-mediated vasodilatation. In SHR only, anandamide caused bradycardia, which was inhibited by AM 251. Furthermore, a pressor response to CB1 receptor antagonism occurred only in SHR, but was not associated with vasoconstriction. Moreover, there was some evidence for CB1 receptor-mediated vasoconstrictor actions of anandamide in SHR, which was not seen in the normotensive strains. CONCLUSIONS AND IMPLICATIONS: The results are consistent with activation of CB1 receptors in SHR by endogenous ligands exerting an antihypertensive effect, but the findings do not indicate enhanced CB1 receptor-mediated vasodilator mechanisms in SHR. PMID- 17700724 TI - Pharmacological onomastics: what's in a name? AB - Drugs are named for their primary receptor target and overt action (agonism, antagonism) but the observation of multiple or collateral efficacies emanating from drugs activating a single receptor target is posing a challenge for drug classification and nomenclature. With increasing abilities to detect alteration in cellular function has come the identification of efficacies that are not necessarily manifest in obvious changes in cell response. Specifically, some agonists selectively activate cellular pathways, demonstrate phenotypic behaviour associated with cell type and some antagonists actively induce receptor internalization without activation. In addition, the effects of allosteric modulators can be linked to the nature of the co-binding ligand posing a similar complication in classification and naming. Thus, accurate labels for this new generation of selective drugs may require identification of receptor partners (G protein type, beta-arrestin) or pathway or, in the case of allosteric modulators, identification of co-binding ligands. The association of distinct phenotypic behaviours with molecules opens the opportunity to better associate clinical effects with distinct pharmacological properties. PMID- 17700722 TI - Cyclic GMP and protein kinase-G in myocardial ischaemia-reperfusion: opportunities and obstacles for survival signaling. AB - It is clear that multiple signalling pathways regulate the critical balance between cell death and survival in myocardial ischaemia-reperfusion. Recent attention has focused on the activation of survival or salvage kinases, particularly during reperfusion, as a common mechanism of many cardioprotective interventions. The phosphatidyl inositol 3'-hydroxy kinase/Akt complex (PI3K/Akt) and p42/p44 mitogen-activated protein kinase cascades have been widely promoted in this respect but the cyclic guanosine 3',5'-monophosphate/cGMP-dependent protein kinase (cGMP/PKG) signal transduction cassette has been less systematically investigated as a survival cascade. We propose that activation of the cGMP/PKG signalling pathway, following activation of soluble or particulate guanylate cyclases, may play a pivotal role in survival signalling in ischaemia reperfusion, especially in the classical preconditioning, delayed preconditioning and postconditioning paradigms. The resurgence of interest in reperfusion injury, largely as a result of postconditioning-related research, has confirmed that the cGMP/PKG pathway is a pivotal salvage mechanism in reperfusion. Numerous studies suggest that the infarct-limiting effects of preconditioning and postconditioning, exogenously donated nitric oxide (NO), natriuretic peptides, phosphodiesterase inhibitors, and other diverse drugs and mediators such as HMG co-A reductase inhibitors (statins), Rho-kinase inhibitors and adrenomedullin, whether given before and during ischaemia, or specifically at the onset of reperfusion, may be mediated by activation or enhancement of the cGMP pathway, either directly or indirectly via endogenous NO generation downstream of PI3K/Akt. Putative mechanisms of protection include PKG regulation of Ca(2+) homeostasis through the modification of sarcoplasmic reticulum Ca(2+) uptake mechanisms, and PKG-induced opening of ATP-sensitive K(+) channels during ischaemia and/or reperfusion. At present, significant technical obstacles in defining the precise roles played by cGMP/PKG signalling include the heavy reliance on pharmacological PKG inhibitors of uncertain selectivity, difficulties in determining PKG activity in intact tissue, and the growing recognition that intracellular compartmentalisation of the cGMP pool may contribute markedly to the nucleotide's biological actions and biochemical determination. Overall, the body of experimental evidence suggests that cGMP/PKG survival signalling ameliorates irreversible injury associated with ischaemia-reperfusion and may be a tractable therapeutic target. PMID- 17700723 TI - Potential to inhibit growth of atherosclerotic plaque development through modulation of macrophage neopterin/7,8-dihydroneopterin synthesis. AB - The rise in plasma neopterin observed with increasing severity of vascular disease is a strong indicator of the inflammatory nature of atherosclerosis. Plasma neopterin originates as the oxidation product of 7,8-dihydroneopterin secreted by gamma-interferon stimulated macrophages within atherosclerotic plaques. Neopterin is increasingly being used as a marker of inflammation during clinical management of patients with a range of disorders including atherosclerosis. Yet the role of 7,8-dihydroneopterin/neopterin synthesis during the inflammatory process and plaque formation remains poorly understood and controversial. This is partially due to the unresolved role oxidants play in atherosclerosis and the opposing roles of 7,8-dihydroneopterin/neopterin. Neopterin can act as pro-oxidant, enhancing oxidant damage and triggering apoptosis in a number of different cell types. Neopterin appears to have some cellular signalling properties as well as being able to chelate and enhance the reactivity of transition metal ions during Fenton reactions. In contrast, 7,8 dihydroneopterin is also a radical scavenger, reacting with and neutralizing a range of reactive oxygen species including hypochlorite, nitric oxide and peroxyl radicals, thus protecting lipoproteins and various cell types including macrophages. This has led to the suggestion that 7,8-dihydroneopterin is synthesized to protect macrophages from the oxidants released during inflammation. The oxidant/antioxidant activity observed in vitro appears to be determined both by the relative concentration of these compounds and the specific chemistry of the in vitro system under study. How these activities might influence or modulate the development of atherosclerotic plaque in vivo will be explored in this review. PMID- 17700725 TI - Activation of BKCa channels via cyclic AMP- and cyclic GMP-dependent protein kinases by eugenosedin-A in rat basilar artery myocytes. AB - BACKGROUND AND PURPOSE: The study investigated whether eugenosedin-A, a 5 hydroxytryptamine and alpha/beta adrenoceptor antagonist, enhanced delayed rectifier potassium (K(DR))- or large-conductance Ca(2+)-activated potassium (BK(Ca))-channel activity in basilar artery myocytes through cyclic AMP/GMP dependent and -independent protein kinases. EXPERIMENTAL APPROACH: Cerebral smooth muscle cells (SMCs) were enzymatically dissociated from rat basilar arteries. Conventional whole cell, perforated and inside-out patch-clamp electrophysiology was used to monitor K(+)- and Ca(2+)-channel activities. KEY RESULTS: Eugenosedin-A (1 microM) did not affect the K(DR) current but dramatically augmented BK(Ca) channel activity in a concentration-dependent manner. Increased BK(Ca) current was abolished by charybdotoxin (ChTX, 0.1 microM) or iberiotoxin (IbTX, 0.1 microM), but not affected by a small conductance K(Ca) blocker (apamin, 100 microM). BK(Ca) current activation by eugenosedin-A was significantly inhibited by an adenylate cyclase inhibitor (SQ 22536, 10 microM), a soluble guanylate cyclase inhibitor (ODQ, 10 microM), competitive antagonists of cAMP and cGMP (Rp-cAMP, 100 microM and Rp-cGMP, 100 microM), and cAMP- and cGMP-dependent protein kinase inhibitors (KT5720, 0.3 microM and KT5823, 0.3 microM). Eugenosedin-A reversed the inhibition of BK(Ca) current induced by the protein kinase C activator, phorbol myristyl acetate (PMA, 0.1 microM). Eugenosedin-A also prevented BK(Ca) current inhibition induced by adding PMA, KT5720 and KT5823. Moreover, eugenosedin-A reduced the amplitude of voltage-dependent L-type Ca(2+) current (I(Ca,L)), but without modifying the voltage-dependence of the current. CONCLUSIONS AND IMPLICATIONS: Eugenosedin-A enhanced BK(Ca) currents by stimulating the activity of cyclic nucleotide dependent protein kinases. Physiologically, this activation would result in the closure of voltage-dependent calcium channels and thereby relax cerebral SMCs. PMID- 17700727 TI - Antihypertensive drugs in combination: additive or greater than additive? PMID- 17700726 TI - The plateau outward current in canine ventricle, sensitive to 4-aminopyridine, is a constitutive contributor to ventricular repolarization. AB - BACKGROUND AND PURPOSE: I(Kur) (Ultra-rapid delayed rectifier current) has microM sensitivity to 4-aminopyridine (4-AP) and is an important modulator of the plateau amplitude and action potential duration in canine atria. Kv1.5 encodes I(Kur) and is present in both atria and ventricles in canines and humans. We hypothesized that a similar plateau outward current with microM sensitivity to 4 AP is present in canine ventricle. EXPERIMENTAL APPROACH: We used established voltage clamp protocols and used 4-AP (50 and 100 microM) to measure a plateau outward current in normal canine myocytes isolated from the left ventricular mid myocardium. KEY RESULTS: Action potential recordings in the presence of 4-AP showed significant prolongation of action potential duration at 50 and 90% repolarization at 0.5 and 1 Hz (P<0.05), while no prolongation occurred at 2 Hz. Voltage clamp experiments revealed a rapidly activating current, similar to current characteristics of canine atrial I(Kur), in approximately 70% of left ventricular myocytes. The IC(50) of 4-AP for this current was 24.2 microM. The concentration of 4-AP used in our experiments resulted in selective blockade of an outward current that was not I(to) or I(Kr). Beta-adrenergic stimulation with isoprenaline significantly increased the 4-AP sensitive outward current density (P<0.05), suggesting a role for this current during increased sympathetic stimulation. In silico incorporation into a canine ventricular cell model revealed selective AP prolongation after current blockade. CONCLUSIONS AND IMPLICATIONS: Our results support the existence of a canine ventricular plateau outward current sensitive to micromolar 4-AP and its constitutive role in ventricular repolarization. PMID- 17700729 TI - [Dual diagnoses and dual messages]. PMID- 17700728 TI - [Talking with physicians]. PMID- 17700730 TI - [Ultrasonography--something for general practice?]. PMID- 17700731 TI - [Diagnostic ultrasound in general practice]. PMID- 17700732 TI - [Photodynamic therapy of facial basal cell carcinoma]. PMID- 17700733 TI - [Use of a new antibiotic in Norway]. PMID- 17700734 TI - [Mental health, school and leisure time of adolescents born "small for gestational age"]. PMID- 17700735 TI - [Whooping cough in children]. PMID- 17700736 TI - [Bullying and health complaints in children and adolescents]. PMID- 17700738 TI - [Breast reconstruction with a thigh flap]. PMID- 17700737 TI - [Diphosphonate therapy and osteonecrosis of the jaw]. PMID- 17700739 TI - [Strengthening of psychoanalytic competence--a leadership task]. PMID- 17700740 TI - [New grasps in a new service]. PMID- 17700741 TI - [Who is a co-author?]. PMID- 17700742 TI - [Refsum disease--a rare cause of polyneuropathy]. PMID- 17700743 TI - [Unbalanced about roseroot]. PMID- 17700744 TI - [Refsum disease--a rare cause of polyneuropathy]. PMID- 17700745 TI - [A rush job and knowledge handling]. PMID- 17700746 TI - [About Linne and modesty]. PMID- 17700748 TI - [Wrong information about health services purchase]. PMID- 17700753 TI - [Acute hepatitis E]. PMID- 17700755 TI - Direct-write patterning of indium-tin-oxide film by high pulse repetition frequency femtosecond laser ablation. AB - Ablation of indium oxide doped with tin oxide (ITO) from glass substrates is described. Laser pulse energy and focus spot size were varied in single-pulse, single-spot ablation tests and for ablation of linear features with scanned multiple pulses. The single-pulse ablation threshold of ITO was smaller than that of the glass substrate so the entire thickness of ITO could be removed in a single pulse or with overlying multiple pulses without the possibility of substrate ablation. Linear features could be created at much higher scanning speeds using a high repetition frequency (100 kHz) Yb fiber amplified laser as compared to a lower repetition frequency (2 kHz) laser. An analysis showed that incubation effects lowered ITO ablation thresholds when pulse frequency was high relative to scanning speed, contributing to large feasible scanning speeds for high pulse frequency lasers. PMID- 17700756 TI - Spatial modal control of two-dimensional photonic crystal Bragg lasers. AB - We investigate the modal losses and field distributions of different order transverse modes supported by the photonic crystal Bragg structure using a transfer matrix method. We find that only the fundamental transverse mode has a single-lobed near field and far field and there exists a trade-off between ensuring lasing in the fundamental transverse mode and reducing the threshold. Employing these design principles, we experimentally demonstrate a large-area, edge-emitting, and single-mode semiconductor photonic crystal Bragg laser with a single-lobed, diffraction-limited far field under continuous wave condition. PMID- 17700757 TI - Critical behavior of a passively mode-locked laser: rational harmonic mode locking. AB - The critical behavior of passive mode locking has been demonstrated in a figure eight fiber laser that performs rational harmonic mode locking (RHML). On both the repetition rate and the pulse amplitude distribution, the observed pulse trains near the threshold exhibit the same regulations as the rational harmonic mode-locked ones. The theory also shows that there should be a middle status of RHML before achieving normal mode locking. It is important to note that the results provide what we believe to be the first confirmed attempt to address a fundamental question: how does a laser become mode locking with an increase of pump power? PMID- 17700758 TI - Spectral anomalies due to temporal correlation in a white-light interferometer. AB - We present what we believe to be the first experimental demonstration of anomalous spectral behavior such as spectral shifts and spectral switches due to temporal correlation around the intensity minima in a white-light interferometer. Unusual behavior in the number of spectral fringes, measured within the source bandwidth, as a function of path delay between the interfering beams is also reported. Experimental observations match well with the spectra calculated by using the interference law in the spectral domain. PMID- 17700759 TI - Hollow-core photonic bandgap fibers based on a square lattice cladding. AB - We propose a novel air-guiding photonic bandgap fiber based on a square lattice cladding. The fiber presents a 20% wider bandgap than is achievable with a conventional triangular-lattice-based cladding and with the choice of a nine-cell core can be effectively single moded at all wavelengths within the bandgap. PMID- 17700760 TI - Multi-optical-wavelength ultrasound-modulated optical tomography: a phantom study. AB - We used multiple optical wavelengths to study ultrasound-modulated optical tomography (UOT) in tissue phantoms. By using intense acoustic bursts and a CCD camera-based speckle contrast detection technique, we observed variations of the ultrasound-modulated signal at various optical absorptions. The experimental variations were found to be highly correlated with predictions from Monte Carlo simulations. By irradiating the sample at two optical wavelengths, we quantitatively estimated the total concentration and the concentration ratio of double dyes in objects embedded in tissue phantoms. The results suggest that UOT can potentially provide noninvasive functional imaging of the total concentration and oxygen saturation of hemoglobin in biological tissue. PMID- 17700761 TI - Manipulating electromagnetic radiation with magnetic photonic crystals. AB - We examine manipulating electromagnetic waves in magnetic photonic crystals (MPCs) with external magnetic fields. We predict new giant magnetoreflectivity and giant magnetorefractivity effects: with an external magnetic field of a magnitude much smaller than the anisotropy field of the ferromagnet, the MPC can be changed from completely reflecting to nonreflecting with corresponding changes in the angle of refraction. Application to the storage of electromagnetic radiation is also discussed. PMID- 17700763 TI - Optical damage control via the Fe2+/Fe3+ ratio in proton-exchanged LiNbO3 waveguides. AB - Intensity thresholds for the onset of optical damage in alpha-phase proton exchanged waveguides on undoped LiNbO(3) have been increased from the substrate value to a factor 500 greater. This has been achieved by increasing the exchange time, which in turn increases the [Fe(2+)]/[Fe(3+)] ratio in the guide. Intensity thresholds have been measured with a single-beam configuration, while [Fe(2+)]/[Fe(3+)] ratios have been determined from decay measurements during optical erasure of photorefractive gratings. In heavily Fe-doped guides, thresholds are too small to be measured, but the dependence of the Fe(2+) absorption on the exchange time appears similar to undoped samples. PMID- 17700762 TI - Wavefront reconstruction of an optical vortex by a Hartmann-Shack sensor. AB - Reconstruction the phase front of a vortex laser beam is conducted by use of a Hartmann-Shack wavefront sensor. The vortex beam in the form of the Laguerre Gaussian LG(0)(1) mode is generated with the help of a spiral phase plate. The new reconstruction technique based on measured wavefront gradients allows one to restore the singular phase surface with good accuracy, whereas the conventional least-squares approach fails. PMID- 17700764 TI - Excitation-density-dependent generation of broadband terahertz radiation in an asymmetrically excited photoconductive antenna. AB - The generation of terahertz (THz) transients in photoconductive emitters has been studied by varying the spatial extent and density of the optically excited photocarriers in asymmetrically excited, biased low-temperature-grown GaAs antenna structures. We find a pronounced dependence of the THz pulse intensity and broadband (>6.0 THz) spectral distribution on the pump excitation density and simulate this with a three-dimensional carrier dynamics model. We attribute the observed variation in THz emission to changes in the strength of the screening field. PMID- 17700765 TI - Power-efficient Fourier domain optical coherence tomography setup for selection in the optical path difference sign using Talbot bands. AB - A power-efficient Fourier domain optical coherence tomography fiber system is presented free of mirror terms. The object and reference beams from the interferometer are spatially separated to illuminate different parts of the diffraction grating in the spectrometer according to a method inspired from the use of Talbot bands. In this way, the system is made sensitive to only one sign of the optical path difference in the interferometer. PMID- 17700766 TI - Influences of pump wavelength and environment temperature on the dual-peaked Brillouin property of a small-core microstructure fiber. AB - The influences of the pump wavelength and temperature on the dual-peaked Brillouin property of a piece of a small-core microstructure fiber are investigated using the heterodyne method. The experimental results indicate that the dispersion characteristics of the acoustical modes participating in the Brillouin scattering are formed by the coupling of two acoustical modes with different acoustical field distributions. The influence of the pump wavelength can contribute to the variation of the acoustical mode wave vectors. On the other hand, the influence of the environment temperature can contribute to the shift of acoustical mode dispersion map by the variation of the material mechanical parameters and thermal expansion. The model and experiment results demonstrate that the height ratio of the two Brillouin peaks can be controlled by adjusting the pump wavelength or environment temperature. PMID- 17700767 TI - Background-free collinear autocorrelation and frequency-resolved optical gating using mode multiplexing and demultiplexing in aperiodically poled lithium niobate waveguides. AB - We use mode multiplexing and demultiplexing in apodized aperiodically poled lithium niobate waveguides to enable characterization of picosecond optical pulses in a collinear but background-free way using autocorrelation and second harmonic frequency-resolved optical gating. PMID- 17700768 TI - Focusing coherent light through opaque strongly scattering media. AB - We report focusing of coherent light through opaque scattering materials by control of the incident wavefront. The multiply scattered light forms a focus with a brightness that is up to a factor of 1000 higher than the brightness of the normal diffuse transmission. PMID- 17700769 TI - Synthesis of 1D Bragg gratings by a layer-aggregation method. AB - We present what we believe to be a novel method for the synthesis of complex 1D (fiber and waveguide) Bragg gratings, which is based on an impedance reconstruction layer aggregation technique. The main advantage brought by the method is the possibility of synthesizing structures containing defects or discontinuities of the size of the local period, a feature that is not possible with prior reported methods. In addition, this enhanced spatial resolution allows the synthesis of very strong fiber Bragg grating devices providing convergent solutions. The method directly renders the refractive index profile n(z) as it does not rely on the coupled-mode theory. PMID- 17700771 TI - Transfer-of-coherence-enhanced stimulated emission and electromagnetically induced absorption in Zeeman split Fg-->Fe=Fg-1 atomic transitions. AB - The probe absorption spectra in single and multiple tripod systems formed when a weak sigma polarized pump and a tunable pi polarized probe interact with a Zeeman split F(g)-->F(e)=F(g)-1 atomic transition are characterized by two interfering stimulated Raman features separated by an electromagnetically induced absorption (EIA) peak at the line center. These Raman features can appear as either sharp stimulated emission peaks or electromagnetically induced transparency windows. In the multitripod systems, the EIA and stimulated emission peaks derive from the combined effects of interference between the stimulated Raman features and transfer of coherence from the excited to ground states. PMID- 17700770 TI - High-energy, high-contrast, multiterawatt laser pulses by optical parametric chirped-pulse amplification. AB - We describe a compact, reliable, high-power, and high-contrast noncollinear optical parametric chirped-pulse amplifier system. With a broadband Ti:sapphire oscillator and grating-based stretching and compression, the chirped pulses are amplified from 0.1 nJ to 122 mJ in type I beta-barium borate optical parametric chirped-pulse amplifiers with a total gain of over 10(9) at 10 Hz repetition rate. Pulse compression down to 19-fs duration achieved after amplification indicates a peak power of 3.2 TW at an average power of 0.62 W. The prepulse contrast is measured to be less than 10(-8) on picosecond time scales. PMID- 17700772 TI - Enhanced superprism effect based on positive/negative lateral shift of reflective beam in a Fabry-Perot filter. AB - It is found that when a light beam is incident obliquely on a thin film Fabry Perot filter (FPF) from different incident media (air or substrate), the reflective beam will be shifted in both the forward and the backward directions. Based on this inverted spatial dispersion effect, two thin film FPFs with different directional lateral shifts are assembled to get a thin film superprism with a wider dispersion band. The thin film samples are fabricated as well as tested, and the results are in approximate agreement with numerical simulation. PMID- 17700773 TI - Unified Mie and fractal scattering by biological cells and subcellular structures. AB - Angle-resolved light scattering spectroscopy of biological cells is investigated in the visible wavelength range. A unified Mie and fractal model is shown to provide an accurate global agreement with light scattering spectra from 1.1 degrees to 165 degrees scattering angles. It is found that light scattering in forward directions (<8 degrees ) is dominated by Mie scattering by the bare cell and nucleus, whereas light scattering at large angles (>20 degrees ) is determined by fractal scattering by subcellular structures. The findings are consistent with the results of experimental investigation of the contributions of different cellular components to light scattering by cells. PMID- 17700774 TI - Versatile second-harmonic interferometer with high temporal resolution and high sensitivity based on a continuous-wave Nd:YAG laser. AB - A second-harmonic interferometer based on a CW Nd:YAG laser is presented. The versatile device measures the line-integrated dispersion at the fundamental and second-harmonic wavelengths. A temporal resolution of 1.25 micros with sensitivity of 1.3 mrad and a temporal resolution of 10 micros with sensitivity of 0.3 mrad are demonstrated for a laser power of 0.6 W. For a laser power of only 150 mW a temporal resolution of 10 micros with sensitivity of 1 mrad is reported. PMID- 17700775 TI - Distributed feedback gratings for surface-plasmon polaritons based on metal nano groove/ridge arrays. AB - The existence of gap states within the first stop band is theoretically investigated for surface-plasmon polaritons propagating along metal surfaces structured with finite arrays of nano-grooves/ridges with imperfections. By means of rigorous calculations of all scattering channels on the basis of the reduced Rayleigh equation, it is shown that a mismatch of the grating period, rather than simple vacant/defect sites, favors the opening of gap states (located at midgap for half-period shifts) as a phase step does in distributed feedback gratings. Quality factors of the resulting surface-plasmon polaritons' resonances are limited by radiative leakage and ohmic losses. PMID- 17700776 TI - Optical bistability effects in a Tm,Ho:YLF laser at room temperature. AB - We demonstrate strong optical bistability in a 2 microm continuous-wave Tm,Ho:YLF laser pumped by a 792 nm laser diode near room temperature. The bistable region is as much as 100 mW wide at 283 K and can be controlled by the temperature of the laser crystal. The influence of crystal temperature on the characteristics of optical bistability is obtained. The influence of the pump-to-mode ratio on the bistable characteristics of the laser is also discussed. To our knowledge this is the first report of optical bistability effects in Tm,Ho:YLF lasers. PMID- 17700777 TI - Hybrid multinary modulation using a phase modulating spatial light modulator and a low-pass spatial filter. AB - We propose a method for performing binary intensity and continuous phase modulation of beams with a spatial light modulator (SLM) and a low-pass spatial filtering 4-f system. With our method it is possible to avoid the use of phase masks in holographic data storage systems or to enhance the phase encoding of the SLM by making it capable of binary amplitude modulation. The data storage capabilities and the limitations of the method are studied. PMID- 17700778 TI - Tunable control of the frequency correlations of entangled photons. AB - We experimentally demonstrate a new technique to control the type of frequency correlations of entangled photon pairs generated by spontaneous parametric downconversion. Frequency-correlated and frequency-anticorrelated photons are produced when a broadband pulse is used as a pump. The method is based on the control of the group velocities of the interacting waves and can be applied in any nonlinear medium and frequency band of interest. PMID- 17700779 TI - Blue light generation in a ridge waveguide MgO:LiNbO3 crystal pumped by a fiber Bragg grating stabilized laser diode. AB - We report cw blue light generation by using a periodically poled MgO:LiNbO(3) crystal with a ridge waveguide pumped by a fiber Bragg grating stabilized laser diode with 0.25 nm spectrum width in the coherent collapse regime. Blue light generation of 73 mW with 27% conversion efficiency and a wide temperature tolerance of 5.7 degrees C were attained. PMID- 17700780 TI - Narrow-linewidth ytterbium-doped fiber amplifier system with 45 nm tuning range and 133 W of output power. AB - We report on a master-oscillator ytterbium-doped fiber amplifier system with up to 133 W of continuous-wave output power using a tunable narrow-linewidth external-cavity diode laser seed source. Stable tunable high-power operation was demonstrated from 1040 nm to 1085 nm with more than 12 dB suppression of amplified spontaneous emission. PMID- 17700781 TI - Microscope enabling multimodality imaging, angle-resolved scattering, and scattering spectroscopy. AB - We present the design, construction, and initial characterization of a multifunctional imaging/scattering spectroscopy system built around a commercial inverted microscope platform. The system enables co-registered brightfield, Fourier-filtered darkfield, and fluorescence imaging; monochromatic angle resolved scattering measurements; and white-light wavelength-resolved scattering spectroscopy from the same field of view. A fiber-based illumination system provides illumination-wavelength flexibility and a good approximation to a point source. The performance of the system in its various data acquisition modes is experimentally verified using fluorescent microspheres. This multifunctional instrument provides a platform for studies on adherent cells from which the biophysical implications of subcellular light scattering can be studied in conjunction with sensitive fluorescence-based techniques. PMID- 17700782 TI - Imaging optically scattering objects with ultrasound-modulated optical tomography. AB - We show the feasibility of imaging objects having different optical scattering coefficients relative to the surrounding scattering medium using ultrasound modulated optical tomography (UOT). While the spatial resolution depends on ultrasound parameters, the image contrast depends on the difference in scattering coefficient between the object and the surrounding medium. Experimental measurements obtained with a CCD-based speckle contrast detection scheme are in agreement with Monte Carlo simulations and analytical calculations. This study complements previous UOT experiments that demonstrated optical absorption contrast. PMID- 17700783 TI - Simulations of hybrid long-range plasmon modes with application to 90 degree bends. AB - We perform rigorous simulations of hybrid long-range modes guided by a central metal core and a two-dimensional dielectric slab. We show that these modes are subject to fewer limitations than conventional long-range plasmon modes in terms of field confinement and guiding performance. These hybrid modes may offer substantial improvements for integrated plasmonic components, as illustrated here by the consideration of 90 degrees bends. PMID- 17700784 TI - Investigation of the center intensity of first- and second-order Laguerre Gaussian beams with linear and circular polarization. AB - The vectorial Debye integral shows that tightly focused Laguerre-Gaussian (LG) beams have a residual intensity at the focal point for linear polarization, for a topological charge of m=1 and 2. We measured the shapes of linearly and circularly polarized LG beams and found that a central intensity appeared at m=1 and 2 for linear and right-handed circular polarization, however, it is completely canceled for left-handed circular polarization. In general, when the orbital angular momentum of the LG beam is parallel to the spin angular momentum of the photons, zero intensity is always achieved at the focus. PMID- 17700785 TI - Broadband all-order polarization mode dispersion compensation via wavelength-by wavelength Jones matrix correction. AB - We demonstrate wideband all-order polarization mode dispersion (PMD) compensation by applying high-speed spectral polarization sensing and ultrafast pulse shaping techniques to characterize and correct the frequency-dependent Jones matrix associated with PMD of optical fibers on a wavelength-by-wavelength basis. We report full compensation of approximately 800 fs pulses distorted to more than 10 ps by a PMD module with approximately 5.5 ps mean differential group delay. The sensing and compensation of Jones matrix take approximately 200 and approximately 500 ms, respectively. PMID- 17700786 TI - Phase stability of terawatt-class ultrabroadband parametric amplification. AB - The phase stability of broadband (280 nm bandwidth) terawatt-class parametric amplification was measured, for the first time to our knowledge, with a combination of spatial and spectral interferometry. Measurements at four different wavelengths from 750 to 900 nm were performed in combination with numerical modeling. The phase stability is better than 1/23 rms of an optical cycle for all the measured wavelengths, depending on the phase-matching conditions in the amplifier. PMID- 17700787 TI - Dual-band pixelless upconversion imaging devices. AB - We have proposed a type of mid-infrared (MIR) and far-infrared (FIR) dual-band imaging device, which employs the photon frequency upconversion concept in a GaN/AlGaN MIR and FIR dual-band detector integrated with a GaN/AlGaN violet light emitting diode. On the basis of the photoresponse of single-period GaN/AlGaN dual band detectors, we present the detailed optimization of multiperiod GaN emitter/AlGaN barrier detectors and their applications to dual-band pixelless upconversion imaging. Satisfying images have been received through the analysis of the modulation transfer function and the upconversion efficiency in the GaN/AlGaN dual-band pixelless upconverters, which exhibit good image resolution, high quantum efficiency, and negligible cross talk. PMID- 17700788 TI - Disappearance of modes in planar Bragg waveguides. AB - We show how the forbidden bands of a Bragg reflector may shrink to points and how some classes of the guided modes of a planar Bragg waveguide may disappear altogether by shrinking with the forbidden bands. We derive the general conditions to determine the missing modes and explain these conditions with examples. It is possible, for example, to design a Bragg waveguide that rejects all antisymmetric modes and supports only symmetric modes for the TE polarization. We also highlight the effect of Brewster incidence on the interpretation of the missing modes for the TM polarization. PMID- 17700789 TI - Sub-60-fs ytterbium-doped fiber laser with a fiber-based dispersion compensation. AB - We present a mode-locked ytterbium fiber laser with a higher-order mode fiber compensating the group-velocity dispersion and partially the third-order dispersion of the single-mode fiber at a wavelength of 1 microm. The generated pulses had an energy of 0.5 nJ and could be dechirped externally to a pulse duration of less than 60 fs. The power spectrum shows a spectral full width at half-maximum of 57 nm. PMID- 17700791 TI - Optical parametric chirped-pulse-amplification contrast enhancement by regenerative pump spectral filtering. AB - We demonstrate an approach to fundamentally improve the contrast of optical parametric chirped-pulse amplifiers (OPCPA). The instantaneous parametric gain couples the temporal variations of the pump-pulse intensity to spectral variations of the intensity of the stretched signal pulse being amplified, which significantly degrade the temporal contrast of the amplified pulse after recompression. Simple and efficient pump-intensity noise reduction in an OPCPA system using a volume Bragg grating in a regenerative amplifier demonstrates contrast improvements up to 30 dB. PMID- 17700790 TI - Binary-phase spatial filter for real-time swept-source optical coherence microscopy. AB - We report a novel scheme to optimize the focusing condition for real-time, swept source optical coherence microscopy. The axial and lateral behaviors of four-zone binary-phase spatial filters are presented numerically. A nearly constant axial intensity distribution along an extended depth of focus of 1.5 mm and a lateral resolution of 5 microm are experimentally verified. The A-line scan rate is up to 16 kHz, yielding a frame rate of 25 Hz and 640 lines per image. PMID- 17700792 TI - Compact 2 W wavelength-tunable Er:ZBLAN mid-infrared fiber laser. AB - We report a high-power diode-pumped wavelength-tunable (2.7-2.83 mum) erbium doped ZBLAN mid-infrared fiber laser. Continuous-wave output of >2 W with a spectral linewidth of 1.27 GHz was obtained. Nevertheless, the wavelength-tunable range was found to shrink with increasing pump power. The gain bandwidth narrowing under strong pumping may be ascribed to the enhanced reabsorption process and the weakened population inversion associated with shorter-wavelength emissions. PMID- 17700793 TI - Fabrication of axicons by cw laser effusion. AB - The fabrication of axicons by cw laser effusion is introduced for the case of a chalcogenide alloy, and experimental results concerning the lateral resolution and the intensity distribution along the optical axis are reported. PMID- 17700794 TI - Efficient angular dispersion compensation in holographic generation of intense ultrashort paraxial beam modes. AB - We experimentally demonstrate that small misalignments of the pulse stretcher or compressor of our chirped-pulse-amplification laser can precompensate for angular chirp when producing ultrashort paraxial beam modes with holographic gratings. Using this approach we can eliminate one of the two gratings needed in our 2f-2f setup [Mariyenko, Opt. Express 13, 7599 (2005)]. This allows for up to an order of magnitude more output power. We see our method as the next step in the production of intense exotic forms of ultrashort pulses, which can be used in the investigation of intense laser-matter interactions. In addition, we produce the first femtosecond (helical-)Ince-Gaussian beams. PMID- 17700795 TI - Three-hole microstructured optical fiber for efficient fiber Bragg grating refractometer. AB - We present a photosensitive three-hole microstructured optical fiber specifically designed to improve the refractive index sensitivity of a standard fiber Bragg grating (FBG) sensor photowritten in the suspended Ge-doped silica core. We describe the specific photowriting procedure used to realize gratings in such a fiber. We then determine their spectral sensitivity to the refractive index changes of material filling the holes surrounding the core. The sensitivity is compared with that of standard FBGs photowritten in a six-hole fiber with a larger core diameter. We demonstrate an improvement in the sensitivity by two orders of magnitude and reach a resolution of 3 x 10(-5) and 6 x 10(-6) around mean refractive index values of 1.33 and 1.40, respectively. PMID- 17700796 TI - Multichannel dispersion compensation using a silicon waveguide-based optical phase conjugator. AB - We experimentally demonstrate dispersion compensation using a silicon-based optical phase conjugator. We achieve simultaneous transmission of four dense wavelength division multiplexing (DWDM) channels spaced at 100 GHz and operating at 10 Gbits/s over 320 km of standard fiber. The measured power penalty at bit error rate of 10(-9) is less than 0.3 dB. PMID- 17700797 TI - Few-optical-cycle pulses in the near-infrared from a noncollinear optical parametric amplifier. AB - We extend the concept of broadband phase matching in a noncollinear optical parametric amplifier (NOPA) to the near-IR. In an 800 nm pumped NOPA using periodically poled stoichiometric lithium tantalate, we amplify a spectrum spanning the 1.1-1.7 microm range and corresponding to two optical cycles of the carrier wavelength. A limited portion of the spectrum is compressed by a prism pair down to 16 fs. PMID- 17700798 TI - Phase matching in monolithic Bragg reflection waveguides. AB - We report what is believed to be the first observation of second-harmonic generation by type I phase matching the bulk chi(xyz)((2))(d(14)) nonlinear coefficient using Bragg reflection waveguides. Second-harmonic power of 0.7 microW was observed for a pump wavelength of 1587.8 nm with an average power of 25.2 mW and a pulse width of approximately 2 ps at a repetition rate of 75.6 MHz. An order of magnitude enhancement between the phase-matched and un-phase-matched second-harmonic conversion efficiency has been observed. Conversion efficiency at the phase-matched wavelengths was 0.001%. The bandwidth of the second harmonic was found to be equal to 0.43 nm, agreeing with the theoretical predictions. PMID- 17700799 TI - Generation of 5 fs, 0.7 mJ pulses at 1 kHz through cascade filamentation. AB - Two-cycle optical pulses with duration of 5 fs and energy of 0.7 mJ have been generated at 1 kHz by compressing the 38 fs laser pulses from a carrier-envelope phase (CEP) controlled Ti:sapphire laser system through a cascade filamentation compression technique. A simple and effective method is developed to suppress multiple filament formation and stabilize a single filament by inserting a soft aperture with an appropriate diameter into the driving laser beam prior to focusing, resulting in an excellent compressed beam quality. The good beam quality and potentially higher peak power make this ultrashort laser pulse source a significant tool for high-field physics applications. PMID- 17700800 TI - Scintillation index of elliptical Gaussian beam in turbulent atmosphere. AB - A tensor method is used to formulate the on-axis scintillation index for an elliptical Gaussian beam (EGB; astigmatic Gaussian beam) propagating in a weak turbulent atmosphere. Variations of the on-axis scintillation of an EGB are studied. It is interesting to find that the scintillation index of an EGB can be smaller than that of a circular Gaussian beam in a weakly turbulent atmosphere under certain conditions and is closely related to the ratio of the beam waist size along the long axis to that along the short axis of the EGB, the wavelength, and the structure constant of the turbulent atmosphere. PMID- 17700801 TI - All-normal-dispersion femtosecond fiber laser with pulse energy above 20 nJ. AB - We report a study of the scaling and limits to pulse energy in an all-normal dispersion femtosecond fiber laser. Theoretical calculations show that operation at large normal cavity dispersion is possible in the presence of large nonlinear phase shifts, owing to strong pulse shaping by spectral filtering of the chirped pulse in the laser. Stable pulses are possible with energies of tens of nanojoules. Experimental results from Yb-doped fiber lasers agree with the trends of numerical simulations. Stable and self-starting pulses are generated with energies above 20 nJ, and these can be dechirped to <200 fs duration. Femtosecond pulses with peak powers near 100 kW are thus available from this simple and practical design. PMID- 17700802 TI - Characterization of a broadband pulse for phase controlled multiphoton microscopy by single beam SPIDER. AB - We present what we believe to be a new version of spectral phase interferometry for direct electric field reconstruction (SPIDER) using only a single-phase and polarization controlled laser beam. Two narrow pulses and one broadband pulse are selected out of an ultrafast laser pulse by a polarization and phase control technique to generate second harmonic generation (SHG) signals, which are equivalent to a spectral shear interferogram in the conventional SPIDER method. The spectral phase of the broadband laser pulse is extracted analytically with double quadrature spectral interferometry (DQSI). An arbitrary spectral phase can be retrieved with great precision and compensated in situ at the sample position of a microscope. This new method requires no separate reference beam and is suitable for nonlinear optical microscopy with a phase controlled laser pulse. PMID- 17700803 TI - Surface plasmon polariton microscope with parabolic reflectors. AB - We report the realization of a two-dimensional optical microscope for surface plasmons polaritons (SPPs) based on parabolic Bragg mirrors. These mirrors are built from lithographically fabricated gold nanostructures on gold thin films. We show by direct imaging by leakage radiation microscopy that the magnification power of the SPP microscope follows basic predictions of geometrical optics. Spatial resolution down to the value set by the diffraction limit is demonstrated. PMID- 17700804 TI - Design and analysis of a noncollinear acousto-optic tunable filter. AB - The design of the noncollinear acousto-optic tunable filter (AOTF) is commonly based on the parallel tangents momentum-matching condition. Previous studies either have used an approximation of the birefringence of the interaction material or have ignored the rotatory property of TeO(2). These approaches would obviously decrease the accuracy of designing an acousto-optic tunable filter (AOTF). We introduce an analysis method of calculating the optimum incident optical angle. Besides, an appropriate optical wedge on the output optical facet is designed to reduce the wavelength dependence of the diffracted beam angle, which is very significant in practical applications of AOTF. PMID- 17700805 TI - Monolithic 160 Gbit/s optical time-division multiplexer. AB - We present the design and experimental characterization of a monolithic optical time-division multiplexer (MUX) for 160 Gbit/s operation based on periodically poled lithium niobate (PPLN) waveguides. Its key figures of merit agree well with theoretical predictions and meet or exceed those of a previously demonstrated PPLN-planar-light-wave-circuit hybrid MUX. The monolithic design has a simpler layout and higher efficiency while keeping the cross talk low. PMID- 17700806 TI - Hydrocarbon-free resonance transition 795-nm rubidium laser. AB - For what we believe to be the first time, an optical resonance transition rubidium laser (5(2)P(1/2)-->5(2)S(1/2)) has been demonstrated with a hydrocarbon free buffer gas. Prior demonstrations of alkali resonance transition lasers have used ethane as either the buffer gas or a buffer gas component to promote rapid fine-structure mixing. However, our experience suggests that the alkali vapor reacts with the ethane producing carbon as one of the reaction products. This degrades long term laser reliability. Our recent experimental results with a "clean" helium-only buffer gas system demonstrate all the advantages of the original alkali laser system, but without the reliability issues associated with the use of ethane. PMID- 17700807 TI - Spectral-domain optical coherence reflectometric sensor for highly sensitive molecular detection. AB - We describe what we believe to be a novel use of spectral-domain optical coherence reflectometry (SD-OCR) for highly sensitive molecular detection in real time. The SD-OCR sensor allows identification of a sensor surface of interest in an OCR depth scan and monitoring the phase alteration due to molecular interaction at that surface with subnanometer optical thickness sensitivity. We present subfemtomole detection sensitivity for etching of SiO(2) molecules and demonstrate its application as a biosensor by measuring biotin-streptavidin binding in a microfluidic device. PMID- 17700808 TI - Picosecond pulse amplification in a core-pumped large-mode-area erbium fiber. AB - Amplification in a single-clad, large-mode-area erbium fiber as an alternative to double-clad Er-Yb amplifiers is presented. Both signal and pump are coupled through a mode-matched splice into the fundamental mode, which ensures preferential gain in the fundamental mode while minimizing the amplified spontaneous emission (ASE). The 875 microm(2) effective area of the Er fiber enables amplification of 6 ps pulses at 1.55 microm wavelength by approximately 33 dB in a single stage to >25 kW peak power with low nonlinear pulse distortion and a diffraction-limited output beam with M(2)<1.1. PMID- 17700809 TI - Sub-10-fs supercontinuum radiation generated by filamentation of few-cycle 800 nm pulses in argon. AB - Focusing 12 fs pulses of 800 nm with moderate energy (0.35 mJ) into atmospheric pressure argon (Ar) gives rise to filamentation (self-focusing) and a supercontinuum with a very broad pedestal, extending to 250 nm. According to the present understanding, the short wavelengths are produced by self-phase modulation in the self-steepened trailing edge of the pulse. Pulses in this spectral range might thus be intrinsically short. Indeed we demonstrate this by extracting the light near the end of the filament, terminating self-focusing by a pressure gradient at a pinhole, beyond which the Ar is pumped away. We obtain pulses of 9.7 fs in the region of 290 nm without the necessity of compression. PMID- 17700810 TI - Plasmon resonance microsensor for droplet analysis. AB - Microscale fiber tip sensors based on the plasmon resonance are reported. The fabrication process derived from our previous approach for manufacturing near field scanning optical microscopy probes has been optimized for sensing applications. A typical tip sensor is a tapered fiber 400 microm in length, coated with a nanoporous thin silver film. The miniaturized geometry of the sensor allows detection in a single droplet of liquid solution (approximately 20 microl). The tip sensor is sensitive for refractive indices between 1.33 and 1.40 with a sensitivity of at least 3 x 10(-4) refractive index unit (RIU)/nm. The Raman scattering enhancement through these microsensors demonstrates the important role played by the localized plasmon resonance. The sensors' linear response covers a large region, interesting for biosensing in aqueous environments such as biomedical applications. PMID- 17700811 TI - Three-dimensional shape measurement with an arbitrarily arranged fringe projection profilometry system. AB - A mathematical description of the absolute out-of-plane height distribution in 3D shape measurement with an arbitrarily arranged fringe projection profilometry system is presented, and a corresponding algorithm is proposed to determine the parameters required for accurate 3D shape determination in practical applications. The proposed technique requires neither a specific and precise experimental setup nor a manual measurement of geometric parameters, and it yields high measurement accuracies while allowing the system components to be arbitrarily set and positioned. Computer simulations and a real experiment have been conducted to verify the validity of the technique. PMID- 17700812 TI - Dynamics of a filtered-feedback laser: influence of the filter width. AB - The behavior of a semiconductor laser subject to filtered optical feedback is studied in dependence on the width of the filter. Of special interest are pure frequency oscillations where the laser intensity is practically constant. We show that frequency oscillations are stable in a large region of intermediate values of the filter width, where the dispersion of the filter is able to compensate for the well-known phase-amplitude coupling of the semiconductor laser. Our stability diagram covers the entire range from a very narrow filter, when the system behaves like a laser with monochromatic optical injection, to a very broad filter, when the laser effectively receives conventional (i.e., unfiltered) optical feedback. PMID- 17700813 TI - Intense laser-driven energetic proton beams from solid density targets. AB - The effects of target density on proton acceleration driven by an intense sub-ps laser pulse are investigated using two-dimensional hybrid particle-in-cell simulations. Results show that at higher density the target-normal-sheath acceleration (TNSA) is more effective than shock acceleration for protons from a plastic target. Furthermore a lower-density target is favorable to higher energy of the TNSA protons. Moreover, the longitudinal electric fields at the target surfaces may reveal typical inhomogeneous structures for a long acceleration time. The conversion efficiency of laser energy into particle (electron, proton, and C(+) ion) energy is found to increase with decreasing target density. PMID- 17700814 TI - A note on an accelerating finite energy Airy beam. AB - A recently derived Airy beam solution to the (1+1)D paraxial equation is shown to obey two salient properties characterizing arbitrary finite energy solutions associated with second-order diffraction; the centroid of the beam is a linear function of the range and its variance varies quadratically in range. Some insight is provided regarding the local acceleration dynamics of the beam. It is shown, specifically, that the interpretation of this beam as accelerating, i.e., one characterized by a nonlinear lateral shift, depends significantly on the parameter a entering into the solution. PMID- 17700815 TI - Random-phase surface-wave solitons in nonlocal nonlinear media. AB - We demonstrate, theoretically and experimentally, incoherent surface solitons in a noninstantaneous nonlocal nonlinear media. These incoherent surface waves are located at the interface between a nonlinear medium with long-range nonlocality and a linear dielectric medium (air). PMID- 17700816 TI - Large nonlinear optical response of polycrystalline Bi3.25La0.75Ti3O12 ferroelectric thin films on quartz substrates. AB - We measure the nonlinear susceptibility of Bi(3.25)La(0.75)Ti(3)O(12) (BLT) thin films grown on quartz substrates using the Z-scan technique with picosecond laser pulses at a wavelength of 532 nm. The third-order nonlinear refractive index coefficient gamma and absorption coefficient beta of the BLT thin film are 3.1 x 10(-10) cm(2)/W and 3 x 10(-5) cm/W, respectively, which are much larger than those of most ferroelectric films. The results show that the BLT thin films on quartz substrates are good candidate materials for applications in nonlinear optical devices. PMID- 17700817 TI - Amplitude point-spread function measurement of high-NA microscope objectives by digital holographic microscopy. AB - We present here a three-dimensional evaluation of the amplitude point-spread function (APSF) of a microscope objective (MO), based on a single holographic acquisition of its pupil wavefront. The aberration function is extracted from this pupil measurements and then inserted in a scalar model of diffraction, allowing one to calculate the distribution of the complex wavefront propagated around the focal point. The accuracy of the results is compared with a direct measurement of the APSF with a second holographic system located in the image plane of the MO. Measurements on a 100 x 1.3 NA MO are presented. PMID- 17700818 TI - Raman-induced localization in Kerr waveguide arrays. AB - We show that during the spatiotemporal compression in a periodic Kerr waveguide array, stimulated Raman scattering can effectively balance the effects of self phase modulation, diffraction, and group-velocity dispersion, eliminating collapse and breakup over a wide range of input powers and leading to stable propagation in a single site. PMID- 17700819 TI - Experimental observation of all-optical non-return-to-zero-to-return-to-zero format conversion based on cascaded second-order nonlinearity assisted by active mode-locking. AB - We report the experimental demonstration of all-optical format conversion by exploiting the cascaded second-harmonic generation and difference-frequency generation (cSHG/DFG) in a periodically poled lithium niobate (PPLN) waveguide assisted by the reflective semiconductor optical amplifier (RSOA)-based active mode-locking. 10 and 20 Gbit/s format conversions from non-return-to-zero (NRZ) to return-to-zero (RZ) are successfully observed. Two schemes with either the NRZ signal or the pump optical clock set at the quasi-phase matching (QPM) wavelength are both verified in the experiment. PMID- 17700821 TI - Eta(1)-2-pyrone metal carbonyl complexes as CO-releasing molecules (CO-RMs): a delicate balance between stability and CO liberation. AB - An evaluation of the CO releasing ability of iron(II) and molybdenum(II) complexes has facilitated the discovery of the most rapid CO releaser, namely [Mo(CO)(3)(eta(5)-C(5)H(5))(eta(1)-{O}-C{=O}-O-CMe=CH-COMe=CBr)]BF(4) (CORM-F10), reported to date. The rate of CO release is related to the overall solution phase stability of the transition metal carbonyl complex. The cytotoxicity and vasodilatory properties of CORM-F10 have been determined. PMID- 17700822 TI - Silylenediamido [(CH3)2Si(NTs)2(2-); Ts = p-CH3C6H4SO2] complexes of iridium: synthesis, structures and facile Si-N bond cleavage. AB - The N,N'-bis(sulfonyl)diaminosilane TsdmsinH(2) (TsdmsinH(2) = (CH(3))(2)Si(NHTs)(2), Ts = p-CH(3)C(6)H(4)SO(2)) reacted with [Cp*IrCl(2)](2) (Cp* = eta(5)-C(5)(CH(3))(5)) in the presence of a base to give the coordinatively unsaturated (silylenediamido)iridium complex [Cp*Ir(Tsdmsin)] (2), which was further converted to the 18e adducts [Cp*Ir(Tsdmsin)L] (L = P(C(6)H(5))(3) (3a), P(OC(2)H(5))(3), CO); the reactions of 2 and 3a with water led to the formation of the imido-bridged dinuclear complex [Cp*Ir(micro(2) NTs)(2)IrCp*] and the bis(amido) complex [Cp*Ir(NHTs)(2){P(C(6)H(5))(3)}], respectively. PMID- 17700823 TI - The effect of micro-CN linkage isomerism and ancillary ligand set on directional metal-metal charge-transfer in cyanide-bridged dimanganese complexes. AB - The reaction of [Mn(CN)L'(NO)(eta(5)-C(5)R(4)Me)] with cis- or trans [MnBrL(CO)(2)(dppm)], in the presence of Tl[PF(6)], gives homobinuclear cyanomanganese(i) complexes cis- or trans-[(dppm)(CO)(2)LMn(micro NC)MnL'(NO)(eta(5)-C(5)R(4)Me)](+), linkage isomers of which, cis- or trans [(dppm)(CO)(2)LMn(micro-CN)MnL'(NO)(eta(5)-C(5)R(4)Me)](+), are synthesised by reacting cis- or trans-[Mn(CN)L(CO)(2)(dppm)] with [MnIL'(NO)(eta(5)-C(5)R(4)Me)] in the presence of Tl[PF(6)]. X-Ray structural studies on the isomers trans [(dppm)(CO)(2){(EtO)(3)P}Mn(micro-NC)Mn(CNBu(t))(NO)(eta(5)-C(5)H(4)Me)](+) and trans-[(dppm)(CO)(2){(EtO)(3)P}Mn(micro-CN)Mn(CNBu(t))(NO)(eta(5)-C(5)H(4)Me)](+) show nearly identical molecular structures whereas cis [(dppm)(CO)(2){(PhO)(3)P}Mn(micro-NC)Mn{P(OPh)(3)}(NO)(eta(5)-C(5)H(4)Me)](+) and cis-[(dppm)(CO)(2){(PhO)(3)P}Mn(micro-CN)Mn{P(OPh)(3)}(NO)(eta(5)-C(5)H(4)Me)](+) differ, effectively in the N- and C-coordination respectively of two different optical isomers of the pseudo-tetrahedral units (NC)Mn{P(OPh)(3)}(NO)(eta(5) C(5)H(4)Me) and (CN)Mn{P(OPh)(3)}(NO)(eta(5)-C(5)H(4)Me) to the octahedral manganese centre. Electrochemical and spectroscopic studies on [(dppm)(CO)(2)LMn(micro-XY)MnL'(NO)(eta(5)-C(5)R(4)Me)](+) show that systematic variation of the ligands L and L', of the cyclopentadienyl ring substituents R, and of the micro-CN orientation (XY = CN or NC) allows control of the order of oxidation of the two metal centres and hence the direction and energy of metal metal charge-transfer (MMCT) through the cyanide bridge in the mixed-valence dications. Chemical one-electron oxidation of cis- or trans [(dppm)(CO)(2)LMn(micro-NC)MnL'(NO)(eta(5)-C(5)R(4)Me)](+) with [NO][PF(6)] gives the mixed-valence dications trans-[(dppm)(CO)(2)LMn(II)(micro NC)Mn(I)L'(NO)(eta(5)-C(5)R(4)Me)](2+) which show solvatochromic absorptions in the electronic spectrum, assigned to optically induced Mn(I)-to-Mn(II) electron transfer via the cyanide bridge. PMID- 17700824 TI - Remarkable isolation, structural characterisation and electrochemistry of unexpected scrambling analogues of 5-ferrocenyl-10,20-diphenylporphyrin. AB - Selective condensation of 5-ferrocenyldipyrromethane, 1, and dipyrromethane, 2, with benzaldehyde, 3, led to 5-ferrocenyl-10,20-diphenylporphyrin, 5. During the condensation, an unusually large amount of scrambling was observed which led to the isolation of two further ferrocenylated porphyrin analogues 6 and 7. The structure of 6 was confirmed by a single-crystal X-ray study. A mechanism is proposed for this atypical scrambling which is likely to involve acid-catalysed reversion of the dipyrromethane synthesis. (1)H NMR further elucidated the structures of each complex and showed the existence of atropisomerism. An electrochemical study (cyclic voltammetry, Osteryoung square wave and linear sweep voltammetry) showed that there exists a linear relationship between the sum of the group electronegativities of meso substituents of the obtained porphyrins and the formal reduction potentials of the two observed ring-centred reduction processes, the meso substituent ferrocenyl-based oxidation process and the first ring-centred oxidation wave. These four relationships could be mathematically quantified. Due to the strong electron-withdrawing properties of the oxidised ferrocenium group, the second ring centred oxidation wave fell outside the potential window of dichloromethane as solvent. PMID- 17700825 TI - The novel sandwich-type heteropolyoxotungstates [M2Bi2(beta-B-MW9O34)2]14- (M = Co(II), Zn(II)): beta-type dimeric heteropolyanions with a transition metal as the central heteroatom and Bi(III) and M as linking atoms. AB - Two new sandwich-type heteropolyoxometalates, Na(14)[Co(2)Bi(2)(beta-B CoW(9)O(34))(2)].48H(2)O (1) and Na(14)[beta-B Zn(2)Bi(2)(ZnW(9)O(34))(2)].51H(2)O (2), have been synthesized at pH = 7.5-8 and characterized by elemental analysis, IR, UV-vis, TG-DSC and electrochemistry. Structural analysis indicates that both polyanions, M(2)Bi(2)(beta-B MW(9)O(34))(2)](14-) (M = Co(II) and Zn(II)), are isomorphic and consist of two unprecedented [beta-B-MW(9)O(34)](12-) subunits linked by two M(II) and two Bi(III) which are coplanar. The polyanions are also the first examples of dimeric heteropolyanions with Bi(III) only as the second (linking) heteroatom and the transition metals (Co(II) or Zn(II)) as the first and second heteroatoms as well. The lower absorption of nu(W-O(d)) (915 cm(-1)) in the IR is a simple and feasible judgment of sandwich-type polyanions with a transition metal ion as a central heteroatom. PMID- 17700826 TI - Closed-pore crystal capable of adsorbing CO2 onto isolated cavities generated by disorderly mixing of substituents on host skeleton. AB - A single crystal adsorbent, [Rh(II)(2)(bza)(4)(2,3-empyz)](n) (2,3-empyz = 2 ethyl-3-methylpyrazine) (1), was synthesized by self-assembly reaction of a Rh(2) benzoate complex and substituted pyrazine linker. The compound consists of one dimensional zigzag chains, which generated a closed-pore structure without channels. The cavities were statistically generated by the static disorder of substituents on pyrazine and are separated by long intervals within the crystal. The property of CO(2) absorption was characterized in this closed-pore system. The CO(2) inclusion structure was determined by single-crystal X-ray diffraction measurements. These studies suggest that CO(2) molecules were adsorbed and diffused in the nonporous crystal with the isolated cavities. PMID- 17700827 TI - Synthesis, reaction and structure of a highly light-stable silver(I) cluster with an Ag4S4N4 core having a tridentate 4N-morpholyl 2-acetylpyridine thiosemicarbazone ligand: use of water-soluble silver(I) carboxylates as a silver(I) source. AB - A novel neutral tetrameric silver(I) cluster [Ag(mtsc)](4) was obtained from reactions of a tridentate (4)N-morpholyl 2-acetylpyridine thiosemicarbazone ligand (N'-[1-(2-pyridyl)ethylidene] morpholine-4-carbothiohydrazide, Hmtsc) and silver(I) sources containing Ag-O bonds (Ag(2)O, Ag(OAc), silver(I) 2-pyrrolidone 5-carboxylate (infinity){[Ag(Hpyrrld)](2)}, silver(I) 5-oxo-2 tetrahydrofurancarboxylate (infinity){[Ag(othf)](2)}, and silver(I) complexes with camphanic acid (infinity){[Ag(ca)]} and (infinity){[Ag(ca)(Hca)]}). The cluster was characterized by elemental analysis, TG/DTA, FTIR and single-crystal X-ray analysis in the solid state. The solution properties of the complexes were investigated using solution molecular weight measurement, ESI-MS and solution ((1)H, (13)C and (31)P) NMR spectroscopy. The obtained cluster is a novel example of a light-stable Ag(I) cluster with a tridentate thiosemicarbazone ligand and the second report of a crystal structure of a thiosemicarbazone silver(I) complex. The reaction of the tetramer with a large excess of PPh(3) gave dimeric complexes, namely, [Ag(micro(S)-mtsc)(PPh(3))](2) and [(PPh(3))(2)Ag(micro(S) mtsc)(2)Ag]. The chloroform solution of the tetrameric complex showed modest and effective activities against selected bacteria (Bacillus subtilis, Staphylococcus aureus and Pseudomonas aeruginosa) and yeasts (Candida albicans and Saccharomyces cerevisiae), respectively, but it did not inhibit the growth of any selected microorganisms in a water-suspension system. PMID- 17700828 TI - One-dimensional phosphinite platinum chains based on hydrogen bonding interactions and phosphinite tetranuclear platinum(II)-thallium(I) complexes. AB - The mononuclear pentafluorophenyl platinum complex containing the chelated diphenylphosphinous acid/diphenylphosphinite system [Pt(C(6)F(5)){(PPh(2)O)(2)H}(PPh(2)OH)] 1 has been prepared and characterised. 1 and the related alkynyl complex [Pt(C[triple bond, length as m dash]CBu(t)){(PPh(2)O)(2)H}(PPh(2)OH)] 2 form infinite one-dimensional chains in the solid state based on intermolecular O-H[dot dot dot]O hydrogen bonding interactions. Deprotonation reactions of [PtL{(PPh(2)O)(2)H}(PPh(2)OH)] (L = C(6)F(5), C[triple bond, length as m-dash]CBu(t), C[triple bond, length as m dash]CPh 3) with [Tl(acac)] yields tetranuclear Pt(2)Tl(2) complexes [PtL{(PPh(2)O)(2)H}(PPh(2)O)Tl](2) (L = C(6)F(5) 4, C[triple bond, length as m dash]CBu(t), C[triple bond, length as m-dash]CPh ). The structure of the tert butylalkynyl derivative , established by X-ray diffraction, shows two anionic discrete units [Pt(C[triple bond, length as m dash]CBu(t)){(PPh(2)O)(2)H}(PPh(2)O)](-) joined by two Tl(i) centres via Tl-O and Pt-Tl bonds. Despite the existence of Pt-Tl interactions, they do not show luminescence. PMID- 17700829 TI - Towards aqueous chiral heptadentate lanthanide complexes as selective shift and relaxation agents for MRS. AB - Magnetic resonance spectroscopy (MRS) is of prime importance in diagnostics and offers a means of analyzing, in vivo, the chemical content of living tissue, as a non-invasive alternative to biopsy. Several heptadentate, lanthanide complexes have been synthesized and their potential to act as shift and relaxation agents in MRS (for lactate, in particular) has been assessed through (1)H NMR analysis. The binding affinity and enantiopurity of the complexes have been modulated by systematic variation of the lanthanide ion and ligand structure, in particular the peripheral electrostatic charge of the complex (cationic versus neutral) and the local charge and steric demand at the metal centre. PMID- 17700830 TI - Alkali metal complexes of a phosphine-borane-stabilised carbanion: influence of co-ligands on structure. AB - The adducts [[(Me(3)Si)(2){Me(2)P(BH(3))}C]K(L)(n)](m) [L = THF, n = 0.5, m = infinity (2a); L = tmeda (2b), pmdeta (2c), n = 1, m = 2] may be synthesised by treatment of solvent-free [[(Me(3)Si)(2){Me(2)P(BH(3))}C]K](infinity) (2) with the corresponding Lewis base (tmeda = N,N,N',N'-tetramethylethylenediamine; pmdeta = N,N,N',N'',N''-pentamethyldiethylenetriamine). X-Ray crystallography reveals that, whereas 2 crystallises with a complex 2-dimensional sheet structure, 2a crystallises as a ribbon-type one-dimensional polymer and both 2b and 2c crystallise as dimers. The corresponding complex with 12-crown-4, [K(12 crown-4)(2)][(Me(3)Si)(2){Me(2)P(BH(3))}C] (2d) crystallises as a separated ion pair. The complexes [[(Me(3)Si)(2){Me(2)P(BH(3))}C]M(pmdeta)](n) [M = Na, n = 1 (6); M = Rb, n = 2 (7)] may be synthesised by treatment of [(Me(3)Si)(2){Me(2)P(BH(3))}C]M with pmdeta. Whereas crystallises as a discrete monomer, compound 7 crystallises as a dimer. Compounds 2, 2a-2d, 6, 7 and the corresponding caesium derivative [[(Me(3)Si)(2){Me(2)P(BH(3))}C]Cs(pmdeta)](2) () provide an opportunity to consider the influence of the ionic radius of the metal and the nature of the co-ligands on the structures of alkali metal complexes of a phosphine-borane-stabilised carbanion. PMID- 17700831 TI - Structure and DNA cleavage properties of two copper(II) complexes of the pyridine pyrazole-containing ligands mbpzbpy and Hmpzbpya. AB - The DNA-cleavage properties of the two copper(II) complexes, [Cu(mbpzbpy)Br(2)](H(2)O)(2.5) (1) and [Cu(mpzbpya)Cl](CH(3)OH) (2), obtained from the ligands 6,6'-bis(3,5-dimethyl-N-pyrazolmethyl)-2,2'-bipyridine) (mbpzbpy) and 6'-(3,5-dimethyl-N-pyrazolmethyl)-2,2'-bipyridine-6-carboxylic acid) (Hmpzbpya), respectively, are reported. Upon coordination to Cu(II) chloride in methanol, one arm of the ligand mbpzbpy is hydrolyzed to form mpzbpya. Under the same experimental conditions, the reaction of mbpzbpy with CuBr(2) does not lead to ligand hydrolysis. The ligand mpzbpya is coordinated to a copper(ii) ion generating a CuN(3)OCl chromophore, resulting in a distorted square-pyramidal environment, whereas with the N(4) mbpzbpy ligand, the Cu(II) ion is four-coordinated in a distorted square planar geometry. Both complexes promote the oxidative DNA cleavage of phiX174 phage DNA in the absence of reductant. The oxidative nature of the DNA cleavage reaction has been confirmed by religation and cell-transformation experiments. Studies using standard radical scavengers suggest the involvement of hydroxyl radicals in the oxidative cleavage of DNA. Although both compounds do convert form I (supercoiled) DNA to form II (nicked, relaxed form), only complex 1 is able to produce small amounts of form III (linearized DNA). This observation may be explained either by the attack of the copper(ii) complexes to only one single strand of DNA, or by a single cleavage event. Statistical analysis of relative DNA quantities present after the treatment with both copper(ii) complexes supports a random mode of DNA cleavage. PMID- 17700832 TI - Coordination and structural studies of crowned-porphyrins. AB - Simple chelating agents have been synthesized using a porphyrin and a covalently linked crown-ether. Depending on the relative spatial arrangement of both motifs, the resulting ligands, either a macrotricycle or bis-macrocycles, differ one from another by their flexibility or their aptitude to chelate bivalent or trivalent cations. The coordination chemistry as well as the structural study of these ligands and complexes are reported. In the particular case of the macrotricycle, the crown-ether motif, perpendicular to the porphyrin induces a side selectivity for the coordination of lead(II) outside the cavity. Furthermore, the coordination of zinc(II) implies a change of conformation of the ligand in which the crown-ether is parallel to the porphyrin. PMID- 17700833 TI - 4,2-Ribbon like ferromagnetic cyano-bridged Fe(III)2Ni(II) chains: a magneto structural study. AB - The low-spin iron(III) complex AsPh(4)[Fe(III)(bpy)(CN)(4)].CH(3)CN (1) [AsPh(4) = tetraphenylarsonium cation] and the heterobimetallic chains [{Fe(III)(L)(CN)(4)}(2)Ni(II)(H(2)O)(2)].4H(2)O with L = bpy (2) and phen (3) [bpy = 2,2'-bipyridine and phen = 1,10-phenanthroline] have been prepared and their structures determined by X-ray diffraction methods. The structure of 1 consists of mononuclear [Fe(bpy)(CN)(4)](-) anions, tetraphenylarsonium cations and acetonitrile molecules of crystallization. The iron(III) is hexacoordinated with two nitrogen atoms of the bidentate bpy and four carbon atoms of four terminal cyanide groups building a distorted octahedral surrounding around the metal atom. 2 and 3 are isomorphous compounds whose structure is made up of neutral 4,2-ribbon like bimetallic chains of formula [{Fe(III)(L)(CN)(4)}(2)Ni(II)(H(2)O)(2)] where the [Fe(III)(L)(CN)(4)](-) unit acts as a bis-monodentate bridging ligand toward the trans-diaquanickel(II) units through two of its four cyanide groups in cis positions. The chains exhibit two orientations in the unit cell and they interact with each other through hydrogen bonds involving the coordination and crystallization water molecules together with the uncoordinated cyanide nitrogen atoms of the [Fe(L)(CN)(4)](-) units. Compounds 2 and 3 behave as ferromagnetic Fe(III)(2)Ni(II) chains which interact ferromagnetically at very low temperatures in the case of 2, whereas metamagnetic like behaviour is observed for with a critical field (H(c)) around 200 G. For H > H(c) the ferromagnetic Fe(III)(2)Ni(II) chains of 3 exhibit a frequency dependence of the out-of-phase ac susceptibility signal at T < 3.5 K. PMID- 17700834 TI - [Co5(mu3-OH)2(btec)2(bpp)]n: a three-dimensional homometallic molecular metamagnet built from the mixed hydroxide/carboxylate-bridged ferrimagnetic-like chains. AB - A three-dimensional homometallic complex [Co(5)(mu(3)-OH)(2)(btec)(2)(bpp)](n) is built from the mixed hydroxide/carboxylate bridged cobalt(ii) chains linked by the 1,2,4,5-benzenetetracarboxylate (btec(4-)) anion and 1,3-bis(4-pyridyl) propane molecule (bpp). Within each chain, two mu(3)-OH-bridged metal triangles connect to each other by sharing a common vertex to give rise to a bow-tie type Co(5)(mu(3)-OH)(2) subunit, which is joined to adjacent subunits by four mu(1,1) carboxylate bridges to form a step-like metal-oxygen backbone. The magnetic studies revealed that the coexistence of ferromagnetic and antiferrimagnetic interactions resulted in a ferrimagnetic-like behavior of the homometallic chains. Below a critical temperature (T(N) = 12.5 K), bulk antiferromagnetic ordering was observed at low field due to the weak interchain antiferromagnetic interactions. A metamagnetic transition occurred at a magnetic field of ca. 5 kOe at 2 K. PMID- 17700835 TI - Asymmetric sulfur atom coordination in a copper(II) dipicolylamine (DPA) complex with a thioglycoside ligand. AB - The 2,2'-dipicolylamine (DPA)-tethered thioglycoside ligand, N,N-bis(2 pyridylmethyl)-2-aminoethyl 1-deoxy-1-thio-2,3,4,6-tetra-O-acetyl-beta-d glucopyranoside (sL1), has been prepared and its copper(II) complex synthesized. Using copper(II) chloride, the copper complex was isolated as a chloride-bound species formulated as [Cu(sL1)Cl(ClO(4))](1). The corresponding O-glycoside complex ([Cu(L1)Cl](ClO(4)), 2) was also prepared using L1 (N,N-bis(2 pyridylmethyl)-2-aminoethyl 2,3,4,6-tetra-O-acetyl-beta-d-glucopyranoside), and both complexes were characterized and compared by means of X-ray crystallography, cyclic voltammetry, electronic absorption and circular dichroism (CD) spectra. Although both complexes exhibited similar copper coordination geometries, the absolute configuration of the O/S chiral center generated by the copper coordination was inverted. The electronic and CD spectra of acetonitrile solutions of 1 and 2 were different likely due to the presence of a copper-sulfur charge-transfer band for 1. Complex also exhibits a large Cotton effect around 700 nm. The corresponding d-d transition of the copper(II) center reveals that the asymmetric copper-sulfur (oxygen) coordination remains even in solution. PMID- 17700836 TI - Pd-H elimination reactions in palladium(II) allylic complexes. AB - The ease of H elimination from the 4- (beta-) position in a series of allylic complexes [Pd(5-C(6)F(5)-1-3-eta(3)-cyclohexenyl)XL](n+) (X, L = Br, N-, P-donor, C(6)Cl(2)F(3); n = -1, 0, +1) was compared by analyzing their decomposition products at 50 degrees C. Pd-H elimination does not occur for cationic complexes, whereas it is the main decomposition pathway for neutral and anionic complexes. In addition to the charge of the complex, the ease of this Pd-H elimination is determined by the trans influence of the ligands (aryl > PMe(3) > Br, N-donor). PMID- 17700837 TI - Palladium catalyzed arylation for the synthesis of polyarenes. AB - We present the current understanding on the mechanism of palladium-catalyzed arylation, which involves a proton abstraction by the base. In addition, we present selected examples of the application of this reaction for the synthesis of large polyarenes to highlight the variety of catalysts and reaction conditions that are currently used. PMID- 17700838 TI - Photochemical transformations of pyridinium salts: mechanistic studies and applications in synthesis. AB - The discovery, understanding and synthetic exploitation of the photochemical transformation of pyridinium salts are described. The investigations surrounding the remarkable transformation of pyridinium salts into a host of structurally complex motifs have helped extend the comprehension of aromatic and heteroaromatic photochemistry. The synthetic community has, in recent years, recognised the potential inherent in these compounds and has since exploited the irradiation of variously substituted pyridinium salts as key steps in the preparation of advanced intermediates in numerous synthetic programmes. PMID- 17700839 TI - Coumarin-derived discodermolide analogues possessing equivalent antiproliferative activity to the natural product--a further simplification of the lactone region. AB - Analogues of discodermolide in which the complete C-1 to C-7 fragment is replaced with a coumarin moiety display equivalent potency to that of the natural product. PMID- 17700840 TI - Improved synthesis of O-linked, and first synthesis of S- linked, carbohydrate functionalised N-carboxyanhydrides (glycoNCAs). AB - An improved method for the synthesis of glycosylated N-carboxyanhydrides, which are monomers for glycopeptide synthesis, is presented. PMID- 17700841 TI - Flow and batch mode focused microwave synthesis of 5-amino-4-cyanopyrazoles and their further conversion to 4-aminopyrazolopyrimidines. AB - A new approach to the synthesis of 5-amino-4-cyanopyrazoles has been developed, utilising a novel flow microwave device. These products are then converted by a batch mode microwave process to structurally more complex dimeric and 'mixed' pyrazolopyrimidine structures. PMID- 17700842 TI - Tuning of fluorescence properties of aminoterpyridine fluorophores by N substitution. AB - Several N-alkyl and N-phenyl derivatives of 6-amino- () and 6,6'-diamino 2,2':6',2''-terpyridine () were synthesized, and their fluorescence properties were studied. A successive red-shift was observed as the number of the N substituted groups increased. It was also shown that the susceptivity of the fluorophores to a solvent varied considerably according to the mode of the N substitution. While the monoamino-tpys (tpy: 2,2':6',2''-terpyridine) suffered almost complete quenching of their fluorescence in ethanol, the fully N-alkylated diamino-tpys and retained their fluorescence. The results show that N substitution is a useful way to tune both the radiation energy and solvent susceptivity of the fluorescence of the amino-tpys. PMID- 17700843 TI - A new azide staining reagent based on "click chemistry". AB - A new staining reagent was prepared and its ability to stain several azide containing agents on TLC plates was determined. PMID- 17700844 TI - In situ Raman spectroscopy as a probe for the effect of power on microwave promoted Suzuki coupling reactions. AB - We report the use of in situ Raman spectroscopy as a probe for the effect of power on microwave-promoted Suzuki coupling reactions. We find that increased initial microwave power leads to greater acceleration of the reaction but that the product yield obtained is essentially independent of initial microwave power. The application of simultaneous cooling lengthens the reaction time but does not alter the relative rates of the Suzuki coupling and deboronation processes. Performing the reaction at an initial microwave power of 5 W leads to an improvement in product yield. PMID- 17700845 TI - Reasons for the exclusive formation of heterodimeric capsules between tetra-tolyl and tetra-tosylurea calix[4]arenes. AB - The selective heterodimerization of tetra-tolyl () and tetra-tosylurea () calixarenes, serendipitously found by Rebek et al. (R. K. Castellano, B. H. Kim and J. Rebek, Jr., J. Am. Chem. Soc., 1997, 119, 12671-12672), has been used for the construction of highly sophisticated macrocycles and well-defined supramolecular assemblies. Regrettably, hitherto, neither the exact structure of these heterodimers nor the reason for their exclusive formation is known. We present molecular dynamics simulations using the AMBER force field in explicit chloroform solvent for the two homodimers, the heterodimer and the two uncomplexed tetra-urea calixarenes. The rigid rotation about the C-S-N-C bond of the tosylurea group has been calculated for a model compound (N-mesylformamide) at the RHF/6-31G* level of theory. The calculations suggest that the heterodimer . is energetically favored over the homodimers by a sterically relaxed conformation of the tosylurea hemisphere in ., by a moderate degree of reorganization of the hemispheres from the uncomplexed to the complexed state and by favorable interactions between the hemispheres. The tosylurea S=O groups are involved in the hydrogen bonding system which results in different sizes of the three capsules in increasing order . < . < .. To prove the computational predictions, 1H NMR experiments have been carried out with solvents/guests differing in shape and size. The largest capsule . prefers the larger guests toluene and p-xylene while the latter is not encapsulated in the smallest capsule .. PMID- 17700846 TI - Chlorofullerene C60Cl6: a precursor for straightforward preparation of highly water-soluble polycarboxylic fullerene derivatives active against HIV. AB - We report for the first time the application of chlorofullerene C60Cl6 as a substrate for straightforward preparation of highly water-soluble fullerene derivatives, promising compounds for investigation of the biological action of fullerenes in vitro and in vivo. Methyl esters of phenylacetic and benzylmalonic acids were used as reagents in the Friedel-Crafts arylation of C60Cl6 that resulted in the corresponding C60(Ar)5Cl compounds with 50-60% yields. The following cleavage of ester groups in phenylacetic and benzylmalonic residues was accomplished almost quantitatively to yield the corresponding fullerene-based acids bearing 5 and 10 carboxylic groups, respectively. The relatively-low solubility of these acids in water can be strongly enhanced (up to 150-200 mg ml( 1)) by their conversion to salts with alkali metal cations. These fullerene salt derivatives showed pronounced anti-HIV action and low toxicity; these two findings point to the necessity for further investigation of the biological properties of the here-reported compounds. PMID- 17700847 TI - Photosensitization of 2'-deoxyadenosine-5'-monophosphate by pterin. AB - UV-A radiation (320-400 nm) induces damages to the DNA molecule and its components through photosensitized reactions. Pterins, heterocyclic compounds widespread in biological systems, participate in relevant biological processes and are able to act as photosensitizers. We have investigated the photosensitization of 2'-deoxyadenosine-5'-monophosphate (dAMP) by pterin (PT) in aqueous solution under UV-A radiation. The effect of pH was evaluated, the participation of oxygen was investigated and the products analyzed. Kinetic studies revealed that the reactivity of dAMP towards singlet oxygen (1O2) is very low and that this reactive oxygen species does not participate in the mechanism of photosensitization, although it is produced by PT upon UV-A excitation. In contrast, analysis of irradiated solutions by means of electrospray ionization mass spectrometry strongly suggested that 8-oxo-7,8-dihydro-2'-deoxyadenosine-5' monophosphate (8-oxo-dAMP) was produced, indicating that the photosensitized oxidation takes place via a type I mechanism (electron transfer). PMID- 17700848 TI - A practical synthesis of (3R,4R)-N-tert-butoxycarbonyl-4-hydroxymethylpyrrolidin 3-ol. AB - The title compound (+)-, required for production of transition state analogue inhibitors of enzymes involved in T-cell-dependent disorders, was synthesized in five steps. A 1,3-dipolar cycloaddition of the nitrone formed from formaldehyde and N-benzylhydroxylamine to diethyl maleate gave the racemic cis-isoxazolidine (+/-)-. Reduction of the N-O bond of this compound gave pyrrolidone (+/-)- in excellent yield. A very efficient enzymic resolution of this racemic product led to the title enantiomer (+)-. This route employs only one chromatographic purification. PMID- 17700849 TI - Longer polyenyl cations in relation to soliton theory. AB - The carotene-like polyenes decapreno-beta-carotene (C50), C54-beta-carotene (C54, first synthesis) and dodecapreno-beta-carotene (C60) with 15, 17 and 19 conjugated double bonds, respectively, were synthesized by double Wittig reactions. Introduction of a leaving group in allylic position failed, and cations were obtained by hydride elimination effected by i) triphenylcarbenium tetrafluoroborate-d15, prepared by a new method, or ii) treatment with trifluoroacetic acid-d. Deuterated reagents were employed for product analysis by 1H NMR. Parallel experiments were performed with beta,beta-carotene (C40). NIR spectra at room temperature and at -15 degrees C were employed for characterisation and stability studies of the cationic products. In CH2Cl2lambdamax in the 900-1350 nm region was recorded. NMR data for the cationic product of beta,beta-carotene obtained by the two new preparation methods were consistent with the two monocations previously characterised. The cationic products of the longer polyenes provided downfield-shifted, broadened signals, compatible with C50-monocation, mixed C54-mono- and dication and C60-dication. Combined NIR and NMR data suggest that the extent of charge delocalisation is limited by the maximum soliton width for cations obtained from linear polyenes with more than ca. 20 sp2-hybridized carbon atoms. PMID- 17700850 TI - Asymmetric synthesis of beta2-amino acids: 2-substituted-3-aminopropanoic acids from N-acryloyl SuperQuat derivatives. AB - Conjugate addition of lithium dibenzylamide to (S)-N(3)-acryloyl-4-isopropyl-5,5 dimethyloxazolidin-2-one (derived from l-valine) and alkylation of the resultant lithium beta-amino enolate provides, after deprotection, a range of (S)-2-alkyl-3 aminopropanoic acids in good yield and high ee. Alternatively, via a complementary pathway, conjugate addition of a range of secondary lithium amides to (S)-N(3)-(2'-alkylacryloyl)-4-isopropyl-5,5-dimethyloxazolidin-2-ones, diastereoselective protonation with 2-pyridone, and subsequent deprotection furnishes a range of (R)-2-alkyl- and (R)-2-aryl-3-aminopropanoic acids in good yield and high ee. Additionally, the boron-mediated aldol reaction of beta-amino N-acyl oxazolidinones is a highly diastereoselective method for the synthesis of a range of beta-amino-beta'-hydroxy N-acyl oxazolidinones. PMID- 17700851 TI - Enantiospecific synthesis of the heparanase inhibitor (+)-trachyspic acid and stereoisomers from a common precursor. AB - The total synthesis of natural (+)-trachyspic acid and its enantiomer is described starting from a common 2-deoxy-d-ribose derivative. The synthesis of the corresponding C3 epimers from the same starting material is also described. Each stereoisomer was assayed for heparanase inhibition. PMID- 17700852 TI - Hydrolysis of 4-imino-imidazolidin-2-ones in acid and the mechanism of cyclization of hydantoic acid amides. AB - The hydrolysis of iminohydantoins generates the same tetrahedral intermediate as that obtained in the cyclization of hydantoic acid amides to hydantoins. The ratio of the products of imine hydrolysis under kinetic control is determined by the relative height of the barriers of the breakdown of to amide or to hydantoin. Thus the partitioning of products unequivocally proves which is the rate determining step in the cyclization reaction-formation or breakdown of . UV and 1H NMR monitoring of the acid catalyzed hydrolysis of four 5-substituted 4-imino 1-methyl-3-(4-nitrophenyl)imidazolidin-2-ones found hydantoins as the only products. The kinetics of hydrolysis of imines were measured in 0.001-1 M HCl. Contrary to the remaining imines, 1,5-dimethyl-4-imino-3-(4 nitrophenyl)imidazolidin-2-one is readily oxidized as stock solution in THF containing peroxides to 1,5-dimethyl-5-hydroxy-4-imino-3-(4 nitrophenyl)imidazolidin-2-one . In all cases, hydrolysis was found to be zero order with respect to [H+]. As imines are fully protonated under the acidity studied, this is evidence of a transition state of a single positive charge. Comparison of imine hydrolysis rates with previous data on rates of cyclization of the corresponding amides of hydantoic acids allowed conditions (acid concentration, substitution pattern-gem-dimethyl effect) to be found that guaranteed kinetic control of the products obtained. Thus it was unequivocally proven that formation of the tetrahedral intermediate is rate determining in the cyclization of hydantoic acid amides. The small steric effects upon methyl substitution at 5-C and a solvent kinetic isotope effect kH/kD of 1.72 favour a mechanism for imine hydrolysis whereby the rate is limited by water attack on the protonated imine concerted with proton transfer from attacking water to a second water molecule. PMID- 17700853 TI - Hosomi-Sakurai reactions of silacyclohexenes. AB - Silacyclic allyl silanes, derived from silene-diene Diels-Alder reactions, combine with acetals in the presence of Lewis acids to afford, following oxidation of the intermediate fluorosilane, either butane-1,4-diols or tetrahydronaphthalenes containing four contiguous chiral centres with moderate to good diastereoselectivity. PMID- 17700854 TI - Synthesis of 2'-deoxyadenosine nucleosides bearing bipyridine-type ligands and their Ru-complexes in position 8 through cross-coupling reactions. AB - The synthesis of the title 2'-deoxyadenosine derivatives bearing bipyridine, phenanthroline or terpyridine ligands and their corresponding RuII-complexes in position 8 linked via acetylene or phenylene tethers was accomplished through cross-coupling reactions. The Suzuki-Miyaura reactions of boronic acids or the Sonogashira reactions of terminal acetylene derivatives of oligopyridine ligands were performed either on protected 8-bromoadenosines in organic solvents or, more efficiently, directly on unprotected nucleosides in aqueous acetonitrile or DMF. Direct cross-coupling reactions of unprotected nucleosides with RuII-complexes or the oligopyridine-boronic acids or -acetylenes gave the Ru-labelled nucleosides in one step in fair to good yields. This method was also proven to be applicable for direct Ru-labelling of dATP. Terpyridine-containing 2'-deoxyadenosine exerted significant antiviral and cytostatic effects. PMID- 17700855 TI - Synthesis and assignment of the absolute configuration of the anti-Helicobacter pylori agents CJ-12,954 and CJ-13,014. AB - The synthesis of the spiroacetal-containing anti-Helicobacter pylori agents (3S,2''S,5''S,7''S)- (ent-CJ-12,954) and (3S,2''S,5''R,7''S)- (ent-CJ-13,014) has been carried out based on the convergent union of a 1:1 mixture of heterocycle activated spiroacetal sulfones and with (3S)-phthalide aldehyde . The synthesis of the (3R)-diastereomers (3R,2''S,5''S,7''S)- and (3R,2''S,5''R,7''S)- was also undertaken in a similar manner by union of (3R)-phthalide aldehyde with a 1:1 mixture of spiroacetal sulfones and . Comparison of the (1)H and (13)C NMR data, optical rotations and HPLC retention times of the synthetic compounds (3S,2''S,5''S,7''S)- and (3S,2''S,5''R,7''S)- and the (3R)-diastereomers (3R,2''S,5''S,7''S)- and (3R,2''S,5''R,7''S)-, with the naturally occurring compounds, established that the synthetic isomers and were in fact enantiomeric to the natural products CJ-12,954 and CJ-13,014. The (2S,8S)-stereochemistry in protected dihydroxyketone , the precursor to the mixture of spiroacetal sulfones and was established via union of readily available (S)-acetylene with aldehyde in which the (4S)-stereochemistry was established via asymmetric allylation. Deprotection and cyclization of protected dihydroxyketone afforded an inseparable 1:1 mixture of spiroacetal alcohols and that were converted into a 1:1 inseparable mixture of spiroacetal sulfones and . Phthalide-aldehyde was prepared via intramolecular acylation of bromocarbamate in which the (3S)-stereochemistry was established via asymmetric CBS reduction of ketone . PMID- 17700857 TI - Communication between the cytoskeleton and the nuclear envelope to position the nucleus. AB - In most eukaryotic cells, the nucleus is localized to a specific location. This highlight article focuses on recent advances describing the mechanisms of nuclear migration and anchorage. Central to nuclear positioning mechanisms is the communication between the nuclear envelope and the cytoskeleton. All three components of the cytoskeleton-microtubules, actin filaments and intermediate filaments-are involved in nuclear positioning to varying degrees in different cell types. KASH proteins on the outer nuclear membrane connect to SUN proteins on the inner nuclear membrane. Together they transfer forces between the cytoskeleton and the nuclear lamina. Once at the outer nuclear membrane, KASH proteins can interact with the cytoskeleton. Nuclear migrations are a component of many cellular migration events and defects in nuclear positioning lead to human diseases, most notably lissencephaly. PMID- 17700858 TI - Moving marks: dynamic histone modifications in yeast. AB - Posttranslational modifications of histones, both in the tails and in the globular cores, alter the functional landscape of chromatin by modulating DNA accessibility and chromatin stability, and by providing an enormous variety of alternative interaction surfaces for trans-acting factors. Complex patterns of acetylation, methylation, phosphorylation, ubiquitylation (and others) result in spatial domains of meaningful chromatin modifications, often referred to as the histone code. Whole genome studies have uncovered striking genome-wide patterns of specific modifications, and individual modifications have been linked to a variety of functional consequences for transcription, replication and repair. A key aspect of the role of histone modifications, however, is their dynamic nature the precise timing of the addition and removal of specific marks is an essential part of the histone code. This review will highlight examples from budding yeast that illustrate the importance of these dynamic modifications in controlling transcription and repair. PMID- 17700859 TI - A genome-scale, constraint-based approach to systems biology of human metabolism. AB - The recent sequencing and annotation of the human genome enables a new era in biomedicine that will be based on an interdisciplinary, systemic approach to the elucidation and treatment of human disease. Reconstruction of genome-scale metabolic networks is an important part of this approach since networks represent the integration of diverse biological data such as genome annotations, high throughput data, and legacy biochemical knowledge. This article will describe Homo sapiens Recon 1, a functionally tested, genome-scale reconstruction of human cellular metabolism, and its capabilities for facilitating the understanding of physiological and disease metabolic states. PMID- 17700860 TI - A view of RNase P. AB - Major progress in the study of RNase P has resulted from crystallography of bacterial catalytic subunits and the discovery of catalytic activity in eukaryotes. Several new substrates have also been identified, primarily in bacteria but also in yeast. Our current world should be called the "RNA-protein world" rather than the "protein world". PMID- 17700861 TI - The physiological and molecular regulation of lipoprotein assembly and secretion. AB - Triglycerides are insoluble in water and yet are transported at milligram per millilitre concentrations in the bloodstream. This is made possible by the ability of the liver and intestine to assemble lipid-protein emulsions (i.e. lipoproteins), which transport hydrophobic molecules. The assembly of triglyceride-rich lipoproteins requires the coordination of protein and lipid synthesis, which occurs on the cytoplasmic surface of the endoplasmic reticulum (ER), and their concerted assembly and translocation into the luminal ER secretory pathway as nascent lipoprotein particles. The availability of lipid substrate for triglyceride production and the machinery for lipoprotein assembly are highly sensitive to nutritional, hormonal, and genetic modulation. Disorders in lipid metabolism or an imbalance between lipogenesis and lipoprotein assembly can lead to hyperlipidemia and/or hepatic steatosis. We selectively review recently-identified machinery, such as transcription factors and nuclear hormone receptors, which provide new clues to the regulation of lipoprotein secretion. PMID- 17700862 TI - Aptamers as elements of bioelectronic devices. AB - A ferrocene labelled aptamer is used as a redox partner of co-immobilised microperoxidase demonstrating a reversible amperometric biomolecular device that could respond to external stimuli in real time. PMID- 17700863 TI - Transcript and proteomic analyses of wild-type and gpa2 mutant Saccharomyces cerevisiae strains suggest a role for glycolytic carbon source sensing in pseudohyphal differentiation. AB - In response to limited nitrogen and abundant carbon sources, diploid Saccharomyces cerevisiae strains undergo a filamentous transition in cell growth as part of pseudohyphal differentiation. Use of the disaccharide maltose as the principal carbon source, in contrast to the preferred nutrient monosaccharide glucose, has been shown to induce a hyper-filamentous growth phenotype in a strain deficient for GPA2 which codes for a Galpha protein component that interacts with the glucose-sensing receptor Gpr1p to regulate filamentous growth. In this report, we compare the global transcript and proteomic profiles of wild type and Gpa2p deficient diploid yeast strains grown on both rich and nitrogen starved maltose media. We find that deletion of GPA2 results in significantly different transcript and protein profiles when switching from rich to nitrogen starvation media. The results are discussed with a focus on the genes associated with carbon utilization, or regulation thereof, and a model for the contribution of carbon sensing/metabolism-based signal transduction to pseudohyphal differentiation is proposed. PMID- 17700864 TI - The strength of EPR and ENDOR techniques in revealing structure-function relationships in metalloproteins. AB - Recent technological and methodological advances have strongly increased the potential of electron paramagnetic resonance (EPR) and electron nuclear double resonance (ENDOR) techniques to characterize the structure and dynamics of metalloproteins. These developments include the introduction of powerful pulsed EPR/ENDOR methodologies and the development of spectrometers operating at very high microwave frequencies and high magnetic fields. This overview focuses on how valuable information about metalloprotein structure-function relations can be obtained using a combination of EPR and ENDOR techniques. After an overview of the historical development and a limited theoretical description of some of the key EPR and ENDOR techniques, their potential will be highlighted using selected examples of applications to iron-, nickel-, cobalt-, and copper-containing proteins. We will end with an outlook of future developments. PMID- 17700865 TI - Charging of metal clusters in helium droplets exposed to intense femtosecond laser pulses. AB - We review the strong field (10(13)-10(16) W cm(-2)) laser excitation of metal clusters (Cd(N), Ag(N) and Pb(N)) embedded in He nanodroplets. Plasmon enhanced ionization obtained by stretching the laser pulses to several hundreds of femtoseconds or by using dual pulses with a suitable optical delay leads to a Coulomb explosion of highly charged atomic ions. The charging dynamics can be well described by corresponding semiclassical Vlasov simulations. The influence of the He environment on the ionization process and on the final charge distribution is discussed. Evidence is found that He(2+) is generated in collisions with highly charged metal ions. In contrast, singly and doubly charged ions with low recoil energies induce the formation of He snowballs with a distinct shell structure around the ion. Laser intensity thresholds for snowball formation and for the ionization of clusters are investigated by applying intensity selective scanning. PMID- 17700866 TI - Prediction of the vapor pressure and vaporization enthalpy of 1-n-alkyl-3 methylimidazolium-bis-(trifluoromethanesulfonyl) amide ionic liquids. AB - The vapor pressures and vaporization enthalpies of a series of 1-n-alkyl-3 methylimidazolium-bis-(trifluoromethanesulfonyl) amide ionic liquids have been predicted with two different approaches using the COSMO-RS method and quantum chemical gas phase calculations. While the calculated enthalpies are in good agreement with the experimental data, COSMO-RS seems to underestimate the vapor pressures by roughly 0.5-4 log units dependent on the IL and approach used. PMID- 17700867 TI - Carbon monoxide adsorption on low-silica zeolites: from single to dual and to multiple cation sites. AB - Infrared spectra of CO adsorbed on the Al-rich Na-A zeolite were analysed by using a combined theoretical and experimental approach, showing that such spectra cannot be interpreted by assigning each IR band to CO interacting with a specific type of single cation site. This concept, which usually works well for high silica zeolites, should not be uncritically extended to Al-rich zeolites that are crowded with cations in configurations which lead to preferential formation of CO adsorption complexes involving more than one cation site. PMID- 17700868 TI - Coarse-grained simulations of ABA amphiphilic triblock copolymer solutions in thin films. AB - We study a coarse-grained model of A(10)-B(20)-A(10) amphiphilic triblock copolymers in aqueous solution under confinement. We focus on the influence of the wall interaction on the morphology of the ensuing self-assembled structures. We also study the dynamics of the polymers. All our simulations are confined between two walls. We study three different combinations of walls: hydrophobic and hydrophobic, hydrophobic and hydrophilic, hydrophilic and hydrophilic. We moreover elucidate the concentration influence. The conformation and behavior of the copolymer in strongly confined systems depend on the type of wall interaction and concentration. PMID- 17700869 TI - The mixed alkali effect in ionically conducting glasses revisited: a study by molecular dynamics simulation. AB - When more than two kinds of mobile ions are mixed in ionic conducting glasses and crystals, there is a non-linear decrease of the transport coefficients of either type of ion. This phenomenon is known as the mixed mobile ion effect or Mixed Alkali Effect (MAE), and remains an unsolved problem. We use molecular dynamics simulation to study the complex ion dynamics in ionically conducting glasses including the MAE. In the mixed alkali lithium-potassium silicate glasses and related systems, a distinct part of the van Hove functions reveals that jumps from one kind of site to another are suppressed. Although, consensus for the existence of preferential jump paths for each kind of mobile ions seems to have been reached amongst researchers, the role of network formers and the number of unoccupied ion sites remain controversial in explaining the MAE. In principle, these factors when incorporated into a theory can generate the MAE, but in reality they are not essential for a viable explanation of the ion dynamics and the MAE. Instead, dynamical heterogeneity and "cooperativity blockage" originating from ion-ion interaction and correlation are fundamental for the observed ion dynamics and the MAE. Suppression of long range motion with increased back-correlated motions is shown to be a cause of the large decrease of the diffusivity especially in dilute foreign alkali regions. Support for our conclusion also comes from the fact that these features of ion dynamics are common to other ionic conductors, which have no glassy networks, and yet they all exhibit the MAE. PMID- 17700870 TI - The dynamics of water evaporation from partially solvated cytochrome c in the gas phase. AB - The study of evaporation of water from biological macromolecules is important for the understanding of electrospray mass spectrometry experiments. In electrospray ionization (ESI), electrically charged nanoscale droplets are formed from solutions of, for example, proteins. Then evaporation of the solvent leads to dry protein ions that can be analyzed in the mass spectrometer. In this work the dynamics of water evaporation from native cytochrome c covered by a monolayer of water is studied by molecular dynamics (MD) simulations at constant energy. A model of the initial conditions of the process is introduced. The temperature of the protein drops by about 100 K during the 400 picoseconds of the simulations. This sharp drop in temperature causes the water evaporation rate to decrease by about an order of magnitude, leaving the protein with 50% to 90% of the original water molecules, depending on the initial temperature of the simulation. The structural changes of the protein upon desolvation were considered through calculations of the radius of gyration and the root mean square (RMS) of the protein. A variation of 0.4 A in the radius of gyration, together with an RMS value of less than 3 A, indicates only minor changes in the overall shape of the protein structure. The water coordination number of the solvation shell is much smaller than that for bulk water. The mobility of water is high at the beginning of the simulations and drops as the simulation progresses and the temperature decreases. Incomplete desolvation of protein ions was also observed in recent experiments. PMID- 17700871 TI - A matrix isolation study on Ac-Gly-NHMe and Ac-l-Ala-NHMe, the simplest chiral and achiral building blocks of peptides and proteins. AB - The infrared absorption (IR) spectra of acetyl-N-methyl-glycine and acetyl-N methyl-alanine have been recorded in dichloromethane and dimethyl sulfoxide-d(6) solution, as well as in Ar and Kr matrices. The spectra were assigned with the help of quantum chemical calculations. Based on the assignments of the matrix isolation IR spectra, in line with theoretical predictions, two different hydrogen bonded conformers were identified, furthermore a third conformer is likely to be present, which cannot be unambiguously identified. In dichloromethane two conformers could be observed, while in dimethyl sulfoxide a single conformer could be identified. Vibrational circular dichroism (VCD) spectra of acetyl-N-methyl-l-alanine have also been recorded in solutions and matrices. These matrix-isolation VCD spectra not only support the assignments of the matrix-isolation IR spectra, but also demonstrate that these spectra can be interpreted much easier with the help of quantum chemical calculations than the VCD spectra recorded in solutions. It is also shown that the rotatory strength of some vibrational transitions changes rapidly as a function of the backbone torsional coordinates; hence the appearance of some regions in the VCD spectra is extremely dependent on any perturbations, e.g. weak intermolecular interactions. PMID- 17700872 TI - X-Ray induced radiation damage in taurine: a combined X-ray diffraction and Raman study. AB - The impact of X-radiation on crystalline taurine has been investigated by time resolved synchrotron X-ray powder and single crystal diffraction and Raman spectroscopy. Multiple data sets have been collected at 120 and 296 K. All the observed effects of radiation, i.e. broadening and shifts of Raman and diffraction lines, a dose dependent irreversible increase in the atomic displacement parameters (ADPs) as well as in one of the unit-cell axes, and an apparent enhancement of electron density in the SO(3) group can be tentatively attributed to primary radical formation predominantly involving the SO(3) group. In secondary reactions molecular species that are distinct from taurine are created in minute quantities, thereby introducing local departure from crystalline order, i.e. enhanced static disorder and a build-up of local strain. Our study provides evidence for ascribing the linear increase in ADPs as well as the expansion of the c axis to the accumulation of foreign species in the crystal, and not to a thermal effect. Once initiated, this process appears to continue also without radiation, however, then at a much reduced rate. PMID- 17700873 TI - Photocatalysis: a promising route for 21st century organic chemistry. AB - One of the main goals of 21st century chemistry is to replace environmentally hazardous processes with energy efficient routes allowing to totally avoid the use and production of harmful chemicals and to maximise the quantity of raw material that ends up in the final product. Selective photocatalytic conversions will play a major role in this evolution and this account shows how photocatalysis is offering an alternative green route for the production of organics. PMID- 17700874 TI - Guanine binding to dirhodium tetracarboxylate anticancer complexes: quantum chemical calculations unravel an elusive mechanism. AB - The reaction mechanism leading to metalated DNA fragments in which guanine-N7,O6 spans the metal-metal bond of dirhodium antitumour complexes in a bridging fashion at equatorial sites has been unravelled by a comprehensive prediction of intermediates and transition states. PMID- 17700875 TI - Bioconjugation of biotinylated PAMAM dendrons to avidin. AB - The biotin-terminated PAMAM dendron has been synthesized and the asymmetric dendron used to modify the protein avidin via non-covalent bioconjugation. PMID- 17700876 TI - Design and synthesis of thiazoline-thiazole hybrid macrocycles possessing strong binding affinity to Pb2+ and Cd2+. AB - Thiazoline-thiazole hybrid macrocycles were synthesized via head-to-tail cyclooligomerization. The macrocycle consisting of eight heterocyclic subunits displays high binding affinity to the heavy metal toxins Pb(2+) and Cd(2+). PMID- 17700877 TI - Ionic dimeric pyrogallol[4]arene capsules. AB - Ionic capsules based on dimeric arrangements of pyrogallol[4]arenes have been structurally authenticated and suggest that there is a degree of flexibility in capsule formation with further potential for multiple guest encapsulation and manipulation in such arrangements. PMID- 17700878 TI - Following a protein kinase activity using a field-effect transistor device. AB - The specific phosphorylation of a peptide-functionalized ion-sensitive field effect transistor device by casein kinase II in the presence of ATP enables the electronic readout of the protein kinase activity; treatment of the phosphorylated surface with alkaline phosphatase results in the regeneration of the active sensing surface. PMID- 17700879 TI - Encapsulation of platinum anticancer drugs by apoferritin. AB - Apoferritin derived from the native protein ferritin was employed to encapsulate anticancer drugs cisplatin and carboplatin. PMID- 17700880 TI - Assembly between gold-thiolate nanoparticles and the organometallic cluster [Fe(eta5-C5H5)(mu3-CO)]4 toward redox sensing of oxo-anions. AB - Covalent assembly between gold-thiolate nanoparticles (AuNPs) and the cluster [Fe(eta(5)-C(5)H(5))(mu(3)-CO)](4), 1, can be achieved either by direct Brust Schriffin-type synthesis using a mixture of undecanethiol and a thiol functionalized with , or by substitution of undecanethiolate ligands in AuNPs by thiolate ligands functionalized with ; cyclic voltammetry of these AuNPs functionalized with allows us to recognize and titrate the oxo-anions H(2)PO(4)( ) and ATP(2-). PMID- 17700881 TI - Thorpe-Ingold effect on the conformation and photophysical properties of dialkylsilylene-spaced divinylarene copolymers. AB - Geminal disubstitution on silicon in dialkylsilylene-spaced divinylarene copolymers may dictate the conformation and photophysical properties of the copolymers, bulky (i)Pr substituted copolymers being more folded than Me substituent analogues. PMID- 17700882 TI - Towards a continuous dynamic kinetic resolution of 1-phenylethylamine using a membrane assisted, two vessel process. AB - A continuous process with two separated reaction vessels provides a solution to the problems surrounding the combination of two catalysts in dynamic kinetic resolution reactions by retaining the biocatalyst in a lower temperature vessel with a microfiltration membrane and allowing the racemisation to occur efficiently in a higher temperature vessel. PMID- 17700883 TI - Synthesis and structures of 1,2-bis(imino)acenaphthene (BIAN) lanthanide complexes that involve the transfer of zero, one, or two electrons. AB - The syntheses and X-ray crystal structures of the first 1,2 bis(imino)acenaphthene (BIAN) complexes of the lanthanides are described. PMID- 17700884 TI - The dramatic acceleration effect of imidazolium ionic liquids on electron transfer reactions. AB - Imidazolium ionic liquids (ILs) exhibited a dramatic acceleration effect on the electron transfer from metal complexes such as (C(5)Me(5))(2)Fe(II) and (C(5)Me(5))(2)Co(II) to the oxygen molecule; this acceleration effect can be ascribed to the stabilization of the oxygen radical anions by coordinating with the acidic C2-H of imidazolium ILs. PMID- 17700885 TI - Co-templating and modelling in the rational synthesis of zeolitic solids. AB - A 'co-templating' strategy supported by molecular modelling has been used to prepare, for the first time, silicoaluminophosphates with the SAV and KFI framework topologies, each of which has a three-dimensionally connected pore system with high specific volume. PMID- 17700886 TI - A mixed-valence Co7 single-molecule magnet with C3 symmetry. AB - The synthesis, structure and magnetic properties of [Co(II)(4)Co(III)(3)(HL)(6)(NO(3))(3)(H(2)O)(3)](2+) [H(3)L = H(2)NC(CH(2)OH)(3)] are reported: the complex is an exchange-biased single molecule magnet. PMID- 17700887 TI - Enhancing SMM properties in a family of [Mn6] clusters. AB - The complex [Mn(6)O(2)(Et-sao)(6)(O(2)C(11)H(15))(2)(EtOH)(6)] has U(eff) = 80 K. PMID- 17700888 TI - pH-Induced formation of metalloligand: increasing structure dimensionality by tuning number of ligand functional sites. AB - Two complexes, 2D [Cu(2)(CN)(2)(4-Hpcih)](n) and 3D [[Cu(2)(CN)(1.5)(4 pcih)].1.25H(2)O](n) (4-Hpcih = 4-pyridinecarbaldehyde isonicotinoyl hydrazone), were obtained using a synthetic approach of pH-induced formation of metalloligands, successfully demonstrating a strategy to increase structure dimensionality by tuning the number of ligand functional sites. PMID- 17700889 TI - Thermodynamically- and kinetically-controlled Friedel-Crafts alkenylation of arenes with alkynes using an acidic fluoroantimonate(v) ionic liquid as catalyst. AB - By employing superacidic fluoroantimonate ionic liquid (IL), [bmim][Sb(2)F(11)], as catalyst, not only thermodynamically-controlled but also kinetically controlled Friedel-Crafts alkenylations of arenes with alkynes have been realized for the first time. PMID- 17700890 TI - Efficient oxidative radical spirolactamization. AB - An efficient xanthate-based method for the preparation of azaspirocyclic cyclohexadienones via an ipso oxidative radical cyclization of p-oxygenated N benzylacetamides and N-phenetylacetamide is described. PMID- 17700891 TI - Towards 'bio-based' Nylon: conversion of gamma-valerolactone to methyl pentenoate under catalytic distillation conditions. AB - Methyl pentenoate, a promising Nylon intermediate, is produced in >95% yield via the transesterification of gamma-valerolactone, a bio-based intermediate, under catalytic distillation conditions. PMID- 17700892 TI - Heterodimeric particle assemblies: preparation of anisotropically connected spherical silica particles via surface-bound gold nanoparticles. AB - Assemblies of heterodimeric particles were prepared through selective coupling of two kinds of spherical silica particles of different sizes by connection with gold nanoparticles attached anisotropically to the particles. PMID- 17700893 TI - Soft landed protein voltammetry. AB - The present work illustrates a new method: soft landed protein voltammetry (SLPV); this experimental procedure is based on the coupling of ion soft landing with a voltammetric technique and allows the electrode surface to be functionalized with biologically active molecules, thus opening up numerous new perspectives ranging from molecular electronics to protein chips. PMID- 17700894 TI - From the sponsor. Workflow solutions with healthcare IT. AB - OBJECTIVE: To discuss trends in information technology (IT) for the future of healthcare. METHOD: To report from the viewpoint of a global healthcare IT enterprise. RESULTS: Healthcare IT consists of far more than electronic storage of information and automation of existing manual processes. It is the linchpin in an effective care process. Systems are available today that coordinate the complex processes across healthcare enterprises - providing alerts and reminders that can help healthcare providers not only operate more effectively but protect patient safety. The next revolution in healthcare information technology - personalized, evidence-based medicine, with information technology at the hub - is on the horizon. CONCLUSIONS: Although the healthcare industry has lagged behind many other industries in the adoption of sophisticated IT systems, perhaps no other industry can benefit as much from its use. Medical informatics subject matter experts must continue to advocate and support IT adoption for both the effects of process improvement and cost containment and for its potential to impact care outcomes. PMID- 17700895 TI - Towards IMIA 2015--the IMIA strategic plan. AB - OBJECTIVE: To report about the IMIA Strategic Plan 'Towards IMIA 2015'. METHOD: Starting in 2004 with a survey of member needs, expectations and wishes, an IMIA task force elaborated this plan. It has been updated by IMIA General Assembly members in 2005 and 2006. RESULTS: A Conceptual Framework for IMIA's strategic plan has been elaborated. The IMIA Strategic Planning Framework stresses the following: (1) IMIA aims to improve biomedical research, clinical practice and public health (VISION); (2) IMIA aims to support investigation and development of advanced information systems and technologies (RESEARCH); (3) IMIA aims that its efforts are carried out in accordance with strict ethical and legal rules (BEHAVIORAL RESPONSIBILITY); (4) IMIA aims to promote education for and about biomedical informatics (EDUCATION); (5) IMIA aims to bridge relevant internal and external groups and organizations (RELATIONSHIP); (6) IMIA aims to incorporate multiple individuals, groups and organizations to constitute the IMIA Association. (REACH). CONCLUSIONS: IMIA plays a major global role in the application of information science and technology in the fields of healthcare and research in medical, health and bio informatics. This framework provides IMIA with an excellent opportunity to focus its plans to ensure the highest probability of success is possible. PMID- 17700896 TI - Biomedical informatics for sustainable health systems. AB - OBJECTIVES: To provide an editorial introduction to the 2007 IMIA Yearbook of Medical Informatics with an overview of its contents and contributors. METHODS: A brief overview of the main theme of "Biomedical Informatics for Sustainable Health Systems", and an outline of the purposes, contents, format, and acknowledgment of contributions for the 2007 IMIA Yearbook. RESULTS: In resonance with the MEDINFO 2007 conference theme "Building Sustainable Health Systems", this issue of the Yearbook examines the role of healthcare informatics in helping face the challenge of sustainability for our health systems, through a number of original contributions, and selected papers published during the past 12 months. CONCLUSION: This timely topic, along with the review and surveys on the main streams of research in medical informatics, offer a complete overview of the development of our field. This current state of affairs is put in the perspective of the fortieth birthday of IMIA, reflecting on the past achievements of the Association, and outlining its potential to continue shaping the world of medical informatics. PMID- 17700897 TI - Biomedical informatics for sustainable health systems. PMID- 17700898 TI - Building a sustainable health system. AB - OBJECTIVES: To conduct a basic sustainability analysis of health systems, and explore models for conceptualising and creating sustainable organizations, based upon the experiences of the environmental sciences and organisational theory. To explore the role of information technologies in assisting health organizations become sustainable enterprises. METHODS: A review of recent literature into sustainable systems and an analysis and extension of the literature to the specific case of healthcare. RESULTS: Many if not all health systems around the globe face dual challenges of increasing demands and diminishing resources, which are ultimately unsustainable. Four physical system conditions which are pre requisites for sustainability of systems--that materials should not be extracted, accumulate or be depleted faster than they can be managed, and that systems should fundamentally meet human needs apply equally to healthcare. For healthcare, in addition to physical material and energy, resources include people, and data, information and knowledge. Further, healthcare is an open system that needs to be sufficiently adaptive to changes if it is to sustain. Information and communication technologies are crucial tools to enable any large and complex modern enterprise to model, measure and then manage business processes. Technologies like organisational simulation, the electronic health record, and decision support are essential tools for sustainable health services. Applied inappropriately however, IT can itself create unsustainable conditions, for example through the accumulation of legacy systems, a situation that adherence to technical standards should mitigate. CONCLUSIONS: It is crucial that our nations undertake a formal sustainability analysis of their health systems, to identify where the most pressing challenges are. In concert, there needs to be a long term process of exploring innovative designs for health services that improve the sustainability of the system as a whole, and there needs to be a will to implement the health system policies, infrastructure and services to ensure that in 20 years time we do have a healthy health system. PMID- 17700899 TI - Sustainable health care systems. Findings from the section on sustainable health care systems. AB - OBJECTIVES: To summarize major current trends and research in the field of sustainable health care systems. METHOD: Synopsis of the articles selected for the IMIA Yearbook 2007. RESULTS: Four excellent articles, four nations and four international peer-reviewed journals representing some important aspects of the research in this field have been selected for the IMIA Yearbook 2007. The first paper focuses on health care spending and use of information technologies in OECD countries; the second paper presents an original model and framework to describe and evaluate the risks and safety of e-health systems; the third paper, a two part paper, reviews several models to support lifetime personal health records and proposes some original approach to this problem. Finally, the last paper presents the evaluation of feasibility, potential, problems and risks of an Internet-based telemedicine network in developing countries of Africa and challenges and opportunities that IT can bring to developing countries. CONCLUSIONS: Sustainability in health care and information technologies is a young but fast growing domain. This new section of the yearbook is promised to a rich future as illustrated in the variety and the importance of the challenges addressed by this 2007 selection. PMID- 17700900 TI - Leveraging information technology to improve quality and safety. AB - OBJECTIVES: To examine five areas that we will be central to informatics research in the years to come: changing provider behavior and improving outcomes, secondary uses of clinical data, using health information technology to improve patient safety, personal health records, and clinical data exchange. METHODS: Potential articles were identified through Medline and Internet searches and were selected for inclusion in this review by the authors. RESULTS: We review highlights from the literature in these areas over the past year, drawing attention to key points and opportunities for future work. CONCLUSIONS: Informatics may be a key tool for helping to improve patient care quality, safety, and efficiency. However, questions remain about how best to use existing technologies, deploy new ones, and to evaluate the effects. A great deal of research has been done on changing provider behavior, but most work to date has shown that process benefits are easier to achieve than outcomes benefits, especially for chronic diseases. Use of secondary data (data warehouses and disease registries) has enormous potential, though published research is scarce. It is now clear in most nations that one of the key tools for improving patient safety will be information technology--many more studies of different approaches are needed in this area. Finally, both personal health records and clinical data exchange appear to be potentially transformative developments, but much of the published research to date on these topics appears to be taking place in the U.S. -more research from other nations is needed. PMID- 17700901 TI - Health and clinical management--impact on clinical outcome. Findings from the section on health and clinical management. AB - OBJECTIVES: To summarize current excellent research in the field of health and clinical management. METHOD: Synopsis of the articles selected for the IMIA Yearbook 2007. RESULTS: Five articles from international peer reviewed journals were selected for the section on health and clinical management of the IMIA Yearbook 2007. They represent outstanding research on computerized provider order entry, computer applications in the field of translational medicine, time efficiency of electronic health records, and deliverance of telemedicine. CONCLUSIONS: In the field of health and clinical management, clinical outcome of computer-supported healthcare, cost-benefit analysis, and barriers and facilitators for technology adoption are still current research topics. PMID- 17700902 TI - Electronic patient records: moving from islands and bridges towards electronic health records for continuity of care. AB - OBJECTIVES: Electronic patient record (EPR) systems are increasingly used and have matured sufficiently so as to contribute to high quality care and efficient patient management. Our objective is to summarize current trends and major achievements in the field of EPR in the last year and to discuss their future prospects. RESULTS: Integrating health data from a variety of sources in a comprehensive EPR is a major prerequisite for e-health and e-research. Current research continues to elaborate architectures, technologies and security concepts. To achieve semantic interoperability standards are developed on different levels, including basic data types, messages, services, architectures, terminologies, ontologies, scope and presentation of EPR content. Standards development organisations have started to harmonize their work to arrive at a consensus standard for EPR systems. Integrating the health care enterprise as a whole will optimize efficient use of resources, logistics and scheduling. CONCLUSIONS: The past few years have seen a myriad of developments of EPR systems. However, it is still a long way, until EPR systems can flexibly fulfill all user requirements and an EHR will become broadly accepted. Semantic interoperability will be a key to successful EPR use, especially to avoid double data entries and to better integrate data recording within local workflows. The patient will become an empowered partner, not only by giving him access to his health data. All this will result in enormous quantities of data. Thus, time has come to determine how relevant data can be presented to the stakeholders adequately. PMID- 17700903 TI - Electronic patient records: some answers to the data representation and reuse challenges. Findings from the section on Patient Records. AB - OBJECTIVES: To summarize current excellent research in the field of patient records. METHOD: Synopsis of the papers selected for the IMIA Yearbook 2007. RESULTS: The Electronic Patient Record encompasses a broad field of research and development. Some current research topics were selected for this IMIA Yearbook: EHR representation and communication standards, and secondary uses of clinical data for research and decision support. Four excellent papers representing the research in those fields were selected for the Patient Records section. CONCLUSION: The best papers selected for this section focus on the analysis and comparison of two important clinical documents representation standards, on direct structured data entry, on the use of Natural Language Processing to detect adverse events, and on the development and evaluation of a clinical text corpus annotated for part-of-speech information. PMID- 17700904 TI - Reflections on the role of open source in health information system interoperability. AB - OBJECTIVES: This paper reflects on the role of open source in health information system interoperability. Open source is a driving force in computer science research and the development of information systems. It facilitates the sharing of information and ideas, enables evolutionary development and open collaborative testing of code, and broadens the adoption of interoperability standards. In health care, information systems have been developed largely ad hoc following proprietary specifications and customized design. However, the wide deployment of integrated services such as Electronic Health Records (EHRs) over regional health information networks (RHINs) relies on interoperability of the underlying information systems and medical devices. METHODS: This reflection is built on the experiences of the PICNIC project that developed shared software infrastructure components in open source for RHINs and the OpenECG network that offers open source components to lower the implementation cost of interoperability standards such as SCP-ECG, in electrocardiography. RESULTS: Open source components implementing standards and a community providing feedback from real-world use are key enablers of health care information system interoperability. CONCLUSIONS: Investing in open source is investing in interoperability and a vital aspect of a long term strategy towards comprehensive health services and clinical research. PMID- 17700905 TI - Health information systems--technology and acceptance. Findings from the section on health information systems. AB - OBJECTIVES: To summarize current outstanding research in the field of health information systems (HIS). METHOD: Synopsis of the articles selected for the IMIA Yearbook 2007. RESULTS: Five articles from three international peer reviewed journals were selected for the HIS section of the IMIA Yearbook 2007. They represent outstanding research on new user interfaces for mobile data entry, smart card based approaches for national eHealth projects, generic system architectures for telemedicine services, new approaches for electronic prescriptions based on ubiquitous computing, and telemedical systems for chronic care in COPD. CONCLUSIONS: In the field of health information systems, evaluation and general architectural aspects of telemedical platforms respectively eHealth infrastructures currently is an important research topic as well as establishing acceptance of new technologies from the users and the organizations point of view. PMID- 17700906 TI - An overview of wearable and implantable medical sensors. AB - OBJECTIVES: To give a brief, introductory overview of current developments and trends in miniaturized medical sensors which will be informative to non specialists in the field. METHODS: Summary of the different types of wearable and implantable sensors with examples of current state-of-the-art devices and systems used in medical applications. RESULTS: After more than a decade of intensive research and development around the world, miniaturized medical sensors are becoming commercially available, allowing increasingly rapid collection of large scale medical data and its wireless transmission to health care centers. However, most sensor systems are not yet in routine use and still restricted to specialized sites, undergoing validation trials, mostly within research laboratories. CONCLUSIONS: Challenges to routine adoption of medical sensor systems often arise from a combination of lack of awareness of the technology among many medical practitioners, technological limitations of the device systems (artifacts and noise resulting from problems in garment fit or device implantation), and open issues of evaluation and validation for the very broad scope of conditions in home-care and ambient environments over which medical sensors need to operate for routine, reliable, practical use. PMID- 17700907 TI - Sensors, medical image and signal processing. Findings from the section on sensor, signal and imaging informatics. AB - OBJECTIVES: To summarize current excellent research in the field of sensor, signal and imaging informatics. METHOD: Synopsis of the articles selected for the IMIA Yearbook 2007. RESULTS: The selection process for this yearbook section "Sensor, signal and imaging informatics" results in five excellent articles, representing research in four different nations. Papers from the fields of brain machine interfaces, sound surveillance in telemonitoring, soft tissue modeling, and body sensors have been selected. CONCLUSION: The selection for this yearbook section can only reflect a small portion of the worldwide copious work in the field of sensors, signal and image processing with applications in medical informatics. However, the selected papers demonstrate, how advances in this field may positively affect future patient care. PMID- 17700908 TI - Free and open source enabling technologies for patient-centric, guideline-based clinical decision support: a survey. AB - OBJECTIVES: Guideline-based clinical decision support is an emerging paradigm to help reduce error, lower cost, and improve quality in evidence-based medicine. The free and open source (FOS) approach is a promising alternative for delivering cost-effective information technology (IT) solutions in health care. In this paper, we survey the current FOS enabling technologies for patient-centric, guideline-based care, and discuss the current trends and future directions of their role in clinical decision support. METHODS: We searched PubMed, major biomedical informatics websites, and the web in general for papers and links related to FOS health care IT systems. We also relied on our background and knowledge for specific subtopics. We focused on the functionalities of guideline modeling tools, and briefly examined the supporting technologies for terminology, data exchange and electronic health record (EHR) standards. RESULTS: To effectively support patient-centric, guideline-based care, the computerized guidelines and protocols need to be integrated with existing clinical information systems or EHRs. Technologies that enable such integration should be accessible, interoperable, and scalable. A plethora of FOS tools and techniques for supporting different knowledge management and quality assurance tasks involved are available. Many challenges, however, remain in their implementation. CONCLUSIONS: There are active and growing trends of deploying FOS enabling technologies for integrating clinical guidelines, protocols, and pathways into the main care processes. The continuing development and maturation of such technologies are likely to make increasingly significant contributions to patient centric, guideline-based clinical decision support. PMID- 17700909 TI - Decision support, knowledge representation and management: a balancing act between clinical use and implementation of sophisticated reasoning techniques? Findings from the section on decision support, knowledge representation and management. AB - OBJECTIVES: To position the papers selected for the IMIA Yearbook 2007 in the context of current research in decision support, knowledge representation and management. METHOD: Synopsis of the articles selected for the IMIA Yearbook 2007. RESULTS: In the Yearbook 2007 the best paper selection of the section Decision support, Knowledge management in Representation' shows, that the evaluation of the influence of decision support on medical behavior and outcome is as important as research on new reasoning technologies and methods. CONCLUSIONS: The best paper selection process shows on the one hand that there is still a deep gap between rather small decision support solutions successfully evaluated in clinical environments and more complex decision support systems using sophisticated reasoning techniques, but lack of clinical use. On the other hand the implementation of decision support systems today benefits from research done in the last decades. PMID- 17700910 TI - Education and consumer health informatics. AB - OBJECTIVES: To report on recent efforts in the field of consumer health informatics (CHI) and education. METHODS: A review of the literature we selected on using search engines and Medline with terms from consumer health informatics and education. Twenty two articles match these criteria. RESULTS: A great diversity of work spans the field of CHI. This relatively new field now faces challenges due to rapidly advancing technologies and the increasing empowerment of citizens connected over the worldwide web. CONCLUSION: The benefits of enhancing CIH components within existing medical curricula are already being noted. Additionally, updated recommendations on health and medical informatics should incorporate CHI. PMID- 17700911 TI - Advances in education and consumer health informatics. Findings from the Section on Education and Consumer Informatics. AB - OBJECTIVES: To summarize current excellent research in the field of education and consumer health informatics. METHOD: Synopsis of the articles on education and consumer health informatics selected for the IMIA Yearbook of Medical Informatics 2007. RESULTS: The consumer health informatics papers selected reflect the growing importance of communication and information retrieval systems in health care both for patients and professionals. Sound exemplary studies point out both the benefit for patients as well as the economic advantages of such systems. On the education sector, an intelligent tutoring system for medical students based on natural language dialogue serves as an example for the advancement and refinement of methods. CONCLUSION: The selected articles demonstrate the potential of advanced communication and information systems in health care. The physician-patient relationship though must not be affected by the introduction of these systems in order to ensure acceptance by both patients and physicians. Therefore these tools should be used in addition to current processes, and not as a replacement. PMID- 17700912 TI - Bioinformatics linkage of heterogeneous clinical and genomic information in support of personalized medicine. AB - OBJECTIVES: Biomedical Informatics as a whole faces a difficult epistemological task, since there is no foundation to explain the complexities of modeling clinical medicine and the many relationships between genotype, phenotype, and environment. This paper discusses current efforts to investigate such relationships, intended to lead to better diagnostic and therapeutic procedures and the development of treatments that could make personalized medicine a reality. METHODS: To achieve this goal there are a number of issues to overcome. Primary are the rapidly growing numbers of heterogeneous data sources which must be integrated to support personalized medicine. Solutions involving the use of domain driven information models of heterogeneous data sources are described in conjunction with controlled ontologies and terminologies. A number of such applications are discussed. RESULTS: Researchers have realized that many dimensions of biology and medicine aim to understand and model the informational mechanisms that support more precise clinical diagnostic, prognostic and therapeutic procedures. As long as data grows exponentially, novel Biomedical Informatics approaches and tools are needed to manage the data. Although researchers are typically able to manage this information within specific, usually narrow contexts of clinical investigation, novel approaches for both training and clinical usage must be developed. CONCLUSION: After some preliminary overoptimistic expectations, it seems clear now that genetics alone cannot transform medicine. In order to achieve this, heterogeneous clinical and genomic data source must be integrated in scientifically meaningful and productive systems. This will include hypothesis-driven scientific research systems along with well understood information systems to support such research. These in turn will enable the faster advancement of personalized medicine. PMID- 17700913 TI - Integrating bioinformatics into clinical practice: progress and evaluation. Findings from the section on bioinformatics. AB - OBJECTIVES: To summarize current excellent research in the field of bioinformatics. METHOD: Synopsis of the articles selected for the IMIA Yearbook 2007. RESULTS: Current research in the field of bioinformatics is characterized by careful evaluation of methods and by improved integration of methods into clinical workflows. Ongoing research on genetic causes of diseases is performed on more and better sources of reference data (genome sets and respective annotations), but is still hampered by insufficient, lacking or biased patient data. The application area of bioinformatics has been broadened, leading to amendment or even replacement of traditional methods in fields like characterization of microorganisms. Researchers carry out thorough statistical analyses in order to ensure quality and methodological correctness of new methods based on bioinformatic approaches which are more and more competitive compared to well-established techniques. CONCLUSIONS: The best paper selection of articles on bioinformatics shows examples of excellent research on methods concerning original development as well as quality assurance of previously reported studies. The crucial role of reliable and comprehensive data sources is affirmed, while technical development draws attention to the increasing problem of comparability of data derived some years ago with weaker equipment and those that are of up-to date quality. PMID- 17700914 TI - The human factors engineering approach to biomedical informatics projects: state of the art, results, benefits and challenges. AB - OBJECTIVES: The objective of this paper is to define a comprehensible overview of the Human Factors approach to biomedical informatics applications for healthcare. The overview starts with a presentation of the necessity of a proper management of Human factors for Healthcare IT projects to avoid unusable products and unsafe work situations. The first section is dedicated to definitions of the Human Factors Engineering (HFE) main concepts. The second section describes a functional model of an HFE lifecycle adapted for healthcare work situations. The third section provides an overview of existing HF and usability methods for healthcare products and presents a selection of interesting results. The last section discusses the benefits and limitations of the HFE approach. METHODS: Literature review based on Pubmed and conference proceedings in the field of Medical Informatics coupled with a review of other databases and conference proceedings in the field of Ergonomics focused on papers addressing healthcare work and system design. RESULTS: Usability studies performed on healthcare applications have uncovered unacceptable usability flaws that make the systems error prone, thus endangering the patient safety. Moreover, in many cases, the procurement and the implementation process simply forget about human factors: following only technological considerations, they issue potentially dangerous and always unpleasant work situations. But when properly applied to IT projects, the HFE approach proves efficient when seeking to improve patient safety, users' satisfaction and adoption of the products. CONCLUSIONS: We recommend that the HFE methodology should be applied to most informatics and systems development projects, and the usability of the products should be systematically checked before permitting their release and implementation. This requires the development of Centers specialized in Human Factors for Healthcare and Patient safety in each Country/Region. PMID- 17700915 TI - Care provider order entry (CPOE): a perspective on factors leading to success or to failure. AB - OBJECTIVE: Authors provide a perspective on factors leading to successful care provider order entry (CPOE) implementations. METHODS: Viewpoint of authors supported by background literature review. RESULTS: Authors review both benefits and challenges related to CPOE implementation using three guiding principles: (1) a clinical approach to clinical systems, which claims that CPOE implementation is analogous to a "good" clinician delivering care to a patient; (2) a commitment to quality, which advocates that no compromises should be made in implementing system functionality and clinical system content - the highest objective for CPOE implementation is to provide better quality of care and increased safety for patients; (3) a commitment to fairness, as evidenced by respect for individuals and support of local autonomy, which advocates for minimizing disruptions to clinician-users' workflows, and adequate local control over CPOE system design and evolution, including clinical content management. CONCLUSIONS: Past experiences with CPOE implementation can inform future installation attempts. Sociocultural factors dominate in determining the success of implementation, and should govern technical factors. PMID- 17700916 TI - Medical informatics in Morocco: Casablanca Medical Informatics Laboratory. AB - BACKGROUND: In 2005, Medical Informatics Laboratory (CMIL) became an independent research unit within the Faculty of Medicine and Pharmacy of Casablanca. CMIL is currently run by three persons (a university professor, a data processing specialist and a pedagogical assistant). The objectives of CMIL are to promote research and develop quality in the field of biomedical data processing and health, and integrate new technologies into medical education and biostatistics. It has four units: Telehealth Unit, Network Unit, Biostatistics Unit, Medical data processing Unit. OBJECTIVES: The present article seeks to give a comprehensive account of Casablanca Medical informatics laboratory (CMIL) activities. For ease of exposition, the article consists of four sections: Section I discusses the background of CMIL; section II is devoted to educational activities; section III addresses professional activities; and section IV lists projects that CMIL is involved in. RESULTS: Since its creation, CMIL has been involved in a number of national and international projects, which have a bearing on Telemedicine applications, E-learning skills and data management in medical studies in Morocco. CONCLUSIONS: It is our belief that the skills and knowledge gained in the past few years would certainly enrich our research activities, and improve the situation of research in Medical informatics in Morocco. PMID- 17700917 TI - The Centre for Health Informatics at the University of New South Wales--a clinical informatics research centre. AB - OBJECTIVES: Building a sustainable health system in the 21st Century will require the reinvention of much of the present day system, and the intelligent use of information and communication technologies (ICT) to deliver high quality, safe, efficient and affordable health care. The Centre for Health Informatics (CHI) is Australia's largest academic research group in this emerging discipline. METHODS: Our research is underpinned by a planning process, based on different future scenarios for the health system, which helps us identify longer-term problems needing a sustained research effort. A research competency matrix is used to ensure that the Centre has the requisite core capabilities in the research methods and tools needed to pursue our research program. RESULTS: The Centre's work is internationally recognized for its contributions in the development of intelligent search systems to support evidence-based healthcare, developing evaluation methodologies for ICT, and in understanding how communication shapes the safety and quality of health care delivery. Centre researchers also are working on safety models and standards for ICT in healthcare, mining complex gene micro array, medical literature and medical record data, building health system simulation methods to model the impact of health policy changes, and developing novel computational methods to automate the diagnosis of 3-D medical images. CONCLUSIONS: Any individual research group like CHI must necessarily focus on a few areas to allow it to develop sufficient research capacity to make novel and internationally significant contributions. As CHI approaches the end of its first decade, it is becoming clear that developing capacity becomes increasingly challenging as the research territory changes under our feet, and that the Centre will continue to evolve and shift its focus in the years to come. PMID- 17700918 TI - Biomedical informatics training at the University of Wisconsin-Madison. AB - OBJECTIVES: The purpose of this paper is to describe biomedical informatics training at the University of Wisconsin-Madison (UW-Madison). METHODS: We reviewed biomedical informatics training, research, and faculty/trainee participation at UW-Madison. RESULTS: There are three primary approaches to training 1) The Computation & Informatics in Biology & Medicine Training Program, 2) formal biomedical informatics offered by various campus departments, and 3) individualized programs. Training at UW-Madison embodies the features of effective biomedical informatics training recommended by the American College of Medical Informatics that were delineated as: 1) curricula that integrate experiences among computational sciences and application domains, 2) individualized and interdisciplinary cross-training among a diverse cadre of trainees to develop key competencies that he or she does not initially possess, 3) participation in research and development activities, and 4) exposure to a range of basic informational and computational sciences. CONCLUSIONS: The three biomedical informatics training approaches immerse students in multidisciplinary training and education that is supported by faculty trainers who participate in collaborative research across departments. Training is provided across a range of disciplines and available at different training stages. Biomedical informatics training at UW-Madison illustrates how a large research University, with multiple departments across biological, computational and health fields, can provide effective and productive biomedical informatics training via multiple bioinformatics training approaches. PMID- 17700919 TI - Research and education for biomedical informatics at Tokyo Medical and Dental University. AB - OBJECTIVES: Based on a basic concept of "Systems Life Science: understanding life and disease as a unified system", we move forward in research, empirical implementation, and making contributions to healthcare policy. METHODS: We integrate bioinformatics and medical informatics for identifying critical issues in biological science and solving medical challenges with a concept of "Systems Life Science" which consists of "Systems Evolutionary Biology" for basic science, "Systems Pathology" for clinical sciences, and an empirical medical informatics for future medicine. RESULTS: Our laboratory is an integrated laboratory consisting of a computational biology group in the School of Biomedical Sciences (SBS), a bioinformatics group in the Medical Research Institute (MRI), and a medical informatics group in the Information Center for Medical Sciences (ICMS) with a philosophy of "Empirical Systems Life Science". CONCLUSIONS: Based on the philosophy of "Empirical Systems Life Science", we continue to forward our research, education, systems implementations, and international standardization efforts. We believe that this approach will become a fundamental and effective way to uncover many of the secrets of life processes, and to help/solve complex issues for future medicine in this post genomic era with exceedingly rapidly growing amounts of -omics data and knowledge. PMID- 17700920 TI - 40 years of IMIA: shaping medical informatics worldwide. PMID- 17700921 TI - IMIA presidential retrospectives on medical informatics. AB - OBJECTIVES: The International Medical Informatics Association (IMIA) celebrates its 40th anniversary in 2007. Three IMIA Presidents from three continents were invited to give their personal retrospectives on the world's largest organization in medical informatics. METHOD: Reports, based on personal reminiscenses. RESULTS AND CONCLUSIONS: IMIA was established in the 1970s by individuals already active in medical informatics in their home countries. It has evolved into a strong international organization based on the mutual trust and friendship of members throughout the world. IMIA serves as a 'bridge' organization both within an interorganizational context and within the broader context of IMIA's professional aims. Being a driving motor for successive waves of change in the field, IMIA helps to significantly improve health care by building bridges across regions, disciplines, and professions, to bridge the distances around the globe. PMID- 17700922 TI - IMIA: coalescing medical informatics worldwide for 40 years. AB - OBJECTIVES: To summarize and highlight the role of IMIA in the past 40 years in becoming the international professional organization that brings together researchers, practitioners, and educators in the field of medical informatics, and more broadly biomedical, nursing, and health informatics METHOD: Outlining developments of medical informatics related to IMIA from 1967 to 2007 in a time line and comparative topic and geographical distribution analyses over selected MEDINFOs from 1980 and selected Yearbooks from 1992 onwards. This illustrates how IMIA, through the global reach of its activities, has helped advance the science and development of informatics across the entire spectrum of biomedical and health care research, education, and practice. RESULTS AND CONCLUSIONS: The contribution of IMIA over the past 40 years has been to sponsor and coordinate international conferences and promote interchange and collaborations in biomedical and health informatics by linking national and regional societies, organizing meetings, high quality publications, and working groups. These have helped the coalescing of the discipline worldwide, promoting full participation and a broad interdisciplinary scope that fulfills the hopes of the pioneers in the field. PMID- 17700923 TI - IMIA--a 40 year organizational overview. AB - OBJECTIVE: To chronicle the history of IMIA, the International Medical Informatics Association, from 1967 to 2007. METHOD: Describing the key events and accomplishments through the terms of office of its presidents. RESULTS AND CONCLUSIONS: The IMIA of today has been shaped by the individuals within it. Those influencing and guiding IMIA from its origins to today include its national representatives, Board and Presidents, working group members, regional liaisons, and MedInfo attendees. PMID- 17700924 TI - IMIA's publication history. AB - OBJECTIVES: This article lines out the various publications by which IMIA presents its work and the state-of-the art of health and biomedical informatics. METHOD: A short history of IMIA and its publications is presented, a reference list completes the view. RESULTS: IMIA looks back on a long and fruitful publication history of more than a hundred publications. CONCLUSION: Starting from its foundation in 1967, IMIA has continually published the results of its activities and conferences, these publications being one of the most visible proofs of the liveliness and up-to-dateness of the organization and the field. PMID- 17700925 TI - Octreotide: a therapeutic option for idiopathic intracranial hypertension. AB - PURPOSE: To study the effects of octreotide, a somatostatin analogue, in patients with Idiopathic Intracranial Hypertension (IIH). METHODS: We performed a prospective, open-label study of the effect of Octreotide on 26 patients with symptoms and signs of IIH, investigated by brain MRI and lumbar puncture. Octreotide was administered subcutaneously, at an initial dose of 0.3 mg/day; and was gradually increased until headache was relieved (upper-dose limit: 1 mg/day). Treatment with octreotide at 1 mg/day was administered for a maximum of six to eight months and afterwards the dose was gradually tapered. Patients were followed prospectively every month for three years. CSF opening pressure was measured before the treatment was started and again in the first follow-up examination, on month one. In all follow-up visits the presence of papilledema was evaluated by fundoscopy; visual fields and visual acuity were also examined. RESULTS: Overall 24/26 patients improved significantly (92%). Headache was relieved within days (1-10, median 7 days). Papilledema subsided in all 24 patients, in up to two months (35 to 68, median 45 days). Visual disturbances, initially presenting in 20 of our patients, improved in 18 (90%). The mean reduction in CSF pressure after treatment was 20.72A+/-10.7 cmH2O (range 2 to 48). Patients were followed for three years after cessation of treatment. No recurrence of papilledema, or any other symptoms, has been observed. CONCLUSIONS: Octreotide resulted in a significant and sustained improvement of IIH in our patients. These results suggest that it may be an effective alternative to existing treatments for IIH. PMID- 17700926 TI - Second lumbrical-interossei latency difference: A strong predictor of median neuropathy at the wrist in uremic patients. AB - PURPOSE: Hand symptoms in uremic patients on dialysis can occur due to peripheral neuropathy, median neuropathy at wrist (carpal tunnel syndrome) or a combination. Routine electrophysiological parameters for diagnosing carpal tunnel syndrome do not differentiate median neuropathy at wrist in cases with concomitant peripheral neuropathy. Measuring 2L-INT latency difference has been described as the most sensitive test in establishing median neuropathy at wrist in cases with severe carpal tunnel syndrome and concomitant peripheral neuropathy. This study tested the significance of 2L-INT latency difference as a predictor of median neuropathy at wrist in uremic patients on dialysis. METHODS: 80 consecutive cases (158 hands) of end-stage renal failure on either hemodialysis or peritoneal dialysis were subjected to routine electrophysiological studies for carpal tunnel syndrome. 2L-INT latency difference was measured in all cases. RESULTS: 132/158 hands (83.5%) had abnormal electrophysiological studies. Routine tests were consistent with neurophysiological carpal tunnel syndrome in 66 (41.8%) hands and 63 of these 66 (95.5%) had prolonged 2L-INT latency difference. Peripheral neuropathy was found in 66 (41.8%) hands but 59 out of these 66 (89.4%) had prolonged 2L-INT latency difference suggesting a concomitant median neuropathy at wrist. Routinely performed tests would have missed median neuropathy at wrist with concomitant peripheral neuropathy in 59 (37.3%) hands. Overall, the incidence of median neuropathy at the wrist in our uremic patients on maintenance dialysis using standard nerve conduction parameters was 41.8%, however the incidences increased substantially to 79.1% if 2L-INT latency difference is included in the criteria for the diagnosis. CONCLUSIONS: Median neuropathy at wrist is common in patients with end-stage renal failure patients on dialysis. Diagnosis of median neuropathy at wrist is difficult in the presence of peripheral neuropathy when using the routine electrophysiological tests. Second Lumbrical-Interossei latency difference is a sensitive electrophysiological test to predict median neuropathy at wrist in presence of peripheral neuropathy. PMID- 17700927 TI - The subclinical incidence of CTS in pregnancy: Assessment of median nerve impairment in asymptomatic pregnant women. AB - PURPOSE: The true incidence of pregnancy related carpal tunnel syndrome (PRCTS) is unknown. Most of the diagnoses of PRCTS are made based only on clinical symptoms. Here, we report a prospective controlled clinical trial assessing the electrophysiological changes in pregnant women to provide objective measure of the median nerve function. METHODS: Pregnant women in the third trimester (n=69) and age-matched non-pregnant women (n=40) asymptomatic for CTS were included in the study. Nerve conduction studies of the median and ulnar nerves across the carpal tunnel were bilaterally performed with the standard techniques. RESULTS: All the median sensory nerve conduction studies (amplitude, latency and velocity) performed from the ring finger and palmar region to wrist showed significant prolongation of median nerve conduction in the pregnant women compared with the control group (*p 1:400 in 38 seropositive individuals. In conclusion, there is a high prevalence of Leptospira spp. antibodies in the area, where it is thus necessary to establish control measures to decrease the risk of environmental exposure to leptospirosis. PMID- 17700945 TI - [Patients' complaints of verbal abuse by health professionals during hospital care in Northeast Brazil]. AB - The current anthropological study focuses on the assessment by patients/citizens concerning the conduct of health professionals in a public general hospital in Fortaleza, Ceara State, Brazil. From January to July 2005 we tracked 13 key informants during hospitalization and analyzed their narratives of the experience. According to our observations, patients develop definite opinions of the caregivers' gestures and expressions during the entire process. In the health professionals, patients appreciate the human ability to express affect, to talk, and to include them in clinical decisions, above and beyond the professionals' technical skills. Patients criticize aloof, cold, and rude attitudes by health professionals, whom patients compare metaphorically to "human quadrupeds". They recommend an affective, empathetic, and ethical approach and clinical communications backed by straight talk, friendly conversation, and respect for daily customs related to life in Northeast Brazil. We contend that this legitimate and critical voice of the patient/citizen provides valuable clues for transforming professional conduct, rehabilitating patients' morale, and building a humane hospital within a context of social inequalities. PMID- 17700946 TI - [The Brazilian Ministry of Health policy model in the 1990s]. AB - This paper analyzes the policy model of the Brazilian Ministry of Health from 1990 to 2002. The methodology included interviews with key actors in the national health policy, document review, and analysis of the Federal budget and official databases. The Brazilian Ministry of Health underwent major changes under the influence of the health reform agenda and the liberal State reform agenda prevailing in the 1990s, shaped by two movements: institutional unification of national policy control and political/administrative decentralization. The Federal role was diminished in terms of direct services provision, and there were changes in financing and regulation. The model in the late 1990s featured strong Federal induction of States and municipalities and the adoption of market regulation strategies. There is no record of a long-term planning effort, which favors distortions in the Federal intervention model and hinders solutions to structural problems in the Brazilian health system. PMID- 17700947 TI - [Occupational risk management in the Brazilian army: normative and practical aspects]. AB - This study aims to describe the risk management method used by the Brazilian Army, ranging from the guidelines, norms, and standards to the implementation of activities in the barracks, providing a brief comparison with key occupational safety provisions by the Ministry of Labor and Employment. A qualitative approach was used, based on triangulation of data collection techniques: document collection; systematic observation; and a semi-structured interview with 24 key informants among the military, divided into three groups, aimed at collecting information on the main hierarchical levels: officers, sergeants, corporals, and privates. We found that the Brazilian Army's risk management method is based on three main documents: Instruction Booklet 32/1, Instruction Booklet 32/2, and the Military Instruction Program. The method only refers to accident risks, overlooking other important aspects covered in the Regulatory Standards of the Ministry of Labor and Employment and other types of risks. PMID- 17700948 TI - [Decentralization, AIDS, and harm reduction: the implementation of public policies in Rio de Janeiro, Brazil]. AB - This paper assesses how decentralization of resources and initiatives by the Brazilian National SDT/AIDS Program has impacted the transfer of funds for programs to prevent HIV/AIDS among injecting drug users in Rio de Janeiro, Brazil (1999-2006). The effects of the decentralization policy on Rio de Janeiro's Syringe Exchange Programs (SEPs) are assessed in detail. Decentralization effectively took place in Rio de Janeiro in 2006, with the virtual elimination of any direct transfer from the Federal government. The elimination of direct transfers forced SEPs to seek alternative funding sources. The structure of local SEPs appears to be weak and has been further undermined by current funding constraints. Of 22 SEPs operating in 2002, only two are still operational in 2006, basically funded by the State Health Secretariat and one municipal government. The current discontinuity of SEP operations may favor the resurgence of AIDS in the IDU population. A more uniform, regulated decentralization process is thus needed. PMID- 17700949 TI - All-cause mortality among Japanese-Brazilians according to nutritional characteristics. AB - The aim of this study was to verify the association between nutritional variables and mortality in a Japanese-Brazilian cohort. In 1993, 647 subjects were interviewed with food frequency questionnaires and scheduled for physical procedures (weight, height, blood pressure) and biochemical tests (oral glucose tolerance test). Student's t test was used to compare the mean values of target variables between living and deceased subjects. Mortality rate and hazard ratios were obtained (crude and adjusted) according to the nutritional variables. Overall mortality rates were 21.4 and 11.7/1,000 person-years for males and females, respectively. Smoking, diabetes, sedentary lifestyle, hypertension, higher mean age, high blood pressure, high blood glucose, and higher percent weight gain and rate of weight gain were observed in the history of deceased subjects. After adjusting for control variables, an increase was observed in mortality among individuals with lower carbohydrate and cholesterol intake. The results suggest that mortality risk factors like age, chronic diseases, sedentary lifestyle, smoking, and inadequate diet must also be acting in the Japanese Brazilian population. PMID- 17700950 TI - [Evaluation of knowledge on prenatal care and pregnancy risk among women living in a peripheral area of Rio Grande, Rio Grande do Sul State, Brazil]. AB - The aim of this study was to assess knowledge on prenatal care and pregnancy risk among women in poor neighborhoods in the city of Rio Grande, Rio Grande do Sul State, Brazil. Data were collected using a cross-sectional design. A standard questionnaire was applied to all pregnant women from poor neighborhoods. Trained interviewers visited these women at home, covering demographic, socioeconomic, and reproductive data and knowledge concerning prenatal care and pregnancy risk factors. A total of 367 pregnant women were interviewed using non-random sampling. Except for urine tests and HIV testing, spontaneously reported as necessary, other procedures were reported by no more than 30% of the women. Digital vaginal examination, clinical breast examination, and Pap smear were reported by a maximum of 7% of the women. Only two-thirds felt that vaginal bleeding and abdominal pain were serious signs during gestation. Other signs and symptoms were reported by a maximum of one-third of the women. In conclusion, knowledge of prenatal tests and situations indicating serious risk fell far short of the desired levels. Improving this level of information in pregnant women could help reduce maternal and child morbidity and mortality. PMID- 17700951 TI - [Government regulation of the private health care market in Brazil: a history of disputes]. AB - This paper reconstructs the dispute between the main social actors with direct interests in the regulation of private health care in Brazil during the period immediately prior to the passage of Act 9.656/98, highlighting the divergences between these actors in relation to 28 central topics for shaping the regulatory framework prevailing in the country since 1998. The material used in the description and systematization of the positions in the regulatory dispute resulted from an empirical, descriptive, comparative study based on document analysis and interviews with key actors. The study systematizes the main points of controversy and consensus among the various actors, particularly highlighting the many points of agreement between proposals by medical organizations and those of users' organizations and consumer defense institutes, thereby suggesting the possibility of establishing an ethical and political bloc committed to the defense of improved health care as opposed to sheer market logic. PMID- 17700952 TI - [Chronic illness from the perspective of patients and health professionals: a qualitative study in Mexico]. AB - Chronic diseases are leading causes of morbidity, mortality, and increasing expenditures in numerous countries. However, little is known about how chronic diseases are perceived and managed by social actors. This article aims to compare the perspectives of health professionals and patients towards chronic diseases, besides analyzing the relationship between these two groups. A qualitative, multi center study was conducted in three Mexican cities: Guadalajara, San Luis Potosi, and Mexico City. Participants included chronically ill individuals, physicians, and other health professionals from primary and secondary health care centers. Data collection used focus groups and interviews. The data were analyzed using discourse analysis. Participants' perceptions varied, from the medicalized view of physicians to that of patients focused on illness and the lifeworld. The participants agreed that there are unequal relationships between health professionals, families, and the chronically ill, but that relationships are more equal among the chronically ill themselves. The article includes by discussing various implications of the findings. PMID- 17700953 TI - Reproducibility of a food frequency questionnaire for adolescents. AB - To assess the reproducibility of a validated 76-item food frequency questionnaire designed to estimate diet in adolescents (Adolescent Food Frequency Questionnaire -AFFQ) in the city of Sao Paulo, Brazil, a test-retest study was conducted (n = 49). Intraclass correlation coefficient (ICC), weighted kappa, and percentage of agreement were used in both crude and energy-adjusted nutrient intakes. Bland Altman plots were used to examine the limits of agreement for energy and macronutrients. The ICC ranged from 0.48 (carbohydrates) to 0.65 (vitamin C) in crude values and from 0.25 (total fat) to 0.58 (vitamin C) in adjusted values. Kappa values ranged from 0.28 (protein and fiber) to 0.56 (unsaturated fat). Bland Altman showed a trend towards larger difference in energy according to increased intake values and a bias towards extreme values for fat intake. The percent of individuals classified in the same category on the two occasions was on average 54.2%. By conclusion, the Adolescent Food Frequency Questionnaire showed reasonable reproducibility and can be used in studies that aim to classify groups into intake categories. PMID- 17700954 TI - HIV prevalence and risk factors in a Brazilian penitentiary. AB - HIV infection among prison inmates shows one of the highest prevalence rates for specific population subgroups, reaching as high as 17% in Brazil and elsewhere in the world. The present study aimed to estimate HIV antibody prevalence and risk factors for infection in male inmates at the Ribeirao Preto Penitentiary, Sao Paulo State, Brazil, from May to August 2003. Using simple random sampling, 333 participants were selected, answered a standardized questionnaire, and had blood samples collected. Enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence were used for HIV serological diagnosis. Overall HIV prevalence among inmates was 5.7% (95%CI: 3.2-8.2). All variables associated with HIV antibodies in the univariate analysis were submitted to unconditional multivariate logistic regression. Independent predictors of HIV infection were: total prison sentence less than five years and sharing needles and syringes. PMID- 17700955 TI - [Clinical and epidemiological determinants of sodium and potassium levels in the colostrum of breastfeeding mothers with and without hypertension in Brazil]. AB - This study aimed to determine whether maternal hypertension and other clinical and epidemiological determinants have an impact on sodium and potassium levels in the 48-hour colostrum of breastfeeding mothers. The study included 105 randomly selected breastfeeding mothers, of whom 72 (68.8%) had normal blood pressure and 33 (31.4%) were hypertensive. Colostrum was collected in-hospital in the morning, and sodium and potassium concentrations were measured using a flame photometer. When sodium and potassium concentrations were compared to the variables age, parity, family history of hypertension, gestational age, birth weight, and socioeconomic factors, colostrum potassium level was associated with maternal age. Average sodium and potassium levels in 48-hour colostrum non-hypertensive and hypertensive breastfeeding mothers showed no significant differences. Thus, breastfeeding by hypertensive mothers probably does not increase the risk of their children developing hypertension in adulthood. PMID- 17700956 TI - [American tegumentary leishmaniasis in children: epidemiological aspects of cases treated in Manaus, Amazonas, Brazil]. AB - Children from birth to 14 years of age with American tegumentary leishmaniasis were monitored at the Foundation for Tropical Medicine in the State of Amazonas, Brazil, from January to December 2005; 147 cases were recorded, 55.78% of which were male and 48.3% from the Rio Preto da Eva district. For 90 patients (67.67%), parents or guardians were interviewed about housing in the area where the infection was presumably acquired and the child's habits. Of the group, 58.89% of the children lived in the presumed area of infection, 60% customarily entered the forest with their parents, 91.11% lived in households with domestic animals, 77.78% of the residences were located within 100 meters of the forest; and 76.67% of the patients had at least one relative with a history of American tegumentary leishmaniasis. The transmission pattern was related to activities in the forest around the houses and the living situation near the primary forest, with cases of American tegumentary leishmaniasis found in very young children, suggesting transmission in and around the house, and in a few cases, children entering the forest. PMID- 17700957 TI - Sexuality, vulnerability to HIV, and mental health: an ethnographic study of psychiatric institutions. AB - This paper presents data from the ethnographic based formative phase of the Interdisciplinary Project on Sexuality, Mental Health, and AIDS (PRISSMA), sponsored by the National Institute of Mental Health (NIMH) and carried out in two psychiatric institutions in the city of Rio de Janeiro, Brazil. Results from ethnographic observations, focus groups, and key informant interviews with different groups of mental health care providers and day hospital and outpatient mental health clients regarding conceptions of sexuality and HIV vulnerability are described. The results suggest a diversity of notions about sexuality by both groups and point out the high HIV sexual risk in this psychiatric population. This formative phase has served as the basis for the cultural adaptation and creation of a Brazilian intervention for HIV prevention in the severely mentally ill, the feasibility of which has been successfully evaluated in the pilot phase. PMID- 17700958 TI - [Intra-domiciliary capture of Panstrongylus rufotuberculatus (Champion, 1899) (Hemiptera, Reduviidae, Triatominae) in Piura, Peru]. AB - Panstrongylus rufotuberculatus is widely distributed in Central and South America. In Peru, it has been found in Tumbes, Piura, and Cuzco. The authors report the presence of P. rufotuberculatus in Chirinos-La Pareja, Suyo district, Ayabaca Province, Piura Region, Peru. Twenty-eight specimens were collected in two of 15 dwellings: three 2nd instar, four 3rd instar, two 4th instar, and eight 5th instar nymphs, three male and eight female, in an intra-domiciliary colony of guinea pigs (Cavia porcellus, raised indoors as a source of diet protein) and beds and bedroom walls. None of the fecal samples were naturally infected with Trypanosoma cruzi. This is the first report of synanthropic presence of P. rufotuberculatus in the region. The finding emphasizes the need for careful entomological and epidemiological surveillance of this and other triatomine species in the Region. PMID- 17700959 TI - [Childhood prevalence of cardiovascular risk factors]. AB - Cardiovascular risk factors were investigated in 356 children 5 to 9 years of age who were treated at a primary care center located in a low-income area in Greater Metropolitan Rio de Janeiro, Brazil. Lipid profile, nutritional status, food intake, and lifestyle were evaluated. 10.7% of the children were overweight, 68.4% had some type of dyslipidemia, and 18.6% showed high LDL-c. To describe the food intake pattern, the answers to the qualitative food questionnaire were submitted to multivariate cluster analysis, producing six basic groups: traditional Brazilian cooking; "modern" food (including diet and light products); fried food; sweets and soft drinks (mixed with other groups); and other poorly defined groups. The high prevalence of cardiovascular risk factors (beginning in childhood) and the evidence of inadequate dietary habits indicate that a preventive family-focused strategy is needed to change the dietary pattern of low income groups towards healthier eating. PMID- 17700961 TI - Too much salt, too little soda: cystic fibrosis. AB - Cystic fibrosis (CF) of the pancreas is the most widely accepted name of the most common fatal inherited single gene defect disease among Caucasians. Its incidence among other races is thought to be significantly less, but mutations in the gene have been reported in most, if not all, major populations. This review is intended to give general concepts of the molecular as well as physiological basis of the pathology that develops in the disease. First, an overview of the organ pathology and genetics is presented, followed by the molecular structure of the gene product (cystic fibrosis transmembrane conductance regulator, CFTR), its properties, functions, and controls as currently understood. Second, since mutations appear to be expressed primarily as a defect in electrolyte transport, effects and mechanisms of pathology are presented for two characteristically affected organs where the etiology is best described: the sweat gland, which excretes far too much NaCl ("salt") and the pancreas, which excretes far too little HCO3(- )("soda"). Unfortunately, morbidity and mortality in CF develop principally from refractory airway infections, the basis of which remains controversial. Consequently, we conclude by considering possible mechanisms by which defects in anion transport might predispose the CF lung to chronic infections. PMID- 17700962 TI - The cystic fibrosis transmembrane conductance regulator Cl- channel: a versatile engine for transepithelial ion transport. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ATP-binding cassette (ABC) transporter superfamily that forms a Cl(-) channel with complex regulation. CFTR is composed of five domains: two membrane spanning domains (MSDs), two nucleotide-binding domains (NBDs) and a unique regulatory domain (RD). The MSDs assemble to form a low conductance (6-10 pS) anion-selective pore with deep intracellular and shallow extracellular vestibules separated by a selectivity filter. The NBDs form a head-to-tail dimer with two ATP-binding sites (termed sites 1 and 2) located at the dimer interface. Anion flow through CFTR is gated by the interaction of ATP with sites 1 and 2 powering cycles of NBD dimer association and dissociation and hence, conformational changes in the MSDs that open and close the channel pore. The RD is an unstructured domain with multiple consensus phosphorylation sites, phosphorylation of which stimulates CFTR function by enhancing the interaction of ATP with the NBDs. Tight spatial and temporal control of CFTR activity is achieved by macromolecular signalling complexes in which scaffolding proteins colocalise CFTR and plasma membrane receptors with protein kinases and phosphatases. Moreover, a macromolecular complex composed of CFTR and metabolic enzymes (a CFTR metabolon) permits CFTR activity to be coupled tightly to metabolic pathways within cells so that CFTR inhibition conserves vital energy stores. CFTR is expressed in epithelial tissues throughout the body, lining ducts and tubes. It functions to control the quantity and composition of epithelial secretions by driving either the absorption or secretion of salt and water. Of note, in the respiratory airways CFTR plays an additional important role in host defence. Malfunction of CFTR disrupts transepithelial ion transport leading to a wide spectrum of human disease. PMID- 17700963 TI - Cystic fibrosis transmembrane conductance regulator: a chloride channel gated by ATP binding and hydrolysis. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that belongs to the ATP-binding cassette (ABC) transporter superfamily. Defective function of CFTR is responsible for cystic fibrosis (CF), the most common lethal autosomal recessive disorder in Caucasian populations. The disease is manifested in defective chloride transport across the epithelial cells in various tissues. To date, more than 1400 different mutations have been identified as CF-associated. CFTR is regulated by phosphorylation in its regulatory (R) domain, and gated by ATP binding and hydrolysis at its two nucleotide-binding domains (NBD1 and NBD2). Recent studies reveal that the NBDs of CFTR may dimerize as observed in other ABC proteins. Upon dimerization of CFTR's two NBDs, in a head-to-tail configuration, the two ATP-binding pockets (ABP1 and ABP2) are formed by the canonical Walker A and B motifs from one NBD and the signature sequence from the partner NBD. Mutations of the amino acids that interact with ATP reveal that the two ABPs play distinct roles in controlling ATP-dependent gating of CFTR. It was proposed that binding of ATP to the ABP2, which is formed by the Walker A and B in NBD2 and the signature sequence in NBD1, is critical for catalyzing channel opening. While binding of ATP to the ABP1 alone may not increase the opening rate, it does contribute to the stabilization of the open channel conformation. Several disease-associated mutations of the CFTR channel are characterized by gating defects. Understanding how CFTR's two NBDs work together to gate the channel could provide considerable mechanistic information for future pharmacological studies, which could pave the way for tailored drug design for therapeutical interventions in CF. PMID- 17700964 TI - Epithelial K+ channels: driving force generation and K+ recycling for epithelial transport with physiological and clinical implications. AB - K(+) channels form a large family of membrane proteins that are expressed in a polarized fashion in any epithelial cell. Based on the transmembrane gradient for K(+) that is maintained by the Na(+)-K(+)-ATPase, these channels serve two principal functions for transepithelial transport: generation of membrane voltage and recycling of K(+). In this brief review, we will outline the importance of this ancient principle by examples of epithelial transport in the renal proximal tubule and gastric parietal cells. In both tissues, K(+) channel activity is rate limiting for transport processes across the epithelial cells and essential for cell volume regulation. Recent experimental data using pharmacological tools and genetically modified animals have confirmed the original physiological concepts and specified the knowledge down to the molecular level. The development of highly active and tissue selective small molecule therapeutics has been impeded by two typical features of K(+) channels: their molecular architecture challenges the design of molecules with high affinity binding and they are expressed in a variety of tissues at the same time. Nevertheless, new insights into pathophysiology, e.g. that K(+) channel inhibition can block gastric acid secretion, render the clinical use of K(+) channel drugs in gastric disease and as kidney transport inhibitors highly attractive. PMID- 17700965 TI - The role of bronchial epithelial cells in airway hyperresponsiveness. AB - It is commonly accepted that airway hyperresponsiveness (AHR) is a chronic airway inflammation although the exact mechanism of its pathogenesis is still unclear. In the past ten years, an epithelial defect hypothesis has gradually gained supports from the main stream. Airway epithelium is no longer considered only as a simple mechanic barrier but an active interface between the inner and outer environment. Bronchial epithelial cells play a critical role in maintenance of homeostasis in the airway local microenvironment through a wide range of physiologic functions including anti-oxidation, exocrine/endocrine secretions, mucus production and antigen presentation under health and stressed/inflamed/injured conditions. It is reasonably hypothesized that disruption of these functional processes or defects in airway epithelium integrity may be the initial steps leading to airway hyperresponsiveness such as in asthma and chronic obstructive pulmonary disease. PMID- 17700966 TI - Cystic fibrosis transmembrane conductance regulator and SLC26 transporters in HCO3- secretion by pancreatic duct cells. AB - Pancreatic duct cells secrete HCO3(-) ions into a HCO3(-)-rich luminal fluid (~140 mmol/L in human) against at least a 6-fold concentration gradient. Candidate mechanisms for HCO3(-) transport across the apical membrane include Cl( )-HCO3(-)exchange by an SLC26 anion transporter and diffusion via the HCO3(-) conductance of cystic fibrosis transmembrane conductance regulator (CFTR). Members of the SLC26 family are known to mediate Cl(-)-HCO3(-) exchange across the apical membrane of other epithelia and both SLC26A6 and SLC26A3 have been detected in pancreatic ducts. Co-expression studies have also revealed that murine slc26a6 and slc26a3 physically interact with CFTR through the STAS domain of slc26 and the R domain of CFTR, resulting in mutually enhanced activity. Other studies have indicated that these exchangers are electrogenic: slc26a6 mediating 1Cl(-)-2HCO3(-) exchange and slc26a3 mediating 2Cl(-)-1HCO3(-) exchange. Recent experiments using isolated pancreatic ducts from slc26a6(-)/(-) mice suggest that slc26a6 mediates most of the Cl(-)-dependent secretion of HCO3(-) across the apical membrane in the mouse and the data are consistent with the reported electrogenicity of slc26a6. However, the role of SLC26A6 in human pancreatic HCO3(-) secretion is less clear because human ducts are capable of secreting much higher concentrations of HCO3(-). The role of SLC26A6 must now be evaluated in a species such as the guinea pig which, like the human, is capable of secreting HCO3(-) at a concentration of ~140 mmol/L. From existing guinea pig data we calculate that a 1Cl(-)-2HCO3(-) exchanger such as slc26a6 would be unable to secrete HCO3(-) against such a steep gradient. On the other hand, the HCO3(-) conductance of CFTR could theoretically support secretion of HCO3(-) to a much higher concentrations. CFTR may therefore play a more important role than SLC26A6 in HCO3(-) secretion by the guinea pig and human pancreas. PMID- 17700967 TI - Effects of Bak Foong Pill and its active components on body functions and gastrointestinal epithelial ion transport. AB - Bak Foong Pill has been used traditionally for treating gynecological disorders for several centuries but also with a newly modified formula for treating postmenopausal symptoms. Cumulating evidence indicates that Bak Foong Pill acts on multi-systems and affects various organ functions. The present review discusses the effects of Bak Foong Pill and its active components on overall body function, with particular focus on the gastrointestinal epithelial ion transport and the related underlying mechanisms. PMID- 17700968 TI - The role of extracellular ATP in the male reproductive tract. AB - In addition to its well established role as a neurotransmitter, extracellular ATP has been considered as a paracrine/autocrine factor, either released from sperm or epithelial cells, in the male reproductive tract and shown to play a versatile role in modulating various reproductive functions. This review summarizes the signal pathways through which ATP induces anion secretion by the epithelia of the epididymis, as well as its epithelium-dependent modulation of smooth muscle contraction of the vas deferens. Finally, the overall role of ATP in coordinating various reproductive events in the male genital tract is discussed. PMID- 17700969 TI - Epithelial ion channels in the regulation of female reproductive tract fluid microenvironment: implications in fertility and infertility. AB - An optimal fluid microenvironment in the female reproductive tract is considered to be crucial for successful reproductive events. Fluid absorption and secretion across the reproductive tract epithelia largely depends on electrolyte transport through the apically and basolaterally located ion channels, working together with an array of other transporters. This review will discuss the role of epithelial sodium channel (ENaC) and the cystic fibrosis transmembrane conductance regulator (CFTR) in regulating the fluid volume and composition of the reproductive tract and their importance in various reproductive events such as sperm capacitation and implantation. Disturbance of the fluid microenvironment due to defects or abnormal regulation of these ion channels as causes for a number of pathological conditions, such as ovarian hyperstimulation syndromes, hydrosalpinx and infertility, is also discussed. PMID- 17700970 TI - Transport protein sorting in polarized epithelial cells. AB - In order to carry out their physiological functions, the cells of transporting epithelial tissues must be able to polarize their cell surface domains. Different collections of membrane transport proteins must be distributed to distinct domains of the plasma membrane, and cells must be coupled to one-another through junctional complexes that help organize polarized domains and regulate the permeability of the paracellular pathway. This exquisite organization requires that epithelial cells possess a sorting apparatus that can target newly synthesized transport proteins to the appropriate surface domains. Furthermore, the transport proteins themselves must possess information embedded within their structures that specifies their sites of ultimate functional residence. The nature of this information, and of the protein-protein interactions involved in its interpretation, is beginning to be elucidated. The initial formation of the polarized state involves signaling cascades that epithelial cells use to orient themselves to sites of cell-cell and cell-matrix contact. Recent evidence suggests that one component of these cascades is a kinase that also serves as a cellular energy sensor. PMID- 17700971 TI - Prerequisite role of persistent cell shrinkage in apoptosis of human epithelial cells. AB - Persistent cell volume reduction is a major hallmark of apoptosis. Recent studies have demonstrated that cell volume reduction is not a passive, secondary event of the apoptotic cell death process. Whole-cell shrinkage, termed apoptotic volume decrease (AVD), takes place soon after stimulation with apoptogen and precedes caspase activation, DNA and cell fragmentation in a variety of cell types including human epithelial cells. The AVD induction is the result of KCl efflux attained by activation of K(+) and Cl(-) channels. Inhibition of AVD induction leads to rescue of the cells from apoptosis. Since the AVD process is coupled to dysfunction of the regulatory volume increase (RVI), apoptotic cells undergo persistent cell shrinkage in human epithelial HeLa cells. When the RVI mechanism was impaired, hypertonic stress itself induced not only persistent cell shrinkage but also apoptotic cell death in HeLa cells. Even under normotonic apoptogen-free conditions, exposure of HeLa cells to Na(+)- or Cl(-)-deficient solution alone can bring about persistent cell shrinkage and thereafter apoptotic cell death. Thus, it is concluded that persistent cell shrinkage, which comprises AVD induction and RVI dysfunction, is a prerequisite to apoptosis induction in human epithelial cells. PMID- 17700972 TI - CD147 and its interacting proteins in cellular functions. AB - CD147 (basigin, EMMPRIN, neurothelin, M6, HAb18G, etc.), a transmembrane glycoprotein, has a broad expression pattern on various epithelial cells with some differences between species, e.g. rat, mouse, chicken and human, but is highly enriched on the surface of cancer cells of epithelial origin such as lung cancer, breast cancer and hepatoma cells. The CD147 antigen consists of two IgSF domains, a transmembrane sequence containing a charged residue (Glu) and a cytoplasmic domain of 40 residues. The particular structural features suggest that it is involved in protein-protein interactions. Although the interacting molecules are still not well known due to unavailability of the 3D structure of CD147, adhesion, coimmunoprecipitation and other studies recently suggest that several proteins, including integrins, cyclophilins, MCT, etc., interact with CD147 as its ligand or receptor candidates to mediate a wide range of cellular functions. PMID- 17700973 TI - DNA-dependent protein kinase activity and radiosensitivity of nasopharyngeal carcinoma cell lines CNE1/CNE2. AB - The present study investigated the relationship between DNA-dependent protein kinase (DNA-PK) and radiosensitivity of nasopharyngeal carcinoma (NPC) cell lines. The dose-survival relationship for NPC cell lines, CNE1 and CNE2, was analyzed using clonogenic formation assay, the activity of DNA-PK of the two cell lines was measured using the Signa TECT DNA-PK assay kit, and the localization and expression of Kus (a heterodimer) and DNA-PKcs protein in CNE1 and CNE2 before irradiation and 15 min, 1 h, 6 h, 12 h, 24 h after 4 Gy irradiation were analyzed by immunofluorescence, laser scanning confocal microscope (LSCM) and Western blot. The results showed that the surviving fraction of CNE1 was higher than that of CNE2 at each dose. The DNA-PK activity of CNE1 was also significantly higher than that of CNE2 before and after irradiation (P<0.05), while the expression of total Ku70/Ku80 in CNE1 and CNE2 had no significant difference. Increasing translocation of Ku70 and Ku80 from the cytoplasm to the nuclei in the two cell lines was observed with increase of irradiation time as detected by Western blot, and the immunofluorescence of the DNA-PK complex subunits showed greater nuclear translocation in CNE1 than CNE2 after irradiation. The results suggest that the relatively higher radio-resistance of CNE1 correlates with the higher activity of DNA-PK as compared to that of more radiosensitive CNE2 (or lower radio-resistance) before and after irradiation. Thus, DNA-PK activity may be a useful predictor of radiosensitivity of NPC. PMID- 17700974 TI - Attenuation of streptomycin ototoxicity by tetramethylpyrazine and its effect on K+ channels in the outer hair cells of guinea pig cochlea. AB - In order to elucidate the mechanism underlying the attenuation of streptomycin ototoxicity by tetramethylpyrazine (TMP), the present study investigated the effect of TMP on the outward K(+) current in the outer hair cells of guinea pig cochlea. Sixty guinea pigs were divided into 6 groups randomly. Auditory brainstem response (ABR) was used to observe the change in thresholds and to evaluate ototoxicity induced by streptomycin. Whole-cell patch-clamp technique was used to observe the effect of TMP on outward K(+) current in isolated outer hair cells. The results showed that TMP attenuated the threshold shift caused by streptomycin and increased the amplitudes of Ca(2+)-sensitive K(+) current [I(K(Ca))] in the outer hair cells. The present data suggest that TMP displays anti-ototoxicity induced by streptomycin. The augmented amplitudes of I(K(Ca)) of the outer hair cells induced by TMP may be one of the mechanisms underlying its ototoxicity-attenuating effect. PMID- 17700975 TI - Caregiver burden and coping: a prospective study of relationship between burden and coping in caregivers of patients with schizophrenia and bipolar affective disorder. AB - INTRODUCTION: Caregivers of patients of schizophrenia and bipolar affective disorder (BAD) experience considerable burden while caring their patients. They develop different coping strategies to deal with this burden. Longitudinal studies are required to assess the relationship between caregiver burden and coping. AIM: The present study was conducted to assess relationship between burden and coping in caregivers of clinically stable patients with schizophrenia and BAD. METHOD: One hundred patients each of schizophrenia and BAD attending a psychiatric outpatient setting and their caregivers were followed up for a period of 6 months. Burden and coping strategies were assessed in the caregivers at baseline, and after 3 and 6 months using the Burden Assessment Schedule (BAS) and Ways of Coping Checklist - Hindi Adaptation (WCC - HA). RESULTS: Burden remained stable over 6 months and was comparable in the two groups of caregivers. Caregivers from both the groups were found to use problem focused coping strategies more often than seek social support and avoidance strategies. Scores on avoidance type of coping showed a positive correlation with the total burden scores and a number of burden factors. CONCLUSION: Caregivers of patients of schizophrenia and BAD face similar levels of burden and use similar types of coping methods to deal with it. Relationship between caregiver burden and coping is quite complex. PMID- 17700976 TI - The development of the child and adolescent versions of the Verona Service Satisfaction Scale (CAMHSSS). AB - BACKGROUND: There is a shortage of comprehensive and validated instruments to measure satisfaction with Child and Adolescent Mental Health Services (CAMHS). This study chose the Verona Service Satisfaction Scale (VSSS as a template for the development of a new CAMHS Satisfaction Scale (CAMHSSS). METHOD: The new questionnaires were developed by involving service users and members of the multidisciplinary team in several stages. The psychometric qualities of the 39 item draft were tested on a random sample. RESULTS: A total of 56 adolescents and 104 parents participated in the study. The acceptability of the questionnaires was excellent, and internal consistency was high. Test-retest reliability was between substantial to moderate for individual items, and high for the seven dimension and the final versions of the scale. The questionnaires differentiated well between satisfied and dissatisfied service users. CONCLUSIONS: Two versions were generated to measure service satisfaction among outpatients (CAMHSSS-39 and 20) and one for inpatients and day-patients (CAMHSSS-Unit). All have good psychometric properties and can be recommended for future studies. PMID- 17700977 TI - Sources of stress and burnout in acute psychiatric care: inpatient vs. community staff. AB - BACKGROUND: Professionals who work alone or in small teams often provide services for people with serious mental health problems in community settings. Stress is common in community teams and this may cause burnout and threaten the quality and stability of the services. This study compares levels of burnout and sources of stress among community and acute ward staff in six European centres. METHODS: A total of 6 acute ward (N = 204) and community staff (N = 209) in 5 different European countries filled out the Maslach Burnout Inventory (MBI), the Mental Health Professional Scale (MHPSS) the Agervold Questionnaire for psychosocial work environment (QPWES) in addition to a comprehensive demographic questionnaire. RESULTS: In the univariate analyses, except for Emotional Exhaustion (MBI), there were no differences in burnout between the two groups of staff. Community teams reported more organisational problems, higher work demands, less contact with colleagues, but also better social relations and more control over their work. The ward staff was more satisfied with the organisational structure and access to colleagues, but complained about lack of control over operating conditions at work. The multivariate analyses identified four groups of staff: (1) a Control-dissatisfied and Contact satisfied group (N = 184) with 2/3 coming from the wards. (2) A Contact-satisfied and Work-demand dissatisfied group (N = 147) with (3/4) from the community staff. (3) A Control- and Contact dissatisfied group (N = 47) with a majority from community teams, and (4) a Contact- and Work demand satisfied group (N = 37) with a majority from the wards. CONCLUSION: Burnout as measured was not a serious problem among community and ward staff members, and did not differentiate between the two groups. Acute ward working implied lack of control but much contact with colleagues, whereas community work entailed more control but demanding work in terms of difficult task and hard-to-find-solutions. PMID- 17700979 TI - A retrospective study examining the socioeconomic backgrounds of women undergoing bilateral breast augmentation at a private independent hospital in the United kingdom. AB - Cosmetic breast augmentation is becoming increasingly popular and acceptable to women in the United Kingdom. This study examined the socioeconomic backgrounds of women undergoing breast augmentation who live in North Warwickshire in the Midlands. The case notes of 98 consecutive breast augmentations performed at a private independent hospital were retrospectively reviewed. The average age of the patient was 34 years (range, 17-53 years). They were requesting, on the average, an increase of 2 bra cup sizes (range, 1-3 cup sizes). The preoperative bra cup size was A/B (range, AA-C), and the postoperative bra cup size was C/D (range, B-E). The average size of the implant used was 270 ml (range, 160-410 ml). The average implant size used currently is considerably larger than that reported in studies 30 years ago. What women perceive as a "natural-appearing" breast has changed over time. The findings show that women from all across the socioeconomic spectrum are undergoing breast augmentation. In particular, the authors found that the largest proportion (34%) of their patients have come from social class IIIn. This is particularly interesting in that this social class is not overrepresented in North Warwickshire. The findings of this study may have implications for cosmetic surgery providers and may document the change in the attitudes of the authors' society toward cosmetic breast augmentation. PMID- 17700980 TI - The efficacy of topical silicone gel elastomers in the treatment of hypertrophic scars, keloid scars, and post-laser exfoliation erythema. AB - BACKGROUND: Dermatix is a Food and Drug Administration (FDA)-registered substantial equivalent to silicone gel sheeting for the prevention and management of hypertrophic scars and keloids. METHODS: A 90-day prospective study evaluated the efficacy of Dermatix, silicone gel sheeting, and a combination of these treatments in improving scars for 30 patients. Each patient had a bilateral scar that served as an untreated control. The outcome measures included profilometry analysis of scar topography before and after punch biopsies of the control and treated scars, symptoms associated with the scars, and patient evaluations of the ease of treatment. RESULTS: The results showed better resolution and improvement of scars with Dermatix treatment or the combined use of Dermatix and silicone gel sheeting than with silicone gel sheeting alone. Wound erythema was reduced, and collagen architectural reorientation was demonstrated histologically. Patients rated Dermatix as easier to use than silicone gel sheeting. Both Dermatix and silicone gel sheeting reduced symptoms of itching, irritation, and skin maceration. CONCLUSION: The results of this study indicate that Dermatix is a useful treatment for the management of abnormal scarring. PMID- 17700981 TI - Classification and treatment of facial tissue atrophy in Parry-Romberg disease. AB - BACKGROUND: This report aims to show procedures that the senior author has used for the rehabilitation of facial deformities in Parry-Romberg disease since 1983. The authors also report the classification they use to plan the most appropriate surgical procedure for these patients. METHODS: For this study, 95 patients (67 females and 28 males) with different types of facial tissue depression were classified according to the depth of the defect so adequate treatment could be planned. The cases were classified into four types. For types 1 and 2, only fat grafts were used, whereas for types 3 and 4, a combined procedure was used according to the case using cartilage and bone grafts, free dermis-fat grafts, and galeal flaps. RESULTS: The results were successful, with few or no complications. Objective examinations showed excellent aesthetic improvement, with obvious deformity alleviated and the emotional status of the patients improved. CONCLUSIONS: The authors' practice frequently sees cases of Parry Romberg disease, which has allowed them to gain significant experience in this field. For depression types 1 and 2, they recommend only fat infiltration, and for types 3 and 4, they favor combined treatment with lipoinjection, galeal flaps, free dermis-fat grafts, and bone and cartilage grafts. Occasionally, in areas of soft tissue with fibrosis, the authors infiltrated around 4 ml of fragmented fascia grafts instead of fat grafts. PMID- 17700982 TI - Breast enlargement after two reduction mastoplasties: a case report. AB - In 1989, a bilateral breast reduction was performed for a large-breasted woman. She returned 1 year later with bilateral breast enlargement as severe as in the original case. The operation was repeated but in a more aggressive way. She became pregnant 2 years later, and both her small breasts began to grow again until they became gigantic. Hormonal tests showed results within the standard limits, and no medical treatment was effective. After the delivery, her breasts reduced in size spontaneously. PMID- 17700983 TI - Biocontrol and PGPR features in native strains isolated from saline soils of Argentina. AB - A bacterial collection of approximately one thousand native strains, isolated from saline soils of Cordoba province (Argentina), was established. From this collection, a screening to identify those strains showing plant growth promotion and biocontrol activities, as well as salt tolerance, was performed. Eight native strains tolerant to 1 M: NaCl and displaying plant growth promotion and/or biocontrol features were selected for further characterization. Strains MEP(2 )18, MRP(2 )26, MEP(2 )11a, MEP(3 )1, and MEP(3 )3b significantly increased the growth of maize seedlings under normal and saline conditions, whereas isolates ARP(2 )3, AEP(1 )5, and ARP(2 )6 were able to increase the root dry weight of agropyre under saline conditions. On the other hand, strains MEP(2 )18 and ARP(2 )3 showed antagonistic activity against phytopathogenic fungi belonging to Sclerotinia and Fusarium genus. Antifungal activity was found in cell-free supernatants, and it was heat and protease resistant. Strains MEP(2)18 and ARP(2)3 were identified as Bacillus sp. and strains MEP(2)11a and MEP(3)3b as Ochrobactrum sp. according to the sequence analysis of 16S rRNA gene. PMID- 17700984 TI - Pumilicin 4, a novel bacteriocin with anti-MRSA and anti-VRE activity produced by newly isolated bacteria Bacillus pumilus strain WAPB4. AB - A total of 34 bacterial strains with anti-methicillin-resistant Staphylococcus aureus (MRSA) activity were isolated from 69 soil and water samples collected from four areas of Thailand. One strain, WAPB4 identified as Bacillus pumilus, showed remarkable antibacterial activity against MRSA, vancomycin-resistant Enterococcus faecalis (VRE), and several Gram-positive test bacteria. Bacteriocin produced by WAPB4 was designated as pumilicin 4. It was heat stable up to 121 degrees C, 15 min and active within the pH range of 3-9. Its activity disappeared when treated with pronase E, chymotrypsin, and trypsin, demonstrating its proteinaceous nature. At high dosage (80 AU mL(-1)), the effect of pumilicin 4 was bactericidal to both MRSA and VRE. Bacteriostasis was observed for a low dose of bacteriocin (20 AU mL(-1)). Purification of pumilicin 4 was performed by a three-step procedure, i.e., solvent extraction, solid phase extraction, and reversed-phase chromatography. The molecular mass of purified pumilicin 4 as determined by mass spectrometry was 1994.62 Dalton. This present study is the first report of a novel bacteriocin, pumilicin 4, produced by B. pumilus that has potential for use as an alternative antibacterial agent for the treatment of infection with MRSA and VRE. PMID- 17700985 TI - Nitric oxide alleviates oxidative damage induced by enhanced ultraviolet-B radiation in cyanobacterium. AB - To study the role of nitric oxide (NO) on enhanced ultraviolet-B (UV-B) radiation (280-320 nm)-induced damage of Cyanobacterium, the growth, pigment content, and antioxidative activity of Spirulina platensis-794 cells were investigated under enhanced UV-B radiation and under different chemical treatments with or without UV-B radiation for 6 h. The changes in chlorophyll-a, malondialdehyde content, and biomass confirmed that 0.5 mM: sodium nitroprusside (SNP), a donor of nitric oxide (NO), could markedly alleviate the damage caused by enhanced UV-B. Specifically, the biomass and the chlorophyll-a content in S. platensis-794 cells decreased 40% and 42%, respectively under enhanced UV-B stress alone, but they only decreased 10% and 18% in the cells treated with UV-B irradiation and 0.5 mM: SNP. Further experiments suggested that NO treatment significantly increased the activities of superoxide dismutase (SOD) and catalase (CAT), and decreased the accumulation of O (2)(-) in enhanced UV-B-irradiated cells. SOD and CAT activity increased 0.95- and 6.73-fold, respectively. The accumulation of reduced glutathione (GSH) increased during treatment with 0.5 mM: SNP in normal S. platensis cells, but SNP treatment could inhibit the increase of GSH in enhanced UV-B-stressed S. platensis cells. Thus, these results suggest that NO can strongly alleviate oxidative damage caused by UV-B stress by increasing the activities of SOD, peroxidase, CAT, and the accumulation of GSH, and by eliminating O (2)(-) in S. platensis-794 cells. In addition, the difference of NO origin between plants and cyanobacteria are discussed. PMID- 17700986 TI - Phylogenetic study of legionella species in pristine and polluted aquatic samples from a tropical Atlantic forest ecosystem. AB - Legionella species are ubiquitous bacteria in aquatic environments. To examine the effect of anthropogenic impacts and physicochemical characteristics on the Legionellaceae population, we collected water from two sites in the Itanhaem River system in the Atlantic Forest of Brazil. One sample was collected from an upstream pristine region, the other from a downstream estuarine region moderately affected by untreated domestic sewage. Cultures on a selective medium failed to isolate Legionella species. Culture-independent methods showed that water from the estuarine aquatic habitat contained DNA sequences homologous to the 16S ribosomal DNA gene of Legionella pneumophila and non-pneumophila species. In pristine water, only two sequences related to L. pneumophila were detected. The results suggest that salinity and anthropogenic factors, such as wastewater discharge, favor a diversity of Legionella species, whereas pristine freshwater selects for Legionella pneumophila. PMID- 17700987 TI - Isolation, identification, and degradation characteristics of phenazine-1 carboxylic acid-degrading strain Sphingomonas sp. DP58. AB - A phenazine-1-carboxylic acid (PCA)-degrading bacterium, strain DP58, was isolated from pimiento rhizosoil. Based on morphology, physiologic tests, 16S rDNA sequence, and phylogenetic characteristics, it was identified as Sphingomonas sp. The PCA-degradation experiments were conducted both in Luria Bertani and inorganic salt medium at 28 degrees C. The relationship between bacterium growth and PCA degradation suggested that strain DP58 could use PCA as the sole source of carbon and nitrogen and was able to completely degrade PCA in 40 hours. Newly isolated strain DP58 represents the first bacterium that can degrade PCA. PMID- 17700989 TI - Transvenous embolization for dural transverse sinus fistulas with occluded sigmoid sinus. AB - Dural transverse sinus arteriovenous fistulas with cortical venous drainage were associated with a high hemorrhagic risk. Dural transverse sinus arteriovenous dural fistulas could be treated by embolization (transarterial or transvenous), surgery or a combination of both. Transvenous packing of the diseased sinus was considered to be a less invasive and effective method of treatment. Occluded sigmoid sinus proximally, especially cases with isolated transverse sinus, could make the transvenous approach difficult. Craniotomy for sinus packing or surgical excision remained the treatment of choice when the percutaneous transvenous approach was not feasible. We reviewed the techniques of transvenous embolization described in the literature and illustrated our techniques in two consecutive cases of transvenous embolization of the dural arteriovenous fistulas through the occluded sigmoid sinus. We concluded that transvenous embolization remains a safe and feasible technique other than surgery for patients with transverse sinus dural fistula, achieving a long-term occlusion of the pathology. PMID- 17700988 TI - Parasporin-2Ab, a newly isolated cytotoxic crystal protein from Bacillus thuringiensis. AB - A novel crystal protein that exhibited potent cytotoxicity against human leukemic T-cells was cloned from the Bacillus thuringiensis TK-E6 strain. The protein, designated as parasporin-2Ab (PS2Ab), was a polypeptide of 304 amino acid residues with a predicted molecular weight of 33,017. The deduced amino acid sequence of PS2Ab showed significant homology (84% identitiy) to parasporin-2Aa (PS2Aa) from the B. thuringiensis A1547 strain. Upon processing of PS2Ab with proteinase K, the active form of 29 kDa was produced. The activated PS2Ab showed potent cytotoxicity against MOLT-4 and Jurkat cells and the EC(50) values were estimated as 0.545 and 0.745 ng/mL, respectively. The cytotoxicity of PS2Ab was significantly higher than that of PS2Aa reported elsewhere. Although both cytotoxins were structurally related, it was thought that the minor differences found were responsible for the different cytotoxicities of PS2Ab and PS2Aa. PMID- 17700990 TI - A pioneering female neurosurgeon: Dr. Aysima Altinok. AB - This article will look at how one female neurosurgeon in Turkey made her mark in the field. In 1954, Dr. Aysima Altinok began her residency training in neurosurgery at Haydarpasa Numune Hospital where the first official department of neurosurgery in Turkey had been founded five years earlier. On November 22, 1959, she successfully completed her training and was certified officially as a neurosurgeon. Hence, Dr. Altinok was a leader in neurosurgery. Dr. Altinok was the chief of the department of neurosurgery from 1968 to 1992 at Bakirkoy Mental and Psychological Health Hospital in Istanbul. She was among the founders of the Turkish Neurosurgical Society in 1968 and was awarded the honour of "Medical Doctor of the Year in Turkey" by the Ministry of Health in 1990. On May 15, 1996, she was accepted as an honorary member of Turkish Society of Neurosurgery for her contributions to neurosurgery. For proving the capability of a woman as a neurosurgeon, her contribution to the world history of neurosurgery should be respected. PMID- 17700991 TI - Effects of the selective endothelin A (ET(A)) receptor antagonist Clazosentan on cerebral perfusion and cerebral oxygenation following severe subarachnoid hemorrhage - preliminary results from a randomized clinical series. AB - OBJECTIVE: To study the effects of clazosentan, a new selective endothelin receptor subtype A antagonist, on cerebral perfusion and cerebral oxygenation following severe aneurysmal subarachnoid haemorrhage (aSAH). METHODS: All 12 patients treated at our institution in the context of a phase IIa, multicenter, randomized trial on clazosentan's safety and efficacy in reducing the incidence of angiographic cerebral vasospasm were included in this substudy. The phase IIa study (n = 34) consisted of two parts: a double-blind, randomized Part A (clazosentan 0.2 mg/kg/h versus placebo) and an open-label Part B (clazosentan 0.4 mg/kg/h for 12 h followed by 0.2 mg/kg/h) for patients with established vasospasm. In parallel to the phase IIa study protocol, which included assessment of vasospasm by angiography and transcranial Doppler sonography, we determined regional cerebral blood flow (rCBF), cerebrovascular resistance, and regional tissue oxygenation. RESULTS: Cerebral perfusion was comparable between treatment groups during the early post-bleeding period (rCBF placebo, 22.6 +/- 3.5 ml/100 g/min versus rCBF clazosentan, 23.9 +/- 1.1 ml/100 g/min). By the time of control angiography (day 8 after aSAH), rCBF decreased by 50% in the placebo group (11.3 +/- 6.7 ml/ 100 g/min) while it remained stable in the clazosentan group (23.5 +/ 12.9 ml/100 g/min). During Part B of the study, all 3 patients who developed haemodynamically relevant vasospasm during placebo treatment, showed a sustained improvement in rCBF upon conversion to clazosentan. CONCLUSIONS: These preliminary data suggest that clazosentan reduces the extent of vasospasm associated impairment of cerebral perfusion following aSAH. Furthermore, clazosentan may exert beneficial actions on overt vasospasm-associated hypoperfusion. PMID- 17700993 TI - A comparison of the measurement properties of the Juvenile Arthritis Functional Assessment Scale with the childhood health assessment questionnaire in daily practice. AB - We compared the measurement properties of a performance test (Juvenile Arthritis Functional Assessment Scale; JAFAS) with a questionnaire-based instrument (Childhood Health Assessment Questionnaire; CHAQ) to measure functional ability in patients with juvenile idiopathic arthritis on the level of individual items. In 28 consecutive children visiting an outpatient paediatrics clinic, the JAFAS (range 0-20) and CHAQ (range 0-3) were applied, and measures of disease activity and joint range of motion (ROM) were determined. Twenty-eight children with a median age of 10 years and median disease duration of 3.2 years were included. The median JAFAS score was 0, and the median CHAQ score was 0.125. Cronbach's alpha was 0.92 for the JAFAS and 0.96 for the CHAQ. The Spearman correlation coefficient between the JAFAS and the CHAQ was 0.55 (P < 0.01). With six out of ten items, the JAFAS classified the child as less disabled than with corresponding CHAQ activities. Overall, associations with measures of disease activity and ROM were higher for the CHAQ than for the JAFAS. A performance test (JAFAS) does not appear to have an added benefit over the questionnaire-based assessment (CHAQ) of physical function in a cross-sectional study. PMID- 17700994 TI - Xylitol conversion by fermentation using five yeast strains and polyelectrolyte assisted ultrafiltration. AB - Batch fermentations for xylitol production were conducted using Candida boidinii (BCRC 21432), C. guilliermondii (BCRC 21549), C. tropicalis (BCRC 20520), C. utilis (BCRC 20334), and P. anomala (BCRC 21359) together with a mixture of sugars simulating lignocellulosic hydrolysates as the carbon source. C. tropicalis had the highest bioconversion yield (Y(P/S)) of 0.79 g g(-1) (g xylitol x g xylose(-1)) over 48 h. Additional fermentations with C. tropicalis achieved Y(P/S) values of 0.6 and 0.39 g g(-1) after 96 and 72 h using urea and soybean meal as the nitrogen sources, respectively. Ethanol and arabitol were also produced in all fermentation. Xylitol in the fermentation broth was recovered by cross-flow ultrafiltration. With prior application of 2 mg polydiallyl dimethylammonium chloride l(-1) on the membrane surface, protein in the permeate was reduced from 7.1 to 1.5 mg l(-1 )after 2 h. PMID- 17700995 TI - Development of efficient method for purified recombinant bovine granulocyte macrophage colony-stimulating factor production with baculovirus-silkworm gene expression system. AB - Recombinant bovine granulocyte-macrophage colony-stimulating factor (rboGM-CSF) was produced by the baculovirus-silkworm expression system. It was purified to 98% by (NH(4))(2)SO(4), followed by a three-step column chromatography with silica gel, ion exchange resin and a metal chelate column. The specific activity of purified rboGM-CSF was 1.6-6.3 x 10(6) ED(50) mg(-1). By this method, the specific activity was raised 160-fold and 21% of the expressed rboGM-CSF was recovered. PMID- 17700996 TI - Isolation and molecular characterization of a cryptic plasmid from Bifidobacterium longum. AB - An isolate from the fecal samples of children was identified as Bifidobacterium longum. A plasmid isolated from it pBIFA24 was 4,892 bp with three open reading frames, ORFI, ORFII, and ORFIII. ORFI encoded a replication protein involved in a rolling-circle replication mechanism, and three sets of tandem repeat sequences featuring iteron structure were identified. Secondary structure prediction analysis of ORFII suggested it was a transmembrane protein. ORFIII showed high amino acid sequence identity with some mobilization proteins and contained an oriT sequence. PMID- 17700997 TI - Pichia pastoris expressing recombinant tilapia growth hormone accelerates the growth of tilapia. AB - Growth manipulation of fish is an important task in aquatic biotechnology. The growth promoting effect of recombinant Pichia pastoris expressing tilapia growth hormone was demonstrated in red tilapia fry (Oreochromis sp.), which were immersed into water containing intact cells of the recombinant yeast. The weight increase of the treated group was 171% relative to the control group after 6 weeks. PMID- 17700998 TI - Brewer's spent grain as raw material for lactic acid production by Lactobacillus delbrueckii. AB - Chemically pre-treated brewer's spent grain was saccharified with cellulase producing a hydrolysate with approx. 50 g glucose l(-1). This hydrolysate was used as a fermentation medium without any nutrient supplementation by Lactobacillus delbrueckii, which produced L-lactic acid (5.4 g l(-1)) at 0.73 g g(-1) glucose consumed (73% efficiency). An inoculum of 1 g dry cells l(-1) gave the best yield of the process, but the pH decrease affected the microorganism capacity to consume glucose and convert it into lactic acid. PMID- 17700999 TI - Prevalence of factor V Leiden (G1691A) and prothrombin (G20210A) among Kurdish population from Western Iran. AB - BACKGROUND: The mutation in factor V (FV) G1691A, known as factor V Leiden, and prothrombin (FII) gene G20210A are the two most prevalent causes of inherited thrombophilia. The present study reports the prevalence of factor V Leiden and the prothrombin G20210A gene mutations among healthy individuals of Kurdish ethnic background in Western Iran. METHODS: Four hundred thirty-four healthy unrelated individuals, 255 male and 179 female, with a mean age of 28.7+/-15.5 from the Kermanshah Province of Iran were studied for prothrombin G20210A mutation. The factor V Leiden mutation was studied in 404 healthy individuals, of whom 232 were male and 172 were female. The factor V Leiden and prothrombin G20210A were detected by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) method using Mnl I and Hind III restriction enzymes, respectively. RESULTS: Among 434 individuals studied for prothrombin G20210A mutation seven carried this mutation as heterozygous (four female subjects and three male), giving a prevalence of 1.6% [95% confidence intervals (CI) 0.5-2.7) and an allele frequency of 0.8%. No homozygous prothrombin 20210AA was found. Factor V G1691A mutation was detected as heterozygous in 11 of 404 healthy individuals (five female and six male) and as homozygous in one male indicating a prevalence of 2.97% (95% CI 1.3-4.6) and allele frequency of 1.6%. CONCLUSIONS: Our results indicated that the factor V Leiden and prothrombin G20210A mutations are not rare among populations of Western Iran and that the relationship between venous thrombophilia and these mutations have to be further studied in Western Iran population, which, in turn, may suggest a causal effect. PMID- 17701000 TI - Chemical zona pellucida thinning with acidified Tyrode's solution: comparison between partial and circumferential techniques. AB - PURPOSE: To compare effectiveness of two different chemical zona thinning techniques. METHOD: We studied 163 patients who had experienced IVF or ICSI failures in two or more cycles. Patients were assigned to one of three groups: zona intact (n=72), partial thinning (n=59), or circumferential thinning (n=73). Before transfer, the zonae pellucidae of embryos were thinned partially or circumferentially using acidified Tyrode's solution. RESULTS: Implantation rates were 8.9% in the intact zona group, 17.6% in the partial thinning group, and 11.9% in the circumferential thinning group: respective clinical pregnancy rates were 16.7% (12/72), 32.2% (19/59), and 27.4% (20/73). Both rates were significantly higher in the partial thinning group than the intact zona group. For circumferential thinning versus zona intact groups, differences fell short of significance. CONCLUSIONS: Following embryo transfer failure, partial thinning would be recommended over circumferential thinning for successful assisted hatching. PMID- 17701001 TI - Sentinel node biopsy versus elective lymph node dissection in patients with cutaneous melanoma in a Japanese population. AB - BACKGROUND: In Japan, elective lymph node dissection (ELND) has been the standard treatment for patients with possible nodal melanoma. Sentinel node biopsy (SNB) has now replaced ELND, not only in Japan but also worldwide. The objective of this study was to compare the interim outcomes of SNB and ELND. METHODS: A retrospective study was conducted among patients with clinically node-negative disease treated at our institute with either SNB (n = 30) or ELND (n = 72). RESULTS: The background was similar in the two groups. Nodal metastases were found in 40.0% of patients in the SNB group, but in only 26.4% in the ELND group (P = 0.173). The median follow-up was 31.5 months for the SNB group and 82 months for the ELND group. The incidence of locoregional recurrence and distant metastasis in the SNB group was 10.0% and 16.7%, respectively, and for the ELND group the incidence was 5.6% and 31.9%, respectively. The 3-year disease-free survival rate was similar in the two groups (P = 0.280), and the 3-year disease free survival rates for node-positive patients were also similar in the two groups (P = 0.90), as were the 3-year disease-free survival rates for node negative patients (P = 0.193). CONCLUSION: This interim result in a Japanese melanoma population with clinically node-negative disease demonstrated that SNB identified more nodal micrometastases than ELND. This increase in accurate staging likely resulted from the reliable identification of the lymph node field by lymphoscintigraphy, as well as the more detailed pathologic examination of the nodes removed in SNB. It is quite reasonable to perform SNB instead of ELND in this population. PMID- 17701002 TI - The impact of real-time tissue elasticity imaging (elastography) on the detection of prostate cancer: clinicopathological analysis. AB - BACKGROUND: We evaluated the accuracy and feasibility of real-time elastography for detecting prostate cancer, using prostatectomy specimens. METHODS: This study was based on clinicopathological findings in 51 patients with prostate cancer who were referred for elastography at the time of prostate biopsy. We compared transverse pathology sections with elastographic moving images (EMIs) to determine the detection rate of cancer, the relationship between tumor location and the elastographic findings, and the relationship between the Gleason score and the elastographic findings. RESULTS: In 15 patients (29%), all EMIs were in complete agreement with tumor location (category I), in 28 patients (55%), the EMIs agreed with tumor location, but showed some disagreement (category II), and in 8 patients (16%) there was disagreement of the elastographic findings with tumor location or the tumors were undetectable by elastography (category III). However, in category III, all tumors were detected as low-echoic by B-mode ultrasonography. We divided the prostate into three different regions (anterior, middle, and posterior), and found that 30/32 (94%) anterior tumors, 13/17 (76%) middle tumors, and 16/28 (57%) posterior tumors were detected by elastography. The proportions of cancers detected by elastography (categories I+II/total) was 100% in the patients with a Gleason score of 6, 85% in those with a score of 7 or 8, and 63% in those with a score of 9 or 10. CONCLUSION: Real-time elastography in conjunction with B-mode ultrasonography significantly improves the detection of prostate cancer. One of the characteristic findings of elastography is its excellent detection of anterior tumors. The low detection rate of high-grade tumors in this analysis was likely due to the predominance of high-grade tumors in a peripheral location compared to the anterior location of the low-grade tumors. PMID- 17701004 TI - Role of 10-Gy boost radiation after breast-conserving surgery for stage I-II breast cancer with a 5-mm negative margin. AB - BACKGROUND: According to the Guidelines for breast-conserving therapy of the Japanese Breast Cancer Society, the surgical margin is "negative" when the minimum distance between the tumor edge and the margin of the resected specimen is more than 5 mm. The value of boost radiation for early breast cancer with a 5 mm negative margin remains unclear. METHODS: A total of 137 patients with stage I II breast cancer underwent breast-conserving surgery between July 1987 and August 2002. All of the patients had negative margins according to the Japanese guidelines. Their median age was 50 years and the median follow-up period was 62 months. The entire ipsilateral breast was irradiated to a total dose of 50 Gy (25 fractions). Then an additional 10 Gy (5 fractions) was given to 79 patients, using 6- to 12-MeV electrons (boost group), while 58 patients (no-boost group) received no further radiation. Factors influencing local recurrence were evaluated by univariate and multivariate analyses. RESULTS: For the entire population, the 5-year overall survival, cause-specific survival, disease-free survival, and local recurrence rates were 96.0%, 96.8%, 94.2%, and 1.67%, respectively. Boost radiation reduced local recurrence, but the improvement was not significant (P = 0.070). Univariate and multivariate analyses failed to detect any factors that were significantly associated with local control. There were no severe complications in either group and there were no differences between the groups in the cosmetic outcome. CONCLUSION: Boost radiation can be performed for stage I-II breast cancer with negative margins (Japanese guidelines), and showed a tendency to decrease local recurrence. A large randomized controlled study is necessary to establish final conclusions. PMID- 17701003 TI - Progression-free survival and overall survival of patients with clear cell carcinoma of the ovary treated with paclitaxel-carboplatin or irinotecan cisplatin: retrospective analysis. AB - BACKGROUND: Irinotecan hydrochloride, a topoisomerase I inhibitor, has been preliminarily recognized as an effective agent against clear cell carcinoma of the ovary (CCC), but there are few clinical data. Our aim was to compare progression-free survival (PFS) between patients treated with irinotecan hydrochloride and cisplatin (CPT-P) and those with treated with paclitaxel and carboplatin (TC). METHODS: One hundred and seventeen patients at International Federation of Gynecology and Obstetrics (FIGO) stages Ic (ascites/malignant washing) - IV were identified by scanning the medical records of ten Japanese hospitals. After complete surgical staging procedures including lymphadenectomy, 35 patients received CPT-P and 82 patients received TC. The PFS and overall survival of the two groups were compared using the Kaplan-Meier method. RESULTS: There was no significant difference in median age, performance status, FIGO stage, rate of optimal cytoreduction, or follow-up period between the CPT-P and TC groups. Two-year and 5-year PFS was 48% and 40%, respectively, in the TC group and 55% and 55%, respectively, in the CPT-P group (P = 0.31). Multiple regression analysis revealed that only residual tumor was an independent prognostic factor for PFS (P < 0.01). CONCLUSION: CPT-P showed a potential therapeutic effect, at least no less than that of TC therapy. Although there was no significant survival benefit in the present retrospective analysis, we recommend that the CPT-P regimen be evaluated in a larger, prospective, clinical trial. PMID- 17701005 TI - Treatment with an oral fluoropyrimidine, S-1, plus cisplatin in patients who failed postoperative gemcitabine treatment for pancreatic cancer: a pilot study. AB - BACKGROUND: This study set out to evaluate, in patients with gemcitabine resistant pancreatic cancer, the response rate and toxicity of S-1 plus cisplatin (CDDP). METHODS: Seventeen patients with histologically diagnosed invasive ductal pancreatic cancer were enrolled in this study. All patients had growing recurrent pancreas cancer despite the administration of gemcitabine. Thirteen patients underwent pancreatectomy, and 2 underwent choledochojejunostomy and gastrojejunostomy without pancreatectomy. S-1 (80 mg/m(2) per day) was orally administered for 21 consecutive days, followed by a 14-day rest period. CDDP (40 mg/m(2)) in 500 ml saline was administered by intravenous drip on day 8. This schedule was repeated every 5 weeks until the occurrence of disease progression, unacceptable toxicities, or the patient's refusal to continue. RESULTS: Five (29.4%) patients achieved a partial response and 2 (11.8%) had stable disease. In 5 of 15 patients (33.3%) who had elevated serum carbohydrate antigen (CA)19-9 levels at the start of treatment the CA19-9 was reduced by more than 50%. The median survival time was 10 months (range, 20 months), with 63.7% and 31.9% of patients alive at 6 and 12 months, respectively. Major adverse reactions in the 15 patients included gastrointestinal toxicities of grade 1 or 2. Only one patient (5.9%) developed grade 3 leucopenia. CONCLUSION: S-1 with CDDP has a promising effect against gemcitabine-resistant pancreatic cancer, with easily manageable toxicities. Further investigation of this regimen is warranted in patients with pancreatic cancer, especially in comparison with gemcitabine. PMID- 17701006 TI - Preliminary experience with a modified premedication protocol that included intravenous diphenhydramine and calcium bromide for the prophylaxis of paclitaxel related hypersensitivity reactions. AB - BACKGROUND: Paclitaxel often causes severe hypersensitivity reactions (HSRs) rapidly after infusion, even in patients given prophylactic therapy. The purpose of this study was to analyze the incidence of paclitaxel-related HSRs in patients with non-small cell lung cancer (NSCLC) retrospectively, and to assess the feasibility of a modified premedication protocol. METHODS: One hundred and seven patients who were pretreated with either a conventional premedication regimen (two doses of dexamethasone) or a short premedication regimen (single dose of dexamethasone with oral diphenhydramine and intravenous ranitidine), prior to paclitaxel infusion were retrospectively analyzed. A modified premedication regimen, consisting of 12.5 ml of Rescalmin (intravenous diphenhydramine 50 mg and calcium bromide 437.5 mg), intravenous ranitidine 100 mg, and intravenous dexamethasone 20 mg, was given 30 min prior to paclitaxel, with oral dexamethasone 8 mg given on the night before the paclitaxel. Patients received paclitaxel intravenously at 175 mg/m(2) over 3 h, followed by carboplatin, AUC 5, over 1 h on day 1 every 3 weeks. RESULTS: In the conventional premedication group, 21 patients had HSRs (32.3%); in 1 of these patients the HSR was considered to be severe (1.5%). In the short premedication group, 19 patients had HSRs (45.2%); in 6 of these patients the HSRs were considered to be severe (14.3%). The incidence of severe HSRs was significantly higher in the short premedication group than in the conventional premedication group (P = 0.027). In the modified premedication protocol study, HSR events were recorded in 14 patients (63.6%); 14 showed flushing, 2 had skin rash, and 1 had tachycardia. No severe HSRs were seen. CONCLUSIONS: The incidence of HSRs in the short premedication group tended to be higher than that in the conventional premedication group. The modified premedication protocol was found to be feasible for preventing paclitaxel-related HSR, but case accumulation is needed. PMID- 17701007 TI - Gemcitabine and cisplatin for advanced urothelial carcinomas: the Ehime University Hospital experience. AB - BACKGROUND: The aim of this study was to evaluate the efficacy and safety of a combined chemotherapy regimen, gemcitabine and cisplatin (GC), in the treatment of advanced urothelial carcinomas. METHODS: Fifty-five patients with advanced urothelial cancer were treated with GC (gemcitabine 1000 mg/m(2) on days 1, 8, and 15; cisplatin 70 mg/m(2) on day 2) every 28 days. The median follow-up was 30 months (range, 3 to 57 months). RESULTS: With the GC therapy, 35 of the 55 patients (63.6%) showed an objective response, with 7 (12.7%) achieving a clinical complete response (CR) and 28 (50.9%), a partial response (PR). GC therapy had a better impact on metastases in the lung and lymph nodes than on metastases in the liver and bone. Lung and lymph nodes showed objective responses of 64.7% and 65.8%, respectively. Eight of the 20 patients (40.0%) who had previously been treated with other regimens showed an objective response, with 1 achieving a CR and 7 achieving a PR. In the 47 patients with metastasis, the median time to progression was 7.0 months (range, 2 to 49 months), and the median overall survival was 12.0 months (range, 3 to 49 months). The 2-year survival rate was 80.0% in the CR group, while it was 55.1% in the PR group and 10.0% in the progressive disease (PD) group. The toxicities associated with GC, particularly mucositis, anorexia, and alopecia, were quite mild. Grade 3-4 toxicity was primarily hematological, including anemia (27.3%), neutropenia (32.7%), and thrombocytopenia (43.6%). CONCLUSION: GC is considered to be a highly effective and well-tolerated regimen for the treatment of advanced urothelial carcinomas, with moderate toxicity. PMID- 17701009 TI - Retrospective analysis of prognosis for scirrhous-type gastric cancer: one institution's experience. AB - BACKGROUND: Scirrhous gastric cancer is biologically aggressive, and the prognosis is poor even with curative surgery. We compared outcomes with different therapies in order to identify prognostic factors. METHODS: Records for 83 patients, who were treated between 1991 and 2004, were evaluated for survival and stage, treatment, and clinicopathological factors. RESULTS: Cumulative 5-year overall survival was 10.2% for all 83 patients, including 27 (32.5%) patients with stage II/III disease and 56 (67.4%) with stage IV disease. The 5-year overall survival rate and median survival time for patients with stage II/III disease after curative surgery were 24.3% and 1150 days. For patients with stage IV disease, 2-year and 5-year survival rates after initial surgery were 13.7% and 0% and median survival was 250 days. In contrast, preoperative chemotherapy for advanced, unresectable disease produced 2-year and 3-year overall survival rates of 53.6% and 26.8% and medican survival was 910 days. CONCLUSION: Aggressive surgery alone does not seem to improve outcome, but preoperative chemotherapy might be beneficial and should be investigated further. PMID- 17701008 TI - Pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine, and effects of CYP3A5 and MDR1 polymorphisms in patients with urogenital cancers. AB - BACKGROUND: We investigated the pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine in patients with urogenital cancer to clarify the significance of monitoring of the serum concentration of paclitaxel. METHODS: Paclitaxel was administered at 175 mg/m(2) or 150 mg/m(2) to patients with hormone-refractory prostate cancer (n = 10) or advanced transitional cell carcinoma (n = 6) along with carboplatin or gemcitabine, respectively. The relationships between pharmacokinetic parameters and hematological adverse effects, as well as pharmacological effects, were examined. The effects of patient characteristics, including single-nucleotide polymorphisms of MDR1(ABCB1), CYP2C8, CYP3A4, and CYP3A5, on the total body clearance of paclitaxel were evaluated. RESULTS: Total body clearance and volume of distribution at a steady-state after the intravenous infusion of paclitaxel were not significantly different between patients with carboplatin or gemcitabine. The percent decreases in neutrophils and platelets for the regimen with gemcitabine were significantly greater than those with carboplatin, and showed a significant positive relationship with the observed concentration at the end of infusion or time above 0.1-microM concentration of paclitaxel. Post-therapy decreases in prostate-specific antigen were not positively correlated with the extent of paclitaxel exposure in the prostate cancer patients. Neither the polymorphisms at exon 26 (C3435T) and at exon 21 (G2677A/T) in MDR1 nor the CYP3A5*1 allele significantly affected the total body clearance of paclitaxel. CONCLUSION: The hematological side effects of paclitaxel were intensified by gemcitabine, and were correlated with paclitaxel pharmacokinetics. Monitoring of the serum concentration of paclitaxel will facilitate the therapy, with less myelosuppression and without any loss of therapeutic efficacy. PMID- 17701011 TI - Hepatic lesion of invasive thymoma: possibility of direct invasion. AB - Thymomas grow slowly but tend to invade the surrounding tissue. We herein report four patients with hepatic lesions of thymomas, which were thought to have directly invaded the liver. These patients had received combined modality treatments throughout the clinical course, and the hepatic lesions appeared a long time after the initial treatment - 11.8 years on average. In these patients, the prognoses after the appearance of hepatic invasion were poor. Appropriate local control in the early stages of the clinical course may therefore be essential for preventing the extrathoracic spread of invasive thymoma. PMID- 17701010 TI - A patient with gastric cancer and liver metastases successfully treated with combination chemotherapy including S-1. AB - We report the case of a 62-year-old man with advanced gastric cancer and multiple liver metastases who was successfully treated with combined chemotherapy including S-1. The patient was clinically diagnosed with stage IV (T3 N2 H1 P0) disease and was initially treated with 100 mg/body per day S-1 administered orally for 21 days and 10 mg/body per day cisplatin (CDDP) infused on days 1-5, 8 12, and 15-19. This chemotherapy resulted in significant reduction of the liver and gastric tumors. After receiving additional CDDP/S-1 administration as an outpatient, the patient's liver masses disappeared as shown on abdominal computed tomography (CT). With the patient's desire and informed consent, he underwent curative surgery with total gastrectomy, D1+alpha lymph node dissection, and partial resection of liver S4. After discharge without any surgical complication, CT revealed regrowth of the S4 liver mass, and combined docetaxel and CDDP was selected as second-line chemotherapy with local radiation therapy against the hepatic metastasis. Additionally, a third regimen with irinotecan and S-1 was given. At 2 years 7 months after the initial treatment, no sign of cancer (including liver metastasis and peritoneal dissemination) has been identified by radiological follow-up examinations. PMID- 17701012 TI - Multiple bilateral choroidal metastasis from anal melanoma. AB - A 58-year-old Caucasian woman with bleeding per rectum had a melanoma of the anal canal. She subsequently presented with visual disturbance and was noted to have bilateral multiple choroidal metastasis, along with other multiple systemic metastases. Orbital radiotherapy led to near complete resolution of the ocular metastasis. PMID- 17701013 TI - Endometrial carcinosarcoma presenting as a tibial metastasis. AB - Metastasis to a lower-extremity bone is an extremely rare event in patients with endometrial carcinoma. A 64-year-old woman presented with progressive right leg pain but no gynecologic complaints. A diagnostic workup revealed primary endometrial carcinosarcoma with an isolated tibial metastasis. Though the patient received only local irradiation to the tibial lesion, complete resolution of symptoms resulted. Six months after the radiotherapy, the intraabdominal disease progressed and the patient died. We note that tibial metastasis is one of the possible presenting symptoms in patients with endometrial malignant tumors. Irradiation can improve their quality of life and so may be effective in the management of symptomatic tibial metastasis. PMID- 17701014 TI - Inflammatory pseudotumor of the lung: a pathological controversy. PMID- 17701015 TI - Salivary gland scintigraphy in gastro-esophageal reflux disease. AB - Gastro-esophageal reflux disease (GERD) is associated with a decreased salivary flow as well as gastric acid production. This study therefore aimed to investigate functional disorders of salivary glands in patients with GERD. METHODS: Thirty-one consecutive patients with GERD underwent salivary gland scintigraphy. RESULTS: If the results defined the optimal cutoff point for determining the decreased salivary secretion as 51 % in parotid glands and 36 % in submandibular glands, a decreased salivary secretion of right parotid gland, left parotid gland, right submandibular gland, and left submandibular gland was found in 39 %, 32 %, 36 %, and 58 %, respectively. Overall, salivary function disorder of at least one major salivary gland was found in 24 patients (78 %) with GERD. There was no difference in the incidence of impaired salivary function between GERD patients with and without erosive esophagitis. Salivary gland function was more frequently diminished than expected in GERD. We concluded that the presence of impaired salivary gland function was considered to be one of risk factors for developing GERD symptoms. PMID- 17701016 TI - Compensatory gastroprotective role of glucocorticoid hormones during inhibition of prostaglandin and nitric oxide production and desensitization of capsaicin sensitive sensory neurons. AB - Glucocorticoid hormones produced in response to various ulcerogenic stimuli contribute to the maintenance of the gastric mucosal integrity. The role of glucocorticoids in gastroprotection becomes especially important where there is deficiency of prostaglandins (PGs) or nitric oxide (NO) or desensitization of capsaicin-sensitive sensory neurons (CSN). It has been found that neither inhibition of PG or NO production nor desensitization of CSN by itself provokes damage in the gastric mucosa of rats with normal corticosterone levels. However, each of these treatments results in mucosal damage in adrenalectomized rats; this effect being prevented by corticosterone replacement. Indomethacin-induced gastric erosions are potentiated to similar degrees by adrenalectomy, inhibition of NO production or desensitization of CSN. The potentiation caused by inhibition of NO production or CSN desensitization is further enhanced by concomitant glucocorticoid deficiency. These results suggest a pivotal compensatory role of glucocorticoids in the maintenance of the gastric mucosal integrity under the adverse conditions where the gastroprotective mechanisms provided by PGs, NO and capsaicin-sensitive sensory neurons are impaired. PMID- 17701017 TI - Role of the appendix in the pathogenesis of ulcerative colitis. AB - Although human appendix has been considered as a vestigial remnant, recent observations have focused attention on the role of the appendix in the pathogenesis of ulcerative colitis (UC). Many case-control studies suggest that previous appendectomy is rare in UC patients. This inverse relation is limited to patients who undergo appendectomy before the age of 20 years. Moreover, several investigators reported the improvement of UC after appendectomy, especially in young patients. In the appendix of UC patients, the CD4/CD8 ratio is significantly increased, and the proportion of CD4+CD69+ (early activation antigen) T cells, but not of CD4+HLA-DR+ (mature activation antigen) T cells, is also significantly increased. These findings suggest that the appendix may be a priming site in the development of UC. Further studies including analysis of CD4+ and CD8+ T cells are necessary to clarify the role of the appendix in the pathogenesis of UC. PMID- 17701018 TI - Regional difference in the healing process of colitis induced by 2,4,6 trinitrobenzene sulfonic acid in rats. AB - We recently reported an improved method to induce colitis by 2,4,6 trinitrobenzene sulfonic acid. This method enabled us to induce colitis at appropriate regions. This study aimed to investigate the regional differences on the healing process of colitis in rats. Colitis was induced at the proximal, middle or distal colon. On Day 10, the size of colitis was large in the order of the middle, distal and proximal colon. Colitis of the proximal colon healed more rapidly than that of the middle colon. Prostaglandin E(2) generation in the normal colonic mucosa was measured. Prostaglandin E(2) generation correlated with sizes of colitis among three regions. It was found that there was the regional difference on the healing process of the colitis and prostaglandin E(2) generation may show the different protective integrity of the colonic mucosa from the fact that higher prostaglandin E(2) generation showed larger colitis size. PMID- 17701019 TI - Interaction of local anaesthetics with lipid membranes under inflammatory acidic conditions. AB - The clinical fact that local anaesthetics do not successfully work in the patients with inflammation has been generally interpreted on the basis of inflamed tissue acidification. In order to verify this hypothesis, the interaction of local anaesthetics with lipid membranes was studied by determining the drug-induced changes of membrane physicochemical property (membrane fluidity) at different pH covering inflammatory acidic conditions. At clinically relevant concentrations, lidocaine, procaine, prilocaine and bupivacaine fluidized 1,2 dipalmitoylphosphatidylcholine membranes with the potency decreased with lowering the pH from 7.9 to 5.9. When treated as the aqueous acidic solution (pH 4.0) similar to marketed injection solutions, lidocaine showed more pronounced pH dependence, so the reduction of its membrane-fluidizing effects at acidic pH theoretically correlated to that of its non-ionized membrane-interactive concentrations. Unlike phosphatidylcholine membranes, however, nerve cell model membranes consisting of different phospholipids and cholesterol were fluidized by lidocaine at pH 6.4-6.9 corresponding to the acidity of inflamed tissues. Cationic lidocaine was effective in fluidizing anionic phosphatidylserine and cardiolipin membranes at pH 6.4, but not zwitterionic phospholipid membranes, whereas it was ineffective on any membranes at pH 2.0 where membrane acidic phospholipids were not ionized. Local anaesthetics are considered to form the ion pairs specifically with counter-ionic phospholipids and act on the membranes of nerve cells even under inflammatory acidic conditions. The drug and membrane interaction causable in inflamed tissue acidification does not support the conventional theory on the local anaesthetic failure associated with inflammation. PMID- 17701020 TI - Angiotensin AT1 receptor blockers suppress ischemia/reperfusion-induced gastric injury in rats. AB - Ischemia/reperfusion (I/R) damages gastric mucosa via reactive oxygen species (ROS) activity. ROS was reportedly produced through angiotensin II stimulation in tissues such as kidney, heart and brain. To determine whether AT1 receptor plays a role in gastric mucosal damage, we examined the effect of AT1 receptor blocker (ARB; losartan, candesartan, valsartan) on I/R-induced gastric injury in rats. I/R produced microscopic gastric hemorrhagic injury, and increased gastric microvascular permeability and H(2)O(2) production in rats. The mucosal lesions induced by I/R were attenuated by pretreatment of each ARB. The increase in microvascular permeability was suppressed by losartan pretreatment. Additionally, I/R-caused H(2)O(2) activation was not observed by pretreatment of losartan, candesartan and valsartan. These results suggest that angiotensin II stimulation via AT1 receptor and following ROS production in the stomach contribute to the pathogenesis of the gastric I/R injury. PMID- 17701021 TI - Anti-inflammatory and analgesic actions of etoricoxib (an NSAID) combined with misoprostol. AB - This study has evaluated the anti-inflammatory and analgesic responses of etoricoxib, a selective COX-2 non-steroidal anti-inflammatory drug combined with misoprostol in pre-clinical assays. Groups of animals (mice and rats) were subjected to rat's paw edema induced by carrageenan, and writhing and formalin tests in mice. Treatment with etoricoxib, misoprostol, and etoricoxib combined with misoprostol inhibited the inflammation process by 35 %, 30 %, and 61 %, respectively in the rat paw edema induced by carrageenan with the greatest effects being obtained in the group treated with etoricoxib combined to misoprostol. In the writhing test, etoricoxib inhibited the number of writhes by 33 %, and by 27 % when combined with misoprostol. In the first phase of the formalin test (nociceptive), treatment with the combination of etoricoxib and misoprostol inhibited significantly this process by 45 %, while in the second phase (inflammatory), etoricoxib inhibited this by 97 %, the etoricoxib + misoprostol inhibited this by 78 %, respectively. The responses observed have demonstrated that the combination of etoricoxib and misoprostol increased the anti-inflammatory response, but it did not show effect in the peripheral analgesic response. PMID- 17701022 TI - [Creatinine clearance in geriatric patients]. PMID- 17701024 TI - Partial sequencing of the genomic RNA of Araujia mosaic virus and comparison of the coat protein sequence with those of other potyviruses. PMID- 17701023 TI - Role of AMP-activated protein kinase gamma 3 genetic variability in glucose and lipid metabolism in non-diabetic whites. AB - AIMS/HYPOTHESIS: AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that acts as an intracellular fuel sensor, directing multiple metabolic pathways in a catabolic direction in times of nutrient shortage. In humans, three different gamma-subunits (gamma(1), gamma(2), gamma(3)) have been identified as AMPK regulators. The AMPKgamma3 (protein kinase, AMP-activated, gamma 3 non catalytic subunit, PRKAG3) isoform plays a role in gene regulation in glucose/lipid metabolism and skeletal muscle glycogen content. We investigated whether PRKAG3, in addition to being expressed in skeletal muscle, is also expressed in human liver. We also investigated whether genetic variance in PRKAG3 is associated with glucose and/or lipid metabolism in non-diabetic whites. MATERIALS AND METHODS: After sequencing a screening cohort (n = 50) in the PRKAG3 locus, we genotyped 1061 participants for frequently found single nucleotide polymorphisms (SNPs). Association analyses between genotypes/haplotypes and metabolic traits were carried out. RESULTS: We detected PRKAG3 expression in human liver and skeletal muscle. Two SNPs (rs692243, rs6436094) with minor allele frequencies of 0.16 and 0.26 respectively and in moderate linkage disequilibrium (D' = 0.92; r (2) = 0.47) were found. rs692243 (C/G) confers a Pro71Ala mutation, while rs6436094 (A/G) is located in the 3' untranslated region. No associations with prediabetic traits such as body fat distribution, insulin resistance or insulin secretion were found (p > 0.15 for all). However, the minor alleles of both SNPs were significantly associated with higher serum LDL-cholesterol and apolipoprotein (Apo) B-100 levels (rs692243: CG:LDL 4.3%, ApoB-100 3.4%; GG:LDL 7.6%, ApoB-100 5.4%; p = 0.008 and p = 0.01 respectively; rs6436094: AG:LDL 3.3%, ApoB-100 1.7%; GG:LDL 11.3%, ApoB-100 11.1%; p = 0.009 and p = 0.05 respectively; dominant model). The GG/GG diplotype homozygous for both minor SNP alleles displayed the highest LDL-cholesterol among all frequent diplotypes (p = 0.059). CONCLUSIONS/INTERPRETATION: While genetic variability in PRKAG3 does not seem to have a major effect on glucose metabolism, it may play an important role in lipoprotein metabolism in humans. PMID- 17701025 TI - Recent Korean isolates of duck hepatitis virus reveal the presence of a new geno- and serotype when compared to duck hepatitis virus type 1 type strains. AB - Duck hepatitis was first reported in 1985 in Korea. The complete nucleotide sequence of two past Korean isolates, DHV-HS and DHV-HSS, isolated in 1994 and 1995, and four recent Korean isolates, AP-03337, AP-04009, AP-04114 and AP-04203 isolated in 2003 and 2004, were determined. Phylogenetic analysis using the 3D protein sequence confirmed that the previously characterized duck hepatitis virus type 1 strains and the six Korean isolates described here constitute a monophyletic group and form two clades/genotypes in which all except the four recent Korean isolates form one group (A) and the recent Korean isolates of 2003 and 2004 constitute a second group (B). Phylogenetic analysis of the VP1 protein supported the division into two different groups. Antisera raised against viruses of group A showed significant neutralizing cross-reaction against a member of the same genotype but not to a strain of group B and vice versa. These results demonstrated that the two genotypes also could be regarded as two different serotypes. PMID- 17701026 TI - Urotensin II acutely increases myocardial length and distensibility: potential implications for diastolic function and ventricular remodeling. AB - Urotensin II (U-II) is a cyclic peptide that may be involved in cardiovascular dysfunction. In the present study, the acute effects of U-II on diastolic properties of the myocardium were investigated. Increasing concentrations of U-II (10(-8) to 10(-6) M) were added to rabbit papillary muscles in the absence (n = 15) or presence of: (1) damaged endocardial endothelium (EE; n = 9); (2) U-II receptor antagonist, urantide (10(-5) M; n = 7); (3) nitric oxide (NO) synthase inhibitor, N(G)-Nitro-L-Arginine (10(-5) M; n = 9); (4) cyclooxygenase inhibitor, indomethacin (10(-5) M; n = 8); (5) NO synthase and cyclooxygenase inhibitors, N(G)-Nitro-L-Arginine (10(-5) M) and indomethacin (10(-5) M), respectively, (n = 8); or (6) protein kinase C (PKC) inhibitor, chelerythrine (10(-5) M; n = 9). Passive length-tension relations were constructed before and after a single concentration of U-II (10(-6) M; n = 3). U-II concentration dependently decreased inotropy and increased resting muscle length (RL). At 10(-6) M, active tension decreased 13.8 +/- 5.4%, and RL increased to 1.007 +/- 0.001 L/L (max). Correcting RL to its initial value resulted in an 18.1 +/- 3.0% decrease in resting tension, indicating decreased muscle stiffness, which was also suggested by the down and rightward shift of the passive length-tension relation. This effect remained unaffected by EE damage and PKC inhibition. In contrast, the presence of urantide and NO inhibition abolished the effects of U-II on myocardial stiffness, while cyclooxygenase inhibition significantly attenuated them. U-II decreases myocardial stiffness, an effect that is mediated by the urotensin-II receptor, NO, and prostaglandins. This represents a novel mechanism of acute neurohumoral modulation of diastolic function, suggesting that U-II is an important regulator of cardiac filling. PMID- 17701030 TI - FTICR-MS applications for the structure determination of natural products. AB - Natural products are a source of unique chemical entities with specific biological activities of great value to the pharmaceutical industry. However, the determination of unknown structures is usually time consuming and often becomes a bottleneck in the effort to develop natural products into effective drugs. The high-performance features of high magnetic field FTMS have greatly alleviated the structural elucidation bottleneck to meet increasingly shorter discovery timelines for drug candidates based on natural products. The high-performance features of high field FTMS include unsurpassed mass measurement accuracy for elemental formula determination, ultra-high mass resolution for component separation, the ability to perform multiple levels of tandem mass spectrometry for structural elucidation, and moderate sensitivity for limited supply of isolates. A number of applications utilizing these properties of FTMS have been reported recently for the structural elucidation of novel natural product structures originating from terrestrial and marine microorganisms. In this review, FTMS methods and their applications for the structural elucidation and characterization of natural products will be reviewed. PMID- 17701027 TI - How effective is it to sequentially switch among Olanzapine, Quetiapine and Risperidone?--A randomized, open-label study of algorithm-based antipsychotic treatment to patients with symptomatic schizophrenia in the real-world clinical setting. AB - RATIONALE: Evidence on sequential trial with atypical antipsychotics has been scarce. OBJECTIVES: We conducted an algorithm-based antipsychotic pharmacotherapy. MATERIALS AND METHODS: In this open-label study, patients with schizophrenia (DSM-IV) were treated with antipsychotic monotherapy, step-by-step, with each trial lasting up to 8 weeks. At baseline, they were highly symptomatic to score more than 54 in the total Brief Psychiatric Rating Scale (BPRS(1-7)) score. When the posttreatment BPRS score was above 70% of the baseline, they were subsequently treated with another and up to three atypicals. Basically, anticholinergics were prohibited, and only adjunctive allowed was lorazepam. The secondary endpoint was a clinical status good enough to be discharged for 66 inpatients and a successful continuation therapy with the same antipsychotic agent for more than 6 months for 12 outpatients. RESULTS: Three groups of 26 patients each were randomized to Olanzapine, Quetiapine, or Risperidone. Thirty nine (50%) responded to the first agent (Olanzapine16, Quetiapine9, Risperidone14), and 14 responded to the second. Only two showed response to the third, and 16 failed to respond to all three antipsychotics, with only 7 dropouts. Overall, there were 22 Olanzapine, 14 Quetiapine, and 19 Risperidone responders. Based on the secondary outcome, 20 Olanzapine-treated (average maximum dose, 15.4 mg), 10 Quetiapine-treated (418 mg), and 20 Risperidone treated (4.10 mg) patients responded. The difference in response as the first choice was significant (p < 0.05). Relative doses of those failing to respond were comparable (Olanzapine 18.3 mg, Quetiapine 564 mg, Risperidone5.47 mg). Extrapyramidal symptoms did not change significantly. CONCLUSIONS: When the first atypical antipsychotic is inadequate, switching to the second is worth trying, although some remain treatment-refractory. Quetiapine may be inferior to Olanzapine and Risperidone in symptomatic patients. PMID- 17701031 TI - Effects of CYP2D6 polymorphisms on neuroleptic malignant syndrome. AB - OBJECTIVE: Neuroleptic malignant syndrome (NMS) is one of the most serious adverse reactions to antipsychotic medications. We accumulated data on Japanese NMS patients and, in a study designed to examine the effects of drug metabolism on the occurrence of NMS, tested the possibility of association between NMS and CYP2D6 polymorphisms. METHODS: We studied 53 patients who had experienced NMS and 112 healthy individuals. We determined what drugs the patients with NMS had been given and retrospectively identified candidates for drugs causing NMS. We screened the prevalence of CYP2D6 genotypes using polymerase chain reaction and restriction fragment length polymorphism analyses. RESULTS: The prevalence of *5 alleles in the group of all patients with NMS was higher than that in the controls, though this difference was not statistically significant (10.4% vs. 5.4%; P = 0.107; odds ratio (OR) 2.05; 95% confidence interval (CI) 0.87-4.80). No association was found between the frequency of *10 alleles and the occurrence of NMS. We found *4 and duplicated alleles in only one patient each among the patients with NMS. A total of 29 patients appeared to have developed NMS as a result of having taking CYP2D6 substrates. The prevalence of *5 alleles in these 29 patient was significantly higher than that in the controls (15.5% vs. 5.4%; P = 0.020; OR 3.25; 95% CI 1.30-8.13). CONCLUSION: Our findings suggest that the CYP2D6*5 allele is likely to affect vulnerability to development of NMS. PMID- 17701032 TI - Persistence with antihypertensive treatments: results of a 3-year follow-up cohort study. AB - OBJECTIVE: Effective treatment of hypertension requires continued prescribing of antihypertensive medications for many years. Persistence in prescribing habits, however, has been reported to be low. The study described herein - which is completely independent of pharmaceutical sponsors - was undertaken to evaluate persistence with antihypertensive treatment in Germany. METHODS: A total of 13,763 newly diagnosed hypertensive patients were identified in the IMS Disease Analyzer database and observed for 3 years after their first antihypertensive prescription. RESULTS: The median age of the study cohort was 65 years, and 56% were female. One in four patient received no more than three prescriptions within 3 years. Persistence was longest for patients whose initial prescription was for a free combination based on angiotensin converting enzyme inhibitors (median: 392.5 days), followed patients initially receiving a fixed combination, including angiotensin II receptor antagonists (208.5 days) and AIIRA monotherapy (168 days). Persistence was shortest with diuretics (57 days). Across all treatment groups, persistence after 3 years was 15.2%. Insurance status, sex and comorbidities were not found to impact persistence. CONCLUSION: Our data indicate that persistence differs markedly among the drug classes (p < or = 0.001) but that even persistence of the best drug class is not sufficient to provide for an adequate blood pressure control in the population. The largest decline in persistence occurred in the first 3 months of treatment. More research is needed to elucidate the causes of this early drop in persistence and to develop effective means of improving the currently unsatisfactory situation. PMID- 17701033 TI - Genetic basis of murine antibacterial defense to streptococcal lung infection. AB - To evaluate the effect of genetic background on antibacterial defense to streptococcal infection, eight genetically diverse strains of mice (A/J, DBA/2J, CAST/Ei, FVB/NJ, BALB/cJ, C57BL/6J, 129/SvImJ, and C3H/HeJ) and tlr2-deficient mice (C57BL/6(tlr2-/-)) were infected with three doses of Streptococcus zooepidemicus (500, 5,000, or 50,000 colony-forming units) by alveolar challenge. There was a range of susceptibility between the strains at each dose and time point (6, 24, and 96 h). At the lowest dose, the 129/SvImJ and C3H/HeJ strains had significantly higher bacterial counts at all time points after infection, when compared to A/J, DBA/2J, CAST/Ei, FVB/NJ, which were resistant to infection at the low dose of innoculum. At the medium dose, 129/SvImJ and C3H/HeJ had higher bacterial counts, while A/J, DBA/2J, and BALB/cJ showed reduced streptococcal growth. After the highest dose of Streptococcus, there were minimal differences between strains, suggesting the protective impact of modifier genes can be overcome. TLR2-deficient animals contained increased bacterial load with reduced cytokines after 96 h when compared to C57BL/6J controls suggesting a role of innate immunity in late antibacterial defense. Overall, we identify vulnerable (129/SvlmJ and C3H/HeJ) and resistant (A/J, FVB, and DBA) mouse strains to streptococcal lung infection, which demonstrate divergent genetic expression profiles. These results demonstrate that innate differences in pulmonary host defense to S. zooepidemicus are dependent on host genetic factors. PMID- 17701034 TI - Characterization of terminal deoxynucleotidyl transferase and polymerase mu in zebrafish. AB - Terminal deoxynucleotidyl transferase (TdT) contributes to the junctional diversity of immunoglobulin and T-cell receptors by incorporating nucleotides in a template-independent manner. A closely related enzyme, polymerase mu (polmu), a template-directed polymerase, plays a role in general end-joining double-strand break repair. We cloned zebrafish TdT and polmu and found them to be 43% identical in amino acid sequence. Comparisons with sequences of other species revealed conserved residues typical for TdT in the zebrafish sequence that support the template independence of this enzyme. Some but not all of these features were identified in zebrafish polmu. In adult fish, TdT expression was most prominent in thymus, pro- and mesonephros, the primary lymphoid organs in teleost fish and in spleen, intestine, and the tissue around the intestine. Polmu expression was detected not only in pro- and mesonephros, the major sites for B lymphocyte development, but also in ovary and testis and in all tissue preparations to a low extent. TdT expression starts at 4 dpf and increases thereafter. Polmu is expressed at all times to a similar extent. In situ studies showed a strong expression of TdT and polmicro in the thymic cortex of 8-week-old fish. The characterization of zebrafish TdT and polmu provide new insights in fish lymphopoiesis and addresses the importance and evolution of TdT and polmu themselves. PMID- 17701035 TI - Production of volatile aroma compounds by bacterial strains isolated from different surface-ripened French cheeses. AB - Twelve bacterial strains belonging to eight taxonomic groups: Brevibacterium linens, Microbacterium foliorum, Arthrobacter arilaitensis, Staphylococcus cohnii, Staphylococcus equorum, Brachybacterium sp., Proteus vulgaris and Psychrobacter sp., isolated from different surface-ripened French cheeses, were investigated for their abilities to generate volatile aroma compounds. Out of 104 volatile compounds, 54 volatile compounds (identified using dynamic headspace technique coupled with gas chromatography-mass spectrometry [GC-MS]) appeared to be produced by the different bacteria on a casamino acid medium. Four out of eight species used in this study: B. linens, M. foliorum, P. vulgaris and Psychrobacter sp. showed a high flavouring potential. Among these four bacterial species, P. vulgaris had the greatest capacity to produce not only the widest varieties but also the highest quantities of volatile compounds having low olfactive thresholds such as sulphur compounds. Branched aldehydes, alcohols and esters were produced in large amounts by P. vulgaris and Psychrobacter sp. showing their capacity to breakdown the branched amino acids. This investigation shows that some common but rarely mentioned bacteria present on the surface of ripened cheeses could play a major role in cheese flavour formation and could be used to produce cheese flavours. PMID- 17701036 TI - Transformation by complementation of a uracil auxotroph of the hyper lignin degrading basidiomycete Phanerochaete sordida YK-624. AB - Phanerochaete sordida YK-624 is a hyper lignin-degrading basidiomycete possessing greater ligninolytic selectivity than either P. chrysosporium or Trametes versicolor. To construct a gene transformation system for P. sordida YK-624, uracil auxotrophic mutants were generated using a combination of ultraviolet (UV) radiation and 5-fluoroorotate resistance as a selection scheme. An uracil auxotrophic strain (UV-64) was transformed into a uracil prototroph using the marker plasmid pPsURA5 containing the orotate phosphoribosyltransferase gene from P. sordida YK-624. This system generated approximately 50 stable transformants using 2 x 10(7) protoplasts. Southern blot analysis demonstrated that the transformed pPsURA5 was ectopically integrated into the chromosomal DNA of all transformants. The enhanced green fluorescent protein (EGFP) gene was also introduced into UV-64. The transformed EGFP was expressed in the co-transformants driven by P. sordida glyceraldehyde-3-phosphate dehydrogenase gene promoter and terminator regions. PMID- 17701037 TI - A phase I clinical trial of low-dose interferon-alpha-2A, thalidomide plus gemcitabine and capecitabine for patients with progressive metastatic renal cell carcinoma. AB - BACKGROUND: We have conducted a phase I trial to determine the maximum tolerated dose of gemcitabine in combination with interferon, thalidomide and capecitabine. METHODS: Patients received oral capecitabine 1,000 mg/m(2 )per day, divided in 2 daily doses, 2 weeks on, 1 week off; subcutaneous interferon-alpha 1 mIU twice a day without an interruption; daily oral thalidomide 200 mg/day for the first 7 days, then escalated to 400 mg/day without an interruption. Gemcitabine was given by intravenous administration over 30 min on day 1, week 1 and day 8, week 2. Initial dose level of gemcitabine was 400 mg/m(2). The dose of gemcitabine was the phase I variable. One cycle was 3 weeks. RESULTS AND DISCUSSION: We treated 12 patients, 6 patients were entered at a dose level of 0 (gemcitabine 400 mg/m(2)) and 6 patients entered at a dose level-1 (gemcitabine 200 mg/m(2)). Eight of 12 patients completed at least 12 weeks of therapy. Three partial responses and two stable disease were observed. The remaining patients had progressive disease. Non-hematologic toxicity was either grade 1 or 2. Hematologic toxicity at dose level 0 consisted of 3 patients with grade 3/4 neutropenia, and 1 patient with grade 3 thrombocytopenia. At dose level-1 grade 1/2 neutropenia was observed. CONCLUSIONS: The completion of our phase I experience determined our maximum tolerated dose to be dose level-1. The phase II trial is currently being proposed for patients with rapidly growing clear cell, other histologies that may contain sarcomatoid elements or collecting duct tumor. PMID- 17701039 TI - Transgenic plants from shoot apical meristems of Vitis vinifera L. "Thompson Seedless" via Agrobacterium-mediated transformation. AB - Shoot apical meristem explants of Vitis vinifera "Thompson Seedless" were used for Agrobacterium-mediated genetic transformation. It was determined that the meristems had to be subjected to a dark growth phase then wounded to obtain transgenic plants. Morphological and histological studies illustrated the role of wounding to expose apical meristem cells for transformation. A bifunctional egfp/nptII fusion gene was used to select kanamycin resistant plants that expressed green fluorescent protein (GFP). Kanamycin at a concentration of 16 mg L(-1) in selection medium resulted in recovery of non-chimeric transgenic plants that uniformly expressed GFP, whereas 8 mg L(-1) kanamycin allowed non-transgenic and/or chimeric plants to develop. Polymerase chain reaction (PCR) and Southern blot analyses confirmed the presence of transgenes and their stable integration into the genome of regenerated plants. Up to 1% of shoot tips produced stable transgenic cultures within 6 weeks of treatment, resulting in a total of 18 independent lines. PMID- 17701038 TI - The role of the glyoxylate cycle in the symbiotic fungus Tuber borchii: expression analysis and subcellular localization. AB - Expression profiles of isocitrate lyase (TbICL), malate synthase (TbMLS) and fructose-1,6-bisphosphatase (TbFBP) from the mycorrhizal ascomycete Tuber borchii were investigated by real-time RT-PCR in fruiting bodies at different stages of maturation. In addition, a time course experiment was set up to determine how the transcription profile of TbICL, TbMLS and TbFBP in axenic-grown mycelia is affected by different carbon sources. The transcript levels of the three genes in the fruiting bodies were all much higher than those measured in the vegetative stage. The investigation on axenic-grown mycelia revealed that the main positive regulator of TbICL and TbMLS gene expression is the availability of acetate and ethanol, while oleic acid is a too complex substrate for the limited degradative capacities of T. borchii. Immunolabelling on axenic-grown mycelia showed a co localization of TbICL and the peroxisomal marker protein FOX2. This result demonstrated that in T. borchii ICL is compartmentalized in peroxisomes. The high induction of TbICL, TbMLS and TbFBP transcription and the translocation of lipids in fruiting bodies let us hypothesize that glyoxylate cycle and gluconeogenesis are key metabolic pathways in the recycling of existing cell material and the channelling towards the biosynthesis of new cell components during the maturation of fruiting bodies. PMID- 17701040 TI - Detection of peritoneal dissemination in gynecological malignancy: evaluation by diffusion-weighted MR imaging. AB - The aim of this study is to evaluate the usefulness of diffusion-weighted (DW) magnetic resonance (MR) imaging in detecting peritoneal dissemination in cases of gynecological malignancy. We retrospectively analyzed MR images obtained from 26 consecutive patients with gynecological malignancy. Peritoneal dissemination was histologically diagnosed in 15 of the 26 patients after surgery. We obtained DW images and half-Fourier single-shot turbo-spin-echo images in the abdomen and pelvis, and then generated fusion images. Coronal maximum-intensity-projection images were reconstructed from the axial source images. Reader interpretations were compared with the laparotomy findings in the surgical records. Receiver operating characteristic (ROC) curves were used to represent the presence of peritoneal dissemination. In addition, the sensitivity and specificity were calculated. DW imaging depicted the tumors in 14 of 15 patients with peritoneal dissemination as abnormal signal intensity. ROC analysis yielded Az values of 0.974 and 0.932 for the two reviewers. The mean sensitivity and specificity were 90 and 95.5%. DW imaging plays an important role in the diagnosis and therapeutic management of patients with gynecological malignancy. PMID- 17701041 TI - Magnetic resonance coronary angiography with Vasovist: in-vivo T1 estimation to improve image quality of navigator and breath-hold techniques. AB - The purpose of the study was to estimate T1 values of blood and myocardium after a single injection of Vasovist and to assess Vasovist for magnetic resonance coronary angiography (MRCA). For all exams 0.05 mmol/kg of Vasovist was injected. T1 values of blood and myocardium were estimated over 30 min after injection. Twelve volunteers were examined on a 1.5-T Siemens system using a SSFP sequence with incrementally increasing inversion times for T1-estimation and a breath-hold 3D IR-FLASH sequence for MRCA. Eleven examinations were performed on 1.5-T Philips system using the Look-Locker approach for T1 estimation and a whole-heart inversion-prepared, 3D SSFP sequence for MRCA. SNR, CNR and image quality were assessed. T1 values of blood (5 min: 230 ms vs. 30 min: 275 ms) and myocardium (5 min: 99 ms vs. 30 min: 130 ms) increased over time. Whereas the blood SNR (1 min: 23.6 vs. 30 min: 21.2) showed no significant differences, the blood-to-myocardium CNR (1 min: 18.1 vs. 30 min: 13.8) and the image quality (1 min: 2.9 vs. 30 min: 3.8) degraded over time. Due to long plasma half-time the T1-shortening effect of Vasovist remains effective over 30 min, which allows for multiple breath-hold or high-resolution MRCA. PMID- 17701042 TI - Non-invasive markers of ureteropelvic junction obstruction. AB - Non-invasive prognosis of the clinical progression of disease is of high interest, especially in newborn and children. Neonatal ureteropelvic (UPJ) junction obstruction needs close and invasive surveillance to determine the necessity of pyeloplasty. A number of groups have initiated research with the aim to find non-invasive biomarkers for UPJ obstruction. Two different strategies have been followed. One strategy, based on the knowledge obtained in animal models of UPJ obstruction, has identified a number of individual urinary markers of severe UPJ obstruction. Combining these markers might allow prediction of which patients will require surgery and in which patients UPJ obstruction will spontaneously resolve. The other strategy is based on urinary proteomics. In this strategy the entire urinary proteome is probed for a set of biomarkers that correlates with the degree of UPJ obstruction. In subsequent steps, these sets of urinary biomarkers are used for prediction of the clinical evolution of UPJ obstruction patients. This proteomic-based strategy allowed prediction, several months in advance, of the clinical evolution of neonates with UPJ-obstruction. Both strategies will be complementary and will hopefully replace in the near future the invasive follow-up of newborns with UPJ obstruction. PMID- 17701043 TI - Technical and anatomical essentials for transrectal ultrasound of the prostate. AB - Transrectal ultrasound (TRUS) of the prostate is a specific urological examination. This morphological imaging technique is often capable of identifying the cause for raised values of prostate-specific antigen (PSA) or of clarifying hard tissue regions found during rectal palpation. Particulary in view of constantly increasing number of patients undergoing PSA tests, there is a rising need for further prostate diagnostics in otherwise asymptomatic men. Especially in the gray zone between 4 and 10 ng/ml the tissue marker PSA is frequently influenced by benign alterations, so that it is not possible--on the basis of the PSA value alone--to differentiate between benign and malignant causes. Only a clearly increased serum PSA value (>20 ng/ml) indicates the presence of a prostate carcinoma at a very high probability. However, it is necessary that all patients whose PSA is elevated, undergo a bioptical tissue sample procedure in order to try to diagnose prostate cancer. Today, we regard the technique of TRUS based transrectal prostate biopsy, carried out with a semi-automatic coil spring device and an 18-gauge needle, as the gold standard. The core problem of visual TRUS assessment lies in its lack of specificity, especially if the examiner has only limited experience. There can be low-echo, cancer-suspicious areas that may be histologically either benign or malignant. Benign prostatic hyperplasia (BPH), vessels, centers of prostatitis as well as shadows and artefacts can often also be low in echo-density. Only adequate application of this technology and experience with this method can lead to satisfying biopsy and diagnostic results. PMID- 17701044 TI - Transurethral ultrasonography-guided injection of adult autologous stem cells versus transurethral endoscopic injection of collagen in treatment of urinary incontinence. AB - In the last years preclinical studies have paved the way for the use of adult muscle derived stem cells for reconstruction of the lower urinary tract. Between September 2002 and October 2004, 42 women and 21 men suffering from urinary stress incontinence (age 36-84 years) were recruited and subsequently treated with transurethral ultrasonography-guided injections of autologous myoblasts and fibroblasts obtained from skeletal muscle biopsies. The fibroblasts were injected into the urethral submucosa, while the myoblasts were implanted into the rhabdosphincter. In parallel, 7 men and 21 women (age 39-83 years) also diagnosed with urinary stress incontinence were treated with standard transurethral endoscopic injections of collagen. Patients were randomly assigned to both groups. After a follow-up of 12 months incontinence was cured in 39 women and 11 men after injection of autologous myoblasts and fibroblasts. Mean quality of life score (51.38 preoperatively, 104.06 postoperatively), thickness of urethra and rhabdosphincter (2.103 mm preoperatively, 3.303 mm postoperatively) as well as contractility of the rhabdosphincter (0.56 mm preoperatively, 1.462 mm postoperatively) were improved postoperatively. Only in two patients treated with injections of collagen incontinence was cured. The present clinical results demonstrate that, in contrast to injections of collagen, urinary incontinence can be treated effectively with ultrasonography-guided injections of autologous myo- and fibroblasts. PMID- 17701045 TI - Solitary rectal ulcer syndrome: clinical findings, surgical treatment, and outcomes. AB - BACKGROUND: Solitary rectal ulcer syndrome (SRUS) is a rare disorder often misdiagnosed as a malignant ulcer. Histopathological features of SRUS are characteristic and pathognomonic; nevertheless, the endoscopic and clinical presentations may be confusing. The aim of the present study was to assess the clinical findings, surgical treatment, and outcomes in patients who suffer from SRUS. MATERIALS AND METHODS: A retrospective chart review was undertaken, from January 1989 to May 2005 for all patients who were diagnosed with SRUS. Data recorded included: patient's age, gender, clinical presentation, past surgical history, diagnostic and preoperative workup, operative procedure, complications, and outcomes. RESULTS: During the study period, 23 patients were diagnosed with SRUS. Seven patients received only medical treatment, and in three patients, the ulcer healed after medical treatment. Sixteen patients underwent surgical treatment. In four patients, the symptoms persisted after surgery. Two patients presented with postoperative rectal bleeding requiring surgical intervention. Three patients developed late postoperative sexual dysfunction. One patient continued suffering from rectal pain after a colostomy was constructed. Median follow-up was 14 (range 2-84) months. CONCLUSION: The results of this study show clearly that every patient with SRUS must be assessed individually. Initial treatment should include conservative measures. In patients with refractory symptoms, surgical treatment should be considered. Results of anterior resection and protocolectomy are satisfactory for solitary rectal ulcer. PMID- 17701046 TI - Esophageal foreign body as a cause of upper gastrointestinal hemorrhage: case report and review of the literature. AB - Foreign body ingestion is a common complaint in the emergency department. Severe upper gastrointestinal (GI) hemorrhage is a rare complication of foreign body ingestion and is always considered to signal aortoesophageal fistula (AEF). We report a rare case of a 65-year-old man with upper GI hemorrhage caused by an ingested duck bone 10 days previously. Instead of AEF, massive erosion and edema were found in the esophagus, highlighting the potentially complex pathology of foreign body ingestion. A literature review of the recognized clinical features of esophageal foreign body is described. Some practical points and pitfalls in the management of esophageal foreign body are presented. For patients with a history of esophageal foreign body ingestion, the clinician must maintain a high index of suspicion and must endeavor to obtain a full history. PMID- 17701047 TI - Audiological and electrocochleography findings in hearing-impaired children with connexin 26 mutations and otoacoustic emissions. AB - We recorded cochlear potentials by transtympanic electrocochleography (ECochG) in three hearing-impaired children with GJB2 mutation who showed otoacoustic emissions. Pure tone thresholds, distortion product otoacoustic emissions (DPOAEs) and, auditory brainstem responses (ABRs) were also obtained. Subjects 1 (35delG/35delG) and 3 (M34T/wt) had profound hearing loss and showed the picture of auditory neuropathy (AN) as DPOAEs were detected with absent ABRs in both ears. The hearing impairment found in subject 2 (35delG/35delG) was profound in the right ear and moderate in the left ear. Both DPOAEs and ABRs with normal latencies and morphology were recorded only from the left ear. On the ECochG recording the cochlear microphonic was obtained from all children. No compound action potential (CAP) was detected in subject 1. A neural response was recorded only from the left ear in subject 2 with a threshold corresponding to the audiometric threshold while no CAP was detected on the right side. The ECochG obtained from subject 3 showed a low-amplitude broad negative deflection which was identifiable down to low stimulus levels. This response decreased in amplitude and duration when utilizing a high-rate stimulation paradigm. The amount of amplitude reduction was close to that calculated for normal ears, thus revealing the presence of an adapting neural component. These findings indicate that patients with GJB2 mutations and preserved outer hair cells function could present with the picture of AN. The hearing impairment is underlain by a selective inner hair cell loss or a lesion involving the synapses and/or the auditory nerve terminals. We suggest that neonatal hyperbilirubinemia may play a role in protecting outer hair cells against the damage induced by GJB2 mutations. PMID- 17701048 TI - Impaired exercise ventilatory mechanics with the self-contained breathing apparatus are improved with heliox. AB - The effect of the self-contained breathing apparatus (SCBA) with compressed air (BA-A) on ventilatory mechanics, work of breathing (WOB), pulmonary function, and respiratory muscle fatigue, was compared with that of a low resistance breathing valve (LRV). Further, the effect of unloading the respiratory muscles with heliox with the SCBA (BA-H) was compared with BA-A and LRV. Twelve men completed three randomized exercise trials on separate days, each consisting of three 10 min bouts of stepping exercise (Bouts 1, 2, and 3) separated by a 5 min recovery. Subjects wore firefighter protective equipment including the SCBA. At rest, FEV(1) and peak expiratory flow rates were lower with BA-A than with LRV, but were higher with BA-H than either with BA-A or LRV. After Bout 3, expiratory reserve volume, expiratory resistive WOB, and inspiratory elastic WOB were increased in BA-A compared to LRV but these were lower with BA-H compared to BA A. After Bout 3, maximal inspiratory and expiratory pressures were reduced with BA-A, but not with LRV or BA-H. In summary, we found that the SCBA reduced resting pulmonary function, and increased expiratory reserve volume, work of breathing, and respiratory muscle fatigue during stepping exercise, and these changes can be reduced with the use of heliox. PMID- 17701049 TI - Do age and baseline LDL cholesterol levels determine the effect of regular exercise on plasma lipoprotein cholesterol and apolipoprotein B levels? AB - Apolipoprotein B (apoB) concentration and age are independently associated with an increased risk for cardiovascular disease. Age is also associated with increased apoB concentration. The purpose of this study was to determine the effects of exercise on apoB and examine the association between age and lipoproteins. Forty-one sedentary individuals exercised for 6 months, four times/week for 40 min between 60 and 85% of their maximal heart rate. Lipids were determined three times: before training, 24 and 72 h after the last training session. Exercise did not alter apoB (1.2+/-0.05 g/l vs. 1.2+/-0.05 g/l; P>0.05), or other lipids or lipoproteins. When participants were sequestered by baseline low density lipoprotein cholesterol (LDLc), total cholesterol (TC) was decreased at 24 h post (6.3+/-0.2 mmol/l vs. 6.0+/-0.2 mmol/l, P<0.05) and LDLc after 24 and 48 h post (4.3+/-0.1 mg/dl vs. 3.9+/-0.1 and 4.1+/-0.2 mg/dl, P<0.05) in the high LDLc group. In the low LDLc group both TC (4.4+/-0.2 mmol/l vs. 4.6+/-0.2 and 4.6+/-0.2 mmol/l, P>0.05) and LDLc (2.6+/-0.1 mmol/l vs. 2.8+/-0.1 and 2.8+/ 0.2 mmol/l, P<0.05) were elevated at 24 h and remained elevated at 72 h post compared to baseline. Age does not affect apoB or lipoproteins in response to exercise. Individuals with high baseline LDLc experienced acute reduction in TC and LDLc produced by each exercise session. PMID- 17701050 TI - Organization and regulation of sex-specific thioredoxin encoding genes in the genus Drosophila. AB - Thioredoxins are small thiol proteins that have a conserved active site sequence, WCGPC, and reduce disulfide bonds in various proteins using the two active site cysteines, a reaction that oxidizes thioredoxin and renders it inactive. Thioredoxin reductase returns thioredoxin to its reduced, active form in a reaction that converts NADPH to NADP(+). The biological functions of thioredoxins vary widely; they have roles in oxidative stress protection, act as electron donors for ribonucleotide reductase, and form structural components of enzymes. To date, three thioredoxin genes have been characterized in Drosophila melanogaster: the generally expressed Thioredoxin-2 (Trx-2) and the two sex specific genes ThioredoxinT (TrxT) and deadhead (dhd). The male-specific TrxT and the female-specific dhd are located as a gene pair, transcribed in opposite directions, with only 470 bp between their transcription start points. We show in this study that all three D. melanogaster thioredoxins are conserved in 11 other Drosophilid species, which are believed to have diverged up to 40 Ma ago and that Trx-2 is conserved all the way to Tribolium castaneum. We have found that the intriguing gene organization and regulation of TrxT and dhd is remarkably well conserved and identified potential conserved regulatory sequences. In addition, we show that the 50-70 C terminal amino acids of TrxT constitute a hyper-variable domain, which could play a role in sexual conflict and male-female co-evolution. PMID- 17701051 TI - Mutation analysis of gastrointestinal stromal tumors: increasing significance for risk assessment and effective targeted therapy. AB - Molecular characterization of gastrointestinal stromal tumors (GISTs) plays an increasing role not only for the patient's prognosis but also for treatment options and in the context of resistance to therapy. Several mutational subtypes in KIT or platelet-derived growth factor receptor-alpha (PDGFRalpha) have been identified to be correlated with a different clinical behavior of GISTs. In KIT exon 11, deletions in the proximal part are associated with a high metastatic risk, whereas duplications in the distal part lead to a less aggressive phenotype. GISTs of the small bowel with a duplication in KIT exon 9 are often high risk tumors. In contrast, PDGFRalpha exon 18 mutated GISTs tend to have a low malignant potential. The authors suggest to include these molecular data together with classical parameters such as mitotic count and tumor size into the risk assessment of GISTs. The first choice for treatment of GISTs is still the surgical resection. In advanced tumors, which cannot be R0 resected, the neoadjuvant treatment with the tyrosine kinase inhibitor imatinib is now well established. Furthermore, an adjuvant treatment of locally R0-resected intermediate and high risk tumors is evaluated in several international clinical trials. For metastatic disease, treatment with imatinib is still the first option, but with new upcoming substances, the molecular characterization of GISTs may become mandatory. Very recently, it has been shown that sunitinib may be especially effective in GISTs with KIT exon 9 mutation, whereas these tumors show only an intermediate response to imatinib. A European Organisation for Research and Treatment of Cancer clinical trial randomizing patients according to their mutational status is under preparation. Secondary resistance to imatinib treatment is increasing, at least partly due to secondary mutations in the tyrosine kinase domain of the KIT receptor. Once a lesion has been shown to carry such a mutation, the local excision may be useful, mean while still responding metastases are further controlled by continuing imatinib. Taken together, the molecular characterization of GISTs turns out to play a central role before and during the treatment with tyrosine kinase inhibitors, which have improved the treatment of GIST patients dramatically. PMID- 17701052 TI - Molecular analysis in combination with iodine staining may contribute to the risk prediction of esophageal squamous cell carcinoma. AB - PURPOSE: Mucosal iodine staining has improved the detection of precancerous lesions of the esophagus. However, this method is unable to exactly evaluate the risk status of the lesions. In the present study, we conducted a molecular analysis combining the iodine staining in esophageal squamous cell carcinomas (ESCC) and different premalignant lesions of the esophagus in order to improve the early diagnosis of ESCC. METHODS: Tumorous and precancerous lesions were procured as iodine-unstained areas in the resected specimens of ESCC patients by means of Lugol's iodine staining. Loss of heterozygosity (LOH) was detected with 35 microsatellite markers frequently reported to be deleted in ESCC. The markers with high frequency of LOH in tumorous and precancerous lesions of the same patient were subjected to further detection in iodine-unstained biopsy samples from the population screening in ESCC high-incidence region. RESULTS: Common alterations were observed at D3S3644, D3S1768, D3S3040, D3S4542, RPL14, D9S169, D13S171 and D13S263 in both cancer tissues and precancerous lesions around tumors. Interestingly, D3S3644, D3S1768, D3S3040, D3S4542, RPL14 and D13S263 were also found with high frequency of LOH in iodine-staining abnormal lesions from the population screening. Most importantly, LOH frequency increased with histological severity. CONCLUSION: Our data suggest that detection of these six markers in combination with iodine staining might contribute to the prediction for the risk of ESCC development and for the diagnosis of patients in preclinical and preneoplastic phase of the disease. PMID- 17701053 TI - Clinical and histologic evaluations of experimental Acanthamoeba keratitis. AB - Amoebic keratitis, a sight-threatening, progressive corneal disease, is commonly caused by ubiquitous, pathogenic, free-living Acanthamoeba spp., which are widely distributed in the environment. We investigated clinical findings and histology of Acanthamoeba keratitis in a rat cornea model. Experimental Acanthamoeba keratitis was induced in Wistar rats by intrastromal inoculation of Acanthamoeba castellanii trophozoites. The clinic features of Acanthamoeba keratitis by day 70 are observed. All rats inoculated with Acanthamoeba developed keratitis. Histologically, the eyes displayed blood vessels, edema, and amoebae in stroma. A mixed cellular response, including neutrophils, mononuclear cells, and spindle shaped cells, was seen. In conclusion, progressive, suppurative Acanthamoeba keratitis can be induced in the rat cornea model. This rat cornea model assists researchers who study the pathogenesis of Acanthamoeba keratitis and devise treatment for this difficult condition. PMID- 17701054 TI - Interaction between the UCP2-866G/A, mtDNA 10398G/A and PGC1alpha p.Thr394Thr and p.Gly482Ser polymorphisms in type 2 diabetes susceptibility in North Indian population. AB - In the recent past, we have observed a possible role of 10398A and 16189C mtDNA and PGC1alpha p.Thr394Thr (rs2970847) and p.Gly482Ser (rs8192673) variant genotypes providing susceptibility/protection against type 2 diabetes mellitus (T2DM) in two North Indian population groups. These initial observations encouraged us to look at the candidate genes in combination with -866G/A (rs659366) polymorphism in uncoupling protein 2 (UCP2) in a single study of a relatively large sample size, constituted of both the cohorts, to unravel an interesting outcome of an additive interaction in-between the studied genes. In a total of 1,686 individuals (762 cases and 924 controls) belonging to Indo European linguistic group from North India, a comparison of risk genotype combinations of: UCP2-866GG, mtDNA 10398A and PGC1alpha p.Thr394Thr or p.Gly482Ser against the protective genotypes: UCP2-866XA, mtDNA 10398G and PGC1alpha p.Thr394Thr (nominal P value = 1.75 x 10(-14), Odds ratio, OR = 5.29, 3.40-8.22 at 95% CI) or PGC1alpha p.Gly482Ser (nominal p value = 4.42 x 10(-24), OR = 8.59, 5.53-13.35 at 95% CI), showed a highly significant difference and increased ORs. In a complex disease, it is always encouraging to find an additive interaction of multiple small effects of the studied candidate gene variations. PMID- 17701055 TI - Impact of melatonin receptors on pCREB and clock-gene protein levels in the murine retina. AB - In several mammalian species, the retina is capable of synthesizing melatonin and contains an autonomous circadian clock that relies on interlocking transcriptional/translational feedback loops involving several clock genes, such as Per1 and Cry2. Our previous investigations have shown remarkable differences in retinae of melatonin-deficient (C57BL) and melatonin-proficient (C3H) mice with regard to the protein levels of PER1, CRY2, and phosphorylated (p) cyclic AMP response element binding protein (CREB). To elucidate the melatonin receptor type possibly responsible for these differences, we have performed immunocytochemical analyses for PER1, CRY2, and pCREB in retinae of melatonin proficient wild type (WT) mice and mice with targeted deletions of the MT1 receptor (MelaaBB) or the MT1 and MT2 receptors (Melaabb) at four different time points. Immunoreactions for PER1, CRY2 and pCREB were localized to the nuclei of cells in the inner nuclear layer (INL) and ganglion cell layer (GC) of all strains. Surprisingly, in MelaaBB and Melaabb the day/night rhythm of pCREB, PER1, and CRY2 levels was not abolished, but the maxima and minima of PER1 were 180 degrees out of phase as compared to the WT. These data suggest that MT1 and MT2 melatonin receptors are not necessary to maintain rhythmic changes in clock gene protein levels in the murine retina, but, as shown for PER1, appear to be involved in internal synchronization. PMID- 17701056 TI - Characterization and tissue-specific expression of phosphatidylcholine transfer protein gene from amphioxus Branchiostoma belcheri. AB - An amphioxus cDNA, encoding phosphatidylcholine transfer protein (AmphiPCTP), was identified for the first time from the gut cDNA library of Branchiostoma belcheri. It contains a 660-bp open reading frame corresponding to a deduced protein of 219 amino acids. Phylogenetic tree analysis showed that AmphiPCTP clustered with PCTP subgroup of PCTP subfamily containing steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domains. AmphiPCTP had an exon-intron organization similar to that of human and rat PCTP genes in terms of both exon number and sequence homology of each exon, suggesting that PCTP has probably maintained a similar function in both amphioxus and mammalian species. Both in situ hybridization histochemistry and whole-mount in situ hybridization revealed a tissue-specific expression pattern of AmphiPCTP with the high levels in the hepatic caecum and primitive gut, including the region where the hepatic caecum will form later during development. This apparently agrees with the hypothesis that amphioxus hepatic caecum is equivalent to vertebrate liver. These results suggest a conserved role of PCTPs in amphioxus as well as mammalian species. PMID- 17701057 TI - Induction of claudins in passaged hTERT-transfected human nasal epithelial cells with an extended life span. AB - The epithelial barrier of the upper respiratory tract, such as that of the nasal mucosa, plays a crucial role in host defense. The epithelial barrier is regulated in large part by the apical-most intercellular junctions, referred to as tight junctions. However, the mechanisms regulating of tight junction barrier in human nasal epithelial cells remain unclear because the proliferation and storage of epithelial cells in primary cultures are limited. In the present study, we introduced the catalytic component of telomerase, the hTERT gene, into primary cultured human nasal epithelial cells and examined the properties of the transfectants, including their expression of tight junctions, compared with primary cultures. The ectopic expression of hTERT in the epithelial cells resulted in adequate growth potential and a longer lifespan of the cells. The properties of the passaged hTERT-transfected cells including tight junctions were similar to those of the cells in primary cultures. The barrier function in the transfectants after treatment with 10% FBS was significantly enhanced with increases of integral tight junction proteins claudin-1 and -4. When the transfectants were treated with TGF-beta, which is assosciated with nasal polyposis and chronic rhinosinusitis, upregulation of only claudin-4 was observed, without a change of barrier function. In human nasal epithelial cells, the claudins may be important for barrier function and a novel target for a drug delivery system. Our results indicate that hTERT-transfected human nasal epithelial cells with an extended lifespan can be used as an indispensable and stable model for studying the regulation of claudins in human nasal epithelium. PMID- 17701058 TI - Current achievements in the production of complex biopharmaceuticals with moss bioreactors. AB - Transgenic plants are promising alternatives for the low-cost and safe pathogen free production of complex recombinant pharmaceutical proteins (molecular farming). Plants as higher eukaryotes perform posttranslational modifications similar to those of mammalian cells. However, plant-specific protein N glycosylation was shown to be immunogenic, a fact that represents a drawback for many plant systems in biopharmaceutical production. The moss Physcomitrella patens offers unique properties as a contained system for protein production. It is grown in the predominant haploid gametophytic stage as tissue suspension cultures in photobioreactors. Efficient secretory signals and a transient transfection system allow the secretion of freshly synthesized proteins to the surrounding medium. The key advantage of Physcomitrella compared to other plant systems is the feasibility of targeted gene replacements. By this means, moss strains with non-immunogenic humanized glycan patterns were created. Here we present an overview of the relevant aspects for establishing moss as a production system for recombinant biopharmaceuticals. PMID- 17701059 TI - Diagnosis and management of hyponatremia in cancer patients. AB - BACKGROUND: Hyponatremia is among the metabolic disturbances encountered in oncology. Risk factors for hyponatremia include chemotherapy, treatment-induced nausea and vomiting, hydration, pain, narcotic drugs, and physical and emotional stress. A common cause of hyponatremia in patients with cancer is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), which may result from ectopic production of arginine vasopressin (AVP) by the tumor tissue. TREATMENT: The AVP-receptor antagonists, a new class of agents, correct hyponatremia by directly blocking the binding of AVP with its receptors. In clinical trials, conivaptan, lixivaptan, tolvaptan, and satavaptan have increased serum osmolality and normalized the serum [Na(+)] in hyponatremia associated with SIADH, cirrhosis, or congestive heart failure. These drugs may have a potential in cancer-related hyponatremia as well. PMID- 17701060 TI - The impact of surgical wait time on patient-based outcomes in posterior lumbar spinal surgery. AB - A prospective observational study was conducted on patients undergoing posterior lumbar spine surgery for degenerative spinal disorders. The study purpose was to evaluate the effect of wait time to surgery on patient derived generic and disease specific functional outcome following surgery. A prolonged wait to surgery may adversely affect surgical outcome. Although there is literature on the effect of wait time to surgery in surgical fields such as oncology, cardiac, opthamologic, and total joint arthroplasty, little is known regarding the effect of wait time to surgery as it pertains to the spinal surgical population. Consecutive patients undergoing elective posterior lumbar spinal surgery for degenerative disorders were recruited. Short-Form 36 and Oswestry disability questionnaires were administered (pre-operatively, and at 6 weeks, 6 months, and 1 year post-operatively). Patients completed a questionnaire regarding their experience with the wait time to surgery. The study cohort consisted of 70 patients with follow-up in 53/70 (76%). Time intervals from the onset of patient symptoms to initial consultation by family physician through investigations, spinal surgical consultation and surgery were quantified. Time intervals were compared to patient specific improvements in reported outcome following surgery using Cox Regression analysis. The effect of patient and surgical parameters on wait time was evaluated using the median time as a reference for those patients who had either a longer or shorter wait. Significant improvements in patient derived outcome were observed comparing post-operative to pre-operative baseline scores. The greatest improvements were observed in aspects relating to physical function and pain. A longer wait to surgery was associated with less improvement in outcome following surgery (SF-36 domains of BP, GH, RP, VT). A longer wait time to surgery negatively influences the results of posterior lumbar spinal surgery for degenerative conditions as quantified by patient derived functional outcome measures. The parameters of pain severity and physical aspects of function appear to be the most significantly affected. PMID- 17701061 TI - Theoretical investigation on the oxidative chlorination performed by a biomimetic non-heme iron catalyst. AB - The present study is a part of an effort to understand the mechanism of the oxidative chlorination, as performed by a biomimetic non-heme iron complex. This catalytically active complex is generated from a peroxide and [(TPA)Fe(III)Cl(2)]+ [TPA is tris(2-pyridylmethyl)amine]. The reaction catalyzed by [(TPA)FeCl(2)]+/ROOH involves either [(TPA)ClFe(V)=O](2+) or [(TPA)ClFe(IV)=O]+ as an intermediate. On the basis of density functional theory the reaction of these two possible catalysts with cyclohexane is investigated. A question addressed is how the competing hydroxylation of the substrate is avoided. It is demonstrated that the high-valent iron complex [(TPA)Cl Fe(V)=O](2+) is capable of stereospecific alkane chlorination, based on an ionic rather than on a radical pathway. In contrast, the results found for [(TPA)ClFe(IV)=O]+ cannot explain the experimental findings. In this case the transition states for chlorination and hydroxylation are energetically too close. The exclusive chlorination of the substrate by Cl-Fe(IV)=O may be explained by an indirect or a direct effect, altering the position of the competing rebound barriers. PMID- 17701062 TI - Characterization of Shewanella oneidensis MtrC: a cell-surface decaheme cytochrome involved in respiratory electron transport to extracellular electron acceptors. AB - MtrC is a decaheme c-type cytochrome associated with the outer cell membrane of Fe(III)-respiring species of the Shewanella genus. It is proposed to play a role in anaerobic respiration by mediating electron transfer to extracellular mineral oxides that can serve as terminal electron acceptors. The present work presents the first spectropotentiometric and voltammetric characterization of MtrC, using protein purified from Shewanella oneidensis MR-1. Potentiometric titrations, monitored by UV-vis absorption and electron paramagnetic resonance (EPR) spectroscopy, reveal that the hemes within MtrC titrate over a broad potential range spanning between approximately +100 and approximately -500 mV (vs. the standard hydrogen electrode). Across this potential window the UV-vis absorption spectra are characteristic of low-spin c-type hemes and the EPR spectra reveal broad, complex features that suggest the presence of magnetically spin-coupled low-spin c-hemes. Non-catalytic protein film voltammetry of MtrC demonstrates reversible electrochemistry over a potential window similar to that disclosed spectroscopically. The voltammetry also allows definition of kinetic properties of MtrC in direct electron exchange with a solid electrode surface and during reduction of a model Fe(III) substrate. Taken together, the data provide quantitative information on the potential domain in which MtrC can operate. PMID- 17701063 TI - Impact of multi-drug-resistant Acinetobacter baumannii on clinical outcomes. AB - We conducted a retrospective matched cohort study to examine the impact of isolation of multi-drug-resistant (MDR) Acinetobacter baumannii on patient outcomes. Cases from whom MDR A. baumannii was isolated in a clinical culture (n = 118) were compared with controls from whom MDR A. baumannii was not isolated (n = 118). Cases and controls were matched according to ward, calendar month of hospitalization, and duration of hospitalization before culture. The following outcomes were compared in multivariable analysis: in-hospital mortality, length of stay, need for mechanical ventilation, and functional status at discharge. MDR A. baumannii was determined to be a pathogen in 72% of cases. In 36% of cases, the patient died, versus 21% of controls (odds ratio [OR] 2.21, 95% confidence interval [CI] 1.17-4.16, P = 0.014). Median length of stay for surviving cases was 17 days, versus 11 for surviving controls (multiplicative effect 1.55, 95% CI 0.99-2.44, P = 0.057). Fifty-two percent of cases required mechanical ventilation, versus 25% of controls (OR 3.72, 95% CI 1.91-7.25, P<0.001); 60% of surviving cases were discharged with reduced functional status, versus 38% of controls (OR 4.4, 95% CI 1.66-11.61, P = 0.003). In multivariable analysis, clinical isolation of MDR A. baumannii remained a significant predictor of mortality (OR 6.23, 95% CI 1.31-29.5, P = 0.021), need for mechanical ventilation (OR 7.34, 95% CI 2.24-24.0, P<0.001), and reduced functional status on discharge (OR 7.93, 95% CI 1.1-56.85, P = 0.039). Thus, MDR A. baumannii acquisition is associated with severe adverse outcomes, including increased mortality, need for mechanical ventilation, and reduced functional status. PMID- 17701064 TI - A theoretically-motivated biaxial tissue culture system with intravital microscopy. AB - Many cell types produce, remodel, and degrade extracellular matrix in response to diverse stimuli, including mechanical loads. Much is known about the molecular biology and biochemistry of the deposition and degradation of collagen, the primary structural constituent of the extracellular matrix in many tissues, yet there has been little modeling of the associated mechanobiology. For example, we do not have quantitative descriptions, or rules, for the kinetics of collagen turnover as a function of altered mechanical loading and we do not know what governs the orientation and pre-stretch at which new fibers are incorporated within extant tissue. In this paper, we use a constrained mixture theory for growth and remodeling of planar soft tissues to motivate a new experimental approach for investigating competing hypotheses on, for example, how new collagen is aligned by synthetic cells. In particular, because stress and strain fields can be homogeneous in a central region of a biaxially tested tissue, and because biaxial testing admits diverse protocols wherein equal stresses can be imposed in the presence of unequal strains or stresses can be maintained in the absence of strain, we report simulations that illustrate the potential utility of biaxial culture studies. Finally, we describe the associated design of a computer controlled system that allows intravital microscopic quantification of collagen density, orientation, and cross-linking at various stages during the adaptation of a native tissue or the development of a tissue engineered equivalent, each subjected to well controlled biaxial loads. PMID- 17701065 TI - Synergistic antiproliferative effects of gamma-tocotrienol and statin treatment on mammary tumor cells. AB - Statins are potent inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase and display anticancer activity, but their clinical use is limited by their high-dose toxicity. Similarly, gamma-tocotrienol, an isoform of vitamin E, also reduces HMGCoA reductase activity and displays potent anticancer activity. Studies were conducted to determine if combined low dose treatment of gamma tocotrienol with individual statins resulted in a synergistic antiproliferative effect on neoplastic mouse +SA mammary epithelial cells. Treatment with 3-4 microM gamma-tocotrienol or 2-8 microM simvastatin, lovastatin or mevastatin alone resulted in a significant decrease, whereas treatment with 10-100 microM pravastatin had no effect on +SA cell growth. However, combined treatment of subeffective doses (0.25 or 10 microM) of individual statins with 0.25-2.0 microM gamma-tocotrienol resulted in a dose-responsive synergistic inhibition in +SA cell proliferation. Additional studies showed that treatment with subeffective doses of individual statins or gamma-tocotrienol alone had no effect, whereas combined treatment of these compounds resulted in a relatively large decrease in intracellular levels of phosphorylated (activated) MAPK, JNK, p38, and Akt. These findings strongly suggest that combined low dose treatment of gamma-tocotrienol with individual statins may have potential value in the treatment of breast cancer without causing myotoxicity that is associated with high dose statin treatment. PMID- 17701066 TI - [Medical classification--the benefit of obligation]. PMID- 17701069 TI - BRISC-an open source pulmonary nodule image retrieval framework. AB - We have created a content-based image retrieval framework for computed tomography images of pulmonary nodules. When presented with a nodule image, the system retrieves images of similar nodules from a collection prepared by the Lung Image Database Consortium (LIDC). The system (1) extracts images of individual nodules from the LIDC collection based on LIDC expert annotations, (2) stores the extracted data in a flat XML database, (3) calculates a set of quantitative descriptors for each nodule that provide a high-level characterization of its texture, and (4) uses various measures to determine the similarity of two nodules and perform queries on a selected query nodule. Using our framework, we compared three feature extraction methods: Haralick co-occurrence, Gabor filters, and Markov random fields. Gabor and Markov descriptors perform better at retrieving similar nodules than do Haralick co-occurrence techniques, with best retrieval precisions in excess of 88%. Because the software we have developed and the reference images are both open source and publicly available they may be incorporated into both commercial and academic imaging workstations and extended by others in their research. PMID- 17701070 TI - Repeat transanal advancement flap repair: impact on the overall healing rate of high transsphincteric fistulas and on fecal continence. AB - PURPOSE: Transanal advancement flap repair (TAFR) has been advocated as the treatment of choice for transsphincteric fistulas passing through the upper or middle third of the external anal sphincter. It is not clear whether previous attempts at repair adversely affect the outcome of TAFR. The purpose of the present study was to evaluate the success rate of a repeat TAFR and to assess the impact of such a second procedure on the overall healing rate of high transsphincteric fistulas and on fecal continence. METHODS: Between January 2001 and January 2005, a consecutive series of 87 patients (62 males; median age, 49 (range, 27-73) years) underwent TAFR. Median follow-up was 15 (range, 2-50) months. Patients in whom the initial operation failed were offered two further treatment options: a second flap repair or a long-term indwelling seton drainage. Twenty-six patients (male:female ratio, 5:2; median age, 51 (range, 31-72) years) preferred a repeat repair. Continence status was evaluated before and after the procedures by using the Rockwood Faecal Incontinence Severity Index (RFISI). RESULTS: The healing rate after the first TAFR was 67 percent. Of the 29 patients in whom the initial procedure failed, 26 underwent a repeat TAFR. The healing rate after this second procedure was 69 percent, resulting in an overall success rate of 90 percent. Both before and after the first attempt of TAFR, the median RFISI was 7 (range, 0-34). In patients who underwent a second TAFR, the median RFISI before and after this procedure was 9 (range, 0-34) and 8 (range, 0-34), respectively. None of these changes were statistically significant. CONCLUSIONS: Repeat TAFR increases the overall healing rate of high transsphincteric fistulas from 67 percent after one attempt to 90 percent after two attempts without a deteriorating effect on fecal continence. PMID- 17701071 TI - A mixed-methods evaluation of health-related quality of life for male veterans with and without intestinal stomas. AB - PURPOSE: Intestinal stomas have a major impact on Cases' lives. It is essential to better understand the areas in which interventions may help to minimize the negative consequences. METHODS: This was a case-control survey study using validated instruments (City of Hope Quality of Life-Ostomy and Short Form 36 for Veterans). Cases were accrued from Veterans Affairs Medical Centers in Tucson, Indianapolis, and Los Angeles. Eligibility included a major intra-abdominal surgical procedure that led to an ostomy (cases), or a similar procedure that did not mandate a stoma (controls). Analysis included quantitative and qualitative responses. RESULTS: The response rate was 48 percent (511/1,063). Cases and controls had relatively similar demographic characteristics. Because of low numbers of female respondents (13 cases and 11 controls), only results for males are reported. Based on both the City of Hope Quality of Life-Ostomy and Short Form 36 for Veterans, cases reported significantly poorer scores on scales/domains reflecting psychologic and social functioning and well being. Additionally, cases reported poorer scores on Short Form 36 for Veterans scales reflecting physical functioning and significantly lower scores on multiple items in the social domain of the City of Hope Quality of Life-Ostomy compared with controls. Two-thirds of cases replied to an open-ended question on their "greatest challenge" related to their ostomy, which led to further clarification of major issues. CONCLUSIONS: Multiple health-related quality of life problems were reported by male veterans with intestinal stomas. The greatest differences between cases and controls were observed in the social and psychologic domains/scales. Findings from this study provide a greater understanding of the challenges faced by ostomates and will inform the development and evaluation of urgently needed intervention strategies. PMID- 17701072 TI - Assessment of dietary intake and trace element status in patients with ileal pouch-anal anastomosis. AB - PURPOSE: Panproctocolectomy and ileal pouch-anal anastomosis is the operation of choice for patients with ulcerative colitis and familial polyposis. The long-term nutritional consequences after pouch surgery are unknown. We have assessed the nutritional status of the essential trace elements-zinc, copper, manganese, and selenium-in patients several years (median, 10 (range, 2-15) years) after surgery. METHODS: Fifty-five patients with uncomplicated ileal pouch-anal anastomosis and 46 healthy control subjects were studied. A dietary assessment of trace element intake was undertaken by using a semiquantitative food frequency questionnaire. The patients' trace elements status for zinc, copper, manganese, and selenium was assessed by measuring their concentrations in blood. RESULTS: The dietary intake of individual trace elements was similar in both groups (all P values > 0.4). There was no significant difference in the concentrations of plasma copper, zinc, and selenium between patients and healthy control subjects (all P values > 0.07). The concentration of whole blood manganese was significantly higher (P = 0.004) in patients (median, 178.5 nmol/l; range, 59-478 nmol/l) compared with healthy control subjects (median, 140 nmol/l; range, 53-267 nmol/l). Four (7 percent) patients had manganese concentrations more than three standard deviations of the mean of control group (>255 nmol/l). CONCLUSIONS: This study shows that patients who have had uncomplicated pouch surgery have a normal dietary intake of trace elements and do not develop deficiencies in copper, zinc, manganese, and selenium. However, these patients may be at increased risk of manganese toxicity. PMID- 17701073 TI - Multimedia article. Anovaginal reconstruction with bilateral x-flaps and sphincteroplasty for cloaca-like deformity after obstetrical injury. AB - PURPOSE: Up to 0.3 percent of complicated vaginal deliveries may result in a cloaca-like deformity with debilitating incontinence and symptoms similar to a rectovaginal fistula because of the lack of the distal rectovaginal septum. This video illustrates the surgical technique of an anovaginal and perineal reconstruction with X-flaps and sphincteroplasty without primary fecal diversion. METHODS: The patients are placed in prone jackknife position. The flaps are marked with a pen. The junction/contact zone between rectal and vaginal mucosa is incised and the septum dissected up to the puborectalis muscle. The X-flaps are mobilized bilaterally. The posterior wall of the vagina and the anterior wall of the anal canal are then reconstructed with two suture layers each. Subsequently, an overlapping sphincteroplasty is performed and the puborectalis muscle centrally approximated. The flaps are then transposed beyond the midline to rebuild a perineal body. For all deeper reconstruction steps, 2/0 polyglactin 910 sutures (Vicryl, Ethicon Inc., Somerville, NJ) are used; the skin is closed with running subcuticular sutures of poliglecaprone 25 (Monocryl, Ethicon Inc.). In the end, the patient has regained a circumferentially proper length of the anal canal and the vagina, a closed ring of the anal sphincter, and a reconstructed perineal body with separation of anus and vagina. CONCLUSIONS: Cloaca-like deformity resulting from severe obstetrical injury is the worst and most debilitating form of sphincter injuries but often is not given appropriate attention. Reconstruction of the original anatomy is more complex than a simple sphincteroplasty, but a prophylactic fecal diversion is usually not necessary. The reseparation of the rectum and the vagina in conjunction with a sphincteroplasty achieves good results. PMID- 17701074 TI - Remote renal injury following partial hepatic ischemia/reperfusion injury in rats. AB - Liver ischemia/reperfusion has been shown to result in injury of remote organs such as the heart and lungs. Whether or not acute liver injury also results in kidney injury has so far not been adequately addressed. In anesthetized Wistar rats, partial (70%) normothermic hepatic ischemia was applied for 75 min. After 24 h of reperfusion, renal injury was assessed by histology, creatinine and blood urea nitrogen (BUN) serum concentrations, renal expression of proinflammatory genes [quantitative real-time polymerase chain reaction (qRT-PCR)], caspase-3 activation (Western blot), and neutrophil accumulation (myeloperoxidase assay). Twenty-four hours after hepatic ischemia, creatinine (0.57+/-0.06 vs. 0.32+/-0.04 mg/dL) and BUN (40.7+/-15.3 vs. 14.3+/-2.0 mg/dL) were increased when compared to sham. qRT-PCR revealed higher renal intercellular adhesion molecule-1 gene expression following hepatic ischemia (166+/-45% when compared to sham) but no differences in renal monocyte chemoattractant protein-1, macrophage inflammatory protein-2, and inducible NO synthase expression. In both groups, kidneys showed no morphological damage and no increase in caspase-3 and myeloperoxidase activity. Severe hepatic ischemia results in a moderate impairment of renal function in rats but does not trigger an inflammatory response in the kidney and does not result in morphological damage of the kidney. PMID- 17701075 TI - [Diabetes mellitus--guidelines for general practice. Revised and expanded 2007 edition]. PMID- 17701076 TI - 13C-detected NMR experiments for measuring chemical shifts and coupling constants in nucleic acid bases. AB - The paper presents a set of two-dimensional experiments that utilize direct (13)C detection to provide proton-carbon, carbon-carbon and carbon-nitrogen correlations in the bases of nucleic acids. The set includes a (13)C-detected proton-carbon correlation experiment for the measurement of (13)C-(13)C couplings, the CaCb experiment for correlating two quaternary carbons, the HCaCb experiment for the (13)C-(13)C correlations in cases where one of the carbons has a proton attached, the HCC-TOCSY experiment for correlating a proton with a network of coupled carbons, and a (13)C-detected (13)C-(15)N correlation experiment for detecting the nitrogen nuclei that cannot be detected via protons. The IPAP procedure is used for extracting the carbon-carbon couplings and/or carbon decoupling in the direct dimension, while the S(3)E procedure is preferred in the indirect dimension of the carbon-nitrogen experiment to obtain the value of the coupling constant. The experiments supply accurate values of (13)C and (15)N chemical shifts and carbon-carbon and carbon-nitrogen coupling constants. These values can help to reveal structural features of nucleic acids either directly or via induced changes when the sample is dissolved in oriented media. PMID- 17701077 TI - Prone position to treat bronchopleural fistula in post-operative acute lung injury. AB - OBJECTIVE: Prone position is used to treat patients with acute lung injury or acute respiratory distress syndrome because it improves gas exchange and respiratory mechanics. When broncho-pleural fistula occurring, the clinical impact of prone position is limited; however, its use could be tried when the fistula is small or other potential treatments are not possible. METHODS: A 45 year-old man with oesophageal cancer submitted to a total oesophagectomy with intrathoracic transposition of the stomach developed post-operatively respiratory failure and pneumothorax, which were worsened by unilateral pleural rupture and severe subcutaneous emphysema produced after an attempt to introduce through anterior chest wall a second drainage tube. RESULTS: Prone position associated with lung protective strategy was implemented during 16-18 h daily and after the change of position PaO2/FiO2 increased of 35% and PaCO2-PetCO2 decreased about 40%; at 4th day under treatment, the subcutaneous emphysema and pneumothorax could not be detected either clinically or radiologically. On the 6th day the lung lesion could not be observed under the CT-scan. CONCLUSIONS: In a patient that underwent a major thoracic surgery the addition of prone positioning to protective lung ventilation rendered possible not only the healing of the acute lung injury, but also the quick repair of a lung rupture owing to a thoracic drainage attempt. PMID- 17701078 TI - Hesperetin attenuates the highly reducing sugar-triggered inhibition of osteoblast differentiation. AB - Diabetic bone disease is associated with increased oxidative damage and 2-deoxy D: -ribose (dRib) is used to induce oxidative damage similar to that observed in diabetics. To determine if hesperetin (3',5,7-trihydroxy-4-methoxyflavanone) could influence osteoblast dysfunction induced by dRib, osteoblastic MC3T3-E1 cells were treated with dRib and hesperetin. Then, markers of osteoblast function and oxidative damage were examined. Hesperetin (10(-7)-10(-5) M) caused a significant elevation of alkaline phosphatase (ALP) activity, collagen content, and total antioxidant potential of MC3T3-E1 cells in the presence of 20 mM dRib (p < 0.05). Moreover, hesperetin (10(-7) M) decreased cellular protein carbonyl (PCO), advanced oxidation protein products (AOPP), and malondialdehyde (MDA) contents of osteoblastic MC3T3-E1 cells in the presence of 20 mM dRib. These results demonstrate that hesperetin attenuates dRib-induced damage, suggesting that hesperetin may be a useful dietary supplement for minimizing oxidative injury in diabetes related bone diseases. PMID- 17701079 TI - Therapeutic management of copper deficiency in buffalo heifers: impact on immune function. AB - To evaluate the magnitude of copper deficiency in Northern India and to examine the various haematobiochemicals, enzymes, vitamins and immune functions affected by copper deficiency, and to identify the parameters which can be of diagnostic importance in copper deficiency, a survey was conducted in 12 districts of Northern India. Significant deficiency of copper was observed in soil, fodder and serum samples of buffalo heifers. Fifty hypocuperaemic buffalo heifers were selected from these areas and were randomly divided into two groups, A and B. The heifers in group A were provided with mineral mixture containing copper sulphate and in group B without copper sulphate. Significant (p<0.01) improvement in serum ceruloplasmin level was observed within 30 days of treatment, while significant (p<0.01) improvement in monoamine oxidase and liver cytochrome oxidase was observed at the 60th day of treatment in group A animals. Significant improvement was observed in T(3) and T(4), in the animals of group A within 60 days of treatment. The values of vitamin A and E showed significant (p<0.01) improvement within 30 days of treatment. The phagocytic activity of neutrophils against Candida albicans significantly (p<0.01) improved in group A within 60 days of treatment. Similarly, significant improvement in superoxide dismutase activity in red blood cells was observed at the 30th day, and in total leukocytes and whole blood at the 60th day in group A animals. Significant improvement in liver copper level was observed at the 30th day of treatment, while in group B the liver copper was significantly (p<0.01) depleted at the 60th day of experimentation. Additional copper supplementation improved growth performance significantly in group A. PMID- 17701080 TI - Genetically modified crops for the bioeconomy: meeting public and regulatory expectations. AB - As the United States moves toward a plant-based bioeconomy, a large research and development effort is focused on creating new feedstocks to meet biomass demand for biofuels, bioenergy, and specialized bioproducts, such as industrial compounds and biomaterial precursors. Most bioeconomy projections assume the widespread deployment of novel feedstocks developed through the use of modern molecular breeding techniques, but rarely consider the challenges involved with the use of genetically modified crops, which can include hurdles due to regulatory approvals, market adoption, and public acceptance. In this paper we consider the implications of various transgenic crops and traits under development for the bioeconomy that highlight these challenges. We believe that an awareness of the issues in crop and trait selection will allow developers to design crops with maximum stakeholder appeal and with the greatest potential for widespread adoption, while avoiding applications unlikely to meet regulatory approval or gain market and public acceptance. PMID- 17701081 TI - Recovery of transgenic plants by pollen-mediated transformation in Brassica juncea. AB - The aroA-M1 encoding the mutant of 5-enolpyruvyl-shikimate-3-phosphate synthase (EPSPS) was introduced into the Brassica juncea genome by sonication-assisted, pollen-mediated transformation. The plasmid DNA and collected pollen grains were mixed in 0.3 mol/L sucrose solution and treated with mild ultrasonication. The treated pollen was then pollinated onto the oilseed stigmas after the stamens were removed artificially. Putative transgenic plants were obtained by screening germinating seeds on a medium containing glyphosate. Southern blot analysis of glyphosate-resistant plants indicated that the aroA-M1 gene had been integrated into the oilseed genome. Western blot analysis further confirmed that the EPSPS coded by aroA-M1 gene was expressed in transgenic plants. The transgenic plants exhibited increased resistance to glyphosate compared to untransformed plants. Some of those transgenic plants had considerably high resistance to glyphosate. The genetic analysis of T1 progeny further confirmed that the inheritance of the introduced genes followed the Mendelian rules. The results indicated that foreign genes can be transferred by pollen-mediated transformation combined with mild ultrasonication. PMID- 17701082 TI - Implementation of a pharmaceutical care service: prescriptionists', pharmacists' and doctors' views. AB - OBJECTIVE: To identify prescriptionists', pharmacists' and doctors' perceptions and experiences of a pharmaceutical care service supported by patient medication records (PMRs). METHOD: Qualitative study employing focus group interviews with 16 prescriptionists and five pharmacists, and semi structured telephone interviews with 11 doctors. MAIN OUTCOME MEASURES: Prescriptionists', pharmacists' and doctors' views, experiences and perceptions of a pharmaceutical care service on Swedish community pharmacies. RESULTS: The provision of pharmaceutical care aided by PMRs had a positive influence on the prescriptionists' and pharmacists' daily work, and on their view of their professional role. They assumed greater professional responsibility, and described greater use of their pharmaceutical knowledge, greater confidence in practice and an increased awareness of their counselling role. They appreciated that the pharmaceutical care service provided an over-all picture of patients' drug use, allowed for follow-up on counselling and made the prescriptionists' and pharmacists' competence tangible for patients. Perceived problems with the pharmaceutical care service included being time-consuming, record keeping being difficult, difficulty in getting understanding/support from colleagues and managers, and difficulty involving doctors. The majority of the doctors reported that they had not taken an active interest in the project, and their opinions of the pharmaceutical care service varied. CONCLUSION: When prescriptionists and pharmacists apply the pharmaceutical care concept and work with PMRs, the patients are more likely to meet confident professionals that are more aware of the individual behind the drug therapy. This will hopefully contribute to informed, motivated medicine users that feel secure in their interactions with their pharmacy and receive, not only drugs, but treatment support. For such a service to be effective, however, it is vital to ensure that the doctors are fully co-operative. PMID- 17701084 TI - Photoproduction of hydrogen by sulfur-deprived C. reinhardtii mutants with impaired photosystem II photochemical activity. AB - Photoproduction of H2 was examined in a series of sulfur-deprived Chlamydomonas reinhardtii D1-R323 mutants with progressively impaired PSII photochemical activity. In the R323H, R323D, and R323E D1 mutants, replacement of arginine affects photosystem II (PSII) function, as demonstrated by progressive decreases in O2-evolving activity and loss of PSII photochemical activity. Significant changes in PSII activity were found when the arginine residue was replaced by negatively charged amino acid residues (R323D and R323E). However, the R323H (positively charged or neutral, depending on the ambient pH) mutant had minimal changes in PSII activity. The R323H, R323D, and R323E mutants and the pseudo-wild type (pWt) with restored PSII function were used to study the effects of sulfur deprivation on H2-production activity. All of these mutants exhibited significant changes in the normal parameters associated with the H2-photoproduction process, such as a shorter aerobic phase, lower accumulation of starch, a prolonged anaerobic phase observed before the onset of H2-production, a shorter duration of H2-production, lower H2 yields compared to the pWt control, and slightly higher production of dark fermentation products such as acetate and formate. The more compromised the PSII photochemical activity, the more dramatic was the effect of sulfur deprivation on the H2-production process, which depends both on the presence of residual PSII activity and the amount of stored starch. PMID- 17701086 TI - The hepatitis B virus protein MHBs(t) sensitizes hepatoma cells to TRAIL-induced apoptosis through ERK2. AB - The TNF-related apoptosis-inducing ligand (TRAIL) has recently been implicated in the death of hepatocytes under infectious but not normal conditions. Infectious agents, such as hepatitis B virus (HBV), may play important roles in regulating the sensitivity of hepatocytes to TRAIL. Our previous studies showed that HBx, a protein encoded by the HBV genome, enhanced TRAIL-induced apoptosis through upregulating Bax. We report here that another HBV protein called MHBs(t) (C terminally truncated middle hepatitis B surface protein) is also a potent regulator of TRAIL-induced apoptosis. Overexpressing MHBs(t) in hepatoma cells enhanced TRAIL-induced apoptosis. Mechanistic studies reveal that MHBs(t) had no effect on Bax or TRAIL receptor expression or procaspase-8 activation, but selectively enhanced the activation of ERK2 (extracellular signal-regulated kinase 2) and the degradation of procaspases-3 and 9. ERK2 activation is required for the MHBs(t) effect because ERK2 inhibition by its inhibitor PD98059 significantly reversed TRAIL-induced apoptosis of MHBs(t)-transfected cells. These results establish that unlike HBx, MHBs(t) enhances TRAIL-induced hepatocyte apoptosis through a novel mechanism that involves ERK2. Therefore, manipulating the ERK2 signaling pathway may provide new therapeutic opportunities to contain hepatic cell death during HBV infection. PMID- 17701087 TI - [Tolerance to perioperative anemia. Mechanisms, influencing factors and limits]. AB - The expected cost explosion in transfusion medicine increases the socio-economic significance of specific institutional transfusion programs. In this context the estimated use of the patient's physiologic tolerance represents an integral part of any blood conservation concept. The present article summarizes the mechanisms, influencing factors and limits of this natural tolerance to anemia and deduces the indication for perioperative red blood cell transfusion. The current recommendations coincide to the effect that perioperative transfusion is unnecessary up to a Hb concentration of 10 g/dl (6.21 mmol/l) even in older patients with cardiopulmonary comorbidity and is only recommended in cases of Hb <6 g/dl (<3.72 mmol/l) in otherwise healthy subjects including pregnant women and children. Critically ill patients with multiple trauma and sepsis do not seem to benefit from transfusions up to Hb concentrations >9 g/dl (>5.59 mmol/l). In cases of massive hemorrhaging and diffuse bleeding disorders the maintenance of a Hb concentration of 10 g/dl (6.21 mmol/l) seems to contribute to stabilization of coagulation. PMID- 17701088 TI - Arsenic status and distribution in soils at disused cattle dip in South Africa. AB - The status and the distribution of arsenic in soils from a disused cattle dip were determined. Elevated total arsenic levels (1,033-1,369 mg/L) were detected in the soils. Significant difference (p < 0.05) between the values for the soils obtained from the contaminated sites and control site (0.15 mg/L) was observed. The level of total arsenic decreased with increase in depth. The peak total arsenic (1,369 mg/L) was obtained at 0 cm depth, indicating the abundance of arsenic at the surface despite the fact that the dip has been out of use for a long time. The total arsenic recorded for different depths were significantly higher than the trigger value of 40 mg/kg. The distribution of arsenic in the different phases showed that arsenic was mostly bound to the residual fractions (52%) and Fe and Al hydroxides (21%). The distribution of arsenic in the order phases was in the following order: exchangeable (14%), carbonates (10%) and soluble (3%). PMID- 17701089 TI - Persistence of ethion residues on cucumber, Cucumis sativus (Linn.) using gas chromatography with nitrogen phosphorus detector. AB - Residues of ethion were estimated in cucumber by gas liquid chromatography following three applications of the insecticide at 375 and 750 g a.i ha(-1). The average initial deposits of ethion on cucumber fruits were found to be 2.40 and 4.97 mg kg(-1) at single and double dosages, respectively. Residues of ethion dissipated below the maximum residue limit (MRL) of 0.5 mg kg(-1) in 7 days. Half life (T1/2) for degradation of ethion on cucumber was observed to be 2.92 days at recommended dosage. A waiting period of 7 days is suggested for safe consumption of cucumber. PMID- 17701090 TI - Ecotoxicological quantitative structure-activity relationships for pharmaceuticals. AB - This paper examined active pharmaceutical ingredients (APIs) acute ecotoxicological modes of action (MOA). It was concluded that the vast majority of APIs acute MOA was non-specific narcosis as; 85% out of 59 APIs had an excess toxicity ratio <7; 70% of the APIs ecotoxicity was overestimated based on a narcotic model; and the majority of APIs Log EC(50)-Log K (ow )regression slopes (-0.49 to -0.86) were within the range of the universal narcosis slopes. However, hydrophobicity is likely not the proper descriptor for assessment of pharmacodynamic APIs chronic ecotoxicity, to asses this accurately new experimental methods need development. PMID- 17701091 TI - Reproductive toxicity of male mice after exposure to nonylphenol. PMID- 17701092 TI - Stress urinary incontinence and counseling and practice of pelvic floor exercises postpartum in low-income Hispanic women. AB - The purpose of the study was to provide estimates of stress urinary incontinence (SUI) and practice of pelvic floor muscle training (PFMT) postpartum as well as counseling during and after pregnancy among Hispanic women. Two hundred Hispanic women were surveyed 6 months postpartum. Twenty-three percent had SUI with onset primarily during pregnancy (70%). Only 20% had received information regarding SUI and PFMT during pregnancy or postpartum. Most women not counseled wished they were (81%). Less counseling occurred among Hispanic women with lower levels of education (odds ratio [OR]= .39; 95% confidence interval [CI]=0.19-0.82; p=0.02) and those whose primary language was Spanish (OR= .36; 95% CI=0.15-0.87; p=0.02), while higher rates occurred among women with a forceps delivery (OR=2.94; 95% CI=1.06-7.78; p=0.03). Fifty-seven percent of women counseled practiced the exercises. Primary reasons for noncompliance were belief that PFMT would not help (47%), and not understanding the instructions (39%). SUI and PFMT counseling is low among Hispanic women. Most women desire such information, and improvement in performance of PFMT among this group is possible. PMID- 17701093 TI - Intrauterine programming of bone. Part 1: alteration of the osteogenic environment. AB - Osteoporosis is believed to partly be programmed in utero. Rat dams were given a low protein diet during pregnancy and 135 offspring studied at different ages. Bone biochemistry showed altered characteristics. Altered in utero diet has consequences for later life. INTRODUCTION: Epidemiological studies suggest skeletal growth is programmed during intrauterine and early postnatal life. We have investigated this in a rat model of maternal protein insufficiency. METHODS: Dams received either 18% w/w (control) or 9% w/w (low protein) diet during pregnancy, and the offspring were studied at selected time points (4, 8, 12, 16, 20, 47 weeks). RESULTS: Alkaline phosphatase activity in controls reached peak levels from 8 to 20 weeks of age. In contrast, restricted diet offspring were at peak levels from 4 weeks of age. Peak levels were similar in both groups. Serum IGF-1 levels were lower in female restricted diet offspring at 4 weeks of age, and serum osteocalcin was significantly higher at 4 weeks of age in male and female offspring from mothers fed the restricted diet, whereas serum 25-OH vitamin D was significantly lower in restricted diet males at 8, 12, and 20 weeks of age. CONCLUSIONS: These data indicate that a low protein diet in utero affected the osteogenic environment in the offspring with effects that persist into late adulthood. These results indicate the key role of the nutritional environment in early development on programming of skeletal development with implicit consequences in later life. PMID- 17701094 TI - Effects of treatment with fluoride on bone mineral density and fracture risk--a meta-analysis. AB - Fluoride has fallen into discredit due to the absence of an anti-fracture effect. However, in this meta-analysis, a fracture reducing potential was seen at low fluoride doses [< or =20 mg fluoride equivalents (152 mg monofluorophosphate/44 mg sodium fluoride)]: OR = 0.3, 95% CI: 0.1-0.9 for vertebral and OR = 0.5, 95% CI: 0.3-0.8 for non-vertebral fractures. INTRODUCTION: Fluoride is incorporated into bone mineral and has an anabolic effect. However, the biomechanical competence of the newly formed bone may be reduced. METHODS: A systematic search of PubMed, Embase, and ISI web of science yielded 2,028 references. RESULTS: Twenty-five eligible studies were identified. Spine BMD increased 7.9%, 95% CI: 5.4-10.5%, and hip BMD 2.1%, 95% CI: 0.9-3.4%. A meta-regression showed increasing spine BMD with increasing treatment duration (5.04 +/- 2.16%/year of treatment). Overall there was no significant effect on the risk of vertebral (OR = 0.8, 95% CI: 0.5-1.5) or non-vertebral fracture (OR = 0.8, 95% CI: 0.5-1.4). With a daily dose of < or =20 mg fluoride equivalents (152 mg monofluorophosphate/44 mg sodium fluoride), there was a statistically significant reduction in vertebral (OR = 0.3, 95% CI: 0.1-0.9) and non-vertebral (OR = 0.5, 95% CI: 0.3-0.8) fracture risk. With a daily dose >20 mg fluoride equivalents, there was no significant reduction in vertebral (OR = 1.3, 95% CI: 0.8-2.0) and non-vertebral (OR = 1.5, 95% CI: 0.8-2.8) fracture risk. CONCLUSIONS: Fluoride treatment increases spine and hip BMD, depending on treatment duration. Overall there was no effect on hip or spine fracture risk. However, in subgroup analyses a low fluoride dose (< or =20 mg/day of fluoride equivalents) was associated with a significant reduction in fracture risk. PMID- 17701095 TI - Structural diversity of bicyclic amino acids. AB - Over the years biomedical research has been constantly oriented towards the development of new therapeutics based on bioactive peptides and their analogues. In particular, the generation of compounds having structures and functions similar to bioactive peptides, named "peptidomimetics", raised much interest among organic and medicinal chemists due to the possibility by using such compounds to improve both potency and stability of peptidic lead compounds. In the context of this research area, unnatural amino acids are of great interest in drug discovery, and their use as new building blocks for the development of peptidomimetics with high diversity level and possessing high-ordered structures is of special interest. In particular, medicinal chemistry has taken advantage of the use of amino acid homologues and of cyclic and polycyclic templates to introduce elements of diversity for the generation of new molecules as drug candidates. Bicyclic amino acids have been developed as reverse turn mimetics and dipeptide isosteres, and the constraint imposed by their structures has been reported as a tool for controlling the conformational preferences of modified peptides. Moreover, synthetic efforts have been driven to the generation of diverse structures based on the modulation of ring size and scaffold decoration by suitable functional groups. Herein is reported an overview of different classes of bicyclic amino acids, taking into account the strategies to achieve structurally diverse templates, and some implications in medicinal chemistry are also disclosed. PMID- 17701096 TI - Taurine release in developing mouse hippocampus is modulated by glutathione and glutathione derivatives. AB - Glutathione (reduced form GSH and oxidized form GSSG) constitutes an important defense against oxidative stress in the brain, and taurine is an inhibitory neuromodulator particularly in the developing brain. The effects of GSH and GSSG and glycylglycine, gamma-glutamylcysteine, cysteinylglycine, glycine and cysteine on the release of [(3)H]taurine evoked by K+-depolarization or the ionotropic glutamate receptor agonists glutamate, kainate, 2-amino-3-hydroxy-5-methyl-4 isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) were now studied in slices from the hippocampi from 7-day-old mouse pups in a perfusion system. All stimulatory agents (50 mM K(+), 1 mM glutamate, 0.1 mM kainate, 0.1 mM AMPA and 0.1 mM NMDA) evoked taurine release in a receptor-mediated manner. Both GSH and GSSG significantly inhibited the release evoked by 50 mM K+. The release induced by AMPA and glutamate was also inhibited, while the kainate-evoked release was significantly activated by both GSH and GSSG. The NMDA-evoked release proved the most sensitive to modulation: L-Cysteine and glycine enhanced the release in a concentration-dependent manner, whereas GSH and GSSG were inhibitory at low (0.1 mM) but not at higher (1 or 10 mM) concentrations. The release evoked by 0.1 mM AMPA was inhibited by gamma-glutamylcysteine and cysteinylglycine, whereas glycylglycine had no effect. The 0.1 mM NMDA-evoked release was inhibited by glycylglycine and gamma-glutamylcysteine. In turn, cysteinylglycine inhibited the NMDA-evoked release at 0.1 mM, but was inactive at 1 mM. Glutathione exhibited both enhancing and attenuating effects on taurine release, depending on the glutathione concentration and on the agonist used. Both glutathione and taurine act as endogenous neuroprotective effectors during early postnatal life. PMID- 17701097 TI - Low dose domoic acid in neonatal rats abolishes nicotine induced conditioned place preference during late adolescence. AB - In this study, neonatal rats were chronically exposed to low, non-convulsive doses of the kainate receptor agonist domoic acid (DOM), or saline. Later, as adolescents, all animals were tested in a nicotine-induced conditioned place preference (CPP) paradigm. As expected, a nicotine-induced CPP was evident in the adolescent control rats, but surprisingly, not in the DOM animals. This study demonstrates the importance of KA receptors in the development of normal adolescent behaviors manifested in response to the rewarding properties of nicotine. PMID- 17701098 TI - Taurine fails to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced striatal dopamine depletion in mice. AB - Taurine, a known antioxidant and neuroprotector has been investigated for its free radical scavenging action in vitro in isolated mitochondria, and tested whether it protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced dopaminergic neurodegeneration in mice. Taurine (0.1-10 mM) did not affect 1-methyl-4-phenyl pyridinium-induced hydroxyl radical production in isolated mitochondria. Systemic administration of taurine (250 mg/kg, i.p.) caused a small, but significant loss of dopamine levels in the striatum of mice. Taurine failed to reverse MPTP-induced striatal dopamine depletion, but caused significant increase in dopamine turnover in these animals. In the light of the present study it may be suggested that consumption of taurine may neither help in scavenging of neurotoxic hydroxyl radicals in the brain mitochondria, nor would it help in blocking the process of neurodegeneration. PMID- 17701099 TI - Mapping the human proteome for non-redundant peptide islands. AB - We describe immune-proteome structures using libraries of protein fragments that define a structural immunological alphabet. We propose and validate such an alphabet as i) composed of letters of five consecutive amino acids, pentapeptide units being sufficient minimal antigenic determinants in a protein, and ii) characterized by low-similarity to human proteins, so representing structures unknown to the host and potentially able to evoke an immune response. In this context, we have thoroughly sifted through the entire human proteome searching for non-redundant protein motifs. Here, for the first time, a complete sequence redundancy dissection of the human proteome has been conducted. The non-redundant peptide islands in the human proteome have been quantified and catalogued according to the amino acid length. The library of uniquely occurring n-peptide sequences that was obtained is characterized by a logarithmic decrease of the number of non-redundant peptides as a function of the peptide length. This library represents a highly specific catalogue of molecular protein signatures, the possible use of which in cancer/autoimmunity research is discussed, with a major focus on non-redundant dodecamer sequences. PMID- 17701100 TI - Prediction of mitochondrial proteins based on genetic algorithm - partial least squares and support vector machine. AB - Mitochondria are essential cell organelles of eukaryotes. Hence, it is vitally important to develop an automated and reliable method for timely identification of novel mitochondrial proteins. In this study, mitochondrial proteins were encoded by dipeptide composition technology; then, the genetic algorithm-partial least square (GA-PLS) method was used to evaluate the dipeptide composition elements which are more important in recognizing mitochondrial proteins; further, these selected dipeptide composition elements were applied to support vector machine (SVM)-based classifiers to predict the mitochondrial proteins. All the models were trained and validated by the jackknife cross-validation test. The prediction accuracy is 85%, suggesting that it performs reasonably well in predicting the mitochondrial proteins. Our results strongly imply that not all the dipeptide compositions are informative and indispensable for predicting proteins. The source code of MATLAB and the dataset are available on request under liml@scu.edu.cn. PMID- 17701101 TI - Chorioretinal anastomosis after photodynamic therapy for polypoidal choroidal vasculopathy: CRA after PDT for PCV. AB - An 80-year-old woman was treated with photodynamic therapy (PDT) to the left eye for polypoidal choroidal vasculopathy (PCV). About 3 months after PDT, her left eye developed a chorioretinal anastomosis with severe atrophy of the retinal pigment epithelium in the macula; visual acuity in this eye was 20/1000. She received a second session of PDT, plus an intravitreal injection of triamcinolone acetonide. About 3 months after the second treatment, the chorioretinal anastomosis was enlarged and the retinal vessels involved in the anastomosis were more dilated. About 1 year after the first PDT, visual acuity in the left eye had stabilized at 20/400. Development of a chorioretinal anastomosis is a distinct possibility following PDT in eyes with PCV, and can lead to poor visual recovery. PMID- 17701102 TI - Duane's retraction syndrome, a case series from Iran. AB - PURPOSE: To determine the relative prevalence of Duane's retraction syndrome (DRS) in a population of Iranian strabismus cases and to describe the clinical features. METHODS: Retrospectively, a population of 7,349 strabismus cases visited during 2000-2003 were evaluated for the diagnosis of DRS. Data regarding onset (noticed age), type, head turn, primary position deviation, narrowing of the palpebral fissure, leash phenomenon, refractive error, amblyopia, and history of surgery were collected. Chi-square test and Student's t-test were used. RESULTS: About 125 DRS cases were diagnosed (prevalence: 1.7%). The noticed age of the syndrome was at birth in 35.6%, during infancy in 25.4%, or childhood in 39.0%; the age at referral ranged from 3.5 months to 65.0 (median: 10.0) years. The female/male and left/right eye involvement ratios were 3:2 and 3.5:1, respectively. The syndrome was of type I in 87.0%, II in 6.5%, and III in 5.7%; 7.2% were bilateral. Horizontal deviations existed in 76.0% and vertical deviations in 12.8%. 26.8% had different degrees of amblyopia. Leash phenomenon was detected in 37.6% of cases. Head turn, primary position deviation (without turn), and orthophoria were observed in 71.2%, 13.6%, and 15.2%. Surgery had been performed in 71.2% of the cases. Vertical deviations and leash phenomenon were more common in types II and III and hypermetropia in type I (P values: 0.036, <0.001, and 0.025, respectively). CONCLUSION: Basic features of our series seem to be comparable with previous reports. The incidences of bilateral involvement and type III syndrome were lower. The proportion of cases with head turn was higher and surgery was performed more frequently. PMID- 17701103 TI - Ocular manifestations in Kabuki syndrome: the first report from Saudi Arabia. AB - BACKGROUND: Kabuki syndrome (KS) is a multiple congenital anomaly syndrome in which ophthalmological examination for the early detection of ocular abnormalities is desired in order to prevent visual impairment. CASE: Retrospective, interventional, case report of a 5-year-old female patient of Arabic origin with features of Kabuki syndrome. OBSERVATION: Patient had neurological deficit, psychomotor retardation, a peculiar face, including large prominent cup shaped ears, broad depressed nasal tip, and high arched palate, and malformed teeth. Her ocular features suggestive of Kabuki syndrome included left upper eyelid congenital ptosis, lagophthalmos, arched eyebrows with temporal sparing of hair, long horizontal palpebral fissures, lateral lower eyelid eversion and resultant epiphora. Other abnormalities included medial lower epicanthal folds, abduction deficit bilaterally, large esotropia, significant hyperopia, right corneal opacity, iris and chorioretinal coloboma. Patient required hyperopic correction and ptosis surgery, which improved her visual functioning. CONCLUSIONS: We report the first case of a Kabuki syndrome patient from Saudi Arabia and stress on the importance of ophthalmological examination in all patients with KS for the early detection of ocular anomalies in order to prevent visual impairment. PMID- 17701104 TI - Underutilization of venous thromboemoblism prophylaxis in medical patients in a tertiary care center. AB - BACKGROUND: New recommendations concerning the use of prophylactic anticoagulation for medically ill patients have been in use for some time now. This study aims at assessing how much house-staff in a tertiary care setting are implementing these new recommendations in the hope that through quantitative analysis of the deficiency we would be able to identify areas of weakness. METHODS: About 250 patients were randomly selected from all patients admitted to the American University of Beirut Medical Center (AUBMC) during the year 2005 and stayed more than 48 h. The risk factor profiles, contraindications to thromboprophylaxis, if present, and whether these patients received the appropriate VTE pharmacologic prophylaxis during their stay in hospital were recorded. RESULTS: About 139 patients were found to have two or more risk factors, with no absolute contraindications. About 37 patients (26.6%) received VTE prophylaxis. Upon reviewing the risk factors profile, the majority of patients (71.3%) were found to have 2-4 risk factors. Among risk factors studied, age > 40 years, admission to ICU, prior VTE, chronic lung disease, infection, respiratory failure, and central venous catheter were significantly associated with receiving prophylaxis. CONCLUSIONS: VTE prophylaxis is underutilized at AUBMC, a tertiary care teaching hospital in the Middle East. Critical care patients were being acceptably anti-coagulated, whereas cancer patients are doing the worst. PMID- 17701105 TI - Challenges in the treatment of patients with essential thrombocythemia and acute coronary syndrome. AB - Essential thrombocythemia (ET) is an acquired clonal hematological stem-cell disorder that is characterized by a persistent increase in platelet count over 600,000/microl and elevated megakaryocyte levels in the bone marrow. Patients with ET are on the one hand at risk of thrombosis and on the other hand of hemorrhagic events especially in patients with very high platelet accounts. We report two illustrative cases with ET and acute coronary syndrome from our recent clinical experience illustrating the challenges in the antithrombotic treatment of these patients. PMID- 17701106 TI - Successful recovery from carotid terminus occlusion after mechanical embolectomy in a fully anticoagulated patient. AB - CASE DESCRIPTION: We describe a case of the patient with multiple contraindications for thrombolysis who underwent successful mechanical embolectomy for occlusion of the right carotid terminus. Her pre-procedural NIHSS was 16. DISCUSSION: The patient demonstrated remarkable recovery within an hour of the procedure, and this clinical improvement was sustained at followup. RESULTS: This case illustrates that mechanical embolectomy is a safe and potentially very effective intervention to treat major intracranial vessel occlusions in patients with multiple contraindications for thrombolysis. PMID- 17701107 TI - An association of prior statin use with decreased perihematomal edema. AB - OBJECTIVE: To investigate the impact of statins on perihematomal edema following spontaneous supratentorial intracerebral hemorrhage (ICH). BACKGROUND: Hematoma expansion and evolution of perihematomal edema are most commonly responsible for neurological deterioration following ICH. A possible role of statins in reducing perihematomal edema has been suggested based on studies in animal models. METHODS: Records of consecutive ICH patients admitted to The Johns Hopkins Hospital from 1999 to 2006 were reviewed. Patients with ICH related to trauma or underlying lesions (e.g., brain tumors, aneurysms, and arterio-venous malformations) and of infratentorial location were excluded. Absolute and relative perihematomal edema were assessed on initial head CT. Using regression analysis, the impact of prior statin use on absolute and relative edema at presentation was assessed correcting for other factors possibly impacting perihematomal edema, such as age, coagulopathy, aspirin use, admission mean arterial pressure (MAP), and blood glucose. RESULTS: A total of 125 consecutive ICH patients were studied. Patients with prior statin exposure had a mean edema volume of 13.2 +/- 9.2 cc compared to 22.3 +/- 18.3 cc in patients who were not using statins at the time of ICH. Following multiple linear regression analysis, we have identified a statistically significant association between prior statin use with reduced early absolute perihematomal edema (P = 0.035). Mean relative perihematomal edema was significantly lower in patients on statins at presentation (0.44) as opposed to 0.81 in patients with no prior statin use. This difference remained statistically significant (P = 0.021) after correcting for other variables. CONCLUSIONS: We report the association between statin use prior to ICH and decreased absolute and relative perihematomal edema. A prospective study analyzing the role of statins in perihematomal edema reduction and the resultant effect on mortality and functional outcomes following ICH is warranted. PMID- 17701108 TI - Prior statin use reduces mortality in intracerebral hemorrhage. AB - OBJECTIVE: To assess the impact of blood glucose, coagulopathy, seizures and prior statin and aspirin use on clinical outcome following intracerebral hemorrhage (ICH). BACKGROUND: Intracerebral hemorrhage (ICH) accounts for 10-15% of all strokes with mortality rates approaching 50%. Glasgow Coma Scale (GCS), ICH volume, age, pulse pressure, ICH location, intraventricular hemorrhage (IVH) and hydrocephalus are known to impact 30-day survival following ICH and are included in various prediction models. The role of other clinical variables in the long-term outcome of these patients is less clear. METHODS: Records of consecutive ICH patients admitted to The Johns Hopkins Hospital from 1999 to 2006 were reviewed. Patients with ICH related to trauma or underlying lesions (e.g. brain tumors, aneurysms, arterio-venous malformations) and of infratentorial location were excluded. The impact of admission blood glucose, coagulopathy, seizures on presentation and prior statin and aspirin use on 30-day mortality and functional outcomes at discharge was assessed using dichotomized Modified Rankin Scale (dMRS) and Glasgow Outcomes scale (dGOS). Other variables known to impact outcomes that were included in the multiple logistic regression analysis were age, admission GCS, pulse pressure, ICH volume, ICH location, volume of IVH and hydrocephalus. RESULTS: A total of 314 patients with ICH were identified, 125 met inclusion criteria. Patients' age ranged from 34 to 90 years (mean 63.5), 57.6 % were male. Mean ICH volume was 32.09 cc (range 1-214 cc). Following multiple logistic regression analysis, prior statin use (P = 0.05) was found to be associated with decreased mortality with a greater than 12-fold odds of survival while admission blood glucose (P = 0.023) was associated with increased 30-day mortality. Coagulopathy, seizures on presentation, and prior aspirin use had no significant impact on 30-day mortality or outcomes at discharge in our study cohort. CONCLUSIONS: The significant association of prior statin use with decreased mortality warrants prospective evaluation of the use of statins following ICH. PMID- 17701109 TI - Delayed decompressive craniectomy improves the long-term outcomes in hypertensive rats with space-occupying cerebral infarction. AB - BACKGROUND AND PURPOSE: No experimental data has been published on the long-term effects of decompressive craniotomy in hypertensive rats with space-occupying cerebral infarction. The aim of the present study was to investigate the efficacy of decompressive craniectomy in a middle cerebral artery occlusion (MCAO) model of hypertensive rats in a prolonged period. METHODS: Totally 92 stroke-prone renovascular hypertensive rats (RHRSP) were subjected to left MCAO by an endovascular occlusion technique. The decompressive craniectomy was performed on 26 RHRSP at 1 and 24 h after MCAO, respectively. Infarct volume, neurological performance, and mortality were evaluated at 1, 2, 4, and 8 weeks after MCAO. RESULTS: The mortality was reduced from 52.5% in controls to 7.7% and 23.1% in the rats underwent craniectomy at 1 and 24 h after MCAO, respectively (P < 0.05, respectively). All of the treated rats presented smaller infarct volume from 1 week to 8 weeks and better neurological performance at 4-8 weeks after MCAO compared to the controls (P < 0.05, respectively). The craniectomy at early stage was more effective than that at late stage in reducing infarct volume and improving neurological performances at 1 and 2 weeks (P < 0.05, respectively). However, there was no significant difference in infarct volume and neurological scores between the treated groups of rats at 4 and 8 weeks after MCAO (P > 0.05). CONCLUSIONS: Although the early craniectomy is more effective than delayed craniectomy in improving short-term outcome, the latter has the similar beneficial effects as early craniectomy on long-term outcome in hypertensive rats with space-occupying cerebral infarction. PMID- 17701110 TI - Focal or subtotal therapy for early stage prostate cancer. AB - Focal treatment for prostate cancer is highly intriguing, but poorly supported by the published literature. Further studies, preferably randomized controlled trials, are needed before this can be considered standard therapy. Focal treatment should be reserved for patients with focal disease. Even "clinically insignificant" synchronous tumors are malignant, and carry risk of progression if not treated with the index lesion. Whether these are likely to progress in this setting compared to those managed with active surveillance is unknown. The limited data regarding subtotal or focal cryotherapy suggest that patients properly evaluated for presence of satellite tumors have a low risk of having large unknown satellite tumors. The author requires office-based saturation biopsy prior to considering focal cryotherapy. Observation of prostatic intraepithelial neoplasia (PIN), atypical findings (ASAP), or cancer on the contralateral biopsy cores excludes the patient from consideration of subtotal therapy. MRI offers a potential additional ability to detect occult contralateral tumors. Younger men paradoxically seem to have greater interest in focal therapy while having a higher risk of future malignancy in the untreated areas based on the years of potential risk. However, no age cutoff is established. Without published data to support its use, lumpectomy or freezing only the focus where cancer is believed to exist, will remain limited. Hemispheric or subtotal treatment decreases the amount of untreated tissue. As a result, the local failure rate would be predicted to be lower but is unknown. When performing subtotal treatment, the author freezes almost the entire gland, sparing only the aspect adjacent to the contralateral neurovascular bundle, and has found this practice to be of highly limited utility based on the issues described. Biopsy should be performed following any treatment that fails to target the entire gland. A positive biopsy should be dealt with based on clinical factors as if the patient had not been treated, and a positive biopsy should not preclude active surveillance if deemed appropriate. PMID- 17701111 TI - [Prevention and higher age]. PMID- 17701112 TI - Preventive home visits to older people in Denmark--why, how, by whom, and when? AB - In Denmark, political decisions improved the implementation of 'preventative thinking' into every-day clinical work. The potential benefits of preventive efforts have been supported by legislative and administrative incentives, and an ongoing effort to remain focused on the benefits of these initiatives towards older people is politically formulated and underlined as part of the new structured municipality reform. Evidence of beneficial effects of health promotion and prevention of disease in old age is well documented. In-home visits with individualised assessments make it possible to reach older persons not normally seen in the health care system. In-home assessment is not just a health check, but also an opportunity to meet individual needs that may be of importance for older people to stay independent. Preventive home visits may be part of an overall culture and strategy to avoid or prevent functional decline. There is an urgent need of an interdisciplinary teamwork and management for such programmes, incorporating flexible cooperation between the primary and secondary health care sector. The value and importance of geriatric and gerontological education is evidence based. PMID- 17701113 TI - [Health in older age: cost of illness and cost-effectiveness of prevention]. AB - The objective of prevention is to avoid or to delay health impairments and diseases. For older people it is important to maintain their independence and to avoid and reduce the need for external help such as nursing care. Good starting points are the strategies for healthy life-style. Physical activity, smoking abstinence, and normal weight have proven to have their positive medical and economic effect on many chronic diseases such as type 2 diabetes mellitus, cardiovascular diseases, and certain types of dementia. The potential of prevention increases as those diseases affect one another. As for other health care, the cost-effectiveness of preventive measures must also be examined. There are few German studies addressing the cost-benefit of the non-medication prevention. Results from international studies can only partly be transferred to the German context. The cost-effectiveness for prevention for elderly people has been very rarely researched. Research in the field of prevention is so far not very well developed as for other health fields. There is a need for more specific research for methods, interventions and target groups. In health economics major challenges arise from different time schedules and various purchasers, as well as from the evaluation of human capital for elderly. PMID- 17701114 TI - [Geriatric health promotion and prevention for independently living senior citizens: programmes and target groups]. AB - BACKGROUND: Nearly all diseases in old age that are epidemiologically important can be reduced or prevented successfully through consequent changes in individual lifestyle, a systematic provision of measures in primary prevention (i.e. vaccination programmes) and the creation of health promoting settings. However, at the moment the amount of potential for preventative interventions is neither systematically nor sufficiently utilised in Germany. METHODS: Two different preventative approaches: a) multidimensional advice session in small groups through an interdisciplinary team at a geriatric centre (seniors come to seek advice offered at a centre) or b) multidimensional advice at the seniors home through one member of the interdisciplinary team from the geriatric centre (expert takes advice to seniors home) were tested simultaneously with a well described study sample of 804 independent community-dwelling senior citizens aged 60 years or over, without need of care and cognitive impairments recruited from general practices. Information about target group specific approaches in health promotion and prevention for senior citizens were retrieved from analyses of sociodemographic, medical, psychological and spacial characteristics of this study sample. RESULTS: The majority of the study sample (580 out of 804 or 72.1%) decided to participate: a) 86.7% (503 out of 580) attended at the geriatric centre and sought advice in group sessions and b) 13.3% (77 out of 580) decided to receive advice in a preventive home visit. A total of 224 seniors (224 out of 804 or 27.9%) refused to participate at all. These three target groups were characterised on the basis of their age, gender, education, social background, health status, health behaviour, use of preventive care, self perceived health, functional disabilities, social net and social participation and distance or accessibility of preventative approaches. The 503 senior citizens who participated in small group sessions at the geriatric centre were characterised as "investors into their health resources". They were mobile and participated actively in their environment. They were open for health promoting advice and capable of understanding and incorporating it into their daily routines (health literacy). Those 224 seniors who refused any participation were characterised as "consumers of their health resources". They did not differ in age and gender from the health investors, but showed less self-efficacy and less self-responsibility and typical behaviour that endangers health in an active way, i.e. smokers or in a passive way, i.e. low physical activity. The 77 seniors who received a preventive home visit were characterised as "people with exhausted health resources". Their mobility was clearly restricted and autonomy was confined to their home environment. This group represented frail elderly people with many risk factors in different domains. CONCLUSION: The strongest reason to refuse participation in health promoting programmes was the personal attitude related to one's own personal health. Taking account of needs and wants of the seniors who refused to participate more people expressed the reason "no interest" in the preventive home visit than in the small group session at the geriatric centre. To strengthen the integration of the GP as a trustworthy person would seem to be more successful to motivate senior citizens to participate in health promoting and preventative programmes in the future. This could succeed in a cooperation with geriatric centres to establish community centres for generally healthy senior citizens. PMID- 17701115 TI - [Prevention of adverse drug reactions in older patients]. AB - Adverse drug reactions are among the most common adverse events and a significant cause of preventable morbidity and mortality. As multimorbidity and polypharmacy are frequent in this population, the elderly are at special risk for adverse drug events, although the calendar age has not been proved as independent risk factor in this context. In particular falls and delirium are clinically significant and typical adverse drug events in the elderly. In this review mechanisms and factors which determine adverse drug re actions are described, and possible strategies for an effective prevention are given. This covers pharmacokinetic, pharmacogenetic and pharmacodynamic aspects as well as factors influencing individual adherence to drug therapy. A significant portion of adverse drug reaction may be prevented by a thorough indication and prudent monitoring of pharmacotherapy. Also adherence to pharmacotherapy may be improved by tailored and individual means referring to the patient's needs and expectancies. In the elderly functional limitations such as reduced cognitive abilities, reduced visual acuity and impaired dexterity determine an ineffective pharmacotherapy and medication errors. Hereby these functional limitations are significant predictors of adverse drug events in the context of self-management of pharmacotherapy. Testing of functional abilities as provided in the geriatric assessment is helpful to identify these factors. Among altered pharmacokinetic factors in the elderly, reduced renal function is most important to avoid overdosage. Although a precise measurement of renal function is not possible in a bed-side manner, an estimation of actual renal function utilizing estimation-formulas should always take place. PMID- 17701116 TI - [Impact of fall risk and fear of falling on mobility of independently living senior citizens transitioning to frailty: screening results concerning fall prevention in the community]. AB - PROBLEM: There is a strong relation between mobility, walking safety and living independently in old age. People with walking problems suffer from fear of falling and tend to restrict their mobility and performance level in the community environment--even before falls occur. This study was planned to test the validity and prognostic value of a fall risk screening instrument ("Sturz Risiko-Check") that has already shown its feasibility, acceptance and reliability, targeting independently living senior citizens. METHODS: The study sample was recruited from a sheltered housing complex in Hamburg (with written consent). Persons with need of professional care ("Pflegestufe" in Germany) were excluded. The residents were asked to fill in the multidimensional questionnaire ("Sturz-Risiko- Check"). In a second step, a trained nurse asked the participants in a phone call about their competence in the instrumental activities of daily living (I-ADL mod. from Lawton, Brody 1969) and about their usual mobility performance level (e.g. frequency and distance of daily walks, use of public transport). According to the number and weight of self-reported risk factors for falling, three groups: "low fall risk", "medium fall risk" and "high fall risk" were classified. Finally, this classification was re-tested after one year, asking for falls and fall related injuries. RESULTS: A total of 112 senior citizens without need of personal care, living in a sheltered housing facility were asked to participate. Acceptance was high (76.1%). Self-reported data from 79 participants concerning falls, fall-risk, mobility and instrumental activities of daily living were included in the statistical analyses. Mean age was 78 (64 to 93) years and associated by a high percentage of women (75.9%) in this sample. The older participants reported 0 to 13 different factors (mean 5) related to a high risk of future falls. Most participants (78.5%) quit cycling because of fear of falling. There was a high incidence in the study sample and over the three risk groups of chronic disorders like cardiac failure (75.9%) and disturbed vision or hearing (64.6%). According to the rising risk of falling over the three risk groups (low, medium and high), there were symptoms of fast functional decline or frailty like diminished walking speed (6.3 vs 36.8 vs 72.0%), sarcopenia (failed chairrise test: 0 vs 18.4 vs 28%) or already perceived fall events (0 vs 5.3 vs 56.0%) and ongoing restriction in basic activities. Those results were proven by the data on fall frequencies after one year (follow-up). We found an increase in falls over all three risk groups (12.5 vs 31.6 vs 28%) with fall-related severe injuries (fractures) in two persons classified in the high fall-risk group. DISCUSSION: The results of the fall-risk screening were useful to classify groups with different probability to fall in the near future. Fear-offalling and symptoms of frailty were related to an increasing risk of falling and loss of mobility and autonomy in still independently living senior citizens. CONCLUSION: The fall-risk screening instrument ("Sturz-Risiko-Check" questionnaire) was useful and valid to predict risk of falling and functional decline in independently living senior citizens transitioning to frailty. This screening will be part of a prevention approach in the City of Hamburg to offer primary and secondary prevention interventions adapted to special target groups of community- dwelling elder people (robust in contrast to frail elderly). The implementation should be accompanied by training sessions for physicians in the primary care sector and health improvement programmes for elder citizens. PMID- 17701117 TI - Combined medical-psychiatric inpatient units: evaluation of the Centre for the Elderly. AB - Considering the large number of elderly patients in acute hospitals who receive medical as well as psychiatric treatment because of relevant comorbidity, adequate interdisciplinary treatment models have to be developed and applied. The Centre for Elderly, a cooperation project between the departments of geriatric and psychogeriatric medicine in a community hospital in Germany, was founded in 2000. In addition to traditionally structured units, the centre consists of interdisciplinary units. Patient-, staff- and hospital-related characteristics influenced by the reformation of both departments were evaluated by comparing hospital-based registry data records containing age, gender, main and minor diagnoses, length of stay and patient transferrals within the centre. Experts working at the centre were asked to take a stand on the development of the treatment quality, allocation of patients, diagnostic procedures, consultation services and information transmission. The number of admissions to the Centre for the Elderly increased within one year. The distribution of the main diagnose groups remained unchanged, with an overlap between the geriatric and psychogeriatric department consisting of the main diagnoses dementia and depression. The length of stay and the number of transferrals decreased significantly in both departments. The majority of the interviewed employees stated that the treatment quality and the allocation of patients were improved. We conclude that interdisciplinary treatment between the departments of psychiatry and geriatric medicine may contribute to the medical needs of subgroups of elderly inpatients suffering from medical-psychiatric comorbidity. PMID- 17701118 TI - [Does the service of the federal government commissioner for patient issues appeal to the elderly?]. AB - BACKGROUND: For the first time, this study investigates to which extent elderly persons write to the federal government commissioner for patient issues in Germany. METHODS: A 33% sampling (n=850) of the written inquiries (correspondence and emails) addressed to the commissioner in the first six months of the year 2005 (n=2580) was investigated. Socio-demographic data were extracted from the material; furthermore, it was registered which diseases the citizens described. RESULTS: Older persons outweigh the younger (69% over 60 years, mean age 63 years). Within the group of the elderly, approximately as many persons belong to the age group 60-69 years and to the age group 70 years and older. Most frequently, the citizens describe chronic diseases of the musculoskeletal system. DISCUSSION: The new service of the federal government commissioner for patient issues appeals to the elderly in Germany. The high proportion of people with chronic illness among the inquirers emphasizes the need for information, advice and support for this target group. Further research is needed on the answers to the inquirers, and on the question how helpful the contact to the government commissioner's office is from the viewpoint of the citizens; furthermore, possible barrieres (e.g. social state) should be analyzed. PMID- 17701119 TI - [Statement to the preliminary report of the IQWiG A05-19B ginkgo-containing preparation at Alzheimers dementia]. PMID- 17701122 TI - Conceptual importance of identifying alcoholic liver disease as a lifestyle disease. AB - The concept that alcoholic liver disease (ALD) is as a toxic disease does not mirror the exact nature of the disease. ALD should be defined as an alcohol associated lifestyle disease, the predisposition to which is largely governed by gene-environment interactions, much like other chronic diseases such as diabetes, atherosclerosis, and neurodegenerative diseases. The epidemiology and pathogenesis of ALD need to be re-addressed from this viewpoint. Specifically, the interactions between alcohol and secondary risk factors (high-fat diet, iron, tobacco, medications, female gender) and comorbidities (viral hepatitis, diabetes) are of urgent epidemiological importance. Molecular characterization of the interfaces of these interactions is essential for revelation or acquisition of new pathogenetic, preventive, and therapeutic insights. PMID- 17701123 TI - Nodular gastritis in Japanese young adults: endoscopic and histological observations. AB - BACKGROUND: Endoscopic findings of nodular gastritis (NG) are characterized by the presence of Helicobacter pylori infection and follicular gastritis. A possible association with diffuse-type gastric cancer has recently been suggested from observations in Japanese. Our aim was to analyze antral nodularity and histological scores in young adults. METHODS: Subjects (55 men and 45 women; age range, 18-25 years) with upper gastrointestinal (GI) symptoms or positive H. pylori antibodies underwent endoscopy. One specimen each was obtained from the greater and lesser curvatures (curves) of the corpus and from those of the antrum. Endoscopic appearance was assessed using 0.2% indigo carmine, and histopathological grading was evaluated by the updated Sydney System. RESULTS: Antral nodularity was identified in none of 17 H. pylori-negative subjects and in 55 of 83 (66.3%) H. pylori-positive subjects. By the distribution of nodular or granular elevated lesions in the antrum, NG was divided into diffuse (n = 27) or nondiffuse (n = 28) types. The diffuse-type NG predominantly affected women (odds ratio, 3.9; 95% confidence interval, 1.5-10). The atrophy scores in the lesser curve of the antrum were significantly higher in the nondiffuse than in the diffuse group. However, the scores for activity, inflammation, and H. pylori density were not significantly different among the three groups. CONCLUSIONS: Diffuse-type NG depended on sex, and antral nodularity seemed to change from the diffuse to the nondiffuse type in association with atrophy. PMID- 17701124 TI - An association between obesity and the prevalence of colonic adenoma according to age and gender. AB - BACKGROUND: Epidemiologic data on obesity as a risk factor for colonic adenoma with respect to gender have not yet been confirmed. Here, we aimed to compare the prevalence of colonic adenoma and of advanced polyps in age-stratified men and women at baseline, to examine the role of body mass index (BMI) on colonic adenoma risk according to age and gender, and to examine the influence of menopausal status. METHODS: A total of 1744 asymptomatic patients (946 men, 798 women) who underwent colonoscopy for cancer screening at Ewha Mokdong Hospital, Seoul, Korea, between February and June 2005, were eligible. BMI was assessed, and histology, size, and location of the adenoma were examined for each patient. Women were interviewed for menopausal status and a history of hormone replacement therapy. RESULTS: A significant increase in the prevalence of colonic adenoma and of advanced polyps was found to occur with age (P for trend < 0.01). The prevalences of adenoma and advanced polyps were higher in men in most age groups (P < 0.01), but no significant difference in prevalences was observed between genderes in patients 70 years of age or older. Moreover, a positive association between BMI and the prevalence of colonic adenoma and advanced polyps was shown in relatively young individuals of both gender (men in their thirties, P < 0.05; women in their forties, P < 0.05), and premenopausal women according to hormonal status (P = 0.01). CONCLUSIONS: Our data suggest that obesity increases the risk of colonic adenoma in relatively young people and in premenopausal women subject to estrogen effects. PMID- 17701125 TI - Evaluation of the effect of Ginkgo biloba extract (EGb 761) on the myenteric plexus of the small intestine of Wistar rats. AB - BACKGROUND: The aging process causes a reduction in the myenteric neuronal population, related to oxidative stress, resulting in malfunctioning of the digestive tract. The purpose of this study was to evaluate the action of Ginkgo biloba extract (EGb 761), an important antioxidant drug, on the myenteric plexus of the jejunum and ileum of rats after treatment for 120 days. METHODS: Fragments of the jejunum and ileum were collected from three groups of rats: a 90-day-old group (group Y), a 210-day-old group (group A), and a 210-day-old group treated daily with the extract EGb 761 (50 mg/kg body weight) (group TA). The analysis was carried out by using the myosin-V immunohistochemical technique. Neuronal densities were estimated, and a study of the neuronal profile area of 500 neurons from each group was carried out. RESULTS: In the jejunum, there was a significant neuronal population reduction of 17% only in group A compared with group Y. In the ileum, there was a significant neuronal reduction of 36% in group A compared with group Y, and a significant reduction in group TA of 20%. The difference in the reduction between groups A and TA in the ileum was also significant. In the jejunum, only group A showed a significant increase in neuronal profile area, but in the ileum, there was a significant increase in both groups A and TA. CONCLUSIONS: A daily dose of 50 mg/kg body weight of Ginkgo biloba extract has a significant neuroprotector effect on the myenteric plexus of the ileum during the aging process in rats. PMID- 17701126 TI - Diagnosis of intestinal amoebiasis by using nested polymerase chain reaction restriction fragment length polymorphism assay. AB - BACKGROUND: Microscopy is unreliable to distinguish the pathogenic Entamoeba histolytica from the nonpathogenic Entamoeba dispar or Entamoeba moshkovskii in stool specimens. METHODS: Nested polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was carried out to detect E. histolytica, E. dispar, and E. moshkovskii DNA in stool samples of 202 patients positive for E. histolytica, E. dispar, or E. moshkovskii by microscopy or culture and in 35 controls. The TechLab E. histolytica II enzyme-linked immunosorbent assay (ELISA) was performed to detect Gal/GalNAc lectin in 45 stool samples positive for E. histolytica, E. dispar, or E. moshkovskii by microscopy or culture. Rapid indirect hemagglutination assay (IHA) was performed to detect serum antiamoebic antibodies in the 85 patients positive for E. histolytica, E. dispar, or E. moshkovskii in their stool specimens and in the 35 controls. RESULTS: Nested PCR RFLP was positive in 175 of 202 (86.6%) patient stool samples and was negative in all 35 negative control stool samples. ELISA was positive in 29 of 45 (64.4%) patient stool samples. The IHA test was positive in 19 of 85 (22.4%) patient serum samples and in one (2.8%) of the 35 control serum samples. Nested PCR-RFLP detected E. histolytica DNA in stool specimens of 12 (63.2%) of 19 seropositive patients, and in 31 (47%) of 66 seronegative patients. TechLab E. histolytica II ELISA detected E. histolytica antigen in stool specimens of six (54.5%) of 11 seropositive patients, and in 23 (67.6%) of 34 seronegative patients. CONCLUSIONS: Nested PCR-RFLP was useful for the specific detection of E. histolytica, E. dispar, and E. moshkovskii in stool samples. PMID- 17701128 TI - Lymphoplasmacytic sclerosing pancreatitis forming a localized mass: a variant form of autoimmune pancreatitis. AB - BACKGROUND: To elucidate the correlation of autoimmune pancreatitis (AIP) and mass-forming pancreatitis, in which a localized mass is formed in the pancreas. METHODS: Nine cases of mass-forming pancreatitis were divided into two groups, one consisting of cases that met the histological diagnostic criteria for AIP by the Japan Pancreas Society (JPS) and the other consisting of cases which did not. Histological findings, immunohistological findings, and pancreatograms were compared between these groups. RESULTS: Six cases met the histological criteria of JPS (group A) and the other three did not (group B). In the mass-forming portion in group A, the wall of the pancreatic duct showed marked thickening. However, the epithelium was well preserved, and dilatation of the branch ducts or protein plugs were rarely observed. All cases showed marked obliterative phlebitis. The IgG4 labeling index (LI) was 25% or more in all but one case. In the portion other than the mass, the lobular structure was well preserved and the IgG4 LI was less than 10%. The pancreatogram showed localized stenosis or obstruction at the site of the mass associated with a normal-appearing main pancreatic duct in the remaining portion. In group B, histological findings typical of chronic pancreatitis with dilated branch ducts and protein plugs were observed. Obliterative phlebitis was not confirmed. The IgG4 LI in the mass forming portion was low (2.3%-11.1%). CONCLUSIONS: There exists a subgroup of AIP showing localized mass formation and stenosis or obstruction of the main pancreatic duct with prominent obliterative phlebitis associated with a normal ductal segment. PMID- 17701127 TI - Coexistence of gastrointestinal stromal tumors with other neoplasms. AB - BACKGROUND: The purpose of this study was to assess the prevalence of other neoplasms in patients with gastrointestinal stromal tumors (GISTs) and to compare clinical and histopathological data in patients with a GIST and accompanying neoplasms and in patients with GIST only. METHODS: The analysis encompassed 82 patients with a GIST from among 330 300 patients whose surgical specimens, biopsies, and autopsies were evaluated between January 1989 and June 2006. A subgroup of patients with other types of neoplasms was selected. RESULTS: Other neoplasms in patients with a GIST were diagnosed in 22 of the 82 (26.8%) patients. The most common accompanying neoplasms were colorectal (nine cases) and gastric (four cases) adenocarcinoma, as well as pancreatic adenocarcinoma (three cases). There was a tendency toward more common localization of a GIST in the small intestine in patients with other neoplasms than in patients with a GIST alone (P < 0.09). Tumors with very low risk of aggressive behavior were more frequent in patients with a GIST accompanied by other neoplasms than in the other group (P < 0.05). No phenotypic differences in GIST cells were found between the two groups. CONCLUSIONS: In almost 27% of the study population, GISTs coexisted with other neoplasms. A greater proportion of patients with a GIST localized in the small intestine and/or characterized by a very low risk of aggressive behavior and accompanying other neoplasms, compared with a GIST alone, most likely reflects the fact that in the first group, GISTs tended to be an incidental finding during surgery. The results were affected by patient selection and the type of tissue material available. PMID- 17701129 TI - Utility of pancreatic duct brushing for diagnosis of pancreatic carcinoma. AB - BACKGROUND: The aim of this study was to evaluate the usefulness of pancreatic duct brushing for diagnosis of pancreatic carcinoma. METHODS: Brush cytology was attempted in 58 patients suspected of having pancreatic malignancy because of stricture of the main pancreatic duct, confirmed by endoscopic retrograde cholangiopancreatography. Thirty-eight patients were finally diagnosed by an operation or the clinical course as having pancreatic carcinoma, and the remaining 20 patients as having chronic pancreatitis. The usefulness of brush cytology for diagnosis of pancreatic carcinoma was estimated. We interpreted failures of pancreatic duct brushing to be false negatives when the lesion was malignant. RESULTS: In 48 of 58 patients (82.8%), brushing was successfully performed and satisfactory specimens were obtained. Brush cytology was positive in 25 of 38 patients with pancreatic carcinoma (sensitivity 65.8%) and negative in all patients without malignancy (specificity 100%). Overall accuracy was 76.4%. During 2001-2005, the number of back-and-forth motions of the brush was increased to more than 30 times. The sensitivity significantly improved from 43.8% in 1997-2000 to 81.8% in 2001-2005 (P < 0.05). The increased success rate of brushing by improvement of skill in manipulating the guidewire and increased number of cells smeared on glass slides by increased back-and-forth motion of the brush may account for this improvement over time. Moreover, the sensitivity in 2001-2005 was 85.7% if failures of brushing with pancreatic carcinoma are excluded. No major complications occurred, except for two patients with a moderate grade of acute pancreatitis. CONCLUSIONS: Although further studies with a large number of patients are needed, our results suggest that with recent improvements of the brushing technique, pancreatic duct brushing is a useful and safe method for the differential diagnosis of malignancy from benign diseases of the pancreas. PMID- 17701130 TI - The long-term outcome of patients with bleeding gastric varices after balloon occluded retrograde transvenous obliteration. AB - BACKGROUND: The purpose of our study was to evaluate the long-term outcome and complications of balloon-occluded retrograde transvenous obliteration (B-RTO) in patients with hemorrhage from gastric fundal varices. METHODS: Thirty-four consecutive patients with bleeding from gastric varices who were treated with B RTO were enrolled in this study between December 1994 and September 2005 (urgent cases, n = 12; elective cases, n = 22). The long-term outcome, complications, and various liver functions were evaluated. RESULTS: Complete obliteration was achieved in 31 of 34 (91%) patients with an acute bleeding episode. In one of the remaining patients, there was a technical failure, and the other two had only partial obliteration. The two patients with partial obliteration did not obtain hemostasis. Thus, the rate of hemostasis was 94% (31/33). Gastric varices disappeared in all patients with complete obliteration during the treatment. The rate of gastric variceal eradication was 91%. Variceal rebleeding from esophageal varices occurred in three patients. The rate of rebleeding was 10% (3/31). Rebleeding from gastric varices was not observed after complete obliteration. None of the patients showed worsening of their Child-Pugh score. Although the 5 year cumulative worsening rate of esophageal varices was 52%, neither portal hypertensive gastropathy nor ectopic varices were observed. The patients with worsening esophageal varices were successfully treated with an endoscopic procedure. The 5-year survival rate was 68%. CONCLUSIONS: B-RTO is useful for treatment of bleeding gastric varices, achieving high eradication of gastric varices, a low rebleeding rate, and a fairly good prognosis with improved hepatic function. PMID- 17701131 TI - Alanine aminotransferase flare-up in hepatitis C virus carriers with persistently normal alanine aminotransferase levels in a hyperendemic area of Japan. AB - BACKGROUND: The clinical features of hepatitis C virus (HCV) carriers with persistently normal alanine aminotransferase (PNALT) levels (ALT < or = 34 IU/l) have not been fully elucidated. We investigated clinical factors associated with ALT flare-up in PNALT individuals in a HCV hyperendemic area of Japan. METHODS: We analyzed 101 HCV carriers who had PNALT between 1993 and 2000. The first occurrence of ALT flare-up (ALT > or = 35 IU/l) between 2001 and 2005 was evaluated by the Kaplan-Meier method. Multivariate analysis of factors predicting ALT flare-up were conducted using Cox proportional hazards models. RESULTS: The mean follow-up period was 2.8 years, and the 5-year cumulative incidence of ALT flare-up was estimated to be 31.8%. In multivariate analysis, an ALT level of 20 34 IU/l and a high serum ferritin level (> or =90 ng/ml) in the most recently available data up to the year 2000, as well as H63D heterozygosity in the HFE gene, were independently and strongly associated with the incidence of ALT flare up (Hazard ratios = 5.6, 3.1, and 4.8, respectively). In addition, HFE H63D heterozygosity was significantly associated with higher serum ferritin levels in subjects with PNALT (153.8 + or - 73.3 ng/ml in subjects with the 63HD genotype vs. 89.4 + or - 51.3 ng/ml in subjects with the 63HH genotype, P = 0.043). CONCLUSIONS: HCV carriers with PNALT in this population were at risk for ALT flare-up. Basal ALT levels, serum ferritin levels, and HFE polymorphism are potentially important predictors of ALT flare-up. PMID- 17701132 TI - Treatment strategy against infection: clinical outcome of continuous regional arterial infusion, enteral nutrition, and surgery in severe acute pancreatitis. AB - BACKGROUND: In severe acute pancreatitis (SAP), infectious complications are the main contributors to high mortality. Since 1995, we have performed continuous regional arterial infusion of protease inhibitor and antibiotics (CRAI) and enteral nutrition (EN) as prevention therapies against infection. When infected pancreatic necrosis was proven, surgical intervention was adapted. The aim of this study was to investigate the clinical outcome of these treatments. METHODS: We examined the relationship between the historical change of treatment strategy and clinical outcome. We divided 84 patients with acute necrotizing pancreatitis into two groups, CRAI (-) and CRAI (+), and compared the outcome. We divided 145 patients with SAP into two groups, EN (-) and EN (+), and compared the outcome. We also analyzed the outcome of surgical treatment. RESULTS: In the CRAI (+) group, the incidence of infection, the frequency of surgery, and the mortality rate were lower than those in CRAI (-) group: 34% versus 51%, 27% versus 63% (P < 0.05), and 37% versus 54%, respectively. In the EN (+) group, the frequency of surgery and the mortality rate were lower than those in the EN (-) group: 23% versus 32% and 19% versus 35% (P < 0.05), respectively. These improvement effects were manifest in stage 3 (9 < or = Japanese Severity Score < or = 14). Treatment outcome of necrosectomy for infected pancreatic necrosis was still poor. Bleeding and abscess-gut fistula were postoperative life-threatening complications. CONCLUSIONS: CRAI and EN may improve the clinical outcome of SAP, reducing infection and averting pancreatic surgery. PMID- 17701133 TI - Rebamipide, a gastro-protective and anti-inflammatory drug, promotes gastric ulcer healing following eradication therapy for Helicobacter pylori in a Japanese population: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: One week of Helicobacter pylori eradication therapy is insufficient for healing of gastric ulcers. We examined the efficacy of rebamipide in gastric ulcer healing following 1 week of eradication therapy in a randomized, double blind, placebo-controlled trial. METHODS: Patients with H. pylori-positive gastric ulcer were enrolled and received 1 week of eradication therapy, followed by 100 mg of rebamipide or placebo for 7 weeks. The primary end point was the gastric ulcer healing rate. RESULTS: Of the 309 patients entered in the trial, 301 completed H. pylori eradication therapy; 154 patients took rebamipide, and 147 took placebo. The healing rate in the rebamipide group was higher than that in the placebo group in the per-protocol analysis-80.0% (104/130) versus 66.1% (82/124) [95% confidence interval (CI), 3.1-24.7; P = 0.013)-and in a full analysis-70.1% (108/154) versus 60.5% (89/147) (95% CI, -1.1 to 20.3; P = 0.080). CONCLUSIONS: Compared with placebo, rebamipide significantly promoted gastric ulcer healing following 1 week of eradication therapy. PMID- 17701134 TI - Primary acinar cell carcinoma of the ampulla of Vater. AB - Acinar cell carcinoma of the pancreatobiliary system is a relatively rare malignant neoplasm arising usually in the pancreatic parenchyma. We experienced a 68-year-old woman who presented with obstructive jaundice due to an ampullary mass 1.0 cm in diameter, detected by abdominal computed tomography and endoscopic examination. The patient underwent a curative surgical operation, and histopathological examination revealed that the tumor was confined to the ampulla of Vater with no continuity to the pancreatic parenchyma. The tumor cells showed acinar or tubular arrangement with eosinophilic to basophilic granular cytoplasm, findings identical to those of acinar cell carcinoma of the pancreas. Immunohistochemically, the tumor cells were positive for lipase. From these findings, we concluded that the tumor was primary acinar cell carcinoma arising in the ampulla of Vater, probably originating from heterotopic pancreatic tissue. This is the first reported case of primary acinar cell carcinoma in the ampulla of Vater. PMID- 17701135 TI - Perihilar cholangiocarcinoma arising in hepatitis C virus-related liver cirrhosis with hepatocellular carcinoma. AB - Liver cirrhosis is reportedly one of the conditions preceding peripheral-type intrahepatic cholangiocarcinoma but not hilar/perihilar cholangiocarcinoma. Herein, we report a case of perihilar cholangiocarcinoma arising in a hepatitis C virus-related cirrhotic liver. The patient was a 69-year-old man. He was diagnosed with hepatitis C virus-related chronic hepatitis at the age of 56 years, and 9 years later, multiple hepatocellular carcinomas were detected by imaging modalities. Despite treatments, including chemotherapy, he died of hepatic failure at the age of 69 years. At autopsy, in addition to multiple nodules of hepatocellular carcinoma, we found a white mucinous and fibrous tumor spreading from the hepatic hilum to the periphery along the left lateral segmental bile ducts in the advanced cirrhotic liver. This tumor was histologically a cholangiocarcinoma that involved mainly the peribiliary glands and showed variable cystic dilation, suggesting that it might have been derived from these peribiliary glands. Immunohistochemically, the cholangiocarcinoma cells were positive for cytokeratin 7 and mucin core protein 1, and negative for cytokeratin 20 and mucin core protein 2. Hilar/perihilar cholangiocarcinoma arising in hepatitis C virus-related liver cirrhosis has rarely been reported. This case warrants further studies to clarify the possible involvement of hepatitis C virus in tumorigenesis of hilar/perihilar cholangiocarcinoma. PMID- 17701136 TI - Simultaneous presence of xanthogranulomatous cholecystitis and gallbladder cancer. PMID- 17701137 TI - Mechanism of inhibition of human secretory phospholipase A2 by flavonoids: rationale for lead design. AB - The human secretory phospholipase A2 group IIA (PLA2-IIA) is a lipolytic enzyme. Its inhibition leads to a decrease in eicosanoids levels and, thereby, to reduced inflammation. Therefore, PLA2-IIA is of high pharmacological interest in treatment of chronic diseases such as asthma and rheumatoid arthritis. Quercetin and naringenin, amongst other flavonoids, are known for their anti-inflammatory activity by modulation of enzymes of the arachidonic acid cascade. However, the mechanism by which flavonoids inhibit Phospholipase A2 (PLA2) remained unclear so far. Flavonoids are widely produced in plant tissues and, thereby, suitable targets for pharmaceutical extractions and chemical syntheses. Our work focuses on understanding the binding modes of flavonoids to PLA2, their inhibition mechanism and the rationale to modify them to obtain potent and specific inhibitors. Our computational and experimental studies focused on a set of 24 compounds including natural flavonoids and naringenin-based derivatives. Experimental results on PLA2-inhibition showed good inhibitory activity for quercetin, kaempferol, and galangin, but relatively poor for naringenin. Several naringenin derivatives were synthesized and tested for affinity and inhibitory activity improvement. 6-(1,1-dimethylallyl)naringenin revealed comparable PLA2 inhibition to quercetin-like compounds. We characterized the binding mode of these compounds and the determinants for their affinity, selectivity, and inhibitory potency. Based on our results, we suggest C(6) as the most promising position of the flavonoid scaffold to introduce chemical modifications to improve affinity, selectivity, and inhibition of PLA2-IIA by flavonoids. PMID- 17701139 TI - [Is liver resection justified for patients with hepatic metastases from breast cancer?]. PMID- 17701138 TI - [R1 resection in the region of the lower gastrointestinal tract: relevance and therapeutic consequences]. AB - Incomplete resection (R1) and local recurrence of colorectal cancer continue to be a significant surgical problem. Radical resection of bowel and lymph node bassin are clearly necessary after incomplete endoscopic resection or local surgical excision. However, the situation is more difficult after previous conventional surgery. Anastomotic recurrence following resection and lymph nodal recurrence can often precede curative reresection. Locoregional lymph node metastases due to incomplete surgical clearance of the lymphatic drainage of colonic cancer may also be cured by radical reresection. Despite application of neoadjuvant therapy, integration of modern surgical concepts such as the circumferential resection margin and advances in surgical technique, R1 resection of rectal cancer remains a major problem. Although primary surgical therapy may be considered in selected cases, this situation will require multimodal therapy in most instances. PMID- 17701140 TI - [Local surgical therapy of venous leg ulcers]. AB - Leg ulcer is a polyaetiologic condition the successful treatment of which is decisively influenced by correct diagnosis of the underlying cause. About 76% of leg ulcer cases are due to chronic venous insufficiency. Nonhealing venous leg ulcers are the domain of local surgical therapy with a variety of symptomatic and causal surgical methods. Shave therapy is the treatment of choice, with relatively low invasiveness and good long-term results. Today subfascial endoscopic perforator vein surgery and the surgical treatment of fascia cruris (fasciotomy, fasciectomy) are used rarely but increasingly indicated. Long lasting healing is decisively influenced by thorough follow-up treatment with complex physical compression treatment and exercises following the surgical treatment of nonhealing venous leg ulcers. PMID- 17701141 TI - [Immunohistochemical and molecular-pathologic investigations in dermatohistology]. AB - Despite sophisticated diagnostic algorithms, pure morphologic diagnosis has reached its limits in many areas of general and dermatologic pathology, especially in the wake of advances in basic sciences. Modern microscopic diagnosis, especially when evaluating lymphocytic and mesenchymal tumors, depends greatly on identifying the expression of surface markers (for example CD3 as T cell surface receptor), signal proteins (cyclin D in cell cycle control) or structural proteins in tumor cells (actin in myogenous cells). Molecular biological methods include those techniques which make it possible to identify cellular and extracellular macro-molecules such as proteins and nucleic acids. At the protein level, the selective identification of proteins on sections via immunohistochemical methods is a widely used and essential component of modern pathologic-anatomic diagnosis. PMID- 17701142 TI - [Dermatopathology in German-speaking Europe. Developments and perspectives]. AB - Dermatopathology is defined as the combination of macroscopic pathology of the skin as part of the clinical diagnosis and microscopic pathology of the skin. Investigative pathology of skin diseases should be integrated into the academic practice of dermatopathology. There is no question that dermatopathology is the most important tool in dermatology for providing a specific diagnosis of skin diseases. Thus it is important to develop and support an approach to insure the highest standards for the practice of dermatopathology. PMID- 17701143 TI - [Micrographically controlled surgery. Goals and reality]. AB - Micrographic control of surgical margins reduces the risk of recurrence following excision of malignant neoplasms and allows for limited re-excisions of incompletely excised tumors. Several methods for checking surgical margins have been proposed. Principally, transverse sections through the entire specimen must be distinguished from longitudinal sections along all lateral margins. Transverse sections do not demonstrate the entire outer surface of the specimen. This may lead to false-negative results with subsequent recurrences. Longitudinal sections along lateral margins distort the architecture of the neoplasm and may make the diagnosis more difficult. Moreover, extensions of the neoplasm that come very close to lateral margins may be included in those sections, the consequence being false-positive results leading to unnecessary re-excisions. Regardless of the method employed, extensions of the neoplasm are not always recognizable, and, therefore, recurrences cannot be excluded. PMID- 17701144 TI - [Lifestyle diseases in dermatology]. AB - Psychosocial disorders and lifestyle trends have become more important in dermatology. Lifestyle diseases are a biopsychosocial phenomenon that can only be diagnosed and treated by paying attention to the quickly changing sociocultural aspects. The naming and popularization of the particular lifestyle diseases takes place by the media, but there is only an imprecise medical classification of these phenomena. This article gives an overview of the current situation and medical conditions of lifestyle diseases and try to assign them to an established psychosomatic diagnosis, based on the clinical symptomatic. Most often somatoform disorders, somatization disorders with a repeated presentation of physical symptoms which cannot be medically objectified or depressive disturbances are found. PMID- 17701145 TI - [Psychosocial factors in psoriasis. A pilot study]. AB - BACKGROUND: The successful treatment of patients with chronic plaque psoriasis depends not only on the method of therapy but also on psychosocial factors. METHODS AND RESULTS: A pilot study was performed on 22 patients with chronic plaque psoriasis. The psychosocial stress, psychiatric features and their changes were assessed over a 3-week inpatient rehabilitation stay in a specialty clinic. The severity of the psoriasis, the subjective degree of suffering and the psychometric variables related to psychosomatic symptoms were assessed before and at the end of the treatment. After the hospitalization, the severity of disease and anger were both significantly decreased, along with an increased interest in social interactions. CONCLUSION: In psoriasis patients, one can distinguish between different psychosocial factors, some of which are more likely to change. Stable attributes such as personality style can impact on compliance as well as on coping behaviors, thereby influencing treatment success. Our study shows that even within a rather short inpatient treatment period of 3 weeks not only the disease severity but also negative psychosocial stressors can be improved. PMID- 17701146 TI - [Indication for artificial nutrition: enteral and parenteral nutrition]. AB - Inadequate oral food intake and impending or manifest malnutrition are an indication for artificial nutrition. Regarding the course of the disease and quality of life this can improve the prognosis and also prolong the life span. The indication for nutritional therapy should be based on the guidelines for enteral/parenteral nutrition, however, the individual life situation of the patient should also be considered and the patient's volition should be respected. Prerequisites for any nutritional concept are careful evaluation of the nutritional status and specification of the nutritional concept adapted to any disease-specific changes in digestive capacity and metabolism. Enteral nutrition, if possible as volitional nutritional support, should be preferred to parenteral nutrition. PMID- 17701147 TI - [Heart failiure]. PMID- 17701148 TI - Exonucleolytic degradation of RNA by p53 protein in cytoplasm. AB - p53 in cytoplasm displays an intrinsic 3'-->5' exonuclease activity. To understand the significance of p53 exonuclease activity in cytoplasm, cytoplasmic extracts of various cell lines were examined for exonuclease activity with different single-stranded RNA (ssRNA) substrates. Using an in vitro RNA degradation assay, we observed in cytoplasmic extracts of LCC2 cells, expressing high levels of endogenous wtp53, an efficient 3'-->5' exonuclease activity with RNA substrates, removing the 3'-terminal nucleotides. Interestingly, RNA containing AU-rich sequences (ARE) is the permissive substrate for exonucleolytic degradation. Evidence that exonuclease function with RNA detected in cytoplasmic extracts is attributed to the p53 is supported by several facts: (1) this activity closely parallels with status and levels of endogenous cytoplasmic p53; (2) the endogenous exonuclease exerts identical RNA substrate specificity and excision profile characteristic for purified baculovirus-or bacterially-expressed wtp53s; (3) the exonuclease activity with ARE RNA is competed out by the presence of ss or double-stranded DNA substrate utilized by p53 protein in cytoplasm; (4) immunoprecipitation by specific anti-p53 antibodies markedly reduced the exonuclease activity with both RNA and DNA substrates; and (5) transfection of the wtp53, but not exonuclease-deficient mutant p53-R175H, into p53-null H1299 or HCT116 cells induced high levels of exonuclease activity with ARE RNA substrate in cytoplasm with characteristic excision profile. The efficient ARE RNA degradation correlates with the efficient binding of p53 to ARE RNA in cytoplasm. The possible role of p53 exonuclease activity in ARE-mRNA destabilization in cytoplasm, which may be important for expression of proteins that control cell growth and/or apoptosis is discussed. PMID- 17701149 TI - Thymosin beta4 and Ac-SDKP: tools to mend a broken heart. AB - Thymosin beta4 - an endogenously occurring 43 amino acid peptide - has recently been shown to possess cardioprotective properties in the setting of acute myocardial infarction. This review focuses on the reported mechanisms of action through which Thymosin beta4 might accomplish this effect and the clinical prospects for its use as a therapeutic agent. PMID- 17701150 TI - [Introduction to the topic: relative value of injury prevention]. PMID- 17701151 TI - [Transthoracic echocardiography as a diagnostic tool in patients with thoracic stab wounds: early ultrasonographic evaluation in the emergency room]. AB - Penetrating chest trauma involving the heart is usually known with a high mortality rate. Neither the absence of hemodynamic depression nor ECG changes exclude a potential fatal injury to the heart. We report on the diagnosis and definitive treatment of a stab wound injury with transected coronary artery, concomittant ventricular penetration, and pulmonary injury.A 37-year-old female was admitted to our emergency room with multiple left-sided gashes (cheek, neck, upper extremity) and a single stab wound in the left thorax. At the scene of the accident the patient's hemodynamic condition was stable with no signs of shock or shortness of breath. Auscultation revealed regular respiratory sound on both lung sides. Hospital transfer by ground was uneventful. Chest X-ray showed left pleural effusion with no signs of pneumothorax. ECG demonstrated regular sinus rhythm without repolarization changes or low voltage. Transthoracic echocardiography revealed pericardial effusion with a swinging heart. The patient was electively intubated in the emergency room and transferred to the operating room for pericardial paracentesis. Median sternotomy was necessary due to extensive bleeding in the drain. Examination of the heart showed a laceration of the left coronary artery (LAD), left ventricle, and upper lobe of the left lung. Cardiopulmonary bypass was instituted and the LAD was ligated proximal to the penetration. The left internal thoracic artery was used for coronary revascularization of the LAD. Postoperative ECG and creatine kinase evaluations excluded myocardial ischemia. The patient was discharged from hospital at POD 10 fully recovered. Transthoracic echocardiography in the emergency room is the diagnostic tool of choice to exclude/confirm a potential cardiac injury. In the case of pericardial effusion, paracentesis sometimes followed by thoracotomy should be performed. The importance of rapid diagnosis and intervention should be emphasized to reduce mortality due to cardiac tamponade or acute myocardial infarction as illustrated by this case. PMID- 17701152 TI - [Successive ruptures of patellar and Achilles tendons. Anabolic steroids in competitive sports]. AB - Derivatives of testosterone or of 19-nor-testosterone are used as anabolics for the purpose of improving performance although the effect of anabolics is known still to be under discussion. The use of anabolic steroids continues among competitive athletes despite increased controls and increasingly frequent dramatic incidents connected with them. Whereas metabolic dysfunction during anabolic use is well documented, ruptures of the large tendons are rarely reported. Within 18 months, a 29-year-old professional footballer needed surgery for rupture of the patellar tendon and of both Achilles tendons. Carefully directed questioning elicited confirmation that he had taken different anabolic steroids regularly for 3 years with the intention of improving his strength. After each operation anabolic steroids were taken again at a high dosage during early convalescence and training. Minimally invasive surgery and open suturing techniques led to complete union of the Achilles tendons in good time. Training and anabolic use (metenolon 300 mg per week) started early after suturing of the patellar tendon including bone tunnels culminated in histologically confirmed rerupture after 8 weeks. After a ligament reconstruction with a semitendinosus tendon graft with subsequent infection, the tendon and reserve traction apparatus were lost. Repeated warnings of impaired healing if anabolic use was continued had been given without success. In view of the high number of unrecorded cases in competitive and athletic sports, we can assume that the use of anabolic steroids is also of quantitative relevance in the operative treatment of tendon ruptures. PMID- 17701153 TI - [Chorea. Causes, diagnosis, and therapy]. AB - The differential diagnosis of chorea includes a growing number of rare diseases. This article gives hints on clinical differences and possible laboratory investigations which may help to identify the underlying disease. The majority of hereditary chorea cases are caused by Huntington's disease. Different courses of disease can be distinguished depending on age at disease onset. The diagnosis can be confirmed genetically. Predictive testing is also possible but should be applied with caution only following internationally accepted guidelines. Our knowledge about treatment of chorea is limited, and studies have focused on the use of neuroleptics only. Their value is often outweighed by serious side effects. All efforts to find disease-modifying therapies for Huntington's disease had negative outcomes so far. To face these therapeutic limitations, the European Huntington's Disease Network was formed as a platform supporting the development and undertaking of clinical studies in Huntington's disease to improve care for these patients. PMID- 17701154 TI - [Progress and tradition. 100 years of the congress held by the German Society of Urology: Vienna 1907-Berlin 2007]. AB - The history of the German Urological Society and their congress reflects the scientific medical achievements of the last 100 years as well as the political and social structure of the twentieth century with the fantastic medical progress and the tremendous catastrophes. The congress in Berlin in 2007 once again links the urological society with the congress in Vienna of 1907. PMID- 17701155 TI - [Urologic Oncology Study Society. Promotor and facilitator of uro-oncologic clinical research]. PMID- 17701156 TI - [Tissue engineering and stem cell research in urology for a reconstructive or regenerative treatment approach]. AB - With the involvement of clinical reconstructive urology in the field of tissue engineering, outstanding results have been achieved in basic research as well as in some clinics. Stem cell research has even opened up possibilities for regenerative aspects. In close cooperation with various disciplines, the Department of Urology at the University of Tubingen investigates different clinical aspects with regard to reconstructive and regenerative urology. The regeneration of the external urethral sphincter requires functionally integrated muscle cells. In addition stricture reconstruction with multilayer urothelium should become less invasive and the re-stricture rate reduced. After the application of differentiating stem cells was proven, the clinical setting needed to be set for legal issues. In addition to the specification of culture media and verification in the animal model, the possibility to harvest omnipotent stem cells out of human testis and to differentiate those into the three germ layers was demonstrated. With the reduced invasiveness of harvesting the urothelium cells by a bladder wash using specific culture fluids, the cell culture was significantly improved enabling successful creation of urothelium by stratification. In addition urothelial cells in a matrix are further improved for endoscopic application. The close cooperation of different disciplines shortens the time to develop therapeutic approaches with a close clinical relationship in reconstructive and regenerative urology. PMID- 17701157 TI - Plasma sex steroid hormones and risk of developing type 2 diabetes in women: a prospective study. AB - AIMS/HYPOTHESIS: Prospective data directly investigating the role of endogenous sex hormones in diabetes risk have been scant, particularly in women. We aimed to examine comprehensively plasma sex hormones in connection with risk of developing type 2 diabetes in postmenopausal women. METHODS: We conducted a prospective, nested case-control study of plasma oestradiol, testosterone and dehydroepiandrosterone sulfate and risk of type 2 diabetes in a cohort of women health professionals with a mean age of 60.3 and 12.2 years since menopause. Among women not using hormone therapy and free of baseline cardiovascular disease, cancer and diabetes, 359 incident cases of type 2 diabetes were matched with 359 controls during an average follow-up of 10 years. RESULTS: Oestradiol and testosterone were each strongly and positively associated with risk of type 2 diabetes. After adjustment for BMI, family history, lifestyle and reproductive variables, the multivariable relative risks (95% CI) comparing the highest vs lowest quintile were 12.6 (2.83-56.3) for total oestradiol (p = 0.002 for trend), 13.1 (4.18-40.8) for free oestradiol (p < 0.001 for trend), 4.15 (1.21-14.2) for total testosterone (p = 0.019 for trend) and 14.8 (4.44-49.2) for free testosterone (p < 0.001 for trend). These associations remained robust after adjusting and accounting for other metabolic syndrome components and baseline HbA(1c) levels. CONCLUSIONS/INTERPRETATION: In postmenopausal women, higher plasma levels of oestradiol and testosterone were strongly and prospectively related to increased risk of developing type 2 diabetes. These prospective data indicate that endogenous levels of sex hormones may play important roles in the pathogenesis of type 2 diabetes. ClinicalTrials.gov ID no.: NCT00000479. PMID- 17701159 TI - [Arthroscopic reconstruction of the rotator cuff. The current gold standard?]. AB - Arthroscopic rotator cuff repair has become the gold standard, and is now accepted throughout the world as the method of choice, for rotator cuff repair. As well as an experienced surgeon and meticulously correct arthroscopic technique, careful patient selection and adequate postoperative management are of decisive importance if a good postoperative outcome is to be achieved. With due consideration for all these factors the success rate is over 90%, as measured not only with reference to objective criteria, but also by patients' reports of their how satisfied they are with the result. This paper aims to report the indications, arthroscopic technique and postoperative protocol, and also the results of arthroscopic rotator cuff repair. PMID- 17701160 TI - Risk of Clostridium difficile diarrhoea in critically ill patients treated with erythromycin-based prokinetic therapy for feed intolerance. AB - OBJECTIVE: To determine the incidence of Clostridium difficile (CD) diarrhoea in feed-intolerant, critically ill patients who received erythromycin-based prokinetic therapy. DESIGN AND SETTING: Prospective observational study in a mixed intensive care unit. METHODS: The development of diarrhoea (> 3 loose, liquid stool per day with an estimated total volume > or = 250ml/day) was assessed in 180 consecutive critically ill patients who received prokinetic therapy (erythromycin only, n = 53; metoclopramide, n 37; combination erythromycin/metoclopramide, n = 90) for feed intolerance. Stool microscopy, culture and CD toxin assay were performed in all patients who developed diarrhoea during and after prokinetic therapy. Diarrhoea was deemed to be related to CD infection if CD toxin was detected. RESULTS: Demographics, antibiotic use and admission diagnosis were similar amongst the three patients groups. Diarrhoea developed in 72 (40%) patients, 9.9 +/- 0.8 days after commencement of therapy, none of whom was positive for CD toxin or bacterial infection. Parasitic infections were found in four aboriginal men from an area endemic for these infections. Diarrhoea was most prevalent in patients who received combination therapy (49%) and was more common than in those who received erythromycin alone (30%) and metoclopramide alone (32%). Diarrhoea was short-lasting with a mean duration of 3.6 +/- 1.2 days. CONCLUSIONS: In critical illness, diarrhoea following the administration of erythromycin at prokinetic doses is not associated with CD but may be related to pro-motility effects of the agent. Prokinetic therapy should be stopped at the onset of diarrhoea and prophylactic use should be strictly avoided. PMID- 17701161 TI - Review of retention strategies in longitudinal studies and application to follow up of ICU survivors. AB - OBJECTIVE: To review the literature on retention strategies in follow-up studies and their relevance to critical care and to comment on the Toronto experience with the acute respiratory distress syndrome (ARDS) and severe acute respiratory syndrome (SARS) follow-up studies. DESIGN AND SETTING: Literature review and two cohort studies in a tertiary care hospital in Toronto, Canada. PATIENTS AND PARTICIPANTS: ARDS and SARS patients. MEASUREMENTS AND RESULTS: Review articles from the social sciences and medicine are summarized and our own experience with two longitudinal studies is drawn upon to elucidate strategies that can be successfully used to attenuate participant drop-out from longitudinal studies. Three key areas for retention of subjects are identified from the literature: (a) respect for patients: respect for their ideas and their time commitment to the research project; (b) tracking: collect information on many patient contacts at the initiation of the study and outline tracking procedures for subjects lost to follow-up; and (c) study personnel: interpersonal skills must be reinforced, flexible working hours mandated, and support offered. Our 5-year ARDS and 1-year SARS study retention rates were 86% and 91%, respectively, using these methods. CONCLUSIONS: Strategies to reduce patient attrition are time consuming but necessary to preserve internal and external validity. When the follow-up system is working effectively, researchers can acquire the necessary data to advance knowledge in their field and patients are satisfied that they have an important role to play in the research project. PMID- 17701162 TI - Risk factors of early redialysis after weaning from postoperative acute renal replacement therapy. AB - OBJECTIVE: The aim of this study was to identify risk factors for redialysis in postoperative patients with acute renal failure (ARF) who had previously been weaned from acute dialysis. Although recovery of renal function is anticipated in patients with ARF, no data have been reported on successful weaning from acute dialysis. DESIGN AND SETTING: Retrospective observational case-control study in a 64-bed surgical ICU. PATIENTS AND METHODS: Success in discontinuing dialysis was defined as cessation from dialysis for at least 30 days. A total of 304 postoperative patients who underwent acute renal replacement therapy in a surgical ICU between July 2002 and April 2005 were included. SOFA score biochemical data and renal function parameters were assessed on the day after the last session of renal replacement therapy, designated as day 0 (D0). RESULTS: We could wean 94 patients (30.9%) from acute dialysis for more than 5 days, and 64 of these (21.1%) were successfully weaned for at least 30days. The independent predictors for resuming dialysis within 30 days were: (a) longer duration of dialysis (OR 1.06), (b) higher SOFA score on D0 (OR 1.44), (c) oliguria (urine output <100cc/8h; OR 4.17) on D1, and (d) age over 65 years (OR 6.35). The area under the ROC curve was 0.880. Two-way analysis of variance with repeated measurements over time showed a larger decline in SOFA score and an increase in urine output in patients with successful cessation of dialysis. Kaplan-Meier analysis showed a significant difference in early resumption of dialysis between patients with or without oliguria at D0. CONCLUSIONS: More than two-thirds of patients weaned from postoperative acute dialysis for more than 5 days were free of dialysis for at least 30 days. Less urine output, longer duration of dialysis, age over 65 years, and higher disease severity score are predictive of a patient's redialysis after initial weaning from acute dialysis. PMID- 17701163 TI - Creating competent and caring physicians: ensuring patients are our North Star. PMID- 17701164 TI - The views of patients and relatives of what makes a good intensivist: a European survey. AB - OBJECTIVE: This study examined the views of adult patients and relatives about desirable characteristics of specialists in intensive care medicine (ICM) to incorporate these into an international competency-based training programme, CoBaTrICE. DESIGN: Convenience sample of patients and relatives administered after discharge from 70 participating ICUs in eight European countries (1,398 evaluable responses). The structured questionnaire included 21 characteristics of medical competence categorised as 'medical knowledge and skills', 'communication with patients', and 'communication with relatives'. It was available in the national languages of the countries involved. Questions were rated by respondents for importance using a four-point Likert scale. Responses to open questions were also invited. RESULTS: Most characteristics were highly rated, with priority given to medical knowledge and skills. Women were more likely to emphasise communication skills. There were no consistent regional differences. Free-text responses welcomed the opportunity to participate. CONCLUSIONS: Patients and relatives with experience of intensive care in different European countries share similar views on the importance of knowledge, skills, decision making and communication in the training of intensive care specialists. These generic patient-centred components of training have been incorporated into the international competency-based ICM training programme, CoBaTrICE. PMID- 17701166 TI - Molecular imaging. PMID- 17701165 TI - Role of glutamate transporters in the modulation of stress-induced lactate metabolism in the rat brain. AB - RATIONALE: Lactate, like glucose, has recently been found to be an energy substrate for neural activity. It is indicated that lactate is produced by astrocytes under the regulation of glutamatergic tone. OBJECTIVES: Using in vivo microdialysis technique, we measured extracellular lactate concentrations in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) of rats. To investigate the role of the glutamate transporter in the modulation of footshock stress-induced energy demands in both brain regions, we attempted to determine whether the footshock stress-induced changes of extracellular lactate concentrations are attenuated by local perfusion of the glutamate uptake inhibitor dihydrokainate (DHK). RESULTS: Perfusion of 1.0 mM DHK produced an increase in basal extracellular lactate levels in the mPFC and BLA, whereas 0.1 mM DHK did not affect lactate concentrations in either region. DHK also attenuated stress-induced increment of extracellular lactate concentrations in the mPFC, and completely prevented it in the BLA. CONCLUSIONS: These results suggest that glutamate transporters regulate lactate availability in astrocytes and indicate that the rapid energy demand induced by glutamate contributes to local lactate production. PMID- 17701167 TI - Interaction between a commercially available St. John's wort product (Movina) and atorvastatin in patients with hypercholesterolemia. AB - OBJECTIVE: The aim of this study was to assess the effect of treatment with a St. John's wort product (Movina) on cholesterol [total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol] and triglyceride levels in patients with hypercholesterolemia on treatment with a stable dose of atorvastatin in a controlled, randomised, open, crossover interaction study. METHODS: Sixteen patients with hypercholesterolemia treated with a stable dose of atorvastatin (10-40 mg/daily) for at least 3 months were treated with Movina one tablet (containing 300 mg of hypericum perforatum) twice daily and control (a commercially available multivitamin tablet Vitamineral). After a run-in period of 4 weeks, patients were randomised to treatment with either Movina or control for 4 weeks in a crossover design. The atorvastatin dose was kept unchanged during the study period (12 weeks), and assessments of total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides were performed in the morning with the patients in the fasting condition. The difference between control and active treatment in LDL cholesterol after 4 weeks of treatment was the primary endpoint. RESULTS: All patients completed the study. The St. John's wort product significantly increased the serum level of LDL cholesterol compared with control (2.66 mmol/l compared with 2.34 mmol/l, p = 0.004). A significant increase in total cholesterol was also observed (5,10 mmol/l compared with 4.78 mmol/l, p = 0.02). No statistically significant change was observed in HDL cholesterol (1.59 mmol/l and 1.56 mmol/l, p = 0.49) or in triglycerides (1.87 mmol/l and 1.94 mmol/l, p = 0.60). No product-related side effects were reported CONCLUSION: An interaction was observed between the studied St.-John's-wort containing product and atorvastatin. Physicians and patients should be aware of this interaction and if treatment with a St. John's wort product is considered necessary, then there may be a need for increasing the dose of atorvastatin. PMID- 17701168 TI - Anatomical parcellation of the brainstem and cerebellar white matter: a preliminary probabilistic tractography study at 3 T. AB - INTRODUCTION: The aims of this study were: (1) to test whether higher spatial resolution diffusion tensor images and a higher field strength (3 T) enable a more accurate delineation of the anatomical tract within the brainstem, and, in particular, (2) to try to distinguish the different components of the corticopontocerebellar paths in terms of their cortical origins. METHODS: The main tracts of the brainstem of four volunteers were studied at 3 T using a probabilistic diffusion tensor imaging (DTI) axonal tracking. The resulting tractograms enabled anatomical well-delineated structures to be identified on the diffusion tensor coloured images. RESULTS: We tracked corticopontine, corticospinal, central tegmental, inferior and superior cerebellopeduncular, transverse, medial lemniscal and, possibly, longitudinal medial fibres. Moreover, DTI tracking allowed a broad delineation of the corticopontocerebellar paths. CONCLUSION: Diffusion tensor coloured images allow a rapid and reliable access to the white matter broad parcellation of the brainstem and of the cerebellum, which can be completed by fibre tracking. However, a more accurate and exhaustive depiction of the anatomical connectivity within the brainstem requires the application of more sophisticated techniques and tractography algorithms, such as diffusion spectrum imaging. PMID- 17701169 TI - Chronic exertional compartment syndrome of the lower extremities: improved screening using a novel dual birdcage coil and in-scanner exercise protocol. AB - OBJECTIVE: The purpose of this study was to design and evaluate an MRI screening protocol for chronic exertional compartment syndrome (CECS) of the lower legs using an in-scanner exercise protocol and novel dual birdcage coil design for improved imaging. MATERIALS AND METHODS: Coil and phantom studies: a custom-made dual birdcage coil designed for this protocol was evaluated for uniformity and signal-to-noise ratio (SNR) compared with a conventional phased-array receive only torso coil and the body coil. Phantom and normal subject studies were performed to confirm coil performance. In-vivo studies: eight unaffected subjects and 42 patients with lower extremity symptoms suggestive of CECS were imaged with the dual birdcage coil and an in-scanner exercise protocol which included imaging at rest, during isometric resisted dorsi flexion, at rest (recovery), during isometric resisted plantar flexion and, again, at rest. Of 42 patients, 14 had confirmed CECS and 28 had lower extremity anomalies attributable to other causes. Ratios of relative T2-weighted signal intensities were calculated for exercise and recovery images compared to baseline after processing of images, including re registration for motion, smoothing and segmentation to remove bone and pulsation artifacts from blood vessels. RESULTS: Receiver operating characteristic (ROC) analysis showed a threshold for the ratio of relative T2-weighted signal intensity of 1.54 to have a sensitivity of 96%, specificity of 90% and accuracy of 96% for CECS. Patients with CECS had their peak ratio of signal intensity compared with baseline during the first recovery period after isometric dorsi flexion, whereas unaffected subjects and patients with other causes of exercise induced lower extremity pain reached their peak values during exercise (P<0.001). CONCLUSION: We have developed the first in-scanner MRI exercise protocol for the assessment of patients with suspected CECS. The technique shows high accuracy, sensitivity and specificity for diagnosis in this small cohort of patients with CECS. Further study may allow this non-invasive test to be used as a triage tool for invasive intracompartmental pressure measurements in patients with suspected CECS. PMID- 17701172 TI - Changes in glucose metabolism and gene expression after transfer of anti angiogenic genes in rat hepatoma. AB - PURPOSE: Human troponin I (TROP), the soluble receptor for vascular endothelial growth factor (sFLT) and angiostatin (ASTAT) are potent inhibitors of endothelial cell proliferation, angiogenesis and tumour growth in vivo. Transfer of these genes into tumours may induce changes not only in perfusion, but also more general ones such as changes in metabolism. The aim of this study was to assess these reactions using FDG-PET and high-throughput methods such as gene profiling. METHODS: We established Morris hepatoma (MH3924A) cell lines expressing TROP, sFLT or ASTAT and quantified (18)F-fluorodeoxyglucose ((18)FDG) uptake by dynamic positron emission tomography (PET) after tumour inoculation in ACI rats. Furthermore, expression of glucose transporter-1 and -3 (GLUT-1 and GLUT-3) as well as hexokinase-1 and -2 were investigated by RT-PCR and immunohistomorphometry. In addition, gene array analyses were performed. RESULTS: (18)FDG uptake, vascular fraction and distribution volume were significantly higher in all genetically modified tumours. Immunohistomorphometry showed an increased percentage of hexokinase-1 and -2 as well as GLUT-1 and -3 immunoreactive (ir) cells. Using gene arrays and comparing all three groups of genetically modified tumours, we found upregulated expression of 36 genes related to apoptosis, signal transduction, stress or metabolism. CONCLUSION: TROP-, sFLT- or ASTAT-expressing MH3924A tumours show enhanced influx of (18)FDG, which seems to be caused by several factors: enhanced exchange of nutrients between blood and tumour, increased amounts of glucose transporters and hexokinases, and increased expression of genes related to apoptosis, matrix and stress, which induce an increased demand for glucose. PMID- 17701173 TI - Functional outcome after endoprosthetic limb-salvage therapy of primary bone tumours--a comparative analysis using the MSTS score, the TESS and the RNL index. AB - Limb-saving therapy for primary bone tumours is the treatment of choice. We aimed at analysing the quality of life of this group of patients by combining three different tools. Eighty-seven patients (46 females, 41 males) with a primary bone tumour of the extremity who had undergone endoprosthetic reconstruction between 1982 and 2000 were included in this retrospective study. The median age at the time of evaluation was 30 (12-73) years. The Toronto Extremity Salvage Score (TESS) and the Reintegration to Normal Living index (RNL) were recorded an average of 5.8 years after reconstruction and the Musculoskeletal Tumour Society Score (MSTS) after an average of 6.5 years. The mean MSTS score was 77% (13-93%). The mean TESS was 82% (22-99%), and the mean RNL index was 87% (32-98%). The subjective satisfaction and acceptance of physical impairment were significantly higher than the objective score (p < 0.001). The TESS was 88% in patients aged 12 25 years, 81% in those aged 26-40 years and 57% in those aged 41-73 years. Parallel recording of the MSTS score, TESS and RNL index provides a better measure reflecting the complex situation of the patients by combining objective and subjective parameters. PMID- 17701174 TI - A multicenter analysis of the FIP1L1-alphaPDGFR fusion gene in Japanese idiopathic hypereosinophilic syndrome: an aberrant splicing skipping the alphaPDGFR exon 12. AB - To study the clinical characteristics of hypereosionophilic syndrome and chronic eosinophilic leukemia (HES/CEL) in Japan, the clinical data of 29 HES/CEL patients throughout the country were surveyed. Moreover, the involvement of the FIP1L1-alphaPDGFR fusion gene resulting from a cryptic del (4)(q12q12) was examined in 24 cases. The FIP1L1-alphaPDGFR messenger RNA (mRNA) was detected in three patients (13% of patients fulfilled WHO criteria and 17% of Chusid criteria). One had a novel fusion transcript, which skipped the exon 12 of alphaPDGFR. The transcript appears to be generated by a splicing mechanism that is different from the previously reported splicing patterns. In silico analysis, the exon skipping was not related to a disruption of the exonic splicing enhancers within the exon but strongly associated with the loss of the vast majority of the FIP1L intron 8a where intronic splicing enhancers were accumulated. Unexpectedly, pseudo-chimera DNA fragments with some shared characteristic features were occasionally generated from healthy control samples by reverse transcriptase polymerase chain reaction (RT-PCR). Considering the relatively low incidence of the FIP1L1-alphaPDGFR transcript positive case, extreme care must therefore be taken when making a diagnosis using RT-PCR before imatinib therapy. PMID- 17701175 TI - Signaling status of IgG B cell receptor (IgG BCR) is indicative for an activated state of circulating B cells in multiple myeloma. AB - Circulating post-switch B cells have been proposed as proliferative and disseminating progenitors in multiple myeloma. It is unclear whether the class switched antigen receptor expressed at the surface of these cells plays a role in their expansion. In this work, the signaling status of IgG B cell receptor (BCR) isolated from the lysates of peripheral blood lymphocytes of 32 patients with IgG multiple myeloma, at the time of diagnosis, was investigated by examining whether phosphorylation of BCR Igalpha and Igbeta signal transducer factors (co receptors) or other signaling molecules was abnormal in these cells when compared with healthy controls. In IgG BCR of normal controls, weak phosphorylation of 56 and 61 kDa Src kinase-related proteins and unphosphorylated co-receptors were found. In myeloma, p56 and p61 kDa proteins, co-receptors, and other IgG BCR associated proteins from the signal cascade were phosphorylated. Myeloma patients can be classified into subgroups by IgG BCR phosphorylation profiles which characteristically coordinated with the level of IgG paraprotein in serum and the stage of disease. There was a correlative trend between the extent of phosphorylation reduction and advanced stage of disease. Reduced phosphorylation was more pronounced with advanced stages of multiple myeloma. PMID- 17701176 TI - The preparation and characterization of anti-VEGFR2 conjugated, paclitaxel-loaded PLLA or PLGA microspheres for the systemic targeting of human prostate tumors. AB - PURPOSE: The objective of this study was to manufacture paclitaxel (PTX) loaded polymeric microspheres, that were surface conjugated with antibodies to vascular endothelial growth factor receptor 2 (anti-VEGFR2), for systemic targeting to angiogenic sites in prostate tumors. METHODS: Microspheres were manufactured in the 1-3 microm size range from poly (l-lactic acid) (PLLA) or poly (lactide-co glycolide) (PLGA) by a modified solvent evaporation method using Polytron homogenization followed by high speed dispersion in poly vinyl alcohol. Antibodies were conjugated to the surface of these microspheres using cyanogen bromide activation of the polymer surface. Cell Binding was determined using human umbilical vein endothelial cells (HUVECs) in vitro. Efficacy determinations were made using human prostate tumors (PC-3) grown subcutaneously in mice. RESULTS: Antibodies were effectively bound to the surface of PLLA and PLGA microspheres. Anti-VEGFR2 conjugated PLLA microspheres bound strongly to HUVEC's. Pilot efficacy studies in mice showed variability but demonstrated a significant inhibition of tumor growth following the systemic administration of a single dose of PTX-loaded anti-VEGFR2 conjugated PLLA microspheres as compared to non antibody-conjugated PTX-loaded microspheres. CONCLUSION: Anti-VEGFR2 conjugated PLLA microspheres containing PTX may offer an effective way of administering a controlled release formulation of the drug to target prostate tumors. PMID- 17701177 TI - Modelling and simulations of multi-component lipid membranes and open membranes via diffuse interface approaches. AB - Diffuse interface (phase field) models are developed for multi-component vesicle membranes with different lipid compositions and membranes with free boundary. These models are used to simulate the deformation of membranes under the elastic bending energy and the line tension energy with prescribed volume and surface area constraints. By comparing our numerical simulations with recent biological experiments, it is demonstrated that the diffuse interface models can effectively capture the rich phenomena associated with the multi-component vesicle transformation and thus offering great functionality in their simulation and modelling. PMID- 17701178 TI - Pathogenesis-related adhesion molecules in Henoch-Schonlein vasculitis. AB - The aim of this study was to reveal the distribution of various inflammation and endothelium-related adhesion molecules, namely, P-selectin, E-selectin, ICAM-1, ICAM-2, ICAM-3 and VCAM-1, on the skin samples of patients with Henoch-Schonlein purpura. Skin biopsies obtained from 12 pediatric patients at the acute purpura phase and from 5 patients at the convalescent phase of the disease were included in the study. Endothelial expression of P-selectin (P < 0.05), endothelial and inflammatory cellular expressions of ICAM-2 (P < 0.05, P < 0.01) and inflammatory cellular expression of ICAM-3 (P < 0.05) were significantly more intense when compared to patients in the convalescent phase. Although endothelial E-selectin and VCAM-1 expressions, and endothelial and inflammatory cellular ICAM-1 expressions displayed a decrease in the convalesant phase, this difference was not found to be statistically significant (P > 0.05). PMID- 17701179 TI - Relative validity of the modified American Shoulder and Elbow Surgeons (M-ASES) questionnaire using item response theory. AB - The modified American Shoulder and Elbow Surgeon's (M-ASES) questionnaire is purported to be a non-region specific functional measure of the entire upper extremity. The purpose of this study was to determine the factor structure of the M-ASES and to determine item-fit of the M-ASES using item response theory (IRT). Analyses included univariate baseline demographics, factor analysis, convergent/construct validation with the SF-12, and graded response IRT of the M ASES. 964 patients of an orthopedic practice with a variety of upper extremity dysfunctions participated in this trial. The M-ASES demonstrated two dimensions (wrist/hand and shoulder dysfunction) and exhibited excellent discrimination and threshold specification. The instrument correlated well with the mental and physical dimensions of the SF-12. The M-ASES should be considered an excellent tool for measure of whole upper extremity dysfunction. PMID- 17701180 TI - Radiological staging of ovarian cancer: imaging findings and contribution of CT and MRI. AB - Ovarian cancer is the most lethal among the gynecologic malignancies with approximately 70% of patients presenting with advanced tumor stage. The prognosis of patients with ovarian cancer is directly related to the tumor stage and residual tumor burden after cytoreductive surgery. Exploratory laparotomy has been the cornerstone in the management of ovarian cancer, as it offers staging and tumor debulking. Understaging at initial laparotomy, however, is a problem in up to 30%, mainly due to insufficient technique and unexpected peritoneal spread outside the pelvis. Sites difficult to assess intraoperatively including the posterior aspect of the liver and the dome of the diaphragm can be well demonstrated with multiplanar imaging. CT and alternatively MRI have been accepted as adjunct imaging modalities for preoperative staging ovarian cancer. Of these, multidetector CT is the imaging modality of choice for staging ovarian cancer. In a multidisciplinary team approach patient management may be guided towards an individualized treatment plan. The contribution of imaging includes (1) surgery planning including referral practice, (2) selection of candidates for primary chemotherapy by demonstration of non (optimally) resectable disease, and (3) tissue sampling in peritoneal carcinomatosis. PMID- 17701181 TI - Quantitative diffusion tensor fiber tracking of age-related changes in the limbic system. AB - Cerebral white matter is known to undergo degradation with aging, and diffusion tensor imaging (DTI) is capable of revealing the white matter integrity. We assessed age-related changes of quantitative diffusivity parameters and fiber characteristics within the fornix and the cingulum. Thirty-eight healthy subjects aged 18-88 years were examined at 3 Tesla using a 1.9-mm isotropic DTI sequence. Quantitative fiber tracking was performed for 3D-segmentation of the fornix and the cingulum to determine fractional anisotropy (FA), mean diffusivity (MD), eigenvalues (lambda1, lambda2, and lambda3), number of fibers (NoF), and mean NoF/voxel (FpV). In the fornix, all diffusivity parameters (FA, MD, and eigenvalues) were moderately correlated with age. Strong and moderate negative correlations for NoF and FpV were found, respectively. In the cingulum, no correlation was observed between FA and age, and only weak correlations for the other quantitative parameters. Differences in correlations between the fornix and the cingulum were significant for all diffusivity parameters and for NoF, but not for FpV. The strongest relative changes per decade of age were found in the fornix: FA -2.1%, MD 4.2%, NoF -10.6%, and FpV -4.6%. Our quantitative 3D fiber tracking approach shows that the cingulum is resistant to aging while the fornix is not. PMID- 17701182 TI - Prediction of myocardial recovery by dobutamine magnetic resonance imaging and delayed enhancement early after reperfused acute myocardial infarction. AB - The purpose was to study dobutamine magnetic resonance cine imaging (DOB-MRI) and delayed myocardial contrast enhancement (DE) early after reperfused acute myocardial infarction (AMI) for the predicion of segmental myocardial recovery and to find the optimal dose of dobutamine. Fifty patients (56+/-12 years, 42 males) with reperfused AMI underwent DOB-MRI and DE studies 3.5 (1-19) days after reperfusion. In DOB-MRI systolic wall thickening (SWT) was measured in 18 segments at rest and during dobutamine at 5, 10 and 20 microg*kg(-1)*min(-1). Dysfunctional segments were identified and the extent of DE was measured for each segment. Segmental recovery was examined after 8 (5-15) months. Two hundred-forty eight segments were dysfunctional with presence of DE in 193. DOB-MRI showed the best prediction of recovery at 10 microg*kg(-1)*min(-1) of dobutamine with sensitivity of 67%, specificity of 63% and accuracy of 66% using a cut-off value for SWT of 2.0 mm. DE revealed a sensitivity of 68%, specificity of 65% and accuracy of 67% using a cut-off value of 46%. Combined analysis of DOB-MRI and DE did not improve diagnostic performance. Early prediction of segmental myocardial recovery after AMI is possible with DOB-MRI and DE. No improvement is achieved by dobutamine >10 microg*kg(-1)*min(-1) or a combination of DOB-MRI and DE. PMID- 17701183 TI - Delineation and segmentation of cerebral tumors by mapping blood-brain barrier disruption with dynamic contrast-enhanced CT and tracer kinetics modeling-a feasibility study. AB - Dynamic contrast-enhanced (DCE) imaging is a promising approach for in vivo assessment of tissue microcirculation. Twenty patients with clinical and routine computed tomography (CT) evidence of intracerebral neoplasm were examined with DCE-CT imaging. Using a distributed-parameter model for tracer kinetics modeling of DCE-CT data, voxel-level maps of cerebral blood flow (F), intravascular blood volume (vi) and intravascular mean transit time (t1) were generated. Permeability surface area product (PS), extravascular extracellular blood volume (ve) and extraction ratio (E) maps were also calculated to reveal pathologic locations of tracer extravasation, which are indicative of disruptions in the blood-brain barrier (BBB). All maps were visually assessed for quality of tumor delineation and measurement of tumor extent by two radiologists. Kappa (kappa) coefficients and their 95% confidence intervals (CI) were calculated to determine the interobserver agreement for each DCE-CT map. There was a substantial agreement for the tumor delineation quality in the F, ve and t1 maps. The agreement for the quality of the tumor delineation was excellent for the vi, PS and E maps. Concerning the measurement of tumor extent, excellent and nearly excellent agreement was achieved only for E and PS maps, respectively. According to these results, we performed a segmentation of the cerebral tumors on the base of the E maps. The interobserver agreement for the tumor extent quantification based on manual segmentation of tumor in the E maps vs. the computer-assisted segmentation was excellent (kappa = 0.96, CI: 0.93-0.99). The interobserver agreement for the tumor extent quantification based on computer segmentation in the mean images and the E maps was substantial (kappa = 0.52, CI: 0.42-0.59). This study illustrates the diagnostic usefulness of parametric maps associated with BBB disruption on a physiology-based approach and highlights the feasibility for automatic segmentation of cerebral tumors. PMID- 17701184 TI - MR thermometry for monitoring tumor ablation. AB - Local thermal therapies are increasingly used in the clinic for tissue ablation. During energy deposition, the actual tissue temperature is difficult to estimate since physiological processes may modify local heat conduction and energy absorption. Blood flow may increase during temperature increase and thus change heat conduction. In order to improve the therapeutic efficiency and the safety of the intervention, mapping of temperature and thermal dose appear to offer the best strategy to optimize such interventions and to provide therapy endpoints. MRI can be used to monitor local temperature changes during thermal therapies. On line availability of dynamic temperature mapping allows prediction of tissue death during the intervention based on semi-empirical thermal dose calculations. Much progress has been made recently in MR thermometry research, and some applications are appearing in the clinic. In this paper, the principles of MRI temperature mapping are described with special emphasis on methods employing the temperature dependency of the water proton resonance frequency. Then, the prospects and requirements for widespread applications of MR thermometry in the clinic are evaluated. PMID- 17701185 TI - Bat breath reveals metabolic substrate use in free-ranging vampires. AB - We analysed the stable carbon isotope ratio in exhaled CO(2) (delta(13)C(breath)) of free-ranging vampires to assess the type of metabolized substrate (endogenous or exogenous substrate) and its origin, i.e. whether the carbon atoms came from a C(4) food web (grass and cattle) or the C(3) food web in which they were captured (a rainforest remnant and its mammals). For an improved understanding of factors influencing the delta(13)C(breath) of vampires, we conducted feeding experiments with captive animals. The mean delta(13)C(breath) of starved bats was depleted in (13)C in relation to the diet by 4.6 per thousand (n = 10). Once fed with blood, delta(13)C(breath )levelled off within a short time approximately 2.2 per thousand above the stable carbon isotope signature of the diet. The median time required to exchange 50% of the carbon atoms in exhaled CO(2) with carbon atoms from the ingested blood was 18.6 min (mean 29.5 +/- 19.0 min, n = 5). The average delta(13)C of wing membrane and fur in free-ranging vampire bats suggested that bats almost exclusively foraged for cattle blood during the past weeks. The delta(13)C(breath) of the same bats averaged -19.1 per thousand. Given that all free-ranging vampires were starving and that the delta(13)C of cattle was more in enriched in (13)C by 5-6 per thousand than the delta(13)C(breath) of vampires, we conclude that the vampire bats of our study metabolised fat that was predominantly built from carbon atoms originating from cattle blood. Since delta(13)C of wing membrane and fur integrates over weeks and months respectively and delta(13)C(breath) over hours and days, we also conclude that vampire bats of the studied population consistently ignored rainforest mammals and chose cattle as their prey during and prior to our study. PMID- 17701186 TI - Visual function in nonsyndromic craniosynostosis: past, present, and future. AB - BACKGROUND: Previous studies on visual function in craniosynostosis have mainly focused on ocular movements and ophthalmologic findings. More recently, some studies also included the assessment of more functional and electrophysiological aspects of vision, such as acuity and visual evoked potentials. METHODS: We reviewed all the relevant publications on visual findings in infants and children with both syndromic and nonsyndromic craniosynostosis and reported our own recent experience on the presurgical assessment of visual function in infants with single suture nonsyndromic craniosynostosis. RESULTS: Most studies report abnormal ophthalmologic findings, mainly strabismus and refractive deficits. Only few recent studies, including ours, have reported the impairment of more functional aspects of vision, such as visual acuity and visual evoked potentials in relation to the various forms of craniosynostoses. DISCUSSION: We suggest a few guidelines for further studies, which may help to better elucidate the mechanisms underlying possible visual impairment in the various types of craniosynostosis. PMID- 17701187 TI - Ethylenevinylalcohol copolymer (Onyx-18) used in endovascular treatment of vein of Galen malformation. AB - BACKGROUND: Vein of Galen malformations (VGM) are rare congenital arteriovenous fistulas that usually present with heart failure in the neonate. Endovascular treatment options in the past have utilized coils, balloons, and acrylics. CASE REPORT: We present, for the first time in the literature, a case of an infant with VGM treated initially with staged coil embolizations followed 1 year later by the transarterial and transvenous catheter based injection of Onyx-18 (ethylenevinylalcohol copolymer) in a single treatment session. The fistula was eliminated, and the infant's cardiopulmonary symptoms were improved. PMID- 17701188 TI - Value of measuring subpopulations of T and B lymphocytes in patients with musculoskeletal tumours. AB - BACKGROUND: Aims of our study were to assess the clinical value of measuring subpopulations of T and B lymphocytes in patients with musculoskeletal tumours as an immunodiagnostic procedure in the primary diagnosis of tumours. METHODS: In this prospective study, blood samples were obtained from 145 patients aged 04-98 years with musculoskeletal tumours. CD3, CD4, CD8, Helper/Suppressor ratio and CD19 subpopulations of lymphocytes were measured in specimens of whole blood in EDTA, upon the principle of Ortho Cytoron Absolute flow cytometry. Histological tumour diagnosis was obtained by the histopathology investigation of biopsy sample and lymphocytes values allocated accordingly. RESULTS: Out of 145 patients, osteomyelitis was diagnosed in 15 (10.34%). Median values of subpopulations of lymphocytes were: CD3 2456, CD4 1479, CD8 929, Helper/Suppressor ratio 1.8 and CD19 560 and all were raised above normal values in patients with osteomyelitis. Results were also calculated for osteosarcomas, Ewing sarcomas, giant cell tumours, chondrosarcomas and other tumours. These causes had median values within normal reference levels. To confidently out rule or confirm diagnosis of osteomyelitis, we measured the cut off point values and they were: CD3 2420, CD4 1400, CD8 873 and CD19 550. CONCLUSIONS: The main clinical use of measuring subpopulations of lymphocytes is in establishing the correct diagnosis between suspected osteomyelitis and other musculoskeletal tumours. Levels of measured subpopulations of lymphocytes above the presented cut off values are important and accurate confirming factor for the clinical diagnosis of suspected osteomyelitis. LEVEL OF EVIDENCE: II. PMID- 17701189 TI - No clinical benefits using a new design of pins for external fixation: a randomized study in 50 patients operated on by the hemicallotasis technique. AB - BACKGROUND: Pin-site infection and pin loosening are complications that can cause discomfort to the patients. The purpose of present study was to evaluate pin-site infection, pain, and the use of medications using the XCaliber pin (Orthofix) with optimized thread and tip design, and the commonly used standard pin (Orthofix) during the procedure of hemicallotasis osteotomy (HCO). MATERIAL AND METHODS: Fifty patients of mean age 51 (35-66) years treated with HCO were randomized to standard pins (Orthofix) or XCaliber pins (Orthofix). Hydroxyapatite-coated pins were used in the metaphyseal bone and non-coated pins in the diaphyseal bone in both groups. Pin sites, pain, and the use of medications were evaluated weekly during the HCO. RESULTS: At week 7 the patients in the XCaliber group had more pain at rest [19 (22) vs. 5 (5) mm, P = 0.01] and during activity [32 (32) vs. 12 (13) mm, P = 0.02] and used more paracetamol (2,100 vs. 925 mg, P = 0.04) than those in the standard group, with similar differences, until the extraction of the pins. There was no difference in the use of antibiotics [10.5 (14.5) days (XCaliber) vs. 7 (7.5) days (standard) (P = 0.16)]. CONCLUSION: The commonly used standard pin has important clinical- and patient-related benefits. PMID- 17701190 TI - Synovial hemangioma in the knee of a 10-month-old boy. AB - Synovial hemangioma is a benign vascular tumor. While mainly affecting the knee, it can also appear in other joints or tissues. The condition is very rare in children. A delay between debut and diagnosis due to its unspecific symptomatology is common. We report a case of a boy affected by an intra articular synovial hemangioma of the knee with a debut at the early age of 10 months, the youngest reported in English literature. PMID- 17701191 TI - Bilateral osteochondritis dissecans of the lateral trochlea of the femur: a case report. AB - Osteochondritis dissecans of the bilateral trochlea of femur is unusual case for orthopedic surgeon. The patient was a healthy 15-year-old male with symptomatic osteochondritis dissecans of the bilateral distal lateral femoral condyle of the trochlea. A surgery on the bilateral knee joints was performed simultaneously. The osteochondral free fragment of the right knee was resected by a minimum open surgery after arthroscopic evaluation. In the left knee the fragment was stabilized with multiple cortical bone pegs harvested from the proximal tibia. The surgery was successful, and the patient was able to play basketball 3 months postoperatively. The course of the right knee is currently under careful observation because of the possibility of recurrence. The left knee has remained in an excellent condition for 18 months following surgery with bone pegs. PMID- 17701192 TI - Prenatal diagnosis of the Rhesus D fetal blood type on amniotic fluid in daily practice. AB - OBJECTIVE: To retrospectively examine the diagnostic accuracy of prenatal RhD blood type genotyping on amniotic fluid, using a combination of two polymerase chain reaction (PCR) methods in daily practice. METHODS: Amniotic fluid was obtained from women undergoing amniocentesis. Two PCR protocols were carried out in two different laboratories. We obtained the postnatal serological RhD status. In cases with differing prenatal and postnatal test results, we investigated the possible error source by different methods. Sensitivity, specificity and the predictive values were calculated. RESULTS: Prenatal RhD genotyping was applied in 1,640 cases, of which the postnatal serologic RhD status was obtained in 927. No discordance between both PCR methods occurred. In nine out of 927 cases differing results between PCR and serologic status were encountered. The sensitivity was 99.5%, the specificity 98.6%, and both positive and negative predictive values 99.1%. CONCLUSION: Prenatal diagnosis of the fetal RhD blood type with PCR from amniotic fluid is highly accurate in daily practice and associated with a minimal sensitivity of 99.5% and a minimal specificity of 98.6%. PMID- 17701193 TI - COX-2 and Her-2/neu are overexpressed in Paget's disease of the vulva and the breast: results of a preliminary study. AB - PURPOSE: Paget's disease (PD) of the breast as well as the vulva is a rare condition that accounts for about 4% of breast neoplasms and 1% of vulvar malignancies. Recurrent disease after breast and vulvar surgery might be a challenge. To evaluate relevant molecules therapeutically, tissue from mammary and vulvar PD lesions was investigated immunohistochemically. METHODS: Histopathologic samples from 11 patients with mammary PD and eight patients with vulvar PD were stained with antibodies against estrogen and progesterone receptors, HER-2/neu and COX-2 followed by semiquantitative evaluation of the staining results. RESULTS: All tested mammary lesions as well as seven out of eight vulvar PD were negative for estrogen and progesterone receptors. Strong membranous staining for HER-2/neu (Score 3) was seen in all cases. Six out of 8 vulvar and 10 out of 11 mammary PD showed COX-2 overexpression. CONCLUSIONS: PD of the breast and vulva are negative for estrogens and progesterons, therefore, anti-hormonal therapy is not indicated. The high frequency of Her-2/neu and COX-2 overexpression, however, suggests that these molecules could be therapeutically relevant in patients with PD. These results require further investigation. PMID- 17701194 TI - Caesarean scar endometriosis presenting as an acute abdomen: a case report and review of literature. AB - OBJECTIVE: To report a case of Caesarean scar endometriosis presenting as acute abdomen and a review of literature. DESIGN: Case report and literature review. PATIENT: A 27-year-old woman presented in Accident and Emergency Department with pain and lump near left edge of pfannenstiel incision scar. INTERVENTION: After initial investigations the patient underwent examination under anesthesia. MAIN OUTCOME MEASURE: Excision of a tumour-like mass adherent to the skin and the surrounding subcutaneous tissue. The mass was dissected free from the surrounding fat tissue and excised with clear margins. RESULT: Histology of the mass confirmed endometriosis in tumour and showed a 2 cm fibrotic nodule within. CONCLUSION: In light of increasing rate of caesarean section, it is important to emphasize the early diagnosis as well as optimum management of scar endometrioma. Many recommendations have been given to modify practices at caesarean section to prevent transplantation of decidual endometrial tissue in the abdominal scar but without any published randomised trials. PMID- 17701195 TI - Spontaneous parapharyngeal haematoma caused by a leaking vertebral artery pseudoaneurysm. AB - We describe an unusual case of spontaneous parapharyngeal haematoma, in a patient with haemophilia. The cause was a leaking extracranial vertebral artery pseudoaneurysm eroding through the atlas at the level of the skull base. The leaking pseudoaneurysm was successfully controlled with embolisation of the vertebral artery. The haematoma caused a cerebral infarct and vocal cord paralysis, requiring external drainage and tracheostomy. This is the first reported case of a parapharyngeal haematoma originating from a vertebral artery pseudoaneurysm where imaging demonstrated a causal link. PMID- 17701196 TI - Analysis of experimental cranial skin wounding from screwdriver trauma. AB - As part of a more extensive investigation of skin wounding mechanisms, we studied wounds created by five common screwdrivers (straight, star, square or Robertson, Posidriv and Phillips) on the shaven foreheads of 12 freshly slaughtered pigs. We fixed the different screwdriver heads to a 5-kg metal cylinder which was directed vertically onto each pig head by a droptube of 700 mm length. We examined skin lesions by photography and also by scanning electron microscopy (SEM). Our evaluation of differences in wound shape and size was based on geometric morphometric methods. Our results show that there are obvious morphological differences between the straight head and the other types. The straight-headed screwdriver penetrates the skin by a mode II crack which results in a compressed skin plug with bundles of collagen fibres forming skin tabs within the actual wound. The sharper-tipped screwdrivers wedge open the skin (mode I), with a clearly defined edge with no skin plugs. Geometric morphometric analysis indicates that shapes of skin wounds created by the five screwdriver types could be classified into three different groups. The straight head results in the most differentiated wound profile, with the Robertson or square and some specimens of star, and also the Posidriv and Phillips giving similar wound outlines. SEM evaluation of wounds created by a new and worn straight-head screwdrivers shows that the outline of the worn screwdriver head is reflected in the shape of the wound it created. PMID- 17701197 TI - Combined intravitreal bevacizumab and photodynamic therapy for neovascular age related macular degeneration. AB - BACKGROUND: Our aim was to evaluate the short-term safety and efficacy of combined photodynamic therapy (PDT) with verteporfin and intravitreal bevacizumab in neovascular age-related macular degeneration (AMD). METHODS: A prospective non randomized interventional case series of 30 eyes of 30 patients with choroidal neovascularization (CNV) caused by AMD was studied. All patients were treated with PDT followed by an intravitreal injection of bevacizumab (1.5 mg) on the same day. Ophthalmic evaluations included determination of best-corrected visual acuity by using ETDRS charts. CNV lesion characteristics were determined by fluorescein angiography, and retinal morphology by optical coherence tomography. Review examinations were performed 1, 4, and 12 weeks following treatment. RESULTS: The median ETDRS letter scores increased by 3 letters after 4 weeks and 4.3 letters after 12 weeks. Median central retinal thickness decreased from the baseline by 145 microm (week 1), 205 microm (week 4), and 171 microm (week 12), respectively (P < 0.0001, for all comparisons). One patient experienced a transient moderate vision loss after 4 weeks post treatment. Leakage on fluorescein angiography was resolved in all patients at week 12. No significant ocular or systemic side-effects were observed. CONCLUSIONS: Short-term results suggest that a single PDT in combination with intravitreal bevacizumab is safe and associated with stabilization of visual acuity and decrease of intraretinal and subretinal fluid accumulation in the macula. Further evaluation of this treatment strategy for neovascular AMD appears warranted. PMID- 17701198 TI - Conjunctival nodules associated with Vogt-Koyanagi-Harada disease. AB - BACKGROUND: To report on conjunctival nodules as an unusual manifestation of Vogt Koyanagi-Harada disease. METHODS: A 24-year-old woman presented with a two-month history of bilateral conjunctival injection and gradually decreased vision. Ophthalmological examinations revealed bilateral granulomatous uveitis and bulbar conjunctival nodules, and a biopsy of the conjunctival nodules was performed. RESULTS: The biopsy specimens showed noncaseating granulomas. The major components of the infiltrating lymphocytes were CD8-positive T cells. Topical corticosteroid therapy reduced the anterior segment inflammation, and the conjunctival nodules disappeared within a week. Afterwards, the patient demonstrated bilateral retinal detachments, sunset glow fundus and alopecia, and, therefore, was diagnosed to have Vogt-Koyanagi-Harada disease four months after the first symptoms. CONCLUSIONS: Conjunctival nodules may represent the primary manifestation of Vogt-Koyanagi-Harada disease. PMID- 17701199 TI - Interethnic differences at the thermometric response to cold test: functional disorders of blood circulation in hand fingers and exposure to hand-arm vibration. AB - OBJECTIVES: To report some notable aspects regarding thermometric response to cold test in black African subjects compared with Caucasians: both groups comprised persons exposed to hand-arm vibration and controls. METHODS: An overall sample of 48 workers was examined in order to study their blood circulation in hand fingers: a control group of 12 healthy Caucasian workers never exposed before to hand-arm vibration; 12 Caucasian workers exposed for several years to vibrating tools and affected by occupational Raynaud's phenomenon; 12 healthy black African workers exposed to hand-arm vibration for almost 3 years; and 12 healthy black African workers never exposed to hand-arm vibration. Computerized skin thermometry was performed and thermometric curves were analyzed according to thermometric interpretation criteria such as the area-over-curve (AOC), the fifth minute of recovery/baseline temperature ratio (5REC/BT) and the temperature at the tenth minute of recovery (10REC) after cold test. RESULTS: Thermometric parameters in Caucasian subjects confirmed the basis of the existing literature in controls (basal finger temperature higher than 32 degrees C and complete recovery to the initial temperature after the cold test) and also in patients with Raynaud's phenomenon (basal temperature often lower than control subjects and slow recovery of finger temperature after cold test). Statistically significant difference was found between healthy Caucasians and healthy black subjects in all the parameters tested: healthy black subjects showed values of AOC and 10REC suggesting almost constantly lower finger temperatures during the thermometry test. Black people, both exposed and non-exposed to hand-arm vibration showed thermometric parameters suggesting poor blood microcirculation, which seems even poorer than in Caucasian people complaining Raynaud's phenomenon. CONCLUSIONS: Our chronothermometric tests suggest some significant interethnic differences in peripheral microcirculation, which seems rather poor in black African subjects in comparison with Caucasians. PMID- 17701200 TI - Coping and sickness absence. AB - OBJECTIVES: The aim of this study is to examine the role of coping styles in sickness absence. In line with findings that contrast the reactive-passive focused strategies, problem-solving strategies are generally associated with positive results in terms of well-being and overall health outcomes; our hypothesis is that such strategies are positively related to a low frequency of sickness absence and with short lengths (total number of days absent) and durations (mean duration per spell). METHODS: Using a prospective design, employees' (N = 3,628) responses on a self-report coping inventory are used to predict future registered sickness absence (i.e. frequency, length, duration, and median time before the onset of a new sick leave period). RESULTS AND CONCLUSIONS: In accordance with our hypothesis, and after adjustment for potential confounders, employees with an active problem-solving coping strategy are less likely to drop out because of sickness absence in terms of frequency, length (longer than 14 days), and duration (more than 7 days) of sickness absence. This positive effect is observed in the case of seeking social support only for the duration of sickness absence and in the case of palliative reaction only for the length and frequency of absence. In contrast, an avoidant coping style, representing a reactive-passive strategy, increases the likelihood of frequent absences significantly, as well as the length and duration of sickness absence. Expression of emotions, representing another reactive-passive strategy, has no effect on future sickness absenteeism. The median time before the onset of a new episode of absenteeism is significantly extended for active problem-solving and reduced for avoidance and for a palliative response. The results of the present study support the notion that problem-solving coping and reactive-passive strategies are inextricably connected to frequency, duration, length and onset of sickness absence. Especially, active problem-solving decreases the chance of future sickness absence. PMID- 17701201 TI - Force control is impaired in the ankle plantarflexors of elderly adults. AB - This study determined the amplitude of force fluctuations for the ankle dorsiflexor (DF) and plantarflexor (PF) muscles of young and elderly adults. Maximal voluntary contraction (MVC) force and isometric DF and PF steadiness (2.5 80% MVC) was assessed in 11 young (23+/-3 years, 5 women, 6 men) and 10 elderly (73+/-6 years, 5 women, 5 men) adults. The coefficient of variation (CV) and power spectrum of the force was measured from the steadiness trials. MVC force was lower for elderly adults for PF (38% lower, P=0.002) but not DF (20% lower, P=0.14). For PF, the CV of force was greater for elderly than young adults at 2.5% (2.64 vs. 1.71%) and 5% MVC (1.78 vs. 1.24%), similar at 10, 50, and 80% MVC, and greater for young than elderly at the 30% MVC target force. For DF, the CV of force was similar for young and elderly at all target forces (P>0.05). The CV of force was 49% lower for the PF compared with DF muscles across all target forces (P<0.0001). This difference was significantly greater at the 2.5 (58%), 5 (58%), and 10% MVC (44%) target forces compared with higher target forces. The power spectra of the force fluctuations for both muscles were consistently dominated by frequencies below 2 Hz. For elderly adults, the neuromuscular factors that underlie both muscle strength and force fluctuations during low force contractions are impaired in the ankle plantarflexors but not the dorsiflexors. PMID- 17701202 TI - Molecular cloning and characterization of phosphorus starvation responsive genes in common bean (Phaseolus vulgaris L.). AB - Common bean (Phaseolus vulgaris L.) is one of the most important food legumes in the world and its production is limited by low phosphate (Pi) availability in many arable soils. To gain better insight into the molecular mechanisms by which common bean adapts to low Pi availability, we generated a suppression subtractive cDNA library to identify genes involved in P starvation responses. Over 240 putative Pi starvation-responsive genes were identified. The identified clones were sequenced and BLASTx/BLASTn analysis revealed an array of 82 genes showing a high degree of sequence homology to known and unknown proteins in the database. Transcript abundance of seven genes representing different functional categories was examined by Northern blot analysis. Six genes were strongly induced/enhanced under Pi deficiency confirming the results of SSH. Full length cDNAs for three genes, representing PvIDS4-like, PvPS2, and PvPT1 were cloned and characterized. The open reading frame (ORF) of PvIDS4-like encodes a 281-amino acid protein, containing a SPX domain. The ORF of PvPS2 gene encodes a 271-amino acid protein coding for a putative phosphatase. The PvPT1 encodes a 531-amino acid protein exhibiting high homology with high affinity Pi transporters. Expression patterns of these three genes in relation to Pi availability were evaluated with two contrasting genotypes (P-inefficient Dor364 and P-efficient G19833). Both Northern and RT-PCR results showed enhanced accumulation of phosphate transporters and phosphatases in P-efficient genotype, implying that in addition to modified root morphology and architecture, increased P transport and phosphatases activity might contribute to efficient Pi acquisition and translocation in G19833 common bean genotype under limited Pi conditions. PMID- 17701203 TI - Distinct leaf developmental and gene expression responses to light quantity depend on blue-photoreceptor or plastid-derived signals, and can occur in the absence of phototropins. AB - Leaf palisade cell development and the composition of chloroplasts respond to the fluence rate of light to maximise photosynthetic light capture while minimising photodamage. The underlying light sensory mechanisms are probably multiple and remain only partially understood. Phototropins (PHOT1 and PHOT2) are blue light receptors regulating responses which are light quantity-dependent and which include the control of leaf expansion. Here we show that genes for proteins in the reaction centres show long-term responses in wild type plants, and single blue photoreceptor mutants, to light fluence rate consistent with regulation by photosynthetic redox signals. Using contrasting intensities of white or broad band red or blue light, we observe that increased fluence rate results in thicker leaves and greater number of palisade cells, but the anticlinal elongation of those cells is specifically responsive to the fluence rate of blue light. This palisade cell elongation response is still quantitatively normal in fully light exposed regions of phot1 phot2 double mutants under increased fluence rate of white light. Plants grown at high light display elevated expression of RBCS (for the Rubisco small subunit) which, together with expected down-regulation of LHCB1 (for the photosynthetic antenna primarily of photosystem II), is also observed in phot double mutants. We conclude that an unknown blue light photoreceptor, or combination thereof, controls the development of a typical palisade cell morphology, but phototropins are not essential for either this response or acclimation-related gene expression changes. Together with previous evidence, our data further demonstrate that photosynthetic (chloroplast-derived) signals play a central role in the majority of acclimation responses. PMID- 17701204 TI - Differential metabolomics unraveling light/dark regulation of metabolic activities in Arabidopsis cell culture. AB - Differential metabolomics based on a non-targeted FT-ICR/MS analysis demonstrated metabolite accumulation patterns reflecting light/dark conditions in Arabidopsis T87 cell culture. First, FT-ICR/MS data sets were converted into metabolome information using the Dr.DMASS software (http://kanaya.naist.jp/DrDMASS/). A quick search of a metabolite-species database, KNApSAcK (http://kanaya.naist.jp/KNApSAcK/), was implemented to assign metabolite candidates to each accurate MS data (<1 ppm) through the prediction of molecular formulas, and the candidate structures were further studied using MS/MS analyses. Specific metabolites representing the culture conditions included sugars, phenylpropanoid derivatives, flavonol aglycons, and a plastid nonmevalonate pathway intermediate. Transcriptomics data were obtained in parallel and analyzed using a transcriptome analysis tool, KaPPA-View (http://kpv.kazusa.or.jp/kappa view/). The specific accumulation patterns of flavonol aglycons were in good agreement with the light/dark regulation of a cytochrome P450 gene, CYP75B, and the build-up of 2-C-methyl-D-erythritol 4-phosphate, a nonmevalonate pathway intermediate, in the light grown cells was also consistent with a gene expression profile. The differential metablomics scheme based on the FT-ICR/MS metabolomics can serve as an evaluation system of metabolic activities contributing to successful identification and proper manipulation of key enzymatic steps in metabolic engineering studies. PMID- 17701210 TI - Abstracts of the 21st European Congress of Pathology, September 8-13, 2007, Istanbul, Turkey. PMID- 17701211 TI - Epithelial-mesenchymal transition (EMT) of renal tubular cells in canine glomerulonephritis. AB - Tubulo-interstitial fibrosis in dogs may result from primary injury to the interstitium or develop secondary to other renal diseases. As in human renal pathology, tubular epithelial cells (TEC) are believed to actively participate in the mechanisms of renal fibrosis. In this study, we examined the changes in the tubular epithelial component in two specific canine diseases. Immunohistochemistry showed the expression of the epithelial marker cytokeratin, the smooth muscle marker alpha-SMA, the mesenchymal marker vimentin and PCNA in 20 dogs with membranous glomerulonephritis and membrano-proliferative glomerulonephritis. Results showed that the loss of the epithelial marker in TEC was directly correlated to the grade of tubulo-interstitial disease present and independent of the type of glomerulonephritis. Varying degrees of vimentin positivity were detected in tubular epithelium in areas of inflammation, and low numbers of scattered alpha-SMA-positive cells were also observed. Immunohistochemistry showed that epithelial tubular cells lose their cytokeratin staining characteristics and transdifferentiate into cells exhibiting key mesenchymal immunophenotypic feature of vimentin-positive staining in both diseases investigated. The integrity of the tubular basement membrane is likely to be fundamental in maintaining the epithelial phenotype of TEC. Animal models provide opportunities for investigating the pathogenesis of renal fibrosis in humans. PMID- 17701212 TI - Ligneous conjunctivitis: a clinicopathological, immunohistochemical, and genetic study including the treatment of two sisters with multiorgan involvement. AB - Ligneous conjunctivitis (LC) is a rare disease characterized by wood-like pseudomembranes developing on the ocular and extraocular mucosae secondary to plasminogen (PLG) deficiency. In this paper, we report two cases of LC in two sisters of 57 and 62 years of age that presented with recurrent, bilateral pseudomembranes on conjunctiva and a history of consanguinity and deafness. Pseudomembranes showed superficial and/or subepithelial deposits of eosinophilic amorphous hyaline, amyloid-like material with a variable proportion of granulation tissue, and inflammatory cells. The eosinophilic deposits were negative for Congo red stain, immunoreactive for fibrinogen, and consistently negative for amyloid A component, transthyretin, beta(2)-microglobulin, albumin, fibronectin, collagen type IV, vimentin, and cytokeratins. Among inflammatory cells, a percentage of positivity of roughly 60% for lymphocytes T (CD3+) and 40% for lymphocytes B (CD8+), with a relation of cytotoxic/helper (CD8/4) T cells of 3:2, was found. In one case, nasal polyps and recurrent gastric peptic ulcer were also characterized by the same subepithelial hyaline deposits. A novel homozygous point mutation c.1856 C>T was found in exon 15 of the PLG gene in both patients. Amniotic membrane transplantation was done in one case with promising results. PMID- 17701213 TI - A case of nephroblastoma histologically mimicking rhabdomyosarcoma. PMID- 17701214 TI - Persistent pulmonary hypertension of the newborn with transposition of the great arteries: successful treatment with bosentan. AB - Persistent pulmonary hypertension of the newborn (PPHN) occurs in 1-4% of neonates with transposition of the great arteries with intact ventricular septum (TGA/IVS). This association is often lethal. To our knowledge, only eight survivors have been described in the literature, two of whom benefited from extracorporeal membrane oxygenation (ECMO). We report two cases of PPHN complicating a TGA/IVS that were refractory to multiple therapies and resolved 48 hours after initiation of bosentan therapy. Bosentan, an oral dual endothelin-1 receptor antagonist, is a new treatment for pulmonary arterial hypertension that was both effective and safe in these two cases of TGA/IVS with PPHN. To our knowledge, it is the first use of bosentan in newborns. PMID- 17701215 TI - Antiproliferative activity of bortezomib alone and in combination with cisplatin or docetaxel in head and neck squamous cell carcinoma cell lines. AB - PURPOSE: Proteasome inhibition has been shown to be effective in multiple myeloma and solid tumor models. In this in vitro study, we investigated the antitumor effect of bortezomib (Velcade((R))) in squamous cell carcinoma of the head and neck (SCCHN) cell lines and examined the interaction of the drug with docetaxel (TAX) and cisplatin (CDDP). METHODS: Dose escalation studies were performed with eight squamous cell carcinoma cell lines using bortezomib alone or in combination with TAX or CDDP. Growth inhibitory and proapoptotic effects were measured quantitatively using cytohistology and western blot analysis. RESULTS: Bortezomib alone showed a significant antiproliferative activity in all SCCHN cell lines (P = 0.012), and the activity was further enhanced by the addition of TAX or CDDP (P U(3)--(k)-->F (N-native, U-unfolded and F-final). To understand the role of interfacial residues on protein stability, a type-2 copper site ligand, His306, has been mutated to an alanine. The characterization of the native state of the mutated protein highlights that this mutation prevents copper ions from binding to the type-2 site and eliminates catalytic activity. No significant alteration of the geometry of the type-1 site is observed. Study of the thermal denaturation of this His306Ala NiR variant by differential scanning calorimetry shows an endothermic irreversible profile, with maximum heat absorption at T (max) approximately equal to 85 degrees C, i.e., 15 degrees C lower than the corresponding value found for wild-type protein. The reduction of the protein thermal stability induced by the His306Ala replacement was also shown by optical spectroscopy. The denaturation pathway of the variant is compatible with the kinetic model N(3)--(k)-->F(3), where the protein irreversibly passes from the native to the final state. No evidence of subunits' dissociation has been found within the unfolding process. The results show that the type-2 copper sites, situated at the interface of two monomers, significantly contribute to both the stability and the denaturation mechanism of NiR. PMID- 17701242 TI - Distribution of tetracycline and streptomycin resistance genes and class 1 integrons in Enterobacteriaceae isolated from dairy and nondairy farm soils. AB - The prevalence of selected tetracycline and streptomycin resistance genes and class 1 integrons in Enterobacteriaceae (n = 80) isolated from dairy farm soil and nondairy soils was evaluated. Among 56 bacteria isolated from dairy farm soils, 36 (64.3%) were resistant to tetracycline, and 17 (30.4%) were resistant to streptomycin. Lower frequencies of tetracycline (9 of 24 or 37.5%) and streptomycin (1 of 24 or 4.2%) resistance were observed in bacteria isolated from nondairy soils. Bacteria (n = 56) isolated from dairy farm soil had a higher frequency of tetracycline resistance genes including tetM (28.6%), tetA (21.4%), tetW (8.9%), tetB (5.4%), tetS (5.4%), tetG (3.6%), and tetO (1.8%). Among 24 bacteria isolated from nondairy soils, four isolates carried tetM, tetO, tetS, and tetW in different combinations; whereas tetA, tetB, and tetG were not detected. Similarly, a higher prevalence of streptomycin resistance genes including strA (12.5%), strB (12.5%), ant(3'') (12.5), aph(6)-1c (12.5%), aph(3'') (10.8%), and addA (5.4%) was detected in bacteria isolated from dairy farm soils than in nondairy soils. None of the nondairy soil isolates carried aadA gene. Other tetracycline (tetC, tetD, tetE, tetK, tetL, tetQ, and tetT) and streptomycin (aph(6)-1c and ant(6)) resistance genes were not detected in both dairy and nondairy soil isolates. A higher distribution of multiple resistance genes was observed in bacteria isolated from dairy farm soil than in nondairy soil. Among 36 tetracycline- and 17 streptomycin-resistant isolates from dairy farm soils, 11 (30.6%) and 9 (52.9%) isolates carried multiple resistance genes encoding resistance to tetracycline and streptomycin, respectively, which was higher than in bacteria isolated from nondairy soils. One strain each of Citrobacter freundii and C. youngae isolated from dairy farm soils carried class 1 integrons with different inserted gene cassettes. Results of this small study suggest that the presence of multiple resistance genes and class 1 integrons in Enterobacteriaceae in dairy farm soil may act as a reservoir of antimicrobial resistance genes and could play a role in the dissemination of these antimicrobial resistance genes to other commensal and indigenous microbial communities in soil. However, additional longer-term studies conducted in more locations are needed to validate this hypothesis. PMID- 17701243 TI - Current status and future perspective of general surgical trainees in the Netherlands. AB - BACKGROUND: The opinions of general surgical trainees about their current training program and their future career plans are important because such information can inform any redesign of surgical training programs as well as future surgical manpower planning. METHODS: A structured questionnaire was sent to 392 general surgical trainees in the Netherlands in 2005. RESULTS: A total of 239 (61%) questionnaires were returned by 66 (28%) women and 173 (72%) men, mean age 31.3 years. On average, trainees worked in the hospital 55 hours per week (range: 22-80 h). The mean number of operative cases performed per year was 195 (range 35-450), and this had been stable since the year 2000. The quality of the supervision by staff surgeons was rated satisfactory. The vast majority of the trainees are also satisfied with the current single year of differentiation/specialized training into one of the subspecialties, although most trainees (83%) would like to enroll in a fellowship before taking a job as a consultant. There was also a desire to take maternity/paternity leave during training. Both male and female trainees expressed the wish to work an average of 52 hours per week as a consultant, and they want these hours to occur in 4.1 days of work per week. CONCLUSIONS: Dutch general surgery trainees are satisfied with their training. They expressed a strong wish for specialization during and after their training. All trainees favored reduced working hours and days of work per week as fully qualified surgeons in the future. PMID- 17701244 TI - Pulmonary superinfection by trichomonads in the course of acute respiratory distress syndrome. AB - The finding of trichomonads in bronchoalveolar lavage fluid (BALF) samples from an acute respiratory distress syndrome (ARDS) patient, never previously reported, incited us to search for these parasites retrospectively in the BALF of patients with ARDS or related pathologies. Eighty-four consecutive BALF samples have been reviewed. Results were compared with data from clinical files of patients included in this study. Detection and identification of trichomonads were based on cytologic characteristics. Subsequently, immunocytochemistry and in situ hybridization were performed in the last case of the series. Our results were as follows: (1) Trichomonads were detected in 25/84 BALFs (20/77 patients). Among the patients testing positive, 17 suffered from ARDS, about 30% of the ARDS patients included in the study. (2) Trichomonads were detected more frequently at a late ARDS stage. (3) No correlation was found between trichomonad detection and other data. (4) Within the group of trichomonad-infected ARDS patients, density of infection correlated with higher mortality. The late detection of these microorganisms in the course of ARDS suggested that trichomonad development is a secondary event. As BALFs obtained early in the course of ARDS were also included in the study, trichomonad incidence could be underestimated. The significance of trichomonad lung colonization in ARDS and its potential pathogenic role are unclear. Nevertheless, the question of an active role of trichomonads in the extension of alveolar lesions or in the limitation of recovery is clearly raised. PMID- 17701245 TI - Compliance with dysphagia recommendations by carers of adults with intellectual impairment. AB - Health risks associated with dysphagia in adults with intellectual impairment are well documented. There is little research into compliance with dysphagia recommendations in environments where care is provided for adults with intellectual impairment. This is a pilot study into carer compliance with Speech Language Pathology recommendations. We aimed to investigate the level of compliance with dysphagia recommendations in day centers and the factors that might affect compliance using a questionnaire. Twenty-seven clients were observed. Results showed an overall high level of compliance with recommendations (82%), with figures ranging from 64% compliance with appropriate utensils to 100% with direct support recommendations. Areas of noncompliance were evident, with level of dependence of clients and training of carers being key issues. Implications for practitioners are discussed. PMID- 17701246 TI - Effect of tactile stimulation on lingual motor function in pediatric lingual dysphagia. PMID- 17701247 TI - A question of rheological control. PMID- 17701248 TI - Pseudoachalasia of the cardia secondary to nongastrointestinal neoplasia. AB - A minor proportion of patients with achalasia eventually have a neoplasm and, as a consequence, pseudoachalasia is diagnosed. A neoplasm may either involve gastrointestinal junction or present a paraneoplastic effect. Over the global diagnoses of achalasia issued in 5 years of experience in our motility unit, we have found 13% (3/23 cases) of pseudoachalasia (2-4% in previous series, probably due to the fact that the population assisted was mainly composed of elderly patients). The origin of the neoplasm was bladder, prostate and metastases from epidermoid carcinoma of vocal chord. Treatment of primary neoplasm, besides classical approach (with dilatation of botulinum injection) may help in the resolution of this clinical disorder. PMID- 17701249 TI - The dynamics of lingual-mandibular coordination during liquid swallowing. AB - Previous literature on tongue-jaw relationships during swallowing has focused on behaviors observed with chewable solid foods. The present investigation was undertaken to evaluate both the nature and stability of coordinative relationships between the jaw and three points located along the midsagittal groove of the tongue--anterior (blade), middle (body), and posterior (dorsum)- during swallowing of thin and honey-thick liquids. A reiterative swallowing paradigm was used, with two task conditions (discrete and sequential), to explore the stability of tongue-jaw coordination across different frequencies of swallowing. Eight healthy participants in two age groups (young, older) performed sets of repeated swallows. Tongue and jaw movements were measured using electromagnetic midsagittal articulography. The data were analyzed in terms of variability in the spatiotemporal movement pattern for each fleshpoint of interest, and the temporal coupling (frequency entrainment) and relative phasing of movement for each tongue segment compared to the mandible. The results illustrate a stereotypical but not invariant sequence of movement phasing in the tongue-jaw complex during liquid swallowing and task-related reductions in variability at higher frequencies of swallowing in tongue dorsum movements. This evidence supports the idea that different segments of the tongue couple with the jaw as a synergy for swallowing, but can modify their coupling relationship to accommodate task demands. PMID- 17701250 TI - Natural-orifice transgastric endoscopic peritoneoscopy in humans: Initial clinical trial. AB - BACKGROUND: Natural-orifice translumenal endoscopic surgery (NOTES) is a possible advancement for surgical interventions. We initiated a pilot study in humans to investigate feasibility and develop the techniques and technology necessary for NOTES. Reported herein is the first human clinical trial of NOTES, performing transoral transgastric diagnostic peritoneoscopy. METHODS: Patients were scheduled to undergo diagnostic laparoscopic evaluation of a pancreatic mass. The findings of traditional laparoscopy were recorded by anatomical abdominal quadrant. A second surgeon, blinded to the laparoscopic findings, performed transgastric peritoneoscopy. Diagnostic findings between the two methods were compared and operative times and clinical course were recorded. Definitive care was based on findings at diagnostic laparoscopy. RESULTS: Ten patients completed the protocol with an average age of 67.6 years. All patients underwent diagnostic laparoscopy followed by successful transgastric access and diagnostic endoscopic peritoneoscopy. The average time of diagnostic laparoscopy was 12.3 minutes compared to 24.8 minutes for the transgastric route. Transgastric abdominal exploration corroborated the decision to proceed to open exploration made during traditional laparoscopic exploration in 9 of 10 patients. Peritoneal or liver biopsies were obtained in four patients by traditional laparoscopy and in one patient by the transgastric access route. Findings were confirmed by laparotomy in nine patients. Eight patients underwent pancreaticoduodenectomy and two underwent palliative gastrojejunostomy and/or hepaticojejunostomy. CONCLUSIONS: Transgastric diagnostic peritoneoscopy is safe and feasible. This study demonstrates the initial steps of NOTES in humans, providing a potential platform for incisionless surgery. Technical issues, including instrumentation, visualization, intra-abdominal manipulation, and gastric closure need further development. PMID- 17701251 TI - Performance differences in laparoscopic surgical skills between true high definition and three-chip CCD video systems. AB - BACKGROUND: Laparoscopic surgery requires surgeons to rely on visual clues for discrimination among differing tissues and for depth of field on a two dimensional screen. High definition (HD) provides a superior image. If there is a measurable advantage with HD television (TV), the increase in the cost of the technology would be justified. METHODS: A digital three-chip CCD camera with a standard monitor (SD system) and a true HD camera (1,080 pixels) with a 16:9 ratio HD monitor (HD system) were compared in clinical and laboratory settings. Three experiments were performed: (1) subjective visual evaluation of the HD and SD systems during actual surgical cases, (2) subjective visual evaluation in a controlled laboratory surgical setting with simultaneous parallel recording, and (3) three laparoscopic surgical task evaluations in a laboratory setting, namely, task A (metric analysis of participants on the surgical simulator), task B (simple eye-hand coordination performance), and task C (knot tying). RESULTS: All 53 participants subjectively evaluated HD as superior to SD in the laboratory setting and during actual surgery. In task B, there was no significant difference between SD and HD (dominant hand: p = 0.19; nondominant hand: p = 0.07). In task C, the knot-tying time was significantly less when performed with HD (mean, 173 +/- 84 s vs 214 +/- 107 s; p = 0.003). Most importantly, subjects with less skill (more documented time required in the basic module on a surgical simulator) improved significantly in the knot-tying task with the HD system (R = 0.631; p = 0.005). CONCLUSION: All the participants preferred HD to SD. High definition significantly improved laparoscopic knot tying, which requires precise depth perception, proving that HD is more than just a pretty picture. PMID- 17701253 TI - A computer tool for the fusion and visualization of thermal and magnetic resonance images. AB - The measurement of temperature variation along the surface of the body, provided by digital infrared thermal imaging (DITI), is becoming a valuable auxiliary tool for the early detection of many diseases in medicine. However, DITI is essentially a 2-D technique and its image does not provide useful anatomical information associated with it. However, multimodal image registration and fusion may overcome this difficulty and provide additional information for diagnosis purposes. In this paper, a new method of registering and merging 2-D DITI and 3-D MRI is presented. Registration of the images acquired from the two modalities is necessary as they are acquired with different image systems. Firstly, the body volume of interest is scanned by a MRI system and a set of 2-D DITI of it, at orthogonal angles, is acquired. Next, it is necessary to register these two different sets of images. This is done by creating 2-D MRI projections from the reconstructed 3-D MRI volume and registering it with the DITI. Once registered, the DITI is then projected over the 3-D MRI. The program developed to assess the proposed method to combine MRI and DITI resulted in a new tool for fusing two different image modalities, and it can help medical doctors. PMID- 17701252 TI - Altered traveling wave propagation and reduced endocochlear potential associated with cochlear dysplasia in the BETA2/NeuroD1 null mouse. AB - The BETA2/NeuroD1 null mouse has cochlear dysplasia. Its cochlear duct is shorter than normal, there is a lack of spiral ganglion neurons, and there is hair cell disorganization. We measured vertical movements of the tectorial membrane at acoustic frequencies in excised cochleae in response to mechanical stimulation of the stapes using laser doppler vibrometry. While tuning curve sharpness was similar between wild-type, heterozygotes, and null mice in the base, null mutants had broader tuning in the apex. At both the base and the apex, null mice had less phase lag accumulation with increasing stimulus frequency than wild-type or heterozygote mice. In vivo studies demonstrated that the null mouse lacked distortion product otoacoustic emissions, and the cochlear microphonic and endocochlear potential were found to be severely reduced. Electrically evoked otoacoustic emissions could be elicited, although the amplitudes were lower than those of wild-type mice. Cochlear cross-sections revealed an incomplete partition malformation, with fenestrations within the modiolus that connected the cochlear turns. Outer hair cells from null mice demonstrated the normal pattern of prestin expression within their lateral walls and normal FM 1-43 dye entry. Overall, these data demonstrate that while tonotopicity can exist with cochlear dysplasia, traveling wave propagation is abnormally fast. Additionally, the presence of electrically evoked otoacoustic emissions suggests that outer hair cell reverse transduction is present, although the acoustic response is shaped by the alterations in cochlear mechanics. PMID- 17701254 TI - Effects and mechanisms of vaginal electrical stimulation on rectal tone and anal sphincter pressure. AB - PURPOSE: This study was designed to evaluate the effect of vaginal electrical stimulation on rectal tone and compliance and anal sphincter pressure and to explore possible mechanisms involved in the effects of vaginal electrical stimulation on rectal tone in conscious dogs. METHODS: Seven dogs inserted with a probe with two ring electrodes were studied. The study included two experiments. The first experiment was composed of two series of sessions rectal tone and compliance; and anal sphincter pressure. Each series included three sessions: vaginal electrical stimulation with long pulses, vaginal electrical stimulation with trains of long pulses, and vaginal electrical stimulation with trains of short pulses. The second experiment was performed in two sessions: vaginal electrical stimulation with long pulses plus guanethidine, and vaginal electrical stimulation with trains of long pulses plus guanethidine. In each session, rectal tone was recorded. RESULTS: 1) Vaginal electrical stimulation with long pulses or trains of long pulses but not trains of short pulses significantly decreased rectal tone and increased anal sphincter pressure. 2) None of the vaginal electrical stimulation methods altered rectal compliance. 3) The inhibitory effect of vaginal electrical stimulation on rectal tone was abolished by guanethidine. CONCLUSIONS: Vaginal electrical stimulation with long pulses or trains of long pulses but not trains of short pulses reduces rectal tone and increases anal sphincter pressure. The inhibitory effect of vaginal electrical stimulation on rectal tone is mediated by the sympathetic pathway. These findings suggest that vaginal electrical stimulation may be a potential therapy for fecal incontinence. PMID- 17701255 TI - CT enterography for Crohn's disease: accurate preoperative diagnostic imaging. AB - PURPOSE: CT enterography (CTE) is a technique that provides detailed images of the small bowel by using a low Hounsfield unit oral contrast media. This study was designed to correlate CTE findings with operative findings in patients with Crohn's disease. METHODS: We performed a retrospective study of all patients with Crohn's disease of the small bowel or colon, who had CTE and subsequent small bowel or colon surgery within three months after the CT examination. CTE findings of stricture, fistula, inflammatory mass, abscess, and combinations of these abnormalities were compared with operative findings. Specialist radiologists and fellowship-trained colorectal surgeons participated in the study. The Fisher's exact test or chi-squared tests were used with respect to categorical data, and the Wilcoxon's rank-sum test was used for quantitative data. RESULTS: In 36 patients, the presence or absence of stricture, fistula, abscess, or inflammatory mass was correctly determined by CTE in 100, 94, 100, and 97 percent, respectively. The accuracy for stricture or fistula number was 83 and 86 percent, respectively. There were nine patients with multiple disease phenotypes identified on CTE of which eight were confirmed at surgery. CTE overestimated or underestimated the extent of disease in 11 patients (31 percent). CONCLUSIONS: CTE is an accurate preoperative diagnostic imaging study for small-bowel Crohn's disease. The ability of this imaging study to detect both luminal and extraluminal pathology is a distinct advantage of CTE compared with small-bowel contrast studies. PMID- 17701256 TI - Plasminogen activator system localization in 60 cases of ductal carcinoma in situ. AB - BACKGROUND: The lack of prognostic factors in ductal carcinoma in situ (DCIS) that reliably identifies biologically aggressive tumors adversely affects optimal management. The urokinase-type plasminogen activator (uPA) system, comprised of its receptor, uPAR, and its inhibitor (PAI-1), are critical elements for tumor invasion and their expression in invasive breast cancer can predict clinical outcome. Expression of the uPA system in DCIS may be relevant in defining histological subsets of DCIS with invasive potential. METHODS: Localization of uPA, uPAR, and PAI-1 was investigated immunohistochemically in 60 DCIS tumors. FISH experiments were performed to determine whether uPA was present in cancer cells themselves or derived from stromal elements. RESULTS: uPA was ubiquitously expressed in the malignant ductal epithelium of 95% (57/60) of DCIS tumors studied. uPA-mRNA was detected in the malignant ductal epithelium but not the adjacent normal ductal epithelium and stromal elements. uPAR was expressed in 27% (6/22) of high-grade and 24% (9/38) of non-high-grade DCIS. In comparing coexpression, uPA and uPAR were coexpressed in only 25% (15/60) of tumors. PAI-1 was infrequently expressed in high grade (3/22) and absent in non-high-grade DCIS. CONCLUSIONS: This study identifies the presence of uPA, uPAR, and PAI-1 in both high-grade and non-high-grade DCIS. It may be speculated that coexpression of uPA and its receptor may identify subsets of DCIS with an increased risk for progression to invasive disease. If so, then expression of uPA system components may have prognostic and therapeutic significance in DCIS. PMID- 17701258 TI - Vacuum effects over the closing of enterocutaneous fistulae: a mathematical modeling approach. AB - Enterocutaneous fistulae are pathological communications between the intestinal lumen and the abdominal skin. Under surgery the mortality of this pathology is very high, therefore a vacuum applying system has been carried previously on attempting to close these fistulae. The objective of this article is the understanding of how these treatments might work through deterministic mathematical modelling. Four models are here proposed based on several assumptions involving: the conservation of the flow in the fistula, a low enough Reynolds number justifying a laminar flow, the use of Poiseuille law to model the movement of the fistulous liquid, as well as phenomenological equations including the fistula tissue and intermediate chamber compressibility. Interestingly, the four models show fistulae closing behaviour during experimental time (t<60 sec). To compare the models, both, simulations and pressure measurements, carried out on the vacuum connected to the patients, are performed. Time course of pressure are then simulated (from each model) and fitted to the experimental data. The model which best describes actual measurements shows exponential pumping flux kinetics. Applying this model, numerical relationship between the fistula compressibility and closure time is presented. The models here developed would contribute to clarify the treatment mechanism and, eventually, improve the fistulae treatment. PMID- 17701257 TI - Clinical practice guidelines for the utilization of positron emission tomography/computed tomography imaging in selected oncologic applications: suggestions from a provider group. AB - PURPOSE: Positron emission tomography, combined with computed tomography (PET/CT) has provided clinicians with useful information regarding the diagnosis, initial staging, restaging, and therapy monitoring of malignancies since the beginning of the current century. Our intent here is to identify the critical steps in clinical workups and follow-up, in the true outpatient clinical setting of a freestanding imaging center, for utilization of PET/CT in four different cancer types. METHODS: The four most common reasons for referrals to our facility were identified by reviewing two years of referral data. They were lung cancer (including solitary pulmonary nodule), lymphomas, breast cancer, and colorectal cancer. A review of published literature from 1996 and later was accepted as evidence of appropriateness for utilizing PET/CT in various clinical scenarios. In addition, a medical advisory board consisting of 15 referring physicians representing various specialties was established to provide practical advice regarding the appropriate use of PET/CT in clinical situations. National Comprehensive Cancer Network (NCCN) guidelines were also referenced to establish a baseline for clinical workups at various stages of disease. RESULTS: Several inconsistencies were identified among the three primary sources of information leading to the establishment of a standardized algorithm for each cancer type. NCCN data did not always agree with published literature, which was also often different from actual clinical practices of referring physicians. The most common inconsistencies included differing opinions from the referrers vs what was published in the NCCN guidelines, especially with regard to the utilization of PET/CT for applications not yet covered by insurance companies. After a reconciliation of the medical advisory board's clinical practices and several published articles, a consensus was established by the medical advisory board for the use of PET/CT imaging for the four cancer types, enabling us to identify the appropriate timing of PET/CT utilization in patient work-ups. CONCLUSIONS: A PET/CT-centric clinical practice decision tree algorithm can be established by assessing a variety of sources of information. Although published literature and NCCN guidelines offer validated guidance to appropriateness, and third party insurance payors have established their own appropriateness standards, our experience showed that inclusion of practical experience from referring physicians who frequently utilize PET/CT imaging provided additional, useful input. PMID- 17701259 TI - On the role of asymptomatic infection in transmission dynamics of infectious diseases. AB - We propose a compartmental disease transmission model with an asymptomatic (or subclinical) infective class to study the role of asymptomatic infection in the transmission dynamics of infectious diseases with asymptomatic infectives, e.g., influenza. Analytical results are obtained using the respective ratios of susceptible, exposed (incubating), and asymptomatic classes to the clinical symptomatic infective class. Conditions are given for bistability of equilibria to occur, where trajectories with distinct initial values could result in either a major outbreak where the disease spreads to the whole population or a lesser outbreak where some members of the population remain uninfected. This dynamic behavior did not arise in a SARS model without asymptomatic infective class studied by Hsu and Hsieh (SIAM J. Appl. Math. 66(2), 627-647, 2006). Hence, this illustrates that depending on the initial states, control of a disease outbreak with asymptomatic infections may involve more than simply reducing the reproduction number. Moreover, the presence of asymptomatic infections could result in either a positive or negative impact on the outbreak, depending on different sets of conditions on the parameters, as illustrated with numerical simulations. Biological interpretations of the analytical and numerical results are also given. PMID- 17701260 TI - Modeling T cell proliferation and death in vitro based on labeling data: generalizations of the Smith-Martin cell cycle model. AB - The fluorescent dye carboxyfluorescein diacetate succinimidyl ester (CFSE) classifies proliferating cell populations into groups according to the number of divisions each cell has undergone (i.e., its division class). The pulse labeling of cells with radioactive thymidine provides a means to determine the distribution of times of entry into the first cell division. We derive in analytic form the number of cells in each division class as a function of time based on the distribution of times to the first division. Choosing the distribution of time to the first division to fit thymidine labeling data for T cells stimulated in vitro under different concentrations of IL-2, we fit CFSE data to determine the dependence of T cell kinetic parameters on the concentration of IL-2. As the concentration of IL-2 increases, the average cell cycle time is shortened, the death rate of cells is decreased, and a higher fraction of cells is recruited into division. We also find that if the average cell cycle time increases with division class then the qualify of our fit to the data improves. PMID- 17701261 TI - Optimal timing of disease transmission in an age-structured population. AB - It is a common medical folk-practice for parents to encourage their children to contract certain infectious diseases while they are young. This folk-practice is controversial, in part, because it contradicts the long-term public health goal of minimizing disease incidence. We study an epidemiological model of infectious disease in an age-structured population where virulence is age-dependent and show that, in some cases, the optimal behavior will increase disease transmission. This provides a rigorous justification of the concept of "endemic stability," and demonstrates that folk-practices may have been historically justified. PMID- 17701262 TI - Surgical education to improve the quality of patient care: the role of practice based learning and improvement. AB - Health care is going through immense change, and concerns regarding the quality of patient care and patient safety continue to be expressed in many national forums. A variety of stakeholders are demanding greater accountability from the health care profession. Education is key to supporting surgeons' efforts to provide high-quality patient care during these challenging times. Educational programs for surgeons should be founded on principles of continuous professional development (CPD) and practice-based learning and improvement (PBLI). CPD focuses on the specific needs of individual surgeons and involves lifelong learning throughout a surgeon's career. It needs to form the basis of PBLI efforts. PBLI involves a cycle of four steps--identifying areas for improvement, engaging in learning, applying new knowledge and skills to practice, and checking for improvement. Ongoing involvement in PBLI activities to address specific learning needs should positively impact a surgeon's practice and improve outcomes of surgical care. PMID- 17701263 TI - Outcomes of cocaine-induced gastric perforations repaired with an omental patch. AB - Crack cocaine has been associated with acute gastric perforation. The appropriate surgical treatment and long-term outcomes remain unclear. A retrospective chart review of all gastroduodenal perforations associated with crack cocaine use was performed. Data abstracted included details of short- and long-term outcomes. Kaplan-Meier methods were used to evaluate surgical outcomes. Over the 14-year period ending December 2005, 16 cases of crack-induced gastric perforations were identified. Most (75%) were treated with an omental patch. The other patients underwent a formal antiulcer operation, including one vagotomy and pyloroplasty (V&P), one vagotomy and antrectomy, one subtotal gastrectomy, and one ulcer excision and V&P. All patients after antiulcer procedures were followed for a median of 63 months (range 27-120) with no recurrences. Follow-up data were available in 75% of the omental patch patients. Recurrence of disease was observed in 56% of these omental patch patients at a median of 20 months (range 11-39). Those without recurrence were followed for a median of 67 months (range 12-96). The recurrence rate was borderline lower in the antiulcer group (P = 0.072). Omental patch closure results in a recurrence rate over 50% compared with no recurrence for formal antiulcer procedures. PMID- 17701264 TI - How many lymph nodes properly stage a periampullary malignancy? AB - The impact of lymphadenectomy in prognosis and staging in periampullary malignancies remains largely undefined. We examined all pancreaticoduodenectomies for periampullary carcinomas in the SEER cancer registry from 1993 through 2003. Overall, 5465 pancreaticoduodenectomies for nonmetastatic periampullary carcinomas were identified. The cohort was comprised of 62.5% pancreatic, 18.9% ampullary, 11.6% distal bile duct, and 7.0% duodenal cancers. A linear association between the number of lymph nodes (LNs) examined and overall survival was observed overall and for pancreas and ampullary cancers for node-negative (N0) disease. Median survival for all patients with localized, N0 disease improved from 24 to 31 months, with sampling of a minimum of 10 LNs, whereas 2 and 5-year survival improved from 52 and 29%, with <10 nodes examined to 58 and 37% with 10+ nodes examined (P<0.001). A 1-month median survival advantage was seen in patients with node-positive disease when more than 10 lymph nodes examined (15 versus 16 months, P<0.001). Significantly better median survival and cure rates are observed after pancreaticoduodenectomy for localized periampullary adenocarcinoma when a minimum of 10 lymph nodes are examined. This benefit likely represents more accurate staging. To optimize the prognostic accuracy and prevent stage migration errors in multicenter trials a minimum of 10 lymph nodes should be obtained and examined before the determination of node-negative disease. PMID- 17701265 TI - A prospective evaluation of laparoscopic versus open left lateral hepatic sectionectomy. AB - BACKGROUND: Left lateral sectionectomy is one of the most commonly performed laparoscopic liver resections, but limited clinical data are actually available to support the advantage of laparoscopic versus open-liver surgery. The present study compared the short-term outcomes of laparoscopic versus open surgery in a case-matched analysis. MATERIALS AND METHODS: Surgical outcome of 20 patients who underwent left lateral sectionectomy by laparoscopic approach (LHR group) from September 2005 to January 2007 were compared in a case-control analysis with those of 20 patients who underwent open left lateral sectionectomy (OHR group). Both groups were similar for: tumor size, preoperative laboratory data, presence of cirrhosis, and histology of the lesion. Surgical procedures were performed in both groups combining the ultrasonic dissector and the ultrasonic coagulating cutter without portal clamping. RESULTS: Compared with OHR, the LHR group had a decreased blood loss (165 mL versus 214 mL, P=0.001), and earlier postoperative recovery (4.5 versus 5.8 days, P=0.003). There were no significant differences in terms of surgical margin and operative time. Morbidity was comparable between the two groups, but two cases of postoperative ascites were recorded in two cirrhotic patients in the OHR. Major complications were not observed in either groups. CONCLUSIONS: Laparoscopic resection results in reduced operative blood loss and earlier recovery with oncologic clearance and operative time comparable with open surgery. Laparoscopic liver surgery may be considered the approach of choice for tumors located in the left hepatic lobe. PMID- 17701266 TI - Right hepatic lobectomy using the staple technique in 101 patients. AB - BACKGROUND: Application of linear stapling devices for extrahepatic vascular control in liver surgery has been well-established. However, the technique for use of stapling devices in hepatic parenchymal transection is not well defined. PURPOSE: To describe the safety and efficacy of our technique for use of vascular stapling devices in hepatic parenchymal transection during open right hepatic lobectomy is the purpose of this study. METHODOLOGY: We reviewed our experience with 101 consecutive open right hepatic lobectomies performed by a single surgeon between January 2003 and July 2006, in which vascular staplers were utilized for the parenchymal transection phase. RESULTS: Of the 101 patients who underwent resection, 53 (52%) were female. The mean age was 58 years. Malignant disease was the indication for resection in the majority of patients (88%). Of those with cancer, 78% (69 of 89) had metastatic colorectal cancer, 6% (5 of 89) had metastatic neuroendocrine tumor, 4% (4 of 89) had hepatocellular carcinoma, 4% (4 of 89) had cholangiocarcinoma, and the remaining 8% were other metastatic cancers. Twelve patients (12%) underwent resection for hepatic adenoma or symptomatic benign disease (FNH or hemangioma). Forty-eight patients (48%) underwent a major ancillary procedure at the time of hepatic resection. Thirty nine patients (39%) had a nonanatomic wedge resection of a left lobe lesion, 27 patients (27%) had one or more lesions treated with radiofrequency ablation (RFA), and 6 patients (6%) were treated with a synchronous bowel resection. The median total operative time was 336 min (range 155-620 min). A Pringle maneuver for temporary vascular inflow occlusion was utilized in all cases, with a median time of 9 min (range 4-17 min). Ten patients (10%) required blood transfusion during surgery or in the postoperative period. The maximum transfusion was 2 U of packed red blood cells (PRBC) in seven patients and 1 U of PRBC in three patients. The mean nadir postoperative hematocrit was 28.2. All patients with malignant disease had tumor-free margins at the completion of the procedure. The average hospital length of stay was 6.0 days. One patient (1%) developed a clinically significant bile leak requiring a postoperative endoscopic retrograde cholangiography (ERCP). No patient required reoperation. The 30 and 60-day postoperative survival was 100%. CONCLUSION: These findings indicate that application of vascular stapling devices for parenchymal transection in major hepatic resection is a safe technique, with low transfusion requirements and minimal postoperative bile leak. The technique allows for rapid transection of the entire right hepatic lobe in under 10 min. Short video clips of the technique will be demonstrated. PMID- 17701267 TI - Risk factors for knee osteoarthritis in Morocco. A case control study. AB - Osteoarthritis (OA) of the knee is the most common form of arthritis. A positive association between obesity and several occupational factors and knee OA has been observed in previous studies in populations of different ethnicity. The aim of this study was to examine the relation between knee OA and body weight and occupational factors in a Moroccan sample of patients with knee OA. Our cases were consecutive patients diagnosed in our department with knee OA utilizing radiography in a 1-year period. No cases displayed established causes of secondary OA. Controls were selected randomly from the general population and were individually matched to each case for age and sex. Interviews were obtained from 95 cases and controls. Detailed information on general health status, height, weight, smoking habits, specific physical loads from occupation and housework, and sports activities was collected. The risk of knee OA increased with higher body mass index, odds ratio (OR) = 3.12 (95% confidence interval [CI] = 1.67-5.81; p < 0.0001). Sitting more than 3 h/day and climbing stairs more than 50 steps/day were associated with decreased risk of knee OA, OR = 0.29 (95% CI = 0.15-0.56; p = 0.02) and 0.48 (95% CI = 0.26-0.91; p < 0.0001), respectively. Overweight is a risk factor for knee OA, whereas sitting and climbing stairs are inversely associated with knee OA. PMID- 17701268 TI - Serum nitric oxide metabolites and disease activity in patients with systemic sclerosis. AB - There is no surrogate marker in serum for defining disease activity in scleroderma (SSc). Nitric oxide (NO), which regulates vasodilation and possesses pro-inflammatory actions, has been implicated in the pathogenesis of SSc. We compared serum NO(x) (total nitrate and nitrite) level in SSc patients to healthy controls and evaluated its correlation with detailed symptomatology and scoring systems for various organ involvement. Symptoms and physical findings that suggested disease activity in regard to various organs were documented. Lung function test, high-resolution computed tomographic (HRCT) scan of thorax and echocardiography were performed. Serum NO(x) was measured by chemiluminescence. Serum NO(x) levels in SSc (n = 43) were significantly higher (72.4 +/- 47.8 microM) than age- and sex-matched controls (n = 41; 37.1 +/- 13.5 microM; p < 0.001). Serum NO(x) were not found to be associated with lung fibrosis defined by lung function parameters or inflammation and fibrosis scores on HRCT. Twenty-two patients were found to have elevated serum NO(x) level defined as mean +/- 2 SD of normal controls. Logistic regression analysis revealed that age (OR 1.12, p = 0.02) and elevated pulmonary arterial pressure (PAP) (n = 9; OR 145.3, p = 0.01) were predictive factors for elevated serum NO(x). Prednisolone use was associated with lower serum NO(x) level (OR 0.06, p = 0.04). Elevated PAP of increasing severity was found to be associated with higher level of serum NO(x) (p = 0.004 by trend). Serum NO(x) in SSc patients were elevated compared to healthy controls. Serum NO(x) level was determined by multiple factors including age, prednisolone use, and elevated PAP. PMID- 17701269 TI - Adult onset Still's disease: a study of 14 cases. AB - We studied the clinical profile, laboratory parameters, disease course, and outcomes of patients with adult onset Still's disease (AOSD). A retrospective analysis of adult patients with Still's disease diagnosed from 2000 to 2004 was carried out. Their clinical features and laboratory findings at presentation, disease course, and outcomes were analyzed. Data of 14 patients with Still's disease were analyzed. The age at disease onset ranged from 16 to 59 years with a mean of 29.85, the male to female ratio being 9:5. The mean duration of illness from onset of symptoms to presentation was 14.5 months (range). The most common clinical manifestations were fever (n = 14), articular symptoms (n = 14), rash (n = 8), weight loss (n = 12), and sore throat (n = 5). Elevated ESR was present in all patients with a mean of 98.3 mm at 1 h. Hepatic enzymes were elevated in seven patients at disease onset. The mean duration of follow up was 19.14 months (range). Three patients progressed to chronic arthropathy. Cyclosporine led to dramatic recovery in five patients. Macrophage activation syndrome (MAS) was present in two patients, one after sulfasalazine therapy. One patient with MAS died. Still's disease, although uncommon, has characteristic constellation of clinical and laboratory features and should be considered in the differential diagnosis of fever of unknown origin. Nonsteroidal anti-inflammatory drugs, steroids, and methotrexate may not be always effective, and cyclosporine is an effective drug in resistant cases. Sulfasalazine should be avoided in cases of AOSD. PMID- 17701270 TI - Non-excision treatment of multiple cutaneous neurofibromas by laser photocoagulation. AB - Neurofibromatosis type 1 (NF-1) is an autosomal dominant disorder characterized by skin tumours derived from peripheral nerves. It is a clinically diagnosed disorder of a mainly cosmetic concern. There are different excision modalities for treatment of cutaneous neurofibromas; however, none is considered to be universally accepted treatment. This study was conducted to evaluate a non excision treatment of multiple cutaneous neurofibromas, using surface and interstitial approaches of neodymium:yttrium aluminum garnet (Nd:YAG) laser (1,064 nm) photocoagulation, depending upon the size and location of the lesions. Twelve patients with multiple cutaneous neurofibromas were included. Surface laser photocoagulation by long-pulsed Nd:YAG laser has been used for treatment of flat lesions, while interstitial laser photocoagulation by continuous wave (CW) Nd:YAG laser has been used for treatment of bulkier lesions. After 14 months of follow up, both approaches of laser photocoagulation have shown different success rates, as denoted by the regression of the lesions, an overall acceptable cosmetic outcome, and, generally, patients' satisfaction. Within the limitations of the present study, laser photocoagulation has proven to be a promising technique that may be an alternative or additive modality for treatment of multiple cutaneous neurofibromas. It is a minimally invasive, office-based technique that could be used safely and effectively, with a limited rate of complications. Surface laser photocoagulation has proven to be an effective tool for treatment of flat lesions, especially those located in exposed areas, with a favourable cosmetic result, while interstitial laser photocoagulation could be reserved for bulkier lesions, especially those located in non-exposed areas. However, further studies are necessary to refine the procedure, and to confirm the present encouraging findings, especially over a longer period of follow up, as well as to evaluate laser parameters for optimization of the technique. PMID- 17701271 TI - Morning light therapy for postpartum depression. AB - Postpartum depression (PPD) is a frequent complication of childbirth, but many women refuse pharmacological treatment. Little data exists on bright light therapy for PPD. Fifteen outpatient women with PPD were randomly assigned to bright light (10,000 lux, n = 10) or dim red light (600 lux, n = 5) and completed a 6-week trial and weekly assessments using self-report depression scales and clinician ratings of symptom course. Both groups showed significant improvement over time on all measures, with no significant difference between conditions. PMID- 17701272 TI - Cloning, expression, and pharmacological activity of BmK AS, an active peptide from scorpion Buthus martensii Karsch. AB - BmK AS is a beta long-chain scorpion peptide from the venom of Buthus martensii Karsch (BmK). It was efficiently expressed as a soluble and functional peptide in Escherichia coli, and purified by metal chelating chromatography. About 4.2 mg/l purified recombinant BmK AS could be obtained. The recombinant BmK AS maintained a similar analgesic activity to the natural one in both the mouse-twisting test and hot-plate procedure. It also exhibited antimicrobial activity against both Gram-positive and Gram-negative bacteria. BmK AS is the first long-chain scorpion peptide reported to have antimicrobial activity, and is a valuable molecular scaffold for pharmacological research. PMID- 17701273 TI - Mutational analysis of the TRE2 oncogene encoding an inactive RabGAP. AB - The TRE2 oncoprotein is structurally related to the RabGAP (GTPase-activating protein) family. However, TRE2 seems enzymatically inactive. Two regions are important for its lack of GAP activity. First, the TBC domain, forming the catalytically active domain of RabGAPs, is non-functional in the oncoprotein. Also involved in TRE2 inactivity is the 93-aa region flanking the TBC domain on the C-terminal side. In order to identify the residues responsible for non functionality, we performed hydrophobic cluster analysis of the oncoprotein sequence, combined with secondary structure prediction, receptor-binding domain analysis, and a tilted peptide calculation. These analyses were complemented with site-directed and random mutagenesis experiments. On the basis of our data, we hypothesize that the lack of secondary structure of the region flanking the TBC domain in TRE2 may explain why this region plays a role in the lack of GAP activity, even when a potentially functional TBC domain is present. PMID- 17701274 TI - Perspectives of biomolecular NMR in drug discovery: the blessing and curse of versatility. AB - The versatility of NMR and its broad applicability to several stages in the drug discovery process is well known and generally considered one of the major strengths of NMR (Pellecchia et al., Nature Rev Drug Discov 1:211-219, 2002; Stockman and Dalvit, Prog Nucl Magn Reson Spectrosc 41:187-231, 2002; Lepre et al., Comb Chem High throughput screen 5:583-590, 2002; Wyss et al., Curr Opin Drug Discov Devel 5:630-647, 2002; Jahnke and Widmer, Cell Mol Life Sci 61:580 599, 2004; Huth et al., Methods Enzymol 394:549-571, 2005b; Klages et al., Mol Biosyst 2:318-332, 2006; Takeuchi and Wagner, Curr Opin Struct Biol 16:109-117, 2006; Zartler and Shapiro, Curr Pharm Des 12:3963-3972, 2006). Indeed, NMR is the only biophysical technique which can detect and quantify molecular interactions, and at the same time provide detailed structural information with atomic level resolution. NMR should therefore be ideally suited and widely requested as a tool for drug discovery research, and numerous examples of drug discovery projects which have substantially benefited from NMR contributions or were even driven by NMR have been described in the literature. However, not all pharmaceutical companies have rigorously implemented NMR as integral tool of their research processes. Some companies invest with limited resources, and others do not use biomolecular NMR at all. This discrepancy in assessing the value of a technology is striking, and calls for clarification--under which circumstances can NMR provide added value to the drug discovery process? What kind of contributions can NMR make, and how is it implemented and integrated for maximum impact? This perspectives article suggests key areas of impact for NMR, and a model of integrating NMR with other technologies to realize synergies and maximize their value for drug discovery. PMID- 17701275 TI - Evidence of molecular alignment fluctuations in aqueous dilute liquid crystalline media. AB - Protein dynamics can be studied by NMR measurements of aqueous dilute liquid crystalline samples. However, the measured residual dipolar couplings are sensitive not only to internal fluctuations but to all changes in internuclear vectors relative to the laboratory frame. We show that side-chain fluctuations and bond librations in the ps-ns time scale perturb the molecular shape and charge distribution of a small globular protein sufficiently to cause a noticeable variation in the molecular alignment. The alignment variation disperses the bond vectors of a conformational ensemble even further from the dispersion already caused by internal fluctuations of a protein. Consequently RDC probed order parameters are lower than those obtained by laboratory frame relaxation measurements. PMID- 17701276 TI - Automatic maximum entropy spectral reconstruction in NMR. AB - Developments in superconducting magnets, cryogenic probes, isotope labeling strategies, and sophisticated pulse sequences together have enabled the application, in principle, of high-resolution NMR spectroscopy to biomolecular systems approaching 1 megadalton. In practice, however, conventional approaches to NMR that utilize the fast Fourier transform, which require data collected at uniform time intervals, result in prohibitively lengthy data collection times in order to achieve the full resolution afforded by high field magnets. A variety of approaches that involve nonuniform sampling have been proposed, each utilizing a non-Fourier method of spectrum analysis. A very general non-Fourier method that is capable of utilizing data collected using any of the proposed nonuniform sampling strategies is maximum entropy reconstruction. A limiting factor in the adoption of maximum entropy reconstruction in NMR has been the need to specify non-intuitive parameters. Here we describe a fully automated system for maximum entropy reconstruction that requires no user-specified parameters. A web accessible script generator provides the user interface to the system. PMID- 17701278 TI - A rice phenomics study--phenotype scoring and seed propagation of a T-DNA insertion-induced rice mutant population. AB - With the completion of the rice genome sequencing project, the next major challenge is the large-scale determination of gene function. As an important crop and a model organism, rice provides major insights into gene functions important for crop growth or production. Phenomics with detailed information about tagged populations provides a good tool for functional genomics analysis. By a T-DNA insertional mutagenesis approach, we have generated a rice mutant population containing 55,000 promoter trap and gene activation or knockout lines. Approximately 20,000 of these lines have known integration sites. The T0 and T1 plants were grown in net "houses" for two cropping seasons each year since 2003, with the mutant phenotypes recorded. Detailed data describing growth and development of these plants, in 11 categories and 65 subcategories, over the entire four-month growing season are available in a searchable database, along with the genetic segregation information and flanking sequence data. With the detailed data from more than 20,000 T1 lines and 12 plants per line, we estimated the mutation rates of the T1 population, as well the frequency of the dominant T0 mutants. The correlations among different mutation phenotypes are also calculated. Together, the information about mutant lines, their integration sites, and the phenotypes make this collection, the Taiwan Rice Insertion Mutants (TRIM), a good resource for rice phenomics study. Ten T2 seeds per line can be distributed to researchers upon request. PMID- 17701277 TI - Isolation and characterization of shs1, a sugar-hypersensitive and ABA insensitive mutant with multiple stress responses. AB - To identify salt tolerance determinants, we screened for double mutants from a T DNA tagged sos3-1 mutant population in the Arabidopsis Col-0 gl1 background. The shs1-1 (sodium hypersensitive) sos3-1 mutant was isolated as more sensitive to NaCl than sos3-1 plants. TAIL-PCR revealed that the introduced T-DNA was located 62 bp upstream of the initiation codon of an adenylate translocator-like protein gene on chromosome IV. SHS1 mRNA did not accumulate in shs1-1 sos3-1 plants although it accumulated in shoots of both sos3-1 and the wild type plants, indicating that this gene is inactive in the mutant. Genetic co-linkage analysis revealed that the mutation causing the phenotype segregated as a recessive, single gene mutation. This mutant showed altered sensitive responses to salt as well as to cold stress. It also demonstrated sugar sensitive and ABA insensitive phenotypes including enhanced germination, reduced growth, altered leaf morphology, and necrosis on leaves at an early growth stage. Sensitivity of sos3 1 shs1-1 root growth to LiCl, KCl, and mannitol was not significantly different from growth of sos3-1 roots. Further, expression of 35S::SHS1 in sos3-1 shs1-1 plants complemented NaCl and sugar sensitivity and partially restored the leaf morphology. PMID- 17701279 TI - No evidence for faster male hybrid sterility in population crosses of an intertidal copepod (Tigriopus californicus). AB - Two different forces are thought to contribute to the rapid accumulation of hybrid male sterility that has been observed in many inter-specific crosses, namely the faster male and the dominance theories. For male heterogametic taxa, both faster male and dominance would work in the same direction to cause the rapid evolution of male sterility; however, for taxa lacking differentiated sex chromosomes only the faster male theory would explain the rapid evolution of male hybrid sterility. It is currently unknown what causes the faster evolution of male sterility, but increased sexual selection on males and the sensitivity of genes involved in male reproduction are two hypotheses that could explain the observation. Here, patterns of hybrid sterility in crosses of genetically divergent copepod populations are examined to test potential mechanisms of faster male evolution. The study species, Tigriopus californicus, lacks differentiated, hemizygous sex chromosomes and appears to have low levels of divergence caused by sexual selection acting upon males. Hybrid sterility does not accumulate more rapidly in males than females in these crosses suggesting that in this taxon male reproductive genes are not inherently more prone to disruption in hybrids. PMID- 17701280 TI - Isolation and characterization of an NAD+-degrading bacterium PTX1 and its role in chromium biogeochemical cycle. AB - Microorganisms can reduce toxic chromate to less toxic trivalent chromium [Cr(III)]. Besides Cr(OH)(3) precipitates, some soluble organo-Cr(III) complexes are readily formed upon microbial, enzymatic, and chemical reduction of chromate. However, the biotransformation of the organo-Cr(III) complexes has not been characterized. We have previously reported the formation of a nicotinamide adenine dinucleotide (NAD(+))-Cr(III) complex after enzymatic reduction of chromate. Although the NAD(+)-Cr(III) complex was stable under sterile conditions, microbial cells were identified as precipitates in a non-sterile NAD(+)-Cr(III) solution after extended incubation. The most dominant bacterium PTX1 was isolated and assigned to Leifsonia genus by phylogenetic analysis of 16S rRNA gene sequence. PTX1 grew slowly on NAD(+) with a doubling time of 17 h, and even more slowly on the NAD(+)-Cr(III) complex with an estimated doubling time of 35 days. The slow growth suggests that PTX1 passively grew on trace NAD(+) dissociated from the NAD(+)-Cr(III) complex, facilitating further dissociation of the complex and formation of Cr(III) precipitates. Thus, organo-Cr(III) complexes might be an intrinsic link of the chromium biogeochemical cycle; they can be produced during chromate reduction and then further mineralized by microorganisms. PMID- 17701281 TI - Effect of treatment of hyperuricemia with allopurinol on blood pressure, creatinine clearence, and proteinuria in patients with normal renal functions. AB - BACKGROUND: Hyperuricemia has been associated with the development of hypertension, cardiovascular, and renal disease. However, there is no data about the effect of lowering uric acid level on hypertension, renal function, and proteinuria in patients with glomerular filtration rate (GFR) >60 ml/min. We therefore conducted a prospective study to investigate the benefits of allopurinol treatment in hyperuricemic patients with normal renal function. MATERIALS AND METHODS: Forty-eight hyperuricemic and 21 normouricemic patients were included in the study. Hyperuricemic patients received 300 mg/day allopurinol for three months. All patients' serum creatinine level, 24-h urine protein level, glomerular filtration rate, and blood pressure levels were measured at baseline and after three months of treatment. RESULTS: A total of 59 patients completed the three-month follow-up period of observation. In the allopurinol group, serum uric acid levels, GFR, systolic and diastolic blood pressure, and C-reactive protein (CRP) levels significantly improved (P < 0.05). However, urine protein excretion remained unchanged (P > 0.05). No correlation was observed between changes in GFR and changes in CRP, or blood pressure in the allopurinol group. No significant changes were observed in the control group (P > 0.05). CONCLUSION: We bring indirect evidence that hyperuricemia increases blood pressure, and decreases GFR. Hence, management of hyperuricemia may prevent the progression of renal disease, even in patients with normal renal function, suggesting that early treatment with allopurinol should be an important part of the management of chronic kidney disease (CKD) patients. Long-term follow-up studies are warranted to identify the benefits of uric acid management on renal function and hypertension. PMID- 17701282 TI - Presentation of the functional receptor-binding domain of the bacterial adhesin F17a-G on bacteriophage M13. AB - Bovine enterotoxigenic Escherichia coli (ETEC) carrying F17a fimbriae attach to the intestinal epithelium by means of the F17a-G adhesin. Since filamentous bacteriophages can be employed for the display of foreign peptides, we tested the applicability of this system to F17a-G. The receptor-binding domain of the F17a-G adhesin was expressed on bacteriophage M13, as an amino-terminal fusion with the phage protein pIII. This domain retained its N-acetyl-beta-D: -glucosamine binding activity. The phage presenting the fimbrial receptor-binding domain elicited an IgG response against F17a-G after intraperitoneal immunisation of mice. PMID- 17701283 TI - Saccharomyces cerevisiae strains from traditional fermentations of Brazilian cachaca: trehalose metabolism, heat and ethanol resistance. AB - Nine indigenous cachaca Saccharomyces cerevisiae strains and one wine strain were compared for their trehalose metabolism characteristics under non-lethal (40 degrees C) and lethal (52 degrees C) heat shock, ethanol shock and combined heat and ethanol stresses. The yeast protection mechanism was studied through trehalose concentration, neutral trehalase activity and expression of heat shock proteins Hsp70 and Hsp104. All isolates were able to accumulate trehalose and activate neutral trehalase under stress conditions. No correlation was found between trehalose levels and neutral trehalase activity under heat or ethanol shock. However, when these stresses were combined, a positive relationship was found. After pre-treatment at 40 degrees C for 60 min, and heat shock at 52 degrees C for 8 min, eight strains maintained their trehalose levels and nine strains improved their resistance against lethal heat shock. Among the investigated stresses, heat treatment induced the highest level of trehalose and combined heat and ethanol stresses activated the neutral trehalase most effectively. Hsp70 and Hsp104 were expressed by all strains at 40 degrees C and all of them survived this temperature although a decrease in cell viability was observed at 52 degrees C. The stress imposed by more than 5% ethanol (v/v) represented the best condition to differentiate strains based on trehalose levels and neutral trehalase activity. The investigated S. cerevisiae strains exhibited different characteristics of trehalose metabolism, which could be an important tool to select strains for the cachaca fermentation process. PMID- 17701284 TI - Study of photosystem 2 heterogeneity in the sulfur-deficient green alga Chlamydomonas reinhardtii. AB - A set of chlorophyll fluorescence methods, including PEA (Plant Efficiency Analyser), PAM (Pulse Amplitude Modulated fluorometer), and picosecond fluorometer, was employed to study PS 2 heterogeneity in sulfur deprived green algae Chlamydomonas reinhardtii. The regression method and JIP test were applied to analyze chlorophyll fluorescence kinetics. The fractions of PS 2 characterized by the energetic disconnection, smaller antenna size, elevated constant rate of primary photochemistry, and inability to maintain DeltapH-dependent energy dissipation increased essentially already after 12 h of incubation in sulfur depleted medium. The amount of PS 2 centers with reduced QA (closed state), QB non-reducing centers with impaired water splitting function, and centers coupled to the plastoquinone pool with the slow cycle rate increased dramatically after 24 h period of deprivation. The mechanisms of PS 2 inactivation under sulfur deprivation are discussed. PMID- 17701285 TI - Newborn screening in Latin America at the beginning of the 21st century. AB - Newborn screening (NBS) in Latin America took its first steps in the mid-1970s. Nevertheless, many years elapsed before it achieved its integration within the public health care system and its systematic and continuous implementation under a programme structure. Latin American countries can be characterized not only by their great geographic, demographic, ethnic, economic and health system diversity, but also by their heterogeneity in NBS activities, which gives rise to variation in degree of organization: countries with optimal fulfilment (Cuba, Costa Rica, Chile, Uruguay); others rapidly expanding their coverage (Brazil, Mexico, Argentina); some others in a recent implementation phase (Colombia, Paraguay, Venezuela, Nicaragua, Peru); others with minimal, isolated and non organized activities (Guatemala, Dominican Republic, Bolivia, Panama, Ecuador); and finally others without any NBS activities at all (El Salvador, Honduras, Haiti). Despite this disparity, a sustained and significant growth in NBS activities has become evident during the last decade, highlighted by implementation of new programmes, increase in coverage, expansion of NBS panels, increasing involvement of governmental and public health authorities, and integration of NBS teams through scientific societies and External Quality Assurance Schemes. Currently, congenital hypothyroidism (CH) is the most widely screened disease, followed by phenylketonuria, with organized NBS programmes for CH in 14 countries. Other diseases usually included in NBS programmes are screened in a lower rate. Every year, around 11.2 million infants are born in Latin America. During 2005, 49.3% of newborns were screened for CH, indicating that around 5.7 million newborns still did not have access to the benefits of NBS. PMID- 17701286 TI - Quality performance of newborn screening systems: strategies for improvement. AB - Newborn metabolic screening is a public health activity with the potential to realize significant health gains for infants affected with a range of congenital conditions. Many of these are inborn errors of metabolism. The activities required to achieve the gains are diverse and carried out by a number of organizations, by families and by many health care professionals. Laboratories have the best-developed quality strategies, which include quality assurance programmes, guidelines, protocols and standards. Two-tier testing and use of multiple markers improve sensitivity and specificity. There are international initiatives to harmonize assay materials and definitions to allow better benchmarking between programmes. Outside the laboratory, standards, education and protocols improve the quality of specimen collection, diagnosis and treatment, which together produce the health gains. PMID- 17701287 TI - Heavy-metal stress induced accumulation of chitinase isoforms in plants. AB - Plant chitinases belong to so-called pathogenesis related proteins and have mostly been detected in plants exposed to phytopathogenic viruses, bacteria or fungi. A few studies revealed that they might also be involved in plant defence against heavy metals. This work was undertaken to monitor the accumulation of chitinases in a set of heavy-metal stressed plants and bring evidence on their involvement during this kind of stress. Roots of different plant species including Vicia faba cvs. Astar and Piestansky, Pisum sativum, Hordeum vulgare, Zea mays and Glycine max were exposed to different concentrations of lead (300 and 500 mg l(-1) Pb(2+)), cadmium (100 and 300 mg l(-1) Cd(2+)) and arsenic (50 and 100 mg l(-1) As(3+)). In each case, the toxicity effects were reflected in root growth retardation to 80-10% of control values. The most tolerant were beans, most sensitive was barley. Extracts from the most stressed roots were further assayed for chitinase activity upon separation on polyacrylamide gels. Our data showed that in each combination of genotype and metal ion there were 2-5 different chitinase isoforms significantly responsive to toxic environment when compared with water-treated controls. This confirms that chitinases are components of plant defence against higher concentrations of heavy metals. In addition, accumulation of some isoforms in response to one but not to other metal ions suggests that these enzymes might also be involved in a more (metal) specific mechanism in affected plants and their biological role is more complex than expected. PMID- 17701288 TI - Down regulation of gyrase A gene expression in E. coli by antisense ribozymes using RT-PCR. AB - Nucleic acid-based gene interference technologies represent promising strategies for specific inhibition of mRNA sequences of choice. Recently, small interfering RNAs have been implicated in inducing endogenous RNase of the RNA-induced silencing complex in the RNA interference pathway to inhibit gene expression and growth of several human viruses. We report down regulation of gene expression of E. coli gyrase A, an essential gene for DNA supercoiling and antibiotic susceptibility in BL21 (DE3) strain of E. coli, using Ribonuclease P based external guide sequence (EGS) technique. EGS directed against gyrase A gene that was cloned into pUC vector, which contains the ampicillin (Amp) resistance gene. The recombinant plasmid pT7EGyrA was transformed into BL21 (DE3) and inductions were performed using IPTG. RT-PCR experiment was done to investigate the down regulation of gyrase A gene. RT-PCR results demonstrated a significant decrease of gyrase A gene after 18 h of induction of the transformants. These experiments showed that the down regulation of the gene was seen after 18 h of induction than earlier hours of induction with IPTG suggesting inhibition of gyrase A gene with profound effect on cell viability. These results demonstrate the utility of EGS RNAs in gene therapy applications, by inhibiting the expression of essential proteins. PMID- 17701289 TI - Passive and active euthanasia: what is the difference? AB - In order to discuss the normative aspects of euthanasia one has to clarify what is meant by active and passive euthanasia. Many philosophers deny the possibility of distinguishing the two by purely descriptive means, e.g. on the basis of theories of action or the differences between acting and omitting to act. Against this, such a purely descriptive distinction will be defended in this paper by discussing and refining the theory developed by Dieter Birnbacher in his "Tun und Unterlassen". On this basis I will suggest a new definition of active and passive euthanasia. PMID- 17701290 TI - Which personal quality of life domains affect the happiness of older South Africans? AB - OBJECTIVE: To ascertain which quality of life domains affect the happiness of older South Africans. METHOD: Seven hundred and ten respondents, aged between 50 years and 93 years, participated in the study. Seven single items assessed satisfaction with: oneself, family life, friendship, one's time to do things, neighbours, social life and health. Responses were summed for overall quality of life. A 31-item scale measured satisfaction with activities (16 items), financial situation (7 items) and people (8 items). One item measured global happiness. RESULTS: Coefficient alpha was 0.90 (7-item quality of life scale), 0.95 (activities scale) and 0.87 (finances and people scales). Although there some racial differences on the 10 quality of life domains and happiness, Black respondents, who acted as caregivers, had a poorer quality of life and were less happy (P < 0.05) than those without these responsibilities. Stepwise multiple regression revealed that satisfaction with social life was the most important predictor of happiness for Blacks and Indians; satisfaction with oneself for Whites, and time to do things for Coloureds. Overall findings suggested that three out of the ten domains adequately represented perceived quality of life, care-giving responsibilities negatively affect quality of life and happiness and race plays a role in predicting happiness. PMID- 17701291 TI - Calcium phosphate formation on plasma immersion ion implanted low density polyethylene and polytetrafluorethylene surfaces. AB - The flexible structure of polymers has enabled them to be useful in a wide variety of medical applications due to the possibility to tailor their properties to suit desired applications. For a long time, there has been an increasing interest in utilizing polymers as matrices for calcium phosphate-based composites with applications in hard tissue implants. On the other side, polymers with application as heart valves, urea catheters and artificial vessels present a case where the formation of minerals (namely calcification) should be avoided. The modification of polymer surfaces by various ion beam treatments for reducing the calcification, as for example plasma immersion ion implantation (PIII), is well known and has a long time effect. This work is part of a wider investigation of the ability of plasma immersion ion implanted polymers to induce calcium phosphate formation from an aqueous solution resembling the human blood plasma. In the experiment described in this paper, topographical and chemical changes were inserted on the surfaces of two conventional polymers (low density polyethylene and polytetrafluorethylene) by PIII with nitrogen ions, and under conditions mimicking the natural mineral formation processes. The effect of the plasma modification on the calcium phosphate nucleation and growth from the aqueous solution was ambiguous. We suppose that the complex combination of surface characteristics influenced the ability of the plasma treated polymer films to induce the formation of a calcium phosphate layer. PMID- 17701292 TI - Preparation and characterization of magnetic poly(epsilon-caprolactone) poly(ethylene glycol)-poly(epsilon-caprolactone) microspheres. AB - In this article, nano-magnetite particles (ferrofluid, Fe3O4) were prepared by chemical co-deposition method. A series of biodegradable triblock poly(epsilon caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCL-PEG-PCL, PCEC) copolymers were synthesized by ring-opening polymerization method from epsilon-caprolactone (epsilon-CL) initiated by poly(ethylene glycol) diol (PEG) using stannous octoate as catalyst. And the magnetic PCEC composite microspheres were prepared by solvent diffusion method. The properties of the ferrofluid, PCEC copolymer, and magnetic PCEC microspheres were studied in detail by SEM, VSM, XRD, Malvern Laser Particle Sizer, 1H-NMR, GPC, and TG/DTG. Effects of macromolecular weight and concentration of polymer, and the time for ultrasound dispersion on properties of magnetic microspheres were also investigated. The obtained magnetic PCEC microspheres might have great potential application in targeted drug delivery system or cell separation. PMID- 17701293 TI - Stimulating effect of silica-containing nanospheres on proliferation of osteoblast-like cells. AB - Silica and silica-based materials have been found widespread application for medical purposes, especially in the fields of bone tissue engineer. Nano-sized silica has been developed too and been considered to be used in bone regeneration. In this study, we observed the biological response of osteoblast like cells to three kinds of silica nanospheres: SNs-A (30-40 nm), SNs-B (70-80 nm), and Silica/OCP (70-80 nm). Cells treated with three kinds of nanospheres always showed higher cell viability than control cells. ALP activity of cells treated with three kinds of silica nanospheres was higher than that of control cells at early time. Both of the two effects were not in a concentration dependent manner. Silica/OCP had better effect on MG-63 cell activity and proliferation than SNs-A and SNs-B. The three kinds of silica nano material all have biological validity on osteoblast-like cells, especially Silica/OCP. PMID- 17701294 TI - Preparation of chitosan-hyaluronate double-walled microspheres by emulsification coacervation method. AB - Chitosan (CHS)-hyaluronate (HA) double-walled microspheres were prepared by emulsification-coacervation method. Tripolyphosphate (TPP) acted as ion crosslinker. The effects of oil/water volume ratio, surfactant, solution pH, TPP concentration, HA concentration, and emulsification time on microspheres fabrication and morphology were examined by Zeta (zeta) potential, Scanning electron microscopy (SEM) and Fourier-transform infrared spectrometry (FT-IR). It was found that TPP concentration, solution pH, surfactant and emulsification time were crucial factors for microspheres fabrication. Spherical microspheres with smooth surface were formed when TPP concentration was 8% or higher. The optimal pH for microspheres formation ranged from 6.0 to 7.0. As for surfactant, the microspheres obtained when span80 was applied alone were shapelier compared with those obtained when both span80 and tween80 were applied. With insufficient emulsification time, vacuous microcapsules, but not compact microspheres were formed. In addition, oil/water volume ratio and HA concentration also affected the microspheres morphology, but less importantly. PMID- 17701296 TI - The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins. AB - The aim of this study was to construct PPT-LDH nanohybrids and compare their tumor inhibition effects with that of free PPT. Anticancer drug podophyllotoxin (PPT) was encapsulated in the galleries of Mg-Al layered double hydroxides (LDHs) by a two-step approach. Tyrosine (Tyr) was first incorporated into the interlayer space by co-precipitation with LDH, prop-opening the layers of Mg-Al/LDH and creating an interlayer environment inviting drug molecules. PPT was subsequently intercalated into the resulting material lamella by an ion exchange process. The intermediate and final products, which can be termed drug-inorganic nanocomposites, have been characterized by powder X-ray diffraction (XRD), UV-VIS spectrophotometer, transmission electron microscopy (TEM) and in cell culture. Our results demonstrate that the interlayer spacing distance of the PPT-LDH nanohybrids (34% w/w of drug/material) is 18.2 A. LDHs do not harm normal cells (293T) based on toxicity tests. Ex-vivo anticancer experiments reveal that the PPT-LDH nanohybrids have higher tumor suppression effects than intercalated PPT. We conclude that the higher tumor inhibition effects of PPT-LDH hybrids result from the inorganic drug delivery vehicle, LDHs. PMID- 17701295 TI - Fabrication of a PLGA-collagen peripheral nerve scaffold and investigation of its sustained release property in vitro. AB - This study deals with the fabrication of a peripheral nerve scaffold prepared with poly (lactic acid-co-glycolic acid) [PLGA] and acellularized pigskin collagen micro particles and the investigation of its sustained release property in vitro. We took bovine serum albumin [BSA] as model drug to investigate the sustained-release property of the scaffold in vitro. The results showed the scaffold could release BSA steadily with a rate of 6.6 ng/d (r=0.994) or so. In a 1-month test period, the accumulative release ratio of BSA from the scaffold was up to 43%, and the shape of the scaffold was still originally well kept. In addition, the scaffold outcome non-immunogenicity, good cell adhesion and biodegradability. The results indicated a scaffold constructed by this technique would be a potential implanting support with prolonged sustained release function, such as for the use of nerve scaffold. PMID- 17701297 TI - 3-D Nanofibrous electrospun multilayered construct is an alternative ECM mimicking scaffold. AB - Extra cellular matrix (ECM) is a natural cell environment, possesses complicated nano- and macro- architecture. Mimicking this three-dimensional (3-D) web is a challenge in the modern tissue engineering. This study examined the application of a novel 3-D construct, produced by multilayered organization of electrospun nanofiber membranes, for human bone marrow-derived mesenchymal stem cells (hMSCs) support. The hMSCs were seeded on an electrospun scaffold composed of poly epsilon-caproloactone (PCL) and collagen (COL) (1:1), and cultured in a dynamic flow bioreactor prior to in vivo implantation. Cell viability after seeding was analyzed by AlamarBlue Assay. At the various stages of experiment, cell morphology was examined by histology, scanning electron microscopy (SEM) and confocal microscopy. RESULTS: A porous 3-D network of randomly oriented nanofibers appeared to support cell attachment in a way similar to traditionally used tissue culture polysterene plate. The following 6 week culture process of the tested construct in the dynamic flow system led to massive cell proliferation with even distribution inside the scaffold. Subcutaneous implantation of the cultured construct into nude mice demonstrated good integration with the surrounding tissues and neovascularization. CONCLUSION: The combination of electrospinning technology with multilayer technique resulted in the novel 3-D nanofiber multilayered construct, able to contain efficient cell mass necessary for a successful in vivo grafting. The success of this approach with undifferentiated cells implies the possibility of its application as a platform for development of constructs with cells directed into various tissue types. PMID- 17701298 TI - Porous bioceramics reinforced by coating gelatin. AB - Porous bioceramics with high porosity for bone tissue engineering were fabricated by the foam impregnation technique, but their mechanical strength was poor, only a mean compressive strength of 1.04+/-0.15 MPa and an mean elastic modulus of 0.1 GPa. In order to reinforce porous ceramics, the ceramic samples were immersed in 5% gelatin solution and gelatin coatings were formed on the inter-surface of their pores. It was found that the mean compressive strength value and the mean elastic modulus value of porous samples coated with gelatin were improved to 5.17+/-0.17 MPa and 0.3 GPa respectively without sacrificing their porosity greatly. Moreover composite samples were not as fragile as sintered ceramics. The results indicated that the gelatin coatings on the inter-surface of pores reinforced porous bioceramics effectively. PMID- 17701299 TI - Variation of crystal structure of hydroxyapatite in calcium phosphate cement by the substitution of strontium ions. AB - New routes were used to introduce strontium into calcium phosphate cement in the present article. The study showed that by mixing 50 wt% amorphous calcium phosphate + amorphous strontium phosphate and 50 wt% dicalcium phosphate dihydrate, hydroxyapatite and Sr-hydroxyapatite precipitated separately in the hydrated cement; whereas, by mixing 50 wt% Sr- amorphous calcium phosphate and 50 wt% dicalcium phosphate dihydrate, strontium can be doped into hydroxyapatite lattice and increase the lattice dimensions and lattice volume. The strontium substituted calcium phosphate cement has potential for use in orthopedic surgeries. PMID- 17701300 TI - Influences of hyaluronan on type II collagen fibrillogenesis in vitro. AB - The effect to the kinetics of type II collagen fibrillogenesis with the addition of hyaluronan (HA), (Mw of 1.8x10(6) Da), at various concentrations of HA (0.01, 0.05 and 0.1 wt.%) for a series of fibril formation systems was examined in this study. Evidences deduced from the turbidity-time curves revealed that the inclusion of HA had minor or no impact to the fibrillogenesis of type II collagen (collagen conc. at 0.2 mg/mL). The apparent rate constants, klag (lag phase) increased slightly but kg (growth phase) decreased not very significantly with addition of HA, as compared to the case of pure collagen. This leads us to believe tentatively that, with the addition of HA to collagen solutions, the nucleation process of the fibril formation might have been sped up slightly whereas the growth process slowed up slightly. However, data from TEM observations on the resulting fibrils indicated that the presence of HA did not significantly affect the diameters and the characteristic D-banding periods of the collagen fiber formed. And, from the statistical analyses, we found only insignificant difference (P>0.05) between the specimens from the various experimental groups. It seems to indicate that the ultimate packing of collagen monomers was probably not interfered or affected significantly by the presence of HA in vitro. PMID- 17701301 TI - The influence of residual stress on the shear strength between the bone and plasma-sprayed hydroxyapatite coating. AB - Plasma-sprayed HA coating (HAC) 50 and 200 microm thick on Ti6Al4V cylinders was transcortically implanted in the femora of canines. Push-out testing of implant bone interfaces showed that the HAC coating exhibited higher shear strength at 50 microm coating than 200 microm one. The plasma-sprayed HACs were exhibited compressive residual stresses and the thicker HAC exhibited higher residual stress than that of the thinner HAC. Due to the structure for 50 and 200 microm implants were the same, meaning similar cohesive strength of the lamellar splats. And, there was no difference in the physiological environment; hence the difference of the shear strength for the 50 and 200 microm-HAC implants could best be attributed to the compressive residual stress existed in the HA coating. PMID- 17701302 TI - Effects of calcination temperature on the drug delivery behaviour of Ibuprofen from hydroxyapatite powders. AB - The effects of heat treatment time and temperature on the delivery behaviour of Ibuprofen from hydroxyapatite particles were investigated in this study. The drug release was seen to follow Fickian diffusion for the initial period of release for all heat treatment conditions. The gradient of Fickian release increased with (1) increasing crystallite size, attributed to the decreasing amount of boundary area, and (2) with decreasing surface area, due to the reduction in porosity and hence tortuosity within the apatite particles. This study has shown that altering the heat treatment conditions used to calcine hydroxyapatite may alter its drug delivery abilities, whereby calcination temperature was noted to influence the drug release behaviour to a greater extent than calcination time. PMID- 17701303 TI - Poly (D,L-lactide)/nano-hydroxyapatite composite scaffolds for bone tissue engineering and biocompatibility evaluation. AB - Biodegradable polymer/bioceramic composite scaffolds can overcome the limitations of conventional ceramic bone substitutes such as brittleness and difficulty in shaping. However, conventional methods for fabricating polymer/bioceramic composite scaffolds often use organic solvents (e.g., the solvent casting and particulate leaching (SC/PL) method), which might be harmful to cells or tissues. In this study, Poly (D,L-lactide)/nano-hydroxyapatite (PDLLA/NHA) composites were prepared by in-situ polymerization, and highly porous scaffolds were fabricated using a novel method, supercritical CO2/salt-leaching method (SC CO2/SL). The materials and scaffolds were investigated by scanning electronic microscopy (SEM), transmission electronic microscopy (TEM) and gel permeation chromatography (GPC). GPC showed that the molecular weight of composites decreased with increase of NHA content. However, the water absorption and compressive strength increased dramatically. The SEM micrographs showed that the scaffolds with pore size about 250 microm were obtained by controlling parameters of SC CO2/SL. The biocompatibility of PDLLA/NHA porous scaffolds were evaluated in vitro and in vivo. The evaluation on the cytotoxicity were carried out by cell relative growth rate (RGR) method and cell direct contact method. The cytotoxicity of these scaffolds was in grade I according to ISO 10993-1. There was no toxicosis and death cases observed in acute systemic toxicity test. And histological observation of the tissue response (1 and 9 weeks after the implantation) showed that there are still some slight inflammation responses. PMID- 17701304 TI - The behaviour of selected yttrium containing bioactive glass microspheres in simulated body environments. AB - The study aims at the manufacture and investigation of biodegradable glass microspheres incorporated with yttrium potentially useful for radionuclide therapy of cancer. The glass microspheres in the SiO2-Na2O-P2O5-CaO-K2O-MgO system containing yttrium were prepared by conventional melting and flame spheroidization. The behaviour of the yttrium silicate glass microspheres was investigated under in vitro conditions using simulated body fluid (SBF) and Tris buffer solution (TBS), for different periods of time, according to half-life time of the Y-90. The local structure of the glasses and the effect of yttrium on the biodegradability process were evaluated by Fourier Transform Infrared (FT-IR) spectroscopy and Back Scattered Electron Imaging of Scanning Electron Microscopy (BEI-SEM) equipped with Energy Dispersive X-ray (EDX) analysis. UV-VIS spectrometry and Inductively Coupled Plasma Mass Spectrometry (ICP-MS) was used for analyzing the release behaviour of silica and yttrium in the two used solutions. The results indicate that the addition of yttrium to a bioactive glass increases its structural stability which therefore, induced a different behaviour of the glasses in simulated body environments. PMID- 17701305 TI - Gelatin sponges (Gelfoam) as a scaffold for osteoblasts. AB - Gelatine sponge because of its flexibility, biocompatibility, and biodegradability, has the potential to be used as a scaffold to support osteoblasts and to promote bone regeneration in defective areas. This study aimed to determine osteoblast proliferation, differentiation, and integration in modified and un-modified gelatine sponges. Three scaffolds were studied: gelatine sponge (Gelfoam), gelatin sponge/mineral (hydroxyapatite) composite, and gelatin sponge/polymer (poly-lactide-co-glycolide) composite. 2-D plastic coverslip was used as control. The gelatin sponges were modified using PLGA coating and mineral deposition to increase biodegradation resistance and osteoblast proliferation respectively. The scaffolds were characterized using Scanning Electron Microscopy (SEM) and X-ray diffraction. Cell number (DNA content), cell-replication rate (thymidine assay), and cell differentiation (alkaline phosphatase activity) were measured 24 h, 3 days, and 1, 2, 3 weeks after the osteoblast-like cells were cultured onto the scaffolds. Cell penetration into the sponges was determined using haematoxylin-eosin staining. Both modified and unmodified gelatine sponges demonstrated ability to support cell growth and cells were able to penetrate into the sponge pores. In a comparison of different scaffolds, cell number and cell replication were highest in sponge/hydroxyapatite composite and lowest in sponge/PLGA composite. PMID- 17701306 TI - Fixation of experimental osteotomies with bioabsorbable SR-polylactide polyglycolide (80/20) polymeric rods. AB - Self-reinforced polylactide-polyglycolide (80/20) composite rods, 2 mm in diameter and 36 mm in length, were implanted into the dorsal subcutaneous tissue of 20 rabbits. Osteotomies of the distal femur were fixed with these rods (2x15 mm) in the rabbits. The follow-up times varied from 3 to 104 weeks. After sacrifice, three-point bending and shear tests and molecular weight measurements were performed for subcutaneously placed rods. Radiological, histological, microradiographic, oxytetracycline-fluorescence, and histomorphometrical studies of the osteotomized and intact control femora were performed. After 6 weeks the mechanical properties had decreased significantly, but osteotomies had healed uneventfully. The present investigation showed that the mechanical strength and fixation properties of SR-Polylactide-glycolide (80/20) rods are suitable for fixation of cancellous bone osteotomies in rabbits provided that the operative technique is correct. The present article is the first report on the application of these rods for fixation of cancellous bone osteotomies. PMID- 17701307 TI - Internalization of hydroxyapatite nanoparticles in liver cancer cells. AB - Hydroxyapatite (HAP) is the main inorganic component of hard tissues and shows excellent biocompatibility and osteoconductivity properties. Nanoparticles of HAP can be synthesised by the precipitation method in distilled water. The needle shaped particles are below 100 nm in size with low-crystallinity and high surfacial activation. Recent studies showed toxic effects of HAP nanoparticles on cancer cells. Other studies focus on the application of HAP nanoparticles as drug and gene delivery system or cell marker. However, to date, the exact internalization pathway of HAP nanoparticles into cells has not been determined. When HAP nanoparticles were added to cell culture medium, the particles immediately became instable and formed agglomerates with a size of about 500-700 nm. Hence, cells seldom encounter single HAP nanoparticles in the environment of cell culture or body fluid. The TEM showed internalized HAP captured by vacuoles in the cytoplasm of the hepatocellular carcinoma cells. The invaginations in the cell membrane before nanoparticle uptake suggested endocytic pathways as internalization mechanism. This study revealed that agglomerated HAP nanoparticles were internalized by cells through the energy-dependent process of clathrin-mediated endocytosis. Depletion of intracellular potassium arrested the formation of coated pit, which inhibited the uptake of HAP. PMID- 17701308 TI - Polyethylene and cobalt-chromium molybdenium particles elicit a different immune response in vitro. AB - Periprosthetic osteolysis is a major clinical problem that limits the long-term survival of total joint arthroplasties. Particles of prosthetic material stimulate immune competent cells to release cytokines, which may cause bone loss and loosening of the prosthesis. This study examined the following hypothesis. Polyethylene and titanium particles elicit a different immune response in vitro. To test these hypotheses, we used the human bone marrow cell culture model that we have established and previously used to examine particle associated cytokine release. Ultra high molecular weight polyethylene (UHMW-PE) induced a proliferation of CD14 positive cells (monocytes/macrophages) whereas cobalt chromium molybdenium (CoCrMb) particles demonstrated an increased proliferation of CD66b positive cells (granulocytes). Light and scanning microscopic evaluation revealed that the UHMW-PE particles, which have built large clusters of particles (O7, 5 microm), were mainly surrounded by the cells and less phagocytosed. On the other hand the smaller particles from CoCrMb have been phagocytosed by the cells. These results provide strong support for our hypothesis: that wear particles derived from prosthetic materials of different material can elicit significantly different biologic responses. In summary the results suggest that the "in vitro" response to wear particles of different biomaterials should be investigated by culture systems of various lineages of cells. PMID- 17701309 TI - Correlation of in vitro and in vivo results of vacuum plasma sprayed titanium implants with different surface topography. AB - Research has proven that rough surfaces improve both biologic and biomechanical responses to titanium (Ti) implants. The purpose of this study was to evaluate the correlation between the expression of bone cell-associated proteins to Vacuum Plasma-Sprayed Titanium implants (VPS-Ti) with different surface textures in vitro and the bone integration in vivo. The biological performances of the surfaces were evaluated over a period of 8 weeks using human bone marrow cell cultures and Gottinger mini pigs. Cells were cultured on VPS-Ti with two respectively different surface-roughnesses (Ra). The level of Osteoprotegerin (OPG), Osteocalcin (OC) and alkaline phosphatase activity (ALP) were evaluated. The bone integration in vivo was evaluated by histomorphological analyses. A cancellous structured titanium (CS-Ti) construct was used as reference material in both study designs. Comparison of data was conducted using the Scheffe tests and the paired t-test with Bonferroni's correction. A comparative analysis was done to measure the degree of association between the in vitro and in vivo data. A total amount of OC was significantly increased for VPS-Ti for cells cultured on both VPS-Ti and CS-Ti, while OPG was only detectable after 8 weeks without any significant differences. The ALP activity on all surfaces was not statistically increased. For VPS-Ti with Ra ranging from 0.025 mm up to 0.059 mm, bone integration response was increased, but there was no statistical difference between the VPS-Ti. Expression of OPG, OC and ALP correlated with the histomorphological data over the 8-week period. The in vitro data suggest the superiority of VPS-Ti over CS-Ti, but more importantly, the biocompatibility of testing an in vitro model to predict the outcome and possible integration of implants in vivo. PMID- 17701310 TI - Degradative and mechanical properties of a novel resorbable plating system during a 3-year follow-up in vivo and in vitro. AB - We tested the tissue reactions and mechanical strength of a novel biodegradable craniomaxillofacial plating system, Inion CPS, in the course of degradation. Plates and screws composed of L-lactide, D-lactide and trimethylene carbonate were implanted to the mandible and dorsal subcutis of 12 sheep. The animals were sacrificed at 6-156 weeks. Histological evaluation was done using paraffin and methylmetacrylate techniques. Degradative and mechanical properties during the follow-up were measured both of in vivo and in vitro implants. In light microscopy, the in vivo implant material began to fragment at 52 weeks and could not be detected at 104 weeks. No significant foreign body reactions were seen in the mandibles. The dorsal subcutis disclosed mild reactions, which were, however, not of clinical significance. The implants in vitro maintained their entire mass for 26 weeks and lost 63-80% of the mass by week 104. The inherent viscosity of the implants in vitro and in vivo diminished uniformly. The screws retained their shear strength for 12-16 weeks. The plates maintained their tensile strength for at least 6 weeks. The maximum capacity of the plates in 3-point bending tests diminished gradually by 87% in 26 weeks. In conclusion, the plates and screws examined maintain adequate strength for the healing period of a bone fracture or osteotomy, producing no harmful foreign body reactions. PMID- 17701311 TI - Effect of biological implant surface coatings on bone formation, applying collagen, proteoglycans, glycosaminoglycans and growth factors. AB - OBJECTIVES: The aim of the present study was to evaluate six different implant surface coatings with respect to bone formation. Being major structural components of the extracellular matrix, collagen, the non-collagenous components decorin/chondroitin sulphate (CS) and the growth factors TGF-beta1/BMP-4 served in different combinations as coatings of experimental titanium implants. MATERIALS AND METHODS: Eight miniature pigs received each six implants in the mandible. The implant design showed two circular recesses along the length axis. Three, four, five and six weeks after implant placement, the animals were sacrificed in groups of two. Bone-implant contact (BIC) was evaluated along the outer implant surface and within the recesses. Bone volume was determined by synchrotron radiation micro computed tomography (SRmicroCT) for one implant of each surface state, 6 weeks after placement. RESULTS: At each week of observation, collagen/CS or collagen/CS/BMP-4 coated implants showed the highest BIC of all surface states. This was statistically significant at week five (p=0.030, p=0.040) and six (p=0.025, p=0.005). SRmicroCT measurements determined the highest bone volume for a collagen/CS coated implant. CONCLUSION: The results indicate that collagen/CS and collagen/CS/BMP-4 lead to a higher degree of bone formation compared to other ECM components. PMID- 17701312 TI - Antibacterial activity of chitosan-based matrices on oral pathogens. AB - Chitosan is a well sought-after polysaccharide in biomedical applications due to its biocompatibility, biodegradability to non-toxic substances, and ease of fabrication into various configurations. However, alterations in the anti bacterial properties of chitosan in various forms is not completely understood. The objective of this study was to evaluate the anti-bacterial properties of chitosan matrices in different configurations against two pathogens-Gram-positive Streptococcus mutans and Gram-negative Actinobacillus actinomycetemcomitans. Two dimensional (2-D) membranes and three-dimensional (3-D) porous scaffolds were synthesized by air drying and controlled-rate freeze drying. Matrices were suspended in bacterial broths with or without lysozyme (enzyme that degrades chitosan). Influences of pore size, blending with Polycaprolactone (PCL, a synthetic polymer), and neutralization process on bacterial proliferation were studied. Transient changes in optical density of the broth, adhesion characteristics, viability, and contact-dependent bacterial activity were assessed. 3-D porous scaffolds were more effective in reducing the proliferation of S. mutans in suspension than 2-D membranes. However, no significant differences were observed on the proliferation of A. actinomycetemcomitans. Presence of lysozyme significantly increased the antibacterial activity of chitosan against A. actinomycetemcomitans. Pore size did not affect the proliferation kinetics of either species, with or without lysozyme. NaOH neutralization of chitosan increased bacterial adhesion whereas ethanol neutralization inhibited adhesion without lowering proliferation. Mat culture tests indicated that chitosan does not allow proliferation on its surface and it loses antibacterial activity upon blending with PCL. Results suggest that the chemical and structural characteristics of chitosan-based matrices can be manipulated to influence the interaction of different bacterial species. PMID- 17701313 TI - Preparation and property of a novel bone graft composite consisting of rhBMP-2 loaded PLGA microspheres and calcium phosphate cement. AB - Calcium phosphate cement (CPC) is a highly promising bone substitute and an excellent carrier for delivering growth factors. Yet, the lack of macro-porosity and osteoinductive ability, limit its use. This study is aimed at developing a novel biodegradable biomaterial for bone repair with both highly osteoconductive and osteoinductive properties. RhBMP-2 loaded PLGA microspheres were incorporated into rhBMP-2/CPC for macropores for bone ingrowth. The compressive strength, crystallinity, microscopic structure, and bioactivity of the composites were investigated. The results showed that with the incorporation of rhBMP-2 loaded PLGA microspheres, the compressive strength was decreased from (29.48+/-6.42) MPa to (8.26+/-3.58) MPa. X-ray diffraction revealed that the crystallinity pattern of HA formed by CPC had no significant change. Inside the composite, the microspheres distributed homogeneously and contacted intimately with the HA matrix, as observed by scanning electron microscopy (SEM). When the PLGA microspheres dissolved after having been emerged in PBS for 56 days, macropores were created within the CPC. The rhBMP-2/PLGA/CPC composite, showing a 4.9% initial release of rhBMP-2 in 24 h, followed by a prolonged release for 28 days, should have a greater amount of rhBMP-2 released compared to the CPC delivery system. When rabbit marrow stromal cells were cocultured with the composite, the alkaline phosphatase (ALP) and osteocalcin (OC) showed a dose response to the rhBMP-2 released from the composite, indicating that the activity of rhBMP-2 was retained. This study shows that the new composite reveals more rhBMP-2 release and osteogenic activity. This novel BMP/PLGA/CPC composite could be a promising synthetic bone graft in craniofacial and orthopedic repairs. PMID- 17701314 TI - In vivo behavior of bioactive phosphate glass-ceramics from the system P2O5-Na2O CaO containing TiO2. AB - Soda lime phosphate bioglass-ceramics with incorporation of small additions of TiO2 were prepared in the metaphosphate and pyrophosphate region, using an appropriate two-step heat treatment of controlled crystallization defined by differential thermal analysis results. Identification and quantification of crystalline phases precipitated from the soda lime phosphate glasses were performed using X-ray diffraction analysis. Calcium pyrophosphate (beta-Ca2P2O7), sodium metaphosphate (NaPO3), calcium metaphosphate (beta-Ca(PO3)2), sodium pyrophosphate (Na4P2O7), sodium calcium phosphate (Na4Ca(PO3)6) and sodium titanium phosphate (Na5Ti(PO4)3) phases were detected in the prepared glass ceramics. The degradation of the prepared glass-ceramics were carried out for different periods of time in simulated body fluid at 37 degrees C using granules in the range of (0.300-0.600 mm). The released ions were estimated by atomic absorption spectroscopy and the surface textures were measured by scanning electron microscopy. Evaluation of in vivo bioactivity of the prepared glass ceramics was carried through implanting the samples in the rabbit femurs. The results showed that the addition of 0.5 TiO2 mol% enhanced the bioactivity while further increase of the TiO2 content decreased the bioactivity. The effect of titanium dioxide on the bioactivity was interpreted on the basis of its action on the crystallization process of the glass-ceramics. PMID- 17701315 TI - The microscopical characterization of membranes poly (L-glycolic-co-lactic acid) with and without added plasticizer: an in vivo study. AB - The development of biodegradable materials has lead to renewed interest in the study of their interactions with the host organism in order to make the resulting products appropriate for use as temporary materials in clinical research, as well as important therapeutic applications. The copolymer poly (L-lactic-co-glycolic acid) or PLGA membranes have been used for several purposes. The physical properties of these materials can be modified by the addition of a plasticizer, such as the triethylcitrate, to provide flexibility and porosity to the implants, and enhance control of the polymer degradation time. Membranes with 7% plasticizer and without plasticizer (triethylcitrate) were compared. Membranes without plasticizer were denser and more compact than those with plasticizer. Two days and 30 days after implantation, the membranes with and without plasticizer showed little degradation. Sixty days and 120 days after implantation, the membranes with 7% plasticizer showed more cell invasion, and tissue adherence, as well as rapid degradation when compared to membranes without plasticizer. PMID- 17701316 TI - Effect of collagen fibril formation on bioresorbability of hydroxyapatite/collagen composites. AB - Porous hydroxyapatite/collagen (HAp/Col) composite is a promising biomaterial and a scaffold for bone tissue engineering. The effect of fibril formation of Col in the porous composite on bioresorbability and mechanical strength was investigated. The fibril formation, in mixing a self-organized HAp/Col nanocomposite and sodium phosphate buffer at a neutral condition, occurred during incubation at 37 degrees C, resulting in gelation of the mixture. The porous composites with and without the incubation were obtained by freeze-drying technique, in which macroscopic open pores were formed. The compressive strength of the porous composite with the incubation (34.1 +/- 1.6 kPa) was significantly higher than that without the incubation (28.0 +/- 3.3 kPa) due to the fibril formation of Col. The implantations of the porous composites treated with a dehydrothermal treatment in bone holes revealed that bioresorption was clearly depended on the fibril formation. The bioresorbability in vivo was almost matched to the in vitro test using enzymatic reaction of collagenase. PMID- 17701317 TI - Effect of biomimetic conditions on mechanical and structural integrity of PGA/P4HB and electrospun PCL scaffolds. AB - The selection of an appropriate scaffold represents one major key to success in tissue engineering. In cardiovascular applications, where a load-bearing structure is required, scaffolds need to demonstrate sufficient mechanical properties and importantly, reliable retention of these properties during the developmental phase of the tissue engineered construct. The effect of in vitro culture conditions, time and mechanical loading on the retention of mechanical properties of two scaffold types was investigated. First candidate tested was a poly-glycolic acid non-woven fiber mesh, coated with poly-4-hydroxybutyrate (PGA/P4HB), the standard scaffold used successfully in cardiovascular tissue engineering applications. As an alternative, an electrospun poly-epsilon caprolactone (PCL) scaffold was used. A 15-day dynamic loading protocol was applied to the scaffolds. Additionally, control scaffolds were incubated statically. All studies were performed in a simulated physiological environment (phosphate-buffered saline solution, T=37 degrees C). PGA/P4HB scaffolds showed a dramatic decrease in mechanical properties as a function of incubation time and straining. Mechanical loading had a significant effect on PCL scaffold properties. Degradation as well as fiber fatigue caused by loading promote loss of mechanical properties in PGA/P4HB scaffolds. For PCL, fiber reorganization due to straining seems to be the main reason behind the brittle behavior that was pronounced in these scaffolds. It is suggested that those changes in scaffolds' mechanical properties must be considered at the application of in vitro tissue engineering protocols and should ideally be taken over by tissue formation to maintain mechanically stable tissue constructs. PMID- 17701318 TI - Preparation of nanosized beta-tricalcium phosphate particles with Zn substitution. AB - Nanosized beta-ZnTCP powders with different Zn contents were prepared through coprecipitation of ACP out of the CaCl2-ZnCl2-Na3PO4-PEG system, and calcination of the ACP precursor at 800 degrees C for 3 h. The characterizations of the products showed that the products belong to beta-TCP phase, and the particles sizes of them are about 300 nm, smaller than that of beta-TCP (500 nm). Both the Zn2p binding energy and lattice parameter variations of beta-TCP evidenced that Zn had substituted for Ca in the lattice. Such nanosized beta-ZnTCP powders could be used as bone repair materials with desired and sustained release of Zn. PMID- 17701319 TI - Basic research on aw-AC/PLGA composite scaffolds for bone tissue engineering. AB - Recently, it has become important to develop effective material to be used as scaffolds for bone tissue engineering. Therefore, we fabricated new three dimensional (3D) scaffolds consisting of biodegradable poly(D,L-lactide-co glycolic acid)(PLGA)(75/25) with anti-washout type AC (aw-AC) particles. The aim of this study was to evaluate this new scaffold concerning its basic properties and biocompatibility. The obtained scaffolds were observed with scanning electron microscopy (SEM), and measured for porosity, shrinkage and biaxial compressive strengths. It was shown that PLGA with aw-AC composite scaffolds (aw-AC/PL) showed a greater strength and stability than PLGA scaffolds (PL). Also, the mass reduction of aw-AC/PL during incubation decreased compared to that of PL. The number of MC3T3-E1 cell in PL and aw-AC/PL was counted at 5 h, 1 week, and 2 weeks after cell seeding. As a result, aw-AC/PL exhibited a superior performance in terms of attachment and proliferation compared to PL. Histologically, aw-AC/PL showed an excellent response toward soft tissues. Therefore, it was shown that aw AC/PL was more biocompatible than PL. In conclusion, it was strongly suggested that aw-AC/PL was more useful for cell transplantation than PL in bone tissue engineering. PMID- 17701320 TI - An open-pored gelatin/hydroxyapatite composite as a potential bone substitute. AB - Gelatin matrix composites reinforced with fine hydroxyapatite (HA) dispersants were investigated in an exploratory study for their suitability as surgical implants. The criteria for the candidate implant material were that it: (1) be benign, (2) have useful mechanical properties under quasi-in vivo environmental conditions, (3) be dimensionally stable, (4) be sterilizable, (5) be completely assimilable, and (6) exhibit contiguous porosity to encourage invasion by the live host tissue. The synthesis of a composite comprised of a HA particulate reinforcement of a cross-linked gelatin matrix was undertaken to provide preliminary data on its swelling behavior and compressive stiffness that is retained after extended immersion in normal saline solution. A new approach leading to a tailorable, open pore microstructure is described. At a sufficiently high ratio of HA to gelatin the attainable compressive stiffness and the resistance to swelling suggests that this composite system offers potential as a versatile surgical implant material. Suggestions for further studies are offered. PMID- 17701322 TI - Latex of immunodiagnosis for detecting the Chagas disease. I. Synthesis of the base carboxylated latex. AB - This article investigates the synthesis of two (monodisperse, carboxylated, and core-shell) latexes, through a batch and a semibatch emulsion copolymerizations of styrene (St) and methacrylic acid (MAA) onto polystyrene latex seeds. A mathematical model of the process was developed that predicts conversion, average particle size, and surface density of carboxyl groups. The model was adjusted to the batch reaction measurements, and then it was used in the design of the semibatch experiment. The semibatch reaction involved an initial homopolymerization of St followed by instantaneous addition of MAA-St-initiator. Compared with the batch reaction results, the semibatch policy more than doubled the surface density of carboxyl groups. The second part of this series describes the development of an immunodiagnosis latex-protein complex for detecting the Chagas disease, by coupling an antigen of Trypanosoma cruzi onto the produced carboxylated latexes. PMID- 17701321 TI - Thermal and spectrophotometric studies of new crosslinking method for collagen matrix with glutaraldehyde acetals. AB - Despite the many existing crosslinking procedures, glutaraldehyde (GA) is still the method of choice used in the manufacture of bioprosthesis. The major problems with GA are: (a) uncontrolled reactivity due to the chemical complexity or GA solutions; (b) toxicity due to the release of GA from polymeric crosslinks; and (c) tissue impermeabilization due to polymeric and heterogeneous crosslinks formation, partially responsible for the undesirable calcification of the bioprosthesis. A new method of crosslinking glutaraldehyde acetals has been developed with GA in acid ethanolic solution, and after the distribution inside de matrix, GA is released to crosslinking. Concentrations of hydrochloride acid in ethanolic solutions between 0.1 and 0.001 mol/L with GA concentration between 0.1 and 1.0% were measured in an ultraviolet spectrophotometer to verify the presence of free aldehyde groups and polymeric compounds of GA. After these measurements, the solutions were used to crosslink bovine pericardium. The spectrophotometric results showed that GA was better protected in acetal forms for acid ethanolic solution with HCl at 0.003 mol/L and GA 1.0%(v/v). The shrinkage temperature results of bovine pericardium crosslinked with acetal solutions showed values near 85 degrees C after the exposure to triethylamine vapors. PMID- 17701323 TI - Fluoride release for restorative materials and its effect on biofilm formation in natural saliva. AB - This study investigated the influence of natural saliva of varying pH on surface biofilm formation of restorative materials and how this influenced fluoride release. Columnar specimens of glass ionomer cement (GIC), resin modified glass ionomer cement (RMGIC), compomer, giomer and composite, were prepared, matured for 24 h at 37 degrees C and 100% humidity, lapped and then placed in natural stimulated saliva with a pH of 3.8 or 7.1. Fluoride release was determined daily using an ion-selective electrode. The surfaces of selected specimens were observed using Confocal Laser Scanning Microscopy in conjunction with a fluorescent dye. The surface biofilm formation and bacterial growth was most dominant under neutral conditions and on the surfaces of GICs compared with other materials. GICs released significantly higher amounts of fluoride than other materials. The results suggest that the increased fluoride release of GICs did not reduce the amount of bacterial growth and biofilm formation on the surfaces of these materials when stored in natural saliva. PMID- 17701324 TI - Endocytosis and interaction of poly (amidoamine) dendrimers with Caco-2 cells. AB - PURPOSE: To investigate the internalization and subcellular trafficking of fluorescently labeled poly (amidoamine) (PAMAM) dendrimers in intestinal cell monolayers. MATERIALS AND METHODS: PAMAM dendrimers with positive or negative surface charge were conjugated to fluorescein isothiocyanate (FITC) and visualized for colocalization with endocytosis markers using confocal microscopy. Effect of concentration, generation and charge on the morphology of microvilli was observed using transmission electron microscopy. RESULTS: Both cationic and anionic PAMAM dendrimers internalized within 20 min, and differentially colocalized with endocytosis markers clathrin, EEA-1, and LAMP-1. Transmission electron microscopy analysis showed a concentration-, generation- and surface charge-dependent effect on microvilli morphology. CONCLUSION: These studies provide visual evidence that endocytic mechanism(s) contribute to the internalization and subcellular trafficking of PAMAM dendrimers across the intestinal cells, and that appropriate selection of PAMAM dendrimers based on surface charge, concentration and generation number allows the application of these polymers for oral drug delivery. PMID- 17701325 TI - Peritoneal macrophage uptake, pharmacokinetics and biodistribution of macrophage targeted PEG-fMLF (N-formyl-methionyl-leucyl-phenylalanine) nanocarriers for improving HIV drug delivery. AB - PURPOSE: To assess in vivo macrophage targeting potential of PEG-fMLF nanocarriers and to investigate their biodistribution, peritoneal macrophage uptake, and pharmacokinetics. METHODS: Multiple copies of fMLF were conjugated to purchased and novel (branched, peptide-based) PEG nanocarriers. Peritoneal macrophage uptake was evaluated in mice 4 hours after IP administration of fluorescence-labeled PEG-fMLF nanocarriers. Pharmacokinetics and biodistribution were determined in rats after IV administration of tritiated PEG-fMLF nanocarriers. RESULTS: Attachment of one, two, or four fMLF copies increased uptake in macrophages by 3.8-, 11.3-, and 23.6-fold compared to PEG without fMLF. Pharmacokinetic properties and tissue distribution also differed between nanocarriers with and without fMLF. Attachment of fMLF residues increased the t(1/2) of PEG(5K) by threefold but decreased the t(1/2) of PEG(20K) by 40%. Attachment of fMLF increased accumulation of nanocarriers into macrophages of liver, kidneys and spleen. However, on a molar basis, penetration was equivalent suggesting nanocarrier size and targeting moieties are important determinants. CONCLUSIONS: These results demonstrate the feasibility for targeting macrophages, a primary HIV reservoir site. However, these studies also suggest that balancing peripheral tissue penetration (a size-dependent phenomenon) versus target cell uptake specificity remains a challenge to overcome. PMID- 17701326 TI - The Readiness for Return-To-Work (RRTW) scale: development and validation of a self-report staging scale in lost-time claimants with musculoskeletal disorders. AB - INTRODUCTION: We report on the development and validation of a 22-item scale assessing stage of readiness for return-to-work, the Readiness for Return-to-Work (RRTW) scale. METHODS: Lost-time claimants (n = 632) completed a telephone survey one month after a work-related musculoskeletal injury. Exploratory and confirmatory factor analyses of readiness items were conducted with two separate samples, and concurrent validity was examined. RESULTS: For workers not working, 60% of the variance was explained by four factors--(1) Precontemplation, (2) Contemplation (3) Prepared for Action-Self-evaluative and (4) Prepared for Action Behavioral. For those working, 58% of the variance was explained by two factors- (1) Uncertain Maintenance and (2) Proactive Maintenance. Confirmatory factor analyses had satisfactory fit indices to confirm the initial model. Concurrent validity of the scale was supported: relationships of readiness with depressive symptoms, fear-avoidance, pain, and general health, were generally in the hypothesized direction. CONCLUSIONS: Psychometric properties of the newly developed instrument suggest that the application of the Readiness for Change model to return-to-work is relevant to work disability research. The instrument may facilitate the offer of stage-specific services tailored to injured workers' needs, and be used for evaluation of return-to-work interventions. PMID- 17701328 TI - Factors influencing perceptions of breast cancer genetic counseling among women in an urban health care system. AB - The study assessed perceptions of breast cancer genetic counseling. Focus groups were conducted with twenty women (ages < = 50 years) in a Midwestern, urban health system identified as at above average risk of developing hereditary breast cancer and referred for breast cancer genetic counseling following mammography. All participants associated the words "breast cancer" with fear. African American women who received breast cancer genetic counseling may have channeled their fear into increased vigilance related to breast health. African American women who did not receive breast cancer genetic counseling were most knowledgeable about it. In contrast, Caucasian women who did not receive it reported uncertainty about the role of genetic counseling and testing in assessing breast cancer risk, mistrust in medical professionals, and lack of trust in the accuracy of genetic tests. The results could be used to help develop interventions to improve informed decision making regarding breast cancer genetic counseling. PMID- 17701329 TI - Distress and family functioning in oncogenetic counselling for hereditary and familial breast and/or ovarian cancers. AB - We conducted a psychological assessment during oncogenetic counseling for hereditary breast/ovarian cancer. Anxiety and depression were assessed with the HAD scale, and family functioning and satisfaction with FACES III. HAD was administered at baseline (t(1)), at risk communication (t(2)), at genetic test result communication, or at first surveillance in not tested subjects (t(3)); FACES III was administered at baseline only. We analysed a total of 185 questionnaires administered to the 37 subjects studied. Although not pathological, distress was significantly higher at t(2) and t(3) (p = 0.027 and p = 0.039, respectively). Health and marital status were significantly associated with distress. In a disease-free condition, anxiety was higher (p = 0.027) at t(2), and for single status, depression increased from t(1) to t(2) (p = 0.026). Families were perceived to be well functioning, and subjects were satisfied with their families. The data collected in this analysis could help to improve the quality of oncogenetic counselling in clinical practice. PMID- 17701330 TI - Maternal confidence in child rearing: comparing data from short-term prospective surveys among Japanese and Vietnamese mothers. AB - OBJECTIVE: To investigate the confidence women feel about child rearing in Japan and Vietnam. METHODS: We conducted a prospective study of 210 Japanese mothers who registered as pregnant in Sukagawa City, Fukushima, and 132 Vietnamese mothers who attended a university hospital in Ho Chi Minh City. Follow-up surveys were conducted via mail approximately 6 weeks after newborn delivery among the Japanese cohort, and at the time of a one-month checkup at the hospital among the Vietnamese cohort. RESULTS: The follow-up rate among these subjects was 67% (N = 140) in Japan and 65% (N = 86) in Vietnam. The proportion of mothers who were not confident about child rearing was 48% (N = 67) in Japan and 63% (N = 54) in Vietnam. In both countries, mothers in the unconfident group reported less happiness and relaxation time with children than mothers in the confident group. Maternal confidence was associated with child rearing experience, although the significance of this factor diminished in a multivariate analysis of the Vietnamese data. While unintended pregnancy and unemployment were related to confidence in child rearing in Japan, educational history was associated with confidence in Vietnam. CONCLUSION: This exploratory study found a high proportion of Japanese and Vietnamese mothers are not confident in child rearing, which calls attention to this understudied issue of confidence among Asian mothers. PMID- 17701331 TI - Maternal work and birth outcome disparities. AB - OBJECTIVES: We tested relations between aspects of maternal work and birth outcomes in a national sample and in subgroups known to experience disparities. METHODS: Three indices of work attributes (Status and Recognition, Physical Demands, and Exposure to Conflict) were derived by factor analysis of variables extracted from the Department of Labor's O*Net database. The indices were linked to the National Longitudinal Survey of Youth using occupation codes for the primary jobs held by women who gave birth between 1979 and 2000 and worked during the quarter prior to birth (n = 3,386 births to n = 2,508 mothers). Multiple regression was used to model birth outcomes as functions of the work attribute indices, controlling for several measures of socioeconomic status and risk factors for adverse birth outcomes. RESULTS: In the full sample, work-related Physical Demands were associated with lower average birthweight and increased odds of preterm birth while Status and Recognition was associated with higher average birthweight and lower odds of fetal growth restriction. In stratified models, Status and Recognition was associated with higher birth weight among women with low (versus high) income and with lower odds of preterm birth among women with low (versus high) education. Physical Demands were associated with higher rates of preterm birth among women with low (versus high) income and education and among African-American mothers (compared to Whites). CONCLUSIONS: The work environment is an important predictor of healthy births. Relations between maternal work attributes and birth outcomes differ by race/ethnicity and socioeconomic status and according to the outcome under investigation. Further research with measures of work attributes specific to maternal work experiences is recommended to confirm our findings. PMID- 17701332 TI - NMDA receptors in hyperammonemia and hepatic encephalopathy. AB - The NMDA type of glutamate receptors modulates learning and memory. Excessive activation of NMDA receptors leads to neuronal degeneration and death. Hyperammonemia and liver failure alter the function of NMDA receptors and of some associated signal transduction pathways. The alterations are different in acute and chronic hyperammonemia and liver failure. Acute intoxication with large doses of ammonia (and probably acute liver failure) leads to excessive NMDA receptors activation, which is responsible for ammonia-induced death. In contrast, chronic hyperammonemia induces adaptive responses resulting in impairment of signal transduction associated to NMDA receptors. The function of the glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in animal models of chronic liver failure or hyperammonemia and in homogenates from brains of patients died in hepatic encephalopathy. The impairment of this pathway leads to reduced cGMP and contributes to impaired cognitive function in hepatic encephalopathy. Learning ability is reduced in animal models of chronic liver failure and hyperammonemia and is restored by pharmacological manipulation of brain cGMP by administering phosphodiesterase inhibitors (zaprinast or sildenafil) or cGMP itself. NMDA receptors are therefore involved both in death induced by acute ammonia toxicity (and likely by acute liver failure) and in cognitive impairment in hepatic encephalopathy. PMID- 17701333 TI - Aquaporins in the brain: from aqueduct to "multi-duct". AB - The aquaporin channel family was first considered as a family of water channels, however it is now clear that some of these channels are also permeable to small solutes such glycerol, urea and monocarboxylates. In this review, we will consider AQP4 and AQP9 expressed in the rodent brain. AQP4 is present on astrocytic end-feet in contact with brain vessels and could be involved in ionic homeostasis. However, AQP4 may also be involved in cell adhesion. AQP4 expression is highly modified in several brain disorders and it can play a key role in the cerebral edema formation. However, the exact role of AQP4 in edema formation is still debated. Recently, AQP4 has been shown to be also involved in astrocyte migration during glial scar formation. AQP9 is expressed in astrocytes and in catecholaminergic neurons. Two isoforms of AQP9 are expressed in brain cells, the shortest isoform is localized in the inner membrane of mitochondria and the longest in the cell membrane. The level of expression of AQP9 is negatively regulated by high concentrations of insulin. Taken together, these results suggest that AQP9 could be involved in brain energy metabolism. The induction of AQP9 in astrocytes is observed with time after stroke onset suggesting participation in the clearance of excess lactate in the extracellular space. These recent exciting results suggest that AQPs may not only be involved in water homeostasis in the brain but could also participate in other important physiological functions. PMID- 17701334 TI - Reinforcing a continuum of care: in-hospital initiation of long-term secondary prevention following acute coronary syndromes. AB - INTRODUCTION: Patients with a history of acute coronary syndrome are particularly susceptible to further vascular or ischemic events. Effective secondary prevention following acute coronary syndrome requires multiple medications targeting the different mechanisms of atherothrombosis. The 2002 American College of Cardiology/American Heart Association guidelines for the management of unstable angina and non ST-segment myocardial infarction and the 2004 guidelines for ST-segment myocardial infarction assign priority to the long-term administration of four critical classes of drugs: antiplatelet agents, in particular aspirin and clopidogrel, beta-blockers, angiotensin-converting enzyme inhibitors, and statins. CONCLUSIONS: Despite clinical trial evidence demonstrating their ability to reduce cardiovascular morbidity and mortality, available preventive pharmacotherapies remain underutilized. Suboptimal compliance with current recommendations, as with other management guidelines, arises from a host of entrenched physician, patient, and system-related factors. Optimal management of acute coronary syndrome acknowledges a continuum of care in which acute stabilization represents a single important component. Early, in hospital implementation of secondary preventive measures reinforces the continuum of care approach, promoting a successful transition from treatment to prevention, inpatient to outpatient management, and, when appropriate, subspecialist to generalist care. PMID- 17701335 TI - Reactions to health-related social control in young adults with type 1 diabetes. AB - Health-related social control refers to individuals' attempts to influence another's health behavior. We describe social control experienced by 109 adults aged 18-35 with Type 1 diabetes, and examine the influence of different types of social control on behavioral and psychological outcomes. Using a self administered questionnaire, telephone interview, and chart review, we assessed individuals' social control experiences, behavioral and psychological reactions, psychological adjustment, metabolic control, socio-demographics, and clinical factors at baseline, and psychological adjustment and metabolic control at 6 months follow-up. Most participants (85%) reported experiencing social control. Regression analyses revealed that more frequent negative control predicted less behavior change and more negative cognitive reactions concurrently, and decreases in psychological adjustment over time. More frequent reinforcement/modeling and structural changes predicted more positive emotional reactions, but were not associated with behavior change, psychological adjustment, or metabolic control. Use of direct persuasion was associated with more pretending of behavior change. These results suggest that negative social control attempts by social network members may be counter-productive. PMID- 17701336 TI - Sensation seeking and visual selective attention in adults with HIV/AIDS. AB - The association between sensation seeking and visual selective attention was examined in 31 adults with the Human Immunodeficiency Virus (HIV). Sensation seeking was measured with Zuckerman's Sensation Seeking Scale Form V (SSS-V). Selective attention was assessed with a perceptual span task, where a target letter-character must be identified in a quickly presented array of nontarget letter-characters. As predicted, sensation seeking was strongly associated (R(2) = .229) with perceptual span performance in the array size 12 condition, where selective attention demands were greatest, but not in the easier conditions. The Disinhibition, Boredom Susceptibility, and Experience Seeking subscales of the SSS-V were associated with span performance. It is argued that personality factors such as sensation seeking may play a significant role in selective attention and related cognitive abilities in HIV positive adults. Furthermore, sensation seeking differences might explain certain inconsistencies in the HIV neuropsychology literature. PMID- 17701337 TI - Start Talking About Risks: development of a Motivational Interviewing-based safer sex program for people living with HIV. AB - The epidemiology of HIV infection in the US in general, and in the southeast, in particular, has shifted dramatically over the past two decades, increasingly affecting women and minorities. The site for our intervention was an infectious diseases clinic based at a university hospital serving over 1,300 HIV-infected patients in North Carolina. Our patient population is diverse and reflects the trends seen more broadly in the epidemic in the southeast and in North Carolina. Practicing safer sex is a complex behavior with multiple determinants that vary by individual and social context. A comprehensive intervention that is client centered and can be tailored to each individual's circumstances is more likely to be effective at reducing risky behaviors among clients such as ours than are more confrontational or standardized prevention messages. One potential approach to improving safer sex practices among people living with HIV/AIDS (PLWHA) is Motivational Interviewing (MI), a non-judgmental, client-centered but directive counseling style. Below, we describe: (1) the development of the Start Talking About Risks (STAR) MI-based safer sex counseling program for PLWHA at our clinic site; (2) the intervention itself; and (3) lessons learned from implementing the intervention. PMID- 17701338 TI - Residential mobility among patients in the VA health system: associations with psychiatric morbidity, geographic accessibility, and continuity of care. AB - This paper reports on residential mobility among patients treated in the Veterans Affairs (VA) health system. We examine mobility in relation to patients' psychiatric disorders, and we assess the impact of mobility on health system geographic accessibility and continuity of care following inpatient discharge. Subjects included 534,002 patients with schizophrenia, bipolar disorder, depression, or with none of these conditions, who received VA services in both FY 01 and FY 02. We report the frequency and predictors of residential moves; we examine distance moved and changes in the proximity of VA providers; and we evaluate associations with timely receipt of outpatient care following inpatient discharges. Approximately 25% of patients with bipolar disorder, 20% with schizophrenia, 16% with depression, and 9% of patients without these conditions completed a residential move in FY 2002. When relocating, patients with schizophrenia and bipolar disorder were more likely to move closer to providers, suggesting greater sensitivity to accessibility barriers. PMID- 17701340 TI - Genetic structure of different populations of walking catfish (Clarias batrachus L.) in Bangladesh. AB - Information on genetic variation is essential for conservation and stock improvement programs. Seven dinucleotide microsatellite loci were analyzed to reveal genetic variability in three wild populations (Kella beel, Hakaluki haor, and Shobornokhali beel) and one hatchery population of the freshwater walking catfish, Clarias batrachus, in Bangladesh. Upon PCR amplification, the alleles were separated on polyacrylamide gel using a sequencing gel electrophoresis system and visualized by the silver-staining method. The loci were polymorphic (P95) in all the populations. Differences were observed in number and frequency of alleles as well as heterozygosity in the studied populations. Current gene diversity (He) was higher than expected under mutation-drift equilibrium, significantly in the Hakaluki haor and Shobornokhali beel populations, indicating a recent genetic bottleneck. Population differentiation (FST) values were significant (P<0.05) in all the population pairs. A relatively high level of gene flow and a low level of FST values were found between wild population pairs compared to hatchery-wild pairs. The unweighted pair group method with averages dendrogram based on genetic distance resulted in two major clusters: the hatchery population was alone in one cluster whereas the three wild populations made another cluster. The results reflect some degree of genetic variability in C. batrachus populations indicating potentialities for improving this species through a selective breeding program. The results revealed a recent bottleneck in some wild populations of C. batrachus. Protection of habitat may help increase the population size and lower the risk of vulnerability of the species in the future. PMID- 17701339 TI - Personality characteristics associated with persistent ADHD in late adolescence. AB - This study focused on the personality characteristics associated with Attention deficit/Hyperactivity disorder (ADHD) in a longitudinal sample of youth, with a particular focus on differences between those with and without persisting ADHD symptoms. Participants with ADHD (n = 90) were initially evaluated when they were 7-11 years old, and re-assessed at 16-22 years of age. Matched control subjects (n = 80) were recruited at the time of the follow-up evaluation. At follow-up, the Kiddie-SADS-PL, a semi-structured psychiatric interview, and the NEO-PI, a self-report personality inventory, were administered. Data were analyzed using multivariate analyses of variance (MANOVA). Results indicate that childhood ADHD is associated with lower scores on the NEO Conscientiousness subscale in adolescents/young adults--irrespective of the degree of ADHD persistence. In contrast, ratings of Neuroticism and Agreeableness appear to be more closely linked to adolescent status; those with persisting symptoms only exhibited increased Neuroticism and decreased Agreeableness. These results suggest that ADHD, and the degree to which symptoms persist into adolescence, may be closely linked to personality structure. PMID- 17701341 TI - Disciplinary style and child abuse potential: association with indicators of positive functioning in children with behavior problems. AB - Reduction of ineffective parenting is promoted in parent training components of mental health treatment for children with externalizing behavior disorders, but minimal research has considered whether disciplinary style and lower abuse risk could also be associated with positive functioning in such children. The present study examined whether lower dysfunctional disciplinary style and child abuse risk was associated with children's positive self-concept, adaptive attributional style, and hopefulness. Recruited from children undergoing treatment for disruptive behavior disorders, 69 mother-child dyads participated, with maternal caregivers reporting on their disciplinary style and abuse potential and children reporting independently on their positive functioning (adaptive attributional style, overall self-concept, and hopelessness). Findings supported the hypothesized association, with lower scores on mothers' dysfunctional discipline style and abuse potential significantly predicting children's reported positive functioning. Future research directions pertaining to more adaptive functioning in children with behavior problems are discussed. PMID- 17701342 TI - International study of health care organization and financing: development of renal replacement therapy in Germany. AB - The German health system represents the case of a global budget with negotiated fees and competing medical insurance companies. Physicians in private practice and non-profit dialysis provider associations provide most dialysis therapy. End stage renal disease (ESRD) modalities are well integrated into the overall health care system. Dialysis therapy, independent of the mode of treatment, is reimbursed at a weekly flat rate. Mandatory health insurance covers health expenses, including those related to ESRD, for more than 90% of the population. Both employees and employers contribute to the premium for this insurance. Private medical insurance covers the remainder of the population. Access to treatment, including dialysis therapy, is uniformly available. PMID- 17701343 TI - Synthetic sulfogalactosylceramide (sulfatide) and its use for the mass spectrometric quantitative urinary determination in metachromatic leukodystrophies. AB - 3-O-Sulfogalactosylceramides (sulfatides) accumulate in the genetic disease metachromatic leukodystrophy which is due to a defect in the catabolic enzyme, arylsulfatase A. Clinical diagnosis is usually confirmed by in vitro enzymatic deficiency of arylsulfatase A activity. The diagnosis may be complicated because of arylsulfatase A pseudo-deficiencies and another cause of MLD, sphingolipid activator B deficiency. As large quantities of sulfatides can be found in the urine in this disease, sulfatiduria appears as an extremely useful test. As recently enzyme replacement is underway, the quantitative determination, using an internal standard, appears particularly useful as a follow-up. Thus a non physiological sulfatide was synthesized for this purpose, i.e. 3-O-sulfo-beta-D C17 galactosylceramide (3-O-Sulfo-D: -Galactosyl-beta1'-->1-N-Heptadecanoyl-D erythro-Sphingosine). It has been prepared through condensation of an azidosphingosine derivative with a protected D galactopyranosyltrichloroacetimidate. Reduction of the azide was followed by acylation of a C-17 fatty acid. The key step was achieved by selective sulfation of the desired hydroxyl group on the sugar residue of the galactosylceramide using the stannylene methodology to give a 3'-sulfated beta-galactosyl C-17 ceramide. PMID- 17701344 TI - Mercury contamination and effects on survival of American avocet and black-necked stilt chicks in San Francisco Bay. AB - We evaluated whether mercury influenced survival of free-ranging American avocet (Recurvirostra americana) and black-necked stilt (Himantopus mexicanus) chicks in San Francisco Bay, California. Using radio telemetry, we radio-marked 158 avocet and 79 stilt chicks at hatching and tracked them daily until their fate was determined. We did not find strong support for an influence of in ovo mercury exposure on chick survival, despite observing a wide range of mercury concentrations in chick down feathers at hatching (0.40-44.31 microg g(-1) fw). We estimated that chick survival rates were reduced by < or =3% over the range of observed mercury concentrations during the 28-day period from hatching to fledging. We also salvaged newly-hatched chicks that were found dead during routine nest monitoring. In contrast to the telemetry results, we found that mercury concentrations in down feathers of dead chicks were higher than those in randomly-sampled live chicks of similar age. However, capture site was the most important variable influencing mercury concentrations, followed by year, species, and hatching date. Although laboratory studies have demonstrated negative effects of environmentally relevant mercury concentrations on chick survival, our results concur with the small number of previous field studies that have not been able to detect reduced survival in the wild. PMID- 17701345 TI - Effects of mercury exposure on the reproductive success of tree swallows (Tachycineta bicolor). AB - An experimental tree swallow population was established in the headwaters of the Shenandoah River, Virginia, USA to assess the accumulation and effects of mercury contamination on birds that eat emergent aquatic insects. One tributary, the South River, was contaminated with mercury before 1950. Reproductive success of swallows nesting within 50 m of this river was compared to that of three uncontaminated reference tributaries in 2005 and 2006. Female swallows on the contaminated stretch of river had significantly elevated blood and feather total mercury (blood: 3.56 +/- 2.41 ppm ww vs. 0.17 +/- 0.15 ppm reference; feather: 13.55 +/- 6.94 ppm vs. 2.34 +/- 0.87 ppm reference), possibly the highest ever reported for an insectivorous songbird. Insects collected by the swallows to be fed to nestlings averaged 0.97 +/- 1.11 ppm dw total mercury, significantly higher than on reference sites. Swallows in the contaminated area produced fewer fledglings than those in reference areas. The effect of mercury contamination on productivity was detectable only for young females in the contaminated area that were breeding for the first time in 2006, a segment of the population that may already have been stressed by inexperience. Tree swallows served as practical and effective biomonitors for mercury levels and effects and have great potential as proxy biomonitors for more logistically challenging birds such as loons or eagles. PMID- 17701346 TI - Cadmium tolerance and accumulation by two species of Iris. AB - Seedlings of Iris lactea var. chinensis (Fisch.) Koidz. and I. tectorum Maxim. were subjected to 0-160 mg l(-1) Cd in hydroponic system and harvested after 42 days to determine effects on root and shoot dry mass. A subset of 16-day-old seedlings was exposed to 1000 mg l(-1) Cd to characterize sub-cellular localization of Cd in root cells. The Cd contents in the shoots of I. lactea var. chinensis reached 529 microg g(-1 )dry weight (dw) at 80 mg l(-1) Cd treatment and in the shoots of I. tectorum reached 232 microg g(-1) dw at 40 mg l(-1) Cd treatment, without showing signs of visible toxicity. The Cd contents in the shoots of both two test species exceeded 100 microg g(-1), the critical value of Cd hyperaccumulator. The indices of tolerance (ITs) of I. lactea var. chinensis were higher than those of I. tectorum under 10-160 mg l(-1)Cd stress. Sub cellular localization of Cd in root cells was evaluated using transmission electron microscopy (TEM) and Cd deposits were found in the cell walls, in the cytoplasm and on the inner surface of xylem vessels in the root tip of I. lactea var. chinensis and I. tectorum. A few cells in the root tip of I. tectorum were necrotic. The results showed that the tolerance and accumulation of Cd by I. lactea var. chinensis were higher than those of I. tectorum, suggesting that I. lactea var. chinensis has potential application in phytoremediation. PMID- 17701347 TI - Plasma B-esterase and glutathione S-transferase activity in the toad Chaunus schneideri (Amphibia, Anura) inhabiting rice agroecosystems of Argentina. AB - B-esterase (BChE: butyrylcholinesterase and CbE: carboxylesterase) and glutathione S-transferase (GST) activity were measured in the plasma of Chaunus schneideri collected in rice fields and surrounding environments and in a reference pristine forest. The chemical criterion based on in-vitro reactivation of BChE activity using pyridine-2-aldoxime methochloride (2-PAM) was also determined. Mean values of plasma BchE, CbE, and GST activity for samples from agricultural areas were different from those for samples from pristine forest. Plasma samples from the two agricultural areas showed positive reactivation of BChE activity after incubation with 2-PAM. Based on our experimental evidence we suggest B-esterases and gluthatione S-transferases can be used in field monitoring as biomarkers of exposure of wildlife to pesticides, because the analysis in non-destructive and is sensitive to anti-ChE agrochemicals. Chemical reactivation of BChE is also a complementary method for assessing the effects of pesticides on toads inhabiting rice fields. Further studies are urgently needed to investigate adverse effects of massive exposure to pesticides experienced by native populations of anurans. PMID- 17701348 TI - Hypermethioninemia increases cerebral acetylcholinesterase activity and impairs memory in rats. AB - In the present study we investigated the effect of chronic hypermethioninemia on rat performance in the Morris water maze task, as well as on acetylcholinesterase (AChE) activity in rat cerebral cortex. For chronic treatment, rats received subcutaneous injections of methionine (1.34-2.68 micromol/g of body weight), twice a day, from the 6th to the 28th day of age; control rats received the same volume of saline solution. Groups of rats were killed 3 h, 12 h or 30 days after the last injection of methionine to AChE assay and another group was left to recover until the 60th day of life to assess the effect of early methionine administration on reference and working spatial memory of rats. AChE activity was also determined after behavioral task. Results showed that chronic treatment with methionine did not alter reference memory when compared to saline-treated animals. In the working memory task, we observed a significant days effect with significant differences between control and methionine-treated animals. Chronic hypermethioninemia significantly increased AChE activity at 3 h, 12 h or 30 days after the last injection of methionine, as well as before or after behavioral test. The effect of acute hypermethioninemia on AChE was also evaluated. For acute treatment, 29-day-old rats received one single injection of methionine (2.68 micromol/g of body weight) or saline and were killed 1, 3 or 12 h later. Results showed that acute administration of methionine did not alter cerebral cortex AChE activity. Our findings suggest that chronic experimental hypermethioninemia caused cognitive dysfunction and an increase of AChE activity that might be related, at least in part, to the neurological problems presented by hypermethioninemic patients. PMID- 17701349 TI - Intracranial stereotaxic cannulation for development of orthotopic glioblastoma allograft in Sprague-Dawley rats and histoimmunopathological characterization of the brain tumor. AB - Glioblastoma is the most common brain tumor that causes significant mortality annually. Limitations of the current therapeutic regimens warrant development of new techniques and treatment strategies in orthotopic animal model for better management of this devastating brain cancer. There are only a few experimental orthotopic models of glioblastoma for pre-clinical testing. In the present investigation, we successfully implanted rat C6 cells via intracranial stereotaxic cannulation in adult Sprague-Dawley rats for development and histoimmunopathological characterization of an advanced orthotopic glioblastoma allograft model, which could be useful for investigating the course of glioblastoma development as well as for testing efficacy of new therapeutic agents. The orthotopic glioblastoma allograft was generated by intracerebral injection of rat C6 cells through a guide-cannula system and after 21 post inoculation days the brain tumor was characterized by histoimmunopathological experiments. Histological staining and immunofluorescent labelings for TERT, VEGF, Bcl-2, survivin, XIAP, and GFAP revealed the distinct characteristics of glioblastoma in C6 allograft, which could be useful as a target for treatment with emerging new therapeutic agents. Our investigation indicated the successful development of intracranial cannulated orthotopic glioblastoma allograft in adult Sprague-Dawley rats, making it as a useful animal model of glioblastoma for pre clinical evaluation of various therapeutic strategies for the management of glioblastoma. PMID- 17701350 TI - Insulysin cleaves the APP cytoplasmic fragment at multiple sites. AB - The amyloid peptide (Abeta) deposited in Alzheimer's disease (AD) is generated by beta- and gamma-secretase processing of a larger integral membrane protein precursor (APP). Intramembrane processing of APP by gamma-secretase also yields an intracellular fragment, CTFgamma (a.k.a. AICD), which is highly conserved and is believed to regulate the transcription of several genes including KAI-1 and GSK3beta. The intracellular domain of APP is also processed by caspase to a 31 aa fragment that was shown to induce apoptosis by several groups. Although large quantities of CTFgamma are generated continuously by neurons, little if any is normally detected in cell lysates, which suggests that it is very rapidly turned over in vivo. Previous studies demonstrated that insulysin (IDE), an Abeta degrading enzyme, is responsible for cytosol-mediated CTFgamma degradation in vitro. Consistent with this finding, knockout mice lacking IDE accumulate CTFgamma to detectable levels in the brain, although its levels remain lower than its precursor, suggesting that it continues to be turned over in the brain. Moreover, when we treated cultured cells with IDE inhibitors, we did not observe an increase in CTFgamma in cell lysates, suggesting that pathways other than IDE are also involved in CTFgamma turnover. To understand CTFgamma turnover further, we have mapped the IDE cleavage sites with the intention of mutating them to examine alternative pathways in future studies. Edman degradation revealed that IDE cleaves CTFgamma at multiple sites to small peptides ranging from 5 to 14 aa. The cleavage sites do not reveal the existence of any sequence specificity for IDE cleavage. Understanding the turnover mechanisms of CTFgamma is critical to the understanding of the signaling function of APP mediated by this fragment. The current study presents the interesting specificity of CTFgamma turnover by IDE, which has been previously identified as the major degrading enzyme for Abeta as well as CTFgamma. In addition, the study provides evidence for the presence of alternative CTFgamma-degrading pathways in the cell. PMID- 17701351 TI - Maternal alcohol consumption increases sphingosine levels in the brains of progeny mice. AB - The effect of 'binge' alcohol upon sphingolipid metabolism in the fetal alcohol syndrome (FAS) was examined in pregnant mice (C57BL/6J) by administering a single dose of alcohol during the third trimester (gestational day 15-16). The control mice were administered a sucrose solution of equal caloric value. Brains from progeny at postnatal days 5, 15, 21 and 30 were dissected into three regions, and sphingolipid concentrations of the brain regions were determined including assay of monoglycosylceramide, ceramide, sphingosine and sphingomyelin. We found that a single dose of ethanol induces an elevation of sphingosine (2-3.5-fold) in the brain of progeny. The level of brain ceramide at a dose of 1.5 g/kg was significantly higher than control. Alcohol consumption during pregnancy induces neuronal loss in progeny brains. Our result suggests that the elevation of sphingosine in progeny brain induced by maternal alcohol consumption may be responsible for observed neuronal loss in FAS. PMID- 17701352 TI - Rasagiline promotes regeneration of substantia nigra dopaminergic neurons in post MPTP-induced Parkinsonism via activation of tyrosine kinase receptor signaling pathway. AB - The anti-Parkinson drug rasagiline (Azilect), an irreversible and selective monoamine oxidase (MAO)-B inhibitor, was shown to possess neuroprotective activities, involving multiple survival pathways among them the up-regulation of protein kinase C (PKC)alpha, PKCepsilon, the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w and the induction of brain-derived- and glial cell line-derived neurotrophic factors (BDNF, GDNF). More recently, employing conventional neurochemical techniques, as well as transcriptomic and proteomic screening tools, combined with a biology-based clustering method, it was shown that rasagiline also possesses neurorescue/neurogenesis activity in mice midbrain dopaminergic neurons when given chronically, post-MPTP (N-methyl-4-phenyl-1,2,3,6 tetrahydropyridine). This action was attributed to the activation of cell signaling mediators associated with neurotrophic factors responsive-tyrosine kinase receptor (Trk) pathway, including ShcC, SOS, AF6, Rin1, and Ras and the increase in the Trk-downstream effecter phosphatidylinositol 3 kinase (PI3K) protein and its substrate, Akt/PKB. It is interesting to determine whether a similar effect is seen in Parkinsonian patients after long-term treatment with rasagiline, which may have implications as a possible disease modifying agent. PMID- 17701354 TI - Background, offence characteristics, and criminal outcomes of Aboriginal youth who sexually offend: a closer look at Aboriginal youth intervention needs. AB - Canada's Aboriginal peoples face a number of social and health issues. Research shows that Aboriginal youths are over-represented in the criminal justice system and youth forensic psychiatric programmes. Within the literature on sex offending youth, there appears to be no published data available to inform clinicians working with adjudicated Aboriginal youth. Therefore, the present study examines the background, offence characteristics, and criminal outcomes of Aboriginal (n = 102) and non-Aboriginal (n = 257) youths who engaged in sexual offending behaviour and were ordered to attend a sexual offender treatment programme in British Columbia between 1985 and 2004. Overall, Aboriginal youths were more likely than non-Aboriginal youths to have background histories of fetal alcohol spectrum disorders (FASD), substance abuse, childhood victimization, academic difficulties, and instability in the living environment. Both Aboriginal and non Aboriginal youths had a tendency to target children under 12-years-old, females, and non-strangers. Aboriginal youths were more likely than non-Aboriginal youths to use substances at the time of their sexual index offence. Outcome data revealed that Aboriginal youths were more likely than their non-Aboriginal counterparts to recidivate sexually, violently, and non-violently during the 10 year follow-up period. Furthermore, the time between discharge and commission of all types of re-offences was significantly shorter for Aboriginal youths than for non-Aboriginal youths. Implications of these findings are discussed with regards to the needs of Aboriginal youth and intervention. PMID- 17701353 TI - Decreased GABAA receptor function in the brain stem during pancreatic regeneration in rats. AB - Gamma amino butyric acid is a major inhibitory neurotransmitter in the central nervous system. In the present study we have investigated the alteration of GABA receptors in the brain stem of rats during pancreatic regeneration. Three groups of rats were used for the study: sham operated, 72 h and 7 days partially pancreatectomised. GABA was quantified by [(3)H]GABA receptor displacement method. GABA receptor kinetic parameters were studied by using the binding of [(3)H]GABA as ligand to the Triton X-100 treated membranes and displacement with unlabelled GABA. GABA(A) receptor activity was studied by using the [(3)H]bicuculline and displacement with unlabelled bicuculline. GABA content significantly decreased (P < 0.001) in the brain stem during the regeneration of pancreas. The high affinity GABA receptor binding showed a significant decrease in B(max) (P < 0.01) and K(d) (P < 0.05) in 72 h and 7 days after partial pancreatectomy. [(3)H]bicuculline binding showed a significant decrease in B(max) and K(d) (P < 0.001) in 72 h pancreatectomised rats when compared with sham where as B(max) and K(d) reversed to near sham after 7 days of pancreatectomy. The results suggest that GABA through GABA receptors in brain stem has a regulatory role during active regeneration of pancreas which will have immense clinical significance in the treatment of diabetes. PMID- 17701355 TI - Finger kinematic modeling and real-time hand motion estimation. AB - This paper describes methods and experimental studies concerned with quantitative reconstruction of finger movements in real-time, by means of multi-camera system and 24 surface markers. The approach utilizes a kinematic model of the articulated hand which consists in a hierarchical chain of rigid body segments characterized by 22 functional degrees of freedom and the global roto translation. This work is focused on the experimental evaluation of a kinematical hand model for biomechanical analysis purposes. From a static posture, a completely automatic calibration procedure, based on anthropometric measures and geometric constraints, computes axes, and centers of rotations which are then utilized as the base of an interactive real-time animation of the hand model. The motion tracking, based on automatic marker labeling and predictive filter, is empowered by introducing constraints from functional finger postures. The validation is performed on four normal subjects through different right-handed motor tasks involving voluntary flexion-extension of the thumb, voluntary abduction-adduction of the thumb, grasping, and finger pointing. Performances are tested in terms of repeatability of angular profiles, model-based ability to predict marker trajectories and tracking success during real-time motion estimation. Results show intra-subject repeatability of the model calibration both to different postures and to re-marking in the range of 0.5 and 2 mm, respectively. Kinematic estimation proves satisfactory in terms of prediction capability (index finger: maximum RMSE 2.02 mm; thumb: maximum RMSE 3.25 mm) and motion reproducibility (R (2) coefficients--index finger: 0.96, thumb: 0.94). During fast grasping sequence (60 Hz), the percentage of residual marker occlusions is less than 1% and processing and visualization frequency of 50 Hz confirms the real-time capability of the motion estimation system. PMID- 17701356 TI - Preapoptotic chromatin changes induced by ultraviolet B irradiation in human erythroleukemia K562 cells. AB - Exponentially growing human erythroleukemia K562 cells were permeabilized and the dose dependent decrease of DNA synthesis rate was measured after ultraviolet (UV B, 290 nm) irradiation. Cells were able to overcome 2 and 5 J/m2 UV doses, partial recovery was observed at 15 J/m2, while at high (25 J/m2) UV dose replicative DNA synthesis remained suppressed. K562 cells were subjected to synchronization prior to and after UV irradiation (24 J/m2) and 18 fractions were collected by centrifugal elutriation. Cell cycle analysis by flow cytometry did not show early apoptotic cells after UV irradiation. The gradual increase in DNA content typical for non-irradiated cells was contrasted by an early S phase block between 2.2 and 2.4 C-values after UV irradiation. Cell cycle dependent chromatin changes after ultraviolet irradiation were seen as a fine fibrillary network covering the mainly fibrous chromatin structures and incompletely folded primitive chromosomes. Based on observations after UV irradiation and on earlier results with cadmium treatment and gamma irradiation, we confirm that typical chromatin changes characteristic to genotoxic agents can be recognized and classified. PMID- 17701357 TI - Apoptosis induced by direct triggering of mitochondrial apoptosis proceeds in the near-absence of some apoptotic markers. AB - Apoptotic cell death is characterized by the activation of the apoptotic signal transduction pathway on one hand and a number of regularly found morphological and biochemical features, such as nuclear condensation and mitochondrial depolarisation. Although much of our knowledge of apoptosis was obtained using noxious stimuli in cell culture, these apoptotic stimuli are likely to have numerous off-target effects that may contribute to or obscure the immediate effects of the apoptotic pathway. We have developed a cellular model where mitochondrial apoptosis is directly triggered by the tetracycline-regulated expression of the pro-apoptotic BH3-only protein Bim(S). We report the comparison of Bim(S)-induced apoptosis with the commonly used apoptotic stimuli staurosporine and UV-light. While the release of mitochondrial cytochrome c and Smac/DIABLO, activation of caspases and nuclear morphological changes occurred with very similar kinetics, striking differences were found in other apoptotic assays. In particular, drop in mitochondrial membrane potential, loss of plasma membrane integrity and the appearance of sub-G1 nuclei were strongly reduced in cells dying upon Bim(S)-induction, compared to staurosporine- or UV-induced apoptosis. The results thus indicate that the link between the apoptotic pathway and commonly used indicators of apoptosis is less tight than it appears from experiments with cytotoxic stimuli. PMID- 17701358 TI - Combination of all-trans retinoic acid and taxol regressed glioblastoma T98G xenografts in nude mice. AB - Glioblastoma is the most prevalent and highly malignant brain tumor that continues to defy current treatment strategies. This investigation used all-trans retinoic acid (ATRA) and taxol (TXL) as a combination therapy for controlling the growth of human glioblastoma T98G xenografted in athymic nude mice. Histopathological examination revealed that ATRA induced differentiation and combination of ATRA and TXL caused more apoptosis than either treatment alone. Combination therapy decreased expression of telomerase, nuclear factor kappa B (NFkappacapital VE, Cyrillic), and inhibitor-of-apoptosis proteins (IAPs) indicating suppression of survival factors while upregulated Smac/Diablo. Combination therapy also changed expression of Bax and Bcl-2 proteins leading to increased Bax:Bcl-2 ratio, mitochondrial release of cytochrome c and apoptosis inducing factor (AIF), and activation of caspase-9. Increased activities of calpain and caspase-3 degraded 270 kD alpha-spectrin at the specific sites to generate 145 kD spectrin breakdown product (SBDP) and 120 kD SBDP, respectively. Further, increased activity of caspase-3 cleaved inhibitor-of-caspase-activated DNase (ICAD). In situ double immunofluorescent labelings showed overexpression of calpain, caspase-12, caspase-3, and AIF during apoptosis, suggesting involvement of both caspase-dependent and caspase-independent pathways for apoptosis. Our investigation revealed that treatment of glioblastoma T98G xenografts with the combination of ATRA and TXL induced differentiation and multiple molecular mechanisms for apoptosis. PMID- 17701359 TI - Myeloperoxidase binds to non-vital spermatozoa on phosphatidylserine epitopes. AB - The heme protein myeloperoxidase is released from stimulated polymorphonuclear leukocytes, a cell species found in increasing amounts in the male and female genital tract of patients with genital tract inflammations. Myeloperoxidase binds only to a fraction of freshly prepared human spermatozoa. The number of spermatozoa able to bind myeloperoxidase raised considerably in samples containing pre-damaged cells or in acrosome-reacted samples. In addition, myeloperoxidase released from zymosan-stimulated polymorphonuclear leukocytes was also able to bind to pre-damaged spermatozoa. The ability of spermatozoa to bind myeloperoxidase coincided with the binding of annexin V to externalized phosphatidylserine epitopes indicating the loss of plasma membrane integrity and with the incorporation of ethidium homodimer I. Myeloperoxidase did not interact with intact spermatozoa. Annexin V and myeloperoxidase bind to the same binding sites as verified by double fluorescence techniques, flowcytometry analyses as well as competition experiments. We demonstrated also that myeloperoxidase is eluted together with pure phosphatidylserine liposomes or liposomes composed of phosphatidylserine and phosphatidylcholine in gel filtration, but not with pure phosphatidylcholine liposomes. In conclusion, myeloperoxidase interacts with apoptotic spermatozoa via binding to externalized phosphatidylserine indicating a yet unknown role of this protein in recognition and removal of apoptotic cells during inflammation. PMID- 17701360 TI - Involvement of both tumor necrosis factor-alpha-induced necrosis and p53-mediated caspase-dependent apoptosis in nephrotoxicity of cisplatin. AB - We previously reported that necrosis occurs predominantly in porcine renal tubular LLC-PK1 cells, when the cells were exposed transiently to a high concentration of cisplatin. Moreover, we demonstrated that generation of reactive oxygen species and subsequent production of tumor necrosis factor-alpha (TNF alpha) through phosphorylation of p38 MAPK are implicated in the pathogenesis of cisplatin-induced renal cell injury. However, some TUNEL-positive cells appeared in renal proximal tubules of rats after systemic injection of cisplatin, suggesting an involvement of apoptosis. In the present study, we found in LLC-PK1 cells that both apoptosis and necrosis were elicited when the cells were exposed to 200 microM cisplatin for 1 h followed by incubation for 24 h in the presence of 20 microM cisplatin. The cisplatin-induced necrosis was largely attenuated by the antioxidant N-acetylcysteine, while apoptosis was prevented by the specific inhibitors for caspases-2, -8, and -3 and a p53 inhibitor pifithrin-alpha but not by the p38 MAPK inhibitor SB203580. On the other hand, SB203580 attenuated the cisplatin-induced increase in TNF-alpha production. These findings suggest that p53-mediated activations of caspases-2, -8 and -3 play a key role in cisplatin induced renal cell apoptosis, while oxidative stress-induced TNF-alpha synthesis via p38 MAPK phosphorylation contributed to the necrosis. PMID- 17701361 TI - Inhibition of apoptotic potency by ligand stimulated thyroid hormone receptors located in mitochondria. AB - We recently reported that shortened thyroid hormone receptor isoforms (TRs) can target mitochondria and acutely modulate inositol 1,4,5 trisphosphate (IP3) mediated Ca2+ signaling when activated by thyroid hormone 3,5,3'-tri iodothyronine (T3). Stimulation occurs via an increase in mitochondrial metabolism that is independent of transcriptional activity. Here, we present evidence that T3-bound xTRbetaA1s inhibit apoptotic activity mediated by cytochrome c release. An assay for apoptotic potency was modified to measure the ability of Xenopus oocyte extracts to induce morphological changes in isolated liver nuclei. Apoptotic potency was significantly decreased when oocyte extract was prepared from xTRbetaA1 expressing oocytes and treated with T3. The ability of T3 treatment to inhibit apoptosis was dependent on the expression of xTRbetaA1s in the mitochondrial fraction, not in the cytosolic fraction. T3 treatment also increased the membrane potential of isolated mitochondria prepared from oocytes expressing xTRbetaA1s but not from wildtype controls. We conclude that T3 acutely regulates cytochrome c release in a potential dependent manner by activating TRs located within mitochondria. PMID- 17701362 TI - Apoptosis of lymphoma cells is abolished due to blockade of cytochrome c release despite Nur77 mitochondrial targeting. AB - Nur77 is reported to undergo translocation to mitochondria in response to apoptotic signaling in a variety of cancer cell lines. It was shown that on the mitochondrial membrane, Nur77 interacts with Bcl-2, leading to the conversion of this protein from a protector to a killer with subsequent release of cytochrome c to the cytosol. Here it is shown that in thymic lymphoma cells resistant to calcium-mediated apoptosis, cytochrome c release is abolished despite of Nur77 mitochondrial targeting. However, cytochrome c release and apoptosis can be restored by treatment with FK506. Hence, the molecular target regulation of the sensitivity of lymphoma cells to calcium signaling is associated with cytochrome c release and is FK506 sensitive. These results provide new insight into the role of FK506-sensitive factors as a critical link between calcium signaling and resistance of lymphoma cells to death. PMID- 17701363 TI - Bioactive compounds and antioxidant capacity of strawberry jams. AB - Strawberries represent the main source of ellagic acid derivatives in the Brazilian diet. They are also good sources of flavonoids, mainly anthocyanins, and phenolic acids, to which many beneficial effects have been attributed. However, as the fruit is not available all the year, the objective of this work was to determine whether the jams could also represent a good source of bioactive compounds. In the current study, five different commercially available strawberry jams were characterized in relation to flavonoids, total phenolics, free and total ellagic acid contents, and antioxidant capacity. Anthocyanins were detected only in two jams at very low content. Kaempferol glycosides were the main flavonoids present (from 0.38 to 1.05 mg/100 g fresh weight, FW), while quercetin glycosides were present in the range 0.14-1.20 mg/100 g FW. Free and total ellagic acid content ranged from 0.4 to 2.9 mg/100 g FW, and from 17.0 to 29.5 mg/100 g FW, respectively. Total phenolics varied from 58 to 136 mg/100 g FW, and the antioxidant capacity from 0.55 to 0.76 mumol BHT (Butylhydroxytoluene) equivalents/g FW. Overall, results indicated that jams can also represent a good source of antioxidant compounds, although compared to the fruit important losses seem to occur. PMID- 17701365 TI - Massive trabecular hypertrophy of the entire right ventricle resembling right ventricular non-compaction in a patient with low pressure giant pulmonary artery aneurysm. PMID- 17701364 TI - Epidemiology of osteoporosis related fractures in Hungary from the nationwide health insurance database, 1999-2003. AB - The Hungarian national health insurance database was screened for fractures of patients aged 50-100, 1999-2003. On average, there were 343 hip, 1,579 forearm, 342 proximal humerus, 48 inpatient vertebral and 2,459 other fractures/100,000 inhabitants/year. INTRODUCTION: The incidence of fractures differs among populations. Our aim was to study the incidence of fractures in Hungary, focusing on classical osteoporotic sites and to compare the results with those of other European countries. METHODS: The Hungarian National Health Insurance Fund database, covering 100% of the population, was screened for fractures of patients aged 50-100, 1999-2003. The search of vertebral fractures was restricted to those admitted to hospital. A gender and age-matched comparison was performed with available data from Europe. RESULTS: There were mean 343 hip, 1,579 forearm, 342 proximal humerus, 48 inpatient vertebral and 2,459 other fractures/100,000 inhabitants/year; the female/male ratio was between 1.2-2.4. Multiple fractures occurred in 23.1% of the cases. Hip fracture incidence in Hungary lies between the rates of northern and southern countries of Europe. CONCLUSIONS: Our study offers nationwide epidemiological data on fractures in Hungary. The incidence of fractures increased by age, regardless of the type of fracture. Incidence of hip fractures in Hungary fits in the previously established geographic trends in Europe. Our results fulfil a need for fracture data from Central Europe. PMID- 17701367 TI - Cor triatriatum sinistrum combined with supracardiac anomalous pulmonary venous return in an adult causing arrhythmogenic heart failure. PMID- 17701366 TI - The paclitaxel-eluting Coroflex Please stent pilot study (PECOPS I) : the one year clinical follow-up. AB - BACKGROUND: The alleged superiority of drug-eluting stents over bare metal devices and those with passive coatings is diminished by a higher incidence of late target vessel thrombosis. METHODS AND RESULTS: Therefore, the one-year clinical outcome of the paclitaxel-eluting Coroflex Please stent in patients with denovo coronary lesions was evaluated in the single-arm PECOPS I pilot study. The clinical data of 96/97 (99%) of the patients included per protocol and of 86/87 (98.9%) of those treated per protocol were available 13.1 +/- 1.8 months following stent deployment. In the inclusion and treatment per protocol groups the incidence of cardiac deaths was 1/96 (1%) and 1/86 (1.2%), of myocardial infarction 3/96 (3.1%) and 1/86 (1.2%), and of target lesion revascularization 9/96 (9.4%) and 8/86 (9.3%). In patients enrolled per protocol two early thromboses (2.1%) occurred one of which two days after premature discontinuation of clopidogrel. In patients treated per protocol one thrombosis was observed after 10 hours. The one-year event-free survival was 83/96 (86.5%) in patients enrolled per protocol and 75/86 (87.2%) in those treated per protocol. CONCLUSION: The one-year clinical outcome of PECOPS I was within the range of other paclitaxel-eluting coronary stents. The relative small number of patients enrolled in PECOPS I precludes to infer any further conclusions. PMID- 17701368 TI - Two cases of LENAS: diagnosis by MRI and biopsy. PMID- 17701369 TI - Anal fistula plug for closure of difficult anorectal fistula: a prospective study. AB - PURPOSE: Complex high and recurrent fistulas remain a surgical challenge. Simple division, i.e., fistulotomy, will likely result in fecal incontinence. Various surgical treatment options for these fistulas have shown disappointing results. Recently a biologic anal fistula plug was developed to treat these high transsphincteric fistulas. To assess the results of the anal fistula plug in patients with complex high perianal fistulas, a prospective, two-center, clinical study was undertaken. METHODS: Between April 2006 and October 2006, a consecutive series of patients with difficult therapy-resistant high fistulas were enrolled. During surgery, the internal fistula tract opening was identified. A conical shaped collagen plug was pulled through the fistula tract. Any remaining portion of the plug that was not implanted in the tract was removed. The plug was fixed at the internal opening with a deep 3/0 polydioxanone suture. RESULTS: Seventeen patients with a median age of 45 (range, 27-75) years were included. Of these patients, 71 percent (12/17) were male. At a median length of follow-up of 7 (range, 3-9) months, 7 of 17 fistulas had healed (41 percent). In ten patients, the fistula recurred. CONCLUSIONS: In these small series of 17 patients with difficult high perianal fistulas, a success rate of 41 percent is noted. Larger series, preferably in trial setting, must be performed to establish the efficacy of the anal fistula plug in perianal fistula. PMID- 17701370 TI - Portal vein thrombi after restorative proctocolectomy: serious complication without long-term sequelae. AB - PURPOSE: Portal vein thrombi have been observed after restorative proctocolectomy and ileal pouch-anal anastomosis, and present as a clinical spectrum of abdominal pain, fever, and leukocytosis. Anticoagulation treatment is usually associated with resolution of symptoms. However, the long-term consequences and effect on pouch function are not known. The purpose of this study was to analyze the long term functional outcome of patients with confirmed portal vein thrombi after restorative proctocolectomy. METHODS: A retrospective study of all patients undergoing restorative proctocolectomy from January 1997 to 2000 was performed. A case-control study was designed that matched 37 patients with confirmed portal vein thrombi in this period with 133 patients without portal vein thrombi; the groups were compared with respect to pouch function and quality of life by using the Global Cleveland Clinic Quality of Life Questionnaire for pelvic pouch patients. RESULTS: The mean follow-up was 4.73 (range, 4.21-7.28) years. The percentage of male patients was 58.8. The most common diagnosis was ulcerative colitis (62.4 percent). There were no significant differences between portal vein thrombi patients and controls with respect to pouch function (number of bowel movements, urgency, incontinence), episodes of pouchitis, or quality of life. CONCLUSIONS: Portal vein thrombi can be a serious complication after restorative proctocolectomy that usually resolves with anticoagulation therapy. Long-term pouch function and quality of life are not affected. PMID- 17701371 TI - Stapled hemorrhoidopexy and Milligan Morgan hemorrhoidectomy in the cure of fourth-degree hemorrhoids: long-term evaluation and clinical results. AB - PURPOSE: The long-term results after stapled hemorrhoidopexy compared with Milligan-Morgan procedure are discussed. METHODS: The clinical data of 100 patients treated by Milligan-Morgan procedure or stapled hemorrhoidopexy for fourth-degree hemorrhoids have been reviewed. All patients were visited and submitted to a questionnaire to evaluate resumption of symptoms, functional results, and recurrence rate. RESULTS: The mean follow-up was 54 months for stapled hemorrhoidopexy and 92 months for the Milligan-Morgan procedure. Postoperative pain and return to normal activity were worse in the Milligan Morgan procedure (Visual Analog Scale 8.56 vs. 5.46, P < 0.001; and 2.4 vs. 2 weeks, P value = 0.018). Eight percent of patients who had stapled hemorrhoidopexy complained of spontaneous pain or pain during defecation vs. 0 percent of patients who underwent the Milligan-Morgan procedure. We noted that there was bleeding in 14 percent of stapled hemorrhoidopexy vs. 0 percent of Milligan-Morgan procedure (P < 0.006), tenesmus in 32 percent of stapled hemorrhoidopexy vs. 0 percent of Milligan-Morgan procedure (P < 0.001), and pruritus in 4 percent of stapled hemorrhoidopexy vs. 0 percent of Milligan-Morgan procedure. Minor leakage was similar in the two groups. Flatus impaired control was less frequent in Milligan-Morgan. The relative risk of recurrence for stapled hemorrhoidopexy compared with Milligan-Morgan procedure was 1.18 (95 percent confidence interval 1< relative risk < 1.4). No statistical difference was noted in patients' satisfaction after the procedures. CONCLUSIONS: Long follow-up seems to indicate more favorable results in Milligan-Morgan procedure in terms of resumption of symptoms and risk of recurrence. PMID- 17701373 TI - Morphology of the levator ani muscle. AB - PURPOSE: This study was designed to show the morphology and to assess the function of the levator ani and the puborectalis by use of CT defecography in a sitting position. Previous studies have suggested that both muscles lift the anus. METHODS: CT defecography datasets from 30 healthy subjects (16 males; aged 22-24 years) were studied. Coronal scans of the pelvis were obtained during the three standard phases of rest, squeeze, and defecation; the multiplanar reconstruction images of the pelvic floor were gained on the workstation, included the coronal, sagittal, and puborectalis planes. Morphometric measurements were noted for the levator ani, puborectalis, genital hiatus, and anus. RESULTS: The levator ani was funnel-shaped at rest in the sitting position; it ascended, becoming plate-shaped during squeeze, and it descended, becoming basin-shaped during defecation. The mean one-half puborectalis length was 73.8 mm and lower case "u"-shaped at rest, 63.5 mm and "v"-shaped during squeeze, and 94.9 mm and capital "U"-shaped during defecation. The mean area of the genital hiatus was 1,762 mm2 at rest, 1,332.4 mm2 during squeeze, and 3,126.8 mm2 during defecation. The mean inward lift of anus was 14.1 mm during squeeze; the mean downward movement of the anus was 18 mm during defecation. CONCLUSIONS: The anus descends and there is no muscle to lift it during defecation; the results indicate that the puborectalis lifts the anus during squeeze. The levator ani muscle does not lift the anus; its main function is to open the genital hiatus and the anus during defecation. The main function of the puborectalis muscle is to shut the genital hiatus and anus during squeeze. PMID- 17701375 TI - Pudendal block with bupivacaine for postoperative pain relief. AB - PURPOSE: Postoperative pain after hemorrhoidectomy is very intense, and the pain at the first postoperative defecation is very intense. Based on our pilot initial results that reflected reduced postoperative pain, we conducted a prospective, randomized, double-blind study to investigate whether the analgesia produced by bilateral pudendal nerve block using a nerve-stimulator could provide better postoperative pain relief compared with the routine technique in use in the Department of Anesthesia. METHODS: After Ethical Committee approval and informed consent, 100 patients scheduled for hemorrhoidectomy were randomized into control (C) and study (P) groups with 50 patients each. Bilateral pudendal nerve block with 0.25 percent bupivacaine was performed with nerve-stimulator. Evaluated parameters were pain severity, duration of analgesia, demand analgesia, and possible technique-related complications. Data were evaluated 6, 12, 18, and 24 hours after surgery completion. The first defecation and patient satisfaction were recorded. RESULTS: Successful pudendal nerves stimulation was achieved in all patients in the study group. The pudendal nerve block group was found to have better postoperative pain relief, reduced need for analgesics, and patient satisfaction. Mean analgesic duration was 23.8 +/- 4.8 hours vs. 3.6 +/- 1 hours. All patients in the pudendal nerve block had spontaneous micturition vs. 48 patients in the control group. The pudendal analgesia was considered excellent by 44 patients and satisfactory by 6 male patients. The six male patients complained because of penile anesthesia. No anesthetic-related local or systemic complications were observed. CONCLUSIONS: In this controlled study, bilateral pudendal nerve block oriented by nerve stimulator provided excellent analgesia with low need for opioids, without local or systemic complications, and without urinary retention. PMID- 17701376 TI - A delay differential model for pandemic influenza with antiviral treatment. AB - The use of antiviral drugs has been recognized as the primary public health strategy for mitigating the severity of a new influenza pandemic strain. However, the success of this strategy requires the prompt onset of therapy within 48 hours of the appearance of clinical symptoms. This requirement may be captured by a compartmental model that monitors the density of infected individuals in terms of the time elapsed since the onset of symptoms. We show that such a model can be expressed by a system of delay differential equations with both discrete and distributed delays. The model is analyzed to derive the criterion for disease control based on two critical factors: (i) the profile of treatment rate; and (ii) the level of treatment as a function of time lag in commencing therapy. Numerical results are also obtained to illustrate the feasible region of disease control. Our findings show that due to uncertainty in the attack rate of a pandemic strain, initiating therapy immediately upon diagnosis can significantly increase the likelihood of disease control and substantially reduce the required community-level of treatment. This suggests that reliable diagnostic methods for influenza cases should be rapidly implemented within an antiviral treatment strategy. PMID- 17701377 TI - Bayesian inference for functional response in a stochastic predator-prey system. AB - We present a Bayesian method for functional response parameter estimation starting from time series of field data on predator-prey dynamics. Population dynamics is described by a system of stochastic differential equations in which behavioral stochasticities are represented by noise terms affecting each population as well as their interaction. We focus on the estimation of a behavioral parameter appearing in the functional response of predator to prey abundance when a small number of observations is available. To deal with small sample sizes, latent data are introduced between each pair of field observations and are considered as missing data. The method is applied to both simulated and observational data. The results obtained using different numbers of latent data are compared with those achieved following a frequentist approach. As a case study, we consider an acarine predator-prey system relevant to biological control problems. PMID- 17701378 TI - How host population dynamics translate into time-lagged prevalence: an investigation of Sin Nombre virus in deer mice. AB - Human cases of hantavirus pulmonary syndrome caused by Sin Nombre virus are the endpoint of complex ecological cascade from weather conditions, population dynamics of deer mice, to prevalence of SNV in deer mice. Using population trajectories from the literature and mathematical modeling, we analyze the time lag between deer mouse population peaks and peaks in SNV antibody prevalence in deer mice. Because the virus is not transmitted vertically, rapid population growth can lead initially to reduced prevalence, but the resulting higher population size may later increase contact rates and generate increased prevalence. Incorporating these factors, the predicted time lag ranges from 0 to 18 months, and takes on larger values when host population size varies with a longer period or higher amplitude, when mean prevalence is low and when transmission is frequency-dependent. Population size variation due to variation in birth rates rather than death rates also increases the lag. Predicting future human outbreaks of hantavirus pulmonary syndrome may require taking these effects into account. PMID- 17701379 TI - Modeling the VEGF-Bcl-2-CXCL8 pathway in intratumoral agiogenesis. AB - Recent experiments show that vascular endothelial growth factor (VEGF) is the crucial mediator of downstream events that ultimately lead to enhanced endothelial cell survival and increased vascular density within many tumors. The newly discovered pathway involves up-regulation of the anti-apoptotic protein Bcl 2, which in turn leads to increased production of interleukin-8 (CXCL8). The VEGF Bcl-2-CXCL8 pathway suggests new targets for the development of anti-angiogenic strategies including short interfering RNA (siRNA) that silence the CXCL8 gene and small molecule inhibitors of Bcl-2. In this paper, we present and validate a mathematical model designed to predict the effect of the therapeutic blockage of VEGF, CXCL8, and Bcl-2 at different stages of tumor progression. In agreement with experimental observations, the model predicts that curtailing the production of CXCL8 early in development can result in a delay in tumor growth and vascular development; however, it has little effect when applied at late stages of tumor progression. Numerical simulations also show that blocking Bcl-2 up-regulation, either at early stages or after the tumor has fully developed, ensures that both microvascular and tumor cell density stabilize at low values representing growth control. These results provide insight into those aspects of the VEGF-Bcl-2-CXCL8 pathway, which independently and in combination, are crucial mediators of tumor growth and vascular development. Continued quantitative modeling in this direction may have profound implications for the development of novel therapies directed against specific proteins and chemokines to alter tumor progression. PMID- 17701380 TI - Intravitreal triamcinolone acetonide for the management of papillophlebitis and associated macular edema. AB - BACKGROUND: To investigate the efficacy of intravitreal injection of triamcinolone acetonide in the management of papillophlebitis and associated cystoid macular edema. METHODS: This study was a retrospective medical records review of four eyes of four patients (three males and one female) who had approximately 2-4 months history of papillophlebitis and associated persistent cystoid macular edema. These patients were treated with a single intravitreal injection of 4 mg triamcinolone acetonide. Mean follow-up time was 15 +/- 4 months. The outcome measures included best corrected visual acuity (BCVA), intraocular pressure (IOP), and central retinal thickness by optical coherence tomography (OCT). RESULTS: The BCVA ranged from 20/100 to 20/60 pre-operation. The mean gain in BCVA was 7 +/- 1 Snellen lines. All eyes had BCVA of 20/20 at the last visit. The mean baseline central retinal thickness as measured by OCT was 529 +/- 53 microm. The mean central retinal thickness by OCT was 235 +/- 15 microm at 1-week follow-up examination. At the last visit the mean central retinal thickness by OCT was 161 +/- 7 microm. One patient experienced an increase in IOP after the first injection and another patient had IOP elevation after the second injection. Both were well controlled with single topical anti glaucoma medication. CONCLUSION: Intravitreal injection of triamcinolone acetonide appears to be an effective treatment for patients with papillophlebitis and associated cystoid macular edema. PMID- 17701382 TI - Hidden aspects of the anaesthesia chart. AB - Anaesthesia is a complex task operating in an uncertain environment. Part of the problem is that many of the technologies developed to assist the anaesthesiologist hinder rather than help, because of increased complexity. We conducted an analysis of the domain in view of redesigning the anaesthesia chart as a digital artefact. We used an ethnographic approach that uncovered aspects of the anaesthesiologist's practice, as well as the fact that the chart was not used as a tool, because of its legal status. PMID- 17701381 TI - A framework for evaluating usability of clinical monitoring technology. AB - Technology design is a complex task, and acceptability is enhanced when usability is central to its design. Evaluating usability is a challenge for purchasers and developers of technology. We have developed a framework for testing the usability of clinical monitoring technology through literature review and experience designing clinical monitors. The framework can help designers meet key international usability norms. The framework includes these direct testing methods: thinking aloud, question asking, co-discovery, performance and psychophysiological measurement. Indirect testing methods include: questionnaires and interviews, observation and ethnographic studies, and self-reporting logs. Inspection, a third usability testing method, is also included. The use of these methods is described and practical examples of how they would be used in the development of an innovative monitor are given throughout. This framework is built on a range of methods to ensure harmony between users and new clinical monitoring technology, and have been selected to be practical to use. PMID- 17701383 TI - Clinical validation of a digital transcutaneous PCO2/SpO2 ear sensor in adult patients after cardiac surgery. AB - OBJECTIVE: The aim of this study was to validate the V-Sign digital sensor (SenTec AG, Therweil, Switzerland) for combined noninvasive assessment of pulse oxymetric oxygen saturation (SpO(2)) and transcutaneous carbon dioxide tension (PtcCO(2)) in adults after cardiac surgery. METHODS: In twenty one patients, aged 51-86 years, simultaneous measurements of blood gases with the V-Sign Sensor and with two Nellcor Durasensors (model DS-100A), one at the opposite earlobe and one with a finger clip, were compared first during hyper-, normo- and hypocapnia and at different pulse rates using a pacemaker, and then at 2-h intervals up to 8 h. Agreement was assessed by Bland-Altman analysis. RESULTS: PtcCO(2) data of three patients were excluded because of calibration failure of the device. Median (range) PtcCO(2) for the remaining patients was 5.49 (3.3-7.6) kPa and arterial carbon dioxide tension (PaCO(2)) was 5.43 (3.61-7.41) kPa. Corresponding mean bias was +0.05 kPa and limits of agreement (LOA) were -1.2/+1.3 kPa. During normo and hypoventilation, mean bias was good at +0.02 and +0.04 kPa respectively, but limits of agreement were poor at -0.67/+0.69 and -0.81/+0.88 kPa. In 10 patients, an initial overshoot of PtcCO(2 )was observed. Mean bias of SpO(2) and pulse rate was close to zero (-1.5% and +0.001 bpm respectively), but limits of agreement were unacceptably high (-21.4/+18.4% and -22.3/+22.3 bpm). CONCLUSIONS: In the present state of development the SenTeC Digital monitor V-Sign device has serious limitations. Additional efforts are necessary to eliminate calibration failures and the initial overshoot of PtcCO(2) as well as to improve detection of SpO(2) and pulse rate. PMID- 17701384 TI - Comparing Entropy and the Bispectral index with the Ramsay score in sedated ICU patients. AB - OBJECTIVE: ENTROPY is a new anesthetic depth monitor based on the analysis of the EEG signal. Our aim has been to evaluate sedation of intubated surgical critically ill patients by means of the Ramsay sedation score, the Bispectral index and ENTROPY, and to analyse the correlation between these variables. METHODS: Sedation was evaluated every 15 min for a 1 h period in 50 non-paralysed postoperative critically ill, intubated patients, enrolled over a 6 month period. A 5 min steady-state period was allowed before each assessment. Both the Bispectral index and the Entropy parameters Response Entropy (RE) and State Entropy (SE), were collected before assessing the Ramsay scale. RESULTS: Mean values for SE, RE and BIS were 53 +/- 27, 60 +/- 30, and 62 +/- 24 respectively. The median value for the Ramsay was 6 (range 1-6). Significant correlation was found between the four variables (SE-BIS: r = 0.79, p < 0.001; RE-BIS: r = 0.80, p < 0.001; SE-Ramsay: rho = -0.71, p < 0.001, RE-Ramsay: rho = -0.72, p < 0.001; BIS-Ramsay: rho = -0.78, p < 0.001; RE-SE: r = 0.98, p < 0.001). An overlap of BIS and Entropy values for every Ramsay score value between 4-6 was found. CONCLUSIONS: ENTROPY, BIS and Ramsay score values correlate significantly in sedated postoperative ICU patients. ENTROPY does not appear superior to BIS for the assessment of sedation in this context. PMID- 17701385 TI - Change in pulse transit time and pre-ejection period during head-up tilt-induced progressive central hypovolaemia. AB - OBJECTIVE: Traditional vital signs such as heart rate (HR) and blood pressure (BP) are often regarded as insensitive markers of mild to moderate blood loss. The present study investigated the feasibility of using pulse transit time (PTT) to track variations in pre-ejection period (PEP) during progressive central hypovolaemia induced by head-up tilt and evaluated the potential of PTT as an early non-invasive indicator of blood loss. METHODS: About 11 healthy subjects underwent graded head-up tilt from 0 to 80 degrees . PTT and PEP were computed from the simultaneous measurement of electrocardiogram (ECG), finger photoplethysmographic pulse oximetry waveform (PPG-POW) and thoracic impedance plethysmogram (IPG). The response of PTT and PEP to tilt was compared with that of interbeat heart interval (RR) and BP. Least-squares linear regression analysis was carried out on an intra-subject basis between PTT and PEP and between various physiological variables and sine of the tilt angle (which is associated with the decrease in central blood volume) and the correlation coefficients (r) were computed. RESULTS: During graded tilt, PEP and PTT were strongly correlated in 10 out of 11 subjects (median r = 0.964) and had strong positive linear correlations with sine of the tilt angle (median r = 0.966 and 0.938 respectively). At a mild hypovolaemic state (20-30 degrees ), there was a significant increase in PTT and PEP compared with baseline (0 degrees ) but without a significant change in RR and BP. Gradient analysis showed that PTT was more responsive to central volume loss than RR during mild hypovolaemia (0-20 degrees ) but not moderate hypovolaemia (50-80 degrees ). CONCLUSION: PTT may reflect variation in PEP and central blood volume, and is potentially useful for early detection of non hypotensive progressive central hypovolaemia. Joint interpretation of PTT and RR trends or responses may help to characterize the extent of blood volume loss in critical care patients. PMID- 17701386 TI - Impact of withdrawal of 450 ml of blood on respiration-induced oscillations of the ear plethysmographic waveform. AB - OBJECTIVE: It has been widely appreciated that ventilation-induced variations in systolic blood pressure during mechanical ventilation correlate with changes in intravascular volume. The present study assessed whether alterations in volume status likewise can be detected with noninvasive monitoring (ear plethysmograph) in non-intubated subjects (awake volunteers). METHODS: Eight healthy adults were monitored with EKG, noninvasive blood pressure, an unfiltered ear plethysmograph, and a respiratory force transduction belt before (PRE) and after (POST) withdrawal of 450 ml of blood from an antecubital vein. Spectral-domain analysis was used to determine the peak ventilatory frequency and the power of the associated variation in the ear plethysmographic tracing; Interphase differences in the respiration-induced plethysmographic variations were assessed by Wilcoxon signed rank test. In addition, the changes in the ear plethysmographic tracing were compared to changes in heart rate and blood pressure. RESULTS: There was a significant increase in respiratory-associated oscillations at the respiratory frequency between the PRE and POST phases (p = 0.012). These changes were detected despite lack of changes in heart rate or blood pressure. CONCLUSIONS: Respiration-induced changes of the ear plethysmographic waveform during spontaneous ventilation increase significantly as a consequence of withdrawal of approximately one unit of blood in healthy volunteers. PMID- 17701387 TI - Forehead reflectance oximetry: a clinical comparison with conventional digit sensors during laparotomic and laparoscopic abdominal surgery. AB - OBJECTIVE: This study compared the performance of forehead reflectance and conventional pulse oximetry (SpO(2)) in mechanically ventilated, anesthetized patients undergoing major abdominal surgery with either laparoscopic or laparotomic techniques. METHODS: SpO(2) was continuously measured both with a forehead reflectance and a conventional digit sensor in 20 ASA physical status I III, anesthetized patients undergoing either a laparotomic (group Laparotomy, n = 10) or laparoscopic (group Laparoscopy, n = 10) major abdominal surgery. SpO(2) values measured with the two sensors were continuously recorded at 10-second intervals during the entire procedure, and then analyzed for consistency. RESULTS: In group Laparotomy finger and forehead readings remained consistently similar during the study period; on the contrary, in group Laparoscopy forehead SpO(2) readings showed a much wider variability. The mean (95% Confidence Intervals) difference between finger and forehead SpO(2) readings was 2.0% (-1.3% to +6.0%) in group Laparotomy and 2.5% (-3.5% to +8.4%) in group Laparoscopy (p = 0.001); however, in group Laparoscopy the mean difference between digit and forehead SpO(2) values increased from 0.2% (CI(95): -2.1% to +2.5%) during the first hour to 4.5% (CI(95): -2.5% to +11-5%) in the second hour (p = 0.0005), and 3.1% (CI(95): -2.4% to + 8.6%) in the third hour of surgery (p = 0.0005). Clinically relevant desaturation (decrease of SpO(2) < 89% for > or =30 s) detected with the forehead sensor in the Laparoscopy group was significantly more frequent and longer lasting than with conventional digit sensor. No differences were observed in group Laparotomy. CONCLUSIONS: Forehead reflectance oximetry is as accurate as conventional digit based oximetry in mechanically ventilated patients undergoing laparotomic surgery in the supine position, but is significantly influenced by patient positioning and pneumoperitoneum during laparoscopic surgery. PMID- 17701388 TI - Synthesis and characteristics of monticellite bioactive ceramic. AB - Mono-phase ceramics of monticellite (CaMgSiO4) were successfully synthesized by sintering sol-gel-derived monticellite powder compacts at 1,480 degrees C for 6 h. The mechanical properties and the coefficient of thermal expansion (CTE) of the monticellite ceramics were tested. In addition, the bioactivity in vitro of the monticellite ceramics was evaluated by investigating their bone-like apatite formation ability in simulated body fluid (SBF), and the biocompatibility in vitro was detected by osteoblast adhesion and proliferation assay. The results showed that the bending strength, fracture toughness and Young's modulus of the monticellite ceramics were about 159.7 MPa, 1.63 MPa m1/2 and 51 GPa, respectively. The CTE was 10.76x10(-6) degrees C(-1) and close to that of Ti-6Al 4V alloy (10.03x10(-6) degrees C(-1)). Furthermore, the monticellite ceramics possessed bone-like apatite-formation ability in SBF and could release soluble ionic products to significantly stimulate cell growth and proliferation. In addition, osteoblasts adhered and spread well on the monticellite ceramics, which indicated good bioactivity and biocompatibility. PMID- 17701389 TI - [Olfactory dysfunction in Parkinson's disease: its role as a new cardinal sign in early and differential diagnosis]. AB - Olfactory dysfunction is a prominent symptom in Parkinson's disease (PD) and found in about 70-100% of patients. In earlier studies significant loss of olfactory function seemed to be unrelated to disease duration, did not correlate with motor function, and was uninfluenced by antiparkinsonian medication. We suggest that the increase of dopaminergic cells in the olfactory bulb is responsible for the hyposmia in PD patients. Interestingly, this olfactory dysfunction is not found in progressive supranuclear palsy or corticobasal degeneration. In multiple system atrophy, the deficit is mild and indistinguishable from cerebellar syndromes of other aetiologies. Intact olfaction has also been reported recently in Parkin disease (PARK 2) and vascular parkinsonism. Olfactory tests may significantly enhance the diagnostic armamentarium in the differential diagnosis of parkinsonian syndromes and indeterminate tremors. Furthermore, olfactory testing may also prove to be a useful aid in the early or "preclinical" detection of PD, once effective disease modifying therapies are found. Braak and coworkers have confirmed the widespread, extranigral pathology in PD and suggested that pathology in the anterior olfactory region may be one of the earliest appearances of neurodegeneration in PD. PMID- 17701390 TI - [Therapeutic drug monitoring in epileptology and psychiatry]. AB - Experts from epileptology and psychiatry reviewed the current significance of therapeutic drug monitoring (TDM) of antiepileptic drugs and psychiatric drugs in a workshop at Bethel Epilepsy Centre in December 2005. TDM has been essential in epileptology for about 30 years, and it is also increasingly important in psychiatry, in which consensus recommendations were published recently. With regard to cost-cutting in the health system, there are discussions about the financial effect of TDM and outsourcing it to bigger laboratories. In psychiatry it has however been shown that sensibly used TDM may lead to reduced costs. Many issues in TDM require the knowledge and experience of specialised laboratories. The use of TDM data for scientific purposes was discussed at the workshop as well. PMID- 17701391 TI - [Cognitive functions of the prefrontal cortex: neuroscience and clinic]. AB - Basic neuroscientific research has greatly contributed to a deeper understanding of the cognitive functions of the prefrontal cortex (PFC). Injuries of the PFC typically give rise to severe cognitive disorders that usually are subsumed under the broad rubric of executive dysfunctions (EDF). The umbrella term of EDF denotes a high-level disorder in the control of thought and action. The existence of EDF is of critical importance for the prognosis of disabilities in daily living, vocational rehabilitation, and social integration. Neuropsychological assessment instruments and intervention programs are discussed. PMID- 17701392 TI - [Medical and urological education in Germany and America. A few historical highlights]. PMID- 17701393 TI - [The interdisciplinary approach to improve treatment quality of prostate cancer. Optimized nerve sparing in radical prostatectomy]. AB - BACKGROUND: After sufficient oncological treatment of prostate cancer the life quality becomes most important. A multi disciplinary research network aims to optimize the diagnostics and the resulting treatment of prostate cancer. METHODS: Main characteristics of the interdisciplinary cooperation are the interlocked individual projects. A major research field is investigation of the whole mounted prostate sections to study the peripheral nerves and the comparison of histological tumor locations with the MRI. Using serial sections of prostate specimens, three-dimensional computer-animated models are created illustrating the tumors histological and immunohistochemical distributions. For nodal staging, a new methodology is investigated to demonstrate single tumor cells in lymphatic tissue lysates. A retrospective evaluation of life quality including the functional outcome is performed by using questionnaire surveys. RESULTS: Anatomical studies gave new insights into the exact localizations of peripheral nerves which may lead to an improvement of the surgical approach in nerve-sparing radical prostatectomy. For the preoperative planning the MRI imaging might need a different interpretation in relation to the topographic location. Studies using molecular markers and their relation and distribution patterns gave new insights regarding interpretation of histological biopsy results concerning the tumor extension. Numerical quantification of tumor cells in each lymph node demonstrated micro metastases in histological negative nodes contributing to the nodal staging. A close connection of the nerve-sparing technique was demonstrated with quality of life aspects and functional results. CONCLUSION: An interdisciplinary approach is mandatory for translational prostate cancer research. As a result, individualized diagnostic and therapeutic approaches improve oncological results and at the same time provide the best quality of life in these patients. PMID- 17701394 TI - Evolutionary analysis of the APA genes in the Phaseolus genus: wild and cultivated bean species as sources of lectin-related resistance factors? AB - The APA (Arcelin/Phytohemagglutinin/alpha-Amylase inhibitor) gene family is composed of various members, present in Phaseolus species and coding for lectin and lectin-related seed proteins having the double role of storage and defense proteins. Here members of the APA family have been identified by immunological, functional, and molecular analyses and representative genes were sequenced in nine wild species of Phaseolus. All taxa possessed at least one member of the true lectin gene. No arcelin type sequences have been isolated from the species examined. Among the wild species studied, only P. costaricensis contained an alpha-amylase inhibitor (alpha-AI). In addition P. augusti, P. maculatus, P. microcarpus, and P. oligospermus showed the presence of the lectin-related alpha amylase inhibitor-like (AIL) genes and alpha-AI activity. Data from Southern blot analysis indicated the presence of only one lectin gene in P. parvulus and P. filiformis, while an extensive gene duplication of the APA locus was found in the other Phaseolus species. Phylogenetic analysis carried out on the nucleotide sequences showed the existence of two main clusters and clearly indicated that lectin-related genes originated from a paralogous duplication event preceding the development of the ancestor to the Phaseolus genus. The finding of detectable alpha-AI activity in species containing AIL genes suggests that exploiting APA genes variability in the Phaseolus genus may represent a valuable tool to find new members that may have acquired insecticidal activities. PMID- 17701395 TI - Generation and characterization of two novel low phytate mutations in soybean (Glycine max L. Merr.). AB - Phytic acid (PA, myo-inositol 1, 2, 3, 4, 5, 6 hexakisphosphate) is important to the nutritional quality of soybean meal. Organic phosphorus (P) in PA is indigestible in humans and non-ruminant animals, which affects nutrition and causes P pollution of ground water from animal wastes. Two novel soybean [(Glycine max L. (Merr.)] low phytic acid (lpa) mutations were isolated and characterized. Gm-lpa-TW-1 had a phytic acid P (PA-P) reduction of 66.6% and a sixfold increase in inorganic P (Pi), and Gm-lpa-ZC-2 had a PA-P reduction of 46.3% and a 1.4-fold increase in Pi, compared with their respective non-mutant progenitor lines. The reduction of PA-P and increase of Pi in Gm-lpa-TW-1 were molar equivalent; the decrease of PA-P in Gm-lpa-ZC-2, however, was accompanied by the increase of both Pi and lower inositol phosphates. In both mutant lines, the total P content remained similar to their wild type parents. The two lpa mutations were both inherited in a single recessive gene model but were non allelic. Sequence data and progeny analysis indicate that Gm-lpa-TW-1 lpa mutation resulted from a 2 bp deletion in the soybean D: -myo-inositol 3 phosphate synthase (MIPS1 EC 5.5.1.4) gene 1 (MIPS1). The lpa mutation in Gm-lpa ZC-2 was mapped on LG B2, closely linked with microsatellite loci Satt416 and Satt168, at genetic distances of approximately 4.63 and approximately 9.25 cM, respectively. Thus this mutation probably represents a novel soybean lpa locus. The seed emergence rate of Gm-lpa-ZC-2 was similar to its progenitor line and was not affected by seed source and its lpa mutation. However, Gm-lpa-TW-1 had a significantly reduced field emergence when seeds were produced in a subtropic environment. Field tests of the mutants and their progenies further demonstrated that the lpa mutation in Gm-lpa-ZC-2 does not negatively affect plant yield traits. These results will advance understanding of the genetic, biochemical and molecular control of PA synthesis in soybean. The novel lpa mutation in Gm-lpa-ZC 2, together with linked simple sequence repeat (SSR) markers, will be of value for breeding productive lpa soybeans, with meal high in digestible Pi eventually to improve animal nutrition and lessen environmental pollution. PMID- 17701396 TI - Linkage disequilibrium in synthetic varieties of perennial ryegrass. AB - Synthetic varieties obtained after three to four panmictic generations are variable, not structured and so can be used for association studies. The pattern of linkage disequilibrium (LD) decay determines whether a genome scan or a candidate gene approach can be used for an association study between genotype and phenotype. Our goal was to evaluate the effect of the number of parents used to build the synthetic varieties on the pattern of LD decay. LD was investigated in the gibberelic acid insensitive gene (GAI) region in three synthetic varieties of perennial ryegrass (Lolium perenne L.) chosen for their contrasted number of parents in the initial polycrosses. Results were compared with those obtained from a core collection. STS and SSR markers were used to evaluate variation, structuration and LD in each variety. As expected, the varieties variability increased with the number of parents almost up to the core collection variability. No structuration was observed in the varieties. Significant LDs were observed up to 1.6 Mb in a variety originated from six related parents and not above 174 kb in a variety originated from 336 parents. These results suggest that a candidate gene approach can be used when varieties have a large number of parents and a genome scan approach can be envisaged in specific regions when varieties have a low number of parents. Nevertheless, we strongly recommend to estimate the pattern of LD decay in the population and in the genomic region studied before performing an association study. PMID- 17701397 TI - Education and evaluation of knowledge and skills in echocardiography: how should we organize? PMID- 17701398 TI - Validation of a skills assessment scoring system for transesophageal echocardiographic monitoring of hemodynamics. AB - OBJECTIVE: Transesophageal echocardiography (TEE) is increasingly used in hemodynamic monitoring in the intensive care unit. This paper describes and validates a scoring system for assessing competence in TEE performed by intensivists for this indication. DESIGN: Prospective study over an 18-month period. SETTINGS: Two medical intensive care units. METHODS: The scoring system is used to assess four aspects of TEE: quality of the views (score out of 14); semiquantitative evaluation of respiratory variations in the superior vena cava, valve regurgitation, size of the right ventricle (score out of 10); accuracy of measurement of velocity-time integrals for pulmonary and aortic flow, peak velocity of the E and A waves of mitral flow, left ventricular fractional area change (score out of 8); summary and proposed treatment (score out of 8). The scoring system was validated by using it to assess intensivists after 1 month (M1), 3 months (M3) and 6 months (M6) of training. TEE was done on a mechanically ventilated, hypotensive patient and scored by comparing the intensivist's examination with that of the expert examiner. The intensivists were divided into two groups of theoretical expertise at the start of training. RESULTS: Nineteen intensivists were evaluated. The scores at M1 for level 0 (no experience in echocardiography) and level 1 (previous experience) were, respectively, 18.5 +/- 4 and 24.7 +/- 5. The scores at M1, M3, and M6 were, respectively, 20.4 +/- 5, 30.4 +/- 5 and 35.7 +/- 3. At M6, the intensivists had performed TEE 29 +/- 10 times. CONCLUSION: The scoring system was discriminatory and sensitive to change, and could be used as a tool to assess an intensivist's mastery of TEE. PMID- 17701399 TI - Haplotypes of vitamin D receptor modulate the circulating levels of lead in exposed subjects. AB - Genetic factors influence whole blood lead (Pb-B) concentrations in lead exposed subjects. This study aimed at examining the combined effects (haplotype analysis) of three polymorphisms (BsmI, ApaI and FokI) in vitamin D receptor (VDR) gene on Pb-B and on the concentrations of lead in plasma (Pb-P), which is more relevant to lead toxicity, in 150 environmentally exposed subjects. Genotypes were determined by RFLP, and Pb-P and Pb-B were determined by inductively coupled plasma mass spectrometry and by graphite furnace atomic absorption spectrometry, respectively. Subjects with the bb (BsmI polymorphism) or ff (FokI polymorphism) genotypes have lower B-Pb than subjects in the other genotype groups. Subjects with the aa (ApaI polymorphism) or ff genotypes have lower P-Pb than subjects in the other genotype groups. Lower Pb-P, Pb-B, and %Pb-P/Pb-B levels were found in subjects with the haplotype combining the a, b, and f alleles for the ApaI, BsmI, and FokI polymorphisms, respectively, compared with the other haplotype groups, thus suggesting that VDR haplotypes modulate the circulating levels of lead in exposed subjects. PMID- 17701400 TI - Electrocatalytic oxidation of dopamine at an ionic liquid modified carbon paste electrode and its analytical application. AB - A room-temperature ionic liquid N-butylpyridinium hexafluorophosphate was used as a binder to construct an ionic liquid modified carbon paste electrode, which was characterized by scanning electron microscopy and electrochemical impedance spectroscopy. The ionic liquid carbon paste electrode (IL-CPE) showed enhanced electrochemical response and strong analytical activity towards the electrochemical oxidation of dopamine (DA). A pair of well-defined quasireversible redox peaks of DA appeared, with the redox peaks located at 215 mV (E (pa)) and 151 mV (E (pc)) (vs. the saturated calomel electrode, SCE) in pH 6.0 phosphate buffer solution. The formal potential (E (0')) was calculated as 183 mV (vs. SCE) and the peak-to-peak separation as 64 mV. The electrochemical behavior of DA on the IL-CPE was carefully investigated. Under the optimal conditions, the anodic peak currents increased linearly with the concentration of DA in the range 1.0 x 10(-6)-8.0 x 10(-4) mol/L and the detection limit was calculated as 7.0 x 10(-7) mol/L (3sigma). The interferences of foreign substances were investigated and the proposed method was successfully applied to the determination of DA injection samples. The IL-CPE fabricated was sensitive, selective and showed good ability to distinguish the coexisting ascorbic acid and uric acid. PMID- 17701401 TI - Diagonal chromatographic selection of cysteinyl peptides modified with benzoquinones. AB - The derivatization of cysteine-containing peptides with benzoquinone compounds is rapid, quantitative and specific in acidic media. The conversion of cysteines into hydrophobic benzoquinone-adducted residues in peptides is used here to alter the chromatographic properties of cysteinyl peptides during liquid chromatography separation. The benzoquinone derivatization is shown to allow the accurate selection of cysteine-containing peptides of bovine serum albumin tryptic digest by diagonal reversed-phase chromatography, which consists of one primary and a series of secondary identical liquid chromatographic separations, before and after a cysteinyl-targeted modification of the peptides by benzoquinone compounds. PMID- 17701402 TI - Proof of principle of a generalized fuzzy Hough transform approach to peak alignment of one-dimensional 1H NMR data. AB - In metabolic profiling, multivariate data analysis techniques are used to interpret one-dimensional (1D) 1H NMR data. Multivariate data analysis techniques require that peaks are characterised by the same variables in every spectrum. This location constraint is essential for correct comparison of the intensities of several NMR spectra. However, variations in physicochemical factors can cause the locations of the peaks to shift. The location prerequisite may thus not be met, and so, to solve this problem, alignment methods have been developed. However, current state-of-the-art algorithms for data alignment cannot resolve the inherent problems encountered when analysing NMR data of biological origin, because they are unable to align peaks when the spatial order of the peaks changes-a commonly occurring phenomenon. In this paper a new algorithm is proposed, based on the Hough transform operating on an image representation of the NMR dataset that is capable of correctly aligning peaks when existing methods fail. The proposed algorithm was compared with current state-of-the-art algorithms operating on a selected plasma dataset to demonstrate its potential. A urine dataset was also processed using the algorithm as a further demonstration. The method is capable of successfully aligning the plasma data but further development is needed to address more challenging applications, for example urine data. PMID- 17701403 TI - Long-term changes in management following n-of-1 trials of stimulants in attention-deficit/hyperactivity disorder. AB - OBJECTIVE: Our objective was to evaluate the long-term impact of n-of-1 trials within-patient randomised, double-blind, cross-over comparisons of stimulant versus placebo or stimulant-on ADHD management. METHODS: Telephone surveys at 3, 6 and 12 months. Main outcome measures included (1) changes in treatment before and after the n-of-1 trial, (2) congruence of management at follow-up with trial result, (3) reasons for any non-congruence, and (4) persistence of the joint patient-doctor decision over 12 months. Patients were children with clinically diagnosed ADHD, aged 5-16 years. RESULTS: A total of 76 patients were followed up; 12 months' data were available for 67 (88%). Management changed from baseline for 46, 48 and 51% at 3, 6 and 12 months respectively. Most responders, 21/37 (57%), remained on the same stimulant at 12 months, compared to 9/24 (37%) non responders. Of the remaining non-responders, 15/24 (62%) either switched (2/24, 8%) or ceased stimulants (13/24, 54%). The rate of congruence with the test result was 45/65 (69%) at 3 months, 44/67 (66%) at 6 months and 40/67 (60%) at 12 months. Persistence with the post-trial decision over 12 months was high (79-85%) whether the decision was to continue or to cease stimulants. CONCLUSIONS: Although not conclusive because there was no control group, our results suggest that n-of-1 trials may improve rational treatment of ADHD. PMID- 17701404 TI - Attitudes toward psychiatric drug treatment: the experience of being treated. AB - BACKGROUND: Effectiveness and tolerability of psychiatric medications are not only determined by the drug's pharmacological profile but through the interaction of different factors, including patients' attitudes toward their prescribed medications. Increased knowledge about those attitudes may help prescribers to improve patient concordance and thereby the effectiveness of the pharmacological therapy. OBJECTIVE: The goal of this study was to assess stable psychiatric outpatients' attitudes toward psychiatric drug treatment and to what extent patients and public opinions on this subject diverge as a consequence of being on this type of medication. METHODS: Two anonymous self-reported questionnaires [Drug Attitude Inventory (DAI)-10 and an abridge version of Beliefs about Medicines Questionnaire (BMQ)] were administered to 270 stable psychiatric outpatients under treatment and 292 citizens naive to psychotropic medication. RESULTS: Psychiatric patients showed a more positive attitude toward medication (DAI score 3.6 vs. -0.7; range -10 to +10; negative to positive). Up to 77% of patients showed positive scores compared with only 36% in the general population. Multiple regression analysis showed that none of the variables in the analysis have a predictive value with regard to the attitude toward psychiatric drugs used. CONCLUSION: The continuous use of psychotropic medication shapes the opinion of the users toward a more beneficial perception of medications, but the opinion on the general population, where stigmatizing attitudes are born, is more negative toward them. For psychiatrists and their patients, trying to achieve a better understanding of each other's expectations and reaching concordance is mandatory. PMID- 17701405 TI - Estimation of CYP2C19 activity by the omeprazole hydroxylation index at a single point in time after intravenous and oral administration. AB - OBJECTIVE: The purpose of this study was to identify the common time point to achieve hydroxylation index (HI: omeprazole plasma concentration/5 hydroxyomeprazole plasma concentration) reflecting AUCOPZ/AUC5OH-OPZ after intravenous (IV) and oral (PO) administration. METHODS: Twenty young and 28 elderly healthy subjects, including different CYP2C19 genotypes, were enrolled in the study. The young subjects received either 40 mg PO or 20 mg IV omeprazole, whereas the elderly subjects received 10 mg IV. The relation between AUCOPZ/AUC5OH-OPZ and HI was determined by Spearman's rank correlation. Multiple stepwise linear regression analysis was performed to identify the common time point to calculate HI that reflects AUCOPZ/AUC5OH-OPZ after IV. RESULTS: In the correlation between HI and AUCOPZ/AUC5OH-OPZ IV at observed time points, HI3h showed the highest correlation coefficients (r = 0.894, p < 0.001) in all 48 subjects. The correlation of HI between IV and PO at observed time points showed that HI3h was highest (r = 0.916, p < 0.001) in 20 young subjects. Additionally, there was no significant difference between HI(3h) of IV and that of PO (12.9 +/- 15.9 and 12.9 +/- 15.1, p = 0.997). The regression equation of HI3h was the best to estimate AUCOPZ/AUC5OH-OPZ (AUCOPZ/AUC5OH-OPZ = 1.37 * HI3h + 0.18 * Age - 7.83, r2 = 0.883, p < 0.001). CONCLUSIONS: This study demonstrated that HI3h after omeprazole IV was able to estimate AUCOPZ/AUC5OH-OPZ, as well as HI3h after PO. Additionally, CYP2C19 activity can be estimated more definitely by using HI after omeprazole IV without intestinal absorption. PMID- 17701406 TI - Comparison of platinum and first-generation Matrix coils in under-packed canine side-wall aneurysms: evaluation of progressive thrombosis. AB - INTRODUCTION: There is much speculation in reference to the occurrence and mechanisms of progressive aneurysm occlusion after treatment with bioactive coils. However, to our knowledge, there are no studies documenting the impact on progressive occlusion in aneurysms that are intentionally under-packed. METHODS: A total of 24 experimental side-wall aneurysms were created in canine common carotid arteries. Of these 24, 9 were treated with Guglielmi detachable coils (GDC) and 15 with first-generation Matrix (Matrix1) coils to packing densities of 22% or less. Angiograms were obtained immediately after treatment and again at the time of explant at 2 weeks, 8 weeks, or 12 weeks, and were graded utilizing the Raymond scale. At the time of the final angiography and explant all aneurysms were histologically processed and evaluated. RESULTS: At the conclusion of initial coiling, near or complete occlusion was achieved in 7 of the 15 aneurysms (47%) treated with Matrix1 coils and in 2 of the 9 (22%) treated with GDC. Of the aneurysms that were incompletely occluded, six of eight (75%) treated with Matrix1 coils and two of seven (29%) treated with GDC showed progressive thrombosis at explant. Histopathological analysis demonstrated that the aneurysms treated with Matrix1 coils had increased fibrocellular tissue and inflammation, with less histological recanalization or vascular spaces, relative to those treated with GDC. CONCLUSION: Experimental wide-necked side-wall canine aneurysms suboptimally treated with first-generation Matrix1 coils had a higher incidence of progressive occlusion and on histological analysis showed evidence of more advanced thrombus organization than did those treated with GDC. PMID- 17701407 TI - Characterization of the peptide-binding specificity of the chimpanzee class I alleles A 0301 and A 0401 using a combinatorial peptide library. AB - Chimpanzees represent important models for studying several human pathogens. In the present study, we utilized a combinatorial peptide library to characterize the binding specificities of the chimpanzee class I molecules Patr A 0301 and A 0401, both of which are present in about 17% of chimpanzees. Patr A 0301 was found to recognize peptides using the canonical position 2/C-terminus spacing, with the small residues S, T, and A being the most preferred in position 2, and the positively charged residues R and K preferred at the C terminus. Patr A 0401 was found to recognize a more complex motif where the C terminus and then the residue in positions 1 and/or 5 are the primary anchors. Like A 0301, the C terminal preference of A 0401 is for positively charged residues. At positions 1 and 5, positively charged and large residues are the most preferred, respectively. Coefficient values derived from the combinatorial library proved to be an efficient means for predicting A 0301 and A 0401 binders. The present data provide detailed information to facilitate the identification of potential T cell epitopes recognized in the context of two common chimpanzee class I alleles, and further validate the combinatorial library approach as an efficient method to characterize class I binding specificities. PMID- 17701408 TI - Biofilms: strategies for metal corrosion inhibition employing microorganisms. AB - Corrosion causes dramatic economic loss. Currently widely used corrosion control strategies have disadvantages of being expensive, subject to environmental restrictions, and sometimes inefficient. Studies show that microbial corrosion inhibition is actually a common phenomenon. The present review summarizes recent progress in this novel strategy: corrosion control using beneficial bacteria biofilms. The possible mechanisms may involve: (1) removal of corrosive agents (such as oxygen) by bacterial physiological activities (e.g., aerobic respiration), (2) growth inhibition of corrosion-causing bacteria by antimicrobials generated within biofilms [e.g., sulfate-reducing bacteria (SRB) corrosion inhibition by gramicidin S-producing Bacillus brevis biofilm], (3) generation of protective layer by biofilms (e.g., Bacillus licheniformis biofilm produces on aluminum surface a sticky protective layer of gamma-polyglutamate). Successful utilization of this novel strategy relies on advances in study at the interface of corrosion engineering and biofilm biology. PMID- 17701409 TI - Substantially monodispersed poly(epsilon-L-lysine)s frequently occurred in newly isolated strains of Streptomyces sp. AB - The presence of poly(epsilon-L-lysine) (epsilon-PL) was found quite frequently by screening various strains of Streptomyces sp. Most of the ten newly obtained epsilon-PLs, when they were produced from glucose, showed a polydispersity index of Mw/Mn = 1.01 using ion-pair chromatography analysis. The polymers were classified into five groups according to their chain lengths. The average numbers of residues in the five groups were 32, 28, 25, 19, and 16, respectively. The use of glycerol instead of glucose resulted in decreases of 10 to 20% in the Mn and slight increases in the Mw/Mn. These observations indicated the chain length and polydispersity of epsilon-PL were primarily determined by each producer strain. Proton and 13C NMR analysis revealed the signals of glycerol-derived ester at the C terminus of the polymer from several producers including the first discovered S. albulus strain, although the percentages of the ester were low under our culture conditions. These results, coupled with the previous observation that SO4(2-) was essential for the polymer production, led to discussion on the mechanistic aspects of monomer activation, elongation, and termination in the biosynthesis of epsilon-PL. PMID- 17701410 TI - Positron emission tomography in the staging of patients with Hodgkin's lymphoma. A prospective multicentric study by the Intergruppo Italiano Linfomi. AB - In this prospective multicentric study, we investigated the contribution of positron emission tomography (PET) scanning to the staging of Hodgkin's lymphoma (HL) by computed tomography (CT) and attempted to determine whether it has any impact on therapeutic approach. One hundred eighty six consecutive patients with HL from six Italian centers were enrolled in this study. They were staged with conventional methods; 2-[fluorine-18]fluoro-2-deoxy-D: -glucose PET scanning were prospectively compared to CT. CT and FDG-PET stages were concordant in 156 patients (84%) and discordant in 30 patients (16%). PET stage in comparison to CT stage was higher in 27 patients (14%) and lower in 3 patients (1%). The programmed treatment strategy was modified in 11 out of 30 patients (37%) after the definition of final stage. If we considered the 123 CT staged patients with localized stage, ten patients (8%) with a change of stage from localized to advanced after PET evaluation were treated with different strategy. FDG-PET was shown to be a relevant, non-invasive method that supplements conventional procedures and should therefore be used routinely to stage HL, particularly in early stage patients, where a change in stage may modify disease management. PMID- 17701411 TI - [Cytological diagnosis of salivary gland tumours]. AB - This review gives a short survey of cytological criteria of the most common salivary gland tumours. The emphasis is on a short and precise as well as practicable summary of the most important cytological criteria and comprehensive presentation without claiming completeness. In addition our own results were compared with other international data and publications. PMID- 17701412 TI - Identification of genes responsive to the application of ethanol on sugarcane leaves. AB - The control of gene expression in precise time and space is a desirable attribute of chemically inducible systems. Ethanol is a chemical inducer with favourable features, such as being inexpensive and easy to apply. The aim of this study was to identify ethanol-responsive genes in sugarcane. The cDNA macroarray technique was adopted to identify transcript changes in sugarcane leaves (Saccharum spp. cv SP80-3280) exposed to ethanol. The expression profiles of sugarcane genes were analysed using nylon filters containing 3,575 cDNA clones from the leaf roll library of the SUCEST project. Seventy expressed sequence tags (ESTs) presented altered expression patterns, including ESTs corresponding to genes related to transcriptional and translational processes, abiotic stress and others. Several genes of unknown function were also identified. Among the 48 ESTs up-regulated by ethanol, an abiotic stress-responsive protein and an unknown function gene presented rapid induction by ethanol. The macroarray data of selected ethanol responsive EST were confirmed by RNA-blot hybridisation. The expression profile of the 48 up-regulated genes was compared in two other cultivars: SP89-1115 and SP90-3414. Surprisingly, no gene showed a similar expression profile in the three cultivars. This result suggests that sugarcane plants have a high diversity in their responses to ethanol. PMID- 17701413 TI - 3D visualization and simulation of frontoorbital advancement in metopic synostosis. AB - OBJECTIVES: Current multislice computed tomography (CT) technology can be used for diagnosis and surgical planning applying computer-assisted three-dimensional (3D) visualization and surgical simulation. The usefulness of a technique for surgical simulation of frontoorbital advancement is demonstrated here in a child with metopic synostosis. MATERIALS AND METHODS: Postprocessing of multi-slice CT data was performed using the software 3D slicer. 3D models were created for the purpose of surgical simulation. These allow planning the course of the osteotomies and individually placing the different bony fragments by an assigned matrix to simulate the surgical result. Photo documentation was obtained before and after surgery. Surgical simulation of the procedure allowed determination of the osteotomy course and assessment of the positioning of the individual bony fragments. CONCLUSIONS: Computer-assisted postprocessing and simulation is a useful tool for surgical planning in craniosynostosis surgery. The time-effort for segmentation currently limits the routine clinical use of this technique. PMID- 17701414 TI - Gastroschisis and exomphalos in Ireland 1998-2004. Does antenatal diagnosis impact on outcome? AB - Antenatal detection of anterior abdominal wall defects (gastroschisis and exomphalos) enables detailed prenatal planning and counselling with appropriate intrauterine transfer, delivery in a tertiary referral centre with prompt access to paediatric surgery and early surgical intervention. The authors believed that there was a relatively low rate of antenatal detection in Ireland and that an improved antenatal screening program would allow increased detection thus avoiding emergency retrievals from peripheral obstetric centres. Our hypothesis was that there was a significant difference in management and outcome in children with anterior abdominal wall defects detected antenatally and those detected at birth. All anterior abdominal wall defects in The Republic of Ireland are assessed and closed in two surgical centres, Our Lady's Hospital for Sick Children, and the Children's University Hospital, Dublin. A retrospective review of all admissions in both centres revealed 96 neonates with anterior wall defects (excluding bladder exstrophy and cloaca) over a 7 year period from 1998 to 2004 inclusive. Medical records, operative reports, neonatal databases and admission details were reviewed. The antenatal data search included anomaly detection, prenatal management plan and intrauterine transfer. Perinatal data included place of birth, weight, gestational age, mode of delivery, time to surgery and type of surgery, the time to establish full enteral feeding and the length of hospital stay were used as overall markers of outcome. Fifty-three patients had gastroschisis and 43 exomphalos with an antenatal detection rate of 53% (n = 28) and 34% (n = 15), respectively, with an overall detection rate of 44%. There was no significant difference in the median birth weight (2.83 vs. 2.85 kg), gestational age at birth (37 vs. 37 weeks), time to full feeding (12 vs.14 days) and length of stay (20 vs. 17 days) between those detected antenatally or postnatally, respectively. About 77 had a primary closure performed of which 63 infants had surgery within the first 24 h of life. There was no difference in the time to surgery, frequency of complications or the surgical outcome in either group. Intrauterine transfer did not affect any outcome measure assessed. The demographics and the presence of associated anomalies did not differ between the groups. The hypothesis that antenatal diagnosis in anterior abdominal wall defects improves outcome has been demonstrated to be false. Despite this result, the importance of antenatal screening and prenatal management of complex foetal conditions with consultation with experienced paediatric and neonatal staff is without doubt. PMID- 17701415 TI - Heterogeneous subgroups in human neuroblastoma for clinically relevant risk stratification. AB - Neuroblastoma is a heterogeneous tumor and that may have a favorable or unfavorable prognosis. In Japan, a nation-wide neuroblastoma mass-screening (MS) project assessed 6-month-old infants between 1985 and 2003, and almost all neuroblastomas, including regressing or maturing tumors were thought to be detected in this period. To evaluate the heterogeneity of neuroblastoma subgroups, we analyzed patients with neuroblastoma who had been diagnosed during this period. The clinical courses of 4,209 patients with neuroblastoma, including 1,560 MS detected patients, whose tumors had been diagnosed between 1971 and 1995 were registered. The 2,520 cases registered between 1985 and 1995 were compared to 1,050 cases registered between 1971 and 1980 and analyzed by a multi-gene target model to determine the age distribution of neuroblastoma incidence. We hypothesized that three target genes were responsible for the progression of neuroblastoma: one pair of tumor suppressor gene alleles, one oncogene, and one gene controlling regression/differentiation. This simulation study revealed that the age distribution at initial diagnosis of neuroblastoma was divided into four groups based on post-fertilization age: 20-40, 40-50, 60-90, and 160-200 weeks. Since neuroblatoma in the first group occurred prenatal, post-natal clinical neuroblastoma can be classified into three age groups: 0-6 months, 1-2 years, and 3-4 years. The 0- to 6-month group consisted of mostly benign tumors, and the two older groups had predominantly malignant phenotypes. Our proposed model could explain qualitatively the distribution of neuroblastoma consisting of one subgroup with a favorable prognosis and two subgroups with unfavorable prognosis. For clinically relevant risk stratification, an age cutoff should be considered by the age distribution of these heterogeneous subgroups. PMID- 17701416 TI - Homozygosity for the K variant of BCHE gene increases the risk for development of neurofibrillary pathology but not amyloid deposits at young ages. AB - The presence of the K variant of the butyrylcholinesterase gene (BCHE-K) has been associated with the severity of Alzheimer's disease (AD)-related neurofibrillary tangles (NFT) and amyloid beta-protein (Abeta). To examine the impact of BCHE-K on the development of initial NFT- and Abeta pathologies in young individuals below the age of 45 years a total of 124 cases (110 cases with NFT-only pathology, 14 cases with Abeta-only pathology) and 104 matched controls were genotyped for BCHE-K. Homozygosity for BCHE-K was highly overrepresented among NFT-only group (8.2%) compared with controls (1%, P = 0.02) or the Abeta-only group (0%). The prevalence of the K allele, however, was comparable among groups. These findings suggest that homozygosity, but not heterozygosity, for BCHE-K is a potential risk factor for the development of NFT pathology in young individuals implicating BCHE-K in the pathogenesis of early AD. PMID- 17701417 TI - The role of chromosomal aberrations in premalignant and malignant lesions in head and neck squamous cell carcinoma. AB - The objectives of this study are to uncover the molecular mechanisms involved in head and neck squamous cell carcinoma (HNSCC) pathogenesis by studying the chromosomal aberrations in both premalignant and malignant patients and to highlight the genotype of HNSCC in Upper Egypt. From March 2001 to December 2003, prospective study was conducted in 41 patients with precancerous, 79 patients with cancerous laryngeal, oesophageal, nasopharyngeal, nasal, and oral lesions and 50 controls in ENT department, Sohag Faculty of Medicine, Sohag, Egypt. Samples taken by punch biopsy were frozen and stored at -80 degrees C and were subjected to histopathological examination. Metaphase cells were digitally imaged and karyotyped. Karyotypes have been analysed via anatomical image capture and compared with standard human chromosome ideograms. In precancerous lesions, there were 41% 3p loss, 51% 3q gain, 29% 8q gain, and 22% 11q13 gain. In malignant lesions, there were 63% 3p13-p24 loss, 59.5% 5q12-23 loss, 49.5% 8p22-p23 loss, 45.5% 9p21-p24 loss, 40.5% 18q22-q23 loss, 66% 3q gain, 39% 8q gain, and 16% 11q13 gain. In conclusion, early diagnosis of HNSCC can be achieved by DNA extraction from suspicious lesions in high-risk groups (smokers and alcoholics) and examination of chromosomal aberrations of 3p, 3q, 8q, and 11q13. If there are high percent of chromosomal aberrations in these chromosomes, active intervention should be done (chemoprevention and regular follow-up of head and neck examination for very early detection and management). PMID- 17701418 TI - Vertebral column kyphoscoliosis and unexpected death. AB - A case of spontaneous gastric perforation is reported in a 75-year-old woman due to massive hemorrhaging from a benign gastric ulcer. Blood was prevented from leaving the stomach due to posterior displacement and rotation of the stomach associated with marked underlying vertebral column kyphoscoliosis. Significant deformity of the spine had caused malpositioning of the stomach as a result of the abnormal shape of the peritoneal and chest cavities. This in turn had led to mechanical obstruction and prevented egress of blood arising from a bleeding arteriole in the base of a chronic gastric ulcer. Rapid distension had resulted from the inability to spontaneously decompress the stomach, which in turn had led to rupture. PMID- 17701419 TI - Relationship between self-reported mental stressors at the workplace and salivary cortisol. AB - OBJECTIVE: To investigate the association between work stress measures and salivary cortisol excretion in working and weekend days. METHODS: In a sample of 68 healthy young call-centre operators dimensions of job stress from the demand control model were related to repeated measures of salivary cortisol on seven samples (at awakening, +30 min, +60 min, + 3 h, +6 h, +9 h, and +12 h after awakening) at two working days and a weekend day. RESULTS: The cortisol excretion on work days was higher than during weekend day with gender-specific differences as women only showed higher significant values for area under the curve (AUC(G)) and Diurnal cycle (chi(2) (2) = 8.10, P < 0.05; chi(2) (2) = 15.75, P < 0.05, respectively). There were no associations between job demand, job control and cortisol excretion, while the sociodemographic characteristics of the call-centre operators showed linear relation with the diurnal pattern of cortisol secretory activity. CONCLUSIONS: The hypothalamic-pituitary adrenocortical axis activation was higher in working day than in weekend day. This activation measured by salivary cortisol was not related to self-reported mental stressors assessed with job strain model. The availability of more specific psychometric scales would be useful to explore the relationship between salivary cortisol levels and measures of mental stress at workplace. PMID- 17701420 TI - Associations of job, living conditions and lifestyle with occupational injury in working population: a population-based study. AB - OBJECTIVES: To assess the roles of job demands, living conditions and lifestyle in occupational injury. METHODS: The sample included 2,888 workers, aged > or =15 years, randomly selected from the north-eastern France. The subjects completed a mailed questionnaire. Data were analyzed with adjusted odds ratios (ORa) computed with the logistic model. RESULTS: In total, 9.2% of workers had an injury during the previous 2 years. The high job demands: tasks at height, handling objects, pneumatic tools, other vibrating hand tools, work in adverse climate, physical workload, vibrating platform, machine tools, cold, heat, awkward posture, noise, hammer, and pace had crude odds ratios between 1.81 and 5.25 for injury. A strong exposure-response relationship was found between the cumulated job demands (CJD, defined by their number) and injury: OR 1.88 (95% CI 1.23-2.87) for CJD1, 4.39 (2.98-4.46) for CJD2-3, and 9.93 (6.70-14.7) for CJD > or = 4, versus CJD0. These ORs decreased to 1.68, 3.70, and 7.15 respectively, when adjusted for sex, age, and living conditions/lifestyle confounders; and to 1.54, 2.99, and 5.45 respectively when also adjusted for job category. The following factors had significant ORa: age <30 years (1.54, 1.12-2.12), male (1.64, 1.18-2.30), smoking (1.60, 1.22-2.10), musculoskeletal disorders (1.54, 1.17-2.04), and frequent drug use for fatigue (2.03, 1.17-3.53). The workmen, farmers/craftsmen/tradesmen, and foremen had a 5.7-8.7-fold while the clerks and technicians a 2.7-3.6-fold higher risk compared with upper class. The risk associated with CJD was twofold higher among the workers aged > or =40 or with frequent drug use for fatigue compared with the others. Obesity had ORa 2.05 (1.11-3.78) among the subjects aged > or =40, and excess alcohol use had ORa 2.44 (1.26-4.72) among those free of disease. CONCLUSIONS: This study identified a wide range of job demands and living conditions/lifestyle which predicted injury. Preventive measures should be conducted to reduce job demands and to help workers to be aware of the risk and to improve their living conditions/lifestyle. PMID- 17701422 TI - Stimulatory actions of di-8-butyl-amino-naphthyl-ethylene-pyridinium-propyl sulfonate (di-8-ANEPPS), voltage-sensitive dye, on the BKCa channel in pituitary tumor (GH3) cells. AB - Di-8-ANEPPS (4-{2-[6-(dibutylamino)-2-naphthalenyl]-ethenyl}-1-(3 sulfopropyl)pyridinium inner salt) has been used as a fast-response voltage sensitive styrylpyridinium probe. However, little is known regarding the mechanism of di-8-ANEPPS actions on ion currents. In this study, the effects of this dye on ion currents were investigated in pituitary GH(3) cells. In whole cell configuration, di-8-ANEPPS (10 microM) reversibly increased the amplitude of Ca(2+)-activated K(+) current. In inside-out configuration, di-8-ANEPPS (10 microM) applied to the intracellular surface of the membrane caused no change in single-channel conductance; however, it did enhance the activity of large conductance Ca(2+)-activated K(+) (BK(Ca)) channels with an EC(50) value of 7.5 microM. This compound caused a left shift in the activation curve of BK(Ca) channels with no change in the gating charge of these channels. A decrease in mean closed time of the channels was seen in the presence of this dye. In the cell-attached mode, di-8-ANEPPS applied on the extracellular side of the membrane also activated BK(Ca) channels. However, neither voltage-gated K(+) nor ether-a go-go-related gene (erg)-mediated K(+) currents in GH(3) cells were affected by di-8-APPNES. Under current-clamp configuration, di-8-ANEPPS (10 microM) decreased the firing of action potentials in GH(3) cells. In pancreatic betaTC-6 cells, di 8-APPNES (10 microM) also increased BK(Ca)-channel activity. Taken together, this study suggests that during the exposure to di-8-ANEPPS, the stimulatory effects on BK(Ca) channels could be one of potential mechanisms through which it may affect cell excitability. PMID- 17701421 TI - Effects of a multi-nutrient supplement on exercise performance and hormonal responses to resistance exercise. AB - The purpose of this study was to determine the influence of a comprehensive multi component nutritional supplement on performance, hormonal, and metabolic responses to an acute bout of resistance exercise. Nine healthy subjects ingested either Muscle Fuel (MF) or a matched placebo (PL) for 7 days. Subjects then reported to the laboratory, ingested the corresponding supplement, and performed two consecutive days of heavy resistance exercise testing with associated blood draws. MF supplementation improved vertical jump (VJ) power output and the number of repetitions performed at 80% of one repetition maximum (1RM). Additionally, MF supplementation potentiated growth hormone (GH), testosterone, and insulin-like growth factor-1 responses to exercise. Concentrations of circulating myoglobin and creatine kinase (CK) were attenuated immediately following resistance exercise during the MF trial, indicating that MF partially mediated some form of exercise-induced muscle tissue damage. In summary MF enhanced performance and hormonal responses associated with an acute bout of resistance exercise. These responses indicate that MF supplementation augments the quality of an acute bout of resistance exercise thereby increasing the endocrine signaling and recovery following heavy resistance exercise. PMID- 17701423 TI - Effect of T3 treatment on the response to ischemia-reperfusion of heart preparations from sedentary and trained rats. AB - We investigated whether swim training modifies the effect of T(3) treatment on rat heart response to ischemia-reperfusion. Homogenates of Langendorff preparations perfused for 25 min after 20-min ischemia were used for biochemical determinations and isolation of mitochondrial fractions. Oxidative damage and antioxidant levels of homogenates, O(2) consumption and H(2)O(2) release rates, oxidative damage, and susceptibility to Ca(2+)-induced swelling of mitochondria were determined. During reperfusion, hyperthyroid hearts displayed significant tachycardia and low inotropic recovery. This pattern was improved by training, which also attenuated tissue oxidative damage and glutathione depletion. Similar training effects were shown in euthyroid preparations. Moreover, training reduced mitochondrial H(2)O(2) production and oxidative damage in hyperthyroid and euthyroid hearts and susceptibility to Ca(2+)-induced swelling only in the hyperthyroid ones. Rates of mitochondrial O(2) consumption were not different in sedentary and trained hyperthyroid rats. However, determination of the oxidative capacity suggested that, in the sedentary rats, O(2) consumption was conditioned by oxidative damage mitochondria have suffered, whereas in trained rats, it was due to changes in mitochondrial characteristics. The above results suggest that moderate training is able to reduce hyperthyroid heart susceptibility to oxidative damage and dysfunction modifying mitochondrial population. PMID- 17701424 TI - Muscle transcriptome adaptations with mild eccentric ergometer exercise. AB - The muscle has a wide range of possibilities to adapt its phenotype. Repetitive submaximal concentric exercise (i.e., shortening contractions) mainly leads to adaptations of muscle oxidative metabolism and endurance while eccentric exercise (i.e., lengthening contractions) results in muscle growth and gain of muscle strength. Modified gene expression is believed to mediate these exercise-specific muscle adjustments. In the present study, early alterations of the gene expression signature were monitored by a muscle-specific microarray. Transcript profiling was performed on muscle biopsies of vastus lateralis obtained from six male subjects before and in a 24-h time course after a single bout of mild eccentric ergometer exercise. The eccentric exercise consisted of 15 min of eccentric cycling at 50% of the individual maximal concentric power output leading to muscle soreness (5.9 on a 0-10 visual analogue scale) and limited muscle damage (1.7-fold elevated creatine kinase activity). Muscle impairment was highlighted by a transient reduction in jumping height after the eccentric exercise. On the gene expression level, we observed a general early downregulation of detected transcripts, followed by a slow recovery close to the control values within the first 24 h post exercise. Only very few regulatory factors were increased. This expression signature is different from the signature of a previously published metabolic response after an intensive endurance-type concentric exercise as well as after maximal eccentric exercise. This is the first description of the time course of changes in gene expression as a consequence of a mild eccentric stimulus. PMID- 17701425 TI - 14-3-3 Proteins are components of the transcription complex of the ATEM1 promoter in Arabidopsis. AB - The AtEm1 and AtEm6 gene products accumulate exclusively in embryos during Arabidopsis seed maturation. The transcription factor ABI3 and the phytohormone abscisic acid are required for normal expression of both genes. However, the expression of these genes occurs in extremely small embryos limiting the availability of tissue to directly study DNA-protein interactions. We generated callus lines derived from embryos to determine if the regulation of Em expression was similar to wild type embryos. Expression of AtEm1 and AtEm6 was strongly induced by abscisic acid in callus derived from wild type embryos, but not in embryo callus derived from ABI3 mutant embryos (abi3-6). Epitopes to 14-3-3 proteins were found in complexes with the AtEm1 promoter in mobility shift experiments using nuclear extracts derived from both wild type and abi3-6 calli. Using phosphorylated peptides that bind to 14-3-3 proteins, we show that 14-3-3 proteins are required for the maintenance of the transcriptional complex generated in nuclear extracts. Chromatin immunoprecipitation experiments using a 14-3-3 antibody display the expected 241-bp band from the AtEm1 promoter. Hence, 14-3-3 proteins are physically present in the AtEm1 transcriptional complex in vivo and are required for the maintenance of the transcriptional complex in vitro. PMID- 17701426 TI - Potato steroidal glycoalkaloid levels and the expression of key isoprenoid metabolic genes. AB - The potato steroidal glycoalkaloids (SGA) are toxic secondary metabolites, and their total content in tubers should not exceed 20 mg/100 g fresh weight. The two major SGA in cultivated potato (Solanum tuberosum) are alpha-chaconine and alpha solanine. SGA biosynthetic genes and the genetic factors that control their expression have not yet been determined. In the present study, potato genotypes exhibiting different levels of SGA content showed an association between high SGA levels in their leaves and tubers and high expression of 3-hydroxy-3 methylglutaryl coenzyme A reductase 1 (hmg1) and squalene synthase 1 (pss1), genes of the mevalonic/isoprenoid pathway. Transcripts of other key enzymes of branches of the isoprenoid pathway, vetispiradiene/sesquiterpene synthase (pvs1) and sterol C24-methyltransferase type1 (smt1), were undetectable or exhibited stable expression regardless of SGA content, respectively, suggesting facilitated precursor flow to the SGA biosynthetic branch. The transcript ratio of solanidine glucosyltransferase (sgt2) to solanidine galactosyltransferase (sgt1) was correlated to the documented chaconine-to-solanine ratio in the tested genotypes. Significantly higher expression of hmg1, pss1, smt1, sgt1 and sgt2 was monitored in the tuber phelloderm than in the parenchyma of the tuber's flesh, targeting the former as the main SGA-producing tissue in the tuber, in agreement with the known high SGA content in the layers directly under the tuber skin. PMID- 17701427 TI - Placental site trophoblastic tumor. AB - Placental site trophoblastic tumor (PSTT) is a rare neoplasm that rises from intermediate trophoblasts and commonly presents with low and variable concentration of HCG immunoactivity in serum, which can be difficult to differentiate from early stage choriocarcinoma/gestational trophoblastic neoplasm (GTN) or quiescent gestational trophoblastic disease. PSTT can occur after a normal pregnancy, spontaneous abortion, termination of pregnancy, ectopic or molar pregnancy. There is a wide clinical spectrum of presentation and behavior ranging from a benign condition to an aggressive disease with fatal outcome. Nontrophoblastic malignancies such as germ cell tumors or other tumors secreting low HCG must also be considered in the differential diagnosis. Because treatments for these conditions are different, a means of differentiating PSTT from other diagnoses is important. Surgery is the cornerstone of treatment. Chemotherapeutic regimen should be EMA/CO for first line chemotherapy; EMA/EP should be used in EMA/CO refractory cases. This article reviews the literatures on this rare but fatal disease. PMID- 17701428 TI - Evidence of plasmotomy in Blastocystis hominis. AB - Blastocystis hominis has been regarded as an enigmatic parasite as many aspects of its basic biology remain uncertain. Many reproductive processes have been suggested for the organism; however, to date, only the binary fission has been proven. Plasmotomy is one of the modes of reproduction previously suggested to be seen in in vitro cultures. The present study provides trichrome and acridine orange staining evidence for the existence of nucleic acid suggestive of division of nucleus into multinucleate forms with the respective cytoplasm dividing giving rise to two or three progeny B. hominis. Transmission electron micrographs further confirmed that these daughter cells had respective surrounding surface coat, mitochondria, and vacuoles. PMID- 17701429 TI - Biological and mechanical consequences of transient intervertebral disc bending. AB - Degenerative mechanisms for the intervertebral disc are unclear, particularly those associated with cumulative trauma. This research focuses on how mechanical loading at levels below those known to cause acute trauma can lead to cellular injury. Mouse-tail discs were subjected to static bending for 1 week, then allowed to recover unloaded for 3 weeks and 3 months. Discs were analyzed using histology, in situ hybridization (collagen and aggrecan gene expression), TUNEL assay for apoptotic cell death, and biomechanics. The bent discs demonstrated loss of annular cellularity on the concave (compressed) side, while the nucleus and convex annulus appeared normal. Chondrocyte-like cells were apparent within the inner, concave annulus on the recovered discs, with evidence of proliferation at the annulus/endplate interface. However, annular architecture and biomechanical properties for the recovered discs were not different from controls, suggesting that restoration of physiologic tissue stress prevents the inner annular degradation noted in previous compression-induced degeneration models. These data demonstrate that cellular injury can be induced by transient compressive stress, and that recellularization is slow in this avascular tissue. Taken together, this suggests that cellular damage accumulation may be an important injury mechanism that is distinct from acute mechanical failure. PMID- 17701430 TI - Squamous cell carcinoma of the oral cavity: a case series analysis of clinical presentation and histological grading of 1,425 cases from Iraq. AB - Peoples in Iraq face a mixture of health hazards associated with poverty. Oral cancer is a major public health issue worldwide; it remains a highly lethal and disfiguring disease. It is primarily a disease of epithelial origin. A total of 1,425 cases of histologically diagnosed squamous cell carcinoma collected from the main centers of pathology in Iraq were analyzed according to age, sex, site, patient complaints at the time of presentation, and histological grading. Patients at their fifth decade of life were the most commonly affected with a male-to-female ratio of 2:1. The lower lip was the most commonly affected site followed by the tongue. The most common clinical complain was ulceration and swelling. More than 70% of the cases were well-differentiated squamous cell carcinoma. Oral cancer is increasingly seen as a major health problem-In line with general trend in the region, the need for interprofessional health care delivery approaches for reducing oral cancer mortality and improving patient's quality of life. PMID- 17701431 TI - The anti-cancer effects of quinolone antibiotics? AB - A previous meta-analysis showed that quinolones administered for prophylaxis of infections among cancer patients reduced all-cause mortality. We extracted from the primary trials infection-related and all-cause mortality as reported and assessed the effect of quinolones on non-infection-related mortality through meta analysis. Among trials comparing quinolones to placebo or no treatment, a significant reduction in non-infection-related mortality was observed (relative risk 0.54, 95% confidence interval 0.32-0.93, 15 trials, 3,320 patients). This finding might represent biased attribution of deaths to infection or might be compatible with an anti-cancer effect of quinolone antibiotics. We present further analyses addressing these possibilities. PMID- 17701432 TI - Community-acquired Acinetobacter infections. AB - Acinetobacter infections have been attracting increasing attention during recent years because they have become common in hospitalized patients, especially in the intensive care unit (ICU) setting. However, the available literature suggests that the pathogen has another fearful potential; it can cause community-acquired infections. We searched PubMed and the reference lists of the initially identified articles and identified six case series regarding a total of 80 patients with community-acquired Acinetobacter baumannii infections; from these, 51 had pneumonia and 29 had bacteremia. Of these 80 patients, 45 (56%) died of the infection. In addition, we identified 26 case reports regarding 43 patients with community-acquired Acinetobacter infections; from these, 38 had pneumonia, two had meningitis, one had soft-tissue infection, one had ocular infection, and one had native valve endocarditis. Comorbidity was commonly present in patients reported in the case series as well as the case reports, mainly, chronic obstructive pulmonary disease, renal disease, and diabetes mellitus; heavy smoking and excess alcohol consumption were also common. Most of the studies originated from China, Taiwan, and tropical Australia. We also identified 12 retrospective or prospective studies (seven from the Far East, two from Oceania, one from N. Guinea, one from Palestine, and one from USA/Canada) that reported the frequency of community-acquired Acinetobacter infections; the range of isolation of Acinetobacter from patients with community-acquired pneumonia in these studies was 1.3%-25.9%. In conclusion, most community-acquired Acinetobacter infections have been reported from countries with tropical or subtropical climate, and mainly affect patients with some form of comorbidity or are associated with heavy smoking and excess alcohol consumption. PMID- 17701433 TI - A nonlinear finite element model of cartilage growth. AB - The long range objective of this work is to develop a cartilage growth finite element model (CGFEM), based on the theories of growing mixtures that has the capability to depict the evolution of the anisotropic and inhomogeneous mechanical properties, residual stresses, and nonhomogeneities that are attained by native adult cartilage. The CGFEM developed here simulates isotropic in vitro growth of cartilage with and without mechanical stimulation. To accomplish this analysis a commercial finite element code (ABAQUS) is combined with an external program (MATLAB) to solve an incremental equilibrium boundary value problem representing one increment of growth. This procedure is repeated for as many increments as needed to simulate the desired growth protocol. A case study is presented utilizing a growth law dependent on the magnitude of the diffusive fluid velocity to simulate an in vitro dynamic confined compression loading protocol run for 2 weeks. The results include changes in tissue size and shape, nonhomogeneities that develop in the tissue, as well as the variation that occurs in the tissue constitutive behavior from growth. PMID- 17701434 TI - Bone ingrowth into a porous coated implant predicted by a mechano-regulatory tissue differentiation algorithm. AB - Bone ingrowth into a porous surface is one of the primary methods for fixation of orthopaedic implants. Improved understanding of bone formation and fixation of these devices should improve their performance and longevity. In this study predictions of bone ingrowth into an implant porous coating were investigated using mechano-reculatory models. The mechano-regulatory tissue differentiation algorithm proposed by Lacroix et al., and a modified version that enforces a tissue differentiation pathway by transitioning from differentiation to bone adaptation were investigated. The modified algorithm resulted in nearly the same behavior as the original algorithm when applied to a fracture-healing model. The algorithms were further compared using micromechanical finite element model of a beaded porous scaffold. Predictions of bone and fibrous tissue formation were compared between the two algorithms and to clinically observed phenomena. Under loading conditions corresponding to a press-fit hip stem, the modified algorithm predicted bone ingrowth into approximately 25% of the pore space, which is similar to that reported in experimental studies, while the original algorithm was unstable. When micromotion at the bone-implant interface was simulated, 20 microm of transverse displacement resulted in soft tissue formation at the bone implant interface and minimal bone ingrowth. In contrast, 10 and 5 microm of micromotion resulted in bone filling 40% of the pore space and a stable interface, again consistent with clinical and experimental observations. PMID- 17701435 TI - General paediatric surgery in Ireland: a crisis in evolution. PMID- 17701436 TI - Increase in observed mental health difficulties one year after acute coronary syndrome: general practitioner survey. AB - BACKGROUND: General practitioners (GPs) are often the first to assess mental health difficulties after acute coronary syndrome (ACS). AIMS: To determine whether GPs observed an increase in mental health difficulties one-year post hospitalisation for ACS. METHODS: Postal survey. RESULTS: GPs rated patients (n = 442) as having probable (GP assessed 10%) or definite (formally assessed 7%) mental health difficulties pre-hospitalisation. Post-hospitalisation the prevalence of probable cases increased significantly to 19% (OR = 4.3, 95% CI 2.1 10.2, P < 0.001). In multivariate analysis, only smoking at index hospitalisation was associated with being assessed as a new case of probable/formal mental health difficulties (RR = 2.1, 95% CI 1.3-3.4, P = 0.003). Forty-seven percent of cases were prescribed some medication for this problem. CONCLUSIONS: GPs recorded a significant increase in mental health difficulties in ACS patients 12 months after hospitalisation, with smoking used as an indicator of new cases. PMID- 17701437 TI - Adverse reaction to Bacille-Calmette-Guerin vaccine in a HIV positive healthcare worker. AB - BACKGROUND: The Bacille-Calmette-Guerin (BCG) vaccine is used in Mycobacterium tuberculosis prophylaxis in at risk tuberculin-negative healthcare workers. Its use is contraindicated however in individuals with HIV infection. AIMS: We herein highlight the case of a healthcare worker who developed a localised reaction at a BCG vaccination site and who was subsequently found to be HIV positive. CONCLUSION: This case emphasises the importance of eliciting risk factors for immunocompromise in individuals for whom BCG vaccination is being considered. PMID- 17701438 TI - Pneumobilia following blunt abdominal trauma. AB - BACKGROUND: Pneumobilia is the presence of gas within the biliary tree. It is an important diagnostic sign in spontaneous biliary enteric fistulae, classically in gallstone ileus. There are a number of other causes including surgically created biliary enteric fistula, instrumentation of the bile duct at endoscopic retrograde cholangiopancreatography, emphysematous cholecystitis and pyogenic cholangitis. Pneumobilia has also been reported following blunt abdominal trauma. The significance of isolated pneumobilia following abdominal trauma has not been conclusively established. METHODS: We present a patient with traumatic pneumobilia following blunt trauma to the abdomen which was managed conservatively. CONCLUSION: Pneumobilia following blunt abdominal trauma is not an absolute indication for laparotomy. PMID- 17701439 TI - Computed tomography in the diagnosis of acute appendicitis: definitive or detrimental? AB - OBJECTIVES: Utilization of computed tomography (CT) scans in patients with presumed appendicitis was evaluated at a single institution to determine the sensitivity of this diagnostic test and its effect on clinical outcome. METHODS: Adult patients (age > 17 years) with appendicitis were identified from hospital records. Findings at surgery, including the incidence of perforation, were correlated with imaging results. RESULTS: During a 3-year period, 411 patients underwent appendectomy for presumed acute appendicitis at our institution. Of these patients, 256 (62%) underwent preoperative CT, and the remaining 155 (38%) patients did not have imaging before the surgery. The time interval between arrival in the emergency room to time in the operating room was longer for patients who had preoperative imaging (8.2 +/- 0.3 h) compared to those who did not (5.1 +/- 0.2 h, p < 0.001). Moreover, this possible delay in intervention was associated with a higher rate of appendiceal perforation in the CT group (17 versus 8%, p = 0.017). CONCLUSIONS: Preoperative CT scanning in patients with presumed appendicitis should be used selectively as widespread utilization may adversely affect outcomes. The potential negative impact of CT imaging includes a delay in operative intervention and a potentially higher perforation rate. PMID- 17701440 TI - Acute and sub-lethal toxicity of three POEA surfactant formulations to Daphnia magna. AB - Polyethoxylated tallowamine (POEA) is a non-ionic surfactant used in many herbicide formulations to increase the ability of active ingredients to penetrate leaf cuticles. However, it has also been shown to disrupt respiratory membranes in aquatic organisms. In this study, Daphnia magna was used to examine the lethal and sub-lethal toxicity of three POEA formulations consisting of 5:1, 10:1, and 15:1 average oxide:tallowamine. The formulation consisting of 10:1 was the most acutely toxic with a 48-h LC50 value of 97.0 microg/L and 15:1 was least toxic at 849.4 microg/L. All formulations inhibited growth at concentrations between 100 and 500 microg/L. PMID- 17701441 TI - Expression of the HPV11 E2 gene in transgenic mice does not result in alterations of the phenotypic pattern. AB - The E2 early protein of human papillomaviruses (HPV) has been found associated with the mitotic spindle therefore being implicated in the partition of the replicated viral DNA to daughter cells. In addition, E2 proteins bind to the upstream regulatory region of the virus and to cellular promoters modulating thereby cellular transcription and differentiation. In many cervical cancers, the E2 reading frame is interrupted upon incorporation of the viral genome into the host DNA. This results in the loss of the E2 mediated transcriptional repression and uncontrolled expression of the viral oncogenes. All these results have been obtained in transfected cells but no information is available on the E2 effects in the context of the entire organism. Transgenic mice were generated expressing the E2 protein of HPV11 under the control of the Ubiquitin C promoter. E2 mRNA is present in all mice tissues analysed and the E2 protein expressed in the skin (the target tissue of HPV11) was shown by Western blotting, albeit at a very low level. Analysis of the transgenic mice shows no major histological changes in the skin or all other tissues investigated. These data indicate that in transgenic mice the human papillomavirus type 11 E2 does not grossly modulate cellular proliferation or differentiation events. PMID- 17701442 TI - Derivation and comparison of C57BL/6 embryonic stem cells to a widely used 129 embryonic stem cell line. AB - Typically, embryonic stem (ES) cells derived from 129 mouse substrains are used to generate genetically altered mouse models. Resulting chimeric mice were then usually converted to a C57BL/6 background, which takes at least a year, even in the case of speed congenics. In recent years, embryonic stem cells have been derived from various mouse strains. However, 129 ES cells are still widely used partially due to poor germline transmission of ES cells derived from other strains. Availability of highly germline-competent C57BL/6 ES cells would enormously facilitate generation of genetically altered mice in a pure C57BL/6 genetic background by eliminating backcrossing time, and thus significantly reducing associated costs and efforts. Here, we describe establishment of a C57BL/6 ES cell line (LK1) and compare its efficacy to a widely used 129SvJ ES cell line (GSI-1) in generating germline chimeras. In contrast to earlier studies, our data shows that highly germline-competent C57BL/6 ES cell lines can be derived using a simple approach, and thus support broader use of C57BL/6 ES cell lines for genetically engineered mouse models. PMID- 17701443 TI - LC-MS/MS determination of dibasic amino acids for the diagnosis of cystinuria. Application in a family affected by a novel splice-acceptor site mutation in the SLC7A9 gene. AB - Cystinuria is an autosomal recessive disorder caused by defective transport of cystine and the dibasic amino acids ornithine, lysine and arginine across cell membranes. Poor solubility of cystine in urine leads to kidney stones and associated symptoms and complications. Mutations of genes SLC3A1 and SLC7A9 encoding for amino acid transport systems are responsible for different types of cystinuria. In this study we describe a new LC-MS/MS assay for these amino acids in urine. Moreover, we report a novel splice-acceptor site mutation in the SLC7A9 gene that we believe is the cause of the phenotype observed in four siblings from a first-cousin marriage. Into the wells of a 96-well microtitre plate, 10 microl of urine was mixed with 90 microl of a solution containing [(2)H4]cystine, [(2)H2]ornithine, [(13)C,(2)H4]arginine and [(2)H5]glutamine that was used as an internal standard for lysine. Chromatographic separation was achieved isocratically and detection was in the selected-reaction monitoring mode. The injection-to-injection time was 8 min. Calibration curves were linear up to 1000 micromol/L. Intra-day (n = 10) and inter-day (n = 6) variations (750 and 10 micromol/L) were less than 11.4%. Urine samples from healthy individuals (n = 135) were analysed and age-matched reference ranges were generated. The method was applied retrospectively and prospectively to analyse samples (n = 13) from nine cystinuria patients. The mutation reported here was not found in 100 controls with similar ethnicity to the studied family and is believed to have consequences for the transcribed mature RNA and protein structure and function. PMID- 17701444 TI - Newborn screening: experiences in the Middle East and North Africa. AB - This review presents the current experiences with newborn screening in the Middle East and North Africa region. The population in the region is about 400 million, with high birth rate and an estimated 10 million newborns per year. The majority of the population is of the Islamic faith and mostly Arab. The population is characterized by a high consanguinity (25-70%) and a high percentage of first cousin marriages. Haemoglobin disorders, inherited metabolic disorders, neurogenetic disorders and birth defects are relatively common among the population. There is a rather slow progress in developing and implementing preventive genetic programmes owing to legal, cultural, political and financial issues. Although research spending is rather soft in the region, there are numerous pilot studies that highlighted the high incidence of genetic defects and the need for newborn screening programmes. Currently, there are only four countries that are executing national newborn screening but they vary from one disease to 23 and coverage is not complete. The region needs to take big steps towards developing national strategies for prevention and should learn from experiences of regional and international screening programmes. PMID- 17701445 TI - Assessment of left ventricular function: comparison of cardiac multidetector-row computed tomography with two-dimension standard echocardiography for assessment of left ventricular function. AB - OBJECTIVE: To compare global Left Ventricular (LV) systolic function assessment by 16-detector row Computed Tomography (MDCT) with Two-Dimensional Standard Echocardiography (2DSE) in a routine cardiology practice setting and to ascertain the degree of correlation between LV volumes and measurements obtained by 2DSE with those measured by MDCT. METHODS: In 52 patients with suspected coronary artery disease, a contrast enhanced MDCT study was performed using retrospective gating without dose modulation for better endocardial delineation. Eight phases of the cardiac cycle were analyzed to identify the end-diastolic and end-systolic phases. 2DSE was performed on the same day. Left ventricular systolic and diastolic volumes and ejection fraction were calculated in 4-chamber, 2-chamber and biplane (average of the two) views. Endocardial tracing was used to measure ventricular volumes by area length method for CT and Simpson's method for echocardiography. RESULTS: On MDCT, mean LV ejection fraction (LVEF) in 4 chamber, 2-chamber and biplane views were 58.4 +/- 12, 59.3 +/- 12 and 59.7 +/- 12% respectively. On 2DSE, mean LVEF in 4-chamber, 2-chamber and biplane views were 58 +/- 14, 57 +/- 16 and 58 +/- 13% respectively. LVEF correlated best using the biplane views (r = 0.59 and P < 0.01) compared to 2-chamber (r = 0.57 and P < 0.01) and 4-chamber views (r = 0.32 and P = 0.02). Biplane measurement by these two techniques correlated well for LV volumes in both diastole (r = 0.69 and P < 0.01) and systole (r = 0.73 and P < 0.01), although MDCT consistently gave higher values. CONCLUSIONS: MDCT can be a useful tool to measure LVEF while patients are undergoing CT coronary angiography. PMID- 17701446 TI - Changes in fungi and mycotoxins in pearl millet under controlled storage conditions. AB - Pearl millet is increasingly being grown as a premium-value grain for the recreational wildlife and poultry industries in the southern US. We conducted three experiments to assess grain mold development in storage conditions typically encountered in the region of production. Variables included production year, temperature, relative humidity, atmosphere, and grain moisture content. In the first experiment, grain was stored for 9 weeks at 20 or 25 degrees C and maintained at 86% or 91% relative humidity (r.h.). In the second experiment, grain was stored for 9 weeks at 20 or 25 degrees C in either air (aerobic) or N2 (anaerobic), and maintained at 100% r.h. In the third experiment, high-moisture grain was stored for 3 weeks at 20 or 25 degrees C and maintained at 100% r.h. Grain was sampled at weekly intervals and plated to determine changes in fungal frequency. Fungi isolated included Fusarium chlamydosporum (19% of grain), Curvularia spp. (14%), F. semitectum (16%), Alternaria spp. (9%), Aspergillus flavus (8%), "Helminthosporium"-type spp. (6%), and F. moniliforme sensu lato (3%). Year of grain production significantly affected isolation frequency of fungi. Isolation frequencies from low-moisture grain were rarely affected by temperature, relative humidity, or atmosphere treatments, but was affected by storage duration for some fungi. Changes in isolation of toxigenic fungi occurred in high-moisture grain. Isolation frequency of F. chlamydosporum increased in grain stored at 86% and 91% r.h. Incidence of A. flavus increased in high moisture grain treatments, particularly at 25 degrees C. Incidence of deoxynivalenol was not affected by storage treatment. Low concentrations of nivalenol were detected in most grain incubated at 100% r.h. Zearalenone was detected only when grain moisture content was 20-22%. Aflatoxin contamination averaged 174 ng g(-1) over all treatments, and increased up to 798 ng g(-1) in high-moisture grain at stored at 25 degrees C. PMID- 17701449 TI - Medical humanities and philosophy of medicine. PMID- 17701450 TI - Standards of care in diagnosis and testing for hereditary colon cancer. AB - Inherited colorectal cancer predisposition involves a rather heterogeneous range of rare, yet relatively well-defined disorders, including Familial Adenomatous Polyposis (FAP), Hereditary Non-polyposis Colorectal Cancer (HNPCC) or Lynch syndrome, Peutz-Jeghers syndrome, Juvenile Polyposis, and their respective variants. Due to their individual rarity and highly specialized genetic diagnostic and management demands, patients and families are often seen in tertiary referral centers. For the practitioner encountering a patient suspected of having one of these conditions, guidance is usually necessary. Fortunately, detailed clinical practice guidelines have been promulgated by leading medical specialty societies. Such guidelines, which specifically do include these conditions, have the effect of codifying best or recommended approaches. It is not clear that such guidelines actually codify standards of care. To the extent such guidelines enunciate a standard of care, their impact on the legal process remains largely undefined. Because clinical practice guidelines are readily available to patients and lawyers alike through easily accessible websites, practitioners may expect to be increasingly held accountable for departing from such guidelines. Since the medical-legal implications are evident, we expect these guidelines to impact the management of familial cancer, even in the persistent absence of clear precedents in the medical malpractice arena. This paper undertakes to provide practitioners and academics some perspective on clinical practice guidelines and their potential for medical-legal application. PMID- 17701451 TI - An investigation of genetic counselor experiences in peer group supervision. AB - Peer supervision groups have been studied in counseling fields including psychotherapy and social work. However, limited research exists regarding genetic counselor peer supervision groups. In the present study five major research questions were investigated: (1) How prevalent is peer group supervision among genetic counselors? (2) What motivates genetic counselors to join and continue to seek peer group supervision? (3) What comprises the content, agenda, and structure of group meetings? (4) What are participants' perceptions of group dynamics, including conflicts, cohesion, and leadership? and (5) What are the perceived benefits and limitations of participating in peer group supervision? A total of 214 genetic counselors completed an online survey, and 70 (34.8%) reported being involved currently in peer group supervision. Fifteen of these 70 respondents were interviewed regarding their experiences in peer group supervision. Inductive analysis of their responses yielded 11 domains and 37 categories. Practice implications and research recommendations are discussed. PMID- 17701452 TI - Parental narratives about genetic testing for hearing loss: a one year follow up study. AB - Few studies examine whether and how parental attitudes towards genetic testing change over time. In this study we interviewed parents of 14 children with newly identified hearing loss at two time points: after referral to genetics and 1 year later. Qualitative analyses of parental narratives indicate that parental attitudes did not change significantly over this time. Parents who perceived genetic testing to be useful continued to value it after testing, while parents who did not perceive it as being useful for their child's future held the same view a year later. The only parents who changed their views regarding the usefulness of genetic testing for hearing loss were those who reported that their children underwent significant changes in their hearing loss or were faced with other life threatening conditions. Parents were also often unaware of the role of the genetic counselor and how genetic counseling could help address many of their lingering questions and concerns. These emergent themes indicate the need for geneticists and genetic counselors to be aware of and sensitized to the questions and attitudes that bring parents to a genetic evaluation, as well as the reasons why parents may not follow up with genetic testing for hearing loss when recommended. PMID- 17701453 TI - A struggle to SURVIVE: to abandon or not to abandon levosimendan? PMID- 17701454 TI - Synthesis of a tetra- and a trisaccharide related to an anti-tumor saponin "Julibroside J28" from Albizia julibrissin. AB - Simple and convergent synthesis of a tetra- and a trisaccharide portions of an antitumor compound Julibroside J(28), isolated from Albizia julibrissin, that showed significant in vitro antitumor activity against HeLa, Bel-7402 and PC-3M 1E8 cancer cell lines is reported. The tetrasaccharide has been synthesized as its p-methoxyphenyl glycoside starting from commercially available D-glucose, L rhamnose and L-arabinose. The trisaccharide part has been synthesized from commercially available N-acetyl D-glucosamine, D-fucose and D-xylose using simple protecting group manipulations. Sulfuric acid immobilized on silica has been used successfully as a Bronsted acid catalyst for the crucial glycosylation steps. PMID- 17701455 TI - Development and evaluation of a patient-rated version of the Camberwell Assessment of Need short appraisal schedule (CANSAS-P). AB - The comprehensive assessment of patients with severe mental health problems includes the evaluation of needs, as this informs service planning, and levels of unmet need have been found to be associated with lower subjective quality of life. The Camberwell Assessment of Need is the most widely used instrument for this purpose. We report the development and evaluation of a new, patient-rated, short form (CANSAS-P). The CANSAS-P exhibited comparable detection of needs with its predecessor, better identification of domains that are problematic for patients to respond to, good test-retest reliability, especially for unmet needs, and generally positive evaluations by patients. We recommend the CANSAS-P as the needs assessment measure of choice for completion by patients. PMID- 17701456 TI - TNFalpha-initiated oxidative/nitrative stress mediates cardiomyocyte apoptosis in traumatic animals. AB - Whole body non-penetrating trauma causes myocardial infarction in humans and mechanical trauma (MT) results in cardiac dysfunction in animals. Our recent study demonstrated that incubation of cardiomyocytes with plasma isolated from MT animals causes significant cardiomyocyte apoptosis that can be blocked by neutralization of TNFalpha. The present study attempted to obtain direct in vivo evidence to support that overproduction of TNFalpha plays a causative role in trauma-induced cardiomyocyte apoptosis. Non-lethal MT caused significant TNFalpha overproduction (2.4-fold at 1.5 h after MT) and increased cardiomyocyte apoptosis (starting 3 h and peaking 12 h after MT). Pharmacological inhibition of TNFalpha with etanercept or TNFalpha gene deletion reduced post-trauma myocyte apoptosis (P<0.01). Expression of iNOS and NADPH oxidase, overproduction of NO and O2-, and excessive protein nitration in the MT heart were all significantly reduced in etanercept-treated or TNFalpha-/- mice, suggesting that oxidative/nitrative stress may contribute to TNFalpha-initiated myocyte apoptosis in MT hearts. Additional experiments demonstrated that inhibiting iNOS (1400W) or NADPH oxidase (apocynin), or scavenging peroxynitrite (FP15) significantly reduced myocyte apoptosis in MT animals (P<0.01). Collectively, these data demonstrated that non lethal mechanical trauma caused significant TNFalpha production that in turn stimulated myocardial apoptosis via oxidative/nitrative stress. PMID- 17701465 TI - A primer of amyloid nomenclature. AB - The increasing knowledge of the exact biochemical nature of the localized and systemic amyloid disorders has made a logical and easily understood nomenclature absolutely necessary. Such a nomenclature, biochemically based, has been used for several years but the current literature is still mixed up with many clinical and histochemically based designations from the time when amyloid in general was poorly understood. All amyloid types are today preferably named by their major fibril protein. This makes a simple and rational nomenclature for the increasing number of amyloid disorders known in humans and animals. PMID- 17701457 TI - Neuropsychiatric effects of prescription drug abuse. AB - Prescription drugs have become a major category of abused substances, and there is evidence that the prevalence of prescription drug abuse may soon overtake that of illicit drugs. Study of prescription drugs has been hampered by vague terminology, since prescription drugs are only separated from other drugs of abuse by social and legal constructs. Reviewed herein is published literature on the abuse of four major categories of abused prescription drugs: sedative hypnotics, stimulants, anabolic steroids, and anticholinergics. The review emphasizes evidence regarding the effects of these drugs on neural systems. Other abused prescription drugs that fall outside of the major categories are also briefly addressed. PMID- 17701458 TI - Intimate partner violence and HIV risks: a longitudinal study of men on methadone. AB - Whereas research has suggested that drug-involved men are at disproportionately high risk of engaging in transmission risk behaviors for HIV and of perpetrating intimate partner violence (IPV) against women, only a few cross-sectional studies have examined the relationship between IPV and HIV/sexually transmitted infection (STI) transmission risks among heterosexual, drug-involved men. This study builds on previous cross-sectional research by using a longitudinal design to examine the temporal relationships between perpetration of IPV and different HIV/STI transmission risks among a random sample of 356 men on methadone assessed at baseline (wave 1), 6 months (wave 2), and 12 months (wave 3). The findings indicate that (1) perpetration of IPV in the past 6 months at wave 1 was associated with having more than one intimate partner, buying sex, and sexual coercion at subsequent waves and that (2) non-condom use, injecting drugs, and sexual coercion at wave 1 were associated with subsequent IPV. The temporal relationships between perpetration of IPV and HIV risks found in this study underscore the need for HIV prevention interventions targeting men on methadone to consider IPV and HIV risks as co-occurring problems. PMID- 17701466 TI - Small molecule inhibitors of Abeta assembly. AB - The Abeta peptide assembles into a variety of distinct types of structures in vitro and in the brain which have different biological consequences. Differential effects of inhibitory small molecules suggest that a sequential monomer - oligomer - fibril mechanism is overly simplistic and that soluble toxic oligomers and fibrils can be formed in common or separate pathways depending on the local environment. As a result, the effects of inhibitors are often assay-dependent because multiple pathways are operating. This review discusses strategies for teasing apart the intricate protein-protein interactions that result in Abeta assembly. PMID- 17701467 TI - Structural analyses of fibrinogen amyloid fibrils. AB - Hereditary fibrinogen amyloidosis is characterized by deposition of amyloid fibrils in renal glomeruli. The subunit protein of the amyloid fibrils is a proteolytic fragment of the fibrinogen Aalpha-chain. To investigate the structure of fibrinogen amyloid, fibrils were extracted from the tissues of a patient and studied by X-ray fiber diffraction and electron microscopy. We have carried out a full structural characterization of amyloid fibrils taken from disease tissue. These studies revealed that ex vivo fibrinogen amyloid fibrils have a cross-beta structure similar to other chemical types of amyloid fibrils. PMID- 17701468 TI - Polyanion induced fibril growth enables the development of a reproducible assay in solution for the screening of fibril interfering compounds, and the investigation of the prion nucleation site. AB - The misfolded conformer of the prion protein (PrP) that aggregates into fibrils is believed to be the pathogenic agent in transmissible spongiform encephalopathies. In order to find fibril interfering compounds a screening assay in solution would be the preferred format to approximate more closely to physical conditions and enable the performance of kinetic studies. However, such an assay is hampered by the high irreproducibility because of the stochastic nature of the fibril formation process. According to published fibril models, the fibrillar core may be composed of stacked parallel beta-strands. In these models positive charge repulsion may reduce the chance of favorable stacking and cause the irreproducibility in the fibril formation. This study shows that the charge compensation by polyanions induced a very strong fibril growth which made it possible to develop a highly reproducible fibril interference assay. The stimulating effect of the polyanions depended on the presence of the basic residues Lys(106), Lys(110) and His(111). The assay was validated by comparison of the 50% fibril inhibition levels of peptide huPrP106-126 by six tetracyclic compounds. With this new assay, the fibrillogenic core (GAAAAGAVVG) of peptide huPrP106-126 was determined and for the first time it was possible to test the inhibition potentials of peptide analogues. Also it was found that variants of peptide huPrP106-126 with proline substitutions at positions Ala(115), Ala(120), or Val(122) inhibited the fibril formation of huPrP106-126. PMID- 17701469 TI - Familial amyloidotic polyneuropathy: long-term follow-up of abdominal fat tissue aspirate in patients with and without liver transplantation. AB - To estimate the evolution of amyloid in tissue, we studied abdominal fat aspirates of cases with familial amyloidotic polyneuropathy (FAP) longitudinally at regular intervals between 1994 and 2006. In 22 cases (13 carriers and nine patients) not yet transplanted median follow-up was 3.3 years (range 0.4-11.3). We found a significant increase in the amyloid grade of fat tissue from 2+ to 4+ and from 0 to 4+ in two of three subjects with follow-ups of >7 years, after 7 and 11 years, respectively. All other subjects remained negative or did not show a significant change. In 11 liver transplant patients, follow-up with fat aspirate was available with a median duration of 3.1 years (range 1.0-10.1). A comparison was made with cardiac amyloid as judged by the cardiac septum diameter and the serum NT-ProBNP (N-terminal pro-B-type natriuretic peptide) level. No stable increase of amyloid in fat was seen in any patient. A stable decrease of amyloid grade was seen in one patient 5 years after transplantation. In contrast, the cardiac septum diameter increased >or=4 mm in six of the 11 transplant patients. Our study shows the diagnostic utility of a regularly repeated fat aspirate in carriers at risk for the development of ATTR amyloidosis. Evolution of amyloid deposition in fat tissue is very gradual. After liver transplantation, amyloid deposition in fat tissue seems to stabilize and may even decrease in the long term, whereas amyloid deposition in cardiac tissue appears to be progressive. PMID- 17701470 TI - In vivo stabilization of mutant human transthyretin in transgenic mice. AB - Transthyretin (TTR) is a 55 kD homotetrameric serum protein transporter of retinol binding protein charged with retinol and thyroxine (T4). The highly amyloidogenic human TTR variant in which leucine at position 55 is replaced by proline (L55P TTR) is responsible for aggressive fatal amyloidosis with peripheral and autonomic neuropathy, cardiomyopathy and nephropathy. Mice bearing one or two copies of a 19.2 kB human genomic fragment containing the entire coding sequence and the known control regions of the L55P TTR transgene, failed to develop TTR amyloidosis even though their sera contained mutant human TTR. The frequency of TTR tissue deposition was increased when the L55P TTR transgene was bred onto a murine TTR-null background. Denaturation of sera from the transgenic animals and murine TTR-knockouts expressing the human L55P TTR transgene revealed that the TTR tetramer was much more stable in the presence of the murine protein because the TTR circulates as hybrid human/murine heterotetramers. Intraperitoneal administration of diflunisal, a non-steroidal anti-inflammatory drug that binds to TTR in its T4-binding site and inhibits fibril formation in vitro, to human L55P TTR transgenic animals in which the murine TTR gene had been silenced, also stabilizes the circulating mutant protein to in vitro urea denaturation. PMID- 17701471 TI - Amyloid fibril formation by human stefin B: influence of pH and TFE on fibril growth and morphology. AB - As shown before, human stefin B (cystatin B) populates two partly unfolded species, a native-like state at pH 4.8 and a structured molten globule state at pH 3.3 (high ionic strength), from each of which amyloid fibrils grow. Here, we show that the fibrils obtained at pH 3.3 differ from those at pH 4.8 and that those obtained at pH 3.3 (protofibrils) do not transform readily to mature fibrils. In addition we show that amorphous aggregates are also a source of fibrils. The kinetics of amyloid fibril formation at different trifluoroethanol (TFE) concentrations were measured. TFE accelerates fibril growth at predenaturational concentrations of the alcohol. At concentrations higher than 10%, the fibrillar yield decreases proportionately as the population of an all alpha-helical, denatured form of the protein increases. At an optimum TFE concentration, the lag and the growth phases are observed, similarly to some other amyloidogenic proteins. Morphology of the protein species at the beginning and the end of the reactions was observed using atomic force microscopy and transmission electron microscopy. Final fibril morphologies differ depending on solvent conditions. PMID- 17701472 TI - Severe amyloid deposition in mammary glands of familial amyloid polyneuropathy patients. AB - Clinical pictures of familial amyloid polyneuropathy (FAP) vary considerably, perhaps because of the many gene mutations of transthyretin (TTR), but even in patients having the most common mutation of TTR (the substitution of methionine for valine at position 30 (ATTRVal30Met)), the age of onset ranges from the late 20s to the early 60s. Although genetic anticipation has been considered to play a role in producing this wide range of ages of onset, the precise pathogenesis is incompletely understood. It has been experimentally shown that murine systemic AA and AApoAII amyloidoses can be transmitted by ingestion of amyloid fibrils themselves or amyloid-like pathological agents. In this study, we examined biopsied mammary glands obtained from three female ATTRVal30Met FAP patients who were of gestation age. Amyloid deposition was commonly seen in the glands and, in the two patients with apparent FAP symptoms, heavy deposits of amyloid surrounded many lactiferous alveoli and ducts, where some deposits of amyloid actually faced the central lumens. These findings raise the possibility that milk from FAP mothers contains ATTR-derived amyloid fibrils and/or fragments, which might be causally related to the development of genetic anticipation in this disease. PMID- 17701473 TI - Secondary amyloidosis in a needle phobic intra-venous drug user. AB - A case of acute-on-chronic renal failure is presented that is the sequela of secondary (AA) amyloidosis in a hepatitis positive intravenous drug user (IVDU) with chronic venous ulceration. The importance of groin examination is stressed when upper limb veins in a suspected IVDU are normal. Recent epidemiological data is discussed that suggests geographical location and the subcutaneous (SC) route of drug administration are both contributing factors to the development of AA amyloidosis and not chronic infection with HIV, HBV or HCV. PMID- 17701475 TI - Regulatory T cells--the renaissance of the suppressor T cells. AB - Immune reactions are stringently regulated and balanced by complex interactions of stimulating and suppressing mechanisms. Dysfunctions of this sophisticated immune regulatory network can lead to a variety of diseases such as autoimmunity, allergy, cancer, and pregnancy disorders. The rediscovery of suppressor T cells a decade ago--now designated as T regulatory cells--set off a huge avalanche of research activities leading to a multitude of preclinical and clinical studies. Herein, we give a comprehensive review about this research on T regulatory cells and the relevance of this suppressive T cell population for the development of innovative immune therapeutic strategies. PMID- 17701476 TI - Sirtuins: the 'magnificent seven', function, metabolism and longevity. AB - The sirtuin family of histone deacetylases (HDACs) was named after their homology to the Saccharomyces cerevisiae gene silent information regulator 2 (Sir2). In the yeast, Sir2 has been shown to mediate the effects of calorie restriction on the extension of life span and high levels of Sir2 activity promote longevity. Like their yeast homologs, the mammalian sirtuins (SIRT1-7) are class III HDACs and require NAD(+) as a cofactor to deacetylate substrates ranging from histones to transcriptional regulators. Through this activity, sirtuins are shown to regulate important biological processes ranging from apoptosis, adipocyte and muscle differentiation, and energy expenditure to gluconeogenesis. We review here the current knowledge regarding the role of sirtuins in metabolism, longevity, and discuss the possible therapeutic applications that could result from the understanding of their function in different organs and pathologies. PMID- 17701477 TI - Management of inherited von Willebrand disease in 2007. AB - Von Willebrand disease (VWD) is the most frequent inherited bleeding disorder and is due to quantitative (types 1 and 3) or qualitative (type 2) defects of von Willebrand factor (VWF). VWD is inherited by autosomal dominant or recessive patterns, but women with mild forms are more symptomatic. VWD is classified in six VWD types (1, 2A, 2B, 2M, 2N, 3) with peculiar phenotype and genotype. The ristocetin cofactor activity (VWF:RCo) is the most useful test for VWD diagnosis, because it can mimic the interactions of VWF with its platelet receptor. Knowledge of the segments of VWF involved in the binding to its receptor and to factor VIII prompted the search for mutations in specific exons of the VWF gene, with mutations causing VWD types 2A, 2B, 2M, 2N localized in exons 18-28. In case of VWD types 1 and 3 the mutations are spread within the entire gene. Desmopressin (DDAVP) is the treatment of choice for type 1 VWD because it can induce release of normal VWF from cellular compartments. In type 3 and in severe forms of types 1 and 2 VWD, DDAVP is not effective and plasma virally inactivated VWF concentrates should be used in bleedings, surgery, and secondary long-term prophylaxis. PMID- 17701478 TI - Cytochrome P450--physiological key factor against cholesterol accumulation and the atherosclerotic vascular process. AB - In the early 1960s liver cytochrome P450 (P450) was known as an enzyme in drug metabolism. By the late 1970s, P450 induction was associated with elevation of plasma high-density lipoprotein cholesterol and apolipoprotein AI indicating a reduced risk of atherosclerotic disease. Later on, 57 human P450 genes have been identified. One P450 enzyme participates in cholesterol synthesis, and several others catabolize it to oxysterols and other metabolites. Oxysterols are physiological ligands specific for liver X receptors (LXRs) in the activation of ATP-binding cassette (ABC) transporter and other cholesterol-lowering genes. Elevation of cholesterol leads to an endogenous induction of P450 and consequently to enhanced generation of oxysterols and activation of genes coding proteins which efflux cholesterol out of cells, transport it to the liver, catabolize and excrete cholesterol into bile, and prevent absorption of cholesterol in the intestine in the processes that maintain cellular cholesterol homeostasis and protect arteries from atherosclerosis. Peroxisome proliferator activated receptors (PPARs) co-operate with LXRs and ABC transporters in cholesterol regulation. Secretion of oxysterol is a direct pathway for cellular cholesterol elimination. Several compounds induce P450 and other genes regulating cholesterol balance and prevent or regress atherosclerosis, whereas inhibition of P450 blocks oxidative reactions, promotes cholesterol accumulation, and enhances the atherosclerotic vascular process. PMID- 17701479 TI - Stroke in atrial fibrillation: update on pathophysiology, new antithrombotic therapies, and evolution of procedures and devices. AB - Atrial fibrillation (AF) is said to be an epidemic, affecting 1%-1.5% of the population in the developed world. The clinical significance of AF lies predominantly in a 5-fold increased risk of stroke. Strokes associated with AF are usually more severe and confer increased risk of morbidity, mortality, and poor functional outcome. Despite the advent of promising experimental therapies for selected patients with acute stroke, pharmacological primary prevention remains the best approach to reducing the burden of stroke. New antithrombotic drugs include both parenteral agents (e.g. a long-acting factor Xa inhibitor idraparinux) and oral anticoagulants, such as oral factor Xa inhibitors and direct oral thrombin inhibitors (ximelagatran, dabigatran). Ximelagatran had shown significant potential as a possible replacement to warfarin therapy, but has been withdrawn because of potential liver toxicity. Its congener dabigatran appears to have a better safety profile and has recently entered a phase III randomized clinical trial in AF. Oral factor Xa inhibitors (rivaroxaban, apixaban, YM150) inhibit factor Xa directly, without antithrombin III mediation, and may prove to be more potent and safe. Selective inhibitors of specific coagulation factors involved in the initiation and propagation of the coagulation cascade (factor IXa, factor VIIa, circulating tissue factor) are at an early stage of development. Additional new agents with hypothetical, although not yet proven, anticoagulation benefits include nematode anticoagulant peptide (NAPc2), protein C derivatives, and soluble thrombomodulin. A battery of novel mechanical approaches for the prevention of cardioembolic stroke has recently been evaluated, including various models of percutaneous left atrial appendage occluders which block the connection between the left atrium and the left atrial appendage, minimally invasive surgical isolation of the left atrial appendage, and implantation of the carotid filtering devices which divert large emboli from the internal to the external carotid artery, preventing the embolic material from reaching intracranial circulation. Despite recent advances and promising new approaches, prevention of recurrent AF may be one of the best protections against AF-related stroke and may reduce the prevalence of stroke by almost 25%. Improved pharmacological and nonpharmacological rhythm control strategies for AF as well as primary prevention of AF with 'upstream' therapy and risk factor modification are likely to produce a larger effect on the reduction of stroke rates in the general population than will specific interventions. PMID- 17701480 TI - Residual adverse changes in arterial endothelial function and LDL oxidation after a mild systemic inflammation induced by influenza vaccination. AB - BACKGROUND: Several clinical studies have suggested possible increase in cardiovascular risk during and in the first weeks after an acute inflammatory disease. Using influenza vaccine as inflammatory stimulus, we investigated whether arterial endothelial dysfunction could persist beyond the inflammatory state, and whether amplified oxidative modification of low-density lipoprotein (LDL) accompanies this vascular disturbance. METHODS AND SUBJECTS: The brachial artery responses to hyperemia (flow-mediated dilatation (FMD), and to sublingual glyceryl trinitrate (GTN), and the carotid intima-media thickness were assessed by external ultrasound in eight healthy male volunteers (age 17-30 y) before, and 2 and 14 days after intramuscular administration of influenza vaccine. Plasma levels of high-sensitivity C-reactive protein (CRP), fibrinogen, cyclic guanosine monophosphate (cGMP), and antibodies against oxidized LDL (oxLDL) were measured at each time point. Data are means+/-standard errors of the mean (SEM). RESULTS: Influenza vaccination caused a slight elevation in CRP (from 0.5+/-0.1 at baseline, to 2+/-0.6 mg/L, P = 0.01) and fibrinogen (from 2.3+/-0.1 to 2.7+/-0.1 g/L, P = 0.01) at 2 days, which completely resolved at 14 days (CRP: 0.6+/-0.2 mg/L, P = 0.9, and fibrinogen: 2.3+/-0.1 g/L, P = 0.8 versus baseline). OxLDL antibody levels rose significantly at 2 days (from 1+/-0.1 at baseline to 2+/ 0.4, P = 0.04), and remained elevated at 14 days (1.7+/-0.3, P = 0.1 versus baseline). FMD of the brachial artery decreased at 2 days (from 8.3+/-1.2% at baseline, to 5.4+/-1%, P = 0.05) with a further decrease at 14 days (4.9+/-0.8%, P = 0.03 versus baseline). The dilatory responses to GTN and the carotid IMT remained unchanged throughout the study period (P>0.5). CONCLUSION: Abnormalities in arterial function and LDL oxidation may persist for at least 2 weeks after a slight inflammatory reaction induced by influenza vaccination. These could explain in part the earlier reported increase in cardiovascular risk during the first weeks after an acute inflammatory disorder. PMID- 17701481 TI - Rabbit articular chondrocytes seeded on collagen-chitosan-GAG scaffold for cartilage tissue engineering in vivo. AB - In this study, we prepared a tri-copolymer porous matrices by natural polymer, collagen (Col), Chitosan (Chi) and Chondroitin (CS). Rabbit articular chondrocytes were isolated from the shoulder articular joints of a rabbit, seeded in Col-Chi-CS scaffold, and implanted subcutaneously in the dorsum of athymic nude mice to tissue engineer articular cartilage in vivo. In vitro studies show that Chondrocytes adhered to the scaffold, where they proliferated and secreted extracellular matrices with time, filling the space within the scaffold. The results of hematoxylin and eosin staining scanning electron microscopy revealed that most of the chondrocytes maintained their typically rounded morphology. After 28 days of culture within Col-Chi-CS scaffold in vitro, the results of histological staining showed forming of cartilage-specific morphological appearance and structural characteristics such as lacunae. Subcutaneous implantation studies in nude mice demonstrated that a homogeneous cartilaginous tissue, which was similar to those of natural cartilage, formed when chondrocytes were seeded in Col-Chi-CS matrix after implant 12 weeks. The tri-copolymer matrix could therefore have potential applications as a three-dimensional scaffold for cartilage tissue engineering. PMID- 17701482 TI - Microbial production of 7-amino-cephalosporanic acid and new generation cephalosporins (cephalothin) by different processing strategies. AB - The development of beta-lactam antibiotics has been a continuous battle of the design of new compounds to withstand inactivation by the ever-increasing diversity of beta-lactamases. Semisynthetic cephalosporins like cephalothin were synthesized from 7-amino-cephalosporanic acid (7-ACA), and thiophene-2-acetic acid using cephalosporin-C acylase enzyme was studied. The production of cephalosporin-C acylase by Pseudomonas diminuta was used and the growth kinetics studied. The optimum condition of enzyme activity was determined by using response surface methodology. A 2(3) full-factorial composite design was employed for experimental design and the result analyzed. The pH value and temperature for optimum activity were 6.5 and 32 degrees C, respectively. The structural analog compound similar to the side-chain of semisynthetic cephalosporins, e.g., thiophene-2-acetic acid, was added. HPLC data analysis indicate that the concentration of cephalothin was 1.6 mg/mL. PMID- 17701484 TI - Primary study on transplantation of endothelialized dermal equivalents into normal rats. AB - This study was designed to determine the ability of human umbilical vein endothelial cells (HUVEC) in dermal equivalent (DE) to form microvessel-like tubes after transplantation into normal rats. A mixture of rat fibroblasts and HUVEC was inosculated into collagen-chitosan sponges to prepare endothelialized dermal equivalents (EDE). After culture in vitro for 24 hours, inosculated cells dispersed throughout the sponges and the equivalents were transplanted subcutaneously into the back of normal Lewis rats. Anti-human specific CD31 antibody was used for immunohistochemical localization of human endothelial cells in sections of EDE excised from rats after grafting. HUVEC in EDE organized into microvessel-like tubes at the end of the first week after transplantation, which still persisted after two weeks. The host microvessels began to pervade both DE and EDE during the second week after transplantation. These results demonstrated that HUVEC in EDE was able to persist and form microvessel-like tubes after transplantation into normal rats, and this is the first time to transplant DE containing HUVEC into normal rats. PMID- 17701483 TI - Impact of orally administered microcapsules on gastrointestinal microbial flora: in-vitro investigation using computer controlled dynamic human gastrointestinal model. AB - Oral administration of artificial cell microcapsules has been proposed for various therapy procedures using biologically active materials. Recently we have designed novel APPPA microcapsules using alginate, poly-L-lysine, pectin, poly-L lysine and alginate that have shown superior oral delivery features. This article investigates, in-vitro using a computer controlled dynamic gastrointestinal (GI) model, effects of APPPA microcapsules on health of gastrointestinal (GI) microbial flora. The impact of APPPA microcapsules on GI bacterial population, total anaerobes, total aerobes, Escherichia coli, Lactobacillus sp. and Staphylococcus sp. has been analyzed. In addition, the effects of microcapsules on GI microbial extracellular enzymatic activities have been investigated. Result shows the altered activities of microbial flora and enzymes due to the use of APPPA microcapsule. The most disparity is observed in the colon ascendans microbial activities. This study would have significant impact on future microcapsule design. However, further in-vivo studies are required. PMID- 17701485 TI - Encapsulation of PEG-urease/PEG-AlaDH within sheep erythrocytes and determination of the system's activity in lowering blood levels of urea in animal models. AB - Urease and AlaDH enzymes immobilized on active PEG derivatives were encapsulated at different ratios within sheep erythrocytes and their activity, encapsulation yields and erythrocyte recovery levels were assessed. Encapsulated derivatives were administered at given dosages and at given intervals to sheep having raised blood urea levels as a result of addition of urea to their feed, and the lowering of their blood urea levels and the change in the amount of ammonia were followed. Results were analyzed using day related NPar. Wilcoxon Signet Ranks test. It was found that 1 ml of PEG-enzyme preparation comprising PEG-urease/PEG-AlaDH at an activity ratio of 3/9 U:U/ml remained active for a period of 2 days, whereas 1 ml erythrocyte preparation, prepared under the same conditions and containing PEG urease/PEG-AlaDH at an activity ratio of 2.15/4.5 U:U/ml, showed activity for a period of 6 days. It was shown that a single dose achieved a daily decrease of 21.7-61.6 mg/L in the blood urea level, and created no significant increase in the blood ammonia levels. No antigenic effect was observed for the PEG-enzyme preparations in the immunological test carried out. PMID- 17701486 TI - Single neural progenitor cells derived from EGFP expressing mice is useful after spinal cord injury in mice. AB - Neural stem cells (NSCs) were widely used for studying the cell's replacement after transplantation in nervous system because of its specific characteristics. However, Stracing the cells after transplantation was still a problem. In the present study, we isolated and cultured the neural stem cells from the C57BL/6J EGFP transgenic mouse (EGFP mice), and identified the capacity for self-renewal and differentiation into the three CNS lineages (neurons, astrocytes, and oligodendrocytes). Then we transplanted the single neural stem cell into the lesion spinal cord. Expression of GFP and differentiation was evaluated at two weeks post-transplantation. The data showed that these neural stem cells derived from the EGFP mice could maintain transgene expression and could differentiate into the MAP2 positive cells after transplantation into the injured spinal cord. The results suggested that NSC expressing EGFP was a useful marker for tracing the cells after transplantation in vivo and functional in the treatment to spinal cord injury. PMID- 17701487 TI - Assay of levodopa in brain by CE. AB - This article reports a CE (capillary electrophoresis) method for the determination of Levodopa (L-DP) in rabbit brain tissue. L-DP was separated and determined on a fused quartz capillary (75 microm ID, 75 cm length, 50 cm effective length, Beckman Co.) with a mobile phase of phosphate buffer (pH = 2.5, 20 mmol/L THAM, 3% carboxymethyl-beta-cyclodextrin), sample pressure 0.6 kPa x 6 s, separation voltage 20 KV, detected at 280 nm and temperature 25 degrees C. The calibration curve was linear (r = 0.9999, n = 6) within the range of 0.5-16 microg/ml for L-DP. The recovery ratio was 87.87%. The mean relative standard deviation (RSD) was 2.73% (n = 5). This method is convenient, rapid, accurate, and brings about good recovery; it can be used for content determination of levodopa in rabbit brain tissue. PMID- 17701488 TI - Lactose biosensor based on lactase and galactose oxidase immobilized in polyvinyl formal. AB - A lactose biosensor was developed by immobilizing lactase and galactose oxidase in a polyvinyl formal membrane and was attached to the oxygen electrode of a dissolved oxygen analyzer for estimation of lactose in milk and food products. The enzyme immobilized polyvinyl formal membrane was characterized by atomic force microscopy. The biosensor showed the linearity for 1-7 g dl(-1) of lactose and can be reused for up to 20 measurements. The effects of pH, temperature and the stability of the immobilized lactase and galactose oxidase in PVF membrane were also studied. The enzyme membrane was found stable up to 35 degrees C and had a shelf-life of more than three months at 4 degrees C. PMID- 17701489 TI - Stroma-free hemoglobin from bovine blood. AB - Isolation and purification of bovine hemoglobin (HbBv) was carried out after reaction of whole blood with carbon monoxide. Washing/centrifugation steps were used to eliminate leukocytes, platelets, and plasma proteins. Hypotonic media and ultrasound radiation were used to lyse red blood cells. Lyse by ultrasound was shown to lead to solutions at the highest concentrations in HbBv, and the least concentrations in major phospholipids contaminants. Additional purification procedures were performed to remove membrane proteins and phospholipids. In the first case, proteins were denatured by thermal treatment, and filtered. To eliminate phospholipids, liquid chromatography was used with strong anion exchangers. Purity of HbBv was evaluated by normal phase high performance liquid chromatography (HPLC), electrophoresis, and size-exclusion HPLC. PMID- 17701490 TI - E. coli K-12 asparaginase-based asparagine biosensor for leukemia. AB - The present work aims at the development of a novel, diagnostic biosensor for monitoring asparagine levels in leukemia. Various immobilization strategies have been applied to improve the stability of the biocomponent (asparaginase). Response time studies have been carried out for different immobilization methods. Phenol Red indicator has been coimmobilized with asparaginase and color visualization approach has been optimized for various asparagine ranges. The detection limit of asparagine achieved with nitrocellulose membrane is 10(-1) M, with silicon gel is 10(-10)-10(-1) M, and with calcium alginate beads is 10(-9) 10(-1) M. Furthermore, the calcium alginate bead system of immobilization has been applied for the asparagine range detection in normal and leukemia serum samples. PMID- 17701491 TI - Alginate beads encapsulation matrix for urease and polyethyleneglycol-urease. AB - Urease was immobilized activated PEG-5000 and encapsulated urease and PEG modified urease within alginate beads. Encapsulated urease and PEG-urease were thoroughly characterized for pH, temperature and stabilities and these properties were compared with free and PEG modified enzyme. A 34 and 57% mass and 19.3 and 43% activity yield of urease and PEG-urease resulted following encapsulation. The average diameter for the beads was found to be 2.5 mm for urease bead and 1.8 mm for PEG-urease bead. The stabilities of PEG-urease beads at pH 6.0 were higher than those of urease beads. PEG-urease beads retained 70% of initial activity after reusing seven times at pH 6.0. Also time dependency of substrate conversion was determined for enzyme beads. PMID- 17701492 TI - Effect of nutrient dilution on feed intake, eating time and performance of hens in early lay. AB - 1. An experiment with 480 ISA Brown layers was conducted to measure the effect of dietary energy (11.8, 11.2 and 10.6 MJ/kg) and non-starch polysaccharides (NSP) (128, 146 and 207 g/kg) concentration, soluble NSP content (64 and 85 g/kg), particle size distribution of the NSP fraction (fine and coarse) and feed form (mash and crumble) on feed intake, eating time and egg performance of laying hens in early lay (from 18 to 26 weeks of age). Twelve experimental diets were tested, each replicated 4 times. 2. Laying hens in early lay that were fed low- or high NSP diets were able to compensate for 10% dietary dilution by 9.5 and 4.9% higher feed intakes, respectively. Feeding crumble or coarsely ground mash did not affect feed intake. 3. Eating time of the hens fed the undiluted diets increased over the experimental period from 16.4 to 24.6% of the observation period, but was not affected by sand or grit addition, particle size distribution or feed form. Feeding high-NSP diets increased eating time by 22%. 4. Egg performance and body weight gain of the hens that were fed low-NSP or high-NSP diets were similar or better compared to the undiluted diets, whereas coarse grinding of the diets showed 7 to 10% lower egg performance and weight gain. Egg performance and weight gain were not affected by feed form. 5. It is concluded that hens in early lay, fed energy-diluted diets, by adding sand or grit (low-NSP) or NSP-rich raw materials (high-NSP) to the control diet, were able to increase their feed intake, resulting in energy intake and egg performance comparable to the control group. Supplementing diets with insoluble NSP also decreased eating rate. Prolonged eating time using insoluble NSP could be useful in reducing feather pecking behaviour. PMID- 17701493 TI - Ammonia emissions from broiler litter: response to bedding materials and acidifiers. AB - 1. In a pen study, NH(3) flux estimates were performed when clean wheat straw or wood shavings were used as bedding materials in combination with two NH(3) control amendments: sodium bisulphate and a commercial premix of phosphoric + hydrochloric + citric acids. 2. Ammonia emissions from wood shavings were 19% greater than from wheat straw around waterers, but statistically similar around feeders. These results could be due to the greater caking observed when wheat straw was used. 3. Sodium bisulphate reduced NH(3) emissions significantly only in the first half of the rearing period; the loss of efficacy in the second half resulted in total NH(3) volatilisation not statistically different from the untreated control. The treatment containing phosphoric + hydrochloric + citric acids did not have a significant effect in decreasing NH(3) emissions. 4. Bird mortality was not affected by the treatments, but broiler weight gain when wheat straw was used was significantly lower than with wood shavings, which could have been caused by the greater caking observed with wheat straw. PMID- 17701494 TI - Controlled atmosphere stunning of broiler chickens. I. Effects on behaviour, physiology and meat quality in a pilot scale system at a processing plant. AB - 1. The effects of controlled atmosphere stunning on the behaviour, physiology and carcase and meat quality of broiler chickens were studied experimentally in a pilot scale plant. 2. Gas mixtures tested were: single phase anoxic mixture (90% Ar in air, <2% O(2)); single phase hypercapnic anoxic mixture (60% Ar, 30% CO(2) in air, <2% O(2)); and biphasic hypercapnic hyperoxygenation mixture (anaesthetic phase, 40% CO(2), 30% O(2), 30% N(2); euthanasia phase, 80% CO(2), 5% O(2), 15% N(2)). 3. Anoxic stunning resulted in the least respiratory disruption, mandibulation and motionlessness, but most head shaking, leg paddling and twitching. Loss of posture occurred soonest with hypercapnic anoxia with the earliest and most twitching and wing flapping in individuals and earliest leg paddling. Biphasic birds were most alert, exhibited most respiratory disruption and mandibulation, and had the latest loss of posture and fewest, but longest bouts of wing flapping and least leg paddling and twitching. 4. Significant and sudden bradycardia and arrhythmia were evident with all gas mixtures and were not related solely to anoxia or hypercapnia. Birds stunned by Ar anoxia showed a slightly more gradual decline from baseline rates, compared with hypercapnic mixtures. 5. Few differences were found between gas mixes in terms of carcase and meat quality. Initial bleeding rate was slowest in biphasic-stunned birds, but total blood loss was not affected. Acceleration of post-mortem metabolism in anoxic-stunned birds was not sufficient to allow de-boning within 5 h without the risk of tough meat. 6. On welfare grounds and taking into account other laboratory and field studies, a biphasic method (using consecutive phases of anaesthesia and euthanasia) of controlled atmosphere stunning of broilers is potentially more humane than anoxic or hypercapnic anoxic methods using argon or nitrogen. PMID- 17701495 TI - Illuminance and UV-A exposure during rearing affects egg production in broiler breeders transferred to open-sided adult housing. AB - 1. Broiler breeders were reared in light-proof accommodation on 8-h photoperiods at an illuminance of 10 (W10), 40 (W40) or 100 lux (W100) from warm-white fluorescent lamps, or 10 lux (UV10) from Arcadia bird lamps (white light plus UV A emission). At 20 weeks, 200 birds from each group were transferred to open sided housing and a 16-h mixture of natural and warm-white fluorescent light. 2. Mortality during rearing and body weight at 20 weeks were similar for all groups. 3. The W10 birds matured 2 d later, had inferior rates of lay over peak production and laid 9 fewer eggs to 60 weeks than the other groups. Mean egg weight, extra large egg production and mortality between 20 and 60 weeks were unaffected by lighting during the rearing period. The UV10 birds had a significantly better rate of lay between 52 and 60 weeks than any of the groups reared on white light. 4. The findings suggest that ultraviolet radiation does not directly affect hypothalamic activity, but that retinally received UV during the rearing period prolongs the laying cycle through a modification of the hormonal control of photorefractoriness. PMID- 17701496 TI - Controlled atmosphere stunning of broiler chickens. II. Effects on behaviour, physiology and meat quality in a commercial processing plant. AB - 1. The effects of controlled atmosphere stunning on behavioural and physiological responses, and carcase and meat quality of broiler chickens were studied experimentally in a full scale processing plant. 2. The gas mixtures tested were a single phase hypercapnic anoxic mixture of 60% Ar and 30% CO(2) in air with <2% O(2), and a biphasic hypercapnic hyperoxygenation mixture, comprising an anaesthetic phase, 40% CO(2), 30% O(2), 30% N(2), followed by an euthanasia phase, 80% CO(2), 5% O(2), 15% N(2). 3. Birds stunned with Ar + CO(2) were more often observed to flap their wings earlier, jump, paddle their legs, twitch and lie dorsally (rather than ventrally) than those stunned with CO(2) + O(2). These behaviours indicate a more agitated response with more severe convulsions during hypercapnic anoxia, thereby introducing greater potential for injury. 4. Heart rate during the first 100 s of gas stunning was similar for both gases, after which it remained constant at approximately 230 beats/min for CO(2) + O(2) birds whereas it declined gently for Ar + CO(2) birds. 5. In terms of carcase and meat quality, there appeared to be clear advantages to the processor in using CO(2) + O(2) rather than Ar + CO(2) to stun broiler chickens, for example, a much smaller number of fractured wings (1.6 vs. 6.8%) with fewer haemorrhages of the fillet. 6. This study supports the conclusions of both laboratory and pilot scale experiments that controlled atmosphere stunning of broiler chickens based upon a biphasic hypercapnic hyperoxygenation approach has advantages, in terms of welfare and carcase and meat quality, over a single phase hypercapnic anoxic approach employing 60% Ar and 30% CO(2) in air with <2% O(2). PMID- 17701497 TI - Heritabilities and genetic correlations of economic traits in Iranian native fowl and estimated genetic trend and inbreeding coefficients. AB - 1. Genetic parameters were estimated in a base population of a closed experimental strain of fowl. Data were obtained on 21 245 Iranian native hens (breeding centre for Fars province) subject to 8 successive generations of selection. This population had been selected for body weight at 12 weeks of age (BW12) and egg number during the first 12 weeks of the laying period (EN), mean egg weight (EW) at weeks 28, 30 and 32, and age at sexual maturity (ASM). 2. The method of multi-traits restricted maximum likelihood with an animal model was used to estimate genetic parameters. Resulting heritabilities for BW12, EN, EW and ASM were 0.68 +/- 0.02, 0.40 +/- 0.02, 0.64 +/- 0.02 and 0.49 +/- 0.02, respectively. 3. Genetic correlations between BW12 and EN, EW and ASM were 0.11 +/- 0.33, 0.54 +/- 0.21 and -0.12 +/- 0.03, respectively. Genetic correlations between EN and EW and ASM were -0.09 +/- 0.03 and -0.85 +/- 0.01, respectively, while between EW and ASM, it was 0.05 +/- 0.03. 4. The overall predicted genetic gains, after 7 generations of selection, estimated by the regression coefficients of the breeding value on generation number were equal to 22.7, 0.17, 0.04 and 1.38, for BW12, EN, EW and ASM, respectively. 5. A pedigree file of 21 245 female and male birds was used to calculate inbreeding coefficients and their influence on production and reproduction traits. Average inbreeding coefficients for all birds, inbred birds, female birds and male birds were 0.048, 0.673, 0.055 and 0.047%, respectively. Regression coefficients of BW12, ASM, EN and EW on inbreeding coefficient for all birds were equal to 0.51 +/- 0.001, 0.31 +/- 0.003, -0.51 +/- 0.003 and 0.03 +/- 0.001, respectively. PMID- 17701498 TI - Antioxidant effects of the water-soluble fraction of baked sponge cake made with silky fowl egg: comparison with White Leghorn egg. AB - 1. The antioxidant effects of the water-soluble fraction of baked sponge cakes made with silky fowl eggs and White Leghorn eggs were studied. The mechanism of the antioxidant effect was also investigated. 2. The antioxidant effect on the oxidation of linoleic acid increased in the water-soluble fraction of cake made with silky eggs. In contrast, Leghorn eggs significantly decreased the rate of antioxidant activity. The browning index of the water-soluble fraction of baked sponge cake made with silky fowl eggs changed from 0.052 to 1.240 after 20 min at 180 degrees C, while that made with Leghorn eggs changed from 0.037 to 0.710. 3. There are correlations between the rate of browning index and antioxidant activity. Superoxide anion (O2(-)) and hydrogen peroxide (H(2)O(2)) in water soluble fractions of baked sponge cakes made with silky fowl eggs and hen's eggs were formed during light exposure for 20 min at 10,000 lux, and their formation could be significantly inhibited by the addition of tryptophan or mannitol, scavengers of hydroxyl radicals (*OH). These results were strong evidence of direct participation of *OH, formed by the Haber-Weiss reaction, in the water soluble fraction of baked sponge cakes. The rate of decrease in active oxygen by scavengers decreased in Leghorn eggs more efficiently than in silky eggs. 4. The present experiments suggested that the use of silky fowl eggs could improve the quality and oxidative stability of baked cakes. PMID- 17701499 TI - Effect of feeding silages or carrots as supplements to laying hens on production performance, nutrient digestibility, gut structure, gut microflora and feather pecking behaviour. AB - 1. An experiment was carried out to examine the suitability of using maize silage, barley-pea silage and carrots as foraging materials for egg-laying hens. Production performance, nutrient digestibility, gastrointestinal characteristics, including the composition of the intestinal microflora as well as feather pecking behaviour were the outcome variables. 2. The protein content of the foraging material (g/kg DM) was on average 69 g in carrots, 94 g in maize silage and 125 g in barley-pea silage. The starch content was highest in the maize silage (312 g/kg DM), and the content of non-starch polysaccharides (NSP) varied from 196 to 390 g/kg, being lowest in carrots. Sugars were just traceable in the silages, whereas carrots contained on average 496 g/kg DM. 3. Egg production was highest in hens fed either carrots or maize silage, whereas hens fed barley-pea silage produced less (219 vs. 208). Although the consumption of foraging material was high (33, 35 and 48% of the total feed intake on 'as fed' basis for maize silage, barley-pea silage and carrots, respectively) only a minor effect on nitrogen corrected apparent metabolisable energy (AME(n)) and apparent digestibility was seen. At 53 weeks of age, hens fed maize silage had AME(n) and apparent digestibility values close to the control group (12.61 and 12.82, respectively), whereas access to barley-pea silage and carrots resulted in slightly lower values (12.36 and 12.42, respectively). Mortality was reduced dramatically in the three groups given supplements (0.5 to 2.5%) compared to the control group (15.2%). 4. Hens receiving silage had greater relative gizzard weights than the control or carrot-fed groups. At 53 weeks of age, the gizzard-content pH of hens receiving silage was about 0.7 to 0.9 units lower than that of the control or carrot-fed hens. Hens fed both types of silage had higher concentrations of lactic acid (15.6 vs. 3.2 micromoles/g) and acetic acid (3.6 vs. 6.1 micromoles/g) in the gizzard contents than the other two groups. The dietary supplements had a minor effect on the composition of the intestinal microflora of the hens. 5. Access to all three types of supplements decreased damaging pecking in general (to feathers as well as skin/cloaca), reduced severe feather pecking behaviour and improved the quality of the plumage at 54 weeks of age. 6. In conclusion, access to different types of foraging material such as silages and carrots improved animal welfare. PMID- 17701500 TI - Effects of citric acid and microbial phytase on amino acid digestibility in broiler chickens. AB - 1. Two experiments with growing chickens were carried out to study the effects of the inclusion of a microbial phytase (Natuphos 5000) and citric acid (CA) in maize-soybean-based diets on the performance and apparent ileal digestibility (AID) of crude protein (CP) and amino acids (AA). In both experiments the diets were formulated to contain the same amounts of energy and protein. 2. In the first experiment, data were analysed as a 2 x 2 factorial arrangement with two concentrations of available phosphorus (AP) from one day to 3 weeks of age (3.5 and 2.2 g/kg) and for 3 to 6 weeks (2.7 and 1.4 g/kg), and two inclusions of commercial phytase (0 and 500 FTU/kg) in each period. The AID of CP and dispensable and indispensable AA were not modified by the AP content of the diet. Addition of phytase improved the AID of CP and dispensable and indispensable AA only at low AP levels. 3. In the second experiment, data were analysed as a 3 x 2 factorial arrangement with three concentrations of citric acid (0, 20 and 50 g/kg) and two inclusions of commercial phytase (0 and 750 FTU/kg). Diets were formulated with deficient contents of AP (2.5 g/kg). Performance was not affected by commercial phytase addition. The addition of CA reduced the weight gain but did not modify the feed intake and gain:feed. In general, the AID of CP and dispensable and indispensable AA were not affected by CA addition. Commercial phytase increased the apparent ileal digestibility of crude protein but had no effect on AID of dispensable and indispensable AA. 4. In conclusion, the present work showed that microbial phytase enhanced AA digestibility in maize-soy-based diet only at very low AP concentrations, and that CA had no affect on the AID of CP and dispensable and indispensable AA. No synergism between CA and microbial phytase was detected. PMID- 17701501 TI - The effects of xylanase supplementation on growth, digestion, circulating hormone and metabolite levels, immunity and gut microflora in cockerels fed on wheat based diets. AB - 1. The xylanase product used in this study was derived from a genetically modified isolate of Aspergillus niger. Two trials were conducted to investigate the effects of xylanase supplementation on growth, digestion, circulating hormone and metabolite levels, immune parameters and composition of the gut microflora in cockerels fed on wheat-based diets. 2. The experimental diets consisted of a wheat-based control diet supplemented with 0 or 0.1% enzyme preparation. The diets were fed between 7 and 21 d of age. 3. Enzyme supplementation improved growth and feed conversion efficiency. The addition of enzyme to wheat-based diet increased the apparent total digestibility of dry matter (DM), crude protein and fat. 4. Enzyme supplementation reduced the relative weight of digestive organs to a certain extent, but there was no significant difference. Enzyme supplementation reduced digesta viscosity in the jejunum. There was no significant difference between the two experimental groups in counts of lactobacillus and coliform bacteria in the caeca. 5. Enzyme supplementation increased the concentration of blood thyroxine (T(4)), insulin-like growth factor I (IGF-I) and insulin, reduced the concentrations of blood uric acid, but had no significant effect on the concentrations of blood glucose and triiodothyronine (T(3)). 6. Enzyme supplementation increased the relative weight of spleen of cockerels, serum antibody titres to Newcastle disease virus (NDV), lymphocyte proliferation in response to phytohaemagglutinin (PHA) and the natural killer (NK) cell activity. 7. It is concluded that supplementation with an enzyme preparation (xylanase), which hydrolyses non-starch polysaccharides can improve growth in cockerels fed on wheat-based diets. This improvement is achieved through enzyme effects on digestion, absorption, metabolism and immunity of cockerels. PMID- 17701502 TI - Influence of dietary tannic acid and polyethylene glycol on growth and intestinal D-xylose absorption of broiler cockerels and activity of serum enzymes. AB - 1. In an experiment on broiler cockerels, the influence of tannic acid (TA) and polyethylene glycol (PEG) on body weight gain (BWG), feed conversion ratio (FCR), weight of intestine and liver, the activities of serum enzymes LDH, AST, ALT and intestinal absorption function were investigated. 2. Broiler cockerels were given either a commercial diet alone (control group) or a commercial diet with TA (20 g/kg), PEG (10 g/kg) or TA plus PEG (20 + 10 g/kg), for 10 d. 3. On the last day of the experiment, all birds and remaining feed were weighed individually and a sample of blood was taken to measure the serum activities of lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The capacity of intestinal cells for the absorption of D xylose was measured. Finally all birds were killed humanely and the intestine and liver were weighed. 4. The results showed that TA significantly reduced BWG and FCR, as well as the activity of LDH, AST and ALT. 5. TA also increased the relative weight of the intestine. Adding PEG alone had no effect on any of the measured parameters. 6. However, PEG improved significantly BWG, FCR and the activity of LDH and AST of TA-fed birds. 7. The plasma D-xylose concentration of experimental birds was similar for all dietary treatments most likely because of temporal separation between feeding the dietary TA and administering the D xylose. 8. It was concluded that the presence of tannins in the GI lumen of the bird was necessary to affect the processes involved in the absorption of simple sugars such as D-xylose, at the level of intestinal absorptive cells. PMID- 17701503 TI - The effect of herbs and their associated essential oils on performance, dietary digestibility and gut microflora in chickens from 7 to 28 days of age. AB - 1. The effect of the dietary inclusion of 5 culinary herbs or their essential oils on the growth, digestibility and intestinal microflora status in female broiler chicks was assessed. From 7 to 28 d of age, either a basal control diet without supplement was given or one of 10 others, consisting of the basal diet with either 10 g/kg herb (thyme, oregano, marjoram, rosemary or yarrow) or 1 g/kg of essential oil. 2. Body mass (BM) and feed consumption (AFC) were measured on a weekly basis and used to calculate chick performance. Total viable counts of lactic acid bacteria, coliforms, anaerobes and Clostridium perfringens were determined at 25 d. Apparent nutrient digestibilities were calculated from the measured values for gross energy, nitrogen (N), dry matter (DM) and organic matter, and sialic acid concentration was also measured. 3. Generally, dietary thyme oil or yarrow herb inclusion had the most positive effects on chick performance, while oregano herb and yarrow oil were the poorest supplements. Only thyme and yarrow in these diets had a different effect when used as a herb or oil on weight gain and BM. 4. Dietary treatment had no effect on the intestinal microflora populations, apparent metabolisable energy (AME) or the calculated coefficients of digestibility. Sialic acid concentration was greatest in the birds given dietary thyme oil, compared with all other treatments except those birds receiving marjoram oil, rosemary herb and the controls. However, less sialic acid was excreted in those birds given diets with oregano or rosemary oils, or oregano herb, than in the controls. 5. Plant extracts in diets may therefore affect chick performance, gut health and endogenous secretions, although the chemical composition of the extract appears to be important in obtaining the optimal effects. PMID- 17701504 TI - Evaluation of an intestinal Lactobacillus reuteri strain expressing rumen fungal xylanase as a probiotic for broiler chickens fed on a wheat-based diet. AB - 1. This study was conducted to evaluate the feasibility of using a transformed Lactobacillus reuteri Pg4 strain harbouring a rumen fungal xylanase gene as a probiotic supplement in a wheat-based poultry diet. 2. A total of 400 broiler chicks was allocated to two treatment groups with or without supplementation with 10(6) colony forming units (cfu)/g of transformed L. reuteri Pg4 in a wheat-based regimen to investigate the performance, intestinal microflora populations, digesta viscosity and excreta ammonia concentrations in these broiler chickens. 3. Supplementation of the wheat-based diet with transformed L. reuteri Pg4 decreased intestinal viscosity, caecal coliform population, and increased body weight gain and ileal villus height and crypt depth from 0 to 21 d of age. It also decreased excreta ammonia concentrations, and increased the caecal total volatile fatty acid (VFA) and lactic acid concentrations from 0 to 21 d and 22 to 37 d of age. 4. Further, it was demonstrated that 40% of the Lactobacillus cells randomly isolated from the digesta of the ileum and caecum of the supplemented group possessed xylanase secretion capability. 5. It appears reasonable to assume, therefore, that the derived benefit is a result of the organism surviving, and the associated performance of some function in the intestinal tract which benefits gut health. PMID- 17701505 TI - Alkaline phosphatase reactivity in the vagina and uterovaginal junction sperm storage tubules of turkeys in egg production: implications for sperm storage. AB - 1. Currently there remains contradictory information on the localisation and possible role of alkaline phosphatase (AP) in the chicken and Japanese quail oviducts. 2. Using turkeys with a hard-shelled egg in their uteri, vaginal and uterovaginal junction mucosae were stretched and fixed as whole mounts prior to the histochemical localisation of AP activity. 3. Scattered AP reactive cells were observed in the vaginal and uterovaginal junction surface epithelia and intense AP reactivity of the sperm-storage tubule (SST) epithelium, localised to its apical border. 4. We suggest that such AP reactivity in hens in egg production may reflect cell differentiation and proliferation in the vagina and SST and possibly a mechanism for the transfer of lipid from the SST epithelia to resident sperm. PMID- 17701506 TI - Sexual difference in ascorbic acid synthesis, tissue ascorbic acid and plasma total antioxidant capacity in mature chickens. AB - 1. An experiment was conducted with commercial White Leghorn type chickens to determine the effect of gender on tissue ascorbic acid concentration, antioxidant capacity and ascorbic acid synthesis. 2. Birds reared and maintained on litter were given a standard layer diet, without supplemental ascorbic acid, from 18 weeks of age. Tissue ascorbic acid concentration, plasma total antioxidant capacity and renal L-gulonolactone oxidase activity were measured at 30 weeks of age. 3. Females and males differed in ascorbic acid synthesis, as measured by renal L-gulonolactone oxidase activity, and tissue ascorbic acid concentration. 4. Plasma total antioxidant capacity and adrenal, gonadal, plasma and pituitary ascorbic acid concentrations were significantly higher in males, whereas ascorbic acid synthesis and splenic and thymic ascorbic acid concentrations were significantly higher in females. 5. L-Gulonolactone oxidase activity was not detected in the comb of cockerels. PMID- 17701507 TI - Publication bias in addiction research. PMID- 17701508 TI - A case study of publication bias in an influential series of reviews of drug education. AB - There has been remarkably little demonstration of the deleterious impact of publication bias within addiction science or indeed in wider healthcare policy and practice. An account is provided here of how publication bias was identified in relation to a series of drug education reviews which have been very influential on subsequent research, policy and practice. Later data analyses unpublished by the same review team demonstrated earlier findings to be unreliable. These later findings were not published. The policy context in which evidence on drug education in schools is produced is considered and the need for unbiased evidence is emphasised. A broadened conception of publication bias is proposed which takes account of the environment in which publication decision making occurs. It is suggested that this is particularly necessary for subjects with such direct policy relevance as the effectiveness of drug education in schools. PMID- 17701509 TI - Fluid skills: drinking games and alcohol consumption among Australian university students. AB - The objective of this study was to assess participation in drinking games among Australian university students; to determine the range of games played, their context and participant motivations; and to analyse the impact of games on alcohol consumption and its adverse consequences. We used a cross-sectional survey incorporating structured interviews and a self-administered questionnaire with students between 18 and 25 years of age at the University of Western Australia. This was a qualitative assessment of drinking game typology and contexts and participant motivation. Quantitative outcomes were rate and frequency of participation in drinking games; amount and rate of alcohol consumption during games; incidence of adverse outcomes following participation. Twenty-seven interview responses and 256 questionnaire responses were analysed for qualitative and quantitative outcomes, respectively. The qualitative analysis enabled categorisation of drinking games by skill and competitive nature, with varying influence on hazardous drinking. Common reported motivations for play included boredom, social pressure and social unease. The associated heavy drinking and possible hazards were well recognised but did not affect the decision to play. In the quantitative arm, most drinkers (74%) reported having participated in a drinking game. Game players reported playing an average of four drinking games in the previous 6 months. An average of six standard drinks was consumed during the most recent game. Pressure to participate from others was reported by 60% of game participants, while 50% reported that they had placed pressure on others to participate. Half (51%) reported an adverse outcome following participation. Loss of consciousness due to drinking was experienced or witnessed by 89% of game players, of whom 63% reported that the person was put to bed, while 54% reported that the person was watched. Participation in drinking games was common, and plays an important social role in this group. Drinking games were associated commonly with binge drinking and adverse outcomes. Future harm minimisation strategies targeting this group should address the particular risks of these games. PMID- 17701510 TI - Non-advertising alcohol promotions in licensed premises: does the Code of Practice ensure responsible promotion of alcohol? AB - INTRODUCTION AND AIMS: Binge drinking is a major public health issue in Australia, particularly among young people. There has been a considerable focus on alcohol advertising, among both researchers and policy makers, resulting in efforts to bring about some level of regulation of unacceptable advertising practices. However - despite the existence of a Code of Practice for Responsible Promotion of Liquor Products which provides 'a framework of practices which are considered acceptable and reasonable' for licensed premises - there are few, if any, data on the nature and extent of promotions which could arguably fall under either 'acceptable' or 'unacceptable' practices. DESIGN AND METHODS: Over an 8 week period we monitored promotions offered by licensed venues (pubs, bars and clubs) in the Wollongong central area. Seventeen venues were identified, and each venue was visited daily for 1 week. Trained research assistants took notes on all promotions/events in visited venues, including both manufacturer- and management initiated. RESULTS: We identified a range of different types of promotions, including low cost and free drinks. Some of the promotions identified could be seen to have a positive public health impact, such as free food and free transport. However, the majority of promotions were of a nature likely to increase the likelihood of excessive drinking. DISCUSSION AND CONCLUSIONS: It is evident from this review that there are numerous examples of promotions which breach both the spirit and the letter of the Code. It is equally evident that the system for monitoring compliance with the Code is fundamentally inadequate. PMID- 17701511 TI - Using population data to examine the prevalence and correlates of neonatal abstinence syndrome. AB - The objective of this study was to determine the population prevalence and correlates of neonatal abstinence syndrome among neonates born to women on methadone, using a cross-sectional analysis of linked population health data. A total of 2941 live births to women actively on methadone at delivery were analysed over an 11-year period (1992 - 2002). Of these births, 796 neonates (27%) were diagnosed with an International Classification of Diseases - 9CM (ICD 9CM) or International Classification of Diseases ICD - 10AM (ICD-10AM) diagnosis related to neonatal withdrawal from exposure to opiates in utero (NAS). There were significant differences found between mothers whose neonates did and did not receive an International Classification of Diseases NAS-related diagnosis. Mothers of neonates with a NAS-related diagnosis had a higher number of previous pregnancies, were more likely to be indigenous, to smoke more heavily and were more likely to present for delivery unbooked. Neonates diagnosed with NAS were admitted to Special Care Nursery more often. NAS is diagnosed less frequently using International Classification of Diseases (ICD) codes than when using clinical scales measuring opiate-related neonatal withdrawal. This suggests that NAS may be under-represented in hospital morbidity databases that use ICD codes to quantify patient throughput and in some circumstances this may result from under-detection of the condition. Future research should therefore seek to determine the validity of NAS recording in hospital morbidity databases reliant on the use ICD codes. PMID- 17701512 TI - Patterns of alcohol intake of pregnant and lactating women in Perth, Australia. AB - INTRODUCTION AND AIMS: Australian alcohol consumption data for women during the period of pregnancy and lactation is limited. The purpose of this paper is to provide current alcohol consumption data for pregnant and lactating women in Perth, Western Australia (WA). Data were collected from 587 women between mid September 2002 and mid-July 2003. DESIGN AND METHODS: Women from two public hospitals with maternity wards in the Perth metropolitan area completed a self administered baseline questionnaire while in hospital or shortly after discharge. All women, regardless of their chosen infant feeding method, were followed-up by telephone interview at 4, 10, 16, 22, 32, 40 and 52 weeks postpartum. Data were analysed to determine alcohol use patterns of the women during the period of pregnancy and lactation and results were compared to national guidelines for alcohol consumption. RESULTS: Approximately 32% of women stopped drinking alcohol during pregnancy. A remaining 35% of pregnant women consumed alcohol during pregnancy, with 82.2% of these women consuming up to two standard drinks per week. At 4, 6 and 12 months postpartum, 46.7%, 47.4% and 42.3% of breastfeeding women were consuming alcohol, respectively. DISCUSSION AND CONCLUSIONS: The majority of breastfeeding women consumed up to two standard drinks per week, which is within levels recommended by national authorities. There is, however, a small proportion of women consuming alcohol at levels above national recommendations for pregnancy and lactation. The development of 'safe' alcohol intake practices, within national recommendations, during the postnatal period would remove any potential health risks to the infant from alcohol exposure at this vulnerable growth stage. PMID- 17701513 TI - Attitudes and beliefs towards methadone maintenance treatment among Australian prison health staff. AB - INTRODUCTION AND AIMS: Justice Health NSW has one of the most extensive prison based methadone programmes in the world. We examine prison health staff attitudes towards methadone treatment and compare these with community methadone staff. DESIGN AND METHODS: A cross-sectional survey of 202 staff employed by Justice Health New South Wales was undertaken in 2003. Results. The mean scores on the various sub-scales were: abstinence-orientation (AO) 2.9 (95% CI 2.8 - 3.0); disapproval of drug use (DDU) 3.3 (95% CI 3.2 - 3.4); knowledge (Know) 2.7 (95% CI 2.4 - 2.9); and toxicity 4.6 (95% CI 4.2 - 5.0). Both the AO and DDU score were correlated negatively with the Know score (r = -0.37 and r = -0.13, respectively). Prison health staff had higher AO (2.9 vs. 2.6, p < 0.001) and DDU (3.3 vs. 2.6, p < 0.001) scores, and lower Know (2.7 vs. 7.0, p < 0.001) scores than methadone staff working in the Australian community. They were more knowledgeable than US community methadone staff about the toxicity of methadone (4.6 vs. 0.0, p < 0.001). DISCUSSION AND CONCLUSIONS: This is the first survey to examine prison health staff attitudes to methadone treatment. Correctional health staff tend to be more abstinence-orientated, more likely to disapprove of drug use, and less knowledgeable about the risks and benefits of methadone than Australian community methadone staff. The findings have important implications for training health staff working in the prison environment with regard to client retention on methadone treatment. PMID- 17701514 TI - Feasibility and acceptability of a mental health screening tool and training programme in the youth alcohol and other drug (AOD) sector. AB - The high prevalence of co-occurring mental health and substance use disorders in young people is well established. Despite this, there are low rates of detection of co-occurring disorders across alcohol and other drug (AOD) services within Australia. This paper describes the development, implementation and evaluation of a mental health screening tool and training programme within the youth AOD sector. Thirty youth AOD workers received training in mental health screening, and the screening tool was subsequently piloted on 84 young people accessing two youth AOD services. Training was evaluated using measures of the trainee's mental health knowledge, attitudes, skills and confidence in mental health screening at baseline and 12-month follow-up. Feedback from young people supported the feasibility, acceptability and relevance of the screening tool. Evaluation of the associated training programme indicated improvements in AOD workers' mental health knowledge, skills and confidence in mental health screening. These findings provide preliminary evidence of the feasibility and acceptability of the mental health screening tool to young people and the effectiveness of the training package within the youth AOD sector. PMID- 17701515 TI - Feasibility and outcomes of an innovative cognitive-behavioural skill training programme for co-occurring disorders in the youth alcohol and other drug (AOD) sector. AB - There are limited treatment options available for young drug users with comorbid mental health problems who present to alcohol and other drug (AOD) services within Australia. While there is some evidence for the use of cognitive-behaviour therapy (CBT) in the treatment of co-occurring disorders, CBT is rarely used to address comorbidity in the AOD sector. This paper describes the development, implementation and evaluation of a brief cognitive-behavioural skills (BCBS) training programme for addressing comorbidity within two youth AOD services in Australia. Ten youth AOD workers completed a 2-day training programme in the BCBS. Training was evaluated using measures of trainees' cognitive-behavioural knowledge, attitudes towards mental health interventions and level of skills and confidence in each of the BCBS pre- and 6 months post-training. The BCBS training had a positive impact on the knowledge, skills and confidence of trainees and was perceived to be highly relevant and appropriate. These findings provide preliminary support for the feasibility and effectiveness of the BCBS training programme for workers within the youth AOD sector. PMID- 17701516 TI - Alcohol consumption of Australian women: results from the Australian Longitudinal Study on Women's Health. AB - INTRODUCTION AND AIMS: Alcohol misuse is responsible for extensive personal harm and high societal costs. Research related specifically to women's alcohol consumption is important due to gender differences in clinical outcomes and disease progression. DESIGN AND METHODS: This study examines longitudinal changes in the patterns of alcohol consumption associated with harm in the long term (chronic) and short term (acute) as defined by the Australian National Health and Medical Research Council. Results are presented for three age cohorts (18 - 23 years, 45 - 50 years and 70 - 75 years) using data from the Australian Longitudinal Study on Women's Health 1996 - 2003. Initial response rates for the study were 41%, 54% and 36% for the Younger, Mid-aged and Older cohort, respectively. RESULTS: The percentages of women that initiated usual weekly consumption in excess of 140 g of alcohol, designated as long-term risky or high risk consumption, between surveys 1 and 2 were 2.7%, 2.1% and 1.7% (Younger, Mid aged and Older cohorts, respectively). Similarly, between surveys 1 and 2, 7.8% of younger women and 2.5% of mid-aged women initiated consumption of 50 g of alcohol on one occasion at least weekly, placing them at risk of alcohol-related harm in the short-term weekly. Examining data across the three time-points in the Younger cohort, 0.3% of women were at risk of alcohol-related harm in the long term across all three time-points, and 9.2% were at risk at one or two time points. The percentage of younger women at risk of alcohol-related harm in the short term at least weekly was 3.4% at risk at all three time-points and 24% at risk at one or two time-points. DISCUSSION AND CONCLUSIONS: This study indicates that there is a small percentage of women who maintain levels of alcohol consumption associated with increased risk of morbidity and mortality over time, but a much larger proportion of women that drink at hazardous levels sporadically during the life course. Prevention efforts may need to target transient high-risk alcohol consumers differently than consistently heavy alcohol consumers. Non response bias and attrition may have caused the prevalence of both entrenched and episodic heavy consumption to be underestimated. PMID- 17701517 TI - Contemporary cocaine use patterns and associated harms in Melbourne and Sydney, Australia. AB - The aim of this paper was to explore the nature of cocaine use and harms through a cross-sectional survey of cocaine users interviewed in the two largest Australian cities of Sydney (n = 88) and Melbourne (n = 77) between October 2004 and January 2005. The study supported previous findings that Australian cocaine users could be classified broadly into two types. The majority of cocaine users interviewed were classified as socially and economically integrated. They were young, employed, well-educated people who generally snorted cocaine on a recreational basis, typically in conjunction with other illicit and licit drugs. A second group of socially and economically marginalised users, residing mainly in Sydney, injected cocaine often in conjunction with heroin. This group reported significantly higher levels of cocaine use, cocaine dependence, criminal behaviour and human immunodeficiency virus (HIV) risk-taking behaviour. Heroin use was found to predict independently higher levels of cocaine use, criminal behaviour, needle sharing and physical problems in this sample, suggesting that increased resources and coverage for combined heroin/cocaine users may have scope for reducing cocaine-related problems in the Australian community. PMID- 17701518 TI - Drink a little; take a few drugs: do nurses have knowledge to identify and manage in-patients at risk of drugs and alcohol? AB - INTRODUCTION AND AIMS: The widespread use of alcohol and other drugs poses particular problems during hospitalisation. Although nurses have been identified as an appropriate group to screen patients and provide acute and ongoing management to people with drug and alcohol-related problems, rates of screening are low. The aims of this study were to identify current practices for screening by nurses working in medical and surgical wards, determine their knowledge relating to problems associated with substance use and identify their self reported skills in managing patients with drug- and alcohol-related problems. DESIGN AND METHODS: A chart audit of medical records was completed and a survey was distributed to nurses working in the study wards. RESULTS: Screening for alcohol and drug use was documented on only 22/79 medical records, and detailed information about quantity and duration of use was recorded in only nine. Overall, the nurses reported that they had little knowledge about substance use problems, and felt that they lacked skills to care adequately for these patients. DISCUSSION AND CONCLUSIONS: The results of this study suggest a need for a comprehensive training and education to ensure that nurses are familiar with policies and protocols for management of patients and to assist nurses to provide evidence-based care and make appropriate referrals to specialist services. PMID- 17701519 TI - Applied communitarian ethics for harm reduction: promoting a dialogue within the field. AB - This piece responds to critical points raised in commentaries on our 2005 HRD paper on the topic of harm reduction ethics, and clarifies other aspects of our original arguments that were misinterpreted. In our view, the goal of ethical engagement in harm reduction is not necessarily the production of an agreed moral framework, but instead reflection and awareness raising around the various values and beliefs underlying harm reduction, and consideration of how these influence policy, practice and research decisions and outcomes. This 'discursive authenticity' as Hathaway has called it, can help to define a new territory of authority for drug users as participants in harm reduction policy, practice and research. PMID- 17701520 TI - Changing the density of alcohol outlets to reduce alcohol-related problems. AB - Increasingly, it seems, legal and political debates regarding the granting of new liquor licences are turning to the issue of whether the number and density of alcohol outlets makes a difference in rates of alcohol consumption and alcohol related harm. But what is the state of the evidence on this question? In this Harm Reduction Digest Livingston, Chikritzhs and Room review the research literature on the effects of density of alcohol sales outlets on alcohol consumption and alcohol-related problems; suggest a new way of conceptualising the relationships; and discuss the implications for reducing alcohol-related harm. PMID- 17701522 TI - Multivesicular liposomes bearing celecoxib-beta-cyclodextrin complex for transdermal delivery. AB - In our work depot delivery systems of celecoxib were developed using multivesicular liposomes. Moreover, the solubility of celecoxib was enhanced by complexing drug with cyclodextrin to overcome the limitation of conventional therapy. The multivesicular liposomes (MVLs) bearing celecoxib-beta -cyclodextrin inclusion complex were prepared by reverse phase evaporation method, and multilamellar vesicles (MLVs)-bearing drug complex was prepared by the cast film method. The formulations were characterized for vesicle size, encapsulation efficiency, and in vitro drug release. In vivo performance of multivesicular liposomes bearing celecoxib-beta -cyclodextrin inclusion complex was evaluated by assessing anti-inflammatory activity using carrageenan-induced rat paw edema volume method. The results were compared with that of celecoxib-cyclodextrin complex and MLVs containing celecoxib-beta -cyclodextrin inclusion complex in equal amounts. Phase solubility studies for the celecoxib-beta -cyclodextrin inclusion complex clearly indicated an increase in aqueous solubility of celecoxib with an increase in beta -CD concentration. The in vitro release studies reveal that MLVs release more than 80% drug within 48 hr whereas MVL formulations release nearly the same amount of drug in 120 hr. In vivo data reveal that reduction in paw volume with MVL formulation was not rapid and fast, but the effect was maintained for prolonged periods, and even after 24 hr there was 40.7 +/- 3.40% reduction in paw volume. MVL formulation showed more sustained and prolonged anti-inflammatory effect compared with plain drug and MLVs. We concluded that multivesicular liposome can be successfully utilized for the sustained delivery of celecoxib. PMID- 17701523 TI - Evaluation of mesoporous TCPSi, MCM-41, SBA-15, and TUD-1 materials as API carriers for oral drug delivery. AB - The feasibility of four mesoporous materials composed of biocompatible Si (TCPSi) or SiO(2) (MCM-41, SBA-15, and TUD-1) were evaluated for oral drug delivery applications. The main focus was to study the effect of the materials different pore systems (unidirectional/2D/3D) and their pore diameters, pore size distributions, pore volumes on the maximal drug load capacity, and release profiles of a loaded active pharmaceutical ingredient. Ibuprofen was used as the model drug. The total pore volume of the mesoporous solid was the main factor limiting the maximum drug load capacity, with SBA-15 reaching a very high drug load of 1:1 in weight due to its high pore volume. Dissolution experiments were performed in HBSS buffers of pH 5.5, 6.8, and 7.4 to mimic the conditions in the small intestine. At pH 5.5 the dissolution rate of ibuprofen released from the mesoporous carriers was significantly faster compared with the standard bulk ibuprofen (86-63% versus 25% released at 45 min), with the fastest release observed from the 3D pore network of TUD-1 carrier. The utilization of mesoporous carriers diminished the pH dependency of ibuprofen dissolution (pK(a) = 4.42), providing an interesting prospect for the formulation of poorly soluble drug compounds. PMID- 17701524 TI - Gatifloxacin biodegradable implant for treatment of experimental osteomyelitis: in vitro and in vivo evaluation. AB - Osteomyelitis is an inflammatory bone disease caused by pyogenic bacteria. The advantages of localized biodegradable therapy for osteomyelitis include high local antibiotic concentration at the site of infection and obviation of the need for removal of the implant after treatment. The purpose of this study was to develop and evaluate a biodegradable implantable delivery system containing gatifloxacin (GAT) for the localized treatment of osteomyelitis, experimentally induced by methicillin resistant Staphylococcus aureus (MRSA). Implants, prepared by solvent casting technique, showed reasonable tensile strength. DSC examination indicated that GAT is present in an amorphous form in the implant. The in vitro release of GAT showed a profile characterized by an initial burst followed by a second stage of gradual delivery over 27 days. The in vivo release study revealed that GAT concentrations achieved during the first 3 weeks after implantation exceeded the MIC of GAT against MRSA by > 100,000 times. Bacterial tibial bone count performed in rabbits tibia 2 and 4 weeks after implantation of GAT implant in infected bone indicated complete eradication of infection in all treated rabbits as indicated by the significant decrease in bacterial count. The results show that the proposed implant may have a promising role in the therapeutic approach to osteomyelitis. PMID- 17701525 TI - In vivo selection and validation of liver-specific ligands using a new T7 phage peptide display system. AB - In vivo phage display is a powerful source of new peptide ligands for specific organ targeting by drugs and gene therapy vectors. Since the introduction of this methodology a decade ago, a number of peptides that preferentially react with organ-specific endothelium and parenchymal markers have been selected. One organ that has been conspicuously missing from these selection studies is the liver, which possesses a multitude of acquired and hereditary disorders and represents a highly important therapeutic target. Herein, we set out to fill this gap by introducing a novel peptide display system containing cloned sequences in the tail fiber protein (p17) of phage T7. The p17 display effectively avoids the innate immune system and is well suited both for selection of new liver-specific ligands and for validation of protein sequences that have been implicated in liver targeting by the use of conventional biochemical methods. PMID- 17701526 TI - Effect of conditions of preparation on the size and encapsulation properties of PLGA-mPEG nanoparticles of cisplatin. AB - The effect of conditions of preparation on the size and encapsulation properties of PLGA-mPEG nanoparticles of cisplatin was investigated. A modified double emulsion method was applied for the preparation of PLGAmPEG nanoparticles of cisplatin, based on the partial or complete replacement of the water of the inner aqueous phase of the emulsion by dimethyl formamide(dmf) or the addition of cisplatin in the form of a complex with poly(glutamic acid). These modifications resulted in significant improvement of cisplatin loading in the PLGA-mPEG nanoparticles. Increased cisplatin loading and encapsulation efficiency were obtained when a relatively low dmf/water ratio, low dmf volume (when pure dmf formed the inner polar phase), or a high drug/polymer ratio were applied. A reduction of average size of nanoparticles was observed with decreasing the amount of PLGA-mPEG added in the formulation or increasing sonication time. The only factor that had a significant effect on size distribution was the sonication time, with the size P.I. being decreased with increasing sonication time. Prolonged sonication, however, decreased cisplatin loading and encapsulation efficiency. From the four lyoprotectant sugars tested (glucose, lactose, mannitol, and trehalose), only mannitol could prevent nanoparticle aggregation upon lyophilization. When appropriate amounts of an effective lyoprotectant were added in nanoparticles before lyophilization, drug loading of the nanoparticles was not affected by nanoparticle lyophilization. PMID- 17701527 TI - Preparation and characterization of solid lipid nanoparticles containing silibinin. AB - The study describes the development of stealth solid lipid nanoparticles (SLNs) as colloidal carriers for silibinin, a drug with very low solubility. Stealth SLNs were constituted mainly of bioacceptable and biodegradable lipids, such as stearic acid and surfactant Brij 78 (polyoxyethylene 20 stearyl ether) and can incorporate amounts of silibinin up to 7.55%. Stealth-loaded SLNs were in the nanometer size range. Thermal analysis (differential scanning calorimetry) showed that silibinin was dispersed in the stealth SLNs at an amorphous state. Release of silibinin from stealth SLNs was very slow. Stealth SLNs were stable without precipitation of silibinin on storage conditions and can be proposed for their parenteral administration. PMID- 17701528 TI - A comparative permeation/release study of different testosterone gel formulations. AB - The major indication for testosterone (T) treatment is male hypogonadism that is characterized by low serum T concentrations. Although a recently developed hydroalcoholic gel, Androgel, containing 1% T addresses many of the problems associated with the more conventional formulations, the bioavailability of T is only 10% requiring 5 to 10 g of gel to be applied daily. The present study was performed to investigate the effect of isopropyl alcohol (IPA) content as a penetration enhancer based on its ability to prevent skin dryness and in turn to increase T permeation from hydroalcoholic gels. Five different hydroalcoholic gel formulations, containing 1% T and carbopol as the gel-forming polymer, were formulated by varying the amount of IPA. The release of T from each gel, including Androgel, was studied in vitro on Franz diffusion cells using cellulose ester and Celgard 2400 as synthetic membranes and hairless guinea pig skin as a natural membrane. The amount of drug released from the gels was analyzed using an HPLC-UV method. The results of release/permeation studies on guinea pig skin showed that all the gels were similar to Androgel, indicating that the addition of IPA does not affect the release of T from hydroalcoholic gels. Although no statistical significant difference was seen, the release profiles of the gels showed a trend of increasing release of T with increasing concentration of IPA. Thus, IPA does have a potential to increase the bioavailability of T from hydroalcoholic gels. PMID- 17701529 TI - Synthesis, characterization, and evaluation of phosphated cross-linked konjac glucomannan hydrogels for colon-targeted drug delivery. AB - Hydrogel systems of konjac glucomannan (KGM) cross-linked with trisodium trimetaphosphate (STMP) were prepared for colon-targeting drug delivery. Swelling degrees of the hydrogels were measured in artificial gastrointestinal fluids and in sodium chloride solution with different concentrations to study their dependence on the cross-linking density and the ionic strength. The absorption of methylene blue was used to characterize the degree of the KGM cross-linking. In vitro release of model drug hydrocortisone was studied in presence and absence of beta -mannanase. KGM cross-linked with STMP was able to retard the release of the poorly water-soluble drug and could be biodegraded enzymatically. Hydrocortisone release was cross-linking density dependent and controlled by degradation of the hydrogles. PMID- 17701533 TI - Benefits of superficial hyperthermia treatment planning: five case studies. AB - PURPOSE: To demonstrate the benefits of treatment planning in superficial hyperthermia. MATERIALS AND METHODS: Five patient cases are presented, in which treatment planning was applied to troubleshoot treatment-limiting hotspots, to select the optimum applicator type and orientation, to assess the risk associated with metallic implants, to assess the feasibility of heating a deeper seated tumour, and to analyse the effective SAR coverage resulting from arrays of multiple incoherent applicators. FDTD simulation tools were used to investigate treatment options, either based on segmented or simplified anatomies. RESULTS: The background, approach and model implementation are presented per case. SAR cross-sections, profiles and isosurfaces are visualized to predict the effective SAR coverage of the target and the location of the maximum power absorption. In addition, the followed treatment strategy and the implications for the clinical treatment are given: for example, higher temperatures, relief of treatment limiting hot-spots or increased power input. CONCLUSIONS: Treatment planning in superficial hyperthermia can be applied to improve clinical routine. Its application supports the selection of the optimum technique in non-standard cases, leading to direct benefits for the patient. In addition, treatment planning has shown to be an excellent tool for education and training for hyperthermia technicians and physicians. PMID- 17701534 TI - Laboratory and clinical basis for hyperthermia as a component of intracavitary chemotherapy. AB - Intraoperative chemotherapy with heat has been identified as a treatment option for patients with cancer spread to peritoneal surfaces. This treatment modality is viewed as a supplement to several other treatments for this group of patients including cytoreductive surgery, systemic chemotherapy, early postoperative intraperitoneal chemotherapy, and long-term bidirectional chemotherapy. The pharmacologic basis for using heat to supplement chemotherapy effects are related to the increased penetration of chemotherapy into tumor with hyperthermia, the delayed clearance of chemotherapy from the peritoneal cavity after direct instillation, and an increased cytotoxicity that has been documented with selected chemotherapy agents. Data to support the use of perioperative hyperthermic intraperitoneal chemotherapy with mucinous appendiceal carcinomatosis comes from a large number of single institution phase II studies. Also, peritoneal and pleural mesothelioma are benefited. In colon cancer carcinomatosis, large phase II multi-institutional trials and a single phase III trial documented an increased median survival of these patients from approximately 1 year to over 2 years. Prophylaxis against peritoneal carcinomatosis in gastric cancer has been demonstrated in phase III trials. In ovarian cancer the rationale for this treatment remains large but its current application is limited. Much work needs to be done to identify a proper clinical perspective on hyperthermia used with chemotherapy in patients with peritoneal surface malignancy. PMID- 17701536 TI - Conformal radiotherapy plus local hyperthermia in patients affected by locally advanced high risk prostate cancer: preliminary results of a prospective phase II study. AB - PURPOSE: Hyperthermia has been used in several trials to treat pelvic cancers without excessive toxicity and with positive results. The aim of this study was to evaluate feasibility and results in terms of biochemical recurrence-free, disease-free survival, overall survival, and treatment toxicity profile of hyperthermia combined with radiotherapy in locally advanced high risk prostate cancer. PATIENTS AND METHODS: From November 1998 to December 2004, 144 patients with locally advanced prostate cancer (LAPC) were enrolled in a phase II study. They were treated using conformal radiotherapy (CRT) plus local hyperthermia (LHT) and androgen suppression therapy (AST). Treatment modalities consisted of: 1) CRT with a mean dose of 74 Gy (2 Gy/fraction/5 fractions per week); 2) LHT: one session per week during the first, second, third, and fourth week of the radiotherapy course; 3) AST was administered as neo-adjuvant and adjuvant therapy in more than 60% of patients. RESULTS: The median follow-up time was 51.7 months. Four patients were lost at follow-up. Of 140 evaluated patients, four died because of intercurrent diseases and 12 because of progression of disease. Patients were evaluated in terms of five-year overall survival (87%), and five year biochemical progression-free survival (49%). No significant side effects, except symptoms related to AST have been reported. No late grade 3 toxicity occurred. CONCLUSIONS: In advanced high risk prostatic cancer, hyperthermia is feasible and well tolerated. It may be useful to enhance the radiotherapy efficacy at intermediate dose in order to avoid higher doses of irradiation which increases acute and late sequelae. The advantage of LHT combined with CRT should be confirmed by a randomized phase III trial, comparing irradiation plus AST with or without hyperthermia. PMID- 17701535 TI - Weekly systemic cisplatin plus locoregional hyperthermia: an effective treatment for patients with recurrent cervical carcinoma in a previously irradiated area. AB - PURPOSE: Patients with recurrent cervical carcinoma within a previously irradiated area respond poorly to chemotherapy. We have treated these patients with simultaneous cisplatin and hyperthermia (CDDP + HT) and investigated response, toxicity, palliative effect and survival. MATERIALS AND METHODS: Between 1992 and 2005 47 patients received CDDP + HT. Response was evaluated by gynaecologic examination and CT-scan. The Common Toxicity Criteria (CTC) were used for evaluation of toxicity and palliative effect. The Kaplan-Meier method was used to estimate survival, and Cox regression analysis to evaluate the influence of prognostic factors. RESULTS: The objective response rate was 55%, palliation was achieved in 74% and operability in 19% of patients. Two patients are currently disease free at 9 years and 18 + months following treatment and 2 remained disease free until death by other causes. The median survival was 8 months and was influenced by duration of disease free interval and tumour diameter. Grade 3-4 haematological toxicity was observed in 36% of patients and renal toxicity was maximum grade 2. CONCLUSION: CDDP + HT results in a high response rate and acceptable toxicity in patients with recurrent cervical cancer. PMID- 17701537 TI - Monitoring of whole-body hyperthermia with transesophageal echocardiography (TEE). AB - Hyperthermia induces tumor cell death by a spectrum of tumor tissue changes. As whole-body hyperthermia (WBH) can cause cardiovascular complications, especially when cardiotoxic cytostatic agents are administered, invasive cardiovascular monitoring during WBH is necessary. WBH requires a great deal of expenditure and bears the risk of severe toxicity. Furthermore cardiovascular stress, alterations of cardiac index and systemic vascular resistance are major problems during WBH. The purpose of this prospective study was to evaluate cardiovascular changes in patients undergoing WBH under general anesthesia using transesophageal echocardiography (TEE) with special focus on left ventricular function. METHODS: Hemodynamic parameters were measured with standard monitoring and TEE at defined time points in 20 patients (ASA III) undergoing WBH: M37 (baseline, body temperature: 37 degrees C) after induction of anesthesia, M39 during warming up (39 degrees C), M41.8 at plateau level (41.8 degrees C), M38 during cooling period (38 degrees C). RESULTS: Invasive monitoring and TEE measurements showed signs of hyperdynamic circulation with significant increase of the heart rate (73.6 +/- 13.7 min(-1) (M37), 104.6 +/- 13.0 min(-1) (M41.8)) and significant decrease of mean blood pressure (74.9 +/- 15.3 mmHg (M37), 65.3 +/- 11.2 mmHg (M41.8)). Cardiac index (CI) nearly doubled and stroke volume index (SVI) increased significantly from M37 to M41.8. Cardiac contractility, fractional area change (FAC) and ejection fraction (EF) increased. At M38 CI, SVI, FAC and EF showed a tendency to decrease compared to M41.8 but remained elevated compared to M37. CONCLUSION: Patients undergoing WBH showed typical signs of hyperdynamic circulation without impairment of left ventricle which could be monitored excellently by TEE. We recommend using TEE especially in patients with an increased cardiac risk. PMID- 17701538 TI - Changes in peripheral lymphocyte subsets in patients after partial microwave ablation of the spleen for secondary splenomegaly and hypersplenism: a preliminary study. AB - PURPOSE: Microwave ablation therapy for secondary splenomegaly and hypersplenism has been shown to be effective from pre-clinical animal models and clinical investigations. This study was performed to determine its effects on the status of peripheral lymphocyte subsets in patients receiving microwave ablation of the spleen. MATERIALS AND METHODS: Ten patients with secondary splenomegaly and hypersplenism received microwave ablation of the spleen during laparoscopy or percutaneously under ultrasound guidance. The percentage peripheral blood T cells, B lymphocytes and NK cells were measured using flow cytometry before and on days 1, 3 and 7 after therapy, as well as 1 and 3 months afterwards. RESULTS: Percentages of CD3(+) and CD4(+) cells increased rapidly 1 month after therapy. There was no significant change in CD8(+), CD4(+)/CD8(+) or NK cells of the pre- and post-therapy levels and B lymphocytes increased significantly after therapy. In patients with an ablation volume (AV) less than 20% (group A), T cells increased 1 month after ablation but decreased 3 months after ablation. B lymphocytes increased significantly after surgery. Levels of NK cells were lower than that before therapy on each testing. In patients with 20-40% AV (group B), levels of T cells, B lymphocytes and NK cells showed an increase. Levels of CD4(+) cells were significantly higher in group B than in group A, 3 months after therapy. CONCLUSIONS: Microwave ablation therapy for splenomegaly and hypersplenism appears to have a favourable effect on peripheral lymphocyte subsets. A relationship may exist between the ablation volume and the level of peripheral lymphocyte subsets. PMID- 17701539 TI - Society of Thermal Medicine Robinson Award 2007. PMID- 17701540 TI - 2007 BSD Award Winner - Olav Dahl. PMID- 17701541 TI - Maurizio Brunori turns 70: nothing but a brilliant future behind him. PMID- 17701543 TI - Searching for neuroglobin's role in the brain. AB - Neuroglobin is a small globin that plays an important role in the protection of brain neurons from ischemic and hypoxic injuries. The molecular mechanisms by which Ngb performs its physiological function are still under debate. Suggestions include oxygen storage and delivery, scavenging of NO and/or reactive oxygen species, oxygen sensing and signal transduction. In recent years, the molecular structures of Ngb with carbon monoxide bound to the heme iron and without an exogenous ligand have been solved, and interesting structural changes have been noticed upon ligand binding. Moreover, equilibrium and kinetic properties of the reactions with ligands have been examined in great detail. Here we summarize the molecular properties of Ngb and discuss them in relation to the potential physiological functions. PMID- 17701542 TI - Histidine and not tyrosine is required for the peroxide-induced formation of haem to protein cross-linked myoglobin. AB - Peroxide-induced oxidative modifications of haem proteins such as myoglobin and haemoglobin can lead to the formation of a covalent bond between the haem and globin. These haem to protein cross-linked forms of myoglobin and haemoglobin are cytotoxic and have been identified in pathological conditions in vivo. An understanding of the mechanism of haem to protein cross-link formation could provide important information on the mechanisms of the oxidative processes that lead to pathological complications associated with the formation of these altered myoglobins and haemoglobins. We have re-examined the mechanism of the formation of haem to protein cross-link to test the previously reported hypothesis that the haem forms a covalent bond to the protein via the tyrosine 103 residue (Catalano, C. E., Choe, Y. S., Ortiz de Montellano, P. R., J. Biol. Chem. 1989, 10534 - 10541). Comparison of native horse myoglobin, recombinant sperm whale myoglobin and Tyr(103) --> Phe sperm whale mutant shows that, contrary to the previously proposed mechanism of haem to protein cross-link formation, the absence of tyrosine 103 has no impact on the formation of haem to protein cross-links. In contrast, we have found that engineered myoglobins that lack the distal histidine residue either cannot generate haem to protein cross-links or show greatly suppressed levels of modified protein. Moreover, addition of a distal histidine to myoglobin from Aplysia limacina, that naturally lacks this histidine, restores the haem protein's capacity to generate haem to protein cross-links. The distal histidine is, therefore, vital for the formation of haem to protein cross-link and we explore this outcome. PMID- 17701544 TI - Allosteric effects on oxidative and nitrosative reactions of cell-free hemoglobins. AB - A review of the oxidative and nitrosative reactions of cell-free hemoglobin-based oxygen carriers (HBOCs) shows that these reactions are intimately linked and are subject to allosteric control. Cross-linking reactions used to produce HBOCs introduce conformational constraints and result in Hbs with reduced responses to heterotropic and homotropic allosteric effectors. The Nernst plots of heme oxidation of cross-linked HBOCs are shifted to higher potentials relative to unmodified Hb in the absence of allosteric effectors, in accord with their T state stabilization and right-shifted Hill plots of O(2) binding. They exhibit enhanced rates of autoxidation and nitrite-induced oxidation, features that appear due to their having more solvent-accessible heme pockets. The stability of their NO-Hb derivatives varies as a result of allosteric effects on the extent of formation of pentacoordinate NO-heme geometry by alpha chains and subsequent oxidation of partner beta chains. The physiological implications of these findings on the safety, efficacy and design of second generation HBOCs are discussed in the framework of a reaction scheme showing linkages between Hb mediated redox reactions. These redox reactions can drive formation of SNO-Hb and other reactive species and are of significance for the use of cell-free Hbs in vivo. PMID- 17701545 TI - Protein dynamics and function: insights from the energy landscape and solvent slaving. AB - Protein motions are complex and a good way to describe them is in terms of a very high-dimensional conformation space. We give here a simple explanation of the conformation space and the energy landscape, the conformational motions and protein reactions, based on an analogy to a traffic problem. The analogy provides insight into the slaving of protein processes to bulk solvent fluctuations, in both the native and unfolded states. PMID- 17701546 TI - Application of the paramagnetic dipole field for solution NMR active site structure determination in low-spin, cyanide-inhibited ferric hemoproteins. AB - The principles for the application of the paramagnetic dipolar field of low-spin, cyanide-inhibited ferrihemoproteins for determining active site structure are briefly described. The ubiquitous dipolar shifts for assigned residues, together with crystal coordinates of some appropriate structural homolog, allow determination of the orientation and anisotropies of the paramagnetic dipolar tensor. The orientation of chi uniquely defines the orientation of the Fe-CN unit, which is tilted variably and sensitively monitors distal steric and H-bond interactions. The mapped dipolar field, in turn, can be used to determine the orientation of mutated residues. Case studies involving unusual genetic variants and point mutants of myoglobins, human hemoglobins, horseradish peroxidase and its substrate complex of heme oxygenase are presented as examples. PMID- 17701547 TI - Common dynamics of globin family proteins. AB - The recently discovered new members of the globin family, neurogobin and cytoglobin, are the object of sustained structural and functional studies aimed at understanding their physiological role and elucidating the impact of their bis his heme hexacoordination. However, no studies have yet considered the dynamics of this protein family, an essential link between structure and function. In this communication, we present normal mode analysis results for neuroglobin, cytoglobin, hemoglobin and myoglobin to provide exploratory insights into globin characteristic motions. Our results show a clear correlation in the protein dynamics of this family. All four globins exhibit a high degree of correlated displacements involving residues in the C, E and F helices and link regions. They suggest that these motions play an important role in the reversible oxygen binding function of these proteins. Further, our results may help rationalize some functional features of the 6c-globins in that they alone exhibit correlated displacements of the G-helix region. PMID- 17701548 TI - Protein structure in the truncated (2/2) hemoglobin family. AB - The discovery of protein sequences belonging to the widespread 'truncated hemoglobin' family has been followed in the last few years by extensive analyses of their three-dimensional structures. Truncated hemoglobins can be classified in three main groups, in light of their overall structural properties. The three groups adopt a 2-on-2 alpha-helical sandwich fold, based on four main alpha helices of the classical 3-on-3 alpha-helical sandwich found in vertebrate and invertebrate globins. Each of the three groups displays sequence and structure specific features. Among these, a protein matrix tunnel system is typical of group I, a Trp residue at the G8 topological site is conserved in groups II and III, and residue TyrB10 is almost invariant in the three groups. Despite sequence variability in the heme distal site region, a strongly intertwined, but varied, network of hydrogen bonds stabilizes the heme ligand in the three protein groups. Fine mechanisms of ligand recognition and stabilization may vary based on group specific distal site residues and on differing ligand diffusion pathways to the heme. Taken together, the structural considerations here presented underline that 'truncated hemoglobins' result from careful editing of the 3-on-3 alpha-helical globin sandwich fold, rather than from simple 'truncation' events. Thus, '2/2Hb' appears the most proper term to concisely address this protein family. PMID- 17701549 TI - Bach1, a heme-dependent transcription factor, reveals presence of multiple heme binding sites with distinct coordination structure. AB - The mammalian transcription factor Bach1 functions as a repressor of the enhancers of heme oxygenase-1 (HO-1) gene (Hmox-1) by forming heterodimers with the small Maf proteins such as MafK. The transcription of Hmox-1 is regulated by the substrate of HO-1, heme. Heme induces expression of Hmox-1 in part by inhibiting the binding of Bach1 to the enhancers and inducing the nuclear export of Bach1. A dipeptide motif of cysteine and proline (CP motif) in Bach1 is essential for the heme-mediated regulation. In this study, we show that five molecules of heme bind to Bach1 by the heme-titration assay. The Bach1-heme complex exhibits an absorption spectrum with a major Soret peak at 371 nm and Raman band at 343 cm(-1) in high amounts of heme and a spectrum containing the major Soret peak at 423 nm at low heme concentrations. The spectroscopic characterization indicates that Bach1 has two kinds of heme-binding sites with different coordination structures. Mutagenesis studies have established that four molecules of heme bind to the cysteine residues of four CP motifs in the C terminus of Bach1. These results raise the possibility that two separated activities of Bach1, DNA-binding and nuclear export, are regulated by heme binding at the different CP motifs of Bach1 respectively, but not by cooperative heme-binding. PMID- 17701550 TI - Ligand pathways in myoglobin: a review of Trp cavity mutations. AB - The pathways for ligand entry and exit in myoglobin have now been well established by a wide variety of experimental results, including pico- to nano- to microsecond transient absorbance measurements and time-resolved X-ray crystallographic measurements. Trp insertions have been used to block, one at a time, the three major cavities occupied by photodissociated ligands. In this work, we review the effects of the L29(B10)W mutation, which places a large indole ring in the initial 'docking site' for photodissociated ligands. Then, the effects of blocking the Xe4 site with I28W, V68W, and I107W mutations and the Xe1 cavity with L89W, L104W, and F138W mutations are described. The structures of four of these mutants are shown for the first time (Trp28, Trp68, Trp107, and Trp 138 sperm whale metMb). All available results support a 'side path' mechanism in which ligands move into and out of myoglobin by outward rotation of the HisE7 side chain, but after entry can migrate into internal cavities, including the distal Xe4 and proximal Xe1 binding sites. The distal cavities act like the pocket of a baseball glove, catching the ligand and holding it long enough for the histidine gate to close and facilitate internal coordination with the heme iron atom. The physiological role of the proximal Xe1 site is less clear because changes in the size of this cavity have minimal effects on overall O(2) binding parameters. PMID- 17701551 TI - Electron transfer kinetics of soluble fragments indicate a direct interaction between complex III and the caa3 oxidase in Thermus thermophilus. AB - The extremely thermophilic bacterium Thermus thermophilus expresses an aerobic respiratory chain resembling that of mitochondria and many mesophilic prokaryotes. Yet, interaction modes between redox partners differ between the thermophilic and mesophilic electron transport chains. While electron transfer in mesophilic organisms such as Paracoccus denitrificans follows a two-step mechanism mostly governed by long-range electrostatic interactions, the electron transfer in thermophiles is mediated mainly by apolar interactions. The terminal branch of the electron path from the bc-complex via the soluble cytochrome c(552) to the ba(3) oxidase has extensively been characterized, whereas contradicting evidence has been put forward on the nature of the physiological substrate(s) of the caa(3) oxidase. We have cloned and expressed a soluble fragment of the hydrophilic cytochrome c domain derived from subunit IIc of the caa(3) oxidase (c(caa)(3)) and characterized its kinetic behaviour in terms of substrate specificity and ionic strength dependency using pre-steady state stopped-flow techniques. The kinetics revealed fast electron transfer between the caa(3) fragment and both, the cytochrome c(552) and the soluble cytochrome c(bc) fragment of the bc-complex, showing only a weak ionic strength dependence. These data suggest a direct intercomplex electron transfer between the bc-complex and the caa(3) oxidase without requirement for a soluble electron shuttle. PMID- 17701552 TI - Twenty-five years of cytochrome oxidase research in Rome with Maurizio Brunori. AB - Cytochrome c oxidase has been for a long time one of the central topics studied in Rome by Maurizio Brunori. The authors of this paper have had the unique opportunity of collaborating with him and his friends worldwide for many years. Among the very large number of papers on this enzyme produced by Maurizio Brunori, just a few have been selected here which are particularly representative for the three of us. Topics deal mostly with the interplay between the electrochemical potential gradient in its components and the electron transfer and the proton translocation reactions of this fascinating enzyme. PMID- 17701553 TI - Cold-adapted signal proteins: NMR structures of pheromones from the Antarctic ciliate Euplotes nobilii. AB - Cell type-specific signal proteins, known as pheromones, are synthesized by ciliated protozoa in association with their self/nonself mating-type systems, and are utilized to control the vegetative growth and mating stages of their life cycle. In species of the most ubiquitous ciliate, Euplotes, these pheromones form families of structurally homologous molecules, which are constitutively secreted into the extracellular environment, from where they can be isolated in sufficient amounts for chemical characterization. This paper describes the NMR structures of En-1 and En-2, which are members of the cold-adapted pheromone family produced by Euplotes nobilii, a species inhabiting the freezing coastal waters of Antarctica. The structures were determined with the proteins from the natural source, using homonuclear (1)H NMR techniques in combination with automated NOESY peak picking and NOE assignment. En-1 and En-2 have highly homologous global folds, which consist of a central three-alpha-helix bundle with an up-down-up topology and a 3(10)-helical turn near the N-terminus. This fold is stabilized by four disulfide bonds and the helices are connected by bulging loops. Apparent structural specificity resides in the variable C-terminal regions of the pheromones. The NMR structures of En-1 and En-2 provide novel insights into the cold-adaptive modifications that distinguish the E. nobilii pheromone family from the closely related E. raikovi pheromone family isolated from temperate waters. PMID- 17701554 TI - Evolution of allosteric models for hemoglobin. AB - We compare various allosteric models that have been proposed to explain cooperative oxygen binding to hemoglobin, including the two-state allosteric model of Monod, Wyman, and Changeux (MWC), the Cooperon model of Brunori, the model of Szabo and Karplus (SK) based on the stereochemical mechanism of Perutz, the generalization of the SK model by Lee and Karplus (SKL), and the Tertiary Two State (TTS) model of Henry, Bettati, Hofrichter and Eaton. The preponderance of experimental evidence favors the TTS model which postulates an equilibrium between high (r)- and low (t)-affinity tertiary conformations that are present in both the T and R quaternary structures. Cooperative oxygenation in this model arises from the shift of T to R, as in MWC, but with a significant population of both r and t conformations in the liganded T and in the unliganded R quaternary structures. The TTS model may be considered a combination of the SK and SKL models, and these models provide a framework for a structural interpretation of the TTS parameters. The most compelling evidence in favor of the TTS model is the nanosecond - millisecond carbon monoxide (CO) rebinding kinetics in photodissociation experiments on hemoglobin encapsulated in silica gels. The polymeric network of the gel prevents any tertiary or quaternary conformational changes on the sub-second time scale, thereby permitting the subunit conformations prior to CO photodissociation to be determined from their ligand rebinding kinetics. These experiments show that a large fraction of liganded subunits in the T quaternary structure have the same functional conformation as liganded subunits in the R quaternary structure, an experimental finding inconsistent with the MWC, Cooperon, SK, and SKL models, but readily explained by the TTS model as rebinding to r subunits in T. We propose an additional experiment to test another key prediction of the TTS model, namely that a fraction of subunits in the unliganded R quaternary structure has the same functional conformation (t) as unliganded subunits in the T quaternary structure. PMID- 17701555 TI - Multiple strategies for O2 transport: from simplicity to complexity. AB - O(2)carriers (extracellular and intracellular as well as monomeric and multimeric) have evolved over the last billion of years, displaying iron and copper reactive centers; very different O(2)carriers may co-exist in the same organism. Circulating O(2)carriers, faced to the external environment, are responsible for maintaining an adequate delivery of O(2)to tissues and organs almost independently of the environmental O(2)partial pressure. Then, intracellular globins facilitate O(2)transfer to mitochondria sustaining cellular respiration. Here, molecular aspects of multiple strategies evolved for O(2)transport and delivery are examined, from the simplest myoglobin to the most complex giant O(2)carriers and the red blood cell, mostly focusing on the aspects which have been mainly addressed by the so called 'Rome Group'. PMID- 17701556 TI - Raddeanalin, a new flavonoid glycoside from the leaves of Salix raddeana Laksh. AB - A new flavonoid glycoside, diosmetin 7-O-beta-D-xylopyranosyl(1-6)-beta-D glucopyranoside, named raddeanalin (1), was isolated from the ethanolic extract of the leaves of Salix raddeana Laksh. together with three known compounds, kaempferol 3-O-glucoside (2), quercetin 3-O-glucoside (3) and quercetin 3-O rutinoside (4). The structure of new compound was established by the spectral data and chemical properties. PMID- 17701557 TI - Effect of 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucoside on lipoprotein oxidation and proliferation of coronary arterial smooth cells. AB - To investigate the effects of 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucoside (THSG), a compound extracted from the root of Polygonum multiflorum Thunb, on lipoprotein (LDL and VLDL) oxidation, proliferation and nitric oxide (NO) content of coronary arterial smooth cells (CASMCs) induced by LDL, VLDL, ox-LDL and ox VLDL. The oxidation level of lipoprotein was determined by thiobabituric acid (TBA) method and agarose gel electrophoresis. The proliferative degree was determined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) method. The NO content was assayed by nitrate reductase method. (1)THSG (0.1 - 100 mumol L(- 1)) could dose-dependently prevent lipoprotein from oxidation induced by Cu(2 + ) and CASMCs. (2)THSG (0.1 - 100 micromol L(- 1)) inhibited porcine CASMCs proliferation elicited by LDL, VLDL, ox-LDL and ox-VLDL. (3)THSG (0.1 - 100 micromol L(- 1)) counterpoised the decrease of NO content in CASMCs evoked by LDL, VLDL, ox-LDL and ox-VLDL. As compared with control, it was found that the threshold concentration of THSG, which significantly exerted the actions mentioned above, were at the concentration of 1 micromol.L(- 1) (P < 0.01). In conclusion, THSG possesses the antagonistic effects on oxidation of lipoprotein, proliferation and decrease of NO content of CASMCs, which partially explain the mechanism of anti-atherosclerosis of Polygonum multiflorum Thunb. PMID- 17701558 TI - A new sesquiterpene lactone with sulfonic acid group from Saussurea lappa. AB - A new sesquiterpene lactone with an unusual sulfonic acid group, 13-sulfo dihydrodehydrocostus lactone (1), was isolated from the roots of Saussurea lappa C. (Compositae), together with a known lignan (2). The structure of 1 was characterized on the basis of spectral evidence including 2DNMR studies. Compound 2 was obtained from this plant for the first time. PMID- 17701559 TI - Antidepressant-like effects of piperine and its derivative, antiepilepsirine. AB - In the present study, antidepressant-like effects of piperine (PIP) and its derivative, antiepilepsirine (AES), were investigated in two depressive models: forced swimming test (FST) and tail suspension test (TST). To further explore the mechanisms underlying their antidepressant-like activities, the brain monoamine levels and monoamine oxidase A and B (MAO-A and MAO-B) activities were also determined. The research results for the first time indicated that after two weeks of chronic administration, PIP and AES at doses of 10-20 mg/kg significantly reduced the duration of immobility in both FST and TST, without accompanying changes in locomotor activity in the open-field test. But at the dose of 80 mg/kg, the antidepressant activity of both PIP and AES returned to the control level in the TST and FST. In the monoamine assay, chronic AES administration significantly elevated the dopamine level in striatum, hypothalamus and hippocampus, and also increased the serotonin level in the hypothalamus and hippocampus. In contrast, chronic treatment of PIP only enhanced the serotonin level in the hypothalamus and hippocampus but did not influence the dopamine level. Moreover, both PIP and AES showed no effects on level of noradrenaline in these brain regions. The MAO activity assay also indicated that PIP and AES showed a minor MAO inhibitory activity. In the present study, we demonstrated that the antidepressant-like effects of PIP and AES might depend on the augmentation of the neurotransmitter synthesis or the reduction of the neurotransmitter reuptake. Antidepressant properties of PIP were supposed to be mediated via the regulation of serotonergic system, whereas the mechanisms of antidepressant action of AES might be due to its dual regulation of both serotonergic and dopaminergic systems. PMID- 17701560 TI - Two new lignans from Mentha spicata L. AB - Two new lignans named spicatolignan A (1) and spicatolignan B (2) have been isolated from the whole herbs of Mentha spicata L. PMID- 17701561 TI - A novel analgesic pyrazine derivative from the leaves of Croton tiglium L. AB - A novel analgesic pyrazine derivative, named crotonine, was isolated from the leaves of Croton tiglium L. The structure was elucidated as 2-(furan-2-yl)-5 (2,3,4-trihydroxy-butyl)-1,4-diazine by spectroscopic analysis. Crotonine inhibited remarkably the acetic acid-induced writhing in mice. PMID- 17701562 TI - Phenyl and phenylethyl glycosides from Picrorhiza scrophulariiflora. AB - A new phenyl glycoside, scrophenoside D (1) and a new phenylethyl glycoside, scroside F (2), together with three known phenylethyl glycosides, scroside A (3), plantainoside D (4), and plantamajoside (5), were isolated from the stems of Picrorhiza scrophulariiflora. Their structures were elucidated by spectroscopic and chemical methods. PMID- 17701563 TI - Lignans from the stems of Sambucus williamsii and their effects on osteoblastic UMR106 cells. AB - Three new lignans, sambucunol A (8) ((+)-erythro-1-(4-hydroxy-3-methoxyphenyl)-2 [4-(4-hydroxy-3-methoxycinnamoyloxypropanyl)-2-hydroxyphenoxy]-1, 3-propanediol), sambucunol B (9) ((+)-threo-1-(4-hydroxyl-3-methoxyphenyl)-2-[4-(4-hydroxy-3 methoxy-cinnamoyloxy propanyl)-2-hydroxyphenoxy]-1, 3-propanediol) and buddlenol G (10) (2-{4-[2, 3-dihydro-3-hydroxymethyl-7-hydroxy-5-(4-hydroxy-3 methoxycinnamoyloxypropanyl)-2-benzofuranyl]-2,6-dimethoxyphenoxy}-1-(4- hydroxy 3-methoxyphenyl) -1, 3-propanediol), along with seven known ones, including ( - ) syringaresinol (1), ( - )-pinoresinol (2), 1, 2-bis(4-hydroxy-3-methoxy phenyl) 1, 3-propanediol (3), ( - )-erythro-1-(4-hydroxy-3-methoxyphenyl)-2-[4-(3-hydroxy propanyl)-2-methoxyphenoxy]-1, 3-propanediol (4), ( - )-threo-1-(4-hydroxy-3 methoxyphenyl)-2-[4-(3-hydroxypropanyl)-2-methoxy phenoxy]-1, 3-propanediol (5), ( - )-lariciresinol (6) and ( - )-dihydrodehydrodiconiferyl alcohol (7), were isolated from the 60% ethanol extract of stems of Sambucus williamsii Hance by chromatographic methods. Their structures were established by spectral analysis. The effects of isolated compounds on the osteoblast-like UMR106 cell proliferation and ALP activities were determined. Compounds 2, 7 and 10 showed stimulating effects both on UMR106 cell proliferation and ALP activity. Compounds 1, 3, 6 and 8 stimulated UMR106 cell proliferation, while compounds 4 and 5 induced ALP activity in UMR106 cell. PMID- 17701564 TI - Two new monoterpene glycosides and a new (+)-jasmololone glucoside from Bidens parviflora Willd. AB - Two new monoterpene glycosides named bidensmenthosides A, B and a new (+) jasmololone glucoside, were isolated from the air-dried whole plant of Bidens parviflora Willd. Their structures were determined as (1S, 3S, 4R)-3-hydroxy-p menth-6-one 3-O-beta-D-glucopyranoside (1), (3R, 4R)-3-hydroxy-p-menth-1 (2)-en-6 one 3-O-beta-D-glucopyranoside (2) and (4R)-hydroxy-3-methyl-2-(2 Z-pentenyl) cyclopent-2-enone 4-O-beta-D-glucopyranoside (3) based on spectroscopic analysis and physiochemical properties, respectively. The bidensmenthosides A, B and aglycone of 3 were found to reduce 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radicals. PMID- 17701565 TI - A novel compound from Hedysarum polybotrys. AB - A polyhydroxyl constituent (1), named as polybotrin, along with two known compounds, were isolated from the roots of Hedysarum polybotrys. Their structures were identified based on chemical and spectroscopic evidence. PMID- 17701566 TI - Arylglycerol glucosides from Dracocephalum forrestii. AB - Three new arylglycerol glucosides, threo-guaiacylglycerol 3-O-(6-O-p hydroxybenzoyl)-beta-D-glucopyranoside (1), threo-guaiacylglycerol 3-O-[6-O-(E)-p coumaroyl]-beta-D-glucopyranoside (2) and threo-guaiacylglycerol 3-O-[6-O-(Z)-p coumaroyl]-beta-D-glucopyranoside (3), together with seven known compounds were isolated from the whole plants of Dracocephalum forrestii and their structures were determined on the basis of spectroscopic evidences. PMID- 17701567 TI - Microbial transformation of neoandrographolide by Aspergillus niger (AS 3.739). AB - The biotransformation of neoandrographolide (1) was investigated by using Aspergillus niger (AS 3.739). Five products were obtained and identified as 8(17),13-ent-labdadien-16,15-olid-19-oic acid (2), 19-hydroxy-8(17),13-ent labdadien-16,15-olide (3), 18-hydroxy-8(17),13-ent-labdadien-16,15-olid-19-oic acid (4), 3alpha-hydroxy-8(17),13-ent-labdadien-16,15-olid-19-oic acid (5) and 8beta,19-dihydroxy-ent-labd-13-en-16,15-olide (6) by spectroscopic and chemical means. Products 4, 5 and 6 are new compounds. PMID- 17701568 TI - Two new compounds from the roots of Lysidice rhodostegia. AB - Two new compounds, lysidicin D (1) and lysidicin E (2), were isolated from the roots of Lysidice rhodostegia. Their structures were elucidated by means of spectroscopic methods. Among them compound 1 showed potent anti-oxidant activity on in vitro. PMID- 17701569 TI - Antibacterial constituents from Stemona sessilifolia. AB - Bioassay-guided fractionation led to the isolation of eight compounds from Stemona sessilifolia. Of the eight isolates, three new bibenzyls, stilbostemins M O (1-3), and a new tocopherol, 6-methoxy-3,4-dehydro-delta-tocopherol (4) were revealed together with four known compounds 3,5-dihydroxy-2'-methoxy bibenzyl (5), 3,5-dihydroxy bibenzyl (6), beta-tocopherol (7), and gamma-tocopherol (8). Compounds 5, 6, and 8 exhibited strong antibacterial activities against Staphylococcus aureus and S. epidermidis. PMID- 17701571 TI - Effects of cross-sectional partitioning on active noise control in round ducts. AB - Active noise control (ANC) is particularly useful in hard-walled ducts where plane waves propagate. Higher order mode waves are much more difficult to control. Basic acoustic principles dictate that the cut-on frequency at which higher order modes will first begin to eclipse simple plane waves in a duct will be determined by the cross-sectional diameter of the duct. The lowest frequency for higher order modes will increase as duct diameter decreases. Therefore, the range of frequencies where plane waves dominate will be greater, and effective control using ANC will be better as duct diameter decreases. The result is that somewhat higher frequencies can be controlled with ANC for smaller diameters. If smaller diameters have broader frequency ranges that can be controlled with ANC, perhaps one could extend the frequency range for a large cross section by partitioning it into smaller cross sections using axial vane splitters. This hypothesis was tested by two methods of cross-sectional partitioning. Partitioning was achieved in one design by inserting a smaller duct inside a large duct. In a second design, a cross-shaped splitter was inserted inside the large duct. Summed ANC insertion loss (IL) at low frequencies (< or =250 Hz) was at least 16 dB and at least 14 dB at middle frequencies (> or =315 Hz). ANC IL results were 1.7 to 2 dB better for the large duct partitioned by a smaller inner duct than the large duct alone (p = 0.0146 for low frequency and p = 0.0333 for middle frequency). ANC insertion loss was 5.6 dB better for the large duct partitioned by a cross-shaped splitter at high frequencies than the large duct alone (p = 0.0003). However, the cross-shaped partition system was 5.8 dB less effective at low frequencies than the large duct ANC IL alone (p < 0.0001). PMID- 17701572 TI - Molecular indicators of prognosis in mantle cell lymphoma in the era of R-hyper CVAD: still an open issue. PMID- 17701573 TI - PET for follicular lymphoma: a work in progress! PMID- 17701574 TI - Peripheral T-cell lymphomas: variably or routinely fluorodeoxyglucose-avid? PMID- 17701575 TI - Prognostic factors for risk-adapted therapy in chronic lymphocytic leukemia - the search continues. PMID- 17701576 TI - Hyperforin modulation of drug resistance: saint or sinner? PMID- 17701577 TI - Decitabine and its role in the treatment of hematopoietic malignancies. AB - DNA methylation is responsible for abnormal silencing of many genes, including tumor suppressor genes, in cancer. Decitabine, an S-phase specific inhibitor of DNA methyltransferase, has been shown to decrease levels of abnormal methylation in neoplasia. Though initially investigated at high doses as a cytotoxic agent, recent studies show that when administered at low doses, the hypomethylating activity of decitabine is increased with a demonstrated increase in activity in hematopoietic malignancies. Multiple clinical trials, both in the United States and in Europe, have demonstrated the efficacy of decitabine in acute myeloid leukemia, chronic myeloid leukemia, and myelodysplastic syndrome (MDS). Recently approved by the United States Food and Drug Administration for the treatment of (MDS), decitabine represents an effective and well-tolerated therapeutic option in this disease, for which treatment options were previously scarce. While the activity in MDS is promising, primary and secondary resistance remain a problem. Investigations of combinations of decitabine with other agents, including histone deacetylase inhibitors, are currently ongoing in the hope of substantially prolonging survival in patients with hematologic malignancies. PMID- 17701578 TI - Incidence, risk factors, and pathogenesis of second malignancies in patients with non-Hodgkin lymphoma. AB - Most Non-Hodgkin's Lymphoma patients will survive their diagnosis. High dose chemotherapy and autologous stem cell transplantation, and radiation therapy have all been implicated as risk factors to secondary cancer development. Herein, we will review the molecular biology, examine the epidemiologic findings, discuss the impact of both chemotherapy and radiotherapy, and focus on the special populations of pediatrics and high dose chemotherapy and autologous stem cell transplantation with regard to secondary cancer development. PMID- 17701579 TI - Hematopoietic stem cell transplantation in peripheral T-cell lymphomas. AB - Peripheral T-cell lymphomas (PTCL) are a rare entity with a dismal outcome. After conventional chemotherapy they showed a worse prognosis compared with B-cell non Hodgkin's lymphoma (NHL), except for anaplastic lymphoma-kinase (ALK)-positive anaplastic large cell lymphomas (ALCL). High-dose chemotherapy followed by autologous stem cell transplantation (SCT) has been evaluated in relapsed patients as well as in the upfront setting. Available data showed an advantage for patients who received transplant as first line treatment whereas results of autografting at relapse have been satisfactory only for ALK-positive ALCLs compared to other PTCL subtypes. Based upon preliminary results, allogeneic SCT can be also considered as an alternative strategy in these lymphomas. Whether or not the postulated graft-versus-lymphoma effect may overcome the poor prognosis of T-cell NHL patients has to be established. PMID- 17701581 TI - Bcl-6 and c-Myc are rarely co-expressed in adult diffuse large B-cell lymphoma. AB - Bcl-6 is expressed in germinal centre derived B-cell non-Hodgkin lymphomas including diffuse large B-cell lymphoma (DLBCL) and is likely to play a major role in driving proliferation of a subset of DLBCLs, especially those of germinal centre B-cell subtype, but the role of c-Myc, which is important for proliferation in various lineages is not known. We used the highly standardised staining conditions of a tissue microarray to characterise co-expression of c-Myc and Bcl-6 in DLBCL. We carried out immunohistochemistry of 73 arrayed cases. The majority (62/73) did not express c-Myc, but 11 cases (15%) showed nuclear staining. 5/53 (9%) of Bcl-6 expressing cases co-expressed c-Myc, whereas a much higher proportion, 6/20 (30%), of Bcl-6 negative cases were positive for c-Myc. Overall survival of c-Myc expressing cases was the same as those that had absent expression. There was no significant correlation between c-Myc expression and DLBCL subtype (germinal centre or non-germinal centre subtypes). PMID- 17701580 TI - Evaluation of the MDR1, ABCG2, Topoisomerases IIalpha and GSTpi gene expression in patients affected by aggressive mantle cell lymphoma treated by the R-Hyper CVAD regimen. AB - The genomic profile of mantle cell lymphoma (MCL) has been reported to be significantly different from that of other indolent lymphoproliferative disorders, Topoisomerase IIalpha, glutathione-s-transferasepi (GSTpi) and ABCG2 (BCRP) chemoresistance genes being over-expressed in MCL. In our study, expression levels of the above mentioned genes plus MDR1 were tested on bone marrow samples from 20 patients treated with Rituximab plus hyper-CVAD regimen, in order to evaluate a possible impact of the chemoresistance phenomenon on this promising treatment regimen. All patients expressed ABCG2 and MDR1 genes; 85% of cases expressed GSTpi and topoisomerase IIalpha. Only ABCG2 were over-expressed in comparison both with marrow from healthy donors and tonsilar CD5+/CD20+ lymphocytes (adopted as normal counterpart of the neoplastic population). The overall response rate of the entire series was 87.5%, with 44% of complete responses. Fifty-seven percent of patients achieved the clearance of minimal residual disease. Levels of tested genes did not condition either quality of clinical response or PFS (76% at 24 months). Nevertheless, an ABCG2 higher expression appeared associated with a worse PFS and levels of this gene paralleled the status of minimal residual disease. A further evaluation of ABCG2 expression in larger series of MCL patients would be suitable. PMID- 17701582 TI - Elderly patients with non-Hodgkin lymphoma who receive chemotherapy are at higher risk for osteoporosis and fractures. AB - To determine risk of osteoporosis and fractures associated with chemotherapy among elderly non-Hodgkin's lymphoma (NHL) patients, a cohort of 13 570 patients aged >/=65 years with incident NHL was identified from SEER-Medicare data with up to 11 years of follow-up. One year prior to the diagnosis, significantly fewer patients had fracture and osteoporosis claims in the chemotherapy group versus no chemotherapy group. However, after NHL diagnosis, patients who received chemotherapy had significantly higher rates of fracture (31% versus 19%, P < 0.001) and osteoporosis (10% versus 8%, P < 0.001), compared with those who did not. The risk of having fracture (odds ratio = 2.24, 95% CI = 2.04 - 2.45) and osteoporosis (odds ratio = 1.27, 95% CI = 1.12 - 1.45) was significantly higher in patients receiving chemotherapy compared with those who did not, after controlling for demographic and tumor factors. In conclusion, use of chemotherapy was significantly associated with increased risk of fracture and osteoporosis in elderly patients with NHL. PMID- 17701583 TI - Aggressive and indolent non-Hodgkin's lymphoma: response assessment by integrated international workshop criteria. AB - Until recently, response assessment in patients with lymphoma was primarily performed by computed tomography (CT). Based on CT, International Workshop Criteria (IWC) were developed and widely used. Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) is a more sensitive and specific imaging technique for the detection of residual disease in lymphoma, and Revised Integrated International Workshop Criteria (IWC + PET) were recently proposed by the members of the International Harmonization Project (IHP), which combine both imaging techniques. We determined whether these new IWC + PET-criteria, can more accurately predict outcome compared to IWC-criteria in aggressive and indolent non-Hodgkin's lymphoma (NHL), and therefore correlated IWC and IWC + PET response with time-to-next-treatment (TNT) in 69 patients with NHL. We demonstrated that IWC + PET-guidelines are highly recommended over IWC-guidelines for patients with potentially-curable and routinely FDG-avid lymphoma. In contrast, no additional value of IWC + PET was demonstrated in a small group of patients with incurable histological subtypes. PMID- 17701584 TI - F-18-fluoro-deoxy-glucose positron emission tomography in the assessment of peripheral T-cell lymphomas. AB - F-18-fluoro-deoxy-glucose positron emission tomography (PET) is highly sensitive and specific in the imaging of B-cell lymphomas. In contrast, its utility in the diagnostic evaluation of T-cell lymphomas is less defined. In this article, we present our finding utilizing PET in peripheral T-cell lymphomas (PTCL). A retrospective review of patients who underwent PET examinations at our institution produced 24 PET examinations among patients with PTCL. A lesion-based analysis was undertaken to evaluate the diagnostic accuracy of PET in PTCL. PET findings were compared with a standard of reference and sensitivity, specificity, positive and negative predictive values were calculated. PET had an overall sensitivity of 86% and specificity of 100%. PET had high sensitivity (95%) at nodal and non-cutaneous extra-nodal sites and poor sensitivity (13%) at cutaneous sites. The mean SUV of abnormal foci in anaplastic large cell lymphoma was 11 mg/ml (range: 3 - 40), and PTCL-unclassified was 8 mg/ml (range: 1 - 23). PMID- 17701585 TI - Hodgkin lymphoma: Response assessment by revised International Workshop Criteria. AB - Until recently, response assessment in patients with Hodgkin's lymphoma (HL) was primarily performed by computed tomography (CT). Based on CT, International Workshop Criteria (IWC) were developed and widely used. Fluorodeoxyglucose positron emission tomography (FDG-PET) has a higher sensitivity and specificity compared with that of CT, and Revised International Workshop Criteria (IWC + PET) were recently proposed, which combine both imaging techniques. We determined whether these integrated IWC + PET-criteria can more accurately predict outcome compared with IWC-criteria in 56 patients with HL. Of the original 56 patients, nine patients relapsed and 47 are still in remission after a median follow-up of 9 years. Based on IWC-criteria, 15 patients had a complete remission (CR) after chemotherapy, 20 had complete remission unconfirmed (CRu), 19 had partial remission (PR) and two had stable disease (SD). In comparison, by IWC + PET, 47 had CR, seven had PR and two had SD. For IWC, outcome was not significantly different in patients with CR/CRu compared to PR (P = 0.61), while for IWC + PET criteria, time-to-next-treatment was significantly shorter in patients with PR compared to CR (P = 0.01). Therefore, IWC + PET-guidelines provide a more accurate response classification compared with that of IWC-guidelines, and are the preferred method for response assessment in patients with Hodgkin's lymphoma. PMID- 17701586 TI - Predictive value and diagnostic accuracy of F-18-fluoro-deoxy-glucose positron emission tomography treated grade 1 and 2 follicular lymphoma. AB - F-18-fluoro-deoxy-glucose positron emission tomography (PET) is a powerful tool for the imaging of aggressive B-cell lymphomas. In contrast, there is relatively little data on PET in follicular lymphoma grade 1 (FL-1) and grade 2 (FL-2). In this manuscript, we present our findings utilizing PET in treated FL-1 and FL-2. A retrospective review of patients who underwent PET examinations at our institution produced 95 PET examinations among 31 patients with FL-1 and FL-2. PET was obtained at initial staging, mid-induction and post-treatment. Results were compared with clinical follow-up. PET had high sensitivity (95%) and specificity (88%) for lesion detection in treated FL-1 and FL-2. Abnormal foci in FL-1 and FL-2 had similar intensities. Post-induction PET positive patients had shorter mean progression free survivals compared with PET negative patients (p value < or =0.001), post-salvage PET positive trended toward shorter mean response duration compared with negative patients (p-value: 0.09). Our results indicate that PET is accurate in the diagnostic assessment of treated FL-1 and FL 2 and, post-treatment PET positive patients are likely to relapse prior to PET negative patients. PMID- 17701587 TI - Multi-drug resistance mediated by P-glycoprotein overexpression is not correlated with ZAP-70/CD38 expression in B-cell chronic lymphocytic leukemia. AB - ZAP-70 and CD38 expression can identify B-cell chronic lymphocytic leukemia with an inferior clinical outcome. Many groups have investigated the meaning of the expression of these two proteins and the correlation with the bad prognosis in B CLL. But nobody has investigated the relation between the multidrug resistance mediated by Pgp overexpression (MDR1) and ZAP-70/CD38 coexpression. Forty-one untreated and stage A patients, either ZAP-70(+)CD38(+) or ZAP-70(-)CD38(-), were tested to determine the MDR1 status. MDR1 was observed in 41% of CLL ZAP 70(+)CD38(+) and in 37% of CLL ZAP-70(-)CD38(-). The difference was not significant (p = 0.745). Patients with ZAP-70 and CD38 positive CLL can not be candidates for MDR1 antagonists. PMID- 17701588 TI - White blood cell count nadir following remission induction chemotherapy is predictive of outcome in older adults with acute myeloid leukemia. AB - Kinetics of white blood cell (WBC) elimination following induction chemotherapy for older adults with acute myeloid leukemia (AML) may serve as a surrogate for its effectiveness and safety by enabling real-time prognostication. We reviewed 122 older adults with AML treated at the Cleveland Clinic. Recursive partitioning analysis was used to identify optimal cut points in nadir WBC count and time to WBC nadir that correlate with survival. Multivariable analysis identified time to WBC nadir less than or equal to 10 days (HR 2.15, 95%CI 1.12 - 4.12, p = 0.02), low WBC nadir (less than 0.04 x 10(9)/l, HR 2.68, 95%CI 1.15 - 6.23, p = 0.02) and high WBC nadir (greater than 0.12 x 10(9)/l HR 1.5, 95%CI 0.96 - 2.37, p = 0.08), as predictors of worse outcomes. Time to WBC nadir predicts survival. The absolute WBC nadir value follows a J-curve, with lower value indicating a worse outcome. PMID- 17701589 TI - Ovarian tissue cryopreservation in hematologic malignancy: ten years' experience. AB - Cryopreservation of ovarian tissue is currently practiced in an attempt to preserve fertility before commencing potentially sterilizing chemotherapy. Clinical and laboratory guidelines are needed to standardize the procedure. Over the last 10 years ovarian tissue was stored in female patients with hematologic malignancies. Patients' records and consultation charts were evaluated, surgical and laboratory reports were revised and ovarian histology was investigated. Fifty six patients with hematologic malignancies (age 24 +/- 5.5) had cryopreserved ovarian tissue. Thirty-three patients had Hodgkin's disease, 14 non-Hodgkin's lymphoma, 6 acute leukemia, and 3 chronic myelocytic leukemia. Harvesting of ovarian tissue was also performed following previous exposure to chemotherapy (33 patients), 13 of them shortly after the chemotherapy. Partial oophorectomy was the preferred surgical procedure. Fertility was restored with ovarian tissue transplantation in a sterilized patient and following fertility treatment in a patient with very low ovarian reserve. We recommend that indications and timing of ovarian tissue banking should be individualized. Patients previously exposed to chemotherapy can consider ovarian tissue freezing. The extent of tissue removed should take into account the large number of follicles lost and the risk of future sterilization. Tissue handling should enable further investigation of primordial follicles and identification of cancer cells. PMID- 17701590 TI - Invasive fungal sinusitis: an effective combined treatment in five haematological patients. AB - Invasive fungal rhinosinusitis (IFR) is a life-threatening infection. Its onset is subtle and a late diagnosis leads to severe complications. Death may occur within a few weeks notwithstanding treatment. We describe a comprehensive pre- and post-operative approach to care for haematological patients with IFR. Five haematological patients with IFR were treated with systemic antifungal therapy and endoscopic surgical debridement of infected tissues, followed by amphotericin B directly instilled in the sinuses by a new type of ethmoidal drainage. The IFR remitted in all cases; after 32 months of follow-up, three patients are still alive, and two have died of other causes. Two of the patients who experienced IFR progression to the brain at the IFR onset are still alive. The pharmacological and surgical approach with the post-operative local therapy by a new ethmoidal drainage system could support radical antifungal sinus treatment, thus improving the overall survival. PMID- 17701591 TI - Hyperforin inhibits P-gp and BCRP activities in chronic lymphocytic leukaemia cells and myeloid cells. AB - We showed previously that hyperforin (HF), a natural phloroglucinol, stimulated apoptosis in B cell chronic lymphocytic leukaemia cells (CLL) and displayed anti angiogenic properties. In the present work, we investigated the effects of hyperforin on the activity of P-gp/MDR1, an ABC (ATP-binding cassette) transporter putatively involved in multidrug resistance (MDR). Ex vivo treatment of CLL cells with HF markedly impaired the activity of P-gp, as measured by the inhibition of the capacity of the treated cells to efflux the rhodamine 123 probe. In addition, most CLL cells expressed breast cancer resistance protein (BCRP), another ABC transporter. The activity of BCRP was also inhibited by HF, as assessed by the impaired capacity of HF-treated CLL cells to efflux the specific probe mitoxantrone. The capacity of HF to reverse P-gp and BCRP activity was confirmed in myeloid leukaemia cell lines, notably in HL-60/DNR cells selected for their resistance to daunorubicine and overexpressing P-gp. Our results therefore suggest that HF might be of interest in the therapy of CLL and other haematological malignancies through its potential capacity to revert MDR in addition to its pro-apoptotic properties. PMID- 17701592 TI - Antitumor effects of cytosine deaminase and thymidine kinase fusion suicide gene under the control of mdr1 promoter in mdr1 positive leukemia cells. AB - The multidrug resistance (mdr) mediated by P-glycoprotein (P-gp), the mdr1 gene product, is one of the major obstacles in leukemia treatment. The present study was designed to explore a suicide gene therapy approach targeting mdr1 for reversal of P-gp-mediated mdr in the mdr positive K562/A02 cells. To study targeted killing effects of cytosine deaminase (CD)-thymidine kinase (TK) fusion suicide gene on multi-drug resistant leukemia, the CD-TK fusion suicide gene expression vector driven by mdr1 promoter was constructed and transferred into K562 and K562/A02 cells using lipofectintrade mark 2000. RT-PCR was used to demonstrate that there were CD and TK genes expression in K562/A02 cells, but not in K562 cells. MTT analysis showed that, compared with that in K562/CDTK, the survival rate of K562/A02-CDTK cells decreased and at the same time the apoptotic rate increased after treatment with GCV and 5-FC (P < 0.05). In vivo studies showed that the tumor volume in the prodrug treated K562/A02-CDTK groups was significantly less than that in the NS-control and K562-CDTK groups (P < 0.05). These findings show that the CD and TK fusion suicide gene expression driven by mdr1 promoter is effective in killing multidrug resistant K562/A02 cells. PMID- 17701593 TI - Expression and modulation of progesterone induced blocking factor (PIBF) and innate immune factors in human leukemia cell lines by progesterone and mifepristone. AB - Progesterone (P), required for successful pregnancy, influences autoimmune, infectious, and malignant diseases via adaptive and innate immune effects. P induces NK inhibitor progesterone induced blocking factor (PIBF) in CD8+ T cells. PIBF isoforms could permit solid tumor immune escape. Expression and modulation of PIBF and innate immune proteins by P in leukemia cells and leukocyte subpopulations have not been reported. Ten T, seven myeloid, six B, five epithelial, fibroblast BG9, G-CSF mobilized CD34+ stem cells, and peripheral blood mononuclear cells were screened for PIBF mRNA by RT-PCR, and protein by immunohistochemistry in SRIK-NKL, MOT, U937, HL60, R-CLL, MD-E, 729pH6neo, SRIH B(ATL), SRIK-B(T-PLL), and MeWo. Cell lines expressing PIBF and exemplifying myeloid/monoblast, natural killer/T, and B lineages were cultured with and without 0.5 - 5 microM P or 0.5 - 0.05 microM mifepristone (RU486) for 24 h. Subsequently they were examined for changes in the expression of mRNA by RT-PCR and protein by immunohistochemistry for PIBF and some innate immune factors. All cells expressed PIBF mRNA; protein only in four (SRIK-NKL, U937, SRIK-B(T-PLL) and HL60) out of 10 cell lines tested. P increased and RU486 decreased PIBF in U937, SRIK-B(T-PLL) and SRIK-NKL. P upregulated TLR-4 in U937, and HNP1 - 3, LL 37, IRAK-2, and IRAK-4 in multiple lines and RU486 down regulated these. PIBF may be used by some leukemias to evade immune surveillance and is a potential therapeutic target. P may impact infection and autoimmunity via effects on LPS receptor, TLR signaling, and antimicrobial peptides. PMID- 17701594 TI - TCR spectratyping revealed T lymphocytes associated with graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. AB - Clonal expansion of T cells after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been observed, but their characteristics remain to be fully elucidated. We report here that CD8(+) T cells were the dominant T lymphocytes seen and T-cell repertoire diversity decreased dramatically during the first 3 months after allo-HSCT. Patients with GVHD grade II - IV had significantly lower T-cell repertoire diversity compared with non-GVHD patients. TCR beta variable gene (TCRBV) subfamily 8, 5.1, 5.2, 4, and 13 were the five most frequently expanded subfamilies among these patients. Among the 49 over expanded clones identified, clonotype "TCR3-5" and "TCR18-5" were isolated from four patients with HLA-A2 allele and skin GVHD. Their frequencies correlated well with skin symptoms (i.e. rash). Moreover, they were detected in donors but not detected in recipients before transplantation. Lastly, three common TCRBV CDR3 motifs shared by T cells related with GVHD were discovered: TGDS, GLAG, and GGG. These findings suggest that TCR spectratyping is helpful for revealing GVHD related T cells and may have utility in early diagnosis. PMID- 17701595 TI - Monocytic skin nodules in chronic myelomonocytic leukemia: clinical response to decitabine therapy. PMID- 17701596 TI - Rituximab for treatment of chemoimmunotherapy naive marginal zone lymphoma. PMID- 17701597 TI - Rituximab-induced serum sickness in a patient with follicular lymphoma. PMID- 17701598 TI - The t(9;14)(p13;q32) is a recurrent but rare abnormality in splenic marginal zone lymphoma. PMID- 17701600 TI - Successful carboxypeptidase G2 rescue of a high-risk elderly Hodgkin lymphoma patient with methotrexate intoxication and renal failure. PMID- 17701601 TI - Hodgkin transformation of newly diagnosed small lymphocytic lymphoma in the gastrointestinal tract. PMID- 17701599 TI - Diffuse large B-cell lymphoma developing following treatment of Waldenstrom's macroglobulinaemia: spontaneous resolution upon cessation of fludarabine. PMID- 17701602 TI - Separate cell culture conditions to promote proliferation or quiescent cell survival in chronic lymphocytic leukemia. PMID- 17701603 TI - Clonal CD8+ lymphocytic proliferation associated with Epstein-Barr virus infection mimicking T-cell leukemia. PMID- 17701604 TI - Acute promyelocytic leukemia in patients aged 70 years and over -- a single center experience of unselected patients. PMID- 17701605 TI - Efficacy of dose escalation of imatinib mesylate in patients with cytogenetic or hematologic resistance. PMID- 17701606 TI - Multiple myeloma and renal cell carcinoma possible association. PMID- 17701607 TI - Lessons learned from a study-group pilot program for medical students perceived to be 'at risk'. AB - BACKGROUND: At the University of New Mexico School of Medicine (UNM-SOM) we have noticed that some first year medical students have difficulty accurately assessing their academic skills and are often afraid to seek help. This leads to marginal performance and sometimes even failure. Therefore, we developed a preemptive intervention using peer-led study groups based on the personalized System of Instruction (PSI). AIM: The goal of this pilot study was to evaluate this approach for assisting students, interms of student success, and cast benefit. METHODS: Thirteen first-year medical students considered to be 'at risk' of academic difficulty took part in a six-month pilot intervention. They participated in structured study groups that were facilitated by upper-level medical students. The groups met twice weekly for up to two hours each time. The at-risk students took short multiple-choice quizzes and discussed major concepts. If students did not achieve 80% or better on the quizzes, they were required to take a second quiz to demonstrate mastery. Summative exam scores from four groups of students were compared: those with Medical College Admission Test (MCAT) scores <25, who received the study group intervention; their classmates with MCAT scores >25 who did not receive the intervention; and two matched groups from the previous year, none of whom had access to the structured study groups. RESULTS: No significant differences in exam scores were seen between the group who received the intervention and the matched group who did not. CONCLUSIONS: Despite this result, we learned several useful lessons about study groups and interactions between first-year and upper-level medical students: (1) Students perceived participation in the study groups as a good learning strategy, but preferred participation not be mandated. It may be preferable to train and encourage students to run their own study groups. (2) Both students and proctors acknowledged interpersonal benefits from the program but, as these benefits can be achieved by other means, an expensive proctor-based program is not, we believe, the best use of academic support resources. (3) Focus in the study groups was on content for the quizzes, but more attention to how-to-learn strategies may have had greater impact. PMID- 17701608 TI - The views of medical education stakeholders on guidelines for cultural diversity teaching. AB - BACKGROUND: The General Medical Council set out the framework within which it expects medical education to develop. Educational guidelines have been developed across the world but their development is less clear in the UK. There has been little work regarding views about educational guidelines. AIM: The research objective was to establish the views of medical education stakeholders towards specific guidelines for teaching in cultural diversity to medical students. METHODS: Sixty-one individuals were interviewed using a semi-structured interview. Thematic analysis was undertaken after the interviews were transcribed verbatim. RESULTS: In total, 51 respondents felt that guidelines would be useful; 17 of these explicitly stipulated that these would only be useful if they were not prescriptive and if they were applied flexibly and were practical. Four respondents, including two policy-makers holding senior positions with medical educational bodies, felt that new guidelines would not be useful, as they already existed in some form. Five respondents were unsure if guidelines would be helpful or not. CONCLUSIONS: Guidelines were considered to be potentially useful for several reasons including to: help clarify what should be taught regarding cultural diversity and how it should be taught, provide justification for teaching the subject, help those unfamiliar with the subject, support those assigned with responsibility for developing such teaching, provide course and curriculum designers with reassurance, increase the credibility of the subject, set standards that serve as a benchmark against which schools can compare themselves with one another and highlight good practice. The reservations expressed suggest that the guidelines need to be developed using a range of stakeholders and have some degree of consensus to ensure that they will be used. The literature relating to attitudes towards clinical practice guidelines has much to contribute to the development of educational guidelines. PMID- 17701609 TI - A new approach to bridging content gaps in the clinical curriculum. AB - BACKGROUND: In 2004-05 Tulane University School of Medicine implemented a longitudinal Interdisciplinary Seminar Series composed of small-group interactive exercises to address topics that are often overlooked during the clinical education of medical students. The series utilizes five adult learning principles. METHODS: Each of 13 seminars is offered at a fixed time slot, repeated two to six times per year. Students are required to attend a minimum of five seminars, of their choice, during years three and four. Students access an online pre-enrollment system that maximizes learning opportunities by limiting the number of participants. Seminars emphasize active learning with small-group problem-solving exercises and multiple interactive techniques. Clinical vignettes, standardized patients, journal articles, and case-based learning are among the learning methods. RESULTS: Seminar evaluations showed strong support in program content and effectiveness (mean = 4.47 on a five-point scale), facilitators (4.63), and learning opportunities (4.51). Additionally, students strongly endorsed individual seminars to classmates (4.47). Twelve of 13 (92%) seminars received scores higher than 4.0 for program content and effectiveness, facilitators and learning opportunities. CONCLUSIONS: The Interdisciplinary Seminar Series has been a valuable addition to the Tulane clinical curriculum. Students report that the success of the series is due to: (a) their ability to select seminars based on their individualized interests and needs; and (b) faculty development of student-centered seminars with active learning opportunities. This Seminar Series differs from interclerkship initiatives at other medical schools where topics are offered less frequently and to a class as a whole. Tulane's program is a longitudinal intervention with multiple opportunities for student participation during their clinical education. Seminars are repeated to allow greater flexibility in student scheduling. Seminar discussions are rich in content since attendees include both third- and fourth year students with variable levels of clinical skills and experiences. PMID- 17701610 TI - Educating clinical educators: using a model of the experience of being a clinical educator. AB - BACKGROUND: Clinical educators are expected to prepare students to be competent beginning practitioners, ready to enter the workforce and meet the demands of competent practice. As part of ensuring the quality of clinical education, universities that provide these programs need to be involved in the education and support of clinical educators. In this paper we examine the preparation and professional development of clinical educators based on research into the experiences of being a clinical educator (McAllister 2001). METHODS: The research approach involved a blend of hermeneutic phenomenology and narrative inquiry. In depth interviews were conducted with five speech pathologists in Australia. Data were analysed using a phenomenological analysis process. RESULTS: Recurrent themes in the research were represented by 12 themed stories to richly portray participants' experiences of being clinical educators. An example is provided in this paper. The research produced a model of The Experience of Being a Clinical Educator. The six dimensions of this model are: a sense of self, of self identity; a sense of relationship with others; a sense of being a clinical educator; a sense of agency or purposeful action; dynamic self-congruence; and the experience of growth and change. CONCLUSION: Becoming and being a clinical educator is a developmental process, mirroring in some ways the developmental process clinical educators strive to facilitate for their students. This journey of growth and development as a clinical educator requires active learning approaches coupled with reflection on one's practice as a clinical educator. The model can be used to educate clinical educators in speech pathology and other professions, given the commonalities in clinical educators' roles across professions. Interactive and reflective strategies are presented in the paper for the development and support of clinical educators across the continuum from novice to professional artist. PMID- 17701611 TI - Professionalism in medical education: the development and validation of a survey instrument to assess attitudes toward professionalism. AB - BACKGROUND AND AIM: This study examined attitudes toward professionalism in an academic medical center. The paper will describe the development and factorial validity of an instrument to measure attitudes toward professionalism in medical education among students, residents and faculty. METHODS: A factor analysis of the intercorrelations of responses to 36 items reflecting the American Board of Internal Medicine (ABIM) elements of professionalism for a sample of 765 medical students, residents and faculty was carried out. Data were collected during the spring of 2004. The study was conducted at the Penn State College of Medicine in Hershey, PA, USA. RESULTS: Main outcome measures include internal consistency reliability estimates (Cronbach's alpha) for each element of professionalism and a principal components analysis of the intercorrelations of responses to the 36 items in the questionnaire. Analysis of responses reveals seven identifiable factors of professionalism: accountability, altruism, duty, enrichment, equity, honor and integrity, and respect. CONCLUSIONS: The Penn State College of Medicine Professionalism Questionnaire is one of the first valid and reliable surveys of attitudes among medical students, residents, and faculty that reflects seven elements of professionalism. PMID- 17701612 TI - World conference on medical education: a window on the globalizing world of medical education? AB - The Association for Medical Education in Europe (AMEE) is a worldwide association for all interested in medical and health professions education (http://www.amee.org). AMEE organizes an annual meeting, the most recent of which (2005) was held in Amsterdam. At this meeting certain countries and regions were better represented than others, while some countries with large populations or a significant role in the history of medical education were almost completely absent from the international scene. At the same time, the themes addressed at the AMEE conference concern issues of international interest, and appear to be leading to internationalization of pedagogical and research methods and policies for educational standards. It is therefore crucial that all parts of the medical education world be well represented. This paper illustrates both the strengths and imbalances of AMEE as a forum for the elaboration of international activities and standards in medical education. Finally, the authors wonder why a tendency to assume international generalizability of concepts and perspectives in medical education is not accompanied by studies that compare and contrast medical education methods, research and values between countries and cultures. PMID- 17701613 TI - Looking forward-looking back: aspects of the contemporary debate about teaching and learning medicine. AB - Does the tired oppositional debate between student-centredness and teacher centredness leave the patient stranded, where the patient is surely the focus of a medical education? How might an authentic patient-centred practice be shaped, informed and nourished theoretically? We describe an intellectual landscape of critical, interdisciplinary inquiry that, so far, many medical educators have not inhabited. For example, texts written to inform medical education rarely examine intellectual premises and ideological implications. We offer a number of theoretical frameworks that can inform critical practice, asking 'why do we do it this way?'; 'what are the alternatives?'; and 'how do we justify our approaches intellectually?' We conclude that medical education needs to take stock of its intellectual resources. PMID- 17701614 TI - Taking forward aims of the Bologna Declaration: European core curriculum--the student's perspective. PMID- 17701615 TI - What is the Net Generation? The challenge for future medical education. AB - The Net Generation is the cohort of young people born between 1982 and 1991 who have grown up in an environment in which they are constantly exposed to computer based technology. It has been suggested that their methods of learning are different from those of previous generations. In a survey of first-year undergraduate students, we found that a large majority started university with experience of using online systems such as blogs and wikis; furthermore, their attitudes to the possible use of such tools in learning were positive. The Net Generation is a challenge to the way that all universities and medical schools provide teaching and learning. We suggest that all educators of this group of students need to be aware of incoming students' skills and experience and do more to promote their use in the undergraduate curriculum. PMID- 17701616 TI - Twelve tips for use of a white board in clinical teaching: reviving the chalk talk. AB - Little has been written on the art of using a board in clinical teaching. The technological development of the white board appears to have coincided with that of the laptop computer and accompanying LCD projector, so that fewer and fewer teaching sessions appear to utilize the board as an efficient teaching tool. I have observed this most commonly among younger faculty who are most comfortable with technology and who may lack training and experience with a blank board. This paper offers suggestions on using the board in clinical teaching in order to enhance the educational process through better engagement of the learners. PMID- 17701617 TI - Twelve tips for creating trigger images for problem-based learning cases. AB - A trigger is the starting point of problem-based learning (PBL) cases. It is usually in the form of 5-6 text lines that provide the key information about the main character (usually the patient), including 3-4 of patient's presenting problems. In addition to the trigger text, most programs using PBL include a visual trigger. This might be in the form of a single image, a series of images, a video clip, a cartoon, or even one of the patient's investigation results (e.g. chest X-ray, pathology report, or urine sample analysis). The main educational objectives of the trigger image are as follows: (1) to introduce the patient to the students; (2) to enhance students' observation skills; (3) to provide them with new information to add to the cues obtained from the trigger text; and (4) to stimulate students to ask questions as they develop their enquiry plan. When planned and delivered effectively, trigger images should be engaging and stimulate group discussion. Understanding the educational objectives of using trigger images and choosing appropriate images are the keys for constructing successful PBL cases. These twelve tips highlight the key steps in the successful creation of trigger images. PMID- 17701618 TI - Migration of doctors for undergraduate medical education. AB - BACKGROUND: Global shortages of healthcare workers in both developed and developing countries are of great concern. Research on physician migration typically focuses on medical school graduates, most often those seeking postgraduate training opportunities elsewhere. DESCRIPTION: An overview of medical school migration patterns is presented in this paper. To put this phenomenon into the broader context of global physician migration, data is also presented on the distribution of medical schools, physician density, the flow of international medical graduates to the US, and the present composition of the US physician workforce. RESULTS: Results of the study indicate that many individuals leave their home country for undergraduate medical education. CONCLUSIONS: Given the movement of students and physicians, both for medical school and for advanced training opportunities, it is evident that some medical schools in the world are training doctors for their home country as well as for the international labor market. Overall, given the internationalization of medical education, collaborative efforts will be needed to develop an adequate, balanced, and well trained global physician workforce. PMID- 17701619 TI - Medical student characteristics associated with time in study: is spending more time always a good thing? AB - BACKGROUND: Time in study may reflect motivation, but may also reflect inefficient study habits. PURPOSE: To determine how time in study relates to motivation and study approaches. METHODS: A total of 173 fourth- and fifth-year students in a six-year curriculum completed diaries over seven consecutive days. Time studying was correlated with motivation and approaches to study. RESULTS: Time in study correlated with achieving motive, achieving strategy, deep strategy, motivation and planning/organisation. Deep motive correlated with time on assignments. Students who were less certain they wanted to work as a doctor undertook less study activity and spent less time with patients. Students who lacked confidence they would make a good doctor spent more time in non-timetabled discretionary study but also spent less time with patients. CONCLUSION: A desire to achieve, certainty of career choice and lack of confidence are associated with time in study. Unconfident students divert their time away from patients. PMID- 17701620 TI - Changing approach to undergraduate studies documented during annual appraisal of medical students. AB - BACKGROUND: Transition from school to university life involves maturation changes in areas of academic and personal life. METHOD: Evaluation of factors involved was studied though analysis of appraisal interview outcomes during the first two years, which documented achievements and goal setting in 511 medical students (98% of two student-year cohorts). Qualitative analysis identified key issues in study skills, aspects of personal lives and differences in approach to university life. RESULTS: Study goals were identified in 71% of first-year students. New study skills goals were set by over one-third of students in year 2, including goals for change in both learning techniques and assessment preparation. Organizational skills deficiencies were identified in 24.5% of first years, and as a new issue in an additional 16% of second years. Personal difficulties had little impact on resolution of study skills goals, whilst imbalances in study leisure activities and organizational skills were significant. Motivation and consideration of career choice remained unresolved in 4.5% of second-year students. Some 63% of second years reported changes in approach to studies following discussion during the previous year's appraisal. CONCLUSION: Appraisals are resource intensive but valued highly by students. Appraisal outcomes provided valuable information elucidating factors affecting transition into university life. PMID- 17701621 TI - Bridging the gap: supporting the transition from medical student to practising doctor--a two-week preparation programme after graduation. AB - Concern exists that the transition from student to doctor is abrupt and stressful, and that new graduates lack both clinical skills and confidence. This paper explores the effect of a preparation programme on the confidence and skills of new graduates commencing their first clinical post. Fifty-three participants in two English hospitals undertook a two-week induction combining life support, emergency and clinical skills training with administrative induction and shadowing the outgoing house officer. Questionnaires and focus groups at the beginning, end, and one month following the programme explored participants' perceptions. Respondents were initially anxious about starting work, concerned mainly about clinical skills; taking responsibility; being alone; non-technical skills; and local geography and procedures. Confidence increased following the programme, and the programme's contents directly mitigated some fears. Shadowing was most highly valued, though experiences varied; acute emergency training was also valued, but clinical skills revision was more variably received. Having commenced work, these perceptions remained. Confidence increased further, but clinical practice still represented a steep learning curve. This programme to support the transition from medical student to practising doctor was useful and effective, but could be improved. Increasing responsibility during shadowing could effect an even smoother transition. PMID- 17701622 TI - Students' perception on medical professionalism: the psychometric perspective. AB - BACKGROUND: The main purpose of this study was to identify and understand the structure of latent traits underlying the concept of medical professionalism of Taiwanese students. METHODS: A 32 item questionnaire assessing medical professionalism derived from the definition by the American Board Internal Medicine (ABIM) was distributed to 133 year seven medical students. A five-point rating scale of importance was used to identify the extent of their values or beliefs in each item. RESULTS: The three items perceived most important were: accountability to patients, respect for patients and their families; and integrity and prudence. The least important component underlying professionalism was 'enduring unavoidable risks to oneself when a patient's welfare is at stake'. Factor analysis resulted in eight factors: 'commitment to care' (factor 1); 'righteous and rule-abiding' (factor 2); 'pursuing quality patient care' (factor 3), 'habit of professional practice' (factor 4); 'interpersonal relationship' (factor 5); 'patient-oriented' issues (factor 6); physician's 'self-development' (factor 7); and finally, 'respect for others' (factor 8). Most of the variance was contributed by factor 1 (34.9%). The mean score of factors ranged from 3.84 (factor 1: commitment to care) to 4.7 (factor 8: respect of others), and the reliability alphas ranged from 0.86 to 0.66. CONCLUSIONS: These results of young physicians' professional values have implications for medical school curriculum for improvement. PMID- 17701623 TI - Students' perceptions of early patient encounters in a PBL curriculum: a first evaluation of the Maastricht experience. AB - INTRODUCTION: Real patient encounters before the clinical phase of undergraduate medical education are recommended to stimulate integration of theory and practice. Such encounters are not easy to integrate into the three phases of the problem-based learning cycle, i.e. preparation, self-study and reporting. The authors studied students' perceptions of problem-based learning with real patient encounters as the starting point for learning. METHOD: Students' perceptions of the programme with real patients were evaluated by means of a questionnaire. Mean item scores on a five-point Likert scale and 95% confidence intervals were calculated. RESULTS: Students showed satisfaction with the patient encounters and said they learned a lot from them. Reporting was also highly rated, particularly the integration of theory and practice. Preparation and self-study received lower scores. DISCUSSION: The findings support the view that real patient encounters can act as a powerful driving force for learning and enhance integration of theory and practice. Student learning might benefit from: better information to students and teachers regarding educational objectives, teacher training and careful selection of patients. In order to gain more insight into learning from patient encounters, further studies should address students' and teachers' views and behaviours in respect of this type of learning. PMID- 17701624 TI - Revitalizing problem based learning: student and tutor attitudes towards a structured tutorial. AB - BACKGROUND: The pre-clinical curriculum at the University of New Mexico School of Medicine is a hybrid model that includes small group, problem-based learning (PBL) tutorials and didactic lectures. A structured tutorial format was piloted for the human sexuality/reproduction organ system block for the PBL component. The objective of this study was to compare the acceptability of the structured format and its effectiveness with that of a traditional PBL tutorial. METHODS: Students were surveyed after the renal/endocrinology block of 2004 (traditional tutorial format) and after the human sexuality/reproduction block of 2004 (structured tutorial format) (n = 70). Survey questions covered the quality of learning and of tutorial. Students (n = 132) and tutors (n = 24) who participated in human sexuality/reproduction in 2004 and 2005 were surveyed for attitudes about the structured tutorial overall and specific components. Means of responses were compared using t-tests. RESULTS: Students indicated that the structured tutorial format supported a greater improvement in their basic science and clinical knowledge and their ability to evaluate information (p < 0.05). The majority of students and tutors recommended the structured format for tutorials in other blocks. CONCLUSIONS: We demonstrated the acceptability of a structured tutorial format to students and faculty. Faculty members perceived greater depth of learning and participation by the students. PMID- 17701625 TI - Development of an instrument to assess professional behaviour of foreign medical graduates. AB - BACKGROUND: Foreign medical graduates have to overcome challenges such as language proficiency and cultural differences. Several studies indicate that foreign medical graduates show deficiencies in professional behaviour. For the assessment of foreign medical graduates' professional behaviour, a more specific and sensitive instrument was needed. The aim of this study was to develop such an instrument. The starting point was the Amsterdam Attitudes and Communications Scale (AACS). Two research questions were addressed: (a) What adaptations of the AACS are needed in order to assess foreign medical graduates' professional behaviour adequately? (b) Is the developed instrument reliable, valid and feasible? METHODS: Our study consisted of 4 phases: (1) a brief literature search; (2) consulting a panel of experts; (3) establishing the content-validity of the instrument; and (4) establishing the feasibility of the instrument as an assessment tool. RESULTS: From the literature and experts in the field we learned that deficiencies in professional behaviour of foreign medical graduates concern mainly language skills and culture related issues. In the instrument we developed special attention was given to these deficiencies. Sub-items were added to every dimension. These sub-items are behavioural descriptions of the respective dimension and serve as a basis for feedback. CONCLUSIONS: The sub-items should enhance constructive feedback, not only focussing on inappropriate behaviour but also by emphasizing adequate behaviours. The validity and reliability of the instrument has to be investigated further and confirmed along the way. PMID- 17701626 TI - Team Objective Structured Bedside Assessment (TOSBA): a novel and feasible way of providing formative teaching and assessment. AB - It can be challenging to teach and assess medical students successfully in the setting of a hospital ward using real patients. We describe a novel method of providing weekly formative clinical assessment and teaching to final year students on an acute medical ward: The Team Objective Structured Bedside Assessment (TOSBA). The TOSBA involves three groups of five students rotating through three ward-based stations (each station consists of an inpatient and facilitator). Each group spends 25 minutes at a bedside station where the facilitator asks consecutive students to perform one of five clinical tasks. Every student receives a standardised grade and is provided with educational feedback at each of the three stations. We report our 15-month experience using the TOSBA format to assess and teach a large number of medical students on a weekly basis. We discuss the advantages and potential drawbacks of our approach. PMID- 17701627 TI - Assessing students' research reports: development of a rating scale. AB - BACKGROUND: There is a lack of explicit criteria for the assessment of students' research reports. Teachers tend to use their own, idiosyncratic sets of implicit criteria. A well-defined set of criteria could foster reliable and valid assessment of students' research reports. AIM: The aim of this study was twofold: to detect the strengths and weaknesses of students' research reports and to develop an assessment tool for students' research papers. METHODS: On the basis of the literature and advice from experts, we developed a list of 19 criteria, comprising 15 specific items and 4 global items. Three raters, using the list, independently scored a sample of 18 research reports. RESULTS: The strengths of the reports were the structure of the results and the description of materials and methods. The weaknesses were the research questions, the grounding of the study in the research literature, the analysis, the statistics, and the clarity of visuals. With three raters, the reliability of the rating scale was reasonable. CONCLUSION: The rating scale seems to be a useful tool for judging and giving feedback on students' research reports. These findings will have to be confirmed in studies with larger samples. PMID- 17701628 TI - Use of 360-degree assessment of residents in internal medicine in a Danish setting: a feasibility study. AB - BACKGROUND: The aim of the study was to explore the feasibility of 360 degree assessment in early specialist training in a Danish setting. Present Danish postgraduate training requires assessment of specific learning objectives. Residency in Internal Medicine was chosen for the study. It has 65 learning objectives to be assessed. We considered 22 of these suitable for assessment by 360-degrees assessment. METHODS: Medical departments of six hospitals contributed 42 interns to the study. Each resident was assessed by ten persons of whom one was a secretary, four were nurses and five senior doctors. The assessors spent 14.5 minutes (median) to fill in the forms. RESULTS: Of the 22 chosen objectives, 15 could reliably be assessed by doctors, 7 by nurses and none by secretaries. CONCLUSIONS: The method was practical in busy clinical departments and was well accepted by the assessors. Reliability of the method was acceptable. It discrimintated satisfactorily between the good and not so good performers. PMID- 17701629 TI - 360 degree assessment (multisource feedback) of UK trainee doctors: field testing of team assessment of behaviours (TAB). AB - BACKGROUND: This study was to see if the team assessment of behaviours (TAB) 360 degree assessment tool was able to identify interpersonal behaviour problems in doctors in training, to see if feedback was useful, to gauge the value of the process by those involved, and to learn lessons about implementing the process for the future. METHODS: TAB was administered to assess interpersonal behaviours of senior house officers in four hospitals in the West Midlands, UK. In addition, questionnaires were sent to all participants, some were interviewed about the whole process, and records kept of the time involved. RESULTS: One hundred and seventy-one SHO volunteers received 1378 assessments. The median number of ratings per SHO was 8 (mode 9). Sixty-four percent of SHOs received 'no concern' ratings in all four behaviours (domains) assessed. Twenty-one percent received one 'some concern' rating. Fifteen percent received more than one 'concern' rating. CONCLUSION: Assessors and trainees found the process practical, valuable and fair. Educational supervisors found it valuable, although only 23% learned something new about their trainees. Clinical tutors valued the system. Administrative staff found it time consuming. The TAB four-domain rating form with its single pass category identified specific concern about volunteer trainees' professional behaviour. Not all trainees received skilled feedback. PMID- 17701630 TI - The development of a scale to measure personal reflection in medical practice and education. AB - AIM: Personal reflection is important for acquiring, maintaining and enhancing balanced medical professionalism. A new scale, the Groningen Reflection Ability Scale (GRAS), was developed to measure the personal reflection ability of medical students. METHOD: Explorative literature study was conducted to gather an initial pool of items. Item selection took place using qualitative and quantitative methods. Medical teachers screened the initial item-pool on relevance, expert analysis was used for screening the fidelity to the criterion and large samples of medical students and medical teachers were used to investigate the psychometric characteristics of the items. Finally, explorative factor analysis was used to investigate the structure of the scale. RESULTS: The psychometric quality and content validity of the GRAS are satisfactory. The items cover three aspects of personal reflection: self-reflection, empathetic reflection and reflective communication. The 23-item scale proved to be easy to complete and to administer. CONCLUSION: The GRAS is a practical measurement instrument that yields reliable data that contribute to valid inferences about the personal reflection ability of medical students and doctors, both at individual and group level. PMID- 17701631 TI - Using an objective structured clinical examination (OSCE) to assess multiple physician competencies in postgraduate training. AB - BACKGROUND: Competency-based models of medical education require reliable and valid assessment of multiple physician roles. AIMS: To develop and evaluate an objective structured clinical examination (OSCE) designed to assess 7 physician competencies (CanMEDS Roles). METHODS: Twenty four candidates from 4 neonatal perinatal medicine training programs participated in a 10-station OSCE. Ten 5 point rating scales were developed and used to assess the CanMEDS Roles of Medical Expert, Communicator, Collaborator, Manager, Health Advocate, Scholar and Professional. Three descriptors of performance anchored the ratings. For each station, examiners completed appropriate CanMEDS ratings, a station-specific binary checklist and an overall process-related global rating. Trained standardized patients (SP) and standardized health professionals (SHP) completed rating scales that assessed verbal and non-verbal expression, empathy and coherence as well as the overall global rating. RESULTS: Each station incorporated 3-5 physician Roles. Interstation alpha was 0.80 for checklist scores and 0.88 for examiners' overall global rating. Median interstation alpha for individual CanMEDS ratings was 0.72 (range 0.08-0.91). There were significant correlations between examiner Medical Expert scores and SP/SHP overall global scores and between examiner Communicator scores and 4 SP/SHP assessments of communication skills. Second year trainees' CanMEDS scores for each competency were significantly higher than those of first year trainees (p < 0.05). CONCLUSIONS: The OSCE may be useful as a reliable and valid method of simultaneously assessing multiple physician competencies. PMID- 17701632 TI - Developing performance-based medical school assessment programs in resource limited environments. AB - While the use of performance-based assessments in medical schools is widespread, there are unique issues associated with developing and establishing simulated clinical examinations when resources are limited. The faculty at the National University of Cuyo (NUC) in Mendoza, Argentina, has successfully implemented an OSCE as part of the medical school graduation requirements. This paper provides an overview of the issues faced by NUC faculty in setting up a standardized patient (SP)-based assessment with only limited resources, and contrasts their experiences with those of other groups, including certification and licensure bodies who have implemented similar types of assessments. Despite their novelty and a lack of technological, staffing, and budgetary resources, with adequate planning, an emphasis on faculty involvement, quality case development, local SP recruitment and training activities, educational programs focused on assessment, and flexibility in creating a physical space to conduct the exam, an effective program for assessing the clinical skills of medical students can be realized. PMID- 17701633 TI - Does physical examination competence correlate with bedside diagnostic acumen? An observational study. AB - AIM: To examine the relationship between a physician's ability to examine a standardized patient (SP) and their ability to correctly identify related clinical findings created with simulation technology. METHOD: The authors conducted an observational study of 347 candidates during a Canadian national specialty examination at the end of post-graduate internal medicine training. Stations were created that combined physical examination of an SP with evaluation of a related audio-video simulation of a patient abnormality, in the domains of cardiology and neurology. Examiners evaluated a candidate's competence at performing a physical examination of an SP and their accuracy in diagnosing a related audio-video simulation. RESULTS: For the cardiology stations, the correlation between the physical examination scores and recognition of simulation abnormalities was 0.31 (p < 0.01). For the neurology stations, the correlation was 0.27 (p < 0.01). Addition of the simulations identified 18% of 197 passing candidates on the cardiology stations and 17% of 240 passing candidates on the neurology stations who were competent in their physical examination technique but did not achieve the passing score for diagnostic skills. CONCLUSIONS: Assessments incorporating SPs without physical findings may need to include other methodologies to assess bedside diagnostic acumen. PMID- 17701634 TI - Students' perception of the characteristics of effective bedside teachers. AB - BACKGROUND AND METHODS: To determine a student perspective of the characteristics of ideal bedside teachers, a 25-item questionnaire was administered to 84 final year medical students. The items were constructed to check for two domains of 'Communication' and of 'Demographics'. The former included behaviours such as providing constructive feedback, respecting patient confidentiality and encouraging critical thinking, while the latter included characteristics such as gender, academic rank and language skills. RESULTS: The students identified the characteristics in the 'Communication' domain as being far more important determinants of ideal bedside teaching than the 'Demographics' domain. Factor analysis showed that of the questions designed to determine communication all but one loaded unequivocally into a single factor, while the demographics were best described by two additional factors. Both these factors represented teacher properties that were difficult or impossible for the teacher to modify, while those in the communication domain were all amenable to change. CONCLUSIONS: These results are consistent with data from the literature on the broader aspects of clinical teaching, and imply that the ideal bedside teaching experience from the perspective of the students is heavily influenced by teacher behaviours than that can be modified. PMID- 17701635 TI - Developing scholarly projects in education: a primer for medical teachers. AB - Boyer and Glassick's broad definition of and standards for assessing scholarship apply to all aspects of education. Research on the quality of published medical education studies also reveals fundamentally important elements to address. In this article a three-step approach to developing medical education projects is proposed: refine the scholarly question, identify appropriate designs and methods, and select outcomes. Refining the scholarly question requires careful attention to literature review, conceptual framework, and statements of problem and study intent. The authors emphasize statement of study intent, which is a study's focal point, and conceptual framework, which situates a project within a theoretical context and provides a means for interpreting the results. They then review study designs and methods commonly used in education projects. They conclude with outcomes, which should be distinguished from assessment methods and instruments, and are separated into Kirkpatrick's hierarchy of reaction, learning, behavior and results. PMID- 17701636 TI - Faculty development in general practice in Germany: experiences, evaluations, perspectives. AB - From 1999 to 2001, the German Society of General Practice and Family Medicine (DEGAM) pioneered a faculty development programme to help general practitioners (GPs) interested in an academic career to develop their skills in teaching, primary care, quality assurance and research. The programme involves five weekend training sessions over 18 months and applies a learner-centred approach. Participants choose the learning formats and switch between the roles of learners, teachers, chair persons and programme organizers. This article evaluates the acceptability and feasibility of the programme. Data were collected over a two-year period from the 16 participants who completed the first training programme. The evaluation involved a focus group, telephone interviews and email questionnaires. Participants appreciated the learner centred format of the programme and gained new teaching and research skills. They also learned to better assess and critically reflect on their professional work as GPs and reported improved academic 'survival skills' due to collaborative networks with colleagues. The faculty development programme proved advantageous for the personal and professional development of the participating GPs. It constitutes a promising tool for the further development of General Practice as an academic discipline that is still in the process of establishing itself at medical schools in Germany. PMID- 17701637 TI - Views of National Health Service (NHS) Ethics Committee members on how education research should be reviewed. AB - BACKGROUND: A Local Research Ethics Committee (LREC) may not be appropriate for reviewing research projects involving trainees as participants. AIMS: This study aimed to obtain views of LREC members regarding education research being reviewed by LRECS. METHODS: A questionnaire describing six medical education research projects was sent to an opportunistic sample of LRECs. Respondents were asked to indicate the type of ethics review and consent that would be required for each project. Free text comments were also invited. RESULTS: The majority of the 68 respondents felt that committee review (LREC or institutional) was required for contacting trainees to obtain taped or written interviews. Most felt that some form of consent was appropriate for all the studies. Themes arising from the free text responses were that: there were concerns about this study itself; the requirements for ethical approval for education research should be no different from those of clinical research; there are problems defining 'research', 'audit' and 'course evaluation'; ethical approval should be acquired for education research but not through LRECs; the COREC system is over-complex; and, high standards of research have to be maintained. CONCLUSION: The majority of ethics committee members feel that most education research needs independent review but not necessarily by LRECs. PMID- 17701638 TI - Effect of an integrated teaching intervention on clinical decision analysis: a randomized, controlled study of undergraduate medical students. AB - A four-hour integrated teaching session on clinical decision analysis has been developed and introduced as part of the Life Long Learning Skills course for medical students at The Chinese University of Hong Kong. The feasibility and effectiveness of teaching the principles and practice of clinical decision analysis to final-year undergraduate medical students was evaluated. One hundred and thirty-two students were randomly assigned to medical (intervention) and surgical rotations (control) and were assessed two weeks before and three weeks following a teaching session. The students' performance was assessed in response to 10 A-type multiple choice question items that incorporated various clinical scenarios requiring decision making and interpreting cost-effectiveness ratios and sensitivity analysis graphs. More students in the intervention group improved their overall performance scores compared with those in the control group (23.4% vs. 7.4%; 16.1% difference; 95% confidence interval [CI], 3.8-28.5%; p = 0.01). Improvements were in interpretation of decision making (22.2% difference; 95% CI, 10.1-34.4%; p < 0.001). No improvements were seen for calculating cost effectiveness ratios or interpreting sensitivity analysis graphs. The overall educational intervention was well received by students and effective in improving students' clinical decision analysis skills under simulated conditions. PMID- 17701639 TI - Patient contact in the first year of basic medical training--feasible, educational, acceptable? AB - BACKGROUND: A new UK medical school uses substantial early patient contact in the first 2 years of an integrated 5-year course. AIMS: To explore the feasibility, educational effectiveness, and acceptability to patients of substantial early patient contact. METHODS: Mixed-methods case study with data from patients, students, and staff gathered via encounter forms, questionnaires, interviews, and focus groups. RESULTS: The curriculum model of recruiting a specific patient case mix to match concurrent theoretical teaching was feasible. Patients were willing to attend specifically to meet students, even if not receiving contemporaneous care. Patient satisfaction with teaching involvement was very high, and most patients were willing to attend further sessions. Although at an early stage of knowledge and skill acquisition, students greatly valued their extensive contact with patients. They perceived it as adding substantially to their learning of clinical medicine, by providing 'real' learning opportunities and linking theory to practice. It was motivating and memorable, and enabled students to meet learning objectives. There was also evidence that it encouraged students to develop a patient-centred approach. CONCLUSIONS: Early, integrated patient contact was both feasible to organise and acceptable to patients. The curriculum model was perceived by all parties to be educationally effective. The indications are that this model will be sustainable but will need consistent intensive support. PMID- 17701641 TI - Mentoring a medical student towards applied research in a developing country. AB - In South Asia, the student-teacher relationship is hierarchical and authoritarian. I and my colleagues spend time and energy teaching students to think, to question and to critically evaluate statements and assumptions. Bishnu Giri was an enthusiastic student willing to think out of the box. Bishnu has been involved in drug utilization studies, investigating factors influencing drug use and in promoting rational use of drugs. He has published a number of articles and has been encouraging other students to participate in research. PMID- 17701640 TI - An innovative model for teaching complex clinical procedures: integration of standardised patients into ward round training for final year students. AB - OBJECTIVES: Ward rounds are an essential activity for doctors in hospital settings and represent complex tasks requiring not only medical knowledge but also communication skills, clinical technical skills, patient management skills and team-work skills. However, although the need for ward round training is emphasized in the published literature, there are currently no reports of ward round training in a simulated setting with standardized patients. METHODS: 45 final year students participated in a ward round training session lasting two hours with three standardized patient scenarios and role-plays. Final year students assumed the role of either doctor, nurse or final year student with role specific instructions and provided each other with peer-feedback during the training session. Training was assessed using final year student focus groups and semi-structured interviews of standardized patients. Written protocols of the focus group as well as the interviews of standardized patients were content analysed. RESULTS: In the course of five focus groups, 204 individual statements were gathered from participating final year students. Ward round training proved to be a feasible tool, well accepted by final year students. It was seen to offer a valuable opportunity for reflection on the processes of ward rounds, important relevant feedback from standardized patients, peer group and tutors. Semi structured standardized patient interviews yielded 17 central comments indicating that ward rounds are a novel and exciting experience for standardized patients. CONCLUSION: Ward round training with standardized patients is greatly appreciated by final year students and is viewed as an important part of their education, easing the transition from observing ward rounds to conducting them on their own. PMID- 17701642 TI - A triangulated approach to the assessment of teaching in childhood epilepsy. AB - BACKGROUND: A comprehensive methodology is needed to assess student teaching. The present study employed a triangulated approach evaluating participant perceptions of learning, critical reflection by the lecturer and peer observation to measure confidence, interest and usefulness of the subject matter. METHODS: Using an interactive lecturing style, seven teaching sessions were delivered to medical students and junior doctors. Rating scales, open-ended questions and focus group discussions evaluated participant perceptions. Critical reflections and observations were made by the lecturer and independent learning consultants. RESULTS: Seventy per cent of participants rated the lecture on the highest scale for usefulness and interest. There was a significant post-lecture increase in clinical confidence in seizure identification (p < 0.0005). Open-ended questions showed that videos were most useful (81/149) and interesting (109/149), and that the presentation of the syndromal classification provided a useful approach (114/149). Focus group discussion, lecturer and peer observation cross-validated these findings and highlighted the importance of expert commentary to the videos and the clinical relevance of material. PMID- 17701643 TI - Placing the patient at the core of teaching. AB - BACKGROUND: In the revised undergraduate medical programme at the University of Dundee, medical students visit a patient with a chronic illness in the patient's own home. Students' learn about the patient's experience of their chronic illness/disease over time. It is known as 'the patient journey'. The concept of 'the patient journey' emerged from Tomorrow's Doctors (2003) in light of the need to increase community-based education. DESCRIPTION: The evaluation was carried out using a focus group. Students indicated that community-based education can show them real life in a home context; early contact with a patient enabled them to have a better understanding of patient-centred medicine; meeting a patient early brings reality and continuity to their careers and a clearer understanding of the patient's condition. CONCLUSIONS: Further work may clarify the specific long-term values of the patient visit and how it may support teaching and learning within the first three years of the curriculum. PMID- 17701644 TI - Using high-fidelity emergency simulation with large groups of preclinical medical students in a basic science course. AB - BACKGROUND: High-fidelity patient simulation is often used to teach clinical patient management and decision-making with small groups. This pilot project determined feasibility for large-group educational presentations using simulation for preclinical basic science courses. METHODS: We developed an emergency patient simulation encounter illustrating basic neuroscience concepts. Physician actors interacted with a high-fidelity simulated patient mannequin in a lecture hall. First and second year medical students were active participants in the 90 minute live event in large groups. Digital video was recorded and written feedback was obtained from participants. RESULTS: The simulation was presented four times to a total of 202 students. Video review demonstrated extensive interaction within the large groups. Case management discussions included basic science topics, autonomic pathways, and neuropharmacology. Student feedback revealed 98% rated the correlation to basic science concepts as very good or outstanding, and 99% rated the same for overall presentation. CONCLUSIONS: Live large-group simulation presentations are feasible in a non-traditional location, correlate with basic science in the preclinical medical curriculum, and are well-received by students. PMID- 17701645 TI - The use of a video interview to enhance gross anatomy students' understanding of professionalism. AB - There is much room for innovation in teaching medical students professionalism. The goal of this exercise was to enhance first-year Gross Anatomy students' understanding of professionalism, including the attributes of confidentiality, respectful behavior and humanism in medicine through a video interview with a donor family member. Survey results demonstrated that students generally agreed that the video helped them better understand professionalism in the context of the gross anatomy laboratory and gave them a deeper respect for donors. Most students strongly agreed that future medical students would benefit from viewing this video interview. PMID- 17701646 TI - Harmonization of the bachelor-master system in the curricula of the medical doctor and the biomedical sciences. Report on a 2 days workshop. PMID- 17701647 TI - European core curriculum--the students' perspective, Bristol, UK, 10 July 2006. AB - The International Federation of Medical Students' Associations (IFMSA) and the European Medical Students' Association (EMSA) are proud to present the first outcome-based core curriculum for medicine from the perspective of the medical students of Europe. It covers 76 learning outcomes grouped around nine domains: (1) Clinical Skills, (2) Communication, (3) Critical Thinking, (4) Health in Society, (5) Lifelong Learning, (6) Professionalism-Attitudes, Responsibilities, and Self-development, (7) Teaching, (8) Teamwork, and (9) Theoretical knowledge. The statement is a result of a long process of international workshops, conferences, and discussions on numerous meetings for medical students and health care professionals all over Europe. Previous conferences resulted in widely recognized policy statements on the 'Bologna Declaration and Medical Education' and 'Quality Assurance in Medical Schools' (Westbye 2004; IFMSA/EMSA 2005). We hope that our European core curriculum from the students' perspective may serve as a foundation for the development of outcome-based core curricula all over Europe, enhancing mobility of students and graduates and promoting excellent health care in the future. PMID- 17701648 TI - Teaching syndromes--a response to learning syndromes. PMID- 17701649 TI - Teaching forensic psychiatry using problem-based learning: a move away from lectures. PMID- 17701650 TI - Student perceptions of the benefits of problem-based learning. PMID- 17701651 TI - A shift from passive teaching at medical conferences to more interactive methods improves physician learning. PMID- 17701652 TI - Piloting the new specialist training year 1 (ST1) interview process--using the OSCE. PMID- 17701657 TI - Chronic kidney disease (CKD) in the elderly -- a geriatrician's perspective. AB - Chronic kidney disease (CKD) is becoming increasingly prevalent among many different populations all over the world, including the US and Europe. Its multitude of complications with devastating outcomes leads to a significantly higher risk for cardio-vascular and all-cause mortality in an individual. However, it is clear now that early detection of CKD might not only delay some of the complications but also prevent them. Therefore, various important public health organizations all over the world have turned their focus and attention to CKD and its risk factors, early detection and early intervention. Nevertheless, the general goals in preventing the increase in CKD and its complications are far from being completely achieved. Why is this so? What is the magnitude and complexity of the problem? How is it affecting the population - are there differences in its affection by age, gender or frail elderly versus the robust? Are we modifying the risk factors appropriately and aggressively? Are there subtle differences in managing the risk factors in those on dialysis versus the non-dialysis CKD patients? Is it important to treat anaemia of CKD aggressively, will it make a difference in the disease progression, its complications or to quality of life? What do these unfortunate individuals commonly succumb to? What do we advise patients who refuse dialysis or those who desire dialysis or transplant? Are there useful non-dialytic treatment recommendations for those who refuse dialysis? What is the role of the physicians caring for the elderly with CKD? When should the primary care givers refer a CKD patient to a nephrologist? The key to eventually controlling incident and prevalent CKD and improve quality of life of affected individuals, lies in not only knowing these and many other vital aspects, but also in applying such knowledge compulsively in day-to-day practice by each and every one us. As CKD is increasingly a disease of the elderly with men being affected more, this review details fairly comprehensively the vital aspects of CKD, especially from a primary care geriatrician's practical standpoint. PMID- 17701658 TI - Testosterone therapy in the aging male. AB - The decline, with aging, in serum concentrations of biologically active forms of testosterone in men is an indisputable fact and some men will eventually develop symptoms of late-onset hypogonadism (LOH) with its clinical consequences. LOH reduces quality of life and may pose important risk factors for frailty, changes in body composition, cardiovascular disease, sexual dysfunction and osteoporosis. Testosterone supplementation in cases of LOH will restore serum testosterone levels into the physiologic range; will restore metabolic parameters to the eugonadal state, increase muscle mass, strength, and function; maintaine or improve BMD reducing fracture risk; will improve neuropsychological function (cognition and mood); libido and sexual functioning; and enhance quality of life. The ultimate goals, however, are to maintain or regain a high quality of life, to reduce disability, to compress major illnesses into a narrow age range and to add life to years. To achieve these goals men must also adjust their lifestyle to optimize dietary habits, as well as to exercise and to abstain from smoking life long. Monitoring these patients is a shared responsibility that cannot be taken lightly. The physician must emphasize to the patient the need for periodic evaluations and the patient must agree to comply with these requirements. The physician's evaluation should include an assessment of the clinical response and monitoring must be tailored to the indications and individual needs of the patient. PMID- 17701659 TI - A four-year efficacy and safety study of the long-acting parenteral testosterone undecanoate. AB - INTRODUCTION: This is a four-year follow-up of 25 men who received parenteral testosterone undecanoate (TU), 1000 mg every 12 weeks for at least four years. This study was a continuation of a 30-week study wherein the effects of TU had been compared to those of parenteral testosterone enanthate. METHODS & RESULTS: Plasma testosterone (T) trough values of the injection interval of 12 weeks): median 11.9 - 15.9 nmol/L (N 10.0-30.0). E2 and SHBG were stable. Body weight, BMI, waist-to-hip ratio remained stable. Total cholesterol, and triglycerides were unchanged but plasma LDL declined while HDL, after an initial reduction over the first 30 weeks, had increased significantly after three years. Leptin levels, bone mineral density, blood pressure, liver function tests, haemoglobin and haematocrit levels remained stable without values above the upper limit of normal. Over the first 12 months of the study there was an increase in prostate volume from 19.7 +/- 8.8 mL to 22.0 +/- 8.4 mL (p < 0.05) but thereafter volumes remained stable, paralleled by an increase in PSA from 0.67 +/- 0.38 microg/dL to 0.75 +/- 0.35 microg/dL (p < 0.05) without any further changes after 12 months. CONCLUSION: TU appears to be a stable and safe treatment modality of hypogonadal men. PMID- 17701660 TI - Analysis of the discriminant ability of shorter versions of the French ADAM questionnaire. AB - OBJECTIVE: To investigate whether shorter versions of the ADAM test, a screening questionnaire for andropause, provide better diagnostic value than the original tool. METHODS: Five thousand and twenty-eight volunteer men aged 50-70 years attending a screening campaign for andropause, provided a fasting blood sample and completed the French ADAM test. Logistic regression analysis identified items that best predict andropause defined as serum free testosterone level below 70 ng/l. ROC curves assessed the diagnostic value of modified versions of the ADAM test, obtained by elimination of the less relevant predictors of andropause. RESULTS: Only four items of the ADAM questionnaire may account for the diagnosis of andropause. These items concerned loss of height, decrease in libido and in enjoyment of life and deterioration in work performance. Item 9 was borderline significant. The area under the ROC curve for the short versions varied slightly from 0.555 to 0.560. As expected, model 6 has a greater specificity (56.02%) than the original tool while the efficiency increased slightly (54.85%). CONCLUSION: The modified versions of the ADAM test do not provide better diagnostic value than the original tool. PMID- 17701662 TI - Fetomaternal alloimmune thrombocytopenia: the questions that still remain. AB - Fetomaternal alloimmune thrombocytopenia (FMAIT) occurs when maternal antibodies are formed to fetal platelet antigens, leading to thrombocytopenia and hemorrhagic complications. The diagnosis is frequently made only after a major hemorrhagic event has occurred during a pregnancy. Identifying patients at risk remains difficult, and the optimal treatment regimen remains to be determined. PMID- 17701661 TI - The validity of androgen assays. AB - Problems in the measurement of androgens and in interpreting results have been reviewed and classified as follows: PREANALYTICAL FACTORS: The exact sampling conditions in relation to circadian and seasonal variations, diet, alcohol, physical activity and posture. PHYSIOLOGICAL AND MEDICAL FACTORS: Androgen levels vary according to the patient's general health, stress, sexual activity and smoking habits. Analytical variables. Sample preservation and storage variables are often unknown. The different androgen assays used have widely differing accuracy and precision and are subject to large inter-laboratory variation, which especially in women and children can render the results of routinely available direct immunoassays meaningless. INTERPRETATION OF RESULTS: Laboratory reference ranges vary widely, largely independent of methodology, and fail to take into account the log-normal distribution of androgen values, causing errors in clinical diagnosis and treatment. Other unknowns are antagonists such as SHBG, estrogens, catecholamines, cortisol, and anti-androgens. As well as age, androgen receptor polymorphisms play a major role in regulating androgen levels and resistance to their action. CONCLUSIONS: Though laboratory assays can support a diagnosis of androgen deficiency in men, they should not be used to exclude it. It is suggested that there needs to be greater reliance on the history and clinical features, together with careful evaluation of the symptomatology, and where necessary a therapeutic trial of androgen treatment given. PMID- 17701663 TI - Bone marker status in mothers and their newborns in Iran. AB - OBJECTIVES: The contribution of maternal skeletal calcium metabolism in pregnancy is evidenced in changes in the markers of bone formation and bone resorption. Changes in maternal bone markers could affect fetal bone mineralization. The aim of this study was to determine the association between maternal and cord blood bone markers. METHODS: Five hundred and fifty-two pregnant women were recruited from Tehran University educating hospitals in the winter of 2002. Maternal and cord blood samples were taken at delivery. The serum was assayed for osteocalcin and crosslaps, calcium, and parathyroid hormone. RESULTS: There was significant correlation between maternal and cord blood serum osteocalcin and crosslaps levels, and the mean cord blood levels of osteocalcin and crosslaps were significantly higher at about 1.59- and 1.62-fold maternal levels, respectively. Serum calcium levels strongly correlated with osteocalcin and crosslaps in mothers (r = 0.21, p = 0.001 and r = 0.25, p = 0.001, respectively). CONCLUSIONS: Skeletal calcium release may play a major role in calcium homeostasis during pregnancy. Because of this, calcium supplements could have an important role in pregnant women in decreasing the risk of subsequent complications such as osteoporosis. PMID- 17701664 TI - ADAM12 as a marker of trisomy 18 in the first and second trimester of pregnancy. AB - BACKGROUND: ADAM12 (a disintegrin and metalloprotease 12) is a placentally derived glycoprotein that appears to be involved in growth and differentiation. The maternal serum concentration of ADAM12 appears to be a very good marker of trisomy 21 in the early first trimester when levels are reduced, and in the second trimester around 16-18 weeks levels are elevated. One small preliminary study of first trimester pregnancies with trisomy 18 found reduced levels in the maternal serum, and we examine herein the potential of ADAM12 as a marker of trisomy 18 in both the first and second trimester of pregnancy. MATERIALS AND METHODS: The concentration of ADAM12 was determined by a time-resolved immunofluorometric assay in 132 first and 12 second trimester cases of trisomy 18, and 389 first and 341 second trimester gestational age-matched control pregnancies. Medians of normal pregnancies were established by polynomial regression and used to determine the population distribution parameters for the trisomy 18 and control groups. Correlation with previously established pregnancy associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (beta-hCG) multiples of the median (MoMs) and nuchal translucency thickness (NT) MoM were determined and used to model the performance of first trimester screening with ADAM12 in combination with other first trimester markers. RESULTS: The maternal serum concentration of ADAM12 in the first trimester was significantly reduced with a median MoM of 0.829 (p < 0.001) and a mean log10 MoM SD of 0.2663 compared to 0.3353 in the controls. In the second trimester small series ADAM12 was significantly increased with a median MoM of 2.09 (p = 0.001) and a mean log10 MoM SD of 0.2607 compared to 0.4318 in controls. There was a significant correlation of ADAM12 MoM with gestational age (r = 0.510) in trisomy 18 cases, and the median MoM increased from 0.51 at 10 weeks to 1.28 at 13 weeks and 2.09 across the 14-18 week window. ADAM12 was correlated with PAPP-A (r = 0.1918) in the first trimester of cases with trisomy 18 but less so with NT (r = 0.1594) and free beta-hCG (r = 0.0938). Modeled detection rates incorporating ADAM12, free beta-hCG, and NT were 92% at 1% false positive rate (88% at 0.5%) A combination of all four markers had a detection rate of 96.5% at a false positive rate of 1% (95% at 0.5%). CONCLUSION: ADAM12 may be a useful addition to early screening for trisomy 18 alongside other chromosomal anomalies, particularly if biochemical screening can occur before 10 weeks. PMID- 17701665 TI - Placental growth hormone is increased in the maternal and fetal serum of patients with preeclampsia. AB - OBJECTIVES: Placental growth hormone (PGH) is a pregnancy-specific protein produced by syncytiotrophoblast and extravillous cytotrophoblast. No other cells have been reported to synthesize PGH Maternal. PGH Serum concentration increases with advancing gestational age, while quickly decreasing after delivery of the placenta. The biological properties of PGH include somatogenic, lactogenic, and lipolytic functions. The purpose of this study was to determine whether the maternal serum concentrations of PGH change in women with preeclampsia (PE), women with PE who deliver a small for gestational age neonate (PE + SGA), and those with SGA alone. STUDY DESIGN: This cross-sectional study included maternal serum from normal pregnant women (n = 61), patients with severe PE (n = 48), PE + SGA (n = 30), and SGA alone (n = 41). Fetal cord blood from uncomplicated pregnancies (n = 16) and PE (n = 16) was also analyzed. PGH concentrations were measured by ELISA. Non-parametric statistics were used for analysis. RESULTS: (1) Women with severe PE had a median serum concentration of PGH higher than normal pregnant women (PE: median 23,076 pg/mL (3473-94 256) vs. normal pregnancy: median 12 157 pg/mL (2617-34 016); p < 0.05), pregnant women who delivered an SGA neonate (SGA: median 10 206 pg/mL (1816-34 705); p < 0.05), as well as pregnant patients with PE and SGA (PE + SGA: median 11 027 pg/mL (1232-61 702); p < 0.05). (2) No significant differences were observed in the median maternal serum concentration of PGH among pregnant women with PE and SGA, SGA alone, and normal pregnancy (p > 0.05). (3) Compared to those of the control group, the median umbilical serum concentration of PGH was significantly higher in newborns of preeclamptic women (PE: median 356.1 pg/mL (72.6-20 946), normal pregnancy: median 128.5 pg/mL (21.6-255.9); p < 0.01). (4) PGH was detected in all samples of cord blood. CONCLUSIONS: (1) PE is associated with higher median concentrations of PGH in both the maternal and fetal circulation compared to normal pregnancy. (2) Patients with PE + SGA had lower maternal serum concentrations of PGH than preeclamptic patients without SGA. (3) Contrary to previous findings, PGH was detectable in the fetal circulation. The observations reported herein are novel and suggest that PGH may play a role in the mechanisms of disease in preeclampsia and fetal growth restriction. PMID- 17701666 TI - Preeclampsia is associated with low concentrations of protein Z. AB - OBJECTIVE: Protein Z, a vitamin K-dependent plasma protein, has an important role in the regulation of the coagulation cascade. Protein Z deficiency has been associated with unexplained pregnancy loss and adverse pregnancy outcome in patients with thrombophilia. This study was conducted to determine if preeclampsia (PE), small for gestational age (SGA), and fetal demise are associated with changes in maternal plasma concentrations of protein Z. STUDY DESIGN: This cross-sectional study included normal pregnant women (N = 71), patients with PE (N = 130), patients who delivered an SGA neonate (N = 58), and patients with fetal demise (N = 58). Maternal plasma protein Z concentrations were measured by a sensitive and specific immunoassay. Protein Z deficiency was defined as maternal plasma concentrations 0.05); and (3) women in the PE and fetal demise groups had significantly higher rates of protein Z deficiency than those with normal pregnancy outcome. CONCLUSIONS: (1) PE, but not SGA or fetal demise, is associated with a significantly lower maternal median plasma concentration of protein Z than normal pregnancy, and (2) a high rate of protein Z deficiency is observed in patients with PE and fetal demise. PMID- 17701667 TI - Acute and chronic respiratory diseases in pregnancy: associations with spontaneous premature rupture of membranes. AB - OBJECTIVE: To examine whether acute and chronic respiratory diseases are associated with an increased risk of spontaneous premature rupture of the membranes (PROM). METHODS: We used the 1993-2004 National Hospital Discharge Survey data of singleton deliveries in the USA (N = 41 250 539). The International Classification of Diseases Ninth Revision was utilized to identify acute (acute upper respiratory diseases, viral/bacterial pneumonia, and acute bronchitis/bronchiolitis) and chronic (chronic bronchitis and asthma) respiratory conditions and spontaneous PROM. All analyses were adjusted for potential confounders. RESULTS: The incidence of PROM was 5%, and rates of acute and chronic respiratory conditions were 2.1 and 9.5 per 1000 pregnancies, respectively. Chronic bronchitis was associated with a reduced risk of PROM (RR 0.39, 95% CI 0.31, 0.48). Asthma was significantly associated with PROM at preterm (RR 1.15, 95% CI 1.14, 1.17) and term (RR 1.27, 95% CI 1.23, 1.30). Stratification by race showed that acute upper respiratory disease was associated with preterm PROM in whites (RR 1.90, 95% CI 1.71, 2.11) and blacks (RR 6.76, 95% CI 5.67, 8.07). Viral/bacterial pneumonia was associated with preterm PROM in blacks and term PROM in both races. Asthma was associated with term PROM in blacks but not whites. CONCLUSIONS: Acute respiratory diseases and asthma during pregnancy are associated with spontaneous PROM, with substantially stronger association among blacks than whites. We speculate that timely diagnosis and treatment, coupled with closely mentoring of pregnant women may help reduce the rate of PROM and associated complications. PMID- 17701668 TI - Maternal vagal tone change in response to methadone is associated with neonatal abstinence syndrome severity in exposed neonates. AB - OBJECTIVE: Though methadone pharmacotherapy is the treatment of choice for opiate dependence during pregnancy in the USA, most methadone-exposed neonates develop neonatal abstinence syndrome (NAS). NAS expression is widely variable among methadone-exposed neonates and only a subset requires pharmacotherapy. This study explores the potential predictors of NAS severity, including aspects of maternal substance use and methadone maintenance histories, concomitant exposure to other licit substances, and individual differences in intrinsic maternal or infant factors that may affect the infant's vulnerability to NAS expression. METHODS: Fifty methadone-maintained pregnant women attending a comprehensive substance abuse treatment facility, received electrocardiogram monitoring at 36 weeks of gestation at the times of trough and peak maternal methadone levels. Vagal tone, an estimate of the magnitude of an individual's respiratory sinus arrhythmia and an indicator of autonomic control, was derived. RESULTS: NAS expression was unrelated to maternal substance abuse history, methadone maintenance history, or psychotropic medication exposure. Male infants displayed more profound NAS symptoms and received more pharmacotherapy to treat NAS (all p < 0.05). NAS expression was related to maternal vagal reactivity; both suppression and activation of maternal vagal tone in response to methadone administration were positively and significantly associated with NAS symptomatology (F (2,44) = 4.15, p < 0.05) and treatment (F (2,44) = 3.39, p < 0.05). Infants of vagal non responder mothers showed substantially lower NAS expression. CONCLUSIONS: NAS severity is associated with maternal vagal tone change in response to methadone administration. PMID- 17701669 TI - Risk factors for placental abruption in a socio-economically disadvantaged region. AB - OBJECTIVE: This study was undertaken in order to determine the risk factors for pregnancies complicated by placental abruption in a socio-economically disadvantaged region in metropolitan Adelaide. METHODS: This was a retrospective case-control study including all singleton pregnancies resulting in placental abruption between 2001 and 2005. RESULTS: The overall incidence of placental abruption was 1.0%; the overall perinatal mortality among the births with abruption was 13%. Univariate analyses showed the following significant risk factors for placental abruption: preterm pre-labor rupture of the membranes (PRE PROM; odds ratio (OR) 4.79, 95% confidence interval (CI) 1.52-15.08), non compliance with antenatal care (OR 2.93, 95% CI 1.06-8.90), severe intrauterine growth restriction (IUGR), and elevated homocysteine levels (OR 45.55, 95% CI 7.05-458.93). Severe IUGR was significantly more common in the abruption group compared with the control group (p = 0.032). In the multivariate analysis, PRE PROM remained a significant independent risk factor for placental abruption. Marijuana use, domestic violence, and mental health problems were more common (borderline significance) in the abruption group. Smoking and preeclampsia were not found to be associated with placental abruption in this study. CONCLUSIONS: In this high-risk population, PRE-PROM and elevated homocysteine levels appear to represent the major risk factors for placental abruption. PMID- 17701670 TI - Maternal-fetal transport kinetics of carboplatin in the perfused human placental lobule: in vitro study. AB - OBJECTIVE: Platinum-containing drugs are widely used in the treatment of various malignancies in humans. There is a paucity of data on maternal-fetal transport characteristics of one such widely used drug, carboplatin, and this prompted us to study its permeation characteristics in the human placenta in vitro. METHODS: Placentae from uncomplicated, normal pregnancies were collected postpartum. Carboplatin, along with antipyrine as internal reference marker were injected as a single bolus (100 ul) into the maternal arterial circulation of isolated perfused placental lobules and perfusate samples collected from both maternal and fetal circulations over a period of 5 minutes. National Culture and Tissue Collection medium, diluted with Earle's buffered salt solution was used as the perfusate. Carboplatin concentration in various samples was determined by atomic absorption spectrophotometry, while antipyrine concentration was assayed by spectrophotometry. Transport and pharmacokinetic data of study and reference substances were computed using appropriate parameters. RESULTS: The differential transport rate of carboplatin for 10, 25, 50, 75, and 90% efflux fractions in fetal venous effluent averaged 0.60, 1.35, 2.52, 3.72, and 4.49 minutes in 12 perfusions, representing 1.16 +/- 0.10, 1.06 +/- 0.06, 1.00 +/- 0.02, 0.98 +/- 0.01, and 0.99 +/- 0.01, respectively, times the antipyrine reference value. Student's t-test did not show any significant difference (p > 0.05) between the control and study group data. The transport fraction (TF) of carboplatin, expressed as the fraction of the drug appearing in the fetal vein during a study period of 5 minutes, averaged 9.00 +/- 0.52% of bolus dose, while antipyrine TF averaged 68.60 +/- 2.01% of injected bolus dose, representing 13.1% of reference marker value. Student's t-test showed carboplatin and reference marker TF values to be significantly different (p < 0.05). Pharmacokinetic parameters such as area under the curve, clearance, time for maximum response, and absorption and elimination rates of study and reference substances showed varying differences. CONCLUSIONS: We report for the first time that carboplatin transport from the maternal to the fetal circulation is relatively small in the human placenta at term. It is reasonable to assume that the risk for the neonate from carboplatin use in pregnancy is minimal when used in emergency clinical situations. PMID- 17701671 TI - Effect of oxytocics on the blood pressure of normotensive Nigerian parturients. AB - BACKGROUND: The single most common direct obstetric disorder accounting for 25% of all maternal deaths globally is severe hemorrhage, generally occurring postpartum. Nearly all these deaths occur in the developing world. The role of oxytocic drugs in the management of the third stage of labor as a strategy to reduce maternal mortality has been emphasized. However, the adverse effects of these oxytocic agents, in particular ergometrine, have not been properly evaluated in our environment. OBJECTIVES: To evaluate the effect of ergometrine and oxytocin on the cardiovascular system when used for active management of the third stage of labor. STUDY DESIGN: A double-blind, randomized controlled study was carried out at the Federal Medical Centre, Makurdi over 24 months. Five hundred and ten patients were randomized to treatment with either 0.5 mg of intramuscular ergometrine or 10 IU of intravenous oxytocin, respectively, as single injections. Their effects on the cardiovascular system were observed using blood pressure as a marker. RESULTS: Ergometrine unlike oxytocin was observed to cause a significant rise in blood pressure, and this effect was most marked in the first 24 hours of the puerperium. CONCLUSIONS: These results suggest that ergometrine may be safe in normotensive parturients but hazardous in hypertensive parturients in whom oxytocin would be a safer option. PMID- 17701673 TI - Euchronism, allochronism, and dyschronism: is internal desynchronization of human circadian rhythms a sign of illness? AB - The authors define a subject as euchronic when the circadian parameters--tau (tau=period), O (acrophse or peak time), A (amplitude), and M (MESOR=24 h rhythm adjusted mean)--of a set of circadian variables are within the confidence limits of appropriate reference values of healthy subjects (HS). We define internal desynchronization as a state in which the circadian tau of a set of rhythms differs from 24 h and when the tau of a given variable differs from that of other variables. Such a state was first observed in singly isolated HS without access to time cues and clues. Herein, data and analyses are presented demonstrating that internal desynchronization appears to be a rather common phenomenon in HS dwelling in their natural environment (i.e., in the presence of usual zeitgebers). This has been documented by longitudinal studies (n approximately=15 days) of the circadian rhythm in sleep-wakefulness, body temperature, right- and left-hand-grip strength, and reaction time involving a total of 246 HS and 134 shift workers (SW), with 45.5% showing good and 54.5% poor SW tolerance. The presence of internal desynchronization observed in SW was associated SW intolerance, with symptoms being sleep alteration/disturbances, sleeping-pill dependence, persisting fatigue (asthenia), mood alteration, and digestive complaints. Internal desynchronization was also documented in groups of HS and tolerant SW, though it was almost the rule among the intolerant SW. The authors introduce two new terms: allochronism to describe the time organization of those SW who evidence internal desynchronization without detectable clinical symptoms, and dyschronism to describe the time organization of those SW who exhibit internal desynchrobization plus the symptoms of SW intolerance or medical illness. The condition of allochronism is not restricted only to SW tolerance, as it was detected in 112 HS without medical complains when exposed to various experimental conditions, including medications and placebos, sojourn in the high Arctic summer, intensive sport training, and task-loaded cognitive performance testing. Dyschronism in SW who are sleep-deprived is associated with persisting fatigue. An unpublished Gallup survey found that 47% of 2478 respondents experienced a state of asthenia during the previous 12 months, with symptoms mimicking those of SW intolerance. In one-third of the cases, the origin of the asthenia was undetermined. Taking into account the high incidence of internal desynchronization found in past investigations and the clinical observation that sleep deprivation is a consequence of many acute and chronic medical conditions (nocturnal pain, nocturnal asthma, etc.), it is suggested that dyschronism may be responsible for the asthenia of unknown origin, at least for some persons. The interindividual (including sex-related) variability in the propensity to exhibit an altered temporal organization, whether it be transient or persistent (i.e., reversible or non-reversible) suggests the involvement of genetic factors. The Dian-Circadian genetic model previously proposed by the authors seems pertinent to conceptualize and explain the various levels and output of internal desynchronization. PMID- 17701674 TI - Allelic variants interaction of CLOCK gene and G-protein beta3 subunit gene with diurnal preference. AB - The 3111 C/T single nucleotide polymorphism (SNP) in the CLOCK gene and the 825C/T SNP in the G-protein beta3 subunit gene (GNB3) have been reported to influence diurnal preference. This study has attempted to characterize the association between the CLOCK gene and GNB3 polymorphisms and diurnal preference in healthy Korean college students. All subjects completed the 13-item Composite Scale for Morningness (CSM). The interaction between the 3111 C/T SNP in the CLOCK gene and the 825 C/T SNP in the GNB3 gene significantly influenced diurnal preference, according to the CSM Performance subscore (F=10.94, p=0.001). However, when the different polymorphisms of the two genes were analyzed independently, no direct correlations with diurnal preference were detected. The CLOCK gene 3111 C/T SNP and GNB3 gene 825 C/T SNP were found to manifest a gene gene interaction that affects diurnal preference. PMID- 17701675 TI - The relationship between the golden spiny mouse circadian system and its diurnal activity: an experimental field enclosures and laboratory study. AB - Examples of animals that switch activity times between nocturnality and diurnality in nature are relatively infrequent. Furthermore, the mechanism for switching activity time is not clear: does a complete inversion of the circadian system occur in conjunction with activity pattern? Are there switching centers downstream from the internal clock that interpret the clock differently? Or does the switch reflect a masking effect? Answering these key questions may shed light on the mechanisms regulating activity patterns and their evolution. The golden spiny mouse (Acomys russatus) can switch between nocturnal and diurnal activity. This study investigated the relationship between its internal circadian clock and its diurnal activity pattern observed in the field. The goal is to understand the mechanisms underlying species rhythm shifts in order to gain insight into the evolution of activity patterns. All golden spiny mice had opposite activity patterns in the field than those under controlled continuous dark conditions in the laboratory. Activity and body temperature patterns in the field were diurnal, while in the laboratory all individuals immediately showed a free-running rhythm starting with a nocturnal pattern. No phase transients were found toward the preferred nocturnal activity pattern, as would be expected in the case of true entrainment. Moreover, the fact that the free-running activity patterns began from the individuals' subjective night suggests that golden spiny mice are nocturnal and that their diurnality in their natural habitat in the field results from a change that is downstream to the internal clock or reflects a masking effect. PMID- 17701676 TI - Influence of constant light and darkness, light intensity, and light spectrum on plasma melatonin rhythms in senegal sole. AB - Light is the most important synchronizer of melatonin rhythms in fish. This paper studies the influence of the characteristics of light on plasma melatonin rhythms in sole. The results revealed that under long-term exposure to constant light conditions (LL or DD), the total 24 h melatonin production was significantly higher than under LD, but LL and DD conditions influenced the rhythms differently. Under LL, melatonin remained at around 224 pg/ml throughout the 24 h, while under DD a significant elevation (363.6 pg/ml) was observed around the subjective evening. Exposure to 1 h light pulses at MD (mid-dark) inhibited melatonin production depending on light intensity (3.3, 5.3, 10.3, and 51.9 microW/cm(2)). The light threshold required to reduce nocturnal plasma melatonin to ML (mid-light) values was 5.3 microW/cm(2). Melatonin inhibition by light also depended on the wavelength of the light pulses: while a deep red light (lambda>600 nm) failed to reduce plasma melatonin significantly, far violet light (lambda(max)=368 nm) decreased indoleamine's concentration to ML values. These results suggest that dim light at night (e.g., moonlight) may be perceived and hence affect melatonin rhythms, encouraging synchronization to the lunar cycle. On the other hand, deep red light does not seem to inhibit nocturnal melatonin production, and so it may be used safely during sampling at night. PMID- 17701677 TI - Melatonin in the regulation of annual testicular events in carp Catla catla: evidence from the studies on the effects of exogenous melatonin, continuous light, and continuous darkness. AB - The physiological significance of melatonin in the regulation of annual testicular events in a major carp Catla catla was evaluated through studies on the effects of graded dose (25, 50, or 100 microg/100 g body wt.) of melatonin exogenously administered for different durations (1, 15, or 30 days) and manipulation of the endogenous melatonin system by exposing the fish to constant darkness (DD) or constant light (LL) for 30 days. An identical experimental schedule was followed during the preparatory (February-March), pre-spawning (April-May), spawning (July-August), and post-spawning (September-October) phases of the annual cycle. Irrespective of the reproductive status of the carp, LL suppressed while DD increased the mid-day and mid-night values of melatonin compared to respective controls. Influences of exogenous melatonin varied in relation to the dose and duration of treatment and the reproductive status of the carp. However, testicular response to exogenous melatonin (at 100 microg, for 30 days) and DD in each reproductive phase was almost identical. Notably, precocious testicular maturation occurred in both DD and melatonin-injected fish during the preparatory phase and in LL carps during the pre-spawning phase. In contrast, testicular functions in both the melatonin-treated and DD fish were inhibited during the pre-spawning and spawning phases, while the testes did not respond to any treatment during the post-spawning phase. In conclusion, this study provided the first experimental evidence that melatonin plays a significant role in the regulation of annual testicular events in a sub-tropical surface-dwelling carp Catla catla, but the influence of this pineal hormone on the seasonal activity of testis varies in relation to the reproductive status of the concerned fish. PMID- 17701678 TI - Circadian variations in coagulation and fibrinolytic factors among four different strains of mice. AB - This study examined circadian variation in coagulation and fibrinolytic parameters among Jcl:ICR, C3H/HeN, BALB/cA, and C57BL/6J strains of mice. Plasma plasminogen activator inhibitor 1 (PAI-1) levels fluctuated in a circadian manner and peaked in accordance with the mRNA levels at the start of the active phase in all strains. Fibrinogen mRNA levels peaked at the start of rest periods in all strains, although plasma fibrinogen levels remained constant. Strain differences in plasma antithrombin (AT) activity and protein C (PC) levels were then identified. Plasma AT activity was circadian rhythmic only in Jcl:ICR, but not in other strains, although the mRNA levels remained constant in all strains. Levels of plasma PC and its mRNA fluctuated in a circadian manner only in Jcl:ICR mice, whereas those of plasma prothrombin, factor X, factor VII, prothrombin time (PT), and activated partial thrombin time (APTT) remained constant in all strains. These results suggest that genetic heterogeneity underlies phenotypic variations in the circadian rhythmicity of blood coagulation and fibrinolysis. The circadian onset of thrombotic events might be due in part to the rhythmic gene expression of coagulation and fibrinolytic factors. The present study provides fundamental information about mouse strains that will help to understand the circadian variation in blood coagulation and fibrinolysis. PMID- 17701679 TI - Malondialdehyde content and circadian variations in brain, kidney, liver, and plasma of mice. AB - In aerobic organisms, the use of oxygen (O(2)) to produce energy is associated with the production of Reactive Oxygen Species (ROS), which reacts with biological molecules to produce oxidized metabolites such as malondialdehyde (MDA). This experiment focused on male Swiss mice 12 weeks of age synchronized for 3 weeks by the 12 h light (rest)/12 h dark (activity) span. Different and comparable groups of animals (n=10) were sacrificed at six different circadian stages: 1, 5, 9, 13, 17, and 21 h after light onset (HALO). The 24 h mean MDA level varied among organs of mice in non-stress conditions and was comparable in brain and liver but lower than in kidney. As the MDA 24 h status constitutes only a part of ROS damages in sites differing by their oxygen use, lipid composition, and detoxification capacity, the temporal patterns of their MDA content were comparatively studied in relationship to the animal rest-activity cycle. The results revealed significant circadian rhythms with the peak time located during the rest span (approximately =5 HALO) for both brain and liver, but during the activity span for the kidney ( approximately =21 HALO) and plasma (approximately =13 HALO). This chronobiological study showed that under physiological conditions, lipid peroxidation depends on several factors. The MDA peak/trough might be used as a tool to detect moments of high/low sensitivity of tissues to ROS attack in rodents. PMID- 17701680 TI - Seasonal variation in the amount of dietary carbohydrate not absorbed from the intestine after breakfast in elderly Japanese females. AB - It was previously shown that there is seasonality in the amount of dietary carbohydrate not absorbed from the intestine after breakfast, the amount of carbohydrate in winter being significantly larger than that in autumn in young Japanese subjects. In order to investigate this phenomenon further, the experiment was repeated on 22 elderly Japanese female subjects (61-78 yrs of age) during the four seasons of the year. The amount of unabsorbed dietary carbohydrate by the breath hydrogen test, which measures the amount of hydrogen in exhaled air, was then estimated. A 6 g solution of lactosucrose, an indigestible trisaccharide, was used for comparison. Two groups of subjects, 16 subjects in Osaka and 6 subjects in Nagano, were studied in the summer (July to August) and autumn (October to November) of 2005 and the winter (January to February) and spring (April to May) of 2006. The following results were found using the pooled data of the total of 22 subjects. With regard to the amount of breath hydrogen excretion of the lactosucrose solution, there was no significant difference between the four seasons. There was a significant seasonal change in the efficiency of dietary carbohydrate absorption from the intestine after breakfast. The percentage of total carbohydrate that was not absorbed was lowest in the spring and highest in the winter. A comparison of the results from studies on the elderly and young subjects revealed the percentage of total carbohydrate that was not absorbed in the elderly was significantly lower than in the young in the winter, spring, and summer. These results indicate that there is seasonal variation in the efficiency of dietary carbohydrate absorption from the intestine among elderly female Japanese subjects as well as young female Japanese subjects. They also suggest that the efficiency of dietary carbohydrate absorption from the intestine after breakfast is retained in these naturally active and healthy elderly subjects. PMID- 17701681 TI - Circadian-rhythm differences among emergency department patients with chronic obstructive pulmonary disease exacerbation. AB - The purpose of the study was determine whether patients with chronic obstructive pulmonary disease (COPD) exacerbation who present to the emergency department (ED) during the night (00:00 to 07:59 h) vs. other times of the day have more severe COPD exacerbation, require more intensive treatment, and have worse clinical outcomes. A multicenter cohort study was completed involving 29 EDs in the United States and Canada. Using a standard protocol, consecutive ED patients with COPD exacerbation were interviewed, and their charts were reviewed. Of 582 patients enrolled, 52% were women, and the median age was 71 yrs (interquartile range, 64-77 yrs). Nighttime patients (15% of cohort) did not differ from patients presenting at other times except that they were less likely to have private insurance, more likely to have a history of corticosteroid use, and have a shorter duration of symptoms exacerbation. Except for a few features indicative of more severe COPD exacerbation (such as higher respiratory rate at ED presentation, greater likelihood of receiving noninvasive positive pressure ventilation, and increased risk of endotracheal intubation), nighttime patients did not differ from other patients with respect to ED management. Nighttime patients were approximately three-fold more likely to be intubated in the ED (odds ratio, 3.46; 95% confidence interval, 1.10-10.9). There were no day-night differences regarding ED disposition and post-ED relapse. Except for some features indicating more severe exacerbation, nighttime ED patients had similar chronic COPD characteristics, received similar treatments in the ED, and had similar clinical outcomes compared with patients presenting to the ED at other times of the day. PMID- 17701682 TI - Seasonality and coronary heart disease deaths in United States firefighters. AB - United States firefighters have a high on-duty fatality rate, and coronary heart disease is the leading cause. Seasonality affects the incidence of cardiovascular events in the general population, but its effects on firefighters are unknown. This study statistically examined the seasonal and annual variation of all on duty coronary heart disease deaths among US firefighters between 1994 and 2004 using the chi-square distribution and Poisson regression model of the monthly fatality counts. It also examined the effect of ambient temperature (apparent as well as wind chill temperature) on coronary heart disease fatalities during the study span using a time-stratified, case-crossover study design. When grouped by season, we observed the distribution of the 449 coronary heart disease fatalities to show a relative peak in winter (32%) and relative nadir in spring (21%). This pattern was significantly different (p=0.005) from the expected distribution under the null hypothesis of season having no effect. The pattern persisted in additional analyses, stratifying the deaths by the type of duty in which the firefighters were engaged at the time of their deaths. In the Poisson regression model of the monthly fatality counts, the overall goodness-of-fit between the actual and predicted case counts was excellent (chi(4)(2)=16.63; p=0.002). Two distinct peaks were detected: one in January-February and the other in August September. Overall temperature was not associated with increased risk of on-duty death. After allowing for different effects of temperature in mild/hot versus cold periods, a 1 degrees C increase was not protective in cold weather; nor did it increase the risk of death in warmer weather. The findings of this study reveal statistical evidence for excess coronary heart disease deaths among firefighters during winter; however, the temporal pattern of coronary heart disease deaths was not linked to temperature variation. The seasonal pattern was also found to be independent of duty-related risks. PMID- 17701683 TI - Seasonal variation of suicide in Brazil. AB - Most of what is known about the seasonal variation in suicide rate originates from studies conducted in the northern hemisphere; very few studies have been done in the southern hemisphere. The purpose of the present study was to explore the possibility that in Brazil, the seasonal variation of suicides is a function of photoperiod. This was accomplished by analyzing monthly suicide data for a 12 yr period (1979 to 1990), within latitudes ranging from 2 degrees N to 33 degrees S. Single cosinor analyses with periods of 12 or 6 months were applied to time series of monthly total and suicidal deaths, separated by gender and state. Significant spring or early summer peaks of suicide were found only in the south of Brazil for both men and women, except for the latter in one state. These peaks did not coincide with those found for total deaths, which occurred in the autumn or winter in all areas. No significant six-month period was found. In the present study, the chance of a suicide was typically 10-17% higher during the peak period than during the other months of the year. Although this moderate seasonal effect might not be sufficient to justify planning large scale prophylactic interventions, those dealing with patients who have suicide ideation should be aware of this high risk time. PMID- 17701684 TI - Effect of time of day on aerobic contribution to the 30-s Wingate test performance. AB - The purpose of this study was to evaluate the effects of time of day on aerobic contribution during high-intensity exercise. A group of 11 male physical education students performed a Wingate test against a resistance of 0.087 kg . kg(-1) body mass. Two different times of day were chosen, corresponding to the minimum (06:00 h) and the maximum (18:00 h) levels of power. Oxygen uptake (.VO(2)) was recorded breath by breath during the test (30 sec). Blood lactate concentrations were measured at rest, just after the Wingate test, and again 5 min later. Oral temperature was measured before each test and on six separate occasions at 02:00, 06:00, 10:00, 14:00, 18:00, and 22:00 h. A significant circadian rhythm was found in body temperature with a circadian acrophase at 18:16+/-00:25 h as determined by cosinor analysis. Peak power (P(peak)), mean power (P(mean)), total work done, and .VO(2) increased significantly from morning to afternoon during the Wingate Test. As a consequence, aerobic contribution recorded during the test increased from morning to afternoon. However, no difference in blood lactate concentrations was observed from morning to afternoon. Furthermore, power decrease was greater in the morning than afternoon. Altogether, these results indicate that the time-of-day effect on performances during the Wingate test is mainly due to better aerobic participation in energy production during the test in the afternoon than in the morning. PMID- 17701685 TI - Ambulatory blood pressure monitoring in the prediction of cardiovascular events and effects of chronotherapy: rationale and design of the MAPEC study. AB - Ambulatory blood pressure (BP) measurements (ABPM) correlate more closely with target organ damage and cardiovascular events than clinical cuff measurements. ABPM reveals the significant circadian variation in BP, which in most individuals presents a morning increase, small post-prandial decline, and more extensive lowering during nocturnal rest. However, under certain pathophysiological conditions, the nocturnal BP decline may be reduced (non-dipper pattern) or even reversed (riser pattern). This is clinically relevant because the non-dipper and riser circadian BP patterns constitute a risk factor for left ventricular hypertrophy, microalbuminuria, cerebrovascular disease, congestive heart failure, vascular dementia, and myocardial infarction. Hence, there is growing interest in how to best tailor and individualize the treatment of hypertension according to the specific circadian BP pattern of each patient. All previous trials that have demonstrated an increased cardiovascular risk in non-dipper as compared to dipper patients have relied on the prognostic significance of a single ABPM baseline profile from each participant without accounting for possible changes in the BP pattern during follow-up. Moreover, the potential benefit (i.e., reduction in cardiovascular risk) associated with the normalization of the circadian BP variability (conversion from non-dipper to dipper pattern) from an appropriately envisioned treatment strategy is still a matter of debate. Accordingly, the MAPEC (Monitorizacion Ambulatoria de la Presion Arterial y Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring and Cardiovascular Events) study was designed to investigate whether the normalization of the circadian BP profile toward more of a dipper pattern by chronotherapeutic strategies (i.e., specific timing during the 24 h of BP-lowering medications according to the 24 h BP pattern) reduces cardiovascular risk. The prospective MAPEC study investigates 3,000 diurnally active men and women >/=18 yrs of age. At inclusion, BP and wrist activity are measured for 48 h. The initial evaluation also includes a detailed medical history, an electrocardiogram, and screening laboratory blood and urine tests. The same evaluation procedure is scheduled yearly or more frequently (quarterly) if treatment adjustment is required for BP control. Cardiovascular morbidity and mortality are thus evaluated on the basis of changes in BP during follow-up. The MAPEC study, now on its fourth year of follow-up, investigates the potential decrease in cardiovascular, cerebrovascular, and renal risk from the proper modeling of the circadian BP profile by the timed administration (chronotherapy) of antihypertensive medication, beyond the reduction of clinic determined daytime or ABPM-determined 24 h mean BP levels. PMID- 17701689 TI - Superior mediastinal teratoma containing well-differentiated bowel. AB - A previously fit and well 14-month-old-girl presented with a 2-month history of worsening cough and wheeze. Chest radiograph revealed a widened mediastinum and thoracic CT showed a large mixed density mass in the superior mediastinum, consistent with a mediastinal teratoma. Her tumor markers were within the normal range. The mass was resected and found to be a mature cystic teratoma. Surprisingly, well-formed bowel-like structures were present, containing all bowel wall layers and having a ganglionated myenteric plexus. The identification of complete sections of bowel in this context is a rare finding and to the best of our knowledge has not been published previously for the mediastinal teratoma. The possibility of secondary neoplasia developing in these areas is a complicating factor. PMID- 17701690 TI - Obesity in children. AB - The alarming increase in obesity in children has become a major health problem in the increased incidence of type 2 diabetes as well as other complications including cardiovascular diseases, hepatic disorders, skeletal abnormalities, malignancies and in particular psychological disorders. Mechanisms of appetite and energy metabolism are mediated through hormones leptin and ghrelin, and neuropeptide-Y neurons as well as genetic factors. Control of obesity is largely through appetite control and physical exercise. PMID- 17701691 TI - Comparison of the amniotic band disruption complex with acardiac twins does not support its vascular origin. AB - The amniotic band disruption complex (ABDC) has been attributed to vascular disruption by some authors, not by others. Acardiac twins (ATs), however, have been generally accepted as a prime example of vascular disruption. In this study a comparison was made of these two entities to determine if they were similar or not, and thus we attempted to resolve the controversy of the mechanisms in the ABDC. A female tendency (2:1) was found in the ABDC in contrast to the "normal" sex distribution (0.88:1) in the ATs (p < 0.001). Most types of malformations (66%) were mutually exclusive, notably those of the cranium/brain, abdominal wall, and most internal organs; 83% were more significantly related to one or other of the entities. The ABDC malformations tended to occur unilaterally, but in the ATs they occurred bilaterally (p < 0.0001); the former tended to involve external organs and the latter internal organs (p < 0.0001). With so many differences, the two entities are unlikely due to the same mechanism: the ABDC is more likely to be due to external disruption. PMID- 17701692 TI - Pathology teach and tell: fibrinogen storage disease in a child with hypofibrinogenemia and decreased ceruloplasmin. AB - The authors present a clinical case of a patient with mild liver disease and coagulopathy. The diagnosis was reached through careful histologic examination of liver biopsy. Electron microscopy played an important role in confirming the diagnosis. PMID- 17701694 TI - Photocatalytic mechanisms of indoleamine destruction by the quinalphos metabolite 2-hydroxyquinoxaline: a study on melatonin and its precursors serotonin and N acetylserotonin. AB - The redox-active quinalphos main metabolite, 2-hydroxyquinoxaline, is particularly effective under excitation by light. We have studied the photocatalytic destruction of melatonin and its precursors, because the cytoprotective indoleamine has been detected in high quantities in mammalian skin. In photooxidation reactions, in which melatonin, N-acetylserotonin and serotonin are destroyed by 2-hydroxyquinoxaline, the photocatalyst is virtually not consumed. Rates of melatonin and serotonin destruction are not changed by the singlet oxygen quencher 1,4-diazabicyclo-(2,2,2)-octane, indicating that this oxygen species is not involved in the primary reactions, so that the persistence of 2-hydroxyquinoxaline has to be explained by redox cycling. This should imply formation of an organic radical, presumably the quinoxaline-2-oxyl radical, from which 2-hydroxyquinoxaline is regenerated by electron abstraction from indolic radical scavengers. Electron donation by 2-hydroxyquinoxaline is demonstrated by reduction of the 2,2'-azino-bis-(3-ethylbenzthiazolinyl-6-sulfonic acid) cation radical under ultrasound excitation. The compound 2-hydroxyquinoxaline interacts with the specific superoxide anion scavenger Tiron. Formation of oligomeric products from melatonin and serotonin is strongly inhibited by sodium dithionite. Products from photocatalytic indolamine conversion are predominantly dimers and oligomers. No kynuramines were detected in the case of serotonin oxidation, and melatonin's otherwise prevailing oxidation product N(1)-acetyl-N(2)-formyl-5 methoxykynuramine, another cytoprotective metabolite, is only formed in relatively small quantities. The proportion between products from melatonin is changed by 1,4-diazabicyclo-(2,2,2)-octane: singlet oxygen, also formed under the influence of excited 2-hydroxyquinoxaline, only affects secondary reactions. PMID- 17701695 TI - Use of sensitive methods for detection of DNA damage on human lymphocytes exposed to p,p'-DDT: Comet assay and new criteria for scoring micronucleus test. AB - Wide distribution, stability and long persistence in the environment of dichlorodiphenyltrichloroethane (DDT), probably the best-known and most useful insecticide in the world, imposes the need for further examination of the effect of this chemical on human health and especially on the human genome. In this study, peripheral blood human lymphocytes from a healthy donor were exposed to 0.025 mg/L concentration of p,p'-DDT at different time periods (1, 2, 24 and 48 h). For the assessment of genotoxic effect, the new criteria for scoring micronucleus test and alkaline comet assay were used. Both methods showed that p,p'-DDT induces DNA damage in low concentration used in this research. Results of micronucleus test showed a statistically significant (p < 0.05) genotoxic effect of p,p'-DDT on human lymphocytes compared with corresponding control and a different exposure time. A comet assay also showed increased DNA damage caused in p,p'-DDT-exposed human lymphocytes than in corresponding control cells for the tail length. Results obtained by measuring the level of DNA migration and incidence of micronuclei (MN), nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) indicate the sensitivity of these tests and their application in detection of primary genome damage after long-term exposure to establish the effect of p,p'-DDT on human genome. PMID- 17701696 TI - Relative influence of the dissolved humic material on the solid-phase extraction efficiency of pesticides from environmental water. AB - The effect of organic matter on the solid-phase extraction (SPE) efficiency for pesticides belonging to different chemical groups (urea-derivatives, carbamates and triazines) and having different polarities, was simultaneously studied for the first time in pure and simulated water samples. SPE was carried out in precolumns packed with C18 silica or styrene-divinylbenzene copolymer PLRP-S phases on-line coupled to high performance liquid chromatography (HPLC) analysis. Retention factors in water (k'(W)) were estimated for 25 compounds and used for the calculation of the theoretical breakthrough volume (Vb(T)) in pure water. Experimental breakthrough volumes (Vb(E)) were first determined using purified and deionized water as the matrix for selected compounds having Vb(T) < 500 mL; then, the same water with an added humic acid sodium salt (HA) at 0.4-5.6 mg/L of dissolved organic carbon (DOC) content, was used as the matrix for compounds having VbE < 500 mL in pure water. Several polar pesticides showed negative linear or logarithmic Vb(E) curves depending on HA content; their recoveries were also determined in environmental samples having low dissolved organic carbon values, between 0.5-6.4 mg/L. A similar behavior was observed for these compounds in simulated and natural water samples, where DOC concentration and the percolated volume (Vp) mainly determine the solute recoveries values. However, the variation of recoveries as a function of DOC content could be negative or null depending on the two examined conditions (Vp lower or larger than Vb(E) in pure water). Results demonstrated that breakthrough volume must always be considered to correctly interpret the participation of dissolved humic material on the SPE efficiency of organic micropollutants in water. PMID- 17701697 TI - Application of a novel cold activated carbon fiber-solid phase microextraction for analysis of organochlorine pesticides in soil. AB - A novel and simple analytical procedure using cold activated carbon fiber-solid phase microextraction (CACF-SPME) was applied to determine organochlorine pesticides (OCs) in soil samples. The pesticides in this study consist of alpha , beta -, gamma -, and delta -hexachlorocyclohexane (HCH). By heating the sample while cooling the fiber, the developed method not only provides better performance in terms of sensitivity, linearity and recovery but also offers shorter adsorption procedure than that of traditional headspace-solid phase microextraction (HS-SPME). The experimental conditions such as the amount of water, adsorption time and adsorption temperature were optimized. Matrix effects were investigated with different types of soils. We concluded that using the standard addition method was required for quantification purposes. The limits of detection obtained using the proposed method range from 0.01 to 0.05 ng/g, and the recoveries for CACF-SPME are in the range of 80.01% to 89.68% with relative standard deviation (RSDs) better than 8.60%. The proposed method was further applied to determine OCs in real agricultural soil. The results are in good agreement with those obtained using traditional ultrasonic extraction. The research demonstrates the suitability of the CACF-SPME for the analysis of OCs in soil. PMID- 17701698 TI - Leaching and half-life of the herbicide tebuthiuron on a recharge area of Guarany aquifer in sugarcane fields in Brazil. AB - This study was undertaken to evaluate the degradation and mobility of the herbicide tebuthiuron (N-[5-(1,1-dimethylethyl)-1,3,4-thiadiazol-2-yl]-N,N' dimethylurea) in soil under field conditions, and its potential for leaching and groundwater contamination. A watershed, Espraiado, located over a recharge area in Brazil, was chosen for soil and water studies. At Espraiado, water samples were collected from seven wells at intervals of three months from March 2004 to June 2006 and analyzed for tebuthiuron. Other samples were taken from city wells located outside of the recharge area. To assess the potential movement to the aquifer, tebuthiuron was also applied to trial plots at the recommended label rate of 1.0 kg/ha a.i. in May of 2004, with and without sugarcane coverage, on sandy soil. Soil samples were collected during the years of 2004 and 2005, at depths intervals of 20 cm from soil surface down to 120 cm and analyzed for tebuthiuron at zero, 3, 30, 60, 90, 120, 150, 180, 240, and 300 days after application. There was no clear effect of sugarcane coverage on the tebuthiuron degradation in soils, but it moved faster into the soil where there was no cover. After 180 days there were no measurable residues in the soil, and tebuthiuron was not found below 40 cm depth in any time. Tebuthiuron had a half-life of 20 days under those conditions. No tebuthiuron residue was found in ground water samples at any sampling time. PMID- 17701700 TI - Adsorption behavior of alpha -cypermethrin on cork and activated carbon. AB - Studies were undertaken to determine the adsorption behavior of alpha cypermethrin [R)-alpha -cyano-3-phenoxybenzyl(1S)-cis-3-(2,2-dichlorovinyl)-2,2 dimethylcyclopropanecarboxylate, and (S)-alpha-cyano-3-phenoxybenzyl (1R)-cis-3 (2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate] in solutions on granules of cork and activated carbon (GAC). The adsorption studies were carried out using a batch equilibrium technique. A gas chromatograph with an electron capture detector (GC-ECD) was used to analyze alpha -cypermethrin after solid phase extraction with C18 disks. Physical properties including real density, pore volume, surface area and pore diameter of cork were evaluated by mercury porosimetry. Characterization of cork particles showed variations thereby indicating the highly heterogeneous structure of the material. The average surface area of cork particles was lower than that of GAC. Kinetics adsorption studies allowed the determination of the equilibrium time - 24 hours for both cork (1-2 mm and 3-4 mm) and GAC. For the studied alpha -cypermethrin concentration range, GAC revealed to be a better sorbent. However, adsorption parameters for equilibrium concentrations, obtained through the Langmuir and Freundlich models, showed that granulated cork 1-2 mm have the maximum amount of adsorbed alpha-cypermethrin (q(m)) (303 microg/g); followed by GAC (186 microg/g) and cork 3-4 mm (136 microg/g). The standard deviation (SD) values, demonstrate that Freundlich model better describes the alpha -cypermethrin adsorption phenomena on GAC, while alpha -cypermethrin adsorption on cork (1-2 mm and 3-4 mm) is better described by the Langmuir. In view of the adsorption results obtained in this study it appears that granulated cork may be a better and a cheaper alternative to GAC for removing alpha -cypermethrin from water. PMID- 17701699 TI - Sorption and predicted mobility of herbicides in Baltic soils. AB - This study was undertaken to determine sorption coefficients of eight herbicides (alachlor, amitrole, atrazine, simazine, dicamba, imazamox, imazethapyr, and pendimethalin) to seven agricultural soils from sites throughout Lithuania. The measured sorption coefficients were used to predict the susceptibility of these herbicides to leach to groundwater. Soil-water partitioning coefficients were measured in batch equilibrium studies using radiolabeled herbicides. In most soils, sorption followed the general trend pendimethalin > alachlor > atrazine approximately amitrole approximately simazine > imazethapyr > imazamox > dicamba, consistent with the trends in hydrophobicity (log K(ow)) except in the case of amitrole. For several herbicides, sorption coefficients and calculated retardation factors were lowest (predicted to be most susceptible to leaching) in a soil of intermediate organic carbon content and sand content. Calculated herbicide retardation factors were high for soils with high organic carbon contents. Estimated leaching times under saturated conditions, assuming no herbicide degradation and no preferential water flow, were more strongly affected by soil textural effects on predicted water flow than by herbicide sorption effects. All herbicides were predicted to be slowest to leach in soils with high clay and low sand contents, and fastest to leach in soils with high sand content and low organic matter content. Herbicide management is important to the continued increase in agricultural production and profitability in the Baltic region, and these results will be useful in identifying critical areas requiring improved management practices to reduce water contamination by pesticides. PMID- 17701701 TI - Behavior of the organophosphorus insecticide fenitrothion in stored faba beans and its biological effects towards experimental animals. AB - Sound whole-seed faba beans were treated with (methyl-(14)C) fenitrothion [O, O dimethyl-O-(3-methyl-4-nitrophenyl) phosphorothioate] at 5 and 10 mg insecticide/kg seeds, a dose normally used in practice. During the 30 weeks of storage period, the penetration and distribution of insecticide residues were studied. The amount of surface residues, internal residues and bound insecticide residues was estimated. Surface residues were found to decrease with the increase in time of storage, whereas internal residues showed a gradual increase with time apparently not dose dependent. Grain-bound residues increased with time and reached to its maximum (14-18%) after 24 weeks of storage. Chromatographic analysis of the internal extracts revealed the presence of the parent compound together with three main metabolites which were found in both free and conjugated form. Feeding mice for 90 days with a diet mixed with total internal fenitrothion residues in stored faba beans led to a reduction in body weight gain, and an appreciable decrease in cholinesterase activity of 32% for plasma and 15% for red blood cells (RBC(S)) after two months of experiment. Also, a significant decrease was showed in both total protein and albumin concentration at the end of feeding period (90 days). Liver and kidney function, as well as lipid profile of treated mice significantly increased at the end of feeding period. After a one-month recovery period, all the examined blood parameters returned to about the control values except blood urea and serum triglyceride. PMID- 17701702 TI - Survival of bio-inoculants on fungicides-treated seeds of wheat, pea and chickpea and subsequent effect on chickpea yield. AB - Survival of Mesorhizobium ciceri (SP(4)) and Azotobacter chroococcum (CBD-15 and M(4)) was tested on chickpea (Cicer arietinum) seeds treated with fungicides bavistin [methyl N-(1H-benzimidazol-2yl) carbamate] and thiram (tetramethyl thiuram disulfide), whereas survival of phosphate solubilizing bacteria (PSB), Pseudomonas striata (27) and Bacillus polymyxa (H(5)) was examined on two cultivars (Arkel and BV) of pea (Pisum sativum) seeds treated with thiram. Viability of Azotobacter chroococcum (W(5)) was also examined on wheat (Triticum aestivum) seeds treated with bavistin, captan (cis-N-trichloromethyl thio-4 cyclohexane-1, 2-dicarboximide) and thiram under laboratory conditions using standard dilution and the plate count technique. All the tested strains of diazotrophs and PSB showed decline in their viable population on prolonged contact with fungicides. However, PSB showed variation in their viable population even with the cultivar. BV cultivar of pea seeds showed better recovery of viable P. striata (10.75 to 10.61 log no. of viable cells with in 0-24 hrs) in the presence of thiram, whereas the Arkel cultivar of pea resulted in better recovery of viable B. polymyxa. Azotobacter chroococcum (W(5)), a potential strain for wheat, showed better survival in the presence of bavistin, compared to thiram and captan. Higher viable population of Mesorhizobium ciceri (SP(4)) and Azotobacter chroococcum (M(4)) was recovered from chickpea seeds treated with bavistin compared to thiram. However, thiram-treated seeds resulted in a greater number of extractable Azotobacter chroococcum (CBD-15). Under field conditions, adverse effect of thiram was reflected on the performance of Mesorhizobium ciceri (SP(4)) and A. chroococcum (M(4)) strains, resulting in reduced root and shoot biomass and grain yield, compared to bavistin treated and culture inoculated treatment. CBD-15 showed better performance in the presence of thiram compared to bavistin. PMID- 17701703 TI - Dissipation of carbofuran and carbaryl on Oolong tea during tea bushes, manufacturing and roasting processes. AB - Carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranol-N-methylcarbamate) and carbaryl (1-naphthyl-N-methylcarbamate) are insecticides widely used in tea plantations. The objective of the present study was to evaluate the dissipation of carbofuran and carbaryl during the growth periods of Oolong tea, processing and roasting. Analysis of the residual insecticides was carried out using high pressure liquid chromatography with a post-column fluorescence detector. Results showed that in the tea field carbofuran dissipated faster then carbaryl. Manufacturing processes of Oolong tea further reduced the carbofuran and carbaryl contents. The persistence of carbofuran and carbaryl was decreased with increasing roasting temperature. From the results, we conclude that the presence of carbofuran and carbaryl in tea can be reduced by proper field management, manufacturing and roasting processes. PMID- 17701704 TI - Controlled release of thiram fungicide from starch-based hydrogels. AB - In order to make the judicious use of thiram fungicide and to exploit the potential of agri-polymers, we have developed the starch- poly(acrylamide) and starch-poly(acrylic acid) based agrichemical delivery system (hydrogels) for its controlled and sustained release. Polymeric networks have been prepared by using N,N'-methylenebisacrylamide (N,N-MBAAm) as crosslinker and ammonium persulfate (APS) as initiator and characterized by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and swelling studies. Release dynamics of thiram fungicide from polymeric matrices has been studied for the evaluation of the diffusion mechanism and diffusion coefficients. It has been established that Non-Fickian diffusion mechanism has occurred for the release of thiram from these polymeric matrices. Furthermore, the initial rate of diffusion of thiram from these polymeric matrices is more as compared to the late stages of diffusion, which is analogous to the trends obtained for the diffusion of water molecules from these polymer matrices. PMID- 17701705 TI - Residues of organochlorine pesticides and PCBs in some Brazilian municipal solid waste compost. AB - Persistent organic pollutants (POPs), organochlorine pesticides and polychlorinated biphenyls (PCBs), listed as per the Stockholm Convention (alpha HCH, beta -HCH, gamma -HCH, p,p'-DDT, o,p'-DDT, p,p'-DDD, p,p'-DDE, aldrin, endrin, dieldrin, PCBs 28, 52, 118, 138, 153, and 180), were analyzed in municipal solid waste (MSW) compost samples from three different Brazilian composting plants located in three Sao Paulo State cities: Araras, Araraquara and Sao Paulo (Vila Leopoldinha). Quantitative and qualitative analyses were carried out using gas chromatography electron capture detection (GC-ECD) and gas chromatography mass spectrometry (GC-MS) (Ion Trap, electron impact ionization), respectively. The samples were analyzed in triplicate and the target POPs were not detected by GC-ECD. Twelve pollutants were identified in two samples when qualitative analysis (GC-MS) was used (beta -HCH, gamma -HCH, p,p'-DDT, o,p'-DDT, p,p'-DDD, and p,p'-DDE, PCBs 28, 118, 138, 153 and 180). The composting process has advantages such as urban solid waste reduction and landfill life-span increase, however the MSW compost quality, which can be utilized for agricultural purposes, should be evaluated and be controlled. This kind of study is the first step in making available information to answer questions regarding MSW compost for sustainable agricultural use, such as the pollutants accumulation in soil and in groundwater, and plants uptake. PMID- 17701706 TI - Biodegradation of endosulfan-contaminated soil in a pilot-scale reactor bioaugmented with mixed bacterial culture. AB - A novel mixed bacterial culture was enriched from an endosulfan (6, 7, 8, 9, 10, 10 - hexachloro-1, 5, 5a, 6, 9, 9a-hexahydro-6, 9-methano-2, 3, 4-benzo (e) dioxathiepin-3-oxide) processing industrial surface soil. The cultures were successful in the degradation of aqueous phase endosulfan in both aerobic and anaerobic conditions. Using the cultures, endosulfan degradation in silty gravel with sand (GM) was examined via pilot scale reactor at an endosulfan concentration of 0.78 +/- 0.01 mg g(- 1) of soil, and optimized moisture content of 40 +/- 1%. During operation, vertical spatial variability in endosulfan degradation was observed within the reactor. At the end of 56 days, maximum endosulfan degradation efficiency of 78 +/- 0.2% and 86.91 +/- 0.2% was observed in the top and bottom portion of the reactor, respectively. Both aerobic and anaerobic conditions were observed within the reactor. However, endosulfan degradation was predominant in anaerobic condition and the total protein concentration in the reactor was declined progressively down the soil depth. Throughout the study, no known intermediate metabolites of endosulfan reported by previous researchers were observed. PMID- 17701707 TI - HPLC determination of chlorate metabolism in bovine ruminal fluid. AB - Salmonella and Escherichia coli are two bacteria that are important causes of human and animal disease worldwide. Chlorate is converted in the cell to chlorite, which is lethal to these bacteria. An HPLC procedure was developed for the rapid analysis of chlorate (ClO(3)(-)), nitrate (NO(3)(-)), and nitrite (NO(2)(-)) ions in bovine ruminal fluid samples. Standard curves for chlorite, nitrite, nitrate, and chlorate were well defined linear curves with R(2) values of 0.99846, 0.99106, 0.99854, and 0.99138, respectively. Concentrations of chlorite could not be accurately determined in bovine ruminal fluid because chlorite reacts with or binds a component(s) or is reduced to chloride in bovine ruminal fluid resulting in low chlorite measurements. A standard curve ranging from 25 to 150 ppm ClO(3)(-) ion was used to measure chlorate fortified into ruminal fluid. The concentration of chlorate was more rapidly lowered (P < 0.01) under anaerobic compared to aerobic incubation conditions. Chlorate alone or chlorate supplemented with the reductants sodium lactate or glycerol were bactericidal in anaerobic incubations. In anaerobic culture, the addition of sodium formate to chlorate-fortified ruminal fluid appeared to decrease chlorate concentrations; however, formate also appeared to moderate the bactericidal effect of chlorate against E. coli. Addition of the reductants, glycerol or lactate, to chlorate-fortified ruminal fluid did not increase the killing of E. coli at 24 h, but may be useful when the reducing equivalents are limiting as in waste holding reservoirs or composting systems required for intense animal production. PMID- 17701708 TI - Piggery waste treatment by using down-flow anaerobic fixed bed reactors. AB - A study of the role of the depth in the performance of laboratory-scale down-flow anaerobic fixed-bed reactors (DFAFBR) was carried out at different nominal hydraulic retention times (HRT(N)) using piggery waste as substrate at different influent concentrations (2, 4, 6 and 8 g COD/L). The profiles of soluble chemical oxygen demand (COD) (SCOD), organic nitrogen (O.N.), ammonia nitrogen (A.N.), pH and electrical conductivity (E.C.) through the reactor depths showed an initial highly active zone, which was located around the first half of the reactor depth, and a second zone with a lower biological activity. It was found that the depth of the active zone decreased as the HRT(N) increased and that the slopes of the profiles obtained increased with the rise in the influent concentration. A hydraulic test showed an increase in the dispersion number when the HRT(N) increased. The reactors showed a hydraulic pattern between plug-flow and back mix. The real values of HRT (Theta) also defined as real contact times were determined to be 0.7, 2.1, 3.4, 4.7, 6.4 and 8 days for values of HRT(N) of 1, 2, 3, 4, 5 and 6 days, respectively. It was found that the concentration of SCOD within the reactor decreased exponentially with the increase in the value of theta. Additionally, the influent concentration had a strong influence on the SCOD variation concentration, mainly at values of theta under 1.5 days, which corresponded to the first part of the reactors. PMID- 17701709 TI - Content and bioconcentration factors of mercury by Parasol Mushroom Macrolepiota procera. AB - The carpophores of Parasol Mushroom and underlying soil substrate collected from several unpolluted and spatially distant sites across Poland were examined to know content and bioconcentration potential of mercury by this species. The total mercury content of the caps of Parasol Mushroom for the particular sites ranged from 1.1 +/- 1.0 to 8.4 +/- 7.4 microg/g dry matter (total range from 0.05 to 22 microg/g dm), while in the stalks were from 0.53 +/- 0.27 to 6.8 +/- 7.1 microg/g dm (total range from 0.078 to 20 microg/g dm). A top soil layer (0-10 cm) showed baseline mercury concentration from 0.022 +/- 0.011 to 0.36 +/- 0.16 microg/g dm (total range from 0.010 to 0.54 microg/g dm). Parasol Mushroom is an effective mercury accumulator in the carpophores and bioconcentration factor (BCF) values of this element in the caps and depending on the sampling site ranged from 16 +/- 6 to 220 +/- 110 (total range from 0.52 to 470), while for the stalks were from 7.6 +/- 2.6 to 130 +/- 96 (total range from 0.52 to 340). It seems reasonable to state that tolerance (maximum allowable concentration) of the total mercury in a single cap of Parasol Mushroom at unpolluted areas should not exceed 25 microg/g dm. A value greater then 25 mu g/g dm will imply an elevated content due to site pollution problems. Nevertheless, knowledge on highly toxic methylmercury content and its fraction in the total mercury content of Parasol Mushroom is lacking. PMID- 17701710 TI - Advanced oxidation treatment of physico-chemically pre-treated olive mill industry effluent. AB - In this study, the applicability of physico-chemical methods was investigated for the pre-treatment of the olive mill effluents prior to the discharge into the common sewerage ending with a municipal wastewater treatment plant. The samples were taken from an olive oil industry operated as three-phase process located in Turkey. Various pre-treatment methods including acid craking, polyelectrolyte and lime additions were applied. Advanced oxidation study using Fenton's process was also investigated following pre-treatment by acid cracking and cationic polyelectrolyte. Acid cracking alone gave satisfactory treatment efficiencies and polyelectrolite additions to the acid-cracked samples enhanced treatment efficiency. Since a complete treatment plant is available at the end of the sewer system, results indicated that the effluents of the investigated industry could be discharged into the municipal sewerage in the case of total chemical oxygen demand (COD(tot)), suspended solid (SS) and volatile suspended solid (VSS) concentrations according to the Turkish Water Pollution Control Regulation after pre-treatment with 5 ppm anionic polyelectrolyte following acid cracking. The minimum COD(tot), SS and VSS removals were observed when raw wastewater was pre treated with lime and the discharge standards to the municipal sewer system could not be met. Advanced oxidation with Fenton's process was applied after acid cracking and cationic polyelectrolyte treatment in order to investigate further reduction in chemical oxygen demand (COD) concentration for minimizing the influence of this industrial discharge on the existing municipal wastewater treatment plant. Results indicated that COD(tot) removal increased up to 89% from 74% after Fenton's oxidation for the acid cracked samples in which cationic polyelectrolite (10 ppm) was added. PMID- 17701711 TI - A novel use of anaerobically digested liquid swine manure to potentially control soybean cyst nematode. AB - Experiments were carried out in two steps to determine the effect of anaerobically digested swine manure on soybean cyst nematode (SCN) egg control. In the first step, liquid swine manure underwent anaerobic digestion to search for the best digestion time for both volatile fatty acids (VFA) and ammonium nitrogen (NH(4)(+)) enrichment. The results showed that about 17 and 28 days of incubation were needed, respectively, to reach the maximal levels of VFA and NH(4)(+) in the manure. In the second step, raw, VFA-enriched, and NH(4)(+) enriched manure were applied separately, at four different rates (25, 50, 100, and 200 mL/pot), to soil pots inoculated with nematode eggs in a greenhouse environment. Soil samples were collected 35 and 61 days after inoculation to determine the effect of such treated manure on SCN egg productivity. The data indicated that the SCN egg counts were inversely related to the manure application rates in a linear manner with correlation coefficients of 0.998, 0.967, and 0.900 for raw, NH(4)(+)-enriched, and VFA-enriched manure for the 35 day samples. While no such relationships were found for the 61-day samples, implying that none of the treatments were still effective 61 days after application. At the four application rates, the VFA-enriched manure performed best in reducing SCN egg counts (by 18.1, 19.5, 34.3, and 18.6%) as compared to the raw manure treatment. In contrast, the NH(4)(+)-enriched manure achieved mostly negative reductions. To achieve the best control of SCN egg growth, the VFA-enriched manure should be used and applied to soybean fields every 35 days. PMID- 17701712 TI - Macrolide resistance in the normal microbiota after Helicobacter pylori treatment. AB - Large-scale chemoprevention of peptic ulcer disease and gastric cancer through eradication of Helicobacter pylori would expose large population groups to antibiotics, which raises concerns about possible dissemination of antibiotic resistance. The objective of this cohort study was to determine whether a triple therapy, containing omeprazole, clarithromycin, and metronidazole, of H. pylori infection increases the prevalence of macrolide resistance in the normal microbiota. 85 patients with a peptic ulcer disease with verified H. pylori infection and 12 dyspeptic patients without positive findings upon endoscopy were included. Minimal inhibitory concentrations of clarithromycin for Staphylococcus, Streptococcus, Enterococcus and Bacteroides spp. were determined from samples taken before and after treatment, and 1 y later. Before treatment, macrolide resistance was observed in 11%, 31%, 9% and 11% of the staphylococci, streptococci, enterococci and Bacteroides, respectively. The number of resistant isolates remained elevated after 1 y, most notably for staphylococci and streptococci. No development of persistent resistance was detected in the untreated control group. Triple therapy including clarithromycin leads to persistent macrolide resistance in the normal microbiota. A prevalent pool of resistance genes in the normal microbiota constitutes an ecological hazard that needs to be considered before global treatment programmes for eradication of H. pylori are implemented. PMID- 17701713 TI - High prevalence of MRSA in household contacts. AB - In a 6-y period, 114 household contacts connected to newly diagnosed MRSA patients screened for MRSA in the southern part of Sweden. In 22 of 51 (43%) families, 1 to 4 household contact(s) connected to a MRSA patient were positive for MRSA. In the 22 families, 42 of 60 (70%) household contacts were positive for MRSA and transmission of MRSA occurred between adult couples, parents and children, grandparent and children and between siblings. Within a family, MRSA positive family members had in all but 1 instance identical MRSA strain genotypes (spa types) making intrafamilial spread of MRSA highly probable. MRSA transmission among household contacts may contribute to the prevalence of MRSA in the community and failure to identify MRSA in household contacts may maintain MRSA colonization in an already known MRSA patient. MRSA screening of family members living in the same household as a known MRSA patient should therefore be considered. PMID- 17701714 TI - A multiplex PCR assay for the detection of respiratory bacteriae in nasopharyngeal smears from children with acute respiratory disease. AB - To elucidate the frequency of infections with pathogenic respiratory bacteriae during an inter-epidemic period a multiplex PCR assay was used to screen nasopharyngeal smears for the presence of DNA specific for Bordetella pertussis, Bordetella parapertussis, Chlamydophila pneumoniae and Mycoplasma pneumoniae. 187 samples from children aged 2-14 y were analysed with this method in addition to classical bacteriology and compared to results obtained with commercially available PCR kits for each single parameter. From 82 samples positive by bacteriology, 8 (4.3%) were also positive by PCR, whereas from 105 negative samples, 12 (6.4%) were positive only by PCR. From the total of 20 samples positive by PCR, 4 were found to be positive for M. pneumoniae, 6 for B. pertussis, 3 for B. parapertussis and 7 for both B. pertussis and B. parapertussis. Multiplex PCR is a very useful approach for the diagnosis of bacterial infections not detectable by classical bacteriology. In some patients, PCR was the only method giving a positive result, and in others double infections were diagnosed only because of the PCR contribution. Combination of classical bacteriology with multiplex PCR allows a precise diagnosis of infections in the upper respiratory tract, resulting in a more effective therapy. PMID- 17701715 TI - Antibodies to recombinant decorin-binding proteins A and B in the cerebrospinal fluid of patients with Lyme neuroborreliosis. AB - Cerebrospinal fluid (CSF) and serum samples from 34 patients with proven neuroborreliosis (NB) and 22 patients with suspected neuroborreliosis (SNB) from Finland were analysed for antibodies to decorin-binding proteins A (DbpA) and B (DbpB). Antibodies to recombinant protein antigens originating from Borrelia burgdorferi sensu stricto, B. afzelii, or B. garinii species were studied by enzyme-linked immunosorbent assay (ELISA). Of the 34 patients with NB, 100% of the CSF and 88% of the serum samples had IgG antibodies to 1 to 3 variants of DbpA and 79% of the CSF and 70% of the serum samples were positive for 1 to 3 DbpB variants. Antibodies to DbpB seemed to be associated with lymphocytic pleocytosis in the CSF and short duration of the disease, whereas antibodies to DbpA in the CSF were observed irrespective of the duration of the disease and lymphocytic pleocytosis. Among the variant antigens, CSF reactivity was mainly with the DbpB from B. garinii, whereas positivity with the DbpA from B. afzelii or B. garinii predominated. The results suggest that CSF antibodies to DbpB might be useful as a marker of active infection whereas antibodies to DbpA seem to persist a long time after acute phases of NB. PMID- 17701716 TI - Rapid 4 to 6 hour detection of extended-spectrum beta-lactamases in a routine laboratory. AB - With the growing frequency of extended-spectrum beta-lactamases (ESBL) among Enterobacteriaceae, treatment of Gram-negative nosocomial infections requires rapid and reliable detection of this enzyme. Quicolor agar (QC agar) (Salubris Inc., Massachusetts, USA) is a novel chromogenic agar medium changing colour within 4 to 6 h due to the metabolic activity of growing bacteria. This study investigated the use of QC agar compared to Mueller Hinton agar (MH) for the detection of ESBL using disk diffusion and E-test. 100 Enterobacteriaceae isolated at Hacettepe University Hospital, of which 50 were predetermined to be ESBL positive and 50 as negative using the CLSI disk diffusion ESBL (phenotypic confirmatory test) criteria. For disk diffusion and E-test, cefotaxime+/ clavulanate (CT/CTL) and ceftazidime+/-clavulanate (TZ/TZL) were used, and for E test, cefepime+/-clavulanate (PM/PML) was also used. QC agar rapid ESBL results for all strains were in agreement with the standard overnight procedure. All 50 ESBL positives were detected by both methods. For the 50 ESBL negatives, QC agar rapid results from E-test and disk diffusion were in complete accordance with the overnight MH results. Moreover, E-test detected 8 additional ESBL positive strains that disk diffusion missed. For disk diffusion, CT/CTL alone detected all 50 ESBL positives while TZ/TZL alone missed 5 ESBL positives. E-test CT/CTL alone confirmed all 50 ESBL positives and identified 4 additional ESBL-positive strains. When used together, E-test CT/CTL, TZ/TZL and PM/PML identified a total of 58 ESBL positives among the 100 strains tested. QC agar can be used for rapid and reliable ESBL detection within 4 to 6 h, using disk diffusion and E-test ESBL reagents. This rapid method should be further validated using genotype characterized ESBL and other beta-lactamase positive strains. PMID- 17701717 TI - Comparison of two oral regimens for the outpatient treatment of low-risk cancer patients with chemotherapy-induced neutropenia and fever: ciprofloxacin plus cefuroxime axetil versus ciprofloxacin plus amoxicillin/clavulanate. AB - The objective of this investigation was to assess retrospectively the safety and the efficacy of oral ciprofloxacin plus cefuroxime axetil compared to the combination of oral ciprofloxacin plus amoxicillin/clavulanate, as initial outpatient treatment, in low-risk cancer patients with fever and neutropenia. We analysed retrospectively 120 episodes of febrile neutropenia, treated on an outpatient basis at 2 different oncology units; 63 episodes were treated with the oral regimen of ciprofloxacin plus amoxicillin/clavulanate and 57 were treated with the combination of oral ciprofloxacin plus cefuroxime. 20 treatment failures were recorded-2 of them among patients receiving ciprofloxacin plus amoxicillin/clavulanate and 18 in the ciprofloxacin plus cefuroxime group. Univariate analysis showed that the administration of ciprofloxacin plus cefuroxime was associated with a worse outcome compared to the regimen ciprofloxacin plus amoxicillin/clavulanate (OR 11, CI 2.42-49.9, p =0.002). In the multivariate model, after adjusting for the absolute number of neutrophils and the duration of neutropenia, the effect of the antibiotic regimen on the outcome disappeared, and no significant differences between the 2 regimens were noted, although the regimen of ciprofloxacin plus cefuroxime was associated with a trend to a worse outcome (OR 4.74, CI 0.72-31.1, p =0.10). In conclusion, the 2 regimens appeared equally safe and effective but prospective studies are needed to confirm these results. PMID- 17701718 TI - Primary vaccination and revaccination of young adults with BCG: a study using immunological markers. AB - Questions have been raised about the effectiveness of Bacille Calmette-Guerin (BCG) vaccination against tuberculosis (TB) in adults. We therefore analysed the immune response after BCG vaccination in primary-vaccinated and revaccinated young adults. 31 tuberculin skin test (TST) negative healthy students were BCG vaccinated; 15 were primary-vaccinated and 16 revaccinated. Tuberculin-induced lymphocyte transformation (LT) and cytokine production of peripheral blood mononuclear cells were studied before BCG vaccination, as well as after 2 months and 1 y. In the primary-vaccinated as well as the revaccinated group the LT response increased after 2 months and remained significantly higher than baseline values after 1 y. In both groups the interferon-gamma (IFN-gamma) levels increased significantly after 2 months and the increase was maintained after 1 y. LT increased more in the revaccinated group than in the primary-vaccinated group, while the increase in IFN-gamma response did not differ between the 2 groups. Both primary vaccination and revaccination of TST negative young adults caused a significant increase in the T-helper 1-type immune response, suggesting a protective effect against TB. The present in vitro results thus support the policy in several low-endemic countries of primary vaccination as well as revaccination of young adults at risk of TB exposure. PMID- 17701720 TI - Is estimated cardiovascular risk higher in HIV-infected patients than in the general population? AB - Cardiovascular disease (CVD) is an increasing concern for human immunodeficiency virus (HIV)-infected patients, and risk assessment is recommended in routine HIV care. The absolute cardiovascular risk in an individual is determined by several factors, and various algorithms may be applied. To date, few comparisons of HIV patients with persons of the same age from the general population have been conducted. We hypothesized that the calculated risk of CVD may be increased in HIV patients. The probability for acute coronary events within 10 y (Framingham Risk Score) and the probability for fatal cardiovascular disease (SCORE algorithm) were assessed in 403 consecutive HIV-positive subjects free from overt cardiovascular disease, as well as in 96 age- and gender-matched control subjects drawn from the general population living in the same geographical area. The average 10-y risk for acute coronary events (Framingham Risk Score) was 7.0%+/-5% in HIV subjects and 6.3%+/-5% in the control group (p =0.32). The 10-y estimated risk for cardiovascular mortality (SCORE algorithm) was 1.23%+/-2.3% and 0.83%+/ 0.9%, respectively (p =0.01). The main contributor to the increased CVD risk was the high proportion of smokers, but not an increase in cholesterol level. In conclusion, a limited increase in estimated risk of CVD was found in HIV-infected patients compared to the general population. In HIV-infected individuals other factors of less value in the general population and not included in any cardiovascular algorithm might be important. In our patients intervention to modify traditional risk factors should be addressed primarily towards modifying smoking habits. PMID- 17701719 TI - Long-term effectiveness of highly active antiretroviral therapy (HAART) in perinatally HIV-infected children in Denmark. AB - The long-term impact of highly active antiretroviral therapy (HAART) on HIV-1 infected children is not well known. The Danish Paediatric HIV Cohort Study includes all patients <16 y of age with HIV-1 infection in Denmark. We report the complete follow-up from 1996 to 2005 of 49 perinatally infected children treated with HAART. Initial HAART included 2 nucleoside reverse-transcriptase inhibitors in combination with either a protease inhibitor (n =38) or a non-nucleoside reverse-transcriptase inhibitor (n =12). 19 (39%) patients were previously treated with mono- or dual therapy. Baseline characteristics were median CD4 percentage 14% and HIV-RNA viral load 4.9 log(10). Within the first 12 weeks of therapy approximately 60% achieved HIV-RNA viral load <500 copies/ml, and this remained stable for up to 8 y, although many children changed the components of HAART. The proportion of children with CD4 percentage >25% increased to 60-70% over the y of treatment. For the total cohort, 245 patient-y of observation were available with only 1 death. During our observation period there were no signs of a waning impact. The challenge remains to maintain a high adherence to therapy as the children grow into adolescence and develop more independence from family and health care staff. PMID- 17701721 TI - Genotypic resistance to lopinavir and fosamprenavir with or without ritonavir of clinical isolates from patients failing protease inhibitors-containing HAART regimens: prevalence and predictors. AB - The aim of this study was to establish the prevalence and predictors of genotypic resistance of HIV-1 to lopinavir and fosamprenavir from patients failing protease inhibitors (PI)-based regimens. We selected 643 HIV-1-infected patients with available treatment history who underwent genotypic resistance assays for virological failure from a clinical site and from the Stanford database. According to the genotypic resistance interpretation of the Stanford algorithm, proportions of viruses showing full susceptibility to fosamprenavir and lopinavir were 32% and 34%, respectively (p =ns). Proportions of viruses fully susceptible to lopinavir/r and fosamprenavir/r according to the Agence Nationale pour la Recherche sur le SIDA (ANRS) algorithm, were 81% and 81%, respectively. According to the Rega algorithm, proportions of viruses showing full susceptibility to fosamprenavir/r and lopinavir were 80% and 70%, respectively (p<0.001). According to the ANRS and Rega interpretations, the time on therapy predicted susceptibility to lopinavir/r, while susceptibility to fosamprenavir/r according to ANRS was predicted by the number of prior PI regimens experienced. According to the Stanford interpretation, prior indinavir exposure predicted resistance to lopinavir/r and fosamprenavir/r while prior nelfinavir use predicted susceptibility to both drugs. After failing PI-based regimens, the majority of viruses retained a predicted susceptibility to fosamprenavir/r and lopinavir/r. In patients failing PIs, the interpretation of genotypic resistance to fosamprenavir may change considerably according to the different algorithms and in respect to the effect of pharmacokinetic boosting with ritonavir. PMID- 17701722 TI - Genotypic analysis of serogroups other than A, B or C of Neisseria meningitidis in China. AB - To serologically and genetically characterize other serogroups (except A, B, and C) of Neisseria meningitidis isolates in China, we collected 56 strains of other serogroups, identified by serogroup typing and multilocus sequence typing (MLST). All of them are non-invasive isolates. The serogroups of the 56 Chinese isolates were W135 (11 isolates), Y (4), X (15), 29E (15), D (1), H (4), I (3), K (2), and non-groupable (1). By MLST, 34 different sequence types (STs) were identified, 28 of which were not found in the MLST database as of July 2006 and seemed to be unique to China. Statistical analysis of the MLST results revealed that, although the Chinese isolates seemed to be genetically divergent, they could be classified into 5 major clonal groups and other minor groups. Among these isolates, none of the well-documented ST complexes found worldwide was present. PMID- 17701723 TI - An assessment of influenza vaccination among health profession students. AB - Health profession students work in close proximity to patients and could be a source of nosocomial influenza. We studied the proportion of health profession students presenting for immunization at an influenza immunization campaign. This assessment is useful to guide future campaigns as we prepare for pandemic influenza. PMID- 17701724 TI - Guillain-Barre syndrome associated with scrub typhus. AB - We report a 42-y-old female with Guillain-Barre syndrome (GBS) who presented with scrub typhus for a duration of 2 weeks. Subsequently, ascending paralysis and facial diplegia developed. GBS was confirmed with nerve conduction studies and cerebrospinal fluid examinations. After administration of intravenous immunoglobulin, symptoms gradually disappeared. PMID- 17701725 TI - Pyogenic liver abscess caused by hypermucoviscous Klebsiella pneumoniae. AB - Community-acquired primary pyogenic liver abscess (PLA) caused by Klebsiella pneumoniae is an emerging infectious entity, with cases reported in the scientific literature over the past 15 y mainly from Taiwan and Asia, but also from Europe and North America. We describe a case of PLA caused by the hypermucoviscous, K1 capsular serotype of Klebsiella pneumoniae in a Canadian man and highlight the unique features of this increasingly common cause of liver abscess. PMID- 17701726 TI - Granulicatella elegans bacteraemia in patients with abdominal infections. AB - Bloodstream infections with Granulicatella (previous Abiotrophia) elegans are rare. A few reported cases were associated with infective endocarditis. Three cases of bacteraemia with G. elegans in patients who were operated for acute abdominal diseases are described. Abdominal foci should be considered when G. elegans is recovered from blood. PMID- 17701727 TI - Injury to the radial nerve caused by fracture of the humeral shaft: timing and neurobiological aspects related to treatment and diagnosis. AB - The radial nerve may not function in association with fractures of the humeral shaft. There are various opinions about the causes and treatment. We report a case of complete rupture of the radial nerve after a fracture of the proximal shaft of the humerus. The nerve injury was treated with grafting and TENDON transfer. Here we discuss diagnoses and treatments including neurobiological aspects of nervous regeneration. We suggest that electrodiagnostic examination after a radial nerve palsy caused by a humeral fracture is done 5-6 weeks after injury and that nerve repair and reconstruction should be done within two, and not later than three, months after injury. PMID- 17701728 TI - Induction of activating transcription factor 3 after different sciatic nerve injuries in adult rats. AB - Staining by activating transcription factor 3 (ATF3), a neuronal marker of nerve injury, was examined by immunocytochemistry in neurons and Schwann cells after crush or transection (regeneration inhibited) of rat sciatic nerve. ATF3 immunoreactivity peaked in neurons after three days and then gradually subsided to normal within 12 weeks after the crush. The response lasted somewhat longer and declined over time in spinal cord neurons but not in those of dorsal root ganglia (DRG) after transection, indicating a differential regulation of sensory and motor neurons. ATF3 expression was more pronounced in Schwann cells, and remained longer after transection, implying that to some extent regenerating axons produce signals that reduce ATF3 expression in Schwann cells. However, even after transection without repair (no contact with regenerating axons), ATF3 expression in Schwann cells in the distal segment decreased over time suggesting that regenerating axons are not entirely responsible for the down-regulation. These findings have clinical implications on when it is worthwhile to reconstruct nerve injuries. PMID- 17701729 TI - Sagittal split advancement osteotomy: comparison of the tendency to relapse after two different methods of rigid fixation. AB - Mandibular advancement was studied in 32 patients with mandibular retrognathia in whom the only intervention was in the mandible. Fifteen patients were treated with fixation by lag screws and 17 with monocortical miniplates. Lateral radiographs were taken preoperatively, postoperatively, 2 months postoperatively, and 1.5 years postoperatively, and mandibular movement analysed. All patients healed uneventfully. Cephalometric analysis of lateral radiographs showed no significant differences between the two groups in skeletal relapse during any of the control periods up to 18 months. Mandibular advancement for treatment of mandibular retrognathia using rigid fixation with either lag screws or miniplates was reproducable with only minor skeletal relapse. PMID- 17701730 TI - Patient-reported outcomes after breast reconstruction with deep inferior epigastric perforator flaps. AB - We assessed patient-reported outcomes in 34 women who had had their breasts reconstructed with a deep inferior epigastric perforator (DIEP) flap, and compared them with those of 24 patients who were waiting for breast reconstruction. Both groups completed the Short Form 36 (SF-36) questionnaire. The DIEP flap group also assessed their preoperative conditions retrospectively and completed a study-specific questionnaire. The DIEP group reported higher SF 36 mental health scores after the operation than before, but no difference on other SF-36 scales. There was no difference on any SF-36 scale between patients who had had DIEP flaps and those waiting for reconstruction. Most of the DIEP group was satisfied with their bodies, the appearance of their breasts after reconstruction, and would have chosen operation again. In conclusion, there was little improvement in generic health-related quality of life after reconstruction with a DIEP flap. However, patients' satisfaction was high after the procedure. PMID- 17701731 TI - Sensitivity after bilateral prophylactic mastectomy and immediate reconstruction. AB - The purpose of this retrospective study was to evaluate the cutaneous somatosensory function and patients' subjective experience after bilateral prophylactic mastectomy and immediate reconstruction with implants. Twenty-four patients treated during an eight-year period were included. Somatosensory examination was made at least two years after the latest surgery to study perception thresholds to touch, warmth, cold, and heat pain, using quantitative techniques. Patients also completed a questionnaire about subjective sensitivity. Sixteen women who had had no previous breast surgery were used as a control group. Most patients reported decreased sensitivity in the breasts, which was confirmed by the results from the quantitative somatosensory examination. The results also showed that the ability to experience sexual feelings in the breast is usually lost after this type of operation, and as many as 14 patients reported spontaneous or stimulus-evoked discomfort in the breasts. PMID- 17701732 TI - Morphoeic basal cell carcinoma of the face. AB - The morphoeic (or sclerosing) basal cell carcinoma (mBCC) is the most aggressive subtype, as it spreads into the dermis beyond the clinically visible or palpable borders, making complete excision difficult. Our aim was to identify variables in the surgical management that might increase the rate of complete resection, so we made a retrospective study of 97 mBCCs. One-stage procedures (frozen section analysis) had a higher rate of complete resection (63 of 69, 91%) than two-stage procedures (permanent section analysis) (19 of 28, 68%, p<0.05). The false negative rate of frozen section analysis was 9%. Experienced surgeons had more complete excisions and a lower rate of operative re-excisions. The use of frozen section analysis is an effective way of judging invasion of margins by mBCC. The estimation of tumour margins and the treatment of mBCC requires substantial clinical experience. PMID- 17701733 TI - Modification of thoracoscopy in pectus excavatum: insertion of both thoracoscope and introducer through a single incision to maximise visualisation. AB - Our modification of the Nuss procedure includes insertion of both the introducer and the thoracoscope through the same skin incision, which enables continuous visualisation of the tip of the introducer during blunt dissection across the mediastinum. From January 2001 to January 2005 we studied 32 consecutive patients whose ages ranged from 3 to 30 years. They had all undergone the modified procedure. The mean operating time was 1 hour 44 minutes (range 43 minutes-4 hours 20 minutes). Blood loss was less than 10 ml. There were no intraoperative bleed complications. The modification that we devised may minimise the risk of cardiothoracic and vascular injuries and the procedure is safe. PMID- 17701734 TI - Single-cuff Bier's block in the forearm: factors affecting its efficacy and need for supplementation with local anaesthetics. AB - Bier's block in the forearm is a safe, effective, and reliable method of regional anaesthesia for operations on the upper extremity. We report 155 patients, of whom only 25 had residual sensation after placement of the block, that required additional local anaesthetic. The purpose of this study was to identify the factors responsible for the residual sensation using the single-cuff Bier's block technique. We recorded all those factors that we thought might have an influence. No patients required conversion to a general anaesthetic. The body mass index, the difference of the systolic and tourniquet pressures, and the site of incision were the three factors correlated with the need for additional anaesthesia. PMID- 17701735 TI - Postoperative dynamic extension splinting compared with fixation with Kirschner wires and static splinting in contractures of burned hands: a comparative study of 57 cases in 9 years. AB - Skin grafting is widely used for the treatment of postburn contractures. Their main disadvantage, a tendency to contract again, can be reduced and better outcomes achieved by postoperative splinting. In this study we compared the outcomes of dynamic and static splinting postoperatively. Of the 57 patients managed by split grafts, 36 (44 hands) had Kirschner (K) wires applied with static splints, whereas 21 (26 hands) had dynamic splinting. The mean age was 11 (range 2-37) and 15 (range 2-50) years in the two groups. Before and after the operation, basic hand functions were evaluated clinically, and the results analysed statistically. The mean follow-up times were 18 and 14 months respectively, and recurrence rates were 22% and 14%. We think that the postoperative dynamic splinting is superior to fixation with K-wires with or without static splints. PMID- 17701736 TI - A pedicled anterolateral thigh flap for abdominal reconstruction after previous degloving injury of the donor site: revascularisation of the donor site. AB - A pedicled anterolateral thigh flap was used to reconstruct an abdominal defect after traumatic degloving of the entire skin of the right upper leg two-and-a half years earlier. There are few reports about revascularisation of skin flaps after previous interruption of the blood supply. As far as I know this is the first report of a revascularised (anterolateral thigh) perforator flap. PMID- 17701737 TI - Injuries to the nerves associated with fractured forearms in children. AB - Partial and complete injured median and ulnar nerves caused by fractures of the radius and ulna, respectively, in which the symptoms of nervous injury were induced at the time of fracture are reported. In cases with complete loss of nervous function early exploration should be considered at the time of reposition or plating of the fractured bones, or both, and in patients in whom nervous dysfunction occurs after the operation. PMID- 17701738 TI - Subdermal fibrous hamartoma of infancy in the hand. AB - A fibrous hamartoma of infancy presented in a 4-month-old girl as three separate masses on her right hand. Magnetic resonance imaging showed that the lesions had indistinct margins, and were infiltrating to the overlying subcuticular layer; there was pathological contrast enhancement and high signal intensity in the bony medulla. The masses were successfully excised. The radiological and physical appearance of fibrous hamartomas in a child may suggest malignancy, but the lesion is typically benign and treatment by local excision is usually successful. PMID- 17701739 TI - Key principles underlying research and practice in AAC. AB - Six principles of AAC research and practice are offered for consideration and discussion within the AAC community. Principle 1 requires the active participation of individuals with complex communication needs (CCN) in all AAC activities. Principle 2 seeks to ensure that theoretical constructs underlying research and development in AAC are grounded, widely accepted, and clearly defined. Principle 3 underscores the need to use ergonomics in the design and development of AAC technologies and instructional strategies. Principle 4 highlights communication partners and the unique roles they play in AAC. Principle 5 accentuates the need to focus on societal roles, relationships, and opportunities made possible by AAC technologies and services. Finally, principle 6 draws attention to the importance of measuring a broad range of AAC outcomes, especially those most significant to primary AAC stakeholders. PMID- 17701740 TI - AAC technologies for young children with complex communication needs: state of the science and future research directions. AB - Augmentative and alternative communication (AAC) technologies offer the potential to provide children who have complex communication needs with access to the magic and power of communication. This paper is intended to (a) summarize the research related to AAC technologies for young children who have complex communication needs; and (b) define priorities for future research to improve AAC technologies and interventions for children with complex communication needs. With the realization of improved AAC technologies, young children with complex communication needs will have better tools to maximize their development of communication, language, and literacy skills, and attain their full potential. PMID- 17701741 TI - AAC technologies to enhance participation and access to meaningful societal roles for adolescents and adults with developmental disabilities who require AAC. AB - In this paper we review published research describing the use of augmentative and alternative communication (AAC) to support societal participation by adolescents and adults with developmental disabilities who require AAC. We focus on three major participation domains: post-secondary education and training, the workplace, and community living and social interaction opportunities. Based on the findings of the review, we highlight five needed areas of research and development related to AAC technology: face to face communication; distance communication and interconnectivity; training and support for system use; adapted applications and cognitive tools; and supports for independent operation, development, and maintenance. PMID- 17701742 TI - AAC for adults with acquired neurological conditions: a review. AB - The purpose of this review is to describe the state of the science of augmentative and alternative communication (AAC) for adults with acquired neurogenic communication disorders. Recent advances in AAC for six groups of people with degenerative and chronic acquired neurological conditions are detailed. Specifically, the topics of recent AAC technological advances, acceptance, use, limitations, and future needs of individuals with amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), brainstem impairment, severe, chronic aphasia and apraxia of speech, primary progressive aphasia (PPA), and dementia are discussed. PMID- 17701743 TI - Access to AAC: present, past, and future. AB - Historically, access in augmentative and alternative communication (AAC) has been conceptualized as the physical operation of AAC technologies; more recently, research and development in the cognitive and social sciences has helped to broaden the concept to include a range of human factors involved in the successful use of AAC technologies in social interactions. The goal of this article is to expand the current understanding of communication access by providing a conceptual framework for examining AAC access, evaluating recent scientific and technical advances in the areas of AAC, and discussing the challenges to accessing AAC technologies for a range of communication activities. PMID- 17701744 TI - Enhancing AAC connections with the world. AB - The availability of new technologies has changed how we control devices, exchange information, and communicate with others. Significant barriers, however, have prevented many individuals who use augmentative and alternative communication (AAC) from accessing the technology and computer-based activities available in today's "Information Society." In this paper we discuss the benefits and challenges to increased interoperability between AAC and mainstream technologies. We outline suggested roles and activities for six stakeholder groups: (a) individuals who use AAC, (b) individuals who assist in selecting and supporting use of AAC devices, (c) AAC researchers, (d) AAC device manufacturers, (e) mainstream application developers and technology manufacturers, and (f) public policy makers. We also provide suggestions for future research, public policy, and technical development. PMID- 17701745 TI - A critical review of the use of Clara cell secretory protein (CC16) as a biomarker of acute or chronic pulmonary effects. AB - Biomarkers associated with asthma aetiology and exacerbation have been sought to shed light on this multifactorial disease. One candidate is the serum concentration of the Clara cell secretory protein (CC16, sometimes referred to as CC10 or uteroglobin). In this review, we examine serum CC16's relation to asthma aetiology and exacerbation. There is evidence that acute exposures to certain pulmonary irritants can cause a transient increase in serum CC16 levels, and limited evidence also suggests that a transient increase in serum CC16 levels can be caused by a localized pulmonary inflammation. Research also indicates that a transient increase in serum CC16 is not associated with measurable pulmonary damage or impairment of pulmonary function. The biological interpretation of chronic changes in serum CC16 is less clear. Changes in serum CC16 concentrations (either transient or chronic) are not specific to any one agent, disease state, or aetiology. This lack of specificity limits the use of serum CC16 as a biomarker of specific exposures. To date, many of the critical issues that must be understood before serum CC16 levels can have an application as a biomarker of effect or exposure have not been adequately addressed. PMID- 17701746 TI - Determination of isocyanate biomarkers in construction site workers. AB - 4,4'-Methylenediphenyl diisocyanate (MDI) is the most important isocyanate in the manufacture of polyurethanes, dyes, pigments and adhesives. High concentrations of isocyanates are a potent respiratory irritant. Therefore, it is important to develop methods to monitor exposure to such compounds. We monitored biological samples from 40 non-exposed and 45 exposed construction site workers. 4,4' Methylenedianiline (MDA) and N-acetyl-4,4'-MDA (AcMDA) were determined from untreated urine (U-MDA, U-AcMDA) and MDA was analysed from acid-treated urine (U MDA-tot). Haemoglobin (Hb) adducts of MDA (Hb-MDA) were determined in all workers. The levels of biomarkers decreased in the following order: U-MDA-tot>U AcMDA>U-MDA>Hb-MDA. The same order was found for the percentage of samples, which were found positive in exposed workers: 100%, 91%, 91%, 27%. The urine levels U MDA-tot correlate with U-MDA, U-AcMDA and Hb-MDA with r=0.79, 0.86 and 0.39, respectively (Spearman rank order, p<0.01). U-AcMDA correlates with U-MDA and Hb MDA with r=0.77 and 0.47, respectively (p<0.01). U-MDA correlates with Hb-MDA (r=0.38, p<0.05). The levels in the controls were significantly lower than in the exposed workers for all compounds (Mann-Whitney test, p<0.01). The median isocyanate-specific IgE-level was higher in the exposed workers, but the difference was statistically not significant. The change of the biomarker levels was compared in a group of workers (n=20), which were analysed prior to isocyanate exposure and after the exposure for approximately 4-7 months. All urine MDA metabolites and the Hb-adduct levels increased significantly (Wilcoxon sign test, p<0.01). Total IgE increased significantly after the exposure with isocyanate activity (p<0.01). With the present work it could be shown that outdoor workers are exposed to a similar extent as workers from a MDI factory. PMID- 17701747 TI - Estimation of urinary cotinine cut-off points distinguishing non-smokers, passive and active smokers. AB - An objective assessment of exposure to tobacco smoke may be accomplished by means of examining particular biomarkers in body fluids. The most common biomarker of tobacco smoke exposure is urinary, or serum, cotinine. In order to distinguish non-smokers from passive smokers and passive smokers from active smokers, it is necessary to estimate cotinine cut-off points. The objective of this article was to apply statistical distribution of urinary cotinine concentration to estimate cut-off points distinguishing the three above-mentioned groups. The examined group consisted of 327 volunteers (187 women and 140 men) who were ethnically homogenous inhabitants of the same urban agglomeration (Sosnowiec, Poland). The values which enabled differentiation of the examined population into groups and subgroups were as follows: 50 microg l(-1) (differentiation of non-smokers from passive smokers), 170 microg l(-1) (to divide the group of passive smokers into two subgroups: minimally and highly exposed to environmental tobacco smoke), 550 microg l(-1) (differentiation of passive smokers from active smokers), and 2100 microg l(-1) (to divide group of active smokers into two subgroups: minimally and highly exposed to tobacco smoke). The results suggest that statistical distribution of urinary cotinine concentration is useful for estimating urinary cotinine cut-off points and for assessing the smoking status of persons exposed to tobacco smoke. PMID- 17701748 TI - An epidemiological study of reproductive function biomarkers in male welders. AB - In a cross-sectional study, the serum concentrations of inhibin B and prolactin of 96 male current welders were compared with the concentrations measured in 96 age-matched referents. Also, 23 patients who were all former welders diagnosed as having welding-related manganism were studied. The current welders' geometric mean (GM) airborne exposure to manganese (Mn) was 121 microg m(-3) (range 7 2320). The serum concentrations of prolactin adjusted for age and smoking habits (GM 193 mIU l(-1) vs. 166 mIU l(-1); p=0.047) and inhibin B adjusted for alcohol consumption (arithmetic mean (AM) 151 ng l(-1) vs. 123 ng l(-1); p=0.001) were higher in the welders compared with the referents. The whole blood Mn concentration was associated with the serum prolactin concentrations. Tobacco smoking resulted in lower serum prolactin concentrations. The GM serum prolactin concentrations of the patients did not significantly differ from that of the referents, but their AM serum inhibin B concentration was statistically significantly lower. The results may suggest an effect of Mn on the pituitary that is reversible upon cessation of exposure. Lower inhibin B concentrations in the patients could point to a functional impairment of the testicular Sertoli cells, that may be caused by a welding fume component or other factors in their work environment. PMID- 17701749 TI - Distinct distribution of HPV types among cancer-free Afro-Caribbean women from Tobago. AB - Human papillomavirus (HPV), a sexually transmitted virus causes cervical carcinomas, and is associated with approximately 36% of oropharyngeal tumours where HPV16 is the predominant genotype. The cervical cancer incidence rate in Trinidad and Tobago is about two times higher than the worldwide rate. We have for the first time determined the prevalence and type distribution of cervical HPV infections among cancer-free Afro-Caribbean women from Tobago, and compared it with the HPV subtypes observed in their oral cavity. Thirty-five per cent of the women were cervical HPV positive. The most common high-risk type detected in the cervix was HPV45 rather than HPV16 and 18. The prevalence of HPV infection in the oral mucosa was 6.6%. The distribution of HPV genotypes in healthy Tobagonian women is different from that reported in studies conducted in European and North American populations. This may have important implications for vaccine introduction in this and other Afro-Caribbean countries. PMID- 17701750 TI - The XRCC3 Thr241Met polymorphism and breast cancer risk: a case-control study in a Thai population. AB - The X-ray repair cross-complementing group 3 gene (XRCC3) belongs to a family of genes responsible for repairing DNA double-strand breaks caused by normal metabolic processes and exposure to ionizing radiation. Polymorphisms in DNA repair genes may alter an individual's capacity to repair damaged DNA and may lead to genetic instability and contribute to malignant transformation. We examined the role of a polymorphism in the XRCC3 gene (rs861529; codon 241: threonine to methionine change) in determining breast cancer risk in Thai women. The study population consisted of 507 breast cancer cases and 425 healthy women. The polymorphism was analysed by fluorescence-based melting curve analysis. The XRCC3 241Met allele was found to be uncommon in the Thai population (frequency 0.07 among cases and 0.05 among controls). Odds ratios (OR) adjusted for age, body mass index, age at menarche, family history of breast cancer, menopausal status, reproduction parameters, use of contraceptives, tobacco smoking, involuntary tobacco smoking, alcohol drinking, and education were calculated for the entire population as well as for pre- and postmenopausal women. There was a significant association between 241Met carrier status and breast cancer risk (OR 1.58, 95% confidence interval (CI) 1.02-2.44). Among postmenopausal women, a slightly higher OR (1.82, 95% CI 0.95-3.51) was found than among premenopausal women (OR 1.48, 95% CI 0.82-2.69). Our findings suggest that the XRCC3 Thr241Met polymorphism is likely to play a modifying role in the individual susceptibility to breast cancer among Thai women as already shown for women of European ancestry. PMID- 17701751 TI - Baseline serum levels of cardiac biomarkers in patients with stable coronary artery disease. AB - Stable coronary artery disease (CAD) can cause repetitive reversible myocardial ischaemia, and it seems to be possible that reversibly injured myocardium releases small amounts of soluble cytoplasmic proteins. Hence, the aim was to evaluate the effect of stable CAD on baseline serum levels of cardiac biomarkers. We studied 68 consecutive outpatients referred for gated myocardial perfusion imaging. Before a treadmill exercise test, blood samples for measurement of creatine kinase (CK), CK-myocardial band (CK-MB) mass, myoglobin, aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were collected. Normal perfusion patterns were detected in 29 (43%) patients (group 1) and perfusion defects were detected in 39 (57%) patients (group 2). Baseline serum levels of biomarkers except CK were significantly higher in group 2 (p=0.001). Stable CAD increases baseline levels of CK-MB mass, myoglobin, AST and LDH in the serum and this increase is related to the extent and severity of the perfusion defect and to some extent the ejection fraction of the left ventricle. PMID- 17701752 TI - Measurement of blood E2F3 mRNA in prostate cancer by quantitative RT-PCR: a preliminary study. AB - The use of serum prostate-specific antigen (PSA) measurements necessitates biopsies for accurate prostate cancer (CaP) diagnosis. Overall efficiency of accurate diagnosis, when PSA levels are used alone, is less than 60%. E2F3 was evaluated as an alternative biomarker using patient blood samples. Expression levels were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and correlated with accurate clinicopathological data. Statistical analysis demonstrated significant differences in E2F3 expression levels (p<0.0001), and high levels of discrimination (receiver operator curve/area under curve analysis values (AUC) >0.88), in particular at early stages of disease development, between benign disease and localized CaP. Limited levels of discrimination were observed at the later stages of disease development, between localized and metastatic disease (p=0.076, AUC=0.633). A cut off point of 0.34 with high specificity for benign disease (92.3%) and sensitivity for CaP diagnosis (81.0%) was identified. At this cut-off point, 85% patients were correctly diagnosed with either malignant or benign disease. This study demonstrates the strength of E2F3 as a potential marker for discriminating benign and malignant disease, addressing the current limitations of serum PSA measurements. PMID- 17701753 TI - Introduction: Speech and language in Williams syndrome. PMID- 17701755 TI - Do children with Williams syndrome really have good vocabulary knowledge? Methods for comparing cognitive and linguistic abilities in developmental disorders. AB - The comparison of cognitive and linguistic skills in individuals with developmental disorders is fraught with methodological and psychometric difficulties. In this paper, we illustrate some of these issues by comparing the receptive vocabulary knowledge and non-verbal reasoning abilities of 41 children with Williams syndrome, a genetic disorder in which language abilities are often claimed to be relatively strong. Data from this group were compared with data from typically developing children, children with Down syndrome, and children with non-specific learning difficulties using a number of approaches including comparison of age-equivalent scores, matching, analysis of covariance, and regression-based standardization. Across these analyses children with Williams syndrome consistently demonstrated relatively good receptive vocabulary knowledge, although this effect appeared strongest in the oldest children. PMID- 17701756 TI - Comprehension of spatial language in Williams syndrome: evidence for impaired spatial representation of verbal descriptions. AB - Individuals with the rare genetic disorder, Williams syndrome, have an unusual cognitive profile with relatively good language abilities but poor non-verbal and spatial skills. This study explored the interaction between linguistic and spatial functioning in Williams syndrome by investigating individuals' comprehension of spatial language. A group of 17 individuals with Williams syndrome and a control group of typically developing children were given two types of picture-matching task in which they were asked to select a picture to match a spoken sentence describing the spatial relation between two items. In the first task this matching could be done on the basis of existing semantic knowledge. In the second, we argue that a mental representation of the spatial relations was required. Results demonstrated that individuals with Williams syndrome were selectively impaired on the second task relative to controls. The study therefore provides support for previous work demonstrating impaired comprehension of spatial language in this population. Furthermore, the results suggest that such impairments reflect a fundamental problem with processing spatial descriptions rather than merely a poor understanding of the semantics of spatial terms, which in turn has implications for the interaction between spatial abilities and language processing in general. PMID- 17701754 TI - Affective prosody in children with Williams syndrome. AB - The aim of the current study was to investigate expressive affect in children with Williams syndrome (WS) in comparison to typically developing children in an experimental task and in spontaneous speech. Fourteen children with WS, 14 typically developing children matched to the WS group for receptive language (LA) and 15 typically developing children matched to the WS groups for chronological age (CA) were recruited. Affect was investigated using an experimental Output Affect task from the Profiling Elements of Prosodic Systems-Child version (PEPS C) battery, and by measuring pitch range and vowel durations from a spontaneous speech task. The children were also rated for level of emotional involvement by phonetically naive listeners. The WS group performed similarly to the LA and CA groups on the Output Affect task. With regard to vowel durations, the WS group was no different from the LA group; however both the WS and the LA groups were found to use significantly longer vowels than the CA group. The WS group differed significantly from both control groups on their range of pitch range and was perceived as being significantly more emotionally involved than the two control groups. PMID- 17701757 TI - Patterns of syntactic development in children with Williams syndrome and Down's syndrome: evidence from passives and wh-questions. AB - This study investigates the syntactic abilities of ten individuals with Williams syndrome (WS) (mean chronological age: 8;9 years; mean mental age: 4;8 years) and Down's syndrome (DS) (mean chronological age: 8;7 years; mean mental age: 4;6 years), matched individually on chronological age, mental age and performance IQ. The syntactic components investigated include the comprehension of passives and the production, comprehension and repetition of wh-questions. Performance is compared to ten younger typically developing (TD) controls matched individually to both experimental groups on mental age (mean chronological age: 4;4 years; mean mental age: 5;0 years). Participants were given a standardized measure of grammatical ability and non-standardized tasks exploring the comprehension of active and passive sentences, and the production, comprehension and repetition of a range of wh-question types: wh-subject, wh-object, which NP-subject and which NP-object. Participants with WS and DS performed similarly on the standardized measure of grammatical ability, as well as on the experimental tasks that tapped comprehension of passives, and production and comprehension of wh-questions. Participants with DS performed significantly more poorly than both the WS cohort and TD controls on the repetition of wh-questions. Both the WS and DS cohorts performed significantly more poorly on most of the syntactic tasks compared to the younger TD controls. Individuals with WS and DS experienced significant difficulties in tasks measuring aspects of syntactic ability and performed more poorly than mental age-matched TD controls. Implications of these findings, with regards to the debates around language "intactness" in WS, as well as the similarities and differences in language abilities in WS and DS, dependent on age and developmental stages studied, are explored. PMID- 17701758 TI - Complex grammar in Williams syndrome. AB - This study investigated knowledge of binding and raising in two groups of children with Williams syndrome (WS), 6-12 and 12-16-years-old, compared to typically developing (TD) controls matched on non-verbal MA, verbal MA, and grammar. In typical development, difficulties interpreting pronouns, but not reflexives, persist until the age of around 6, while raising is not mastered until about the age of 8 or 9. If grammar in WS is delayed, but develops in a fashion parallel to TD population, similar patterns of difficulties may be expected, although it has not been established whether the grammatical development is ever complete in the individuals with this disorder. Knowledge of the principle of binding which states that a reflexive must have a c-commanding antecedent, was found to be intact in all the participants, in line with previous reports in the literature. In contrast, children with WS younger than 12 showed a poorer performance on personal pronouns, like two groups of younger matched TD controls, suggesting a previously unreported delay in the acquisition of constraints regulating coreferential interpretation of pronouns. Both groups of children with WS showed an extremely limited comprehension of raised, as opposed to unraised structures. The revealed patterns indicate that, like in unimpaired populations, different aspects of grammar mature at distinct stages of language development in WS: reflexive binding is acquired earlier than constraints governing coreference. However, development of raising seems exceptionally delayed, and perhaps even unattainable, as data from several adults with WS studied in Perovic and Wexler (2006) show. If, as hypothesized by Hirsch and Wexler, the late development of raising is related in TD children to lack of maturation of the knowledge of A-chains or defective phases, it seems reasonable to hypothesize that the even later development of these structures in WS is related to an even later (if ever) maturation of the knowledge of these grammatical forms. PMID- 17701759 TI - Measuring ethnicity in New Zealand: developing tools for health outcomes analysis. AB - OBJECTIVE: This study examines the development of new tools for analysing links between ethnicity and health outcomes. In a New Zealand context, it focuses on (1) how ethnicity is increasingly articulated as a social construct, (2) how individuals belonging to more than one ethnic group have been recorded and reported in research, and (3) health research and policy implications of the growing proportion of New Zealanders who claim multi-ethnic affiliations. DESIGN: New Zealand provides a microcosm in which to consider ethnicity, indigeneity, migration and intermarriage, and their interacting effects on society, culture, identity and health outcomes. Against a backdrop of historical debates about the measurement of race, and then ethnicity, the paper explores recent changes in the recording and reporting of ethnicity in the five-yearly Census of Population and Dwellings, and in death registrations. These changes are then considered in relation to the study of ethnic health disparities and the development of policies to overcome them. RESULTS: In the 2001 Census, of those who responded to the ethnicity question, at a level 1 classification 7.9% gave more than one response. In relation to the indigenous people of New Zealand, of all those who recorded Maori as one or more of their ethnic groups, only 56% recorded Maori only. In the younger age groups, less than half the Maori ethnic group were Maori only. Single ethnic categories disguise considerable within-group diversity in outcomes. CONCLUSION: While single ethnic group disparity studies have been useful in the past, we suggest that more sophisticated ways of conceptualising and analysing ethnicity data in relation to health disparities are now required in New Zealand. Based on the New Zealand experience, we also suggest that as international migration continues, and as intermarriage becomes more frequent in most countries, there will be pressure to move from single group race-based measures towards culturally-based complex ethnicity measures. PMID- 17701760 TI - Tobacco control policy initiatives and UK resident Bangladeshi male smokers: community-based, qualitative study. AB - OBJECTIVE: To reflect on recent proposed tobacco control initiatives in the socio cultural context of the smoking behaviours of UK resident Bangladeshi men. DESIGN: Cross-sectional study using focus groups and one-to-one interviews conducted in English and Sylheti. Eighty-one men, aged 18-64 years, were recruited from the Bangladeshi community of Tower Hamlets, London, during 2002. Participants were purposively selected to reflect their age, place of birth and tobacco-use status. The discussions were tape-recorded and subsequently transcribed. The transcripts were analysed using 'framework' principles. Three of the current themes for tobacco control -- smoke-free workplace environments, access to alternative sources of tobacco, and use and availability of nicotine replacement therapy -- were used to organise the data. RESULTS: Smoking initiation and use was confirmed as linked to gender, age, religion and tradition. Continued smoking was supported by anxieties about harassment in younger respondents, the migration experience of older respondents, and the unskilled employment opportunities available in the restaurant trade. These employment opportunities, whilst providing social support, did not support smoking regulations, in contrast to the practices observed in the general employment market. Levels of knowledge about the health risks of smoking varied by age. Three cheaper alternative tobacco types were readily accessible for use: contraband, roll-ups and traditional chewing tobacco in paan (chewing tobacco mixed with areca nut rolled in a betel leaf). Despite the latter's associations with use by women, younger respondents described the transition to chewing tobacco in paan as a smoking cessation aid instead of nicotine replacement therapy. There was confusion about the purpose, availability and efficacy of nicotine replacement therapy. Respondents reported isolation and marginalisation from current tobacco control initiatives, including much NHS Stop Smoking Service provision. CONCLUSION: The socio-cultural context of the smoking behaviours of this group of Bangladeshi men was linked to a reported isolation and exclusion from current tobacco control initiatives. These initiatives should be inclusive and address the reported needs of this community. The findings have implications for service development. Addressing these findings will help to inform the implementation of relevant public health policy initiatives for tobacco control to meet the needs of this community. PMID- 17701761 TI - State anti-tobacco advertising and smoking outcomes by gender and race/ethnicity. AB - OBJECTIVE: This paper examines overall and gender- and racial/ethnic-specific relationships between exposure to state-sponsored anti-tobacco televised advertising and smoking-related outcomes among US middle and high school students using five years of cross-sectional nationally representative data. DESIGN: Nationally representative 8th, 10th, and 12th grade student sample data for 1999 2003 were merged with commercial ratings data on mean potential audience exposure to network and cable television anti-tobacco advertising across the 74 largest US designated market areas, resulting in a final sample size for analysis of 122,340. Associations between state-sponsored anti-tobacco televised advertising exposure and youth smoking-related beliefs and behaviours were modelled while controlling for relevant individual and environmental factors as well as other televised tobacco-related advertising. RESULTS: Higher potential for exposure to state anti-tobacco advertising within the previous four months was generally associated with decreasing odds of current smoking across groups. In addition, such exposure was related, to varying degrees, with decreased perceptions that most/all friends smoked, stronger five-year intentions not to smoke, and increased perceived harm of smoking. These relationships appeared possibly to be weaker for Asian students. CONCLUSIONS: The results from these analyses indicate that state anti-tobacco advertising significantly relates to beneficial outcomes - especially regarding current smoking behaviour -- among US youth as a whole. PMID- 17701762 TI - Self-reported anxiety, sleeping problems and pain among Turkish-born immigrants in Sweden. AB - OBJECTIVES: To study whether symptoms of self-reported anxiety, sleeping problems and severe pain are more common among Turkish-born immigrants in Sweden than among Swedes, and whether age and socio-economic status can explain this hypothesised difference. DESIGN: Two random samples were studied -- the Swedish National Board of Health and Welfare Immigrant Survey, and the Swedish Annual Level-of-Living Survey, both from 1996. A total of 526 Turkish-born immigrants in Sweden were compared with 2,854 Swedish controls, all aged between 27 and 60 years. Data were analysed by sex, in an age-adjusted model; and a full model also included age, education, marital status, employment and country of origin (logistic regression). RESULTS: In the full model, odds ratios were 2.12 (1.43 3.15) for anxiety, 2.60 (1.82-3.72) for sleeping problems, and 2.14 (1.50-3.05) for severe pain among Turkish-born men, and 2.44 (1.69-3.53) for anxiety, 3.01 (2.09-4.33) for sleeping problems, and 2.59 (1.80-3.71) for severe pain among Turkish-born women, using the Swedish controls as references. CONCLUSIONS: Being a Turkish-born immigrant in Sweden significantly increases the risks for self reported anxiety, sleeping problems and severe pain, even after adjusting for age and socio-economic status (education, marital status and employment). PMID- 17701764 TI - Gender issues in cardiovascular medicine. PMID- 17701763 TI - Cultural considerations in developing church-based programs to reduce cancer health disparities among Samoans. AB - OBJECTIVES: We examined receptivity to developing church-based cancer programs with Samoans. Cancer is a leading cause of death for Samoans, and investigators who have found spiritually linked beliefs about health and illness in this population have suggested the Samoan church as a good venue for health-related interventions. DESIGN: We interviewed 12 pastors and their wives, held focus groups with 66 Samoan church members, and engaged a panel of pastors to interpret data. All data collection was conducted in culturally appropriate ways. For example, interviews and meetings started and ended with prayer, recitation of ancestry, and an apology for using words usually not spoken in group setting (such as words for body parts), and focus groups were scheduled to last five hours, conferring value to the topic and allowing time to ensure that cancer concepts were understood (increasing the validity of the data collected). RESULTS: We found unfamiliarity with the benefits of timely cancer screening, but an eagerness to learn more. Church-based programs were welcome, if they incorporated fa'aSamoa (the Samoan way of life) -- including a strong belief in the spiritual, a hierarchical group orientation, the importance of relationships and obligations, and traditional Samoan lifestyle. This included training pastors to present cancer as a palagi (White man) illness versus a Samoan (spiritual) illness, about which nothing can be done, supporting respected laity to serve as role models for screening and witnesses to cancer survivorship, incorporating health messages into sermons, and sponsoring group education and screening events. CONCLUSION: Our findings inform programming, and our consumer-oriented process serves as a model for others working with minority churches to reduce cancer health disparities. PMID- 17701765 TI - Quality of life in breast cancer patients. PMID- 17701766 TI - Magnesium ion inhibits spontaneous and induced contractions of isolated uterine muscle. AB - AIM: Magnesium sulfate, mainly used in obstetrics to treat eclamptic convulsions, is currently questioned as to its clinical tocolytic effect. We aimed to study the relaxant action (if any) of magnesium sulfate on in vitro pregnant and non pregnant myometrium. METHODS: Myometrial strips, harvested from five pregnant women (35-39 gestational weeks) during Cesarean procedures indicated for dystocia or scared uterus and five non-pregnant women during hysterectomy or myomectomy for benign conditions, were placed in a Krebs-Henseleit solution organ bath and the isometric force was registered. We assessed the effect of Mg2+ (magnesium sulfate) at different concentrations (0.50-10 mM) on spontaneous and oxytocin induced (1 microM) myometrial contractility. RESULTS: Mg2+ temporarily reduced spontaneous myometrial contractions in a dose-dependent manner, with efficient regimens at 2.0-2.5 mM, and arrested contractility completely at 3 mM. Oxytocin induced contractions were reduced by 30-40% at 8 mM and decreased further at 9-10 mM. Induced contractions were reduced, in a dose-dependent and time-dependent manner (maximum effect at 20 min), at higher Mg2+ concentrations and with non significant proportional differences between pregnant and non-pregnant myometrium. CONCLUSIONS: The present in vitro study suggests a possible benefit of Mg2+ in the inhibition of spontaneous myometrial contractility, but not of uterine-induced hyperactivity. PMID- 17701767 TI - Ovulation induction treatment and risk of borderline ovarian tumors. AB - AIM: Research has suggested an association between the use of ovulation induction drugs and the risk of ovarian cancer. It has also been proposed that there may be pre-cancerous alterations in the ovary which themselves are the cause of infertility. The aim of the present study was to evaluate the relationship between the use of ovulation induction drugs and the appearance of borderline ovarian tumors. MATERIAL AND METHODS: This was a case-control study in which the study group comprised 42 women with a borderline ovarian tumor and the control group comprised 257 women with benign ovarian pathology. RESULTS: No differences were found between the borderline tumor and control groups (14.3% vs. 27.2%, respectively) in terms of infertility history. Nor were there any differences between the groups with respect to the type of drug used, whether clomiphene citrate (9.5% vs. 6.2%, respectively) or gonadotropins (7.1% vs. 10.1%, respectively). Analysis in terms of the number of cycles administered also failed to reveal any differences. The mean number of cycles with clomiphene citrate/gonadotropins was 2.50 +/- 1.00 and 3.00 +/- 2.64 in the borderline tumor group and 2.44 +/- 1.75 and 3.27 +/- 2.25 in the control group. CONCLUSIONS: Our series produced no evidence that ovulation induction treatment predisposes women to the development of borderline ovarian tumors. PMID- 17701768 TI - Tumor necrosis factor-alpha activates nuclear factor-kappaB but does not regulate progesterone production in cultured human granulosa luteal cells. AB - BACKGROUND: The role of tumor necrosis factor-alpha (TNF-alpha) in granulosa luteal cell function and steroidogenesis is still controversial. Our aim was to examine the steroidogenic response, together with the simultaneous expression and activation of nuclear factor-kappaB (NF-kappaB), in cultured human granulosa luteal cells (GLCs) following administration of TNF-alpha. MATERIALS AND METHODS: This prospective controlled study was conducted in the Human Reproduction Division at the Institute of Maternal and Child Research, Faculty of Medicine, University of Chile and the San Borja Arriaran Hospital, National Health Service, Santiago, Chile. GLCs were obtained from aspirates of follicles from women undergoing in vitro fertilization (IVF). Thirty-two women undergoing IVF for tubal-factor and/or male-factor infertility participated in this study. Protein levels of NF-kappaB, the NF-kappaB inhibitor IkappaBalpha and steroidogenic acute regulatory protein (StAR) were determined by Western blot and localization of NF kappaB was studied by indirect immunofluorescence. Progesterone production was determined by radioimmunoassay. RESULTS: TNF-alpha did not affect the expression of StAR protein or the synthesis of progesterone. NF-kappaB was expressed in the GLCs and activated by TNF-alpha, resulting in degradation of IkappaBalpha and mobilization of the p65 NF-kappaB subunit into the nucleus. CONCLUSIONS: These results indicate that TNF-alpha did not modulate steroidogenesis in cultured human GLCs. However, NF-kappaB was activated by TNF-alpha. Therefore the activation of NF-kappaB via the TNF-alpha pathway is likely associated with other preovulatory granulosa cell processes important for human ovarian function. PMID- 17701769 TI - Ocular surface changes over the menstrual cycle in women with and without dry eye. AB - AIM: To analyze whether dry eye symptoms and ocular surface parameters change during different phases of the menstrual cycle. METHOD: Twenty-nine women of fertile age and with regular, 26-29-day menstrual cycles were included in the study. Fourteen subjects suffered and 15 did not suffer from dry eye symptoms. Symptoms were scored by the validated Ocular Surface Disease Index questionnaire. Tear production was evaluated with the Schirmer I test and the Schirmer II test (Jones test); tear stability with tear breakup time and Ferning test; and degree of dryness by the tear function index and imprint conjunctival cytology. Degree of inflammation was evaluated with conjunctival brush cytology and concentration of exudated serum albumin in tears. Hormonal cytology procedures were applied to exfoliated cells in tears. Patients were analyzed during menstruation, in the follicular phase and the luteal phase over two consecutive cycles, and results were statistically evaluated. RESULTS: Subjective symptoms, tear production and stability, surface dryness and inflammation were significantly related to hormonal fluctuations in the menstrual cycle. In particular, the impairment of these functions appeared to be related to the estrogen peak occurring during the follicular phase, especially in patients with dry eye. CONCLUSION: The ocular surface is confirmed to be an estrogen-dependent unit; clinicians should take into account these cyclic variations during examination of subjects affected by symptoms of eye dryness. PMID- 17701770 TI - Breast cancer incidence and hormone replacement therapy: results from the MISSION study, prospective phase. AB - BACKGROUND: The MISSION Study (Menopause: Risk of Breast Cancer, Morbidity and Prevalence) is a historical-prospective study with random patient selection to determine breast cancer incidence in postmenopausal women with or without hormone replacement therapy (HRT). The first prospective follow-up phase started on 5 January 2004 and the cut-off date for data collection was 30 June 2006. PARTICIPANTS: Patients were divided into two groups: an 'exposed group' of women on HRT regimens commonly prescribed in France or who had stopped < or =5 years previously; and an 'unexposed group' of women who had never received HRT or stopped >5 years previously. In total 6755 patients were included; and prospective data were available for 4949 patients: 2693 in the exposed group and 2256 in the unexposed group. Women in the exposed group were younger, less overweight, and had fewer first-degree family histories of breast cancer than women of the unexposed group. Mean duration of HRT exposure was 8.3 years, with 31% being exposed for > or =10 years. RESULTS: The incidence of new breast cancer cases was 0.64% in the exposed group and 0.70% in the unexposed group (relative risk RR(exposed/unexposed) = 0.914, 95% confidence interval = 0.449-1.858; not modified when adjusted for age). Mean age at breast cancer diagnosis was similar in both groups. Breast cancer incidence in the exposed group was not significantly affected by the route of estradiol administration (cutaneous 0.69%; oral 0.52%) or HRT type (estradiol alone 0.28%; estradiol + progesterone 0.40%; estradiol + synthetic progestin 0.94%). CONCLUSION: No evidence was found for an increased risk of breast cancer in women exposed to HRT compared with non-exposed women. PMID- 17701771 TI - Comparison of the effects of raloxifene and low-dose hormone replacement therapy on bone mineral density and bone turnover in the treatment of postmenopausal osteoporosis. AB - OBJECTIVE: The aim of the present study was to compare the effects of raloxifene and low-dose hormone replacement therapy (HRT) on bone mineral density (BMD) and bone turnover markers in the treatment of postmenopausal osteoporosis. METHODS: Forty-two postmenopausal osteoporotic women, who were randomized to receive raloxifene 60 mg or estradiol 1 mg/norethisterone acetate 0.5 mg daily for 1 year, were studied. All women received calcium 600 mg/day and vitamin D 400 IU/day. BMD and markers of bone turnover were measured at baseline and at 12 months. RESULTS: After 12 months of treatment, there were statistically significant increases in BMD in both groups at all sites (all p < 0.05). For the lumbar spine, the increase in BMD was 2.3% for raloxifene compared with 5.8% for low-dose HRT and corresponding values for total body BMD were 2.9% for raloxifene and 4.6% for low-dose HRT; the increases being significantly greater in the low dose HRT group (p < 0.001 and p = 0.02, respectively). Although the increase in BMD at the hip was significant for both raloxifene (2.1%) and low-dose HRT (3.2%) compared with baseline, the difference between the two regimens did not reach statistical significance. The decrease in serum C-terminal telopeptide fragment of type I collagen and serum osteocalcin levels for the low-dose HRT group (-53% and -47%, respectively) was significantly greater than for the raloxifene group ( 23% and -27%, respectively; both p < 0.01). CONCLUSIONS: In postmenopausal women with osteoporosis, low-dose HRT produced significantly greater increases in BMD of the lumbar spine and total body and greater decreases in bone turnover than raloxifene at 12 months. PMID- 17701773 TI - An analysis of ovarian cancer in the Million Women Study. AB - In a reanalysis of the Million Women Study (MWS), their authors concluded that prolonged use of hormone replacement therapy (HRT) in postmenopausal women increases the risk of ovarian cancer. Although statistically significant their results are clinically irrelevant, since the attributable risk over 5 years is only 4 per 10 000 HRT users, a figure that is not confirmed by other large studies. This risk is much lower than those associated with obesity, lack of physical exercise, smoking and nulliparity, all of which are preventable. Therefore HRT should continue to be prescribed for symptom relief and improvement of quality of life because the benefits far outweigh the very low potential risks. PMID- 17701772 TI - Quality of life and postmenopausal symptoms among women in a rural district of the capital city of Turkey. AB - OBJECTIVE: To determine menopause-related symptoms and quality of life in women aged 40-80 years living in a rural area of Turkey. METHODS: A total of 338 women were evaluated in this cross-sectional study. As data sources we used a questionnaire that elicited information on the descriptive, fertility and menopausal characteristics of the women, the Menopause Rating Scale (MRS) and the Short Form-36 (SF-36). RESULTS: The mean age at menopause was 46.5 +/- 0.4 years. The complaint stated most often as 'severe or very severe' was 'hot flushes and sweating' (50.7%). The physical functioning, physical role, bodily pain, general health, social functioning, emotional role and mental health scores of postmenopausal women were statistically higher (p < 0.05) than those of premenopausal women. Scores on physical function, physical role, general health and social function decreased significantly with age in postmenopausal women (p < 0.05), while none of the quality-of-life domain scores differed significantly with age in premenopausal women. CONCLUSIONS: Quality of life is worse in postmenopausal women than premenopausal women, and in older than younger women in the postmenopausal period. Thus rural populations are primarily in need of public health care in the postmenopausal period. PMID- 17701774 TI - Iodine and thyroid hormones during pregnancy and postpartum. AB - Iodine is a trace element essential for synthesis of the thyroid hormones, triiodothyronine and thyroxine. These hormones play a vital role in the early growth and development stages of most organs, especially the brain. The World Health Organization (WHO) has declared that, after famine, iodine deficiency is the most avoidable cause of cerebral lesions including different degrees of mental retardation and cerebral paralysis. The main function of iodine in vertebrates is to interact with the thyroid hormones. During pregnancy sufficient quantities of iodine are required to prevent the appearance of hypothyroidism, trophoblastic and embryonic or fetal disorders, neonatal and maternal hypothyroidism, and permanent sequelae in infants. Thyroid hormone receptors and iodothyronine deiodinases are present in placenta and central nervous tissue of the fetus. A number of environmental factors influence the epidemiology of thyroid disorders, and even relatively small abnormalities and differences in the level of iodine intake in a population have profound effects on the occurrence of thyroid abnormalities. The prevalence of disorders related to iodine deficit during pregnancy and postpartum has increased. Iodine supplementation is an effective measure in the case of pregnant and lactating women. However, it is not implemented and the problem is still present even in societies with theoretically advanced health systems. During pregnancy and postpartum, the WHO recommends iodine intake be increased to at least 200 microg/day. Side-effects provoked by iodine supplementation are rare during pregnancy at the recommended doses. PMID- 17701776 TI - Computer aided analysis of phonocardiogram. AB - In the present paper analysis of phonocardiogram (PCG) records are presented. The analysis has been carried out in both time and frequency domains with the aim of detecting certain correlations between the time and frequency domain representations of PCG. The analysis is limited to first and second heart sounds (S1 and S2) only. In the time domain analysis the moving window averaging technique is used to determine the occurrence of S1 and S2, which helps in determination of cardiac interval and absolute and relative time duration of individual S1 and S2, as well as absolute and relative duration between them. In the frequency domain, fast Fourier transform (FFT) of the complete PCG record, and short time Fourier transform (STFT) and wavelet transform of individual heart sounds have been carried out. The frequency domain analysis gives an idea about the dominant frequency components in individual records and frequency spectrum of individual heart sounds. A comparative observation on both the analyses gives some correlation between time domain and frequency domain representations of PCG. PMID- 17701777 TI - Time division multiplexing based method for compressing ECG signals: application for normal and abnormal cases. AB - The proposed ECG compression method combines three major approaches based on time division multiplexing (TDM) and multilevel wavelet decomposition followed by parametrical modelling. Before applying these techniques, a pre-processing step is required, which consists of detecting and aligning different beats. Even though this compression method is regarded as a lossy method, we will show how a high compression ratio (CR) can be achieved by preserving the major medical information within the ECG. Several normal and abnormal signals from various databases are used to evaluate the performance of the proposed technique. PMID- 17701778 TI - Automatic seed initialization for the expectation-maximization algorithm and its application in 3D medical imaging. AB - Statistical partitioning of images into meaningful areas is the goal of all region-based segmentation algorithms. The clustering or creation of these meaningful partitions can be achieved in number of ways but in most cases it is achieved through the minimization or maximization of some function of the image intensity properties. Commonly these optimization schemes are locally convergent, therefore initialization of the parameters of the function plays a very important role in the final solution. In this paper we perform an automatically initialized expectation-maximization algorithm to partition the data in medical MRI images. We present analysis and illustrate results against manual initialization and apply the algorithm to some common medical image processing tasks. PMID- 17701779 TI - Knowledge based system with embedded intelligent heart sound analyser for diagnosing cardiovascular disorders. AB - Cardiovascular disease (CVD) is the leading cause of death worldwide, and due to the lack of early detection techniques, the incidence of CVD is increasing day by day. In order to address this limitation, a knowledge based system with embedded intelligent heart sound analyser (KBHSA) has been developed to diagnose cardiovascular disorders at early stages. The system analyses digitized heart sounds that are recorded from an electronic stethoscope using advanced digital signal processing and artificial intelligence techniques. KBHSA takes into account data including the patient's personal and past medical history, clinical examination, auscultation findings, chest x-ray and echocardiogram, and provides a list of diseases that it has diagnosed. The system can assist the general physician in making more accurate and reliable diagnosis under emergency conditions where expert cardiologists and advanced equipment are not readily available. To test the validity of the system, abnormal heart sound samples and medical data from 40 patients were recorded and analysed. The diagnoses made by the system were counter checked by four senior cardiologists in Malaysia. The results show that the findings of KBHSA coincide with those of cardiologists. PMID- 17701780 TI - Mathematical model of an amperometric biosensor for the design of an appropriate instrumentation system. AB - In this paper, a mathematical model for a membrane based amperometric biosensor is developed. The model is based on a diffusion mechanism related to Michaelis Menten kinetics. The model is developed for an intensive stirred condition, so it has been assumed that the thickness of the diffusion layer is negligible. The model can be used to investigate the regularities and kinetics of the amperometric biosensor, and to develop any simulation methods to study the biosensor. The model shows that current I(t) generated during the specific biosensor enzymatic reaction mainly depends on the number of electrons generated and the area of working electrode. The model also describes the effect of background current in the biosensor. The validity of the developed model has been verified by designing a computer based instrumentation system for the amperometric biosensor. Repeated real time experiments were carried out, and the results obtained are in excellent agreement with the amount determined by high performance liquid chromatographic technique (HPLC), with an accuracy of +/-1.5%. PMID- 17701781 TI - Development of a fibre optic goniometer system to measure lumbar and hip movement to detect activities and their lumbar postures. AB - If sitting postures influence the risk of developing low back pain then it is important that quantification of sedentary work activities and simultaneous measurement of lumbar postural characteristics takes place. The objective of this study was to develop a system for identifying activities and their associated lumbar postures using fibre optic goniometers (FOGs). Five student subjects wore two FOGs attached to the lumbar spine and hip for 8 min while being recorded using a video camera when sitting, standing and walking. Observer Software was used to code the video recording, enabling the sagittal movement characteristics of each FOG to be described for individual activities. Results indicated that each activity produced unique data, and could be independently identified from their motion profiles by three raters (k = 1). The data will be used to develop algorithms to automate the process of activity detection. This system has the potential to measure behaviour in non-clinical settings. PMID- 17701782 TI - A review of high frequency oscillation ventilation in the neonate. AB - In this study the use of high frequency oscillation (HFO) to treat neonates with respiratory failure is analysed. The theories behind gas exchange during HFO are reviewed and its specific application to neonatal care discussed. The mechanical performance of three HFO ventilators currently in use is compared with the views of medical staff operating them on a regular basis. The complex interactions between initial ventilator settings have led to difficulties in accurately comparing performance characteristics and ventilation strategies; each ventilator is seen to have its own strengths and weaknesses that contribute to the ventilator selection made. These interactions together with the specific HFO modes available on each ventilator should be taken into account when using a HFO for the first time or when switching from an alternative ventilation method. Medical staff who care for neonates suggest staff education and training into the variations of HFO will greatly improve its use in neonatal medicine. PMID- 17701783 TI - The false premise in measuring body-support interface pressures for preventing serious pressure ulcers. AB - Presently, commercial cushioning products for pressure ulcer prevention are being evaluated for their protective effect exclusively based on interfacial pressures between the cushion/mattress and the patient. However, interface pressures cannot predict elevated mechanical stresses in deep tissues adjacent to bony prominences. Such deep tissue stress concentrations are associated with local ischaemia and hypoxia, which over time result in deep tissue necrosis, particularly of muscle tissue. In order to demonstrate this phenomenon, a physical phantom of the mechanical interaction between the ischial tuberosities (IT) and gluteus muscles of the buttocks was built, incorporating geometric replica of the human IT and real (bovine) muscle tissue. Internal muscle stresses directly under the IT were five to 11-fold greater than stresses at more distal locations, and a Pearson correlation test showed that they could not have been predicted from the interface pressures in the phantom. Accordingly, though pressure ulcer prevention clinics which utilize routine sitting pressure measurements report effective outcomes, the present results highlight a problem in using body-support pressure measurements to predict the risk for pressure related deep tissue injury. PMID- 17701784 TI - Time-frequency characterization of atrial fibrillation from surface ECG based on Hilbert-Huang transform. AB - In this paper, based on Hilbert-Huang transform (HHT), we develop a new non invasive time-frequency analysis method to characterize the dynamic behaviour of atrial fibrillation (AF) from surface ECG. We first extract f waves from single lead ECG records of AF patients using PCA analysis. To capture the non-stationary behaviours of AF signals at different time scales, we use HHT to find the Hilbert spectrum and instantaneous frequency (IF) distribution of residual signals from principal component analysis. Two important feature variables, namely mean IF (mIF) and index of frequency stability over time (IS), are derived from the IF distribution, and in combination will be able to effectively discriminate two different AF types: self-terminating and non-terminating termination. The proposed AF signal decomposition and analysis method will help us efficiently differentiate individual AF patients, advance our understanding of AF mechanisms, and provide useful guidelines for improving administration of AF patients, especially paroxysmal AF. PMID- 17701788 TI - Hyperprolactinaemia. AB - Hyperprolactinaemia is a common condition with varied aetiology. It is more frequent in women, but also seen in men and even in adolescence and childhood. Prolactin is mainly a lactogenic hormone but has other actions. Most cases present with amenorrhoea and infertility and are managed by gynaecologists. However, multidisciplinary involvement may be required in some cases. Evidence relating to aetiology, clinical features, pathogenesis and management has been discussed. PMID- 17701789 TI - Physical violence during pregnancy. AB - Globally, women suffer due to violence. Violence during pregnancy is being increasingly recognised as a clinical as well as public health problem. The objectives of the present study were: to find out the extent and causes of violence during pregnancy; the relation of violence with, age, education, occupation; and to study the immediate effects of violence during pregnancy. A total of 2,000 pregnant women (health seekers or their friends or relatives) irrespective of age and socioeconomic status, were interviewed using a pre designed, semistructured, pre-tested questionnaire in local language, with some open-ended questions. Out of the 2,000 pregnant women interviewed, 952 (47.6%) had been physically hit or slapped or kicked, at some time during pregnancy, many repeatedly. Though more teenagers (65.63%) and illiterate women (70.32%) were assaulted, those with a postgraduate education (41.08%) had also suffered. A total of 71.7% had been hit by their husbands - 32.4% were hit on the back and 161 (16.9%) on abdomen. Of the women who were assaulted during pregnancy, 30.25% had also suffered violence when non-pregnant. The present study reveals that violence is a common problem during pregnancy. While attempts need to be made to prevent this, it is essential that the healthcare providers who manage these women are aware of the possibility. PMID- 17701790 TI - The impact of a dedicated antenatal clinic on the obstetric and neonatal outcomes in adolescent pregnant women. AB - This retrospective observational study was designed to study the impact of a dedicated antenatal clinic service on obstetric and neonatal outcomes among teenage mothers in the maternity unit of a district general hospital in the UK. Outcomes were measured to investigate improvement in obstetric and neonatal outcomes before, and 12 months after the establishment of dedicated clinic for teenage pregnant women. Significant improvement in the birth weight was observed p = 0.01. A modest decrease in neonatal admission to special care unit by 6% was observed. Rate of spontaneous vaginal deliveries increased p = 0.0009. There was significant uptake of contraception and continuation of breast-feeding in this group of young women (p < 0.0001). PMID- 17701791 TI - Antenatal blood donation for pregnant Nigerian mothers: the husbands' perspective. AB - This cross-sectional study was designed to evaluate the knowledge, attitude and motivation of husbands of pregnant mothers towards antenatal blood donation. A total of 700 husbands of pregnant mothers in Abakaliki, south-east Nigeria were interviewed over a 1-year period using a questionnaire. A total of 640 respondents completed the questionnaires giving a response rate of 91%. They had a mean age of 26.2 +/- 4 years with a range of 21 - 50 years. All the respondents had heard about blood donation but only 39% were well informed about it. One third (33.1%) of respondents were willing to donate blood and the main motivating factor was their wives' previous experience with bleeding during pregnancy/delivery. Other motivating factors to blood donation included previous donation, information on blood donation and husband participation in antenatal programme. Two-thirds of respondents were unwilling to donate because of fear, misconception and availability of paid blood donors. Higher educational status was significantly associated with willingness to donate blood (p < 0.05). The willing blood donors showed a more positive attitude towards blood donation and were of the view that the donated blood if not used for their wives would benefit others. The non-donors on the other hand had a selfish attitude and would prefer to procure blood only when their wives needed blood transfusion. An intensive donor recruitment campaign, including mobilising husbands of pregnant mothers and providing information and education on all aspects of blood donation, will help correct some of the misconceptions about blood donation. This will increase the number of voluntary blood donors and thus increase available banked blood for pregnant women. PMID- 17701792 TI - A 4-year analysis of caesarean delivery in a Nigerian teaching hospital: one quarter of babies born surgically. AB - Between January 2001 and December 2004, a total of 2,922 deliveries were conducted at the University of Nigeria Teaching Hospital , Enugu. Caesarean section accounted for 740 deliveries, an incidence of 25.3%. A total of 62.2% of caesarean sections were done as emergencies, while 37.8% were done as elective procedures and 64.8% were booked patients. Repeat caesarean sections accounted for 59.2% of elective cases and 18.7% of emergency cases. Fetal distress was responsible for 11. 6% of emergency cases, however 35.6% of babies delivered for clinically diagnosed fetal distress had Apgar scores 7 and above. A total of 85.6% of patients were between 25 - 29 years of age; 31% were primigravida, while 54.4% were Gravida 2 - 4. There were seven (0.6%) maternal deaths and 73 (9.2%) stillbirths. It was concluded that reduction of primary caesarean section rate and repeat caesarean rates should be the main target of any strategy to reduce caesarean section rate. Other measures to reduce the caesarean section rate and recommendations are discussed. PMID- 17701793 TI - Trials and tribulations of the current national consent form. AB - The aim of this survey was to evaluate patients' understanding of the current standardised National Health Service consent form. Of the 285 patients, 47% were performed as emergency and 53% as elective procedures. Almost all patients indicated that they understood the consent form. Although the benefits of the procedure were known in 94%, only 69% were aware of the risks associated with the performed operation. Less than 40% claimed to have been informed about the risk of requiring additional surgery. Patients undergoing elective surgery were significantly more likely to be aware of the risks, the likelihood of additional surgery and the fact that the consultant may not be performing the operation. Although the current national consent form introduced by the Department of Health appears to be understood by obstetric and gynaecology patients, there appears to be a need for improved counselling regarding the attendant risks and benefits of surgery, especially for patients undergoing emergency surgery. PMID- 17701794 TI - What did the doctor say? AB - It is well known that 40 - 80% of information provided by clinicians is forgotten immediately by patients. Furthermore, 50% of the information remembered is incorrect. Research has shown that receiving written communication meets with high satisfaction from patients. According to the NHS plan to improve healthcare delivery, it has been recommended that patients should receive copies of letters written by doctors and that the policy would be implemented in full by April 2004. A total of 100 consecutive patients undergoing day-case gynaecological surgery under a single consultant were sent a postal questionnaire. Questions included were whether the letter was helpful, informative, reassuring, confusing or alarming. Patients were further asked whether they would prefer a similar communication in the future. A total of 78 patients replied. Of these, 67 patients found the letter helpful and preferred to have similar communication in future. Only two patients found the letter confusing and one of these was alarmed as well. Overall, 62 patients found the letter reassuring. The majority of the patients found the copy of GP discharge letter helpful, informative, non-alarming and reassuring and wanted a similar communication in the future. The extra workload involved was minimal and the extra expense involved only an extra page, envelope and postage. PMID- 17701795 TI - The combined oral contraceptive pill and the assumed 28-day cycle. AB - Some studies involving women taking the combined oral contraceptive pill (COCP) have on occasion assumed the COCP group to have a rigid 28-day pharmaceutically driven cycle. Anecdotal evidence suggests otherwise, with many women adjusting their COCP usage to alter the time between break-through bleeds for sporting and social reasons. A prospective field study involving 533 scuba diving females allowed all menstrual cycle lengths (COCP and non-COCP) to be observed for up to three consecutive years (St Leger Dowse et al. 2006). A total of 29% of women were COCP users who reported 3,241 cycles. Of these cycles, only 42% had a rigid 28-day cycle, with the remainder varying in length from 21 to 60 days. When performing studies involving the menstrual cycle, it should not be assumed that COCP users have a rigid confirmed 28-day cycle and careful consideration should be given to data collection and analysis. The effects of differing data interpretations are shown. PMID- 17701796 TI - Identification of a vaginal pacemaker: An immunohistochemical and morphometric study. AB - Vaginal electric waves spread caudally in the vagina. We investigated the hypothesis that electric waves originate from a centre of interstitial cells of Cajal (ICCs) in the proximal vagina. Specimens (0.75 x 0.75 cm) were obtained from the vaginal walls of 23 cadavers (age 38.2 +/- 10.2 years). Sections were prepared for immunohistochemical investigations using the specific ICC marker, C kit. Morphometric studies for image analysis using a Leica imaging system were performed. C-kit positive cells were detected in vaginal smooth muscle. Results from image analyser revealed that mean area percent of positive immunoreactivity for C-kit in the upper part of posterior vaginal wall was significantly higher (p < 0.0001) than of areas in other vaginal walls, and also significantly higher (p < 0.05) in circular than in longitudinal muscle layer. Studies have shown that the greatest collection of ICCs occurred in the upper part of the posterior vaginal wall. The vaginal electric waves are suggested to originate from this 'centre' and spread caudally. PMID- 17701797 TI - Uterine innervation in fibroids: a qualitative study. AB - This study describes the innervation of uterine fibroids in a retrospective survey of archived material. A total of 24 uteri containing fibroids were identified; four nulliparous uteri with single large fundal fibroids (200 - 320 g) and 20 multiparous uteri with one, or more, fibroids (80 - 230 g). Tissue blocks from the uterine isthmus and the fibroids, were identified, sectioned and stained for nerves with anti-S100 using a standard immunohistochemical regimen. Normal uterine innervation includes concentrations of nerves in the subserosal layer and at the endometrial-myometrial interface with sparse neurovascular bundles distributed throughout the myometrial stroma. Nulliparous uteri with single large fibroids demonstrated relatively normal patterns of innervation with nerves distributed throughout the stroma of the fibroid. In multiparous uteri with fibroids, there were no nerves detectable in the substance of the fibroids. Increased numbers of nerve fibres were observed in the pseudo-capsule of some fibroids and may reflect compression of normal myometrial tissue and their contained nerves, or, a minor degree of nerve fibre proliferation. This study demonstrates that fibroids in multiparous uteri do not contain nerves. Single, large nulliparous fibroids situated at the uterine fundus appear to contain relatively normal patterns of innervation. PMID- 17701798 TI - Predicting the presence of rectovaginal endometriosis from the clinical history: a retrospective observational study. AB - Rectovaginal endometriosis is a severe variant of endometriosis. Common presenting symptoms for endometriosis include dysmenorrhoea, pelvic pain and dyspareunia. It is now recognised that there are other less traditional symptoms of endometriosis that are also relatively common. The aim of this study is to assess the relative strength of each of the potential symptoms of rectovaginal endometriosis and compare these with the laparoscopic and histological findings. In this retrospective, observational study the overall prevalence of rectovaginal endometriosis in the group was 31.4%. The presence of dyschesia gave a likelihood ratio of 1.27 (95% CI: 0.56 - 2.89) with a predictive prevalence of rectovaginal endometriosis of 37%. Apareunia and nausea or abdominal bloating were particularly strong markers for rectovaginal disease with a predictive prevalence of 87% and 89%, respectively. The classical symptoms often attributed to irritable bowel syndrome are also common in women with rectovaginal disease. PMID- 17701799 TI - Audit of compliance with NICE guidelines on the use of tension-free vaginal tape slings for stress incontinence. AB - The aim of this audit was to assess adherence to the National Institute of Clinical Excellence (NICE) guidelines in inserting tension-free vaginal tape (TVT) slings for urodynamic stress incontinence, in gynaecology and urology settings in a district general hospital. It included 95 patients (79 inserted by gynaecologists and 16 by urologists) who had TVT sling insertion from 2002 until 2005, at the Royal Bournemouth Hospital. Conservative measures were tried by 43 patients (45.3%) and documentation of risk factors varied between 70% for failure and intermittent catheterisation and 1% for laparotomy and dyspareunia. Compliance was significantly better and more consent was obtained by senior medical staff when insertions were carried out by gynaecologists than when they were carried out by urologists. All insertions were carried out by consultants or under their direct supervision. The audit highlighted the need to ensure that conservative measures are tried before resorting to this minimally invasive technique and that proper patient counselling is documented on the consent form. Development of patient information leaflets and specific consent forms as well as better cooperation between gynaecologists and urologists is likely to improve compliance with the guideline. PMID- 17701800 TI - Short-term complications of the trans-obturator foramen procedure for urinary stress incontinence. AB - This paper reports the efficacy and complications of the trans-obturator foramen procedure (TOT). The effect of TOT on co-existing urgency and urge incontinence and voiding difficulty were also noted. It reports on patients (31) undergoing TOT (Obtape) from April 2005 to April 2006, who were sent a questionnaire. The mean age was 53 years, mean parity 2.3, mean duration of incontinence 6.2 years and the mean duration of follow-up was 9 months. All patients had significant stress incontinence. Co-existing urge incontinence was present in 70%; no intraoperative complications. One patient had a urinary tract infection (UTI) and one, catheterisation for 5 days. A total of 16.6% of patients developed sling erosion. There was a 93% response rate to the postal survey, indicating a 31% complete cure of urinary incontinence; 65% a significant improvement and 3.5% failure. Urge incontinence disappeared in 66%, no de-novo urgency and 8% reported slower voiding. Satisfaction was 8.9 on a 1 - 10 Scale. The success rate of the TOT procedure was high, helping both stress and concomitant urge incontinence, but due to an unacceptably high erosion rate, Obtape was discontinued. PMID- 17701801 TI - Can thyroid dysfunction explicate severe menopausal symptoms? AB - Many of the menopausal manifestations look like those accredited to thyroid hyperfunction or hypofunction. Can thyroid dysfunction explicate severe menopausal symptoms? The study comprised 350 women with different menopausal symptoms. All women had serum TSH, T3 and free T4 estimated. Women with thyroid dysfunction were appropriately treated and other women were treated with ERT. The study showed that 21 women (6%) had hypothyroidism and 18 (5.1%) had hyperthyroidism. Marked improvement in the menopausal-like symptoms occurred after treatment of the thyroid dysfunction. Elderly women with severe or resistant menopausal symptoms can be offered TSH, T3 and T4 assays to rule out the thyroid disturbances before attempting hormone replacement therapy. PMID- 17701802 TI - Collaboration with the voluntary sector in setting up an early medical abortion service in the PCT. AB - The 1967 Abortion Act and the 1990 Human Fertilisation and Embryology Act amendment allow abortions in acute hospitals or licensed premises only. Provision of abortions in community unlicensed premises is unlicensed and not legal. At abortion assessment, counselling, chlamydia testing and/or treatment/partner notification and a contraceptive package is included. This works towards the overall aim of reducing unwanted pregnancies and reducing the burden of sexually transmitted infections in the community, thus removing the silo approach to abortion. A 92% completed abortion outcome was achieved. Route of administration of misoprostol will be reconsidered. Efficacy could be improved by vaginal administration. The findings support the introduction of an early medical abortion service in collaboration with a partner organisation. Our experience provides useful preliminary data for others contemplating a similar service, with room for improvement. PMID- 17701803 TI - Efficacy of a single misoprostol regimen in the first and second trimester termination of pregnancy. AB - A total of 273 women underwent termination of pregnancy (TOP) with a single regimen of misoprostol (400 microg orally and 800 microg vaginally), without mifepristone. A total of 98 (35.9%) were first trimester and 175 (64.1%) second trimester gestations. Of these women, 189 (69.2%) responded to a single administration of misoprostol and 84 (30.8%) required between two and six administrations of misoprostol. The medical TOP was complete in 90.8% of all cases. A surgical intervention was needed in 23 (27.4%) of those requiring repeated administrations of misoprostol vs only two (1.1%) of those responding to a single administration. Age, parity and gestational age did not affect the response rate to the misoprostol regimen. The need for a D&C was related to the response to misoprostol: most D&Cs were needed in cases of repeat administrations of misoprostol. This study shows the feasibility of medical TOP in the developing world. It has the great advantage of significantly reducing the need for surgical termination where the required skills are scarce. PMID- 17701804 TI - The impact of health education on reproductive health knowledge among adolescents in a rural Nigerian community. AB - This intervention study was to evaluate the impact of reproductive health education on the knowledge and attitude of adolescents in a rural Nigerian community to reproductive health issues. It compared adolescents in a secondary school (study group), which received health education on reproductive health with another secondary school (control group), which did not receive any. The impact of the programme was evaluated with a pre-test baseline knowledge and post-test gain in the knowledge 6 weeks later, using the same questionnaire. A total of 180 students selected by systematic sampling from each of the two randomly selected schools in Item, a rural community in south-east Nigeria participated in the programme. While all the respondents have heard of reproductive health and could identify at least one of its components, their knowledge of it prior to the health education were defective and were obtained mainly from peers and the mass media. Such information was incomplete and often coloured with cultural and religious bias. However, there was a significant (p < 0.05) gain in correct knowledge following the health education. The students in the study group showed a positive and permissive attitude towards reproductive health education and there was a drop in risky sexual behaviour following the intervention. Pre marital sex (94.3%), pregnancy prevention and abortion (88.5%) and sexually transmitted infections (82.8%) were common reproductive health problems raised by the students. Reproductive health education as part of the school curriculum will provide an effective means of improving knowledge and reducing reproductive health problems among adolescents in developing countries. PMID- 17701805 TI - A retroperitoneal pregnancy of an anencephalic fetus. PMID- 17701806 TI - Adnexal torsion in the 10th week of a twin gestation. PMID- 17701807 TI - Acute myocardial infarction in pregnancy recurring in the puerperium. PMID- 17701808 TI - Leucopenia and atrial fibrillation: rare presentations of thyrotoxicosis in the first trimester. PMID- 17701809 TI - Septic shock post tooth extraction in pregnancy. PMID- 17701810 TI - Fire smoke inhalation in pregnancy. PMID- 17701811 TI - Pelvic radiotherapy damage to the endometrium causing morbid adherence of placenta. A new risk factor? PMID- 17701812 TI - Gonadotrophin releasing hormone analogues for the management of placenta accreta: A novel concept. PMID- 17701813 TI - A case of bilateral inferior rectal nerve damage in normal labour and delivery followed by spontaneous recovery. PMID- 17701814 TI - Ectopic breast tissue of the vulva. PMID- 17701815 TI - A rare case of multiple accessory breast tissue in the axillae, lower abdomen and vulval areas. PMID- 17701817 TI - Bladder stone: An unusual cause of chronic dyspareunia. PMID- 17701816 TI - Lightning does strike twice: recurrent ipsilateral tubal pregnancy following partial salpingectomy for ectopic pregnancy. PMID- 17701819 TI - Carcinosarcoma of the uterine cervix initially interpreted as myoma nascens. PMID- 17701818 TI - A benign Mullerian cyst of the uterus. PMID- 17701820 TI - Endometrioid adenocarcinoma of the ovary arising from endometriosis and presenting as an acute abdomen. PMID- 17701821 TI - Unknown primary site of serous papillary adenocarcinoma involving inguinal, iliac and obturator lymph nodes co-existing with endometrial adenocarcinoma. PMID- 17701823 TI - WAERS: an application for Web-assisted estimation of relative survival. AB - Net cancer survival estimation is usually performed by computing relative survival (RS), which is defined as the ratio between observed and expected survival rates. The mortality of a reference population is required in order to compute the expected survival rate, which can be performed using a variety of statistical packages. A new Web interface to compute RS, called WAERS, has been developed by the Catalan Institute of Oncology. The reference population is first selected, and then the RS of a cohort is computed. A remote server is used for this purpose. A mock example serves to illustrate the use of the tool with a hypothetical cohort, for which RS is estimated based on three different reference populations (a province of Spain, an autonomous community (Region), and the entire Spanish population). At present, only mortality tables for different areas of Spain are available. Future improvements of this application will include mortality tables of Latin American and European Union countries, and stratified (control variable) analysis. This application can be also useful for cohort mortality studies and for registries of several diseases. PMID- 17701824 TI - Performance evaluation of wavelet-based ECG compression algorithms for telecardiology application over CDMA network. AB - The use of wireless networks bears great practical importance in instantaneous transmission of ECG signals during movement. In this paper, three typical wavelet based ECG compression algorithms, Rajoub (RA), Embedded Zerotree Wavelet (EZ), and Wavelet Transform Higher-Order Statistics Coding (WH), were evaluated to find an appropriate ECG compression algorithm for scalable and reliable wireless tele cardiology applications, particularly over a CDMA network. The short-term and long-term performance characteristics of the three algorithms were analyzed using normal, abnormal, and measurement noise-contaminated ECG signals from the MIT-BIH database. In addition to the processing delay measurement, compression efficiency and reconstruction sensitivity to error were also evaluated via simulation models including the noise-free channel model, random noise channel model, and CDMA channel model, as well as over an actual CDMA network currently operating in Korea. This study found that the EZ algorithm achieves the best compression efficiency within a low-noise environment, and that the WH algorithm is competitive for use in high-error environments with degraded short-term performance with abnormal or contaminated ECG signals. PMID- 17701825 TI - Virtual palpation of skeletal landmarks with multimodal display interfaces. AB - The 3D location of skeletal landmarks on CT datasets is an important procedure, used in many research and clinical contexts. The standard procedure involves the segmentation of the CT images, the creation of a 3D surface bone model, and the location of the landmarks on this surface. However, the segmentation is time consuming and requires skilled operators and sophisticated software. The aim of the present study is to evaluate the efficacy of a multimodal display interface to direct volumetric interactive visualization in performing a virtual palpation task. An expert operator used the CT dataset of a patient's thigh region to locate 14 femoral skeletal landmarks. This operation was repeatedly performed using different CT data representation; the accuracy and repeatability were compared to those achievable with the conventional procedure based on the segmented 3D surface. When a multimodal display interface (formed by an orthogonal slice, RXCT and interactive isosurface views) was used to perform the virtual palpation directly on the CT data, the average coordinates of the landmarks did not differ significantly from those located on the 3D surface, and the measurement repeatability was actually better with the multimodal display of the volumetric data than with the 3D surface. Thus, we can conclude that skeletal virtual palpation can be performed directly on the CT dataset, as far as the virtual palpation is performed with a multimodal display interface. PMID- 17701826 TI - Knowledge-based generation of diagnostic hypotheses and therapy recommendations for toxoplasma infections in pregnancy. AB - Primary infection of pregnant women with the parasite Toxoplasma gondii results in infections of the unborn by transplacental transmission in about 50% of the cases. The degree of possible damage depends on the duration of parasitical impact on fetal tissues. The web-based software system ToxoNet processes the results of serological antibody tests performed during pregnancy by means of a knowledge base containing medical knowledge on the interpretation of toxoplasmosis serology findings. For this purpose, it matches the results of all serological investigations of maternal blood with the content of the knowledge base and generates interpretive reports consisting of a diagnostic hypothesis, recommendations for therapy, and proposals for further investigations. Fuzzy sets are used to formalize certain intervals between subsequent investigations to take the varying immune responses of individual patients into account. In a retrospective study, ToxoNet classified 100% of the trivial serological cases and about 87.8% of the more complex cases correctly. ToxoNet comprises a knowledge base, a system for interpretation, and a knowledge acquisition and modification program. It is available on the WWW by accessing a medical knowledge-base server via standard browsers. PMID- 17701827 TI - Entry requirements and membership homogeneity in online patient groups. AB - The objective was to explore a relationship between the economics of religion and the attributes of online patient groups by testing the hypotheses that (1) the harsher the entry requirements to an online patient group, the more active its members are; and (2) membership homogeneity in a given group is reflected in the educational level of group members. Online groups were randomly chosen from the 'Yahoo groups' category of 'Illnesses'. The hypothesis about entry requirements was narrowed by defining those requirements as either 'Open', 'Register', or 'Closed'. The number of messages over a 4-month period in each of 162 different groups was tallied. The hypothesis about membership homogeneity was refined by counting the citations in messages and by predicting the educational level of members (as reflected in the average word length of messages) based on these citation counts. Across 162 groups, the number of messages was significantly less in Open groups than in Register groups and less in Register groups than in Closed groups. Across 14 groups, the average word length of messages in a group positively correlated with the number of citations in that group. The hypothesis is supported that increased group entry barriers correspond to increased group message activity and members tend to be similar within a group. These attributes could be used to help design effective groups. PMID- 17701828 TI - Are we measuring the right end-points? Variables that affect the impact of computerised decision support on patient outcomes: a systematic review. AB - Previous reviews of electronic decision-support systems (EDSS) have often treated them as a single category, and factors that may modify their effectiveness of EDSS have not been examined. The objective was to summarise the evidence associating the use of computerised decision support and improved patient outcomes. PubMed/Medline and the Database of Abstracts were searched for randomised controlled trials (RCT) of EDSS from 1 January 1994 to 31 January 2006. Twenty-four RCT studies from 97 reviewed were selected, eight of them examined systems supporting decisions for patients who presented with an acute illness, and 16 studies enrolled patients with chronic conditions. Overall, 13 (54%) of the studies showed a positive result, and 11 (46%) were with no impact. Critiquing and consultative systems showed the impact in 71% and 47% of studies, respectively. All systems targeting decisions related to acute disease improved patient outcomes compared with 38% of systems focused on the management of chronic conditions (P = 0.005). Provision of EDSS improves prescribing practices and treatment outcomes of patients with acute illnesses; however, EDSS were less effective in primary care. Complex interventions as clinical EDSS may require new metrics of assessment to describe the impact on patient outcomes. PMID- 17701829 TI - Obtrusiveness of information-based assistive technologies as perceived by older adults in residential care facilities: a secondary analysis. AB - With the anticipated growth in the older adult population in the next few years, information designers are examining new ways for assistive technologies to support independent living and quality of life for adults as they age. Central to the role of assistive technology to support and enhance quality of life is the development of non-obtrusive technologies. Despite the importance of non obtrusiveness to the design of assistive technologies, there remains no standard definition of obtrusiveness or measurement instrument. A conceptual framework for obtrusiveness in home telehealth technologies has recently been proposed but has not yet been tested empirically. This project performed a secondary analysis of focus group and interview data to explore the presence of the dimensions of the obtrusiveness framework in older adults' responses to information-based assistive technologies in residential care facilities. We found the existing data contained examples of each dimension (physical, usability, privacy, function, human interaction, self-concept, routine, and sustainability) and 16 of the 22 subcategories proposed by the obtrusiveness framework. These results provide general support for the framework, although further prospective validation research is needed. Potential enhancements to the framework are proposed. PMID- 17701830 TI - In vitro metabolism of eupatilin by multiple cytochrome P450 and UDP glucuronosyltransferase enzymes. AB - Eupatilin, a pharmacologically active flavone derived from Artemisia plants, is extensively metabolized to eupatilin glucuronide, 4-O-desmethyleupatilin and 4-O desmethyleupatilin glucuronide in human liver microsomes. This study characterized the human liver cytochrome P450 (CYP) and UDP glucuronosyltransferase (UGT) enzymes responsible for the metabolism of eupatilin. The specific CYPs responsible for O-demethylation of eupatilin to the major metabolite, 4-O-desmethyleupatilin were identified using a combination of correlation analysis, immuno-inhibition, chemical inhibition in human liver microsomes and metabolism by human cDNA-expressed CYP enzymes. UGT enzymes involved in the eupatilin glucuronidation were identified using pooled human liver microsomes and human cDNA-expressed UGT enzymes. Eupatilin was predominantly metabolized by CYP1A2 and, to a lesser extent, CYP2C8 mediated O demethylation of eupatilin to 4-O-desmethyleupatilin. Eupatilin glucuronidation was catalysed by UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, and UGT1A10. PMID- 17701831 TI - Functional involvement of organic cation transporter1 (OCT1/Oct1) in the hepatic uptake of organic cations in humans and rats. AB - The contribution of organic cation transporters to the saturable component in the hepatic uptake of 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), cimetidine, and metformin was examined by the use of human/rat organic cation transporter (hOCT1/rOct1)-expressing cells and human/rat hepatocytes. Transfection of rOct1 resulted in a considerable increase in the uptake of metformin, whereas that of hOCT1 resulted in only a slight increase. All test compounds (MPP, TEA, cimetidine, and metformin) accumulated in human and rat hepatocytes in a carrier-mediated manner. The Km values for the uptake of MPP, TEA, cimetidine, and metformin into human and rat hepatocytes were comparable with those into hOCT1 and rOct1-expressing cells, respectively. In addition, the relative uptake activities, which were obtained by normalizing the intrinsic uptake clearances of TEA, cimetidine, and metformin against those values of MPP in human and rat hepatocytes, were similar with the uptake activities in hOCT1 and rOct1, respectively. These results suggest that the saturable component in the hepatic uptake of these cationic compounds may be mediated mainly by hOCT1/rOct1; therefore, it is meaningful to evaluate the saturable uptake profile of cationic compounds by the liver using both hOCT1/rOct1-expressing cells and human/rat hepatocytes. PMID- 17701832 TI - The metabolism of the 5HT3 antagonists ondansetron, alosetron and GR87442 I: a comparison of in vitro and in vivo metabolism and in vitro enzyme kinetics in rat, dog and human hepatocytes, microsomes and recombinant human enzymes. AB - The metabolism of the structurally related 5HT3 antagonists ondansetron, alosetron and GR87442 in the rat, dog and human was determined in hepatocytes, liver microsomes and human recombinant microsomes. The profiles of phase I metabolites were similar in human hepatocytes and microsomes. The metabolites of all three compounds produced in rat, dog and human microsomes and hepatocytes were similar to those seen in vivo, with the major routes of metabolism being N dealkylation and/or hydroxylation. There was more extensive metabolic processing in hepatocytes than in microsomes; however, sequential metabolism was less extensive in vitro compared with in vivo. The pharmacokinetics of the three 5HT3 antagonists investigated were dominated by CYP3A4 (and/or 2C9) compared with CYP1A2 in man, possibly determined by enzyme capacity rather than relative enzyme affinity. These data support the use of rat, dog and human hepatocytes for the prediction of in vivo metabolites of ondansetron, alosetron and GR87442. PMID- 17701833 TI - The metabolism of the 5HT3 antagonists, ondansetron, alosetron and GR87442 II: investigation into the in vitro methods used to predict the in vivo hepatic clearance of ondansetron, alosetron and GR87442 in the rat, dog and human. AB - The in vitro clearances of the 5HT3 antagonists, ondansetron, alosetron and GR87442 were investigated. Intrinsic clearances using either metabolite formation or substrate depletion methods were equivalent (R2 = 0.95). Hepatocytes from preclinical species were superior to microsomes for the prediction of hepatic clearance (CL(H)), whereas the predictions from human microsomes and hepatocytes were similar. Using a non-restrictive model, seven of the nine CL(H) predictions using hepatocytes were within 2-fold of the in vivo CL(H) values. If the unbound fraction was included, the clearance of the compounds was generally under predicted by both in vitro models. However, for the most metabolically stable compound, GR87442, the non-restrictive model over-predicted CLp. This and the possibility of extrahepatic metabolism indicate that the restrictive model is more appropriate for prediction of CL(H). The rank order of metabolic stability correlated with that in vivo. All three compounds were more metabolically stable in human than in the preclinical animal species examined. PMID- 17701834 TI - Use of Freund's Complete Adjuvant (FCA) in inflammatory pain models: consequences on the metabolism and pharmacokinetics of the non-peptidic delta receptor agonist SNC80 in the rat. AB - This study was initiated to characterize the metabolism and pharmacokinetics of SNC80 in rats and to evaluate the impact of Freund's complete adjuvant (FCA) induced inflammation on its body disposition. In vitro, the disappearance and intrinsic clearance (CL(int)) of SNC80 were measured following incubations in recombinant rat CYPs and in phenotyped liver microsomes from naive and 24-h FCA treated rats. The unbound fraction (f(u)) was assessed by ultrafiltration. Based on the Clint values, in vivo blood clearance of 3.35 and 2.48 L/h/kg were predicted in naive and FCA-treated rats. In vivo, SNC80 was administered to naive and 24-h FCA-treated rats at 10 micromol/kg i.v. and 50 micromol/kg p.o. The naive animals showed high plasma clearance (3.1 L/h/kg), low renal clearance (<0.02 L/h/kg) and poor bioavailability (<4%). Following i.v. administration, plasma clearance was lower (22%) in FCA-treated vs. untreated rats. Despite the decreases in f(u) (approximately 30%) and CL(int) (approximately 40%) in vitro, in vivo the apparent bioavailability and oral clearance were not significantly different between FCA-treated and naive rats. Hepatic and possibly intestinal losses contribute to the low bioavailability of SNC80. Non-hepatic mechanisms may compensate for the decrease in plasma clearance found in FCA-treated rats, preventing an increase in the oral bioavailability of SNC80. PMID- 17701835 TI - Disposition and metabolic fate of prasugrel in mice, rats, and dogs. AB - The disposition and metabolism of prasugrel, a thienopyridine prodrug and a potent inhibitor of platelet aggregation in vivo, were investigated in mice, rats, and dogs. Prasugrel was rapidly absorbed and extensively metabolized. In the mouse and dog, maximum plasma concentration of radioactivity was observed in less than 1 h after an oral [14C]prasugrel dose. Most of the administered prasugrel dose was recovered in the faeces of rats and dogs (72% and 52-73%, respectively), and in mice urine (54%). Prasugrel is hydrolysed by esterases to a thiolactone, which is subsequently metabolized to thiol-containing metabolites. The main circulating thiol-containing metabolite in the three animal species is the pharmacologically active metabolite, R-138727. The thiol-containing metabolites are further metabolized by S-methylation and conjugation with cysteine. PMID- 17701836 TI - [The influence of published studies and position papers on the prescription of peri- and post-menopausal hormone therapy]. AB - Until the end of the 1990's it was thought that hormone therapy has a lot of positive health effects and should be prescribed for nearly all women. Recently conducted studies have shown that menopausal hormone therapy has a higher health risk especially for breast cancer and cardiovascular disease. In this study we investigated to what extent hormone therapy changes could be identified during the past years. We therefore analysed data of a German health insurance (Gmunder ErsatzKasse=GEK) from 2001-2005. It was shown, that studies and recommendations, as well as statements of different German institutions, which were published during this period lead to an important decrease in respect of hormone therapy prevalence. It seems that the most important impact of this topic came from the results of the Women's Health Initiative study (WHI) and the followed controversial discussion in Germany. In respect of the individual five years age groups the changes were very different and for the older women especially there were no decreases detectable. It must be expected that frequently the diagnoses of Osteoporosis results in a treatment of hormone therapy over a long period and that the recommendations and statements (as mentioned above) are not implemented sufficiently. Therefore, it is necessary to conduct an evidence based hormone therapy treatment in the practitioners daily work, to keep health risks low. Furthermore, physicians should be more engaged to show their patients alternatives instead of hormone therapy. They should also advise and support their treated patients how to quit hormone therapy. PMID- 17701837 TI - [Prevention of overweight and obesity in the workplace. BASF-health promotion campaign "trim down the pounds--losing weight without losing your mind"]. AB - BACKGROUND: The rise in the prevalence of overweight and obesity and their associated diseases is leading to substantial health and socio-economic problems in industrialized countries. The Commission of the European Community indicates that workplaces are a setting that has a strong potential for health promotion and disease prevention. Against this background the department of occupational medicine and health protection of the BASF Aktiengesellschaft initiated a health promotion campaign "Trim down the pounds--Losing weight without losing your mind" on the prevention of overweight and obesity at the workplace. SUBJECTS AND METHODS: The target group included all overweight and obese employees among the 34,000 employees at the BASF site in Ludwigshafen. Overweight and obese employees should reduce weight (either in lowering their body mass index (BMI) by 2 points or by reducing their BMI to less than 25 kg/m2) over a period of nine months assisted by a health promotion programme and normal-weight colleagues (weight loss helpers). All participants were monitored by occupational physicians, this was also to detect obesity-related diseases. A prize money of euro 10,000 for successful participants and their weight-loss helpers was drawn by lot. RESULTS: A total of 2,062 employees took part in the health promotion campaign (1,313 overweight and obese employees and 749 weight-loss helpers). 708 overweight participants attended the weight-control measurement after nine months, 658 people had succeeded in reducing their body weight, 440 of them had lowered their BMI by more than 2 points. 83% of those attending the weight-control measurement had a weight-loss helper. Medical benefits were shown by improvement of laboratory parameters and detection of obesity-related diseases. CONCLUSION: The health promotion campaign "Trim down the pounds" demonstrated that the workplace is a promising focal point for conducting prevention programmes based on the proximity of occupational medical services to the employee. Prevention of overweight and obesity in the workplace is possible by promoting healthy diets in workplace-canteens and physical activity programs like "walking in the lunch break". These programs are substantially strengthened by occupational medical activities in detecting obesity-related diseases. Health promotion at the workplace can be viewed as a benefit to employee and employer alike with employers benefiting from a reduction of lost productivity costs. PMID- 17701838 TI - [Sedentary lifestyles. Classification of different target groups for the promotion of health-enhancing physical activities]. AB - The article investigates different sub-groups of sedentary adults based on their socio-demographic characteristics and perceived barriers to physical activity. Data stem from the Germans Survey of Sedentary Adults (n=10.000) and the data analysis used logistic regressions and cluster analysis. The results indicate that sedentary adults are a diverse group when socio-demographic characteristics and perceived barriers to physical activity are considered. Barriers such as lack of social contacts or time for physical activity are perceived by specific subgroups of this population. In contrast, only few sedentary adults report multiple barriers to physical activity. The results also provide indications for potentially successful strategies to promote physical activity among sedentary adults. PMID- 17701839 TI - ["Living an active life"--sports, exercise and health in middle-aged and older adults. An empirical database on physical activity, health behavior and lifestyle in the 50- to 70-year-old residential population of Baden-Wuerttemberg]. AB - In a society with an aging population, the preventive healthcare importance of physical activity in middle-aged and older adults is growing. The purpose of the study "Living an active life - age and aging in Baden-Wuerttemberg" is to acquire generalisable data of practical relevance for the 50- to 70-year-old population of Baden-Wuerttemberg. The main themes of this study are sports, exercise, and health-related and lifestyle aspects--from both a current and a biographical perspective. Following conceptualization and a test run, the survey was conducted by means of a computer-assisted telephone interview (CATI) in the period from May to October 2006. 982 men and 1,020 women responded. The percentage of respondents with a high level of education was disproportionately high, as is frequently the case for telephone surveys. Due to the resultant bias, the data was weighted by age, gender and education on the basis of the German Microcensus 2004. In addition to serving as a health report on the middle-aged and older adult population, this basic survey generated representative data on physical/sporting activity among older people in Baden-Wuerttemberg, and can be used as a reliable basis for designing future preventive measures. First analyses show that people with higher educational levels and good health, and non-smokers, people with balanced diet and normal weight are more likely to do sporting activities. PMID- 17701840 TI - [Passive-house schools--a tool for improving indoor air quality in schools?]. AB - In Germany, some schools have already been built according to the passive-house standard as an answer to the discussion of climate change and energy saving. For European passive construction, a prerequisite is an annual heating requirement of less than 15 kWh/(m2a) (4755 Btu/ft2/yr). Efficient heat recovery from exhaust air using an air-to-air heat exchanger reduces energy consumption and is considered to improve indoor air quality as well. However, data on indoor air quality have been lacking up to now. Here, the data on indoor air quality in a passive house school are presented. MATERIAL AND METHODS: In the passive-house school in Frankfurt/M in summer time ventilation is performed by opening the windows. In winter time a mechanical ventilation system provides air at 14-16 m3/person h, with the incoming air being heated by an air-to-air heat exchanger. CO2 levels were obtained during 3 school days in one classroom in summer time, and during 5 days in two classrooms in winter time. In 5-minute intervals a continuous documentation of the number of persons present in the room, their activity and ventilation was done parallel to the measurements. RESULTS: Mean CO2 levels in summer time were 1127 ppm, and 946 ppm in winter time. Regarding only those measurements with people present in the classroom, the air quality standard of 1000 ppm (Pettenkofer's level) was exceeded in two thirds of the measurements in summer and in winter, with 5% (summer) and 10% (winter) of the levels exceeding the guideline value (DIN 1946) of 1500 ppm. Considering the guideline values of the "new" DIN EN 13779, 9-21% of the measurements exceeded 1400 ppm, i.e., "low air quality". DISCUSSION: Mean CO2 levels in the passive-house school were comparable to those in conventionally ventilated schools, i.e., ventilation via opening the windows, whereas maximal levels were lower in the passive-house school than in other schools. The guideline value of 1500 ppm was exceeded on 33% of the measurement days, the level of 1400 ppm was exceeded in 92% of the days. According to these data, indoor air quality should be improved not only in conventionally ventilated schools but also in passive-house schools. In addition to the mechanical ventilation, ventilation by opening the windows during breaks is necessary. Therefore, sufficient capacity for opening the windows should be available. This is mandatory not only for summer time ventilation but also in case of problems with the mechanical ventilation system. As a result air quality should be an important issue in passive houses as well, in addition to the focus on energy saving. PMID- 17701841 TI - [Postgraduate training for general practitioners in the Netherlands--a model for Germany? Description of postgraduate training and critical comparison]. AB - Unlike in other countries, postgraduate training in Germany is not attached to academic centres. Content and duration of postgraduate training are stipulated by the federal medical boards, with the process being unstructured and solely at the responsibility of the trainee. As a model for a structured postgraduate training programme, the Dutch training system for general practitioners is described in detail. The most important difference is the funding of trainees and training facilities within the frame of structured training programmes by the Dutch Ministry of Health. Acquisition of qualifications thus becomes more important than the work performance of the trainee. After reforming graduate medical training, it is now time to rethink postgraduate training in Germany. PMID- 17701844 TI - Halting the natural history of hepatitis B viral infection: a paradigm shift. AB - The 2007 American Association for the Study of Liver Diseases (AASLD) practice guidelines for managing chronic hepatitis B virus (HBV) infection recommend pharmacologic therapy for patients with alanine aminotransferase (ALT) activity higher than 2 times the upper limit of normal and serum HBV DNA concentration higher than 20,000 IU/mL. Findings reported over the past several years, however, indicate that HBV infection associated with ALT activity and serum HBV DNA concentrations below these treatment thresholds can progress to serious liver disease, such as cirrhosis or hepatocellular carcinoma. These findings suggest that these treatment thresholds may be too conservative. Moreover, emerging data suggest that, in some patient populations, the appropriate goal of therapy may be sustained suppression of HBV DNA with maintenance antiviral therapy. A satellite symposium conducted during the 57th Annual Meeting of the AASLD in Boston, Massachusetts, presented new findings relative to the course of HBV infection. PMID- 17701845 TI - Customizing the management of chronic hepatitis B virus infection. AB - As of October 2006, 6 medications are approved in the United States for the management of chronic hepatitis B virus (HBV) infection: 2 formulations of interferon and 4 oral nucleos(t)ide analogues. For the treating practitioner, tailoring the pharmaceutical regimen according to patient features and clinical circumstances can be a challenge. First-line therapeutic regimens for the management of HBV infection include monotherapy with a U.S. Food and Drug Administration-approved agent that has potent on-treatment viral response and low rates of resistance; in the future, these regimens may include a combination of more than one nucleos(t)ide analogue or a combination of a nucleos(t)ide analogue and pegylated interferon. The oral nucleos(t)ide analogues are generally better tolerated than interferon; however, they can be expensive when administered for lengthy periods and can also lead to medication resistance. Lamivudine, the first approved nucleoside analogue for the treatment of HBV infection, has a very high resistance profile; in fact, lamivudine exposure increases viral resistance to other commercially available nucleos(t)ide analogues: entecavir, telbivudine, and adefovir. For these reasons, the 2007 American Association for the Study of Liver Diseases (AASLD) guidelines no longer recommend lamivudine as first-line therapy for the management of HBV infection. A satellite symposium conducted during the 57th Annual Meeting of the AASLD in Boston, Massachusetts, presented approaches to customizing the management of chronic HBV infection. The presentation highlighted recent findings suggesting that early, profound, and sustained viral suppression improves the probability of sustained virologic response and reduces the likelihood of nucleos(t)ide resistance. PMID- 17701846 TI - Treating chronic hepatitis B infection in patients who are pregnant or are undergoing immunosuppressive chemotherapy. AB - As our understanding of the natural history of hepatitis B virus (HBV) infection increases, so do the patient circumstances for which anti-HBV therapy is considered. For example, patients with chronic HBV infection that is negative for hepatitis B surface antigen can experience hepatitis flares during or after cytotoxic chemotherapy and thus are potential candidates for anti-HBV therapy. Also, although passive-active immunoprophylaxis is highly effective in preventing the vertical transmission of HBV, high maternal serum HBV DNA concentrations have been associated with the failure of immunoprophylaxis; for this reason, clinicians may consider administering anti-HBV therapy during pregnancy. However, prophylactic anti-HBV therapy can be both complex and controversial. A satellite symposium conducted during the 57th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, Massachusetts, presented approaches to treating HBV infection in patients who are pregnant and in those who are preparing to receive chemotherapy. PMID- 17701853 TI - Balloon sphincteroplasty for removing difficult bile duct stones. AB - BACKGROUND AND STUDY AIMS: Extraction of common bile duct stones at endoscopic retrograde cholangiopancreatography can be technically challenging when the size of the stone exceeds that of an endoscopic sphincterotomy. The aim of this study was to evaluate the efficacy and safety of papillary balloon dilation after sphincterotomy for extraction of these difficult-to-remove bile duct stones. PATIENTS AND METHODS: This was a prospective study of all patients with large common bile duct stones that could not be extracted using a stone retrieval balloon and basket after endoscopic sphincterotomy. These patients underwent papillary dilation using a radial expansion balloon after maximum sphincterotomy. Biliary ductal clearance was then reattempted using a stone retrieval balloon and/or basket. The success rate and the complication rate for the papillary balloon dilation technique were assessed. RESULTS: A total of 60 patients (16 men, 44 women; mean age 58, range 28 - 73) were enrolled in this study. The mean stone size was 16 mm (range 12 - 20 mm). After maximum sphincterotomy and papillary balloon dilation, ductal clearance was achieved in 57/60 patients (95 %); three patients required adjunctive mechanical lithotripsy for stone extraction. Bleeding occurred in five patients (8.3 %) and was managed conservatively in all cases. CONCLUSIONS: Papillary balloon dilation after endoscopic sphincterotomy is an effective and safe technique for retrieval of difficult common bile duct stones. The procedure is technically safe and obviates the need for mechanical lithotripsy in a majority of patients. PMID- 17701854 TI - Long-term follow-up of complete Barrett's eradication endoscopic mucosal resection (CBE-EMR) for the treatment of high grade dysplasia and intramucosal carcinoma. AB - BACKGROUND AND STUDY AIMS: In patients with Barrett's esophagus (BE), targeted endoscopic mucosal resection (EMR) of visible lesions of high grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) is effective, but carries the risk of leaving in place synchronous lesions and Barrett's epithelium with the potential for recurrent disease. We evaluated the safety and long-term efficacy of complete Barrett's eradication EMR (CBE-EMR) for the treatment of patients with HGD or IMC, independently of the presence of macroscopically visible lesions or surgical risk. PATIENTS AND METHODS: 26 consecutive patients with BE and HGD or IMC underwent CBE-EMRs, which were performed with the endoscopic cap suction method and/or a 2.3-mm monofilament mucosectomy snare. Endoscopic follow up after completion of resection was carried out to assess the rate of residual or recurrent BE with or without HGD or IMC. RESULTS: 24 patients completed the study. They underwent a total of 44 EMR sessions with a median of 3 pieces (range 1-8) removed per session. Two patients with immediate bleeding were successfully managed endoscopically. Three patients developed an early esophageal stricture that was completely resolved with a single endoscopic dilation. After a median follow-up of 28 months (range 15-51 months), persistent endoscopic and histologic eradication of BE was demonstrated in 21 patients (87.5 %). In two patients, Barrett's epithelium was detected beneath the neosquamous epithelium 3 months after completion of the resection. In the remaining patient, IMC was found in a nodule seen and removed by EMR at 12-month surveillance endoscopy. CONCLUSIONS: CBE-EMR is a safe and highly effective long-term treatment that should be offered to all patients with Barrett's esophagus with HGD and IMC. PMID- 17701855 TI - Endoscopic band ligation for the treatment of rectal Dieulafoy lesions: risks and disadvantages. PMID- 17701857 TI - [Sonographic course of alcoholic fatty liver by interobserver and digital evaluation of liver echogenicity]. AB - BACKGROUND: The reversibility of alcoholic fatty liver is well-known. The present study aims to investigate whether sonographic controls can document this reversibility under abstinence therapy with respect to inter-observer variability. METHODS: 59 male patients with alcohol dependency were examined by ultrasound at the beginning and the end of a long-term in-patient withdrawal therapy. Fatty liver was graded qualitatively (no, slight, moderate and severe fatty liver). The sonographic liver sections were registered digitally per examination and were subsequently evaluated by means of the PC by two independent experts. Additionally, a digital texture analysis of representative hepatic and renal regions was performed. The pixel intensity ratio of liver and kidney was used as a measure of liver echogenicity. RESULTS: In the ultrasound examination, the 59 patients had the following severity grade of fatty liver initially: 18 (31 %) severe, 19 (32 %) moderate, 22 (37 %) slight. 37 patients (63 %) showed sonographically an improvement of the initial severity grade within 79 +/- 26 days (p < 0.0001, 95 % confidence interval: 50 - 74 %). The evaluation by the independent experts revealed 47 and 54 % improvement, respectively. The overall degree of agreement between the 3 ratings concerning grading and course was high (intraclass coefficient = 0.896). However, there was a marked deviation between the several grading levels (agreement 15 - 86 %). The categorical differentiation between no/slight versus moderate/severe fatty liver revealed an agreement of between 81 and 91 %. The mean pixel intensity ratio showed an improvement of 17 % (p < 0.0001). CONCLUSIONS: After 3 months abstinence an improvement of alcoholic fatty liver can be consistently documented in about 50 % of the cases by sonography. The interobserver variability on differentiating no/slight versus moderate/severe fatty liver was low. The digital texture analysis confirmed the range of reversibility and could play a role in quantifying the sonographic degree of fatty infiltration. PMID- 17701858 TI - Propofol sedation in outpatient colonoscopy by trained practice nurses supervised by the gastroenterologist: a prospective evaluation of over 3000 cases. AB - BACKGROUND AND STUDY AIMS: Propofol has several advantages for sedation in endoscopic procedures. Sedation administered by anaesthesiologists is associated with high costs. In this study the safety of propofol sedation administered by trained practice nurses under the supervision of the gastroenterologist in a cohort of outpatients of an ambulatory practice for gastroenterology in Germany is evaluated. METHODS: During a period of 21 months all patients referred to colonoscopy were eligible for this prospective observational study. The familiar CRC risk of the individuals, indication, completeness and results of the colonoscopy were registered together with the dose of propofol used. Propofol was administered by intermittent intravenous bolus titration by trained practice nurses under supervision of the gastroenterologist. Oxygen saturation, heart rate and blood pressure were recorded constantly during the procedure and adverse cardiopulmonary events were monitored by the endoscopy team. A respiratory event was defined as an episode of apnoea or laryngospasm requiring assisted ventilation. 23 % of the patients received supplemental oxygen. RESULTS: A total of 3641 colonoscopies were recorded. 33 individuals were sedated with midazolam and were excluded from the evaluation. 3610 individuals were sedated with propofol (119 +/- 39 mg, mean dose +/- S. D.). 40 % of the procedures were performed as combined gastroscopy and colonoscopy. The cecum was reached in 99 % of the colonoscopies. Respiratory events occurred in five patients (0.14 %). Assisted ventilation in all cases was performed by mask ventilation. Bradycardia (HF < 60/min) and arterial hypotension (RR < 90 mmHg) occurred in 0.5 and 0.3 % of the colonoscopies, respectively, but medical intervention was necessary only in 0.2 % for both types of event. Minor events of hypoxaemia were observed in 51 patients (1.4 %), but only 1/3 of these events occurred in patients supplemented with oxygen. CONCLUSIONS: Propofol can be administered safely for ambulatory colonoscopy by trained practice nurses, with careful monitoring under supervision of the gastroenterologist. PMID- 17701859 TI - [Accidental cannulation of the hepatic artery following needle-knife sphincterotomy]. AB - The use of needle-knife sphincterotomy has become an established technique for precut sphincterotomy to achieve am otherwise inaccessible bile duct. The present case report describes an accidental cannulation of the proper hepatic artery following needle-knife sphincterotomy. The endoscopic retrograde cholangiopancreaticography (ERCP) was performed for diagnosis and treatment of a pancreatitis presumably caused by cholelithiasis. After guide-wire placement and angiography of the artery through the papilla, there were no further complications. The distance between the catheter and the hepatic hilus was seen under X-ray control. PMID- 17701860 TI - Severe gastrointestinal disease due to HIV-1-seronegative AIDS. AB - An HIV-1 seronegative man presented with odynophagia, dysphagia, diarrhea, tenesmus and a 50-lb weight loss. A large esophageal ulcer and a rectal fissure were identified endoscopically. Stool samples and biopsy specimens from the esophageal ulcer, duodenum, colon and rectum were negative for pathogens. Seronegative AIDS was suspected, and high levels of HIV-1 mRNA (> 242,000 copies/mL) were detected. The esophageal ulcer responded to oral steroids and the HIV-1 infection to highly active anti-retroviral therapy (HAART). The virus isolated from the patient and an HIV-1 seropositive, asymptomatic, female sex worker with whom he had recently terminated a one-year heterosexual relationship showed sequence homology, indicating her as the source of his virus. The unusual presentation of severe gastrointestinal disease in an HIV-1 seronegative man with HIV-1 viremia underscores the importance of including AIDS in the differential diagnosis of wasting syndrome (i. e., B-type symptoms such as fever, night sweats, weight loss) in patients who are HIV-1 seronegative but at risk for AIDS. PMID- 17701861 TI - [Coincidental squamous cell cancers of the esophagus and head and neck: risk and surveillance]. AB - Patients suffering from head and neck cancer (HNC) have or will develop a second esophageal squamous cell cancer (ESCC) in 5 - 14 %. When a second esophageal neoplasm occurs in a HNC patient, the prognosis is generally determined by the ESCC, and unfortunately it is poor. Prospective clinical studies in Japan, Brazil, Taiwan, France and Germany have shown that screening or surveillance using Lugol chromoesophagoscopy enables early detection of second esophageal neoplasias. Such a surveillance results in a survival benefit for HNC patients. Vice versa, ESCC patients also have a risk of 9.3 - 11.4 % for a head and neck cancer. Periodic otolaryngeal examination and pharyngoscopy is recommended for curatively treated ESCC patients. Patients with a so-called field cancerisation of the airways and upper digestive tract thus require an interdisciplinary management and monitoring. PMID- 17701862 TI - [News from the Cochrane Library: probiotics for the prevention of paediatric antibiotic-associated diarrhoea]. AB - Based on a meta-analysis published in 2006 on the prevention of paediatric antibiotic-associated diarrhoea with probiotics a Cochrane review by the same authors has been released within the current edition of the Cochrane Library (Issue 2, 2007). The per protocol analysis showed a relative risk for the incidence of AAD of 0.49 (0.32; 0.74). These findings could not be confirmed by the intention to treat analysis. These data are promising, but future studies will be necessary to clarify the role of probiotics for the prevention of AAD. PMID- 17701863 TI - [Endoscopic highlights 2006--most important papers from DDW, DGVS and UEGW]. PMID- 17701864 TI - [Use of infliximab in ulcerative colitis]. AB - Infliximab, a chimeric monoclonal anti-tumour necrosis factor alpha (TNF) antibody has dramatically changed the management of various chronic inflammatory disorders such as Crohn's disease (CD), rheumatoid arthritis, ankylosing spondylitis or psoriasis. This drug is well established for the treatment of CD in case of steroid-refractoriness, failure to respond to an immunosuppressant agent or fistulizing disease. The immunological concept that ulcerative colitis (UC) reflects primarily a T-helper cell type-2 mediated disease prevented the earlier use of anti-TNF agents in this disease. Promising initial pilot studies in steroid-refractory UC patients led to two large placebo-controlled trials in patients with moderate to severe UC. These studies clearly showed a benefit for infliximab treatment in UC with mucosal healing and improved life quality. Infliximab therefore can be used in patients not responding adequately to steroids and/or immunosuppressants. Furthermore, one study showed evidence that infliximab might also be effective in severe, intravenous steroid-refractory UC. Therefore, infliximab might be used alternatively to cyclosporine A or tacrolimus in this patient group. Infliximab has now been established as an additional treatment option in patients with chronic-active UC not responding to an immunosuppressive agent and/or in case of severe acute UC. Experienced gastroenterologists should be involved in the decision making for such a therapy to balance thoroughly the benefit/risk ratio for our patients. PMID- 17701867 TI - The MERITs of evidence-based clinical practice in neurology. AB - We examine the relevance of evidence-based clinical practice (EBCP) in the field of clinical neurosciences, emphasize feasible methods for neurologists to incorporate EBCP into their practice, draw attention to available EBCP resources for the neurosciences, highlight how EBCP has been incorporated into clinical neuroscience training programs, present other EBCP initiatives in neurology, and describe the Mayo Clinic Evidence-Based Clinical Practice, Research, Informatics, and Training (MERIT) Center EBCP programs. PMID- 17701868 TI - Brain tumors: current issues in diagnosis and management. AB - There has been significant progress made in the diagnosis and treatment of brain tumors over the past 15 years. This has largely been due to significant advances in radiographic imaging capabilities that have allowed for much earlier detection of disease, both new and recurrent. Advances in surgical and radiotherapy techniques and technology have also affected the care of these patients. More recent advances in chemotherapy options and double and triple crossover clinical trials are beginning to have an impact in the treatment of malignant brain tumors. This article will address the 4 most common brain tumors practicing physicians see and will review the current concepts in treating these tumors. PMID- 17701869 TI - Alternative therapies for seizures: promises and dangers. AB - Complementary and alternative medicine (CAM) is increasingly being used for a multitude of medical problems, one of them being seizures. This article discusses the prevalence of CAM use for seizures and epilepsy. Evidence-based data regarding CAM for epilepsy are presented as well as potential safety concerns regarding ephedra and cannabis use. PMID- 17701870 TI - Gender-specific challenges in the management of epilepsy in women. AB - The management of epilepsy in women encompasses a complex interplay between seizures, sex steroid hormones, and antiepileptic drugs (AEDs). These interactions impact every aspect of the sexual and reproductive health of women with epilepsy throughout their lifetimes. Neurologists comfortable treating seizures may feel unprepared to handle questions related to reproductive health. Several cases are provided to illustrate commonly encountered queries from women with epilepsy about catamenial epilepsy, pregnancy, breast-feeding, contraception, menopause, and bone health. Available evidence is reviewed, and guidelines for management are provided. PMID- 17701871 TI - Intravenous immunoglobulin therapy for neuromuscular disorders. AB - Treatment of specific immune-mediated neuromuscular disorders involves consideration of many factors including severity of illness, concurrent medical problems, supportive therapies, and immune-modulating therapies. Many immune modulating therapies are available, including steroids, an increasing number of immunosuppressive drugs, plasmapheresis, and intravenous immunoglobulin (IVIG). Deciding on which immune-modulating therapy involves selecting from those with proven efficacy for a specific disorder and global considerations of which therapies are most appropriate for an individual patient's circumstances. IVIG has become a commonly used therapy as it is well tolerated, easily administered, and is often efficacious with a relatively rapid action. IVIG has become a first line therapy for several immune-mediated demyelinating polyneuropathies and may play a role in treating exacerbations of myasthenia gravis and selected chronic treatment-refractory cases of Lambert-Eaton myasthenic syndrome, dermatomyositis, and polymyositis. PMID- 17701872 TI - Approach to the evaluation of small fiber peripheral neuropathy and disorders of orthostatic intolerance. AB - Small fiber peripheral neuropathy is a frequently encountered neurological disorder, which can be difficult to diagnose. In this article, the differential diagnosis of small fiber neuropathy is discussed, along with role of autonomic testing, skin biopsy, and quantitative sensory testing, in establishing a definitive diagnosis of small fiber peripheral neuropathy. Disorders of orthostatic intolerance, including postural orthostatic tachycardia syndrome (POTS), are also discussed, emphasizing diagnostic evaluation and a treatment approach to these disorders. PMID- 17701873 TI - Differentiating Parkinson's disease from other parkinsonian disorders. AB - In 1817, James Parkinson formally described the shaking palsy that is now known as idiopathic Parkinson's disease (PD). Symptoms of PD, however, existed for thousands of years before that time. Descriptions evolved significantly until the term PARKINSONISM was eventually coined to describe neurologic disorders characterized by the presence of tremor, rigidity, and bradykinesia in addition to loss of postural reflexes and freezing. In this article, we present some useful clinical pearls in distinguishing idiopathic PD from atypical parkinsonism or drug-induced parkinsonism. PMID- 17701874 TI - Evaluation of rapidly progressive dementia. AB - The evaluation of patients with rapidly progressive dementia can be challenging, largely due to the rarity of the conditions responsible for such fulminant presentations of dementia. This article presents a framework for categorizing such disorders based on the underlying pathophysiology, including degenerative, inflammatory, vascular, toxic, metabolic, neoplastic, and infectious causes of rapidly progressive dementia. Diagnostic approaches, representative imaging abnormalities, and treatment options for these uncommon conditions are also presented. PMID- 17701875 TI - Intracerebral hemorrhage. AB - Intracerebral hemorrhage has recently transitioned from being a neurosurgical entity into a condition where nonsurgeons have more participation in the medical decision making. Despite recent advances in the management of intracerebral hemorrhage (i.e., STICH trial and recombinant factor VII trial), guidelines published in 1999 remain the only available therapeutic consensus. The goal of this review is to address frequently encountered case scenarios when managing patients with spontaneous or nontraumatic intracerebral hemorrhage, both acutely and long-term. PMID- 17701876 TI - Current issues in endovascular surgical neuroradiology. AB - Endovascular surgical neuroradiology is a newly recognized specialty within the American Medical Association. Remarkable advances in the specialty with regard to stroke prevention and therapy as well as the treatment of ruptured and unruptured cerebral aneurysms have provided patients and their treating physicians with novel treatment options that complement existing therapy. The issues surrounding the efficacy of endovascular treatment of intracranial atherosclerosis and cerebral aneurysms will be reviewed using a case-based learning format. PMID- 17701877 TI - Determining brain death: back to the basics. AB - The subject of brain death usually becomes clinically relevant during a tremendously stressful time. For most practitioners, the need to make a diagnosis of brain death occurs infrequently. Since the introduction of the concept of brain death, the criteria have been refined to their current state. The historical background and the current standards and guidelines used to diagnose brain death will be reviewed. Potential future changes in brain death criteria when contemplating organ donation in the critically ill patient will be discussed. PMID- 17701878 TI - Comparison of insulin glargine versus NPH insulin in people with Type 2 diabetes mellitus under outpatient-clinic conditions for 18 months using a basal-bolus regimen with a rapid-acting insulin analogue as mealtime insulin. AB - AIMS: To assess the effects of a structured in-patient diabetes training programme in people with Type 2 diabetes mellitus on a basal-bolus regimen using insulin glargine or NPH insulin and rapid-acting insulin analogues with respect to glycaemic control, weight development and incidence of hypoglycaemia in an outpatient-clinic setting. PATIENTS AND METHODS: This was a prospective, non randomized, single centre, comparative observational study including 119 subjects. Pre-study treatment was a basal-bolus regimen with NPH insulin and a rapid-acting insulin analogue. Subjects either continued with NPH insulin (n=56) or were switched over to insulin glargine (n=63) at the discretion of the investigator (aiming at equal numbers in each group). Patients then attended routine out-patient follow up visits for 18 months. RESULTS: HbA1c in the insulin glargine group improved statistically significant by -0.49%; [95%CI, -0.26, 0.71; p<0.001; HbA1c at endpoint 6.95+/-0.71%], whereas in the NPH group the reduction by -0.12% [95%CI, -0.31, 0.06; p=0.189; HbA1c at endpoint 7.22+/-0.74%] was statistically not significant. After 18 months of treatment the difference between treatment groups was 0.37% (p<0.015). Mean weight gain was significantly higher in the NPH group than in the glargine group (2.1 vs. 0.25 kg; p=0.025). A lower risk of hypoglycaemia in the glargine group (0.50 vs. 0.71 episodes/patient/month) did not reach statistical significance (p=0.081). CONCLUSIONS: Following a structured in-patient diabetes training programme glycaemic control in people with Type 2 diabetes mellitus on a basal-bolus regimen improved significantly only with insulin glargine suggesting that training alone may not be sufficient to further improve metabolic control in relatively well controlled patients on NPH insulin. Therefore, in addition to a structured training programme also the insulin regimen should be optimized, e.g. by introduction of an insulin analogue. PMID- 17701879 TI - Beta-adrenergic and opioidergic modulation of cortisol secretion in response to acute stress. AB - The modulatory action of beta-adrenergic and opioidergic pathways on the cortisol response to acute stressors was investigated using gonadectomized male miniature pigs. Three types of stressors, nose-snare (NS, for 2 min. each on four occasions at 30 min. intervals); high intensity cracker blasts (CB, two blasts at 3 min intervals) and ACTH (1 i.u./kg BW, i.v.) were utilized 80 min after start of blood sampling. For assessment of cortisol blood samples were withdrawn every 20 min for 200 min. In addition, animals received i.v. injections of either isoproterenol (5 microg/ kg) or propranolol (0.5 mg/kg) or naloxone (1 mg/kg) 15 or 30 min before the application of stressor. Stress of repeated NS application as well as ACTH treatment, resulted in immediate secretion of cortisol (p<0.001). Blast of crackers resulted in a transient increase in cortisol (p<0.05). Isoproterenol stimulated the basal cortisol secretion for about 20 min in unstressed pigs (p <0.01) but propranolol had no effects. Isoproterenol also reinforced (p<0.05) the effect of CB, but had no effect on the cortisol response to nose-snare. In contrast, response to NS was reduced (p=0.02) by propranolol. Neither isoproterenol nor propranolol altered the cortisol response to ACTH application. Pretreatment with naloxone significantly increased the cortisol response to NS (p<0.01) and to CB (p<0.01), but had no effects on ACTH-induced cortisol release. In conclusion, the beta-adrenergic involvement is evident in the cortisol response to acute stress of nose-snare. Furthermore, the results indicate that activation of endogenous opioid system during stress mitigates adrenal response. PMID- 17701880 TI - Weight-bearing intensity produces charcot deformity in injured neuropathic feet in diabetes. AB - The purpose of the study was to investigate the relationship between the intensity of unrestrained weight bearing after a non-fracture injury (e.g. sprain), and the development of osteoarthropathic deformities of the foot (Charcot foot) in patients with diabetic neuropathy. METHODS: 34 diabetic patients (14 Type 1, 20 Type 2) with foot bone injuries were studied in retrospect. At onset of injury symptoms (e.g. foot swelling), 32 of 34 feet displayed unremarkable X-ray, but pathologic MR imaging (e.g. bone marrow edema along the Lisfranc and/or the Chopart joint). Cumulative load forces after the onset of symptoms until treatment by total contact cast (TCC) were estimated using the product of body weight and number of weeks of ambulation (kg x week) as a surrogate. Feet were classified in 3 groups according to the degree of foot deformities found at the start of treatment with TCC: Feet without deformities (group A, n=16), feet with minor deformities (partially reduced plantar arch (group B, n=6) and feet with major deformities (collapsed plantar arch, group C, n=12) RESULTS: Feet in group A had been exposed to 262 (95% CI 135-390) kg x week, compared to 974 (95% CI 342-1606) in group B, and to 2348 (95% CI 1265 3430) kg x week in group C (p<0.05 between groups), indicative of a dose-response relationship between weight-bearing and progressive foot deformities. Destruction along the Lisfranc joint was observed in 2/16 feet in group A, versus 18/18 feet in group B and C combined (p<0.001). In group A, the undeformed feet were healed without major deformities (except for 2 non-compliant patients), whereas in group B and C feet remained as deformed as they were at TCC application. CONCLUSION: Unrestrained weight-bearing of injured foot bones and joints of more than 400 kg x week (equivalent to 8 weeks of normal walking by a person of 50 kg body weight) prompts Charcot deformities, with disintegration of the Lisfranc joint. Early off loading by TCC treatment allows healing without deformities. PMID- 17701881 TI - Protective effects of chronic melatonin treatment against renal ischemia/reperfusion injury in streptozotocin-induced diabetic rats. AB - AIMS: The purpose of this study was to investigate the effects of chronic administration of melatonin on renal ischemia/reperfusion (IR) injury in streptozotocin (STZ)-induced diabetic rats. METHODOLOGY: Male Sprague-Dawley rats were divided into six groups: control (C), diabetes mellitus (DM), control+IR (C+IR), DM+IR, Melatonin+IR (Mel+IR), DM+Mel+IR. Diabetic and non-diabetic rats were given melatonin 4 mg/kg/day, i.p., for 15 days. The left renal artery and vein of rats were occluded for 30 min at the 18th day, followed by 24 h of reperfusion. RESULTS: In comparison with control group, the levels of malondialdehyde (MDA), protein carbonyl (PC) and and nitric oxide (NO) were determined to be higher in the renal homogenates of DM, DM+IR and C+IR groups. MDA and NO levels were found to be similar in the DM+melatonin+IR and control groups. The most significant histological damage was found in the DM+IR group and this damage was significantly reduced by melatonin. CONCLUSION: Chronic melatonin treatment reduces renal injury by reducing lipid oxidation and NO production in STZ-induced diabetic rats exposed to IR. PMID- 17701882 TI - The HMG-CoA reductase inhibitor cerivastatin lowers advanced glycation end products in patients with type 2 diabetes. AB - Although the association between type 2 diabetes mellitus (DM) and cardiovascular diseases is well-documented, current knowledge regarding reasons for the increased prevalence of atherosclerosis in DM is incomplete. Advanced glycosylation end-products (AGE) may play an important role in the development of atherosclerosis in diabetic patients. We examined the effect of the HMG-CoA reductase inhibitor (HMGRI) cerivastatin on serum concentration of AGE-CML in patients with elevated fasting glucose, impaired glucose tolerance or DM. The study was a multicenter, double-blind, randomized, parallel-group comparison of cerivastatin at 0.4 mg daily for 12 weeks (n=34) and placebo (n=35). Patients were characterized by combined hyperlipoproteinemia and the preponderance of dense LDL. Primary objective of the study was the effect of cerivastatin on the concentration of dense LDL subfractions. Here we report on the effect of cerivastatin on the concentration of AGE-CML. After 12 weeks of treatment cerivastatin reduced cholesterol, apolipoprotein B, LDL cholesterol and the concentration of dense LDL. Furthermore, cerivastatin significantly lowered the concentration of AGE-CML by 21% ( P=0,005; compared to -7,5% in the placebo group). The effect on AGE-CML was correlated with the reduction in LDL cholesterol (r=0.355, P=0.003) and LDL apoB (r=0.239, P=0.05). In addition to the lipid-lowering effects of HMGRI, the reduction of AGE-CML observed in our study may entail an improvement of the cardiovascular prognosis in patients with chronic hyperglycemia. PMID- 17701883 TI - Effects of short-term propylthiouracil treatment on p wave duration and p wave dispersion in patients with overt hypertyroidism. AB - BACKGROUND: P-wave duration is defined as the time measured from the onset to the offset of the P-wave in surface electrocardiogram (ECG). Prolonged P wave duration and increased P wave dispersion (PWD) have been reported to carry an increased risk for atrial fibrillation. AIM: Our aim was to evaluate the role of hyperthyroidism on P wave duration and dispersion, to investigate the effect of anti-thyroid therapy on P wave duration and dispersion. MATERIAL AND METHODS: A total of 44 consecutive subjects (22 patients with newly diagnosed overt hyperthyroidism and 22 randomly selected euthyroid healthy subjects) were enrolled in the study. Transthoracic echocardiography, 12 lead surface ECG and thyroid hormone levels were studied at the time of enrollment, in the first and third months of the 6-8 mg/kg/day propylthiouracil therapy. Patients were followed-up for 3 months. RESULTS: Patient and control groups were consisted of age and sex matched subjects. Baseline left atrial diameter was similar between the patient and control groups (3.4+/-0.3 cm and 3.4+/-0.3 cm respectively, p=0.813). The maximum P-wave duration (P maximum) was 113.1+/-6.6 and 105.7+/-4.1 ms in patient and control groups (p=0.001). PWD was 31.5+/-9.5 and 25.2+/-5.9 ms in patient and control groups respectively (p=0.015). At the third month of propylthiouracil treatment P maximum and PWD were decreased in the patient group at statistically significant level and returned back in normal limits (p<0.001 and p=0.001). CONCLUSION: P wave duration and PWD are found prolonged in hyperthyroid patients and propylthiouracil treatment decreased them effectively. This mechanism may establish how the anti-thyroid treatment may prevent the development of atrial fibrillation in hyperthyroid patients. PMID- 17701884 TI - Influence of body mass index on measured and calculated androgen parameters in adult women with Hirsutism and PCOS. AB - There is growing evidence that obesity in women lead to a more severe form of hyperandrogenism and other endocrine abnormalities which may have some health implications later in life. Obese females are at higher risk for metabolic syndrome due to severe hyperandrogenemia. Calculated values for free testosterone are equivalent to those obtained by equilibrium dialysis, which is one of the reference measurement procedures (RMP) for estimation of free testosterone and may be capable of replacing values estimated using RMP's. For adult women correlations of body mass index (BMI) with calculated free (cFT) and bioavailable testosterone (cBT) are still rare, while these data are reported for peripubertal and adolescent girls. In this study we aimed to investigate the association between BMI and different androgen parameters (including calculated free and bioavailable testosterone, free androgen index, and sex hormone-binding globulin [SHBG]) in adult women with Hirsutism and with PCOS. In hirsute women with BMI > or = 25 kg/m2 measured total testosterone (TT) was significantly higher, SHBG was significantly lower and the calculated androgen parameter (FAI, cFT and cBT) were significantly higher compared to women with BMI < 25 kg/m2. In PCOS women with BMI > or = 25 kg/m2 TT was significantly higher, SHBG was significantly lower and the calculated androgen parameter (FAI, cFT and cBT) were also significantly higher compared to women with BMI < 25 kg/m2. In both the Hirsutism and PCOS group there was a positive correlation between BMI and TT, cFT, and cBT, while BMI was negatively correlated with SHBG. In summary, in adult women with Hirsutism and PCOS obesity is associated with increased levels of TT and decreased levels of SHBG resulting in significant elevated calculated free and bioavailable testosterone levels. Obesity might lead to a more severe form of hyperandrogenism with elevated calculated free and bioavailable testosterone in the study population. PMID- 17701885 TI - Impaired deoxyribonuclease activity in monoglandular and polyglandular autoimmunity. AB - OBJECTIVE: The enzyme desoxyribonuclease (DNase) degrades DNA during early apoptosis. Impaired DNase activity might increase susceptibility to autoimmune diseases. This study examined for the first time DNase activity in endocrine autoimmunity. METHODS: Included were 112 patients with monoglandular (MGA) or polyglandular autoimmunity (PGA), their 93 healthy relatives, and 41 healthy controls. Serum DNase activity was quantified with a solid phase enzyme immunometric assay comprising degradation of the specific immobilized DNase substrate, formation of enzyme conjugate complexes using horseradish peroxidase conjugate solution, and enzymatic colour reaction. RESULTS: The Bland-Altman plot of the interassay differences suggested good reproducibility (n=96). Compared to healthy controls (median 9.8, range 5.2-16.7 ng/ml), DNase activity was markedly lowered in patients with endocrine autoimmunity (5.8, 2.6-26.2 ng/ml; p<0.0001). Corresponding values in the following MGA, PGA, and relatives groups were 4.8 (2.8-19.0) ng/ml, 7.9 (2.6-26.2) ng/ml, and 8.4 (1.5-19.0) ng/ml, respectively. When MGA patients were splitted up by disease, patients with type 1 diabetes had the lowest DNase activity (3.6, 3.2-3.9 ng/ml) which positively correlated with HbA1c in females (r=0.486, p=0.041). Pathological reduction of DNase activity (below 5 ng/ml) was noted in 54%, 31%, 24%, and 0% of MGA, PGA, relatives, and controls, respectively. Anti-ds-DNA and anti-nucleosome antibodies were negative in the patients with MGA and PGA. CONCLUSIONS: These findings indicate the potential relevance of DNase activity in patients with monoglandular and polyglandular autoimmunity and their clinically healthy relatives. The impaired DNase activity might reduce removal of circulating self- or pathogen-derived DNA thereby favoring autoimmune mechanisms by Toll-like receptor 9 co-activation. PMID- 17701886 TI - Cardiovascular collapse associated with beta blockade in thyroid storm. AB - We describe three cases of thyroid storm who developed sudden cardiorespiratory arrest soon after the administration of propranolol orally. CASE 1: A 43 years old Chinese lady presented with complaints of fever and chills. She had a urinary tract infection and also had signs of overt thyrotoxicosis. She was diagnosed to have thyroid storm and was started on oral propranolol, carbimazole and intravenous hydrocortisone and ceftriaxone. Soon after propranolol was given orally she developed an asystolic cardiorespiratory arrest. CASE 2: A 72 years old Chinese gentleman presented with confusion, fever and rapid atrial fibrillation. He was diagnosed to have thyroid storm and was started on oral propranolol, carbimazole and intravenous hydrocortisone and ceftriaxone. He developed a cardiorespiratory arrest about 6 hours after commencement of therapy. CASE 3: A 48-year-old Chinese gentleman presented with complains of dyspnoea and palpitations. He was diagnosed to have thyroid storm and was started on oral propranolol, carbimazole, intravenous hydrocortisone and antibiotics. About 12 hours after admission, he developed a cardiorespiratory arrest. All three patients developed cardiorespiratory arrest soon after the administration of propranolol orally. We conclude that in selective patients who have low output cardiac failure in association with severe thyrotoxicosis, it maybe advisable to avoid use of a beta blocker. A safer alternative is the use of ultra short-acting beta-blockers, such as intravenous esmolol, with extreme caution. PMID- 17701887 TI - A special case of bilateral ovarian metastases in a woman with papillary carcinoma of the thyroid. AB - Papillary thyroid carcinoma is a slow growing tumor with low metastatic potential. The most frequent sites of distant metastases are lung and bone; less frequent sites are brain, liver, kidney, and skin. Ovarian metastases from papillary thyroid carcinoma are exceptional. We describe a case of bilateral ovarian metastases from a papillary thyroid carcinoma associated with autoimmune thyroiditis in a 38-year-old woman who underwent thyroidectomy and cervical lymph node dissection 7 years before, followed by 948 mCi of 131I. A primary ovarian cancer could be excluded by the typical pathological aspects of a papillary thyroid carcinoma in a context of an aggressive form of thyroid cancer. On the other hand, the clinical history and the absence of normal thyroid epithelium and teratomatous components could exclude a papillary thyroid carcinoma arising in struma ovarii. This is a singular case of papillary thyroid carcinoma metastasizing to the ovary, combined with an autoimmune thyroiditis. PMID- 17701888 TI - The unique case of adrenocortical malignant and functioning oncocytic tumour. AB - Adrenocortical oncocytoma is extremely rarely found. Only a little more than thirty cases of adrenal oncocytoma, mainly nonfunctioning and benign, have been reported in the literature. Adrenal mass 150 x 160 x 172 mm in size and enlarged periarterial lymph nodes were found in CT examination performed in 51-year-old male. Main complaints: weight loss, general asthenia and abdominal pain. PHYSICAL EXAMINATION: elevated blood pressure (180/120 mmHg), no features typical of Cushing's syndrome. Abnormal laboratory findings: oral glucose tolerance test revealed diabetes, elevated serum dehydroepiandrosterone-sulfate (1101.9 microg/dl; normal, 59-452), elevated serum cortisol following overnight 1 mg dexamethasone test (5.1 microg/dl; normal, <1.8), increased urinary excretion of 17- hydroxycorticosteroids (18.1 mg/24 h; normal, 2.0-7.0) with pathological response to high-dose dexamethason test (16.6 mg/24). On laparotomy, the lesion was considered unresectable because of evident - confirmed by intraoperative ultrasound - tumour infiltration of the inferior caval vein. The large biopsy specimen was obtained for histological examination in which tumour fulfilled criteria proposed by Bisceglia et al. for adrenocortical oncocytic borderline tumour. On immunohistochemistry, the lesion showed cytoplasmic reaction for cytokeratin, vimentin and synaptophysin. The presented case appears to be the first malignant and functioning adrenocortical oncocytic tumour reported and confirms the complexity of its biology. PMID- 17701889 TI - The effects of NN414, a SUR1/Kir6.2 selective potassium channel opener in subjects with type 2 diabetes. AB - Reducing the workload of the beta cell by inhibiting insulin secretion may provide beneficial effects for patients with type 2 diabetes. The aim of this study was to investigate the effect of NN414, a beta cell selective potassium channel opener in patients with type 2 diabetes. 24 patients were treated for seven days (placebo, 1.5, 4.5, and 10 mg/kg). In accordance with the pharmacological profile a significant and selective inhibition of insulin secretion was observed (1 h post dose). There were no statistically significant effects on overall glycaemic control. Based on OGTT derived parameters a borderline significant improvement in beta-cell function (1st and 2nd phase insulin secretion) was observed from Day 1 to Day 7. PMID- 17701890 TI - Identification of genetic variants contributing to cisplatin-induced cytotoxicity by use of a genomewide approach. AB - Cisplatin, a platinating agent commonly used to treat several cancers, is associated with nephrotoxicity, neurotoxicity, and ototoxicity, which has hindered its utility. To gain a better understanding of the genetic variants associated with cisplatin-induced toxicity, we present a stepwise approach integrating genotypes, gene expression, and sensitivity of HapMap cell lines to cisplatin. Cell lines derived from 30 trios of European descent (CEU) and 30 trios of African descent (YRI) were used to develop a preclinical model to identify genetic variants and gene expression that contribute to cisplatin induced cytotoxicity in two different populations. Cytotoxicity was determined as cell-growth inhibition at increasing concentrations of cisplatin for 48 h. Gene expression in 176 HapMap cell lines (87 CEU and 89 YRI) was determined using the Affymetrix GeneChip Human Exon 1.0 ST Array. We identified six, two, and nine representative SNPs that contribute to cisplatin-induced cytotoxicity through their effects on 8, 2, and 16 gene expressions in the combined, Centre d'Etude du Polymorphisme Humain (CEPH), and Yoruban populations, respectively. These genetic variants contribute to 27%, 29%, and 45% of the overall variation in cell sensitivity to cisplatin in the combined, CEPH, and Yoruban populations, respectively. Our whole-genome approach can be used to elucidate the expression of quantitative trait loci contributing to a wide range of cellular phenotypes. PMID- 17701891 TI - Oral curcumin mitigates the clinical and neuropathologic phenotype of the Trembler-J mouse: a potential therapy for inherited neuropathy. AB - Mutations in myelin genes cause inherited peripheral neuropathies that range in severity from adult-onset Charcot-Marie-Tooth disease type 1 to childhood-onset Dejerine-Sottas neuropathy and congenital hypomyelinating neuropathy. Many myelin gene mutants that cause severe disease, such as those in the myelin protein zero gene (MPZ) and the peripheral myelin protein 22 gene (PMP22), appear to make aberrant proteins that accumulate primarily within the endoplasmic reticulum (ER), resulting in Schwann cell death by apoptosis and, subsequently, peripheral neuropathy. We previously showed that curcumin supplementation could abrogate ER retention and aggregation-induced apoptosis associated with neuropathy-causing MPZ mutants. We now show reduced apoptosis after curcumin treatment of cells in tissue culture that express PMP22 mutants. Furthermore, we demonstrate that oral administration of curcumin partially mitigates the severe neuropathy phenotype of the Trembler-J mouse model in a dose-dependent manner. Administration of curcumin significantly decreases the percentage of apoptotic Schwann cells and results in increased number and size of myelinated axons in sciatic nerves, leading to improved motor performance. Our findings indicate that curcumin treatment is sufficient to relieve the toxic effect of mutant aggregation-induced apoptosis and improves the neuropathologic phenotype in an animal model of human neuropathy, suggesting a potential therapeutic role in selected forms of inherited peripheral neuropathies. PMID- 17701893 TI - Physical exercise-induced hypoglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic beta cells. AB - Exercise-induced hyperinsulinism (EIHI) is a dominantly inherited hypoglycemic disorder characterized by inappropriate insulin secretion during anaerobic exercise or on pyruvate load. We aimed to identify the molecular basis of this novel disorder of beta -cell regulation. EIHI mapped to chromosome 1 (LOD score 3.6) in a genome scan performed for two families with 10 EIHI-affected patients. Mutational analysis of the promoter of the SLC16A1 gene, which encodes monocarboxylate transporter 1 (MCT1), located under the linkage peak, revealed changes in all 13 identified patients with EIHI. Patient fibroblasts displayed abnormally high SLC16A1 transcript levels, although monocarboxylate transport activities were not changed in these cells, reflecting additional posttranscriptional control of MCT1 levels in extrapancreatic tissues. By contrast, when examined in beta cells, either of two SLC16A1 mutations identified in separate pedigrees resulted in increased protein binding to the corresponding promoter elements and marked (3- or 10-fold) transcriptional stimulation of SLC16A1 promoter-reporter constructs. These studies show that promoter-activating mutations in EIHI induce SLC16A1 expression in beta cells, where this gene is not usually transcribed, permitting pyruvate uptake and pyruvate-stimulated insulin release despite ensuing hypoglycemia. These findings describe a novel disease mechanism based on the failure of cell-specific transcriptional silencing of a gene that is highly expressed in other tissues. PMID- 17701892 TI - Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. AB - Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages. PMID- 17701894 TI - Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes. AB - Down syndrome caused by chromosome 21 trisomy is the most common genetic cause of mental retardation in humans. Disruption of the phenotype is thought to be the result of gene-dosage imbalance. Variations in chromosome 21 gene expression in Down syndrome were analyzed in lymphoblastoid cells derived from patients and control individuals. Of the 359 genes and predictions displayed on a specifically designed high-content chromosome 21 microarray, one-third were expressed in lymphoblastoid cells. We performed a mixed-model analysis of variance to find genes that are differentially expressed in Down syndrome independent of sex and interindividual variations. In addition, we identified genes with variations between Down syndrome and control samples that were significantly different from the gene-dosage effect (1.5). Microarray data were validated by quantitative polymerase chain reaction. We found that 29% of the expressed chromosome 21 transcripts are overexpressed in Down syndrome and correspond to either genes or open reading frames. Among these, 22% are increased proportional to the gene dosage effect, and 7% are amplified. The other 71% of expressed sequences are either compensated (56%, with a large proportion of predicted genes and antisense transcripts) or highly variable among individuals (15%). Thus, most of the chromosome 21 transcripts are compensated for the gene-dosage effect. Overexpressed genes are likely to be involved in the Down syndrome phenotype, in contrast to the compensated genes. Highly variable genes could account for phenotypic variations observed in patients. Finally, we show that alternative transcripts belonging to the same gene are similarly regulated in Down syndrome but sense and antisense transcripts are not. PMID- 17701895 TI - DLX5 and DLX6 expression is biallelic and not modulated by MeCP2 deficiency. AB - Mutations in MECP2 and Mecp2 (encoding methyl-CpG binding protein 2 [MeCP2]) cause distinct neurological phenotypes in humans and mice, respectively, but the molecular pathology is unclear. Recent literature claimed that the developmental homeobox gene DLX5 is imprinted and that its imprinting status is modulated by MeCP2, leading to biallelic expression in Rett syndrome and twofold overexpression of Dlx5 and Dlx6 in Mecp2-null mice. The conclusion that DLX5 is a direct target of MeCP2 has implications for research on the molecular bases of Rett syndrome, autism, and genomic imprinting. Attempting to replicate the reported data, we evaluated allele-specific expression of DLX5 and DLX6 in mouse x human somatic cell hybrids, lymphoblastoid cell lines, and frontal cortex from controls and individuals with MECP2 mutations. We identified novel single nucleotide polymorphisms in DLX5 and DLX6, enabling the first imprinting studies of DLX6. We found that DLX5 and DLX6 are biallelically expressed in somatic cell hybrids and in human cell lines and brain, with no differences between affected and control samples. We also determined expression levels of Dlx5 and Dlx6 in forebrain from seven male Mecp2-mutant mice and eight wild-type littermates by real-time quantitative reverse-transcriptase polymerase chain reaction assays. Expression of Dlx5 and Dlx6, as well as of the imprinted gene Peg3, in mouse forebrain was highly variable, with no consistent differences between Mecp2-null mutants and controls. We conclude that DLX5 and DLX6 are not imprinted in humans and are not likely to be direct targets of MeCP2 modulation. In contrast, the imprinting status of PEG3 and PEG10 is maintained in MeCP2-deficient tissues. Our results confirm that MeCP2 plays no role in the maintenance of genomic imprinting and add PEG3 and PEG10 to the list of studied imprinted genes. PMID- 17701896 TI - Arts syndrome is caused by loss-of-function mutations in PRPS1. AB - Arts syndrome is an X-linked disorder characterized by mental retardation, early onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Linkage analysis in a Dutch family and an Australian family suggested that the candidate gene maps to Xq22.1-q24. Oligonucleotide microarray expression profiling of fibroblasts from two probands of the Dutch family revealed reduced expression levels of the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1). Subsequent sequencing of PRPS1 led to the identification of two different missense mutations, c.455T-->C (p.L152P) in the Dutch family and c.398A-->C (p.Q133P) in the Australian family. Both mutations result in a loss of phosphoribosyl pyrophosphate synthetase 1 activity, as was shown in silico by molecular modeling and was shown in vitro by phosphoribosyl pyrophosphate synthetase activity assays in erythrocytes and fibroblasts from patients. This is in contrast to the gain-of-function mutations in PRPS1 that were identified previously in PRPS-related gout. The loss-of-function mutations of PRPS1 likely result in impaired purine biosynthesis, which is supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients. To replenish low levels of purines, treatment with S-adenosylmethionine theoretically could have therapeutic efficacy, and a clinical trial involving the two affected Australian brothers is currently underway. PMID- 17701897 TI - Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum. AB - Mutations in the RMRP gene lead to a wide spectrum of autosomal recessive skeletal dysplasias, ranging from the milder phenotypes metaphyseal dysplasia without hypotrichosis and cartilage hair hypoplasia (CHH) to the severe anauxetic dysplasia (AD). This clinical spectrum includes different degrees of short stature, hair hypoplasia, defective erythrogenesis, and immunodeficiency. The RMRP gene encodes the untranslated RNA component of the mitochondrial RNA processing ribonuclease, RNase MRP. We recently demonstrated that mutations may affect both messenger RNA (mRNA) and ribosomal RNA (rRNA) cleavage and thus cell cycle regulation and protein synthesis. To investigate the genotype-phenotype correlation, we analyzed the position and the functional effect of 13 mutations in patients with variable features of the CHH-AD spectrum. Those at the end of the spectrum include a novel patient with anauxetic dysplasia who was compound heterozygous for the null mutation g.254_263delCTCAGCGCGG and the mutation g.195C ->T, which was previously described in patients with milder phenotypes. Mapping of nucleotide conservation to the two-dimensional structure of the RMRP gene revealed that disease-causing mutations either affect evolutionarily conserved nucleotides or are likely to alter secondary structure through mispairing in stem regions. In vitro testing of RNase MRP multiprotein-specific mRNA and rRNA cleavage of different mutations revealed a strong correlation between the decrease in rRNA cleavage in ribosomal assembly and the degree of bone dysplasia, whereas reduced mRNA cleavage, and thus cell-cycle impairment, predicts the presence of hair hypoplasia, immunodeficiency, and hematological abnormalities and thus increased cancer risk. PMID- 17701898 TI - Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes PIPKI gamma of the phophatidylinsitol pathway. AB - Lethal congenital contractural syndrome (LCCS) is a severe form of arthrogryposis. To date, two autosomal recessive forms of the disease (LCCS and LCCS2) have been described and mapped to chromosomes 9q34 and 12q13, respectively. We now describe a third LCCS phenotype (LCCS3)--similar to LCCS2 yet without neurogenic bladder. Using 10K single-nucleotide-polymorphism arrays, we mapped the disease-associated gene to 8.8 Mb on chromosome 19p13. Further analysis using microsatallite markers narrowed the locus to a 3.4-Mb region harboring 120 genes. Of these genes, 30 candidates were sequenced, which identified a single homozygous mutation in PIP5K1C. PIP5K1C encodes phosphatidylinositol-4-phosphate 5-kinase, type I, gamma (PIPKI gamma ), an enzyme that phophorylates phosphatidylinositol 4-phosphate to generate phosphatidylinositol-4,5-bisphosphate (PIP(2)). We demonstrate that the mutation causes substitution of aspartic acid with asparagine at amino acid 253 (D253N), abrogating the kinase activity of PIPKI gamma . Thus, a defect in the phosphatidylinositol pathway leading to a decrease in synthesis of PIP(2), a molecule active in endocytosis of synaptic vesicle proteins, culminates in lethal congenital arthrogryposis. PMID- 17701899 TI - Flexible design for following up positive findings. AB - As more population-based studies suggest associations between genetic variants and disease risk, there is a need to improve the design of follow-up studies (stage II) in independent samples to confirm evidence of association observed at the initial stage (stage I). We propose to use flexible designs developed for randomized clinical trials in the calculation of sample size for follow-up studies. We apply a bootstrap procedure to correct the effect of regression to the mean, also called "winner's curse," resulting from choosing to follow up the markers with the strongest associations. We show how the results from stage I can improve sample size calculations for stage II adaptively. Despite the adaptive use of stage I data, the proposed method maintains the nominal global type I error for final analyses on the basis of either pure replication with the stage II data only or a joint analysis using information from both stages. Simulation studies show that sample-size calculations accounting for the impact of regression to the mean with the bootstrap procedure are more appropriate than is the conventional method. We also find that, in the context of flexible design, the joint analysis is generally more powerful than the replication analysis. PMID- 17701900 TI - Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (cmtx5). AB - We have identified missense mutations at conserved amino acids in the PRPS1 gene on Xq22.3 in two families with a syndromic form of inherited peripheral neuropathy, one of Asian and one of European descent. The disease is inherited in an X-linked recessive manner, and the affected male patients invariably develop sensorineural hearing loss of prelingual type followed by gating disturbance and visual loss. The family of European descent was reported in 1967 as having Rosenberg-Chutorian syndrome, and recently a Korean family with the same symptom triad was identified with a novel disease locus CMTX5 on the chromosome band Xq21.32-q24. PRPS1 (phosphoribosyl pyrophosphate synthetase 1) is an isoform of the PRPS gene family and is ubiquitously expressed in human tissues, including cochlea. The enzyme mediates the biochemical step critical for purine metabolism and nucleotide biosynthesis. The mutations identified were E43D, in patients with Rosenberg-Chutorian syndrome, and M115T, in the Korean patients with CMTX5. We also showed decreased enzyme activity in patients with M115T. PRPS1 is the first CMT gene that encodes a metabolic enzyme, shedding a new light on the understanding of peripheral nerve-specific metabolism and also suggesting the potential of PRPS1 as a target for drugs in prevention and treatment of peripheral neuropathy by antimetabolite therapy. PMID- 17701901 TI - PLINK: a tool set for whole-genome association and population-based linkage analyses. AB - Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis. PMID- 17701903 TI - The genetics of congenital amusia (tone deafness): a family-aggregation study. AB - Congenital amusia (commonly known as "tone deafness") is a lifelong impairment of music perception that affects 4% of the population. To estimate whether congenital amusia can be genetically transmitted, its prevalence was quantified by direct auditory testing of 71 members of 9 large families of amusic probands, as well as of 75 members of 10 control families. The results confirm that congenital amusia is expressed by a deficit in processing musical pitch but not musical time and also show that the pitch disorder has a hereditary component. In amusic families, 39% of first-degree relatives have the same cognitive disorder, whereas only 3% have it in the control families. The identification of multiplex families with a high relative risk of experiencing a musical pitch deficit ( lambda(s)=10.8; 95% confidence interval 8-13.5) enables the mapping of genetic loci for hereditary amusia. PMID- 17701902 TI - NOBOX homeobox mutation causes premature ovarian failure. AB - NOBOX (newborn ovary homeobox gene) is an oocyte-specific homeobox gene that plays a critical role in early folliculogenesis and represents a candidate gene for nonsyndromic ovarian failure. We investigated whether mutations in the NOBOX gene cause premature ovarian failure (POF). We sequenced the NOBOX gene in 96 white women with POF and discovered seven known single-nucleotide polymorphisms and four novel variations, two of which, p.Arg355His and p.Arg360Gln, cause missense mutations in the homeobox domain. Electrophoretic mobility shift assay (EMSA) confirmed that the missense mutation, p.Arg355His, disrupted NOBOX homeodomain binding to NOBOX DNA-binding element (NBE) and had a dominant negative effect on the binding of wild-type NOBOX to DNA. Our findings demonstrate that NOBOX mutations can cause POF. PMID- 17701904 TI - Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3), a modulator of the phosphatidylinositol-3-kinase/Akt pathway. AB - Lethal congenital contractural syndrome type 2 (LCCS2) is an autosomal recessive neurogenic form of arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord. We previously mapped LCCS2 to 6.4 Mb on chromosome 12q13 and have now narrowed the locus to 4.6 Mb. We show that the disease is caused by aberrant splicing of ERBB3, which leads to a predicted truncated protein. ERBB3 (Her3), an activator of the phosphatidylinositol-3-kinase/Akt pathway--regulating cell survival and vesicle trafficking--is essential for the generation of precursors of Schwann cells that normally accompany peripheral axons of motor neurons. Gain-of-function mutations in members of the epidermal growth-factor tyrosine kinase-receptor family have been associated with predilection to cancer. This is the first report of a human phenotype resulting from loss of function of a member of this group. PMID- 17701905 TI - CHMP4B, a novel gene for autosomal dominant cataracts linked to chromosome 20q. AB - Cataracts are a clinically diverse and genetically heterogeneous disorder of the crystalline lens and a leading cause of visual impairment. Here we report linkage of autosomal dominant "progressive childhood posterior subcapsular" cataracts segregating in a white family to short tandem repeat (STR) markers D20S847 (LOD score [Z] 5.50 at recombination fraction [theta] 0.0) and D20S195 (Z=3.65 at theta =0.0) on 20q, and identify a refined disease interval (rs2057262-(3.8 Mb) rs1291139) by use of single-nucleotide polymorphism (SNP) markers. Mutation profiling of positional-candidate genes detected a heterozygous transversion (c.386A-->T) in exon 3 of the gene for chromatin modifying protein-4B (CHMP4B) that was predicted to result in the nonconservative substitution of a valine residue for a phylogenetically conserved aspartic acid residue at codon 129 (p.D129V). In addition, we have detected a heterozygous transition (c.481G-->A) in exon 3 of CHMP4B cosegregating with autosomal dominant posterior polar cataracts in a Japanese family that was predicted to result in the missense substitution of lysine for a conserved glutamic acid residue at codon 161 (p.E161K). Transfection studies of cultured cells revealed that a truncated form of recombinant D129V-CHMP4B had a different subcellular distribution than wild type and an increased capacity to inhibit release of virus-like particles from the cell surface, consistent with deleterious gain-of-function effects. These data provide the first evidence that CHMP4B, which encodes a key component of the endosome sorting complex required for the transport-III (ESCRT-III) system of mammalian cells, plays a vital role in the maintenance of lens transparency. PMID- 17701906 TI - Genomewide weighted hypothesis testing in family-based association studies, with an application to a 100K scan. AB - For genomewide association (GWA) studies in family-based designs, we propose a novel two-stage strategy that weighs the association P values with the use of independently estimated weights. The association information contained in the family sample is partitioned into two orthogonal components--namely, the between family information and the within-family information. The between-family component is used in the first (i.e., screening) stage to obtain a relative ranking of all the markers. The within-family component is used in the second (i.e., testing) stage in the framework of the standard family-based association test, and the resulting P values are weighted using the estimated marker ranking from the screening step. The approach is appealing, in that it ensures that all the markers are tested in the testing step and, at the same time, also uses information from the screening step. Through simulation studies, we show that testing all the markers is more powerful than testing only the most promising ones from the screening step, which was the method suggested by Van Steen et al. A comparison with a population-based approach shows that the approach achieves comparable power. In the presence of a reasonable level of population stratification, our approach is only slightly affected in terms of power and, since it is a family-based method, is completely robust to spurious effects. An application to a 100K scan in the Framingham Heart Study illustrates the practical advantages of our approach. The proposed method is of general applicability; it extends to any setting in which prior, independent ranking of hypotheses is available. PMID- 17701907 TI - Evidence of still-ongoing convergence evolution of the lactase persistence T 13910 alleles in humans. AB - A single-nucleotide variant, C/T(-13910), located 14 kb upstream of the lactase gene (LCT), has been shown to be completely correlated with lactase persistence (LP) in northern Europeans. Here, we analyzed the background of the alleles carrying the critical variant in 1,611 DNA samples from 37 populations. Our data show that the T(-13910) variant is found on two different, highly divergent haplotype backgrounds in the global populations. The first is the most common LP haplotype (LP H98) present in all populations analyzed, whereas the others (LP H8 H12), which originate from the same ancestral allelic haplotype, are found in geographically restricted populations living west of the Urals and north of the Caucasus. The global distribution pattern of LP T(-13910) H98 supports the Caucasian origin of this allele. Age estimates based on different mathematical models show that the common LP T(-13910) H98 allele (approximately 5,000-12,000 years old) is relatively older than the other geographically restricted LP alleles (approximately 1,400-3,000 years old). Our data about global allelic haplotypes of the lactose-tolerance variant imply that the T(-13910) allele has been independently introduced more than once and that there is a still-ongoing process of convergent evolution of the LP alleles in humans. PMID- 17701908 TI - Recent genetic selection in the ancestral admixture of Puerto Ricans. AB - Recent studies have used dense markers to examine the human genome in ancestrally homogeneous populations for hallmarks of selection. No genomewide studies have focused on recently admixed groups--populations that have experienced admixing among continentally divided ancestral populations within the past 200-500 years. New World admixed populations are unique in that they represent the sudden confluence of geographically diverged genomes with novel environmental challenges. Here, we present a novel approach for studying selection by examining the genomewide distribution of ancestry in the genetically admixed Puerto Ricans. We find strong statistical evidence of recent selection in three chromosomal regions, including the human leukocyte antigen region on chromosome 6p, chromosome 8q, and chromosome 11q. Two of these regions harbor genes for olfactory receptors. Interestingly, all three regions exhibit deficiencies in the European-ancestry proportion. PMID- 17701911 TI - Standardization of an orthotopic mouse brain tumor model following transplantation of CT-2A astrocytoma cells. AB - Animal models of glial-derived neoplasms are needed to study the biological mechanisms of glioma tumorigenesis and those that sustain the disease state. With the aim to develop and characterize a suitable in vivo experimental mouse model for infiltrating astrocytoma, with predictable and reproducible growth patterns that recapitulate human astrocytoma, this study was undertaken to analyze the long-term course of a syngeneic orthotopically implanted CT-2A mouse astrocytoma in C57BL/6J mice. Intracranial injection of CT-2A cells into caudate-putamen resulted in development of an aggressive tumor showing typical features of human glioblastoma multiforme, sharing close histological, immunohistochemical, proliferative, and metabolic profiles. To simulate metastatic disease to the brain, CT-2A cells were injected through the internal carotid artery. Tumors identical to those obtained by intracranial injection were obtained. Finally, CT 2A cells were re-isolated from experimental brain tumors and transcranially re injected into the caudate-putamen of healthy mice. These cells generated new tumors that were indistinguishable from the initial ones, suggesting in vivo self renewal of tumor cells. Small-animal models are essential for testing novel biological therapies directed against relevant molecular targets. In a preliminary study, experimental CT-2A tumors were chronically treated with the small molecule 77427, a gastrin-releasing peptide (GRP) blocker compound that inhibits angiogenesis. Treated animals developed significantly smaller tumors than controls, suggesting an antitumor action for 77427 in glioblastomas. We conclude that the orthotopic CT-2A tumor model, as described herein, is appropriate to explore the mechanisms of glioma development and for preclinical trials of promising drugs. PMID- 17701910 TI - Oxidative damage in age-related macular degeneration. AB - Epidemiologic studies have suggested that elderly patients who consumed diets rich in antioxidants throughout their lives are less likely to be afflicted with age-related macular degeneration (AMD). This led to the Age-Related Eye Disease Study, which showed that supplements containing antioxidant vitamins and zinc reduce the risk of progression to severe stages of AMD. Despite these data that indirectly implicate oxidative damage in the pathogenesis of AMD, there has not been any direct demonstration of increased oxidative damage in the retinas of patients with AMD. In this study, we used biomarkers of oxidative damage in postmortem eyes from patients with AMD and comparably aged patients without AMD to directly assess for oxidative damage. Sections from 4 eyes with no pathologic features of AMD showed no immunofluorescent staining for markers of oxidative damage, while sections from 8 of 12 eyes with advanced geographic atrophy showed evidence of widespread oxidative damage in both posterior and anterior retina. Only 2 of 8 eyes with choroidal neovascularization and 2 of 16 eyes with diffuse drusen and no other signs of AMD showed evidence of oxidative damage. These data suggest that widespread oxidative damage occurs in the retina of some patients with AMD and is more likely to be seen in patients with advanced geographic atrophy. This does not rule out oxidative damage as a pathogenic mechanism in patients with CNV, but suggests that a subpopulation of patients with geographic atrophy may have a major deficiency in the oxidative defense system that puts the majority of cells in the retina at risk for oxidative damage. PMID- 17701912 TI - Low expression of FGF1 (fibroblast growth factor-1) in rat parasympathetic preganglionic neurons. AB - Fibroblast growth factor-1 (FGF1), a member of the FGF family of growth factors, is localized in cholinergic neurons where it has trophic activity. We recently reported that cholinergic neurons in the dorsal motor nucleus of the vagus (DMNV) contain little FGF1, raising the possibility that FGF1 is not localized to parasympathetic preganglionic cholinergic neurons. To clarify this issue, we investigated the co-localization of FGF1 with cholinergic neuron markers in the Edinger-Westphal nucleus (EWN), salivatory nucleus, DMNV, and sacral parasympathetic nucleus by double immunofluorescence using antibodies to FGF1 and choline acetyltransferase (ChAT). The neurons in the EWN were devoid of FGF1. In the salivatory nucleus, 13% of ChAT-positive neurons were also positive for FGF1. In the DMNV, only 8% of ChAT-positive neurons contained FGF1, and in the sacral parasympathetic nucleus, 18% of ChAT-positive neurons were FGF1-positive. We also confirmed that a large number of ChAT-positive motor neurons in the oculomotor nucleus, facial nucleus, hypoglossal nucleus, and spinal motor neurons contained FGF1. The results confirmed that parasympathetic preganglionic neurons are largely devoid of FGF1, which is a unique feature among cholinergic neurons. PMID- 17701913 TI - Primary hepatic malignant fibrous histiocytoma: a case report and review of the literature. AB - Primary malignant fibrous histiocytoma (MFH) of the liver remains extremely rare with only several cases having been reported in literature. We report a case of hepatic MFH in a 53-year-old man who presented with upper abdominal pain, and weight loss for one month. Ultrasound and computed tomography (CT) scan showed a large mass with fine tumor vessels over the left lobe of the liver. Histopathological findings indicated a mesenchymal tumor consisting of spindle cells in storiform pattern intermingled with histiocyte-like cells and giant cells. Immunohistochemically, most tumor cells expressed vimentin, alpha-1 anti chymotrypsin, alpha-1 antitrypsin and CD68. Morphological and immunohistochemical findings support that the tumor should be classified as a primary malignant fibrous histiocytoma. The literatures is briefly reviewed. PMID- 17701915 TI - Actin cytoskeletal organization in human osteoblasts grown on different dental titanium implant surfaces. AB - The understanding of the cellular basis of osteoblastic cell-biomaterial interaction is crucial to the analysis of the mechanism of osseointegration. Cell adhesion is a complex process that is dependent on the cell types and on the surface microtopography and chemistry of the substrate. We have studied the role of microtopography in modulating cell adhesion, in vitro, using a human osteoblastic cell line for the assessment of actin cytoskeletal organization. Through application of CLSM combining reflection and fluorescence, 2D or 3D images of cytoskeleton were obtained. On smooth surfaces, Ti CP machined, predominantly planar bone cells with an axial ratio of 1.1 were randomly oriented, with stress fibers running in all directions, and thin filopodia. On TiCP Osseotite surfaces the osteoblastic cells conformed to the irregular terrain of the sustrate with focal adhesion sites only established on the relative topographical peaks separated for a longer distance than in the machined surface, and defined wide lamellopodia and long filopodia, with enhanced expression of stress fibers, forming large clear focal contacts with the rough surface. The cytoskeletal organization of cells cultured on rough titanium supports an active role for the biomaterial surface in the events that govern osteoblastic cell adhesion. The results enforce the role of the rough sustrate surface in affecting osteoblastic cell adhesion and provide valuable information for the design of material surfaces that are required for the development of an appropriate osteogenic surface for osteoblastic anchorage, compared to machined surface, in dental implants. PMID- 17701914 TI - Endothelin-1 and endothelin-converting enzyme-1 in human granulomatous pathology of eyelid: an immunohistochemical and in situ hybridization study in chalazia. AB - Endothelin-1 (ET-1), a potent vasoconstrictor peptide, is involved in several functions of eye pathophysiology, such as regulation of intraocular tension and retinal reactive vasoconstriction. As ET-1 pro-inflammatory and fibrosing activity is emerging in different fields of pathology, we investigated the expression of ET-1 and endothelin-converting enzyme-1 (ECE-1) in chalazia, granulomatous lesions of the eyelid. ET-1 and ECE-1 were analyzed by immunohistochemistry (IHC) in twenty surgically removed chalazia, with regard to expression in eyelid structures and inflammatory infiltrate. Phenotype of ET-1 expressing inflammatory cells was established by double immunofluorescence. The cellular localization of prepro-ET-1 (pp-ET-1) mRNA and ECE-1 mRNA was studied by nonisotopic in situ hybridization (ISH). Neutrophils (PMNs), macrophages and T lymphocytes were scattered in stroma, around alveoli and grouped in lipogranulomas. PMNs, macrophages, basal epithelium of meibomian adenomers and central ducts immunostained for ET-1. ECE-1 protein was found in meibomian adenomers, conjunctival epithelium, tarsal mucous glands and in inflammatory cells. Hybridization signals for pp-ET-1 mRNA and ECE-1 mRNA were recognized in healthy and degenerating meibomian ducts, adenomers, inflammatory cells, as well as in vessel walls. ECE-1 mRNA was also present in conjunctival epithelium and Henle's crypts. Our findings suggest that the multifunctional peptide ET-1 may have a role in molecular genesis of tissue damage in chalazia. ET-1 cytokine activity is likely to support the migration of inflammatory cells and the setting of lipogranulomas; ET-1 stimulation might contribute to proliferation of fibroblasts and collagen synthesis. ET-1 upregulation on meibomian adenomers and ducts may further enhance granulomas formation by stimulating lipid release. PMID- 17701916 TI - Apoptosis in peripheral neuroblastic tumors. Immunohistochemical expression of bcl-2 and p53 is related to DNA fragmentation. AB - We examined 111 cases of neuroblastoma (NB), searching for how NB relates to apoptotic control and other prognostic factors. Immunohistochemistry using avidin biotin-peroxidase was carried out for bcl-2 and p53 proteins. Apoptosis was analyzed by in situ detection of chromosomal breakdown. DNA ladders were detected by electrophoresis and amplification of MYCN was carried out by PCR and Southern blot. Statistical analyses were performed with Pearson's chi2 and Kruskal-Wallis tests and Cox's regression. We found expression of bcl-2 protein mainly in cases of neuroblastoma without differentiation and in stages 3 and 4. Expression of p53 protein showed a correlation with bcl-2 and the apoptotic phenomenon; apoptosis was found mainly in favorable cases. Multivariate analysis showed bcl-2 protein expression to be the most independent risk factor. The study of apoptosis could be important for the design of therapies to treat neuroblastoma. PMID- 17701917 TI - Expression of certain proteins in the subfornical organ and cerebrospinal fluid of spontaneously hypertensive rats. AB - The objective of this study was to analyze the proteins in the cerebrospinal fluid of spontaneously hypertensive rats and to study their possible role in the relationship between hydrocephalus, arterial hypertension and variations in the subfornical organ. Brains and cerebrospinal fluid from control Wistar-Kyoto rats and spontaneously hypertensive rats sacrificed with chloral hydrate were used. Cerebrospinal fluid and extract of subfornical organ were processed by protein electrophoresis. Antisera against protein bands of 141, 117 and 48 kDa and Concanavalin A were used for immunohistochemical and western blot study of the subfornical organ, adjacent circumventricular structures and cerebrospinal fluid. Ventricular dilation in the spontaneously hypertensive rats and the presence of quite a lot of protein bands in the cerebrospinal fluid of the hypertensive rats, which were either not observed or scarcely present in the cerebrospinal fluid of the Wistar-Kyoto rats, were confirmed. The subfornical organ, third ventricle ependyma and choroideus plexus showed immunoreactive material for antibodies against 141kDa, 117 and 48 kDa proteins band (anti-B1, anti-B2 and anti-B3). The larger amount of the immunoreactive material was found in the subfornical organ of the spontaneously hypertensive rat. Our results and the alterations observed by other authors in the subfornical organ in hydrocephalic and hypertensive rats support the possibility that this circumventricular organ, some proteins of the cerebrospinal fluid and ventricular dilation could be connected with the physiopathology of this type of hypertension. PMID- 17701918 TI - Cell contribution of vasa-vasorum to early arterial intimal thickening formation. AB - In occluded femoral artery segments, intimal thickening occurred and abundant neovascularization from the surrounding microcirculation developed. Under these conditions, the contribution of vasa-vasorum as a source of supplementary population of cells during the early intimal thickening formation was studied. Using a technique that specifically labels venules, predominantly postcapillary venules, a marker-Monastral Blue B-was used as a tracer to follow the pericyte, endothelial cell and monocyte/macrophage lineages. In the first two days of the experiment, the marker was restricted to the wall of the periarterial microcirculation, being incorporated by endothelial cells, pericytes and some monocytes/macrophages crossing the venule walls. Later, the marker continues to be observed in some of the following cells: endothelial cells and pericytes of the newly-formed vessels, fibroblast-like cells, transitional cells between pericytes and fibroblast-like cells, macrophages migrating into the interstitium, myointimal cells and neoendothelial cells of the arterial lumen. These findings provide evidence that, during arterial intimal thickening formation in occluded arterial segments, the periarterial microvascularization contributes, in addition to recruited macrophages, newly-formed endothelial cells and a supplementary population of fibroblast-like cells and myointimal cells. PMID- 17701919 TI - NFKB and NFKBI polymorphisms in relation to susceptibility of tumour and other diseases. AB - Nuclear factor-kappaB (NF-kappaB) is responsible for the expression by regulating many genes for immune response, cell adhesion, differentiation, proliferation, angiogenesis and apoptosis. The function of NF-kappaB is inhibited by binding to NF-kappaB inhibitor (IkappaB), and imbalance of NF-kappaB and IkappaB has been associated with development of many diseases, including tumours. In this review, we focus on polymorphisms of the NFKB and NFKBI genes in relation to development of common inflammatory diseases including ulcerative colitis (UC), Crohn's disease (CD), rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, giant cell arthritis, type 1 diabetes, multiple sclerosis, celiac disease, and Parkinson's disease, as well as susceptibility of several cancers, such as oral squamous cell carcinoma, colorectal cancer (CRC), hepatocellular carcinoma, breast cancer and myeloma. PMID- 17701920 TI - Morphological and functional changes in experimental ocular hypertension and role of neuroprotective drugs. AB - Glaucoma is a neurodegenerative disease characterized by progressive loss of retinal ganglion cell axons and their cell bodies in the retina. Elevated intraocular pressure (IOP) is considered to be the major risk factor associated with the development of this neuropathy. Randomized controlled clinical trials have demonstrated that in some patients the disease progresses, even after lowering the IOP. Several researchers have devised ways to induce elevated IOP in the rat eye with the aim of impeding the flow of aqueous humour out of the eye. Chronic ocular hypertension in rats induces morphofunctional changes in the optic nerve head and retina. Death of ganglion cells is thought to follow an apoptotic pathway. Changes have also been reported in neuronal and non-neuronal cells, levels of cyclooxygenase, and nitric oxide synthase, endothelin 1 and brain derived neurotrophic factor. Other mechanisms include intracellular electrolyte imbalance, microglial phagocytosis and elevated glutamate levels. Neuroprotection is the treatment strategy by preventing neuronal death. Hypotensive drugs (beta blockers, alpha-agonists and prostaglandins), Ca++ channel blockers, NMDA antagonists and nitric oxide synthase inhibitors have been used as neuroprotective drugs in experimental models of glaucoma. PMID- 17701921 TI - Epigenetic remodelling of DNA in cancer. AB - DNA methylation regulates gene expression in normal cells. This epigenetic mechanism acts in at least two different ways: at global genomic level by targeting repetitive sequences distributed among the whole genome (LINEs, SINEs, satellite DNA, transposons) and at local level by targeting CpG islands in promoter regions. Both epigenetic mechanisms are involved in the carcinogenetic process; however, different evidences suggest that promoter hypermethylation occurring in genes involved in cell-cycle regulation, DNA repair, cell signalling, transcription and apoptosis likely plays a prominent role. Opposite to genetic defects DNA hypermethylation is a reversible process that can be handled through "epigenetic drugs" in a wide spectrum of tumors. Along this line, recent data have demonstrated the ability of DNA hypomethylating agents to up regulate and/or induce the expression of genes silenced by promoter hypermethylation in cancer. Particularly relevant seems the ability of these drugs to modulate the expression of genes coding for molecules crucial for tumor immunogenicity and immune recognition of neoplastic cells by host's immune system, such as Cancer Testis Antigens, HLA class I molecules, costimulatory molecules. These evidences, coupled to the well-known cytotoxic, pro-apoptotic, and differentiating activities of epigenetic drugs, encourage to design and to develop new therapeutic strategies able to circumvent the immune escape of neoplastic cells and to potentiate the efficacy of immunotherapy in cancer patients. This review will provide an update on the most recent information about aberrant DNA methylation in cancer and on innovative therapeutic strategies of "epigenetic remodelling" of human malignancies, with particular attention to the immunologic and immunotherapeutic potential of this approach. PMID- 17701923 TI - Penile replantation, science or myth? A systematic review. AB - INTRODUCTION: Penile amputation is a rare urologic condition for which immediate surgical replantation is warranted. The surgical technique used for repair has been modified and refined. Our aim was to assess the effects of several interventions and management for amputated penis after replantation. MATERIALS AND METHODS: We searched the MEDLINE (January 1966 to May 2007), EMBASE (January 1988 to January 2007), CINAHL (January 1982 to January 2007), PsycLIT (January 1984 to January 2007), ERIC (January 1984 to January 2007), and the bibliographic data of relevant articles; hand-searched conference proceedings; and contacted investigators to locate studies. All reported cases of penile replantation were studied. We assessed all titles, abstracts, and extracted data from the articles identified for inclusion. Outcome measures included cosmetic outcomes, acceptability, operative time, restoration of erectile function, sensibility of the glans, and long-term outcomes. RESULTS: Eighty patients had undergone penile replantation. There was considerable variation in the interventions, patients, and outcome measures. The majority of the reported cases in this area continue to be of moderate quality, although more recent cases have been of higher quality in terms of both patients' demographics and surgical techniques. Data were not available in all of the cases for many of the outcomes expected to be reported. There were several important variations in the cases studied. CONCLUSION: The value of the various microsurgical techniques for replantation of the penis remains uncertain. Meticulous microsurgical techniques by experienced surgeons can reduce skin, urethra, and graft loss complications and produce a functional organ; nonetheless, such complications are still highly prevalent. PMID- 17701924 TI - Renal replacement therapy in Iran. PMID- 17701925 TI - Human amniotic membrane as a suitable matrix for growth of mouse urothelial cells in comparison with human peritoneal and omentum membranes. AB - INTRODUCTION: For tissue engineering of the urinary tract system, cell culture requires to be established in vitro and an appropriate matrix acting as cell carrier should be developed. The aim of the present study was to assess the proliferation quality of mouse urothelial cells on 3 natural matrixes of human amniotic membrane (AM), peritoneum, and omentum, and to compare them with collagen matrix. MATERIALS AND METHODS: Mouse urothelial cells were isolated by collagenase IV, and the urothelial cells (105 cells per milliliter) were cultured on the AM, peritoneum, omentum, and collagen. The pattern of growth and asymmetric unit membrane formation were analyzed by histologic examination and immunocytochemistry on the detached urothelium with pancytokeratin and uroplakin III, respectively. Electron micrographs were taken and cell layers, organelles, desmosomes, and junctions were studied. RESULTS: Immunocytochemistry of cultivated cells confirmed the urothelial cells phenotype. Up to 4 cell layers were obtained on the AM and 1 to 2 layers on the peritoneum. Distribution of the urothelial cells on the omentum was not favorable, which was due to its large pores. Cell proliferation started later on the AM (7th day) compared to collagen (3rd day). Also, apoptosis started later on the AM (after 14 days) compared to collagen (7 days). CONCLUSION: These results showed that the AM can act as a cell carrier for culture of the urothelial cells, and its exceptional properties such as having various growth factors, availability, and cost-effectiveness make it a unique biological matrix for urothelial culture. PMID- 17701926 TI - Blind puncture in comparison with fluoroscopic guidance in percutaneous nephrolithotomy: a randomized controlled trial. AB - INTRODUCTION: Our aim was to evaluate blind puncture in percutaneous nephrolithotomy (PCNL) for decreasing the risk of radiation. MATERIALS AND METHODS: One hundred candidates for PCNL were randomly assigned into 2 groups. Blind access was performed for the patients in group 1 and the standard access using fluoroscopy for those in group 2. In group 1, displacement of the targeted calyx in the prone position was estimated by fluoroscopy comparing to the image on intravenous urography. Puncture of the calyx was attempted 3 cm to 4 cm below the marked site of the targeted calyx with a 30 angle. If the access to the collecting system was felt and urine came out, the site of puncture would be controlled by fluoroscopy. If the access failed, we would repeat puncturing up to 5 times. RESULTS: The mean time to access was 6.6 +/- 2.1 minutes and 5.5 +/- 1.7 minutes in groups 1 and 2, respectively (P = .008). The mean time of radiation exposure was 0.95 +/- 0.44 minutes in group 2. A successful puncture to the targeted calyx was achieved in 50% and 90% of the patients in groups 1 and 2, respectively (P < .001) and a successful calculus removal in 62% and 100% of the patients in groups 1 and 2 (P < .001). CONCLUSION: Although about half of the patients benefited from blind access in our study, this technique can not be solely relied on, and fluoroscopy or ultrasonography should be available for prevention of complications. PMID- 17701927 TI - Ethanolic extract of nigella sativa L seeds on ethylene glycol-induced kidney calculi in rats. AB - INTRODUCTION: The aim of this study was to investigate the effects of the ethanolic extract of Nigella sativa L (NS) seeds on kidney calculi in rats. MATERIALS AND METHODS: Thirty-two Wistar rats were randomly divided into 4 groups: group A received tap drinking water for 30 days (intact control). Groups B, C, and D received 1% ethylen glycol for induction of calcium oxalate calculus formation. As the preventive, and treatment subjects, rats in groups C and D received ethanolic extract of NS, 250 mg/kg, in drinking water since day 0 and day 14, respectively. Urine was collected on days 0, 7, 14, and 30 of the study period. After 30 days, the kidneys were removed and prepared for histologic evaluation of calcium oxalate deposits. Urine calcium oxalate concentrations were determined by atomic absorption. RESULTS: The number of CaOx deposits was significantly greater in group B (P = .001). Calcium oxalate concentrations in the urine on days 14 and 30 increased significantly in group B and were higher than those in group C (P = .006 and P = .002, respectively). Urine oxalate concentration in group D decreased on day 30 and was lower than that in group B (P = .04). CONCLUSION: Treatment of rats with ethanolic extract of NS reduced the number of calcium oxalate deposits in a group of rats that received ethanolic extract of NS. The NS could also lower the urine concentration of calcium oxalate. We suggest further studies on the therapeutic and preventive effects of the NS on kidney calculus formation in human. PMID- 17701928 TI - Urinary tract infection in term neonates with prolonged jaundice. AB - INTRODUCTION: The aim of this study was to evaluate the frequency of urinary tract infection (UTI) in neonates with prolonged jaundice. MATERIALS AND METHODS: Newborn infants with jaundice lasted more than 2 weeks were included in this study. Patients who had other signs or symptoms were excluded. Workup of prolonged hyperbilirubinemia was performed, including direct Coomb's test, blood group of the neonate and the mother, complete blood count, blood smear, glucose-6 phosphate dehydrogenase (G6PD), reticulocyte count, serum level of bilirubin (unconjugated and conjugated), thyroid function tests (serum thyroxine [T4] and thyroid-stimulating hormone), urinalysis, and suprapubic urine culture. Pediatric nephrologists carried out further investigation including kidney function tests, renal ultrasonography, voiding cystourethrography, and Technetium Tc 99m dimercaptosuccinic acid renal scintigraphy for patients with a positive urine culture for microorganisms. RESULTS: Of 100 neonates who were evaluated, 43 were boys and 57 were girls. All of the neonates were breastfed. Six suffered from UTI (4 boys and 2 girls). Reflux was detected on voiding cystourethrography in 1 and cortical defect in the kidney on renal scan in 2 boys. CONCLUSION: In our region, with a high rate of breastfeeding, UTI remains as an important cause of prolonged jaundice. Despite the high rate of urogenital system abnormality accompanied by neonatal UTI, there was not a significant difference between the signs and symptoms of jaundice in patients with and without UTI. Performing urine cultures should be considered as a routine procedure in the evaluation of every infant with prolonged jaundice. PMID- 17701929 TI - Role of PTEN gene in progression of prostate cancer. AB - INTRODUCTION: The aim of this study was to clarify the role of PTEN gene in progression of prostate cancer. MATERIALS AND METHODS: A total of 51 formalin fixed paraffin-embedded specimens of prostate cancer were analyzed for PTEN mutations. Tissue microdissection and polymerase chain reaction/single-strand conformation polymorphism methods were used. Clinical and pathologic data of the patients were reviewed with regard to PTEN mutation. RESULTS: The Gleason score (GS) was less than 7 in 29 (56.8%), 7 in 11 (21.6%), and greater than 7 in 11 (21.6%). Tumor stage was IIa, IIb, IIc, and IV in 14 (27.4%), 4 (7.8%), 21 (41.2%), and 12 (23.6%) patients, respectively. Eleven of 12 stage IV tumors had metastases at the time of presentation. Six of 51 cases (11.6%) showed mutation in PTEN which had involved exones 1, 2, and 5. Two of these cases had localized and the others had advanced prostate cancer. One case of the tumors with PTEN mutation had a GS of 7 and 5 had GSs greater than 7. Patients with a positive mutation of PTEN had a significantly greater GS (P < .001), lower survival rate (P = .001), higher tendency to metastasis (P = .002), and higher prostate specific antigen (P = .03). Cox proportional hazard model showed that only GS was significantly correlated with mortality (P = .03). CONCLUSION: Patients with prostate cancer who had PTEN mutation had also a significantly greater GS, poorer prognosis, and higher rate of metastasis. However, this mutation cannot predict the prognosis and the GS is a more precise factor. PMID- 17701930 TI - Relation between HER-2 gene expression and Gleason score in patients with prostate cancer. AB - INTRODUCTION: HER-2 is a proto-oncogene of the tyrosine kinase receptor family on chromosome 17. Overexpression of this gene affects the growth and prognosis of some tumors. This study was performed to evaluate the expression of the HER-2 gene in patients with prostate cancer and its relation with the Gleason score. MATERIALS AND METHODS: Pathology specimens of all men with prostate cancer who had undergone radical prostatectomy without any supportive treatment were studied. The Gleason scores of the specimens and the expression of HER-2 gene were examined. The expression of HER-2 was scored between zero and 3+ in accordance with the HercepTest method. Patients with scores of 2+ and 3+ were considered to be positive for HER-2 overexpression. RESULTS: Of 150 cancerous prostate specimens evaluated, 20 (13.3%) were positive for HER-2 gene overexpression. A weakly positive HER-2 overexpression (2+) was seen in 15 of them (75%) and the remaining 5 (25%) were strongly positive. The Gleason score was not different between the HER-2-positive and HER-2-negative patients (P = .08). Fourteen out of 97 patients (14.4%) with a Gleason score less than 7 and 6 out of 53 (11.3%) with scores of 7 or greater were positive for HER-2 overexpression. CONCLUSION: The frequency of HER-2 gene overexpression is not very high in our patients with prostate cancer, and we failed to show any association of HER-2 expression and the Gleason score. PMID- 17701931 TI - Atherosclerosis after kidney transplantation: changes of intima-media thickness of carotids during early posttransplant period. AB - INTRODUCTION: The aim of this study was to evaluate atherosclerotic changes in the carotid artery following kidney transplantation. MATERIALS AND METHODS: Twenty-six nonsmoker kidney allograft recipients who did not have cardiovascular disease or diabetes mellitus were enrolled in the study. The carotid intima-media thickness (IMT) was measured at 12 points using B-mode ultrasonography. The mean of the measured values was considered as the patient's IMT. We followed the patients and changes in the carotid IMT were evaluated every 2 months up to the 6th posttransplant month. RESULTS: The mean age of the patients at transplantation was 41.5 +/- 11.1 years. The mean baseline IMT was 0.84 +/- 0.22 mm. During the follow-up period it reached 0.85 +/- 0.22 mm, 0.87 +/- 0.23 mm (P = .01), and 0.88 +/- 0.24 mm (P = .002) after 2, 4, and 6 months, respectively. The IMT measures significantly correlated with the age and body mass index. Using the IMT cutoff points of 0.75 mm for stroke and 0.82 mm for MI, we found that 57.7% and 68% of the patients were at the risk of stroke at baseline and 6 months after transplantation (P < .001). Also, 46.2 % of the patients were at the risk of MI at baseline that rose to 53.8% at the end of the study (P < .001). CONCLUSION: Atherosclerosis is an early event after kidney transplantation even in asymptomatic patients and those without major risk factors such as cardiovascular disease, diabetes mellitus, and smoking. Early diagnosis and treatment of atherosclerosis is of utmost importance. PMID- 17701933 TI - Hygroma renalis: an extremely rare renal lesion. PMID- 17701932 TI - Sexual dysfunction in epileptic men. AB - INTRODUCTION: The aim of this study was to evaluate the frequency of sexual dysfunction among epileptic patients. MATERIALS AND METHODS: Eighty married men between 22 and 50 years with a confirmed diagnosis of epilepsy were enrolled in this study. Patients with other neurological diseases, hypertension, cardiovascular diseases, diabetes mellitus, underlying urogenital diseases, and impaired general health status were excluded. Furthermore, those with mental health problems were identified by the standardized General Health Questionnaire 28 and were excluded. Demographic and clinical characteristics of the disease were evaluated, and sexual function was assessed by the self-administered questionnaire of the International Index of Erectile Function-15 (IIEF-15). RESULTS: Of 80 patients, 34 (42.5%) had erectile dysfunction. There were no differences between the patients in the 3 age groups in the IIEF scores. Type of seizure had a significant correlation with erectile function score (P = .008). None of the IIEF domains scores were different between the patients with controlled epilepsy and those with uncontrolled epilepsy during the previous 6 months. However, frequency of epileptic seizures (before treatment) correlated with the scores for erectile function (r = 0.31; P = .005), orgasmic function (r = 0.23; P = .04), and sexual desire (r = 0.24; P = .03). CONCLUSION: It seems that the main aspects of sexual activity such as erectile function, orgasmic function, and sexual desire are frequently impaired in epileptic patients. Our findings were also indicative of a higher risk of sexual dysfunction in patients with partial seizures. PMID- 17701934 TI - Results of inadvertent administration of bacillus Calmette-Guerin for treatment of transitional cell carcinoma of bladder. PMID- 17701935 TI - Bladder perforation during laparoscopic donor nephrectomy. PMID- 17701936 TI - Urology as a specialty in the history of contemporary medicine in Iran. PMID- 17701937 TI - Predictive value of common symptom combinations in diagnosing colorectal cancer. AB - BACKGROUND: This study compared the diagnostic values of age and single symptoms of colorectal cancer with those of age and symptom combinations. METHODS: Consecutive patients with lower gastrointestinal symptoms referred to a surgical clinic over a 12-year period were studied prospectively. The diagnostic value of age and common symptoms of bowel cancer, individually and in combination, was determined by measuring positive predictive value, sensitivity and specificity. RESULTS: In total, 467 (5.5 per cent) of 8529 patients had colorectal cancer. Symptom combination analyses showed that patients presenting with rectal bleeding and change in bowel habit without anal symptoms had the highest risk of cancer. Those with rectal bleeding and perianal symptoms without change in bowel habit were at the lowest risk of having cancer. Symptom subgroups defined by age had positive predictive values for cancer that varied from less than 1 to 35 per cent. CONCLUSION: Symptom combinations defined by age have greater diagnostic value than single symptoms alone. PMID- 17701938 TI - Laparoscopic subtotal cholecystectomy without cystic duct ligation. AB - BACKGROUND: Cholecystectomy is made hazardous by distortion of the anatomy of Calot's triangle by acute or chronic inflammation. Laparoscopic subtotal cholecystectomy (LSTC) without cystic duct ligation is an alternative to conversion to open surgery in difficult cases. METHODS: This prospective study included all cholecystectomies performed in a district general hospital upper gastrointestinal unit between 2003 and 2005, after the introduction of LSTC. RESULTS: Of 889 laparoscopic cholecystectomies, 28 LSTCs without cystic duct ligation were performed in 18 men and ten women of median age 68 years. Median operating time was 90 min and median duration of hospital stay was 3 days. Two temporary bile leaks resolved spontaneously on days 14 and 19. Three patients required endoscopic retrograde cholangiopancreatography, extraction of bile duct stones and stent insertion for persistent leaks. All five bile leaks were expected from peroperative findings. One patient had a myocardial infarction and one developed a subphrenic abscess. There were no deaths. Open conversion rates were reduced from 5.0 per cent in 1997-2002 to 0.3 per cent in 2005 (P < 0.001). CONCLUSION: LSTC without cystic duct ligation is an alternative to open conversion when dissection of Calot's triangle is hazardous. Bile leaks are predictable and readily managed. PMID- 17701939 TI - Neoadjuvant chemotherapy for operable breast cancer. AB - BACKGROUND: Neoadjuvant chemotherapy for early breast cancer can avoid mastectomy by shrinkage of tumour volume. This review assesses the effectiveness of neoadjuvant chemotherapy on clinical outcome. METHODS: All randomized trials comparing neoadjuvant and adjuvant chemotherapy for early breast cancer were reviewed systematically and meta-analyses were performed. RESULTS: Fourteen studies randomizing 5500 women were eligible for analysis. Overall survival was equivalent in both groups. In the neoadjuvant group, the mastectomy rate was lower (relative risk 0.71 (95 per cent confidence interval (c.i.) 0.67 to 0.75)) without hampering local control (hazard ratio 1.12 (95 per cent c.i. 0.92 to 1.37)). Neoadjuvant chemotherapy was associated fewer adverse effects. CONCLUSION: Neoadjuvant chemotherapy is an established treatment option for early breast cancer. PMID- 17701940 TI - Developing theory in a practice profession. PMID- 17701941 TI - Developing a parenting skills-and-support intervention for mothers with eating disorders and pre-school children part 1: Qualitative investigation of issues to include. AB - OBJECTIVE: This study aimed to (i) identify themes and issues that might usefully be addressed in a skills-and-support intervention for mothers with eating disorders who have children less than 5 years of age, and (ii) determine the most appropriate format for such an intervention. METHOD: Focus groups and individual interviews were conducted with seven mothers with eating disorders and pre-school children, and four local health professionals working with mothers of pre-school children. RESULTS: Thematic analysis of interview transcripts revealed 10 themes: 'Passing on Traits', 'Food Preparation and Provision', 'Interactions Around Food and Mealtimes', 'Mother's Intake', 'Self Care', 'Self Identity and Parental Expectations', 'Impact on General Parent-Child Relationship', 'Need for Control', 'The Group Experience' and 'Practicalities and Format'. DISCUSSION: Findings highlight a number of difficulties and concerns experienced by mothers with eating disorders who have pre-school age children. An intervention incorporating the identified themes could provide important support to this patient group and potential benefit to their offspring. PMID- 17701942 TI - The experience of 'feeling fat' in women with anorexia nervosa, dieting and non dieting women: an exploratory study. AB - OBJECTIVE: To provide a preliminary, systematic exploration of some features associated with the experience of 'feeling fat'. METHOD: Women with anorexia nervosa (N = 16), women who were dieting (N = 15) and non-dieting women (N = 17) took part in a semi-structured interview. RESULTS: Feeling fat was common in all three groups of women. It was associated with distress, negative emotions, internal and external body sensations, images in a range of modalities, negative self beliefs and a first memory of feeling fat. Differences specifically characteristic of those with anorexia nervosa were identified, including feeling fatter, greater associated distress, more negative emotions, greater 'emotional' belief in cognitions, a richer experience, an earlier first memory, greater strength of negative self beliefs and a link to restricting behaviour. Some qualitative data are reported. CONCLUSIONS: The experience of feeling fat can be 'unpacked' in a way that may be useful in cognitive therapy for those with anorexia nervosa. PMID- 17701943 TI - Recurrent binge eating (RBE) and its characteristics in a sample of young women in Germany. AB - OBJECTIVE: To examine the characteristics of recurrent binge eating (RBE) in a non-treatment-seeking sample from the general population. RBE individuals are described in terms of socio-economic status, general psychopathology, and comorbidity rates of mental disorders. METHOD: Participants were 1877 German females aged 18-24 years from a population-based epidemiological study. RESULTS/DISCUSSION: The point prevalence of RBE in our sample was 0.9% (N = 17). Compared to healthy women, subjects with RBE suffered more often from comorbid mental disorders and also exhibited more general psychopathology: They were similar to women with other mental disorders and other eating disorders (EDs). RBE seems to be a syndrome of clinical significance itself and might be an important risk factor for the development of further EDs, especially binge eating disorder (BED) and other mental disorders. PMID- 17701944 TI - Eating disorder not otherwise specified in an inpatient unit: the impact of altering the DSM-IV criteria for anorexia and bulimia nervosa. AB - OBJECTIVE: To evaluate (1) the Eating Disorder Not Otherwise Specified (EDNOS) prevalence in an eating disorder inpatient unit; (2) the impact of altering the diagnostic criteria for anorexia nervosa and bulimia nervosa on the prevalence of EDNOS. METHOD: One hundred and eighty six eating disorder patients consecutively hospitalised were included in the study. The prevalence of anorexia nervosa, bulimia nervosa and EDNOS was evaluated with the Eating Disorder Examination (EDE). The EDNOS prevalence was recalculated after the alteration of three diagnostic criteria for anorexia nervosa and one for bulimia nervosa. RESULTS: Seventy eight patients (41.9%) met the diagnostic criteria for anorexia nervosa, 33 (17.8%) for bulimia nervosa and 75 (40.3%) for EDNOS. The alteration of the DSM-IV diagnostic criteria reduced the prevalence of EDNOS to 28 cases (15%). CONCLUSION: EDNOS is a very frequent diagnostic category in an inpatient setting. Altering the diagnostic criteria for anorexia nervosa and bulimia nervosa reduced significantly the prevalence of EDNOS. PMID- 17701945 TI - Illness perception in eating disorders and psychosocial adaptation. AB - OBJECTIVE: The current study is based on the framework of the Self-Regulatory Model of Illness (SRM). The aim of this work was to examine perception of illness in eating disorder (ED) patients and investigate whether illness perception is related to psychosocial adaptation in these patients. METHOD: A total of 98 female ED patients completed the specific eating disorders Spanish version of the Revised Illness Perception Questionnaire (IPQ-R) and a range of adjustment variables including the Psychosocial Adjustment to Illness Scale (PAIS) and the Hospital Anxiety and Depression Scale (HAD). RESULTS: ED patients reported a moderate number of physical symptoms, and perceived their illness as controllable, treatable, highly distressing, as a chronic condition and with serious consequences. Emotional representation was the most significant dimension related to emotional adjustment. Illness identity and cure dimensions were the most significant dimensions associated with psychosocial adaptation. CONCLUSION: This study shows that patients' illness perceptions are related to illness adaptation. Illness identity was associated with emotional and psychosocial adjustment, and having faith that treatment may control the illness was related to positive benefits for ED. These results suggest that a psychological intervention, which addresses patients' illness representations, may assist in their adjustment to ED. PMID- 17701946 TI - Which elements in the treatment of eating disorders are necessary 'ingredients' in the recovery process?--A comparison between the patient's and therapist's view. AB - BACKGROUND: Little is known about which therapeutic 'ingredients' in the treatment of eating disorders (anorexia nervosa (AN), bulimia nervosa (BN) and binge eating disorder (BED)) are needed for recovery. Remarkably, most studies on this topic have neglected the patient's view. METHOD: In this study, a large sample of eating disorder patients (n = 132) was invited to evaluate which elements in the treatment they consider to be helpful and effective in their recovery process. These results were compared to the view of 49 eating disorder experts. RESULTS: Following the patient's view, 'improving self-esteem', 'improving body experience' and 'learning problem solving skills', were considered as core elements in their treatment. No major differences were found between the different patient samples when comparing the patient's and therapist's view. DISCUSSION: The findings suggest that therapists and patients share more or less the same view about the basic and effective elements in the treatment. PMID- 17701948 TI - Within-stage racial differences in tumor size and number of positive lymph nodes in women with breast cancer. AB - BACKGROUND: Black women have higher breast cancer mortality rates, are more likely to be diagnosed at an advanced stage of disease, and have worse stage-for stage survival than white women. It was hypothesized that differences in the tumor size and number of positive lymph nodes within each disease stage contribute to the survival disparity. METHODS: In the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, black and white women diagnosed with a first primary tumor (TNM stage I-IIIA breast cancer) between 1988 and 2003 were identified. The demographic and clinical characteristics were compared by race. Logistic regression models of the association between race and tumor size and lymph node status were developed. Cox proportional hazards models of the association between mortality and race, tumor size, lymph node status, and other covariates were also examined. RESULTS: Among 256,174 SEER cases (21,861 black and 234,313 white women), more black than white women with lymph node-negative breast cancer had tumors measuring >or=2.0 cm. Adjusted for tumor size, more black than white women had >or=1 positive lymph nodes (odds ratio [OR], 1.24; 95% confidence interval [95% CI], 1.20-1.28). The age-adjusted and TNM stage-adjusted mortality rate ratio for blacks versus whites was 1.56 (95% CI, 1.51-1.61). Adjustment for within-stage differences in tumor size and lymph node involvement were found to have a negligible effect. With adjustment for additional covariates, the rate ratio was 1.39 (95% CI, 1.35 1.44). In addition, the rate ratio reflecting racial disparity increased as the stage of disease increased. CONCLUSIONS.: Adjusting for within-stage differences in tumor size and lymph node status did not appear to reduce the racial disparity. The finding that disparities increased with higher stage of disease suggests that interventions aimed at reducing these differences should target women with more advanced disease. PMID- 17701949 TI - Randomized clinical trial comparing partial parotidectomy versus superficial or total parotidectomy. AB - BACKGROUND: In recent decades the treatment of benign parotid tumours has shifted from superficial or total parotidectomy to partial parotidectomy. This study examined whether current surgical techniques improved functional outcomes after surgery for benign parotid tumours. METHODS: One hundred and one patients were assigned randomly to conventional (49 patients) or function-preserving (52) surgery. The latter consisted of modified facelift incision, greater auricular nerve preservation, partial parotidectomy and coverage with parotid fascia. RESULTS: The mean duration of operation was 0.7 h shorter and the overall complication rate significantly lower in the functional surgery group. In this group, more patients were satisfied with their scars and facial contours, the auricular nerve sensory recovery rate was high, and transient facial paralysis and Frey's syndrome were infrequent (12 and 6 per cent respectively). Stimulated salivary flow on the operated side decreased to 71.9 per cent after function preserving surgery compared with 20.7 per cent after conventional operation. There was no tumour recurrence in either group during a mean follow-up of 48 months. CONCLUSION: Compared with conventional procedures, function-preserving surgery for benign parotid tumours improved cosmetic, sensory and salivary functions, and reduced the duration of surgery and operative morbidity. PMID- 17701950 TI - Smooth bootstrap methods for analysis of longitudinal data. AB - In analysis of longitudinal data, the variance matrix of the parameter estimates is usually estimated by the 'sandwich' method, in which the variance for each subject is estimated by its residual products. We propose smooth bootstrap methods by perturbing the estimating functions to obtain 'bootstrapped' realizations of the parameter estimates for statistical inference. Our extensive simulation studies indicate that the variance estimators by our proposed methods can not only correct the bias of the sandwich estimator but also improve the confidence interval coverage. We applied the proposed method to a data set from a clinical trial of antibiotics for leprosy. PMID- 17701951 TI - Differences in prognostic factors and survival among white and Asian men with prostate cancer, California, 1995-2004. AB - BACKGROUND: There are very limited data concerning survival from prostate cancer among Asian subgroups living in the U.S., a large proportion of whom reside in California. There do not appear to be any published data on prostate cancer survival for the more recently immigrated Asian subgroups (Korean, South Asian [SA], and Vietnamese). METHODS: A study of prognostic factors and survival from prostate cancer was conducted in non-Hispanic whites and 6 Asian subgroups (Chinese, Filipino, Japanese, Korean, SA, and Vietnamese), using data from all men in California diagnosed with incident prostate cancer during 1995-2004 and followed through 2004 (n = 116,916). Survival was analyzed using Cox proportional hazards models. RESULTS: Whites and Asians demonstrated significant racial differences in all prognostic factors: age, summary stage, primary treatment, histologic grade, socioeconomic status, and year of diagnosis. Every Asian subgroup had a risk factor profile that put them at a survival disadvantage compared with whites. Overall, the 10-year risk of death from prostate cancer was 11.9%. However, in unadjusted analyses Japanese men had significantly better survival than whites; Chinese, Filipino, Korean, and Vietnamese men had statistically equal survival; and SA men had significantly lower survival. On multivariate analyses adjusting for all prognostic factors, all subgroups except SA and Vietnamese men had significantly better survival than whites; the latter 2 groups had statistically equal survival. CONCLUSIONS: Traditional prognostic factors for survival from prostate cancer do not explain why most Asian men have better survival compared with whites, but they do explain the poorer survival of SA men compared with whites. PMID- 17701952 TI - Young age colorectal cancer and identification of hereditary non-polyposis colorectal cancer cohorts. PMID- 17701955 TI - Retroperitoneal sarcoma. PMID- 17701954 TI - Tyrosine kinase inhibitors for the treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is a heterogeneous disorder, with the greatest prevalence in children, but it also affects adults, and has an increasing incidence with age. Chromosomal abnormalities in ALL have been frequently described, the most common is the Philadelphia chromosome (Ph). The resulting fusion gene, BCR-ABL1, encodes for a chimerical oncoprotein (BCR-ABL) with constitutive tyrosine kinase activity, which leads to uncontrolled cell proliferation, reduced apoptosis, and impaired cell adhesion. Treating Philadelphia chromosome-positive (Ph+) ALL patients with conventional chemotherapy has not substantially improved their long-term outcomes. Recently, however, BCR-ABL-targeted strategies have been successfully adopted. Imatinib is an oral competitive inhibitor of ABL with demonstrated phase 2 efficacy in patients with treatment-naive and pretreated ALL. Despite its efficacy, imatinib may induce specific resistance in a large proportion of patients, mainly because of the occurrence of ABL1 mutations. Therefore, novel inhibitors have been developed. Dasatinib is a multitargeted kinase inhibitor of BCR-ABL, SRC, C-KIT, PDGFRs, and ephrin A receptor kinases. Unlike imatinib, it binds both the active and inactive BCR-ABL as well as the majority of ABL mutants. Dasatinib is approved for treatment of imatinib-pretreated Ph+ ALL, and chronic myeloid leukemia (CML) on the basis of phase 2 trials that demonstrated impressive efficacy and favorable tolerability profiles. Nilotinib is another BCR-ABL targeted agent that is similar in structure to imatinib but has significantly greater binding affinity. It also has demonstrated promising efficacy in Ph+ ALL but is still being evaluated in phase 2 trials. In this article, the authors reviewed current knowledge on novel tyrosine-kinase inhibitors in adult Ph+ ALL patients. PMID- 17701956 TI - Therapy may unmask hypoplastic myelodysplastic syndrome that mimics aplastic anemia. AB - BACKGROUND: Rarely, patients who present with pancytopenia and are diagnosed initially with aplastic anemia (AA) subsequently develop a myelodysplastic syndrome (MDS). There has been controversy regarding whether the initial diagnosis of AA is correct or whether these patients have hypocellular MDS at the onset of pancytopenia. METHODS: The authors studied bone marrow (BM) specimens from patients who were diagnosed initially with AA and subsequently with MDS from a cohort of 128 consecutive patients who had AA during the period from 1993 to 2004. Cytogenetic and fluorescence in situ hybridization (FISH) analyses were performed to assess for monosomy 7 retrospectively in a subset of patients. RESULTS: Twelve patients were identified (age range, 26-79 years). At the time they were diagnosed with AA, there was no evidence of dysplasia, the median BM cellularity was 5% (range, from <1% to 15%), and all patients had a normal karyotype. Therapy for 11 patients included immunomodulating agents, which were accompanied by growth factors in 4 patients and 1 patient underwent BM transplantation. One patient received growth factors only. The median interval to the diagnosis of MDS was 9 months (range, 2-43 months). The median BM cellularity was 30% (range, 5-90%), and dysplastic changes were observed in all patients. Nine patients had an abnormal karyotype, and monosomy 7 was the most common abnormality (n = 5 patients). FISH detected monosomy 7 in 6 samples at the time MDS was diagnosed and in 2 samples at the time AA was diagnosed. CONCLUSIONS: The detection of monosomy 7 in specimens that were considered AA and the short time interval to a subsequent diagnosis of MDS suggests that these patients had hypoplastic MDS at the onset of pancytopenia. Therapy may allow the detection of MDS by enhancing cell growth. PMID- 17701957 TI - Magnetic resonance image-guided salvage brachytherapy after radiation in select men who initially presented with favorable-risk prostate cancer: a prospective phase 2 study. AB - BACKGROUND: The authors prospectively evaluated the late gastrointestinal (GI) and genitourinary (GU) toxicity and prostate-specific antigen (PSA) control of magnetic resonance imaging (MRI)-guided brachytherapy used as salvage for radiation therapy (RT) failure. METHODS: From October 2000 to October 2005, 25 men with a rising PSA level and biopsy-proven, intraprostatic cancer at least 2 years after initial RT (external beam in 13 men and brachytherapy in 12 men) who had favorable clinical features (Gleason score < or =7, PSA < 10 ng/mL, negative pelvic and bone imaging studies), received MRI-guided salvage brachytherapy to a minimum peripheral dose of 137 gray on a phase 1/2 protocol. Estimates of toxicity and cancer control were calculated using the Kaplan-Meier method. RESULTS: The median follow-up was 47 months. The 4-year estimate of grade 3 or 4 GI or GU toxicity was 30%, and 13% of patients required a colostomy and/or urostomy to repair a fistula. An interval < 4.5 years between RT courses was associated with both outcomes with a hazard ratio of 12 (95% confidence interval [95% CI], 1.4-100; P = .02) for grade 3 or 4 toxicity and 25 (95% CI, 1.1-529; P = .04) for colostomy and/or urostomy. PSA control (nadir +2 definition) was 70% at 4 years. CONCLUSIONS: The current results indicated that MRI-guided salvage brachytherapy in men who are selected based on presenting characteristics and post-failure PSA kinetics can achieve high PSA control rates, although complications requiring surgical intervention may occur in 10% to 15% of patients. Prospective randomized studies are needed to characterize the relative cancer control and toxicity after all forms of salvage local therapy. PMID- 17701958 TI - Autoimmune pancreatitis. AB - BACKGROUND: Approximately 2 per cent of pancreatic masses resected for suspected malignancy are found instead to be a form of chronic pancreatitis defined by a characteristic lymphoplasmacytic infiltrate. This condition is now commonly classified as 'autoimmune pancreatitis'. METHODS: A literature review of autoimmune pancreatitis was performed using Medline and PubMed. The reference lists of identified articles were searched for further relevant publications. RESULTS: Patients are predominantly 55-65 years old and present with obstructive jaundice, abdominal pain and weight loss. Imaging may show a mass of malignant appearance or pancreatobiliary tree strictures precipitating surgical exploration. Raised serum levels of IgG4 and specific autoantibodies, when combined with particular radiological features and a biopsy negative for malignancy, enable a preoperative diagnosis and successful treatment with steroids. CONCLUSION: Autoimmune pancreatitis is not uncommon and steroid treatment can effect a dramatic improvement. Care is needed to ensure that pancreatic cancer is not misdiagnosed. PMID- 17701959 TI - Dimerization of a PACAP peptide analogue in DMSO via asparagine and aspartic acid residues. AB - To optimize the stability of a peptide development candidate for the treatment of type II diabetes, formulation studies were initiated in organic solvents and compared to results obtained in aqueous solutions. Stability was assessed by reversed phase liquid chromatography (RPLC) and electrospray ionization mass spectrometry (ESI-MS). Previous studies had shown deamidation and hydrolysis to be the primary mechanisms of degradation in aqueous formulations. Surprisingly, the use of an organic solvent did not decrease the rate of degradation and, as presented here, produced degradation products including dimers. We propose here that deamidation can readily occur in polar anhydrous organic solvents such as DMSO and that the dimer forms through intermolecular nucleophilic attack of an amino acid side chain on a stabilized cyclic imide intermediate. PMID- 17701960 TI - Does reporting heterogeneity bias the measurement of health disparities? AB - Heterogeneity in reporting of health by socio-economic and demographic characteristics potentially biases the measurement of health disparities. We use anchoring vignettes to identify socio-demographic differences in the reporting of health in Indonesia, India and China. Homogeneous reporting by socio-demographic group is rejected and correcting for reporting heterogeneity tends to reduce slightly estimated disparities in health by education (not China) and to increase those by income. But the method does not reveal substantial reporting bias in measures of health disparities. PMID- 17701961 TI - Alternative methods for eye and skin irritation tests: an overview. AB - The evaluation of eye and skin irritation potential is essential to ensuring the safety of individuals in contact with a wide variety of substances designed for industrial, pharmaceutical or cosmetic use. The Draize rabbit eye and skin irritancy tests have been used for 60 years to attempt to predict the human ocular and dermal irritation of such products. The Draize test has been the standard for ocular and dermal safety assessments for decades. However, several aspects of the test have been criticised. These include: the subjectivity of the method; the overestimation of human responses; and the method's cruelty. The inadequacies of the Draize test have led to several laboratories over the last 20 years making efforts to develop in vitro assays to replace it. Protocols that use different types of cell cultures and other methods have been devised to study eye and skin irritation. Different commercial kits have also been developed to study eye and skin irritation, based on the action of chemicals on these tissues. This article presents a review of the main alternatives developed to replace the use of animals in the study of chemical irritation. Particular attention is paid to the reproducibility of each method. PMID- 17701962 TI - Randomized clinical trial of the effect of adding subfascial endoscopic perforator surgery to standard great saphenous vein stripping. AB - BACKGROUND: This randomized trial was undertaken to investigate the fate of incompetent perforating veins (IPVs) following saphenofemoral ligation and stripping of the great saphenous vein (GSV), with or without subfascial endoscopic perforator surgery (SEPS). METHODS: Patients with venous reflux (greater than 0.5 s) of the GSV and additional IPVs were allocated randomly to standard surgery (saphenofemoral ligation, stripping and phlebectomies alone) or with the addition of SEPS. Patients with ulceration, recurrent veins, deep venous reflux/thrombosis or saphenopopliteal reflux were excluded. Duplex ultrasonography was carried out before operation, and at 1 week, 6 weeks, 6 months and 1 year after surgery. Quality of life questionnaires were completed and visual analogue scale scores collected at the same time points. RESULTS: Thirty-eight patients were allocated to SEPS and 34 to the no SEPS group. Two patients in the no SEPS group were excluded (one withdrew and the other had the wrong treatment). There were no differences between the two groups with respect to pain, mobility or quality of life scores during follow-up. A significantly higher proportion of patients in the no SEPS group had IPVs on duplex imaging at 1 year (25 of 32 versus 12 of 38; P < 0.001). CONCLUSION: IPVs do not remain closed following standard varicose vein surgery. The addition of SEPS was not associated with significant morbidity but did reduce the number of IPVs. Up to 1 year this had no effect on recurrence rates or quality of life, but late results remain to be seen. REGISTRATION NUMBER: ISRCTN18288048 (http://www.controlled trials.com). PMID- 17701963 TI - Local excision of rectal tumours by transanal endoscopic microsurgery (Br J Surg 2007; 94: 627-633). PMID- 17701965 TI - Responding for brain stimulation reward in the bed nucleus of the stria terminalis in alcohol-preferring rats following alcohol and amphetamine pretreatments. AB - The bed nucleus of the stria terminalis (BNST) has been reported to release increased levels of extracellular dopamine (DA) following the systemic administration of abused drugs in outbred rats. This study examined the BNST as a novel locus for supporting operant responding for brain stimulation reward (BSR) in rats bred for alcohol preference while determining any potentiating effects of ethanol (EtOH) (0.125-1.25 g/kg, i.p.) and amphetamine (0.25-1.60 mg/kg, i.p.) on BSR within the BNST. Also examined was the capability of D1 receptor blockade to attenuate any observed potentiation. Following surgical implantation, alcohol preferring (P) and non-preferring (NP) rats responded to a range of descending frequencies (300-20 Hz) as evaluated by a rate-frequency paradigm. The results revealed that the BNST was capable of supporting BSR in P but not NP rats. Also, amphetamine pretreatment produced a significant leftward shift in the rate frequency function in P rats with significant reductions observed in three other measures of reward threshold, while EtOH only lowered the minimum frequency needed to produce responding. The effects of systemic amphetamine were successfully attenuated by the unilateral infusion of the D1 receptor antagonist SCH 23390 (5.0 microg) into the contralateral nucleus accumbens. The results suggest the BNST is capable of supporting BSR performance in P, but not NP rats, possibly due to increased sensitivity to the electrical stimulation-induced DA release of BSR in the innately DA "deficient" limbic system of P rats. PMID- 17701966 TI - Faecal incontinence (Br J Surg 2007; 94: 134-144). PMID- 17701967 TI - Region-specific effects of a tyrosine-free amino acid mixture on amphetamine induced changes in BOLD fMRI signal in the rat brain. AB - BACKGROUND: Acute depletion of tyrosine using a tyrosine-free amino acid mixture offers a novel dietary approach to inhibit activated dopamine pathways in the brain. This study investigated the potential of in vivo functional magnetic resonance imaging (fMRI) methods as a noninvasive means to detect effects of tyrosine depletion on dopamine function. METHODS: Changes in blood-oxgenation level dependent (BOLD) contrast induced by administration of the dopamine releasing agent, amphetamine (3 mg/kg i.v.), were measured in halothane anaesthetised rats. RESULTS: Amphetamine evoked changes in BOLD signal intensity with the greatest effects observed in the nucleus accumbens (-7.7%), prefrontal cortex (-13.6%), and motor cortex (+12.5%). Pretreatment with a tyrosine-free amino acid mixture attenuated the response to amphetamine in some regions (nucleus accumbens and prefrontal cortex), but not others (motor cortex). Amphetamine itself had no effect in thalamus and hippocampus but, surprisingly, increased the BOLD signal after the amino acid mixture. CONCLUSION: These experiments demonstrate that amphetamine evokes region-specific changes in the BOLD signal in rats, and that this effect is attenuated in some but not all regions by tyrosine depletion. The data support the application of fMRI techniques for studying the effects of tyrosine depletion on dopamine function in animals and also humans. PMID- 17701969 TI - Prenatal stress alters limbo-corticostriatal Homer protein expression. AB - Early environmental stress influences developmental processes resulting in alterations in behavior and brain function, including abnormalities in glutamate neurotransmission. Here, we assessed the influence of prenatal stress on limbo corticostriatal expression of Homer proteins that are critical elements in glutamatergic signaling. Pregnant, female Sprague-Dawley rats were subjected to either no treatment or to restraint stress 3 times per day for the last 7 days of gestation. At 21 d of age, offspring were sacrificed and brain tissue was rapidly extracted. Immunoblotting revealed regionally specific increases in certain Homer protein isoforms within prefrontal cortex and limbic structures, whereas the striatum exhibited a reduction in Homer 1a levels. These findings indicate that stress during development can produce enduring perturbations in Homer protein expression that likely contribute to glutamatergic and behavioral abnormalities observed following early environmental stress. PMID- 17701970 TI - Electrospun-modified nanofibrous scaffolds for the mineralization of osteoblast cells. AB - Biocompatible polycaprolactone (PCL) and hydroxyapatite (HA) were fabricated into nanofibrous scaffolds for the mineralization of osteoblasts in bone tissue engineering. PCL and PCL/HA nanofibrous surface were modified using oxygen plasma treatment and showing 0 degrees contact angle for the adhesion and mineralization of osteoblast cells. The fiber diameter, pore size and porosity of nanofibrous scaffolds were estimated to be 220-625 nm, 3-20 microm, and 87-92% respectively. The ultimate tensile strength of PCL was about 3.37 MPa and PCL/HA was 1.07 MPa to withstand the long term culture of osteoblasts on nanofibrous scaffolds. Human fetal osteoblast cells (hFOB) were cultured on PCL and PCL/HA surface modified and unmodified nanofibrous scaffolds. The osteoblast proliferation rate was significantly (p < 0.001) increased in surface-modified nanofibrous scaffolds. FESEM showed normal phenotypic cell morphology and mineralization occurred in PCL/HA nanofibrous scaffolds, HA acting as a chelating agent for the mineralization of osteoblast to form bone like apatite for bone tissue engineering. EDX and Alizarin Red-S staining indicated mineral Ca(2+) and phosphorous deposited on the surface of osteoblast cells. The mineralization was significantly increased in PCL/HA-modified nanofibrous scaffolds and appeared as a mineral nodule synthesized by osteoblasts similar to apatite of the natural bone. The present study indicated that the PCL/HA surface-modified nanofibrous scaffolds are potential for the mineralization of osteoblast for bone tissue engineering. PMID- 17701972 TI - Fabricate coaxial stacked nerve conduits through soft lithography and molding processes. AB - In this article we present a new way to fabricate nerve conduits with various multi-channels patterns by microfabrication. Soft lithography was used to manufacture silicon-based structures and replicate them with PDMS for producing nerve conduit subunit molds. After that, 3% chitosan/acetic acid solution was filled into PDMS molds and then hardened and peeled off. Nerve conduit subunits were fabricated repeatedly by a set of methods for mass production. Afterward, a plurality of conduit subunits stacked coaxially and coated with outer membrane to form the whole nerve conduit. Because of the precise capability of soft lithography, it is well-suited for nerve conduits with complex designs, such as a combination of multiple degradation control and drug delivery system. Besides, the miniaturization and batch processes are serviceable to the economic effect and the utilization in industry. PMID- 17701971 TI - The formation of tertiary dentin after pulp capping with a calcium phosphate cement, loaded with PLGA microparticles containing TGF-beta1. AB - The aim of the current study was to evaluate the effect of a calcium phosphate material equipped with poly (lactic-co-glycolic acid) microspheres for pulp capping, and to measure the dentin bridge formation, when using various concentrations of transforming growth factor (TGF) beta1. Preset samples were made (2 mm diameter; 2 mm height), containing 0 (controls), 20, or 400 ng TGF beta1. These were placed in goat incisors. Incisors capped with glass-ionomer cement only were used as negative controls. Twelve weeks after pulp capping, the incisors were retrieved, processed for histology, and graded on basis of tertiary dentin formation. The results showed that new dentin formation was seen in all samples, except the negative controls. The histological grading indicated significant differences between the samples loaded with high amount of TGF-beta1 versus the three other groups (p < 0.05). In conclusion, our study demonstrated that the composite with 400 ng TGF-beta1 was able to trigger resident stem cells in the pulp to differentiate into odontoblast-like cells and to induce the formation of tertiary dentin. The material might be a good candidate for vital pulp therapy. Production and manipulation methods could be improved for follow-up studies. PMID- 17701973 TI - Synthesis and characterization of biodegradable networks providing saturated solution prolonged delivery. AB - Numerous peptide drugs require continuous and local delivery to obtain optimum therapeutic effect. Herein, we describe the incorporation of a model peptide drug, vitamin B12, as well as goserelin acetate, in biodegradable elastomer cylinders through photo-cross-linking. The elastomer was prepared from acrylated star-poly(epsilon-caprolactone-co-D,L-lactide). Release was manipulated through the incorporation of poly(ethylene glycol) diacrylate (PEGD) into the network at concentrations up to 30% (w/w). The PEGD in the network caused rapid swelling that remained constant throughout the release period. The degree of swelling was low, ranging from 10 to 45% (w/w), and increasing as the PEGD content increased. Release proceeded with a minimal initial burst, and extended periods of nearly constant release, ranging from approximately 5 to 70% mass fraction released, were obtained. The release rate was independent of particle size and increased as the cylinder diameter decreased, as the amount of PEGD increased, as the molecular weight of PEGD increased, and as the agent loading increased. Moreover, goserelin acetate, which has a comparable diffusivity but greater aqueous solubility, was released at a greater rate than vitamin B12. This release behavior is explained as a balance between agent dissolution in the swollen polymer matrix and diffusion through the polymer matrix bulk. PMID- 17701974 TI - Preparation and physical properties of tricalcium phosphate laminates for bone tissue engineering. AB - This article describes the processing and characterization of tricalcium phosphate (TCP) laminates fabricated by stacking individual TCP sheets for bone tissue engineering. In particular, the influences of sintering temperature (900, 1000, 1100, or 1200 degrees C) on the physical properties of TCP laminates are discussed. After sintering the TCP laminates, we confirmed from the X-ray diffraction pattern that beta-TCP was transformed to alpha-TCP at a temperature between 1100 and 1200 degrees C. The Vickers hardness value increased with increasing sintering temperature, up to 1200 degrees C. Meanwhile, both flexural strength and modulus increased with increasing sintering temperature up to 1100 degrees C, but decreased massively when the laminates were sintered at 1200 degrees C. Additionally, field-emission scanning electron microscope observation after flexural test showed interlaminar delamination in the TCP laminates sintered at 1200 degrees C, whereas interlaminar delamination was not observed in TCP laminates sintered at 900, 1000, and 1100 degrees C. Accordingly, this explains the massive reduction in flexural properties at a sintering temperature of 1200 degrees C. The results of this investigation indicate that the physical properties of TCP laminates strongly depend upon the sintering temperatures, so that the choice of sintering temperature is an important factor for successful bone-tissue engineering applications of TCP laminates. PMID- 17701976 TI - All good things. PMID- 17701975 TI - In vitro and in vivo study to the biocompatibility and biodegradation of hydroxyapatite/poly(vinyl alcohol)/gelatin composite. AB - A novel porous composite material composed of hydroxyapatite, poly(vinyl alcohol) (PVA), and gelatin (Gel) was fabricated by emulsification. Scanning electron microscopy showed that the material had a well-interconnected porous structure including many macropores (100-500 microm) and micropores (less than 20 microm) on their walls. The composite had a porosity of 78% and showed high water absorption up to 312.7% indicating a good water-swellable behavior that is a characteristic of hydrogel materials. When immersed in water, the scaffold's weight continuously decreased. After immersion in simulated body fluid, the weight continuously increased because Ca(2+) and PO(3-) (4) ions deposited on the surface and the internal surfaces of the material pores. The deposit was proved to be carbonated hydroxyapatite by thin-film X-ray diffraction, Fourier transform infrared spectroscopy and energy dispersive X-ray analysis. The composite was detected to be non-cytotoxicity by MTT assay. The HA/PVA/Gel material was also implanted subcutaneously in the dorsal region of adult female rats. After 12 weeks of implantation, the porous material adhered tightly with the surrounding tissue, and the ingrowth of fibrous tissue as well as the material's partial degradation was observed, which partly indicated that the composite was biocompatible in vivo. In conclusion, the porous HA/PVA/Gel composite is a promising scaffold for cartilage tissue engineering with more studies. PMID- 17701977 TI - Eating one's words: Part III. Mentalisation-based psychotherapy for anorexia nervosa--an outline for a treatment and training manual. AB - This paper presents a new outline for psychotherapy with persons with anorexia nervosa. 'Model on mentalisation' is the intellectual and empirical framework for this contribution. Mentalisation is defined as the ability to understand feelings, cognitions, intentions and meaning in oneself and in others. The capacity to understand oneself and others is a key determinant of self organisation and affect regulation, and is acquired in early attachment relationships. Impaired mentalisation is documented and described as a central psychopathological feature in anorexia nervosa. Psychotherapeutic enterprise with individuals with compromised mentalising capacity should be an activity that is specifically focused on the rehabilitation of this function, with special emphasis on how the body is representing mental states. The paper describes psychotherapeutic goals, stances and techniques. It is intended that this outline will be further developed into manuals as a basis for therapy, training and research. PMID- 17701978 TI - The derivatives of the Wnt3a lineage in the central nervous system. AB - The dorsal midline of the vertebrate neural tube is a source of signals that direct cell fate specification and proliferation. Using genetic fate mapping in the mouse and a previously generated Wnt3aCre line, we report here that genetically labeled cells of the Wnt3a lineage migrate widely from the dorsal midline into the dorsal half of the adult brain and spinal cord, contributing to diverse structures in the diencephalon, midbrain, and brainstem and extensively populating the rostral spinal cord. Conspicuously, many of these structures are linked in specific functional networks. Wnt3a lineage cells populate nuclei of the central auditory system from the medulla to thalamus, and the trigeminal sensory system from the cervical spinal cord to the midbrain. Our findings reveal the rich contributions of the Wnt3a lineage to a variety of brain structures and show that functionally integrated nuclei can share a molecular identity, provided by transient gene expression early in their development. PMID- 17701979 TI - The foraging gene of Drosophila melanogaster: spatial-expression analysis and sucrose responsiveness. AB - The ability to identify and respond to food is essential for survival, yet little is known about the neural substrates that regulate natural variation in food related traits. The foraging (for) gene in Drosophila melanogaster encodes a cGMP dependent protein kinase (PKG) and has been shown to function in food-related traits. To investigate the tissue distribution of FOR protein, we generated an antibody against a common region of the FOR isoforms. In the adult brain we localized FOR to neuronal clusters and projections including neurons that project to the central complex, a cluster within the dorsoposterior region of the brain hemispheres, a separate cluster medial to optic lobes and lateral to brain hemispheres, a broadly distributed frontal-brain cluster, axon bundles of the antennal nerve and of certain subesophageal-ganglion nerves, and the medulla optic lobe. These newly described tissue distribution patterns of FOR protein provide candidate neural clusters and brain regions for investigation of neural networks that govern foraging-related traits. To determine whether FOR has a behavioral function in neurons we expressed UAS-for in neurons using an elav-gal4 driver and measured the effect on adult sucrose responsiveness (SR), known to be higher in rovers than sitters, the two natural variants of foraging. We found that pan-neuronal expression of for caused an increase in the SR of sitters, demonstrating a neural function for PKG in this food-related behavior. PMID- 17701980 TI - A novel mutation in the central rod domain of lamin A/C producing a phenotype resembling the Emery-Dreifuss muscular dystrophy phenotype. AB - Lamins are the principal components of the nuclear lamina, a network constituting the major structural framework of the nuclear envelope. Alterations in lamin A/C have been associated with a heterogeneous series of human disorders known as laminopathies. We report the finding of a novel deletion in the central rod domain of lamin A/C exon 3 gene in four members of the same family. This genetic alteration was likely responsible for the relatively homogeneous clinical phenotype observed in our three patients, represented by a prominent cardiac conduction-system disease necessitating permanent pacemaker implantation, and limited skeletal involvement manifested by spinal rigidity and contractures. The findings from these cases further expand the clinical spectrum associated with mutations in the LMNA gene. PMID- 17701981 TI - Architectonic analysis of the auditory-related areas of the superior temporal region in human brain. AB - Architecture of auditory areas of the superior temporal region (STR) in the human was analyzed in Nissl-stained material to see whether auditory cortex is organized according to principles that have been described in the rhesus monkey. Based on shared architectonic features, the auditory cortex in human and monkey is organized into three lines: areas in the cortex of the circular sulcus (root), areas on the supratemporal plane (core), and areas on the superior temporal gyrus (belt). The cytoarchitecture of the auditory area changes in a stepwise manner toward the koniocortical area, both from the direction of the temporal polar proisocortex as well as from the caudal temporal cortex. This architectonic dichotomy is consistent with differences in cortical and subcortical connections of STR and may be related to different functions of the rostral and caudal temporal cortices. There are some differences between rhesus monkey and human auditory anatomy. For instance, the koniocortex, root area PaI, and belt area PaA show further differentiation into subareas in the human brain. The relative volume of the core area is larger than that of the belt area in the human, but the reverse is true in the monkey. The functional significance of these differences across species is not known but may relate to speech and language functions. PMID- 17701982 TI - Cold environmental stress induces detrusor overactivity via resiniferatoxin sensitive nerves in conscious rats. AB - AIMS: We determined if cold environmental stress induced detrusor overactivity in conscious rats. We then examined the role of resiniferatoxin (RTX)-sensitive nerves in this response. METHODS: Three days prior to cystometric investigation, the urinary bladders of 12 female rats were cannulated. Six of the rats were treated with RTX 24 hr prior to cystometric investigation. The rats were exposed to three ambient temperature conditions: room temperature (RT, 27 degrees C) for 20 min, low temperature (LT, 4 degrees C) for 40 min, and RT again for 20 min. During each exposure, cystometric patterns of the rats were recorded. Additionally, neuronal structures of urinary bladders were visualized by immunohistochemistry. RESULTS: When the conscious rats were suddenly transferred from RT to LT, the cooled rats exhibited micturition patterns of detrusor overactivity. After 20 min at LT, the response slowly improved. After returning to RT, the overactive detrusor response disappeared, reverting to patterns similar to those before transfer to LT. When the RTX-treated rats were exposed with cold stress, they also exhibited detrusor overactivity. However, it was significantly mitigated compared to the non-RTX-treated normal rats. The normal rats had distinct neuronal structures labeled with S100 and calcitonin gene related peptide antibodies in the urinary bladders, but the RTX-treated rats had few. CONCLUSION: Detrusor overactivity of the conscious rats was induced by cold environmental stress. A portion of the cold-stress detrusor overactivity might be mediated by RTX-sensitive neurological pathway. The cold-stress model would be useful to investigate lower urinary tract functions. PMID- 17701983 TI - Defects in vestibular sensory epithelia and innervation in mice with loss of Chd7 function: implications for human CHARGE syndrome. AB - CHD7 is a chromodomain gene mutated in CHARGE syndrome, a multiple anomaly condition characterized by ocular coloboma, heart defects, atresia of the choanae, retarded growth and development, genital hypoplasia, and ear defects including deafness and semicircular canal dysgenesis. Mice with heterozygous Chd7 deficiency have circling behavior and semicircular canal defects and are an excellent animal model for exploring the pathogenesis of CHARGE features. Inner ear vestibular defects have been characterized in heterozygous Chd7-deficient embryos and early postnatal mice, but it is not known whether vestibular defects persist throughout adulthood in Chd7-deficient mice or whether the vestibular sensory epithelia and their associated innervation and function are intact. Here we describe a detailed analysis of inner ear vestibular structures in mature mice that are heterozygous for a Chd7-deficient, gene-trapped allele (Chd7(Gt/+)). Chd7(Gt/+) mice display variable asymmetric lateral and posterior semicircular canal malformations, as well as defects in vestibular sensory epithelial innervation despite the presence of intact hair cells in the target organs. These observations have important functional implications for understanding the clinical manifestations of CHD7 mutations in humans and for designing therapies to treat inner ear vestibular dysfunction. PMID- 17701984 TI - Molecular guidance cues necessary for axon pathfinding from the ventral cochlear nucleus. AB - During development, multiple guidance cues direct the formation of appropriate synaptic connections. Factors that guide developing axons are known for various pathways throughout the mammalian brain; however, signals necessary to establish auditory connections are largely unknown. In the auditory brainstem the neurons whose axons traverse the midline in the ventral acoustic stria (VAS) are primarily located in the ventral cochlear nucleus (VCN) and project bilaterally to the superior olivary complex (SOC). The circumferential trajectory taken by developing VCN axons is similar to that of growing axons of spinal commissural neurons. Therefore, we reasoned that netrin-DCC and slit-robo signaling systems function in the guidance of VCN axons. VCN neurons express the transcription factor, mafB, as early as embryonic day (E) 13.5, thereby identifying the embryonic VCN for these studies. VCN axons extend toward the midline as early as E13, with many axons crossing by E14.5. During this time, netrin-1 and slit-1 RNAs are expressed at the brainstem midline. Additionally, neurons within the VCN express RNA for DCC, robo-1, and robo-2, and axons in the VAS are immunoreactive for DCC. VCN axons do not reach the midline of the brainstem in mice mutant for either the netrin-1 or DCC gene. VCN axons extend in pups lacking netrin-1, but most DCC-mutant samples lack VCN axonal outgrowth. Stereological cell estimates indicate only a modest reduction of VCN neurons in DCC-mutant mice. Taken together, these data show that a functional netrin-DCC signaling system is required for establishing proper VCN axonal projections in the auditory brainstem. PMID- 17701985 TI - Projections of the lateral reticular nucleus to the cochlear nucleus in rats. AB - The lateral reticular nucleus (LRN) resides in the rostral medulla and caudal pons, is implicated in cardiovascular regulation and cranial nerve reflexes, and gives rise to mossy fibers in the cerebellum. Retrograde tracing data revealed that medium-sized multipolar cells from the magnocellular part of the LRN project to the cochlear nucleus (CN). We sought to characterize the LRN projection to the CN using BDA injections. Anterogradely labeled terminals in the ipsilateral CN appeared as boutons and mossy fibers, and were examined with light and electron microscopy. The terminal field in the CN was restricted to the granule cell domain (GCD), specifically in the superficial layer along the anteroventral CN and in the granule cell lamina. Electron microscopy showed that the smallest LRN boutons formed 1-3 synapses, and as boutons increased in size, they formed correspondingly more synapses. The largest boutons were indistinguishable from the smallest mossy fibers, and the largest mossy fiber exhibited 15 synapses. Synapses were asymmetric with round vesicles and formed against thin dendritic profiles characterized by plentiful microtubules and the presence of fine filopodial extensions that penetrated the ending. These structural features of the postsynaptic target are characteristic of the terminal dendritic claw of granule cells. LRN projections are consistent with known organizational principles of non-auditory inputs to the GCD. PMID- 17701987 TI - The nature of high-pressure voiding in small boys and its relation with the influence of a transurethral catheter. AB - AIMS: To disclose the nature of the high-pressure voiding observed in small boys and to determine the influence of a transurethral catheter on voiding urodynamic parameters and reproducibility of these parameters. MATERIALS AND METHODS: Video urodynamic studies (V-UDSs) were repeated twice in a single session using two different sized, 18G (O1.15 mm) and 7.4Fr (O2.50 mm), catheters in 9 boys aged 7.3 months (2-17) and compared with the maximum voiding detrusor pressure (P(det max)) values. Separately, in 20 boys aged 8.9 (1-34) months, V-UDSs using an 18G catheter were repeated twice, and fluoroscopic images and UDS were continuously recorded during the whole voiding phase and analyzed. RESULTS: There was no significant difference between the mean P(det max) measured by the 18G and 7.4Fr catheters (102.0 +/- 22.5 vs. 94.7 +/- 25.6 cmH(2)O, P = 0.42). Intermittent interruptions of the urinary stream due to detrusor-sphincter dyscoordination were observed in 92.5% (37/40) of voiding cycles. The true maximum voiding detrusor pressure (T-P(det max)), the maximum detrusor pressure recorded only when the urinary stream was actually detected, on the first and second voiding cycles were 86.9 +/- 30.3 and 89.0 +/- 31.7 cmH(2)O, respectively. The mean difference between P(det max) and T-P(det max) was 5.6 +/- 11.4 cmH(2)O. The minimum detrusor pressure during voiding (33.6 +/- 18.4 and 30.8 +/- 16.3 cmH(2)O), the opening detrusor pressure and the number of stream interruptions were reproducible. CONCLUSIONS: Small boys commonly void intermittently with a high detrusor pressure, which may be mainly due to detrusor-sphincter dyscoordination rather than the outflow obstruction caused by a transurethral catheter. PMID- 17701989 TI - Regulation of heat shock protein 70 release in astrocytes: role of signaling kinases. AB - The ability to mount a successful stress response in the face of injury is critical to the long-term viability of individual cells and to the organism in general. The stress response, characterized in part by the upregulation of heat shock proteins, is compromised in several neurodegenerative disorders and in some neuronal populations, including motoneurons (MNs). Because astrocytes have a greater capacity than neurons to survive metabolic stress, and because they are intimately associated with the regulation of neuronal function, it is important to understand their stress response, so that we may to better appreciate the impact of stress on neuronal viability during injury or disease. We show that astrocytes subjected to hyperthermia upregulate Hsp/c70 in addition to intracellular signaling components including activated forms of extracellular signal-regulated kinase (ERK1/2), Akt, and c-jun N-terminal kinase/stress activated protein kinase (JNK/SAPK). Furthermore, astrocytes release increasing amounts of Hsp/c70 into the extracellular environment following stress, an event that is abrogated when signaling through the ERK1/2 and phosphatidylinositol-3 kinase (PI3K) pathways is compromised and enhanced by inhibition of the JNK pathway. Last, we show that the Hsp/c70 is released from astrocytes in exosomes. Together, these data illustrate the diverse regulation of stress-induced Hsp/c70 release in exosomes, and the way in which the balance of activated signal transduction pathways affects this release. These data highlight how stressful insults can alter the microenvironment of an astrocyte, which may ultimately have implications for the survival of neighboring neurons. PMID- 17701990 TI - Regulation of actomyosin contractility by PI3K in sensory axons. AB - Phosphatidylinositol 3-kinase (PI3K) activity is known to be required for the extension of embryonic sensory axons. Inhibition of PI3K has also been shown to mediate axon retraction and growth cone collapse in response to semaphorin 3A. However, the effects of inhibiting PI3K on the neuronal cytoskeleton are not well characterized. We have previously reported that semaphorin 3A-induced axon retraction involves activation of myosin II, the formation of an intra-axonal F actin bundle cytoskeleton, and blocks the formation of F-actin patches that serve as precursors to filopodial formation in axons. We now report that inhibition of PI3K results in activation of myosin II in axons. Inhibition of myosin II activity, or its upstream regulatory kinase RhoA-kinase, blocked axon retraction induced by inhibition of PI3K. In addition, inhibition of PI3K also induced intra axonal F-actin bundles, which likely serve as a substratum for myosin II-based force generation during axon retraction. In axons, filopodia are formed from axonal F-actin patch precursors. Analysis of axonal F-actin patch formation in eYFP-actin expressing neurons revealed that inhibition of PI3K blocked formation of axonal F-actin patches, and thus filopodial formation. These data provide insights into the regulation of the neuronal cytoskeleton by PI3K and are consistent with the notion that decreased levels of PI3K activity mediate axon retraction and growth cone collapse in response to semaphorin 3A. PMID- 17701991 TI - Multiple trajectories of physical aggression among adolescent boys and girls. AB - Latent growth mixture modeling was used to identify discrete patterns of physical aggression from Grades 7 to 11 among a sample of 1,877 youth. Four trajectory classes adequately explained the development of physical aggression in both boys and girls: Low/No Aggression; Persistent High Aggression; Desisting Aggression, characterized by decreasing risk throughout adolescence; and Adolescent Aggression, characterized by low early risk that increases until Grade 9, levels out, and then declines in late adolescence. Girls were less likely than boys were to be in any trajectory besides the Low/No Aggression trajectory. Parental supervision, deviant peer association, academic orientation, impulsivity, and emotional distress at Grade 7 were all strongly associated with trajectory class membership. These associations did not differ by gender. These findings strongly suggest that the processes involved in the development of physical aggression in adolescence operate similarly in boys and girls. PMID- 17701992 TI - Use of palm trees as a sleeping site for hamadryas baboons (Papio hamadryas hamadryas) in Ethiopia. AB - Hamadryas baboons sleep on cliffs throughout their range, and this can be attributed to the safety cliffs provide against predators in the absence of tall trees. In this paper, we report the first documented occurrence of hamadryas baboons sleeping in doum palm trees rather than on cliffs. Data derive from a study of hamadryas baboons at the Filoha site in lowland Ethiopia. During all-day follows, data were collected on travel patterns, band activity, and location. Variation in the baboons' home range was characterized using vegetation transects. We discovered that one band in this population, Band 3, occasionally slept in doum palm trees (Hyphaene thebaica). The palm tree sleeping site differed from other palm fragments in the baboons' home range in that it contained a higher density of palm trees. Possible factors influencing this unique use of palm trees as a sleeping site include access to palm fruit, avoiding contact with Afar nomads, avoiding sharing sleeping cliffs with other bands, protection from predators, and the lack of cliffs in a section of the baboons' home range. Evidence from this study suggests that the palm tree sleeping site is used because it affords better protection from predators than other palm fragments in an area of the band's home range that does not contain cliffs. PMID- 17701993 TI - Impact of anisosmotic conditions on structural and functional integrity of cumulus-oocyte complexes at the germinal vesicle stage in the domestic cat. AB - During cryopreservation, the immature oocyte is subjected to anisosmotic conditions potentially impairing subsequent nuclear and cytoplasmic maturation in vitro. In preparation for cryopreservation protocols and to characterize osmotic tolerance, cat cumulus-oocyte complexes (COC) at the germinal vesicle (GV) stage were exposed for 15 min to sucrose solutions ranging from 100 to 2,000 mOsm and then examined for structural integrity and developmental competence in vitro. Osmolarities > or =200 and < or =750 mOsm had no effect on incidence of oocyte nuclear maturation, fertilization success, and blastocyst formation compared to control COC (exposed to 290 mOsm). This relatively high osmotic tolerance of the immature cat oocyte appeared to arise from a remarkable stability of the GV chromatin structure as well as plasticity in mitochondrial distribution, membrane integrity, and ability to maintain cumulus-oocyte communications. Osmolarities <200 mOsm only damaged cumulus cell membrane integrity, which contributed to poor nuclear maturation but ultimately had no adverse effect on blastocyst formation in vitro. Osmolarities >750 mOsm compromised nuclear maturation and blastocyst formation in vitro via disruption of cumulus-oocyte communications, an effect that could be mitigated through 1,500 mOsm by adding cytochalasin B to the hyperosmotic solutions. These results (1) demonstrate, for the first time, the expansive osmotic tolerance of the immature cat oocyte, (2) characterize the fundamental role of cumulus-oocyte communications when tolerance limits are exceeded, and (3) reveal an interesting hyperosmotic tolerance of the immature oocyte that can be increased two-fold by supplementation with cytochalasin B. PMID- 17701994 TI - Evaluation of the chemical compatibility of plastic contact materials and pharmaceutical products; safety considerations related to extractables and leachables. AB - A review is provided on the general topic of the compatibility of plastic materials with pharmaceutical products, with specific emphasis on the safety aspects associated with extractables and leachables related to such plastic materials. PMID- 17701995 TI - Loss of the cisternal organelle in the axon initial segment of cortical neurons in synaptopodin-deficient mice. AB - The axon initial segment of cortical neurons contains the so-called cisternal organelle, an enigmatic formation of stacked endoplasmic reticulum and interdigitating plates of electron-dense material. This organelle shows many structural similarities to the spine apparatus, a cellular organelle found in a subpopulation of dendritic spines. Whereas roles in calcium signaling and protein trafficking have been proposed for the spine apparatus, little is yet known about the physiological function of its putative axonal counterpart. Considering the structural similarity of these two organelles, we hypothesized that synaptopodin, a protein essential for the formation of the dendritic spine apparatus, could also be a component of the cisternal organelle. By using immunofluorescence microscopy, we found that synaptopodin is indeed located within the axon initial segments of principal neurons in the mouse neocortex and hippocampus. Pre embedding immunogold labeling demonstrated a close association of synaptopodin immunoreactivity with the dense plates of cisternal organelles. In synaptopodin deficient mice, ultrastructural analysis of identified axon initial segments of CA1 pyramidal cells revealed a lack of cisternal organelles similar to the reported lack of spine apparatuses in these mutants. However, in vitro patch clamp recording of mutant neurons showed that the lack of cisternal organelles did not lead to any changes in basic electrophysiological parameters of action potentials. Taken together, our data demonstrate that synaptopodin is an essential component of the cisternal organelle of axons and of the dendritic spine apparatus, two organelles that are structurally and molecularly related. PMID- 17701996 TI - Demography, life history and migrations in a Mexican mantled howler group in a rainforest fragment. AB - This paper represents the results of a long-term study (1996-2003) on the demographic changes over time of a Mexican mantled howler (Alouatta palliata mexicana) group in a rainforest fragment (40 ha) in Los Tuxtlas, Mexico, with a follow-up census 3 years later (2006). In addition to demographic and life history parameters, we describe six dispersal events. Our results suggest that this group has been expanding during the study period, growing from six to 12 individuals, with an annual average intrinsic growth rate of 0.07, an infant survivorship of 67%, and an average immature to female ratio of 0.90. This increase in size is probably related to the high food availability in their home range. However, fragment isolation may be negatively affecting the dispersal patterns typical of the species, which could result in a loss of genetic variability over time. PMID- 17701997 TI - Coemergence of regularity and complexity during neural network development. AB - With the growing recognition that rhythmic and oscillatory patterns are widespread in the brain and play important roles in all aspects of the function of our nervous system, there has been a resurgence of interest in neuronal synchronized bursting activity. Here, we were interested in understanding the development of synchronized bursts as information-bearing neuronal activity patterns. For that, we have monitored the morphological organization and spontaneous activity of neuronal networks cultured on multielectrode-arrays during their self-executed evolvement from a mixture of dissociated cells into an active network. Complex collective network electrical activity evolved from sporadic firing patterns of the single neurons. On the system (network) level, the activity was marked by bursting events with interneuronal synchronization and nonarbitrary temporal ordering. We quantified these individual-to-collective activity transitions using newly-developed system level quantitative measures of time series regularity and complexity. We found that individual neuronal activity before synchronization was characterized by high regularity and low complexity. During neuronal wiring, there was a transient period of reorganization marked by low regularity, which then leads to coemergence of elevated regularity and functional (nonstochastic) complexity. We further investigated the morphology activity interplay by modeling artificial neuronal networks with different topological organizations and connectivity schemes. The simulations support our experimental results by showing increased levels of complexity of neuronal activity patterns when neurons are wired up and organized in clusters (similar to mature real networks), as well as network-level activity regulation once collective activity forms. PMID- 17701998 TI - Diaphragmatic defects and limb deficiencies - taking sides. AB - Diaphragmatic defects and limb deficiencies usually occur as independent anomalies, as a polytopic field defect (in which ipsilateral anomalies might be expected) or as wider pattern of defects, potentially involving disturbance of laterality or the midline (in which bilateral or contralateral defects would occur). Data on cases from previous studies and/or the literature were used to determine whether there is an association between the sides involved in the defects. The 88 adequately described cases identified included 20 with de Lange syndrome, seven with Poland anomaly, four with trisomy 18, 52 with other patterns of multiple malformations and five with diaphragmatic and limb defects alone. Evaluation of the position of the limb (left, right, bilateral) and the diaphragmatic defects (left, right, bilateral) did not show significant association in patterns of sidedness (P = 0.48). In 56% of cases, the limb deficiencies were bilateral. Among the 32 unilateral cases, 19 (59%) were ipsilateral (15 left; 4 right) and 13(41%) were contralateral (P = 0.38). Eleven of the 13 contralateral cases had left sided diaphragmatic defects and right sided limb deficiency; four had de Lange syndrome and nine had other patterns of multiple anomalies. Only cases with Poland anomaly or otherwise isolated defects showed a trend towards ipsilateral defects. Most cases with multiple congenital anomalies, had limbs defects on both the right and left (57%) or both sides of the diaphragm were affected (an additional 10%), indicating a widespread dysmorphogenetic process rather than a more restricted field defect. In other cases, defects were bilateral or, if unilateral, reflected the propensities for diaphragmatic defects to more often involve the left side, and limb defects, the right. PMID- 17701999 TI - Reproduction phase-related variations in neuropeptide Y immunoreactivity in the olfactory system, forebrain, and pituitary of the female catfish, Clarias batrachus (Linn.). AB - The aim of this study was to determine whether neuropeptide Y (NPY) immunoreactivity in the cells and fibers in the forebrain and pituitary of Clarias batrachus is linked to the annual reproductive cycle. A steady rise in luteinizing hormone (LH) immunoreactivity was seen in the pituitary through preparatory (February-April) and prespawning (May-June) phases; it was greatly reduced during spawning (July-August; P < 0.001) and partially replenished during postspawning (September-November; P < 0.01) through resting (December-January) phases. Although NPY immunoreactivity in olfactory receptor neurons and olfactory nerve layer in olfactory bulb was gradually augmented during resting through prespawning phases (P < 0.001), attaining a peak in spawning phase (P < 0.001), a dramatic decline was encountered during postspawning phase (P < 0.001). A similar pattern was also observed in NPY-containing fibers of the medial olfactory tract (MOT) and pituitary. However, a different pattern of NPY immunoreactivity was observed in the neurons of nucleus entopeduncularis (NE) and nucleus preopticus periventricularis (NPP). Whereas these neurons and fibers in the forebrain showed significant augmentation during the resting through prespawning phases (P < 0.001), the immunoreactivity dramatically declined during spawning (P < 0.001) and was partially replenished in the postspawning phase. Testosterone injection of juveniles significantly augmented (P < 0.001) NPY immunoreactivity in NE neurons. We suggest that NPY cells of NE and NPP, and related fiber systems, might be involved in processing of sex steroid-borne information and regulation of the gonadotropin-releasing hormone-LH axis. PMID- 17702000 TI - Cyclosporin-A treatment attenuates delayed cytoskeletal alterations and secondary axotomy following mild axonal stretch injury. AB - Following central nervous system trauma, diffuse axonal injury and secondary axotomy result from a cascade of cellular alterations including cytoskeletal and mitochondrial disruption. We have examined the link between intracellular changes following mild/moderate axonal stretch injury and secondary axotomy in rat cortical neurons cultured to relative maturity (21 days in vitro). Axon bundles were transiently stretched to a strain level between 103% and 106% using controlled pressurized fluid. Double-immunohistochemical analysis of neurofilaments, neuronal spectrin, alpha-internexin, cytochrome-c, and ubiquitin was conducted at 24-, 48-, 72-, and 96-h postinjury. Stretch injury resulted in delayed cytoskeletal damage, maximal at 48-h postinjury. Accumulation of cytochrome-c and ubiquitin was also evident at 48 h following injury and colocalized to axonal regions of cytoskeletal disruption. Pretreatment of cultures with cyclosporin-A, an inhibitor of calcineurin and the mitochondrial membrane transitional pore, reduced the degree of cytoskeletal damage in stretch injured axonal bundles. At 48-h postinjury, 20% of untreated cultures demonstrated secondary axotomy, whereas cyclosporin A-treated axon bundles remained intact. By 72-h postinjury, 50% of control preparations and 7% of cyclosporin A-treated axonal bundles had progressed to secondary axotomy, respectively. Statistical analyses demonstrated a significant (p < 0.05) reduction in secondary axotomy between treated and untreated cultures. In summary, these results suggest that cyclosporin-A reduces progressive cytoskeletal damage and secondary axotomy following transient axonal stretch injury in vitro. PMID- 17702001 TI - Development of the swimbladder and its innervation in the zebrafish, Danio rerio. AB - Many teleosts including zebrafish, Danio rerio, actively regulate buoyancy with a gas-filled swimbladder, the volume of which is controlled by autonomic reflexes acting on vascular, muscular, and secretory effectors. In this study, we investigated the morphological development of the zebrafish swimbladder together with its effectors and innervation. The swimbladder first formed as a single chamber, which inflated at 1-3 days posthatching (dph), 3.5-4 mm body length. Lateral nerves were already present as demonstrated by the antibody zn-12, and blood vessels had formed in parallel on the cranial aspect to supply blood to anastomotic capillary loops as demonstrated by Tie-2 antibody staining. Neuropeptide Y-(NPY-) like immunoreactive (LIR) fibers appeared early in the single-chambered stage, and vasoactive intestinal polypeptide (VIP)-LIR fibers and cell bodies developed by 10 dph (5 mm). By 18 dph (6 mm), the anterior chamber formed by evagination from the cranial end of the original chamber; both chambers then enlarged with the ductus communicans forming a constriction between them. The parallel blood vessels developed into an arteriovenous rete on the cranial aspect of the posterior chamber and this region was innervated by zn-12 reactive fibers. Tyrosine hydroxylase- (TH-), NPY-, and VIP-LIR fibers also innervated this area and the lateral posterior chamber. Innervation of the early anterior chamber was also demonstrated by VIP-LIR fibers. By 25-30 dph (8-9 mm), a band of smooth muscle formed in the lateral wall of the posterior chamber. Although gas in the swimbladder increased buoyancy of young larvae just after first inflation, our results suggest that active control of the swimbladder may not occur until after the formation of the two chambers and subsequent development and maturation of vasculature, musculature and innervation of these structures at about 28-30 dph. PMID- 17702002 TI - Analysis of connexin subunits required for the survival of vestibular hair cells. AB - Mutations in connexin (Cx) genes are responsible for a large proportion of human inherited prelingual deafness cases. The most commonly found human Cx mutations are either Cx26 or Cx30 deletions. Histological observations made in the organ of Corti of homozygous Cx26 and Cx30 gene knockout mice show that cochlear hair cells degenerate after the onset of hearing. However, it is unclear whether vestibular hair cells undergo similar degeneration in connexin knockout mice. To address this question, we first examined expression patterns of Cx26 and Cx30 in the saccule, utricle, and ampulla by immunolabeling. In wild-type mice, Cx26 and Cx30 immunoreactivity was found extensively in vestibular supporting cells and connective tissue cells, and the two Cxs were co-localized in most gap junction (GJ) plaques. Targeted deletion of the Cx30 gene, which caused little change in Cx26 expression pattern, resulted in a significant and age-related loss of vestibular hair cells only in the saccule. dUTP nick end labeling (TUNEL) staining also revealed on-going apoptosis specifically in saccular hair cells of Cx30(-/-) mice. These results indicated that hair cell survival in the utricle and ampulae does not require Cx30. Importantly, over-expressing the Cx26 gene from a modified bacterial artificial chromosome in the Cx30(-/-) background rescued the saccular hair cells. These results suggest that it is the reduction in the total amount of GJs rather than the specific loss of Cx30 that underlies saccular hair cell death in Cx30(-/-) mice. Hybrid GJs co-assembled from Cx26 and Cx30 were not essential for the survival of saccular hair cells. PMID- 17702004 TI - Neurofibromatosis type 1 is a genetic skeletal disorder. PMID- 17702003 TI - Deletion of EphA4 enhances deafferentation-induced ipsilateral sprouting in auditory brainstem projections. AB - Axonal selection of ipsilateral and/or contralateral targets is essential for integrating bilateral sensory information and for coordinated movement. The molecular processes that determine ipsilateral and contralateral target choice are not fully understood. We examined this target selection in the developing auditory brainstem. Ventral cochlear nucleus (VCN) axons normally project to the medial nucleus of the trapezoid body (MNTB) only on the contralateral side. However, after unilateral removal of cochlear input in neonates, we found that axons from the unoperated VCN sprout and project to MNTB bilaterally. We found that EphA4 is expressed in the mouse auditory brainstem during development and during a sensitive period for ipsilateral sprouting, so we hypothesized that deletion of the Eph receptor EphA4 would impair target selection in these auditory pathways. Lipophilic dyes were used to evaluate quantitatively the brainstem projections in wild-type and EphA4-null mice. VCN-MNTB projections in EphA4-null mice were strictly contralateral, as in wild-type mice. However, after deafferentation, EphA4-null mice had a significant, threefold increase in the proportion of axons from the intact VCN that sprouted into ipsilateral MNTB compared with wild-type mice. Heterozygous mice had a twofold increase in these projections. These results demonstrate that EphA4 influences auditory brainstem circuitry selectively in response to deafferentation. Although this axon guidance molecule is not by itself necessary for appropriate target choice during normal development, it is a strong determinant of ipsilateral vs. contralateral target choice during deafferentation-induced plasticity. PMID- 17702005 TI - Fetal trisomy 5 mosaicism: case report and literature review. PMID- 17702006 TI - Zellweger syndrome resulting from maternal isodisomy of chromosome 1. AB - Zellweger syndrome (ZS) is an autosomal recessive peroxisomal disorder that results from mutations in one of the peroxisome biogenesis (PEX) genes. This is the first patient reported with uniparental disomy (UPD) resulting in ZS, in this case maternal isodisomy of chromosome 1 involving reduction to homoallelism of a frameshift mutation within PEX 10. Other reported cases of UPD1, and evidence for the imprinting of genes on chromosome 1, are reviewed. The molecular findings in this patient have important implications for molecular testing and genetic counseling in ZS. PMID- 17702007 TI - Prenatal diagnosis of a small chromosome 2-derived supernumerary marker, and review of the reported cases. PMID- 17702008 TI - Interferon regulatory factor 6 (IRF6) is associated with oral-facial cleft in individuals that originate in South America. PMID- 17702009 TI - ICF syndrome: high variability of the chromosomal phenotype and association with classical Hodgkin lymphoma. AB - We report on two sibs with ICF syndrome (immunodeficiency, centromeric heterochromatin instability, and facial anomalies) diagnosed in the elder brother based on the typical chromosomal abnormalities present in 56% of metaphases from cultured lymphocytes. In a previous cytogenetic analysis this diagnosis had been missed due to low manifestation of the ICF chromosomal phenotype. Hypomethylation of classical satellites 2 and 3, and of alpha-satellite DNA was shown in the lymphocytes of the younger sister. At 7 years of age the boy presented with hemiplegia due to tumerous invasion of the right brachial plexus. Histopathology revealed classical Hodgkin lymphoma, a neoplasia which might have been facilitated by the underlying genetic defect. PMID- 17702010 TI - Polymorphisms in folate and homocysteine metabolizing genes and chromosome damage in mothers of Down syndrome children. AB - We recently observed an association between combinations of polymorphisms in the methylenetetrahydrofolate reductase (MTHFR 677C > T or 1298A > C) and reduced folate carrier (RFC-1 80G > A) genes and the risk of a Down syndrome (DS) pregnancy in young Italian women. Others have observed an association between a methionine synthase (MTR 2756A > G) gene polymorphism and the risk of a DS offspring in Italy. Moreover, in a separate study, we observed an increased frequency of both binucleated micronucleated cells (BNMN) and chromosome malsegregation events in peripheral lymphocytes of mothers of DS individuals aged less than 35 years at conception (MDS) in respect to controls. The aim of the present study was to evaluate chromosome damage, measured by means of the micronucleus assay, in peripheral lymphocytes of a group of women (n = 34) who had a DS child in young age (<35 years) and in a control group (n = 35), and to correlate them with MTHFR 677C > T and 1298A > C, RFC-1 80G > A and MTR 2756A > G polymorphisms. We observed an increased frequency of BNMN in the MDS group compared to the control group (17.13 +/- 8.31 per thousand vs. 10.28 +/- 4.53 per thousand; P < 0.001), and, in the general population, a correlation between years of age and BNMN frequency (P = 0.05). A significant correlation between the frequency of BNMN and the MTHFR 677C > T polymorphism (P = 0.038) was also found. Present results indicate that MDS are more prone to chromosome damage than control mothers; moreover the contribution of folate and homocysteine metabolizing gene polymorphisms seems to have an effect on the baseline frequency of BNMN lymphocytes. PMID- 17702011 TI - Narrowing the DYT6 dystonia region and evidence for locus heterogeneity in the Amish-Mennonites. AB - The DYT6 gene for primary torsion dystonia (PTD) was mapped to chromosome 8p21 q22 in two Amish-Mennonite families who shared a haplotype of marker alleles across a 40 cM linked region. The objective of this study was to narrow the DYT6 region, clinically characterize DYT6 dystonia in a larger cohort, and to determine whether DYT6 is associated with dystonia in newly ascertained multiplex families. We systematically examined familial Amish-Mennonite dystonia cases, identifying five additional members from the original families, as well as three other multiplex Amish-Mennonite families, and evaluated the known DYT6 haplotype and recombination events. One of the three new families carried the shared haplotype, whereas the region was excluded in the two other families, suggesting genetic heterogeneity for PTD in the Amish-Mennonites. Clinical features in the five newly identified DYT6 carriers were similar to those initially described. In contrast, affected individuals from the excluded families had a later age of onset (46.9 years vs. 16.1 years in the DYT6), and the dystonia was both more likely to be of focal distribution and begin in the cervical muscles. Typing of additional markers in the DYT6-linked families revealed recombinations that now place the gene in a 23 cM region surrounding the centromere. In summary, the DYT6 gene is in a 23 cM region on chromosome 8q21-22 and does not account for all familial PTD in Amish-Mennonites. PMID- 17702012 TI - A family with an autosomal dominant mesomelic dysplasia resembling mesomelic dysplasia Savarirayan and Nievergelt types. PMID- 17702013 TI - Pure segmental trisomy 1q42-qter in a boy with a severe phenotype. PMID- 17702014 TI - Growth hormone analysis and treatment in Ellis-van Creveld syndrome. AB - Little is known on growth, growth hormone (GH) levels and GH treatment in patients with Ellis-van Creveld syndrome (EvC). The aim of the present study was to assess growth, growth hormone status and the possible effectiveness of GH treatment in literature and in a small series of EvC patients. A review of literature indicated retarded growth for most EvC patients (-2 to -4.5 SDS) and minimal data on GH levels or treatment which did not allow any conclusion. We studied eight EvC patients, seven of whom were treated with GH. Four were GH deficient (GHD) and four were GH sufficient. In all patients treated with GH, first year growth velocity increased. In three of the four GHD and in one GH sufficient patient a gain in height SDS was noted. In the present small EvC series GHD occurred more often than expected. Patient acquisition through the Growth Hormone Database will have caused a significant bias, but the present results indicate that GH treatment may improve growth in at least some patients with EvC. Therefore we conclude that EvC patients may benefit from being tested for GHD and, if indicated, treated. In addition a prospective study to evaluate GH status and linear growth in patients with EvC as well as the potential effectiveness of GH treatment is warranted. PMID- 17702015 TI - Prenatal detection and outcome of congenital diaphragmatic hernia (CDH) associated with deletion of chromosome 15q26: two patients and review of the literature. AB - Congenital diaphragmatic hernia (CDH) is a severe birth defect characterized by a defect in the diaphragm with pulmonary hypoplasia and postnatal pulmonary hypertension. Approximately 50% of CDH cases are associated with other non pulmonary congenital anomalies (so called non-isolated CDH) and in 5-10% of cases there is a chromosomal etiology. The majority of CDH cases are detected prenatally. In some cases prenatal chromosome analysis reveals a causative chromosomal anomaly, most often aneuploidy. Deletion of 15q26 is the most frequently described structural chromosomal aberration in patients with non isolated CDH. In this paper we report on two patients with a deletion of 15q26 and phenotypes similar to other patients with CDH caused by 15q26 deletions. This phenotype consists of intra-uterine growth retardation, left-sided CDH, cardiac anomalies and characteristic facial features, similar to those seen in Fryns syndrome. We propose that when this combination of birth defects is identified, either pre- or postnatally, further investigations to confirm or exclude a deletion of 15q26 are indicated, since the diagnosis of this deletion will have major consequences for the prognosis and, therefore, can affect decision making. PMID- 17702016 TI - A microduplication of CBP in a patient with mental retardation and a congenital heart defect. AB - Rubinstein-Taybi syndrome is a well-characterized genetic syndrome caused by haploinsufficiency of CBP in a majority of individuals. In 10% of cases a microdeletion in 16p13.3 affecting CBP is detected. We report on a patient with a de novo 345-480 kb micro-duplication the region, encompassing only CBP and TRAP1. This boy presented with various minor physical anomalies, moderate mental retardation, and an atrial septal defect, but none of the other typical characteristics of the Rubinstein-Taybi syndrome, such as the broad thumbs and first toes or facial characteristics. This finding implicates CBP as one of the causative genes for the trisomy 16p13 syndrome, and indicates this is a contiguous gene syndrome. PMID- 17702017 TI - Two siblings with 46,XY DSD, congenital adrenal hypoplasia, aniridia, craniofacial, and skeletal abnormalities and intrauterine growth retardation: a new syndrome? AB - We report on two siblings with an unusual constellation of congenital anomalies comprising 46,XY disorder of sex development (DSD), congenital adrenal hypoplasia, aniridia, dysmorphic facial features, intrauterine growth retardation, and minor skeletal abnormalities. This combination of abnormalities is yet to be recognized in the medical literature. As such, we propose that our patients represent either a new dysmorphic syndrome or a thus far unrecognized variation of a known syndrome, such as IMAGe syndrome. The sibling recurrence suggests autosomal recessive or X-linked patterns of inheritance. PMID- 17702018 TI - Massive arm edema following arteriovenous dialysis shunt creation in a patient with ipsilateral permanent pacemaker. AB - Asymptomatic subclavian vein occlusion following insertion of a permanent pacemaker (PPM) or implantable cardioverter-defibrillator (ICD) is not uncommon. We report a case of a dual-chamber PPM in a patient with an unrecognized left subclavian vein occlusion who developed massive left arm edema following ipsilateral implantation of an arteriovenous (AV) hemodialysis graft. We recommend that patients with pre-existing PPM or ICD leads who are in need of vascular access for hemodialysis should have the AV shunts placed in the contralateral arm. If this is unavoidable, then preoperative subclavian vein screening for patency should be mandatory, even in asymptomatic patients. Sonography is an appropriate initial test in such a situation. PMID- 17702019 TI - Role of sonography in the diagnosis of ectopic pregnancy. AB - This review addresses the use of sonography in the evaluation of patients suspected of having ectopic pregnancy. The use of transvaginal and transabdominal sonography and the role of Doppler imaging in the early diagnosis of ectopic pregnancy are discussed. Various sonographic findings and pitfalls of ectopic pregnancy are analyzed, with emphasis on their diagnostic efficacies. PMID- 17702020 TI - Comparison of face-to-face and internet interventions for body image and eating problems in adult women: an RCT. AB - OBJECTIVE: The aim of this study was to compare the outcomes following an eight session, small group, therapist-led, intervention for body dissatisfaction, and disordered eating in adult women, delivered either in face-to-face or synchronous, internet mode. METHOD: Community women with high body dissatisfaction and internet access were randomly assigned to either face-to-face delivery (N = 42), internet delivery (N = 37), or delayed treatment control (N = 37). All groups were assessed at baseline and 8-9 weeks later. The intervention groups were reassessed at 6-months follow-up. RESULTS: Both intervention groups showed large improvements in body dissatisfaction compared with the delayed treatment control and these improvements were maintained at follow-up. However, posttreatment improvements were greater in the face-to-face than internet intervention. CONCLUSION: In adult women, it is desirable to deliver the body image intervention in a face-to-face mode, but the internet mode is effective and has the potential to increase access to therapy. PMID- 17702021 TI - Long-term stability of eating disorder diagnoses. AB - OBJECTIVE: Data on the stability of eating disorder (ED) diagnoses (DSM-IV) over 12 years are presented for a large sample (N = 311) of female eating disordered patients with anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). METHOD: Assessments were made at the beginning of therapy and 2-, 6-, and 12-year follow-ups. Diagnoses were derived from the Structured Inventory for Anorexic and Bulimic Eating Disorders. Possible diagnostic outcome categories were AN, BN, BED, NOS, no ED, and deceased. RESULTS: At all follow-ups, more patients changed from AN or BED to BN than vice versa. No diagnostic crossover from AN to BED or vice versa occurred. BED showed the greatest variability and AN had the greatest stability over time. While the long-term outcome of BN and BED is similar, AN had a considerably worse long-term outcome than either BN or BED. CONCLUSION: Of the ED diagnoses, AN was most stable and BED most variable. The considerable diagnostic flux between BN and BED and similarities in course and outcome of BN and BED point to common biological and psychological maintaining processes. AN and BED are nosologically quite distant. PMID- 17702022 TI - Parenting children with Proteus syndrome: experiences with, and adaptation to, courtesy stigma. AB - Courtesy stigma refers to the stigmatization an unaffected person experiences due to his or her relationship with a person who bears a stigma. Parents of children with genetic conditions are particularly vulnerable to courtesy stigma, but little research has been done to explore this phenomenon. The purpose of this study was to investigate the courtesy stigma experiences of parents of children with Proteus syndrome (PS) and related overgrowth conditions. Thematic analysis of transcripts from 31 parents identified three distinct themes: stigma experiences, social-emotional reactions to stigmatizing encounters, and coping responses. Four types of stigmatizing experiences were identified: intrusive inquires, staring and pointing, devaluing remarks, and social withdrawal. Additionally, we uncovered eight strategies parents used to cope with courtesy stigma: attributing cause, assigning meaning to social exchanges, concealing, withdrawing socially, taking the offensive, employing indifference, instructing and learning from family, and educating others. Parents' choices of strategy type were found to be context dependent and evolved over time. This is the first study to document the adaptive evolution of coping strategies to offset courtesy stigma by parents of children with genetic conditions. These results provide groundwork for genetic counseling interventions aimed at addressing issues of courtesy stigma and further investigation of the phenomenon itself. PMID- 17702023 TI - Prevalence of encephalocele in Texas, 1999-2002. AB - Encephaloceles are congenital malformations characterized by a sac-like protrusion of the brain and/or its' covering membranes through an opening in the skull. The etiology of encephalocele is considered to be complex, and in most cases the causes of this condition remain elusive. The present study was undertaken to determine the prevalence of encephalocele among deliveries to Texas residents during 1999-2002, and to identify maternal and demographic factors associated with encephalocele. Data were examined from 125 infants and fetuses with encephalocele and no identified chromosome abnormality; identified in Texas and delivered in 1999-2002. During the same period there were 1,449,943 live births. The birth prevalence of encephalocele and both crude and adjusted prevalence ratios were estimated from these data. Compared with the offspring of White women, encephaloceles were significantly more common among the offspring of Hispanic women (adjusted prevalence ratio: 1.91, 95% confidence interval (CI) 1.34-2.70). In addition, compared to the offspring of women 25-29 years of age, encephaloceles were more common among the offspring of women 20-24 years of age (adjusted prevalence ratio: 1.52, 95% CI 1.01-2.27) and those less than 20 years of age (adjusted prevalence ratio: 1.55, 95% CI 0.98-2.45). These findings add to the existing literature on the descriptive epidemiology of encephalocele. PMID- 17702024 TI - Interferon-beta treatment and the natural history of relapsing-remitting multiple sclerosis. PMID- 17702025 TI - Enantioselective synthesis of (2R, 3S)- and (2S, 3R)-4,4,4-trifluoro-N-Fmoc-O tert-butyl-threonine and their racemization-free incorporation into oligopeptides via solid-phase synthesis. AB - An efficient method for the enantioselective synthesis of (2R, 3S)- and (2S, 3R) 4,4,4-trifluoro-N-Fmoc-O-tert-butyl-threonine on multigram scales was developed. Absolute configurations of the two stereoisomers were ascertained by X-ray crystallography. Racemization-free coupling conditions for the incorporation of tfT into oligopeptides were then explored. For solution-phase synthesis, tfT racemization was not an issue under conventional coupling conditions. For solid phase synthesis, the following conditions were identified to achieve racemization free synthesis: if tfT (3.0 equiv) was not the first amino acid to be linked to the resin (1.0 equiv), the condition is 2.7 equiv DIC/3.0 equiv HOBt as the coupling reagent at 0 degrees C for 20 h; if tfT (3.0 equiv) was the first amino acid to be linked to the resin (1.0 equiv), then 1.0 equiv of CuCl(2) needs to be added to the coupling reagent. PMID- 17702027 TI - Female gonadal hormones, migraine, and spreading depression. PMID- 17702026 TI - Zolpidem and its effects on hypoxic encephalopathy. PMID- 17702028 TI - Confounders in natural history of interferon-beta-treated relapsing multiple sclerosis. PMID- 17702029 TI - Muscle Nogo-A: a marker for amyotrophic lateral sclerosis or for denervation? PMID- 17702030 TI - Evidence of thalamic dysfunction in Huntington disease by proton magnetic resonance spectroscopy. AB - Our objective was to investigate thalamic neuronal dysfunction in patients with Huntington disease (HD). We performed localized single-voxel proton magnetic resonance spectroscopy (MRS) of the thalamus in 22 HD patients and 25 healthy individuals. The mean age of patients was 48.5 years (ranging from 32 to 71 years). Age at onset varied between 20 and 66 years (mean 38.9 years). The expanded CAG repeat ranged from 40 to 52 (mean 45.2) CAGs. The mean age of control group was 35.4 years, ranging from 19 to 67 years. N-acetylaspartate (NAA) relative to creatine (NAA/Cr) values in the thalamus of HD patients were decreased when compared with controls (P = 0.0001). The spectroscopic findings were not correlated with motor impairment. However, there was a positive correlation between duration of disease and motor impairment (P = 0.02, r = 0.48), and a tendency for positive correlation between duration of disease and NAA/Cr (P = 0.059, r = 0.4). We found decreased NAA/Cr values in the thalamus of patients with HD, indicating neuronal loss or dysfunction. This is in agreement with previous studies that indicated the involvement of mitochondrial dysfunction in the neurodegenerative process of HD. PMID- 17702031 TI - Riluzole in Huntington's disease: a 3-year, randomized controlled study. AB - OBJECTIVE: We conducted a randomized double-blind trial of riluzole in Huntington's disease to investigate the efficacy of this antiexcitotoxic drug in slowing disease progression. METHODS: The study included 537 adult patients with a clinical diagnosis of Huntington's disease confirmed by genotyping. Patients were randomized (2:1) to treatment with riluzole (50mg twice daily) or placebo for 3 years. Concomitant use of antichoreic medication was forbidden, and introduction of such medication was a predefined end point. The primary outcome measure was change in a combined score derived from the motor and total functional capacity subscores of the Unified Huntington's Disease Rating Scale. Safety was also evaluated. RESULTS: A total of 379 patients completed the study (mean age, 47 [standard deviation, 9.5] years; 50% female patients). The principal reason for discontinuation was introduction of antichoreic medication. The median change from baseline in the combined score (primary outcome) for the "per protocol" population was 13.7 (95% confidence interval, 11.1-17.2) in the placebo group and 14.3 (95% confidence interval, 11.7-16.6) in the riluzole group. No intergroup difference in outcome could thus be demonstrated (p = 0.93, Mann-Whitney U test). No differences in secondary efficacy outcome variables were observed except for more frequent recourse to antichoreic medication in the placebo group. No unexpected adverse events were reported, and tolerability was acceptable. INTERPRETATION: No neuroprotective or beneficial symptomatic effects of riluzole in Huntington's disease were demonstrated. PMID- 17702032 TI - Sodium phenylbutyrate in Huntington's disease: a dose-finding study. AB - Transcriptional dysregulation in Huntington's disease (HD) is mediated in part by aberrant patterns of histone acetylation. We performed a dose-finding study in human HD of sodium phenylbutyrate (SPB), a histone deacetylase inhibitor that ameliorates the HD phenotype in animal models. We used a dose-escalation/de escalation design, using prespecified toxicity criteria and standard clinical and laboratory safety measures. The maximum tolerated dose was 15 g/day. At higher doses, toxicity included vomiting, lightheadedness, confusion, and gait instability. We saw no significant laboratory or electrocardiographic abnormalities. Gene expression changes in blood suggested an inverse dose response. In conclusion, SPB at 12 to 15 g/day appears to be safe and well tolerated in human HD. PMID- 17702033 TI - Benign hereditary chorea revisited: a journey to understanding. AB - Benign hereditary chorea (BHC) has been characterized as an autosomal dominant disorder manifesting nonprogressive chorea without dementia. However, there has been controversy regarding its existence. Diagnosis has been based solely on clinical criteria with many patients and families demonstrating "atypical" features and until recently, no diagnostic test was available for confirmation. Since 2002, mutations in the thyroid transcription factor (TITF-1) gene have been identified as resulting in some cases of BHC. Additionally, the clinical spectrum has expanded to include abnormalities in thyroid and lung with the putative mechanism of disease resulting from gene haploinsufficiency and reduced protein product. This review summarizes both a historical perspective and our current understanding of BHC. PMID- 17702034 TI - Primary lateral sclerosis mimicking atypical parkinsonism. AB - Primary lateral sclerosis (PLS), the upper motor neurone variant of motor neurone disease, is characterized by progressive spinal or bulbar spasticity with minimal motor weakness. Rarely, PLS may present with clinical features resembling parkinsonism resulting in occasional misdiagnosis as one of the atypical parkinsonian syndromes. Here we describe five patients initially referred with a diagnosis of levodopa-unresponsive atypical parkinsonism (n = 4) or primary progressive multiple sclerosis (n = 1), but subsequently found to have features consistent with PLS instead. Onset age varied from 49 to 67 years. Unilateral limb slowness or clumsiness was the initial complaint in four, and bulbar symptoms in one. Repeated finger/foot tapping was slow in all five, but without fatiguing or decrement. Spasticity with hyperreflexia, exaggerated jaw jerk and extensor plantar responses were eventually seen in all patients. Anterior horn cell involvement developed in three cases. Early gait disturbances resulting in falls were seen in all patients and none of them responded to dopaminergic medications. Two patients underwent dopamine transporter (DaT) SPECT scanning with normal results. Other features included emotional lability (n = 5) and cognitive impairment involving frontal subcortical systems (n = 1). In conclusion, these cases represent a subgroup of PLS patients in whom pyramidal slowness may be mistaken for akinesia, and spasticity misconstrued as rigidity, leading to an erroneous diagnosis of atypical parkinsonism. However, the absence of fatiguing and decrement on repeated finger/foot tapping should help to distinguish these patients from the true atypical parkinsonian syndromes. PMID- 17702035 TI - Hypoglycemia in hospitalized patients treated with antihyperglycemic agents. AB - OBJECTIVE: To determine the incidence and manifestations of hypoglycemia in hospitalized patients receiving antihyperglycemic therapy. RESEARCH DESIGN AND METHODS: The study was a 3-month prospective review of consecutive medical records of all adult, nonpregnant hospitalized patients at a 675-bed university hospital who experienced at least 1 blood glucose (BG) C) of the TITF-1 gene was detected in a mother and her daughter. Two additional patients carried a de novo SGCE nonsense mutation in exon 3 (R97X) and a novel SGCE missense mutation in exon 6 (G227V). Both TITF-1 mutation carriers presented with infancy-onset, nonprogressive chorea, which responded to alcohol intake. In addition, dystonia of the neck and trunk as well as fleeting jerky movements of the distal limbs could be observed. The mutually exclusive appearance of lightning-like myoclonic jerks triggered by action in SGCE mutation carriers and of continuous chorea of all limbs in TITF-1 mutation carriers phenotypically discriminated both genetic disorders. TITF-1 mutations should be considered in choreiform movement disorders with onset in infancy even in the presence of dystonia and myoclonic jerks. PMID- 17702045 TI - An examination of the rheological and mucoadhesive properties of poly(acrylic acid) organogels designed as platforms for local drug delivery to the oral cavity. AB - This study examined the rheological/mucoadhesive properties of poly(acrylic acid) PAA organogels as platforms for drug delivery to the oral cavity. Organogels were prepared using PAA (3%, 5%, 10% w/w) dissolved in ethylene glycol (EG), propylene glycol (PG), 1,3-propylene glycol (1,3-PG), 1,5-propanediol (1,5-PD), polyethylene glycol 400 (PEG 400), or glycerol. All organogels exhibited pseudoplastic flow. The increase in storage (G') and loss (G'') moduli of organogels as a function of frequency was minimal, G'' was greater than G'' (at all frequencies), and the loss tangent <1, indicative of gel behavior. Organogels prepared using EG, PG, and 1,3-propanediol (1,3-PD) exhibited similar flow/viscoelastic properties. Enhanced rheological structuring was associated with organogels prepared using glycerol (in particular) and PEG 400 due to their interaction with adjacent carboxylic acid groups on each chain and on adjacent chains. All organogels (with the exception of 1,5-PD) exhibited greater network structure than aqueous PAA gels. Organogel mucoadhesion increased with polymer concentration. Greatest mucoadhesion was associated with glycerol-based formulations, whereas aqueous PAA gels exhibited the lowest mucoadhesion. The enhanced network structure and the excellent mucoadhesive properties of these organogels, both of which may be engineered through choice of polymer concentration/solvent type, may be clinically useful for the delivery of drugs to the oral cavity. PMID- 17702046 TI - Paternal uniparental isodisomy for chromosome 14 with mosaicism for a supernumerary marker chromosome 14. AB - Uniparental disomy (UPD) describes the inheritance of two homologous chromosomes from a single parent. Disease phenotypes associated with UPD and chromosomal imprinting, rather than with mutations, include Beckwith-Wiedemann syndrome (paternal UPD11p), Angelman syndrome (paternal UPD15), Prader-Willi syndrome (maternal UPD15), and transient neonatal diabetes (paternal UPD6). Here we report on the first case of paternal uniparental isodisomy of chromosome 14 with a mosaicism for a supernumerary marker chromosome 14. The patient demonstrated a small thorax with a 'coat hanger' shape of the ribs, kyphoscoliosis, hypoplasia of the maxilla and mandible, a broad nasal bridge with anteverted nares, contractures of the wrists with ulnar deviation bilaterally, diastasis recti, and marked muscle hypotonia. Vertical skin creases under the chin and stippled epiphyses of the humeri were features not previously described in patients with paternal UPD14. This case illustrates that as with the finding of an isochromosome, a supernumerary marker chromosome can be an important clue to the presence of UPD14. PMID- 17702047 TI - Prenatal ascertainment of OEIS complex/cloacal exstrophy - 15 new cases and literature review. AB - Omphalocele-exstrophy of the bladder-imperforate anus-spinal defects (OEIS) complex or cloacal exstrophy (EC), describes a rare grouping of more commonly occurring component malformations [Carey et al., 1978]. The etiology is unknown, but likely heterogeneous. While postnatal identification of its associated gastrointestinal, spinal, and genitourinary systems delineates the extent and natural history of OEIS complex, prenatal findings may provide additional information regarding early detection, possible causative factors, and outcome. The purposes of this study were to: (1) present the prenatal ascertainment of OEIS complex in this series of 15 cases identified through several different sources compared to the literature, and (2) discuss the relationship of these prenatal findings to possible abnormal developmental mechanisms causing OEIS complex. These 15 cases indicate that OEIS complex may be difficult to diagnose prenatally, and that the full extent of abnormalities may not be clear until postnatal exam. Confusion with limb-body wall complex (two of our cases) and pentalogy of Cantrell (one of our cases) can occur. Anal/gastrointestinal malformations and genital ambiguity are under-ascertained. Conversely, prenatal defects may resolve postnatally, yet may provide clues for pathogenetic mechanisms. For instance, the finding of nuchal thickening in our three cases (one reported) suggests vascular/hemodynamic compromise early in embryologic development, or intrathoracic compression leading to jugular lymphatic obstruction may play a role. The association of twinning and OEIS complex suggests they may occur as early as blastogenesis. Our three sets of discordant twins also suggest a non-genetic etiology for OEIS complex of uteroplacental insufficiency. This study also indicates that OEIS complex may be more common than previously thought. PMID- 17702048 TI - Ehlers-Danlos syndrome due to tenascin-X deficiency: muscle weakness and contractures support overlap with collagen VI myopathies. PMID- 17702049 TI - Dehydrosteroid measurements in maternal urine or serum for the prenatal diagnosis of Smith-Lemli-Opitz syndrome (SLOS). AB - In a large multi-center trial involving prenatal screening for Smith-Lemli-Opitz syndrome (SLOS), we evaluated maternal urine and serum steroid analysis as a non invasive diagnostic alternative to amniotic fluid sterol analysis. Candidate steroid ratios included: 7-dehydropregnanetriol/pregnanetriol (7-PT/PT), 8 dehydropregnanetriol/PT (8-PT/PT), the sum of these two (7 + 8-PT/PT), and dehydroestriol/estriol (DHE3/E3). Results are presented from 19 SLOS pregnancies, and 732 reference pregnancies that were screen positive for SLOS but negative on testing in amniotic fluid. Steroid ratios are expressed as multiples of the 75th centile (MoS), rather than multiples of the median, as most reference measurements were undetectable. All four urine ratios were available in 12 SLOS pregnancies; the median 7-PT/PT MoS was 94, with no overlap between affected and reference pregnancies in the second trimester. The separation between these groups increased by 27% per week. The other three ratios performed similarly in urine, with (7 + 8)-PT/PT ratios being marginally superior, due to fewer high reference outliers. All four steroid ratios in urine were diagnostic for SLOS between 14 and 22 weeks' gestation. In six SLOS pregnancies in which all serum analytes were measured, the median 7-PT/PT MoS was 71, and there was slight overlap in the second trimester. The separation increased by 28% per week. Steroid ratios in serum were less definitive than in urine but might be useful in certain circumstances, at 14 weeks gestation or later. Urine testing performance prior to 14 weeks gestation appears promising, but reference data are sparse. PMID- 17702050 TI - Diagnosing dementia -- ICD-10 not so bad after all: a comparison between dementia criteria according to DSM-IV and ICD-10. AB - BACKGROUND: The discrepancy between results of diagnosing dementia with ICD-10 and DSM-IV has been shown by several studies. Our aim was to show that the two diagnostic systems are more or less alike if ICD-10 is interpreted in the way we believe is in the intention of the ICD-10 authors. METHODS: Two hundred and seven patients consecutively referred patients and their caregivers were interviewed and the patients were clinically examined. Algorithms using criteria for the World health Organization's International classification of Diseases, 10(th) revision (ICD-10) and the American Psychiatric Association's, the fourth edition (DSM-IV) were followed to diagnose dementia. RESULTS: A diagnosis of dementia was made for 198 patients and there was 100% agreement (kappa = 1,0) between ICD-10 and DSM-IV diagnosis. CONCLUSION: In the ICD-10 criteria 'decline in other cognitive abilities such as abstraction, judgement, problem solving' has been interpreted in a way that all the above executive functions must be impaired for diagnosing dementia. According to our interpretation these are meant to be examples of functions which may be compromised in demented patients.The results of our study demonstrate that this interpretation of ICD-10 has shown that the authors of ICD-10 and DSM-IV have succeeded in harmonising the two systems. However, the ICD-10 criteria are phrased in a way that leaves much to individual interpretation. WHO has to define the ICD criteria in such a way that there is uniformity in its interpretation. PMID- 17702051 TI - Effect of patulin on the interdigitating dendritic cells (IDCs) of rat thymus. AB - Patulin is a common fungal contaminant of ripe apples used for the production of apple juice concentrates and it is also present in other fruits, vegetables and food products. Patulin is a secondary metabolite produced by species of the genera Penicillium, Aspergillus and Byssochlamys. Patulin has been reported to be mutagenic, carcinogenic and teratogenic. Antigen-presenting cells (APCs) are of prime importance in the innate immune response; they capture antigen in tissues and then migrate to the lymphoid organs to present the antigen to T lymphocytes. Thus, they are crucial for the initiation of immunity. Interdigitating dendritic cells (IDCs) are a subset of APCs that are present at the lymphatic organs. In the thymus, they act in positive and negative selection during T cell development. In the present study, patulin was administered orally to growing male rats aged 5-6 weeks. A dose of 0.1 mg kg(-1) bw day(-1) was given to rats for a period of 60 or 90 days daily. The effect of patulin on the IDCs of thymus was investigated by transmission electron microscopy (TEM), and the results were evaluated in terms of cell destruction. In the rats of the control group, it was observed that the IDCs had an indented nucleus, a clear cytoplasm and numerous membrane extensions. In the cytoplasm, a well-developed golgi complex, mitochondria, granular endoplasmic reticulum and a small number of lysosomal structures were observed. At day 60 of patulin-treated rat groups (P-60), loss of cristae in mitochondria and chromatin margination and lysis in the nucleus were found. It was observed that the IDCs had a perinuclear area of cytoplasm surrounded by a peripheral electron-lucent zone. In the cytoplasm of the 90-day patulin-treated rat group (P-90), a peripheral electron-lucent zone was also found, similar to the P-60 group. Additionally increase in vesicular and lysosomal structures, increase in apoptotic bodies and condensation of chromatin in the nucleus were noted. It was observed that patulin leads to apoptotic body formation and cell apoptosis in the IDCs of rat thymus especially in the P-90 treated groups. PMID- 17702052 TI - Developing a simple laboratory test for Alzheimer's disease: measuring acetylcholinesterase in saliva - a pilot study. PMID- 17702053 TI - Short/long heterozygotes at 5HTTLPR and white matter lesions in geriatric depression. AB - OBJECTIVE: We examined the relationship between 5HTTLPR genotype and volume of magnetic resonance imaging (MRI) brain lesions. METHOD: We studied 217 older depressed patients and 141 individuals in the comparison group using a standard brain MRI protocol to calculate lesion volumes. Genotype at 5HTTLPR was determined for each subject. RESULTS: In age-adjusted models, the l/s genotype was associated with increased volume of total and white-matter lesions among depressed patients. This relationship lost significance in models controlling for reported hypertension. CONCLUSIONS: The finding that 5HTTLPR heterozygotes have higher vascular lesion volumes may be related to development of hypertension. PMID- 17702054 TI - Levator co-activation is a significant confounder of pelvic organ descent on Valsalva maneuver. AB - OBJECTIVE: A Valsalva maneuver is used clinically and on imaging in order to determine female pelvic organ prolapse. We have examined the potential confounding effect of levator co-activation at the time of a Valsalva maneuver and the impact of repetition with biofeedback instruction. METHODS: Fifty nulliparous women at 36-38 weeks' gestation received 3D/4D translabial ultrasound investigation in the dorsal resting position after bladder emptying. Valsalva maneuvers were recorded initially and after repeated attempts with visual biofeedback both during the maneuver and after, with the operator demonstrating findings on the ultrasound monitor, in order to abolish levator co-activation. Offline analysis was subsequently undertaken. RESULTS: Significant differences between first and optimal Valsalva maneuver were found for bladder neck position, bladder neck descent, hiatal sagittal diameter and hiatal area on Valsalva. In a minority of women (22/50) we observed a reduction in the sagittal hiatal diameter on first Valsalva maneuver, indicating levator co-activation. A reduction in sagittal diameter was seen in only 11/50 after instruction. Levator co-activation was associated with significantly lower bladder neck descent. CONCLUSION: The Valsalva maneuver is frequently accompanied by a pelvic floor muscle contraction. Levator co-activation may be a substantial confounder, reducing pelvic organ descent. Without repetition and digital, auditory or visual biofeedback, women may not perform a correct Valsalva maneuver. Biofeedback markedly reduces the likelihood of levator co-activation but does not abolish it completely. PMID- 17702055 TI - The development of a rating scale to screen social and emotional detachment in children and adolescents. AB - Rating scales to assess psychopathic characteristics in children and adolescents show a considerable item overlap with rating scales to assess attention deficit hyperactivity disorder (ADHD), oppositional-defiant disorder (ODD) and conduct disorder (CD) symptoms. The aim of this study is to preliminary test a short questionnaire clinicians can use to screen the unique characteristics of psychopathy. Parental ratings of psychopathic characteristics and symptoms of ADHD, ODD and CD were gathered in a community sample of 2535 4-18-year-old Dutch children. The dimensionality of the ratings was determined by factor analysis and related to ADHD, ODD and CD. Two factors emerged covering egocentric-narcissistic and callous-unemotional characteristics. To avoid unnecessary stigmatization of youngsters the first factor is referred to as the "social detachment dimension" and the second as the "emotional detachment dimension". Parental ratings were reliable across all age and gender groups, and correlated moderately with ODD and CD, but not with ADHD. Preliminary findings support a two-dimensional syndrome depicting respectively narcissistic and unemotional characteristics. The syndrome is associated with ODD and CD symptoms and possibly depicts a subtype of the ODD/CD childhood disorder. PMID- 17702056 TI - Depression or apathy and functional recovery after stroke. AB - OBJECTIVES: While depression and apathy are common after stroke, past studies have done little to examine the influence of these two symptoms on functional outcome respectively. This study was designed to examine the effect of depression or apathy on functional recovery after stroke in 237 Japanese stroke patients. METHODS: We assessed the psychological status using self-rating scales [the Zung Self-Rating Depression Scale (SDS) for depression and the Apathy Scale (AS) for apathy] and an observer-rating scale [the Neuropsychiatric Inventory (NPI)]. We assessed physical disability using the Functional Independence Measurement (FIM). Post-hoc test and multiple regression analysis were used to determine the independent effects of post-stroke depression and apathy on functional outcome. RESULTS: Depression was observed in 75 (31.6%) using SDS and 88 (40.2%) using NPI, and apathy in 95 (40.1%) using AS and 42 (19.2%) using NPI, respectively. Post-hoc test and multiple regression analysis indicated that the cognitive variable (Mini-Mental State Examination: MMSE score) and AS score, but not SDS score, correlated negatively with improvement in FIM. CONCLUSIONS: Apathy might be more frequently associated with functional abilities and likely interact with the recovery process as compared with depression after stroke. PMID- 17702057 TI - pFind 2.0: a software package for peptide and protein identification via tandem mass spectrometry. AB - This paper describes the pFind 2.0 software package for peptide and protein identification via tandem mass spectrometry. Firstly, the most important feature of pFind 2.0 is that it offers a modularized and customized platform for third parties to test and compare their algorithms. The developers can create their own modules following the open application programming interface (API) standards and then add it into workflows in place of the default modules. In addition, to accommodate different requirements, the package provides four automated workflows adopting different algorithm modules, executing processes and result reports. Based on this design, pFind 2.0 provides an automated target-decoy database search strategy: The user can just specify a certain false positive rate (FPR) and start searching. Then the system will return the protein identification results automatically filtered by such an estimated FPR. Secondly, pFind 2.0 is also of high accuracy and high speed. Many pragmatic preprocessing, peptide scoring, validation, and protein inference algorithms have been incorporated. To speed up the searching process, a toolbox for indexing protein databases is developed for high-throughput applications and all modules are implemented under a new architecture designed for large-scale parallel and distributed searching. An experiment on a public dataset shows that pFind 2.0 can identify more peptides than SEQUEST and Mascot at the 1% FPR. It is also demonstrated that this version of pFind 2.0 has better usability and higher speed than its previous versions. The software and more detailed supplementary information can both be accessed at http://pfind.ict.ac.cn/. PMID- 17702058 TI - Modeling ssDNA electrophoretic migration with band broadening in an entangled or cross-linked network. AB - We use a coarse-grained model proposed by Graham and Larson based on the temporary network model by Schieber et al.. [1] to simulate the electrophoretic motion of ssDNA and corresponding band broadening due to dispersion. With dimensionless numbers reflecting the experimental physical properties, we are able to simulate ssDNA behavior under weak to moderate electric field strengths for chains with 8-50 entanglements per chain ( approximately 1000-8500 base pairs), and model smoothly the transition from reptation to oriented reptation. These results are fitted with an interpolation equation, which allows the user to calculate dimensionless mobilities easily from input parameters characterizing the gel matrix, DNA molecules, and field strengths. Dimensionless peak widths are predicted from mobility fluctuations using the central limit theorem and the assumption that the mobility fluctuations are Gaussian. Using results from previous studies of ssDNA physical properties (effective charge xiq and Kuhn step length b(K)) and sieving matrix properties (pore size or tube diameter a), we give scaling factors to convert the dimensionless values to "real" experimental values, including the mobility, migration distance, and time. We find that the interpolation equation fits well the experimental data of ssDNA mobilities and peak widths, supporting the validity of the coarse-grained model. The model does not account for constraint release and hernia formation, and assumes that the sieving network is a homogeneous microstructure with no temperature gradients and no peak width due to injection. These assumptions can be relaxed in future work for more accurate prediction. PMID- 17702059 TI - Native PAGE eliminates the problem of PEG-SDS interaction in SDS-PAGE and provides an alternative to HPLC in characterization of protein PEGylation. AB - PEGylation of proteins has become an increasingly important technology in recent years. However, determination and characterization of the PEGylation products are problematic especially for the reaction mixture containing various modified proteins, unreacted PEG, and unmodified protein. A comparative study was carried out with two HPLC methods and two electrophoresis methods for characterization of the reaction mixture in PEGylation of HSA with PEG 5000, 10000, and 20000. RP HPLC fails to give the correct information about the reaction of PEG 20000. Size exclusion HPLC (SE-HPLC) produced very poor resolution on the PEG 5000 reaction. SDS-PAGE can run multiple samples of all PEGylation but the bands were smeared or broadened probably due to the interaction between PEG and SDS. On the other hand, native PAGE eliminates the problem of PEG-SDS interaction and provides better resolutions for all samples. Various PEGylated products and unmodified protein migrate differentially in native PAGE under nondenatured conditions. The results demonstrated that native PAGE could be a good alternative to HPLC and SDS-PAGE for the analysis of PEG-protein conjugates especially for characterization of the PEGylation mixture. PMID- 17702060 TI - Reliability of high-throughput genotyping of whole genome amplified DNA in SNP genotyping studies. AB - Whole genome amplification (wga) of DNA is being widely implemented in many laboratories to extend the life of samples only available in limited quantities for genetic analysis. We determined the reliability of wgaDNA genotypes in three sets of replicates from the same individuals: (i) 23 pairs of genomic DNA (gDNA), (ii) 43 pairs gDNA versus wgaDNA, and (iii) 29 pairs of independently amplified wgaDNA. Amplification was performed using multiple displacement amplification (MDA). Genotyping was successful for both DNA types for 1268 out of 1534 SNPs from 164 cardiovascular candidate genes assayed in a single Illumina panel. Amplified DNA failed for 77 SNPs (6%) that were genotyped successfully with genomic material. Percent of successful SNP calls, and concordance between pairs and kappa statistics (kappa) were determined. A total of 54 110 genotypes from gDNA-wgaDNA pairs were available for concordance analysis. Mean kappa for gDNA wgaDNA pairs was 0.99. Concordance between gDNA-wgaDNA pairs was higher than amongst wgaDNA pairs (mean kappa for the 29 independently amplified pairs of wgaDNA was 0.95; interquartile range: 0.93-1.00). A statistical analysis of those SNPs which failed to genotype from amplified DNA only revealed that those loci were more likely to be closer to the telomeres and in locally GC-rich sequences. In summary, the MDA method produces wgaDNA samples that can be genotyped using high-throughput technology with a very high reproducibility to the original DNA but with slightly lower call rates. DNA amplification methodologies provide a useful solution for current and future large-scale genetic analyses especially with limited quantities of samples and DNA. PMID- 17702063 TI - Determination of tetracycline residues in honey by CZE with ultraviolet absorbance detection. AB - We have developed a sensitive CE method to determine eight tetracyclines (TCs) (chlortetracycline, demeclocycline, doxycycline, methacycline, minocycline, oxytetracycline, TC, and rolitetracycline (RTC)) in honey samples. The running buffer was 150 mM sodium borate (pH 9.8) and 2.5% 2-propanol with 15 s hydrodynamic injection at 25 kV. We have also developed an SPE procedure with a C18 cartridge as a clean-up step. Analytes were detected at 360 nm in less than 16 min. LODs ranged in honey from 23.9 microg/kg for TC to 49.3 microg/kg for RTC. Seven samples of Spanish honey of different floral origins were examined. None of them showed contamination with these antibiotics using the proposed method. PMID- 17702061 TI - Specific and genotypic identification of Cryptosporidium from a broad range of host species by nonisotopic SSCP analysis of nuclear ribosomal DNA. AB - The accurate identification of Cryptosporidium (Protozoa: Apicomplexa) species and genotypes is central to the understanding of the transmission and to the diagnosis and control of cryptosporidiosis. In this study, we demonstrate the effectiveness of nonisotopic SSCP analysis of a approximately 300 bp region of the small subunit (pSSU) of ribosomal DNA for the specific identification of and delineation among 18 different Cryptosporidium species and genotypes from a wide range of hosts. This mutation scanning approach allowed the rapid and reliable differentiation between species/genotypes differing by as little as 1.3% in the pSSU sequence, with the capacity to detect point mutations. The present findings confirm the usefulness of this tool for the rapid genetic screening of Cryptosporidium samples from any host species, providing a foundation for detailed systematic, epidemiological and ecological studies. Although applied herein to pSSU, this low cost approach should be applicable to a wide range of genetic loci for population genetic investigations of Cryptosporidium. PMID- 17702064 TI - Measurement of glycogen synthase activity in crude extracts by CE. AB - Glycogen synthase catalyzes the incorporation of UDP-glucose into glycogen. The activity of the enzyme is usually measured either by a spectrophotometric method or by a radioassay. The first one is not suitable because of the difficulties regarding the use of coupled enzymes in crude extracts, while the second is a time-consuming method involving glycogen isolation and manipulation of radioactivity. We have used a CZE technique as a novel approach to measure glycogen synthase activity. The separations were performed at 22 kV (36 microA) in uncoated capillaries (53 cmx50 microm). Sample injection time was 30 s and nucleotides were monitored at 254 nm. Best resolution was achieved in 20 mM tetraborate buffer, pH 9.2. Curves of absorbance as a function of UDP and UDP glucose concentration were linear. Enzyme activity in oocyte extracts was linear with respect to time (up to15 min) and enzyme concentration. The K(m app.) for UDP-glucose was 0.87 mM, a value identical to the one reported using the radioassay. CZE enables easy quantitation of compounds, high sensitivity, and automation of the process. Small sample sizes are required, interferences by auxiliary enzymes and manipulation of radioactivity are avoided, and analysis time is significantly diminished. PMID- 17702065 TI - Low EOF rate measurement based on constant effective mobility in microchip CE. AB - A new method for quickly determining low EOF rates (micro(EOF)) in microchip CE is described. The measurement is based on the notion that the effective mobility (micro(eff)) of an analyte is a constant in a certain BGE. The micro(eff) of an analyte is determined in a reference fast-electroosmosis microchip, and the apparent mobility (micro(app)) of the analyte can be determined in the microchip with unknown low electroosmosis, and then micro(EOF) in the low-electroosmosis microchip can be calculated according to the equation mu(EOF) = micro(app) - micro(eff). By an indirect method or other conventional methods, micro(eff) can be easily measured in the reference microchip. The proposed method is particularly useful for low-electroosmosis measurements in wall-modified microchannels. PMID- 17702066 TI - Fabrication of poly(methyl methacrylate) microfluidic chips by redox-initiated polymerization. AB - In this report, a method based on the redox-initiated polymerization of methyl methacrylate (MMA) has been developed for the rapid fabrication of poly(methyl methacrylate) (PMMA) microfluidic chips. MMA containing 2-2'-azo-bis isobutyronitrile was allowed to prepolymerize in a water bath to form a viscous prepolymer solution that was subsequently mixed with MMA containing a redox initiation couple of benzoyl peroxide/N,N-dimethylaniline. The dense molding solution was sandwiched between a silicon template and a piece of 1-mm-thick PMMA plate. The polymerization could complete within 50 min under ambient temperature. The images of raised microfluidic structures on the silicon template were precisely replicated into the synthesized PMMA substrate during the redox initiated polymerization of the molding solution. The chips were subsequently assembled by the thermal bonding of the channel plates and the covers. The new fabrication approach obviates the need for special equipment and significantly simplifies the process of fabricating PMMA microdevices. The attractive performance of the novel PMMA microchips has been demonstrated in connection with contactless conductivity detection for the separation and detection of ionic species. PMID- 17702067 TI - Improved STR typing of telogen hair root and hair shaft DNA. AB - Today the STR typing of telogen hair and hair shafts is regarded as a challenge. The small DNA quantity in the hair is highly degraded. Another problem are PCR inhibitors in the hair. In particular hair pigments, the melanins, are known to inhibit PCR. Hairs are exposed to sunlight and partly to chemical oxidation processes, which make them even more difficult to analyze. To increase the chances of a correct typing of hair, the small amount of DNA must be successfully isolated and the inhibitors have to be removed or neutralized. Furthermore, miniSTR typing improves the analysis of stains with degraded DNA like it is the case with hair. We introduce a nonorganic extraction method and in addition a miniSTR concept which is promising in typing stains with little and degraded DNA, especially hairs. The miniSTR concept including five database STRs (SE33, VWA, TH01, FGA, D3S1358) and the gender typing system Amelogenin was optimized for the amplification of hair DNA. Compared to commercial STR kits, this approach resulted in considerably higher success rates. PMID- 17702068 TI - Identification and relative quantification of adenosine to inosine editing in serotonin 2c receptor mRNA by CE. AB - A new method has been developed allowing the identification and relative quantification of different forms of mRNA after RNA editing. This method was applied to the serotonin 2c receptor mRNA that potentially exhibits 32 different forms after adenosine to inosine editing at five different sites located in a row of 13 nucleotides. CE was used to characterize fluorescently labeled ssDNA molecules on the basis of their conformational polymorphism. The relative amount of these 32 mRNA forms has been estimated by measuring the fluorescence intensity of each individual DNA strand. Accuracy of quantification was established by diluting one form into another or into a mixture of cDNA, showing linear and precise proportion of each form (0.06 or =4 cm (vs <4 cm: HR, 1.23; 95% CI, 1.15-1.30) were additional factors that increased the risk of mortality among patients with stage IB disease. Bronchioloalveolar carcinoma and Asian ethnicity were associated with decreased mortality risk in stage I NSCLC. CONCLUSIONS: Stage I NSCLC with poorly differentiated histology and stage IB NSCLC with non-upper lobar tumor location or tumor size > or =4 cm carried an increased mortality risk. PMID- 17702092 TI - HTR2C haplotypes and antipsychotics-induced weight gain: X-linked multimarker analysis. AB - The 5HT2C receptor (HTR2C) has been hypothesized to represent an important modulator in feeding behavior. Evidence was based on the observation that knock out mice for the HTR2C receptor gene develop obesity and that many antipsychotics (AP) with potent HTR2C antagonism may induce weight gain in susceptible individuals. Pharmacogenetic studies focusing either on the Cys23Ser polymorphism or on the -759C/T promoter polymorphism of the X-linked HTR2C receptor gene revealed significant findings for the -759C/T polymorphism, however, no study has performed haplotype analyses for both polymorphisms. METHODS: We analyzed three functional polymorphisms (Cys23Ser, -759C/T, and (GT)12-18/(CT) 4-5) of the HTR2C in 139 schizophrenic patients mainly treated with clozapine. Weight gain was assessed over a time course of 6-14 weeks (mean 8.2 weeks). RESULTS: Single marker and haplotype analysis revealed no significant associations with AP induced weight gain. The haplotype Long-C-Ser was protective against weight gain, but the number of subjects available for that analysis was small. CONCLUSIONS: Our pilot study did not detect any significant haplotype conferring risk for antipsychotic-induced weight gain although the statistical model took into account the X-linked heterogeneity and did correct for confounding factors (i.e., ethnicity, medications, clinical response, time of assessment). PMID- 17702094 TI - The elderly diabetic's eyes. AB - This review article attempts to clarify current and future issues concerning diabetic retinopathy in the elderly. This retinopathy is often part of multiple geriatric ophthalmological diseases (cataract, glaucoma, age-related macular degeneration [ARMD]). Current management is insufficient. A variety of factors come together to aggravate the situation: the increase in the number of elderly diabetic patients and the decrease in the number of ophthalmologists. Through a review of the literature, seriously lacking in prospective studies specific to the geriatric population, we discuss the epidemiology, the screening problems, and the various issues concerning the overall ophthalmologic and diabetologic management inherent to these patients' age and condition. We stress the seriousness of the visual disability of the older subject, but also the overall morbidity and mortality. We observe that recommendations can only be based on expert opinion. Each section includes a warning on the high iatrogenic risk in this area. The caregiver should avoid two pitfalls: a lax attitude related to fear or defeatism and excessive interventionism that may be inappropriate to the patient's condition. PMID- 17702093 TI - The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in philadelphia chromosome-negative cells. AB - BACKGROUND: Clonal cytogenetic abnormalities (CCA) were detected in Philadelphia chromosome (Ph)-negative cells in some patients with chronic myeloid leukemia (CML) who attained a cytogenetic response to imatinib mesylate. In some patients, CCA/Ph-negative status was associated with myelodysplasia or acute myeloid leukemia. The objective of the current study was to determine the prognostic impact of CCA/Ph-negative cells. METHODS: The authors compared the pretherapeutic risk factors (Kruskall-Wallis test), exposure to cytotoxic drugs (chi-square test), and overall and progression-free survival (Kaplan-Meyer and logistic regression analysis, respectively) of 515 patients with mostly chronic-phase CML who were treated with imatinib mesylate after failure of interferon-alpha according to whether they attained a major cytogenetic response (MCR) (n = 324 patients), an MCR with CCA/Ph-negative status (n = 30 patients), or no MCR (n = 161 patients). RESULTS: CCA/Ph-negative status most frequently involved chromosomes Y, 8, and 7. No significant differences in pretherapeutic risk factors were detected between patients who attained an MCR with and without CCA/Ph-negative cells, except that exposure to alkylating agents was more frequent in patients with CCA/Ph-negative cells, and overall and progression-free survival were identical. With a median follow-up of 51 months, only 2 patients developed myelodysplastic syndromes (MDS). CONCLUSIONS: The overall prognosis for patients who had CML with CCA/Ph-negative status was good and was driven by the CML response to imatinib mesylate. Isolated CCA/Ph-negative cells in the absence of morphologic evidence of MDS do not justify a change in therapy. PMID- 17702096 TI - Coronary heart disease and cardiovascular autonomic neuropathy in the elderly diabetic. AB - Diabetes and old age come together to increase the frequency and severity of coronary heart disease. Often clinically nearly silent, symptoms frequently manifest dramatically, to such an extent that the question of screening should be raised, as in younger subjects. Preventing these manifestations relies on better management of the cardiovascular risk factors and obtaining good blood glucose control, but here progress remains necessary, which also requires adapting to the older patient's clinical and psychological condition. Cardiovascular autonomic neuropathy is a frequent degenerative complication in diabetics, particularly in the oldest subjects. The most severe types have serious clinical consequences, thus a higher mortality factor, but the mechanisms remain poorly understood. As for coronary heart disease, the therapeutic tools have expanded these last few years and should be thought out in relation to the geriatric evaluation, with the objective of improving these patients' quality of life. Therefore, a necessary distinction should be made between subjects who have aged successfully, whose management, ultimately, differs little from younger subjects, and frail elderly individuals for whom exploratory techniques and treatment should be adapted. PMID- 17702095 TI - The oral cavity of elderly patients in diabetes. AB - Diabetes mellitus is a common and growing global health problem leading to several complications. Among these periodontal diseases are considered as the sixth complication of diabetes mellitus. This article reviews the relationship between diabetes and oral health, particularly focusing on periodontal diseases, dental caries and xerostomia. There is a bidirectional interrelationship between diabetes and periodontal diseases. Periodontitis is more prevalent and severe in patients with diabetes than in normal population. Therapy of periodontal infection contributes to a positive glycaemic control management and enables reduction of the burden of complications of diabetes mellitus. Diabetics have an increased predisposition to the manifestation of oral diseases like candidiasis which is associated with poor glycaemic control and therapeutic dentures. This predisposition also contributes to xerostomia, which may be due to increased glucose levels in oral fluids or immune dysregulation. PMID- 17702097 TI - Congestive heart failure in the elderly diabetic. AB - The elderly diabetic is a potential congestive heart failure patient. Cardiac involvement is multifactorial, particularly ischemic conditions because of the accumulation at that age of vascular risk factors and therefore the frequency of coronary damages. The elderly diabetic very often has high blood pressure, with the risk of developing a hypertensive heart disease. Beyond these issues, the effects of chronic hyperglycaemia and insulin resistance on the heart specifically alter left ventricle compliance and therefore diastolic function, thus accelerating the effects proper to aging. No specific recommendation has been published on the management of the elderly diabetic with congestive heart failure. Even at an advanced age, with a clinical diagnosis of congestive heart failure that is sometimes difficult to make, the cardiological evaluation should be conducted rigorously within a global evaluation, and treatment should follow the same rules as in younger patients, with great caution given to the iatrogenic risks inherent to this population. PMID- 17702098 TI - Diabetic nephropathy in the elderly. AB - Renal impairment is frequent in aged diabetic patients, notably with type 2 diabetes. It results from a multifactorial pathogeny, particularly the combined actions of hyperglycaemia, arterial hypertension and ageing. Diabetic nephropathy (DN) is associated with an increased cardiovascular mortality. DN often leads to end stage renal failure (ESRF) which causes specific problems of decision and practical organization of extra-renal epuration in diabetic and aged patients. In the absence of renal biopsy, clinical signs are often insufficient to assess the diabetic origin of a nephropathy in an elderly diabetic patient. Prevention of DN is principally based on tight glycaemic and blood pressure control. The progression of renal lesions can be retarded by strict blood pressure control, notably by blocking of the renin-angiotensin system, if well tolerated in aged patients. It is absolutely necessary to avoid the worsening of renal lesions by potentially nephrotoxic products, notably non steroidal anti-inflammatory drugs (NSAIDs) and iodinated contrast media. At the stage of renal failure, it is important to adapt the antidiabetic treatment, and in the majority of the cases, to switch to insulin when glomerular filtration rate (GFR) is below 30 ml/mn/1.73 m2. PMID- 17702099 TI - Diabetic foot disease in the elderly. AB - Elderly diabetic patients are particularly burdened by foot disease. The main causes for foot disease are peripheral neuropathy, foot deformities and peripheral arterial disease (PAD). Other risk factors include poor vision, gait abnormalities, reduced mobility an medical co-morbidities. The risk of major amputations increases with age, along with the increased prevalence of these risk factors. Th true risk of amputation and other burdens of foot disease in the elderly are likely underestimated by current epidemiological data. Th prevalence of neuropathy, foot deformities and PAD as well as the risk of amputation all increase with age even in non-diabetic patients. The principles of prevention and management of diabetic foot disease may also apply to large segments of the elderly non-diabetic population. Foot ulcer prevention relies on the identification of high risk patients and avoidance of triggering events, such as ill-fitting shoes, walking barefoot or poor self-care. PAD is a major cause of amputation and should be prevented by lifelong attention to glycaemic control, treatment of hypertension and dyslipidemia, and avoidance of smoking. The treatment of foot ulcers relies on pressure relief (off-loading), wound debridement, and treatment of infection and ischemia. It requires an individualized approach considering the patient's co-morbidities and functional status. Off-loading remains essential, but devices such as total contact casts or crutches can only rarely be implemented. However, providing adapted standard foot wear and insisting on its consistent use even at home is often effective. The benefits of aggressive vascular or orthopaedic surgery should be weighed against the risks of prolonged hospitalisation and resulting functional decline. Greater attention to prevention and individualized care are needed to reduce the burden of diabetic foot disease in the elderly. PMID- 17702100 TI - Disability and quality of life in elderly people with diabetes. AB - To implement preventive policies of disability in older diabetic people, the role of diabetes in the disablement process should be investigated. Diabetes mellitus is consistently associated with a higher prevalence of disability at all states, as well as with a progression in disability states and may be considered as a brake on recovery. This association is partially explained by existing complications, associated conditions (obesity, depression, arterial hypertension) treatment burden, and other social characteristics (lower income, lower educational level). Finally, in the disablement process, the role of altered muscle metabolism due to diabetes, aging, nutrition and sedentary lifestyle may represent a major target for interventions to improve functions and potentially activities in elderly people. PMID- 17702101 TI - Diabetes and education in the elderly. AB - Diabetes mellitus (DM) in the elderly is a chronic disease where self management is a key aspect. This includes lifestyle modification (diet and exercise), medication compliance and hypoglycaemia management. Education is an important part of this process and the specific needs of the older population with DM have been underlined. The literature has shown that education through a multidisciplinary approach may improve the glycaemic control in selected elderly patients with DM. This article will focus on the evidences from the medical literature and the multiple challenges of teaching in this population. PMID- 17702102 TI - Non pharmacological treatments in elderly diabetics. AB - Among the therapeutic resources available for the elderly diabetic, diet and exercise are often neglected because patients are reluctant to make changes and significant amount of time of healthcare providers and physicians is required for patient education. Diet and exercise work in synergy to lower the biological parameters of diabetes control. Diet in the elderly diabetic patient is based essentially on the nutritional recommendations for the elderly subject, diabetic or non diabetic. Recent studies on exercise demonstrate the value of resistance training in increasing muscle mass, preferably over endurance training. The benefits obtained also involve autonomy and quality of life. Taking up exercise is not devoid of disadvantages because of the frequent co-morbidity at this age. PMID- 17702103 TI - More on high-low agreements. PMID- 17702104 TI - TransforMED and rebuilding family medicine. PMID- 17702105 TI - TransforMED and rebuilding family medicine. PMID- 17702106 TI - How do you define "new patient"? PMID- 17702112 TI - More tributes... PMID- 17702111 TI - Here is where all the MTs have gone. PMID- 17702113 TI - Atrazine is safe. PMID- 17702114 TI - Pieces of a paranoid past. A plan moves ahead to reconstruct East Germany's shredded secret police files. PMID- 17702115 TI - Does sleeping after a meal lead to weight gain? PMID- 17702117 TI - Comments on AVMA support of companion animal and equine research institute. PMID- 17702118 TI - High time for the DVM Year of the Woman. PMID- 17702119 TI - [Pimecrolimus and vaccinations]. PMID- 17702121 TI - [Duration of anticoagulant therapy and risk of recidivation of TEN--editorial]. PMID- 17702120 TI - [Surgical treatment of giant emphysematous lung bullae]. AB - OBJECTIVE: Lack of Brazilian publications regarding this disease in Brazil led us to perform the current work to describe the historical evolution and to analyze results of the surgical treatment of Giant Emphysematous Lung Bullae at the Santa Casa de Sao Paulo. METHODS: We have retrospectively assessed, between January 1979 and June 2005, the medical records of 83 patients submitted to one of four surgical modalities: the thoracoscopic bullectomy, VATS bullectomy, VATS bullae drainage and bullae drainage with local anesthesia, totaling 92 surgeries. Parameters analyzed were hospitalization time, post-surgical complications, perioperative and late mortality in addition to clinical and functional pre- and post- surgical parameters. RESULTS: Morbidity was 40.2% and early post-surgical mortality 4.3%. Post-surgical complications were associated to the patient's morbid history. Factors such as diffuse pulmonary emphysema, multiple bullae and age did not influence early complications. There was an improvement in the symptomatology and functional results in 94.5% of the patients. There was no return on he operated bullae. Mortality five years after surgery was of 18.3% and arose, primarily from clinical progression of the diffuse pulmonary emphysema. CONCLUSIONS: Several surgical modalities were performed to treat the emphysematous lung bullae, from bullectomy to thoracotomy, at the initial phase until drainage of the bullae with local anesthesia and sprayed talc, the currently preferred modality. Regardless of the method used, however, notwithstanding the relatively high morbidity, post-surgical results are highly favorable with low mortality and uncontestable clinical-functional improvement of the operated patients. PMID- 17702122 TI - [Clinical experience in treatment with the long-term insulin analogue glargin in a diabetes centre]. AB - OBJECTIVE: To assess the experience obtained by a diabetes centre in the treatment of patients with type 1 diabetes with the long-term insulin analogue glargin. PATIENT SAMPLE AND METHOD: 136 patients with type 1 diabetes mellitus (DM) were evaluated on a retrospective basis for the period from March 2004 to march 2005. We monitored HbA(1c) before the treatment with glargin, after 3 months, again after 6 months, and finally after 1 year of therapy. We evaluated the effectiveness of treatment with glargin insulin based upon diabetes compensation at the start of treatment. We also compared glycaemia variability in the 6 months prior to treatment initiation and the 6 months after the application of glargin insulin, this was done using the standard glycaemia deviation obtained from the patients' glucometers. In addition we evaluated the changes in total, basal and bolus daily dose of insulin after the change in therapy. RESULTS: The results were evaluated in the form of a median and the percentile of 25 and 75. Before the glargin therapy started, HbA(1c) was 7.4 (6.5-8.5)%. It decreased dramatically to 7.0 (6.2-8.1)% after 3 months of therapy (p < 0.01), to 7.2 (6.3 8.2)% after 6 months of therapy (p < 0.05), and reached the level of 7.1 (6.1 8.2)% after one year (p < 0.01). Analysis of glycemic profiles during the 6 months before and 6 months after transfer to glargin insulin therapy showed a significant decrease in the variability as evaluated by the decrease in standard deviations from the original 4.9 (4.3-5.6) mmol/l to 4.5 (3.9-5.1) mmol/l (p < 0.001). The total daily dose of insulin prior to treatment and after 6 months of therapy with glargin decreased from 44 (35-56) IU/day to 42 (34-53) IU/day (p = 0.01). There was no change in the basal dose of insulin after the change in therapy--it remained at 20 (12-28), (16-26) IU/day. The dose of bolus administered insulin decreased from 24 (18-32) to 21 (17-29) IU/day (p < 0.01). CONCLUSION: A dramatic improvement in HbA(lC) and a dramatic decrease in glycaemia variability are associated with glargin insulin treatment. The dose ofglargin insulin does not differ from that of NPH. PMID- 17702123 TI - [The influence of long-term therapy with the insulin pump (CSII) in patients with type 1 diabetes mellitus on metabolic compensation and on the incidence of hypoglycaemia. Comparison with intensified conventional insulin therapy (MDI)]. AB - The principal objective of this paper is to verify, in clinical practice, the long-term affect (7 to 8 year follow up) and safety of insulin pump treatment in type 1 diabetes mellitus patients and to compare the results for diabetes compensation in patients treated with the insulin pump with a control group of patients treated with intensified insulin therapy using the MDI (multiple daily injection) method. PATIENT SAMPLE AND METHOD: We followed up 35 patients treated with the insulin pump and 35 patients in the control group. We evaluated the monitored parameters for both patient groups at the beginning and at the end of the follow up period. With respect to glycated haemoglobin, we evaluated the results on a yearly basis, and also on year by year changes. We assessed the incidence of hypoglycaemia in both groups on a yearly basis. The following aspects were considered in order to determine the level of statistical significance of the different parameters: (1) we compared the initial state with that seen at the end of the follow up, (2) we analysed the year by year changes in glycated haemoglobin, (3) we compared the patients treated with the insulin pump with those in the control group. Diabetes compensation was evaluated on the basis of measurement of glycated haemoglobin and calculation of glycaemia. Comparison of the incidence of hypoglycaemia was done for all hypoglycemic events and then separately for severe hypoglycaemia. Also evaluated were changes in weight and in insulin dose in 24 hours. RESULTS: The group of patients treated with the insulin pump recorded a dramatic decrease in glycated haemoglobin in the course of the follow up, p < 0.001, and also in average glycaemia, p < 0.001. In the control group only a transitory significant decrease of HbA1c, p < 0.05, was recorded in the first and second year of follow up, later the result was insignificant, i.e. p > 0.05, as compared with the initial state. In this group of patients, no significant improvement in average glycaemia, p > 0.05, was recorded when compared with the initial state. Comparison ofthe two groups of patients showed that HbA(1c), p < 0.001, and average glycaemia, p < 0.001, were worse with statistical significance in patients treated with the insulin pump at the beginning of the follow up. At the end of the follow up period, there was no significant difference between the two groups in terms ofglycated haemoglobin, p > 0.05, but a statistically significant difference was recorded in average glycaemia, p < 0.001, in favour of the group of patients treated with the insulin pump. The use of the insulin pump resulted in a statistically significant decrease in the incidence of severe hypoglycaemic events as compared with the control group, p = 0.010. This decrease was reflected in the measured parameters from the third year of the study to the end of follow up. However, at the beginning of the study and in the first and second years of follow up there was no statistically significant difference between the two groups in terms of incidence of severe hypoglycaemic episodes, p > 0.05. No statistically significant difference between the two groups was recorded in the incidence of all hypoglycaemic episodes from the beginning of the follow up to its end, p > 0.05. In both groups of patients, a statistically significant gain in weight was seen from the beginning of the study to the end of the follow up period, however, its statistical significance was lower (p < 0.05) in the group of patients treated with insulin pump than in the control group (p < 0.001). We proved a statistically significant decrease in daily insulin dose (p < 0.001 )was required in the group of patients treated with insulin pump, whilst no statistically significant change in the dose was recorded in the control group (p > 0.05). CONCLUSION: In the course of the follow up, we proved that treatment with the insulin pump in type 1 diabetes is more beneficial to patients than MDI treatment. This was reflected by both better compensation of diabetes and a lower incidence of severe hypoglycaemic episodes. PMID- 17702124 TI - [The subpopulation of CD34+ cells and their importance in the healing of grafts in family-related allogenic transplants of peripheral stem cells]. AB - CURRENT STATUS: The determination of concentration of CD34+ cells is the standard method for evaluation of the quality of a bone marrow graft and of peripheral stem cells. Although the relationship between the dose of CD34+ cells and the speed of graft healing in autologous transplants is a proven fact, it may not always be the case in allogenic transplants. PATIENTS AND METHOD: The correlation between the dose of CD34+ cell subpopulations and the speed of healing was monitored in patients indicated for allogenic transplantation of haematopoietic stem cells. The patients were divided according to the type of preparatory regimen they underwent for the purpose of analysis; one group contained those under a myeloablative regimen; a second group contained those under a non myeloablative regimen. The data was subject to analysis of variance in regression models and non-parametric tests. RESULTS: From among the monitored subpopulations, CD34+36+ cells had the greatest effect on the healing process and were the most significant predictor of the speed of healing in patients under a myeloablative regimen. Nevertheless, a dose ofCD34+ cells continued to be the best healing predictor in patients under a non-myeloablative regimen. Also subpopulations of CD34+38+ and CD34+61+ cells had a significant effect on the speed of healing in both groups. CONCLUSION: Haematopoietic stem cells and progenitor cells defined by co-expression of specific antigens are likely to play a role, through different mechanisms of action, in the process of healing in patients in different pre-transplant regimens. While the dose of CD34+ cells is still the one which correlates best with the speed of healing in patients who underwent transplantation after non-myeloablative regimen, the dose of CD34+36+ cells appears to be a better predictor for the speed of healing after myeloablative regimens. PMID- 17702125 TI - [Essential thrombocytemia and other myeloproliferations with thrombocytemia in the data of the register of patients treated with Thromboreductin till the end of 2006]. AB - Since 2005, registers of patients treated with Thromboreductin (anagrelid) kept by some centres in the Czech Republic have been supplied with data concerning patients whose treatment with this preparation started in 2004. The purpose of the register is to record responses to therapy by Thromboreductin and adverse events in patients with essential thrombocytemia and other myeloproliferations, and to subsequently analyse the data. Another objective is to detect predisposition to clinical symptomatology and disease complications. Apart from thrombocyte count, additional risk factors are monitored. The database currently contains data for 336 patients. Initial analyses of data from the register point to the fact that anagrelid is a highly effective thromboreductive agent the administration of which is associated with relatively low incidence of adverse events (11.8 %) of mild and usually transitory nature. The therapeutic objective is attained at a relatively slow rate (according to overall stratification under 400 or under 600 x 10(9)/l thrombocytes), which is probably due to insufficient dose adjustment. PMID- 17702126 TI - [The optimum length of anticoagulation therapy after venous thromboembolism- universal or individualised approach?]. AB - Long-term peroral anticoagulation treatment is indicated after a thromboembolic event. The length of treatment should be based on balancing the risk of recurrence against the risk of bleeding complications. The minimum period of treatment is 3 months and can be reduced in certain cases; however, for many patients, a longer period of treatment may be recommendable. The presence or absence of a provoking factor and the nature of such a factor are of primary relevance when deciding on the length of treatment. Patients after a thromboembolic event provoked by a transitory (reversible) risk factor (surgery, accident, estrogen treatment etc.) have a very low risk of recurrence and a three month treatment period is sufficient for them. In the remaining cases, extended treatment is recommendable, spanning from 6 to 12 months minimally. The type and scope of the event and the number of possible previous events should also be considered. Patients with a malignancy have a higher risk of recurrence and benefit most from long-term therapy with low-molecular weight heparin. Male sex, some thrombophilias and, according to some studies, the presence of residual thrombus in the vein, all increase the risk of recurrence. D-dimer detection results may also be useful in determining treatment length. They should be measured both before discontinuation of treatment and, more importantly, one month after treatment termination. A negative result in the D-dimer detection test means that there is a very low recurrence risk whilst a positive result indicates high risk of recurrence, in which case renewal of anticoagulation therapy should be considered. Deciding on the length of therapy is a complex process and should involve interdisciplinary cooperation. PMID- 17702127 TI - [Cardiotoxicity of antracycline treatment in the light of new biochemical diagnostic options]. AB - Oncologic patients often receive treatment which is potentially cardiotoxic. Cardiotoxic complications range from fairly mild (relatively benign arrhythmias) to life threatening conditions (ischemia/myocardial infarction, heart failure, cardiomyopathy). The toxic effect of chemotherapy drugs may impair the integrity of the sarcomere, cause the release of bioactive substances into both tissues and the circulatory system and, consequently, cause necrosis/apoptosis of myocytes. A marker of the scope and severity of damage to the myocardium can be assessed by measuring the levels of cardiac markers in the serum. Cardiologic research is currently focused on the identification of new biochemical markers with a high degree of specificity, sensitivity and predictive value that might be used in the timely detection of myocardial abnormalities. The informative value of currently measured cardiac markers (myoglobin, CK-MB mass, CK-MB, and partly CK) is insufficient. There is growing evidence of the usefulness ofnatriuretic peptides and cardiac troponins in the diagnosing and monitoring of early and late, clinical and subclinical cardiotoxiticy resulting from anti-tumour therapy. The article summarises clinical studies concerning the diagnosis and monitoring of cardiotoxicity with the use of natriuretic peptides and cardiac troponins in former oncological patients. PMID- 17702128 TI - [Genetic factors and the risk of cardiovascular diseases]. AB - The objective of the study is to summarise the hereditary factors of cardiovascular diseases based on current knowledge, focus will be applied to genetic markers of multifactorial forms of cardiovascular diseases based on atherosclerosis, including their interaction with traditional risk factors. PMID- 17702129 TI - [New knowledge in the heredity of autoimmune diabetes. 1st part--Monogenetically determined types of autoimmune diabetes]. AB - The incidence of type 1 diabetes (DM1) varies greatly among different nations and ethnic groups. Precise mapping of DM1 incidence and its trends is useful in the study of the interaction of genetic and non-genetic factors which influence the manifestation and course of the disease. Important progress has been made in the understanding of the mechanisms of autoimmune diabetes by the study of genes and autoimmune forms of monogenetic diabetes. PMID- 17702130 TI - [Is familial hypercholesterolemia under control in the Czech Republic?]. AB - In 1997, the Czech Republic joined the international project MedPed (Make early diagnosis to Prevent early deaths), the principal objective of which is to dramatically reduce the number of deaths caused by the premature clinical manifestations of atherosclerosis in patients with familial hypercholesterolemia (FH). Stress has been laid on a timely diagnosis, especially in family members of patients who have already been diagnosed with the disease, and on timely application of adequate hypolipidemic therapy. A network of centres dealing with severe inborn dyslipidemias has been set up under the auspices of the Czech Society for Atherosclerosis. As many as 3,208 cases of dyslipidemia from 2377 families have been detected thanks to the network and to the contribution of cooperating doctors; this represents 16% of the estimated number of 20,000 patients with FH in this country. However, the disease is far from being under control in the Czech Republic. The principal objective for the immediate future is to dramatically increase the number of people screened within affected families; thus multiplying the current rate of diagnosed and treated patients with FH within each family from its current value of 1.3. PMID- 17702131 TI - [Hypogonadism, a serious complication of chronic renal insufficiency]. AB - Hypogonadism is a frequent complication in patients with chronic renal insufficiency (CHRI). From a pathogenetic point of view, it is a disorder at the level of the hypothalamus caused by central inhibition of the pulsatile generation of gonadotropin releasing hormone (GnRH) and by a primary disorder of gonads. The cause of hypogonadism in dialysed patients is not completely known. The effect of inhibition of erythropoietin production is believed to be one of the factors, as well as the adverse effects of complicated therapeutic procedures and malnutrition. In men, the affection manifests itself as a disorder of sexual functions, inhibition ofspermatogenesis, premature andropause and severe fatigue syndrome. Menstruation disorders, premature menopause and anovulation cycles are frequent symptoms in dialysed women. Androgen or estrogen substitution improves the quality of life in both sexes and slows down the loss of bone mass. Complete remission of hypogonadism is obtained, in the majority of patients, by renal transplant. The overview study deals with the pathogenesis, diagnosis and treatment of hypogonadism in dialysed patients. PMID- 17702132 TI - [The position of neoadjuvant chemotherapy in the treatment of non-small-cell lung carcinoma]. AB - Surgical treatment of patients with non-small-cell lung carcinoma (NSCLC) offers greatest chances for long-term survival. However, the treatment is applicable only to patients diagnosed at an early stage of the disease, i.e. at stage I or II. The five year survival rate of patients operated at stage IIIA is as low as 23%. Hence there is a great need for improving survival results, especially in the sphere of systemic chemotherapy, as most tumour relapses involve the formation of metastases. Even though neoadjuvant chemotherapy in the operable stages of NSCLC still appeared very promising as a method of treatment a couple of years ago, recently published results have shown that its role has not yet been fully clarified and is still a subject of research. Additional results from randomised studies are necessary before neoadjuvant therapy may become a treatment standard. The dilemma as to whether or not to apply adjuvant, neoadjuvant or both types of chemotherapy in patients operated on for NSCLC therefore remains unsolved. On the whole, the positive role of neoadjuvant chemotherapy does not appear to be proven in the treatment of operable stage I and II NSCLS. In contrast, results of randomised studies first published in 2004 were in favour of post-surgical adjuvant chemotherapy as opposed to surgical treatment alone in NSCLC stage IB, II and IIIA. The question of whether it is better to apply chemotherapy prior to or after surgery can only be answered by the extensive randomised studies underway. The role of neoadjuvant chemotherapy in patients with NSCLC at clinical stage IIIA remains uncertain. The most rational approach to such patients appears to be neoadjuvant chemotherapy or chemotherapy with subsequent surgery. PMID- 17702133 TI - [Malignant arrhythmia in a patient with variant (Prinzmetal's) angina pectoris]. AB - Malignant arrhythmia is a frequent complication of myocardial ischemia due to the occurrence of coronary artery spasm. The paper describes a patient with variant angina pectoris with an ICD implant who was repeatedly resuscitated for circulatory arrest in malignant arrhythmia. During myocardial ischemia the ECG showed elevations in the ST segments in the region of the ventral cardiac wall, with the formation of permanent polymorphous chamber tachycardia. External defibrillation was necessary due to recurrent tachyarrhythmias. A spasm developed when the RIA (radio immuno assay) was introduced during coronarography. The spasm started in the periphery of the artery and extended as far as the area of bifurcation with RD, with transitory closure of the artery and the development of chamber tachycardia. The patient fully recovered after the addition of Ca blocker, nitrate depot and the withdrawal of the beta-blocker. PMID- 17702134 TI - [Occurrence of an exceptional complication in an attempt to apply temporary pacemaking]. AB - The case study reports the case of a female patient who, during an admission exam in an area medical centre, presented with severe symptomatic bradyarrhythmia and the need for temporary external pacemaking. The first attempt to perform temporary transvenous pacemaking failed and was accompanied by a rare but serious iatrogenic complication which necessitated heart surgery. The case study is completed with illustrative figures. PMID- 17702135 TI - [Improvement in the results of treatment of selected blood diseases and changes in the costs of such treatment. Issues for economists and other experts]. AB - The text maps the changes in treatment results and costs for three haematological diseases; multiple myeloma; diffuse large B-cell lymphoma and chronic myeloid leukaemia. At the beginning of the 1990's, the alkeran-prednisone combination was the golden standard in the treatment of myeloma. In the mid 1990's, the treatment results in younger patients were dramatically improved by high-dose chemotherapy with autologous transplantation. The first decade of the new millennium has brought about even better results after the introduction of thalidomide in the initial treatment in patients not indicated for transplantation. Improvement is also expected in patients of a younger age group thanks to the combination of new drugs with autologous transplantation. A breakthrough in the treatment of patients with diffuse large cell lymphoma was the introduction in the treatment regimen of high-dose chemotherapy with autologous transplantation, and primarily the introduction of a new drug--a monoclonal antibody antiCD20, rituximab, in initial treatment. The golden standard for patients with chronic leukaemia in the early 1990's was hydroxyurea treatment. This was replaced by a new golden standard--interferon alpha, which was, in turn, replaced by the specific blocker of bcr-abl thyrosine kinase-imatinib. The text contains tables and charts showing the therapeutic benefit of the options mentioned above and the related costs. PMID- 17702136 TI - [Qualified decisions based on credible data are necessary]. AB - This paper is a reaction to an article giving evidence on the growth in the cost of treatment of selected malignant blood diseases. The relationship between the market and health care is explained, as well as the principles of public and private health insurance. Principal decision-making factors such as scientifically proven data, personal or group values and preferences and political and logistic potential are referred to. Private health insurance in Great Britain is used to exemplify the strong and weak points of private health insurance in general. The author brings attention to the need for systematic negotiation with health insurance companies in making use of available data related both to the scope of the issue and potential solutions to it. In addition the author points out the importance of quality health services and efficient organisation of oncological health care. In the long run, the most important factor, from the author's point of view, is systematic exploitation of the Health 21 programme, which is integral to the European health care policy. PMID- 17702137 TI - [Cost of medication in the Czech Republic--causes of growth in costs and solution proposals]. AB - The costs of medication represent a great part of total health costs in the Czech Republic. In the sphere of drugs, as in other segments of the health sector in this country, constant pressure is put on the growth in expenditure irrespective of the actual growth of the economy. The article is a reaction to the paper by Adam Z et al, Improvement in the results of treatment of selected blood diseases and changes in the costs of such treatment Issues for economists and other experts. The article presents data on the trend towards a growth of costs in the health sector and the causes of such a trend, with special focus on expenditure for expensive cancer drugs. Also included are proposals for financing options for cancer drugs. Rather than to make a direct recommendation for Czech health policy, the author's intention is to provoke discussion about the options for a sustainable system of Czech drug policy financing. PMID- 17702138 TI - [Contribution of Department of Nephrology of L. Pasteur Teaching Hospital and the UPJS Medical Faculty, Kosice (SK), to Czech nephrology]. AB - The paper deals with the contribution of L. PasteurTeaching Hospital and the UPJS Medical Faculty, Kosice, to Czech nephrology studies between 1954 and 2006. Specific reference is made to cooperation with different clinics, wards and institutes in Prague, Hradec Kralove, Pilsen and Brno in the sphere of therapeutic and proactive care, teaching activities, lecturing and publishing activities, as well as active involvement in research projects. Cooperation in all the above spheres attained and maintained high level, promoted the creation of friendly relations between Czech nephrology experts and the staff of the 1 st and 4th Internal Clinics and, beginning with 1997, of the Clinic of Nephrology, fostered solidarity between the two nations and has been to a great extent sustained to this day. PMID- 17702139 TI - Insider ethnography: tinker, tailor, researcher or spy? AB - Maxine Simmons reflects on her experiences as an 'insider' ethnographer - a senior manager undertaking research with nurse consultants within her own employing organisation - and the issues that arose as a result. PMID- 17702140 TI - Practitioner to researcher: reflections on the journey. AB - Cara J Bailey is embarking on a study of end-of-life issues in an emergency department where she is known. Being a 'familiar face' among the department's staff raises a number of methodological and ethical questions that are explored here. PMID- 17702141 TI - Experiences of a novice researcher. AB - Karen Clancy, a nurse consultant but a novice researcher reflects on her study of patients with respiratory disease living at home with long-term oxygen therapy. She explores the dual role of researcher and clinician, and concludes with suggestions designed to help other novice researchers. PMID- 17702142 TI - The supervisor-student relationship in developing methodology. AB - In this article, Carmel Seibold explores the unique relationship between supervisor and student in one aspect of the supervision process: choosing a methodology. It outlines the journey of discovery made by two of her higher degree research students, Susan White and Sonia Reisenhofer, in choosing an appropriate methodology for their respective qualitative studies. PMID- 17702143 TI - Interviewing women: using reflection to improve practice. AB - Caryl Skene uses a model of reflection to revisit her experience as a novice researcher In doing so, she highlights the skills required to undertake qualitative research and suggests that nursing experience alone does not equip a researcher with those skills. A significant part of her reflection concentrates on the relationship between the researcher and the research, and the impact it may have on the research process and on those involved in it. PMID- 17702144 TI - Older adults' participation in research. AB - Research with older adults involves unique challenges, says US-based researcher Cynthia S Jacelon, but it offers benefits to both researcher and subjects, providing negative stereotypes can be overcome. PMID- 17702145 TI - An investigation of factors that determine when men with erectile disorder present for treatment. AB - This study by Sangan Sookdeb explored the factors that determine the time interval between men suffering the onset of erectile disorder and their presentation for treatment. As prognosis is considered to be related negatively to the length of time a man suffers erectile disorder understanding factors that delay presentation may identify changes in practice methods that will encourage earlier presentation. PMID- 17702146 TI - 'I remember thinking to myself that I have a story to tell'. AB - Angela Knight Jackson, acting R&D lead nurse, Heart of Birmingham Teaching Primary Care Trust, talks about the factors that have contributed to her success. PMID- 17702147 TI - National Ambulatory Medical Care Survey: terrorism preparedness among office based physicians, United States, 2003-2004. AB - OBJECTIVES: This investigation describes terrorism preparedness among U.S. office based physicians and their staffs in identification and diagnosis of terrorism related conditions, training methods and sources, and assistance with diagnosis and reporting. METHODS: The National Ambulatory Medical Care Survey (NAMCS) is an annual national probability survey of approximately 3,000 U.S. nonfederal, office based physicians. Terrorism preparedness items were added in 2003 and 2004. RESULTS: About 40 percent of physicians or their staffs received training for anthrax or smallpox, but less than one-third received training for any of the other exposures. About 42.2 percent of physicians, 13.5 percent of nurses, and 9.4 percent of physician assistants and nurse practitioners received training in at least one exposure. Approximately 56.2 percent of physicians indicated that they would contact state or local public health officials for diagnostic assistance more frequently than federal agencies and other sources. About 67.1 percent of physicians indicated that they would report a suspected terrorism related condition to the state or local health department, 50.9 percent to the Centers for Disease Control and Prevention (CDC), 27.5 percent to the local hospital, and 1.8 percent to a local elected official's office. Approximately 78.8 percent of physicians had contact information for the local health department readily available. About 53.7 percent had reviewed the diseases reportable to health departments since September 2001, 11.3 percent had reviewed them before that month, and 35 percent had never reviewed them. PMID- 17702148 TI - [The proximity of trusted persons brings safety and strength]. PMID- 17702149 TI - [Targeted management of challenging behavior in persons with dementia: the "Serial Trial Intervention" (STI)]. PMID- 17702150 TI - [Nursing of patients with tracheostomy: competence controls anxiety]. PMID- 17702151 TI - [Compression stockings for prevention of thrombosis: knee length or thigh length?]. PMID- 17702152 TI - [Problems from general practice--solutions for general practice: administering antibiotics correctly]. PMID- 17702153 TI - [Empathy in nursing care--its dimensions and impact on cancer patients]. AB - As part of their professional activity nurses have to perform emotional and relationship-related work. Without doubt the ability to show empathy is a fundamental requirement to acting in a helpful way. Based on neuropsychological knowledge, in this article it is investigated to what extent it is possible for nurses to understand life of a cancer patient with the help of empathetic behaviour in order to honour it accordingly and influence it positively. Different forms of empathy are introduced, and they are discussed regarding their usefulness for development of empathetic competence in nursing. PMID- 17702155 TI - [Control of employees: detective allowed, blood sample not]. PMID- 17702154 TI - [The art of conversation with patients: "patients tell nothing irrelevant" (interview by Dorit Kobusch)]. PMID- 17702156 TI - [Human images in nursing--4: Anthroposophy: wisdom from the human]. PMID- 17702157 TI - [Immigration of nursing personnel from Africa: wealthier countries stand in the way of responsibility]. PMID- 17702158 TI - [Step by step toward nursing competence--3: Oral hygiene: special sensitivity required]. PMID- 17702159 TI - [Recognizing and understanding illnesses: fever as leading symptom]. PMID- 17702161 TI - A material curiosity. Interview by Alison Stoddart. PMID- 17702160 TI - Cancer informatics in the post genomic era. Toward information-based medicine. PMID- 17702162 TI - Developing the chemistry of monovalent phosphorus. AB - Electrophilic terminal phosphinidene complexes can be seen as singlet phosphinidenes stabilized by complexation with electron withdrawing metallic centers. They allow the development of an original P(I) chemistry whose latest results are summarized. These include the description of the first stable electrophilic terminal phosphinidene complexes, new precursors for the widely used transient [RP-M(CO)5] complexes (M = Cr, Mo, W), new substituents at phosphorus, new reactions and new decomplexation techniques. Finally, a different approach is proposed for stabilizing singlet phosphinidenes by formation of adducts with nitrogen bases such as N-methylimidazole. The resulting zwitterions are potentially equivalent to singlet nucleophilic phosphinidenes. Their synthetic potential remains to be explored. PMID- 17702163 TI - Self-assembly of a heterometallic molecular triangle using an ambidentate ligand and self-selection for a single linkage isomer. AB - Self-assembly and self-selection of a single linkage isomer of a mixed-metal molecular triangle with ferrocene functionality have been achieved using an ambidentate ligand, and the product was characterized by multinuclear NMR spectroscopy and X-ray single crystal structure determination. PMID- 17702164 TI - Rigidity-modulated conformation control: a strategy for incorporating flexible building motifs into metallacycles. AB - A rigidity-modulated strategy for the conformational control of a flexible motif in the self-assembly of metallacycles is described; the span of the rigid ligand directs the conformation of the flexible motif by fixing the M ... M separation, thereby dictating the structure of the metallacycles. PMID- 17702165 TI - Ultrasonic chemical oxidative degradations of 1,3-dialkylimidazolium ionic liquids and their mechanistic elucidations. AB - A highly efficient process for oxidative degradation of 1,3-dialkylimidazolium ionic liquids in hydrogen peroxide/acetic acid aqueous medium assisted by ultrasonic chemical irradiation is, for the first time, described. It is shown that more than 93% of the 1,3-dialkylimidazolium cation with the corresponding Cl , Br-, BF4- and PF6- counter-anions at a concentration of 2.5 mM can be degraded at 50 degrees C within 12 h while at 72 h the conversions approach 99%. A tentative mechanism for the degradation of these ILs is for the first time proposed through a detailed kinetic analysis of several characteristic transients and/or immediate products, which are identified during the ILs degradation using GC-MS. The results clearly indicate that three hydrogen atoms in the imidazolium ring are the first sites preferably oxidized, followed by cleavage of the alkyl groups attached to the N atoms from the ring. The nature of the alkyl chain length on the imidazolium ring and the type of counter anion do not seem to affect the degradation process. Further, selective fragmentations of C-N bonds of the imidazolium or derived ring lead to ring opening, forming degraded intermediates. It is also shown that acetoxyacetic acid and biurea are the final kinetically stable degraded products from the ILs under the degradation conditions. PMID- 17702166 TI - Color tuning associated with heteroleptic cyclometalated Ir(III) complexes: influence of the ancillary ligand. AB - We report the preparation of a series of new heteroleptic Ir(III) metal complexes chelated by two cyclometalated 1-(2,4-difluorophenyl)pyrazole ligands (dfpz)H and a third ancillary bidentate ligand (L=X). Such an intricate design lies in a core concept that the cyclometalated dfpz ligands always warrant a greater pi pi* gap in these series of iridium complexes. Accordingly, the lowest one-electron excitation would accommodate the pi* orbital of the ancillary L=X ligands, the functionalization of which is then exploited to fine-tune the phosphorescent emission wavelengths. Amongst the L=X ligands designed, three classes (series 1 3) can be categorized, and remarkable bathochromic shifts of phosphorescence were observed by (i) replacing the 2-benzoxazol-2-yl substituent (1a) with the 2 benzothiazol-2-yl group (1b) in the phenolate complexes, (ii) converting the pyridyl group (2a) to the pyrazolyl group (2b) and even to the isoquinolyl group (2c) in the pyrazolate complexes and (iii) extending the pi-conjugation of the benzimidazolate ligand from 3a to 3b. Single-crystal X-ray diffraction study on complex [(dfpz)Ir(bzpz)] (2b) was conducted to confirm their general molecular architectures. Complex 2b was also used as a representative example for fabrication of multilayered, green-emitting phosphorescent OLEDs using the direct thermal evaporation technique. PMID- 17702167 TI - Structures, dynamic behaviour, and reactivity of P-cyclopentadienyl-substituted 1,3,2-diazaphospholenes. AB - P-Cyclopentadienyl-substituted 1,3,2-diazaphospholenes were prepared by salt metathesis from NaCp or LiCp* and 2-chloro-1,3,2-diazaphospholenes. Comprehensive spectroscopic and X-ray diffraction studies revealed a significant lengthening of the phosphorus-carbon bonds as compared with typical P-C bond distances, and the presence of fluxional molecular structures in solution and solid state as a consequence of circumambulatory migration of the diazaphospholene moiety around the Cp-ring. The P-C bond lengthening is accompanied by the capability to react with transition metal complexes under P-C bond activation and cyclopentadienyl transfer. At the same time, 2-Cp-diazaphospholenes react with strong bases under deprotonation to afford a phosphinyl-cyclopentadienide anion that reacts further with FeCl2 to a 1,1'-bisphosphinyl-ferrocene. The ambivalent behaviour of the diazaphospholenes offers interesting prospects to develop new synthetic methods for functional cyclopentadienyl complexes. PMID- 17702169 TI - Cyanide-bridged linkage isomers with catecholateruthenium(II) centres bound to Mn(I) or M(alkyne) units. AB - Two series of stable cyanide-bridged linkage isomers, namely [(o O2C6Cl4)(Ph3P)(OC)2Ru(mu-XY)MnL(NO)(eta-C5Me5)] (XY = CN or NC, L = CNBu(t) or CNXyl) and [(o-O2C6Cl4)L(OC)2Ru(mu-XY)M(CO)(PhC-CPh)Tp'] {M = Mo or W, L = PPh3 or P(OPh)3, Tp' = hydrotris(3,5-dimethylpyrazolyl)borate} have been synthesised; pairs of isomers are distinguishable by IR spectroscopy and cyclic voltammetry. The molecular structure of [(o-O2C6Cl4)(Ph3P)(OC)2Ru(mu-NC)Mo(CO)(PhC-CPh)Tp'] has the catecholate-bound ruthenium atom cyanide-bridged to a Mo(CO)(PhC[triple band]CPh)Tp' unit in which the alkyne acts as a four-electron donor; the alignment of the alkyne relative to the Mo-CO vector suggests the fragment (CN)Ru(CO)2(PPh3)(o-O2C6Cl4) acts as a pi-acceptor ligand. The complexes [(o O2C6Cl4)(Ph3P)(OC)2Ru(mu-XY)Mn(NO)L(eta-C5Me5)] undergo three sequential one electron oxidation processes with the first and third assigned to oxidation of the ruthenium-bound o-O2C6Cl4 ligand; the second corresponds to oxidation of Mn(I) to Mn(n). The complexes [(o-O2C6Cl4)L(OC)2Ru(mu-XY)M(CO)(PhC[triple band]CPh)Tp'] are also first oxidised at the catecholate ligand; the second oxidation, and one-electron reduction, are based on the M(CO)(PhC[triple band]CPh)Tp' fragment. Chemical oxidation of [(o-O,C6Cl4)(Ph3P)(OC)2Ru(mu XY)MnL(NO)(eta-C5Me5)] with [Fe(eta-C5H4COMe)(eta-C5H5)][BF4], or of [(o O2C6Cl4)L(OC)2Ru(mu-XY)M(CO)(PhC[triple band]CPh)Tp'] with AgBF4, gave the paramagnetic monocations [(o-O2C6Cl4)(Ph3P)(OC)2Ru(mu-XY)MnL(NO)(eta-C5Me5)]+ and [(o-O2C6Cl4)L(OC)2Ru(mu-XY)M(CO)(PhC[triple band]CPh)Tp']+, the ESR spectra of which are consistent with ruthenium-bound semiquinone ligands. Linkage isomers are distinguishable by the magnitude of the 31P hyperfine coupling constant; complexes with N-bound Ru(o-O2C6Cl4) units also show small hyperfine coupling to the nitrogen atom of the cyanide bridge. PMID- 17702170 TI - Pentamethylcyclopentadienyl-iridium(III) complexes with pyridylamino ligands: synthesis and applications as asymmetric catalysts for Diels-Alder reactions. AB - Reaction of the dimer [(Cp*IrCl)2(P-Cl)2] with chiral pyridylamino ligands (pyam, L1-L5) in the presence of NaSbF6 gave complexes [Cp*IrCl(pyam)][SbF6] 1-5 as diastereomeric mixtures, which have been fully characterised, including the X-ray molecular structure determination of the complexes (S(Ir),R(N),R(C)) [Cp*IrClL1][SbF6] 1a and (R(Ir),S(N),S(C))-[Cp*IrClL5][SbF6] 5a. Treatment of these cations with AgSbF6 affords the corresponding aqua species [Cp*Ir(pyam)(H2O)][SbF6]2 6-10 which have been also fully characterised. The molecular structure of the complex (S(Ir),R(N),R(C))-[Cp*IrL,(H2O)][SbF6]2 6 has been determined by X-ray diffractometric methods. The aqua complexes [Cp*Ir(pyam)(H2O)][SbF6]2 (6, pyam = L2 (7), L3 (8)) evolve to the cyclometallated species [Cp*Ir{kappa3(N,N',C)-(R)-(C6H4)CH(CH3)NHCH2C5NH4}][SbF6] (11), [Cp*Ir{kappa3(N,N',C)-(R)-(C10H6)CH(CH3)-NHCH2C5NH4)}][SbF6] (12), and [Cp*Ir{kappa3(N,N',C)-(R)-(C10H6)CH(CH3)NHCH2C9NH6)}][SbF6] (13) respectively, via intramolecular activation of an ortho C-H aryl bond. Complexes 6-10 are enantioselective catalysts for the Diels-Alder reaction between methacrolein and cyclopentadiene. Reaction occurs rapidly at room temperature with good exo : endo selectivity (from 81 : 19 to 98 : 2) and moderate enantioselectivity (up to 72%). The involved intermediate Lewis acid-dienophile compounds [Cp*Ir(pyam)(methacrolein)][SbF]2 (pyam = L4 (14), L5 (15)) have been isolated and characterised. PMID- 17702168 TI - High boron content carboranyl-functionalized aryl ether derivatives displaying photoluminescent properties. AB - The reaction of alpha,alpha'-bis(3,5-bis(bromomethyl)phenoxy-p-xylene (3) with 4 equiv of the monolithium salt of 1-Ph-1,2-C2B10H11 or 1-Me-1,2-C2B10H11 gave the corresponding neutral carboranyl-functionalized aryl ether derivatives closo-4 and closo-5, respectively. These compounds contain four closo clusters that were degraded using basic conditions with KOH in EtOH, affording the corresponding nido-6 and nido-7 as potassium salts. Nido species were also isolated with tetramethylammonium as cation giving compounds nido-8 and nido-9 in good yield. The potassium salts showed good solubility in water and polar solvents. All these compounds were characterized by 1H, 11B and 13C NMR spectroscopy and UV-vis. The electronic data in different solvents indicated a solvatochromic shift for all compounds and a red shift of the absorption maxima for the nido species with respect to the closo derivatives. These neutral and anionic carboranyl functionalized aryl ether derivatives represent a new family of high boron content luminescent compounds that show strong fluorescence emission in different solvents at room temperature. This phenomenon is very interesting considering the fact that none of the precursors have such a property. The fluorescence emission depends on the cluster substituent (Ph or Me) and the solvent polarity. Additionally, the fluorescence emission intensity was clearly dependent on the solvent polarity; the closo species showed strongest fluorescence intensities in the non-polar solvents, while anionic species were highly emissive in polar solvents. PMID- 17702171 TI - Theoretical studies on structures and spectroscopic properties of a series of novel mixed-ligand Ir(III) complexes [Ir(Mebib)(ppy)X]. AB - The series of novel mixed-ligand iridium(III) complexes Ir(Mebib)(ppy)X (Mebib = bis(N-methylbenzimidazolyl)benzene and ppy = phenylpyridine; X = Cl, 1; X = C[triple band]CH, 2; X = CN, 3) have been investigated theoretically to explore their electronic structures and spectroscopic properties. The ground and excited state geometries have been fully optimized at the B3LYP/LANL2DZ and CIS/LANL2DZ levels, respectively. The optimized geometry structural parameters agree well with the corresponding experimental results. The HOMO of 1 and 3 are mainly localized on the Ir atom, Mebib, and ppy ligand, but that of 2 has significant X ligand composition. Absorptions and phosphorescences in CH2 Cl2 media have been calculated using the TD-DFT level of theory with the PCM model based on the optimized ground and excited state geometries, respectively. The lowest lying absorptions of 1 and 3 at 444 and 416 nm are attributed to a {[d(yz)(Ir) + pi(Mebib) + pi(ppy)] --> [pi*(Mebib)]} transition with metal-to-ligand, ligand-to ligand, and intra-ligand charge transfer (MLCT/LLCT/ILCT) character, whereas that of 2 at 458 nm is related to a {[d(yz)(Ir) + pi(Mebib) + pi(ppy) + pi(C[triple band]CH)] --> [pi*(Mebib)]} transition with MLCT/LLCT/ILCT and X ligand-to-ligand charge transfer (XLCT) transition character. The phosphorescence of 1 and 3 at 565 and 543 nm originates from the 3{[dy(yz)(Ir) + pi(Mebib) + pi(ppy)] [pi*(Mebib)]} excited state, while that of 2 at 576 nm originates from the 3{[d(yz)(Ir) + pi(Mebib) + pi(ppy) + pi(C[triple band]CH)] [pi*(Mebib)]} excited state. The calculation results show that the absorption and emission transition character can be changed by altering the pi electron-withdrawing ability of the X ligand and the phosphorescent color can be tuned by adjusting the X ligand. PMID- 17702172 TI - Differing reactivities of p[triple band]CMe and P[triple band]CBu(t) towards a triphosphabenzene and a tetraphosphabarrelene: synthesis of new phosphaalkyne pentamers (P5C5Me(n)Bu(t)(5-n) n = 0, 1 or 2). AB - The reaction of excess P[triple band]CMe with the triphosphabenzene, 1,3,5 P3C3Bu(t)3, yields a phosphaalkyne pentamer, P5C5Me2Bu(t)3, which displays a pentaphosphaisolumibullvalene core structure. Its treatment with [W(CO)5(THF)] gives a complex of this cage, [{W(CO)5}2(mu-eta1:eta1-P5C5Me2Bu(t)3)], which has been structurally characterised. In contrast, the previously reported reaction of P[triple band]CBu(t) with 1,3,5-P3C3Bu(t)3, affords, in addition to the known tetraphosphabarrelene, 1,3,5,7-P4C4Bu(t)4, a new phosphaalkyne pentamer (P55C5Bu(t)5), which has a partially unsaturated "open cage" core. Although P[triple band]CBu(t) does not react with 1,3,5,7-P4C4Bu(t)4, the reaction of P[triple band]CMe with the tetraphosphabarrelene is shown to give a mixture of products. Treatment of these with [W(CO)5(THF)] leads to the isolation of the tungsten carbonyl complex, [{W(CO)} {W(CO)4}(mu-eta1:eta4-P5C5MeBu(t)4)], which has been structurally characterised. This study suggests that P[triple band]CMe has a significantly greater reactivity towards cycloadditions than its bulkier counterpart, P[triple band]CBu(t). PMID- 17702173 TI - Ancillary ligand determination of the spin location in both oxidised and reduced forms of diruthenium complexes bridged by bis-bidentate 1,4-bis(2-phenolato)-1,4 diazabutadiene. AB - The rare bridging mode of 1,4-bis(2-phenolato)-1,4-diazabutadiene = glyoxalbis(2 hydroxyanil) (L(2-)) is adopted in {(mu-L(2-))[Ru11(bpy)22}2+ (1(2+)), obtained as bis-perchlorate. Four well accessible redox forms of 1(n) (n = 4+, 3+, 2+, +) have been characterised by UV-VIS-NIR spectroelectrochemistry. The (3+) and (+) intermediates have also been investigated by EPR, both showing radical-type signals close to g = 2. This observation stands in stark contrast to EPR results previously obtained for the related {(mu-L)[Ru(acac)2]2(n), n = + and -, both of which exhibit metal-centred spin. In combination with the UV-VIS-NIR spectra these results suggest the preferential involvement of the multistep ligand redox system L(n-) in the electron transfer processes. The relative stabilisation of Ru11 by pi-accepting bpy is made responsible for the oxidation of the ligand L(2 ) instead of the metal. PMID- 17702174 TI - Rationalizing the different products in the reaction of N2 with three-coordinate MoL3 complexes. AB - The reaction of N2 with three-coordinate MoL3 complexes is known to give rise to different products, N-MoL3, L3Mo-N-MoL3 or Mo2L6, depending on the nature of the ligand L. The energetics of the different reaction pathways are compared for L = NH2, NMe2, N((i)Pr)Ar and N((t)Bu)Ar (Ar = 3,5-C6H3Me2) using density functional methods in order to rationalize the experimental results. Overall, the exothermicity of each reaction pathway decreases as the ligand size increases, largely due to the increased steric crowding in the products compared to reactants. In the absence of steric strain, the formation of the metal-metal bonded dimer, Mo2L6, is the most exothermic pathway but this reaction shows the greatest sensitivity to ligand size varying from significantly exothermic, -403 kJ mol(-1) for L = NMe2, to endothermic, +78 kJ mol(-1) for L = N((t)Bu)Ar. For all four ligands, formation of N-MoL3 via cleavage of the N2 bridged dimer intermediate, L3Mo-N-N-MoL3, is strongly exothermic. However, in the presence of excess reactant MoL3, formation of the single atom-bridged complex L3Mo-N-MoL3 from N-MoL3 + MoL3 is both thermodynamically and kinetically favoured for L = NMe2 and N((i)Pr)Ar, in agreement with experiment. In the case of L = N((t)Bu)Ar, the greater steric bulk of the (t)Bu group results in a much less exothermic reaction and a calculated barrier of 66 kJ mol(-1) to formation of the L3Mo-N MoL3 dimer. Consequently, for this ligand, the energetically and kinetically favoured product, consistent with the experimental data, is the nitride complex L3Mo-N. PMID- 17702175 TI - Linear copper 'chain' complexes with bulky tritopic hydrazone ligands--structural and magnetic studies. AB - Tritopic 2,6-picolyl-bis-hydrazone ligands with bulky terminal groups derived from phenyl-pyridyl ketone do not form the expected [3 x 3] grids on reaction with copper(II), but instead form Cu8 'pinwheels', and in the present case linear trinuclear, pentanuclear and chain structures also. Direct bridging between copper ions occurs through micro2-N-N diazine groups, and longer O-C-N hydrazone connections, leading to moderately strong antiferromagnetic exchange between adjacent metal centres. Structural and magnetic properties are discussed in the context of specific orthogonal and non-orthogonal bridges, which can be distinguished and quantified. PMID- 17702176 TI - [Clinical study of 38 cases of pheochromocytoma --correlation between the instability of intraoperative blood pressure and 24-hour urinary vanillylmandelic acid]. AB - Pheochromocytoma is a rare tumor of chromaffin tissues most commonly arising from the adrenal medulla. We retrospectively reviewed the records of 38 patients with pheochromocytoma who underwent surgical treatment between 1977 and 2004 at our Yokohama City University Medical Center and Yokohama City University Hospital. Twenty two patients (57.9%) were females and 16 (42.1%) were males. The most frequent symptoms were headache (58%). One patient had bilateral adrenal tumors and pathological examination revealed malignant pheochromocytoma. Six patients had an extra-adrenal tumor and in 2 patients the tumor occurred in the urinary bladder. Twelve patients (31.6%) had sustained hypertension, 21 patients (55.3%) had paroxysmal hypertension and 5 patients (13.1%) remained normotensive. The 24 h urinary total metanephrines and vanillylmandelic acid (VMA) were the most sensitive biochemical tests for the diagnosis of pheochromocytoma. The sensitivity of urinary total metanephrines was 92.0% for all the patients and was 92.3% for the patients without paroxysmal hypertension. Fifteen patients had intraoperative hypertensive reactions in the surgical manipulation or hypotension after tumor resection. This group had more urinary excretion of VMA before surgery, compared with that with stable intraoperative blood pressure (p < 0.005). PMID- 17702177 TI - [Patients with clinically unconfirmed positive urinary cytology --retrospective analysis of clinical courses]. AB - We retrospectively analyzed the clinical courses of 7 patients with clinically unconfirmed positive urine cytology characterized by persistent positive urine cytology but without any evidence of tumor by endoscopy or image diagnosis during the time from January 1999 to June 2004. A past history of urothelial cancer was found in 5 patients. In 2 of these 5 patients, transurethral resection of the bladder mucosa and ureteroscopy done as the initial examination identified bladder cancer and ureteral cancer, respectively. Urothelial cancer was found in the remaining 3 patients by subsequent endoscopy, image diagnosis and surgical resection that were done in the follow-up period of 8 months. Two patients who did not have a history of urothelial cancer were diagnosed as having bladder cancer and ureteral cancer in the initial or subsequent examination. Patients with clinically unconfirmed positive urine cytology should be carefully followed up with endoscopy and image diagnosis since the subsequent examinations tend to identify urothelial cancer in the upper urinary tract or bladder. PMID- 17702178 TI - Prostatic volume and volume-adjusted prostate-specific antigen as predictive parameters for T1c prostate cancer. AB - We examined the usefulness of the volume-adjusted prostate-specific antigen (PSA) parameters for prediction of T1c prostate cancer on 210 patients who had abnormal PSA levels but no abnormal findings in digital transrectal examination (DRE) or transrectal ultrasonography (TRUS). PSA, prostate volume (PV), transition zone volume (TZV), PSAD (PSA/PV) and PSATZD (PSA/TZV) were assessed with the receiver operating characteristic (ROC) curve and the area under the curve (AUC). Simple and stepwise logistic regression models were used to calculate the odds ratios of these parameters. Fifty-three (25.2%) of all 210 patients and 31 (19.9%) of 156 patients with intermediate PSA levels had biopsy-proved prostate cancer. The ROC curves of all patients revealed that PSA, PV, TZV, PSAD and PSATZD had significant predictive values, while AUCs of PV, PSAD and PSATZD had significant predictive values as compared to that of PSA. In the patients with intermediate PSA levels, the ROC curves revealed that PV, TZV, PSAD and PSATZD had significant predictive values, but there were no significant differences in AUCs among these parameters. The stepwise logistic regression analysis showed that PV and PSATZD were significant predictive parameters in all patients and that PSATZD was the only significant predictive parameter in the patients with intermediate PSA levels. In conclusion, not only PSAD and PSATZD but also PV and TZV had significant predictive values in discriminating prostate cancer. However, the multivariate analysis showed that PSATZD had the strongest predictive value in all patients and in those with intermediate PSA levels. PMID- 17702179 TI - [Laparoscopic sacrocolpopexy for post-hysterectomy vaginal vault prolapse]. AB - Laproscopic sacrocolpopexy offers a minimally invasive approach to correct post hysterectomy vaginal vault prolapses. Herein we present our surgical technique and results. Through the transperitoneal approach, the retroperitoneal space was dissected along the right edge of the rectum and a polypropylene mesh is sutured to the vaginal apex and the anterior longitudinal ligament of the sacrum. We sutured the mesh to the sacrum with 2-0 PDS. To prevent bleeding from the pre sacral vessels, occasionally we used a bone anchor system, Straight-In, in sacral fixation. Nine patients underwent this operation since August 19, 2005. The patient's age ranged from 48 to 78 years old. The median operation time was 250 minutes and the blood loss was 80.7 ml. The median post-operative hospital stay was 8.3 days. We experienced no peri- or post-operative complications. The vagina was well fixed post-operatively in all patients. Laparoscopic sacrocolpopexy is a minimally invasive treatment for vault prolapse and offers a high quality of life to patients. PMID- 17702180 TI - [Renal adenoma treated with partial nephrectomy: a case report]. AB - We report a case of renal adenoma which was diagnosed as renal cell carcinoma preoperatively. A 78-year-old man, who had been under observation for bladder cancer for 4 years, was incidentally found to have a small right renal tumor at follow-up computed tomography (CT). Enhanced CT demonstrated a tumor which was hypervascular, 10 x 10 mm size, at the lower pole of the right kidney. There was no evidence of distant metastasis. The preoperative diagnosis was renal cell carcinoma, cT1aN0M0, and we performed right partial nephrectomy. The histopathorogical finding was renal adenoma. Renal adenomas are benign tumors and not uncommon in autopsy cases. However, when they are detected clinically, it is difficult to distinguish them from renal cell carcinoma preoperatively. PMID- 17702181 TI - Case of retroperitoneal solitary fibrous tumor. AB - Solitary fibrous tumor (SFT) of the retroperitoneal space is rare. We report a case of retroperitoneal tumor, diagnosed as SFT. A 69-year-old woman presented with right lower abdominal swelling, and was referred to our hospital with suspicion of right renal tumor. Abdominal ultrasound and computerized tomography (CT) showed a mass (about 15 x 14 x 10 cm) in the right abdomen. The tumor was thought to be right renal rumor, and right radical nephrectomy was performed. In the excised specimen the tumor was not connected to gastrointestinal tract, peritoneum, or right kidney. The histological and immunohistochemical examination of the specimen revealed SFT. The tumor has malignant potential with partially increased mitotic activity and cellularity in the histological examination. The patient is healthy and without evidence of recurrence or metastasis 26 months from surgery. PMID- 17702182 TI - [Two cases of urethrovaginal fistula repaired by Martius labial-rotation flap]. AB - Urethrovaginal fistulas are rare. In case 1, a 48-year-old woman had undergone transvaginal drainage for an paraurethral abscess. In case 2, a 33-year-old woman had undergone resection of vaginal varicocele with massive bleeding during pregnancy. Postoperatively both patients complained of total incontinence. Urethroscopy and urethrography revealed an urethrovaginal fistula in each case. Repair ofurethrovaginal fistula using Martius labial-rotation flap was performed and the fistula was closed in both cases. We concluded that repair of urethrovaginal fistula using Martius labial-rotation flap may be useful for patients with urethrovaginal fistula. PMID- 17702183 TI - [Recrudescence of prostate cancer with low serum level of PSA and high serum level of CEA and CA19-9: a case report]. AB - We report a case of primary adenocarcinoma of the prostate producing carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). A 64-year old man referred to our hospital with dysbasia. Two years ago, he was diagnosed with prostate cancer at another hospital and received radiotherapy and endocrine therapy. Serum CEA and CA 19-9 levels were increased to 3,990 ng/ml and 11,700 U/ml at the time of our hospitalization. However, his serum PSA level remained low. After hospitalization, the disease rapidly progressed and he died a month later. In the histology of autopsy specimen, the prostate showed no sign of malignancy, but bone showed metastasis of prostate cancer. Immunohistochemical staining for CEA and PSA demonstrated the existence of each protein in bone metastasis. PMID- 17702184 TI - [Combined small-cell carcinoma/adenocarcinoma of prostate: report of two cases]. AB - We report two cases of combined small-cell carcinoma (SCC) and adenocarcinoma of prostate. Case 1 was a 76-year-old man with loss of appetite and body weight and neck lymphadenopathies. Whole body computed tomography (CT) revealed prostatic swelling, pancreatic mass, para-aortic lymphadenopathies, and multiple lung nodules. Elevation of tumor markers (prostate specific antigen [PSA, 1,760 ng/ml] and neuron-specific enolase [NSE, 88 ng/ml]) was noted. Needle biopsy of the prostate demonstrated both SCC and adenocarcinoma. Only within the part of SCC, were neuroendocrine (NE) markers (chromogranin A [CgA], NCAM, and synaptophysin [SNP]) expressed. Maximum androgen blockade (MAB) resulted in a decrease of PSA (5.13 ng/ml) but an increase of NSE (810 ng/ml). Cytotoxic chemotherapy was not possible because of his poor performance state and renal dysfunction. The patient died three months after the diagnosis. Case 2 was a 69-year-old male with dysuria. The symptom and elevated serum PSA (23.1 ng/ml) prompted prostatic needle biopsy, which demonstrated combined SCC/adenocarcinoma. NE markers (CgA and SNP) were weakly expressed in the part of SCC. Serum NSE was 6.9 ng/ml. After MAB, serum PSA dropped to the normal range (0.192 ng/ml) and the effect of MAB was judged as complete response (CR). The patient has been alive for 15 months with no signs of relapse. Treatment of combined SCC and adenocarcinoma of prostate poses a dilemma. In Case 1, MAB was effective for adenocarcinoma but not for SCC. The opposite situation would be expected with systemic chemotherapy. However, the histologically similar Case 2 achieved CR with MAB alone. Much remains to be elucidated to better manage combined SCC/adenocarcinoma of prostate. PMID- 17702185 TI - [Case of testicular venous hemangioma]. AB - A case of a testicular venous hemangioma is presented. A 65-year-old man complained of left testicular swelling. Physical examination and ultrasonography revealed a 2.0 x 1.6 x 1.5 cm roundish, well demarcated isoechoic elastic hard tumor in the left testis. No other abnormal findings including tumor markers were observed. Since preoperative examination did not rule out malignancy, we performed left high orchiectomy. Pathological diagnosis was a venous hemangioma of the left testis. Venous hemangioma is a rare entity among the testicular solid lesions. PMID- 17702186 TI - Massive leiomyosarcoma of the spermatic cord. AB - A 56-year-old man was diagnosed with a right testicular tumor. Orchiectomy with high ligation of the spermatic cord was performed. Histological examination revealed leiomyosarcoma of the spermatic cord. Distant metastases were not found. The patient was treated with adjuvant radiation therapy to control the disease, since a high incidence of local recurrence has been reported. The patient had no evidence of disease 24 months postoperatively. PMID- 17702187 TI - [Cryptorchidism: update on diagnosis and therapy]. AB - The incidence of cryptorchidism at 3 month-old boy is 0.8% which is close to that of an adult, and its diagnosis can be done at 3 months old. In case of cryptorchidism both MRI and USG are helpful to locate an undescended testis. If genitalia is pigmented too weakly, serum testosterone should be measured to rule out hypogonadism. Pathological changes of basement membrane and mitochondria in an undescended testis at 1 year-old boy suggests an earlier orchiopexy at least between 1 and 2 years at age, although if it is unilateral case an orchiopexy may be done by 4 years old. Fertility and malignancy are also discussed in cases with cryptorchidism. PMID- 17702188 TI - [Molecular and anatomical studies of testicular descent]. AB - The mechanism of testicular descent is multifactorial, and the process is known to occur in two steps accompanied by different anatomies and hormonal regulation. In the first step, the testis descends from the lower pole of the kidney to the pelvic cavity near the bladder neck as a result of the swelling reaction of the gubernaculum. Next, in the second step, the testis descends into the scrotum through the inguinal canal via the gubernacular migration. The first step is androgen-independent, whereas the second step depends on the androgen action. Recently, several molecular studies on testicular descent have been reported. Several factors, such as androgen, calcitonin gene-related peptide (CGRP), epidermal growth factor (EGF), Hoxa-10 and insulin-like factor 3 (INSL3) have been suggested to be possible regulators of testicular descent. Because cryptorchidism has been frequently shown in androgen-insensitive human and mice (TFM-mice), androgen has been thought to play an important role in testicular descent. CGRP, which is released from the genitofemoral nerve, has been suggested to mediate the inguinoscrotal testicular descent. The epidermal growth factor (EGF) may promote both testosterone-induced wollfian duct differentiation and testicular descent by activating the androgen responsive systems. In male mice, a targeted disruption of the HOXA 10 gene causes cryptorchidism and the cryptorchid testes in these mutant mice are located in the lower abdominal cavity, whereas the cryptorchid testes in male mice lacking the INSL3 gene or its receptor Lgr8 were located in the abdominal cavity high. Recently, estrogens or environmental endocrine disruptors have also been suspected to induce a down-regulated INSL3 expression and thus disturb testicular descent. PMID- 17702189 TI - [Individualized treatment of undescended testis]. AB - Undescended testis is one of the most common congenital anomalies requiring surgery. The guideline for the treatment of undescended testis was published by Japanese Society of Pediatric Urology in 2005. However, the management of undescended testis has been still controversial, particularly in case of impalpable testis including abdominal testis. In this article, we review our experience and published reports of orchiopexy for undescended testis and emphasize that the anatomical condition of undescended testis should be applied to individualized surgical treatment. PMID- 17702190 TI - [Cryptorchidism and assisted reproductive technique]. AB - The influence of cryptorchidism on male infertility is well-known. In this article the incidence of disturbance of spermatogenesis in cryptorchid patients and effect of assisted reproductive technique on such patients is reviewed. PMID- 17702191 TI - [Future treatment strategies for cryptorchidism to improve spermatogenesis]. AB - Orchiopexy is one of the most frequently used surgical procedures for cryptorchidism and has been shown to have a beneficial effect on fertility. However, orchiopexy, especially for bilateral cryptorchidism, does not always guarantee subsequent fertility and paternity. Compared with a control group, paternity was significantly compromised in men with previous bilateral, but not unilateral cryptorchidism. Recent techniques of assisted reproductive technology, especially testicular sperm extraction with intracytoplasmic sperm injection (TESE-ICSI), have brought revolutionary changes in clinical therapy for infertiliy. If spermatozoa exists in testis of infertile men, logically there is a possibility of paternity. However, our study demonstrated that about 20% of pubertal boys who had had orchiopexy, were predicted to have lost their future paternity potential even if TESE-ICSI were conducted, because they were predicted to have no spermatozoa in the testis. To prevent or reverse the damage of spermatogenesis at prepuberty or puberty, we should not take a wait-and-see attitude but should consider a countermeasure for the pubertal boys who had had bilateral orchiopexy in childhood, especially when the serum follicle stimulating hormone level is elevated and testicular volume is lowered, before paternity is lost. In this review, we discuss the potential approaches including epidermal growth facter therapy, gene therapy and stem-cell therapy for cryptorchid patients in the future. PMID- 17702192 TI - Pharmacokinetics, tissue distribution and excretion of gambogic acid in rats. AB - The plasma pharmacokinetics, excretion, and tissue distribution of gambogic acid (GA), a novel anti-tumor drug, were investigated after intravenous (i.v.) bolus administration in rats. Plasma profiles were obtained after i.v. administration of GA at the doses of 1, 2 and 4 mg/kg. The elimination half-life (tl/2) values for GA were estimated to be 14.9, 15.7 and 16.1 min, while the mean area under concentration-time curve (AUC(t)) values were 54.2, 96.1 and 182.4 microg min/ml, respectively. GA was mainly excreted into the bile (36.5% over 16 h). The cumulative sum of fecal excretion within 48 h was 1.26% of the i.v. administered dose. No GA was detected in the urine after i.v. administration. GA had a limited tissue distribution, with the highest concentrations being found in the liver. GA reached its maximal concentration in all tissues at 5 min post-dose. In conclusion, the present observations indicated that GA was rapidly eliminated from the blood and transferred to the tissues. Moreover, the majority of GA appeared to be excreted into the bile within 16 h of i.v. administration. PMID- 17702193 TI - An improved HPLC method for determination of nifuratel in human plasma and its application to pharmacokinetics studies. AB - A rapid, simple and sensitive high-performance liquid chromatography (HPLC) method was established for the quantification of nifuratel in human plasma and applied to a study of its pharmacokinetics. A test and a reference formulation were investigated and compared, and the study group consisted of 24 healthy male volunteers. The analytical technique was based on a single extraction of the drug from the plasma with chloroform, using ornidazole as internal standard (IS). The chromatographic system consisted of a 5-microm 4.6 mmX250 mm C18 analytical column and the mobile phase consisted of methanol and purified water (45:55, v/v). Nifuratel and ornidazole concentrations were detected by ultraviolet (UV) absorbance at a wavelength of 254 nm. The lower limit of detection and quantification was 0.5 ng ml(-1), and the calibration curves were linear over a concentration range of 0.5-160 ng ml(-1) nifuratel in the plasma. The results showed that the area under the plasma concentration-time curve (AUC), time to maximum observed plasma concentration (Tmax), maximum concentration reached in the concentration profile (Cmax), and elimination half-life (t1/2) between the test tablets and the reference tablets demonstrated no significant difference (P>0.05). The relative bioavailability amounted to 103.13% +/-8.73%. PMID- 17702194 TI - Pharmacokinetics of astragaloside iv in beagle dogs. AB - In this study, the pharmacokinetics of Astragaloside iv (AGS-IV) in Beagle dogs was studied by high performance liquid chromatography (HPLC) coupled with tandem mass spectrometry (MS). The concentrations of the drugs in plasma were determined after i.v. administration of 0.5, 1, 2 mg.kg(-1) AGS-IV and p.o. administration of 10 mg.kg(-1) AGS-IV. The areas under concentration-time curve (AUC) were linearly correlated to the doses administrated. The absolute bioavailability of AGS-IV after p.o. administration was found to be 7.4%. The plasma protein binding rate of AGS-IV was about 90% within a concentration range of 250-1000 ng.ml(-1). There was no significant species difference regarding the pharmacokinetics of AGS IV between the rat and the Beagle dog. PMID- 17702195 TI - Interaction of alcoholic extracts of hops with pentobarbital and diazepam in mice. AB - The interaction of alcoholic extracts of Magnum, Aroma and wild genotype hops with drugs that lower the activity of the central nervous system (CNS) was studied in mice. Hops drying and preparation of extracts were performed according to standard pharmacological procedures for preparing total alcoholic extracts of medicinal plants, i.e. in a ratio of one part dry herbs to two parts of 70% alcohol, with evaporation to dryness so that the extracts no longer contained any alcohol. The mice received four doses intraperitoneally (i.p.) of 0.5% aqueous solutions of the above-mentioned extracts, which were dissolved in warm physiological solution to make up a 0.5% aqueous solution, 24, 16, 4 and 0.5 hours before pentobarbital (40 mg/kg) or diazepam (3 mg/kg) administration. The hypnotic action of pentobarbital and the effect of diazepam on the coordination of movements (rotating rod method) were measured. It was found that hops extracts influenced the action of the investigated drugs, and that the extracts of the Magnum and Aroma genotypes suppressed the hypnotic action of pentobarbital and diazepam. Tert-butanolic extracts also suppressed the action of these two drugs but to a lesser extent, whereas wild hops extracts did not exert any significant effects compared to controls. PMID- 17702196 TI - Adapting therapy with repeated short-infusions to inter individual variability between patients. AB - Because of the wide inter individual variability between patients and their marked differences in drug response, one of the major issues that arises is adapting the therapy in question to the particular patient. In hospital, it is possible to vary the conditions of intravenous (i.v.) drug delivery by means of short infusions repeated at certain intervals. In this study, review of this process has been presented, and a therapeutic method described. It essentially consists of two stages. The first concerns the time of the first infusion, and the course of drug elimination: from two analyses of the drug concentrations in the blood made at two different times, the pharmacokinetic parameters of the patient are determined. Stage 2 consists of repeated short infusions and the therapy is adapted to the particular patient by varying the conditions involved. Thus, either the amount of the dose based on the rate of infusion or the time interval between the repeated infusions are varied. In order to reach a general solution, master curves are built by using dimensionless numbers as co-ordinates, such as time expressed in terms of the half-life t0.5 of the drug, and the drug concentration at the peaks defined as a fraction of the first unchanged peak concentration. PMID- 17702197 TI - Anthracycline-based combined chemotherapy in the mouse model. AB - Our research was aimed at establishing if and how selenium (Se) ion, N acetylcysteine (NAC), sodium salt of monoketocholic acid (MKH) and superoxide dismutase (SOD), administered in the experimental animal model, could affect the possible cytotoxicity associated with anthracycline-based combined chemotherapy with doxorubicin, vincristine and prednisolone (DVP). The following biochemical parameters were investigated: the extent of lipid peroxidation (LPx), and the activity of peroxidase (Px), catalase (CAT), glutathione-peroxidase (GSHPx), and xanthine-oxidase (XOD). A statistical increase in LPx activity was obtained by SOD, MKH, DVPSe and DVPMKH. All chemotherapeutic agents reduced Px activity in a statistically significant manner. There was no statistical significance for the results regarding the effects of the administered substances on GSHPx activity. The results for DVP, SOD, MKH, DVPSOD, DVPSe and DVPMKH showed reduced XOD activity which was statistically significant, which was lowest in the case of MKH, while NAC and Se reduced the activity of this enzyme but statistically non significant. NAC, Se, DVP, MKH and DVPMKH caused a reduction in CAT activity, while DVPSOD and DVPSe caused an increase of the latter. PMID- 17702199 TI - A national approach to day surgery. PMID- 17702201 TI - At your convenience: preoperative assessment by telephone. AB - This article describes how practitioners in one trust have worked in partnership with colleagues at NHS Direct to develop a telephone preoperative assessment service for elective day case surgery patients. The service has improved theatre utilisation by reducing the numbers of 'did not attends' (DNAs) and ensures the safe preparation of appropriately selected patients for day case surgery. It has reduced the number of trips to hospital patients need to make and, more recently, the length of time spent there. PMID- 17702198 TI - Effect of cholic acid and its keto derivatives on the analgesic action of lidocaine and associated biochemical parameters in rats. AB - This study examined the effect of the structure and concentration of cholic acid and its keto derivatives on the local analgesic action of lidocaine in rats, measured by an analgesimetric method. The increase in bile acid concentrations in the administered lidocaine solution increased the duration of local anesthesia. It was found that the introduction of keto groups into the cholic acid molecule yielded derivatives with lower promotory action, i.e. decreased the duration of local anesthesia. The biochemical parameters investigated indicated that the keto derivatives of cholic acid exhibited no toxicity compared to that of cholic acid itself. PMID- 17702202 TI - Anaesthesia for day surgery. AB - The Department of Health (DH) proposes that 75% of elective surgery should be performed as a day case procedure (NHS Plan 2000). To achieve this some modification of the traditional selection criteria may be required and careful thought given to the patient pathway, including the anaesthetic technique. Successful anaesthesia for day case surgery requires a balanced anaesthetic technique and multidisciplinary input which commences at booking, runs through preoperative assessment and continues to a nurse-led discharge. Suitable patients need to be selected (Digner 2007), prepared both physically and psychologically, undergo minimally invasive surgery with a suitable anaesthetic technique encompassing good pain relief and the avoidance of postoperative nausea and vomiting (PONV). Pain and PONV are the most common causes for a patient to require unplanned admission (Junger 2001). PMID- 17702203 TI - Bunions: their origin and treatment. AB - As theatre practitioners we are on our feet for long periods of time. How many of us can truthfully say that we treat our feet with the respect that they deserve, for example, wearing the correct footwear and generally taking good care of our feet? It is established that theatre clogs, while practical, are not a fashion statement. Most of us probably take our feet for granted--that is until something becomes painful or a deformity occurs. One common and often painful deformity of the foot is a bunion. This article describes how bunions occur and explores the surgical options. PMID- 17702204 TI - Inguinal hernia repair. AB - In excess of 100,000 inguinal hernia repairs are performed in the UK each year (Devlin & Kingsnorth 1998). It is the most commonly performed general surgical procedure and is routinely undertaken in patients receiving local anaesthesia in the day case setting. The Royal College of Surgeons has recommended that > 50% inguinal hernias are undertaken on day cases, although at present this figure is only 30% (RCSE 1993). This article defines hernias and describes the aetiology and surgical treatment of inguinal and femoral hernia. The differences between the traditional and laparoscopic repair of hernias are explored as well as the use of materials such as polypropylene mesh to enhance the repair. The need for thromboprophylaxis and antibiotic therapy are outlined together with patient discharge advice. PMID- 17702205 TI - Palliation of tracheobronchial carcinoma: the role of cryosurgery. AB - Bronchoscopy is a common day case procedure that can aid in the diagnosis and treatment of tracheobronchial disorders. The controlled application of extreme cold through a bronchoscope to endobronchial lesions (malignant and benign) is known as endobronchial cryosurgery. This procedure improves respiratory function and reduces shortness of breath and is performed in a cycle of three treatments. This article describes the instrumentation required, how cryosurgery is performed and how endobronchial cryosurgery can improve the patient's functional status and survival. PMID- 17702207 TI - Kilner's needle holder. AB - Anyone who has assisted, single-handedly, at a long plastic surgery operation, which will inevitably involve dozens of skin sutures, will have blessed the name of Thomas Pomfret Kilner (1890-1964) and his needle holder. This ingenious instrument combines the dual functions of a stitch-cutting scissors with a needle holder, so that the surgeon can put in a stitch, tie it and cut it without having, on each occasion, to put down the needle holder and pick up a pair of scissors, or to get his assistant to snip it for him. PMID- 17702206 TI - Standardised analgesia packs after day case orthopaedic surgery. AB - Two of the advantages of day surgery are less disruption to patients' lives and the comfort of recovering at home. However, despite advances in analgesic and anaesthetic techniques, pain following day surgery is not well managed: recent studies have shown that between 30-60% of patients suffer moderate to severe pain during the first 24 hours after discharge home following day surgery (Beauregard et al 1998, McGrath et al 2004, Pavlin et al 2004). A significant proportion of patients (25-30%) continue to report pain of this severity at seven days following day surgery (Beauregard et al 1998, Watt-Watson 2004). This article reviews published studies of patient experiences of pain and analgesia consumption after day case surgery and provides a model for the introduction of standardised take-home analgesic packs. PMID- 17702208 TI - Flight deck disturbance management: a simulator study of diagnosis and recovery from breakdowns in pilot-automation coordination. AB - OBJECTIVE: To examine operator strategies for diagnosing and recovering from errors and disturbances as well as the impact of automation design and time pressure on these processes. BACKGROUND: Considerable efforts have been directed at error prevention through training and design. However, because errors cannot be eliminated completely, their detection, diagnosis, and recovery must also be supported. Research has focused almost exclusively on error detection. Little is known about error diagnosis and recovery, especially in the context of event driven tasks and domains. METHOD: With a confederate pilot, 12 airline pilots flew a 1-hr simulator scenario that involved three challenging automation-related tasks and events that were likely to produce erroneous actions or assessments. Behavioral data were compared with a canonical path to examine pilots' error and disturbance management strategies. Debriefings were conducted to probe pilots' system knowledge. RESULTS: Pilots seldom followed the canonical path to cope with the scenario events. Detection of a disturbance was often delayed. Diagnostic episodes were rare because of pilots' knowledge gaps and time criticality. In many cases, generic inefficient recovery strategies were observed, and pilots relied on high levels of automation to manage the consequences of an error. CONCLUSION: Our findings describe and explain the nature and shortcomings of pilots' error management activities. They highlight the need for improved automation training and design to achieve more timely detection, accurate explanation, and effective recovery from errors and disturbances. APPLICATION: Our findings can inform the design of tools and techniques that support disturbance management in various complex, event-driven environments. PMID- 17702209 TI - On the independence of compliance and reliance: are automation false alarms worse than misses? AB - OBJECTIVE: Participants performed a tracking task and system monitoring task while aided by diagnostic automation. The goal of the study was to examine operator compliance and reliance as affected by automation failures and to clarify claims regarding independence of these two constructs. BACKGROUND: Background data revealed a trend toward nonindependence of the compliance reliance constructs. METHOD: Thirty-two undergraduate students performed the simulation that presented the visual display while dependent measures were collected. RESULTS: False alarm-prone automation hurt overall performance more than miss-prone automation. False alarm-prone automation also clearly affected both operator compliance and reliance, whereas miss-prone automation appeared to affect only operator reliance. CONCLUSION: Compliance and reliance do not appear to be entirely independent of each other. APPLICATION: False alarms appear to be more damaging to overall performance than misses, and designers must take the compliance-reliance constructs into consideration. PMID- 17702210 TI - Alternative computer mouse design and testing to reduce finger extensor muscle activity during mouse use. AB - OBJECTIVE: The purpose of this study was to design and test alternative computer mouse designs that attempted to reduce extensor muscle loading of the index and middle fingers by altering the orientation of the button switch direction and the force of the switch. BACKGROUND: Computer users of two-button mouse designs exhibit sustained lifted finger behaviors above the buttons, which may contribute to hand and forearm musculoskeletal pain associated with intensive mouse use. METHODS: In a repeated-measures laboratory experiment, 20 participants completed point-and-click, steering, and drag tasks with four alternative mouse designs and a reference mouse. Intramuscular and surface electromyography (EMG) measured muscle loading, and movement times recorded by software provided a measure of performance. RESULTS: Changing the direction of the switch from a conventional downward to a forward design reduced (up to 2.5% maximum voluntary contraction [MVC]) sustained muscle activity (10th percentile EMG amplitude distribution) in the finger extensors but increased (up to 0.6% MVC) flexor EMG and increased movement times (up to 31%) compared with the reference mouse (p < .001). Implementing a high switch force design also increased flexor EMG but did not differ in movement times compared with the reference mouse (p < .001). CONCLUSION: The alternative mouse designs with altered switch direction reduced sustained extensor muscle loading; however, trade-offs with higher flexor muscle loading and lower performance existed. APPLICATION: Potential applications of this study include ergonomic and human computer interface design strategies in reducing the exposure to risk factors that may lead to upper extremity musculoskeletal disorders. PMID- 17702211 TI - Optimizing emergency awakening to audible smoke alarms: an update. AB - OBJECTIVE: This review examines research on arousal from sleep in an emergency. It considers whether the current smoke alarm signal is optimal for waking those most at risk of dying in a fire and, if not, how it may be improved. BACKGROUND: The fire fatality rate during the sleeping period is approximately three times greater than at other times. METHOD: Four key areas are reviewed: (a) the characteristics of four signals (high-frequency beeping, Temporal 3, voice, and naturalistic sounds); (b) how human characteristics alter arousal to different signals; (c) research comparing the effectiveness of different alarms in different sleeping populations; and (d) acoustical, methodological, and theoretical implications. RESULTS: Significant risk factors for staying asleep include high levels of background noise, being a heavy sleeper, sleep deprivation, being a child, hypnotics, alcohol intoxication, and hearing impairment. The high-frequency beeping signal was significantly less effective than either a voice alarm or mixed-frequency beeping in waking selected at-risk groups. CONCLUSION: The alternative signals were more effective in arousing various groups of sleepers than was the high-frequency signal currently used in smoke alarms. APPLICATION: Replacement of the current smoke alarm signal with one of a lower frequency is likely to wake more people more quickly and save lives. PMID- 17702212 TI - The effect of phone design on upper extremity discomfort and muscle fatigue. AB - OBJECTIVE: To compare a small cellular clamshell phone with a traditional office phone in the development of discomfort and muscle fatigue over time during phone use. BACKGROUND: Phone use involves low-level static exertions that may be influenced by phone design. Phone design and its interactions with anthropometry may change shoulder and hand postures assumed during use, which in turn may modify the length-strength relationship and moment arms of the muscles. METHOD: Ten adults participated in a study that simulated phone use using a small clamshell and a traditional office phone. Discomfort information and electromyographic (EMG) muscle activity were monitored on four upper extremity muscles. Discomfort and fatigue data (EMG median frequency shifts) were analyzed to assess differences between phones as well as differing effects attributable to anthropometry. RESULTS: Median frequency shifts supported discomfort claims and indicated muscle fatigue in the deltoid and thenar muscles. Biomechanical measures demonstrated that participants with short limb lengths developed more severe signs of thenar fatigue. Participants with longer arms developed greater discomfort in the neck, shoulder, and back. The deltoid confirmed this occurrence, showing signs of muscle fatigue. CONCLUSION: Phone design and anthropometry influenced the development of discomfort and fatigue during phone use. Phone design dictated grip style, resulting in differing discomfort and fatigue levels. Anthropometry influenced the severity of the discomfort and fatigue present in the shoulder and hand. APPLICATION: Use of small clamshell phones may contribute to a lack of rest and recovery from typical workday exposures. It should be explored from an ergonomic perspective. PMID- 17702213 TI - The effects of LCD anisotropy on the visual performance of users of different ages. AB - OBJECTIVE: The present study examined the visual discrimination speed and accuracy while using an LCD and a CRT display. BACKGROUND: LCDs have ergonomic advantages, but their main disadvantage is that they provide inconsistent photometric measures depending on the viewing angle (anisotropy). METHOD: Independent variables were screen type (LCD and CRT), viewing angle (0 degrees, 11 degrees, 41 degrees, 50 degrees, and 56 degrees) and user's age (teenagers, young adults, and middle-aged adults). Dependent variables were speed and accuracy in a visual discrimination task and user's ratings. RESULTS: The results corroborated the negative impact of LCD anisotropy. Visual discrimination times were by 7.6% slower when an LCD was used instead of a CRT. Performance differences increased with increasing viewing angle for both screens, but performance decrements were larger for the LCD. Young adults showed the best visual performance, as compared with teenagers and middle-aged adults. Effects of anisotropy were found for all age groups, although the performance of middle-aged adults was affected more when extended viewing angles were adopted. CONCLUSION: LCD anisotropy is a limiting factor for visual performance, especially in work settings where fast and accurate reactions are necessary. APPLICATION: The outcomes of this research allow ergonomic guidelines for electronic reading. PMID- 17702214 TI - Performance consequences of alternating directional control-response compatibility: evidence from a coal mine shuttle car simulator. AB - OBJECTIVE: To investigate error and reaction time consequences of alternating compatible and incompatible steering arrangements during a simulated obstacle avoidance task. BACKGROUND: Underground coal mine shuttle cars provide an example of a vehicle in which operators are required to alternate between compatible and incompatible steering configurations. METHODS: This experiment examines the performance of 48 novice participants in a virtual analogy of an underground coal mine shuttle car. Participants were randomly assigned to a compatible condition, an incompatible condition, an alternating condition in which compatibility alternated within and between hands, or an alternating condition in which compatibility alternated between hands. RESULTS: Participants made fewer steering direction errors and made correct steering responses more quickly in the compatible condition. Error rate decreased over time in the incompatible condition. A compatibility effect for both errors and reaction time was also found when the control-response relationship alternated; however, performance improvements over time were not consistent. Isolating compatibility to a hand resulted in reduced error rate and faster reaction time than when compatibility alternated within and between hands. CONCLUSION: The consequences of alternating control-response relationships are higher error rates and slower responses, at least in the early stages of learning. APPLICATION: This research highlights the importance of ensuring consistently compatible human-machine directional control response relationships. PMID- 17702215 TI - Overlapping melodic alarms are almost indiscriminable. AB - OBJECTIVE: We explore how accurately and quickly nurses can identify melodic medical equipment alarms when no mnemonics are used, when alarms may overlap, and when concurrent tasks are performed. BACKGROUND: The international standard IEC 60601-1-8 (International Electrotechnical Commission, 2005) has proposed simple melodies to distinguish seven alarm sources. Previous studies with nonmedical participants reveal poor learning of melodic alarms and persistent confusions between some of them. The effects of domain expertise, concurrent tasks, and alarm overlaps are unknown. METHOD: Fourteen intensive care and general medical unit nurses learned the melodic alarms without mnemonics in two sessions on separate days. In the second half of Day 2 the nurses identified single alarms or pairs of alarms played in sequential, partially overlapping, or nearly completely overlapping configurations. For half the experimental blocks nurses performed a concurrent mental arithmetic task. RESULTS: Nurses' learning was poor and was no better than the learning of nonnurses in a previous study. Nurses showed the previously noted confusions between alarms. Overlapping alarms were exceptionally difficult to identify. The concurrent task affected response time but not accuracy. CONCLUSION: Because of a failure of auditory stream segregation, the melodic alarms cannot be discriminated when they overlap. Directives to sequence the sounding of alarms in medical electrical equipment must be strictly adhered to, or the alarms must redesigned to support better auditory streaming. APPLICATION: Actual or potential uses of this research include the implementation of IEC 60601-1-8 alarms in medical electrical equipment. PMID- 17702216 TI - Effects of sleep loss on team decision making: motivational loss or motivational gain? AB - OBJECTIVE: To examine the effects of 30 hr of sleep loss and continuous cognitive work on performance in a distributed team decision-making environment. BACKGROUND: To date, only a few studies have examined the effect of sleep loss on distributed team performance, and only one other to our knowledge has examined the relationship between sleep loss and social-motivational aspects of teams (Hoeksema-van Orden, Gaillard, & Buunk, 1998). METHOD: Sixteen teams participated; each comprised 4 members. Three team members made threat assessments on a military surveillance task and then forwarded their judgments electronically to a team leader, who made a final assessment on behalf of the team. RESULTS: Sleep loss had an antagonistic effect on team decision-making accuracy and decision time. However, the performance loss associated with fatigue attributable to sleep loss was mediated by being part of a team, as compared with performing the same task individually - that is, we found evidence of a "motivational gain" effect in these sleepy teams. We compare these results with those of Hoeksema-van Orden et al. (1998), who found clear evidence of a "social loafing" effect in sleepy teams. CONCLUSION: The divergent results are discussed in the context of the collective effort model (Karau & Williams, 1993) and are attributable in part to a difference between independent and interdependent team tasks. APPLICATION: The issues and findings have implications for a wide range of distributed, collaborative work environments, such as military network-enabled operations. PMID- 17702217 TI - Spatial compatibility effects with tool use. AB - OBJECTIVE: We explored constraints in responding to spatially variable stimuli when hand movements are transformed into inverse movements of a tool. BACKGROUND: Generally, the spatial compatibility between stimuli and responses is a powerful determinant of performance. However, many tasks require the use of simple tools such as first-class levers that transform hand movements into inverted movements of a tool. What types of compatibility effects arise with such tools? METHOD: Participants moved the tip of a pointer to the left or right according to the color of a stimulus. The pointer was manipulated either directly, so that a hand movement caused a pointer movement in the corresponding direction, or indirectly, so that the hand moved the pointer in the opposite direction. RESULTS: Responding was faster when the location of stimulus and the movement direction of the tool corresponded than when they did not correspond, independent of the movement direction of the hand. This occurred when stimulus location was task relevant (Experiment 1) as well as when it was task irrelevant (Experiment 2). Furthermore, responding was delayed when the hand and the relevant end of the tool moved in noncorresponding rather than corresponding directions. CONCLUSION: These results point to two distinct compatibility effects in tool use: one that relates to the transformation of stimuli into goals and one that relates to the transformation of goals into movements. APPLICATION: Potential applications of this research include the prediction and possibly manipulation of unwanted "fulcrum effects" in laparoscopic surgery and other first-class lever movements. PMID- 17702218 TI - Gaze behavior of spotters during an air-to-ground search. AB - OBJECTIVE: This study was designed to develop methods for evaluating the gaze behaviors of spotters during air-to-ground search and to compare field-derived measures with previous lab results. Secondary aims were to assess adherence to a prescribed scan path, evaluate search effectiveness, and determine the predictors of task success. BACKGROUND: Crashed aircraft must be located quickly to minimize loss of life, often requiring visual search from the air. METHOD: Eye movements were measured in 10 volunteer spotters while they searched from the air for ground targets. Visual acuity, contrast levels, and performance on a lab-based search task were also measured. RESULTS: Results were similar to those of previous lab-based studies of air-to-ground search. Task success could be predicted best from a combination of gaze and laboratory variables, and as in previous research, experience was not one of them. CONCLUSIONS: In both lab and field research, performance is poor. Improvements in air search and rescue success will depend upon improvements in training, the refinement of scan tactics, changes to the task methods or environment, or modifications to parameters of the search exercise. APPLICATION: Spotters were unable to reliably search their assigned area, which has implications for the current search training program and in-the-air protocol. PMID- 17702219 TI - Visual field magnification and touch perception when exploring surfaces with the index finger and a rigid instrument. AB - OBJECTIVE: The aim of this project was to compare texture discrimination when both touch and vision were perturbed. BACKGROUND: Texture discrimination is important in the workplace. How textures are identified with the finger and with instruments when vision is magnified with lenses or video cameras is unclear. METHOD: Sandpaper was explored with the index finger or a metal instrument (hemostat), using normal or magnified vision. The forces generated during exploration were measured, and participants rated surface roughness. RESULTS: With the finger, the perception of roughness was unaffected with magnification; with the instrument, magnified surfaces were perceived as rougher (p < .05). Forces during finger exploration were unaffected by magnification; forces with the instrument increased under magnification (p < .05). CONCLUSION: Visual characteristics of the working field can influence the exploration and perception of materials. With the finger, mechanoreceptors that directly detect textures are activated, and with the instrument, receptors sensitive to vibrations are stimulated. APPLICATION: The higher forces produced when using instruments under magnification could lead to material damage. Attenuated perception of texture when exploring with tools may lead to difficulty in accurate touch perception. This could create problems in industrial tasks such as grading wool or identifying surface imperfections on manufactured materials, as well as in clinical settings such as dentistry or surgery in which instruments are used during tissue identification. PMID- 17702220 TI - Spatial audio displays improve the detection of target messages in a continuous monitoring task. AB - OBJECTIVE: The detection of target messages in a background of competing speech and the identification of the color/number combinations in those messages were examined in a continuous monitoring task. BACKGROUND: Previous research has shown that if listeners know when and where to listen, speech-on-speech intelligibility is improved when signals are presented via a 3-D audio display as compared with a diotic display. However, the effect of display type on detection of infrequent target messages in a continuous monitoring task has not been examined. METHOD: Participants were required to monitor five communications channels conveying messages at random intervals under each of three audio display conditions: diotic, all channels in front, and channels separated in azimuth (3-D). RESULTS: Message detection sensitivity was significantly higher for the 3-D condition than for the in-front condition but did not differ significantly between the in-front and the diotic conditions. There were no differences in response criteria across conditions. Color/number identification sensitivity also was significantly higher for the 3-D condition than for the in-front condition but did not differ significantly between the in-front and the diotic conditions. CONCLUSION: A 3-D audio display enhances both message detection and message identification in a continuous monitoring task. APPLICATION: Three-dimensional audio displays would be particularly beneficial in environments such as aviation, in which the information conveyed to operators via the auditory modality can be crucial to the safe and effective performance of their work. PMID- 17702221 TI - The utility of a virtual reality locomotion interface for studying gait behavior. AB - OBJECTIVE: To investigate the effect of optic flow on gait behavior during treadmill walking using an immersive virtual reality (VR) setup and compare it with conventional treadmill walking (TW) and overground walking (OW). BACKGROUND: Previous research comparing TW with OW speculated that a lack of optic flow (relative visual movement between a walker and the environment) during TW may have led to perceptual cue conflicts, resulting in differences in gait behavior, as compared with OW. METHOD: Participants walked under three locomotion conditions (OW, TW, and TW with VR [TWVR]) under three walking constraint conditions (no constraint, a temporal/pacing constraint, and a spatial/path following constraint). Presence questionnaires (PQs) were administered at the close of the TWVR trials. Trials were subjected to video analysis to determine spatiotemporal and kinematics variables used for comparison of locomotion conditions. RESULTS: ANOVA revealed gait behavior during TWVR to be between that of OW and TW. Speed and cadence during TWVR were significantly different from those of TW, whereas knee angle was comparable to that of OW. Correlation analysis of PQ scores with gait measures revealed a positive linear association of the distraction subfactor of the PQ with walking speed during TWVR, suggesting an increase in the sense of presence in the virtual environment led to increases in walking speed. CONCLUSION: The results demonstrate that providing optic flow during TW through VR has an impact on gait behavior. APPLICATION: This study provides a basis for developing simple VR locomotion interface setups for gait research. PMID- 17702222 TI - Toward developing an approach for alerting drivers to the direction of a crash threat. AB - OBJECTIVE: This study explored the potential for auditory and haptic spatial cuing approaches to alert drivers to the direction of a crash threat. BACKGROUND: For an automobile equipped with multiple crash avoidance systems, effective cuing of the crash threat direction may help the driver avoid the crash. Because the driver may not be looking in the direction of a visual crash alert, nonvisual crash alerts were explored as an additional means of directing attention to a potential crash situation. METHODS: In this in-traffic study, 32 drivers were asked to verbally report alert direction in the absence of any crash threats. Driver localization accuracy and response time were examined as a function of eight alert locations surrounding the vehicle and four directional alert approaches (auditory, haptic, haptic and auditory, and haptic and nondirectional auditory). The auditory directional alert approach used four speakers and broadband alert sounds, and the haptic directional alert approach used vibrations generated at various locations on the bottom of the driver's seat. RESULTS: Overall, relative to the auditory alert approach, the three approaches that included the haptic seat alert component reduced correct localization response times by 257 ms and increased percentage correct localization from 32% to 84%. CONCLUSION: These results suggest that seat vibration alerts are a promising candidate for alerting drivers to the direction of a crash threat. APPLICATION: These findings should facilitate developing a multimodality integrated crash alert approach for vehicles equipped with multiple crash avoidance systems. PMID- 17702223 TI - Visual attention in driving: the effects of cognitive load and visual disruption. AB - OBJECTIVE: This study investigates the effect of cognitive load on guidance of visual attention. BACKGROUND: Previous studies have shown that cognitive load can undermine driving performance, particularly drivers' ability to detect safety critical events. Cognitive load combined with the loss of exogenous cues, which can occur when the driver briefly glances away from the roadway, may be particularly detrimental. METHOD: In each of two experiments, twelve participants engaged in an auditory task while performing a change detection task. A change blindness paradigm was implemented to mask exogenous cues by periodically blanking the screen in a driving simulator while a change occurred. Performance measures included participants' sensitivity to vehicle changes and confidence in detecting them. RESULTS: Cognitive load uniformly diminished participants' sensitivity and confidence, independent of safety relevance or lack of exogenous cues. Periodic blanking, which simulated glances away from the road-way, undermined change detection to a greater degree than did cognitive load; however, drivers' confidence in their ability to detect changes was diminished more by cognitive load than by periodic blanking. CONCLUSION: Cognitive load and short glances away from the road are additive in their tendency to increase the likelihood of drivers missing safety-critical events. APPLICATION: This study demonstrates the need to consider the combined consequence of cognitive load and brief glances away from the road in the design of emerging in-vehicle devices and the need to provide drivers with better feedback regarding these consequences. PMID- 17702224 TI - Learning headway estimation in driving. AB - OBJECTIVE: The main purpose of the present study was to examine to what extent the ability to attain a required headway of 1 or 2 s can be improved through practical driving instruction under real traffic conditions and whether the learning is sustained after a period during which there has been no controlled training. BACKGROUND: The failure of drivers to estimate headways correctly has been demonstrated in previous studies. METHODS: Two methods of training were used: time based (in seconds) and distance based (in a combination of meters and car lengths). For each method, learning curves were examined for 18 participants at speeds of 50, 80, and 100 km/hr. RESULTS: The results indicated that drivers were weak in estimating headway prior to training using both methods. The learning process was rapid for both methods and similar for all speeds; thus, after one trial with feedback, there was already a significant improvement. The learning was retained over time, for at least the 1 month examined in this study. CONCLUSION: Both the time and distance training of headway improved drivers' ability to attain required headways, with the learning being maintained over a retention interval. The learning process was based on perceptual cues from the driving scene and feedback from the experimenter, regardless of the formal training method. APPLICATION: The implications of these results are that all drivers should be trained in headway estimation using an objective distance measuring device, which can be installed on driver instruction vehicles. PMID- 17702225 TI - Stress appraisals and training performance on a complex laboratory task. AB - OBJECTIVE: We investigated whether training performance on a complex laboratory task differs for trainees whose stress appraisals denote challenge or threat. BACKGROUND: Past research outside a training context found better performance on tasks when stress appraisals denoted challenge (in which perceived situational demands are commensurate with perceived resources) as opposed to threat (in which perceived coping resources fall short of the demands of the stressor). METHOD: College students performed Space Fortress during 80 3-min practice trials, 20 tests, and posttests (retention, transfer, secondary task interference). Stress appraisals were measured with a two-item scale (Experiments 1-3) or an eight-item scale (Experiment 3) with (Study 1) or without (Experiments 2 and 3) brief hands on experience. RESULTS: In all experiments, training improved performance and challenged trainees outperformed threatened trainees throughout training as well as on some baseline and posttraining tests. CONCLUSIONS: These studies are the first to document that stress appraisals predict training performance. They suggest that little information about a task is needed for appraisals to account for a significant amount of variance (11%) in training performance. Investigating the dynamic interplay of stress appraisals and training will increase the understanding of stress appraisals and of training. APPLICATION: Stress appraisals may improve training if used as a screening tool and/or by implementing interventions aimed at changing appraisals from threat to challenge. PMID- 17702226 TI - Unsafe acts in photos have an impact. PMID- 17702227 TI - The role of safety in business continuity. PMID- 17702228 TI - What a mesh! PMID- 17702229 TI - Distributing safety. PMID- 17702230 TI - Integrity first: living the honor code. PMID- 17702231 TI - The sounds of safety. PMID- 17702232 TI - The lowdown on backup alarms in retail stores. PMID- 17702233 TI - 1926.59 builds a foundation for safer works sites. PMID- 17702234 TI - A behind-the-scenes look at your fall protection equipment. PMID- 17702235 TI - Know your threshold. AB - A fall protection survey should be performed to identify potential fall hazards. A fall protection policy should then be developed and employees trained as needed. PMID- 17702236 TI - Electrical hazard assessment: first step in meeting OSHA standards. PMID- 17702237 TI - Making the grade. PMID- 17702238 TI - Spill response: utilizing local resources. PMID- 17702239 TI - The big one's coming, so get ready. PMID- 17702240 TI - Use employee assistance to manage risk. PMID- 17702241 TI - Firefighter rehab gets an upgrade. PMID- 17702242 TI - Storm warning. PMID- 17702243 TI - New rules for teen workers. PMID- 17702244 TI - Hurting the bottom line. PMID- 17702245 TI - Insole insights. PMID- 17702246 TI - Robot to the rescue. PMID- 17702248 TI - The danger of 'rubber-stamping' specs. PMID- 17702247 TI - Debunking emergency equipment myths. PMID- 17702249 TI - [Bioremediation of contaminated aquatic ecosystems, an impossible mission?]. PMID- 17702250 TI - [Molecular study of Argentine strains of Bacillus anthracis]. AB - Bacillus anthracis is one of the most monomorphic bacteria known and epidemiological studies of this microorganism have been hampered by the lack of molecular markers. For the genotyping of fourteen Argentine field strains and the vaccine strain Steme 34F2 the presence or absence of the virulence plasmids as well as vrrA locus containing a variable-number tandem repeat (VNTR) and presenting a polymorphism involving five variants, were analyzed. Strains were isolated from cows, sheep and pigs during outbreaks occurred in Buenos Aires, Entre Rios, Santa Fe and La Pampa in the past fifty years. All of the field strains presented plasmids pXO1 and pXO2, except for a strain isolated from pig that only presented plasmid pXO2. All the strains and the vaccine strain belonged to the same VNTR variant that was defined by sequencing the vrrA locus from three of the isolates and the strain 34F2. These sequences were completely identical and corresponded to the variant VNTR4. Thus, the fourteen Argentine B. anthracis strains studied showed great uniformity at molecular level even though they had been isolated from different mammal species within a wide time period and covering an extensive geographical area. PMID- 17702251 TI - [Useful phenotypic characteristics for presumptive identification of Candida guilliermondii]. AB - Candida guilliermondii developed a pink-purplish colony on CHROMagar Candida. In the micromorphology in milk-tween 80 1% agar at 28 degrees C after 48 h of incubation C. guilliermondii showed small (3-5 microm), spherical yeasts without pseudohyphaes. This Candida species presented a characteristic cluster of blastospores with pseudohyphaes radiating from the centre at 96 h. The trehalose sucrose assimilation assay was applied to the C. guilliermondii isolates which proved negative for trehalose and positive for sucrose. These results allowed for the presumptive identification of C. guilliermondii. The results were concordant in 100% of the isolates with the identification of the C. guilliermondii species by the ID 32C and Vitek YBC methods. Such automated methods offered Candida famata as a second option, with a reliability percentage of 10%. Micromorphological studies increase yeast identification reliability, especially among species presenting similar biochemical profiles. PMID- 17702252 TI - Intramammary infections during the periparturient period in Argentine dairy heifers. AB - Prevalence of intramammary infections at prepartum and postpartum in primigravid heifers from five dairy herds located in the central dairy area of Argentina was determined. Mammary secretion samples from 140 heifers (560 mammary quarters) were obtained 14 days prior to the expected calving day and within 7 days after parturition and subjected to bacteriological analysis. No clinical mastitis cases were detected during the study. The number of infected heifers in at least one mammary quarter at pre and postpartum was 87 (62.2%) and 53 (37.8%), respectively. The most prevalent mastitis pathogens at prepartum among samples yielding a positive bacteriological culture were coagulase-negative staphylococci (69.07%), Staphylococcus aureus (12.71%) and Streptococcus uberis (4.42%). A decrease on isolation frequency of coagulase-negative staphylococci (53.41%) and S. uberis (2.27%) was observed at postpartum, while that of S. aureus showed an increase (21.59%). Presence of intramammary infections appeared to be associated with some management conditions. These results highlighted the need to improve diagnosis and control measures in replacement heifers. PMID- 17702253 TI - Prolonged fecal shedding of Shiga toxin-producing Escherichia coli among children attending day-care centers in Argentina. AB - In this report we describe the detection and duration of fecal shedding of Shiga toxin-producing Escherichia coil (STEC) O157 and non-O157 in symptomatic and asymptomatic cases during four events occurred among children in day-care centers in Argentina. In each event, the cases were identified among children, family contacts and staff members of the Institution. The isolates were characterized by pheno-genotyping and subtyping methods. The STEC fecal shedding was prolonged and intermittent. Strains O157:H7 (1st event); O26:H11 (2nd event); O26:H11 (3rd event) and O145:NM (4th event) were shed during 23-30, 37, 31 and 19 days, respectively. Considering the possibility of STEC intermittent long-term shedding, symptomatic and asymptomatic individuals should be excluded from the Institution until two consecutive stool cultures obtained at least 48 h apart, test negative. PMID- 17702254 TI - [Bacteremia due to Abiotrophia defectiva in a febrile neutropenic pediatric patient]. AB - The presence of Granulicatella spp. in bacteremic episodes of neutropenic patients was recently highlighted whereas Abiotrophia defectiva, was only isolated in cases of infectious endocarditis. The aim of this study is to describe a case of A.defectiva bacteremia in a leukemic and febrile (40 degrees C) neutropenic (200 GB/mm3) boy. A.defectiva was only isolated from one of the two processed blood samples. Although the patient was undergoing an episode of varicela which could have accounted as the possible cause of fever, A. defectiva was considered a significant finding because this species is not part of the commensal skin flora. This case suggests that both A. defectiva and Granulicatella spp. should be regarded as possible causes of bacteremia in immunocompromised patients. PMID- 17702255 TI - [Nonpuerperal breast abscess caused by Finegoldia magna]. AB - Finegoldia magna is a species of strictly anaerobic gram-positive cocci, arranged in pairs, tetrads, and clusters. These organisms are components of the normal flora of the skin, gastrointestinal and genitourinary female tracts, and oral cavity. They are asaccharolytic and their major energy sources are aminoacids and peptones. The species is usually isolated in polymicrobial cultures from abscesses, soft tissue infections, bone and joints. In the case herein presented, F. magna was recovered in pure culture from a nonpuerperal breast abscess, which adds to the two reported cases in related literature. Species identification was performed by special potency disks, standard bacteriological anaerobic tests, and production of saccharolytic and proteolytic enzymes. Antimicrobial susceptibility testing was performed by using the epsilometric test. The agents assayed and MICs (microg/ml) values were: penicillin, 0.064; cephalotin, 1; metronidazole, 0.25; minocycline, < 0.016; azithromycin, 4; claritromycin, 2. We would like to highlight the importance of identifying anaerobic gram-positive cocci at species level, and of determining the antimicrobial susceptibility pattern, when they are isolated in pure culture from appropriate samples, as in the case presently reported. PMID- 17702257 TI - [Methods for the detection of beta-lactamase producing enterococci]. PMID- 17702256 TI - [Investigation of Trichomonas vaginalis through different methodologies during pregnancy]. AB - The aim of this study was to conduct a survey regarding the prevalence of trichomoniasis in pregnant patients and to evaluate the utility of different diagnostic methods. Two hundred and twenty three vaginal swab specimens from pregnant women were prospectively examined. Trichomonas vaginalis was investigated by various microscopic examinations, solid culture medium and liquid culture medium. The sensitivity and specificity of microscopy were evaluated by considering both culture media as the "gold standards". The prevalence of T. vaginalis obtained by both culture media (liquid plus solid media) was 4.5% (10/223). The prevalence of T. vaginalis obtained by direct smear, May-Grunwald Giemsa staining, sodium acetate-acetic acid-formalin (SAF)/Methylene blue staining-fixing technique, solid medium and liquid medium was 1.3%, 1.8%, 1.8% and 4.5%, respectively. The sensitivity of the direct smear was 30 %, but for the May-Grunwald Giemsa staining and the SAF/Methylene blue staining-fixing technique was 40%. Considering the three microscopic examinations altogether, the sensitivity rose to 50% and the specificity was 100% for all of them. The solid medium detected only 50% of the positive cases; the liquid medium detected 100%. Due to the low sensitivity obtained with microscopy in asymptomatic pregnant patients, we recommend the use of the liquid medium during pregnancy, in order to provide an early treatment. PMID- 17702258 TI - [Acquired parasitosis due to sushi ingestion]. PMID- 17702259 TI - [Influence of penicillin minimum inhibitory concentration in the synergy between penicillin and gentamicin in viridans-group streptococci]. AB - Penicillin resistance rates higher than 60% have been recorded in viridans group streptococci by some authors during the 90's and recently such resistance was associated with higher levels of mortality in bacteremia. The lowest minimum inhibitory concentration of penicillin for which synergy with aminoglycosides is not yet possible is still unknown. In order to try to dilucidate this puzzle, a study on the susceptibility to penicillin of 28 strains of viridans group streptococci isolated from significant samples in the Hospital de Pediatria "Prof. Dr. Juan P. Garrahan" was carried out. Seven mitis group isolates presenting different susceptibility patterns were selected for performing time killing curves with penicillin, gentamicin, and penicillin plus gentamicin, using higher and lower penicillin concentrations than their minimal inhibitory concentrations. Synergy was not observed when the penicillin concentration was lower than the minimum inhibitory concentration, at least in these strains with minimum inhibitory concentrations of gentamicin > or = 16 microg/ml. When using penicillin in higher concentrations than the minimum inhibitory concentration, synergy was found in five of the seven strains. Aminoglycoside-modifying enzymes were found in the two other streptococci. PMID- 17702260 TI - [Isolation, characterization and typing of Escherichia coil 0157:H7 strains from beef products and milk]. AB - Shiga toxin (Stx)-producing Escherichia coli (STEC) is an emergent pathogen associated with foodborne diseases, especially foodstuffs of animal origin. A total of 250 beef samples (ground beef and hamburgers) obtained from retail outlets in Santa Fe and Santo Tome cities, and 150 milk samples from bulk tank milk from dairy barns of the region were analyzed by selective enrichment and immunomagnetic separation. Escherichia coli O157:H7 stx2, eae and ehxA positive strains were isolated from three (1.2%) beef samples. The strains could be differentiated by pulsed-field gel electrophoresis, phagetyping and genotyping of stx. The milk samples were negative for STEC O157. These findings confirm the role of food of animal origin in the epidemiology of E. coli O157:H7 - associated diseases. PMID- 17702261 TI - [Antimicrobial activity of honey the southeast of Buenos Aires Province against Escherichia coli]. AB - This study assessed the susceptibility of Escherichia coli to the antimicrobial activity of honeys by different techniques. Honeys used were from the southeast region of Buenos Aires province. In order to evaluate antimicrobial activity against Escherichia coli ATCC 25922, solutions containing 0, 1, 5, 10, 25 and 50% (w/v) of honey were prepared. Liquid media (Mueller-Hinton and Mac Conkey broths) were used to assess the Minimal Inhibitory Concentration (MIC) by the serial dilution test. The minimal bactericidal concentration (MBC) was determined by counting on nutritive and Mac Conkey agar. In addition, for the evaluation of total antibacterial activity, the agar diffusion method was used. A reduction of microbial growth of 96% in Mueller-Hinton broth and of 90% in Mac Conkey broth by honey solutions containing 50% and 25% (w/v), was respectively observed. The bactericide action of honey in nutritive agar proved negative. The MBC value in Mac Conkey agar was 25% (w/v) of honey. The methods used for measuring the antibacterial activity in the present work were adequate to prove that honeys are active against E. coli at 25 and 50% (w/v) concentrations. The results obtained by the dilution method with Mueller-Hinton broth and the agar diffusion method were both concordant. PMID- 17702263 TI - Chronic insomnia and MRI-measured hippocampal volumes: a pilot study. AB - STUDY OBJECTIVES: Morphometric analysis of magnetic resonance imaging brain scans was used to investigate possible neuroanatomic differences between patients with primary insomnia compared to good sleepers. DESIGN: MRI images (1.5 Tesla) of the brain were obtained from insomnia patients and good sleepers. MRI scans were analyzed bilaterally by manual morphometry for different brain areas including hippocampus, amygdala, anterior cingulate, orbitofron-tal and dorsolateral prefrontal cortex. SETTING: University Hospital Sleep Center and Radiology Department PARTICIPANTS: 8 unmedicated physician-referred patients with chronic primary insomnia (3 males, 5 females; 48.4 + 16.3 years) and 8 good sleepers matched for age, sex, body mass index, and education. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Patients with primary insomnia demonstrated significantly reduced hippocampal volumes bilaterally compared to the good sleepers. None of the other regions of interest analyzed revealed differences between the 2 groups. CONCLUSIONS: These pilot data raise the possibility that chronic insomnia is associated with alterations in brain structure. Replication of the findings in larger samples is needed to confirm the validity of the data. The integration of structural, neuropsychological, neuroendocrine and polysomnographic studies is necessary to further assess the relationships between insomnia and brain function and structure. PMID- 17702264 TI - Nightly treatment of primary insomnia with eszopiclone for six months: effect on sleep, quality of life, and work limitations. AB - STUDY OBJECTIVES: To evaluate 6 months' eszopiclone treatment upon patient reported sleep, fatigue and sleepiness, insomnia severity, quality of life, and work limitations. DESIGN: Randomized, double blind, controlled clinical trial. SETTING: 54 research sites in the U.S. PATIENTS: 830 primary insomnia patients who reported mean nightly total sleep time (TST) < or = 6.5 hours/night and/or mean nightly sleep latency (SL) >30 min. INTERVENTION: Eszopiclone 3 mg or matching placebo. MEASUREMENTS: Patient-reported sleep measures, Insomnia Severity Index, Medical Outcomes Study Short-Form Health Survey (SF-36), Work Limitations Questionnaire, and other assessments measured during baseline, treatment Months 1-6, and 2 weeks following discontinuation of treatment. RESULTS: Patient-reported sleep and daytime function were improved more with eszopiclone than with placebo at all months (P <0.001). Eszopiclone reduced Insomnia Severity Index scores to below clinically meaningful levels for 50% of patients (vs 19% with placebo; P <0.05) at Month 6. SF-36 domains of Physical Functioning, Vitality, and Social Functioning were improved with eszopiclone vs placebo for the Month 1-6 average (P < 0.05). Similarly, improvements were observed for all domains of the Work Limitations Questionnaire with eszopiclone vs placebo for the Month 1-6 average (P <0.05). CONCLUSIONS: This is the first placebo-controlled investigation to demonstrate that long-term nightly pharmacologic treatment of primary insomnia with any hypnotic enhanced quality of life, reduced work limitations, and reduced global insomnia severity, in addition to improving patient-reported sleep variables. PMID- 17702265 TI - CSF hypocretin-1 levels and clinical profiles in narcolepsy and idiopathic CNS hypersomnia in Norway. AB - OBJECTIVE: To evaluate the relationship between CSF hypocretin-1 levels and clinical profiles in narcolepsy and CNS hypersomnia in Norwegian patients. METHOD: CSF hypocretin-1 was measured by a sensitive radioimmunoassay in 47 patients with narcolepsy with cataplexy, 7 with narcolepsy without cataplexy, 10 with idiopathic CNS hypersomnia, and a control group. RESULTS: Low hypocretin-1 values were found in 72% of the HLA DQB1*0602 positive patients with narcolepsy and cataplexy. Patients with low CSF hypocretin-1 levels reported more extensive muscular involvement during cataplectic attacks than patients with normal levels. Hypnagogic hallucinations and sleep paralysis occurred more frequently in patients with cataplexy than in the other patient groups, but with no correlation to hypocretin-1 levels. CONCLUSION: About three quarters of the HLA DQB1*0602 positive patients with narcolepsy and cataplexy had low CSF hypocretin-1 values, and appear to form a distinct clinical entity. Narcolepsy without cataplexy could not be distinguished from idiopathic CNS hypersomnia by clinical symptoms or biochemical findings. PMID- 17702266 TI - Identification of differentially expressed genes in blood cells of narcolepsy patients. AB - STUDY OBJECTIVE: A close association between the human leukocyte antigen (HLA) DRB1*1501/DQB1*0602 and abnormalities in some inflammatory cytokines have been demonstrated in narcolepsy. Specific alterations in the immune system have been suggested to occur in this disorder. We attempted to identify alterations in gene expression underlying the abnormalities in the blood cells of narcoleptic patients. DESIGNS: Total RNA from 12 narcolepsy-cataplexy patients and from 12 age- and sex-matched healthy controls were pooled. The pooled samples were initially screened for candidate genes for narcolepsy by differential display analysis using annealing control primers (ACP). The second screening of the samples was carried out by semiquantitative PCR using gene-specific primers. Finally, the expression levels of the candidate genes were further confirmed by quantitative real-time PCR using a new set of samples (20 narcolepsy-cataplexy patients and 20 healthy controls). RESULTS: The second screening revealed differential expression of 4 candidate genes. Among them, MX2 was confirmed as a significantly down-regulated gene in the white blood cells of narcoleptic patients by quantitative real-time PCR. CONCLUSION: We found the MX2 gene to be significantly less expressed in comparison with normal subjects in the white blood cells of narcoleptic patients. This gene is relevant to the immune system. Although differential display analysis using ACP technology has a limitation in that it does not help in determining the functional mechanism underlying sleep/wakefulness dysregulation, it is useful for identifying novel genetic factors related to narcolepsy, such as HLA molecules. Further studies are required to explore the functional relationship between the MX2 gene and narcolepsy pathophysiology. PMID- 17702267 TI - Insufficient non-REM sleep intensity in narcolepsy-cataplexy. AB - STUDY OBJECTIVES: To compare electroencephalogram (EEG) dynamics during nocturnal sleep in patients with narcolepsy-cataplexy and healthy controls. Fragmented nocturnal sleep is a prominent feature and contributes to excessive daytime sleepiness in narcolepsy-cataplexy. Only 3 studies have addressed changes in homeostatic sleep regulation as a possible mechanism underlying nocturnal sleep fragmentation in narcolepsy-cataplexy. DESIGN, SETTING AND PARTICIPANTS: Baseline sleep of 11 drug-naive patients with narcolepsy-cataplexy (19-37 years) and 11 matched controls (18-41 years) was polysomnographically recorded. The EEG was subjected to spectral analysis. INTERVENTIONS: None, baseline condition. MEASUREMENTS AND RESULTS: All patients with narcolepsy-cataplexy but no control subjects showed a sleep-onset rapid eye movement (REM) episode. Non-REM (NREM) REM sleep cycles were longer in patients with narcolepsy-cataplexy than in controls (P = 0.04). Mean slow-wave activity declined in both groups across the first 3 NREM sleep episodes (P<0.001). The rate of decline, however, appeared to be steeper in patients with narcolepsy-cataplexy (time constant: narcolepsy cataplexy 51.1 +/- 23.8 minutes [mean +/- SEM], 95% confidence interval [CI]: 33.4-108.8 minutes) than in controls (169.4 +/- 81.5 minutes, 95% CI: 110.9-357.6 minutes) as concluded from nonoverlapping 95% confidence interval of the time constants. The steeper decline of SWA in narcolepsy-cataplexy compared to controls was related to an impaired build-up of slow-wave activity in the second cycle. Sleep in the second cycle was interrupted in patients with narcolepsy cataplexy, when compared with controls, by an increased number (P = 0.01) and longer duration (P = 0.01) of short wake episodes. CONCLUSIONS: Insufficient NREM sleep intensity is associated with nonconsolidated nocturnal sleep in narcolepsy cataplexy. The inability to consolidate sleep manifests itself when NREM sleep intensity has decayed below a certain level and is reflected in an altered time course of slow-wave activity across NREM sleep episodes. PMID- 17702268 TI - Correlates of serum C-reactive protein (CRP)--no association with sleep duration or sleep disordered breathing. AB - STUDY OBJECTIVES: Increasing evidence suggests that alterations in sleep duration are associated with cardiovascular disease (CVD) and mortality. Additionally, sleep disordered breathing (SDB), which is associated with disturbed nighttime sleep and hypoxemia, may be an independent risk factor for CVD. The inflammatory marker, C-reactive protein (CRP), is an important predictor of CVD. We investigated potential associations between circulating CRP, sleep duration, and SDB. DESIGN: Cross-sectional Study. POPULATION: Participants were 907 adults from the Wisconsin Sleep Cohort Study (WSCS). MEASUREMENTS AND RESULTS: CRP was measured after overnight polysomnography. The relationships between CRP and sleep parameters were evaluated using multiple linear regression with and without controlling for age, sex, and body mass index (BMI) and other potential confounders. CRP was found to be higher for women and had a strong positive correlation with age and BMI. CRP showed a significant positive association with current smoking, waist-hip ratio (WHR), LDL-cholesterol, triglycerides, leptin, and insulin, independent of age, sex, and BMI. Significant independent negative associations for CRP were observed with HDL-cholesterol (HDL), insulin sensitivity (quantitative insulin sensitivity check index [QUICKI]), and hours of exercise. There was a significant positive association between CRP levels and the apnea-hypopnea index (AHI, the measure of SDB), but these relationships were not significant after adjustment for age, sex, and BMI. No significant association between CRP levels and measures of sleep duration (polysomnographic and self reported) were found. CONCLUSION: There was no significant association between CRP levels and sleep duration. The lack of an independent association between CRP levels and SDB suggests that the reported relationship between these 2 variables may be primarily driven by their association with obesity. PMID- 17702269 TI - Endothelial dysfunction and C-reactive protein in relation with the severity of obstructive sleep apnea syndrome. AB - STUDY OBJECTIVES: To investigate flow-mediated dilatation (FMD) and C-reactive protein (CRP) levels in patients with obstructive sleep apnea syndrome (OSAS) in relation with the severity of respiratory disturbances and hypoxemia. DESIGN: After subjects had completed nocturnal polysomnography, FMD was measured in the brachial artery, and blood samples were obtained to determine serum CRP levels. SETTING: Sleep laboratory in Seoul National University Bundang Hospital. PATIENTS: Ninety men: 22 normal controls, 28 subjects with mild to moderate OSAS, and 40 with severe OSAS. MEASUREMENTS AND RESULTS: FMD was found to be correlated with oxygen desaturation index (ODI), percentage of time below 90% O2 saturation, average O2 saturation, lowest O2 saturation, systolic blood pressure, apnea hypopnea index (AHI), and body mass index. In addition, CRP was correlated with body mass index, waist-to-hip ratio, neck circumference, diastolic pressure, average O2 saturation and percentage of time below 90% O2 saturation but not with AHI. Stepwise multiple regression showed that the ODI was a significant determinant of FMD (adjusted R2 = 10%, beta = -0.33, P < 0.01). In addition, body mass index (beta = 0.25, P < 0.05) and waist-to-hip ratio (beta = 0.21, P < 0.05) were found to be significantly correlated with CRP (adjusted R2 = 12%, P < 0.05), independently of other factors. There was no correlation between FMD and CRP. CONCLUSION: As a marker of nocturnal hypoxemia, ODI rather than AHI might better explain the relationship between OSAS and FMD. Because body mass index and waist to-hip ratio were identified as risk factors of high serum CRP in OSAS, obesity should be considered when predicting cardiovascular complications in OSAS. PMID- 17702270 TI - Performance on the continuous performance test in children with ADHD is associated with sleep efficiency. AB - STUDY OBJECTIVE: To examine whether the level of sleep efficiency of children diagnosed with ADHD moderates their performance on the Continuous Performance Test (CPT) while receiving a placebo and while receiving methylphenidate (MPH). DESIGN: Nightly sleep actigraphic assessment during a double-blind, placebo controlled, crossover clinical study (1 week of 0.5 mg/kg MPH; 1 week of placebo) were obtained on 37 children between 6 and 12 years of age with a DSM-IV diagnosis of ADHD. Subjects were divided into 2 groups based on the mean sleep efficiency score during the placebo condition, with subjects above and below the mean placed in the Poor Sleep Group (PSG) and Good Sleep Group (GSG), respectively. SETTING: Vigilance testing was conducted in the laboratory; sleep was assessed in the home. MEASUREMENTS: Sleep was monitored using actigraphy for 2 weeks. In addition, parents were asked to complete nightly sleep logs and a sleep questionnaire. The Conners' Continuous Performance Test (CPT) was used to assess vigilance. RESULTS: Significant interaction of Sleep Group with Medication was found on 1 CPT factor. CONCLUSIONS: The findings of the present study support the hypothesis that sleep moderates performance on CPT in children with ADHD while receiving placebo or MPH. PMID- 17702271 TI - Trends in medication prescribing for pediatric sleep difficulties in US outpatient settings. AB - OBJECTIVES: This study examined trends in physician-prescribing of medications for children with sleep difficulties in outpatient settings in the US. Additionally, we explored the incidence of physician prescribing patterns of medications with high abuse potential for children with sleep difficulties. METHODS: A cross-sectional study was conducted on patients aged < or =17 years with sleep difficulties from 1993-2004 using data from the National Ambulatory Medical Care Survey (NAMCS). Office visits were considered related to sleep difficulties if relevant ICD-9 codes were recorded and if sleep difficulties were reported as the reason for the visits. Medications were retrieved using the NAMCS drug codes, and all analyses were weighted to determine national estimates. RESULTS: During 1993 to 2004, approximately 18.6 million visits occurred for sleep related difficulty in children. The highest percentage of visits were by school-aged children (6 to 12 years). Pediatricians saw 35% of patients, psychiatrists saw 24%, and general/family practice physicians saw 13% of the patients. Eighty-one percent of visits among children with sleep difficulties resulted in a prescription for a medication. Many of these medications prescribed lack FDA approved labeling to assure their effectiveness and safety in this population. CONCLUSION: The findings of this study suggest that physicians frequently prescribed medications for sleep difficulties in children in US outpatient settings. Of particular concern is prescribing of many unapproved medications for this population. PMID- 17702272 TI - Cardiac autonomic regulation during sleep in idiopathic REM sleep behavior disorder. AB - OBJECTIVE: To assess cardiac autonomic and respiratory changes from stage 2 non rapid eye movement sleep (NREM) to rapid eye movement (REM) sleep in subjects with idiopathic REM sleep behavior disorder (RBD) and controls. We tested the hypothesis that REM-related cardiorespiratory activation is altered in subjects with RBD. DESIGN: Retrospective case-control study. SETTING: University hospital based sleep research laboratory. PATIENTS: Ten subjects with idiopathic RBD (2 women, mean age 63.4 +/- 6.2 years) and 10 sex- and age-matched controls (mean age 63.9 +/- 6.3 years). INTERVENTION: One-night polysomnography was used to assess R-R variability during NREM and REM sleep. MEASUREMENTS AND RESULTS: Spectral analysis of R-R interval and respiration were performed. Mean R-R interval, low-frequency (LF) and high-frequency (HF) components in both absolute and normalized units (LFnu and HFnu), and the LF/HF ratio were obtained from 5 minute electrocardiogram segments selected during NREM and REM sleep under stable conditions (stable breathing pattern, no microarousals or leg movements). Respiratory frequency was also assessed. Values obtained were then averaged for each stage and analyzed by 2 x 2 analysis of variance with group (RBD subjects and controls) as factor and state (NREM and REM) as repeated measures. RR interval, HF, and HFnu components decreased from NREM to REM in controls but did not change in RBD subjects (Interaction P < 0.05). LFnu (interaction P < 0. 001), LF/HF (interaction P < 0. 001), and respiratory frequency (interaction P < 0. 05) increased from NREM to REM sleep in controls but remained stable in RBD subjects. CONCLUSION: REM-related cardiac and respiratory responses are absent in subjects with idiopathic RBD. PMID- 17702273 TI - REM sleep behavior disorder in patients with guadeloupean parkinsonism, a tauopathy. AB - STUDY OBJECTIVE: To describe sleep characteristics and rapid eye movement (REM) sleep behavior disorder in patients with Guadeloupean atypical parkinsonism (Gd PSP), a tauopathy resembling progressive supranuclear palsy that mainly affects the midbrain. It is possibly caused by the ingestion of sour sop (corossol), a tropical fruit containing acetogenins, which are mitochondrial poisons. DESIGN: Sleep interview, motor and cognitive tests, and overnight videopolysomnography. PATIENTS: Thirty-six age-, sex-, disease-duration- and disability-matched patients with Gd-PSP (n = 9), progressive supranuclear palsy (a tauopathy, n = 9), Parkinson disease (a synucleinopathy, n = 9) and controls (n = 9). SETTINGS: Tertiary-care academic hospital. RESULTS: REM sleep behavior disorder was found in 78% patients with Gd-PSP (43% of patients reported having this disorder several years before the onset of parkinsonism), 44% of patients with idiopathic Parkinson disease, 33% of patients with progressive supranuclear palsy, and no controls. The percentage of muscle activity during REM sleep was greater in patients with Gd-PSP than in controls (limb muscle activity, 8.3%+/-8.7% vs 0.1%+/- 0.2%; chin muscle activity, 24.3%+/- 23.7% vs 0.7%+/-2.0%) but similar to that of other patient groups. The latency and percentage of REM sleep were similar in patients with Gd-PSP, patients with Parkinson disease, and controls, whereas patients with progressive supranuclear palsy had delayed and shortened REM sleep. CONCLUSION: Although Gd-PSP is a tauopathy, most patients experience REM sleep behavior disorder. This suggests that the location of neuronal loss or dysfunction in the midbrain, rather than the protein comprising the histologic lesions (synuclein versus tau aggregation), is responsible for suppressing muscle atonia during REM sleep. Subjects with idiopathic REM sleep behavior disorder should avoid eating sour sop. PMID- 17702274 TI - Disorders of arousal from sleep and violent behavior: the role of physical contact and proximity. AB - STUDY OBJECTIVES: To review medical and legal case reports to determine how many appear to support the belief that violence against other individuals that occurs during Disorders of Arousal - sleepwalking, confusional arousal, and sleep terrors - is triggered by direct physical contact or close proximity to that individual and does not occur randomly or spontaneously. DESIGN: Historical review of case reports in the medical and legal literature. MEASUREMENTS AND RESULTS: A total of 32 cases drawn from medical and legal literature were reviewed. Each case contained a record of violence associated with Disorders of Arousal; in each, details of the violent behavior were available. Violent behaviors associated with provocations and/or close proximity were found to be present in 100% of confusional arousal patients and 81% of sleep terror patients. Violent behaviors were associated with provocation or close proximity in 40%-90% of sleepwalking cases, depending on whether the legal verdict and other factors were taken into account. Often the provocation was quite minor and the response greatly exaggerated. The specific manner in which the violence was triggered differed among sleepwalking, confusional arousals, and sleep terrors. CONCLUSIONS: In the cases reviewed, violent behavior directed against other individuals associated with Disorders of Arousal most frequently appeared to follow direct provocation by, or close proximity to, another individual. Sleepwalkers most often did not seek out victims, but rather the victims sought out or encountered the sleepwalker. These conclusions are tempered by several limitations: the selection of cases was not random and may not represent an accurate sample of violent behaviors associated with Disorders of Arousal. Also, final verdicts by juries in reported legal cases should not be confused with scientific proof of the presence or absence of sleepwalking. The pathophysiology of Disorders of Arousal with and without violent behavior could be associated with normally occurring deactivation of the frontal lobes during slow wave sleep (SWS) connected via atypically active thalamocortical pathways to the limbic areas. It is not known if the violent sleepwalker, confusional arousal patient, or sleep terror patient differs from other patients with these disorders. The conclusions of this case series await confirmation by the results of future sleep laboratory based studies. PMID- 17702276 TI - Sleep and EEG spectra in rats recorded via telemetry during surgical recovery. AB - STUDY OBJECTIVE: To determine sleep and EEG spectra in rats during surgical recovery. DESIGN: Sleep, activity, and EEG spectral power were examined in rats via telemetry on days 1, 2, 3, 7, 14, and 15 after implantation surgery. RESULTS: NREM sleep and total sleep were increased on days 1 and 2 compared to later days. REM sleep was decreased on days 2 and 3 compared to days 14 and 15, and activity was decreased on days 1 and 2 compared to later days. EEG power (0.5-5 Hz for NREM and wakefulness, and 5.5-10 Hz for REM and wakefulness) was increased on days 1-3 compared to days 7, 14, and 15. CONCLUSION: The results are discussed in terms of their implications for post-surgery stabilization of sleep and potential relevance for sleep after injury. PMID- 17702277 TI - A novel constructive-optimizer neural network for the traveling salesman problem. AB - In this paper, a novel constructive-optimizer neural network (CONN) is proposed for the traveling salesman problem (TSP). CONN uses a feedback structure similar to Hopfield-type neural networks and a competitive training algorithm similar to the Kohonen-type self-organizing maps (K-SOMs). Consequently, CONN is composed of a constructive part, which grows the tour and an optimizer part to optimize it. In the training algorithm, an initial tour is created first and introduced to CONN. Then, it is trained in the constructive phase for adding a number of cities to the tour. Next, the training algorithm switches to the optimizer phase for optimizing the current tour by displacing the tour cities. After convergence in this phase, the training algorithm switches to the constructive phase anew and is continued until all cities are added to the tour. Furthermore, we investigate a relationship between the number of TSP cities and the number of cities to be added in each constructive phase. CONN was tested on nine sets of benchmark TSPs from TSPLIB to demonstrate its performance and efficiency. It performed better than several typical Neural networks (NNs), including KNIES_TSP_Local, KNIES_TSP_Global, Budinich's SOM, Co-Adaptive Net, and multivalued Hopfield network as wall as computationally comparable variants of the simulated annealing algorithm, in terms of both CPU time and accuracy. Furthermore, CONN converged considerably faster than expanding SOM and evolved integrated SOM and generated shorter tours compared to KNIES_DECOMPOSE. Although CONN is not yet comparable in terms of accuracy with some sophisticated computationally intensive algorithms, it converges significantly faster than they do. Generally speaking, CONN provides the best compromise between CPU time and accuracy among currently reported NNs for TSP. PMID- 17702278 TI - Three-dimensional image mosaicking using multiple projection planes for 3-D visualization of roadside standing buildings. AB - A novel image-mosaicking technique suitable for 3-D visualization of roadside buildings on websites or mobile systems is proposed. Our method was tested on a roadside building scene taken using a side-looking video camera employing a continuous set of vertical-textured planar faces. A vertical plane approximation of the scene geometry for each frame was calculated using sparsely distributed feature points that were assigned 3-D data through bundle adjustments. These vertical planes were concatenated to create an approximate model on which the images could be backprojected as textures and blended together. Additionally, our proposed method includes an expanded crossed-slits projection around far-range areas to reduce the "ghost effect," a phenomenon in which a particular object appears repeatedly in a created image mosaic. The final step was to produce seamless image mosaics using Dijkstra's algorithm to find the optimum seam line to blend overlapping images. We used our algorithm to create efficient image mosaics in 3-D space from a sequence of real images. PMID- 17702275 TI - Serotonin and serotonin transporter gene variant in rotating shift workers. AB - STUDY OBJECTIVES: Because serotonin (5-HT) is a neurotransmitter associated with circadian rhythm regulation, we explored a possible relation among 5-HT, serotonin metabolite, 5-hydroxyindolacetic acid (5HIAA), and the functional polymorphism of the serotonin transporter gene (SLC6A4) promoter with rotating shift work. DESIGN AND PARTICIPANTS: 683 men were included in this study: 437 day workers were compared with 246 rotating shift workers. RESULTS: Platelet 5-HT content differed significantly (P = 0.002) between day workers (41.28+/-1.99 pg/mg) and rotating shift workers (37.91+/-4.16 pg/mg); 5-HIAA content was also significantly (P = 0.00004) higher in day workers (11.40+/-0.82 pg/mg) than in rotating shift workers (9.33+/-1.02 pg/ mg). We looked for further differences in SLC6A4 promoter (5-HTTLPR, 44 bp insertion: long (L)/deletion: short (S) alleles). We found a significant (P = 0.016) difference in genotype distribution between day workers LL: 126 (28.8%), LS: 202 (46.2%), and SS: 109 (24.9%), and rotating shift workers LL: 47 (19.1%), LS: 124 (50.4%), and SS: 75 (30.5%). When we divided the subjects between workers with less and more than 60 month rotating shift-work exposure, the difference in SLC6A4 genotypes frequency was only significant in the group with > or =60 months (P = 0.011). In addition, there was a significantly lower content of platelet 5-HIAA in S allele carriers in comparison with the other genotypes (SS: 9.2+/-1.0 pg/mg vs. SL/LL: 11.0+/-0.8 pg/mg, P <0.02). CONCLUSIONS: Platelet 5-HT and 5-HIAA contents were significantly lower in rotating shift workers than day workers, and there was a significant association between the S variant of SLC6A4 promoter and shift work. These findings may be important for targeting effective therapeutic strategies to ameliorate the associated comorbidities and behavioral problems in rotating shift workers. PMID- 17702279 TI - Predicting wafer-lot output time with a hybrid FCM-FBPN approach. AB - Output-time prediction is a critical task to a wafer fab. To further enhance the accuracy of wafer-lot output-time prediction, the concept of input classification is applied to Chen's fuzzy backpropagation network (FBPN) approach in this paper by preclassifying wafer lots with the fuzzy c-means (FCM) classifier before predicting the output times. In this way, similar wafer lots are clustered in the same category. The data of wafer lots of different categories are then learned with different FBPNs but with the same topology. After learning, these FBPNs form an FBPN ensemble that can be applied in predicting the output time of a new lot. The output of the FBPN ensemble determines the cycle/output time forecast and is obtained by aggregating the outputs of the component FBPNs. Production simulation is applied in this paper to generate test data. According to experimental results, the prediction accuracy of the hybrid FCM-FBPN approach was significantly better than those of many existing approaches. PMID- 17702280 TI - Logistic model tree extraction from artificial neural networks. AB - Artificial neural networks (ANNs) are a powerful and widely used pattern recognition technique. However, they remain "black boxes" giving no explanation for the decisions they make. This paper presents a new algorithm for extracting a logistic model tree (LMT) from a neural network, which gives a symbolic representation of the knowledge hidden within the ANN. Landwehr's LMTs are based on standard decision trees, but the terminal nodes are replaced with logistic regression functions. This paper reports the results of an empirical evaluation that compares the new decision tree extraction algorithm with Quinlan's C4.5 and ExTree. The evaluation used 12 standard benchmark datasets from the University of California, Irvine machine-learning repository. The results of this evaluation demonstrate that the new algorithm produces decision trees that have higher accuracy and higher fidelity than decision trees created by both C4.5 and ExTree. PMID- 17702282 TI - On the properties of prototype-based fuzzy classifiers. AB - The use of natural language rules that are able to handle vague and, possibly, even contradicting knowledge in order to model formal dependences is an intriguing idea. Fuzzy IF-THEN rules have been proposed as classification methods that can easily be defined and interpreted by humans or built automatically by learning algorithms. This paper gives an intuitive insight into the properties and the behavior of prototype-based fuzzy classifiers, using formal descriptions and visualization methods. This can help to avoid some common peculiarities and pitfalls in the manual or automated design of fuzzy classifiers. PMID- 17702281 TI - Autoconfiguration of a dynamic nonoverlapping camera network. AB - In order to monitor sufficiently large areas of interest for surveillance or any event detection, we need to look beyond stationary cameras and employ an automatically configurable network of nonoverlapping cameras. These cameras need not have an overlapping field of view and should be allowed to move freely in space. Moreover, features like zooming in/out, readily available in security cameras these days, should be exploited in order to focus on any particular area of interest if needed. In this paper, a practical framework is proposed to self calibrate dynamically moving and zooming cameras and determine their absolute and relative orientations, assuming that their relative position is known. A global linear solution is presented for self-calibrating each zooming/focusing camera in the network. After self-calibration, it is shown that only one automatically computed vanishing point and a line lying on any plane orthogonal to the vertical direction is sufficient to infer the dynamic network configuration. Our method generalizes previous work which considers restricted camera motions. Using minimal assumptions, we are able to successfully demonstrate promising results on synthetic, as well as on real data. PMID- 17702283 TI - A multivariate heuristic model for fuzzy time-series forecasting. AB - Fuzzy time-series models have been widely applied due to their ability to handle nonlinear data directly and because no rigid assumptions for the data are needed. In addition, many such models have been shown to provide better forecasting results than their conventional counterparts. However, since most of these models require complicated matrix computations, this paper proposes the adoption of a multivariate heuristic function that can be integrated with univariate fuzzy time series models into multivariate models. Such a multivariate heuristic function can easily be extended and integrated with various univariate models. Furthermore, the integrated model can handle multiple variables to improve forecasting results and, at the same time, avoid complicated computations due to the inclusion of multiple variables. PMID- 17702285 TI - Indirect iterative learning control for a discrete visual servo without a camera robot model. AB - This paper presents a discrete learning controller for vision-guided robot trajectory imitation with no prior knowledge of the camera-robot model. A teacher demonstrates a desired movement in front of a camera, and then, the robot is tasked to replay it by repetitive tracking. The imitation procedure is considered as a discrete tracking control problem in the image plane, with an unknown and time-varying image Jacobian matrix. Instead of updating the control signal directly, as is usually done in iterative learning control (ILC), a series of neural networks are used to approximate the unknown Jacobian matrix around every sample point in the demonstrated trajectory, and the time-varying weights of local neural networks are identified through repetitive tracking, i.e., indirect ILC. This makes repetitive segmented training possible, and a segmented training strategy is presented to retain the training trajectories solely within the effective region for neural network approximation. However, a singularity problem may occur if an unmodified neural-network-based Jacobian estimation is used to calculate the robot end-effector velocity. A new weight modification algorithm is proposed which ensures invertibility of the estimation, thus circumventing the problem. Stability is further discussed, and the relationship between the approximation capability of the neural network and the tracking accuracy is obtained. Simulations and experiments are carried out to illustrate the validity of the proposed controller for trajectory imitation of robot manipulators with unknown time-varying Jacobian matrices. PMID- 17702284 TI - Choosing parameters of kernel subspace LDA for recognition of face images under pose and illumination variations. AB - This paper addresses the problem of automatically tuning multiple kernel parameters for the kernel-based linear discriminant analysis (LDA) method. The kernel approach has been proposed to solve face recognition problems under complex distribution by mapping the input space to a high-dimensional feature space. Some recognition algorithms such as the kernel principal components analysis, kernel Fisher discriminant, generalized discriminant analysis, and kernel direct LDA have been developed in the last five years. The experimental results show that the kernel-based method is a good and feasible approach to tackle the pose and illumination variations. One of the crucial factors in the kernel approach is the selection of kernel parameters, which highly affects the generalization capability and stability of the kernel-based learning methods. In view of this, we propose an eigenvalue-stability-bounded margin maximization (ESBMM) algorithm to automatically tune the multiple parameters of the Gaussian radial basis function kernel for the kernel subspace LDA (KSLDA) method, which is developed based on our previously developed subspace LDA method. The ESBMM algorithm improves the generalization capability of the kernel-based LDA method by maximizing the margin maximization criterion while maintaining the eigenvalue stability of the kernel-based LDA method. An in-depth investigation on the generalization performance on pose and illumination dimensions is performed using the YaleB and CMU PIE databases. The FERET database is also used for benchmark evaluation. Compared with the existing PCA-based and LDA-based methods, our proposed KSLDA method, with the ESBMM kernel parameter estimation algorithm, gives superior performance. PMID- 17702286 TI - A generalized time-frequency subtraction method for robust speech enhancement based on wavelet filter banks modeling of human auditory system. AB - We present a new speech enhancement scheme for a single-microphone system to meet the demand for quality noise reduction algorithms capable of operating at a very low signal-to-noise ratio. A psychoacoustic model is incorporated into the generalized perceptual wavelet denoising method to reduce the residual noise and improve the intelligibility of speech. The proposed method is a generalized time frequency subtraction algorithm, which advantageously exploits the wavelet multirate signal representation to preserve the critical transient information. Simultaneous masking and temporal masking of the human auditory system are modeled by the perceptual wavelet packet transform via the frequency and temporal localization of speech components. The wavelet coefficients are used to calculate the Bark spreading energy and temporal spreading energy, from which a time frequency masking threshold is deduced to adaptively adjust the subtraction parameters of the proposed method. An unvoiced speech enhancement algorithm is also integrated into the system to improve the intelligibility of speech. Through rigorous objective and subjective evaluations, it is shown that the proposed speech enhancement system is capable of reducing noise with little speech degradation in adverse noise environments and the overall performance is superior to several competitive methods. PMID- 17702287 TI - Model-free execution monitoring in behavior-based robotics. AB - In the near future, autonomous mobile robots are expected to help humans by performing service tasks in many different areas, including personal assistance, transportation, cleaning, mining, or agriculture. In order to manage these tasks in a changing and partially unpredictable environment without the aid of humans, the robot must have the ability to plan its actions and to execute them robustly and safely. The robot must also have the ability to detect when the execution does not proceed as planned and to correctly identify the causes of the failure. An execution monitoring system allows the robot to detect and classify these failures. Most current approaches to execution monitoring in robotics are based on the idea of predicting the outcomes of the robot's actions by using some sort of predictive model and comparing the predicted outcomes with the observed ones. In contrary, this paper explores the use of model-free approaches to execution monitoring, that is, approaches that do not use predictive models. In this paper, we show that pattern recognition techniques can be applied to realize model-free execution monitoring by classifying observed behavioral patterns into normal or faulty execution. We investigate the use of several such techniques and verify their utility in a number of experiments involving the navigation of a mobile robot in indoor environments. PMID- 17702288 TI - A simulated annealing algorithm for prioritized multiobjective optimization- implementation in an adaptive model predictive control configuration. AB - This paper presents a new stochastic algorithm for solving hierarchical multiobjective optimization problems. The algorithm is based on the simulated annealing concept and returns a single solution that corresponds to the lexicographic ordering approach. The algorithm optimizes simultaneously the multiple objectives by assigning a different initial temperature to each one, according to its position in the hierarchy. A major advantage of the proposed method is its low computational cost. This is very critical, particularly, for online applications, where the time that is available for decision making is limited. The method is tested in a number of benchmark problems, which illustrate its ability to find near-optimal solutions even in nonconvex multiobjective optimization problems. The results are comparable with those that are produced by state-of-the-art multiobjective evolutionary algorithms, such as the Nondominated Sorting Genetic Algorithm II. The algorithm is further applied to the solution of a large-scale problem that is formulated online, when a multiobjective adaptive model predictive control (MPC) configuration is adopted. This particular control scheme involves an adaptive discrete-time model of the system, which is developed using the radial-basis-function neural-network architecture. A key issue in the success of the adaptation strategy is the introduction of a persistent excitation constraint, which is transformed to a top-priority objective. The overall methodology is applied to the control problem of a pH reactor and proves to be superior to conventional MPC configurations. PMID- 17702289 TI - Robust H infinity control for networked systems with random packet losses. AB - In this paper, the robust H infinity control problem is considered for a class of networked systems with random communication packet losses. Because of the limited bandwidth of the channels, such random packet losses could occur, simultaneously, in the communication channels from the sensor to the controller and from the controller to the actuator. The random packet loss is assumed to obey the Bernoulli random binary distribution, and the parameter uncertainties are norm bounded and enter into both the system and output matrices. In the presence of random packet losses, an observer-based feedback controller is designed to robustly exponentially stabilize the networked system in the sense of mean square and also achieve the prescribed H infinity disturbance-rejection-attenuation level. Both the stability-analysis and controller-synthesis problems are thoroughly investigated. It is shown that the controller-design problem under consideration is solvable if certain linear matrix inequalities (LMIs) are feasible. A simulation example is exploited to demonstrate the effectiveness of the proposed LMI approach. PMID- 17702290 TI - On robotic optimal path planning in polygonal regions with pseudo-Euclidean metrics. AB - This paper presents several results on some cost-minimizing path problems in polygonal regions. For these types of problems, an approach often used to compute approximate optimal paths is to apply a discrete search algorithm to a graph G(epsilon) constructed from a discretization of the problem; this graph is guaranteed to contain an epsilon-good approximate optimal path, i.e., a path with a cost within (1 + epsilon) factor of that of an optimal path, between given source and destination points. Here, epsilon > 0 is the user-defined error tolerance ratio. We introduce a class of piecewise pseudo-Euclidean optimal path problems that includes several non-Euclidean optimal path problems previously studied and show that the BUSHWHACK algorithm, which was formerly designed for the weighted region optimal path problem, can be generalized to solve any optimal path problem of this class. We also introduce an empirical method called the adaptive discretization method that improves the performance of the approximation algorithms by placing discretization points densely only in areas that may contain optimal paths. It proceeds in multiple iterations, and in each iteration, it varies the approximation parameters and fine tunes the discretization. PMID- 17702291 TI - The kernel common vector method: a novel nonlinear subspace classifier for pattern recognition. AB - The common vector (CV) method is a linear subspace classifier method which allows one to discriminate between classes of data sets, such as those arising in image and word recognition. This method utilizes subspaces that represent classes during classification. Each subspace is modeled such that common features of all samples in the corresponding class are extracted. To accomplish this goal, the method eliminates features that are in the direction of the eigenvectors corresponding to the nonzero eigenvalues of the covariance matrix of each class. In this paper, we introduce a variation of the CV method, which will be referred to as the modified CV (MCV) method. Then, a novel approach is proposed to apply the MCV method in a nonlinearly mapped higher dimensional feature space. In this approach, all samples are mapped into a higher dimensional feature space using a kernel mapping function, and then, the MCV method is applied in the mapped space. Under certain conditions, each class gives rise to a unique CV, and the method guarantees a 100% recognition rate with respect to the training set data. Moreover, experiments with several test cases also show that the generalization performance of the proposed kernel method is comparable to the generalization performances of other linear subspace classifier methods as well as the kernel based nonlinear subspace method. While both the MCV method and its kernel counterpart did not outperform the support vector machine (SVM) classifier in most of the reported experiments, the application of our proposed methods is simpler than that of the multiclass SVM classifier. In addition, it is not necessary to adjust any parameters in our approach. PMID- 17702292 TI - Explanation of Bayesian networks and influence diagrams in Elvira. AB - Bayesian networks (BNs) and influence diagrams (IDs) are probabilistic graphical models that are widely used for building diagnosis- and decision-support expert systems. Explanation of both the model and the reasoning is important for debugging these models, alleviating users' reluctance to accept their advice, and using them as tutoring systems. This paper describes some explanation options for BNs and IDs that have been implemented in Elvira and how they have been used for building medical models and teaching probabilistic reasoning to pre- and postgraduate students. PMID- 17702293 TI - A self-learning fuzzy discrete event system for HIV/AIDS treatment regimen selection. AB - The U.S. Department of Health and Human Services Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS) treatment guidelines are modified several times per year to reflect the rapid evolution of the field (e.g., emergence of new antiretroviral drugs). As such, a treatment-decision support system that is capable of self-learning is highly desirable. Based on the fuzzy discrete event system (FDES) theory that we recently created, we have developed a self-learning HIV/AIDS regimen selection system for the initial round of combination antiretroviral therapy, one of the most complex therapies in medicine. The system consisted of a treatment objectives classifier, fuzzy finite state machine models for treatment regimens, and a genetic-algorithm-based optimizer. Supervised learning was achieved through automatically adjusting the parameters of the models by the optimizer. We focused on the four historically popular regimens with 32 associated treatment objectives involving the four most important clinical variables (potency, adherence, adverse effects, and future drug options). The learning targets for the objectives were produced by two expert AIDS physicians on the project, and their averaged overall agreement rate was 70.6%. The system's learning ability and new regimen suitability prediction capability were tested under various conditions of clinical importance. The prediction accuracy was found between 84.4% and 100%. Finally, we retrospectively evaluated the system using 23 patients treated by 11 experienced nonexpert faculty physicians and 12 patients treated by the two experts at our AIDS Clinical Center in 2001. The overall exact agreement between the 13 physicians' selections and the system's choices was 82.9% with the agreement for the two experts being both 100%. For the seven mismatched cases, the system actually chose more appropriate regimens in four cases and equivalent regimens in another two cases. It made a mistake in one case. These (preliminary) results show that 1) the System outperformed the nonexpert physicians and 2) it performed as well as the expert physicians did. This learning and prediction approach, as well as our original FDESs theory, is general purpose and can be applied to other medical or nonmedical problems. PMID- 17702295 TI - Two new Bayesian approximations of belief functions based on convex geometry. AB - In this paper, we analyze from a geometric perspective the meaningful relations taking place between belief and probability functions in the framework of the geometric approach to the theory of evidence. Starting from the case of binary domains, we identify and study three major geometric entities relating a generic belief function (b.f.) to the set of probabilities P: 1) the dual line connecting belief and plausibility functions; 2) the orthogonal complement of P; and 3) the simplex of consistent probabilities. Each of them is in turn associated with a different probability measure that depends on the original b.f. We focus in particular on the geometry and properties of the orthogonal projection of a b.f. onto P and its intersection probability, provide their interpretations in terms of degrees of belief, and discuss their behavior with respect to affine combination. PMID- 17702294 TI - Alignment-free cancelable fingerprint templates based on local minutiae information. AB - To replace compromised biometric templates, cancelable biometrics has recently been introduced. The concept is to transform a biometric signal or feature into a new one for enrollment and matching. For making cancelable fingerprint templates, previous approaches used either the relative position of a minutia to a core point or the absolute position of a minutia in a given fingerprint image. Thus, a query fingerprint is required to be accurately aligned to the enrolled fingerprint in order to obtain identically transformed minutiae. In this paper, we propose a new method for making cancelable fingerprint templates that do not require alignment. For each minutia, a rotation and translation invariant value is computed from the orientation information of neighboring local regions around the minutia. The invariant value is used as the input to two changing functions that output two values for the translational and rotational movements of the original minutia, respectively, in the cancelable template. When a template is compromised, it is replaced by a new one generated by different changing functions. Our approach preserves the original geometric relationships (translation and rotation) between the enrolled and query templates after they are transformed. Therefore, the transformed templates can be used to verify a person without requiring alignment of the input fingerprint images. In our experiments, we evaluated the proposed method in terms of two criteria: performance and changeability. When evaluating the performance, we examined how verification accuracy varied as the transformed templates were used for matching. When evaluating the changeability, we measured the dissimilarities between the original and transformed templates, and between two differently transformed templates, which were obtained from the same original fingerprint. The experimental results show that the two criteria mutually affect each other and can be controlled by varying the control parameters of the changing functions. PMID- 17702296 TI - A wavelet-based multiresolution approach to solve the stereo correspondence problem using mutual information. AB - In this correspondence, we propose a wavelet-based hierarchical approach using mutual information (MI) to solve the correspondence problem in stereo vision. The correspondence problem involves identifying corresponding pixels between images of a given stereo pair. This results in a disparity map, which is required to extract depth information of the relevant scene. Until recently, mostly correlation-based methods have been used to solve the correspondence problem. However, the performance of correlation-based methods degrades significantly when there is a change in illumination between the two images of the stereo pair. Recent studies indicate MI to be a more robust stereo matching metric for images affected by such radiometric distortions. In this short correspondence paper, we compare the performances of MI and correlation-based metrics for different types of illumination changes between stereo images. MI, as a statistical metric, is computationally more expensive. We propose a wavelet-based hierarchical technique to counter the increase in computational cost and show its effectiveness in stereo matching. PMID- 17702297 TI - Constructing PCA baseline algorithms to reevaluate ICA-based face-recognition performance. AB - The literature on independent component analysis (ICA)-based face recognition generally evaluates its performance using standard principal component analysis (PCA) within two architectures, ICA Architecture I and ICA Architecture II. In this correspondence, we analyze these two ICA architectures and find that ICA Architecture I involves a vertically centered PCA process (PCA I), while ICA Architecture II involves a whitened horizontally centered PCA process (PCA II). Thus, it makes sense to use these two PCA versions as baselines to reevaluate the performance of ICA-based face-recognition systems. Experiments on the FERET, AR, and AT&T face-image databases showed no significant differences between ICA Architecture I (II) and PCA I (II), although ICA Architecture I (or II) may, in some cases, significantly outperform standard PCA. It can be concluded that the performance of ICA strongly depends on the PCA process that it involves. Pure ICA projection has only a trivial effect on performance in face recognition. PMID- 17702298 TI - Generative and discriminative learning by CL-Net. AB - This correspondence presents a two-stage classification learning algorithm. The first stage approximates the class-conditional distribution of a discrete space using a separate mixture model, and the second stage investigates the class posterior probabilities by training a network. The first stage explores the generative information that is inherent in each class by using the Chow-Liu (CL) method, which approximates high-dimensional probability with a tree structure, namely, a dependence tree, whereas the second stage concentrates on discriminative learning to distinguish between classes. The resulting learning algorithm integrates the advantages of both generative learning and discriminative learning. Because it uses CL dependence-tree estimation, we call our algorithm CL-Net. Empirical tests indicate that the proposed learning algorithm makes significant improvements when compared with the related classifiers that are constructed by either generative learning or discriminative learning. PMID- 17702299 TI - Observer-based H infinity control for T-S fuzzy systems with time delay: delay dependent design method. AB - This correspondence studies the problem of observer-based H infinity control for time-delay Takagi-Sugeno (T-S) fuzzy systems. It provides a delay-dependent linear matrix inequality (LMI)-based method for the control design. It is known that the key important problem in the literature, even for delay-independent case, lies in the difficulty of decoupling matrix variables in corresponding matrix inequalities. This correspondence suggests a decoupling technique for solving matrix inequalities with coupled variables, and provides an LMI-based algorithm by adopting the idea of the cone complementarity problem. The derivation relies on the appropriate choice of Lyaponuv-Krasovskii functionals which incorporate the intersections among local systems. Illustrative examples are given to show the effectiveness of the present delay-dependent result. PMID- 17702300 TI - In defense of fuzzy association analysis. AB - This short correspondence is a reply to a recently published paper by Verlinde et al. in which the authors empirically compared fuzzy and nonfuzzy association analysis and, on the basis of their results, questioned the usefulness of a fuzzy approach. Although we highly welcome the critical examination of the topic and definitely agree that fuzzy extensions of existing methods call for a thorough justification, the empirical comparison presented in the aforementioned paper is in our opinion not objective and extensive enough to fully warrant the conclusions drawn from the results. Apart from some general comments on the claims raised in their paper, we present empirical results based on an alternative experimental setup that lead to different conclusions. PMID- 17702301 TI - Quality-based fusion of multiple video sensors for video surveillance. AB - In this correspondence, we address the problem of fusing data for object tracking for video surveillance. The fusion process is dynamically regulated to take into account the performance of the sensors in detecting and tracking the targets. This is performed through a function that adjusts the measurement error covariance associated with the position information of each target according to the quality of its segmentation. In this manner, localization errors due to incorrect segmentation of the blobs are reduced thus improving tracking accuracy. Experimental results on video sequences of outdoor environments show the effectiveness of the proposed approach. PMID- 17702302 TI - An organizational evolutionary algorithm for numerical optimization. AB - Taking inspiration from the interacting process among organizations in human societies, this correspondence designs a kind of structured population and corresponding evolutionary operators to form a novel algorithm, Organizational Evolutionary Algorithm (OEA), for solving both unconstrained and constrained optimization problems. In OEA, a population consists of organizations, and an organization consists of individuals. All evolutionary operators are designed to simulate the interaction among organizations. In experiments, 15 unconstrained functions, 13 constrained functions, and 4 engineering design problems are used to validate the performance of OEA, and thorough comparisons are made between the OEA and the existing approaches. The results show that the OEA obtains good performances in both the solution quality and the computational cost. Moreover, for the constrained problems, the good performances are obtained by only incorporating two simple constraints handling techniques into the OEA. Furthermore, systematic analyses have been made on all parameters of the OEA. The results show that the OEA is quite robust and easy to use. PMID- 17702303 TI - Scaling genetic programming to large datasets using hierarchical dynamic subset selection. AB - The computational overhead of genetic programming (GP) may be directly addressed without recourse to hardware solutions using active learning algorithms based on the random or dynamic subset selection heuristics (RSS or DSS). This correspondence begins by presenting a family of hierarchical DSS algorithms: RSS DSS, cascaded RSS-DSS, and the balanced block DSS algorithm, where the latter has not been previously introduced. Extensive benchmarking over four unbalanced real world binary classification problems with 30000-500000 training exemplars demonstrates that both the cascade and balanced block algorithms are able to reduce the likelihood of degenerates while providing a significant improvement in classification accuracy relative to the original RSS-DSS algorithm. Moreover, comparison with GP trained without an active learning algorithm indicates that classification performance is not compromised, while training is completed in minutes as opposed to half a day. PMID- 17702304 TI - A novel stabilization criterion for large-scale T-S fuzzy systems. AB - This correspondence studies the stabilization problem of large-scale Takagi Sugeno fuzzy systems. A novel stabilization criterion with decentralized parallel distributed compensation (PDC) fuzzy controller is proposed. The criterion contains two inequalities and one negative definite matrix to be satisfied. The effects of all interconnection terms and all decentralized PDC gains are entirely included in the negative definite matrix. The size of the matrix depends on the number of subsystems; the more the number of subsystems is, the larger the size of the matrix is. By using the linear matrix inequality method, the inequalities in the criterion can be solved to synthesize the local feedback gain of each PDC fuzzy controller such that the whole closed-loop large-scale fuzzy system is asymptotically stable. Finally, we give a practical example to illustrate the effectiveness of the proposed criterion. PMID- 17702305 TI - Face recognition by regularized discriminant analysis. AB - When the feature dimension is larger than the number of samples the small sample size problem occurs. There is great concern about it within the face recognition community. We point out that optimizing the Fisher index in linear discriminant analysis does not necessarily give the best performance for a face recognition system. We propose a new regularization scheme. The proposed method is evaluated using the Olivetti Research Laboratory database, the Yale database, and the Feret database. PMID- 17702306 TI - Errors and adverse events in otolaryngology. PMID- 17702307 TI - Type A personality in patients with dizziness. PMID- 17702308 TI - Beyond a tympanic membrane perforation: a superb view of normal middle ear structures. PMID- 17702309 TI - Endoscopic view of a nasopharyngeal tumor. PMID- 17702310 TI - Laryngeal amyloidosis: a case of 'Adidas-stripes' larynx. PMID- 17702311 TI - Laryngeal squamous papilloma. PMID- 17702312 TI - Severe muscle spasm of the neck secondary to osteomyelitis of the atlantoaxial joint. PMID- 17702313 TI - Solitary fibrous tumor of the maxillary sinus. PMID- 17702314 TI - The 'Toyota-like' otolaryngology office. PMID- 17702315 TI - Subglottic cysts: a cause of pediatric stridor. PMID- 17702316 TI - Bilateral cerebellopontine angle metastatic melanoma: a case report. AB - Although melanoma accounts for approximately 1% of all malignancies, melanoma metastases to the cerebellopontine angles (CPAs) are exceedingly rare. Here we describe a patient with melanoma metastases to the internal auditory canals and CPAs who presented with a remote history of cutaneous melanoma. This patient had a rapidly progressive hearing loss, vestibulopathy, and facial nerve dysfunction. Magnetic resonance imaging demonstrated bilateral, enhancing CPA lesions but was otherwise nonspecific. The diagnosis required a careful history, unilateral surgical resection for tissue acquisition, and histopathologic confirmation. A search for primary cutaneous melanoma at the time of presentation was negative. However, the history of cutaneous melanoma 8 years earlier distinguishes this patient's metastatic disease from solitary primary intracranial melanoma, an equally rare disease. Treatment consists of surgical excision, radiation, chemotherapy, and immunotherapy. The prognosis for patients with melanoma metastases is generally poor, but isolated reports of long-term survival have been described. Metastatic disease to the CPAs must be included in the differential diagnosis for any patient presenting with rapid-onset VIIth or VIIIth cranial nerve symptoms. PMID- 17702317 TI - Otogenic tension pneumocephalus caused by therapeutic lumbar CSF drainage for post-traumatic hydrocephalus: a case report. AB - Tension pneumocephalus occurs when a continuous flow of air accumulates in the intracranial cavity and produces a mass effect on the brain. We describe a case in which tension pneumocephalus was caused by the performance of continuous lumbar CSF drainage in a middle-aged man who had experienced a temporal bone fracture. Continuous lumbar CSF drainage is commonly performed in patients with temporal bone or basilar skull fractures to treat concomitant post-traumatic CSF rhinorrhea, CSF otorrhea, and/or hydrocephalus. However; to the best of our knowledge, there has been no previously reported case of tension pneumocephalus occurring as a complication of this procedure in a patient with a temporal bone fracture. PMID- 17702318 TI - The effect of nasal steroid administration on intraocular pressure. AB - The effect of systemic steroid administration on intraocular pressure (IOP) is well established. However less attention has been paid to the effect of steroids when administered in a nasal spray. We conducted a study to investigate a possible association between nasal steroids and elevated IOP in 54 patients who were being treated for allergic rhinitis. IOP was measured before the patients started therapy and thereafter every 5 days during that therapy. Follow-up ranged from 27 to 35 days (mean: 31). Statistical analysis revealed no significant elevation in IOP after nasal steroid administration. It seems that short-term administration of nasal steroids does not cause significant IOP elevation. Nevertheless, their long-term effects on this pressure should be investigated. PMID- 17702319 TI - The prevalence of Samter's triad in patients undergoing functional endoscopic sinus surgery. AB - We conducted a retrospective study to determine the prevalence of Samter's triad (nasal polyps, asthma, and aspirin sensitivity) in 208 consecutively presenting patients who had undergone functional endoscopic sinus surgery (FESS) for chronic rhinosinusitis from September 2001 through August 2003. Overall, Samter's triad was found in 10 patients (4.8%); subgroup analyses showed that the prevalence of Samter's triad was 5.9% in adults, 9.4% in patients with nasal polyps alone, 16.9% in patients with asthma alone, and 25.6% among patients with both polyps and asthma. On average, patients with Samter's triad had undergone approximately 10 times as many previous FESS procedures as had the patients without Samter's triad (mean: 5.2 vs. 0.53; p < 0.001). In addition to Samter's triad, four other factors were independently and significantly associated with a higher number of previous FESS procedures: nasal polyps alone, asthma alone, both polyps and asthma, and cystic fibrosis alone. Finally, at 6 months following their most recent surgery, patients with Samter's triad had significantly higher rates of symptom recurrence (nasal obstruction, facial pain, postnasal drip, and anosmia) and a recurrence of nasal polyps. PMID- 17702320 TI - An aggressive psammomatoid ossifying fibroma of the sinonasal tract: report of a case. AB - Aggressive psammomatoid ossifying fibromas (APOFs) represent a subgroup of related fibro-osseous lesions that appears to be unique to the nasal cavity, paranasal sinuses, and orbit. These rare lesions are characterized by distinctive histomorphologic features and a tendency to affect younger patients. Histologically they are benign, but clinically they are locally aggressive. We report the case of a 15-year-old boy who had a large APOF in the left ethmoid and sphenoid sinuses. The location of this tumor made this case unusual. PMID- 17702321 TI - Undifferentiated metastatic carcinoma and myoepithelioma: two rare causes of hypervascular masses of the parapharyngeal space. AB - We report 2 unusual cases of hypervascular masses in the parapharyngeal space. The first case involved a poorly differentiated metastatic carcinoma of oropharyngeal origin that mimicked a carotid body tumor. The second case involved a highly vascular myoepithelioma located in the parapharyngeal space. PMID- 17702322 TI - Intratracheal ectopic thyroid: case report and review. AB - Intratracheal ectopic thyroid tissue is a rare abnormality that can cause airway obstruction. The symptoms can easily be confused with those of bronchial asthma. We describe the case of a 40-year-old man with subglottic thyroid tissue and multinodular goiter who had been misdiagnosed earlier with bronchial asthma. After the correct diagnosis was established, the lesion was excised via an external approach. We also discuss the clinical features and management of intratracheal thyroid tissue. PMID- 17702323 TI - The prevalence and effect of asthma on adults with chronic rhinosinusitis. AB - We conducted a retrospective review of 145 consecutively presenting adults treated for chronic rhinosinusitis (CRS) in a tertiary care institution. Our goals were to determine (1) the prevalence of asthma in these patients, (2) the prevalence of specific CRS symptoms in both asthmatic and nonasthmatic patients, and (3) the frequency of surgical treatmentfor CRS in patients with and without asthma. We found that asthma was present in 23.4% of CRS patients, a much higher rate than the 5% prevalence of asthma in the general adult population. Patients with asthma had a significantly higher prevalence of nasal polyps (47 vs. 22%; p = 0.004), olfactory dysfunction (26 vs. 6%; p = 0.001), and nasal congestion (85 vs. 60%; p = 0.027) than did those without asthma. Patients without asthma had a significantly higher prevalence of headache (72 vs. 53%; p = 0.037) and rhinorrhea (58 vs. 38%; p = 0.047). The prevalence ofpostnasal drip and environmental allergies in the two groups was similar Although the difference between the proportions of patients with and without asthma who required primary sinus surgery was not statistically significant (76 vs. 64%; p = 0.175), patients with asthma did require significantly more revision sinus procedures overall (mean: 2.9 vs. 1.5; p = 0.003). PMID- 17702324 TI - Kikuchi-Fujimoto disease: a report of 3 cases. AB - Cervical lymphadenopathy has many underlying etiologies. One of its rare causes is Kikuchi-Fujimoto disease (Kikuchi's disease, histiocytic necrotizing lymphadenitis). We discovered such a cause in a 37-year-old woman who had presented with malaise, night sweats, and weight loss in addition to cervical lymphadenopathy. We based our diagnosis on excisional lymph node biopsy. We also review 2 other cases of Kikuchi's disease that were diagnosed by others at our institution. Clinically and histologically, Kikuchi's disease is very similar to lymphoma, and distinguishing the two is difficult. However, despite the fact that Kikuchi's disease is benign, an accurate diagnosis is important because misdiagnosis might lead to unnecessary surgery and/or chemotherapy. PMID- 17702325 TI - Castleman's disease: three case reports and a review of the literature. AB - Castleman's disease is a rare lymphoproliferative disorder that is easily misdiagnosed. When it occurs in the head/neck and thorax, it can pose a diagnostic dilemma because of its lack of any specific presenting characteristics and distinguishing radiographic features. An accurate histopathologic diagnosis and careful staging are crucial to planning treatment. The highly vascular nature of the tumor makes surgical management challenging, and it warrants preoperative embolization whenever possible. We report 3 cases of Castleman's disease that involved the head/neck and thorax. We also review the presenting clinical features of Castleman's disease, its histopathologic characteristics, and the diagnostic and treatment challenges that it poses. PMID- 17702326 TI - Wastewater treatment plants as a pathway for aquatic contamination by pharmaceuticals in the ebro river basin (northeast Spain). AB - The occurrence of 28 pharmaceuticals of major human consumption in Spain, including analgesics and anti-inflammatories, lipid regulators, psychiatric drugs, antibiotics, antihistamines, and beta-blockers, was assessed along the Ebro river basin, one of the biggest irrigated lands in that country. Target compounds were simultaneously analyzed by off-line solid-phase extraction, followed by liquid chromatography-tandem mass spectrometry. The loads of detected pharmaceuticals and their removal rates were studied in seven wastewater treatment plants (WWTPs) located in the main cities along the basin. Total loads ranged from 2 to 5 and from 0.5 to 1.5 g/d/1,000 inhabitants in influent and effluent wastewaters, respectively. High removal rates (60-90%) were achieved mainly for analgesics and anti-inflammatories. The other groups showed lower rates, ranging from 20 to 60%, and in most cases, the antiepileptic carbamazepine, macrolide antibiotics, and trimethoprim were not eliminated at all. Finally, the contribution of WWTP effluents to the presence of pharmaceuticals in receiving river waters was surveyed. In receiving surface water, the most ubiquitous compounds were the analgesics and anti-inflammatories ibuprofen, diclofenac, and naproxen; the lipid regulators bezafibrate and gemfibrozil; the antibiotics erythromycin, azithromycin, sulfamethoxazole, trimethoprim, and less frequently, ofloxacin; the antiepileptic carbamazepine; the antihistamine ranitidine; and the beta-blockers atenolol and sotalol. Although levels found in WWTP effluents ranged from low microg/L to high ng/L, pharmaceuticals in river waters occurred at levels at least one order of magnitude lower (low ng/L range) because of dilution effect. From the results obtained, it was proved that WWTP are hot spots of aquatic contamination concerning pharmaceuticals of human consumption. PMID- 17702327 TI - Analysis of glutathione endpoints for measuring copper stress in Chlamydomonas reinhardtii. AB - Glutathione (GSH) is the most abundant nonprotein thiol in eukaryotic cells and it protects cells by functioning as an antioxidant and a metal-binding ligand. Because glutathione readily undergoes oxidation-reduction reactions to combat oxidative stress, intracellular ratios of the reduced (GSH) to the oxidized (GSSG) forms of glutathione may serve as an important biomarker of exposure and effect of trace metals in eukaryotic cells. We compared sensitivity of glutathione ratios in the freshwater alga Chlamydomonas reinhardtii to the traditional endpoints of cell growth rates and chlorophyll a following exposure to Cu for periods of 6 and 24 h. A response of the GSH:GSSG ratio to Cu concentration was observed at Cu levels of 40 and 80 nM after exposure for both 6 and 24 h. The concentration of total GSH at 24 h was roughly half the value at 6 h after exposure to either 40 or 80 nM Cu. A response for cell growth rate was observed only at 24 h, whereby the average specific growth rate decreased from about 1.1 to 0.4 d(-1). The total Cu concentrations eliciting a cell response of 50%, effect concentrations (EC50s), after 24 h of exposure were similar (49.2, 49.8, and 38.2 nM Cu) and not significantly different for GSH:GSSG ratio, GSH levels, and specific growth, respectively. Total cell-associated Cu concentrations after exposure for 24 h were calculated from the EC50 endpoints and ranged from 13.3 to 17.0 fg/cell. Overall, thiol ratios were indicative of toxicity resulting from exposure to Cu, but precision may be greater for the cell growth rate endpoints. PMID- 17702328 TI - Evaluating mercury biomagnification in fish from a tropical marine environment using stable isotopes (delta13C and delta15N). AB - Concentrations of total mercury (T-Hg) and methylmercury (MeHg) were measured in zooplankton and 13 fish species from a coastal food web of the Gulf of Oman, an arm of the Arabian Sea between Oman and Iran. Stable isotope ratios (delta13C and delta15N) also were determined to track mercury biomagnification. The average concentration of T-Hg in zooplankton was 21 +/- 8.0 ng g(-1) with MeHg accounting 10% of T-Hg. Total mercury levels in fish species ranged from 3.0 ng g(-1) (Sardinella longiceps) to 760 ng g(-1) (Rhizoprionodon acutus) with relatively lower fraction of MeHg (72%) than that found in other studies. The average trophic difference (Deltadelta13C) between zooplankton and planktivorous fish (Selar crumenopthalmus, Rastrelliger kanagurta, and S. longiceps) was higher (3.4 per thousandth) than expected, suggesting that zooplankton may not be the main diet or direct carbon source for these fish species. However, further sampling would be required to compensate for temporal changes in zooplankton and the influence of their lipid content. Trophic position inferred by delta15N and and slopes of the regression equations (log10[T-Hg] = 0.13[delta15N] - 3.57 and log10[MeHg] = 0.14[delta15N] - 3.90) as estimates of biomagnification indicate that biomagnification of T-Hg and MeHg was lower in this tropical ocean compared to what has been observed in arctic and temperate ecosystems and tropical African lakes. The calculated daily intake of methylmercury in the diet of local people through fish consumption was well below the established World Health Organization (WHO) tolerable daily intake threshold for most of the fish species except Euthynnus affinis, Epinephelus epistictus, R. acutus, and Thunnus tonggol, illustrating safe consumption of the commonly consumed fish species. PMID- 17702329 TI - Accumulation and transfer of contaminants in killer whales (Orcinus orca) from Norway: indications for contaminant metabolism. AB - Blubber tissue of one subadult and eight male adult killer whales was sampled in Northern Norway in order to assess the degree and type of contaminant exposure and transfer in the herring-killer whale link of the marine food web. A comprehensive selection of contaminants was targeted, with special attention to toxaphenes and polybrominated diphenyl ethers (PBDEs). In addition to assessing exposure and food chain transfer, selective accumulation and metabolism issues also were addressed. Average total polychlorinated biphenyl (PCB) and pesticide levels were similar, approximately 25 microg/g lipid, and PBDEs were approximately 0.5 microg/g. This makes killer whales one of the most polluted arctic animals, with levels exceeding those in polar bears. Comparing the contamination of the killer whale's diet with the diet of high-arctic species such as white whales reveals six to more than 20 times higher levels in the killer whale diet. The difference in contaminant pattern between killer whales and their prey and the metabolic index calculated suggested that these cetaceans have a relatively high capacity to metabolize contaminants. Polychlorinated biphenyls, chlordanes, and dichlorodiphenyldichloro-ethylene (DDE) accumulate to some degree in killer whales, although toxaphenes and PBDEs might be partly broken down. PMID- 17702331 TI - Influence of the temperature gradient in blubber on the bioaccumulation of persistent lipophilic organic chemicals in seals. AB - Seals constitute an important link in food webs of the Arctic environment and are an important vector of persistent lipophilic organic pollutants to top predators (e.g., polar bears) and humans. Two fugacity-based, non-steady state, mechanistic lifetime models were assembled to explore the influence of the temperature gradient in the insulating blubber on the distribution and bioaccumulation of persistent lipophilic organic pollutants in seals. The behavior of a two compartment model that distinguishes between the gastrointestinal tract and the seal itself was compared with a three-compartment model, in which a separate blubber compartment was implemented with a temperature gradient through the insulation layer. In both models, equilibrium partitioning between the animal's tissues, blood, and milk was assumed. The models were parameterized for ringed seals (Phoca hispida) and evaluated using field data for bioaccumulation of polychlorinated biphenyls in this species. The two-compartment model resulted in predicted concentrations below reported field data. This was in particular the case for females, for which the elimination of the contaminants via milk was overpredicted by up to one order of magnitude. The three-compartment model with its consideration of the temperature gradient in blubber yielded predictions that were much more consistent with the field data. It also predicted a fractionation of polychlorinated biphenyl congeners between different blubber layers, as well as between blubber and blood or milk, which was in good qualitative agreement with observations reported in the literature. This work indicates that the temperature gradient in the blubber has an impact on the bioaccumulation of persistent lipophilic organic pollutants in seals and in marine mammals in general. PMID- 17702330 TI - Interference of contaminated sediment extracts and environmental pollutants with retinoid signaling. AB - Retinoids are known to regulate important processes such as differentiation, development, and embryogenesis. Some effects, such as malformations in frogs or changes in metabolism of birds, could be related to disruption of the retinoid signaling pathway by exposure to organic contaminants. A new reporter gene assay has been established for evaluation of the modulation of retinoid signaling by individual chemicals or environmental samples. The bioassay is based on the pluripotent embryonic carcinoma cell line P19 stably transfected with the firefly luciferase gene under the control of a retinoic acid-responsive element (clone P19/ A15). The cell line was used to characterize the effects of individual chemicals and sediments extracts on retinoid signaling pathways. The extracts of sediments from the River Kymi, Finland, which contained polychlorinated dioxins and furans and polycyclic aromatic hydrocarbons (PAHs), significantly increased the potency of all-trans retinoic acid (ATRA), while no effect was observed with the extract of the sediment from reference locality. Considerable part of the effect was caused by the labile fraction of the sediment extracts. Also, several individual PAHs potentiated the effect of ATRA; on the other hand, 2,3,7,8 tetrachlorodibenzo-p-dioxin and several phthalates showed slightly inhibiting effect. These results suggest that PAHs could be able to modulate the retinoid signaling pathway and that they could be responsible for a part of the proretinoid activity observed in the sediment extracts. However, the effects of PAHs on the retinoic acid signaling pathways do not seem to be mediated directly by crosstalk with aryl hydrocarbon receptor. PMID- 17702332 TI - Application of a source apportionment model in consideration of volatile organic compounds in an urban stream. AB - Position-dependent concentrations of trichloroethylene and methyl-tert-butyl ether are considered for a 2.81-km section of the Aberjona River in Massachusetts, USA. This river flows through Woburn and Winchester (Massachusetts, USA), an area that is highly urbanized, has a long history of industrial activities dating to the early 1800s, and has gained national attention because of contamination from chlorinated solvent compounds in Woburn wells G and H. The river study section is in Winchester and begins approximately five stream kilometers downstream from the Woburn wells superfund site. Approximately 300 toxic release sites are documented in the watershed upstream from the terminus of the study section. The inflow to the river study section is considered one source of contamination. Other sources are the atmosphere, a tributary flow, and groundwater flows entering the river; the latter are categorized according to stream zone (1, 2, 3, etc.). Loss processes considered include outflows to groundwater and water-to-atmosphere transfer of volatile compounds. For both trichloroethylene and methyl-tert-butyl ether, degradation is neglected over the timescale of interest. Source apportionment fractions with assigned values alphainflow, alpha2, alpha3, etc. are tracked by a source apportionment model. The strengths of the groundwater and tributary sources serve as fitting parameters when minimizing a reduced least squares statistic between water concentrations measured during a synoptic study in July 2001 versus predictions from the model. The model fits provide strong evidence of substantial unknown groundwater sources of trichloroethylene and methyl-tert-butyl ether amounting to tens of grams per day of trichloroethylene and methyl-tert-butyl ether in the river along the study section. Modeling in a source apportionment manner can be useful to water quality managers allocating limited resources for remediation and source control. PMID- 17702333 TI - Sorption and degradation in soils of veterinary ionophore antibiotics: monensin and lasalocid. AB - Monensin and lasalocid are polyether ionophores commonly used in the beef and poultry industries for the prevention of coccidial infections and promotion of growth. These ionophores can exhibit higher toxicity than many other antibiotics; thus, evaluating their fate in the environments associated with concentrated feed operations is important. Sorption of monensin and lasalocid was measured in eight soils of varying physiochemical composition. Organic carbon-normalized sorption coefficients (log Koc) ranged from 2.1 to 3.8 for monensin and from 2.9 to 4.2 for lasalocid and were inversely correlated to equilibrium soil-solution pH. Degradation of lasalocid and monensin in two contrasting soils with and without manure amendment was measured in moist soils at 23 degrees C and 0.03 MPa moisture potential. The half-life of both compounds in the fresh nonsterile soils was less than 4 d, for which monensin degraded slightly faster than lasalocid. Fresh liquid manure amendments did not significantly alter degradation of either compound. Based on parallel 60Co-sterilized soil experiments, some abiotic degradation of monensin was apparent, whereas lasalocid only degraded in the presence of microbes. Analysis of beef-derived lagoon effluent used for irrigation confirmed that monensin can be present at low-ppb to low-ppm concentrations in the aqueous and suspended solids fractions, respectively; however, subsequent analysis of drainage water in a nearby ditch suggested that attenuation by soil after land application will greatly reduce the amount entering surface waters. PMID- 17702334 TI - Estimating dioxin-like polychlorinated biphenyl toxic equivalents from total polychlorinated biphenyl measurements in fish. AB - Polychlorinated biphenyls (PCBs) are 209 related compounds, a dozen of which are known as dioxin-like PCBs (dl-PCBs) and are among the most toxic PCBs. Polychlorinated biphenyls contribute to many adverse effects to human health, including cancer, and are a major cause of fish advisories in North America. It is a common perception that individual PCB compounds, especially dl-PCBs, rather than total PCB need to be quantified to predict the environmental hazard because of differences in their toxicity potential and distribution among various environmental matrices, including aquatic food webs. Because the current analytical methods for quantifying dl-PCBs are complex and four- to fivefold more expensive, limited fish samples are analyzed for dl-PCBs. Using what likely is the largest dl-PCB fish data set (n = 912) with a wide distribution of fish species (n = 22), size (19-112 cm), weight (100-14,300 g), sex (male:female, 51:49), and PCB contamination level (20-7,300 ng/g wet wt), we show that the comparatively less expensive and rapid measurements of total PCB in fish can be utilized to assess dl-PCB-related toxicological hazard, measured as 2,3,7,8 tetrachlorodibenzo-p-dioxin toxic equivalents (TEQ). A regression equation of dl PCB-related TEQ (i.e., TEQdl-PCB) to total PCB in fish is presented (TEQdi-PCB = [2.56 x 10(-5)]CtotalPCB, r = 0.89, p < 0.001). The regression was evaluated by applying it to three independent data sets of substantial sizes (n = 55, 141, and 176). The TEQdl-PCB estimated using the regression and total PCB measurements were within a reasonable factor of two to three of the TEQdl-PCB calculated from the dl-PCB measurements. The successful evaluation indicates versatility of the regression. PMID- 17702335 TI - Sorption of tylosin A, D, and A-aldol and degradation of tylosin A in soils. AB - Heightened concerns regarding the potential impact on soil and water quality of veterinary antibiotics warrant a better understanding of the environmental fate of antibiotics in soil. Sorption of the macrolides tylosin A (TA), tylosin D, and TA-aldol was measured in several soils and evaluated with respect to soil pH, organic matter content, percentage clay, and cation-exchange capacity (CEC). Tylosin and related compounds exhibit similar sorption characteristics and generally are strongly sorbed, with sorption being well and positively correlated to surface area, clay content, and CEC. Sorption coefficients normalized by CEC were within a narrow range (10(4.1+/-0.21 L/molc) for all but one soil; however, good extraction recoveries with only methanol for most soils suggested that hydrophobic processes also contribute to sorption. Aerobic degradation of TA over a three-month period in two freshly collected agricultural soils and 60Co irradiated soils indicated that both abiotic and microbial processes contribute to TA transformation. The abiotic process was much slower and dominated in the first two weeks, followed by rapid microbial degradation within 3 d. Three primary degradation products were identified using liquid chromatography with full-scan mass spectrometry, with unconfirmed identifications of TA having the aldehyde group oxidized to an acid (m/z = 932) in both soils and tyslosin B (m/z = 772) as well as tylosin B having the aldehyde group oxidized to an acid (m/z = 788) in the sandy soil. PMID- 17702336 TI - Intersex in Japanese medaka (Oryzias latipes) used as negative controls in toxicologic bioassays: a review of 54 cases from 41 studies. AB - Histologic assessment of the gonads to detect intersex has become a valuable end point in reproductive toxicologic testing for fish, and many studies have solidly linked intersex with exposure to endocrine active substances (EAS). An assumption in such studies is that spontaneous intersex does not occur in control fish. Using historical data derived from toxicologic tests with Japanese medaka (Oryzias latipes), we report a retrospective study in which we identified 54 individual instances of intersex (testicular oocytes or ovarian testicular tissue) in control medaka from 15 of 41 selected toxicologic studies. These studies, comprised of previously unpublished data, had been conducted at three geographically distant laboratories, each of which utilized unique water sources, employed somewhat different culture protocols, and maintained distinct medaka breeding colonies. During our histologic examinations, we also identified three germ cell neoplasms that had been inadvertently diagnosed as intersex. In the present report, we review potential causes of intersex, discuss possible reasons why spontaneous intersex has rarely been reported, and propose suggestions for the judicious interpretation of intersex results in medaka studies involving EAS. PMID- 17702337 TI - Bioavailability and microbial adaptation to elevated levels of uranium in an acid, organic topsoil forming on an old mine spoil. AB - An old mine spoil at a 19th-century mining site with considerable residues of uranium (400-800 mg U/kg) was investigated with respect to U concentrations in soil and plants and tolerance to U in the soil microbial community in order to describe the bioavailability of U. Measurements of soil fractions representing water-soluble U, easily exchangeable U, and U bound to humified organic matter showed that all fractions contained elevated concentrations of U. Plant U concentrations were only 10 times higher at the mine spoil site compared to the reference site (3 mg U/kg vs 0.3 mg U/kg), while the most easily available soil fractions contained 0.18 to 0.86 mg U/kg soil at the mine spoil. An ecotoxicity bioassay using incorporation of [3H]thymidine into the indigenous microbial communities of the two soils in the presence of increasing U concentrations showed that microorganisms at the mining site were sensitive to U but also that they had acquired a substantial tolerance toward U (EC50, the effective concentration reducing activity by 50% of UO2-citrate was approximately 120 microM as compared to 30 microM in the reference soil). In the assay, more than 40% of the microbial activity was maintained in the presence of 1 mM UO2-citrate versus 3% in the reference soil. We conclude that U-enriched mining waste can contain sufficiently elevated concentrations of bioavailable U to affect indigenous microorganisms and that bioavailable U imposes a selection pressure that favors the development of a highly uranium-tolerant microbial community, while plant uptake of U remains low. PMID- 17702338 TI - Effect of in vitro and in vivo organotin exposures on the immune functions of murray cod (Maccullochella peelii peelii). AB - Murray cod (Maccullochella peelii peelii) is an iconic native Australian freshwater fish and an ideal species for ecotoxicological testing of environmental pollutants. The species is indigenous to the Murray-Darling basin, which is the largest river system in Australia but also the ultimate sink for many environmental pollutants. The organotins tributyltin (TBT) and dibutyltin (DBT) are common pollutants of both freshwater and marine environments and are also known for their immunotoxicity in both mammals and aquatic organisms. In this study, TBT and DBT were used as exemplar immunotoxins to assess the efficiency of immune function assays (i.e., mitogen-stimulated lymphoproliferation, phagocytosis in head kidney tissue, and serum lysozyme activity) and to compare the sensitivity of Murray cod to other fish species. The organotins were lethal to Murray cod at concentrations previously reported as sublethal in rainbow trout (i.e., intraperitoneal [i.p.] lethal dose to 75% of the Murray cod [LD75] = 2.5 mg/kg DBT and i.p. lethal dose to 100% of the Murray cod [LD100] = 12.5 mg/kg TBT and DBT). In vivo TBT exposure at 0.1 and 0.5 mg/kg stimulated the phagocytic function of Murray cod (F = 6.89, df = 18, p = 0.004), while the highest concentration of 2.5 mg/kg TBT decreased lymphocyte numbers (F = 7.92, df = 18, p = 0.02) and mitogenesis (F = 3.66, df = 18, p = 0.035). Dibutyltin was the more potent immunosuppressant in Murray cod, causing significant reductions in phagocytic activity (F = 5.34, df = 16, p = 0.013) and lymphocyte numbers (F = 10.63, df = 16, p = 0.001). PMID- 17702339 TI - Sensitivity of mottled sculpins (Cottus bairdi) and rainbow trout (Onchorhynchus mykiss) to acute and chronic toxicity of cadmium, copper, and zinc. AB - Studies of fish communities of streams draining mining areas suggest that sculpins (Cottus spp.) may be more sensitive than salmonids to adverse effects of metals. We compared the toxicity of zinc, copper, and cadmium to mottled sculpin (C. bairdi) and rainbow trout (Onchorhynchus mykiss) in laboratory toxicity tests. Acute (96-h) and early life-stage chronic (21- or 28-d) toxicity tests were conducted with rainbow trout and with mottled sculpins from populations in Minnesota and Missouri, USA, in diluted well water (hardness = 100 mg/L as CaCO3). Acute and chronic toxicity of metals to newly hatched and swim-up stages of mottled sculpins differed between the two source populations. Differences between populations were greatest for copper, with chronic toxicity values (ChV = geometric mean of lowest-observed-effect concentration and no-observed-effect concentration) of 4.4 microg/L for Missouri sculpins and 37 microg/L for Minnesota sculpins. Cadmium toxicity followed a similar trend, but differences between sculpin populations were less marked, with ChVs of 1.1 microg/L (Missouri) and 1.9 microg/L (Minnesota). Conversely, zinc was more toxic to Minnesota sculpins (ChV = 75 microg/L) than Missouri sculpins (chronic ChV = 219 microg/L). Species-average acute and chronic toxicity values for mottled sculpins were similar to or lower than those for rainbow trout and indicated that mottled sculpins were among the most sensitive aquatic species to toxicity of all three metals. Our results indicate that current acute and chronic water quality criteria for cadmium, copper, and zinc adequately protect rainbow trout but may not adequately protect some populations of mottled sculpins. Proposed water quality criteria for copper based on the biotic ligand model would be protective of both sculpin populations tested. PMID- 17702340 TI - Toxicity of cadmium to early life stages of brown trout (Salmo trutta) at multiple water hardnesses. AB - Toxicity of cadmium to early life stages of brown trout (Salmo trutta) was determined at multiple water hardnesses. Increasing water hardness decreased cadmium toxicity. Postswimup fry were much more sensitive than embryos and larvae. Chronic values from early life stage tests initiated with eyed embryos were 3.52, 6.36, and 13.6 microg Cd/L at water hardnesses of 30.6, 71.3, and 149 mg/L, respectively. In tests initiated with 30-d postswimup fry, chronic values were 1.02, 1.83, and 6.54 microg Cd/L at water hardnesses of 29.2, 67.6, and 151 mg/L, respectively. Higher chronic values from the early life stage tests compared to tests initiated with swimup fry likely are caused by acclimation during cadmium-tolerant embryo and larval stages. Growth was not affected by cadmium in the early life stage tests but was negatively affected in tests initiated with fry at water hardnesses of 29.2 and 67.6 mg/L. Concentrations of cadmium that reduced growth were higher than those that increased mortality. Median lethal concentrations for swimup fry after 96 h were 1.23, 3.90, and 10.1 microg Cd/L at water hardnesses of 29.2, 67.6, and 151 mg/L, respectively. Test results enable prediction of acute mortality of brown trout swimup fry based on cadmium concentration and water hardness. PMID- 17702341 TI - A lateral flow immunoassay for rapid evaluation of vitellogenin levels in plasma and surface mucus of the copper redhorse (Moxostoma hubbsi). AB - We tested a lateral flow immunoassay (LFIA) for detecting vitellogenin (VTG) in plasma and surface mucus of copper redhorse, Moxostoma hubbsi, a threatened fish species. The LFIA detected VTG in samples from estradiol-induced fish, though there was no reaction in samples from noninduced individuals. The minimum detection range was 0.08 to 0.60 microg VTG/ml, comparable to other methods. The LFIA has the potential to detect exposure to estrogenic endocrine-disrupting chemicals. PMID- 17702343 TI - Influence of alkylphenols and trace elements in toxic, genotoxic, and endocrine disruption activity of wastewater treatment plants. AB - Toxicity and endocrine interference of influent and effluent waters from domestic and industrial wastewater treatment plants were determined. In addition, chemical analyses were performed to detect the presence of 17beta-estradiol, 17alpha ethinyl estradiol, nonylphenol, 4-octylphenol, and p-t-octylphenol as well as lead, copper, and cadmium in these matrices. The results showed that despite low acute toxic potential, most of the samples tested showed both genotoxicity and endocrine interference. Furthermore, to establish whether the observed effects were caused by the alkylphenols and the heavy metals detected, toxic, genotoxic, and endocrine interference tests also were performed on pure chemicals. The acute toxicity was measured on the crustacean Daphnia magna. The estrogenic activity was determined by using the yeast estrogen screen with Saccharomyces cerevisiae RMY326, whereas the SOS Chromotest and Ames test detected the genotoxicity on Escherichia coli PQ37 and Salmonella typhimurium TA98 and TA100, respectively. The results showed that the toxicity found in the matrices did not match the values found for pure chemicals, but a clear correlation was found between alkylphenols and genotoxicity. Both heavy metals and alkylphenols took part in the endocrine interference activity. PMID- 17702342 TI - Mixtures of metals and polynuclear aromatic hydrocarbons elicit complex, nonadditive toxicological interactions in meiobenthic copepods. AB - The acute toxicity of metal-polynuclear aromatic hydrocarbon (PAH) mixtures (i.e., Cd, Hg, Pb, fluoranthene, and phenanthrene) associated with sediments was assessed in two benthic copepods. Schizopera knabeni was exposed to sediment amended with single contaminants and mixtures. Adult S. knabeni were highly tolerant of single-contaminant exposures to phenanthrene, Cd, Hg, and Pb as well as a mixture of Cd, Hg, and Pb. Binary experiments revealed that although phenanthrene was synergistic with Cd and Hg, the phenanthrene-Cd synergism was much stronger (2.8 times more lethal than predicted). When a mixture of Cd, Hg, and Pb was combined with phenanthrene, a synergistic response was observed, eliciting 1.5 times greater lethality than predicted. A Cd-phenanthrene synergism in S. knabeni was also observed in aqueous exposures, suggesting that the interaction was related to a pharmacological insult rather than a sediment related exposure effect. An antagonism between Cd, Hg, and Pb was indicated, and this antagonism may have moderated the Cd-phenanthrene synergism in mixtures containing Cd, Hg, Pb, and phenanthrene. Experiments with Amphiascoides atopus revealed that phenanthrene and fluoranthene were each synergistic with Cd in aqueous exposures. Our studies suggest that interactive toxicity among metal-PAH mixtures may be common among benthic copepods and that strong synergistic effects observed in binary mixtures may be moderated in more diverse contaminant mixtures. However, the strength of the observed synergisms raises concerns that established sediment quality criteria may not be protective for organisms jointly exposed to PAH and metals, especially Cd-PAH mixtures. PMID- 17702344 TI - Effect of four organochlorine pesticides on the reproduction of freshwater rotifer Brachionus calyciflorus Pallas. AB - Effects of four organochlorine pesticides, including dichlorodiphenyltrichloroethane (DDT), dicofol, endosulfan, and lindane, on the reproduction of freshwater rotifer Brachionus calyciflorus were studied by 3-d population growth tests. Compared to the control, dichlorodiphenyltrichloroethane at 0.64 mg/L, dicofol at 0.8 and 1.2 mg/L, endosulfan at 7.0 mg/L, and lindane at 14.0 mg/L all significantly decreased the population growth rate of the rotifers. Dichlorodiphenyltrichloroethane at concentrations higher than 0.16 mg/L, dicofol at concentrations higher than 0.025 mg/L, endosulfan at concentrations higher than 0.875 mg/L, and lindane at 14.0 mg/L all significantly decreased the mictic rate of the rotifers. Dichlorodiphenyltrichloroethane at 0.24 and 0.32 mg/L increased significantly the fertilization rate, but DDT at 0.64 mg/L inhibited completely the occurrence of fertilized mictic females. Dichlorodiphenyltrichloroethane at 0.32 and 0.64 mg/L, dicofol at 1.2 mg/L, and endosulfan at 7.0 mg/L all significantly decreased the ratio of ovigerous females to nonovigerous females, but the reverse was true for lindane at 7.0 mg/L. Dichlorodiphenyltrichloroethane at 0.0025 and 0.01 mg/L increased significantly the ratio of mictic females to amictic females, but the reverse was true for dicofol at 0.8 mg/L. Both population growth rate and mictic rate of the rotifers were suitable endpoints for assessing the effects of the four organochlorine insecticides on the reproduction of the rotifers, and the latter was more sensitive. PMID- 17702345 TI - Long-term sediment bioassay of lead toxicity in two generations of the marine amphipod Elasmopus laevis, S.I. Smith, 1873. AB - Sediments are evaluated for toxicity by measuring mortality in a single cohort of amphipods in either acute (10-d) or chronic (28-d) bioassays. This investigation differed from conventional bioassays in four ways: Sublethal effects (fecundity) were estimated; the testing period was 60+ d; two successive generations were examined; and Elasmopus laevis Smith, 1873, amphipods were employed. Four test sediments were created between 58 and 424 microg/g of lead using the 30-microg/g whole-sediment as the control. Bioaccumulated lead at 60 d varied as a linear function of lead concentration in the sediments. Fecundity, as estimated by offspring-per-chamber and/or percent reproductive success, was reduced as sediment lead concentrations increased and reproduction was delayed compared with the control. The reduction in offspring production per test chamber varied significantly as an inverse function of lead sediment concentration, best described by a curvilinear exponential equation. It was concluded that E. laevis exposed to 118 microg/g and higher could not maintain a population as large as that in the control. Although the current sediment quality guideline for lead stipulates that adverse biological effects likely will occur above 218 microg/g, this study revealed a statistically significant negative reproductive response at 118 microg/g lead, and suggests that the current regulatory guideline for lead, based on lethality, should be reconsidered. PMID- 17702346 TI - Decreased toxicity to terrestrial plants associated with a mixture of methyl tert butyl ether and its metabolite tert-butyl alcohol. AB - The influence of the main fuel oxygenate methyl tert-butyl ether (MTBE) and its key metabolite, tert-butyl alcohol (TBA), on the growth of a plant seedling was studied separately and in combination. The test plants were mung bean (Phaseolus radiatus), cucumber (Cucumis sativus), wheat (Triticum aestivum), sorghum (Sorghum bicolor), kale (Brassica alboglabra), Chinese cabbage (Brassica campestris), and sweet corn (Zea mays). The growth of all the plants was adversely affected by TBA and MTBE. The 5-d median effective concentration (EC50) for the plants exposed to MTBE and TBA were in the range of 680 to 1,000 mg MTBE/kg soil (dry wt) and 1,200 to 3,500 mg TBA/kg soil (dry wt), respectively. The relative order of the sensitivity rankings is almost the same for MTBE and TBA. Methyl tert-butyl ether is more toxic than TBA to most of the test species. Based on the EC50 values, MTBE is approximately 1.5 to 3 times more potent than TBA. The sum of the toxic unit (TU) at 50% inhibition of the mixture (EC50mix) was calculated from the dose (TU-based)-response relationships using the trimmed Spearman-Karber method. The combined effect of MTBE + TBA on the plant growth was less than additive because the EC50mix values were greater than I TU. This phenomenon may be due to the competition of MTBE and TBA in terms of their intake by plants. The combined effects of MTBE and TBA should be taken into account to assess their risk in gasoline-contaminated sites. PMID- 17702347 TI - Effects of sodium chloride on chronic silver toxicity to early life stages of rainbow trout (Oncorhynchus mykiss). AB - The chronic (early life stage) toxicity of silver to rainbow trout (Oncorhynchus mykiss) was determined in flow-through exposures. Rainbow trout embryos were exposed to silver (as AgNO3) from 48 h or less postfertilization to 30 d postswimup in soft water in the presence and absence of 49 mg/L of NaCl (30 mg/L of Cl). The studies determined effect levels for rainbow trout exposed throughout an extended development period and assessed possible protective effects of sodium chloride. Lowest-observed-effect concentrations were greater than 1.25 microg/L of dissolved silver for survival, mean day to hatch, mean day to swimup, and whole-body sodium content in both studies. Whole-body silver concentrations increased significantly at 0.13 microg/L of dissolved silver in unmodified water and at 1.09 microg/L of dissolved silver in amended water. The maximum-acceptable toxicant concentration for growth was greater than 1.25 microg/L of dissolved silver in unmodified water and 0.32 microg/L of dissolved silver in amended water. Whole-body silver concentrations were more sensitive than survival and growth end points in unmodified water. Interpretation of sodium chloride effects on chronic silver toxicity to rainbow trout was complicated by differences in measured effect levels that were potentially the result of strain differences between test organisms in the two studies. PMID- 17702348 TI - Effects of insecticide exposure on feeding inhibition in mayflies and oligochaetes. AB - The present study examined the effects of pulse exposures of the insecticide imidacloprid on the mayfly, Epeorus longinmanus Eaton (Family Heptageniidae), and on an aquatic oligochaete, Lumbriculus variegatus Miller (Family Lumbriculidae). Pulse exposures of imidacloprid are particularly relevant for examination, because this insecticide is relatively soluble (510 mg/L) and is most likely to be at effect concentrations during runoff events. Experiments examined the recovery of organisms after a 24-h pulse exposure to imidacloprid over an environmentally realistic range of concentrations (0, 0.1, 0.5, 1, 5, and 10 microg/L). Effects on feeding were measured by quantifying the algal biomass consumed by mayflies or foodstuffs egested by oligochaetes. Imidacloprid was highly toxic, with low 24-h median lethal concentrations (LC50s) in early mayfly instars (24-h LC50, 2.1 +/- 0.8 microg/L) and larger, later mayfly instars (24-h LC50, 2.1 +/- 0.5 microg/L; 96-h LC50, 0.65 +/- 0.15 microg/L). Short (24-h) pulses of imidacloprid in excess of 1 microg/L caused feeding inhibition, whereas recovery (4 d) varied, depending on the number of days after contaminant exposure. In contrast to mayflies, oligochaetes were relatively insensitive to imidacloprid during the short (24-h) pulse; however, immobility of oligochaetes was observed during a 4-d, continuous-exposure experiment, with 96-h median effective concentrations of 6.2 +/- 1.4 microg/L. Overall, imidacloprid reduced the survivorship, feeding, and egestion of mayflies and oligochaetes at concentrations greater than 0.5 but less than 10 microg/L. Inhibited feeding and egestion indicate physiological and behavioral responses to this insecticide. PMID- 17702349 TI - Influence of feeding ecology on blood mercury concentrations in four species of turtles. AB - Mercury is a relatively well-studied pollutant because of its global distribution, toxicity, and ability to bioaccumulate and biomagnify in food webs: however, little is known about bioaccumulation and toxicity of Hg in turtles. Total Hg (THg) concentrations in blood were determined for 552 turtles representing four different species (Chelydra serpentina, Sternotherus odoratus, Chrysemys picta, and Pseudemys rubriventris) from a Hg-contaminated site on the South River (VA, USA) and upstream reference sites. Methylmercury and Se concentrations also were determined in a subset of samples. Because the feeding ecology of these species differs drastically, stable isotopes of carbon (delta13C) and nitrogen (delta15N) were employed to infer the relationship between relative trophic position and Hg concentrations. Significant differences were found among sites and species, suggesting that blood can be used as a bioindicator of Hg exposure in turtles. We found differences in THg concentrations in turtles from the contaminated site that were consistent with their known feeding ecology: C. serpentina > or = S. odoratus > C. picta > P. rubriventris. This trend was generally supported by the isotope data, which suggested that individual turtles were feeding at more than one trophic level. Methylmercury followed similar spatial patterns as THg and was the predominant Hg species in blood for all turtles. Blood Se concentrations were low in the system, but a marginally positive relationship was found between THg and Se when species were pooled. The blood THg concentrations for the turtles in the present study are some of the highest reported in reptiles, necessitating further studies to investigate potential adverse effects of these high concentrations. PMID- 17702350 TI - Statistical analysis of cytochrome P4501A biomarker measurements in fish. AB - Induction of the cytochrome P4501A (CYP1A) enzyme system in fish is a common biomarker of exposure to aromatic hydrocarbons. Induction of CYP1A can be measured at a number of steps in the transcription-translation-functional protein pathway using a variety of techniques. The present study examined the range of these measurements from 94 published papers in an attempt to examine the statistical characteristics of each method. Cytochrome P4501A induction, as measured by catalytic ethoxyresorufin-O-deethylase (EROD) activity, protein levels (enzyme-linked immunosorbent assay, Western blot analysis, and immunohistochemistry), and mRNA levels (Northern blot analysis and reverse transcription-polymerase chain reaction), was analyzed. When possible, the variance structure, effect size determination, and dose-response modeling of each method of measurement in the laboratory and field were examined. Conclusions from this analysis include: 1) Because of interlaboratory and interspecies variability, general end-point determinations will need to be defined in terms of the statistically detectable fold-change of measurements relative to control or reference values, and 2) fold-change in EROD activity provides the most robust measure of the dose responsiveness of aromatic hydrocarbons within specific chemical classes (e.g., polycyclic aromatic hydrocarbons). The relationship between the ability to measure statistical differences in induction level and the biological significance of those measurements has yet to be defined. To utilize these biomarkers in a risk assessment context, this relationship must be addressed at the scientific and management levels. PMID- 17702351 TI - Mixture and single-substance acute toxicity of selective serotonin reuptake inhibitors in Ceriodaphnia dubia. AB - Selective serotonin reuptake inhibitors (SSRIs) are neurologically active drugs that can contaminate surface waters and have the potential to negatively affect aquatic organisms. In this investigation, the 48-h acute toxicity of mixtures (binary and quaternary) of four common SSRIs (fluoxetine [Prozac], sertraline [Zoloft], paroxetine [Paxil], and citalopram [Celexa]) were determined in the daphnid Ceriodaphnia dubia. Logistic regression was used to model mortality data and to investigate the applicability of concentration addition and independent action models to explain observed mortality. The concentrations estimated to induce 50% mortality in 48 h for the individual SSRIs sertraline, fluoxetine, paroxetine, and citalopram were 0.48 to 0.66, 1.23 to 1.84, 2.23 to 3.57, and 10.47 to 14.53 microM, respectively. Concentration addition was a better predictor of mixture effects than independent action and suggested that the tested SSRIs have a similar mechanism of action. Results indicate that environmental hazard assessments should be conservative and consider that acutely toxic effects in aquatic organisms can be additive for each SSRI in a mixture. PMID- 17702352 TI - Effects of dissolved organic carbon on the toxicity of copper to the developing embryos of the Pacific oyster (Crassostrea gigas). AB - The effects of humic acid (HA) on copper speciation and its subsequent toxicity to the sensitive early life stages of the Pacific oyster (Crassostrea gigas) are presented. Differential pulse anodic stripping voltammetry with a hanging mercury drop electrode was used to measure the copper species as labile copper (LCu; free ion and inorganic copper complexes) and total copper (TCu) with respect to increasing HA concentration. The TCu and LCu 50% effect concentrations (EC50s) in the absence of HA were 20.77 microg/L (95% confidence interval [CI], 24.02-19.97 microg/L) and 8.05 microg/L (95% CI, 9.6-5.92 microg/L) respectively. A corrected dissolved organic carbon (DOC) concentration (HA only) of 1.02 mg/L was required to significantly increase the TCu EC50 to approximately 41.09 microg/L (95% CI, 44.27-37.52 microg/L; p < 0.05), almost doubling that recorded when DOC (as HA) was absent from the test media. In contrast, the LCu EC50 was unaffected by changes in DOC concentration and was stable throughout the corrected DOC concentration range. The absence of change in the LCu EC50, despite increased HA concentration, suggests that the LCu fraction, not TCu, was responsible for the observed toxicity to the oyster embryo. This corresponds with the current understanding of copper toxicity and supports the free-ion activity model for copper toxicity. PMID- 17702353 TI - Interactions of silver, cadmium, and copper accumulation in green mussels (Perna viridis). AB - Metal interaction is vital for assessing the use of aquatic organisms in monitoring metal contamination. The present study examined the interactions between Ag and Cd accumulation and between Ag and Cu accumulation in the green mussel (Perna viridis). Accumulation of Ag and Cd in the whole tissue of green mussels exposed to 5 microg/L of Ag and 20 microg/L of Cd for two weeks was independent; however, interaction was observed at the subcellular level. Approximately 25% of Ag shifted from the insoluble fraction (IF) to the metallothionein-like protein in the presence of Cd, which probably resulted from the competition of Cd on IF in the Ag-Cd coexposure. On the other hand, coexposure of the mussels to Ag (5 microg/L) and Cu (30 microg/L) for two weeks increased the Ag and Cu concentrations in the tissue synergistically (two- to fivefold), but Ag and Cu subcellular distributions were similar in the coexposed and the singly exposed mussels. Exposure to Ag alone increased the dietary uptake of Ag by 30%, but the effect was reduced in the presence of Cd. No interaction, however, was observed between uptake rates of metals from the dissolved phase. To conclude, a significant interaction was observed for total Ag and Cu accumulation, but not for total Ag and Cd accumulation, in the mussels. Metal interaction is more likely to be observed at the subcellular level than at the whole-tissue level. PMID- 17702354 TI - Aquatic invertebrate resting egg sensitivity to glutaraldehyde and sodium hypochlorite. AB - Ballast tank treatment technologies are currently in development to reduce the risk of acquiring or transporting viable aquatic organisms that could be introduced to ecosystems and become invasive. Aquatic invertebrate resting eggs represent a challenge to such technologies because of morphological and biochemical adaptations to stress that also protect eggs from artificial stressors. To evaluate the potential efficacy of chemical biocides for ballast tank treatment, the present study examined the acute toxicity of glutaraldehyde and sodium hypochlorite on resting eggs of the freshwater cladoceran Daphnia mendotae and marine brine shrimp (Artemia sp.). Glutaraldehyde was toxic to resting eggs of Artemia sp., as indicated by a lethal concentration to 90% of organisms (LC90) of 95% confidence interval (226 +/- 10 mg/L). Daphnia mendotae, in contrast, displayed erratic responses to glutaraldehyde. Sodium hypochlorite was similarly toxic to resting eggs of Artemia sp. and D. mendotae, which displayed LC90s of 86.5 +/- 3.0 and 78.3 +/- 1.6 mg/L, respectively. Burial in sediment protected resting eggs from toxicants. The present results corroborate those from previous investigations of resting egg sensitivity to artificial stressors, supporting the conclusions that resting eggs are less sensitive than other life stages to artificial stressors and that chemical biocide concentrations effective against other life stages may be ineffective against resting stages. PMID- 17702355 TI - Dynamic energy budget as a basis to model population-level effects of zinc-spiked sediments in the gastropod Valvata piscinalis. AB - This paper presents original toxicity test designs and mathematical models that may be used to assess the deleterious effects of toxicants on Valvata piscinalis (Mollusca, Gastropoda). Results obtained for zinc, used as a reference toxicant, are presented. The feeding behavior, juvenile survival, growth, age at puberty, onset of reproduction, number of breedings during the life cycle, and fecundity were significantly altered when the snails were exposed to zinc-spiked sediments. Dynamic energy budget models (DEBtox) adequately predicted the effects of zinc on the V. piscinalis life cycle. They also provided estimates for lifecycle parameters that were used to parameterize a demographic model, based on a Z transformed life-cycle graph. The effect threshold for the population growth rate (lambda) was estimated at 259 mg/kg dry sediment of zinc, showing that significant changes in abundance may occur at environmental concentrations. Significant effects occurring just above this threshold value were mainly caused by the severe impairment of reproductive endpoints. Sensitivity analysis showed that the value of lambda depended mainly on the juvenile survival rate. The impairment of this latter parameter may result in extinction of V. piscinalis. Finally, the present study highlights advantages of the proposed modeling approach in V. piscinalis and possible transfer to other test species and contaminants. PMID- 17702356 TI - Non-myxomatous flail mitral valve: clinical and echocardiographic characteristics and long-term clinical outcome. AB - BACKGROUND AND AIM OF THE STUDY: Chordal rupture leading to flail mitral valve and mitral regurgitation (MR) is considered to be caused primarily by myxomatous mitral valve disease. The study aim was to determine the prevalence and clinical and echocardiographic characteristics of non-myxomatous versus myxomatous flail mitral valve. METHODS: A total of 96 patients with flail mitral valve was identified from an echocardiography database and classified as either myxomatous (n = 36; 37%) or non-myxomatous (n = 60; 63%), based on echocardiographic mitral valve anatomy (systolic leaflet buckling). In 10 other patients the etiology was indeterminate. The clinical and echocardiographic characteristics and outcome at five years were compared between groups. RESULTS: Patients with non-myxomatous mitral valve were older than those with myxomatous mitral valve (mean age 76 +/- 9 versus 61 +/- 12 years; p <0.0001), and were more likely to have aortic sclerosis, mitral annulus and papillary muscle calcification (odds ratio 3.6, 95% CI 1.2-10.8, p = 0.02) and to have short duration of symptoms (< or =1 month, p <0.02). There was no inter-group difference in MR severity, but non-myxomatous patients had higher systolic pulmonary artery pressure (52 +/- 16 versus 42 +/- 13 mmHg, p = 0.008). During the five-year follow up period, non-myxomatous patients had a poorer crude survival and survival free from rehospitalization for heart failure (p = 0.02), and were less likely to have mitral valve surgery (p = 0.015). However, these differences were abolished when data were adjusted for age. CONCLUSION: Among patients with flail mitral valve referred for echocardiography, more than half were non-myxomatous in origin, most likely due to wear and tear. Non-myxomatous flail mitral valve was associated with older age, degenerative calcific valvular changes, and more recent onset of symptoms. Age-adjusted survival free of heart failure was similar in both non-myxomatous and myxomatous patients. PMID- 17702357 TI - Myocardial apoptosis predicts postoperative course after aortic valve replacement in patients with severe left ventricular hypertrophy. AB - BACKGROUND AND AIM OF THE STUDY: Myocardial apoptosis has been implicated in heart failure and post-infarct remodeling. In some patients with severe aortic stenosis, delayed valvular replacement is associated with a poor in-hospital outcome. The study aim was to evaluate the impact of cardiomyocyte apoptosis on the postoperative course after aortic valve replacement (AVR) for severe aortic stenosis. METHODS: During elective AVR, myocardial biopsies were obtained from the left ventricle of 11 patients with severe left ventricular hypertrophy (LVH), and the samples analyzed for apoptosis. RESULTS: The mean apoptotic rate was 10.4 +/- 3.7 per thousand. (range: 5-16 per thousand). The apoptotic rate correlated directly with preoperative NYHA functional class, duration of intensive care unit (ICU) stay, number of days of postoperative acute renal insufficiency, and serum level of troponin T at 24 h; the apoptotic rate correlated inversely with cardiac index at 24 h postoperatively. At multivariate analysis, the apoptotic rate and left ventricular mass index were independent predictors of prolonged ICU stay. The apoptotic rate and duration of cardiopulmonary bypass were predictive of the duration of postoperative acute renal insufficiency. CONCLUSION: The study results showed an association between myocardial apoptosis and postoperative outcome in patients with severe LVH submitted for AVR. Non-invasive correlates of apoptosis may be introduced as a means of identifying patients at a higher operative risk, and may help in the evaluation of asymptomatic patients with severe aortic stenosis. Anti-apoptotic strategies before and during surgery would possibly ameliorate the surgical results. PMID- 17702358 TI - Undersized mitral annuloplasty inhibits left ventricular basal wall thickening but does not affect equatorial wall cardiac strains. AB - BACKGROUND AND AIM OF THE STUDY: Undersized mitral annuloplasty has been widely employed for patients with ischemic mitral regurgitation. Beyond correction of mitral regurgitation, ring annuloplasty is postulated to normalize global left ventricular (LV) shape, thereby decreasing LV wall stress and promoting reverse LV remodeling. The effect of undersized annuloplasty on regional transmural LV wall thickening and strain patterns, however, has not been examined. METHODS: In nine sheep, transmural radiopaque beadsets were inserted into the anterobasal and equatorial lateral LV walls, with additional markers silhouetting the left ventricle and mitral annulus. Four-dimensional marker dynamics were studied with biplane videofluoroscopy (open-chest) before and after tightening a Paneth-type mitral annuloplasty suture. LV volumes, mitral dimensions, transmural circumferential, longitudinal, and radial systolic strains, and end-diastolic (ED) and end-systolic (ES) remodeling strains in the two LV regions were computed. RESULTS: In the anterobasal LV wall close to the mitral annulus, annuloplasty increased ED wall thickness and surprisingly reduced systolic radial strain (wall thickening) at all transmural depths. Radial subepicardial, midwall, and subendocardial wall-thickening strains at ES in the anterobasal LV site were 0.25 +/- 0.15, 0.33 +/- 0.16, and 0.47 +/- 0.29, respectively, before tightening the suture annuloplasty, compared to 0.13 +/- 0.12, 0.15 +/- 0.18, and 0.20 +/- 0.26 after tightening. In the equatorial lateral LV wall further away from the annulus, most LV transmural systolic and remodeling strains did not change. CONCLUSION: Simulated undersized annuloplasty acutely decreased transmural systolic LV wall thickening in the anterobasal region, without substantially affecting transmural deformations in the lateral LV wall. These acute effects of undersized annuloplasty require a better understanding as they may potentially be deleterious, and a direct ventricular approach may be needed as an adjunct to promote reverse LV remodeling. PMID- 17702359 TI - Atrioventricular disruption managed by ex-situ repair and autotransplantation. AB - Atrioventricular groove disruption remains one of the most devastating complications following mitral valve replacement. Herein are described two cases that were successfully managed by ex-situ repair and autotransplantation. PMID- 17702360 TI - Prevalence, referral patterns, testing, and surgery in aortic valve disease: leaving women and elderly patients behind? AB - BACKGROUND AND AIM OF THE STUDY: The prevalence of aortic valve disease is not well defined, and it is not known to what degree gender and age affect testing and surgery for this condition. The study aim was to describe the prevalence of aortic valve disease in the United States population by extrapolating from administrative claims databases; and to investigate differences associated with gender and age in referral, diagnostic testing, and aortic valve replacement (AVR). METHODS: A claims database of approximately five million privately insured beneficiaries and a 5% sample of Medicare beneficiaries were queried for patients with aortic valve disease. Prevalence was calculated by age group and gender, and extrapolated to the 2005 US population. The proportion of patients with a cardiologist or cardiovascular surgeon visit, performance of echocardiography or stress testing, and AVR within a year of diagnosis was determined. RESULTS: The extrapolated prevalence of aortic valve disease in the US in 2005 was 1.8% (approximately 5.2 million people); in persons aged > or =65 years, prevalence was 10.7%. Women were seen by a specialist, underwent diagnostic tests and underwent AVR at rates significantly lower than men, as did patients aged > or =80 years compared to those aged 65-79 years. AVR was performed at approximately half the rate in women (1.4%) compared to men (2.7%, p <0.001), and in patients aged > or =80 years (1.1%) compared to those aged 65-79 years (2.5%, p <0.001). CONCLUSION: In 2005, approximately 5.2 million adults in the US were estimated to have a diagnosis of aortic valve disease. Advanced age and female gender were associated with lower rates of specialist visits, diagnostic testing, and AVR. PMID- 17702361 TI - Twenty-seven-year experience with composite valve graft replacement of the aortic root. AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to assess early and late outcome in patients undergoing composite valve graft replacement (CVGR) of the aortic root by means of the Bentall procedure, and to identify predictors of early and late death associated with this surgical approach. METHODS: Between August 1975 and July 2002, 162 consecutive patients underwent a Bentall procedure for CVGR. Demographic, treatment and clinical outcome data from these patients were gathered, reviewed, and analyzed. Potential predictors of early and late mortality were analyzed. RESULTS: The study population was predominantly male (n = 132; 81.5%) and middle-aged (mean age 51.3 +/- 15.8 years; range: 10-79 years). The main indications for surgery were annuloaortic ectasia (n = 75; 46.3%), aortic dissection (n = 44; 27.2%) and Marfan syndrome (n = 34; 21%). Reoperation was required in 37 cases (22.8%). The mean follow up was 74 months. Early (in hospital) mortality was 1.9% (n = 3). The only independent determinant of early mortality was cardiopulmonary bypass time (p = 0.025). Late mortality was 27.7% (n = 44). On multivariate analysis, the only independent risk factors for late mortality were age >60 years (p = 0.044) and left ventricular ejection fraction <50% (p = 0.037). Actuarial survival rates were 92.9%, 77%, 56.2%, and 47.1% at one, five, 10, and 15 years, respectively. Rates of freedom from reoperation on the aortic root and ascending aorta were 90.6% and 72.5% at five and 15 years, respectively. No false aneurysms were observed at any coronary reimplantation sites. CONCLUSION: In this series, the Bentall procedure was associated with low operative mortality and good early and late results. This suggests that the procedure may be considered as a reference to other operations on the aortic root, at least in adult patients. PMID- 17702362 TI - Effect of statin treatment on aortic valve and coronary artery calcification. AB - BACKGROUND AND AIM OF THE STUDY: Conflicting data exist regarding statins and the progression of aortic valve disease. Hence, further information is required to determine if statin treatment has a beneficial effect on aortic valve calcification, and whether the inflammatory status of the patient affects aortic valve disease progression. The study aim was to evaluate the concomitant effect of statin treatment on aortic valve and coronary artery calcification and to compare results with the inflammatory status of the patient. METHODS: Sixty-one patients with moderate to severe aortic stenosis (AS) were enrolled in this single-center, prospective observational study evaluating progression of aortic valve calcification. Patients underwent baseline and one-year echocardiography and electron-beam computed tomography. Blood samples were withdrawn at baseline and at one year for measurement of inflammatory biomarkers. RESULTS: There was no significant reduction in calcium accumulation in the aortic valve of the statin group compared to the non-statin group, but there was trend towards less progression of calcification for the statin group. A significant inhibition of the coronary artery calcification volume score was observed for the statin group compared to the non-statin group. On echocardiography, statin treatment had no significant impact on aortic valve stenosis. Patients with serum LDL level >130 mg/dl showed less progression of coronary artery calcification when treated with statin drugs. The level of high-sensitivity C-reactive protein (hsCRP) significantly correlated with the progression of calcification for both the aortic valve and coronary arteries. CONCLUSION: Whilst there was no significant benefit of statin treatment on aortic valve calcification over one year, there was a decreased progression of coronary artery calcification. The baseline level of hsCRP was predictive of progression of both aortic valve and coronary artery calcification, and may identify a high-risk population requiring aggressive control, either with statins or emerging drugs targeted at the inflammatory process of atherosclerosis. PMID- 17702363 TI - Effects of serum levels of novel atherosclerotic risk factors on aortic valve calcification. AB - BACKGROUND AND AIM OF THE STUDY: Aortic valve calcification (AVC) is a common condition that is found predominantly in the elderly. Clinical and histopathologic data prove that AVC is an active, progressive disease involving an atherosclerotic process. The possible role of novel coronary risk factors in the development of AVC were evaluated. METHODS: A total of 285 consecutive patients (age >60 years) who had been admitted to the authors' cardiology outpatient clinic was enrolled. Each patient underwent two-dimensional Doppler echocardiography. Serum levels of lipoprotein(a) (Lp(a)), homocysteine (Hcy), uric acid and C-reactive protein (CRP) were monitored and compared between patients with AVC and subjects with otherwise normal aortic valve morphology. RESULTS: AVC was detected in 112 patients. Compared to controls, patients with AVC were significantly older (73.0 +/- 7.4 versus 68.5 +/- 6.7 years; p <0.0001) and, in addition to higher dyslipidemia, had significantly higher serum levels of Lp(a) (27.4 (range: 13.0-47.5) versus 19.9 (range: 10.7-36.1) mg/dl; p = 0.033) and CRP (6.7 (4.5-10.2) versus 5.6 (3.9-8.0) mg/l; p = 0.008). Serum Hcy and uric acid levels were similar between the groups. Multivariate analysis identified age and serum levels of Lp(a) or CRP as independent determinants of AVC. CONCLUSION: AVC is common in elderly patients admitted to cardiology clinics. In addition to advanced age, high serum levels of Lp(a) and CRP are independent predictors of the condition. PMID- 17702364 TI - The Ross operation for aortic valve disease: previous sternotomy results in improved long-term outcome. AB - BACKGROUND AND AIM OF THE STUDY: Progressive pulmonary autograft dilatation and failure following a Ross operation continues to be of major concern. It is hypothesized that the pulmonary autograft may perform better over the longer follow up period if the Ross operation is performed as a reoperation rather than a primary operation. The basis for this hypothesis is that the epicardial and mediastinal fibrosis encountered at reoperation may inadvertently provide additional support for the pulmonary autograft during the follow up period. METHODS: To test this hypothesis, 281 patients (mean age 24 +/- 9 years) who underwent a Ross operation over a 16-year period were retrospectively analyzed. The patient population was divided into two subgroups in whom the Ross operation was performed: (i) as the first cardiac operation, through a sternotomy incision (primary-Ross; n = 180); and (ii) after the patient had undergone a previous sternotomy (prior-sternotomy; n = 101). A recent follow up examination was achieved in 93% of patients. RESULTS: Early and overall mortality was 2.1% and 6.4%, respectively, and there was no significant difference between the subgroups. At 12-year follow up, freedom from reoperation on the autograft, or valve-related death was 87 +/- 6% versus 71 +/- 9% in favor of the prior sternotomy subgroup (p = 0.06). At 12-year follow up, freedom from valve-related death, or reoperation on the pulmonary autograft, or severe aortic regurgitation was 87 +/- 5% versus 71 +/- 7% (p = 0.03) in favor of the prior-sternotomy subgroup. CONCLUSION: The results of a preliminary analysis suggest that additional benefit is accrued when the Ross operation is performed during re sternotomy. This should encourage surgeons to attempt repair of the aortic valve during the initial surgery, with the knowledge that - if needed - the Ross operation can be performed safely at later surgery, and with possible additional benefit to the patient during the follow up period. PMID- 17702365 TI - Outcome of pregnancy in women after pulmonary autograft valve replacement for congenital aortic valve disease. AB - BACKGROUND AND AIM OF THE STUDY: The pulmonary autograft has been recommended as the valve of choice for aortic valve replacement (AVR) in young women contemplating pregnancy. However, current information on maternal and perinatal outcome of pregnancy in women with pulmonary autograft valve replacement is limited. METHODS: Using a nationwide Dutch registry (CONCOR) and a local Belgian tertiary care center database, 17 women (age range: 18 to 45 years) with pulmonary autograft valve replacement were enrolled into the study. Twelve pregnancies were observed among five different women, including one miscarriage and one elective abortion. RESULTS: Clinically significant (non-)cardiac complications were documented in two of 10 completed pregnancies. Complications included: (i) placental abruption necessitating Cesarean delivery at 29 weeks' gestation, further complicated by postpartum hemorrhage; and (ii) preterm premature rupture of the membranes resulting in premature delivery at 29 weeks' gestation with postpartum demise of the immature born child. Two women reported primary female infertility, but both became pregnant after hormonal substitution therapy. Four women reported irregularities of their natural menstrual cycle (menorrhagia, dysmenorrhea, polymenorrhea, oligomenorrhea, or amenorrhea). CONCLUSION: Successful pregnancy in women with pulmonary autograft valve replacement is possible, although serious and clinically significant events occurred during gestation. Infertility and menstrual cycle disorders appear to be more prevalent. PMID- 17702366 TI - Outcome after aortic valve replacement: comparison of homografts with mechanical prostheses. AB - BACKGROUND AND AIM OF THE STUDY: Aortic valve replacement (AVR) in younger patients is conventionally performed using a mechanical prosthesis (MP), although homograft (HG) implantation is an accepted alternative. This study compares, retrospectively, the follow up of these two dissimilar prostheses. METHODS: Since 1990, a total of 147 Sorin Bicarbon MPs and 285 HGs have been implanted at the authors' institution, and compared statistically for survival, reoperation rate and valve-dependent complications. Only patients aged <70 years were included in the study. RESULTS: The demographic parameters of both patient groups differed with regards to gender, age at the time of implantation, and duration of follow up. Survival was superior in the HG group (log-rank, p = 0.01). Sixteen of 42 late deaths in the MP group were valve-related due to cerebral infarction (n = 7), ventricular arrhythmias (n = 3), or ventricular failure (n = 6). Six of 24 deaths after HG implantation were valve-related (all prosthesis infections). The choice of valve type and patient age were independent risk factors in the multivariate analysis. Freedom from reoperation was superior after MP implantation (log rank, p = 0.007); in six MP patients the indications for redo surgery were prosthesis infection (n = 2) and paravalvular leak (n = 4). In 20 HG patients, redo surgery was required due to prosthesis infection (n = 12), stenotic degeneration (n = 2), regurgitation > grade II (n = 4), or paravalvular leak (n = 2). Age at the time of implantation and valve type were independent risk factors. Thromboembolic complications were mainly seen in MP patients (log rank, p <0.001): there were five ischemic infarctions and 11 transient ischemic attacks (TIAs) compared to three TIAs among HG patients. Cerebral bleeding was found in only 18 cases after MP implantation, and in no cases after HG implantation. In the multivariate analysis, the type of prosthesis was an independent risk factor. CONCLUSION: As expected, these data confirm a longer time period without need for reoperation after MP implantation, but demonstrate a significantly higher survival and fewer complications after AVR with HG. PMID- 17702367 TI - Non-bacterial thrombotic endocarditis in an adult 14 months after cryopreserved aortic allograft valve implantation. AB - Cryopreserved aortic allograft tissue is used to correct aortic valve disease in adults and to reconstruct the right ventricular outflow tract in children with congenital heart disease. In adults, allograft durability is regarded as comparable to or better than that of manufactured bioprostheses, with failure usually due to slow fibrocalcific degeneration. Normally, allograft semilunar valves have excellent hemodynamics and low rates of infectious endocarditis and thromboembolism. The role of immune-mediated inflammation in post-implant allograft valve performance is slow in onset, and variable. Herein is presented the case of a male adult with rapid deterioration of the aortic valve homograft wall, without loss of the valve leaflets, resulting in severe aortic regurgitation. The pathological findings were consistent with classical marantic (sterile) endocarditis with acute and chronic inflammatory changes associated with advanced atherosclerotic lesions in the allograft aortic wall tissue resulting in thrombosis and subsequent cerebral embolization. PMID- 17702368 TI - One thousand Carpentier-Edwards pericardial valves in the aortic position: what has changed in the past 20 years, and what are the effects on hospital complications? AB - BACKGROUND AND AIM OF THE STUDY: Over the past 20 years, both the typical age and co-morbidity of patients referred for aortic valve replacement (AVR) have increased. In order to assess the effect of these changes on hospital complications, an evaluation was conducted of patient characteristics within this time period. METHODS: This retrospective study included 1,000 consecutive patients who underwent AVR with a pericardial valve. Concomitant coronary artery bypass grafting (CABG) was performed in 610 cases. Among 25 preoperative and five perioperative factors, and eight hospital complications, the changes in incidence that occurred during the periods 1986-1991, 1992-1996, 1997-2001, and 2002-2006, were investigated. Predictive factors for non-cardiac hospital complications required further exploration, as these were the only complications to increase significantly with time; however, this type of complication is less lethal. RESULTS: Significant increases were identified in age, and in the incidence of non-cardiac co-morbidity, previous CABG and preoperative congestive heart failure (p mostly <0.0001). Among hospital complications, only non-cardiac problems showed a significant increase. The independent predictors included previous CABG (p = 0.004), concomitant CABG (p = 0.006), renal impairment (p = 0.008), conduction defects (p = 0.010), previous pacemaker implantation (p = 0.014), chronic obstructive lung disease (p = 0.015), and concomitant carotid artery surgery (p = 0.032). CONCLUSION: During the past 20 years, patients referred for AVR have become older and have more co-morbidity. However, the incidence only of non-cardiac hospital complications was increased. Previous and concomitant surgery, as well as non-cardiac co-morbidity, are important predictors that must be taken into account at referral, but should not contraindicate AVR. PMID- 17702369 TI - Predicted patient outcome after aortic valve replacement with Medtronic Stentless Freestyle bioprostheses. AB - BACKGROUND AND AIM OF THE STUDY: Knowledge on long-term patient outcome after implantation with the Medtronic Stentless Freestyle bioprosthesis is incomplete due to a limited follow up. In the present study, microsimulation was used to extrapolate the available primary data and to calculate the life expectancy and lifetime risks of valve-related events after aortic valve replacement (AVR) with the Freestyle bioprosthesis. METHODS: Eleven-year follow up data from 725 patients (mean age 72 +/- 8 years; range: 36-92 years) who underwent AVR with a Medtronic Freestyle bio-prosthesis were used to calculate the hazards of structural valvular deterioration (SVD) and of other valve-related events. Age dependent Weibull distributions were used to model SVD. These results were incorporated into a mathematical microsimulation model, which then calculated the long-term outcomes for patients of any given age and gender. RESULTS: The annual hazards for thromboembolism and endocarditis were 2.9% and 0.45% per patient year, respectively. For example, for a 72-year-old male patient the median time to SVD was 20.0 (17.8-22.4) years. The life expectancy, reoperation-free life expectancy and event-free life expectancy of this patient was 10.4, 9.7, and 7.2 years, respectively. The patient had a higher life expectancy compared to age and gender-matched persons in the general population. His lifetime risk of reoperation due to SVD was 15%. CONCLUSION: The Medtronic Stentless Freestyle bioprosthesis performs well and offers a low lifetime risk of reoperation for elderly patients requiring AVR. The performance of the valve and the selective patient population might explain the higher life expectancy compared to age and gender-matched persons in the general population. PMID- 17702370 TI - The effect of tip angle on cavitation potential during closure of a bileaflet prosthesis model. AB - BACKGROUND AND AIM OF THE STUDY: Mechanical heart valve (MHV) cavitation has been widely investigated by negative pressure transient (NPT) measurements. Whilst NPT is believed to be the cause of cavitation as the valve occluder approaches its fully closed position, some valves are also more prone to cavitation initiation. The study aim was to determine the effect of tip angle on the occluder trailing edge for the MHV closure flow field and cavitation potential. METHODS: Three pairs of 1:1 transparent bileaflet models, with different tip angles (30 degrees, 60 degrees and 90 degrees), were used in a pulsatile mock loop. Particle image velocimetry (PIV) and micro-tip pressure catheters were applied respectively for the closure flow and transient pressure investigations. A mechanism was designed to enable triggering when the valve occluder approached its closing position. RESULTS: The transient pressure showed two maximum pressure drops, the magnitudes of which differed with various angle designs. A series of flow fields with continuously narrowing gap channels was captured. Different flow features were demonstrated for the three valve models. CONCLUSION: The tip angle design on the occluder trailing edge affected both the NPT magnitude and MHV closure flow field. The 60 degrees and 30 degrees valves had higher vorticity and fluid deceleration rate within the squeeze flow and occluder sudden stop respectively, which correlated with their larger pressure drops for the first and second NPT peaks. PMID- 17702371 TI - Force generation of different human cardiac valve interstitial cells: relevance to individual valve function and tissue engineering. AB - BACKGROUND AND AIM OF THE STUDY: Cardiac valves perform highly sophisticated functions that depend upon the specific characteristics of the component interstitial cells (ICs). The ability of valve ICs to contribute to these functions may be related to the generation of different types of tension within the valve structure. The study aim was to characterize cellular morphology and the forces generated by valve ICs and to compare this with morphology and forces generated by other cell types. METHODS: Cultured human valve ICs, pericardial fibroblasts and vascular smooth muscle cells were seeded in 3-D collagen gels and placed in a device that accurately measures the forces generated. Cell morphology was determined in seeded gels fixed in glutaraldehyde, stained with toluidine blue and visualized using a high-definition stereo light microscope. RESULTS: Valve ICs generated an average peak force of 30.9 +/- 10.4 dynes over a 24-h period which, unlike other cell types tested, increased as cell density decreased (R = 0.67, p <0.0001). The temporal pattern of force generation in mitral valve cells was significantly faster than in aortic or tricuspid cells (p <0.05). Microscopic examination revealed the formation of cellular processes establishing a cell/cell and cell/matrix network. When externally induced changes in matrix tension occurred, the valve ICs unlike the other cell types - did not respond to restore the previous level of tension. CONCLUSION: Human cardiac valve ICs produce a specific pattern of force generation that may be related to the individual function of each heart valve. The specialized function of these cells may serve as a guide for the choice of candidate cells for tissue engineering heart valves. PMID- 17702373 TI - Subdural hematoma after open-heart surgery. AB - Four cases are described of acute subdural hematoma that occurred after valve replacement in patients receiving anticoagulant therapy. All four patients experienced rapid deterioration of consciousness or neurological dysfunction, to varying degrees, between two and 42 days after valve replacement; emergency brain computed tomography scanning demonstrated the presence of subdural hematoma. The neurological problems were completely resolved by removal and drainage of the hematoma in three patients, while conservative management was performed with no aggravation of neurological symptoms in the fourth patient. PMID- 17702372 TI - In-vivo repopularization of a tissue-engineered heart valve in a human subject. AB - A 63-year-old male with a massively calcified aortic valve showed an active lifestyle. Therefore, valve replacement was completed using the Ross procedure. During postoperative echocardiographic control, a ventricular septal defect was noted which was closed surgically. During this reoperation, a biopsy sample was taken from the wall of the tissue-engineered heart valve which was used to reconstruct the right ventricular outflow tract. A persistent monolayer of endothelial cells and host recellularization of the deeper layer was demonstrated histologically. The postoperative course was uneventful, and the patient rapidly recovered. After six years, he remains in excellent health. PMID- 17702374 TI - [Revision of the European Position Paper on Rhinosinusitis and Nasal Polyposis (EP3OS) with particular attention to acute and recurrent rhinosinusitis]. PMID- 17702375 TI - [Bacterial internalization and intracellular activity of quinolones and macrolides]. PMID- 17702376 TI - [New organization will increase donation frequency]. PMID- 17702377 TI - [Vitamin D deficiency--a neglected condition]. PMID- 17702378 TI - [Time is significant in stroke. TIA and stroke are to be investigated immediately -by analogy with chest pain and myocardial infarction]. PMID- 17702379 TI - [Few but potentially severe injuries following intravaginal slingplasty. Reports to the Personskadereglering AB scrutinized]. PMID- 17702380 TI - [Health-related reference intervals for B-type natriuretic peptides. The suitability for decision limits in outpatient care is still not clear]. PMID- 17702381 TI - [There is difference between decision limits and reference intervals. Reference intervals are based on measurements in healthy individuals, decision limits on measurements in patients]. PMID- 17702382 TI - [Computer viruses and computer network breakdowns threaten patient safety. Incident reports or Lex Maria reports required when the patient is at risk]. PMID- 17702384 TI - [Towards an expensive, discriminating health care system]. PMID- 17702383 TI - [Acute aortic dissection in pregnancy--risk of double death]. PMID- 17702385 TI - [Good the silence is interrupted at last!]. PMID- 17702386 TI - [No to for-profit health care]. PMID- 17702387 TI - [Concerning the Medical Society's new guidelines for life support care: let the current ethical decisions be valid]. PMID- 17702388 TI - [The Medical Products Agency's preparations prior to the new EU regulation on children and drugs]. PMID- 17702389 TI - [Dangerousness and harmlessness of the HPV vaccine]. PMID- 17702390 TI - [Cyclic nucleotide phosphodiesterase IV expression, activity and targeting in cells of cardiovascular system]. AB - Cyclic nucleotide second messages (cAMP and cGMP) play a central role in signal transduction and regulation of physiologic responses. The only way to inactivate them is to degrade them through the action of phosphodiesterases (PDEs). Recent advances show that PDE4, a cAMP specific phosphodiesterase, has specific functions in regulating the activities of the cardiovascular system. PDE4 is expressed in the cells of cardiovascular systems including cardiomyocytes, vascular smooth muscle cells, and vascular endothelial cells. The expression level of PDE4 is shown to be downregulated in the failure hearts, while it is upregulated in hypertrophied hearts. And PDE4 deficiency in mice is associated with a cardiac phenotype comprised of a progressive, age-related cardiomyopathy, accelerated heart failure after myocardial infarction and exercise-induced arrhythmias. Local levels of cAMP regulate the precise opening of the ryanodine receptor complex (RyR2) which releases calcium at the start of a heartbeat. Loss or inhibition of PDE4 activity increases calcium flow through RyR2, and causes leakiness and heart failure in mice. These finding may show us a new target for treating cardiovascular diseases. PMID- 17702391 TI - [Natural products in clinical trials: antiparasitic, antiviral and neurological drugs]. AB - This paper describes natural products, semi-synthetic natural products and natural product-derived compounds used for treating antiparasitic, antiviral and neurological disease that were being evaluated in clinical trials or in registration from 1998 to the end of 2005. PMID- 17702392 TI - [Protective effects of breviscapine against cultured rat hippocampal neuronal toxicity induced by glutamate]. AB - The aim of this study was to investigate the effects of breviscapine on cultured rat hippocampal neuronal toxicity induced by glutamate. Primary hippocampal neurons were prepared from 2 day-old SD rats. After 8 days cultured in vitro, the cultures subjected to 30 min treatment of 0.1, 0.5 and 1.0 mmol x L(-1) L glutamate, separately. Breviscapine (10, 20 and 40 micromol x L(-1)) was added into the cultures during 30 min treatment of L-glutamate and for the following 24 h respectively. After 24 h of L-glutamate treatment, flow cytometric analysis of Annexin V (marks apoptosis) and PI (propidium iodide, marks necrosis) labeling cells showed that L-glutamate dose-dependently induced hippocampal neuronal apoptosis and necrosis. In agreement with these results, RT-PCR experiments indicated a biphasic regulation of X-chromosome-linked inhibitor of apoptosis protein (XIAP) mRNA after L-glutamate treatment, i. e up-regulation by 0.1 mmol x L(-1) L-glutamate and down-regulation by 0.5 and 1.0 mmol x L(-1) L-glutamate. However, breviscapine markedly reduced apoptosis and necrosis due to toxicity of 0.5 mmol L(-1) L-glutamate. Compared with the vehicle-treated L-glutamate group, the apoptosis was reduced by 30.4% and 40.1%, and necrosis was reduced by 32.5% and 38.8%, after treatment by breviscapine of 20 and 40 micromol x L(-1). Meanwhile, breviscapine obviously reversed the down-regulation of XIAP expression induced by L-glutamate (up-regulation by 45.1% and 54.9% when compared with that of the vehicle-treated glutamate group). The results from the detection of confocal laser scanning microscopy with Fluo-3, a Ca2+ probe showed an obvious increase in intracellular Ca2+ during L-glutamate treatment; and breviscapine of 20 or 40 micromol x L(-1) significantly slowed down glutamate-induced Ca2+ influx and lowered the intracellular Ca2+ peak in hippocampal neurons (P < 0.01). These results suggest that neuroprotective effect of breviscapine against glutamate excitotoxicity was associated with inhibition of the accumulation of intracellular Ca2+ and up-regulation of XIAP expression in hippocampal neurons. PMID- 17702393 TI - [Simultaneous determination of the inhibitory potency of compounds on the activity of five cytochrome P-450 enzymes using a cocktail probe substrates method]. AB - This study developed a method for simultaneously assessing the inhibitory potency of compounds on five major cytochrome P-450 ( CYP450) enzymes using a cocktail of probe substrates. A cocktail selective substrates consisting of the phenacetin (PN, CYP1A2), dextromethorphan (DM, CYP2D6), tolbutamide (TB, CYP2C9), omeprazole (OPZ, CYP2C19) and midazolam (MPZ, CYP3A4) was incubated with human liver microsomes. The concentrations of the substrate metabolites paracetamol, dextrorphan, 4-hydroxytolbutamide, 5-hydroxyomeprazole and 1'-hydroxymidazolam were determined by LC/MS/MS in a single assay sample. The method was validated by incubating known CYP inhibitors--alpha-naphthoflavone (ANF, CYP1A2), quinidine (QND, CYP2D6), sulfaphenazole (SUL, CYP2C9), fluconazole (FLU, CYP2C19) and ketoconazole (KET, CYP3A4) with the individual substrates and with the substrate cocktail. The IC50 values were then determined. The IC50s (micromol x L(-1)) were in good agreement with those obtained with individual substrates (alpha naphthoflavone, 0.18 vs 0.26; quinidine, 0.058 5 vs 0.058 4; sulfaphenazole, 0.48 vs 0.45; fluconazol, 17.5 vs 11.4; ketoconazole, 0.22 vs 0.24) and with previously reported values in the literature. This cocktail probe substrate method can be utilized for the rapid simultaneous determination of the inhibition potential of compounds on the five CYP450 enzymes. PMID- 17702394 TI - [In vitro anti-angiogenic action of lambda-carrageenan oligosaccharides]. AB - This study was designed to evaluate the inhibition effect of lambda-carrageenan oligosaccharides on neovascularization in vitro by chick chorioallantoic membrane (CAM) model and human umbilical vein endothelial cell ( HUVEC). lambda Carrageenan oligosaccharides caused a dose-dependent decrease of the vascular density of CAM, and adversely affected capillary plexus formation. At a high concentration of 1 mg x mL(-1), this compound inhibited the endothelial cell proliferation, while low concentration of lambda-carrageenan oligosaccharides (< 250 microg x mL(-1)) affected the cell survival slightly (> 95%). Different cytotoxic sensitivity of lambda-carrageenan oligosaccharides in three kinds of cells was observed, of which HUVEC is the most sensitive to this oligosaccharides. The inhibitory action of lambda-carrageenan oligosaccharides on the endothelial cell invasion and migration was also observed at relatively low concentration (150 - 300 microg x mL(-1)) through down-regulation of intracellular matrix metalloproteinases-2 (MMP-2) expression on endothelial cells. Current observations demonstrated that lambda-carrageenan oligosaccharides are potential angiogenesis inhibitor with combined effects of inhibiting invasion, migration and proliferation. PMID- 17702396 TI - [Synthesis of methotrexate-poly (ethylene glycol) conjugate and their anti-tumor activity in vitro]. AB - To improve the physical property and bioactivity of methotrexate, this paper investigated the new formation of conjugate methotrexate-poly (ethylene glycol) and in vitro anti-tumor activity of the synthesized conjugate. The conjugate of methotrexate-poly (ethylene glycol), which was verified by the spectroscopy analysis of UV, IR and 13C NMR, was synthesized by chemical catalysis and micro wave irritation. The determination for the conjugate of solubility in water and distribution coefficient in octanol-water system of the conjugate was done to examine its deliquescence property. The solubility in water and the distribution coefficient of the conjugate was greatly improved, which was increased by 128 folds and 5 folds, respectively. The in vitro anti-tumor activity of the conjugate was tested by mouse L(1210) leukaemia cells, and the synthesized conjugate showed the same anti-tumor activity as the original methotrexate. Compared to the reported literature, the modification of methotrexate by poly (ethylene glycol) is more rapid and convenient. PMID- 17702395 TI - Effect of resveratrol on baroreceptor activity of carotid sinus in anesthetized male rats. AB - This study is to evaluate the effect of resveratrol on carotid baroreceptor activity (CBA). The functional curve of carotid baroreceptor (FCCB) was constructed and the functional parameters of carotid baroreceptor were measured by recording sinus nerve afferent discharge in anesthetized male rats with perfused isolated carotid sinus. Resveratrol (30, 60 and 120 micromol x L(-1)) inhibited CBA, which shifted FCCB to the right and downward. There was a marked decrease in peak slope (PS) and peak integral value (PIV) of carotid sinus nerve charge in a concentration-dependent manner. Pretreatment with N(omega)-nitro-L arginine methyl ester (L-NAME, 100 micromol x L(-1)), an inhibitor of nitric oxide synthase (NOS), eliminated the inhibitory effect of resveratrol. Pretreatment with Bay K8644 (an agonist of L-type calcium channel, 500 nmol x L( 1)) abolished the effect of resveratrol on CBA. A potent inhibitor of tyrosine phosphatase (sodium orthovanadate, 1 mmol x L(-1)) did not influence the effect of resveratrol on CBA. Resveratrol inhibits carotid baroreceptor activity, which may be mediated by the locally released NO and decreased calcium influx. Several studies have showed a cardioprotective effect of resveratrol, with the penetrating study of resveratrol, it may show a potential value in the clinical treatment of cardiovascular disease as an alternative medicine. PMID- 17702397 TI - [Preparation and biological activity of poly (gamma-glutamic acid) -cisplatin conjugate]. AB - Preparation of a poly (gamma-glutamic acid)-cisplatin conjugate was introduced and its in vitro antitumor effect was investigated. Poly (gamma-glutamic acids) was obtained by using fermentation methods. The hydrolyzed small molecular weight of poly (gamma-glutamic acids) was prepared by acid hydrolysis. The interaction between poly (gamma-glutamic acids) -cisplatin conjugate (PGA-CDDP) and DNA was investigated by PCR model. MTT assay was used to investigate the in vitro anticancer activity of the conjugate. Apoptosis assay of the conjugate was investigated by FCM assay and the in vivo toxicity was also proceeded. The results showed that the poly (gamma-glutamic acids) -cisplatin conjugate was obtained successfully and its yield is 10% - 12%. It has obvious antitumor effects on human liver tumor BEL7404 cells, human lung tumor H446 cells and human colon tumor RKO cells. At the same time, it also has apoptosis effects on the three kinds of tumor cell lines. The in vivo toxicity of PGA-CDDP was examined in normal mice and the results showed that the in vivo toxicity of this conjugate was significantly lower than that of free CDDP. In conclusion, the poly (gamma glutamic acids) -cisplatin conjuate could be used as a potential clinic antitumor drug. The poly (gamma-glutamic acids) obtained by fermentation can be used as a valuable drug carrier system. PMID- 17702398 TI - A new alkaloid from Salsola collina. AB - Salsola collina is widely distributed in droughty and semi-droughty area, which is used as a kind of folk remedy in traditional Chinese medicine for treatment of hypertension. The study is on the chemical constituents of this herb from its aerial parts to obtain its active constituents. Dried and crushed aerial parts of this herb were extracted three times with 95% EtOH at reflux. The ethanol extracts were combined and concentrated under reduced pressure at 70 degrees C to yield residue, which was suspended in water and successively partitioned with light petroleum, chloroform and n-butanol. The chloroform and n-butanol fractions were treated by various chromatographic techniques, such as silica gel, C18 reversed-phase silica gel and macroporous resin column chromatography. Compounds were elucidated by their physicochemical properties and spectroscopic analysis. In the course of our study on searching biological active components from this herb, a new alkaloid together with three known alkaloids were isolated and identified as N-transferuloyl-3-methyldopamine (1), 3-[4-(beta-D glucopyranosyloxy)-3-methoxyphenyl]-N-[2-(4-hydroxyl-3-methoxyphenyl) ethyl]-2 propenamide (2), salsoline A (3), salsoline B (4). Compound 4 is a new compound and named as salsoline B, while compound 2 was obtained in Salsola collina for the first time. PMID- 17702399 TI - [Chemical constituents of Ligularia duciformis]. AB - Ligularia duciformis is a plant of the Ligularia genus (Compositae) which has been reported to have therapeutic effects of treating diseases such as bronchitis and coughing. In order to find out the bioactive components, the 85% ethanol extract of the root and rhizome of L. duciformis was treated by solvents extraction and column chromatography on silica gel and Sephadex LH-20. Six compounds were obtained from the ethyl acetate fraction and identified as 3 methoxy-4-hydroxyphenylpropyl caffeate (I), 6beta, 8beta-dihydroxyeremophil-7 (11)-en-12, 8alpha-olide (II), 6beta, 8alpha-dihydroxyeremophil-7 (11)-en-12, 8beta-olide (III), 6beta-hydroxyeremophil-7 (11)-en-12, 8alpha-olide (IV), stigmasterol (V) and beta-daucosterol (VI) by analysis of their physic-chemical constants and spectral data. Compound I is a new compound and compounds II - V were isolated from L. duciformis for the first time. The antitussive effect of the compounds is under evaluation. PMID- 17702400 TI - Chemical constituents from leaves of Celastrus gemmatus Loes. AB - To study the chemical constituents from the leaves of Celastrus gemmatus Loes., chromatographic methods were used to isolate and purify the chemical constituents, their structures were elucidated by the physiochemical characteristics and spectral data. Nine compounds were obtained and identified as (-)-massoniresinol 3a-O-beta-D-glucopyranoside (1), ambrosidine (2), isolariciresinol 9-O-beta-D-glucopyranoside (3), kaempferol 3-O-beta-D glucopyranoside (astragalin) (4), kaempferol 3-O-rutinoside (5), kaempferol 3-O neohesperidoside (6), apigenin 7-O-beta-D-glucuronide (7), apigenin 7-O-beta-D glucuronide methyl ester (8) and D-sorbitol (9). Compound 1 is a new compound, the others are isolated from this genus for the first time, and this is the first time to report lignan compounds from genus Celastrus. PMID- 17702401 TI - [Development and identifiability analysis of parent-metabolite pharmacokinetic model for risperidone and its main active metabolite 9-hydroxyrisperidone]. AB - To develop a parent-metabolite pharmacokinetic model for risperidone (RIP) and its major active metabolite (9-hydroxyrisperidone) and investigate their pharmacokinetics characteristics in healthy male volunteers, twenty-two healthy volunteers were orally given a single dose of 2 mg RIP. Plasma samples were collected in the period of 96 hours and concentrations of RIP and 9 hydroxyrisperidone were measured by a validated HPLC/MS method. CYP2D6 phenotypes were identified by the T1/2 of RIP and 9-hydroxyrisperidone according to the literature. Model structure identifiability analysis was performed by the similarity transformation approach to investigate whether the unknown parameters of the proposed model could be estimated from the designed experiment. Pharmacokinetics parameters were estimated using weighted least squares method, and the final pharmacokinetics model were tested and evaluated by Monte Carlo simulation. Eighteen volunteers were phenotyped as extensive metabolizers (EM) and four volunteers were identified as intermediate metabolizers (IM). The final model included central and peripheral compartment for both parent (RIP) and metabolite (9-hydroxyrisperidone) respectively. Model structure identifiability analysis indicated that the proposed model was local identifiable. However, if the ratio of RIP converted to 9-hydroxyrisperidone was assumed to be 32% in EM, and 22% in IM, the model could be globally identifiable. The predicted time concentration curve and AUC(0-t), C(max), T(max) of RIP and 9-hydroxyrisperidone estimated by the established model were in agreement with the observations and noncompartment analysis. Rate constant of RIP conversion to 9-hydroxyrisperidone was (0.12 +/- 0.08) h(-1) and (0.014 +/- 0.007) h(-1) for EM and IM, respectively. Elimination rate constants of RIP were (0.25 +/- 0.18) and (0.05 +/ 0.23) h(-1) for EM and IM, respectively. Model validation result showed that all parameters derived from the concentration data fitted well with the theoretical value, with mean prediction error of most PK parameter within +/- 15%. The established model well defined the disposition of RIP and 9-hydroxyrisperidone simultaneously and showed large inter-individual pharmacokinetics variation in different CYP2D6 phenotype. The model also provide a useful approach to characterize pharmacokinetics of other parent-metabolite drugs. PMID- 17702402 TI - [Related substances in purified alliin determined by HPLC-MS/MS]. AB - To study the related substances in purified alliin, HPLC-MS/MS method carried out on a Phenomenex NH2 column was used for screen and identification of the related substances with full scan MS spectra determination of their [M + H] + ions and then the analyses of the retention time, product MS spectra and/or chemical reference standards. The full scan HPLC-MS chromatogram showed that there were seven major related substances in the purified alliin and their m/z of the [M + H] + ions with increasing retention were 116, 133, 147, 152, 175, 178 and 178, separately. And they were identified as proline, asparagine, glutamine, methiin, arginine, isoalliin and cycloalliin (both were isomers of alliin), respectively. The major related substances in purified alliin are amino acids, homologen and the isomers of alliin. PMID- 17702403 TI - [Interaction between anticancer drugs and DNA studied by using electrospray ionization mass spectrometry]. AB - To elucidate further sequence selectivity and nature of the binding of anticancer drugs to DNA, the interaction between anticancer drugs, which are minor groove ligands (distamycin A, DM and netropsin, NP) and intercalator (mitoxantrone, MT), and DNA were studied by electrospray ionization mass spectrometry. The 2 : 1 specific complex of DM and AT-rich DNA were observed principally, while only 1 : 1 specific complex of NP and AT-rich DNA were observed. MT specifically binds to GC-rich DNA. In addition, DM binds to DNA containing 5 A/T bases minor groove almost in a 2 : 1 mode and does not bind to DNA containing 3 A/T bases minor groove. NP binds most strongly to DNA containing 4 A/T bases minor groove. The 1 : 1 specific complex of MT and 6-mer DNA was also observed. The result of competitive binding experiment shows that DM binds more strongly to AT-rich DNA than NP does. These results provide bases for investigating the mechanism of interaction between the drugs and DNA and for improving the structure of target drug. PMID- 17702404 TI - [Preparation and characterization of the puerarin submicron emulsion]. AB - To decrease the hemolysis side effect of puerarin, the basic formula and preparation of puerarin submicron emulsion were optimized and the physicochemical properties were evaluated. Puerarin submicron emulsions were prepared by phase inversion-ultrasound combining with phospholipids complexes technology. The effects of preparative parameters, such as emulsification time, stirring velocity and ultrasound time, on mean diameter, span of dispersity, entrapment efficiency and overall desirability were investigated. The three dimensional response surface graphs were produced by second-order polynomial and liner equation, which predict the optimal experiment conditions. All response variables were found to be greatly dependent on three independent variables. Second-order polynomial equations were fitter than liner equations for this study. The optimal emulsification time, stirring velocity and ultrasound time was 15 min, 2 000 r x min(-1), 30 min, respectively. The mean diameter, span of dispersity, entrapment efficiency, drug content and zeta potential of emulsions prepared by the method were 228.23 nm, 0.628 4, 84. 32%, 9.98 mg x mL(-1), - 29.03 mV, respectively. Puerarin submicron emulsion was prepared by the optimized preparation method. The narrow particle diameter distribution, high envelopment efficacy and good stability were obtained. The physicochemical properties were suitable for the requirement of the intravenous emulsion. PMID- 17702405 TI - Guar gum/ethylcellulose coated pellets for colon-specific drug delivery. AB - The aim of this work was to investigate guar gum/ethylcellulose mix coated pellets for potential colon-specific drug delivery. The coated pellets, containing 5-fluorouracil as a model drug, were prepared in a fluidized bed coater by spraying the aqueous/ethanol dispersion mixture of guar gum and ethylcellulose. The lag time of drug release and release rate were adjustable by changing the ratio of guar gum to ethylcellulose and coat weight gain. In order to find the optimal coating formulation that was able to achieve drug targeting to the colon, the effect of two independent variables (the ratio of guar gum to ethylcellulose and the coat weight gain) on drug release characteristics was studied using 3 x 4 factorial design and response surface methodology. Results indicated that drug release rate decreased as the proportion of ethylcellulose in the hybrid coat and the coat weight gain increased. When the ratio of guar gum to ethylcellulose was kept in the range of 0.2 to 0.7, and the coat weight gain in the range of 250% to 500%, the coated pellets can keep intact for about 5 h in upper gastrointestine and achieve colon-specific drug delivery. The pellets prepared under optimal conditions resulted in delayed-release sigmoidal patterns with T(5%) (time for 5% drug release) of 5.1 - 7.8 h and T(90%) (time for 90% drug release) of 9.8 - 16.3 h. Further more, drug release was accelerated and T(90%) of the optimum formulation pellets decreased to 9.0 - 14.5 h in pH 6.5 phosphate buffer with hydrolase. It is concluded that mixed coating of guar gum and ethylcellulose is able to provide protection of the drug load in the upper gastrointestinal tract, while allowing enzymatic breakdown of the hybrid coat to release the drug load in the colon. PMID- 17702406 TI - [Characteristics of nobiletin-loaded nanoemulsion and its in vivo distribution in mice]. AB - The purpose of this study was to prepare the nobiletin-loaded nanoemulsions (NOB NE) and study its in vivo distribution in mice. The characteristics and stability of the unloaded and drug-loaded nanoemulsions were investigated. The size, apparent viscosity and pH value of NOB-NE were respectively (15.5 +/- 2.9) nm, (3.10 +/- 0.33) mPa x s and 6.56 +/- 0.05, which were all higher than those of unloaded nanoemulsions. The zeta potential of unloaded and drug-loaded nanoemulsions carried negative charge. The NOB-NE after diluted by 5% glucose solution was stable in 8 h, and there was no significant difference in the size, content and diluted stability of its preconcentrate in long-term storage. The concentration of nobiletin in plasma and tissues was determined by HPLC after intravenous administration of NOB-NE. Based on AUC(0-t), MRT and C(max), the nanoemulsions delivered more nobiletin into the brain and kidney compared to those of nobiletin solution. The brain and kidney targeting efficiency was improved. In addition, the results fitting using SAAM II software show that the higher drug concentration of the NOB-NE in the brain might be owed to the quicker transport rate from the blood to the brain, and that in the kidney relate to the probable accumulation effect. These results indicate that the in vivo distribution of NOB-NE with consistent quality in mice could be changed and its brain and kidney targeting absorption capability was enhanced comparing with nobiletin solution. PMID- 17702407 TI - [Dextran-spermine polycation as a vector for gene transfection in vitro]. AB - This work reports the properties of dextran-spermine polycation (DSP) as a gene vector and its gene transfection efficiency in vitro. Oxidized dextran was reacted by reductive amination with spermine to obtain DSP, the resulted polycation was then incubated with plasmid pEGFP to form polyplexes by electrostatic interactions. DSP formed stable polyplexes when the weight ratio (DSP/DNA) varied from 4 : 1 to 20 : 1. The particle size and zeta potential of polyplexes were in the range of 162.6 - 187.9 nm and increased from + 8.45 mV to + 39.6 mV, respectively. DSP could effectively protect condensed DNA from DNase I degradation, and it showed strong buffering capacity in a certain pH range. The highest yields of transfection efficiency were found to be as high as Lipofectamine 2000 when the polyplexes were transfected to SMMC-7721 and BHK-21 cells at the weight ratio of 8 : 1. This research indicates that dextran-spermine polycation is a highly active gene vector in vitro. PMID- 17702408 TI - [Improving the solubility of fraxinellone to increase its oral bioavailability and hepatoprotective action against acute liver injury in mice]. AB - Fraxinellone, the major component of Cortex Dictamni, is naturally degraded limonids compound. Fraxinellone has significant anti-inflammatory activity in acute liver injury model. However, the low solubility and permeability of fraxinellone limited its potential application and even therapeutic effects. The aim of the paper is to increase oral bioavailability of fraxinellone, thus improving its hepatoprotection effect in vivo. We evaluated the effects of different pH values and different solubilizer (PEG 6000, PVP K30, HP-beta-CD, F68 and SDS) on the solubility of fraxinellone. The results showed that HP-beta-CD increased solubility of fraxinellone up to 155 times compared to that of water. More than 2. 1 mg mL1 fraxinellone can be resolved when adding 20% HP-beta-CD. Mouse acute liver injury model induced hy CCl4 was used to evaluate in vivo activity of fraxinellone with or without HP-beta-CD. The result shows that the hepatoprotective activity of fraxinellone in 20% HP-beta-CD solution has been significantly improved compared with that of fraxinellone solution without HP beta-CD: the former inhibited 59 percent the increase of enzyme activity of ALT in liver, while the latter only inhibited 20 percent. A LC-MS/MS method was also developed to determine the oral bioavailability of fraxinellone. Fraxinellone solution with or without HP-betaCD were administered intra-gastrically to rats, and it was found that the bioavailahility of fraxinellone with HP-beta-CD was 23%, while only 5% without HP-beta-CD. The result showed that HP-beta-CD can significantly increase the solubility and permeability of fraxinellone, and improve bioavailability 3. 5 fold in vivo acute liver injury model as well as administration. PMID- 17702409 TI - [The hypocalcemia effect of salmon calcitonin ultra-flexible liposomes after intranasal administration in rats]. AB - This article describes the preparation of salmon calcitonin ultra-flexible liposomes and their hypocalcemia effect after intranasal administration in rats. Both the conventional liposomes and ultra-flexible liposomes were prepared by rotary evaporation-sonication and extrusion. The morphology of ultra-flexible liposomes was observed with transmission electronic microscope. The size and size distribution and their zeta potential were determined by dynamic light scattering. The mean size of ultra-flexible liposomes with DC-Chol was no more than 120 nm, while the mean size of the conventional liposomes was 256.5 nm. The results showed the content of sodium deoxycholate have significant effect on the mean particle size of liposomes. The ultra-flexible liposomes were intranasal administrated at the dose of 5.0 microg x kg(-1); the concentration of serum calcium was determined by OCPC method. The results showed that the salmon calcitonin solution only slightly lowered serum calcium levels and the conventional liposomes could improve the effect of decreased serum calcium level (D%), and the ultra-flexible liposomes had the best effect on the decreased serum calcium level, and the hypocalcemia effect was correlated with the content of sodium deoxycholate which was present in the liposomes. Moreover the ciliotoxicity of ultra-flexible nanoliposomes on nasal mucocilia was investigated with the electron microscope scanning. The results showed that the ultra-flexible liposomes markedly reduced the ciliotoxicity of sodium deoxycholate on nasal mucous. Thereby the ultra-flexible liposomes significantly enhanced the hypocalcemia effect of serum calcium after intranasal administration in rats. The ultra-flexible liposomes could be an effective carrier for intranasal delivery of the peptide and protein drugs. PMID- 17702410 TI - [Present status and future work of the head and neck surgery]. PMID- 17702411 TI - [Clinical analysis of dermatofibrosarcoma protuberans in head and neck]. AB - OBJECTIVE: To evaluate the prognosis of dermatofibrosarcoma protuberans (DFSP) in head and neck after deferent treatment. METHODS: The clinical data of 28 cases of DFSP in head and neck from 1982 to 2005 were analyzed retrospectively. Eleven cases were treated with wide excision, and 17 with limited excision. Twenty four cases had surgical resection alone (S), and 4 preoperative or postoperative radiotherapy (S + R) of 40-65 Gy. Eighteen cases received immediate reconstruction. RESULTS: The overall recurrence rate was 21.4% (6/28), the recurrence rate of wide excision group was 0 (0/11), compared with 35.3% (6/17) in the limited excision group (P = 0.033); the recurrence rate of S + R group was 0 (0/4), compared with 25.0% (6/24) in S group, but there was no significant deference (P = 0.357). The overall 5-year survival rate was 88.9%. The 5-year recurrence free survival rate was 100% in wide excision group, compared with 59.6% in the limited excision group (chi2 = 3.933, P = 0.047). CONCLUSIONS: Wide excision could significantly reduce the recurrence rate of DFSP in head and neck, when the adequate margin couldn't be achieved or the excision margin was positive, adjuvant radiotherapy might be helpful. The immediate reconstruction was necessary when the defect was large. PMID- 17702412 TI - [Multi-modalities for reconstruction of circumferential defects in the pharyngoesophageal region]. AB - OBJECTIVE: To investigate the feasibility of multi-modalities in the reconstruction of circumferential defects after resection of cancers in pharyngoesophageal regions, and to compare the pros and cons between different surgical procedures. METHODS: According to the nature and extend of defects, five different methods including pectoralis major myocutaneous flap, laryngeal tube replacement, free jejunum, free forearm flap and gastric pull-up were used to reconstruct the circumferential pharyngoesophageal defects in 72 patients. Function of deglutition and restoration of swallowing was regularly followed up and objectively evaluated. RESULTS: A total of 35 cases of pectoralis major myocutaneous (PM) flaps, 8 cases of laryngeal tube replacement, 12 cases of free jejunum, 12 cases of free forearm flaps and 16 cases of gastric pull-up were performed. Different complications including wound infection, pharyngeal fistula, partial necrosis of PM flap, partial necrosis of gastric wall, stricture of anastomotic site were encountered in 15 cases. All patients survived the operation except one due to partial necrosis of the gastric wall. Two of 4 patients who developed anastomotic stricture can ingest half-liquid food, the remaining cases regained normal deglutition function. The mean postoperative follow-up time was 1. 6 years with 2-year survival rate of 45.3%. CONCLUSIONS: Circumferential defects resulting from resection of carcinomas in pharyngoesophageal region can be reconstructed with different operative techniques depending on the nature and extend of the defects. Once the operative indications are properly selected, the good reconstructive results are to be achieved. PMID- 17702413 TI - [Investigation of the characters of cervical lymph node metastases of primary malignant tumor beyond head and neck]. AB - OBJECTIVE: To investigate the characters of cervical lymph node metastases of primary tumors beyond head and neck. METHODS: Among 466 cases of malignant tumor with cervical lymph node metastases treated in Peking Union Medical College Hospital from January 1989 to June 2004, 77 cases of tumor which sites primarily beyond head and neck were studied. Retrospective analysis of their clinical characters was done by LEVEL system. RESULTS: The primary sites of these 77 cases of malignant tumor consisted of lung, stomach, esophagus, galactophore, colon, mediastinum, ovary, uterus, pancreas, liver, mesentery, adrenal gland and rectum. The frequency of cervical lymph node metastases was 81.8% (63/77) in LEVEL V (50 in the left), 11.7% (9/77) in LEVEL IV, 5.2% (4/77) in LEVEL III, 1.3% (1/77) in LEVEL I separately. The proportion of the metastases of malignant tumor from primary site beyond head and neck in each region was 2.1% in LEVEL I, 3.7% in LEVEL III, 14.3% in LEVEL IV, 70.8% in LEVEL V. Among the cervical lymph node metastases of primary tumor beyond head and neck, 51.9% were low-grade adenocarcinoma, 15.6% were medial-grade adenocarcinoma, 11.7% were low-grade squamous cell carcinoma, 10.4% were medial-grade squamous carcinoma. CONCLUSIONS: The cervical lymph node metastases of malignant tumor might be seen from many organs beyond head and neck. The metastases from primary sites beyond head and neck usually focus on LEVEL V (81.8%), especially in the left. And the primary tumors beyond head and neck metastasis in this region were more than the tumors from head and neck locally. The histological type of the primary tumors were frequently low-medial grade carcinomas. PMID- 17702414 TI - [Surgical approaches for different stages of nasopharyngeal angiofibromas]. AB - OBJECTIVE: To explore the optical surgical approaches for the resection of early and advanced stage of nasopharyngeal angiofibromas. METHODS: Twenty two male patients aged 9 - 30 years (median 16 years) hospitalized in Xiangya Hospital from June 2003 to July 2006 with nasopharyngeal angiofibroma were recruited. Five operative approaches were selected according classification of juvenile nasopharyngeal angiofibroma described by Fisch. Six cases with stage I nasopharyngeal angiofibroma underwent endoscopic transnasal surgery. Six cases with stage II and 2 cases with stage III underwent endoscopic endonasal middle meatal transmaxillary-antrum approach. Three cases with stage III and 2 cases with stage IV underwent endoscopic endonasal middle and inferior meatal approach with extended transmaxillary-antrum resection. One case with stage IV underwent microscopic preauricula infratemporal fossa approaches combined with endoscopic endonasal middle and inferior meatal transantral approach. Two cases with stage IV underwent nasomaxillary osteotomy approach. RESULTS: After surgery, CT scan or MR image showed that total removal of the tumor was achieved in 21 patients. One patient who received subtotal resection were performed by second endoscopic surgery and obtained total resection. No postoperative complications have been encountered in all treated patients. Nine months to 3 years follow up indicated that no cases recurred after surgery. CONCLUSIONS: Appropriate surgical approach should be selected according to the clinical classification and whether the tumor has extended into whole nasal cavity, lateral fossa infratemporalis, intracranial or not. Such approaches might better facilitate the complete removal of nasopharyngeal angiofibromas and reduce the surgery-related injury. PMID- 17702415 TI - [Gene mapping for autosomal dominant nonsyndromic hearing loss DFNA11]. AB - OBJECTIVE: To map the gene locus in a Chinese pedigree with autosomal dominant nonsyndromic hearing loss. METHODS: A genome wide screening was performed with 394 microsatellite markers distributed with an average spacing of 10 cM (ABI Prism Linkage Mapping Set 2, Applied Biosystems, Foster City, CA, U.S.A.). RESULTS: Affected family members showed a bilateral, symmetrical, progressive neurosensory deafness. Significant linkage was found to marker D1 S937 (maximum two point LOD score of 5. 71 at theta = 0.05) on chromosome 11q. The position of the novel deafness locus, DFNA11, was delimited by analysis of the recombinant haplotypes (D11S165-D11S1874). This analysis placed DFNA11 between the proximal marker D11S1314 and the distal marker D11S898, which define a critical interval of 25.34 cM. CONCLUSIONS: Mapping of the DFNA11 locus further confirms the great genetic heterogeneity underlying the autosomal dominant forms of hereditary deafness. Reports of more families with hearing impairment linked to this locus should contribute to the identification of the responsible gene, providing insights into the auditory function and the molecular pathophysiology of age related hearing loss. PMID- 17702416 TI - [One case of cholesteatoma in middle ear]. PMID- 17702417 TI - [Diagnosis and therapy for benign paroxysmal positional vertigo of the anterior semicircular canal]. AB - OBJECTIVE: To analyse the video-oculographic findings of positional tests and evaluate the efficacy of canalith repositioning procedure (CRP) in patients with paroxysmal positional vertigo ( BPPV) of the anterior semicircular canal (ASC). METHODS: A retrospective study of 31 patients with ASC BPPV. Then the CRP was performed. RESULTS: Twenty-two individuals (70.97%) presented a unilateral positional nystagmus during the Dix-Hallpike test, in 17 individuals had torsional nystagmus component, 5 individuals only had pure positional down beat nystagmus. Nine patients presented bilateral positional nystagmus, 7 individuals had torsional component positional nystagmus, in 2 patients the direction of the torsional component were the same during right and left Dix-Hallpike test, in 4 patients the torsional component were concurrent with positional down beat nystagmus but the direction could not be ascertained clinically, in 2 patients had pure positional down beat nystagmus. Nineteen patients (61.29%) had unilateral lesion, 11 patients had the left ASC BPPV, 8 patients had right ASC BPPV. Eleven patients had with both ASC and PSC BPPV in the ipsilateral. Twenty one patients (67.74%) were cured, 29 patients (93.55%) were improved, 2 (6.45%) patients were inefficacy. CRP effectively resolved the nystagmus and vertigo in 14 patients (45.16%) when applied only once, The average number of CRP was 1.7 times, there were 5 patients recurrence during the follow-up. CONCLUSIONS: ASC BPPV was not a common condition. The torsional nystagmus component of ASC BPPV might be weak during the Dix-Hallpike test. The positional nystagmus of ASC BPPV was triggered bilaterally. Based on these findings, CRP could be one of the most effective treatment methods for ASC BPPV. PMID- 17702418 TI - [Clinical types, diagnosis and endoscopic surgery of choanal polyps]. AB - OBJECTIVE: To investigate the clinical type, diagnosis and prognosis of endoscopic surgery of choanal polyp (CP). METHODS: Thirty four cases of CP treated between January 1998 to December 2005 were retrospectively reviewed. Pathogenesis, original sites, clinical manifestation, its relationship with paranasal sinuses, methods and effects of endoscopic surgery on CP were analysed. RESULTS: (1) In this study, 18 cases originated from the cyst or polyp in sinus (among them, 17 from maxillary sinus, 1 from posterior ethmoid sinus). (2) Five cases from nasal fontanelles or sphenoethmoidal recess, mucosa of sphenoidal ostium, accompanied with homolateral empyema or mucosal edema of maxillary sinus or sphenoid sinus. (3) Eleven cases from middle turbinate, uncinate process, olfactory cleft, nasal septum and anterior wall mucosa of ethmoidal sinus with normal adjacent sinus. (4) All cases were treated by complete excision of the CP and open sinus procedures of the affected ones with intranasal endoscopic approach. No recurrence was observed during the follow-up. CONCLUSIONS: (1) We propose to divide the CP into three clinical types: intrasinus, sinus obstruction and simple ones. We also suggest to abide by the operation principal based on clinical types and to select rational methods and extent of operation. (2) Definite diagnosis and clinical type can be obtained by endoscopic examination and CT scan of sinus before operation. (3) Endoscopic surgery is precise and mini invasive in treatment of CP and complete removal of CP root can effectively reduces the recurrence. PMID- 17702419 TI - [Morphological study of adenoid by endoscopy and its clinical significance]. AB - OBJECTIVE: To observe the natural process of adenoid growth and degeneration as the age grows, to investigate the related clinical significance and pathologic characteristics of hypertrophied adenoid. METHODS: Totally 2650 (age 2 to 87) cases with nasal obstruction or/and other symptoms were included in the patients group, and 810 (age 3 to 85) subjects without symptoms were included as the control group. Morphological characteristics examined with nasal endoscope. Biopsy was performed for 39 cases. The adenoid was calcified as 4 degrees according to the size. RESULTS: In the patient group, age 2 to 9, degree III and degree II adenoid were 81.1% (198/244) and 18.9% (46/244) respectively. And adenoid of children whose age 2 to 5 was 100.0% in degree III; In above 10 years old group, the adenoid was mostly degree II. In age 60 to 69 group, degree 0 was (66.5%), and in age 81 or above, degree 0 reaches 100%. And 19 years old was the youngest age at which adenoid of degree 0 started to be found and 21 was the oldest age at which there is no adenoid of degree III. In the control group, compared with the patient group, no statistical significant difference found in all other groups except in age 2 to 9 (degree III 57.9%, 22/38, degree II 42.1%, 16/38). Shapes of adenoids at degree II varied while degree I were almost like peeled orange. Pathologically, among children there are abundant of adenoidal lymph tissue, while in adults the lymph tissue getting less as age grows but with evident inflammation reaction. Among patients, the incidence of sinusitis and snoring was higher in degree III group compared with others, 47.4% and 18.7% respectively, and the differences is statistically significant (chi2 = 51.28, P < 0.01; chi2 = 40.26, P < 0.01). CONCLUSIONS: Adenoid volume of children (age < 10) is the biggest, especially of children under 5 years old. PMID- 17702420 TI - [Effect of poloxamer 407 on the middle ear and inner ear after regional perfusion in guinea pigs]. AB - OBJECTIVE: To observe the biodegradation and absorption of poloxamer 407 in vivo, and the effect of poloxamer 407 on the middle ear and inner ear after regional perfusion in guinea pigs. METHODS: The right ears of 10 guinea pigs as experimental group were perfused with 20% poloxamer 407 in situ gel 100 microl in round window niche, with the left ears as control group with normal saline. Another two animals without treatment were in negative control group. Auditory function was investigated before and 3, 7, 14, 28, 49 days after perfusion, and the histology of bulles after auditory brainstem response (ABR) each examination were examined by means of serial section after paraffin imbedding. RESULTS: The poloxamer gel was almost biodegraded and discharged 49 days after perfusion, only few gel remained in the middle ear cavity under light microscope. The ABR threshold to filtered clicks was elevated after perfusion with poloxamer 407, and was recovered to normal at 49 days after perfusion. The morphology of the mucosa of middle ear cavity, round window membrane, Corti's and vestibular organs were not significantly damaged after poloxamer 407 perfusion. CONCLUSIONS: Poloxamer 407 can be biodagraded in vivo or discharged via eustachian tube, and causes no inflammation on the middle ear cavity. There are temporary changes on auditory function of inner ear after topical perfusion with poloxamer 407 in round window can cause, but no irreversible damage on function and morphology of cochlear and vestibular organs. PMID- 17702421 TI - [Correlation of cyclooxygenase 2 with upstream mitogen-activated protein kinase, nuclear factor kappa B signal transduction pathway in middle turbinate mucosa of chronic rhinosinusitis]. AB - OBJECTIVE: To detect the expression and correlation of cyclooxygenase 2 (COX 2)and key enzymes both of mitogen activated protein kinase (MAPK) and nuclear factor-kappa B( NF-KB) pathways in middle turbinate mucosa of chronic rhinosinusitis (CRS) and to investigate their roles in CRS pathogenesis. METHODS: Twenty-four lateral mucosa of CRS middle turbinates were equally divided into 3 groups according to FESS-97 Haikou criterion (CRS type I stage 2 in group 1, type II stage 2 in group 2, and type III in group 3), and 8 normal mucosa were enrolled as control. Immunohistochemistry and fluorescent real time quantitative polymerase chain reaction (FQ-RT-PCR) were performed to detect the expression of COX-2, ERK, p38MAPK, JNK and NF-kappaB subunits. The correlations between cox-2 and MAPK, NF-kappaB pathway were statistically treated by Pearson test. RESULTS: Positive expressions of COX-2, ERK, p38MAPK and NF-kappaB subunits were detected in CRS groups, which were stronger than those in control group, by immunohistochemistry and FQ-RT-PCR (P < 0.05). Statistic difference was not found among CRS groups (P > 0.05). Negative expression of JNK was detected in all groups. Significantly positive correlation between protein and RNA expression of COX-2,ERK,p38MAPK and NF-kappaB subunits in each CRS group was confirmed by Pearson correlation treatment (P < 0.05). Significantly positive correlation of protein and RNA expression between COX-2 and ERK, p38MAPK in same CRS group was also founded (P < 0.05). The expression of COX-2 and the nucleic expression of NF kappaB subunits in same CRS group was proved to be positively correlated (P < 0.05). CONCLUSIONS: Upregulated expression of COX-2 is correlated with upstream ERK, p38MAPK and NF-kappaB pathway in CRS. It indicates the involvement of ERK, p38MAPK and NF-kappaB signal transduction pathway in regulation of COX-2 in CRS. PMID- 17702422 TI - [Impacts of socioeconomic and environmental factors on self-reported prevalence of allergic rhinitis in eleven cities in China]. AB - OBJECTIVE: Recent findings suggest that environmental factors play important roles in the etiology of allergic rhinitis, however, data on the impacts of socioeconomic and environmental factors on self-reported prevalence of allergic rhinitis in China is sparse, which is the aim of this study. METHODS: Telephone interviews were performed in 11 cities throughout the mainland of China, and the association between environmental factors and self-reported prevalence of allergic rhinitis were evaluated by multiple linear correlation tests. RESULTS: In total, there was no association between the adjusted self-reported prevalence of allergic rhinitis and socioeconomic factors such as GDP, GDP per capita, gross output value of industry and gross output value of industry per capita, while the adjusted self-reported prevalence of allergic rhinitis was positively correlated with the concentration of SO2, and no association was found between adjusted self reported rate of allergic rhinitis and either meteorological factors including annual average temperature, annual average relative humidity, annual hours of sunshine and annual precipitation or other air pollution factors including NO2 and PMl0. CONCLUSIONS: The study demonstrates that the self-reported prevalence of allergic rhinitis in 11 cities in China was positively correlated with the concentration of SO2, and the strategy of prevention for allergic rhinitis could be conducted according to the results. Prevalence; PMID- 17702423 TI - [Technique of rat cochlea slicing and study of rat spiral ganglion neurons by infrared visual slice patch clamp method]. AB - OBJECTIVE: To establishing the cochlea slice technique and infrared visual slice patch clamp method in order to observe the electrophysiological characteristics of rat spiral ganglion neurons (SGN) METHODS: SD rats were divided into three groups according to postnatal days old (0-2 d, 3-6 d and 7-14 d). Making slice of SD rat cochlear quickly, using infrared differential interference contrast (IR DIC) technique, together with slice patch clamp, the electrophysiological characteristics of rat spiral ganglion neurons were observed, and factors which affected the quality of cochlear slice and recording of patch clamp were analyzed. RESULTS: The success rate of 3-6 days SD was the highest, and 2-4 pieces of slice could be made from each cochlea. Cochlea connecting with partial skull and integrity of cochlear hull were the key for making slice, and the angle of modiolus axis should be adjusted to be parallel to the knife and the preparing time should be shorter. The SGN cell of good condition could be easily found and the seal test became easier with the help of infrared visual slice patch clamp method. The rest membrane potential was (-45.6 +/- 5.3) mV (x +/- s, n=52) and the current of Na+ and K+ could be activated. CONCLUSIONS: Cochlear slice technique can retain structural integrity, cell viability and their association in cochlea, which suggest that this technique provides carrier for electrophysiological study of rat spiral ganglion neurons, and patch clamp with infrared videomicroscopy method can be used to make direct real-time observation in electrophysiological experiments of SGN, which can provide important technique support and reference for deep study of electrophysiological characteristics of SGN and auditory neurotransmission in cochlea. PMID- 17702424 TI - [Expression of mucin 5B in chronic rhinosinusitis]. PMID- 17702425 TI - [Analysis of the performance of 18F-fluoro-2-deoxyglucose positron emission tomography in primary tumor detection in metastatic neck cancers]. PMID- 17702426 TI - [Effect of psychological factors in patients with sudden deafness]. PMID- 17702427 TI - [One pedigree report of Treacher Collins syndrome]. PMID- 17702428 TI - [Clinical analysis of infectious mononucleosis misdiagnosed as purulent tonsillitis]. PMID- 17702429 TI - [Bilateral cochlear implantation in a post-lingually deafened Mandarin-speaking patient]. PMID- 17702430 TI - [Malignant pleomorphic adenoma of nasal cavity: report of a case]. PMID- 17702431 TI - [Tuberculous otitis media]. PMID- 17702432 TI - [Gene therapy of head and neck neoplasms]. PMID- 17702433 TI - [Mother-to-infant HCV transmission--rate and course of HCV infection in children]. AB - OBJECT: to establish the rate and course of HCV infection in infants born to HCV infected mothers and to determine abilities of prevention. METHODS: 155 children born to HCV infected mothers were observed from birth until age 18-48 months. Serum of infants was tested for HCV-RNA (RT-PCR, Amplicor v 2.0 Roche), for anti HCV (EIA v. 2) and ALT activity. Infants were classified as HCV infected if their serum was found to be positive for HCV-RNA at least twice during first year of life. In 11 mothers and their newborns serum and PBMC from venous blood and from the umbilical cord were collected during delivery and examined-using nested RT PCR. RESULTS: The overall HCV vertical infection rate was 11%. Transmission occurred more frequently in children with intrapartum exposure to maternal blood by percutaneus inoculation. None of the infected infants had clinical symptoms of hepatitis. ALT abnormal activity was detected in 43% of infected children. HCV RNA was detected in mothers' serum and PBMC collected during delivery in 9 (9/11) samples. HCV-RNA was detected in samples from umbilical cord in serum in 7 (7/11) and in PBMC in 4 (4/11) cases. CONCLUSIONS: The risk of HCV vertical infection in present study was high. Intrapartum percutaneus exposure to maternal blood increased transmission rates. Further investigation to determine the effectiveness of antiviral therapy in prevention of mother-to-infant HCV transmission should be performed. The role of PBMC in mother-to-child HCV transmission should be investigated. PMID- 17702434 TI - [Treatment with natural interferon (alfaferone) in clinical practice--our experience]. AB - The aim of the study was to estimate effectiveness and adverse events of alfaferone therapy in hepatitis B and/or C. MATERIALS AND METHODS: 25 patients treated with alfaferone in Department of Infectious Diseases and Hepatology in Bydgoszcz were included into the study. That group contained 6 women, 8 men (age 19-68) and 11 children age 9-17. The natural interferon was applicated to 2 patients with acute hepatitis C, to 11 patients with chronic hepatitis C combined with ribavirine, to 10 with chronic hepatitis B and to 2 patients coinfected with HBV and HCV with ribavirin. RESULTS: In 6 cases alfaferone was given as retherapy, to following 3 patients because of bad toleration of recombinant interferon alpha (INFalpha) the drug was switched to natural interferon. 16 patients were naive. Main adverse events were: flu like syndrome (9), psychiatric disorders (8), which in 2 cases were the cause of discontinuing therapy. Leucopenia (6) and thrombocytopenia (5) observed before treatment didn't get worse. Thrombocytopenia below of 50,000/ml wasn't contraindication for use of alfaferone. HCV viremia was undetected in one case with acute hepatitis C. SVR was reached in 5 patients with chronic hepatitis C. Two of these 5 patients had been unsuccessfully treated with INFalpha before. Seroconversion HBeAg/anti-HBe was observed in 1 patient and undetectable HBV in 3 cases. The therapeutic effect wasn't achieved in 2 patients coinfected with HBV and HCV. CONCLUSION: Alfaferone can be used in hepatitis B and/or C treatment in cases with leuco- and thrombocytopenia, as retherapy and as continuation of treatment with INFalpha when hematological complication appears. Therapeutic effectiveness was observed in hepatitis C. PMID- 17702435 TI - [PEG IFN alpha-2a in the treatment of chronic hepatitis C in patients with treatment failure]. AB - Despite the significant advances that have been made in the treatment of chronic hepatitis C the efficacy of treatment response seems to be unsatisfactory. Treatment failure concern above one half of treated patients. It is estimated that the number of non-responders will be systematically increased. For these reasons as treatment strategies in these patients there is a need to define optimal way to use new therapies as: extending of treatment duration, higher initial doses of administered medications, an increase of patients adherence, changing of kind of pegylated interferon or treatment combinations PEG IFN + RBV with other drugs, especially HCV-enzymes inhibitors. In the work the data of efficacy of retherapy with PEG IFN alfa-2a+RBV administered during 72 weeks were present. Retreatment with PEG IFN alpha-2a and RBV in patients who fail to achieve SVR in the treatment with PEG IFN alpha-2b+RBV revealed high early viral response, in patients with advanced liver histology too. In the future there are planned treatment of chronic hepatitis C with combined therapy with IFN, specific HCV-enzymes inhibitors and antiviral medications. PMID- 17702436 TI - [Transmission of HIV-1 drug resistance among newly diagnosed patients in Poland]. AB - OBJECTIVE: HIV-1 drug resistance is becoming a growing concern. It is estimated that one out of ten newly diagnosed persons in Europe acquires HIV drug resistant strain. The aim of this study was to determine the transmission of drug resistance and identify the resistance patterns among naive patients in Poland. METHODS: The patients were asked to complete a brief questionnaire concerning demographic and epidemiological data. Viral load and CD4/CD8 counts were detemined before drug resistance testing. The sequencing assay was performed according to manufacturer's protocol. MAIN OBSERVATIONS: In the analysed cohort 14.7% of patients acquired HIV-1 drug resistant strains; further 9.5% were infected with strains with "possibly lowered susceptibility". RESULTS: In all cases resistance to single class of antiretroviral drugs were identified. In the class of PIs resistance to NFV was the most common. The rates of drug resistance among NNRTIs were almost the same--about 5%. In the NRTI class the resistance to AZT and d4T was the most frequent. HIV-1 subtype B was identified in 88.8% of cases. CONCLUSIONS: The results of this study document high transmission rate of drug resistance in Poland and justify the necessity of common DR testing in our country. PMID- 17702437 TI - [Relationship between inflammatory changes revealed in cerebrospinal fluid and prognosis in acute viral encephalitis]. AB - OBJECTIVE: To assess the relationship between inflammatory changes in cerebrospinal fluid (CSF) and prognosis in patients with acute viral encephalitis (AVE). PATIENTS AND METHODS: retrospective medical records analysis of 99 cases of AVE, 37 females and 62 males, age 4-71. Patients were assigned to 2 subgroups: group I--without inflammatory changes in CSF (cytosis < or = 10/mm3 - 40 cases) and group II--with detectable abnormalities in CSF (cytosis >10/mm3 - 59 cases). Long term prognosis and unfavorable outcome were assessed at the moment of discharge from hospital and with a use of questionnaire sent to patients and were described as: 0--complete recovery, 1--long-term disabilities, 2--death. MAIN OBSERVATIONS: Among 99 patients with acute viral encephalitis complete recovery was observed in 61% of cases, in 32% the disease resulted in long term consequences and disabilities and 7% died from reasons related to encephalitis. RESULTS: Patients without inflammatory changes in CSF statistically significantly (p < 0.05) more frequently suffered from coma, early epileptic episodes, respiratory disorders, unfavorable outcome and epilepsy. In a group II statistically significantly more often fever and Herpes simplex etiology were observed. CONCLUSIONS: (1) Among 99 patients in 32% AVE resulted in long-term (subtle as well as severe) disabilities and 7% died from reasons related to AVE. (2) Patients without inflammatory abnormalities in CSF tended to have more severe clinical course and worse prognosis than those with detectable increase of CSF cytosis (>10 cells/mm3). PMID- 17702438 TI - [Mumps in patients hospitalized in Bydgoszcz in the years 1991-2003]. AB - The case records of 1185 people, who were hospitalized because of epidemic parotitis at Department of Infectious Diseases in Bydgoszcz in the years 1991 2003 has been analyzed. An increase of the number of cases in the years: 1994, 1997/1998, 2003 has been indicated, especially in boys in the pre-school and school age. The most frequent complication in the course of mumps was meningitis, pancreatitis et orchitis. The only permament complication of the mumps was unilateral hypoacusis present in 5 patients. We observed that lumbar puncture is less frequently performed in cases of clinical mild neuroinfections in the course of mumps at the same we observed a tendency to shorten the time of hospitaliz ation to one week. In the light of conducted researches, the introduction of suggested vaccines against mumps does not seem to have had significant influence on the epidemiology of this disease. PMID- 17702439 TI - [Concentration of sFas and sFasL in the supernatant of PBMC culture from the patients with late lyme borreliosis]. AB - OBJECTIVE: Persistent, inadequate inflammatory response present in late Lyme borreliosis may be driven by activated T lymphocytes. We estimated synthesis of extracellular proteins: soluble Fas receptor (sFas) and its ligand (sFasL), which might protect T lymphocytes from physiologic apoptosis, in the peripheral blood mononuclear cell (PBMC) culture from patients with late borreliosis. METHODS: Lyme borreliosis group (LB) consisted of 20 patients with Lyme borreliosis present for >6 months. Six patients without any active infection constituted the control group (K). PBMC were incubated for 7 days with phytohemaglutinine or suspension of Borrelia afzeli (Ba), B. garinii (Bg) and B. burgdorferi sensu stricto (Bss) spirochetes. sFas and sFasL concentrations were measured in the culture supernatant with ELISA. RESULTS: In LB mean sFasL concentration was increased significantly under stimulation with phytohemaglutinine, Ba and Bg, and, with borderline significance, with Bss, in comparison with unstimulated culture. sFas also tended to increase, which was significant with phytohemaglutinine and borderline with Bg. In K sFas and sFasL was not significantly increased under antigenic stimulation. CONCLUSIONS: Increased synthesis of antiapoptotic factors by PBMC from patients with late borreliosis incubated with B. burgdorferi antigens may suggest impaired apoptosis of T lymphocytes contributing to persistent inflammatory response in this patients. PMID- 17702440 TI - [Clinical forms of neuroborreliosis--the analysis of patients diagnosed in department of infectious diseases and neuroinfection medical academy in Bialystok between 2000-2005]. AB - Increased morbidity of viral tick borne encephalitis since the 90's indicates growing risk of Rother tick borne diseases, including neuroborreliosis. Analysis of demographical, epidemiological and clinical data of patients hospitalised in Departament on Infectious Diseases and Neuroinfections in years 2000-2005 revealed that among patients with Lyme disease 13% were with neuroborreliosis with broad spectrum of neurologic symptoms as cranial nerves paresis (mainly n.VII), as well concentration and memory disturbances, and general symptoms. Some of patiets did not recall tick bite and did not present earlier borreliosis symptoms. Imaging only supports recognitio. PMID- 17702441 TI - [Prevalence of borreliosis among forestry workers in Kujawsko-Pomorskie voivodeship]. AB - Prevalence and clinical manifestation of borreliosis were analyzed. Evaluation of frequency of anti-Borrelia burgdorferi in sera collected from forestry workers were performed too. MATERIALS AND METHODS: 113 forestry workers from Kujawsko Pomorskie voivodeship were examined (56 from Szubin district, 29 from Runowo district and 28 from Lutowko district). Duration of works, frequency of exposition for tick, presence of erythema migrans (EM) in the past and present manifestation of Lyme disease were analyzed. Serological studies were performed in each case. RESULTS: Duration of works balanced between one and 47 years. In 92 cases exposition took place more than one time. 24 suffered from EM in the past but only two of them were treated with antibiotics because of this manifestation. 14 of 113 patients suffered from Lyme arthritis. Serological markers of infection with B.b. were finding in 37 cases. CONCLUSIONS: (1) Not every infection with B.b. are clinically manifested. (2) The risk of infection with B.b. is higher in patient frequently exposed on ticks. (3) There is no correlation between duration of works in a forest and frequency of B.b. infection in forestry workers what indicate that infected with B.b. ticks expanded on kujawsko-pomorskie voivodeship recently. (4) Forestry workers should be systematically examined because of high risk of Lime disease. (5) The information about borreliosis should be widespread. PMID- 17702442 TI - [Diagnostic difficulties in neuroborreliosis in children]. AB - OBJECTIVE: Analysis of clinical picture in children hospitalized because of suspicion of neuroborreliosis and evaluation of usefulness of testing serum and cerebrospinal fluid (CSF) for specific antibodies. MATERIAL AND METHODS: 23 children (age: 13 months - 15.5 years) were hospitalized: 11 children with facial palsy, 2 children with radiculopathy and 10 children with headache. In 21 children lumbar puncture and CSF examination was done. Serum of all children and CSF of 21 children were tested by ELISA for specific antibodies (IDEIA DakoCytomation). RESULTS: Meningeal signs in physical examination were found in 4 children and inflammatory CSF changes in 8 children. Specific antibodies in sera of 19 children and in CSF of 7 children. Neuroborreliosis was diagnosed in 12 children: in 9 facial palsy (in 6 with inflammatory CSF changes), in 2 Bannwarth's syndrome and in 1 aseptic meningitis. Diagnosis was confirmed by detection of specific antibodies in sera of 10 children and in CSF of 6 children. CONCLUSIONS: Meningitis in the course of neuroborreliosis is not always accompanied by meningeal signs. Positive serology is not an unequivocal confirmation of neuroborreliosis especially if symptoms are nonspecific (e.g. headache). PMID- 17702443 TI - [Lactobacillus speciesas opportunistic pathogens in children]. AB - The purpose of this research was the analysis of the Lactobacillus spp. strain occurrence in diagnostic materials obtained in the clinical pediatric hospital as well as to evaluate the phenotypic features of isolated strains and bile salts hydrolase (BSH) activity. Isolated strains were grown booth on media routinely used in clinical microbiology (TSA, Columbia + 5% sheep blood, D-coccosel) and on selective media (MRS) to isolated Lactobacillus bacteria. Strains were identified on the basis of biochemical profile in API 50CH test. Strains morphology and appearance of bile salts hydrolase activity were determined. During the research 107 Lactobacillus strains were isolated in oncology ward (37%), pulmonology (24%), home marrow transplantation (10%), intensive care unit (11%), and others. The strains were isolated from blood (9%), cerebrospinal fluid (1%), peritoneal fluid (1%), intestinal fistula (1%), respiratory tract (81%) and others. L. rhamnosus species dominated. The isolates grew poorly on routine media white on selective (MRS) media they grew well. Bile salts hydrolase (BSH) activity was detected in 20% of the strains. The results of the research show that Lactobacillus rods colonise patients with lowered immunity and may be the source of serious opportunistic infections in children. Phenotypic features, including many similar to Enterococcus species, make the diagnosis of these bacteria difficult. The use of MRS media can make it easier to isolate Lactobacillus rods from clinical materials. PMID- 17702444 TI - [Mycobacterium avium subsp. paratuberculosis in inflammatory bowel diseases]. AB - In the paper results were presented of a study on manifestation of infection with Mycobacterium avium subsp.paratuberculosis in 16 patients aged 15-42 years with Lesniowski-Crohn disease (group 1), in 20 patients aged 21-50 years with ulcerative colitis (group 2) and in 12 healthy individuals aged 23-60 years (group 3, control). All the ill patients were subjected to surgery, involving partial or total resection of large intestine, while individuals in group 3 (control) were subjected to colonoscopy with sampling of large intestine. Using mechanical/enzymatic technique DNA was extracted from the tissue material and was identified using PCR-ELISA technique (Mycobacterium paratuberculosis PCR; Institut Pourquier-France). Colour reaction was evoked using the TMB substrate. In the studies presence of Mycobacterium avium subsp. paratuberculosis was noted in 10 (62.5%) patients with Lesniowski-Crohn disease, in 5 (25%) patients with ulcerative colitis and in 1 patient 1 (8.3%) patient of the control group. The obtained results permit to suggest that Mycobacterium avium subsp. paratuberculosis bacteria participate in etiopathogenesis of Lesniowski-Crohn disease. PMID- 17702445 TI - [Acute gastroenteritis in Isolation Ward III Voivodeship Hospital in Warsaw 2001 2005]. AB - Study was done to evaluate changes of serotypes of Salmonella, clinical pattern, methods of treatment of patients who were hospitalized in our ward between 2001 2005. Among 129 patients with microbiologicaly confirmed Salmonella serotype S. enteritidis is prevalent. No changes of etiology were detected. Signs and treatment was not significantly changed. The most common source of infection were poultry products. PMID- 17702446 TI - [Typhoid fever imported from the tropic in Poland]. AB - We present three cases of typhoid fever imported to Poland from India in the beginning of the year 2006 treated in our Zoonosis and Tropical Medicine Department. Two of them, with mild course of the disease, were vaccinated with Typhim Vi vaccine, the third didn't obtain any, and had very heavy, almost classical course of the disease. All of them behaved in India in improper way, probably also because were convinced they were protected by the vaccine. We emphasize that proper prophylaxis against typhoid fever for travelers should consist of vaccination with two vaccines, oral Ty 21a and parenteral Typhim Vi and it doesn't release travelers from avoiding risky behavior. PMID- 17702447 TI - [Difficulties of diagnosis of Hirschsprung disease in an 8-year-old girl]. AB - This report presents the difficulty in diagnosing of Hirschsprung disease in an 8 year-old girl admitted to hospital with an acute diarrhea. Authors underline that the definite diagnosis of disease is confirmed by a full-thickness rectal biopsy and findings that indicate an absence of ganglion cells. PMID- 17702448 TI - [Parasitophobic patient suffering from scabies treated with ivermectin--a case report]. AB - We present a case of an atypical, difficult to diagnose crusted scabies caused by the invasion of non-human parasite (probably horse scabies Psoroptes equi) treated successfully by a rarely used in Europe antiparasitic agent-ivermectin. This inconvenient parasitemia additionally triggered parasitophobia--all of that together complicates the approach. PMID- 17702449 TI - [Achievements and failure of WHO during realization of the control programmes of the communicable diseases during twentieth century]. AB - Eradication of smallpox in 1977 in the world was the greatest achievement of the health status of the world population. It is also greatest cost benefit achievement not only in the health control programmes, but also in general economy. This achievement was possible from from two main reasons: (a) because vertical, well organized programmes was implemented and (b) during realization of the program change of strategy was introduced. That change allowed to speed up the efficacy of the epidemiological results (active epidemiological methodology was implemented). The essential contribution of Prof. dr J. Kostrzewski in the eradication programme was leadership of WHO International Commissions in the years 1977-1979 to evaluate eradications status of smallpox in 8 Asian and African countries. This contribution allowed to resume results of eradication of smallpox in the world in December 1979. Failures were observed during realization of control programme of 5 infectious diseases having efficient vaccines and control programme of malaria. It is possible to accept supposition that main reason why it happenes was not sufficient effort to apply (use) vertical initiatives. Prof. J. Kostrzewski was essentially involved during preparation of those programmes to eliminate those 5 communicable diseases buy his health status and the age after 1990 limited his possibility to be engaged directly in the realization to those programmes. PMID- 17702451 TI - [The scope of epidemiologic surveillance in selected European countries]. AB - The article presents: the historical outline of development of current surveillance systems in epidemiology, laws regulating surveillance issues in particular countries of E.U., purposes, tasks of ECDC, the scope of surveillance on infections diseases in selected European Countries. PMID- 17702450 TI - [Proposals concerning ways of control of hepatitis B in Poland since 2008]. AB - Improving of epidemiological situation of hepatitis B was reached by universal vaccination of infants, adolescents and vaccination of adults in high risk groups. Elimination of cases in the age group 0-10 and decreasing about 90% of number of notified cases observed in the years 1989-2004 was observed. Changes of the programme of vaccination since 2008 would be necessary to introduce. The first group of children vaccinated basically in the first year of life would grow up then to 14. Resignation of basic vaccination in 14 is necessary. Introducing of booster dose seems to be available in 14, opposite immunological memory, because: very high incidence rate of hepatitis B in past was noted in Poland; still now high incidence rate is noted in the groups 15-19 and 20-24 also in some voyvodships; documented immunological memory lasts only 15 years. This problem should be evaluated during routine vaccination and scheme of vaccination should be changed as soon as possible, not later than after 5 years. Except vaccination also improving of sterilization of medical and cosmetic equipment in autoclaves and hygiene measures especially in voyvodships: lodzkie, swiqtokrzyskie, kujawsko pomorskie and dolnoslaske where rate of hepatitis B is the highest is necessery. PMID- 17702452 TI - [Measles elimination programme on the world and Poland]. AB - Measles is still one of the leading causes of children mortality, despite of availability of a cheap, effective and safe vaccine for more than 40 years. Effective global eradication of smallpox and the success of polio eradication have provided an incentive to achieve the measles eradication all over the world. Elimination is achieved when no endemic measles cases has been observed in given area. This study analyzes epidemiological situation of measles, measles vaccination and laboratory diagnosis. In this report we describe the role of Global Measles Laboratory Network and integrated measles/rubella surveillance. The National Laboratory in Poland is based at the Department of Virology in National Institute of Hygiene, Warsaw. Following the implementation of 2-dose measles vaccine schedule the epidemiologic situation of measles has improved. In 2006 results of genotyping indicate that recent outbreaks were caused by local strains of the virus (D4 and D5). PMID- 17702454 TI - [Factors influencing vaccination coverage improvement in Malopolskie voivodeship according to opinion of health care providers]. AB - The alarming low immunization rates in Malopolskie voivodeship in the last years of XX century required introducing a program aiming at improvement of vaccination performance in this area. The high efficacy of these, both educational and organizing, efforts were documented by increase of vaccination coverage by approximately twenty percent within six years. The study based on structured questionnaires was conducted among health care providers to identify the essential factors that had influence on improvement of vaccination coverage. The higher level of knowledge and the changing of physicians and parents attitudes to vaccinations have been revealed as a main factors contributing a better immunization rates. The conclusions of this study could be used by public health institutions to continue the efforts of achievement a high and stable level of vaccination coverage in Malopolskie voivodeship. PMID- 17702453 TI - [Factors influencing vaccination coverage improvement in Malopolskie voivodeship according to parents opinion]. AB - This study sought to determine parents opinion about the most important factors that led to improvement of vaccination performance in Malopolskie voivodeship. The study based on structured questionnaire was conducted among 263 mothers. It revealed that the main factors which had influence on higher immunization coverage in children were the changing of parents attitudes to vaccinations and a better cooperation between them and health care providers based on a great deal of confidence. PMID- 17702455 TI - [Biography of Assistant Professor Med. Meiczyslaw Bilek--100th anniversary of birth]. PMID- 17702456 TI - Mutation of a gene encoding a putative ribokinase leads to reduced salt tolerance under potassium limitation in Bacillus subtilis. AB - The Bacillus subtilis L-42 mutant strain, which displays limited growth and inability to cope with hyperosmotic shock in a defined medium with a K+ concentration of < 1 mmol/L, was isolated by non-specific transposon insertional mutagenesis followed by an enrichment selection in media with K+ concentration < 0.5 mmol/L. The growth rate (as the main physiological characteristic) was determined to test the viability of the isolated mutant in media with various concentrations of K+, different values of osmolarity and pH. The mutant revealed a significant decrease in growth rate when cultivated in media with K+ concentration < 1 mmol/L and at hyperosmolarity. Localization of the insertional mutation was provided, based on genetic characteristics of the used transposon. Only 1 insertion of recombinant transposon was found in the mutant chromosome, localized into the yxkO gene (a putative ribokinase with unknown biological function). PMID- 17702457 TI - Importance of biofilm in Candida parapsilosis and evaluation of its susceptibility to antifungal agents by colorimetric method. AB - The ability of C. parapsilosis (an important cause of nosocomial infections) to produce biofilm was evaluated in 32 bloodstream isolates and 85 strains isolated from skin. The biofilm formation was found in 19 (59%) blood isolates and only in 33 (39%) isolates from skin. The antifungal susceptibility was assessed for amphotericin B, itraconazole and voriconazole in planktonic and biofilm form of the 19 biofilm-positive bloodstream strains by broth microdilution method according to NCCLS standards. The method was modified by the use of resazurin as a colorimetric indicator of the metabolically active cells which makes the determination of the effect of antifungal agents easier. Biofilm forms of all strains were more resistant than their planktonic form. PMID- 17702458 TI - Effect of protein kinase inhibitors on protein phosphorylation and germination of aerial spores from Streptomyces coelicolor. AB - In vitro phosphorylation reaction using extracts prepared from cells in the exponential phase of growth and aerial spores of Streptomyces coelicolor displayed the presence of multiply phosphorylated proteins. Effect of protein kinase inhibitors (PKIs) (geldanamycin, wortmannin, apigenin, genistein, roscovitine, methyl 2,5-dihydroxycinnamate, rapamycin, staurosporine) was determined on protein phosphorylation and on germination of spores. The in vitro experiments showed differences in phosphoprotein pattern due to the presence of PKIs. Cultivation of aerial spores with PKIs led to a significant delay in germ tube emergence and filament formation. However, none of the tested PKIs completely blocked the germination process. These results indicate that protein kinases of spores form complex networks sharing common modulating site that plays an important role in proper timing of early developmental events. PMID- 17702460 TI - Purification and biochemical characterization of a mycelial alkaline phosphatase without DNAase activity produced by Aspergillus caespitosus. AB - Biochemical properties of a termostable alkaline phosphatase obtained from the mycelium extract of A. caespitosus were described. The enzyme was purified 42 fold with 32% recovery by DEAE-cellulose and concanavalin A-Sepharose chromatography. The molar mass estimated by Sephacryl S-200 or by 7% SDS-PAGE was 138 kDa and 71 kDa, respectively, indicating a homodimer. Temperature and pH optima were 80 degrees C and pH 9.0. This enzyme was highly glycosylated (approximately 74% saccharide content). The activity was enhanced by Mg2+ (19 139%), NH4+ (64%), Na+ (51%) and Mn2+ (38%). 4-Nitrophenyl phosphate (4-NPP) was preferentially hydrolyzed, but glucose 1-phosphate (93%), UTP (67%) and O phosphoamino acids also acted as substrates. V(lim) and K(m) were 3.78 nkat per mg protein and 270 micromol/L in the absence of Mg2+ and 7.35 nkat per mg protein and 410 micromol/L in the presence of Mg2+, using 4-NPP as substrate. The purified alkaline phosphatase removed the 5'-phosphate group of a linearized plasmid without showing DNAase activity, indicating its potential for recombinant DNA technology. PMID- 17702459 TI - Impact of mitochondrial function on yeast susceptibility to antifungal compounds. AB - Saccharomyces cerevisiae pell and crd1 mutants deficient in the biosynthesis of mitochondrial phosphatidylglycerol (PG) and cardiolipin (CL) as well as Kluyveromyces lactis mutants impaired in the respiratory chain function (RCF) containing dysfunctional mitochondria show altered sensitivity to metabolic inhibitors. The S. cerevisiae pell mutant displayed increased sensitivity to cycloheximide, chloramphenicol, oligomycin and the cell-wall perturbing agents caffeine, caspofungin and hygromycin. On the other hand, the pel1 mutant was less sensitive to fluconazole, similarly as the K. lactis mutants impaired in the function of mitochondrial cytochromes. Mitochondrial dysfunction resulting either from the absence of PG and CL or impairment of the RCF presumably renders the cells more resistant to fluconazole. The increased tolerance of K. lactis respiratory chain mutants to amphotericin B, caffeine and hygromycin is probably related to a modification of the cell wall. PMID- 17702461 TI - Hydrogen peroxide and superoxide anion production during acetic acid-induced yeast programmed cell death. AB - Hydrogen peroxide production in yeast cells undergoing programmed cell death in response to acetic acid occurred in the majority of live cells 15 min after death induction and was no longer detectable after 60 min. Superoxide anion production was found later, 60 and 90 min after death induction when cells viability was 60 and 30%, respectively. In cells protected from death due to acid stress adaptation neither hydrogen peroxide nor superoxide anion could be observed after acetic acid treatment. The early production of hydrogen peroxide in cells in which survival was 100% could play a major role in acetic acid-induced programmed cell death signaling. Superoxide anion is assumed to be generated in cells already en route to acetic acid-induced programmed cell death. PMID- 17702463 TI - Structural analysis of a polysaccharide from Chlorella kessleri by means of gas chromatography-mass spectrometry of its saccharide alditols. AB - Interpretation of gas chromatographic-mass spectrometric data of oligosaccharide alditols was used to determine their structures and to derive the structure of a water soluble polysaccharide isolated from Chlorella kessleri. 1H- and 13C-NMR was employed to assess the configuration of glycosidic bonds and individual monosaccharides were assigned to the L or D series by means of gas chromatography of the acetylated (S)-2-butyl glycosides. PMID- 17702462 TI - Differences in osmotolerant and cell-wall properties of two Zygosaccharomyces rouxii strains. AB - The osmotolerant and cell wall properties of the two most studied wild-type Zygosaccharomyces rouxii strains (CBS 732 and ATCC 42981) were examined. Differences in their (1) tolerance to high salt content in the medium, (2) resistance to the lysing enzymes Lyticase and Zymolyase, (3) cell-wall polymer content and (4) cell wall micromorphology suggested that the less osmotolerant CBS 732 strain possesses a more rigid cell wall than the more osmotolerant ATCC 42981, whose cell wall seems to be more flexible and elastic. PMID- 17702464 TI - Removal of 2,4-dinitrotoluene from concrete using bioremediation, agar extraction, and photocatalysis. AB - Three methods, i.e. bioremediation by application of bacteria-laden agar, physical absorption of DNT by agar, or illumination by UV light were evaluated for the removal of 2,4-dinitrotoluene (DNT) from building-grade concrete. DNT biodegradation by Pseudomonas putida TOD was turned "on" and "off" by using toluene as a co-substrate thus allowing for rate-limiting step assessment. Bioremediation efficiency can be > 95-97% in 5-7 d if the process occurs at optimum growth temperature with the biological processes appearing to be rate limiting. Sterile agar can remove up to 80% of DNT from concrete thus allowing DNT desorption and biodegradation to be conducted separately. Photoremediation results in 50% DNT removal in 9-12 d with no further removal, most likely due to mass transfer limitations. PMID- 17702465 TI - Diversity of fliC gene in commensal Escherichia coli derived from various mammals. AB - Relations between the diversity of the fliC gene conditioning flagellum protein in E. coli and the source of the strain origin are presented. The fliC genes have been identified and characterized in commensal E. coli derived from 10 healthy animal species living in Zoo Safari Park (Poland). The fliC gene was found in 150 strains by the PCR method. The amplifiedfliC products revealed single bands within the range 1.26-2.16 kbp. Forty restriction patterns (classed by restriction analysis with the use of RsaI (PCR-RFLP RsaI; R-types) were determined. The neighbor-joining method was employed to illustrate the distribution of the kinds of R-types. There are 3-8 various R-types of a diversified frequency of occurrence in strains. Application of PCR-RFLP RsaI permitted the identification of alleles of fliC genes characteristic for E. coli and the estimation of their diversity among the animal species. The transmission ways of E. coli fliC+ between organisms of different species were determined and confirmed the role of transmission and horizontal gene transfer in the generation of the allelic diversity of fliC gene in natural E. coli populations. PMID- 17702466 TI - Properties of the strains Enterococcus haemoperoxidus and E. moraviensis, new species among enterococci. AB - Antibiotic susceptibility or resistance, urease activity, detection of the structural genes for bacteriocin production, bacteriocin activity as well as sensitivity of the isolates to enterocins (Ent) A and M were determined in 23 isolates of new species Enterococcus haemoperoxidus and E. moraviensis. The majority of the strains were antibiotic sensitive and exhibited low urease activity (< 10 nkat/mL). The most frequently detected genes for Ent were entA and entP. However, only the strain 466 of E. haemoperoxidus produced an antibacterial substance with inhibitory activity against 21 G+ indicators. It was partially purified reaching an activity of up to 12 800 AU/mL. This bacteriocin active strain also possessed the genes for EntA and EntP. The other strains did not inhibit the indicator strains. The substance produced by the 466 strain was active even after a 5-months storage at +4 and -20 degrees C. This substance has proteolytic and hydrophilic character, pH optimum of bacteriocin production by this strain being between 4 and 7. While E. moraviensis strains showed sensitivity to EntA (produced by E. faecium EK13) and to EntM (produced by E. faecium AL41), E. haemoperoxidus strains were sensitive to EntA (except strain 382) but less sensitive to the treatment by EntM. PMID- 17702467 TI - Treatment of orthopedic infections caused by resistant staphylococci. AB - During 1999-2005 we treated 15 patients with linezolid for relevant infections of locomotion apparatus (7 cases with endoprosthesis infection, 5x osteomyelitis and 3x another infection). With the exception of one case the antibiotic therapy was always combined with appropriate surgical intervention. Average period of linezolid administration was 26 d; linezolid was applied from the beginning intravenously on average for 10 d, and then orally for 16 d (average). There were no undesirable effects in the file. Success rate reached 86.6%. MRSA strains were proved by standard methods: growth on Mueller-Hinton agar with increased concentration of NaCl and 2 mg/L of oxacilline, and measuring inhibitory zones around cephoxitine disk. The sensitivity to other antibiotics was specified by disk-diffusion test; that to linezolid was verified by E-test. Linezolid represents a medical reserve for the treatment of multiresistant Gram-positive infections or for emergencies, when allergy onset, high toxicity risk, intolerance, etc. do not allow to use other, in vitro effective, antibiotics. PMID- 17702468 TI - Prevalence of active infection with Chlamydia pneumoniae and human cytomegalovirus in patients with type II diabetes mellitus. AB - By promoting the inflammatory process in the arterial wall, Chlamydia pneumoniae (CPN) and human cytomegalovirus (CMV) participate in the pathogenesis of cardiovascular disease (CVD). Since patients with diabetes mellitus (DM) are at high risk of CVD, we studied markers of CMV and CPN infection in DM patients as possible predictors of cardiovascular complications. The seroprevalence rates of CMV in 44 DM patients and matched controls were 74 and 88%, respectively. Compared with controls, patients showed lower titers of IgG against CMV (p < 0.001) and higher titers of genus-specific IgA against CPN (p = 0.006). The titers of genus-specific IgG and prevalence rates of type-specific anti-CPN IgA, IgG or IgM were similar in both DM patients and controls. Serological markers of either active or recent CPN infection were detected in 54% of patients and 59% of controls. However, CPN DNA was not detected in the blood of any DM patient. CMV DNA was found in the blood of 1 (2.3%) patient. The results do not indicate an increased rate of CMV or CPN infection in patients with type II DM. PMID- 17702469 TI - Characteristics of Staphylococcus aureus isolated from rabbits. AB - The occurrence of Staphylococcus aureus in rabbit feces, cecum and meat and its enterotoxin production, susceptibility to antibiotics and its sensitivity or resistance to bacteriocins produced by enterococci with probiotic properties were determined. Isolates were resistant to ampicillin, penicillin, phosphomycin and methicillin; a high percentage of susceptibility was also recorded to vancomycin, chloramphenicol, tetracycline and tobramycin. S. aureus isolates did not produce enterotoxins and were sensitive to partially purified enterocins (PPB) EK13, AL41 and EF2019 in the range of 100 to 12800 AU/mL; all S. aureus isolates, except the strain SA 2A/3, exhibited the highest sensitivity to PPB EK13. On the other hand, all strains were resistant to PPB CCM4231. PMID- 17702471 TI - Jaw and order. AB - It is well-accepted that the jaw plays an active role in influencing vowel height. The general aim of the current study is to further investigate the extent to which the jaw is active in producing consonantal distinctions, with specific focus on coronal consonants. Therefore, tongue tip and jaw positions are compared for the German coronal consonants /s, f, t, d, n, l/, that is, consonants having the same active articulators (apical/laminal) but differing in manner of articulation. In order to test the stability of articulatory positions for each of these coronal consonants, a natural perturbation paradigm was introduced by recording two levels of vocal effort: comfortable, and loud without shouting. Tongue and jaw movements of five speakers of German were recorded by means of EMMA during /aCa/ sequences. By analyzing the tongue tip and jaw positions and their spatial variability we found that (1) the jaw's contribution to these consonants varies with manner of articulation, and (2) for all coronal consonants the positions are stable across loudness conditions except for those of the nasal. Results are discussed with respect to the tasks of the jaw, and the possible articulatory adjustments that may accompany louder speech. PMID- 17702472 TI - The relationship between musical skills, music training, and intonation analysis skills. AB - Few attempts have been made to look systematically at the relationship between musical and intonation analysis skills, a relationship that has been to date suggested only by informal observations. Following Mackenzie Beck (2003), who showed that musical ability was a useful predictor of general phonetic skills, we report on two studies investigating the relationship between musical skills, musical training, and intonation analysis skills in English. The specially designed music tasks targeted pitch direction judgments and tonal memory. The intonation tasks involved locating the nucleus, identifying the nuclear tone in stimuli of different length and complexity, and same/different contour judgments. The subjects were university students with basic training in intonation analysis. Both studies revealed an overall significant relationship between musical training and intonation task scores, and between the music test scores and intonation test scores. A more detailed analysis, focusing on the relationship between the individual music and intonation tests, yielded a more complicated picture. The results are discussed with respect to differences and similarities between music and intonation, and with respect to form and function of intonation. Implications of musical training on development of intonation analysis skills are considered. We argue that it would be beneficial to investigate the differences between musically trained and untrained subjects in their analysis of both musical stimuli and intonational form from a cognitive point of view. PMID- 17702473 TI - Measuring syntactic complexity in spontaneous spoken Swedish. AB - Hesitation disfluencies after phonetically prominent stranded function words are thought to reflect the cognitive coding of complex structures. Speech fragments following the Swedish function word att 'that' were analyzed syntactically, and divided into two groups: one with att in disfluent contexts, and the other with att in fluent contexts. Complexity was calculated in terms of a number of measures related to syntactic tree structures produced by the analysis tool GRAMMAL. Results showed that disfluent att is in general associated with significantly higher mean complexity values than fluent att. This information can be used to predict whether the function word at the beginning of a fragment is likely to be disfluent or not. Two kinds of statistical classification algorithms (Bayesian and neural networks) were used to test this hypothesis. The best result was 71% correctly classified cases, which is significantly better than a system that is based on selecting the data's majority class. PMID- 17702470 TI - Candidiasis--do we need to fight or to tolerate the Candida fungus? AB - Candidiases, infections caused by germination forms of the Candida fungus, represent a heterogeneous group of diseases from systemic infection, through mucocutaneous form, to vulvovaginal form. Although caused by one organism, each form is controlled by distinct host immune mechanisms. Phagocytosis by polymorphonuclears and macrophages is generally accepted as the host immune mechanism for Candida elimination. Phagocytes require proinflammatory cytokine stimulation which could be harmful and must be regulated during the course of infection by the activity of CD8+ and CD4+ T cells. In the vaginal tissue the phagocytes are inefficient and inflammation is generally an unwanted reaction because it could damage mucosal tissue and break the tolerance to common vagina antigens including the otherwise saprophyting Candida yeast. Recurrent form of vulvovaginal candidiasis is probably associated with breaking of such tolerance. Beside the phagocytosis, specific antibodies, complement, and mucosal epithelial cell comprise Candida eliminating immune mechanisms. They are regulated by CD4+ and CD8+ T cells which produce cytokines IL-12, IFN-gamma, IL-10, TGF-beta, etc. as the response to signals from dendritic cells specialized to sense actual Candida morphotypes. During the course of Candida infection proinflammatory signals (if initially necessary) are replaced successively by antiinflammatory signals. This balance is absolutely distinct during each candidiasis form and it is crucial to describe and understand the basic principles before designing new therapeutic and/or preventive approaches. PMID- 17702474 TI - Caught in the ACT: the timing of aspiration and voicing in East Bengali. AB - East Bengali is a language that displays a four-way contrast of voiced/voiceless and aspirated/unaspirated oral stops and affricates in all word positions. Additionally, in intervocalic position there is a quantity contrast between long and short obstruents. In this production study we investigate medial palato alveolar affricates and stops at the labial, dental, retroflex, and velar places of articulation and address the problems of VOT measurements. We introduce a different approach of measuring lag times, henceforth called after closure time (ACT). The results show that this approach can do away with the extra notion of breathy voice to distinguish between the voiced aspirates and unaspirates. Moreover, as a result of analyzing the aspirated stops and affricates, an additional term (superimposed aspiration -SA) had to be introduced. The results of combining the notions of ACT and SA show that aspiration, measured from the point of release, is timed equally for voiced and voiceless stops. However, the difference in voice emerges in a trade-off relationship between ACT and SA. The factors used for analysis were voice, aspiration, quantity, and place of articulation in correlation to closure duration, the length of the preceding vowel, ACT, and SA. PMID- 17702477 TI - Leading light. PMID- 17702478 TI - Better loos for schools. PMID- 17702479 TI - Dear Gordon... PMID- 17702480 TI - Talking on a youth challenge. PMID- 17702481 TI - Acute leukaemia in childhood. PMID- 17702482 TI - An evaluation of a primary care-based weight management initiative. AB - Obesity is a significant issue in public health. There is a wealth of research that will be discussed as part of this article that identifies what has been effective in helping obese people reach a healthy weight. Health visitors and practice nurses are ideally situated to provide evidence-based support and monitoring to those living with obesity who want to improve their health and well being. This article evaluates a primary-care-based weight management programme that was devised from the research evidence available. A total of nine women were offered a combination of interactive group education sessions, monitoring and supoort over a period of six months. Success was measured using quantitative and qualitative measures. The intervention effectively reduced the BMI of participants and demonstrated the adverse effects obesity has on individual quality of life. PMID- 17702483 TI - Postnatal support for drug users: evaluation of a specialist health visiting service. AB - Women who misuse drugs require a high level of support during their pregnancy and in the postnatal period. A service to provide additional support to such women in the postnatal period was developed in Scotland, through the integration of a specialist health visitor (SHV) working within the existing multi-agency drug support team (DST). This paper reports on a study to identify views and experiences of both the women who use the service, and the health and social care professionals working with the SHV service, of its effects. Results revealed that specific aspects of the SHV service were viewed positively by women and professionals. However, potential for confusion over lines of accountability between professionals could exist. Also, meeting the complex needs of these women in a sustained way in the community may remain problematic. PMID- 17702484 TI - Health Impact Assessment as a framework for evaluation of local complex projects. AB - Health impact assessment (HIA) has been used to predict effects of a local parenting strategy and develop an evaluation framework. Methods used included literature searches, inequalities profiling, interviews with key informants and a review of available cost data. Four priority areas, where parenting can potentially impact, were identified: education, antisocial behaviour, lifestyle choices and mental health. The results concerning mental health are presented here. Improving the quality of parenting can impact on a child's mental health. The costs relating to the mental health outcomes are high and parenting is a cost effective method to address the family dynamics that impact on this. Intermediary indicators, including clear boundaries, time spent as a family and parental involvement can be used to evaluate the intervention in the short-term, although there are difficulties in their measurement. The HIA process can improve cross sectorial working, increased community participation and keep inequalities on the agenda. PMID- 17702485 TI - Anti-social adolescents conduct disorder: a review. PMID- 17702486 TI - The good, the bad and the worrying. PMID- 17702488 TI - [Anthrax in the canton of Zurich between 1878 and 2005]. AB - Historical records reporting cases of animal anthrax in the canton of Zurich between 1878 and 2005 were analysed on the level of political communities regarding occurrence and number of cases, animals affected, and number of communities affected. Data were correlated with industrial activities (tanning, wool and horse hair processing) in a community and to the prevailing meteorological conditions. A total of 830 cases of animal anthrax has been recorded in 140 of 171 communities. Occurrence correlated with industrial activities in a community such as companies handling potentially contaminated materials (hides, fur, wool, hair, meat, or bone meal). The influence of wool processing companies (P = 0. 004) and tanneries (P = 0. 032) was significant whereas horse hair processing had no effect. However, a statistical relationship between the number of cases reported and meteorological data (rainfall, mean temperature) was not found. PMID- 17702489 TI - [Rumenocentesis: a suitable technique for analysis of rumen juice pH in cattle?]. AB - In the United States, rumenocentesis has been recommended especially for early diagnosis of subacute rumen acidosis (SARA). The objective of the current study was to evaluate health risks due to the technique ofrumenocentesis and to measure pH in ruminal juice using a commercial indicator paper (Pehanon) and a pH electrode (reference method). After 11 dairy cows underwent rumenocentesis, the clinical status of those animals was evaluated daily, and cows were slaughtered as well as pathologically--anatomically examined on day 7. During the observation period, the following pathological clinical signs were evident: forced inspiration (3 cows), transient episode of hyperthermia (2 cows), increased tension of the abdominal wall (8 cows) and positive foreign body tests (3 cows). One cow had to be culled on day 7 because of severe generalised septic peritonitis spreading from the site of rumenocentesis. At slaughter, hematoma formation in the area of the puncture site was found in 9 out of 10 cows. It was concluded that the severe complications encountered with this technique do not legitimate rumenocentesis as a routine procedure for collection of rumen juice samples in cows under Swiss conditions. The correlation between the pH reference method and the commercial indicator paper was the high (r = 0.926). PMID- 17702490 TI - [Efficacy, tolerance and acceptability of Incontex in spayed bitches with urinary incontinence]. AB - A clinical study about efficacy and acceptance of Incontex in spayed bitches with urinary incontinence was performed. In a randomised, double-blinded study the efficacy and acceptance of Incontex (Dr. E. Graub AG, Bern, Schweiz) in bitches with urethral sphincter incompetence due to spaying was evaluated under field conditions. The active ingredient of the Incontex Syrup is phenylpropanolamine (PPA), an alpha1-adrenergic agonist. The study was performed using 24 spayed, incontinent bitches. Over a first period of treatment of 30 days the bitches received either Incontex, at 1.5 mg/kg twice per day, or a placebo. In the second period of 30 days all 24 bitches were treated with Incontex at the recommended dose. Any changes in the incontinence compared with the situation before the study were evaluated. RESULTS: Of 24 bitches 21 (88%) became continent and in 2 bitches (8%) urinary incontinence improved. In only 1 bitch (4%) the medication did have no effect. Five bitches (21%) showed side effects. The acceptance of Incontex was good. CONCLUSION AND CLINICAL RELEVANCE: Incontex can be recommended as an efficient and well-tolerated medication for the treatment of bitches with urinary incontinence after spaying. The oral application of 1.5mg/kg BW phenylpropanolamine twice daily has been approved. PMID- 17702492 TI - Ohio moves to full-risk managed Medicaid. PMID- 17702491 TI - Needle tract implantation after fine needle aspiration biopsy (FNAB) of transitional cell carcinoma of the urinary bladder and adenocarcinoma of the lung. AB - This paper reports three clinical cases of needle tract implantation of neoplastic cells on the abdominal and thoracic wall after ultrasound (US) fine needle aspiration biopsy (FNAB). Primary tumors were two transitional cell carcinomas of the urinary bladder (2 dogs) and one pulmonary adenocarcinoma (1 cat). All three masses grew up along the needle tract. To our knowledge, the seeding of pulmonary adenocarcinoma cells after FNAB on the thoracic wall has never been reported in veterinary medicine. PMID- 17702494 TI - Capitated specialty group rethinks IT conversion. Recommends examining needs and processes under capitation before changing IT platforms. PMID- 17702493 TI - States adopt incentives for Medicaid programs. PMID- 17702496 TI - Frequency of calpain-3 c.550delA mutation in limb girdle muscular dystrophy type 2 and isolated hyperCKemia in German patients. AB - OBJECTIVE: Calpain-3 deficiency is the most common cause of autosomal-recessive limb girdle muscular dystrophy (LGMD2). The c.550delA mutation in the CAPN3 gene was frequently identified in LGMD2A patients from Eastern Europe and is considered a Slavic founder mutation. METHODS: We screened for the c.550delA mutation in unrelated German patients with LGMD2 (n = 98) and in patients with asymptomatic or minimally symptomatic (myalgia or fatigue) hyperCKemia of unknown origin (n = 102). Results of Western blot analysis were available in 75 patients with LGMD2 and 65 patients with hyperCKemia. In samples that were heterozygous for the c.550delA mutation, the whole CAPN3 gene was analyzed by sequencing in order to detect the second mutation. RESULTS: The c.550delA mutation was found in 8.1% of LGMD2 (n = 1 homozygous, n = 7 heterozygous) and 1.9% of hyperCKemia patients (n = 2 heterozygous). In 8 of the 9 hetrozygous patients, a second CAPN3 mutation was identified by direct sequencing. Two mutations (Val509Phe and Gln565Stop) have not been reported before. Absent or deficient calpain-3 protein in Western blot analysis was found in 22.5% of the LGMD2 patients and 11% of the patients with hyperCKemia. Western blot results were available in 9 out of the 10 patients with genetically confirmed LGMD2A and were clearly abnormal in 6 patients, suspicious in 2 and entirely normal in 1. Two LGMD2 patients with the c.550delA mutation and onset within the first 2 decades had joint contractures. Muscle biopsy revealed inflammatory changes in three patients. CONCLUSION: The CAPN3 gene mutation c.550delA is rather frequently observed in German patients with LGMD2, but also occasionally in cases with isolated hyperCKemia. PMID- 17702495 TI - Pathology and genetics of frontotemporal lobar degeneration: an update. AB - Frontotemporal lobar degeneration (FTLD) is a common form of dementia that usually afflicts patients in their mid-life. Clinically, patients with FTLD present with changes in behavior and/or language dysfunction. According to their underlying neuropathological substrate, these neurodegenerative conditions can now be classified into two main groups: those with tau pathology (tauopathies), and those without tau pathology. In the majority of nontauopathy disorders the recently identified TAR DNA-binding protein-43 (TDP-43) is found as the major inclusion protein (TDP-43 proteinopathies), and TDP-43 is also present in motor neuron inclusions of amyotrophic lateral sclerosis. Presently, mutations in 4 genes (MAPT, PGRN, VCP, CHMP2B) are known to cause diverse types of FTLD pathology. Here, we summarize the recent neuropathological and genetic advances in FTLD research. PMID- 17702497 TI - Absence of major accumulation of mitochondrial ND5 mutations in Parkinson patient muscle. AB - The pathogenesis of the selective loss of dopaminergic neurons in idiopathic Parkinson's disease (PD) has not been understood up to now. Respiratory chain dysfunction and accumulation of mitochondrial DNA deletions to biochemically relevant levels have been observed in the dopaminergic neurons. However, respiratory chain defects have also been reported in other tissues, pointing to a generalized component of oxidative stress in PD. Recently, somatic point mutations in a narrow region of the complex I polypeptide ND5 (codons 120 - 150) were suggested to separate PD patients from age-matched controls, using frontal cortex homogenates. OBJECTIVE: The present study intended to analyze whether those recently described ND5 mutations may also generally occur in skeletal muscle tissue of PD patients, in which complex I dysfunction had been measured earlier with biochemical approaches. MATERIAL: Skeletal muscle biopsy samples of 5 PD individuals with a previously characterized biochemical complex I defect and of 5 age-matched controls were used. METHOD: DNA was extracted from the muscle samples. The relevant ND5 region was PCR-cloned using a high fidelity Pfu polymerase and a low number of PCR cycles (15). Amean number of 96 clones were randomly selected from the ampicillin plates and sequenced by the dye terminator method to allow the detection of low abundance mutations with a sensitivity around 1%. RESULTS: Mutations between codons 120 and 150 were only slightly more frequent in PD versus controls (60 versus 40% of samples affected), while this ratio had been 100 versus 12.5% in frontal cortex. CONCLUSIONS: In contrast to results reported for PD frontal cortex, low-level ND5 mutations between codons 120 and 150 do not accumulate severely in biochemically affected skeletal muscle samples of PD patients. PMID- 17702498 TI - A neuroepithelial tumor showing combined histological features of dysembryoplastic neuroepithelial tumor and pleomorphic xanthoastrocytoma--a case report and review of the literature. AB - A neuroepithelial tumor showing combined histological features of dysembryoplastic neuroepithelial tumor (DNT) and pleomorphic xanthoastrocytoma (PXA) is described. The patient was a 60-year-old male with a long-standing temporal lobe tumor and seizures. After a long, dormant period, the tumor, which had been localized in the left uncus, re-grew rapidly and extended into the subarachnoidal space and brain stem. The post-operative specimens disclosed two distinct components: an intra-cortical, cystic lesion containing mucinous materials and an extra-cortical, nodular lesion involving the leptomeninges. The former contained oligodendroglia-like small, round cells placed along axonal processes, plus mature neurons situated against mucinous materials (DNT-like component, WHO Grade I). The latter contained spindle and/or pleomorphic cells expressing glial fibrillary acidic protein, having bizarre nuclei and atypical mitotic figures. A reticulin network was developed among the tumor cells (PXA like component, WHO Grade III). This case illustrates an unusual composite brain tumor, combined DNT and PXA. PMID- 17702499 TI - Spinal metastasis from renal cell carcinoma, 31 years following nephrectomy--case report. AB - Most renal cell carcinomas recur or metastasize within 2 years. We present a 62 year-old lady with metastatic renal cell carcinoma in the spine, 31 years following nephrectomy of the primary tumor. This is the longest interval between diagnosis of primary renal cell carcinoma and metastasis reported in the literature. PMID- 17702500 TI - Intravascular large B-cell lymphoma presenting with neurological syndromes: clinicopathologic study. AB - Intravascular lymphoma or intravascular lymphomatosis (IVL) is an uncommon extranodal lymphoma, which gives rise to exclusively intravascular tumor growth. In 1/3 of the reported cases the disease debuts with involvement of the nervous system, which is particularly susceptible. Over the clinical course of the disease, 2/3 of the patients will present neurological symptoms. Owing to its characteristic growth pattern, IVL can give rise to very different central or peripheral nervous system neurological syndromes. Not infrequently a single patient will present more than one neurological syndrome. Moreover, the specificity of the neurological tests is low. All these factors explain the difficulties involved in diagnosing this entity and the fact that in most cases the diagnosis is established on autopsy study. This article presents the clinical, biological, radiological and post-mortem neuropathological findings in an immunocompetent patient with IVL. The onset was a cauda equina syndrome and showed multiple and varied neurological manifestations during the course of the disease, which progressed in the months before death. Spinal cord biopsy performed in life did not provide diagnostic findings because the vessels showed no neoplastic involvement. Immunohistochemical findings demonstrated large B-cell lymphoma. A review of the neurological features described in previously published cases of IVL is provided. PMID- 17702501 TI - The creation of the essentialism story: an exercise in metahistory. AB - The essentialism story is a version of the history of biological classification that was fabricated between 1953 and 1968 by Ernst Mayr, who combined contributions from Arthur Cain and David Hull with his own grudge against Plato. It portrays pre-Darwinian taxonomists as caught in the grip of an ancient philosophy called essentialism, from which they were not released until Charles Darwin's 1859 Origin of Species. Mayr's motive was to promote the Modern Synthesis in opposition to the typology of idealist morphologists; demonizing Plato served this end. Arthur Cain's picture of Linnaeus as a follower of 'Aristotelian' (scholastic) logic was woven into the story, along with David Hull's application of Karl Popper's term, 'essentialism', which Mayr accepted in 1968 as a synonym for what he had called 'typological thinking'. Although Mayr also pointed out the importance of empiricism in the history of taxonomy, the essentialism story still dominates the secondary literature. The history of the first telling of the essentialism story exposes its scant basis in fact. PMID- 17702502 TI - The Beer/Bethe/Uexkull paper (1899) and misinterpretations surrounding 'vitalistic behaviorism'. AB - In the history of behaviorism the paper of the three physiologists Theodor Beer, Albrecht Bethe and Jakob von Uexkull from 1899 plays an important role. Many researchers were influenced by this paper and identified it as fundamental for objective psychological research. But during the period of its adoption (1900 1925) psychologists did not notice that Beer, Bethe and Uexkull had distanced themselves from their own paper, because it had been ignored in physiological and biological discussions. Moreover, one of the three (Beer) had to resign from the scientific community because of private scandal and another one (Uexkull) changed all of his views and left the base of objective science for subjective vitalism. However, this did not change his adoption of behaviorism. PMID- 17702503 TI - The search for purpose in a post-Darwinian universe: George Bernard Shaw, 'creative evolution', and Shavian eugenics: 'The dark side of the force'. AB - The Irish playwright and socialist George Bernard Shaw has been of marginal concern for historians of biology because his vitalist Lamarckism has been viewed as out of step with contemporary science. However, Julian Huxley and J.B.S. Haldane were certainly of the opinion that Shaw was a man of influence in this regard and took pains to counter his views in their own attempts to engage the public in science. Previously, Shaw's colleague and friend H.G. Wells had also agued with Shaw from his own mechanistic neo-Darwinian perspective. The very public debate between Shaw and Wells, which continued to concern Huxley and Haldane, shows that public concern over the moral implications of Darwinism has a long history. Taking into account the opinions of John Maynard Smith on this matter, I suggest that a consideration of Shaw in this context can give us an understanding of the historical popularity of vitalist teleology as well as of the persistent ambivalence to the non-normative character of Darwinism. PMID- 17702504 TI - Why there was a useful plausible analogy between geodesic domes and spherical viruses. AB - In 1962, Donald Caspar and Aaron Klug published their classic theory of virus structure. They developed their theory with an explicit analogy between spherical viruses and Buckminster Fuller's geodesic domes. In this paper, I use the spherical virus-geodesic dome case to develop an account of analogy and deductive analogical inference based on the notion of an isomorphism. I also consider under what conditions there is a good reason to claim an experimentally untested analogy is plausible. PMID- 17702505 TI - God? A scientist answers a scientist. PMID- 17702506 TI - Continuous blood volume monitoring and "dry weight" assessment. AB - There are two distinct facets of adequate fluid balance control in haemodialysis patients--estimation of dry weight (DW) as the target and adequate ultrafiltration (UF) strategy, i.e. the way to reach the target in a possibly symptom-free way. The article reviews the continuous blood volume monitoring (CBVM) based procedures to deal with the former facet-DW determination. The existing approaches are divided in three groups--methods defining certain alert value of relative blood volume (RBV) reduction, methods working with RBV response to constant UF rate, and methods evaluating dynamics of RBV response to UF pulse or chain of UF pulses. While the first and the third approaches are relatively easy to automate, the second group of methods are suitable mainly for observational evaluations only. All the discussed methods, without exception, need large-scale verification, as they all were evaluated in the majority by their authors only and on small patient cohorts. PMID- 17702507 TI - Relative blood volume based biofeedback during haemodialysis. AB - Intra-dialytic hypotension is the most frequently occurring complication during haemodialysis and can lead to serious complications. Devices that continuously and non-invasively monitor relative blood volume (RBV) changes during HD are being advocated as a tool to maintain an adequate volume of the intravascular compartment in order to avoid dialysis hypotension. Nowadays, most manufacturers have incorporated a RBV monitor in their dialysis apparatus and two manufacturers have designed biofeedback devices that control intra-dialytic RBV changes. The goal of RBV based biofeedback systems is to prevent a severe or abrupt decrease in blood volume in order to prevent the development of dialysis hypotension. Biofeedback technologies can diminish the severity and/or frequency of dialysis hypotension. At present, however, a completely symptom-free HD is not a reality. The major reasons for this are patient characteristics such as cardiovascular co morbidity and high UF rates and a lack of understanding of the relation between RBV changes and blood pressure/cardiovascular stability. PMID- 17702508 TI - Microbiological monitoring of dialysis water systems--which culture method? AB - PROBLEM: Assurance of adequate water quality is one of the most important aspects of ensuring a safe and effective delivery of haemodialysis. There are several different culture methods recommended in the various guidelines on the microbiological testing of water for dialysis. AIMS: The aim was to investigate whether or not there was a significant difference in the microbiological results obtained using the various recommended culture methods. METHODS: Current guidelines suggest that samples for microbiological analysis should be cultured using a low nutrient media such as Reasoner's 2A but vary in recommending temperature and time. Over a six month period, samples were sent to an independent laboratory and cultured using three different times and temperatures. Samples were cultured at 22 degrees C for 7 days (ERA-ERCA, EDTNA-ERCA), 37 degrees C for 2 days (AAMI and ISO) and 30 degrees C for 5 days (ISO, EP). RESULTS: The bacterial culture method used was R2A media at the incubation temperatures and times indicated. During an extensive microbiological survey of several water systems, the results from the laboratory gave conflicting results for the three methods. Results showed that several of sample sets returned results with a difference in recovery by a factor of between 10 and 1000. CONCLUSIONS: Culturing using the stated temperature and times produces large variations in reported levels of contamination. Culturing at the different temperatures and incubation times can produce results which may give a false sense of security by not indicating a contamination problem. Standardising on a single method is desirable in order to produce consistently valid results. PMID- 17702509 TI - Needle stick injuries--risk from blood contact in dialysis. AB - This paper will examine the experience of Needle Stick Injuries (NSI) in Germany. There is evidence that these experiences have relevance for the whole of Europe. The protective measures described in this paper are important for the safety of all health care workers. This paper will describe incidents of NSI with reference to sero-conversion after the incident. The protection of health care workers is of prime importance and this paper will discuss the most successful methods of protection. The paper will examine briefly the cost of these protective measures. PMID- 17702511 TI - Evaluation of response to various erythropoiesis--stimulating proteins using anemia management software. AB - BACKGROUND: European Best Practice Guidelines recommend haemoglobin (Hb) concentration >11 g/dl in patients with CKD stage 5. Hb can be increased with erythropoiesis-stimulating proteins (ESPs); however, 5-10% of patients respond poorly. The primary aim of this prospective observational study was to educate nurses to assess Hb response to ESPs and to identify potential causes of hyporesponse (blood loss, iron deficiency, infection and inflammation, inefficacious dialysis, medication, vitamin deficiency, malnutrition, secondary hyperparathyroidism, or pure red cell aplasia). The secondary aims were to follow anaemia parameters and identify the frequency and causes of hyporesponse to ESPs for 6 months. Lastly, the various ESPs used in the study population were analyzed separately. METHODS: Dialysis patients (n=402) from 18 centers in Belgium and the Grand Duchy of Luxembourg were included. Using anaemia management software (ARAMIS), nurses recorded Hb, ESP dose, and potential causes for hyporesponse every 4 weeks. RESULTS: The proportion of patients treated with darbepoetin alpha, epoetin alpha, and epoetin beta was 64%, 19%, and 17%, respectively. After 6 months, 79% of patients had Hb >11 g/dl. The patient incidence of hyporesponse during the study was 14%, and a mean 9% of patients were hyporesponsive at any given time. The most common potential causes of hyporesponse were iron deficiency (being reported in 39% of hyporesponse events), medication (immunosuppressive agents, ACE inhibitors), secondary hyperparathyroidism and inflammation/malnutrition. CONCLUSIONS: The ARAMIS tool served as an educational tool allowing efficient follow-up of Hb and ESP dose, and identification of potential causes of hyporesponse. Mean prevalence of hyporesponse was 9%, with iron deficiency as most commonly reported potential causative factor. PMID- 17702510 TI - Calciphylaxis: calcific uraemic arteriolopathy--a case study. AB - Having worked in nephrology for more than 20 years, and never encountering this condition before, we came across three patients who had been diagnosed with calciphylaxis in the space of 12 months. This condition is also known as calcific uraemic arteriolopathy and is a syndrome of medical calcification of the small arteries, which leads to painful ischaemia of the surrounding subcubitis and skin (1). Prevalence of 1-4% has been estimated in various haemodialysis populations. Also 1% per year in dialysis patients has also been suggested (3). The mortality rate for distal lesions is 23%, whilst the mortality for proximal lesions is 63% (4). The pathogenesis of this condition remains uncertain. However, vascular calcium deposition is thought to be important, and raised serum phosphate levels were associated with a substantially increased risk of calciphylaxis. Although PTH levels were high, plasma PTH was not consistently higher in patients with calciphylaxis than controls (5). The important aspect of the condition for the patients is the sheer pain and distress suffered, as well as the high mortality rate. Therefore, the implications for nurses are early detection, to allow speedy treatment to take place and involvement of the multidisciplinary team to enhance care and provide as much support as possible, thus facilitating optimal outcome and comfort. PMID- 17702512 TI - Selection of donor and organ viability criteria: expanding donation criteria. AB - Donation criteria have been becoming more flexible over the years. Currently, the only absolute exclusion criteria are human immunodeficiency virus infection (HIV), uncontrolled tumor disease and bacterial or viral infections. ClinicaL. conditions dictate organ viability criteria: biochemical, morphological and functional, that must be fulfilled by the donors and their organs in order to focus the decision on which donor organs can be used. These criteria attempt to assure that the transplanted organs function after the extraction, transformation, implantation and reperfusion process without transmitting any infectious or tumour disease. In recent years, the gross and microscopic appearance has become one of the fundamental criteria for selection of potentially viable organs. At present, there is no age limit for hepatic and renal donation; the principal contra-indication is chronic organ damage. The use of each organ must be decided individually after a profound analysis of all the viability criteria, weighing the advantages and disadvantages of the implant of a certain organ for the recipient. PMID- 17702513 TI - Merits and limitations of the measurement of relative blood volume changes during haemodialysis. PMID- 17702514 TI - Should we provide ultrapure dialysis fluid? Summary of the EDTNA/ERCA Journal Club discussion Winter 2006. AB - The paper discussed during winter 2006 was an editorial in Nephrology, Dialysis and Transplantation (NDT) entitled "Ultrapure dialysis fluid--how pure is it and do we need it" by Dr Ingrid Ledebo PhD of Gambro Corporate Research, Sweden. Thirteen people from seven different countries contributed to the wide-ranging discussion whose topics ranged from the most cost effective way of producing ultrapure dialysis fluid (UPDF) to the environmental impact of heat sanitisation and the industrial-scale bleeding of the Limulus horseshoe crab. Different methods of disinfection such as heat and UV light were discussed as well as the requirement and funding for microbial detection assays and their various sensitivities. Participants concluded that the available evidence supported the use of UPDF as standard, but identified financial pressures, via differing reimbursement systems, as the main barrier to its universal introduction. PMID- 17702515 TI - The rising star of technology in home care. PMID- 17702517 TI - Going Wireless ... finally, really on the road! PMID- 17702516 TI - Telemanagement--the third wave of telecare. PMID- 17702518 TI - Telehealth: is it the silver bullet? AB - The focus of our CQI Investigation was to determine whether home telehealth is the "Silver Bullet" in reducing re-hospitalizations, managing visits per episode, implementing disease management strategies, and improving patient satisfaction. In this article, we will discuss the challenges of developing and implementing a telehealth program in a free standing non-profit agency, the program design and its components, and obstacles encountered including those presented by home care staff and area physicians. When we started this project, we had no idea what the results would be. There were some surprises along the way. PMID- 17702519 TI - Telehealthcare cost to deliver is the bottom line. PMID- 17702520 TI - Implementing your new software system: tips to help ease the transition. PMID- 17702521 TI - OASIS NPV: Paving the way for 2008. PMID- 17702522 TI - A bit of heaven in 6A at flight level 32. PMID- 17702523 TI - CMS discusses medical review/program integrity initiatives for hospice. PMID- 17702524 TI - Creative solutions for chronic care. PMID- 17702525 TI - The Bytes and the Board. PMID- 17702526 TI - Metabolism of benzo[a]pyrene in human bronchoalveolar H358 cells using liquid chromatography-mass spectrometry. AB - Benzo[ a]pyrene (B[ a]P), a representative polycyclic aromatic hydrocarbon (PAH), is metabolically activated by three enzymatic pathways: by peroxidases (e.g., cytochrome P450 peroxidase) to yield radical cations, by P4501A1/1B1 monooxygenation and epoxide hydrolase to yield diol epoxides, and by P4501A1/1B1 monooxygenation, epoxide hydrolase, and aldo-keto reductases (AKRs) to yield o quinones. In humans, a major exposure site for environmental and tobacco smoke PAH is the lung; however, the profile of B[ a]P metabolites formed at this site has not been well characterized. In this study, human bronchoalveolar H358 cells were exposed to B[ a]P, and metabolites generated by peroxidase (B[ a]P-1,6- and B[ a]P-3,6-diones), from cytochrome P4501A1/1B1 monooxygenation [3-hydroxy-B[ a]P, B[ a]P-7,8- and 9,10- trans-dihydrodiols, and B[ a]P- r-7, t-8, t-9, c-10 tetrahydrotetrol (B[ a]P-tetraol-1)], and from AKRs (B[ a]P-7,8-dione) were detected and quantified by RP-HPLC, with in-line photo-diode array and radiometric detection, and identified by liquid chromatography-mass spectrometry (LC-MS). Progress curves showed a lag phase in the formation of 3-hydroxy-B[ a]P, B[ a]P-7,8- trans-dihydrodiol, B[ a]P-tetraol-1, and B[ a]P-7,8-dione over 24 h. Northern blot analysis showed that B[ a]P induced P4501B1 and AKR1C isoforms in H358 cells in a time-dependent manner, providing an explanation for the lag phase. Pretreatment of H358 cells with 10 nM 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) eliminated this lag phase but did not alter the levels of the individual metabolites observed, suggesting that both B[ a]P and TCDD induction ultimately yield the same B[ a]P metabolic profile. The one exception was B[ a]P-3,6-dione which was formed without a lag phase in the absence and presence of TCDD, suggesting that the peroxidase responsible for its formation was neither P4501A1 nor 1B1. Candidate peroxidases that remain include PGH synthases and uninduced P450 isoforms. This study shows that the P4501A1/1B1 and AKR pathways are inducible in human lung cells and that the peroxidase pathway was not. It also provides evidence that each of the pathways of PAH activation yields their distinctive metabolites in H358 human lung cells and that each pathway may contribute to the carcinogenic process. PMID- 17702528 TI - Affinity-based turbidity sensor for glucose monitoring by optical coherence tomography: toward the development of an implantable sensor. AB - We investigated the feasibility of constructing an implantable optical-based sensor for seminoninvasive continuous monitoring of analytes. In this novel sensor, analyte concentration-dependent changes induced in the degree of optical turbidity of the sensing element can be accurately monitored by optical coherence tomography (OCT), an interferometric technique. To demonstrate proof-of-concept, we engineered a sensor for monitoring glucose concentration that enabled us to quantitatively monitor the glucose-specific changes induced in bulk scattering (turbidity) of the sensor. The sensor consists of a glucose-permeable membrane housing that contains a suspension of macroporous hydrogel particles and concanavalin A (ConA), a glucose-specific lectin, that are designed to alter the optical scattering of the sensor as a function of glucose concentration. The mechanism of modulation of bulk turbidity in the sensor is based on glucose specific affinity binding of ConA to pendant glucose residues of macroporous hydrogel particles. The affinity-based modulation of the scattering coefficient was significantly enhanced by optimizing particle size, particle size distribution, and ConA concentration. Successful operation of the sensor was demonstrated under in vitro condition where excellent reversibility and stability (160 days) of prototype sensors with good overall response over the physiological glucose concentration range (2.5-20 mM) and good accuracy (standard deviation 5%) were observed. Furthermore, to assess the feasibility of using the novel sensor as one that can be implanted under skin, the sensor was covered by a 0.4 mm thick tissue phantom where it was demonstrable that the response of the sensor to 10 mM glucose change could still be measured in the presence of a layer of tissue shielding the sensor aiming to simulate in vivo condition. In summary, we have demonstrated that it is feasible to develop an affinity-based turbidity sensor that can exhibit a highly specific optical response as a function of changes in local glucose concentration and such response can be accurately monitored by OCT suggesting that the novel sensor can potentially be engineered to be used as an implantable sensor for in vivo monitoring of analytes. PMID- 17702527 TI - Comparison of the cytotoxicity of the nitroaromatic drug flutamide to its cyano analogue in the hepatocyte cell line TAMH: evidence for complex I inhibition and mitochondrial dysfunction using toxicogenomic screening. AB - Flutamide (FLU) is an antiandrogen primarily used in the treatment of metastatic prostate cancer. It is an idiosyncratic hepatotoxicant that sometimes results in severe liver toxicity. FLU possesses a nitroaromatic group, which may be a contributor to its mechanism of toxicity. A nitro to cyano analogue of FLU (CYA) was synthesized and used to test this hypothesis in the TGFalpha-transfected mouse hepatocyte cell line (TAMH). MTT cell viability assays and confocal microscopy showed that hepatocytes are more sensitive to cytotoxicity caused by FLU than CYA (LD 50 75 vs 150 microM, respectively). Despite the structural modification, the antiandrogen activity of CYA is comparable to that of FLU. Comparisons of transcriptomic changes caused by FLU with those caused by a panel of known cytotoxicants [acetaminophen, tetrafluoroethylcysteine, diquat, and rotenone (ROT)] indicated that FLU results in a temporal gene expression pattern similar to ROT, a known inhibitor of complex I of the electron transport chain. A subsequent microarray analysis comparing FLU to CYA and ROT revealed many similarities among these three compounds; however, FLU and ROT result in more substantial changes than CYA in the expression of genes associated with oxidative phosphorylation, fatty acid beta-oxidation, antioxidant defense, and cell death pathways. Electron microscopy confirmed that FLU leads to mitochondrial toxicity that has some similarities to the mitochondrial effects of ROT, but the morphologic changes caused by FLU were greater in scope with both intra- and intercellular manifestations. Biochemical studies confirmed that both ROT and FLU deplete cellular ATP levels and inhibit complex I of the electron transport chain to a greater extent than CYA. Thus, as compared to CYA, the nitroaromatic group of FLU enhances cytotoxicity to hepatocytes, likely through mechanisms involving mitochondrial dysfunction and ATP depletion that include complex I inhibition. PMID- 17702529 TI - Dynamic cell fractionation and transportation using moving dielectrophoresis. AB - This study presents a new cell manipulation method using a moving dielectrophoretic force to transport or fractionate cells along a microfluidic channel. The proposed moving dielectrophoresis (mDEP) is generated by sequentially energizing a single electrode or an array of electrodes to form an electric field that moves cells continuously along the microchannel. Cell fractionation is controlled by the applied electrical frequency, and cell transportation is controlled by the interelectrode activation time. The applicability of this method was demonstrated to simultaneously fractionate and transport Saccharomyces cerevisiae yeast cells, both viable and nonviable, by operating at conditions under which the cells were subjected to positive and negative dielectrophoresis, respectively. Compared to the conventional dielectrophoresis (cDEP and traveling wave dielectrophoresis (twDEP), moving dielectrophoresis allows cells to be separated on the basis of the real part of the Clausius-Mossotti factor, as in cDEP, but yet allows the direct transportation of separated cells without using fluid flow, as in twDEP. This dielectrophoresis technique provides a new way to manipulate cells and can be readily implemented on programmable multielectrode devices. PMID- 17702530 TI - Investigations of the effects of gender, diurnal variation, and age in human urinary metabolomic profiles. AB - Metabolomics may have the capacity to revolutionize disease diagnosis through the identification of scores of metabolites that vary during environmental, pathogenic, or toxicological insult. NMR spectroscopy has become one of the main tools for measuring these changes since an NMR spectrum can accurately identify metabolites and their concentrations. The predominant approach in analyzing NMR data has been through the technique of spectral binning. However, identification of spectral areas in an NMR spectrum is insufficient for diagnostic evaluation, since it is unknown whether areas of interest are strictly caused by metabolic changes or are simply artifacts. In this paper, we explore differences in gender, diurnal variation, and age in a human population. We use the example of gender differences to compare traditional spectral binning techniques (NMR spectral areas) to novel targeted profiling techniques (metabolites and their concentrations). We show that targeted profiling produces robust models, generates accurate metabolite concentration data, and provides data that can be used to help understand metabolic differences in a healthy population. Metabolites relating to mitochondrial energy metabolism were found to differentiate gender and age. Dietary components and some metabolites related to circadian rhythms were found to differentiate time of day urine collection. The mechanisms by which these differences arise will be key to the discovery of new diagnostic tests and new understandings of the mechanism of disease. PMID- 17702531 TI - Effect of magnetic field strength on NMR-based metabonomic human urine data. Comparative study of 250, 400, 500, and 800 MHz. AB - Metabonomic analysis of urine utilizing high-resolution NMR spectroscopy and chemometric techniques has proven valuable in characterizing the biochemical response to an intervention. To assess the effect of magnetic field strength on information contained in NMR-based metabonomic data sets, 1H NMR spectra were acquired on 250-, 400-, 500-, and 800-MHz instruments, respectively, on the same set of human urine samples collected before and after dietary interventions with milk and with meat proteins. Partial least-squares regression discriminant analyses (PLS-DA) were performed in order to elucidate the ability of the 1H spectra acquired at various field strengths to identify possible spectral differences and discriminate between pre- and postintervention samples. The loadings from PLS-DA contained the same spectral regions, implying that the same metabolites were involved in the discrimination independent of magnetic field strength. The investigation revealed a strong increase in prediction performance and thereby spectral information content when increasing the magnetic field strength from 250 to 500 MHz, while from 500 to 800 MHz the increase was less pronounced. PMID- 17702532 TI - Is combination therapy with inhaled anticholinergics and beta2-adrenoceptor agonists justified for chronic obstructive pulmonary disease? AB - Chronic obstructive pulmonary disease (COPD) is a debilitating condition characterised by progressive, irreversible airflow limitation. The economic and social burden of the disease is enormous. The treatment of COPD is guided by the stage of the disease and is aimed primarily at control of symptoms. Bronchodilators are the cornerstone of pharmacological management of COPD. Short acting bronchodilators (beta(2)-adrenoceptor agonists and anticholinergics) have been available for many years and have been extensively studied as individual agents and in combination. When administered in combination, short-acting bronchodilators provide superior bronchodilation compared with individual agents given alone. However, the improvement in bronchodilation does not translate into an improvement in quality-of-life (QOL) indices. More recently, long-acting beta(2)-adrenoceptor agonists (LABAs) and anticholinergics have been introduced, and current guidelines recommend regular use of these agents in COPD of Global initiative for chronic Obstructive Lung Disease (GOLD) stage II or more. Combining short-acting anticholinergics with LABAs for daily use has been evaluated, but this combination does not confer any advantage in terms of subjective improvement or prevention of exacerbations. Combining the long-acting anticholinergic tiotropium bromide with formoterol given once or twice daily improves airway obstruction and hyperinflation. However, the effects of combinations of long-acting bronchodilators on patients' symptom scores, QOL and exacerbations remain to be studied. Ultra-LABAs, which are in development, may enable use of a combination of long-acting bronchodilators in a single inhaler for once-daily use, thus simplifying the regimen. This article discusses the results of various clinical trials comparing the efficacy of bronchodilators given alone or in combination to patients with COPD, with emphasis on the effects of these agents on bronchodilation, symptomatic and objective improvements in QOL and prevention of exacerbations. PMID- 17702533 TI - Viscosupplementation with hyaluronans for osteoarthritis of the knee: clinical efficacy and economic implications. AB - Treatment with intra-articular viscosupplementation with hyaluronan (hyaluronic acid) and its derivatives is an important component of the management of osteoarthritis (OA) of the knee. Several intra-articular hyaluronan formulations are now available that vary in their physical properties, duration of effect and treatment schedules. Although aspects regarding their mechanism of action are not completely understood, numerous clinical trials, systematic reviews and meta analyses have confirmed the efficacy of intra-articular hyaluronan therapies for relieving OA-related pain and improving joint function. Data indicate that intra articular hyaluronan preparations provide OA pain relief that is comparable to or greater than that observed with conventional treatment, NSAID medications, intra articular corticosteroids, arthroscopic lavage, physical therapy and exercise. Other studies indicate that multiple courses of hyaluronan are effective. Intra articular hyaluronan formulations are well tolerated and are associated with a low incidence of adverse effects, usually localised to the injected joint. Local adverse events associated with intra-articular hyaluronan products are typically mild to moderate in severity, benign and transient, although their aetiology is unknown. The cost effectiveness of intra-articular hyaluronan has been demonstrated, but only in a limited number of studies. Cost savings with intra articular hyaluronan can also be realised with reduction of NSAID medication use and the possibility of delaying total knee replacement, which can reduce the need for costly revision procedures. Because different intra-articular hyaluronan formulations require different numbers of injections and office visits, are associated with variable treatment costs, and provide varying degrees of efficacy, not all intra-articular hyaluronan formulations may be equally cost effective over time. PMID- 17702534 TI - Targeting vascular endothelial growth factor: a promising strategy for treating age-related macular degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the industrialised world. While treatment options for advanced AMD have been rather limited until recently, the introduction of intravitreal injections of anti-angiogenic agents appears to be a promising and revolutionary mode of treatment for this blinding disease. Vascular endothelial growth factor (VEGF) appears to play a pivotal role in the pathogenesis of choroidal neovascularisation, one of the cornerstones of advanced AMD. Pegaptanib, the first anti-VEGF treatment approved for AMD patients, is a VEGF-neutralising aptamer that specifically inhibits one isoform of VEGF (VEGF-165). Although evidence suggested that pegaptanib was superior to previous treatment options, results with this agent were still unsatisfactory. Ranibizumab is a humanised anti-VEGF monoclonal antibody fragment that inhibits all isotypes of VEGF. This new drug has demonstrated a high efficacy profile in terms of inhibiting disease progression and even improving visual acuity. Bevacizumab is a full-length anti VEGF antibody that was originally approved for use in metastatic colon cancer and is under investigation as a low-cost off-label alternative for patients with AMD. There is growing evidence that this drug may be an effective and safe alternative to the more expensive ranibizumab, although prospective multicentre trials are required to fully investigate this issue. Undoubtedly, the concept of directly injecting anti-VEGF drugs into the vitreal cavity brings new hope to many AMD patients. PMID- 17702536 TI - Direct medical costs of serious gastrointestinal ulcers among users of NSAIDs. AB - BACKGROUND: The occurrence and prevention of gastrointestinal ulcers during use of NSAIDs has become a major healthcare issue. OBJECTIVE: To determine the direct medical costs of serious NSAID-related ulcer complications. METHOD: An observational cost-of-illness study was conducted in a large general hospital serving a population of 152,989 persons. From November 2001 to December 2003 all consecutive patients hospitalised with serious NSAID-related ulcer complications were identified. Serious NSAID-related ulcer complications were defined as ulcerations of the stomach or proximal duodenum causing perforation, obstruction or bleeding that occurred during the use of NSAIDs, necessitating hospitalisation of the patient. Data were retrieved with respect to days hospitalised and the number and type of diagnostic and therapeutic interventions. The main outcome measure was estimated mean direct medical costs of resources used. RESULTS: A total of 104 patients were hospitalised with serious NSAID-related ulcer complications (incidence 31.4 per 100,000 persons per year). Most patients were elderly (mean 70.4 years, SD 16.7). In-hospital mortality was 10.6%. Mean direct medical costs were euro 8375 (95% CI 7067, 10 393). On the basis of these results, we estimated that approximately 5105 people are hospitalised with serious NSAID-related ulcer complications in The Netherlands each year, of whom 541 die in hospital. The total annual direct medical costs for serious NSAID related ulcer complications in The Netherlands were estimated to be euro 42,754 375 (95% CI 36 077 035, 53 056 265). CONCLUSIONS: Serious NSAID-related ulcer complications have a mortality rate of 10.6% in The Netherlands and the annual direct medical costs to the country of such complications are approximately euro 42,750 000. PMID- 17702535 TI - Community and long-term care management of Parkinson's disease in the elderly: focus on monoamine oxidase type B inhibitors. AB - Parkinson's disease affects up to 1 million people in the US, most of them elderly. Motor and non-motor symptoms can be significantly disabling to the point of necessitating institutionalisation. Age-related changes in drug absorption, distribution, metabolism and excretion complicate the treatment of elderly patients with Parkinson's disease. General management principles include initiation of medication at low doses with gradual titration based on clinical effects, avoidance of certain classes of drugs (e.g. anticholinergics), and attention to polypharmacy and its risk for potentially toxic drug interactions. Levodopa remains the most efficacious anti-Parkinson's disease medication and should be the cornerstone of therapy in the elderly Parkinson's disease patient. Use of dopamine receptor agonists, amantadine and anticholinergic drugs in the elderly is limited by high risk for psychotoxicity. Catechol-O-methyltransferase inhibitors may be used to augment levodopa in the setting of 'wearing off' (i.e. motor fluctuations). Monoamine oxidase type B (MAO-B) inhibitors can be used across the spectrum of disease severity, but selegiline (deprenyl), the prototype in this class, is characterised by low and erratic bioavailability of the parent drug and conversion to amphetamine metabolites that may increase the risk of adverse events. A new orally disintegrating tablet formulation overcomes some of these limitations. Rasagiline is a new, selective, second-generation MAO-B inhibitor that is chemically and metabolically distinct from selegiline. The favourable safety profile of rasagiline in the elderly and its once-daily formulation may maximise drug adherence and improve outcomes. PMID- 17702538 TI - Environmental contaminants in bald eagle eggs from the Aleutian archipelago. AB - We collected 136 fresh and unhatched eggs from bald eagle (Haliaeetus leucocephalus) nests and assessed productivity on eight islands in the Aleutian archipelago, 2000 to 2002. Egg contents were analyzed for a broad spectrum of organochlorine (OC) contaminants, mercury (Hg), and stable isotopes of carbon (delta13C) and nitrogen (delta15N). Concentrations of polychlorinated biphenyls (SigmaPCBs), p,p'-dichlorodiphenyldichloroethylene (DDE), and Hg in bald eagle eggs were elevated throughout the archipelago, but the patterns of distribution differed among the various contaminants. Total PCBs were highest in areas of past military activities on Adak and Amchitka Islands, indicating local point sources of these compounds. Concentrations of DDE and Hg were higher on Amchitka Island, which was subjected to much military activity during World War II and the middle of the 20th century. Concentrations of SigmaPCBs also were elevated on islands with little history of military activity (e.g., Amlia, Tanaga, Buldir), suggesting non-point sources of PCBs in addition to point sources. Concentrations of DDE and Hg were highest in eagle eggs from the most western Aleutian Islands (e.g., Buldir, Kiska) and decreased eastward along the Aleutian chain. This east to-west increase suggested a Eurasian source of contamination, possibly through global transport and atmospheric distillation and/or from migratory seabirds. Eggshell thickness and productivity of bald eagles were normal and indicative of healthy populations because concentrations of most contaminants were below threshold levels for effects on reproduction. Contrary to our predictions, contaminant concentrations were not correlated with stable isotopes of carbon (delta13C) or nitrogen (delta15N) in eggs. These latter findings indicate that contaminant concentrations were influenced more by point sources and geographic location than trophic status of eagles among the different islands. PMID- 17702537 TI - Withdrawal of fall-risk-increasing drugs in older persons: effect on mobility test outcomes. AB - BACKGROUND: Previously, we have shown that withdrawal of fall-risk-increasing drugs (FRIDs) as a single intervention reduces falls incidence. Improvement of mobility may be an important factor in this finding and we therefore tested whether mobility tests improved after FRID withdrawal. METHODS: In a prospective cohort study of 137 geriatric outpatients (age 77.7 +/- 5.7 years), FRIDs were withdrawn in all fallers, if possible, between April 2003 and November 2004. All patients underwent mobility testing at baseline, including a 10m walking test (WT), Timed 'Up & Go' Test (TUGT), Functional Reach Test (FRT), isometric quadriceps femoris muscle strength and a body sway test. Retesting occurred at a mean follow-up of 6.7 months. The effect of FRID withdrawal (discontinuation or dose reduction) on test outcomes was calculated using both multivariate linear and binary logistic regression analyses. RESULTS: In the group of fallers with FRID withdrawal all mobility tests improved, as opposed to non-fallers and fallers without FRID withdrawal. After adjustment for confounders, the odds ratio of no improvement was 0.14 (95% CI 0.03, 0.59) for the TUGT, 0.19 (95% CI 0.04, 0.86) for the 10m WT, 0.48 (95% CI 0.14, 1.57) for the FRT, 0.46 (95% CI 0.14, 1.48) for the quadriceps strength test and 0.49 (95% CI 0.15, 1.62) for the body sway test. CONCLUSION: The results of this study suggest that FRID withdrawal may be effective as a single intervention in a geriatric setting. In addition to reducing falls (as shown in our previous study), FRID withdrawal significantly improved 10m WT and TUGT results over a mean follow-up period of 6.7 months. These tests may therefore be useful tools for monitoring the clinical effect of FRID withdrawal. PMID- 17702539 TI - In situ and laboratory bioassays with Chironomus riparius larvae to assess toxicity of metal contamination in rivers: the relative toxic effect of sediment versus water contamination. AB - We used bioassays employing head capsule width and body length increase of Chironomus riparius larvae as end points to evaluate metal contamination in streams. Bioassays were performed in situ near an abandoned Portuguese goldmine in the spring of 2003 and 2004. Bioassays also were performed under laboratory conditions with water and sediment collected from each stream to verify if laboratory bioassays could detect in situ toxicity and to evaluate the relative contribution of sediment and water to overall toxicity. We used field sediments with control water and control sediments with field water to discriminate between metal contamination in water and sediment. Field water with dry and sieved, organic matter-free, and nontreated sediments was used to determine the toxicity of heavy metals that enter the organism through ingested material. In both in situ and laboratory bioassays, body length increase was significantly inhibited by metal contamination, whereas head capsule width was not affected. Body length increase was more affected by contaminated sediment compared to contaminated water. The lowest-effect level of heavy metals was observed in the dry and sieved sediment that prevented ingestion of sediment particles by larvae. These results suggest that body length increase of C. riparius larvae can be used to indicate the impact of metal contamination in rivers. Chironomus riparius larvae are more affected by heavy metals that enter the organism through ingested sediment than by heavy metals dissolved in the water column. Nevertheless, several factors, such as the particle size and organic matter of sediment, must be taken into account. PMID- 17702540 TI - Fate of atrazine in a grassed phytoremediation system. AB - Atrazine is a well-known contaminant of surface waters and has been implicated in point-source pollution at agrochemical dealerships in the Midwest. Although the fate of atrazine has been well documented in soil and water, little is known about the fate of this contaminant and its metabolites within a grassed system. In the present study, [U-ring-14C]atrazine was added to soil in closed systems to determine the fate of the parent compound and its metabolites in soil, including degradation and movement into plants and air. Soil was treated with 25 mg/kg [14C]labeled atrazine and allowed to age for 5 d. Four systems then were amended with a mixture of prairie grasses, and the remaining four chambers were maintained as unvegetated controls. Dissipation and distribution of parent compound and metabolites were recorded for 21 d. Plant uptake of [14C]residue was less than 0.5% of applied radioactivity. Approximately 2% of total applied [14C]atrazine was mineralized to [14C]CO2, with no differences between vegetated and unvegetated systems. Mass balance recoveries were 76% for grassed systems and 77.5% for unvegetated controls. Approximately 40% of applied radioactivity remained bound to the soil following extraction. The most prevalent extractable compound detected in the soil was the parent, atrazine; major metabolites in soil were deethylatrazine (DEA) and didealkylatrazine (DDA). Leaf tissue contained concentrations of atrazine and key metabolites, i.e., DEA, DDA, and deisopropylatrazine (DIA), above those allowed in forage grasses by the U.S. Environmental Protection Agency; another key metabolite, hydroxyatrazine, was the most prevalent compound identified in both leaf and root tissue. PMID- 17702541 TI - How does crop type influence risk from pesticides to the aquatic environment? AB - National-level risk mapping was undertaken to identify specific situations within England with the greatest potential for impacts on aquatic biodiversity from normal agricultural use of pesticides. Calculations of exposure via spray drift and drainflow were differentiated by landscape type, region, and crop and then compared with toxicity to the indicator organisms Daphnia magna and algae. The approach incorporated regional-level information regarding pesticide usage derived from farm visits. Risk was calculated for individual water bodies and then aggregated and mapped for each of 5,760 individual catchments ranging in area up to 248 km2. Type of crop adjacent to water was the major driver for risk, and orchards were identified as the crop associated with the greatest potential risk to the aquatic environment. Crops such as cereals, oilseeds, and potatoes are more widely grown in England but have potential risk an order of magnitude smaller than that for orchards. Several of the pesticides that contribute most to risk have been withdrawn from use since collection of the most recent usage data. Driven by crop distribution, surface waters adjacent to orchards in the midwest and southeast of England are predicted to be most at risk of ecological impacts from agricultural pesticide use. This information can be used in targeting monitoring campaigns designed to protect the aquatic environment. PMID- 17702542 TI - Toxicity of nitrogenous fertilizers to eggs of snapping turtles (Chelydra serpentina) in field and laboratory exposures. AB - Many reptiles oviposit in soil of agricultural landscapes. We evaluated the toxicity of two commonly used nitrogenous fertilizers, urea and ammonium nitrate, on the survivorship of exposed snapping turtle (Chelydra serpentina) eggs. Eggs were incubated in a community garden plot in which urea was applied to the soil at realistic rates of up to 200 kg/ha in 2004, and ammonium nitrate was applied at rates of up to 2,000 kg/ha in 2005. Otherwise, the eggs were unmanipulated and were subject to ambient temperature and weather conditions. Eggs were also exposed in the laboratory in covered bins so as to minimize loss of nitrogenous compounds through volatilization or leaching from the soil. Neither urea nor ammonium nitrate had any impact on hatching success or development when exposed in the garden plot, despite overt toxicity of ammonium nitrate to endogenous plants. Both laboratory exposures resulted in reduced hatching success, lower body mass at hatching, and reduced posthatching survival compared to controls. The lack of toxicity of these fertilizers in the field was probably due to leaching in the soil and through atmospheric loss. In general, we conclude that nitrogenous fertilizers probably have little direct impacts on turtle eggs deposited in agricultural landscapes. PMID- 17702543 TI - Contaminant-associated alteration of immune function in black-footed albatross (Phoebastria nigripes), a North Pacific predator. AB - Environmental pollution is ubiquitous and can pose a significant threat to wild populations through declines in fitness and population numbers. To elucidate the impact of marine pollution on a pelagic species, we assessed whether toxic contaminants accumulated in black-footed albatross (Phoebastria nigripes), a wide ranging North Pacific predator, are correlated with altered physiological function. Blood samples from adult black-footed albatrosses on Midway Atoll, part of the Hawaiian (USA) archipelago, were analyzed for organochlorines (e.g., polychlorinated biphenyls [PCBs] and chlorinated pesticides), trace metals (silver, cadmium, tin, lead, chromium, nickel, copper, zinc, arsenic, selenium, and total mercury), and a sensitive physiological marker, peripheral white blood cell immune function (mitogen-induced lymphocyte proliferation and macrophage phagocytosis). We found a positive significant relationship between organochlorines, which were highly correlated within individual birds (p < 0.001, r > 0.80, Spearman correlation for all comparisons; PCBs, 160 +/- 60 ng/ml plasma [mean +/- standard deviation]; DDTs, 140 +/- 180 ng/ml plasma; chlordanes, 7.0 +/ 3.6 ng/ml plasma; hexachlorobenzene, 2.4 +/- 1.5 ng/ml plasma; n = 15) and increased lymphocyte proliferation (p = 0.020) as well as percentage lymphocytes (p = 0.033). Mercury was elevated in black-footed albatrosses (4,500 +/- 870 ng/ml whole blood, n = 15), and high mercury levels appeared to be associated (p = 0.017) with impaired macrophage phagocytosis. The associations we documented between multiple contaminant concentrations and immune function in endangered black-footed albatrosses provide some of the first evidence that albatrosses in the North Pacific may be affected by environmental contamination. Our results raise concern regarding detrimental health effects in pelagic predators exposed to persistent marine pollutants. PMID- 17702544 TI - Time- and concentration-dependent metabolic and genomic responses to exposure to resin acids in brown trout (Salmo trutta m. lacustris). AB - The presence of metabolically conjugated resin acids (RAs) in the bile is considered to be a sensitive indicator for exposure of fish to pulp and paper industry effluents; however, to our knowledge, no comprehensive kinetic study of this response has been made. Juvenile brown trout (Salmo trutta m. lacustris) were exposed to a waterborne mixture of seven RAs (wood rosin) in time (0.1-192.0 h; average concentration, 8 microg/L) and dose (average concentrations, 0, 0.6, 4, 14, and 78 microg/L; 10 d) series, and total RAs were analyzed in bile. In time-dependent exposure, total RAs in bile increased up to 24 h. In concentration dependent exposure, RAs increased along with the concentration of RAs in water, revealing a high-capacity biotransformation and elimination system in trout liver. In concentration-dependent exposures, the effects on the hepatic transcriptome was studied using a high-density cDNA microarray, and dose dependent changes were found in a large number of genes. Resin acids interfered with iron metabolism, as evidenced by the decrease in transcripts for iron transporters and heme-containing proteins. Expression of genes encoding for enzymes degrading reactive oxygen species also decreased. Coordinated down regulation of the protein biosynthesis machinery could result from inhibition of the energy metabolism. A number of changes in gene expression indicated recovery and remodeling of hepatic tissues. We conclude that analysis of total RAs in the bile provides a sensitive and quantitative tool for assessing the exposure of fish to waterborne RAs, whereas multiple gene expression analyses are able to elucidate simultaneous cellular functions for use as potential biomarkers of RAs. PMID- 17702545 TI - Chemical structure-based predictive model for methanogenic anaerobic biodegradation potential. AB - Many screening-level models exist for predicting aerobic biodegradation potential from chemical structure, but anaerobic biodegradation generally has been ignored by modelers. We used a fragment contribution approach to develop a model for predicting biodegradation potential under methanogenic anaerobic conditions. The new model has 37 fragments (substructures) and classifies a substance as either fast or slow, relative to the potential to be biodegraded in the "serum bottle" anaerobic biodegradation screening test (Organization for Economic Cooperation and Development Guideline 311). The model correctly classified 90, 77, and 91% of the chemicals in the training set (n = 169) and two independent validation sets (n = 35 and 23), respectively. Accuracy of predictions of fast and slow degradation was equal for training-set chemicals, but fast-degradation predictions were less accurate than slow-degradation predictions for the validation sets. Analysis of the signs of the fragment coefficients for this and the other (aerobic) Biowin models suggests that in the context of simple group contribution models, the majority of positive and negative structural influences on ultimate degradation are the same for aerobic and methanogenic anaerobic biodegradation. PMID- 17702546 TI - Effects of methylmercury on reproduction in American kestrels. AB - Sixty breeding pairs of captive American kestrels (Falco sparverius) were exposed to a range of sublethal dietary concentrations of mercury (Hg), in the form of methylmercuric chloride, and their subsequent reproduction was measured. Egg production, incubation performance, and the number and percent of eggs hatched decreased markedly between 3.3 and 4.6 mg/kg dry weight of Hg (1.2 and 1.7 mg/kg wet wt), in the diet. The number of fledglings and the percent of nestlings fledged were reduced markedly at 0.7 mg/kg dry weight (0.3 mg/kg wet wt) and declined further between 2 and 3.3 mg/kg dry weight (0.7 and 1.2 mg/kg wet wt). Dietary concentrations of >or=4.6 mg/kg dry weight (1.7 mg/kg wet wt) were associated with total fledging failure. The estimated decline in fledged young per pair (24%, Bayesian regression) for kestrels consuming 0.7 mg/kg dry weight (0.3 mg/ kg wet wt) raises concerns about population maintenance in areas subject to high inputs of anthropogenic Hg. Mercury concentrations in 20 second-laid eggs collected from all groups were related to dietary concentrations of Hg, and the Hg concentrations in 19 of these eggs were related to eggs laid and young fledged. Concentrations of Hg in eggs from the highest diet group (5.9 mg/kg dry wt; 2.2 mg/kg wet wt) were higher than egg concentrations reported for either wild birds or for captive birds (nonraptors) fed dry commercial food containing 5 mg/kg methylmercury. Accumulation ratios of Hg from diets to eggs were higher than those reported for feeding studies with other species. PMID- 17702547 TI - [Association of streptococcal pharyngitis with complicated appendicitis]. AB - Streptococcal pharyngitis can be accompanied by right lower abdominal quadrant pain, which often is linked to mesenteric adenitis. We report on a case of such misleading association in a child. CASE REPORT: A 6-year-old child presented pain in the right lower abdominal quadrant and fever with 39 degrees C temperature for 24 h; clinical examination showed pharyngeal erythema and local abdominal tenderness. Strep-test was positive. Abdominal ultrasound visualized signs of appendicitis. The child was operated on for complicated appendicitis. COMMENTS: The association of pharyngitis and appendicitis is particularly misleading because mesenteric adenitis is the most common cause of right lower quadrant tenderness in children with pharyngitis. PMID- 17702548 TI - [Nonoperative management of splenic trauma in children]. AB - In haemodynamically stable children with splenic trauma, conservative treatment is recommended to preserve the spleen and prevent potentially lethal post splenectomy infectious complications. We report on the case of a 11-year-old child who suffered a fistula of a huge subcapsular splenic hematoma into the colon, 16 days after the traumatism. Decision to sustain the non-operative treatment allowed the preservation of the spleen without complications. PMID- 17702549 TI - [Treatment of airway inflammation in cystic fibrosis]. AB - Cystic fibrosis airway inflammation is characterized by neutrophilic efflux and high levels of proinflammatory cytokines such as IL-8 and IL-6. Inhaled corticosteroids are widely used despite lack of evidence of efficacity. Despite evidence of efficacity of ibuprofen, many clinicians have chosen not to use this therapy because of concerns regarding potential side effects. Azithromycin has antiinflammatory properties and is effective in cystic fibrosis (CF) patients. Deoxyribonuclease (rhDNase) has been shown to improve lung function in patients with cystic fibrosis and may also have a positive effect on inflammation. Other antiinflammatory drugs are in the process of validation. PMID- 17702550 TI - [Socially vulnerable children: experience in a medico-social consultation unit of a French university hospital]. PMID- 17702551 TI - [The National Federation of Pediatricians and Neonatologists changes title to the French Society of Neonatology]. PMID- 17702552 TI - Semi-supervised learning of the hidden vector state model for extracting protein protein interactions. AB - OBJECTIVE: The hidden vector state (HVS) model is an extension of the basic discrete Markov model in which context is encoded as a stack-oriented state vector. It has been applied successfully for protein-protein interactions extraction. However, the HVS model, being a statistically based approach, requires large-scale annotated corpora in order to reliably estimate model parameters. This is normally difficult to obtain in practical applications. METHODS AND MATERIALS: In this paper, we present two novel semi-supervised learning approaches, one based on classification and the other based on expectation-maximization, to train the HVS model from both annotated and un annotated corpora. RESULTS AND CONCLUSION: Experimental results show the improved performance over the baseline system using the HVS model trained solely from the annotated corpus, which gives the support to the feasibility and efficiency of our approaches. PMID- 17702553 TI - Diabetic and non-diabetic subjects with ischemic stroke: differences, subtype distribution and outcome. AB - BACKGROUND AND AIM: Diabetes mellitus increases the risk of stroke, and pathophysiological changes of diabetic cerebral vessels may differ in comparison with non-diabetic ones; nonetheless, the clinical and prognostic profile of stroke in diabetic patients is not yet fully understood. On this basis, the aim of our study was to evaluate cerebrovascular risk factor prevalence in diabetic stroke patients in comparison with non-diabetics, to analyze whether diabetics have a different prevalence of stroke subtypes as classified by the TOAST classification, and determine whether diabetics and non-diabetics have a different prognosis. METHODS AND RESULTS: We enrolled 102 diabetics and 204 non diabetic subjects with acute ischemic stroke, matched by sex and age (+/-3 years). We used as outcome indicators the Scandinavian Stroke Scale (SSS) score at admission and the modified Rankin disability scale at discharge and at a 6 month follow-up. We classified ischemic stroke according to the TOAST classification. Diabetes was associated with lacunar ischemic stroke subtype, with a record of hypertension, and with a better SSS score at admission. The association of diabetes with lacunar stroke remained significant even after adjustment for hypertension or for large artery atherosclerotic and cardioembolic stroke subtypes. CONCLUSION: Our study shows some significant differences in acute ischemic stroke among diabetics in comparison with non-diabetics (higher frequency of hypertension, higher prevalence of lacunar stroke subtype, lower neurological deficit at admission in diabetics). PMID- 17702555 TI - Maternal nutritional condition and genetic differentiation affect brood size and offspring body size in Nicrophorus. AB - In most animal species, brood size and body size exhibit some variation within and between populations. This is also true for burying beetles (genus Nicrophorus), a group in which the body size of offspring depends critically on the number of offspring competing for food due to the discrete nature of resource used for larval nutrition (vertebrate carcasses). In one species, brood size and body size are correlated with population density, and appear to be phenotypically plastic. We investigated potential proximate causes of between-population variation in brood size and body size in two species, Nicrophorus vespilloides and Nicrophorus defodiens. Our first experiment supported the notion that brood size is phenotypically plastic, because it was affected by environmental variation in adult nutritional condition. We found that the pre-breeding nutritional status of female N. vespilloides affected the number of eggs they laid, the number of surviving larvae in their broods, and the body size of their offspring. We do not know whether this plasticity is adaptive because greater offspring body size confers an advantage in contests over breeding resources, or whether starved females are constrained to produce smaller clutches because they cannot fully compensate for their poor pre-breeding nutritional status by feeding from the carcass. Our second experiment documents that brood size, specifically the infanticidal brood-size adjustment behavior, has undergone genetic differentiation between two populations of N. defodiens. Even under identical breeding conditions with identical numbers of first-instar larvae, females descended from the two populations produced broods of different size with corresponding differences in offspring body size. PMID- 17702554 TI - Supercritical fluid drying of carbohydrates: selection of suitable excipients and process conditions. AB - The processibility of 15 carbohydrates, more or less commonly used, was investigated as excipients in supercritical fluid drying. The focus was on the ability to produce amorphous powder, the stability of the powders towards crystallisation, and the residual water and ethanol content. The aqueous solutions were sprayed into a pressurised carbon dioxide-ethanol mixture flowing cocurrently through a coaxial two-fluid nozzle. The powder characteristics appeared to be influenced by the supersaturation level reached during the SCF drying process and by the properties of the sugar species, such as water solubility and glass transition temperature, or the solution viscosities. The stability and the residual solvent content of a selected set of sugars and some mixtures were further analysed. The stability of amorphous powders was investigated at 4 degrees C, room temperature, 40 and 50 degrees C. Lactose, maltose, trehalose, raffinose, cyclodextrin, low-molecular-weight dextran and inulin could form free-flowing powders that remained amorphous during the 3-month stability study. Sucrose had to be mixed with other sugars to form a stable amorphous powder. Ethanol could be entrapped in supercritical fluid dried low molecular-weight sugars, whereas polysaccharide powders were free of ethanol. Measures to prevent or overcome the presence of ethanol are discussed. PMID- 17702557 TI - Host-pathogen interactions: pas de deux. PMID- 17702556 TI - Crosstalk at the initial encounter: interplay between host defense and ameba survival strategies. AB - The host-parasite relationship is based on a series of interplays between host defense mechanisms and parasite survival strategies. Progress has been made in understanding the role of host immune response in amebiasis. While host cells elaborate diverse mechanisms for pathogen expulsion, amebae have also developed complex strategies to modulate host immune response and facilitate their own survival. This paper will give an overview of current research on the mutual interactions between host and Entamoeba histolytica in human and experimental amebiasis. Understanding this crosstalk is crucial for the effective design and implementation of new vaccines and drugs for this leading parasitic disease. PMID- 17702558 TI - Interleukin-12 and tuberculosis: an old story revisited. AB - Our understanding of the role of interleukin (IL)-12 in controlling tuberculosis has expanded because of increased interest in other members of the IL-12 family of cytokines. Recent data show that IL-12, IL-23 and IL-27 have specific roles in the initiation, expansion and control of the cellular response to tuberculosis. Specifically, IL-12, and to a lesser degree IL-23, generates protective cellular responses and promotes survival, whereas IL-27 moderates the inflammatory response and is required for long-term survival. Paradoxically, IL-27 also limits bacterial control, suggesting that a balance between bacterial killing and tissue damage is required for survival. Understanding the balance between IL-12, IL-23 and IL-27 is crucial to the development of immune intervention in tuberculosis. PMID- 17702559 TI - The role of leukocytes bearing Natural Killer Complex receptors and Killer Immunoglobulin-like Receptors in the immunology of malaria. AB - The biology of Natural Killer (NK) cells and other NK Receptor (NKR)(+) leukocytes has largely been elucidated in viral or cancer systems, and involvement in other diseases or infectious states is less clearly defined. Recently, however, clear evidence has emerged for a role in malaria. NK cells and NKR(+) leukocytes significantly control susceptibility and resistance to both malaria infection and severe disease syndromes in murine models, in dependence upon receptors encoded within the Natural Killer Complex (NKC). Plasmodium falciparum can rapidly activate human NKR(+) gammadelta T cells and NK cells in vitro, and these responses are controlled partly by NKR loci encoded within the human syntenic NKC and Killer Immunoglobulin-like Receptor (KIR) genomic regions. Neither erythrocytes nor malaria parasites express HLA or MHC Class I-like homologues, or obvious stress-type ligands, suggesting the possibility of novel NKR recognition mechanisms. Parasite-derived ligands such as P. falciparum Erythrocyte Membrane Protein-1 (PfEMP-1) and glycosylphosphatidylinositol (GPI) regulate some of these diverse responses. Population-based immunogenetic analyses should allow the identification of NKC and KIR loci controlling innate and adaptive immune responses to malaria and associated with altered risk of infection and disease. PMID- 17702560 TI - Defensins in the immunology of bacterial infections. AB - Defensins are a component of the host response against bacterial infections. Multiple studies suggest a linked upregulation of beta-defensins and pro inflammatory cytokines expression in various tissues, as well as the possibility of mutual induction. Recent data demonstrate the importance of nucleotide-binding oligomerization proteins for the expression of defensins, and associate low levels of alpha-defensins expression by intestinal Paneth cells with susceptibility to Crohn's disease of the ileum. A novel anti-toxin activity has been identified for several alpha- and theta-defensins, expanding the repertoire of the antimicrobial functions of defensins. It has been shown that bacterial proteins can inactivate the action of defensins, and that pathogen type III secretion systems (T3SS) manipulate defensins expression via T3SS-mediated inhibition of the NF-kappaB pathway. PMID- 17702562 TI - Ancestral animal genomes reconstruction. AB - Reconstructing the evolutionary history of all species is an essential objective for evolutionary biologists. Much effort has been devoted to ancestral genome reconstruction. Numbered genome sequencing of current and extinct organisms enables evolutionary biologists to compare genomic data and reconstruct ancestral genomes. Long-term conservation of karyotype, gene order or gene sequence are clues to the heritage of each species and these data can be used by evolutionary biologists to synthesize distant ancestral genomes. In this review, we referred to the recent advances in ancestral genomes reconstruction and the insight it gives on genome evolution. Special attention is devoted to the use of this knowledge to understand the evolution of the immune system genes. PMID- 17702561 TI - Alternatively activated macrophages in helminth infections. AB - Helminthic parasites can trigger highly polarized immune responses typically associated with increased numbers of CD4(+) Th2 cells, eosinophils, mast cells, and basophils. These cell populations are thought to coordinate an effective response ultimately leading to parasite expulsion, but they also play a role in the regulation of associated pathologic inflammation. Recent studies suggest that macrophages, conventionally associated with IFN-gamma-dominant Th1-type responses to many bacteria and viruses, also play an essential role in the Th2-type inflammatory response. These macrophages are referred to as alternatively activated macrophages (AAMPhis) as they express a characteristic pattern of cell surface and secreted molecules distinct from that of classically activated macrophages (CAMPhis) associated with microbe infections. In this review, we will discuss recent findings regarding the role of AAMPhis in the development of disease and host protection following helminth infection. PMID- 17702563 TI - Plasma treatment of air pollution control residues. AB - Air pollution control (APC) residues from waste incineration have been blended with silica and alumina and the mix melted using DC plasma arc technology. The chemical composition of the fully amorphous homogeneous glass formed has been determined. Waste acceptance criteria compliance leach testing demonstrates that the APC residue derived glass releases only trace levels of heavy metals (Pb (<0.007mg/kg) and Zn (0.02mg/kg)) and Cl(-) (0.2mg/kg). These are significantly below the limit values for disposal to inert landfill. It is concluded that plasma treatment of APC residues can produce an inert glass that may have potential to be used either in bulk civil engineering applications or in the production of higher value glass-ceramic products. PMID- 17702564 TI - Thymic generation and regeneration: a new paradigm for establishing clinical tolerance of stem cell-based therapies. AB - Tolerance to tissue-engineering products is a major obstacle hindering the clinical application of this rapidly advancing technology. Manipulation of central tolerance, by establishing thymus chimerism of both donor and host derived haemopoietic cells (haemopoietic stem cell transplant--HSCT), should purge any T cells reactive to potential donor organ or tissue transplant. A functional thymus, however, is required to induce chimerism and repopulate the peripheral T cell pool, but age-related thymic atrophy and damage caused by ablative conditioning regimes significantly reduce thymic function and increase incident of infection-dependent morbidity and mortality. Thus rejuvenation of the thymus alongside HSCT may potentiate the use of this strategy in the clinic. In addition, the use of thymic epithelial progenitor cell technology may allow growth of ex vivo thymic tissue for use in clinical situations of immunodeficiency as well as in establishing tolerance to tissue/organ products derived from the same source. PMID- 17702566 TI - Barrel cortex and whisker-mediated behaviors. AB - Neural networks of the rodent barrel cortex are particularly tractable for developing a quantitative understanding of response transformations in a cortical column. A column in barrel cortex consists of approximately 10 compartments. Two thalamic input pathways, a sensory lemniscal one and sensorimotor paralemniscal one, are transformed to approximately 7 population outputs, each with distinct spatiotemporal response characteristics. Granular and supragranular layers are sites of segregated processing in lemniscal and paralemniscal pathways, whereas infragranular layers are sites of intracolumnar, lemniscal/paralemniscal integration. Individual thalamocortical connections are relatively weak, and a considerable fraction of thalamocortical afferents contributes to each sensory response. Intracortically, relatively few but strong synaptic connections contribute to sensory responses, and responses are rapidly terminated by inhibition. Overall cortical population activity is very low. Whiskers mediate a wide range of behaviors and many natural tactile behaviors occur very rapidly. Vibrissal object recognition can be size invariant and motion invariant and is based on the tactile 'Gestaltwahrnehmung' of shape. PMID- 17702565 TI - Recombinant factor VIIa should be used in massive obstetric haemorrhage. PMID- 17702567 TI - Clinical and psychometric validation of a questionnaire module, the EORTC QLQ OG25, to assess health-related quality of life in patients with cancer of the oesophagus, the oesophago-gastric junction and the stomach. AB - AIM: To combine and test the EORTC questionnaires for assessing quality of life (HRQL) for oesophageal (QLQ-OES18) and stomach cancer (QLQ-STO22), into a single questionnaire for tumours of the oesophagus, oesophago-gastric junction or stomach. METHODS: The QLQ-OES18, QLQ-STO22 and seven modified items were administered to 300 patients with oesophageal (n=148), junctional (n=66), or gastric cancer (n=86). Semi-structured interviews assessed item and scale preference and multi-trait scaling analyses confirmed the scale structure of the new module (QLQ-OG25). This was further tested for validity. RESULTS: The QLQ OG25 has six scales, dysphagia, eating restrictions, reflux, odynophagia, pain and anxiety. Scales have good reliability (alpha range 0.67-0.87) and they distinguish between tumour sites and disease stage. Scales do not correlate highly with scores from the core questionnaire, thus indicating that the module was addressing separate HRQL aspects. CONCLUSION: The QLQ-OG25 is recommended to supplement the EORTC QLQ-C30 when assessing HRQL in patients with oesophageal, junctional or gastric cancer. PMID- 17702568 TI - Dexamethasone in the maintenance phase of acute lymphoblastic leukaemia treatment: is the risk of lethal infections too high? AB - We report an increased incidence of infectious deaths during maintenance treatment of the ninth protocol for acute lymphoblastic leukaemia of the Dutch Childhood Oncology Group (DCOG-ALL-9). The main difference in maintenance treatment between DCOG-ALL-9 and the DCOG-ALL-7 and DCOG-ALL-8 protocols is the interruption of methotrexate and 6-mercaptopurine by vincristine (2mg/m(2) weekly) and dexamethasone (6mg/m(2) daily) for 14 days every 7 weeks in the DCOG ALL-9 protocol. The 1107 children treated with the DCOG-ALL-7, DCOG-ALL-8 or DCOG ALL-9 protocol were included and screened for infectious death during maintenance treatment (July 1988-July 2002). Seven of the 510 children died of severe infections during the maintenance phase of DCOG-ALL-9, compared to none of the 597 patients during the DCOG-ALL-7 and DCOG-ALL-8 protocols (1.37% versus 0.0%; p=0.013). Results from the current study suggest that repeated, prolonged exposure to dexamethasone results in an increase of lethal infections from 0% to 1.37%. In the dosing-schedule used, the advantage of dexamethasone may not outweigh the higher risk of infectious death. PMID- 17702569 TI - Effect of pH on anoxic sulfide oxidizing reactor performance. AB - The effects of pH on the performance of anoxic sulfide oxidizing (ASO) reactor were evaluated. Performance was investigated under various operational conditions at influent pH range of 4-11. At the influent pH of 7-7.5 during loading tests and HRT tests, the sulfide oxidation was partial. In general, the amount of sulfate formed decreased with the increasing sulfide and nitrite loadings. The bacterial communities in ASO reactors were more sensitive to acidic pH compared with alkaline pH, as nitrite and sulfide removal rates dropped significantly when exposed to acidic pH 3. High dissolved bisulfide ions, nitrite and excess of sulfate (>300 mg/L) might have inhibited the sulfide oxidation under highly acidic and alkaline conditions in the ASO reactor. Based on sulfide and nitrite removal efficiencies, the ASO reactor can be operated in a wide range of pH, i.e. 5-11. PMID- 17702570 TI - Soil quality and barley growth as influenced by the land application of two compost types. AB - Agricultural use of organic residues offers an attractive method for their safe disposal and a valuable source of organic amendments and nutrients. A field experiment was conducted to investigate the influences of 0, 25, 50 and 100 t/ha spent mushroom compost (SMC), forced aeration compost (FAC) and inorganic fertilizer on soil properties and yield of barley (Hordeum vulgare). The considered soil properties (0-15 cm), after a growing season, included pH, EC, available P, Kjeldahl N, available cations, DTPA extractable elements, soil OC content, and bulk density and grain yield was also determined. Application of organic materials increased organic status of the soil and nutrient content. The effectiveness of the two composts on improving the productivity of the soil varied. SMC produced strongest correlations between soil nutrient levels and plant yield. Neither compost raised soil copper and zinc to levels that were of concern and high application rates decreased iron content. PMID- 17702571 TI - Characterization of functional microbial community in a membrane-aerated biofilm reactor operated for completely autotrophic nitrogen removal. AB - The 16S rDNA-based molecular technique was applied to investigate the functional microbial community of a membrane-aerated biofilm (MAB) that was used for completely autotrophic nitrogen removal over nitrite (CANON). The relationships among two kinds of key bacteria responsible for CANON: aerobic ammonia-oxidizing bacteria (AOB) and Anammox bacteria, and their possible distributions in the MAB were discussed based on the microbial community analysis. FISH analysis showed the existence of two visible active layers in experimental MAB. One is the partial nitrifying layer located in the region of oxygen-rich membrane-biofilm interface, dominated by NSO190-positive AOB. The other is the Anammox active layer located in the region of anoxic liquid-biofilm interface, dominated by PLA46 and AMX820-positive Anammox microorganisms. As a result of this study, the AOB as well as Anammox bacteria were present and active in experimental MABR, and the cooperation between AOB and Anammox bacteria was considered to be responsible for CANON. PMID- 17702572 TI - Anaerobic digestion of grass silage in batch leach bed processes for methane production. AB - Anaerobic digestion of grass silage in batch leach bed reactors, with and without a second stage upflow anaerobic sludge blanket (UASB) reactor, was evaluated. Sixty six percent of the methane potential in grass was obtained within the 55 days solids retention time in the leach bed-UASB process without pH adjustment, whereas in the one-stage leach bed process 20% of the methane potential in grass was extracted. In two-stage operation, adjustment of the pH of influent to the leach bed reactor to 6 with HCl led to inhibition of both hydrolysis/acidogenesis and methanogenesis. In the leach bed-UASB process 39% of the carbohydrates and 58% of the acid soluble lignin were solubilised within the 49 days of operation, whereas Klason lignin was most recalcitrant. The methane potential of the digestates varied from 0.141 to 0.204 m3 CH4 kg(-1) added volatile solids. PMID- 17702573 TI - Rice straw fermentation using lactic acid bacteria. AB - To efficiently utilize rice straw and lessen its disposal problem on the environment, a lactic acid bacteria community, SFC-2 was developed from natural fermentation products of rice straw by continuous enrichment with the MRS-S broth (MRS broth with sucrose), and used to accelerate the fermentation of air-dried straws. The SFC-2 could rapidly lower the pH of the broth and produce high levels of lactic acid. Using a combination of plate isolation, denaturing gradient gel electrophoresis (DGGE) and 16S rDNA sequencing, the microbial composition of the SFC-2 was classified into Lactobacillus, mainly comprised of L. fermentum, L. plantarum and L. paracacei. An evaluation of the fermentation effect of SFC-2 on rice straw showed that it lowered the pH and significantly (P<0.05) increased lactic acid concentration in the straw. Further analysis with DGGE indicated that L. plantarum, L. fermentum and L. paracasei were the dominant species during fermentation. PMID- 17702574 TI - Drosophila BubR1 is essential for meiotic sister-chromatid cohesion and maintenance of synaptonemal complex. AB - The partially conserved Mad3/BubR1 protein is required during mitosis for the spindle assembly checkpoint (SAC). In meiosis, depletion causes an accelerated transit through prophase I and missegregation of achiasmate chromosomes in yeast [1], whereas in mice, reduced dosage leads to severe chromosome missegregation [2]. These observations indicate a meiotic requirement for BubR1, but its mechanism of action remains unknown. We identified a viable bubR1 allele in Drosophila resulting from a point mutation in the kinase domain that retains mitotic SAC activity. In males, we demonstrate a dose-sensitive requirement for BubR1 in maintaining sister-chromatid cohesion at anaphase I, whereas the mutant BubR1 protein localizes correctly. In bubR1 mutant females, we find that both achiasmate and chiasmate chromosomes nondisjoin mostly equationally consistent with a defect in sister-chromatid cohesion at late anaphase I or meiosis II. Moreover, mutations in bubR1 cause a consistent increase in pericentric heterochromatin exchange frequency, and although the synaptonemal complex is set up properly during transit through the germarium, it is disassembled prematurely in prophase by stage 1. Our results demonstrate that BubR1 is essential to maintain sister-chromatid cohesion during meiotic progression in both sexes and for normal maintenance of SC in females. PMID- 17702575 TI - Spontaneous metatool use by New Caledonian crows. AB - A crucial stage in hominin evolution was the development of metatool use -- the ability to use one tool on another [1, 2]. Although the great apes can solve metatool tasks [3, 4], monkeys have been less successful [5-7]. Here we provide experimental evidence that New Caledonian crows can spontaneously solve a demanding metatool task in which a short tool is used to extract a longer tool that can then be used to obtain meat. Six out of the seven crows initially attempted to extract the long tool with the short tool. Four successfully obtained meat on the first trial. The experiments revealed that the crows did not solve the metatool task by trial-and-error learning during the task or through a previously learned rule. The sophisticated physical cognition shown appears to have been based on analogical reasoning. The ability to reason analogically may explain the exceptional tool-manufacturing skills of New Caledonian crows. PMID- 17702576 TI - Optineurin negatively regulates TNFalpha- induced NF-kappaB activation by competing with NEMO for ubiquitinated RIP. AB - NF-kappaB essential modulator (NEMO), the regulatory subunit of the IkappaB kinase (IKK) that activates NF-kappaB, is essential for NF-kappaB activation. NEMO was recently found to contain a region that preferentially binds Lys (K)63 linked but not K48-linked polyubiquitin (polyUb) chains, and the ability of NEMO to bind to K63-linked polyUb RIP (receptor-interacting protein) is necessary for efficient tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation. Optineurin is a homolog of NEMO, and mutations in the optineurin gene are found in a subset of patients with glaucoma, a neurodegenerative disease involving the loss of retinal ganglion cells. Although optineurin shares considerable homology with NEMO, in resting cells, it is not present in the high-molecular-weight complex containing IKKalpha and IKKbeta, and optineurin cannot substitute for NEMO in lipopolysaccharide (LPS)-induced NF-kappaB activation. On the other hand, the overexpression of optineurin blocks the protective effect of E3-14.7K on cell death caused by the overexpression of TNFalpha receptor 1 (TNFR1). Here we show that optineurin has a K63-linked polyUb-binding region similar to that of NEMO, and like NEMO, it bound K63- but not K48-linked polyUb. Optineurin competitively antagonized NEMO's binding to polyUb RIP, and its overexpression inhibited TNFalpha-induced NF-kappaB activation. This competition occurs at physiologic protein levels because microRNA silencing of optineurin resulted in markedly enhanced TNFalpha-induced NF-kappaB activity. These results reveal a physiologic role for optineurin in dampening TNFalpha signaling, and this role might provide an explanation for its association with glaucoma. PMID- 17702577 TI - Temporal environmental variability drives the evolution of cooperative breeding in birds. AB - Many vertebrates breed in cooperative groups in which more than two members provide care for young. Studies of cooperative breeding behavior within species have long highlighted the importance of environmental factors in mediating the paradox of why some such individuals delay independent breeding to help raise the offspring of others. In contrast, studies involving comparisons among species have not shown a similarly clear evolutionary-scale relationship between the interspecific incidence of cooperative breeding and any environmental factors. Here, we use a phylogenetically controlled comparative analysis of a complete, socially diverse group of birds-45 species of African starlings-to show that cooperative breeding is positively associated with living in semiarid savanna habitats and with temporal variability in rainfall. Savanna habitats are not only highly seasonal, but also temporally variable and unpredictable, and this temporal variability directly influences individual reproductive decisions in starlings and helps explain interspecific patterns of sociality. Cooperative breeding is likely to be adaptive in temporally variable environments because it allows for both reproduction in harsh years and sustained breeding during benign years. This "temporal variability" hypothesis might help explain the phylogenetic and geographic concentrations of cooperatively breeding vertebrates in savanna like habitats and other temporally variable environments worldwide. PMID- 17702578 TI - The Him gene reveals a balance of inputs controlling muscle differentiation in Drosophila. AB - Tissue development requires the controlled regulation of cell-differentiation programs. In muscle, the Mef2 transcription factor binds to and activates the expression of many genes and has a major positive role in the orchestration of differentiation. However, little is known about how Mef2 activity is regulated in vivo during development. Here, we characterize a gene, Holes in muscle (Him), which our results indicate is part of this control in Drosophila. Him expression rapidly declines as embryonic muscle differentiates, and consistent with this, Him overexpression inhibits muscle differentiation. This inhibitory effect is suppressed by mef2, implicating Him in the mef2 pathway. We then found that Him downregulates the transcriptional activity of Mef2 in both cell culture and in vivo. Furthermore, Him protein binds Groucho, a conserved, transcriptional corepressor, through a WRPW motif and requires this motif and groucho function to inhibit both muscle differentiation and Mef2 activity during development. Together, our results identify a mechanism that can inhibit muscle differentiation in vivo. We conclude that a balance of positive and negative inputs, including Mef2, Him, and Groucho, controls muscle differentiation during Drosophila development and suggest that one outcome is to hold developing muscle cells in a state with differentiation genes poised to be expressed. PMID- 17702579 TI - Specific alleles of bitter receptor genes influence human sensitivity to the bitterness of aloin and saccharin. AB - Variation in human taste is a well-known phenomenon. However, little is known about the molecular basis for it. Bitter taste in humans is believed to be mediated by a family of 25 G protein-coupled receptors (hT2Rs, or TAS2Rs). Despite recent progress in the functional expression of hT2Rs in vitro, up until now, hT2R38, a receptor for phenylthiocarbamide (PTC), was the only gene directly linked to variations in human bitter taste. Here we report that polymorphism in two hT2R genes results in different receptor activities and different taste sensitivities to three bitter molecules. The hT2R43 gene allele, which encodes a protein with tryptophan in position 35, makes people very sensitive to the bitterness of the natural plant compounds aloin and aristolochic acid. People who do not possess this allele do not taste these compounds at low concentrations. The same hT2R43 gene allele makes people more sensitive to the bitterness of an artificial sweetener, saccharin. In addition, a closely related gene's (hT2R44's) allele also makes people more sensitive to the bitterness of saccharin. We also demonstrated that some people do not possess certain hT2R genes, contributing to taste variation between individuals. Our findings thus reveal new examples of variations in human taste and provide a molecular basis for them. PMID- 17702580 TI - Slide-and-cluster models for spindle assembly. AB - BACKGROUND: Mitotic and meiotic spindles are assemblies of microtubules (MTs) that form during cell division to physically separate sister chromosomes. How the various components of spindles act together to establish and maintain the dynamic bipolar structure of spindles is not understood. Interactions between MTs and motors have been studied both experimentally and theoretically in many contexts, including the self-organization of arrays of MTs by motors and the competition between different classes of motors to move a single load. This work demonstrates how the interplay between two types of motors together with continual nucleation of MTs by chromosomes could organize the MTs into spindles. RESULTS: We propose a slide-and-cluster model based on four known molecular activities: MT nucleation near chromosomes, the sliding of MTs by a plus-end-directed motor, the clustering of their minus ends by a minus-end-directed motor, and the loss of MTs by dynamic instability. Our model applies to overlapping, nonkinetochore MTs in anastral spindles, and perhaps also to interpolar MTs in astral spindles. We show mathematically that the slide-and-cluster mechanism robustly forms bipolar spindles with sharp poles and a stable steady-state length. This model accounts for several experimental observations that were difficult to explain with existing models. Three new predictions of the model were tested and verified in Xenopus egg extracts. CONCLUSIONS: We show that a simple two-motor model could create stable, bipolar spindles under a wide range of physical parameters. Our model is the first self-contained model for anastral spindle assembly and MT sliding (known as poleward flux). Our experimental results support the slide-and cluster scenario; most significantly, we find that MT sliding slows near spindle poles, confirming the model's primary prediction. PMID- 17702581 TI - Microarray analysis and functional genomics identify novel components of melanopsin signaling. AB - BACKGROUND: Within the mammalian retina, there exists a third photoreceptive system based upon a population of melanopsin (Opn4) expressing photosensitive retinal ganglion cells (pRGCs; also termed ipRGCs or intrinsically photosensitive RGCs). Here, we use a microarray-based approach, which we term transcriptional recalibration, coupled with functional genomics to identify downstream targets of melanopsin signaling. RESULTS: In a mouse with genetically ablated rods and cones (rd/rd cl), approximately 30% of the ocular transcriptome is transiently regulated in response to nocturnal light exposure (3112 genes). A total of 163 of these genes were associated with the "intracellular signaling" gene ontology term. On the basis of their similarity to invertebrate phototransduction genes, 14 were selected for further study. Laser capture microdissection demonstrated that eight of these genes (Gnas, Gnb2l1, Gnaq, Prkcz, Pik3r1, Inadl, Slc9a3r1, and Drd1a) colocalized with melanopsin. The impact of genetic ablation of one of these genes, protein kinase C zeta (Prkcz), was assessed. Prkcz-/- animals show attenuated phase-shifting responses to light, reduced period lengthening under constant light, and attenuated pupillary responses at high irradiances, as well as impaired light-induced gene expression in the suprachiasmatic nuclei (SCN). These attenuated responses are indistinguishable from the deficits observed in melanopsin knockout mice. CONCLUSIONS: Here, we show that (1) Prkcz plays an as yet unidentified role in melanopsin signaling, (2) the proteins of seven further light-regulated genes emerge as strong candidates in melanopsin signaling, and (3) transcriptional recalibration may provide a powerful new approach for dissecting unmapped signaling pathways. PMID- 17702582 TI - Normal pressure values and repeatability of the Emed ST4 system. AB - The aims of this study were to assess the repeatability of the Emed ST4 system and identify the range of pressure values observed in the normal foot. Fifty three healthy subjects, 17 females (32%) and 36 males (68%), were recruited. Measurements were performed on two occasions approximately 12 days apart. Peak pressure (PP), contact area (CA), contact time (CT), pressure-time integral (PTI), force-time integral (FTI) and instant of peak pressure (IPP) were recorded. The coefficient of repeatability (CR) was less than 16.9% for all 122 parameters considered. The highest areas of PP were found under the second and third metatarsal heads, with mean (S.D.) equal to 361 kPa (104) and 330 kPa (84), respectively, followed by the great toe 321 kPa (141) and heel 313 kPa (77). CA was highest under the heel at 35 cm(2) (5). The percentage CT was in the range 75 85% under the metatarsal heads, and 70% under the hallux. PTI was highest under metatarsal heads one to three and hallux. FTI was highest under the heel. Emed ST4 system was found to be repeatable. The ranges of the parameters documented can be applied in orthopaedic clinics as part of the assessment of pathological conditions. PMID- 17702584 TI - Recombinant activated factor VII for a warfarinised Jehovah's Witness with an acute subdural haematoma. AB - Recombinant activated factor VII (rFVIIa) (NovoSeven; Novo Nordisk A/S, Bagsvaerd, Denmark) is a haemostatic agent first developed for bleeding associated with haemophilia and trauma, but for which the indications continue to expand. Recent reports have suggested efficacy for various types of intracranial haemorrhage and for patients with abnormalities of coagulation. We report a warfarin-anticoagulated Jehovah's Witness patient with an acute subdural haematoma for whom rFVIIa was used perioperatively. The haematoma was surgically evacuated without excessive blood loss and the patient eventually made a good recovery, returning to independent self-care. PMID- 17702583 TI - Can a "novice" do aneurysm surgery? Surgical outcomes in a low-volume, non subspecialised neurosurgical unit. AB - The objective of this paper is to review the results of a junior general neurosurgeon performing aneurysm surgery and compare these to the remainder of his low-volume unit. Prospectively collected data was analysed for 114 aneurysms clipped in 99 patients between July 2001 and May 2005. Overall there was a 0.9% mortality rate and 10.8% complication rate. The favourable outcome rate for the unit was 100% for unruptured aneurysms, 90.4% for grades 1-3 patients and 30% for poor grade patients (grades 4 and 5). The novice neurosurgeon had no mortality and a favourable outcome rate of 94.7% for grades 1-3 patients and 50% for poor grade patients. Acceptable results can be obtained with cerebral aneurysm surgery in a low-volume centre by Australian-trained, non-subspecialty neurosurgeons. PMID- 17702585 TI - Interaction of human gingival fibroblasts with PVA/gelatine sponges. AB - Tissue engineering scaffolds should be able to reproduce optimal microenvironments in order to support cell attachment, three-dimensional growth, migration and, regarding fibroblasts, must also promote extracellular matrix production. Various bioactive molecules are employed in the preparation of spongy scaffolds to obtain biomimetic matrices by either surface-coating or introducing them into the bulk composition of the biomaterial. The biomimetic properties of a spongy matrix composed of PVA combined with the natural component gelatine were evaluated by culturing human gingival fibroblasts on the scaffold. Cell adhesion, morphology and distribution within the scaffold were assessed by histology and electron microscopy; viability and metabolic activity as well as extracellular matrix production were analyzed by MTT assay, cytochemistry and immunocytochemistry. Fibroblasts interacted positively with PVA/gelatine. They adhered to the PVA/gelatine matrix in which they had good spreading activity and active metabolism; fibroblasts were also able to produce extracellular matrix molecules (type I collagen, fibronectin and laminin) compared to bi-dimensionally grown cells. The in situ creation of a biological matrix by human fibroblasts together with the ability to produce growth factor TGF-beta1 and the intracellular signal transduction molecule RhoA, suggests that this kind of PVA/gelatine sponge may represent a suitable support for in vitro extracellular matrix production and connective tissue regeneration. PMID- 17702586 TI - Gadolinium sheet converter for neutron radiography. AB - This work describes a methodology developed for the confection of gadolinium sheet converter for neutron radiography using the gadolinium chloride (GdCl3) as material converter. Though manufactured at a relatively low cost, they are as good as the sheet converter on the market. Here, we present neutron radiography of the penetrameter, the edge spread function, the modulation transfer function and characteristic curves for each set sheet-AA400 Kodak film. PMID- 17702587 TI - Progressive dysfunction of the cholesterol biosynthesis pathway in the R6/2 mouse model of Huntington's disease. AB - We have recently reported significantly reduced levels of the mRNA of genes critical for the cholesterol biosynthesis pathway in the brains of mice and patients with Huntington's disease (HD), which are indicative of a biological dysfunction. We here show that the brains of R6/2 transgenic mice have progressively decreasing levels of the cholesterol precursors, lathosterol and lanosterol, and declining 3-hydroxy-3-methylglutaryl coenzyme A reductase activity starting from pre-symptomatic stages. We also show that, despite the progressive reduction of brain cholesterol biosynthesis, steady-state levels of total cholesterol remain constant, thus suggesting that compensatory mechanisms are in operation. These in vivo findings indicate a consistent and progressive reduction in the activity of the cholesterol biosynthesis pathway in HD brain. The defect occurs early in these mice and generates lower levels of newly synthesized cholesterol and its intermediates, which may affect different aspects of the disease. PMID- 17702588 TI - Robotic-assisted closure of atrial septal defect under real-time three dimensional echo guide: in vitro study. AB - BACKGROUND: Several advances in robotic technology and imaging systems have enabled the broad application of minimally invasive techniques in cardiac surgery. We have previously demonstrated that real-time three-dimensional echocardiography (RT3DE) provided adequate imaging and anatomic detail to act as a sole guide for surgical task performance. In this study, we examined the feasibility of robotic-assisted RT3DE-guided repair of atrial septal defect (ASD) in an in vitro study. MATERIALS AND METHODS: Exp. I: An RT3DE system with x4 matrix transducer (Sonos 7500, Philips Medical Systems, Andover, MA) was compared to two-dimensional echo (2DE) in the performance of common surgical tasks with the da Vinci Robotic Surgical System (Intuitive Surgical, Sunnyvale, CA). Completion times and deviation of suture from an echogenic target (mm) were measured. Exp. II: Porcine ASDs (n=10) were created and closed with robotic assisted direct suturing in a water bath. During all experiments the operator was blinded to the target and operated only under ultrasonic guidance. RESULTS: Compared to 2DE guidance, completion times improved by 70% (p<0.0001) and deviation of suture by the robotic system was significantly smaller (2DE: 4+/ 2mm, 3DE: 0.2+/-0.3mm, p=0.0002) in RT3DE-guided tasks. RT3DE provided satisfactory images and sufficient anatomical detail for suturing. All surgical tasks were successfully performed with accuracy. CONCLUSIONS: These initial experiments demonstrate the feasibility of robotic-assisted direct closure of ASD under RT3DE guidance. An endoscopic port access approach may be possible with refinements in telemanipulator technology and further development of the transesophageal echo transducer. PMID- 17702589 TI - Efficacy and safety of perioperative infusion of levosimendan in patients with compromised cardiac function undergoing open-heart surgery: importance of early use. AB - OBJECTIVE: Levosimendan is a promising new inotrope. We investigate the proper time for its infusion during or after open-heart surgery to avoid complications related with low-output syndrome and high dosage of inotropes. METHODS: Forty five consecutive patients were randomised to receive levosimendan in addition to the conventional therapy, its infusion starting in the operating theatre (Group OT) or in the ICU (Group ICU) when low-output syndrome was certified and were consequently dependent on classical inotropic support and IABP. Levosimendan was infused at a rate of 0.1 microg/kg min without loading dose, the infusion being for at least 24h to a maximum 48 h. RESULTS: Levosimendan was well tolerated, with the simultaneous infusion of norepinephrine if required. Its efficacy was identical in both groups with improvement in the haemodynamic and functional status of patients (amelioration of stroke volume, cardiac index and mixed venous blood oxygen saturation, increase of left ventricular ejection fraction by echo study, de-escalation of traditional inotropes, subtraction of IABP and reduction in BNP plasma levels). The ICU stay and hospital stay were significantly decreased in patients of Group OT, compared to patients of Group ICU. Four patients died because of multiple organs dysfunction syndrome (MODS) due to sepsis (all patients of Group ICU). CONCLUSION: Levosimendan is a safe and efficient choice in the management of low-output syndrome during and after open heart surgery. The shortening of hospitalisation and the trend for better outcome confirm its clear superiority when the infusion starts from the operating theatre. PMID- 17702590 TI - Emergency treatment of chest trauma--an e-learning simulation model for undergraduate medical students. AB - OBJECTIVE: Appropriate emergency measures are essential in improving the outcome of patients with thoracic injuries. Pathophysiological background and basic principles of emergency treatment decisions should be already taught in undergraduate medical curricula. The effectiveness of a computer simulation model on thoracic trauma management was evaluated. METHODS: Forty-one students were enrolled in this pre-test/post-test self-controlled study. Learning experience was based on a complex computer simulation model demonstrating basic mechanisms of thoracic injuries and facilitating the interactive application of various emergency measures. RESULTS: Pre-test multiple-choice results were 72.2% (66.9 77.5) correct answers, which increased significantly to 86.5% (82.6-90.4) in the post-test (p<0.001). The students spent 30 min (23-36) with the interactive learning object. Content analysis of open-ended feedback revealed a highly significant overall positive judgement (p<0.001), where the importance of 'trial and error' learning, the possibility of being able to 'view a process' and the simplicity of the model were particularly stressed. CONCLUSIONS: Computer simulation of chest trauma emergency treatment options is a safe and efficient learning approach in undergraduate medical education, which is highly appreciated by the students. PMID- 17702591 TI - Giant mature teratoma of the pericardium. PMID- 17702592 TI - Anatomic repair of a left main coronary artery aneurysm. PMID- 17702593 TI - Mitral annulus calcification: determinants of repair feasibility, early and late surgical outcome. AB - OBJECTIVE: The aim of this study was to determine the factors influencing the feasibility of valve repair and the surgical outcome in patients with mitral annulus calcification. METHODS: In 124 patients with mitral annulus calcification undergoing surgery, two entities were distinguished: Barlow disease (myxomatous leaflets, n=60) and fibroelastic deficiency (FED) (normal leaflets, n=64). The calcification score was lower (1.9 vs 2.8); the annulus was more dilated (ring 35 vs 32 mm) and ruptured chordae were more frequent (77% vs 37%) in Barlow than in FED (p<0.001). The clinical profile was different: age (60+/-14 vs 73+/-8 years, p<0.001), systemic hypertension (22% vs 70%, p<0.001), chronic renal insufficiency (5% vs 22%, p<0.01), cancer (7% vs 25%, p<0.01). Multifocal atherosclerosis was less frequent in Barlow than in FED: carotid disease (17% vs 54%, p<0.001), aortic atheroma (21% vs 51%, p<0.001) and coronary disease (22% vs 56%, p<0.01). Echocardiography showed two different patterns in Barlow and FED: aortic valve stenosis (1.7% vs 31%), left atrial diameter (54 vs 49 mm), left ventricular end-diastolic diameter (62 vs 54 mm), interventricular septal thickness (11 vs 13 mm), and systolic pulmonary pressure (40 vs 56 mmHg), respectively (p<0.001). Bacterial endocarditis was observed in 24 cases (19%). RESULTS: The surgical technique was a valve repair in 68% and a replacement in 32%. The repair rate depended upon the extent of annulus calcifications (p<0.001) and the type of degenerative disease (95% vs 44% in Barlow and FED p<0.001). In hospital mortality was 14% (Barlow: 5% vs FED: 23%, p<0.01). The mean follow-up was 50+/-41 months. Overall 5-year year survival was 76% (Barlow: 90% vs FED: 64%, p<0.001) and survival free from cardiac event was 69% at 5 years (Barlow: 87% vs FED: 52%, p<0.001). Five-year survival was higher following repair than replacement (84% vs 64% p<0.001). Chronic renal insufficiency and bacterial endocarditis were two predictors of early and late death (p<0.01). CONCLUSIONS: The aetiopathogeny of the degenerative mitral disease responsible for annulus calcifications corresponded to distinct anatomical, clinical and echographic patterns. It was a main determinant of repair feasibility, early and late surgical outcome. PMID- 17702594 TI - Coronary atherosclerosis of the donor heart--impact on early graft failure. AB - OBJECTIVE: Due to the shortage of donor hearts, the criteria for organ acceptability have been considerably extended and donor grafts with coronary atherosclerosis are among those offered. This study evaluated whether and to what degree pre-existing coronary atherosclerosis may be acceptable. METHODS: A total of 1253 consecutive HTx recipients were investigated retrospectively for donor transmitted coronary atherosclerosis (DCAS). Donor-transmitted coronary atherosclerosis was defined as focal atherosclerosis with stenosis of at least 50%. Inclusion criteria were absence of pre-HTx angiogram but performance of angiogram or autopsy within 6 months after heart transplantation. Kaplan-Meier analysis and log-rank test were used. RESULTS: Eighty-five out of 1253 (6.8%) cases were excluded, since coronary evaluation was not performed within 6 months (n=45) or hearts had undergone pre-transplant angiography (n=40). In 1086 patients no donor-transmitted coronary atherosclerosis was found (NDCAS group) and in 82 patients (7%) donor-transmitted coronary atherosclerosis was diagnosed by angiography (n=49) or autopsy (n=33). Single-vessel donor-transmitted coronary atherosclerosis was found in 53/82 patients (DCAS1 group) and double- or triple vessel donor-transmitted coronary atherosclerosis in 26/82 patients (DCAS2/3 group). Three of the 82 patients with donor-transmitted coronary atherosclerosis were excluded since the autopsy report was unclear regarding degree of atherosclerosis. Early after heart transplantation the 30-day mortality in the NDCAS and DCAS1 groups was 12.2% versus 13.2% whereas in the DCAS2/3 group it was 61.5%. Beyond the first year the annual decrease with and without donor transmitted coronary atherosclerosis (single-vessel disease) is comparable. CONCLUSIONS: Donor screening without coronary angiogram overlooks significant atherosclerotic lesions in a considerable number of cases (7.0%). Therefore, angiographic donor screening should be performed. Donor grafts with single-vessel coronary atherosclerosis may be accepted as marginal hearts; however, in our opinion, revascularisation (CABG, PTCA) should be considered. Grafts with two- or even three-vessel coronary atherosclerosis seem to have a serious risk for early graft failure. Beyond the first year the outcome of healthy grafts and grafts with donor-transmitted coronary atherosclerosis seems to be comparable. PMID- 17702595 TI - Comparison of the safety and efficacy of paclitaxel plus gemcitabine combination in young and elderly patients with locally advanced or metastatic non-small cell lung cancer. A retrospective analysis of the Southern Italy Cooperative Oncology Group trials. AB - We retrospectively assessed tolerability and efficacy of paclitaxel plus gemcitabine combination in 259 patients with locally advanced or metastatic non small cell lung cancer (NSCLC) enrolled in three randomized SICOG trials according to their age (70 years) at study entry. Apart from age, demographic and clinical characteristics were similar in the two groups. Response rate of paclitaxel plus gemcitabine was similar in younger and in elderly (36% versus 30%). Chemotherapy was well tolerated, but severe neutropenia (12% versus 7%), anaemia (6.6% versus 1.8%), and vomiting (5% versus 0) were more frequent in elderly patients. Both median progression-free survival (PFS, 5.5 months versus 4.2 months), and overall survival (OS, 11.1 months versus 9.1 months) resulted slightly prolonged for younger patients. However, only stage and performance status resulted independently affecting PFS and OS. In conclusion, paclitaxel plus gemcitabine were similarly tolerated and active in younger and elderly patients. This regimen should be considered an option for the management of fit elderly patients. PMID- 17702596 TI - Novel therapeutic strategies combining antihormonal and biological targeted therapies in breast cancer: focus on clinical trials and perspectives. AB - Several models have been proposed to explain the mechanisms of endocrine resistance including aberrant growth-signaling pathways, and have led to the rational design of studies combining hormonotherapy with signal transduction inhibitors (STI) in advanced breast cancer. This article reviews the current status of these clinical trials. Preliminary results from the randomized controlled trials are rather disappointing. The mTOR inhibitor temsirolimus and the farnesyl transferase inhibitor tipifarnib combined with letrozole did not show any benefit compared to letrozole alone. As neoadjuvant therapy, gefinitib did not enhance the response rate induced by anastrozole. Interesting results were obtained with exemestane combined to celecoxib but should be further explored with adequate cardiac monitoring. Trastuzumab combined with anastrozole was more effective than anastrozole in terms of response rate and progression free survival but not survival. Several controlled trials as first- or second line therapy have started recently and over the next few years we should learn whether this approach will provide significant gains in efficacy. PMID- 17702597 TI - Modification of miR gene expression pattern in human colon cancer cells following exposure to 5-fluorouracil in vitro. AB - MicroRNAs (miRNAs) are small noncoding RNA molecules produced by miR genes which are able to control the expression of a large number of cellular proteins by targeting mRNAs of protein coding genes. It has been suggested that modification of miR gene expression could be an important factor in the development and maintenance of the neoplastic state. It is also reasonable to hypothesize that antineoplastic drugs could be able to alter miR gene expression pattern since most of them are able to interfere with nucleic acid metabolism and gene expression. Here we show that 5-fluorouracil (5-FU), a classical antimetabolite largely used in the clinic, is able to change significantly the expression of several miR genes. In colon cancer cells, at a clinically relevant concentration, the drug up-regulates or down-regulates in vitro the expression of 19 and 3 miR genes, respectively, by a factor of not less than two-fold. In some instances, 5 FU up-regulates miR genes that are already over-expressed in neoplastic tissues, including, for example, miR-21 that is associated with anti-apoptotic functions characterizing malignant cells. In this case, it is possible that drug-induced miR gene dysregulation could be the expression of cellular response to the toxic effects of the agent. On the contrary, in other instances the drug influences the expression of miR genes in a direction that is opposite to that induced by neoplastic transformation. A typical example is provided by miR-200b, that is up regulated in various tumors and down-regulated by treatment with the antimetabolite. Noteworthy, it is known that miR-200b suppresses a gene that codes for a protein tyrosine phosphatase (PTPN12) that inactivates products of oncogenes, such as c-Abl, Src or Ras. In conclusion, the present results support the hypothesis that 5-FU can alter profoundly miR gene expression pattern. This effect could be responsible, at least in part, of the multi-target pleiotropic influence manifested by the drug on malignant cells. PMID- 17702598 TI - Development of a time-resolved method for photodissociation mechanistic study of protonated peptides: use of a voltage-floated cell in a tandem time-of-flight mass spectrometer. AB - Photodissociation at 266 nm of some protonated peptides was investigated using a tandem-TOF spectrometer equipped with a cell near its first time focal point where the laser was irradiated. When a high voltage was applied to the cell, each product ion peak split into several components with different flight times. One of these was due to in-cell direct formation of the product ion and another due to post-cell formation. Those in between were due to consecutive dissociations, the first steps of which occurred inside the cell and the second steps outside the cell. A method based on flight time calculation was developed to analyze these components and to identify the intermediate ion for each consecutive component. The technique allows time-resolved photodissociation mechanistic studies on a 100-ns timescale. PMID- 17702599 TI - Analysis of PBDEs in soil, dust, spiked lake water, and human serum samples by hollow fiber-liquid phase microextraction combined with GC-ICP-MS. AB - A novel method for the analysis of four polybrominated diphenyl ethers (PBDEs) in environmental and human serum samples based on hollow fiber-liquid phase microextraction (HF-LPME) followed by gas chromatography-inductively coupled plasma mass spectrometric (GC-ICP-MS) detection has been developed. The organic solvent in the porous hollow fiber was first dipped into the sample for extraction at a given time, and the retracted organic phase was introduced into the GC-ICP-MS for analysis. The addition of methanol has a strong effect on the HF-LPME extraction efficiency. Other significant parameters affecting the extraction efficiency of HF-LPME were also studied. HF-LPME was effective to isolate the analytes from the complex matrix. Under the optimized conditions, the detection limits of the proposed method varied from 15.2 to 40.5 ng/L. In general, the relative standard deviations (RSDs) were less than 10%. Good linearity was obtained with the correlation coefficients all better than 0.999. The proposed method is simple, quick, few microliters of organic solvent required, and is especially suitable for the analysis of the real sample with small amount available. The overall process of HF-LPME with GC-ICP-MS was applied successfully for the determination of polybrominated diphenyl ethers (PBDEs) in environmental and spiked human serum samples, and the results were satisfactory. PMID- 17702600 TI - Isomeric differentiation of green tea catechins using gas-phase hydrogen/deuterium exchange reactions. AB - Hydrogen/deuterium exchange reactions in a quadrupole ion trap mass spectrometer are used to differentiate galloylated catechin stereoisomers (catechin gallate and epicatechin gallate; gallocatechin gallate and epigallocatechin gallate) and the nongalloylated analogs (catechin and epicatechin, gallocatechin and epigallocatechin). Significant differences in the hydrogen/deuterium exchange behavior of the four pairs of deprotonated catechin stereoisomers are observed upon reaction with D(2)O. Interestingly, the nongalloylated catechins undergo H/D exchange to a much greater extent than the galloylated species, incorporating deuterium at both aromatic/allylic and active phenolic sites. Nongalloylated catechin isomers are virtually indistinguishable by their H/D exchange kinetics over a wide range of reaction times (0.05 to 10 s). Our experimental results are explained using high-level ab initio calculations to elucidate the subtle structural variations in the catechin stereoisomers that lead to their differing H/D exchange kinetics. PMID- 17702601 TI - GDNF selectively promotes regeneration of injury-primed sensory neurons in the lesioned spinal cord. AB - Axonal regeneration within the CNS fails due to the growth inhibitory environment and the limited intrinsic growth capacity of injured neurons. Injury to DRG peripheral axons induces expression of growth associated genes including members of the glial-derived neurotrophic factor (GDNF) signaling pathway and "preconditions" the injured cells into an active growth state, enhancing growth of their centrally projecting axons. Here, we show that preconditioning DRG neurons prior to culturing increased neurite outgrowth, which was further enhanced by GDNF in a bell-shaped growth response curve. In vivo, GDNF delivered directly to DRG cell bodies facilitated the preconditioning effect, further enhancing axonal regeneration beyond spinal cord lesions. Consistent with the in vitro results, the in vivo effect was seen only at low GDNF concentrations. We conclude that peripheral nerve injury upregulates GDNF signaling pathway components and that exogenous GDNF treatment selectively promotes axonal growth of injury-primed sensory neurons in a concentration-dependent fashion. PMID- 17702603 TI - Breaking the bottleneck: eukaryotic membrane protein expression for high resolution structural studies. AB - The recombinant expression of eukaryotic membrane proteins has been a major stumbling block in efforts to determine their structures. In the last two years, however, five such proteins have yielded high-resolution X-ray or electron diffraction data, opening the prospect of increased throughput for eukaryotic membrane protein structure determination. Here, we summarize the major expression systems available, and highlight technical advances that should facilitate more systematic screening of expression conditions for this physiologically important class of targets. PMID- 17702602 TI - Differentiation of the Drosophila serotonergic lineage depends on the regulation of Zfh-1 by Notch and Eagle. AB - Elucidating mechanisms that differentiate motor neurons from interneurons are fundamental to understanding CNS development. Here we demonstrate that within the Drosophila NB 7-3/serotonergic lineage, different levels of Zfh-1 are required to specify unique properties of both motor neurons and interneurons. We present evidence that Zfh-1 is induced by Notch signaling and suppressed by the transcription factor Eagle. The antagonistic regulation of zfh-1 by Notch and Eagle results in Zfh-1 being expressed at low levels in the NB 7-3 interneurons and at higher levels in the NB 7-3 motor neurons. Furthermore, we present evidence that the induction of Zfh-1 by Notch occurs independently from canonical Notch signaling. We present a model where the differentiation of cell fates within the NB 7-3 lineage requires both canonical and non-canonical Notch signaling. Our observations on the regulation of Zfh-1 provide a new approach for examining the function of Zfh-1 in motor neurons and larval locomotion. PMID- 17702604 TI - Threat in dreams: an adaptation? AB - Revonsuo's influential Threat Simulation Theory (TST) predicts that people exposed to survival threats will have more threat dreams, and evince enhanced responses to dream threats, compared to those living in relatively safe conditions. Participants in a high crime area (South Africa: n=208) differed significantly from participants in a low crime area (Wales, UK: n=116) in having greater recent exposure to a life-threatening event (chi([1,N=186])(2)=14.84, p<.00012). Contrary to TST's predictions, the SA participants reported significantly fewer threat dreams (chi([1,N=287])(2)=6.11, p<.0134), and did not differ from the Welsh participants in responses to dream threats (Fisher's Exact test, p=.2478). Overall, the incidence of threat in dreams was extremely low-less than 20% of dreams featured realistic survival threats. Escape from dream threats occurred in less than 2% of dreams. We conclude that this evidence contradicts key aspects of TST. PMID- 17702605 TI - A novel approach to clinical-radiological correlations: Anatomo-Clinical Overlapping Maps (AnaCOM): method and validation. AB - We present a new clinical-radiological correlation method (AnaCOM) that aims at establishing structure-function relationships. We validated AnaCOM by assessing the location of lesions that are associated with altered performances in a well studied task: the verbal fluency task. We retrospectively reviewed 64 brain damaged patients who had focal lesions in a variety of cortical sites due to stroke, hemorrhage or tumor surgery. All patients were tested for verbal fluency at the time of the MRI examination. MRI volumes were normalized using a mask covering brain lesions and artifacts. The brain lesions were then segmented using the normalized MRI. In each patient, a verbal fluency score was assigned to each voxel in the segmented area. Subsequently, segmentations were superimposed and voxels were gathered in clusters defined by the overlap of the patients' lesion. For each cluster, the scores were statistically compared to those obtained by controls for the same task. This process allowed the construction of cluster-by cluster statistical maps of anatomo-clinical correlations. As expected, the statistical map indicated that two regions were significantly associated with a deficit in the fluency task: one located in Broca's area and the other in the preSMA. AnaCOM does not require a priori selection of the location of lesions or task scores. The method complements the functional imaging techniques, as it tells which regions are necessary for a given function and it explores cortical regions as well as the white matter. PMID- 17702607 TI - Visualization of the deep cerebellar nuclei using quantitative T1 and rho magnetic resonance imaging at 3 Tesla. AB - The cerebellum coordinates movement, thought and emotion through its feedback projections from the deep cerebellar nuclei. Despite recent advancement in our understanding of the functions of the cerebellar cortex, little is known about the functional correlates of the deep cerebellar nuclei in humans. This is mainly due to the inability of current MRI techniques to visualize the cerebellar nuclei and therefore perform in vivo clinico-anatomical correlation studies in patient populations. Here we visualize in vivo the detailed anatomy of the dentate nucleus and other cerebellar nuclei using quantitative T1 and proton density (rho) imaging. Compared to conventional qualitative T1, T2 or T2*-weighted imaging, quantitative T1 and proton density (rho) imaging facilitates direct visualization of the dentate and interposed nuclei, allowing us to perform segmentation and volumetric measurements of the dentate nucleus. Also the fine architecture of the microgyric and macrogyric dentate nucleus was visible on the high-resolution images. The high concentration of paramagnetic iron within the cerebellar nuclei and the resulting local field inhomogeneities surrounding the iron-containing nuclei is believed to be responsible for the observed effect on T1 and proton density signal. The application of this technique to disorders with cerebellar dysfunction could provide new insight into pathologies like autism and movement disorders. PMID- 17702608 TI - Molecular phylogeny and diversification of freshwater shrimps (Decapoda, Atyidae, Caridina) from ancient Lake Poso (Sulawesi, Indonesia)--the importance of being colourful. AB - Ancient Lake Poso on the Indonesian island Sulawesi hosts a highly diverse endemic fauna, including a small species flock of atyid Caridina shrimps, which are characterized by conspicuous colour patterns. We used a mtDNA based molecular phylogeny to test the assumption of a monophyletic origin and intralacustrine radiation of the species flock and to assess the species specificity of some colour morphs. Our data reveal a rapid radiation of Caridina in the entire Poso drainage system, but provide no strong evidence for a monophyletic radiation of the lake species. Nevertheless each lacustrine species shows a varying degree of substrate or trophic specialization, usually considered a hallmark of adaptive radiation. Two distinct colour forms previously attributed to a single species, C. ensifera, lack distinguishing qualitative morphological characters, but are shown to be two different species. In contrast, morphologically rather distinct lake species lacking specific colour patterns may be hybridizing with riverine taxa. These results suggest that colour may play a similar role in species recognition and possibly speciation in ancient lake Caridina as hypothesized, e.g. for some African cichlids. PMID- 17702609 TI - Molecular phylogenetics and reproductive incompatibility in a complex of cryptic species of aphid parasitoids. AB - We infer the phylogeny of a complex of cryptic species and populations of parasitic wasps and examine how reproductive incompatibility maps onto the molecular phylogeny. We used four nuclear (28S-D2, ITS1, ITS2, ArgK) and two mitochondrial (COI, COII) gene regions to analyze relationships among populations in the Aphelinus varipes species complex (Hymenoptera: Aphelinidae) from throughout Eurasia (France, Georgia, Israel, China, Korea and Japan) and from three aphid hosts (Aphis glycines, Diuraphis noxia and Rhopalosiphum padi; Hemiptera: Aphididae). A combined analysis of 21 genotypes of Aphelinus resulted in six most-parsimonious trees, and successive approximations character-weighting selected two of these as best supported by the data. All six gene regions were necessary to fully resolve the relationships among taxa. Four clades within the A. varipes complex were distinguished: (1) Aphelinus kurdjumovi, (2) Aphelinus hordei, (3) Aphelinus atriplicis, Aphelinus varipes, and Aphelinus albipodus, and (4) Aphelinus certus (populations from China, Korea, and Japan). Based on rates of nucleotide substitutions, these clades diverged between 78 and 526 thousand years ago during a period of repeated glaciations in Eurasia. In laboratory crosses, A. kurdjumovi, A. hordei, and A. varipes were reproductively incompatible with one another and all other populations. A. atriplicis was incompatible with these three species, but not with A. certus. The populations of A. certus from China, Japan, and Korea were reproductively compatible with one another but not with the other populations. Thus, with one exception, entities that were phylogenetically distinct were also reproductively incompatible with one another. Our evidence on molecular differentiation and reproductive incompatibility supports recognition of at least five cryptic species in the A. varipes complex. We discuss likely reasons for the high rate of speciation in this complex. PMID- 17702610 TI - Psychiatric diagnoses of patients with psychogenic non-epileptic seizures. AB - OBJECTIVE: Our purpose was to present and discuss the psychiatric diagnoses of patients who presented psychogenic non-epileptic seizures (PNES) during video electroencephalographic monitoring (VEEG). METHODS: Out of 98 patients, a total of 28 patients presented PNES during the diagnostic procedure. In those cases in which the PNES that occurred during VEEG were validated by clinical history (clinical validation), and by showing the recorded event on video to an observer close to the patient (observer validation), was defined psychogenic non-epileptic seizure disorder (PNESD). Psychiatric diagnoses were made according to DSM-IV. RESULTS: In 27, psychogenic non-epileptic seizures disorder was diagnosed. Fourteen patients presented only with psychogenic non-epileptic seizure disorder, 13 with both psychogenic non-epileptic seizures disorder and epilepsy, and one patient with epilepsy only. Psychiatric diagnoses were: 17 (63%) patients with conversion disorder, five (19%) with somatization disorder, two (7%) with dissociative disorder NOS, two (7%) with post-traumatic stress disorder and one (4%) with undifferentiated somatoform disorder. CONCLUSIONS: Dissociative conversion non-epileptic seizures are the most frequent finding, representing the pseudoneurological manifestation of mental disorders that have these symptoms as a common feature. Provisionally, they may be defined as dissociative-conversion non-epileptic seizure disorders. PMID- 17702606 TI - Robust detection of ocular dominance columns in humans using Hahn Spin Echo BOLD functional MRI at 7 Tesla. AB - Cells in the mammalian brain tend to be grouped together according to their afferent and efferent connectivity, as well as their physiological properties. The columnar structures of neocortex are prominent examples of such modular organization, and have been studied extensively in anatomical and physiological experiments in rats, cats and monkeys. The importance of noninvasive study of such structures, in particular in human subjects, cannot be overemphasized. Not surprisingly, therefore, many attempts were made to map cortical columns using functional magnetic resonance imaging (fMRI). Yet, the robustness, repeatability, and generality of the hitherto used fMRI methodologies have been a subject of intensive debate. Using differential mapping in a high magnetic field magnet (7 T), we demonstrate here the ability of Hahn Spin-Echo (HSE) BOLD to map the ocular dominance columns (ODCs) of the human visual cortex reproducibly over several days with a high degree of accuracy, relative to expected spatial patterns from post-mortem data. On the other hand, the conventional Gradient-Echo (GE) blood oxygen level dependent (BOLD) signal in some cases failed to resolve ODCs uniformly across the selected gray matter region, due to the presence of non specific signals. HSE signals uniformly resolved the ODC patterns, providing a more generalized mapping methodology (i.e. one that does not require adjusting experimental approaches based on prior knowledge or assumptions about functional organization and vascular structure in order to avoid confounding large vessel effects) to map unknown columnar systems in the human brain, potentially paving the way both for the study of the functional architecture of human sensory cortices, and of brain modules underlying specific cognitive processes. PMID- 17702611 TI - Gene expression profiling of normal and ruptured canine anterior cruciate ligaments. AB - OBJECTIVE: To identify genes which may be involved in the development of anterior cruciate ligament (ACL) laxity and rupture in a naturally occurring canine osteoarthritis (OA) model. DESIGN: Three groups of dog were studied: (1) dogs with ACL rupture; (2) dogs with intact ACLs from a breed predisposed to ACL rupture; (3) dogs with intact ACLs from a breed at very low risk of rupture. The transcriptomes of the ACLs from each group were compared using a whole genome microarray and quantitative reverse transcriptase polymerase chain reaction. Differential gene expression in ruptured canine ACLs was compared with that published in the literature for ruptured human ACLs. RESULTS: No significant differences were identified between the gene expression profiles of normal ACLs of a breed predisposed to ACL rupture when compared to a breed relatively resistant to ACL rupture. A general pattern of increased protease and extracellular structural matrix gene expression was identified in the ruptured ACLs when compared to intact ACLs. The gene expression profiles of ruptured canine ACLs demonstrate similar patterns to those previously reported for ruptured human ACLs. CONCLUSIONS: A transcriptomic basis to breed specific risk for the development of canine ACL rupture was not identified. Although changes in matrix associated gene expression in the ruptured ACL are similar between humans and dogs, the molecular events which may predispose to ACL laxity and rupture were not defined. PMID- 17702613 TI - Administration of corticosterone after memory reactivation disrupts subsequent retrieval of a contextual conditioned fear memory: dependence upon training intensity. AB - Reactivation of stabilized memories returns them to a labile state and causes them to undergo extinction or reconsolidation processes. Although it is well established that administration of glucocorticoids after training enhance consolidation of contextual fear memories, but their effects on post-retrieval processes are not known. In this study, we first asked whether administration of corticosterone after memory reactivation would modulate subsequent expression of memory in rats. Additionally, we examined whether this modulatory action would depend upon the strength of the memory. We also tested the effect of propranolol after memory reactivation. Adult male Wistar rats were trained in a fear conditioning system using moderate (0.4 mA) or high shock (1.5 mA) intensities. For reactivation, rats were returned to the chamber for 90 s 24h later. Immediately after reactivation, rats were injected with corticosterone (1, 3 or 10mg/kg) or vehicle. One, 7 and 14 days after memory reactivation, rats were returned to the context for 5 min, and freezing behavior was scored. The findings indicated that corticosterone when injected after memory reactivation had no significant effect on recall of a moderate memory, but it impaired recall of a strong memory at a dose of 3mg/kg. Propranolol (5mg/kg) given after the reactivation treatment produced a modest impairment that persisted over three test sessions. Further, the results showed that corticosterone, but not propranolol deficit was reversed by a reminder shock. These findings provide evidence that administration of glucocorticoids following memory reactivation reduces subsequent retrieval of strong, but not moderate, contextual conditioned fear memory likely via acceleration of memory extinction. On the other hand, propranolol-induced amnesia may result from blockade of reconsolidation process. Further studies are needed to determine the underlying mechanisms. PMID- 17702614 TI - Electrolytic lesions of dorsal CA3 impair episodic-like memory in rats. AB - Episodic memory is the ability to recollect one's past experiences occurring in an unique spatial and temporal context. In non-human animals, it is expressed in the ability to combine "what", "where" and "when" factors to form an integrated memory system. During the search for its neural substrates, the hippocampus has attracted a lot of attentions. Yet, it is not yet possible to induce a pure episodic-like memory deficit in animal studies without being confounded by impairments in the spatial cognition. Here, we present a lesion study evidencing direct links between the hippocampus CA3 region and the episodic-like memory in rats. In a spontaneous object exploration task, lesioned rats showed no interaction between the temporal and spatial elements in their memory associated with the objects. In separate tests carried out subsequently, the same animals still expressed abilities to process spatial, temporal, and object recognition memory. In conclusions, our results support the idea that the hippocampus CA3 has a particular status in the neural mechanism of the episodic-like memory system. It is responsible for combining information from different modules of cognitive processes. PMID- 17702612 TI - Stress and emotional memory retrieval: effects of sex and cortisol response. AB - In some situations, memory is enhanced by stressful experience, while in others, it is impaired. The specific components of the stress-response that may result in these differing effects remain unclear, and the current study sought to address this knowledge gap. Forty healthy participants (20 women, 20 men) were exposed to emotionally arousing and neutral pictures. Twenty-four hours later, 20 participants underwent a social stressor (speech and math tests), and 20 underwent a control reading task, both followed by a delayed free recall task. Cortisol responders to the stress condition (5 men and 1 woman) showed reduced memory retrieval for both neutral and emotionally arousing pictures. Men and women in the stress condition who did not produce a cortisol response showed increased retrieval of unpleasant pictures compared to controls. The results provide further evidence that cortisol is a primary effector in the stress induced memory retrieval deficit. At the same time, stress can enhance memory retrieval performance, especially for emotional stimuli, when the cortisol response is absent. PMID- 17702615 TI - The feedback phase of type I interferon induction in dendritic cells requires interferon regulatory factor 8. AB - Dendritic cells (DCs) produce type I interferons (IFNs) in greater amounts than other cells, but the mechanisms remain elusive. Here we studied the role of a transcription factor, IRF8, in DC induction of type I IFNs. Upon newcastle disease virus (NDV) infection, bone marrow-derived plasmacytoid and conventional DCs induced IFN transcripts, exhibiting two-phase kinetics. The second, amplifying phase represented an IFN feedback response that accounted for much of IFN protein production. Induction of second phase transcription required IRF8. Mouse cytomegalovirus (MCMV) and Toll-like receptor-mediated IFN induction in DCs also required IRF8. Chromatin immunoprecipitation analysis showed that IRF7, IRF8, and RNA polymerase II were recruited to the IFN promoters upon stimulation. Moreover, sustained RNA polymerase II recruitment to the promoters critically depended on IRF8. Together, these data indicate that IRF8 magnifies the second phase of IFN transcription in DCs by prolonging binding of basic transcription machinery to the IFN promoters, thereby playing a role in innate immunity. PMID- 17702618 TI - Structural insights into the clathrin coat. AB - Clathrin is a cytoplasmic protein best known for its role in endocytosis and intracellular trafficking. The diverse nature of clathrin has recently become apparent, with strong evidence available suggesting roles in both chromosome segregation and reassembly of the Golgi apparatus during mitosis. Clathrin functions as a heterohexamer, adopting a three-legged triskelion structure of three clathrin light chains and three heavy chains. During endocytosis clathrin forms a supportive network about the invaginating membrane, interacting with itself and numerous adapter proteins. Advances in the field of structural biology have led us to a greater understanding of clathrin in its assembled state, the clathrin lattice. Combining techniques such as X-ray crystallography, NMR, and cryo-electron microscopy has allowed us to piece together the intricate nature of clathrin-coated vesicles and the interactions of clathrin with its many binding partners. In this review I outline the roles of clathrin within the cell and the recent structural advances that have improved our understanding of clathrin clathrin and clathrin-protein interactions. PMID- 17702617 TI - Remodeling the model organism: matrix metalloproteinase functions in invertebrates. AB - The matrix metalloproteinase (MMP) family of extracellular proteases is conserved throughout the animal kingdom. Studies of invertebrate MMPs have demonstrated they are involved in tissue remodeling. In Drosophila, MMPs are required for histolysis, tracheal growth, tissue invasion, axon guidance, and dendritic remodeling. Recent work demonstrates that MMPs also participate in Drosophila tumor invasion. In Caenorhabditis elegans an MMP is involved in anchor cell invasion; a Hydra MMP is important for regeneration and maintaining cell identity; and a sea urchin MMP degrades matrix to allow hatching. In worms and in flies, MMPs are regulated by the JNK pathway. PMID- 17702616 TI - Membrane type 1-matrix metalloproteinase: substrate diversity in pericellular proteolysis. AB - Enzymes in the matrix metalloproteinase (MMP) family have been linked to key events in developmental biology for almost 50 years. Biochemical, cellular and in vivo analyses have established that pericellular proteolysis contributes to numerous aspects of ontogeny including ovulation, fertilization, implantation, cellular migration, tissue remodeling and repair. Surface anchoring of proteinase activity provides spatial restrictions on substrate targeting. This review will utilize membrane type 1 MMP (MT1-MMP) as an example to highlight substrate diversity in pericellular proteolysis catalyzed by a membrane anchored MMP. PMID- 17702620 TI - Boosting in equine influenza vaccination schedules: timing and time for a re evaluation of requirements of national and international authorities. PMID- 17702619 TI - Paradoxical effects of two oximes on nitric oxide production by purified NO synthases, in cell culture and in animals. AB - We have studied the impact of two novel compounds TO-85 (2,6-di-(alpha-aziridino alpha-hydroxyiminomethyl)pyridine and TO-133 (bis-(diaziridinoglyoximato)copper), designed as NO donors, on nitrite production by cell cultures, NO production in rat tissues and their ability to inhibit purified NO synthases (NOS). Both substances induced considerable increase of nitrite production in cell cultures. When NO production was assayed in rat organs by means of ESR using Fe(DETC) as a spin trap the anticipated NO-increasing activity of TO-85 was observed only in kidneys; the NO level increasing almost 10-fold. Treatment of rats with TO-133, decreased the NO concentration in brain cortex, cerebellum and liver. When the drugs were administered to animals with high level of iNOS expression induced by LPS, TO-85 did not significantly modify the LPS-induced NO production; administration of TO-133 caused a significant decrease of NO production in blood, brain cortex and cerebellum. Only high concentrations of TO-85 were capable of inhibiting iNOS (IC50=7 mM), the substance inhibited eNOS at lower concentrations (IC50=250 microM). Inhibitory activities of TO-85 on nNOS were dependent on BH4 concentrations, suggesting eventual competition of TO-85 with BH4 when the substance interacts with nNOS. TO-133 reduced eNOS activity with IC50=200 microM, nNOS activity with IC50=200 microM, iNOS activity was not much affected by this substance. Thus, the two tested compounds manifest opposite effects on NO production by purified enzymes and in cell culture. The pattern of the NO synthesis modification in a living animal appears to be even more complex. Our results stress the importance of direct measurements of NO in the tissues using the ESR method. PMID- 17702621 TI - KIT-positive gastrointestinal stromal tumours in two Spanish ibex (Capra pyrenaica hispanica). AB - Gastrointestinal mesenchymal tumours from two Spanish ibex (Capra pyrenaica hispanica) were examined grossly, histologically and immunohistochemically. One neoplasm was a 1.5 kg tan multinodular cavitated mass in the forestomach. The other tumour was a firm mural mass 1.2 cm in diameter in the colon. Microscopically, both tumours were formed mainly by spindle shaped cells arranged in closely packed interlacing fascicles. Neoplastic cells in both tumours labelled positively for KIT (CD117), vimentin and alpha-smooth muscle actin. These findings suggest that both neoplasms were gastrointestinal stromal tumours and most likely to be derived from the interstitial cells of Cajal or their progenitor cells. PMID- 17702623 TI - [Fifteen practical questions concerning gestational diabetes]. AB - With a review of the current literature, a clarification on screening and management of gestational diabetes is hereby set out, within the frame of a Clinical Expert Series. According to the ethnic group, the prevalence varies from 1 to 14%. The treatment is based on dietary advice, insulin. The ACHOIS study demonstrates that the treatment of gestational diabetes significantly decreases perinatal complications (4 to 1%). The place of the oral treatment (glyburide) remains to be defined. In most countries, diagnosis rests on oral glucose test tolerance: Sullivan 50 g glucose test (1 hour) and 100 g test of glucose if positive (3 hours); WHO 75 g test (2 hours). The screening can be systematic or only on risk factors (wide variations between studies). Screening of gestational diabetes is required because its management improves pregnancy outcomes. Despite this, there is no consensus on the strategy of screening and diagnosis. PMID- 17702622 TI - Microalbuminuria and urinary albumin excretion: French clinical practice guidelines. AB - Urinary albumin excretion (UAE) may be assayed on a morning urinary sample or a 24 h-urine sample. Values defining microalbuminuria are: 1) 24-h urine sample: 30 300 mg/24 h; 2) morning urine sample: 20-200 mg/ml or 30-300 mg/g creatinine or 2.5-25 mg/mmol creatinine (men) or 3.5-35 mg/mmol (women); 3) timed urine sample: 20-200 mug/min. The optimal use of semi-quantitative urine test-strip is not clearly defined. It is generally believed that microalbuminuria reflects a generalized impairment of the endothelium; however, no definite proof has been obtained in humans. IN DIABETIC SUBJECTS: Microalbuminuria is a marker of increased risk of cardiovascular (CV) and renal morbidity and mortality in type 1 and type 2 diabetic subjects. The increase in UAE during follow-up is associated with greater CV and renal risks in type 1 and type 2 diabetic subjects; its decrease during follow-up is associated with lower risks. IN NON-DIABETIC SUBJECTS: Microalbuminuria is a marker of increased risk for diabetes mellitus, deterioration of renal function, CV morbidity and all-cause mortality. It is a marker of increased risk for the development of hypertension in normotensive subjects, and is associated with unfavorable outcome in patients with cancer and lymphoma. Persistence of elevated UAE during follow-up is associated with poor outcome in some hypertensive subjects. Measurement of UAE may be recommended in hypertensive medium-risk subjects with 1 or 2 CV risk factors in whom CV risk remains difficult to assess, and in those with refractory hypertension: microalbuminuria indicates a high CV risk and must lead to strict control of arterial pressure. Studies focused on microalbuminuria in non-diabetic non hypertensive subjects are limited; most of them suggest that microalbuminuria predicts CV complications and deleterious outcome. Subjects with a history of CV or cerebrovascular disease have an even greater CV risk if microalbuminuria is present than if it is not; however, in all cases, therapeutic intervention must be aggressive regardless of whether microalbuminuria is present or not. It is not recommended to measure UAE in non-diabetic non-hypertensive subjects in the absence of history of renal disease. Monitoring of renal function (UAE, serum creatinine and estimation of GFR) is recommended annually in all subjects with microalbuminuria. MANAGEMENT: In patients with microalbuminuria, weight reduction, sodium restriction (<6 g per day), smoking cessation, strict glucose control in diabetic subjects, strict arterial pressure control are necessary; in diabetic subjects: use of maximal doses of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) are recommended; ACEI/ARB and thiazides have synergistic actions on arterial pressure and reduction of UAE; in non-diabetic subjects, any of the five classes of anti hypertensive medications (ACEI, ARB, thiazides, calcium channel blockers or beta blockers) can be used. PMID- 17702624 TI - Accuracy and reproducibility of pleural effusion cytology. AB - The increasing number of Malignant Mesothelioma (MM) cases that arrive for expert examinations to court for compensation reasons in subjects exposed to asbestos, in many instances rely exclusively on cytological smears of pleural effusion. We evaluated the accuracy and reproducibility of cytological pleural effusions, based on morphological criteria alone. Nine pathologists and eight residents from seven institutions in north-east Italy blindly examined 45 smears of MM (17), metastases (14) and benign effusions (14), in two rounds. Diagnoses had been confirmed by immunohistochemical and clinical follow-up, and eventually at autopsy. Diagnostic accuracy, interobserver and intraobserver agreement in the distinction of benign vs malignant cases, and in the differentiation of primary from metastatic malignancies, were evaluated. The distinction of benign from malignant smears resulted rather satisfactory (k=0.514), but markedly decreased in differentiation of MM from metastases (overall agreement: k=0.343), as well as when readings from residents were analyzed (k=0.132). Cytology is a useful and reliable tool in the identification of malignancies, but when the distinction of primary from metastatic tumors is addressed morphological criteria alone are not sufficient for a definite diagnosis of MM and the use of cell blocks, immunohistochemistry (IHC) and molecular ancillary techniques are recommended. PMID- 17702625 TI - Disparities of care in veterans with Parkinson's disease. AB - BACKGROUND: Disparities of Parkinson's disease (PD) care have not been assessed. METHODS: We examined the medical records of 309 (83%) non-Hispanic White and 65 (17%) non-White Los Angeles veterans with PD from 1998 to 2004 to determine if care quality as measured by 10 PD indicators different by race/ethnicity. RESULTS: In multivariate modeling, adherence to indicators was higher among non Hispanic Whites (71% vs. 65%, risk ratio 1.15, 95% CI [1.07-1.32]) compared to non-Whites. Differences in adherence by race/ethnicity were greatest for depression treatment (p<0.05). CONCLUSIONS: We detected disparities in quality of PD care, particularly in depression treatment. Future research should determine causes for these so that interventions can be designed to reduce such disparities. PMID- 17702626 TI - Bilateral hemifacial spasm: a series of 10 patients with literature review. AB - Bilateral hemifacial spasm (HFS) is a rare movement disorder posing diagnostic doubt with other facial dyskinesias. In this report, we describe clinical, radiological and therapeutic features of 10 patients with bilateral HFS. The prevalence of bilateral HFS in our sample was of 2.6%. Clinical characteristics of our patients did not differ from the classic features of unilateral cases. The mean latency for contralateral facial nerve involvement was of 33.3 months. In only one case a vascular abnormality was seen. We conclude that bilateral HFS is rare and that clinical differentiation with other facial dyskinesias should be promptly made to introduce appropriate therapy. PMID- 17702627 TI - Natural killer cells of Parkinson's disease patients are set up for activation: a possible role for innate immunity in the pathogenesis of this disease. AB - Neuroinflammation in Parkinson's disease (PD) involves activation of microglia, participation of several inflammatory cytokines, prostaglandins, complement and systemic activation of natural killer (NK) cells, suggesting that innate immunity has a role in the pathogenesis of this disease. In this study, we examined NK activity and the expression of its regulatory molecules in peripheral lymphocytes of PD patients and compared the results with those of healthy controls. Expression of the inhibitory NKG2A receptors was significantly lower in PD, causing PD patients to be susceptible in a condition for NK activation after NK cells bind to target cells via these receptors. PMID- 17702628 TI - Predictors of impulsivity and reward seeking behavior with dopamine agonists. AB - Three hundred consecutive patients taking DA either for Parkinson's disease (PD, 207), restless legs syndrome (RLS, 89), or both (4) were interviewed about changes in gambling, spending, sexual activity, or other impulsive activities subsequent to DA. Regression models identified risk factors for impulsivity. Overall, 19.7% reported any increased impulsivity: 30 gambling, 26 spending, 11 sexual activity, and 1 wanton traveling. Only 11/59 felt the change was deleterious. Increased impulsivity correlated with a younger age (p=0.01), larger doses of DA (p<0.001), and PD, as opposed to RLS (p<0.01), but this lost significance after correcting for dose (p=0.09). Increased impulsivity is common but usually not deleterious. PMID- 17702629 TI - Characteristics of depression in Parkinson's disease: evaluating with Zung's Self Rating Depression Scale. AB - The purpose of the study was to elucidate characteristics of depression in Parkinson's disease (PD). Fifty-eight PD patients were evaluated with Zung's Self Rating Depression Scale (SDS) and the Unified Parkinson's Disease Rating Scale (UPDRS). Scores for "suicidal ideation" on the SDS correlated with posture and gait disturbances on the UPDRS. Twenty-six patients with spinocerebellar degeneration (SCD) were also evaluated with the SDS. SDS scores for "indecisiveness" and "constipation" were significantly higher in PD patients than SCD patients. Our results suggest that depression is common in disabled persons but PD patients might have a characteristic clinical presentation. PMID- 17702630 TI - The economic impact of Parkinson's disease. AB - Patients with Parkinson's disease (PD) experience progressive disability and reduced quality of life due to both motor and non-motor complications. The cost of illness escalates as PD progresses, placing an economic burden on the healthcare system, society and patients themselves. Overall cost estimates vary from country to country, but the largest component of direct cost is typically inpatient care and nursing home costs, while prescription drugs are the smallest contributor. Indirect costs arising from lost productivity and carer burden tend to be high. The total cost in the UK has been estimated to be between pound 449 million and pound 3.3 billion annually, depending on the cost model and prevalence rate used. Management strategies that minimise the impact of disease progression and maximise quality of life should help ensure optimal resource utilisation. PMID- 17702631 TI - Deep brain stimulation and continuous dopaminergic stimulation in advanced Parkinson's disease. AB - Patients receiving oral levodopa, the standard treatment for Parkinson's disease (PD), eventually develop motor fluctuations and dyskinesias. Treatment options for patients with these symptoms include high-frequency deep brain stimulation of the subthalamic nucleus (STN-DBS) or continuous dopaminergic stimulation (CDS). STN-DBS is the prevalent surgical therapy for PD and has shown efficacy, but behavioural disorders, including cognitive problems, depression and suicidality have been reported. CDS can be achieved with oral dopamine agonists with a long half-life, transdermal or subcutaneous delivery of dopamine agonists, or intestinal levodopa infusion. Of these, duodenal levodopa infusion appears to be the most promising option in terms of both efficacy and safety. PMID- 17702632 TI - Continuous dopaminergic stimulation--from theory to clinical practice. AB - Patients with advanced Parkinson's disease (PD) experience worsening motor fluctuations and dyskinesia. Management options include deep brain stimulation of the subthalamic nucleus (STN-DBS), subcutaneous apomorphine (in combination with oral levodopa) or continuous duodenal levodopa administration. We have used all three therapies at our clinic in Milan and report our experience. Apomorphine infusion reduced daily off time but did not improve dyskinesia; long-term treatment was associated with impulse control disorders. STN-DBS provided motor benefit, but was associated with behavioural changes including attempted suicide. Duodenal levodopa produced significant clinical benefit without behavioural changes and allowed patients to discontinue all other PD medications. Duodenal levodopa should be considered in PD patients with advanced disease. PMID- 17702633 TI - Evaluation of the Dutch version of the Parkinson's Disease Questionnaire 39. AB - The psychometric properties of the Dutch version of the Parkinson's disease questionnaire 39 (PDQ39-DV) were tested in 177 patients with Parkinson's disease (PD). Internal consistency of 7 of the 8 scales was adequate (>or=0.70), but was insufficient for 'bodily discomfort' (0.59). Correlation between the PDQ39 and other instruments in this study, the SCOPA-psychosocial questionnaire, Euroqol 5D, hospital anxiety and depression scale, and a visual analogue scale for quality of life, were 0.82, 0.74, 0.63 and -0.54, respectively. The factor analysis yielded 8 factors, which accounted for 65% of the variance and revealed only small differences with the original UK version. We conclude that the PDQ39 DV displays satisfactory psychometric properties and is an appropriate instrument to assess quality of life in Dutch patients with PD. PMID- 17702635 TI - Posttraumatic hemiballism with focal discrete hemorrhage in contralateral subthalamic nucleus. AB - Although head trauma has occasionally been described as a cause of hemiballism, relevant traumatic lesion involving subthalamic nucleus (STN) has rarely been reported. We report a 49-year-old man with focal and discrete traumatic STN hemorrhage, which presented as transient contralateral hemiballism. Although such discrete STN lesion is not infrequently found in patients with post-stroke hemiballism, it has not been reported in posttraumatic hemiballism. PMID- 17702636 TI - Sensorimotor disturbances in neck disorders affecting postural stability, head and eye movement control. AB - The receptors in the cervical spine have important connections to the vestibular and visual apparatus as well as several areas of the central nervous system. Dysfunction of the cervical receptors in neck disorders can alter afferent input subsequently changing the integration, timing and tuning of sensorimotor control. Measurable changes in cervical joint position sense, eye movement control and postural stability and reports of dizziness and unsteadiness by patients with neck disorders can be related to such alterations to sensorimotor control. It is advocated that assessment and management of abnormal cervical somatosensory input and sensorimotor control in neck pain patients is as important as considering lower limb proprioceptive retraining following an ankle or knee injury. Afferent information from the cervical receptors can be altered via a number of mechanisms such as trauma, functional impairment of the receptors, changes in muscle spindle sensitivity and the vast effects of pain at many levels of the nervous system. Recommendations for clinical assessment and management of such sensorimotor control disturbances in neck disorders are presented based on the evidence available to date. PMID- 17702637 TI - Overexpression of MMP9 in macrophages attenuates pulmonary fibrosis induced by bleomycin. AB - Pulmonary fibrosis is a common response to a variety of lung injuries, characterized by fibroblast/myofibroblast expansion and abnormal accumulation of extracellular matrix. An increased expression of matrix metalloprotease 9 (MMP9) in human and experimental lung fibrosis has been documented, but its role in the fibrotic response is unclear. We studied the effect of MMP9 overexpression in bleomycin-driven lung fibrosis using transgenic mice expressing human MMP9 in alveolar macrophages (hMMP9-TG). At 8 weeks post-bleomycin, the extent of fibrotic lesions and OH-proline content were significantly decreased in the TG mice compared to the WT mice. The decreased fibrosis in hMMP9-TG mice was preceded by a significant reduction of neutrophils and lymphocytes in bronchoalveolar lavage (BAL) at 1 and 4 weeks post-bleomycin, respectively, as well as by significantly less TIMP-1 than the WT mice. From a variety of cytokines/chemokines investigated, we found that BAL levels of insulin-like growth factor binding protein-3 (IGFBP3) as well as the immunoreactive protein in the lungs were significantly lower in hMMP9-TG mice compared with WT mice despite similar levels of gene expression. Using IGFBP-3 substrate zymography we found that BAL from TG mice at 1 week after bleomycin cleaved IGFBP-3. Further, we demonstrated that MMP9 degraded IGFBP-3 into lower molecular mass fragments. These findings suggest that increased activity of MMP9 secreted by alveolar macrophages in the lung microenvironment may have an antifibrotic effect and provide a potential mechanism involving IGFBP3 degradation. PMID- 17702638 TI - Programmed cell death: from novel gene discovery to studies on network connectivity and emerging biomedical implications. PMID- 17702640 TI - The role of the interferon regulatory factor (IRF) family in dendritic cell development and function. AB - Dendritic cells (DCs) are powerful sensors of foreign pathogens as well as cancer cells and provide the first line of defence against infection. They also serve as a major link between innate and adaptive immunity. Immature DCs respond to incoming danger signals and undergo maturation to produce high levels of proinflammatory cytokines including type I interferons (IFNs) to establish innate immunity. They then present antigens to T lymphocytes to stimulate lasting specific immune responses. Recent studies point to the importance of DCs in the induction of peripheral tolerance. Transcription factors of the IRF family have emerged as crucial controllers of many aspects of DC activity, playing an essential role in the establishment of early innate immunity. Furthermore, eight of the nine members of the IRF family have been shown to control either the differentiation and/or the functional activities of DCs. In this review, we focus on three aspects of DC properties that are under the control of IRFs: (1) the development and differentiation, (2) maturation in response to toll-like receptor (TLR) signalling and the production of anti-microbial cytokines, and (3) activation and expansion of lymphocytes to generate protective or tolerogenic immune responses. PMID- 17702639 TI - Innate immune evasion by hepatitis C virus and West Nile virus. AB - Antiviral immunity in mammals involves several levels of surveillance and effector actions by host factors to detect viral pathogens, trigger alpha/beta interferon production, and to mediate innate defenses within infected cells. Our studies have focused on understanding how these processes are regulated during infection by hepatitis C virus (HCV) and West Nile virus (WNV). Both viruses are members of the Flaviviridae and are human pathogens, but they each mediate a very different disease and course of infection. Our results demonstrate common and unique innate immune interactions of each virus that govern antiviral immunity and demonstrate the central role of alpha/beta interferon immune defenses in controlling the outcome of infection. PMID- 17702641 TI - Efficient computational fluid dynamics mesh generation by image registration. AB - Most implementations of computational fluid dynamics (CFD) solutions require a discretisation or meshing of the solution domain. The production from a medical image of a computationally efficient mesh representing the structures of interest can be time consuming and labour-intensive, and remains a major bottleneck in the clinical application of CFD. This paper presents a method for deriving a patient specific mesh from a medical image. The method uses volumetric registration of a pseudo-image, produced from an idealised template mesh, with the medical image. The registration algorithm used is robust and computationally efficient. The accuracy of the new algorithm is measured in terms of the distance between a registered surface and a known surface, for image data derived from casts of the lumen of two different vessels. The true surface is identified by laser profiling. The average distance between the surface points measured by the laser profiler and the surface of the mapped mesh is better than 0.2 mm. For the images analysed, the new algorithm is shown to be 2-3 times more accurate than a standard published algorithm based on maximising normalised mutual information. Computation times are approximately 18 times faster for the new algorithm than the standard algorithm. Examples of the use of the algorithm on two clinical examples are also given. The registration methodology lends itself immediately to the construction of dynamic mesh models in which vessel wall motion is obtained directly using registration. PMID- 17702642 TI - The development of high-throughput screening approaches for stem cell engineering. AB - It has become increasingly clear that both soluble factors, such as growth factors, and insoluble factors, including the surfaces on which cells grow, can have controlling effects on stem cell behavior and differentiation. While much progress has been made in biomaterial design and application, the rational design of biomaterial cues to direct stem cell behavior and differentiation remains challenging. Recent advances in automated, high-throughput methods for synthesizing and screening combinatorial biomaterial libraries and cellular microenvironments promise to accelerate the discovery of factors that control stem cell behavior. Specific examples include miniaturized, automated, combinatorial material synthesis and extracellular matrix screening methods as well microarrayed methods for creating local microenvironments of soluble factors, such as small molecules, siRNA, and other signaling molecules. PMID- 17702643 TI - Plant autophagy--more than a starvation response. AB - Autophagy is a conserved mechanism for the degradation of cellular contents in order to recycle nutrients or break down damaged or toxic material. This occurs by the uptake of cytoplasmic constituents into the vacuole, where they are degraded by vacuolar hydrolases. In plants, autophagy has been known for some time to be important for nutrient remobilization during sugar and nitrogen starvation and leaf senescence, but recent research has uncovered additional crucial roles for plant autophagy. These roles include the degradation of oxidized proteins during oxidative stress, disposal of protein aggregates, and possibly even removal of damaged proteins and organelles during normal growth conditions as a housekeeping function. A surprising regulatory function for autophagy in programmed cell death during the hypersensitive response to pathogen infection has also been identified. PMID- 17702644 TI - Targets of RNA-directed DNA methylation. AB - RNA-directed DNA methylation contributes substantially to epigenetic regulation of the plant genome. Methylation is guided to homologous DNA target sequences by 24 nt 'heterochromatic' small RNAs produced by nucleolar-localized components of the RNAi machinery and a plant-specific RNA polymerase, Pol IV. Plants contain unusually large and diverse populations of small RNAs, many of which originate from transposons and repeats. These sequences are frequent targets of methylation, and they are able to bring plant genes in their vicinity under small RNA-mediated control. RNA-directed DNA methylation can be removed by enzymatic demethylation, providing plants with a versatile system that facilitates epigenetic plasticity. In addition to subduing transposons, RNA-directed DNA methylation has roles in plant development and, perhaps, stress responses. PMID- 17702646 TI - Detection of human papillomavirus genotypes 16/18/45 by hybrid capture hybridisation genotyping probe in clinical specimens: the first report. PMID- 17702645 TI - DNA adduct formation in human hepatoma cells treated with 3-nitrobenzanthrone: analysis by the (32)P-postlabeling method. AB - 3-Nitrobenzanthrone (3-nitro-7H-benz[d,e]anthracen-7-one, 3-NBA) is a powerful mutagen and a suspected human carcinogen existing in diesel exhaust and airborne particulates. Recently, one of the major presumed metabolites of 3-NBA, 3 aminobenzanthrone (3-ABA), was detected in human urine samples. Here we analyzed DNA adducts formed in 3-NBA-exposed human hepatoma HepG2 cells by a (32)P postlabeling/thin layer chromatography (TLC) method and a (32)P postlabeling/polyacrylamide gel electrophoresis (PAGE) method. With HepG2 cells exposed to 3-NBA (0.36-36.4 microM) for 3h, we obtained three spots or bands corresponding to adducted nucleotides. Two were assigned as 2-(2'-deoxyadenosin N(6)-yl)-3-aminobenzanthrone-3'-phosphate (dA3'p-N(6)-C2-ABA) and 2-(2' deoxyguanosin-N(2)-yl)-3-aminobenzanthrone-3'-phosphate (dG3'p-N(2)-C2-ABA), with identical mobilities to those of synthetic standards on PAGE analysis. The chemical structure of the substance corresponding to the other spot or band could not be identified. Quantitative analyses revealed that the major adduct was dA3'p N(6)-C2-ABA and its relative adduct labeling (RAL) value at 36.4 microM of 3-NBA was 200.8+/-86.1/10(8)nucleotide. PMID- 17702647 TI - Excessive ventilation during early phase of exercise: a new predictor of poor long-term outcome in patients with chronic heart failure. AB - BACKGROUND: Studies demonstrating prognostic value of excessive exercise ventilation in chronic heart failure (CHF) have focused on data derived from the whole cardiopulmonary exercise test (CPET). Whether ventilatory response to early phase of exercise is useful for risk stratification in CHF is unknown. METHODS AND RESULTS: We evaluated 216 patients with systolic CHF who underwent CPET (age: 60+/-11 years, NYHA class [I/II/III/IV]: 18/104/77/17). Ventilatory response to exercise (slope of regression line relating ventilation to carbon dioxide production) was calculated from the whole exercise test (VE-VCO(2)-all) and from the first 3 min of exercise (early phase - VE-VCO(2)-3 min). During follow-up (mean: 40+/-20 months, >3 years in survivors), 89 (41%) CHF patients died. High VE-VCO(2)-all and VE-VCO(2)-3 min predicted poor outcome in single predictor analyses, and in multivariable models when adjusted for prognosticators (age, NYHA class, ejection fraction, peak VO(2)) (P<0.0001). In receiver operating characteristic curve analysis, areas under curve for 3-year follow-up were similar for VE-VCO(2)-all and VE-VCO(2)-3 min. VE-VCO(2)-3 min maintained its prognostic value in patients taking beta-blockers (P<0.0001) and those unable to perform maximal CPET (P=0.0009). CONCLUSIONS: In CHF patients, excessive ventilation assessed over the first 3 min predicts poor outcome. Assessment of ventilatory response to exercise for prognostic stratification may be extended to patients unable to perform maximal CPET. PMID- 17702648 TI - Novel biochemical properties of a CRP/FNR family transcription factor from Mycobacterium tuberculosis. AB - Cyclic AMP (cAMP) receptor protein (CRP)/fumarate nitrate reductase regulator (FNR) family proteins are actively associated with defense against low oxygen stress, starvation and extreme temperature conditions. They are DNA-binding proteins and regulate target genes carrying the regulatory CRP/FNR cognate nucleotide sequence elements. Recombinant protein encoded by the Mycobacterium tuberculosis ORF Rv3676, a putative CRP/FNR regulator, was purified from Escherichia coli and was found to exist as dimer, devoid of any metal cation cofactor. Purified rRv3676 exhibited cAMP binding in a concentration-dependent manner. At lower concentrations of cAMP (6-10 microM) rRv3676 shows positive cooperativity; at 10 microM cAMP the protein exists in the most open conformation. rRv3676 could bind specifically to the putative CRP/FNR nucleotide sequence elements as evident from electrophoretic mobility shift assay. PMID- 17702649 TI - Improving live attenuated bacterial carriers for vaccination and therapy. AB - Live attenuated bacteria are well established as vaccines. Thus, their use as carriers for prophylactic and therapeutic macromolecules is a logical consequence. Here we describe several experimental applications of bacteria to carry heterologous macromolecules into the murine host. First, Listeria monocytogenes are described that are able to transfer eukaryotic expression plasmids into host cells for gene therapy. High multiplicities of infection are still required for efficient gene transfer and we point out some of the bottlenecks that counteract a more efficient transfer and application in vivo. Then, we describe Salmonella enterica serovar Typhimurium (S. typhimurium) as an expression plasmid transfer vehicle for oral DNA vaccination of mice. We demonstrate that the stabilization of the plasmid transformants results in an improved immune response. Stabilization was achieved by replacing the origin of replication of the original high-copy-number plasmid by a low-copy-number origin. Finally, we describe Salmonella carriers for the improved expression of heterologous proteins. We introduce a system in which the plasmid is carried as a single copy during cultivation but is amplified several fold upon infection of the host. Using the same in vivo inducible promoter for both protein expression and plasmid amplification, a substantial increase in antigen expression in vivo can be achieved. A modification of this approach is the introduction of inducible gene expression in vivo with a low-molecular-weight compound. Using P(BAD) promoter and L-arabinose as inducer we were able to deliberately activate genes in the bacterial carrier. No background activity could be observed with P(BAD) such that an inducible suicide gene could be introduced. This is adding an important safety feature to such live attenuated carrier bacteria. PMID- 17702650 TI - Engineering of cytomegalovirus genomes for recombinant live herpesvirus vaccines. AB - The advances of sequence knowledge and genetic engineering hold a great promise for a rational approach to vaccine development. Herpesviruses are important pathogens of all vertebrates. They cause acute and chronic infections and persist in their hosts for life. In man there are eight herpesviruses known and most of them can be linked to diseases. To date only one licensed vaccine against a human herpesvirus exists and there is no proven successful concept on rational design for herpesvirus vaccines available. Here, we use new reverse genetic systems, based on the 230-kb mouse cytomegalovirus genome to explore new methods of vaccine delivery and of virus attenuation. With regard to virus delivery, we show that the bacterial transfer of the infectious DNA in vivo is theoretically possible but not yet a practical option. With regard to a rational approach of virus attenuation, we consider a selective deletion of viral genes that modulate the immune response of the host. PMID- 17702651 TI - Yersinia enterocolitica: subversion of adaptive immunity and implications for vaccine development. AB - Enteric Yersinia spp. invade Peyer's patches, disseminate to lymphoid tissues, and induce mucosal and systemic immune responses. Many virulence factors of Yersinia enterocolitica have been investigated in detail and were found to act on host cells involved in innate and adaptive immunity. Recent work explored as to whether attenuated Y. enterocolitica or recombinant components of Y. enterocolitica can be used as tools for vaccination. We and others have tested whether by means of the type three secretion system in attenuated Y. enterocolitica strains antigens might be delivered to antigen-presenting cells in order to induce CD8 and CD4 T cell responses. Alternatively, recombinant components of Y. enterocolitica such as invasin protein which binds to beta1 integrins of host cells have been tested for their ability to target antigen along with microparticles (fused to invasin) to antigen-presenting cells and to act as adjuvant. The work summarized in this article demonstrates that Y. enterocolitica and its components might be useful tools for novel vaccination strategies; in fact, invasin when fused to antigen and coated to microparticles might induce both CD4 and CD8 T cell responses. Likewise, attenuated Y. enterocolitica live carrier strains were reported to induce both CD8 and some CD4 T cell responses. However, we need to know more about how Y. enterocolitica subverts functions of antigen-presenting cells in order to design mutants with optimized antigen delivery features and deletion in those virulence factor that contribute to subversion of innate or adaptive immune responses. PMID- 17702652 TI - Rational design of vaccines against tuberculosis directed by basic immunology. AB - Tuberculosis represents a serious problem for public health worldwide, and effective vaccines are urgently required. This represents a significant challenge as the causative bacterial agent, Mycobacterium tuberculosis, has developed strategies to persist in infected hosts despite the presence of potent T-cell mediated immune responses. New advances in basic immunology are giving us improved understanding of what constitutes a protective immune response and ways this response is manipulated by the bacillus. Such insights should inform us how to design more effective vaccination strategies against intracellular pathogens. PMID- 17702653 TI - A vaccine against Helicobacter pylori: towards understanding the mechanism of protection. AB - Helicobacter pylori infection remains a significant global public health problem. Vaccine development against this infection appears to be feasible but has not yet delivered its promise in clinical trials. Efforts to improve current vaccination strategies would greatly benefit from a better molecular understanding of the mechanism of protection. Here, we review recent developments in this field. PMID- 17702654 TI - Thermoregulatory responses of junior lifesavers wearing protective clothing. AB - This study investigated the influence of protective clothing worn to prevent marine stinger envenomation on the thermoregulatory responses of pre-pubescent surf lifesavers exercising in situ under hot and humid conditions (27 degrees C, 78% relative humidity). Participants performed beach and water activities typically associated with junior surf lifesaving competition in a randomised cross-over design on two separate occasions 7 days apart: one wearing a full length Lycra stinger suit (S) and one wearing normal swimwear (SW). Skin (T(SK)) and core (T(C)) body temperatures, skin blood flow (SKBF), heart rate (HR), body mass, thermal comfort and perceived effort were assessed pre-, mid- (following beach activities) and post-exercise (following water activities). Sweat rates were compared between S and SW. T(C) was greater following beach activities for S (37.78 degrees C+/-0.06) compared to SW (37.60 degrees C+/-0.07; p<0.05) and male participants experienced greater T(C) (37.97 degrees C+/-0.09) than their female counterparts (37.71 degrees C+/-0.07 degrees C). T(SK) following both the beach and water activities were lower than pre-exercise (p<0.05). SKBF was significantly increased for calf across time (p<0.01). Male participants experienced a higher HR for S compared to female participants (p<0.01) while the opposite applied to SW (p<0.01). There were no gender or between-condition differences for sweat rate or perceived effort. There was evidence of heat storage while stinger suits were worn during beach activities in the absence of any differences in exercise intensity or sweat rate. The results of the present study suggest that the stinger suits should be limited to water-based activities. PMID- 17702656 TI - Psychoneuroendocrine stress response may impair neutrophil function in complex regional pain syndrome. AB - In order to elucidate the interaction between pain, stress and innate immunity in complex regional pain syndrome (CRPS), we assessed pain and stress levels in CRPS patients and compared ex vivo functions of neutrophils between patients with CRPS and healthy volunteers. As compared with healthy volunteers, the following major alterations in CRPS patients were found: (I) elevated stress score (PTSS-10) and stress hormone concentrations, (II) decreased expression of the CD62L and CD11b/CD18 on neutrophils, (III) impaired ability of autologous plasma to enhance the capability of neutrophils to phagocytose zymosan particles, and (IV) a negative correlation between PTSS-10 values and autologous plasma enhanced phagocytosis. In vitro incubation of neutrophils with catecholamines decreased phagocytosis of zymosan. In conclusion, CRPS patients exhibit signs of impaired innate immunity which might reflect the immunological consequence of an immunosuppressive neuroendocrine stress response. PMID- 17702657 TI - Microvascular dysfunction in left apical ballooning syndrome: Primary cause or secondary phenomenon? PMID- 17702658 TI - Direct transoral manipulation to reduce a displaced odontoid fracture: a technical note. AB - BACKGROUND CONTEXT: Irreducible anteriorly displaced odontoid fractures are usually treated with posterior atlantoaxial fusion. PURPOSE: To present an alternative for fracture reduction and anterior stabilization for displaced odontoid fractures. STUDY DESIGN: A technique for reduction of odontoid fractures is reported. PATIENT SAMPLE: Case study of a single patient with an odontoid fracture. OUTCOME MEASURES: Only fracture reduction and fracture healing were evaluated. METHODS: After a failed trial of closed reduction with skeletal traction, a patient with an anteriorly displaced odontoid fracture was taken to the operating room for attempted closed reduction and odontoid screw placement. RESULTS: Fracture reduction was achieved with routine maneuvers supplemented by posterior translation through direct oropharyngeal pressure with a padded laryngoscope blade. CONCLUSIONS: Direct transoral reduction of odontoid fractures is safe and feasible and can be used to assist in reduction of anteriorly displaced fractures. PMID- 17702659 TI - Risk of pancreatitis in 14,000 individuals with celiac disease. AB - BACKGROUND & AIMS: The aim of this study was to examine the risk of pancreatitis in patients with celiac disease (CD) from a general population cohort. METHODS: By using Swedish national registers, we identified 14,239 individuals with a diagnosis of CD (1964-2003) and 69,381 reference individuals matched for age, sex, calendar year, and county of residence at the time of diagnosis. Cox regression estimated the hazard ratios (HRs) for a subsequent diagnosis of pancreatitis. We restricted analyses to individuals with more than 1 year of follow-up and no diagnosis of pancreatitis before or within 1 year after study entry. Conditional logistic regression estimated the association of pancreatitis with subsequent CD. RESULTS: CD was associated with an increased risk of subsequent pancreatitis of any type (HR, 3.3; 95% confidence interval [CI], 2.6 4.4; P < .001; on the basis of 95 positive events in individuals with CD vs 163 positive events in reference individuals) and chronic pancreatitis (HR, 19.8; 95% CI, 9.2-42.8; P < .001; on the basis of 37 and 13 positive events, respectively). Adjustment for socioeconomic index, diabetes mellitus, alcohol-related disorders, or gallstone disease had no notable effect on the risk estimates. The risk increase for pancreatitis was only found among individuals with CD diagnosed in adulthood. Pancreatitis of any type (odds ratio, 3.2; 95% CI, 2.5-4.3; P < .001) and chronic pancreatitis (odds ratio, 7.3; 95% CI, 4.0-13.5; P < .001) were associated with subsequent CD. CONCLUSIONS: This study suggests that individuals with CD are at increased risk of pancreatitis. PMID- 17702660 TI - The use of immunoglobulin g4 immunostaining in diagnosing pancreatic and extrapancreatic involvement in autoimmune pancreatitis. AB - BACKGROUND & AIMS: Autoimmune pancreatitis (AIP) is recognized increasingly as a multisystem disorder. We evaluated the use of immunoglobulin (Ig)G4 immunostaining of pancreatic and extrapancreatic biopsy specimens to make a definitive diagnosis of AIP. METHODS: Seventeen biopsy specimens and 3 gallbladder resections were assessed from 11 patients with clinical and radiologic features of AIP. Biopsy specimens from pancreas, liver, colon, stomach, duodenum, bone marrow, salivary gland, and kidney were analyzed morphologically, immunostained for IgG4-positive plasma cells, and compared with controls. RESULTS: Positive IgG4 immunostaining enabled a definitive diagnosis in 10 of 11 (91%) AIP patients. In both pancreatic and extrapancreatic tissues, high levels of IgG4 immunostaining (>10 IgG4-positive plasma cells/high-power field) were found in 17 of 20 (85%) specimens from AIP patients compared with 1 of 175 (0.6%) specimens from controls (P < .05). Positive extrapancreatic IgG4 immunostaining was found in 8 of 11 (73%) patients, including all those with diagnostic features in the pancreas. Increased tissue IgG4 was found irrespective of serum IgG4 level. CONCLUSIONS: The finding of IgG4 immunostaining within a range of clinically involved tissues supports the hypothesis that AIP is a multisystem disease. Positive IgG4 immunostaining in extrapancreatic tissues may allow a definitive diagnosis of AIP to be made in those with evidence of pancreatic disease, without the necessity of pancreatic biopsy or surgical exploration. Immunostaining of involved tissue for IgG4 may be particularly useful when AIP is suspected clinically but the serum IgG4 level is normal. PMID- 17702661 TI - Histopathologic variability between the right and left lobes of the liver in morbidly obese patients undergoing Roux-en-Y bypass. AB - BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) has been shown to occur in >90% of significantly obese patients. At present, diagnosis of the more severe form of NAFLD, nonalcoholic steatohepatitis (NASH), requires a liver biopsy. Conflicting data exist on the degree of sampling variability seen with percutaneous liver biopsy. Our aim was to assess for significant regional differences in histopathology between the right and left lobes of the liver in morbidly obese patients undergoing bariatric surgery. METHODS: Morbidly obese patients undergoing bariatric surgery at Wilford Hall Medical Center were eligible for study enrollment. Patients with chronic liver disease other than NAFLD were excluded. All patients underwent intraoperative liver biopsy, one from the right lobe and one from the left lobe, with a 14-gauge Tru-cut biopsy needle. Histopathologic features of NAFLD were compared by a hepatopathologist who examined biopsy specimens from the 2 hepatic lobes and was blinded to patient identification and site of origin of biopsy. Agreement between the 2 biopsy specimens was assessed by using the kappa coefficient. RESULTS: Forty-three patients (predominantly female) with body mass index median of 46.2 kg/m2 were enrolled. Agreement for steatosis was 93% (kappa = 0.91), inflammation 74% (kappa = 0.58), ballooning necrosis 84% (kappa = 0.73), fibrosis 98% (kappa = 0.96), and for the NAFLD activity score > or =5 was 93% (kappa = 0.83). CONCLUSIONS: Minimal variability was found for steatosis, NAFLD activity score > or =5, and fibrosis in samples of liver obtained from the right and left lobes of the liver in a group of morbidly obese, predominately female patients undergoing bariatric surgery. Histopathologic findings of necroinflammation appear to have the greatest degree of sampling variability. In contrast with previously published data, excellent agreement was seen for fibrosis in biopsy specimens obtained at surgery from right and left lobes of the liver. PMID- 17702663 TI - Atomic force microscopy evaluation of the effects of a novel antimicrobial multimeric peptide on Pseudomonas aeruginosa. AB - In this article we evaluated by atomic force microscopy (AFM) the effects of the (novel) tetrabranched antimicrobial peptide SB006 on morphology and mechanical properties of the gram-negative bacterium Pseudomonas aeruginosa. AFM imaging showed that SB006 causes the appearance of significant fragmentariness in the bacterial membrane and a severe volume decrease. Quantitative evaluation of the degree of fragmentariness was allowed by a new ad hoc image analysis procedure. The rigidity of the treated and untreated bacteria was measured through AFM tip nanoindentation measurements, and no differences registered. These results support the membrane interaction hypothesis, according to which SB006 targets the bacterial membranes and disrupts their permeability (allowing the leakage of cytoplasmic material and the subsequent shrinkage), but it does not affect the bacterium wall, which determines its rigidity. PMID- 17702664 TI - Ischemic bowel after laparoscopic Roux-en-Y gastric bypass: limited resection based on fluorescein assessment of bowel viability. PMID- 17702662 TI - Colorectal cancer risks in relatives of young-onset cases: is risk the same across all first-degree relatives? AB - BACKGROUND & AIMS: During the last 15 years, several single-gene mendelian disorders have been discovered that might account for some of the familial aggregation detected in large population studies of colorectal cancer (CRC). Mutations in DNA mismatch repair (MMR) genes cause hereditary nonpolyposis colorectal cancer-Lynch syndrome, the most common of the recognized CRC predisposition syndromes, in which one major feature is a young age for cancer onset. However, for young-onset microsatellite stable (MSS) CRC, the familial risk for CRC is unknown. METHODS: Patients with CRC who were <50 years old were identified through Minnesota Cancer Surveillance System (MCSS) and Mayo Clinic, Rochester, MN. CRCs in which the DNA MMR function was deficient as evidenced by high level microsatellite instability and/or loss of expression of MMR gene product by immunostaining were excluded. A total of 278 probands (131 from MCSS; 147 from Mayo Clinic) were included. Data on 1862 relatives were collected, of whom 68 were found to have had CRC, and an additional 165 had primary cancers of other types. RESULTS: Compared with Surveillance Epidemiology and End Results program data, relatives of young-onset CRC probands had increased risks for CRC. This relative risk (RR) was increased among first-degree relatives (RR, 1.65; 95% confidence interval [CI], 1.29-2.07) and was greater for siblings (RR, 2.67; 95% CI, 1.50-4.41) than parents (RR, 1.5; 95% CI, 1.14-1.94). CONCLUSIONS: We studied 278 probands with young-onset MSS CRC. We determined that the RR for CRC was greatest in siblings, which is consistent with an autosomal recessive inheritance pattern. PMID- 17702665 TI - Early history of bariatric surgery. PMID- 17702666 TI - Evaluation of expectations and knowledge in bariatric surgery patients. AB - BACKGROUND: Preoperative psychosocial evaluations of bariatric surgery candidates primarily focus on screening for psychiatric co-morbidities. However, the role of weight loss expectations and knowledge about surgery can also influence patients' postoperative behavior. The purpose of this study was to investigate preoperative patient knowledge and expectations about postoperative weight loss. METHODS: Data on the knowledge and expectations were extracted from a database of psychosocial evaluations of 334 bariatric surgery candidates. Expectations were measured by patient report of the expected pounds to be lost. Knowledge was operationalized using the University of Virginia Bariatric Knowledge Scale, a 22-item multiple choice scale, that assesses knowledge about medical, nutritional, and psychosocial components related to bariatric surgery. The data were analyzed using frequencies, descriptive statistics, and analysis of variance. RESULTS: The data on weight loss expectations from 217 preoperative patients indicated that, compared with the average weight loss data presented in published reports, 65% of patients overestimated the degree of weight loss and only 25% of patients maintained accurate expectations of weight loss. Knowledge data on the nutritional, medical, and behavioral components of the surgery were available for 96 patients. The items frequently answered incorrectly included expected weight loss and the utility of surgery in increasing the ability to make changes in diet and exercise. The mean body mass index differences were observed to determine the accuracy of weight loss expectations CONCLUSION: The results of our study have shown that a significant number of bariatric surgery patients present with misconceptions about weight loss. The preoperative psychosocial evaluation can be used as an intervention to use psychoeducation, cognitive restructuring, and behavioral interventions to improve patients' knowledge and expectations. PMID- 17702667 TI - Using instrumented paper diaries to document self-monitoring patterns in weight loss. AB - Self-monitoring of eating is associated with successful weight loss, but adherence is imperfect and deteriorates over time. Moreover, intentionally or not, many individuals have difficulty keeping faithful records. We used instrumented paper diaries (IPDs) to study self-monitoring in randomly chosen participants in the PREFER trial, a behavioral treatment for weight-loss study. The diaries they used to self-report eating were periodically replaced with IPDs at various times during an 18-month weight-loss program, consisting of three successive phases: intense treatment (n=35), less-intense treatment (n=13), and maintenance (n=16). We compared electronically documented self-monitoring data, showing when and how often IPDs were used, with self-reported data, then compared the electronically validated adherence and weight loss. Self-reported diary usage exceeded IPD-documented usage while the electronic data demonstrated a significant decline in self-monitoring over time. Diary recording often was not timely. Percentage weight lost correlated significantly with frequency of IPD use (p=.001) and the number of diary entries made within 15 min of opening the IPD (p=.002). This is the first study to document patterns of self-monitoring among participants in a weight-loss program, which demonstrated that individuals may falsify the times and frequency of self-monitoring. Furthermore, our results showed that adherence to self-monitoring and the timeliness of recording significantly correlate with improved weight loss. PMID- 17702668 TI - N-desmethylclozapine an M1 receptor agonist enhances nitric oxide's cardiac vagal facilitation in the isolated innervated rat right atrium. AB - We have previously determined that neuronal nitric oxide (NO) may partly mediate its established cholinergic effect via activation of muscarinic type 1 (M1) receptors located at the preganglionic/postganglionic synapse. In this series of experiments we set out to confirm this finding using an M1 agonist. Experiments were carried out on the isolated vagally innervated right atrium in the presence of atenolol (4 microM). The right vagus was stimulated at 4, 8, 16, 32 Hz; pulse duration 1 ms at 20 V for 20 s and the effect on cardiac interval (ms) assessed. N-desmethylclozapine (100 nM), a potent M1 agonist, enhanced the vagally induced increase in cardiac interval, a lower concentration of 50 nM had no significant effect on cardiac interval. This effect was prevented by pre-treatment of the atria with the neuronal NO synthase inhibitor 1 (2 trifluoromethylphenyl)imidazole (TRIM) at 0.14 mM. The vagal stimulation protocol was repeated in order to rule out a reduction in vagal effectiveness which may have been due to the experimental stimulation protocol used in this study. TRIM (0.14 mM) alone causes a small but significant attenuation of the vagally induced increase in cardiac interval. These results show that agonism of M1 receptors on cardiac vagal preganglionic fibres enhances vagal cardiac effects which can be prevented by a neuronal NO inhibitor. PMID- 17702669 TI - Parasite vaccines: the new generation. AB - Parasites cause some of the most devastating and prevalent diseases in humans and animals. Moreover, parasitic infections increase mortality rates of other serious non-parasitic infections caused by pathogens such as HIV-1. The impact of parasitic diseases in both industrialised and developing countries is further exacerbated by the resistance of some parasites to anti-parasitic drugs and the absence of efficacious parasite vaccines. Despite years of research, much remains to be done to develop effective vaccines against parasites. This review focuses on the more recent vaccine strategies such as DNA and viral vector-based vaccines that are currently being used to develop vaccines against parasites. Obstacles yet to be overcome and possible advantages and disadvantages of these vaccine modalities are also discussed. PMID- 17702670 TI - Direct electrochemistry and electrocatalysis of hemoglobin on undoped nanocrystalline diamond modified glassy carbon electrode. AB - Direct electrochemistry of hemoglobin (Hb) was observed at glassy carbon electrode (GCE) modified with undoped nanocrystalline diamond (UND) and Hb multilayer films via layer-by-layer assembly. UV-VIS absorbance spectroscopy, electrochemical impedance spectroscopy and cyclic voltammograms were employed to characterize the film. The results showed that the UND had the effect of enhancing the electron transfer between Hb and the electrode surface. Hb in the multilayer films maintained its bioactivity and structure. It also exhibited a good catalytic activity towards the reduction of H(2)O(2). The reciprocal of catalytic current showed a linear dependence on the reciprocal of H(2)O(2) concentration ranging from 0.5 microM to 0.25 mM with a detection limit of 0.4 microM. The apparent Michaelis-Menten constant was estimated to be 0.019 mM. PMID- 17702671 TI - Highly resistant macromolecular components and low rate of generation of endogenous damage: two key traits of longevity. AB - Key characteristics relating oxidative damage to aging and longevity are reviewed. Available information indicates that the specific composition of tissue macromolecules (proteins, lipids and mitochondrial DNA) in long-lived animal species gives them an intrinsically high resistance to modification that likely contributes to the superior longevity of these species. This is obtained in the case of lipids by decreasing fatty acid unsaturation, and in the proteins by lowering their methionine content. Long-lived animals also show low rates of reactive oxygen species (ROS) generation and oxidative damage at their mitochondria. On the other hand, dietary restriction decreases mitochondrial ROS production and oxidative damage to mitochondrial DNA and proteins. These changes are due to the decreased intake of dietary proteins (not of lipids or carbohydrates) of the dietary restricted animals. In turn, these effects of protein restriction seem to be specifically due to the lowered methionine intake of the protein and dietary restricted animals. It is emphasized that both a low rate of generation of endogenous damage and an intrinsically high resistance to modification of tissue macromolecules are key traits of animal longevity. PMID- 17702672 TI - Superiority of nasal mask pressure over mouth pressure, as a surrogate of diaphragm twitch-related esophageal pressure, in healthy humans. AB - Assessing diaphragm function is clinically and physiologically pertinent. It can rely on the measurement of pressure responses to phrenic stimulation. Combining mouth pressure (Pm) with cervical magnetic stimulation (CMS) is painless and easy to perform, but Pm-CMS poorly reflects esophageal pressure (Pes-CMS) because of poor pressure transmission across the airway. We reasoned that the mouth opening and neck flexion that are associated with the measurement of Pm-CMS would impair upper airway dynamics and further hinder pressure transmission. Therefore, we assessed the CMS-related pressure measured in a nasal mask (Pmask; mouth closed) without neck flexion as a possible surrogate of Pes-CMS, in 14 men and 3 women, age 24.5+/-2.2. Pes-CMS was 15.7+/-4.3 cmH2O, significantly higher than Pm-CMS (13.5+/-5.6 cmH2O, P<0.0001) but not different from Pmask-CMS (15.2+/-4.9 cmH2O). The concordance correlation coefficient was low (0.6808) between Pes-CMS and Pm CMS. It was higher between Pes-CMS and Pmask-CMS (0.8730). Pm-CMS wrongly classified five subjects as abnormal (<10 cmH2O), versus 1 for Pmask and 5 for Pm (P=0.025). Passing and Bablok regressions found no difference between Pes-CMS and Pmask-CMS, but identified a systematic difference and a proportional error between Pes-CMS and Pm-CMS. We conclude that Pmask-CMS is a better surrogate of Pes-CMS than Pm-CMS. PMID- 17702673 TI - The air hunger response of four elite breath-hold divers. AB - Normal subjects terminate breath-holds due to intolerable 'air hunger'. We hypothesize that competitive breath-hold divers might have increased tolerance of air hunger. We tested the air hunger (AH) response of four divers who could hold their breath for 6-9 min. Tidal volume and respiratory rate were controlled by mechanical ventilation (ventilation approximately 0.16 L min(-1) kg(-1)). AH was induced by raising PCO2 and rated using a visual analog scale whose maximum was defined as intolerable. SpO2 was maintained at >97%. Three divers reported the same uncomfortable urge to breathe as normal subjects; the slopes of their responses were within normal range. Both resting CO2 and AH threshold were shifted to higher CO2 in some divers. Diver 3 was unique amongst neurologically intact subjects we have studied: he denied feeling an urge to breathe, and denied discomfort. We conclude that elite divers' strategies to tolerate intense air hunger are a minor factor in their ability to tolerate long breath-holds. PMID- 17702674 TI - Enantioselective quantification of omeprazole and its main metabolites in human serum by chiral HPLC-atmospheric pressure photoionization tandem mass spectrometry. AB - Omeprazole is a proton pump inhibitor drug in widespread use for the reduction of gastric acid production. It is also proposed as a test substance for the phenotyping of cytochrome CYP3A4 and CYP2C19 enzyme activities. For this purpose, it is necessary to quantify, additionally to omeprazole, the two main metabolites 5-hydroxyomeprazole and omeprazole-sulfon in human plasma. Since omeprazole is a racemic mixture of two enantiomers and its enzymatic decomposition depends in part on its chiral configuration, full information about its metabolic breakdown can only be gained by enantioselective quantification of the drug and its metabolites. We introduce a new LC-MS/MS method that is capable to simultaneously quantify omeprazole and its two main metabolites enantioselectively in human serum. The method features solid-phase extraction, normal phase chiral HPLC separation and atmospheric pressure photoionization tandem mass spectrometry. As internal standards serve stable isotope labeled omeprazole and 5 hydroxyomeprazole. The calibration functions are linear in the range of 5-750 ng/ml for the omeprazole enantiomers and omeprazole-sulfon, and 2.5-375 ng/ml for the 5-hydroxyomeprazole enantiomers, respectively. Intra- and inter-day relative standard deviations are <7% for omeprazole and 5-hydroxyomeprazole enantiomers, and <9% for omeprazole-sulfon, respectively. PMID- 17702675 TI - Estimation of carvedilol in human plasma by using HPLC-fluorescence detector and its application to pharmacokinetic study. AB - A simple, precise and sensitive high performance liquid chromatography procedure has been developed for determination of carvedilol in human plasma. The method was developed on Lichrosphere R CN column using a mobile phase of acetonitrile/20 mM ammonium acetate buffer with 0.1% triethylamine (pH adjusted to 4.5) (40/60, v/v). The peaks were detected by using fluorescence detector (excitation wavelength 282 nm and emission wavelength 340 nm). Carvedilol and domperidone (internal standard) were extracted by liquid-liquid extraction procedure using dichloromethane. This method was specific and had a linearity range of 1-128 ng/ml with intra- and inter-day precision (%C.V.) less than 15%. The accuracy ranges from 87.3 to 100.88% and the recovery of carvedilol was 69.90%. The stability studies showed that carvedilol in human plasma was stable during short term period for sample preparation and analysis. This method was used to assay the carvedilol in human plasma samples obtained from subjects who had been given an oral tablet of 12.5 mg carvedilol. PMID- 17702676 TI - Determinants of obesity in transition economies: the case of Russia. AB - This paper examines human obesity, measured as weight and body mass index (BMI), and its determinants in Russia. Obesity increased dramatically during transition from a planned to a market economy, by 38%. We determine the factors contributing to rising obesity using individual level data from the Russia Longitudinal Monitoring Survey for 1994 and 2004. We find a strong positive effect of diet/caloric intake and a strong negative effect of smoking on weight and BMI. Gender, education, and income are other major determinants of obesity. Our analysis provides information on dietary patterns and other determinants of obesity in Russia which is essential for formulation and implementation of effective policies designed to reduce the problem and improve the health of the population. PMID- 17702677 TI - The connection between metal ion affinity and ligand affinity in integrin I domains. AB - Integrins are cell-surface heterodimeric proteins that mediate cell-cell, cell matrix, and cell-pathogen interactions. Half of the known integrin alpha subunits contain inserted domains (I domains) that coordinate ligand through a metal ion. Although the importance of conformational changes within isolated I domains in regulating ligand binding has been reported, the relationship between metal ion binding affinity and ligand binding affinity has not been elucidated. Metal and ligand binding by several I domain mutants that are stabilized in different conformations are investigated using isothermal titration calorimetry and surface plasmon resonance studies. This work suggests an inverse relationship between metal ion affinity and ligand binding affinity (i.e. constructs with a high affinity for ligand exhibit a low affinity for metal). This trend is discussed in the context of structural studies to provide an understanding of interplay between metal ion binding and ligand affinities and conformational changes. PMID- 17702678 TI - Phosphorylation sites of Arabidopsis MAP kinase substrate 1 (MKS1). AB - The Arabidopsis MAP kinase 4 (MPK4) substrate MKS1 was expressed in Escherichia coli and purified, full-length, 6x histidine (His)-tagged MKS1 was phosphorylated in vitro by hemagglutinin (HA)-tagged MPK4 immuno-precipitated from plants. MKS1 phosphorylation was initially verified by electrophoresis and gel-staining with ProQ Diamond and the protein was digested by either trypsin or chymotrypsin for maximum sequence coverage to facilitate identification of phosphorylated positions. Prior to analysis by mass spectrometry, samples were either desalted, passed over TiO(2) or both for improved phosphopeptide detection. As MAP kinases generally phosphorylate serine or threonine followed by proline (Ser/Thr-Pro), theoretical masses of potentially phosphorylated peptides were calculated and mass spectrometric peaks matching these masses were fragmented and searched for a neutral-loss signal at approximately 98 Da indicative of phosphorylation. Additionally, mass spectrometric peaks present in the MPK4-treated MKS1, but not in the control peptide map of untreated MKS1, were fragmented. Fragmentation spectra were subjected to a MASCOT database search which identified three of the twelve Ser-Pro serine residues (Ser72, Ser108, Ser120) in the phosphorylated form. PMID- 17702680 TI - Indentation stiffness of aging human costal cartilage. AB - Costal cartilage, connecting the ribs and sternum, serves a mechanical function in the body. It undergoes structural changes with aging but it is unclear if its material properties are affected by these changes. To investigate this question, experimental indentation load-relaxation tests were performed on human costal cartilage as a function of specimen age and sex. The experimental data were fit to spherical indentation ramp-relaxation solutions generated previously by elastic-viscoelastic correspondence [Mattice JM, Lau AG, Oyen ML and Kent RW. Spherical indentation load-relaxation of soft biological tissues. J Mater Res 2006;8:2003-10]. Numerical values of short- and long-time shear modulus and of material time-constants were examined as a function of age. Costal cartilage calcification was assessed with blinded scoring of computed tomography reconstructions of the ribcage and mechanical properties were correlated with calcification score. Overall, the costal cartilage midsubstance was slightly stiffer than articular cartilage, and did not show significant variation in stiffness with age or specimen calcification. Increased age did result in increased local variability of the indentation stiffness results. Future studies will be required to address the findings of the current study that although calcification did increase with age, the calcification was primarily found on the costal cartilage periphery, thus insignificantly affecting the midsubstance stiffness. PMID- 17702681 TI - Electrospun linear polyethyleneimine scaffolds for cell growth. AB - Unique biocompatible scaffolds were produced by electrospinning cross-linked linear polyethyleneimine (PEI) with succinic anhydride and 1,4-butanediol diglycidyl ether. Nonwoven mats of PEI fibers in the range of 1600-687nm were evaluated as interaction scaffolds for normal human fibroblast (NHF) cells. The electrospun scaffolds were characterized by Fourier transform infrared spectroscopy and ultraviolet-visible spectroscopy. The growth of the NHF cells was followed by scanning electron microscopy as well as optical and fluorescence microscopies. Cell viability was evaluated by staining with propidium iodide for dead cells and fluorescein diacetate for live cells. Immunofluorescence with fixed cells on the scaffolds was examined by staining the endoplasmic reticulum with rabbit anti-GRP 78/Alexa 488 goat anti-rabbit and staining the nuclei with 4'-6'-diamidino-2-phenylindole. Fluorescence studies confirmed that NHF cells attached and spread throughout the cross-linked linear polyethyleneimine scaffold. The attachment and spreading of cells suggests that electrospun linear polyethyleneimine scaffolds support growth of normal human fibroblasts cells. Thus, these biomaterial scaffolds may be useful in tissue engineering. PMID- 17702679 TI - Structural similarities and functional diversity of eukaryotic discoidin-like domains. AB - The discoidin domain is a approximately 150 amino acid motif common in both eukaryotic and prokaryotic proteins. It is found in a variety of extracellular, intracellular and transmembrane multidomain proteins characterized by a considerable functional diversity, mostly involved in developmental processes. The biological role of the domain depends on its interactions with different molecules, including growth factors, phospholipids and lipids, galactose or its derivatives, and collagen. The conservation of the motif, as well as the serious physiological consequences of discoidin domain disorders underscore the importance of the fold, while the ability to accommodate such an extraordinarily broad range of ligand molecules makes it a fascinating research target. In present review we characterize the distinctive features of discoidin domains and briefly outline the biological role of this module in various eukaryotic proteins. PMID- 17702682 TI - The effect of simvastatin on bone formation and ceramic resorption in a peri implant defect model. AB - Experimental use of statins as stimulators of bone formation suggests they may have widespread applicability in the field of orthopaedics. With their combined effects on osteoblasts and osteoclasts, statins have the potential to enhance resorption of synthetic materials and improve bone ingrowth. In this study, the effect of oral and local administration of simvastatin to a beta tricalcium phosphate (betaTCP)-filled defect around an implant was compared with recombinant human bone morphogenetic protein 2 (rhBMP2). On hundred and sixty-two Sprague Dawley rats were assigned to treatment groups: local application of 0.1, 0.9 or 1.7 mg of simvastatin, oral simvastatin at 5, 10 or 50 mg kg(-1) day(-1) for 20 days, local delivery of 1 or 10 microg of rhBMP2, or control. At 6 weeks rhBMP2 increased serum tartrate-resistant acid phosphatase 5b levels and reduced betaTCP area fraction, particle size and number compared with control, suggesting increased osteoclast activity. There was reduced stiffness and increased mechanical strength with this treatment. Local simvastatin resulted in a decreased mineral apposition rate at 6 weeks and increased fibrous area fraction, betaTCP area fraction, particle size and number at 26 weeks. Oral simvastatin had no effect compared with control. Local application of rhBMP2 increased resorption and improved mechanical strength whereas simvastatin was detrimental to healing. Oral simvastatin was ineffective at promoting either ceramic resorption or bone formation. The effect of statins on the repair of bone defects with graft substitute materials is influenced by its bioavailability. Thus, further studies on the optimal delivery system are needed. PMID- 17702683 TI - The ad hoc perforator flap for contracture release. AB - Release and autografting remains a mainstay of treatment of cutaneous and joint associated contractures. However, owing to secondary contraction of grafts and the increase of children undergoing burn reconstructive surgery, recurrence of contractures is not uncommon. Locally available, well-vascularised tissue that will contract minimally and grow with the patient is the ideal for contracture release. Many 'predesigned' cutaneous flaps have been described, but use of these may involve tailoring a defect to fit a known flap. We introduce the concept of the 'ad hoc' perforator flap, an improvised island flap based on a perforator, innominate or otherwise, that happens to be adjacent to a particular soft-tissue defect and can be reliably raised on scarred skin. We carried out a retrospective analysis of all patients undergoing contracture release within our unit. Twenty three ad-hoc perforator flaps in 20 patients were carried out between 2000 and 2005. Eleven of the 20 patients were children, and all but one case was subsequent to a burn injury. Fifteen of the 23 flaps were upper limb. In one case, a significant complication involving total flap loss occurred. Only one patient required a skin graft to close the flap donor site, and no patients required revisional surgery for contracture recurrence. The ad hoc perforator flap is a safe and simple technique for the management of contractures, and fulfils the ideal of well-vascularised tissue that can grow with the patient. The flap can be designed as required and, with experience, the concept is applicable not only to contracture release, but many other reconstructive scenarios. PMID- 17702685 TI - New parents' experiences of postnatal care in Sweden. AB - PURPOSE: The aim was to study new parents' satisfaction with postnatal care and to estimate the proportion of fathers who were given the option of spending the night at the postnatal ward. PROCEDURES: A questionnaire was mailed to new parents 6 months after the birth of their child in a Swedish hospital. The main outcome was overall satisfaction with postnatal care. FINDINGS: Two hundred and ninety-four new mothers and 280 new fathers completed the questionnaire. Thirty four percent of the mothers were dissatisfied with the overall postnatal care. The strongest associated factors for new mothers' dissatisfaction were: unfriendly and unhelpful staff (RR 10.3; 3.2-32), lack of support from staff (RR 6.4; 2.3-17.5), new fathers not permitted to stay overnight (RR 5.2; 1.8-14.5), dissatisfaction with postnatal checks of the woman herself (RR 2.6; 1.1-6.3) and dissatisfaction with practical breast-feeding support (RR 1.6; 1.2-2.1). Sixty three percent of the fathers were given the option of spending the night at the postnatal ward. The fathers who chose not to spend the night on the ward were older, had other children and were dissatisfied that they were not allowed to play a greater role in the care of their newborn baby. MAIN CONCLUSIONS: In order to increase patient satisfaction, the needs of the new family must be highlighted and more support and help provided to new parents on the postnatal ward. It is essential to have family oriented postnatal care and to give fathers the opportunity to stay overnight and involve them in the care of their newborn baby. PMID- 17702686 TI - [Screening for early detection of lung cancer: conflict between clinical and public health viewpoints]. AB - In Hungary, lung cancer, gradually increasing among women, is the leading cause of cancer mortality. The screening, using chest x-ray and sputum cytology as screening tool, does not reduce the mortality from lung cancer, therefore, screening for lung cancer is not recommended. The low-dose spiral CT is a sensitive and promising method, however, its specificity is far from being ideal. The results of the on-going RCTs are expected in a few years time, and so far it is not applicable for routine screening. In this country, the one-third of lung cancer cases are detected by the routine chest x-ray for tuberculosis, obligatory by law, and most of the detected cases are still resectable, but this does not have any influence on the mortality. According to our view, the detection of the lung cancer, particularly in those at high risk, is a by-product of periodic chest x-ray aiming at early detection of tuberculosis, however, mass screening for lung cancer as public health measure is not recommended. For the time being, the implementation of tobacco control measures is the only way to reduce the risk of lung cancer in the long run. PMID- 17702687 TI - [Web-based manuscript submission system]. PMID- 17702688 TI - [Dietary survey in Hungary, 2003-2004. Micronutrients: vitamins]. AB - The 3rd Hungarian National Nutritional Survey was carried out as a part of the National Population Health Study and the data collection was done in November/December of 2003. The survey comprised a sample of adults above 19 year of age, the dietary questionnaires of 1179 people could be evaluated. The results of energy and macro-nutrient intake were published in 2005, and the results of the mineral intake in 2007, in the Hungarian Medical Journal. This paper focuses on the intake of vitamins. For the evaluation of the results authors used the data of the two previous national surveys, data of some dietary studies of other countries, and the home and international intake recommendations. In respect of the data found in the present survey, it is a favourable trend that the intake of vitamins retinol equivalent, B1 , B6 and B12 , and niacin, as well as biotin was sufficient both in case of men and women, together with adequate vitamin E intake for men. However the intake of vitamin B2 , C, D, together with pantothenic acid and folic acid of both men and women did not meet the criteria of the Hungarian recommendations, besides the vitamin E intake of women was insufficient as well. In Hungary the intake of vitamin D, biotin, folic acid and pantothenic acid was measured at first at this National Dietary Survey. The authors vigorously stress the importance of the varied and healthy nutrition in the adequate vitamin supply of the population. PMID- 17702689 TI - [Treatment of large, esophageal perforations and mediastinitis with a covered, removable metallic endoprosthesis and mediastinal drainage]. AB - The application of covered metallic stents in the treatment of benign strictures and perforations is still in the early stages, because their removal is difficult and may cause tissue proliferation. The therapeutic effect and the efficiency of a new method for the extraction of a removable metallic stent were examined in three patients treated for oesophageal perforation. Two of the three patients were dilated with a balloon catheter because of corrosive oesophageal stenosis, and the oesophagus was perforated. In one patient mediastinal drainage, and jejunostomy and in the other primary suturing and drainage were performed. Sepsis and mediastinitis developed due to the oesophageal perforation and the fistula caused by the mediastinal drain in the first patient, and the insufficiency of the suture in the second patient. The oesophageal defects were sealed on day 8 and 10 after the perforation, and surgery by a covered stent. In the third patient, the oesophageal rupture caused by the dilatation and the attempt to stent a malignant obstruction was sealed with a covered stent within 2 hours. Parenteral nutrition and broad-spectrum antibiotic therapy were started. Three days after the interventions, swallowing tests with water-soluble contrast medium (Gastrografin) did not reveal any extravasations. Feeding via a nasogastric tube, and later oral feeding was started. After transient mediastinal drainage, the stents were removed on day 35 and 74 after implantation. Both openings healed completely. Restenoses above the stents were dilated again. The rupture of the malignant oesophagus in the third patient, following early, permanent stenting, healed without drainage and with no complications. Even with mediastinitis and concomitant sepsis, large oesophageal perforations can be treated successfully with removable, covered metallic stents and adequate mediastinal drainage. PMID- 17702690 TI - [Assessment of serum interleukin-6 with a rapid test. The diagnosis of neonatal sepsis can be established or ruled out]. AB - INTRODUCTION: The mortality rate from sepsis is high and the risk of sepsis increases in prematurity in proportion to the decrease in birth weight. MATERIAL AND METHOD: The authors report the assessment of serum interleukin-6 levels in 12 term, at-risk newborn infants after birth and 60 VLBW neonates after detection of non-specific signs of infection or sepsis, treated in NICU at the Semmelweis University, 1st Department of Obstetrics and Gynecology in 2005-2006. The serum IL-6 level with a rapid test (Milenia Quickline IL-6 and PicoScan system) was investigated. The simultaneous assessment of C-reactive protein levels was analysed as well. RESULTS: The assessment of serum interleukin-6 and CRP levels for the early diagnosis of sepsis can be established or ruled out. The sensitivity of serum IL-6 level assessment was 100%. There were no false negative cases. The positive predictive value was 93%. There was a significant difference between the sepsis and infection group of VLBW infants in the serum Il-6 levels ( p = 0.048), and between the infection and non-infection groups in the interleukin 6 levels ( p < 0.005). CONCLUSIONS: In comparing the diagnostic value of IL-6 measurement in VLBW infants with signs of infection to the diagnostic methods currently in use, results showed that a combination of early assessment of IL-6 and CRP seems to increase diagnostic accuracy in attempting to differentiate between septic and nonseptic patients. Such increased accuracy will decrease neonatal morbidity as well as the financial cost of treatment. PMID- 17702691 TI - [The ski camp doctor's role in the the prevention of winter sport accidents]. AB - Skiing is a risky sport for many, even for children and beginners. When the ski group is escorted by doctors who are able to provide advanced life support on the scene and are trained either in the field of emergency medicine or in travel medicine, a good possibility is given for the prevention of ski-accidents and for decreasing the number of travel related illnesses. This fact has led to the basic idea of training ski-camp doctors in Hungary. There is no similar initiative in the Hungarian literature. Therefore the article tries to summarise the medical knowledge and requirements of a ski-camp doctor, and analyses the prevention tasks of the doctor as well. The camp doctor must be well informed and highly trained in the field of emergency and travel medicine. The main tasks are: pre travel advice, treatment of the common (travel-related) diseases, providing basic and advanced life-support on the scene, and to organise the hospitalisation and repatriation of patient, in cooperation with the hospital and insurance doctor. Moreover, the prevention should start before departure: the estimation of the physical and health condition of the skiers, a continuous care of the chronic people, and supervision of the place (hygienic circumstances, rescue forces available, the condition of the ski slopes, etc.) are vital--as for the primary prevention. The secondary level of the prevention is the treatment of the injured/sick persons, and assistance in the medical evacuation. During the training, not only postgraduate medical, mountain and alpine medicine lessons have been provided, but basic legal and insurance information as well. Moreover, the doctors received ski-course from professional ski-trainers in order to improve their ski-technique and skills on different slopes and off-piste places. In the future the local mountain rescue and air-rescue forces have to be involved in postgraduate training. Hopefully different travel-insurance companies and travel offices will use the trained doctors as a medical escort for ski- and school groups. The presence of a ski-camp doctor could minimise the risk of sport activity for chronic (diabetic, cardiac, etc.) patients, for the beginners and for the elderly. Besides the primary prevention, a secondary level of prevention can be ensured by ski-camp doctors as well. PMID- 17702695 TI - [Interview with Dr. Erzsebet Feher by Gyorgyi B. Kiraly]. PMID- 17702696 TI - Novel patterning of nano-bioceramics: template-assisted electrohydrodynamic atomization spraying. AB - The ability to create patterns of bioactive nanomaterials particularly on metallic and other types of implant surfaces is a crucial feature in influencing cell response, adhesion and growth. In this report, we uncover and elucidate a novel method that allows the easy deposition of a wide variety of predetermined topographical geometries of nanoparticles of a bioactive material on both metallic and non-metallic surfaces. Using different mesh sizes and geometries of a gold template, hydroxyapatite nanoparticles suspended in ethanol have been electrohydrodynamically sprayed on titanium and glass substrates under carefully designed electric field conditions. Thus, different topographies, e.g. hexagonal, line and square, from hydroxyapatite nanoparticles were created on these substrates. The thickness of the topography can be controlled by varying the spraying time. PMID- 17702697 TI - Role of modern chemistry in sustainable arable crop protection. AB - Organic chemistry has been, and for the foreseeable future will remain, vitally important for crop protection. Control of fungal pathogens, insect pests and weeds is crucial to enhanced food provision. As world population continues to grow, it is timely to assess the current situation, anticipate future challenges and consider how new chemistry may help meet those challenges. In future, agriculture will increasingly be expected to provide not only food and feed, but also crops for conversion into renewable fuels and chemical feedstocks. This will further increase the demand for higher crop yields per unit area, requiring chemicals used in crop production to be even more sophisticated. In order to contribute to programmes of integrated crop management, there is a requirement for chemicals to display high specificity, demonstrate benign environmental and toxicological profiles, and be biodegradable. It will also be necessary to improve production of those chemicals, because waste generated by the production process mitigates the overall benefit. Three aspects are considered in this review: advances in the discovery process for new molecules for sustainable crop protection, including tests for environmental and toxicological properties as well as biological activity; advances in synthetic chemistry that may offer efficient and environmentally benign manufacturing processes for modern crop protection chemicals; and issues related to energy use and production through agriculture. PMID- 17702698 TI - Production of Wnt inhibitors by myeloma cells: potential effects on canonical Wnt pathway in the bone microenvironment. AB - Osteoblast impairment occurs within multiple myeloma cell infiltration into the bone marrow. Canonical Wnt signaling activation in osteoprogenitor cells is involved in osteoblast formation through the stabilization of dephosphorylated beta-catenin and its nuclear translocation. The effects of multiple myeloma cells on Wnt signaling in human mesenchymal/osteoprogenitor cells are unclear. In 60 multiple myeloma patients checked, we found that among the Wnt inhibitors, Dickkopf-1 and secreted frizzled-related protein-3 were produced by multiple myeloma cells. However, although multiple myeloma cells or multiple myeloma bone marrow plasma affected expression of genes in the canonical Wnt signaling and inhibited beta-catenin stabilization in murine osteoprogenitor cells, they failed to block the canonical Wnt pathway in human mesenchymal or osteoprogenitor cells. Consistently, Wnt3a stimulation in human osteoprogenitor cells did not blunt the inhibitory effect of multiple myeloma cells on osteoblast formation. Consequently, despite the higher Wnt antagonist bone marrow levels in osteolytic multiple myeloma patients compared with nonosteolytic ones, beta-catenin immunostaining was not significantly different. Our results support the link between the production of Wnt antagonists by multiple myeloma cells and the presence of bone lesions in multiple myeloma patients but show that myeloma cells do not inhibit canonical Wnt signaling in human bone microenvironment. PMID- 17702699 TI - Supervised exercise training combined with ginkgo biloba treatment for patients with peripheral arterial disease. AB - OBJECTIVES: To evaluate whether a combination of supervised exercise training and ginkgo biloba treatment is a better treatment than exercise training alone for patients with peripheral arterial disease. DESIGN: A 24-week double-blind, placebo-controlled ginkgo biloba trial with the first 12-week period as a non exercise control stage and the second 12-week period as an exercise training stage. SETTING: Exercise physiology laboratory. SUBJECTS: Twenty-two subjects with peripheral arterial disease. INTERVENTIONS: The subjects were randomly allocated into a ginkgo or a placebo group. During the first stage, the ginkgo group ingested standardized ginkgo biloba tablets with a daily dosage of 240 mg, while the placebo group received placebo tablets. During the second stage, all subjects engaged in a supervised treadmill-walking programme while continuing to take the same dosage of ginkgo biloba or placebo tablets. MAIN MEASURES: Walking capacity on treadmill, oxygen consumption during exercise, peripheral haemodynamics and blood viscosity were measured at baseline, and after the first and the second stages of treatment. RESULTS: The ginkgo group did not show significant changes in most of the measured variables after each stage of treatment, except that the maximal walking time was significantly increased after the combined treatment (from 236 +/- 112 seconds to 557 +/- 130 seconds, P < 0.001). However, similar response was also found in the placebo group after exercise training (from 384 +/- 125 seconds to 820 +/- 146 seconds, P < 0.001). CONCLUSION: Supervised exercise training combined with ginkgo biloba treatment did not produce greater beneficial effects than exercise training alone in patients with peripheral arterial disease. PMID- 17702700 TI - Effects of movement imagery and electromyography-triggered feedback on arm hand function in stroke patients in the subacute phase. AB - OBJECTIVE: To investigate the effects of movement imagery-assisted electromyography (EMG)-triggered feedback (focused on paretic wrist dorsiflexors) on the arm-hand function of stroke patients. DESIGN: Single-blinded, longitudinal, multicentre randomized controlled trial. Measurements were performed (on average) 54 days post stroke (baseline), three months later (post training) and at 12 months post baseline. SETTING: Two rehabilitation centres. SUBJECTS: Twenty-seven patients with a first-ever, ischaemic, subacute stroke. INTERVENTIONS: A reference group received conventional electrostimulation, while the experimental group received arm-hand function training based on EMG-triggered feedback combined with movement imagery. Both groups were trained for three months, 5 days/week, 30 minutes/day, in addition to their therapy as usual. MAIN MEASURES: Arm-hand function was evaluated using the upper extremity-related part of the Brunnstrom Fugl-Meyer test and the Action Research Arm test. RESULTS: During training, Brunnstrom Fugl-Meyer scores improved 8.7 points and Action Research Arm scores by 19.4 points (P < 0.0001) in both groups relative to baseline results, rising to 13.3 and 28.4 points respectively at one year follow up (P < 0.0001). No between-group differences were found at any time. CONCLUSIONS: EMG-triggered feedback stimulation did not lead to more arm-hand function improvement relative to conventional electrostimulation. However, in contrast to many clinical reports, a significant improvement was still observed in both groups nine months after treatment ceased. PMID- 17702701 TI - Breathing-enhanced upper extremity exercises for patients with multiple sclerosis. AB - OBJECTIVE: To explore the effectiveness of breathing-enhanced upper extremity exercises on the respiratory function of patients with multiple sclerosis. DESIGN: Randomized controlled study of six-week duration. SUBJECTS: Forty patients with multiple sclerosis (age 39.2 +/- 7 years; Kurtzke Expanded Disability Status Scale scores: 4.51 +/- 1.55) randomly divided into two groups. METHODS: The training group followed a six-week home training programme designed to strengthen accessory respiratory muscles. Controls performed no exercises. All subjects submitted to baseline and post-training tests of spirometry, respiratory muscle strength and 6-minute walking. They were also assessed with pulmonary dysfunction and exertion fatigue indices. RESULTS: Spirometry revealed clear improvement in forced expiratory volume in 1 second (FEV1) (+13%, P = 0.003) resulting in higher FEV1/FVC (forced vital capacity) (+8.5%, P = 0.03). Maximal inspiratory pressure (P (Imax)) increased by +7.1% but not significantly. Maximal expiratory pressure (P(Emax)) and FVC were significantly higher (by +7.1%, P = 0.0066 and +4.8%, P = 0.036 respectively) with respect to baseline measures. Pulmonary dysfunction was reduced (-9%, P = 0.002) while 6-minute walking distance was longer (+16%, P = 0.029) at equal exertion fatigue level. CONCLUSIONS: The programme improved most pulmonary performance measures and had clinical significance. Its sustained application may prevent respiratory complications frequently observed in the later stages of multiple sclerosis. PMID- 17702702 TI - Effects of an intensive rehabilitation programme on patients with Huntington's disease: a pilot study. AB - OBJECTIVE: To investigate the effects of an intensive, inpatient rehabilitation programme on individuals affected by Huntington's disease. DESIGN: A pilot study. Within-subjects design. SETTING: Inpatient rehabilitation home of the Italian welfare system. SUBJECTS: Forty patients, early and middle stage of the disease, were recruited to an intensive, inpatient rehabilitation protocol. INTERVENTIONS: The treatment programme included respiratory exercises and speech therapy, physical and occupational therapy and cognitive rehabilitation exercises. The programme involved three-week admission periods of intensive treatment that could be repeated three times a year. MAIN MEASURES: A standard clinical assessment was performed at the beginning of each admission using the Zung Depression Scale, Mini-Mental State Examination (MMSE), Barthel Index, Tinetti Scale and Physical Performance Test (PPT). Tinetti and PPT were also used at the end of each admission to assess the outcomes in terms of motor and functional performance. RESULTS: Each three-week period of treatment resulted in highly significant (P < 0.001) improvements of motor performance and daily life activities. The average increase was 4.7 for Tinetti and 5.21 for PPT scores. No carry-over effect from one admission to the next was apparent but at the same time, no motor decline was detected over two years, indicating that patients maintained a constant level of functional, cognitive as well as motor performance. CONCLUSIONS: Intensive rehabilitation treatments may positively influence the maintenance of functional and motor performance in patients with Huntington's disease. PMID- 17702703 TI - Pilot randomized controlled trial to assess the impact of additional supported standing practice on functional ability post stroke. AB - OBJECTIVE: To investigate whether provision of additional standing practice increases motor recovery and mobility post stroke. DESIGN: A pilot randomized controlled trial. SETTING: A stroke rehabilitation unit in the UK. PARTICIPANTS: Seventeen participants, seven women and ten men, age range 51-92 admitted to the unit 6-58 days post stroke. INTERVENTION: Each participant was randomly allocated into a control (conventional physiotherapy) or treatment (conventional therapy plus an additional session of standing practice) group. The period of intervention ranged from 14 to 28 days dependent upon length of stay on the unit. OUTCOME MEASURES: The Gross Functional Tool Section of the Rivermead Motor Assessment, the Trunk Control Test and the Berg Balance Scale were used on admission to the study, at weekly intervals during the intervention, and at 12 weeks (after discharge). RESULTS: Of the 17 participants recruited, three withdrew from the additional intervention group citing fatigue as a barrier and 15 completed the study. Participants completing additional standing practice demonstrated higher scores in all motor measures at week 12, but this difference was not statistically significant. There was a statistically significant difference (P < 0.05) in the changes in Berg Balance score when comparing week 1 with week 12, in support of the group receiving extra standing practice. CONCLUSIONS: A larger study is required to establish the value of additional standing practice after stroke. This pilot demonstrates that the Gross Functional Tool Section of the Rivermead Motor Assessment and the Berg Balance Scale would be useful in such a study. Fatigue may be a significant barrier to ability to participate in more intensive programmes so screening participants for severe fatigue may be useful. PMID- 17702704 TI - Validation of the Stroke Specific Quality of Life Scale (SS-QOL): test of reliability and validity of the Danish version (SS-QOL-DK). AB - OBJECTIVE: To test the reliability and validity of the Danish version of the Stroke Specific Quality of Life Scale version 2.0 (SS-QOL-DK), an instrument for evaluation of health-related quality of life. DESIGN: A correlational study. SETTING: A stroke unit that provides acute care and rehabilitation for stroke patients in Frederiksborg County, Denmark. SUBJECTS: One hundred and fifty-two stroke survivors participated; 24 of these performed test-retest. INTERVENTION: Questionnaires were sent out and returned by mail. A subsequent telephone interview assessed functional level and missing items. MAIN OUTCOME MEASURES: Test-retest was measured using Spearman's r, internal consistency was estimated using Cronbach's alpha, and evaluation of floor and ceiling values in proportion of minimum and maximum scores. Construct validity was assessed by comparing patients' scores on the SS-QOL-DK with those obtained by other test methods: Beck's Depression Index, the General Health Survey Short Form 36 (SF-36), the Barthel Index and the National Institutes of Health Stroke Scale, evaluating shared variance using coefficient of determination, r2. Comparing groups with known scores assessed known-group validity. Convergent and discriminant validity were assessed. RESULTS: Test-retest of SS-QOL-DK showed excellent stability, Spearman's r = 0.65-0.99. Internal consistency for all domains showed Cronbach's alpha = 0.81-0.94. Missing items rate was 1.0%. Most SS-QOL-DK domains showed moderately shared variance with similar domains of other test methods, r2 = 0.03 0.62. Groups with known differences showed statistically significant difference in scores. Item-to-scale correlation coefficients of 0.37-0.88 supported convergent validity. CONCLUSIONS: SS-QOL-DK is a reliable and valid instrument for measuring self-reported health-related quality of life on group level among people with mild to moderate stroke. PMID- 17702705 TI - The Physical Activity and Disability Survey (PADS): reliability, validity and acceptability in people with multiple sclerosis. AB - OBJECTIVE: To explore the test-retest reliability and construct validity of the standardized Physical Activity and Disability Survey (PADS) and its acceptability to people with multiple sclerosis. DESIGN: Participants completed the PADS twice with seven days between repeated measures, while also wearing an Actical accelerometer. Semi-structured interview questions were used to explore the acceptability of the PADS. SUBJECTS: Thirty participants were recruited from the Multiple Sclerosis Society of Auckland, New Zealand. Mean age of participants was 54 years (range 27-76). MAIN MEASURES: Physical Activity and Disability Survey (PADS) and Actical accelerometer. RESULTS: A wide range of standardized PADS scores were recorded at each time-point (ranges 6.7-83.3 and 6.7-87.4). While standardized PADS scores between time-points had a high intraclass correlation coefficient of 0.92 (95% confidence interval (CI) 0.88, 0.98), Bland-Altman 95% limits of agreement (-17.4, 17.4) were modest. Accelerometer activity counts were not accurately predicted by standardized PADS scores (wide 95% prediction intervals). Participants reported the PADS was easy to understand and complete, enabling them to give an accurate picture of their physical activity. CONCLUSIONS: The PADS appears to be a potentially appropriate measure of activity for people with multiple sclerosis, particularly in terms of the wide range of activities it covers and its ability to detect varying levels of physical activity. We suggest the test-retest reliability and validity of the PADS could be improved with some minor revisions. PMID- 17702706 TI - Sensitivity, specificity and predictive value of the clinical trunk muscle endurance tests in low back pain. AB - OBJECTIVE: To describe the sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of five clinical tests used to measure trunk muscle endurance in low back pain. DESIGN: A cross-sectional non experimental design. SETTING: Orthopaedic and physical therapy departments of four hospitals and outpatient physical therapy clinics, Tehran, Iran. SUBJECTS: Convenience sample of 200 subjects participated in this study. Subjects were categorized into four groups: men without low back pain (N = 50, mean (SD) age = 38 (12) years), women without low back pain (N = 50, mean (SD) age = 43 (11) years), men with low back pain (N = 50, mean (SD) age = 39 (12) years) and women with low back pain (N = 50, mean (SD) age = 43 (12) years). MAIN MEASURES: Five clinical static endurance tests of trunk muscles such as: Sorensen test, prone isometric chest raise test, prone double straight-leg raise test, supine isometric chest raise test and supine double straight-leg raise test were measured in each group. RESULTS: The result of receiver operating characteristics (ROC) curve analysis revealed that in a separate analysis of data for men and women, among all tests, the prone double straight-leg raise test had the highest sensitivity, specificity and predictive value in low back pain compared with other performed tests. CONCLUSIONS: It seems that the prone double straight-leg raise test has more sensitivity, specificity and predictive value in low back pain than other tests and could be used as a useful clinical method for testing the spinal muscle endurance to predict the probability of the occurrence of low back pain. PMID- 17702707 TI - Predictors for persistent neck/shoulder pain, medical care-seeking due to neck/shoulder pain and sickness absence. AB - OBJECTIVE: To determine whether symptoms and clinical signs can predict persistent neck/shoulder pain, future medical care-seeking and sickness absence. DESIGN: A population-based cohort was followed prospectively over a 5-6 year period. SETTING: Subjects from the district of Norrtalje (Sweden). SUBJECTS: Subjects with self-rated neck/shoulder pain were included (n = 1471). MAIN MEASURES: Cox regression analyses were used to test the predictive value of single and combinations of symptoms and clinical signs obtained with questionnaires and simple tests concerning persistent neck/shoulder pain, future medical care-seeking and sickness absence. RESULTS: Several symptoms and clinical signs were associated with the outcomes of interest: the relative risk (RR) for persistent neck/shoulder pain was 1.38 (95% confidence interval (CI) 1.14-1.52) for subjects with pain for over three months at baseline and concerning future medical care-seeking RR was 2.10 (95% CI 1.73-2.54) for subjects who had previously sought medical care. An episode of sickness absence during the year of enrolment increased the risk for future sickness absence (RR = 2.42, 95% CI 1.95 3.00). Having five or seven concurrent symptoms and clinical signs was common and more strongly associated with persistent pain (RR = 1.77, 95% CI 1.39 - 2.27) and future medical care-seeking (RR = 4.51, 95% CI 2.54-9.94), respectively, but not concerning sickness absence. CONCLUSION: By simply counting the number of concurrent symptoms and clinical signs, it is possible to predict persistent neck/shoulder pain and future medical care-seeking, but not sickness absence. PMID- 17702708 TI - Family-centred care in family-specific teams. AB - OBJECTIVE: To evaluate the perceptions and views of parents and rehabilitation and special education professionals on the family-centredness of care delivered and received. DESIGN: Descriptive study with comparison of ratings in family specific teams. SETTING: Five paediatric facilities in the Netherlands. SUBJECTS: Parents of children with cerebral palsy and professionals providing their children's rehabilitation and educational services. MAIN MEASURES: The Dutch Measure of Processes of Care for families (MPOC-NL) and the Measure of Processes of Care for service providers (MPOC-SP). Data were collected and analysed per family. RESULTS: In total 38 MPOC-NLs and 204 MPOC-SPs were returned. The family specific team analysis of importance ratings yielded significant differences (P < 0.05) on all domains between parents, rehabilitation professionals and special education professionals. For Enabling and partnership (P < 0.01) and Specific information about the child (P < 0.01), parents considered the behaviours to be significantly more important than rehabilitation professionals. The problem-score analyses showed that in all domains a considerable number of parents (19-38%) did not receive the care they deemed important. CONCLUSION: Family-specific analyses of MPOC importance ratings revealed differences in attitudes towards importance of specific care behaviours of team members, which subsequently may have caused the relatively high incidence of parents not receiving the care they deemed important. This underscores the need to explore and attune opinions on what constitutes proper service delivery. PMID- 17702709 TI - Serum and dialysate potassium concentrations and survival in hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: Controlling serum potassium is an important goal in maintenance hemodialysis patients. We examined the achievement of potassium balance through hemodialysis treatments and the associated fluctuations in serum potassium. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A 3-yr (July 2001 to June 2004) cohort of 81,013 maintenance hemodialysis patients from all DaVita dialysis clinics across the United States were studied. Nine quarterly-averaged serum potassium groups (< 4.0, > or = 6.3 mEq/L and seven increments in-between) and four dialysate potassium concentration groups were created in each of the 12 calendar quarters. The death risk associated with predialysis potassium level and dialysate potassium concentration was examined using unadjusted, case-mix adjusted, and malnutrition-inflammation-adjusted time-dependent survival models. RESULTS: Serum potassium correlated with nutritional markers. Serum potassium between 4.6 and 5.3 mEq/L was associated with the greatest survival, whereas potassium < 4.0 or > or = 5.6 mEq/L was associated with increased mortality. The death risk of serum potassium > or = 5.6 mEq/L remained consistent after adjustments. Higher dialysate potassium concentration was associated with increased mortality in hyperkalemic patients with predialysis serum potassium > or = 5.0 mEq/L. CONCLUSIONS: A predialysis serum potassium of 4.6 to 5.3 mEq/L is associated with the greatest survival in maintenance hemodialysis patients. Hyperkalemic patients who undergo maintenance hemodialysis against lower dialysate bath may have better survival. Limitations of observational studies including confounding by indication should be considered when interpreting these results. PMID- 17702710 TI - Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE): rationale and design overview. AB - BACKGROUND AND OBJECTIVES: The dramatically high rates of mortality and cardiovascular morbidity observed among dialysis patients highlights the importance of identifying and implementing strategies to lower cardiovascular risk in this population. Results from clinical trials undertaken thus far, including trials on lipid reduction, normalization of hematocrit, and increased dialysis dosage, have been unsuccessful. Available data indicate that abnormalities in calcium and phosphorus metabolism, as a result of either secondary hyperparathyroidism alone or the therapeutic measures used to manage secondary hyperparathyroidism, are associated with an increased risk for death and cardiovascular events. However, no prospective trials have evaluated whether interventions that modify these laboratory parameters result in a reduction in adverse cardiovascular outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events is a global, phase 3, double-blind, randomized, placebo-controlled trial evaluating the effects of cinacalcet on mortality and cardiovascular events in hemodialysis patients with secondary hyperparathyroidism. Approximately 3800 patients from 22 countries will be randomly assigned to cinacalcet or placebo. Flexible use of traditional therapies will be permitted. The primary end point is the composite of time to all-cause mortality or first nonfatal cardiovascular event (myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular disease, including lower extremity revascularization and nontraumatic amputation). RESULTS: The study will be event driven (terminated at 1882 events) with an anticipated duration of approximately 4 yr. CONCLUSIONS: Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events will determine whether management of secondary hyperparathyroidism with cinacalcet reduces the risk for mortality and cardiovascular events in hemodialysis patients. PMID- 17702711 TI - Idiopathic IgA nephropathy: pathogenesis, histopathology, and therapeutic options. AB - IgA nephropathy is one of the most common causes of glomerulonephritis in the world. Proliferative and crescentic forms of IgA are found in up to 30% of cases and are associated with nephrotic-range proteinuria, accelerated hypertension, and accelerated decline toward ESRD. Despite its prevalence and clinical importance, there is no unifying nomenclature or consensus for the treatment of specific histologic subgroups. As a consequence, the development of clinically effective treatment regimens for IgA nephropathy have lagged behind other, less common forms of glomerulonephritis. Herein is reviewed the pathogenesis and histologic subtypes of IgA nephropathy and how conventional and immunosuppressive therapies have an impact on renal survival and recurrence rates. The use of known clinical risk factors for disease progression in conjunction with specific histologic features can be a guide to both induction and consolidation therapies for individual patients with IgA nephropathy. PMID- 17702712 TI - Associations of body size with metabolic syndrome and mortality in moderate chronic kidney disease. AB - BACKGROUND AND OBJECTIVES: Obesity is associated with metabolic syndrome and poor outcomes in those with normal kidney function but better survival in dialysis patients. We examined whether chronic kidney disease (CKD) modifies the association of obesity with metabolic syndrome and mortality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Analyses of 15,355 participants in limited access, public use Atherosclerosis Risk in Communities Study database. RESULTS: The prevalence of metabolic syndrome in (BMI) groups < 20, 20 to 24.9, 25 to 29.9, 30 to 34.9, and > or = 35 kg/m2 were 1, 6, 17, 28, and 35% and 9, 15, 32, 46, and 58% in participants without (n = 14,894) and with CKD (n = 461), respectively. Using BMI 20 to 24.9 kg/m2 as the reference, there was a U-shaped association of BMI with mortality in a parametric survival model of death. An interaction term of BMI and CKD added to the model was significant. In participants with (BMI) > or = 25 kg/m2, each 1-kg/m2 increase in BMI was associated with increased hazard of death only in those without CKD. Adjustment for components of metabolic syndrome, markers of inflammation, and cardiovascular conditions abolished these associations in participants without CKD but became protective in participants with CKD. CONCLUSIONS: The prevalence of obesity parallels metabolic syndrome in populations with and without CKD. However, the presence of CKD modifies the associations of obesity with mortality. PMID- 17702713 TI - BK virus nephropathy in pediatric renal transplant recipients: an analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry. AB - BACKGROUND AND OBJECTIVES: There is limited information regarding BK virus nephropathy in pediatric kidney transplantation. The objective of this study was to evaluate cases of BK virus nephropathy in the North American Pediatric Renal Trials and Collaborative Studies database. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using a questionnaire that was sent to North American Pediatric Renal Trials and Collaborative Studies centers, we assessed the incidence, risk factors, clinical features, and outcomes of BK virus nephropathy in pediatric renal transplant recipients who received a transplant between 2000 and 2004. RESULTS: BK virus nephropathy was reported in 25 (4.6%) of 542 patients at a median onset of 10.1 mo after transplantation. The median age was 11 yr. All patients who were tested reported BK viruria, and 19 (91%) of 21 who had plasma tested reported BK viremia. Treatment of BK virus nephropathy included reduction of immunosuppression (84%), cidofovir (24%), leflunomide (8%), and intravenous Ig (20%). Simultaneous rejection treatment was reported in four (16%). The median creatinine was 2.0 mg/dl at a mean follow-up of 24 mo. There were six (24%) graft failures in the patients with BK virus nephropathy at a mean of 24 mo after diagnosis. Rejection occurred in eight (32%) after diagnosis. Multivariate analysis showed that use of polyclonal induction therapy and zero HLA DR mismatch were associated with the development of BK virus nephropathy. CONCLUSIONS: This first multicenter, retrospective, cohort study of BK virus nephropathy in pediatric renal transplant recipients found a BK virus nephropathy incidence of 4.6% and identified polyclonal induction and zero HLA DR mismatch as significant risk factors for BK virus nephropathy. PMID- 17702714 TI - Therapeutic drug monitoring of mycophenolic acid. PMID- 17702715 TI - Subdural hematomas in chronic dialysis patients: significant and increasing. AB - BACKGROUND AND OBJECTIVES: Subdural hematoma is a known complication of long-term hemodialysis. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: The US Renal Data System was used to determine the occurrence rate of nontraumatic subdural hematoma in long-term dialysis patients and to evaluate time trends. RESULTS: The occurrence rate of subdural hematoma in long-term dialysis patients is 10 times higher than that of the general population. From 1991 to 2002, the occurrence rate of subdural hematoma in hemodialysis patients doubled, whereas it did not change in peritoneal dialysis patients. CONCLUSIONS: This high occurrence rate of subdural hematoma and its recent increase may be related to increased use of anticoagulants in long-term hemodialysis patients. PMID- 17702716 TI - Inflammatory marker mania in chronic kidney disease: pentraxins at the crossroad of universal soldiers of inflammation. PMID- 17702717 TI - Role of mycophenolate mofetil in the treatment of lupus nephritis. PMID- 17702718 TI - Do we have a pill for renal fibrosis? PMID- 17702719 TI - Metabolic syndrome: an emerging threat to renal function. PMID- 17702720 TI - Obesity is associated with secondary hyperparathyroidism in men with moderate and severe chronic kidney disease. AB - BACKGROUND AND OBJECTIVES: Obesity is associated with secondary hyperparathyroidism in the general population. The objective of this study is to explore whether the same association is present in patients with chronic kidney disease. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Linear regression models were used to examine the association between intact parathyroid hormone level and body mass index in 496 male US veterans (age 69.4 +/- 10.2 yr, 22.8% black) who had chronic kidney disease stages 2 to 5 and were not yet on dialysis (estimated GFR 31.8 +/- 11.2 ml/min per 1.73 m2). RESULTS: Higher intact parathyroid hormone was associated with higher body mass index after adjustment for age, race, diabetes, and serum calcium and phosphorus levels. This association was independent of age, race, diabetes status, and serum calcium and phosphorus but was limited to patient groups with lower albumin (P = 0.005 for the interaction term) or higher white blood cell count (P = 0.026 for the interaction term). CONCLUSIONS: Higher body mass index is associated with secondary hyperparathyroidism in patients who have chronic kidney disease and are not yet on dialysis, especially in patients with evidence of malnutrition and inflammation. Confirmation of these findings in other patient groups with chronic kidney disease and better characterization of the underlying mechanisms of action will be necessary before advocating weight loss as a means to treat secondary hyperparathyroidism in chronic kidney disease. PMID- 17702721 TI - Spectrum of renal pathology in hematopoietic cell transplantation: a series of 20 patients and review of the literature. AB - BACKGROUND AND OBJECTIVES: Hematopoietic cell transplantation is a common treatment option for a variety of hematopoietic malignancies. As a result of the use of total body irradiation and/or chemotherapeutic agents, renal dysfunction often ensues. Many pharmacologic agents, such as cyclosporine and high-intensity conditioning regimens, have been linked with thrombotic microangiopathy. In addition, an association between membranous nephropathy and graft-versus-host disease has been reported in this clinical setting. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: A study of autologous and allogeneic hematopoietic cell transplantation patients with renal dysfunction was conducted to document the spectrum of renal manifestations. The pathology files at the University of Washington and University of Chicago Medical Centers were reviewed, and 20 patients with a kidney biopsy after hematopoietic cell transplantation were identified. The histologic findings were correlated with relevant clinical information. RESULTS: A wide spectrum of renal diseases could be classified into four categories: (1) Complications related to hematopoietic cell transplantation (conditioning regimen, immunosuppression, or posttransplantation complications), (2) podocytopathy, (3) membranous nephropathy, or (4) recurrence or persistence of original hematologic disease. Pathologic diagnoses included thrombotic microangiopathy, polyoma virus nephropathy, acute kidney injury/acute tubular necrosis, acute and chronic interstitial nephritis, minimal-change disease, "tip" variant of focal segmental glomerulosclerosis, membranous nephropathy, amyloidosis, and myeloma cast nephropathy. Membranous nephropathy, minimal-change disease, and amyloidosis were common causes of severe proteinuria. Because of the conditioning regimens, posttransplantation complications, and potential nephrotoxic agents used during hematopoietic cell transplantation, it was difficult to attribute the subsequent renal dysfunction to specific factors. CONCLUSIONS: The renal biopsy remains essential for diagnosing the underlying injury that can affect one or more compartments of the kidney in this unique clinical setting. PMID- 17702722 TI - Routine use of ambulatory blood pressure monitoring in potential living kidney donors. AB - BACKGROUND AND OBJECTIVES: Most transplant centers exclude prospective living kidney donors with hypertension from donation. Centers routinely identify hypertension using BP measured in the clinic, but it is not clear that clinic BP accurately detects the presence or absence of hypertension in potential donors. We therefore conducted a prospective study to determine the impact of routine ambulatory BP monitoring on diagnosis of hypertension in potential donors and the value of other baseline characteristics in predicting ambulatory BP results. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We compared classification of hypertension status by clinic BP and by ambulatory BP monitoring in 178 potential living kidney donors. RESULTS: Of 63 individuals with hypertension by clinic BP, 62% had white-coat hypertension by ambulatory BP and were therefore eligible to donate. Of 115 individuals who were normotensive by clinic BP, 17% had masked hypertension by ambulatory BP and were excluded from donation. Individuals with masked hypertension were older, were more likely to be male, and had a somewhat higher clinic BP than individuals with sustained normotension. Individuals with white-coat hypertension had a somewhat lower clinic diastolic BP than individuals with sustained hypertension. CONCLUSIONS: Routine ambulatory BP monitoring may identify a large number of individuals with white-coat hypertension and a smaller but significant number of individuals with masked hypertension, ensuring adequate protection of potential donors and accurate assessment of donor risk. Differences in baseline characteristics are small and are not clinically useful in distinguishing individuals with masked hypertension from individuals with sustained normotension or individuals with white-coat hypertension from individuals with sustained hypertension, demonstrating the importance of ambulatory BP monitoring in this population. PMID- 17702723 TI - Mycophenolate mofetil for induction therapy of lupus nephritis: a systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVES: Although the accepted standard of care for induction of lupus nephritis has been cyclophosphamide, recent trials suggest that mycophenolate mofetil may be as or more effective and less toxic. A systematic review and meta-analysis were performed to determine the risk for failure to induce remission of lupus nephritis in patients who were treated with mycophenolate mofetil compared with cyclophosphamide. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Studies were identified by a search of electronic databases, bibliographies, and conference proceedings and by contacting experts. Randomized trials that compared mycophenolate mofetil with cyclophosphamide for induction therapy in adults with biopsy-proven lupus nephritis were eligible. The primary outcome was failure to induce a remission of nephritis as defined by the original studies (based on proteinuria, renal function, and urine sediment). RESULTS: Four studies that included 268 patients and had homogeneous results across studies were identified. In a fixed-effects model, the pooled relative risk for failure to induce remission for mycophenolate mofetil compared with cyclophosphamide was 0.70. The relative risk for the composite outcome of death or end-stage renal disease for mycophenolate mofetil compared with cyclophosphamide was 0.44. Leukopenia and amenorrhea occurred more frequently in cyclophosphamide-treated patients. CONCLUSIONS: Treatment of lupus nephritis with mycophenolate mofetil compared with cyclophosphamide reduces the risk for failure to induce remission during induction therapy and may reduce the risk for death or end-stage renal disease. Mycophenolate mofetil may be considered as a first-line induction therapy for the treatment of lupus nephritis in patients without severe renal dysfunction. PMID- 17702724 TI - Identifying patients at risk for microalbuminuria via interaction of the components of the metabolic syndrome: a cross-sectional analytic study. AB - BACKGROUND AND OBJECTIVES: The objective of this study was to investigate correlates of risk for having microalbuminuria in individuals with one or more cardiovascular risk factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study involved 1919 individuals who attended general practice settings, were aged 55 to 75 yr, and did not have a history of cardiovascular events or diabetes but had one or more cardiovascular risk factors. A tree-based regression technique and multivariate analysis were used to identify distinct, homogeneous subgroups of patients with different likelihood of having microalbuminuria; interaction between correlates of microalbuminuria and risk for microalbuminuria was also investigated. RESULTS: The prevalence of microalbuminuria was 5.9%. Patients who did not have hypertension and had postload glycemia < 140 mg/dl showed the lowest prevalence of microalbuminuria (1.9%) and represented the reference class. The likelihood of microalbuminuria was seven times higher in men with hypertension and homeostatic model assessment levels in the upper tertile and four times higher in women with the same characteristics. Individuals with hypertension and lower homeostatic model assessment levels and normotensive individuals with postload glycemia > or = 140 mg/dl had a more than three-fold increased likelihood of having microalbuminuria. Treatment with statins was associated with a 54% reduction in the likelihood of having microalbuminuria, whereas levels of triglycerides > 150 mg/dl and fibrinogen levels in the upper tertile were associated with a significantly higher risk for microalbuminuria. CONCLUSIONS: The likelihood of having microalbuminuria in a population-based study of elderly individuals is strongly related to the interaction between the components of the metabolic syndrome, particularly hypertension, insulin resistance, and impaired glucose tolerance. PMID- 17702725 TI - Titrating rituximab to circulating B cells to optimize lymphocytolytic therapy in idiopathic membranous nephropathy. AB - BACKGROUND AND OBJECTIVES: Rituximab, given in four weekly doses, is a promising treatment for idiopathic membranous nephropathy and other immune-mediated diseases and lymphoproliferative disorders. This multidose regimen, however, may cause hypersensitivity reactions and is extremely expensive. This study was aimed at evaluating whether titrating rituximab to circulating CD20 B cells may improve safety and limit costs of treatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a matched-cohort, single-center, controlled study, the outcome of 12 new incident patients who had idiopathic membranous nephropathy and nephrotic syndrome and received a B cell-driven treatment was compared with that of 24 historical reference patients who were given the standard protocol of four weekly doses of 375 mg/m2. RESULTS: Only one patient needed a second dose to achieve full CD20 cell depletion. At 1 yr, time course of the components of nephrotic syndrome and the proportion of patients who achieved disease remission (25%) was identical in both groups. Persistent CD20 cell depletion was achieved in all patients. Costs for rituximab treatment and hospitalizations totalled 3770.90 euros ($4902.20) and 13,977.60 euros ($18,170.80) with the B cell-driven and the four-dose protocol, respectively. One patient on standard protocol had a severe adverse reaction at second rituximab dose. Thus, B cell titrated as effectively as standard rituximab treatment achieves B cell depletion and idiopathic membranous nephropathy remission but is fourfold less expensive, allowing for more than 10,000 euros, approximately $13,000 in savings per patient. CONCLUSIONS: Avoiding unnecessary reexposure to rituximab is extremely cost-saving and may limit the production of antichimeric antibodies that may increase the risk for adverse reactions and prevent re-treatment of disease recurrences. PMID- 17702726 TI - Fistula first initiative: advantages and pitfalls. PMID- 17702727 TI - Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. AB - BACKGROUND AND OBJECTIVES: Pirfenidone is an orally available antifibrotic agent that has shown benefit in animal models of pulmonary and renal fibrosis and in clinical trials of pulmonary fibrosis, multiple sclerosis, and hepatic cirrhosis. Our objective was to determine whether pirfenidone slows the loss of renal function in focal segmental glomerulosclerosis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: An open-label trial was performed to evaluate the safety and efficacy of pirfenidone in patients with idiopathic and postadaptive focal segmental glomerulosclerosis. The monthly change in estimated GFR, expressed as ml/min per 1.73 m2, was compared between the baseline period and the treatment period. During both periods, patients received angiotensin antagonist therapy if tolerated. Twenty-one patients were enrolled, and 18 patients completed a median of 13 mo of pirfenidone treatment. RESULTS: The monthly change in GFR improved from a median of -0.61 ml/min per 1.73 m2 (interquartile range -1.31 to -0.41) during the baseline period to -0.45 ml/min per 1.73 m2 (interquartile range -0.78 to -0.16) with pirfenidone therapy. This change represents a median of 25% improvement in the rate of decline (P < 0.01). Pirfenidone had no effect on BP or proteinuria. Adverse events attributed to therapy included dyspepsia, sedation, and photosensitive dermatitis. CONCLUSIONS: It is concluded that pirfenidone is an attractive candidate for placebo-controlled trials in patients with progressive chronic kidney disease. PMID- 17702728 TI - Single-use versus reusable dialyzers: the known unknowns. AB - The practice of reusing dialyzers has been widespread in the United States for decades, with single use showing signs of resurgence in recent years. Reprocessing of dialyzers has traditionally been acknowledged to improve blood membrane biocompatibility and prevent first-use syndromes. These proposed advantages of reuse have been offset by the introduction of more biocompatible membranes and favorable sterilization techniques. Moreover, reuse is associated with increased health hazard from germicide exposure and disposal. Some observational studies have also pointed to an increased mortality risk with dialyzer reuse, and the potential for legal liability is another concern. The desire to save cost is the major driving force behind the continued practice of dialyzer reuse in the United States. It is imperative that future research focus on the environmental consequences of dialysis, including the need for more optimal management of disinfectant-related waste with reuse, and solid waste with single use. The dialysis community has a responsibility to explore ways to mitigate environmental consequences before single-use and a more frequent dialysis regimen becomes a standard practice in the United States. PMID- 17702729 TI - Are patients who have metabolic syndrome without diabetes at risk for developing chronic kidney disease? Evidence based on data from a large cohort screening population. AB - BACKGROUND AND OBJECTIVES: Recently, metabolic syndrome (MS) was suggested to be an independent risk factor for chronic kidney disease (CKD). This study explored the relationship between MS and risk for development of CKD that is independent of diabetes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study population consisted of 4607 adult (age >18 yr) individuals who did not have diabetes or CKD at baseline and were successfully followed for 3 yr in the Tehran Lipid and Glucose Study, a prospective, population-based study of risk factors for atherosclerosis and diabetes. Individuals with and without MS at baseline were compared regarding development of new CKD. RESULTS: A total of 1010 (21.9%) individuals met criteria for MS at baseline. During the follow-up, 38 (3.4%) individuals in MS group and 73 individuals (2.0%) of 3590 people in non-MS group developed CKD (OR = 1.88, 95% CI; 1.26-2.8). After exclusion of individuals with hypertension at baseline (n = 798), 406 people (10.7%) were defined as having MS. After follow-up, 62 (1.82%) people in the MS group and eight (1.98%) people in non-MS group developed CKD (OR = 0.925, 95% CI; 0.446-1.917; P = 0.844). CONCLUSIONS: The results of this study suggest that MS is a cluster of multiple risk factors, and, as a cluster, it is a significant risk for CKD. The risk of MS for developing CKD is highly affected by the presence of diabetes and hypertension, and it seems that clustering of individual risk factors is more plausibly associated with risk for developing CKD than a unique biologic phenomenon. PMID- 17702730 TI - Renal provider recognition of symptoms in patients on maintenance hemodialysis. AB - BACKGROUND AND OBJECTIVES: Although several studies have found that the burden of symptoms in patients who are on maintenance hemodialysis is substantial, little is known about renal providers' awareness of these symptoms. The aim of this study was to assess renal provider recognition of symptoms and their severity in hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Dialysis Symptom Index, a 30-item measure of symptoms and their severity, was administered to patients during a routine hemodialysis session. Immediately after surveying patients, the renal provider who evaluated the patient completed the Dialysis Symptom Index to report the symptoms that he or she believed were present in that patient. Sensitivity, specificity, and positive and negative predictive values of provider reports of symptoms were calculated using patient reports as the reference standard. Patient-provider agreement on the presence and severity of symptoms was assessed using the kappa statistic. RESULTS: Surveys were completed by 75 patients and 18 providers. For 27 of 30 symptoms, the sensitivity of provider responses was <50%, and provider responses for 25 symptoms were characterized by positive predictive values of <75%. kappa scores for 25 symptoms including those pertaining to pain, sexual dysfunction, sleep disturbance, and psychologic distress were <0.20, indicating poor provider recognition of these symptoms. Providers underestimated the severity of 19 of 30 symptoms. CONCLUSIONS: Renal providers are largely unaware of the presence and severity of symptoms in patients who are on maintenance hemodialysis. Implementation of a standardized symptom assessment process may improve provider recognition of symptoms and promote use of symptom-alleviating treatments. PMID- 17702731 TI - Hypothesis: Dent disease is an underrecognized cause of focal glomerulosclerosis. AB - BACKGROUND AND OBJECTIVES: Dent disease is a hereditary form of progressive renal failure characterized by hypercalciuria and proximal tubular dysfunction. The clinical presentation is often insidious with the majority of patients remaining asymptomatic throughout childhood. Despite the seemingly mild, early course, more than 20% of 32 asymptomatic patients in one study had biopsy evidence of focal glomerulosclerosis. Furthermore, end-stage renal disease often occurs in men in early to middle adulthood. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This article describes two male patients who presented with asymptomatic proteinuria and were found to have focal glomerulosclerosis. Despite the absence of nephrocalcinosis on renal ultrasound, the diagnosis of Dent disease was considered because of unexplained proteinuria. Subsequent history revealed renal calculi in each maternal family. RESULTS: The clinical diagnosis of Dent disease was established by intermittent hypercalciuria and low molecular weight proteinuria and confirmed through mutational analysis. CONCLUSIONS: It is hypothesized that a diagnosis of Dent disease may be unrecognized in patients with unexplained proteinuria and idiopathic focal glomerulosclerosis. PMID- 17702732 TI - Plasma pentraxin 3 in patients with chronic kidney disease: associations with renal function, protein-energy wasting, cardiovascular disease, and mortality. AB - BACKGROUND AND OBJECTIVES: Plasma protein pentraxin 3 concentrations are elevated in a wide range of diseased states. However, no study has evaluated protein pentraxin 3 in patients with chronic kidney disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Plasma protein pentraxin 3 concentrations were analyzed in relation to GFR, inflammation, cardiovascular disease, and protein energy wasting in 71 patients with stages 3 to 4 chronic kidney disease, 276 patients with stage 5 chronic kidney disease, and 61 control subjects. Survival (5 yr) in patients with stage 5 chronic kidney disease was analyzed in relation to protein pentraxin 3 levels. RESULTS: Both patient groups with chronic kidney disease had higher protein pentraxin 3 concentrations than control subjects, with the highest concentration in patients with stage 5 chronic kidney disease. In all patients with chronic kidney disease, protein pentraxin 3 correlated negatively with GFR and positively with inflammatory markers. Patients with protein-energy wasting, inflammation, and cardiovascular disease had higher concentrations of protein pentraxin 3 than their counterparts. Patients with high protein pentraxin 3 levels had higher all-cause and cardiovascular mortality. After adjustment for age, gender, C-reactive protein, and cardiovascular disease, all-cause mortality was still significantly higher in patients with high protein pentraxin 3. Finally, protein pentraxin 3 showed a predictive value of mortality similar to that of IL-6 and better than C-reactive protein. CONCLUSION: Plasma protein pentraxin 3 increases as GFR declines and is associated with the presence of cardiovascular disease and protein-energy wasting. Furthermore, in patients with chronic kidney disease, elevated protein pentraxin 3 predicted all-cause mortality. PMID- 17702733 TI - Pain, sleep disturbance, and quality of life in patients with chronic kidney disease. AB - BACKGROUND AND OBJECTIVES: Few studies have assessed sleep disturbances or perception of pain in patients with early-stage chronic kidney disease. It was hypothesized that perception of pain and sleep disturbance would increase with chronic kidney disease stage, that pain and sleep disturbance would correlate with psychosocial variables, and that there would be a higher prevalence of pain and sleep disturbances in patients with chronic kidney disease compared with general medical patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 92 predialysis patients with chronic kidney disease and 61 general medical outpatients were evaluated using the Beck Depression Inventory, Illness Effects Questionnaire, Multidimensional Scale of Perceived Social Support, Satisfaction with Life Scale, Karnofsky Scale, Pittsburgh Sleep Questionnaire, and McGill Pain questionnaire. RESULTS: With the exception of expected differences in serum creatinine, estimated GFR, Karnofsky score, albumin, and hemoglobin, there were no significant differences between groups. A total of 69% of patients with chronic kidney disease experienced pain; 55.2% had disordered sleep. Pain was associated with quality-of-life indicators, including depression, burden of illness, and life satisfaction. Disordered sleep correlated with depression, illness burden, social support, and pain frequency. There were no differences in perception of pain or sleep disturbance between patients with chronic kidney disease and control patients. CONCLUSIONS: Pain is common in patients with early stage chronic kidney disease and is associated with patients' perception of lower quality of life. The prevalence of pain, sleep disturbance, and abnormal psychologic status of patients with chronic kidney disease may be similar to outpatients with other chronic medical illnesses. PMID- 17702735 TI - Rise of pay for performance: implications for care of people with chronic kidney disease. AB - Many health care providers and policy makers believe that health care financing systems fail to reward high-quality care. In recent years, federal and private payers have begun to promote pay for performance, or value-based purchasing, initiatives to raise the quality of care. This report describes conceptual issues in the design and implementation of pay for performance for chronic kidney disease and ESRD care. It also considers the implications of recent ESRD payment policy changes on the broader goals of pay for performance. Congressionally mandated bundle payment demonstration for dialysis, newly implemented case-mix adjustment of the composite rate, and G codes for the monthly capitation payment are important opportunities to understand facility and provider behavior with particular attention to patient selection and treatment practices. Well-designed payment systems will reward quality care for patients while maintaining appropriate accountability and fairness for health care providers. PMID- 17702734 TI - Low urine pH: a novel feature of the metabolic syndrome. AB - BACKGROUND AND OBJECTIVES: The metabolic syndrome is associated with alterations in renal function. An overly acidic urine has been described as a renal manifestation of the metabolic syndrome in patients with kidney stone disease. This study examined the association between the metabolic syndrome and urine pH in individuals without a history of nephrolithiasis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 148 adults who were free of kidney stones were evaluated in this outpatient cross-sectional study. Height, weight, BP, fasting blood, and 24-h urine chemistries were obtained. Urine pH was measured by pH electrode. The following features of the metabolic syndrome were evaluated: BP; body mass index; and serum triglyceride, glucose, and HDL cholesterol concentrations. The degree of insulin resistance was assessed by the homeostasis model assessment of insulin resistance. RESULTS: Participants with the metabolic syndrome had a significantly lower 24-h urine pH compared with participants without the metabolic syndrome. Mean 24-h urine pH, adjusted for age, gender, creatinine clearance, and 24-h urine sulfate, decreased from 6.15, 6.10, 5.99, 5.85, to 5.69 with increasing number of metabolic syndrome abnormalities. An association was observed between 24-h urine pH and each metabolic feature. After adjustment for age, gender, creatinine clearance, urine sulfate, and body mass index, a significant inverse relationship was noted between 24-h urine pH and the degree of insulin resistance. CONCLUSIONS: An unduly acidic urine is a feature of the metabolic syndrome and is associated with the degree of insulin resistance. PMID- 17702736 TI - Hormonal and hemodynamic effects of aliskiren and valsartan and their combination in sodium-replete normotensive individuals. AB - BACKGROUND AND OBJECTIVES: An AT1 receptor antagonist induces a counterregulatory renin release whose intensity and duration reflect the magnitude of the renin angiotensin blockade. We investigated whether a renin inhibitor may neutralize this counterregulation and amplify the effects of AT1 receptor antagonists. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In 12 normotensive male individuals who were on a high-sodium diet, a double-blind, placebo-controlled, randomized, crossover design was used to study the hormonal and BP effects of single oral administrations of 300 mg of the renin inhibitor aliskiren, 320 mg of valsartan, and a combination of these two drugs, each at half dosage (150 mg of aliskiren and 160 mg of valsartan). RESULTS: Valsartan (320 mg) increased plasma renin activity and angiotensin I and angiotensin II levels, but 300 mg of aliskiren decreased them for 48 h. Aliskiren (300 mg) stimulated immunoreactive renin release more strongly than 320 mg of valsartan, decreased urinary aldosterone excretion for longer than 320 mg of valsartan, and had a similar BP lowering effect as 320 mg of valsartan. In combination, 150 mg of aliskiren neutralized the valsartan (160 mg)-induced increase in plasma angiotensins for 48 h. The renin and aldosterone effects of the combination of 150 mg of aliskiren and 160 mg of valsartan were similar to those of 300 mg of aliskiren and greater than those of 320 mg of valsartan. When plasma drug concentrations were taken into account, the combination of 150 mg of aliskiren and 160 mg of valsartan had a synergistic effect on renin release. The BP-lowering effect of 150 mg of aliskiren and 160 mg of valsartan was similar to that of 300 mg of aliskiren and 320 mg of valsartan at peak but was more prolonged. CONCLUSION: The stronger and longer lasting effects on plasma active renin and urinary aldosterone of aliskiren, alone or in combination, demonstrate a more effective blockade of the renin-angiotensin system than that obtained with 320 mg of valsartan alone. PMID- 17702738 TI - Use of antimicrobial catheter lock solutions to prevent catheter-related bacteremia. AB - Catheter-related bacteremia is an important source of morbidity and mortality in hemodialysis patients. A number of well-designed, controlled, prospective trials using antimicrobial catheter lock solutions to prevent catheter-related bacteremia have shown a dramatic, statistically significant decrease in not only infection but also mortality related to catheter-related bacteremia. Despite evidence of significant benefit, these locks are not routinely used in the United States. This review describes the epidemic problem of catheter-related bacteremia, reviews recent clinical trials with antimicrobial catheter lock solutions, and discusses current options and potential indications for catheter lock solutions in the hemodialysis population. PMID- 17702737 TI - Comparison of stage at diagnosis of cancer in patients who are on dialysis versus the general population. AB - BACKGROUND AND OBJECTIVES: Frequent medical encounters in patients with ESRD on dialysis may allow early detection of malignancies despite low rates of cancer screening in this population. It is therefore unclear whether dialysis patients are disadvantaged in terms of cancer diagnosis. This study compared stage at diagnosis of cancer in a population-based sample of patients with ESRD versus the general population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Surveillance, Epidemiology, and End Results Medicare database was used to identify patients with ESRD and incident cancers from 1992 through 1999. Modified Poisson regression models were used to predict nonlocalized stage of cancer at diagnosis in patients with ESRD versus the general population, adjusting for demographics, cancer site, region, year of diagnosis, and comorbidity. Two general population comparisons were used: Standardized Surveillance, Epidemiology, and End Results public-use data and Medicare control subjects without ESRD matched 3:1 to patients with ESRD. RESULTS: A total of 1629 patients with ESRD and incident cancer were identified. Overall, the likelihood of nonlocalized stage at diagnosis was not significantly different for patients with ESRD versus the standardized Surveillance, Epidemiology, and End Results general population or matched Medicare control subjects. Stratifying by cancer site, colorectal cancers were significantly more likely to be diagnosed earlier in the ESRD group, whereas prostate cancers were significantly more likely to be diagnosed at a later stage. CONCLUSIONS: With the exception of prostate cancer, patients with ESRD are not more likely to present with later stage malignancies compared with the general population. PMID- 17702739 TI - Gender and the renal nitric oxide synthase system in healthy humans. AB - BACKGROUND AND OBJECTIVES: It is widely known that men with kidney disease progress to ESRD at a much greater rate than do women. The mechanism for these gender differences is not clear, but reduced availability of nitric oxide is thought to contribute to the age-related decline in renal plasma flow observed in both healthy men and women. Animal models suggest that the renal vasculature of men may be significantly more dependent on nitric oxide than that of women. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Renal plasma flow response to the nonspecific nitric oxide synthase inhibitor nitro-L-arginine methyl ester (L NAME) was measured by para-aminohippurate clearance technique in 21 healthy, normotensive (8 male, 13 female) individuals in balance on a high-salt diet. RESULTS: There were striking differences between the genders in the renal hemodynamic response to L-NAME according to age, a difference that remained even after adjustment for other significant covariates. In men, the fall in renal plasma flow induced by L-NAME increased remarkably with increasing age. In women, there was no influence of age on the renovascular response to L-NAME. Neither age nor gender predicted the mean arterial pressure response to L-NAME. CONCLUSIONS: The renal vasculature of men becomes more dependent on nitric oxide with age compared with that of women, suggesting that any renal disease that interferes with nitric oxide production may, over time, cause existent kidney damage to progress more quickly in men relative to women. PMID- 17702740 TI - Investigating the interaction between osteoprotegerin and receptor activator of NF-kappaB or tumor necrosis factor-related apoptosis-inducing ligand: evidence for a pivotal role for osteoprotegerin in regulating two distinct pathways. AB - Osteoprotegerin (OPG) binds the ligand for receptor activator of nuclear factor kappaB (RANKL) to prevent association with its receptor RANK and inhibit osteoclast-mediated bone resorption. OPG has been reported, recently, to inhibit tumor necrosis factor-related apoptosis-induced ligand (TRAIL)-induced tumor cell apoptosis. This raises the possibility that OPG may play a unique role in regulating these two signaling pathways. However, there are little data on the interactions between OPG, RANKL, and TRAIL, and the relative affinity of OPG for these two ligands is unknown. In the present study we examined the ability of OPG to bind native human TRAIL and RANKL under physiological conditions. Native TRAIL was expressed in Escherichia coli, purified to homogeneity, and shown to induce human myeloma cell apoptosis. OPG inhibited native TRAIL from binding the TRAILR1 at 37 degrees C in vitro. Similarly, OPG prevented RANKL from binding to RANK. TRAIL also prevented OPG-mediated inhibition of RANKL from binding RANK. The affinity of OPG for native TRAIL and RANKL at 37 degrees C was determined by plasmon surface resonance analysis. OPG had a binding affinity for TRAIL of 45 nM, whereas the affinity of OPG for RANKL was 23 nM. These data suggest that OPG can bind both RANKL and TRAIL and that the affinity of OPG for these two ligands is of a similar order of magnitude. Furthermore, OPG prevented TRAIL-mediated reductions in cell viability, whereas TRAIL inhibited OPG-mediated inhibition of osteoclastogenesis in vitro. This highlights the pivotal role of OPG in regulating the biology of both RANKL and TRAIL. PMID- 17702741 TI - High affinity binding of epibatidine to serotonin type 3 receptors. AB - Epibatidine and mecamylamine are ligands used widely in the study of nicotinic acetylcholine receptors (nAChRs) in the central and peripheral nervous systems. In the present study, we find that nicotine blocks only 75% of (125)I-epibatidine binding to rat brain membranes, whereas ligands specific for serotonin type 3 receptors (5-HT(3)Rs) block the remaining 25%. (125)I-Epibatidine binds with a high affinity to native 5-HT(3)Rs of N1E-115 cells and to receptors composed of only 5-HT(3A) subunits expressed in HEK cells. In these cells, serotonin, the 5 HT(3)R-specific antagonist MDL72222, and the 5-HT(3)R agonist chlorophenylbiguanide readily competed with (125)I-epibatidine binding to 5 HT(3)Rs. Nicotine was a poor competitor for (125)I-epibatidine binding to 5 HT(3)Rs. However, the noncompetitive nAChR antagonist mecamylamine acted as a potent competitive inhibitor of (125)I-epibatidine binding to 5-HT(3)Rs. Epibatidine inhibited serotonin-induced currents mediated by endogenous 5-HT(3)Rs in neuroblastoma cell lines and 5-HT(3A)Rs expressed in HEK cells in a competitive manner. Our results demonstrate that 5-HT(3)Rs are previously uncharacterized high affinity epibatidine binding sites in the brain and indicate that epibatidine and mecamylamine act as 5-HT(3)R antagonists. Previous studies that depended on epibatidine and mecamylamine as nAChR-specific ligands, in particular studies of analgesic properties of epibatidine, may need to be reinterpreted with respect to the potential role of 5-HT(3)Rs. PMID- 17702742 TI - A role for myosin 1e in cortical granule exocytosis in Xenopus oocytes. AB - Xenopus oocytes undergo dynamic structural changes during maturation and fertilization. Among these, cortical granule exocytosis and compensatory endocytosis provide effective models to study membrane trafficking. This study documents an important role for myosin 1e in cortical granule exocytosis. Myosin 1e is expressed at the earliest stage that cortical granule exocytosis can be detected in oocytes. Prior to exocytosis, myosin 1e relocates to the surface of cortical granules. Overexpression of myosin 1e augments the kinetics of cortical granule exocytosis, whereas tail-derived fragments of myosin 1e inhibit this secretory event (but not constitutive exocytosis). Finally, intracellular injection of myosin 1e antibody inhibits cortical granule exocytosis. Further experiments identified cysteine string proteins as interacting partners for myosin 1e. As constituents of the membrane of cortical granules, cysteine string proteins are also essential for cortical granule exocytosis. Future investigation of the link between myosin 1e and cysteine string proteins should help to clarify basic mechanisms of regulated exocytosis. PMID- 17702743 TI - Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC 1alpha muscle-specific knock-out animals. AB - The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) is a key integrator of neuromuscular activity in skeletal muscle. Ectopic expression of PGC-1alpha in muscle results in increased mitochondrial number and function as well as an increase in oxidative, fatigue resistant muscle fibers. Whole body PGC-1alpha knock-out mice have a very complex phenotype but do not have a marked skeletal muscle phenotype. We thus analyzed skeletal muscle-specific PGC-1alpha knock-out mice to identify a specific role for PGC-1alpha in skeletal muscle function. These mice exhibit a shift from oxidative type I and IIa toward type IIx and IIb muscle fibers. Moreover, skeletal muscle-specific PGC-1alpha knock-out animals have reduced endurance capacity and exhibit fiber damage and elevated markers of inflammation following treadmill running. Our data demonstrate a critical role for PGC-1alpha in maintenance of normal fiber type composition and of muscle fiber integrity following exertion. PMID- 17702744 TI - Myoferlin regulates vascular endothelial growth factor receptor-2 stability and function. AB - Myoferlin and dysferlin are members of the ferlin family of membrane proteins. Recent studies have shown that mutation or genetic disruption of myoferlin or dysferlin promotes muscular dystrophy-related phenotypes in mice, which are the result of impaired plasma membrane integrity. However, no biological functions have been ascribed to myoferlin in non-muscle tissues. Herein, using a proteomic analysis of endothelial cell (EC) caveolae/lipid raft microdomains we identified myoferlin in these domains and show that myoferlin is highly expressed in ECs and vascular tissues. The loss of myoferlin results in lack of proliferation, migration, and nitric oxide (NO) release in response to vascular endothelial growth factor (VEGF). Western blotting and surface biotinylation experiments show that loss of myoferlin reduces the expression level and autophosphorylation of VEGF receptor-2 (VEGFR-2) in native ECs. In a reconstituted cell system, transfection of myoferlin increases VEGFR-2 membrane expression and autophosphorylation in response to VEGF. In vivo, VEGFR-2 levels and VEGF-induced permeability are impaired in myoferlin-deficient mice. Mechanistically, myoferlin forms a complex with dynamin-2 and VEGFR-2, which prevents CBL-dependent VEGFR-2 polyubiquitination and proteasomal degradation. These data are the first to report novel biological activities for myoferlin and reveal the role of membrane integrity to VEGF signaling. PMID- 17702745 TI - Regulation of ephexin1, a guanine nucleotide exchange factor of Rho family GTPases, by fibroblast growth factor receptor-mediated tyrosine phosphorylation. AB - Fibroblast growth factor (FGF) signal is implicated in not only cell proliferation, but cell migration and morphological changes. Several different Rho family GTPases downstream of the Ras/ERK pathway are postulated to mediate the latter functions. However, none have been recognized to be directly coupled to FGF receptors (FGFRs). We have previously reported that EphA4 and FGFRs hetero oligomerize through their cytoplasmic domains, trans-activate each other, and transduce a signal for cell proliferation through a docking protein, FRS2alpha (Yokote, H., Fujita, K., Jing, X., Sawada, T., Liang, S., Yao, L., Yan, X., Zhang, Y., Schlessinger, J., and Sakaguchi, K. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 18866-18871). Here, we have found that ephexin1, a guanine nucleotide exchange factor for Rho family GTPases, constitutes another downstream component of the receptor complex. Ephexin1 directly binds to the kinase domain of FGFR mainly through its DH and PH domains. The binding appears to become weaker and limited to the DH domain when FGFRs become activated. FGFR-mediated phosphorylation of ephexin1 enhances the guanine nucleotide exchange activity toward RhoA without affecting the activity to Rac1 or Cdc42. The FGFR-mediated tyrosine phosphorylation includes, but is not limited to, the residue (Tyr-87) phosphorylated by Src family kinase, which is known to be activated following EphA4 activation. The Tyr-to-Asp mutations that mimic the tyrosine phosphorylation in some of the putative FGFR-mediated phosphorylation sites increase the nucleotide exchange activity for RhoA without changing the activity for Rac1 or Cdc42. From these results, we conclude that ephexin1 is located immediately downstream of the EphA4-FGFR complex and the function is altered by the FGFR-mediated tyrosine phosphorylation at multiple sites. PMID- 17702747 TI - Mechanistic roles of leptin in osteogenic stimulation in thoracic ligament flavum cells. AB - Obesity is a risk factor for thoracic ossification of ligament flavum (TOLF) that is characterized by ectopic bone formation in the spinal ligaments. Hyperleptinemia is a common feature of obese people, and leptin, an adipocyte derived cytokine with proliferative and osteogenic effects in several cell types, is believed to be an important factor in the pathogenesis of TOLF. However, how leptin might stimulate cell osteogenic differentiation in TOLF is not totally understood. We reported here that leptin-induced osteogenic effect in TOLF cells is associated with activation of signaling molecules STAT3, JNK, and ERK1/2 but not p38. Blocking STAT3 phosphorylation with a selective inhibitor, AG490, significantly abolished leptin-induced osteogenic differentiation of TOLF cells, whereas blocking ERK1/2 and JNK phosphorylation with their selective inhibitors PD98059 and SP600125, respectively, had only marginal effects. In addition, we showed that STAT3 interacted with Runt-related transcription factor 2 (Runx2) in the nucleus, and STAT3, Runx2, and steroid receptor coactivator steroid receptor coactivator-1 were components of the transcription complex recruited on Runx2 target gene promoters in response to leptin treatment. Our experiments identified STAT3, Runx2, and steroid receptor coactivator-1 as critical molecules in mediating leptin-stimulated cell osteogenesis in TOLF. PMID- 17702746 TI - CD44 regulates hepatocyte growth factor-mediated vascular integrity. Role of c Met, Tiam1/Rac1, dynamin 2, and cortactin. AB - The preservation of vascular endothelial cell (EC) barrier integrity is critical to normal vessel homeostasis, with barrier dysfunction being a feature of inflammation, tumor angiogenesis, atherosclerosis, and acute lung injury. Therefore, agents that preserve or restore vascular integrity have important therapeutic implications. In this study, we explored the regulation of hepatocyte growth factor (HGF)-mediated enhancement of EC barrier function via CD44 isoforms. We observed that HGF promoted c-Met association with CD44v10 and recruitment of c-Met into caveolin-enriched microdomains (CEM) containing CD44s (standard form). Treatment of EC with CD44v10-blocking antibodies inhibited HGF mediated c-Met phosphorylation and c-Met recruitment to CEM. Silencing CD44 expression (small interfering RNA) attenuated HGF-induced recruitment of c-Met, Tiam1 (a Rac1 exchange factor), cortactin (an actin cytoskeletal regulator), and dynamin 2 (a vesicular regulator) to CEM as well as HGF-induced trans-EC electrical resistance. In addition, silencing Tiam1 or dynamin 2 reduced HGF induced Rac1 activation, cortactin recruitment to CEM, and EC barrier regulation. We observed that both HGF- and high molecular weight hyaluronan (CD44 ligand) mediated protection from lipopolysaccharide-induced pulmonary vascular hyperpermeability was significantly reduced in CD44 knock-out mice, thus validating these in vitro findings in an in vivo murine model of inflammatory lung injury. Taken together, these results suggest that CD44 is an important regulator of HGF/c-Met-mediated in vitro and in vivo barrier enhancement, a process with essential involvement of Tiam1, Rac1, dynamin 2, and cortactin. PMID- 17702748 TI - A ferritin-responsive internal ribosome entry site regulates folate metabolism. AB - Cytoplasmic serine hydroxymethyltransferase (cSHMT) enzyme levels are elevated by the expression of the heavy chain ferritin (H ferritin) cDNA in cultured cells without corresponding changes in mRNA levels, resulting in enhanced folate dependent de novo thymidylate biosynthesis and impaired homocysteine remethylation. In this study, the mechanism whereby H ferritin regulates cSHMT expression was determined. cSHMT translation is shown to be regulated by an H ferritin-responsive internal ribosome entry site (IRES) located within the cSHMT mRNA 5'-untranslated region (5'-UTR). The cSHMT 5'-UTR exhibited IRES activity during in vitro translation of bicistronic mRNA templates, and in MCF-7 and HeLa cells transfected with bicistronic mRNAs. IRES activity was depressed in H ferritin-deficient mouse embryonic fibroblasts and elevated in cells expressing the H ferritin cDNA. H ferritin was shown to interact with the mRNA-binding protein CUGBP1, a protein known to interact with the alpha and beta subunits of eukaryotic initiation factor eIF2. Small interference RNA-mediated depletion of CUGBP1 decreased IRES activity from bicistronic templates that included the cSHMT 3'-UTR in the bicistronic construct. The identification of this H ferritin responsive IRES represents a mechanism that accounts for previous observations that H ferritin regulates folate metabolism. PMID- 17702749 TI - The UT-A1 urea transporter interacts with snapin, a SNARE-associated protein. AB - The UT-A1 urea transporter mediates rapid transepithelial urea transport across the inner medullary collecting duct and plays a major role in the urinary concentrating mechanism. To transport urea, UT-A1 must be present in the plasma membrane. The purpose of this study was to screen for UT-A1-interacting proteins and to study the interactions of one of the identified potential binding partners with UT-A1. Using a yeast two-hybrid screen of a human kidney cDNA library with the UT-A1 intracellular loop (residues 409-594) as bait, we identified snapin, a ubiquitously expressed SNARE-associated protein, as a novel UT-A1 binding partner. Deletion analysis indicated that the C-terminal coiled-coil domain (H2) of snapin is required for UT-A1 interaction. Snapin binds to the intracellular loop of UT-A1 but not to the N- or C-terminal fragments. Glutathione S transferase pulldown experiments and co-immunoprecipitation studies verified that snapin interacts with native UT-A1, SNAP23, and syntaxin-4 (t-SNARE partners), indicating that UT-A1 participates with the SNARE machinery in rat kidney inner medulla. Confocal microscopic analysis of immunofluorescent UT-A1 and snapin showed co-localization in both the cytoplasm and in the plasma membrane. When we co-injected UT-A1 with snapin cRNA in Xenopus oocytes, urea influx was significantly increased. In the absence of snapin, the influx was decreased when UT-A1 was combined with t-SNARE components syntaxin-4 and SNAP23. We conclude that UT-A1 may be linked to the SNARE machinery via snapin and that this interaction may be functionally and physiologically important for urea transport. PMID- 17702750 TI - Long-acting kappa opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase. AB - Norbinaltorphimine (NorBNI), guanidinonaltrindole, and atrans-(3R,4R)-dimethyl-4 (3-hydroxyphenyl) piperidine (JDTic) are selective kappa opioid receptor (KOR) antagonists having very long durations of action in vivo despite binding non covalently in vitro and having only moderately high affinities. Consistent with this, we found that antagonist treatment significantly reduced the subsequent analgesic response of mice to the KOR agonist U50,488 in the tail-withdrawal assay for 14-21 days. Receptor protection assays were designed to distinguish between possible explanations for this anomalous effect, and we found that mice pretreated with the readily reversible opioid antagonists naloxone or buprenorphine before norBNI responded strongly in the tail-flick analgesia assay to a subsequent challenge with U50,488 1 week later. Protection by a rapidly cleared reagent indicates that norBNI did not persist at the site of action. In vitro binding of [(3)H]U69,593 to KOR showed that K(d) and Bmax values were not significantly affected by prior in vivo norBNI exposure, indicating that the agonist binding site was intact. Consistent with the concept that the long lasting effects might be caused by a functional disruption of KOR signaling, both norBNI and JDTic were found to stimulate c-Jun N-terminal kinase (JNK) phosphorylation in HEK293 cells expressing KOR-GFP but not in untransfected cells. Similarly, norBNI increased phospho-JNK in both the striatum and spinal cord in wild type mice but not in KOR knock-out mice. Pretreatment of mice with the JNK inhibitor SP600125 before norBNI attenuated the long acting antagonism. Together, these results suggest that the long duration KOR antagonists disrupt KOR signaling by activating JNK. PMID- 17702751 TI - The oxidase DsbA folds a protein with a nonconsecutive disulfide. AB - One of the last unsolved problems of molecular biology is how the sequential amino acid information leads to a functional protein. Correct disulfide formation within a protein is hereby essential. We present periplasmic ribonuclease I (RNase I) from Escherichia coli as a new endogenous substrate for the study of oxidative protein folding. One of its four disulfides is between nonconsecutive cysteines. In general view, the folding of proteins with nonconsecutive disulfides requires the protein disulfide isomerase DsbC. In contrast, our study with RNase I shows that DsbA is a sufficient catalyst for correct disulfide formation in vivo and in vitro. DsbA is therefore more specific than generally assumed. Further, we show that the redox potential of the periplasm depends on the presence of glutathione and the Dsb proteins to maintain it at-165 mV. We determined the influence of this redox potential on the folding of RNase I. Under the more oxidizing conditions of dsb(-) strains, DsbC becomes necessary to correct non-native disulfides, but it cannot substitute for DsbA. Altogether, DsbA folds a protein with a nonconsecutive disulfide as long as no incorrect disulfides are formed. PMID- 17702753 TI - Mapping the interacting domains of STIM1 and Orai1 in Ca2+ release-activated Ca2+ channel activation. AB - STIM1 and Orai1 are essential components of Ca(2+) release-activated Ca(2+) channels (CRACs). After endoplasmic reticulum Ca(2+) store depletion, STIM1 in the endoplasmic reticulum aggregates and migrates toward the cell periphery to co localize with Orai1 on the opposing plasma membrane. Little is known about the roles of different domains of STIM1 and Orai1 in protein clustering, migration, interaction, and, ultimately, opening CRAC channels. Here we demonstrate that the coiled-coil domain in the C terminus of STIM1 is crucial for its aggregation. Amino acids 425-671 of STIM1, which contain a serine-proline-rich region, are important for the correct targeting of the STIM1 cluster to the cell periphery after calcium store depletion. The polycationic region in the C-terminal tail of STIM1 also helps STIM1 targeting but is not essential for CRAC channel activation. The cytoplasmic C terminus but not the N terminus of Orai1 is required for its interaction with STIM1. We further identify a highly conserved region in the N terminus of Orai1 (amino acids 74-90) that is necessary for CRAC channel opening. Finally, we show that the transmembrane domain of Orai1 participates in Orai1-Orai1 interactions. PMID- 17702752 TI - Purification, sequencing, and molecular identification of a mammalian PP-InsP5 kinase that is activated when cells are exposed to hyperosmotic stress. AB - Mammalian cells utilize multiple signaling mechanisms to protect against the osmotic stress that accompanies plasma membrane ion transport, solute uptake, and turnover of protein and carbohydrates (Schliess, F., and Haussinger, D. (2002) Biol. Chem. 383, 577-583). Recently, osmotic stress was found to increase synthesis of bisdiphosphoinositol tetrakisphosphate ((PP)2-InsP4), a high energy inositol pyrophosphate (Pesesse, X., Choi, K., Zhang, T., and Shears, S. B. (2004) J. Biol. Chem. 279, 43378-43381). Here, we describe the purification from rat brain of a diphosphoinositol pentakisphosphate kinase (PPIP5K) that synthesizes (PP)2-InsP4. Partial amino acid sequence, obtained by mass spectrometry, matched the sequence of a 160-kDa rat protein containing a putative ATP-grasp kinase domain. BLAST searches uncovered two human isoforms (PPIP5K1 (160 kDa) and PPIP5K2 (138 kDa)). Recombinant human PPIP5K1, expressed in Escherichia coli, was found to phosphorylate diphosphoinositol pentakisphosphate (PP-InsP5) to (PP)2-InsP4 (Vmax = 8.3 nmol/mg of protein/min; Km = 0.34 microM). Overexpression in human embryonic kidney cells of either PPIP5K1 or PPIP5K2 substantially increased levels of (PP)2-InsP4, whereas overexpression of a catalytically dead PPIP5K1(D332A) mutant had no effect. PPIP5K1 and PPIP5K2 were more active against PP-InsP5 than InsP6, both in vitro and in vivo. Analysis by confocal immunofluorescence showed PPIP5K1 to be distributed throughout the cytoplasm but excluded from the nucleus. Immunopurification of overexpressed PPIP5K1 from osmotically stressed HEK cells (0.2 M sorbitol; 30 min) revealed a persistent, 3.9 +/- 0.4-fold activation when compared with control cells. PPIP5Ks are likely to be important signaling enzymes. PMID- 17702755 TI - Purification, cloning, and expression of an alpha/beta-galactoside alpha-2,3 sialyltransferase from a luminous marine bacterium, Photobacterium phosphoreum. AB - A novel sialyltransferase, alpha/beta-galactoside alpha-2,3-sialyltransferase, was purified from the cell lysate of a luminous marine bacterium, Photobacterium phosphoreum JT-ISH-467, isolated from the Japanese common squid (Todarodes pacificus). The gene encoding the enzyme was cloned from the genomic library of the bacterium using probes derived from the NH(2)-terminal and internal amino acid sequences. An open reading frame of 409 amino acids was identified, and the sequence had 32% identity with that of beta-galactoside alpha-2,6 sialyltrasferase in Photobacterium damselae JT0160. DNA fragments that encoded the full-length protein and a protein that lacked the sequence between the 2nd and 24th residues at the NH(2) terminus were amplified by polymerase chain reactions and cloned into an expression vector. The full-length and truncated proteins were expressed in Escherichia coli, producing active enzymes of 0.25 and 305 milliunits, respectively, per milliliter of the medium in the lysate of E. coli. The truncated enzyme was much more soluble without detergent than the full length enzyme. The enzyme catalyzed the transfer of N-acetylneuraminic acid from CMP-N-acetylneuraminic acid to disaccharides, such as lactose and N acetyllactosamine, with low apparent K(m) and to monosaccharides, such as alpha methyl-galactopyranoside and beta-methyl-galactopyranoside, with much lower apparent K(m). Thus, this sialyltransferase is unique and should be very useful for achieving high productivity in E. coli with a wide substrate range. PMID- 17702754 TI - Pro-apoptotic Bim induction in response to nerve growth factor deprivation requires simultaneous activation of three different death signaling pathways. AB - Bim is a pro-apoptotic member of the Bcl-2 family that is induced and contributes to neuron death in response to nerve growth factor (NGF) deprivation. Past work has revealed that Bim is downstream of multiple independent transcriptional pathways in neurons, including those culminating in activation of the c-Jun, FoxO, and Myb transcription factors. This study addresses the issue of whether the three signaling pathways are redundant with respect to Bim induction or whether they act cooperatively. Examination of the proximal Bim promoter reveals binding sites for FoxO, Mybs, and, as shown here, c-Jun. We find that mutation of any one of these types of sites abolishes induction of a Bim promoter-driven reporter in response to NGF deprivation. Moreover, down-regulation of either c Jun, FoxOs, or Mybs by short hairpin RNAs blocks induction of Bim promoter reporter activity triggered by withdrawal of NGF. This was the case for reporters driven by either the proximal promoter or a promoter that also includes additional regulatory elements in the first intron of the Bim gene. Such short hairpin RNAs also suppressed the induction of endogenous Bim protein. These findings thus indicate that the Bim promoter acts as a coincidence detector that optimally responds to the simultaneous activation of three different pro apoptotic transcriptional pathways. Such a mechanism provides a "fail-safe" that prevents neurons from dying by accidental activation of any single pathway. It also permits neurons to utilize individual pathways such as JNK signaling for other purposes without risk of demise. PMID- 17702756 TI - Translocation of a phycoerythrin alpha subunit across five biological membranes. AB - Cryptophytes, unicellular algae, evolved by secondary endosymbiosis and contain plastids surrounded by four membranes. In contrast to cyanobacteria and red algae, their phycobiliproteins do not assemble into phycobilisomes and are located within the thylakoid lumen instead of the stroma. We identified two gene families encoding phycoerythrin alpha and light-harvesting complex proteins from an expressed sequence tag library of the cryptophyte Guillardia theta. The proteins bear a bipartite topogenic signal responsible for the transport of nuclear encoded proteins via the ER into the plastid. Analysis of the phycoerythrin alpha sequences revealed that more than half of them carry an additional, third topogenic signal comprising a twin arginine motif, which is indicative of Tat (twin arginine transport)-specific targeting signals. We performed import studies with several derivatives of one member using a diatom transformation system, as well as intact chloroplasts and thylakoid vesicles isolated from pea. We demonstrated the different targeting properties of each individual part of the tripartite leader and show that phycoerythrin alpha is transported across the thylakoid membrane into the thylakoid lumen and protease protected. Furthermore, we showed that thylakoid transport of phycoerythrin alpha takes place by the Tat pathway even if the 36 amino acid long bipartite topogenic signal precedes the actual twin arginine signal. This is the first experimental evidence of a protein being targeted across five biological membranes. PMID- 17702757 TI - DNA polymerase proofreading: active site switching catalyzed by the bacteriophage T4 DNA polymerase. AB - DNA polymerases achieve high-fidelity DNA replication in part by checking the accuracy of each nucleotide that is incorporated and, if a mistake is made, the incorrect nucleotide is removed before further primer extension takes place. In order to proofread, the primer-end must be separated from the template strand and transferred from the polymerase to the exonuclease active center where the excision reaction takes place; then the trimmed primer-end is returned to the polymerase active center. Thus, proofreading requires polymerase-to-exonuclease and exonuclease-to-polymerase active site switching. We have used a fluorescence assay that uses differences in the fluorescence intensity of 2-aminopurine (2AP) to measure the rates of active site switching for the bacteriophage T4 DNA polymerase. There are three findings: (i) the rate of return of the trimmed primer-end from the exonuclease to the polymerase active center is rapid, >500 s( 1); (ii) T4 DNA polymerase can remove two incorrect nucleotides under single turnover conditions, which includes presumed exonuclease-to-polymerase and polymerase-to-exonuclease active site switching steps and (iii) proofreading reactions that initiate in the polymerase active center are not intrinsically processive. PMID- 17702758 TI - One step construction of PCR mutagenized libraries for genetic analysis by recombination cloning. AB - Recombination cloning encompasses a set of technologies that transfer gene sequences between vectors through site-specific recombination. Due in part to the instability of linear DNA in bacteria, both the initial capture and subsequent transfer of gene sequences is often performed using purified recombination enzymes. However, we find linear DNAs flanked by loxP sites recombine efficiently in bacteria expressing Cre recombinase and the lambda Gam protein, suggesting Cre/lox recombination of linear substrates can be performed in vivo. As one approach towards exploiting this capability, we describe a method for constructing large (>1 x 10(6) recombinants) libraries of gene mutations in a format compatible with recombination cloning. In this method, gene sequences are cloned into recombination entry plasmids and whole-plasmid PCR is used to produce mutagenized plasmid amplicons flanked by loxP. The PCR products are converted back into circular plasmids by transforming Cre/Gam-expressing bacteria, after which the mutant libraries are transferred to expression vectors and screened for phenotypes of interest. We further show that linear DNA fragments flanked by loxP repeats can be efficiently recombined into loxP-containing vectors through this same one-step transformation procedure. Thus, the approach reported here could be adapted as general cloning method. PMID- 17702759 TI - Repeat-associated siRNAs cause chromatin silencing of retrotransposons in the Drosophila melanogaster germline. AB - Silencing of genomic repeats, including transposable elements, in Drosophila melanogaster is mediated by repeat-associated short interfering RNAs (rasiRNAs) interacting with proteins of the Piwi subfamily. rasiRNA-based silencing is thought to be mechanistically distinct from both the RNA interference and microRNA pathways. We show that the amount of rasiRNAs of a wide range of retroelements is drastically reduced in ovaries and testes of flies carrying a mutation in the spn-E gene. To address the mechanism of rasiRNA-dependent silencing of retrotransposons, we monitored their chromatin state in ovaries and somatic tissues. This revealed that the spn-E mutation causes chromatin opening of retroelements in ovaries, resulting in an increase in histone H3 K4 dimethylation and a decrease in histone H3 K9 di/trimethylation. The strongest chromatin changes have been detected for telomeric HeT-A elements that correlates with the most dramatic increase of their transcript level, compared to other mobile elements. The spn-E mutation also causes depletion of HP1 content in the chromatin of transposable elements, especially along HeT-A arrays. We also show that mutations in the genes controlling the rasiRNA pathway cause no derepression of the same retrotransposons in somatic tissues. Our results provide evidence that germinal Piwi-associated short RNAs induce chromatin modifications of their targets. PMID- 17702761 TI - Biochemical reconstitution of abasic DNA lesion replication in Xenopus extracts. AB - Cellular DNA is under constant attack from numerous exogenous and endogenous agents. The resulting DNA lesions, if not repaired timely, could stall DNA replication, leading to genome instability. To better understand the mechanism of DNA lesion replication at the biochemical level, we have attempted to reconstitute this process in Xenopus egg extracts, the only eukaryotic in vitro system that relies solely on cellular proteins for DNA replication. By using a plasmid DNA that carries a site-specific apurinic/apyrimidinic (AP) lesion as template, we have found that DNA replication is stalled one nucleotide before the lesion. The stalling is temporary and the lesion is eventually replicated by both an error-prone mechanism and an error-free mechanism. This is the first biochemical system that recapitulates efficiently and faithfully all major aspects of DNA lesion replication. It has provided the first direct evidence for the existence of an error-free lesion replication mechanism and also demonstrated that the error-prone mechanism is a major contributor to lesion replication. PMID- 17702760 TI - High-precision mapping of protein protein interfaces: an integrated genetic strategy combining en masse mutagenesis and DNA-level parallel analysis on a yeast two-hybrid platform. AB - Understanding networks of protein-protein interactions constitutes an essential component on a path towards comprehensive description of cell function. Whereas efficient techniques are readily available for the initial identification of interacting protein partners, practical strategies are lacking for the subsequent high-resolution mapping of regions involved in protein-protein interfaces. We present here a genetic strategy to accurately map interacting protein regions at amino acid precision. The system is based on parallel construction, sampling and analysis of a comprehensive insertion mutant library. The methodology integrates Mu in vitro transposition-based random pentapeptide mutagenesis of proteins, yeast two-hybrid screening and high-resolution genetic footprinting. The strategy is general and applicable to any interacting protein pair. We demonstrate the feasibility of the methodology by mapping the region in human JFC1 that interacts with Rab8A, and we show that the association is mediated by the Slp homology domain 1. PMID- 17702762 TI - Filtering genes to improve sensitivity in oligonucleotide microarray data analysis. AB - Many recent microarrays hold an enormous number of probe sets, thus raising many practical and theoretical problems in controlling the false discovery rate (FDR). Biologically, it is likely that most probe sets are associated with un-expressed genes, so the measured values are simply noise due to non-specific binding; also many probe sets are associated with non-differentially-expressed (non-DE) genes. In an analysis to find DE genes, these probe sets contribute to the false discoveries, so it is desirable to filter out these probe sets prior to analysis. In the methodology proposed here, we first fit a robust linear model for probe level Affymetrix data that accounts for probe and array effects. We then develop a novel procedure called FLUSH (Filtering Likely Uninformative Sets of Hybridizations), which excludes probe sets that have statistically small array effects or large residual variance. This filtering procedure was evaluated on a publicly available data set from a controlled spiked-in experiment, as well as on a real experimental data set of a mouse model for retinal degeneration. In both cases, FLUSH filtering improves the sensitivity in the detection of DE genes compared to analyses using unfiltered, presence-filtered, intensity-filtered and variance-filtered data. A freely-available package called FLUSH implements the procedures and graphical displays described in the article. PMID- 17702763 TI - Vir-Mir db: prediction of viral microRNA candidate hairpins. AB - MicroRNAs have been found in various organisms and play essential roles in gene expression regulation of many critical cellular processes. Large-scale computational prediction of miRNAs has been conducted for many organisms using known genomic sequences; however, there has been no such effort for the thousands of known viral genomes. Some viruses utilize existing host cellular pathways for their own benefit. Furthermore, viruses are capable of encoding miRNAs and using them to repress host genes. Thus, identifying potential miRNAs in all viral genomes would be valuable to virologists who study virus-host interactions. Based on our previously reported hairpin secondary structure and feature selection filters, we have examined the 2266 available viral genome sequences for putative miRNA hairpins and identified 33 691 hairpin candidates in 1491 genomes. Evaluation of the system performance indicated that our discovery pipeline exhibited 84.4% sensitivity. We established an interface for users to query the predicted viral miRNA hairpins based on taxonomic classification, and a host target gene prediction service based on the RNAhybrid program and the 3'-UTR gene sequences of human, mouse, rat, zebrafish, rice and Arabidopsis. The viral miRNA prediction database (Vir-Mir) can be accessed via http://alk.ibms.sinica.edu.tw. PMID- 17702764 TI - A randomized library approach to identifying functional lox site domains for the Cre recombinase. AB - The bacteriophage P1 Cre/loxP site-specific recombination system is a useful tool in a number of genetic engineering processes. The Cre recombinase has been shown to act on DNA sequences that vary considerably from that of its bacteriophage recognition sequence, loxP. However, little is known about the sequence requirements for functional lox-like sequences. In this study, we have implemented a randomized library approach to identify the sequence characteristics of functional lox site domains. We created a randomized spacer library and a randomized arm library, and then tested them for recombination in vivo and in vitro. Results from the spacer library show that, while there is great plasticity, identity between spacer pairs is the most important factor influencing function, especially in in vitro reactions. The presence of one completely randomized arm in a functional loxP recombination reaction revealed that only three wild-type loxP arms are necessary for successful recombination in Cre-expressing bacteria, and that there are nucleotide preferences at the first three and last three positions of the randomized arm for the most efficiently recombined sequences. Finally, we found that in vitro Cre recombination reactions are much more stringent for evaluating which sequences can support efficient recombination compared to the 294-CRE system. PMID- 17702765 TI - Muscleblind-like 1 interacts with RNA hairpins in splicing target and pathogenic RNAs. AB - The MBNL and CELF proteins act antagonistically to control the alternative splicing of specific exons during mammalian postnatal development. This process is dysregulated in myotonic dystrophy because MBNL proteins are sequestered by (CUG)n and (CCUG)n RNAs expressed from mutant DMPK and ZNF9 genes, respectively. While these observations predict that MBNL proteins have a higher affinity for these pathogenic RNAs versus their normal splicing targets, we demonstrate that MBNL1 possesses comparably high affinities for (CUG)n and (CAG)n RNAs as well as a splicing target, Tnnt3. Mapping of a MBNL1-binding site upstream of the Tnnt3 fetal exon indicates that a preferred binding site for this protein is a GC-rich RNA hairpin containing a pyrimidine mismatch. To investigate how pathogenic RNAs sequester MBNL1 in DM1 cells, we used a combination of chemical/enzymatic structure probing and electron microscopy to determine that MBNL1 forms a ring like structure which binds to the dsCUG helix. While the MBNL1 N-terminal region is required for RNA binding, the C-terminal region mediates homotypic interactions which may stabilize intra- and/or inter-ring interactions. Our results provide a mechanistic basis for dsCUG-induced MBNL1 sequestration and highlight a striking similarity in the binding sites for MBNL proteins on splicing precursor and pathogenic RNAs. PMID- 17702766 TI - Protein/DNA arrays identify nitric oxide-regulated cis-element and trans-factor activities some of which govern neuroblastoma cell viability. AB - Toxic nitric oxide (NO) levels can regulate gene expression. Using a novel protein/DNA array, we show that toxic NO levels regulate the binding of trans factors to various cis-elements in neuroblastoma cells, including CRE and those recognized by the transcription factors AP1, AP2, Brn-3a, EGR, E2F1 and SP1. Functionality of some of the cis-elements was confirmed by electro mobility shift and reporter assays. Interestingly, CREB, AP-1, Brn-3a, EGR and E2F1 can control mammalian cell viability. NO induced the anti-apoptotic Bcl-2 protein and its mRNA prior to the onset of death of 30-60% of the cells. Promoter analysis of the bcl-2 gene confirmed the involvement of a CRE in NO-dependent bcl-2 transcription. Neuroblastoma cells over-expressing bcl-2 became much more resistant to NO-induced apoptosis; conversely, Bcl-2 knockdown cells were rendered markedly more sensitive to NO. Together these results suggest that Bcl-2 counteracts NO-induced apoptosis in a fraction of the cell population. Thus, NO stimulates the binding of many trans-factors to their cognate cis-elements, some of which can regulate cell viability through transcriptional activation of target genes. Our results emphasize that a DNA/protein array approach can reveal novel, global transcription factor activities stimulated by cell death-regulating molecules. PMID- 17702767 TI - Avoiding false-positive signals with nuclease-vulnerable molecular beacons in single living cells. AB - There have been a growing number of studies where molecular beacons (MBs) are used to image RNA expression in living cells; however, the ability to make accurate measurements can be hampered by the generation of false-positive signals resulting from non-specific interactions and/or nuclease degradation. In the present study, we found that such non-specific signals only arise in the nucleus of living cells. When MBs are retained in the cytoplasmic compartment, by linking them to quantum dots (QDs), false-positive signals are reduced to marginal levels. Consequently, MB-QD conjugates were used to measure the expression of the endogenous proto-oncogene c-myc in MCF-7 breast cancer cells by quantifying the total fluorescent signal emanating from individual cells. Upon the addition of tamoxifen, measurements of MB fluorescence indicated a 71% reduction in c-myc expression, which correlated well with RT-PCR measurements. Variations in MB fluorescence resulting from instrumental fluctuations were accounted for by imaging fluorescent calibration standards on a daily basis. Further, it was established that measurements of the total fluorescent signal were not sensitive to the focal plane. Overall, these results provide evidence that accurate measurements of RNA levels can be made when MBs are retained in the cytoplasm. PMID- 17702769 TI - Systemic inflammation as a risk factor for atherothrombosis. AB - Several chronic inflammatory disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and chronic infections that are associated with a chronic inflammatory state, such as human immunodeficiency virus (HIV) infection, are associated with an increased incidence of cardiovascular disease (CVD). Cardiovascular mortality is a major cause of death in patients with these disorders. Direct effects and indirect sequelae of systemic inflammation promote atherothrombotic vascular disease. Pathophysiological processes promoting atherogenesis can initiate years before the diagnosis of a chronic inflammatory disease is made, and since exposure to risk factors in this pre-clinical phase is widespread, early cardiovascular protection in these patients seems warranted. PMID- 17702768 TI - Vitamin D supplementation to prevent infections: a sub-study of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438). PMID- 17702770 TI - Efficacy and safety of interferon-alpha in the treatment of corticodependent uveitis of paediatric Behcet's disease. AB - OBJECTIVE: To report both the efficacy and safety of interferon-alpha-2a (IFN alpha) therapy in corticodependent uveitis of paediatric Behcet's disease (BD). METHODS: Data from seven children affected with corticodependent uveitis of BD and treated with IFN-alpha were reviewed retrospectively. IFN-alpha was injected sub-cutaneously thrice a week at dosages of 1.5-3 M(ons) IU according to the children's weight. Efficacy was judged on the ability of IFN-alpha to induce a corticosteroid (CS)-sparing effect while maintaining remission. All adverse events (AE) were recorded. RESULTS: The children included four boys and three girls. Mean age at onset of uveitis was 8.6 yrs and mean follow-up duration was 7.14 yrs. All children had a high level of corticodependence and five of them received additional DMARDs. A remarkable CS-sparing effect with remission maintenance was achieved in 5 out of 7 patients after a mean period of 14.6 months of IFN-alpha administration. The remission was sustained in four of the five patients (mean = 4.8 yrs), even after IFN-alpha was discontinued in three of them. The other patient relapsed 1.5 yrs after IFN-alpha discontinuation. The last two patients faced early severe adverse events attributed to IFN-alpha: retinal venous thrombosis and major depression. CONCLUSION: IFN-alpha has a potent CS-sparing effect in paediatric BD patients suffering from severe uveitis. However, the possibility of major side-effects with this treatment calls for careful monitoring. PMID- 17702771 TI - Geographical and demographic clustering of gonorrhoea in London. AB - BACKGROUND: Gonorrhoea is an important cause of sexual ill health and is concentrated in geographical areas and demographic groups. This study explores the distribution of gonorrhoea across London. METHODS: Epidemiological data on all gonorrhoea cases were collected from 13 major genitourinary clinics in London between 1 June and 30 November 2004. Samples were stored centrally and typed using NG-MAST. The postcode of each case's main residence was used to calculate incidence of gonorrhoea by borough using data from the UK 2001 census and a population survey on residence of men who have sex with men (MSM). RESULTS: 2,891 cases were confirmed, 1,822 of which had postcode data, resided in London, and had their strain successfully typed. There was a very high incidence of gonorrhoea in MSM (1,834 per 100,000 population) and heterosexuals of black ethnicity (392 per 100,000). The incidence among heterosexuals was highest in City of London (390 per 100,000, 95% CI 213 to 566), Southwark (308 per 100,000, 95% CI 280 to 336), Hackney (284 per 100,000, 95% CI 254 to 313), and Lambeth (216 per 100,000, 95% CI 194 to 239) and was not associated with measures of social deprivation (correlation coefficient = 0.0008, p = 0.97) but was strongly associated with black ethnicity (correlation coefficient = 0.48, p = 0.01). 45% of cases had one of the 21 major strains; eight of these strains were significantly clustered geographically and persisted for a shorter duration than those that were not clustered. Patients travelled a mean of 7.7 km from their home to the clinic. CONCLUSIONS: High gonorrhoea incidence in London is observed in MSM and heterosexuals of black ethnicity. Endemic strains in both MSM and heterosexuals are diagnosed at multiple clinics. Interventions, including partner notification, must therefore operate between clinics. PMID- 17702772 TI - Mild traumatic brain injury does not predict acute postconcussion syndrome. AB - BACKGROUND: The aetiology of postconcussion syndrome (PCS) following mild traumatic brain injury (mTBI) remains controversial. Identifying acute PCS (within the first 14 days after injury) may optimise initial recovery and rehabilitation, identify those at risk and increase understanding of PCS. OBJECTIVE: To examine predictors of acute outcome by investigating the relationship between preinjury psychiatric disorder, demographic factors, injury related characteristics, neuropsychological and psychological variables and acute PCS. METHODS: Prospective study of consecutive trauma admissions to a level 1 trauma hospital. The final sample comprised 90 patients with mTBI and 85 non brain injured trauma controls. Individuals were administered a PCS checklist, and neuropsychological and psychological measures. Multiple imputation of missing data in multivariable logistic regression and bivariate logistic regressions were used to predict acute PCS at a mean of 4.90 days after injury. RESULTS: Diagnosis of acute PCS was not specific to mTBI (mTBI 43.3%; controls 43.5%). Pain was associated with acute PCS in mTBI. The strongest effect for acute PCS was a previous affective or anxiety disorder (OR 5.76, 95% CI 2.19 to 15.0). Females were 3.33 times more likely than males to have acute PCS (95% CI 1.20 to 9.21). The effect of acute post-traumatic stress and neuropsychological function on acute PCS was relatively small. Higher IQ was associated with acute PCS. CONCLUSIONS: There is a high rate of acute PCS in both mTBI and non-brain injured trauma patients. PCS was not found to be specific to mTBI. The use of the term PCS may be misleading as it incorrectly suggests that the basis of PCS is a brain injury. PMID- 17702773 TI - Understanding the psychiatric prodrome of Huntington disease. PMID- 17702774 TI - Progression of dystonia: learning from distorted feedback? PMID- 17702775 TI - Is there any such thing as a secondary generalised seizure? PMID- 17702776 TI - Neurological picture. FDG-PET in meningeal lymphomatosis. PMID- 17702777 TI - Observation of a nervous disease attended by disturbed sleep, at times lethargic and at times convulsive. Edme Chauvot de Beauchene (1786). PMID- 17702778 TI - Glucocerebrosidase gene mutation is a risk factor for early onset of Parkinson disease among Taiwanese. AB - BACKGROUND: Mutations in the glucocerebrosidase (GBA) gene have recently been identified as contributing to the development of Parkinson disease (PD) in Ashkenazi Jews. METHODS: To investigate whether this finding can be confirmed in a Taiwanese population, we conducted a case control study in a cohort of 518 PD patients and 339 controls for the three common GBA mutations in Taiwan, L444P, RecNciI and R120W, using PCR restriction enzyme assay and DNA sequencing. RESULTS: Heterozygous GBA mutations were detected in 16 PD patients (3.1%) and four controls (1.2%). Although this difference was not statistically significant (p = 0.0703), the average age at disease onset of the 16 PD patients (50.6 (12.3) years) was significantly younger than that of the total patient group (63.8 (10.5) years; p = 0.0007) and the non-carrier patient group (64.2 (10.2) years; p = 0.0005). After stratification by age, the frequency of mutation carriers was significantly higher for the early onset PD (EOPD, age at onset < or = 50 years) group than for age matched controls (12.9% vs 1.8%; p = 0.0335) and there was a trend towards an increased risk of the mutation carrier with EOPD (odds ratio 8.30; 95% CI 1.45 to 156.53). Clinically, all 16 patients carrying a GBA mutation presented with a typical parkinsonian phenotype and experienced a good or excellent response to levodopa. CONCLUSIONS: Mutations of the GBA gene may be associated with the development of EOPD in Taiwan. PMID- 17702779 TI - Sporadic adult onset dystonia: sensory abnormalities as an endophenotype in unaffected relatives. AB - BACKGROUND: Most patients with adult onset primary torsion dystonia (AOPTD) have the sporadic form of the disease. They may however be the only manifesting family members of a poorly penetrant genetic disorder. Sensory changes, including structural abnormalities of the primary sensory cortex, are found in AOPTD. Spatial discrimination threshold (SDT), a measure of sensory cortical organisation, is abnormal in AOPTD and in unaffected relatives of patients with familial AOPTD. Our hypothesis was that abnormal SDTs might be found in unaffected relatives of patients with sporadic AOPTD. METHODS: SDTs were assessed at the index finger bilaterally by a grating orientation task. Normal age related SDTs were derived from 141 control subjects aged 20-64 years. SDTs were considered abnormal when greater than 2.5 SD above the control mean. In total, 105 of 171 (61%) eligible unaffected siblings and offspring of patients with cervical dystonia had SDT examined. RESULTS: Fourteen of 48 siblings (29%) and 10 of 57 (18%) offspring were found to have an abnormal SDT. Only five of the 20 patients examined had abnormal SDTs. In 11 of the 25 families, no abnormality was found in an unaffected relative. In the 14 families where at least one unaffected relative had an abnormal SDT, 14 of 37 siblings (38%) and 10 of 33 offspring (30%) had abnormal SDTs. CONCLUSION: Sensory abnormalities found in unaffected relatives of patients with apparently sporadic AOPTD may be a surrogate marker for the carriage of an abnormal gene. PMID- 17702780 TI - Paraoxonase promoter and intronic variants modify risk of sporadic amyotrophic lateral sclerosis. AB - BACKGROUND: The paraoxonases, PON1-3, play a major protective role both against environmental toxins and as part of the antioxidant defence system. Recently, non synonymous coding single nucleotide polymorphisms (SNPs), known to lower serum PON activity, have been associated with sporadic ALS (SALS) in a Polish population. A separate trio based study described a detrimental allele at the PON3 intronic variant INS2+3651 (rs10487132). Association between PON gene cluster variants and SALS requires external validation in an independent dataset. AIMS: To examine the association of the promoter SNPs PON1(-162G>A) and PON1( 108T>C); the non-synonymous functional SNPs PON1(Q192R and L55M) and PON2(C311S and A148G); and the intronic marker PON3(INS2+3651A>G), with SALS in a genetically homogenous population. METHODS: 221 Irish patients with SALS and 202 unrelated control subjects were genotyped using KASPar chemistries. Statistical analyses and haplotype estimations were conducted using Haploview and Unphased software. Multiple permutation testing, as implemented in Unphased, was applied to haplotype p values to correct for multiple hypotheses. RESULTS: Two of the seven SNPs were associated with SALS in the Irish population: PON1(55M) (OR 1.52, p = 0.006) and PON3(INS2+3651 G) (OR 1.36, p = 0.03). Two locus haplotype analysis showed association only when both of these risk alleles were present (OR 1.7, p = 0.005), suggesting a potential effect modification. Low functioning promoter variants were observed to influence this effect when compared with wild type. CONCLUSIONS: These data provide additional evidence that genetic variation across the paroxanase loci may be common susceptibility factors for SALS. PMID- 17702781 TI - Lateral medullary ischaemic events in young adults with hypoplastic vertebral artery. AB - OBJECTIVE: To present three cases of young adults with lateral medullary ischaemic events associated with a hypoplastic vertebral artery (VA). All three patients had two additional atherosclerotic or non-atherosclerotic risk factors for stroke. PATIENTS AND METHODS: One female, aged 40 years, and two males, aged 38 and 37 years, each with two risk factors for stroke, presented to the emergency department with acute onset of symptoms and findings consistent with lateral medullary syndrome. All three patients underwent emergency CT scan of the brain followed by MRI and magnetic resonance angiography (MRA). RESULTS: The CT scans were negative in all patients. MRI revealed a lateral medullary lesion in only one patient. All three patients had a hypoplastic VA ipsilateral to the clinical ischaemic event on MRA. CONCLUSIONS: Hypoplasia of VA is not considered a risk factor for stroke as it is a common variant in up to 75% of the general population. However, in our patients, hypoplastic VA coexisted with two risk factors and resulted in stroke. Thus although a hypoplastic VA may not be an uncommon asymptomatic finding, it may contribute to stroke if additional risk factors are present. PMID- 17702782 TI - Anti-aquaporin 4 antibody in Japanese multiple sclerosis: the presence of optic spinal multiple sclerosis without long spinal cord lesions and anti-aquaporin 4 antibody. AB - BACKGROUND: Anti-aquaporin 4 (AQP4) antibodies were found in patients with neuromyelitis optica (NMO) and Japanese optic-spinal multiple sclerosis (OSMS). OBJECTIVE: To review the clinical features and investigate anti-AQP4 antibodies of Japanese patients with multiple sclerosis (MS), with or without long spinal cord lesions (LCL). METHODS: Anti-AQP4 antibodies were examined in the sera of 128 consecutive Japanese patients by the immunofluorescence method using AQP4 transfected cells. RESULTS: The 45 LCL-MS patients included 28 with a long spinal cord lesion extending contiguously over three vertebral segments on sagittal T2 weighted images (long T2 lesion) and 17 with segmental cord atrophy extending more than three vertebral segments. We identified 25 patients with anti-AQP4 antibody with LCL and anti-AQP4 antibody. Anti-AQP4 antibody was found in 12/17 (70.6%) LCL-MS patients with segmental cord atrophy, and in 13/28 (46.4%) LCL-MS patients without segmental long cord atrophy (p = 0.135, Fisher's exact test). Seropositive MS patients with LCL had more relapses than seronegative patients (p = 0.0004, Mann-Whitney U test). 9 patients with OSMS were negative for anti-AQP4 antibody who did not show LCL. CONCLUSION: These results suggest that an anti AQP4 antibody is found not only in MS patients with long T2 lesions but also in patients with segmental cord atrophy extending more than three vertebral segments. It is a marker of LCL-MS showing frequent exacerbations. Japanese OSMS cases comprised those that were identical to NMO cases and those that were more closely related to classic MS. PMID- 17702783 TI - Neuro-Sweet disease: report of the first autopsy case. AB - BACKGROUND: Neuro-Sweet disease is a rare condition of central nervous involvement accompanied by cutaneous Sweet lesions. Neuropathological changes in neuro-Sweet disease are unknown. OBJECTIVE: To describe post-mortem findings of the first case of neuro-Sweet disease. RESULTS: A 44-year-old Japanese man developed recurrent episodes of cerebral and brainstem encephalitis with cutaneous Sweet lesions from the age of 34 years. His HLA typing was B54 and Cw1, and the symptoms and MRI abnormalities markedly subsided following corticosteroid therapy. Histologically, there were multiple lesions of perivascular cuffing of small venules by macrophages without vasculitis in the thalamus, temporal lobe, basal ganglia, pons, leptomeninges or ventricular ependym. CONCLUSIONS: The core neuropathological findings were: perivascular cuffing around particularly small veins; absence of granulomatous or necrotic angitis; mainly macrophage infiltration; and the thalamus being most affected. In the present case, the diagnosis of neuro-Sweet disease was made by skin biopsy 5 years after the onset of the central neuron system symptoms. We should pay more attention to skin lesions in steroid responsive recurrent encephalitis in patients who are HLA-B54 or Cw1 positive. PMID- 17702784 TI - Pontine hyperperfusion in sporadic hyperekplexia. AB - OBJECTIVE: To explore with neuroimaging techniques the anatomical and functional correlates of sporadic hyperekplexia. METHODS: Two elderly women with sporadic hyperekplexia underwent neurophysiological assessment, MRI of the brain and proton magnetic resonance spectroscopy (1H-MRS) of the brainstem and frontal lobes. Regional cerebral blood flow was investigated with single photon emission tomography (SPECT) during evoked startles and at rest. RESULTS: Both patients showed excessively large and non-habituating startle responses. In both patients, MRI showed impingement of the brainstem by the vertebrobasilar artery, lack of frontal or brainstem abnormalities on 1H-MRS and hyperperfusion in the dorsal pons and cingulate cortex, and superior frontal gyrus at SPECT during evoked startles. CONCLUSIONS: In our patients with hyperekplexia, the vertebrobasilar arteries were found to impinge on the brainstem. Neurophysiological findings and neurofunctional imaging of evoked startles indicated a pontine origin of the movement disorder modulated by activation in cortical, especially frontal, areas. The neurofunctional correlates of evoked startles in human sporadic hyperekplexia are similar to those observed for the startle circuit in animals. PMID- 17702785 TI - Neurological picture. Devastating calcinosis in a patient with adult onset myositis. PMID- 17702786 TI - Chronic meningitis and thalamic involvement in a woman: Fabry disease expanding phenotype. PMID- 17702787 TI - Peripheral neuropathy in chromosome16q22.1 linked autosomal dominant cerebellar ataxia. PMID- 17702788 TI - Recurrent herpes simplex virus encephalitis secondary to carbamazepine induced hypogammaglobulinaemia. PMID- 17702789 TI - Treatment of Guillain-Barre syndrome with mycophenolate mofetil: a pilot study. PMID- 17702790 TI - Counting, analysing and reporting exacerbations of COPD in randomised controlled trials. AB - BACKGROUND: Clinical trials measure exacerbations of chronic obstructive pulmonary disease (COPD) inconsistently. A study was undertaken to determine if different methods for ascertaining and analysing COPD exacerbations lead to biased estimates of treatment effects. METHODS: Information on the methods used to count, analyse and report COPD exacerbation rates was abstracted from clinical trials of long-acting bronchodilators or long-acting bronchodilator/inhaled steroid combination products published between 2000 and 2006. Data from the Canadian Optimal Therapy of COPD Trial was used to illustrate how different analytical approaches can affect the estimate of exacerbation rates and their confidence intervals. RESULTS: 22 trials (17,156 patients) met the inclusion criteria and were reviewed. None of the trials adjudicated exacerbations or determined independence of events. 14/22 studies (64%) introduced selection bias by not analysing outcome data for subjects who prematurely stopped study medications. Only 31% of trials used time-weighted analyses to calculate the mean number of exacerbations/patient-year and only 15% accounted for between-subject variation. In the Canadian Optimal Therapy of COPD Trial the rate ratio for exacerbations/patient-year was 0.85 when all data were included in a time weighted analysis, but was overestimated as 0.79 when data for those who prematurely stopped study medications were excluded and was further overestimated as 0.46 when a time-weighted analysis was not conducted; p values ranged from 0.03 to 0.24 depending on how exacerbations were determined and analysed. CONCLUSIONS: Clinical trials have used widely different methods to define and analyse COPD exacerbations and this can lead to biased estimates of treatment effects. Future trials should strive to include blinded adjudication and assessment of the independence of exacerbation events, and trials should report time-weighted intention-to-treat analyses with adjustments for between-subject variation in COPD exacerbations. PMID- 17702791 TI - Validation of FEV6 in the elderly: correlates of performance and repeatability. AB - BACKGROUND: Forced expiratory volume in 6 s (FEV6) has been proposed as a more easily measurable parameter than forced vital capacity (FVC) to diagnose airway disease using spirometry. A study was undertaken to estimate FEV6 repeatability, to identify correlates of a good quality FEV6 measurement and of volumetric differences between FEV6 and FVC in elderly patients. METHODS: 1531 subjects aged 65-100 years enrolled in the SA.R.A project (a cross-sectional multicentre non interventional study) were examined. FEV6 was measured on volume-time curves that achieved satisfactory start-of-test and end-of-test criteria. Correlates of FEV6 achievement were assessed by logistic regression. RESULTS: Valid FEV6 and FVC measurements were obtained in 82.9% and 56.9%, respectively, of spirometric tests with an acceptable start-of-test criterion. Female sex, older age, lower educational level, depression, cognitive impairment and lung restriction independently affected the achievement of FEV6 measurement. Good repeatability (difference between the best two values <150 ml) was found in 91.9% of tests for FEV6 and in 86% for FVC; the corresponding figures in patients with airway obstruction were 94% and 78.4%. Both FEV6 and FVC repeatability were affected by male sex and lower education. Male sex, airway obstruction and smoking habit were independently associated with greater volumetric differences between FEV6 and FVC. CONCLUSIONS: In elderly patients, FEV6 measurements are more easily achievable and more reproducible than FVC although 1/6 patients in this population were unable to achieve them. PMID- 17702792 TI - Children's eligibility and coverage: recent trends and a look ahead. AB - We used data from the 1996-2005 Medical Expenditure Panel Survey to track changes in children's public insurance eligibility and coverage. During the 2001-2005 "postexpansion" period, eligibility was approximately constant, while public enrollment increased rapidly and uninsurance declined. Nevertheless, as of 2005, 62 percent of all uninsured children (5.5 million) continued to be eligible but not enrolled. We present detailed estimates of their characteristics by age, income, race/ethnicity, health status, and nativity/citizenship. We also examine the impact of potential changes in SCHIP income thresholds--both an expansion and a rollback--and estimate the number and characteristics of the children potentially affected. PMID- 17702793 TI - Orthodontic orthognathic surgical treatment of a subject with Williams Beuren syndrome a follow-up from 8 to 25 years of age. AB - This article presents a survey of characteristic features of Williams-Beuren syndrome (WBS) as reported in the literature and the interdisciplinary treatment of a subject with WBS with special regard to morphological and functional disorders. Typical features of a patient with WBS and his dental development in a follow-up from 8 to 25 years of age are shown. Early orthodontic treatment approaches, later combined orthodontic-orthognathic surgical procedures, and the status 5 years after surgery are presented. PMID- 17702794 TI - In vitro colour stability of aesthetic brackets. AB - Contrary to their popularity in satisfying aesthetic demands, plastic brackets still present some problems because of their decreased hardness and wear resistance. A problem of plastic brackets is discolouration, due to ultraviolet (UV) light and food dyes. The aim of this study was to investigate the colour stability of aesthetic brackets during UV irradiation and exposure to food dyes. Four different polymer brackets were exposed in a Suntest CPS+ ageing device to a xenon lamp to simulate natural day light. Because most tooth-coloured bracket systems are used in adult treatment, red wine, coffee, and tea were chosen as food colourants. After 24 and 72 hours of exposure, colour measurements were performed by means of a spectrophotometer according to the CIE L*a*b* system and colour changes (DeltaE*) were computed. Statistical differences were investigated using three-way analysis of variance (ANOVA). With the exception of the Aesthetic Line bracket, almost all investigated polymer brackets showed clinically unacceptable discolouration during in vitro exposure to colourants. Most of the brackets became yellower after UV light treatment. In spite of the short exposure period of 72 hours, almost all polymer brackets showed undesirable discolouration. These current in vitro findings indicate that even newly developed plastic brackets, consisting of composite materials or modern polymers (polyoxymethylene) may have clinically unacceptable colour stability in the long term. PMID- 17702795 TI - Frictional properties of aesthetic brackets. AB - The purpose of this study was to compare the frictional properties of two self ligating aesthetic brackets, Opal (Ultradent Products) and Oyster (Gestenco Int.), with those of four conventionally ligated aesthetic brackets, Transcend (3M Unitek), Inspire (Ormco), Allure (GAC Int.), and Image (Gestenco Int.). Friction was tested with different wire dimensions and qualities [stainless steel (SS) wire 0.017 x 0.025 inches; SS 0.019 x 0.025 inches; TMA 0.019 x 0.025 inches] using a Zwick testing machine. All brackets had a 0.022-inch slot and the prescription of an upper first premolar of the Roth system (tip: 0 degrees, torque: -7 degree). Each bracket/archwire combination was tested 10 times and each test was performed with a new bracket/wire sample that was pulled through twice. Additionally, two sets of 30 Opal brackets each were aged with an ageing machine under standardized conditions for 9-10 and 18-20 months, respectively. Friction of the aged brackets was tested with identical wire dimensions and qualities using the same testing procedure. All data were statistically analysed with unsigned comparisons of all bracket/wire combinations using GLM and the Games-Howell post hoc test. The results showed Opal brackets to have the lowest frictional forces for all wire dimensions and qualities. Furthermore, friction was lower at a significant level (P 0.05). The median ranking of photographs 1, 2, 3, 4, and 10 were identical to the AC of IOTN. The photographs representing IOTN AC 7 and 8 were allocated the same median rank of 7 and AC 5 and 9 were allocated corresponding median ranks of 6 and 8, respectively. There were no significant differences in median cut-off points for treatment need among the three groups of subjects (P > 0.05), indicating that the mean threshold at which treatment would be sought was AC 4. PMID- 17702797 TI - Cost-effectiveness and patient satisfaction: Hawley and vacuum-formed retainers. AB - In the United Kingdom (UK) over the last 10 years, there has been a significant increase in the use of vacuum-formed retainers (VFRs) rather than conventional Hawley retainers. There are currently no data to compare the cost-effectiveness of this change in practice. The two aims of this study were to compare (1) the cost-effectiveness of VFRs and Hawley retainers over 6 months, from the perspective of the National Health Service, orthodontic practice, and the patient and (2) patient satisfaction in the two retainer groups. A randomized controlled trial (RCT) was carried out in a specialist orthodontic practice. Three hundred and ninety-seven eligible patients were randomized to one of two retainer groups, and followed up for 6 months. All subjects were invited to complete patient satisfaction questionnaires. Additional data were collected for the cost analysis from the patient records and national databases. Descriptive and bivariate analyses were used to compare patient satisfaction between retainer groups. In all, 196 subjects were randomized to the Hawley group (mean age 14 years 8 months, 63 per cent female, 37 per cent male) and 201 to the VFR group (mean age 15 years, 59 per cent female, 41 per cent male). VFRs were more cost-effective than Hawley retainers from all perspectives. The majority of subjects showed a preference for VFRs compared with Hawley retainers. There were also fewer breakages than in the Hawley group. PMID- 17702798 TI - Multitomographic evaluation of the dental effects of two different rapid palatal expansion appliances. AB - Rapid palatal expansion (RPE) is widely used in the treatment of transverse maxillary deficiencies. Generally, there are two types of RPE appliances: banded and bonded expanders. The purpose of this prospective study was to compare the dental effects of banded and bonded appliances. The study consisted of 23 patients (13 females and 10 males) with a bilateral maxillary deficiency. Twelve patients (seven females and five males) with a mean age of 14.8 +/- 0.3 years were treated with banded RPE and 11 patients (six females and five males) with a mean age of 15.1 +/- 0.7 years with bonded RPE. Multitomographic radiographs were taken before (T0) and at the end (T1) of expansion while the patients were wearing an acrylic mandibular appliance in which ball bearings and bars were embedded. Statistical analyses of the measurements at T0 and T1 were undertaken with a paired t-test, and the difference between the groups assesed with a Student's t-test. In both groups, the angle between the radiographic image of the bar and the axial inclination of the upper first premolar and molar teeth was (5.34 and 2.73 degrees for the right premolars, 5.17 and 2.28 degrees for the left premolars, 11.83 and 3.73 degrees for the right molars, and 9.75 and 5.64 degrees for the left molars in the banded and bonded groups, respectively. The distance from the vestibular cortical plate to the palatal root of these teeth (1.17 and 1.23 mm for the right premolars, 2.46 and 1.09 mm for the left premolars, 2.75 and 0.64 mm for the right molars, 2.23 and 0.96 mm for the left molars in the banded and bonded groups, respectively) increased (both P < 0.01). These increases indicated buccal tipping of the teeth. Comparison of the two groups showed that tipping of the first molar and premolar teeth in the banded group was significantly more than in the bonded group (P < 0.01 and P < 0.001, respectively). PMID- 17702799 TI - Shear bond strength of orthodontic brackets bonded to different ceramic surfaces. AB - This study was undertaken to measure the shear bond strength (SBS) of stainless steel brackets bonded to different ceramic surfaces, to compare the SBS of the different ceramics with each other and with conventional ceramo-metal porcelains, and to determine the mode of failure for each group following debonding. A total of 60 ceramic crowns were constructed on extracted teeth and divided into three equal groups as follows: In-Ceram ceramic crowns, IPS-Impress ceramic crowns, and conventional ceramo-metal porcelain. Standard edgewise metal premolar brackets were bonded to the prepared porcelain surfaces. After bonding, all samples were tested in shear mode on an Instron universal testing machine. Statistical analysis was undertaken using analysis of variance, LSD, and chi-squared tests. The results showed that the SBS for the ceramo-metal and the In-Ceram groups were comparable, with mean values of 80.54 +/- 13.44 N and 78.87 +/- 13.47 N, respectively. The IPS-Impress group showed the weakest SBS which averaged 67.40 +/- 8.99 N. This was significantly lower than that of the conventional ceramo metal porcelain (P < 0.001) and the In-Ceram surface (P < 0.01). The mode of failure in the ceramo-metal group was between the porcelain surface and adhesive and in the other two ceramic groups, between the brackets and adhesive (P < 0.001). The SBS of orthodontic brackets to the three tested ceramic surfaces were adequate for orthodontic use. PMID- 17702800 TI - An in vitro investigation of the influence of self-ligating brackets, low friction ligatures, and archwire on frictional resistance. AB - This study, performed using a specially designed apparatus that included 10 aligned brackets, evaluated the frictional resistance generated by conventional stainless steel (SS) brackets (Victory Series), self-ligating Damon SL II brackets, Time Plus brackets, and low-friction ligatures (Slide) coupled with various SS, nickel-titanium (NiTi), and beta-titanium (TMA) archwires. All brackets had a 0.022-inch slot and the orthodontic wire alloys were 0.016, 0.016 x 0.022, and 0.019 x 0.025 inch NiTi, 0.017 x 0.025 inch TMA, and 0.019 x 0.025 inch SS. Each bracket-archwire combination was tested 10 times. Coupled with 0.016 inch NiTi, Victory brackets generated the most friction and Damon SL II the least (P < 0.001); with 0.016 x 0.022 inch NiTi, the self-ligating brackets (Time and Damon SL II) generated significantly lower friction (P < 0.001) than Victory Series and Slide ligatures; with 0.019 x 0.025 inch SS or 0.019 x 0.025 inch NiTi, Slide ligatures generated significantly lower friction than all other groups. No difference was observed among the four groups when used with a 0.017 x 0.025-inch TMA archwire. These findings suggest that the use of an in vitro testing model that includes 10 brackets provides information about the frictional force of the various bracket-archwire combinations. PMID- 17702801 TI - Oestrogenicity of orthodontic adhesive resins. AB - The purpose of this study was to assess the oestrogenic action of a chemically cured, no-mix (Rely-a-Bond) and a light-cured (Reliance) orthodontic adhesive resin. The adhesives were bonded to 40 stainless steel maxillary incisor brackets (Diamond) divided into two equal groups, employing a method which simulated the clinical handling of materials. In total, three series of specimens were prepared for each adhesive-bracket group. All specimens were immersed in normal saline. Samples of eluent were removed from each group at 1 day and 1 week following incubation and tested for oestrogenicity by measuring their effect on the proliferation of the oestrogen-responsive MCF-7 breast cancer cells, while an oestrogen-insensitive cell line (MB-231 human breast adenocarcinoma) was used as a control. Three-way analysis of variance with adhesive, concentration of eluent, and immersion period were used as discriminating variables. No evidence was found of stimulation of proliferation of these cells, indicating the absence of any oestrogenicity of orthodontic adhesive eluents. PMID- 17702802 TI - Three-dimensional hard tissue palatal size and shape in Down syndrome subjects. AB - The aim of the present study was to evaluate palatal morphology in Down syndrome (Ds) subjects, focusing on the effect of dental formula on the hard palate to assist clinicians when planning dental rehabilitation. Palatal landmarks were digitized with a three-dimensional (3D) computerized digitizer on the dental casts of 47 Ds subjects (23 dentate males, 9 edentulous males, and 15 dentate females) aged 20-45 years, 37 dentate reference individuals (20 males and 17 females) aged 30-39 years, and 14 edentulous reference males aged 55-72 years. The co-ordinates of the palatal landmarks were used to construct a mathematical equation of palatal shape, independent of dimensions. Palatal length, slope, width, and maximum palatal height in both the sagittal and frontal planes were measured. In males, palatal length, width, and height were significantly influenced by both the syndrome and edentulism (analysis of variance, P < 0.05). The same measurements were significantly reduced in Ds compared with dentate females (t-test, P < 0.05). In the sagittal plane, Ds did not modify palatal shape; in the frontal plane, Ds individuals showed a higher palate. Overall, palatal shape was influenced by both Ds and edentulousness. Therefore, Ds seems to alter the normal palatal size and shape, although verification on larger samples is required. The findings of the present study may encourage more interdisciplinary dentofacial therapy in the dental and orthodontic care of Ds subjects. PMID- 17702804 TI - Open angle glaucoma effects on preattentive visual search efficiency for flicker, motion displacement and orientation pop-out tasks. AB - BACKGROUND/AIM: Preattentive visual search (PAVS) describes rapid and efficient retinal and neural processing capable of immediate target detection in the visual field. Damage to the nerve fibre layer or visual pathway might reduce the efficiency with which the visual system performs such analysis. The purpose of this study was to test the hypothesis that patients with glaucoma are impaired on parallel search tasks, and that this would serve to distinguish glaucoma in early cases. METHODS: Three groups of observers (glaucoma patients, suspect and normal individuals) were examined, using computer-generated flicker, orientation, and vertical motion displacement targets to assess PAVS efficiency. The task required rapid and accurate localisation of a singularity embedded in a field of 119 homogeneous distractors on either the left or right-hand side of a computer monitor. All subjects also completed a choice reaction time (CRT) task. RESULTS: Independent sample T tests revealed PAVS efficiency to be significantly impaired in the glaucoma group compared with both normal and suspect individuals. Performance was impaired in all types of glaucoma tested. Analysis between normal and suspect individuals revealed a significant difference only for motion displacement response times. Similar analysis using a PAVS/CRT index confirmed the glaucoma findings but also showed statistically significant differences between suspect and normal individuals across all target types. CONCLUSIONS: A test of PAVS efficiency appears capable of differentiating early glaucoma from both normal and suspect cases. Analysis incorporating a PAVS/CRT index enhances the diagnostic capacity to differentiate normal from suspect cases. PMID- 17702806 TI - Investigation of the lactate shuttle in skeletal muscle mitochondria. PMID- 17702808 TI - Habituation, desensitization and sensitization of the Hering Breuer reflex in normal and Mecp2 /y knockout mice. PMID- 17702810 TI - The delta2 'ionotropic' glutamate receptor functions as a non-ionotropic receptor to control cerebellar synaptic plasticity. AB - The delta2 glutamate receptor (GluRdelta2) belongs to the ionotropic glutamate receptor (iGluR) family and plays a crucial role in the induction of cerebellar long-term depression (LTD), a form of synaptic plasticity underlying motor learning. Nevertheless, the mechanisms by which GluRdelta2 regulates cerebellar LTD have remained elusive. Because a mutation occurring in lurcher mice causes continuous GluRdelta2 channel activity that can be abolished by 1 naphtylacetylspermine (NASP), a channel blocker for Ca(2+)-permeable iGluRs, GluRdelta2 is thought to function as an ion channel. Here, we introduced a mutant GluRdelta2 transgene, in which the putative channel pore was disrupted, into GluRdelta2-null Purkinje cells using a virus vector. Surprisingly and similar to the effect of the wild-type GluRdelta2 transgene, the mutant GluRdelta2 completely rescued the abrogated LTD in GluRdelta2-null mice. Furthermore, NASP did not block LTD induction in wild-type cerebellar slices. These results indicate that GluRdelta2, a member of the iGluR family, does not serve as a channel in the regulation of LTD induction. PMID- 17702809 TI - alpha2-Noradrenergic receptors activation enhances excitability and synaptic integration in rat prefrontal cortex pyramidal neurons via inhibition of HCN currents. AB - Stimulation of alpha(2)-noradrenergic (NA) receptors within the PFC improves working memory performance. This improvement is accompanied by a selective increase in the activity of PFC neurons during delay periods, although the cellular mechanisms responsible for this enhanced response are largely unknown. Here we used current and voltage clamp recordings to characterize the response of layer V-VI PFC pyramidal neurons to alpha(2)-NA receptor stimulation. alpha(2)-NA receptor activation produced a small hyperpolarization of the resting membrane potential, which was accompanied by an increase in input resistance and evoked firing. Voltage clamp analysis demonstrated that alpha(2)-NA receptor stimulation inhibited a caesium and ZD7288-sensitive hyperpolarization-activated (HCN) inward current. Suppression of HCN current by alpha(2)-NA stimulation was not dependent on adenylate cyclase but instead required activation of a PLC-PKC linked signalling pathway. Similar to direct blockade of HCN channels, alpha(2)-NA receptor stimulation produced a significant enhancement in temporal summation during trains of distally evoked EPSPs. These dual effects of alpha(2)-NA receptor stimulation - membrane hyperpolarization and enhanced temporal integration - together produce an increase in the overall gain of the response of PFC pyramidal neurons to excitatory synaptic input. The net effect is the suppression of isolated excitatory inputs while enhancing the response to a coherent burst of synaptic activity. PMID- 17702811 TI - In vitro modulation of endogenous rhythms by AC electric fields: Syncing with clinical brain stimulation. PMID- 17702812 TI - Increased secretory capacity of mouse adrenal chromaffin cells by chronic intermittent hypoxia: involvement of protein kinase C. AB - Previous studies have shown that catecholamine secretion from the adrenal medulla plays a critical role in chronic intermittent hypoxia (CIH)-induced alterations in cardiovascular function. In the present study we examined the cellular mechanisms associated with the effects of CIH on adrenal chromaffin cell catecholamine secretion. Experiments were performed on adult male mice (C57/BL6) that were exposed to 1-4 days of CIH or to normoxia. Perforated patch electrical capacitance recordings were performed on freshly prepared adrenal medullary slices that permit separating the chromaffin cell secretion from sympathetic input. CIH resulted in a significant increase in the readily releasable pool (RRP) of secretory granules, and decreased stimulus-evoked Ca(2+) influx. Continuous hypoxia (CH) either for 2.5 h (equivalent to hypoxic duration accumulated over 4 days of CIH) or for 4 days were ineffective in evoking changes in the RRP and Ca(2+) influx. CIH activated PKC in adrenal medullae as evidenced by increased phosphorylation of PKC at Thr(514) and PKC inhibitors prevented CIH induced increases in the RRP and restored stimulus-evoked attenuation of Ca(2+) influx. CIH resulted in elevated thio-barbituric acid reactive substances (TBARSs, an index of oxidized proteins) and an antioxidant prevented CIH-induced changes in the RRP, suggesting the involvement of reactive oxygen species (ROS). These results demonstrate that CIH increases the RRP in adrenal chromaffin cells via ROS-mediated activation of PKC and suggest that CIH can directly affect the secretory capacity of chromaffin cells and contribute, in part, to elevated catecholamine levels. PMID- 17702813 TI - Cognitive and emotional information processing: protein synthesis and gene expression. AB - Recent findings suggest that functional plasticity phenomena such as long-term potentiation (LTP) and long-term depression (LTD) - cellular processes underlying memory - are restricted to functional dendritic compartments. It was also shown, however, that a relatively strong activation of a synaptic input can abolish compartment restrictions. Our data support these findings and we present one cellular pathway responsible for uncompartmentalization of the normally localized plasticity processes by the action of rolipram, an inhibitor of type 4 phosphodiesterases. In contrast with compartment-restricted information processing, uncompartmentalization requires transcription. In the search for system relevance of compartmentalization versus uncompartmentalization we describe firstly data which show that more cognitive information processing in rats' behaviour may follow rules of compartmentalization, whereas stressful, more life-threatening, inputs abolish compartment-restricted information processing involving transcription. Our findings allow us to suggest that consolidation of processes which take place during the cognitive event most probably depend on local protein synthesis, whereas stress immediately induces gene expression in addition, resulting in a compartment-unspecific up-regulation of plasticity related proteins (PRPs), providing the entire neuron with a higher level of 'reactiveness'. These data would provide a specific functional cellular mechanism to respond differentially and effectively to behaviourally weighted inputs. PMID- 17702814 TI - Sustained increase of somatosensory cortex excitability by tactile coactivation studied by paired median nerve stimulation in humans correlates with perceptual gain. AB - Cortical excitability can be reliably assessed by means of paired-pulse stimulation techniques. Recent studies demonstrated particularly for motor and visual cortex that cortical excitability is systematically altered following the induction of learning processes or during the development of pathological symptoms. A recent tactile coactivation protocol developed by Godde and coworkers showed that improvement of tactile performance in humans can be achieved also without training through passive stimulation on a time scale of a few hours. Tactile coactivation evokes plastic changes in somatosensory cortical areas as measured by blood oxygenation level-dependent (BOLD) activation in fMRI or SEP dipole localization, which correlated with the individual gain in performance. To demonstrate changes in excitability of somatosensory cortex after tactile coactivation, we combined assessment of tactile performance with recordings of paired-pulse SEPs after electrical median nerve stimulation of both the right coactivated and left control hand at ISIs of 30 and 100 ms before, 3 h after and 24 h after tactile coactivation. Amplitudes and latencies of the first and second cortical N20/P25 response components were calculated. For the coactivated hand, we found significantly lowered discrimination thresholds and significantly reduced paired-pulse ratios (second N20/P25 response/first N20/P25 response) at an ISI of 30 ms after tactile coactivation indicating enhanced cortical excitability. No changes in paired-pulse behaviour were observed for ISIs of 100 ms. Both psychophysical and cortical effects recovered to baseline 24 h after tactile coactivation. The individual increase of excitability correlated with the individual gain in discrimination performance. For the left control hand we found no effects of tactile coactivation on paired-pulse behaviour and discrimination threshold. Our results indicate that changes in cortical excitability are modified by tactile coactivation and were scaled with the degree of improvement of the individual perceptual learning. Conceivably, changes of cortical excitability seem to constitute an additional important marker and mechanism underlying plastic reorganization. PMID- 17702815 TI - Muscle fatigue: what, why and how it influences muscle function. AB - Much is known about the physiological impairments that can cause muscle fatigue. It is known that fatigue can be caused by many different mechanisms, ranging from the accumulation of metabolites within muscle fibres to the generation of an inadequate motor command in the motor cortex, and that there is no global mechanism responsible for muscle fatigue. Rather, the mechanisms that cause fatigue are specific to the task being performed. The development of muscle fatigue is typically quantified as a decline in the maximal force or power capacity of muscle, which means that submaximal contractions can be sustained after the onset of muscle fatigue. There is even evidence that the duration of some sustained tasks is not limited by fatigue of the principal muscles. Here we review experimental approaches that focus on identifying the mechanisms that limit task failure rather than those that cause muscle fatigue. Selected comparisons of tasks, groups of individuals and interventions with the task failure approach can provide insight into the rate-limiting adjustments that constrain muscle function during fatiguing contractions. PMID- 17702816 TI - Responses evoked in single sympathetic nerve fibres of the rat tail artery by systemic hypoxia are dependent on core temperature. AB - No direct evidence exists of the changes evoked by systemic hypoxia in sympathetic nerves to the rat cutaneous circulation, and of the concomitant changes in cutaneous blood flow. Here we investigated responses evoked by two levels of systemic hypoxia (12% and 8% inspired O(2)) in single sympathetic units supplying tail caudal ventral artery (CVA) in spontaneously breathing anaesthetized rats, whilst simultaneously recording tail blood flow and vascular resistance (TVR) from the CVA, under conditions of modest hypothermia and hyperthermia. During modest hypothermia and normoxia, TVR was high and CVA unit activity was present, with marked respiratory modulation and a rhythmictiy (T rhythm) that was often independent of respiration. Hypoxia evoked a graded fall in TVR indicating vasodilatation, but there were no consistent changes in CVA unit firing rate or T-rhythm frequency, although respiratory modulation increased. By contrast, during hyperthermia, TVR was low and CVA unit activity was absent. Systemic hypoxia evoked graded increases in TVR, indicating vasoconstriction, and in 8% O(2) there was recommencement of firing in some CVA units, at low discharge rate, with respiratory modulation but no T-rhythm. These results indicate that the changes evoked by systemic hypoxia in TVR and sympathetic nerve activity to CVA are dependent on core temperature. During modest hypothermia, hypoxia-induced cutaneous vasodilatation in the tail is independent of sympathetic activity, whereas during hyperthermia, when sympathetic activity is 'switched off', severe hypoxia initiates respiratory related low level activity, causing cutaneous vasoconstriction. PMID- 17702817 TI - Thrombospondin-1 expression and localization in the developing ovine lung. AB - Fetal lung growth is critically dependent on the degree to which the lungs are expanded by liquid, although the mechanisms involved are unknown. As thrombospondin-1 (TSP-1) can regulate cell proliferation, attachment, spreading and angiogenesis, we investigated the effects of alterations in fetal lung expansion on TSP-1 expression in sheep. TSP-1 mRNA levels were investigated using Northern blot analysis and in situ hybridization, whereas the protein levels were determined by immunohistochemistry. Early growth response 1 (EGR1) mRNA levels were measured by quantitative real-time PCR. TSP-1 was expressed in type-II alveolar epithelial cells and fibroblasts and its mRNA levels increased from 100.0 +/- 14.0% in control fetuses to 347.5 +/- 73.6% at 36 h of increased lung expansion (P < 0.05), and were reduced to 39.4 +/- 6.1% of control levels (100.0 +/- 20.4%) at 20 days of decreased lung expansion (P < 0.05). The percentage of cells positive for TSP-1 mRNA increased from 1.9 +/- 0.4% to 5.2 +/- 0.8% at 36 h of increased fetal lung expansion (P < 0.01). The proportion of tissue stained positive for TSP-1 protein doubled at 36 h of increased lung expansion (23.3 +/- 2.2%) compared to controls (11.7 +/- 3.2%; P < 0.05). Conversely, at 20 days of decreased lung expansion, the percentage of tissue that stained positive for TSP 1 was halved (25.7 +/- 3.2%) compared to controls (39.8 +/- 3.3%; P < 0.05). The increase in TSP-1 expression may be due to increased mRNA levels of the transcription factor EGR1 at 36 h of increased lung expansion (2.7 +/- 0.7-fold of control levels (1.0 +/- 0.2); P < 0.05). Given the known functions of TSP-1 and its localization within the lung, we speculate that TSP-1 may have a significant role in regulating fetal lung growth. PMID- 17702818 TI - Involvement of an enterocyte renin-angiotensin system in the local control of SGLT1-dependent glucose uptake across the rat small intestinal brush border membrane. AB - There is increasing evidence that locally produced angiotensin AII (AII) regulates the function of many tissues, but the involvement of enterocyte-derived AII in the control of intestinal transport is unknown. This study examined whether there is a local renin-angiotensin system (RAS) in rat villus enterocytes and assessed the effects of AII on SGLT1-dependent glucose transport across the brush border membrane (BBM). Gene and protein expression of angiotensinogen, ACE, and AT(1) and AT(2) receptors were studied in jejunal and ileal enterocytes using immunocytochemistry, Western blotting and RT-PCR. Mucosal uptake of d [(14)C]glucose by everted intestinal sleeves before and after addition of AII (0 100 nm) to the mucosal buffer was measured in the presence or absence of the AT(1) receptor antagonist losartan (1 microm). Immunocytochemistry revealed the expression of angiotensinogen, ACE, and AT(1) and AT(2) receptors in enterocytes; immunoreactivity of AT(1) receptor and angiotensinogen proteins was especially pronounced at the BBM. Expression of angiotensinogen and AT(1) and AT(2) receptors, but not ACE, was greater in the ileum than the jejunum. Addition of AII to mucosal buffer inhibited phlorizin-sensitive (SGLT1-dependent) jejunal glucose uptake in a rapid and dose-dependent manner and reduced the expression of SGLT1 at the BBM. Losartan attenuated the inhibitory action of AII on glucose uptake. AII did not affect jejunal uptake of l-leucine. The detection of RAS components at the enterocyte BBM, and the rapid inhibition of SGLT1-dependent glucose uptake by luminal AII suggest that AII secretion exerts autocrine control of intestinal glucose transport. PMID- 17702819 TI - Functional expression of ionotropic purinergic receptors on mouse taste bud cells. AB - Neurotransmitter receptors on taste bud cells (TBCs) and taste nerve fibres are likely to contribute to taste transduction by mediating the interaction among TBCs and that between TBCs and taste nerve fibres. We investigated the functional expression of P2 receptor subtypes on TBCs of mouse fungiform papillae. Electrophysiological studies showed that 100 microm ATP applied to their basolateral membranes either depolarized or hyperpolarized a few cells per taste bud. Ca(2+) imaging showed that similarly applied 1 mum ATP, 30 microm BzATP (a P2X(7) agonist), or 1 microm 2MeSATP (a P2Y(1) and P2Y(11) agonist) increased intracellular Ca(2+) concentration, but 100 microm UTP (a P2Y(2) and P2Y(4) agonist) and alpha,beta-meATP (a P2X agonist except for P2X(2), P2X(4) and P2X(7)) did not. RT-PCR suggested the expression of P2X(2), P2X(4), P2X(7), P2Y(1), P2Y(13) and P2Y(14) among the seven P2X subtypes and seven P2Y subtypes examined. Immunohistostaining confirmed the expression of P2X(2). The exposure of the basolateral membranes to 3 mm ATP for 30 min caused the uptake of Lucifer Yellow CH in a few TBCs per taste bud. This was antagonized by 100 microm PPADS (a non-selective P2 blocker) and 1 microm KN-62 (a P2X(7) blocker). These results showed for the first time the functional expression of P2X(2) and P2X(7) on TBCs. The roles of P2 receptor subtypes in the taste transduction, and the renewal of TBCs, are discussed. PMID- 17702820 TI - A critical role of the cAMP sensor Epac in switching protein kinase signalling in prostaglandin E2-induced potentiation of P2X3 receptor currents in inflamed rats. AB - Sensitization of purinergic P2X receptors is one of the mechanisms responsible for exaggerated pain responses to inflammatory injuries. Prostaglandin E2 (PGE2), produced by inflamed tissues, is known to contribute to abnormal pain states. In a previous study, we showed that PGE2 increases fast inactivating ATP currents that are mediated by homomeric P2X3 receptors in dorsal root ganglion (DRG) neurons isolated from normal rats. Protein kinase A (PKA) is the signalling pathway used by PGE2. Little is known about the action of PGE2 on ATP currents after inflammation, although the information is crucial for understanding the mechanisms underlying inflammation-induced sensitization of P2X receptors. We therefore studied the effects of PGE2 on P2X3 receptor-mediated ATP currents in DRG neurons dissociated from complete Freund's adjuvant (CFA)-induced inflamed rats. We found that PGE2 produces a large increase in ATP currents. PKCepsilon, in addition to PKA, becomes involved in the modulatory action of PGE2. Thus, PGE2 signalling switches from a solely PKA-dependent pathway under normal conditions to both PKA- and PKC-dependent pathways after inflammation. Studying the mechanisms underlying the switch, we demonstrated that cAMP-responsive guanine nucleotide exchange factor 1 (Epac1) is up-regulated after inflammation. The Epac agonist CPT-OMe mimics the potentiating effect of PGE2 and occludes the PKC mediated PGE2 action on ATP currents. These results suggest that Epac plays a critical role in P2X3 sensitization by activation of de novo PKC-dependent signalling of PGE2 after inflammation and would be a useful therapeutic target for pain therapies. PMID- 17702821 TI - The nature of corticospinal paths driving human motoneurones during voluntary contractions. AB - The properties of the human motor cortex can be studied non-invasively using transcranial magnetic stimulation (TMS). Stimulation at high intensity excites corticospinal cells with fast conducting axons that make direct connections to motoneurones of human upper limb muscles, while low-intensity stimulation can suppress ongoing EMG. To assess whether these cells are used in normal voluntary contractions, we used TMS at very low intensities to suppress the firing of single motor units in biceps brachii (n = 14) and first dorsal interosseous (FDI, n = 6). Their discharge was recorded with intramuscular electrodes and cortical stimulation was delivered at multiple intensities at appropriate times during sustained voluntary firing at approximately 10 Hz. For biceps, high-intensity stimulation produced facilitation at 17.1 +/- 2.1 ms (lasting 2.4 +/- 0.9 ms), while low-intensity stimulation (below motor threshold) produced suppression (without facilitation) at 20.2 +/- 2.1 ms (lasting 7.6 +/- 2.2 ms). For FDI, high intensity stimulation produced facilitation at 23.3 +/- 1.2 ms (lasting 1.8 +/- 0.4 ms), with suppression produced by low-intensity stimulation at 25.2 +/- 2.6 ms (lasting 7.5 +/- 2.6 ms). The difference between the onsets of facilitation and suppression was short: 3.1 +/- 1.2 ms for biceps and 2.0 +/- 1.5 ms for FDI. This latency difference is much less than that previously reported using surface EMG recordings ( approximately 10 ms). These data suggest that low-intensity cortical stimulation inhibits ongoing activity in fast-conducting corticospinal axons through an oligosynaptic (possibly disynaptic) path, and that this activity is normally contributing to drive the motoneurones during voluntary contractions. PMID- 17702823 TI - Influence of adapting speed on speed and contrast coding in the primary visual cortex of the cat. AB - Adaptation is a ubiquitous property of the visual system. Adaptation often improves the ability to discriminate between stimuli and increases the operating range of the system, but is also associated with a reduced ability to veridically code stimulus attributes. Adaptation to luminance levels, contrast, orientation, direction and spatial frequency has been studied extensively, but knowledge about adaptation to image speed is less well understood. Here we examined how the speed tuning of neurons in cat primary visual cortex was altered after adaptation to speeds that were slow, optimal, or fast relative to each neuron's speed response function. We found that the preferred speed (defined as the speed eliciting the peak firing rate) of the neurons following adaptation was dependent on the speed at which they were adapted. At the population level cells showed decreases in preferred speed following adaptation to speeds at or above the non-adapted speed, but the preferred speed did not change following adaptation to speeds lower than the non-adapted peak. Almost all cells showed response gain control (reductions in absolute firing capacity) following speed adaptation. We also investigated the speed dependence of contrast adaptation and found that most cells showed contrast gain control (rightward shifts of their contrast response functions) and response gain control following adaptation at any speed. We conclude that contrast adaptation may produce the response gain control associated with speed adaptation, but shifts in preferred speed require an additional level of processing beyond contrast adaptation. A simple model is presented that is able to capture most of the findings. PMID- 17702822 TI - Ca2+-dependent ATP release from A549 cells involves synergistic autocrine stimulation by coreleased uridine nucleotides. AB - Extracellular ATP is a potent surfactant secretagogue but its origin in the alveolus, its mechanism(s) of release and its regulatory pathways remain unknown. Previously, we showed that hypotonic swelling of alveolar A549 cells induces Ca(2+)-dependent secretion of several adenosine and uridine nucleotides, implicating regulated exocytosis. In this study, we examined sources of Ca(2+) for the elevation of intracellular Ca(2+) concentration ([Ca(2+)](i)) evoked by acute 50% hypotonic stress and the role of autocrine purinergic signalling in Ca(2+)-dependent ATP release. We found that ATP release does not directly involve Ca(2+) influx from extracellular spaces, but depends entirely on Ca(2+) mobilization from intracellular stores. The [Ca(2+)](i) response consisted of slowly rising elevation, representing mobilization from thapsigargin (TG) insensitive stores and a superimposed rapid spike due to Ca(2+) release from TG sensitive endoplasmic reticulum (ER) Ca(2+) stores. The latter could be abolished by hydrolysis of extracellular triphospho- and diphosphonucleotides with apyrase; blocking P2Y(2)/P2Y(6) receptors of A549 cells with suramin; blocking UDP receptors (P2Y(6)) with pyridoxal phosphate 6-azophenyl-2',4'-disulfonic acid (PPADS); emptying TG-sensitive stores downstream with TG or caffeine in Ca(2+) free extracellular solution; or blocking the Ca(2+)-release inositol 1,4,5 triphosphate receptor channel of the ER with 2-aminoethyldiphenylborinate. These data demonstrate that the rapid [Ca(2+)](i) spike results from the autocrine stimulation of IP(3)/Ca(2+)-coupled P2Y, predominantly P2Y(6), receptors, accounting for approximately 70% of total Ca(2+)-dependent ATP release evoked by hypotonic shock. Our study reveals a novel paradigm in which stress-induced ATP release from alveolar cells is amplified by the synergistic autocrine/paracrine action of coreleased uridine and adenosine nucleotides. We suggest that a similar mechanism of purinergic signal propagation operates in other cell types. PMID- 17702825 TI - Novel human CD4+ T lymphocyte subpopulations defined by CD300a/c molecule expression. AB - The CD300c (CMRF-35A) and CD300a (CMRF-35H) molecules are leukocyte surface proteins that are part of a larger family of immunoregulatory molecules encoded by a gene complex on human chromosome 17. The CMRF-35 monoclonal antibody binds to an epitope common to both molecules, expressed on most human leukocyte populations, apart from B lymphocytes and a subpopulation of CD4(+) and CD8(+) T lymphocytes. We describe the CMRF-35(pos) and CMRF-35(-) fractions of CD4(+) T lymphocytes. The CMRF-35(pos) fraction can further be divided into CMRF-35(++) and CMRF-35(+)CD4(+) T lymphocyte subpopulations. Resting peripheral CD4(+) T lymphocytes express CD300a mRNA and very low amounts of CD300c. Activation results in an initial decrease in CD300a gene expression before an increase in both CD300a and CD300c gene expression. The up-regulated expression of these genes was associated with increased CMRF-35 binding to activated T lymphocytes. The CMRF-35(-) fraction of CD4(+) T lymphocytes proliferated to a greater extent than the CMRF-35(pos) fraction, in response to mitogens or allogeneic antigen. The poor proliferation of the CMRF-35(pos) CD4(+) in response to mitogens was explained by increased apoptosis within this subpopulation. The recall antigen, tetanus toxoid, stimulated the CMRF-35(++)CD4(+)CD45RO(+) but not the CMRF-35( )CD4(+)CD45RO(+) subpopulation. Resting CMRF-35(++) CD4(+) lymphocytes express low levels of IFN-gamma mRNA. Within 18 h following in vitro activation, CMRF 35(++) CD4(+) lymphocytes express more IFN-gamma mRNA and protein compared with the CMRF-35(-)CD4(+) lymphocytes, however, after 24 h, both the CMRF-35(+) and CMRF-35(-)CD4(+) T lymphocytes were able to produce IFN-gamma. The CMRF 35(++)CD4(+) T lymphocyte population contains the Th(1) memory effector cells. PMID- 17702826 TI - Using the Bland-Altman method to measure agreement with repeated measures. PMID- 17702824 TI - Stimulatory and costimulatory effects of IL-18 directed to different small intestinal CD43 T cell subsets. AB - This study has examined the stimulatory and costimulatory effects of IL-18 on two subsets of murine small intestinal intraepithelial lymphocytes (IELs) defined by the expression of the CD43 S7 glycoform. Data from gene array studies and real time PCR indicated that S7(+) IELs had significantly higher levels of gene expression for the IL-18 receptor and the IL-18R accessory protein than S7(-) IELs. IL-18 costimulation of IELs in conjunction with CD3-induced activation resulted in significantly greater proliferation than CD3 stimulation alone. In CFSE dilution experiments, IL-18 costimulation favored the S7(+) IEL population. IL-18 costimulation did not affect apoptosis of either S7(-) or S7(+) IELs compared with CD3 stimulation alone. Although IL-18 costimulation did not alter the total number of IFN-gamma-producing cells relative to CD3 stimulation alone, twice as many S7(+) IELs were IFN-gamma -secreting cells than S7(-) IELs in both CD3-stimulated and IL-18-costimulated cultures. Notably, direct IL-18 stimulation in the absence of CD3 activation induced an IFN-gamma response that was predominantly directed to the S7(+) population, indicating that IL-18 is itself an IFN-gamma activational signal for intestinal T cells. In contrast, direct IL 18 stimulation of IELs did not generate TNF-alpha-producing cells, indicating a differential response in the activation of proinflammatory cytokines following IL 18 exposure. These findings point to distinctly different activational effects of IL-18 on IELs, both with regard to the type of functional responses elicited and with respect to the IEL subsets affected. PMID- 17702827 TI - The balanced concept of fluid resuscitation. PMID- 17702828 TI - IL-18 and SC5b-9 for predicting neurocognitive dysfunction after cardiopulmonary bypass. PMID- 17702829 TI - Ultrasound-guided sciatic nerve block: description of a new approach at the subgluteal space. PMID- 17702830 TI - Oral clonidine vs midazolam in the prevention of sevoflurane-induced agitation in children. PMID- 17702831 TI - Use of LMA-ProSeal drain tube for oesophogastric instrumentation. PMID- 17702832 TI - Levosimendan in septic shock: a case series. PMID- 17702833 TI - Dexmedetomidine sedation during cataract surgery under regional anaesthesia. PMID- 17702834 TI - Day case surgery and obesity. PMID- 17702836 TI - Suppressing the excitability of spinal motoneurons by extracellularly applied electrical fields: insights from computer simulations. AB - The effect of extracellularly applied electrical fields on neuronal excitability and firing behavior is attributed to the interaction between neuronal morphology and the spatial distribution and level of differential polarization induced by the applied field in different elements of the neuron. The presence of voltage gated ion channels that mediate persistent inward currents (PICs) on the dendrites of spinal motoneurons enhances the influence of electrical fields on the motoneuronal firing behavior. The goal of the present study was to investigate, with a realistic motoneuron computer model, the effects of extracellularly applied electrical fields on the excitability of spinal motoneurons with the aim of reducing the increased motoneuronal excitability after spinal cord injury (SCI). Our results suggest that electrical fields could suppress the excitability of motoneurons and reduce their firing rate significantly by modulating the magnitude of their dendritic PIC. This effect was achieved at different field directions, intensities, and polarities. The reduction in motoneuronal firing rate resulted from the reduction in the magnitude of the dendritic PIC reaching the soma by the effect of the applied electrical field. This reduction in PIC was attributed to the dendritic field induced differential polarization and the nonlinear current-voltage relationship of the dendritic PIC-mediating channels. Because of the location of the motoneuronal somata and initial segment with respect to the dendrites, these structures were minimally polarized by the applied field compared with the extended dendrites. In conclusion, electrical fields could be used for suppressing the hyperexcitability of spinal motoneurons after SCI and reducing the level of spasticity. PMID- 17702838 TI - Energy flux, more so than energy balance, protein intake, or fitness level, influences insulin-like growth factor-I system responses during 7 days of increased physical activity. AB - The purpose of this study was to determine the impact of dietary factors and exercise-associated factors on the response of IGF-I and its binding proteins (IGFBPs) during a period of increased physical activity. Twenty-nine men completed a 4-day (days 1-4) baseline period of a controlled energy balanced diet while maintaining their normal physical activity level followed by 7 days (days 5 11) of a 1,000 kcal/day increase in physical activity above their normal activity levels. Two subject groups, one sedentary (Sed, mean Vo(2peak): 39 mlxkg(-1)xmin( 1), n = 7) and one fit (FIT1, mean Vo(2peak): 56 ml.kg(-1)xmin(-1), n = 8) increased energy intake to maintain energy balance throughout the 7-day intervention. In two other fit subject groups (FIT2, n = 7 and FIT3, n = 7), energy intake remained at baseline resulting in a 1,000 kcal/day exercise-induced energy deficit. Of these, FIT2 received an adequate protein diet (0.9 g/kg), and FIT3 received a high-protein diet (1.8 g/kg). For all four groups, IGF-I, IGFBP 3, and the acid labile subunit (ALS) were significantly decreased by day 11 (27 +/- 4%, 10 +/- 2%, and 19 +/- 4%, respectively) and IGFBP-2 significantly increased by 49 +/- 21% following day 3. IGFBP-1 significantly increased only in the two negative energy balance groups, FIT2 (38 +/- 6%) and FIT3 (46 +/- 8%). Differences in initial fitness level and dietary protein intake did not alter the IGF-I system response to an acute increase in physical activity. Decreases in IGF I were observed during a moderate increase in physical activity despite maintaining energy balance, suggesting that currently unexplained exercise associated mechanisms, such as increased energy flux, regulate IGF-I independent of energy deficit. PMID- 17702837 TI - Retention of intravenously infused [13C]bicarbonate is transiently increased during recovery from hard exercise. AB - The effects of exercise on energy substrate metabolism persist into the postexercise recovery period. We sought to derive bicarbonate retention factors (k) to correct for carbon tracer oxidized, but retained from pulmonary excretion before, during, and after exercise. Ten men and nine women received a primed continuous infusion of [(13)C]bicarbonate (sodium salt) under three different conditions: 1) before, during, and 3 h after 90 min of exercise at 45% peak oxygen consumption (Vo(2peak)); 2) before, during, and 3 h after 60 min of exercise at 65% Vo(2peak); and 3) during a time-matched resting control trial, with breath samples collected for determination of (13)CO(2) excretion rates. Throughout the resting control trial, k was stable and averaged 0.83 in men and women. During exercise, average k in men was 0.93 at 45% Vo(2peak) and 0.94 at 65% Vo(2peak), and in women k was 0.91 at 45% Vo(2peak) and 0.92 at 65% Vo(2peak), with no significant differences between intensities or sexes. After exercise at 45% Vo(2peak), k returned rapidly to control values in men and women, but following exercise at 65% Vo(2peak), k was significantly less than control at 30 and 60 min postexercise in men (0.74 and 0.72, respectively, P < 0.05) and women (0.75 and 0.76, respectively, P < 0.05) with no significant postexercise differences between men and women. We conclude that bicarbonate/CO(2) retention is transiently increased in men and women for the first hour of postexercise recovery following endurance exercise bouts of hard but not moderate intensity. PMID- 17702839 TI - Oscillatory pressure wave transmission from the upper airway to the carotid artery. AB - Snoring-associated vibration energy transmission from the upper airway to the carotid artery has been hypothesized as a potential atherosclerotic plaque initiating/rupturing event that may provide a pathogenic mechanism linking snoring and embolic stroke. We examined transmission of oscillatory pressure waves from the pharyngeal lumen to the common carotid artery wall and lumen in seven male, anesthetized, spontaneously breathing New Zealand White rabbits. Airflow was monitored via a pneumotachograph inserted in series in the intact trachea. Fifteen 20-s runs of, separately, 40-, 60-, and 90-Hz oscillatory pressure waves [pressure amplitude in the trachea (Ptr(amp)), amplitude 2-20 cmH(2)O] were generated by a loudspeaker driven by a sine wave generator and amplifier and superimposed on tidal breathing via the cranial tracheal connector. Pressure transducer-tipped catheters measured pressure amplitudes in the tissues adjacent to the common carotid artery bifurcation (Pcti(amp)) and within the lumen (carotid sinus; Pcs(amp)). Data were analyzed using power spectrum analysis and linear mixed-effects statistical modeling. Both the frequency (f) and amplitude of the injected pressure wave influenced Pcti(amp) and Pcs(amp), in that ln Pcti(amp) = 1.2(Ptr(amp)) + 0.02(f) - 5.2, and ln Pcs(amp) = 0.6(Ptr(amp)) + 0.02(f) - 4.9 (both P < 0.05). Across all frequencies tested, transfer of oscillatory pressure across the carotid artery wall was associated with an amplitude gain, as expressed by a Pcs(amp)-to-Pcti(amp) ratio of 1.8 +/- 0.3 (n = 6). Our findings confirm transmission of oscillatory pressure waves from the upper airway lumen to the peripharyngeal tissues and across the carotid artery wall to the lumen. Further studies are required to establish the role of this incident energy in the pathogenesis of carotid artery vascular disease. PMID- 17702840 TI - Muscling in on the genetics of quantitative disease traits. PMID- 17702842 TI - Kidney gene expression analysis in a rat model of intrauterine growth restriction reveals massive alterations of coagulation genes. AB - In this study, low birth weight was induced in rats by feeding the dams with a low-protein diet during pregnancy. Kidneys from the fetuses at the end of gestation were collected and showed a reduction in overall and relative weight, in parallel with other tissues (heart and liver). This reduction was associated with a reduction in nephrons number. To better understand the molecular basis of this observation, a transcriptome analysis contrasting kidneys from control and protein-deprived rats was performed, using a platform based upon long isothermic oligonucleotides, strengthening the robustness of the results. We could identify over 1800 transcripts modified more than twice (772 induced and 1040 repressed). Genes of either category were automatically classified according to functional criteria, making it possible to bring to light a large cluster of genes involved in coagulation and complement cascades. The promoters of the most induced and most repressed genes were contrasted for their composition in putative transcription factor binding sites, suggesting an overrepresentation of the AP1R binding site, together with the transcription induction of factors actually binding to this site in the set of induced genes. The induction of coagulation cascades in the kidney of low-birth-weight rats provides a putative rationale for explaining thrombo-endothelial disorders also observed in intrauterine growth restricted human newborns. These alterations in the kidneys have been reported as a probable cause for cardiovascular diseases in the adult. PMID- 17702841 TI - A role for androgens in regulating circadian behavior and the suprachiasmatic nucleus. AB - The suprachiasmatic nucleus (SCN) of the hypothalamus is the locus of a master circadian clock controlling behavioral and physiological rhythms, including rhythmic secretion of gonadal hormones. Gonadectomy results in marked alteration of circadian behaviors, including lengthened free-running period, decreased precision of daily onset of running, and elimination of early-evening but not late-night activity bouts. Androgen replacement restores these responses. These aspects of rhythmicity are thought to be regulated by the brain clock, although the site of androgen action remains unknown. Anatomically, the rodent SCN is composed of a ventrolateral core and a dorsomedial shell, and the present studies show that androgen receptors (AR) are localized to the ventrolateral core SCN. Using a transgenic mouse bearing dual reporter molecules driven by the AR targeted to both membrane and nucleus, we find that projections of AR-containing cells form a dense plexus in the core, with their fibers appearing to exit the SCN dorsally. In a second transgenic strain, in which the retinorecipient gastrin releasing peptide cells express a green fluorescent protein reporter, we show that gastrin-releasing peptide cells contain AR. Through immunocytochemistry, we also show that SCN AR cells express FOS after a light pulse. Importantly, gonadectomy reduces the FOS response after a phase-shifting light pulse, whereas androgen replacement restores levels to those in intact animals. Taken together, the results support previous findings of a hypothalamic neuroendocrine feedback loop. As such, the SCN regulates circadian rhythms in gonadal hormone secretion, and in turn, androgens act on their receptors within the SCN to alter circadian function. PMID- 17702843 TI - Differential activation of the sympathetic innervation of adipose tissues by melanocortin receptor stimulation. AB - Melanocortins are implicated in the control of energy intake/expenditure. Centrally administered melanotan II (MTII), a synthetic melanocortin 3/4-receptor agonist, decreases adiposity beyond that accountable by food intake decreases. Melanocortin-4 receptor (MC4-R) mRNA is expressed on sympathetic nervous system (SNS) outflow neurons to white adipose tissue (WAT) in Siberian hamsters, suggesting a role in lipid mobilization. Therefore, we tested whether third ventricular injections of MTII increased sympathetic drive to WAT and interscapular brown adipose tissue (IBAT) using norepinephrine turnover (NETO) as a measure of sympathetic drive. We also tested for MTII-induced changes in lipolysis-related WAT gene expression (beta3-adrenoceptors, hormone sensitive lipase) and IBAT thermogenesis (beta3-adrenoceptor, uncoupling protein-1). Finally, we tested whether third ventricularly injected MTII, a highly selective MC4-R agonist (cyclo[beta-Ala-His-D-Phe-Arg-Trp-Glu]NH2) increased or agouti related protein decreased IBAT temperature in hamsters implanted with sc IBAT temperature transponders. Centrally administered MTII provoked differential sympathetic drives to WAT and IBAT (increased inguinal WAT, dorsosubcutaneous WAT and IBAT NETO, but not epididymal WAT and retroperitoneal WAT NETO). MTII also increased circulating concentrations of the lipolytic products free fatty acids and glycerol but not plasma catecholamines, suggesting lipid mobilization via WAT SNS innervation and not via adrenal medullary catecholamines. WAT or IBAT gene expression was largely unaffected by acute MTII treatment, but IBAT temperature was increased by MTII and the MC4-R agonist and decreased by agouti-related protein. Collectively, this is the first demonstration of central melanocortin agonist stimulation of WAT lipolysis through the SNS and confirms melanocortin induced changes in BAT thermogenesis. PMID- 17702844 TI - Nutritional influences on reproductive neuroendocrine output: insulin, leptin, and orexigenic neuropeptide signaling in the ovine hypothalamus. AB - This study investigated how changing nutritional status may alter reproductive neuroendocrine (LH) output via circulating leptin and insulin signaling through orexigenic hypothalamic pathways. Thin sheep were given an increasing nutritional plane (INP), sheep with intermediate adiposity a static nutritional plane (SNP), and fat sheep a decreasing nutritional plane (DNP) for 6 wk. Mean group adiposities converged by wk 6, LH output increased in INP, remained unchanged in SNP, and decreased in DNP sheep. Plasma and cerebrospinal fluid (CSF) insulin and plasma leptin concentrations increased in INP but did not change in the SNP and DNP groups. In INP sheep, LH output correlated positively with adiposity and plasma and CSF insulin concentrations and negatively with orexigenic neuropeptide Y gene expression in the hypothalamic arcuate nucleus (ARC). In DNP sheep, LH output correlated positively with adiposity, CSF leptin concentrations, and ARC proopiomelanocortin gene expression and negatively with leptin receptor (OB-Rb) and agouti-related peptide gene expression in the ARC. These data are consistent with the feedback response to an increasing nutritional plane being mediated by increasing circulating insulin entering the brain and stimulating LH via inhibition of hypothalamic neuropeptide Y and the response to a decreasing nutritional plane being mediated by altered hypothalamic leptin signaling brought about by increased OB-Rb expression and decreased melanocortin signaling. Because end point adiposity was similar yet LH output was different, the hypothalamus apparently retains a nutritional memory, based on changes in orexigenic neuropeptide expression, that influences contemporary neuroendocrine responses. PMID- 17702845 TI - Interleukin-11 promotes migration, but not proliferation, of human trophoblast cells, implying a role in placentation. AB - Trophoblast growth and invasion of the uterine endometrium are critical events during placentation and are tightly regulated by factors produced within the trophoblast-endometrial microenvironment. Deficiencies in placentation can result in early miscarriage or preeclampsia and intrauterine growth restriction, leading to impaired fetal health. The latter has been linked to major adult health disorders. IL-11 is essential for blastocyst implantation in mice. In humans, IL 11 and its receptor IL-11 receptor alpha (IL-11Ralpha) are maximally expressed in the decidua and chorionic villi during early pregnancy; however, the role of IL 11 in trophoblast function is unknown. Therefore, we examined whether IL-11Ralpha is expressed in human first trimester implantation sites, and whether IL-11 influences proliferation and migration of a human extravillous trophoblast (EVT) hybridoma cell line and primary EVT cells, used as models for EVT. Immunoreactive IL-11Ralpha localized to subpopulations of interstitial and endovascular EVT cells in vivo. In EVT cells in vitro, IL-11: 1) stimulated phosphorylation of signal transducer and activator of transcription-3; 2) was without effect on EVT cell proliferation; and 3) stimulated significant migration of EVT-hybridoma cells (no endogenous IL-11), whereas in primary EVT, blocking endogenous IL-11 inhibited EVT migration by 30-40%. These data demonstrate that IL-11 stimulates human EVT migration, but not proliferation, likely via signal transducer and activator of transcription-3, indicating an important role for IL-11 in placentation. PMID- 17702846 TI - Activation of nuclear factor-kappaB by high molecular weight and globular adiponectin. AB - Adipose tissue secretes a wide range of hormones named adipokines, and these may play a role in obesity-related inflammation. Adiponectin is an exceptional adipokine because low plasma concentrations are associated with obesity, type 2 diabetes, and cardiovascular diseases. It has been observed that plasma adiponectin concentrations are elevated during inflammatory conditions like preeclampsia and arthritis. Nuclear factor-kappaB (NF-kappaB) is an essential transcription factor for expression of inflammation-related proteins. We have used U937 cells stably transfected to express luciferase under the control of NF kappaB to examine if adiponectin may modulate NF-kappaB activity. Physiological concentrations of native adiponectin induced NF-kappaB activity. This effect was relatively strong compared with proinflammatory adipokines like leptin, resistin, and IL-6. The enhanced NF-kappaB activity was attributed to the high molecular weight adiponectin isoforms. NF-kappaB was not activated by mutated adiponectin that is unable to form high molecular weight complexes. Furthermore, the C terminal fragment, globular adiponectin, markedly increased NF-kappaB reporter activity, cytokine release, and mRNA expression of inflammation marker genes, at higher levels than stimulation with TNF-alpha and lipopolysaccharide. NF-kappaB activation by globular adiponectin was not affected by antibody inhibition of toll-like receptor 4 or TNF receptors 1 and 2 but was attenuated by inhibitors of p38 MAPK, phosphatidylinositol 3-kinase, and protein kinase C. Analyses of the p65 subunit of NF-kappaB in different leukocyte cell lines showed activation of two monocytic cell lines (U937 and THP-1) by native and globular adiponectin. Our results indicate that adiponectin has proinflammatory properties in monocytic cells. PMID- 17702847 TI - Chorionic gonadotropin down-regulates the expression of the decoy inhibitory interleukin 1 receptor type II in human endometrial epithelial cells. AB - Secretion of embryonic IL-1beta seems to be the first response of the blastocyst to receptive endometrium, inducing molecular changes that are essential for attachment of the blastocyst. Here, we report that human chorionic gonadotropin (hCG), a glycoprotein hormone that plays a critical role in the initiation and maintenance of pregnancy, markedly down-regulates the expression of the decoy inhibitory IL-1 receptor type II (IL-1R2) in human endometrial epithelial cells. Treatment with hCG resulted in a dose-dependent decrease in IL-1R2 soluble and membrane bound protein forms and mRNA steady-state levels, whereas no significant effect on the expression of the activating IL-1 receptor type I (IL-1R1) was seen. Cell infection with the wild-type human LH/chorionic gonadotropin receptor corroborated the aforementioned data, whereas cell infection with the constitutively activated LH chorionic gonadotropin receptor led to similar effects on IL-1R2 and IL-1R1 expression without hCG treatment. Cloning of human IL-1R2 gene promoter in the pGL3 luciferase reporter vector and transient transfection experiments further showed a significant dose-dependent diminution of IL-1R2 promoter activity in response to hCG. These data suggest that hCG, by down-regulating the expression of IL-1R2, a potent and specific inhibitor of IL 1, without affecting the expression of the functional activating IL-1R1, diminishes the ability of endometrial epithelial cells to counterbalance the local effects of IL-1, making these cells probably more responsive to the cytokine. In view of IL-1's role as an embryonic signal, these data reveal a new mechanism by which hCG sustains human pregnancy and promotes embryonic growth. PMID- 17702848 TI - Ceramide and adenosine 5'-monophosphate-activated protein kinase are two novel regulators of 11beta-hydroxysteroid dehydrogenase type 1 expression and activity in cultured preadipocytes. AB - Increased activity of intracellular glucocorticoid reactivating enzyme, 11beta hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in obese adipose tissue contributes to adipose dysfunction. As recent studies have highlighted a potential role of preadipocytes in adipose dysfunction, we tested the hypothesis that a variety of metabolic stress mediated by ceramide or AMP-activated protein kinase (AMPK) would regulate 11beta-HSD1 in preadipocytes. The present study is the first to show that 1) expression of 11beta-HSD1 in 3T3-L1 preadipocytes was robustly induced when cells were treated with cell-permeable ceramide analogue C(2) ceramide, bacterial sphingomyelinase, and sphingosine 1-phosphate, 2) 5 aminoimidazole-4-carboxamide ribonucleoside (AICAR)-induced activation of AMPK augmented the expression and enzyme activity of 11beta-HSD1, and 3) these results were reproduced in human preadipocytes. We demonstrate for the first time that C(2) ceramide and AICAR markedly induced the expression of CCAAT/enhancer-binding protein (C/EBP) beta and its binding to 11beta-HSD1 promoter. Transient knockdown of C/EBPbeta protein by small interfering RNA markedly attenuated the expression of 11beta-HSD1 induced by C(2) ceramide or AICAR. The present study provides novel evidence that ceramide- and AMPK-mediated signaling pathways augment the expression and activity of 11beta-HSD1 in preadipocytes by way of C/EBPbeta, thereby highlighting a novel, metabolic stress-related regulation of 11beta-HSD1 in a cell-specific manner. PMID- 17702849 TI - Prostaglandin F2alpha suppresses rat steroidogenic acute regulatory protein expression via induction of Yin Yang 1 protein and recruitment of histone deacetylase 1 protein. AB - Prostaglandin F2alpha (PGF2alpha) plays a pivotal role in ovarian luteolysis by inhibiting the expression of steroidogenic acute regulatory (StAR) protein, leading to a decrease in intracellular cholesterol transport and luteal steroid production. Previously we have demonstrated that the transcription factor Yin Yang 1 (YY1) bound to three regions in the StAR promoter in vitro and repressed promoter activity. This study further defined the YY1-mediated PGF2alpha effect on the inhibition of StAR protein expression through YY1 interaction with a single region in the StAR promoter in vivo. PGF2alpha consistently suppressed StAR mRNA and protein expression in cultured luteal cells in a dose-dependent manner. PGF2alpha also enhanced YY1 protein expression and binding to its cis element in a time-dependent pattern that preceded the decline in StAR protein levels. The StAR promoter region bound by YY1 was also associated with histone deacetylase 1 (HDAC1). PGF2alpha treatment promoted HDAC1 binding to and suppressed the histone H3 acetylation in this region. On the contrary, YY1 knockdown decreased HDAC1 binding, increased histone H3 acetylation, enhanced StAR protein expression, and negated PGF2alpha effect on StAR protein expression. Luciferase assays showed that YY1 overexpression inhibited StAR promoter activity and the addition of a HDAC inhibitor, trichostatin A, abrogated the effect of YY1. Trichostatin A-treated luteal cells displayed increased StAR protein expression. These data indicate that PGF2alpha enhances a direct YY1/StAR promoter interaction and the recruitment of HDAC1 to the promoter, thereby preventing transcriptional activation of the StAR gene. PMID- 17702850 TI - Induction of CXCL1 by extracellular matrix and autocrine enhancement by interleukin-1 in rat pancreatic beta-cells. AB - As we showed previously, the extracellular matrix (ECM) derived from rat bladder carcinoma cells (804G-ECM) has positive effects on rat primary beta-cell function and survival in vitro. The aim of this study was to define beta-cell genes induced by this ECM with a specific focus on cytokines. Analysis of differential gene expression by oligonucleotide microarrays, RT-PCR, and in situ hybridization was performed to identify cytokine mRNA induced by this matrix. Four cytokines were overexpressed on 804G-ECM compared with poly-L-lysine: C-X-C motif ligand 1 (CXCL1), CXCL2, interferon-inducible protein-10, and IL-1beta. A time-course experiment indicated that maximal induction by 804G-ECM of CXCL1/2 and interferon inducible protein-10 occurred at 4 h. Stimulation of CXCL1 release by beta-cells on 804G-ECM was confirmed at the protein level. Moreover, secreted CXCL1 was shown to be functionally active by attracting rat granulocytes. Preventing the interaction of beta1 integrins and laminin-5 (a major component of 804G-ECM) with specific antibodies resulted in a 40-50% inhibition of CXCL1 expression. Using the nuclear factor-kappaB pathway inhibitor Bay 11-7082 it is demonstrated that CXCL1 expression and secretion are dependent on nuclear factor-kappaB activation. IL-1 secreted by beta-cells plated on 804G-ECM was found to be a key soluble mediator because treatment of cells with the IL-1 receptor antagonist significantly reduced both CXCL1 gene expression and secretion. It is concluded that ECM induces expression of cytokines including CXCL1 with amplification by IL 1 acting via a positive autocrine feedback loop. PMID- 17702851 TI - Fish glucose transporter (GLUT)-4 differs from rat GLUT4 in its traffic characteristics but can translocate to the cell surface in response to insulin in skeletal muscle cells. AB - In mammals, glucose transporter (GLUT)-4 plays an important role in glucose homeostasis mediating insulin action to increase glucose uptake in insulin responsive tissues. In the basal state, GLUT4 is located in intracellular compartments and upon insulin stimulation is recruited to the plasma membrane, allowing glucose entry into the cell. Compared with mammals, fish are less efficient restoring plasma glucose after dietary or exogenous glucose administration. Recently our group cloned a GLUT4-homolog in skeletal muscle from brown trout (btGLUT4) that differs in protein motifs believed to be important for endocytosis and sorting of mammalian GLUT4. To study the traffic of btGLUT4, we generated a stable L6 muscle cell line overexpressing myc-tagged btGLUT4 (btGLUT4myc). Insulin stimulated btGLUT4myc recruitment to the cell surface, although to a lesser extent than rat-GLUT4myc, and enhanced glucose uptake. Interestingly, btGLUT4myc showed a higher steady-state level at the cell surface under basal conditions than rat-GLUT4myc due to a higher rate of recycling of btGLUT4myc and not to a slower endocytic rate, compared with rat-GLUT4myc. Furthermore, unlike rat-GLUT4myc, btGLUT4myc had a diffuse distribution throughout the cytoplasm of L6 myoblasts. In primary brown trout skeletal muscle cells, insulin also promoted the translocation of endogenous btGLUT4 to the plasma membrane and enhanced glucose transport. Moreover, btGLUT4 exhibited a diffuse intracellular localization in unstimulated trout myocytes. Our data suggest that btGLUT4 is subjected to a different intracellular traffic from rat GLUT4 and may explain the relative glucose intolerance observed in fish. PMID- 17702852 TI - Intrafetal insulin-like growth factor-I infusion stimulates adrenal growth but not steroidogenesis in the sheep fetus during late gestation. AB - We investigated the effects of an intrafetal infusion of IGF-I on adrenal growth and expression of the adrenal steroidogenic and catecholamine-synthetic enzyme mRNAs in the sheep fetus during late gestation. Fetal sheep were infused for 10 d with either IGF-I (26 microg/kg.h; n = 14) or saline (n = 10) between 120 and 130 d gestation, and adrenal glands were collected for morphological analysis and determination of the mRNA expression of steroidogenic and catecholamine-synthetic enzymes. Fetal body weight was not altered by IGF-I infusion; however, adrenal weight was significantly increased by 145% after IGF-I infusion. The density of cell nuclei within the fetal adrenal cortex (the zona glomerulosa and zona fasciculata), and within the adrenaline synthesizing zone of the adrenal medulla, was significantly less in the IGF-I-infused fetuses compared with the saline infused group. Thus, based on cell-density measurements, there was a significant increase in cell size in the zona glomerulosa and zona fasciculata of the adrenal cortex and in the adrenaline-synthesizing zone of the adrenal medulla. There was no effect of IGF-I infusion on the adrenal mRNA expression of the steroidogenic or catecholamine-synthetic enzymes or on fetal plasma cortisol concentrations. In summary, infusion of IGF-I in late gestation resulted in a marked hypertrophy of the steroidogenic and adrenaline-containing cells of the fetal adrenal in the absence of changes in the mRNA levels of adrenal steroidogenic or catecholamine synthetic enzymes or in fetal plasma cortisol concentrations. Thus, IGF-I infusion results in a dissociation of adrenal growth and function during late gestation. PMID- 17702853 TI - Kisspeptin synchronizes preovulatory surges in cyclical ewes and causes ovulation in seasonally acyclic ewes. AB - We determined whether kisspeptin could be used to manipulate the gonadotropin axis and ovulation in sheep. First, a series of experiments was performed to determine the gonadotropic responses to different modes and doses of kisspeptin administration during the anestrous season using estradiol-treated ovariectomized ewes. We found that: 1) injections (iv) of doses as low as 6 nmol human C terminal Kiss1 decapeptide elevate plasma LH and FSH levels, 2) murine C-terminal Kiss1 decapeptide was equipotent to human C-terminal Kiss1 decapeptide in terms of the release of LH or FSH, and 3) constant iv infusion of kisspeptin induced a sustained release of LH and FSH over a number of hours. During the breeding season and in progesterone-synchronized cyclical ewes, constant iv infusion of murine C-terminal Kiss1 decapeptide-10 (0.48 mumol/h over 8 h) was administered 30 h after withdrawal of a progesterone priming period, and surge responses in LH occurred within 2 h. Thus, the treatment synchronized preovulatory LH surges, whereas the surges in vehicle-infused controls were later and more widely dispersed. During the anestrous season, we conducted experiments to determine whether kisspeptin treatment could cause ovulation. Infusion (iv) of 12.4 nmol/h kisspeptin for either 30 or 48 h caused ovulation in more than 80% of kisspeptin treated animals, whereas less than 20% of control animals ovulated. Our results indicate that systemic delivery of kisspeptin provides new strategies for the manipulation of the gonadotropin secretion and can cause ovulation in noncyclical females. PMID- 17702854 TI - Polymorphisms and haplotypes of the estrogen receptor-beta gene (ESR2) and cardiovascular disease in men and women. AB - BACKGROUND: Cohort studies suggest an association between variation in the estrogen receptor-alpha gene (ESR1) and cardiovascular disease (CVD), but data are lacking for the effect of variation in the estrogen receptor-beta gene (ESR2). METHODS: Three polymorphisms of the ESR2 gene, and their associated haplotypes, were evaluated in 296 white women from the Women's Health Study and 566 white men from the Physicians' Health Study who developed CVD [myocardial infarction (MI) or ischemic stroke], each matched 1:1 to a member of the cohort study who remained free from CVD. Blood samples and cardiovascular risk information were collected at baseline. RESULTS: Women, but not men, who developed CVD or MI, but not ischemic stroke, were more likely to have the rs1271572 polymorphism variant T allele (P = 0.05 and 0.02) and less likely to have the rs1256049 polymorphism variant A allele (P = 0.003 and 0.004). No associations were observed for rs4986938. In conditional logistic multivariate regression, the rs1271572 variant was associated with increased odds of CVD [odds ratio (OR) = 1.49, 95% CI: 1.10-2.01] and MI (OR = 1.46, 95% CI: 0.96-2.23), whereas the rs1256049 variant was associated with decreased odds of CVD (OR = 0.37, 95% CI: 0.17-0.79) and MI (OR = 0.25, 95% CI: 0.09-0.73) in women. A common haplotype that included the rs1271572 variant was associated with a 7-fold increased risk of MI in women. CONCLUSIONS: Two tightly linked polymorphisms of ESR2 were associated with risk of CVD, particularly MI, in women but not men. Additional studies of ESR2 genetic variation and risk of CVD are warranted. PMID- 17702855 TI - Serum proprotein convertase subtilisin kexin type 9 is correlated directly with serum LDL cholesterol. AB - BACKGROUND: Proprotein convertase subtilisin kexin type 9 (PCSK9) is gaining attention as a key regulator of serum LDL-cholesterol (LDLC). This novel serine protease causes the degradation of hepatic LDL receptors by an unknown mechanism. In humans, gain-of-function mutations in the PCSK9 gene cause a form of familial hypercholesterolemia, whereas loss-of-function mutations result in significantly decreased LDLC and decreased cardiovascular risk. Relatively little is known about PCSK9 in human serum. METHODS: We used recombinant human PCSK9 protein and 2 different anti-PCSK9 monoclonal antibodies to build a sandwich ELISA. We measured PCSK9 and lipids in 55 human serum samples and correlated the results. We used the anti-PCSK9 antibodies to assay lipoprotein particle fractions separated by sequential flotation ultracentrifugation. RESULTS: Serum concentrations of PCSK9 ranged from 11 to 115 microg/L and were directly correlated with serum concentrations of LDLC (r = 0.45, P = 0.001) and total cholesterol (r = 0.50, P = 0.0003), but not with triglycerides (r = 0.15, P = 0.28) or HDL cholesterol concentrations (r = 0.13, P = 0.36). PCSK9 was not detectable in any lipoprotein particle fraction, including LDL. CONCLUSIONS: PCSK9 is present in human serum, likely not associated with specific lipoprotein particles. The circulating concentrations of human PCSK9 are directly correlated with LDL and total cholesterol concentrations. PMID- 17702856 TI - Methanol-associated matrix effects in electrospray ionization tandem mass spectrometry. AB - BACKGROUND: Matrix effects can profoundly reduce the performance of electrospray ionization mass spectrometry. Preliminary observations indicated that the methanol used in the mobile phase could be a source of differential ionization or ion suppression. METHODS: Drug stability studies, analysis of biological extracts, mixing experiments, and postcolumn infusions were used to test 9 commercial methanols for ionization differences in liquid chromatography-tandem mass spectrometry assays for immunosuppressants. Area responses for the drugs and internal standards were compared for mobile phases prepared with each selected methanol. Postcolumn infusion experiments were performed to confirm the degree of ionization differences occurring at the ion source, and to evaluate the proportions of ammonium, sodium, and potassium adducts. RESULTS: The decrease in signal for the immunosuppressant drugs was shown to result from differential ionization associated with the selected methanols. Product ion intensity varied by 10-fold among the methanols tested. For sirolimus, tacrolimus, and mycophenolic acid, the percentage change in ionization was the same for the drug and its corresponding internal standard. Postcolumn sirolimus infusion evaluation revealed that a 1000-fold analyte concentration difference did not affect ionization. The proportions of ammonium, sodium, and potassium adducts of sirolimus precursor ions differed in relation to the source of methanol. CONCLUSIONS: Organic solvents used in mobile phases and extract preparation of biological samples may be associated with ion suppression, affecting adduct formation and assay sensitivity. PMID- 17702857 TI - Quantification of ZAP70 mRNA in B cells by real-time PCR is a powerful prognostic factor in chronic lymphocytic leukemia. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is heterogeneous with respect to prognosis and clinical outcome. The mutational status of the immunoglobulin variable heavy chain region (IGHV) has been used to classify patients into 2 groups in terms of overall survival (OS) and clinical characteristics, but the labor-intensive nature and the cost of this time-consuming analysis has prompted investigations of surrogate markers. METHODS: We developed a standardized quantitative real-time reverse transcription-PCR (qPCR) method to measure zeta chain (TCR)-associated protein kinase (ZAP70) mRNA in purified CD19(+) cells. We evaluated this and other methods (flow cytometry analyses of ZAP70 and CD38 proteins and qPCR analysis of lipoprotein lipase mRNA) in a cohort of 108 patients (median follow-up, 82 months) to evaluate any associations with IGHV mutational status, OS, and treatment-free survival (TFS). RESULTS: The association between qPCR-measured ZAP70 and IGHV mutational status was statistically significant [chi(2) (1) = 50.95; P <0.0001], and the value of Cramer's V statistic (0.72) indicated a very strong relation. This method also demonstrated sensitivity, specificity, and positive and negative predictive values of 87.8%, 85.7%, 87.5%, and 86%, respectively. ZAP70 expression was significantly associated with OS (P = 0.0021) and TFS (P <0.0001). ZAP70(+) patients had significantly shorter median TFS (24 months) than ZAP70(-) patients (157 months) (P <0.0001). Moreover, qPCR-measured ZAP70 expression has greater prognostic power than IGHV mutational status and the other prognostic markers tested. CONCLUSIONS: ZAP70 mRNA quantification via qPCR is a strong surrogate marker of IGHV mutational status and a powerful prognostic factor. PMID- 17702858 TI - Novel serum biomarker candidates for liver fibrosis in hepatitis C patients. AB - BACKGROUND: Liver biopsy is currently the gold standard for assessing liver fibrosis, and no reliable noninvasive diagnostic approach is available. Therefore a suitable serologic biomarker of liver fibrosis is urgently needed. METHODS: We used a proteomics method based on 2-dimensional gel electrophoresis to identify potential fibrosis biomarkers. Serum samples from patients with varying degrees of hepatic scarring induced by infection with the hepatitis C virus (HCV) were analyzed and compared with serum from healthy controls. RESULTS: We observed the most prominent differences when we compared serum samples from cirrhotic patients with healthy control serum. Inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) fragments, alpha1 antichymotrypsin, apolipoprotein L1 (Apo L1), prealbumin, albumin, paraoxonase/arylesterase 1, and zinc-alpha2-glycoprotein were decreased in cirrhotic serum, whereas CD5 antigen-like protein (CD5L) and beta2 glycoprotein I (beta2GPI) were increased. In general, alpha2 macroglobulin (a2M) and immunoglobulin components increased with hepatic fibrosis, whereas haptoglobin and complement components (C3, C4, and factor H-related protein 1) decreased. Novel proteins associated with HCV-induced fibrosis included ITIH4 fragments, complement factor H-related protein 1, CD5L, Apo L1, beta2GPI, and thioester-cleaved products of a2M. CONCLUSIONS: Assessment of hepatic scarring may be performed with a combination of these novel fibrosis biomarkers, thus eliminating the need for liver biopsy. Further evaluation of these candidate markers needs to be performed in larger patient populations. Diagnosis of fibrosis during early stages will allow early treatment, thereby preventing fibrosis progression. PMID- 17702859 TI - Novel neutrophil-derived proteins in bronchoalveolar lavage fluid indicate an exaggerated inflammatory response in pediatric cystic fibrosis patients. AB - BACKGROUND: Airway inflammation in cystic fibrosis (CF) is exaggerated and characterized by neutrophil-mediated tissue destruction, but its genesis and mechanisms remain poorly understood. To further define the pulmonary inflammatory response, we conducted a proteome-based screen of bronchoalveolar lavage fluid (BALF) collected from young children with and without CF experiencing endobronchial infection. METHODS: We collected BALF samples from 45 children younger than 5 years and grouped them according to the presence of respiratory pathogens: > or = 1 x 10(5) colony-forming units (CFU)/mL BALF (18 and 12 samples with and without CF, respectively) and <1 x 10(5) CFU/mL (23 and 15 samples). BALF proteins were analyzed with SELDI-TOF mass spectrometry (MS) and H4 ProteinChips. Proteins were identified and characterized using trypsin digestion, tandem MS, Fourier transform ion cyclotron resonance MS, immunoblotting, and ELISA. RESULTS: The SELDI-TOF MS BALF profiles contained 53 unique, reliably detected proteins. Peak intensities of 24 proteins differed significantly between the CF and non-CF samples. They included the neutrophil proteins, alpha-defensin 1 and 2, S100A8, S100A9, and S100A12, as well as novel forms of S100A8 and S100A12 with equivalent C-terminal deletions. Peak intensities of these neutrophil proteins and immunoreactive concentrations of selected examples were significantly higher in CF than non-CF samples. CONCLUSIONS: Small neutrophil derived BALF proteins, including novel C-terminal truncated forms of S100A proteins, are easily detected with SELDI-TOF MS. Concentrations of these molecules are abnormally high in early CF lung disease. The data provide new insights into CF lung disease and identify novel proteins strongly associated with CF airway inflammation. PMID- 17702860 TI - Fetuin-A is an independent predictor of death after ST-elevation myocardial infarction. AB - BACKGROUND: Fetuin-A inhibits inflammation and has a protective effect against myocardial ischemia. Its deficiency has been found to be associated with cardiovascular death in patients with end-stage renal failure disease. We investigated the association between plasma fetuin-A and clinical outcome after ST-elevation acute myocardial infarction (STEMI). METHODS: We measured fetuin-A in 284 consecutive patients with STEMI and correlated these data with the occurrence of death at 6 months (n = 25). We also measured fetuin-A in a control group and chose the 95th percentile as the cutoff to define abnormality. RESULTS: Patient mean (SD) age was 60 (14) years, and creatinine clearance was 83 (31) mL/min; 82% were men. Mean (SD) plasma fetuin-A concentrations at admission [188 (69) mg/L, P = 0.01] and at day 3 [163 (57) mg/L, P <0.0001] were lower in patients than in controls [219 (39) mg/L; 95th percentile 140 mg/L]. Fetuin-A <140 mg/L was observed in 20% of patients at admission vs 40% at day 3 (P <0.001). Fetuin-A concentrations did not correlate with peak cardiac troponin values but did correlate inversely with C-reactive protein (CRP) and NT-pro-brain natriuretic peptide (NT-proBNP). Fetuin-A <140 mg/L at admission (OR = 3.3, P = 0.03) and at day 3 (OR = 6.3, P = 0.002) was an independent correlate of death at 6 months, irrespective of NT-proBNP, CRP, or Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) risk score. Conversely, fetuin-A > or = 140 mg/L was associated with an excellent survival rate [negative predictive value (NPV) = 97% overall], even in high-risk populations with CADILLAC risk score > or = 6 (NPV = 90% in patients). CONCLUSIONS: Fetuin-A is an important predictor of death at 6 months in STEMI patients independent of NT-proBNP, CRP, and CADILLAC risk score. PMID- 17702861 TI - Induction of autoimmune disease in CTLA-4-/- mice depends on a specific CD28 motif that is required for in vivo costimulation. AB - CTLA-4-deficient mice develop a lethal autoimmune lymphoproliferative disorder that is strictly dependent on in vivo CD28 costimulation. Nevertheless, it is not known whether there is a specific site on the CD28 molecule that is required for induction of autoimmunity. Using CTLA-4-deficient mice expressing CD28 molecules with various point mutations in the CD28 cytosolic tail, the present study documents that in vivo costimulation for induction of autoimmune disease strictly requires an intact C-terminal proline motif that promotes lymphocyte-specific protein tyrosine kinase Lck binding to the CD28 cytosolic tail, because point mutations in C-terminal proline residues (Pro-187 and Pro-190) completely prevented disease induction. In contrast, in vivo costimulation for disease induction did not require either an intact YMNM motif or an intact N-terminal proline motif, which, respectively, promote phosphoinositide 3-kinase and IL2 inducible T cell kinase binding to the CD28 cytosolic tail. Thus, in vivo CD28 costimulation for induction of autoimmune disease is strictly and specifically dependent on an intact C-terminal proline motif that serves as a lymphocyte specific protein tyrosine Lck kinase binding site in the CD28 cytosolic tail. PMID- 17702862 TI - Human C-reactive protein slows atherosclerosis development in a mouse model with human-like hypercholesterolemia. AB - Increased baseline values of the acute-phase reactant C-reactive protein (CRP) are significantly associated with future cardiovascular disease, and some in vitro studies have claimed that human CRP (hCRP) has proatherogenic effects. in vivo studies in apolipoprotein E-deficient mouse models, however, have given conflicting results. We bred atherosclerosis-prone mice (Apob(100/100)Ldlr(-/-)), which have human-like hypercholesterolemia, with hCRP transgenic mice (hCRP(+/0)) and studied lesion development at 15, 30, 40, and 50 weeks of age. Atherosclerotic lesions were smaller in hCRP(+/0)Apob(100/100)Ldlr(-/-) mice than in hCRP(0/0)Apob(100/100)Ldlr(-/-) controls, as judged from the lesion surface areas of pinned-out aortas from mice at 40 and 50 weeks of age. In lesions from 40-week-old mice, mRNA expression levels of several genes in the proteasome degradation pathway were higher in hCRP(+/0)Apob(100/100)Ldlr(-/-) mice than in littermate controls, as shown by global gene expression profiles. These results were confirmed by real-time PCR, which also indicated that the activities of those genes were the same at 30 and 40 weeks in hCRP(+/0)Apob(100/100)Ldlr(-/-) mice but were significantly lower at 40 weeks than at 30 weeks in controls. Our results show that hCRP is not proatherogenic but instead slows atherogenesis, possibly through proteasome-mediated protein degradation. PMID- 17702863 TI - New results of intersection numbers on moduli spaces of curves. AB - We present a series of results we obtained recently about the intersection numbers of tautological classes on moduli spaces of curves, including a simple formula of the n-point functions for Witten's tau classes, an effective recursion formula to compute higher Weil-Petersson volumes, several new recursion formulae of intersection numbers and our proof of a conjecture of Itzykson and Zuber concerning denominators of intersection numbers. We also present Virasoro and KdV properties of generating functions of general mixed kappa and psi intersections. PMID- 17702864 TI - Binomial parameters differ across neocortical layers and with different classes of connections in adult rat and cat neocortex. AB - Binomial model-based analysis compared excitatory connections involving different classes of neurons in different neocortical layers. Single-sweep excitatory postsynaptic potentials (EPSPs) from dual intracellular recordings in adult cat and rat slices were measured. For data subsets corresponding to first EPSPs exhibiting different degrees of posttetanic potentiation and second, third etc. EPSPs in trains at different interspike intervals, coefficient of variation (CV), transmission failure rates (F), variance (V), and V/M were plotted against mean EPSP amplitude (M). Curves derived from binomial models in which subsets varied only in p (release probability) were fit and parameters q (quantal amplitude), and n (number of release sites) were estimated. Estimates for q and n were similar for control subsets and subsets recorded during Ca(2+) channel blockade, only p varied. Estimates from the four methods were powerfully correlated, but when CV, F, V, and V/M were plotted against M, different types of connections occupied different regions of parameter space. Comparisons of linear fits to V/M against M plots and of parameter estimates indicated that these differences were significant. Connections between pyramids in different layers and inputs to different cell classes in the same layer differed markedly. Monte Carlo simulations of more complex models subjected to simple binomial model-based analysis confirmed the significance of these differences. Binomial models, either simple, in which p and q are identical at all terminals involved, or more complex, in which they differ, adequately describe many neocortical connections, but each class uses different combinations of n, mean p, and mean q. PMID- 17702865 TI - The two oxidized forms of the trinuclear Cu cluster in the multicopper oxidases and mechanism for the decay of the native intermediate. AB - Multicopper oxidases (MCOs) catalyze the 4e(-) reduction of O(2) to H(2)O. The reaction of the fully reduced enzyme with O(2) generates the native intermediate (NI), which undergoes a slow decay to the resting enzyme in the absence of substrate. NI is a fully oxidized form, but its spectral features are very different from those of the resting form (also fully oxidized), because the type 2 and the coupled-binuclear type 3 Cu centers in the O(2)-reducing trinuclear Cu cluster site are isolated in the resting enzyme, whereas these are all bridged by a micro(3)-oxo ligand in NI. Notably, the one azide-bound NI (NI(Az)) exhibits spectral features very similar to those of NI, in which the micro(3)-oxo ligand in NI has been replaced by a micro(3)-bridged azide. Comparison of the spectral features of NI and NI(Az), combined with density functional theory (DFT) calculations, allows refinement of the NI structure. The decay of NI to the resting enzyme proceeds via successive proton-assisted steps, whereas the rate limiting step involves structural rearrangement of the micro(3)-oxo-bridge from inside to outside the cluster. This phenomenon is consistent with the slow rate of NI decay that uncouples the resting enzyme from the catalytic cycle, leaving NI as the catalytically relevant fully oxidized form of the MCO active site. The all-bridged structure of NI would facilitate electron transfer to all three Cu centers of the trinuclear cluster for rapid proton-coupled reduction of NI to the fully reduced form for catalytic turnover. PMID- 17702866 TI - SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation. AB - SOX (SRY type HMG box) proteins are transcription factors that are predominantly known for their roles during development. During melanocyte development from the neural crest, SOX10 regulates microphthalmia-associated transcription factor, which controls a set of genes critical for pigment cell development and pigmentation, including dopachrome tautomerase and tyrosinase. We report here that another SOX factor, SOX9, is expressed by melanocytes in neonatal and adult human skin and is up-regulated by UVB exposure. We demonstrate that this regulation is mediated by cAMP and protein kinase. We also show that agouti signal protein, a secreted factor known to decrease pigmentation, down-regulates SOX9 expression. In adult and neonatal melanocytes, SOX9 regulates microphthalmia associated transcription factor, dopachrome tautomerase, and tyrosinase promoters, leading to an increase in the expression of these key melanogenic proteins and finally to a stimulation of pigmentation. SOX9 completes the complex and tightly regulated process leading to the production of melanin by acting at a very upstream level. This role of SOX9 in pigmentation emphasizes the poorly understood impact of SOX proteins in adult tissues. PMID- 17702868 TI - A nonmineralized approach to abrasion-resistant biomaterials. AB - The tooth-like mouthparts of some animals consist of biomacromolecular scaffolds with few mineral components, making them intriguing paradigms of biostructural materials. In this study, the abrasion resistance of the jaws of one such animal, the bloodworm Glycera dibranchiata, has been evaluated by nanoindentation, nanoscratching, and wear testing. The hardest, stiffest, and most abrasion resistant materials are found within a thin (<3 microm) surface layer near the jaw tip and a thicker (10-20 microm) subsurface layer, both rich in unmineralized Cu. These results are consistent with the supposition that Cu ions are involved in the formation of intermolecular coordination complexes between proteins, creating a highly cross-linked molecular network. The intervening layer contains aligned atacamite [Cu(2)(OH)(3)Cl] fibers and exhibits hardness and stiffness (transverse to the alignment direction) that are only slightly higher than those of the bulk material but lower than those of the two Cu-rich layers. Furthermore, the atacamite-containing layer is the least abrasion-resistant, by a factor of approximately 3, even relative to the bulk material. These observations are broadly consistent with the behavior of engineering polymer composites with hard fiber or particulate reinforcements. The alignment of fibers parallel to the jaw surface, and the fiber proximity to the surface, are both suggestive of a natural adaptation to enhance bending stiffness and strength rather than to endow the surface regions with enhanced abrasion resistance. PMID- 17702870 TI - Familial mortality in the Utah population database: characterizing a human aging phenotype. AB - We examine the effects of familial longevity and familial mortality on mortality rates for 10 leading causes of death in a Utah Population Database (UPDB) cohort. Familial excess longevity (FEL) and familial standardized mortality ratios (FSMR) were estimated for 666,921 individuals born from 1830 through 1963, who survived to at least age 40. Cox regression analysis shows that familial death and familial longevity have independent effects on cause-specific mortality rates for 10 leading causes of death. A family history of disease increases one's risk of dying from the same cause, whereas a family history of longevity is protective, except in the case of cancer. Families with greater longevity do not die of causes distinct from other members of the cohort, but they die from the same causes at reduced rates. Individuals from longer lived families have lower mortality from most age-related diseases including heart disease, stroke, and diabetes, but not cancer. PMID- 17702869 TI - Forerunner genes contiguous to RB1 contribute to the development of in situ neoplasia. AB - We used human bladder cancer as a model system and the whole-organ histologic and genetic mapping strategy to identify clonal genetic hits associated with growth advantage, tracking the evolution of bladder cancer from intraurothelial precursor lesions. Six putative chromosomal regions critical for clonal expansion of intraurothelial neoplasia and development of bladder cancer were identified by using this approach. Focusing on one of the regions, which includes the model tumor suppressor RB1, we performed allelotyping of single-nucleotide polymorphic sites and identified a 1.34-Mb segment around RB1 characterized by a loss of polymorphism associated with the initial expansion of in situ neoplasia. This segment contains several positional candidate genes referred to by us as forerunner genes that may contribute to such expansion. We subsequently concentrated our efforts on the two neighbor genes flanking RB1, namely ITM2B and CHC1L, as well as P2RY5, which is located inside RB1. Here, we report that ITM2B and P2RY5 modulated cell survival and were silenced by methylation or point mutations, respectively, and thus by functional loss may contribute to the growth advantage of neoplasia. We also show that homozygous inactivation of P2RY5 was antecedent to the loss of RB1 during tumor development, and that nucleotide substitutions in P2RY5 represent a cancer predisposing factor. PMID- 17702867 TI - Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice. AB - Although Parkinson's disease (PD) is characterized primarily by loss of nigrostriatal dopaminergic neurons, there is a concomitant loss of norepinephrine (NE) neurons in the locus coeruleus. Dopaminergic lesions induced by 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP) are commonly used to model PD, and although MPTP effectively mimics the dopaminergic neuropathology of PD in mice, it fails to produce PD-like motor deficits. We hypothesized that MPTP is unable to recapitulate the motor abnormalities of PD either because the behavioral paradigms used to measure coordinated behavior in mice are not sensitive enough or because MPTP in the absence of NE loss is insufficient to impair motor control. We tested both possibilities by developing a battery of coordinated movement tests and examining motor deficits in dopamine beta-hydroxylase knockout (Dbh-/-) mice that lack NE altogether. We detected no motor abnormalities in MPTP treated control mice, despite an 80% loss of striatal dopamine (DA) terminals. Dbh-/- mice, on the other hand, were impaired in most tests and also displayed spontaneous dyskinesias, despite their normal striatal DA content. A subset of these impairments was recapitulated in control mice with 80% NE lesions and reversed in Dbh-/- mice, either by restoration of NE or treatment with a DA agonist. MPTP did not exacerbate baseline motor deficits in Dbh-/- mice. Finally, striatal levels of phospho-ERK-1/2 and DeltaFosB/FosB, proteins which are associated with PD and dyskinesias, were elevated in Dbh-/- mice. These results suggest that loss of locus coeruleus neurons contributes to motor dysfunction in PD. PMID- 17702871 TI - Attenuation of age-related muscle wasting and weakness in rats after formoterol treatment: therapeutic implications for sarcopenia. AB - We investigated the potential of the beta(2)-adrenoceptor agonist formoterol to increase mass and force-producing capacity of extensor digitorum longus (EDL) and soleus muscles from young, adult, and old rats. In addition, we examined the result of formoterol withdrawal. Young (3 month), adult (16 month), and old (27 month) F344 rats were treated with either formoterol (25 microg/kg/day, i.p.) or saline vehicle for 4 weeks. Another group of rats (for each age) was similarly treated with formoterol, followed by a withdrawal period of 4 weeks. Formoterol treatment increased EDL muscle mass and the force-producing capacity of both EDL and soleus muscles, without a concomitant increase in heart mass in adult and old rats. The hypertrophy and increased force-producing capacity of EDL muscles persisted 4 weeks after withdrawal of treatment. The findings have major implications for potential clinical trials utilizing beta(2)-agonists for sarcopenia. PMID- 17702873 TI - Testing interventions to preserve walking ability: progress against disability, one step at a time. PMID- 17702872 TI - Age-associated oxidative macromolecular damages in rat brain regions: role of glutathione monoester. AB - The generation of reactive oxygen species (ROS) and resultant oxidative stress has been implicated in the mechanism of brain dysfunction due to age-related neurodegenerative diseases. We have evaluated the efficacy of glutathione monoester (GME) when administered intraperitoneally (12 mg/kg body weight) for 20 days on glutathione, ROS, superoxide anion production, lipid peroxidation (LPO), protein carbonyls, thiol status, oxidative DNA damage products such as 8-hydroxy deoxy guanosine and DNA protein cross-links in discrete brain regions of young and aged rats. An age associated increase in ROS, superoxide anion production, LPO, protein oxidation, and DNA damage products in cortex, striatum, and hippocampus was observed which was reversed by GME. Contradictorily, a decline in the levels of glutathione, total thiol, and nonprotein and protein thiols was observed which was also reversed upon GME administration. These findings suggest that GME administration inhibits free radical-induced oxidative macromolecular damage in aged rats and thereby protects the brain from ROS. PMID- 17702874 TI - Impaired attention predicts motor performance decline in older community-dwellers with normal baseline mobility: results from the Italian Longitudinal Study on Aging (ILSA). AB - BACKGROUND: Cognitive decline, particularly when executive functions are compromised, may worsen motor performance (MP) decline in the elderly population. We investigated whether a global test, a memory test, and an attention test predicted MP decline in older community-dwellers with normal baseline MP participating in the Italian Longitudinal Study on Aging (ILSA). METHODS: One thousand fifty-two ILSA participants (71.2 +/- 4.8 years old, mean +/- standard deviation [SD], 67% men), with normal baseline MP were reassessed after 3 years using the same MP battery. Participants whose MP score reduction from baseline to follow-up was > 75 percentile were considered to be MP decliners. Global cognition, memory, and attention were assessed using the Mini-Mental State Examination (MMSE), the Babcock Story Recall Test (BSRT), and the Digit Cancellation Test (DCT), respectively. The baseline score on each test was examined as a potential predictor of decline in global MP or in single motor tasks. RESULTS: Baseline scores on the three cognitive tests were worse among the 166 MP decliners, compared with nondecliners. Participants in the lowest quartile of DCT had a > 2-fold higher adjusted risk of declining than did participants in the highest quartile (odds ratio = 2.47, 95% confidence interval, 1.29-4.74). Conversely, MMSE and BSRT scores no longer predicted MP decline after adjustment. Impaired attention strongly predicted the decline in attention-demanding tasks (tandem walking), but also affected routine tasks (walking). CONCLUSIONS: Impairment in a test measuring attention predicts MP decline among older community-dwellers with normal baseline MP. This finding is consistent with the hypothesis that attentional and executive dysfunction is a major determinant of mobility disability in elderly persons. PMID- 17702875 TI - Cognitive function, gait speed decline, and comorbidities: the health, aging and body composition study. AB - BACKGROUND: Emerging evidence indicates an association between cognitive function and physical performance in late life. This study examines the relationship between cognitive function and subsequent gait speed decline among high functioning older adults. METHODS: Measures of global cognitive function (Modified Mini Mental State Examination [3MS]) and executive control function (ECF) (a clock drawing task [CLOX 1] and the 15-item Executive Interview [EXIT 15]) were obtained in the Health, Aging, and Body Composition Study in 1999-2000. Gait-speed (meters/second) was assessed over 20 meters at usual pace. Using a mixed model, we assessed the relationship between baseline cognitive function and gait-speed change over 3 years. RESULTS: Two thousand, three hundred forty-nine older adults (mean age 75.6 +/- 2.9 years) completed the assessments. After adjustment for baseline gait speed, a 1-standard-deviation (SD) lower performance on each cognitive test was associated with greater gait-speed decline over 3 years: 0.016 m/s for the 3MS (SD = 8.1), 0.009 m/s for CLOX 1 (SD = 2.4), and 0.012 m/s for EXIT 15 (SD = 4.1) (p <.0005 for all). After adjustment for comorbidities, the effect size was attenuated for 3MS and CLOX 1, and the association for EXIT 15 was no longer significant. Depression score was most strongly associated with the EXIT 15 effect reduction. CONCLUSION: Global and executive cognitive functions predict declines in gait speed. The association of ECF with gait speed decline is attenuated by comorbid conditions, particularly depression. Elucidation of the mechanisms underlying these associations may point to new pathways for the treatment of physical decline associated with diminished cognitive function. PMID- 17702876 TI - Physical fitness and 4-year mortality in an 80-year-old population. AB - BACKGROUND: Because little is known about the relationship between physical fitness and mortality among very elderly people, we evaluated this association in a Japanese population of 80-year-old community residents. METHODS: Among 1282 80 year-old residents of Fukuoka Prefecture, Japan, 697 individuals (277 men and 420 women) underwent physical fitness tests of handgrip strength, isometric leg extensor strength, isokinetic leg extensor power, stepping rate, and one-leg standing time. Four years later, the dates and causes of death among the participants during those years were analyzed based on data from resident registration cards and from official death certificates. RESULTS: During the 4 year follow-up period, 107 individuals (58 men and 49 women) died. Of these deaths, 27 were due to cardiovascular disease (CVD), 27 to cancer, 22 to pneumonia, and the rest to other causes. The relative hazard ratios (HR) for all cause mortality, adjusted for various confounding factors, fell with increases in stepping rate, and the HR for pneumonia mortality fell with increases in leg extensor strength. In contrast, there was no association between cardiovascular or cancer mortality and physical fitness. CONCLUSIONS: A partial association was found between impaired physical fitness at the age of 80 years and increased mortality in the 4 years thereafter. Mortality due to all causes was related only to stepping rate, and mortality due to pneumonia was related to leg extensor strength. Mortality due to CVDs or cancers was not associated with physical fitness. PMID- 17702877 TI - High body mass index and physical impairments as predictors of walking limitation 22 years later in adult Finns. AB - BACKGROUND: Our aim was to study the effects of high body mass index (BMI) and physical impairments in midlife on later life walking limitation. METHODS: Primarily middle-aged persons (aged 32-72 years) with no walking limitation at baseline (n = 840) were followed-up for 22 years as a part of the Mini-Finland Follow-up Survey. Incident walking limitation (walking speed < 1.2 m/s or difficulty in walking 0.5 km) was predicted by measured BMI, handgrip strength, squatting test, and self-reported running difficulties. RESULTS: Twenty-one percent of the participants developed walking limitation. After adjustment for multiple potential confounders, high BMI, low handgrip strength, impaired squatting, and running difficulties were significant predictors of incident walking limitation. The odds ratio (OR) of walking limitation was 4.55 (95% confidence interval [CI], 1.32-15.74) for squatting difficulties and 2.39 (95% CI, 1.26-4.55) for major running difficulties as compared to participants with no difficulties. The corresponding ORs for handgrip strength and BMI were 0.56 (95% CI, 0.38-0.81) and 1.39 (95% CI, 1.10-1.75) per an increment of 1 standard deviation. For persons in the highest BMI tertile who had two or more physical impairments, the adjusted risk of walking limitation was 4.5 times higher in comparison to normal weight persons with no physical impairments. CONCLUSIONS: In primarily middle-aged persons, BMI and simple tests of physical impairment strongly predicted the development of walking limitation 22 years later. In addition, physical impairments coexisting with high BMI predisposed to later life walking limitation more than high BMI alone. Therefore, increasing physical fitness by physical activity and promoting weight loss in middle age may prevent mobility limitation and subsequent disability in old age. PMID- 17702878 TI - Knee strength maintained despite loss of lean body mass during weight loss in older obese adults with knee osteoarthritis. AB - BACKGROUND: The effects of weight loss on muscle function in older adults have not been well studied. This study determined the effects of a 6-month weight-loss intervention on muscle strength and quality in older obese adults with knee osteoarthritis. METHODS: Participants were randomized to a weight loss (WL) (n = 44, 70 +/- 6 years) or weight stable (WS) (n = 43, 69 +/- 6 years) group. The WL intervention consisted of weekly educational meetings, a meal replacement diet, and a three-session-per-week structured exercise program to achieve 10%-12% weight loss. The WS intervention included bimonthly group meetings and newsletters. Body composition and knee extensor strength were measured at baseline and after intervention. RESULTS: The WL group decreased body weight, lean body mass, fat mass, and percent body fat (p <.001 for all). Concentric extension strength increased 25% in WL (p >.05), whereas eccentric extension decreased 6% in WS (p =.028). Concentric muscle quality (strength per kg body weight or lean body mass) increased in WL (p <.05), whereas eccentric muscle quality decreased in WS (p <.05). Changes in lean body mass and fat mass were inversely associated with changes in most muscle strength and quality measures (p <.05). Men and women did not differ in response to the intervention in knee strength outcomes. CONCLUSIONS: Hypocaloric dieting in combination with exercise training had beneficial effects on muscle strength/quality, despite loss of lean body mass in this sample of older men and women. Greater fat loss was associated with greater gains in muscle strength and quality. More studies are needed regarding the mechanisms by which loss of fat mass increases muscle strength and quality. PMID- 17702879 TI - Factors associated with pharmacologic treatment of osteoporosis in an older home care population. AB - BACKGROUND: A number of studies have shown low rates of osteoporosis treatment. Few, if any, have assessed a comprehensive range of functional and clinical correlates of treatment coverage. Our objective was to examine which sociodemographic, clinical, and functional characteristics are associated with pharmacotherapy for osteoporosis among community-based seniors. METHODS: The study sample included 48,689 home care clients aged >/= 65 years in Ontario, Canada. Treatment coverage (calcium and vitamin D and/or anti-osteoporotic drugs) was assessed in two subgroups, clients with a diagnosis of osteoporosis (without fracture) and those with a prevalent fracture. Sociodemographic, health, and functional measures available from the Resident Assessment Instrument for Home Care (RAI-HC) were assessed as correlates of treatment in multivariable logistic regression analyses. RESULTS: Approximately 59% of clients with a diagnosis of osteoporosis were receiving pharmacotherapy, compared with 27% of those with a prevalent fracture. For both subgroups, treatment coverage was significantly lower among clients with at least three chronic conditions, health instability, fewer than nine medications, functional impairment, and depressive symptoms and among those clients who were widowed. Among clients with a diagnosis of osteoporosis, treatment was positively associated with cognitive impairment and negatively associated with confinement to a wheelchair or bed. Men with a prevalent fracture were significantly less likely to receive treatment, particularly in the absence of an osteoporosis diagnosis. CONCLUSIONS: Many older adults with presumed osteoporosis in our study were not receiving drug therapy for this condition. Indicators of clinical instability and functional decline appear to represent influential factors in treatment decisions. Despite a lower likelihood of treatment among men with a prevalent fracture, this sex difference in treatment largely disappeared in the presence of an osteoporosis diagnosis. PMID- 17702880 TI - Efficacy and safety of statin monotherapy in older adults: a meta-analysis. AB - BACKGROUND: Statin therapy significantly reduces cardiovascular events. Older patients, however, are less likely to be prescribed statins than younger patients due to concern over lack of indication, lower predictive value of cholesterol levels, and increased risk of adverse events. To determine the effect of statins on all-cause mortality and on major cardiovascular events, including stroke, we performed a meta-analysis of statin trials that included older adult participants. METHODS: Mortality, cardiovascular events, and adverse event outcomes were extracted from published randomized, placebo-controlled clinical trials of persons aged 60 years and older. RESULTS: Data on 51,351 patients were evaluated. Statins reduced all-cause mortality by 15% (95% confidence interval, 7%-22%), coronary heart disease (CHD) death by 23% (15%-29%), fatal or nonfatal myocardial infarction (MI) by 26% (22%-30%), and fatal or nonfatal stroke by 24% (10%-35%). The relative risk of cancer comparing statins to placebo was 1.06 (0.95-1.18). Adverse event data were not consistently reported. CONCLUSIONS: Statin therapy significantly reduced all-cause and CHD mortality, as well as risk of stroke and MI. Statin therapy should be offered to older patients at high risk of atherosclerotic disease events. PMID- 17702881 TI - HipWatch: osteoporosis investigation and treatment after a hip fracture: a 6 month randomized controlled trial. AB - OBJECTIVE: We aimed to determine whether a novel Patient Empowerment and Physician Alerting (PEPA) intervention would improve the proportion of seniors who were investigated and treated for osteoporosis after hip fracture. METHODS: We undertook a 6-month randomized controlled trial (RCT) in 48 women and men >/= 60 years old who had suffered a hip fracture and were admitted to a tertiary-care university hospital. The primary outcome measure was the proportion of participants offered one or more osteoporosis-specific 'best practices' measured using the Diagnosis and Management Questionnaire (DMQ). Participant responses were validated in part by physician report. RESULTS: In the PEPA intervention group, 19 (68%) were offered one or more components of best practice care compared with 7 (35%) in the 'usual care' group (p <.05). In the PEPA group, 15 (54%) (p <.01) were prescribed bisphosphonate therapy, 8 (29%) (p <.01) had a bone mineral density scan, 11 (39%) were prescribed calcium and vitamin D (p =.32), and 9 (32%) (p <.01) were prescribed exercise. In the usual care group, 0 (0%) were prescribed bisphosphonate therapy, a bone mineral density assessment, or exercise and 6 (30%) were prescribed calcium and vitamin D. CONCLUSIONS: This simple, inexpensive PEPA intervention resulted in far superior clinical management than did usual care in a population at high risk of future hip fracture. PMID- 17702882 TI - The influence of marital status on stage at diagnosis and survival of older persons with melanoma. AB - BACKGROUND: Melanoma incidence and mortality had a sustained increase in the last 3 decades in the United States, especially among white older men. Little is known about the relationship between marital status and melanoma outcomes in older people. The objective of this study was to determine the association between marital status and stage at diagnosis and survival of older persons with cutaneous melanoma. METHODS: Data are from the Surveillance, Epidemiology and End Results (SEER) registries-Medicare-linked database (1991-1999). The sample consisted of 14,630 men and women 65 years old and older. The outcomes were melanoma stage at diagnosis and melanoma specific survival. The main independent variable, marital status, was used in four categories: married, single, separated or divorced, and widowed. Other covariates include sociodemographics, stage at diagnosis, tumor characteristics (body site and histology), and comorbidity index. Logistic regression and survival analyses techniques were used. RESULTS: Multivariate analyses showed that, compared with married persons, widowed persons were more likely to be diagnosed with late-stage (regional or distant) versus early-stage (in situ or localized) melanoma (odds ratio = 1.31, 95% confidence interval [CI], 1.13-1.52). In addition, after controlling for all other variables (sociodemographics, stage at diagnosis, tumor characteristics, and comorbidity), widowed persons were at increased risk of death from melanoma (hazard ratio = 1.23, 95% CI, 1.06-1.44). CONCLUSION: Older widowed persons were more likely to be diagnosed at late stage and to die from melanoma than were older married persons. PMID- 17702883 TI - Differences in the association between apolipoprotein E genotype and mortality across populations. AB - BACKGROUND: The gene for apolipoprotein-E (APOE) has three common alleles (epsilon2, epsilon3, and epsilon4) that have been shown to be associated with differences in the risk of death in persons older than 60 years in European populations. However, previous research suggests that they may not be associated with mortality in African Americans, and the evidence in Asians is mixed. It is now possible to examine the effects of these genotypes on mortality in African American, Chinese, Japanese, and Korean populations. METHODS: The analysis is based on two types of published data: genotype by age and mortality by genotype. Demographic synthesis uses a multistate model to combine data from these case control and cohort studies to provide maximum likelihood estimates of the relative risks of death. RESULTS: In general, the APOE epsilon2 allele is associated with 5%-10% lower mortality than the epsilon3/3 genotype. The epsilon4/4 allele is generally associated with a moderately high relative risk of death. The epsilon3/4 genotype is associated with 22% excess risk in Europeans and U.S. whites and with about 35% in Chinese. However, there is no evidence of excess risk with epsilon3/4 among African Americans and little excess risk among Japanese and Koreans. The relationship between genotype and mortality is consistent within these ethnic groups. For example, the estimates of R(3/4) for Japanese in Japan and Hawaii are both low, and the estimates for Chinese in Taiwan and Shanghai are relatively high. CONCLUSIONS: . The relationship between APOE genotype and mortality differs across population groups but shows little evidence of variation within groups. PMID- 17702884 TI - Nonpharmacological treatment of agitation: a controlled trial of systematic individualized intervention. AB - OBJECTIVE: The objective of this study was to examine the efficacy of a systematic algorithm for providing individualized, nonpharmacological interventions for reducing agitated behaviors in nursing home residents with dementia. METHODS: This placebo-controlled study combined nomothetic and ideographic methodologies. The study was conducted in 12 nursing home buildings in Maryland; 6 were used as treatment facilities, and 6 as control facilities. Participants were 167 elderly nursing home residents with dementia. Interventions were tailored to the individual profiles of agitated participants using a systematic algorithm that considered type of agitation and unmet needs. Interventions were then designed to fulfill the need in a manner that matched the person's cognitive, physical, and sensory abilities, and their lifelong habits and roles. Interventions were provided for 10 days during the 4 hours of greatest agitation. Direct observations of agitation were recorded by trained research assistants via the Agitated Behavior Mapping Instrument (ABMI). Evaluation of positive and negative affect was also based on direct observation and assessed via Lawton's Modified Behavior Stream. Data analysis was performed via SPSS software. RESULTS: The implementation of personalized, nonpharmacological interventions resulted in statistically significant decreases in overall agitation in the intervention group relative to the control group from baseline to treatment (F(1,164) = 10.22, p =.002). In addition, implementation of individualized interventions for agitation resulted in statistically significant increases in pleasure and interest (F(1,164) = 24.22, p <.001; F(1,164) = 20.66, p <.001). CONCLUSIONS: The findings support the use of individualized nonpharmacological interventions to treat agitation in persons with dementia and underscore the importance for clinicians of searching for underlying reasons for agitated behaviors. PMID- 17702885 TI - Comparison of the health and functional status between older inpatients with and without cancer admitted to a geriatric/internal medicine unit. AB - BACKGROUND: Cancer is predominantly a disease in the population aged 65 years and older. Previous studies have suggested that older cancers patients seen in oncology departments are healthy with few comorbidities. Relatively little is known about the health and functional status of older cancer inpatients, especially outside oncology units. The purpose of this study is to compare the health and functional status of older cancer and noncancer inpatients admitted to a geriatric/internal medicine unit. METHODS: A retrospective chart review was conducted on inpatients 65 years old and older, who had been hospitalized during a period of 2 years in the geriatric/internal medicine unit. The health and functional status of 144 inpatients with active cancer was compared to that of 682 inpatients without active cancer. Eight domains were compared: functional status, comorbidity, medication, nutritional status, neurosensory deficits, cognition, mood, and mobility. The hospitalization measures (length of stay, death, need for palliative care) were also compared. RESULTS: We found that inpatients with active cancer were younger, had less comorbidity and less cognitive impairment, but were more depressed and at greater risk for malnutrition than patients without cancer. These two groups were similar in terms of functional status, neurosensory deficit, and mobility. Cancer patients had a significantly shorter length of stay, required more palliative care, and were more likely to die during hospitalization. CONCLUSION: These findings indicate that older cancer patients admitted to a geriatric/internal medicine unit present with multiple active geriatric problems, have characteristics distinct from those of traditional geriatric patients, and require specific care and management. PMID- 17702886 TI - LOW specificity limits the use of the cerebrospinal fluid AB1-42/P-TAU181P ratio to discriminate alzheimer's disease from vascular dementia. PMID- 17702888 TI - Geranylgeranylacetone, an inducer of the 70-kDa heat shock protein (HSP70), elicits unfolded protein response and coordinates cellular fate independently of HSP70. AB - Geranylgeranylacetone (GGA), an antiulcer agent, has the ability to induce 70-kDa heat shock protein (HSP70) in various cell types and to protect cells from apoptogenic insults. However, little is known about effects of GGA on other HSP families of molecules. We found that, at concentrations >/=100 microM, GGA caused selective expression of 78-kDa glucose-regulated protein (GRP78), an HSP70 family member inducible by endoplasmic reticulum (ER) stress, without affecting the level of HSP70 in various cell types. Induction of ER stress by GGA was also evidenced by expression of another endogenous marker, CCAAT/enhancer-binding protein-homologous protein (CHOP); decreased activity of ER stress-responsive alkaline phosphatase; and unfolded protein response (UPR), including activation of the activating transcription factor 6 (ATF6) pathway and the inositol requiring ER-to-nucleus signal kinase 1-X-box-binding protein 1 (IRE1-XBP1) pathway. Incubation of mesangial cells with GGA caused significant apoptosis, which was attenuated by transfection with inhibitors of caspase-12 (i.e., a dominant-negative mutant of caspase-12 and MAGE-3). Dominant-negative suppression of IRE1 or XBP1 significantly attenuated apoptosis without affecting the levels of CHOP and GRP78. Inhibition of c-Jun NH(2)-terminal kinase, the molecule downstream of IRE1, by 1,9-pyrazoloanthrone (SP600125) did not improve cell survival. Blockade of ATF6 by 4-(2-aminoethyl) benzenesulfonyl fluoride enhanced apoptosis by GGA, and it was correlated with attenuated induction of both GRP78 and CHOP. Overexpression of GRP78 or dominant-negative inhibition of CHOP significantly attenuated GGA-induced apoptosis. These results suggested that GGA triggers both proapoptotic (IRE1-XBP1, ATF6-CHOP) and antiapoptotic (ATF6-GRP78) UPR and thereby coordinates cellular fate even without induction of HSP70. PMID- 17702889 TI - Evaluation of action mechanisms of toxic chemicals using JFCR39, a panel of human cancer cell lines. AB - We previously established a panel of human cancer cell lines, JFCR39, coupled to an anticancer drug activity database; this panel is comparable with the NCI60 panel developed by the National Cancer Institute. The JFCR39 system can be used to predict the molecular targets or evaluate the action mechanisms of the test compounds by comparing their cell growth inhibition profiles (i.e., fingerprints) with those of the standard anticancer drugs using the COMPARE program. In this study, we used this drug activity database-coupled JFCR39 system to evaluate the action mechanisms of various chemical compounds, including toxic chemicals, agricultural chemicals, drugs, and synthetic intermediates. Fingerprints of 130 chemicals were determined and stored in the database. Sixty-nine of 130 chemicals ( approximately 60%) satisfied our criteria for the further analysis and were classified by cluster analysis of the fingerprints of these chemicals and several standard anticancer drugs into the following three clusters: 1) anticancer drugs, 2) chemicals that shared similar action mechanisms (for example, ouabain and digoxin), and 3) chemicals whose action mechanisms were unknown. These results suggested that chemicals belonging to a cluster (i.e., a cluster of toxic chemicals, a cluster of anticancer drugs, etc.) shared similar action mechanism. In summary, the JFCR39 system can classify chemicals based on their fingerprints, even when their action mechanisms are unknown, and it is highly probable that the chemicals within a cluster share common action mechanisms. PMID- 17702890 TI - Myristyl trimethyl ammonium bromide and octadecyl trimethyl ammonium bromide are surface-active small molecule dynamin inhibitors that block endocytosis mediated by dynamin I or dynamin II. AB - Dynamin is a GTPase enzyme involved in membrane constriction and fission during endocytosis. Phospholipid binding via its pleckstrin homology domain maximally stimulates dynamin activity. We developed a series of surface-active small molecule inhibitors, such as myristyl trimethyl ammonium bromide (MiTMAB) and octadecyltrimethyl ammonium bromide (OcTMAB), and we now show MiTMAB targets the dynamin-phospholipid interaction. MiTMAB inhibited dynamin GTPase activity, with a Ki of 940 +/- 25 nM. It potently inhibited receptor-mediated endocytosis (RME) of transferrin or epidermal growth factor (EGF) in a range of cells without blocking EGF binding, receptor number, or autophosphorylation. RME inhibition was rapidly reversed after washout. The rank order of potency for a variety of MiTMAB analogs on RME matched the rank order for dynamin inhibition, suggesting dynamin recruitment to the membrane is a primary cellular target. MiTMAB also inhibited synaptic vesicle endocytosis in rat brain nerve terminals (synaptosomes) without inducing depolarization or morphological defects. Therefore, the drug rapidly and reversibly blocks multiple forms of endocytosis with no acute cellular damage. The unique mechanism of action of MiTMAB provides an important tool to better understand dynamin-mediated membrane trafficking events in a variety of cells. PMID- 17702892 TI - Anti-inflammatory effects of alphav integrin antagonism in acute kidney allograft rejection. AB - Integrin-mediated cell adhesion and signaling is essential to vascular development and inflammatory processes. Elevated expression of integrin alpha(v)beta(3) has been detected in ischemia-reperfusion injury and rejecting heart allografts. We thus hypothesized that the inhibition of alpha(v)-associated integrins may have potent anti-inflammatory effects in acute kidney allograft rejection. We studied the effects of a peptidomimetic antagonist of alpha(v) integrins in two rat models of renal allotransplantation, differing in degree of major histocompatibility complex mismatch. Integrin alpha(v)beta(3) was up regulated in rejecting renal allografts. Integrin antagonist reduced the histological signs of acute rejection, the intensity of the mononuclear cell infiltration, and cell proliferation in the grafted kidneys. This could be correlated to a reduced leukocyte-endothelial interaction and an improved peritubular microcirculation observed by intravital microscopy. In vitro under laminar flow conditions, the arrest of monocytes to interleukin-1beta-activated endothelium was decreased. Furthermore, in co-culture models the proliferation and transmigration of monocytes/macrophages, endothelium, and fibroblasts induced by renal tubular epithelia was efficiently inhibited by alpha(v) integrin antagonism. These data reveal an important role of this integrin subclass in leukocyte recruitment and development and maintenance of acute rejection; blockade of alpha(v) integrins may provide a new therapeutic strategy to attenuate acute allograft rejection. PMID- 17702891 TI - Bcl-w protects hippocampus during experimental status epilepticus. AB - Experimentally evoked seizures can activate the intrinsic mitochondrial cell death pathway, components of which are modulated in the hippocampus of patients with temporal lobe epilepsy. Bcl-2 family proteins are critical regulators of mitochondrial dysfunction, but their significance in this setting remains primarily untested. Presently, we investigated the mitochondrial pathway and role of anti-apoptotic Bcl-2 proteins using a mouse model of seizure-induced neuronal death. Status epilepticus was evoked in mice by intra-amygdala kainic acid, causing cytochrome c release, processing of caspases 9 and 7, and death of ipsilateral hippocampal pyramidal neurons. Seizures caused a rapid decline in hippocampal Bcl-w levels not seen for either Bcl-2 or Bcl-xl. To test whether endogenous Bcl-w was functionally significant for neuronal survival, we investigated hippocampal injury after seizures in Bcl-w-deficient mice. Seizures induced significantly more hippocampal CA3 neuronal loss and DNA fragmentation in Bcl-w-deficient mice compared with wild-type mice. Quantitative electroencephalography analysis also revealed that Bcl-w-deficient mice display a neurophysiological phenotype whereby there was earlier polyspike seizure onset. Finally, we detected higher levels of Bcl-w in hippocampus from temporal lobe epilepsy patients compared with autopsy controls. These data identify Bcl-w as an endogenous neuroprotectant that may have seizure-suppressive functions. PMID- 17702893 TI - Aberrant mucosal mast cell protease expression in the enteric epithelium of nematode-infected mice lacking the integrin alphavbeta6, a transforming growth factor-beta1 activator. AB - Infection of mice with the nematode Trichinella spiralis triggers recruitment and differentiation of intraepithelial intestinal mucosal mast cells expressing mouse mast cell protease 1 (Mcpt-1), which contributes to expulsion of the parasite. Expression of Mcpt-1 is transforming growth factor (TGF)-beta1-dependent in vitro. TGF-beta1, which is secreted within tissues as a biologically inactive complex with latency-associated peptide, requires extracellular modification to become functionally active. The integrin-alpha(nu)beta(6) mediates local activation of TGF-beta(1) in association with epithelia. Using T. spiralis infected beta(6)(-/-) mice, we show accumulation of mucosal mast cells in the lamina propria of the small intestine with minimal recruitment into the epithelial compartment. This was accompanied by a coordinate reduction in expression of both Mcpt-1 and -2 in the jejunum and increased tryptase expression, whereas Mcpt-9 became completely undetectable. In contrast, the cytokine stem cell factor, a regulator of mast cell differentiation and survival, was significantly up-regulated in T. spiralis-infected beta(6)(-/-) mice compared with infected beta(6)(+/+) controls. Despite these changes, beta(6)(-/-) mice still appeared to expel the worms normally. We postulate that compromised TGF beta(1) activation within the gastrointestinal epithelial compartment is a major, but not the only, contributing factor to the observed changes in mucosal mast cell protease and epithelial cytokine expression in beta(6)(-/-) mice. PMID- 17702894 TI - Stromally expressed c-Jun regulates proliferation of prostate epithelial cells. AB - Stromal-epithelial interactions play a critical role in development of benign prostatic hyperplasia. We have previously shown that stromal cells associated with prostatic carcinoma can potentiate proliferation and reduce cell death of prostatic epithelial cells. Genetic alterations in stromal cells affect stromal epithelial interactions and modulate epithelial growth. The c-Jun proteins that are early transcription factor molecules have been shown to regulate stromal epithelial interactions via paracrine signals. Moreover, the Jun-family member proteins have been shown to play an important role in proper development of the genitourinary organs. In this study, we show that c-Jun protein in fibroblasts regulates production and paracrine signals of insulin-like growth factor-1 (IGF 1). c-jun(+/+) fibroblasts secrete higher levels of IGF-1 and stimulate benign prostatic hyperplasia-1 cellular proliferation. In addition, stromally produced IGF-1 up-regulates epithelial mitogen-activated protein kinase, Akt, and cyclin D protein levels while down-regulating the cyclin-dependent kinase inhibitor p27. These data suggest that stromally expressed c-Jun may promote prostatic epithelial proliferation through IGF-1 as a paracrine signal that, in turn, can promote prostate epithelial proliferation. Identification of the signal transduction pathways between prostate epithelial cells and the surrounding stromal cells will improve our understanding of the normal and abnormal biology in prostatic diseases. PMID- 17702895 TI - Essential role for Rap1 GTPase and its guanine exchange factor CalDAG-GEFI in LFA 1 but not VLA-4 integrin mediated human T-cell adhesion. AB - Regulated adhesion of T cells by the integrins LFA-1 (lymphocyte function associated antigen-1) and VLA-4 (very late antigen-4) is essential for T-cell trafficking. The small GTPase Rap1 is a critical activator of both integrins in murine lymphocytes and T-cell lines. Here we examined the contribution of the Rap1 regulatory pathway in integrin activation in primary CD3(+) human T cells. We demonstrate that inactivation of Rap1 GTPase in human T cells by expression of SPA1 or Rap1GAP blocked stromal cell-derived factor-1alpha (SDF-1alpha) stimulated LFA-1-ICAM-1 (intercellular adhesion molecule-1) interactions and LFA 1 affinity modulation but unexpectedly did not significantly affect binding of VLA-4 to its ligand VCAM-1 (vascular cell adhesion molecule 1). Importantly, silencing of the Rap1 guanine exchange factor CalDAG-GEFI inhibited SDF-1alpha- and phorbol 12-myristate 13-acetate (PMA)-induced adhesion to ICAM-1 while having no effect on adhesion to VCAM-1. Pharmacologic inhibition of Phospholipase C (PLC) blocked Rap1 activation and inhibited cell adhesion and polarization on ICAM-1 and VCAM-1. Protein kinase C (PKC) inhibition led to enhanced levels of active Rap1 concomitantly with increased T-cell binding to ICAM-1, whereas adhesion to VCAM-1 was reduced. Thus, PLC/CalDAG-GEFI regulation of Rap1 is selectively required for chemokine- and PMA-induced LFA-1 activation in human T cells, whereas alternate PLC- and PKC-dependent mechanisms are involved in the regulation of VLA-4. PMID- 17702896 TI - Cdc42 critically regulates the balance between myelopoiesis and erythropoiesis. AB - The Rho GTPase Cdc42 regulates adhesion, migration, and homing, as well as cell cycle progression, of hematopoietic stem cells, but its role in multilineage blood development remains unclear. We report here that inducible deletion of cdc42 in cdc42-floxed mouse bone marrow by the interferon-responsive, Mx1-Cre mediated excision led to myeloid and erythroid developmental defects. Cdc42 deletion affected the number of early myeloid progenitors while suppressing erythroid differentiation. Cdc42-deficient mice developed a fatal myeloproliferative disorder manifested by significant leukocytosis with neutrophilia, myeloid hyperproliferation, and myeloid cell infiltration into distal organs. Concurrently, Cdc42 deficiency caused anemia and splenomegaly accompanied with decreased bone marrow erythroid burst-forming units (BFU-Es) and colony-forming units-erythroid (CFU-Es) activities and reduced immature erythroid progenitors, suggesting that Cdc42 deficiency causes a block in the early stage of erythropoiesis. Cdc42 activity is responsive to stimulation by SCF, IL3, SDF 1alpha, and fibronectin. The increased myelopoiesis and decreased erythropoiesis of the knockout mice are associated with an altered gene transcription program in hematopoietic progenitors, including up-regulation of promyeloid genes such as PU.1, C/EBP1alpha, and Gfi-1 in the common myeloid progenitors and granulocyte macrophage progenitors and down-regulation of proerythroid gene such as GATA-2 in the megakaryocyte-erythroid progenitors. Thus, Cdc42 is an essential regulator of the balance between myelopoiesis and erythropoiesis. PMID- 17702897 TI - Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. AB - Hemolysis and hemoglobinemia contribute to serious clinical sequelae in hemolytic disorders. In paroxysmal nocturnal hemoglobinuria (PNH) patients, hemolysis can contribute to thromboembolism (TE), the most feared complication in PNH, and the leading cause of disease-related deaths. We evaluated whether long-term treatment with the complement inhibitor eculizumab reduces the rate of TE in patients with PNH. Clinical trial participants included all patients in the 3 eculizumab PNH clinical studies, which recruited patients between 2002 and 2005 (n = 195); patients from these studies continued treatment in the current multinational open label extension study. Thromboembolism rate with eculizumab treatment was compared with the pretreatment rate in the same patients. The TE event rate with eculizumab treatment was 1.07 events/100 patient-years compared with 7.37 events/100 patient-years (P < .001) prior to eculizumab treatment (relative reduction, 85%; absolute reduction, 6.3 TE events/100 patient-years). With equalization of the duration of exposure before and during treatment for each patient, TE events were reduced from 39 events before eculizumab to 3 events during eculizumab (P < .001). The TE event rate in antithrombotic-treated patients (n = 103) was reduced from 10.61 to 0.62 events/100 patient-years with eculizumab treatment (P < .001). These results show that eculizumab treatment reduces the risk of clinical thromboembolism in patients with PNH. This study is registered at http://clinicaltrials.gov (study ID no. NCT00122317). PMID- 17702899 TI - Increased TSLP availability restores T- and B-cell compartments in adult IL-7 deficient mice. AB - Interleukin 7 (IL-7) plays a crucial role in adult lymphopoiesis, while in fetal life its effect can be partially compensated by TSLP. Whether adult hematopoietic progenitor cells are unresponsive to TSLP or whether TSLP is less available in adult microenvironments is still a matter of debate. Here, we show that increased TSLP availability through transgene (Tg) expression fully restored lymphopoiesis in IL-7-deficient mice: it rescued B-cell development, increased thymic and splenic cellularities, and restored double-negative (DN) thymocytes, alphabeta and gammadelta T-cell generation, and all peripheral lymphoid compartments. Analysis of bone marrow chimeras demonstrated that hematopoietic progenitor cells from adult wild-type mice efficiently differentiated toward B- and T-cell lineages in lethally irradiated IL-7 deficient mice provided TSLP Tg was expressed in these mice. In vitro, TSLP promoted the differentiation of uncommitted adult bone marrow progenitors toward B and T lineages and the further differentiation of DN1 and DN2 thymocytes. Altogether, our results show that adult hematopoietic cells are TSLP responsive and that TSLP can sustain long-term adult lymphopoiesis. PMID- 17702898 TI - Establishment of transplantable porcine tumor cell lines derived from MHC-inbred miniature swine. AB - The lack of transplantable tumors has limited assessment of graft-versus-tumor effects following hematopoietic cell transplantation in clinically relevant large animal models. We describe the derivation and characterization of porcine tumor cell lines with initial efforts of tumor transplantation using immunocompromised mice and highly inbred sublines of Massachusetts General Hospital major histocompatibility complex (MHC)-inbred miniature swine. Autopsies were performed routinely on swine that died unexpectedly or had suspicion of malignancy based on clinical symptoms or peripheral blood analysis. Tissue samples were obtained for pathology, phenotyped by flow cytometry, and placed in culture. Based on growth, lines were selected for passage into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice and miniature swine. Porcine tumor recipients were preconditioned with total body irradiation from 0 to 500 cGy or with a 30 day course of oral cyclosporine. We identified 19 cases of hematologic tumors. Nine distinct tumor cell lines were established from 8 of these cases, including 3 derived from highly inbred sublines. In vivo tumor growth and serial transfer were observed in immunocompromised mice for one tumor cell line and in miniature swine for 1 of 2 tumor cell lines expanded for this purpose. These results suggest the possibility of developing a transplantable tumor model in this large animal system. PMID- 17702900 TI - Serum cytokeratin-18 fragments as quantitative markers of epithelial apoptosis in liver and intestinal graft-versus-host disease. AB - Graft-versus-host disease (GVHD) is the main complication of allogeneic stem cell transplantation. However, diagnosis of GVHD and evaluation of response to immunosuppressive treatment is sometimes difficult. Since apoptosis is the histopathologic hallmark in GVHD, we investigated whether active GVHD-induced target organ destruction is mirrored by serum levels of the caspase-cleaved neo epitope of cytokeratin-18 fragments (CK18Fs). Serum CK18F kinetics was monitored by M30 antibody-based enzyme-linked immunosorbent assay (ELISA) in 50 patients who fulfilled histopathologic and/or clinical criteria diagnostic for GVHD. Both intestinal and hepatic GVHD were consistently associated with significant elevations of CK18F levels over baseline. Responses of GVHD to immunosuppressive therapy were paralleled by CK18F decreases, whereas resistant GVHD was characterized by persistent CK18F rises. Clinical conditions that might represent relevant differential diagnoses, such as toxic mucositis, noncomplicated, infection-related diarrhea, and veno-occlusive disease were not associated with CK18F elevations. In conclusion, CK18F monitoring provides a serum marker for quantitative assessment of GVHD-associated apoptotic activity in intestinal and hepatic GVHD. Although apoptosis is not GVHD-specific, CK18Fs may help to distinguish active GVHD from GVHD-unrelated conditions with similar symptoms, and to monitor response to immunosuppressive treatment. Prospective studies are warranted to evaluate how CK18Fs may assist in the diagnosis, grading, and treatment guidance of GVHD. PMID- 17702901 TI - Expression of cannabinoid CB1 receptors in models of diabetic neuropathy. AB - A clearer understanding of the mechanisms underlying the development and progression of diabetic neuropathy is likely to indicate new directions for the treatment of this complication of diabetes. In the present study we investigated the expression of cannabinoid CB(1) receptors in models of diabetic neuropathy. PC12 cells were differentiated into a neuronal phenotype with nerve growth factor (NGF) (50 ng/ml) in varying concentrations of glucose (5.5-50 mM). CB(1) receptor expression was studied at the mRNA level by reverse transcriptase-polymerase chain reaction (RT-PCR) and at the protein level via immunohistochemical and Western blot analysis. CB(1) expression was also compared in dorsal root ganglia (DRG) removed from streptozotocin-induced diabetic rats versus control animals. Total neurite length induced by NGF was reduced in cells cultured in 20 to 50 mM glucose at day 6 (P < 0.01 versus 5.5 mM; n = 6). Cell viability assays conducted in parallel on day 6 confirmed that the total cell numbers were not significantly different among the various glucose concentrations (P = 0.86; n = 12). RT-PCR, immunohistochemical, and Western blot analysis all revealed down-regulation of the CB(1) receptor in cells treated with high glucose (P < 0.05; n = 4-5 for each), and in DRG removed from diabetic rats compared with controls (P < 0.01; n = 5 for immunohistochemistry, and n = 3 for Western blot). These results suggest that high glucose concentrations are associated with decreased expression of CB(1) receptors in nerve cells. Given the neuroprotective effect of cannabinoids, a decline in CB(1) receptor expression may contribute to the neurodegenerative process observed in diabetes. PMID- 17702903 TI - Kappa agonist-induced reinstatement of cocaine seeking in squirrel monkeys: a role for opioid and stress-related mechanisms. AB - Kappa opioid agonists were at one time proposed as candidate pharmacotherapies for cocaine addiction, mainly because of their ability to decrease dopamine neurotransmission and attenuate the behavioral effects of cocaine in laboratory animals. Recent studies, however, suggest that kappa agonists also may mimic and/or enhance some of the effects of cocaine through mechanisms related to stress. The current study used a reinstatement procedure to examine the ability of the kappa agonists spiradoline and enadoline to reinstate extinguished cocaine seeking in squirrel monkeys previously trained to self-administer cocaine under a second-order schedule of i.v. drug injection. Opioid- and stress-related mechanisms were evaluated in antagonism studies with the opioid antagonists naltrexone and nor-binaltorphimine (nor-BNI), the corticotropin-releasing factor receptor antagonist butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H pyrrolo [2,3-d]pyrimidin-4-yl]amine (CP 154,526), and the alpha(2)-adrenoceptor agonist clonidine combined with either spiradoline or enadoline. When tested alone, priming with spiradoline and enadoline induced significant reinstatement of cocaine-seeking behavior to approximately 45% of the maximum reinstatement induced by cocaine. Reinstatement of cocaine seeking induced by intermediate doses of spiradoline was greater in the presence than in the absence of response contingent presentations of a cocaine-paired stimulus. Spiradoline- and enadoline induced reinstatement of drug seeking was attenuated by naltrexone but not by nor BNI. Spiradoline-induced reinstatement of cocaine seeking was also antagonized by CP 154,526 and clonidine. The results point to interactions between a subpopulation of kappa opioid receptors and central corticotropin-releasing factor and noradrenergic stress systems in the reinstatement of cocaine seeking induced by kappa agonists. PMID- 17702904 TI - Tomoscintigraphy improves the determination of the embryologic origin of parathyroid adenomas, especially in apparently inferior glands: imaging features and surgical implications. AB - Identification of the embryologic origin of hyperfunctioning parathyroid adenomas in primary hyperparathyroidism (PHPT) could determine the most suitable approach for minimally invasive surgery. The aim of this study was to prospectively evaluate the reliability of a new, combined protocol for the preoperative localization and determination of the embryologic origin of parathyroid adenomas. METHODS: Anterior dual-isotope ((123)I/(99m)Tc-sestamibi) static planar imaging followed by tomoscintigraphy (SPECT acquisition) centered over the 140-keV photopeak (combined protocol) was performed on 35 consecutive patients with sporadic PHPT. On the basis of anatomic considerations, adenomas were classified as superior (P4 derived) if they were located above the isthmus or posterior to the thyroid on SPECT images, despite their apparently middle to inferior position, and as inferior (P3 derived) if the foci were located in inferior and anterior positions or along the thyrothymic tract. Parathyroid ultrasonography was performed on all patients. RESULTS: A total of 36 adenomas were removed: 34 solitary adenomas and 1 double adenoma (for totals of 19 P3-derived and 17 P4 derived adenomas). Pinhole subtraction imaging, SPECT, and ultrasonography sensitivities for detecting adenomas were 86%, 78%, and 77%, respectively. False positive contralateral images were observed only with ultrasonography (3 cases). Positive SPECT results were associated with higher gland weights. Thirteen glands were identified by SPECT as posterior glands, despite their apparently inferior position, and were removed through an appropriate lateral endoscopic approach. Eleven (85%) of these glands had a P4 origin. Only 2 corresponded to large P3 derived adenomas (>2 g). CONCLUSION: By reclassifying apparently inferior adenomas as P4-derived adenomas prolapsed behind the thyroid gland, SPECT provides information about the most suitable surgical approach for avoiding recurrent laryngeal nerve injury. Additional pinhole images should increase the detection of small adenomas. The combined protocol offers both advantages. PMID- 17702902 TI - 3,4-Methylenedioxymethamphetamine- and 8-hydroxy-2-di-n-propylamino-tetralin induced hypothermia: role and location of 5-hydroxytryptamine 1A receptors. AB - The popular drug of abuse 3,4-methylenedioxymethamphetamine (MDMA) has complex interactions with thermoregulatory systems, resulting in either hyperthermia or hypothermia. MDMA induces hypothermia when given to animals housed at a low ambient temperature. In this study we report that MDMA (7.5 mg/kg i.p.) given at normal ambient temperatures of 24 to 25 degrees C caused, in conscious freely moving rats, hypothermia (mean decrease from baseline of 1.1 +/- 0.06 degrees C at 40 min). Pretreating animals with a 0.5 mg/kg i.p. dose of the 5 hydroxytryptamine 1A (5-HT(1A)) antagonist N-[2-[4-(2-methoxyphenyl)-1 piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY 100635) not only prevented MDMA-induced hypothermia, but resulted in the development of hyperthermia (mean temperature increase from baseline of 0.74 +/- 0.2 degrees C at 120 min). After treatment with WAY 100635, MDMA also elicited an enhanced tachycardia (mean increases in heart rate from baseline of 110 +/- 16 beats/min at 90 min). To identify the location of 5-HT(1A) receptors responsible for hypothermia induced by MDMA, we first investigated the role of 5-HT(1A) receptors in the rostral raphe pallidus (rRP) in decreases in temperature evoked by the known 5-HT(1A) agonist 8-hydroxy-2-di-n-propylamino-tetralin (DPAT). Microinjections of 0.5 nmol of WAY 100635 into the rRP significantly attenuated DPAT (0.2 mg/kg i.p.)-elicited hypothermia. In parallel experiments, we found that microinjections of WAY 100635 into the rRP, while significantly augmenting MDMA-mediated tachycardia, did not alter body temperature. These results demonstrate that although hypothermia mediated by both MDMA and DPAT shares a common dependence on the activation of 5-HT(1A) receptors, the location of these receptors is different for each drug. PMID- 17702905 TI - Easy method of patient positioning for convergent-beam cardiac SPECT. AB - The use of convergent-beam SPECT can increase detection sensitivity; however, the projection data are likely to be truncated if the patient is not properly positioned. This article describes a patient-positioning method that has been adopted in our hospital for cardiac SPECT scans when convergent-beam collimators are used. METHODS: The system that we use has 3 detector heads and a patient table (i.e., bed) with 3 locking positions: left, center, and right. When convergent-beam collimators are used in a cardiac SPECT scan, the patient table is locked in the left position, and a noncircular contour orbit is set up. RESULTS: We were able to acquire truncation-free cardiac projections for all of our patients. CONCLUSION: Patient positioning in convergent-beam SPECT is important. If the patient is not positioned properly, then the heart may be truncated in some projection views. The use of the left locking position of the patient table positions the heart at the center of rotation, and the heart is not truncated in the projection data. PMID- 17702906 TI - Cost-effectiveness analysis of subtraction scintigraphy in patients with acute lower gastrointestinal tract hemorrhage. AB - (99m)Tc-labeled red blood cell scintigraphy is a powerful detection and localization tool that may be confounded by false-positive and false-negative findings. Subtraction scintigraphy has been used in the evaluation of acute lower gastrointestinal tract hemorrhage (LGIH) to reduce the impact of interpretive confounders. The aim of this investigation was to evaluate the cost-effectiveness of the addition of subtraction scintigraphy in the evaluation of patients with acute LGIH. METHODS: The clinical phase of this research was a retrospective clinical study with a repeated-measures design including randomized control and experimental groups. A total of 49 patient studies were included in the sample. Studies were randomized and interpreted by 4 independent physicians. Decision tree analysis was used to model direct costs and the potential risks of procedures for 2 diagnostic strategies for patients with acute LGIH: conventional scintigraphy alone and conventional scintigraphy combined with subtraction scintigraphy. The transition probabilities (or branching fraction at each decision node) for scintigraphy were based on the clinical results of this investigation. All other transition probabilities were derived from previously cited data. RESULTS: Combining subtraction techniques with conventional scintigraphy reduced the overall costs of procedures for patients with acute LGIH by $74 per patient and reduced deaths by 17.6% and complications by 15.7%. For conventional scintigraphy alone, 8.8% of patients presenting for scintigraphic evaluation of acute LGIH would undergo unnecessary angiograms, and 2.8% would have unnecessary surgery. These figures were reduced to just 5.4% and 1.8%, respectively, with the addition of subtraction scintigraphy. CONCLUSION: The use of subtraction scintigraphy as an adjunct to conventional scintigraphy for patients with acute LGIH may provide both cost and outcome benefits. PMID- 17702907 TI - Lead pig for use with screw cap vials. AB - A lead pig specifically designed for use with solid screw cap vials is described. METHODS: The salient features of this design include a compressible polyethylene sleeve, which is housed in the lower section of the pig, and a partially recessed O-ring, which is housed in the upper section of the pig. These features permit both the vial and the cap to be secured independently without the risk of overtightening. Fingertip radiation exposure associated with repetitively opening and closing a screw cap vial containing a sample of (18)F was monitored by use of a fingertip dosimeter. RESULTS: The cumulative fingertip radiation exposure resulting from opening and closing a screw cap vial containing 200 MBq of (18)F FDG 3 times was 307 muSv without the aid of this lead pig, as compared with 6 muSv when using this device. CONCLUSION: Use of this lead pig with screw cap vials can significantly reduce fingertip radiation exposure and decrease the likelihood of accidental radioactive contamination of research personnel. PMID- 17702908 TI - Trends of radiopharmaceutical use at Mayo Clinic Rochester. AB - The field of radiology is continuously changing. The purpose of this study was to identify the effect of technologic advances on nuclear medicine during the past 15 y. METHODS: The number of radiopharmaceutical doses dispensed at Mayo Clinic (Rochester, Minnesota) from 1990 through 2004 was tracked. The number of doses was equivalent to the number of scans performed. RESULTS: Since 1990, the number of bone scans decreased by 38%. Brain scans using (99m)Tc have increased by 166%. The number of cardiac doses dispensed increased 184% from 1990 through 1999 but decreased 3% between 2000 and 2004. The number of lung scans decreased 52% from 1992 through 1999 and increased 66% from 1999 through 2004. The number of kidney scans decreased 67% since 1990. Since its introduction in 1993, the use of (111)In-pentetreotide has increased 16-fold. PET data showed a 602% increase in the number of procedures from 2001 through 2004. CONCLUSION: The number of bone, lung, and kidney scans has decreased because of advances in other imaging modalities. Although the number of cardiac imaging scans increased during most of the study period, the recent rate of growth has declined, possibly because of the availability of alternative procedures such as stress echocardiography. The number of brain and lung scans performed has increased, partially because of the development of new protocols. PET and tumor imaging have shown a substantial increase because of increasing numbers of approved indications and Medicare reimbursement. PMID- 17702909 TI - Signatures of electron fractionalization in ultraquantum bismuth. AB - Because of the long Fermi wavelength of itinerant electrons, the quantum limit of elemental bismuth (unlike most metals) can be attained with a moderate magnetic field. The quantized orbits of electrons shrink with increasing magnetic field. Beyond the quantum limit, the circumference of these orbits becomes shorter than the Fermi wavelength. We studied transport coefficients of a single crystal of bismuth up to 33 tesla, which is deep in this ultraquantum limit. The Nernst coefficient presents three unexpected maxima that are concomitant with quasi plateaus in the Hall coefficient. The results suggest that this bulk element may host an exotic quantum fluid reminiscent of the one associated with the fractional quantum Hall effect and raise the issue of electron fractionalization in a three-dimensional metal. PMID- 17702910 TI - Multicolor super-resolution imaging with photo-switchable fluorescent probes. AB - Recent advances in far-field optical nanoscopy have enabled fluorescence imaging with a spatial resolution of 20 to 50 nanometers. Multicolor super-resolution imaging, however, remains a challenging task. Here, we introduce a family of photo-switchable fluorescent probes and demonstrate multicolor stochastic optical reconstruction microscopy (STORM). Each probe consists of a photo-switchable "reporter" fluorophore that can be cycled between fluorescent and dark states, and an "activator" that facilitates photo-activation of the reporter. Combinatorial pairing of reporters and activators allows the creation of probes with many distinct colors. Iterative, color-specific activation of sparse subsets of these probes allows their localization with nanometer accuracy, enabling the construction of a super-resolution STORM image. Using this approach, we demonstrate multicolor imaging of DNA model samples and mammalian cells with 20- to 30-nanometer resolution. This technique will facilitate direct visualization of molecular interactions at the nanometer scale. PMID- 17702911 TI - Crystal structure of an ancient protein: evolution by conformational epistasis. AB - The structural mechanisms by which proteins have evolved new functions are known only indirectly. We report x-ray crystal structures of a resurrected ancestral protein-the approximately 450 million-year-old precursor of vertebrate glucocorticoid (GR) and mineralocorticoid (MR) receptors. Using structural, phylogenetic, and functional analysis, we identify the specific set of historical mutations that recapitulate the evolution of GR's hormone specificity from an MR like ancestor. These substitutions repositioned crucial residues to create new receptor-ligand and intraprotein contacts. Strong epistatic interactions occur because one substitution changes the conformational position of another site. "Permissive" mutations-substitutions of no immediate consequence, which stabilize specific elements of the protein and allow it to tolerate subsequent function switching changes-played a major role in determining GR's evolutionary trajectory. PMID- 17702914 TI - Grants management. NSF survey of applicants finds a system teetering on the brink. PMID- 17702913 TI - Pork and punishment. PMID- 17702912 TI - Synchrony dynamics during initiation, failure, and rescue of the segmentation clock. AB - The "segmentation clock" is thought to coordinate sequential segmentation of the body axis in vertebrate embryos. This clock comprises a multicellular genetic network of synchronized oscillators, coupled by intercellular Delta-Notch signaling. How this synchrony is established and how its loss determines the position of segmentation defects in Delta and Notch mutants are unknown. We analyzed the clock's synchrony dynamics by varying strength and timing of Notch coupling in zebra-fish embryos with techniques for quantitative perturbation of gene function. We developed a physical theory based on coupled phase oscillators explaining the observed onset and rescue of segmentation defects, the clock's robustness against developmental noise, and a critical point beyond which synchrony decays. We conclude that synchrony among these genetic oscillators can be established by simultaneous initiation and self-organization and that the segmentation defect position is determined by the difference between coupling strength and noise. PMID- 17702915 TI - South Africa. Firing of AIDS policy champion seen as setback. PMID- 17702916 TI - Neuroscience. Enzyme keeps old memories alive. PMID- 17702917 TI - Endocrine disrupters. Controversy continues after panel rules on bisphenol A. PMID- 17702919 TI - Marine geology. Support is drying up for Noah's flood filling the Black Sea. PMID- 17702918 TI - Molecular evolution. Resurrected proteins reveal their surprising history. PMID- 17702920 TI - Alan Krensky interview. Drawing a map for the twenty-seven divisions in NIH's army. PMID- 17702921 TI - Ornithology. Gambling on a ghost bird. PMID- 17702922 TI - Biodiversity. Predicting oblivion: are existing models up to the task? PMID- 17702923 TI - Evolution. Jumping genes hop into the evolutionary limelight. PMID- 17702924 TI - Biofuels and the environment. PMID- 17702925 TI - The tobacco industry and the Data Quality Act. PMID- 17702926 TI - Explorer XII: spinning faster than expected. PMID- 17702927 TI - Life in science. Stop--look--jump. PMID- 17702928 TI - An update on a misconduct investigation. PMID- 17702929 TI - Environment. Carbon mitigation by biofuels or by saving and restoring forests? PMID- 17702930 TI - Biochemistry. Getting into and through the outer membrane. PMID- 17702932 TI - Geophysics. The need to study speed. PMID- 17702931 TI - Cell biology. Aneuploidy in the balance. PMID- 17702933 TI - Neuroscience. Synapses here and not everywhere. PMID- 17702934 TI - Oceans. A change in circulation? PMID- 17702935 TI - Plant speciation. AB - Like the formation of animal species, plant speciation is characterized by the evolution of barriers to genetic exchange between previously interbreeding populations. Prezygotic barriers, which impede mating or fertilization between species, typically contribute more to total reproductive isolation in plants than do postzygotic barriers, in which hybrid offspring are selected against. Adaptive divergence in response to ecological factors such as pollinators and habitat commonly drives the evolution of prezygotic barriers, but the evolutionary forces responsible for the development of intrinsic postzygotic barriers are virtually unknown and frequently result in polymorphism of incompatibility factors within species. Polyploid speciation, in which the entire genome is duplicated, is particularly frequent in plants, perhaps because polyploid plants often exhibit ecological differentiation, local dispersal, high fecundity, perennial life history, and self-fertilization or asexual reproduction. Finally, species richness in plants is correlated with many biological and geohistorical factors, most of which increase ecological opportunities. PMID- 17702936 TI - Human genome ultraconserved elements are ultraselected. AB - Ultraconserved elements in the human genome are defined as stretches of at least 200 base pairs of DNA that match identically with corresponding regions in the mouse and rat genomes. Most ultraconserved elements are noncoding and have been evolutionarily conserved since mammal and bird ancestors diverged over 300 million years ago. The reason for this extreme conservation remains a mystery. It has been speculated that they are mutational cold spots or regions where every site is under weak but still detectable negative selection. However, analysis of the derived allele frequency spectrum shows that these regions are in fact under negative selection that is much stronger than that in protein coding genes. PMID- 17702937 TI - Effects of aneuploidy on cellular physiology and cell division in haploid yeast. AB - Aneuploidy is a condition frequently found in tumor cells, but its effect on cellular physiology is not known. We have characterized one aspect of aneuploidy: the gain of extra chromosomes. We created a collection of haploid yeast strains that each bear an extra copy of one or more of almost all of the yeast chromosomes. Their characterization revealed that aneuploid strains share a number of phenotypes, including defects in cell cycle progression, increased glucose uptake, and increased sensitivity to conditions interfering with protein synthesis and protein folding. These phenotypes were observed only in strains carrying additional yeast genes, which indicates that they reflect the consequences of additional protein production as well as the resulting imbalances in cellular protein composition. We conclude that aneuploidy causes not only a proliferative disadvantage but also a set of phenotypes that is independent of the identity of the individual extra chromosomes. PMID- 17702938 TI - Coherent optical spectroscopy of a strongly driven quantum dot. AB - Quantum dots are typically formed from large groupings of atoms and thus may be expected to have appreciable many-body behavior under intense optical excitation. Nonetheless, they are known to exhibit discrete energy levels due to quantum confinement effects. We show that, like single-atom or single-molecule two- and three-level quantum systems, single semiconductor quantum dots can also exhibit interference phenomena when driven simultaneously by two optical fields. Probe absorption spectra are obtained that exhibit Autler-Townes splitting when the optical fields drive coupled transitions and complex Mollow-related structure, including gain without population inversion, when they drive the same transition. Our results open the way for the demonstration of numerous quantum level-based applications, such as quantum dot lasers, optical modulators, and quantum logic devices. PMID- 17702939 TI - Deep ultraviolet light-emitting hexagonal boron nitride synthesized at atmospheric pressure. AB - Materials emitting light in the deep ultraviolet region around 200 nanometers are essential in a wide-range of applications, such as information storage technology, environmental protection, and medical treatment. Hexagonal boron nitride (hBN), which was recently found to be a promising deep ultraviolet light emitter, has traditionally been synthesized under high pressure and at high temperature. We successfully synthesized high-purity hBN crystals at atmospheric pressure by using a nickel-molybdenum solvent. The obtained hBN crystals emitted intense 215-nanometer luminescence at room temperature. This study demonstrates an easier way to grow high-quality hBN crystals, through their liquid-phase deposition on a substrate at atmospheric pressure. PMID- 17702940 TI - Temporal variability of the Atlantic meridional overturning circulation at 26.5 degrees N. AB - The vigor of Atlantic meridional overturning circulation (MOC) is thought to be vulnerable to global warming, but its short-term temporal variability is unknown so changes inferred from sparse observations on the decadal time scale of recent climate change are uncertain. We combine continuous measurements of the MOC (beginning in 2004) using the purposefully designed transatlantic Rapid Climate Change array of moored instruments deployed along 26.5 degrees N, with time series of Gulf Stream transport and surface-layer Ekman transport to quantify its intra-annual variability. The year-long average overturning is 18.7 +/- 5.6 sverdrups (Sv) (range: 4.0 to 34.9 Sv, where 1 Sv = a flow of ocean water of 10(6) cubic meters per second). Interannual changes in the overturning can be monitored with a resolution of 1.5 Sv. PMID- 17702941 TI - Observed flow compensation associated with the MOC at 26.5 degrees N in the Atlantic. AB - The Atlantic meridional overturning circulation (MOC), which provides one-quarter of the global meridional heat transport, is composed of a number of separate flow components. How changes in the strength of each of those components may affect that of the others has been unclear because of a lack of adequate data. We continuously observed the MOC at 26.5 degrees N for 1 year using end-point measurements of density, bottom pressure, and ocean currents; cable measurements across the Straits of Florida; and wind stress. The different transport components largely compensate for each other, thus confirming the validity of our monitoring approach. The MOC varied over the period of observation by +/-5.7 x 10(6) cubic meters per second, with density-inferred and wind-driven transports contributing equally to it. We find evidence for depth-independent compensation for the wind-driven surface flow. PMID- 17702942 TI - Reduced egg investment can conceal helper effects in cooperatively breeding birds. AB - Cooperative breeding systems are characterized by nonbreeding helpers that assist breeders in offspring care. However, the benefits to offspring of being fed by parents and helpers in cooperatively breeding birds can be difficult to detect. We offer experimental evidence that helper effects can be obscured by an undocumented maternal tactic. In superb fairy-wrens (Malurus cyaneus), mothers breeding in the presence of helpers lay smaller eggs of lower nutritional content that produce lighter chicks, as compared with those laying eggs in the absence of helpers. Helpers compensate fully for such reductions in investment and allow mothers to benefit through increased survival to the next breeding season. We suggest that failure to consider maternal egg-investment strategies can lead to underestimation of the force of selection acting on helping in avian cooperative breeders. PMID- 17702943 TI - Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKM zeta. AB - Little is known about the neuronal mechanisms that subserve long-term memory persistence in the brain. The components of the remodeled synaptic machinery, and how they sustain the new synaptic or cellwide configuration over time, are yet to be elucidated. In the rat cortex, long-term associative memories vanished rapidly after local application of an inhibitor of the protein kinase C isoform, protein kinase M zeta (PKMzeta). The effect was observed for at least several weeks after encoding and may be irreversible. In the neocortex, which is assumed to be the repository of multiple types of long-term memory, persistence of memory is thus dependent on ongoing activity of a protein kinase long after that memory is considered to have consolidated into a long-term stable form. PMID- 17702944 TI - Detection of near-atmospheric concentrations of CO2 by an olfactory subsystem in the mouse. AB - Carbon dioxide (CO2) is an important environmental cue for many organisms but is odorless to humans. It remains unclear whether the mammalian olfactory system can detect CO2 at concentrations around the average atmospheric level (0.038%). We demonstrated the expression of carbonic anhydrase type II (CAII), an enzyme that catabolizes CO2, in a subset of mouse olfactory neurons that express guanylyl cyclase D (GC-D+ neurons) and project axons to necklace glomeruli in the olfactory bulb. Exposure to CO2 activated these GC-D+ neurons, and exposure of a mouse to CO2 activated bulbar neurons associated with necklace glomeruli. Behavioral tests revealed CO2 detection thresholds of approximately 0.066%, and this sensitive CO2 detection required CAII activity. We conclude that mice detect CO2 at near-atmospheric concentrations through the olfactory subsystem of GC-D+ neurons. PMID- 17702945 TI - Structure of the membrane protein FhaC: a member of the Omp85-TpsB transporter superfamily. AB - In Gram-negative bacteria and eukaryotic organelles, beta-barrel proteins of the outer membrane protein 85-two-partner secretion B (Omp85-TpsB) superfamily are essential components of protein transport machineries. The TpsB transporter FhaC mediates the secretion of Bordetella pertussis filamentous hemagglutinin (FHA). We report the 3.15 A crystal structure of FhaC. The transporter comprises a 16 stranded beta barrel that is occluded by an N-terminal alpha helix and an extracellular loop and a periplasmic module composed of two aligned polypeptide transport-associated (POTRA) domains. Functional data reveal that FHA binds to the POTRA 1 domain via its N-terminal domain and likely translocates the adhesin repeated motifs in an extended hairpin conformation, with folding occurring at the cell surface. General features of the mechanism obtained here are likely to apply throughout the superfamily. PMID- 17702947 TI - Science careers. Carving a career in translational research. PMID- 17702946 TI - Structure and function of an essential component of the outer membrane protein assembly machine. AB - Integral beta-barrel proteins are found in the outer membranes of mitochondria, chloroplasts, and Gram-negative bacteria. The machine that assembles these proteins contains an integral membrane protein, called YaeT in Escherichia coli, which has one or more polypeptide transport-associated (POTRA) domains. The crystal structure of a periplasmic fragment of YaeT reveals the POTRA domain fold and suggests a model for how POTRA domains can bind different peptide sequences, as required for a machine that handles numerous beta-barrel protein precursors. Analysis of POTRA domain deletions shows which are essential and provides a view of the spatial organization of this assembly machine. PMID- 17702948 TI - Science careers. Translational institute unites unlikely partners at Penn. PMID- 17702949 TI - Science careers. European programs offer translational training. PMID- 17702950 TI - Information processing streams in rodent barrel cortex: the differential functions of barrel and septal circuits. AB - Rodent somatosensory cortex contains an isomorphic map of the mystacial whiskers in which each whisker is represented by neuronal populations, or barrels, that are separated from each other by intervening septa. Separate afferent pathways convey somatosensory information to the barrels and septa that represent the input stages for 2 partially segregated circuits that extend throughout the other layers of barrel cortex. Whereas the barrel-related circuits process spatiotemporal information generated by whisker contact with external objects, the septa-related circuits encode the frequency and other kinetic features of active whisker movements. The projection patterns from barrel cortex indicate that information processed by the septa-related circuits is used both separately and in combination with information from the barrel-related circuits to mediate specific functions. According to this theory, outputs from the septal processing stream modulate the brain regions that regulate whisking behavior, whereas both processing streams cooperate with each other to identify external stimuli encountered by passive or active whisker movements. This theoretical view prompts several testable hypotheses about the coordination of neuronal activity during whisking behavior. Foremost among these, motor brain regions that control whisker movements are more strongly coordinated with the septa-related circuits than with the barrel-related circuits. PMID- 17702951 TI - The hippocampal CA1 region and dentate gyrus differentiate between environmental and spatial feature encoding through long-term depression. AB - Novel spatial information is encoded in the hippocampus by plastic changes of synaptic properties. Novel space consists of several types of information that may evoke differential synaptic responses in individual hippocampal subregions. To examine this possibility, we recorded field potentials from the dentate gyrus (DG) and CA1 region in freely moving adult rats. Stimulation protocols that were marginally subthreshold for the induction of persistent long-term potentiation (LTP) or long-term depression (LTD) were implemented, concurrent with exposure to novel spatial information. We found that in both hippocampal subregions, exploration of a novel empty hole board facilitated LTP. However, LTD facilitation was subregion specific and dependent on the nature of the cues. In the CA1 region, partially concealed cues had a facilitatory effect on LTD. LTD in the DG was facilitated by large directional cues. Thus, although LTP was facilitated uniformly in both areas by the same novel environment, LTD was facilitated in a region-specific manner, based on the nature of the cue. This implies that spatial changes within an environment elicit local changes of synaptic weights dependent on the type of information and, hence, generate a complete cognitive map as a consequence of cooperation of synaptic plasticity in all participating subregions. PMID- 17702952 TI - Mast cell-mediated long-lasting increases in excitability of vagal C fibers in guinea pig esophagus. AB - Several esophageal pathologies are associated with an increased number of mast cells in the esophageal wall. We addressed the hypothesis that activation of esophageal mast cells leads to an increase in the excitability of local sensory C fibers. Guinea pigs were actively sensitized to ovalbumin. The mast cells in the esophagus were selectively activated ex vivo by superfusion with ovalbumin. Action potential discharge in guinea pig vagal nodose esophageal C-fiber nerve endings was monitored in the isolated (ex vivo) vagally innervated esophagus by extracellular recordings. Ovalbumin activated esophageal mast cells, leading to the rapid release of approximately 20% of the tissue histamine stores. This was associated with a consistent and significant increase in excitability of the nodose C fibers as reflected in a two- to threefold increase in action potential discharge frequency evoked by mechanical (increases in intraluminal pressure) stimulation. The increase in excitability persisted unchanged for at least 90 min (longest time period tested) after ovalbumin was washed from the tissue. This effect could be prevented by the histamine H1 receptor antagonist pyrilamine, but once the increase in excitability occurred, it persisted in the nominal absence of histamine and could not be reversed even with large concentrations of the histamine receptor antagonist. In conclusion, activation of esophageal mast cells leads to a pronounced and long-lived increase in nociceptive C-fiber excitability such that any sensation or reflex evoked via the vagal nociceptors will likely be enhanced. The effect is initiated by histamine acting via H1 receptor activation and maintained in the absence of the initiating stimulus. PMID- 17702953 TI - C-type natriuretic peptide enhances amylase release through NPR-C receptors in the exocrine pancreas. AB - Several studies show that C-type natriuretic peptide (CNP) has a modulatory role in the digestive system. CNP administration reduces both jejunal fluid and bile secretion in the rat. In the present study we evaluated the effect of CNP on amylase release in isolated pancreatic acini as well as the receptors and intracellular pathways involved. Results showed that all natriuretic peptide receptors were expressed not only in the whole pancreas but also in isolated pancreatic acini. CNP stimulated amylase secretion with a concentration-dependent biphasic response; maximum release was observed at 1 pM CNP, whereas higher concentrations gradually attenuated it. The response was mimicked by a selective natriuretic peptide receptor (NPR-C) agonist and inhibited by pertussis toxin, strongly supporting NPR-C receptor activation. CNP-evoked amylase release was abolished by U-73122 (PLC inhibitor) and 2-aminoethoxydiphenyl borate (2-APB) [an inositol 1,4,5-triphosphate (IP(3)) receptor antagonist], partially inhibited by GF-109203X (PKC inhibitor), and unaltered by ryanodine or protein kinase A (PKA) and protein kinase G (PKG) inhibitors. Phosphoinositide hydrolysis was enhanced by CNP at all concentrations and abolished by U-73122. At 1 and 10 pM, CNP did not affect cAMP or guanosine 3',5'-cyclic monophosphate (cGMP) levels, but at higher concentrations it increased cGMP and diminished cAMP content. Present findings show that CNP stimulated amylase release through the activation of NPR-C receptors coupled to the PLC pathway and downstream effectors involved in exocytosis. The attenuation of amylase release was likely related to cAMP reduction. The augmentation in cGMP supports activation of NPR-A/NPR-B receptors probably involved in calcium influx. Present findings give evidence that CNP is a potential direct regulator of pancreatic function. PMID- 17702954 TI - Involvement of AMP-activated protein kinase in beneficial effects of betaine on high-sucrose diet-induced hepatic steatosis. AB - Although simple steatosis was originally thought to be a pathologically inert histological change, fat accumulation in the liver may play a critical role not only in disease initiation, but also in the progression to nonalcoholic steatohepatitis and cirrhosis. Therefore, prevention of fat accumulation in the liver may be an effective therapy for multiple stages of nonalcoholic fatty liver disease (NAFLD). Promising beneficial effects of betaine supplementation on human NAFLD have been reported in some pilot clinical studies; however, data related to betaine therapy in NAFLD are limited. In this study, we examined the effects of betaine on fat accumulation in the liver induced by high-sucrose diet and evaluated mechanisms by which betaine could attenuate or prevent hepatic steatosis in this model. Male C57BL/6 mice weighing 20 +/- 0.5 g (means +/- SE) were divided into four groups (8 mice per group) and started on one of four treatments: standard diet (SD), SD+betaine, high-sucrose diet (HS), and HS + betaine. Betaine was supplemented in the drinking water at a concentration of 1% (wt/vol) (anhydrous). Long-term feeding of high-sucrose diet to mice caused significant hepatic steatosis accompanied by markedly increased lipogenic activity. Betaine significantly attenuated hepatic steatosis in this animal model, and this change was associated with increased activation of hepatic AMP activated protein kinase (AMPK) and attenuated lipogenic capability (enzyme activities and gene expression) in the liver. Our findings are the first to suggest that betaine might serve as a therapeutic tool to attenuate hepatic steatosis by targeting the hepatic AMPK system. PMID- 17702955 TI - Stimulation of voltage-dependent Ca2+ channels by NO at rat myenteric neurons. AB - The aim of the present study was to characterize the action of the neurotransmitter NO on rat myenteric neurons. A NO donor such as GEA 3162 (10(-4) mol/l) induced an increase in the intracellular Ca2+ concentration as indicated by an increase in the fura 2 ratio in ganglia loaded with this Ca2+-sensitive fluorescent dye. The effect of GEA 3162 was strongly reduced in the absence of extracellular Ca2+, suggesting an influx of Ca2+ from the extracellular space evoked by NO. A similar nearly complete inhibition was observed in the presence of Ca2+ channel blockers such as Ni2+ (5 x 10(-4) mol/l) or nifedipine (10(-6) mol/l). Whole cell patch-clamp recordings confirmed the activation of voltage dependent Ca2+ channels, measured as inward current carried by Ba2+, by the NO donor. The peak Ba2+-carried inward current increased from -100 +/- 19 to -185 +/ 34 pA in the presence of sodium nitroprusside (10(-4) mol/l). The consequence was a hyperpolarization of the membrane, which was blocked by intracellular Cs+ and thus most probably reflects the activation of Ca2+-dependent K+ channels. Furthermore, at least two subtypes of NO synthases, NOS-1 (neuronal form) and NOS 3 (endothelial form), were found as transcripts in mRNA isolated from the rat myenteric ganglia. The expression of these NO synthases was confirmed immunohistochemically. These observations suggest that NO, released from nitrergic neurons within the enteric nervous system, not only affects target organs such as smooth muscle cells in the gut but has in addition profound effects on the enteric neurons themselves, the key players in the regulation of many gastrointestinal functions. PMID- 17702956 TI - Intra-arterial fibrinolysis for acute ischemic stroke: the message of melt. PMID- 17702957 TI - Treadmill aerobic training improves glucose tolerance and indices of insulin sensitivity in disabled stroke survivors: a preliminary report. AB - BACKGROUND AND PURPOSE: Insulin resistance and glucose intolerance are highly prevalent after stroke, contributing to worsening cardiovascular disease risk and a predisposition to recurrent stroke. Treadmill exercise training (T-AEX) increases aerobic capacity (Vo(2) peak) in chronic stroke patients, suggesting intensity levels that may be adequate to improve glucose metabolism. We compared the effects of a progressive T-AEX intervention to an attention-matched stretching intervention (CONTROL) on glucose tolerance and indices of insulin sensitivity in stroke survivors. METHODS: Participants had hemiparetic gait after remote (>6 months) ischemic stroke. They were randomized to 6-month T-AEX or a duration matched reference CONTROL program of supervised stretching exercises. Main outcome measures were glucose and insulin responses during a 3-hour oral glucose tolerance test (OGTT). RESULTS: Forty-six subjects (T-AEX=26, CONTROL=20) completed OGTT testing before and after the interventions. T-AEX increased Vo(2) peak (+15% versus -3% Delta, P<0.01) compared with CONTROL. There were significant reductions in fasting insulin (-23% versus +9% Delta, P<0.05) and the total integrated 3-hour insulin response (-24% versus +3% Delta, P<0.01) in T-AEX compared with CONTROL. In patients with abnormal glucose tolerance at baseline, T AEX resulted in a significant 14% decrease in 3-hour glucose response (n=12, P<0.05). Fifty-eight percent of T-AEX participants with abnormal baseline OGTT (7 of 12) improved glucose tolerance status at 2 hours compared with <10% (1 of 11) of impaired CONTROLS (P<0.05). CONCLUSIONS: These preliminary findings suggest that progressive aerobic exercise can reduce insulin resistance and prevent diabetes in hemiparetic stroke survivors. Larger clinical trials are needed to definitively establish the use of structured exercise training for stimulating metabolic improvement poststroke. PMID- 17702958 TI - Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke: the middle cerebral artery embolism local fibrinolytic intervention trial (MELT) Japan. AB - BACKGROUND AND PURPOSE: The Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) Japan was organized to determine the safety and clinical efficacy of intraarterial infusion of urokinase (UK) in patients with stroke within 6 hours of onset. METHODS: Patients with ischemic stroke presenting within 6 hours of onset and displaying occlusions of the M1 or M2 portion of the middle cerebral artery on carotid angiography were randomized to the UK or control groups. Clinical outcome was assessed by the modified Rankin Scale, National Institutes of Health Stroke Scale, and Barthel Index. RESULTS: The Independent Monitoring Committee recommended stopping the trial after approval of intravenous infusion of recombinant tissue plasminogen activator in Japan. A total of 114 patients underwent randomization, 57 patients in each group. Background characteristics were comparable between the 2 groups. The primary end point of favorable outcome (modified Rankin Scale 0 to 2) at 90 days was somewhat more frequent in the UK group than in the control group (49.1% and 38.6%, OR: 1.54, 95% CI: 0.73 to 3.23) but did not reach a significant level (P=0.345). However, excellent functional outcome (modified Rankin Scale 0 to 1) at 90 days, a preplanned secondary end point, was more frequent in the UK group than in the control group (42.1% and 22.8%, P=0.045, OR: 2.46, 95% CI: 1.09 to 5.54). There were significantly more patients with National Institutes of Health Stroke Scale 0 or 1 at 90 days in the UK group than the control group (P=0.017). The 90-day cumulative mortality was 5.3% in the UK group and 3.5% in the control group (P=1.000), and intracerebral hemorrhage within 24 hours of treatment occurred in 9% and 2%, respectively (P=0.206). CONCLUSIONS: The trial was aborted prematurely and the primary end point did not reach statistical significance. Nevertheless, the secondary analyses suggested that intraarterial fibrinolysis has the potential to increase the likelihood of excellent functional outcome. PMID- 17702959 TI - Mouse model of in situ thromboembolic stroke and reperfusion. AB - BACKGROUND AND PURPOSE: Early reperfusion using tissue-type plasminogen activator is the only therapeutic agent to treat focal cerebral ischemia with proven efficacy in patients. Nevertheless, novel insights into the pathophysiology of neurons, glial cells, and the fate of the endothelium after stroke call for the use of new strategies to improve stroke treatment alone or in combination with tissue-type plasminogen activator-induced thrombolysis. Unfortunately, despite the plethora of drugs that display clear beneficial effects in animal models of experimental ischemia, their subsequent use in clinical trials has proven disappointing. As such, one is forced to consider that new animal models of focal cerebral ischemia may be required before clinical evaluation of a new molecule. METHODS: In situ microinjection of purified murine thrombin was used to trigger a local clot formation in anesthetized mice. Cerebral blood velocity was measured continuously throughout the duration of the study. The efficiency of recombinant tissue-type plasminogen activator to induce thrombolysis and its subsequent effect on infarct volume were then measured. RESULTS: In situ thrombin injection leads to a reproducible clot formation and cortical brain injury. Recombinant tissue-type plasminogen activator-induced thrombolysis reduced infarct volume by 36.8% when compared with untreated control mice. CONCLUSIONS: We describe an original and reproducible mouse model of in situ clot formation and reperfusion, which could be used to investigate new therapeutic strategies to improve stroke treatment. PMID- 17702960 TI - Is there a direct link between cerebrovascular activity and cerebrospinal fluid pressure-volume compensation? AB - BACKGROUND AND PURPOSE: Cerebral blood flow is coupled to brain metabolism by means of active modulation of cerebrovascular resistance. This homeostatic vasogenic activity is reflected in slow waves of cerebral blood flow velocities (FV) which can also be detected in intracranial pressure (ICP). However, effects of increased ICP on the modulation of cerebral blood flow are still poorly understood. This study focused on the question whether ICP has an independent impact on slow waves of FV within the normal cerebral perfusion pressures range. METHODS: Twenty patients presenting with communicating hydrocephalus underwent a diagnostic intraventricular constant-flow infusion test. Blood flow velocities in the middle cerebral artery and posterior cerebral arteries were measured using Transcranial Doppler. Pulsatility index, FV variability of slow vasogenic waves (3 to 9 bpm), ICP, and arterial blood pressure were simultaneously monitored. RESULTS: During the test, ICP increased from a baseline of 11 (6) mm Hg to a plateau value of 21 (6) mm Hg (P=0.00005). Although the infusion did not induce significant changes in cerebral perfusion pressures, FV, pulsatility index, or index of autoregulation, the magnitude of FV vasogenic waves at plateau became inversely correlated to ICP (middle cerebral artery: r=-0.58, P<0.01; posterior cerebral arteries: r=-0.54, P<0.01). CONCLUSIONS: This study shows that even moderately increased ICP can limit the modulation of cerebral blood flow in both vascular territories within the autoregulatory range of cerebral perfusion pressures. The exhaustion of cerebrospinal fluid volume buffering reserve during infusion studies elicits a direct interaction between the cerebrospinal fluid space and the cerebrovascular compartment. PMID- 17702961 TI - MRI-based and CT-based thrombolytic therapy in acute stroke within and beyond established time windows: an analysis of 1210 patients. AB - BACKGROUND AND PURPOSE: The use of intravenous thrombolysis is restricted to a minority of patients by the rigid 3-hour time window. This window may be extended by using modern imaging-based selection algorithms. We assessed safety and efficacy of MRI-based thrombolysis within and beyond 3 hours compared with standard CT-based thrombolysis. METHODS: Five European stroke centers pooled the core data of their CT- and MRI-based prospective thrombolysis databases. Safety outcomes were predefined as symptomatic intracranial hemorrhage and mortality. Primary efficacy outcome was a favorable outcome (modified Rankin Scale 0 to 1). We performed univariate and multivariate analyses for all end points, including age, National Institutes of Health Stroke Scale, treatment group (CT <3 hours, MRI <3 hours and >3 hours), and onset to treatment time as variables. RESULTS: A total of 1210 patients were included (CT <3 hours: N=714; MRI <3 hours: N=316; MRI >3 hours: N=180). Median age, National Institutes of Health Stroke Scale, and onset to treatment time were 69, 67, and 68.5 years (P=0.66); 12, 13, and 14 points (P=0.019); and 130, 135, and 240 minutes (P<0.001). Symptomatic intracranial hemorrhage rates were 5.3%, 2.8%, and 4.4% (P=0.213); mortality was 13.7%, 11.7%, and 13.3% (P=0.68). Favorable outcome occurred in 35.4%, 37.0%, and 40% (P=0.51). Age and National Institutes of Health Stroke Scale were independent predictors for all safety and efficacy outcomes. The overall use of MRI significantly reduced symptomatic intracranial hemorrhage (OR: 0.520, 95% CI: 0.270 to 0.999, P=0.05). Beyond 3 hours, the use of MRI significantly predicted a favorable outcome (OR: 1.467; 95% CI: 1.017 to 2.117, P=0.040). Within 3 hours and for all secondary end points, there was a trend in favor of MRI-based selection over standard <3-hour CT-based treatment. CONCLUSIONS: Despite significantly longer time windows and significantly higher baseline National Institutes of Health Stroke Scale scores, MRI-based thrombolysis is safer and potentially more efficacious than standard CT-based thrombolysis. PMID- 17702963 TI - An interactive association of common sequence variants in the neuropeptide Y gene with susceptibility to ischemic stroke. AB - BACKGROUND AND PURPOSE: Knowledge of the genetic architecture of ischemic stroke has been quite limited. Most significant associations of candidate genes with ischemic stroke have been difficult to replicate. This might be because the associations were not strong enough for results to be consistent, and testing a mixture of heterogeneous ischemic strokes might lead to confounded genetic associations. METHODS: A preliminary association analysis with 28 sequence variants in 18 candidate genes (ACE, AGT, AGTR1, BDNF, CRP, F13B, LIF, MMP9, NPPA, NPY, PTGS2, SELP, SERPINE1, SREBF2, TFPI, THBD, VCAM1, and VEGF) revealed that NPY might be the most responsible for the susceptibility of ischemic stroke. Forty-five variants were discovered in the NPY gene by full sequencing, and 5 polymorphisms were selected based on their allele frequency and linkage disequilibrium estimates to conduct a thorough examination of their associations with ischemic stroke and its subtypes classified by TOAST. This study was conducted with 271 patients with ischemic stroke and 455 control subjects. RESULTS: In contrast to a slight significance for an allelic association with ischemic stroke, remarkable discrepancies between haplotype frequencies of control subjects and patients were found. Especially, TA and CC of the haplotypes composed of C4112T and A6411C in the NPY gene were associated with increased risk (P=1.8 x 10(-21), P=2.0 x 10(-13)). The interchanged haplotypes, TC and CA, were protective against the diseases (P=9.3 x 10(-12), P=6.0 x 10(-17)). The associations were also shown in major subtypes of ischemic stroke. CONCLUSIONS: This remarkable haplotypic association suggested that the interaction between the 2 common sequence polymorphisms in NPY contributed to a great amount of phenotypic variability of ischemic stroke. PMID- 17702962 TI - Erythropoietin promotes neuronal replacement through revascularization and neurogenesis after neonatal hypoxia/ischemia in rats. AB - BACKGROUND AND PURPOSE: Erythropoietin (EPO) has been well characterized and shown to improve functional outcomes after ischemic injury, but EPO may also have unexplored effects on neurovascular remodeling and neuronal replacement in the neonatal ischemic brain. The current study investigates the effects of exogenous administration of EPO on revascularization and neurogenesis, 2 major events thought to contribute to neuronal replacement, in the neonatal brain after hypoxia/ischemia (H/I). METHODS: Seven-day-old rat pups were treated with recombinant human EPO or vehicle 20 minutes after H/I and again on postischemic days 2, 4, and 6. Rats were euthanized 7 or 28 days after H/I for evaluation of infarct volume, revascularization, neurogenesis, and neuronal replacement using bromodeoxyuridine incorporation, immunohistochemistry, and lectin labeling. Neurological function was assessed progressively for 28 days after H/I by gait testing, righting reflex and foot fault testing. RESULTS: We demonstrate that exogenous EPO-enhanced revascularization in the ischemic hemisphere correlated with decreased infarct volume and improved neurological outcomes after H/I. In addition to vascular effects, EPO increased both neurogenesis in the subventricular zone and migration of neuronal progenitors into the ischemic cortex and striatum. A significant number of newly synthesized cells in the ischemic boundary expressed neuronal nuclei after EPO treatment, indicating that exogenous EPO led to neuronal replacement. CONCLUSIONS: Our data suggest that treatment with EPO contributes to neurovascular remodeling after H/I by promoting tissue protection, revascularization, and neurogenesis in neonatal H/I-injured brain, leading to improved neurobehavioral outcomes. PMID- 17702964 TI - A twin study of post-traumatic stress disorder symptoms and asthma. AB - RATIONALE: Studies have suggested heightened anxiety among adults with asthma; the mechanism of this association is not known. OBJECTIVES: To determine the association between post-traumatic stress disorder (PTSD) symptoms and asthma among adults, and to examine if this association is due to confounding by environmental and genetic factors. METHODS: Data were obtained from twins in the Vietnam Era Twin Registry, which includes male veteran twin pairs born between 1939 and 1956 who served during the Vietnam era (1965-1975). Measurements included a symptom scale for PTSD, history of a doctor diagnosis of asthma, and sociodemographic and health confounding factors. Co-twin control analytic methods used mixed-effects logistic regression to account for the paired structure of the twin data and to examine the association between PTSD symptoms and asthma in all twins. Separate analyses were conducted within twin pairs and according to zygosity. MEASUREMENTS AND MAIN RESULTS: PTSD symptoms were associated with a significantly increased likelihood of asthma (P(trend) < 0.001) even after adjustment for confounding factors. Among all twins, those in the highest quartile of PTSD symptoms were 2.3 times as likely (95% confidence interval, 1.4 3.7) to have asthma compared with those in the lowest quartile. These findings persist when examined within twin pairs and when stratified by zygosity. CONCLUSIONS: Symptoms of PTSD were associated with an elevated prevalence of asthma. Even after careful adjustment for familial/genetic factors and other potential confounding factors, an association between PTSD symptoms and asthma remains. Efforts to understand this comorbidity may be useful in identifying modifiable environmental risk factors contributing to this pattern and therefore in developing more effective prevention and intervention strategies. PMID- 17702965 TI - Comprehensive testing of positionally cloned asthma genes in two populations. AB - RATIONALE: Replication of gene-disease associations has become a requirement in complex trait genetics. OBJECTIVES: In studies of childhood asthma from two different ethnic groups, we attempted to replicate associations with five potential asthma susceptibility genes previously identified by positional cloning. METHODS: We analyzed two family-based samples ascertained through an asthmatic proband: 497 European-American children from the Childhood Asthma Management Program and 439 Hispanic children from the Central Valley of Costa Rica. We genotyped 98 linkage disequilibrium-tagging single-nucleotide polymorphisms (SNPs) in five genes: ADAM33, DPP10, GPR154 (HUGO name: NPSR1), HLA G, and the PHF11 locus (includes genes SETDB2 and RCBTB1). SNPs were tested for association with asthma and two intermediate phenotypes: airway hyperresponsiveness and total serum immunoglobulin E levels. MEASUREMENTS AND MAIN RESULTS: Despite differing ancestries, linkage disequilibrium patterns were similar in both cohorts. Of the five evaluated genes, SNP-level replication was found only for GPR154 (NPSR1). In this gene, three SNPs were associated with asthma in both cohorts, although the opposite alleles were associated in either study. Weak evidence for locus-level replication with asthma was found in the PHF11 locus, although there was no overlap in the associated SNP across the two cohorts. No consistent associations were observed for the three other genes. CONCLUSIONS: These results provide some further support for the role of genetic variation in GPR154 (NPSR1) and PHF11 in asthma susceptibility and also highlight the challenges of replicating genetic associations in complex traits such as asthma, even for genes identified by linkage analysis. PMID- 17702966 TI - Free and total cortisol levels as predictors of severity and outcome in community acquired pneumonia. AB - RATIONALE: High cortisol levels are of prognostic value in sepsis. The predictive value of cortisol in pneumonia is unknown. Routinely available assays measure serum total cortisol (TC) and not free cortisol (FC). Whether FC concentrations better reflect outcome is uncertain. OBJECTIVES: To investigate the predictive value of TC and FC in community-acquired pneumonia (CAP). METHODS: Preplanned subanalysis of a prospective intervention study in 278 patients presenting to the emergency department with CAP. MEASUREMENTS AND MAIN RESULTS: TC, FC, procalcitonin, C-reactive protein, leukocytes, clinical variables, and the pneumonia severity index (PSI) were measured. The major outcome measures were PSI and survival. TC and FC, but not C-reactive protein or leukocytes, increased with increasing severity of CAP according to the PSI (P < 0.001). TC and FC levels on presentation in patients who died during follow-up were significantly higher as compared with levels in survivors. In a receiver operating characteristic analysis to predict survival, the area under the receiver operating characteristic curve (AUC) was 0.76 (95% confidence interval, 0.70-0.81) for TC and 0.69 (0.63-0.74) for FC. This was similar to the AUC of the PSI (0.76 [0.70 0.81]), and better as compared with C-reactive protein, procalcitonin, or leukocytes. In univariate analysis, only TC, FC, and the PSI were predictors of death. In multivariate analysis, the predictive potential of TC equaled the prognostic power of PSI points. CONCLUSIONS: Cortisol levels are predictors of severity and outcome in CAP to a similar extent to the PSI, and are better than routinely measured laboratory parameters. In CAP, the prognostic accuracy of FC is not superior to TC. Clinical trial registered with www.controlled-trials.com (ISRCTN04176397). PMID- 17702967 TI - Apolipoprotein E genotype and response of carbon monoxide poisoning to hyperbaric oxygen treatment. AB - RATIONALE: Hyperbaric oxygen (HBO2) reduced the incidence of cognitive sequelae 6 weeks after carbon monoxide (CO) poisoning compared with normobaric oxygen (NBO2). The apolipoprotein (APOE) epsilon4 allele predicts unfavorable neurologic outcome after brain injury and stroke. OBJECTIVES: To assess the effects of the epsilon4 allele on 6-week cognitive sequelae after CO poisoning. METHODS: We tested APOE genotypes in 86 of 152 CO-poisoned patients from our randomized trial. Logistic regression was used to control for risk factors while testing for effects with the epsilon4 allele or interactions with epsilon4 and treatment on 6 week and 6- and 12-month cognitive sequelae. MEASUREMENTS AND MAIN RESULTS: We enrolled 86 patients: 44 received HBO2 and 42 NBO2 therapy. A total of 31 (36%) patients had at least one epsilon4 allele. Six-week cognitive sequelae rates for patients treated with HBO2 and NBO2, respectively: epsilon4 allele absent, 11% (3/27) and 43% (12/28); epsilon4 allele present, 35% (6/17) and 29% (4/14). The epsilon4 allele was not associated with 6-week cognitive sequelae, 27% (15/55) without and 32% (10/31) with the epsilon4 allele (P = 0.323). The interaction between the epsilon4 allele and treatment was significantly associated with 6 week cognitive sequelae (P = 0.048). The interaction between the epsilon4 allele and treatment was not associated with 6- and 12-month cognitive sequelae. CONCLUSIONS: HBO2 therapy reduces cognitive sequelae after CO poisoning in the absence of the epsilon4 allele. Because apolipoprotein genotype is unknown at the time of poisoning, we recommend that patients with acute CO poisoning receive HBO2. PMID- 17702968 TI - Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. AB - RATIONALE: It is unclear when the pathologic features of asthma first appear. We hypothesized that eosinophilic airway inflammation and epithelial reticular basement membrane (RBM) thickening, absent in wheezy infants, would be present in preschool children with severe, recurrent wheeze. OBJECTIVES: To compare RBM thickness and inflammation in endobronchial biopsies (EBs) from wheezy preschool children and age-matched control subjects. METHODS: EBs were obtained from wheezy preschool children (aged 3 mo to 5 yr), undergoing a clinically indicated fiberoptic bronchoscopy. Subjects undergoing fiberoptic bronchoscopy to investigate stridor acted as nonasthmatic controls. RBM thickness was measured and the density of subepithelial, immunologically distinct inflammatory cells was determined and expressed as a volume fraction (%). EBs from 16 children (median age, 29 [7-57] mo) with wheeze confirmed by video questionnaire (confirmed wheezers [CWs]), 14 with reported wheeze (reported wheezers [RWs]) (median age, 17 [8-58] mo), and 10 control subjects (median age, 19 [5-42] mo) were assessed. MEASUREMENTS AND MAIN RESULTS: RBM thickness in the three groups was as follows: CWs: median, 4.6 (range, 2.9-8.0) microm; RWs: median, 3.5 (2.1-5.4) microm; control subjects: median, 3.8 (2.5-4.7) microm. RBM was significantly thicker in CWs than in control subjects (P < 0.05). Eosinophil density was as follows: CWs: median, 1.07% (range, 0.0-3.52%); RWs: median, 0.72% (0.0-2.04%); control subjects: median, 0.0% (0.0-1.05%). Eosinophilic inflammation was significantly greater in CWs compared with control subjects (P < 0.05). There were no between group differences for any other inflammatory cell phenotype. CONCLUSIONS: The characteristic pathologic features of asthma in adults and school-aged children develop in preschool children with confirmed wheeze between the ages of 1 and 3 years, a time when intervention may modify the natural history of asthma. PMID- 17702969 TI - Prenatal exposure to fluoxetine induces fetal pulmonary hypertension in the rat. AB - RATIONALE: Fluoxetine is a selective serotonin reuptake inhibitor antidepressant widely used by pregnant women. Epidemiological data suggest that fluoxetine exposure prenatally increases the prevalence of persistent pulmonary hypertension syndrome of the newborn. The mechanism responsible for this effect is unclear and paradoxical, considering the current evidence of a pulmonary hypertension protective fluoxetine effect in adult rodents. OBJECTIVES: To evaluate the fluoxetine effect on fetal rat pulmonary vascular smooth muscle mechanical properties and cell proliferation rate. METHODS: Pregnant rats were treated with fluoxetine (10 mg/kg) from Day 11 through Day 21 of gestation. MEASUREMENTS AND MAIN RESULTS: Fetuses were delivered by cesarean section. As compared with controls, fluoxetine exposure resulted in fetal pulmonary hypertension as evidenced by an increase in the weight ratio of the right ventricle to the left ventricle plus septum (P = 0.02) and by an increase in pulmonary arterial medial thickness (P < 0.01). Postnatal mortality was increased among experimental animals, and arterial oxygen saturation was 96 +/- 1% in 1-day-old control animals and significantly lower (P < 0.01) in fluoxetine-exposed pups (79 +/- 2%). In vitro, fluoxetine induced pulmonary arterial muscle contraction in fetal, but not adult, animals (P < 0.01) and reduced serotonin-induced contraction at both ages (P < 0.01). After in utero exposure to a low fluoxetine concentration the pulmonary arterial smooth muscle cell proliferation rate was significantly increased in fetal, but not adult, cells (P < 0.01). CONCLUSIONS: In contrast to the adult, fluoxetine exposure in utero induces pulmonary hypertension in the fetal rat as a result of a developmentally regulated increase in pulmonary vascular smooth muscle proliferation. PMID- 17702970 TI - Effect of laparotomy on clearance and cytokine induction in Staphylococcus aureus infected lungs. AB - RATIONALE: Staphylococcus aureus is a major pathogen complicating postsurgical care. OBJECTIVES: To test the effect of sterile laparotomy (LAP) on pulmonary clearance of S. aureus in a murine model. METHODS: Control and LAP mice were infected intranasally with 10(8) cfu of S. aureus. Microbial clearance, pulmonary leukocyte recruitment, and cytokine profiles were compared between the groups. Antibody neutralization or cytokine gene knockout mice were used to evaluate the role of cytokines. MEASUREMENTS AND MAIN RESULTS: Laparotomy resulted in a 10 fold increase in S. aureus lung colony-forming units on Days 2 and 3 postinfection. Both groups cleared the infection by Day 4. No defect in leukocyte recruitment into the lungs was observed in infected LAP animals; however, an increase in the number of Mac-3-positive cells and a significant decrease of cells with high surface expression of Fc-gammaR suggest suboptimal activation of leukocytes in the lungs of infected LAP animals. Infected LAP mice had decreased expression of interferon (IFN)-gamma and increased expression of mRNA for IL-13 in the lungs on Day 1 postinfection and decreased levels of IL-6, keratinocyte derived chemokine (KC), and macrophage inflammatory protein-2 (MIP-2) in bronchoalveolar lavage at Day 2 postinfection. Neutralization of IFN-gamma mimicked the effect of LAP with impaired clearance on Day 2. CONCLUSIONS: Sterile LAP induced temporary deactivation of innate immune responses to pulmonary S. aureus challenge. Impaired microbial clearance was accompanied by altered cytokine expression and suboptimal activation of pulmonary leukocytes. Lack of early IFN-gamma induction in the infected lungs of LAP animals is a likely mechanism contributing to the observed phenotype. PMID- 17702971 TI - Re: "Nighttime exposure to electromagnetic fields and childhood leukemia: an extended pooled analysis". PMID- 17702972 TI - An evaluation of classification rules based on date of symptom onset to identify health-care associated infections. AB - The date of symptom onset is often used to distinguish health-care-associated from community-acquired infections. Those patients developing symptoms early in an inpatient stay are considered to have community-acquired infection, while those developing symptoms later are considered nosocomially infected. The authors evaluate the performance of this approach, showing how misclassification rates depend on the disease incubation period and the incidence rate ratio of infection among inpatients versus community members. The authors provide quantitative results for selecting classification rules that designate infections as health care associated or community acquired. These techniques allow the selection of disease-specific cutoffs to distinguish community- from nosocomially acquired infections that perform well for important illnesses. For example, a rule classifying those who develop flu symptoms in the first 1.5 days of their hospital stay as having community-acquired influenza and those developing symptoms later as having nosocomial infection has a positive predictive value and a negative predictive value of at least 87%. A cutoff of 6 days will identify community-acquired Legionnaires' disease with a positive predictive value and a negative predictive value of at least 77%. These results increase the utility of classifying infections by use of the date of onset by providing theoretically sound measures of performance, and they are applicable beyond the hospital setting. PMID- 17702973 TI - Directed acyclic graphs, sufficient causes, and the properties of conditioning on a common effect. AB - In this paper, the authors incorporate sufficient-component causes into the directed acyclic graph (DAG) causal framework in order to make apparent several properties of conditioning on a common effect. By incorporating sufficient causes on a graph, it is possible to detect conditional independencies within strata of the conditioning variable which are not evident on DAGs without the representation of sufficient causes. It is also possible to determine the sign of the conditional covariance of two causes when conditioning on their common effect if some knowledge of the sufficient-cause mechanisms for the common effect is available. The incorporation of sufficient causes within the DAG framework also allows for the representation of interactions on DAGs and for the unification of several different causal frameworks. For illustration, the results are applied to an example concerning the familial coaggregation of two disorders. PMID- 17702974 TI - A cytogenetically characterized, genome-anchored 10-Mb BAC set and CGH array for the domestic dog. AB - The generation of a 7.5x dog genome assembly provides exciting new opportunities to interpret tumor-associated chromosome aberrations at the biological level. We present a genomic microarray for array comparative genomic hybridization (aCGH) analysis in the dog, comprising 275 bacterial artificial chromosome (BAC) clones spaced at intervals of approximately 10 Mb. Each clone has been positioned accurately within the genome assembly and assigned to a unique chromosome location by fluorescence in situ hybridization (FISH) analysis, both individually and as chromosome-specific BAC pools. The microarray also contains clones representing the dog orthologues of 31 genes implicated in human cancers. FISH analysis of the 10-Mb BAC clone set indicated excellent coverage of each dog chromosome by the genome assembly. The order of clones was consistent with the assembly, but the cytogenetic intervals between clones were variable. We demonstrate the application of the BAC array for aCGH analysis to identify both whole and partial chromosome imbalances using a canine histiocytic sarcoma case. Using BAC clones selected from the array as probes, multicolor FISH analysis was used to further characterize these imbalances, revealing numerous structural chromosome rearrangements. We outline the value of a combined aCGH/FISH approach, together with a well-annotated dog genome assembly, in canine and comparative cancer studies. PMID- 17702975 TI - How old is your heart? PMID- 17702977 TI - Profilin-1: an unexpected molecule linking vascular inflammation to the actin cytoskeleton. PMID- 17702976 TI - Is phospholamban or troponin I the "prima donna" in beta-adrenergic induced lusitropy? PMID- 17702978 TI - ecSOD controls the delicate balance of reactive oxygen species in bone marrow and ischemic tissue needed for neovascularization. PMID- 17702979 TI - Targeting interferon-gamma to treat atherosclerosis. PMID- 17702980 TI - Cardiac energy metabolism in obesity. AB - Obesity results in marked alterations in cardiac energy metabolism, with a prominent effect being an increase in fatty acid uptake and oxidation by the heart. Obesity also results in dramatic changes in the release of adipokines, such as leptin and adiponectin, both of which have emerged as important regulators of cardiac energy metabolism. The link among obesity, cardiovascular disease, lipid metabolism, and adipokine signaling is complex and not well understood. However, optimizing cardiac energy metabolism in obese subjects may be one approach to preventing and treating cardiac dysfunction that can develop in this population. This review discusses what is presently known about the effects of obesity and the impact adipokines have on cardiac energy metabolism and insulin signaling. The clinical implications of obesity and energy metabolism on cardiac disease are also discussed. PMID- 17702981 TI - Lentiviral rescue of vascular endothelial growth factor receptor-2 expression in flk1-/- embryonic stem cells shows early priming of endothelial precursors. AB - The vascular endothelial growth factor (VEGF) family and its receptors are important for vascular development and maintenance of blood vessels, as well as for angiogenesis, the formation of new vessels. Loss of VEGF receptor-2 (VEGFR-2; designated Flk-1 in mouse) results in arrest of vascular and hematopoietic development in vivo. We used lentiviral transduction to reconstitute VEGFR-2 expression in flk1-/- embryonic stem (ES) cells. VEGF-induced vasculogenesis and sprouting angiogenesis were rescued in transduced ES cultures differentiating in vitro as EBs. Although the transgene was expressed in the pluripotent stem cells and lacked linage restriction during differentiation, the extent of endothelial recruitment was similar to that in wild-type EBs. Reconstitution of VEGFR-2 in flk1-/- ES cells allowed only precommitted precursors to differentiate into functional endothelial cells able to organize into vascular structures. Chimeric EB cultures composed of wild-type ES cells mixed with flk1-/- ES cells or reconstituted VEGFR-2-expressing ES cells were created. In the chimeric cultures, flk1-/- endothelial precursors were excluded from wild-type vessel structures, whereas reconstituted VEGFR-2-expressing precursors became integrated together with wild-type endothelial cells to form chimeric vessels. We conclude that maturation of endothelial precursors, as well as organization into vascular structures, requires expression of VEGFR-2. Disclosure of potential conflicts of interest is found at the end of this article. PMID- 17702982 TI - Spinal GABAergic transplants attenuate mechanical allodynia in a rat model of neuropathic pain. AB - Injury to the spinal cord or peripheral nerves can lead to the development of allodynia due to the loss of inhibitory tone involved in spinal sensory function. The potential of intraspinal transplants of GABAergic cells to restore inhibitory tone and thus decrease pain behaviors in a rat model of neuropathic pain was investigated. Allodynia of the left hind paw was induced in rats by unilateral L5 6 spinal nerve root ligation. Mechanical sensitivity was assessed using von Frey filaments. Postinjury, transgenic fetal green fluorescent protein mouse GABAergic cells or human neural precursor cells (HNPCs) expanded in suspension bioreactors and differentiated into a GABAergic phenotype were transplanted into the spinal cord. Control rats received undifferentiated HNPCs or cell suspension medium only. Animals that received either fetal mouse GABAergic cell or differentiated GABAergic HNPC intraspinal transplants demonstrated a significant increase in paw withdrawal thresholds at 1 week post-transplantation that was sustained for 6 weeks. Transplanted fetal mouse GABAergic cells demonstrated immunoreactivity for glutamic acid decarboxylase and GABA that colocalized with green fluorescent protein. Intraspinally transplanted differentiated GABAergic HNPCs demonstrated immunoreactivity for GABA and beta-III tubulin. In contrast, intraspinal transplantation of undifferentiated HNPCs, which predominantly differentiated into astrocytes, or cell suspension medium did not affect any behavioral recovery. Intraspinally transplanted GABAergic cells can reduce allodynia in a rat model of neuropathic pain. In addition, HNPCs expanded in a standardized fashion in suspension bioreactors and differentiated into a GABAergic phenotype may be an alternative to fetal cells for cell-based therapies to treat chronic pain syndromes. PMID- 17702983 TI - Differential response of adult and embryonic mesenchymal progenitor cells to mechanical compression in hydrogels. AB - Cells in the musculoskeletal system can respond to mechanical stimuli, supporting tissue homeostasis and remodeling. Recent studies have suggested that mechanical stimulation also influences the differentiation of MSCs, whereas the effect on embryonic cells is still largely unknown. In this study, we evaluated the influence of dynamic mechanical compression on chondrogenesis of bone marrow derived MSCs and embryonic stem cell-derived (human embryoid body-derived [hEBd]) cells encapsulated in hydrogels and cultured with or without transforming growth factor beta-1 (TGF-beta1). Cells were cultured in hydrogels for up to 3 weeks and exposed daily to compression for 1, 2, 2.5, and 4 hours in a bioreactor. When MSCs were cultured, mechanical stimulation quantitatively increased gene expression of cartilage-related markers, Sox-9, type II collagen, and aggrecan independently from the presence of TGF-beta1. Extracellular matrix secretion into the hydrogels was also enhanced. When hEBd cells were cultured without TGF-beta1, mechanical compression inhibited their differentiation as determined by significant downregulation of cartilage-specific genes. However, after initiation of chondrogenic differentiation by administration of TGF-beta1, the hEBd cells quantitatively increased expression of cartilage-specific genes when exposed to mechanical compression, similar to the bone marrow-derived MSCs. Therefore, when appropriately directed into the chondrogenic lineage, mechanical stimulation is beneficial for further differentiation of stem cell tissue engineered constructs. PMID- 17702984 TI - Acceleration of sensory neural regeneration and wound healing with human mesenchymal stem cells in immunodeficient rats. AB - The sensory nerve is highly involved in lower extremity wound healing. In diabetic and vascular diseases, impaired nerve function and blood flow delay wound healing. Tissue regeneration using adult stem cells is a targeted therapeutic modality in disorders of nerve and blood supply. Effective delivery using an autologous vascularized fascial flap as a vehicle of stem cells leads to severed sensory nerve recovery, local tissue blood flow, and wound healing. Human MSCs (hMSCs) were transfected with green fluorescent protein (GFP) cDNA and tested for efficiency and proliferation in vitro. The nude rat model with femoral vessel and saphenous nerve severance and ligation was wrapped with a vascularized epigastric flap for GFP-hMSC, fibroblast growth factor-2 (FGF-2), or a combination of both after 2 weeks. Maximum nerve conduction velocity recovered to 70% of the presurgical level in the GFP-hMSC- and FGF-2-treated group at 2 weeks. Blood flow and nerve conduction velocity were positively correlated at 1 week. Wound healing in the ipsilateral paw had significantly improved by 1 week. Histologically, blood vessels and nerves are very organized, and regenerated neuron immunoreactivity of GAP-43 and a nerve regrowth marker of S-100 were remarkable in the human GFP (hGFP)-hMSC and FGF-2-treated group at 2 weeks; therefore, sensory nerve regeneration, blood flow, and wound healing were improved by the administration of stem cells and FGF-2 via a vascularized flap. This may be implicated in clinical denervated and reduced circulation tissue wound healing. PMID- 17702985 TI - Isolation of a bone marrow-derived stem cell line with high proliferation potential and its application for preventing acute fatal liver failure. AB - Transplantation of hepatocytes or hepatocyte-like cells of extrahepatic origin is a promising strategy for treatment of acute and chronic liver failure. We examined possible utility of hepatocyte-like cells induced from bone marrow cells for such a purpose. Clonal cell lines were established from the bone marrow of two different rat strains. One of these cell lines, rBM25/S3 cells, grew rapidly (doubling time, approximately 24 hours) without any appreciable changes in cell properties for at least 300 population doubling levels over a period of 300 days, keeping normal diploid karyotype. The cells expressed CD29, CD44, CD49b, CD90, vimentin, and fibronectin but not CD45, indicating that they are of mesenchymal cell origin. When plated on Matrigel with hepatocyte growth factor and fibroblast growth factor-4, the cells efficiently differentiated into hepatocyte-like cells that expressed albumin, cytochrome P450 (CYP) 1A1, CYP1A2, glucose 6-phosphatase, tryptophane-2,3-dioxygenase, tyrosine aminotransferase, hepatocyte nuclear factor (HNF)1 alpha, and HNF4alpha. Intrasplenic transplantation of the differentiated cells prevented fatal liver failure in 90%-hepatectomized rats. In conclusion, a clonal stem cell line derived from adult rat bone marrow could differentiate into hepatocyte-like cells, and transplantation of the differentiated cells could prevent fatal liver failure in 90%-hepatectomized rats. The present results indicate a promising strategy for treating human fatal liver diseases. PMID- 17702986 TI - Disruption of heparan and chondroitin sulfate signaling enhances mesenchymal stem cell-derived osteogenic differentiation via bone morphogenetic protein signaling pathways. AB - Cell surface heparan sulfate (HS) and chondroitin sulfate (CS) proteoglycans have been implicated in a multitude of biological processes, including embryonic implantation, tissue morphogenesis, wound repair, and neovascularization through their ability to regulate growth factor activity and morphogenic gradients. However, the direct role of the glycosaminoglycan (GAG) sugar-side chains in the control of human mesenchymal stem cell (hMSC) differentiation into the osteoblast lineage is poorly understood. Here, we show that the abundant cell surface GAGs, HS and CS, are secreted in proteoglycan complexes that directly regulate the bone morphogenetic protein (BMP)-mediated differentiation of hMSCs into osteoblasts. Enzymatic depletion of the HS and CS chains by heparinase and chondroitinase treatment decreased HS and CS expression but did not alter the expression of the HS core proteins perlecan and syndecan. When digested separately, depletion of HS and CS chains did not effect hMSC proliferation but rather increased BMP bioactivity through SMAD1/5/8 intracellular signaling at the same time as increasing canonical Wnt signaling through LEF1 activation. Long-term culturing of cells in HS- and CS-degrading enzymes also increased bone nodule formation, calcium accumulation, and the expression of such osteoblast markers as alkaline phosphatase, RUNX2, and osteocalcin. Thus, the enzymatic disruption of HS and CS chains on cell surface proteoglycans alters BMP and Wnt activity so as to enhance the lineage commitment and osteogenic differentiation of hMSCs. PMID- 17702987 TI - Mouse leukocyte-associated Ig-like receptor-1 (mLAIR-1) functions as an inhibitory collagen-binding receptor on immune cells. AB - Leukocyte-associated Ig-like receptor-1 (LAIR-1) is a cell-surface molecule that functions as an inhibitory receptor on various immune cells. We developed mAbs to study the expression of mouse leukocyte-associated Ig-like receptor-1 (mLAIR-1) on primary immune cells and established that it is expressed on the majority of cells of the immune system, including T cells, NK cells, monocytes and dendritic cells. Furthermore, mLAIR-1 is inducibly expressed on blood granulocytes in vivo and is differentially expressed upon T cell activation in vitro. Unexpectedly, mLAIR-1 was not expressed on splenic and blood B220(+) B cells. Similar to its human homolog, mLAIR-1 interacted with high affinity with a wide range of collagen molecules. Furthermore, mLAIR-1 specifically interacted in a hydroxyproline-dependent manner with synthetic collagen Gly-Pro-Hyp peptides. We show, for the first time, that mLAIR-1 cross-linking with its ligands inhibits CD3-induced T cell stimulation in vitro. Given the similarities between the mouse and human receptors, mLAIR-1 may serve as a good model to assess the role of the LAIR-1 receptors in regulation of immune responses. PMID- 17702988 TI - Function of NKT cells, potential anti-HIV effector cells, are improved by beginning HAART during acute HIV-1 infection. AB - NKT cells are a subset of lymphocytes that share features of T cells and NK cells and bridge the innate and adaptive immune responses. They are able to be infected by HIV, but their function in HIV-infected individuals is not known. NKT cell percentage and function was measured in individuals with acute HIV infection before and 1 year into highly active anti-retroviral therapy (HAART). This study demonstrates that percentages of both CD161+ NKT cells and CD161+, CD4+ NKT cells decline within the first few months after HIV-1 infection, but initiating therapy during the acute infection period can prevent a further decline in these NKT cell subsets during the first year. NKT cell function is also impaired during early HIV infection, but significantly improved by effective treatment with HAART. Finally, preservation of NKT cell function may be important in HIV-infected individuals, as NKT cells display an anti-HIV-1 activity in vitro, mediated by IFN-gamma secretion. PMID- 17702989 TI - Ifi202, an IFN-inducible candidate gene for lupus susceptibility in NZB/W F1 mice, is a positive regulator for NF-kappaB activation in dendritic cells. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies and lupus nephritis. The [New Zealand black (NZB) x New Zealand white (NZW)]F1 (BWF1) mouse has been recognized as an important animal model of human SLE. The T(h)1-prone phenotype of BWF1 mice has been shown to contribute to the development of the lupus. However, the molecular basis for T(h)1 skewing in BWF1 mice has not been clarified. We noticed that IL-6, IL-12 and other proinflammatory cytokines as well as IkappaB-zeta induction were higher in mature bone marrow-derived dendritic cells (BMDCs) from NZB and BWF1 mice than those from NZW mice. The expression of an IFN-inducible gene Ifi202, a candidate gene for lupus, was almost undetectable in NZW BMDCs. Thus, we hypothesized that Ifi202 is involved in elevated IL-12 production from BWF1 BMDCs. Overexpression of Ifi202 enhanced the LPS-induced IkappaB-zeta, IL-12p40 and NF-kappaB promoter activities, while anti-sense (AS) RNA against Ifi202 strongly suppressed them in a monocytic cell line, RAW 264.7. Furthermore, overexpression of Ifi202 enhanced LPS-induced IL-12p40 and IkappaB-zeta mRNA induction while Ifi202 AS RNA suppressed these in RAW 264.7 cells. In addition, forced expression of Ifi202 enhanced IL-12p40 mRNA induction in NZW BMDCs. Thus, Ifi202 is an important NF kappaB activator in DCs and involved in IL-12 production, which may account for a T(h)1-prone phenotype of BWF1 mice. PMID- 17702991 TI - Less unique variance than meets the eye: overlap among traditional neuropsychological dimensions in schizophrenia. AB - The magnitude of the overlap among dimensions of neuropsychological test performance in schizophrenia has been the subject of perennial controversy. This issue has taken on renewed importance with the recent focus on cognition as a treatment target in schizophrenia. A substantial body of factor analytic literature indicates that dimensions are separable in schizophrenia. However, this literature is generally uninformative as to whether the separable dimensions are independent, weakly correlated, or strongly correlated. Factor analyses have often used methods (ie, principal components analysis with orthogonal rotation) that preclude this determination, and correlations among factor-based domain composites and underlying measures have been reported infrequently in these studies. Current meta-analyses of reported "between-dimension" correlations for individual neuropsychological measures and for cognitive domain composite variables indicate that cognition variables in schizophrenia are correlated, on average, at a "medium" level of r = 0.37 for individual measures from different cognitive dimensions and r = 0.45 for domain composites. Because these are mean bivariate correlations, the multiple correlation of an individual measure with all the other measures in a cognitive battery is likely to be higher. Measure reliabilities of 0.80 or less also imply greater commonality among traditional neuropsychological measures. In short, there are underappreciated constraints on the amount of reliable cognitive performance variance in traditional neuropsychological test batteries that is free to vary independently. The ability of such batteries to reveal cognitive domain-specific treatment effects in schizophrenia may be much more limited than is generally assumed. PMID- 17702990 TI - The phenomenological critique and self-disturbance: implications for ultra-high risk ("prodrome") research. AB - Recent years have witnessed widespread interest in the early phase of schizophrenia and other psychotic disorders. Strategies have been introduced to attempt to identify individuals in the prepsychotic or prodromal phase. The most widely used of these approaches is the ultra-high risk (UHR) approach, which combines known trait and state risk factors for psychotic disorder. However, researchers guided by phenomenological theory have argued that modern psychiatry's neglect of subjective experience has compromised researchers' understanding of psychotic disorder and has thereby limited efforts at prospective and early identification. Phenomenological research indicates that disturbance of the basic sense of self may be a core marker of psychotic vulnerability, particularly of schizophrenia spectrum disorders. It is argued that identifying self-disturbance in the UHR population may provide a means of further "closing in" on individuals truly at high risk of psychotic disorder, thus supplementing the UHR identification approach. This would be of practical value in the sense of reducing inclusion of "false-positive" cases in UHR samples and of theoretical value in the sense of shedding light on core features of psychotic pathology. The strong explanatory power and empirical findings to date invite further research into the role of self-disturbance as a phenotypic vulnerability marker for psychotic disorder. PMID- 17702993 TI - A novel bioabsorbable conduit augments healing of avascular meniscal tears in a dog model. AB - BACKGROUND: Avascular meniscal tears are a common and costly problem for which current treatment options are limited. HYPOTHESIS: A bioabsorbable conduit will allow for vascular tissue ingrowth that is associated with histologic and biomechanical evidence for avascular meniscal tear healing superior to that associated with meniscal trephining in dogs. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty-five dogs underwent medial arthrotomy with creation of anterior and posterior tears in the medial menisci (N = 50 tears). The dogs were assigned treatments for their menisci: conduit (n = 29 tears) or trephine (n = 21 tears). Dogs were assessed for lameness by subjective scoring after surgery and sacrificed at 6, 12, or 24 weeks and assessed for articular cartilage damage, gross and histologic appearance of the operated menisci, and maximal load-to failure values using tensile testing of meniscal tears. Tears were considered to demonstrate biomechanical integrity when histologic partial to complete healing was noted in conjunction with a measured load to failure that was significantly greater than controls. RESULTS: Based on histologic assessment, the conduit was associated with complete (n = 4) or partial (n = 5) healing in all avascular defects at 12 and 24 weeks after surgery in this study. No healing was seen in defects treated by trephination and repair. No lameness associated with surgery or meniscal treatment was noted after 4 weeks. No articular cartilage damage was noted in any joint. At both 12 and 24 weeks, mean load to failure for normal menisci (43.2 N and 28.6 N, respectively) was significantly (P < .017) higher than conduit-treated (22.3 N and 16.0 N, respectively) and trephine-treated (0.6 N and 2.1 N, respectively) menisci, and load to failure for conduit-treated menisci was significantly (P or= 90%. CONCLUSIONS: Good functional performance and knee muscle strength can be achieved and maintained over time in the majority of patients with ACL injury treated with rehabilitation and early activity modification but without reconstructive surgery. PMID- 17703003 TI - Clinical outcomes of the DANE TJ technique to treat ulnar collateral ligament insufficiency of the elbow. AB - BACKGROUND: Many improvements in ulnar collateral ligament reconstruction have been made since Jobe et al first described the procedure. A novel elbow ulnar collateral ligament reconstruction technique that combines interference screw fixation on the ulna with docking of the graft on the humeral side (DANE TJ) has been reported. HYPOTHESIS: Outcomes of ulnar collateral ligament reconstructions performed with the DANE TJ technique are as good as other recently published results of ulnar collateral ligament reconstruction, particularly in cases of insufficient bone stock on the sublime tubercle and revision reconstructions. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: During a 3-year period, 22 athletes were treated with surgical reconstruction of the ulnar collateral ligament using proximal docking and distal interference screw fixation of the ligament (DANE TJ technique). All patients had a history, physical examination findings, and magnetic resonance imaging results consistent with ulnar collateral ligament injury. Patients were evaluated at a mean of 36 months postoperatively. Outcomes were classified using a modified Conway Scale. RESULTS: At the most recent follow-up, 19 of 22 patients had excellent results. There were 2 fair results and 1 poor result. The poor result was in a revision case. The 2 other revision ulnar collateral ligament reconstructions had excellent outcomes. When used in 2 cases of sublime tubercle avulsions, the results were excellent. Postoperative complications occurred in 4 patients: 2 developed ulnar neuritis, and 2 required second surgeries for lysis of adhesions. Three of these 4 patients went on to have excellent outcomes. CONCLUSION: Clinically, the initial results compare favorably with other published techniques of elbow ulnar collateral ligament reconstruction. These early data support the use of the DANE TJ technique for revision cases and cases of sublime tubercle insufficiency. PMID- 17703004 TI - Assertive community treatment in psychiatry. PMID- 17703005 TI - Umbilical cord clamping after birth. PMID- 17703006 TI - Obstructive sleep apnoea. PMID- 17703007 TI - Effects of air pollution on health. PMID- 17703008 TI - Developing nurse prescribing in the UK. PMID- 17703009 TI - Rise of the doctor-manager: Management skills need to be systematically learnt. PMID- 17703010 TI - Payment for treatment adherence: Drug misusers are likely to abuse the system. PMID- 17703011 TI - Payment for treatment adherence: Incentives help vulnerable patients to stay well. PMID- 17703012 TI - The profession's future: Is the BMJ fit for purpose? PMID- 17703013 TI - Uvula angio-oedema: ENT form of Saturday night palsy. PMID- 17703014 TI - Medicines funding: Value for money is nothing new. PMID- 17703015 TI - ABCD of dignifying care: We need imaginative approaches to training. PMID- 17703016 TI - NICE delays decision on drugs for macular degeneration. PMID- 17703017 TI - High Court upholds NICE decision to limit treatments for Alzheimer's disease. PMID- 17703018 TI - GMC to look into higher number of complaints against overseas trained doctors. PMID- 17703019 TI - Audit Scotland calls for more evidence of effective care for long term illness. PMID- 17703020 TI - UK heart surgeons improve patients' survival. PMID- 17703021 TI - Extreme weather affects half a billion people each year. PMID- 17703022 TI - South African health minister sacked after attending AIDS conference. PMID- 17703023 TI - Skin cancer is on the increase but incidence of lung cancer is falling. PMID- 17703024 TI - FDA needs more funding, NEJM says, amid questions about antidiabetes drug. PMID- 17703038 TI - An unenviable role. PMID- 17703039 TI - Internal affairs. PMID- 17703040 TI - Is depression overdiagnosed? Yes. PMID- 17703041 TI - Is depression overdiagnosed? No. PMID- 17703042 TI - Potential of electronic personal health records. PMID- 17703043 TI - Medical education research remains the poor relation. PMID- 17703045 TI - Investigation of suspected breast cancer. PMID- 17703044 TI - Carpal tunnel syndrome. PMID- 17703050 TI - Conservation of essential design features in coiled coil silks. AB - Silks are strong protein fibers produced by a broad array of spiders and insects. The vast majority of known silks are large, repetitive proteins assembled into extended beta-sheet structures. Honeybees, however, have found a radically different evolutionary solution to the need for a building material. The 4 fibrous proteins of honeybee silk are small ( approximately 30 kDa each) and nonrepetitive and adopt a coiled coil structure. We examined silks from the 3 superfamilies of the Aculeata (Hymenoptera: Apocrita) by infrared spectroscopy and found coiled coil structure in bees (Apoidea) and in ants (Vespoidea) but not in parasitic wasps of the Chrysidoidea. We subsequently identified and sequenced the silk genes of bumblebees, bulldog ants, and weaver ants and compared these with honeybee silk genes. Each species produced orthologues of the 4 small fibroin proteins identified in honeybee silk. Each fibroin contained a continuous predicted coiled coil region of around 210 residues, flanked by 23-160 residue length N- and C-termini. The cores of the coiled coils were unusually rich in alanine. There was extensive sequence divergence among the bee and ant silk genes (<50% similarity between the alignable regions of bee and ant sequences), consistent with constant and equivalent divergence since the bee/ant split (estimated to be 155 Myr). Despite a high background level of sequence diversity, we have identified conserved design elements that we propose are essential to the assembly and function of coiled coil silks. PMID- 17703051 TI - Combining models of protein translation and population genetics to predict protein production rates from codon usage patterns. AB - Genes are often biased in their codon usage. The degree of bias displayed often changes with expression level and intragenic position. Numerous indices, such as the codon adaptation index, have been developed to measure this bias. Although the expression level of a gene and index values are correlated, the heuristic nature of these metrics limits their ability to explain this relationship. As an alternative approach, this study integrates mechanistic models of cellular and population processes in a nested manner to develop a stochastic evolutionary model of a protein's production rate (SEMPPR). SEMPPR assumes that the evolution of codon bias is driven by selection to reduce the cost of nonsense errors and that this selection is counteracted by mutation and drift. Through the application of Bayes' theorem, SEMPPR generates a posterior probability distribution for the protein production rate of a given gene. Conceptually, SEMPPR's predictions are based on the degree of adaptation to reduce the cost of nonsense errors observed in the codon usage pattern of the gene. As an illustration, SEMPPR was parameterized using the Saccharomyces cerevisiae genome and its predictions tested using available empirical data. The results indicate that SEMPPR's predictions are as reliable index based ones. In addition, SEMPPR's output is more easily interpreted and its predictions could be improved through refinements of the models upon which it is built. PMID- 17703052 TI - A comparative and phylogenetic analysis of the alpha-actinin rod domain. AB - Alpha-actinin is a ubiquitous actin-binding protein, composed of 3 domains; an actin-binding domain and a calcium-binding domain at the termini, connected by a rod domain composed by 1, 2, or 4 spectrin repeats (SRs). To understand how the rod domain has evolved during evolution, we have analyzed and compared the amino acid residue heterogeneity and phylogeny of the SRs of alpha-actinins of vertebrates, invertebrates, fungi, and several protozoa. The repeats of vertebrate alpha-actinins show a high degree of similarity, whereas repeats of invertebrates, fungi, and, in particular, of protozoa are more divergent. In the phylogeny, SR1 of all species were clustered together, independent of the number of repeats in the protein. It was also obvious that the second and last repeat in fungi (SR2) grouped with the fourth and last repeat of vertebrates and invertebrates (SR4). Therefore, the phylogeny implied that the rod domain of the cenancestral alpha-actinin only contained one SR. It was also obvious that SR2 of fungi are related to SR4 of vertebrates and invertebrates, implying that in the second intragenic duplication 2 repeats (i.e., what become SR2 and SR3) were inserted between the initial 2 repeats that become SR1 and SR4. PMID- 17703053 TI - Deleterious mutations can surf to high densities on the wave front of an expanding population. AB - There is an increasing recognition that evolutionary processes play a key role in determining the dynamics of range expansion. Recent work demonstrates that neutral mutations arising near the edge of a range expansion sometimes surf on the expanding front leading them rather than that leads to reach much greater spatial distribution and frequency than expected in stationary populations. Here, we extend this work and examine the surfing behavior of nonneutral mutations. Using an individual-based coupled-map lattice model, we confirm that, regardless of its fitness effects, the probability of survival of a new mutation depends strongly upon where it arises in relation to the expanding wave front. We demonstrate that the surfing effect can lead to deleterious mutations reaching high densities at an expanding front, even when they have substantial negative effects on fitness. Additionally, we highlight that this surfing phenomenon can occur for mutations that impact reproductive rate (i.e., number of offspring produced) as well as mutations that modify juvenile competitive ability. We suggest that these effects are likely to have important consequences for rates of spread and the evolution of spatially expanding populations. PMID- 17703054 TI - Insights into the evolution of themotilin/ghrelin-associated family and their receptors. PMID- 17703055 TI - Statistics of the log-det estimator. AB - The log-det estimator is a measure of divergence (evolutionary distance) between sequences of biological characters, DNA or amino acids, for example, and has been shown to be robust to biases in composition that can cause problems for other estimators. We provide a statistical framework to construct high-accuracy confidence intervals for log-det estimates and compare the efficiency of the estimator to that of maximum likelihood using time-reversible Markov models. The log-det estimator is found to have good statistical properties under such general models. PMID- 17703056 TI - Mapping the human proteome using antibodies. PMID- 17703057 TI - Artificial rearing with docosahexaenoic acid and n-6 docosapentaenoic acid alters rat tissue fatty acid composition. AB - Docosahexaenoic acid (DHA; 22:6n-3) and n-6 docosapentaenoic acid (DPAn-6; 22:5n 6) are components of enriched animal feed and oil derived from Schizochytrium species microalgae. A one generation, artificial rearing model from day 2 after birth onward (AR) and a dam-reared control group (DAM) were used to examine DPAn 6 feeding on the fatty acid composition of various rat tissues at 15 weeks of age. Four AR diets were based on an n-3 fatty acid-deficient, 18:2n-6-based artificial milk with 22:6n-3 and/or 22:5n-6 added: AR-LA, AR-DHA, AR-DPAn-6, and AR-DHA+DPAn-6. The 22:6n-3 levels for the DAM, AR-DHA, and AR-DHA+DPAn-6 groups tended to be similar and higher than in the AR-LA and AR-DPAn-6 groups. The levels of 22:5n-6 tended to be higher only in the absence of dietary 22:6n-3. Adipose levels of 22:5n-6 was the only exception, as 22:5n-6 was significantly higher in AR-DHA+DPAn-6 than was observed in either the DAM or the AR-DHA group. There were no differences in 20:4n-6 levels within the tissues examined. In conclusion, 22:5n-6 replaces 22:6n-3 in the absence of 22:6n-3 only and does not appear to compete with 22:6n-3 in the presence of dietary 22:6n-3, suggesting that oils containing 22:5n-6 and 22:6n-3 may be a good dietary source of 22:6n-3. PMID- 17703058 TI - A rapid, small-scale procedure for the structural characterization of lipid A applied to Citrobacter and Bordetella strains: discovery of a new structural element. AB - Endotoxins [lipopolysaccharides (LPSs)] are part of the outer cell membrane of Gram-negative bacteria. Their biological activities are associated mainly with the lipid component (lipid A) and even more specifically with discrete aspects of their fine structure. The need for a rapid and small-scale analysis of lipid A motivated us to develop a procedure that combines direct isolation of lipids A from bacterial cells with sequential release of their ester-linked fatty acids by a mild alkali treatment followed by MALDI-MS analysis. This method avoids the multiple-step LPS extraction procedure and lipid A isolation. The whole process can be performed in a working day and applied to lyophilized bacterial samples as small as 1 mg. We illustrate the method by applying it to the analysis of lipids A of three species of Citrobacter that were found to be identical. On the other hand, when applied to two batches of Bordetella bronchiseptica strain 4650, it highlighted the presence, in one of them, of hitherto unreported hexosamine residues substituting the lipid A phosphate groups, possibly a new camouflage opportunity to escape a host defense system. PMID- 17703059 TI - Defining adapted physical activity: international perspectives. AB - The purpose of this study was to describe international perspectives concerning terms, definitions, and meanings of adapted physical activity (APA) as (a) activities or service delivery, (b) a profession, and (c) an academic field of study. Gergen's social constructionism, our theory, guided analysis of multiple sources of data via qualitative methodology. Data sources were online surveys, APA literature, and expertise of researchers. Findings, with the identification of further considerations, were provided for each APA component to stimulate reflection and further inquiry among international professionals with diverse backgrounds. PMID- 17703060 TI - Reporting gender, race, ethnicity, and sociometric status: guidelines for research and professional practice. AB - The purpose of this study was to determine what trends exist in the identification and description of participants used in data-based studies published in Adapted Physical Activity Quarterly and the Journal of Teaching in Physical Education. Data were analyzed using frequency counts for journals and time periods from the 1980s to 2005 with chi-square tests on gender, race, ethnicity, and socioeconomic status. Results indicate, for example, that across the time span both journals published articles reporting males first over females, X2 (3) = 22.16, p < .001. Trend data also reveal that even today most data-based studies in these journals fail to report race, ethnicity, and socioeconomic status. Findings are discussed with guiding principles for future research. PMID- 17703061 TI - Physical education for students with spina bifida: mothers' perspectives. AB - This study described the meaning 7 mothers of children with spina bifida ascribed to their children's physical education, the mothers' roles in the schools, and the importance of the IEP in home and school communication. The stories of 4 mothers of elementary and 3 mothers of secondary aged children were gathered using the phenomenological methods of semistructured interviews, artifacts, and field notes. The thematic analysis revealed three themes: a good thing but . . . , connection to sports, and beyond the curriculum. The mothers valued their children's participation in physical education and provided instrumental support to teachers and teaching associates. They also valued sport as an avenue for developing sport specific skills, which in turn enriched the school experience. The findings are discussed within the context of Peters' (1996) model of disablement. PMID- 17703062 TI - Convergent validity between two motor tests: movement-ABC and PDMS-2. AB - The aim of this study was to investigate the convergent validity of the Movement Assessment Battery for Children (M-ABC) and the Peabody Developmental Motor Scales - 2 (PDMS-2). Thirty-one 4- and 5-year-old children (mean age 4 years 11 months, SD 6 months), all recruited from a clinical setting, took part in the study. Children were tested on the M-ABC and the PDMS-2 in a counterbalanced order on the same occasion. The results showed that the total scores on the two tests correlated well (rs = .76). However, when the ability of the two tests to identify children with difficulties was examined, agreement between them was low (K = .29), with the PDMS-2 being less sensitive to mild motor impairment in this population. Taken together, these findings suggest that clinicians need to be aware that, although measuring a similar construct, these tests are not interchangeable. PMID- 17703063 TI - Responsibilities and training needs of paraeducators in physical education. AB - This study describes responsibilities and training needs of paraeducators in physical education. Paraeducators (n =138) employed in 34 midwestern schools received a 27-item questionnaire. Of the 138 paraeducators contacted, 76 responded, resulting in a 55.1% response rate. Only 16% of the total respondents (n = 76) reported receiving specific training in physical education; however, 68 (90%) indicated a willingness to be trained. Less than half (n = 29, 38%) indicated participating in physical education by escorting students, providing cues, and working individually with students. Fewer than eight (28%) of the physical education paraeducators assisted with assessments, shared IEP suggestions, or helped implement behavior modification programs. The most desired training areas included activity modifications, attributes of students with disabilities, and knowledge of motor development. PMID- 17703064 TI - Exploring dynamics in living cells by tracking single particles. AB - In the last years, significant advances in microscopy techniques and the introduction of a novel technology to label living cells with genetically encoded fluorescent proteins revolutionized the field of Cell Biology. Our understanding on cell dynamics built from snapshots on fixed specimens has evolved thanks to our actual capability to monitor in real time the evolution of processes in living cells. Among these new tools, single particle tracking techniques were developed to observe and follow individual particles. Hence, we are starting to unravel the mechanisms driving the motion of a wide variety of cellular components ranging from organelles to protein molecules by following their way through the cell. In this review, we introduce the single particle tracking technology to new users. We briefly describe the instrumentation and explain some of the algorithms commonly used to locate and track particles. Also, we present some common tools used to analyze trajectories and illustrate with some examples the applications of single particle tracking to study dynamics in living cells. PMID- 17703065 TI - Computational models of molecular self-organization in cellular environments. AB - The cellular environment creates numerous obstacles to efficient chemistry, as molecular components must navigate through a complex, densely crowded, heterogeneous, and constantly changing landscape in order to function at the appropriate times and places. Such obstacles are especially challenging to self organizing or self-assembling molecular systems, which often need to build large structures in confined environments and typically have high-order kinetics that should make them exquisitely sensitive to concentration gradients, stochastic noise, and other non-ideal reaction conditions. Yet cells nonetheless manage to maintain a finely tuned network of countless molecular assemblies constantly forming and dissolving with a robustness and efficiency generally beyond what human engineers currently can achieve under even carefully controlled conditions. Significant advances in high-throughput biochemistry and genetics have made it possible to identify many of the components and interactions of this network, but its scale and complexity will likely make it impossible to understand at a global, systems level without predictive computational models. It is thus necessary to develop a clear understanding of how the reality of cellular biochemistry differs from the ideal models classically assumed by simulation approaches and how simulation methods can be adapted to accurately reflect biochemistry in the cell, particularly for the self-organizing systems that are most sensitive to these factors. In this review, we present approaches that have been undertaken from the modeling perspective to address various ways in which self-organization in the cell differs from idealized models. PMID- 17703066 TI - Femtochemistry in enzyme catalysis: DNA photolyase. AB - Photolyase uses light energy to split UV-induced cyclobutane pyrimidine dimers in damaged DNA. This photoenzyme encompasses a series of elementary dynamical processes during repair function from early photoinitiation by a photoantenna molecule to enhance repair efficiency, to in vitro photoreduction through aromatic residues to reconvert the cofactor to the active form, and to final photorepair to fix damaged DNA. The corresponding series of dynamics include resonance energy transfer, intraprotein electron transfer, and intermolecular electron transfer, bond breaking-making rearrangements and back electron return, respectively. We review here our recent direct studies of these dynamical processes in real time, which showed that all these elementary reactions in the enzyme occur within subnanosecond timescale. Active-site solvation was observed to play a critical role in the continuous modulation of catalytic reactions. As a model system for enzyme catalysis, we isolated the enzyme-substrate complex in the transition-state region and mapped out the entire evolution of unmasked catalytic reactions of DNA repair. These observed synergistic motions in the active site reveal a perfect correlation of structural integrity and dynamical locality to ensure maximum repair efficiency on the ultrafast time scale. PMID- 17703067 TI - Describing the structure and assembly of protein filaments by EPR spectroscopy of spin-labeled side chains. AB - In this review we summarize our approach to the study of Intermediate Filament (IF) structure and assembly by electron paramagnetic resonance (EPR) spectroscopy of site-directed spin labels. Using vimentin, a homopolymeric type III IF protein, we demonstrate that this approach serves as a general paradigm for studying protein filament structure and assembly. These strategies will be useful in exploring the structure and assembly properties of other filamentous or aggregation-prone systems. PMID- 17703069 TI - Durward William John Cruickshank (1924-2007). PMID- 17703070 TI - Diffuse scattering from large-angle, thermally induced, orientational disorder in molecular crystals. AB - Large-angle rotational motion (libration) characteristic of molecular solids has not been properly included in many scattering calculations because of the need to develop scattering theory through small-angle approximations. A simple but effective approach to calculating the influence of large-angle librations on the thermal disorder scattering given by molecular solids is to treat the molecules as independent librators, each in a harmonic potential well, using the mathematics appropriate for large-angle rotations. The resulting probability distribution for angular misorientations is Gaussian and this distribution can be used to smear the molecular form factor, enabling the librational influence on the scattering to be calculated. It is shown how to apply this direct approach quite generally and by way of examples the technique is used with the molecular solids sulfur hexafluoride (SF(6)), adamantane (C(10)H(16)) and buckminsterfullerene (C(60)). For these materials, the molecular Fourier transform (i.e. the molecular form factor) have been calculated in selected planes in reciprocal space, followed by the separate effects of librational and translational smearing. It is found that the librational smearing produces a large effect on the form factor, particularly at larger scattering vectors, that is not sensitive to approximations in the argument. Additionally, the Debye Waller effect of vibrational motion is included in the calculations, showing quantitatively the decreasing influence of vibrations on the scattering with increasing scattering vector. Both effects illustrate with pedagogic clarity how different processes modify the basic molecular scattering. PMID- 17703071 TI - Structural phase and amplitude measurement from distances in convergent-beam electron diffraction patterns. AB - The structure of a periodic object, such as a crystal, may be described by an infinite series of Fourier coefficients and phases. In associating this with scattering theory appropriate to any radiation, a classic problem arises, namely, the determination of phases from the resulting discrete diffraction pattern. The solution to this phase problem is presented in this paper in which the first direct measurement of structural phase by inspection of convergent-beam electron diffraction patterns is described. PMID- 17703072 TI - Random tilings of compact Euclidean 3-manifolds. AB - Deterministic and random tilings for the ten compact Euclidean 3-manifolds are introduced. The main tools are substitution rules generating non-periodic planar patterns and a set of pre-axioms defined for each manifold. The sets of random tilings are obtained by suitable tile flips in the substitution atlas which allows us to compute their configurational entropies. The inflation rules in two dimensions together with one-dimensional substitutions in a perpendicular direction induce non-periodic three-dimensional tilings by triangular prisms which can be transformed into simplicial structures. PMID- 17703073 TI - A charge-flipping algorithm incorporating the tangent formula for solving difficult structures. AB - The 'charge-flipping' method proposed by Oszlanyi & Suto [Acta Cryst. (2004), A60, 134-141] has been extended to include the direct-methods tangent formula within the iterative process. The tangent formula acts as a corrective influence allowing for solutions at resolutions poorer than 1 A. The resulting algorithm solves difficult structures in minutes rather than days or not at all. Modifications include (i) flipping a percentage of charge rather than charge below a threshold value and critically (ii) dampening the magnitude of charge above the threshold; this impedes tangent-formula solutions comprising one or two very intense peaks in the electron density which is commonly known as the 'uranium atom solution'. For data at poor resolution, an alternate charge flipping regime avoids uranium atom solutions by truncating electron-density pixels that are greater than half the maximum value. PMID- 17703068 TI - Molecular basis for HEF1/NEDD9/Cas-L action as a multifunctional co-ordinator of invasion, apoptosis and cell cycle. AB - Upregulation of the scaffolding protein HEF1, also known as NEDD9 and Cas-L, has recently been identified as a pro-metastatic stimulus in a number of different solid tumors, and has also been strongly associated with pathogenesis of BCR-Abl dependent tumors. As the evidence mounts for HEF1/NEDD9/Cas-L as a key player in metastatic cancer, it is timely to review the molecular regulation of HEF1/NEDD9/Cas-L. Most of the mortality associated with cancer arises from uncontrolled metastases, thus a better understanding of the properties of proteins specifically associated with promotion of this process may yield insights that improve cancer diagnosis and treatment. In this review, we summarize the extensive literature regarding HEF1/NEDD9/Cas-L expression and function in signaling relevant to cell attachment, migration, invasion, cell cycle, apoptosis, and oncogenic signal transduction. The complex function of HEF1/NEDD9/Cas-L revealed by this analysis leads us to propose a model in which alleviation of cell cycle checkpoints and acquired resistance to apoptosis is permissive for a HEF1/NEDD9/Cas-L-promoted pro-metastatic phenotype. PMID- 17703074 TI - Scanning of magnetic space groups and the analysis of non-magnetic domain walls. AB - Similarly to atomic positions in a crystal being fixed, or at least constrained by the space group of that crystal, the displacements of atoms in a domain wall are determined or constrained by the symmetry of the wall given by the sectional layer group of the corresponding domain pair. The sectional layer group can be interpreted as comprised of operations that leave invariant a plane transecting two overlapping structures, the domain states of the two domains adhering to the domain wall. The procedure of determining the sectional layer groups for all orientations and positions of a transecting plane is called scanning of the space group. Scanning of non-magnetic space groups has been described and tabulated. It is shown here that the scanning of magnetic groups can be determined from that of non-magnetic groups. The information provided by scanning of magnetic space groups can be utilized in the symmetry analysis of domain walls in non-magnetic crystals since, for any dichromatic space group, which expresses the symmetry of overlapped structures of two non-magnetic domains, there exists an isomorphic magnetic space group. Consequently, a sectional layer group of a magnetic space group expresses the symmetry of a non-magnetic domain wall. Examples of this are given in the symmetry analysis of ferroelectric domain walls in non-magnetic perovskites. PMID- 17703075 TI - The introduction of structure types into the Inorganic Crystal Structure Database ICSD. AB - Both the approach used and the progress made in the assignment of structure types to the crystal structures contained in the ICSD database are reported. Extending earlier work, an hierarchical set of criteria for the separation of isopointal structures into isoconfigurational structure types is used. It is shown how these criteria, which include the space group (number), Wyckoff sequence and Pearson symbol, c/a ratio, beta ranges, ANX formulae and, in certain cases, the necessary elements and forbidden elements, may be used to uniquely identify the representative structure types of the compounds contained in the ICSD database. PMID- 17703076 TI - Three-periodic nets and tilings: natural tilings for nets. AB - Rules for determining a unique natural tiling that carries a given three-periodic net as its 1-skeleton are presented and justified. A computer implementation of the rules and their application to tilings for zeolite nets and for the nets of the RCSR database are described. PMID- 17703077 TI - Can the interaction density be measured? The example of the non-standard amino acid sarcosine. AB - The experimental charge density rho(r) of the non-standard amino acid sarcosine has been determined based on an extensive and complete data set measured at 100 K to high resolution (sin theta/lambda = 1.18 A(-1)) by single-crystal X-ray diffraction. Anisotropic thermal motion of the H atoms, obtained from TLS + ONIOM cluster methods, was included in the structural model. Based on the multipole model geometry, the theoretical Hartree-Fock interaction density of a molecule in the crystal has been calculated with CRYSTAL98. It manifests itself in local rearrangements of rho(r) and can be reproduced with a multipole projection via simulated structure factors. An attempt has also been made to obtain the interaction density from a combination of experimental and theoretical charge densities using either a whole-molecular calculation or the invariom database. Agreement with the periodic Hartree-Fock interaction density is qualitative. It is shown that invarioms reproduce the features of the theoretical multipole projected whole-molecular electron density, and can be used to approximate it. PMID- 17703078 TI - Idler energy dependence of nonlinear diffraction in X --> X + EUV parametric down conversion. AB - The idler energy dependence was investigated for the rocking curve of nonlinear diffraction in parametric down-conversion of X-rays into extreme ultraviolet. The line shape of the rocking curve changed drastically from a nearly Lorentzian peak to a dip as the idler energy decreased. The rocking curve was analyzed using the Fano formula. PMID- 17703080 TI - Distribution of intraductal lesions in small invasive ductal carcinoma of the pancreas. AB - AIMS: To investigate the distribution of intraductal lesions in small invasive ductal carcinoma (IDC) of the pancreas. METHODS: In 21 cases with IDCs microscopically < or = 20 mm in diameter, the intraductal lesions around a mass were studied histologically and mapped according to the pancreatic intraepithelial neoplasia (PanIN) classification. RESULTS: PanIN-3, PanIN-2, PanIN-1B and PanIN-1A were found in 17, 10, 20 and 21 of 21 cases, respectively, and were divided into lesions in adjacent and distal areas, respectively defined as within and beyond 10 mm from the mass as follows: 100% (17/17), 100% (10/10), 95.0% (19/20) and 90.5% (19/21) in the former, while 23.5% (4/17), 50.0% (5/10), 90.0% (18/20) and 95.2% (20/21) in the latter. PanIN-3 lesions were predominantly found in the area adjacent to the mass. In some cases, significant PanIN-3 appeared to show a consecutive geographic extension around the mass via the main pancreatic duct (MPD). The distance of PanIN-3 spread was within 25 (mean 10.5) mm from the mass edge. PanIN-2 lesions were found in the area adjacent to the mass and discontinuous with the mass or PanIN-3 lesions. PanIN-1B and PanIN-1A tended mainly to exist sporadically throughout the entire pancreas. In the MPD, PanIN-3 was found in 14 (82.4%) of 17 cases and in 36 (32.1%) of 112 lesions, which was most frequent in intraductal lesions. CONCLUSIONS: PanIN-3 lesions might be an intraductal extension of the main tumor. The resection margin of 25 mm, at least longer than 11 mm, from the mass edge will be necessary. PMID- 17703081 TI - Magnetic resonance cholangiopancreatography in the preoperative assessment of patients with biliary pancreatitis. AB - BACKGROUND: The ultimate treatment of acute biliary pancreatitis (ABP) is undoubtedly laparoscopic cholecystectomy, but controversy remains about the optimal imaging method in the preoperative assessment of these patients. In this study, we evaluated the usefulness of magnetic resonance cholangiopancreatography (MRCP) in detecting common bile duct (CBD) stones and associated pathologies in patients with ABP. At the same time, we tried to determine the natural transit time of gallstones from gallbladder to duodenum in ABP. METHODS: Between February 1999 and October 2006 a prospective observational study was conducted and 104 consecutive patients with ABP were recruited. MRCP findings were correlated with subsequent endoscopic retrograde cholangiopancreatography, endoscopic ultrasonography, intraoperative cholangiography or clinical follow-up. RESULTS: MRCP correctly predicted the presence of CBD stones in 19 out of 104 patients, and there were two false-positive and four false-negative results. The ability of MRCP to detect CBD stones was: positive predictive value 90.5%, negative predictive value 95.2%, sensitivity 82.6%, specificity 97.5% and overall accuracy 94.2%. MRCP performed within 48 h after admission showed CBD stones in 28.6% of the patients decreasing to 8.0% after 1 week. MRCP disclosed cholecystitis in 25 patients, anatomical variants of the cystic duct in 10 patients and a wide variety of other abnormalities of the upper abdominal cavity. CONCLUSION: MRCP is highly accurate in the preoperative detection of CBD stones and other biliopancreatic pathologies in patients with gallstone pancreatitis. PMID- 17703082 TI - Identification of methylation-associated gene expression in neuroendocrine pancreatic tumor cells. AB - BACKGROUND: CpG islands methylation is the main epigenetic modification found in human tumors leading to transcriptional silencing of certain tumor suppressor genes. Reacquisition of p16/CDKN2A tumor suppressor gene expression by 5-aza-2' deoxycytidine results in concurrent growth inhibition of neuroendocrine pancreatic tumor cells. However, the growth suppressive effects of 5-aza-2' deoxycytidine is unlikely to be solely attributable to the restored p16/CDKN2A function, but rather a consequence of re-expression of additional genes silenced by de novo methylation. In an effort to validate DNA methylation as an important mechanism in neuroendocrine tumorigenesis and metastatic spread, we attempted to isolate methylation-specific transcripts in neuroendocrine pancreatic tumor cells. METHODS: Differentially expressed methylation-associated genes were identified by cDNA-representational difference analysis (cDNA-RDA). Differential expression was confirmed by semiquantitative RT-PCR using insert specific primers. RESULTS: We identified 48 differently expressed gene fragments and methylation-associated expression was confirmed by semi-quantitative RT-PCR. 52,3% (25 of 48) showed elevated expression levels after 5-aza-2'-deoxycytidine treatment, whereas 47.7% revealed lower expression levels. 7 fragments showed homology to genes with unknown function. Interestingly, 5-aza-2'-deoxycytidine treatment led to re-expression of cofillin whereas matriptase expression levels were significantly lower. Both genes have been associated with metastatic spread and tissue invasion. The other differentially expressed genes play an unknown role in the course of neuroendocrine tumorigenesis. CONCLUSION: DNA methylation appears to be an important molecular mechanism in the process of neuroendocrine pancreatic tumorigenesis and metastatic spread. The definition of DNA methylation patterns associated with neuroendocrine pancreatic tumors might open up the potential for a new sensitive diagnostic tool and might serve as a new antitumor target. PMID- 17703083 TI - Endovascular treatment of arterial bleeding in patients with pancreatitis. AB - PURPOSE: To assess the technical and clinical success of endovascular treatment of arterial bleeding in pancreatitis. MATERIALS AND METHODS: From 1992 to 2005, 28 patients with pancreatitis underwent endovascular treatment of associated arterial lesions. Fifteen patients were affected by acute pancreatitis and 13 by chronic pancreatitis. The diagnosis was obtained according to medical history and clinical and laboratory evidence of disease. Arterial involvement was diagnosed by non-invasive imaging and angiography. After treatment, all patients underwent CT scanning at a minimum of 15, 30 and 90 days. We evaluated the feasibility of embolization and patients' survival at 90 days. RESULTS: Transcatheter embolization was feasible in 26/28 patients (93%). In 2 patients with acute pancreatitis, selective catheterization failed so we could not proceed with the angiographic approach. After treatment, there were 3/26 rebleeds (11.5%), all of whom died within the first week. At 90 days' follow-up, 21/26 patients (81%) were alive. Two of 26 patients (8%) suffered splenic complications. Among the 13 patients with acute pancreatitis, 8 (61.5%) were alive after 90 days. All 13 patients with chronic pancreatitis were alive after 90 days. CONCLUSIONS: Comparing our results with the surgical literature, we found that embolization is less invasive and, at least, as successful as surgery. Thus, it should be considered the first choice in pancreatitis arterial complications. PMID- 17703084 TI - Pancreatic acinar cell carcinoma with excessive alpha-fetoprotein expression. AB - We report a case of acinar cell carcinoma of the pancreas associated with excessively elevated levels of serum alpha-fetoprotein (>32,000 ng/ml). Abdominal computed tomography scan revealed a large pancreatic mass with infiltration of the splenic artery. Because of inoperability, palliative combination chemotherapy with gemcitabine and mitomycin C was administered. This regimen was associated with clinical improvement and dramatic decreases in both tumor size and serum alpha-fetoprotein. However, the patient died 7 months later from acute severe cardiac failure. PMID- 17703085 TI - Deregulation of cell cycle machinery in pancreatic cancer. AB - Disrupted cell cycle machinery is commonly thought to result in loss of proliferative control. Standard therapies target these rapidly dividing cells, yet they are ineffective against pancreatic cancer, suggesting that its development and/or progression might deviate from standard paradigms. Supposedly essential cell cycle components are actually dispensable in mice, and accumulating evidence indicates that they play more diverse roles during apoptosis, signal transduction, and cell migration. A better understanding of how pancreatic cancer cells proliferate and the contribution of disrupted cell cycle machinery would provide much needed opportunities for developing new diagnostic and therapeutic options to improve patient outcome. PMID- 17703087 TI - Pancreatic stellate cells potentiate proinvasive effects of SERPINE2 expression in pancreatic cancer xenograft tumors. AB - We have previously reported that inducible overexpression of the serine protease inhibitor nexin 2 (SERPINE2) significantly increases local invasiveness of subclones of the pancreatic cancer cell-line SUIT-2 in nude mouse xenografts. This was associated with a striking increase of extracellular matrix deposition in the invasive tumors. Pancreatic stellate cells (PSCs) have recently been identified as the major source of fibrosis in pancreatic adenocarcinomas. Here we report that co-injection of PSCs and tumor cells dramatically enhances the invasive potential of serine protease inhibitor Nexin 2 (SERPINE2)-expressing SUIT-2 cells. 100% (24 of 24) of the SERPINE2-expressing tumors with PSCs grew aggressively invasive, as compared to 39% of SERPINE2-negative tumors with PSCs and 27% of SERPINE2-expressing tumors without PSCs. In contrast to pure cancer cell preparations, SERPINE2 overexpression in the presence of PSCs also resulted in increased tumor growth. Histological evaluation demonstrated the presence of large amounts of ECM deposits co-localizing with cells staining positive for the PSC marker alpha-SMA. We conclude that PSCs actively proliferate in pancreatic cancer xenograft tumors and significantly contribute to the local invasive potential of the tumors. Presence of PSCs enhances the pro-invasive effects of SERPINE2 expression, and SERPINE2 influences tumor growth (as opposed to invasiveness) only in the presence of PSCs. Our data thus suggest that SERPINE2 is an important modulator of tumor cell/host interactions in pancreatic cancer. PMID- 17703088 TI - Expression patterns of Ets2 protein correlate with bone-specific proteins in cell seeded three-dimensional bone constructs. AB - The transcription factor Ets2 and its transcriptional targets osteopontin (OPN) and osteocalcin (OC) are expressed in tissue-engineered bone constructs in vitro. Up to now little is known about the role of Ets2 in tissue-engineering applications. This study was intended to investigate the hypothesis that protein expression of Ets2 is correlated with the expression of bone-specific proteinsin tissue-engineeredbone constructs. Cell-seeded three-dimensional bone constructs manufactured with osteoblastic cells and poly(lactic-co-glycolic acid) polymer fleeces over a period of 21 days were analyzed by SDS-PAGE and Western blotting. The protein expression of OPN, OC, osteonectin and collagen type I was analyzed. Cellularity, alkaline phosphatase-specific activity and histology confirmed the osteoblastic phenotype of the constructs. Correlations between Ets2 expression and OPN and Ets2 and collagen type I expression could be detected during the phase of late osteoblastic differentiation between days 9 and 21. The correlation between OC and collagen type I was significant in this late stage of osteoblastic differentiation. These results suggest that there is a strong interplay of Ets2 with bone-specific proteins in cell-seeded three-dimensional bone constructs. This study is a crucial step to elucidate the complex interplay of bone-related proteins in the application of bone tissue engineering. PMID- 17703089 TI - Diet-derived nutrients modulate the effects of amylin on c-Fos expression in the area postrema and on food intake. AB - The pancreatic hormone amylin decreases food intake via activation of area postrema (AP) neurons. We investigated whether amylin's potency to reduce food intake and to induce c-Fos expression in the AP/nucleus of the solitary tract region is affected by the feeding conditions and specifically by the macronutrient composition of the diet. Whereas a low dose of amylin (5 microg/kg s.c.) induced very little c-Fos expression in ad libitum chow fed rats, it caused a strong c-Fos expression in 24-hour food-deprived rats and in rats that received a nutrient-deficient non-caloric mash (NCM; vanilla-flavoured cellulose) 24 h before injection. To reveal the contribution of single nutrients to the low c-Fos expression after chow feeding, amylin-induced c-Fos was analyzed after feeding NCM that was selectively supplemented with glucose, fat (lard), or protein (casein), matching the intake of these nutrients of chow-fed rats. While the rats fed NCM supplemented with glucose or fat displayed an equally strong amylin induced activation as fasted rats or rats fed plain NCM, a significantly lower c Fos expression was observed in rats fed a protein-supplemented NCM or a NCM containing all three nutrients. In line with this lower activation, the same dose of amylin failed to reduce food intake in NCM/protein-fed rats, while amylin caused a reduction in feeding when animals received NCM, NCM/glucose, or NCM/fat. Interestingly, amylin effectively reduced food intake in ad libitum chow fed rats despite the low level of amylin-induced c-Fos expression in the AP under these conditions. We conclude that the anorectic potential of amylin may be attenuated by diet-derived proteins, whereas this effect appears to be overridden when the amount of carbohydrates/fat is high relative to the protein content, such as, e.g., in standard chow. PMID- 17703090 TI - Maintenance of homeostasis for thyroid hormone in the adult rat brain: possible involvement of a nuclear-mediated phenomenon. AB - During adult-onset peripheral hypothyroidism, the brain maintains normal levels of thyroid hormone for some time through a mechanism of 'central homeostasis'. Although onset, duration, and termination of such a homeostatic phenomenon have been recently evaluated in rat models, the mechanism behind remains unknown. During our investigation to understand the mechanism further, we injected the protein synthesis blockers actinomycin D and cycloheximide along with propylthiouracil to adult male rats during the days of onset (day 2) and termination (day 20) of the homeostatic mechanism. We evaluated synaptosomal T(3) level and neuronal Na(+)-K(+)-ATPase and acetylcholinesterase activities along with deiodinase II activity and cyclic adenosine monophosphate level in the cerebral cortex. The results indicated prevalence of unchanged or lower levels of synaptosomal T(3) on the 2nd and on the 20th day, respectively. Such a condition has been parallely supported by reflections in cerebrocortical deiodinase II activity and cyclic adenosine monophosphate levels. The activities of cerebrocortical synaptosomal Na(+)-K(+)-ATPase and acetylcholinesterase, which are the two important physiological parameters for neuronal function, have been found to be supportive of the involvement of a neuronal protein-mediated factor in the 'on' and 'off' reactions in central homeostasis during peripheral hypothyroidism. The results of our study indicate that the expression of 'central thyroid hormone homeostasis' is a genomic nuclear-mediated mechanism. PMID- 17703091 TI - Relation between serum calcium, phosphate, parathyroid hormone and 'nondipper' circadian blood pressure variability profile in patients with normal renal function. AB - BACKGROUND AND AIMS: In patients with renal disease, an association between abnormal circadian blood pressure profile and abnormalities in bone and mineral metabolism, including vascular calcifications, is well known. However, such a link has not yet been reported in hypertensive patients with normal renal function. We aimed to evaluate if higher serum phosphate, calcium, parathyroid hormone (PTH) level and the calcium x phosphate (Ca x P) product would be associated with a nondipper hypertension, in patients with normal renal function and without any PTH disorder. METHODS: 190 hypertensive subjects with the following inclusion criteria were enrolled: (1) normal phosphate and PTH levels; (2) glomerular filtration rate (GFR) >60 ml/min, and (3) no history of calcium, phosphate, vitamin D medication and hyperparathyroidism. RESULTS: Of the total population, 76 patients (40%) were classified as dippers and 114 (60%) as nondippers. Nondipper patients had higher levels of phosphate (3.70 +/- 0.61 vs. 3.35 +/- 0.44 mg/dl, p = 0.001), Ca x P product (35.4 +/- 6.5 vs. 31.5 +/- 5.0, p = 0.001) and PTH (75.7 +/- 28.8 vs. 46.6 +/- 17.1 pg/ml, p = 0.000) compared to dipper patients. Independent predictors (multiple regression) for nondipper hypertension were PTH (beta = 0.43, p = 0.001) and phosphate (beta = 0.9, p = 0.03). CONCLUSION: We demonstrate a graded independent relation between higher levels of phosphate, PTH, Ca x P product and the risk of nondipping in hypertensive patients with an estimated GFR of >60 ml/min and normal mineral metabolism. PMID- 17703092 TI - Isolated cardiac sarcoidosis associated with the expression of a splice variant coding for a truncated BTNL2 protein. AB - A 33-year-old woman presented with clinical signs of heart failure and previously diagnosed complete atrioventricular block. DNA sequencing revealed a homozygous point mutation in exon 5 of the btnl2 gene coding for a truncated protein which lacks the membrane-anchoring motif. This single nucleotide polymorphism is known to be a risk factor for sarcoidosis. Indeed, endomyocardial biopsy demonstrated multiple nonnecrotizing granulomas composed of epitheloid cells and moderate numbers of multinucleated giant cells. Because no other organs were affected, isolated cardiac sarcoidosis was diagnosed and treated with corticosteroids. Thus, detection of the disease-associated btln2 allele may help to identify patients with sarcoidosis as the underlying cause of heart failure. PMID- 17703093 TI - Complication of laparoscopic detorsion of adnexal mass. AB - Detorsion of an ischemic adnexal mass has recently been advocated for most cases of twisted adnexa. Usually, the affected ovary regains some or all of its vitality and function. However, when the ovary is completely necrotic, it may form an abscess if it contains tissue components that cannot be eliminated by the peritoneal immune system. We report a case of pelvic abscess formation in a detorsed ovary that previously contained an unsuspected dermoid cyst. We call for an extensive inspection of the detorsed ovary before ending the laparoscopic operation, and if it remains necrotic and is suspected of containing a dermoid cyst, it should be removed promptly. PMID- 17703094 TI - Sequence polymorphisms of major German cockroach allergens Bla g 1, Bla g 2, Bla g 4, and Bla g 5. AB - BACKGROUND: The allergenicity of allergens could be influenced by amino acid substitutions in B- or T-cell epitope regions. The German cockroach is known to produce potent allergens inducing strong IgE-mediated allergic reactions. This study was performed to investigate sequence variations in major allergens of the German cockroach. METHODS: Reverse transcriptase PCR was used to amplify the cDNA sequences encoding major allergens of the German cockroach (Bla g 1, Bla g 2, Bla g 4, and Bla g 5). RESULTS: The deduced amino acid sequences revealed 38 Bla g 1 variants with 1-7 amino acid substitutions (98.6-99.8% identity), 28 Bla g 2 variants with 1-3 substitutions (99.1-99.7%), 27 Bla g 4 variants with 0-32 substitutions (82.4-100%), and 8 Bla g 5 variants with 1-2 substitutions (99.0 99.5%), respectively. Bla g 1 and Bla g 2 showed sporadic amino acid substitutions despite the divergence in their sequences. Bla g 4 exhibited frequent variations, with clusters of substitutions in residues 29-38, 52-80, and 132-155. Sequence variations in Bla g 4 imply the presence of multiple isoforms and isoallergens, which may in turn have various effects on the IgE-binding capacity and T-cell responsiveness. Only 8 variants were found in Bla g 5, with infrequent amino acid changes of one or two residues. CONCLUSIONS: Analyses of T cell and IgE-binding epitope regions would clarify the effect of sequence polymorphisms on allergenicity, which in turn will aid in the design of allergen formulations for diagnosis and immunotherapy for cockroach allergies. PMID- 17703095 TI - Effect of an instantaneous controlled pressure drop on in vitro allergenicity to lupins (Lupinus albus var Multolupa). AB - BACKGROUND: Lupin seed flour has been reported as a causative agent of allergic reactions, especially in patients with allergy to peanut. Previous studies have demonstrated that autoclave treatment can considerably reduce the allergenicity of lupins. AIMS: The aim of this work was to evaluate the effect of instantaneous controlled pressure drop (detente instantanee controlee, DIC) treatment on lupin in vitro allergenicity. METHODS: Lupin cotyledons were subjected to instantaneous controlled pressure drop at several pressure and time conditions (3, 4.5 and 6 bar for 1, 2 and 3 min, respectively). Immunoreactivity to raw and DIC-treated extracts was evaluated by Western blot using a serum pool from 19 sensitized patients. RESULTS: Depending on the operating parameters used during DIC treatment, a reduction in protein solubility of lupin seed was observed. Moreover, drastic modifications in protein profiles were observed after DIC treatment by SDS-PAGE analysis. Western blot experiments showed that the decreases in IgE binding to lupin proteins were associated with the increases in steam pressure and time treatment, and binding was completely abolished by DIC at 6 bar for 3 min. CONCLUSIONS: The results suggest that DIC treatment could produce a reduction in lupin allergenicity. PMID- 17703096 TI - Clinical aspects and molecular analysis of Chinese patients with Wiskott-Aldrich syndrome in Taiwan. AB - BACKGROUND: Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency, characterized by microthrombocytopenia, eczema and recurrent infections. More than 441 patient mutations have been described all over the world, mainly based on Caucasian and Japanese people. There have been few reported cases involving Chinese WAS patients. OBJECTIVE: We investigated Chinese WAS patients in Taiwan since 1980. METHODS: All WAS patients met the diagnosis criteria. Clinical manifestations, immunological functions, gene sequencing and the WAS protein (WASP) expression were analyzed. RESULTS: Eleven male Chinese WAS patients were enrolled, presenting as classic WAS phenotype, correlative to the expression level of WASP and the severity of infections. Seven patients had autoimmune disorders, encompassing autoimmune hemolysis in 4, lymphoproliferative disorders in 2 and ulcerative colitis in 1 patient. As well as prophylactic monthly intravenous immunoglobulin infusion, splenectomy was performed on 2 patients. Five patients received hematopoietic stem cell transplantation. The causes of mortality were mass bleeding, sepsis and Epstein Barr virus-associated lymphoproliferative disorders in 3 nontransplant patients and acute graft failure and cytomegalovirus pneumonitis in 2 transplant patients. Nine patients received genetic analysis and revealed 4 unique mutations. None had the X-linked thrombocytopenia phenotype. CONCLUSIONS: All of the recognized Chinese WAS patients had the classic phenotype. Most mutations involved exon 1 of the WASP gene and none had the X-linked thrombocytopenia phenotype. This may be attributable to genetic variation, although selection bias may exist. PMID- 17703097 TI - Proinflammatory impact of Staphylococcus epidermidis on the nasal epithelium quantified by IL-8 and GRO-alpha responses in primary human nasal epithelial cells. AB - BACKGROUND: Bacterial etiology of chronic rhinosinusitis (CRS) still remains controversial. Whereas Staphylococcus aureus enterotoxins have been detected in CRS, the impact of Staphylococcus epidermidis, a major commensal inhabitant of the nose, has not been studied. Among others, serine and cysteine proteases have been identified as factors of virulence in S. epidermidis. METHODS: S. epidermidis was examined in tissue biopsies of 30 CRS patients (16 with nasal polyposis) using standard procedures. Primary human nasal epithelial cells from inferior nasal turbinates (HNECs), from nasal polyps (NPECs) and A549 airway epithelial cells were stimulated with S. epidermidis supernatants DSM20044 or ATCC35984 and the IL-8 and GRO-alpha response was quantified by ELISA. Protease triggered chemokine responses and involvement of NF-kappaB were investigated by addition of protease or NF-kappaB inhibitors. Activation of NF-kappaB was demonstrated by quantitative DNA binding assay. RESULTS: S. epidermidis was the most frequently isolated bacteria in the majority of CRS patients. HNECs and NPECs revealed no different IL-6 and IL-8 synthesis following stimulation with DSM20044 or ATCC35984. Stimulation of HNECs and A549 cells with S. epidermidis supernatants resulted in increased IL-8 and GRO-alpha expression which could be suppressed by the serine protease inhibitor AEBSF and the NF-kappaB inhibitor BAY 11 but not by the cysteine protease inhibitor E64. Results obtained for A549 cells were similar to HNECs. CONCLUSION: S. epidermidis was present in the majority of CRS specimens. Proinflammatory impact of S. epidermidis supernatants on nasal epithelial cells was demonstrated by serine protease-triggered and NF kappaB-dependent chemokine responses. PMID- 17703099 TI - Association analysis of tyrosine kinase FYN gene polymorphisms in asthmatic children. AB - BACKGROUND: FYN is nonreceptor tyrosine kinase that represents the earliest detectable signaling response after antigen-activated inflammatory cells. Studies in animal models of allergic asthma have shown that inhibitors of tyrosine kinases exert an anti-inflammatory effect. In the FYN gene, several polymorphisms have been described. There have, however, been no studies analyzing the impact of FYN gene polymorphisms on the course and severity of asthma. The aim of this study was to analyze the possible relationship between three polymorphisms ( 93A/G, Intron10+37C/T and Ex12+894T/G) in the FYN gene and asthma. METHODS: We analyzed 120 pediatric asthmatic patients aged from 6 to 18 years. The diagnosis of allergic asthma was based on clinical manifestation, lung function test and positive skin prick tests and/or an increased IgE level. The control group consisted of 187 healthy subjects. The polymorphisms were genotyped with use of the PCR-RFLP method. RESULTS: We observed an association of the -93A/G polymorphism and the presence of asthma (p = 0.014 for genotypes and p = 0.019 for alleles) and in the subgroup of 55 patients with severe asthma (p = 0.042 for genotypes and p = 0.021 for alleles). We also found an association of the Ex12+894T/G polymorphism in the whole group analyzed (p = 0.067 for genotypes and p = 0.024 for alleles), but not in the subgroup with severe asthma. For the Intron10+37T/C polymorphism, we did not find a significant difference between the whole group of asthmatic patients and the control group nor between the subgroup with severe asthma and the control group. In the linkage disequilibrium analysis, we observed a modest linkage between -93A/G and Intron10+37T/C polymorphisms (lod = 18.7, D' = 0.62, 95% CI: 0.51-0.71, r2 = 0.29); however, it was not strong enough to generate any haplotypes. CONCLUSIONS: The results may suggest a relationship between the FYN polymorphisms and allergic asthma. PMID- 17703098 TI - House dust and storage mite extracts influence skin keratinocyte and fibroblast function. AB - BACKGROUND: The bodies of allergy-causing dust and storage mites likely contain many bioreactive molecules, including some that are allergenic. These molecules may penetrate the epidermis and dermis of the skin. However, little is known about the effects that most of the molecules from mites have on the function of cells in the skin, the overall inflammatory and immune reactions and the manifestation of allergic disease. The purpose of this research was to determine the response of cultured skin cells (keratinocytes and fibroblasts) to extracts of house dust and storage mites. METHODS: Normal human epidermal keratinocytes and dermal fibroblasts were cultured with varying doses of extracts of the storage mites Acarus siro, Chortoglyphus arcuatus or Lepidoglyphus destructor or of the house dust mites Dermatophagoides farinae, D. pteronyssinus or Euroglyphus maynei in the absence or presence of lipopolysaccharide. Culture supernatants were collected 24 h later and assayed for the presence of various chemokines and cytokines. RESULTS: Keratinocytes constitutively secreted interleukin (IL)-1 receptor antagonist/IL-1F3, growth-related oncogene alpha and transforming growth factor alpha, and these secretions were modulated by extracts of 1 or more of the mites tested. Mite extracts also modulated the production of IL-6, IL-8, monocyte chemoattractant protein 1, macrophage colony-stimulating factor and vascular endothelial growth factor from fibroblasts. CONCLUSIONS: The effects that mite extracts exerted on both keratinocytes and fibroblasts varied among the house dust mite species, among the storage mite species and between the house dust and storage mites. This study showed that extracts of mites contain substances that modulate the production of proinflammatory cytokines and chemokines secreted by normal human epidermal keratinocytes and dermal fibroblasts, and therefore may influence the course of pathophysiology in the skin in atopic dermatitis. PMID- 17703100 TI - Skin testing correlates negatively with high-activity ACP1 *B/*C genotype. AB - BACKGROUND: Previous studies have shown a negative association between ACP1 *B/*C genotype and total IgE level. ACP1 (acid phosphatase locus 1) is a polymorphic phosphotyrosine phosphatase that interacts with IL4-RA and is involved in T cell receptor signaling. METHODS: In the present paper, we have studied the relationship between *B/*C genotype which shows high ACP1 activity and skin testing in 300 adult subjects referred for allergic manifestations. ACP1 genotypes were determined by DNA analysis. RESULTS: There is a significant negative correlation between the intensity of skin test reaction and *B/*C genotype (p = 0.01). The proportion of *B/*C genotype is lower in allergic subjects with intense skin reaction than in allergic subjects with moderate skin reaction and in healthy controls. CONCLUSIONS: This new observation confirms by a different approach the relationship between ACP1 polymorphism and allergic manifestations, suggesting that high ACP1 activity protects against these manifestations. PMID- 17703101 TI - Standardization of skin tests for diagnosis and prevention of hypersensitivity reactions to oxaliplatin. AB - BACKGROUND: Platinum salts can cause allergic sensitization. Recently, hypersensitivity reactions to oxaliplatin, the most recent platinum coordination complex introduced into clinical practice, have been reported. OBJECTIVE: To validate and standardize skin tests to diagnose and possibly prevent hypersensitivity reactions to oxaliplatin. The secondary aims were to confirm IgE mediated pathogenesis of the clinical manifestations and to evaluate skin tests to predict patients at risk of hypersensitivity reactions to oxaliplatin. METHODS: We performed skin tests at increasing concentrations of oxaliplatin on 15 patients never exposed to platinum salts, on 10 patients treated with oxaliplatin without any adverse reactions, and on 4 patients who had shown hypersensitivity reactions to the drug. Moreover we performed skin tests on 8 additional patients starting before the 5th dose and following a course of chemotherapy. RESULTS: A positive skin reaction to the prick test at a concentration of 1 mg/ml was seen in 1 patient with hypersensitivity reactions. The intradermal test was positive in all the patients with hypersensitivity reactions at a concentration of 0.1 mg/ml. It was negative in the 15 nonexposed subjects, and in the 10 patients who had been exposed to oxaliplatin without hypersensitivity reactions. The skin test administered to patients before chemotherapy was positive in one case. CONCLUSION: A skin prick test at a concentration of 1 mg/ml and, in the case of a negative response, an intradermal test at the optimal concentration of 0.1 mg/ml should be used, starting from the 5th course of therapy, to diagnose and prevent hypersensitivity reactions to oxaliplatin. PMID- 17703102 TI - Dietary fish or seafood consumption is not related to cerebrovascular disease risk in twin veterans. AB - BACKGROUND/AIMS: The results of studies about dietary fish consumption and stroke risk have been conflicting. We sought to examine the relationship between dietary fish and seafood consumption and the risk of stroke or transient ischemic attack (TIA). METHODS: We used data from the National Academy of Sciences-National Research Council Twin Registry, a prospective cohort of white male twins born in the US (1917-1927). Participants were asked about fish and seafood consumption in 1972 and 1985. Self-report or death-certificate report of stroke or TIA was obtained in 1996-1998. RESULTS: Among 5,355 participants, 579 (10.8%) had a stroke or TIA. In unmatched analyses, dietary fish and seafood consumption was not associated with stroke or TIA: 10.4% (91/872) of frequent fish or seafood consumers had a stroke or TIA versus 10.9% (488/4,483) of infrequent consumers, p = 0.70. In an analysis of matched twin pairs, frequent fish or seafood consumption was also not associated with stroke or TIA: hazard ratio 0.89, 95% CI 0.59-1.36. CONCLUSIONS: These data, from a prospective cohort of white male twins, do not support an association between dietary fish and seafood consumption and stroke or TIA. PMID- 17703103 TI - Effect of maternal administration of betamethasone on peripheral arterial development in fetal rabbit lungs. AB - OBJECTIVES: Glucocorticoids promote lung maturation and reduce the incidence of respiratory distress syndrome in premature newborns. We hypothesized that betamethasone (BM), which is known to induce thinning of the alveolar walls, would also thin the arterial media and adventitia of intra-parenchymatic vessels in developing rabbit lungs. STUDY DESIGN: 112 fetuses from 21 time-mated, pregnant, giant white rabbits received maternal injections of BM at either 0.05 or 0.1 mg/kg/day on days 25-26 of gestational age. Controls received either saline (10 does, 56 fetuses) or no injection (10 does, 59 fetuses). Fetuses were harvested from day 27 onwards until term (day 31). 44 additional fetuses (8 does) were harvested between days 23 and 26. Endpoints were wet lung-to-body weight ratio, vascular morphometric indices and immunohistochemistry staining for alpha smooth muscle actin, Flk-1, vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). ANOVA (Tukey's test) and independent t test (p < 0.05) were used for comparison between BM and saline groups. RESULTS: Maternal BM injected on days 25-26 to pregnant rabbits induced a significant decrease in fetal body and lung weight and the lung-to-body weight ratio in the preterm pups shortly after injection. BM led to a dose-dependent thinning of the arterial media and adventitia (pulmonary arteries with an external diameter (ED) of <100 microm), to an increase in the percentage of non-muscularized peripheral vessels (ED <60 microm), in eNOS and VEGF immunoreactivity of the endothelial and smooth muscle cells in the pulmonary vessels and to an increase in Flk-1-positive pulmonary epithelial cell density. CONCLUSIONS: Maternal administration of BM caused thinning of the arterial wall of pulmonary vessels (ED <100 microm) and a decrease in muscularization in peripheral vessels (ED <60 microm). This coincided with increased expression of Flk-1 in the endothelium and smooth muscle cells of the pulmonary arteries. All the effects studied were dose-dependent. PMID- 17703104 TI - Transcutaneous bilirubin measurement: evaluation of Bilitest. AB - OBJECTIVE: The early discharge of neonates from hospitals makes transcutaneous measurement of total serum bilirubin concentration a useful tool to monitor neonatal jaundice. The objective of this study was to evaluate the Bilitest BB 77trade mark (Bertocchi SRL Elettromedicali, Cremona, Italy), a new device for noninvasive transcutaneous total bilirubin measurement. METHODS: We studied 241 newborn infants > or =32 weeks of gestation admitted to the Neonatal Nursery of Careggi University Hospital, Florence. These infants had total serum bilirubin (TSB) levels measured by a standard laboratory test [corrected] as part of their normal care, and transcutaneous bilirubin (TcB) levels were obtained within 10 min after heel pricking. RESULTS: There was a good correlation between TSB and TcB values. The linear regression plot showed a general underestimation of Bilitest BB 77 measurement compared to standard laboratory test; the negative difference between Bilitest BB 77 values and TSB increased at higher bilirubin levels, as confirmed by the Bland-Altman error plot. To visualize the accuracy of the Bilitest BB 77 measurements, ROC curves plot sensitivity versus specificity and the maximum range of difference between Bilitest BB 77 and TSB were considered. Pearson correlation analysis demonstrated that Bilitest BB 77 accuracy was independent of gestational and postnatal age of newborns. CONCLUSION: We conclude that the Bilitest BB 77, a new device for bilirubin transcutaneous measurement, shows a good correlation with standard laboratory method and has the merit to be quite inexpensive and does not need calibration with consumable or disposable parts. However, because TcB measurements with Bilitest BB 77 underestimated STB levels particularly at STB > or =12 mg/dl, serum bilirubin measurements are still required when treatment with phototherapy or exchange transfusion is being considered. PMID- 17703105 TI - Early effects of lipopolysaccharide on cytokine release, hemodynamic and renal function in newborn piglets. AB - BACKGROUND: Gram-negative sepsis in newborns is associated with high mortality and morbidity. Lipopolysaccharide (LPS) and cytokines released upon exposure to gram-negative sepsis are well known to be involved in the pathophysiology. OBJECTIVE: In this report we investigate cytokine release, hemodynamic, and renal function induced by LPS in a newborn animal model with the intention to further examine early changes in gram-negative sepsis. METHODS: Five 7- to 10-day-old domestic piglets were anesthetized and catheters placed in the jugular veins, left ventricle, and femoral artery. Urine output was monitored via suprapubic cystostomy. Mean arterial pressure, heart rate, and arterial blood gases were continuously monitored. Thirty minutes after line placement and obtaining baseline values, 0.06 mug/kg LPS were administered intravenously. One, 2, and 3 h later samples were taken to monitor tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, endothelin, and nitric oxide (NO)/nitrate via ELISA. In addition, blood flow was assessed by the microsphere method. RESULTS: Our data show an initial surge of TNF-alpha and IL-1beta at 1 h after exposure to LPS. NO/nitrate, endothelin, and hemodynamic as well as metabolic changes became apparent mostly 3 h after exposure, by which time TNF-alpha and IL-1beta fell back to baseline. CONCLUSIONS: Our sepsis model suggests a brief initial TNF alpha and IL-1beta surge following LPS challenge; however, their effects become apparent by the time the levels are already subsiding. The emergence of vasoactive substances, NO and endothelin, precedes the first substantial clinical symptoms. PMID- 17703106 TI - Left atrial appendage mimicking an intra-cardiac vegetation in preterm neonates. AB - Infective endocarditis is emerging as a significant cause of morbidity in the neonatal intensive care with an incidence ranging from 0.07 to 4.3%. The rise in incidence may be explained by the increasing availability of echocardiography facilities in the neonatal unit. The diagnosis of infective endocarditis has major therapeutic implications as the neonate is treated with potentially toxic drugs and exposed to prolonged intravenous catheters. However, the consequences of a missed diagnosis of endocarditis in preterm neonates are unknown and may potentially lead to significant long-term cardiac complications. Onsite echocardiography in the neonatal unit by neonatologists may improve the speed of diagnosis in cases of endocarditis. However, lack of adequate training and experience in normal echocardiographic views may increase the false-positive rate. The posterior mitral valve leaflet is rarely affected due to the low velocity of blood passing through and because of the absence of prosthesis. We report 2 cases of the left atrial appendage rarely mimicking a posterior mitral valve leaflet vegetation, leading to an erroneous diagnosis of infective endocarditis. The features which distinguish the left atrial appendage from a posterior mitral valve leaflet vegetation are illustrated. PMID- 17703107 TI - Simultaneous and sequential bilateral sudden sensorineural hearing loss: are they different from unilateral sudden sensorineural hearing loss? AB - AIM: To compare bilateral (BSSHL) with unilateral (USSHL) sudden sensorineural hearing loss. METHODS AND SUBJECTS: Two hundred and thirty-two patients with USSHL, 11 with simultaneous BSSHL and 7 with sequential BSSHL, who were older than 15 years had onset of hearing loss <30 days, no head injuries or history of acoustic trauma. All patients received the same treatment (prednisolone). RESULTS: Hearing loss was more severe in simultaneous BSSHL in comparison to sequential BSSHL (p = 0.01) or USSHL (p = 0.03). Autoimmune diseases were far more common in simultaneous BSSHL (36% of patients) than USSHL. Positive antinuclear antibody was found in half of BSSHL patients and in only 8% of unilateral cases (p = 0.01). The frequency of hearing improvement was much lower in simultaneous BSSHL than in USSHL (p = 0.001). Complete or partial improvement was noted in 74% of unilateral cases versus 27% in simultaneous bilateral cases. Patients with sequential BSSHL improved in a similar way to unilateral cases. CONCLUSIONS: Simultaneous BSSHL, sequential BSSHL and USSHL may have a completely different profile and should not be managed as one disease. Hearing loss, underlying autoimmune diseases, antinuclear antibodies, and improvement/recovery of hearing loss vary in a degree that implies different pathophysiology and prognosis. PMID- 17703109 TI - Extracellular matrix induces doxorubicin-resistance in human osteosarcoma cells by suppression of p53 function. AB - BACKGROUND: Osteosarcoma is the most common primary malignant bone tumor in childhood and adolescence. The several chemotherapy-resistant cases of osteosarcoma are at a higher risk of relapse and adverse outcome. OBJECTIVE: The aim of the current study was to determine the role of extracellular matrix in the resistance developed against chemotherapeutic treatments of human osteosarcoma cells. MATERIALS AND METHODS: A cell line, named OSCORT was established from the biopsy of a 17-year-old male patient with primary osteosarcoma. Cell proliferation, apoptosis and quantification of DNA damage after treatments with doxorubicin were investigated in classical and three-dimensional cell culture systems using an extracellular matrix gel. The experimental results were related to the clinical observations of the case. RESULTS: The cells cultured in extracellular matrix gel have shown resistance to doxorubicin similar to that seen in the clinical case, as demonstrated by their proliferation, apoptosis and doxorubicin-induced DNA damage characteristics. Among the extracellular matrix components, the heparan sulfate proteoglycan and-to a lesser extent-fibronectin were involved in the doxorubicin resistance. Laminin and nidogen did not decrease the cytoreductive effect of doxorubicin, while collagen IV even increased it. The extracellular matrix gel decreased the protein levels of p53 and abrogated its cell nuclear translocalization. The most frequent known mutations in the p53 gene were not found in OSCORT cells. CONCLUSION: The current study provides experimental evidence for an epigenetical, extracellular matrix-induced loss of p53 function, which lead to a potent chemotherapy resistance showing accordance with the clinical experience. PMID- 17703110 TI - Natural human gene correction by small extracellular genomic DNA fragments. AB - Classical gene targeting employs natural homologous recombination for a gene correction using a specially designed and artificially delivered DNA construct but the method is very inefficient. On the other hand, small DNA fragments in the form of tiny chromatin-like particles naturally present in blood plasma can spontaneously penetrate into human cells and cell nuclei. We hypothesized that these natural DNA nanoparticles with recombinagenic free ends might be effective agents for gene replacement therapy. We demonstrate that a mixture of small fragments of total human chromatin from non-mutant cells added to a culture medium without transfection agents efficiently repaired a 47 base pair deletion in the CASP3 gene in 30% of treated human MCF7 breast cancer cells, as shown by restoration of caspase-3 apoptotic function and CASP3 DNA and mRNA structure. Such an innate gene replacement mechanism might function naturally in an organism using its own apoptotic DNA fragments. This mechanism might enable human cancer cell phenotype normalization in the presence of excess normal cells. PMID- 17703111 TI - DNA damage leaves its mark on chromatin. AB - DNA organization into chromatin has a major influence on the cellular response to DNA damage. Recent studies in various systems ranging from yeast to human cells stress the importance of chromatin not simply as a barrier to DNA repair processes but also as an active contributor to the DNA damage response. Indeed, modulations of chromatin organization involving various degrees of rearrangements, such as histone modifications and even nucleosome displacement, can promote efficient repair and also participate in checkpoint signaling. Here, we survey recent progress in delineating how chromatin rearrangements provide crosstalk with the DNA damage response. In particular, we highlight new data on histone dynamics at damage sites and discuss their functional importance for the stable propagation of specific chromatin states. PMID- 17703112 TI - The effects of nonprofessional caregivers on the rehospitalization of elderly recipients in home healthcare. AB - The purpose of this study is to evaluate the effects of the presence and types of nonprofessional caregivers on the rehospitalization of elderly recipients in home healthcare (HHC). Outcome and Assessment Information Set records of 9832 elderly recipients discharged from hospitals were selected for multivariate analyses. The likelihood of rehospitalization among elderly recipients of HHC did not vary on the basis of the presence and types of nonprofessional caregivers. The findings suggest that when elderly patients are receiving formal HHC services, their risk for rehospitalization is not affected by the presence or the specific types of nonprofessional caregivers. PMID- 17703113 TI - Developing a model of social capital: relationships in primary care. AB - We have developed a model of social capital to enhance relationships within primary care practices that promote organizational success and improve patient care outcomes. The model extends the meaning and the value of social capital by providing dimensions, attributes, and operational definitions that can be used to measure outcomes and guidelines to develop future interventions. Our model brings new insight and logic to understanding relationships to create resources to improve primary care practices. Furthermore, our model provides a preliminary focus on the value of integrating registered nurses into the work of primary care practices and as facilitators of social capital. PMID- 17703114 TI - "It just alienated us": a case study to explore the impact of assisted reproductive technology on family relationships. AB - New reproductive technologies have the capacity to impact on both personal and healthcare relationships. This article utilizes a case study approach to unpack experiences of one couple who encountered immense and unforeseen difficulties as a result of treatment with assisted reproductive technology. Findings of this case reveal both difficulties and breaches in obtaining informed consent and the consequences these breaches have on relationships. Comprehensive information contributes to positive relationships between patients and healthcare providers. Maintaining supportive relationships between all parties concerned with assisted reproductive technology services is essential, as rifts in these relationships can be devastating and long-lasting. PMID- 17703115 TI - Theory development in nursing and healthcare informatics: a model explaining and predicting information and communication technology acceptance by healthcare consumers. AB - About 110 million American adults are looking for health information and services on the Internet. Identification of the factors influencing healthcare consumers' technology acceptance is requisite to understanding their acceptance and usage behavior of online health information and related services. The purpose of this article is to describe the development of the Information and Communication Technology Acceptance Model (ICTAM). From the literature reviewed, ICTAM was developed with emphasis on integrating multidisciplinary perspectives from divergent frameworks and empirical findings into a unified model with regard to healthcare consumers' acceptance and usage behavior of information and services on the Internet. PMID- 17703116 TI - As the worm turns: hope as meaning construction in the wake of grief and loss. AB - This article presents findings from reimmersion in the data from a study on hope in Australian youth. Carried out in 2002 using a Gadamerian hermeneutic phenomenological approach, the study explored meanings that young people ascribed to their experiences of hope. It was clear from original analysis that the participants expressed hope as a driving force characterized by a necessity for human connectedness and the need to have options and choices in life which when experienced produced feelings of at-one-with. However, missing from this description is the acknowledgement of hope as an embodied experience that enabled resolution of grieving and loss. Reimmersion in the data added new dimensions to my understanding of hope and how it functions in people's lives. In this sense, engagement in secondary analysis fulfilled the goal of philosophic hermeneutics, which is to understand what is involved in the process of understanding itself. PMID- 17703117 TI - Toward a holistic conceptualization of empathy for nursing practice. AB - This article proposes a new holistic conceptualization of empathy for nursing practice that allows different aspects of the literature to be understood. This study is based on the data of a doctoral study exploring the nature of empathy on an oncology ward. The findings revealed that empathy is not a single phenomenon. Four different forms of empathy were identified, namely, empathy as an incident, empathy as a way of knowing, empathy as a process, and empathy as a way of being. These different forms of empathy can be understood in terms of a continuum of empathy development and suggest a new way of conceptualizing empathy that can be depicted diagrammatically. PMID- 17703118 TI - Willingness and its relevance to nursing. AB - Nursing practice is embedded in contexts that inhibit or constrain emancipatory relationships. This article explores willingness in relation to agency and actualization fostered by emancipative relationships in nursing practice. Opportunities for emancipative choice are possible only when nurses are willing to engage in critical reflection, authentic discourses, and risk congruent action within the constraints of dominant paradigms. PMID- 17703120 TI - Relational practice and nursing obligations. AB - Nursing relationships and the enactment of nursing values and goals in contemporary healthcare contexts are becoming increasingly challenging. Using a relational inquiry lens, the authors examine the interface of relationships, ethics, and effective nursing practice and the way in which personal and contextual elements continuously influence and shape nursing relationships in many ways. The nursing obligations underpinning relational practice are examined, and the way in which relational inquiry can enhance nurses' ability to navigate through the highly complex, multifaceted, and contextually dependent moments of contemporary nursing practice is illustrated. PMID- 17703121 TI - The effects of past relationship and obligation on health and health promotion in women caregivers of adult family members. AB - The social expectation that women will care for family members persists despite evidence that many women have difficult or abusive past relationships with their parents and partners. Little is known about how past relationship influences the health of women caring for adult family members. On the basis of earlier grounded theory research, we tested the theory that past relationship and obligation predict health outcomes and health promotion in 236 women caregivers of adult family members. Structural equation modeling demonstrated support for the theory, with 56% of the variance in health outcomes and 11% of the variance in health promotion accounted for by the model. PMID- 17703123 TI - Dimensions of caring: psychometric evaluation of the caring assessment tool. AB - The increase in relationship-centered professional practice models has expanded the interest in the measurement of caring. Using a cross-sectional descriptive study of 557 adults from 5 acute care institutions, a factor analysis and reliability statistics were used to revise the Caring Assessment Tool. Eight independent factors (mutual problem solving, attentive reassurance, human respect, encouraging manner, appreciation of unique meanings, healing environment, affiliation needs, and basic human needs) explained 62.6% of the variance in caring. The findings provide insight into patients' assessment of caring in nursing and offer a baseline evaluation of the psychometric properties of the Caring Assessment Tool. PMID- 17703122 TI - Flying under the radar: engagement and retention of depressed low-income mothers in a mental health intervention. AB - A randomized trial of in-home psychotherapy for depressive symptoms that targeted low-income mothers of infants and toddlers used innovative design features to reduce stigma and enhance acceptability. Despite these features, advanced practice psychiatric mental health nurses used specialized, relationship-based strategies to engage and retain these high-risk mothers in the intervention. Data revealed that the nurses needed to diligently maintain contact, provide encouragement, use empathy for rapid assessment and response, and control the intensity of the relationship-based contacts in order to retain mothers. PMID- 17703125 TI - Using the Roy Adaptation Model to explore the dynamics of quality of life and the relationship between lung transplant candidates and their caregivers. AB - Using theory to support nursing research may be considered superfluous by some authors, yet a theoretical framework provides structure and consistency to a research study. This article presents the use of the Roy Adaptation Model within the theoretical framework underpinning an investigation of quality of life as perceived by lung transplant candidates and their caregivers. Each step of the research process is identified in this article and the link to the theoretical framework is demonstrated. The use of nursing frameworks to guide research strengthens the theoretical framework itself and also adds another dimension to the body of nursing knowledge. PMID- 17703124 TI - Strangers in strange lands: a metasynthesis of lived experiences of immigrant asian nurses working in Western countries. AB - Nurses from Asian countries make up the majority of immigrant nurses globally. Although there are a limited number of studies on the lived experiences of Asian nurses working in Western countries, the development of nursing science will be impeded if the rich understanding gleaned from these studies is not synthesized. Using Noblit and Hare's (Meta-ethnography: Synthesizing Qualitative Studies. Newbury Park, Calif: Sage; 1988) procedures, a metasynthesis was conducted on 14 studies that met preset selection criteria. Four overarching themes emerged: (a) communication as a daunting challenge; (b) differences in nursing practice; (c) marginalization, discrimination, and exploitation; and (d) cultural differences. Based on the metasynthesis, a large narrative and expanded interpretation was constructed and implications for nursing knowledge development, clinical practice, and policy making are elaborated. PMID- 17703126 TI - Novel drugs targeting hypertension: renin inhibitors. AB - The first renin inhibitor, aliskiren, will soon enter the clinical arena. This review summarizes the potential differences between renin inhibitors and the currently existing blockers of the renin-angiotensin system (RAS) [ie, the ACE inhibitors and the angiotensin II type 1 (AT(1)) receptor antagonists], taking also into consideration the recently discovered (pro)renin receptor. This receptor not only activates the inactive precursor of renin, prorenin, but it also exerts direct renin/prorenin-induced effects, independently of angiotensin. The review ends with a brief overview of the available (pre)clinical aliskiren data and a description of its safety profile. PMID- 17703127 TI - ACE2: a new target for cardiovascular disease therapeutics. AB - The discovery of angiotensin-converting enzyme 2 (ACE2) in 2000 is an important event in the renin-angiotensin system (RAS) story. This enzyme, an homolog of ACE, hydrolyzes angiotensin (Ang) I to produce Ang-(1-9), which is subsequently converted into Ang-(1-7) by a neutral endopeptidase and ACE. ACE2 releases Ang-(1 7) more efficiently than its catalysis of Ang-(1-9) by cleavage of Pro(7)-Phe(8) bound in Ang II. Thus, the major biologically active product of ACE2 is Ang-(1 7), which is considered to be a beneficial peptide of the RAS cascade in the cardiovascular system. This enzyme has 42% identity with the catalytic domain of ACE, is present in most cardiovascular-relevant tissues, and is an ectoenzyme as ACE. Despite these similarities, ACE2 is distinct from ACE. Since it is a monocarboxypeptidase, it has only 1 catalytic site and is insensitive to ACE inhibitors. As a result, ACE2 is a central enzyme in balancing vasoconstrictor and proliferative actions of Ang II with vasodilatory and antiproliferative effects of Ang-(1-7). In this review, we will summarize the role of ACE2 in the cardiovascular system and discuss the importance of ACE2-Ang-(1-7) axis in the control of normal cardiovascular physiology and ACE2 as a potential target in the development of novel therapeutic agents for cardiovascular diseases. PMID- 17703128 TI - PPAR activation: a new target for the treatment of hypertension. AB - Hypertensive patients are at increased risk for cardiovascular complications. Inhibition of different pathophysiological mechanisms involved in hypertension and hypertension-related target organ damage may revert or prevent the progression of the pathological changes observed and reduce the occurrence of cardiovascular events. One of the new targets that may prevent or regress hypertensive vascular, renal, and perhaps brain changes in hypertension is the activation of nuclear receptors that have metabolic effects but also exert antiinflammatory action, the peroxisome proliferator activator receptor (PPAR) activators alpha and gamma. This review will discuss some of the evidence, both experimental and clinical, that suggests that activation of PPAR alpha and/or gamma in hypertension may exert beneficial cardiovascular protective effects. PMID- 17703129 TI - Can the protective actions of JAK-STAT in the heart be exploited therapeutically? Parsing the regulation of interleukin-6-type cytokine signaling. AB - Activation of the transcription factor signal transducers and activators of transcription (STAT) 3 is a defining feature of the interleukin (IL)-6 family of cytokines, which include IL-6, leukemia inhibitory factor, and cardiotrophin-1. These cytokines, as well as STAT3 activation, have been shown to be protective for cardiac myocytes and necessary for ischemia preconditioning. However, the mechanisms that regulate IL-6-type cytokine signaling in cardiac myocytes are largely unexplored. We propose that the protective character of IL-6-type cytokine signaling in cardiac myocytes is determined principally by three mechanisms: redox status of the nonreceptor tyrosine kinase Janus kinase 1 (JAK) 1 that activates STAT3, phosphorylation of STAT3 within the transcriptional activation domain on serine 727, and STAT3-mediated induction of suppressor of cytokine signaling (SOCS) 3 that terminates IL-6-type cytokine signaling. Moreover, we hypothesize that hyperactivation of the JAK kinases, particularly JAK2, mismatched STAT3 serine-tyrosine phosphorylation or heightened STAT3 transcriptional activity, and SOCS3 induction may ultimately prove detrimental. Here we summarize recent evidence that supports this hypothesis, as well as additional possible mechanisms of JAK-STAT regulation. Understanding how IL-6 type cytokine signaling is regulated in cardiac myocytes has great significance for exploiting the therapeutic potential of these cytokines and the phenomenon of preconditioning. PMID- 17703130 TI - Flavin adenine dinucleotide may release preformed stores of nitrosyl factors from the vascular endothelium of conscious rats. AB - This study determined whether flavin adenine dinucleotide (FAD) may elicit vasodilation in conscious rats via release of preformed endothelium-derived nitrosyl factors. Injections 1-6 (inj(1-6)) of FAD (2.5 micromol/kg, IV) elicited pronounced and equivalent vasodilator responses in saline-treated rats. Inj(1) of FAD elicited pronounced vasodilation in L-NAME-treated rats pretreated with the nitric oxide (NO) synthesis inhibitor, NG-nitro-L-arginine (L-NAME; 50 micromol/kg, IV), whereas Inj(2-6) elicited progressively smaller responses such that inj(6) elicited minor responses. The vasodilator responses elicited by the endothelium-dependent agonist, acetylcholine, were markedly attenuated in L-NAME treated rats that had received inj(1-6) of FAD but not in saline-treated rats that had received inj(1-6) of FAD. The vasodilator actions of L-S-nitrosocysteine and the NO donor, sodium nitroprusside, were not diminished after the injections of FAD in saline- or in L-NAME-treated rats. Binding studies demonstrated that the densities of muscarinic M3 receptors were increased in thoracic aorta endothelium of rats treated with L-NAME + inj(1-6) of saline or L-NAME + inj(1-6) of FAD as compared to rats treated with saline + inj(1-6) of saline or saline + inj(1-6) of FAD. The progressive loss of response to injections of FAD in L-NAME treated rats coupled with the loss of response to acetylcholine suggests that FAD elicits the use-dependent depletion of vesicular pools of nitrosyl factors in endothelial cells that cannot be replenished in the absence of NO synthesis. PMID- 17703131 TI - Impairment of endothelium-dependent relaxation of rat aortas by homocysteine thiolactone and attenuation by captopril. AB - To explore the effects of angiotensin-converting enzyme (ACE) inhibitors on endothelial dysfunction induced by homocysteine thiolactone (HTL). Both endothelium-dependent relaxation and nondependent relaxation of thoracic aortic rings in rats induced by acetylcholine (Ach) or sodium nitroprusside (SNP) and biochemical parameters including malondialdehyde (MDA) and nitric oxide (NO) were measured in rat isolated aorta. Exposure of aortic rings to HTL (3 to 30 mM) for 90 minutes made a significant inhibition of endothelium-dependent relaxation induced by Ach, decreased contents of NO, and increased MDA concentration in aortic tissue. After incubation of aortic rings with captopril (0.003 to 0.03 mM) attenuated the inhibition of endothelium-dependent relaxation (EDR) and significantly resisted the decrease of NO content and elevation of MDA concentration caused by HTL (30 mmol/L) in aortic tissues, a similarly protective effect was observed when the aortic rings were incubated with both N acetylcysteine (0.05 mM). Treatment with enalaprilat (0.003 to 0.01 mM) made no significant difference with the HTL (30 mM) group regarding EDR, but enalaprilat (0.03 mM) and losartan (0.03 mM) could partly restore the EDR in response to HTL (30 mM). Captopril was more effective than enalaprilat and losartan in attenuation of the inhibition of on acetylcholine-stimulated aortic relaxation by HTL in the same concentration. Moreover, superoxide dismutase (SOD, 200 U/mL), which is a scavenger of superoxide anions, apocynin (0.03 mM), which is an inhibitor of NADPH oxidase, and l-Arginine (3 mmol/L), a precursor of nitric oxide (NO), could reduce HTL (30 mM)-induced inhibition of EDR. After pretreatment with not only the NO synthase inhibitor Nomega-nitro-l-arginine methyl ester (L-NAME, 0.01 mM) but also the free sulfhydryl group blocking agent p-hydroxymercurybenzoate (PHMB, 0.05 mM) could abolish the protection of captopril and N-acetylcysteine, respectively. These results suggest that mechanisms of endothelial dysfunction induced by HTL may include the decrease of NO and the generation of oxygen free radicals and that captopril can restore the inhibition of EDR induced by HTL in isolated rat aorta, which may be related to scavenging oxygen free radicals and may be sulfhydryl-dependent. PMID- 17703132 TI - The survival time post-cecal ligation and puncture in sinoaortic denervated rats. AB - Arterial baroreflex (ABR) function is an important determinant factor in prognosis of many cardiovascular diseases. The present work was designed to study the relationship between ABR function and the survival time of septic shock in a cecal ligation and puncture (CLP) rat model. The dysfunction of ABR was introduced by sinoaortic denervation (SAD). It was found that the survival time after CLP was significantly reduced in SAD rats compared with sham-operated rats (12.7 +/- 2.92 hours versus 15.0 +/- 4.01 hours; P < 0.05). Furthermore, significant differences were also seen when the results were expressed by Kaplan Meier survival curves. Compared with the baseline values, both noradrenaline and adrenaline significantly increased in both SAD and Sham groups after CLP, but we found the baseline of noradrenaline was significantly elevated in SAD rats. In addition, the TNF-alpha, noradrenaline, and adrenaline levels of the SAD group were significantly higher than those of the Sham group at 5 hours post-CLP. In conclusion, the present work demonstrates that ABR function was related to the survival time in CLP-induced lethal shock model. The loss of inhibition in the sympathetic activity and in the release of some inflammatory cytokines during CLP induced septic shock related to baroreflex and/or chemoreflex dysfunction may be the mechanisms involved in the poorer prognosis in septic shock. PMID- 17703133 TI - Propionyl-L-carnitine prevents age-related myocardial remodeling in the rabbit. AB - Age-related cardiac remodeling is characterized by changes in myocardial structure, which include fibrosis (ie, increased collagen concentration). The pathogenetic mechanisms of age-related cardiac changes and possible pharmacologic interventions are still a matter of investigation. A morphometric analysis of collagen accumulation was performed in Sirius Red-stained left ventricular sections of 3-month-old and 5-6-year-old animals after a 9-month period of propionyl-L-carnitine treatment (PLC; 120 mg Kg(-1) day(-1) per os); aged rabbits showed decreased interstitial collagen accumulation and no changes in cellularity and apoptotic rate compared to controls. Age-related expression of vascular cell adhesion molecule-1 (VCAM-1)-positive microvessels was also reduced in PLC treated rabbits. In vitro, the 16-hour, 10-microM PLC treatment reduced collagen type 1 and VCAM-1 transcripts, which were investigated by reverse transcription polymerase chain reaction, more markedly in cardiac fibroblasts from aged donors. In the latter, the anti-VCAM-1 antibody treatment was found to be associated with a reduction in collagen type I transcripts. Our results demonstrated that long term PLC treatment partially prevents age-related interstitial remodeling and suggests that a more complex interstitial cell-to-cell signaling regulates senescent myocardium properties. PMID- 17703134 TI - Dietary effects of structured lipids and phytosteryl esters on cardiovascular function in spontaneously hypertensive rats. AB - This study examined the dietary effects of sesame oil (SO)-based structured lipids (SL) and phytosteryl esters (PE) on cardiovascular function in conscious spontaneously hypertensive rats (SHR) fed high-fat (HF) diets (20% w/w fat). The dietary groups were as follows: normal diet (4.5% w/w fat), SO, SO fortified with PE (SOP), SL, and SL fortified with PE (SLP). Mean arterial blood pressures were similar in all groups, whereas resting heart rates (HR) were higher in all HF-fed groups. The pressor responses to the alpha1-adrenoceptor agonist, phenylephrine (5 microg/kg), were similar in all groups. However, the pressor responses to phenylephrine (10 microg/kg) were diminished in SO- or SL-fed SHR, whereas they were not diminished in SOP- or SLP-fed SHR. The depressor responses elicited by the nitric oxide (NO) donor, sodium nitroprusside (5 and 10 microg/kg), were not diminished in HF-fed rats. Baroreflex-mediated changes in HR were variously decreased in the HF-fed groups, and this decrease tended to be greater in SOP and SLP than in SO and SL groups. The depressor and tachycardic responses elicited by the beta-adrenoceptor agonist, isoproterenol, were equivalent in all groups. The depressor responses elicited by the endothelium-dependent agonist, acetylcholine (0.1 microg/kg), and the hypertension elicited by the NO synthesis inhibitor, NG nitro-L-arginine methylester (25 micromol/kg), were similar in all groups. These findings demonstrate that (1) HF diets increase resting HR and impair baroreflex function in SHR, whereas they do not obviously affect endothelium-dependent vasodilation, and (2) fortification with PE may be deleterious to cardiovascular function (eg, baroreflex activity) in SHR. PMID- 17703135 TI - Fasudil attenuates myocardial fibrosis in association with inhibition of monocyte/macrophage infiltration in the heart of DOCA/salt hypertensive rats. AB - OBJECTIVE: To determine the effects of fasudil, a Rho-kinase inhibitor, on mineralocorticoid-induced myocardial remodeling, we investigated whether fasudil would suppress myocardial fibrosis and inflammation in deoxycorticosterone acetate (DOCA)/salt hypertensive rats. METHODS: Sprague-Dawley rats treated with DOCA combined with 1% NaCl and 0.2% KCl in the drinking water after receiving left nephrectomy were given fasudil (10 mg/kg/day; n = 20) or vehicle (n = 20). Systolic blood pressure (SBP) was measured biweekly. Myocardial monocyte/macrophage infiltration and myocardial fibrosis were determined histologically. Expressions of mRNA of procollagen I (PI), procollagen III (PIII), monocyte chemoattractant protein (MCP)-1, interleukin (IL)-6, type-1 plasminogen activator inhibitor (PAI-1), transforming growth factor (TGF)-beta1, and c-fos were determined. RESULTS: SBP was significantly increased on day 14 after treatment with DOCA/salt. Extent of interstitial and perivascular fibrosis was significantly increased on day 28. Expressions of mRNA of PI, PIII, MCP-1, IL 6, PAI-1, TGF-beta1, and c-fos were significantly increased on day 14. Although SBP did not differ between the fasudil and vehicle groups, extent of monocyte/macrophage infiltration and fibrosis was attenuated in the fasudil group. Expressions of mRNA of these factors except TGF-beta1 were also attenuated. CONCLUSION: Fasudil attenuates myocardial fibrosis possibly via suppression of monocyte/macrophage infiltration of the heart in DOCA/salt hypertensive rats. PMID- 17703136 TI - Effects of combined therapy with a Rho-kinase inhibitor and prostacyclin on monocrotaline-induced pulmonary hypertension in rats. AB - Pulmonary hypertension (PH) is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells, and migration of inflammatory cells, for which no satisfactory treatment has yet been developed. We have previously demonstrated that long-term inhibition of Rho kinase, an effector of the small GTPase Rho, ameliorates monocrotaline-induced PH in rats and hypoxia-induced PH in mice. We also have reported that prostacyclin and its oral analogue, beraprost sodium (BPS), may lack direct inhibitory effect on Rho-kinase in vitro, suggesting that combination therapy with a Rho-kinase inhibitor and BPS is effective for the treatment of PH. In this study, we addressed this point in monocrotaline-induced PH model in rats. Male Sprague Dawley rats were given a subcutaneous injection of monocrotaline (60 mg/kg). They were maintained with or without the treatment with a Rho-kinase inhibitor, fasudil (30 mg/kg/day), BPS (200 microg/kg/day), or a combination of both drugs for 3 weeks. The combination therapy, when compared with each monotherapy, showed significantly more improvement in PH, right ventricular hypertrophy, and pulmonary medial thickness without any adverse effects. Plasma concentrations of fasudil were not affected by BPS. These results suggest that combination therapy with a Rho-kinase inhibitor and prostacyclin exerts further beneficial effects on PH. PMID- 17703137 TI - Tetramethylpyrazine-eluting stents prevented in-stent restenosis in a porcine model. AB - OBJECTIVE: Tetramethylpyrazine, a drug originally isolated from the rhizome of Ligusticum walliichi, is an inhibitor of phosphodiesterase and inhibits platelet aggregation and smooth muscle cell proliferation. The effect of the tetramethylpyrazine-eluting stent (TES) on preventing in-stent restenosis was investigated in comparison with control bare metal stents in a porcine coronary stent restenosis model. METHODS: The TES was prepared by spray-coating the 2.5 to 3.0 mm x 15 to 20 mm bare metal stents with Tetramethylpyrazine monomer, methyl methacrylate copolymer, and polyglycolic acid. Stent overdilation injury (stent:artery = 1.1 to 1.2:1.0) was made with control bare stents (n = 5) and TES (n = 5) in porcine coronary arteries. Follow-up quantitative coronary angiography (QCA) and histopathological assessments of stented coronary arteries were performed 4 weeks after stenting. RESULTS: Quantitative coronary angiography showed the late lumen loss (0.28 +/- 0.08 mm versus 1.70 +/- 0.52 mm; P = 0.004) and percentage diameter stenosis (10.0 +/- 2.1% versus 60.2 +/- 23.5%; P = 0.01) were significantly lower in the TES group than that in the control group. Histopathological assessments of stented coronary arteries showed that the injury score and the in-stent area were similar between the groups (P > 0.05), whereas the lumen area was significantly larger (4.34 +/- 0.93 mm2 versus 1.29 +/- 1.02 mm2; P = 0.011) in the TES group than that in the control group. The number of proliferating cell nuclear antigen-positive cells was also significantly decreased in the TES group compared with the control group (14.7 +/- 2.5% versus 23.6 +/- 3.2%; P = 0.008). Moreover, apoptosis was enhanced in TES group while regrowth of endothelium was similar between the groups. CONCLUSIONS: TES inhibited the neointimal hyperplasia and reduced in-stent restenosis in a porcine coronary artery restenosis model. PMID- 17703138 TI - Long-term administration of 3-deazaadenosine does not alter progression of advanced atherosclerotic lesions in apolipoprotein E-deficient mice. AB - Inflammatory mechanisms are involved in initiation and progression of atherosclerotic lesions. Previous studies demonstrated antiinflammatory and consecutive antiatherosclerotic effects of the adenosine analogue 3 Deazaadenosine (c(3) Ado) on early lesion development. The present study evaluated the effect of long-term administration of c(3) Ado in a mouse model of advanced atherosclerosis. Apolipoprotein E-deficient mice (age, 35 weeks; n = 31) with already established advanced atherosclerotic lesions were fed either a diet supplemented with c Ado or a regular chow diet for 21 weeks. Treatment resulted in a significant reduction of serum homocysteine levels. Lesion size and lesion morphology, such as frequency of intraplaque hemorrhage, size of necrotic cores, thickness of fibrous caps, and macrophage content within the plaque, were not different between the groups. Lesion calcification, expression of alpha-actin, and intercellular adhesion molecule-1, but not vascular cell adhesion molecule-1, were inhibited by treatment with c(3) Ado. We could not detect any effect on serum concentrations of interleukin-10 (IL-10) and interleukin-1beta (IL-1beta) or on soluble adhesion molecules intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Electromobility shift assays of protein extracts isolated from aortas did not demonstrate different binding activities of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) after treatment with c Ado. Long-term treatment with the adenosine analogue 3 Deazaadenosine did not show significant effects on progression and stability of advanced atherosclerotic lesions in older apolipoprotein E-deficient mice. A potential antiatherosclerotic effect of c(3)Ado (eg, mediated through inhibition of adhesion molecules) might therefore be limited to prevention of early lesion formation and does not seem to play a relevant role in modifying advanced atherosclerotic disease. PMID- 17703139 TI - Pharmacokinetic and pharmacodynamic interaction between tolvaptan, a non-peptide AVP antagonist, and furosemide or hydrochlorothiazide. AB - The pharmacokinetic and pharmacodynamic interactions between tolvaptan and furosemide or hydrochlorothiazide (HCTZ) were determined in a single-center, randomized, open-label, parallel-arm, 3-period crossover study conducted in healthy white (Caucasian) men. A total of 12 subjects were enrolled in the study, with 6 subjects assigned to each of two treatment arms. Subjects in Arm 1 received 30 mg of tolvaptan, 80 mg of furosemide, and 30 mg of tolvaptan + 80 mg of furosemide. Subjects in Arm 2 received 30 mg of tolvaptan, 100 mg of HCTZ, and 30 mg pf tolvaptan + 100 mg of HCTZ. Doses were separated by a 48-hour washout. Blood and urine samples were collected at scheduled timepoints during the 24 hours after administration of study drug for the determination of pharmacokinetic and pharmacodynamic parameters. No clinically significant changes were noted in the pharmacokinetic profiles of tolvaptan and furosemide or tolvaptan and HCTZ when coadministered. Free water clearance, 24-hour urine volume, plasma sodium and argentine vasopressin concentrations, and plasma osmolality were higher, and urine osmolality was lower when tolvaptan was administered either alone or in combination with furosemide or HCTZ, compared with furosemide or HCTZ administered alone. At 24 hours postdose, plasma renin activity was increased after furosemide or HCTZ administered alone or with tolvaptan, but it was unchanged after tolvaptan alone. Tolvaptan did not significantly affect the natriuretic activity of furosemide or HCTZ. Furosemide and HCTZ did not significantly affect the aquaretic activity of tolvaptan. Tolvaptan administered alone or in combination with furosemide or HCTZ was safe and well tolerated at the given doses. PMID- 17703143 TI - Drugs for sexually transmitted infections. PMID- 17703144 TI - Drugs for allergic disorders. PMID- 17703145 TI - Clinical picture of craniopharyngioma in childhood. AB - This cross sectional and observational study was carried out among the admitted patients of the department of Neurosurgery, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka during the period of 1st March 2004 to 31st March 2005. Among the all intracranial tumours, 2.5-04% are Craniopharyngiomas. Although there is a bi-modal age distribution-1st peak at 5-10 years and the 2nd peak at 55-65 years, the common patients are children (9% of childhood tumour). A typical child with Craniopharyngioma (CP) is short, obese and half blind and has a poor school record. The study has been undertaken to know in details, how child patients with Craniopharyngiomas in Bangladesh present their disease at the hospital. Earlier diagnosis and management may improve the quality of life and longivity. The average age of the patients was 13 years ranging from 07 to 17 years. The vast majority patients were admitted with visual problems as their presenting complaints. Among the patients 33% had total blindness of which 03 had primary optic atrophy and 1 has secondary optic atrophy. Among the remaining 08 patients, 75% were found to have field defect. All patients showed fundal changes ranging from early papilloedema to optic atrophy. We found major endocrinological deficiency in child patients with Craniopharyngioma in 17% cases. Raised Prolactin level may not be significant, because it could be due to stalk effect. Although 25% patients were of short stature, their hormonal profile was within normal range according to age and sex. PMID- 17703146 TI - Changes of placental diameter thickness and cotyledon in eclampsia. AB - The study was done to see the changes of placental diameter, thickness and number of cotyledons in eclapmsia. A total 45 placenta, 25 from eclamptic mother and 20 from normal pregnant mother were collected from Gynaecology and Obstetric department of Mymensingh Medical College and Hospital (MMCH). Study was done in Anatomy department of Mymensingh Medical College (MMC). Macroscopic study of the formol saline fixed placentas revealed that, compared to the controls there was trend of less placental diameter in eclamptic group(p=0.0004). Cotyledon number was found to be significantly less in eclampsia (p=0.0001). However there was no significant difference in placental thickness in eclamptic placenta than that of normal group. Statistical significance of difference between two groups was calculated by using Students "t" test. A difference between the two groups was considered to be significant when p<0.005. The morphological changes in placenta are possibly due to reduced uteroplacental blood flow in eclampsia. PMID- 17703147 TI - Persistence of low serum iron and high total iron binding capacity in pregnant women. AB - A cross sectional descriptive type of study was done in 98 women of reproductive age. Among them 25 were in control group of non pregnant women and 73 were pregnant women of 1st, 2nd and 3rd trimester of pregnancy with and without iron supplementation. The period of study was July 2004 to June 2005. The main objective of our study was to compare serum iron and total iron binding capacity in pregnant and non pregnant women. In present study serum iron was significantly increased in 2nd and 3rd trimester of pregnancy that was supplemented with iron when compared with the same category of women who were not supplemented with iron. On the other hand serum total iron binding capacity (TIBC) was significantly increased in 3rd trimester of pregnancy that was not supplemented with iron when compared with the same category of women who were supplemented with iron. It is evident that the significantly low serum iron and high TIBC in pregnant women is due in part to dietary iron deficiency. Therefore, iron therapy in pregnancy is helpful to maintain the serum iron and TIBC nearer to that of non pregnant normal women. PMID- 17703148 TI - Morphological study of parathyroid in relation to thyroid gland of Bangladeshi people. AB - The morphological study was done to see the number and location of parathyroid glands in relation to thyroid gland of Bangladeshi people to increase the knowledge regarding variational anatomy in our population. Sixty post mortem tissue block containing thyroid and parathyroids along with surrounding structures were collected from 48 male and 12 female cadavers of different age groups and fixed in 10% formol saline solution. Gross and fine dissections were carried out to study the topographic relationship and number of parathyroid glands in relation to thyroid gland. In the present study, findings were compared with the findings of Western and Bangladeshi researchers. In the present study, the so-called typical number of parathyroid glands that is 2 pairs per person (in relation to thyroid gland) was externally visible only in fifty percent (50%) of cases. According to this study, middle third of posterior border of thyroid gland lodged most of the glands (60-65%). PMID- 17703149 TI - Hypoglycemic effect of Catharanthus roseus in normal and streptozotocin-induced diabetic rats. AB - The effects of crude juice (at 0.5 and 1 ml/kg b.w.) and aqueous extract (at 0.30 and 0.45 gm/kg b.w.) of leaves of Catharanthus roseus on serum glucose level in streptozotocin induced diabetic rats were examined at 8 hours, 12 hours and 24 hours following single oral administration. The administration of crude juice at 1 ml/kg b.w. continued for another 9 doses (total 10 single morning doses given) and its effect was examined on the 4th and 11th day. The rats were made diabetic by single intraperitoneal injection of streptozotocin at 45 mg/kg b.w. Glibenclamide was used in the study for comparison. The crude leaf juice at 0.5 and 1 ml/kg b.w. reduced the serum glucose level in streptozotocin induced diabetic rats throughout the 24-hour period significantly (P varies between 0.05 and 0.001 at different times). The aqueous extract at 0.30 and 0.45 gm/kg reduced the serum glucose level in streptozotocin diabetic rats at 8 and 12 hour significantly (P varies between 0.05 to 0.01 at different times) but not at the 24 hour. Glibenclamide, at 500 mug/kg, also reduced the serum glucose level in streptozotocin induced diabetic rats throughout the 24-hour period (P<0.001). The crude leaf juice at 1 ml/kg also significantly reduced the serum glucose level in the streptozotocin induced diabetic rats on the 4th and 11th day (P<0.001 on both occasions). The effect of crude leaf juice at 1 ml/kg b.w administered daily orally over a 10 day period was also examined on a group of normal rats at different times. The study showed significant reduction at 8 hr (P<0.05), 12 hr, 24 hr and on the 4th day (P<0.01 on these 3 occasions) and also on the 11th day (P<0.001). PMID- 17703150 TI - Efficacy of azithromycin in the treatment of childhood typhoid Fever. AB - An intervention study was carried out in Paediatric wards for a period of one year from January 2003 to December 2003 to determine the efficacy and safety of azithromycin in the treatment of uncomplicated childhood typhoid fever. A total of 50 cases were enrolled in the study. The inclusion criteria of the cases were: documented fever for more than 7 days plus two or more of the following clinical features: toxic appearance, abdominal tenderness, hepatomegaly, splenomegaly, diarrhoea, constipation and coated tongue plus positive Widal test and/or blood culture positivity. Patients who had complication like gastrointestinal tract (GIT) haemorrhage; intestinal perforation and/or shock were excluded from the study. Data were collected in a structured questionnaire. Azithromycin was given at a dose of 10mg/kg /day for a period of 07 days. The time to defervescence was 3.82+/-1.49 days. The minimum defervescence time was 02 days and maximum was 07 days. Clinical cure rate was 94%. No serious adverse effect was noted related to azithromycin therapy except nausea, vomiting, and jaundice. Prior treatment with antibiotics did not affect defervescence time (P>0.05). Pre-treatment febrile period has got positive and linear correlation with clinical response (r = +0.593). It was found that once daily administration of oral azithromycin for seven days in the treatment of uncomplicated typhoid fever was effective and reasonably safe. PMID- 17703151 TI - Comparison of efficacy between Tamsulosin and Finasteride on symptomatic Benign Prostatic Hyperplasia. AB - This prospective study was done to compare the efficacy of Tamsulosin and Finasteride for the medical treatment of symptomatic Benign Prostatic Hyperplasia (BPH) at the surgery and urology outpatient department of Mymensingh Medical College Hospital during the period from January 2003 to December 2004. Closely matched 70 patients in the age range of 50-80 years presented with lower urinary tract symptoms and clinically diagnosed as BPH were selected in the present study. Among them, 36 patients (Group I) and 34 patients (Group II) were treated with Tamsulosin (0.4 mg once daily) and Finasteride (5 mg once daily) for a duration of 06 months respectively. The efficacy of two drugs was compared on the basis of IPSS and Qmax. The base-line parameters of both groups were statistically insignificant. A significant improvement of IPSS and Qmax was found after 06 months of treatment in both groups (P<0.001). A significant improvement of IPSS Qmax was found in both groups (p<0.001) during follow-up at 1st, 2nd, 4th and 6th month. It was also observed that Tamsulosin improved the IPSS and Qmax more quickly than Finasteride. PMID- 17703152 TI - Diagnostic efficacy of Aldehyde test in late cases of Kala-azar. AB - This case control study was carried out in the Paediatric wards of Mymensingh Medical College Hospital for a period of one year from April 2002 to March 2003 to determine the sensitivity, specificity and predictive values of Aldehyde test in the diagnosis of Kala-azar. A total of seventy five febrile cases of Kala-azar from Paediatric wards were enrolled in the study and Seventy five controls having splenomegaly with or without fever were also included from the same source. Aldehyde test was done in both cases and controls. Diagnosis of Kala-azar was confirmed by demonstration of Leish-man-Don-o-van body (LD) in bone marrow or splenic aspirates. Out of 75 parasitologically proven cases of Kala-azar, AT was positive in 56 cases. The sensitivity irrespective of duration of illness was 74.6%. We found sensitivity of AT increases with the duration of illness where AT was sensitive in 34.7% cases having fever for less than 3 months, 90.90% with fever for 3 months to less than 6 months and 100% with fever for 6 months or more in duration. Specificity of AT was calculated as 96% with positive and negative predictive values of 94.9% and 79.1% respectively. So AT is a very sensitive and specific test with high positive and negative predictive values. Considering the cost, availability, simplicity, sensitivity, and specificity we would recommend the Aldehyde test as an important diagnostic tool for field diagnosis of Kala azar especially after three months of febrile illness. PMID- 17703153 TI - Histopathology based cancer pattern in Mymensingh region of Bangladesh. AB - To our knowledge, population-based published data regarding the cancer profile in Mymensingh region of Bangladesh is not available. This study was designed to provide information regarding the frequencies of cancers through sample data retrieved from histopathology (surgical pathology) laboratory based cancer registry from two laboratories in Mymensingh. All malignant tumours recorded in 2006 in the register of pathology laboratory of Mymensingh Medical College and one private pathology laboratory in Mymensingh town were taken as sample data for analysis in terms of age groups, gender and types of cancer with relation to site. A total of 470 cases diagnosed as cancer were found in the register, of which males were 249(53%) and females were 221(47%) with male to female ratio 1.2: 1. Highest numbers of cases were found in the age group of 51-60 years. In male group frequency of malignant tumours was found in the age group of 51-60 years and the female group it is 41-50 years. Top five sites of cancer, irrespective of sex, were of stomach, uterine cervix, colo-rectum, lymph nodes and breast. According to decreasing order of frequency, in the males, the top five cancers were of stomach, lymph node, oesophagus, urinary bladder and colo rectum. In the female groups these were of uterine cervix, breast, ovary, colo rectum and stomach. Cancer cases in the age group of 51-60 years were significantly higher in males than in females (p<0.001). The commonest cancers in males and females were of stomach and cervix, respectively. As the analysis was based only on surgical specimens, the exact incidence of cancer of lung and liver could not be evaluated. Because, majorities of the malignancies in these organs are diagnosed mainly on cytological examination. Population-based cancer registry should be maintained to explore the exact patterns of cancer in the study region. Cervical cancer screening program and eradication of H. pylori infection program may be helpful for the reduction of incidence of cancer in this region. PMID- 17703154 TI - Evaluation of 35 cases of abdominal lymphoma. AB - Abdominal lymphoma is not a common clinical entity in Bangladesh. Still, in our Clinical practice we come across such problem occasionally. Because of their rarity and variable unusual behaviour, such case may present a major challenge even to experienced clinicians. Thirty five cases are reported in this series of which 29 were male and 6 were female (M:F = 4.8:1). Cases were collected from BSMMU, DMCH, MMCH, different clinics of Dhaka. Mean age was 36.7 years. Out of 35 cases 20(57.15%) had primary abdominal lymphoma, 08(22.85%) had secondary lymphomatous involvement, 07(20%) were cases of nodal lymphomas with or without superficial lymphnode involvement. All patients presented with gastrointestinal symptoms with or without an abdominal lump. Duration of symptoms of these patients ranged from 03 months to 02 years. In only 02 patients a clinical diagnosis of lymphoma was made pre-operatively. Various operative procedures were performed according to circumstances. Most common site of involvement was small intestine followed by large intestine, mesenteric lymphnodes, rectum and stomach. Among 35 cases, 28(80%) were Non-Hodgkin's, lymphoma 05(14.28%) were Hodgkin's and lymphoma 2(5.71%) were unclassified. All of the patients were referred to oncologist. Some of the patients received chemotherapy. The patients were followed up for a variable period. This study showed that abdominal lymphoma has a good prognosis provided diagnosed and treated early. PMID- 17703155 TI - The relationship of placental weight with birth weight. AB - To assess the relationship between placental weight and birth weight, two hundred forty six pregnant mothers, who were otherwise healthy, were prospectively followed in a city hospital during antenatal period until delivery and immediate post-partum period. Height of mothers was measured initially and weight measured at each visit during the antenatal check-up. Placental weight and birth weight of babies were measured by one of the authors immediately after delivery by a weighing scale. Eighty one percent of the mothers were between the age group of 20-29 years. The BMI of 92% mothers was 18.5 and above. Most of the mothers came both with primigravida (42%) or second gravida (33%) and in 25% cases 3rd or onwards. In 49% cases the placental weight was between 401-500 gm, in 30% cases >500 gm and in 21% cases 400 gm or less. There was delivery of appropriate-birth weight babies in 85% cases and low-birth-weight babies in 15% cases. It was observed that a very strong correlation existed between placental weight and birth weight (r = 0.391, p<0.001). Even this correlation was stronger in small for gestational age babies. However, there was no correlation between placental weight and APGAR score at one minute. It is concluded that increment of birth weight occurs with increase of placental weight. If placental weight can be measured by ultrasonography in second or early third trimester of pregnancy birth weight is possible to be assessed and appropriate measure can be taken to increase the birth weight. PMID- 17703156 TI - Doppler evaluation of left to right shunt (Qp/Qs) in patients with isolated ventricular septal defect (Vsd). AB - A prospective observational study was carried out in the department of cardiology, Bangabandhu Sheikh Mujib Medical University (BSMMU) in collaboration with the department of cardiology, Combined Military Hospital (CMH), Dhaka from January 2000 to October 2001. All the patients were clinically evaluated. ECG & Doppler echocardiography were done.All the patients underwent cardiac catheterization. Complex congenital heart disease & cyanotic heart disease patients were excluded from the study. Doppler estimated pulmonary to systemic blood flow ratio (Qp/Qs) was done by conventional (velocity time integral method) method. In cardiac catheterization Qp/Qs ratio derived from oximetric data which has become a well established part of clinical practice. Doppler derived Qp/Qs were compared with catheter derived Qp/Qs. 30 patients with VSD were included. In those patients Doppler derived Qp/Qs ranged from maximum 4.5 to minimum 1.10. Mean (+/-SD) was 1.88+/-0.86 In patients with VSD mean (+/-SD) Qp/Qs at catheterization was 1.80+/-0.80. Qp/Qs ranged from maximum 4.10 to minimum 1.1 In those patients the correlation coefficient for invasively determined Qp/Qs versus Doppler estimated Qp/Qs was .92 (standard error of estimate [SEE] = 0.19) & the line of regression passed close to the origin. The results of this study demonstrate that The Doppler technique allows the noninvasive evaluation of Qp/Qs with a high degree of accuracy & allows determination of the stage of VSD by the consecutive assessment of shunt magnititude. PMID- 17703157 TI - Personal series with clinical review of fracture penis. AB - Penile fracture is an uncommon Urological emergency. In flaccid state it allows significant degree of deformation without any injury to the vital structures but in erected state it is vulnerable to blunt injury. The tumescent corpora cavernosa may have got injured due to nonphysiological bending of penile shaft. The true incidence of penile fracture is not known even in western countries. It is either under reported or hidden for potential social embracement. We have reviewed all of our cases of penile fracture and has been conducted a retrospective study in the Department of Urology, Bangladesh Medical College, Dhaka. The study period was from October 2001 to January 2006. The sample size was 23. All patients have got classical history of penile fracture. The time between the onset of symptom and seeking of medical care ranges from 02 hours to 07 days. The diagnosis was made on the basis of history and clinical examination only. All the patients were underwent surgery. The potency was well preserved in all of our patients. The local tissue healing process is better among the patients, reported earlier. The overall result is excellent. PMID- 17703158 TI - Placental changes in eclampsia and fetal outcome. AB - Eclampsia-a common pregnancy induced disorder that poses a great threat to the fetus secondary to the placental changes. Since placenta is mostly vascular organ, the present comparative study was designed to examine microscopic vascular changes as well as to observe their impact on the macroscopic dimensions of the placenta and on the fetus in eclamptic and normal pregnant women. The study was carried out in the department of Anatomy, Bangabandu Sheik Mujib Medical University (BSMMU) during the period of October 2000 to August 2001. Forty human placentas were collected just after Caesarian section at 37 to 40 weeks of gestation: 20 from mothers with eclampsia and 20 from non-diabetic, non eclamptic, normotensive control mothers. Compared to the Control group the value regarding weight, volume, diameter and thickness were significantly smaller values in the Eclampsia group (p<0.001). Microscopically there was a general tendency of increased intimal thickness due to atherosclerotic type of changes in eclampsia in 1st, 2nd and last branching sites of chorionic arteries. Statistical significance difference was observed more in case of the 1st and 2nd branching site (p<0.001). The positive correlation between placental and neonatal weight reached a significant level. Although not all the significant findings support each other. Considering the tendencies of increased intimal thickness and suggestions from other studies, it seems that in the eclamptic placentas, successful compensatory effort against chorionic arterial atherosclerosis fails to protect the fetuses and placentas face more severe forms of atherosclerosis, and consequently gave rise to smaller babies. PMID- 17703159 TI - Evaluation of stentangioplasty in university cardiac center. AB - In this ongoing prospective study conducted in University Cardiac Center, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, from July 2004 to January 2006. Fifty (50) patients (mean age 56+/-7.2 years) underwent stentangioplasty were evaluated. The study group of 50 patients consisted of 42 (84%) men and 08 (16%) women. The aim of this study was to evaluate in-hospital success, failure and complications during the procedures. About risk factors 19(38%) had hypertension, 13(26%) were smoker, 11(22%) suffered from diabetes mellitus, 05(10%) had family history of ischaemic heart disease. Average left ventricular ejection fraction was 54+/-7. Target vessel percutaneous coronary angioplasty (PTCA) were done in 61 vessel, intracoronary stent implanted in 58 vessels, direct stenting were done in 35 cases, failed PTCA were in 03(6%) cases and two had dissection. The native vessels had a mean reference diameter of 2.91 mm and their luminal diameter increased significantly after percutaneous coronary intervention (PCI). All the patients were discharged by one to three days of the procedure with improvement of their clinical condition. In conclusion, intracoronary stent deployment in coronary artery stenosis following balloon angioplasty is a valid and beneficial strategy with good in-hospital results. PMID- 17703160 TI - Seropositivity and pattern of dengue infection in Dhaka city. AB - Bangladesh is experiencing resurgence of' dengue endemic since 2000. In an attempt to see the pattern of' dengue infection we analyzed retrospectively results of 225 blood samples from patients having fever and clinically suspected to have been suffering from dengue fever who were tested for dengue IgM and IgG in Health Care Development Project (HCDP), Dhaka, an enterprise of Diabetic Association of Bangladesh (DAB) one of the largest private health care facility provider in Bangladesh. Out of 225 samples tested, a total of 156(69.33%) cases were serologically positive for dengue and 69(30.67%) were negative. Of the positive cases, 70(44.87%) were positive for Dengue IgM and 86(55.13%) were positive for Dengue IgG. which showed statistical difference between male and female (p<0.05). Both IgM and IgG, were positive in 23(14, 74%) cases. The mean age +/-SD of affected is 36.86+/-17.60 years and the maximum number of positive cases 114(73.08%) diagnosed were in the months between July-December. It is evident from the present study that dengue is endemic in Dhaka city particularly during monsoon and rainy season. Secondary dengue is more common than primary dengue and both preventive and curative measures are needed to combat this menace. PMID- 17703161 TI - Results of emergency appendectomy for appendicular mass. AB - Emergency appendectomy was done on 1142 patients during the period of July 1990 to January 2003 to evaluate the results. Of which 656(57.44%) were male and 496(42.56%) were female. The mean age was 22.21+/-3.93 years (04-85 years). The duration of pain before admission was 3.05+/-0.94 days (01-17 days) and 708(62%) patients presented with palpable mass; ultrasonogram revealed additional lump in 114(9.98%) patients, rest of the lump (28.02%) was detected during operation. 342(30%) patients had appendix abscess and 228(19.96%) had loculated collection. Eight patients had tuberculosis and four had carcinoma in addition. All had appendicitis except two of which one patient had carcinoid tumor and one had enteric fever perforation. Operative time ranged from 15-85 minutes (29.38+/-3.19 minutes). The average hospital stay was 4.22+/-0.82 days (03-17 days). There was no failure, faecal fistula or death. The overall wound related complication was 22.86% of which 14.62% was very minor and overall intra abdominal complication was 4.12%. Persistent wound pain was in 43(3.87%) and hypertrophied scar was found in 05 (0.45%) patients. 05(0.45%) patients needed exploration for persistent sinus one of which was tuberculosis and remaining was due to suture material. Remote complications like RTI, UTI, and DVT was found in 04(0.35%) patients. There was no death, no faecal fistula and no failure. It seems that emergency appendectomy could safely be done in appendix mass without any increased risk of mortality and morbidity. PMID- 17703162 TI - Perosteal osteosarcoma of clavicle-treated by limb salvaging surgery (total cleidectomy). AB - Osteosarcoma of clavicle is extremely rare. Improved survival in patients with osteosarcomas has been associated with recent advances in imaging techniques, histopathological methods, surgery and chemotherapy. In most cases the diagnosis can be made with confidence on the x-ray appearance. Other imaging studies like- radioisotope scans may show up-skip lesions, computed tomography (CT) and magnetic resonance imaging (MRI) show the extend of the tumour. Incisional biopsy or excisional biopsy is carried out after careful clinical study and proper investigations. A 30 years old cultivator with a late case of primary osteosarcoma of clavicle was treated with pre-operative and post-operative chemotherapy and was managed with surgical excision of tumor with limb sparing. The patient was clinically disease free for about 08 (eight) months. Then the patient developed recurrences and died 11 (eleven) months after operation. PMID- 17703163 TI - External carotid ligation in extensive haemangioma of tongue & lip. AB - Two patients were admitted in the surgical unit of Mymensingh Medical college Hospital on September 2005 & April 2006. The first case was a lady of 18 years presented with sudden huge enlargement of tongue & lower lip for 07 days resulting difficulty in deglutition & respiration. Since childhood she noticed multiple elevated bluish spots over the tongue, cheek & lips. The second case was a young man of 20 years presented with multiple diffuse swelling of lips, left side of face, cheek, lower eyelid since birth, which was gradually increasing in size. Colour Doppler evaluation of the lesions in both the cases revealed features suggestive of haemangioma. Bilateral external carotid artery ligation by skin crease incision at the level of upper border of thyroid cartilage was done in both the cases. In first case, tongue size reduced back to oral cavity in post operative period. After 04 weeks of operation tongue size became almost normal with only multiple bluish residual swelling. In second case, the swelling size gradually reduced in post operative period. Both the patients are under regular follow up. PMID- 17703164 TI - Herpes zoster ophthalmicus in an otherwise healthy 7 years child. AB - A 07 years otherwise healthy child, non vaccinated for chickenpox and with a history of chickenpox infection at 02 years of age presented with red colored lesions in right upper lid, right side of forehead, vertex and right side of nose and defective vision in right eye in Mymensingh Medical College Hospital, 20 days after the appearance of blister in the same region. On examination granulation tissue was present on the same area. There was no hair and skin over that area. Lesion was strictly limited to right side of midline. Eyelashes of right upper lid were absent and there was defective closure of eyelids. Best corrected visual acuity of right eye was 3/60 and of left eye was 6/6. There was ciliary congestion of right eye with haziness of cornea at interpalpebral region of right eye. Corneal sensitivity was reduced and there was uniform fluorescein staining at central part of cornea. Mild flare and cells were present in anterior chamber. Fundus examination revealed no abnormality. He was treated with systemic acyclovir, antibiotics, topical acyclovir, antibiotic and atropine. Corneal ulcer and skin lesions were healed, but the patient developed cicatricial ectropion of right upper lid and best corrected visual acuity of right eye was reduced to 6/60 due to corneal opacity. So early diagnosis and treatment of herpes zoster ophthalmicus is mandatory to prevent sight threatening complications. PMID- 17703165 TI - Temporomandibular joint reconstruction using costochondral graft. AB - Reconstruction of the temporomandibular joint (TMJ) after release of ankylosis by condylectomy is a challenging problem in maxillo-facial surgery. A successful reconstruction implies correct restoration of form and, in children, future symmetrical growth. Bilateral bony ankylosis of the temporomandibular joint in a female patient was diagnosed in the Oral and Maxillofacial Surgery Department of Bangabandhu Sheik Mujib Medical University (BSMMU) at the time when she had severe facial deformity with typical bird face appearance. The condition was treated with costochondral graft following a bilateral condylectomy. At the time of treatment, there was an expectation that further orthognathic surgery or bone grafting would be required to correct the skeletal deformity. However, with the release of the ankylosis and growth of the costochondral graft, a good functional and esthetic result can be achieved without further surgery. It is important that dentists be aware of the clinical signs and symptoms of TMJ ankylosis, to allow early diagnosis and treatment. PMID- 17703166 TI - Hepatitis B viral infection with nephrotic syndrome treated with lamivudine. AB - A 04 years old boy with 02 months history of generalized oedema and scanty micturition was diagnosed as nephrotic syndrome with hepatitis B viral infection. He had evidence of active viral replication. After 01 month treatment with oral lamivudine, his urine became protein free and after 04 months, he had seroconversion from HBeAg+ve to HBeAg-ve. Lamivudine was continued for 01 year. He had no relapse after discontinuation of therapy and remained well after 36 months of completion of therapy. He had no evidence of active viral replication during this period, however HBsAg remained positive indication carrier state. As most children with HBV associated nephropathy have no evidence of chronic hepatitis, all such children must undergo HBV screening and for chronic liver disease if HBV screening is positive. As such children do not respond to prednisolone or other immunosuppresive therapy which might harm them, antiviral therapy should be considered. Lamivudine is a suitable alternative to IFN alpha owing to its low cost, ease of administration and fewer side effects. PMID- 17703167 TI - Duplex evidence of recanalization of deep venous thrombosis with conservative management. AB - A female patient was admitted in vascular surgery department of Bangabandhu Sheikh Mujib Medical University (BSMMU) after confirmation of diagnosis with duplex ultrasonographic examination. The patient was treated with intra-venous heparin for 10 (ten) days and elevation of the affected limb with application of crepe bandage. Later on the patient was discharged with oral anti-coagulant e.g. Tab. Warfarin for 06 (six) months along with application of crepe bandage on the affected limb. During the patient received oral anti-coagulant therapy the patient was asked to do Prothrombin time every week for adjustment of dose of oral anti-coagulant therapy. After 01 (one) month duplex ultrasonographic examination of deep veins of the affected limb was performed, which showed good recanalization of deep and superficial veins of right lower limb. It can be stated that, serious complications like pulmonary embolism can be avoided with effective and timely treatment of deep venous thrombosis with complete recanalization. PMID- 17703168 TI - Evaluation of inhaled insulin therapy for diabetes mellitus. AB - Inhaled insulin (INH) is a novel, non-injectable alternative route of delivery of insulin for the management of diabetes mellitus (DM). It is an important breakthrough in the history of diabetes mellitus and an attractive means of treatment for many patients. Though insulin is one of the fundamental tools for management of DM, many patients and physicians are reluctant to initiate and intensify the insulin regime in appropriate time due to various reasons called psychological insulin resistance (PIR). Exubera, one of the inhaled insulin devices has been approved by FDA and European Union in early 2006. It delivers short acting human insulin powder in aerosol form. There are lot of ongoing studies regarding the efficacy and safety of INH. Inhaled insulin showed similar pharmacokinetic and glucodynamic behavior like that of subcutaneously administered rapid acting human insulin analogues like aspart, lispro and glulisine. It consistently improves glycemic control when used in combination with longer acting subcutaneous insulin regime in patient with type 1 and type 2 DM. It may be used to replace or supplement oral antidiabetic therapy in type 2 diabetic patients. Available study reports showed its tolerability and safety with an overall similar risk of hypoglycemia to that of subcutaneous insulin. So far, no significant clinically meaningful pulmonary functional changes have been noted with the use of INH. Various reports showed high level of patients satisfaction and an acceptable new modality of non-invasive treatment. However, long term follow up studies are needed to evaluate the safety profiles of inhaled insulin. PMID- 17703169 TI - Smoking cessation-dream or reality! PMID- 17703170 TI - Progress toward global eradication of dracunculiasis, January 2005-May 2007. AB - The World Health Assembly first adopted a resolution calling for the eradication of dracunculiasis (Guinea worm disease) in 1986, when an estimated 3.5 million cases were reported in 20 countries, and 120 million persons were at risk for the disease. This report describes the continued progress of the dracunculiasis eradication program worldwide during July 2005-May 2007. As of May 2007, dracunculiasis was still endemic in nine of the 20 countries cited in 1986; in 2006, approximately 98% of dracunculiasis cases worldwide were reported from Ghana and Sudan, and five other countries reported fewer than 30 cases each. The number of dracunculiasis cases increased from 10,674 in 2005 to 25,217 cases in 2006, with nearly all of the increase reported in Sudan, before decreasing from 9,510 during January-May 2006 to 4,460 cases during January-May 2007. Continued intensification of interventions against transmission of dracunculiasis will be necessary to eradicate dracunculiasis in the nine countries where the disease remains endemic. PMID- 17703171 TI - Scombroid fish poisoning associated with tuna steaks--Louisiana and Tennessee, 2006. AB - Scombroid fish poisoning is an acute illness that occurs after eating fish containing high levels of histamine or other biogenic amines. Symptoms typically include facial flushing, sweating, rash, a burning or peppery taste in the mouth, diarrhea, and abdominal cramps and usually resolve within several hours without medical intervention. More severe symptoms (e.g., respiratory distress, swelling of the tongue and throat, and blurred vision) can occur and require medical treatment with antihistamines. In late 2006, two outbreaks of scombroid fish poisoning occurred, one in Louisiana and one in Tennessee. To determine the source of the outbreaks and to implement control measures, CDC and the state health departments in Louisiana and Tennessee conducted epidemiologic investigations, and the Food and Drug Administration (FDA) conducted traceback investigations of the product. This report describes the results of those investigations, which indicated that the outbreaks in Louisiana and Tennessee were associated with tuna steaks from Indonesia and Vietnam, respectively. The majority of seafood eaten in the United States is imported. FDA programs to identify and prevent seafood hazards such as scombroid fish poisoning have made substantial progress but are able to inspect only a small proportion of seafood entering the United States. The only effective method for prevention of scombroid fish poisoning is consistent temperature control of fish at /=95% vaccination coverage for the following: hepatitis B vaccine; diphtheria and tetanus toxoids and pertussis vaccine, diphtheria and tetanus toxoids and acellular pertussis vaccine, or diphtheria and tetanus toxoids vaccine (DTP/DTaP/DT); poliovirus vaccine; measles, mumps, and rubella (MMR) vaccine; and varicella vaccine. To assess progress toward national goals and determine vaccination coverage among children in kindergarten, data were analyzed from reports submitted to CDC by 49 states and the District of Columbia (DC) for the 2006-07 school year. This report summarizes findings from that analysis, which indicated that approximately 75% of states have reached the 2010 objective of at least 95% coverage for all of the vaccines recommended by the Advisory Committee on Immunization Practices (ACIP) for children in kindergarten. These results underscore the effectiveness of school-entry requirements in increasing vaccination coverage but highlight a need for more standardized vaccination reporting among states. PMID- 17703173 TI - West Nile virus update--United States, January 1--august 14, 2007. AB - This report summarizes 2007 West Nile virus (WNV) surveillance data reported to CDC through ArboNET as of 3 a.m. Mountain Daylight Time, August 14, 2007. A total of 27 states have reported 444 cases of human WNV illness to CDC. A total of 241 (54%) cases for which such data were available occurred in males; median age of patients was 48 years (range: 2-96 years). Dates of illness onset ranged from March 25 to August 5; 15 cases were fatal. PMID- 17703174 TI - CD158K/KIR3DL2 transcript detection in lesional skin of patients with erythroderma is a tool for the diagnosis of Sezary syndrome. AB - The distinction between Sezary syndrome (SS) and benign erythrodermic inflammatory diseases (EID) is difficult to make both clinically and on skin biopsies, since histomorphology can provide nonspecific results. New markers of circulating malignant Sezary cells have been recently described, especially CD158k/KIR3DL2 and T-plastin, but it has not been yet determined whether they could help in the diagnosis of erythroderma in skin samples. In this study, 13 frozen skin specimens from 10 SS patients and 26 from EID were analyzed for CD158k/KIR3DL2 expression using immunohistochemistry with AZ158 mAb, which also recognizes the monomeric CD158e/KIR3DL1 receptor. Although positive in all SS samples, immunohistochemistry appeared to not reliably discriminate between SS and EID. Therefore in all samples disclosing a significant staining with AZ158 mAb, CD158k/KIR3DL2, CD158e/KIR3DL1 and T-plastin mRNA expression were analyzed on the same skin specimen using conventional and/or quantitative real-time reverse transcription (RT)-PCR. Interestingly, only CD158k/KIR3DL2 transcripts were found to be significantly overexpressed in skin biopsies from patients with SS (P<0.0001), including when normalization to CD3 expression was achieved (P=0.0003). In light of these findings, CD158k/KIR3DL2 transcripts appear to be a unique molecular marker of SS in skin samples, allowing differential diagnosis with benign EID in routine practice. PMID- 17703175 TI - Gadd45a activation protects melanoma cells from ultraviolet B-induced apoptosis. AB - Epidemiological and biological studies indicate that solar UVB radiation is involved in cutaneous malignant melanoma etiology. Indeed, melanocytes are very frequently exposed to solar UV radiation, which induces cell damage and may promote cell transformation. We previously showed that melanocytes and melanoma cells exposed to UVB radiation activates a p53-independent pathway involving Gadd45a and, more recently, that Gadd45a plays a critical role in UVB-induced G2 cell cycle arrest of melanoma cells. In this study, we demonstrate that the inhibition of UV-induced Gadd45a overexpression by RNA interference results in a dramatic increase of cell death. We identify this cell death as apoptosis, with activation of Caspase-3 and a decrease in Bcl-x(L) expression. Furthermore, we show that inhibition of UV-induced Gadd45a overexpression also leads to increased sensitivity of melanoma cells to therapeutic agents such as DTIC and Cisplatin. We conclude that UVB-induced Gadd45a overexpression protects melanoma cells from apoptosis, both by causing a G2 cell cycle arrest and by inhibiting the mitochondrial apoptotic pathway. These observations suggest that Gadd45a inactivation could be a useful way to sensitize melanoma cells to chemotherapy. JID journal club article: For questions, answers, and open discussion about this article please go to http://network.nature.com/group/jidclub PMID- 17703176 TI - Gene expression profiling of lichen planus reflects CXCL9+-mediated inflammation and distinguishes this disease from atopic dermatitis and psoriasis. AB - Here, we present data of a gene expression profiling approach to apply the diagnostic value and pathological significance of this method in different inflammatory skin diseases, using whole skin biopsies. Initially, SAGE was performed to identify frequent tags differentially expressed in various skin diseases. On the basis of these results, a new skin pathology-oriented PIQOR microarray was designed. Lichen planus (LP) was chosen as a model disease to evaluate this system. Controls included healthy skin, atopic dermatitis (AD), and psoriasis (Pso). Gene expression analyses using the topic-defined microarray followed by unclassified clustering was able to discriminate LP from AD and Pso. Genes significantly expressed in LP included type I IFN inducible genes and a specific chemokine expression pattern. The CXCR3 ligand, CXCL9, was the most significant marker for LP. In situ hybridization and immunohistochemistry confirmed the results and revealed that keratinocytes are type I IFN producers in LP skin lesions. Our results show that gene expression profiling using a skin specific microarray is a reliable method to identify patients with LP in the chosen context and reflect recent models concerning the pathogenesis of this disease. Gene expression profiling might complement the diagnostic spectrum in dermatology and may provide new pathogenetic insights. PMID- 17703177 TI - Differential expression in lupus-associated IL-10 promoter single-nucleotide polymorphisms is mediated by poly(ADP-ribose) polymerase-1. AB - Systemic lupus erythematosus (SLE) is a complex, multifactorial autoimmune disease characterized by the dysregulation of T and B cells that leads to hyperactivity of B cells and production of autoantibodies, and involves both environmental and genetic factors. Interleukin-10 (IL-10) is a candidate susceptibility gene in SLE. In particular, three IL-10 promoter single-nucleotide polymorphisms (SNPs; -1082A/G, -819T/C and -592A/C) are strongly associated with the pathogenesis of SLE. We found that the homozygous GCC haplotype linked to greater SLE severity confers higher IL-10 gene transcriptional activity than the ATA haplotype in macrophages that encounter apoptotic cells, because of the differential DNA binding to the -592 SNP by a nuclear protein uniquely induced by apoptotic cells. We identified this protein as poly(ADP-ribose) polymerase-1, confirmed its physiological role and characterized its molecular properties in modulating IL-10 production during phagocytosis of apoptotic cells. This study unveils a novel direct link between DNA damage repair/apoptosis pathways and IL 10-mediated immune regulation. PMID- 17703178 TI - Contribution of genetic studies in rodent models of autoimmune arthritis to understanding and treatment of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic and potentially debilitating autoimmune disease. While novel therapies have emerged in recent years, disease remission is rarely achieved. RA is a complex trait, and the identifying of its susceptibility and severity genes has been anticipated to generate new targets for therapeutic intervention. However, finding those genes and understanding their function has been a challenging task. Studies in rodent intercrosses and congenics generated from inbred strains have been an important complementary strategy to identify arthritis genes, and understand how they operate to regulate disease. Furthermore, these new rodent arthritis genes will be new targets for therapeutic interventions, and will identify new candidate genes or candidate pathways for association studies in RA. In this review-opinion article I discuss RA genetics, difficulties involved in gene identification, and how rodent models can facilitate (1) the discovery of both arthritis susceptibility and severity genes, (2) studies of gene-environment interactions, (3) studies of gene-gender interactions, (4) epistasis, (5) functional characterization of the specific genes, (6) development of novel therapies and (7) how the information generated from rodent studies will be useful to understanding and potentially treating RA. PMID- 17703180 TI - Cannabis; adverse effects from an oromucosal spray. AB - BACKGROUND: An oromucosal spray has been developed from the major components of marijuana (cannabis), including tetrahydrocannabinol (THC) and cannabidiol (CBD), in alcohol with a peppermint flavouring, designed to be administered as a spray under the tongue or on the buccal mucosa to relieve pain in multiple sclerosis. Although the available evidence indicates its efficacy in this respect, some patients develop oral burning sensation, stinging or white lesions, probably burns. OBJECTIVE: To investigate the oral side-effects of oromucosal cannabis spray in multiple sclerosis (MS) patients. DESIGN: A small open observational study. SUBJECTS AND METHODS: A series of nine patients with MS who had been using a marijuana oromucosal spray for at least four weeks, were asked to attend for oral examination. Patients were asked whether they had ever experienced symptoms (dryness; bad taste; stinging) associated with use of the spray. A standard oral examination was carried out using a dental light, and the presence of any mucosal lesions recorded. Where mucosal lesions were present, patients were advised to discontinue the spray and re-attend after four weeks for re-examination. For ethical reasons, biopsies were not undertaken at the first visit. RESULTS: Of nine patients invited to participate, eight attended. All admitted to a stinging sensation on using the oromucosal cannabis spray, and four had visible oral mucosal white lesions in the floor of the mouth. CONCLUSIONS: Although the white lesions observed were almost certainly burns, resolving or improving on discontinuation of use of the medication, the high alcohol concentration of the oromucosal cannabis spray raises concern in relation to chronic oral use. PMID- 17703179 TI - Positive replication and linkage disequilibrium mapping of the chromosome 21q22.1 malaria susceptibility locus. AB - Four cytokine receptor genes are located on Chr21q22.11, encoding the alpha and beta subunits of the interferon-alpha receptor (IFNAR1 and IFNAR2), the beta subunit of the interleukin 10 receptor (IL10RB) and the second subunit of the interferon-gamma receptor (IFNGR2). We previously reported that two variants in IFNAR1 were associated with susceptibility to malaria in Gambians. We now present an extensive fine-scale mapping of the associated region utilizing 45 additional genetic markers obtained from public databases and by sequencing a 44 kb region in and around the IFNAR1 gene in 24 Gambian children (12 cases/12 controls). Within the IFNAR1 gene, a newly studied C --> G single-nucleotide polymorphism (IFNAR1 272354c-g) at position -576 relative to the transcription start was found to be more strongly associated with susceptibility to severe malaria. Association was observed in three populations: in Gambian (P=0.002), Kenyan (P=0.022) and Vietnamese (P=0.005) case-control studies. When all three studies were combined, using the Mantel-Haenszel test, the presence of IFNAR1 -576G was associated with a substantially elevated risk of severe malaria (N=2444, OR=1.38, 95% CI: 1.17 1.64; P=1.7 x 10(-4)). This study builds on previous work to further highlight the importance of the type-I interferon pathway in malaria susceptibility and illustrates the utility of typing SNPs within regions of high linkage disequilibrium in multiple populations to confirm initial positive associations. PMID- 17703181 TI - Predictors of maternal mortality and near-miss maternal morbidity. AB - OBJECTIVE: To identify risk factors for life-threatening maternal outcomes. STUDY DESIGN: Hospital charts were reviewed for cases of maternal mortality or near miss and for controls overmatched 1:3. Significant risk factors were identified through simple and best subsets multiple logistic regression. RESULT: Eight cases of mortality and 69 near-miss cases were found. Significant risk factors with their odds ratios and 95% confidence intervals are: age 35 to 39 years (2.3, 1.2 to 4.4) and >39 years (5.1, 1.8 to 14.4); African-American race (7.4, 2.5 to 22.0) and Hispanic ethnicity (4.2, 1.3 to 13.2); chronic medical condition (2.7, 1.5 to 4.8); obesity (3.0, 1.7 to 5.3); prior cesarean (5.2, 2.8 to 9.8) and gravidity (1.2, 1.1 to 1.5 per pregnancy). In multivariable logistic regression, race remained significant while controlling for other significant factors and markers of socioeconomic status. CONCLUSION: Some risk factors can be modified through medical care, education or social support systems. Racial disparity in outcome is confirmed and is unexplained by traditional risk factors. PMID- 17703182 TI - Decreased neonatal tibial bone ultrasound velocity in term infants born after breech presentation. AB - OBJECTIVE: Fetuses found to be in the breech presentation have limited motion of their lower limbs. The aim of this study was to test the hypothesis that bone speed of sound (SOS) would be lower in infants born after breech presentation than in those born after vertex presentation. STUDY DESIGN: We studied 127 singleton, appropriate for gestational age, term infants delivered by a scheduled cesarean delivery at approximately 38 weeks of gestation because of breech presentation or repeat elective cesarean section with vertex presentation. We used the Sunlight Omnisense 7000p device to measure axially transmitted SOS of the right tibia within the first 96 h of life. RESULT: Fifty-three infants studied (42%) were born by cesarean section after breech presentation compared to 74 vertex controls. Bone SOS was significantly lower in the breech presentation group, even after taking into account the effect of gender and parity (as well as gestational age at birth and birth weight). CONCLUSION: Bone SOS is lower in infants born after breech presentation than in those born after vertex presentation. We speculate that limited motion of lower limbs in fetuses found to be in the breech presentation leads to a decrease in bone mineralization and strength. PMID- 17703183 TI - Nasal continuous positive airway pressure affects pre- and postprandial intestinal blood flow velocity in preterm infants. AB - OBJECTIVE: To measure the effect of nasal continuous positive airway pressure (CPAP) on intestinal blood flow velocity responses to enteral feedings and left ventricular output (LVO). STUDY DESIGN: Eighteen infants completed the study (birth weight 1793+/-350 g, gestational age 32.1+/-1.1 weeks). On the day infants were weaned from CPAP to room air, pre- and postprandial (0, 30, 60 and 90 min after feeding) mean velocity (MV), peak systolic velocity (PSV) and end diastolic velocity (EDV) were measured for one feeding given when receiving CPAP ('on CPAP'), and for one feeding given after CPAP had been discontinued ('off CPAP'). Preprandial LVO was measured before and after CPAP discontinuation. RESULT: MV and PSV were significantly lower when infants were on CPAP (P<0.05). Maximum postprandial MV, PSV and EDV occurred at 30 min when on CPAP and at 60 min when off CPAP. Preprandial LVO was similar when infants were on and off CPAP. CONCLUSION: CPAP administration affects pre- and postprandial intestinal blood flow velocity, which may impact tolerance to enteral feedings. PMID- 17703184 TI - A randomized controlled trial of synchronized nasal intermittent positive pressure ventilation in RDS. AB - OBJECTIVE: Comparison of outcomes of infants with respiratory distress syndrome (RDS), post-surfactant, extubated to synchronized nasal intermittent positive pressure ventilation (SNIPPV) or continued on conventional ventilation (CV). STUDY DESIGN: Prospective post-surfactant randomized controlled trial of primary mode SNIPPV compared with CV in infants (born from July 2000 to March 2005) with birth weights (BW) of 600 to 1250 g. Primary mode SNIPPV was defined as its use in the acute phase of RDS, following the administration of the first dose of surfactant. RESULT: There were no significant differences in the maternal demographics, antenatal steroid use, mode of delivery, BW, gestational age, gender or Apgar at 5 min between infants continued on CV (n=21) and those extubated to primary mode SNIPPV (n=20). Significantly, more babies in the CV group had the primary outcome of bronchopulmonary dysplasia (BPD)/death, compared to the SNIPPV group (52 versus 20%, P=0.03). There was no difference in the incidence of other common neonatal morbidities. There were no differences in the Mental or Psychomotor Developmental Index scores on follow-up between the two groups. CONCLUSION: Infants of BW 600 to 1250 g with RDS receiving surfactant with early extubation to SNIPPV had a significantly lower incidence of BPD/death. Primary mode SNIPPV is a feasible method of ventilation in small premature infants. PMID- 17703185 TI - Extremely low birth weight infants are at high risk for auditory neuropathy. AB - Auditory neuropathy (AN) is a condition in which transmission of sound to the brain is abnormal. This is reflected as an electrophysiologic profile of normal otoacoustic emissions (OAE), with abnormal auditory brainstem evoked responses (ABR). Functionally speech perception is impaired and management strategies remain controversial. AN can be missed if high-risk newborns are screened for hearing loss with only OAE testing. The rate of sensorineural hearing loss (SNHL) in high-risk nursery infants is 10 times greater compared with normal term newborns. Therefore, we hypothesize that infants from the neonatal intensive care unit (NICU) are at significantly higher risk for AN than normal term infants. OBJECTIVE: The objective of this study is to establish a prevalence rate and characterize risk factors for NICU graduates who demonstrate the AN electrophysiologic profile. STUDY DESIGN: This retrospective study examined infants admitted to the NICU at Kapi'olani Medical Center for Women and Children in Honolulu, HI from 1999 through 2003. Infants were screened with automated ABR. Diagnostic testing and OAE were performed before discharge if the ABR was abnormal. Hospital courses of 24 AN, 71 SNHL and 95 gestational age (GA)-matched control infants with normal hearing were reviewed. RESULT: With a SNHL prevalence of 16.7/1000, the rate for AN was 5.6/1000 NICU infants. Compared to infants with SNHL, infants with AN were significantly younger (GA 28.3+/-4.8 AN vs 32.9+/-5.2 weeks SNHL, P<0.0001) and smaller (BW 1318+/-894 AN vs 1968+/-1006 g SNHL). Nearly two-thirds of the AN infants were ELBW and had significantly longer hospital stays compared to SNHL infants of the same birth weight group. Exposure to furosemide, aminoglycosides, vancomycin or dexamethasone was associated with increased AN but not SNHL. Peak bilirubin level correlated with SNHL but not AN. CONCLUSION: Low birth weight NICU infants are at significant risk for AN. ELBW infants are at significantly higher risk for both AN and SNHL. Infants admitted to the NICU should be routinely screened by automated ABR and if abnormal, further evaluation should be started before hospital discharge. Early identification of AN will result in better understanding of this disorder and lead to the development of appropriate intervention strategies. PMID- 17703186 TI - PAPP-A levels as an early marker of idiopathic preterm birth: a pilot study. AB - OBJECTIVE: To evaluate late PAPP-A levels as predictive of preterm birth in symptomatic women. STUDY DESIGN: Prospective cohort study of singleton gestations, 23 to 34 weeks, and symptoms of preterm labor. PAPP-A, IGF-I and IGF III analysis were performed. Primary end point was delivery < or =7 days. Accuracy and optimally predictive PAPP-A values were based on receiver operator characteristic (ROC) curves. RESULT: In all, 26 women (51%) delivered < or =7 days post-admission (Group 1); 25 women (49%) >7 days (Group 2). Group 1 mean PAPP-A=38 000 vs 55 333 for Group 2 (P<0.04). Group 1 mean gestational age at delivery=29 weeks vs 37 weeks for Group 2 (P<0.00014). PAPP-A level < or =30,000 mU l(-1) had highest specificity (88%), sensitivity (50%), and positive predictive (81%) and negative predictive (62%) values for delivery < or =7 days. ROC area under curve=0.703. CONCLUSION: PAPP-A levels < or =30,000 mU l(-1) at admission was associated with increased risk for preterm birth < or =7 days, supporting active management and therapeutic approach in these women. PMID- 17703187 TI - Safety and efficacy of high-frequency jet ventilation in neonatal transport. AB - OBJECTIVE: To evaluate the safety and efficacy of high-frequency jet ventilation for transporting critically ill hypoxic neonates to an extracorporeal membrane oxygenation (ECMO) center. STUDY DESIGN: We conducted a retrospective cohort study of 38 transported neonates. Safety was assessed by the comparison of cardiopulmonary variables before and after transport from referring hospital to our ECMO unit. Efficacy was assessed as the effect on ventilation and efficiency of pulmonary gas exchange after conversion from a conventional mechanical ventilator or a high-frequency oscillator to a high-frequency jet ventilator+/ inhaled nitric oxide. RESULT: The pre- and post transport vital signs remained stable, regardless of the type of ventilator used. Pre-transport pneumothorax was the main problem, but no transport-related deaths occurred. We found significant improvement in the ventilation of the neonates transported with a high frequency jet ventilation+/-inhaled nitric oxide that were deficient in those transported with conventional mechanical ventilation+inhaled nitric oxide (P<0.05). The improvement started before transport upon changing the mode of ventilation to a high-frequency jet ventilator. CONCLUSION: Independent of the use of inhaled nitric oxide, high frequency jet ventilation appears to provide better ventilation than conventional mechanical ventilation and is safe to transport pre ECMO neonates. PMID- 17703188 TI - Structural basis of the collagen-binding mode of discoidin domain receptor 2. AB - Discoidin domain receptor (DDR) is a cell-surface receptor tyrosine kinase activated by the binding of its discoidin (DS) domain to fibrillar collagen. Here, we have determined the NMR structure of the DS domain in DDR2 (DDR2-DS domain), and identified the binding site to fibrillar collagen by transferred cross-saturation experiments. The DDR2-DS domain structure adopts a distorted jellyroll fold, consisting of eight beta-strands. The collagen-binding site is formed at the interloop trench, consisting of charged residues surrounded by hydrophobic residues. The surface profile of the collagen-binding site suggests that the DDR2-DS domain recognizes specific sites on fibrillar collagen. This study provides a molecular basis for the collagen-binding mode of the DDR2-DS domain. PMID- 17703189 TI - The CNS glycoprotein Shadoo has PrP(C)-like protective properties and displays reduced levels in prion infections. AB - The cellular prion protein, PrP(C), is neuroprotective in a number of settings and in particular prevents cerebellar degeneration mediated by CNS-expressed Doppel or internally deleted PrP ('DeltaPrP'). This paradigm has facilitated mapping of activity determinants in PrP(C) and implicated a cryptic PrP(C)-like protein, 'pi'. Shadoo (Sho) is a hypothetical GPI-anchored protein encoded by the Sprn gene, exhibiting homology and domain organization similar to the N-terminus of PrP. Here we demonstrate Sprn expression and Sho protein in the adult CNS. Sho expression overlaps PrP(C), but is low in cerebellar granular neurons (CGNs) containing PrP(C) and high in PrP(C)-deficient dendritic processes. In Prnp(0/0) CGNs, Sho transgenes were PrP(C)-like in their ability to counteract neurotoxic effects of either Doppel or DeltaPrP. Additionally, prion-infected mice exhibit a dramatic reduction in endogenous Sho protein. Sho is a candidate for pi, and since it engenders a PrP(C)-like neuroprotective activity, compromised neuroprotective activity resulting from reduced levels may exacerbate damage in prion infections. Sho may prove useful in deciphering several unresolved facets of prion biology. PMID- 17703190 TI - Crystal structure of a Kir3.1-prokaryotic Kir channel chimera. AB - The Kir3.1 K(+) channel participates in heart rate control and neuronal excitability through G-protein and lipid signaling pathways. Expression in Escherichia coli has been achieved by replacing three fourths of the transmembrane pore with the pore of a prokaryotic Kir channel, leaving the cytoplasmic pore and membrane interfacial regions of Kir3.1 origin. Two structures were determined at 2.2 A. The selectivity filter is identical to the Streptomyces lividans K(+) channel within error of measurement (r.m.s.d.<0.2 A), suggesting that K(+) selectivity requires extreme conservation of three dimensional structure. Multiple K(+) ions reside within the pore and help to explain voltage-dependent Mg(2+) and polyamine blockade and strong rectification. Two constrictions, at the inner helix bundle and at the apex of the cytoplasmic pore, may function as gates: in one structure the apex is open and in the other, it is closed. Gating of the apex is mediated by rigid-body movements of the cytoplasmic pore subunits. Phosphatidylinositol 4,5-biphosphate-interacting residues suggest a possible mechanism by which the signaling lipid regulates the cytoplasmic pore. PMID- 17703191 TI - Essential role for TAX1BP1 in the termination of TNF-alpha-, IL-1- and LPS mediated NF-kappaB and JNK signaling. AB - The NF-kappaB transcription factor is normally transiently activated by proinflammatory cytokines and bacterial lipopolysaccharide (LPS); however, persistent NF-kappaB activation is commonly observed in inflammatory disease and malignancy. The ubiquitin editing enzyme A20 serves an essential role in the termination of TNF-alpha- and LPS-mediated NF-kappaB signaling by inactivating key signaling molecules. However, little is known about how A20 is regulated and if other molecules play a role in the termination of NF-kappaB signaling. Here we demonstrate that Tax1-binding protein 1 (TAX1BP1) is essential for the termination of NF-kappaB and JNK activation in response to TNF-alpha, IL-1 and LPS stimulation. In TAX1BP1-deficient mouse fibroblasts, TNF-alpha-, IL-1- and LPS-mediated IKK and JNK activation is elevated and persistent owing to enhanced ubiquitination of RIP1 and TRAF6. Furthermore, in the absence of TAX1BP1, A20 is impaired in RIP1 binding, deubiquitination of TRAF6 and inhibition of NF-kappaB activation. Thus, TAX1BP1 is pivotal for the termination of NF-kappaB and JNK signaling by functioning as an essential regulator of A20. PMID- 17703192 TI - TBP paralogs accommodate metazoan- and vertebrate-specific developmental gene regulation. AB - In addition to TATA-binding protein (TBP), a key factor for transcription initiation, the metazoan-specific TBP-like factor TLF/TRF2 and the vertebrate specific factor TBP2/TRF3 are known to be required for transcription of specific subsets of genes. We have combined an antisense-knockdown approach with transcriptome profiling to determine the significance and biological role of TBP independent transcription in early gastrula-stage Xenopus laevis embryos. Here, we report that, although each of the TBP family members is essential for embryonic development, relatively few genes depend on TBP in the embryo. Most of the transcripts that depend on TBP in the embryo are also expressed maternally and in adult stages, and show no functional specialization. In contrast, TLF is linked to preferential expression in embryos and shows functional specialization in catabolism. A requirement for TBP2 is linked to vertebrate-specific embryonic genes and ventral-specific expression. Therefore TBP paralogs are essential for the gene-regulatory repertoire that is directly linked to early embryogenesis. PMID- 17703193 TI - The TATA-binding protein regulates maternal mRNA degradation and differential zygotic transcription in zebrafish. AB - Early steps of embryo development are directed by maternal gene products and trace levels of zygotic gene activity in vertebrates. A major activation of zygotic transcription occurs together with degradation of maternal mRNAs during the midblastula transition in several vertebrate systems. How these processes are regulated in preparation for the onset of differentiation in the vertebrate embryo is mostly unknown. Here, we studied the function of TATA-binding protein (TBP) by knock down and DNA microarray analysis of gene expression in early embryo development. We show that a subset of polymerase II-transcribed genes with ontogenic stage-dependent regulation requires TBP for their zygotic activation. TBP is also required for limiting the activation of genes during development. We reveal that TBP plays an important role in the degradation of a specific subset of maternal mRNAs during late blastulation/early gastrulation, which involves targets of the miR-430 pathway. Hence, TBP acts as a specific regulator of the key processes underlying the transition from maternal to zygotic regulation of embryogenesis. These results implicate core promoter recognition as an additional level of differential gene regulation during development. PMID- 17703194 TI - Two-dimensional gel electrophoresis for identifying proteins that bind DNA or RNA. AB - Electrophoretic mobility shift assays (EMSAs) are commonly used to analyze nucleic acid-protein interactions. When nucleic acid is bound by protein, its mobility during gel electrophoresis is reduced. Similarly, the final position of protein within a complex is shifted when compared to its free state. Here we provide a protocol for a simple approach that uses these mobility differences to identify nucleic acid-binding proteins. Following EMSA, denaturing gel electrophoresis is implemented to provide a second dimension of separation. Protein that binds a specific nucleic acid is identified as a spot(s) whose presence at a particular position(s) is dependent on nucleic acid within the initial binding reaction. The polypeptide in a spot can be subsequently identified by mass spectrometry. As EMSAs can be performed using partially purified or cell extracts, this approach substantially reduces the need for protein purification. It should facilitate the identification of a nucleic acid binding protein within approximately 4 d. PMID- 17703196 TI - A fluorescence-based double retrograde tracer strategy for charting central neuronal connections. AB - Microspheres (beads) tagged with different fluorescent markers can be used for double retrograde axonal tracing of CNS connections. They have several advantages over other double tracer techniques, including ease-of-use, high transport efficiency, distinctive cell labeling and the ability to produce well-defined injection sites. In this protocol we describe the basic procedure for their use, some common problems and how these can be overcome. The protocol, including animal surgery, preparation and delivery of tracer can be completed in approximately 0.5 d. Subsequent histological processing (excluding survival time) can be completed in 0.5-1 d. PMID- 17703195 TI - Electrophoretic mobility shift assay (EMSA) for detecting protein-nucleic acid interactions. AB - The gel electrophoresis mobility shift assay (EMSA) is used to detect protein complexes with nucleic acids. It is the core technology underlying a wide range of qualitative and quantitative analyses for the characterization of interacting systems. In the classical assay, solutions of protein and nucleic acid are combined and the resulting mixtures are subjected to electrophoresis under native conditions through polyacrylamide or agarose gel. After electrophoresis, the distribution of species containing nucleic acid is determined, usually by autoradiography of 32P-labeled nucleic acid. In general, protein-nucleic acid complexes migrate more slowly than the corresponding free nucleic acid. In this protocol, we identify the most important factors that determine the stabilities and electrophoretic mobilities of complexes under assay conditions. A representative protocol is provided and commonly used variants are discussed. Expected outcomes are briefly described. References to extensions of the method and a troubleshooting guide are provided. PMID- 17703197 TI - A light microscope-based double retrograde tracer strategy to chart central neuronal connections. AB - This protocol describes a double retrograde tracing method to chart divergent projections in the CNS using light microscope techniques. It is based on immunohistochemical visualization of retrograde transport of cholera toxin b subunit (CTb) and silver enhancement of a gold-lectin conjugate. Production of the gold-lectin is explained in detail, and a technique is offered to record through the injection pipettes, to help guide accurate placement of injections. Visualization of the two tracers results in light brown staining of CTb-labeled neurons and labeling by black particles of gold-lectin-containing neurons. Both types of label are easily recognized in the same neuron. The labeling is permanent and is well suited for studies in which large areas of the brain need to be surveyed. The whole procedure (excluding survival time) takes approximately 5-7 d to complete. PMID- 17703198 TI - Preparation of the functionalizable methionine surrogate azidohomoalanine via copper-catalyzed diazo transfer. AB - The azide functional group has assumed a prominent role in chemical biology efforts in recent years. Azides may be readily introduced into proteins upon replacement of methionine residues with the non-canonical amino acid azidohomoalanine (AHA). This protocol describes a synthetic route to AHA based on the copper-catalyzed conversion of amines to azides. An alternate protocol for the preparation of AHA is presented in a companion paper. The synthesis and purification of AHA via the route described herein can be completed in 3-4 days. PMID- 17703199 TI - Synthesis of the functionalizable methionine surrogate azidohomoalanine using Boc homoserine as precursor. AB - This protocol describes a synthetic route to the non-canonical amino acid azidohomoalanine (AHA) using protected homoserine as a starting material. An alternative route to AHA is presented in a companion paper. This synthesis can be completed in 5 days. PMID- 17703200 TI - The partial reduction of electron-deficient pyrroles: procedures describing both Birch (Li/NH3) and ammonia-free (Li/DBB) conditions. AB - The partial reduction of electron-deficient pyrroles using either Birch (Li/NH(3)) or ammonia-free (Li/di-tert-butyl biphenyl) conditions allows formation of pyrroline compounds in good yield and, when combined with a reductive alkylation or similar approach, leads to highly functionalized, synthetically useful compounds. This methodology has been proven in the syntheses of several complex natural products, all of which show interesting biological activity. This protocol describes in detail the following stages of the partial reduction procedure: formation of the reducing solution, partial reduction of the pyrrole compound and finally quench of the resulting anion/dianion using either protonating agents or an aldehyde. The ammonia-free conditions described herein are particularly useful for reactions requiring the use of reactive electrophiles, such as acid chlorides or enolizable aldehydes, which are incompatible with the standard Birch reduction conditions. The reaction procedure for the ammonia Birch reduction (procedure A) takes about 9.5 h to complete. Those described for the ammonia-free reductions, procedure B and procedure C, can be expected to take approximately 33 and 8 h, respectively. PMID- 17703201 TI - Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. AB - Mass spectrometry (MS)-based proteomics measures peptides derived from proteins by proteolytic cleavage. Before performing the analysis by matrix-assisted laser desorption/ionization-tandem mass spectrometry (MALDI-MS/MS), nanoelectrospray MS/MS (NanoES-MS/MS) or liquid chromatography-MS/MS (LC-MS/MS), the peptide mixtures need to be cleaned, concentrated and often selectively enriched or pre fractionated, for which we employ simple, self-made and extremely economical stop and-go-extraction tips (StageTips). StageTips are ordinary pipette tips containing very small disks made of beads with reversed phase, cation-exchange or anion-exchange surfaces embedded in a Teflon mesh. The fixed nature of the beads allows flexible combination of disks with different surfaces to obtain multi functional tips. Disks containing different surface functionalities and loose beads such as titania and zirconia for phosphopeptide enrichment can be combined. Incorporation into an automated workflow has also been demonstrated. Desalting and concentration takes approximately 5 min while fractionation or enrichment takes approximately 30 min. PMID- 17703202 TI - Frontal affinity chromatography-mass spectrometry. AB - Frontal affinity chromatography (FAC) is a biophysical method for the discovery and characterization of molecular interactions in a flow-based system. Several different modes of analysis are possible by interfacing to the mass spectrometer, including robust single-compound characterizations as well as high-throughput screening of over 1,000 compounds per run. The method supports thermodynamic and kinetic characterization of interactions for a wide range of molecular species and possesses similarities to flow-based biosensors such as surface plasmon resonance. It offers sensitive detection of ligands present well below their respective dissociation constants, and can be assembled from readily available laboratory components. Direct coupling of the FAC cartridge to the mass spectrometer is useful for the interrogation of single compounds or mixtures of limited complexity. An offline fractionation schema is more appropriate for discovery-mode applications. A high-performance FAC system enabling both modes can be assembled in 2-3 h. Measurements of dissociation constants can be made with such a system in 0.5-3 h, and the system supports higher-throughput screening modes at a rate of 10,000 compounds d(-1). PMID- 17703203 TI - Detecting antigens by quantitative immuno-PCR. AB - The quantitative immuno-PCR (qIPCR) technology combines the advantages of flexible and robust immunoassays with the exponential signal amplification power of PCR. The qIPCR allows one to detect antigens using specific antibodies labeled with double-stranded DNA. The label is used for signal generation by quantitative PCR. Because of the efficiency of nucleic acid amplification, qIPCR typically leads to a 10- to 1,000-fold increase in sensitivity compared to an analogous enzyme-amplified immunoassay. A standard protocol of a qIPCR assay to detect human interleukin 6 (IL-6) using a sandwich immunoassay combined with real-time PCR readout is described here. The protocol includes initial immobilization of the antigen, and coupling of this antigen with antibody-DNA conjugates is then carried out by (a) the stepwise assembly of biotinylated antibody, streptavidin and biotinylated DNA, (b) the use of a biotinylated antibody and an anti-biotin DNA conjugate or (c) the employment of an anti-IL-6 antibody-DNA conjugate. Following the assembly of signal-generating immunocomplexes, real-time PCR is used to amplify and record the signal. Depending on the coupling strategy, the qIPCR assays require 4-7 h with only about 3 h hands-on-time. The use of qIPCR assays enables the detection of rare biomarkers in complex biological samples that are poorly accessible by conventional immunoassays. Therefore, qIPCR offers novel opportunities for the biomedical analysis of, for instance, neurodegenerative diseases and viral infections as well as new tools for the development of novel pharmaceuticals. PMID- 17703204 TI - Methylation-sensitive single-nucleotide primer extension (Ms-SNuPE) for quantitative measurement of DNA methylation. AB - Methylation-sensitive single-nucleotide primer extension (Ms-SNuPE) is a technique that can be used for rapid quantitation of methylation at individual CpG sites. Treatment of genomic DNA with sodium bisulfite is used to convert unmethylated Cytosine to Uracil while leaving 5-methylcytosine unaltered. Strand specific PCR is performed to generate a DNA template for quantitative methylation analysis using Ms-SNuPE. SNuPE is then performed with oligonucleotide(s) designed to hybridize immediately upstream of the CpG site(s) being interrogated. Reaction products are electrophoresed on polyacrylamide gels for visualization and quantitation by phosphorimage analysis. The Ms-SNuPE technique is similar to other quantitative assays that use bisulfite treatment of genomic DNA to discriminate unmethylated from methylated Cytosines (i.e., COBRA, pyrosequencing). Ms-SNuPE can be used for high-throughput methylation analysis and rapid quantitation of Cytosine methylation suitable for a wide range of biological investigations, such as checking aberrant methylation changes during tumorigenesis, monitoring methylation changes induced by DNA methylation inhibitors or for measuring hemimethylation. Approximately two to four CpG sites can be interrogated in up to 40 samples by Ms-SNuPE in less than 5 h, after PCR amplification of the desired target sequence and preparation of PCR amplicons. PMID- 17703205 TI - Practical Proline-catalyzed asymmetric Mannich reaction of aldehydes with N-Boc imines. AB - This protocol describes a procedure for the synthesis of alpha, beta-branched-b amino aldehydes via Proline-catalyzed asymmetric Mannich reaction of aldehydes with N-tert-butoxycarbonyl-imines. The crystalline beta-amino aldehydes are formed in good yields and extremely high levels of diastereo- and enantioselectivities without the need for chromatographic purification and are readily oxidized to the corresponding beta-amino acids. The protocol can be completed in approximately 14 h on small scales or up to 30 h on larger scales. PMID- 17703206 TI - A protocol for isolation and visualization of yeast nuclei by scanning electron microscopy (SEM). AB - This protocol details methods for the isolation of yeast nuclei from budding yeast (Saccharomyces cerevisiae) and fission yeast (Schizosaccharomyces pombe), immuno-gold labeling of proteins and visualization by field emission scanning electron microscopy (FESEM). This involves the removal of the yeast cell wall and isolation of the nucleus from within, followed by subsequent processing for high resolution microscopy. The nuclear isolation step can be performed in two ways: enzymatic treatment of yeast cells to rupture the cell wall and generate spheroplasts (cells that have partially lost their cell wall and their characteristic shape), followed by isolation of the nuclei by centrifugation or homogenization; and whole cell freezing followed by manual cell rupture and centrifugation. This protocol has been optimized for the visualization of the yeast nuclear envelope (NE), nuclear pore complexes (NPCs) and associated cyto skeletal structures. Samples once processed for FESEM can be stored under vacuum for weeks, allowing considerable time for image acquisition. PMID- 17703207 TI - Site-specific incorporation of nitroxide spin-labels into 2'-positions of nucleic acids. AB - A protocol is described for the incorporation of nitroxide spin-labels into specific 2'-sites within nucleic acids. This labeling strategy facilitates the investigation of nucleic acid structure and dynamics using electron paramagnetic resonance (EPR) spectroscopy and macromolecular complex formation using paramagnetic relaxation enhancement NMR spectroscopy. A spin-labeling reagent, 4 isocyanato TEMPO, which can be prepared in one facile step or obtained commercially, is used for postsynthetic modification of site-specifically 2' amino-modified nucleic acids. This spin-labeling protocol has been applied primarily to RNA, but is also applicable to DNA. Subsequently, EPR spectroscopic analysis of the spin-labeled nucleic acids allows for the measurements of distances, solvent accessibilities and conformation dynamics. Using the spin labeling strategy described here, spin-labeled samples can be prepared in 2-4 d. PMID- 17703208 TI - Derivation of human embryonic stem cells from single blastomeres. AB - This protocol details a method to derive human embryonic stem (hES) cells from single blastomeres. Blastomeres are removed from morula (eight-cell)-stage embryos and cultured until they form multicell aggregates. These blastomere derived cell aggregates are plated into microdrops seeded with mitotically inactivated feeder cells, and then connected with neighboring microdrops seeded with green fluorescent protein-positive hES cells. The resulting blastomere derived outgrowths are cultured in the same manner as blastocyst-derived hES cells. The whole process takes about 3-4 months. PMID- 17703209 TI - Digital karyotyping. AB - Detection of copy number variation in the human genome is important for identifying naturally occurring copy number polymorphisms as well as alterations that underlie various human diseases, including cancer. Digital karyotyping uses short sequence tags derived from specific genomic loci to provide a quantitative and high-resolution view of copy number changes on a genome-wide scale. Genomic tags are obtained using a combination of enzymatic digests and isolation of short DNA sequences. Individual tags are linked into ditags, concatenated, cloned and sequenced. Tags are matched to reference genome sequences and digital enumeration of groups of neighboring tags provides quantitative copy number information along each chromosome. Digital karyotyping libraries can be generated in about a week, and library sequencing and data analysis require several additional weeks. PMID- 17703210 TI - Characterizing peptides in individual mammalian cells using mass spectrometry. AB - Cell-to-cell chemical signaling plays multiple roles in coordinating the activity of the functional elements of an organism, with these elements ranging from a three-neuron reflex circuit to the entire animal. In recent years, single-cell mass spectrometry (MS) has enabled the discovery of cell-to-cell signaling molecules from the nervous system of a number of invertebrates. We describe a protocol for analyzing individual cells from rat pituitary using matrix-assisted laser desorption/ionization MS. Each step in the sample preparation process, including cell stabilization, isolation, sample preparation, signal acquisition and data interpretation, is detailed here. Although we employ this method to investigate peptides in individual pituitary cells, it can be adapted to other cell types and even subcellular sections from a range of animals. This protocol allows one to obtain 20-30 individual cell samples and acquire mass spectra from them in a single day. PMID- 17703211 TI - An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression. AB - Colorectal cancer is a life-threatening disease that can develop spontaneously or as a complication of inflammatory bowel diseases. Mouse models are essential tools for the preclinical testing of novel therapeutic options in vivo. Here, we provide a highly reliable protocol for an experimental mouse model to study the development of colon cancers. It is based on the mutagenic agent azoxymethane (AOM), which exerts colonotropic carcinogenicity. Repeated intraperitoneal administration of AOM results in the development of spontaneous tumors within 30 weeks. As an alternative option, inflammation-dependent tumor growth can be investigated by combining the administration of AOM with the inflammatory agent dextran sodium sulfate in drinking water, which causes rapid growth of multiple colon tumors per mouse within 10 weeks. Different scoring systems including number of tumors and tumor size identify factors promoting or inhibiting tumor initiation and/or tumor progression, respectively. PMID- 17703212 TI - The detection and quantification of growth cone collapsing activities. AB - Growth cone guidance during development, as well as axonal extension in neural repair and plasticity, is strongly regulated by both attractive (growth promoting) and repulsive (growth-inhibiting) guidance molecules. The growth cone collapse assay has been widely and successfully used for the identification and purification of molecules that are repulsive to growth cones or inhibit axonal outgrowth. Here we provide a detailed description of the assay, which uses the morphology of the growth cone after exposure to a test protein as the readout. With the modifications detailed in this protocol, this assay can be used for the biochemical enrichment of proteins with a collapsing activity and for the identification of a collapsing activity of a known protein or gene. This assay does not require very specialized equipment and can be established by every lab with experience in neuronal cell culture. It can be completed in 3 d. PMID- 17703214 TI - Synthesis of pyrimidines by direct condensation of amides and nitriles. AB - A protocol for the single-step synthesis of pyrimidine derivatives by condensation of N-vinyl or N-aryl amides with nitriles is described. Gram-scale synthesis of 4-tert-butyl-2-phenyl-7,8-dihydro-6H-pyrano[3,2-d]pyrimidine serves as a representative procedure for this methodology for azaheterocycle synthesis. This chemistry involves amide activation with trifluoromethanesulfonic anhydride in the presence of 2-chloropyridine and the necessary nitrile. Nucleophilic addition of the nitrile to an activated intermediate followed by annulation affords the pyrimidine product in a single step. The total time necessary for the completion of this procedure is approximately 3 h. This chemistry has been applied to a wide range of amides and nitriles including optically active derivatives. PMID- 17703213 TI - Site-directed alkylation of cysteine to test solvent accessibility of membrane proteins. AB - This protocol describes a detailed method to study the static and dynamic features of membrane proteins, as well as solvent accessibility, by utilizing the lactose permease of Escherichia coli (LacY) as a model. The method relies on the use of functional single-Cys mutants, an affinity tag and a PhosphoImager. The membrane-permeant, radioactive thiol reagent N-[ethyl-1-14C]ethylmaleimide ([14C]NEM) is used to detect site-directed alkylation of engineered single-Cys mutants in situ. The solvent accessibility of the Cys residues is also determined by blockage of [14C]NEM labeling with membrane-impermeant thiol reagents such as methanethiosulfonate ethylsulfonate (MTSES). The labeled proteins are purified by mini-scale affinity chromatography and analyzed by gel electrophoresis. Gels are dried and exposed to a PhosphoImager screen for 1-5 d, and incorporation of radioactivity is visualized. Initial results can be obtained in 24 h. PMID- 17703215 TI - Tracking intracellular protein movements using photoswitchable fluorescent proteins PS-CFP2 and Dendra2. AB - A number of photoactivatable GFP-like fluorescent proteins (PAFPs) have been reported whose fluorescence can be switched on or whose fluorescent state can be modified by relatively intense irradiation at a specific wavelength. The use of these proteins gives unique opportunities to photolabel and track fusion proteins in a living cell. Here, we provide a protocol for the primary visualization, photoactivation and tracking of two monomeric PAFPs recently developed in our lab. Both these proteins, PS-CFP2 and Dendra2, are fluorescent and can be visualized before photoactivation. Upon photoactivation, their excitation and emission spectra undergo a dramatic red shift. The brightness of their initial and photoconverted states, along with the high dynamic ranges of both proteins, make them an attractive tool for protein photolabeling. Excluding genetic constructs cloning, cell culturing and transfection, the whole protocol may take anywhere from 10 min to several hours, depending on motility of the protein being studied. PMID- 17703216 TI - Identification of target mRNAs of regulatory RNA-binding proteins using mRNP immunopurification and microarrays. AB - RNA-binding proteins (RBPs) frequently regulate the post-transcriptional fate of target mRNAs. To identify novel target mRNAs of RBPs, we incubate total RNA with recombinant RBP and immunoselect the messenger-ribonucleoproteins using a specific anti-RBP antibody. The mRNA composition of the supernatant and/or immunoprecipitated fraction is analyzed using dual-color microarrays in comparison with control reaction. From start to finish, the protocol takes approximately 6 d. PMID- 17703217 TI - Assessing the delivery efficacy and internalization route of cell-penetrating peptides. AB - Developing efficient delivery vectors for bioactive molecules is of great importance within both traditional and novel drug development, such as oligonucleotide (ON)-based therapeutics. To address delivery efficiency using cell-penetrating peptides (CPPs), we here present a protocol based on splice correction utilizing both neutral and anionic antisense ONs, either covalently conjugated via a disulfide bridge or non-covalently complexed, respectively, that generates positive readout in the form of luciferase expression. The decisive advantage of using splice correction for evaluation of CPPs is that the ON induces a biological response in contrast to traditionally used methods, for example, fluorescently labeled peptides. An emerging number of studies emphasize the role of endocytosis in translocation of CPPs, and this protocol is also utilized to determine the relative contribution of different endocytic pathways in the uptake of CPPs, which provides valuable information for future design of novel, more potent CPPs for bioactive cargoes. PMID- 17703218 TI - Improvement of erectile function with Prelox: a randomized, double-blind, placebo controlled, crossover trial. AB - In a randomly allocated, double-blind, placebo-controlled, crossover design, 50 patients with mild to moderate erectile dysfunction (ED) were treated for 1 month with placebo or a combination of L-arginine aspartate and Pycnogenol (Prelox). Patients reported sexual function from diaries. Testosterone levels and endothelial NO synthase (e-NOS) were monitored along with routine clinical chemistry. Intake of Pycnogenol for 1 month restored erectile function to normal. Intercourse frequency doubled. e-NOS in spermatozoa and testosterone levels in blood increased significantly. Cholesterol levels and blood pressure were lowered. No unwanted effects were reported. Prelox is a promising alternative to treat mild to moderate ED. PMID- 17703220 TI - Immediate- and late-hemodynamic coronary effects of tadalafil in men with erectile dysfunction and coronary artery disease. AB - We investigated whether coronary flow reserve (CFR) can be modified by tadalafil, a long-acting phosphodiesterase 5 (PDE5) inhibitor, in patients with documented coronary artery disease (CAD). CFR was non-invasively evaluated in 12 men with a positive history for erectile dysfunction (ED) and angiographically documented CAD, in the distal portion of the left anterior descending coronary artery, free from critical stenosis, with contrast enhanced echocardiography at time zero (T0). Then, after 20 mg tadalafil was orally administered CFR measurement was repeated after 2 h (T1) and after 24 h (T2). Doppler curves suitable for the analysis were obtained in all patients (CFR feasibility: 100%). The peak diastolic velocity after adenosine infusion increased from 71.3+/-14.3 cm/s at T0 to 82.5+/-24.0 at T1 (P=NS) and to 89.5+/-21.1 at T2 (P=0.0010). CFR after tadalafil increased significantly from 2.6+/-0.3 at T0 to 3.1+/-0.7 at T1 (P=0.0078) and a further increment was found at T2 (3.5+/-0.9; P=0.0010 vs T0). Our study shows that oral administration of tadalafil exerts a long standing, potentially beneficial effect on coronary microvasculature in patients with ED. PMID- 17703219 TI - Effect of sildenafil administration on penile hypoxia induced by cavernous neurotomy in the rat. AB - Hypoxia is a normal, physiological condition in penile tissue, which is interrupted by reoxygenation associated to sleep-related erections. We previously described in the rat that a penile fibrosis and overexpression of the pro fibrotic endothelin-1 type B receptor (ETB) are associated to prolonged (3 months) hypoxia induced by the bilateral surgical resection of the cavernous nerves (bilateral cavernous neurotomy (BCN)). The aim of the present study was to define the time frame in which BCN induces hypoxia and ETB overexpression in the penile tissue. In addition, we studied the time-dependency of the rescuing effect of an acute administration of the phosphodiesterase type 5 inhibitor, sildenafil. We found that BCN induced penile hypo-oxygenation (immunohistochemistry for Hypoxyprobe), penile ETB mRNA overexpression (quantitative real-time reverse transcriptase polymerase chain reaction) and hypersensitivity to the ETB agonist IRL-1620 (in vitro contractility study). Sildenafil treatment was able to counteract all these alterations (penile hypoxygenation, hyper-sensitivity to IRL 1620 and ETB overexpression), with its effect being more evident the earlier it was administered. PMID- 17703221 TI - Assessment of sexual function/dysfunction via patient reported outcomes. AB - The recent recognition of the high prevalence of sexual dysfunctions and disorders in our society, along with the substantial investment of the pharmaceutical industry in the field of sexual functioning, has resulted in a significant expansion in the development of valid and reliable measures of sexual function/dysfunction. The instruments tend to be brief self-report inventories, typically requiring 10-20 min of patient time for completion. Most measures were initially developed as screening and outcomes measures for use in clinical drug trials of new treatments for sexual dysfunction, but are beginning to see more widespread use in the clinic. All these instruments must adhere to recently prescribed rigorous guidelines set forth by the Food and Drug Administration, and have been demonstrated to be valid and reliable indicators of the status and quality of sexual functioning in both men and women. The constructs that form the framework of our diagnostic system for sexual dysfunctions are not amenable to direct physical measurement, so that currently they must be assessed via these self-report scales. Although not as precise as physical measures, these inventories do an admirable job of quantifying and registering sexual functioning status in a concise and reliable manner, and have become indispensable tools in our clinical and research programs. PMID- 17703222 TI - Hypogonadism is associated with overt depression symptoms in men with erectile dysfunction. AB - Depression and hypogonadism are associated with erectile dysfunction (ED). We evaluated the prevalence of both conditions in men presenting to an ED specialty clinic, and tested whether hypogonadism correlated with the presence of depressive symptoms using a validated questionnaire. From July 2001 to June 2003, 157 men referred to an ED specialty clinic prospectively filled the Center for Epidemiologic Studies Depression Scale (CES-D), the abbreviated International Index of Erectile Function (IIEF-5) and had testosterone serum levels drawn. Median age was 53 (range=21-85 years). Hypogonadism, defined as serum T (testosterone)<300 mg/dl, was present in 36% of patients. This proportion was higher in men over the median age compared to younger patients (45 and 26%, respectively, P=0.002). Overt depression symptoms, defined as a CES-D> or =22, were found in 24% of men. Mean age of men with overt depression was 49.9+/-10.1 years vs 55.1+/-15.8 years for those with CES-D<22 (P=0.02). Hypogonadal men were more likely to have overt depression scores compared to eugonadal counterparts (35 vs 18%, P=0.02). This association was statistically stronger after correcting for age in a multivariate linear model (P=0.005). The relative risk of having overt depression was 1.94 times higher in men with hypogonadal testosterone level (95% confidence interval: 1.13 to 3.7). We conclude that in an ED referral population, symptoms of hypogonadism and depression symptoms are fairly prevalent, and that overt depression symptoms are strongly associated with hypogonadism. Clinicians should consider testosterone measurements in all men with high depression symptom scores. PMID- 17703223 TI - Cutaneous microcirculatory function predicts the responsiveness to tadalafil in patients with erectile dysfunction and coronary artery disease. AB - Despite the proven clinical efficacy of phosphodiesterase inhibitors in the treatment of erectile dysfunction (ED), some patients do not respond to the medication. By means of nailfold capillary microscopy in patients with concomitant coronary artery disease (CAD) and ED, it was evaluated whether the extent of microvascular dysregulation predicts the responsiveness to tadalafil (TAD) in terms of erectile function. The ED of each patient was assessed by the International Index of Erectile Function (IIEF). Patients presenting both, documented CAD and ED, showed a significantly reduced capillary red blood cell velocity (v(RBC)) at rest and after 3 min of ischemia compared with age-matched controls. At 2 h after intake of 20 mg of TAD, a significant increase of v(RBC) at rest as well as during postischemic hyperemia was found. Patients who reported no improvement of their ED after the use of TAD demonstrated no changes in the duration of postischemic (DpH) hyperemia, or even a reduction of the DpH. The majority of the patients, who reported at least one successful sexual intercourse due to TAD, had a prolongation of DpH. We conclude that assessment of microvascular regulation by nailfold capillary microscopy can predict the probability of a treatment failure with phosphodiesterase inhibitors in patients with ED. Moreover, as endothelial dysfunction is the common underlying pathophysiological process of ED and cardiovascular diseases, the test may help to identify patients at risk for the development of atherosclerosis and following cardiovascular events. PMID- 17703224 TI - HIV-1 over time: fitness loss or robustness gain? PMID- 17703225 TI - Campylobacter jejuni: molecular biology and pathogenesis. AB - Campylobacter jejuni is a foodborne bacterial pathogen that is common in the developed world. However, we know less about its biology and pathogenicity than we do about other less prevalent pathogens. Interest in C. jejuni has increased in recent years as a result of the growing appreciation of its importance as a pathogen and the availability of new model systems and genetic and genomic technologies. C. jejuni establishes persistent, benign infections in chickens and is rapidly cleared by many strains of laboratory mouse, but causes significant inflammation and enteritis in humans. Comparing the different host responses to C. jejuni colonization should increase our understanding of this organism. PMID- 17703226 TI - Modelling an outbreak of an emerging pathogen. AB - To illustrate the usefulness of mathematical models to the microbiology and medical communities, we explain how to construct and apply a simple transmission model of an emerging pathogen. We chose to model, as a case study, a large (>8,000 reported cases) on-going outbreak of community-acquired meticillin resistant Staphylococcus aureus (CA-MRSA) in the Los Angeles County Jail. A major risk factor for CA-MRSA infection is incarceration. Here, we show how to design a within-jail transmission model of CA-MRSA, parameterize the model and reconstruct the outbreak. The model is then used to assess the severity of the outbreak, predict the epidemiological consequences of a catastrophic outbreak and design effective interventions for outbreak control. PMID- 17703227 TI - Unifying themes in host defence effector polypeptides. AB - It is said that nature is the greatest innovator, yet molecular conservation can be equally powerful. One key requirement for the survival of any host is its ability to defend against infection, predation and competition. Recent discoveries, including the presence of a multidimensional structural signature, have revealed a previously unforeseen structural and functional congruence among host defence effector molecules spanning all kingdoms of life. Antimicrobial peptides, kinocidins, polypeptide venoms and other molecules that were once thought to be distinct in form and function now appear to be members of an ancient family of host defence effectors. These molecules probably descended from archetype predecessors that emerged during the beginning of life on earth. Understanding how nature has sustained these host defence molecules with a potent efficacy in the face of dynamic microbial evolution should provide new opportunities to prevent or treat life-threatening infections. PMID- 17703228 TI - FcRn: the neonatal Fc receptor comes of age. AB - The neonatal Fc receptor for IgG (FcRn) has been well characterized in the transfer of passive humoral immunity from a mother to her fetus. In addition, throughout life, FcRn protects IgG from degradation, thereby explaining the long half-life of this class of antibody in the serum. In recent years, it has become clear that FcRn is expressed in various sites in adults, where its potential function is now beginning to emerge. In addition, recent studies have examined the interaction between FcRn and the Fc portion of IgG with the aim of either improving the serum half-life of therapeutic monoclonal antibodies or reducing the half-life of pathogenic antibodies. This Review summarizes these two areas of FcRn biology. PMID- 17703229 TI - Calcium signalling in lymphocyte activation and disease. AB - Calcium signals in cells of the immune system participate in the regulation of cell differentiation, gene transcription and effector functions. An increase in intracellular levels of calcium ions (Ca2+) results from the engagement of immunoreceptors, such as the T-cell receptor, B-cell receptor and Fc receptors, as well as chemokine and co-stimulatory receptors. The major pathway that induces an increase in intracellular Ca2+ levels in lymphocytes is through store-operated calcium entry (SOCE) and calcium-release-activated calcium (CRAC) channels. This Review focuses on the role of Ca2+ signals in lymphocyte functions, the signalling pathways leading to Ca2+ influx, the function of the recently discovered regulators of Ca2+ influx (STIM and ORAI), and the relationship between Ca2+ signals and diseases of the immune system. PMID- 17703230 TI - Minimizing leakage of value from R&D alliances. AB - Alliances, which are a key component of the research and development (R&D) strategies of most major pharmaceutical companies, demand significant management time and resources. There is no doubt that considerable value can be derived from R&D alliances, and much has been written about how companies can maximize such value, but the issue of how the associated risks can be minimized has been neglected in comparison. Here, we summarize recent trends in alliance formation and discuss approaches to minimize risk in alliances, which are growing in importance as alliance activity increases. PMID- 17703231 TI - Regulation of apoptosis by C. elegans CED-9 in the absence of the C-terminal transmembrane domain. AB - Bcl-2 proteins regulate apoptosis in organisms as diverse as mammals and nematodes. These proteins are often localized at mitochondria by a C-terminal transmembrane domain. Although the transmembrane domain and mitochondrial localization are centrally involved in specific cases of vertebrate Bcl-2 activity, the significance of this localization is not clear for all species. Studying the Caenorhabditis elegans Bcl-2 homolog CED-9, we found that the transmembrane domain was both necessary and sufficient for localization at mitochondrial outer membranes. Furthermore, we found that in our assays, ced-9 transgenes lacking the transmembrane domain, although somewhat less active than equivalent transgenes derived from wild-type ced-9, rescued embryonic lethality of ced-9(lf) animals and responded properly to upstream signals in controlling the fate of Pn.aap neurons. Both of these apoptotic activities were retained in a construct where CED-9 lacking the transmembrane domain was targeted to the cytosolic surface of the endoplasmic reticulum and derived organelles, suggesting that in wild-type animals, accumulation at mitochondria is not essential for CED 9 to either inhibit or promote apoptosis in C. elegans. Taken together, these data are consistent with a multimodal character of CED-9 action, with an ability to regulate apoptosis through interactions in the cytosol coexisting with additional evolutionarily conserved role(s) at the membrane. PMID- 17703232 TI - Enforced covalent trimerization increases the activity of the TNF ligand family members TRAIL and CD95L. AB - Variants of human TRAIL (hTRAIL) and human CD95L (hCD95L), encompassing the TNF homology domain (THD), interact with the corresponding receptors and stimulate CD95 and TRAILR2 signaling after cross-linking. The murine counterparts (mTRAIL, mCD95L) showed no or only low receptor binding and were inactive/poorly active after cross-linking. The stalk region preceding the THD of mCD95L conferred secondary aggregation and restored CD95 activation in the absence of cross linking. A corresponding variant of mTRAIL, however, was still not able to activate TRAIL death receptors, but gained good activity after cross-linking. Notably, disulfide-bonded fusion proteins of the THD of mTRAIL and mCD95L with a subdomain of the tenascin-C (TNC) oligomerization domain, which still assembled into trimers, efficiently interacted with their cognate cellular receptors and robustly stimulated CD95 and TRAILR2 signaling after secondary cross-linking. Introduction of the TNC domain also further enhanced the activity of THD encompassing variants of hTRAIL and hCD95L. Thus, spatial fixation of the N terminus of the THD appears necessary in some TNF ligands to ensure proper receptor binding. This points to yet unanticipated functions of the stalk and/or transmembrane region of TNF ligands for the functionality of these molecules and offers a broadly applicable option to generate recombinant soluble ligands of the TNF family with superior activity. PMID- 17703233 TI - DAP kinase regulates JNK signaling by binding and activating protein kinase D under oxidative stress. AB - The stress-activated kinase JNK mediates key cellular responses to oxidative stress. Here we show that DAP kinase (DAPk), a cell death promoting Ser/Thr protein kinase, plays a main role in oxidative stress-induced JNK signaling. We identify protein kinase D (PKD) as a novel substrate of DAPk and demonstrate that DAPk physically interacts with PKD in response to oxidative stress. We further show that DAPk activates PKD in cells and that induction of JNK phosphorylation by ectopically expressed DAPk can be attenuated by knocking down PKD expression or by inhibiting its catalytic activity. Moreover, knockdown of DAPk expression caused a marked reduction in JNK activation under oxidative stress, indicating that DAPk is indispensable for the activation of JNK signaling under these conditions. Finally, DAPk is shown to be required for cell death under oxidative stress in a process that displays the characteristics of caspase-independent necrotic cell death. Taken together, these findings establish a major role for DAPk and its specific interaction with PKD in regulating the JNK signaling network under oxidative stress. PMID- 17703234 TI - Crosstalk among Bcl-2 family members in B-CLL: seliciclib acts via the Mcl-1/Noxa axis and gradual exhaustion of Bcl-2 protection. AB - Seliciclib (R-roscovitine) is a cyclin-dependent kinase inhibitor in clinical development. It triggers apoptosis by inhibiting de novo transcription of the short-lived Mcl-1 protein, but it is unknown how this leads to Bax/Bak activation that is required for most forms of cell death. Here, we studied the effects of seliciclib in B-cell chronic lymphocytic leukemia (B-CLL), a malignancy with aberrant expression of apoptosis regulators. Although seliciclib-induced Mcl-1 degradation within 4 h, Bax/Bak activation occurred between 16 and 20 h. During this period, no transcriptional changes in apoptosis-related genes occurred. In untreated cells, prosurvival Mcl-1 was engaged by the proapoptotic proteins Noxa and Bim. Upon drug treatment, Bim was quickly released. The contribution of Noxa and Bim as a specific mediator of seliciclib-induced apoptosis was demonstrated via RNAi. Significantly, 16 h after seliciclib treatment, there was accumulation of Bcl-2, Bim and Bax in the 'mitochondria-rich' insoluble fraction of the cell. This suggests that after Mcl-1 degradation, the remaining apoptosis neutralizing capacity of Bcl-2 is gradually overwhelmed, until Bax forms large multimeric pores in the mitochondria. These data demonstrate in primary leukemic cells hierarchical binding and crosstalk among Bcl-2 members, and suggest that their functional interdependence can be exploited therapeutically. PMID- 17703235 TI - Caspase-1 inflammasomes: choosing between death and taxis. PMID- 17703236 TI - Genome-wide association studies provide new insights into type 2 diabetes aetiology. AB - Human geneticists are currently in the middle of a race. Thanks to a new technology in the form of 'genome-wide chips', investigators can potentially find many novel disease genes in one large experiment. Type 2 diabetes has been hot out of the blocks with six recent publications that together provide convincing evidence for six new gene regions involved in the condition. Together with candidate approaches, these studies have identified 11 confirmed genomic regions that alter the risk of type 2 diabetes in the European population. One of these regions, the fat mass and obesity associated gene (FTO), represents by far the best example of an association between common variation and fat mass in the general population. PMID- 17703237 TI - The Decapentaplegic morphogen gradient: from pattern formation to growth regulation. AB - Morphogens have been linked to numerous developmental processes, including organ patterning and the control of organ size. Here we review how different experimental approaches have led to an unprecedented level of molecular knowledge about the patterning role of the Drosophila melanogaster morphogen Decapentaplegic (DPP, the homologue of vertebrate bone morphogenetic protein, or BMP), the first validated secreted morphogen. In addition, we discuss how little is known about the role of the DPP morphogen in the control of organ growth and organ size. Continued efforts to elucidate the role of DPP in D. melanogaster is likely to shed light on this fundamental question in the near future. PMID- 17703238 TI - Mechanistic approaches to the study of evolution: the functional synthesis. AB - An emerging synthesis of evolutionary biology and experimental molecular biology is providing much stronger and deeper inferences about the dynamics and mechanisms of evolution than were possible in the past. The new approach combines statistical analyses of gene sequences with manipulative molecular experiments to reveal how ancient mutations altered biochemical processes and produced novel phenotypes. This functional synthesis has set the stage for major advances in our understanding of fundamental questions in evolutionary biology. Here we describe this emerging approach, highlight important new insights that it has made possible, and suggest future directions for the field. PMID- 17703240 TI - NTP toxicity studies of dimethylaminopropyl chloride, hydrochloride (CAS No. 5407 04-5) administered by Gavage to F344/N rats and B6C3F1 mice. AB - Dimethylaminopropyl chloride, hydrochloride is used primarily as an industrial and research organic chemical intermediate acting as an alkylating reagent in Grignard and other types of reactions. It is also used as a pharmaceutical intermediate for the synthesis of many types of drugs, as an agricultural chemical intermediate, as a photographic chemical intermediate, and as a biochemical reagent for enzyme and other studies. Human occupational or other accidental exposure can occur by inhalation, ingestion, or skin absorption. Male and female F344/N rats and B6C3F1 mice received dimethylaminopropyl chloride, hydrochloride (greater than 99% pure) in water by gavage for 2 weeks or 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. In the 2-week toxicity studies, groups of five male and five female F344/N rats and B6C3F1 mice were administered doses of 0, 6.25, 12.5, 25, 50, or 100 mg dimethylaminopropyl chloride, hydrochloride/kg body weight in deionized water by gavage, 5 days per week for 16 days. All dosed male and female rats and mice survived until the end of the 2-week study; one vehicle control female mouse died early. Mean body weights of all dosed groups of rats and mice were similar to those of the vehicle control groups. No gross or microscopic lesions were considered related to dimethylaminopropyl chloride, hydrochloride administration. In the 3-month toxicity studies, groups of 10 male and 10 female F344/N rats and B6C3F1 mice were administered doses of 0, 6.25, 12.5, 25, 50, or 100 mg/kg in deionized water by gavage, 5 days per week for 3 months. One male rat in the 50 mg/kg group died during week 12 of the study, and one female mouse in the 100 mg/kg group died during week 9 and another during week 13. The final mean body weights of 50 mg/kg male rats and 50 mg/kg female mice were significantly less than those of the vehicle controls. Possible chemical-related clinical findings in rats included lethargy in one 50 mg/kg male and one 100 mg/kg male, tremors in one 100 mg/kg male, and ataxia in one 50 mg/kg male and two 100 mg/kg males. Absolute lung weights in the 25, 50, and 100 mg/kg groups of female mice were significantly less than those of the vehicle controls. Total serum bile acid concentrations were increased in 50 mg/kg male rats and 100 mg/kg male and female rats. The incidence of goblet cell hypertrophy of the nose was significantly increased in 100 mg/kg male rats compared to the vehicle controls. There were no significant histopathologic findings in mice. Dimethylaminopropyl chloride, hydrochloride was mutagenic in the Salmonella typhimurium base substitution strains TA100 and TA1535, with and without hamster or rat liver S9 activation enzymes; no mutagenic activity was seen in TA97 or TA98. No increase in the frequency of micronucleated erythrocytes was seen in peripheral blood of male or female mice administered dimethylaminopropyl chloride, hydrochloride for 3 months by gavage. In summary, dimethylaminopropyl chloride, hydrochloride caused increased incidences of goblet cell hypertrophy in the nose of male rats and increased serum bile acid concentrations in male and female rats. In mice, dimethylaminopropyl chloride, hydrochloride caused deaths in females administered 100 mg/kg. The estimated no-observed-effect levels were 50 mg/kg per day for male rats and female mice, 100 to 200 mg/kg per day for female rats, and greater than 100 mg/kg per day for male mice. Synonyms: 3 Chloropropyldimethyl-ammonium chloride; (3-chloropropyl)dimethylamine, hydrochloride; N-(3-chloropropyl)-N,N-dimethylammonium chloride; 3-dimethylamino 1-propyl chloride hydrochloride; 3-dimethylaminopropyl chloride hydrochloride; DMPC; 1-propylamine, 3-chloro-N,N-dimethyl-, hydrochloride. PMID- 17703239 TI - Integrating physical and genetic maps: from genomes to interaction networks. AB - Physical and genetic mapping data have become as important to network biology as they once were to the Human Genome Project. Integrating physical and genetic networks currently faces several challenges: increasing the coverage of each type of network; establishing methods to assemble individual interaction measurements into contiguous pathway models; and annotating these pathways with detailed functional information. A particular challenge involves reconciling the wide variety of interaction types that are currently available. For this purpose, recent studies have sought to classify genetic and physical interactions along several complementary dimensions, such as ordered versus unordered, alleviating versus aggravating, and first versus second degree. PMID- 17703241 TI - Canadian economic evaluation of budesonide-formoterol as maintenance and reliever treatment in patients with moderate to severe asthma. AB - OBJECTIVES: To compare the cost-effectiveness of budesonide-formoterol in a single inhaler used as both maintenance and reliever medication versus clinician directed titration of salmeterol-fluticasone as maintenance medication, plus salbutamol taken as needed, in controlling asthma in adults and adolescents. METHODS: A Canadian economic evaluation was conducted based on the results of a large (n=2143), open-label, randomized, controlled effectiveness trial in which health resource use was prospectively collected. The primary outcome measurement was the time to the first severe exacerbation. Costs included direct medical costs (physician and emergency room visits, hospitalizations, asthma drug costs, etc) and productivity (absenteeism). The time horizon was one year, which corresponded to the duration of the clinical trial. Prices were obtained from 2005 Canadian sources. Both health care and societal perspectives were considered, and deterministic univariate sensitivity analyses were conducted. RESULTS: In the clinical trial, budesonide-formoterol as maintenance and reliever treatment was superior to salmeterol-fluticasone with respect to the time to the first severe exacerbation, overall rate of exacerbations and use of as-needed reliever medication. The annualized rate of severe exacerbations was 0.24 events/patient in the budesonide-formoterol arm and 0.31 events/patient in the salmeterol-fluticasone arm (P=0.0025). From a health care perspective, the mean cost per patient-year was $1,315 in the budesonide-formoterol arm versus $1,541 in the salmeterol-fluticasone arm. From a societal perspective, the mean cost per patient-year was $1,538 in the budesonide-formoterol arm and $1,854 in the salmeterol-fluticasone arm. Budesonide-formoterol was dominant (more effective and less expensive) in the base case analysis from both perspectives. The results were robust under sensitivity testing. CONCLUSIONS: The strategy that allows budesonide-formoterol to be used in a single inhaler as both maintenance and reliever medication proved to be more effective and less expensive than a strategy of clinician-directed titration of salmeterol-fluticasone with salbutamol as reliever therapy. PMID- 17703242 TI - Cost-effectiveness of various diagnostic approaches for occupational asthma. AB - BACKGROUND: Diagnosis of occupational asthma (OA) by specific inhalation challenge (SIC) can be costly and is not always available. The use of sputum testing to avoid this in some patients may be a more cost-effective alternative. OBJECTIVES: To compare the cost-effectiveness of SIC with serial measurements of sputum cell counts (sputum testing) and peak expiratory flow (PEF) monitoring. METHODS: Clinical data and testing costs for OA in 49 patients were collected during a previously published trial, modelled and compared using TreeAge Pro. Clinical outcome was the percentage of accurately diagnosed patients, using SIC as the gold standard. The PEF approach used the most accurate assessment of five experts who were blinded to SIC results. Differences in the proportion of eosinophils during periods on and off work were used for the sputum testing approach and in PEF/sputum for the combined approach. Unit costs were estimated from charges in Canadian hospitals. Data were analyzed by one-way and two-way analyses, and by probabilistic sensitivity analysis using a Monte Carlo simulation technique. RESULTS: The PEF approach had an estimated accuracy of 52% and cost $365 per patient tested. Compared with PEF monitoring, sputum testing was more accurate and cost an estimated $255 for each additional OA patient correctly diagnosed. SIC costs per additional correct diagnosis were $11,032 compared with sputum testing and $6,458 compared with PEF monitoring. The combined PEF/sputum testing approach was not cost-effective in the base case analysis, but cannot be excluded according to probabilistic sensitivity analyses. CONCLUSIONS: Although SIC remains the reference test to diagnose OA, when this test is not available, sputum testing is a cost-effective alternative to PEF for diagnosis of OA. PMID- 17703243 TI - Sputum neutrophilia can mask eosinophilic bronchitis during exacerbations. AB - BACKGROUND: Exacerbations of airway disease are eosinophilic, neutrophilic, both or neither. The primary objective of the present study was to identify whether the treatment of a neutrophilic bronchitis can unmask an associated eosinophilia. METHODS: A retrospective survey of 2160 consecutive sputum cell counts from 1343 patients with airway disease was conducted to identify patients with an isolated neutrophilic bronchitis, which was defined as a sputum total cell count of greater than or equal to 12 x 10(6) cells/g of sputum and a proportion of neutrophils of 80% or greater. The characteristics of the patients who subsequently demonstrated sputum eosinophilia (3% or greater) within eight weeks of resolving the neutrophilia were compared with the patients who subsequently did not have sputum eosinophilia. RESULTS: Two hundred thirty-seven patients had 273 neutrophilic exacerbations. The sputum was re-examined within eight weeks in 65 patients (27.4%), of whom 38 (58.5%) had resolution of the neutrophilic bronchitis after treatment with an antibiotic. Of these 38 patients, 13 (34%) showed eosinophilia. CONCLUSIONS: A neutrophilic exacerbation of airway disease was observed to mask sputum eosinophilia in one-third of patients who had sputum cell counts available before and after antibiotic therapy. Hence, the absence of sputum eosinophilia during an infective exacerbation should not be used as an indication to reduce the dose of corticosteroids. To optimize therapy, repeat sputum cell count measurements are recommended after antibiotic treatment before changing corticosteroid treatment. PMID- 17703244 TI - Ventilation and perfusion lung scintigraphy of allergen-induced airway responses in atopic asthmatic subjects. AB - BACKGROUND: Both ventilation (V) and perfusion (Q) of the lungs are altered in asthma, but their relationships with allergen-induced airway responses and gas exchange are not well described. METHODS: The effects of aerosolized allergen provocation of V/Q abnormalities in nonsmoking, male atopic asthmatics (six dual responders and two isolated early responders) were compared with measurements of airflow limitation (forced expiratory volume in 1 s [FEV(1)]), gas exchange (arterial oxygen saturation, arterial oxygen partial pressure and alveolar arterial oxygen gradient) and airway reactivity (provocative concentration of histamine causing a decrease of 20% in FEV(1)). V and Q lung scans at 30 min and 6 h following allergen challenge and changes in all variables were compared with prechallenge data. Digital image data were registered to baseline scans, and quantitative comparisons of changes made were supported by qualitative assessments of the images. RESULTS: All subjects showed evidence of impaired gas exchange, as reflected by lowered arterial oxygen tension and widened alveolar arterial oxygen gradients. Baseline V/Q scans were abnormal, and there were allergen-induced changes in V and Q at 30 min, with scans at 6 h showing additional changes in Q, particularly in dual responders. Allergen-induced gas trapping was evident at 30 min and was sustained at 6 h. CONCLUSIONS: Regional patterns of V and Q derived from lung scintigraphy showed a wider range of disturbances than were indicated by the magnitude of airflow limitation and arterial hypoxemia following allergen provocation, and they remained abnormal despite normalization of FEV(1). Imaging of regional abnormalities of gas exchange may be relevant in the evaluation of patients with asthma. PMID- 17703245 TI - Paradoxical embolization in an adult cystic fibrosis patient. AB - Cystic fibrosis patients with an implantable venous access device (IVAD) and a patent foramen ovale (PFO) are at an increased risk of developing paradoxical embolism. A 33-year-old patient who had a cerebrovascular accident in the above setting is described. She had been anticoagulated because she had thrombosis of the tip of the indwelling catheter, and her PFO was closed percutaneously followed by replacement of her IVAD. She made a full neurological recovery. Echocardiography and prophylactic closure of the PFO, when present, as primary prevention for paradoxical embolism may be warranted in cystic fibrosis patients before placement of an IVAD. PMID- 17703246 TI - Catamenial hemoptysis and pneumothorax in a patient with cystic fibrosis. AB - Hemoptysis or pneumothorax that recurs with the onset of menses is strongly suggestive of thoracic endometriosis syndrome (TES). TES is a rare disorder, with relatively few cases reported in the literature. A 32-year-old woman with cystic fibrosis, who over a period of several months had experienced recurrent catamenial hemoptysis and pneumothoraces, including an episode of life threatening hemoptysis that coincided with menstruation, is presented. Thoracic computed tomography and magnetic resonance imaging scans, as well as a bronchoscopic evaluation that demonstrated endobronchial lesions that disappeared after menses, support the diagnosis of TES in the present patient. The patient was treated empirically with danazol and subsequently underwent a successful double-lung transplantation. Danazol was discontinued postoperatively, and she was started on an oral contraceptive. Eighteen months post-transplant, she has not experienced a recurrence of her catamenial symptoms, despite having resumed a regular menstrual cycle. PMID- 17703247 TI - The difficult colonoscopy. PMID- 17703250 TI - Hospitalization-based major comorbidity of inflammatory bowel disease in Canada. AB - OBJECTIVE: To define the patterns of hospitalization for known major comorbidities associated with inflammatory bowel disease (IBD) in Canada. METHODS: The data source was the Statistics Canada Health Person Oriented Information hospital database (1994/1995 to 2003/2004). The number of stays for a diagnosis of Crohn's disease or ulcerative colitis by the International Classification of Diseases, ninth edition, codes 555 or 556, or the International Classification of Diseases, 10th edition, Canadian Enhancement, codes K50 or K51, was extracted. Age- and sex-specific and age-adjusted rates of hospitalization for selected IBD-related comorbidities were assessed. RESULTS: Rates of Hodgkin's disease and non-Hodgkin's lymphoma were low in the hospitalized IBD population. Rates for colon cancer, rectal cancer, pulmonary emboli and deep venous thromboembolism were generally higher among IBD patients younger than 50 years of age compared with the non-IBD hospitalized population. CONCLUSIONS: IBD was associated with life-threatening comorbidities such as venous thromboembolic disease and colon cancer among persons younger than 50 years of age to a greater extent than the general hospitalized population. Recent secular trends in rates of non-Hodgkin's lymphomas will need to be followed to determine whether the whole population, including IBD patients who receive immunomodulating therapies, are at increased risk. PMID- 17703248 TI - Management of solitary 1 cm to 2 cm liver nodules in patients with compensated cirrhosis: a decision analysis. AB - OBJECTIVES: Current guidelines, based on expert opinion, recommend that suspected 1 cm to 2 cm hepatocellular carcinoma (HCC) detected on screening be biopsied and, if positive, treated (eg, resection or transplantation). Alternative strategies are immediate treatment or observation until disease progression occurs. METHODS: A Markov decision model was developed that compared three management strategies - immediate resection, biopsy and resection if positive, and ultrasound surveillance every three months until disease progression - for a single 1 cm to 2 cm liver nodule suspicious for HCC following ultrasound screening and computed tomography confirmation. The cohort included 55-year-old patients with compensated cirrhosis and no significant comorbidities. The model used in the present study incorporated the probabilities of false-positive and false-negative results, needle-track seeding, HCC recurrence, cirrhosis progression and death. The quality-adjusted life expectancy (LE) and the unadjusted LE were evaluated and the model's strength was assessed with sensitivity analyses. RESULTS: In the base case analysis, biopsy, resection and surveillance yielded an unadjusted LE of 60.5, 59.7 and 56.6 months, respectively, and a quality-adjusted LE of 46.6, 45.6 and 43.8 months, respectively. In probabilistic sensitivity analyses, biopsy was the preferred strategy 69.5% of the time, resection 30.5% of the time and surveillance never. Resection was the optimal decision if the sensitivity of biopsy was very low (less than 0.45) or if the accuracy of the imaging tests resulted in a high percentage of HCC-positive patients (greater than 76%) in the screened cohort, as with expert interpretation of triphasic computed tomography. CONCLUSIONS: The present model suggests that biopsy is the preferred management strategy for these patients. When postimaging probability of HCC is high or pathology expertise is lacking, resection is the best alternative. Surveillance is never the optimal strategy. PMID- 17703249 TI - Helicobacter pylori infection in Ontario: prevalence and risk factors. AB - BACKGROUND: Helicobacter pylori has been classified by the World Health Organization as a type I carcinogen. Nearly 50% of the world's population is estimated to be infected with H pylori. Prevalence patterns of the infection are different between developing and developed countries. The present study had two objectives - to estimate the prevalence of H pylori infection in Ontario, and to evaluate the relationship between the infection and various demographic characteristics and selected lifestyle factors. METHODS: Ten microlitres of plasma were aliquoted from stored blood of 1306 men and women, 50 to 80 years of age, from Ontario. The blood samples belonged to control patients of a colorectal cancer population-based study group. Serological testing was used to detect H pylori infection; information was obtained on dietary intake and lifestyle habits, as well as past and present medical history, education, income, number of siblings, ethnicity and place of birth. RESULTS: The overall weighted seroprevalence of H pylori was 23.1% (95% CI 17.7% to 29.5%), with men having higher infection rates (29.4%, 95% CI 21.1% to 39.3%) than women (14.9%, 95% CI 10.1% to 21.4%). Seroprevalence of the infection increased significantly with age and number of siblings. Increased risk was also associated with being nonwhite, being born outside of Canada and immigrating at 20 years of age or older. An inverse association with seroprevalence was found for education and alcohol consumption. CONCLUSION: The prevalence of H pylori infection in Ontario is comparable with that of other developed countries. Age, sex, number of siblings, ethnicity, place of birth and age at immigration are among the factors associated with H pylori infection. PMID- 17703251 TI - Ileocolonic ulcer treated by endoscopic application of collagen polyvinylpyrrolidone. AB - Ulceration is a complication that may occur after an ileocolonic anastomosis. Most of the etiologies remain speculative. The case of a 33-year-old woman with eosinophilic colitis is reported, in whom a colectomy with an ileocolonic anastomosis was performed. After four months, the patient presented with a stenosis in the ileocolonic anastomosis, necessitating surgical restoration. Four weeks later, the patient presented with rectal bleeding, and a colonoscopy showed an ulcer in the anastomosis. Collagen-polyvinylpyrrolidone was applied into and on the surface of the ulcer, and five days later the procedure was repeated. Follow-up endoscopies at seven days and three months showed complete healing of the ulcer and the patient remained without bleeding throughout a further four weeks of follow-up tests. It was concluded that this biological product could be an excellent treatment for these lesions. PMID- 17703253 TI - Numeracy. PMID- 17703252 TI - Dramatic reduction in tumour size in hepatocellular carcinoma patients on thalidomide therapy. PMID- 17703254 TI - The role of enhanced external counterpulsation in the treatment of angina and heart failure. AB - As the incidence of angina and heart failure continue to rise, new therapeutic options will be needed to treat patients who remain symptomatic or who are intolerant to current treatment. Enhanced external counterpulsation (EECP) is a noninvasive modality being investigated in both angina and congestive heart failure patients. It has been proven to provide symptomatic benefit in angina patients, but has not been proven to show an increase in life expectancy or decrease in cardiovascular events. EECP in heart failure has been proven to be safe, but its efficacy is still uncertain. The present paper summarizes the current literature on the clinical use of EECP in angina and heart failure. PMID- 17703256 TI - A p.R870H mutation in the beta-cardiac myosin heavy chain 7 gene causes familial hypertrophic cardiomyopathy in several members of an Indian family. AB - Familial hypertrophic cardiomyopathy is an autosomal dominant genetic disorder characterized mainly by left ventricular hypertrophy and myocyte disarray; it is the most common cause of sudden death in otherwise healthy individuals. More than 270 mutations in genes encoding the cardiac sarcomere have been identified. Attempts to establish a genotype-phenotype correlation for each of the mutations have not been highly successful. It has been suggested that additional genetic loci, as well as nongenetic factors such as lifestyle, gender and age, may play a role in modulating the clinical presentation of the disease. The p.R870H mutation has been identified as the cause of familial hypertrophic cardiomyopathy in an Indian family. The results indicate that the disease phenotype varied among various affected members of the family, and the variation may be attributed to factors, such as gender and gene dosage. PMID- 17703255 TI - Polytherapy with two or more antihypertensive drugs to lower blood pressure in elderly Ontarians. Room for improvement. AB - BACKGROUND: Although guidelines now recommend polytherapy to achieve blood pressure targets, little is know about which antihypertensive drugs are combined in clinical practice. OBJECTIVE: To examine current practices for the coprescribing of antihypertensive agents. METHODS: A population-based cohort study was performed using linked administrative databases on all Ontario residents 66 years of age or older who were newly treated for hypertension between July 1, 1994, and March 31, 2002, and did not have diabetes or other relevant comorbidities. All patients were followed for two years to determine which antihypertensives were prescribed concurrently. RESULTS: Of the 166,018 patients in the described cohort, 1819 (1%) were prescribed a combination therapy tablet as their first-line therapy. The number of patients prescribed antihypertensive polytherapy within the first two years of diagnosis increased from 2071 (21%) of the 9825 hypertensive patients starting treatment in the second half of 1994 to 2578 (37%) of the 6988 hypertensive patients beginning treatment in the first quarter of 2002 (P<0.0001). Overall, 11,003 (27%) of polytherapy prescriptions were for drugs without additive hypotensive effects when combined and this proportion did not change over time. CONCLUSIONS: Although there has been an increase in the use of polytherapy in elderly hypertensive patients without comorbidities in Ontario over the past decade, more than one quarter of the two drugs prescribed together have not been proven to have additive hypotensive effects. Because this likely contributes to suboptimal blood pressure control rates, future guidelines and educational programs should devote increased attention to the choice of optimal polytherapy combinations. PMID- 17703257 TI - Preferences of patients with heart failure for prognosis communication. AB - BACKGROUND: Communication about prognosis is fundamental to discussions and planning for end-of-life (EOL) care for patients with advanced heart failure (HF). Little is known about the preferences of patients that could guide communication about prognosis. OBJECTIVES: To identify the preferences of patients with advanced HF regarding communication about their prognosis and its implications. METHODS: A qualitative study using a grounded theory methodology, based on one-to-one interviews with 20 patients recruited from Heart Function Clinic at the McMaster University Medical Centre in Hamilton, Ontario. RESULTS: The following four main themes about patient preferences were identified: level of wellness--patients wanted to learn about their prognosis and its implications at a time of optimal cognitive function, and not when their capacity for EOL decision making was diminished; opportunity to be informed--patients preferred physicians to initiate discussions about prognosis at the time of diagnosis; tell the truth--there was a strong preference for physicians to disclose prognostic possibilities, treatments and outcomes associated with HF, including the possibilities of deterioration and death; and maintain hope--there was a need for truth to be balanced with hope. Hope for quality of life, symptom control and control over EOL decisions were important to participants. CONCLUSIONS: The findings suggested that communication about prognosis between patients and physicians may be difficult and deferred. Preferences identified by patients offer guidance to physicians in planning and initiating dialogue about prognosis. PMID- 17703258 TI - Mitral insufficiency and morbidity and mortality in left ventricular dysfunction. AB - BACKGROUND: Mitral insufficiency is known to occur in a substantial proportion of patients with heart failure. Its relationship with morbidity and mortality is poorly described. METHODS: The mortality and hospitalization for heart failure were retrospectively examined in patients who underwent baseline echocardiography in the Studies Of Left Ventricular Dysfunction (SOLVD) treatment and prevention trials. The presence and grade of mitral insufficiency was assessed, and patients with and without mitral insufficiency were compared. RESULTS: Patients with left ventricular dysfunction and mitral insufficiency had greater than twofold increased risk of death or admission for heart failure over two years (RR 2.38, 95% CI 1.43 to 3.97). This excess risk persisted after adjustment for the severity of heart failure, etiology and differences in treatment (RR 1.82, 95% CI 1.04 to 3.17; P=0.04). The presence of moderate mitral insufficiency versus no insufficiency was associated with even greater independent risk (RR 2.20, 95% CI 1.01 to 4.80; P=0.05). Results were consistent with binary and ordinal analysis of mitral insufficiency. CONCLUSION: The presence of mitral insufficiency in patients with left ventricular dysfunction is independently associated with adverse outcomes, including death and hospitalization for heart failure. This has potentially important clinical implications for the assessment and management of patients with heart failure. PMID- 17703259 TI - Comparison of computed tomographic angiography versus rubidium-82 positron emission tomography for the detection of patients with anatomical coronary artery disease. AB - BACKGROUND: The present study compared computed tomographic coronary angiography (CTA) and positron emission tomography (PET) for the detection of significant anatomical coronary artery stenosis as defined by conventional invasive coronary angiography (CICA). METHODS: The study protocol was approved by the local ethics board, and informed consent was obtained from all patients. Of the 26 patients (mean age 57+/-9 years, 18 men) who prospectively underwent CTA and rubidium-82 PET before CICA, 24 patients had a history of chest pain. Images were interpreted by expert readers and assessed for the presence of anatomically significant coronary stenosis (50% luminal diameter stenosis or greater) or myocardial perfusion defects. Diagnostic test characteristics were analyzed using patient based, territory-based, vessel-based and segment-based analyses. RESULTS: In the 24 patients referred for chest pain, CTA had similar sensitivity to PET, but was more specific (sensitivity 95% [95% CI 72% to 100%] versus 95% [95% CI 72% to 100%], respectively; specificity 100% [95% CI 46% to 100%] versus 60% [95% CI 17% to 93%], respectively) in the detection of patients with anatomical coronary artery stenosis of 50% or greater. On a per-segment basis of all 26 patients, CTA had a sensitivity, specificity, positive predictive value and negative predictive value of 72%, 99%, 91% and 95%, respectively, in all coronary segments. CONCLUSIONS: Coronary CTA has a similar sensitivity and specificity to rubidium 82 PET for the identification of patients with significant anatomical coronary artery disease. PMID- 17703260 TI - Safety and efficiency of recombinant activated factor VII in postcardiotomy massive hemorrhage. AB - Postoperative massive hemorrhage is a difficult clinical situation after cardiac surgery. Recombinant activated factor VII (rf-VIIa) can be a useful adjunct to surgical hemostasis and blood product transfusion. Four cases of massive hemorrhage treated with rf-VIIa after complex cardiac surgery are reported. A review of the literature and possible guidelines for the use of rf-VIIa in cardiac surgery are provided. PMID- 17703261 TI - Intercostal muscle twitching: an unusual manifestation of extracardiac stimulation related to right ventricular outflow tract pacing. AB - The present case report describes a patient who underwent successful dual-chamber pacemaker implantation with active ventricular lead fixation at a high septal region in the right ventricular outflow tract. Unexpectedly, stimulation at a high output in the right ventricular outflow tract caused an unusual extracardiac stimulation, specifically, intercostal muscle twitching. PMID- 17703262 TI - Long-term morphological changes in a cryopreserved pulmonary valve homograft. AB - Pulmonary homografts (PHs) are frequently used to replace the native pulmonary valve in the Ross procedure, and in the reconstruction of the right ventricular outflow tract. The case of a 25-year-old man whose PH was replaced 12 years after undergoing the Ross procedure is reported. The clinical cause of the PH failure was stenosis. Morphological studies showed cusp tissue degeneration with tears and calcification, as well as pannus growth on the flow and nonflow surfaces of the cusps and the pulmonary artery graft. The durability of this PH was likely due to a combination of low pressure on the right side of the heart and the patient's age at surgery. PMID- 17703264 TI - Biomechanical stability of a volar locking-screw plate versus fragment-specific fixation in a distal radius fracture model. AB - Eight matched pairs of cadaveric radii were osteotomized by removing a 4-mm dorsal wedge of bone at the level of the sigmoid notch designed to simulate dorsal comminution. They were then fixed with either a volar locking-screw plate or fragment-specific fixation. All constructs underwent biomechanical testing in a custom-designed, custom-fabricated 4-point bending device. No statistically significant difference in stiffness was noted between the groups. Linear displacement and angulation at the osteotomy site were significantly less in the group with fragment-specific fixation at loads expected to be encountered during postoperative rehabilitation. Angulation at the osteotomy site was significantly less in the locking-screw plate group at higher loads. PMID- 17703265 TI - Vitallium cup arthroplasty: case report of a 57-year follow-up. PMID- 17703266 TI - Ipsilateral intertrochanteric and pipkin fractures: an unusual case. PMID- 17703267 TI - Treatment of radiation-induced soft-tissue fibrosis and concomitant acetabular osteonecrosis: a case report. PMID- 17703268 TI - Carpal tunnel syndrome: using self-report measures of disease to predict treatment response. AB - Initial self-report assessments of symptom severity in patients with carpal tunnel syndrome was retrospectively examined. At initial evaluation, 86 patients completed a self-administered questionnaire previously shown to be reproducible, internally consistent, and responsive to clinical change. Within the next 2 years, 50 patients underwent carpal tunnel release; of the other 36 patients, 23 were managed adequately with conservative treatment alone, and 13 were lost to follow-up. Initial mean symptom severity scores were statistically significantly higher for the surgery group (P = .000012). Significantly higher symptom severity scores on self-administered questionnaires at initial evaluation from patients who eventually undergo carpal tunnel release may be of value in planning treatment. PMID- 17703269 TI - Workers' compensation, return to work, and patient satisfaction after carpal tunnel decompression. AB - In the study reported here, we assessed satisfaction and return to work in workers' compensation (WC) patients after carpal tunnel decompression. Eighty of the 362 patients who underwent surgery met the study criteria; 42 of the 80 were found for follow-up; 40 of the 42 participated in the telephone questionnaire; 15 (38%) of the 40 received WC; and 39 (98%) of the 40 returned to work. Mean age of the 40 respondents was 47 years, and mean follow-up was 29 months. WC involvement was not related to return to work and did not affect satisfaction with overall outcome but was related to dissatisfaction with job factors and timing of return to work. PMID- 17703270 TI - Relationships between insulin-like growth factor-I (IGF-I) and OPG, RANKL, bone mineral density in healthy Chinese women. AB - Serum IGF-I level was negatively correlated with OPG and OPG/RANKL ratio, but positively correlated with RANKL. Serum OPG level in the highest quintile of IGF I was significantly lower than that in the lowest. We conclude that the effect of IGF-I on bone remodeling may be mediated by the OPG/RANKL system. INTRODUCTION: Insulin-like growth factor I (IGF-I) is an important factor in coupling bone remodeling, activating both formation and resorption. Compared with the many studies on the role of IGF-I in bone formation, the information regarding its effects on bone resorption is limited and conflicting. The balance of the two peptides produced by osteoblasts, osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL), is critical for the bone resorption process. Our study was designed to analyze the relationships of serum concentrations of IGF-I with OPG, RANKL, OPG/RANKL ratio as well as BMDs in healthy Chinese women. METHODS: BMDs at lumbar spine and proximal femur in 504 pre- and postmenopausal women were measured by DXA. Serum levels of IGF-I, OPG and RANKL were also measured. Pearson's correlation and partial correlation analysis, ANOVA, covariance analysis and stepwise multiple regression analysis were used as appropriate. RESULTS: Age was negatively correlated with serum levels of IGF-I (r = -0.702, p < 0.001). IGF-I was negatively correlated with OPG and OPG/RANKL ratio, but positively correlated with RANKL. The relationship between IGF-I and BMDs disappeared after adjustment for age. In postmenopausal women, IGF-I was lower in women with osteoporosis than in those with normal BMD (p = 0.056), but no differences were found among OPG, RANKL and OPG/RANKL ratio. Serum levels of OPG in the highest quintile of IGF-I were significantly lower than those in the lowest quintile of IGF-I, while no difference was found in RANKL. In the multiple regression analysis model, serum levels of IGF-I were the main determinants of the bone mass in Chinese women. CONCLUSIONS: In conclusion, the relationship between decreasing IGF-I and BMDs in healthy Chinese women influenced by age, whereas the effect of IGF-I on bone remodeling (bone resorption) may be mediated by the OPG/RANKL system. PMID- 17703271 TI - Association between myostatin gene polymorphisms and peak BMD variation in Chinese nuclear families. AB - We identified 17 polymorphisms in myostatin by sequencing, and three informative single nucleotide polymorphisms (SNPs) were selected for further observation for their association with peak BMD of women in 401 Chinese nuclear families. Our results suggest that genetic polymorphisms in myostatin likely play a role in attainment of peak BMD in Chinese women. INTRODUCTION: Myostatin is a TGF-beta family member that is a negative regulator of skeletal muscle growth. MATERIALS AND METHODS: We identified SNPs in myostatin by direct sequencing. Furthermore, using a quantitative transmission disequilibrium test (QTDT). we tested and further test whether SNPs were associated with peak bone mineral density (BMD) variation at the spines and hips of 401 Chinese nuclear families. We identified 17 polymorphisms in myostatin by sequencing. Next, we selected three informative SNPs for further observation of an association with peak BMD of premenopausal women in 401 Chinese nuclear families. RESULTS: Using QTDT for the within-family association, we found significant association between rs2293284 and total hip, femoral neck, and trochanter BMD (all p < 0.05), while rs7570532 was associated with total hip and trochanter BMD (p = 0.034 and p = 0.035, respectively). The within-family association was significant between BMI and +2278G > A (p = 0.022). Subsequent permutations were in agreement with these significant within-family association results. Moreover, analyses of the haplotypes confer further evidence for association of rs2293284 and rs7570532 with hip peak BMD variation. CONCLUSIONS: These results suggest, for the first time, the genetic polymorphisms in myostatin likely play a role in attainment of peak BMD in Chinese women. PMID- 17703272 TI - Variations along the 24-hour cycle of circulating osteoprotegerin and soluble RANKL: a rhythmometric analysis. AB - The variability of serum osteoprotegerin (OPG) and soluble RANKL (sRANKL) along the 24-h cycle was assessed in 20 healthy women. No rhythmic variations of serum OPG, sRANKL or sRANKL/OPG ratio were detected as a group phenomenon. Timing of sampling is unlikely to influence the results of measurements of circulating OPG and sRANKL. INTRODUCTION: Physiological bone turnover shows diurnal variations. The aim of the study was to assess variability of OPG and sRANKL serum levels along the 24-h cycle. METHODS: Blood was collected from 20 healthy women (median age 31 years, range 25-65 years) at 4-h intervals between 08:00 and 24:00 and at 2-h intervals between 24:00 and 08:00. Serum albumin, cortisol, osteocalcin (OC), C-terminal telopeptide of type I collagen (CTX), OPG and total sRANKL were measured. Temporal variations were assessed by the COSINOR model. RESULTS: Circadian rhythms of cortisol and albumin documented a normal synchronization within the circadian structure. Serum OC and CTX showed rhythmic variations, peaking at night-time. Rhythmic variations of serum OPG, sRANKL and sRANKL/OPG ratio were not detected as a group phenomenon. On an individual basis, rhythmic changes were detected in ten patients for OPG and eight patients for sRANKL, with very small amplitudes and heterogeneous acrophases. CONCLUSIONS: The absence of consistent rhythmic variations of circulating OPG and sRANKL levels may reflect the absence of rhythmic variations of their expression in the bone microenvironment. Were this the case, the nocturnal rise of bone resorption should be accounted for by different, not RANKL/OPG-mediated factors. Since circulating OPG and sRANKL may derive from sources other than bone, rhythmicity could be masked by non-rhythmic or non-synchronized rhythmic expression in these sources. Timing of sampling is unlikely to influence the results of measurements of circulating OPG and sRANKL. PMID- 17703273 TI - Cavernous transformation of the portal vein: three-dimensional dynamic contrast enhanced MR angiography. AB - BACKGROUND: To investigate characteristic features of three-dimensional dynamic contrast-enhanced MR angiography (3D DCE-MRA) and validate its clinical significance for the diagnosis of cavernous transformation of the portal vein (CTPV). METHODS: 3D DCE-MRA, along with subsequent data processing using three dimensional reconstruction, was performed in 33 CTPV patients. We observed 33 emboli in the portal vein, 29 in the left and/or right portal branches, 18 in the superior mesenteric vein, and nine emboli in the splenic vein. RESULTS: The main presentation of CTPV on 3D DCE-MRA was the replacement of the normal configuration of the portal vein by numerous distorted hepatopetal collateral vessels, the presence of arterio-portal venous shunts, and the appearance of hepatofugal collateral vessels in the abdominal cavity and wall. CONCLUSION: 3D DCE-MRA can be used to simultaneously characterize the portal system and collateral vessels, and can improve the diagnosis and clinical treatment of CTPV. PMID- 17703274 TI - Molecular identification of the ichthyosporean protist "Pseudoperkinsus tapetis" from the mytilid mussel Adipicola pacifica associated with submerged whale carcasses in Japan. AB - A protist tentatively designated "Pseudoperkinsus tapetis" belonging to the eukaryotic group Ichthyosporea (Mesomycetozoa) was previously isolated from carpet shell clams in Galicia (northwest Spain). In the present study, based on molecular data, a potential P. tapetis specimen was identified from the gill tissues of the mussel Adipicola pacifica associated with whale carcasses (generating chemosynthetic-based ecosystems) collected at shelf depths in the northwest Pacific (southwest Japan). Small subunit ribosomal DNA sequences (1751 sites) of the genotypes of P. tapetis from Spain and Japan were almost identical (only one substitution and one insertion/deletion difference). On the other hand, differences of 10 and 8 substitutions were found in two internal transcribed spacer regions of ribosomal DNA, ITS1 (288 sites) and ITS2 (251 sites) between these two genotypes, respectively, indicating that they are genetically different at the population level. These findings suggest that P. tapetis occurs worldwide and can associate with (and possibly infect) various types of bivalves. Further, a PCR method to specifically detect the P. tapetis cells in the host was also established. PMID- 17703275 TI - Detecting asymmetries in balance control with system identification: first experimental results from Parkinson patients. AB - Cognitive processes can influence balance in various ways, but not all changes in postural performance can easily be identified with the naked clinical eye. Various studies have shown that dynamic posturography is able to detect more subtle changes in balance control. For patients with Parkinson's disease (which is typically an asymmetric disease), changes in the symmetry of balance control might provide a sensitive measure of cognitive influences on balance. Here, we describe a new posturography technique that combines dynamic platform perturbations with system identification techniques to detect such asymmetries in balance control of two patients with Parkinson's disease. Results were compared to those of six healthy controls. Our pilot data show clear asymmetries in dynamic balance control, even though patients themselves were not aware of this and had no subjective problems with stability or standing. We also found asymmetries in weight bearing, but the asymmetries in dynamic balance contribution were larger. Finally, asymmetries in weight bearing and dynamic balance in patients were not tightly coupled as in healthy controls. Future studies could incorporate this approach when examining the influence of mental decline on postural regulation. PMID- 17703276 TI - Y-chromosome haplogroup N dispersals from south Siberia to Europe. AB - In order to reconstruct the history of Y-chromosome haplogroup (hg) N dispersals in north Eurasia, we have analyzed the diversity of microsatellite (STR) loci within two major hg N clades, N2 and N3, in a total sample of 1,438 males from 17 ethnic groups, mainly of Siberian and Eastern European origin. Based on STR variance analysis we observed that hg N3a is more diverse in Eastern Europe than in south Siberia. However, analysis of median networks showed that there are two STR subclusters of hg N3a, N3a1 and N3a2, that are characterized by different genetic histories. Age calculation of STR variation within subcluster N3a1 indicated that its first expansion occurred in south Siberia [approximately 10,000 years (ky)] and then this subcluster spread into Eastern Europe where its age is around 8 ky ago. Meanwhile, younger subcluster N3a2 originated in south Siberia (probably in the Baikal region) approximately 4 ky ago. Median network and variance analyses of STR haplotypes suggest that south Siberian N3a2 haplotypes spread further into Volga-Ural region undergoing serial bottlenecks. In addition, median network analysis of STR data demonstrates that haplogroup N2 A is represented by two subclusters, showing recent expansion times. The data obtained allow us to suggest Siberian origin of haplogroups N3 and N2 that are currently widespread in some populations of Eastern Europe. PMID- 17703277 TI - CC chemokine receptor-2A is frequently overexpressed in glioblastoma. AB - Macrophages and monocytes migrate in response to chemotactic cytokines such as monocyte chemoattractant protein 1 (MCP-1/CCL2) in a variety of tissues including the central nervous system. Overexpression of MCP-1 has been reported in glioblastoma (GBM), which correlates to prominent macrophage infiltration characterized by this tumor type, but whether MCP-1 receptor is also expressed by the neoplastic cells remains unclear. Expression of MCP-1 and its receptor, CC chemokine receptor 2 (CCR2), were examined in GBM using cDNA microarrays and validated in two independent microarray datasets. We investigated the expression of the CCR2A isoform in human glioma cell lines and GBM, and found overexpression of CCR2A in most GBM specimens examined when compared to normal brain tissues. CCR2A is mainly localized in the cytoplasm of neoplastic cells, and pronounced neuronal cytoplasmic CCR2A immunoreactivity in tumor-infiltrating area was associated with prior chemo/radiation therapy. Glioma cells ectopically overexpressing CCR2A demonstrated increased migration compared to vector transfected cells in vitro. Inhibition of MCP-1 synthesis suppressed migration of CCR2A-overexpressed glioma cells. Our data suggest that CCR2A might be associated with the pathobiology of GBM such as host response to treatment and tumor cell migration. PMID- 17703279 TI - Prenuptial perfume: alloanointing in the social rituals of the crested auklet (Aethia cristatella) and the transfer of arthropod deterrents. AB - Alloanointing, the transfer of chemicals between conspecifics, is known among mammals, but hitherto, the behavior has not been documented for birds. The crested auklet (Aethia cristatella), a colonial seabird of Alaskan and Siberian waters, alloanoints during courtship with fragrant aldehydes that are released from specialized wick-like feathers located in the interscapular region. Crested auklets solicit anointment at the colony, and prospective mates rub bill, breast, head, and neck over wick feathers of their partners. This distributes aldehydes over the head, neck, and face where the birds cannot self-preen. The resulting chemical concentrations are sufficient to deter ectoparasites. Auklets that emit more odorant can transfer more defensive chemicals to mates and are thus more sexually attractive. Behavioral studies showed that crested auklets are attracted to their scent. Wild birds searched for dispensers that emitted their scent and rubbed their bills on the dispensers and engaged in vigorous anointment behaviors. In captive experiments, naive crested auklets responded more strongly to synthetic auklet scent than controls, and the greatest behavioral response occurred during early courtship. This study extends scientific knowledge regarding functions of alloanointing. Alloanointing had previously been attributed to scent marking and individual recognition in vertebrates. Alloanointing is described here in the context of an adaptive social cue--the transfer of arthropod deterrents between prospective mates. PMID- 17703278 TI - Genetic and genomic approaches to develop rice germplasm for problem soils. AB - Soils that contain toxic amounts of minerals or are deficient in essential plant nutrients are widespread globally and seriously constrain rice production. New methods are necessary to incorporate the complex adaptive traits associated with tolerance of these abiotic stresses, while simultaneously retaining the high yield potential of rice varieties when conditions are favorable. Significant progress in the genetic characterization of stress response pathways and recent advances in genomics have provided powerful tools for in-depth dissection of tolerance mechanisms. Additionally, tolerance of most of these abiotic stresses in rice is controlled by a few QTLs with large effects despite the intricacy of the numerous traits involved. Genetic dissection of these QTLs and their incorporation into high-yielding varieties will significantly enhance and stabilize rice productivity in these problem soils. Current efforts at IRRI and in rice breeding programs worldwide are seeking to explore diverse germplasm collections and genetically dissect the causal mechanisms of tolerance to facilitate their use in breeding. This review focuses on salinity and P and Zn deficiency as the major problems encountered in rice soils, and examines current understanding of the mechanisms involved and efforts toward germplasm improvement. PMID- 17703280 TI - Measurement of functional residual capacity by helium dilution during partial support ventilation: in vitro accuracy and in vivo precision of the method. AB - OBJECTIVE: Measurement of functional residual capacity (FRC) during controlled and especially during assisted ventilation remains a challenge in the physiological evaluation of ventilated patients. To validate a bag-in-box closed helium dilution technique allowing measurements both during pressure-controlled (PCV) and pressure-support ventilation (PSV). DESIGN AND SETTING: Experimental study on lung models containing different volumes, and measurements in patients in the intensive care unit of a university hospital. In patients measurements were performed in duplicate during controlled and assisted ventilation. PATIENTS: Thirty-three patients (aged 57+/-17 years) mechanically ventilated with PCV and PSV. MEASUREMENTS AND RESULTS: In the lung model assessment of accuracy showed an overall mean difference between FRC measurements and lung model volume of 0.5% (2 SD 5.7%). In patients assessment of repeatability showed a bias between duplicate FRC measurements of -1+/-70 ml (95% CI -141 to +139 ml). The coefficient of variation was of 3.2% for all measurements with a comparable repeatability in PSV and PCV mode (coefficient of variation of 3.4 and 3.2%, respectively). During the rebreathing period a small reduction in tidal volume (-8.5+/-5.4%) and mean airway pressure (-2.3+/-4.7%) was observed with only a 0.3 cmH2O mean increase in PEEP and no change in respiratory rate and I/E ratio. CONCLUSIONS: This specifically designed closed helium dilution bag-in-box technique allows accurate FRC measurement with good repeatability during both partial PSV and PVC without exposing patients to disconnection and changes in PEEP. PMID- 17703281 TI - Post-ICU consequences of patient wakefulness and sedative exposure during mechanical ventilation. AB - OBJECTIVE: To determine the relationship between measures of critical illness (sedative/analgesic administration, wakefulness and organ dysfunction), intensive care unit (ICU) recall and symptoms of posttraumatic stress disorder. DESIGN: Prospective, observational study with post-ICU follow-up. SETTING: Medical and surgical ICUs at a teaching hospital. PATIENTS: Two hundred seventy-seven subjects requiring >36h of mechanical ventilation were enrolled; 149 completed follow-up interviews 2 months later and 80 at 6 months. INTERVENTIONS: None. RESULTS: ICU recall was greater for events occurring at the end of critical illness; however, 18% of subjects had amnesia for the entire ICU course. Factual ICU recall was weakly associated with increased wakefulness during mechanical ventilation (r2=0.03-0.11, p<0.05). Posttraumatic stress disorder prevalence was 17% at 2 months and 15% at 6 months. The avoidance-numbing cluster had the highest specificity (91%) for a formal diagnosis and the re-experiencing cluster had the lowest (69%). Recall of a delirious memory during critical illness was associated with more severe posttraumatic stress symptoms, but there was no association between posttraumatic stress symptoms and factual recall of ICU events. Neither ICU recall nor posttraumatic stress symptoms were associated with the intensity of sedative administration during mechanical ventilation. Posttraumatic stress symptoms were lowest in patients either the most awake during mechanical ventilation or the least awake. CONCLUSION: Wakefulness during mechanical ventilation has a greater influence on post-ICU recall and posttraumatic stress symptoms than sedative drug exposure or severity of illness. It is difficult to predict the future psychological consequences of an individual patient's critical illness. PMID- 17703284 TI - Location memory biases reveal the challenges of coordinating visual and kinesthetic reference frames. AB - Five experiments explored the influence of visual and kinesthetic/proprioceptive reference frames on location memory. Experiments 1 and 2 compared visual and kinesthetic reference frames in a memory task using visually-specified locations and a visually-guided response. When the environment was visible, results replicated previous findings of biases away from the midline symmetry axis of the task space, with stability for targets aligned with this axis. When the environment was not visible, results showed some evidence of bias away from a kinesthetically-specified midline (trunk anterior-posterior [a-p] axis), but there was little evidence of stability when targets were aligned with body midline. This lack of stability may reflect the challenges of coordinating visual and kinesthetic information in the absence of an environmental reference frame. Thus, Experiments 3-5 examined kinesthetic guidance of hand movement to kinesthetically-defined targets. Performance in these experiments was generally accurate with no evidence of consistent biases away from the trunk a-p axis. We discuss these results in the context of the challenges of coordinating reference frames within versus between multiple sensori-motor systems. PMID- 17703283 TI - Nicotinic acetylcholine receptors in the ventral tegmental area mediate the dopamine activating and reinforcing properties of ethanol cues. AB - RATIONALE: Cues associated with alcohol can elicit craving, support drug-seeking and precipitate relapse. OBJECTIVES: We investigated the possible involvement of nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area (VTA) in the conditioned reinforcing properties of ethanol-associated stimuli in the rat. MATERIALS AND METHODS: First, using in vivo microdialysis, we analyzed the effect of VTA perfusion of the nonselective nAChR antagonist mecamylamine (MEC) or the selective alpha4beta2* nAChR antagonist dihydro-beta-erythroidine (DHbetaE) on the nucleus accumbens (nAc) dopaminergic response to the presentation of an ethanol-associated conditioned stimulus (CS). Second, rats were trained to associate a tone+light CS with the presentation of 10% ethanol and were subsequently tested on the acquisition of a new instrumental response with conditioned reinforcement (CR) after local VTA infusion of MEC, DHbetaE, or alpha Conotoxin MII (alpha-CtxMII, a selective alpha3beta2* and alpha6* nAChR antagonist). RESULTS: The ethanol-associated CS elevated nAc dopamine, an effect that was blocked by VTA perfusion of MEC but not DHbetaE. Systemic administration of MEC or local VTA infusion of MEC or alpha-CtxMII selectively blocked ethanol associated CR, whereas systemic DHbetaE had no effect. CONCLUSIONS: We hypothesize a novel mechanism by which alcohol-associated cues promote drug seeking behavior via activation of dopamine-stimulating alpha-CtxMII-sensitive nAChRs in the VTA. Pharmacological manipulations of selective nAChRs may thus be possible treatment strategies to prevent cue-induced relapse. PMID- 17703285 TI - Influence of expectation on postural disturbance evoked by proprioceptive stimulation. AB - Recent experiments have shown that the vestibular channel of balance control differs fundamentally from the visual channel. Whereas the response to a visual perturbation can be suppressed if the subject has awareness that an upcoming disturbance is likely to be caused by an external agent rather than by self motion, a similar assumption cannot be made concerning the vestibular system. The present experiment investigated whether postural responses evoked by a proprioceptive perturbation (vibration of the Achilles' tendon at 90 Hz for 2.2 s) are either automatic and immune to expectation (similarly to vestibular responses) or cognitively penetrable (similarly to visual responses). Subjects (n = 12) stood on a force platform while stimuli were delivered either by the subject himself (self-triggered condition) or by the experimenter. For the latter condition, the stimulus was delivered either without warning (unpredictable condition) or at a fixed interval (500 ms) following an auditory cue (precue condition). Results showed that the backward CoP displacement induced by vibration was delayed by approximately 500 ms in the expected and self-triggered conditions compared to the unexpected condition. However, once initiated, the velocity of the backward displacement was higher in the self-triggered condition as compared to the unexpected condition. After a period of 2.2 s of vibration, the amplitude of this backward CoP displacement was similar in the three experimental conditions. Therefore, although expectation appears to delay the upcoming of the main backward body sway, it does not appear to be able to weight the impact of the proprioceptive stimulation. This suggested that afferents provided by the different sensory channels involved in postural control are not similarly susceptible to high level processes such as expectation. PMID- 17703286 TI - Asymmetric interlimb transfer of concurrent adaptation to opposing dynamic forces. AB - Interlimb transfer of a novel dynamic force has been well documented. It has also been shown that unimanual adaptation to opposing novel environments is possible if they are associated with different workspaces. The main aim of this study was to test if adaptation to opposing velocity dependent viscous forces with one arm could improve the initial performance of the other arm. The study also examined whether this interlimb transfer occurred across an extrinsic, spatial, coordinative system or an intrinsic, joint based, coordinative system. Subjects initially adapted to opposing viscous forces separated by target location. Our measure of performance was the correlation between the speed profiles of each movement within a force condition and an 'average' trajectory within null force conditions. Adaptation to the opposing forces was seen during initial acquisition with a significantly improved coefficient in epoch eight compared to epoch one. We then tested interlimb transfer from the dominant to non-dominant arm (D --> ND) and vice-versa (ND --> D) across either an extrinsic or intrinsic coordinative system. Interlimb transfer was only seen from the dominant to the non-dominant limb across an intrinsic coordinative system. These results support previous studies involving adaptation to a single dynamic force but also indicate that interlimb transfer of multiple opposing states is possible. This suggests that the information available at the level of representation allowing interlimb transfer can be more intricate than a general movement goal or a single perceived directional error. PMID- 17703282 TI - Cardiovascular responses produced by 5-hydroxytriptamine:a pharmacological update on the receptors/mechanisms involved and therapeutic implications. AB - The complexity of cardiovascular responses produced by 5-hydroxytryptamine (5-HT, serotonin), including bradycardia or tachycardia, hypotension or hypertension, and vasodilatation or vasoconstriction, has been explained by the capability of this monoamine to interact with different receptors in the central nervous system (CNS), on the autonomic ganglia and postganglionic nerve endings, on vascular smooth muscle and endothelium, and on the cardiac tissue. Depending, among other factors, on the species, the vascular bed under study, and the experimental conditions, these responses are mainly mediated by 5-HT(1), 5-HT(2), 5-HT(3), 5 HT(4), 5-ht(5A/5B), and 5-HT(7) receptors as well as by a tyramine-like action or unidentified mechanisms. It is noteworthy that 5-HT(6) receptors do not seem to be involved in the cardiovascular responses to 5-HT. Regarding heart rate, intravenous (i.v.) administration of 5-HT usually lowers this variable by eliciting a von Bezold-Jarisch-like reflex via 5-HT(3) receptors located on sensory vagal nerve endings in the heart. Other bradycardic mechanisms include cardiac sympatho-inhibition by prejunctional 5-HT(1B/1D) receptors and, in the case of the rat, an additional 5-ht(5A/5B) receptor component. Moreover, i.v. 5 HT can increase heart rate in different species (after vagotomy) by a variety of mechanisms/receptors including activation of: (1) myocardial 5-HT(2A) (rat), 5 HT(3) (dog), 5-HT(4) (pig, human), and 5-HT(7) (cat) receptors; (2) adrenomedullary 5-HT(2) (dog) and prejunctional sympatho-excitatory 5-HT(3) (rabbit) receptors associated with a release of catecholamines; (3) a tyramine like action mechanism (guinea pig); and (4) unidentified mechanisms (certain lamellibranch and gastropod species). Furthermore, central administration of 5-HT can cause, in general, bradycardia and/or tachycardia mediated by activation of, respectively, 5-HT(1A) and 5-HT(2) receptors. On the other hand, the blood pressure response to i.v. administration of 5-HT is usually triphasic and consists of an initial short-lasting vasodepressor response due to a reflex bradycardia (mediated by 5-HT(3) receptors located on vagal afferents, via the von Bezold-Jarisch-like reflex), a middle vasopressor phase, and a late, longer lasting, vasodepressor response. The vasopressor response is a consequence of vasoconstriction mainly mediated by 5-HT(2A) receptors; however, vasoconstriction in the canine saphenous vein and external carotid bed as well as in the porcine cephalic arteries and arteriovenous anastomoses is due to activation of 5-HT(1B) receptors. The late vasodepressor response may involve three different mechanisms: (1) direct vasorelaxation by activation of 5-HT(7) receptors located on vascular smooth muscle; (2) inhibition of the vasopressor sympathetic outflow by sympatho-inhibitory 5-HT(1A/1B/1D) receptors; and (3) release of endothelium derived relaxing factor (nitric oxide) by 5-HT(2B) and/or 5-HT(1B/1D) receptors. Furthermore, central administration of 5-HT can cause both hypotension (mainly mediated by 5-HT(1A) receptors) and hypertension (mainly mediated by 5-HT(2) receptors). The increasing availability of new compounds with high affinity and selectivity for the different 5-HT receptor subtypes makes it possible to develop drugs with potential therapeutic usefulness in the treatment of some cardiovascular illnesses including hypertension, migraine, some peripheral vascular diseases, and heart failure. PMID- 17703287 TI - Influence of gravitoinertial force level on the subjective vertical during recumbent yaw axis body tilt. AB - We tilted recumbent subjects at various angles about their yaw (foot to head) axis and had them indicate the direction of their subjective vertical and apparent head midline about the same axis. One set of tests was conducted during parabolic flight maneuvers where the background gravitoinertial acceleration varied from 0 to 1.8g. The blindfolded subjects (n = 6) were tested supine and at tilts of 60 degrees and 30 degrees left and right about their horizontal long body axis. They used a gravity neutral joystick to indicate their subjective vertical or their head midline continuously from the high force through the 0g portions of parabolas. In 0g, all subjects felt supine and oriented the joystick perpendicular to their body when indicating the subjective vertical. This points to strong influences of the symmetric somatic touch and pressure cues from the apparatus on orientation when the otolith organs are unloaded. In contrast to the settings in 0g, settings of the subjective vertical in 1g and 1.8g varied as a function of body orientation. However, the settings did not differ between 1g and 1.8g test conditions. Subjective vertical judgments were also made by subjects (n = 11) in the Brandeis slow rotation room, with the room stationary and rotating at a speed that produced a 2g resultant of gravitational and centrifugal acceleration. There were no differences between settings of the subjective vertical made in 1g and 2g. The similarity of 1g and hyper-g settings during recumbent yaw tilts, both in parabolic flight and in the rotating room, contrasts with the previously observed, strong influence which force levels above 1g have on settings of the subjective vertical during tilt of the body in pitch or roll. The findings for all three axes are consistent with a recently developed model of static spatial orientation. PMID- 17703289 TI - Intracellular localization of human respiratory syncytial virus L protein. AB - Replication and transcription of the human respiratory syncytial virus (hRSV) genome is carried out by the ribonucleocapsid complex (RNA together with N, P, M2 1 and L proteins), with the L protein being responsible for all enzymatic activities. In the present study, we obtained anti-L polyclonal sera in mice. These antibodies were functional in immunofluorescence and Western blotting assays in hRSV-infected HEp-2 cells. In the immunofluorescence assays, we detected inclusion bodies in the anti-L staining, similar to the ones seen by anti-N or anti-P staining. The results presented here provide the first evidence of the intracellular localization of the hRSV L protein. PMID- 17703288 TI - Emerging and disappearing synergies in a hierarchically controlled system. AB - The purpose of the study was to explore the ability of the central nervous system (CNS) to organize synergies at two levels of a hypothetical control hierarchy involved in two-hand, multi-finger tasks. We investigated indices (DeltaV) of finger force co-variation across trials as reflections of synergies stabilizing the total force (F (TOT)). Subjects produced constant force with one or two finger-pairs (from one hand or two hands). In trials starting with one finger pair, subjects added another finger-pair without changing F (TOT). In trials starting with two finger-pairs, subjects removed one of the finger-pairs without changing F (TOT). Adding or removing a finger-pair resulted in a transient drop in DeltaV computed for the finger-pair that remained active throughout the trial. This drop in DeltaV was seen simultaneously with force changes. Compared to the original steady-state, addition of a finger-pair led to a significant drop in DeltaV at the newly established steady-state. This drop eliminated negative co variation among finger forces that had stabilized F (TOT). In contrast, in trials starting with two finger-pairs, no negative co-variation between finger forces within-a-pair was seen. Removing a finger-pair led to the emergence of negative co-variation between finger forces at the new steady-state. The DeltaV index computed across two finger-pairs confirmed the existence of negative force co variation. The emergence and disappearance of force stabilizing synergies within a finger-pair may signal limitations in the ability of the CNS in forming synergies at two different hierarchical levels. PMID- 17703290 TI - Complete nucleotide sequences of cotton leaf curl Rajasthan virus and its associated DNA beta molecule infecting tomato. PMID- 17703291 TI - Gated SPECT imaging to detect changes in myocardial blood flow during progressive coronary occlusion. AB - BACKGROUND: The ability to track dynamic changes in myocardial blood flow (MBF) and wall motion with serial gated perfusion imaging may be a limiting factor in assessing new therapies. The purpose of this study was to determine whether gated Tc-99 m sestamibi (MIBI) SPECT imaging can track small changes in MBF in a model of progressive ischemia. METHODS: Eight pigs (20 kg) underwent lateral thoracotomy for placement of an ameroid constrictor on the left circumflex coronary artery (LCX) and indwelling femoral and left atrial catheters for serial microsphere determinations of absolute MBF. Animals underwent concurrent left atrial microsphere and Tc-99 m sestamibi (0.3 mCi/Kg IV) injections at weekly intervals over 6 weeks per animal. Gated SPECT imaging was acquired for each injection using high resolution collimation and standard processing. The animals were sacrificed on day 42. Mean signal intensity (SI) from regions of interest (ROI) corresponding to control and ischemic MBF by microspheres was measured for three SPECT short-axis images. Mean contrast ratio (MCR) was calculated from the ratio of ischemic to control SI per slice. Regional wall motion (RWM) from gated images was scored 1-5 using a 16 segment model and a score index (RWMI) was calculated. RESULTS: MBF decreased progressively (27% below resting values [P < 0.0001]) but with a clear and significant partial recovery by day 42 (13% improvement from peak ischemia, [P < 0.01]). SPECT perfusion and gated RWM closely paralleled the dynamic pattern of MBF caused by the ameroid constrictor. SPECT MCR decreased 21% from baseline scans in the LCX territory (P < 0.0001) and improved 11% from peak ischemia (P < 0.01) while the gated RWMI (1.0 at baseline) peaked at 1.36 and improved to 1.13 by day 42. CONCLUSION: Gated SPECT-a technique readily available-tracks dynamic changes in MBF closely with both perfusion and RWM. For trials of new therapies for the alleviation of chronic ischemia, these findings have direct implications for measuring efficacy. PMID- 17703292 TI - 3-Dimensional planning of endovascular procedures with multi-detector computed tomography (MDCT): impact on procedural results and clinical outcome? PMID- 17703293 TI - X-ray computed tomography coronary angiography--defining the role of a new technique. PMID- 17703294 TI - Comparison of intravascular ultrasonic imaging with versus without incomplete stent apposition at follow-up after drug-eluting stent implantation. AB - BACKGROUND: Incomplete stent apposition (ISA) at follow-up has been reported to be more common after drug-eluting stent (DES) implantation than after bare-metal stent (BMS) implantation. The aim of this study was to use intravascular ultrasound (IVUS) to evaluate the coronary characteristics after drug-eluting stent implantation in patients with ISA at follow-up. METHODS: From the IVUS database of our institute, a total of 89 patients with 125 native lesions who underwent DES implantation into de novo lesions with IVUS imaging at 6-month follow-up were identified, and 15 (16.9%) patients had documented ISA at follow up by IVUS. The ISA group was compared with a matched control group of patients (n = 30) who had no evidence of ISA at follow-up. RESULTS: Of the 15 documented ISA at follow-up after DES implantation, two located at the edge (within 5 mm from stent margin) while 13 in the body of the stent. The maximum area and arc of ISA measured 5.3 +/- 2.2 mm(2) and 163 +/- 67 degrees , respectively. In patients with ISA, the maximum EEM area of stent segment with ISA was significantly larger than the adjacent stent segment without ISA (24.1 +/- 3.3 vs. 20.1 +/- 3.1 mm(2), P = 0.002), while stent area, plaque plus media (P&M) area and intrastent lumen area were comparable (P > 0.05). Compared to the matched control cohort without ISA at follow-up, the maximum EEM area was also significantly larger (24.1 +/- 3.3 vs. 18.8 +/- 4.2 mm(2), P < 0.001), while the areas of reference EEM and lumen, stent, P&M behind the stent, intimal hyperplasia and intrastent lumen were all comparable between the two groups (P > 0.05). CONCLUSION: ISA at follow-up after DES implantation for de novo coronary lesions was associated with a larger EEM area. PMID- 17703295 TI - Treatment of wide-necked intracranial aneurysms with a novel self-expanding two zonal endovascular stent device. AB - INTRODUCTION: Endovascular treatment of intracerebral wide-necked aneurysms carries the risk of incomplete embolisation and recanalisation of the aneurysm as well as coil protrusion into the parent artery and embolic complications. We present preliminary results with the placement of a novel tightly braided stent across the aneurysm neck which might lead to thrombosis of these aneurysms. METHODS: A bifurcation artery aneurysm was created in a male New Zealand White Rabbit. After 4 weeks, a novel highly flexible stent with a central tightly braided mesh was placed across the aneurysm neck. Diagnostic angiography was performed during the procedure and immediately after stent deployment as well as 2 and 4 weeks following stent placement. Histological analyses, including microscopic investigations for evaluating intra-aneurysmal thrombosis and proliferation of the intima, were performed after 1 month. RESULTS: Intra aneurysmal flow reduction due to stent placement was achieved as early as 45 min after deployment. Unchanged complete occlusion of the aneurysm could be observed by angiography 2 and 4 weeks post-stent deployment. Histological analysis confirmed angiographical findings of complete aneurysm occlusion and excluded significant neointimal coverage. CONCLUSION: This newly designed flexible stent may offer the potential to expand endovascular treatment of wide-necked intracranial aneurysms. PMID- 17703297 TI - Improved expression of a soluble single chain antibody fusion protein containing tumor necrosis factor in Escherichia coli. AB - The immunocytokine scFvMEL/TNF is a fusion protein composed of tumor necrosis factor (TNF-alpha) and a single-chain Fv antibody scFvMEL targeting the melanoma associated gp240 antigen. The fusion protein containing thioredoxin and a hexa histidine tag was expressed in two Escherichia coli host cells, AD494 (DE3) pLysS and T7 Express I (q). The cell growth and expression level of target protein, His tagged scFvMEL/TNF, were highly dependent on the induction temperature, inducer types and host strains. The ratio of insoluble to soluble target proteins was found to be controllable and could be minimized using cold shock conditions at less than 18 degrees C. The total productivity of soluble target protein was further improved by high cell density cultivation using a DO-STAT feeding strategy. The scFvMEL/TNF purified under their conditions was specifically cytotoxic to gp240-antigen positive melanoma A375-M cells as previously described. PMID- 17703298 TI - Quantification of anammox populations enriched in an immobilized microbial consortium with low levels of ammonium nitrogen and at low temperature. AB - Anaerobic ammonium oxidizing (anammox) bacteria present in microbial communities in two laboratory-scale upflow anoxic reactors supplied with small amounts of ammonium (<3 mg/l) at low temperature were detected and quantified. The reactors, operated at 20 degrees C, were seeded with an immobilized microbial consortium (IMC) and anaerobic granules (AG) from an upflow anaerobic sludge blanket (UASB) treating brewery wastewater. Our results showed that complete ammonium and nitrite removal with greater than 92% total nitrogen removal efficiency was achieved in the reactor inoculated with both the IMC and AG, while that of the reactor inoculated with only the IMC was lower than 40%; enrichment was successful after the addition of AG. Quantitative fluorescence in situ hybridization (FISH) analysis confirmed that anammox bacteria were present only in the reactor inoculated with an IMC and AG. The copy number of the 16S-rRNA gene of the anammox bacteria calculated by most probable number-polymerase chain reaction (MPN-PCR) from the total DNA extracted from both reactors (2.5 x 10(4) copies/mug of DNA) was two orders lower than that of the domain bacteria (2.5 x 10(6) copies/mug of DNA). The results revealed that immobilized multiple seed sludges were optimal for anammox enrichment at low temperature and ammonium concentrations. PMID- 17703296 TI - Parenchymal abnormalities associated with developmental venous anomalies. AB - INTRODUCTION: To report a retrospective series of 84 cerebral developmental venous anomalies (DVAs), focusing on associated parenchymal abnormalities within the drainage territory of the DVA. METHODS: DVAs were identified during routine diagnostic radiological work-up based on magnetic resonance imaging (MRI) (60 cases), computed tomography (CT) (62 cases) or both (36 cases). Regional parenchymal modifications within the drainage territory of the DVA, such as cortical or subcortical atrophy, white matter density or signal alterations, dystrophic calcifications, presence of haemorrhage or a cavernous-like vascular malformation (CVM), were noted. A stenosis of the collecting vein of the DVA was also sought for. RESULTS: Brain abnormalities within the drainage territory of a DVA were encountered in 65.4% of the cases. Locoregional brain atrophy occurred in 29.7% of the cases, followed by white matter lesions in 28.3% of MRI investigations and 19.3% of CT investigations, CVMs in 13.3% of MRI investigations and dystrophic calcification in 9.6% of CT investigations. An intracranial haemorrhage possibly related to a DVA occurred in 2.4% cases, and a stenosis on the collecting vein was documented in 13.1% of cases. Parenchymal abnormalities were identified for all DVA sizes. CONCLUSION: Brain parenchymal abnormalities were associated with DVAs in close to two thirds of the cases evaluated. These abnormalities are thought to occur secondarily, likely during post-natal life, as a result of chronic venous hypertension. Outflow obstruction, progressive thickening of the walls of the DVA and their morphological organization into a venous convergence zone are thought to contribute to the development of venous hypertension in DVA. PMID- 17703299 TI - Functional sex differences in human primary auditory cortex. AB - BACKGROUND: We used PET to study cortical activation during auditory stimulation and found sex differences in the human primary auditory cortex (PAC). Regional cerebral blood flow (rCBF) was measured in 10 male and 10 female volunteers while listening to sounds (music or white noise) and during a baseline (no auditory stimulation). RESULTS AND DISCUSSION: We found a sex difference in activation of the left and right PAC when comparing music to noise. The PAC was more activated by music than by noise in both men and women. But this difference between the two stimuli was significantly higher in men than in women. To investigate whether this difference could be attributed to either music or noise, we compared both stimuli with the baseline and revealed that noise gave a significantly higher activation in the female PAC than in the male PAC. Moreover, the male group showed a deactivation in the right prefrontal cortex when comparing noise to the baseline, which was not present in the female group. Interestingly, the auditory and prefrontal regions are anatomically and functionally linked and the prefrontal cortex is known to be engaged in auditory tasks that involve sustained or selective auditory attention. Thus we hypothesize that differences in attention result in a different deactivation of the right prefrontal cortex, which in turn modulates the activation of the PAC and thus explains the sex differences found in the activation of the PAC. CONCLUSION: Our results suggest that sex is an important factor in auditory brain studies. PMID- 17703300 TI - Potential contribution of naive immune effectors to oral tumor resistance: role in synergistic induction of VEGF, IL-6, and IL-8 secretion. AB - The aim of this study is to identify the phenotype of resistant oral tumors, and to delineate the contribution of immune effectors to resistance of oral tumors. UCLA-1 oral tumors which were resistant to NK cell mediated cytotoxicity secreted increased amounts of IL-6, IL-1beta, GM-CSF, and IL-8 when cultured with or without immune effectors. In addition, the levels of vascular endothelial growth factor (VEGF) secretion in the co-cultures of naive immune effectors with UCLA-1 rose significantly when compared to tumor cells alone. IL-2 activated NK cells decreased VEGF secretion in all tumor cells. However, NK cells which were induced to undergo cell death with anti-CD16 antibody were not only unable to decrease VEGF secretion, but they also contributed further to the increase in VEGF secretion by oral tumors. Overall, we show in this paper that naive as well as non-viable immune effectors may contribute to the growth and resistance of oral tumors by triggering the secretion of key tumor cell growth factors. PMID- 17703301 TI - Control of lymphocyte infiltration of lung tumors in mice by host's genes: mapping of four Lynf (lymphocyte infiltration) loci. AB - Tumor infiltration by lymphocytes is essential for cell-mediated immune elimination of tumors in experimental systems and in immunotherapy of cancer. Presence of lymphocytes in several human cancers has been associated with a better prognosis. We present evidence that individual propensity to tumor infiltration is genetically controlled. Infiltrating lymphocytes are present in 50% of lung tumors in O20/A mice, but in only 10% of lung tumors in OcB-9/Dem mice. This difference has been consistent in experiments conducted over 8 years in two different animal facilities. To test whether this strain difference is controlled genetically, we analyzed the presence of infiltrating lymphocytes in N ethyl-N-nitroso-urea (ENU) induced lung tumors in (O20 x OcB-9) F(2) hybrids. We mapped four genetic loci, Lynf1 (Lymphocyte infiltration 1), Lynf2, Lynf3, and Lynf4 that significantly modify the presence and intensity of intra-tumoral infiltrates containing CD4(+) and CD8(+) T lymphocytes. These loci appear to be distinct from the genes encoding the molecules that are presently implicated in lymphocyte infiltration. Our findings open a novel approach for the assessment of individual propensity for tumor infiltration by genotyping the genes of the host that influence this process using DNA from any normal tissue. Such prediction of probability of tumor infiltration in individual cancer patients could help considerably to assess their prognosis and to decide about the application and the type of immunotherapy. PMID- 17703302 TI - Detection of the JAK2V617F mutation in patients with slightly elevated platelets or hemoglobin without a secondary cause. AB - Recently, an activating somatic mutation of Janus kinase 2 (JAK2V617F) was identified in the myeloproliferative disorders (MPDs). In this study, we investigated the occurrence of JAK2V617F in patients with slightly elevated platelets or hemoglobin without a secondary cause, who did not meet the criteria of polycythemia vera or essential thrombocythemia. Six out of 18 patients (33%) were positive for the JAK2 mutation, and five of these six patients had a history of thrombosis. These findings suggest that apart from thrombocytosis/erythrocytosis, other mechanisms exist that cause thrombosis, and more patients with a latent form of MPD are likely to exist. Future studies will have to elucidate how to treat these patients. PMID- 17703303 TI - Characterisation of mucosal changes in the alimentary tract following administration of irinotecan: implications for the pathobiology of mucositis. AB - PURPOSE: The pathobiology of alimentary tract (AT) mucositis is complex and there is limited information about the events which lead to the mucosal damage that occurs during cancer treatment. Various transcription factors and proinflammatory cytokines are thought to play important roles in pathogenesis of mucositis. The aim of this study was to determine the expression of nuclear factor-kappaB (NF kappaB), tumor necrosis factor (TNF) and interleukins-1beta (IL-1beta) and -6 (IL 6) in the AT following the administration of the chemotherapeutic agent irinotecan. METHODS: Eighty-one female dark Agouti rats were assigned to either control or experimental groups according to a specific time point. Following administration of irinotecan, rats were monitored for the development of diarrhoea. The rats were killed at times ranging from 30 min to 72 h after administration of irinotecan. Oral mucosa, jejunum and colon were collected and standard immunohistochemical techniques were used to identify NF-kappaB, TNF, IL 1beta and IL-6 within the tissues. Sections were also stained with haematoxylin and eosin for histological examination. RESULTS: Irinotecan caused mild to moderate diarrhoea in a proportion of the rats that received the drug. Altered histological features of all tissues from rats administered irinotecan were observed which included epithelial atrophy in the oral mucosa, reduction of villus height and crypt length in the jejunum and a reduction in crypt length in the colon. Tissue staining for NF-kappaB, TNF and IL-1beta and IL-6 peaked at between 2 and 12 h in the tissues examined. CONCLUSIONS: This is the first study to demonstrate histological and immunohistochemical evidence of changes occurring concurrently in different sites of the AT following chemotherapy. The results of the study provide further evidence for the role of NF-kappaB and associated pro inflammatory cytokines in the pathobiology of AT mucositis. The presence of these factors in tissues from different sites of the AT also suggests that there may be a common pathway along the entire AT causing mucositis following irinotecan administration. PMID- 17703305 TI - Neurosprora crassa RAD5 homologue, mus-41, inactivation results in higher sensitivity to mutagens but has little effect on PCNA-ubiquitylation in response to UV-irradiation. AB - The DNA replication machinery stalls at damaged sites on DNA. Postreplicaton repair (PRR) is a system to avoid cell death in such circumstances of deadlock. In Saccharomyces cerevisiae, the Rad6/Rad18 heterodimer plays pivotal roles in PRR. It promotes translesion synthesis via the monoubiquitylation of the DNA sliding clamp, PCNA. Ubc13/Mms2/Rad5 can extend the ubiquitin chain from this monoubiquitylated PCNA with a non-canonical lysine 63-linked ubiquitin-chain, resulting in an error-free mode of bypass. In this study, we identified and characterized the RAD5 homolog in Neurospora crassa, which we named mus-41. A mus 41 mutant was sensitive to several DNA-damaging agents including UV and MMS. Genetic analyses indicated that uvs-2 (RAD18 homolog) was epistatic to mus-41, suggesting a role for mus-41 in postreplication repair. Additionally, it was shown that mus-41 has a role independent from TLS gene upr-1 (REV3 homolog) and works in the error-free pathway, indicating that the function of mus-41 as a RAD5 homolog is also conserved in N. crassa. However, mus-41 is not essential for the ubiquitylation of PCNA that is detected in the wild-type background, suggesting that there is another ubiquitin ligase catalyzing ubiquitylation of PCNA in response to UV in N. crassa. PMID- 17703306 TI - Aseptic meningitis associated with chronic sulindac use for osteoarthritis: a case report. AB - We report a case of aseptic meningitis thought to be associated with chronic sulindac use in a patient with osteoarthritis. The patient was hospitalized with an acute onset of headache, nuchal rigidity, nausea, and blurred vision. Brain imaging was unremarkable and a lumbar puncture revealed a lymphocytic pleocytosis. No infectious source was identified. The patient reported taking sulindac over the past year, it was discontinued, and symptoms promptly resolved. This case underscores the importance of obtaining a thorough drug history in conjunction with the knowledge of causative medications associated with aseptic meningitis. Given the widespread use of nonsteroidal anti-inflammatory drugs, clinicians must recognize that aseptic meningitis is a possible adverse effect of these medications. PMID- 17703304 TI - NALP inflammasomes: a central role in innate immunity. AB - Inflammasomes are cytoplasmic multiprotein complexes that mediate the maturation of the proinflammatory cytokines interleukin-1beta (IL-1beta), IL-18, and possibly IL-33 by controlling the activation of the inflammatory caspases-1 and 5. Assembly of inflammasomes depends on NOD-like receptor (NLR) family members such as NALPs, NAIP, and IPAF. Various microbial and endogenous stimuli activate different types of inflammasomes. This article focuses on the Pyrin domain containing NLRs, known as NALP proteins. Recent findings provide exciting insights into how these proteins might be activated and also provide evidence of the critical role of the NALP inflammasomes in innate immunity and inflammatory diseases. PMID- 17703308 TI - Which statin should be used together with colchicine? Clinical experience in three patients with nephrotic syndrome due to AA type amyloidosis. AB - Colchicine and statins are well known drugs that cause myopathy and neuropathy. Co-administration of certain drugs with statins may increase myotoxic effect, causing myopathy and varying degrees of rhabdomyolysis. Therefore, it is very crucial to know which statin should be used during a combination therapy including colchicine and other drugs. We present three cases with AA amyloidosis secondary to familial Mediterranean fever, who developed neuromyopathy while receiving the combination of colchicine and statin. We also briefly discussed the different metabolic pathways of statins and colchicine when used together. PMID- 17703307 TI - Two cases of eosinophilic vasculitis with thrombosis. AB - Vasculitides are characterized by vessel wall inflammation of unknown etiology. We report two cases of eosinophilic vasculitis and hypereosinophilia with thrombosis. They have been treated with a high-dose glucocorticoid and anticoagulation. These cases emphasize that thrombosis should be anticipated in patients with eosinophilic vasculitis. PMID- 17703309 TI - Successful rituximab-CHOP treatment of systemic lupus erythematosus associated with diffuse large B-cell non-Hodgkin lymphoma. AB - The authors discuss the case of a 76-year-old female patient who has been suffering from subacute cutaneous lupus erythematosus since 1983. In 1999 she was diagnosed with systemic lupus erythematosus (SLE) based on her symptoms of malar rash, polyarthritis, leukopenia, autoimmune hemolytic anemia and positive anti DNA antibody test. For this she received methylprednisolone and cyclophosphamide. After 3 years of remission, symptoms of cutaneous vasculitis appeared in 2004, which transitionally responded to treatment with azathioprin and methylprednisolone. Her cutaneous symptoms, however, progressed quickly along with generalized lymphadenopathy, splenomegaly and thrombocytopenia. Immunohistological evaluation of the lymph node biopsy showed diffuse large B cell lymphoma. She developed complete remission after treatment with six-cycle R CHOP (rituximab, and reduced doses of cyclophosphamide, vincristin, adriablastin, methylprednisolone). SLE became inactive and her symptoms of vasculitis resolved. The authors are bringing attention to one of the possible late complications of systemic lupus, and also underscoring that treatment with rituximab (+CHOP) was beneficial not only for the lymphoma but the SLE as well. PMID- 17703311 TI - Hypothalamic activity during altered salt and water balance in the snake Bothrops jararaca. AB - The effects of water and salt overload on the activities of the supraoptic and paraventricular nuclei and the adjacent periventricular zone of the hypothalamus of the snake Bothrops jararaca were investigated by measurements of Fos-like immunoreactivity (Fos-ir). Both water and salt overload resulted in changes in body mass, plasma osmolality, and plasma concentrations of sodium, potassium, and chloride. Hyper-osmolality increased Fos immunoreactivity in the rostral supraoptic nucleus (SON), the paraventricular nucleus (PVN), and adjacent periventricular areas. Both hyper- and hypo-osmolality increased Fos immunoreactivity in the intermediate SON, but not in other areas of the hypothalamus. Immunostaining was abundant in cerebrospinal fluid (CSF)-contacting tanycyte-like cells in the ependymal layer of the third ventricle. These data highlight some features of regional distribution of Fos immunoreactivity that are consistent with vasotocin functioning as a hormone, and support the role of hypothalamic structures in the response to disruption of salt and water balance in this snake. PMID- 17703310 TI - Mass spectrometry based proteomics in urine biomarker discovery. AB - All organisms contain 1,000s of proteins and peptides in their body fluids, which undergo disease-specific changes. Advances in the understanding of the functional relevance of these polypeptides under different (patho)physiological conditions and the identification of indicative changes with disease would greatly enhance diagnosis and therapy. The low-molecular-weight proteome, also termed peptidome, provides a rich source of information. Due to its lower molecular weight, the peptidome can be assessed without the need for sample manipulation like tryptic digests. This advantage facilitates comparative analysis but it also raises technical challenges differing from those in proteomics. The first part of this manuscript, is focused on the low-molecular-weight urinary proteome and reviews methodological aspects of sample collection, preparation, analysis, and data evaluation. The second part summarizes the recent progress in the definition and identification of clinically relevant polypeptide markers. PMID- 17703312 TI - Myosin isoforms and fibre types in limb muscles of Australian marsupials: adaptations to hopping and non-hopping locomotion. AB - Using immunohistochemistry and SDS-PAGE, we studied the myosin heavy chain (MyHC) composition and fibre type distribution of hindlimb muscles of hopping and non hopping Australian marsupials. We showed that hindlimb muscles of a bandicoot (Isoodon obesulus, order Peramelomorphia) and a small macropodoid, the brushtail bettong (Bettongia penicillata) expressed four MyHCs, slow, 2a, 2x and 2b, and had the corresponding fibre types as other macropods reported earlier. The fastest and most powerful 2b fibres predominated in most bettong hindlimb muscles, but were absent in the gastrocnemius and the flexor digitorum profundus, which are involved in elastic strain energy saving during hopping. The gastrocnemius of four large macropodids also showed little or no 2b MyHC, whereas this isoform was abundant in their tibialis anterior, which is not involved in elastic energy saving. In contrast, 2b MyHC predominated in the gastrocnemius of four non-hopping marsupials. These results suggest that absence of 2b fibres may be a general feature of macropodoid muscles involved in elastic energy saving. Large eutherians except llamas and pigs also have no 2b fibres. We hypothesize that 2x and 2a fibres perform better than 2b fibres in the storage and recovery of kinetic energy during locomotion in both marsupials and eutherians. PMID- 17703314 TI - A novel approach for treatment of sacrococcygeal pilonidal sinus: less is more. AB - BACKGROUND: The surgical management of sacrococcygeal pilonidal sinus (PS) is still a matter of discussion. Therapy ranges from complete wide excision with or without closure of the wound to excochleation of the sinus with a brush. In this paper, we introduce a novel limited excision technique. The aim of this study was to assess the morbidity and recurrence rate of this technique. MATERIALS AND METHODS: Limited excision consisted of a selective extirpation of the sinus after tagging the tract with methylene blue. Ninety-three consecutive patients, who underwent surgery between 2001 and 2004, were analyzed. The patients' survey was performed by mail questionnaire and telephone interview inquiring recurrence, time off work, and time to wound healing. RESULTS: Seventy-three percent of the patients were treated in an outpatient setting. With a median follow-up of 2 years, the recurrence rate was 5%. The median time off work was 2 weeks. The median wound healing time was 5 weeks. CONCLUSION: Limited excision for PS can be done in an outpatient setting with a low recurrence rate and short time off work. PMID- 17703313 TI - Role of ecdysone 20-monooxygenase in regulation of 20-hydroxyecdysone levels by juvenile hormone and biogenic amines in Drosophila. AB - The effects of increased levels of dopamine (feeding flies with dopamine precursor, L: -dihydroxyphenylalanine) and octopamine (feeding flies with octopamine) on ecdysone 20-monooxygenase activity in young (2 days old) wild type females (the strain wt) of Drosophila virilis have been studied. L: dihydroxyphenylalanine and octopamine feeding increases ecdysone 20-monooxygenase activity by a factor of 1.6 and 1.7, respectively. Ecdysone 20-monooxygenase activity in the young (1 day old) octopamineless females of the strain Tbetah ( nM18 ), in females of the strain P845 (precursor of Tbetah ( nM18 ) strain) and in wild type females (Canton S) of Drosophila melanogaster have been measured. The absence of octopamine leads to a considerable decrease in the enzyme activity. We have also studied the effects of juvenile hormone application on ecdysone 20-monooxygenase activity in 2-day-old wt females of D. virilis and demonstrated that an increase in juvenile hormone titre leads to an increase in the enzyme activity. We discuss the supposition that ecdysone 20-monooxygenase occupies a key position in the regulation of 20-hydroxyecdysone titre under the conditions that lead to changes in juvenile hormone titre and biogenic amine levels. PMID- 17703316 TI - Germline mutations of the MYH gene in Korean patients with multiple colorectal adenomas. AB - BACKGROUND: Most investigations on MutY human homolog (MYH)-associated polyposis (MAP) have been conducted in Western countries. Limited data on MAP in Asia are currently available. The present study investigated germline mutations of the MYH gene among patients with 10 to 99 adenomatous colorectal polyps and familial adenomatous polyposis (FAP) without adenomatous polyposis coli (APC) germline mutations in Korea. MATERIALS AND METHODS: The study population included 46 patients with 10 to 99 adenomatous polyps in the colorectum and 16 FAP patients with no identified APC germline mutations. Subjects were screened for MYH germline mutations, and we additionally screened for MYH mutations in 96 normal control individuals. RESULTS: Two of 46 (4.3%) patients with multiple polyps displayed heterozygous biallelic germline mutations of the MYH gene. A 39-year old male patient with biallelic MYH mutations (p.G272E and p.A359V) received total proctocolectomy for rectal cancer and 36 colorectal polyps. A 58-year-old female patient with biallelic MYH mutations (p.Q253X and p.Q440P) received right hemicolectomy for ascending colon cancer and 16 colonic polyps. The frequency of biallelic MYH mutation in 14 of 46 multiple-polyp patients, who had 15 to 99 polyps, was 14.3% (2 of 14). No biallelic MYH mutations were detected in the 32 patients with 10 to 14 colorectal polyps, 16 FAP patients, or 96 normal controls. CONCLUSION: We identified biallelic MYH germline mutations in 2 of 14 (14.3%) Korean patients with 15 to 99 colorectal polyps. In this study, there was no Y165C or G382D hot-spot mutation, which had been reported most frequently in previous studies. PMID- 17703315 TI - The proinflammatory CXC-chemokines GRO-alpha/CXCL1 and MIG/CXCL9 are concomitantly expressed in ulcerative colitis and decrease during treatment with topical corticosteroids. AB - BACKGROUND: Ulcerative colitis is characterized by relapsing mucosal inflammation where the lesions include tissue-damaging granulocytes. In addition, T cells and natural killer (NK) cells play important pathophysiologic roles. Chemokines are a large family of peptides that play key roles in the regulation of inflammation. The CXC-chemokines, growth-related oncogene (GRO)-alpha/CXCL1 and interleukin (IL)-8/CXCL8, both recruit neutrophils and possess mitogenic properties, whereas the interferon-dependent CXC-chemokines monokine induced by gamma-interferon (MIG)/CXCL9, interferon-gamma inducible protein of 10 kD/CXCL10, and IFN inducible T cell alpha chemoattractant/CXCL11 recruit and activate T cells and NK cells. MATERIALS AND METHODS: The expression of CXC-chemokines was studied in eight controls and in 11 patients suffering from ulcerative colitis in the distal part of the colon, before and during topical treatment with corticosteroids. Perfusates (obtained before, after 7 days, and after 28 days of treatment) and pinch biopsies (obtained before and after 28 days of treatment) were collected by colonoscopy. The rectal release of GRO-alpha and MIG was determined by enzyme linked immunosorbent assay (ELISA), and tissue expression of the chemokines was detected in colonic tissue by immunohistochemistry. RESULTS: In perfusates, high levels of GRO-alpha, IL-8, and MIG were detected compared with controls (p=0.02, 0.005, and p=0.03, respectively). During treatment with corticosteroids, both GRO alpha and MIG decreased. In clinical nonresponders, characterized by sustained inflammation, the levels of GRO-alpha and MIG remained elevated. Both epithelial cells and granulocytes, present in the submucosa, expressed GRO-alpha and MIG as detected by immunohistochemistry. CONCLUSIONS: CXC-chemokines are likely to be important in the pathophysiology of ulcerative colitis and may become targets for novel treatment strategies. In addition, GRO-alpha may serve as a marker of disease activity. PMID- 17703317 TI - Colorectal anastomosis using a novel double-stapling technique for lower rectal carcinoma. AB - BACKGROUND: The conventional double-stapling technique (DST) using a standard linear stapler horizontally is sometimes difficult to apply to an anastomosis where the pelvis is narrow or the anastomosis is ultralow. In this report, we review our experiences of a novel DST (IO-DST) that employs vertical division of the rectum using an endostapler. MATERIALS AND METHODS: One-hundred and five consecutive patients who underwent low anterior resection for rectal carcinoma below the peritoneal reflection were enrolled into this study. The clinical, oncological, and functional outcomes were studied retrospectively. RESULTS: The median distance from the anal verge to the tumor was 5.0 cm in "high risk" T1 tumors and 6.5 cm in more-advanced tumors. More than 2 cm of distal surgical margin was obtained in 80.6% of the patients with tumors deeper than T1. The median distance from the anal verge to the anastomosis was 4.2 cm in T1 tumors and 4.0 cm in more-advanced tumors. The median blood loss was 315 ml, and the median operative time was 262 min. There was no mortality in the IO-DST. Recurrence presented in 12 (13.0%) of the patients who underwent curative surgery, with local recurrence in four patients (4.3%) during a median follow-up of 46.2 months. However, no patients experienced suture-line recurrence. The early bowel frequency was four times/day after stoma closure in patients with transient covering colostomy and 3.5 times/day in patients without colostomy. The late bowel frequency was three times/day in patients with transient covering colostomy, and two times/day in patients without colostomy. CONCLUSIONS: The IO DST is a feasible and safe procedure for facilitating lower anastomosis in rectal carcinoma below the peritoneal reflection. PMID- 17703319 TI - Pancreatic fistula after pancreaticoduodenectomy: the impact of a standardized technique of pancreaticojejunostomy. AB - BACKGROUND: The leading cause for morbidity and mortality after pancreaticoduodenectomy is a pancreatic anastomotic leak and fistula. The two most commonly performed anastomoses after pancreaticoduodenectomy are pancreaticogastrostomy (PG) and pancreaticojejunostomy (PJ). The role of standardization on outcomes after pancreaticoduodenectomy has not been sufficiently addressed. AIM: The goal is to study the impact of a standardized technique of pancreatic anastomosis (PJ) after pancreaticoduodenectomy in a tertiary referral cancer teaching hospital. MATERIALS AND METHODS: A single institution database was analyzed over 15 years. The entire data were subdivided into two periods, viz., period A (1992 to 2001), when PG (dunking) was predominantly used, and period B (2003-2007), when a standardized technique of PJ (duct to mucosa) was employed. RESULTS: There were 144 pancreaticoduodenectomies performed during period A with a pancreatic fistula rate of 16%. During period B, 123 pancreaticoduodenectomies were performed with a pancreatic fistula rate of 3.2% (p < 0.0005). CONCLUSIONS: It appears that a standardized approach to the pancreatic anastomosis and a consistent practice of a single technique can help to reduce the incidence of complications after pancreaticoduodenectomy. PMID- 17703320 TI - Uneventful splenectomy and cholecystectomy in a patient treated with anti interleukin-6 receptor antibody therapy. AB - INTRODUCTION: Interleukin-6 (IL-6) is a multifunctional cytokine that regulates various aspects of the immune responses, acute phase reactions, and hematopoiesis. In rodent models, IL-6 has been suggested to be one of the essential mediators for optimal acute phase responses to infection and tissue damage. However, in humans, the roles of IL-6 in acute phase responses after surgery remain poorly understood. CASE REPORT: We present the first case report of successful splenectomy and cholecystectomy in a severe autoimmune-associated hemolytic anemia patient during treatment with a humanized anti-IL-6 receptor antibody. DISCUSSION: This unique case suggests that IL-6 is not an essential cytokine to safely perform surgical intervention and to prevent postoperative complications and that surgical intervention may not be contraindicated but can be selected as a therapeutic modality in patients treated with anti-IL-6 receptor antibody therapy. PMID- 17703321 TI - Ecdysone receptor expression in developing and adult mushroom bodies of the ant Camponotus japonicus. AB - Mushroom bodies (MBs) are insect brain centers involved in sensory integration and memory formation. In social Hymenoptera, MBs are large and comprise larger number of Kenyon cells and have repeatedly been implied to underlie the social behaviors. In the present study, to facilitate our understanding of the neural basis of social behaviors, two complementary DNAs (cDNAs) encoding presumed ecdysone receptor isoforms (CjEcR-A and CjEcR-alpha) were identified in the developing brains of the carpenter ant Camponotus japonicus. Sequence comparison indicated that these CjEcR proteins had common DNA- and hormone-binding domains linked to different N-terminal regions. The alignment of the distinct regions with other insects EcRs indicated that CjEcR-A is the ant homologue of EcR-A, and CjEcR-alpha has a novel type of A/B region. Immunohistochemical analyses of the MBs of C. japonicus with the common region antibody demonstrated that these CjEcRs appear in all neuroblasts, neurons, and glia cells during neurogenesis, whereas expression is confined to the neurons, disappearing in the glia cells in newly emerged workers. Less expression was observed in the forager MBs. These findings suggest that CjEcRs are involved in maturation and development of ant MBs. PMID- 17703322 TI - Activity of 8.O.4'-neolignans against Trypanosoma cruzi. AB - The in vitro evaluation of a series of 8.O.4'-neolignans (in their ketone, alcohol, and acetylated forms) on the proliferation of Trypanosoma cruzi led to the detection of three compounds with interesting activities against T. cruzi epimastigotes. These compounds also inhibited the in vitro differentiation of epimastigotes to trypomastigotes. When tested against HeLa cells, the same compounds did not affect the cell vitality and showed a low influence on cell viability as measured by dimethylthiazol diphenyltetrazolium bromide reduction. The three phenylpropanoid moieties tested did not show any activity against T. cruzi. One of the tested compounds, compound 4 (3,4-methylenedioxi7-oxo-1'-allyl 3',5'-dimethoxy-8.O.4'-neolignan) showed the best performance in both trypanocide and cytotoxic assays, suggesting that it should be considered as a leading structure for further research. PMID- 17703323 TI - High-density oligonucleotide array with sub-kilobase resolution reveals breakpoint information of submicroscopic deletions in nevoid basal cell carcinoma syndrome. AB - Small submicroscopic genomic deletions and duplications constitute up to 15% of all mutations underlying human monogenic diseases. In this study, we used newly designed high-resolution oligonucleotide microarrays with a median distance between the probes of 776 bp (average probe interval 2,271 bp) to detect gene deletions in nevoid basal cell carcinoma syndrome (NBCCS) patients. NBCCS, also called Gorlin syndrome, is characterized by developmental defects and tumorigenesis such as medulloblastomas and basal cell carcinomas, caused by mutations of the human patched-1 (PTCH1) gene. Two out of three deletions could not be detected by a conventional chromosomal analysis. A submicroscopic deletion as small as 165 kb was detected affecting only PTCH1, whereas the other two deletions were much larger (5 and 11 Mb). We demonstrated not only the exact number of genes involved in the deletion but also rapidly determined the junction sequences after pinpointing the breakpoint regions in all individuals analyzed. This report of an array-based determination of junction sequences of long deletions circumvented a labor-intensive analysis such as Southern blotting or FISH. Alu-mediated recombination in one case and non-homologous end joining in the other two were probably implicated in the generation of deletions. This method will contribute to the understanding of molecular pathogenesis of gene deletions as well as rapid genetic testing. PMID- 17703325 TI - The annotation of gene HgAffx.13168.1.S1_at. PMID- 17703324 TI - Frataxin gene point mutations in Italian Friedreich ataxia patients. AB - Friedreich ataxia (FRDA) is associated with a GAA-trinucleotide-repeat expansion in the first intron of the FXN gene (9q13-21), which encodes a 210-amino-acid protein named frataxin. More than 95% of patients are homozygous for 90-1,300 repeat expansion on both alleles. The remaining patients have been shown to be compound heterozygous for a GAA expansion on one allele and a micromutation on the other. The reduction of both frataxin messenger RNA (mRNA) and protein was found to be proportional to the size of the smaller GAA repeat allele. We report a clinical and molecular study of 12 families in which classical FRDA patients were heterozygous for a GAA expansion on one allele. Sequence analysis of the FXN gene allowed the identification of the second disease-causing mutation in each heterozygous patient, which makes this the second largest series of FRDA compound heterozygotes reported thus far. We have identified seven mutations, four of which are novel. Five patients carried missense mutations, whereas eight patients carried null (frameshift or nonsense) mutations. Quantitation of frataxin levels in lymphoblastoid cell lines derived from six compound heterozygous patients showed a statistically significant correlation of residual protein levels with the age at onset (r = 0.82, p < 0.05) or the GAA expansion (r = -0.76, p < 0.1). In the group of patients heterozygous for a null allele, a strong (r = -0.94, p < 0.01) correlation was observed between the size of GAA expansion and the age at onset, thus lending support to the hypothesis that the residual function of frataxin in patients' cells derive exclusively from the expanded allele. PMID- 17703327 TI - Abstracts of the Society of General Internal Medicine 29th Annual Meeting, April 26-29, 2006, Los Angeles, California, USA. PMID- 17703326 TI - [Airway management]. AB - Managing the difficult airway poses an enormous challenge for anaesthesiologists, intensivists and A&E physicians, particularly because of the high probability of a potentially fatal outcome. Development and (pre-) clinical distribution of supraglottic airway devices (e.g. LMA, LT) and their enhancements, as well as the broad acceptance of awake fibre-optic intubation, led to a profound change in the strategy for managing the difficult airway. This is reflected in the revised ASA guidelines, implementing the use of the laryngeal mask airway and fibre-optic intubation. In view of the utmost importance of this topic the German Society of Anaesthesiology and Intensive Care Medicine (DGAI) framed an independent German guideline, considering German national terms and conditions. In analogy algorithms and guidelines of the ILCOR, ERC and ATLS were revised as well as those of many other national anaesthesiological boards. Nevertheless, massive national and international deficits exist in implementing these guidelines into practice and the implicated structural requirements with respect to education, reflection, team building and equipment concerning the individual institution. PMID- 17703334 TI - Elevated serum receptor activator of NFkappaB ligand (RANKL), osteoprotegerin (OPG), matrix metalloproteinase (MMP)3, and ProMMP1 in patients with juvenile idiopathic arthritis. AB - We studied the serum levels of receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), pro-matrix metalloproteinase (MMP) 1, MMP3, and tissue inhibitor of metalloproteinase (TIMP) 1 in patients with juvenile idiopathic arthritis (JIA) and correlated these with different disease variables. Sera of 70 patients with JIA (ILAR 2001 criteria) and 33 age- and sex-matched controls were assayed by enzyme-linked immunosorbent assay. Nonparametric tests were used for analysis of data. The subtype distribution of the JIA patients was: enthesitis-related arthritis (ERA) 24, polyarticular 22, systemic onset 13, oligoarticular 8, and others 3. The median level of RANKL, OPG, pro-MMP1, MMP3, and TIMP-1 were elevated in JIA patients as compared to controls (p < 0.001). There was no difference in levels among different types of JIA. RANKL/OPG ratio was elevated in all subtypes of JIA. MMP3/TIMP-1 ratio correlated with measures of disease activity including swollen and tender joint count, erythrocyte sedimentation rate, and disease activity score (rS 0.28, p < 0.05). Ours is the first study to show elevated RANKL in serum of patients with JIA. Further, our data suggest that patients with ERA have similar levels to other forms of JIA. Association of the MMP3/TIMP-1 ratio with disease activity suggests that it may be a useful biomarker for follow-up. PMID- 17703333 TI - Severe invalidating pain syndrome associated with benznidazole therapy for Chagas' disease. AB - Chagas' disease is an endemic parasitic disease and constitutes an important health problem in Latin American countries. The increasing number of immigrants from these countries has resulted in a rise in diagnosis and consequently in the treatment of this disease in developed countries not familiar with this condition. Currently, benznidazole is used for treatment of this condition. However, undesirable effects have been reported with this treatment, and there are few data about continuous long-term use of this drug. We describe a case of invalidating pain syndrome in a 31-year-old Bolivian woman with Chagas' disease while receiving benznidazole therapy. Because of the number of cases with this condition will probably increase because of immigration, a better understanding of the side effects of the treatment of this disease is essential. PMID- 17703336 TI - Bilateral coronary-pulmonary artery fistulae associated with severe aortic insufficiency: an interesting association causing myocardial ischemia. AB - BACKGROUND: Coronary artery fistula (CAF) is defined as a direct communication of a coronary artery with a cardiac chamber, great vessel or other vascular structure, bypassing the myocardial capillary bed. Congenital CAFs joining into the pulmonary artery are rare cardiac anomalies. CAFs arising from two coronary arteries are even more rare especially when combined with valvular heart disease. The coincidence of CAFs with aortic insufficiency is relatively rare and sometimes might cause myocardial ischemia. RESULTS: We present a case of bilateral coronary-pulmonary artery fistula combined with severe aortic insufficiency causing myocardial ischemia and who subsequently underwent fistula ligation during aortic valve surgery. PMID- 17703335 TI - Uptake and retention of the photosensitizer mono-L-asparthyl chlorine e6 in experimental malignant glioma. AB - The objective of the study was to investigate the potential of mono-L-aspartyl chlorine e6 (NPe6), a water-soluble photosensitizer derived from chlorophyll, for use in photodynamic diagnosis (PDD) of malignant brain tumor. A C6 glioma cell line was transplanted in the SD rat brain to create a brain tumor model. Five days after transplantation, NPe6 was administrated via the tail vein at concentrations ranging from 1.25 to 10 mg/kg; then the skull was opened in the rat brain, the site of tumor transplant was irradiated with a diode laser beam at 664 nm, and the time-course intensity and distribution of emerging fluorescence were observed. Furthermore, the correlation between fluorescence distribution and histopathological findings was investigated in the removed brain. Fluorescence was observed in the site of brain tumor transplant from 5 min after injection, and stable fluorescence was recognized at the site until 4 h after administration. No differences were noted in fluorescence intensity at NPe6 doses of 2.5 mg/kg or more; therefore, it was possible to estimate the optimal dose range. Fluorescence distribution had a clear correlation with tumor cell density, and it was possible to capture the margin of tumor cell invasion with fluorescence. The photosensitizer NPe6 is capable of assessing tumor cell density in malignant glioma tissue in terms of differences in fluorescence intensity. The usefulness of PDD using 5-aminoleveulinic acid during surgery for malignant glioma has been recognized in recent years. The results of the present study suggested the potential of NPe6 as a promising photosensitizer for use in PDD for accurate grasp of the extent of removal during the course of malignant glioma surgery. PMID- 17703337 TI - Two case reports of pneumomediastinum. AB - BACKGROUND: We present two cases of pneumomediastinum in patients who presented to the accident and emergency department of a large teaching hospital. One case had a history of inhalational drug abuse, which may have contributed to the event, while the other had no obvious precipitating factors. AIMS: To evaluate the presenting symptoms, physical signs, diagnosis and management of pneumomediastinum with a review of the literature. METHODS: We describe two cases of pneumomediastinum with a literature review. CONCLUSIONS: Pneumomediastinum is an uncommon entity, first described almost 400 years ago. It presents with relatively non-specific symptoms and signs and will require radiological investigations to clarify the diagnosis. Treatment is conservative but will require close observation for the development of complications and occult visceral perforation. Complete resolution can be expected. PMID- 17703338 TI - The image-guided surgery toolkit IGSTK: an open source C++ software toolkit. AB - This paper presents an overview of the image-guided surgery toolkit (IGSTK). IGSTK is an open source C++ software library that provides the basic components needed to develop image-guided surgery applications. It is intended for fast prototyping and development of image-guided surgery applications. The toolkit was developed through a collaboration between academic and industry partners. Because IGSTK was designed for safety-critical applications, the development team has adopted lightweight software processes that emphasizes safety and robustness while, at the same time, supporting geographically separated developers. A software process that is philosophically similar to agile software methods was adopted emphasizing iterative, incremental, and test-driven development principles. The guiding principle in the architecture design of IGSTK is patient safety. The IGSTK team implemented a component-based architecture and used state machine software design methodologies to improve the reliability and safety of the components. Every IGSTK component has a well-defined set of features that are governed by state machines. The state machine ensures that the component is always in a valid state and that all state transitions are valid and meaningful. Realizing that the continued success and viability of an open source toolkit depends on a strong user community, the IGSTK team is following several key strategies to build an active user community. These include maintaining a users and developers' mailing list, providing documentation (application programming interface reference document and book), presenting demonstration applications, and delivering tutorial sessions at relevant scientific conferences. PMID- 17703339 TI - Predicting breast attenuation in patients undergoing myocardial perfusion scintigraphy: a digital x-ray study. AB - Attenuation artifacts are the most common sources of error in myocardial single photon emission computed tomography (SPECT) imaging. Breast artifacts are the most frequent causes of false positive planar images in female subjects. The purpose of this study was to predict breast adverse attenuation by measuring breast tissue thickness with digital x-ray. Sixty-five consecutive female patients with angina pectoris, who were referred to myocardial perfusion scintigraphy were enrolled in this study. Eighteen patients with normal perfusion imaging and normal coronary angiography composed the first group, whereas the second group consisted of 28 patients with a positive exercise electrocardiogram with anterior ischemia on myocardial perfusion imaging and greater than 50% left anterior descending artery stenosis on angiography. Nineteen patients in the third group had normal exercise electrocardiograms and normal coronary angiographies, but anterior ischemia on perfusion imaging. Digital x-ray records were obtained for measuring breast tissue thickness and Hounsfield density. The rate of breast adverse attenuation was 40% (19/47) in patients with anterior ischemia. The sensitivity and specificity of the prediction of breast adverse attenuation (lateral density less than 550 Hounsfield) were 79% and 11%, respectively. When breast attenuation for a breast thickness greater than 6 cm measured in the left anterior oblique view was predicted, the sensitivity and specificity were 79% and 93%, respectively. In conclusion, breast thickness greater than 6 cm measured from the left anterior oblique view with digital x-ray can predict breast adverse attenuation in female patients, and thereby may decrease the number of unnecessary invasive diagnostic procedures to be performed. PMID- 17703340 TI - Resetting behavior in a model of bursting in secretory pituitary cells: distinguishing plateaus from pseudo-plateaus. AB - We study a recently discovered class of models for plateau bursting, inspired by models for endocrine pituitary cells. In contrast to classical models for fold homoclinic (square-wave) bursting, the spikes of the active phase are not supported by limit cycles of the frozen fast subsystem, but are transient oscillations generated by unstable limit cycles emanating from a subcritical Hopf bifurcation around a stable steady state. Experimental time courses are suggestive of such fold-subHopf models because the spikes tend to be small and variable in amplitude; we call this pseudo-plateau bursting. We show here that distinct properties of the response to attempted resets from the silent phase to the active phase provide a clearer, qualitative criterion for choosing between the two classes of models. The fold-homoclinic class is characterized by induced active phases that increase towards the duration of the unperturbed active phase as resets are delivered later in the silent phase. For the fold-subHopf class of pseudo-plateau bursting, resetting is difficult and succeeds only in limited windows of the silent phase but, paradoxically, can dramatically exceed the native active phase duration. PMID- 17703341 TI - Underexpression of mineralocorticoid receptor in colorectal carcinomas and association with VEGFR-2 overexpression. AB - BACKGROUND: The human mineralocorticoid receptor (MR) is a steroid receptor widely expressed in colorectal mucosa. A significant role for the MR in the reduction of vascular endothelial growth factor receptor-2 (VEGFR-2) mRNA levels has been demonstrated in vitro. To evaluate a potential contribution of MR to colorectal carcinoma progression, we analyzed the expression of MR in relation to VEGFR-2. METHODS: Fresh human colorectal cancer tissue and adjacent normal mucosa were harvested from 48 consecutive patients. MR and VEGFR-2 mRNA expression levels were determined by real-time reverse transcriptase-polymerase chain reaction and correlated with clinicopathological parameters. RESULTS: A decline of MR expression was observed in all carcinomas compared to normal mucosa. Expression of MR was a median of 11-fold lower in carcinoma compared to the normal mucosa, irrespective of the location, size, stage, and differentiation. MR was a median of 20-fold underexpressed in carcinomas with VEGFR-2 overexpression vs only 9-fold in carcinomas with VEGFR-2 underexpression (p = 0.035, Mann Whitney test). CONCLUSIONS: These findings support the hypothesis that reduction of MR expression may be one of the early events involved in colorectal carcinoma progression. The inverse association between MR and VEGFR-2 expression in carcinoma suggests a potential tumor-suppressive function for MR. PMID- 17703342 TI - Plasma exchange therapy for steroid-refractory superimposed relapses in secondary progressive multiple sclerosis. PMID- 17703344 TI - The correct interpretation and lectotypification of the name Cardamine fallax (Brassicaceae). AB - The name Cardamine fallax (O. E. Schulz) Nakai, based on Cardamine flexuosa subsp. fallax O. E. Schulz, is lectotypified by the specimen originating from Japan (Mama-mura, Shimosa) in accordance with the original description and with the current use of the name by the majority of Japanese and Korean authors. Contrary to the treatment in the recent editions of the Flora of China and Flora of Japan, hexaploid C. fallax is considered here as a taxon different from diploid C. parviflora L. The main morphological difference between these two species is in the shape of cauline leaves. Those of C. parviflora are pinnatisect (lower ones seldom pinnate), with oblanceolate to linear, entire or almost entire segments or leaflets, and those of C. fallax are pinnate, usually with petiolulate, lobate, pinnatipartite to pinnatisect leaflets. The distribution area of C. fallax includes Japan, Korea and Eastern China. PMID- 17703343 TI - A novel mutation in the GFAP gene in a familial adult onset Alexander disease. PMID- 17703345 TI - Alternating current (AC) iontophoretic transport across human epidermal membrane: effects of AC frequency and amplitude. AB - PURPOSE: As a continuing effort to understand the mechanisms of alternating current (AC) transdermal iontophoresis and the iontophoretic transport pathways in the stratum corneum (SC), the objectives of the present study were to determine the interplay of AC frequency, AC voltage, and iontophoretic transport of ionic and neutral permeants across human epidermal membrane (HEM) and use AC as a means to characterize the transport pathways. MATERIALS AND METHODS: Constant AC voltage iontophoresis experiments were conducted with HEM in 0.10 M tetraethyl ammonium pivalate (TEAP). AC frequencies ranging from 0.0001 to 25 Hz and AC applied voltages of 0.5 and 2.5 V were investigated. Tetraethyl ammonium (TEA) and arabinose (ARA) were the ionic and neutral model permeants, respectively. In data analysis, the logarithm of the permeability coefficients of HEM for the model permeants was plotted against the logarithm of the HEM electrical resistance for each AC condition. RESULTS: As expected, linear correlations between the logarithms of permeability coefficients and the logarithms of resistances of HEM were observed, and the permeability data were first normalized and then compared at the same HEM electrical resistance using these correlations. Transport enhancement of the ionic permeant was significantly larger than that of the neutral permeant during AC iontophoresis. The fluxes of the ionic permeant during AC iontophoresis of 2.5 V in the frequency range from 5 to 1,000 Hz were relatively constant and were approximately 4 times over those of passive transport. When the AC frequency decreased from 5 to 0.001 Hz at 2.5 V, flux enhancement increased to around 50 times over passive transport. CONCLUSION: While the AC frequency for achieving the full effect of iontophoretic enhancement at low AC frequency was lower than anticipated, the frequency for approaching passive diffusion transport at high frequency was higher than expected from the HEM morphology. These observations are consistent with a transport model of multiple barriers in series and the previous hypothesis that the iontophoresis pathways across HEM under AC behave like a series of reservoirs interconnected by short pore pathways. PMID- 17703346 TI - Indomethacin-saccharin cocrystal: design, synthesis and preliminary pharmaceutical characterization. AB - PURPOSE: To design and prepare cocrystals of indomethacin using crystal engineering approaches, with the ultimate objective of improving the physical properties of indomethacin, especially solubility and dissolution rate. MATERIALS AND METHODS: Various cocrystal formers, including saccharin, were used in endeavours to obtain indomethacin cocrystals by slow evaporation from a series of solvents. The melting point of crystalline phases was determined. The potential cocrystalline phase was characterized by DSC, IR, Raman and PXRD techniques. The indomethacin-saccharin cocrystal (hereafter IND-SAC cocrystal) structure was determined from single crystal X-ray diffraction data. Pharmaceutically relevant properties such as the dissolution rate and dynamic vapour sorption (DVS) of the IND-SAC cocrystal were evaluated. Solid state and liquid-assisted (solvent-drop) cogrinding methods were also applied to indomethacin and saccharin. RESULTS: The IND-SAC cocrystals were obtained from ethyl acetate. Physical characterization showed that the IND-SAC cocrystal is unique vis-a-vis thermal, spectroscopic and X-ray diffraction properties. The cocrystals were obtained in a 1:1 ratio with a carboxylic acid and imide dimer synthons. The dissolution rate of IND-SAC cocrystal system was considerably faster than that of the stable indomethacin gamma-form. DVS studies indicated that the cocrystals gained less than 0.05% in weight at 98%RH. IND-SAC cocrystal was also obtained by solid state and liquid assisted cogrinding methods. CONCLUSIONS: The IND-SAC cocrystal was formed with a unique and interesting carboxylic acid and imide dimer synthons interconnected by weak N-Hcdots, three dots, centeredO hydrogen bonds. The cocrystals were non hygroscopic and were associated with a significantly faster dissolution rate than indomethacin (gamma-form). PMID- 17703348 TI - Determining if a system is heterogeneous: the analysis of single molecule rotational correlation functions and their limitations. AB - Single molecule spectroscopy can be utilized to measure distributions of individual molecular properties that may be averaged out in the ensemble measurement. For example, complex dynamics in disordered systems can be investigated by observing single molecule rotations via fluorescence spectroscopy. The rotational time of a single transient can be calculated from the correlation function of the reduced linear dichroism signal which fluctuates over time as the molecule reorients in its surroundings. Distributions of rotational time constants can be used to characterize the heterogeneity of molecular environments in the material. This paper reviews some theoretical studies on (1) the high numerical aperture effects on the final correlation function, and how it can be related to optical anisotropy decays in a bulk measurement; (2) the statistical errors resulting from the finite observation length that will propagate into distributions of rotational times. These lead to the discussions on how to interpret correctly the distribution of properties measured from a set of single molecule data, and to determine if in fact the system is heterogeneous. PMID- 17703349 TI - Laser-induced fluorescence at 488 nm excitation for detecting benign and malignant lesions in stomach mucosa. AB - This work aims the detection of the histopathologic alterations of in vitro human gastric mucosa using spectral informations from laser-induced fluorescence spectroscopy (LIFS) technique with excitation at 488 nm (argon laser). A total of 108 biopsies with endoscopic diagnosis of gastritis and gastric cancer were obtained at the antral gastric region, from 35 patients with dyspeptic digestive complaints. The biopsies were collected during the endoscopic examination. On each biopsy fragment the autofluorescence spectrum was collected in two random points, through a fiber-optic catheter coupled to the excitation laser. The fluorescence emission spectra collected by the fibers were directed to the spectrograph and detected by the CCD camera. The spectra were then separated in groups (N, normal; LI, light inflammation; MI, moderated inflammation; CA, adenocarcinoma), based on the histopathology. The ratio between the emission wavelengths 550 and 600 nm was used as a diagnostic parameter. Analysis of fluorescence spectra was able to identify the normal tissue from adenocarcinoma lesions with 100% of sensibility and specificity. The ratio intensities between inflammation (light and moderated), although presented significantly statistical differences when compared to the normal mucosa, do not furnish enough sensibility and specificity for use as an identification method due to high variations. LIFS, with excitation of 488 nm, could be used in the differentiation of normal tissue and neoplasic lesions, assisting a less invasive diagnosis. PMID- 17703347 TI - An in silico transwell device for the study of drug transport and drug-drug interactions. AB - PURPOSE: Validate and exemplify a discrete, componentized, in silico, transwell device (ISTD) capable of mimicking the in vitro passive transport properties of compounds through cell monolayers. Verify its use for studying drug-drug interactions. METHODS: We used the synthetic modeling method. Specialized software components represented spatial and functional features including cell components, semi-porous tight junctions, and metabolizing enzymes. Mobile components represented drugs. Experiments were conducted and analyzed as done in vitro. RESULTS: Verification experiments provided data analogous to those in the literature. ISTD parameters were tuned to simulate and match in vitro urea transport data; the objects representing tight junction (effective radius of 6.66 A) occupied 0.066% of the surface area. That ISTD was then tuned to simulate pH dependent, in vitro alfentanil transport properties. The resulting ISTD predicted the passive transport properties of 14 additional compounds, individually and all together in one in silico experiment. The function of a two-site enzymatic component was cross-validated with a kinetic model and then experimentally validated against in vitro benzyloxyresorufin metabolism data. Those components were used to exemplify drug-drug interaction studies. CONCLUSIONS: The ISTD is an example of a new class of simulation models capable of realistically representing complex drug transport and drug-drug interaction phenomena. PMID- 17703350 TI - Fluorescence enhancement of CdSe Q-Dots with intense femtosecond laser irradiation. AB - Effects of intense femtosecond (fs) laser irradiation on the optical properties of cadmium selenide (CdSe) nanocrystals are studied. We present the changes in emission and absorption of laser (800 nm, 110 fs, Ti-Sapphire) irradiated CdSe nanocrystals dispersed in dimethylformamide (DMF). It is observed that the absorbance of CdSe nanocrystals capped with trioctylphosphine (TOP) increases with the number of laser pulses. The trap state luminescence intensity of these crystals degrades, whereas the band edge luminescence intensity shows an increase as a function of the fs laser irradiation. We also report strong two photon absorption and reduction in the trap state luminescence intensity after irradiation with the laser pulses. PMID- 17703351 TI - Study on the interaction between florasulam and bovine serum albumin. AB - In this paper, the interaction between florasulam (FU, 2',6',8-trifluoro-5 methoxy [Kragh-Hansen U, Molecular aspects of ligand binding to serum albumin. Pharmacol Rev 33(1):17-53 1981; Carter DC and Ho JX, Structure of serum albumin. Adv Protein Chem 45:153-203 1994; He XM, and Carter DC, Atomic structure and chemistry of human serum albumin. Nature 358(6383):209-215 1992] triazolo [1,5 c]pyrimidine-2-sulfonanilide) and bovine serum albumin (BSA) was investigated by fluorescence, ultraviolet absorption (UV) and Far-UV circular dichroism (CD) spectrometries. A strong fluorescence quenching was observed and the quenching mechanism was considered as static quenching. The binding constant of FU with BSA at 299 and 309 K were obtained as 1.5 x 10(4) and 7.1 x 10(3) l mol(-1), respectively. There was one binding site between FU and BSA. The thermodynamic parameters enthalpy change (DeltaH) and entropy change (DeltaS) were calculated as -57.89 kJ mol(-1) and -113.6 J mol(-1) K(-1), respectively, which indicated that the acting force between FU and BSA was mainly hydrogen bond and Van der Waals force. According to the Forster non-radiation energy transfer theory, the average binding distance between donor (BSA) and acceptor (FU) was obtained (r = 1.59 nm). The investigations of the UV/Vis and CD spectra of the system showed that the conformation of BSA was changed in presence of FU. PMID- 17703352 TI - Spectrofluorimetric determination of dopamine using chlorosulfonylthenoyltrifluoroacetone-europium probe. AB - A new spectrofluorimetric method was developed for the determination of trace amounts of dopamine (DA). Using chlorosulfonylthenoyltrifluoroacetone (CTTA) europium ion (Eu(3+)) as a fluorescent probe, in a buffer solution at pH = 10.0, DA can remarkably enhance the fluorescence intensity of the CTTA-Eu(3+) complex at lambda = 612 nm; the enhanced fluorescence intensity of Eu(3+) is proportional to the concentration of DA. Optimum conditions for the determination of DA were also investigated. The linear range and detection limit for the determination of DA were 5.0 x 10(-8) approximately 1.6 x 10(-5) mol/l and 3.2 x 10(-8) mol/l. This method is simple, practical and relatively free of interference from coexisting substances, and can be applied to assess DA in injection and human serum samples with good precision and accuracy. PMID- 17703354 TI - A third verdict option: exploring the impact of the not proven verdict on mock juror decision making. AB - In most adversarial systems, jurors in criminal cases consider the binary verdict alternatives of "Guilty" and "Not guilty." However, in some circumstances and jurisdictions, a third verdict option is available: Not Proven. The Not Proven verdict essentially reflects the view that the defendant is indeed culpable, but that the prosecution has not proven its case beyond a reasonable doubt. Like a Not Guilty verdict, the Not Proven verdict results in an acquittal. The main aim of the two studies reported here was to determine how, and under what circumstances, jurors opt to use the Not Proven verdict across different case types and when the strength of the evidence varies. In both studies, jurors were more likely to choose a Not Proven verdict over a Not Guilty verdict when the alternative was available. When evidence against the defendant was only moderately strong and a Not Proven verdict option was available (Study 2), there was also a significant reduction in the conviction rate. Results also showed that understanding of the Not Proven verdict was poor, highlighting inadequacies in the nature of judicial instructions relating to this verdict. PMID- 17703353 TI - Psychosocial issues in families affected by maple syrup urine disease. AB - The primary aim of this study was to ascertain the psychosocial issues faced by families affected by maple syrup urine disease (MSUD). The psychosocial adjustment and quality of life of children with MSUD were also described. Participants included 55 families and their children (ages 5 to 18 years) and teachers. Measures included a MSUD Family Survey, the Behavior Assessment System for Children (BASC) and the Pediatric Quality of Life Inventory (PedsQL). Parents reported via the MSUD Family Survey that the greatest sources of stress were financial and emotional. Many parents reported difficulty interacting with the medical staff and with schools. On the BASC, half of the children fell within the average range in psychosocial adjustment, although there were elevations in scales measuring attention, hyperactivity, and learning problems. On the PedsQL, the mean quality of life scores were closer to children with cancer than to a healthy sample. Despite the emotional and financial burden, parents reported that MSUD has also had a positive influence on their lives, leading to a world-view that is more compassionate and caring. PMID- 17703355 TI - The effects of accomplice witnesses and jailhouse informants on jury decision making. AB - The present study presents one of the first investigations of the effects of accomplice witnesses and jailhouse informants on jury decision-making. Across two experiments, participants read a trial transcript that included either a secondary confession from an accomplice witness, a jailhouse informant, a member of the community or a no confession control. In half of the experimental trial transcripts, the participants were made aware that the cooperating witness providing the secondary confession was given an incentive to testify. The results of both experiments revealed that information about the cooperating witness' incentive (e.g., leniency or reward) did not affect participants' verdict decisions. In Experiment 2, participant jurors appeared to commit the fundamental attribution error, as they attributed the motivation of the accomplice witness and jailhouse informant almost exclusively to personal factors as opposed to situational factors. Furthermore, both experiments revealed that mock jurors voted guilty significantly more often when there was a confession relative to a no confession control condition. The implications of the use of accomplice witness and jailhouse informant testimony are discussed. PMID- 17703356 TI - The gender differences in the relaxation to levosimendan of human internal mammary artery. AB - PURPOSE: The mechanism of the vasorelaxation to levosimendan varies depending on the vascular bed and species studied. Here, we examined the vasorelaxation to levosimendan as well as its modification by various potassium channel antagonists in human internal mammary artery (IMA) obtained from male and female patients. METHODS: IMA grafts were supplied from 27 male and 19 age-matched female patients undergoing coronary bypass operation. The contraction to noradrenaline and relaxation to levosimendan were studied in IMA rings obtained from both gender. The relaxations to levosimendan were also assessed in the presence of glibenclamide (10 microM), an adenosine triphosphate-sensitive potassium channel (K(ATP)) blocker, or charybdotoxin (100 nM), a calcium-activated potassium channel (K(Ca)) blocker, or 4-aminopyridine(1 mM), a voltage-sensitive potassium channel (K(v)) inhibitor. RESULTS: Concentration-response curves to noradrenaline were not different in IMA rings from either gender. Pretreatment with levosimendan (3 x 10(-7) M) slightly modified the contractions to noradrenaline in both gender. Levosimendan (10(-9)-10(-5) M) produced concentration-dependent relaxation in IMA rings, contracted by noradrenaline (5 x 10(-6) M), from males and females. The vasodilatory effects of levosimendan were more pronounced in the arteries from males (83%) than females (69%), in term of the maximal relaxation (E (max)). Charybdotoxin and glibenclamide significantly inhibited the relaxation to levosimendan in the arteries from males but not in those of females. CONCLUSIONS: The vasodilating efficacy of levosimendan and its relaxation mechanism differs between the arteries from males and females, which may have clinical consequences in the treatment of heart failure. PMID- 17703357 TI - Establishment of a new human glioblastoma multiforme cell line (WJ1) and its partial characterization. AB - (1) A new human glioblastoma multiforme (GBM) cell line, WJ1, was established from the tissue derived from a 29-year-old patient diagnosed with a grade IV GBM. (2) The WJ1 cell line has been subcultured for more than 80 passages in standard culture media without feeder layer or collagen coatings. (3) GBM cells grow in vitro with distinct morphological appearance. Ultrastructural examination revealed large irregular nuclei and pseudo-inclusion bodies in nuclei. The cytoplasm contained numerous immature organelles and a few glia filaments. Growth kinetic studies demonstrated an approximate population doubling time of 60 h and a colony forming efficiency of 4.04%. The karyotype of the cells was hyperdiploid, with a large subpopulation of polyploid cells. Drug sensitivities of DDP, VP-16, tanshinone IIA of this cell line were assayed. They showed a dose- and time-dependent growth inhibition effect on the cells. (4) Orthotopic transplantation of GBM cells into athymic nude mice induced the formation of solid tumor masses about 6 weeks. The cells obtained from mouse tumor masses when cultivated in vitro had the same morphology and ultrastructure as those of the initial cultures. (5) This cell line may provide a useful model in vitro and in vivo in the cellular and molecular studies as well as in testing novel therapies for human glioblastoma multiforme. PMID- 17703358 TI - Interaction of a Salmonella enteritidis O-antigen octasaccharide with the phage P22 tailspike protein by NMR spectroscopy and docking studies. AB - The tailspike protein P22 recognizes an octasaccharide derived from the O-antigen polysaccharide of Salmonella enteritidis in a shallow groove and molecular docking successfully identifies this binding region on the protein surface. Analysis by 2D (1)H,(1)H-T-ROESY and transferred NOESY NMR experiments indicate that the bound octasaccharide ligand has a conformation similar to that observed in solution. The results from a saturation transfer difference NMR experiment show that a large number of protons in the octasaccharide are in close contact with the protein as a result of binding. A comparison of the crystal structure of the complex and a molecular dynamics simulation of the octasaccharide with explicit water molecules suggest that only minor conformational changes are needed upon binding to the tailspike protein. PMID- 17703359 TI - Umbilical cord blood stem cell mediated downregulation of fas improves functional recovery of rats after spinal cord injury. AB - Human umbilical cord blood stem cells (hUCB), due to their primitive nature and ability to develop into nonhematopoietic cells of various tissue lineages, represent a potentially useful source for cell-based therapies after spinal cord injury (SCI). To evaluate their therapeutic potential, hUCB were stereotactically transplanted into the injury epicenter, one week after SCI in rats. Our results show the presence of a substantial number of surviving hUCB in the injured spinal cord up to five weeks after transplantation. Three weeks after SCI, apoptotic cells were found especially in the dorsal white matter and gray matter, which are positive for both neuron and oligodendrocyte markers. Expression of Fas on both neurons and oligodendrocytes was efficiently downregulated by hUCB. This ultimately resulted in downregulation of caspase-3 extrinsic pathway proteins involving increased expression of FLIP, XIAP and inhibition of PARP cleavage. In hUCB-treated rats, the PI3K/Akt pathway was also involved in antiapoptotic actions. Further, structural integrity of the cytoskeletal proteins alpha tubulin, MAP2A&2B and NF-200 has been preserved in hUCB treatments. The behavioral scores of hind limbs of hUCB-treated rats improved significantly than those of the injured group, showing functional recovery. Taken together, our results indicate that hUCB-mediated downregulation of Fas and caspases leads to functional recovery of hind limbs of rats after SCI. PMID- 17703360 TI - Activation of the human FPRL-1 receptor promotes Ca2+ mobilization in U87 astrocytoma cells. AB - The human formyl peptide receptor like 1 (FPRL-1) is a variant of the Gi-coupled formyl-peptide receptor. Functional FPRL-1 is endogenously expressed in the U87 astrocytoma cell line and there is accumulating evidence to suggest that FPRL-1 may be involved in neuroinflammation associated with the pathogenesis of Alzheimer's disease. In this study, we examined the ability of FPRL-1 to mobilize intracellular Ca2+ in U87 astrocytoma cells, as well as in Chinese hamster ovary (CHO) cells stably expressing FPRL-1. We showed that Trp-Lys-Tyr-Met-Val-Met-NH2 (WKYMVM), a specific agonist for FPRL-1, stimulated Ca2+ influx in both U87 and FPRL-1/CHO cells. These effects can be inhibited by the FPRL-1 selective antagonist, WRW4. Involvement of Gi proteins was demonstrated with the use of pertussis toxin, while inhibitors of store-operated channels (SOC) including 1-[2 (4-methoxyphenyl)]-2-[3-(4-methpxyphenyl)propoxy]ethyl-1H-imidazole hydrochloride (SKF96365) and 2-aminoethoxydiphenyl borate (2-APB) were found to abolish the WKYMVM-induced Ca2+ increase. However, intracellular Ca2+ mobilization in both cell lines were unaffected by the phospholipase Cbeta inhibitor U73122 or selective ryanodine receptor inhibitors. Our data demonstrated that activation of Gi-coupled FPRL-1 can lead to Ca2+ influx possibly via SOCs in U87 and FPRL-1/CHO cells. PMID- 17703361 TI - PS1 expression is downregulated by gonadal steroids in adult mouse brain. AB - Mutations in presenilin (PS) 1 and PS2 genes are associated with early onset (< or =65 years) of Alzheimer's disease (AD). PS1 is involved in gamma-secretase mediated cleavage of beta-amyloid precursor protein (APP), but its regulation is poorly understood. Sex steroids influence APP cleavage pathways resulting in reduced burden of both intra- and extra-cellular nonamyloidogenic products. As gonadal hormones are implicated in AD and their levels change with age, we have analyzed the effect of 17beta-estradiol and testosterone on PS1 expression in the cerebral cortex of adult and old AKR mice of both sexes. Northern and Western blot analysis revealed that PS1 mRNA and protein expression followed similar pattern of regulation. PS1 expression was downregulated by 17 beta-estradiol and testosterone in the cerebral cortex of females and adult male, but upregulated in old male mice. Such sex-dependent regulation of PS1 expression during aging by gonadal steroids might account for the PS-related brain functions. PMID- 17703362 TI - Cognitive dysfunction in chronic hepatitis C: a review. AB - The hepatitis C virus (HCV) is a common blood-borne illness that affects up to 2% of the world's population and almost 4 million Americans. Cognitive impairment, or difficulty with thinking, has become a well-established symptom in persons with end stage liver disease. It was previously assumed that cognitive impairment was a consequence of cirrhosis-associated hepatic encephalopathy. Recent evidence, however, suggests that approximately one-third of people with chronic HCV experience cognitive impairment even in the absence of cirrhosis and that its occurrence is unrelated to other indices of liver function, such as laboratory values, viral load, and genotype. In the present review, evidence outlining the presence of cognitive deficits associated with HCV, possible etiological factors, effects of antiviral therapy, and co-infection with human immunodeficiency virus (HIV) is presented. Implications of these findings and directions for future work are discussed. PMID- 17703363 TI - Visceral and somatic hypersensitivity in TNBS-induced colitis in rats. AB - Inflammation of visceral structures in rats has been shown to produce visceral/somatic hyperalgesia. Our objectives were to determine if trinitrobenzene sulfonic acid (TNBS) induced colitis in rats leads to visceral/somatic hypersensitivity. Male Sprague-Dawley rats (200-250 g) were treated with 20 mg of TNBS in 50% ethanol (n = 40) or an equivalent volume of ethanol (n = 40) or saline (n = 25) via the colon. Colonic distension, Von Frey, Hargreaves, and tail reflex tests were used to evaluate for visceral, mechanical, and thermal sensitivity. The rats demonstrated visceral hypersensitivity at 2-28 days following TNBS administration (P < 0.0001). The ethanol-treated rats also demonstrated visceral hypersensitivity that resolved after day 14. TNBS-treated rats demonstrated somatic hypersensitivity at days 14-28 (P < 0.0001) in response to somatic stimuli of the hind paw. TNBS colitis is associated with visceral and somatic hypersensitivity in areas of somatotopic overlap. This model of colitis should allow further investigation into the mechanisms of visceral and somatic hypersensitivity. PMID- 17703364 TI - Aromatase cytochrome P450 enzyme expression in human pituitary. AB - Aromatase (P450AROM) converts testosterone to estrogen. This conversion could be important in normal physiology and estradiol-induced tumorigenesis in human pituitary. The objective of this study was to examine the expression of P450AROM in normal human pituitary and determine the gender difference. We examined aromatase expression in 19 normal human pituitary glands [13 males, 6 females, median age: 30 years (interquartile ranges, IQR: 23-63)] obtained from autopsy. We demonstrated aromatase gene expression levels by quantitative RT-PCR and aromatase protein with immunohistochemical staining in normal male and female human pituitary. Although median relative expression level of aromatase mRNA of male individuals [median DeltaCt = 42.6 (IQR: 7.6-93.9)] was higher than the female individuals [median DeltaCt = 3.9 (IQR:0-44.8)], we could not determine a significant gender difference in aromatase mRNA levels (p = 0.2). The difference between the aromatase protein density by immunohistochemistry was not significant between genders (p = 0.78). The aromatase levels were also not correlated with the age of the study subjects (p = 0.42 r = -0.21). The results indicate that aromatase enzyme is present in human pituitary. The amount and the density of the enzyme show a large variance among different individuals. Although higher mRNA expression was observed in male pituitary compared to female pituitary, there was no statistically significant difference for gender or age. PMID- 17703365 TI - A participatory study of school dropout and behavioral health of Latino adolescents. AB - The dropout of Latino adolescents from public schools has been linked to behavioral health issues such as delinquency and family conflict. Greater understanding is needed about the interplay of cultural, social, and developmental factors in this process. This article reports the findings of 14 group interviews conducted using a participatory approach with Latinos in a large school district in the southeastern USA. Findings support the need for comprehensive school-based interventions along the continuum from early intervention to intensive treatment for Latino adolescents who are at risk of dropping out. Participatory research is recommended for identifying strategies that integrate culturally and developmentally appropriate adaptations into existing behavioral health and dropout prevention services. PMID- 17703366 TI - Contamination indices and heavy metal concentrations in urban soil of Ibadan metropolis, southwestern Nigeria. AB - An assessment was conducted on soils of Ibadan metropolis using geochemical approach in order to establish the concentration of heavy metals and develop geoaccumulation index maps. Petrographic studies and X-ray diffractograms showed that soils of Ibadan were derived from the weathering of the bedrocks. The concentrations of Cu, Pb, and Zn were found to be greater in soils more than the background. Positive correlation occurred between Cu, Pb, and Zn indicated a common anthropogenic source in the soil while Mn, Cr, and Ni were found to be naturally enriched. The geoaccumulation index maps revealed significant enrichment factor (Ef 20) and index of geoaccumulation (Igeo) beyond class four (heavily contaminated) for Cu, Pb, and Zn in densely populated and industrial areas, whereas Cd is enriched in sparsely populated areas, agricultural areas and a few spots in densely populated areas. PMID- 17703368 TI - Uncertainties in the selection of applicants for medical school. AB - Decisions about admissions to medical school are based on assessments of the applicants' cognitive achievements and non-cognitive traits. Admission criteria are expected to be fair, transparent, evidence-based and legally defensible. However, unlike cognitive criteria, which are highly reliable and moderately valid, the reliability and validity of the non-cognitive criteria are low or uncertain. Their uncertain predictive value is due not only to their limited validity, but also to the unknown prevalence of the desirable non-cognitive traits in the applicants' pool. Consequently, the use of non-cognitive admission criteria inevitably leads to rejection of an unknown proportion of applicants who have a desirable trait and selection of applicants who lack this trait. We propose that, rather than using non-cognitive admission criteria, admission officers should assist prospective applicants to make informed decisions based on a reflective self-appraisal whether or not to apply to medical school. To this end, medical schools should disseminate information on the strains of medical training and practice, the frequency of medical errors and the most common causes of dissatisfaction and burn-out among practicing physicians. Such information may improve the self-selection process and thereby enrich the applicants' pool for individuals with appropriate motivation. The final selection of medical students may then be based either on past academic achievements, or on a lottery, or on various combinations thereof. PMID- 17703367 TI - Distribution and abundance of western gray whales off northeastern Sakhalin Island, Russia, 2001-2003. AB - In 2001-2003, >60,000 km of aerial surveys and 7,700 km of vessel surveys were conducted during June to November when critically endangered Korean-Okhotsk or western gray whales (Eschrichtius robustus) were present off the northeast coast of Sakhalin Island, Russia. Results of surveys in all years indicated gray whales occurred in predominantly two areas, (1) adjacent to Piltun Bay, and (2) offshore from Chayvo Bay, hereafter referred to as the Piltun and offshore feeding areas. In the Piltun feeding area, the majority of whales were observed in waters shallower than 20 m and were distributed from several hundred meters to approximately 5 km from the shoreline. In the offshore feeding area during all years, the distribution of gray whales extended from southwest to northeast in waters 30-65 m in depth. During all years, the distribution and abundance of whales changed in both the Piltun and offshore feeding areas, and both north south and inshore-offshore movements were documented within and between feeding seasons. The discovery of a significant number of whales feeding in the offshore area each year was a substantial finding of this study and raises questions regarding western gray whale abundance and population levels, feeding behavior and ecology, and individual site-fidelity. Fluctuations in the number of whales observed within the Piltun and offshore feeding areas and few sightings outside of these two areas indicate that gray whales move between the Piltun and offshore feeding areas during their summer-fall feeding season. Seasonal shifts in the distribution and abundance of gray whales between and within both the Piltun and offshore feeding areas are thought, in part, to be a response to seasonal changes in the distribution and abundance of prey. However, the mechanism driving the movements of whales along the northeast coast of Sakhalin Island is likely very complex and influenced by a multitude of factors. PMID- 17703369 TI - Effect of pharmaceutical care programme on blood pressure and quality of life in a Nigerian pharmacy. AB - OBJECTIVE: The study aimed at evaluating the effect of pharmaceutical care programme on blood pressure and quality of life of patients who visit a Nigerian community pharmacy. METHOD: A non-randomised, single-site, crossover design was used. Patients served as their own control. They underwent 5 months of usual care and another 5 months of pharmaceutical care. MAIN OUTCOME MEASURE: Blood pressure and quality of life measured before implementation of pharmaceutical care and at the end served as main outcome measures. Other end-points assessed at baseline and at the end of investigation included smoking cessation, adherence to therapy, exercise, salt restriction, alcohol moderation and self blood pressure measurement. RESULTS: Twenty four (24) patients out of the 40 recruited completed the study. Mean reductions were significant after pharmaceutical care intervention for systolic BP (14.3+/-14.4 mmHg) and diastolic BP (10.8+/-10.7 mmHg). There was a significant mean increase in number of patients that adhered to salt restriction (-36%), aerobic exercise (-46%), self BP measurement (-46%), alcohol moderation (-33%) and drug adherence (-16.7%). There was a positive increase of -11.4 and -3.2 for physical health and social health domain of quality of life evaluation respectively. CONCLUSION: Pharmaceutical care programme could produce a beneficial effect on hypertensive patients. PMID- 17703371 TI - Cardiofaciocutaneous (CFC) syndrome associated with muscular coenzyme Q10 deficiency. AB - The cardiofaciocutaneous (CFC) syndrome is characterized by congenital heart defect, developmental delay, peculiar facial appearance with bitemporal constriction, prominent forehead, downslanting palpebral fissures, curly sparse hair and abnormalities of the skin. CFC syndrome phenotypically overlaps with Noonan and Costello syndromes. Mutations of several genes (PTPN11, HRAS, KRAS, BRAF, MEK1 and MEK2), involved in the mitogen-activated protein kinase (MAPK) pathway, have been identified in CFC-Costello-Noonan patients. Coenzyme Q10 (CoQ10), a lipophilic molecule present in all cell membranes, functions as an electron carrier in the mitochondrial respiratory chain, where it transports electrons from complexes I and II to complex III. CoQ10 deficiency is a rare treatable mitochondrial disorder with various neurological (cerebellar ataxia, myopathy, epilepsy, mental retardation) and extraneurological (cardiomyopathy, nephropathy) signs that are responsive to CoQ10 supplementation. We report the case of a 4-year-old girl who presented a CFC syndrome, confirmed by the presence of a pathogenic R257Q BRAF gene mutation, together with a muscular CoQ10 deficiency. Her psychomotor development was severely impaired, hindered by muscular hypotonia and ataxia, both improving remarkably after CoQ10 treatment. This case suggests that there is a functional connection between the MAPK pathway and the mitochondria. This could be through the phosphorylation of a nuclear receptor essential for CoQ10 biosynthesis. Another hypothesis is that K-Ras, one of the proteins composing the MAPK pathway, might be recruited into the mitochondria to promote apoptosis. This case highlights that CoQ10 might contribute to the pathogenesis of CFC syndrome. PMID- 17703370 TI - Outcome of enzyme replacement therapy in patients with Gaucher disease type I. The Romanian experience. AB - AIM: This study reports the first evaluation of therapeutic response in Romanian patients with Gaucher disease type I, after therapy with Cerezyme recently became available in our country. PATIENTS AND METHODS: 24 patients (11-50 years) received Cerezyme 20-60 U/kg every two weeks for at least 18 months. Haemoglobin, platelet count, volume of the liver and spleen, plasma chitotriosidase and the severity score were assessed every 6 months; skeletal radiography and osteodensitometry were also monitored. RESULTS: Eleven patients were splenectomized before start of therapy. Eight patients had anaemia (mean haemoglobin 9.4 g/dl) and 14 patients, of whom 13 were without splenectomy, had thrombocytopenia (mean 65,692/mm3). Haemoglobin values normalized after 6 months and the platelet count increased to 147,818/mm3 after 18 months of treatment. Splenomegaly improved (mean 13.8x to 5.6x normal), hepatomegaly improved (mean 1.4x to 1.06x normal), the severity score decreased (mean 15.9 to 8.4), plasma chitotriosidase levels showed a reduction from 40,956 to 11,266 nmol/h per ml plasma. Bone disease improved clinically in all patients; bone radiography and osteodensitometry showed no further disease progress. We observed a mean weight gain of 4.3 kg, an improvement in quality of life, and the absence of therapeutic adverse events. CONCLUSIONS: Enzyme replacement therapy administered for 18 months in Romanian patients with Gaucher disease type I led to a marked improvement in haematological parameters and hepato- and splenomegaly. In the majority of patients we observed no further progress of bone disease; for an improvement in skeletal disease, a longer treatment period is required. PMID- 17703372 TI - Parotid gland involvement, the presenting sign of high grade non-Hodgkin lymphoma in two patients with Gaucher disease and sicca syndrome. AB - Increased risk of haematological malignancies has been described in Gaucher disease patients; however, high-grade lymphoma has been rarely observed. We report two patients with Gaucher disease and sicca syndrome diagnosed with aggressive lymphoma involving the parotid gland. A 29-year-old woman with Gaucher disease developed tumour of the left parotid gland. She reported chronic arthralgias, xerostomia and xerophthalmia. Parotid gland biopsy disclosed diffuse large B-cell lymphoma. No lymphadenopathy was found. Bone biopsy revealed focal lymphomatous infiltration consistent with stage IV disease. MACOP-B chemotherapy regimen (cyclophosphamide, adriamycin, methotrexate, bleomycin, vincristine, prednisone) resulted in complete remission for 15 years. A 76-year-old patient with Gaucher disease suffered from dry-mouth feeling. He developed a left parotid gland tumour. CT scan disclosed diffuse lymphadenopathy, pleural effusion and multiple lung nodules. A cervical lymph node biopsy revealed mantle cell lymphoma. Fine-needle aspiration of the parotid gland showed lymphoma cells. Immunochemotherapy with fludarabine, cyclophosphamide and rituximab resulted in complete remission. Accumulation of the glucocerebroside in Gaucher disease activates macrophages, inducing release of pro-inflammatory cytokines which may be involved in the pathogenesis of second malignancy. Patients with Gaucher disease bear an increased risk of haematological malignancies; however, aggressive lymphoma has been described only occasionally. In both our patients the presenting sign of lymphoma was tumour of the parotid gland. The patients suffered from sicca syndrome, which increases risk for developing lymphoma. The underlying Gaucher disease and sicca syndrome might be implicated as immunological triggers for lymphoma occurrence and its propensity for the parotid gland in these patients. PMID- 17703373 TI - Deficiency of the carnitine transporter (OCTN2) with partial N-acetylglutamate synthase (NAGS) deficiency. AB - A patient with recurrent episodes of hyperammonaemia (highest ammonia level recorded 229 micromol/L, normal 9-33) leading to altered levels of consciousness was diagnosed with partial N-acetylglutamate synthase (NAGS) deficiency (9% residual activity) at age 5 years and was treated with ammonia-conjugating agents (Ucephan 250 mg/kg per day and later sodium phenylbutyrate 200-250 mg/kg per day) for 15 years. A chronically low serum carnitine level (pretreatment plasma free carnitine 4 nmol/L, normal 37 +/- 8 nmol/L; total carnitine 8 nmol/L, normal 46 +/- 10) was assumed to be secondary and was treated with supplemental carnitine (30-50 mg/kg per day). Hypoglycaemia (blood sugar 35 mg/dl, normal 70-100), cardiomegaly, and fatty liver were also noted at diagnosis. The patient died unexpectedly at age 20 years. In retrospect, it was learned that the patient had stopped his carnitine without medical consultation several weeks prior to his death. Additional molecular investigations identified two mutations (R254X and IVS3 + 1G > A) in the patient's OCTN2 (SLC22A5) gene, consistent with a diagnosis of primary carnitine deficiency due to carnitine transporter defect. R245X is a founder mutation in Southern Chinese populations. It is unknown whether the original NAGS deficiency was primary or secondary, but molecular analysis of the NAGS gene failed to identify mutations. Urea cycle enzyme expression may be affected by fatty acid suppression of an AP-1 binding site in the promoter enhancer region of the urea cycle gene. Regardless, it is clear that the NAGS abnormality has led to delay of recognition of the OCTN2 defect, and modified the clinical course in this patient. PMID- 17703375 TI - Loneliness and health-related quality of life for the empty nest elderly in the rural area of a mountainous county in China. AB - OBJECTIVE: To estimate whether loneliness was associated with quality of life and examined the influence of socio-economic factors in the empty nest elderly. METHODS: The 36-Item Short-Form Health Survey (SF-36) and UCLA Loneliness Scale (UCLA-LS) were used to assess the quality of life and loneliness for 275 empty nest and 315 not empty nest rural elders in a county, China. T tests, Pearson's correlations and linear regression analysis were used to examine the difference in SF-36 and UCLA-LS scores, correlations of the two scores between the two groups, and socio-economic determinants of loneliness among the empty nest elders. RESULTS: Empty nest group, in comparison with not empty nest group, had higher level of loneliness (95% confidence interval [CI] = -3.361 to -.335), lower physical (95% CI = .228 to 6.044) and mental (95% CI = .866 to 6.380) scores. Loneliness was negatively correlated with all the 36-Item Short-Form Health Survey scales in both groups. Social supports and income were negatively associated with loneliness, whereas education level and being single were positively associated with loneliness for the empty nest group. CONCLUSIONS: Reducing the level of loneliness may be helpful to improve the quality of life for the empty nest elders. PMID- 17703374 TI - The balancing act: psychiatrists' experience of moral distress. AB - Experiences of moral distress encountered in psychiatric practice were explored in a hermeneutic phenomenological study. Moral distress is the state experienced when moral choices and actions are thwarted by constraints. Psychiatrists describe struggling 'to do the right thing' for individual patients within a societal system that places unrealistic demands on psychiatric expertise. Certainty on the part of the psychiatrist is an expectation when judgments of dangerousness and/or the need for coercive treatments are made. This assumption, however, ignores the uncertainty and complexity of reality. Society entrusts psychiatrists to care for and treat those among its most vulnerable members: persons deemed to have a severely diminished capacity for autonomy due to a mental disorder. Simultaneously, psychiatrists are held accountable by society for the protection of the public. Moral distress arose for psychiatrists in their efforts to fulfill both roles. They described an 'outsider/insider' status and the ways in which they attempted to cope with moral distress. PMID- 17703376 TI - [Sonographical diagnosis of pneumoretroperitoneum as a result of retroperitoneal perforation]. AB - A retroperitoneal perforation is a rare incident. It can occur as a complication of ERCP with papillotomy (0.2-0.5%). Leakage of contrast agent during endoscopy raises the suspicion that this complication has occurred but doesn't always give sufficient information about the leakage extent. In the case of extreme gas emission, a plain abdominal X-ray shows classic pneumoretroperitoneum. The abdominal CT scan can display small amounts of free air which is why it is used for diagnosis in such cases. Ultrasonography also provides a reliable diagnosis and is a good method for monitoring the progression of the condition. Alternative causes of pneumoretroperitoneum can be: trauma, inflammation, infection, tumor as well as ERCP and other interventional procedures, especially endoscopies. Presacral retroperitoneal pneumoradiography was used for the diagnosis of retroperitoneal tumors in the 70 s but is no longer used today. Perforations into the retroperitoneal space come from several locations in the gastrointestinal tract. In the different types of lesions the gas can penetrate the compartments and reach as far as the mediastinum, the intraabdominal cavity, subcutaneum (cervical) or the scrotal compartment (compartment shift). Based on 11 cases (7 perforations during ERCP, 2 perforation during colonoscopy, 2 cases with damage of the distal esophagus), we show the most extensive presentation of the sonographical picture of pneumoretroperitoneum. Typical signs on abdominal ultrasound are an increased echogenicity around the right kidney ("overcasted" or "covered" kidney), air dorsal to the gallbladder, around the duodenum and the head of the pancreas and especially ventral to the great abdominal vessel which can lead to the picture of "vanishing" vessels. The extent of free air is easy to assess. Even very small amounts are detectable ventral to the right kidney. In most cases, a conservative approach with no oral intake, antibiotic coverage, and analgesia in close gastroenterological-surgical cooperation is indicated. Especially after ERCP abscess formation is repeatedly described, sometimes even with a lethal outcome. Sonography is a suitable method for detecting free air in the retro-peritoneum. Pneumoretroperitoneum following bowel-perforation can be effectively shown by ultrasound, it is possible to assess the extent of free air, and sonographic monitoring of the treatment is possible and successful. PMID- 17703377 TI - Ultrasonography in evaluation of Achilles and patella tendon thickness. AB - Despite the general acknowledgement that measurement of tendon thickness by ultrasonography (US) is an integral part of clinical examination of tendons in both symptomatic and asymptomatic athletes, there is no consensus on where and how the tendons should be measured. PURPOSE: This study aims to evaluate the Achilles and patellar tendons by ultrasonography with the intention of establishing a consensus for measuring the thickness of Achilles and patellar tendons in future studies. MATERIALS AND METHODS: This study includes three sub studies, evaluating: 1. Achilles and patellar tendon thickness in relation to the distance from the attachment at the calcaneus or patella, 2. longitudinal versus transversal US scan for measurement of the tendon thickness by examining the tendons in both longitudinal and transversal scan planes twice by the same observer, and 3. differences in tendon thickness using three different US measurement methods, when measuring both the sagittal AP thickness and the "true" thickness (measured perpendicular to the greatest width) twice by the same observer. A total of 209 tendons were included. RESULTS: Normal Achilles tendons have the same thickness in the distal 5 cm-long section. Patellar tendons are more cone-shaped proximally. There is no significant difference between the longitudinal and transversal scan except when applied on abnormal patellar tendons. The tendon thickness and coefficient of variation is smaller when measuring the true thickness compared to the AP thickness. CONCLUSION: The true tendon thickness is less than the AP thickness, because the AP-thickness is dependent upon the rotation of the tendon. Moreover, the true thickness is a more precise measurement. In future measurements, the true thickness of tendons could be measured in either transversal or longitudinal scan. When measuring abnormal patellar tendons, however, it is necessary to apply a longitudinal scan as this is the only method allowing the examiner to record the distance from the point where the thickness is measured to the bony attachment. The measurement can thereby be repeated at exactly the same point during subsequent controls. PMID- 17703378 TI - [Bilateral fixed dislocation of the long head of the biceps tendon]. AB - In general, dislocations of the long head of the biceps tendon are associated with partial or complete rotator cuff rupture on the side of the affected shoulder. We report about a patient with bilateral fixed and painless dislocation of the tendon of the long biceps head. By using functional ultrasound, correct diagnosis was facilitated and accelerated. PMID- 17703381 TI - [Endoscopic endonasal dacryocystorhinostomy by means of Kerrison Forceps]. PMID- 17703382 TI - Submucosal endoscopic esophageal myotomy: a novel experimental approach for the treatment of achalasia. AB - BACKGROUND AND STUDY AIMS: The most permanent method of treating achalasia is a surgical myotomy. Because of the requirement for a mucosal incision and the risk of perforation, this procedure has not generally been approached endoscopically. We hypothesized that we could perform a safe and robust myotomy by working in the submucosal space, accessed from the esophageal lumen. MATERIALS AND METHODS: Four pigs were used for this experiment. Baseline lower esophageal sphincter (LES) pressures were recorded and the pigs underwent upper endoscopy using a standard endoscope. A submucosal saline lift was created approximately 5 cm above the LES and a small nick was made in the mucosa in order to facilitate the introduction of a dilating balloon. After dilation, the scope was introduced over the balloon into the submucosal space and advanced toward the now visible fibers of the LES. The circular layer of muscle was then cleanly incised using an electrocautery knife in a distal-to-proximal fashion, without complications. The scope was then withdrawn back into the lumen and the mucosal defect was closed with endoscopically applied clips. The entire procedure took less than 15 minutes. Manometry was repeated on day 5 after the procedure and the animals were euthanized on day 7. RESULTS: LES pressures fell significantly from an average of 16.4 mm Hg to an average of 6.7 mm Hg after the myotomy. The necropsy examinations revealed no evidence of mediastinitis or peritonitis. CONCLUSIONS: Endoscopic submucosal esophageal myotomy is feasible, safe, and effective in the short term. It has the potential for being useful in patients with achalasia. The submucosal space is a novel and potentially important field of operation for endoscopic procedures. PMID- 17703383 TI - Endoscopic, bioptic, and manometric findings in eosinophilic esophagitis before and after steroid therapy: a case series. AB - BACKGROUND AND AIM: Eosinophilic esophagitis can be associated with a wide range of endoscopic patterns. The aim of the present case series report is to describe and classify endoscopic appearances before and after corticoid therapy in relation to histopathology and manometry. PATIENTS AND METHODS: In 30 patients (m : f, 27 : 3; mean age 36.2 years) with eosinophilic esophagitis, endoscopic findings were prospectively classified according to luminal diameter and mucosal pattern. Manometric and bioptic histopathologic findings were also recorded. Endoscopy was repeated following a 3-month course of steroid therapy. RESULTS: In total, 20 % of patients showed a concentric esophageal stricture, and in 57 % simultaneous contraction rings were visible. Mucosal alterations consisted of granular mucosa (20 %), longitudinal furrows (33 %) and transversal undulations (3 %). Lower esophageal sphincter dysfunction and distal esophageal dysfunctional manometry were seen in 73 % and 57 % of cases, respectively. Following steroids, the esophagus showed a normal caliber in 97 % of patients, and 63 % of patients had normal mucosa. CONCLUSIONS: The most frequent findings were narrowing of the esophageal lumen, which returned to normal following steroid treatment to a larger extent than mucosal alterations. PMID- 17703384 TI - Predicting presence of intestinal metaplasia and dysplasia in columnar-lined esophagus: a multivariate analysis. AB - BACKGROUND AND STUDY AIMS: In patients with presumed Barrett esophagus we evaluated clinical risk factors that could predict the presence of intestinal metaplasia and dysplasia in biopsies of columnar-lined esophagus (CLE), independently of histological results. PATIENTS AND METHODS: In 908 patients with CLE of length > or = 2 cm, data on age, sex, reflux symptoms, tobacco and alcohol use, medication use, and upper gastrointestinal endoscopy findings were prospectively collected. Multivariate logistic regression analysis was performed, and a model for predicting the histological results was developed. RESULTS: In 127/908 patients, biopsies of CLE did not contain intestinal metaplasia. Of the 781 patients with intestinal metaplasia, 663 patients (85%) had no dysplasia, and 118 (15%) had low grade dysplasia (LGD). The most important predictors for the presence of intestinal metaplasia were length of CLE, size of hiatal hernia, and male sex, while among those with intestinal metaplasia, age and male sex were most important for the presence of LGD. Multivariate combinations of these predictors yielded reliable models, which were able to discriminate intestinal metaplasia well from no intestinal metaplasia (area under receiver operating characteristic [ROC] curve 0.82), but only reasonably discriminated LGD from no dysplasia (area under ROC 0.65). CONCLUSIONS: A simple model based on clinical findings can be used to predict the presence of intestinal metaplasia in biopsies from CLE. In contrast, predicting the presence of LGD versus no dysplasia in intestinal metaplasia is more difficult. Predictions from these models may aid decision making on whether a patient with CLE should have surveillance, in view of the known sampling error at endoscopy and interobserver variability at histology. PMID- 17703385 TI - Clinical outcome after endoscopic mucosal resection for esophageal squamous cell carcinoma invading the muscularis mucosae--a multicenter retrospective cohort study. AB - BACKGROUND AND STUDY AIMS: Endoscopic mucosal resection (EMR) is now commonly indicated for esophageal squamous cell carcinoma (ESCC) within the lamina propria mucosa. However, EMR for ESCC that has invaded the muscularis mucosa is controversial because the risk of lymph node metastasis is not negligible. We conducted a multicenter retrospective cohort study to investigate the incidence of lymph node metastasis and survival after EMR for ESCC invading the muscularis mucosa. PATIENTS AND METHODS: A total of 104 patients with 111 lesions invading the muscularis mucosa, were retrospectively studied at eight institutes. No patients exhibited evidence of metastasis of lymph nodes or distant organs prior to EMR. Overall and cause-specific survival rates were calculated from the date of EMR to the date of death or the most recent follow-up visit. Survival curves were plotted according to the Kaplan-Meier method. RESULTS: In total, 86 patients (82.7%) who did not receive further treatment such as chemotherapy, irradiation therapy, chemoradiotherapy, or esophagectomy after EMR were followed up. Only two patients (1.9%) developed lymph node metastasis after EMR. With a median follow up period of 43 months (range, 8-134 months), overall and cause-specific survival rates at 5 years after EMR were 79.5% and 95.0%, respectively. CONCLUSIONS: EMR for ESCC that invades the muscularis mucosa has curative potential as a minimally invasive treatment option. PMID- 17703386 TI - The efficacy and safety of duodenal stenting: a prospective multicenter study. AB - BACKGROUND AND STUDY AIMS: Duodenal stenting has become a popular treatment in cases of malignant stenosis. However, a prospective evaluation of the efficacy and morbidity of this procedure has not been performed. A prospective multicenter study of duodenal stenting was conducted by the Societe Francaise d'Endoscopie Digestive (SFED). PATIENTS AND METHODS: A total of 51 patients were selected (mean age 72), the majority (69%) having pancreatic adenocarcinoma. Palliative treatment was chosen because of irresectability (61.2%), inoperability (18.4%), or both (20.4 %). Enteral Wallstent prostheses were used, and the patients were followed up on day 3, after 1 month, and then every month, with weight measurement, and symptomatic and laboratory evaluation. RESULTS: One prosthesis was sufficient in 46 patients. Stent positioning and deployment were correct in 50/51 patients (98%). Twenty patients also underwent biliary stenting in addition to the duodenal stenting. On day 3, 43 patients (84%) were able to tolerate soft solids or a full diet. Six complications were attributed to stenting: three intestinal hemorrhages, two cases of peritonitis due to bowel perforation, and one case of septicemia, and these led to five deaths (mortality 9.8%). Stent dysfunction was observed in 12 cases (23.5%) after a mean delay of 75 days, comprising 11-malignant obstructions and one migration: a new stent was inserted inside the first one and was effective in eight cases; and no treatment was given in the other four patients because of their clinical state. The median survival was 71.5 days. CONCLUSIONS: Palliative endoscopic treatment of malignant duodenal stenosis using metallic prostheses is highly feasible, even with associated biliary stenting. Symptomatic improvement is fast. However, the mortality and the obstruction rate are high, suggesting that a prospective trial comparing this treatment with surgery is still required. PMID- 17703387 TI - Double-balloon colonoscopy after failed conventional colonoscopy: a pilot series with a new instrument. AB - BACKGROUND AND STUDY AIMS: The endoscopes that were developed for double-balloon enteroscopy have been successfully used in cases of failed colonoscopy. This study was a pilot series in which a new colonoscope was tested that utilized this double-balloon principle. PATIENTS AND METHODS: A total of 29 patients (5 men, 24 women; mean age 54 years) in whom conventional colonoscopy had failed were included in this study. Both the failed colonoscopy and the double-balloon colonoscopy procedures were performed under general anesthesia, the usual practice in France. A prototype instrument (working length 152 cm, diameter 9.4 mm) designed to incorporate the principles of double-balloon enteroscopy was used. The completeness of colonoscopy was assessed according to conventional criteria by the achievement of a stable position in the cecum. The indicatons for the procedure, the time to reach the cecum, the need for fluoroscopic control, and adverse events were recorded. RESULTS: The previous colonoscopy failed due adhesions (n = 16), or to long or fixed loops (n = 13). Complete colonoscopy using the balloon method was achieved in 28/29 patients, taking an average time of 18 +/- 14 minutes; a long sigmoid loop limited the examination to the left flexure in one patient. Balloon colonoscopy using double-balloon methodology was used in 24 patients and the instrument was used without an overtube (i. e. using a single-balloon technique) in five patients. Fluoroscopy was used in 16 patients to monitor endoscope progression. No complications were reported. CONCLUSIONS: Double-balloon colonoscopy enables full colonic examination in almost all patients with a previous incomplete colonoscopy. The overtube should be used in most cases. The use of fluoroscopic assessment of scope progression could be reduced further with increasing experience. PMID- 17703388 TI - Risk factors for complication following ERCP; results of a large-scale, prospective multicenter study. AB - BACKGROUND AND STUDY AIMS: Analyses of endoscopic retrograde cholangiopancreatography (ERCP) complication are often constrained by the number of endpoints observed. This large-scale study aimed to identify the principal risk factors for ERCP complication. PATIENTS AND METHODS: This was a prospective multicenter study of ERCP complications, based in five English regions. An exploratory univariable analysis of patients' first recorded procedures identified potentially important patient- and procedure-related factors. For overall complications and pancreatitis, variables significant in univariable analysis were included in multiple regression. RESULTS: A total of 66 centers collected data on 5264 ERCPs, performed on 4561 patients. A therapeutic intervention was attempted in 3447/4561 (76%) of patients as part of their first recorded ERCP. Following first recorded ERCP, 230 patients (5.0%) suffered > or = 1 complication: pancreatitis in 74 (1.6%), cholangitis in 48 (1.0 %), hemorrhage in 40 (0.9%), perforation in 20 (0.4%), and miscellaneous in 54 (1.2%). Significant factors from multiple regression were included in a multi-level analysis, which incorporated variables measured at the level of the endoscopist and hospital. For overall complication, risk factors ( P value, odds ratio [OR], 95% confidence interval [CI]) were: cannulation attempts > 1 ( P = 0.094, OR 1.32, 95% CI 0.95-1.83), precut ( P = 0.033, OR 1.55, 95 % CI 1.04-2.32), and suspected sphincter of Oddi dysfunction ( P = 0.121, OR 1.97, 95 % CI 0.84-4.64). For pancreatitis, risk factors ( Pvalue, OR, and 95 % CI) were: cannulation attempts > 1 ( P = 0.0001, OR 3.14, 95% CI 1.74-5.67), female sex ( P < 0.001, OR 2.22, 95% CI 1.43-3.45), age ( P < 0.002, OR 1.09 per 5 year decrease, 95% CI 1.03-1.15), and performance in a district (as opposed to university) hospital ( P = 0.034, OR 2.41, 95% CI 1.08-5.41). CONCLUSION: Careful patient selection combined with skilled cannulation minimizes complications. Higher-risk procedures should be performed in specialist centers. PMID- 17703389 TI - Case series of transpancreatic septotomy as precutting technique for difficult bile duct cannulation. AB - BACKGROUND AND STUDY AIMS: Transpancreatic septotomy can be used instead of other precut techniques to facilitate bile duct cannulation after multiple failed attempts. Within the framework of a prospective randomized study on pentoxifylline, precut cases were retrospectively analyzed. PATIENTS AND METHODS: Of 320 endoscopic retrograde cholangiopancreatographies (ERCPs) in 306 patients with various indications who had a naive papilla, 34 cases of transpancreatic septotomy were identified and compared with 15 needle-knife sphincterotomies; six patients had received both techniques for bile duct access. Complications were defined according to consensus criteria. RESULTS: In the 55 patients in whom precutting techniques were employed, the use of both techniques alone or in combination resulted in a final common bile duct cannulation rate of 81.8%. Five patients developed complications (9.1%). Of the two cases of pancreatitis (3.6%), one was mild and one severe (combined group). Of the three cases with hemorrhage, one was mild (transpancreatic septotomy) and two severe (needle knife). In patients who underwent conventional pull-type sphincterotomy (n = 242), 6.2% developed complications (nine pancreatitis and six hemorrhage). CONCLUSION: In cases of difficult bile duct cannulation, transpancreatic septotomy seems to be a safe alternative to needle-knife precutting with reasonable success rates. It should be studied in prospective randomized trials. PMID- 17703390 TI - A randomized controlled trial on use of propofol alone versus propofol with midazolam, ketamine, and pentazocine "sedato-analgesic cocktail" for sedation during ERCP. AB - BACKGROUND AND AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) requires adequate patient sedation in order to carry out the procedure successfully. Propofol sedation is being increasingly used during ERCP. There are limited data to evaluate the efficacy of synergistic agents with propofol for sedation during ERCP. The aims of the current study were: (i) to compare patient sedation and tolerance during ERCP using either propofol alone or a "sedato analgesic cocktail" for induction, along with propofol for maintenance, and (ii) to prospectively compare complications related to both sedation regimens. PATIENTS AND METHODS: This was a double-blind, randomized controlled trial with patients receiving either intravenous propofol alone (Group A) or a sedato analgesic cocktail (midazolam, ketamine, and pentazocine plus propofol) (Group B) for induction; all patients received propofol for maintenance. Patient sedation and tolerance were assessed using 100-mm visual analog scales (VAS). RESULTS: A total of 199 patients undergoing ERCP were randomized (Group A, n = 104 vs. Group B, n = 95). Clinical characteristics were similar in both groups. Patient tolerance VAS scores were higher in Group B when assessed independently by both endoscopist ( P = 0.002) and anesthetist ( P = 0.001). The differences in scores occurred predominantly in younger patients. The mean propofol requirement was 192 mg in Group A and 131 mg in Group B; the mean difference was 61 mg (95%CI 40-82 mg). Patients reported equivalent levels of satisfaction with both sedation regimens. On multivariate analysis, "cocktail" use ( P = 0.013) and increasing age ( P = 0.027) significantly improved patient tolerance during ERCP. Caution during "cocktail" induction is required as transient oxygen desaturation occurs. CONCLUSION: During ERCP, propofol with a sedato-analgesic cocktail for induction results in improved patient tolerance compared with propofol alone, particularly in younger patients. Generalizations from this study to the Western world and to different cultural groups require further study. PMID- 17703391 TI - The influence of endoscopic biliary stents on the accuracy of endoscopic ultrasound for pancreatic head cancer staging. AB - BACKGROUND AND STUDY AIMS: Biliary stents have been found to interfere with endoscopic ultrasound (EUS) tumor (T) and nodal (N) staging in patients with periampullary cancer. Our aim was to determine whether this also occurs in patients with pancreatic head cancer. PATIENTS AND METHODS: We studied a consecutive series of patients who were undergoing preoperative EUS for diagnosis and staging of suspected pancreatic cancer, some of whom had biliary stents in situ and some of whom did not. The main end point was the uni- and multivariate association of biliary stenting with T and N mis-staging by EUS. The surgical T and N stages were used as gold standards. RESULTS: A total of 65 patients were identified (19 with biliary stents in situ and 46 without). Surgical stage T4 was found more frequently in patients with stents (53% vs. 22%, P = 0.014). The T stage by EUS was correct in 85% of the patients without biliary stents and in 47% of the patients with stents. The frequency of mis-staging by EUS was significant only among patients with a biliary stent. The distribution by EUS N stage did not differ significantly from the surgical N-stage distribution in the two groups of patients. According to the multivariate analysis, patients with stents were 6.55 times more likely to be incorrectly T staged (95% confidence interval [CI] 1.69 25.49) and 3.71 times more likely to be incorrectly N staged (95% CI 1.11-12.45) than patients without stents. CONCLUSIONS: The results add support to the recommendation that EUS staging of pancreatic head neoplasms should be performed prior to stent placement. PMID- 17703392 TI - Intensive training over 5 days improves colonoscopy skills long-term. AB - BACKGROUND AND AIMS: Poor standards in colonoscopy services and the introduction of a colorectal cancer screening program in the United Kingdom have highlighted the need to establish high-quality training and competency assessments in colonoscopy. The aims of this study were to evaluate the effectiveness of a 1 week hands-on colonoscopy course utilizing novel assessment tools. METHODS: Twenty-one doctors with varying colonoscopy experience who attended an accelerated colonoscopy training week (ACTW) were prospectively studied. They were trained and assessed in key aspects of colonoscopy. Knowledge was assessed with a multiple choice question (MCQ) paper. Practical hand skills were taught and evaluated using a computer simulator and live case teaching. Actual colonoscopy performance was assessed using Direct Observation of Procedural Skills scores (DOPS) and an objective tri-split video score of insertion technique. Two independent trainers taught and assessed the trainees at the start and end of the ACTW and at a median of 9 months' follow-up. RESULTS: Following training there were significant improvements in the MCQ score (P < 0.001), the simulator test case times (P = 0.02, P = 0.003), and the global DOPS score (P < or = 0.02). All improvements following the accelerated training were sustained at a median follow-up of 9 months. CONCLUSIONS: This study is the first in the literature to describe the positive, sustained impact of an intensive hands-on colonoscopy training course. Measurements of performance in key areas of skill acquisition improved following training. PMID- 17703393 TI - Challenging endoscopy reprocessing guidelines: a prospective study investigating the safe shelf life of flexible endoscopes in a tertiary gastroenterology unit. AB - BACKGROUND AND STUDY AIMS: Professional practice guidelines for endoscope reprocessing recommend reprocessing endoscopes between each case and proper storage following reprocessing after the last case of the list. There is limited empirical evidence to support the efficacy of endoscope reprocessing prior to use in the first case of the day; however, internationally, many guidelines continue to recommend this practice. The aim of this study is to estimate a safe shelf life for flexible endoscopes in a high-turnover gastroenterology unit. MATERIALS AND METHODS: In a prospective observational study, all flexible endoscopes in active service during the 3-week study period were microbiologically sampled prior to reprocessing before the first case of the day (n = 200). The main outcome variables were culture status, organism cultured, and shelf life. RESULTS: Among the total number of useable samples (n = 194), the overall contamination rate was 15.5%, with a pathogenic contamination rate of 0.5%. Mean time between last case one day and reprocessing before the first case on the next day (that is, shelf life) was 37.62 h (SD 36.47). Median shelf life was 18.8 h (range 5.27-165.35 h). The most frequently identified organism was coagulase negative Staphylococcus, an environmental nonpathogenic organism. CONCLUSIONS: When processed according to established guidelines, flexible endoscopes remain free from pathogenic organisms between last case and next day first case use. Significant reductions in the expenditure of time and resources on reprocessing endoscopes have the potential to reduce the restraints experienced by high turnover endoscopy units and improve service delivery. PMID- 17703394 TI - Safe storage of endoscopes: change in our guidelines? PMID- 17703395 TI - 30 years of ERCP and still the same problems? PMID- 17703396 TI - Preoperative endoscopic retrograde cholangiopancreatographic treatment of complicated choledochal cysts in children: a retrospective case series. AB - We report our experience with endoscopic retrograde cholangiopancreatography (ERCP-)based interventions in children with complicated choledochal cysts that are refractory to conservative management. Between 1999 and 2006, 42 children (12 boys, 30 girls; median age 3 years, range 2-14.5 years) were admitted for surgical treatment of choledochal cysts. Seven of these patients (16.7%; one boy, six girls; median age 3 years, range 2-12 years) showed signs of complicated choledochal cysts, and presented with pancreatitis/cholangitis (n = 4) and obstructive jaundice (n = 3). The anatomical classification of the cysts was type Ic (n = 3), type If (n = 3), and type IV (n = 1). ERCP was successfully performed in 6/7 patients, and therapeutic interventions included removal of debris (n = 3), sphincterotomy (n = 3), and stent placement (n = 4). One patient required blood transfusion for post-sphincterotomy bleeding. The patient in whom the ERCP failed underwent ultrasound-guided percutaneous transhepatic biliary drainage. Definitive surgery was performed after a median interval of 10 days (range 7-68 days) after the ERCP intervention. PMID- 17703397 TI - French Society of Digestive Endoscopy SFED guideline: monitoring of patients with Barrett's esophagus. PMID- 17703399 TI - [Zoonoses or animal diseases and animals in terminology of infectious diseases]. PMID- 17703400 TI - [Bat rabies in Europe and the Czech Republic]. AB - In 2005, six children were treated in our department who had been in contact with a bat infected with European bat lyssavirus 1 (EBL1). In the Czech Republic, this was the first confirmed case of rabies since 2002, but the fourth case of bat rabies since 1994. All the cases were related to Southern Moravia and bat species which almost do not migrate. This suggests only endemic prevalence of EBL1 in this country. Bat rabies is different from rabies in terrestic mammals. Based on genetic analyses, the lyssavirus genus may be divided into 6 genotypes of which genotypes 1 (rabies virus), 5 (EBL1) and 6 (EBL2) are found in Europe. The infectious cycles of bat lyssaviruses are limited solely to bat populations, in particular the Eptesicus serotinus species and the Myotis genus. Transmission to other mammals is rare. In Europe, four cases of human infection and death due to rabies caused by any of bat lyssaviruses have been reported. Immunologically, bat lyssaviruses are very similar to the common rabies virus. Therefore, the standard prophylactic methods are sufficient. Because of a different natural reservoir, the Czech Republic may be still considered a rabies-free country. However, contacts with bats always pose a risk of rabies. PMID- 17703401 TI - [Q fever]. AB - Coxiella burnetii, the causative agent of Q fever, is a Gram negative coccobacillus. It resides and replicates in the host s monocytes and macrophages. The developmental cycle of C. burnetii includes macrocellular and microcellular forms and the formation of spore-like bodies. It undergoes a phase variation of outer cell surface antigens from virulent phase I to avirulent phase II after passaging in the yolk sac of embryonated chicken eggs or in cell cultures. C. burnetii belongs to the most resistant bacteria. The main reservoirs of C. burnetii are cattle, sheep and goats. Human Q fever usually results from inhalation of contaminated aerosols. Acute infection mostly takes the course of a flu-like disease, atypical pneumonia or hepatitis, the chronic form resembles endocarditis. Laboratory examinations are based on the presence of antibodies. The drugs of choice are broad-spectrum antibiotics. PMID- 17703402 TI - [Utilization of the knowledge of antibiotic pharmacokinetics in the treatment of thoracic empyema]. AB - AIM OF THE STUDY: To confirm whether respecting the pharmacokinetics of beta lactam antibiotics in the treatment of thoracic empyema substantially influences the lengths of antibiotic therapy, thoracic drainage and hospital stay. MATERIAL AND METHODS: During a 30-month period, we compared two groups of patients treated for empyema, one with the standard administration of antibiotics, i.e. a 30 minute bolus, the other with the administration infusion time prolonged to 2 to 3 hours. We observed how rapidly inflammatory markers decreased (C-reactive protein, leukocytes), the lengths of thoracic drainage, antibiotic administration and hospital stay. The results were statistically compared. RESULTS: The study involved 58 patients with the average age of 57 years, the majority of whom were men (50). The empyema aetiology was mostly parapneumonic. The results of primary cultivation were dominated by Gram-positive cocci and anaerobes. Gram-negative bacteria, as well as fungi, were mainly cultured as secondary hospital microflora. Both groups were comparable as to the size, age distribution, male to female ratio and microbiological spectrum of the cultured pathogens. Already the fourth postoperative day, statistically significant difference occurred in the C reactive protein level and white cell count. The lengths of chest drainage, administration of antibiotics and hospital stay were 1 to 2 days shorter in the latter group. However, the decrease was not statistically significant. CONCLUSION: The prolongation of antibiotic administration infusion time contributed to faster inflammation regression, shorter antibiotic therapy and thus shorter hospital stay without increased costs. Although the aforementioned parameters were not statistically significant, we consider any shortening of antibiotic administration time and hospital stay to be beneficial for patients. The approach should be recommended for clinical practice, especially in the treatment of severe infections. PMID- 17703403 TI - [Detection of active varicella-zoster virus (VZV) infection in patients with neurological complications]. AB - OBJECTIVES: When introduced into routine virological diagnosis of nervous system infections, PCR detection of viral DNA revealed the varicella-zoster virus (VZV) in cerebrospinal fluid (CSF) at much higher rates than expected. The aim of the study was to evaluate the frequency of VZV DNA detection in CSF of patients with neurological symptoms in correlation with their VZV-specific serological findings and clinical symptoms. MATERIAL AND METHODS: A total of 438 patients followed up in the neurology departments of the Motol and Kralovske Vinohrady University Hospitals and the Department of Infectious Diseases of the Bulovka University Hospital were screened for the presence of VZV-specific antibodies in serum and intrathecal antibodies in CSF. A home-brew nested PCR assay was used for detection of VZV DNA in CSF. Positive results were correlated with clinical findings. RESULTS: Intrathecal antibodies against VZV were detected in 19.6 % of the studied patients, VZV-specific IgM antibodies were present in serum of 17.3 % of the patients and VZV DNA was recorded in CSF of 9.4 % of the patients. The clinical diagnosis was confirmed in 16 patients positive for VZV DNA in CSF: encephalitis as a complication of neonatal varicella in a 2-week child; encephalitis or meningoencephalitis in 5 adult patients of whom three had a history of herpes zoster, one suffered from severe haemorrhagic focal encephalitis with fatal complications and one had encephalitis and myelitis; neuropathies in 4 patients, two with inflammatory polyneuropathy of unknown origin and two with brachial plexopathy, in one case preceded by herpes zoster; epileptic symptoms in 2 patients; multiple sclerosis in 3 patients and nonspecific symptoms of chronic fatigue in one patient. CONCLUSIONS: 1) PCR proved to be a suitable method for diagnosing VZV-mediated nervous system infections. 2) VZV DNA can be present in CSF of patients with a wide range of neurological symptoms, even with no history of either herpes zoster or varicella. 3) VZV DNA detection in CSF needs to be interpreted with caution and in correlation with case histories, clinical findings and electrophysiological and imaging data, especially in patients with chronic inflammatory disease receiving immunosuppressive therapy. PMID- 17703404 TI - [A sepsis caused by Capnocytophaga canimorsus: diagnostic and therapeutic options]. AB - The authors present a case report of a patient with sepsis caused by Gram negative rod Capnocytophaga canimorsus resulting from a dog bite. The infection had a course of septic shock progressing into multiorgan failure and serious ischemic damage to the extremities. The etiologic agent was identified utilizing molecular genetic methods and its detailed microbiologic characteristics are provided below. The report also outlines diagnostic and therapeutic options of this otherwise most likely under-diagnosed infection. PMID- 17703405 TI - [Abscessing lymphadenitis in a 1.5-year-old boy]. AB - At present, Bartonella species are increasingly important as infectious agents in both animals and humans. Bartonella henselae, the most frequently diagnosed species, is known to cause numerous clinical syndromes in both immunocompetent and immunocompromised patients. In healthy individuals, the infection is most commonly manifested as the so-called cat scratch disease. The manifestations include erythema or papule at the point of entry of infection (site of injury) and regional lymphadenitis. The aim of the case report is to present the disease as one of possible causes of colliquative cervical lymphadenitis. PMID- 17703406 TI - [Eye involvement of borrelia aetiology]. AB - We present a case of eye involvement -- intermediate uveitis -- during tick-borne borreliosis in a 10-year-old boy. Ophthalmologic examination revealed impaired vision, apparent thick floating whitish opacity in the vitreous humour of the left eye and fine fibres in the vitreous humour of the right eye. Sonographic examination confirmed hyperechogenic opacity in the vitreous humour. An autoimmune process was suspected but not confirmed. Serological examination showed IgG antibodies against three pathogenic borreliae and borderline values of IgM antibodies against Borrelia garinii were found by immunoblot. The boy was treated with intravenous ceftriaxone for 21 days. The subsequent sonographic examination showed only minute sporadic echogenicity. Biomicroscopically, only residual opacity in the vitreous humour was found. Isolated eye involvement of borrelia aetiology is rare. The discussion provides a review of similar cases of uveitis including diagnosis of the eye form as published in literature. PMID- 17703407 TI - [A contribution to recommendations on vaccination against rabies in the Czech Republic]. AB - The article deals with the problems of rabies in the Czech Republic after declaration of the "rabies free" status and with vaccination after attack by an unknown animal. In 2004, the Czech Republic was declared a rabies free country by the International Institute for Animal Infection seated in Paris (OIE). This status enables not to vaccinate if man is attacked by an unknown animal within a distance more than 50 km from the border on the country with rabies incidence. PMID- 17703408 TI - In utero transmission of Nipah virus: role played by pregnancy and vertical transmission in Henipavirus epidemiology. PMID- 17703409 TI - Modernization of the medical Sherlock Holmes. PMID- 17703410 TI - Vertical transmission and fetal replication of Nipah virus in an experimentally infected cat. AB - A female adult cat developed clinical disease 13 days after subcutaneous inoculation with Nipah virus (NiV) and was discovered to be pregnant at necropsy. Viral genome was detected in a variety of specimens, including blood, serum, tonsil swabs, and urine, up to 3 days before the onset of disease. Samples collected postmortem, including placenta, uterine fluid, and fetal tissues, were also positive for NiV genome, and the placenta and uterine fluid contained high levels of recoverable virus. The high levels of viral shedding in the adult combined with fetal viral replication suggests that both vertical and horizontal transmission of NiV could play a role in spillover events, an essential element in the epidemiology of Henipavirus infection. PMID- 17703412 TI - Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. AB - BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of severe lower respiratory tract infection in infants. Only a proportion of children infected with RSV require hospitalization. Because known risk factors for severe disease, such as premature birth, cannot fully explain differences in disease severity, genetic factors have been implicated. METHODS: To study the complexity of RSV susceptibility and to identify the genes and biological pathways involved in its development, we performed a genetic association study involving 470 children hospitalized for RSV bronchiolitis, their parents, and 1008 random, population controls. We analyzed 384 single-nucleotide polymorphisms (SNPs) in 220 candidate genes involved in airway mucosal responses, innate immunity, chemotaxis, adaptive immunity, and allergic asthma. RESULTS: SNPs in the innate immune genes VDR (rs10735810; P=.0017), JUN (rs11688; P=.0093), IFNA5 (rs10757212; P=.0093), and NOS2 (rs1060826; P=.0031) demonstrated the strongest association with bronchiolitis. Apart from association at the allele level, these 4 SNPs also demonstrated association at the genotype level (P=.0056, P=.0285, P=.0372, and P=.0117 for the SNPs in VDR, JUN, IFNA5, and NOS2, respectively). The role of innate immunity as a process was reinforced by association of the whole group of innate immune SNPs when the global test for groups of genes was applied (P=.046). CONCLUSION: SNPs in innate immune genes are important in determining susceptibility to RSV bronchiolitis. PMID- 17703411 TI - Pan-viral screening of respiratory tract infections in adults with and without asthma reveals unexpected human coronavirus and human rhinovirus diversity. AB - BACKGROUND: Between 50% and 80% of asthma exacerbations are associated with viral respiratory tract infections (RTIs), yet the influence of viral pathogen diversity on asthma outcomes is poorly understood because of the limited scope and throughput of conventional viral detection methods. METHODS: We investigated the capability of the Virochip, a DNA microarray-based viral detection platform, to characterize viral diversity in RTIs in adults with and without asthma. RESULTS: The Virochip detected viruses in a higher proportion of samples (65%) than did culture isolation (17%) while exhibiting high concordance (98%) with and comparable sensitivity (97%) and specificity (98%) to pathogen-specific polymerase chain reaction. A similar spectrum of viruses was identified in the RTIs of each patient subgroup; however, unexpected diversity among human coronaviruses (HCoVs) and human rhinoviruses (HRVs) was revealed. All but one of the HCoVs corresponded to the newly recognized HCoV-NL63 and HCoV-HKU1 viruses, and >20 different serotypes of HRVs were detected, including a set of 5 divergent isolates that formed a distinct genetic subgroup. CONCLUSIONS: The Virochip can detect both known and novel variants of viral pathogens present in RTIs. Given the diversity detected here, larger-scale studies will be necessary to determine whether particular substrains of viruses confer an elevated risk of asthma exacerbation. PMID- 17703413 TI - alpha-Defensin inhibits influenza virus replication by cell-mediated mechanism(s). AB - The innate immune system mounts the first host response to pathogens. Because alpha-defensins, which are cationic antimicrobial peptides of polymorphonuclear neutrophils and other leukocytes, are important effectors of the innate immune system, we studied the antiviral activity of human alpha-defensin-1 (also known as "human neutrophil peptide-1" [HNP-1]) against influenza virus in vitro. Treatment of cell cultures with HNP-1 soon after infection resulted in marked inhibition of influenza virus replication and viral protein synthesis. This effect was not due to cytotoxicity or to a direct effect on the virus. Treatment of cells with HNP-1 followed by its removal before infection also inhibited viral replication, suggesting that the inhibition was due to the modulation of cellular pathways. HNP-1 treatment inhibited protein kinase C (PKC) activation in infected cells, suggesting the involvement of the PKC pathway. Our data expand the previously known activity of alpha -defensins against influenza virus. Characterizing the mechanism of action of alpha -defensins may lead to the identification of new strategies for prevention and therapy. PMID- 17703415 TI - Tumor necrosis factor-alpha and interleukin-1 beta play a critical role in the resistance against lethal herpes simplex virus encephalitis. AB - BACKGROUND: The innate immune response after herpes simplex type 1 (HSV-1) encephalitis could be protective or, paradoxically, implicated in neuronal damage. We investigated the role of the innate immune response in such infection using a C57BL/6 mouse knockout (KO) model for tumor necrosis factor (TNF)-alpha and/or interleukin (IL)-1beta. METHODS: Encephalitis was induced by intranasal infection with a clinical strain of HSV-1 in 1-month-old KO or wild-type (WT) mice. Mice were monitored for survival, brain viral load was quantified by real time polymerase chain reaction, and the inflammatory response was assessed by in situ hybridization in groups of mice killed on days 3-7. RESULTS: WT mice had a significantly higher mean life expectancy (P=.0001, log-rank test) than other groups. IL-1beta and TNF-alpha KO mice had a similar mean life expectancy, and encephalitis was lethal to all TNF-alpha /IL-1beta-deficient mice. Brain viral loads were lower in WT than in KO mice that had disseminated viral replication in the pons and medulla. Moreover, TNF- alpha and IL-1beta KO mice failed to initiate an adequate immune response, as shown by the virtual absence of expression of proinflammatory molecules in the brain. CONCLUSION: These data clearly demonstrate the importance of TNF-alpha and IL-1beta in protection against HSV-1 encephalitis in this mouse model. PMID- 17703414 TI - Human herpesvirus-8 infection and oral shedding in Amerindian and non-Amerindian populations in the Brazilian Amazon region. AB - BACKGROUND: Human herpesvirus type 8 (HHV-8) is hyperendemic in Amerindian populations, but its modes of transmission are unknown. METHODS: Antibodies against either HHV-8 lytic antigen or HHV-8 latency-associated nuclear antigen (LANA) were detected, by immunofluorescence assays, in 339 Amerindians and 181 non-Amerindians from the Brazilian Amazon. Serological markers of oro-fecal (hepatitis A), parenteral (hepatitis B and C), and sexual (herpes simplex virus type 2 and syphilis) transmission were measured by specific ELISAs. Salivary HHV 8 DNA was detected by use of a nested polymerase chain reaction assay and was sequenced. RESULTS: Antibodies against either lytic antigen or LANA were detected in 79.1% of Amerindians and in 6.1% of non-Amerindians (adjusted seroprevalence ratio [SR], 12.63 [95% confidence interval {CI}, 7.1-22.4]; P<.0001). HHV-8 seroprevalence increased with age among Amerindians (P(Trend) < .001) and already had high prevalence in childhood but was not sex specific in either population. The 2 populations did not differ in seroprevalence of oro-fecal or parenteral markers, but seroprevalence of markers of sexual transmission was lower among Amerindians. HHV-8 DNA in saliva was detected in 47 (23.7%) of 198 HHV-8 seropositive Amerindians. Detection of HHV-8 DNA decreased with age (P(Trend) < .04) and was more common in men (SR, 2.14 [95% CI, 1.3-3.5]; P=.003). A total of 36 (76.6%) of the 47 saliva HHV-8 DNA samples were sequenced, and all clustered as subtype E. CONCLUSION: The data support the hypothesis of early acquisition and horizontal transmission, via saliva, of HHV-8 subtype E in Amerindian populations. PMID- 17703416 TI - Cellular immunity to mumps virus in young adults 21 years after measles-mumps rubella vaccination. AB - BACKGROUND: Measles-mumps-rubella (MMR) vaccination has decreased the incidence of measles, mumps, and rubella virus infections in several countries. However, the persistence of MMR vaccine-induced immunity in the absence of endemic infection has remained unknown. METHODS: The persistence of cellular and humoral immunity to mumps virus was studied in 50 individuals (group A) who had been vaccinated twice with MMR vaccine during early childhood and were followed up for 21 years after their first vaccination. Eleven individuals (group B) with naturally acquired immunity to mumps virus were studied for comparison. RESULTS: Anti-mumps virus IgG antibodies were detectable (titer > or = 230) in 72% of the vaccinees. A mumps antigen-specific lymphoproliferative response (defined as a stimulatory index [SI] > or = 3) was observed in 98% of group A subjects (mean+/ SD SI, 26+/-30 [range, 0.5-252]) and in 100% of group B subjects (mean+/-SD SI, 22+/-27 [range, 5-123]). Significant mumps antigen-specific interferon- gamma production was detected in 73% of subjects in both groups A and B, and interleukin-10 production was detected in 40% and 36% of group A and B subjects, respectively. CONCLUSIONS: All presently seronegative vaccinees (n=14) had mumps antigen-specific lymphoproliferative responses, and only 1 of the seropositive vaccinees (n=36) was devoid of detectable cellular immunity. The results suggest a very long persistence of vaccine-induced anti-mumps virus cellular immunity. PMID- 17703417 TI - Profile of viral load, integration, and E2 gene disruption of HPV58 in normal cervix and cervical neoplasia. AB - The clinical utility of viral-load and integration status of human papillomavirus (HPV) infection remains uncertain. We examined 75 women infected with HPV58, a worldwide rare type found to be prevalent in cervical cancers in eastern Asia. Viral load was significantly higher for cervical intraepithelial neoplasia (CIN) 1/2, but those for a normal control group and for CIN 3 or cancer overlapped substantially. A pure integrated genome was found for all lesion grades, giving a poor positive predictive value (23.1%) for cancer. The pure episomal form's negative predictive value for cancer was only 76.3%. Mixed patterns of E2 gene disruption were common and often involved the amino-terminal and hinge regions. Disruption of the whole E2 gene was rare and was restricted to high-grade lesions. The HPV58 variant E67-HK-2 was more likely to exist in the pure episomal form. Routinely collected cervical samples contain a heterogeneous population of viruses, hampering the application of viral load and integration testing in clinical settings. PMID- 17703418 TI - Cutaneous human papillomaviruses found in sun-exposed skin: Beta-papillomavirus species 2 predominates in squamous cell carcinoma. AB - BACKGROUND: A spectrum of cutaneous human papillomaviruses (HPVs) is detectable in nonmelanoma skin cancers, as well as in healthy skin, but the significance that the presence of these types of HPV DNA has for the pathogenesis of skin cancer remains unclear. METHODS: We studied 349 nonimmunosuppressed patients with skin lesions (82 with squamous cell carcinomas, 126 with basal cell carcinomas, 49 with actinic keratoses, and 92 with benign lesions). After superficial skin had been removed by tape, paired biopsy samples--from the lesion and from healthy skin from the same patient--were tested for HPV DNA. Risk factors for HPV DNA were analyzed in multivariate models. RESULTS: Overall, 12% of healthy skin samples were positive for HPV DNA, compared with 26% of benign lesions, 22% of actinic keratoses, 18% of basal cell carcinomas, and 26% of squamous cell carcinomas. HPV DNA was associated with sites extensively exposed to the sun, both for the lesions (odds ratio [OR], 4.45 [95% confidence interval {CI}, 2.44 8.11]) and for the healthy skin samples (OR, 3.65 [95% CI 1.79-7.44]). HPV types of Beta-papillomavirus species 2 predominate in squamous cell carcinomas (OR, 4.40 [95% CI, 1.92-10.06]), whereas HPV types of Beta-papillomavirus species 1 are primarily found in benign lesions (OR, 3.47 [95% CI, 1.72-6.99]). CONCLUSIONS: Cutaneous HPV types are primarily detected at sites extensively exposed to the sun. HPV types of Beta-papillomavirus species 2, but not of species 1, are associated with squamous cell carcinoma. PMID- 17703419 TI - Serological evidence of possible human infection with Tioman virus, a newly described paramyxovirus of bat origin. AB - Tioman virus, a relatively new paramyxovirus, was isolated from fruit bats (Pteropus species) on Tioman Island, Malaysia, in 2001. The objective of this study was to determine the prevalence of antibodies to T. virus in island inhabitants, by use of comparative ELISA and serum neutralization assays. Of the 169 human sera analyzed, 5 (approximately 3.0%) were positive for T. virus, by comparative ELISA. Of these 5 sera, 3 (1.8% of the total) had neutralizing antibodies against T. virus, suggesting previous infection of this study population by this virus or a similar virus. PMID- 17703420 TI - The impact of HIV status and type on the clearance of human papillomavirus infection among Senegalese women. AB - BACKGROUND: Persistent infection with human papillomavirus (HPV) is associated with the development and progression of HPV-related disease, including cervical intraepithelial neoplasia (CIN) and invasive cervical cancer. METHODS: We examined the impact of human immunodeficiency virus (HIV) status and type on the clearance of HPV infection among 614 Senegalese women enrolled in a longitudinal study of HPV and CIN. Women were examined every 4 months for HPV DNA. Clearance was defined as 2 consecutive negative HPV DNA test results. RESULTS: Cox proportional hazard regression with time-dependent covariates indicated that HIV positive women were less likely to clear HPV infection (adjusted hazard ratio [HR], 0.31 [95% confidence interval {CI}, 0.21-0.45]) than HIV-negative women. Among HIV-positive women, those with CD4 cell counts <200 or from 200 to 500 cells/microL showed a 71% (adjusted HR, 0.29 [95% CI, 0.11-0.76]) and 32% (adjusted HR, 0.68 [95% CI, 0.31-1.48]) reduction in the likelihood of HPV clearance, respectively, compared with those with CD4 cell counts >500 cells/microL. HIV-2 infection was associated with an increased likelihood of HPV clearance (adjusted HR, 2.46 [95% CI, 1.17-5.16]), compared with that for HIV-1 infection. CONCLUSIONS: HIV infection reduces the likelihood of HPV clearance. Among HIV-positive women, immunosuppression, as measured by CD4 cell count, reduces the likelihood of HPV clearance, and HIV type appears to be associated with HPV clearance. PMID- 17703421 TI - Coinfection and superinfection in patients with long-term, nonprogressive HIV-1 disease. AB - Human immunodeficiency virus 1 (HIV-1) dual infections are considered important because they have been related to AIDS progression. We identified dual infections in 2 patients with long-term, nonprogressive HIV-1 disease; the first patient was diagnosed as being already coinfected, on the basis of the first sample analyzed, but a previous superinfection could not be excluded; the second patient was diagnosed as having a superinfection, on the basis of the 9-year difference between the viral dating of the 2 strains. Dual infections occur in patients with long-term, nonprogressive disease, with no immediate clinical manifestations. Such occurrences could indicate a general phenomenon in natural HIV-1 infections. PMID- 17703422 TI - Porcine thymic grafts protect human thymocytes from HIV-1-induced destruction. AB - Human immunodeficiency virus type 1 (HIV-1) infection depletes thymocytes and destroys thymic structure. Functional, tolerant human T cells develop in vivo in immunodeficient mice receiving porcine thymus and human fetal liver fragments under the kidney capsule. In this model, we evaluated the potential of porcine thymus to protect human thymocytes from the effects of HIV-1. Compared with that observed in control mice with human thymic grafts, porcine thymus attenuated human thymocyte depletion by the CCR5-tropic isolate JR-CSF without preventing thymocyte infection. Porcine thymus protected human thymocytes from infection and depletion by a CXCR4-tropic HIV-1 isolate without reducing peripheral blood viral loads or T cell infection. Human thymocytes from human but not porcine grafts showed decreased Bcl-2 expression and increased apoptosis after NL4.3 infection. Thus, porcine thymus protects human thymocytes from the cytopathic effect of HIV 1, suggesting a possible approach to achieving immune restoration in patients with acquired immunodeficiency syndrome who have incomplete responses to antiretroviral therapy. The model allows analysis of the mechanisms of HIV mediated thymic dysfunction. PMID- 17703423 TI - Staphylococcus aureus colonization and infection in New York State prisons. AB - Methicillin-resistant Staphylococcus aureus is increasingly responsible for staphylococcal outbreaks in prison. There is limited information on the source of the outbreak strains, risk factors for infection, and transmission of these strains within a prison. We conducted a survey to determine the prevalence of nasal colonization with S. aureus in 2 New York State prisons. S. aureus isolates from clinical cultures collected from all New York State prisons during a 6-month period were compared with the colonizing strains. Analyses were conducted to determine whether prison-level characteristics were associated with colonization or infection with S. aureus. The colonization rate was 25.5% (124/487); 10.5% of the isolates were methicillin resistant, all were staphylococcal chromosomal cassette (SCC)mec type IV, and 61.5% were Panton Valentine leukocidin (PVL) positive. Surprisingly, 21.6% of the methicillin-susceptible isolates were also PVL positive. Of the clinical isolates, 48.3% were methicillin resistant, with 93.1% of the latter being SCCmec type IV and 48.3% being PVL positive. The predominant clone was USA 300. Prison-level risk factors for infection included the proportion of inmates with drug offenses, the length of inmate stay, and the jail from which inmates originated. This study suggests that both new and long term inmates act as sources of S. aureus strains, with the more virulent of the latter preferentially being selected as pathogens. PMID- 17703424 TI - Capsular polysaccharide masks clumping factor A-mediated adherence of Staphylococcus aureus to fibrinogen and platelets. AB - BACKGROUND: Clumping factor A (ClfA) is a Staphylococcus aureus cell wall associated adhesin that mediates staphylococcal binding to fibrinogen and platelets. Our goals were to determine whether expression of capsular polysaccharide (CP) affected ClfA-mediated adherence of S. aureus and to assess whether the length of the ClfA repeat region influenced this interaction. METHODS: ClfA constructs with repeat regions of different lengths were introduced into isogenic S. aureus strains that expressed CP5, CP8, or no CP. S. aureus binding to fibrinogen was assessed in rabbit plasma and on fibrinogen-coated microtiter plates. Adherence of S. aureus strains to platelets was evaluated by flow cytometry and confocal microscopy. RESULTS: As the length of the ClfA repeat region increased, binding of acapsular S. aureus to fibrinogen-coated microtiter plates was enhanced. By contrast, encapsulated S. aureus expressing the full length ClfA were poorly adherent. The acapsular S. aureus mutant strain showed a 2-fold increase in platelet binding, compared with the isogenic encapsulated strains. By contrast, platelet aggregation was unaffected by CP production. CONCLUSION: CP expression inhibits S. aureus ClfA-mediated binding to fibrinogen and platelets, and a full-length repeat region cannot overcome this inhibition. These findings have important implications for vaccine development, given that CP may mask surface adhesins. PMID- 17703425 TI - Serum antipneumococcal antibodies and pneumococcal colonization in adults with chronic obstructive pulmonary disease. AB - Antibodies to pneumococcus are thought to represent the primary mechanism of naturally acquired resistance to colonization. Here, however, we show that, in patients with chronic obstructive pulmonary disease (COPD), resistance to pneumococcal colonization is not associated with higher concentrations of serum anti-capsular or -noncapsular antibodies. We compared preacquisition serum antibody concentrations to capsular antigens 6B, 7F, 14, 19F, and 23F from patients with COPD who did and did not acquire pneumococcal respiratory tree colonization over the course of 2 years. Colonized patients did not have lower anti-capsular antibody concentrations than control subjects who did not acquire pneumococcus. We found no difference in functional antibody concentrations between colonized patients and control subjects. Furthermore, colonized patients had significantly higher preacquisition concentration of antibody directed against the whole cell and pneumococcal surface protein A than control subjects. We thus conclude that, in adult patients with COPD, resistance to pneumococcal colonization is unlikely to be determined by higher serum antibody concentrations to pneumococcal antigens. PMID- 17703426 TI - Presence of nonhemolytic pneumolysin in serotypes of Streptococcus pneumoniae associated with disease outbreaks. AB - Pneumolysin is an important virulence factor of the human pathogen Streptococcus pneumoniae. Sequence analysis of the ply gene from 121 clinical isolates of S. pneumoniae uncovered a number of alleles. Twenty-two strains were chosen for further analysis, and 14 protein alleles were discovered. Five of these had been reported previously, and the remaining 9 were novel. Cell lysates were used to determine the specific hemolytic activities of the pneumolysin proteins. Six strains showed no hemolytic activity, and the remaining 16 were hemolytic, to varying degrees. We report that the nonhemolytic allele reported previously in serotype 1, sequence type (ST) 306 isolates is also present in a number of pneumococcal isolates of serotype 8 that belong to the ST53 lineage. Serotype 1 and 8 pneumococci are known to be associated with outbreaks of invasive disease. The nonhemolytic pneumolysin allele is therefore associated with the dominant clones of outbreak-associated serotypes of S. pneumoniae. PMID- 17703427 TI - Streptococcus pneumoniae surface-exposed glutamyl tRNA synthetase, a putative adhesin, is able to induce a partially protective immune response in mice. AB - Glutamyl tRNA synthetase (GtS) has been found to be among the Streptococcus pneumoniae cell wall-derived proteins that have age-dependent immunogenicity in children. Here, GtS was cloned, expressed, and purified and then was used to immunize 7-week-old BALB/c OlaHsd mice. Serum obtained from mice immunized with recombinant (r) GtS cross-reacted with a 55.9-kDa protein, identified as GtS, in the cell wall fraction derived from genetically and capsularly unrelated strains of S. pneumoniae. Surface localization of GtS was further confirmed using flow cytometry analysis. The rGtS and anti-rGtS antiserum significantly inhibited the adhesion of 3 pairs of encapsulated and unencapsulated strains of S. pneumoniae to A549 cells. Thirty-nine percent of rGtS-immunized mice survived a lethal bacterial challenge, whereas no control mice survived. These results suggest that GtS, an age-dependent S. pneumoniae antigen, is a surface-located adhesin that is capable of inducing a partially protective immune response against S. pneumoniae in mice. PMID- 17703428 TI - Tumor necrosis factor (TNF) receptor-1 (TNFp55) signal transduction and macrophage-derived soluble TNF are crucial for nitric oxide-mediated Trypanosoma congolense parasite killing. AB - Control of Trypanosoma congolense infections requires an early cell-mediated immune response. To unravel the role of tumor necrosis factor (TNF) in this process, 6 different T. congolense strains were used in 6 different gene deficient mouse models that included TNF(-/-), TNF receptor-1 (TNFp55)(-/-), and TNF receptor-2 (TNFp75)(-/-) mice, 2 cell type-specific TNF(-/-) mice, as well as TNF-knock-in mice that expressed only membrane-bound TNF. Our results indicate that soluble TNF produced by macrophages/neutrophils and TNFp55 signaling are essential and sufficient to control parasitemia. The downstream mechanism in the control of T. congolense infection depends on inducible nitric oxide synthase activation in the liver. Such a role for nitric oxide is corroborated ex vivo, because the inhibitor N(G)-monomethyl-l-arginine blocks the trypanolytic activity of the adherent liver cell population, whereas exogenous interferon- gamma that stimulates nitric oxide production enhances parasite killing. In conclusion, the control of T. congolense infection depends on macrophage/neutrophil-derived soluble TNF and intact TNFp55 signaling, which induces trypanolytic nitric oxide. PMID- 17703429 TI - A brief response to Sealey and Laragh. PMID- 17703431 TI - Cross-talk related to insulin and angiotensin II binding on myocardial remodelling in diabetic rat hearts. AB - This study focused on the regulation and affinity modulation of angiotensin II (Ang II) binding to its receptor subtypes (AT(1)- and AT(2)-receptor) in the coronary endothelium (CE) and cardiomyocytes (CM) of Sprague-Dawley male rats in normal (N), normal treated with losartan (NL), streptozotocin-induced diabetic (D), insulin-treated diabetic (DI), losartan-treated diabetic (DL), and diabetic co-treated with insulin and losartan (DIL). Heart perfusion was used to estimate Ang II binding affinity (tau=1/k-(n)) to its receptor subtypes on CE and CM. Diabetes decreased tau value on CE and increased it on CM as compared to normal. In DL group, the tau value decreased on CE but was normalised on CM. Insulin treatment alone (DI) or with losartan (DIL) restored t to normal on both CE and CM. Western blot results for AT(1)-receptor density showed an increase in diabetics compared to normal with no normalising effect with insulin treatment. The AT(1)-receptor density was normalised in the diabetic groups treated with losartan +/- insulin. Results for AT(2)-receptor regulation revealed a significant difference between untreated (D) and losartan-treated (DL, DIL) diabetic groups. All of these data show the interrelated pathway and cross-talk between insulin and Ang II system indicating potentially negative effects on the diabetic heart. PMID- 17703430 TI - The blockade of the renin-angiotensin system reverses tacrolimus related cardiovascular toxicity at the histopathological level. AB - INTRODUCTION: In this study, we investigate the toxic effects of tacrolimus (FK506) on the cardiovascular system at the histopathological level in a rat model and whether these effects can be reversed by the blockade of the renin angiotensin system (RAS) by either an angiotensin-converting enzyme inhibitor (ACE-inhibitors) or an angiotensin receptor antagonist (ARB). METHODS AND RESULTS: Thirty-one Wistar rats were divided into four groups. FK506 group was treated with FK506 intraperitoneally (i.p.), FK506+ACE-inhibitors and FK506+ARB groups were treated with either quinapril or valsartan orally in addition to FK506. Control group was treated with saline i.p. Histological and immunohistochemical staining of cardiovascular tissue in the FK506 group showed increased vacuolar degeneration (11.2 vs. 5.8, p=0.008), arterial hyalinosis (10.7 vs. 6.3, p=0.036), transforming growth factor-beta (TGF-beta) (12.2 vs. 4.8, p=0.001) and vascular endothelial growth factor expression (VEGF) (10.7 vs. 6.3, p=0.036), elastic van Gieson (11.5 vs. 5.5, p=0.004), and periodic acid Schiff stain scores (12.5 vs. 4.5, p<0.001) compared to the control group. Immunohistochemical scores showed that expression of TGF-beta is up-regulated, and bone morphogenic protein (BMP-7) is down-regulated with FK506 toxicity. Adding RAS blockade with either an ACE-inhibitor or an ARB could reverse FK506 induced changes. Both FK506+ACE-inhibitors and FK506+ARB groups demonstrated decrease in arterial hyalinosis (22.1 vs. 14.4 (FK506+ACE-inhibitor) and 13.6 (FK506+ARB), p=0.09) and vacuolar degeneration (23.1 vs. 16.1 (FK506+ACE inhibitor) and 12.4 (FK506+ARB), p=0.006) scores compared to the FK506 group. CONCLUSION: Blockade of RAS could reverse the histopathological signs of FK506 induced cardiac toxicity in a rat model. PMID- 17703432 TI - Activation of protective and damaging components of the cardiac renin-angiotensin system after myocardial infarction in experimental diabetes. AB - INTRODUCTION: Diabetes is associated with prolonged apoptotic cell death of cardiac myocytes and adverse remodelling after myocardial infarction (MI). Because the renin-angiotensin system (RAS) has a major role in the remodelling, we studied whether diabetes is associated with altered regulation of RAS after MI in rats. METHODS: Male Wistar rats were randomised to receive either streptozotocin (diabetic group) or citrate buffer (control group) intravenously. MI was produced four weeks later by ligating the left descending coronary artery. The rats were sacrificed 1, 4 and 12 weeks after the operation. Angiotensin converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE 2), angiotensin type 1 and 2 receptors (AT(1)-receptor, AT(2)-receptor), and connective tissue growth factor (CTGF) mRNA expression were determined. RESULTS: The expression of both protective and damaging components of RAS increased after MI. However, myocardial ACE 2 and AT(2)-receptor messenger ribonucleic acid (mRNA) expression levels were significantly lower in diabetic compared to non-diabetic rats 1 week after MI. In contrast, AT(1)-receptor, ACE and CTGF mRNA levels were up-regulated in diabetic as compared with non-diabetic rats 12 weeks after MI. CONCLUSION: The activation of the protective components of RAS (ACE 2 and AT(2)-receptor) was blunted early after MI in diabetic rats, whereas the levels of ACE, AT(1) receptor and CTGF mRNA leading to adverse effects on myocardium, were elevated in diabetic as compared with non-diabetic rats. This unbalanced activation of the RAS may influence the pathophysiology of myocardial injury in diabetes after MI. PMID- 17703433 TI - Beneficial versus harmful effects of Angiotensin (1-7) on impulse propagation and cardiac arrhythmias in the failing heart. AB - INTRODUCTION: The presence of Angiotensin (1-7) (Ang 1-7) and ACE 2 in the ventricle of cardiomyopathic hamsters as well as the influence of Ang (1-7) on membrane potential, impulse propagation and cardiac excitability were investigated. METHODS: Histology and immunochemistry were used to demonstrate the presence of Ang (1-7) and ACE 2 in the ventricle of cardiomyopathic hamsters. Measurements of transmembrane potentials, conduction velocity and refractoriness were made using conventional intracellular microelectrodes. The influence of Ang (1-7) on sodium pump current was investigated in voltageclamped myocytes isolated from the ventricle. RESULTS: The results indicated the presence of Ang (1-7) and ACE 2 in myocytes of cardiomyopathic hamsters. Moreover,Ang (1-7) (10(-8) M) hyperpolarised the heart cell, increased the conduction velocity, and reduced transiently the action potential duration. The cardiac refractoriness was also increased by the heptapeptide, an effect in part reduced by an inhibitor of mas receptor. These findings indicate that Ang (1-7) has important antiarrhythmic properties. However, the beneficial effects of Ang (1-7) are dose-dependent because at higher concentration (10(-7) M) the heptapeptide elicited an appreciable increase of action potential duration and early-after depolarisations. Since losartan (10(-7) M) did not counteract this effect of the high dose of the heptapeptide, it is possible to conclude that activation of AT(1)-receptors is not involved in this effect of Ang (1-7). To investigate the mechanism of the hyperpolarising action of Ang (1-7) the influence of the heptapeptide on the sodium potassium pump current was studied in myocytes isolated from the ventricle of cardiomyopathic hamsters. The peak pump current density was measured under voltage clamp using the whole cell configuration. The results indicated that Ang (1-7) (10(-8) M) enhanced the electrogenic sodium pump, an effect suppressed by ouabain (10(-7) M). CONCLUSIONS: Ang (1-7) has beneficial effects on the failing heart by activating the sodium pump, hyperpolarising the cell membrane and increasing the conduction velocity. These effects as well as the increment of refractoriness indicate that Ang (1-7) has antiarrhythmic properties. At higher concentrations (10(-7) M), however, the heptapeptide induced early-after depolarisations which leads to the conclusion that an optimal generation of Ang (1-7) must be achieved to permit a protective role of Ang (1-7) on cardiac arrhythmias. PMID- 17703434 TI - Low-dose renin inhibitor and low-dose AT(1)-receptor blocker therapy ameliorate target-organ damage in rats harbouring human renin and angiotensinogen genes. AB - We studied the effects of extremely low-dose human renin inhibition (aliskiren) with low angiotensin II receptor blockade (losartan) in a novel double-transgenic rat model harbouring both human renin and angiotensinogen genes. We found that low-dose aliskiren and low-dose losartan effectively reduced mortality and target organ damage with minimal, non-significant, effects on blood pressure (BP). Our data suggest that renin-angiotensin system (RAS) inhibition ameliorates target organ damage in an Ang II-driven model of hypertension. Direct renin inhibition is equally efficacious in this regard. Our study does not fully answer the question of BP-lowering versus RAS inhibition. This question is important and was at least partially addressed with our low-dose model. PMID- 17703435 TI - Short- and long-term glycaemic control and the state of the renin system in type 1 diabetes mellitus. AB - Renin system blockade in diabetes exerts a strong positive influence on complications, especially nephropathy. In hyperglycaemic diabetic subjects, however, blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors results in a marked rise in plasma renin. We investigated whether glycaemic fluctuations measured in hours, or those measured in weeks by Haemoglobin A(1C) (HbA(1C)) , influenced the plasma renin response to captopril. Fifty-four type 1 diabetic subjects were studied in high-salt balance. After an all night fast and in the supine position, baseline serum glucose level was drawn. Iv. glucose and insulin were then administered to keep serum glucose between 100 and 150 mg/dL (target). When target was reached, captopril 25 mg pre os was administered and plasma renin activity (PRA) and finger stick glucose were drawn, then serially every 45 minutes for 225 minutes. Baseline glucose and baseline PRA were drawn hours apart. Peak PRA corresponded to the renin level at peak captopril effect, 90' after administration. Renin response (RR) = peak PRA - baseline PRA. Correlation of baseline glucose with baseline PRA was weak (r=0.3, p=0.02), but strong with peak PRA (r=0.65; p=0.002). Drop in glucose had a weak, negative correlation with baseline PRA (r=-0.3, p=0.03) but a much stronger one with peak PRA (r=-0.7, p<0.0001). After adjustment for baseline PRA and baseline glucose, mean RR correlated strongly with mean drop in glucose (r=-0.72; p=0.008). Conversely, HbA1C correlated with none of the measures of renin system activation (r=0.05;p=0.7). In type 1 diabetic subjects, short-term hyperglycaemia, but not long-term glycaemic control, enhanced the RR to captopril. PMID- 17703436 TI - Renoprotective effects of telmisartan in the 5/6 nephrectomised rats. AB - The purpose of this study was to investigate the renoprotective effect of telmisartan on the advanced stages of nephropathy in rats with 5/6 nephrectomy (5/6 Nx). Telmisartan was orally administered for 12 weeks to rats that previously underwent 5/6 Nx or sham operations. After completion of the administration period, the degree of renal injury was examined histopathologically using indices of glomerulosclerosis and lesions of the renal tubule and interstitium. An immunohistochemical staining for transforming growth factor-beta (TGF-beta1) was also performed. The suppression of urinary protein was statistically significant in surviving animals dosed with telmisartan. The enalapril group's urinary protein was also significantly suppressed for these same parameters in surviving animals. Histopathologically, telmisartan significantly decreased the progression of glomerulosclerosis and the interstitial cell infiltration at all doses tested. As assessed by immunohistochemical staining the TGF-beta1 reactivity in the glomerular tissue tended to decrease in the telmisartan group when compared to the vehicle group. Thus, telmisartan ameliorates the progressive nephropathy in the remaining kidney after 5/6 Nx by non-haemodynamic as well as antihypertensive actions of the drug. PMID- 17703437 TI - Spotlight on renin: Nonproteolytic activation of prorenin by the (pro)renin receptor is blocked by decoy peptide. PMID- 17703438 TI - Comment on developmental toxicity evaluation on Vorinostat and relationship with HDAC inhibition. PMID- 17703440 TI - Comparative proteome analysis of the embryo proper and yolk sac membrane of day 11.5 cultured rat embryos. AB - BACKGROUND: Proteomic analysis of cultured postimplantation rat embryos is expected to be useful for investigation into embryonic development. Here we analyzed protein expression in cultured postimplantation rat embryos by two dimensional electrophoresis (2-DE) and mass-spectrometric protein identification. METHODS: Rat embryos were cultured from day 9.5 for 48 h or from day 10.5 for 24 h. Proteins of the embryo proper and yolk sac membrane were isolated by 2-DE and differentially analyzed with a 2-D analysis software. Selected protein spots in the 2-DE gels were identified by matrix-assisted laser desorption/ionization-time of flight tandem mass spectrometric analysis and protein database search. RESULTS: About 800 and 1,000 protein spots were matched through the replicate 2 DE gels each from one embryo in the embryo proper and yolk sac membrane, respectively, and virtually the same protein spots were observed irrespective to the length of culture period. From protein spots specific to the embryo proper (126 spots) and yolk sac membrane (304 spots), proteins involved in tissue characteristic functions, such as morphogenesis and nutritional transfer, were identified: calponin, cellular retinoic acid binding protein, cofilin, myosin, and stathmin in the embryo proper, and Ash-m, dimerization cofactor of hepatocyte nuclear factor, ERM-binding phosphoprotein, cathepsin, and legumain in the yolk sac membrane. CONCLUSION: Proteomic analysis of cultured postimplantation rat embryos will be a new approach in developmental biology and toxicology at the protein level. PMID- 17703441 TI - An improved flow cytometric method using FACS Lysing Solution for measurement of ZAP-70 expression in B-cell chronic lymphocytic leukemia. AB - BACKGROUND: B-cell expression of ZAP-70, normally expressed in T and NK cells, correlates with poor prognosis in B-CLL. Poor discrimination between ZAP-70 positive and negative cells hampers routine application of flow cytometry. We examined the usefulness of FACS Lysing Solution. METHODS: ZAP-70 expression in 65 healthy volunteers was measured by four-color flow cytometry, comparing FACS Lysing Solution for fixation and permeabilization with the Fix & Perm kit. Separation between ZAP-70 positive T cells and negative B cells was based on a ratio of median ZAP-70 staining of T cells to B cells. In 25 B-CLL patients, ZAP 70 expression was estimated using the lower limit of the fluorescence range corresponding with 98% of ZAP-70 positive T cells as threshold marker as well as a ratio of B-CLL cell to internal T-cell median ZAP-70 staining. RESULTS: Use of FACS Lysing Solution resulted in approximately fourfold increased separation between ZAP-70 positive T cells and negative B cells, when compared with the Fix & Perm kit. In B-CLL samples, ZAP-70 negative and positive B-cell expression could be clearly discerned. CONCLUSIONS: FACS Lysing Solution is a simple procedure that markedly improves discrimination between ZAP-70 positive and negative cells. PMID- 17703442 TI - Cytologic findings in struma ovarii. PMID- 17703443 TI - Cytomegalovirus inclusions on a cervical pap test: report of a well-known organism at an uncommon site. PMID- 17703444 TI - Case report: metastatic renal carcinoid to the thyroid diagnosed by fine needle aspiration biopsy. AB - We report a case of primary renal carcinoid arising in a horseshoe kidney. To the best of our knowledge this is the first case to be reported in the cytology literature, which has been diagnosed by fine needle aspiration (FNA). A 32-year old male, presented to the Emory University Hospital, with a renal mass arising in a horseshoe kidney; along with a thyroid mass. FNA of the renal mass resulted in an initial diagnosis of renal cell carcinoma, unclassified. A thyroid aspiration was attempted later, and revealed a neuroendocrine morphology. This was compared with the renal aspiration and both of them were found to have similar morphology. With the help of immunostains, a diagnosis of renal carcinoid tumor metastatic to the thyroid was made. Thus, we demonstrate that renal carcinoid, being a rare entity, can pose a diagnostic challenge. PMID- 17703445 TI - Endoscopic ultrasound-guided fine-needle aspiration of undifferentiated carcinoma with osteoclast-like giant cells of the pancreas: a report of 2 cases with literature review. AB - Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas is rare. Histologically it mimics the giant cell tumor of the bone and may be associated with a ductal adenocarcinoma. We recently encountered two such cases, both of which were biopsied by EUS-guided FNA. Abundant multinucleated osteoclast like giant cells and many uniform mononuclear cells were present in case 1 so that the diagnosis was made. In case 2, many mononuclear tumor cells with vacuolated and basophilic cytoplasm were present, and rare osteoclast-like giant cells were seen. A diagnosis of adenocarcinoma was made. In both cases, no conspicuous nuclear pleomorphism was noted in the mononuclear cells or the multinucleated giant cells. The histology of case 2 revealed a pure undifferentiated carcinoma with osteoclast-like giant cells. In addition, a liver biopsy revealed globular amyloidosis. To our knowledge, this is the first report of pancreatic undifferentiated carcinoma with osteoclast-like giant cells sampled by EUS-guided FNA and the first case of hepatic globular amyloidosis associated with this tumor. PMID- 17703446 TI - Evaluation of agreement between conventional and liquid-based cytology in cervical cancer early detection based on analysis of 2,091 smears: experience at the Brazilian National Cancer Institute. AB - The aim of this work was to evaluate the agreement between conventional cytology (CC) and liquid-based cytology (LBC) in cervical cancer early detection. The results of CC and LBC (DNACitoliq in 2,059 women aged 25-59 years were compared. The percent agreement, kappa coefficient, prevalence-adjusted bias-adjusted kappa coefficient (PABAK), and Chamberlain's percent positive agreement (PPA) were calculated. The percent agreement between the two methods was very good (80% and 79%, respectively, for normal versus ASCUS+; and normal versus ASCUS, AGUS and LSIL+ vs. HSIL+). The kappa coefficient indicates slight agreement (0.26 and 0.23, respectively), but when PABAK was used the agreement was good (0.61 and 0.68, respectively). PPA was high for normal results (79.2%) and low for the remaining categories. To conclude, in this study, agreement between LBC and CC was only good for normal results, which involves the majority of cases and positively influences the overall agreement rate. PMID- 17703447 TI - Giant cell carcinoma of the lung impact of diagnosis and review of cytological features. AB - Giant cell carcinoma of the lung is a specific type of lung carcinoma characteristically associated with a highly aggressive clinical behavior. This tumor comprises approximately 1-5% of all lung cancers, affecting a similar patient population as other primary pulmonary carcinomas. It is not routinely treated surgically, owing to the fact that it is metastatic at the time of diagnosis. The cytological diagnosis of this entity on aspiration biopsy has an appreciable impact on patient care. We retrospectively examined 15 cases of lung fine-needle aspirates in which a diagnosis of giant cell carcinoma or large cell carcinoma with giant cell features was made. We applied the criteria for cytological diagnosis of giant cell carcinoma previously set forth in the literature. In cases where there is a tissue diagnosis, we compared the results with the corresponding fine-needle aspirates and correlated them with patient survival. Conclusions are made regarding the reliability of the diagnostic criteria of this malignancy. PMID- 17703448 TI - Fine needle aspiration biopsy diagnosis of metastatic prostate carcinoma to inguinal lymph node. AB - Carcinoma of the prostate is predominantly a disease of older men. Men younger than 50 years of age account for approximately 1% of all patients diagnosed with prostate cancer. Patients generally present with urinary symptoms and rarely with metastatic disease. Lymphatic spread typically occurs to the obturator and internal iliac nodes. We report a case of an aggressive prostate adenocarcinoma in a 47-year-old white male who presented with nausea, vomiting, and enlarged inguinal lymph nodes for 1 month. A fine needle aspiration biopsy (FNAB) and immunohistochemical stains performed on the FNAB revealed metastatic prostatic adenocarcinoma. The initial clinical presentation of inguinal lymphadenopathy, the age of the patient and the cytologic features made this an unusual case. PMID- 17703449 TI - Flow cytometric immunophenotyping of cancer cells in effusion specimens: diagnostic and research applications. AB - Flow cytometry (FCM) immunophenotyping is frequently used as an ancillary technique for the diagnosis of hematological malignancies or for measurement of DNA content. In recent years, we applied FCM to the diagnosis of metastatic adenocarcinoma and malignant mesothelioma in effusions. We established a panel of antibodies that allows for rapid and effective differentiation between epithelial cells, mesothelial cells, and leukocytes. FCM was subsequently used for quantitative analysis of integrin subunits. Recently, we studied different parameters of the immune response, including HLA molecules and chemokine receptors, using this method. Our data suggest that FCM is an effective method for the characterization of cancer cells in clinical effusion specimens in both the diagnostic and research setting, and that this method is comparable to immunohistochemistry in terms of sensitivity and specificity, with the additional advantage of providing quantitative data. This review discusses previous work in this area and the future potential of this method in the characterization of tumor cells in serous effusions. PMID- 17703450 TI - Concordance between thyroid nodule sizes measured by ultrasound and gross pathology examination: effect on patient management. AB - Ultrasound examination (US) is an essential tool in the evaluation of thyroid nodules. The size determined by US is used to distinguish between clinical vs. nonclinical thyroid nodules i.e. greater than or equal to or less than 1 cm. In this study, we evaluated the concordance between the sizes of thyroid nodules measured by US and by gross examination after thyroidectomy. This study included 664 nodules that underwent fine-needle aspiration (FNA) and subsequent excision in 621 patients; 580 had single and 41 patients had multiple (39 with 2, and 2 with 3 nodules) nodules. Both US and gross pathology measurements were taken in three dimensions. The nodule sizes as measured by US were stratified into five groups: A: or=5.1 cm. FNA diagnoses were categorized into: Benign (n = 59), Neoplastic / Indeterminate (n = 342), Suspicious (n = 123), Malignant (n = 106), and nondiagnostic (n = 34). Upon excision 278 (42%) nodules were classified as malignant and 386 (58%) as benign. In group A the concordance between US and excisional size was 78.5%, group B 56%, group C 34.5%, group D 40% and group E 52.5%. Only 14 (14/664 2%) nodules measured 0.9993) within test ranges. The established method showed good precision and accuracy with overall intra-day and inter-day variations of 1.73-3.06 and 3.89%-4.92%, respectively, and overall recoveries of 97.63-99.39% for the three compounds analyzed. The method developed was successfully applied to quantify the main triterpenoid glycosides in Centella asiatica extracts from different companies. PMID- 17703475 TI - Blending chitosan with polycaprolactone: porous scaffolds and toxicity. AB - The preparation and characterization of porous scaffolds from chitosan-PCL blends by freeze extraction, freeze gelation and freeze drying is reported. Using freeze extraction, stable structures were obtained only from PCL, but these were not porous. No stable scaffolds were obtained using the freeze gelation process. Stable scaffolds of chitosan/PCL mixtures could not be obtained using 77% acetic acid by any of these techniques. With 25% aqueous acetic acid, stable scaffolds of chitosan/PCL mixtures were obtained by the freeze drying technique. The stability and pore morphology of freeze dried scaffolds were dependent on the relative mass ratio of chitosan and PCL. A chorioallantoic membrane assay showed that formed 3D chitosan/PCL mixtures were not toxic to vasculature. PMID- 17703476 TI - The oil-absorbing property of polyhydroxyalkanoate films and its practical application: a refreshing new outlook for an old degrading material. AB - Polyhydroxyalkanoates (PHAs) have attracted the attention of academia and industry because of their plastic-like properties and biodegradability. However, practical applications as a commodity material have not materialized because of their high production cost and unsatisfactory mechanical properties. PHAs are also believed to have high-value applications as an absorbable biomaterial for tissue engineering and drug-delivery devices because of their biocompatibility. However, research in these areas is still in its very early stages. The main problem faced by proponents of PHAs is the lack of a niche area where PHAs will be the most desired material in terms of its function during use rather than because of its eco-friendly virtues after use. Here, we report on the oil absorbing property of PHA films and its potential applications. By comparing with some of the existing commercial products, the potential application of PHAs as cosmetic oil-blotting films is revealed for the first time. Besides having the ability to rapidly absorb and retain oil, PHA films also have a natural oil indicator property, showing obvious changes in opacity following oil absorption. Surface analysis revealed that the surface structures such as porosity and smoothness exert great influence on the rapid oil-absorption properties of the PHA films. These newly discovered properties could be exploited to create a niche area for the practical applications of PHAs. PMID- 17703477 TI - Validation of a simple HPLC method for assay of haplamine and its metabolites in plasma suitable for pharmacokinetic application in rats. AB - A simple HPLC method with ultraviolet detection has been developed and validated for the simultaneous determination of haplamine and its metabolites (trans/cis 3,4-dihydroxyhaplamine) in rat. A liquid-liquid extraction was used to extract the compounds from rat plasma. The analysis was performed on a C(18) Nucleosil Nautilus column. The mobile phase consisted of water (A) and a mixture of methanol and acetonitrile (85:15; v/v) (B) used in gradient mode (38-40% B for 10 min, 40-58% B for 49 min, 58-38% B for 1 min, and 38% for 5 min) pumped at 1 mL/min. The calibration curves showed good linearity with correlation coefficients greater than 0.999 for the analytes in the investigated concentration range. The lower limit of detection was 0.007, 0.008 and 0.009 microg/mL and the lower limit of quantification was 0.014, 0.017 and 0.018 microg/mL for haplamine, and trans/cis-3,4-dihydroxyhaplamine, respectively. The method was applied to a preliminary pharmacokinetic study in rats. This method proved to meet fully the standards required of experimental pharmacokinetic studies and should be used in further preclinical investigation. PMID- 17703478 TI - Synthesis of 4-[2-(N,N-dimethylamino)ethylaminosulfonyl]-7-N-methylhydrazino 2,1,3-benzoxadiazole (DAABD-MHz) as a derivatization reagent for aldehydes in liquid chromatography/electrospray ionization-tandem mass spectrometry. AB - Benzofurazan derivatization reagent, 4-[2-(N,N-dimethylamino)ethylaminosulfonyl] 7-N-methylhydrazino-2,1,3-benzoxadiazole (DAABD-MHz), for aldehydes in liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS), was synthesized. DAABD-MHz reacted with aliphatic aldehydes under mild conditions. The generated derivatives were separated on a reversed-phase column and detected by ESI-MS/MS with detection limits of 30-60 fmol on-column. Upon collision-induced dissociation, a single and intense fragment ion at m/z 151 was observed. These results suggested that DAABD-MHz was suitable as a derivatization reagent in LC/ESI-MS/MS. PMID- 17703479 TI - Sarcomas: genetics, signalling, and cellular origins. Part 2: TET-independent fusion proteins and receptor tyrosine kinase mutations. AB - Although the mechanisms that underlie sarcoma development are still poorly understood, the identification of non-random chromosomal translocations and receptor tyrosine kinase mutations associated with defined sarcoma types has provided new insight into the pathogenesis of these tumours. In Part 1 of the review (J Pathol 2007;213:4-20), we addressed sarcomas that express fusion genes containing TET gene family products. Part 2 of the review summarizes our current understanding of the implications of fusion genes that do not contain TET family members in sarcoma development, as well as that of specific mutations in genes encoding receptor tyrosine kinases (RTKs). The final section will serve as a summary of both reviews and will attempt to provide a synthesis of some of the emerging principles of sarcomagenesis. PMID- 17703480 TI - Characterization of phenolic compounds in Erigeron breviscapus by liquid chromatography coupled to electrospray ionization mass spectrometry. AB - Erigeron breviscapus is an important herbal drug for the treatment of cardiovascular and cerebral vessel diseases. In this study, phenolic compounds were extracted from the whole plant of E. breviscapus and analyzed by high performance liquid chromatography/electrospray ionization mass spectrometry. A total of 53 compounds were identified or tentatively characterized based on their UV and mass spectra. These compounds included caffeoylquinic acids (CQAs), CQA glucosides, malonyl-CQAs, acetyl-CQAs, caffeoyl-2,7-anhydro-3-deoxy-2 octulopyranosonic acids (CDOAs), caffeoyl-2,7-anhydro-2-octulopyranosonic acids (COAs), flavones, flavonols and flavonones. Most of them were reported for the first time from E. breviscapus and nineteen of them belonged to new compounds. The MS(n) spectra of CQA glucosides were similar to CQAs and they were discriminated by their retention times. No caffeic acid related ions (X(0) (-), Y(0) (-) and Z(0) (-)) were observed in MS(n) spectra of acyl-CQAs compared to those of CQAs. Fragment ions ((2,5)O(-), (3,6)O(-) and (4,6)O(-)) corresponding to ring cleavage were shown in MS(n) spectra of CDOAs and COAs, characteristic of this class of compounds. The 5,6,7-trihydroxyl-substituted flavones were dominant in E. breviscapus. Their [A--H](-) ions underwent the loss of a molecule of H(2)O, followed by the loss of CO, which was used to discriminate from other hydroxyl-substituted flavones. Our results are the first comprehensive analysis of E. breviscapus constituents and will be helpful for the quality control of the herb of E. breviscapus and its related preparations. PMID- 17703481 TI - Quantitative retention-activity relationship models for quinolones using biopartitioning micellar chromatography. AB - A simple and reproducible quantitative retention-activity relationship (QRAR) model utilizing biopartitioning micellar chromatography was developed for the biological parameter estimation of drugs. The correlation between retention factors of quinolones obtained in physiological conditions (pH, ionic strength) and biological activities was investigated using different second-order polynomial models. The predictive and interpretative ability of the chromatographic models was evaluated in terms of cross-validated data (RMSEC, RMSECV and RMSECVi). The aim was to obtain adequate QRAR models of half-life, clearance, volume of distribution, plasma protein combination rate, area under concentration-time curve and toxicity (LD50) of quinolones, and to elucidate the advantages and limitations of using a single parameter as independent variable for describing and estimating the activities. PMID- 17703482 TI - Determination of two HMG-CoA reductase inhibitors, pravastatin and pitavastatin, in plasma samples using liquid chromatography-tandem mass spectrometry for pharmaceutical study. AB - We developed a method for determining pravastatin or pitavastatin, 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, in plasma using liquid chromatography and tandem mass spectrometry (LC-MS/MS). Pravastatin, pitavastatin and the internal standard fluvastatin were extracted from plasma with solid-phase extraction columns and eluted with methanol. After drying the organic layer, the residue was reconstituted in mobile phase (acetonitrile:water, 90:10, v/v) and injected onto a reversed-phase C(18) column. The isocratic mobile phase was eluted at 0.2 mL/min. The ion transitions recorded in multiple reaction monitoring mode were m/z 423 --> 101, 420 --> 290 and 410 --> 348 for pravastatin, pitavastatin and fluvastatin, respectively. The coefficient of variation of the assay precision was less than 12.4%, the accuracy exceeded 89%. The limit of detection was 1 ng/mL for all analytes. This method was used to measure the plasma concentration of pitavastatin or pravastatin from healthy subjects after a single 4 mg oral dose of pitavastatin or 40 mg oral dose of pravastatin. This is a very simple, sensitive and accurate analytic method to determine the pharmacokinetic profiles of pitavastatin or pravastatiny. PMID- 17703483 TI - Talking biotech with the public. AB - In the estimation of risks involved in complex technical applications, such as, for example, gene technology or nanotechnology, the problem of communication between science and the wider society becomes evident. The path towards transparent, authentic and credible communication must be built upon the reconciliation of the risk perceptions of the scientist--and of his or her institution--with the corresponding ideas of risk and communication existing in the society. Additionally, to accomplish goal-oriented discourse within the public sphere and to realistically assess his or her effective options when addressing this public, the scientist is faced with the necessity of reflecting upon his or her own determining assumptions on the condition, constitution and functionalities of this "public". Combined with the use of modern tools--and supported with supplementary coaching and organizational consultation--such a foundation allows the establishment of targeted communication with specific groups. PMID- 17703484 TI - Portals, blogs and co.: the role of the Internet as a medium of science communication. AB - While the use of the Internet for the exchange of scientific data was characterised by exclusivity during its pioneer era, the active employment of the medium today, by a broad social spectrum of users in the exchange of information, for dialogue and in the accumulation of knowledge, displays an almost unbounded inclusion. Blo and online encyclopaedias based on the 'Wikipedia' model have contributed to the formation of a marketplace in which the free expression of opinions and the relaying of information occur. Counted among the ideas which have been popularised in the wake of this phenomenon, "lay journalism" and the "wisdom of the masses" are seen to be integral to the new 'web 2.0'. Consequently, the ever-increasing information disseminated in the web has been diluted in quality and authenticity, resulting in the presentation of new challenges to online science journalism. In reference to the public debate surrounding green gene technology, the communications platform bioSicherheit.de, which receives more than one million visitors per year, will be examined as an example of an agent that retrieves and mobilises information on biological safety research and that successfully has established itself as an intermediary between the scientific community and the broader public. PMID- 17703485 TI - Options for a rational dialogue on the acceptance of biotechnology. AB - This paper explores how framing discussions about biotechnology in different ways influences how scientists, policy makers, and members of the public communicate with each other, to either inhibit or promote acceptance. It argues for the use of new techniques to create a rational dialogue with the public, based on scientific knowledge, that allows them to fully participate as informed stakeholders in debates about new technologies. Several different outlooks on the role of science in society are presented. Effectively communicating these different positions to the public requires innovative approaches. Drawing on advances in scientific communication practices, we briefly describe four principles that consider not only the scientific content, but also its delivery. New views need to be delivered with confidence, to be sensible within existing frameworks of understanding and not overwhelming, to reveal both potentially positive and negative aspects, and to promote interactive discussion with stakeholders. The authors conclude using the regional initiative in Southern Africa--the African Policy Dialogues on Biotechnology--as an illustration of this approach, where discussions started by first seeking agreement about establishing a process for dialogue, rather than initially trying to achieve consensus on any substantive points. PMID- 17703486 TI - Experiences from the implementation of a biosafety system in Slovenia. AB - The development and implementation of an effective national biosafety system is important for several key reasons: to ensure safe access to products of modern biotechnology, to build public confidence, to encourage the growth of domestic modern biotechnology, and to comply with international standards and agreements. There is no single best approach in the development and implementation of a national biosafety system and each country is faced with unique challenges. Slovenia is a small country and a new EU Member State. However, it has developed and implemented an efficient national biosafety system. The key elements of this system are administrative procedure, risk assessment, enforcement, and public participation and information. PMID- 17703487 TI - Intellectual property, genetically modified crops and bioethics. AB - The implementation of a new technology is almost always surrounded by a debate on the moral and social implications that may arise. The debate with regard to genetically modified (GM) crops has been one of the longest and most controversial. However, one area of the debate that receives less attention is the role that intellectual property can play. The introduction of an effective and yet appropriate intellectual property system addressing society's particular needs can eliminate some of these issues. This paper looks at whether the situation in Europe is meeting our current needs and also addresses the role intellectual property can play in the debate over the introduction of GM crops in developing countries. PMID- 17703488 TI - The context of embryonic development and its ethical relevance. AB - Research on human stem cells and embryos creates ethical issues. Here I discuss ten frequently used arguments against research and point out their weaknesses. These arguments include the possessed potentiality of the embryo per se and, in contrast to other cell systems, the "slippery slope" argument, the right of disposal of parents, totipotency versus pluripotency, the burden of proof for research, natural versus artificial, and three arguments based on the precaution principle (the open biological questions, uncertainty regarding clinically applicable therapies, and the problem solving rule). I finally suggest a different answer to the ethical questions concerning research on human embryos and embryonic stem cells, which takes into consideration their biological context. PMID- 17703489 TI - Attitudes, values, and socio-demographic characteristics that predict acceptance of genetic engineering and applications of new technology in Australia. AB - Studies of community reactions to biotechnology and genetic engineering (GE), in particular, have identified a number of correlates of acceptance, including the field of application of a technology and various characteristics of the perceiver. Factor analysis of acceptability ratings (N=686) of 12 applications of new technologies revealed three factors, denoting medical, societal, and indulgent applications. Acceptability ratings of each application and of GE in principle were regressed onto 18 demographic, attitudinal, trust, and value variables previously identified as potential correlates of acceptance. Predictive profiles for acceptance of medical and societal applications were largely similar. General receptiveness toward science and technology was the primary predictor of GE acceptance and a major predictor of acceptance for each application area. Environmental concern and self-transcendent (e.g., pro-nature) values did not predict acceptance in any instance. Findings clarify considerations associated with acceptance of biotechnological innovations and support arguments against knowledge- and trust-deficit explanations of resistance to technology. PMID- 17703490 TI - Bringing scientists to the people--the Co-Extra website. AB - Disseminating and facilitating access to science-based information is a necessity to enable the public to make informed decisions about appropriate uses of biotechnology products. It is also one of the major objectives of Co-Extra, a European-funded project addressing co-existence of genetically modified organisms and non-genetically modified organisms in Europe and their traceability. To this end, a dynamic and interactive website has been developed as the core element of the Co-Extra external communication strategy. This website has been designed to make it attractive and accessible to a large audience in a very simple and practical manner, building on practical experiences gained in the development of other websites related to biotechnology and genetically modified organisms. The website delivers popularized information for the general public as well as scientific data meant primarily for the more expert readers. It also provides for various permanent tools allowing multidirectional interaction with its visitors. Content is displayed using a web-based platform, based on a sophisticated Content Management System. First results indicate a high level of interest from the general public and from experts, showing that the content of this website can contribute by communicating science-based information to improve awareness and understanding of biotechnology. PMID- 17703491 TI - Biotechnology: the language of multiple views in Maori communities. AB - In Aotearoa (New Zealand), the government funded studies on communicating biotechnology to different sectors in the community from 2003 to 2006. Subsequently, a researcher covering the Maori sector performed a content analysis of data gathered in the community. Qualitative analysis methods included examining text from participant interviews, focus groups, government documents, newspapers, Internet sites, and current literature. Content was coded by identifying common themes in the English and the Maori language. Words like genetic modification (GM), genetic engineering (GE), and biotechnology were explained to provide a basic understanding between the communities and researcher. The terminology applied in the research was essential to achieve communication between the researcher and the community. The resultant themes represented seven views to interpret the communities association with biotechnology: purist Maori, religious Maori, anti Maori, pro Maori, no Maori, uncertain Maori, and middle Maori views. The themes are taken from the analysis of data compiled after 3 years of completing different stages of a research project. The views indicate that a common understanding can be achieved in the diverse range of Maori tribal communities providing those communicating biotechnology can identify the view and interpretations communities associate with biotechnology. This knowledge is essential for government agencies, researchers, community practitioners, scientist, and businesses that desire to dialogue with Maori communities in the language of biotechnology. PMID- 17703492 TI - Transparent communication strategy on GMOs: will it change public opinion? AB - Innovations are central for the economic growth; however, the use of new technologies needs to be widely accepted in the general public and the society as a whole. Biotechnology in general, and the use of genetic engineering in food production in particular are seen critically by the European public and perceived as "risky", and a transatlantic divide between European and US citizens has been observed. This review investigates the reasons for those differing perceptions and proposes new strategies to communicate the benefits of biotechnology in agriculture to a broader public. When analyzing the dialogue process that has taken place between public, scientists, governmental organizations and industry, questions arise on what has been done differently in Europe, in order to propose new, more successful and efficient communication strategies for the future. PMID- 17703493 TI - The difficulty of structuring and focusing the co-existence debate in Europe. AB - The co-existence debate in Europe is wide and difficult. In this paper some recommendations are given on how to make progress in the debate. Not with the goal of pushing GMOs, but with the goal of achieving genuine freedom of choice. PMID- 17703494 TI - Synthetic biology through the prism of scenarios. PMID- 17703495 TI - Subcellular shotgun proteomics in plants: looking beyond the usual suspects. AB - In this review we examine the current state of analytical methods used for shotgun proteomics experiments in plants. The rapid advances in this field in recent years are discussed, and contrasted with experiments performed using current widely used procedures. We also examine the use of subcellular fractionation approaches as they apply to plant proteomics, and discuss how appropriate sample preparation can produce a great increase in proteome coverage in subsequent analysis. We conclude that the conjunction of these two techniques represents a significant advance in plant proteomics, and the future of plant biology research will continue to be enriched by the ongoing development of proteomic analytical technology. PMID- 17703496 TI - Allowing for uncertainty due to missing data in meta-analysis--part 1: two-stage methods. AB - Analysis of a randomized trial with missing outcome data involves untestable assumptions, such as the missing at random (MAR) assumption. Estimated treatment effects are potentially biased if these assumptions are wrong. We quantify the degree of departure from the MAR assumption by the informative missingness odds ratio (IMOR). We incorporate prior beliefs about the IMOR in a Bayesian pattern mixture model and derive a point estimate and standard error that take account of the uncertainty about the IMOR. In meta-analysis, this model should be used for four separate sensitivity analyses which explore the impact of IMORs that either agree or contrast across trial arms on pooled results via their effects on point estimates or on standard errors. We also propose a variance inflation factor that can be used to assess the influence of trials with many missing outcomes on the meta-analysis. We illustrate the methods using a meta-analysis on psychiatric interventions in deliberate self-harm. PMID- 17703497 TI - Modulation of scratching behavior by silencing an endogenous cyclooxygenase-1 gene in the skin through the administration of siRNA. AB - BACKGROUND: RNA interference (RNAi) is rapidly becoming a major tool that is revolutionizing research in the bioscience and biomedical fields. To apply the RNAi technique in vivo, it is crucial to develop appropriate methods of guiding the short interfering RNA (siRNA) molecules to the right tissues and cells. Here, we demonstrate an efficient method for performing gene knockdown in the body skin using the in vivo electro-transduction of siRNA. Using this method, we examined whether the targeted silencing of the cyclooxygenase (COX) gene in the skin could modulate the scratching behavior of an atopic dermatitis mouse model. METHODS: NC/Nga mice were used as the atopic dermatitis model. Using our optimized in vivo electroporation conditions, siRNAs were introduced into the skin; the silencing efficiency was then analyzed by Western blotting, measuring the levels of prostaglandins, and immunohistochemistry. The scratching behaviors of the mice were measured using an automatic system. RESULTS: Targeted silencing of the COX-1 gene using our in vivo siRNA technique significantly accelerated the scratching behavior of NC/Nga mice, whereas the COX-2 siRNA showed no effect. In addition, the effect of COX-1 siRNA was mimicked by treatment with a COX-1-selective inhibitor (SC-560). CONCLUSIONS: We have demonstrated the successful silencing of endogenous gene expression in the skin using the intradermal transfection of unmodified siRNA via electroporation. Using this method, we revealed that COX- 1 mediated prostaglandins may act as endogenous inhibitors of scratching behavior. PMID- 17703498 TI - Genome-wide expression analysis of Middle Eastern papillary thyroid cancer reveals c-MET as a novel target for cancer therapy. AB - In an attempt to find genes that may be of importance in malignant progression of papillary thyroid carcinoma (PTC) in the Middle East, which therefore can be targeted in cancer therapy, we screened and validated the global gene expression in PTC using cDNA expression arrays and immunohistochemistry (IHC) on tumour tissue microarrays. Twenty-nine PTC tissue specimens were compared with seven non cancerous thyroid specimens by use of cDNA microarray. Results for selected genes were confirmed by quantitative real-time PCR. Protein expression of selected genes was further studied using a tissue microarray consisting of 536 PTCs and compared with histologically non-cancerous tissue samples. One hundred and ninety six genes were overexpressed in PTC tissues relative to non-cancerous thyroid tissues. The genes that were up-regulated in PTC were involved in cell cycle regulation, cell signaling, and oncogenesis. Among these genes, c-MET was identified by immunohistochemical methods as a protein that is overexpressed in 37% of PTCs and was significantly associated with more aggressive behaviour, eg higher stage, nodal involvement, and tall cell variant (p value = 0.01, 0.01 and 0.04, respectively). In this study, 55% of the PTC cases expressed activated AKT (P-AKT), which suggests that activated AKT may play an important role in PTC tumourigenesis. The fact that most of the PTC cases that had activated AKT showed overexpression of c-MET (p = 0.027) leads us to hypothesize that c-MET may be an alternative mechanism of AKT activation in Middle Eastern PTCs. Finally, our data suggest that c-MET dysregulation is associated with aggressive behaviour and may serve as a molecular biomarker and potential therapeutic target in this disease. PMID- 17703499 TI - Effects of thyroxine replacement on lipid profile and endothelial function after thyroidectomy. AB - BACKGROUND: Hypothyroidism is a risk factor for atherosclerotic cardiovascular disease. This study investigated the effects of L-thyroxine replacement therapy on lipid profile and endothelial function after thyroidectomy in patients with overt transient non-autoimmune hypothyroidism. METHODS: Twenty-two patients with non-toxic multinodular goitre treated by total or near-total thyroidectomy and 22 healthy individuals matched for age, sex and body mass index were studied. Lipid profile and endothelial function were determined in each patient at the euthyroid phase before thyroidectomy (stage 1), the hypothyroid phase 3 weeks after surgery (stage 2), and the euthyroid phase 3 months (stage 3) and 6 months (stage 4) after the start of thyroxine treatment. RESULTS: The lipid profile and endothelial function deteriorated between stage 1 and stages 2 and 3. Findings at stage 4 were similar to those at stage 1. There was a positive correlation between serum thyroid-stimulating hormone (TSH) and total cholesterol (r(s) = 0.588, P < 0.001), and a negative correlation between serum TSH and flow-mediated arterial dilatation (r(s) = 0.506, P < 0.001). Total cholesterol and TSH were independent determinants of endothelial function. CONCLUSION: A 3-week hypothyroid period after thyroidectomy led to a more atherogenic lipid profile and impaired endothelial function that persisted for at least 3 months. PMID- 17703500 TI - Impact of the smallest surgical margin on local control in soft tissue sarcoma. AB - BACKGROUND: The aim was to review a single-institution experience of a prospective treatment protocol for soft tissue sarcoma of the extremity and trunk wall, with particular focus on the smallest surgical margin leading to local control. METHODS: The study included 270 patients who had surgery for soft tissue sarcoma at Helsinki University Central Hospital between 1987 and 1997. Resection margins were measured prospectively from tumour specimens. Radiotherapy was administered if the smallest margin measured less than 2.5 cm, irrespective of tumour grade. RESULTS: With a median follow-up of 6.6 years, the 5-year local control rate was 76.4 per cent. On multivariable analysis, the smallest surgical margin around the sarcoma (after radiotherapy) was prognostic for local control. A margin of at least 2.5 cm was associated with a local recurrence-free rate of 89.2 per cent at 5 years. Tumour size, depth or grade and patient's age had no independent prognostic effect on local control. CONCLUSION: Surgical margin had independent prognostic value for local control. A surgical margin of 2-3 cm provided reasonable local control of soft tissue sarcoma, even without radiotherapy. Radiotherapy is recommended for smaller margins, irrespective of tumour grade. PMID- 17703501 TI - Clinical prognostic scoring system to aid decision-making in gastro-oesophageal cancer. AB - BACKGROUND: Accurate prediction of prognosis in gastro-oesophageal cancer remains challenging. The aim of this study was to develop a robust model for outcome prediction. METHODS: The study included 220 patients with gastric or oesophageal cancer newly diagnosed over a 2-year period. Patients were staged and underwent treatment following discussion at a multidisciplinary team (MDT) meeting. Clinical and investigative variables were collected, including performance and nutritional status, and serum C-reactive protein (CRP) level. Primary endpoints were death within 12 and 24 months. RESULTS: Overall median survival was 13 months. Advanced clinical stage (P < 0.001), reduced performance score (P < 0.001), weight loss exceeding 2.75 per cent per month (P = 0.026) and serum CRP concentration above 5 mg/l (P = 0.031) were identified as independent prognostic indicators in multivariable analysis. A prognostic score was constructed using these four variables to estimate a probability of death. Applying the model gave an area under the receiver-operator characteristic curve of 0.84 and 0.85 for prediction of death at 12 and 24 months respectively (both P < 0.001). CONCLUSION: This model accurately estimated the probability of death within 12 and 24 months. This may aid the MDT decision-making process. PMID- 17703502 TI - Allowing for uncertainty due to missing data in meta-analysis--part 2: hierarchical models. AB - We propose a hierarchical model for the analysis of data from several randomized trials where some outcomes are missing. The degree of departure from a missing-at random assumption in each arm of each trial is expressed by an informative missing odds ratio (IMOR). We require a realistic prior for the IMORs, including an assessment of the prior correlation between IMORs in different arms and in different trials. The model is fitted by Monte Carlo Markov Chain techniques. By applying the method in three different data sets, we show that it is possible to appropriately capture the extra uncertainty due to missing data, and we discuss in what circumstances it is possible to learn about the IMOR. PMID- 17703503 TI - Chemical reactivity indices and mechanism-based read-across for non-animal based assessment of skin sensitisation potential. AB - The skin sensitisation potential of chemicals is currently assessed using in vivo methods where the murine local lymph node assay (LLNA) is typically the method of first choice. Current regulatory initiatives are driving the impetus for the use of in vitro/in silico alternative approaches to provide the relevant information needed for the effective assessment of skin sensitisation, for both hazard characterisation and risk assessment purposes. A chemical must undergo a number of steps for it to induce skin sensitisation but the main determining step is formation of a stable covalent association with carrier protein. The ability of a chemical to react covalently with carrier protein nucleophiles relates to both its electrophilic reactivity and its hydrophobicity. This paper focuses on quantitative indices of electrophilic reactivity with nucleophiles, in a chemical mechanism-of-action context, and compares and contrasts the experimental approaches available to generate reactivity data that are suitable for mathematical modelling and making predictions of skin sensitisation potential, using new chemistry data correlated against existing in vivo bioassay data. As such, the paper goes on to describe an illustrative example of how quantitative kinetic measures of reactivity can be usefully and simply applied to perform mechanism-based read-across that enables hazard characterisation of skin sensitisation potential. An illustration of the types of quantitative mechanistic models that could be built using databases of kinetic measures of reactivity, hydrophobicity and existing in vivo bioassay data is also given. PMID- 17703504 TI - Determinants of skin sensitisation potential. AB - Skin sensitisation is an important toxicological endpoint. The possibility that chemicals used in the workplace and in consumer products might cause skin sensitisation is a major concern for individuals, for employers and for marketing. In European REACH (Registration, Evaluation, and Authorisation of Chemicals) legislation, the sensitising potential should therefore be assessed for chemicals below the 10 ton threshold. Development of methods for prediction of skin sensitisation potential without animal testing has been an active research area for some time, but has received further impetus with the advent of REACH and the EU Cosmetics Directive (EU 2003). This paper addresses the issue of non-animal based prediction of sensitisation by a mechanistic approach. It is known that the sequence of molecular, biomolecular and cellular events between exposure to a skin sensitiser and development of the sensitised state involves several stages, in particular penetration through the stratum corneum, covalent binding to carrier protein, migration of Langerhans cells, presentation of the antigen to naive T-cells. In this paper each of these stages is considered with respect to the extent to which it is dependent on the chemical properties of the sensitiser. The evidence suggests that, although penetration of the stratum corneum, stimulation of migration and maturation of Langerhans cells, and antigen recognition are important events in the induction of sensitisation, except in certain specific circumstances they can be taken for granted. They are not important factors in determining whether a compound will be a sensitiser or not, nor are they important factors in determining how potent one sensitiser will be relative to another. The ability to bind covalently to carrier protein is the major structure-dependent determinant of skin sensitisation potential. A chemistry-based prediction strategy is proposed involving reaction mechanistic domain assignment, reactivity and hydrophobicity determination, and application of quantitative mechanistic modelling (QMM) or read-across. PMID- 17703505 TI - Discovering functions and revealing mechanisms at molecular level from biological networks. AB - With the increasingly accumulated data from high-throughput technologies, study on biomolecular networks has become one of key focuses in systems biology and bioinformatics. In particular, various types of molecular networks (e.g., protein protein interaction (PPI) network; gene regulatory network (GRN); metabolic network (MN); gene coexpression network (GCEN)) have been extensively investigated, and those studies demonstrate great potentials to discover basic functions and to reveal essential mechanisms for various biological phenomena, by understanding biological systems not at individual component level but at a system-wide level. Recent studies on networks have created very prolific researches on many aspects of living organisms. In this paper, we aim to review the recent developments on topics related to molecular networks in a comprehensive manner, with the special emphasis on the computational aspect. The contents of the survey cover global topological properties and local structural characteristics, network motifs, network comparison and query, detection of functional modules and network motifs, function prediction from network analysis, inferring molecular networks from biological data as well as representative databases and software tools. PMID- 17703506 TI - Methods, algorithms and tools in computational proteomics: a practical point of view. AB - Computational MS-based proteomics is an emerging field arising from the demand of high throughput analysis in numerous large-scale experimental proteomics projects. The review provides a broad overview of a number of computational tools available for data analysis of MS-based proteomics data and gives appropriate literature references to detailed description of algorithms. The review provides, to some extent, discussion of algorithms and methods for peptide and protein identification using MS data, quantitative proteomics, and data storage. The hope is that it will stimulate discussion and further development in computational proteomics. Computational proteomics deserves more scientific attention. There are far fewer computational tools and methods available for proteomics compared to the number of microarray tools, despite the fact that data analysis in proteomics is much more complex than microarray analysis. PMID- 17703507 TI - Proteomic applications in ecotoxicology. AB - Within the growing body of proteomics studies, issues addressing problems of ecotoxicology are on the rise. Generally speaking, ecotoxicology uses quantitative expression changes of distinct proteins known to be involved in toxicological responses as biomarkers. Unlike these directed approaches, proteomics examines how multiple expression changes are associated with a contamination that is suspected to be detrimental. Consequently, proteins involved in toxicological responses that have not been described previously may be revealed. Following identification of key proteins indicating exposure or effect, proteomics can potentially be employed in environmental risk assessment. To this end, bioinformatics may unveil protein patterns specific to an environmental stress that would constitute a classifier able to distinguish an exposure from a control state. The combined use of sets of marker proteins associated with a given pollution impact may prove to be more reliable, as they are based not only on a few unique markers which are measured independently, but reflect the complexity of a toxicological response. Such a proteomic pattern might also integrate some of the already established biomarkers of environmental toxicity. Proteomics applications in ecotoxicology may also comprise functional examination of known classes of proteins, such as glutathione transferases or metallothioneins, to elucidate their toxicological responses. PMID- 17703511 TI - Does your heart really need protein? Yes, but you're better off getting your protein from tofu, vegetables, fish and chicken, as opposed to higher-fat options such as red meat and eggs. PMID- 17703509 TI - Analysis of protein phosphorylation on a proteome-scale. AB - Phosphorylation, the most intensively studied and common PTM on proteins, is a complex biological phenomenon. Its complexity manifests itself in the large numbers of proteins that attach it, remove it and recognise it as a protein code. Since the first report of protein phosphorylation on vitellin 100 years ago, a wide variety of biochemical and analytical chemical approaches have been developed to enrich and detect protein phosphorylation. The last 5 years have witnessed a renaissance in methodologies capable of characterising protein phosphorylation on a proteome-scale. These technological advances have allowed identification of hundreds to thousands of phosphorylation sites in a proteome and have resulted in a profound paradigm shift. For the first time, using quantitative MS, the topology and significance of global phosphorylation networks may be investigated, marking a new era of cell signalling research. This review addresses recent technological advances in the purification of phosphorylated proteins and peptides and current MS-based strategies used to qualitatively and quantitatively probe these enriched phosphoproteomes. In addition, we review the application of complementary array-based technologies to derive signalling networks from kinase-substrate interactions and discuss future challenges in the field. PMID- 17703510 TI - Determination of hydrolytic degradation products of nerve agents by injection port fluorination in gas chromatography/mass spectrometry for the verification of the Chemical Weapons Convention. AB - Retrospective detection and identification of markers of chemical warfare agents are important aspects of verification of the Chemical Weapons Convention. Alkyl alkylphosphonic acids (AAPAs) and alkylphosphonic acids (APAs) are important markers of nerve agents. We describe the development and optimization of a new gas chromatography/mass spectrometry (GC/MS) injection port fluorination method for the derivatization of AAPAs and APAs. The process involved the injection of acids with trifluoroacetic anhydride in GC/MS, where acids are converted into their corresponding volatile fluorides. Various reaction conditions such as fluorinating agent, injection port temperature and splitless time were optimized. The maximum reaction efficiency of the acids with trifluoroacetic anhydride was observed at 230 degrees C injection port temperature with a splitless time of 2 min. APAs showed best analytical efficiencies at 400 degrees C injection port temperature, while the other conditions were similar to those of AAPAs. The linearities of response for APAs and AAPAs were in the range of 1-25 and 5-100 microg mL(-1), respectively, with limits of detection ranging from 500 pg to 800 ng mL(-1). PMID- 17703513 TI - Ask the doctors. Trans fatty acids have ben in the news a lot lately. What are these and do they really pose a risk for heart disease? PMID- 17703512 TI - Options sought after drug study. Patients who take rosiglitazone might consider pioglitazone instead. PMID- 17703514 TI - Ask the doctors. I sustained major damage to my heart two years ago. My ejection fraction is around 20 percent. My most recent echocardiogram indicates that my heart is slightly enlarged. I am on an ACE inhibitor and a beta blocker at the maximum doses. Other than the heart damage, I am in good health. I have no trouble walking two miles or riding my bike. I go to work every day. I wonder what things will look like for me as I get older? What about life expectancy? PMID- 17703516 TI - I bruise so easily. Is there anything I can do to prevent bruises? PMID- 17703515 TI - I read recently about an inexpensive new eye test that can diagnose Alzheimer's disease in its early stage. Since Alzheimer's runs in our family, we're very interested in learning more. Is the test generally available and how does it work? PMID- 17703517 TI - Diagnosis: herpes simplex esophagitis. PMID- 17703518 TI - Diagnosis: acute HIV-1 infection. PMID- 17703519 TI - The changing face of meningococcal disease in West Africa. PMID- 17703520 TI - Additional thoughts on foie gras production. PMID- 17703522 TI - Testing their metal. PMID- 17703521 TI - Centrifugation versus simple flotation. PMID- 17703523 TI - NMR probe gets new geometry. PMID- 17703524 TI - Using the electrochemistry of the electrospray ion source. PMID- 17703525 TI - Fingerprints reveal drug habits. PMID- 17703526 TI - Catching doping athletes. PMID- 17703527 TI - Yearly zoledronic acid in postmenopausal osteoporosis. PMID- 17703528 TI - Yearly zoledronic acid in postmenopausal osteoporosis. PMID- 17703529 TI - Yearly zoledronic acid in postmenopausal osteoporosis. PMID- 17703530 TI - Yearly zoledronic acid in postmenopausal osteoporosis. PMID- 17703531 TI - Antiretroviral drugs and the risk of myocardial infarction. PMID- 17703532 TI - Antiretroviral drugs and the risk of myocardial infarction. PMID- 17703533 TI - Stop misleading readers about ANSI's Z358.1. PMID- 17703534 TI - [Personal responsibility is needed in health care]. PMID- 17703536 TI - H&HN eight decades of health care. The 1970s. PMID- 17703537 TI - Outbreak news. Marburg haemorrhagic fever, Uganda. PMID- 17703539 TI - WHO Clinical trial registry platform: addition of China and India. PMID- 17703538 TI - Summary of discussions and recommendations of the 13th informal consultation of the WHO Global Polio Laboratory Network, June 2007. PMID- 17703540 TI - H&HN eight decades of health care. Banks aim to play a bigger role in hospital investment strategies. PMID- 17703541 TI - All aboard the European gravy train? PMID- 17703543 TI - Bibliography. Current world literature. Movement disorders. PMID- 17703542 TI - Variety is the spice of eukaryotic life. PMID- 17703544 TI - Rite of passage? Why young adults become uninsured and how new policies can help. AB - Young adults (ages 19 to 29) are one of the largest segments of the U.S.population without health insurance: 13.3 million lacked coverage in 2005. Young adults often lose coverage at age 19 or upon high school or college graduation. Nearly two of five college graduates and one-half of high school graduates who do not enroll in college will be uninsured for a time during the first year after graduation. Several states have passed laws to expand coverage of dependent young adults up to age 24 or 25 under parents' insurance policies. Three policy changes could further help uninsured young adults gain coverage and prevent others from losing it: extending eligibility for public insurance programs beyond age 18; extending dependents' eligibility for their parents' private coverage beyond age 18 or 19; and ensuring that colleges require full- and part-time students to have coverage, and that colleges offer coverage to them. PMID- 17703545 TI - Guidelines for investigating stillbirths: an update of a systematic review. AB - OBJECTIVE: To identify formal, publicly available guidelines for stillbirth investigation and to identify the most appropriate clinical practice guideline (or component of a guideline) for use in Alberta. METHODS: A systematic literature search was conducted to identify primary and secondary research studies published between January 1985 and August 2006 and formal, publicly available guidelines on the subject of stillbirth investigation. The Cochrane Library, PubMed, EMBASE, CINAHL, HealthSTAR, Science Citation Index, BIOSIS, and the NHS and CRD databases were searched. The methodological quality of the selected primary research studies was assessed according to specific criteria. RESULTS: All six of the publicly available clinical practice guidelines selected for this review outlined similar steps in the stillbirth investigation but differed about which tests to include and which components should be core or additional investigations. They agreed on including several elements for routine investigation, such as complete autopsy and detailed examination of the cord and placenta. Of 61 retrieved primary research studies, only seven met the inclusion criteria. No studies compared the value of specific guidelines. Although reviewed evidence highlights the value of fetal autopsy and placental examinations as integral components of stillbirth investigation, the value of other components is still not clear. CONCLUSIONS: No firm scientific judgement could be made about which clinical practice guideline for stillbirth investigation is the most appropriate or which components are essential. Currently here is no generally accepted reference guideline for stillbirth investigation. Fetal autopsy and placental examination remain important components, assuming the postmortem examination is of high quality. These data may be helpful in counselling parents who are considering whether or not to consent to a postmortem examination. PMID- 17703546 TI - Practical ethics. A fresh start? AB - You are a newly hired CEO and need to hire a chief operating officer. You really wanted to hire a previous employee, Joe, a COO whose abilities put him ahead of the competition. He was a star performer who has a gift for working with physicians--something that needs special attention at your hospital. Now you've learned he's had several public scenes while drinking in restaurants. He's told you those were isolated incidents, due to personal problems that are over. He'd like to move and make a fresh start. What do you do? PMID- 17703547 TI - [Emergency psychiatry]. PMID- 17703548 TI - Proceedings of a workshop on molecular methods in immunohematology, September 25 26, 2006, Bethesda, Maryland, USA. PMID- 17703549 TI - The black sites: a rare look inside the C.I.A.'s secret interrogation program. PMID- 17703550 TI - Man with a plan: Herbert Spencer's theory of everything. PMID- 17703551 TI - [8th Statewide Diabetology Symposium. Hradec Kralove, 2-3 June 2006]. PMID- 17703552 TI - [XXVI Young Internist Seminar. Olomouc, 31 May--1 June 2007. Abstracts]. PMID- 17703553 TI - A report from ANA's 2007 quadrennial policy conference Nursing Care in Life, Death, and Disaster. PMID- 17703554 TI - Assessing the impact of Hurricane Katrina on persons with disabilities. PMID- 17703556 TI - Health-related biotechnologies for infectious disease control in Africa: Ethical, Legal and Social Implications (ELSI) of transfer and development. AB - The African continent is disproportionately affected by infectious diseases. Malaria, HIV/AIDS, tuberculosis, and more "neglected" diseases including African trypanosomiasis, Buruli ulcer, leishmaniasis, onchocerciasis and trachoma continue to dramatically impact social and economic development on the continent. Health biotechnologies provide potential to develop effective strategies for the fight against the vicious circle of poverty and infections by helping in the development and improvement of novel affordable drugs, diagnostics and vaccines against these diseases. As the prospects of this emerging biotechnology research and deployment of its products become a reality in Africa, there is a need to consider the ethical, legal and social implications of both the scientific and technological advances and their use in the communities. The article provides a short overview of the potential values of biotechnology, issues involved in its transfer and presents the rationale, design and recommendations of the international workshop/symposium held in April 2005 at the International Institute for Tropical Agriculture (IITA) in Ibadan, Nigeria. PMID- 17703557 TI - Applying genomics-related technologies for Africa's health needs. AB - While the past century has seen significant improvement in life expectancies in the developed world, it has also witnessed diseases like HIV/AIDS, malaria and tuberculosis ravage populations in the developing world. In some Sub-Saharan African countries, life expectancies have plummeted to less than 40 years--nearly half of those in developed countries. Unequal access to the benefits of science and technology, including medical advances, exacerbate this disparity. In order to address the challenge of global health inequities and strengthen the role of science and technology innovation in contributing to real solutions, the Canadian Program on Genomics and Global health (CPGGH), based at the University of Toronto, has identified three guiding questions: Which genomics-related technologies are most likely to improve the health of people in developing countries?; How can developing countries harness these technologies for health development?; and What can industrialized countries do to assist developing countries? PMID- 17703558 TI - Building bioinformatics capacity in West Africa. AB - African scientists need more bioinformatics training in order to make innovative contributions to global biotechnology. To address the bioinformatics skills gap in West Africa, various training initiatives have been established in the sub region. We present the activities of the West African Biotechnology Workshops (http://www.wabw.org/) in the past three years, and report on a symposium on bioinformatics and applied genomics in West Africa. To establish and sustain regional and national networks, stronger and increased government commitment by way of financial and infrastructural support for bioinformatics capacity building in West Africa is required. PMID- 17703559 TI - Concept paper: establishment of a diagnostics platform for South Africa. AB - This concept paper focuses on diagnostics as one of the key areas of strategic importance. Lifelab intends to specialise in the research and development of in vitro diagnostic test systems specifically for diseases of relevance to the Southern African region. The use of diagnostic tests is an essential but costly element in the diagnosis and treatment of infectious diseases and in particular, HIV/AIDS. Consistent with the need to improve affordability and accessibility, the strategy will be to research, develop, and manufacture promising diagnostic test systems and through mutually beneficial partnerships with joint venture companies and distributors, rapidly introduce these diagnostic systems to the market. PMID- 17703560 TI - Applications of biotechnology techniques to the study of medicinal plants. AB - Medicinal plants are widely used world wide to address a variety of health problems. The major obstacles faced in the study of medicinal plants include inaccurate identification and speciation, low yield of bioactive metabolites prepared by chemical methods, variability of traditional protocols etc. In the present article we review a range of biotechnological methods that can be employed to facilitate medicinal plant studies. DNA-based techniques like PCR, RFLP, AFLP, RAPD and sequencing can be employed to resolve ambiguities in plant identification and speciation. In vitro plant organ and tissue culture methods can be employed to produce bioactive metabolites (alkaloids, flavonoids, terpenoids etc) under defined conditions. Recombinant DNA techniques can be used to manipulate metabolic pathways and produce protein pharmaceuticals such as antibodies, and protein hormones. The new disciplines of Bioinformatics and Genomics can find application in drug discovery from plant-based products. We conclude that biotechnological procedures can enhance and advance the studies of medicinal plants. PMID- 17703561 TI - Establishing an insect disease vector functional genomics training center in Africa. AB - The genome sequences for many insects vector of human diseases are now available and promise the development of a set of new, powerful tools that can be used to develop innovative approaches to control these diseases. The African continent, which is the most severely affected by vector borne diseases, lacks adequate infrastructures and personal resources required for rational use of genomic information. To fill this gap, the African Center for Training in Functional Genomics of Insect vectors of Human Disease (AFRO VECTGEN) was initiated by WHO/TDR and the Department of Medical Entomology and Vector Ecology (DMEVE) of the Malaria Research and Training Center (MRTC) in Mali. The aim of the AFRO VECTGEN program is to train young scientists in functional genomics who will ultimately use genome sequence data for research on insect vector of human disease. The program could trigger collaborative research and will benefit from an existing vector biology network in Mali, which was built around research grants funded by the National Institutes of Health, USA and WHO/TDR. PMID- 17703563 TI - African culture and medical ethics. PMID- 17703562 TI - West African Bioethics Training Program: Raison D'etre. AB - There has been increase in the amount of research and services provided for diseases that are predominantly prevalent in developing countries. In addition, the amount of clinical trials conducted in developing countries for diseases in general and for those that contribute substantial proportions of the disease burden of the population has increased. Furthermore, interest in genomics and its potential for improving understanding of gene-environment-disease interactions and population history has drawn researchers to developing countries including Africa. These factors have highlighted the need for sound ethics training for researchers and members of ethics review committees. Increased training of bioethicists will enhance the contributions of developing countries bioethicists to the global research ethics discourse thereby enriching it. Such bioethicists will be able to drawn on their rich multicultural and multi-religious to inform discussions and issues. In this essay, I discuss the West African Bioethics Training, a United States National Institutes of Health supported training program for biomedical researchers and bioethicists in West Africa. PMID- 17703564 TI - Ethical review of health-related biotechnology research in Africa: a role for the Pan African Bioethics Initiative (PABIN). AB - The paper reviews the status of nature and functions of the Pan African Bioethics Initiative (PABIN) a voluntary organization, founded in 2001 by leading members of the African health research and bioethics communities, with the aim of enhancing ethical awareness in Africa, in general, and building ethical clearance capacity in all African countries in particular. PABIN, with a membership drawn from more than 20 African countries is a member of the forum of the WHO/TDR Strategic Initiative for Developing Capacity in Ethical Review (SIDCER). PABIN works closely with its sister forums in Asia, Latin America, Eastern Europe, and North America as well as other continental and international organizations that promote bioethics in health research. PABIN has conducted three conferences and several seminars in collaboration with continental and international partners on subjects of ethical concerns in Africa. Strategically, PABIN aims at assisting in the development of competent in-country bioethics review systems in all African countries. Notable among the contemporary issues that is on the PABIN agenda is addressing the repercussions of the active pursuit by pharmaceutical and other commercial interests from the Western developed countries to conduct all sorts of clinical biomedical trials on African populations before marketing such biotechnological products and services. This drive has brought with it highly controversial ethical issues at a time when both technical and organizational capacity are lacking in much of Africa to address the ethical concerns that are arising from some health-related researches. PABIN seeks to assure that the expected health and social benefits derivable from biotechnology are reaped in accordance with internationally accepted norms. PMID- 17703565 TI - Health related biotechnology transfer in Africa: a critique from a capabilities approach. AB - This article addresses the issues related to the ethical justification for technology transfer in Africa. Two well held but conflicting points of views are examined and an alternative line of thought that seeks to resolve and reconcile the differences between the two view points is proposed. The necessity for developing countries to adapt to new technologies in order to escape the cycle of underdevelopment and economic subservience, and the more culturalist approach, that considers biotechnology to be a form of neocolonialism that local cultures must resist in order to preserve their community values. The conditions of a participative model based on the thoughts of Amartya Sen and Nancy Frazer are analyzed, and conclusions that could associate practical social justice and a negotiated model of development are drawn, bearing in mind the fact that this proposition, without being a mere utopia, remains a horizon of action for global bioethics and models of justice. PMID- 17703566 TI - Health-related biotechnology in Africa: managing the legislative and regulatory issues. AB - The challenges that most African countries face in an attempt to join the ongoing quest for the development and transfer of the products derived from health biotechnology are threefold: High research costs, inadequate regulatory capacity and unfavourable intellectual property arrangements. It is argued in this paper that these challenges are representative of the legislative and regulatory issues that require proper management in order to enable African countries to focus on the key research areas that are related to the burden of diseases that are prevalent in the region and to harness the products of such research for the benefit of the region. This paper discusses the challenges involved in managing the legislative and regulatory issues in health biotechnology and proposes specific ideas on the way forward for Africa. The methodology used is a review of the manner in which three African countries, Cameroon, Kenya and Nigeria, have encountered and dealt with such regulatory challenges. The review is carried out from policy and legal analysis perspectives. PMID- 17703567 TI - Potential benefits and harm of biotechnology in developing countries: the ethics and social dimensions. AB - The world has experienced phenomenal growth in science and knowledge since the second-world war. Infectious disease conditions that were almost always fatal in the early 1900s are now being effectively treated with antibiotics and other modalities emanating from science and prevented through the general improvements in vaccination, nutrition, sanitation and availability of safe water to many more people. Biotechnology as one aspect of this growth in knowledge and practice has particular potential to enable the development and increased accessibility of rapid and efficient diagnostic, preventive and health promotion tools, restoration of water quality, soil and other natural resources. This has the potential to make our environment much safer and also agriculturally more productive. Development of new biotechnology, especially in medicine, is essentially the domain of developed nations, and in Africa, a few countries like South Africa, Kenya and Egypt are leading the way. In this paper, we discuss the risks and benefits of biotechnology especially regarding human health in developing countries. We have drawn significantly from the ethical tenets of beneficence, autonomy of individuals, fairness or justice and informed consent. PMID- 17703568 TI - Global health public-private partnerships: IAVI, partnerships and capacity building. AB - New developments in biotechnology and the need to overcome the lack of incentive for investment in vaccines for diseases affecting Africa have led to the promotion of product development public-private partnerships (PPP). Our work at the ESRC INNOGEN Research Centre assesses the way in which these collaborative mechanisms approach their mission of getting science to work for the poor and what they contribute to broader development objectives, particularly in relation to capacity building. Case study research of the International AIDS Vaccine initiative (IAVI) and their work on the ground in Africa and India has highlighted two legal related issues. First, by working as a PPP the organisation has changed the 'ownership' of science, making the process more flexible and emphasising a bottom-up dialogue process while advocating a private sector ethos. Second--whether intentionally or not--the partnership's emphasis on advocacy and communications has increased the importance of knowledge generation and management activities within the partnership and its availability to stakeholders. This paper attempts to ascertain the impact of these issues for the building of health research capacity. PMID- 17703569 TI - Socioeconomic and pedagogical issues in biotechnology in Africa: a sociologist's viewpoint. PMID- 17703570 TI - Health-related biotechnology transfer to Africa: principal-agency relationship issues. AB - The aim of this paper is to stimulate debate on the agency (principal-agent) in health-related biotechnology research. It attempts to answer the following questions: What is health-related biotechnology and biotechnology research? What is an agency? What factors are likely to undermine the principal's capacity to exercise informed consent? When might the principal-agency problem arise? How could the agency in biotechnology transfer be strengthened in Sub-Saharan Africa (SSA)? The transfer of health-related biotechnology to SSA ought to be preceded by research to ascertain the effectiveness of such technologies on population health. In that process, the national ethical review committee (REC), as an agent of every human research subject (principal), ought to ensure that international principles (e.g. beneficence, non-malfeasance, autonomy, justice, dignity, truthfulness and honesty) for human experimentation are observed by biotechnology researchers in order to satisfy moral, ethical and legal requirements. The key factors that undermine principals' sovereignty in exercising their right to informed consent to participate in biotechnology trials are discussed. The paper ends with a list of activities that can strengthen the agency, e.g. legislative requirement that all health-related biotechnology transfer should be preceded by rigorous evaluation; continuous update of the agents knowledge of the contents of the international ethical guidelines; and education of potential and actual principals on their human rights; among others. PMID- 17703572 TI - Immigration of nurses: problems, prospects and challenges. PMID- 17703571 TI - Mothers' level of satisfaction with postnatal care. PMID- 17703573 TI - Multiple trauma--patient factors and duration of hospital stay. PMID- 17703574 TI - Ogilvie's syndrome--a case report. PMID- 17703575 TI - G-proteins and GPCrs: from the beginning. AB - From the point of view of a participant observer, I tell the discovery stories of trimeric G-proteins and GPCRs, beginning in the 1970s. As in most such stories, formidable obstacles, confusion, and mistakes make eventual triumphs even more exciting. Because these pivotally important signaling molecules were discovered before the recombinant DNA revolution, today's well-trained molecular biologist may find it amazing that we learned anything at all. PMID- 17703576 TI - Modeling GPCRs. AB - Many GPCR models have been built over the years for many different purposes, of which drug-design undoubtedly has been the most frequent one. The release of the structure of bovine rhodopsin in August 2000 enabled us to analyze models built before that period to learn things for the models we build today. We conclude that the GPCR modeling field is riddled with "common knowledge". Several characteristics of the bovine rhodopsin structure came as a big surprise, and had obviously not been predicted, which led to large errors in the models. Some of these surprises, however, could have been predicted if the modelers had more rigidly stuck to the rule that holds for all models, namely that a model should explain all experimental facts, and not just those facts that agree with the modeler's preconceptions. PMID- 17703577 TI - QSAR modeling of GPCR ligands: methodologies and examples of applications. AB - GPCR ligands represent not only one of the major classes of current drugs but the major continuing source of novel potent pharmaceutical agents. Because 3D structures of GPCRs as determined by experimental techniques are still unavailable, ligand-based drug discovery methods remain the major computational molecular modeling approaches to the analysis of growing data sets of tested GPCR ligands. This paper presents an overview of modern Quantitative Structure Activity Relationship (QSAR) modeling. We discuss the critical issue of model validation and the strategy for applying the successfully validated QSAR models to virtual screening of available chemical databases. We present several examples of applications of validated QSAR modeling approaches to GPCR ligands. We conclude with the comments on exciting developments in the QSAR modeling of GPCR ligands that focus on the study of emerging data sets of compounds with dual or even multiple activities against two or more of GPCRs. PMID- 17703578 TI - Privileged structures in GPCRs. AB - Certain kinds of ligand substructures recur frequently in pharmacologically successful synthetic compounds. For this reason they are called privileged structures. In seeking an explanation for this phenomenon, it is observed that the privileged structure represents a generic substructure that matches commonly recurring conserved structural motifs in the target proteins, which may otherwise be quite diverse in sequence and function. Using sequence-handling tools, it is possible to identify which other receptors may respond to the ligand, as dictated on the one hand by the nature of the privileged substructure itself or by the rest of the ligand in which a more specific message resides. It is suggested that privileged structures interact with the partially exposed receptor machinery responsible for the switch between the active and inactive states. Depending on how they have been designed to interact, one can predispose these substructures to favour either one state or the other; thus privileged structures can be used to create either agonists or antagonists. In terms of the mechanism of recognition, the region that the privileged structures bind to are rich in aromatic residues, which explains the prevalence of aromatic groups and atoms such as sulphur or halogens in many of the ligands. Finally, the approach described here can be used to design drugs for orphan receptors whose function has not yet been established experimentally. PMID- 17703579 TI - Designing compound libraries targeting GPCRs. AB - The design of compound libraries targeting GPCRs is of primary interest in pharmaceutical research because of their important role as signaling receptors and the herewith linked dominant place in the discovery portfolios. In the present symposium chapter, we outline GPCR compound library design strategies recently followed by our group and discuss them in a more general context. PMID- 17703580 TI - Orphan seven transmembrane receptor screening. AB - Drug discovery has successfully exploited the superfamily of seven transmembrane receptors (7TMR), with over 35% of clinically marketed drugs targeting them. However, it is clear that there remains an undefined potential within this protein family for successful drugs of the future. The human genome sequencing project identified approximately 720 genes that belong to the 7TMR superfamily. Around half of these genes encode sensory receptors, while the other half are potential drug targets. Natural ligands have been identified for approximately 215 of these, leaving 155 receptors classified as orphan 7TMRs having no known ligand. Deorphanisation of these receptors by identification of natural ligands has been the traditional method enabling target validation by use of these ligands as tools to define biological relevance and disease association. Such ligands have been paired with their cognate receptor experimentally by screening of small molecule and peptide ligands, reverse pharmacology and the use of bioinformatics to predict candidate ligands. In this manuscript, we review the methodologies developed for the identification of ligands at orphan 7TMRs and exemplify these with case studies. PMID- 17703581 TI - The role of GPCR dimerisation/oligomerisation in receptor signalling. AB - A wide range of techniques have been employed to examine the quaternary structure of G-protein-coupled receptors (GPCRs). Although it is well established that homo dimerisation is common, recent studies have sought to explore the physical basis of these interactions and the role of dimerisation in signal transduction. Growing evidence hints at the existence of higher-order organisation of individual GPCRs and the potential for hetero-dimerisation between pairs of co expressed GPCRs. Here we consider how both homo-dimerisation/oligomerisation and hetero-dimerisation can regulate signal transduction through GPCRs and the potential consequences of this for function of therapeutic medicines that target GPCRs. Hetero-dimerisation is not the sole means by which co-expressed GPCRs may regulate the function of one another. Heterologous desensitisation may be at least as important and we also consider if this can be the basis for physiological antagonism between pairs of co-expressed GPCRs. Although there may be exceptions (Meyer et al. 2006), a great deal of recent evidence has indicated that most G-protein-coupled receptors (GPCRs) do not exist as monomers but rather as dimers or, potentially, within higher-order oligomers (Milligan 2004b; Park et al. 2004). Support for such models has been provided by a range of studies employing different approaches, including co-immunoprecipitation of differentially epitope-tagged but co-expressed forms of the same GPCR, co operativity in ligand binding and a variety of resonance energy transfer techniques (Milligan and Bouvier 2005). Only for the photon receptor rhodopsin has the organisational structure of a GPCR been studied in situ. The application of atomic force microscopy to murine rod outer segment discs indicated that rhodopsin is organised in a series of parallel arrays of dimers (Liang et al. 2003) and based on this, molecular models were constructed to try to define and interpret regions of contact between the monomers (Fotiadis et al. 2004). Only for relatively few other GPCRs are details of the molecular basis of dimerisation available but within this limited data set, recent studies on the dopamine D2 receptor suggest a means by which information on the binding of an agonist can be transmitted between the two elements of the dimer via the dimer interface (Guo et al. 2005). Although the availability of cDNAs encoding molecularly defined GPCRs has allowed high-throughput screening for ligands that modulate GPCR function, this is performed almost exclusively in heterologous cell lines transfected to express only the specific GPCR of interest. Given that the human genome contains some 400-450 genes encoding non-chemosensory GPCRs, it is clear that any individual cell of the body may express a considerable number of GPCRs. Interactions between these, either via hetero-dimerisation, via heterologous desensitisation or via the integration of downstream signals can potentially alter the pharmacology, sensitivity and function of receptor agonists and hence produce varied responses. In this article, we will use specific examples to consider the role of homo-dimerisation/oligomerisation in GPCR function and whether either direct hetero-dimerisation or heterologous desensitisation between pairs of co-expressed GPCRs affects the function of the receptor pairs. PMID- 17703582 TI - Deorphanization of G-protein-coupled receptors. AB - G-protein-coupled receptors constitute one of the major families of drug targets. Orphan receptors, for which the ligands and function are still unknown, are an attractive set of future targets for presently unmet medical needs. Screening strategies have been developed over the years in order to identify the natural ligands of these receptors. Natural or chimeric G-proteins that can redirect the natural coupling of receptors toward intracellular calcium release are frequently used. Potential problems include poor expression or trafficking to the cell surface, constitutive activity of the receptors, or the presence of endogenous receptors in the cell types used for functional expression, leading to nonspecific responses. Many orphan receptors characterized over the last 10 years have been associated with previously known bioactive molecules. However, new and unpredicted biological mediators have also been purified from complex biological sources. A few old and recent examples, including nociceptin, chemerin, and the F2L peptide are illustrated. Future challenges for the functional characterization of the remaining orphan receptors include the potential requirement of specific proteins necessary for quality control, trafficking or coupling of specific receptors, the possible formation of obligate heterodimers, and the possibility that some constitutively active receptors may lack ligands or respond only to inverse agonists. Adapted expression and screening strategies will be needed to deal with these issues. PMID- 17703583 TI - Virus-encoded G-protein-coupled receptors: constitutively active (dys)regulators of cell function and their potential as drug target. AB - G-protein-coupled receptors encoded by herpesviruses such as EBV, HCMV and KSHV are very interesting illustrations of the (patho)physiological importance of constitutive GPCR activity. These viral proteins are expressed on the cell surface of infected cells and often constitutively activate a variety of G proteins. For some virus-encoded GPCRs, the constitutive activity has been shown to occur in vivo, i.e., in infected cells. In this paper, we will review the occurrence of virus-encoded GPCRs and describe their known signaling properties. Moreover, we will also review the efforts, directed towards the discovery of small molecule antagonist, that so far have been mainly focused on the HCMV encoded GPCR US28. This virus-encoded receptor might be involved in cardiovascular diseases and cancer and seems an interesting target for drug intervention. PMID- 17703584 TI - Modulation of GPCR conformations by ligands, G-proteins, and arrestins. AB - G-protein-coupled receptors (GPCRs) have traditionally been thought to adopt two conformations: the inactive unliganded conformation and the active ligand-bound conformation. Interactions with G-proteins in cells and membranes are known to modulate the affinity of the receptor for ligand and therefore the conformation of the receptor. Such observations led to the proposal of the ternary complex model. However, subsequent studies of constitutively active GPCRs led to the development of an extended version of this model to account for active conformations of the receptor in the absence of agonist. A significant difficulty with many of the studies, upon which this latter model was based, is the lack of knowledge of receptor and G-protein concentrations due to the two-dimensional nature of the membranes used to perform the measurements. Over the past decade, we have studied the interaction of GPCRs, G-proteins, arrestins, and ligands in solubilized systems, where the concentration of each component can be defined. Here we summarize results of these studies as they pertain to the regulation of GPCR conformations and affinities for interacting species. PMID- 17703585 TI - High content screening to monitor G protein-coupled receptor internalisation. AB - G protein-coupled receptors (GPCRs) fulfil a broad diversity of physiological functions in areas such as neurotransmission, respiration, cardiovascular action, pain and more. Consequently, they are considered as the most successful group of therapeutic targets on the pharmaceutical market, and the search for compounds that interfere with GPCR function in a specific and selective way is a major focus of the pharmaceutical industry. High Content Screening (HCS), a combination of fluorescence microscopic imaging and automated image analysis, has become a frequently employed tool to study test compound effects in cellular disease modelling systems. One way to functionally analyse the effect of test compounds on GPCRs by HCS relies on the broadly observed phenomenon of desensitisation. Agonist stimulation of most GPCRs leads to their intracellular phosphorylation and subsequent internalisation, resulting in the termination of receptor signalling and the seclusion of the GPCR from further extracellular stimulation. Complementary to other functional GPCR drug discovery assays, GPCR internalisation assays enable a desensitisation-focussed pharmacological analysis of test compounds. PMID- 17703586 TI - High-throughput lead finding and optimisation for GPCR targets. AB - Driven by past successes and the detailed knowledge of signalling cascades and physiological processes, G-protein-coupled receptors are taking a prominent place in the portfolios of many pharmaceutical companies. To successfully address this target class, scientists need not only a good understanding of the specific receptor under investigation, but also the right tools from assay technology, reagent production to a hit-to-lead process that acknowledges the importance of parameters beyond potency and embraces the gain in knowledge of the last decade. This manuscripts attempts to summarise some of the changes and progress made across the pharmaceutical industry to design an efficient and effective strategy for finding and optimising small molecules modulating the activity of GPCRs. PMID- 17703587 TI - Osteogenic and chondrogenic differentiation: comparison of human and rat bone marrow mesenchymal stem cells cultured into polymeric scaffolds. AB - Hyaluronan-based scaffold were used for in vitro commitment of human and rat bone marrow mesenchymal stem cells (MSC). Cells were cultured either in monolayer and in 3D conditions up to 35 days. In order to monitor the differentiating processes molecular biology and morphological studies were performed at different time points. All the reported data supported the evidence that both human and rat MSC grown onto hyaluronan-derived three-dimensional scaffold were able to acquire a unique phenotype of chondrocytes and osteocytes depending on the presence of specific differentiation inducing factors added into the culture medium without significative differences in term of time expression of extracellular matrix proteins. PMID- 17703588 TI - Tendon crimps and peritendinous tissues responding to tensional forces. AB - Tendons transmit forces generated from muscle to bone making joint movements possible. Tendon collagen has a complex supramolecular structure forming many hierarchical levels of association; its main functional unit is the collagen fibril forming fibers and fascicles. Since tendons are enclosed by loose connective sheaths in continuity with muscle sheaths, it is likely that tendon sheaths could play a role in absorbing/transmitting the forces created by muscle contraction. In this study rat Achilles tendons were passively stretched in vivo to be observed at polarized light microscope (PLM), scanning electron microscope (SEM) and transmission electron microscope (TEM). At PLM tendon collagen fibers in relaxed rat Achilles tendons ran straight and parallel, showing a periodic crimp pattern. Similarly tendon sheaths showed apparent crimps. At higher magnification SEM and TEM revealed that in each tendon crimp large and heterogeneous collagen fibrils running straight and parallel suddenly changed their direction undergoing localized and variable modifications. These fibril modifications were named fibrillar crimps. Tendon sheaths displayed small and uniform fibrils running parallel with a wavy course without any ultrastructural aspects of crimp. Since in passively stretched Achilles tendons fibrillar crimps were still observed, it is likely that during the tendon stretching, and presumably during the tendon elongation in muscle contraction, the fibrillar crimp may be the real structural component of the tendon crimp acting as shock absorber. The peritendinous sheath can be stretched as tendon, but is not actively involved in the mechanism of shock absorber as the fibrillar crimp. The different functional behaviour of tendons and sheaths may be due to the different structural and molecular arrangement of their fibrils. PMID- 17703589 TI - The mechanism of transduction of mechanical strains into biological signals at the bone cellular level. AB - As appears from the literature, the majority of bone researchers consider osteoblasts and osteoclasts the only very important bony cells. In the present report we provide evidence, based on personal morphofunctional investigations, that such a view is incorrect and misleading. Indeed osteoblasts and osteoclasts undoubtedly are the only bone forming and bone reabsorbing cells, but they are transient cells, thus they cannot be the first to be involved in sensing both mechanical and non-mechanical agents which control bone modeling and remodeling processes. Briefly, according to our view, osteoblasts and osteoclasts represent the arms of a worker; the actual operation center is constituted by the cells of the osteogenic lineage in the resting state. Such a resting phase is characterized by osteocytes, bone lining cells and stromal cells, all connected in a functional syncytium by gap junctions, which extends from the bone to the vessels. We named this syncytium the Bone Basic Cellular System (BBCS), because it represents the only permanent cellular background capable first of sensing mechanical strains and biochemical factors and then of triggering and driving both processes of bone formation and bone resorption. As shown by our studies, signalling throughout BBCS can occur by volume transmission (VT) and/or wiring transmission (WT). VT corresponds to the routes followed by soluble substances (hormones, cytokines etc.), whereas WT represents the diffusion of ionic currents along cytoplasmic processes in a neuron-like manner. It is likely that non mechanical agents first affect stromal cells and diffuse by VT to reach the other cells of BBCS, whereas mechanical agents are first sensed by osteocytes and then issued throughout PMID- 17703590 TI - Cytoskeletal reorganization in skeletal muscle differentiation: from cell morphology to gene expression. AB - Actin cytoskeleton profoundly influence a variety of signaling events, including those related to cell growth, survival and differentiation. Recent evidence have provided insights into the mechanisms underlying the ability of cytoskeleton to regulate signal transduction cascades involved in muscle development. This review will deal with the most recent aspects of this field paying particular attention to the role played by actin dynamics in the induction of skeletal muscle-specific genes. PMID- 17703591 TI - Sarcoglycan subcomplex in normal and pathological human muscle fibers. AB - Sarcoglycans are a sub-complex of transmembrane proteins which are part of the dystrophin-glycoprotein complex (DGC). They are expressed above all in the skeletal, cardiac and smooth muscle. Although numerous studies have been conducted on the sarcoglycan sub-complex in skeletal and cardiac muscle, the manner of distribution and localization of these proteins along the non junctional sarcolemma is still not clear. Furthermore, there are unclear data about the actual role of sarcoglycans in human skeletal muscle affected by sarcoglycanopathies. In our studies on human skeletal muscle, normal and pathological, we determined the localization, distribution and interaction of these glycoproteins. Our results, on normal human skeletal muscle, showed that the sarcoglycans can be localized both in the region of the sarcolemma over the I band and over the A band, hypothesizing a correlation between regions of the sarcolemma occupied by costameres and the metabolic type of the fibers (slow and fast). Our data on skeletal muscle affected by sarcoglycanopathy confirmed the hypothesis of a bidirectional signaling between sarcoglycans and integrins and the interaction of filamin2 with both sarcoglycans and integrins. In addition, we have recently demonstrated, in smooth muscle, the presence of alpha-SG, in contrast with data of other Authors. Finally, we analyzed the association between contractile activity and quantitative correlation between alpha- and epsilon-SG, in order to better define the arrangement of sarcoglycan subcomplex. PMID- 17703592 TI - Stem cell-mediated muscle regeneration and repair in aging and neuromuscular diseases. AB - One of the most exciting aspirations of current medical science is the regeneration of damaged body parts. The capacity of adult tissues to regenerate in response to injury stimuli represents an important homeostatic process that until recently was thought to be limited in mammals to tissues with high turnover such as blood and skin. However, it is now generally accepted that each tissue type, even those considered post-mitotic, such as nerve or muscle, contains a reserve of undifferentiated progenitor cells, loosely termed stem cells, participating in tissue regeneration and repair. Skeletal muscle regeneration is a coordinate process in which several factors are sequentially activated to maintain and preserve muscle structure and function upon injury stimuli. In this review, we will discuss the role of stem cells in muscle regeneration and repair and the critical role of specific factors, such as IGF-1, vasopressin and TNF alpha, in the modulation of the myogenic program and in the regulation of muscle regeneration and homeostasis. PMID- 17703593 TI - Anatomy of emotion: a 3D study of facial mimicry. AB - Alterations in facial motion severely impair the quality of life and social interaction of patients, and an objective grading of facial function is necessary. A method for the non-invasive detection of 3D facial movements was developed. Sequences of six standardized facial movements (maximum smile; free smile; surprise with closed mouth; surprise with open mouth; right side eye closure; left side eye closure) were recorded in 20 healthy young adults (10 men, 10 women) using an optoelectronic motion analyzer. For each subject, 21 cutaneous landmarks were identified by 2-mm reflective markers, and their 3D movements during each facial animation were computed. Three repetitions of each expression were recorded (within-session error), and four separate sessions were used (between-session error). To assess the within-session error, the technical error of the measurement (random error, TEM) was computed separately for each sex, movement and landmark. To assess the between-session repeatability, the standard deviation among the mean displacements of each landmark (four independent sessions) was computed for each movement. TEM for the single landmarks ranged between 0.3 and 9.42 mm (intrasession error). The sex- and movement-related differences were statistically significant (two-way analysis of variance, p=0.003 for sex comparison, p=0.009 for the six movements, p<0.001 for the sex x movement interaction). Among four different (independent) sessions, the left eye closure had the worst repeatability, the right eye closure had the best one; the differences among various movements were statistically significant (one-way analysis of variance, p=0.041). In conclusion, the current protocol demonstrated a sufficient repeatability for a future clinical application. Great care should be taken to assure a consistent marker positioning in all the subjects. PMID- 17703594 TI - New findings on 3-D microanatomy of cellular structures in human tissues and organs. An HRSEM study. AB - We present here findings obtained on a large number of human tissues over a period of more than ten years, by our modification of the Osmium maceration method for high resolution scanning electron microscopy (HRSEM). Data are documented by original pictures which illustrate both some 3-D intracellular features not previously shown in human tissues, and results obtained in our current studies on mitochondrial morphology and on the secretory process of salivary glands. We have demonstrated that mitochondria of cells of practically all human tissues and organs have usually tubular cristae, and that even the cristae that look lamellar are joined to the inner mitochondrial membrane by tubular connexions similar to the crista junctions later seen by electron tomography. Concerning salivary glands an important result is the development of a morphometric method that allows the quantitative evaluation of the secretory events. PMID- 17703595 TI - Non-traditional large neurons in the granular layer of the cerebellar cortex. AB - The granular layer of the cerebellar cortex is composed of two groups of neurons, the granule neurons and the so-called large neurons. These latter include the neuron of Golgi and a number of other, lesser known neuron types, generically indicated as non-traditional large neurons. In the last few years, owing to the development of improved histological and histochemical techniques for studying morphological and chemical features of these neurons, some non-traditional large neurons have been morphologically well characterized, namely the neuron of Lugaro, the synarmotic neuron, the unipolar brush neuron, the candelabrum neuron and the perivascular neuron. Some types of non-traditional large neurons may be involved in the modulation of cortical intrinsic circuits, establishing connections among neurons distributed throughout the cortex, and acting as inhibitory interneurons (i.e., Lugaro and candelabrum neurons) or as excitatory ones (i.e., unipolar brush neuron). On the other hand, the synarmotic neuron could be involved in extrinsic circuits, projecting to deep cerebellar nuclei or to another cortex regions in the same or in a different folium. Finally, the perivascular neuron may intervene in the intrinsic regulation of the cortex microcirculation. PMID- 17703596 TI - The solitary chemosensory cells and the diffuse chemosensory system of the airway. AB - Solitary chemosensory cells (SCCs), which resemble taste bud cells, are present in the epidermis and oropharynx of most primary aquatic vertebrates. Recent studies have led to the description of SCCs also in mammals too. In the airway and digestive apparatus, these elements form a diffuse chemosensory system. SCCs do not aggregate into groups and in SCCs, as in taste bud cells, immunoreactivity forthe G-protein subunit alpha-gustducin and for other molecules of the chemoreceptive cascade was found. Questions remain about the role of the diffuse chemosensory system in control of complex functions (e.g. airway surface liquid secretion) and about the involvement of chemoreceptors in respiratory diseases. Therapeutic actions targeting chemoreceptors could be tested in the treatment of respiratory diseases. PMID- 17703597 TI - The modality of transendothelial passage of lymphocytes and tumor cells in the absorbing lymphatic vessel. AB - The modality of transendothelial passage of the macromolecules and cells (lymphocyte and cancer cells) in the absorbing lymphatic vessel (ALV) and the tumor-associated absorbing lymphatic (TAAL) vessel is studied. On the basis of the peculiar plasticity of the lymphatic endothelial cell of these vessels (lacking a continuous basement membrane, pores and open junctions) the endothelial wall organizes formation of the intraendothelial channel, by means of molecular interactions as yet unidentified. The remarkable finding of the intravasation of lymphocyte and experimental tumor cancer cells (T84 colon Adenocarcinoma, B16 melanoma in nude mice and spontaneous prostate adenocarcinoma in transgenic mice) should be stressed. This intravasation takes place, under both physiologic and pathological conditions, following the same transendothelial morphological modality, i.e. the intraendothelial channel - a dynamic and transient entity - is probably also induced by similar molecular interactions, a crucial point that merits future research. PMID- 17703598 TI - Scatter factor-dependent branching morphogenesis: structural and histological features. AB - Branching morphogenesis is a multi-step process that controls the formation of polarised tubules starting from hollow cysts. Its execution entails a series of rate-limiting events which include reversible disruption of cell polarity, dismantling of intercellular contacts, acquisition of a motile phenotype, stimulation of cell proliferation, and final re-establishment of cell polarity for creation of the definitive structures. Branching morphogenesis takes place physiologically during development, accounting for the establishment of organs endowed with a ramified architecture such as glands, the respiratory tract and the vasculartree. In cancer, aberrant implementation of branching morphogenesis leads to deregulated proliferation, protection from apoptosis and enhanced migratory/invasive properties, which together exacerbate the aggressive features of neoplastic cells. Under both physiological and pathological conditions, branching morphogenesis is mainly accomplished by a family of growth factors known as scatter factors. In this review, we will summarise the current knowledge on the biological and functional roles of scatter factors during branching morphogenesis, with a special emphasis on the phenotypic (structural and histological) consequences of scatter factor activity in different tissues. PMID- 17703599 TI - Models of epithelial histogenesis. AB - Epithelial tissues emerge from coordinated sequences of cell renewal, specialization and assembly. Like corresponding immature tissues, adult epithelial tissues are provided by stem cells which are responsible for tissue homeostasis. Advances in epithelial histogenesis has permitted to clarify several aspects related to stem cell identification and dynamics and to understand how stem cells interact with their environment, the so-called stem cell niche. The development and maintenance of epithelial tissues involves epithelial-mesenchymal signalling pathways and cell-matrix interactions which control target nuclear factors and genes. The tooth germ is a prototype for such inductive tissue interactions and provides a powerful experimental system for the study of genetic pathways during development. Clonogenic epithelial cells isolated from developing as well mature epithelial tissues has been used to engineer epithelial tissue equivalents, e.g. epidermal constructs, that are used in clinical practise and biomedical research. Information on molecular mechanisms which regulate epithelial histogenesis, including the role of specific growth/differentiation factors and cognate receptors, is essential to improve epithelial tissue engineering. PMID- 17703600 TI - Adult stem cells: the real root into the embryo? AB - During embryonic development, a pool of cells may become a reserve of undifferentiated cells, the embryo-stolen adult stem cells (ESASC). ESASC may be responsible for adult tissue homeostasis, as well as disease development. Transdifferentiation is a sort of reprogramming of ESASC from one germ layer derived tissue towards another. Transdifferentiation has been described to take place from mesoderm to ectodermal- or endodermal-derived tissues and viceversa but not from ectodermal- to endodermal-derived tissues. We hypothesise that two different populations of ESASC could exist, the first ecto/mesoblast-committed and the second endo/mesoblast-committed. If confirmed, this hypothesis could lead to new studies on the molecular mechanisms of cell differentiation and to a better understanding of the pathogenesis of a number of diseases. PMID- 17703601 TI - Extracellular matrix and growth factors in the pathogenesis of some craniofacial malformations. AB - The normal development of cranial primordia and orofacial structures involves fundamental processes in which growth, morphogenesis, and cell differentiation take place and interactions between extracellular matrix (ECM) components, growth factors and embryonic tissues are involved. Biochemical and molecular aspects of craniofacial development, such as the biological regulation of normal or premature cranial suture fusion, has just begun to be understood, thanks mainly to studies performed in the last decade. Several mutations has been identified in both syndromic and non-syndromic craniosynostosis patients throwing new light onto the etiology, classification and developmental pathology of these diseases. In the more common craniosynostosis syndromes and other skeletal growth disorders, the mutations were identified in the genes encoding fibroblast growth factor receptor types 1-3 (FGFR1, 2 and 3) where they are dominantly acting and affect specific and important protein binding domain. The unregulated FGF signaling during intramembranous ossification is associated to the Apert and Crouzon syndrome. The non syndromic cleft of the lip and/or palate (CLP) has a more complex genetic background if compared to craniosynostosis syndrome because of the number of involved genes and type of inheritance. Moreover, the influence of environmental factor makes difficult to clarify the primary causes of this malformation. ECM represents cell environment and results mainly composed by collagens, fibronectin, proteoglycans (PG) and hyaluronate (HA). Cooperative effects of ECM and growth factors regulate regional matrix production during the morphogenetic events, connective tissue remodelling and pathological states. In the present review we summarize the studies we performed in the last years to better clarify the role of ECM and growth factors in the etiology and pathogenesis of craniosynostosis and CLP diseases. PMID- 17703602 TI - The nuclear envelope, human genetic diseases and ageing. AB - Here we present an overview of the experimental evidence and of the conceptual basis for the involvement of lamins and nuclear envelope proteins in a group of genetic diseases collectively referred to as laminopathies. Some of these diseases affect a specific tissue (skeletal and/or cardiac muscles, subcutaneous fat, peripheral nerves), while others affect a variety of tissues; this suggests that the pathogenic mechanism of laminopathies could reside in the alteration of basic mechanisms affecting gene expression. On the other hand, a common feature of cells from laminopathic patients is represented by nuclear shape alterations and heterochromatin rearrangements. The definition of the role of lamins in the fine regulation of heterochromatin organization may help understanding not only the pathogenic mechanism of laminopathies but also the molecular basis of cell differentiation and ageng. PMID- 17703604 TI - Neuroendocrine regulation and tumor immunity. AB - The morphogenetic events leading to the transendothelial passage of lymphoid and tumoral cells are analyzed in light of a very recent and global theory of intercellular communication designated as the Triune Information Network (TIN). The TIN system is based on the assumption that cell-cell interactions primarily occur through cell surface informations or topobiological procesess, whose mechanisms rely upon expression of adhesion molecules, and are regulated by an array of locally-borne (autocrine/paracrine signals and autonomic inputs) and distantly-borne (endocrine secretions) messages. The final aim of the TIN is to control homeostatic functions crucial for the organism survival, like morphogenesis. Knowledge of the TIN signals involved in lymphoid and tumoral cell intravasation might offer a new perspetive to study the mechanisms of tumor immunity. Recognition of tumor target cells by immune cytotoxic effectors, in fact, can be considered a notable case of TIN-mediated cell to cell interaction. In particular, Natural Killer (NK) cells play a role in the cell-mediated control of tumor growth and metastatic spreading. Cell targeting and killing are dependent on the different NK cell receptors and on the efficacy of NK cells after cytokine and monoclonal antibody administration in cancer therapy. Since efficacy of NK cell-based immunotheraphy has been proven in KIR-mismatch regimens or in TRAIL-dependent apoptosis, the ability to manipulate the balance of activating and inhibitory receptors on NK cells and of their cognate ligands as well as the sensitivity of tumor cells to apoptosis, opens new perspectives for NK cell based immunotherapy. PMID- 17703603 TI - Nuclear phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3-kinase, Akt, and PTen: emerging key regulators of anti-apoptotic signaling and carcinogenesis. AB - Inositol lipid-derived second messengers have long been known to have an important regulatory role in cell physiology. Phosphatidylinositol 3-kinase (PI3K) synthesizes the second messenger 3,4,5'-phosphatidylinositol trisphosphate (Ptdlns 3,4,5P3) which controls a multitude of cell functions. Down-stream of PI3K/PtdIns 3,4,5P3 is the serine/threonine protein kinase Akt (protein kinase B, PKB). Since the PI3K/ PtdIns 3,4,5P3 /Akt pathway stimulates cell proliferation and suppresses apoptosis, it has been implicated in carcinogenesis. The lipid phosphatase PTEN is a negative regulator of this signaling network. Until recently, it was thought that this signal transduction cascade would promote its anti-apoptotic effects when activated in the cytoplasm. Several lines of evidence gathered over the past 20 years, have highlighted the existence of an autonomous nuclear inositol lipid cycle, strongly suggesting that lipids are important components of signaling pathways operating at the nuclear level. PI3K, PtdIns(3,4,5)P3, Akt, and PTEN have been identified within the nucleus and recent findings suggest that they are involved in cell survival also by operating in this organelle, through a block of caspase-activated DNase and inhibition of chromatin condensation. Here, we shall summarize the most updated and intriguing findings about nuclear PI3K/ PtdIns(3,4,5)P3/Akt/PTEN in relationship with carcinogenesis and suppression of apoptosis. PMID- 17703605 TI - Science and Engineering Ethics at Springer. PMID- 17703606 TI - Correction and use of biomedical literature affected by scientific misconduct. AB - The purpose of this study was to identify and describe published research articles that were named in official findings of scientific misconduct and to investigate compliance with the administrative actions contained in these reports for corrections and retractions, as represented in PubMed. Between 1993 and 2001, 102 articles were named in either the NIH Guide for Grants and Contracts ("Findings of Scientific Misconduct") or the U.S. Office of Research Integrity annual reports as needing retraction or correction. In 2002, 98 of the 102 articles were indexed in PubMed. Eighty-five of these 98 articles had indexed corrections: 47 were retracted; 26 had an erratum; 12 had a correction described in the "comment" field. Thirteen had no correction, but 10 were linked to the NIH Guide "Findings of Scientific Misconduct", leaving only 3 articles with no indication of any sort of problem. As of May 2005, there were 5,393 citations to the 102 articles, with a median of 26 citations per article (range 0-592). Researchers should be alert to "Comments" linked to the NIH Guide as these are open access, and the "Findings of Scientific Misconduct' reports are often more informative than the statements about the retraction or correction found in the journals. PMID- 17703607 TI - A code of ethics for the life sciences. AB - The activities of the life sciences are essential to provide solutions for the future, for both individuals and society. Society has demanded growing accountability from the scientific community as implications of life science research rise in influence and there are concerns about the credibility, integrity and motives of science. While the scientific community has responded to concerns about its integrity in part by initiating training in research integrity and the responsible conduct of research, this approach is minimal. The scientific community justifies itself by appealing to the ethos of science, claiming academic freedom, self-direction, and self-regulation, but no comprehensive codification of this foundational ethos has been forthcoming. A review of the professional norms of science and a prototype code of ethics for the life sciences provide a framework to spur discussions within the scientific community to define scientific professionalism. A formalization of implicit principles can provide guidance for recognizing divergence from the norms, place these norms within a context that would enhance education of trainees, and provide a framework for discussing externally and internally applied pressures that are influencing the practice of science. The prototype code articulates the goal for life sciences research and the responsibilities associated with the freedom of exploration, the principles for the practice of science, and the virtues of the scientists themselves. The time is ripe for scientific communities to reinvigorate professionalism and define the basis of their social contract. Codifying the basis of the social contract between science and society will sustain public trust in the scientific enterprise. PMID- 17703608 TI - The ethics of biometrics: the risk of social exclusion from the widespread use of electronic identification. AB - Discussions about biotechnology tend to assume that it is something to do with genetics or manipulating biological processes in some way. However, the field of biometrics-the measurement of physical characteristics-is also biotechnology and is likely to affect the lives of more people more quickly than any other form. The possibility of social exclusion resulting from the use of biometrics data for such uses as identity cards has not yet been fully explored. Social exclusion is unethical, as it unfairly discriminates against individuals or classes of people. Social exclusion is unethical, as it unfairly discriminates against individuals or classes of people. This article looks at some of the ways in which social exclusion might arise from the use of biometric data, and introduces a model of balancing individual interests with which to analyse whether it is justified to run the risk of excluding some members of society for the benefit of others. PMID- 17703609 TI - The obesity epidemic: medical and ethical considerations. AB - Obesity is increasingly becoming a problem for Western societies, to the extent that politicians, scientists, patient organisations and the media now refer to it as 'the obesity epidemic'. Concerns about the damaging effect of increasing body weight on public health has led to a strong growth in the amount of scientific work on the condition, with the medical professions leading the way. This article discusses that, first of all, scientific evidence for obesity-associated mortality is at best ambiguous, and proposes that at least some of contemporary medical preoccupation with obesity has a moral origin in that it seeks to correct unwanted or immoral behaviour. It then continues to reflect on the effect of the conceptual transformation of healthy children into patients, and concludes with some reflections on the ethical implications of the obesity disease for the wellbeing of children. PMID- 17703610 TI - A case for a duty to feed the hungry: GM plants and the third world. AB - This article is concerned with a discussion of the plausibility of the claim that GM technology has the potential to provide the hungry with sufficient food for subsistence. Following a brief outline of the potential applications of GM in this context, a history of the green revolution and its impact will be discussed in relation to the current developing world agriculture situation. Following a contemporary analysis of malnutrition, the claim that GM technology has the potential to provide the hungry with sufficient nourishment will be discussed within the domain of moral philosophy to determine whether there exists a moral obligation to pursue this end if and only if the technology proves to be relatively safe and effective. By using Peter Singer's duty of moral rescue, I argue that we have a moral duty to assist the third world through the distribution of such GM plants. I conclude the paper by demonstrating that my argument can be supported by applying a version of the Precautionary Principle on the grounds that doing nothing might be worse for the current situation. PMID- 17703611 TI - Questioning nuclear waste substitution: a case study. AB - This article looks at the ethical quandaries, and their social and political context, which emerge as a result of international nuclear waste substitution. In particular it addresses the dilemmas inherent within the proposed return of nuclear waste owned by Japanese nuclear companies and currently stored in the United Kingdom. The UK company responsible for this waste, British Nuclear Fuels Limited (BNFL), wish to substitute this high volume intermediate-level Japanese owned radioactive waste for a much lower volume of much more highly radioactive waste. Special focus is given to ethical problems that they, and the UK government, have not wished to address as they move forward with waste substitution. The conclusion is that waste substitution can only be considered an ethical practice if a set of moderating conditions are observed by all parties. These conditions are listed and, as of yet, they are not being observed. PMID- 17703612 TI - Protecting people in research: a comparison between biomedical and traffic research. AB - Traffic research shares a fundamental dilemma with other areas of empirical research in which humans are potentially put at risk. Research is justified because it can improve safety in the long run. Nevertheless, people can be harmed in the research situation. Hence, we need to balance short-term risks against long-term safety improvements, much as in other areas of research with human subjects. In this paper we focus on ethical issues that arise when human beings are directly affected in the performance of research by examining how the ethical requirements in biomedical research can inform traffic research. After introducing the basic ethical requirements on biomedical research, each of the major requirements is discussed in relation to traffic research. We identify the main areas where biomedical research and traffic research differ, and where the ethical requirements from the former cannot easily be transferred to the latter. Finally, we argue that there is a need for systematic studies of the ethics of traffic research and point to some of the issues that need to be addressed. PMID- 17703613 TI - A course treating ethical issues in physics. AB - A course focusing on ethical issues in physics has been taught to undergraduate students at Eastern Michigan University since 1988. The course covers both responsible conduct of research and ethical issues associated with how physicists interact with the rest of society. Since most undergraduate physics majors will not have a career in academia, it is important that a course such as this address issues that will be relevant to physicists in a wide range of job situations. There is a wealth of published work that can be drawn on for reading assignments. PMID- 17703614 TI - [REIN annual report 2005. Renal Epidemiology and Information Network & Agence de la biomedecine]. AB - In 2005, 6,021 patients with end-stage renal disease living in fourteen regions covering 45 millions inhabitants (73% of the French population), started renal replacement therapy (dialysis or preemptive graft): median age was 70 years; 3% had a preemptive graft. The overall crude annual incidence rate of renal replacement therapy for end-stage renal disease was 139 per million population (pmp) in thirteen regions that met exhaustivity, with significant differences in sex and age-adjusted incidence across regions (92 to 171 pmh). At initiation, 48% of the patients had at least one cardiovascular disease and 36% diabetes (89% Type 2 non-insulin-dependent diabetes). On December 31, 2005, 21,813 patients living in these fourteen regions were on dialysis: median age was 69 years. The overall crude prevalence rate of dialysis was 539 pmp in thirteen regions. On December 31, 2005, 19,491 patients were living with a functioning graft : median age was 53 years. The overall crude prevalence rate for these patients was 390 pmp in thirteen regions. The overall crude prevalence rate of renal replacement therapy for end-stage renal disease was 929 pmp in thirteen regions, with significant differences in age-adjusted prevalence across regions (732 to 1009 pmh). In the 2002-05 cohort of 11,632 incident patients, the overall one-year survival rate was 82%, 72% at 2 years and 62% at 3 years. Survival decreased with age, but remained above 50% at 2 years in patients older than 75 at RRT initiation. Among the 5,902 new patients starting dialysis in 2005 in the 14 regions, 7% had a BMI lower than 18,5 kg/m2 and 16% a BMI higher than 30. At initiation, 63% had an haemoglobin value lower than 11 g/ l and 9% an albumin value lower than 25 g/l. The first haemodialysis was started in emergency in 30% of the patients and with a catheter in 46%. On December 31, 2005, 8% treated in the dialysis units of the fourteen regions received peritoneal dialysis, of which 35% were treated with automated peritoneal dialysis. 94% of the patients on haemodialysis had 3 sessions per week, with a median duration of 4 hours. In 2005, 1,911 patients received a renal graft. On December 31, 2005, 4,634 patients were on the waiting List for a renal graft in the transplantation centres of the 14 regions. PMID- 17703615 TI - [Coronary artery bypass grafting in patients with dialysis-dependent renal failure]. AB - From January 1995 to May 2003, 36 patients with dialysis-dependent renal failure underwent coronary artery bypass grafting. We performed the operation with cardiopulmonary bypass (group On) in 17 cases and without cardiopulmonary bypass (group Off) in 19 patients [off-pump coronary artery bypass grafting (OPCAB) 15, minimally invasive direct coronary artery bypass (MIDCAB) 4]. There were no statistical differences regarding mean age, sex, duration of dialysis, preoperative hypertension, diabetes and peripheral and cerebral vascular diseases. Mean operation time and the number of bypass grafts were 315 +/- 53 minutes, 2.8 +/- 0.8 grafts in group On and 284 +/- 78 minutes, 2.4 +/- 1.1 grafts in group Off, respectively (not significant). Seventeen patients (100%) of group On and 12 patients (63%) needed blood transfusion. Hospital stay after operation was significantly longer in group On (40 days) of group Off than that in group Off (26 days). After the operation, continuous hemodiafiltration (CHDF) was used in 10 cases (59%) in group On and 3 cases (16%) in group Off. In coronary artery bypass grafting (CABG) on dialysis patient, it is very effective to have various operation techniques, such as off-pump bypass and on-pump beating bypass. Also control of water-electrolyte balance using early postoperative CHDF is useful. However, off-pump cases could be controlled by conventional hemodialysis. PMID- 17703616 TI - [Perioperative coronary spasm in the modified Bentall's operation for localized dissecting aneurysm of Valsalva sinuses]. AB - A 55-year-old man had suffered from chest oppression while asleep for 1 to 2 years. Moderate aortic regurgitation and aneurysm of Valsalva sinuses were revealed by echocardiography. It was diagnosed as chronic localized dissecting aneurysm of Valsalva sinuses during the operation, and modified Bentall's operation was performed. The patient was extubated 2 hours after the operation. ST segment depression in leads I, aV(L) and V3-V6, and elevation in leads III and aV(R) suddenly occurred 5 hours after the operation. However, hemodynamics was very stable, and he complained of no chest pain. Cardiac asystole was detected 7 hours after the operation, and percutaneous cardiopulmonary support as well as intraaortic balloon pumping (IABP) was immediately started. Emergency coronary angiography revealed acute myocardial infarction due to severe coronary spasm in the left coronary artery. The patient expired on the 3rd postoperative day. PMID- 17703617 TI - [Extrapleural pneumonectomy for relapsed solitary fibrous tumors of the pleura with pleural dissemination]. AB - We report a case of a 62-year-old female with a prior thoracotomy for solitary fibrous tumor of the diaphragmatic pleura. There was no clear evidence of malignant solitary fibrous tumor of the pleura (SFTP). In the 19th postoperative month, she had a disseminated recurrence of SFTP in the left thoracic cavity. There was no evidence of metastasis from medical imaging. Accordingly, a left extrapleural pneumonectomy was performed. Pathological examination revealed a disseminated recurrence of malignant SFTP, showing a higher grade of malignancy, because the resected specimen was identical to the only section suspicious of malignancy in the previous tumor. She had no complaint and kept better performance status until the 7th postoperative month after the re-resection, when she had a recurrence in the left thoracic cavity and dissemination in the peritoneal cavity. She died of the recurrence 15 months after the re-resection and 34 months after the prior thoracotomy. PMID- 17703618 TI - [Mitral valve repair with anterior leaflet augmentation for rheumatic mitral valve disease]. AB - A 74-year-old male with congestive heart failure was referred to our hospital, and massive mitral regurgitation as well as aortic stenosis and regurgitation were detected by echocardiography. His mitral valve was successfully repaired with anterior leaflet augmentation with the equine pericardial patch followed by aortic valve replacement. Postoperative transthoracic Doppler echocardiography revealed no mitral regurgitation. The patient recovered uneventfully and was discharged on the 19th postoperative day. At 2 years and 2nd month after the operation, he is well without limitation of daily activities and any evidence of mitral regurgitation. PMID- 17703619 TI - [Tricuspid valve repair for active infective endocarditis in a drug addict]. AB - We report a case of tricuspid valve endocarditis in a drug addict. A 30-year-old man who had a history of intravenous drug abuse was admitted with complaints of high fever and dyspnea. Chest computed tomography showed multiple thromboembolism in the bilateral lungs. Blood culture was positive with methicillin sesitive Staphylococcus aureus, and echocardiography showed severe tricuspid valve regurgitation and vegetations attached to the tricuspid valve. Because infection was uncontrollable, he underwent surgery. We removed a part of posterior leaflet including vegetations, and performed tricuspid valve repair using the autologous pericardium. The patient's postoperative course was uneventful. Subsequent echocardiography showed no vegetations and regurgitation of the tricuspid valve. He has remained free from endocarditis for 10 months after surgery. PMID- 17703620 TI - [Video-assisted thoracoscopic surgery for ligation of anomalous systemic arterial supply to pulmonary sequestration]. AB - A 52-year old female with anomalous systemic arterial supply to pulmonary sequestration was reported. The patient was admitted because of an abnormal lung shadow on chest X-ray film. Computed tomography (CT) showed an anomalous systemic arterial supply to pulmonary sequestration of the left lower lung without lung infection. Video-assisted thoracoscopic surgery for ligation of the anomalous systemic artery was performed. Postoperative course has been uneventful for 14 months after surgery. Blood supply increased to the left lower lung by 3 dimensional CT after surgery. The ligation of anomalous systemic arterial is enough for this disease. PMID- 17703621 TI - [Minimally invasive technique for harvesting a saphenous vein via one small incision]. AB - We report a minimally invasive technique for harvesting a saphenous vein graft (SVG) via 1 small skin incision. The expected advantages of this technique are better cosmetic results and fewer wound complications than the conventional open technique or the bridging technique. The SVG, 10-15 cm in length, can be harvested by about 3 cm-long single small skin incision. SaphLITE Retractor System (Genzyme Srugical Products, Cambridge), SLS Hematostatic Clip System (Vitalitec International, Plymouth), and curved scissors were necessary instruments for this technique. It is feasible for cases that require a shorter length of SVG. PMID- 17703622 TI - [Surgical repair of coarctation of the aorta in adults]. AB - We report the surgical treatment of coarctation of the aorta (CoA) in 3 adults, 2 women and 1 man, aged between 18 and 32 years old. All of the patients had blood pressure gradients higher than 70 mmHg between the upper and lower limbs. In 2 patients, we simply clamped the aorta and excised the CoA: while in the other patient, we excised the CoA using partial extracorporeal circulation with a femoro-femoral (F-F) bypass. Reconstruction was done by an end to end anastomosis in 2 patients and with an artificial tube graft in 1 patient who regulred the extended aortic arch repair. Postoperatively, the pressure gradients between the upper and lower limbs dropped to below 20 mmHg in intensive care unit (ICU). Two of the patients have now stopped taking antihypertensive drugs and the other patient is taking half the preoperative dose. PMID- 17703623 TI - [Lobectomy for local recurrence of lung cancer after 3-dimensional-conformal radiotherapy]. AB - An 85-year-old man was diagnosed as having primary cancer located in the middle lobe (squamous cell carcinoma cT1N0M0 stage IA). Because of his general conditions and status as an octogenarian, 3-dimensional-conformal radiotherapy (3D-CRT, 75Gy in 25 fractions) was selected. The therapeutic response was partial remission, and the adverse reaction was radiation pneumonitis (grade 2). Seventeen months after 3D-CRT, local recurrence was detected. Surgery was performed. Thoracoscopic findings demonstrated scarring fibrosis in the middle lobe and there was no adhesion in the pulmonary hilum. Therefore, video-assisted thoracoscopic lobectomy was performed safely. The patient was discharged on the 10th days post operatively without complication. After 12 months follow-up, there has been no recurrence. PMID- 17703624 TI - [Indication and timing of mitral valvular surgery]. AB - Patients with mitral regurgitation are increasing while those with mitral stenosis are decreasing. In addition, percutaneous transluminal mitral commissurotomy (PTMC) technique has dramatically reduced surgical indication of mitral stenosis. At the present time, the most important topic would be the surgical indication of asymptomatic patients with severe mitral regurgitation and preserved left ventricular function. In this context, feasibility of mitral valve repair, in other words, the skill and experience of the surgeon becomes very important. In this paper, we described issues about the timing and indication of mitral valvular surgery based on "American College Cardiology/American Heart Association (ACC/AHA) 2006 practice guidelines for the management of patients with valvular heart disease". PMID- 17703625 TI - [Diagnosis and management of chronic obstructive pulmonary disease]. AB - Chronic obstructive pulmonary disease (COPD) is defined by the presence of airflow limitation, measured by the forced expiratory volume in 1 second (FEV1) after the administration of bronchodilator. Here the beta2-reversibility is defined by postbronchodilator FEV1-prebronchodilator FEV1 > 12% of pre bronchodilator FEV1. The simple classification of disease severity into 4 stages is recommended based postbronchodilator FEV1. Bronchodilator medications are central to the symptomatic management of COPD. The principal bronchodilator treatments are beta2-agonists, anticholinergics, theophylline, and a combination of these drugs. Treatments including inhaled glucocorticosteroids are recommended to only severe COPD patients with the FEV1 < 50% predicted and to those who repeat exacerbations. Inhaled bronchodilators and systemic glucocorticosteroids are effective treatments for exacerbations of COPD. Noninvasive intermittent positive pressure ventilation in acute exacerbations reduces mortality, decreases the need for invasive mechanical ventilation and intubation, and decreases the length of hospital stay. PMID- 17703626 TI - [Radical operation of tetralogy of Fallot with left single coronary and long-term follow up; report of a case]. AB - We report a long-term result of a radical repair of tetralogy of Fallot combined with left single coronary in 57-year-old woman. She was in severe respiratory failure and severe cyanosis. The repair was monocusp patch reconstruction of right ventricle (RV) out flow tract after cutting off the right coronary artery (RCA) and coronary artery bypass graft (CABG) to RCA with saphenous vein graft. The post operative course for these 11 years, she had been in controllable congestive heart failure from postoperative pulmonary regurgitation and myocardial ischemy owing to obstract of RCA graft. PMID- 17703627 TI - [Aortic arch aneurysm with aortopulmonary fistula; report of a case]. AB - A 77-year-old female was admitted to our hospital due to congestive heart failure. Computed tomography and angiography showed a saccular aneurysm with aortopulmonary fistula in the aortic arch. The patient underwent total arch replacement and patch closure of the pulmonary artery in an urgent operation. She was discharged after uneventful postoperative course, although staged sternal closure and 5 days of respiratory management were needed. A few cases of aortic arch aneurysm with perforation to the pulmonary artery are operated with success, which depends on severity of congestive heart failure and urgency. Therefore, it should be diagnosed exactly and rapidly. In the operation, special care should be taken to avoid right heart failure and postoperative respiratory distress. PMID- 17703628 TI - [Posterior mediastinal hemangioma successfully resected with cardiopulmonary bypass; report of a case]. AB - Mediastinal hemangioma is a rare tumor. We report a case of a 62-year-old woman with a posterior mediastinal hemangioma. She had a history of right breast cancer and a follow-up chest radiography revealed a mass located in the left posterior mediastinum. The size was about 80 mm in diameter. The tumor surrounded the descending thoracic aorta and involved intercostal arteries. Complete excision could be achieved by decompressing the descending aorta with the aid of partial cardiopulmonary bypass and the aortic cross-clamp. Histologically, the tumor was diagnosed as a benign hemangioma. It was reported that hemangioma would reccur after subtotal excision. To employ cardiopulmonary bypass was a very effective approach for the purpose of complete excision in our case. PMID- 17703629 TI - [Mycobacterium intracellulare lung disease that was detected by follow-up after pulmonary resection for lung cancer; report of a case]. AB - The patient was a 61-year-old woman diagnosed with lung cancer who underwent lower right lobectomy in March 2003. Brochopleural fistula developed in the 3rd postoperative month and subsequent chest drainage stopped the air leak. Chest X ray on follow-up in August 2006, revealed nodular shadows in the lower right field and computed tomography of the thorax showed clusters of small nodules in the right S2. The bronchial washing specimen showed acid-fast bacilli, which was identified as Mycobacterium intracellulare by DNA-DNA hybridization. The patient showed radiological improvement following combination therapy with rifampicin, ethambutol, clarithromycin, and streptomycin. PMID- 17703630 TI - [Usefulness of the thoracoscopic surgery under local anesthesia and irrigation for the patient with Bacillus cereus empyema; report of a case]. AB - The case was 54-year-old male with some risks such as chronic heart failure, atrial fibrillation, and liver chirrhosis. He was admitted because of severe back pain and diagnosed as empyema by preoperative thoracentesis. By thoracoscopic procedures under local anesthesia, fibrinopurulent tissues were cleaned as much as possible and 3 of chest tubes were replaced. The final diagnosis was Bacillus cereus pyothorax by bacterial cultures of pleural effusion. Intrathoracic cavity was cleaned with physiological saline solution. The patient made favorable progress and recovered. Thoracoscopic surgery under local anesthesia with thoracic irrigation was so effective and safe methods to control the infection. PMID- 17703631 TI - What future for vascular neurosurgery? PMID- 17703632 TI - Combining insulins for optimal blood glucose control in type I and 2 diabetes: focus on insulin glulisine. AB - Normalization of blood glucose is essential for the prevention of diabetes mellitus (DM)-related microvascular and macrovascular complications. Despite substantial literature to support the benefits of glucose lowering and clear treatment targets, glycemic control remains suboptimal for most people with DM in the United States. Pharmacokinetic limitations of conventional insulins have been a barrier to achieving treatment targets secondary to adverse effects such as hypoglycemia and weight gain. Recombinant DNA technology has allowed modification of the insulin molecule to produce insulin analogues that overcome these pharmacokinetic limitations. With time action profiles that more closely mimic physiologic insulin secretion, rapid acting insulin analogues (RAAs) reduce post prandial glucose excursions and hypoglycemia when compared to regular human insulin (RHI). Insulin glulisine (Apidra) is a rapid-acting insulin analogue created by substituting lysine for asparagine at position B3 and glutamic acid for lysine at position B29 on the B chain of human insulin. The quick absorption of insulin glulisine more closely reproduces physiologic first-phase insulin secretion and its rapid acting profile is maintained across patient subtypes. Clinical trials have demonstrated comparable or greater efficacy of insulin glulisine versus insulin lispro or RHI, respectively. Efficacy is maintained even when insulin glulisine is administered post-meal. In addition, glulisine appears to have a more rapid time action profile compared with insulin lispro across various body mass indexes (BMIs). The safety and tolerability profile of insulin glulisine is also comparable to that of insulin lispro or RHI in type 1 or 2 DM and it has been shown to be as safe and effective when used in a continuous subcutaneous insulin infusion (CSII). In summary, insulin glulisine is a safe, effective, and well tolerated rapid-acting insulin analogue across all BMIs and a worthy option for prandial glucose control in type 1 or 2 DM. PMID- 17703635 TI - Metoprolol succinate extended release/hydrochlorothiazide combination tablets. AB - Lowering elevated blood pressure (BP) with drug therapy reduces the risk for catastrophic fatal and nonfatal cardiovascular events such as stroke and myocardial infarction. Given the heterogeneity of hypertension as a disease, the marked variability in an individual patient's BP response, and low response rates with monotherapy, expert groups such as the Joint National Committee (JNC) emphasize the value of combination antihypertensive regimens, noting that combinations, usually of different classes, have additive antihypertensive effects. Metoprolol succinate extended-release tablet is a beta-1 (cardio selective) adrenoceptor-blocking agent formulated to provide controlled and predictable release of metoprolol. Hydrochlorothiazide (HCT) is a well established diuretic and antihypertensive agent, which promotes natruresis by acting on the distal renal tubule. The pharmacokinetics, efficacy, and safety/tolerability of the antihypertensive combination tablet, metoprolol extended release hydrochlorothiazide, essentially reflect the well-described independent characteristics of each of the component agents. Not only is the combination product more effective than monotherapy with the individual components but the combination product allows a low-dose multidrug regimen as an alternative to high-dose monotherapy, thereby, minimizing the likelihood of dose related side-effects. PMID- 17703633 TI - Manidipine-delapril combination in the management of hypertension. AB - High blood pressure (BP) is the major cardiovascular risk factor and the main cause of death around the world. Control of blood pressure reduces the high mortality associated with hypertension and the most recent guidelines recommend reducing arterial BP values below 140/90 mmHg for all hypertensive patients (130/80 in diabetics) as a necessary step to reduce global cardiovascular risk, which is the fundamental objective of the treatment. To achieve these target BP goals frequently requires combination therapy with two or more antihypertensive agents. Although the combination of a diuretic and an angiotensin converting enzyme inhibitor (ACEI) is the most commonly used in the clinical practice, the combination of an ACEI and a calcium channel blocker may have an additive antihypertensive effect, a favorable effect on the metabolic profile, and an increased target organ damage protection. The new oral fixed combination manidipine 10 mg/delapril 30 mg has a greater antihypertensive effect than both components of the combination separately, and in non-responders to monotherapy with manidipine or delapril the average reduction of systolic and diastolic BP is 16/10 mmHg. The combination is well tolerated and the observed adverse effects are of the same nature as those observed in patients treated with the components as monotherapy. However, combination therapy reduces the incidence of ankle edema in patients treated with manidipine. PMID- 17703634 TI - Is the fixed-dose combination of telmisartan and hydrochlorothiazide a good approach to treat hypertension? AB - Blockade of the renin-angiotensin system with selective AT1 receptor antagonists is recognized as an effective mean to lower blood pressure in hypertensive patients. Among the class of AT1 receptor antagonists, telmisartan offers the advantage of a very long half-life. This enables blood pressure control over 24 hours using once-daily administration. The combination of telmisartan with hydrochlorothiazide is a logical step because numerous previous studies have demonstrated that sodium depletion enhances the antihypertensive efficacy of drugs interfering with the activity of the renin-angiotensin system (RAS). In accordance with past experience using similar compounds blocking the RAS, several controlled studies have now demonstrated that the fixed-dose combination oftelmisartan/hydrochlorothiazide is superior in lowering blood pressure than either telmisartan or hydrochlorothiazide alone. Of clinical interest also is the observation that the excellent clinical tolerance of the angiotensin II receptor antagonist is not affected by the association of the low-dose thiazide. Thus telmisartan/hydrochlorothiazide is an effective and well-tolerated antihypertensive combination. Finally, the development of fixed-dose combinations should improve drug adherence because of the one-pill-a-day regimen. PMID- 17703636 TI - Risk reduction with clopidogrel in the management of peripheral arterial disease. AB - Peripheral arterial disease (PAD) is a condition typified by decreased arterial blood flow in the non-coronary branches of the aorta as a result of chronic atherosclerosis. Despite the higher prevalence of PAD compared with other cardiovascular entities such as myocardial infarction and stroke, far less import is given to its diagnosis and treatment. In this review, we highlight principal diagnostic and therapeutic considerations in the management of PAD and its complications. We particularly emphasize the role of clopidogrel in the reduction of risks associated with PAD. PMID- 17703638 TI - Rimonabant for treating tobacco dependence. AB - Tobacco use continues to cause 5 million preventable deaths worldwide each year. Despite effective treatments being available, these are underutilized and cessation rates remain low. As tobacco use has complex physiological effects, there are multiple opportunities for novel pharmacological agents to play a role in a comprehensive treatment plan. The endocannabinoid system has been linked to the nicotine reward pathways in animal models. Rimonabant, a selective cannabinoid receptor (type 1) blocker, has been shown in some early clinical trials to have some positive effects in increasing abstinence rates of smokers attempting to stop. In addition, smokers who stop smoking with the assistance of rimonabant may gain less weight than those using placebo. However, the results from these few trials have not been entirely consistent and so its role as an aid to smoking cessation remains to be determined. PMID- 17703637 TI - Fixed combination of losartan and hydrochlorothiazide and reduction of risk of stroke. AB - A fixed-dose combination of losartan/hydrochlorothiazide (HCTZ) therapy may be a logical choice for antihypertensive treatment, including for initial therapy in patients with blood pressure elevation >20/10 mmHg above treatment target. The renin-angiotensin-aldosterone-system-activating effect of hydrochlorothiazide augments the efficacy of blocking the angiotensin II type 1 (AT1) receptor with losartan. Some adverse effects associated with hydrochlorothiazide, including increased risk for new-onset diabetes mellitus, may be offset by losartan. Losartan was frequently administered with hydrochlorothiazide in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, in which there was a 25% risk reduction for stroke in the losartan-based compared with the atenolol-based treatment group. The efficacy, tolerability, and convenience of losartan/HCTZ combination therapy may increase patient compliance and lower risk for stroke, a devastating outcome in patients with hypertension. PMID- 17703639 TI - Multivariate risk assessment and risk score cards in hypertension. AB - Cardiovascular disease represents the leading cause of morbidity and mortality in Western countries, and hypertension-related cardiovascular events affect about 37 million people per year, worldwide. In this perspective, hypertensive patients are at increased risk to experience cardiovascular events during life-long period, and treatment of high blood pressure represents one of the most effective strategies to reduce global cardiovascular risk. However, due to its multifactorial pathophysiology and its frequent association with other relevant risk factors and clinical conditions, treatment of hypertension requires an integrated approach, including life-style measures, antihypertensive drugs and other therapies. Yet, worldwide general practitioners continue to focus their attention on the management of a single risk factor, eg, blood pressure, rather than to global cardiovascular risk profile. In this view, modem strategies of cardiovascular prevention in hypertensive patients should move from a single risk factor based approach toward a more comprehensive risk evaluation in the individual patient. In other words, it is important to define the global cardiovascular risk to manage hypertensive patients at high-risk, rather than to focus on the high level of a single risk factor, for reducing cardiovascular morbidity and mortality in the general population, as well as in hypertensive population. PMID- 17703640 TI - Management of acute coronary syndromes with fondaparinux. AB - Fondaparinux is the first selective inhibitor of the coagulation factor Xa which is commercially avaliable for clinical use. It has been approved for the prevention of venous thromboembolism in patients undergoing orthopedic surgery and for the initial therapy of venous thromboembolism. In randomized clinical trials the value of fondaparinux in the treatment of ST-elevation myocardial infarction (STEMI) has been investigated. The PENTALYSE study showed that fondaparinux was at least as effective and safe as unfractionated heparin in 333 patients with STEMI undergoing fibrinolysis with t-PA. In the recent large OASIS 6 trial with 12,092 patients the treatment with 2.5 mg fondaparinux daily significantly reduced death and reinfarctions until day 30 compared with guideline recommended usual care and compared with unfractionated heparin (9.7% vs 11.2%, p = 0.008) without increasing major bleedings (1.0% vs 1.3%, p = 0.13). This advantage was predominantly seen in the subgroups of patients with fibrinolysis and without early reperfusion therapy. However, in the subgroup of primary percutaneous coronary interventions (PCIs) no clinical benefit of fondaparinux was found, but there were more catheter thrombosis and acute thrombotic complications. In summary, fondaparinux is a new antithrombin that is an efficient, safe, and easy to use in treatment for STEMI patients, particularly those not undergoing primary PCI. PMID- 17703641 TI - Early retirement and the influence on healthcare budgets and insurance premiums in a diabetes population. AB - OBJECTIVES: To contribute to current discussions about budget impact modeling, two different approaches for the impact of a new pharmaceutical product were analyzed: firstly considering the impact on annual healthcare expenditures only, and secondly additional inclusion of lost insurance premiums due to possible early retirement in patients with chronic diseases. METHODS: The dynamic model calculates the budget impact from two different perspectives: (a) the impact on healthcare expenditures and (b) on expenditures as well as on health insurance revenues due to premiums. The latter approach could especially be useful for patients with chronic diseases who have higher probabilities of early retirement. Early retirement rates and indirect costs were derived from published data. Healthcare premiums were calculated based on an average premium and a mean income. Epidemiological input data were obtained from the literature. Time horizon was 10 years. RESULTS: Results in terms of reimbursement decisions of the budget impact analysis varied depending on the assumptions made for the insurance premiums, costs, and early retirement rate. Sensitivity analyses revealed that in extreme cases the decision for accepting a new pharmaceutical product would probably be negative using approach (a), but positive using approach (b). CONCLUSIONS: Depending on the disease and population of interest in a budget impact analysis, not only the healthcare expenditures for a health insurance have to be considered but also the revenue side for an insurance due to retirement should be included. PMID- 17703642 TI - Noninvasive measurements of arterial stiffness: repeatability and interrelationships with endothelial function and arterial morphology measures. AB - BACKGROUND: Many noninvasive arterial assessment techniques have been developed, measuring different parameters of arterial stiffness and endothelial function. However, there is little data available comparing different devices within the same subject. Therefore, the purpose of this study was to examine the repeatability and interrelationships between 3 different techniques to measure arterial stiffness and to compare this with forearm-mediated dilation. METHODS: Carotid-radial pulse wave velocity was measured by the Sphygmocor (SPWV) and Complior (CPWV) devices, cardio-ankle vascular index (CAVI) was measured by the VaSera device, vascular structure and function was assessed using ultrasonography and evaluated for reliability and compared in 20 apparently healthy, college-aged men and women. RESULTS: The intraclass correlation coefficient and standard error of the mean for the Sphygmocor (R = 0.56, SEM = 0.69), Complior (R = 0.62, SEM = 0.69), and VaSera (R = 0.60, SEM = 0.56), indicated moderate repeatability. Bland Altman plots indicated a mean difference of 0.11 +/- 0.84 for SPWV, 0.13 +/- 1.15 for CPWV, and -0.43 +/- 0.90 for CAVI. No significant interrelationships were found among the ultrasound measures and SPWV, CPWV, and CAVI. CONCLUSIONS: The three noninvasive modalities to study arterial stiffness reliably measures arterial stiffness however, they do not correlate with ultrasound measures of vascular function and structure in young and apparently healthy subjects. PMID- 17703643 TI - Severe supraaortal atherosclerotic disease resembling Takayasu's Arteritis. AB - We report a case of a 64 year-old man whose clinical presentation and neuroimaging findings strikingly resembled those found in Takayasu's Arteritis which is characterized by the triad of absent radial pulses, ischemic retinopathy, and carotid sinus hyperreflexia causing syncopes. Angiographically, the patient exhibited severe atherosclerotic changes of the supraaortic large vessels. Stent-assisted angioplasty resulted in both clinical improvement and increased cerebral blood flow as measured by angiography and ultrasound. PMID- 17703644 TI - Psychiatry: de-professionalisation. PMID- 17703645 TI - Social network among people with persistent mental illness: associations with sociodemographic, clinical and health-related factors. AB - BACKGROUND: Social interaction is crucial for whether a person will successfully accomplish important life tasks. AIM AND METHOD: This study investigated the importance of sociodemographic, clinical and self-perceived health-related factors for social interaction among 103 individuals with persistent mental illness, mainly psychoses, visiting an outpatient unit. RESULTS: Bivariate analyses pointed to several relationships, especially between the health-related variables and both quantitative and qualitative aspects of the social network. In multivariate analyses, higher levels of quality of life, self-esteem, being a cohabitant, and living in a house were related to higher ratings on different aspects of the social network. Older age was associated with fewer close relationships but more adequate social integration. CONCLUSIONS: The social network appeared to be a function of both self-perceptions and sociodemographic influences. The influence is probably dynamic and, for example, just as a better quality of life may lead to more social interaction, a more developed social network probably promotes better quality of life. Therefore, interventions in mental health care that target social interaction constitute a powerful resource and should be part of the support for people with severe and persistent mental illness. PMID- 17703646 TI - Burnout and job satisfaction in New Zealand psychiatrists: a national study. AB - OBJECTIVES: To estimate the prevalence of burnout and the level of job satisfaction among New Zealand psychiatrists, and to ascertain relationships between socio-demographic variables, job satisfaction and burnout in the target population. METHOD: In phase one of the study a postal survey was mailed out to every practising psychiatrist on record as well as all doctors working in psychiatry without specialist qualifications (MOSS). Three questionnaires were used: a socio-demographic questionnaire, the Maslach Burnout Inventory (MBI) and a Job Diagnostic Survey (JSS). Regression analysis was performed on returned data sets using socio-demographic characteristics as explanatory variables and score components of the MBI and JDS as the outcome measures. RESULTS: The results showed that the prevalence of burnout in New Zealand psychiatrists is cause for concern. Two-thirds of all psychiatrists described moderate to severely high levels of emotional exhaustion, with a similar proportion describing low levels of personal accomplishment. Depersonalisation did not appear to be a major problem in the population. Job satisfaction remained relatively high despite the high prevalence of burnout, although there was a relationship between burnout and job satisfaction scores. CONCLUSIONS: This study has demonstrated a high prevalence of burnout and factors associated with it among New Zealand psychiatrists. Further research is needed to ascertain why job satisfaction remains high in the presence of burnout, and factors predisposing to, or protective of, burnout. PMID- 17703647 TI - The contributions of culture and ethnicity to New Zealand mental health research findings. AB - BACKGROUND AND MATERIAL: In the last five years a number of studies have been conducted in specialist psychiatric and primary care populations in New Zealand which have allowed comparisons in terms of clinical phenomena and therapeutic experiences between Maori (the indigenous people of New Zealand) and non-Maori. These studies were reviewed in terms of the methodology used, their major findings and their implications. DISCUSSION: In specialist psychiatric services Maori were more likely to present with hallucinations and/or aggression and less likely to present with depression and/or episodes of self-harm. They were overly represented in those with schizophrenia. Maori were more likely to be involved in acts of aggression and to be secluded, and an equivalent episode of care for Maori appeared to be significantly more costly than for non Maori. Other studies, conducted in prison and community-based samples, suggested that Maori were less likely to access care and, when given a diagnosis of depression, less likely to be prescribed anti-depressant medication.The rates of depression were significantly higher in Maori (women) and Maori were also overly represented in those with anxiety and substance misuse disorders. These differences remained even after the sample was standardised for socio-economic status. Further exploration of the genesis and implications of these findings, derived from a strong and relatively well-defined indigenous people, may usefully inform the more general issues of culture and its significance for diagnosis, classification and service use. CONCLUSIONS: While the methodologies used and the actual results gained differed across studies, there do seem to be differences in phenomenological profiles at presentation, in the diagnostic patterns, the cost of care, and the therapeutic experiences between Maori and non-Maori New Zealanders. These differences may reflect actual differences between certain ethnic groups, which then explain the differences in the experiences of those users, or they may reflect inadequacies on the parts of non-MAori clinicians, their diagnostic tools and the services in which they operate, in catering for Maori patients. PMID- 17703648 TI - Stigma and explanatory models among people with schizophrenia and their relatives in Vellore, south India. AB - BACKGROUND: Stigma associated with mental illness affects patients and their families. Diverse beliefs about the cause and treatment of schizophrenia are common among patients and their relatives. AIM: To study the association between stigma and beliefs about illness in patients and their relatives. METHOD: Standard instruments were used to assess beliefs about illness and about stigma among patients with schizophrenia and relatives in Vellore, south India. RESULTS: The majority of the patients and their relatives simultaneously held multiple and contradictory models of illness and its treatment. Stigma among patients with schizophrenia and their relatives is associated with specific beliefs about causes of mental illness. CONCLUSIONS: Beliefs may play a role in mitigating or may aggravate the effects of stigma. The cross-sectional study design precludes definitive conclusions on direction of the causal association. PMID- 17703649 TI - The needs of parents with a mental illness who have young children: an Australian perspective on service delivery options. AB - BACKGROUND AND AIMS: This article discusses a collaborative approach to assisting parents with a mental illness who have children aged 5 years and under and explores themes found in the literature, focus groups with consumers and workshops with clinicians working with parents who have a mental illness. METHOD: Focus groups and workshops were held for consumers and clinicians. The workshops included information about a proposed group intervention and discussions about themes found in the literature review and previous focus groups. RESULTS: Using thematic analysis, the gaps identified in the focus groups and workshops were classified into five main categories--namely, interagency collaboration, a need for accessible support groups, a need for information and resources about mental illness, and parenting issues related to mental illness and independence. This information informed the development of a treatment package. CONCLUSION: The content of the proposed treatment package has been informed by the findings of the literature review, focus groups and workshops. The sessions focus on topics about parenting and managing mental health and consumers are actively involved at the outset in their own care and the care of their child. The intervention will be trailed in clinical settings to establish efficacy and effectiveness. PMID- 17703651 TI - Analyzing vocational outcomes of individuals with psychiatric disabilities who received state vocational rehabilitation services: a data mining approach. AB - This study examines factors affecting vocational outcomes in the vocational rehabilitation process for individuals experiencing psychiatric disabilities who had received state vocational rehabilitation (VR) services. A data mining approach was used to analyze the Rehabilitation Services Administration FY 2001 Case Service Report (RSA-911). Receiving job placement services was found to be the most important variable differentiating individuals who were working from those who were not working. Results regarding vocational outcomes suggest a positive effect for persons receiving job placement services. PMID- 17703650 TI - The Camden Schizophrenia Surveys. III: Five-year outcome of a sample of individuals from a prevalence survey and the importance of social relationships. AB - BACKGROUND: Most studies of outcome in schizophrenia have focused on incidence cohorts or samples identified through specialist mental health services; population-based samples provide a more complete picture of the effectiveness of community services. AIMS: To examine whether outcome predictors, derived from studies of selected patients with prolonged schizophrenia, would emerge in a largely community-dwelling population sample. METHODS: A follow-up sample of 114 adults with schizophrenia was identified via two censuses of key informants conducted for two prevalence surveys in North London, five years apart. Symptomatic, clinical and functional outcomes were assessed after five years. A composite score was derived for each individual. Multiple Linear Regression analyses were conducted in two phases to derive a best subset of predictors for global outcome. RESULTS: After five years, 33% were worse and 62% were better overall. The four best predictors (social isolation, living apart from relatives, longer illness and being an inpatient at first census) accounted for 32% of the variance in outcome of those with schizophrenia and related diagnoses. CONCLUSIONS: Social relationships during the course of illness are an important predictor of overall outcome and relationships with friends and family each seem to make a positive contribution. Policy and service developments should focus on improving participation in community life for people with schizophrenia, particularly their social connectedness. PMID- 17703652 TI - Acculturation and mental health among ghanaians in The Netherlands. AB - BACKGROUND: The current literature on the relationship between cultural adaptation and mental health is premature to offer a comprehensive explanation about the ways acculturation exerts either positive or adverse effects on the mental health of migrants. AIM: This study is an empirical approach towards understanding the magnitude of the relationship between consequences of cultural adaptation and psychological distress. METHODS: Two samples of Ghanaian migrants in The Netherlands were included: a clinical group (n = 36) and a non-clinical community group (n = 97). Data were acquired by administering a semi-structured interview. Quantified data were analysed using multivariate techniques. RESULTS: Contradictory to our hypotheses, the reported level of mental health symptoms in both groups was relatively low, suggesting a substantial resilience among the Ghanaian group. Confirming our hypotheses, specific dimensions of the acculturation process were associated with health status, particularly affiliation with cultural traditions and feelings of loss concerning the country of birth. CONCLUSIONS: Acculturation demands capture critical elements of migrants' experiences that warrant professional interventions tailored to their specific needs. A subtle balance between holding on to the supportive cultural traditions together with moderate involvement in ruminating about pre-migration life, in conjunction with acquiring instrumental skills of the host culture, is a starting position for better health. PMID- 17703653 TI - Study of cellular adhesion with scanning acoustic microscopy. AB - A mechanical scanning acoustic reflection microscope was applied to living cells (e.g., osteoblasts) to observe their undisguised shapes and to evaluate their adhesive conditions at a substrate interface. A conditioned medium was collected from a bone-metastatic breast cancer cell line, MDA-MB-231, and cultured with an immature osteoblast cell line, MC3T3-E1. To characterize the cellular adhesion, MC3T3-E1 osteoblasts were cultured with or without MDA-MB-231 conditioned medium for 2 days, then assayed with the scanning acoustic reflection microscope. At 600 MHz the scanning acoustic reflection microscope clearly indicated that MC3T3-E1 cells cultured with MDA-MB-231 conditioned medium had both an abnormal shape and poor adhesion at the substrate interface. The results are compared with those obtained with laser scanning confocal microscopy and are supported by a simple multilayer model. PMID- 17703654 TI - Imaging of local stiffness of damaged polycrystalline copper: nondestructive evaluation by resonance ultrasound microscopy. AB - The distribution of the local stiffness of a polycrystalline copper exposed to a creep test was studied by resonance ultrasound microscopy. The local effective modulus was evaluated from the resonance frequency of the isolated langasite oscillator touching the specimen. Defects appeared predominantly on grain boundaries, and they were clearly visualized by the stiffness microscopy through the significant decrease of the effective stiffness. The stiffness within the grains becomes lower regardless of invisible defects. The stiffness distribution was quantitatively analyzed by the contact model between two anisotropic bodies and by the micromechanics modeling. The microscopic stiffness shows much higher sensitivity to the defects than the macroscopic stiffness. PMID- 17703655 TI - Acoustic microscopy of internal structure of resistance spot welds. AB - Acoustic microscopy, although relatively new, has many advantages within the industrial quality control process. Its high degree of sensitivity, resolution, and reliability make it ideal for use in resistance spot weld analysis, aiding in visualization of small-scale nugget failures, as well as other defects, at various depths. Acoustic microscopy makes it possible to inspect fine detail of internal structures, providing reliable inspection and characterization of weld joints. Besides weld size measurements, this technique is able to provide high resolution, three-dimensional images of the weld nuggets, revealing possible imperfections within its microstructure that may affect joint quality. The high degree of accuracy allows one to consider the results of acoustic microscopy an authoritative measure of weld size, particularly in the case of high strength steels, dual phase steel, USIBOR steel, etc. Indeed, this technique is effective even when both conventional ultrasound and hammer and chisel methods are not. In this paper, the potential of scanning acoustic microscopy as a means to provide qualitative and quantitative information about the internal microstructure of the resistance spot welds is demonstrated. Thus, acoustic microscopy is shown to be a unique and effective laboratory instrument for the evaluation and calibration of weld quality. PMID- 17703656 TI - Elliptical-Tukey chirp signal for high-resolution, air-coupled ultrasonic imaging. AB - A new signal processing method, which uses a modified chirp signal for air coupled ultrasonic imaging, is described. A combination of the elliptical and Tukey window functions has been shown to give a better performance than the Hanning windowing used in most pulse-compression algorithms for air-coupled applications. The elliptical-Tukey chirp signal provides an improvement in both the resolution of images and signal-to-noise ratios. In addition, this type of signal also reduces the level of signal voltages required to drive the source transducer while maintaining the performance of the system. This approach, thus, may have wide interest in all forms of wide bandwidth ultrasonic imaging. PMID- 17703657 TI - Advanced reflector characterization with ultrasonic phased arrays in NDE applications. AB - Ultrasonic arrays are increasingly widely used in nondestructive evaluation (NDE) due to their greater flexibility and potentially superior performance compared to conventional monolithic probes. The characterization of small defects remains a challenge for NDE and is of great importance for determining the impact of a defect on the integrity of a structure. In this paper, a technique for characterizing reflectors with subwavelength dimensions is described. This is achieved by post-processing the complete data set of time traces obtained from an ultrasonic array using two algorithms. The first algorithm is used to obtain information about reflector orientation and the second algorithm is used to distinguish between point-like reflectors that reflect uniformly in all directions and specular reflectors that have distinct orientations. Experimental results are presented using a commercial 64-element, 5-MHZ array on two aluminum test specimens that contain a number of machined slots and side-drilled holes. The results show that the orientation of 1-mm-long slots can be determined to within a few degrees and that the signals from 1-mm-long slots can be distinguished from that from a 1-mm-diameter circular hole. Techniques for quantifying both the orientation and the specularity of measured signals are presented and the effect of processing parameters on the accuracy of results is discussed. PMID- 17703658 TI - In vivo ultrasound biomicroscopy of skin: spectral system characteristics and inverse filtering optimization. AB - High-frequency ultrasound (HFUS) in the 20 MHz to 100 MHz range has to meet the opposite requirements of good spatial resolution and of high penetration depth for in vivo ultrasound biomicroscopy (UBM) of skin. The attenuation of water, which serves as sound propagation medium between utilized single element transducers and the skin, becomes very eminent with increasing frequency. Furthermore, the spectra of acquired radio frequency (rf) echo signals change over depth because of the diffracted sound field characteristics. The reduction of the system's center frequency and bandwidth causes a significant loss of spatial resolution over depth. In this paper, the spectral characteristics of HFUS imaging systems and the potential of inverse echo signal filtering for the optimization of pulse-echo measurements is analyzed and validated. A Gaussian model of the system's transfer function, which takes into account the frequency dependent attenuation of the water path, was developed. Predictions of system performance are derived from this model and compared with measurement results. The design of a HFUS skin imaging system with a 100 MHz range transducer and a broadband driving electronics is discussed. A time-variant filter for inverse rf echo signal filtering was designed to compensate the system's depth-dependent imaging properties. Results of in vivo measurements are shown and discussed. PMID- 17703659 TI - Assessment of anisotropic tissue elasticity of cortical bone from high resolution, angular acoustic measurements. AB - Assessment of anisotropic elastic properties at the tissue level is still one of the major challenges in bone research. In previous studies, bone sections were cut in different directions relative to a principle axis of symmetry. This causes a high preparation and measurement effort. We have developed a new acoustic scanning procedure that allows one to measure the angular dependence of the acoustic impedance of cylindrically shaped samples (diameter: 4.4 mm) with a single measurement. Our scanning acoustic microscope was equipped with a rotational stage, and a scanning procedure was developed that measures the surface reflection of the rotating cylinder. It was shown in a previous study that the acoustic impedance derived from the reflection coefficient is highly correlated with the elastic coefficient in the probing direction. From the angular reflection, the independent elastic coefficients were derived using assumptions of transverse isotropy and continuum micromechanical model constraints. This method was applied to the inspection of human femoral bone samples. Four cylinders were prepared from the anterior, posterior, medial, and lateral regions. The measurements were performed with a 50 MHz transducer, providing a lateral resolution of 23 microm. Remarkable structural and elastic variations were observed between the four samples. The means and standard deviations of the derived elastic coefficients were: c33 = 29.9 +/- 5.0 GPa, c11 = 21.9 +/- 2.1 GPa, c12 = 9.2 +/- 1.5 GPa, c13 = 9.7 +/- 1.6 GPa, and c44 = 6.7 +/- 1.2 GPa. The results demonstrate that microstructural and anisotropic elastic tissue parameters can be assessed by ultrasound in very small bone samples. PMID- 17703660 TI - Ultrasonic tissue characterization of atherosclerosis by a speed-of-sound microscanning system. AB - We have been developing a scanning acoustic microscope (SAM) system for medicine and biology featuring quantitative measurement of ultrasonic parameters of soft tissues. In the present study, we propose a new concept sound speed microscopy that can measure the thickness and speed of sound in the tissue using fast Fourier transform of a single pulsed wave instead of burst waves used in conventional SAM systems. Two coronary arteries were frozen and sectioned approximately 10 microm in thickness. They were mounted on glass slides without cover slips. The scanning time of a frame with 300 x 300 pixels was 90 s and two dimensional distribution of speed of sound was obtained. The speed of sound was 1680 +/- 30 m/s in the thickened intima with collagen fiber, 1520 +/- 8 m/s in the lipid deposition underlying the fibrous cap, and 1810 +/- 25 m/s in a calcified lesion in the intima. These basic measurements will help in the understanding of echo intensity and pattern in intravascular ultrasound images. PMID- 17703661 TI - An optimization method for quantitative impedance tomography. AB - A near-field ultrasonic tomography method providing high resolution imaging for soft tissue in the reflection mode is reported. When the Born approximation is valid, the main limitation of this method is that it requires an incident pulse with infinite bandwidth, whereas the incident pulses used in practice have a limited bandwidth, which makes quantitative reconstruction impossible. The reconstructed image is qualitative in the sense that it is a band-pass filtered reconstruction of the impedance distribution. An optimization method based on the use of the geometrical information provided by the tomographic reconstruction is developed to obtain the quantitative information required. The object was approximated locally by an equivalent canonical body, on the basis of the previous global estimation. The inversion procedure is then carried out using the minimization of a cost function, which is the average over frequency of the difference between the measured field scattered by the object and the estimated field scattered by the equivalent canonical body. Assuming the object to be homogeneous by regions, the last step consists of assigning the estimated local impedance value to the region of interest. When the geometry of the real body is almost canonical, the optimization method yields accurate impedance assessments. PMID- 17703662 TI - Effects of fine metal oxide particle dopant on the acoustic properties of silicone rubber lens for medical array probe. AB - The effects of fine metal oxide particles, particularly those of high-density elements (7.7 to 9.7 x 10(3) kg/m3), on the acoustic properties of silicone rubber have been investigated in order to develop an acoustic lens with a low acoustic attenuation. Silicone rubber doped with Yb2O3 powder having nanoparticle size of 16 nm showed a lower acoustic attenuation than silicone rubber doped with powders of CeO2, Bi2O3, Lu2O3 and HfO2. The silicone rubber doped with Yb2O3 powder showed a sound speed of 0.88 km/s, an acoustic impedance of 1.35 x 10(6) kg/m2s, an acoustic attenuation of 0.93 dB/mmMHz, and a Shore A hardness of 55 at 37 degrees C. Although typical silicone rubber doped with SiO2 (2.6 x 10(3) kg/m3) shows a sound speed of about 1.00 km/s, heavy metal oxide particles decreased the sound velocities to lower than 0.93 km/s. Therefore, an acoustic lens of silicone rubber doped with Yb2O3 powder provides increased sensitivity because it realizes a thinner acoustic lens than is conventionally used due to its low sound speed. Moreover, it has an advantage in that a focus point is not changed when the acoustic lens is pressed to a human body due to its reasonable hardness. PMID- 17703663 TI - High-accuracy data acquisition architectures for ultrasonic imaging. AB - This paper proposes a novel architecture for a data acquisition system intended to support the next generation of ultrasonic imaging instruments operating at or above 100 MHz. Existing systems have relatively poor signal-to-noise ratios and are limited in terms of their maximum data sampling rate, both of which are improved by a combination of embedded averaging and embedded interleaved sampling. "On-the-fly" pipelined operation minimizes control overheads for signal averaging. A two-clock sampling timing system provides for effective sampling rates that are a factor of 20 or more above the basic sampling rate of the analog to-digital converter (ADC). The system uses commercial field-programmable gate array devices operated at clock frequencies commensurable with the ADC clock. Implementation is via the Xilinx Xtreme digital signal processing development kit, available at low cost. Sample rates of up to 2160 MHz have been achieved in combination with up to 16384 coherent averages using the above-mentioned off-the shelf hardware. PMID- 17703664 TI - Adaptive beamforming applied to medical ultrasound imaging. AB - We have applied the minimum variance (MV) adaptive beamformer to medical ultrasound imaging and shown significant improvement in image quality compared to delay-and-sum (DAS). We demonstrate reduced mainlobe width and suppression of sidelobes on both simulated and experimental RF data of closely spaced wire targets, which gives potential contrast and resolution enhancement in medical images. The method is applied to experimental RF data from a heart phantom, in which we show increased resolution and improved definition of the ventricular walls. A potential weakness of adaptive beamformers is sensitivity to errors in the assumed wavefield parameters. We look at two ways to increase robustness of the proposed method; spatial smoothing and diagonal loading. We show that both are controlled by a single parameter that can move the performance from that of a MV beamformer to that of a DAS beamformer. We evaluate the sensitivity to velocity errors and show that reliable amplitude estimates are achieved while the mainlobe width and sidelobe levels are still significantly lower than for the conventional beamformer. PMID- 17703665 TI - Model-based correction of diffraction effects of the virtual source element. AB - A method for ultrasonic synthetic aperture imaging using finite-sized transducers is introduced that is based on a virtual source (VS) concept. In this setup, a focused transducer creates a VS element at its focal point that facilitates the use of synthetic aperture focusing technique (SAFT). It is shown that the performance of the VS method may be unsatisfactory due to the distortion introduced by the diffraction effects of the aperture used for creating the VS element. A solution to this problem is proposed that consists of replacing the classical SAFT by the extended synthetic aperature focusing technique (ESAFT) algorithm presented in our earlier works. In ESAFT, the full geometry of the VS is modeled, instead of applying the simplified point source approximation used when VS is combined with classical SAFT. The proposed method yields a substantial improvement in spatial resolution compared to that obtained using SAFT. Performance of the proposed algorithm is first demonstrated on simulated data, then verified on real data acquired with an array system. PMID- 17703666 TI - On time-domain model-based ultrasonic array imaging. AB - This paper treats time-domain model-based Bayesian image reconstruction for ultrasonic array imaging and, in particular, two reconstruction methods are presented. These two methods are based on a linear model of the array imaging system and they perform compensation in both the spatial and temporal domains using a minimum mean squared error (MMSE) criterion and a maximum a posteriori MAP) estimation approach, respectively. The presented estimators perform compensation for both the electrical and acoustical wave propagation effects for the ultrasonic array system at hand. The estimators also take uncertainties into account, and, by the incorporation of proper prior knowledge, high-contrast superresolution reconstruction results are obtained. The novel nonlinear MAP estimator constrains the scattering amplitudes to be positive, which applies in applications where the scatterers have higher acoustic impedance than the surrounding medium. The linear MMSE and nonlinear MAP estimators are compared to the traditional delay-and-sum (DAS) beamformer with respect to both resolution and signal-to-noise ratio. The algorithms are compared using both simulated and measured data. The results show that the model-based methods can successfully compensate for both sidelobes and grating lobes, and they have a superior temporal and lateral resolution compared to DAS beamforming. The ability of the nonlinear MAP estimator to suppress noise is also superior compared to both the linear MMSE estimator and the DAS beamformer. PMID- 17703667 TI - Sparse deconvolution of B-scan images. AB - In this paper, a new computationally efficient sparse deconvolution algorithm for the use on B-scan images from objects with relatively few scattering targets is presented. It is based on a linear image formation model that has been used earlier in connection with linear minimum mean squared error (MMSE) two dimensional (2-D) deconvolution. The MMSE deconvolution results have shown improved resolution compared to synthetic aperture focusing technique (SAFT), but at the cost of increased computation time. The proposed algorithm uses the sparsity of the image, reducing the degrees of freedom in the reconstruction problem, to reduce the computation time and to improve the resolution. The dominating task in the algorithm consists in detecting the set of active scattering targets, which is done by iterating between one up-dating pass that detects new points to include in the set, and a down-dating pass that removes redundant points. In the up-date, a spatiotemporal matched filter is used to isolate potential candidates. A subset of those are chosen using a detection criterion. The amplitudes of the detected scatterers are found by MMSE. The algorithm properties are illustrated using synthetic and real B-scan. The results show excellent resolution enhancement- and noise-suppression capabilities. The involved computation times are analyzed. PMID- 17703668 TI - Photoacoustic imaging of multiple targets using gold nanorods. AB - Photoacoustic (PA) imaging has been used mainly for anatomical and functional imaging. Although functionalized nanoparticles also have been developed for PA molecular imaging, only single targeting has been demonstrated. In this study, PA imaging of multiple targets using gold nanorods is demonstrated experimentally using HER2 and CXCR4 as target molecules. The two corresponding monoclonal antibodies were conjugated to two types of gold nanorod with different aspect ratios. Gold nanorods with mean aspect ratios of 5.9 and 3.7 exhibited peak optical absorptions at 1000 and 785 nm, respectively. Appropriate selection of laser irradiation wavelength enhances PA signals by 7-12 dB and allows signals from gold nanorods corresponding to specific bindings to be distinguished. This approach potentially allows the expression levels of different oncogenes of cancer cells to be revealed simultaneously. PMID- 17703669 TI - A high-frame rate high-frequency ultrasonic system for cardiac imaging in mice. AB - We report the development of a high-frequency (30-50 MHz), real-time ultrasonic imaging system for cardiac imaging in mice. This system is capable of producing images at 130 frames per second (fps) with a spatial resolution of less than 50 microm. A novel mechanical sector probe was developed that utilizes a magnetic drive mechanism and custom-built servo controller for high speed and accuracy. Additionally, a very light-weight (< 0.28 g), single-element transducer was constructed and used to reduce the mass load on the motor. The imaging electronics were triggered according to the angular position of the transducer in order to compensate for the varying speed of the sector motor. This strategy ensured the production of equally spaced scan lines with minimal jitter. Wire phantom testing showed that the system axial and lateral resolutions were 48 microm and 72 microm, respectively. In vivo experiments showed that high frequency ultrasonic imaging at 130 fps is capable of showing a detailed depiction of a beating mouse heart. PMID- 17703670 TI - New demodulation method for efficient phase-rotation-based beamforming. AB - In this paper, we present a new demodulation method to reduce hardware complexity in phase-rotation-based beamforming. Due to its low sensitivity to phase delay errors, quadrature demodulation, which consists of mixing and lowpass filtering, is commonly used in ultrasound machines. However, because it requires two lowpass filters for each channel to remove harmonics after mixing, the direct use of quadrature demodulation is computationally expensive. To alleviate the high computational requirement in quadrature demodulation, we have developed a two stage demodulation technique in which dynamic receive focusing is performed on the mixed signal instead of the complex baseband signal. Harmonics then are suppressed by using only two lowpass filters. When the number of channels is 32, the proposed two-stage demodulation reduces the necessary number of multiplications and additions for phase-rotation beamforming by 82.7% and 88.2%, respectively, compared to using quadrature demodulation. We have found from simulation and phantom studies that the proposed method does not incur any significant degradation in image quality in terms of axial and lateral resolution. These preliminary results indicate that the proposed two-stage demodulation method could contribute to significantly reducing the hardware complexity in phase-rotation-based beamforming while providing comparable image quality. PMID- 17703671 TI - Performance evaluation of coherence-based adaptive imaging using clinical breast data. AB - Sound-velocity inhomogeneities degrade both the spatial resolution and the contrast in diagnostic ultrasound. We previously proposed an adaptive imaging approach based on the coherence of the data received in the channels of a transducer array, and we tested it on phantom data. In this study, the approach was tested on clinical breast data and compared with a correlation-based method that has been widely reported in the literature. The main limitations of the correlation-based method in ultrasonic breast imaging are the use of a near field, phase-screen model and the integration errors due to the lack of a two dimensional (2-D) array. In contrast, the proposed coherence-based method adaptively weights each image pixel based on the coherence of the receive-channel data. It does not make any assumption about the source of the focusing errors and has been shown to be effective using 1-D arrays. This study tested its in vivo performance using clinical breast data acquired by a programmable system with a 5 MHz, 128-channel linear array. Twenty-five cases (6 fibroadenomas, 10 carcinomas, 6 cysts, and 3 abscesses) were investigated. Relative to nonweighted imaging, the average improvements in the contrast ratio and contrast-to-noise ratio for the coherence-based method were 8.57 dB and 23.2%, respectively. The corresponding improvements when using the correlation-based method were only 0.42 dB and 3.35%. In an investigated milk-of-calcium case, the improvement in the contrast was 4.47 dB and the axial and lateral dimensions of the object were reduced from 0.39 to 0.32 mm and from 0.51 to 0.43 mm, respectively. These results demonstrate the efficacy of the coherence-based method for clinical ultrasonic breast imaging using 1-D arrays. PMID- 17703672 TI - Characteristics of pure-shear mode BAW resonators consisting of (1120) textured ZnO films. AB - Thickness pure-shear mode film bulk acoustic wave resonators (FBARs) made of (1120) textured ZnO films have been fabricated. We also have fabricated FBAR structure consisting of two layers of the (1120) textured ZnO film with opposite polarization directions. This FBAR structure operated in second overtone pure shear mode and allowed shear-mode FBARs at higher frequency. The effective electromechanical coupling coefficients k2 of pure-shear mode FBAR and second overtone pure-shear mode FBAR in this study were found to be 3.3% and 0.8%, respectively. The temperature coefficient of frequency (TCF) of thickness extensional mode FBAR, pure-shear mode FBAR, and second overtone pure-shear mode FBAR were measured in the temperature range of 10-60 degrees C. TCF values of 63.1 ppm/degrees C, -34.7 ppm/degrees C, and -35.6 ppm/degrees C were found for the thickness extensional mode FBAR, the pure-shear mode FBAR, and the second overtone pure-shear mode FBAR, respectively. These results demonstrated that pure shear mode ZnO FBARs have more stable temperature characteristics than the conventional thickness extensional mode ZnO FBARs. PMID- 17703673 TI - Accurate measurement of anhydride fluorhydric acid concentration in controlled gaseous flow with STW sensors. AB - This paper presents theoretical and experimental developments for the implementation of surface acoustic waves (SAW) sensors able to detect small concentrations of anhydride fluorhydric (HF) acid in air. Solutions based on the use of surface transverse waves (STW) on quartz (YXlt)/36 degrees/90 degrees have been analyzed to evaluate their sensitivity to HF. Devices have been tested first in a NH4F solution to evaluate the kinetics of the reaction. Measurements then were performed under various gaseous conditions to characterize the sensors when they are submitted to different controlled dilutions of HF in air. STW resonators have been successfully tested in different conditions, with capabilities to detect HF concentration much smaller than 1 ppm. PMID- 17703674 TI - Analysis and suppression of side radiation in leaky SAW resonators. AB - This paper discusses side acoustic radiation in leaky surface acoustic wave (LSAW) resonators on rotated Y-cut lithium tantalite substrates. The mechanism behind side radiation, which causes a large insertion loss, is analyzed by using the scalar potential theory. This analysis reveals that side radiation occurs when the guiding condition is not satisfied, and the LSAW most strongly radiates at the frequency in which the LSAW velocities in the grating and busbar regions approximately correspond to each other. Based on these results, we propose a "narrow finger structure," which satisfies the guiding condition and drastically suppresses the side radiation. Experiments show that the resonance Q of the proposed structure drastically improves to over 1000 by suppressing the side radiation, which is three times higher than for a conventional structure. Applying the proposed resonators to the ladder-type SAW filters, ultra-low-loss and steep cut-off characteristics are achieved in the range of 800 MHz and 1.9 GHz. PMID- 17703675 TI - Analysis of a vibrating interventional device to improve 3-D colormark tracking. AB - Ultrasound guidance of interventional devices during minimally invasive surgical procedures has been investigated by many researchers. Previously, we extended the methods used by the Colormark tracking system to several interventional devices using a real-time, three-dimensional (3-D) ultrasound system. These results showed that we needed to improve the efficiency and reliability of the tracking. In this paper, we describe an analytical model to predict the transverse vibrations along the length of an atrial septal puncture needle to enable design improvements of the tracking system. We assume the needle can be modeled as a hollow bar with a circular cross section with a fixed proximal end and a free distal end that is suspended vertically to ignore gravity effects. The initial results show an ability to predict the natural nodes and antinodes along the needle using the characteristic equation for free vibrations. Simulations show that applying a forcing function to the device at a natural antinode yields an order of magnitude larger vibration than when driving the device at a node. Pulsed wave spectral Doppler data was acquired along the distal portion of the needle in a water tank using a 2-D matrix array transesophageal echocardiography probe. This data was compared to simulations of forced vibrations from the model. These initial results suggest that the model is a good first order approximation of the vibrating device in a water tank. It is our belief that knowing the location of the natural nodes and antinodes will improve our ability to drive the device to ensure the vibrations at the proximal end will reach the tip of the device, which in turn should improve our ability to track the device in vivo. PMID- 17703676 TI - The effects of desiccation on skull bone sound speed in porcine models. AB - Pre- and postdesiccation sound speeds through ex vivo porcine skull specimens were determined by time-of-flight measurements with propagated broadband pulses centered at 0.97 MHz (Os 12.7 mm, -6-dB band-width = 58%). The measured longitudinal sound speed in the 13 porcine samples (predesiccation average sound speed = 1727 +/- 57 ms(-1)) changed by a statistically significant +2.3% after deionized water reconstitution (paired t-test, alpha = 0.05, p = 0.0332). PMID- 17703677 TI - Women of the 1950s and the "normative" life course: the implications of childlessness, fertility timing, and marital status for psychological well-being in late midlife. AB - We explore women's psychological well-being in late midlife in relation to childlessness and timing of entry into motherhood. Using two U.S. surveys, Health and Retirement Study (HRS) (1992) and National Survey of Families and Households (NSFH) (Sweet, Bumpass, & Call, 1988), we assess the well-being of childless women in their 50s compared to mothers with early, delayed, or normatively timed first births. We focus on the cohorts born between 1928 and 1941, who experienced strong normative pressures during the baby boom with regard to marriage and child bearing. We find few differences among childless women but lower well-being among early mothers, related to singlehood and poorer socioeconomic status. Unmarried mothers are significantly disadvantaged regardless of maternal timing, controlling for socioeconomic status. Current maternal demands are independently related to well-being and help to explain observed differences in family satisfaction. Overall, childlessness and off-time child-bearing are related to midlife well-being through their link with more proximate factors, particularly current marital status, health, and socioeconomic status. PMID- 17703679 TI - Health and life satisfaction of ethnic minority older adults in mainland China: effects of financial strain. AB - China has achieved indisputable economic growth in the past decades but, with it, unbalanced development across region and socio-economic groups. Little is known about how this impacts the lives of minority older adults who tend to live in remote inland areas. This study is the first attempt to examine and compare the relationships between financial strain, health conditions, and life satisfaction among ethnic minority and non-minority older adults in mainland China. Research data was obtained from respondents aged 60 and over who participated in the National Survey of the Aged Population in China (N = 995) in 2000. Hierarchical linear regression revealed financial strain to be significantly associated with life satisfaction and health, however functional health measurements of ADL were only associated for ethnic minority groups after controlling for socio demographic variables. The impact of underdeveloped socio-economic levels and unfavorable living environments on health and life satisfaction is stronger among minority groups and warrants further attention. PMID- 17703678 TI - Strategic self development for successful aging at work. AB - Two studies involving 265 participants were conducted to assess the content and range of strategies used by employees to age successfully in the workplace. Study 1 included 64 individuals ranging in age from 23 to 61. These individuals were asked to list up to five activities they have pursued in five potentially important areas of development. Content analyses on these activities were then conducted for purposes of item development. In the second study, the sample was limited to 201 older workers, defined as employees age 40 and older. Participants completed several scales examining the frequency with which they engaged in activities related to successful aging at work. Factor analyses indicated seven major types of strategies: 1) Relationship Development, 2) Security, 3) Continuous Learning, 4) Stress-Relief, 5) Skill Extension, 6) Career Management, and 7) Conscientiousness. Analyses indicated that each strategy domain was positively related to perceived success. Furthermore, hierarchical regression analyses indicated that Security, Relationship Development, Continuous Learning, and Career Management strategies were predictive of success above and beyond important characteristics of the individual or employing organization. The results also indicated that age moderated the relationship between strategy use and perceived success for two strategy domains. Relationship Development and Skill Extension strategies were less strongly related to perceived success as employees aged. Implications of these findings are discussed in relation to theory development, application, and future research. PMID- 17703680 TI - The Grey Nomad phenomenon: changing the script of aging. AB - This article explores a relatively new and little understood phenomenon, that of the Australian Grey Nomads. Every year increasing numbers of older Australians take to the road. This article explores the phenomenon both empirically and theoretically. A grounded approach is used by which the experience is explored from an ethnographic account involving interviews with some 400 travelers, including in-depth taped interviews with 26 traveling groups. The data is analyzed and discussed in terms of "Ulyssean" aging. The Ulyssean lifestyle requires the freedom to pursue personal choice and new, personally risky experience. Issues of health, personal development, and social networks are discussed in relation to the literature on aging. In particular, it is argued that the Grey Nomad phenomenon fundamentally challenges the dominant decline model of aging. It presents a picture instead of these older Australians taking active and very positive control of their lives, regardless of financial and health conditions. In doing so, they are rewriting the dominant social script for aging. PMID- 17703681 TI - [After taking non-steroidal anti-inflammatory agents. What is the cause of the "blue spot?" ]. PMID- 17703682 TI - [Patient after abdominal operation in medically futile status. Would you assist him in dying?]. PMID- 17703683 TI - [More labor complications and greater diabetes risk after gestational diabetes. Risky omission of blood glucose testing (interview by Dr. Dirk Einecke)]. PMID- 17703684 TI - [Recognizing gestational diabetes and treatment. What can the family physician do?]. PMID- 17703685 TI - [Where Echinococcus lurks and where not. May wild berries still be consumed without concern? (interview by Dr. Judith Neumaier)]. PMID- 17703686 TI - [Pain management in the family practice. Treat the cause before the pain becomes a disease in itself]. PMID- 17703688 TI - [Basic pain management care by the family physician]. AB - After a cleardiagnosis has been made, many acute as well as chronic pain symptoms can be treated by the family physician on an outpatient basis. For the step therapy of chronic pain, particular attention must be given to the side effects. In some cases, side effects necessitate the use of comedication, such as for nausea, constipation or depression. Particularly complex pain treatments should still be treated by the specialist. PMID- 17703687 TI - [A family physician, a pharmacist and a lawyer take a stand. What must be considered in morphine therapy?]. PMID- 17703689 TI - [Ambulatory pain management for children in the family practice]. AB - Effective pain management is possible for children just as for adults and is especially demanded by all experts. Nevertheless, many children still receive inadequate pain management care, whether it is after operations, for infections or for chronic painful conditions. There are clear therapeutic concepts for the treatment of children even in the family practice which include the use of short acting opioids depending on the intensity of the pain and symptoms. PMID- 17703690 TI - [Patient information. Migraine]. PMID- 17703691 TI - [Heat stress disorder]. PMID- 17703692 TI - [Efficient diagnostics for elevated transaminases]. AB - The diagnosis of the cause of elevated transaminases is carried out stepwise. First, a medical history is taken and a physical examination and sonography of the abdomen are performed. The second step includes laboratory tests for chronic hepatitis B and C, hereditary haemochromatosis, Wilson's disease, autoimmune hepatitis and alpha-1-antitrypsin deficiency. The third step comprises the identification of possible extrahepatic causes. Serological tests to exclude celiac disease should be first carried out when TSH and CK values do not yield an indicative finding. PMID- 17703693 TI - [Reflux disease: standards, news and trends]. AB - Proton pump inhibitors (PPI) are currently the standard treatment for reflux disease. A symptom correlated diagnosis with the help of 24-h-pH-metry and/or multiple intraluminal impedance (MII) allows the objective and differentiated classification of endoscopy-negative patients despite PPI symptoms. PMID- 17703694 TI - [New first line therapy of chronic hepatitis B. Primary therapy goal: effective virus suppression]. PMID- 17703698 TI - The legal status of abortion in the states if Roe v. Wade is overruled. AB - This article explores the legal status of abortion in the States if the Supreme Court overrules Roe v. Wade, 410 U.S. 113 (1973), and Doe v. Bolton, 410 U.S. 179 (1973), as modified by Planned Parenthood v. Casey, 505 U.S. 833 (1992). Although an overruling decision eventually could have a significant effect on the legal status of abortion, the immediate impact of such a decision would be far more modest than most commentators-on both sides of the issue-believe. More than two thirds of the States have repealed their pre-Roe laws or have amended those laws to conform to Roe v. Wade, which allows abortion for any reason before viability and for virtually any reason after viability. Pre-Roe laws that have been expressly repealed would not be revived by the overruling of Roe. Only three States that repealed their pre-Roe laws (or amended them to conform to Roe) have enacted post-Roe laws attempting to prohibit some or most abortions throughout pregnancy. Those laws have been declared unconstitutional by the federal courts and are not now enforceable. Of the less than one-third of the States that have retained their pre-Roe laws, most would be ineffective in prohibiting abortions. This is (1) because the laws, by their express terms or as interpreted, allow abortion on demand, for undefined health reasons or for a broad range of reasons (including mental health), or (2) because of state constitutional limitations. In yet other States, the pre-Roe laws prohibiting abortion may have been repealed by implication, due to the enactment of comprehensive post-Roe laws regulating abortion. In sum, no more than twelve States, and possibly as few as eight, would have enforceable laws on the books that would prohibit most abortions in the event Roe, Doe and Casey are overruled. In the other States (and the District of Columbia) abortion would be legal for most or all reasons throughout pregnancy. Although the long-term impact of reversing Roe could be quite dramatic, the author concludes that the immediate impact of such a decision would be very limited. This article is current through May 1st, 2007. PMID- 17703695 TI - [Treatment in every detected virus replication. New guideline for therapy of hepatitis B publicized]. PMID- 17703699 TI - Fifty years of organ transplants: the successes and the failures. AB - More than fifty years have now passed since the first successful human organ transplant. During that time, substantial progress has been made in both surgical techniques and immunosuppressive drug therapy. As a result, transplant success rates have improved dramatically, and thousands of recipients of kidneys, hearts, livers, and lungs have been granted both longer and healthier lives. At the same time, however, many more thousands of patients have died while waiting in vain for a cadaveric donor organ to become available due to a severe and persistent shortage of such organs. That shortage, in turn, is directly attributable to the National Organ Transplant Act of 1984, which proscribes payment to potential organ donors, even if that would increase supply. This atavistic policy and the shortage and deaths it has spawned provides a stirring example of the tendency for public policy to lag behind technological advancement, particularly in the medical field. But the tide of medical opinion may be turning on this issue, and some form of donor payments may soon emerge. PMID- 17703700 TI - Natural disaster, unnatural deaths: the killings on the life care floors at Tenet's Memorial Medical Center after Hurricane Katrina. AB - This article examines the meaning of the killing of four patients with disabilities on the Life Care ward of Tenet's Memorial Medical Center in New Orleans in anticipation of hurricane Katrina. None were terminally ill. None were in pain. None knew their lives were about to end. None were evacuated. The victims had one thing in common: they all had chosen to be designated as Do Not Resuscitate (DNR) patients. All were killed with overdoses of medications that had not been prescribed for them. Dr. Daniel Nuss of the Louisiana State University School of Medicine and Dr. Floyd Burras, President of the Louisiana Medical Society defend the doctor's actions as involuntary euthanasia or mercy killing. Was this euthanasia, or homicide? At Memorial, the term DNR took on a new meaning--Do Not Rescue. In this new Memorial model, patient autonomy to control and choose one's medical treatment, yields to the physician's unilateral power to arbitrarily decide who lives and who dies. The author concludes that doctors and hospitals must observe the rule of law, even in times of natural disaster. PMID- 17703701 TI - Gonzales v. Carhart. PMID- 17703703 TI - High blood pressure increases costs under capitation. PMID- 17703702 TI - Study: Medicaid P4P needs good coordination between plans and providers. PMID- 17703704 TI - Drug utilization still growing, though price increases moderate for common nonspecialty drugs. PMID- 17703705 TI - Getting into ecstasy: comparing moderate and heavy young adult users. AB - In this article, the authors examine factors associated with initial and present Ecstasy use among young adults. Face-to-face structured interviews were conducted in Atlanta, Georgia among 261 active Ecstasy users. The median age at which respondents first heard of Ecstasy was 16 years, whereas the median age of first Ecstasy use was 18 years. Initial Ecstasy use frequently involved polydrug use, including alcohol (50.4%). In terms of their current use, 47.5% of respondents were considered heavy Ecstasy users (using on 10 or more separate occasions in the last 90 days). White respondents, those who used more than one pill during their initial use, and those who used again within one month after their initial use were more likely to be current heavy Ecstasy users. Women, those who waited a longer time between initial and subsequent Ecstasy use, and those who considered themselves in the upper SES bracket were less likely to be current heavy Ecstasy users. A better understanding of initial and current Ecstasy use patterns, including polydrug use, is essential for effective prevention and intervention efforts. PMID- 17703707 TI - Cannabis and psychosis: what is the link? AB - Growing evidence supports the hypothesis that cannabis consumption is a risk factor for the development of psychotic symptoms. Nonetheless, controversy remains about the causal nature of the association. This review takes the debate further through a critical appraisal of the evidence. An electronic search was performed, allowing to identify 622 studies published until June 1st 2005. Longitudinal studies and literature reviews were selected if they addressed specifically the issues of the cannabis/psychosis relationship or possible mechanisms involved. Ten epidemiological studies were relevant: three supported a causal relationship between cannabis use and diagnosed psychosis; five suggested that chronic cannabis intake increases the frequency of psychotic symptoms, but not of diagnosed psychosis; and two showed no causal relationship. Potential neurobiological mechanisms were also identified, involving dopamine, endocannabinoids, and brain growth factors. Although there is evidence that cannabis use increases the risk of developing psychotic symptoms, the causal nature of this association remains unclear. Contributing factors include heavy consumption, length and early age of exposure, and psychotic vulnerability. This conclusion should be mitigated by uncertainty arising from cannabis use assessment, psychosis measurement, reverse causality and control of residual confounding. PMID- 17703706 TI - Experiences of gamma hydroxybutyrate (GHB) ingestion: a focus group study. AB - GHB (gamma hydroxybutyrate) is a significant new drug of abuse added to the United States Controlled Substance Act in 2000. The majority of the published literature on GHB consists of clinical case reports, mainly from emergency departments, and a collection of laboratory-based studies, focused mainly on anesthesia. While comments about the various experiences and behaviors of human users are often included in such studies or reports, these aspects of GHB are only just beginning to be systematically investigated or detailed. Reported here are data from a qualitative study using focus group methods on the consumption habits, experiences, and beliefs of GHB users. A total of 51 people, 30 men and 21 women, mean age of 31.1+/-7.6 years (range 18 to 52 years), who report having used GHB for an average of 4.3+/-2.5 years (range one to 11 years), were interviewed in 10 separate groups held in 2004. This article discusses broadly the general experience of the GHB high, major perceived benefits including sexual responses to the drug, perceived risks and dangers of ingestion, co-ingestion, and various contexts of use. It concludes with a discussion of the implications drawn from this information for clinicians treating patients who use GHB. PMID- 17703708 TI - Subjective effects of Salvia divinorum. AB - Salvia divinorum is a hallucinogenic plant native to Mexico, where the Mazatec Indians use it in divinatory rituals as a facilitator for contacting the spirits of the dead. A number of traditions surrounding the ritualistic use of Salvia are still observed. Generally the leaves are chewed for the visionary effects. Salvia has recently been embraced by Western drug cultures, where the traditional methods of ingestion are generally eschewed for the more immediately effective technique of smoking the dried leaves. This article discusses the history and indigenous cultural uses of Salvia before outlining its rediscovery in the 1960s and its subsequent introduction to the Western drug scenes (particularly Britain) since the mid 1990s. Qualitative data from 10 Salvia users were collected by means of email interviews. The participants were asked to provide as in-depth responses as possible. No time or space limit on answers was imposed. Their responses to each question are presented verbatim. The effects of Salvia appear to vary between users and seem sensitive to situational factors. Users who understand something of the ritualistic setting for traditional use would appear to have a fuller experience than those who do not. PMID- 17703709 TI - Self-medication hypothesis of substance use: testing Khantzian's updated theory. AB - Substance use research has been a salient focus for mental health professionals in recent years. Several organizations, including the American Psychological Association, have been pressing for more substance use research, particularly clinically relevant, theory-based investigations. However, there are few theories of substance use, and even fewer with scientific support. One theory is the Self Medication Hypothesis by Khantzian (1977, 1974), a theory with 30 years of research. However, recent modifications in Khantzian's theory (1999) have not been properly tested. Specifically, two areas require further investigation: Khantzian's belief that more negative affect should be related directly to more substance use, and expanding the number of affective states examined, including alexithymia, to better operationalize Khantzian's belief that several painful and ambiguous forms of affect may be implicated in the self-medicating process. The current study assessed anxiety, depression, hostility and alexithymia levels in 70 methadone maintenance treatment patients. Results indicated that affective measures did not have the expected relationship with reported substance use. The authors advocate for the exploration of multiple factors, not merely emotional regulation, in the variability of substance use. PMID- 17703711 TI - An open-label pilot study of risperidone in the treatment of methamphetamine dependence. AB - Psychopharmacological treatments for methamphetamine (MA) dependence have questionable efficacy. Open-label risperidone was evaluated in veterans seeking MA dependence treatment. Participants (N = 11) received four weeks of risperidone. They provided weekly self-reports of substance use, urine drug screens, and adverse effects. Neuropsychological assessments and psychiatric symptomatology (Brief Symptom Inventory; BSI) were measured at baseline and follow-up. The eight completers had an average risperidone dose of 3.6 mg/day and decreased days of MA use during the trial from a mean of 13.0 (SD = 6.5) in the 30 days prior to starting risperidone to a mean of 0.125 (SD = 0.4; t = 5.7, p = .001), When measured over time, fine motor function (Grooved Peg Board Dominant Hand) was the only neuropsychological domain to improve significantly. No other domain changed significantly from baseline to follow-up among study completers. BSI data were converted to demographically corrected T-scores utilizing appropriate normative data (mean = 50, SD = 10). BSI somatization T-scores declined from a mean of 59.0 (SD = 8.4) to 51.8 (SD = 8.3; t = 2.7, p <.05), and positive symptom distress declined from a mean of 52.8 (SD =8.0) to 41.7 (SD = 8.6; t= 3.0, p <.05). Risperidone was well tolerated and associated with decreased MA use. PMID- 17703710 TI - The relationship between lifetime abuse and suicidal ideation in a sample of injection drug users. AB - This study examined the relationship between lifetime abuse and suicidal ideation in a sample of 245 injection drug users (IDUs) who attended the Baltimore Needle Exchange Program and received a referral for opiate agonist therapy. Data were obtained from baseline interviews and HIV antibody tests. The sample mean age was 42.2 (SD = 8.1 ); 77% were African American; 69% were male. Overall, 27% reported thoughts of suicide in the last six months, and lifetime emotional, physical and sexual abuse was reported by 17%, 12% and 10%, respectively. In bivariate analyses, recent suicidal ideation was associated with emotional (odds ratio [OR] = 3.2; p = 0.001), physical (OR = 2.5; p = 0.026), and sexual abuse (OR = 5.0; p < 0.001). In multiple logistic regression models controlling for HIV status and Center for Epidemiological Studies Depression (CES-D) score, individuals who experienced emotional abuse were more than twice as likely to report recent suicidal ideation (adjusted odds ratio [AOR] = 2.6; p = 0.011); those who experienced sexual abuse were four times more likely to report suicidal ideation (AOR = 4.0; p = 0.004). These findings suggest that emotional and sexual abuse might be risk factors for suicidality among IDUs and also might suggest that suicide prevention should be an integral part of drug treatment for treatment seeking IDUs. PMID- 17703712 TI - Mental health provider perspectives on co-occurring substance use among severely mentally ill clients. AB - This qualitative study explores strategies used by mental health providers (N = 17) to address substance use problems among seriously mentally ill (SMI) clients and their perspectives on barriers to treatment and how treatment can be improved. Providers identified numerous strategies, yet these were countered with perceptions of multiple obstacles, leaving them frustrated, helpless, and hopeless about their clients' substance use. Results suggest that, in addition to improving access to quality dual-diagnosis treatment, larger issues of poverty and social isolation must also be addressed. Not doing so limits what providers can do for SMI clients and could reduce the effect of larger system-level improvements. PMID- 17703713 TI - A faith-based intervention for cocaine-dependent Black women. AB - The purpose of the present study was to obtain preliminary data on the effectiveness of a faith-based treatment adjunct for cocaine-using homeless mothers in residential treatment. The Bridges intervention utilizes various Black church communities to provide culturally-relevant group activities and individual mentoring from volunteers. Eighteen women who were recent treatment admissions were randomly assigned to receive Standard Treatment plus Bridges or Standard Treatment with an Attention Control. Participants were assessed at intake and three and six months after intake. Bridges treatment resulted in significantly better treatment retention (75% vs. 20% at six months) than standard residential treatment alone. In addition, Bridges produced superior outcomes at the six month follow-up assessment on a secondary measure of cocaine abstinence. Creating a community of social support through Black churches appears feasible and promising, and may be a cost-effective means of providing longer-term post treatment support for cocaine-addicted women. PMID- 17703714 TI - Mobility of hard drug users: patterns and characteristics relevant for deconcentration of facilities. AB - Mobility is related to problematic hard drug use. It remains unclear, however, to what extent the availability of care facilities attracts drug users. The aim of the study is to gain insight into the mobility of problematic hard drug users, with particular focus on the possibilities for deconcentration of facilities. Quantitative and qualitative methods were used: a survey and in-depth interviews with problematic hard drug users. The results show that the extent of mobility is not related to specific characteristics of the target group. The most relevant concepts related to possible deconcentration/displacement of problematic drug users are the nature of mobility and visibility of the users. A high level of mobility does not necessarily lead to more visibility and nuisance. Having a structured daily pattern (housing and/or working) largely determines visibility. More purposeful movement of drug users is associated with a lower level of visibility and nuisance. Mobility of users is strongly determined by the need to buy drugs. Low-threshold facilities are not a trigger for mobility as such, and need to be located near places where drug users stay and/or close to well-known dealing areas. PMID- 17703715 TI - The effect of extreme marijuana use on the long-term course of bipolar I illness: a single case study. AB - The effect of marijuana on bipolar disorder has never been systematically evaluated. Subjective reports by patients suggest an overall positive effect, but these may be unreliable. We herein report a case in which mood data was prospectively collected over two years of total substance abstinence and two years of extreme marijuana use. Marijuana use did not alter the total number of days of abnormal mood, however, marijuana was associated with an increase in the number of hypomanic days and a decrease in the number of depressed days. While not conclusive, the data suggest that marijuana may indeed have an effect on mood in bipolar patients that needs to be systematically examined. PMID- 17703716 TI - Did this CNA strike this nursing home patient? Collins v. North Carolina Dep't of Health and Human Services, 2006 COA05-1487 S.E.2nd. PMID- 17703717 TI - Nurse's pleadings in wrongful termination case deficient. Case on point: Lagace v Mills Peninsula Hospital, No. A113911 (Cal.App. Dist.1 01/29/2007) -CA. PMID- 17703718 TI - FL: five-year delay in discipline action v. LPN: nurse failed to prove denial of due process. Henderson v. Department of Health, No. 5D06-977 (Fla. App. 04/13/2007) So.2d -FL. PMID- 17703719 TI - The reference you give may come back to bite you. Case on point: Kevorkian v. Glass, 913 a.2d 1043 -RI (2007). PMID- 17703720 TI - Viscosity of hydrogel pharmaceutical products and the rate of diffusion of ibuprofen hydrotropic binding through model phase boundary in vitro. AB - The aim of the carried out investigations was to establish relation between rheological parameters of market hydrogels containing ibuprofen and therapeutic agent diffusion coefficient dependent on their prescription. An attempt was made to estimate rheological parameters (structural viscosity, kinetics of volatile components loss) effect on pharmaceutical availability Q and the order of the process of mass exchange through artificial and natural phase boundary. Designed for skin anti-inflammatory hydrogels containing ibuprofen in the form of hydrotropic adduct with lysine (Ibufen, Dolofast), in the form of sodium salt (Nurofen) and in the form of molecular fragmentation of acidic form (Dolgit) were tested. The rate of volatile components loss was estimated with gravimetric method, viscosity measurements of therapeutic agents aqueous solutions were performed with Ubbelohde viscosimeter, while hydrogels rheological parameters - with cone-plate digital rheometer. The rate of ibuprofen penetration through phase boundary (Viscing dialysis membrane and pig perimastoid dermis) into dialysis fluid was determined in vitro. The kinetics of this process was monitored by measuring electric conduction Deltalambda = f(t) of model dialysis fluid. Viscometric measurements of aqueous solutions of ibuprofen lysine salt and ibuprofen sodium salt, by determining boundary viscosity gradient GLL(eta) and calculation of hydrodynamic radius Robs, enabled the applicative solution of Einstein-Smoluchowski equation (D = kT/6Pi r eta) and the estimation of structural value of therapeutic agent diffusion coefficient. Tracing the dependence between diffusion coefficient and shear rate enabled to recognize the preferences of preparations to the process of mass exchange on the phase boundary. An association was confirmed between the determined and calculated rheological parameters and the process of mass exchange on phase boundary through selected dialysis membranes. Mass exchange on phase boundary was found to be the derivative of the process of diffusion and its quantitative aspect depends on the kind of the applied membrane (it is the function of the quantity of statistically distributed pores on the unit of its surface [cm2]). Ibuprofen penetration through an artificial and natural phase boundary is complex. Its mechanism is between the kinetics of "0" and "II" order. The quantitative differentiation of the process of mass exchange between hydrotropic ibuprofen forms: ibuprofen lysine salt > ibuprofen sodium salt > ibuprofen in the form of acid molecule results from the carried out experimental study. PMID- 17703721 TI - [The evaluation of the properties of the silicone-rod and tissue reation after 5,5 years period of implantation]. AB - In this study we presented a case of prolonged detention of the temporary flexor tendon prosthesis after implantation in the hand. The silicone-rod removed after more than 5 years was subject to an examination: scanning microscopy, measurement of hardness, scanning differential calorimetry, spectroscopy in infra-red and resistance examinations. The obtained results were compared with a findings after examinations of the new, not used silicone-rod. The greatest changes were observed in maximum value of tensile strength (sigmaB) of the material after test of uniaxial tensile tests, which was about 30% smaller for a silicone-rod after implantation. The other result of investigations didn't reveal an important differences between a new and a used rod. The comparison of the tissue reaction was performed by collection a part of sheath in described case and a part of sheath produced around a rod after 10 weeks period of implantation. The generation of a capsules consisted of fibrous connective tissue with concomitant inflammation process was observed in both cases in histopathological view. Silicone rubber is a material which preserve its most important properties even after prolonged period of implantation. PMID- 17703722 TI - [Influence of material on biocompatibility of intraocular lenses]. AB - There are many types of intraocular lenses (IOL), different in optic features and materials. The first indication for IOL implantation was aphakia after cataract surgery. The problem of aphakia exists as long as cataract is treated, that is at least 45 hundreds of years. Correction of aphakia using glasses is uncomfortable for patients and even impossible in some cases. The invention of an artificial intraocular lens was a crucial event in the history of ophthalmology. Nowadays there are more indications for cataract surgery and implantation of intraocular lens, including correction of refractive errors. The first intraocular lenses were made of rigid plastic: polymethylmethacrylate (PMMA). In present times foldable intraocular lenses made of soft material: silicone, hydrogel and acrylic compounds are also produced. In this paper 4 groups of intraocular lenses: PMMA, silicone, hydrogel, acrylic and their influence on biocompatibility are discussed. This article contains also description of two types of IOL biocompatibility: uveal and capsular. Their clinical aspects, especially posterior capsule opacification are discussed. Factors affecting biocompatibility are shortly described. Some historical applications of IOL are presented. Regarding the latest experimental studies on improving IOL biocompatibility, results of IOL surface modification tests are presented. New perspective technologies of intraocular artificial lens production such as single crystal materials are also discussed. PMID- 17703724 TI - Membrane transport of the non-homogeneous non-electrolyte solutions: mathematical model based on the Kedem-Katchalsky and Rayleigh equations. AB - Mathematical model of the volume and solute flows through artificial polymeric membrane under occurrence of the concentration boundary layers on both sides of this membrane is presented. This nonlinear model, based on the Kedem-Katchalsky and Rayleigh equations, describes the volume flux generated by osmotic and hydrostatic forces, thicknesses of the concentration boundary layers, concentrations and hydrostatic pressures on the membrane-concentrations boundary layers' borders. Besides, this model shows that the volume flows and individual forces causes the flows influences on the thickness of concentration boundary layers. The nonlinear equations for volume flux, concentration and thickness of concentration boundary layers can be used to numerical calculation in linear regime of the hydrodynamical stability. PMID- 17703723 TI - [Polymer and oligomer based doxorubicin carriers]. AB - Doxorubicin and other anthracycline derivatives play an important role in the treatment of many malignant diseases. Unfortunately, clinical effectiveness of this class of drugs is limited by cumulative cardiotoxicity which occurs in significant percentage of patients at cumulative dose in the range 450-600 mg/m2. Therefore, several strategies have been developed to reduce cardiotoxicity of doxorubicin and its analogues. One of the possible ways leading to the improvement of anticancer selectivity of doxorubicin is the design of polymer and olygomer carriers which may transport drug molecules more efficiently and more specifically. Synthetic polymers are of increasing interest as therapeutic agents owing to their enhanced pharmacokinetic profiles relative to small molecule drugs. Currently a new class of multifunctional polymers is being prepared that can "mask" biologically active compounds, such as cytotoxic agents, until they reach target sites, but which can then release the agent in situ to effect the therapy. The legitimacy of the development of polymer based doxorubicine carriers is supported by the growing number of clinical reports indicating that the use of hydrophilic polymers or polymer coated liposomes as a platform for delivery of the drug results in better therapeutic effects than the free drug. In this article we present the most promising strategies directed at the development of improved anthracycline drugs formulations based of polymer and olygomer carriers. We review: 1) polyethylenoglycol-coated ("pegylated") liposomal doxorubicin; 2) extracellulary tumor-activated prodrugs which are conjugates of doxorubicin with peptides; 3) doxorubicin coated by higly polymerised glycosoaminoglycans; 4) conjugates of doxorubicin with copolymer of N-(2-hydroxypropyl)methacrylamide. PMID- 17703725 TI - Membrane transport of the non-homogeneous ternary solutions: mathematical model of thicknesses of the concentration boundary layers. AB - We have presented the mathematical model, which can be the basis of determination of a numerical algorithm for the thickness of concentration boundary layers calculation for ternary nonelectrolyte solutions. This model is based on Rayleigh equation and second Kedem-Katchalsky equation for ternary solutions. In proposed model, the thickness of concentration boundary layers is controlled by concentration Rayleigh number. PMID- 17703726 TI - [Mathematical model of the membrane transport of ternary non-electrolyte solutions: the role of volume flows in creation of concentration boundary layers]. AB - The mathematical model of the thickness of concentration boundary layers controlling by concentration Rayleigh number and volume flows for ternary non electrolyte solution was presented. The equations determining of this model can be used to numerical calculations. PMID- 17703727 TI - Chemical Constituents from the Stems of Morinda citrifolia Linn. AB - Studies on the chemical constituents of the stems of Morinda citrifolia, Linn. have led to the isolation of two new compounds, morindicone (9-hydroxy-2-methoxy 4-methyl-3,10-anthracenedione, 1) and morinthone (4-methoxy-3-heptadecylxanthone, 2), as well as two known constituents, 1-hydroxy-2-methylanthraquinone (3) and 2 hydroxymethylanthraquinone (4). Their structures were elucidated by spectral analysis including 2D NMR techniques. PMID- 17703728 TI - Two new coumarin glucosides from the roots of Angelica apaensis and their anti platelet aggregation activity. AB - Two new coumarin glucosides, 11-O-beta-D-glucopyranosyl thamnosmonin (1) and 12-O beta-D-glucopyranosyl gosferol (2), were isolated from the roots of Angelica apaensis. Their structures were elucidated spectroscopically. Both compounds showed weak inhibitory effects on rabbit platelet aggregation induced by PAF, AA and APD. PMID- 17703729 TI - Synthesis and anti-inflammatory activity of certain piperazinylthienylpyridazine derivatives. AB - In this study, a novel series of 2-(4-substituted piperazin-l-ylmethyl)-6-(thien 2-yl)-2H-pyridazin-3-ones (3a-f), 2-(4-substituted piperazin-l-yl carbonylmethyl) 6-(thien-2-yl)-2H-pyridazin-3-ones (4a-c) and 2-[2-(4-substituted piperazin-l ylcarbonylethyl)]-6-(thien-2-yl)-2H-pyridazin-3-ones (5a,b) were prepared from 6 (thien-2-yl)-2H- pyridazin-3-one (1). In addition, 3-(4-substituted piperazin-l ylcarbonyl methyl thio)-6-(thien-2-yl) pyridazines (6a-c) and 3-[2-(4 substitutedpiperazin-1-ylcarbonyl ethylthio]-6-(thien-2-yl) pyridazines (7a,b) were synthesized. Furthermore, 5-(4-substituted piperazin-l-ylmethyl)-6-(thien-2 yl)-2H-pyridazin-3-ones (12a,b) were prepared. The structures of the new compounds were confirmed by elemental analysis as well as by 1H-NMR, IR and MS data. Some of the newly prepared compounds were subjected to evaluation for their anti-inflammatory activity against carrageenan-induced paw edema at a dose of 10 mg/kg using indomethacin as the reference standard. PMID- 17703730 TI - Cephalosporolides H and I, Two Novel Lactones from a Marine-Derived Fungus, Penicillium sp. AB - Two novel lactones, Cephalosporolides H (1) and 1 (2), were isolated from the lyophilized culture broth of the marine-derived fungus, Penicillium sp. The structures were elucidated on the basis of extensive 1D- and 2D-NMR, as well as HRESI-MS spectroscopic analyses. The relative stereochemistries of the compounds were assessed by comparison of the NOESY analysis and spectral data with those in the literature. PMID- 17703731 TI - Isocoumarin Derivatives from the Sea Squirt-derived Fungus Penicillium stoloniferum QY2-10 and the Halotolerant Fungus Penicillium notatum B-52. AB - Two isocoumarin derivatives, stoloniferol A (1) and B (2), a known 5alpha, 8alpha epidioxy-23-methyl-(22E, 24R)-ergosta-6, 22-dien-3beta-ol (3), and a known dihydrocitrinone (4) were isolated from the ethyl acetate extract of the sea squirt-derived fungus, Penicillium stoloniferum QY2-10, and a halophilic fungus, Penicillium notatum B-52, respectively. Their structures were elucidated by spectroscopic methods and optical rotation. The stereochemistry of 2 was determined on the basis of different NOE experiments and chemical transformation. Compound 3 showed cytotoxicity against P388 cells, with an IC50 value of 4.07 microM. PMID- 17703732 TI - Effects of triterpenoids and flavonoids isolated from Alnus firma on HIV-1 viral enzymes. AB - Triterpenoids and flavonoids isolated from Alnus firma S. Z. were found to inhibit HIV-1 virus replication and controlled its essential enzymes. In this study, the inhibition of HIV-1 viral replication and its essential enzymes, such as reverse transcriptase, protease and alpha-glucosidase, were observed using 18 Korean plant extracts. Among the extracts, the methanol extract of Alnus firma leaves showed potent inhibition against the HIV-1 induced cytopathic effect (CPE) in MT-4 cells on microscopic observation (the minimum concentration for complete inhibition of HIV-1 induced CPE, IC=50 microg/mL). Thus, 14 compounds were isolated and identified from the methanol extract of Alnus firma leaves. Of these compounds, the alnustic acid methyl ester exhibited inhibition against HIV-1 protease, with an IC50 of 15.8 microM, and quercetin, quercitrin and myricetin 3 O-beta-D-galactopyranoside displayed inhibition against HIV-1 reverse transcriptase, all with IC50 values of 60 microM. Based on these results, the viral replication inhibition of the methanol extract of Alnus firma leaves was adjudged to be acutely related to the protease inhibition activation of the alnustic acid methyl ester as well as the reverse transcriptase inhibition activation of flavonoids. PMID- 17703733 TI - Plant phenolics as prolyl endopeptidase inhibitors. AB - Prolyl endopeptidase (PEP, EC 3.4.21.26), a serine protease, is widely distributed in various organs, particularly in the brains of Alzheimer's disease patients. The expression of PEP in Alzheimer's patients has been found to be significantly higher than that of the normal person, suggesting that a specific PEP inhibitor can be a good candidate for an anti-amnestic drug. In the current study, thirty-nine plant phenolics were investigated to determine their roles as prolyl endopeptidase (PEP) inhibitors. Nineteen compounds such as 1,2,3 trigalloyl glucopyranoside, 1,2,6-trigalloyl glucopyranoside, 1,2,3,4,6 pentagalloyl gluco-pyranoside, 1,2,6-trigalloyl alloside, 1,3,6-trigalloyl alloside, 1,2,3,6-tetragalloyl alloside, acetonyl geraniin, corilagin, elaeocarpusin, euphorscopin, geraniin, helioscopin B, helioscopinin A, helioscopinin B, jolkinin, macranganin, rugosin E, supinanin, and teracatain exhibited strong inhibition against PEP (IC50 26.7 - 443.7 x 10(-9) M). Rugosin E (IC50 26.7 x 10(-9) M) showed the most effective inhibition followed by 1,2,6 trigalloyl glucopyranoside (IC5031.4 x 10(-9) M) and macranganin (IC5042.6 x 10( 9) M). No significant structure-activity relationship was found; however, at least, three pyrogallol groups seem to be a minimal requirement for stronger activity against PEP All 19 active compounds inhibited PEP in a non-competitive mode with a substrate in Dixon plots. They did not show significant effects against other serine proteases such as trypsin, chymotrypsin and elastase, indicating that they were relatively specific PEP inhibitors. PMID- 17703734 TI - The effect of tripeptide-copper complex on human hair growth in vitro. AB - The tripeptide-copper complex, described as a growth factor for various kinds of differentiated cells, stimulates the proliferation of dermal fibroblasts and elevates the production of vascular endothelial growth factor, but decreased the secretion of transforming growth factor-beta1 by dermal fibroblasts. Dermal papilla cells (DPCs) are specialized fibroblasts, which are important in the morphogenesis and growth of hair follicles. In the present study, the effects of L-alanyl-L-histidyl-L-lysine-Cu2+ (AHK-Cu) on human hair growth ex vivo and cultured dermal papilla cells were evaluated. AHK-Cu (10(-12) - 10(-9) M) stimulated the elongation of human hair follicles ex vivo and the proliferation of DPCs in vitro. Annexin V-fluorescein isothiocyanate/propidium iodide labeling and flow cytometric analysis showed that 10(-9) M AHK-Cu reduced the number of apoptotic DPCs, but this decrease was not statistically significant. The ratio of Bcl-2/Bax was elevated, and the levels of the cleaved forms of caspase-3 and PARP were reduced by treatment with 10(-9) M AHK-Cu. The present study proposed that AHK-Cu promotes the growth of human hair follicles, and this stimulatory effect may occur due to stimulation of the proliferation and the preclusion of the apoptosis of DPCs. PMID- 17703735 TI - Activities of clindamycin, synercid, telithromycin, linezolid, and mupirocin against Gram-positive coccal strains resistant to erythromycin in Korea. AB - The antibacterial activities of clindamycin, synercid, telithromycin, linezolid and mupirocin were evaluated against erythromycin-resistant Gram-positive coccal clinical isolates collected in Korean hospitals. In Staphylococcus aureus, synercid, linezolid and mupirocin were the most active agents. Against coagulase negative staphylococci (CNS), synercid, linezolid and mupirocin were also active. Telithromycin and synercid resistance was common against enterococci, only linezolid and mupirocin were active. The reason of low activity of telithromycin against staphylococci and enterococci is because most of the isolates were constitutively resistant to erythromycin. Synercid, telithromycin, linezolid and mupirocin were active against streptococci. PMID- 17703736 TI - A study on the antitumoral and differentiation effects of peganum harmala derivatives in combination with ATRA on leukaemic cells. AB - Plant derived agents may exert a new approach to the treatment of leukaemia. The present study was an evaluation of proliferation, cytotoxicity and differentiation of harmine and harmaline on HL60 cells, alone or in combination with ATRA and G-CSF. Counting of cells, viability, MTT assay, morphology, NBT reduction and flow cytometry analysis were performed using CD11b and CD 14 monoclonal antibodies. The data showed that harmine and harmaline reduced proliferation in dose and time dependent manner. Optimal antiproliferative concentration of these agents was chosen. However, both agents in higher doses were cytotoxic. Combination of ATRA, G-CSF and each agent alone, particularly harmaline in optimal dose, resulted in partially additive decrease in cell proliferation. Cells treated with both harmaline and ATRA demonstrated some morphological changes and NBT positivity, but the extent of changes observed following treatment with harmaline was less than ATRA. Flow cytometric analysis showed that ATRA induced a neutrophilic differentiation, while harmaline led to a predominantly monocytic differentiation. Combination of harmine and harmaline with ATRA and G-CSF did not change the extent of differentiation, and the cells differentiated into the neutrophilic lineage. This shows that the direction of differentiation is dominantly determined by ATRA. These preliminary data implies a new approach in treatment of leukemia. PMID- 17703737 TI - Protective effect of magnolol on TBHP-induced injury in H460 cells partially via a p53 dependent mechanism. AB - The aim is to investigate the effect of Magnolol preserved H460 cells from an oxidative agent tert-butylhydroperoxide (TBHP)-induced cell death. Magnolol augmented cell survival ratio after TBHP challenged. The protective action of this drug was more efficacious than that of N-acetylcysteine (NAC) which is a putative antioxidant. DNA damage, detected by the comet assay, was diminished after treatment of Magnolol. The cells viability decreased after treatment with 0.15 mM TBHP for 24 h, accompanied by inducing apoptotic death of the cells. Cytotoxicity and apoptosis induced by TBHP were significantly inhibited or attenuated after pretreatment with 20 microM Magnolol. Magnolol contributes to the cells survival through downregulated the p53 phosphorylation and PTEN expression, and upregulated Akt phosphorylation. Taken together, Magnolol was effective against DNA single strand breaks (SSB) formation, cytotoxicity and lipid peroxidation induced by TBHP, and its effects on p53 phosphorylation, PTEN and Akt phosphorylation were due to its antioxidative function, and partially via a p53 dependent mechanism in this protective effects. PMID- 17703738 TI - Effects of tributyltin acetate on dopamine biosynthesis and L-DOPA-induced cytotoxicity in PC12 cells. AB - The effects of tributyltin acetate (TBTA) on dopamine biosynthesis and L-3,4 dihydroxyphenylalanine (L-DOPA)-induced cytotoxicity in PC12 cells were examined. TBTA at concentrations of 0.1-0.2 microM inhibited dopamine biosynthesis by reducing tyrosine hydroxylase (TH) activity and TH gene expression in PC12 cells. TBTA at 0.1-0.4 microM also reduced L-DOPA (20-50 microM)-induced increases in dopamine content for 24 h in PC12 cells. TBTA at concentrations up to 0.3 microM did not affect cell viability. However, TBTA at concentrations higher than 0.4 microM caused apoptotic cytotoxicity. Exposure of PC12 cells to non-cytotoxic (0.1 and 0.2 microM) or cytotoxic (0.4 microM) concentrations of TBTA with L-DOPA (20, 50 and 100 microM) significantly increased the cell loss and the percentage of apoptotic cells after 24 or 48 h compared with TBTA or L-DOPA alone. These data suggest that TBTA inhibits dopamine biosynthesis and enhances L-DOPA-induced cytotoxicity in PC12 cells. PMID- 17703739 TI - Activation of professional antigen presenting cells by acharan sulfate isolated from giant African snail, Achatina fulica. AB - Acharan sulfate isolated from the giant African snail, Achatina fulica, has been reported to have antitumor activity in vivo. In an effort to determine the mechanisms of its antitumor activity, we examined the effects of acharan sulfate on professional antigen presenting cells (APCs). Acharan sulfate increased the phagocytic activity, the production of cytokines such as TNF-alpha and IL-1beta, and the release of nitric oxide on a macrophage cell line, Raw 264.7 cells. In addition, acharan sulfate induced phenotypic and functional maturation of immature dendritic cells (DCs). Immature DCs cultured with acharan sulfate expressed higher levels of class II MHC molecules and major co-stimulatory molecules such as B7-1, B7-2, and CD40. Functional maturation of immature DCs cultured in the presence of acharan sulfate was confirmed by the increased allostimulatory capacity and IL-12 production. These results suggest that the antitumor activity of acharan sulfate is partly due to the activation of professional antigen presenting cells. PMID- 17703740 TI - Preparation and evaluation of ketorolac tromethamine gel containing genipin for periodontal diseases. AB - Ketorolac tromethamine gel (KT gel) and ketorolac tromethamine gel containing genipin (KTG gel) were prepared and their therapeutic effects on periodontitis were evaluated. The skin permeation rate of ketorolac from the KT gel and KTG gel was 5.75+/-0.53 and 5.82 +/- 0.74 microg/cm2/ h, respectively. The skin permeation rate of genipin from the KTG gel was 10.13 +/- 1.47 microg/ cm2/h. The tensile strength of the KTG gel was larger than the KT gel. After 4 weeks, the periodontal pocket depth of the KTG gel group (3.22 +/- 0.20 mm) significantly decreased compared with the non-treated group (4.50 +/- 0.25 mm) and the KT group (3.84 +/- 00.26 mm). The KTG gel did not induce separation of the stratum corneum and subcutaneous tissue, and the collagen layers of the corium were closer, more fibrous, and showed longer connections than in the other groups. The KTG gel appears to be effective against gingivitis in the periodontal pocket through its increased anti-inflammatory activity and the crosslinking of genipin with the biological tissue. PMID- 17703742 TI - Matrix properties of a new plant gum in controlled drug delivery. AB - A new plant gum, Okra (extracted from the pods of Hibiscus esculentus), has been evaluated as a controlled-release agent in modified release matrices, in comparison with sodium carboxymethyl cellulose (NaCMC) and hydroxypropylmethyl cellulose (HPMC), using Paracetamol as a model drug. Tablets were produced by direct compression and the in-vitro drug release was assessed in conditions mimicking the gastro intestinal system, for 6 h. Okra gum matrices provided a controlled-release of Paracetamol for more than 6 h and the release rates followed time-independent kinetics. The release rates were dependent on the concentration of the drug present in the matrix. The addition of tablet excipients, lactose and Avicel, altered the dissolution profile and the release kinetics. Okra gum compared favourably with NaCMC, and a combination of Okra gum and NaCMC, or on further addition of HPMC resulted in near zeroorder release of paracetamol from the matrix tablet. The results indicate that Okra gum matrices could be useful in the formulation of sustained-release tablets for up to 6 h. PMID- 17703741 TI - Degradation kinetics of water-insoluble lauroyl-indapamide in aqueous solutions: prediction of the stabilities of the drug in liposomes. AB - The aim of this study was to explore the degradation kinetics of water-insoluble lauroyl-indapamide in solutions and predict the stabilities of lauroyl-indapamide encapsulated in liposomes. Buffer-acetone (9:1) was used as the reaction solution and the reaction temperature was maintained at 60 degrees C. The correlation of the apparent degradation constants (k(obs)) of lauroyl-indapamide in liposomes and in buffer-acetone solutions at different pH has been explored. The degradation of lauroyl-indapamide in solutions was found to follow pseudo-first order kinetics and was significantly dependent on the pH values. Lauroyl indapamide was the most stable at pH 6.8, increasing or decreasing the pH of the solutions would decrease its stabilities. Buffer concentration had some effects on the stabilities of lauroyl-indapamide. The degradation active energies Ea were 68.19 kJ x mol(-1), 131.75 kJ x mol(-1) and 107.72 kJ x mol(-1) at pH3.6, 6.8 and 12 respectively in acetone-free buffer solutions (0.05M) calculated according to the Arrhenius equation with the extrapolation method. The apparent degradation constants (kobs) of lauroyl-indapamide in liposome and in buffer-acetone (9:1) solutions showed a good correlation at different pH levels, which indicates that the stabilities of the drug that dissolved in acetone-buffer mixture solutions can be used to predict the stabilities of the drug in liposomes as well. PMID- 17703743 TI - Determination of bevantolol in human plasma by high performance liquid chromatography using solid phase extraction technique. AB - A method was developed and fully validated for the determination of bevantolol, an adrenergic-receptor blocker, in human plasma. Bevantolol and betaxolol as internal standard (I.S) were extracted from 1 mL of human plasma by solid phase extraction technique using Sep-pak silica cartridge. Chromatographic separation was accomplished under isocratic conditions using a reverse-phase C8 analytical column and mixture of dibasic ammonium phosphate (pH 5.7; 50 mM)-acetonitrile (75:25, v/v) as mobile phase, with a detection wavelength at 220 nm. The method was proved to be specific by testing six different human plasma sources. Linearity was established for the concentration ranges of 40-1600 ng/mL with correlation coefficent of 0.9995. The lower limit of quantification 40 ng/mL with precision of 10.9% as C.V%. PMID- 17703744 TI - The effect of 1-furan-2-yl-3-pyridine-2-yl-propenone on pharmacokinetic parameters of warfarin. AB - 1-Furan-2-yl-3-pyridine-2-yl-propenone (FPP-3) is an investigatory drug which has a dual inhibitory action on cyclooxygenase (COX) and 5-lipoxygenase (5-LOX). We examined its effect on the pharmacokinetics of warfarin. Three consecutive days of pretreatment with 17 mg/kg of FPP-3 had no significant effect on the pharmacokinetic parameters of warfarin when orally administered to rats. A higher dosage of FPP-3 however, did cause significant changes in the pharmacokinetic parameters of wafarin. The cytochrome P450 activity test demonstrated that the metabolism of R-warfarin was significantly inhibited by FPP-3 while there was little or no inhibition of the metabolism of S-warfarin, which is mainly responsible for its anticoagulant effect. Therefore, it appears that the alteration in the pharmacokinetic parameters of warfarin was due to the inhibitory effect of FPP-3 on the metabolism of R-warfarin. Although there was a significant increase in the plasma concentration, the area under the curve, half life of warfarin, and prothrombin time were not significantly changed. Based on these findings, the pharmacokinetic drug interaction between FPP-3 and warfarin mainly involves R-warfarin and, therefore, this interaction may not be of clinical significance in terms of warfarin-related toxicity. PMID- 17703745 TI - Liquid chromatography-electrospray ionization tandem mass spectrometric determination of lornoxicam in human plasma. AB - A rapid, sensitive and selective liquid chromatography-electrospray ionization tandem mass spectrometric (LC-ESI-MS/MS) method for the determination of lornoxicam in human plasma was developed. Lornoxicam and isoxicam (internal standard) were extracted from human plasma with ethyl acetate at acidic pH and analyzed on a Sunfire C18 column with the mobile phase of methanol:ammonium formate (10 mM, pH 3.0) (70:30, v/v). The analyte was detected using a mass spectrometer, equipped with electrospray ion source. The instrument was set in the multiple-reaction-monitoring mode. The standard curve was linear (r = 0.9998) over the concentration range of 0.50-500 ng/mL. The coefficient of variation and relative error for intra- and inter-assay at four QC levels were 0.7 to 4.2% and 4.5 to 5.0%, respectively. The recoveries of lornoxicam and isoxicam were 87.8% and 66.5%, respectively. The lower limit of quantification for lornoxicam was 0.50 ng/mL using a 200 pL plasma sample. This method was successfully applied to a pharmacokinetic study of lornoxicam after oral administration of lornoxicam (8 mg) to humans. PMID- 17703746 TI - Investigation on the absorption kinetics of chlorogenic acid in rats by HPLC. AB - Chlorogenic acid (ChA), a major phenolic compound in the Flos Lonicerae, is widely used in the traditional Chinese medicine practice. The purpose of this study is to report the pharmacokinetic parameters of ChA in rats after oral administration and explore its absorption profile briefly. A two-compartment model was proposed and validated through the program to explain the apparent triphasic phenomenon of ChA in rats after intragastric administration. A rapid absorption and a relatively slow distribution followed by a slower elimination phase were observed. At the administered doses of 200, 400 and 600 mg/kg, the values of absorption half-life (t 1/2 Ka) were 10.23, 18.66 and 28.13 min. The values of distribution half-life (t1/2) were 12.35, 31.04 and 39.19 min. And the values of elimination half-life (t1/2P) were 231.64, 337.23 and 420.81 min. The volume of distribution at the three doses were 55.26, 35.56, 32.22 L/kg, respectively. The AUC0-->infinity (area under the concentration-time curve) was not proportional to the administered dose. In the range of the doses examined, the absorption pharmacokinetics of ChA in rats was based on nonlinear kinetics. PMID- 17703747 TI - Reconsidering change and continuity in later life: toward an innovation theory of successful aging. AB - This article examines the patterns and meanings of innovation in the activities of a group of retirees with an eye toward understanding the place and value of innovation in the aging process. Starting with a consideration of continuity theory, as a perspective that simply describes typical patterns of activity, and activity theory that prescribes expansion of activities as a key to well-being, this article highlights the characteristics, meanings and perceived benefits of a wide variety of innovative activities. The study utilized in-depth semi structured interviews with a purposive sample of 20 male and female retirees involved in a "Learning and Retirement" program. Innovations that both preserve a sense of self (internal continuity) as well as those that allow one to strike out in entirely new direction are described, and, using a process of constant comparison, their motivational dynamics are explored. Given previous arguments that activity can be indiscriminate and disintegrative in some circumstances, we nevertheless suggest that innovation can be growth producing and liberating, even in later life, while at the same time generally protecting a sense of internal continuity. PMID- 17703748 TI - Lifespan creativity in a non-Western artistic tradition: a study of Japanese ukiyo-e printmakers. AB - Western cultures' conceptions about creativity emphasize originality and final products; Eastern cultures, skill and process. Does this cultural difference impact how creativity unfolds over the lifespan? To examine this, we investigated Japanese "ukiyo-e" printmaking (c. 1670-1865). Almost 2,000 illustrations of datable prints by 44 artists were found in 36 art books. Career landmarks (earliest, most frequent, and latest illustrated print) and eminence ratings were estimated for each artist. Results are largely consistent with prior research on Western samples: artists' career peaks vary greatly, averaging around age 40, and the most prolific artists usually (but not always) created the most popular prints. However, ukiyo-e artists show a more positive relation between career peak and eminence than Western artists, peak slightly later than their French (but not American) counterparts, and older artists created the most famous prints, compared to the West. Trans-historically, early-peaking ukiyo-e artists are concentrated between 1780 and 1800. PMID- 17703749 TI - Short-term changes in general and memory-specific control beliefs and their relationship to cognition in younger and older adults. AB - We examined short-term changes in younger and older adults' control beliefs. Participants completed measures of general and memory-specific competence and locus of control on 10 bi-monthly occasions. At each occasion, participants rated their control beliefs prior to and following completion of a battery of cognitive tasks. Exposure to the set of cognitively demanding tasks led to declines in older adults' ratings of both general and memory-specific competence compared to little change or increases in younger adults' ratings. Older adults were also more inconsistent in their reported locus of control beliefs across the 10 occasions. Analyses examining the relationship between control beliefs and actual cognitive performance revealed few significant effects, suggesting that short term changes in perceived control are not driven by monitoring changes in actual performance. The results suggest the importance of assessing short-term as well as long-term changes in perceived control to obtain a complete picture of aging related changes. PMID- 17703750 TI - Changes in health outcomes among older husband caregivers: a one-year longitudinal study. AB - This one-year longitudinal study carried out on a sample of 232 older husband caregivers sought to describe changes in psychological distress and self perceived health, and to examine relationships between factors drawn primarily from Pearlin's model of caregiving and changes in these two health outcomes. Prediction analyses shows that nearly two thirds of the husbands have unsuccessful outcomes with respect to these two dimensions, that is, most husbands obtain either steadily poor scores at both times of the study or worse scores on one or both outcomes. Higher levels of education and informal instrumental support at time 1, as well as an increase in role overload, are predictive of unsuccessful outcome for psychological distress, whereas an increase in self-efficacy predicts successful outcome for self-perceived health. Overall, husband caregivers vary in their response to caregiving over time. The findings support previous study results showing subjective stressors, rather than objective stressors, and caregiver resources to be significant predictors of caregiving outcomes. PMID- 17703755 TI - [Writing to better communicate]. PMID- 17703756 TI - [Writing, knowledge and nurses]. PMID- 17703757 TI - [Patient's records, nursing care records]. PMID- 17703758 TI - [Focus charting for clinical writing]. PMID- 17703759 TI - [Old-style writing and sanitized writing]. PMID- 17703760 TI - ["Floating" writing]. PMID- 17703761 TI - [Writing about another, writing about yourself]. PMID- 17703762 TI - [Caring-writing]. PMID- 17703763 TI - [Voluntary therapy, a therapy for the 21st century?]. PMID- 17703764 TI - [Recent advances in the study of macrolide glycosyltransferases]. AB - Catalyzed by a family of enzymes called glycosyltransferases (GTases), glycosylation reactions are essential for the bioactivities of macrolide antibiotics which have been widely applied. Additionally, glycosylation is also an important strategy of microbial to get macrolide antibiotic resistance. Studies on the structure, function and application areas of macrolide GTases will lay the stable groundwork for the combinatorial biology. This paper introduced in detail the biological functions of macrolide glycosylation, and then made an in depth discussion on the families and discoveries of macrolide GTases. The resistance mechanism with macrolide glycosyltion and the correlative GTases MGT have been reviewed afterwards. According to the flexible substrate specificity of macrolide GTases, the combinatorial biological applications on them were also seriously summarized here. At the end, the authors made a developmental prospect of macrolide GTases based on the studies of the research group. PMID- 17703765 TI - [Recent advances in the study of synthesis and activity of vancomycin derivatives]. AB - Vancomycin was enlisted as a drug of the last resort for the treatment of resistant gram-positive bacterial infections. However, the emergence of vancomycin-resistant bacteria has created an urgent need for new active analogues of vancomycin. Summing up the last ten years work of this field, the review introduced the antibiotic mechanism of vancomycin and summarized the vancomycin derivatives based on the modifications of vancomycin, dimmer of vancomycin and the vancomycin mimetics. The connection of modified location and function with antibacterial activity was also discussed. PMID- 17703766 TI - [Effects of ErbB signal and protein kinase B on monkey cardiocyte apoptosis induced by rapid pacing]. AB - This study is to investigate the roles of neuregulin receptor ErbB2 and protein kinase B (PKB) in pacing-induced heart failure of rhesus monkey. Rapid pacing was used to induce heart failure in rhesus monkey. Aorta intubatton was used to perform hemodynamic measurements, 17 days after pacing. N-Terminal pro-brain natriuretic peptide (BNP), one of the most important molecular marker of heart failure, was also measured by the method of electrochemical luminescence immunoassay. The mRNA expressions of ErbB2, PKB and Bcl-xl were detected in the left ventricular free walls by RT-PCR method. The expressions of phospho-PKB and Bcl-xl on protein level were also detected by Western blotting. The contractibility of cardiac muscle decreased significantly, which consisted with the increase of BNP. Compared with control group, the mRNA expressions of ErbB2, PKB and Bcl-xl were depressed, and similar results were also found in the protein expression analysis of phospho-PKB and Bcl-xl. The expressions of ErbB2, PKB and Bcl-xl were down-regulated during heart failure in rhesus monkey which suggested the important roles of ErbB2 receptor and PKB in the mechanism of heart failure. PMID- 17703767 TI - [Protective effect of madecassoside against reperfusion injury after regional ischemia in rabbit heart in vivo]. AB - This study is to investigate if madecassoside can protect against myocardial reperfusion injury in rabbit heart in vivo. The ischemia reperfusion model was established. Left ventricular function and ECG were monitored at the ischemia and reperfusion period. The infarct areas were expressed as percentage. The levels of LDH, CK, MDA and SOD were measured and C-reactive protein (CRP) in serum was measured by ELISA kit. Cardiomyocyte apoptosis were measured by TUNEL staining. A monoclonal rabbit anti-goat Bcl-2 proteins as primary antibody was used for Bcl-2 immunohistochemical staining. Treatment with madecassoside (3.2, 1.6 and 0.8 mg x kg(-1)) i.v. during ischemia reperfusion injury attenuated myocardial damage, that is, characteristic of decreasing infarct size, decreasing LDH and CK release. Activities of SOD were diminished and MDA level increased obviously in control group whereas pretreatment with madecassoside significantly blunted the decrease of SOD activity, markedly reduced the levels of MDA, CRP and cardiomyocyte apoptosis, and upregulated the expression of Bcl-2. Madecassoside has the protective effect against myocardial ischemia reperfusion injury, and effects of anti-lipid peroxidation, enhancement of SOD activity, anti inflammation and anti-apoptosis. PMID- 17703768 TI - [Synthesis and bioactivies of salicylic acid-g-chitosan derivatives]. AB - To prepare the derivatives of salicylic acid-g-chitosan and study their synergistic and complementary actions, the synergism of anti-inflammatory action of the derivatives was investigated with the experiments of xylene-induces mice ear edema, the analgesic activities by the tartaric emetic-induced mice twist test and the hot-plate test, and the complementary effects between salicylic acid and chitosan through morphological changes of stomach mucous membrane of rat, separately. The anti-inflammatory activities of salicylic acid-g-chitosan derivatives for anti-inflammatory activities were more potent than that of salicylic acid and chitosan and dexamethasone cream in external use, and more potent than that of aspirin orally. However, immediate analgesic activity of the derivatives was lower than that of aspirin and persistent activity was similar as that of aspirin. And the stomach mucous membrane morphology change of the derivatives was much milder than that of aspirin. The salicylic acid grafted chitosan derivatives showed synergistic and complementary effect on the anti inflammatory and analgesic activities and so on. PMID- 17703769 TI - Repeated oral treatment with polysaccharide sulfate reduces insulin resistance and dyslipidemia in diabetic dyslipidemic rat model. AB - Polysaccharide sulfate (PSS) is a new type of antiatherosclerotic medicine for its effects of anticoagulation, anti-thrombosis and modulation of dyslipidemia. However, it is still uncertain whether PSS could modulate the diabetic dyslipidemia or not. Here, the rat model of diabetic dyslipidemia was developed and the effects of PSS on glucose and lipid levels were investigated in this animal model. Wistar rats were iv injected with streptozotocin 20 mg x kg(-1) after feeding with high fat diet for one and a half month. Then, rats received orally PSS (30, 90, and 180 mg x kg(-1)) for 1 month. After oral treatment with PSS (90 and 180 mg x kg(-1)) for 1 month, the levels of triglyceride (TG), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) were significantly reduced and the level of high density lipoprotein-cholesterol (HDL-C) increased, compared with diabetic control rats. Moreover, PSS (30, 90, and 180 mg x kg(-1)) had a tendency to reduce glucose and insulin levels, and significantly increased insulin sensitivity index. Our results suggest that PSS could improve insulin sensitivity and relieve dyslipidemia in diabetic dyslipidemic rats. PMID- 17703771 TI - [Synthesis of derivatives of (9S) -9-hydroxyl-12-methylene erythromycin A and their antibacterial activity in vitro]. AB - The derivatives of (9S)-9-hydroxyl-12-methylene erythromycin A were synthesized by using erythromycin A as a starting material. An intermediate (9S)-9,11-O isopropylidene-6-O-allyl-2' ,4"-O-bis(benzoyl)-12,21-anhydro erythromycin A 12 was obtained. The antibacterial activity in vitro of two compounds, 6 and 11, was tested. The preliminary biological test showed that two compounds exhibited less potent antibacterial activity in vitro. PMID- 17703770 TI - [Synthesis of chrysin derivatives and their interaction with DNA]. AB - Using chrysin as a leading compound, intermediate 5, 7-dihydroxy-6, 8-bis (hydroxymethyl) flavone (1) was synthesized by hydroxymethylation. The intermediate reacted with different alcohols to afford 5, 7-dihydroxy-6, 8-bis ( methoxymethyl) flavone (2), 6, 8-bis (ethoxymethyl) -5, 7dihydroxyflavone (3), 6, 8-bis-(butoxymethyl)-5, 7-dihydroxyflavone (4), 6, 8-bis (pentyloxymethyl) -5,7 dihydroxy flavone (5) and 6, 8-bis-(ethoxymethyl) -5-hydroxy-7-methoxyflavone (6). These compounds were characterized by IR, 1H NMR, 13C NMR and element analysis. The crystal structure of 6 was determined by X-ray crystal diffraction. The interaction of the derivatives with CT-DNA was studied by fluorescent spectroscopy. According to the Stern-Volmer equation, the quenching constants of the compounds 1 - 4 were measured, separately, they were K(q1) = 9.71 x 10(3) L x mol(-1), K(q2) = 2.25 x 10(4) L x mol(-1), K(q3) = 1.03 x 10(4) L x mol(-1) and K(q4) = 7.96 x 10(3) L x mol(-1). Compounds 1-4 showed higher binding affinity with DNA than chrysin did. The results provided the experimental basis for developing a more effective flavonoid and worthing further thoroughly study. PMID- 17703772 TI - [A new anthraquinone from the root of Lasianthus acuminatissimus]. AB - To study the constituents from the chloroform extract of the roots of Lasianthus acuminatissimus Merr., various chromatographic techniques were used to separate and purify the constituents. The structure was established on the basis of ID, 2D NMR and HRMS spectroscopic analysis. A new compound was isolated and identified, which was 3, 8-dihydroxy-1-methoxy-2-methoxymethyl-9,10-anthraquinone (I). Compound I is a new anthraquinone, namely lasianthurin. PMID- 17703773 TI - [Isolation and structure identification of chemical constituents from Saposhnikovia divaricata (Turcz.) Schischk]. AB - Fourteen compounds were isolated from the ethanol extraction of Saposhnikovia divaricata (Turcz.) Schischk using column chromatographic methods after enrichment by macroporous adsorptive resins. They were identified as fangfengalpyrimidine (1), clemiscosin A (2), 5-hydroxy-8-methoxypsoralen (3), sec O-glucosylhamaudol (4), hamaudol (5), nodakenetin (6), prim-O-glucosylcimifugin (7), cimifugin (8), 4'-O-beta-D-glucosyl-5-O-methylvisamminol (9), 5-O methylvisamminol (10), marmesin (11), adenosine (12), daucosterol (13) and beta sitosterol (14) by physico-chemical properties and spectral data. Compound 1 is a new compound. Compounds 2 and 3 were isolated from umbelliferae plants and Saposhnikovia divaricata (Turcz.) Schischk for the first time respectively. PMID- 17703774 TI - Terpenoids and flavonoids from Laggera pterodonta. AB - To study the chemical constituents of aerial parts of Laggera pterodonta (DC.) Benth., the air-dried aerial parts of this plant were powered and extracted with boiling water and purified by silica gel column chromatography and recrystallized. Eleven compounds were obtained from L. pterodonta. They were identified as to be 6-O-beta-D-glucopyranosyl-carvotanacetone (1), pterodontic acid (2), 1beta-hydroxy pterondontic acid (3), pterodontoside A (4), pterodondiol (5), pterodontriol B (6), 5-hydroxy-3,4', 6,7-tetramethoxyflavone (7), artemitin (8), chrysosplenetin B (9), quercetin (10) and beta-sitosterol (11). Compound 1 is a new monoterpene glucoside. Compounds 10 and 11 were isolated from this plant for the first time. Compounds 2 and 5 showed moderate activity against bacteria including Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, Mycobacteium phlei and Bacillus circulans by paper disc diffusion method, while they both displayed no activity against Escherichia coli. PMID- 17703775 TI - [Pharmacokinetics and biodistribution of 3H-norcantharidin in mice]. AB - A single dose of 3H-norcantharidin solution was intragastrically given, blood, tissues, urine and feces were collected as scheduled, and radioactivity in these samples was determined by tritium tracing method to investigate the pharmacokinetics, tissue distribution and excretion of norcantharidin in Kunming mice. The pharmacokinetic characteristics of norcantharidin were evaluated by DAS version 2.0. The blood concentration reached to maximum 0. 5 h after intragastric administration. The radioactivity in tissues was high in small intestine, gallbladder, stomach, adrenal gland, kidney, heart and uterus 15 minutes after administration, descending with time, and high in gallbladder, adrenal gland and uterus 3 hours post dosing. The 24 h accumulative excretion ratio of urine and feces were 65.40% and 1.33% respectively. 3H-norcantharidin was easily absorbed after orally given to mice, the radioactivity was high and existed for a long time in gallbladder, adrenal gland and uterus, and low but also existed for a long-time in large intestine, thymus and fat tissue. 3H-norcantharidin was declined quickly in small intestine, stomach, kidney and heart, and occurred rarely in brain. Norcantharidin was excreted mainly by urinary route and seldom in feces, which may be the cause of the urinary stimulation side effects observed. Because the radioactivity measured were the sum of 3H labeled norcantharidin and its metabolites, further studies on the disposition of norcantharidin in mammal animals, on the separation or identification of metabolites and, if any, on their activities, are fairly needed. PMID- 17703776 TI - [Metabolism of trans-resveratrol-3-O-glucoside in vitro in rat tissues]. AB - To study the metabolism of trans-resveratrol-3-O-glucoside (TRG) in vitro in rat tissues, the incubation with cell-free extracts from rat stomach, duodenum, jejunum, ileum and liver was performed, separately. After TRG was incubated with the tissue extracts at 37 degrees C for up to 90 min, the deglycosylation of TRG was (3.50 +/- 0.24) % for stomach, (65.7 +/- 5.94)% for duodenum, (83.5 +/- 6.43)% for jejunum, (77.6 +/- 6.26)% for ileum and (9.62 +/- 1.21)% for liver, separately. It was observed that the small intestine extracts were more active in deglycosylation of TRG than the liver extract, which suggested that the small intestine mucosa played an important role in deglycosylation of TRG. It was assumed that the deglycosylation of TRG was catalyzed by beta-glucosidase in small intestine mucosa. PMID- 17703777 TI - [Analysis of supercritical fluid extracts of Radix caulophylli with gas chromatography-mass spectrometry]. AB - To analyze the constituents in supercritical fluid CO2 extraction (SFE-CO2) of Radix caulophylli, the Radix caulophylli was extracted with SFE-CO2, and analyzed by gas chromatography-mass spectrometry (GC-MS). The GC-MS analysis with a DB-5MS capillary column (30 mm x 0.32 mm ID, 0.25 microm film thickness) was used. The inlet temperature was maintained at 280 degrees C. The column oven was held at 80 degrees C for 2 min, then programmed from 80 to 280 degrees C at 5 degrees C x min(-1) and, finally, held for 4 min. Helium at a constant flow rate of 2.0 mL x min(-1) was used as the carrier gas. The mass spectrometry conditions were as follows: ionization energy, 70 eV; ion source temperature, 200 degrees C. The mass selective detector was operated in the TIC mode (m/z was from 40 - 500). For the first time 49 peaks were separated and identified, the compounds were quantitatively determined by normalization method, and the identified compounds represent 97.44% of total GC peak areas. Viz, n-hexadecanoic acid (31.4%), (E, E) -9, 12-octadecadienoic acid (26.54%), (Z)-7-tetradecenal (9.4%), hexadecenoic acid (3.23%), 10-undecenal (3.22%), octadecanoic acid (2.25%), and caulophylline (1.76%) etc. The results will provide important foundation for understanding the constituents and further exploitation of Radix caulophylli. PMID- 17703778 TI - [Application of HPLC-ESI-ITMS in the quality control of carboxyterminal sequence confirmation for insulin and insulin chain B]. AB - Application of HPLC-ESI-ITMS in the quality control of carboxyterminal sequence confirmation for insulin and insulin chain B was studied. The solution of intact insulin or insulin chain B was added to the solution of carboxypeptidase P (CPP) and carboxypeptidase Y (CPY). Fractions of appropriate volume were removed at some appointed time points, acidified with the same amount of 1% formic acid to stop the digestion, and then briefly vortexed for HPLC-ESI-ITMS analysis. Mobile phase A consisted of 0.02% TFA in 98% ultra-pure water and 2% acetonitrile. Mobile phase B consisted of 0.02% TFA in 98% acetonitrile and 2% ultra-pure water. The solution used for post-column fix consisted of propionic acid and isopropyl alcohol (20 : 80, v/v). Chromatographic separation was carried out on a reversed-phase column (Zorbax Prosphere C18, 300A, 5 microm, 2.1 mm ID x 150 mm length). The molecular weights of the multiply charged ions representing consecutive truncated losses of carboxyterminal amino acids were determined by the use of HPLC-ESI-ITMS. The differences between the consecutive truncated peptides are the experimental weights of the carboxyterminal amino acid residues. The carboxyterminal amino acid residue Ala, which released from chain B of intact insulin, was confirmed in the nanomolar concentration range by analyzing the molecular weight of the truncated peptides. Another one carboxyterminal amino acid Ala was confirmed in the nanomolar concentration range of insulin chain B. In the quality control for recombinant DNA product or natural protein, the confirmation of 1 - 3 carboxyterminal amino acid residues is regarded to be up to standard. One amino acid residue of insulin or insulin chain B could be confirmed accurately in the nanomolar concentration range. The results showed that intact insulin could be directly sequenced in the quality control without separating chain B from chain A. There would be no need to separate chain A from chain B to identify carboxyterminal of intact insulin. Furthermore, the method saved us a lot of trouble from the preparation and purification of insulin chain A and chain B. PMID- 17703779 TI - [Difference absorption of l-tetrahydropalmatine and dl-tetrahydropalmatine in intestine of rats]. AB - To investigate the difference in absorptive of tetrahydropalmatine (THP) and l tetrahydropalmatine (l-THP) in rat intestine as well as the mechanism of the absorption of THP, in situ single pass perfusion model was used and the concentration of THP in perfusate was determined by HPLC. The absorption rate constant (k(a)) and effective permeability values (P(eff)) of THP had no significant difference (P > 0.05) at concentration of 8, 16 and 32 microg x mL( 1) in perfusion or in four different regions of intestine of rat (duodenum, jejunum, ileum, colon). The absorption of l-THP and THP in jejunum had significant difference (P < 0.05). The k(a) and P(eff) of THP increased obviously when verapamil was co-perfused with THP, while those of l-THP were not influenced by verapamil. The absorption of THP in intestine showed the passive diffusion process, and without a special absorption region. The stereoselective absorption difference may result from stereoselective combination of P-glycoprotein with d THP. PMID- 17703780 TI - [The distribution of azidothymidine palmitate galactosylated liposomes in mice]. AB - Hepatocytes act as a reservoir for the human immunodeficiency viruses (HIV) and are responsible for its continual dissemination in the peripheral circulation. For this reason, galactosylated liposomes (GalLs) containing home-made [(2 lactoylamido) ethylamino] formic acid cholesterol ester (CH-ED-LA ) as a homing device were prepared to study the biodistribution of the liposomal azidothymidine palmitate (AZTP) in mice. Four liposomes of the present study, soybean phosphatidylcholine (SPC)/cholesterol(CH)/CH-ED-LA (80 : 10: 10, 10% GalLs), SPC/CH/CH-ED-LA (80 : 15:5, 5% GalLs), SPC/CH/CH-ED-LA (80 : 17 : 3, 3% GallLs) and SPC/CH (80 : 20, CL) incorporated AZTP were prepared by ethanol-injection method followed by ultrasonic-dispersion and characterized by entrapped efficiency which was more than 95% and their mean diameter was less than 100 nm, respectively. The effects of the addition upon the liposomal membrane potential and AZTP content were also unseen. The distributions of AZT in various organs were determinated by reversed phase HPLC after intravenous administration via tail vein in mice, at a dose of 15.85 mg x kg(-1) AZT solution and 30 mg x kg(-1) AZTP (at equimolar doses) in CL or GalLs, respectively. Compared to AZT control solution, the half-life of AZT in each group of AZTP liposomes increased significantly (P < 0.05). In addition, the concentration-averaged overall drug targeting efficiency (r(e)) of the liver presented by AZTP CL and GalLs containing 3% , 5% , 10% (mol/mol) CH-ED-LA increased 1.32 and 1.48, 2.13, 1.50 times as that of AZT solution, respectively. These results indicate that liposomes containing such novel galactosylated lipid, CH-ED-LA, had remarkably improved the targetability of AZTP to liver, and are anticipated to be a potential candidate for liver targeting delivery carriers. PMID- 17703781 TI - [The entrapped efficiency of BSA liposome]. AB - BSA liposomes were prepared with approximately 100 nm mean particle size under rather gentle experiment conditions, and two-colorimetric coomassie brilliant blue protein was employed to measure the free drug in the entrapped efficiency (EE%) determination of BSA liposomes. Gel filtration was used to measure the EE%, and several Sephadex gels were examined by the separation of liposomes and free drug. To determine the free drug, three methods were compared on two-colorimetric UV spectrophotography, Bradford and two-colorimetric coomassie brilliant blue, separately. Two-colorimetric coomassie brilliant blue process increased the accuracy and improved the sensitivity of the assay about 20-fold comparing with the Bradford method. Two-colorimetric coomassie brilliant blue assay appeared to be more sensitive and showed broader dynamic range to measure the free BSA in the EE% determination of BSA liposome. PMID- 17703782 TI - [Preparation of lectin-conjugated PLGA nanoparticles and evaluation of their in vitro bioadhesive activity]. AB - In this study, wheat germ agglutinin (WGA), tomato lectin (TL) and asparagus pea lectin (AL) were covalently coupled to conventional poly lactic-co-glycolic acid (PLGA) nanoparticles using a carbodiimide method to take the bioadhesive properties. The influences of the amounts of activating agents and lectins, as well as the activating time and incubating time on the effect of lectin conjugating were investigated to optimize the preparation conditions. The mean diameters of the performed nanoparticles with or without lectin conjugation ranged from (140.7 +/- 5.7) nm to (245.6 +/- 18.3) nm. The yields of lectin conjugating and the lectin surface concentrations on nanoparticles were determined by Lowry's methods, and were calculated to be (18.97 +/- 2.9)% - (20.15 +/- 2.4)% and (9.46 +/- 1.45)--(10.05 +/- 1.19) microg x mg(-1), respectively. The in vitro bioadhesive activities of nanoparticles were evaluated by pig gastric mucin (PM) binding experiments. After incubation at room temperature for 60 min, the equilibria of binding between nanoparticles and PM reached. The percentages of the bulk PM which had interacted with different lectin-conjugated PLGA nanoparticles were 15.5%, 12.1% and 11.8%, respectively. The conjugation of lectin enhanced the interaction about 2.4 - 3.2 fold compared with that of the non-conjugated one. A mathematical model was used based on the Langmuir equation, and the rate constants of interaction (k) were calculated to be 2.373 x 10(-3), 1.536 x 10(-3) and 1.714 x 10(-3) (microg x min/mL)(-1), respectively. These interactions could be competitively inhibited by their corresponding sugars of lectins. The results suggested that lectin-conjugated PLGA nanoparticles greatly promoted the interaction with PM in vitro compared with the conventional PLGA nanoparticles, thus would improve the bioadhesion on gastrointestinal mucosa after oral administration resulting in a prolonged residence time in the gastrointestinal tract. PMID- 17703783 TI - [Preparation and characterization of biotinylated chitosan nanoparticles]. AB - Biotinylated chitosan nanoparticles (Bio-CS-NP) were prepared for the active delivery to cancer cells and its characterization was investigated in this study. The preparation process included two steps. First, biotinylated chitosan ( Bio-CS ) was obtained through a reaction between sulfosuccinimidobiotin and chitosan (CS). Second, Bio-CS-NP were prepared by the precipitation of Bio-CS with sodium chloride solution. With a biotin reagent box, the conjugation densities of biotin on the surface of Bio-CS-NP were determined. The morphology and diameter of the nanoparticles were assayed by transmission electron microscope (TEM) and laser light scattering particle analyzer, respectively. The uptake of nanoparticles by human hepotacarcinoma HepG2 cells, for example, Bio-CS-NP and chitosan nanoparticles (CS-NP) without any modification, was quantitatively examined. The results indicated that the conjugation densities of biotin on the surface of Bio CS-NP were 2.2 biotin CS. Bio-CS-NP were spherical, smooth on the surface. The average diameter was 296.8 nm. The polydispersion index was 0.155. The uptake of Bio-CS-NP by HepG2 cells was much higher than that of CS-NP (P < 0.05). It demonstrated that Bio-CS-NP can be applied as a new vehicle to actively deliver anticancer drugs to tumor cells. The method for the determination of biotin was simple and practical. PMID- 17703784 TI - [Effects of the stilbene extracts from Cajanus cajan L. on ovariectomy-induced bone loss in rats]. AB - The Cajanus cajan L. is a natural plant, which contains lots of potential active components. The effects of the stilbene extracts from Cajanus cajan L. (sECC) on ovariectomy (OVX)-induced bone loss in rats were identified. All experimental female rats were divided into 6 groups, i. e. sham-operated rats, OVX rats, 17beta-estradiol (E2)-treated rats, sECC-treated rats with three dosages, 50, 100, and 200 mg x kg(-1), separately. Two weeks after the operation, different dosage of sECC, E2 or deionized water were given to the 6 groups of rats, respectively for another 8 weeks through stomach. Then, all rats were killed. The body weight and uterus wet weight were measured. Contents of serum E2, follicle stimulating hormone (FSH), and luteinizing hormone (LH) were measured by radioimmunoassay. Femoral morphology was observed by HE stain. The results showed that there were no changes of the uterine weight and serum E2 concentration in sECC-treated rats compared with OVX rats. However, the serum FSH and LH concentrations reduced by 11.5% and 15.2% (P < 0.05), respectively. By HE staining, it is found that the 60% of the femur structure had been significantly improved in OVX rats treated with 200 mg x kg(-1) of sECC. The trabeculae were thicker and larger than that of OVX rats. It is clear that sECC improved femoral morphological structure and decreased FSH and LH contents without affecting serum E2 level and uterine weight in OVX rats. The results suggested that sECC had potential action in treatment of postmenopausal osteoporosis. PMID- 17703785 TI - [Content of gentiopicroside and loganic acid in Radix gentianae and their fingerprints]. AB - To develop a HPLC-DAD-ESI-TOF/MS analysis method for the determination of gentiopicroside and loganic acid in Radix gentianae samples and for the research of their fingerprints. The samples were extracted using ASE for 10 min under 100 degrees C and 9.65 MPa, and divided into water phase and chloroform phase and analyzed them with HPLC-DAD-ESI-TOF/MS method respectively. Based on this method, the HPLC fingerprints of Radix gentianae were established. Comparing the spectrogram and mass spectrum of the chromatogram peak with the reference value, three compounds in water phase were identified as gentiopicroside, asafetida acid and loganic acid. There is no report of the compounds in chloroform phase. The content of gentiopicroside and loganic acid in samples of different groups were determined, separately. The fingerprints were compared by the software of the similarity evaluation system for chromatographic fingerprint. The water phase fingerprint congruence coefficients of samples from six different areas were above 0.90, however, the chloroform phase fingerprint congruence coefficients were within 0.62 -0.99. This method can be used for determination of potent component in Radix gentianae and its quality control. Radix gentianae from different producing areas have the largest diversities, and the diversities embodied in the content of chloroform phase compounds. PMID- 17703786 TI - Effect of evaluation threat on procrastination behavior. AB - The author evaluated the effects of evaluation apprehension and trait procrastination on behaviors. The author examined private university students from southern California (N = 72) on two independent variables: evaluation threat (manipulated) and trait procrastination (nonmanipulated). The author found a significant interaction effect between type of evaluation threat and level of trait procrastination on the number of days to complete an assigned essay. Post hoc analyses showed high trait procrastinators in the high evaluation threat group significantly delayed returning essays compared with those in the low evaluation threat group. Also, in the low evaluation threat group, low trait procrastinators delayed more than did high trait procrastinators. These results suggest that educators can reduce behavioral delays by increasing evaluation threat, depending on a student's level of trait procrastination. PMID- 17703787 TI - Cold hearts and bleeding hearts: disciplinary differences in university students' sociopolitical orientations. AB - Many people believe that a university education leads to the liberalization of students' worldviews. The author aimed to investigate whether such differences occur across disciplines and whether they are due to self-selection or socialization within disciplines. The author conducted 3 correlational studies of university students (N = 223, N = 531) and alumni (N = 143). The results clearly supported the self-selection hypothesis and suggested that students from all disciplines generally endorse liberal or left-wing attitudes. These findings have theoretical implications for the study of belief system development (primarily the impressionable years hypothesis), and they contribute to a greater understanding of how a university education affects the sociopolitical orientations of students. PMID- 17703788 TI - Ghosts from the past: an examination of romantic relationships and self discrepancy. AB - Researchers have previously reported a negative association between romantic involvement and the discrepancy between the actual self and the ideal self. The authors present a schema-based model of romantic involvement and self-discrepancy to help explain this association, focusing on the impact of terminated relationships--"ghosts from the past." In Study 1, participants primed with a past relationship reported increased self-discrepancy relative to participants primed with a present relationship. Study 2 indicated that this increased self discrepancy was the result of reexperiencing emotionally negative past romantic relationships. Study 3 revealed the role of depressive affect in negative past romantic relationships. Finally, Study 4 indicated that depressive affect mediated the relation between reexperiencing negative past romantic relationships and experiencing self-discrepancy. PMID- 17703789 TI - Predictors of subjective well-being among college youth in Lebanon. AB - The authors investigated the prevalence and predictors of subjective well-being (SWB) in a particular Middle Eastern culture: that of Lebanon. The authors examined personality constructs of self-esteem, optimism, and positive affect in relation to SWB. The authors surveyed a sample of 689 individuals between the ages of 17 and 24 by using four instruments with established cross-cultural validity: (a) the Satisfaction with Life Scale (SWLS; E. Diener, R. Emmons, R. J. Larsen, & S. Griffin, 1985), (b) the Positive and Negative Affect Schedule (PANAS; D. Watson, L. A. Clark, & A. Tellegen, 1988), (c) the Rosenberg Self Esteem Scale (RSE; M. Rosenberg, 1965), and (d) the revised Life Orientation Test (LOT-R; M. F. Scheier, C. S. Carver, & M. W. Bridges, 1994). The results indicated that college youth's SWB was positively correlated with self-esteem, optimism, and positive affect. Examining the demographic variable of gender, the authors found that men had higher scores on positive affect than did women. A trend emerged that suggested that language dominance and socioeconomic status were associated with SWB levels. The results suggest that internal personality constructs are more predictive of satisfaction with life than are demographic variables. PMID- 17703790 TI - Jurors' locus of control and defendants' attractiveness in death penalty sentencing. AB - The authors examined the relationship between jurors' locus of control and defendants' attractiveness in death penalty sentencing. Ninety-eight participants voluntarily served as mock jurors. The authors administered J. B. Rotter's (1966) Internal-External Locus of Control Scale to participants and then randomly assigned them to a group with either an attractive or an unattractive defendant (represented by photographs). Participants read a murder vignette and selected a punishment--either a lifetime jail sentence or the death penalty-for the defendant. Results indicated that neither jurors' locus of control nor defendants' attractiveness influenced sentencing. However, jurors' age and gender significantly influenced sentencing. Men, with the exception of the youngest men, were more likely than women to choose the death penalty. Additionally, young women were more likely than older women to select the death penalty. The authors discuss the implications of these results for the study of jury behavior and bias. PMID- 17703791 TI - The dynamic relation between organizational and professional commitment of highly educated research and development (R&D) professionals. AB - Researchers of the work-related commitment of professionals have investigated the possibility of conflict between organizational and professional forms of commitment. Drawing on the organizational socialization literature, the authors hypothesized that both forms of commitment would change with increasing organizational tenure. Specifically, the authors proposed that the patterns of change of the 2 forms of commitment would be complementary: Organizational commitment would take a U-shaped pattern of change, whereas professional commitment would take an inverse U-shaped pattern. The results, based on data collected from a sample of 204 research and development (R&D) professionals with PhDs, confirmed the U-shaped pattern of organizational commitment and the complementary relation between the 2 forms of commitment during the first 14 months after organizational entry. These findings suggest the importance of maintaining a balance between organizational and professional commitment and provide a method for identifying the critical period for interventions designed to increase retention of R&D professionals during their early organizational socialization. PMID- 17703792 TI - Intragroup variability among Northern Irish Catholics and Protestants. PMID- 17703793 TI - National Ambulatory Medical Care Survey: 2005 summary. AB - OBJECTIVES: This report describes ambulatory care visits made to physician offices in the United States. Statistics are presented on selected characteristics of the physician's practice, the patient, and the visit. METHODS: The data presented in this report were collected in the 2005 National Ambulatory Medical Care Survey (NAMCS), a national probability sample survey of visits to nonfederal office-based physicians in the United States. Sample data are weighted to produce annual national estimates of doctor visits. RESULTS: During 2005, an estimated 963.6 million visits were made to physician offices in the United States, an overall rate of 331.0 visits per 100 persons. In one-quarter of office visits, electronic medical records were utilized by physicians, while at 83.9 percent of visits, claims were submitted electronically. As the baby boomer generation aged, there was a shift in utilization, as the majority of visits in 1995 were by patients 25-44 years of age compared with 2005, when most visits were by patients 45-64 years of age. In 2005, 52.7 percent of office visits were made by patients with at least one chronic condition. Hypertension was the most frequent condition (22.8 percent), followed by arthritis (14.3 percent), hyperlipidemia (13.5 percent), and diabetes (9.8 percent). Medication therapy was reported at 679.2 million office visits, accounting for 70.5 percent of all office visits. In 2005, there were about 2.0 billion drugs prescribed, resulting in an overall rate of 210.7 drugs per 100 visits. Drugs with amoxicillin were more likely to be new prescriptions (85.4 percent), while ibuprofen and acetaminophen were just as likely to be a new or continued drug. The overall mean time spent with a physician, excluding psychiatrists, has not changed since 1995; however, visits with a duration of 6-10 minutes decreased by 28% from 1995, while visits lasting 16-30 minutes increased by 20%. PMID- 17703795 TI - Consulting on the patient with type 2 diabetes: matching medication to disease mechanism. AB - Type 2 diabetes places a significant burden on the health care system today and its incidence is expected to increase at an alarming rate over the next 20 years. Type 2 diabetes is associated with increasing insulin resistance and beta-cell dysfunction, and with macro- and microvascular complications (including cardiovascular disease, retinopathy, peripheral neuropathy, and end-stage renal disease). The primary rationale for intensive management of type 2 diabetes is to reduce or prevent microvascular and cardiovascular events; therefore, treatment goals encompass glycemic, blood pressure, and lipid targets. Thiazolidinediones (TZDs) improve insulin sensitivity and preserve beta-cell function, and clinical evidence supports the early use of these agents in preventing the progression of diabetes in high-risk patients. The durability of glycemic control with monotherapy varies among orally available antidiabetic agents, and, inevitably, patients with type 2 diabetes will require a combination of antidiabetic agents to reach glycemic goals. Fixed-dose combination therapy is associated with increased adherence to the treatment regimen and improved outcomes. Intensive management of patients with type 2 diabetes has been shown to decrease the rate of complications and reduce health care costs. PMID- 17703794 TI - National Hospital Ambulatory Medical Care Survey: 2005 emergency department summary. AB - OBJECTIVE: This report presents the most current (2005) nationally representative data on visits to hospital emergency departments (ED) in the United States. Statistics are presented on selected hospital, patient, and visit characteristics. Selected trends in ED utilization from 1995 through 2005 are also presented. METHODS: Data are from the 2005 National Hospital Ambulatory Medical Care Survey (NHAMCS), the longest continuously running nationally representative survey of hospital ED and outpatient department (OPD) utilization. The NHAMCS collects data on visits to emergency and outpatient departments of nonfederal, short-stay, and general hospitals in the United States. Sample data are weighted to produce annual national estimates. RESULTS: During 2005, an estimated 115.3 million visits were made to hospital EDs, about 39.6 visits per 100 persons. This represents on average roughly 30,000 visits per ED in 2005, a 31 percent increase over 1995 (23,000). Visit rates have shown an increasing trend since 1995 for persons 22-49 years of age, 50-64 years of age, and 65 years of age and over. In 2005, about 0.5 million (0.4 percent) of visits were made by homeless individuals. Nearly 18 million patients arrived by ambulance (15.5 percent). At 1.9 percent of visits, the patient had been discharged from the hospital within the previous 7 days. Abdominal pain, chest pain, fever, and cough were the leading patient complaints, accounting for nearly one-fifth of all visits. Abdominal pain was the leading illness-related diagnosis at ED visits. There were an estimated 41.9 million injury-related visits or 14.4 visits per 100 persons. Diagnostic and screening services were provided at 71.1 percent of visits, and procedures were performed at 47.3 percent of visits. Medications were either given in the ED or prescribed at discharge at 76.7 percent of visits, resulting in 204.9 million drug mentions. On average, patients spent 56.3 minutes waiting to see a physician, and 3.3 hours for the full duration of their ED visit. About 12 percent of ED visits resulted in hospital admission. The average total length of stay for those admitted was 5.2 days, and the leading principal hospital discharge diagnosis was nonischemic heart disease. PMID- 17703796 TI - Retirement income adequacy after PPA and FAS 158: part one--plan sponsors' reactions. PMID- 17703797 TI - Prescribing controlled substances: a review and new thoughts for the future. PMID- 17703799 TI - Healthy babies are worth the wait. PMID- 17703798 TI - The effects of music therapy on pain. AB - The findings of Bally et al.'s (2003) study failed to support the use of music therapy to decrease pain. Therefore, this research cannot be used in the group research utilization project to teach nurses the effects of music on lessening pain. A feasibility issue for teaching nurses on the effects of music would be the large sum of money it would take to educate the nurses and purchase the music and stereo equipment needed. Future research suggestions would be to include additional research participants, and to study more than two separate procedures, which are more invasive. PMID- 17703800 TI - Analysis of music therapy. Research report. PMID- 17703801 TI - Metabolic-syndromic sensorineural hearing loss and increased noise vulnerability. PMID- 17703802 TI - Glomus tympanicum. PMID- 17703803 TI - Endoscopic view of a long-term inferior meatal antrostomy. PMID- 17703804 TI - Vocal fold scar/sulcus vocalis. PMID- 17703805 TI - Sinonasal polyps. PMID- 17703806 TI - Nasal cavernous hemangioma. PMID- 17703807 TI - Radiation-induced osteosarcoma of the maxillary sinus. PMID- 17703808 TI - ENG, sinusoidal vertical-axis rotation, and otoacoustic emissions testing in a man whose disabling dizziness had culminated in forced retirement. PMID- 17703809 TI - Distal esophageal spasm. PMID- 17703810 TI - HCPCS codes. PMID- 17703811 TI - Long-term follow-up of a multiloculated arachnoid cyst of the middle cranial fossa. AB - Arachnoid cysts are benign intracranial lesions that are typically diagnosed incidentally. We describe the case of a 56-year-old man who presented with a multiloculated arachnoid cyst of the middle cranial fossa that extended into the sphenoid sinus. The lesion was identified on computed tomography of the head, which had been obtained for an unrelated investigation. However, establishing a definitive diagnosis proved to be difficult. Because the cyst had caused extensive skull base erosion, the patient was managed conservatively with close observation. We report the radiographic progression of this lesion during more than a decade of follow-up, and we review the literature pertaining to the presentation, pathophysiology, and treatment of arachnoid cysts. PMID- 17703813 TI - Management of a type II nasoethmoid orbital fracture and near-penetration of the intracranial cavity with transnasal canthopexy. AB - Nasoethmoid orbital fractures are perhaps the most complicated aspect of craniomaxillofacial trauma. Involvement of the medial canthal tendon markedly increases the complexity of the repair. We report a case of type II nasoethmoid orbital fracture in a 32-year-old man that was managed without formal medial canthal tendon repair; instead, we used open reduction and internal fixation of the central fragment and the nasoethmoid complex. However, during the immediate postoperative period, we noted anterior and inferior displacement of the medial canthus. We took the patient back to the operating room to address the detachment. Revision surgery was successful, and at the 6-month follow-up, his medial canthi were completely symmetrical in all dimensions. We describe our intraoperative technique and measures to prevent complications that can help the surgeon intraoperatively. We also discuss an important point that has not been adequately addressed in the literature to date--that is, the fact that the use of the frontoethmoid suture line and the anterior ethmoid artery as a guide to the skull base can be inaccurate. Problems associated with this inaccuracy can be avoided by carefully reviewing preoperative computed tomography, which can help keep the surgeon from entering the intracranial cavity while fixing the medial canthal tendon during transnasal canthal repair. PMID- 17703812 TI - Eosinophilic granuloma: bilateral temporal bone involvement. AB - Eosinophilic granuloma is an uncommon condition that is characterized by unifocal or multifocal osteolytic lesions that often affect the skull. Unilateral lesions of the temporal bone are not uncommon, but bilateral temporal bone lesions are rare. In fact, to the best of our knowledge, fewer than 20 such cases have been reported during the past 40 years. We report a new case of bilateral temporal bone eosinophilic granuloma, and we review the disease process and its treatment. PMID- 17703814 TI - Dislocation of the turbinate: a rare complication of middle turbinate surgery. AB - We describe a rare complication of turbinate surgery--dislocation of the turbinate--in a woman who had undergone surgical treatment for nasal obstruction 10 years earlier. Removal of the displaced yet still-viable turbinate resulted in resolution of her symptoms. PMID- 17703815 TI - Cholesteatoma of the maxillary sinus. AB - Cholesteatoma of the maxillary sinus is a rare condition, but it should be considered in the differential diagnosis of any slowly expanding lesion of the maxillary sinus. Because the keratinizing squamous epithelium continues to desquamate and expand, thereby causing erosion of the surrounding structures, the cholesteatoma sac must be removed completely. We describe a case of cholesteatoma of the maxillary sinus in an 18-year-old woman. PMID- 17703816 TI - Schwannoma of the tonsil. AB - Between 25 and 48% of schwannomas have been reported to occur in the head and neck region; the acoustic nerve is involved in most cases. Schwannomas arising in the tonsil are extremely uncommon. We report a case of tonsillar schwannoma in a 23-year-old woman. We also review the literature on this rare entity. PMID- 17703817 TI - Burkitt's lymphoma of the base of the tongue: a case report and review of the literature. AB - Burkitt's lymphoma is a highly aggressive, mature B cell non-Hodgkin's lymphoma that is rare outside Africa. We report a case of Burkitt's lymphoma presenting as a rapidly expanding tongue-base mass that caused airway obstruction in an 80-year old Palestinian man living in California. According to our review of the literature, this is only the third reported case of Burkitt's lymphoma arising in the base of the tongue. We also discuss the incidence, epidemiology, genetics, prognosis, and treatment of this malignancy. Because Burkitt's lymphoma is one of the fastest-growing tumors in humans, rapid diagnosis and treatment are important. Treatment involves brief-duration, high-intensity chemotherapy and central nervous system prophylaxis. It is important for the otolaryngologist to recognize this disease and to understand the steps necessary to treat this aggressive tumor. PMID- 17703818 TI - Shangaan patients and traditional healers management strategies of hypertension in Limpopo Province. AB - The study explored the cultural care beliefs, values and attitudes of Shangaans patients' and traditional healers' management strategies of hypertension in the Limpopo Province. The study aimed to describe the cultural values, beliefs and practices including taboos, rituals and religion within the world-view of the Shangaans. The study was undertaken in the Mopani region of the Greater Giyani area, with the purpose of recommending improvements to patient care in this area. Data collection was done by conducting focus groups and individual interviews. The following themes emerged: Hypertension, The traditional healer: the instrumental role, Traditional medicine versus Western medicine, Magico-religious healings, Cultural beliefs of Shangaans and hypertension, Experiences of hypertensive patients with regard to traditional healers and hypertension. PMID- 17703819 TI - The meaning and effect of HIV/AIDS stigma for people living with AIDS and nurses involved in their care in the North West Province, South Africa. AB - The five countries with the highest HIV prevalence rates in the world are situated in southern Africa, and South Africa, with an estimated 4.7 million people living with HIV (PLWA), has more cases of HIV/AIDS than any other country. AIDS stigma and discrimination continue to impact on those living with and affected by the HIV disease and their health-care providers, particularly in southern Africa, where the burden of AIDS is so significant. Stigma has become a major problem in the provision of care for PLWA in Africa. A five-year multinational African study on perceived AIDS stigma was undertaken. The North West Province in South Africa formed part of this study. The first phase focused on exploring and describing the meaning and effect of stigma for PLWA and nurses involved in their care. This article focuses on the data for the North West Province, South Africa. An exploratory descriptive qualitative research design was used. Through focus groups the critical incident method was applied to gain respondents' emic and etic views. The study was conducted in the Potchefstroom district and the Kayakulu area. Purposive voluntary sampling was utilised. The open coding technique was used for data analysis. Three types of stigma (received, internal and associated stigma) and several dimensions for each type of stigma were identified. Recommendations for interventions, a measuring scale and the formulation of a conceptual model were formulated. PMID- 17703820 TI - Job satisfaction of registered nurses in a community hospital in the Limpopo Province in South Africa. AB - Nurses are confronted daily with the demands of an increased workload and insufficient facilities in the public healthcare sector in South Africa. The purpose of the study was therefore to determine the degree ofjob satisfaction of registered nurses in a community hospital in the Limpopo Province of South Africa. A quantitative descriptive design was used to meet the objectives of the study. The population was not sampled because of the small size of it. All the registered nurses who had one or more years experience in this hospital were included in the study. A self-administered questionnaire was used to collect data from them regarding the working conditions in the hospital including the emotional and social climate. The questionnaire was based on an instrument developed by Humphries and Turner (1989:303) to determine the degree of job satisfaction of nursing staff in a unit for elderly mentally retarded patients. The findings indicated that the majority of the respondents were dissatisfied about the working conditions and emotional climate in the hospital while they were fairly satisfied with the social climate. The workload and degree of fair remuneration, under the working conditions, were the most highly rated as dissatisfying (83% of the participants) while under the emotional climate they indicated that the pressure under which they worked was highly dissatisfying (82% of the participants). As the results indicated that the social climate was satisfactory; having a best friend at work and the chance to help other people while at work, were rated positively by 88% and 76% of the participants respectively. Recommendations made included that managers have to show the staff that their best interest is their number one concern. Leaders have to be available for the staff and being willing to buffer the stress caused by increased workload and insufficient resources. Greater visibility of supervisory staff should therefore be encouraged. PMID- 17703821 TI - Community participation in primary health care projects of the Muldersdrift Health and Development Programme. AB - After numerous teething problems (1974-1994), the Department of Nursing Education of WITS University took responsibility for the Muldersdrift Health and Development Programme (MHDP). The nursing science students explored and implemented an empowerment approach to community participation. The students worked with MHDP health workers to improve health through community participation, in combination with primary health care (PHC) activities and the involvement of a variety of community groups. As the PHC projects evolved over time, the need arose to evaluate the level of community participation and how much community ownership was present over decision-making and resources. This led to the question "What was the level of community participation in PHC projects of the MHDP?" Based on the question the following objectives were set, i.e. (i) to evaluate the community participation in PHC initiatives; (ii) to provide the project partners with motivational affirmation on the level of community participation criteria thus far achieved; (iii) to indicate to participants the mechanisms that should still be implemented if they wanted to advance to higher levels of community participation; (iv) to evaluate the MHDP's implementation of a people-centred approach to community participation in PHC; and (v) the evaluation of the level of community participation in PHC projects in the MHDP. An evaluative, descriptive, contextual and quantitative research design was used. Ethical standards were adhered to throughout the study. The MHDP had a study population of twenty-three (N=23) PHC projects. A purposive sample of seven PHC initiatives was chosen according to specific selection criteria and evaluated according to the "Criteria to evaluate community participation in PHC projects" instrument (a quantitative tool). Structured group interviews were done with PHC projects' executive committee members. The Joint Management Committee's data was collected through mailed self-administered questionnaires. Validity and reliability were ensured according to strict criteria. Thereafter results were analysed and plotted on a radiating arm continuum. The following factors had component scores: organization, leadership, resources, management; needs and skills. A spider graph was produced after each factor's continuum was connected in a spoke figuration that brought them together at the base where participation was at its most narrow. The results are presented and a graph and discussion is provided on each of the PHC projects. The research results indicated that although community participation was broadened, there was minimal success in forcing a shift in power over decision-making and resources. This demonstrated that power over planning and resources should remain in the hands of the partners if community participation was to remain progressive and sustained. Results furthermore indicated that the people-centred approach to With regard to the Joint Management Committee's evaluation of community participation, it was concluded that power over decision-making and resources remained with health professionals rather than with the community, and that a people-centred approach had not been adopted. PMID- 17703822 TI - Learners' knowledge and and perceptions of voluntary counselling and testing for HIV and AIDS in the Free State Province. AB - The study investigated the perceptions of the youth regarding Voluntary Counselling and Testing (VCT) and sexual aspects related to HIV and AIDS. The study was grounded in qualitative methodology, using 4 focus group interviews for data collection triangulating the results with field notes and literature. The participants of the four focus groups proved to be well informed on the topic and had clear perceptions concerning several aspects. They were very positive regarding the advantages of VCT for the prevention and management of HTV and AIDS. The participants recognised the need for the youth to be better informed about VCT and HIV and AIDS. They were much concerned by the lack of parental involvement in sexual education as well as the permissiveness of the youth who partook in alcohol and drug abuse as well as prostitution. Participants of the study stated that this problem was exacerbated by poverty and poor socio economic conditions. PMID- 17703823 TI - Patients' and family members' knowledge and views regarding diabetes mellitus and its treatment. AB - Diabetes mellitus affects millions of people worldwide and its related complications continue to be of great concern. The outcome of diabetes depends mainly on the patient's self-management. Health care professionals therefore have a major responsibility to assist patients to acquire the essential knowledge, skills and attitudes towards self-management. A quantitative survey was conducted to identify diabetic patients and family members' knowledge and views about diabetes and its treatment regimen. A convenient sample of 32 diabetics and 32 family members who attended two health care facilities in the Mopani district, Limpopo Province, was drawn. Two similar questionnaires, one for each group respectivevly, were completed by the subjects. The data was analysed by a computer programme, the Statistical Package for Social Sciences. Findings revealed that the diabetics and family members lack adequate knowledge on diabetes and its treatment. Recommendations regarding the required health education and assistance to be given to these patients and their family members were made. PMID- 17703824 TI - The health and fitness profiles of nurses in KwaZulu-Natal. AB - Backpain has been recognized as a problem in hospitals, with up to 50% of healthcare staff reporting symptoms (Smedly, Egger, Cooper and Coggon, 1997 and Engels, van der Guilden, Senden and van't Hof 1996). The general purpose of this study was to determine the health and fitness profiles of nurses working in a public hospital. It was hypothesized that there is a correlation between the prevalence of lower back pain and being overweight or obese amongst nurses. One hundred and seven nurses from a local hospital in KwaZulu Natal participated in this study. Responses from a health questionnaire examining medical history, dietary, exercise and lifestyle patterns were analyzed. Fitness tests determined flexibility (sit and reach), muscular strength (back and grip strength), aerobic capacity (Astrand-Rhyming cycle) and anthropometrical data (percent body fat and BMI). Results suggested overall poor health and fitness profiles and a high incidence of back pain correlating with increased body fat percentages, thus accepting the hypothesis. The need for health and wellness intervention strategies in hospitals for the nurses was emphasized. PMID- 17703825 TI - Substance abuse and the risk of readmission of people with schizophrenia at Amanuel Psychiatric Hospital, Ethiopia. AB - Frequent readmissions of people with schizophrenia pose considerable pressure on the psychiatric service provision of Amanuel Psychiatric Hospital. The purpose of the study was to ascertain factors mainly contributing to the rate of readmissions of people with schizophrenia. Descriptive survey methods and qualitative focus group interviews were employed to conduct the study. Random sampling techniques were used to select 43 respondents of people with schizophrenia from 231 people with schizophrenia who were readmitted for two or more times in the last two years and who gained access during the time of the study. Structured interviews were used for respondents of people with schizophrenia. Fourteen (N=14) family members/caregivers were selected using purposive sampling methods for focus group discussions. Quantitative data was analyzed using the SPSS Version 11.00 program and the qualitative data was analyzed by generating themes and categories. The results suggest that alcohol and khat abuse were contributing factors for the rate of readmissions of people with schizophrenia into the Amanuel Psychiatric Hospital. It was found that communities contribute to the problems of substance abuse by providing and/or selling it to those mentally ill people. The study also revealed that patients use alcohol and khat in order to tolerate the severe side effects of the anti psychotic drugs, to suppress hunger due to shortage of food and to avoid drowsiness. Raising community awareness, psycho-education, strengthening the capacities of caretakers and laws to prevent substance abuse, as well as campaigning to prevent people from abusing mentally ill sufferers, should be established. PMID- 17703826 TI - The experience of childbrith in first-time mothers who received narcotic analgesics during the first stage of labour. AB - This research has focused on the birthing experience of first-time mothers who received the narcotic analgesic combination of Pethidine and Hydroxyzine during the first stage of labour. A qualitative research methodology was used to collect data. Unstructured interviews were held with first-time mothers to obtain accounts of their experience of childbirth. These narrations were audio-taped while the participants were still being cared for in the postnatal ward of the hospital where delivery took place. Nine interviews were conducted with first time mothers who gave birth normally vaginally after a normal pregnancy and who received a narcotic analgesic in the first stage of labour. The transcribed interviews were analyzed using Tesch's method of descriptive analysis (in Creswell, 1994:115). Four themes with sub-themes emerged from the analysis. The participants reported on the physical experience of labour and described experiencing a lot of pain for which analgesics were given. They also described how these drugs dulled the pain but made them sleepy and unable to cooperate with the midwives. They described their emotional experiences, which included joy and happiness as well as anxiety, anger and despondence. They also reported that they were not sufficiently informed about labour and child-birth. In the last theme they described the methods they used to help them cope with labour including distracting techniques, leaning on a supportive person or praying. Guidelines to help midwives overcome these problems were developed. PMID- 17703827 TI - The management of infant developmental needs by community nurses. Part 1: description of the responsibilities of community nurses with regard to the management of infant developmental needs. AB - This article is one of two that describes the responsibilities of community nurses, according to their legal scope of practice, with regard to the management of developmental needs of infants in primary health care clinics in South Africa. A subsequent article describes the development of guidelines for the support of community nurses to address the developmental needs of infants 0-2 years. While evidence confirms that developmental surveillance should be incorporated into the ongoing health care of the infant, such services are not consistently provided in health care settings and, if provided, the delivery thereof suffers from significant inadequacies. A case study strategy was used to investigate the phenomenon and content analysis utilised to analyze the data. The Transactional Model of Development was selected to interpret the data obtained in the study. Findings of the study show that infant developmental care is not included to its fullest potential in the health care delivered to infants and their families, thereby indicating that community nurses do not meet the standards of the profession with regard to the management of infant developmental needs. Health service managers need to review their commitment and type of support to community nurses, if infant developmental care, as part of community nurses' responsibilities, is to be effective and of high quality. Furthermore, community nurses and other health care professionals must recognize the nature and potential of inter-professional collaboration to ensure positive outcomes for infants with developmental delays and disabilities. PMID- 17703828 TI - The management of infant developmental needs by community nurses. Part 2: the development of guidelines for the support of community nurses in the management of infant developmental needs. AB - In the previous article, the author described, according to the scope of practice of registered nurses, the responsibilities of community nurses with regard to the management of infant developmental needs in primary health care clinics in South Africa. In this article, the focus is on the development of guidelines for the support of community nurses in fulfilling these responsibilities. Before the development of the guidelines is addressed, a brief overview of the background of the study, assumptions of the researcher and the methodology of the study is given. The development of the set of guidelines (DEFINE HOPE) is set against the background of the drive to improve the quality of developmental care for infants and their families. As guidelines help to translate scientific information into statements, it could be valuable to community nurses to improve their delivery of developmental care. To gather evidence for the formulation of the guidelines, the researcher utilised the themes identified during the analysis process in phase one of the research; investigated research articles; and compared findings and recommendations of the articles with the research findings obtained in phase one. In addition to the research findings and literature review, a focus group (health care professionals represented in the case study), was utilised to assist with the final development and validation of the guidelines. The researcher adapted a number of desirable attributes for guidelines, which are indicated in the literature, to compile the criteria for validation of the guidelines. In conclusion, guidelines are necessary to support community nurses in finding "best practice" within their scope of practice to ensure higher quality of developmental care to families with infants 0-2 years. PMID- 17703829 TI - Low-grade inflammation in chronic kidney disease patients before the start of renal replacement therapy: sources and consequences. AB - Low-grade inflammation is a common feature of chronic kidney disease (CKD) already before the start of renal replacement therapy, and evidence suggests that persistent inflammation may also be per se a risk factor for progression of CKD and vascular disease. Many factors, including retention of pro-inflammatory cytokines, advanced glycation end products, reactive oxygen species, autonomic dysfunctions and volume overload may contribute to inflammation when renal function declines. The aim of the present review is to summarize the causes and consequences of a chronic inflammatory state in the CKD population before start of renal replacement therapy, with special emphasis in polymorphnuclear leukocyte priming, which may be a key mediator in the induction of a vicious circle of oxidative stress and inflammation in CKD. A more thorough characterization of uremic retention solutes with regard to their specific pro- and anti-inflammatory properties is needed. PMID- 17703830 TI - Cinacalcet HCI (Sensipar/Mimpara) is an effective chronic therapy for hemodialysis patients with secondary hyperparathyroidism. AB - AIMS: This 1-year double-blind, placebo-controlled, multicenter study evaluated the long-term safety and efficacy of cinacalcet for the treatment of secondary hyperparathyroidism in patients receiving hemodialysis. METHOD: Patients were randomly assigned in a 1:1 ratio to cinacalcet or control treatment groups. The initial dose of cinacalcet (or matching placebo) was 30 mg. Doses were titrated every 3 or 4 weeks based on the intact parathyroid hormone (iPTH) response and safety profile. Sequential doses included 30, 60, 90, 120 and 180 mg/d. Phosphate binders and vitamin D sterols were adjusted per protocol as needed to control levels of calcium and phosphorus. Efficacy and safety were compared between treatment groups among patients who completed the study (52 total weeks of treatment). Reasons for withdrawal are presented for patients who did not complete the study. RESULTS: A total of 210 patients completed 52 weeks of double blinded treatment with cinacalcet (n = 99) or placebo (n = 111). Over the last 6 months of the study, a greater proportion of patients in the cinacalcet group than the control group achieved an iPTH level < or = 250 pg/ml (61.6 vs. 9.9%, p < 0.001) or a > or = 30% decrease in iPTH from baseline (81.8 vs. 21.6%, p < 0.001). Mean iPTH levels decreased by -47.8% in the cinacalcet group and increased by +12.9% in the control group. Mean percentage changes in other laboratory values in the cinacalcet and control groups included the following: serum calcium -6.5 vs. +0.9% (p < 0.001), serum phosphorus -3.6 vs. -1.1% (p = 0.465), and Ca x P -9.9 vs. -0.3% (p = 0.006). The most commonly reported adverse events related to study drug by the investigators included nausea (13% cinacalcet, 5% control), investigator-reported hypocalcemia (11% cinacalcet, 1% control), vomiting (9% cinacalcet, 2% control), dyspepsia (5% cinacalcet, 4% control), and diarrhea (5% cinacalcet, 2% control). CONCLUSIONS: Treatment with cinacalcet is a safe and effective therapy for long-term control of secondary hyperparathyroidism. 1-year therapy with cinacalcet was associated with sustained, clinically significant reductions in calcium, Ca x P and iPTH which allowed a greater percentage of patients to achieve NKF-KDOQI target goals for PTH and Ca x P. PMID- 17703831 TI - The prognostic value of the C-reactive protein levels in HD patients with death risk from infection. AB - AIMS: Infection is considered the second leading cause of death in dialysis patients with end-stage renal disease (ESRD). However, infection prevalence as primary cause of death still seems to be underreported in the literature. We investigated the role of C-reactive protein (CRP) levels shortly before death as predictor of dying from an infection as primary cause of death in this patient group. METHOD: Between January 1997 through March 2006, we defined the primary causes of death in 231 of the 481 incident patients in our single-center study, who died during this time and assessed the overall prevalence of infection at different predefined CRP cutpoints (between 2 and 300 mg/l). By means of an adjusted multiple logistic regression model, we calculated the odds ratio of (log) CRP for death in 346 survivors and non-survivors with available CRP levels within 5 days of death. In the 96 non-survivors (i.e. cases) of this group, the association of (log) CRP and causes of death was determined by the multiple linear regression model. RESULTS: Infection as a primary cause of death was initially diagnosed in 42% of the 231 non-survivors by standard parameters and clinically. However, the rate of patients possibly dying from this disease increased accordingly when also including cases without any clinical infection signs but with CRP values higher than a given cutpoint (between 2 and 300 mg/l), e.g. when including all cases with CRP cutpoints higher than 100 mg/l, overall prevalence of infection as cause of death increases to 57% (95% CI = 51-64%). Infection was significantly associated with higher CRP levels compared with cardiac death (p < 0.001), with an odds ratio of log CRP for death of 5.4 (95% CI = 3.8-7.7). CONCLUSIONS: Prevalence of infection as primary cause of death in ESRD patients may be even higher than currently stated in the literature. Therefore, to reduce mortality, infections should be further avoided and controlled in the future. PMID- 17703832 TI - The first human cell line-derived erythropoietin, epoetin-delta (Dynepo), in the management of anemia in patients with chronic kidney disease. AB - AIMS: To evaluate the efficacy and safety of the first human cell line-derived erythropoietin, epoetin-delta, in the management of anemia in patients with chronic kidney disease. METHODS: This was a multicenter, randomized, double blind, parallel-group, active-control, Phase III study. Patients aged > or = 18 years with chronic renal disease requiring hemodialysis, with hemoglobin (Hb) levels in the range 9.6-12.4 g/dl, and who had been treated with recombinant erythropoietin for > or = 90 days before study entry were eligible. In the initial double-blind comparative study phase, patients were randomized in a 3:1 ratio to 24-week treatment with either intravenous (i.v.) epoetin-delta (ED) or epoetin-alpha (EA). Patients then entered a 28-week open-label phase, receiving i.v. ED at a dose equal to that of i.v. ED or EA which they received at the end of the blinded phase. RESULTS: In total, 752 patients were randomized, of whom 555 patients subsequently received ED and 191 patients EA, with 583 patients (77.5%) completing the double-blind phase and entering the open-label phase. There was no significant difference between groups for the primary endpoint: the average Hb level from Weeks 12-24 of the study. The adjusted mean average Hb level for the modified intent-to-treat (mITT) population was 11.57 g/dl in the ED group (n = 491, mean dose 63.5 IU/kg) and 11.56 g/dl in the EA group (n = 175, mean dose 62.8 IU/kg). Efficacy was maintained on long-term use. Data for Weeks 12-52 show that ED maintained patients' Hb levels in the target range (10-12 g/dl) with a mean Hb level of 11.31 g/dl at a mean ED dose of 63.7 IU/kg. ED therapy was well tolerated, with a similar overall incidence of adverse events (AEs) (94.4%) to the EA group (92.1%) in the double-blind phase (most common events: hypotension, upper respiratory tract infection, muscle cramps, headache). AEs occurring during the open-label phase were generally similar in type and frequency to those reported during the double-blind phase. CONCLUSIONS: The human cell line-derived erythropoietin, epoetin-delta, provides an effective, well tolerated new option for the management of anemia in patients with chronic kidney disease. PMID- 17703833 TI - Recovery of acute renal failure following bilateral renal artery angioplasty and stenting. AB - Atherosclerotic renovascular disease commonly coexists with chronic kidney disease, and its optimal management remains unsettled. In this case report, we describe a 75-year-old woman with chronic kidney disease and critical atherosclerotic bilateral renal artery stenosis, who presented with a hypertensive emergency and developed acute renal failure following antihypertensive treatment. Bilateral percutaneous transluminal renal angioplasties (PTRA) with stent placement were performed and resulted in immediate recovery of renal function. The existing literature on this impressive response to PTRA is reviewed and discussed. PMID- 17703834 TI - Postpartum hemolytic uremic syndrome in a patient with preexisting hypertension and resolving preeclampsia. AB - Postpartum hemolytic uremic syndrome (PHUS) is an uncommon and potentially devastating complication of pregnancy. We report a case of PHUS in a patient with chronic hypertension and preceding preeclampsia. Since early and appropriate therapy results in remission in most patients with PHUS, the sometimes subtle differences between this syndrome and preeclampsia are reviewed. PMID- 17703836 TI - Rapid onset intratubular calcification following renal transplantation requiring urgent parathyroidectomy. AB - BACKGROUND: Secondary hyperparathyroidism is a common complication of end-stage renal disease often requiring parathyroidectomy. Renal transplant with the restoration of normal renal function often allows resolution of hyperparathyroidism, avoiding the need for parathyroid surgery. However, a proportion of patients with hyperparathyroidism become overtly hypercalcemic after renal transplantation which poses management dilemmas between medical and surgical treatment. CASE: We present the case of a 48-yearold man with end-stage renal failure known to have secondary hyperparathyroidism who received a living related renal transplant. Postoperatively he developed prompt hypercalcemia, polyuria, polydipsia and rapid onset intratubular calcification, leading to acute tubular necrosis diagnosed on renal biopsy on Day 7 post transplantation. He underwent surgical parathyroidectomy with resolution of his hypercalcemia and improved renal transplant function. DISCUSSION: This case emphasizes the need for good management of secondary hyperparathyroidism together with close surveillance of PTH in patients awaiting renal transplantation. With good renal transplant function hyperparathyroidism usually resolves. Posttransplant surgical parathyroidectomy should be reserved for severe progressive end organ damage. PMID- 17703835 TI - Severe emphysematous pyelonephritis in a renal allograft: successful treatment with percutaneous drainage and antibiotics. AB - Emphysematous pyelonephritis is a rare, severe gas-forming infection of the kidney. Herein we report a case of a 51-year-old man who had received a cadaveric renal transplant 12 years ago. Post-transplant diabetes mellitus occurred 8 years later. He experienced urinary tract infection with graft pain one week before admission and presented with septic shock at the emergency room. Plain X-ray of the abdomen showed retroperitoneal air. A computed tomography scan of the abdomen showed retroperitoneal and extraperitoneal air being released from the graft kidney. These findings were compatible with extensive emphysematous pyelonephritis. The patient underwent percutaneous drainage. Blood culture and urine culture yielded Escherichia coli. After repeated percutaneous drainage and strong antibiotics for a prolonged period, the patient finally recovered. PMID- 17703838 TI - Pseudohyperkalemia identified in a myelofibrosis patient exhibiting giant platelets and nucleated red blood cells. PMID- 17703837 TI - Peritonitis associated with Pasteurella multocida in peritoneal dialysis patients -case report and review of the literature. AB - Pasteurella multocida is a zoonotic pathogen found in the oral cavities of domestic dogs and cats and other wild and domestic animals. 14 cases ofperitoneal dialysis-associated Pasteurella multocida peritonitis linked to animal contact have been reported in the literature to date. In each case, the source of infection was believed to be a domestic cat or cats. One case of spontaneous bacterial peritonitis has been reported in a cirrhotic patient and was not linked to animal contact. Poor hygiene in relation to pets was considered the source of infection. We describe the first case of Pasteurella multocida peritonitis in a patient undergoing continuous ambulatory peritoneal dialysis (CAPD) believed to be caused by contact with dogs and discuss the relevant literature. PMID- 17703840 TI - A case of hydronephrosis caused by a precaval right lower polar artery. PMID- 17703839 TI - Renal angiomyolipoma with a minimal fatty component mimicking renal cell carcinoma. PMID- 17703841 TI - 12 months cinacalcet therapy in hemodialysis patients with secondary hyperparathyroidism: effect on bone markers. PMID- 17703842 TI - Ultrasound in medical education: a vertical curriculum at the University of South Carolina School of Medicine. PMID- 17703843 TI - Pyroderma gangrenosum: resolution after treatment for Helicobacter pylori. PMID- 17703844 TI - 100 consecutive thyroidectomies performed by a single surgeon in an upstate South Carolina teaching hospital: an outcome analysis. AB - An experienced surgeon in a community hospital with surgical resident participation can perform thyroid surgery safely. An outcome analysis of 100 consecutive thyroidectomies showed a 1.2% incidence of permanent recurrent nerve injury and no cases of permanent hypo-parathyroidism. Temporary hypocalcemia was common (in total thyroidectomy patients) but was easily treated with oral calcium supplementation. Total thyroidectomy is an acceptable treatment for hyperthyroidism in those patients who are unable or unwilling to receive Radioiodine ablation. PMID- 17703845 TI - Short term medical missions: when, where, and why. PMID- 17703846 TI - I'm baffled. PMID- 17703847 TI - Tomorrow's stethoscope: the hand-held ultrasound device? PMID- 17703848 TI - The seven basic virtues in medicine: V. Faith. PMID- 17703849 TI - [The path: from where to where?]. PMID- 17703850 TI - [Geriatric homes: a non desired "good"]. AB - The great problems which affect old people on this beginning of the XXI century, are not limited to illness. The morbid processes have other causes associated with them:forgetfulness, loneliness, insecurity and, specially, the lack of trust on the actual socio-political structures. This reflection treats the data collected from afield work developed in the city of Viana do Castelo, and the results show that the old people are now living alone, in precarious socio relational conditions and with few resources to face their needs. The desired proximity with and by the citizen, at all levels, faces the distance and misconception of the supporting structures at the moment. PMID- 17703851 TI - ["Advanced nursing": a sense for the development of the profession and the discipline]. PMID- 17703852 TI - [Parent-child relations: social support network and coping styles in adolescence]. PMID- 17703853 TI - [Vulnerability of human beings]. PMID- 17703854 TI - [Alberto's victory over ALS (amyotrophic lateral sclerosis): defense mechanism vs coping strategies]. PMID- 17703855 TI - [The presence of love in ethical care]. PMID- 17703856 TI - Selective management of obstructive submandibular sialadenitis. AB - We aimed to describe the effect of our surgical and sialoendoscopic technique for diagnosis and treatment of chronic obstructive submandibular sialadenitis. METHODS: Between January 2004 and June 2006, 68 patients presented with obstructive symptoms and were diagnosed and treated by interventional sialoendoscopy or excision. The patients all had radiographs and then, if the sialolith could not be found, diagnostic sialoendoscopy. The obstruction was treated by operation or interventional sialoendoscopy depending on the size, shape, site, and quality of the sialolith. RESULTS: Forty-nine patients had sialoliths shown radiographically, and the features of 19 were found endoscopically and were of three types: radiolucent (n=6), in the branch (n=3), mucus plug (n=3), and stenotic (n=7). Twenty-seven obstructions were successfully removed surgically, giving a success rate of 27/31 (87%). Twenty-seven patients were treated by interventional sialoendoscopy, and in 22 cases the sialoliths were removed directly by sialoendoscopy (22/27, 81%). Obstructive symptoms were relieved in 9 of 10 cases without stones. CONCLUSION: Operation or sialoendoscopy can be used to treat the obstruction in the submandibular gland. PMID- 17703857 TI - Levels and bioaccumulation of organochlorine pesticides (OCPs) and polybrominated diphenyl ethers (PBDEs) in fishes from the Pearl River estuary and Daya Bay, South China. AB - Fifty fish samples were collected from the Pearl River estuary (PRE) and Daya Bay, South China and were analyzed for DDTs, HCHs, chlordanes and polybrominated biphenyl ethers (PBDEs). Except the high concentrations of DDT observed in fishes, the concentrations of HCHs, chlordanes and PBDEs were low when compared to other regions. BDE-47 was the predominant PBDE congener and the BDE-209 concentrations were relatively low, despite its high concentration in surface sediments. The absence of significant increase of DDT, HCH, chlordane and PBDE concentrations towards higher delta15N values, as well as the lack of a significant correlation (p<0.1) between log concentrations (lipid normalized) and delta15N, may indicate a weak biomagnification of these chemicals in the food webs. Good agreement was observed between their concentrations and lipid contents of the organisms. Bioconcentration was suggested to be responsible for the accumulation of OCPs and PBDEs in the lower trophic organisms in the studied subtropical waters. PMID- 17703858 TI - Accumulation of nine metals and one metalloid in the tropical scallop Comptopallium radula from coral reefs in New Caledonia. AB - Uptake of waterborne Cd, Co, Mn and Zn was determined in laboratory experiments using radiotracer techniques (109Cd, 57Co, 54Mn and 65Zn). Labelled Zn was mainly accumulated in the digestive gland (65%) and Co in kidneys (81%); Cd and Mn were similarly distributed in digestive gland and gills. In a complementary field study, Ag, As, Cd, Co, Cr, Cu, Fe, Mn, Ni, and Zn were analysed in scallops collected at two stations showing different contamination levels. Digestive gland and kidneys displayed the highest concentrations. Ag, As, Cd, and Fe differed in soft tissues from the two stations, suggesting that Comptopallium radula could be a valuable local biomonitor species for these elements. Low Mn and Zn concentrations found in kidneys suggest that their content in calcium-phosphate concretions differs from the other pectinids. Preliminary risk considerations suggest that As would be the only element potentially leading to exposure of concern for seafood consumers. PMID- 17703859 TI - Risk associated with glucosamine and chondroitin sulfate treatment. PMID- 17703860 TI - Comparison of MC4PC and MDL-QSAR rodent carcinogenicity predictions and the enhancement of predictive performance by combining QSAR models. AB - This report presents a comparison of the predictive performance of MC4PC and MDL QSAR software as well as a method for combining the predictions from both programs to increase overall accuracy. The conclusions are based on 10 x 10% leave-many-out internal cross-validation studies using 1540 training set compounds with 2-year rodent carcinogenicity findings. The models were generated using the same weight of evidence scoring method previously developed [Matthews, E.J., Contrera, J.F., 1998. A new highly specific method for predicting the carcinogenic potential of pharmaceuticals in rodents using enhanced MCASE QSAR-ES software. Regul. Toxicol. Pharmacol. 28, 242-264.]. Although MC4PC and MDL-QSAR use different algorithms, their overall predictive performance was remarkably similar. Respectively, the sensitivity of MC4PC and MDL-QSAR was 61 and 63%, specificity was 71 and 75%, and concordance was 66 and 69%. Coverage for both programs was over 95% and receiver operator characteristic (ROC) intercept statistic values were above 2.00. The software programs had complimentary coverage with none of the 1540 compounds being uncovered by both MC4PC and MDL QSAR. Merging MC4PC and MDL-QSAR predictions improved the overall predictive performance. Consensus sensitivity increased to 67%, specificity to 84%, concordance to 76%, and ROC to 4.31. Consensus rules can be tuned to reflect the priorities of the user, so that greater emphasis may be placed on predictions with high sensitivity/low false negative rates or high specificity/low false positive rates. Sensitivity was optimized to 75% by reclassifying all compounds predicted to be positive in MC4PC or MDL-QSAR as positive, and specificity was optimized to 89% by reclassifying all compounds predicted negative in MC4PC or MDL-QSAR as negative. PMID- 17703861 TI - MRI study of corpus callosum in patients with borderline personality disorder: a pilot study. AB - This pilot study examined the integrity of the corpus callosum in a sample of patients with borderline personality disorder (BPD), as abnormalities in inter hemispheric communication could possibly be involved in illness pathophysiology. We utilized magnetic resonance imaging (MRI) signal intensity (SI) and morphometric measures. Ten BPD and 20 healthy control subjects were assessed for current and past Axis I and Axis II comorbidities and histories of childhood abuse. Regional CC SI and areas were measured with semi-automated software from three-dimensional gradient echo imaging scans. Analysis of covariance was conducted to evaluate the results. No significant differences were observed between BPD and controls in the SI or area of any CC region. Abnormalities in interhemispheric connectivity do not appear necessary for the development of BPD. Further studies with larger samples are needed to confirm this preliminary finding. PMID- 17703863 TI - [Face allotransplantation: anatomical study, potential partial and total facial allografts harvesting and clinical application]. AB - The authors evaluated the technical aspects of harvesting facial tissues in order to perform a facial allotransplantation by conducting dissections in 15 fresh cadavers. They developped anatomical models of harvesting the inferior two thirds and the totality of the face. The approach consisted in harvesting the totality of the facial soft tissues including the muscles and their innervation, in that way harvesting is fast and associated to minimal tissular trauma. The vessels were dissected at their origin at the level of the external carotid artery and the internal jugular vein. The vascular anatomy within the facial flaps was evaluated by transillumination and radiographic (Rx) studies and the authors concluded that the vascular network is rich and sufficient in both partial and full size face transplants. Another important aspect of that study was the restauration of the donor's face. This was achieved in a fast and aesthetically satisfying way with the use of a resin mask. After switching the facial soft tissues on the bony structures of the different subjects, the facial appearence that they observed was rather mixed. In conclusion, that study showed that a face allotransplantation is sound from a technical point of view and could achieve good results in selected cases which are discussed. PMID- 17703862 TI - Antioxidant activities of Toona Sinensis leaves extracts using different antioxidant models. AB - The aim of the present study was to investigate the antioxidant activity of aqueous extracts of Toona sinensis (TS; 0-100 microg/mL) and gallic acid (0-50 microg/mL), with the purified natural phenolic components evaluated using different antioxidant models. It was found that the TS extracts and gallic acid possess effective antioxidant activity against various oxidative systems in vitro, including the scavenging of free and superoxide anion radicals, reducing power, and metal chelation. However, antioxidant activity in terms of metal chelation was not observed for the gallic acid. Moreover, TS extracts and gallic acid appear to possess powerful antioxidant properties with respect to oxidative modification of human LDL induced by CuSO4, AAPH or sodium nitroprusside, as assessed by the relative electrophoretic mobility, TBARS formation, and cholesterol degradation of oxidized LDL. Furthermore, AAPH-induced oxidative hemolysis, lipid peroxidation, and decline in superoxide dismutase (SOD) activity in human erythrocytes were prevented by both the TS extracts and the gallic acid. Our findings suggest that T. sinensis may act as a chemopreventative agent, providing antioxidant properties and offering effective protection from atherogenesis. PMID- 17703864 TI - Effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on methylmercury-induced locomotor deficits and cerebellar toxicity in mice. AB - Chelating therapy has been reported as a useful approach for counteracting mercurial toxicity. Moreover, 2,3-dimercapto-1-propanesulfonic acid (DMPS), a tissue-permeable metal chelator, was found to increase urinary mercury excretion and decrease mercury content in rat brain after methylmercury (MeHg) exposure. We evaluated the capability of DMPS to reduce MeHg-induced motor impairment and cerebellar toxicity in adult mice. Animals were exposed to MeHg (40 mg/L in drinking water, ad libitum) during 17 days. In the last 3 days of exposure (days 15-17), animals received DMPS injections (150 mg/kg, i.p.; once a day) in order to reverse MeHg-induced neurotoxicity. Twenty-four hours after the last injection (day 18), behavioral tests related to the motor function (open field and rotarod tasks) and biochemical analyses on oxidative stress-related parameters (cerebellar glutathione, protein thiol and malondyaldehyde levels, glutathione peroxidase and glutathione reductase activities) were carried out. Histological analyses for quantifying cellular damage and mercury deposition in the cerebellum were also performed. MeHg exposure induced a significant motor deficit, observed as decreased locomotor activity in the open field and decreased falling latency in the rotarod apparatus. DMPS treatment displayed an ameliorative effect toward such behavioral parameters. Cerebellar glutathione and protein thiol levels were not changed by MeHg or DMPS treatment. Conversely, the levels of cerebellar thiobarbituric acid reactive substances (TBARS), a marker for lipid peroxidation, were increased in MeHg-exposed mice and DMPS administration minimized such phenomenon. Cerebellar glutathione peroxidase activity was decreased in the MeHg exposed animals, but DMPS treatment did not prevent such event. Histological analyses showed a reduced number of cerebellar Purkinje cells in MeHg-treated mice and this phenomenon was completely reversed by DMPS treatment. A marked mercury deposition in the cerebellar cortex was observed in MeHg-exposed animals (granular layer>Purkinje cells>molecular layer) and DMPS treatment displayed a significant ameliorative effect toward these phenomena. These findings indicate that DMPS displays beneficial effects on reversing MeHg-induced motor deficits and cerebellar damage in mice. Histological analyses indicate that these phenomena are related to its capability of removing mercury from cerebellar cortex. PMID- 17703865 TI - The effect of dietary glycine on the hepatic tumor promoting activity of polychlorinated biphenyls (PCBs) in rats. AB - Polychlorinated biphenyls (PCBs) are ubiquitious lipophilic environmental pollutants. Some of the PCB congeners and mixtures of congeners have tumor promoting activity in rat liver. The mechanism of their activity is not fully understood and is likely to be multifactorial. The aim of this study was to investigate if the resident liver macrophages, Kupffer cells, are important in the promoting activity of PCBs. The hypothesis of this study was that the inhibition of Kupffer cell activity would inhibit hepatic tumor promotion by PCBs in rats. To test our hypothesis, we studied the effects of Kupffer cell inhibition by dietary glycine (an inhibitor of Kupffer cell secretory activity) in a rat two-stage hepatocarcinogenesis model using 2,2',4,4',5,5' hexachlorobiphenyl (PCB-153, a non-dioxin-like PCB) or 3,3',4,4' tetrachlorobiphenyl (PCB-77, a dioxin-like PCB) as promoters. Diethylnitrosamine (DEN, 150 mg/kg) was administered to female Sprague-Dawley rats, which were then placed on an unrefined diet containing 5% glycine (or casein as nitrogen control) starting two weeks after DEN administration. On the third day after starting the diets, rats received PCB-77 (300 micromol/kg), PCB-153 (300 micromol/kg), or corn oil by i.p. injection. The rats received a total of 4 PCB injections, administered every 14 days. The rats were euthanized on the 10th day after the last PCB injection, and the formation of altered hepatic foci expressing placental glutathione S-transferase (PGST) and the rate of DNA synthesis in these foci and in the normal liver tissue were determined. Glycine did not significantly affect foci number or volume. PCB-153 did not significantly increase the focal volume, but increased the number of foci per liver, but only in the rats not fed glycine; PCB-77 increased both the foci number and their volume in both glycine-fed and control rats. Glycine did not alter the PCB content of the liver, but did increase the activity of 7-benzyloxyresorufin O dealkylase (BROD) in liver microsomes from PCB-153 treated rats. However, glycine did not affect the induction of ethoxyresorufin O-dealkylase activity by PCB-77 in liver microsomes. Glycine diminished hepatocyte proliferation in PGST-positive foci, but not in normal tissue. Overall these results do not support the hypothesis that dietary glycine inhibits the promoting activities of PCBs. The observations that PCB-153 increased the number of foci per liver in control rats but not glycine-fed rats and that dietary glycine reduced cell proliferation in PGST-positive foci, however, do not allow us to completely rule out a role for dietary glycine. But the data overall indicate that Kupffer cells likely do not contribute to the tumor promoting activities of PCB-77 and PCB-153. PMID- 17703867 TI - Reversal of lindane-induced impairment of step-down passive avoidance and oxidative stress by neurosteroids in rats. AB - Neurosteroids (NS) are recognized as important modulators of functioning of the nervous system. Lindane, an organochlorine pesticide has been shown to adversely affect memory and induce oxidative stress on both acute and chronic exposure. The present study was designed to explore the modulation of effects of lindane over cognitive function by progesterone (PROG), pregnenolone sulfate (PREG-S) and 4' chlorodiazepam (4CD). Cognitive function was assessed using step-down latency (SDL) on a passive avoidance apparatus and transfer latency (TL) on a plus maze. Oxidative stress was assessed by examining brain malondialdehyde (MDA) and non protein thiol (NP-SH) levels. A significant reduction in SDL was found for the lindane treated group at weeks 6 and 7 as compared to control (p<0.001). One-week treatment by PREG-S or 4CD antagonized the effect of lindane on SDL. PROG failed to modulate the effect of lindane on SDL. Lindane caused a significant prolongation of TL as compared to control (p<0.001) from second week onwards. One week administration of PROG, PREG-S or 4CD was unable to reverse this prolongation of TL. Lindane produced a statistically significant increase in the brain MDA levels (p<0.001) and significant decrease in the brain NP-SH levels (p<0.001). Treatment with PREG-S and 4CD attenuated the effect of lindane on MDA (p<0.001) and NP-SH levels. PROG failed to influence oxidative stress induced by lindane. Results of the present study thus show that some NS have potential in reversing cognitive dysfunction and oxidative stress induced by toxicants like lindane in the brain. PMID- 17703866 TI - Role of nitric oxide system in hydroxyl radical generation in rat striatum due to carbon monoxide poisoning, as determined by microdialysis. AB - We explored the possible role of the nitric oxide (NO) system in hydroxyl radical (*OH) generation induced by carbon monoxide (CO) poisoning in rat striatum by means of microdialysis with the use of NO synthase (NOS) inhibitors, N(G)-nitro-L arginine methyl ester (L-NAME) and N(G)-monomethyl-L-arginine (L-NMMA), as well as L-arginine (L-Arg; the NOS substrate) and D-arginine (D-Arg). The CO-induced *OH generation was suppressed by both L-Arg and D-Arg. It was also suppressed by L-NAME, which inhibits generation of reactive oxygen species (ROS) via neuronal NOS (nNOS) and inducible NOS, but not via endothelial NOS. In contrast, L-NMMA, which inhibits only ROS generation via inducible NOS, potentiated the *OH generation. L-Arg completely reversed the L-NAME effect and partly reversed the L NMMA effect. D-Arg reversed the L-NAME effect more potently than did L-Arg, resulting in much more *OH generation than was observed with CO alone, and also potentiated the L-NMMA effect. On the other hand, W-7, an antagonist of calmodulin, which is critical for nNOS activity, had no effect on the CO-induced *OH generation. These findings suggest that complex mechanisms operate in *OH generation in rat striatum upon CO poisoning and that the NO system might not be included among those mechanisms. PMID- 17703868 TI - A cis and trans adenine-dependent hairpin ribozyme against Tpl-2 target. AB - Ribozymes are catalytic RNAs that possess the property of cutting an RNA target via site-specific cleavage after sequence-specific recognition. Ribozymes can moreover cleave multiple substrate molecules. An increasing number of studies show that ribozymes are particularly well adapted tools against cancer, silencing or down-regulating gene expression at the RNA level. We have constructed an adenine-dependent hairpin ribozyme that cleaves the sequence at nucleotides A(225)(downward arrow)G(226) relative to the start codon of translation of the Tpl-2 kinase mRNA; this serine/threonine kinase activates the mitogen-activated protein kinase pathway implicated in cell proliferation in breast cancer. An adenine-dependent hairpin ribozyme 1 (ADHR1) was previously isolated using the Systematic Evolution of Ligands by EXponential enrichment procedure. Switch on/switch off ribozymes are particularly useful since high amounts of stable ribozyme can be produced in the absence of adenine and the ribozyme specifically cleaves its target in the presence of adenine. The ADHR1 target sequence was replaced by a sequence derived from the Tpl-2 kinase mRNA. The resulting Tpl-2 ribozyme is active in cis cleavage: kinetic studies have been performed as a function of Mg2+ concentration, adenine concentration, as well as at different pH and with various cofactors. Finally, the Tpl-2 ribozyme was shown to cleave its target in trans successfully. These findings demonstrate that a potential therapeutic ribozyme can be produced by simple sequence modification. PMID- 17703869 TI - Is there a difference in metal ion-based inhibition between members of thionin family: Molecular dynamics simulation study. AB - Thionins have a considerable potential as antimicrobial compounds although their application may be restricted by metal ion-based inhibition of membrane permeabilizing activity. We previously reported the properties associated with the proposed mechanism of metal ion-based inhibition of beta-purothionin. In this study, we investigated the effects of metal ions on alpha-hordothionin which differs from beta-purothionin by eight out of 45 residues. Three of the differing residues are thought to be involved in the mechanism of metal ion-based inhibition in beta-purothionin. The structure and dynamics of alpha-hordothionin were explored using unconstrained molecular dynamics (MD) simulations in explicit water as a function of metal ions. Although the global fold is almost identical to that of beta-purothionin, alpha-hordothionin displays reduced fluctuating motions. Moreover, alpha-hordothionin is more resistant to the presence of metal ions than beta-purothionin. Mg(+2) ions do not affect alpha-hordothionin, whereas K(+) ions induce perturbations in the alpha2 helix, modify dynamics and electrostatic properties. Nevertheless, these changes are considerably smaller than those in beta-purothionin. The proposed mechanism of metal ion-based inhibition involves the hydrogen bonding network of Arg5-Arg30-Gly27, which regulates dynamic unfolding of the alpha2 C-end which is similar to beta purothionin response. The key residues responsible for the increased resistance for alpha-hordothionin are Gly27 and Gly42 which replace Asn27 and Asp42 involved into the mechanism of metal ion-based inhibition in beta-purothionin. Comparison of MD simulations of alpha-hordothionin with beta-purothionin reveals dynamic properties which we believe are intrinsic properties of thionins with four disulphide bonds. PMID- 17703871 TI - Integrated landscape planning and remuneration of agri-environmental services. Results of a case study in the Fuhrberg region of Germany. AB - Until now, existing remuneration of environmental services has not sufficiently supported the goals of spending money more effectively on the environment and of motivating farmers. Only a small share of the budgets for agriculture in the EU, as well as in US and other countries, is available for buying environmental goods and services beyond the level of good farming practice (GFP). This combined with the insufficient targeting of compensation payments to areas where special measures are needed leads to an unsatisfactorily low impact of agri-environment measures compared to other driving forces that stimulate the intensification of farming. The goal of this paper is to propose a management concept that enhances the ecological and cost efficiency of agri-environment measures. Components of the concept are a comprehensive environmental information base with prioritised goals and targets (available in Germany from landscape planning) and new remuneration models, which complement conventional compensation payments that are based upon predetermined measures and cost. Comprehensive landscape planning locates and prioritises areas which require environmental action. It contains the information that authorities need to prioritise funding for environmental services and direct measures to sites which need environmental services beyond the level of GFP. Also appropriate remuneration models, which can enhance the cost efficiency of public spending and the motivation of the farmers, can be applied on the base of landscape planning. Testing of the planning methodology and of one of the remuneration models (success-oriented remuneration) in a case study area ("Fuhrberger Feld" north of Hanover, Germany) demonstrated the usability of the concept and led to proposals for future development of the methodology and its application in combination with other approaches. PMID- 17703870 TI - Anticipated Performance Index of some tree species considered for green belt development in and around an urban area: a case study of Varanasi city, India. AB - It is well established that trees help to reduce air pollution, and there is a growing impetus for green belt expansion in urban areas. Identification of suitable plant species for green belts is very important. In the present study, the Air Pollution Tolerance Index (APTI) of many plant species has been evaluated by analyzing important biochemical parameters. The Anticipated Performance Index (API) of these plant species was also calculated by considering their APTI values together with other socio-economic and biological parameters. Based on these two indices, the most suitable plant species for green belt development in urban areas were identified and recommended for long-term air pollution management. PMID- 17703872 TI - Inorganic pigments made from the recycling of coal mine drainage treatment sludge. AB - Continuous industrial development increases energy consumption and, consequently, the consumption of fossil fuels. Coal mineral has been used in Brazil as a solid fuel for thermoelectric generators for several years. However, coal exploitation affects the environment intensely, mainly because Brazilian coal contains excess ash and pyrite (iron disulfide). According to the local coal industry syndicate, the average annual coal run per mine is 6 million ton/year; 3.5 million ton/year are rejected and disposed of in landfills. Besides pyrite, Brazilian coal contains Mn, Fe, Cu, Pb, Zn, Ge, Se, and Co. Additionally, the water used for coal beneficiation causes pyrite oxidation, forming an acid mine drainage (AMD). This drainage solubilizes the metals, transporting them into the environment, making treatment a requirement. This work deals with the use of sedimented residue from treated coal mine drainage sludge to obtain inorganic pigments that could be used in the ceramic industry. The residue was dried, ground and calcined ( approximately 1250 degrees C). The calcined pigment was then micronized (D(50) approximately 2mum). Chemical (XRF), thermal (DTA/TG), particle size (laser), and mineralogical (XRD) analyses were carried out on the residue. After calcination and micronization, mineralogical analyses (XRD) were used to determine the pigment structure at 1250 degrees C. Finally, the pigments were mixed with transparent glaze and fired in a laboratory roller kiln (1130 degrees C, 5min). The results were promising, showing that brown colors can be obtained with pigments made by residues. PMID- 17703873 TI - Microbial remediation of nitro-aromatic compounds: an overview. AB - Nitro-aromatic compounds are produced by incomplete combustion of fossil fuel or nitration reactions and are used as chemical feedstock for synthesis of explosives, pesticides, herbicides, dyes, pharmaceuticals, etc. The indiscriminate use of nitro-aromatics in the past due to wide applications has resulted in inexorable environmental pollution. Hence, nitro-aromatics are recognized as recalcitrant and given Hazardous Rating-3. Although several conventional pump and treat clean up methods are currently in use for the removal of nitro-aromatics, none has proved to be sustainable. Recently, remediation by biological systems has attracted worldwide attention to decontaminate nitro aromatics polluted sources. The incredible versatility inherited in microbes has rendered these compounds as a part of the biogeochemical cycle. Several microbes catalyze mineralization and/or non-specific transformation of nitro-aromatics either by aerobic or anaerobic processes. Aerobic degradation of nitro-aromatics applies mainly to mono-, dinitro-derivatives and to some extent to poly-nitro aromatics through oxygenation by: (i) monooxygenase, (ii) dioxygenase catalyzed reactions, (iii) Meisenheimer complex formation, and (iv) partial reduction of aromatic ring. Under anaerobic conditions, nitro-aromatics are reduced to amino aromatics to facilitate complete mineralization. The nitro-aromatic explosives from contaminated sediments are effectively degraded at field scale using in situ bioremediation strategies, while ex situ techniques using whole cell/enzyme(s) immobilized on a suitable matrix/support are gaining acceptance for decontamination of nitrophenolic pesticides from soils at high chemical loading rates. Presently, the qualitative and quantitative performance of biological approaches of remediation is undergoing improvement due to: (i) knowledge of catabolic pathways of degradation, (ii) optimization of various parameters for accelerated degradation, and (iii) design of microbe(s) through molecular biology tools, capable of detoxifying nitro-aromatic pollutants. Among them, degradative plasmids have provided a major handle in construction of recombinant strains. Although recombinants designed for high performance seem to provide a ray of hope, their true assessment under field conditions is required to address ecological considerations for sustainable bioremediation. PMID- 17703874 TI - Epileptic fits and epilepsy in the elderly: general reflections, specific issues and therapeutic implications. AB - Seizures and epilepsy are commonly encountered in the elderly. Diagnosis is not always straightforward as reliable history is often difficult to obtain and EEG findings can be non-specific. When to treat and how may be difficult choices as adequate studies in elderly are rather scarce. Treatment should be based on careful assessment and comparison of risk/benefit profiles of various anti epileptic drugs (AEDs) in this specific elderly population. Since most AEDs are effective in terms of seizure control in the elderly, the choice of treatment is often determined by tolerability, pharmacokinetic profile and drug interactions of AEDs. As recently introduced AEDs have a better safety profile compared to older agents it seems logical to initiate treatment in the frail elderly patient with those more modern AEDs. In this review some distinctive clinical features of epilepsy in the elderly are discussed in three sections (general issues, special issues and selected treatment options with special reference to medicinal treatment). PMID- 17703875 TI - Coprecipitation of gold(III), palladium(II) and lead(II) for their flame atomic absorption spectrometric determinations. AB - An enrichment-separation procedure based on the coprecipitation of gold(III), palladium(II) and lead(II) ions with nickel(II)-5-methyl-4-(2-thiazolylazo) resorcinol complex has been developed. The analytical parameters including pH, amounts of 5-methyl-4-(2-thiazolylazo) resorcinol, sample volume, etc. was investigated for quantitative recoveries of Au(III), Pd(II) and Pb(II). Interference due to various cations and anions has also been investigated. The detection limits for analyte ions by 3sigma were 2.6 microg L(-1) for lead, 1.5 microg L(-1) for gold, 2.1 microg L(-1) for palladium. The accuracy of the method was evaluated by the analysis of certified reference materials (NIST SRM 2711 Montana soil, GBW 07309 Stream sediment). The proposed procedure was successfully applied to environmental samples for the determinations of analytes. PMID- 17703876 TI - Removal of colour and COD from synthetic textile wastewaters using O3, PAC, H2O2 and HCO3-. AB - This study aimed to investigate removal of colour and chemical oxygen demand (COD) from synthetic textile wastewaters using O3, powder activated carbon (PAC), H2O2 and HCO3- in a semi-batch reactor. 1:2 metal complex dyestuffs containing two molecules of dyestuffs versus a chromium atom was used. Experiments were conducted under the various pHs (3-12), temperatures (18-70 degrees C), ozone doses (164-493 mg min(-1)). The combined effect of substances used on the removal of colour and COD was investigated. The mechanisms of colour and COD removal on the PAC were explained on the basis of the results of Fourier transform infrared spectroscopy (FTIR). In addition, the zeta potential values of PAC, ozonated PAC and ozonated PAC contaminated with intermediates were determined. The zeta potential values and FTIR plots of PAC particulates showed that PAC acted as an adsorbent in the combined processes. It was thought that all of the substances used in the semi-batch reactor had the combined effect on the removal of colour and COD because of the short treatment time of 5 min and high efficiencies of the removal of colour and COD. The efficiencies of removal of colour and COD in combination were compared with adsorption and ozonation only. In this study, the efficiencies of colour and COD removal during a reaction time of 30 min were obtained as 99 and 95%, respectively. At the result of this study, it was concluded that O3, PAC and H2O2 were an important substances for the removal of colour and COD from synthetic textile wastewater when they were used in combination. PMID- 17703877 TI - Phosphate removal from solution using steel slag through magnetic separation. AB - Steel slag with magnetic separation was used to remove phosphate from aqueous solutions. The influence of adsorbent dose, pH, and temperature on phosphate removal was investigated in a series of batch experiments. Phosphate removal increased with the increasing temperature, adsorbent dose and decreased with increasing initial phosphate concentrations, while it was at its peak at pH of 5.5. The phosphate removal predominantly occurred through ion exchange. The specific surface area of the steel slag was 2.09m2/g. The adsorption of phosphate followed both Langmuir and Freundlich isotherms. The maximum adsorption capacity of the steel slag was 5.3mgP/g. The removal rates of total phosphorus (TP) and dissolved phosphorus (DP) from secondary effluents were 62-79% and 71-82%, respectively. Due to their low cost and high capability, it was concluded that the steel slag may be an efficient adsorbent to remove phosphate both from solution and wastewater. PMID- 17703878 TI - Mercury emissions from coal combustion: modeling and comparison of Hg capture in a fabric filter versus an electrostatic precipitator. AB - Mercury emissions from coal combustion must be reduced, in response to new air quality regulations in the U.S. Although the most mature control technology is adsorption across a dust cake of powdered sorbent in a fabric filter (FF), most particulate control in the U.S. associated with coal combustion takes the form of electrostatic precipitation (ESP). Using recently developed models of mercury adsorption within an ESP and within a growing sorbent bed in a FF, parallel analyses of elemental mercury (Hg(0)) uptake have been conducted. The results show little difference between an ESP and a FF in absolute mercury removal for a low-capacity sorbent, with a high-capacity sorbent achieving better performance in the FF. Comparisons of fractional mercury uptake per-unit-pressure-drop provide a means for incorporating and comparing the impact of the much greater pressure drop of a FF as compared to an ESP. On a per-unit-pressure-drop basis, mercury uptake within an ESP exhibited better performance, particularly for the low-capacity sorbent and high mass loadings of both sorbents. PMID- 17703879 TI - Study of ambient ozone phytotoxicity in Ukraine and ozone protective effect of some antioxidants. AB - The aim of the study was to assess ambient ozone phytotoxicity in Kyiv (Ukraine) using bioindicator clover plants (Trifolium subterraneum cv. Geraldton) and to test some natural and synthetic antioxidants as ozone protectants. The results obtained showed that ambient ozone concentrations were high enough to cause visible leaf injury in clover. All used substances showed partial ozone protective effect on clover. Water extracts from the leaves of plants, known to contain flavonoids-antioxidants showed weaker ozone protective effect and were less stable in the field conditions than synthetic antioxidants. Among the studied extracts, those from Ocimum basilicum and Tagetes patula were more effective as ozone protectants than the one from Salvia sclarea. PMID- 17703880 TI - Comparison of various advanced oxidation processes for the degradation of 4 chloro-2 nitrophenol. AB - In the present study an attempt is made efficiently to degrade USEPA listed 4 chloro-2-nitrophenol (4C-2-NP), widely available in bulk drug and pesticide wastes using various advanced oxidation processes (AOPs). A comparative assessment using various AOPs (UV, H(2)O(2,) UV/H(2)O(2), Fenton, UV/Fenton and UV/TiO(2)) was attempted after initial optimization studies, viz., varying pH, peroxide concentration, iron concentration, and TiO(2) loading. The degradation of the study compound was estimated using chemical oxygen demand (COD) reduction and compound reduction using spectrophotometric methods and further validated with high performance liquid chromatography (HPLC). The degradation trends followed the order: UV/Fenton > UV/TiO(2) > UV/H(2)O(2) > Fenton > H(2)O(2) > UV(.) It can be inferred from the studies that UV/Fenton was the most effective in partial mineralization of 4C-2-NP. However, lower costs were obtained with H(2)O(2). Kinetic constants were evaluated using first order equations to determine the rate constant K. PMID- 17703881 TI - Different mechanisms of lysophosphatidylcholine-induced Ca(2+) mobilization in N2a mouse and SH-SY5Y human neuroblastoma cells. AB - In mice, lysophosphatidylcholine (LPC) was found to be a physiological substrate of neuropathy target esterase, which is also bound by organophosphates that cause a delayed neuropathy in human and some animals. However, the mechanism responsible for causing the different symptoms in mice and humans that are exposed to neuropathic organophosphates still remains unknown. In the present study, we examined and compared the effect of exogenous LPC on intracellular Ca(2+) overload in mouse N2a and human SH-SY5Y neuroblastoma cells. LPC caused an intracellular Ca(2+) level ([Ca(2+)](i)) increase in both N2a and SH-SY5Y cells; moreover, the amplitude was higher in N2a cells than that in SH-SY5Y cells. Preincubation of the cells with verapamil, an L-type Ca(2+) channel blocker, did not affect the LPC-induced Ca(2+) increase in N2a cells, verapamil inhibited the response by 23% in SH-SY5Y cells. In Ca(2+)-free medium, LPC produced a significant [Ca(2+)](i) decrease in N2a cells, while it caused 64% of total [Ca(2+)](i) increase in SH-SY5Y cells. The results of a cell viability test suggest that N2a cells were more sensitive to LPC than were SH-SY5Y cells. These data suggested that the LPC-induced [Ca(2+)](i) increase was produced in each cell line through different mechanisms. In particular, the [Ca(2+)](i) increase occurred via entry through a permeabilized membrane in N2a cells, but through L type Ca(2+) channels as well as by Ca(2+) release from intracellular Ca(2+) stores in SH-SY5Y cells. Thus, the symptomatic differences of organophosphate induced neurotoxicity between mice and humans are probably not related to the diverse amplitudes of intracellular Ca(2+) overload produced by LPC. Moreover, the demyelination effect induced by LPC in mice may be a consequence of its detergent effect on membranes. PMID- 17703882 TI - Potential biomarkers for dementia in Trinidad and Tobago. AB - Biomarkers that could possibly discriminate between healthy controls and patients with dementias of the Alzheimer's type (AD) and vascular dementia (VaD) were investigated. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition TR (DSM IV TR) was used to diagnose for dementia in Trinidad. Healthy seniors greater than 60 years old were controls. All participants were administered the Mini-Mental State Examination (MMSE) and had blood analyzed for levels of C-reactive protein (CRP), total homocysteine (tHcy) and microglial antibodies (MgAb). Plasma tHcy was determined on the Abbot AxSym, serum CRP concentrations were measured using the Tina-Quant sCRP (Latex) high sensitive immunoturbidimetric assay and serum MgAb were examined on frozen rat brain sections. The study was carried out on 29 patients that fulfilled the inclusion criteria and 46 controls. Of the patients 65.5% had AD and 34.5% had VaD. Significant differences were found between the mean MMSE scores of the different types of dementias and controls. MgAb presence as well as tHcy were able to distinguish between controls and dementia of the AD and VaD type, respectively. The MMSE is a good discriminative tool for dementias. Serum MgAbs are a possible biomarker for Alzheimer disease pathology and tHcy is elevated in patients with vascular dementia. PMID- 17703883 TI - Circadian motor asymmetries before and after prolonged wakefulness in humans. AB - It was hypothesized that the relative superiority of the non-dominant hand movements during late evening could arise from a more pronounced homeostatic deactivation of the left hemisphere. We tested such hypothesis collecting motor activity before and after prolonged wakefulness. Fifty-one right-handed subjects wore actigraphs on both left and right wrist for three consecutive days (baseline sleep deprivation-sleep recovery). We replicated higher motor activity in left hand respect to the right hand at 22:00 and 23:00 h, but only in baseline condition. The results provide the evidence that circadian motor asymmetries do not seem to express homeostatic processes. PMID- 17703884 TI - Systemic blockade of complement C5a receptors reduces lipopolysacharride-induced responses in the paraventricular nucleus and the central amygdala. AB - The complement anaphylatoxin C5a is a potent mediator of the innate immune response to infection. Recent evidence also reveals that C5a contributes to central nervous system effects in addition to its well-known peripheral functions. However, it is not known if C5a has a role in the activation of the hypothalamic-pituitary-adrenal (HPA) axis; a critical cascade that exemplifies neuroimmune interactions between the periphery and the brain. In the present study we examined if systemic pre-treatment with a C5a receptor antagonist, PMX53, can affect lipopolysaccharide-induced (LPS; 1 mg/kg, i.p.) activation of the HPA axis in the rat. Using Fos protein as a marker of neuronal activation, we found that systemic administration of PMX53 reduced the LPS-induced activation of paraventricular corticotropin-releasing factor (PVN CRF) and central amygdala cells. However, PMX53 did not alter LPS-induced responses in the bed nucleus of the stria terminalis, nucleus tractus solitarius and ventrolateral medulla. Our findings demonstrate that C5a may have a role in the activation of the HPA axis in response to systemic LPS. PMID- 17703885 TI - Pregabalin in patients with central neuropathic pain: a randomized, double-blind, placebo-controlled trial of a flexible-dose regimen. AB - The effective treatment of patients suffering from central neuropathic pain remains a clinical challenge, despite a standard pharmacological approach in combination with anticonvulsants and antidepressants. A randomized, double blinded, placebo-controlled trial evaluated the effects of pregabalin on pain relief, tolerability, health status, and quality of life in patients with central neuropathic pain caused by brain or spinal cord injuries. At baseline and 4 weeks after the start of treatment subjects were evaluated with standard measures of efficacy: pain intensity measured by visual analog scale, health status (Pain Disability Index and EQ-5D) and quality of life (SF-36). Forty patients received escalating doses of either pregabalin (150, 300, and 600mg/day) or matching placebo capsules. In both groups, patients started with 1 capsule per day (either 150mg of pregabalin or placebo). If pain relief was insufficient, patients were titrated to a higher dose. There was a statistically significant decrease in mean pain score at endpoint for pregabalin treatment, compared with placebo (P=0.016). Follow-up observation showed no significant difference in Pain Disability Index scores between the two groups. The pregabalin group, however, showed a statistically significant improvement for the EQ-5D. Pregabalin treatment led to a significant improvement in the bodily pain domain of the SF36. In the other domains, more favorable scores were reported without reaching statistical significance. Pregabalin, in a flexible-dose regime, produced clinically significant reductions in pain, as well as improvements in health status in patients suffering from severe central neuropathic pain. PMID- 17703886 TI - Emotional control of nociceptive reactions (ECON): do affective valence and arousal play a role? AB - Prior research suggests emotional picture-viewing modulates motoric (nociceptive flexion reflex), autonomic (skin conductance response, heart rate acceleration), and subjective (pain rating) reactions to noxious electrodermal stimulation. The present study sought to determine whether emotional valence and arousal contribute to nociception modulation. To do so, pictures varying in emotional content (erotica, food, neutral, loss, attack) were chosen to manipulate emotional valence (pleasant=erotic and food; unpleasant=loss and attack) and arousal (low=food and loss; moderate=erotica and attack). Pictures were presented in pseudorandom order to elicit emotional processing while noxious electric stimulations were delivered to the sural nerve. Nociceptive flexion reflex (NFR) magnitude, skin conductance response (SCR), heart rate (HR) acceleration, and subjective pain ratings to each stimulation were measured, standardized, averaged by picture content, and analyzed. Results suggested that picture-viewing explained 52% of the variance in the multivariate combination of the nociceptive reactions and modulated them in parallel. Pleasant pictures inhibited reactions, whereas unpleasant pictures enhanced them. However, only erotica and attack pictures elicited significant modulation relative to neutral pictures, suggesting arousal also contributed. An exploratory multilevel analysis also supported this conclusion. Together, these data suggest emotional control of nociceptive reactions (ECON) is associated with a valence-by-arousal interaction. Implications of these findings for how emotional picture-viewing can be used to study supraspinal modulation are discussed. PMID- 17703888 TI - Central pain after brain trauma--a neglected problem in neglected victims. PMID- 17703887 TI - Postoperative Analgesic THerapy Observational Survey (PATHOS): a practice pattern study in 7 central/southern European countries. AB - Surveys evaluating pain in hospitals keep on showing that postoperative pain (POP) remains undertreated. At the time when guidelines are edited and organisational changes are implemented, more recent data are necessary to check the impact of these measures on daily practice and needs for improvement. This prospective, cross-sectional, observational, multi-centre practice survey was performed in 2004-2005 in 7 European countries. It was conducted in surgical wards of a randomised sample of hospitals. Data on POP management practices following surgery in adult in-patients were collected anonymously via a standardised multiple choice questionnaire. Among 1558 questionnaires received from 746 European hospitals, 59% were provided by anaesthetists and 41% by surgeons. There are no regular on-site staff training programmes on POP management in the institution for 34% of the respondents, patients are systematically provided with POP information before surgery for 48% of respondents; balanced analgesia following major surgery and regular administration of analgesics are largely used; 25% of respondents have specific written POP management protocols for all patients in their ward; 34% of respondents say that pain is not assessed and 44% say that pain scores are documented in the patient's chart. This largest ever performed survey confirms the extensive body of evidence that current POP management remains suboptimal and identifies needs for improvement on European surgical wards. However, the wide use of balanced analgesia and the regular administration of analgesics are indicators of ongoing change. PMID- 17703889 TI - A comparison of modifications of the McMaster method for the enumeration of Ascaris suum eggs in pig faecal samples. AB - The comparative efficacies of seven published McMaster method modifications for faecal egg counting were evaluated on pig faecal samples containing Ascaris suum eggs. Comparisons were made as to the number of samples found to be positive by each of the methods, the total egg counts per gram (EPG) of faeces, the variations in EPG obtained in the samples examined, and the ease of use of each of the methods. Each method was evaluated after the examination of 30 samples of faeces. The positive samples were identified by counting A. suum eggs in one, two and three sections of newly designed McMaster chamber. In the present study compared methods were reported by: I-Henriksen and Aagaard [Henriksen, S.A., Aagaard, K.A., 1976. A simple flotation and McMaster method. Nord. Vet. Med. 28, 392-397]; II-Kassai [Kassai, T., 1999. Veterinary Helminthology. Butterworth Heinemann, Oxford, 260 pp.]; III and IV-Urquhart et al. [Urquhart, G.M., Armour, J., Duncan, J.L., Dunn, A.M., Jennings, F.W., 1996. Veterinary Parasitology, 2nd ed. Blackwell Science Ltd., Oxford, UK, 307 pp.] (centrifugation and non centrifugation methods); V and VI-Gronvold [Gronvold, J., 1991. Laboratory diagnoses of helminths common routine methods used in Denmark. In: Nansen, P., Gronvold, J., Bjorn, H. (Eds.), Seminars on Parasitic Problems in Farm Animals Related to Fodder Production and Management. The Estonian Academy of Sciences, Tartu, Estonia, pp. 47-48] (salt solution, and salt and glucose solution); VII Thienpont et al. [Thienpont, D., Rochette, F., Vanparijs, O.F.J., 1986. Diagnosing Helminthiasis by Coprological Examination. Coprological Examination, 2nd ed. Janssen Research Foundation, Beerse, Belgium, 205 pp.]. The number of positive samples by examining single section ranged from 98.9% (method I), to 51.1% (method VII). Only with methods I and II, there was a 100% positivity in two out of three of the chambers examined, and FEC obtained using these methods were significantly (p<0.01) higher comparing to remaining methods. Mean FEC varied between 243 EPG (method I) and 82 EPG (method IV). Examination of all three chambers resulted in four methods (I, II, V and VI) having 100% sensitivity, while method VII had the lowest 83.3% sensitivity. Mean FEC in this case varied between 239 EPG (method I) and 81 EPG (method IV). Based on the mean FEC for two chambers, an efficiency coefficient (EF) was calculated and equated to 1 for the highest egg count (method I) and 0.87, 0.57, 0.34, 0.53, 0.49 and 0.50 for remaining methods (II-VII), respectively. Efficiency coefficients make it possible not only to recalculate and unify results of faeces examination obtained by any method but also to interpret coproscopical examinations by other authors. Method VII was the easiest and quickest but least sensitive, and method I the most complex but most sensitive. Examining two or three sections of the McMaster chamber resulted in increased sensitivity for all methods. PMID- 17703890 TI - The role of dogs as reservoirs of Leishmania parasites, with emphasis on Leishmania (Leishmania) infantum and Leishmania (Viannia) braziliensis. AB - Leishmania parasites cause a group of diseases collectively known as leishmaniases. The primary hosts of Leishmania are sylvatic mammals of several orders (Rodentia, Marsupialia, Carnivora, etc.). Under certain circumstances, particularly in peridomestic and domestic transmission foci, synanthropic and domestic animals can act as source of infection for phlebotomine sand fly vectors. Dogs have long been implicated as the main domestic reservoirs of Leishmania (Leishmania) infantum, the aetiological agent of zoonotic visceral leishmaniasis, and there exists an increasing trend to regard dogs as the main domestic reservoirs of Leishmania (Viannia) braziliensis, the most widespread aetiological agent of American tegumentary leishmaniasis. However, insights derived from recent research indicate that not dogs but humans are probably the most important domestic reservoirs of L. (V.) braziliensis. In the present article, the role of dogs as reservoirs of Leishmania parasites, with emphasis on L. (L.) infantum and L. (V.) braziliensis, is reviewed. PMID- 17703891 TI - Would pancreas duct-epithelium-derived stem/progenitor cells enhance islet allograft survival by means of islets recruitment and tolerance induction in Edmonton protocol era? AB - Rates of insulin independence at 1 year with current Edmonton protocol are impressive. However, obstacles such as the restricted availability of donor pancreas, coupled with recipient's pharmacologic immunosuppression, have lent strong impetus to the search for new sources of insulin-producing cells. But work with stem cells has not yet produced cells with the phenotype of true beta cells. Recently the data have shown that the presence of duct-epithelium in clinical islet transplantation may improve the long-term metabolic outcome. The underlying mechanisms are not well understood. The pancreatic duct-epithelium has been considering as a pool of pancreatic stem/progenitor cells, cytokeratin-19 positive stem cells, which have been proved to be capable of differentiating into endocrine cells and inducing immune tolerance. Based on these findings, we speculate that pancreatic stem/progenitor cells derived from ductal epithelium may enhance islet allograft survival through two aspects: islet recruitment and tolerance induction. The proposition may have clues on the further improvement in clinical islet transplantation long-term outcome. PMID- 17703892 TI - Antiemetic placebo: reduce adverse drug interactions between chemotherapeutic agents and antiemetic drugs in cancer patients. AB - Cancer patients receiving chemotherapy often require a wide range of drugs to manage symptoms of their cancer. The adverse drug interactions are common in the field of medical oncology. Chemotherapy-induced nausea and vomiting (CINV) continues to have a considerable effect on the physical and psychological well being of patients with cancer, despite significant advances in antiemetic drugs since the 1990s. Fortunately, evidence-based interventions suggested that to a certain extent antiemetic effects can be achieved by use of placebo appropriately. Placebo effect can be reinforced by conferring much meaning. Thus physician can replace antiemetic drugs with reinforced meaningful antiemetic placebo to get better prevention and treatment efficacy for CINV while reduce the unnecessary adverse drug interactions induced by antiemetic drugs and chemotherapeutic agents. PMID- 17703893 TI - Odontogenic differentiation of adipose-derived stem cells for tooth regeneration: necessity, possibility, and strategy. AB - Tooth regeneration using tissue engineering concepts is a promising biological approach to solving problems of tooth loss in elderly patients. The seeding cells, however, for tooth regeneration such as odontoblasts from dental germ, stem cells from dental pulp and deciduous teeth, and ectomesenchymal cells from the first branchial arch are difficult, even impossible to harvest in clinic. Bone marrow mesenchymal stem cells have odontogenic capacity, but their differentiation abilities significantly decrease with the increasing age of the donors. Therefore, the cells mentioned above are not practical in the clinical application of tooth regeneration in the old. Adipose derived stem cells have many clinical advantages over bone marrow mesenchymal stem cells, and their differentiation potential can be maintained with aging. Here we propose the hypothesis that adipose derived stem cells could be induced into odontogenic lineage and might be used as suitable seeding cells for tooth regeneration to replace the lost tooth of elderly patients. PMID- 17703894 TI - Sipatrigine could have therapeutic potential for major depression and bipolar depression through antagonism of the two-pore-domain K+ channel TREK-1. AB - Major depressive disorder (MDD) is a chronic, recurring and potentially life threatening mental illness. Current treatments are inadequate - many depression medications, although safe and effective, generally have a slow onset of clinical benefit and around half of the MDD patients do not show full remission with optimized treatment. Therefore, there is still a need for the development of faster-acting and more effective medication for MDD. Recent studies have demonstrated that the TREK-1 protein, one of the 17 members of the two-pore domain K+ (K2P) potassium channel family, is inhibited by the antidepressant fluoxetine. Deletion of TREK-1 in mice caused a substantially reduced elevation of corticosterone levels under stress, and produced behaviour similar to that of naive animals treated with fluoxetine in various behavioural tests. These findings suggested that the blocker of the TREK-1 channel might potentially be a new type of antidepressant. Sipatrigine (BW619C89), a neuroprotective agent, has been found to be a potent antagonist of TREK-1. Its related compound, lamotrigine, has been approved for the treatment of bipolar depression and is used to supplement antidepressant medication in patients with treatment-resistant depression. Furthermore, in addition to its antagonistic effect on TREK-1, sipatrigine is also a glutamate release inhibitor. Excessive glutamatergic neurotransmission is associated with depressive-like behaviours and inhibiting glutamate neurotransmission may be implicated in antidepressant therapeutic mechanisms. From the above findings of the effects of sipatrigine on TREK-1 and glutamate neurotransmission, it is hypothesised that sipatrigine could have potential therapeutic effects for MDD or bipolar depression. Further evaluation of its antidepressant therapeutic and toxic effects in animal models is needed before clinical application. PMID- 17703895 TI - A Contribution to solve the problem of the need for consolidative radiotherapy after intensive chemotherapy in advanced stages of Hodgkin's lymphoma--analysis of a quality control program initiated by the radiotherapy reference center of the German Hodgkin Study Group (GHSG). AB - PURPOSE: The role of radiotherapy (RT) after intensive chemotherapy in patients with advanced stage Hodgkin's lymphoma (HL) is still unclear. The German Hodgkin Study Group (GHSG) randomized HD12 trial was designed to test whether consolidative RT in the region of initial bulky disease and of residual disease is necessary after effective chemotherapy. A quality control program based on a multidisciplinary panel of radiation oncologists, radiologists, and medical oncologists who reviewed all patients' staging and restaging imaging was initiated. METHODS AND MATERIALS: A total of 1661 patients aged 16 to 65 years with HL in Stage IIB (large mediastinal mass and/or E-lesions) or Stage III to IV were randomized from January 1999 to January 2003 according to a factorial design between: 8 esc.BEACOPP + RT (arm A), 8 esc.BEACOPP non-RT (arm B), 4+4BEACOPP + RT (arm C), 4+4BEACOPP non-RT (arm D). RESULTS: In the fifth interim analysis, 1449 patients were eligible for the arm comparison with regard to RT. After a median observation time of 48 months the FFTF rate was 86% and the OS 92%. The FFTF was 95% in the RT arms A+C and 88% in the non-RT arms B+D: no sequential significant difference. One thousand and eighty four patients were evaluated by the panel. The panel defined initial bulky disease in 800 patients and residual disease in 600 patients. The panel recommended continuation of therapy according to the randomization for 934 of 1084 patients and additive RT independently from the randomization arm for 145 of 1084 patients. CONCLUSIONS: The study showed that RT can be reduced substantially after effective chemotherapy. However, because of the irradiation of 10% of patients in the non-RT arms, equivalent effectiveness of a non-RT strategy cannot be proved. A substantial limitation of consolidative RT according to expert panel recommendations appears to be possible without reducing effectiveness. PMID- 17703896 TI - 10-year survival and quality of life in patients with high-risk pN0 prostate cancer following definitive radiotherapy. AB - PURPOSE: To evaluate long-term overall survival (OS), cancer-specific survival (CSS), clinical progression-free survival (cPFS), and health-related quality of life (HRQoL) following definitive radiotherapy (RT) given to T(1-4p)N(0)M(0) prostate cancer patients provided by a single institution between 1989 and 1996. METHODS AND MATERIALS: We assessed outcome among 203 patients who had completed three-dimensional conformal RT (66 Gy) without hormone treatment and in whom staging by lymphadenectomy had been performed. OS was compared with an age matched control group from the general population. A cross-sectional, self-report survey of HRQoL was performed among surviving patients. RESULTS: Median observation time was 10 years (range, 1-16 years). Eighty-one percent had high risk tumors defined as T(3-4) or Gleason score (GS) > or =7B (4+3). Among these, 10-year OS, CSS, and cPFS rates were 52%, 66%, and 39%, respectively. The corresponding fractions in low-risk patients (T(1-2) and GS < or =7A [3+4]) were 79%, 95%, and 73%, respectively. Both CSS and cPFS were predicted by GS and T classification; OS was associated with GS only. High-risk, but not low-risk, patients had reduced OS compared with the general population (p < 0.0005). When pelvis-related side effects were included in multivariate analyzes together with physical function and pain, sexual, urinary, and bowel function were not independently associated with self-reported global quality of life. CONCLUSIONS: Despite surgically proven (p)N(0), RT with dosage <70 Gy as monotherapy does not give satisfactory CSS rates after 10 years in patients with T(3-4) or GS > or =7B. PMID- 17703897 TI - The role of awareness and working memory in human transitive inference. AB - The human ability to perform transitive inference (TI) is an area of debate from a neurocognitive standpoint. Some studies emphasize a stimulus driven medial temporal lobe process [Preston, A.R., Shrager, Y., Dudukovic, N.M., Gabrieli, J.D., 2004. Hippocampal contribution to the novel use of relational information in declarative memory. Hippocampus 14, 148-152; Titone, D., Ditman, T., Holzman, P., Eichenbaum, H., Levy, D., 2004. A transitive inference test of relational memory in schizophrenia. Schizophr. Res. 68, 235-247; Van Elzakker, M., O'Reilley, R., Rudy, J., 2003. Transivity, flexibility, conjenctive representation and the hippocampus: an empirical analysis. Hippocampus 13, 334 340] while others emphasize a higher-level frontal lobe strategy that requires the flexible maintenance of information in working memory [Waltz, J., Knowlton, B., Holyoak, K., Boone, K., Mishkin, F., de Menedezes Santos, M., Thomas, C., Miller, B., 1999. A system for relational reasoning in human prefrontal cortex. Psychol. Sci. 10, 119-125]. In two experiments we investigated when and how adults employ different cognitive strategies during TI by evaluating the interaction between task instructions and individual differences in working memory capacity. Participants engaged in a paired discrimination task involving a 6-unit TI hierarchy and were either prior aware, prior unaware or serendipitously aware of the hierarchical relationship among stimulus items. Both prior aware participants and serendipitously aware participants were more likely to engage in a logic-based strategy compared to unaware participants who relied upon stimulus driven strategies. Individual differences in working memory were associated with the acquisition of awareness in the serendipitously aware group and with the maintenance of awareness in the prior aware group. These findings suggest that the capacity for TI may be supported by multiple neurocognitive strategies, and that the specific strategy employed is dependent upon both task- and participant related factors. PMID- 17703898 TI - Integrating cooperative breeding into theoretical concepts of cooperation. AB - In cooperative breeding systems, some individuals help to raise offspring that are not their own. While early explanations for such altruistic behaviour were predominantly based on kin selection, recent evidence suggests that direct benefits may be important in the maintenance of cooperation. To date, however, discussions of cooperative breeding have made little reference to more general theories of cooperation between unrelated individuals (while these theories rarely address cooperative breeding). Here, we attempt to integrate the two fields. We identify four key questions that can be used to categorise different mechanisms for the maintenance of cooperative behaviour: (1) whether or not individuals invest in others; (2) whether or not this initial investment elicits a return investment by the beneficiary; (3) whether the interaction is direct, i.e. between two partners, or indirect (involving third parties) and (4) whether only actions that increase the fitness of the partner or also fitness reducing actions (punishment) are involved in the interaction. Asking these questions with regards to concepts in the literature on cooperative breeding, we found that (a) it is often straightforward to relate these concepts to general mechanisms of cooperation, but that (b) a single term (such as 'pay-to-stay', 'group augmentation' or 'prestige') may sometimes subsume two or more distinct mechanisms, and that (c) at least some mechanisms that are thought to be important in cooperative breeding systems have remained largely unexplored in the theoretical literature on the evolution of cooperation. Future theoretical models should incorporate asymmetries in power and pay off structure caused for instance by dominance hierarchies or partner choice, and the use of N-player games. The key challenges for both theoreticians and empiricists will be to integrate the hitherto disparate fields and to disentangle the parallel effects of kin and non kin based mechanisms of cooperation. PMID- 17703901 TI - Effects of caprylic acid and triacylglycerols of both caprylic and capric acid in rabbits experimentally infected with enteropathogenic Escherichia coli O103. AB - Eighty-eight rabbits weaned at the age of 35 days were divided into four groups. Rabbits of the first two groups were fed a granulated feed, free of antimicrobials. Rabbits of the 3rd and the 4th groups were fed the same diet, supplemented with caprylic acid at 5 g/kg, and with triacylglycerols (TAG) of caprylic and capric acid at 10 g/kg, respectively. Rabbits of the 2nd, 3rd and 4th groups were challenged orally with 10(9) cells of Escherichia coli of the O103 serogroup. Numbers of coliform bacteria in faeces of non-infected rabbits averaged 4.66 log(10)cfu/g. Six days after inoculation, caprylic acid and TAG of caprylic and capric acid decreased faecal output of coliforms from 10.18+/-0.62 to 7.79+/-0.48 log(10)cfu/g and 8.04+/-0.50 log(10)cfu/g, respectively. In the 2nd, 3rd and 4th groups 15, 11 and 9 infected rabbits died, respectively. However, the differences in mortality rate were not statistically significant. Surviving rabbits were slaughtered at 53 days of age. In caecal contents of infected rabbits, numbers of coliform bacteria were significantly reduced from 8.71 log(10)cfu/g to 5.55-5.83 log(10)cfu/g in treated groups. It can be concluded that both antimicrobial lipids are active against coliform bacteria, and may improve the resistance of weaned rabbits to enterocolitis. PMID- 17703900 TI - Cooperative breeders do cooperate. PMID- 17703899 TI - Rounding a corner of a bent termite tunnel and tunnel traffic efficiency. AB - Subterranean termites construct underground tunnels, tens to hundreds of feet, to reach feeding sites and to transport food items to their nest. To ensure a high rate food return to the nest, an optimized tunnel should be constructed. We found that termites (Coptotermes formosanus Shiraki) fill the corner of a bent tunnel with soil particles excavated from tunnel tip where their digging behavior is activated. The corner-filling behavior, eventually, made a sharp corner smooth rounded. In the present study, we showed that the corner-filling behavior could play an important role in improving the tunnel traffic efficiency. To do this, we compared the termites' time spent for passing corners between with a right-angled flat tip (RA-corner), corresponding to the sharp corner, and with a rounded tip (R-corner) corresponding to the smooth-rounded corner. As a result, the passing time in the R-corner was significantly shorter than in the RA-corner. In addition, tunnel width effect was discussed in terms of individual movement. PMID- 17703902 TI - Management of neonatal endocrinopathies--best practice guidelines. AB - Neonatal emergencies are uncommon, but may lead to significant morbidity and mortality if not recognised and managed promptly. Disorders of sex development, hypoglycaemia, thyrotoxicosis and calcium balance are discussed, with emphasis on the clinical assessment, investigations and management of these disorders in the acute setting. PMID- 17703903 TI - Partitioning, diffusivity and clearance of skin permeants in mammalian dermis. AB - The partition coefficients (K(de)) and diffusivities (D(de)) of compounds in mammalian dermis were examined through an analysis of in vitro permeation data obtained from the literature combined with experimental results with the test permeant, (3)H-testosterone. The literature data involved 26 compounds ranging in molecular weight from 18 to 476 Da and four species-human, guinea pig, rat and mouse. Testosterone was studied by permeation and desorption measurements employing excised human dermis in the presence and absence of external serum albumin. Mathematical models for both K(de) and D(de) were developed. The K(de) model involved ionization, binding to extravascular serum proteins and partitioning into a small lipid compartment. The D(de) model employed a free diffusivity with a liquid-like size dependence multiplied by a binding factor derived from K(de). An additional analysis considered in vivo dermal concentration profiles of topically applied permeants. Literature data for 5 of 6 permeants were shown to be well described by a previously published model for capillary clearance in the dermis, which leads to an exponential decay of concentration with depth. Computed decay lengths (1/e values) ranged from 210 to 920 microm, and the corresponding clearance rate constants k(de) ranged from 0.9 x 10(-4) to 14 x 10(-4)s(-1) (n=8). Departures from the exponential decay profile are discussed in terms of non-uniform capillary clearance and incomplete attainment of a steady-state. PMID- 17703904 TI - Three-dimensional surface reconstruction for cartridge cases using photometric stereo. AB - In forensic science, automated firearms identification is an important and yet unsolved problem. On the way to the solution, one of the most important phases is data acquisition. To be able to identify firearms in a reliable way, all the striated and impressed marks on metallic surfaces of cartridge cases should be visible. But two-dimensional images of cartridge cases are very sensitive to the type and direction of the light source(s). Depending on illumination conditions, the images of marks change drastically and sometimes they simply disappear. But, if the three-dimensional (3D) topography of the surface is obtained, the geometry of the marks, which is independent of the illumination, is available. Thus, by providing illumination independent features that can be used for automated matching, 3D data have the potential to make automated matching much reliable. In the literature on data acquisition for automated firearms identification, a few different ways of three-dimensional surface extraction are described, like laser interferometry or laser profilometry. This study presents a real life application of another method, photometric stereo, for the acquisition of 3D topographic data for cartridge cases, which is the one used in BALISTIKA Ballistics Image Analysis and Recognition System. In order to construct 3D topographic data, first of all, two-dimensional images were acquired using a specially designed set-up. After the images were calibrated radiometrically, photometric stereo method was applied. In order to minimize the low-frequency errors in the final surface, a surface fitting algorithm was used. The method uses low-cost equipment and image acquisition is not time-consuming. Results were compared to interferometric measurement values for error assessment. PMID- 17703905 TI - The extreme longevity: the state of the art in Italy. PMID- 17703906 TI - Breast US in patients who had microcalcifications with low concern of malignancy on screening mammography. AB - PURPOSE: To review ultrasound (US) findings in patients who have suspicious microcalcifications with low concern of malignancy (BI-RADS category 4A) on screening mammography and to evaluate helpful findings in differentiating benign and malignant lesions. MATERIALS AND METHODS: Between August 2005 and July 2006, 192 patients showed microcalcifications only, without mass or associated density, on screening mammography. Among them, we selected 82 patients who had microcalcifications with low concern of malignancy (category 4A) that were pathologically confirmed by surgical excision after wire localization (n=23) or biopsy (n=59). Breast US was performed in 37/82 cases and we analyzed the US findings for the calcification areas in these patients, evaluating the findings with benign or malignant pathological results. We correlated US findings with mammographic calcifications using mammography-guided 2D-localization for the calcifications before US examination. RESULTS: There were 12 malignant lesions (32.4%) including 3 invasive ductal carcinomas (IDC), one microinvasive ductal carcinoma (MIDC), 8 ductal carcinoma in situ (DCIS) and 25 benign lesions (67.6%) including 2 atypical ductal hyperplasias (ADH). IDC showed calcifications within heterogeneous hypoechoic parenchyma or calcifications within complex hypoechoic masses of taller-than-wide shape on US. One MIDC showed calcifications within heterogeneous hypoechoic parenchyma and six DCIS showed negative findings, or calcifications with a small nodule, or only calcifications on US. The most common positive US finding in benign lesions was cysts with calcifications. In 24/37 cases (64.8%) with negative US findings, 18 (75%) were benign lesions and 6 (25%) were DCIS. CONCLUSION: In patients with category 4A microcalcifications without associated findings on screening mammography, negative US findings had a high rate of benign results (18/24, 75%). Visible calcifications within heterogeneous hypoechoic parenchyma or mass on US increased the probability of malignancy. PMID- 17703907 TI - Right top pulmonary vein: evaluation with 64 section multidetector computed tomography. AB - PURPOSE: To evaluate the incidence and anatomic features of the rare variant of the pulmonary veins named "right top pulmonary vein" as depicted with 64 section multidetector computed tomography (MDCT). MATERIALS AND METHODS: MDCT of 610 patients obtained over 12 months period for diagnosis of suspected thoracic or cardiac pathology were routinely reviewed in transverse and 3D images. The frequency of right top pulmonary vein (RTPV) was determined and anatomic features were also documented. RESULTS: Right top pulmonary vein (RTPV) is a supernumerary vein arising from the roof of the right part of the left atrium separately from the orifice of the right superior pulmonary vein. It crosses behind the intermediate bronchus and drains mainly posterior segment of the right upper lobe but also receives few subsegmental branches of superior segment of the right lower lobe. It was detected in 2.2% of patients (14/610). The mean diameter of RTPV was 5.1 mm. CONCLUSION: The RTPV is a rare venous drainage variation of pulmonary veins. It is important to be aware of this anatomic pattern for avoiding misinterpretation of pulmonary venographic findings, inadvertent ablation of pulmonary vein and perioperative bleeding during video assisted thorocoscopic lobectomy. PMID- 17703908 TI - REMOVED: Physicochemical properties of the potent influenza neuraminidase inhibitor, peramivir (BCX-1812). AB - This article has been removed, consistent with Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The Publisher apologizes for any inconvenience this may cause. PMID- 17703909 TI - Analgesic adherence measurement in cancer patients: comparison between electronic monitoring and diary. AB - Adherence to analgesics in cancer patients has scarcely been studied. In this study, the Medication Event Monitoring System (MEMS) and medication diaries were compared with respect to feasibility and adherence measurements. Forty-six outpatients with nociceptive pain caused by cancer were asked to use MEMS for their analgesics and to record their medication usage in a diary for four weeks. Seventy-nine percent of the patients used MEMS for the full four-week period; 70% did so for the diary. The majority of patients were satisfied with both MEMS and diary. Adherence data assessed by MEMS and diary were comparable. Patients used the amount of analgesics adequately (taking adherence: 87%) but took them irregularly (timing adherence: 53%). Subgroup analyses in patients using single and multiple analgesic regimens confirmed the comparable suitability of both methods. MEMS and a medication diary are equally useful for analgesic adherence measurement in cancer patients with pain. PMID- 17703911 TI - Effective analgesic score: a "marker" of the effects of chemotherapy on pain in advanced cancer patients? PMID- 17703910 TI - Validation of single-item linear analog scale assessment of quality of life in neuro-oncology patients. AB - Assessment of patient quality of life (QOL) requires balancing the details provided by multi-item assessments with the reduced burden of single-item assessments. In this project, we investigated the psychometric properties of single-item Linear Analog Scale Assessments (LASAs) for patients with newly diagnosed high-grade gliomas. Measures included QOL LASAs (overall, physical, emotional, spiritual, intellectual), Symptom Distress Scale (SDS), Profile of Mood States (POMS; overall, confusion, fatigue), and Functional Assessment of Cancer Therapy-Brain (FACT-Br; overall, brain, physical, emotional). Associations of LASA measures with SDS, POMS, and FACT-Br domains and with Eastern Cooperative Oncology Group performance score (PS) and Mini-Mental State Examination (MMSE) were assessed. Repeated measures ANOVA models compared the change over time of LASAs and SDS, POMS, and FACT-Br. Two hundred five patients completed the assessments across three time points. To allow comparison across measures, all scores were converted to a scale of 0-100, with higher scores indicating better QOL. LASA mean scores ranged from 60 to 78; SDS, POMS, and FACT-Br ranged from 62 to 81. FACT-Br physical (P<0.001) and POMS fatigue subscale (P=0.005) decreased over time, as did LASA physical (P=0.08). LASA scales were strongly associated with corresponding scales on SDS, POMS, and FACT-Br (0.44 or =20 U/mg of the E. coli expressed EK sample provided by Sigma (Cat. No. E4906). This procedure produced approximately 53 mg of EK per 500 mL of cell culture, which was much higher than previous reports, thus providing a basis for large-scale production of EK and for further applications in biotechnology. PMID- 17703947 TI - A correlation analysis of protein characteristics associated with genome-wide high throughput expression and solubility of Streptococcus pneumoniae proteins. AB - We have developed and evaluated a highly parallel protein expression and purification system using ORFs derived from the pathogenic bacterium Streptococcus pneumoniae as a representative test case in conjunction with the Gateway cloning technology. Establishing high throughput protein production capability is essential for genome-wide characterization of protein function. In this study, we focused on protein expression and purification outcomes generated from an expression vector which encodes an NH(2)-terminal hexa-histidine tag and a COOH-terminal S-tag. Purified recombinant proteins were validated by SDS-PAGE, followed by in-gel digestion and identification by MALDI-TOF/TOF analysis. Starting with 1360 sequence-validated destination clones we examined correlation analyses of expression and solubility of a wide variety of recombinant proteins. In total, 428 purified proteins (31%) were recovered in soluble form. We describe a semi-quantitative scoring method using an S-tag assay to improve the throughput and efficiency of expression and solubility studies for recombinant proteins. Given a relatively large dataset derived from proteins representing all functional groups in a microbial genome we correlated various protein characteristics as they relate to protein expression outcomes. PMID- 17703948 TI - Preparation of recombinant murine tumor necrosis factor-alpha in Escherichia coli: a rapid method to remove tags from fusion proteins by thrombin-cleavage and ion-exchange chromatography. AB - A recombinant protein of murine tumor necrosis factor (TNF)-alpha was expressed in Escherichia coli (E. coli) by using a pET Trx Fusion System. The fusion protein was effectively solubilized and purified by Ni-affinity chromatography. A high concentration of thrombin quickly and specifically cleaved the introduced site between the tags and the target fragment. We found that thrombin tightly bound to an ion-exchange resin, CM-Sepharose, under conditions avoiding adsorption of most proteins. By passing through the column, thrombin was quickly removed from the reaction mixtures. These methods appear to be widely potentially useful to remove the tags from recombinant fusion proteins. Prepared recombinant TNF demonstrated cytotoxic effects to L929 cells at very low concentrations with an EC50 value of 0.19+/-0.02 pM. In addition, immunization of a rabbit with the protein induced a neutralizing antibody. The methods used in this study appear to be useful to prepare significant amount of soluble functional recombinant proteins in E. coli. PMID- 17703949 TI - Purification of CREB to apparent homogeneity: removal of truncation products and contaminating nucleic acid. AB - The cAMP response element binding protein (CREB) is a mammalian transcription factor which regulates the expression of many cellular genes. CREB is commonly expressed in Escherichia coli and purified by heat-extraction followed by affinity chromatography. We have discovered that although this purification yields a reasonably pure product which is active in DNA-binding and functional assays, it contains a large amount of nucleic acid as well as CREB truncation products and other polypeptides. Consequently, this CREB is inadequate for use in biophysical studies including crystallography, and spectroscopic analysis such as analytical ultracentrifugation, FRET, and circular dichroism. We revised the purification protocol to incorporate expression in the Rosetta host strain, nuclease treatment, and denaturing/high salt size-exclusion chromatography. We typically obtain 10mg of CREB per liter of culture media that is 99% homogenous, free of nucleic acid, and amenable to biophysical studies. Comparison of CREB from the original and revised protocols shows similar affinities for the cAMP response element (CRE) but small differences in their secondary structures when assayed by limited proteolysis and circular dichroism. PMID- 17703950 TI - Symmetry: A guide to its application in 2D electron crystallography. AB - A defining property of a crystal is its symmetry. This mini-review sets out to summarize all aspects that define 2D crystallographic symmetry as applied to the study of macromolecular structure. It begins by defining molecular point symmetries, before covering crystallographic symmetry operations in 2D, common notation, a summary of crystallographic plane groups and theoretical methods and important considerations for the identification and application of symmetry in 2D crystal images for 3D structure determination. While many of the concepts covered here may be equally applicable to point symmetry and space group symmetry in 3D, this review has been written from the perspective of 2D electron crystallography and deals specifically with symmetry operations and crystallographic space groups in 2D crystal projection images. PMID- 17703951 TI - Characterization of antisera raised against stickleback (Gasterosteus aculeatus) MHC class I and class II molecules. AB - The three-spined stickleback (Gasterosteus aculeatus) is an important model organism for investigations on the maintenance of polymorphism of the major histocompatibility complex (MHC) of vertebrates. Analysis of functional aspects of MHC diversity in stickleback would benefit from the availability of MHC specific reagents. Here we characterize antisera raised against recombinant fusion proteins of stickleback MHC class I alpha and class II alpha and beta. Western blot analysis using recombinant proteins confirmed the specificity of the antisera. In brain and muscle preparations, neither of the MHC types was detectable. High levels of each MHC receptor type were observed in gills and spleen and lower levels in head kidneys. In histological sections of gills, epithelial cells of primary and secondary lamellae stained positive with MHC class I antiserum, while single, scattered cells stained positive for MHC class II. In sections of spleen and head kidney, considerable numbers of cells positive for either MHC type were detected. Molecular weight shift in SDS-PAGE after deglycosylation of MHC class I alpha and class II beta confirmed the predicted glyco-protein character of the molecules. The majority of MHC II alpha was not glycosylated; only a small fraction of MHC II alpha was susceptible to deglycosylation. This suggests differential expression of the two stickleback MHC II alpha genes (Gaac-DAA, Gaac-DBA) only one of which (Gaac-DBA) has a site for N linked glycosylation. PMID- 17703952 TI - Effect of environmental parameters on immune response of the Indian spiny lobster, Panulirus homarus (Linnaeus, 1758). AB - The high export value of the Indian spiny lobster Panulirus homarus increasingly attracts the aquaculturists for farming and fattening. However, lack of knowledge on the effect of environmental parameters on the immune system of this animal could result in high mortality, which ultimately may cause major loss to the industry. Here, we report the effect of salinity (20, 25, 35, 40, and 45 per thousand), pH (5.0, 8.0, and 9.5), dissolved oxygen (DO) (1 and 5 mg L(-1)), and ammonia-N concentration (0, 0.5, 1.5 and 3 mg L(-1)) on the immune response of P. homarus measured in the haemolymph in terms of Total Haemocyte Count (THC), phenoloxidase (PO) activity, and NBT-reduction. Our data showed significant reduction (P<0.05) in THC, and NBT-reduction at lower (20 per thousand) and higher (45 per thousand) salinities. However, PO activity showed significant disparity, showing an increasing trend from 20 to 45 per thousand. Significant reduction (P<0.05) in THC and PO activity under acidic and alkaline conditions, under hypoxic condition (1 mg L(-1)), and at the higher ammonia-N concentrations than their respective optimal conditions were observed. Thus, suggesting that extreme environmental parameters can induce modifications in the immune system of the spiny lobster P. homarus, which may enhance their susceptibility to opportunistic pathogens. The humoral parameters such as THC, PO activity, and NBT reduction can be used as potential stress indicators for healthy management of spiny lobsters. PMID- 17703953 TI - Characterization of a ras-related nuclear protein (Ran protein) up-regulated in shrimp antiviral immunity. AB - Diseases caused by viruses, especially white spot syndrome virus (WSSV), are the greatest challenge to worldwide shrimp aquaculture. Therefore, the innate immunity of shrimp has attracted extensive attentions these years. To date, however, no mechanism of immuno-related signal transduction pathway has been reported. In this investigation, an important signal transduction factor-Ran gene encoding ras-related nuclear protein (Ran protein) was characterized in shrimp. The shrimp Ran gene, without introns when compared with genomic DNA, was 645 bp in length. The GTP-binding assay showed that the Ran protein had GTP-binding activity. The results of RT-PCR and Western blot indicated that the transcript and protein of Ran were detected in every tissue of shrimp including hepatopancreas, haemolymph, gill, intestine, heart and muscle. In the WSSV resistant and WSSV-infected shrimp at 4h postinfection, the Ran gene was obviously up-regulated, indicating that it played a role in shrimp immunity against virus infection. This study, therefore, might provide a clue to elucidate shrimp innate immunity. PMID- 17703954 TI - cDNA cloning and tissue expression of plasma lysozyme in the eastern oyster, Crassostrea virginica. AB - The cDNA sequence of a 17,861 Da lysozyme first purified from plasma of eastern oysters (Crassostrea virginica) was identified and its complete amino acid sequence deduced. The amino acid sequence of the plasma lysozyme, designated cv lysozyme 1, contained both a unique and a conserved region when compared to the amino acid sequences of other bivalve lysozymes. In situ hybridisation located cv lysozyme 1 gene expression in mantle and gill cells in standard histological sections. Quantitative real-time RT-PCR detected cv-lysozyme 1 expression in all organs examined and circulating haemocytes. The number of cv-lysozyme 1 mRNA transcripts was particularly high in mantles and labial palps suggesting those organs are the main sites of cv-lysozyme 1 synthesis. Cv-lysozyme 1 enzyme activity measured by lysing Micrococcus lysodeikticus bacteria and expressed in units per gram tissue was highest in mantles, labial palps and gills. Most cv lysozyme 1 enzyme activity in oysters was found in plasma. Cv-lysozyme 1 main organs of synthesis, its abundance in plasma and its strong antimicrobial properties suggest its main role is in oyster host defences. PMID- 17703955 TI - Interaction of viscoelastic tissue compliance with lumbar muscles during passive cyclic flexion-extension. AB - Human and animal models using electromyography (EMG) based methods have hypothesized that viscoelastic tissue properties becomes compromised by prolonged repetitive cyclic trunk flexion-extension which in turn influences muscular activation including the flexion-relaxation phenomenon. Empirical evidence to support this hypothesis, especially the development of viscoelastic tension relaxation and its associated muscular response in passive cyclic activity in humans, is incomplete. The objective of this study was to examine the response of lumbar muscles to tension-relaxation development of the viscoelastic tissue during prolonged passive cyclic trunk flexion-extension. Activity of the lumbar muscles remained low and steady during the passive exercise session. Tension supplied by the posterior viscoelastic tissues decreased over time without corresponding changes in muscular activity. Active flexion, following the passive flexion session, elicited significant increase in paraspinal muscles EMG together with increase in the median frequency. It was concluded that reduction of tension in the lumbar viscoelastic tissues of humans occurs during cyclic flexion extension and is compensated by increased activity of the musculature in order to maintain stability. It was also concluded that the ligamento-muscular reflex is inhibited during passive activities but becomes hyperactive following active cyclic flexion, indicating that moment requirements are the controlling variable. It is conceived that prolonged routine exposure to cyclic flexion minimizes the function of the viscoelastic tissues and places increasing demands on the neuromuscular system which over time may lead to a disorder and possible exposure to injury. PMID- 17703956 TI - Functional networks underlying latent inhibition learning in the mouse brain. AB - The present study reports the first comprehensive map of brain networks underlying latent inhibition learning and the first application of structural equation modeling to cytochrome oxidase data. In latent inhibition, repeated exposure to a stimulus results in a latent form of learning that inhibits subsequent associations with that stimulus. As neuronal energy demands to form learned associations changes, so does the induction of the respiratory enzyme cytochrome oxidase. Therefore, cytochrome oxidase can be used as an endpoint metabolic marker of the effects of experience on regional brain metabolic capacity. Quantitative cytochrome oxidase histochemistry was used to map brain regions in mice trained on a tone-footshock fear conditioning paradigm with either tone preexposure (latent inhibition), conditioning only (acquisition), conditioning followed by tone alone (extinction), or no handling or conditioning (naive). The ventral cochlear nucleus, medial geniculate, CA1 hippocampus, and perirhinal cortex showed modified metabolic capacity due to latent inhibition. Structural equation modeling was used to determine the causal influences in an anatomical network of these regions and others thought to mediate latent inhibition, including the accumbens and entorhinal cortex. An uncoupling of ascending influences between auditory regions was observed in latent inhibition. There was also a reduced influence on the accumbens from the perirhinal cortex in both latent inhibition and extinction. The results suggest a specific network with a neural mechanism of latent inhibition that appears to involve sensory gating, as evidenced by modifications in metabolic capacity and effective connectivity between auditory regions and reduced perirhinal cortex influence on the accumbens. PMID- 17703957 TI - Spingosine-1-phosphate stimulates proliferation and counteracts interleukin-1 induced nitric oxide formation in articular chondrocytes. AB - OBJECTIVE: Sphingosine-1-phosphate (S1P) is a messenger molecule, with important functions in inflammation and wound healing. The present study was performed to elucidate a possible role of S1P signaling in articular chondrocytes. METHODS: Human and bovine primary chondrocytes were cultured in monolayer. Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to detect S1P receptor mRNA. Proliferation of S1P stimulated chondrocytes was measured by 3H thymidine uptake. Supernatants of cultured bovine chondrocytes stimulated with S1P alone or in combination with interleukin-1beta (IL-1beta) were tested for nitric oxide (NO) formation and expression of inducible nitric oxide synthase (iNOS). Matrixmetalloprotease-13 (MMP-13) and aggrecanase-1 (ADAMTS-4) were evaluated using real-time PCR. Glycosaminoglycan (GAG) loss from bovine cartilage explants was evaluated using the dimethylene blue method. RESULTS: S1P1, S1P2 and S1P3 but not S1P4 and S1P5 receptor mRNA were detected in human and bovine chondrocytes. S1P dose dependently induced proliferation in bovine and human chondrocytes. S1P significantly reduced NO formation and iNOS mRNA and protein expression, both in un-stimulated and IL-1beta stimulated bovine chondrocytes. Furthermore, S1P dose dependently inhibited IL-1beta induced expression of ADAMTS 4 and MMP-13 and diminished IL-1beta mediated GAG depletion from cartilage explants. CONCLUSION: These results suggest that S1P provides an anti-catabolic signal in articular chondrocytes. PMID- 17703958 TI - Neuronal fusion pore assembly requires membrane cholesterol. AB - Cholesterol has been proposed to play a critical role in regulating neurotransmitter release and synaptic plasticity. The neuronal porosome/fusion pore, the secretory machinery at the nerve terminal, is a 12-17 nm cup-shaped lipoprotein structure composed of cholesterol and a number of proteins, among them calcium channels, and the t-SNARE proteins Syntaxin-1 and SNAP-25. During neurotransmission, synaptic vesicles dock and fuse at the porosome via interaction of their v-SNARE protein with t-SNAREs at the porosome base. Membrane associated neuronal t-SNAREs interact in a circular array with liposome associated neuronal v-SNARE to form the t-/v-SNARE ring complex. The SNARE complex along with calcium is required for the establishment of continuity between opposing bilayers. Here we show that although cholesterol is an integral component of the neuronal porosome and is required for maintaining its physical integrity and function, it has no influence on the conformation of the SNARE ring complex. PMID- 17703959 TI - Signals in pathological CNS extracts of ALS mice promote hMSCs neurogenic differentiation in vitro. AB - The capability of MSCs to differentiate into neurons has been proven by many studies. Recently, other studies have cast doubt on MSCs neurogenic differentiation with non-physiological chemical inducing agents in vitro. This present study was designed to use conditioned medium to investigate whether signals from pathological condition of ALS were competent to induce a program of neurogenic differentiation in expanded cultures of hMSCs. Incubation of hMSCs with conditioned medium prepared from CNS extracts of ALS mice (SOD1-G93A ALS mice) resulted in a time-dependent morphological change from fibroblast-like into neuron-like, concomitant with increase in the expression of Nestin and subsequent beta-tubulin III, NSE and GAP43. Moreover, signals in pathological CNS extracts of ALS mice were more effective in promoting hMSCs neurogenic differentiation than those in physiological extracts of normal adult mice. These results show that pathological condition of ALS is endowed with capacity to induce hMSCs neurogenic differentiation and hMSCs have shown a potential candidate in cellular therapy for ALS. PMID- 17703961 TI - Asymptomatic shedding of herpes simplex virus (HSV) in the oral cavity. AB - OBJECTIVE: The aim of this study was to investigate the rate of herpes simplex virus (HSV) shedding from the oral cavity, because recent studies suggest that shedding is more frequent than originally reported. Factors that could influence the rate and duration of shedding from the oral cavity were examined. METHODS: Existing epidemiologic data from 22 reports of HSV shedding from more than 3,500 individuals were analyzed with regard to demographics, frequency of sampling, and methodologic assays. RESULTS: HSV-1 was more likely to be detected than HSV-2 in the oral cavity of asymptomatic persons (7.5 odds ratio, 95% confidence interval 4.4-12.8; P < .0001). The rate of shedding was highly variable among individuals, ranging from none to 92% of days tested, and occurred in seropositive and seronegative individuals. In cell culture studies, the rate of detection on a single day was 6.3%. Polymerase chain reaction studies provided a different picture. HSV-1 DNA was present in 97 of 180 patients (53.9%) at multiple visits, with a rate of daily detection of 33.3%. The mean duration of shedding was between 1 and 3 days, but more than 3 days in about 10% of patients. CONCLUSIONS: At least 70% of the population shed HSV-1 asymptomatically at least once a month, and many individuals appear to shed HSV-1 more than 6 times per month. Shedding of HSV-1 is present at many intraoral sites, for brief periods, at copy numbers sufficient to be transmitted, and even in seronegative individuals. The dental implications of these findings are discussed. PMID- 17703962 TI - Conventional radiographs: are they still the standard in localization of projectiles? AB - The penetration of air gun pellets in facial soft tissue can cause major problems during the removal of foreign bodies, although conventional radiography, computed tomography, image-guided surgical removal, and ultrasound have been applied to facilitate the procedure. It was the aim of the present case report to introduce a modified intraoperative method for the localization of air gun pellets, based on the use of radiopaque markers in conventional radiographs. A 66-year-old patient attempted to commit suicide by using an air gun. The pellet hit the right temporal region. A computed tomographic (CT) scan was acquired to localize the foreign body. The first attempt to remove the pellet through the penetrating wound failed. Because of a dislodgement of the pellet, the CT scan could no longer be used for the localization of the air gun pellet. As the air gun pellet was positioned under the zygomatic arch, ultrasound was unable to identify its position. Successful intraoperative localization of the projectile was performed after fixation of radiopaque markers to the skin in the region of the estimated localization, with conventional radiographs in 2 planes, acquired with a mobile dental x-ray device. Although the markers remained attached to the patient as reference makers, the air gun pellet was removed easily. The use of radiopaque markers in conventional radiographs in 2 planes allows fast, intraoperative localization of radiopaque foreign bodies within soft tissue. The procedure can be carried out with a conventional x-ray device that should be available in every oral and maxillofacial practice. The use of reference markers should be considered a standard procedure for the localization of radiopaque foreign bodies in the head and neck. PMID- 17703960 TI - Enhanced neuronal excitability in rat CA1 pyramidal neurons following trace eyeblink conditioning acquisition is not due to alterations in I M. AB - Previous work done by our laboratory has demonstrated a reduction of the post burst afterhyperpolarization (AHP) and accommodation following trace eyeblink conditioning in rabbit CA1 pyramidal neurons. Our laboratory has also demonstrated a reduction in the AHP in rat CA1 pyramidal neurons following spatial learning. In the current study we have extended our findings in rabbits by showing a reduction in both the AHP and accommodation in F344 X BN rat CA1 pyramidal neurons following acquisition of trace eyeblink conditioning. A component current of the AHP, I(M), was evaluated with a specific blocker of this current, and showed no apparent contribution to the learning-related increase in neuronal excitability. Rather, a reduction in an isoproterenol-sensitive component of the AHP, presumably sI(AHP), was observed to underlie the learning specific change. PMID- 17703963 TI - Cephalometric characteristics and dentofacial abnormalities of pycnodysostosis: report of four cases from Brazil. AB - Pycnodysostosis (PKND) is a human autosomal recessive genetic disorder characterized mainly by osteosclerosis of the skeleton, severe bone fragility, and short stature. This syndrome usually presents very typical craniofacial deformities, such as beaked nose, micrognathia, hypoplastic midface, open mouth posture, grooved palate, anterior cross-bite, dental crowding, and over-retained deciduous teeth. Early diagnosis and intervention are of the utmost importance. Four cases from the northeast of Brazil are reported including 2 siblings. Features included maxillary retrusion, reduced facial height, open bite, and bone fracture history. Very poor oral hygiene, severe dental caries, and periodontal disease were also present. PMID- 17703964 TI - Central giant cell granuloma of the jaw: a review of the literature with emphasis on therapy options. AB - Central giant cell granuloma (CGCG) is a benign lesion of the jaws with an unknown etiology. Clinically and radiologically, a differentiation between aggressive and non-aggressive lesions can be made. The incidence in the general population is very low and patients are generally younger than 30 years. Histologically identical lesions occur in patients with known genetic defects such as cherubism, Noonan syndrome, or neurofibromatosis type 1. Surgical curettage or, in aggressive lesions, resection, is the most common therapy. However, when using surgical curettage, undesirable damage to the jaw or teeth and tooth germs is often unavoidable and recurrences are frequent. Therefore, alternative therapies such as injection of corticosteroids in the lesion or subcutaneous administration of calcitonin or interferon alpha are described in several case reports with variable success. Unfortunately, randomized clinical trials are very rare or nonexistent. In the future, new and theoretically promising therapy options, such as imatinib and OPG/AMG 162, will be available for these patients. PMID- 17703965 TI - Validity of a newly developed ultraminiature cordless EMG measurement system. AB - To verify validity of a newly developed ultraminiature EMG measurement system (BMS), the ability of BMS to record masseteric EMG was compared with that of a conventional polygraph system (PG) in the daytime. Effective distance between the transmitter unit and receiver unit of BMS was also examined. Subjects were 12 healthy volunteers. During tapping, maximum clenching, and gum chewing of all subjects, distinct bursts were observed in EMG recorded by BMS as well as PG. RMS values of maximum clenching measured by BMS and PG showed a linear and significant correlation, and there was no significant difference between the data of BMS and PG. When distance between the transmitter unit and receiver unit of BMS was 100 cm or less, no artifact signal was observed. Having obtained these findings suggesting ability for precise measurement in the daytime, we are planning to use BMS in home sleep studies in the next step. PMID- 17703966 TI - Orofacial granulomatosis of the lower lip and cheek: report of a case. AB - Orofacial granulomatosis (OFG) is a granulomatous disease of the orofacial region. This clinicopathological entity describes patients with oral lesions characterized by persistent and/or recurrent labial enlargement, ulcers, and a variety of other orofacial features, which on biopsy have lymphedema and noncaseating granulomas. The cause is idiopathic but appears to represent an abnormal immune reaction. This may be a manifestation of Crohn's disease (CD) since some patients with oral lesions develop typical bowel symptoms of CD in ensuing months to years; tooth-associated infections, sarcoidosis, food or contact allergies, and viruses have also been implicated in causing OFG. Clinical features of OFG are highly variable and sometimes so insidious that signs and symptoms are frequently not severe enough to cause alarm. The lips are most commonly involved and demonstrate a nontender, persistent swelling. Because of the relatively nonspecific clinical findings associated with granulomatous diseases, a microscopic diagnosis of granulomatous inflammation often presents a diagnostic dilemma for clinicians. We report a case of OFG of the lower lip and cheek and describe its management to add to the current body of literature on the subject. PMID- 17703967 TI - Synovial sarcoma of the temporomandibular joint area: report of a case. AB - Synovial cell sarcoma is a relatively rare tumor of mesenchymal origin. It is a high-grade neoplasm that microscopically shows a monophasic or biphasic cellular pattern and includes epithelial features as well as supporting tissue features. Surgical excision is the primary mode of treatment. Postoperative radiotherapy and chemotherapy also is seen to be helpful. Between 3% and 10% of cases originate in the head and neck. A review of relevant literature shows less than 10 cases of synovial cell sarcoma of the temporomandibular joint area reported in the English literature. We report an additional case of biphasic synovial cell sarcoma arising in the temporomandibular joint area, which caused ear pain, tinnitus, and hearing loss, and we further discuss the clinical features, histopathology, differential diagnosis, and treatment modality. PMID- 17703968 TI - Evaluation of precision of length determination with 3 electronic apex locators: Root ZX, Elements Diagnostic Unit and Apex Locator, and RomiAPEX D-30. AB - OBJECTIVE: The aim of this study was to perform a comparative analysis of precision of 3 apex locators: Root ZX, Elements Diagnostic Unit and Apex Locator, and RomiAPEX D-30. STUDY DESIGN: Forty extracted single-rooted human teeth were selected. After endodontic access, measurement of the anatomical tooth length was visually performed by insertion of a K-file size 10 until its tip could be observed at the apical foramen with aid of a light microscope at 8x magnification. Following, the teeth were placed in a plastic box with alginate and electronically measured with the 3 apex locators at 1-mm short of the apical foramen. RESULTS: The results revealed a precision rate of 97.5% for Root ZX, 95% for Elements Diagnostic Unit and Apex Locator, and 92.5% for RomiAPEX D-30, with no statistically significant difference between them (chi-square test, P > .05). CONCLUSION: The results confirm that all these electronic devices can accurately determine the root canal length within 1 mm from the apical constriction. PMID- 17703969 TI - Retromolar space analysis in relation to selected linear and angular measurements for an Iraqi sample. AB - BACKGROUND: Radiographic diagnosis of the presence, position, and degree of third molar formation is a crucial part of integral treatment planning for the development of this tooth. Shortage of eruption space between lower second molar and the ramus has long been identified as a major factor in the etiology of lower third molar impaction. The purpose of the present investigation was to evaluate the validity of some angular and linear measurements made on digital panoramic imaging to be used as a reference for early prediction of lower third molar eruption or impaction. SUBJECTS AND METHODS: Digital panoramic imaging was done on 50 individuals with full dentition and a class I occlusal relationship. The sample was divided into full-eruption and marginal-eruption groups. Nine variables (linear measurements and angles) were measured for every individual to determine the minimal and maximal values of each variable and these variables were correlated to each other using Pearson's correlation equation. RESULTS: Lower eruption space measurements for the marginal-eruption group were smaller by more than 3 to 4 mm than that of the full-eruption group. The beta-angle, the angle formed between the long axes of lower second and third molars, showed a marked increase in their values (9 degrees to 10 degrees) when the marginal eruption group is compared to the full-eruption group. CONCLUSION: Third molar angle (alpha-angle), beta-angle, and gonial angle together with lower eruption space measurements are the variables that should be taken into consideration when early prediction of lower third molar eruption is performed. PMID- 17703970 TI - Cytotoxic effects of hard-setting cements applied on the odontoblast cell line MDPC-23. AB - OBJECTIVE: The present study evaluated the cytotoxic effects of hard setting applied on the odontoblastlike cells MDPC-23. STUDY DESIGN: Eighty round-shaped samples were prepared with the following experimental materials: calcium hydroxide, Vitrebond, RelyX Luting, and RelyX Unicem. The samples were placed in serum-free culture medium and incubated for 24 hours or 7 days at 37 degrees C with 5% CO2 and 95% air. The odontoblast cells were plated in the wells and incubated for 72 hours. After this period, the complete culture medium was replaced by the extracts obtained from every sample, and the methyltetrazolium assay was carried out to evaluate the cell metabolism. RESULTS: For the 24-hour period, the experimental materials calcium hydroxide, Vitrebond, RelyX Luting, and RelyX Unicem decreased the cell metabolic activity by 91.52%, 81.14%, 78.17%, and 2.64%, respectively. For the 7-day period, calcium hydroxide, Vitrebond, RelyX Luting, and RelyX Unicem decreased the metabolic activity of the MDPC-23 cells by 91.13%, 87.27%, 79.04%, and 10.51%, respectively. CONCLUSION: RelyX Unicem presented the lowest cytopathic effects to the cultured odontoblast cell line. PMID- 17703971 TI - A quantitative evaluation of sealing ability of 4 obturation techniques by using a glucose leakage test. AB - OBJECTIVE: The aim of this study was to evaluate the sealing ability of 4 different obturation techniques by using a glucose leakage test. STUDY DESIGN: Eighty extracted single-rooted maxillary incisors were selected for the study. The teeth were decoronated and the root canals prepared using ProFile rotary instruments to an apical dimension of size 40 (0.06 taper). The specimens were then randomly divided into 4 experimental groups (n = 15) and filled with gutta percha and sealer by using either cold lateral compaction, warm vertical compaction, Thermafil, or the E & Q Plus system. Another 10 teeth each served as the positive and negative controls. A glucose leakage model was used for quantitative evaluation of the coronal-to-apical microleakage at 24 hours, 1, 2, 3, 5, 8, and 12 weeks. RESULTS: No significant difference in the cumulative amount of leakage was found among the 4 groups at 24 hours and 1 week (Kruskal Wallis test, P > .05). Lateral compaction showed significantly more leakage than the other 3 techniques at longer intervals (Mann-Whitney U test, P < .008). No significant difference was found between vertical compaction, Thermafil, and E & Q Plus at all observation times. CONCLUSIONS: Warm vertical compaction, Thermafil, and the E & Q Plus system showed a better sealing result than cold lateral compaction of gutta-percha at extended observation periods. The glucose leakage method used in this study was able to provide a nondestructive, quantitative, and long-term evaluation of the sealing ability of root canal fillings. PMID- 17703972 TI - The Aspergillus nidulans cetA and calA genes are involved in conidial germination and cell wall morphogenesis. AB - The Aspergillus nidulans genes cetA (AN3079.2) and calA (AN7619.2) encode a novel class of fungal thaumatin-like proteins of unknown function. Deletion of cetA does not result in an observable phenotype [Greenstein, S., Shadkchan, Y., Jadoun, J., Sharon, C., Markovich, S., Osherov, N., 2006. Analysis of the Aspergillus nidulans thaumatin-like cetA gene and evidence for transcriptional repression of pyr4 expression in the cetA-disrupted strain. Fungal Genet. Biol. 43, 42-53]. We prepared knockout calA and calA/cetA A. nidulans strains. The calA mutants were phenotypically identical to the wild-type. In contrast, the cetA/calA double mutant showed a synthetic lethal phenotype suggesting that the two genes affect a single function or pathway: most of its conidia were completely inhibited in germination. Many collapsed and underwent lysis. A few showed abnormal germination characterized by short swollen hyphae and abnormal hyphal branching. Nongerminated conidia contained a single condensed nucleus suggesting a block in early germination. This is the first functional analysis of the novel cetA/calA family of thaumatin-like genes and their role in A. nidulans conidial germination. We show that CETA and CALA are secreted proteins that together play an essential role in early conidial germination. PMID- 17703973 TI - Transient disruption of non-homologous end-joining facilitates targeted genome manipulations in the filamentous fungus Aspergillus nidulans. AB - We have developed a transiently disrupted nkuA system in Aspergillus nidulans for efficient gene targeting. The nkuA disruption was made by inserting a counter selectable marker flanked by a direct repeat (DR) composed of nkuA sequences. In the disrupted state, the non-homologous end-joining (NHEJ) activity is abolished and gene targeting can be performed with success rates identical to those obtained with permanent nkuA knock-out strains. When gene targeting is complete, the functional nkuA allele can be re-established via a simple selection step, thereby eliminating the risk that defective NHEJ influences subsequent analyses of the manipulated strain. Our system will facilitate construction of large numbers of defined mutations in A. nidulans. Moreover, as the system can likely be adapted to other filamentous fungi, we expect it will be particularly beneficial in species where NHEJ cannot be restored by sexual crossing. PMID- 17703974 TI - Synergistic interaction between meloxicam and aminoguanidine in formalin-induced nociception in mice. AB - OBJECTIVES: The objective of this study was to examine the nature of interaction between cyclooxygenase-2 inhibitor meloxicam and inducible nitric oxide synthase inhibitor aminoguanidine in formalin-induced nociception in mice and the possible therapeutic advantage. METHODS: Antinociceptive effect of meloxicam (1, 3, 10 and 30 mg/kg, oral) and aminoguanidine (10, 30, 100 and 300 mg/kg, oral) and their combinations was examined in formalin-induced paw licking model in mice. Analysis of variance and isobolographic method were employed to identify the nature of antinociceptive interaction. RESULTS: Higher doses of meloxicam (10 and 30 mg/kg) and aminoguanidine (100 and 300 mg/kg) produced significant reduction in paw licking time (antinociceptive) in late phase of formalin-induced nociception. Combination of sub-threshold dose of meloxicam (3 mg/kg) with increasing doses of aminoguanidine (10, 30, 100 and 300 mg/kg) resulted in synergistic antinociceptive effect. Similarly, co-administration of sub-threshold dose of aminoguanidine (30 mg/kg) with increasing doses of meloxicam (1, 3, 10 and 30 mg/kg) produced significant reduction in formalin-induced paw licking behaviour. The experimental ED(50) for combination with their confidence limits are below the confidence interval of theoretical line of additive interaction, suggesting synergistic nature of interaction between meloxicam and aminoguanidine in isobolographic analysis. CONCLUSION: Co-administration of meloxicam and aminoguanidine showed synergistic antinociceptive effect which might possibly reduce gastrointestinal toxicity associated with the use of meloxicam. PMID- 17703975 TI - Precision and sensitivity optimization of quantitative measurements in solid state NMR. AB - This work presents a methodology for optimizing the precision, accuracy and sensitivity of quantitative solid state NMR measurements based on the external reference method. It is shown that the sample must be exclusively located within and completely span the coil region where the NMR response is directly proportional to the sample amount. We describe two methods to determine this "quantitative" coil volume, based on whether the probe is equipped or not with a gradient coil. In addition, to improve the sensitivity and the accuracy, an optimum rotor packing design is described, which allows the sample volume of the rotor to be matched to the quantitative coil volume. Experiments conducted on adamantane and NaCl, which are representative of a soft and hard material, respectively, show that one order of magnitude increase in experimental precision can be achieved with this methodology. Interestingly, the precision can be further improved by using the ERETIC method in order to compensate for most instrumental instabilities. PMID- 17703977 TI - Effect of ascites on bone density measurement in cirrhosis. AB - Cirrhosis is an independent risk factor for the development of osteoporosis. The presence of ascites in patients with cirrhosis may affect the accuracy of bone density measurement in the spine. Twenty cirrhotic patients had bone mineral density (BMD) measurements of the lumbar spine, femoral neck, hip, and total body using dual-energy X-ray absorptiometry (DXA; Lunar Prodigy) before and after large-volume paracentesis. To establish short-term precision of DXA measurement, 28 healthy adults also had duplicate BMD measurements on the same day. After paracentesis (6.4+/-2.0 L), there was a significant increase in the spine BMD of 4.2% (p=0.003) and in the total hip BMD of 1.3% (p=0.002), but there was no change in the femoral neck or total body. No significant differences (p>0.1) were seen in duplicate BMD measurements at any site among the healthy cohort. Within patient changes in spine (p=0.001) and total hip (p=0.001) BMD measurements were significantly greater in patients with ascites than in the healthy cohort. These changes in BMD measurements were not associated with age, gender, amount of fluid removed, or time interval between measurements. These results suggest that ascites cause a fluid artifact in the soft tissue and bone interface that can falsely lower BMD measurements, particularly in the spine. PMID- 17703976 TI - The safety and effects of the beta-blocker, nadolol, in mild asthma: an open label pilot study. AB - Beta-blockers are currently contraindicated in asthma because their acute administration may be associated with worsening bronchospasm. However, their effects and safety with their chronic administration are not well evaluated. The rationale for this pilot study was based on the paradigm shift that was observed with the use of beta-blockers in congestive heart failure, which once contraindicated because of their acute detrimental effects, have now been shown to reduce mortality with their chronic use. We hypothesized that certain beta blockers may also be safe and useful in chronic asthma therapy. In this prospective, open-label, pilot study, we evaluated the safety and effects of escalating doses of the beta-blocker, nadolol, administered over 9 weeks to 10 subjects with mild asthma. Dose escalation was performed on a weekly basis based on pre-determined safety, lung function, asthma control and hemodynamic parameters. The primary objective was to evaluate safety and secondary objectives were to evaluate effects on airway hyperresponsiveness, and indices of respiratory function. The escalating administration of nadolol was well tolerated. In 8 out of the 10 subjects, 9 weeks of nadolol treatment produced a significant, dose-dependent increase in PC20 that reached 2.1 doubling doses at 40 mg (P<0.0042). However, there was also a dose-independent 5% reduction in mean FEV1 over the study period (P<0.01). We conclude that in most patients with mild asthma, the dose-escalating administration of the beta-blocker, nadolol, is well tolerated and may have beneficial effects on airway hyperresponsiveness. Our findings warrant further testing in future larger trials. PMID- 17703978 TI - Thermal relationships and exercise physiology in anuran amphibians: integration and evolutionary implications. AB - Thermal and water balance are coupled in anurans, and species with particularly permeable skin avoid overheating more effectively than minimizing variance of body temperature. In turn, temperature affects muscle performance in several ways, so documenting the mean and variance of body temperature of active frogs can help explain variation in behavioral performance. The two types of activities studied in most detail, jumping and calling, differ markedly in duration and intensity, and there are distinct differences in the metabolic profile and fiber type of the supporting muscles. Characteristics of jumping and calling also vary significantly among species, and these differences have a number of implications that we discuss in some detail throughout this paper. One question that emerges from this topic is whether anuran species exhibit activity temperatures that match the temperature range over which they perform best. Although this seems the case, thermal preferences are variable and may not necessarily reflect typical activity temperatures. The performance versus temperature curves and the thermal limits for anuran activity reflect the thermal ecology of species more than their systematic position. Anuran thermal physiology, therefore, seems to be phenotypically plastic and susceptible to adaptive evolution. Although generalizations regarding the mechanistic basis of such adjustments are not yet possible, recent attempts have been made to reveal the mechanistic basis of acclimation and acclimatization. PMID- 17703979 TI - Type 2 diabetes mellitus: epidemiology, pathophysiology, unmet needs and therapeutical perspectives. AB - In France, prevalence of drug-treated diabetes reached 3.60% in 2005, with 92% of type 2 diabetic patients. In 2007, there are probably nearly 3000 000 diagnosed or undiagnosed diabetic patients. Ageing of the population and increase in obesity are the main causes of this "diabetes epidemic". Type 2 diabetes is a multifactorial disease, defined as resulting from defects in insulin secretion (including abnormalities in pulsatility and kinetics, quantitative and qualitative abnormalities of insulin, beta-cell loss progressing with time) associated with insulin resistance (affecting liver, and skeletal muscle) and increased glucagon secretion. The lack of compensation of insulin resistance by augmented insulin secretion results in rise in blood glucose. To achieve satisfactory glycaemic control in order to prevent diabetes related complications, drug therapy is generally required in addition to life style changes. Currently available oral therapies offer a large panel of complementary drugs, but they have several contraindications and side effects. In spite of major advances in the management of type 2 diabetes, and the strictness of new guidelines, some goals remain unachieved and the new family of insulin-secretors (DPP-IV inhibitors, GLP-1 analogues) should enrich therapeutic approaches. PMID- 17703981 TI - [What a healthy lifestyle stands for at the menopause: the role of the gynaecologist]. AB - Post-menopausal osteoporosis is a public health problem, because of its extreme frequency and its related fractures. Gynaecologists play an important role in the early detection of patients whose bones are at risk. During the consultation, a routine examination, asking pertinent questions and taking height and weight measurements, allows for the discovery of modifiable risk factors - diet, life style: physical activity, alcohol and tobacco consumption, etc. Gynaecologists are in a particularly good position to intervene. Indeed, they can inform and advise these patients at risk, by recommending a diet rich in calcium, vitamin D and protein, maintaining a healthy BMI, a sufficient exposure to sunlight, daily physical activity with a preference for weight-bearing exercise, avoiding smoking and excessive alcohol. These simple changes for a healthy life style can slow down the loss of bone density, and this well before any loss due to estrogen deficiency. PMID- 17703982 TI - [In vitro fertilization (IVF): why doing it in stimulated cycles?]. AB - Assisted reproductive technology is a difficult course for the couples. Our purpose is to be effective without damaging the patient and the child to be born. The cumulative rates of success are strictly dependent on the number of oocytes and on the obtained top quality embryos and thus on the realization of an effective stimulation. The risk of multiple pregnancies can be adjusted by an adapted policy of transfer. The transfer of a fresh embryo followed by cycles of frozen embryos transfers gives very satisfactory cumulative pregnancy rates. PMID- 17703980 TI - A pediatric case of pyomyositis presenting with septic pulmonary emboli. AB - Pyomyositis is a suppurative infection of skeletal muscle most commonly caused by Staphylococcus aureus. It is mainly encountered in children and immunocompromised. Eight year old previously healthy girl presented with confusion, fever and swelling of the right knee two days after a trauma. Abdominal ultrasonography and computerized tomography taken upon development of hematemesis revealed no pathology in the abdomen, but potential bleeding sites in lung sections. Thorax CT images were interpreted in favor of septic pulmonary emboli due to the presence of peripheral nodular consolidation areas with central cavitation, mostly pathchy in medial areas. S. aureus was isolated in the blood culture. At the end of third week of hospitalization, gadolinium enhanced contrast MRI of right extremity was taken to evaluate right extremity swelling and revealed abscess formation as expected in the clinical progress of pyomyositis. Pyomyositis and septic pulmonary emboli are a rare association. This case demonstrates that the high index of suspicion in pediatric cases with muscle findings and septic pulmonary findings and early institution of therapy may improve the prognosis. PMID- 17703983 TI - Experimental investigation of cavitational bubble dynamics under multi-frequency system. AB - Acoustic emission spectra measurements have been carried out under mono and multi frequency acoustic sources to understand the fundamental difference in bubble/cavity dynamics. The effect of introducing the dual and triple frequency acoustic waves of different frequency on the sono-chemical yield has also been investigated experimentally. The introduction of a second wave has increased the number of cavitating bubbles and as well as the collapsing intensity of cavities resulting into higher sono-chemical yield, and better effective utilization of reactor volume with a large number of resonating cavitating bubbles. To get the information about the intensity of each of the cavity oscillating events, decomposition of the pressure signal measured by the hydrophone in the frequency domain of the FFT power spectrum has been carried out. Inverse fourier reconstruction technique, has been used to elaborate the dynamics of the cavitating bubbles in the multi-frequency system. PMID- 17703984 TI - Association between Parkinson's disease and glucocerebrosidase mutations in Brazil. AB - OBJECTIVE: To evaluate the association between parkinsonism and mutations in the glucocerebrosidase gene (GBA) in Brazilian patients. METHODS: We searched for three GBA common mutations (N370S, L444P and G377S) in 65 Brazilian patients affected by PD with disease onset before the age of 55 and compared the results to 267 age- and sex-matched controls. RESULTS: GBA mutations were detected at a significantly higher frequency among Parkinson's disease patients (2/65=3%), when compared to the control group (0/267): P=0.0379. CONCLUSION: These results provide further evidence for GBA mutations being a possible hereditary risk factor for PD. PMID- 17703985 TI - Further evidence of genetic heterogeneity in familial essential tremor. AB - Familial essential tremor (FET) is a common hereditary movement disorder with phenotypic variability and genetic heterogeneity. To date, linkage analyses revealed three loci associated to essential tremor (ET) (ETM1 on 3q13, ETM2 on 2p22-25, and a locus on 6p23). We performed a genetic analysis of these candidate chromosomal regions in a fifth-generation Italian kindred with autosomal-dominant ET. Of the 22 clinically evaluated family members, nine were affected by ET. The genetic study indicates that the ET in this family is not associated to any of the known ET loci. These findings support evidence of further genetic heterogeneity for such disease. PMID- 17703986 TI - The role of interferon-alpha in the treatment of chronic myeloid leukemia. AB - Biological agents have long been used in the treatment of cancer, and interferon alpha was the first human cytokine to be widely studied in this setting. Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder for which interferon alpha has demonstrated substantial activity. In the 1980s interferon-alpha became first-line therapy for patients with chronic-phase CML, not eligible for allogeneic stem cell transplantation. Following the discovery of the leukemic oncogene BCR/ABL and its causal association with CML, the potent BCR/ABL tyrosine kinase inhibitor imatinib mesylate was developed. Imatinib proved to be superior to interferon-alpha in all outcome measures, making imatinib the new standard of care for patients with CML. There is both clinical and laboratory evidence suggesting imatinib therapy alone is not curative in CML, whereas IFN has induced a low but reproducible curative effect in some patients. This unique activity may be the basis for the reincorporation of IFN into the management of CML. These observations may be best explained by imatinib's negligible activity against the leukemic stem cell (LSC) population. This review discusses the history of interferon-alpha in the treatment of CML, the evolution of molecularly targeted therapies, and some of the lessons we have learned from years of informative research in CML. It also explores the new challenge of managing minimal residual disease in the imatinib era, and addresses the promising role for LSC-directed therapies in the future treatment of CML. PMID- 17703987 TI - Tonometer prism sterilisation: a local and UK national survey. AB - PURPOSE: First to audit local adherence to a protocol of use of an alcohol wipe for each tonometry, and secondly to assess current practice nationally in the UK. METHOD: The audit was carried out at two units: The West Kent Eye Centre at the Princess Royal University Hospital (Orpington, UK) and Queen Mary's Hospital (Sidcup, UK). The standard set for this audit was 100% sterilisation. During a 1 week period in November 2005, the number of alcohol wipes was counted in each consultation room after outpatient clinics, with the doctors being assessed blind to the survey. The number of Goldman applanation tonometry intra-ocular pressures recorded by each clinician was counted by inspection of the medical records of patients seen. Secondly, departments listed in the UK Directory of Training Posts were contacted by telephone and the senior nurse was interviewed. They were asked directly about their department's tonometer prism sterilisation and management. RESULTS: The local audit showed only 54% of tonometry measurements were associated with sterilisation using an alcohol-impregnated wipe. The national survey included 140 of the 152 UK training departments. Thirty-three (23.6%) departments used disposable tonometer prisms routinely. The remaining 107 (76.4%) used non-disposable prisms. Eighty-five (60.7%) departments provided sodium hypochlorite for prism sterilisation, with 69 (81.2%) of these departments providing more than one prism/clinician to allow full exposure to the disinfectant. Twenty-two (15.7%) departments used alcohol wipes. Only 8 (7.5%) of the 107 departments using non-disposable prisms tracked these prisms, despite Royal College of Ophthalmologists guidelines that they should be. These same 8 (7.5%) departments replaced the non-disposable prisms as per manufacturer guidelines. 19.3% of charge nurses were aware of a policy for tonometry in patients with, or at risk of, prion disease. CONCLUSIONS: This study highlights that sterilisation of tonometer prisms was inconsistent in a local audit. Nationally, practices were varied. The majority of ophthalmology departments continued to use non-disposable tonometer prisms, but few seemed aware of the Royal College of Ophthalmologists' recommendation that disposable prisms are used in patients at risk of prion disease, and few track tonometer heads or replace them according to manufacturers guidelines. Use of disposable tonometer prisms would seem to reduce concerns about sterilisation, as well as prevent spread of common pathogens. PMID- 17703988 TI - Mapping the genome landscape using tiling array technology. AB - With the availability of complete genome sequences for a growing number of organisms, high-throughput methods for gene annotation and analysis of genome dynamics are needed. The application of whole-genome tiling microarrays for studies of global gene expression is providing a more unbiased view of the transcriptional activity within genomes. For example, this approach has led to the identification and isolation of many novel non-protein-coding RNAs (ncRNAs), which have been suggested to comprise a major component of the transcriptome that have novel functions involved in epigenetic regulation of the genome. Additionally, tiling arrays have been recently applied to the study of histone modifications and methylation of cytosine bases (DNA methylation). Surprisingly, recent studies combining the analysis of gene expression (transcriptome) and DNA methylation (methylome) using whole-genome tiling arrays revealed that DNA methylation regulates the expression levels of many ncRNAs. Further capture and integration of additional types of genome-wide data sets will help to illuminate additional hidden features of the dynamic genomic landscape that are regulated by both genetic and epigenetic pathways in plants. PMID- 17703990 TI - Bacterial morphogenesis: learning how cells make cells. AB - Bacteria furnish tractable models for complex biological processes, and morphogenesis is now taking its turn. We can already explain in general terms how such elementary forms as rods and cocci are produced, and the shapes of several individual organisms are coming into focus. In most bacteria shape is maintained by the cell wall, specifically the peptidoglycan layer, which has the attributes of a strong stiff fabric. Compliance of that fabric with turgor pressure is an important aspect of morphogenesis. The shape of the wall sacculus is determined by the way it is deposited, which is controlled by a cytoskeleton made up of two molecular families. One, related to the eukaryotic tubulins, is responsible for the construction of the septum and the poles. The other, related to eukaryotic actins, localizes peptidoglycan synthesis in the lateral walls of rod-shaped cells. Just how the cytoskeleton itself is organized remains to be discovered, but it seems likely that, as in eukaryotes, the cytoskeleton is produced by self organized assembly, guided by the fabric of the cell. PMID- 17703991 TI - Diversity-generating retroelements. AB - Parasite adaptation to dynamic host characteristics is a recurrent theme in biology. Diversity-generating retroelements (DGRs) are a newly discovered family of genetic elements that function to diversify DNA sequences and the proteins they encode. The prototype DGR was identified in a temperate bacteriophage, BPP 1, on the basis of its ability to generate variability in a gene that specifies tropism for receptor molecules on host Bordetella species. Tropism switching is a template-dependent, reverse transcriptase mediated process that introduces nucleotide substitutions at defined locations within a target gene. This cassette based mechanism is theoretically capable of generating trillions of different amino acid sequences in a distal tail fiber protein, providing a vast repertoire of potential ligand-receptor interactions. Variable residues are displayed in the context of a specialized C-type lectin fold, which has evolved a unique solution for balancing protein diversity against structural stability. Homologous DGRs have been identified in the chromosomes of diverse bacterial species. These unique genetic elements have the potential to confer powerful selective advantages to their hosts, and their ability to generate novel binding specificities and dynamic antimicrobial agents suggests numerous applications. PMID- 17703992 TI - Spectrophotometric study of anionic azo-dye light yellow (X6G) interaction with surfactants and its micellar solubilization in cationic surfactant micelles. AB - Solubilization and interaction of azo-dye light yellow (X6G) at/with cationic surfactants cetyltrimethylammonium bromide (CTAB) and cetylpyridinium chloride (CPC) was investigated spectrophotometricaly. The effect of cationic micelles on solubilization of anionic azo dye in aqueous micellar solutions of cationic surfactants was studied at pH 7 and 25 degrees C. The binding of dye to micelles implied a bathochromic shift in dye absorption spectra that indicates dye surfactant interaction. The results showed that the solubility of dye increased with increasing surfactant concentration, as a consequence of the association between the dye and the micelles. The binding constants, K(b), were obtained from experimental absorption spectra. By using pseudo-phase model, the partition coefficients between the bulk water and surfactant micelles, K(x), were calculated. Gibbs energies of binding and distribution of dye between the bulk water and surfactant micelles were estimated. The results show favorable solubilization of dye in CTAB micelles. PMID- 17703993 TI - Irradiated lithium formate and amino acids. AB - Radiation-induced free radicals in solids show a microwave saturation effect when studied by electron spin resonance. A comparison is made between such effects in lithium formate and amino acids. The relative effectiveness of neutrons against high-energy photons is also considered. PMID- 17703995 TI - Coupling between punch efficacy and body stability for elite karate. AB - In order to be successful in karate, it is necessary to apply the highest punch impulse at impact while maintaining dynamic body stability during the entire action. Here we test two different techniques to execute a specific karate punch and we compare expert and novice performances to explore the punch efficacy at different skill levels. Each participant, standing on a force platform, was asked to punch a 25kg box as hard as possible. The Centre of Pressure (CoP) migration and the kinematics of the upper limb were analysed. Experts (compared to novices) showed, as expected, higher upper limb velocity, punch impulse and a larger box displacement. Interestingly, while the CoP area considered both during and after the punch was the same for both groups, the amount of backward CoP displacement per unit of impulse applied was significantly lower for experts compared to novices. Collectively these results show the specific strategy used to maintain body stability in karate experts. PMID- 17703994 TI - Severe Epstein-Barr virus-associated hemophagocytic syndrome in six adult patients. AB - BACKGROUND: EBV associated hemophagocytic syndrome (HPS) is an aggressive and potentially life-threatening condition. So far, most EBV associated HPS has been characterized mainly in infants and children in Asian countries. RESULTS: Here, we report six cases of EBV associated HPS occurring in previously healthy adults in a non-endemic area within a short period of 3 years. All patients presented with fever, hepatosplenomegaly and pancytopenia as well as disturbed liver function tests and coagulopathy. Half were diagnosed as having lymphoma. While EBV-specific serological assays were non-diagnostic in four of the six patients, the presence of EBV DNA in plasma allowed the diagnosis of EBV associated HPS in all patients. CONCLUSION: EBV associated HPS may be more prevalent in non Japanese adults than was previously considered. Screening for hemophagocytic syndrome, in adults as well as in children, should include real-time PCR for EBV. PMID- 17703996 TI - EMG activity is not elevated during exercise-related transient abdominal pain. AB - Skeletal muscle cramp has been proposed as the aetiology of exercise-related transient abdominal pain (ETAP). The aim of this study was to determine whether or not localised electromyographic (EMG) activity indicative of skeletal muscle cramp is elevated during ETAP. Surface EMG activity was quantified at the site of ETAP in 14 symptomatic individuals (ETAP group) while the pain was present and after the pain subsided. Additionally, measurements were taken in another 14 subjects (Comparison group) who performed the same experimental procedure but did not experience ETAP. In the ETAP group, localised EMG activity did not increase when the pain was present or decrease when the pain subsided. The level of EMG activity detected while the pain was present was indistinguishable from noise (0.20+/-0.18microV). No difference was observed between the ETAP and Comparison groups in the level of localised EMG activity (p=0.89) at any time. After the pain subsided in the ETAP group, EMG activity was recorded at the site of the pain while the subjects performed a diaphragm-dependent sniff manoeuvre (8.3+/ 0.7microV) and a maximum voluntary contraction of the abdominal muscles (17.5+/ 0.7microV). It was concluded that ETAP is not associated with elevated EMG activity, suggesting that the pain is not the result of muscle cramping. PMID- 17703997 TI - Physiological and electromyographic responses during 40-km cycling time trial: relationship to muscle coordination and performance. AB - The purpose of this study was to compare the oxygen uptake (VO(2)), respiratory exchange ratio (RER), cadence and muscle activity during cycling a 40-km time trial (TT), and to analyse the relationship between muscle activity and power output (PO). Eight triathletes cycled a 40-km TT on their own bicycles, which were mounted on a stationary cycle simulator. The VO(2), RER and muscle activity (electromyography, EMG) from tibialis anterior (TA), gastrocnemius medialis (GA), biceps femoris (BF), rectus femoris (RF) and vastus lateralis (VL) of the lower limb were collected. The PO was recorded from the cycle simulator. The data were collected at the 3rd, 10th, 20th, 30th and 38th km. The root mean square envelope (RMS) of EMG was calculated. The VO(2) and PO presented a significant increase at the 38th km (45.23+/-8.35 ml kg min(-1) and 107+/-7.11% of mean PO of 40-km, respectively) compared to the 3rd km (38.12+/-5.98 ml kg min(-1) and 92+/-8.30% of mean PO of 40-km, respectively). There were no significant changes in cadence and RER throughout the TT. The VL was the only muscle that presented significant increases in the RMS at the 10th km (22.56+/-3.05% max), 20th km (23.64+/-2.52% max), 30th km (25.27+/-3.00% max), and 38th km (26.28+/-3.57%max) when compared to the 3rd km (21.03+/-1.88%max). The RMS of VL and RF presented a strong relationship to PO (r=0.89 and 0.86, respectively, p<0.05). The muscular steady state reported for cycling a 30-min TT seems to occur in the 40-km TT, for almost all assessed muscles, probably in attempt to avoid premature muscle fatigue. PMID- 17703998 TI - Does an eccentric chainring improve conventional parameters of neuromuscular power? AB - This study compared the conventional parameters of anaerobic cycling power in physically active non-cyclists using the Pro-Race system and a traditional chainring. The force-velocity test was chosen for this purpose because it is the shortest validated cycling laboratory test in which each parameter of maximal anaerobic power can be estimated. The power output (W(max)) and the force at which W(max) is produced (F(opt)) were significantly improved with the eccentric chainring (1100+/-227W versus 1006+/-197W and 1.39+/-0.15N/kg body mass versus 1.13+/-0.16N/kg body mass with the eccentric and round designs, respectively; P<0.006 and P<0.0004, respectively). The power gained (delta power) was significantly correlated with the eccentric chainring F(opt) (r=0.649; P<0.05), the mid-thigh circumference (r=0.685; P<0.05), the estimated lean thigh volume (r=0.765; P<0.01) and the estimated lean lower limb volume (r=0.665; P<0.05). We concluded that the eccentric chainring significantly improved the estimated anaerobic power output during a force-velocity test by increasing the force component, F(opt). Cautious interpretation of our results suggests that the subjects with physical attributes that contribute to developing high forces may have a significant advantage in performing with the eccentric chainring. PMID- 17704001 TI - Images in cardiovascular medicine: prosthetic aortic valve and conduit dehiscence with large periconduit cavity, ascending aortic aneurysm and severe mitral regurgitation. AB - Prosthetic aortic valve and conduit dehiscence with periconduit cavity and ascending aortic aneurysm is an uncommon complication of aortic root surgery. It is usually recognizable at echocardiography due to an abnormal position of the prosthetic valve and conduit in relation to the native aortic annulus in conjunction with an abnormal echolucent periconduit space that fills with color flow. Mitral regurgitation is an unusual complication of this condition. We present a patient with severe mitral regurgitation secondary to prosthetic aortic valve and conduit dehiscence with a large periconduit cavity and aneurysm of the intervalvular fibrosa. The mechanism of mitral regurgitation is secondary to functional involvement of the anterior mitral valve leaflet and intervalvular fibrosa with anterior mitral leaflet restriction in conjunction with mild left ventricular remodeling. Significant mitral regurgitation persisted post resection of the periconduit cavity and aortic valve replacement, requiring mitral valve replacement. This case study reports a new mechanism of mitral regurgitation in the setting of prosthetic aortic valve and conduit dehiscence. PMID- 17704000 TI - Apoptosis in the skeletal muscle of untreated children with juvenile dermatomyositis: impact of duration of untreated disease. AB - Juvenile dermatomyositis (JDM) is the most common myopathy in children with characteristic skin rash and muscle weakness, in which longer duration of untreated disease was associated with less muscle weakness. The duration of untreated inflammation may alter the apoptotic pathways involved in skeletal muscle damage. Diagnostic muscle biopsies from 14 untreated patients were stained for apoptosis markers. TUNEL-positive nuclei and caspase 3 were detected within the laminin layer, indicating apoptosis of skeletal muscle nuclei. Untreated JDM disease duration greater than 2 months ("long"), was associated with higher Fas positive cell counts in the perivascular region compared with the "short" disease duration group, 2 months or less. Within the "long" duration group, higher Fas positive cell counts were positively associated with increased TUNEL-positive nuclei and caspase 3. We conclude that the duration of untreated disease (chronic inflammation) influences the mode of continuing cell damage and death in children with JDM. PMID- 17704002 TI - Effectiveness of diazepam rectal gel in adults with acute repetitive seizures and prolonged seizures: a single-center experience. AB - Many adults with epilepsy have breakthrough seizures despite treatment with antiepileptic drugs (AEDs), requiring them to have a rescue medication as part of a comprehensive treatment plan. We evaluated the effectiveness and tolerability of rectal diazepam in the treatment of breakthrough seizures in adult patients with epilepsy. We identified 50 such patients who had used diazepam rectal gel for clusters of seizures defined as acute repetitive seizures, prolonged seizures, or both, in the previous 18 months. Information on diagnoses, dose, frequency of use, reasons for use, safety, and efficacy was collected. Diazepam rectal gel was effective in stopping seizures in 45 patients (90%). Somnolence was reported in most patients, but no other adverse events were reported. Diazepam rectal gel demonstrates efficacy and tolerability as a seizure rescue medication for adult patients with a variety of seizure types, and may help improve quality of life. PMID- 17704003 TI - Can pentobarbital replace amobarbital in the Wada test? AB - To investigate the usefulness of pentobarbital (PTB) in the Wada test, 32 patients injected with PTB and 28 patients injected with amobarbital (AMB) were retrospectively analyzed. The AMB and PTB groups did not significantly differ with respect to mean time for recovery to grade III or V motor activity and duration of EEG delta slowing. The incidence of drowsiness or confusion after injection was lower in the PTB group (P=0.043). Language lateralization was well established in both groups. Fifty-three percent of patients in the PTB group and 46.2% in the AMB group with unilateral temporal lobe epilepsy had memory dominance in the nonepileptic hemisphere. The usefulness of PTB in terms of language and memory lateralization was found to be equivalent to that of AMB. Moreover, PTB produced drowsiness and confusion less frequently than AMB, although one patient in the PTB group experienced transient respiratory depression without any sequelae. PMID- 17704004 TI - Physical exercise in epilepsy: the case in favor. PMID- 17704005 TI - Depression and suicide in epileptic victims: a population-based study of suicide victims during the years 1988-2002 in northern Finland. AB - Patients with epilepsy are known to have comorbid affective disorders and a higher risk for suicide compared with the general population. Epilepsy, depression, and suicidal behavior have been shown to have common pathogenic mechanisms in their etiology. We evaluated the association between epilepsy, suicidal behavior, and depression by using the comprehensive database of all suicides (n=1877) committed in northern Finland during the years 1988-2002 with information on all hospital-treated somatic and psychiatric disorders. Hospital treated epilepsy occurred in 1.3% of the victims. Compared with other suicide victims, those with epilepsy were more often female, were older, and had significantly more often suffered from depression. Epilepsy was first diagnosed 8.8 (3.9-11.6) years before suicide, and depression, about 1 year after epilepsy diagnosis. Interictal depression among patients with chronic epilepsy is often classified as atypical or chronic depression, or it can mimic a dysthymic disorder. Therefore, diagnosis and treatment of depression among patients with epilepsy constitute a great challenge in clinical practice. PMID- 17704006 TI - Chronic widespread pain in veterans of the first Gulf War: impact of deployment status and associated health effects. AB - Our study sought to 1) determine if deployment status is associated with chronic widespread pain (CWP), and 2) evaluate whether veterans with CWP have greater psychiatric comorbidity, higher health care utilization, and poorer health status than veterans without CWP. Five years after the conclusion of the first Gulf War (August 1990 to June 1991), we conducted a cross-sectional study of veterans who listed Iowa as the home of record using a stratified sampling design to determine their health status. We compared the prevalence of CWP between deployed and nondeployed veterans. Logistic and multiple linear regression models were constructed to test whether CWP was associated with comorbidities and health related outcomes of interest. Five hundred ninety of 3695 veterans interviewed (16%) had CWP. Gulf deployment was associated with higher prevalence of CWP than deployment elsewhere (OR = 2.03, 95%CI = 1.60-2.58), after adjustment. Both deployed and nondeployed veterans with CWP reported more health care utilization and comorbidities and lower health-related quality of life scores than veterans without CWP. Deployed veterans were more likely to have CWP than nondeployed veterans, and CWP was associated with poor health outcomes. Military and medical personnel should be aware that efforts to prevent, identify, and treat CWP in veterans returning from the current war may be needed. PERSPECTIVE: This article indicates that deployed veterans may have an increased risk for development of CWP, which is associated with greater healthcare utilization and comorbidity and lower quality of life. The risk of poor health outcomes suggests that veterans returning from the present conflict should be screened for CWP on their return. PMID- 17704008 TI - Prognostic Bayesian networks I: rationale, learning procedure, and clinical use. AB - Prognostic models are tools to predict the future outcome of disease and disease treatment, one of the fundamental tasks in clinical medicine. This article presents the prognostic Bayesian network (PBN) as a new type of prognostic model that builds on the Bayesian network methodology, and implements a dynamic, process-oriented view on prognosis. A PBN describes the mutual relationships between variables that come into play during subsequent stages of a care process and a clinical outcome. A dedicated procedure for inducing these networks from clinical data is presented. In this procedure, the network is composed of a collection of local supervised learning models that are recursively learned from the data. The procedure optimizes performance of the network's primary task, outcome prediction, and handles the fact that patients may drop out of the process in earlier stages. Furthermore, the article describes how PBNs can be applied to solve a number of information problems that are related to medical prognosis. PMID- 17704007 TI - Inflammation-induced enhancement of the visceromotor reflex to urinary bladder distention: modulation by endogenous opioids and the effects of early-in-life experience with bladder inflammation. AB - Abdominal electromyographic (EMG) responses to noxious intensities of urinary bladder distention (UBD) are significantly enhanced 24 hours after zymosan induced bladder inflammation in adult female rats. This inflammation-induced hypersensitivity is concomitantly inhibited by endogenous opioids because intraperitoneal (i.p.) naloxone administration before testing significantly increases EMG response magnitude to UBD. This inhibitory mechanism is not tonically active because naloxone does not alter EMG response magnitude to UBD in rats without inflammation. At the dose tested, naloxone does not affect bladder compliance in rats with or without inflammation. The effects of i.p. naloxone probably result from blockade of a spinal mechanism because intrathecal naloxone also significantly enhances EMG responses to UBD in rats with inflammation. Rats exposed to bladder inflammation from P90-P92 before reinflammation at P120 show similar hypersensitivity and concomitant opioid inhibition, with response magnitudes being no different from that produced by inflammation at P120 alone. In contrast, rats exposed to bladder inflammation from P14-P16 before reinflammation at P120 show markedly enhanced hypersensitivity and no evidence of concomitant opioid inhibition. These data indicate that bladder inflammation in adult rats induces bladder hypersensitivity that is inhibited by an endogenous opioidergic mechanism. This mechanism can be disrupted by neonatal bladder inflammation. PERSPECTIVE: The present study observed that bladder hypersensitivity resulting from acute bladder inflammation is suppressed by an opioid-inhibitory mechanism. Experiencing bladder inflammation during the neonatal period can impair the expression of this opioid inhibitory mechanism in adulthood. This suggests that bladder insults during development may permanently alter visceral sensory systems and may represent 1 cause of painful bladder disorders. PMID- 17704009 TI - Genetic characterisation of Trypanosoma brucei s.l. using microsatellite typing: new perspectives for the molecular epidemiology of human African trypanosomiasis. AB - The pathogenic agent of human African trypanosomiasis (HAT) is a trypanosome belonging to the species Trypanosoma brucei s.l. Molecular methods developed for typing T. brucei s.l. stocks are for the most part not polymorphic enough to study genetic diversity within T. brucei gambiense (T. b. gambiense) group 1, the main agent of HAT in West and Central Africa. Furthermore, these methods require high quantities of parasite material and consequently are hampered by a selection bias of the isolation and cultivation techniques. In this study, we evaluated the potential value of microsatellite markers (eight loci) in the genetic characterisation of T. brucei s.l. compared to the multi-locus enzyme electrophoresis reference technique. Stocks isolated in Ivory Coast and reference stocks were used for this purpose. Microsatellite markers were shown to be polymorphic enough to evidence the existence of genetic diversity within T. b. gambiense group 1 and to show the existence of mixed infections. Furthermore, they were able to amplify trypanosome DNA directly from field samples without the usual culturing stages. While the ability of microsatellite markers to detect mixed infections in such field samples is currently being discussed, they appear to be useful to study the parasite population's geographical structure and may provide new insight into their reproductive mode, a topic that is still under debate. Thus, use of microsatellite markers will contribute to the study of the influence of parasite genetics in the diversity of responses to HAT and may contribute to the improvement of HAT molecular diagnosis. PMID- 17704011 TI - The 3rd Japan-US DNA Repair Meeting, Sendai, Japan, May 7-11, 2007. PMID- 17704010 TI - An AP site can protect against the mutagenic potential of 8-oxoG when present within a tandem clustered site in E. coli. AB - Ionizing radiation induces clustered DNA damaged sites, defined as two or more lesions formed within one or two helical turns of the DNA through passage of a single radiation track. It is now established that clustered DNA damage sites are found in cells and present a challenge to the repair machinery of the cell but to date, most studies have investigated the effects of bi-stranded lesions. A subset of clustered DNA damaged sites exist in which two or more lesions are present in tandem on the same DNA strand. In this study synthetic oligonucleotides containing an AP site 1, 3 or 5 bases 5' or 3' to 8-oxo-7,8-dihydroguanine (8 oxoG) on the same DNA strand were synthesized as a model of a tandem clustered damaged sites. It was found that 8-oxoG retards the incision of the AP site by exonuclease III (Xth) and formamidopyrimidine DNA glycosylase (Fpg). In addition the rejoining of the AP site by xrs5 nuclear extracts is impaired by the presence of 8-oxoG. The mutation frequency arising from 8-oxoG within a tandem clustered site was determined in both wild type and mutant E. coli backgrounds. In wild type, nth, fpg and mutY null E. coli, the mutation frequency is slightly elevated when an AP site is in tandem to 8-oxoG, compared with when 8-oxoG is present as a single lesion. Interestingly, in the double mutant mutY/fpg null E. coli, the mutation frequency of 8-oxoG is reduced when an AP site is present in tandem compared with when 8-oxoG is present as a single lesion. This study demonstrates that tandem lesions can present a challenge to the repair machinery of the cell. PMID- 17704012 TI - Determination of serum uric acid using high-performance liquid chromatography (HPLC)/isotope dilution mass spectrometry (ID-MS) as a candidate reference method. AB - Uric acid is an important diagnostic marker of catabolism of the purine nucleosides, and accurate measurements of serum uric acid are necessary for proper diagnosis of gout or renal disease appearance. A candidate reference method involving isotope dilution coupled with liquid chromatography/mass spectrometry (LC/MS) has been described. An isotopically labeled internal standard, [1,3-(15)N(2)] uric acid, was added to serum, followed by equilibration and protein removal clean up to prepare samples for liquid chromatography/mass spectrometry electrospray ionization (LC/MS-ESI) analyses. (M-H)(-) ions at m/z 167 and 169 for uric acid and its labeled internal standard were monitored for LC/MS. The accuracy of the measurement was evaluated by a comparison of results of this candidate reference method on lyophilized human serum reference materials for uric acid (Standard Reference Materials SRM909b) with the certified values determined by gas chromatography/mass spectrometry reference methods and by a recovery study for the added uric acid. The method performed well against the established reference method of ion-exchange followed by derivatization isotope dilution (ID) gas chromatography mass spectrometry (ID-GC/MS). The results of this method for uric acid agreed well with the certified values and were within 0.10%. The amounts of uric acid recovered and added were in good agreement for the three concentrations. This method was applied to determine uric acid in samples of frozen serum pools. Excellent precision was obtained with within-set CVs of 0.08-0.18% and between-set CVs of 0.02-0.07% for LC/MS analyses. Liquid chromatography/tandem mass spectrometry electrospray ionization (LC/MS/MS-ESI) analysis was also performed. The LC/MS and LC/MS/MS results were in very good agreement (within 0.14%). This LC/MS method, which demonstrates good accuracy and precision, and is in the speed of analysis without the need for a derivatization stage, qualifies as a candidate reference method. This method can be used as an alternative reference method to provide an accuracy base to which the routine methods can be compared. PMID- 17704013 TI - Separation of scutellarin from crude extracts of Erigeron breviscapus (vant.) Hand. Mazz. by macroporous resins. AB - Scutellarin, a flavone glycoside, popularly used in the treatment of heart disease, has been efficiently separated using macroporous resins from crude extracts of Chinese medicinal plant Erigeron breviscapus (vant.) Hand. Mazz. HPD 800 resin offered the best adsorption and desorption capacity for scutellarin among the eight macroporous resins tested, and its adsorption data at 25 degrees C fit best to the Langmuir isotherm. The dynamic adsorption and desorption experiments have been carried out on a HPD-800 resin packed column to optimize the separation process of scutellarin from the crude extracts of E. breviscapus. After one run treatment with HPD-800 resin, the scutellarin content in the product was increased 15.69-fold from 2.61% to 40.96% with a recovery yield of 95.01%. The preparative separation process via adsorption-desorption method developed in this study provides a new approach for scale-up separation and purification of scutellarin for its wide pharmaceutical use. PMID- 17704014 TI - Rapid and sensitive bioanalytical method for measurement of fluvoxamine in human serum using 4-chloro-7-nitrobenzofurazan as pre-column derivatization agent: application to a human pharmacokinetic study. AB - A sensitive and rapid high-performance liquid chromatographic method for the analysis of fluvoxamine, a selective serotonin reuptake inhibitor in human serum, is described using 4-chloro-7-nitrobenzofurazan as pre-column derivatization agent. The drug and an internal standard (fluoxetine) were extracted from 0.25 mL of serum using ethyl acetate as extracting solvent and subjected to pre-column derivatization by the reagent. A mobile phase consisting of methanol and sodium phosphate buffer (0.05 M; pH 2.8) containing 1 mL/L triethylamine (72:28 v/v) was used and chromatographic separation was performed on a Shimpack CLC-C18 (150 mm x 4.6mm) column. The fluorescence derivatives of the drugs were monitored at excitation and emission wavelengths of 470 and 537 nm, respectively. The calibration curve was linear over the concentration range of 0.5-240 ng/mL with a limit of quantification (LOQ) of 0.5 ng/mL using 0.25 mL serum sample. The method validation was performed for its selectivity, specificity, sensitivity, precision and accuracy. In this method, which was applied in a randomized cross-over bioequivalence study of two different fluvoxamine preparations in 24 healthy volunteers, the sensitivity and run time of analysis were significantly improved. PMID- 17704015 TI - Purification and characterization of a novel glucosyltransferase specific to 27beta-hydroxy steroidal lactones from Withania somnifera and its role in stress responses. AB - Sterol glycosyltransferases catalyze the synthesis of diverse glycosterols in plants. Withania somnifera is a medically important plant, known for a variety of pharmacologically important withanolides and their glycosides. In this study, a novel 27beta-hydroxy glucosyltransferase was purified to near homogeneity from cytosolic fraction of W. somnifera leaves and studied for its biochemical and kinetic properties. The purified enzyme showed activity with UDP-glucose but not with UDP-galactose as sugar donor. It exhibited broad sterol specificity by glucosylating a variety of sterols/withanolides with beta-OH group at C-17, C-21 and C-27 positions. It transferred glucose to the alkanol at C-25 position of the lactone ring, provided an alpha-OH was present at C-17 in the sterol skeleton. A comparable enzyme has not been reported earlier from plants. The enzyme is distinct from the previously purified W. somnifera 3beta-hydroxy specific sterol glucosyltransferase and does not glucosylate the sterols at C-3 position; though it also follows an ordered sequential bisubstrate reaction mechanism, in which UDP-glucose and sterol are the first and second binding substrates. The enzyme activity with withanolides suggests its role in secondary metabolism in W. somnifera. Results on peptide mass fingerprinting showed its resemblance with glycuronosyltransferase like protein. The enzyme activity in the leaves of W. somnifera was enhanced following the application of salicylic acid. In contrast, it decreased rapidly on exposure of the plants to heat shock, suggesting functional role of the enzyme in biotic and abiotic stresses. PMID- 17704016 TI - Visual outcomes and perinatal adversity. AB - Preterm birth per se, the neonatal environment, retinopathy of prematurity (ROP) and neurological damage are all causes of visual impairment and the impact of these factors is discussed in relation to the resultant ophthalmic deficits. Visual acuity impairments range from blindness, due to ROP or cortical visual impairment, which can be identified at an early age, to subtle deficits related to preterm birth only identified at a later age. Visual function deficits are not limited to visual acuity but can affect contrast sensitivity, field of vision and colour vision. Strabismus and refractive errors are also very common in children following perinatal adversity. Although more is now known about the types of deficits affecting these children, there is still a poor understanding of how these deficits impact on a child's functional ability. The impact of these ophthalmic deficits on the long term ophthalmic care required, and the role of perinatal factors, is discussed. PMID- 17704017 TI - Straight line repair of unilateral cleft lip: new operative method based on 25 years experience. AB - The resultant scar in the primary repair of unilateral cleft lip should ideally be straight and the mirror image of the philtrum on the non-cleft side. In 1993, we reported a new operative technique for unilateral cleft lip, in which we designed a straight line for the incision on the white lip. In order to produce the nostril floor, we used the white lip tissue in the area between the alar base and alveolus at the cleft side as a flap. We also used a small triangular flap above the white skin roll to prevent Cupid's peak from being drawn up. Unlike the rotation-advancement method, our technique does not leave a transverse scar at the alar base. Instead, it leaves a scar only along the line coincident with the natural philtral ridge. However, during observations of our patients, we noticed that the small triangular flap designed to be 1.5mm tended to become a conspicuous angular scar as the patients grew older. In addition, drooping of Cupid's peak on the cleft side was often observed with this small triangular flap. To make it less conspicuous, we made some modifications to the small flap above the white skin roll. With this new technique, we designed a semi-circular flap (1.5 x 3mm) above the white skin roll, instead of the small triangular flap. The suture line of our refined procedure draws a gentle curve, which looks almost straight because of skin elasticity. Moreover, the semi-circular flap causes less drooping of the upper lip than the triangular flap. We believe that revising the shape of the small flap on the white skin roll greatly improves patients' appearance. In this report, we present our refined techniques of primary repair of unilateral cleft lip. PMID- 17704018 TI - Improved alpha-amylase and Helicobacter pylori inhibition by fenugreek extracts derived via solid-state bioconversion using Rhizopus oligosporus. AB - The present research investigated the enrichment of fenugreek (Trigonella foenum graceum) seed substrate with phenolic antioxidants and L-DOPA via fungal-based solid-state bioconversion (SSB) system. This approach using food grade fungus Rhizopus oligosporus, was chosen because it has been demonstrated to be effective in other seed and food substrates for improving health-relevant functionality and has long history of use for food processing in Asia. The protein content and beta glucosidase activity of the substrate which reflects fungal growth, increased with incubation time in conjunction with enhanced phenolic content and also suggested its possible involvement in phenolic mobilization. The antioxidant activity assayed by beta-carotene bleaching and DPPH free radical scavenging methods both indicated high activity during early growth stage (days 4-6) followed by reduced activity during later growth stage (days 8-20). A direct association between higher phenolic contents during early growth stage (days 4-6) and antioxidant activity suggested a link to mobilization of polymeric and hydrophobic phenolic forms. The L-DOPA content of the fenugreek extract fluctuated during the course of bioconversion with higher levels during days 6-10 (1.5-1.7 mg/g DW). The SSB process substantially improved the in vitro porcine alpha-amylase inhibition activity by 75 % on day 4 which correlated to higher levels of total phenolics and related antioxidant activity of the extracts. The high alpha-amylase inhibitory activity also coincided with high L-DOPA content on day 6. These results have implications for diet-based diabetes management. The same bioconversion stage had Helicobacter pylori inhibitory activity, which has implications for ulcer management. PMID- 17704019 TI - Recycled palm oil is better than soy oil in maintaining bone properties in a menopausal syndrome model of ovariectomized rat. AB - Palm oil is shown to have antioxidant, anticancer and cholesterol lowering effects. It is resistant to oxidation when heated compared to other frying oils such as soy oil. When a frying oil is heated repeatedly, it forms toxic degradation products, such as aldehydes which when consumed, may be absorbed into the systemic circulation. We have studied the effects of taking soy or palm oil that were mixed with rat chow on the bone histomorphometric parameters of ovariectomised rats. Female Sprague-Dawley rats were divided into eight groups: (1) normal control group; (2) ovariectomised-control group; (3) ovariectomised and fresh soy oil; (4) ovariectomised and soy oil heated once; (5) ovariectomised and soy oil heated five times; (6) ovariectomised and fresh palm oil; (7) ovariectomised and palm oil heated once; (8) ovariectomised and palm oil heated five times. These oils were mixed with rat chow at weight ratio of 15:100 and were given to the rats daily for six months. Ovariectomy had caused negative effects on the bone histomorphometric parameters. Ingestion of both fresh and once-heated oils, were able to offer protections against the negative effects of ovariectomy, but these protections were lost when the oils were heated five times. Soy oil that was heated five times actually worsens the histomorphometric parameters of ovariectomised rats. Therefore, it may be better for postmenopausal who are at risk of osteoporosis to use palm oil as frying oil especially if they practice recycling of frying oils. PMID- 17704020 TI - High prevalence of goiter in an iodine replete area: do thyroid auto-antibodies play a role? AB - INTRODUCTION: Despite long standing iodine supplementation in Iran the prevalence of goiter remains high in some areas. This may suggest that causes other than iodine deficiency, such as autoimmune thyroid diseases, should also be considered. We therefore assessed the prevalence of anti-thyroid antibodies in children living in an inland area in Iran and correlated these findings with prevalence of goiter within this region. METHODS: In a cross-sectional study, 1948 students were selected by multistage random cluster sampling from the 108 primary schools (age, 7-13 year-old) of the urban and rural areas of Semirom. After obtaining written consent from their parents, the children were examined by endocrinologists for goiter grading. Grade 2 goitrous children (108 cases) were compared with non-goitrous children (111 children as control group) for anti thyroid antibodies. RESULTS: Overall, 36.7% of 1948 students had goiter. The mean urinary iodine excretion level was 1.49+/-0.7 micromol/L. This was within normal limits. Of 219 children studied, 4.3% presented with subclinical hypothyroidism, and 7.3% had positive anti-thyroid antibodies. There was non-significant difference of positive thyroperoxidase antibody (anti-TPO) (Odds Ratio= 3.2, p= 0.13) but significant difference of anti Tg between goitrous and non goitrous children (Odds Ratio: 5.6, 95% CI: 1.18-26.0, p: 0.015). CONCLUSION: This study suggests that autoimmunity may be one of the mechanisms responsible for goiter persistence after iodine replenishment in this iodine deficient region, but the role of other factors should also be considered. PMID- 17704021 TI - Four week supplementation with mixed fruit and vegetable juice concentrates increased protective serum antioxidants and folate and decreased plasma homocysteine in Japanese subjects. AB - Fruit and vegetable consumption has been inversely associated with the risk of chronic diseases including cancer and cardiovascular disease, with the beneficial effects attributed to a variety of protective antioxidants, carotenoids and phytonutrients. The objective of the present study was to determine the effect of supplementation with dehydrated concentrates from mixed fruit and vegetable juices (Juice Plus+R) on serum antioxidant and folate status, plasma homocysteine levels and markers for oxidative stress and DNA damage. Japanese subjects (n=60; age 27.8 yrs; BMI 22.1) were recruited to participate in a double-blind placebo controlled study and were randomized into 2 groups of 30, matched for sex, age, BMI and smoking status (39 males, 22 smokers; 21 females, 13 smokers). Subjects were given encapsulated supplements containing mixed fruit and vegetable juice concentrates or a matching placebo for 28 days, with blood and urine samples collected at baseline, day 14 and day 28 for analytical testing. Compared with the placebo, 28 day supplementation significantly increased the concentration of serum beta-carotene 528% (p<0.0001), lycopene 80.2% (p<0.0005), and alpha tocopherol 39.5% (p<0.0001). Serum folate increased 174.3% (p<0.0001) and correlated with a decrease in plasma homocysteine of -19.9% (p<0.03). Compared with baseline, measures of oxidative stress decreased with serum lipid peroxides declining -10.5% (p<0.02) and urine 8OHdG decreasing -21.1% (p<0.02). Evaluation of data from smokers only (n=17) after 28 days of active supplementation showed comparable changes. CONCLUSION: In the absence of dietary modification, supplementation with the fruit and vegetable juice concentrate capsules proved to be a highly bioavailable source of phytonutrients. Important antioxidants were elevated to desirable levels associated with decreased risk of disease while markers of oxidative stress were reduced, and folate status improved with a concomitant decrease in homocysteine, and these benefits occurred to a similar extent in smokers when compared to non-smokers. PMID- 17704022 TI - Effects of gamma-tocopherol supplementation on thrombotic risk factors. AB - OBJECTIVE: The antioxidant activity of vitamin E is derived primarily from alpha tocopherol (alpha-T) and gamma-tocopherol (gamma-T). Results of epidemiological studies have demonstrated an inverse relationship between vitamin E intake and coronary disease. However, the results of clinical trials using alpha-T are equivocal. We determined the effect of 5 weeks of 100 mg/d or 200 mg/d gamma-T supplementation on thrombotic markers such as platelet reactivity, lipid profile and the inflammation marker C-reactive protein (CRP). METHODS AND RESULTS: Fourteen healthy subjects consumed 100 mg/day while 13 consumed 200 mg/d of gamma T and 12 received placebo (soybean capsules with less than 5 mg/d gamma-T) in a double-blinded parallel study design. Fasting pre and post dose blood samples were analysed. Blood gamma-T concentrations increased significantly (p<0.05) relative to dose during the intervention period. Both groups receiving active ingredients showed significantly lower platelet activation after supplementation (p<0.05). Subjects consuming 100 mg/d gamma-T had significantly decreased LDL cholesterol, platelet aggregation and mean platelet volume (MPV) (p<0.05). Little effect of gamma-T was observed on other parameters. CONCLUSIONS: These data suggest that gamma-T supplementation may have a permissive role in decreasing the risk of thrombotic events by improving lipid profile and reducing platelet activity. PMID- 17704023 TI - The effect of n - 3 PUFA/gamma-cyclodextrin complex on serum lipids in healthy volunteers--a randomized, placebo-controlled, double-blind trial. AB - OBJECTIVES: This study was carried out to examine whether serum triglyceride concentrations were decreased by administration of n-3 polyunsaturated fatty acid (PUFA)/gamma-cyclodextrin (gamma-CD) complex-containing capsules as reported previously with n-3PUFA without gamma-CD. STUDY DESIGN: A placebo-controlled double-blind study with healthy subjects (n=35) and hypertriglyceridemic subjects (n=7) of 35-66 years of age was performed. The subjects were randomized to a group (n-3 group) supplemented with n-3PUFA/gamma-CD-containing capsules (660 mg EPA + 280 mg DHA/day) or a control group supplemented with capsules containing essentially no n-3 PUFA for 8 weeks with stratification by sex, age, and serum triglyceride levels in a double blind manner. Fasting blood samples were obtained at the start of administration and 4 and 8 weeks afterward. RESULTS: EPA concentrations in the total phospholipid fraction of red blood cells increased significantly in all subjects in the n-3 group, whereas no changes were seen in the control group. Triglyceride levels were significantly decreased (-17%) in the n-3 group compared with the control group at week 8. The following serum lipids did not significantly change over time: total-cholesterol, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol. Only two subjects in the n-3 group guessed at the end of the study that their capsules were active. CONCLUSION: n-3 PUFA/gamma-CD complex lowered triglyceride levels in normal and slightly hypertriglyceridemic subjects. There was a possibility that gamma-CD might at least partly cover the smell and aftertaste of fish oil. PMID- 17704024 TI - The effect of early nutritional supplementation with a mixture of probiotic, prebiotic, fiber and micronutrients in infants with acute diarrhea in Indonesia. AB - A randomized double blind clinical trial was conducted to assess the efficacy of a special infant formula containing Lactobacillus rhamnosus LMG P-22799 (probiotic: 5 x 10(8) CFU/100mL), inulin (prebiotic: 0.15 g/100mL), dietary fiber (soy polysaccharides: 0.2 g/100mL) and increased amounts of zinc+iron (+0.4 and +0.6 mg/100mL, respectively) as active ingredients for the early dietary management of 58 Indonesian well-nourished male infants aged 3-12 months suffering from acute diarrhea with moderate dehydration. After adequate oral rehydration, the patients were randomly assigned to receive either a low lactose infant formula supplemented with added precooked rice (1.5 g/100mL) with the above active ingredients (study group) or a low lactose infant formula with added precooked rice without the above active ingredient supplement (control group). No antibiotic, anti-secretory drug or antiemetic was given at all. Both study and control groups showed similar outcomes for weight gain and stool weight. The duration of diarrhea was significantly shorter in the study group than in the control group (1.63 versus 2.45 days; p<0.05; for the study and control group respectively). No treatment failure or other side effects were observed during the course of the study. The present study supports the evidence for the efficacy of a special anti-diarrhea infant formula containing probiotic, prebiotic, fiber and iron+zinc after oral rehydration by shortening the duration of infantile diarrhea in developing countries. However, from the results of our study we cannot discern the individual contribution of the active ingredients and also not whether they may act independent from each other or in a synergistic way. PMID- 17704025 TI - The validity of the World Health Organisation's obesity body mass index criteria in a Turkish population: a hospital-based study. AB - Our aim was to determine the relationship between body fat percentage (BF%) and body mass index (BMI) and to evaluate the validity of World Health Organisation's BMI cut-off values for obesity. Adult out-patients (n=909, 249 men, 660 women), mean age; 40.5 +/- 14.1 years were included. According to WHO's BMI criteria, 440 subjects were obese (79 men, 361 women). The BF% of participants were measured using a bioelectrical impedance analysis (BIA) system (TANITA). Randomly selected 30 patients were also subjected to the dual-energy X-ray absorptiometry (DEXA) procedure for evaluation of the validity of TANITA measurements. The BF% results obtained by DEXA and TANITA revealed good correlation (r =0.952, p= 0.382). There was a positive correlation between BF% and BMI (p<0.001) for both methods. Cut off values for BMI were calculated as 28.0 kg/m2 for women, 28.2 kg/m2 for men, if obesity was defined as BF >= 25% in men, >= 35% in women according to WHOfs criteria. Using the new cut-off values, the frequency of obesity increased up to 33.9% in our group. The increase was more pronounced in men (67.1% vs. 26.6%). The WHO cut-off values underestimated the frequency of obesity in this population. Further studies are warranted for different ethnic groups. PMID- 17704026 TI - Food security, selection, and healthy eating in a Pacific Community in Auckland New Zealand. AB - When an infant is brought home to the family, it is often a time of emotional, economic and physical stress due to the extra demands placed on parents. Household food security means "access at all times to enough and nutritionally appropriate food to provide the energy and nutrients needed to maintain an active and healthy life". Questions about food security were asked of 1376 Pacific Island mothers (as part of the Pacific Island Family Study) approximately six weeks after the birth of their baby. Due to lack of money food sometimes ran out in 39.8% of households and in a further 3.8% food often ran out. Variety of foods was limited by lack of money in 39.3%. Foods that were still bought when money was limited included bread (97%), milk (95%), meat and chicken (91%), vegetables and fruit (83%), rice or pasta (82%), breakfast cereals (69%), fish or shellfish (50%) and biscuits or chips (44%). Alcohol (1%), soft drinks (11%), ice cream (12%) and fruit juice (21%) were the least often bought. Energy density (MJ/kg) and nutrient-density of typical foods limited by lack of money were analysed. Rice, bread and fatty meats provided the most calories per dollar and fruit and vegetables the least. The best protein-value for money was from minced beef, chicken and tinned tuna and the most fibre-rich foods included baked beans and mixed vegetables. Food security is a major problem for Pacific families. The environment of food availability, choice and cost requires attention to help close the health gap. PMID- 17704027 TI - Effect of purple sweet potato leaf consumption on the modulation of the antioxidative status in basketball players during training. AB - The aim of this study was to evaluate the effect of purple sweet potato leaves (PSPLs) consumption on antioxidative status and its modulation of that status in basketball players during training period. Fifteen elite basketball players were enrolled in this study. The seven-week study consisted of a run-in (week 1), PSPLs diet (daily consumption of 200 g PSPLs) (weeks 2, 3), washout (weeks 4, 5), and control diet (low polyphenol, with the amount of carotenoids adjusted to the same level as that of PSPLs) (weeks 6, 7). Blood and urine samples were taken for biochemical analysis. Compared with the control group, the results showed that PSPLs consumption led to a significant increase of plasma polyphenol concentration and vitamin E and C levels. Low density lipoprotein (LDL) lag time was significantly longer in the PSPLs group. A significant decrease of urinary 8 hydroxy-2-deoxyguanosine (8-OHdG) was noted; however, there was no significant change in plasma glutathione (GSH), total antioxidant status (TAS) and malondialdehyde + 4-hydroxy-2(E)-nonenal level after consuming the PSPLs diet. In conclusion, consumption of PSPLs diet for 2 weeks may reduce lipid and DNA oxidation that can modulate the antioxidative status of basketball players during training period. PMID- 17704028 TI - Rising trends in BMI of Saudi adolescents: evidence from three national cross sectional studies. AB - OBJECTIVE: To examine the trends in body mass index (BMI) of Saudi male adolescents between 1988 and 1996. METHODS: The data set came from three major population-based cross sectional studies. They all involve nationally representative samples and were conducted between 1988 and 1996. BMI was calculated from body height and mass and plotted at the 50(th) and 90(th) percentiles. RESULTS: BMI of Saudi adolescents progressively increased at both 50(th) and 90(th) percentiles between 1988 and 1996. The increases in BMI during the eight-year period ranged from 9.6 to 10.8% at the 50 (th) percentiles and from 10.9 to 13.9% at the 90th percentiles. At ages 15-18 years, the yearly increase in median BMI from 1988 to 1996 averaged 0.246 kg/m(2). CONCLUSION: The rising trends in BMI between 1988 and 1996 are indication of increasing obesity among Saudi male adolescents. More attention to the promotion of healthy nutrition and physical activity throughout childhood and adolescence is required. PMID- 17704029 TI - Milk consumption is a risk factor for prostate cancer in Western countries: evidence from cohort studies. AB - We have previously found a positive association between milk consumption and prostate cancer risk using meta-analysis to analyze published case-control studies. In the present study, further meta-analysis was conducted to estimate the summary relative risk (RR) between the consumption of milk and dairy products and prostate cancer from cohort studies published between 1966- 2006. We found 18 relevant articles and 13 independent studies were available for our analysis. The summary RR was 1.13 (95% confidence interval = 1.02-1.24) when comparing the highest with the lowest quantile of consumption. The summary RRs by study stratification showed a positive association. A dose-response relationship was identified when combining the studies that partitioned the consumption by quintiles. We also evaluated the effects of some limitations, such as dairy classification, prostate cancer stages and publication bias, in the present study. These findings, together with the previous study, suggest that the consumption of milk and dairy products increases the risk of prostate cancer. This is biologically plausible since milk contains considerable amounts of fat, hormones, and calcium that are associated with prostate cancer risk. PMID- 17704030 TI - Intake of vitamin A-rich foods and lung cancer risk in Taiwan: with special reference to garland chrysanthemum and sweet potato leaf consumption. AB - A case-control study was conducted to investigate the association between the consumption of local common foods that are rich in vitamin A and the risk of lung cancer in Taiwan. A total of 301 incident lung cancer cases, 602 hospital controls, and 602 neighborhood controls were recruited. The consumption of 13 food items and vitamin supplements was estimated by use of a food frequency questionnaire. The conditional logistic regression models were used to estimate the adjusted odds ratios (AOR) and 95% confidence intervals (CI) for lung cancer risk with each control group as reference by adjustment of covariates. A reduced risk for lung cancer was found to be associated with increased intakes of vitamin A, alpha-carotene, and beta-carotene from 13 food items. More servings of vegetables (AOR for the highest versus the lowest quartile = 0.67-0.70, 95% CI = 0.42-1.08, (plinear trend )= 0.04), garland chrysanthemum (AOR for the highest versus the lowest tertile = 0.58-0.74, 95% CI = 0.37-1.14, (plinear trend )<= 0.04) and sweet potato leaves (AOR for the highest versus the lowest tertile = 0.43-0.65, 95% CI = 0.28-0.96, (plinear trend )<= 0.03) were associated with the reduced risk for lung cancer. In conclusion, higher consumption of vitamin A-rich vegetables, especially garland chrysanthemum and sweet potato leaves might provide potential protection from lung cancer. PMID- 17704031 TI - Short-term effectiveness of an individual counseling program for impaired fasting glucose and mild type 2 diabetes in Japan: a multi-center randomized control trial. AB - The aim of this study is to evaluate the short-term effectiveness of our individual-based counseling program and tools among individuals in ordinary Japanese communities with impaired fasting glucose (IFG) and mild type 2 diabetes. A total of 233 eligible participants (age 30-69 years) in 14 local study centers were randomly assigned to an intervention group (INT, N=119) and a control group (CONT, N=114). During the 4-month intervention, the INT received 4 individual counseling sessions and one reminder on life style modification. The CONT received only an explanation of blood test results and general information on diabetes. Baseline characteristics did not differ significantly between groups. Percentages of participants with desirable changes in glycemic level and weight were significantly higher in INT than CONT: fasting plasma glucose reduction of more than 10 mg/dL (39% in INT vs. 26% in CONT, p=0.045), hemoglobinA1c reduction greater than 0.3% (14% vs. 4%, p=0.01), and weight reduction of more than 4 kg (13% vs. 4%, p=0.025). Decreases in total energy intake and percentage of heavy alcohol drinkers (more than 46 g/day) were significantly greater in INT than CONT. The increase in percentages of participants who engaged in leisure time physical activity more than 12 times per month was significantly greater in INT than CONT. Our program resulted in life style modification and glycemic level improvement in the short-term among individuals with IFG and mild type 2 diabetes. Results indicated that the program was sufficiently effective and feasible for implementation in ordinary communities. PMID- 17704032 TI - Tocotrienol levels in adipose tissue of benign and malignant breast lumps in patients in Malaysia. AB - Data on dietary exposure to vitamin E by plasma or adipose tissue concentrations of alpha-tocopherol (alpha-T) in observational studies have failed to provide consistent support for the idea that alpha-T provides women with any protection from breast cancer. In contrast, studies indicate that alpha, gamma, and delta tocotrienols but not alpha-T have potent anti-proliferative effects in human breast cancer cells. Our aim was to investigate whether there was a difference in tocopherol and tocotrienol concentrations in malignant and benign adipose tissue, in a Malaysian population consuming predominantly a palm oil diet. The study was undertaken using fatty acid levels in breast adipose tissue as a biomarker of qualitative dietary intake of fatty acids. The major fatty acids in breast adipose tissue of patients (benign and malignant) were oleic acid (45-46%), palmitic (28-29%) and linoleic (11-12%). No differences were evident in the fatty acid composition of the two groups. There was a significant difference (p=0.006) in the total tocotrienol levels between malignant (13.7 +/- 6.0 microg/g) and benign (20+/-6.0 microg/g) adipose tissue samples. However, no significant differences were seen in the total tocopherol levels (p=0.42) in the two groups. The study reveals that dietary intake influences adipose tissue fatty acid levels and that adipose tissue is a dynamic reservoir of fat soluble nutrients. The higher adipose tissue concentrations of tocotrienols in benign patients provide support for the idea that tocotrienols may provide protection against breast cancer. PMID- 17704033 TI - Multiple micronutrient fortification of salt and its effect on cognition in Chennai school children. AB - AIM: To test the efficacy of a multiple micronutrient fortified salt in improving the micronutrient status and health of school children and its effect on cognition. METHODS: A salt fortified with multiple micronutrients was developed containing chelated ferrous sulphate, microencapsulated vitamin A, B1, B2, B6, B12, folic acid, niacin, calcium pantothenate and iodine. The efficacy of the fortified salt was assessed in 7-11 year old school children in Chennai, India. In the experimental group (N=63), the food in the school kitchen was cooked with the fortified salt for a period of one year. The control group (N=66) consisted of day scholars who did not eat at the school. Hemoglobin, red blood cell count, hematocrit, serum vitamin A, urinary iodine and prevalence of angular stomatitis were measured at baseline and at the end of the study after one year. A battery of 7 memory tests (The personal information test, the Mann-Suiter Visual memory screen for objects, The digit span forward test, The digit span backward test, The delayed response test, The Benton Visual Retention Test and The Cattells retentivity test), one test for attention and concentration (Letter cancellation test) and one test for intelligence (Raven's coloured progressive matrices) were administered to all the children at baseline and endline. RESULTS: There was a significant (p<0.05) improvement in the experimental group in hemoglobin, red cell count, urinary iodine and serum vitamin A whereas in the control group there was a statistically significant decline (p<0.05) in hemoglobin, hematocrit, red cell count and urinary iodine. Angular stomatitis was eliminated from baseline 30.4% in the experimental group whereas it increased from 3.25% to 25.5% in the control group. In 4 tests out of the 7 memory tests and in the letter cancellation test for attention, the mean increment in scores in the experimental group is significantly more (p<0.05) than the control group. There was no significant improvement in overall intelligence as seen in the Ravens progressive matrices between the experimental and control groups. CONCLUSION: The study shows that the multiple micronutrient fortified salt is effective in improving multiple micronutrient status and cognition in children. PMID- 17704034 TI - Determinants of child malnutrition during the 1999 economic crisis in selected poor areas of Indonesia. AB - There is empirical evidence at the national level that suggests the 1999 Indonesian economic crisis impact was very heterogeneous both between urban and rural areas and across regions. A cross sectional study of the nutritional status of children and its determinants was performed in urban poor areas of Jakarta, and rural areas of Banggai in Central Sulawesi, and Alor-Rote in East Nusa Tenggara. Two-stage cluster sampling was used to obtain 1078 households with under-five children in the urban poor area of Jakarta, and 262 and 631 households with under-five children each for the rural areas of Banggai and Alor-Rote, respectively. Data collection for both studies was performed from January 1999 to June 2001. The study shows that wasting affected more children in the urban poor areas of Jakarta than in the other study areas. On the other hand, stunting and anemia were significantly more severe among children 6-59 months of age in the rural area of Alor-Rote compared to the other study areas. The high prevalence of infectious diseases was significantly related to the higher prevalence of wasting in the study areas of Jakarta and Banggai, and also significantly related to the higher prevalence of stunting and anemia in the study area of Alor-Rote. To avert this kind of health impact of a economic downturn, there is a need to improve the nutritional and health status of under-five children and their mothers through the existing health care system, provide basic health services and improve the capacity of health staff across Indonesia as part of the decentralization process. PMID- 17704035 TI - Anemia in pregnancy in Malaysia: a cross-sectional survey. AB - Anemia is the most prevalent nutritional deficiency during pregnancy. Except for a study conducted 10 years ago in Kelantan, Malaysia's available statistics are based on isolated small urban maternity hospital studies from the 1980s. There was therefore, a need for a large study at national level to estimate the magnitude of the problem in the country as well as to understand its epidemiology. This multi-center, cross-sectional study was conducted from February to March 2005, to assess the prevalence of anemia. Multistage stratified random sampling technique was used and 59 Ministry of Health (MOH) primary health care clinics were selected. Our final dataset consisted of 1,072 antenatal mothers from 56 clinics. The overall prevalence of anemia in this population was 35 % (SE 0.02) if the cut off level is 11 g/dL and 11 % (SE 0.03) if the cut-off level is 10 g/dL. The majority was of the mild type. The prevalence was higher in the teenage group, Indians followed by Malays and Chinese being the least, grandmultiparas, the third trimester and from urban residence. After multiple linear regression analysis, only gestational age remained significant. These findings are useful for our Maternal Health program planners and implementers to target and evaluate interventions. Work is in progress for outcomes and cost effectiveness studies to best tackle this problem. In conclusion, the prevalence of anemia is 35% and mostly of the mild type and more prevalent in the Indian and Malays. PMID- 17704036 TI - Influences on maternal and child nutrition in the highlands of the northern Lao PDR. AB - In two remote northern provinces of the Lao People's Democratic Republic, provincial and district teams were trained and subsequently conducted a qualitative study using a participatory approach to investigate people's knowledge, attitudes, beliefs and practices in relation to women's and children's nutrition. Using focus group discussions, key informant interviews, and structured observation, the teams found that certain nutrition behaviours, including food taboos, may contribute to the high prevalence of child malnutrition and micronutrient deficiencies in these northern provinces. Ethnic groups gave details of nutrition-related beliefs and practices; the teams found that many of these are likely to be amenable to change through relatively low cost nutrition promotion informed by these findings. In particular, barriers to exclusive breastfeeding, food taboos and hygiene behaviour could be addressed. The study also demonstrated that with appropriate training, supervision and support, local teams are able to plan and conduct a large-scale qualitative study. PMID- 17704037 TI - Effects of continuous enteral L-arginine in a rat model of the short bowel syndrome. AB - The objective of this study was to evaluate whether continuous enteral supplementation of L-arginine can stimulate intestinal adaptation in a rat model of short bowel syndrome (SBS). Male Sprague-Dawley rats were randomly divided into three groups of 10 each: Sham rats underwent bowel transaction and received continuous enteral nutrition (Control group, Con group), SBS rats underwent 75% small bowel resection and received continuous enteral nutrition (SB group), and SBS rats underwent 75% bowel resection and received continuous enteral nutrition supplemented with L-arginine (300 mg/Kg/d) (SB-Arg group). Fat absorbability, plasma free fatty acids, parameters of intestinal adaptation, enterocyte proliferation and apoptosis were determined on day 15 after operation. After massive small bowel resection, rats had significant bowel adaptation. Compared with SB untreated rats, SB rats supplemented with L-arginine demonstrated a significant increase in fat absorbability, plasma level of free fatty acids, ileal mucosal weight and DNA content, jejunal and ileal mucosal protein content, jejunal and ileal villus length, crypt depth and mucosal thickness. L-arginine supplementation increased enterocyte proliferation, while decreasing enterocyte apoptosis. We suggest that after massive small bowel resection, continuous enteral supplementation of L-arginine can stimulate intestinal adaptation. L arginine may be a trophic factor to stimulate intestinal adaptation in rats of SBS. PMID- 17704038 TI - A national study on the prevalence of obesity among 16,127 Malaysians. AB - A population-based cross-sectional study was conducted in all states of Malaysia with the aim to determine the prevalence of obesity among Malaysians aged fifteen years and above and factors associated. A stratified two-stage cluster sampling design with proportional allocation was used. Trained interviewers using a standardized protocol obtained the weight and height measurements and other relevant information. Subjects with a body mass index >= 30 kg/m2 were labelled as obese. The results show that the overall national prevalence of obesity among Malaysians aged 15 years old and above was 11.7% (95% CI = 11.1 - 12.4%). The prevalence of obesity was significantly higher in females (13.8%) as compared to 9.6% in males (p< 0.0001). Prevalence of obesity was highest amongst the Malays (13.6%) and Indians (13.5%) followed by the indigenous group of "Sarawak Bumiputra" (10.8%) and the Chinese (8.5%). The indigenous group of "Sabah Bumiputra" had the lowest prevalence of 7.3%. These differences are statistically significant (p< 0.0001). Logistic regression analysis results show that there was a significant association between obesity and age, gender, ethnicity urban/rural status and smoking status. The prevalence of obesity amongst those aged >= 18 years old has markedly increased by 280% since the last National Health and Morbidity Survey in 1996. CONCLUSION: The overall prevalence of obesity in Malaysia is very high as compared to 1996. There is an urgent need for a comprehensive integrated population-based intervention program to ameliorate the growing problem of obesity in Malaysians. PMID- 17704039 TI - Comparisons of attitudes and practices between obese and normal weight women in Taiwan. AB - This study was designed to obtain baseline data regarding self-reported body image, attitudes toward overweight people, and dietary behaviors of normal-weight and obese women in Taiwan. Fifty obese women (BMI >= 27) and age-matched normal weight women participated in this study. Written questionnaires were used for data collection. Simple frequency and t-test were used to analyze data. In general, the majority of normal-weight women perceived themselves as being heavier than their actual body weight. The normal-weight group had more high inaccurate images of their bodies than that of the obese group (72% vs. 24%). Obese and normal-weight women had similar attitudes to overweight people, but some of their attitudes showed significant differences. Obese women would prefer to consume more fried foods and drink sugar-containing foods than would normal weight women (p < 0.05). Education about accurate perceptions of what is normal weight for women and adopting energy-diluted foods for obese women is needed in the future. PMID- 17704040 TI - Prevalence of overweight and obesity and its associated factors in aboriginal Taiwanese: findings from the 2001 National Health Interview Survey in Taiwan. AB - The study was undertaken to assess the prevalence of obesity in Taiwanese aborigines and to identify the associated factors. Data for this study were from the "2001 National Health Interview Survey (NHIS)" that conducted in-home, face to-face, interviews on 6,592 households (26,658 persons) of a national probability sample in Taiwan. Aborigine-dense mountainous areas are over-sampled. BMI values were used to indicate obesity status. Logistic regression analyses were used to determine the significance of the association of the variables with the obesity status. Results showed that approximately 10.5% of aboriginal men and 14.5% of women compared to 4.1% and 3.5% of their non-aboriginal counterparts were obese (BMI > 30). An additional 45.1% of aboriginal men and 33.3% of women compared to 27.6% and 17.7% of their non-aboriginal counterparts were overweight (BMI 25-30). Regression analyses revealed few associations with increased risk of obesity in the aborigines. However, the aborigines and non-aborigines were distinctly different from each other in socio-economic status, lifestyle, environmental factors and attitude toward obesity. Results indicate that obesity is more prevalent among the aborigines but the causal reasons are not apparent. The public health authorities should develop more culturally appropriate community-based intervention strategies to promote the health of the aborigines. PMID- 17704042 TI - Thyroid nodules - stepwise diagnosis and management. AB - Thyroid nodules are common in clinical practice. They may be solitary within a "normal" thyroid gland or dominant within a multinodular goiter. The incidence of thyroid nodules has been on the rise in recent decades, mainly due to the wider use of neck imaging. Therefore, the incidental finding of a thyroid nodule in an asymptomatic patient is not rare. The differential diagnosis of a thyroid nodule is crucial, as malignancy necessitates surgery, while strict patient follow-up is necessary in the case of benignity. Fine-Needle Aspiration biopsy is considered to be the "gold standard" in the selection of patients for surgery. Ultrasonography (US) can be used to determine changes in the size of nodules during follow-up or to detect recurrent lesions in patients suspected for thyroid malignancy, although there are no specific US findings that suggest malignancy. Surgery is mandatory in cytologically malignant nodules or in cases suspicious for malignancy. The definite diagnosis and consequent therapy is based on the histological findings after surgery. In this review we present an approach to thyroid nodules in five distinct steps, from the clinical or incidental finding of a nodule to the suggested treatment baselines. PMID- 17704041 TI - Anti-obesity drug use before professional treatment in Taiwan. AB - Between July 2004 and June 2005, a cross-sectional study was performed to determine the prevalence and patterns of anti-obesity medicine use among subjects seeking obesity treatment in Taiwan. Eighteen obesity outpatient clinics were selected via a random stratified sampling method and 1,060 first-visit clients (791 females and 269 males) aged above 18 years were enrolled and then completed a self-administered questionnaire. The prevalence of anti-obesity medicine use was 50.8%; more females than male used anti-obesity medicines (53.6% vs. 42.4%). Of the 1,060 subjects, 17.1% had used orlistat, 21.1% had taken sibutramine, and 18.3% had utilized un-proven drugs such as cocktail therapy and other anti obesity drugs. Furthermore, 23.6% and 22.4% of subjects indicated that they concurrently used Chinese herbal preparations and dietary supplements, respectively. Logistic regression analyses demonstrated that the odds ratio (OR) for anti-obesity medicine use was substantially higher in females (OR, 1.9; 95% CI, 1.3-2.6), those aged 18-24 years (OR, 1.6; 95% CI, 1.0-2.6), those with a body mass index (BMI) >35 kg/m2 (OR, 3.4; 95% CI, 2.1-5.7) and respondents concurrently using Chinese herbal preparations (OR, 1.7; 95% CI, 1.2-2.4) and dietary supplements (OR, 2.2; 95% CI, 1.6-3.1). In conclusion, the prevalence of anti-obesity drugs use is high among Taiwanese adults before they seek obesity treatment. Young, obese females, and those who had taken Chinese herbal preparations/dietary supplements had a high likelihood to report using anti obesity medicines. Use of unproven weight-loss drugs is common and warrants further investigation. PMID- 17704043 TI - Coronary calcification in patients with end-stage renal disease: a novel endocrine disorder? AB - Cardiovascular mortality is significantly increased among patients with end-stage renal disease. The commonly observed vascular calcification in such patients has been considered as one of the causative factors. In patients undergoing dialysis, the incidence of coronary artery calcification is 2-5 times higher compared to patients with normal renal function and angiographically demonstrated coronary artery disease. Moreover, epidemiological studies have revealed a significant correlation of the extent of coronary artery calcification with the severity of underlying atherosclerotic lesions. Vascular calcification was initially considered as a passive process of hydroxyapatite deposition due to elevated plasma concentrations of calcium and phosphate. Nevertheless, there is a growing body of evidence that vascular calcification is an actively regulated and cell mediated process. This phenomenon includes phenotypic alterations of vascular smooth muscle cells mainly resulting from an imbalance between promoters (such as increased Ca x P product) and inhibitors (fetuin-A, GLA protein, osteoprotegerin) of mineral deposition. With regard to the therapeutic approach, despite the evident effectiveness of both traditional and innovative remedies in the management of metabolic and electrolytic abnormalities of patients with end-stage renal disease, an individualized intervention based on etiopathogenesis is really required. PMID- 17704044 TI - Endocrine evaluation of patients after brain injury: what else is needed to define specific clinical recommendations? PMID- 17704045 TI - Early metabolic defects following gestational diabetes in three ethnic groups of anti-GAD antibodies negative women with normal fasting glucose. AB - OBJECTIVE: To characterise early metabolic abnormalities and the impact of ethnicity following gestational diabetes mellitus (GDM). DESIGN: Women with a history of GDM belonging to three different ethnic groups were evaluated. Using the insulin-modified, frequently-sampled intravenous glucose tolerance test (FSIVGTT) and HOMA we studied 34 European, 16 South Asian and 10 Afro-Caribbean women with normal fasting glucose following GDM and 44 European, 16 South Asian and 19 Afro-Caribbean controls to assess insulin action and secretion. RESULTS: European post-GDM women had lower insulin sensitivity by FSIVGTT [0.6 (0.1-5.1) vs 1.5 (0.8-2.8) x10(-4).min(-1).pmol(-1).l(-1), p=0.010, adjusted for BMI p=0.054] and by HOMA [72(22-235) vs 153(55-421)%, p=0.004, adjusted for BMI p=0.006], and reduced -cell function [lower disposition index 0.05(0.01-0.40) vs 0.11(0.05-0.25)min(-1), p=0.017] compared with controls. South Asian post-GDM women had decreased -cell function [lower HOMA (%B) (73 (37-147) vs 124 (59-262) %, p=0.048 and acute insulin response to glucose (463 (131-1639) vs 1039 (393 2748) pmol/l h, p=0.052] than controls. Afro-Caribbean post-GDM women had lower glucose disappearance rate [1.3(0.6-2.8) vs 2.6 (1.8-3.8) 10(-2)/min, p=0.003] than controls, suggesting subtle glucose intolerance. CONCLUSIONS: Women with a history of GDM of three different ethnic groups, even in the presence of normal fasting glucose, display a range of metabolic abnormalities, including -cell dysfunction with variable insulin resistance. These derangements may be influenced by ethnicity. PMID- 17704046 TI - Data on pubertal development in Greek boys. A longitudinal study. AB - OBJECTIVE: Longitudinal data on boys' puberty evolution are not available in Greece and very few such studies have been reported world-wide. We present data from a longitudinal study on height, weight, BMI and age at the different pubertal stages in Greek boys. DESIGN: At the start of the study 204 prepubertal boys aged 8-10 years, were enrolled. Measurements were carried out every 3-6 months for 7.5 years. RESULTS: At pubertal stage G2 the mean age and SD was 10.3 (1.0), the height 143.4 cm or 82.3% of final height and the BMI 18.6 kg/m(2). Mean age at peak height velocity was 13.2 (1.0) years and at final height 17.1 (0.9) years. At peak height velocity, the height accounted for 91.5% of the final height. The time elapsed from the beginning to the end of puberty (duration of pubertal process) was 6.2 (0.6) years. The height gain during puberty was 31.0 (4.0) cm and the weight gain 36.3 (8.1)kg. CONCLUSIONS: Longitudinal data on pubertal development are rather sparse, especially for males. Although the present study was carried out in an urban population of the Athens region, the data could be useful in delineating prognosis of puberty evolution and final height in boys. PMID- 17704047 TI - A newly detected mutation of the RET protooncogene in exon 8 as a cause of multiple endocrine neoplasia type 2A. AB - Multiple endocrine neoplasia type 2A (MEN2A) is a syndrome of familial neoplasias characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and hyperplasia of the parathyroid glands. RET protooncogene mutations are responsible for MEN 2A. Mutations in exons 10 or 11 have been identified in more than 96% of patients with MEN 2A. We herein report for the first time a patient with MEN 2A harboring a mutation (Gly(533)Cys) in exon 8. A 66-year old male patient was referred to our department for bilateral adrenal nodules. The patient's family history was remarkable in that his mother had pheochromocytoma. Biochemical evaluation and findings of the magnetic resonance imaging of the adrenals were compatible with the diagnosis of bilateral pheochromocytomas. The patient underwent laparoscopic bilateral adrenalectomy and histological examination confirmed the preoperative diagnosis of pheochromocytoma. Absence of phenotypic characteristics of VHL or NF1 and elevated calcitonin levels both basal and post pentagastrin stimulation, raised the possibility of MEN 2A syndrome. Total thyroidectomy was performed and histological examination showed the presence of MTC. Direct sequencing of exon 8 from the patient's genomic DNA revealed the mutation c.1,597G-->T (Gly533Cys). Although this missense point mutation has been associated with familial MTC (FMTC), to the best of our knowledge mutations in exon 8 have not previously been identified in patients with MEN 2A. In conclusion, in patients with clinical suspicion of MEN 2A syndrome, analysis of RET exon 8 should be considered when the routine evaluation of MEN 2A-associated mutations is negative. Furthermore, patients with FMTC and exon 8 mutations should also be screened for pheochromocytoma. PMID- 17704048 TI - Diabetes and the 'Natural Faculties' in the Galenic treatises. PMID- 17704049 TI - Attitudes toward women and tolerance for sexual harassment among reservists. AB - Women are more likely to experience sexual harassment in some work settings than others; specifically, work settings that have a large proportion of male workers, include a predominance of male supervisors, and represent traditional male occupations may be places in which there is greater tolerance for sexual harassment. The focus of the study was to document attitudes toward women among military personnel, to identify demographic and military characteristics associated with more positive attitudes toward women, and to examine associations between attitudes toward women and tolerance for sexual harassment. The study was based on data from 2,037 male and female former Reservists who reported minimal or no experiences of sexual harassment and no sexual assault in the military. Results suggest that attitudes toward women vary across content domains, are associated with several key demographic and military characteristics, and predict tolerance for sexual harassment. Implications of the findings and future directions are discussed. PMID- 17704050 TI - Modern-day comfort women: the U.S. Military, transnational crime, and the trafficking of women. AB - The trafficking of women has been a lucrative moneymaker for transnational organized crime networks, ranking third, behind drugs and arms, in criminal earnings. The U.S. military bases in South Korea were found to form a hub for the transnational trafficking of women from the Asia Pacific and Eurasia to South Korea and the United States. This study, conducted in 2002, examined three types of trafficking that were connected to U.S. military bases in South Korea: domestic trafficking of Korean women to clubs around the military bases in South Korea, transnational trafficking of women to clubs around military bases in South Korea, and transnational trafficking of women from South Korea to massage parlors in the United States. PMID- 17704052 TI - Lifetime and current sexual assault and harassment victimization rates of active duty United States Air Force women. AB - From a stratified random sample, 2,018 active-duty United States Air Force women completed a telephone survey dealing with sexual assault and harassment. The lifetime prevalence of rape among Air Force women (28%) was more than twice as high as the prevalence in a national sample (13%). Nearly half of the military sample had been the victims of rape, molestation, or attempted sexual assault. The majority of both initial rapes (75%) and most recent rapes (56%) involved assault by civilians when the victims were civilians. Family members perpetrated 29% of initial rapes and 33% of most recent rapes. Regarding military status of the perpetrator, 14% of first-time victims were raped by a military member, 26% of multiple-time victims were raped by a military member, 31.8% of military women were sexually harassed by a military supervisor or boss, and 26.7% of military women were sexually harassed by a military coworker. PMID- 17704053 TI - Rape rates and military personnel in the United States: an exploratory study. AB - This study involves a test of the cultural spillover hypothesis through a state level analysis of the relationship between rape rates and the proportion of military personnel in the population. A statistically significant correlation not predicted by this hypothesis was found between rape rates and the proportion of Air Force personnel in the population. Further exploration revealed that this was largely because of the high correlation between the Air Force and the Indian population. Multivariate analyses revealed that the proportion of Indian women in the population was the main predictor of rape rates. Per capita alcohol consumption was also found to be positively correlated with both rape rates and Air Force personnel but was not significantly related to rape in the multivariate analysis. PMID- 17704054 TI - Analysis and implications of the omission of offenders in the DoD Care for Victims of Sexual Assault Task Force report. AB - This note addresses the weaknesses in the Department of Defense (DoD) Care for Victims of Sexual Assault Task Force (CVSATF) Report, released in May 2004. Sound policy and protocol cannot be developed to prevent and to respond to sexual assault in the military if the role of sex offenders is not understood, yet the report excludes information relevant to understanding sex offender behavior and to responsibility. Shortcomings in the CVSATF recommendations to improve military definitions of sexually violent behavior and data collection are summarized, as are limitations in the recommendations for sexual assault prevention strategies. This analysis highlights problems with the DoD CVSATF recommendations to improve offender accountability and secure safety for communities and discusses how the military social climate is prohibitive to facilitating these goals. This note suggests that policy and procedures guided by recommendations that omit information about sex offenders may actually leave communities at continued risk of sexual assault. PMID- 17704055 TI - The Saccharomyces homolog of mammalian RACK1, Cpc2/Asc1p, is required for FLO11 dependent adhesive growth and dimorphism. AB - Nutrient starvation results in the interaction of Saccharomyces cerevisiae cells with each other and with surfaces. Adhesive growth requires the expression of the FLO11 gene regulated by the Ras/cAMP/cAMP-dependent protein kinase, the Kss1p/MAPK, and the Gcn4p/general amino acid control pathway, respectively. Proteomics two-dimensional DIGE experiments revealed post-transcriptionally regulated proteins in response to amino acid starvation including the ribosomal protein Cpc2p/Asc1p. This putative translational regulator is highly conserved throughout the eukaryotic kingdom and orthologous to mammalian RACK1. Deletion of CPC2/ASC1 abolished amino acid starvation-induced adhesive growth and impaired basal expression of FLO11 and its activation upon starvation in haploid cells. In addition, the diploid Flo11p-dependent pseudohyphal growth during nitrogen limitation was CPC2/ASC1-dependent. A more detailed analysis revealed that a CPC2/ASC1 deletion caused increased sensitivity to cell wall drugs suggesting that the gene is required for general cell wall integrity. Phosphoproteome and Western hybridization data indicate that Cpc2p/Asc1p affected the phosphorylation of the translational initiation factors eIF2 alpha and eIF4A and the ribosome associated complex RAC. A crucial role of Cpc2p/Asc1p at the ribosomal interface coordinating signal transduction, translation initiation, and transcription factor formation was corroborated. PMID- 17704056 TI - Regulation of E2F1 function by the nuclear corepressor KAP1. AB - KAP1 is a nuclear corepressor with conserved domains for RING finger, B boxes, leucine zipper alpha helical coiled-coil region, plant homeo domain finger, and bromo domain. The plant homeo domain finger and bromo domain of KAP1 cooperatively function as a transcription repression domain by recruiting the histone deacetylase complex NuRD and histone H3 lysine 9-specific methyltransferase SETDB1. Here we report that KAP1 binds the E2F1 transcription factor in a retinoblastoma protein (pRb)-independent fashion and inhibits E2F1 activity. KAP1 stimulates formation of E2F1-HDAC1 complex and inhibits E2F1 acetylation. Ectopic expression of KAP1 represses E2F1 transcription and apoptosis functions independent of pRb. Depletion of endogenous KAP1 in pRb deficient Saos2 cells by RNA interference increases E2F1 acetylation level, stimulates E2F1 transcriptional activity, and sensitizes apoptosis response to DNA damage. Therefore, KAP1 contributes to the negative regulation of E2F1 and may serve as a partial backup to prevent E2F1-mediated apoptosis in the absence of pRb. PMID- 17704057 TI - Anti-hepatitis C virus activity of tamoxifen reveals the functional association of estrogen receptor with viral RNA polymerase NS5B. AB - Hepatitis C virus (HCV) is a major causative agent of hepatocellular carcinoma. HCV genome replication occurs in the replication complex (RC) around the endoplasmic reticulum membrane. However, the mechanisms regulating the HCV RC remain widely unknown. Here, we used a chemical biology approach to show that estrogen receptor (ESR) is functionally associated with HCV replication. We found that tamoxifen suppressed HCV genome replication. Part of ESRalpha resided on the endoplasmic reticulum membranes and interacted with HCV RNA polymerase NS5B. RNA interference-mediated knockdown of endogenous ESRalpha reduced HCV replication. Mechanistic analysis suggested that ESRalpha promoted NS5B association with the RC and that tamoxifen abrogated NS5B-RC association. Thus, ESRalpha regulated the presence of NS5B in the RC and stimulated HCV replication. Moreover, the ability of ESRalpha to regulate NS5B was suggested to serve as a potential novel target for anti-HCV therapeutics. PMID- 17704058 TI - Conserved glutamate residues are critically involved in Na+/nucleoside cotransport by human concentrative nucleoside transporter 1 (hCNT1). AB - Human concentrative nucleoside transporter 1 (hCNT1), the first discovered of three human members of the SLC28 (CNT) protein family, is a Na+/nucleoside cotransporter with 650 amino acids. The potential functional roles of 10 conserved aspartate and glutamate residues in hCNT1 were investigated by site directed mutagenesis and heterologous expression in Xenopus oocytes. Initially, each of the 10 residues was replaced by the corresponding neutral amino acid (asparagine or glutamine). Five of the resulting mutants showed unchanged Na+ dependent uridine transport activity (D172N, E338Q, E389Q, E413Q, and D565N) and were not investigated further. Three were retained in intracellular membranes (D482N, E498Q, and E532Q) and thus could not be assessed functionally. The remaining two (E308Q and E322Q) were present in normal quantities at cell surfaces but exhibited low intrinsic transport activities. Charge replacement with the alternate acidic amino acid enabled correct processing of D482E and E498D, but not of E532D, to cell surfaces and also yielded partially functional E308D and E322D. Relative to wild-type hCNT1, only D482E exhibited normal transport kinetics, whereas E308D, E308Q, E322D, E322Q, and E498D displayed increased K50(Na+) and/or Km(uridine) values and diminished Vmax(Na+) and Vmax(uridine) values. E322Q additionally exhibited uridine-gated uncoupled Na+ transport. Together, these findings demonstrate roles for Glu-308, Glu-322, and Glu-498 in Na+/nucleoside cotransport and suggest locations within a common cation/nucleoside translocation pore. Glu-322, the residue having the greatest influence on hCNT1 transport function, exhibited uridine-protected inhibition by p-chloromercuriphenyl sulfonate and 2-aminoethyl methanethiosulfonate when converted to cysteine. PMID- 17704059 TI - Role of ADAM-9 disintegrin-cysteine-rich domains in human keratinocyte migration. AB - ADAM-9 belongs to a family of transmembrane, disintegrin-containing metalloproteinases involved in protein ectodomain shedding and cell-cell and cell matrix interactions. The aim of this study was to analyze the expression of ADAM 9 in skin and to assess the role of this proteolytic/adhesive protein in skin physiology. In normal skin, ADAM-9 expression was detected in both the epidermis and dermis and in vitro in keratinocytes and fibroblasts. Here we report that ADAM-9 functions as a cell adhesion molecule via its disintegrin-cysteine-rich domain. Using solid phase binding assays and antibody inhibition experiments, we demonstrated that the recombinant disintegrin-cysteine-rich domain of ADAM-9 specifically interacts with the beta1 integrin subunit on keratinocytes. This was corroborated by co-immunoprecipitation. In addition, engagement of integrin receptors by the disintegrin-cysteine-rich domain resulted in ERK phosphorylation and increased MMP-9 synthesis. Treatment with the ERK inhibitor PD98059 inhibited MMP-9 induction. Furthermore, the presence of the soluble disintegrin-cysteine rich domain did not interfere with cell migration on different substrates. However, keratinocytes adhering to the immobilized disintegrin-cysteine-rich domain showed increased motility, which was partially due to the induction of MMP 9 secretion. In summary, our results indicate that the ADAM-9 adhesive domain plays a role in regulating the motility of cells by interaction with beta1 integrins and modulates MMP synthesis. PMID- 17704061 TI - Single molecule imaging of Tid1/Rdh54, a Rad54 homolog that translocates on duplex DNA and can disrupt joint molecules. AB - The Saccharomyces cerevisiae Tid1 protein is important for the recombinational repair of double-stranded DNA breaks during meiosis. Tid1 is a member of Swi2/Snf2 family of chromatin remodeling proteins and shares homology with Rad54. Members of this family hydrolyze ATP and promote 1) chromatin remodeling, 2) DNA topology alterations, and 3) displacement of proteins from DNA. All of these activities are presumed to require translocation of the protein on DNA. Here we use single-molecule visualization to provide direct evidence for the ability of Tid1 to translocate on DNA. Tid1 translocation is ATP-dependent, and the velocities are broadly distributed, with the average being 84 +/- 39 base pairs/s. Translocation is processive, with the average molecule traveling approximately 10,000 base pairs before pausing or dissociating. Many molecules display simple monotonic unidirectional translocation, but the majority display complex translocation behavior comprising intermittent pauses, direction reversals, and velocity changes. Finally, we demonstrate that translocation by Tid1 on DNA can result in disruption of three-stranded DNA structures. The ability of Tid1 translocation to clear DNA of proteins and to migrate recombination intermediates may be of critical importance for DNA repair and chromosome dynamics. PMID- 17704062 TI - The development of a preliminary ultrasonographic scoring system for features of hand osteoarthritis. AB - OBJECTIVES: Painful osteoarthritis (OA) of the hand is common and a validated ultrasound (US) scoring system would be valuable for epidemiological and therapeutic outcome studies. US is increasingly used to assess peripheral joints, though most of the US focus in rheumatic diseases has been on rheumatoid arthritis. We aimed to develop a preliminary US hand OA scoring system, initially focusing on relevant pathological features with potentially high reliability. METHODS: A group of experts in the fields of OA, US and novel tool development agreed on domains and suggested scaling of the items to be used in US hand OA scoring systems. A multi-observer reliability exercise was then performed to evaluate the draft items. RESULTS: Synovitis (grey scale and Power Doppler) and osteophytes (representing activity and damage domains) were included and evaluated as the initial components of the scoring system. All three features were evaluated for their presence/absence and if present were scored using a 1-3 scale. The reliability exercise demonstrated intra-reader kappa values of 0.444 1.0, 0.211-1.0 and 0.087-1.0 for grey scale synovitis, power Doppler and osteophytes respectively. Inter-reader reliability kappa values were 0.398, 0.327 and 0.530 grey-scale synovitis, power Doppler and osteophytes respectively. Without extensive standardisation, both intra- and inter-reader reliability were moderately good. CONCLUSIONS: The draft scoring system demonstrated substantive to almost perfect percentage exact agreement on the presence/absence of the selected OA features and moderate to substantive percentage exact agreement on semi-quantitative grading. This preliminary process provides a good basis from which to further develop an US outcome tool for hand OA that has the potential to be utilised in multicentre clinical trials. PMID- 17704063 TI - Individualising the Western Ontario and McMaster Universities osteoarthritis index (WOMAC) function subscale: incorporating patient priorities for improvement to measure functional impairment in hip or knee osteoarthritis. AB - OBJECTIVE: Recommended outcome measures in osteoarthritis are standardised scales identical for each patient. As patient-specific scales are of increasing interest when considering patient priorities in outcome assessment, this study aims to validate individualised forms of the Western Ontario and McMaster Universities osteoarthritis index (WOMAC) function subscale. PATIENTS AND METHODS: WOMAC function subscale data were prospectively obtained from 1218 outpatients with hip or knee osteoarthritis requiring non-steroidal anti-inflammatory drugs. Patients also rated the importance to remove disability in each activity of the WOMAC function subscale, and selected the five activities they considered the most important to be improved upon. After treatment, patients again completed the WOMAC function subscale. Several individualisation methods were evaluated: methods whereby the score of each item is multiplied by, or added to, its importance, and methods based on the five most important activities (WOMAC top 5). Psychometric properties of individualised scales were compared to those of the WOMAC function subscale. RESULTS: The missing data rate was 11%, 13% and 2% for the WOMAC function, its individualised forms and the WOMAC top 5, respectively. Combining severity and importance of each item did not improve the properties of the scales. The WOMAC top 5 was the most responsive scale (standardised response mean: 0.96 vs 0.80, p<0.001). CONCLUSION: Because of its better responsiveness, ease of use, low missing data rate and ability to highlight patient priorities, the WOMAC top 5 could be an interesting tool in therapeutic evaluation in hip or knee osteoarthritis. PMID- 17704060 TI - Defective metabolic signaling in adenylate kinase AK1 gene knock-out hearts compromises post-ischemic coronary reflow. AB - Matching blood flow to myocardial energy demand is vital for heart performance and recovery following ischemia. The molecular mechanisms responsible for transduction of myocardial energetic signals into reactive vasodilatation are, however, elusive. Adenylate kinase, associated with AMP signaling, is a sensitive reporter of the cellular energy state, yet the contribution of this phosphotransfer system in coupling myocardial metabolism with coronary flow has not been explored. Here, knock out of the major adenylate kinase isoform, AK1, disrupted the synchrony between inorganic phosphate P(i) turnover at ATP consuming sites and gamma-ATP exchange at ATP synthesis sites, as revealed by (18)O-assisted (31)P NMR. This reduced energetic signal communication in the post ischemic heart. AK1 gene deletion blunted vascular adenylate kinase phosphotransfer, compromised the contractility-coronary flow relationship, and precipitated inadequate coronary reflow following ischemia-reperfusion. Deficit in adenylate kinase activity abrogated AMP signal generation and reduced the vascular adenylate kinase/creatine kinase activity ratio essential for the response of metabolic sensors. The sarcolemma-associated splice variant AK1beta facilitated adenosine production, a function lost in the absence of adenylate kinase activity. Adenosine treatment bypassed AK1 deficiency and restored post ischemic flow to wild-type levels, achieving phenotype rescue. AK1 phosphotransfer thus transduces stress signals into adequate vascular response, providing linkage between cell bioenergetics and coronary flow. PMID- 17704064 TI - Loss-of-function mutations in the filaggrin gene: no contribution to disease susceptibility, but to autoantibody formation against citrullinated peptides in early rheumatoid arthritis. AB - OBJECTIVES: Autoantibody formation to citrullinated (pro)filaggrin has proven to be a highly specific serological marker for rheumatoid arthritis (RA). To test the potential relevance of mutations of the filaggrin (FLG) gene for disease susceptibility and elicitation of humoural autoimmunity in RA, a case-control association study of three loss-of-function FLG variants was performed. METHODS: DNA was obtained from 282 patients with early RA (mean disease duration: 6.5 months) and from 376 control individuals. Three loss-of-function variants of the FLG gene (*R501X, *2282del4 and *3702del1) were genotyped. RESULTS: No significant differences in genotype frequencies were observed between control probands and the population of RA patients. The FLG*3702del1 allele was not identified in any of the patients nor controls, and none of the probands was homozygous or compound heterozygous. In the RA cohort, heterozygous carriers of either of the FLG variants exhibited a significantly elevated prevalence of autoantibodies to citrullinated peptides (CCP-2) (80%) compared to non-carriers (51.9%) (p = 0.018, odds ratio: 3.71 (1.20-11.46)). CONCLUSIONS: The investigated FLG variants do not confer an overall risk for the development of RA. However, loss-of-function mutations in the FLG gene may contribute to the development of humoural autoimmunity, targeting citrullinated determinants in early RA. PMID- 17704065 TI - Selective p38MAPK isoform expression and activation in antineutrophil cytoplasmatic antibody-associated crescentic glomerulonephritis: role of p38MAPKalpha. AB - OBJECTIVE: Crescentic glomerulonephritis (crGN) is a frequent and life threatening manifestation of antineutrophil cytoplasmatic antibody-associated vasculitis. Up-regulation of proinflammatory cytokines contributes to renal damage by activation of p38 mitogen-activated protein kinases (MAPKs). However, it is unclear which of the four p38MAPK isoforms are expressed, activated and hence of major importance in crGN. METHODS: Kidney biopsies of patients with antineutrophil cytoplasmatic antibody-positive crGN and control samples were investigated for the expression and phosphorylation of p38MAPK isoforms and downstream target kinase MAPKAP2 by immunohistochemistry. Expression and functional activation of p38MAPK isoforms by TNF was also assessed in a human podocyte cell line by reverse transcription-polymerase chain reaction, immunoblotting and kinase array. RESULTS: Strong expression of p38MAPKalpha, beta and gamma isoforms was found in glomerular podocytes and crescents. Infiltrating leucocytes showed predominant p38MAPKalpha expression. Activation of p38MAPK and its downstream mediator MAPKAP2 was found in crGN confined to glomerular podocytes, crescents and inflammatory infiltrates. Interestingly, corticosteroid treatment before kidney biopsy diminished p38MAPK activation in crGN. Activated p38MAPK co-localised with alpha, beta and gamma isoforms in podocytes and crescents, while leucocytes showed mainly p38MAPKalpha activation. In a human podocyte cell line mRNA and protein of all four p38MAPK isoforms was expressed but only p38MAPKalpha was activated upon challenge with TNF. CONCLUSIONS: This study shows selective p38MAPK isoform expression and activation in crGN. Podocytes and podocyte-induce crescent formation is the main source of p38MAPK activation in crGN. TNF is a potent and selective activator of the alpha-isoform in podocytes, which therefore appears as a main contributor to proinflammatory signalling in the glomerulum of crGN. PMID- 17704066 TI - The additive effect of individual genes in predicting risk of knee osteoarthritis. AB - OBJECTIVE: Genetic factors are important determinants of osteoarthritis (OA) but most individual genetic associations appear relatively modest. We aimed to answer whether carrying several genetic variants associated with knee OA could result in a greater risk of OA. METHODS: Genotypes for 36 single nucleotide polymorphisms (SNPs) in 17 candidate genes previously associated with OA were analysed in 298 men and 305 women diagnosed with knee OA who met American College of Rheumatology (ACR) criteria, and in 297 male and 299 female age- and ethnicity-matched controls. The S-sum statistic method was used to select SNPs that contributed to knee OA, separately for men and women, and the coefficients from a logistic regression were used to add the genotypes in a new genetic risk variable. RESULTS: The odds ratio for individuals in the top quartile of the "genetic risk" variable compared to those in the bottom quartile was found to be 8.68 (95% CI 5.20-14.49, p<2x10(-16)) for women and 5.06 (95% CI 3.10-8.27, p<1x10(-10)) for men. CONCLUSIONS: Our data suggest that the additive information from a number of genetic variants can predict a substantial proportion of risk of knee OA. PMID- 17704068 TI - -463 G/A myeloperoxidase promoter polymorphism in giant cell arteritis. AB - OBJECTIVE: To investigate potential associations between-463 G/A myeloperoxidase (MPO) promoter polymorphism and susceptibility to, and clinical features of giant cell arteritis (GCA). METHODS: A total of 156 patients with biopsy-proven GCA who were residents of Reggio Emilia, Italy, and 235 population-based controls from the same geographic area were genotyped for-463 G/A promoter polymorphism of the MPO gene by molecular methods. The patients were subgrouped according to the presence or absence of polymyalgia rheumatica and severe ischaemic complications (visual loss and/or cerebrovascular accidents). RESULTS: The distribution of the MPO-G/A genotype differed significantly between patients with GCA and the controls (p(corr) = 0.003). Allele G was significantly more frequent in patients with GCA than in the controls (p(corr) = 0.0002, OR 2.0, 95% CI 1.4 to 2.9). Homozygosity for the G allele was significantly more frequent in patients with GCA than in controls (p(corr) = 0.0002, OR 2.2, 95% CI 1.4 to 3.4). No significant associations were found when patients with GCA with and without polymyalgia rheumatica or with and without severe ischaemic complications were compared. CONCLUSIONS: Our findings show that the-463 G/A promoter polymorphism of the MPO gene is associated with GCA susceptibility and support a role for MPO in the pathophysiology of GCA. PMID- 17704067 TI - The phosphorycholine moiety of the filarial nematode immunomodulator ES-62 is responsible for its anti-inflammatory action in arthritis. AB - OBJECTIVE: In countries where parasitic infections are endemic, autoimmune disease is relatively rare, leading to the hypothesis that parasite-derived immunomodulators may protect against its development. Consistent with this, we have previously demonstrated that ES-62, a 62 kDa phosphorylcholine (PC) containing glycoprotein that is secreted by filarial nematodes, can exert anti inflammatory action in the murine collagen-induced arthritis (CIA) model and human rheumatoid arthritis-derived synovial tissue cultures. As a first step to developing ES-62-based drugs, the aim of this study was to determine whether the PC-moiety of ES-62 was responsible for its anti-inflammatory actions. METHODS: We compared the anti-inflammatory activity of a PC-free form of recombinant ES-62 (rES-62) and a synthetic PC-ovalbumin conjugate (OVA-PC) with that of native ES 62 in the CIA model and synovial tissues from patients with rheumatoid arthritis. RESULTS: The anti-inflammatory actions of ES-62 in CIA appear to be dependent on the PC moiety as indicated by the reduction in severity of disease and also suppression of collagen-specific T helper 1 cytokine production observed when testing OVA-PC, but not rES-62. Interestingly, the anti-inflammatory activity of PC did not correlate with a reduction in anti-collagen IgG2a levels. Also, the ES 62-mediated suppression of interferon-gamma from human patient tissues could be mimicked by OVA-PC but not rES-62 or ovalbumin. CONCLUSIONS: In countries where filariasis is endemic the reduced detection of inflammatory diseases, such as rheumatoid arthritis may be because of the anti-inflammatory action of the PC moieties of ES-62. PC may thus provide the starting point for the development of novel, safe immunomodulatory therapies. PMID- 17704069 TI - Change in self-reported outcomes and objective physical function over 7 years in middle-aged subjects with or at high risk of knee osteoarthritis. AB - OBJECTIVE: In the present work, we describe the clinical course and predictors of change in self-reported outcomes and objectively assessed physical function over time in middle-aged subjects at high risk of, or with knee osteoarthritis (OA). METHODS: We examined 259 subjects (mean (SD) age 52.6 (10.4)) at mean 18 and 25 years after previous meniscectomy and 50 population-based age- and sex-matched reference subjects with the Knee injury and Osteoarthritis Outcome Score (KOOS), one-leg hop for distance and number of knee-bendings in 30 s. Radiographic OA was defined as equivalent to Kellgren and Lawrence grade 2 or worse. RESULTS: At first assessment, meniscectomised subjects reported worse pain, function and quality of life compared with the reference group (p<0.001). They also performed fewer knee-bendings per 30 s (27 vs 31, p = 0.02). The meniscectomised patients worsened over the 4-10-year observation time in all measured outcomes (p<0.001), and to a greater extent than the reference group in pain (-5, 95% CI -10 to 0) and one-leg hop (-11, 95% CI -18 to -3). Being a woman, or having radiographic knee OA, enhanced the worsening in self-reported and objectively assessed outcomes. Older age and a higher body mass index (BMI) influenced objectively assessed physical function, but not self-reported outcomes. CONCLUSION: Worsening over time in knee-related pain and function is greater in meniscectomised subjects compared with reference subjects. Rehabilitative efforts may be warranted in middle-aged meniscectomised patients, especially in women and those who have developed radiographic knee OA, who are at greater risk of worsening. PMID- 17704071 TI - Directional asymmetry in responses of local interneurons in the crayfish deutocerebrum to hydrodynamic stimulation of the lateral antennular flagellum. AB - We have recorded spiking responses from single, bimodally sensitive local interneurons (Type I) in the crayfish deutocerebrum to hydrodynamic and odorant stimuli flowing in two directions past the lateral antennular flagellum. Changing the direction of seamless introductions (meaning, with minimal variations of fluid velocity magnitude) of odorant flow past the flagellum, from proximal- >distal to distal-->proximal, did not consistently affect the dose-dependent responses of Type I neurons. By contrast, changing the direction of an abruptly initiated flow of water (or odorant) past the flagellum resulted in consistently larger numbers of spikes in response to this hydrodynamic stimulation when the flow direction was proximal-->distal. This response asymmetry is discussed in relation to its possible relevance regarding antennular flicking behavior. The putative involvement of flagellar hydrodynamic receptors, the beaked hairs, and the hydrodynamic flow asymmetries they are exposed to, are examined theoretically in the accompanying paper. PMID- 17704070 TI - Unsteady locomotion: integrating muscle function with whole body dynamics and neuromuscular control. AB - By integrating studies of muscle function with analysis of whole body and limb dynamics, broader appreciation of neuromuscular function can be achieved. Ultimately, such studies need to address non-steady locomotor behaviors relevant to animals in their natural environments. When animals move slowly they likely rely on voluntary coordination of movement involving higher brain centers. However, when moving fast, their movements depend more strongly on responses controlled at more local levels. Our focus here is on control of fast-running locomotion. A key observation emerging from studies of steady level locomotion is that simple spring-mass dynamics, which help to economize energy expenditure, also apply to stabilization of unsteady running. Spring-mass dynamics apply to conditions that involve lateral impulsive perturbations, sudden changes in terrain height, and sudden changes in substrate stiffness or damping. Experimental investigation of unsteady locomotion is challenging, however, due to the variability inherent in such behaviors. Another emerging principle is that initial conditions associated with postural changes following a perturbation define different context-dependent stabilization responses. Distinct stabilization modes following a perturbation likely result from proximo-distal differences in limb muscle architecture, function and control strategy. Proximal muscles may be less sensitive to sudden perturbations and appear to operate, in such circumstances, under feed-forward control. In contrast, multiarticular distal muscles operate, via their tendons, to distribute energy among limb joints in a manner that also depends on the initial conditions of limb contact with the ground. Intrinsic properties of these distal muscle-tendon elements, in combination with limb and body dynamics, appear to provide rapid initial stabilizing mechanisms that are often consistent with spring-mass dynamics. These intrinsic mechanisms likely help to simplify the neural control task, in addition to compensating for delays inherent to subsequent force- and length-dependent neural feedback. Future work will benefit from integrative biomechanical approaches that employ a combination of modeling and experimental techniques to understand how the elegant interplay of intrinsic muscle properties, body dynamics and neural control allows animals to achieve stability and agility over a variety of conditions. PMID- 17704072 TI - Analytical and numerical investigation of the flow past the lateral antennular flagellum of the crayfish Procambarus clarkii. AB - Analytical and numerical methodologies are combined to investigate the flow fields that approach and pass around the lateral flagellum of the crayfish Procambarus clarkii. Two cases are considered, the first being that of a free flicking flagellum and the second corresponding to a flagellum fixed inside a small bore tube. The first case is the natural one while the second corresponds to the experimental configuration investigated by Mellon and Humphrey in the accompanying paper. In that study the authors observed a hydrodynamic-dependent asymmetry in the spiking responses recorded from single, bimodally sensitive local interneurons (Type I) in the crayfish deutocerebrum, whereby the direction of an abruptly initiated flow of freshwater (or odorant) past the flagellum resulted in consistently larger numbers of spikes in response to the hydrodynamic stimulation when the flow direction was proximal-to-distal. In this communication we show that the proximal-to-distal and the distal-to-proximal flows produced in the flagellum-in-tube experiment correspond closely to the flows associated with the downward and upward flicks, respectively, of a free-flicking flagellum. We also show from calculations of the drag forces acting on the putative mechanoreceptor sensilla circumferentially distributed around a free-flicking flagellum that there are at least three sources of hydrodynamic asymmetry possibly related to the electrophysiological asymmetry observed: (i) the sense of the drag forces acting on medial and lateral mechanoreceptors changes in the same way for both with change in flick direction; (ii) during a downward (an upward) flick, a ventral (dorsal) mechanoreceptor experiences a larger drag force magnitude than a dorsal (ventral) mechanoreceptor; (iii) because of the difference in speeds between downward and upward flicks, the magnitudes of the drag forces acting on medial, lateral and ventral mechanoreceptors during a downward flick are about two times larger relative to the forces acting on medial, lateral and dorsal mechanoreceptors during an upward flick. All three of these naturally occurring hydrodynamic asymmetries are correctly reproduced in the flagellum-in-tube experiment. PMID- 17704073 TI - Swimming in the upside down catfish Synodontis nigriventris: it matters which way is up. AB - Synodontis nigriventris is a surface-feeding facultative air-breather that swims inverted with its zoological ventral side towards the water surface. Their near surface drag is about double the deeply submerged drag (due to wave drag) and roughly twice the sum of frictional and pressure drags. For streamlined technical bodies, values of wave drag augmentation near the surface may be five times the deeply submerged values. However, the depth dependence of drag is similar for fish and streamlined technical bodies, with augmentation vanishing at about 3 body diameters below the surface. Drag ;inverted' is approximately 15% less than that ;dorsal side up' near the surface. Consistent with this, at any given velocity, tailbeat frequency is lower and stride length higher for inverted swimming in surface proximity (P<0.05). Deeply submerged, there are no significant differences in drag and kinematics between postures (P>0.05). At the critical Froude number of 0.45, speeds in surface proximity correspond to prolonged swimming that ends in fatigue. To exceed these speeds, the fish must swim deeply submerged and this behaviour is observed. Inverted swimming facilitates efficient air breathing. Drag dorsal side up during aquatic surface respiration is 1.5 times the value for the inverted posture. Fast-starts are rectilinear, directly away from the stimulus. Average and maximum velocity and acceleration decrease in surface proximity (P<0.05) and are higher inverted (maximum acceleration: 20-30 m s(-2); P<0.05) and comparable to locomotor generalists (e.g. trout). Mechanical energy losses due to wave generation are about 20% for inverted and 40% for dorsal side up, and lower than for trout fast starting in shallow water (70% losses); bottom effects and large amplitude C starts (c.f. relatively low amplitude rectilinear motions in S. nigriventris) enhance resistance in trout. S. nigriventris probably evolved from a diurnal or crepuscular 'Chiloglanis-like' benthic ancestor. Nocturnality and reverse countershading likely co-evolved with the inverted habit. Presumably, the increased energy cost of surface swimming is offset by exploiting the air-water interface for food and/or air breathing. PMID- 17704074 TI - Preferences based on spectral differences in acoustic signals in four species of treefrogs (Anura: Hylidae). AB - Frogs have two inner ear organs, each tuned to a different range of frequencies. Female treefrogs (Hylidae) of three species in which males produce calls with a bimodal spectrum (Hyla chrysoscelis, H. versicolor, H. arenicolor) preferred alternatives with a bimodal spectrum to alternatives with a single high-frequency peak. By contrast, females of H. avivoca, in which males produce calls with a single, high-frequency peak, preferred synthetic calls with a single high frequency peak to calls with a bimodal spectrum. These results are consistent with the expectations of the matched-filter hypothesis and run counter to the predictions of the pre-existing bias hypothesis. At moderate to high playback levels (85-90 dB), females of H. avivoca and of two of three mtDNA-defined lineages of H. versicolor preferred unimodal signals with a high-frequency peak to those with a low-frequency peak. Females of H. chrysoscelis, H. arenicolor and the third lineage of H. versicolor did not show a preference, indicating that receiver mechanisms may be at least as evolutionarily labile as call structure. Spectral-peak preferences of gray treefrogs from Missouri, USA were intensity dependent. Whereas females chose low-frequency calls at 65 dB spl, there was either no preference (H. chrysoscelis) or a preference for high-frequency calls (H. versicolor) at 85 and 90 dB spl. These non-linear effects indicate that there is an increasing influence of high-frequency energy on preferences as females approach calling males, and these results serve to emphasize that playback experiments conducted at a single level may have limited generality. PMID- 17704075 TI - Temperature adaptation in two bivalve species from different thermal habitats: energetics and remodelling of membrane lipids. AB - We compared lipid dynamics and the physiological responses of blue mussels Mytilus edulis, a cold-adapted species, and oysters Crassostrea virginica, a warmer-water species, during simulated overwintering and passage to spring conditions. To simulate overwintering, animals were held at 0 degrees C, 4 degrees C and 9 degrees C for 3 months and then gradually brought to and maintained at 20 degrees C for 5 weeks to simulate spring-summer conditions. Changes in lipid class and fatty acid composition were related to clearance rate and oxygen consumption. We found major differences between species in triglyceride (TAG) metabolism during overwintering. Mussels used digestive gland TAG stores for energy metabolism or reproductive processes during the winter, whereas oysters did not accumulate large TAG stores prior to overwintering. Mussel TAG contained high levels of 20:5n-3 compared to levels in oysters and in the diet. This may help to counteract the effect of low temperature by reducing the melting point of TAG and thus increasing the availability of storage fats at low temperature. Mussels seemed better able to mobilise 20:5n-3 and 18:4n-3 than other fatty acids. We also found that both bivalves underwent a major remodelling of membrane phospholipids. The unsaturation index decreased in the gills and digestive glands of both species during the early stages of warming, principally due to decreases in 22:6n-3 and 20:5n-3. In digestive glands, the unsaturation index did not increase with decreasing temperature beyond a threshold attained at 9 degrees C whereas a perfect negative relationship was observed in gills, as predicted by homeoviscous adaptation. The presence of digestive enzymes and acids in the digestive gland microenvironment may lead to specific requirements for membrane stability. That oysters had lower metabolic rates than mussels coincides with a lower unsaturation index of their lipids, as predicted by Hulbert's theory of membranes as metabolic pacemakers. Both species showed increased 20:4n-6 levels in their tissues as temperature rose, suggesting an increasing availability of this fatty acid for eicosanoid biosynthesis during stress responses. The contrast between the species in TAG dynamics and the similarity of their phospholipid remodelling emphasises the essential functional role of membrane phospholipid structure and the contrasting use of TAG by oysters and mussels during overwintering. PMID- 17704077 TI - Assessment of repeated displays: a test of possible mechanisms. AB - Many animals signal their resource holding potential (RHP) to deter competitors from engaging them in potentially costly fights. Studies of this opponent assessment function have generated important insights into signal design and evolution. In the case of sounds, rate of production is often a salient feature. We used digital video playback to conduct analogous experiments exploring the importance of temporal variation in visual signals. Our study focused on the push up display of male Jacky dragons Amphibolurus muricatus, an Australian agamid lizard. This stereotyped movement-based signal is commonly performed during male male contests. A previous study has shown that Jacky dragons responses are influenced by the overall display rate of a video conspecific. We built upon this finding by investigating the effect of short-term variation in display rate. Each playback sequence varied systematically across a different combination of display parameters, while keeping the total number of push-ups constant. Other potential cues, such as morphology and the characteristics of individual motor patterns, were precisely controlled. The aggressive signalling and locomotor behaviour of subject males varied significantly between sequences. Most notably, performance of throat expansions, a typical agamid threat posture, was suppressed by video sequences with temporal clumping of displays. These results show that lizards are sensitive to differences in the temporal fine structure of display sequences and suggest that display concentration is an important assessment cue. PMID- 17704076 TI - Developmental changes in central O2 chemoreflex in Rana catesbeiana: the role of noradrenergic modulation. AB - The in vitro brainstem preparation from Rana catesbeiana shows a functional central O(2) chemoreflex. Acute brainstem exposure to hypoxic superfusate elicits lung burst frequency responses that change over the course of development. Based on studies suggesting that brainstem noradrenergic neurons are involved in this reflex, we tested the following two hypotheses in vitro: (1) activation of adrenoceptors is necessary for the expression of the fictive lung ventilation response to hypoxia, and (2) changes in fast, Cl(-)-dependent neurotransmission (GABA/glycine) contribute to developmental changes in noradrenergic modulation. Experiments were performed on preparations from pre-metamorphics tadpoles (TK stages V-XIII) and adult bullfrogs. Acute exposure to hypoxic superfusate (98% N(2), 2% CO(2)) increased fictive lung ventilation frequency in the pre metamorphic group, whereas a decrease was observed in adults. Buccal burst frequency was unchanged by hypoxia. Noradrenaline (NA; 5 micromol l(-1)) bath application mimicked both fictive breathing responses and application of the alpha(1)-antagonist prazosine (0.5 micromol l(-1)) blocked the lung burst response to hypoxia in both groups. Blocking GABA(A)/glycine receptors with a bicuculine/strychnine mixture (1.25 micromol l(-1)/1.5 micromol l(-1), respectively) or activation of GABA(B) pre-synaptic autoreceptors with baclofen (0.5 micromol l(-1)) prevented the lung burst response to hypoxia and to the alpha(1)-agonist phenylephrine (25 micromol l(-1)) in both stage groups. We conclude that NA modulation contributes to the central O(2) chemoreflex in bullfrog, which acts via GABA/glycine pathways. These data suggest that maturation of GABA/glycine neurotransmission contributes to the developmental changes in this chemoreflex. PMID- 17704078 TI - Small but powerful: the oribatid mite Archegozetes longisetosus Aoki (Acari, Oribatida) produces disproportionately high forces. AB - We investigated the holding and pulling forces generated by claws of the microarthropod Archegozetes longisetosus (Chelicerata, Acari, Oribatida) on three substrates with different roughness (R(a)=0.05 microm, 1 microm, 30 microm). Holding forces were measured perpendicular to the substrate using a strain gage force transducer; pulling forces were measured parallel to the substrate using an analytical scale. We found a significant positive correlation of surface roughness and the forces generated. Mites produced holding forces on horizontal rough surfaces (R(a)=30 microm) of up to 1180 times their weight; on vertical rough surfaces (R(a)=30 microm) they can pull with 530 times their weight, effectively involving only two pairs of legs. The relative forces are five times higher than theoretically expected for organisms of this size (<1 mm, 100 microg) and higher than any relative forces reported for insect claws. Muscles involved in claw action produced stresses up to 1170 kN m(-2), a value that is only excelled by decapod crustacean claw closer muscles. Ours is the first study of performance by chelicerate apoteles and claws and also the first to measure forces generated by any microarthropod. PMID- 17704079 TI - Effects of mass and body composition on fasting fuel utilisation in grey seal pups (Halichoerus grypus Fabricius): an experimental study using supplementary feeding. AB - This study used supplementary feeding to test the hypothesis that fuel partitioning during the postweaning fast in grey seal pups is affected by size and composition of energy reserves at weaning, and by extra provisioning. Mass and body composition changes were measured during suckling and fasting to investigate the effect of natural differences in energy reserves at weaning on subsequent allocation of fat and protein to energy use. We fed seven pups for 5 days after weaning, to investigate the effect of increased fuel availability, and particularly protein, on fuel utilisation. After correcting for protein used during the moult, the proportional contribution of fat was 86-99% of total energy use. Pups with greater energy reserves, i.e. those that were heavier and fatter at weaning, had higher rates of fat and energy use. There was no significant relationship between adiposity at weaning and proportional contribution of fat to energy use, perhaps due to a limited sample size or range of body masses and adiposity. Supplemented individuals used energy, specifically fat, much faster and utilised proportionally less of their endogenous protein by departure than non-supplemented individuals. Fat metabolism contributed a similar percentage to daily energy use in both groups. These findings show that pups spare protein, even when energy use is dramatically increased. Pups that receive greater maternal provisioning and lay down more protein may have increased survival chances at sea. This study highlights the importance of protein reserves in first year survival of grey seal pups. PMID- 17704080 TI - The hungry caterpillar: an analysis of how carbohydrates stimulate feeding in Manduca sexta. AB - In most insects, the taste of carbohydrates stimulates an immediate appetitive response. The caterpillar of Manduca sexta is an exception to this general pattern. Despite eliciting a strong peripheral gustatory response, high concentrations of carbohydrates (e.g. glucose or inositol) stimulate the same intensity of biting as water during 2-min tests. We suspected that the lack of feeding stimulation reflected the fact that prior studies used single carbohydrates (e.g. sucrose), which M. sexta would rarely encounter in its host plants. We hypothesized that the feeding control system of M. sexta responds selectively to carbohydrate mixtures. To test this hypothesis, we ran three experiments. First, we stimulated the two taste sensilla that respond to carbohydrates (the lateral and medial styloconic) with a battery of carbohydrates. These sensilla responded exclusively to sucrose, glucose and inositol. Second, we determined the response properties of the carbohydrate sensitive taste cells within both sensilla. We found that one class of carbohydrate-sensitive taste cell responded to sucrose, and two other classes each responded to glucose and inositol. Third, we examined the initial biting responses of caterpillars to disks treated with solutions containing single carbohydrates (sucrose, glucose or inositol) or binary mixtures of these carbohydrates. The only solutions that stimulated sustained biting were those that activated all three classes of taste cell (i.e. sucrose+inositol or sucrose+glucose). We propose that the brain of M. sexta monitors input from the different classes of carbohydrate-sensitive taste cell, and generates protracted feeding responses only when all three classes are activated. PMID- 17704081 TI - Antarctic fish can compensate for rising temperatures: thermal acclimation of cardiac performance in Pagothenia borchgrevinki. AB - Antarctic fish Pagothenia borchgrevinki in McMurdo Sound, Antarctica, inhabit one of the coldest and most thermally stable of all environments. Sea temperatures under the sea ice in this region remain a fairly constant -1.86 degrees C year round. This study examined the thermal plasticity of cardiac function in P. borchgrevinki to determine whether specialisation to stable low temperatures has led to the loss of the ability to acclimate physiological function. Fish were acclimated to -1 degree C and 4 degrees C for 4-5 weeks and cardiac output was measured at rest and after exhaustive exercise in fish acutely transferred from their acclimation temperature to -1, 2, 4, 6 and 8 degrees C. In the -1 degree C acclimated fish, the factorial scope for cardiac output was greatest at -1 degree C and decreased with increasing temperature. Increases in cardiac output with exercise in the -1 degree C acclimated fish was achieved by increases in both heart rate and stroke volume. With acclimation to 4 degrees C, resting cardiac output was thermally independent across the test temperatures; furthermore, factorial scope for cardiac output was maintained at 4, 6 and 8 degrees C, demonstrating thermal compensation of cardiac function at the higher temperatures. This was at the expense of cardiac function at -1 degrees C, where there was a significant decrease in factorial scope for cardiac output in the 4 degrees C acclimated fish. Increases in cardiac output with exercise in the 4 degrees C acclimated fish at the higher temperatures was achieved by changes in heart rate alone, with stroke volume not varying between rest and exercise. The thermal compensation of cardiac function in P. borchgrevinki at higher temperatures was the result of a change in pumping strategy from a mixed inotropic/chronotropic modulated heart in -1 degrees C acclimated fish at low temperatures to a purely chronotropic modulated heart in the 4 degrees C acclimated fish at higher temperatures. In spite of living in a highly stenothermal cold environment, P. borchgrevinki demonstrated the capacity to thermally acclimate cardiac function to elevated temperatures, thereby allowing the maintenance of factorial scope and the support of aerobic swimming at higher temperatures. PMID- 17704082 TI - Absence of eye shine and tapetum in the heterogeneous eye of Anthocharis butterflies (Pieridae). AB - Insect eyes are composed of spectrally heterogeneous ommatidia, typically with three different types. The ommatidial heterogeneity in butterflies can be identified non-invasively by the colorful eye shine, the reflection from the tapetal mirror located at the proximal end of the ommatidia, which can be observed by epi-illumination microscopy. Since the color of eye shine is determined by the spectral properties of the ommatidia, it has been tentatively related to color vision. In the course of a survey of ommatidial heterogeneity in butterflies, we found that members of the pierid genus Anthocharis lack the eye shine. We therefore carried out anatomy of the eye of the yellow tip, Anthocharis scolymus, and correlated it with the absence of the tapetum. The butterfly tapetum is a remnant of the ancestral moth tapetum, a trait that has been completely lost in the papilionids and also, as now appears, in the genus Anthocharis. Anatomical investigations also revealed that, considering rhabdom shape, peri-rhabdomal pigment clusters and autofluorescence, the ommatidia can be divided in at least two different types, which are randomly distributed in the retina. PMID- 17704083 TI - Distance, shape and more: recognition of object features during active electrolocation in a weakly electric fish. AB - In the absence of light, the weakly electric fish Gnathonemus petersii detects and distinguishes objects in the environment through active electrolocation. In order to test which features of an object the fish use under these conditions to discriminate between differently shaped objects, we trained eight individuals in a food-rewarded, two-alternative, forced-choice procedure. All fish learned to discriminate between two objects of different shapes and volumes. When new object combinations were offered in non-rewarded test trials, fish preferred those objects that resembled the one they had been trained to (S+) and avoided objects resembling the one that had not been rewarded (S-). For a decision, fish paid attention to the relative differences between the two objects they had to discriminate. For discrimination, fish used several object features, the most important ones being volume, material and shape. The importance of shape was demonstrated by reducing the objects to their 3-dimensional contours, which sufficed for the fish to distinguish differently shaped objects. Our results also showed that fish attended strongly to the feature ;volume', because all individuals tended to avoid the larger one of two objects. When confronted with metal versus plastic objects, all fish avoided metal and preferred plastic objects, irrespective of training. In addition to volume, material and shape, fish attended to additional parameters, such as corners or rounded edges. When confronted with two unknown objects, fish weighed up the positive and negative properties of these novel objects and based their decision on the outcome of this comparison. Our results suggest that fish are able to link and assemble local features of an electrolocation pattern to construct a representation of an object, suggesting that some form of a feature extraction mechanism enables them to solve a complex object recognition task. PMID- 17704084 TI - Kinematic analysis of an appetitive food-handling behavior: the functional morphology of Syrian hamster cheek pouches. AB - Prodigious food hoarding in Syrian hamsters Mesocricetus auratus Waterhouse is strongly linked to appetite and is made possible by large internal cheek pouches. We provide a functional analysis of the cheek pouch and its associated retractor muscle. Frame-by-frame analysis of videotaped pouch-filling behavior revealed multiple jaw cycles for each food item pouched and the use of more jaw cycles to pouch large food items ( approximately 2.5 g chow pellets) than small (corn kernels or sunflower seed with husks). These results stand in contrast to previously reported pouching kinematics in the externally pouched Dipodomys deserti, which uses only one jaw cycle per pouching event. Comparison of pouching and mastication in the same individuals also suggests that in Syrian hamsters, feeding jaw cycles are modulated to accommodate pouch filling primarily by the addition of a pause between fast open and fast close phases, which we call ;gape phase'. Contrary to previous assertions, the retractor muscle does not merely provide structural support for the full pouch during locomotion. Video analysis of ten hamsters with unilaterally denervated retractor muscles and electrophysiological study of an anaesthetized subject confirmed that retractor muscle activity during pouch filling increases pouching efficiency for food items subsequent to the first. PMID- 17704085 TI - Thermal preference of Caenorhabditis elegans: a null model and empirical tests. AB - The preferred body temperature of ectotherms is typically inferred from the observed distribution of body temperatures in a laboratory thermal gradient. For very small organisms, however, that observed distribution might misrepresent true thermal preferences. Tiny ectotherms have limited thermal inertia, and so their body temperature and speed of movement will vary with their position along the gradient. In order to separate the direct effects of body temperature on movement from actual preference behaviour on a thermal gradient, we generate a null model (i.e. of non-thermoregulating individuals) of the spatial distribution of ectotherms on a thermal gradient and test the model using parameter values estimated from the movement of nematodes (Caenorhabditis elegans) at fixed temperatures and on a thermal gradient. We show that the standard lab strain N2, which is widely used in thermal gradient studies, avoids high temperature but otherwise does not exhibit a clear thermal preference, whereas the Hawaiian natural isolate CB4856 shows a clear preference for cool temperatures ( approximately 17 degrees C). These differences are not influenced substantially by changes in the starting position of worms in the gradient, the natal temperature of individuals or the presence and physiological state of bacterial food. These results demonstrate the value of an explicit null model of thermal effects and highlight problems in the standard model of C. elegans thermotaxis, showing the value of using natural isolates for tests of complex natural behaviours. PMID- 17704086 TI - Increased non-linear locomotion alters diaphyseal bone shape. AB - Comparative studies of vertebrate morphology that link habitual locomotor activities to bone structural properties are often limited by confounding factors such as genetic variability between groups. Experimental assessment of bone's adaptive response to altered activity patterns typically involves superimposing exercise onto a normal locomotor repertoire, making a distinction between qualitative changes to locomotor repertoires and quantitative increases in activity level difficult. Here, we directly tested the hypothesis that an increase in turning activity, without the application of exercise per se, will alter femoral cross-sectional shape. Thirty day-old female BALB/cByJ mice (n=10 per group) were single-housed for 8 weeks in custom-designed cages that either accentuated linear or turning locomotion or allowed subjects to freely roam standard cages. Consistent with a lack of difference in physical activity levels between groups, there were no significant differences in body mass, femoral length, midshaft cortical area, and individual measures of mediolateral (ML) and anteroposterior (AP) bending rigidity. However, the ratio of ML to AP diaphyseal rigidity, an indicator of cross-sectional shape, was significantly greater (P<0.05) in turning subjects than in linear or control subjects. Considering that across all groups mice were genetically identical and had equivalent levels of bone quantity and physical activity, differences in femoral shape were attributed to qualitative differences in locomotor patterns (i.e. specific locomotor modes). These data indicate that increased turning can alter distribution of bone mass in the femoral diaphysis, and that turning should be considered in efforts to understand form-function relationships in vertebrates. PMID- 17704087 TI - Functional identification of an osmotic response element (ORE) in the promoter region of the killifish deiodinase 2 gene (FhDio2). AB - The physiological role played by thyroid hormones (TH) in hydro-osmotic homeostasis in fish remains a controversial issue. Previous studies have shown that in Fundulus heteroclitus (killifish) hypo-osmotic stress increases liver iodothyronine deiodinase type 2 (D2) mRNA and D2 activity. In this study we identified two conserved osmotic response element (ORE) motifs in the promoter region of the killifish D2 gene (FhDio2) and examined their possible role in the transcriptional regulation of FhDio2 during hypo-osmotic stress. As assessed by the electrophoretic mobility shift assay, results from in vivo and in vitro experiments demonstrate that exposure to an abrupt hyposmotic challenge triggers in the liver of killifish a strong nuclear recruitment of a putative osmotic response element binding protein (OREBP). This protein-DNA binding is time dependent, attains a maximum within 2-8 h after the osmotic stress, and is followed by a significant increase in D2 activity. Furthermore, protein-DNA binding and the subsequent elevation in enzyme activity were blocked by the tyrosine kinase inhibitor genistein. Thus, during hypo-osmotic stress, a putative OREBP kinase-activated pathway stimulates FhDio2 transcription and enzymatic activity. These data and the fact that D2 is the major enzyme providing local intracellular T(3) suggest that TH plays a direct role in osmoregulation in fish, possibly by participating in hepatic ammonia metabolism. This study provides important insight into the physiological role of TH in hydro-osmotic homeostasis in fish. PMID- 17704088 TI - Simulation as an additional tool for investigating the performance of standard operating procedures in anaesthesia. AB - BACKGROUND: In medicine, the use of standard operating procedures (SOPs) is often evaluated using questionnaires (QUES). However, QUES can have limitations with regard to method, thus leading to errors. Simulation (SIM) offers another opportunity for evaluation. We hypothesized that medical errors in the evaluation of SOPs using QUES could be detected by SIM, and that SIM is better qualified to demonstrate applied medicine. METHODS: We investigated the use of SOPs in anaesthesia, rapid sequence induction (RSI), by means of a QUES (n=42) or SIM (n=42) among 84 anaesthesiologists. Seven measures for preventing aspiration during induction of anaesthesia were examined and evaluated according to a predetermined points system. RESULTS: The average number of times that precautionary measures to prevent aspiration were mentioned in the QUES [4.8 (0.9)] or performed during SIM [5.0 (1.1)] did not differ between the two groups. Pre-oxygenation was the most frequently described or performed measure (95% vs 93%). However, other measures, such as avoidance of positive pressure ventilation (45% vs 85%), differed significantly between the two groups. CONCLUSIONS: QUES and SIM are powerful instruments for evaluating the implementation of SOPs such as RSI. SIM demonstrates automated behaviours and thus more clearly represents behaviours used in clinical practice than is possible to demonstrate using QUES. Using a combination of these two instruments, method errors resulting from the individual instruments can be reduced. PMID- 17704089 TI - Sciatica: a review of history, epidemiology, pathogenesis, and the role of epidural steroid injection in management. AB - Radicular pain in the distribution of the sciatic nerve, resulting from herniation of one or more lumbar intervertebral discs, is a frequent and often debilitating event. The lifetime incidence of this condition is estimated to be between 13% and 40%. Fortunately, the majority of cases resolve spontaneously with simple analgesia and physiotherapy. However, the condition has the potential to become chronic and intractable, with major socio-economic implications. This review discusses the history, epidemiology, pathophysiology, and natural history of sciatica. A Medline search was performed to obtain the published literature on the sciatica, between 1966 and 2006. Hand searches of relevant journals were also performed. Epidemiological factors found to influence incidence of sciatica included increasing height, age, genetic predisposition, walking, jogging (if a previous history of sciatica), and particular physical occupations, including driving. The influence of herniated nucleus pulposus and the probable cytokine mediated inflammatory response in lumbar and sacral nerve roots is discussed. An abnormal immune response and possible mechanical factors are also proposed as factors that may mediate pain. The ongoing issue of the role of epidural steroid injection in the treatment of this condition is also discussed, as well as potential hazards of this procedure and the direction that future research should take. PMID- 17704090 TI - Enjoying work or burdened by it? How anaesthetists experience and handle difficulties at work: a qualitative study. AB - BACKGROUND: The aim of this study was to explore difficulties at work from anaesthetists' own perspective and to examine how anaesthetists handle and cope with situations that are perceived as difficult and potentially stressful. METHODS: Two sets of interviews were conducted with 19 specialist anaesthetists in Sweden. The first set of interviews aimed at finding how the anaesthetists experienced difficulties at work. It consisted of in-depth interviews based on one open-ended question. We analysed the interviews with a phenomenological method, looking for themes in anaesthetists' descriptions of difficulties at work. In the second set, the interviews were semi-structured with open-ended questions, based on themes found in the first interview set. These interviews aimed at exploring how the interviewees described their ways of handling difficulties and how they coped with potentially stressful situations. RESULTS: Analysis of the first set of interviews resulted in five themes, describing how the anaesthetists experienced difficulties at work. All interviewees talked about difficulties related to more than one of the themes. The second set of interviews revealed two main categories of ways of handling difficulties. First, problem solving consisted of descriptions of methods for handling difficult situations which aimed at solving problems, and second, coping strategies described ways of appraising potentially stressful situations that minimized stress, despite the problem not being solved. CONCLUSIONS: The anaesthetists interviewed in this study maintained that they enjoyed work and could see no external obstacles to doing a good job. They had arrived at a reconciliation of their work with its inherent difficulties and problems. Getting access to their coping strategies might help young anaesthetists to come to terms with their work. PMID- 17704092 TI - Effects of delta-opioid receptor stimulation and inhibition on hippocampal survival in a rat model of forebrain ischaemia. AB - BACKGROUND: It has been reported that delta-opioid (DOP) receptor agonists may be neuroprotective in the central nervous system. However, the DOP agonist [d Ala(2), d-Leu(5)]enkephalin (DADLE) does not produce neuroprotection in severe forebrain ischaemia. The aim of this study was to examine the effects of DADLE on hippocampal neurone survival against less severe forebrain ischaemia. METHODS: Intraperitoneal injection of DADLE (0 or 16 mg kg(-1)) in male Sprague-Dawley rats was performed 30 min before ischaemia. Severe (10 min), moderate (8 min), or mild (6 min) forebrain ischaemia was produced by bilateral carotid occlusion combined with hypotension (35 mm Hg) under isoflurane (1.5%) anaesthesia. Naltrindole (10 mg kg(-1)) (DOP antagonist) was administered 30 min before DADLE in order to confirm DOP receptor activation in the neuroprotective efficacy of DADLE. Naltrindole alone was also administered 30 min before ischaemia to examine endogenous DOP agonism as a self-protecting mechanism against ischaemia. All animals were evaluated neurologically and histologically after a 1 week recovery period. RESULTS: DADLE improved neurone survival in hippocampal CA3 and dentate gyrus (DG) sectors. CA1 neurones were not protected against moderate and mild ischaemia. Naltrindole abolished DADLE neuroprotection in the CA3 and DG after both moderate and mild ischaemia. Interestingly, regardless of co-administration of DADLE, naltrindole significantly worsened neuronal injury in the CA1 region after mild ischaemia. CONCLUSIONS: These results suggest that DADLE provides limited neuroprotection to relatively ischaemia-resistant regions but not to selectively vulnerable regions. This was probably mediated by DOP stimulation. Pre-ischaemic treatment with a DOP antagonist, regardless of co-administration of DADLE, worsened neuronal damage at the selectively vulnerable regions only after mild forebrain ischaemia. These data suggest that DOP activation with endogenous DOP ligand may be involved in self-protecting ischaemia-sensitive regions of the brain. PMID- 17704091 TI - Narcotrend-assisted propofol/remifentanil anaesthesia vs clinical practice: does it make a difference? AB - BACKGROUND: The Narcotrend is a computer-based EEG monitor designed to measure the depth of anaesthesia. The aim of the present study is to test the hypothesis that the intraoperative level of anaesthetic depth differs if decision-making is guided by Narcotrend monitoring or not. METHODS: Forty-eight patients undergoing elective surgery were randomized to receive a Narcotrend-controlled propofol/remifentanil anaesthetic regimen or standard clinical practice. In the EEG group, anaesthesia was adjusted to achieve a Narcotrend level of D2-E0, which is recommended for moderate to deep anaesthetic depth for surgery. EEG values were recorded continuously every 20 s in both groups. Depending on data distribution, group comparisons of the EEG parameters, propofol plasma concentration, and recovery characteristics were performed by analysis of variance for repeated measurements or non-parametric statistics. RESULTS: About 62 (sd 29)% of the Narcotrend values were within the target level in the EEG group during maintenance of anaesthesia; this was true for 64 (26)% of the data in the non-EEG group. The variance of the Narcotrend data was significantly lower in the EEG group compared with the non-EEG group [median: 0.4 (range: 3.5) vs 0.6 (2.5); P = 0.048]. There was no difference in propofol or remifentanil dosage, propofol plasma concentrations, and time for extubation. Ten minutes after extubation, visual analogue scores for nausea indicated a lower incidence in the Narcotrend group [7 (15) vs 24 (34); P = 0.005]. CONCLUSIONS: Guidance of anaesthesia with the Narcotrend-monitor leads to fewer deviations from a defined target than clinical assessment of anaesthetic depth only. This results in lower scores of nausea in the immediate period after anaesthesia. PMID- 17704093 TI - Atrial enhancement by cardiovascular magnetic resonance in cardiac amyloidosis. PMID- 17704094 TI - Treatment of anaemia in chronic heart failure--optimal approach still unclear. PMID- 17704095 TI - Biventricular ICD implant using endocardial LV lead placement from the left subclavian vein approach and transseptal puncture via the transfemoral route. AB - We present the case of a 72 years old diabetic male patient with severe dilated ischaemic cardiomyopathy and New York Heart Association functional class III symptoms and previous unsuccessful attempts to cardiac resynchronization therapy using the conventional epicardial left ventricular (LV) pacing through the coronary sinus. He also had an indication for ICD implantation. We successfully implanted a biventricular ICD system from the standard left subclavian vein approach using endocardial placement of the LV lead via a transfemorally performed transeptal puncture. This technique offered him a suitable alternative to either a thoracoscopic LV lead placement (not routinely performed in our centre) or a high-risk thoracotomy procedure and multisite pacing using epicardial leads. PMID- 17704096 TI - Late left ventricular lead displacement and treatment with a new endovenous active fixation lead. AB - Left ventricular (LV) lead displacement is an early complication of biventricular pacemakers and leads to loss of capture, diaphragmatic pacing, and symptomatic deterioration, requiring a revision procedure. We report a case of late LV lead displacement following a coughing fit and treatment with a lead with a new principle of active fixation. PMID- 17704097 TI - Well-being and consumer culture: a different kind of public health problem? AB - The concept of well-being is now of interest to many disciplines; as a consequence, it presents an increasingly complex and contested territory. We suggest that much current thinking about well-being can be summarized in terms of four main discourses: scientific, popular, critical and environmental. Exponents of the scientific discourse argue that subjective well-being is now static or declining in developed countries: a paradox for economists, as incomes have grown considerably. Psychological observations on the loss of subjective well-being have also entered popular awareness, in simplified form, and conceptions of well being as happiness are now influencing contemporary political debate and policy making. These views have not escaped criticism. Philosophers understand well being as part of a flourishing human life, not just happiness. Some social theorists critique the export of specific cultural concepts of well-being as human universals. Others view well-being as a potentially divisive construct that may contribute to maintaining social inequalities. Environmentalists argue that socio-cultural patterns of over-consumption, within the neo-liberal economies of developed societies, present an impending ecological threat to individual, social and global well-being. As the four discourses carry different implications for action, we conclude by considering their varied utility and applicability for health promotion. PMID- 17704099 TI - Associations between urinary phthalate monoesters and thyroid hormones in pregnant women. AB - BACKGROUND: Maternal hypothyroidism during pregnancy can cause adverse effects in the fetus. Scientific evidence has shown that probable thyroid-like function of some phthalates in vitro and in vivo, and phthalates exposure, can begin in utero. This study investigated the association between phthalate exposure and thyroid hormones in pregnant women. METHODS: Serum and spot urine samples were collected from 76 Taiwanese pregnant women at second trimester. Thyroid hormones, including thyroid-stimulating hormone (TSH), triiodothyronine (T(3)), thyroxine (T(4)) and free T(4) (FT(4)) were analysed in serum samples, and five urinary phthalate monoesters, including mono butyl phthalate (MBP), monoethyl phthalate (MEP) and mono ethylhexyl phthalate (MEHP), were measured. RESULTS: Urinary MBP, MEP and MEHP, the median levels of which were 81.8, 27.7 and 20.6 ng/ml, respectively, were the predominant substances in the urinary phthalate monoesters. Significant mild negative correlations were found between T(4) and urinary MBP (R = -0.248, P < 0.05), and between FT(4) and urinary MBP (R = 0.368, P < 0.05). After adjusting for age, BMI and gestation, urinary MBP levels showed negative associations with FT(4) and T(4) (FT(4): beta = -0.110, P < 0.001; T(4): beta=-0.112, P = 0.003). CONCLUSIONS: Exposure to di-n-butyl phthalate (DBP) may affect thyroid activity in pregnant women, but how DBP affects thyroid function is unclear. Further studies are needed to elucidate the mechanism of action and to investigate whether any other factors related to DBP exposure alter the thyroid function. PMID- 17704098 TI - Fetal alcohol syndrome: a prospective national surveillance study. AB - OBJECTIVE: To describe the epidemiology of cases of fetal alcohol syndrome (FAS) seen by Australian paediatricians. METHODS: Active, national case-finding using the Australian Paediatric Surveillance Unit (APSU). Monthly reporting of incident cases aged <15 years by paediatricians between January 2001 and December 2004. RESULTS: Over 1150 paediatricians submitted reports each month to the APSU. Of 169 reported cases, 92 fulfilled the study criteria for FAS. There was a significant increase in the number of children reported each year from 2001 to 2004. Of 92 children, 53.3% were male, 35.7% were preterm (<37 weeks' gestation) and 64.6% were of low birth weight (<2.5 kg). Most (94.4%) had high risk exposure to alcohol in utero and 78.3% were exposed to one or more additional drugs. The median age at diagnosis was 3.3 years (range: newborn to 11.9 years): 6.5% were diagnosed at birth and 63% by 5 years of age. Of the 92 cases, 56% had growth deficiency, 53.2% had microcephaly, 85.9% had evidence of central nervous system dysfunction, 24% had additional birth defects, 5.4% had sensorineural deafness and 4.3% had visual impairment. Of children with FAS, 65% were Indigenous, 51% had a sibling with FAS, and only 40.2% lived with a biological parent. CONCLUSION: Our data are the only prospective national data available on FAS throughout the world. These findings highlight the severity, complexity and impact of FAS, the need for effective strategies for prevention, and the necessity for education to facilitate earlier diagnosis, referral and reporting of cases. PMID- 17704100 TI - Is maternal obesity related to semen quality in the male offspring? A pilot study. AB - BACKGROUND: Obesity is a strong predictor of fecundity and maternal obesity may well program semen quality during pregnancy, but to our knowledge, no published studies have evaluated this hypothesis. METHODS: From a Danish pregnancy cohort established in 1984-87, 347 out of 5109 sons were selected for a follow-up study conducted from February 2005 to January 2006. Semen and blood samples were analyzed for conventional semen characteristics and reproductive hormones and related to information on maternal pre-pregnant body mass index (BMI) that was available for 328 men. Of these, 34 were sons of underweight, and 25 sons of overweight, mothers. RESULTS: Inhibin B decreased with increasing maternal BMI (P = 0.04) and the point estimates for sperm concentration, semen volume, percent motile sperm, testosterone and FSH suggested an impaired reproductive status among sons of overweight mothers, but none of the trends were statistically significant. CONCLUSIONS: The results suggest that there may be an effect of high maternal BMI on the sons' semen quality, but the study had only enough power to justify a critical evaluation of the hypothesis in a larger study. PMID- 17704101 TI - Regulation of C-C motif chemokine ligand 2 and its receptor in human decidual stromal cells by pregnancy-associated hormones in early gestation. AB - BACKGROUND: Decidua is in close contact with the fetal trophoblasts, and involved in immune relationship of mother to fetus. However, the roles of decidua and decidual stromal cells (DSC) in materno-fetal immune regulation remain to be elucidated. In the present study, the expression and regulation of chemokines and their receptors in decidua and DSCs were investigated. METHODS AND RESULTS: The transcription of 18 chemokine receptors in human first-trimester decidual tissue and DSC were first analysed by RT-PCR. Among these receptors, C-C motif chemokine receptor-2 (CCR2) was highly transcribed. It was demonstrated by RT-PCR and immunostaining that both CCR2 and its major ligand, C-C motif chemokine ligand 2 (CCL2, monocyte chemoattractant protein-1), were expressed in decidua and DSC. We then detected CCL2 in the supernatant of primary cultures of DSC by enzyme-linked immunosorbent assay. It was shown that DSC secreted CCL2 spontaneously and continuously over 72 h (21.72 +/- 2.34 ng/ml), and the CCR2 antagonist RS102895 and an inhibitor of the map kinase kinase/mitogen-activated protein kinase (ERK/MAPK) signal pathway decreased significantly the CCL2 secretion of DSC (both P < 0.05). We further studied effects of the pregnancy-associated hormones, estrogen, progesterone or HCG on CCL2 secretion by DSC. CCL2 secretion by DSC was up-regulated by estrogen, progesterone or HCG. CONCLUSIONS: CCR2 and CCL2 are co expressed by human first-trimester DSC and decidual tissue. CCL2 is secreted in an autocrine manner through the ERK/MAPK pathway, and is up-regulated by the pregnancy-associated hormones, estrogen, progesterone and HCG, which suggests that CCL2 may play an important role at materno-fetal interface. PMID- 17704102 TI - Doctors' and nurses' attitudes towards neonatal ethical decision making in Ireland. AB - OBJECTIVE: To explore the clinical staff attitudes towards ethical decision making in neonatal intensive care units (NICUs) in Ireland, to establish differences between doctors and nurses and to compare attitudes in Ireland with those in Europe. DESIGN: Cross-sectional study by means of an anonymous questionnaire. 64 doctors and 228 nurses in seven NICUs participated (response rates 74% and 81%, respectively). Through factor analysis the staff answers to 12 attitude statements were used to build a score whose range varied from 0 (preservation of life in any case) to 10, indicating a more individualised approach according to the patient's best interests. MAIN OUTCOME MEASURE: Staff attitudes to ethical decision making in NICU. RESULTS: Mean values of attitude scores were 5.8 (95% CI 5.3 to 6.2) for doctors, and 6.0 (95% CI 5.5 to 6.5) for nurses. Respondents with experience in follow-up of NICU graduates had significantly higher scores (6.7 vs 5.4, p = 0.018), while the opposite was true among more religious staff (5.8 vs 6.9, p = 0.026) and particularly for minority religions such as Muslim (4.1, 95% CI 3.1 to 5.2). Scores were higher after age 30 for nurses, and after age 40 for doctors, suggesting the adoption of a less vitalistic viewpoint as respondents grow older and more experienced. Among doctors, a relationship was found between the attitude score and their self reported non-treatment practices. CONCLUSIONS: In Ireland, NICU doctors and nurses hold similar attitudes towards ethical decision making. Personal and professional factors have a statistically significant impact on attitude score. Compared with the rest of Europe, attitudes in Ireland appear more similar to those of southern rather than northern European countries. PMID- 17704103 TI - Bone status of children aged 5-8 years, treated with dexamethasone for chronic lung disease of prematurity. AB - BACKGROUND: It is not known whether treatment with dexamethasone in the neonatal period may lead to reduced bone mineral density in childhood. METHODS: Anthropometric and bone densitometry measurements were taken of children aged 5-8 years who had chronic lung disease (CLD) in the neonatal period (n = 22). 15 of these children were treated with dexamethasone. A control group consisted of children born preterm who did not develop CLD (n = 29). RESULTS: Total body bone mineral content and bone mineral apparent density of the lumbar spine were lower in children whose CLD was treated with dexamethasone in the neonatal period, compared with the preterm controls. CONCLUSION: Dexamethasone treatment in the neonatal period appears to cause impairment of mineralisation which persists into childhood. PMID- 17704105 TI - Probable early-onset group B streptococcal neonatal sepsis: a serious clinical condition related to intrauterine infection. AB - BACKGROUND: The estimated incidence of true early-onset group B streptococcal (GBS) neonatal infection is based on positive GBS blood or cerebrospinal fluid (CSF) culture results, but the real burden of disease is underestimated owing to the high incidence of culture-negative sepsis possibly because of antibiotic administration to the mother. OBJECTIVE: To examine the rate of probable early onset GBS neonatal sepsis and to assess its impact on total GBS neonatal disease. DESIGN: A multicentre longitudinal prospective surveillance of 107,021 deliveries. RESULTS: The rates of culture-proven and probable early-onset GBS sepsis were 0.39 and 0.47 per 1000 live births, respectively. Of great concern was the finding of three deaths related to the infection in the group with probable early-onset GBS sepsis. CONCLUSIONS: The use of chemoprophylaxis in GBS colonised pregnant women, especially when it is incomplete, may not be sufficient to prevent clinical neonatal infection, but may inhibit the growth of GBS in blood and CSF cultures. In assessing the effectiveness of GBS prophylaxis, it is advisable to consider the incidence of culture-positive and probable culture negative GBS neonatal infection. PMID- 17704104 TI - Long-term outcome after neonatal intraparenchymal echodensities with porencephaly. AB - OBJECTIVE: To compare long-term neurodevelopmental and functional outcomes of neonatal intensive care unit (NICU) survivors with neonatal intraparenchymal echodensities (IPE) with porencephaly on cranial ultrasonography with matched controls. To compare the developmental trajectories of these infants over the childhood years with those of matched controls. DESIGN: Cohort study. SETTING: Tertiary level NICU and the Neonatal Follow-Up Programme (NFUP) in Vancouver, Canada. PATIENTS: NICU survivors with birth weights <1250 g, born between 1983 and 1985. METHODS: Cranial ultrasound scans of NICU subjects with grade 4 intraventricular haemorrhage (IVH) were reviewed by a neuroradiologist and cases were defined, using stringent criteria, as IVH with IPE with porencephaly. Controls with normal cranial ultrasound findings were selected case-matched for birth weight and sex. Prospective sequential multidisciplinary assessments were performed up to 17 years in the NFUP. Mann-Whitney U test was used to compare outcomes between cases and controls. RESULTS: Of 385 eligible patients, 14 met IPE and porencephaly criteria and 10 survived to discharge. All cases with IPE and porencephaly had one or more impairments, significantly different from preterm controls (p<0.001). At all ages assessed, rates of motor, cognitive and overall impairment were significantly higher in the cases (p< or =0.002 for all tests). Most cases at adolescence were ambulatory, required learning assistance in school and had social challenges. CONCLUSIONS: Children with neonatal IPE and porencephaly have a much worse long-term neurodevelopmental outcome than children with normal cranial ultrasound findings. PMID- 17704106 TI - Quality of neonatal care and outcome. AB - High quality of care in neonatology implies providing an appropriate level of care to well newborn babies as well as more specialised care for the few babies who need it. Audit, surveillance and outcome studies may not always capture the complexity of quality of care and its contribution to outcome, and a more focused approach to standards of care evaluation may be required. Future progress in this field in the UK would benefit from a more coordinated approach from different organisations to bring together expertise in large database, management and analysis, audit and a national profile for feedback, evidence-based guidelines and guidelines development skills, expertise in the practice of changes together with the promotion by credible perinatal authorities of clinical practice. PMID- 17704108 TI - Early complicated hypertension, hypokalaemia and salt taste abnormality: a possible link? PMID- 17704109 TI - Cardiovascular remodelling and extracellular fluid excess in early stages of chronic kidney disease. AB - BACKGROUND: Patients with a mild to moderate decrease of glomerular filtration rate (GFR) are at risk of cardiovascular (CV) events and CV remodelling has been demonstrated in patients with advanced chronic kidney disease (CKD). However, early stages of CKD and the mechanisms involved in these modifications have not been studied. METHODS: A total of 104 patients with early CKD (mean GFR 60+/-21 ml/min/1.73 m(2)) had cardiac and vascular ultrasound study and measurement of extracellular fluid by multifrequence spectroscopic bioimpedance. RESULTS: GFR decline was associated with left ventricular (LV) remodelling or hypertrophy in 58 and 68% of DOQI-2 and DOQI-3 patients, respectively and impaired LV diastolic function. GFR decrease was also associated with common carotid remodelling and increased aorta stiffness. Cardiac and vascular remodelling were significantly associated with an excess of extracellular fluid (ECFe) evidenced as early as DOQI-2 stage. In multivariate analysis with adjustment for GFR, ECFe, age and systolic blood pressure (sBP), GFR was no longer independently associated with cardiac and vascular remodelling, whereas ECFe was an independent determinant of LV hypertrophy, left atrium enlargement, common carotid diameter and intima media thickness. CONCLUSION: This study shows that CV remodelling and ECF excess occurred at a very early stage of CKD. The independent association between ECF excess and cardiac and vascular remodelling and hypertrophy may be instrumental in the increased cardiovascular risk in CKD patients. Early therapeutic control of ECF may reduce CV events in CKD patients. PMID- 17704107 TI - A beta-galactoside alpha2,6-sialyltransferase produced by a marine bacterium, Photobacterium leiognathi JT-SHIZ-145, is active at pH 8. AB - A gene encoding a sialyltransferase produced by Photobacterium leiognathi JT-SHIZ 145 was cloned, sequenced, and expressed in Escherichia coli. The sialyltransferase gene contained an open reading frame of 1494 base pairs (bp) encoding a predicted protein of 497 amino acid residues. The deduced amino acid sequence of the sialyltransferase had no significant similarity to mammalian sialyltransferases and did not contain sialyl motifs, but did show high homology to another marine bacterial sialyltransferase, a beta-galactoside alpha2,6 sialyltransferase produced by P. damselae JT0160. The acceptor substrate specificity of the new enzyme was similar to that of the alpha2,6 sialyltransferase from P. damselae JT0160, but its activity was maximal at pH 8. This property is quite different from the properties of all mammalian and bacterial sialyltransferases reported previously, which have maximal activity at acidic pH. In general, both sialosides and cytidine-5'-monophospho-N acetylneuraminic acid, the common donor substrate of sialyltransferases, are more stable under basic conditions. Therefore, a sialyltransferase with an optimum pH in the basic range should be useful for the preparation of sialosides and the modification of glycoconjugates, such as asialo-glycoproteins and asialo glycolipids. Thus, the sialyltransferase obtained from P. leiognathi JT-SHIZ-145 is a promising tool for the efficient production of sialosides. PMID- 17704110 TI - The TGF-beta-induced gene product, betaig-h3: its biological implications in peritoneal dialysis. AB - BACKGROUND: TGF-beta is involved in peritoneal changes during long-term peritoneal dialysis (PD). TGF-beta induces betaig-h3 in several cell lines, and betaig-h3 may be a marker for biologically active TGF-beta. However, no study has reported induction of betaig-h3 in human peritoneal mesothelial cells (HPMCs) or its involvement in PD-related peritoneal membrane changes. METHODS: We used cultured HPMCs to investigate the biological roles of betaig-h3 during mesothelial cell injury and repair, employing the adhesion, spreading, scratching and cell migration assays. Changes in betaig-h3 expression after high glucose exposure in vivo were also evaluated using an animal chronic PD model. RESULTS: In vitro, TGF-beta1 induced betaig-h3 in cultured HPMCs, and betaig-h3-mediated mesothelial cell adhesion occurred via alphavbeta3 integrin. betaig-h3 enhanced mesothelial cell adhesion and migration and, in part, wound healing during mesothelial cell injury. The animal study demonstrated that compared to the control group, betaig-h3 concentrations in the dialysate effluent increased in the dialysis group with alterations in peritoneal structure and function during PD, and betaig-h3 positively correlated with peritoneal solute transport. Immunohistochemical and immunoblotting results showed that betaig-h3 localizes in the mesothelium and submesothelial matrix of the parietal peritoneum, and in the vascular endothelium of omentum. betaig-h3 protein expression was higher in the dialysis group. CONCLUSION: In vitro, betaig-h3 induced by TGF-beta1 in HPMCs improved adhesion and migration of HPMCs during wound healing. In the chronic infusion model of PD, betaig-h3 played a role in the functional deterioration of the peritoneal membrane, which is associated with fibrosis. PMID- 17704111 TI - Lack of association between thrombosis-associated and cytokine candidate gene polymorphisms and acute rejection or vascular complications after kidney transplantation. AB - BACKGROUND: Acute rejection episodes and vascular complications are common after renal transplantation and have negative impact on the long-term patient and graft survival. We investigated whether the risks of acute rejection, thrombosis, infarction and graft loss could be predicted based on the presence of functional polymorphisms in the genes of the coagulation and endothelial inflammation cascade. METHODS: The study consisted of 772 consecutive cadaver kidney transplantations from a single centre. The effects of gene polymorphisms FVL, F5R2, FII G20210A, MTHFR C677T, F13A1 V34L, TFPI P151L, PROC W380G, TNF G(-308)A, IL10 A(-592)C, IL10 A(-1082)G and IL6 C(-174)G of recipients and donors were investigated. RESULTS: We were unable to find statistically significant associations between any of the studied polymorphisms and clinical outcomes. CONCLUSIONS: Our results indicate that high-risk renal transplant candidates cannot be identified through the routine analysis of the polymorphisms. PMID- 17704112 TI - Pathological variants of focal segmental glomerulosclerosis in an adult Dutch population--epidemiology and outcome. AB - BACKGROUND: A working group has defined five subtypes of focal segmental glomerulosclerosis (FSGS) based on light microscopic assessment (Columbia classification). Limited information is available on the prognostic and therapeutic implications of this classification in a European population. We conducted a retrospective analysis in 93 adult patients with biopsy-proven FSGS to determine the clinical features and outcome of FSGS variants. METHODS: Renal biopsy specimens of adult patients (>16 years) diagnosed with FSGS between 1980 and 2003 were reviewed according to the Columbia classification without the knowledge of clinical outcome. The medical records were reviewed for clinical data. Primary outcomes were remission rate and renal survival. RESULTS: The frequencies of the FSGS variants were: 32% NOS (FSGS not otherwise specified), 37% tip, 26% perihilar and 5% collapsing. Cellular FSGS was not found in the biopsies. The nephrotic syndrome was less frequent in FSGS NOS (57%) and perihilar FSGS (25%) compared to the tip variant (97%). Renal function was significantly better in patients with the tip variant compared to FSGS NOS (P<0.05). Glomerular sclerosis and hyalinosis was most severe in patients with perihilar FSGS, intermediate in FSGS NOS and the least severe in patients with the tip variant. Patients with perihilar FSGS were less likely to receive immunosuppressive medication. Renal survival at 5 years was significantly better for patients with the tip variant (78% for tip vs 63% and 55% for FSGS NOS and perihilar FSGS; P=0.02). Type of FSGS and serum creatinine concentration were independent predictors of renal survival. Remission rate was higher in patients with the tip variant (P=0.1). CONCLUSION: The collapsing variant was rare in our population. Renal survival and remission rates were higher in patients with the tip variant. Use of the classification scheme for FSGS may be clinically useful. PMID- 17704113 TI - European rational approach for the genetics of diabetic complications--EURAGEDIC: patient populations and strategy. AB - BACKGROUND: Diabetic nephropathy is likely to be a complex genetic trait. To date, most diabetic nephropathy candidate gene studies have tested a limited number of genes and variants in small sized populations, or in populations that were poorly matched or phenotyped. The main objective of the EURAGEDIC study was to address these problems. METHODS: Single nucleotide polymorphisms (SNPs) in candidate genes were tested for association with overt diabetic nephropathy (persistent albuminuria >300 mg/24 h) in a large (n=2499) Type 1 diabetes case/control study. Testing for transmission disequilibrium in 541 independent parent-offspring trios with or without diabetic nephropathy was applied for validation of consistency. Candidate genes were selected based on previous linkage studies, knowledge of metabolic pathways, and animal models. A comprehensive SNP discovery in more than 100 candidate genes was performed by direct sequencing. RESULTS: In total, 1176 cases with diabetic nephropathy and 1323 diabetic controls with longstanding normoalbuminuria were included from three European populations (Denmark, Finland, France). Data were collected on HbA(1c), blood pressure, urinary albumin excretion rate, kidney function, retinopathy, smoking, medication and cardiovascular disease. To summarize the relevant non-genetic predictors for diabetic nephropathy a baseline phenotypic model fitted to EURAGEDIC data included the covariates: sex, diabetes duration, HbA(1c) and smoking as well as pair-wise interactions. CONCLUSIONS: The EURAGEDIC study is designed and powered to identify and validate common alleles as genetic risk factors for diabetic nephropathy in Type 1 diabetic patients. PMID- 17704114 TI - Importance of renal mass on graft function outcome after 12 months of living donor kidney transplantation. AB - BACKGROUND: Few studies have directly measured the kidney weight and investigated donor parameters related to it. The aim of this study was to evaluate the kidney weight and its relationship to creatinine clearance (CrCl) after 12 months post transplantation. METHODS: A total of 123 recipients of renal transplantation from living donors were evaluated. Demographic and anthropometric data from donors and recipients were collected in the pre-operative phase. Data about kidney weight were obtained through kidney measurement using an electronic weighing machine at the moment of transplantation. Glomerular filtration rate (GFR) was estimated through CrCl (modification of diet in renal disease formula) at the 1st, 6th, 12th and 18th month post-transplantation. RESULTS: The mean value of kidney weight was 170 +/- 31 g (166.4 +/- 29.2 g in women and 177.5 +/- 32.5 g in men). The kidney weight had a correlation with the donor's BMI (r = 0.43, P < 0.001) and with the CrCl on the 12th month (r = 0.31, P = 0.001). Using multiple linear regression, the kidney weight could be predicted through the BMI and donor's gender (R(2) = 0.21; P < 0.01). The CrCl after 12 months had a significant correlation with the graft weight/recipient weight ratio and with the donor age (R(2) = 0.22; P < 0.01). CONCLUSION: The kidney weight can be estimated using the donor's gender and BMI. The kidney weight significantly influences the CrCl 12 months after transplantation. PMID- 17704115 TI - Pulse wave velocity--a useful tool for cardiovascular surveillance in pre dialysis patients. AB - BACKGROUND: Cardiovascular mortality is high among patients with chronic kidney disease. Pulse wave velocity (PWV) is a simple method used for arterial distensibility evaluation. Few data are available concerning PWV in pre-dialysis patients. The aim of this study was to evaluate the association between PWV and cardiovascular disease in pre-dialysis. METHODS: One hundred and four patients were submitted to PWV analysis, coronary artery calcium (CAC) determination with a multi-slice CT scan of the coronary arteries, echocardiogram and a carotid intima-media thickness (IMT) evaluation, with a high resolution ultrasound. The demographic characteristics and laboratory tests results were studied. RESULTS: The mean age of those studied was 54.4 +/- 11.5 years, 60% were males and the mean creatinine clearance was 40 ml/min/1.73 m(2). The mean PWV was 12.2 +/- 3.4 m/s and it was significantly higher in males, diabetics, those with creatinine clearance <60 ml/min and proteinuria > or =1 g/24 h. PWV was correlated with systolic blood pressure, age, triglycerides, total cholesterol and 24 h proteinuria. In the multiple regression analysis, PWV was significantly associated with diabetes, age, systolic blood pressure and cholesterol. Fifty eight patients (56%) presented coronary calcification and PWV correlated with coronary calcium score (R = 0.48; P < 0.001) and calcium volume (R = 0.50; P < 0.001). Moreover, PWV was higher in patients with coronary calcification (13.4 +/ 3.6 m/s vs 10.7 +/- 2.4 m/s; P < 0.001). The mean left ventricular mass index (LVMI) was 106 +/- 31 g/m(2) and 24% of patients had left ventricular hypertrophy, while 19 (18.3%) patients had left ventricular dysfunction. PVW was correlated with LVMI (R = 0.25; P = 0.01) while no association could be seen between PWV and the ejection fraction or left ventricular dysfunction. A correlation between the IMT and PWV was observed (R = 0.27; P = 0.005). In addition, those with a thicker IMT had a higher PWV (13.2 +/- 3.4 m/s vs 11. 2 +/ 3.2 m/s; P = 0.003). CONCLUSION: PWV is associated with cardiovascular disease in pre-dialysis patients and can be a useful tool to identify patients with increased cardiovascular risk. PMID- 17704116 TI - Nucleotide sequence and transfer properties of two novel types of Actinobacillus pleuropneumoniae plasmids carrying the tetracycline resistance gene tet(H). AB - OBJECTIVES: To analyse the sequence and transfer properties of two tetracycline resistance plasmids found in clinical isolates of Actinobacillus pleuropneumoniae in order to assess their role in the spread of tetracycline resistance. METHODS: The plasmids designated p9956 and p12494 were purified from A. pleuropneumoniae and completely sequenced. The transfer properties of both plasmids were evaluated by electroporation and/or conjugation into Pasteurella multocida and Escherichia coli. RESULTS: Both plasmids showed a modular structure consisting of three regions involved in mobilization, tetracycline resistance or replication. The mobilization regions included the mobA gene, encoding a relaxase, a protein involved in plasmid transfer. The tetracycline resistance regions were closely related and consisted of the tet(H) gene and its repressor gene tetR. The tetracycline resistance phenotype was transferred successfully to P. multocida and in the case of p9956 also to E. coli by electroporation of the plasmids. Moreover, plasmid p9956 could be mobilized in E. coli with the assistance of RP4 conjugal transfer functions. CONCLUSIONS: For the first time, the complete sequences of two tet(H)-carrying plasmids from A. pleuropneumoniae were determined. These two plasmids differed from one another and from known tet(H) carrying plasmids from Pasteurella or Mannheimia spp. Structural analysis confirmed that these plasmids consisted of segments that have been previously detected in members of the families Pasteurellaceae and Enterobacteriaceae. PMID- 17704117 TI - Therapeutic drug monitoring of the HIV protease inhibitor atazanavir in clinical practice. AB - BACKGROUND: Therapeutic drug monitoring (TDM) is being applied for a number of antiretroviral agents. Little is known about the use of TDM for atazanavir. METHODS: This is a retrospective cohort analysis on the use of TDM of atazanavir at three clinical sites in The Netherlands. Patients were divided into three groups: (i) all patients with evaluable data of plasma atazanavir concentrations and its relationship with hyperbilirubinaemia; (ii) patients who started atazanavir without documented evidence of protease inhibitor (PI) mutations; (iii) patients who started atazanavir with documented evidence of PI mutations. The genotypic inhibitory quotient (GIQ) was calculated by dividing the mean atazanavir plasma trough concentration by the number of PI mutations. RESULTS: A total of 108 patients were included; 70 (65.8%) were using atazanavir/ritonavir (300/100 mg once daily). No significant relationship was observed between atazanavir plasma trough concentration and antiviral response in patients starting atazanavir without PI mutations (group 2; n = 82). In contrast, a significant relationship was observed between atazanavir GIQ and treatment response in patients starting atazanavir while having PI mutations (group 3; n = 26). The cut-off value for GIQ most predictive of virological failure was 0.23 mg/L/mutation: patients (n = 8) with a GIQ equal to or below this value had 50% virological failure whereas patients (n = 18) with a GIQ above 0.23 mg/L/mutation had only 11% virological failure (chi(2): P = 0.030). Atazanavir plasma trough concentrations were significantly related with the occurrence of increased total bilirubin concentrations. CONCLUSIONS: TDM of atazanavir might be beneficial for patients with documented PI resistance or patients with hyperbilirubinaemia. PMID- 17704118 TI - Abortion is associated with increased expression of FasL in decidual leukocytes and apoptosis of extravillous trophoblasts: a role for CRH and urocortin. AB - Human reproduction is remarkably inefficient, with more than half of spontaneous conceptions failing to complete the first trimester. However, little is known on the molecular events that take place at the implantation site during abortion. Here, we examined the hypothesis that the expression of the proapoptotic Fas/FasL system at the implantation site is impaired in abortions. We found that, in contrast to normal pregnancy, abortive deciduas contain leukocytes that are positive for FasL and extravillous trophoblasts (EVTs), which show increased expression of Fas and increased rates of apoptosis. In addition, the neuropeptides, corticotropin-releasing hormone and urocortin, were elevated in placental material obtained from abortions. In vitro, these peptides induced the expression of FasL in decidual lymphocytes (DL) obtained from elective termination of pregnancy placentas and thus potentiated the cells' ability to induce Fas-mediated apoptosis in an EVT-based hybridoma cell line. Finally, DL from abortion sites effectively induced apoptosis of EVT without prior treatment. It is possible that these events may impede successful early placentation and thus contribute to the pathophysiology of human abortion. PMID- 17704120 TI - Biodiversity informatics: organizing and linking information across the spectrum of life. AB - Biological knowledge can be inferred from three major levels of information: molecules, organisms and ecologies. Bioinformatics is an established field that has made significant advances in the development of systems and techniques to organize contemporary molecular data; biodiversity informatics is an emerging discipline that strives to develop methods to organize knowledge at the organismal level extending back to the earliest dates of recorded natural history. Furthermore, while bioinformatics studies generally focus on detailed examinations of key 'model' organisms, biodiversity informatics aims to develop over-arching hypotheses that span the entire tree of life. Biodiversity informatics is presented here as a discipline that unifies biological information from a range of contemporary and historical sources across the spectrum of life using organisms as the linking thread. The present review primarily focuses on the use of organism names as a universal metadata element to link and integrate biodiversity data across a range of data sources. PMID- 17704119 TI - ERp57 is a potential biomarker for human fertilization capability. AB - Human infertility is a growing concern and while many assisted reproductive technologies exist, their success rates are low. Thus, developing tests, possibly by assessing proteins involved in fertilization, that could predict the outcome of these technologies is of great significance. To identify candidate proteins, we used two-dimensional polyacrylamide gel electrophoresis and MALDI-TOF techniques and detected the ERp57 protein from human testis protein profile. Immunohistochemistry showed that ERp57 was mostly located in spermatogenic cell cytoplasm from spermatocytes to the spermatozoa phases and in Leydig cells of human testes; it was also present at low levels in Sertoli cells. ERp57 was evident in human spermatozoa, primarily in the acrosome and tail; moreover, it appeared to translocate to the equatorial segment after the acrosome reaction. During sperm capacitation, the ERp57 protein underwent post-translational modification. Blocking ERp57 with antibodies significantly inhibited human sperm from penetrating zona-free hamster oocytes in a dose-dependent manner. Finally, expression levels of ERp57 were associated with fertility; they were decreased dramatically in IVF patients with low fertilization rates compared with those with high rates or to fertile sperm donors. Taken together, these results show that ERp57 is a component of human sperm acrosome proteins, which play a critical role in gamete fusion. Furthermore, ERp57 could be a novel phenotype marker for male infertility and has the potential to be used to assess sperm selection for IVF. PMID- 17704121 TI - Does bilateral internal thoracic artery harvest increase the risk of mediastinitis? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether bilateral internal thoracic artery (BITA) coronary bypass increases the risk for mediastinitis. Using the reported search 140 papers were identified. Twenty-four papers represented the best evidence on the subject and the author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study comments and weaknesses were tabulated. In general, BITA grafting carries a 2.5- to 5-fold higher risk for mediastinitis after CABG. This risk is about 1.3-4.7% in non diabetic patients compared to 0.2-1.2% for single internal thoracic artery (SITA) grafting. For diabetic patients with BITA grafting the risk of mediastinitis is significantly increased and can be as high as >10% in some series. However, for patients who undergo BITA harvest using skeletonization the risk is significantly lower and may be similar to patients receiving SITA graft only at around 0.4 2.6%. BITA grafting can be performed with acceptable risk in all patients including higher risk patients such as diabetics, in whom skeletonization of the internal thoracic arteries should be strongly considered rather than pedicled harvest. PMID- 17704122 TI - Acute ventricular septal defect treated with an Impella recovery as a 'bridge therapy' to heart transplantation. AB - We present the case of a 59-year-old male, admitted to hospital for cardiogenic shock due to massive infero-lateral myocardial infarction. Angiography showed occlusion of the right coronary artery and widespread critical lesions of both the anterior descending and circumflex artery. Echocardiography showed inferior akinesia with a large posterior ventricular septal defect (VSD). The haemodynamic instability induced us to use a left ventricular assist device (L-VAD) like Impella for easiness of its percutaneous implantation and for its duration. We obtained the stabilisation of the patient and the improvement of the clinical conditions. The location of the ventricular septal defect (VSD), from one side, and the serious and widespread coronaropathy (not suitable for any kind of revascularisation), from the other side, led us to choose heart transplantation for this patient. Heart transplantation was performed on the 12th day after myocardial infarction without complication and the patient was discharged on the 35th postoperative day. In our opinion, when the position of the VSD is unseemly and there coexists a widespread coronaropathy not eligible for revascularisation, heart transplantation may represent an efficacious alternative. Moreover, the use of L-VAD, reducing interventricular shunt and ensuring an adequate cardiac output, allows to obtain clinical stabilisation before heart transplantation. PMID- 17704124 TI - Lung cancer resection rate in south Manchester: is it comparable to international standards? Results of a prospective tracking study. AB - The UK has been reported to have the lowest resection and survival rates for lung cancer patients. These reports were based largely on retrospective data from the cancer registry and are now outdated. To monitor the present day surgical resection rate at our institution all newly diagnosed cases of lung cancer presenting to us were enrolled into a prospective tracking study. From September 2003 to March 2005 all suspected primary lung cancer referrals to the North West Lung Centre were tracked to identify patients with newly diagnosed lung cancer. The histology of 247 patients confirmed to be new lung cancer cases were small cell (SCLC), non-small cell (NSCLC) and mixed cancers in 33 (16%), 170 (83.5%) and 1 (0.5%) patients, respectively, while 43 patients had no histological confirmation. Overall, 43 patients (17%) underwent surgery while chemotherapy and radiotherapy were used in 91 (38%) and 43 (17%), respectively. Out of 170 confirmed NSCLC patients, 43 (25%), 65 (38%) and 27 (16%) patients underwent surgery, chemotherapy and radiotherapy, respectively. The remaining 35 (20%) did not receive any treatment because of patient wishes or poor condition. The surgical resection rates were 17% for all lung cancers and 25% for NSCLC. Current surgical resection rates at the South Manchester University Hospital are comparable to international standards. Similar data from the rest of the UK are required to determine the national resection rate, which may not be as low as once thought to be. PMID- 17704123 TI - Arginine vasopressin is an ideal drug after cardiac surgery for the management of low systemic vascular resistant hypotension concomitant with pulmonary hypertension. AB - Low systemic vascular resistance (SVR) hypotension concomitant with pulmonary hypertension (PH) is difficult to manage postoperatively because they are often catecholamine-resistant. So, we applied arginine vasopressin (AVP), which is a potent vasoconstrictor in a specific condition, for post-cardiotomy refractory low SVR hypotension concomitant with PH. We treated nine cases of postoperative refractory vasodilatory hypotension concomitant with PH even after conventional treatment that included nitric oxide inhalation and/or intraaortic balloon pump. AVP was administrated with 0.05 approximately 0.1 U/min intravenously. After AVP administration, the mean systemic arterial pressure increased from 47.3+/-9.5 to 76.5+/-12.2 mmHg (P<0.01) and SVR increased from 488.1+/-92.7 to 1188+/-87 dynes x s x cm(-5) (P<0.01). Fortunately, even though the cardiac index decreased, it remained in a normal range. Alteration in the PVR was not significant, but the Pp/Ps became somewhat lower (0.66+/-0.2 to 0.47+/-0.16, P<0.01). AVP increased the urine output and improved oxygenation. AVP improved systemic circulation (increased systemic blood pressure with maintaining cardiac output) without deterioration of pulmonary hypertension. AVP is an ideal drug for treating refractory low SVR hypotension concomitant with PH. But its indication must be limited. PMID- 17704125 TI - Quality of life evolution after surgery for primary or secondary spontaneous pneumothorax: a prospective study comparing different surgical techniques. AB - The objective of the present study is to evaluate quality of life (QoL) evolution after video-assisted thoracic surgery (VATS) and anterolateral thoracotomy (AT) for primary and secondary spontaneous pneumothorax, which has not been studied prospectively until now. From January 2003 to December 2004, QoL was prospectively recorded in 20 consecutive patients, using the European Organisation for Research and Treatment of Cancer (EORTC) QoL Questionnaire-C30 and the lung specific module LC-13. Questionnaires were administered before surgery and 1, 3, 6 and 12 months postoperatively (MPO) with response rates of 100%, 85%, 80%, 65% and 60%, respectively. In this prospective, non-randomized study, all patients had wedge resection and apical pleurectomy, 45% by video assisted thoracic surgery (VATS), and 55% by anterolateral thoracotomy (AT). In general, patients QoL subscales improved after surgery. After VATS, pain (3 MPO P=0.012), dyspnoea (1 MPO P=0.030) and thoracic pain (1 MPO P=0.038) decreased significantly. After AT, a significant increase was seen in general QoL (1 MPO P=0.036, 3 MPO P=0.034, 12 MPO P=0.025), physical (6 MPO P=0.025) and emotional functioning (12 MPO P=0.017). Dyspnoea (12 MPO P=0.042) and coughing (6 MPO P=0.046) decreased after AT. After surgery, AT and VATS are comparable in QoL evolution with the exception of a significant difference at 1 MPO in physical, role and cognitive functioning (P=0.002, P=0.002 and P=0.0018, respectively) and dyspnoea (P=0.041) in favour of VATS. Comparing VATS and AT in QoL evolution, significant differences are seen in thoracic pain evolution in favour of VATS (6 MPO P=0.037). After surgery, AT and VATS are comparable in QoL subscales with exception of a significant difference at 1 MPO in favour of VATS. Dyspnoea and coughing improved after surgery. PMID- 17704126 TI - Live cell imaging of repetitive DNA sequences via GFP-tagged polydactyl zinc finger proteins. AB - Several techniques are available to study chromosomes or chromosomal domains in nuclei of chemically fixed or living cells. Current methods to detect DNA sequences in vivo are limited to trans interactions between a DNA sequence and a transcription factor from natural systems. Here, we expand live cell imaging tools using a novel approach based on zinc finger-DNA recognition codes. We constructed several polydactyl zinc finger (PZF) DNA-binding domains aimed to recognize specific DNA sequences in Arabidopsis and mouse and fused these with GFP. Plants and mouse cells expressing PZF:GFP proteins were subsequently analyzed by confocal microscopy. For Arabidopsis, we designed a PZF:GFP protein aimed to specifically recognize a 9-bp sequence within centromeric 180-bp repeat and monitored centromeres in living roots. Similarly, in mouse cells a PZF:GFP protein was targeted to a 9-bp sequence in the major satellite repeat. Both PZF:GFP proteins localized in chromocenters which represent heterochromatin domains containing centromere and other tandem repeats. The number of PZF:GFP molecules per centromere in Arabidopsis, quantified with near single-molecule precision, approximated the number of expected binding sites. Our data demonstrate that live cell imaging of specific DNA sequences can be achieved with artificial zinc finger proteins in different organisms. PMID- 17704127 TI - The PMC2NT domain of the catalytic exosome subunit Rrp6p provides the interface for binding with its cofactor Rrp47p, a nucleic acid-binding protein. AB - The exosome complex is a key component of the cellular RNA surveillance machinery and is required for normal 3' end processing of many stable RNAs. Exosome activity requires additional factors such as the Ski or TRAMP complexes to activate the complex or facilitate substrate binding. Rrp47p promotes the catalytic activity of the exosome component Rrp6p, but its precise function is unknown. Here we show that recombinant Rrp47p is expressed as an apparently hexameric complex that specifically binds structured nucleic acids. Furthermore, pull-down assays demonstrated that Rrp47p interacts directly with the N-terminal region of Rrp6p that contains the functionally uncharacterized PMC2NT domain. Strains expressing a mutant form of Rrp6p lacking the N-terminal region failed to accumulate Rrp47p at normal levels, exhibited a slow growth phenotype characteristic of rrp47-Delta mutants and showed RNA processing defects consistent with loss of Rrp47p function. These findings suggest Rrp47p promotes Rrp6p activity by facilitating binding via the PMC2NT domain to structural elements within RNA. Notably, characterized Rrp6p substrates such as the 5.8S+30 species are predicted to contain helices at their 3' termini, while others such as intergenic or antisense cryptic unstable transcripts could potentially form extensive double-stranded molecules with overlapping mRNAs. PMID- 17704128 TI - Identification of determinants in the protein partners aCBF5 and aNOP10 necessary for the tRNA:Psi55-synthase and RNA-guided RNA:Psi-synthase activities. AB - Protein aNOP10 has an essential scaffolding function in H/ACA sRNPs and its interaction with the pseudouridine(Psi)-synthase aCBF5 is required for the RNA guided RNA:Psi-synthase activity. Recently, aCBF5 was shown to catalyze the isomerization of U55 in tRNAs without the help of a guide sRNA. Here we show that the stable anchoring of aCBF5 to tRNAs relies on its PUA domain and the tRNA CCA sequence. Nonetheless, interaction of aNOP10 with aCBF5 can counterbalance the absence of the PUA domain or the CCA sequence and more generally helps the aCBF5 tRNA:Psi55-synthase activity. Whereas substitution of the aNOP10 residue Y14 by an alanine disturbs this activity, it only impairs mildly the RNA-guided activity. The opposite effect was observed for the aNOP10 variant H31A. Substitution K53A or R202A in aCBF5 impairs both the tRNA:Psi55-synthase and the RNA-guided RNA:Psi-synthase activities. Remarkably, the presence of aNOP10 compensates for the negative effect of these substitutions on the tRNA: Psi55 synthase activity. Substitution of the aCBF5 conserved residue H77 that is expected to extrude the targeted U residue in tRNA strongly affects the efficiency of U55 modification but has no major effect on the RNA-guided activity. This negative effect can also be compensated by the presence of aNOP10. PMID- 17704129 TI - Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment. AB - Oxidative stress is thought to play a role in the pathogenesis of Alzheimer's disease (AD) and increased oxidative DNA damage has been observed in brain tissue from AD patients. Base excision repair (BER) is the primary DNA repair pathway for small base modifications such as alkylation, deamination and oxidation. In this study, we have investigated alterations in the BER capacity in brains of AD patients. We employed a set of functional assays to measure BER activities in brain tissue from short post-mortem interval autopsies of 10 sporadic AD patients and 10 age-matched controls. BER activities were also measured in brain samples from 9 amnestic mild cognitive impairment (MCI) subjects. We found significant BER deficiencies in brains of AD patients due to limited DNA base damage processing by DNA glycosylases and reduced DNA synthesis capacity by DNA polymerase beta. The BER impairment was not restricted to damaged brain regions and was also detected in the brains of amnestic MCI patients, where it correlated with the abundance of neurofibrillary tangles. These findings suggest that BER dysfunction is a general feature of AD brains which could occur at the earliest stages of the disease. The results support the hypothesis that defective BER may play an important role in the progression of AD. PMID- 17704130 TI - Does distance matter? Variations in alternative 3' splicing regulation. AB - Alternative splicing constitutes a major mechanism creating protein diversity in humans. This diversity can result from the alternative skipping of entire exons or by alternative selection of the 5' or 3' splice sites that define the exon boundaries. In this study, we analyze the sequence and evolutionary characteristics of alternative 3' splice sites conserved between human and mouse genomes for distances ranging from 3 to 100 nucleotides. We show that alternative splicing events can be distinguished from constitutive splicing by a combination of properties which vary depending on the distance between the splice sites. Among the unique features of alternative 3' splice sites, we observed an unexpectedly high occurrence of events in which a polypyrimidine tract was found to overlap the upstream splice site. By applying a machine-learning approach, we show that we can successfully discriminate true alternative 3' splice sites from constitutive 3' splice sites. Finally, we propose that the unique features of the intron flanking alternative splice sites are indicative of a regulatory mechanism that is involved in splice site selection. We postulate that the process of splice site selection is influenced by the distance between the competitive splice sites. PMID- 17704131 TI - In silico detection of tRNA sequence features characteristic to aminoacyl-tRNA synthetase class membership. AB - Aminoacyl tRNA synthetases (aaRS) are grouped into Class I and II based on primary and tertiary structure and enzyme properties suggesting two independent phylogenetic lineages. Analogously, tRNA molecules can also form two respective classes, based on the class membership of their corresponding aaRS. Although some aaRS-tRNA interactions are not extremely specific and require editing mechanisms to avoid misaminoacylation, most aaRS-tRNA interactions are rather stereospecific. Thus, class-specific aaRS features could be mirrored by class specific tRNA features. However, previous investigations failed to detect conserved class-specific nucleotides. Here we introduce a discrete mathematical approach that evaluates not only class-specific 'strictly present', but also 'strictly absent' nucleotides. The disjoint subsets of these elements compose a unique partition, named extended consensus partition (ECP). By analyzing the ECP for both Class I and II tDNA sets from 50 (13 archaeal, 30 bacterial and 7 eukaryotic) species, we could demonstrate that class-specific tRNA sequence features do exist, although not in terms of strictly conserved nucleotides as it had previously been anticipated. This finding demonstrates that important information was hidden in tRNA sequences inaccessible for traditional statistical methods. The ECP analysis might contribute to the understanding of tRNA evolution and could enrich the sequence analysis tool repertoire. PMID- 17704132 TI - A facilitated tracking and transcription mechanism of long-range enhancer function. AB - In the human epsilon-globin gene locus, the HS2 enhancer in the Locus Control Region regulates transcription of the embryonic epsilon-globin gene located over 10 kb away. The mechanism of long-range HS2 enhancer function was not fully established. Here we show that the HS2 enhancer complex containing the enhancer DNA together with RNA polymerase II (pol II) and TBP tracks along the intervening DNA, synthesizing short, polyadenylated, intergenic RNAs to ultimately loop with the epsilon-globin promoter. Guided by this facilitated tracking and transcription mechanism, the HS2 enhancer delivers pol II and TBP to the cis linked globin promoter to activate mRNA synthesis from the target gene. An insulator inserted in the intervening DNA between the enhancer and the promoter traps the enhancer DNA and the associated pol II and TBP at the insulator site, blocking mid-stream the facilitated tracking and transcription mechanism of the enhancer complex, thereby blocking long-range enhancer function. PMID- 17704133 TI - The three transfer RNAs occupying the A, P and E sites on the ribosome are involved in viral programmed -1 ribosomal frameshift. AB - The -1 programmed ribosomal frameshifts (PRF), which are used by many viruses, occur at a heptanucleotide slippery sequence and are currently thought to involve the tRNAs interacting with the ribosomal P- and A-site codons. We investigated here whether the tRNA occupying the ribosomal E site that precedes a slippery site influences -1 PRF. Using the human immunodeficiency virus type 1 (HIV-1) frameshift region, we found that mutating the E-site codon altered the -1 PRF efficiency. When the HIV-1 slippery sequence was replaced with other viral slippery sequences, mutating the E-site codon also altered the -1 PRF efficiency. Because HIV-1 -1 PRF can be recapitulated in bacteria, we used a bacterial ribosome system to select, by random mutagenesis, 16S ribosomal RNA (rRNA) mutations that modify the expression of a reporter requiring HIV-1 -1 PRF. Three mutants were isolated, which are located in helices 21 and 22 of 16S rRNA, a region involved in translocation and E-site tRNA binding. We propose a novel model where -1 PRF is triggered by an incomplete translocation and depends not only on the tRNAs interacting with the P- and A-site codons, but also on the tRNA occupying the E site. PMID- 17704135 TI - Ligand recognition determinants of guanine riboswitches. AB - Guanine riboswitches negatively modulate transcription upon guanine binding. The aptamer domain is organized around a three-way junction which forms the ligand binding site. Using currently available 89 guanine aptamer sequences, a consensus secondary structure is deduced and reveals differences from the previously identified aptamer consensus. Three positions are found to display different nucleotide requirements. Using a 2-aminopurine binding assay, we show that variations are allowed depending on the aptamer context. However, changes at position 48 markedly decrease ligand binding in a context-independent fashion. This is consistent with previous observations with the adenine riboswitch in which position 48 was proposed to interact with position 74, which normally base pairs with the ligand. The in vivo transcriptional control of endogenous Bacillus subtilis guanine riboswitches was studied using RT-qPCR assays. The ratio of elongated/terminated transcripts is decreased in presence of a high concentration of guanine but is dependent on the riboswitch analyzed. In general, the aptamer 2AP complex affinity correlates well with the in vivo regulation efficiency of the corresponding riboswitch. These studies suggest that core variations of guanine aptamers are used to produce a spectrum of ligand binding affinities which is used in vivo by host riboswitches to perform gene regulation. PMID- 17704136 TI - Choreography for nucleosomes: the conformational freedom of the nucleosomal filament and its limitations. AB - Eukaryotic DNA is organized into nucleosomes by coiling around core particles of histones, forming a nucleosomal filament. The significance for the conformation of the filament of the DNA entry/exit angle (alpha) at the nucleosome, the angle of rotation (beta) of nucleosomes around their interconnecting DNA (linker DNA) and the length of the linker DNA, has been studied by means of wire models with straight linkers. It is shown that variations in alpha and beta endow the filament with an outstanding conformational freedom when alpha is increased beyond 60-90 degrees, owing to the ability of the filament to change between forward right-handed and backward left-handed coiling. A wealth of different helical and looped conformations are formed in response to repeated beta sequences, and helical conformations are shown to be able to contract to a high density and to associate pairwise into different types of double fibers. Filaments with random beta sequences are characterized by relatively stable loop clusters connected by segments of higher flexibility. Displacement of core particles along the DNA in such fibers, combined with limited twisting of the linkers, can generate the beta sequence necessary for compaction into a regular helix, thus providing a model for heterochromatinization. PMID- 17704134 TI - Tup1-Ssn6 and Swi-Snf remodelling activities influence long-range chromatin organization upstream of the yeast SUC2 gene. AB - The traditional model for chromatin remodelling during transcription has focused upon the remodelling of nucleosomes at gene promoters. However, in this study, we have determined that Tup1-Ssn6 and Swi-Snf chromatin remodelling activities extend far upstream of the SUC2 gene promoter into the intergenic region of the Saccharomyces cerevisiae chromosome. We mapped the nucleosomal array over a 7.5 kb region that encompassed the SUC2 gene promoter and upstream region but was devoid of other transcriptionally active genes. Nucleosome positioning over this region was determined under conditions of glucose repression and derepression, and in snf2, ssn6 and snf2 ssn6 mutant strains. A map detailing remodelling events extending as much as 5 kb upstream of the SUC2 gene promoter underlines the roles of the Tup1-Ssn6 and Swi-Snf complexes in respectively organizing and disrupting nucleosome arrays. The gene specificity of these events suggests a role in gene regulation. We propose that long-range chromatin remodelling activities of Swi-Snf and Tup1-Ssn6 may ultimately influence whether the chromosomal state of the SUC2 gene is proficient for transcription. These data raise the possibility that remodelling of extensive chromatin domains may be a general property of the Swi-Snf and Tup1-Ssn6 complexes. PMID- 17704137 TI - Beta-catenin binds to the downstream region and regulates the expression C reactive protein gene. AB - C-Reactive protein (CRP) is a major acute-phase response protein, which is activated by various cytokines. We investigated the mechanism of TNF-alpha induced CRP expression and found that the p50 subunit of NF-kappaB was responsible for the transcriptional activation of CRP. Since the p50 protein acts as a positive regulator of CRP expression without an inherent transactivation domain, we looked for an interaction partner that could provide p50 with such a domain. We found that beta-catenin enhanced the expression of a CRP mRNA in concert with p50 subunit. Protein-protein interaction between p50 and beta catenin was important for CRP expression and their interactions to CRP promoter were induced after TNF-a treatment. Since gene expression depends upon the proximity of promoters and distal regulatory sites, we explored the long-range genomic interaction at the CRP locus by chromosome conformation capture (3C). We identified a binding site for beta-catenin in the downstream of CRP gene by 3C and confirmed TNF-alpha-induced association of beta-catenin and p50 by chromatin immunoprecipitation and co-immunoprecipitation assays. Our findings provide evidence that transcription of the CRP gene depends upon p50 and beta-catenin proteins, which is accompanied by close proximity between promoter and the downstream region of CRP gene. PMID- 17704138 TI - Hairpin structure within the 3'UTR of DNA polymerase beta mRNA acts as a post transcriptional regulatory element and interacts with Hax-1. AB - Aberrant expression of DNA polymerase beta, a key enzyme involved in base excision repair, leads to genetic instability and carcinogenesis. Pol beta expression has been previously shown to be regulated at the level of transcription, but there is also evidence of post-transcriptional regulation, since rat transcripts undergo alternative polyadenylation, and the resulting 3'UTR contain at least one regulatory element. Data presented here indicate that RNA of the short 3'UTR folds to form a strong secondary structure (hairpin). Its regulatory role was established utilizing a luciferase-based reporter system. Further studies led to the identification of a protein factor, which binds to this element-the anti-apoptotic, cytoskeleton-related protein Hax-1. The results of in vitro binding analysis indicate that the formation of the RNA-protein complex is significantly impaired by disruption of the hairpin motif. We demonstrate that Hax-1 binds to Pol beta mRNA exclusively in the form of a dimer. Biochemical analysis revealed the presence of Hax-1 in mitochondria, but also in the nuclear matrix, which, along with its transcript-binding properties, suggests that Hax-1 plays a role in post-transcriptional regulation of expression of Pol beta. PMID- 17704139 TI - Wwox suppresses prostate cancer cell growth through modulation of ErbB2-mediated androgen receptor signaling. AB - The expression of the WWOX tumor suppressor gene is lost or reduced in a large fraction of various cancers, including prostate cancer. We previously reported that Wwox overexpression induced apoptosis and suppressed prostate cancer growth in vitro and in vivo. In this study, pathways through which Wwox contributes to control of prostate cancer cell growth have been investigated. We found that Wwox interacts with Ap2gamma and prevents it from entering the nucleus to bind the ERBB2 promoter region to activate transcription of ERBB2, a mediator of androgen receptor activity and prostate cancer cell growth at limiting androgen concentration. Ectopic expression of Wwox reduced ErbB2 protein expression in vitro and expression of Wwox protein inversely correlated with expression of ErbB2 protein in prostate cancer tissues. Furthermore, Wwox suppressed Ap2gamma/ErbB2-induced prostate cancer cell growth and suppressed prostate specific antigen secretion through interaction with Ap2gamma and down-modulation of ErbB2, an effect that required functional androgen receptor. PMID- 17704140 TI - Down-regulation of placenta growth factor by promoter hypermethylation in human lung and colon carcinoma. AB - Two recent clinical trials have shown that the placenta growth factor (PlGF) is up-regulated after bevacizumab treatment in colorectal cancer and after SU11248 treatment in metastatic renal cell carcinoma. The regulation of expression for the vascular endothelial growth factor (VEGF) has been well documented in human tumors; however, the data for PlGF are lacking. We investigated the epigenetic regulation of PlGF and correlated the results with clinicopathologic features. We used plgf promoter analysis, cDNA microarray, immunohistochemistry, and Northern blot analysis to determine the expression level of PlGF in 22 human lung carcinoma and 11 colorectal tumors and in 12 cell lines. Sodium bisulfite modification of genomic DNA followed by methylation-specific PCR (MSP) and sequencing were used to determine the methylation status of the PlGF promoter. Treatments with 5-aza-2'-deoxycytidine and trichostatin A (TSA) were used to reactivate PlGF expression. Significance analysis showed that PlGF expression level was low in human lung and colorectal tumor tissues and in cell lines. PlGF gene promoter was hypermethylated. Treatment with the demethylating agent 5-Aza dC restored PlGF transcript expression in the lung and colon carcinoma cell lines. By combining the results from cDNA microarray, immunohistochemistry, and MSP, we report, for the first time, that the PlGF gene promoter is methylated, and methylation may be one of the mechanisms that contributes to the low PlGF expression level in human lung and colorectal tumor tissues and cell lines. PMID- 17704141 TI - Neurogranin controls the spatiotemporal pattern of postsynaptic Ca2+/CaM signaling. AB - Neurogranin (Ng) is a postsynaptic IQ-motif containing protein that accelerates Ca(2+) dissociation from calmodulin (CaM), a key regulator of long-term potentiation and long-term depression in CA1 pyramidal neurons. The exact physiological role of Ng, however, remains controversial. Two genetic knockout studies of Ng showed opposite outcomes in terms of the induction of synaptic plasticity. To understand its function, we test the hypothesis that Ng could regulate the spatial range of action of Ca(2+)/CaM based on its ability to accelerate the dissociation of Ca(2+) from CaM. Using a mathematical model constructed on the known biochemistry of Ng, we calculate the cycle time that CaM molecules alternate between the fully Ca(2+) saturated state and the Ca(2+) unbound state. We then use these results and include diffusion of CaM to illustrate the impact that Ng has on modulating the spatial profile of Ca(2+) saturated CaM within a model spine compartment. Finally, the first-passage time of CaM to transition from the Ca(2+)-free state to the Ca(2+)-saturated state was calculated with or without Ng present. These analyses suggest that Ng regulates the encounter rate between Ca(2+) saturated CaM and its downstream targets during postsynaptic Ca(2+) transients. PMID- 17704142 TI - Stretching to understand proteins - a survey of the protein data bank. AB - We make a survey of resistance of 7510 proteins to mechanical stretching at constant speed as studied within a coarse-grained molecular dynamics model. We correlate the maximum force of resistance with the native structure, predict proteins which should be especially strong, and identify the nature of their force clamps. PMID- 17704143 TI - Investigating the interaction of saposin C with POPS and POPC phospholipids: a solid-state NMR spectroscopic study. AB - The interaction of Saposin C (Sap C) with negatively charged phospholipids such as phosphatidylserine (PS) is essential for its biological function. In this study, Sap C (initially protonated in a weak acid) was inserted into multilamellar vesicles (MLVs) consisting of either 1-palmitoyl-2-oleoyl-sn glycero-3-[phospho-L-serine] (negatively charged, POPS) or 1-palmitoyl-2-oleoyl sn-glycero-3-phosphocholine (neutrally charged, POPC). The MLVs were then investigated using solid-state NMR spectroscopy under neutral pH (7.0) conditions. The (2)H and (31)P solid-state NMR spectroscopic data of Sap C-POPS and Sap C-POPC MLVs (prepared under the same conditions) were compared using the (2)H order parameter profiles of the POPC-d(31) or POPS-d(31) acyl chains as well as the (31)P chemical shift anisotropy width and (31)P T(1) relaxation times of the phospholipids headgroups. All those solid-state NMR spectroscopic approaches indicate that protonated Sap C disturbs the POPS bilayers and not the POPC lipid bilayers. These observations suggest for the first time that protonated Sap C inserts into PS bilayers and forms a stable complex with the lipids even after resuspension under neutral buffer conditions. Additionally, (31)P solid-state NMR spectroscopic studies of mechanically oriented phospholipids on glass plates were conducted and perturbation effect of Sap C on both POPS and POPC bilayers was compared. Unlike POPC bilayers, the data indicates that protonated Sap C (initially protonated in a weak acid) was unable to produce well-oriented POPS bilayers on glass plates at neutral pH. Conversely, unprotonated Sap C (initially dissolved in a neutral buffer) did not interact significantly with POPS phospholipids allowing them to produce well-oriented bilayers at neutral pH. PMID- 17704144 TI - A Mycobacterium tuberculosis-derived lipid inhibits membrane fusion by modulating lipid membrane domains. AB - Tuberculosis is an infectious and potentially fatal disease caused by the acid fast bacillus Mycobacterium tuberculosis (MTB). One hallmark of a tuberculosis infection is the ability of the bacterium to subvert the normal macrophage defense mechanism of the host immune response. Lipoarabinomannan (LAM), an integral component of the MTB cell wall, is released when MTBs are taken into phagosomes and has been reported to be involved in the inhibition of phago lysosomal (P-L) fusion. However, the physical chemistry of the effects of LAM on lipid membrane structure relative to P-L fusion has not been studied. We produced membranes in vitro composed of dioleoylphosphatidylcholine, sphingomyelin, and cholesterol to simulate phagosomal lipid membranes and quantified the effects of the addition of LAM to these membranes, using fluorescence resonance energy transfer assays and atomic force microscopy. We found that LAM inhibits vesicle fusion and markedly alters lipid membrane domain morphology and sphingomyelin chollesterol/dioleoylphosphatidylcholine ratios. These data demonstrate that LAM induces a dramatic reorganization of lipid membranes in vitro and clarifies the role of LAM in the inhibition of P-L fusion and the survival of the MTB within the macrophage. PMID- 17704145 TI - Visco-elastic membrane tethers extracted from Escherichia coli by optical tweezers. AB - Tethers were created between a living Escherichia coli bacterium and a bead by unspecifically attaching the bead to the outer membrane and pulling it away using optical tweezers. Upon release, the bead returned to the bacterium, thus showing the existence of an elastic tether between the bead and the bacterium. These tethers can be tens of microns long, several times the bacterial length. Using mutants expressing different parts of the outer membrane structure, we have shown that an intact core lipopolysaccharide is a necessary condition for tether formation, regardless of whether the beads were uncoated polystyrene or beads coated with lectin. A physical characterization of the tethers has been performed yielding visco-elastic tether force-extension relationships: for first pull tethers, a spring constant of 10-12 pN/mum describes the tether visco-elasticity, for subsequent pulls the spring constant decreases to 6-7 pN/mum, and typical relaxation timescales of hundreds of seconds are observed. Studies of tether stability in the presence of proteases, lipases, and amylases lead us to propose that the extracted tether is primarily composed of the asymmetric lipopolysaccharide containing bilayer of the outer membrane. This unspecific tethered attachment mechanism could be important in the initiation of bacterial adhesion. PMID- 17704146 TI - Structural change and nucleotide dissociation of Myosin motor domain: dual go model simulation. AB - We investigated the structural relaxation of myosin motor domain from the pre power stroke state to the near-rigor state using molecular dynamics simulation of a coarse-grained protein model. To describe the spontaneous structural change, we propose a dual Go-model-a variant of the Go-like model that has two reference structures. The nucleotide dissociation process is also studied by introducing a coarse-grained nucleotide in the simulation. We found that the myosin structural relaxation toward the near-rigor conformation cannot be completed before the nucleotide dissociation. Moreover, the relaxation and the dissociation occurred cooperatively when the nucleotide was tightly bound to the myosin head. The result suggested that the primary role of the nucleotide is to suppress the structural relaxation. PMID- 17704149 TI - Stability of the Shab K+ channel conductance in 0 K+ solutions: the role of the membrane potential. AB - Shab channels are fairly stable with K(+) present on only one side of the membrane. However, on exposure to 0 K(+) solutions on both sides of the membrane, the Shab K(+) conductance (G(K)) irreversibly drops while the channels are maintained undisturbed at the holding potential. Herein it is reported that the drop of G(K) follows first-order kinetics, with a voltage-dependent decay rate r. Hyperpolarized potentials drastically inhibit the drop of G(K). The G(K) drop at negative potentials cannot be explained by a shift in the voltage dependence of activation. At depolarized potentials, where the channels undergo a slow inactivation process, G(K) drops in 0 K(+) with rates slower than those predicted based on the behavior of r at negative potentials, endowing the r-V(m) relationship with a maximum. Regardless of voltage, r is very small compared with the rate of ion permeation. Observations support the hypothesized presence of a stabilizing K(+) site (or sites) located either within the pore itself or in its external vestibule, at an inactivation-sensitive location. It is argued that part of the G(K) stabilization achieved at hyperpolarized potentials could be the result of a conformational change in the pore itself. PMID- 17704147 TI - An unusual transduction pathway in human tonic smooth muscle myosin. AB - The motor protein myosin binds actin and ATP, producing work by causing relative translation of the proteins while transducing ATP free energy. Smooth muscle myosin has one of four heavy chains encoded by the MYH11 gene that differ at the C-terminus and in the active site for ATPase due to alternate splicing. A seven amino-acid active site insert in phasic muscle myosin is absent from the tonic isoform. Fluorescence increase in the nucleotide sensitive tryptophan (NST) accompanies nucleotide binding and hydrolysis in several myosin isoforms implying it results from a common origin within the motor. A wild-type tonic myosin (smA) construct of the enzymatic head domain (subfragment 1 or S1) has seven tryptophan residues and nucleotide-induced fluorescence enhancement like other myosins. Three smA mutants probe the molecular basis for the fluorescence enhancement. W506+ contains one tryptophan at position 506 homologous to the NST in other myosins. W506F has the native tryptophans except phenylalanine replaces W506, and W506+(Y499F) is W506+ with phenylalanine replacing Y499. W506+ lacks nucleotide induced fluorescence enhancement probably eliminating W506 as the NST. W506F has impaired ATPase activity but retains nucleotide-induced fluorescence enhancement. Y499F replacement in W506+ partially rescues nucleotide sensitivity demonstrating the role of Y499 as an NST facilitator. The exceptional response of W506 to active site conformation opens the possibility that phasic and tonic isoforms differ in how influences from active site ATPase propagate through the protein network. PMID- 17704148 TI - Biophysical characterization of anticoagulant hemextin AB complex from the venom of snake Hemachatus haemachatus. AB - Hemextin AB complex from the venom of Hemachatus haemachatus is the first known natural anticoagulant that specifically inhibits the enzymatic activity of blood coagulation factor VIIa in the absence of factor Xa. It is also the only known heterotetrameric complex of two three-finger toxins. Individually only hemextin A has mild anticoagulant activity, whereas hemextin B is inactive. However, hemextin B synergistically enhances the anticoagulant activity of hemextin A and their complex exhibits potent anticoagulant activity. In this study we characterized the nature of molecular interactions leading to the complex formation. Circular dichroism studies indicate the stabilization of beta-sheet in the complex. Hemextin AB complex has an increased apparent molecular diameter in both gas and liquid phase techniques. The complex formation is enthalpically favorable and entropically unfavorable with a negative change in the heat capacity. Thus, the anticoagulant complex shows less structural flexibility than individual subunits. Both electrostatic and hydrophobic interactions are important for the complexation; the former driving the process and the latter helping in the stabilization of the tetramer. The tetramer dissociates into dimers and monomers with the increase in the ionic strength of the solution and also with increase in the glycerol concentration in the buffer. The two dimers formed under each of these conditions display distinct differences in their apparent molecular diameters and anticoagulant properties. Based on these results, we have proposed a model for this unique anticoagulant complex. PMID- 17704150 TI - Phase transitions of the coupled membrane-cytoskeleton modify cellular shape. AB - Formation of protrusions and protein segregation on the membrane is of a great importance for the functioning of the living cell. This is most evident in recent experiments that show the effects of the mechanical properties of the surrounding substrate on cell morphology. We propose a mechanism for the formation of membrane protrusions and protein phase separation, which may lay behind this effect. In our model, the fluid cell membrane has a mobile but constant population of proteins with a convex spontaneous curvature. Our basic assumption is that these membrane proteins represent small adhesion complexes, and also include proteins that activate actin polymerization. Such a continuum model couples the membrane and protein dynamics, including cell-substrate adhesion and protrusive actin force. Linear stability analysis shows that sufficiently strong adhesion energy and actin polymerization force can bring about phase separation of the membrane protein and the appearance of protrusions. Specifically, this occurs when the spontaneous curvature and aggregation potential alone (passive system) do not cause phase separation. Finite-size patterns may appear in the regime where the spontaneous curvature energy is a strong factor. Different instability characteristics are calculated for the various regimes, and are compared to various types of observed protrusions and phase separations, both in living cells and in artificial model systems. A number of testable predictions are proposed. PMID- 17704153 TI - Distributivity and processivity in multisite phosphorylation can be distinguished through steady-state invariants. AB - Multisite protein phosphorylation and dephosphorylation are key cellular regulatory mechanisms but their system properties have been difficult to study in vivo and in vitro. Here we show by mathematical analysis that steady-state invariants enable the mechanism of the kinase or the phosphatase to be determined from steady-state measurements. Invariants exist when both enzymes act distributively (i.e., nonprocessively), making at most one modification in each molecular encounter. For instance, in the sequential case, in any experiment involving the same ingredients, the quantity [S(i-1)][S(i+1)]/[S(i)](2) always has the same value, where [S(i)] denotes the steady-state concentration of the i th phospho-form. For a two-site substrate, if either enzyme exhibits processivity, so that more than one modification can be made in each molecular encounter, the degree of processivity can be estimated from changes in this invariant. We discuss the experimental and theoretical challenges in extending these results. PMID- 17704152 TI - How dopamine transporter interacts with dopamine: insights from molecular modeling and simulation. AB - By performing homology modeling, molecular docking, and molecular dynamics simulations, we have developed three-dimensional (3D) structural models of both dopamine transporter and dopamine transporter-dopamine complex in the environment of lipid bilayer and solvent water. According to the simulated structure of dopamine transporter-dopamine complex, dopamine was orientated in a hydrophobic pocket at the midpoint of the membrane. The modeled 3D structures provide some detailed structural and mechanistic insights concerning how dopamine transporter (DAT) interacts with dopamine at atomic level, extending our mechanistic understanding of the dopamine reuptake with the help of Na(+) ions. The general features of the modeled 3D structures are consistent with available experimental data. Based on the modeled structures, our calculated binding free energy (DeltaG(bind) = -6.4 kcal/mol) for dopamine binding with DAT is also reasonably close to the experimentally derived DeltaG(bind) value of -7.4 kcal/mol. Finally, a possible dopamine-entry pathway, which involves formation and breaking of the salt bridge between side chains of Arg(85) and Asp(476), is proposed based on the results obtained from the modeling and molecular dynamics simulation. The new structural and mechanistic insights obtained from this computational study are expected to stimulate future, further biochemical and pharmacological studies on the detailed structures and mechanisms of DAT and other homologous transporters. PMID- 17704154 TI - Model of polarization and bistability of cell fragments. AB - Directed cell motility is preceded by cell polarization-development of a front rear asymmetry of the cytoskeleton and the cell shape. Extensive studies implicated complex spatial-temporal feedbacks between multiple signaling pathways in establishing cell polarity, yet physical mechanisms of this phenomenon remain elusive. Based on observations of lamellipodial fragments of fish keratocyte cells, we suggest a purely thermodynamic (not involving signaling) quantitative model of the cell polarization and bistability. The model is based on the interplay between pushing force exerted by F-actin polymerization on the cell edges, contractile force powered by myosin II across the cell, and elastic tension in the cell membrane. We calculate the thermodynamic work produced by these intracellular forces, and show that on the short timescale, the cell mechanics can be characterized by an effective energy profile with two minima that describe two stable states separated by an energy barrier and corresponding to the nonpolarized and polarized cells. Cell dynamics implied by this energy profile is bistable-the cell is either disk-shaped and stationary, or crescent shaped and motile-with a possible transition between them upon a finite external stimulus able to drive the system over the macroscopic energy barrier. The model accounts for the observations of the keratocyte fragments' behavior and generates quantitative predictions about relations between the intracellular forces' magnitudes and the cell geometry and motility. PMID- 17704151 TI - Coarse-grained free energy functions for studying protein conformational changes: a double-well network model. AB - In this work, a double-well network model (DWNM) is presented for generating a coarse-grained free energy function that can be used to study the transition between reference conformational states of a protein molecule. Compared to earlier work that uses a single, multidimensional double-well potential to connect two conformational states, the DWNM uses a set of interconnected double well potentials for this purpose. The DWNM free energy function has multiple intermediate states and saddle points, and is hence a "rough" free energy landscape. In this implementation of the DWNM, the free energy function is reduced to an elastic-network model representation near the two reference states. The effects of free energy function roughness on the reaction pathways of protein conformational change is demonstrated by applying the DWNM to the conformational changes of two protein systems: the coil-to-helix transition of the DB-loop in G actin and the open-to-closed transition of adenylate kinase. In both systems, the rough free energy function of the DWNM leads to the identification of distinct minimum free energy paths connecting two conformational states. These results indicate that while the elastic-network model captures the low-frequency vibrational motions of a protein, the roughness in the free energy function introduced by the DWNM can be used to characterize the transition mechanism between protein conformations. PMID- 17704155 TI - Noise-limited frequency signal transmission in gene circuits. AB - To maintain normal physiology, cells must properly process diverse signals arising from changes in temperature, pH, nutrient concentrations, and other factors. Many physiological processes are controlled by temporal aspects of oscillating signals; that is, these signals can encode information in the frequency domain. By modeling simple gene circuits, we analyze the impact of cellular noise on the fidelity and speed of frequency-signal transmission. We find that transmission of frequency signals is "all-or-none", limited by a critical frequency (f(c)). Signals with frequencies f(c) are severely corrupted or completely lost in transmission. We argue that f(c) is an intrinsic property of a gene circuit and it varies with circuit parameters and additional feedback or feedforward regulation. Our results may have implications for understanding signal processing in natural biological networks and for engineering synthetic gene circuits. PMID- 17704156 TI - Conformations of flanking bases in HIV-1 RNA DIS kissing complexes studied by molecular dynamics. AB - Explicit solvent molecular dynamics simulations (in total almost 800 ns including locally enhanced sampling runs) were applied with different ion conditions and with two force fields (AMBER and CHARMM) to characterize typical geometries adopted by the flanking bases in the RNA kissing-loop complexes. We focus on flanking base positions in multiple x-ray and NMR structures of HIV-1 DIS kissing complexes and kissing complex from the large ribosomal subunit of Haloarcula marismortui. An initial x-ray open conformation of bulged-out bases in HIV-1 DIS complexes, affected by crystal packing, tends to convert to a closed conformation formed by consecutive stretch of four stacked purine bases. This is in agreement with those recent crystals where the packing is essentially avoided. We also observed variants of the closed conformation with three stacked bases, while nonnegligible populations of stacked geometries with bulged-in bases were detected, too. The simulation results reconcile differences in positions of the flanking bases observed in x-ray and NMR studies. Our results suggest that bulged out geometries are somewhat more preferred, which is in accord with recent experiments showing that they may mediate tertiary contacts in biomolecular assemblies or allow binding of aminoglycoside antibiotics. PMID- 17704157 TI - Stable stochastic dynamics in yeast cell cycle. AB - Chemical reactions in cells are subject to intense stochastic fluctuations. An important question is how the fundamental physiological behavior of the cell is kept stable against those noisy perturbations. In this study, a stochastic model of the cell cycle of budding yeast was constructed to analyze the effects of noise on the cell-cycle oscillation. The model predicts intense noise in levels of mRNAs and proteins, and the simulated protein levels explain the observed statistical tendency of noise in populations of synchronous and asynchronous cells. Despite intense noise in levels of proteins and mRNAs, the cell cycle is stable enough to bring the largely perturbed cells back to the physiological cyclic oscillation. The model shows that consecutively appearing fixed points are the origin of this stability of the cell cycle. PMID- 17704158 TI - Live-cell transforms between Ca2+ transients and FRET responses for a troponin-C based Ca2+ sensor. AB - Genetically encoded Ca(2+) sensors promise sustained in vivo detection of Ca(2+) signals. However, these sensors are sometimes challenged by inconsistent performance and slow/uncertain kinetic responsiveness. The former challenge may arise because most sensors employ calmodulin (CaM) as the Ca(2+)-sensing module, such that interference via endogenous CaM may result. One class of sensors that could minimize this concern utilizes troponin C as the Ca(2+) sensor. Here, we therefore probed the reliability and kinetics of one representative of this class (cyan fluorescence protein/yellow fluorescent protein-fluorescence resonance energy transfer (FRET) sensor TN-L15) within cardiac ventricular myocytes. These cells furnished a pertinent live-cell test environment, given substantial endogenous CaM levels and fast reproducible Ca(2+) transients for testing sensor kinetics. TN-L15 was virally expressed within myocytes, and Indo-1 acutely loaded to monitor "true" Ca(2+) transients. This configuration permitted independent and simultaneous detection of TN-L15 and Indo-1 signals within individual cells. The relation between TN-L15 FRET responses and Indo-1 Ca(2+) transients appeared reproducible, though FRET signals were delayed compared to Ca(2+) transients. Nonetheless, a three-state mechanism sufficed to map between measured Ca(2+) transients and actual TN-L15 outputs. Overall, reproducibility of TN-L15 dynamics, coupled with algorithmic transforms between FRET and Ca(2+) signals, renders these sensors promising for quantitative estimation of Ca(2+) dynamics in vivo. PMID- 17704159 TI - How directional translocation is regulated in a DNA helicase motor. AB - PcrA helicase from Bacillus stearothermophilus is one of the smallest motor proteins structurally known in full atomic detail. It translocates progressively from the 3' end to the 5' end of single-stranded DNA utilizing the free energy from ATP hydrolysis. The similarities in structure and reaction pathway between PcrA helicase and F1-ATPase suggest a similar mechanochemical mechanism at work in both systems. Previous studies of PcrA translocation demonstrated a domain stepping mechanism in which, during one ATP hydrolysis cycle, the pulling together and pushing apart of two translocation domains is synchronized with alternating mobilities of the individual domains such that PcrA moves unidirectionally along single-stranded DNA. To substantiate this translocation mechanism, this study applies molecular dynamics simulations, elastic network theory, and multiple sequence alignment to analyze the system. The analysis provides further evidence that directional translocation of PcrA is regulated allosterically through synchronization of ATP hydrolysis and domain mobilities. We identify a set of essential residues coevolutionarily coupled in related helicases that should be involved in the allosteric regulation of these motor proteins. PMID- 17704160 TI - Conformation of DNA GG intrastrand cross-link of antitumor oxaliplatin and its enantiomeric analog. AB - Downstream processes that discriminate between DNA adducts of a third generation platinum antitumor drug oxaliplatin and conventional cisplatin are believed to be responsible for the differences in their biological effects. These different biological effects are explained by the ability of oxaliplatin to form DNA adducts more efficient in their biological effects. In this work conformation, recognition by HMG domain protein and DNA polymerization across the major 1,2-GG intrastrand cross-link formed by cisplatin and oxaliplatin in three sequence contexts were compared with the aid of biophysical and biochemical methods. The following major differences in the properties of the cross-links of oxaliplatin and cisplatin were found: i), the formation of the cross-link by oxaliplatin is more deleterious energetically in all three sequence contexts; ii), the cross link of oxaliplatin bends DNA slightly but systematically less in all sequence contexts tested; iii), the affinity of HMG domain protein to the cross-link of oxaliplatin is considerably lower independent of the sequence context; and iv), the Klenow fragment of DNA polymerase I pauses considerably more at the cross link of oxaliplatin in all sequence contexts tested. We have also demonstrated that the chirality at the carrier ligand of oxaliplatin can affect its biological effects. PMID- 17704162 TI - Giant unilamellar vesicles electroformed from native membranes and organic lipid mixtures under physiological conditions. AB - In recent years, giant unilamellar vesicles (GUVs) have become objects of intense scrutiny by chemists, biologists, and physicists who are interested in the many aspects of biological membranes. In particular, this "cell size" model system allows direct visualization of particular membrane-related phenomena at the level of single vesicles using fluorescence microscopy-related techniques. However, this model system lacks two relevant features with respect to biological membranes: 1), the conventional preparation of GUVs currently requires very low salt concentration, thus precluding experimentation under physiological conditions, and 2), the model system lacks membrane compositional asymmetry. Here we show for first time that GUVs can be prepared using a new protocol based on the electroformation method either from native membranes or organic lipid mixtures at physiological ionic strength. Additionally, for the GUVs composed of native membranes, we show that membrane proteins and glycosphingolipids preserve their natural orientation after electroformation. We anticipate our result to be important to revisit a vast variety of findings performed with GUVs under low- or no-salt conditions. These studies, which include results on artificial cell assembly, membrane mechanical properties, lipid domain formation, partition of membrane proteins into lipid domains, DNA-lipid interactions, and activity of interfacial enzymes, are likely to be affected by the amount of salt present in the solution. PMID- 17704161 TI - Specific and selective peptide-membrane interactions revealed using quartz crystal microbalance. AB - The skin secretions of Australian tree frogs are rich in peptides with potential antimicrobial activity. They interrupt bacterial cell membranes, although precisely how and whether all peptides have the same mechanism is not known. The interactions of three of these peptides-aurein 1.2, maculatin 1.1, and caerin 1.1 with supported phospholipid bilayers-are examined here using quartz crystal microbalance and atomic force microscopy. These approaches enabled us to reveal variations in material structure and density as a function of distance from the sensor surface when comparing mass sensorgrams over a range of harmonics of the natural resonance of the sensor crystal and hence obtain for the first time to our knowledge a mechanistic assessment of membrane disruption. We found that caerin inserted into the bilayer in a transmembrane manner, regardless of concentration and phospholipid composition consistent with a pore-forming mechanism. In contrast, maculatin and aurein interacted with membranes in a concentration-dependent manner. At low concentrations (<5 microM), maculatin exhibited transmembrane incorporation whereas aurein was limited to surface association. Upon reaching a threshold value of concentration, both peptides lysed the membrane. In the case of maculatin, the lysis progressed in a slow, concentration-dependent manner, forming mixed micelles, as shown by atomic force microscopy imaging. Aurein-induced lysis proceeded to a sudden disruption, which is consistent with the "carpet" mechanism. Both maculatin and aurein exhibit specificity toward phospholipids and thus have potential as candidates as antimicrobial drugs. PMID- 17704163 TI - Simulation of Ca-calmodulin-dependent protein kinase II on rabbit ventricular myocyte ion currents and action potentials. AB - Ca-calmodulin-dependent protein kinase II (CaMKII) was recently shown to alter Na(+) channel gating and recapitulate a human Na(+) channel genetic mutation that causes an unusual combined arrhythmogenic phenotype in patients: simultaneous long QT syndrome and Brugada syndrome. CaMKII is upregulated in heart failure where arrhythmias are common, and CaMKII inhibition can reduce arrhythmias. Thus, CaMKII-dependent channel modulation may contribute to acquired arrhythmic disease. We developed a Markovian Na(+) channel model including CaMKII-dependent changes, and incorporated it into a comprehensive myocyte action potential (AP) model with Na(+) and Ca(2+) transport. CaMKII shifts Na(+) current (I(Na)) availability to more negative voltage, enhances intermediate inactivation, and slows recovery from inactivation (all loss-of-function effects), but also enhances late noninactivating I(Na) (gain of function). At slow heart rates, with long diastolic time for I(Na) recovery, late I(Na) is the predominant effect, leading to AP prolongation (long QT syndrome). At fast heart rates, where recovery time is limited and APs are shorter, there is little effect on AP duration, but reduced availability decreases I(Na), AP upstroke velocity, and conduction (Brugada syndrome). CaMKII also increases cardiac Ca(2+) and K(+) currents (I(Ca) and I(to)), complicating CaMKII-dependent AP changes. Incorporating I(Ca) and I(to) effects individually prolongs and shortens AP duration. Combining I(Na), I(Ca), and I(to) effects results in shortening of AP duration with CaMKII. With transmural heterogeneity of I(to) and I(to) downregulation in heart failure, CaMKII may accentuate dispersion of repolarization. This provides a useful initial framework to consider pathways by which CaMKII may contribute to arrhythmogenesis. PMID- 17704165 TI - The role of secondary structure in the entropically driven amelogenin self assembly. AB - Amelogenin, the major extracellular enamel matrix protein, plays critical roles in controlling enamel mineralization. This generally hydrophobic protein self assembles to form nanosphere structures under certain solution conditions. To gain clearer insight into the mechanisms of amelogenin self-assembly, we first investigated the occurrences of secondary structures within its sequence. By applying isothermal titration calorimetry (ITC), we determined the thermodynamic parameters associated with protein-protein interactions and with conformational changes during self-assembly. The recombinant porcine full length (rP172) and a truncated amelogenin lacking the hydrophilic C-terminal (rP148) were used. Circular dichroism (CD) measurements performed at low concentrations (<5 microM) revealed the presence of the polyproline-type II (PPII) conformation in both amelogenins in addition to alpha-helix and unordered conformations. Structural transition from PPII/unordered to beta-sheet was observed for both proteins at higher concentrations (>62.5 microM) and upon self-assembly. ITC measurements indicated that the self-assembly of rP172 and rP148 is entropically driven (+DeltaS(A)) and energetically favorable (-DeltaG(A)). The magnitude of enthalpy (DeltaH(A)) and entropy changes of assembly (DeltaS(A)) were smaller for rP148 than rP172, whereas the Gibbs free energy change of assembly (DeltaG(A)) was not significantly different. It was found that rP172 had higher PPII content than rP148, and the monomer-multimer equilibrium for rP172 was observed in a narrower protein concentration range when compared to rP148. The large positive enthalpy and entropy changes in both cases are attributed to the release of ordered water molecules and the associated entropy gain (due to the hydrophobic effect). These findings suggest that PPII conformation plays an important role in amelogenin self-assembly and that rP172 assembly is more favorable than rP148. The data are direct evidence for the notion that hydrophobic interactions are the main driving force for amelogenin self-assembly. PMID- 17704164 TI - Direct observation of active protein folding using lock-in force spectroscopy. AB - Direct observation of the folding of a single polypeptide chain can provide important information about the thermodynamic states populated along its folding pathway. In this study, we present a lock-in force-spectroscopy technique that improves resolution of atomic-force microscopy force spectroscopy to 400 fN. Using this technique we show that immunoglobulin domain 4 from Dictyostelium discoideum filamin (ddFLN4) refolds against forces of approximately 4 pN. Our data show folding of this domain proceeds directly from an extended state and no thermodynamically distinct collapsed state of the polypeptide before folding is populated. Folding of ddFLN4 under load proceeds via an intermediate state. Three state folding allows ddFLN4 to fold against significantly larger forces than would be possible for a mere two-state folder. We present a general model for protein folding kinetics under load that can predict refolding forces based on chain-length and zero force refolding rate. PMID- 17704166 TI - The molecular mechanism of monolayer-bilayer transformations of lung surfactant from molecular dynamics simulations. AB - The aqueous lining of the lung surface exposed to the air is covered by lung surfactant, a film consisting of lipid and protein components. The main function of lung surfactant is to reduce the surface tension of the air-water interface to the low values necessary for breathing. This function requires the exchange of material between the lipid monolayer at the interface and lipid reservoirs under dynamic compression and expansion of the interface during the breathing cycle. We simulated the reversible exchange of material between the monolayer and lipid reservoirs under compression and expansion of the interface. We used a mixture of dipalmitoyl-phosphatidylcholine, palmitoyl-oleoyl-phosphatidylglycerol, cholesterol, and surfactant-associated protein C as a functional analog of mammalian lung surfactant. In our simulations, the monolayer collapses into the water subphase on compression and forms bilayer folds. On monolayer reexpansion, the material is transferred from the folds back to the interface. The simulations indicate that the connectivity of the bilayer aggregates to the monolayer is necessary for the reversibility of the monolayer-bilayer transformation. The simulations also show that bilayer aggregates are unstable in the air subphase and stable in the water subphase. PMID- 17704167 TI - Lateral pressure profile, spontaneous curvature frustration, and the incorporation and conformation of proteins in membranes. AB - Lipid-protein interactions are an important determinant of the stability and function of integral and transmembrane proteins. In addition to local interactions at the lipid-protein interface, global interactions such as the distribution of internal lateral pressure may also influence protein conformation. It is shown here that the effects of the membrane lateral pressure profile on the conformation or insertion of proteins in membranes are equivalent to the elastic response to the frustrated spontaneous curvature, c(o), of the component lipid monolayer leaflets. The chemical potential of the protein in the membrane is predicted to depend linearly on the spontaneous curvature of the lipid leaflets, just as does the contribution of the protein to the elastic bending energy of the lipid, and to be independent of the hydrophobic tension, gamma(phob), at the lipid-water interface. Analysis of the dependence of protein partitioning or conformational transitions on spontaneous curvature of the constituent lipids gives an experimental estimate for the cross-sectional intramembrane shape of the protein or its difference between conformations. Values in the region of 50-110 A(2) are estimated for the effective cross sectional shape changes on the insertion and conductance transitions of alamethicin, and on the activation of CTP:phosphocholine cytidylyltransferase or rhodopsin in lipid membranes. Much larger values are estimated for the mechanosensitive channel, MscL. Values for the change in intramembrane shape may also be used, together with determinations of lipid relative association constants, to estimate contributions of direct lipid-protein interactions to the lateral pressure experienced by the protein. Changes in chemical potential approximately 12 kJ mol(-1) can be estimated for radial changes of 1 A in a protein of diameter 40 A. PMID- 17704168 TI - Continuous fluorescence microphotolysis and correlation spectroscopy using 4Pi microscopy. AB - Continuous fluorescence microphotolysis (CFM) and fluorescence correlation spectroscopy (FCS) permit measurement of molecular mobility and association reactions in single living cells. CFM and FCS complement each other ideally and can be realized using identical equipment. So far, the spatial resolution of CFM and FCS was restricted by the resolution of the light microscope to the micrometer scale. However, cellular functions generally occur on the nanometer scale. Here, we develop the theoretical and computational framework for CFM and FCS experiments using 4Pi microscopy, which features an axial resolution of approximately 100 nm. The framework, taking the actual 4Pi point spread function of the instrument into account, was validated by measurements on model systems, employing 4Pi conditions or normal confocal conditions together with either single- or two-photon excitation. In all cases experimental data could be well fitted by computed curves for expected diffusion coefficients, even when the signal/noise ratio was small due to the small number of fluorophores involved. PMID- 17704169 TI - Molecular dynamics simulations of two tandem octarepeats from the mammalian prion protein: fully Cu2+-bound and metal-free forms. AB - Molecular dynamics simulations have been conducted on a model fragment (Ac PHGGGWGQPHGGGW-NH(2)) of the prion protein octarepeat domain, both in the Cu(2+) bound and metal-free forms. The copper-bound models are based on the consensus structure of the core Cu(2+)-binding site of an individual octarepeat, relevant to the fully Cu(2+)-occupied prion protein octarepeat region. The model peptides contain Cu(2+) bound through a His imidazole ring and two deprotonated amide N atoms in the peptide backbone supplied by the following two Gly residues. Both the copper-bound and metal-free models have been simulated with the OPLS all-atom force field with the GROMACS molecular dynamics package. These simulations, with two tandem copper-binding sites, represent the minimum model necessary to observe potential structuring between the copper-binding sites in the octarepeat region. The GWGQ residues constitute a flexible linker region that predominantly adopts a turn, serving to bring adjacent His residues into close proximity. The consequent formation of stable structures demonstrates that the copper-bound octarepeat region allows the copper-coordinating sites to come into van der Waals contact, packing into particular orientations to further stabilize the bend in the GWGQ linker region. PMID- 17704170 TI - Simultaneous tether extraction from endothelial cells and leukocytes: observation, mechanics, and significance. AB - It has been hypothesized, from earlier studies on single-tether extraction from individual leukocytes and human umbilical vein endothelial cells, that during rolling of leukocytes on the endothelium, simultaneous extraction of membrane nanotubes (tethers) occurs, resulting in enhancement of the force decrease on the adhesive bond. In this study, using the micropipette aspiration technique and fluorescence microscopy, we show that tethers are indeed extracted simultaneously when an endothelial cell and a leukocyte are separated after brief contact and adhesion, and the endothelial cell contributes much more to the composite tether length. In addition, the constitutive relationship for simultaneous tether extraction is determined with neutrophils and T-lymphocytes as force transducers, and cytokine-stimulated human umbilical vein and dermal microvascular endothelial cells as substrates, respectively. This relationship is consistent with that derived theoretically from the constitutive equations for single-tether extraction from either cell alone. Moreover, we show that simultaneous tether extraction was likely terminated by receptor-ligand bond dissociation. With a biomechanical model of leukocyte rolling, we predict the force history of the adhesive receptor-ligand bond and show that it is remarkably similar for different leukocyte-endothelial cell pairs. Simultaneous tether extraction therefore represents a generic mechanism for stabilizing leukocyte rolling on the endothelium. PMID- 17704171 TI - Solution conformation of wild-type and mutant IgG3 and IgG4 immunoglobulins using crystallohydrodynamics: possible implications for complement activation. AB - We have employed the recently described crystallohydrodynamic approach to compare the time-averaged domain orientation of human chimeric IgG3wt (wild-type) and IgG4wt as well as two hinge mutants of IgG3 and an IgG4S331P (mutation from serine to proline at position 331, EU numbering) mutant of IgG4. The approach involves combination of the known shape of the Fab and Fc regions from crystallography with hydrodynamic data for the Fab and Fc fragments and hydrodynamic and small angle x-ray scattering data for the intact IgG structures. In this way, ad hoc assumptions over hydration can be avoided and model degeneracy (uniqueness problems) can be minimized. The best fit model for the solution structure of IgG3wt demonstrated that the Fab regions are directed away from the plane of the Fc region and with a long extended hinge region in between. The best fit model of the IgG3m15 mutant with a short hinge (and enhanced complement activation activity) showed a more open, but asymmetric structure. The IgG3HM5 mutant devoid of a hinge region (and also devoid of complement-activation activity) could not be distinguished at the low-resolution level from the structure of the enhanced complement-activating mutant IgG3m15. The lack of inter heavy-chain disulphide bond rather than a significantly different domain orientation may be the reason for the lack of complement-activating activity of the IgG3HM5 mutant. With IgG4, there are significant and interesting conformational differences between the wild-type IgG4, which shows a symmetric structure, and the IgG4S331P mutant, which shows a highly asymmetric structure. This structural difference may explain the ability of the IgG4S331P mutant to activate complement in stark contrast to the wild-type IgG4 molecule which is devoid of this activity. PMID- 17704172 TI - The effect of charge-charge interactions on the kinetics of alpha-helix formation. AB - The formation of the monomeric alpha-helix represents one of the simplest scenarios in protein folding; however, our current understanding of the folding dynamics of the alpha-helix motif is mainly based on studies of alanine-rich model peptides. To examine the effect of peptide sequence on the folding kinetics of alpha-helices, we studied the relaxation kinetics of a 21-residue helical peptide, Conantokin-T (Con-T), using time-resolved infrared spectroscopy in conjunction with a laser-induced temperature jump technique. Con-T is a neuroactive peptide containing a large number of charged residues that is found in the venom of the piscivorous cone snail Conus tulipa . The temperature-jump relaxation kinetics of Con-T is distinctly slower than that of previously studied alanine-based peptides, suggesting that the folding time of alpha-helices is sequence-dependent. Furthermore, it appears that the slower folding of Con-T can be attributed to the fact that its helical conformation is stabilized by charge charge interactions or salt bridges. Although this finding contradicts an earlier molecular dynamics simulation, it also has implications for existing models of protein folding. PMID- 17704173 TI - Unifying the various incarnations of active hair-bundle motility by the vertebrate hair cell. AB - The dazzling sensitivity and frequency selectivity of the vertebrate ear rely on mechanical amplification of the hair cells' responsiveness to small stimuli. As revealed by spontaneous oscillations and forms of mechanical excitability in response to force steps, the hair bundle that adorns each hair cell is both a mechanosensory antenna and a force generator that might participate in the amplificatory process. To study the various incarnations of active hair-bundle motility, we combined Ca(2+) iontophoresis with mechanical stimulation of single hair bundles from the bullfrog's sacculus. We identified three classes of active hair-bundle movements: a hair bundle could be quiescent but display nonmonotonic twitches in response to either excitatory or inhibitory force steps, or oscillate spontaneously. Extracellular Ca(2+) changes could affect the kinetics of motion and, when large enough, evoke transitions between the three classes of motility. We found that the Ca(2+)-dependent location of a bundle's operating point within its force-displacement relation controlled the type of movement observed. In response to an iontophoretic pulse of Ca(2+) or of a Ca(2+) chelator, a hair bundle displayed a movement whose polarity could be reversed by applying a static bias to the bundle's position at rest. Moreover, such polarity reversal was accompanied by a 10-fold change in the kinetics of the Ca(2+)-evoked hair-bundle movement. A unified theoretical description, in which mechanical activity stems solely from myosin-based adaptation, could account for the fast and slow manifestations of active hair-bundle motility observed in frog, as well as in auditory organs of the turtle and the rat. PMID- 17704174 TI - Interaction of an amphipathic peptide with phosphatidycholine/phosphatidylethanolamine mixed membranes. AB - The effect of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) in mixed membranes with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) on interaction with a class A amphipathic peptide, Ac-DWLKAFYDKVAEKLKEAF-NH(2) (Ac 18A-NH(2)), was investigated. The fluorescence lifetime of 2-(9 anthroyloxy)stearic acid and (2)H NMR spectra were used to evaluate the penetration of water molecules into the membrane interface and the order of lipid acyl chains, respectively. The results demonstrated that DOPE in the mixed membranes decreased the fluorescence lifetime and increased the acyl-chain order, and that Ac-18A-NH(2) affected them more for membranes with higher DOPE fractions. The partition coefficient (K(p)) of the peptide to the mixed membranes was increased with the increase in the DOPE mole fractions. From the temperature dependence of the K(p) values, the binding of Ac-18A-NH(2) to POPC/DOPE mixed membranes was found to be entropy-driven. The formation of an alpha-helix at the membrane's surface is supposed to induce positive curvature strain, which decreases the headgroup hydration and acyl-chain order of lipids. Thus, the binding of Ac-18A-NH(2) to membranes is entropically more favorable at higher DOPE fractions since the peptide's insertion into the membrane can decrease the order parameter and unfavorable headgroup hydration, which explains the enhanced peptide binding. PMID- 17704176 TI - How to assemble the parts: structures of protein complexes from their components. PMID- 17704175 TI - An inactivation gate in the selectivity filter of KCNQ1 potassium channels. AB - Inactivation is an inherent property of most voltage-gated K(+) channels. While fast N-type inactivation has been analyzed in biophysical and structural details, the mechanisms underlying slow inactivation are yet poorly understood. Here, we characterized a slow inactivation mechanism in various KCNQ1 pore mutants, including L273F, which hinders entry of external Ba(2+) to its deep site in the pore and traps it by slowing its egress. Kinetic studies, molecular modeling, and dynamics simulations suggest that this slow inactivation involves conformational changes that converge to the outer carbonyl ring of the selectivity filter, where the backbone becomes less flexible. This mechanism involves acceleration of inactivation kinetics and enhancement of Ba(2+) trapping at elevated external K(+) concentrations. Hence, KCNQ1 slow inactivation considerably differs from C type inactivation where vacation of K(+) from the filter was invoked. We suggest that trapping of K(+) at s(1) due to filter rigidity and hindrance of the dehydration-resolvation transition underlie the slow inactivation of KCNQ1 pore mutants. PMID- 17704177 TI - High-resolution structure of a Na+/H+ antiporter dimer obtained by pulsed electron paramagnetic resonance distance measurements. AB - Transient or partial formation of complexes between biomacromolecules is a general mechanism used to control cellular functions. Several of these complexes escape structure determination by crystallographic means. We developed a new approach for determining the structure of protein dimers in the native environment (e.g., in the membrane) with high resolution in cases where the structure of the two monomers is known. The approach is based on measurements of distance distributions between spin labels in the range between 2 and 6 nanometers by a pulsed electron paramagnetic resonance technique and explicit modeling of spin label conformations. By applying this method to the membrane protein homodimer of the Na(+)/H(+) antiporter NhaA of Escherichia coli, the structure of the presumably physiological dimer was determined. It reveals two points of contact between the two monomers, with one of them confirming results of earlier cross-linking experiments. PMID- 17704178 TI - The last few frames of the voltage-gating movie. PMID- 17704180 TI - Structure of membrane-embedded M13 major coat protein is insensitive to hydrophobic stress. AB - The structure of a membrane-embedded alpha-helical reference protein, the M13 major coat protein, is characterized under different conditions of hydrophobic mismatch using fluorescence resonance energy transfer in combination with high throughput mutagenesis. We show that the structure is similar in both thin (14:1) and thick (20:1) phospholipid bilayers, indicating that the protein does not undergo large structural rearrangements in response to conditions of hydrophobic mismatch. We introduce a "helical fingerprint" analysis, showing that amino acid residues 1-9 are unstructured in both phospholipid bilayers. Our findings indicate the presence of pi-helical domains in the transmembrane segment of the protein; however, no evidence is found for a structural adaptation to the degree of hydrophobic mismatch. In light of current literature, and based on our data, we conclude that aggregation (at high protein concentration) and adjustment of the tilt angle and the lipid structure are the dominant responses to conditions of hydrophobic mismatch. PMID- 17704179 TI - Dynamics of the Kv1.2 voltage-gated K+ channel in a membrane environment. AB - All-atom molecular dynamics simulations are used to better understand the dynamic environment experienced by the Kv1.2 channel in a lipid membrane. The structure of the channel is stable during the trajectories. The pore domain keeps a well defined conformation, whereas the voltage-sensing domains undergo important lateral fluctuations, consistent with their modular nature. A channel-like region at the center of the S1-S4 helical bundle fills rapidly with water, reminiscent of the concept of high-dielectric aqueous crevices. The first two arginines along S4 (R294 and R297) adopt an interfacial position where they interact favorably with water and the lipid headgroups. The following two arginines (R300 and R303) interact predominantly with water and E226 in S2. Despite the absence of a structurally permanent gating pore formed by protein residues and surrounding the S4 helix, as traditionally pictured, the charged residues are located in a favorable environment and are not extensively exposed to the membrane nonpolar region. Continuum electrostatic computations indicate that the transmembrane potential sensed by the charged residues in the voltage sensor varies abruptly over the outer half of the membrane in the arginine-rich region of S4; thus, the voltage gradient or membrane electric field is "focused". Interactions of basic residues with the lipid headgroups at the intracellular membrane-solution interface reduce the membrane thickness near the channel, resulting in an increased transmembrane field. PMID- 17704181 TI - One-dimensional elastic continuum model of enterocyte layer migration. AB - Necrotizing enterocolitis is the leading cause of death from gastrointestinal disease in preterm infants. It results from an injury to the mucosal lining of the intestine, leading to translocation of bacteria and endotoxin into the circulation. Intestinal mucosal defects are repaired by the process of intestinal restitution, during which enterocytes migrate from healthy areas to sites of injury. In this article, we develop a mathematical model of migration of enterocytes during experimental necrotizing enterocolitis. The model is based on a novel assumption of elastic deformation of the cell layer and incorporates the following effects: i), mobility promoting force due to lamellipod formation, ii), mobility impeding adhesion to the cell matrix, and iii), enterocyte proliferation. Our model successfully reproduces the behavior observed for enterocyte migration on glass coverslips, namely the dependence of migration speed on the distance from the wound edge, and the finite propagation distance in the absence of proliferation that results in an occasional failure to close the wound. It also qualitatively reproduces the dependence of migration speed on integrin concentration. The model is applicable to the closure of a wound with a linear edge and, after calibration with experimental data, could be used to predict the effect of chemical agents on mobility, adhesion, and proliferation of enterocytes. PMID- 17704182 TI - Nonnative protein polymers: structure, morphology, and relation to nucleation and growth. AB - Thermally induced aggregates of alpha-chymotrypsinogen A and bovine granulocyte colony stimulating factor in acidic solutions were characterized by a combination of static and dynamic light scattering, spectroscopy, transmission electron microscopy, and monomer loss kinetics. The resulting soluble, high-molecular weight aggregates (approximately 10(3)-10(5) kDa) are linear, semiflexible polymer chains that do not appreciably associate with one another under the conditions at which they were formed, with classic power-law scaling of the radius of gyration and hydrodynamic radius with weight-average molecular weight (M(w)). Aggregates in both systems are composed of nonnative monomers with elevated levels of beta-sheet secondary structure, and bind thioflavine T. In general, the aggregate size distributions showed low polydispersity by light scattering. Together with the inverse scaling of M(w) with protein concentration, the results clearly indicate that aggregation proceeds via nucleated (chain) polymerization. For alpha-chymotrypsinogen A, the scaling behavior is combined with the kinetics of aggregation to deduce separate values for the characteristic timescales for nucleation (tau(n)) and growth (tau(g)), as well as the stoichiometry of the nucleus (x). The analysis illustrates a general procedure to noninvasively and quantitatively determine tau(n), tau(g), and x for soluble (chain polymer) aggregates, as well as the relationship between tau(n)/tau(g) and aggregate M(w). PMID- 17704183 TI - Exact low-force kinetics from high-force single-molecule unfolding events. AB - Mechanical forces play a key role in crucial cellular processes involving force bearing biomolecules, as well as in novel single-molecule pulling experiments. We present an exact method that enables one to extrapolate, to low (or zero) forces, entire time-correlation functions and kinetic rate constants from the conformational dynamics either simulated numerically or measured experimentally at a single, relatively higher, external force. The method has twofold relevance: 1), to extrapolate the kinetics at physiological force conditions from molecular dynamics trajectories generated at higher forces that accelerate conformational transitions; and 2), to extrapolate unfolding rates from experimental force extension single-molecule curves. The theoretical formalism, based on stochastic path integral weights of Langevin trajectories, is presented for the constant force, constant loading rate, and constant-velocity modes of the pulling experiments. For the first relevance, applications are described for simulating the conformational isomerization of alanine dipeptide; and for the second relevance, the single-molecule pulling of RNA is considered. The ability to assign a weight to each trace in the single-molecule data also suggests a means to quantitatively compare unfolding pathways under different conditions. PMID- 17704184 TI - Metal ions stabilize a dimeric molten globule state between the open and closed forms of malic enzyme. AB - Malic enzyme is a tetrameric protein with double dimer quaternary structure. In 3 5 M urea, the pigeon cytosolic NADP(+)-dependent malic enzyme unfolded and aggregated into various forms with dimers as the basic unit. Under the same denaturing conditions but in the presence of 4 mM Mn(2+), the enzyme existed exclusively as a molten globule dimer in solution. Similar to pigeon enzyme (Chang, G. G., T. M. Huang, and T. C. Chang. 1988. Biochem. J. 254:123-130), the human mitochondrial NAD(+)-dependent malic enzyme also underwent a reversible tetramer-dimer-monomer quaternary structural change in an acidic pH environment, which resulted in a molten globule state that is also prone to aggregate. The aggregation of pigeon enzyme was attributable to Trp-572 side chain. Mutation of Trp-572 to Phe, His, Ile, Ser, or Ala abolished the protective effect of the metal ions. The cytosolic malic enzyme was completely digested within 2 h by trypsin. In the presence of Mn(2+), a specific cutting site in the Lys-352-Gly Arg-354 region was able to generate a unique polypeptide with M(r) of 37 kDa, and this polypeptide was resistant to further digestion. These results indicate that, during the catalytic process of malic enzyme, binding metal ion induces a conformational change within the enzyme from the open form to an intermediate form, which upon binding of L-malate, transforms further into a catalytically competent closed form. PMID- 17704186 TI - Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen. AB - Congenital diaphragmatic hernia (CDH) is a developmental anomaly that results in significant mortality and morbidity. The underlying etiology is poorly understood. Insights will arise from an understanding of the mechanisms by which the teratogen nitrofen induces CDH in rodent models. In this study, we use in vitro cell assays in conjunction with whole animal rodent studies to test hypotheses regarding nitrofen's mechanism of action. The first component examined the interaction of nitrofen with various aspects of the retinoid signaling pathway including uptake proteins, binding proteins, receptors, conversion, and degradation enzymes. The second component examined the interactions of nitrofen and vitamins A, C, and E to test the hypothesis that nitrofen was functioning as an antioxidant to interfere with retinoid signaling. Third, we performed a series of experiments examining the interaction of nitrofen and thyroid signaling. Collectively, the data suggest that the primary aspect of retinoid signaling affected by nitrofen is via inhibition of the rate-limiting enzymes controlling retinoic acid synthesis. Retinoid signaling perturbations do not appear to involve oxidative effects of nitrofen. Any substantial roles of nitrofen-induced perturbations of thyroid hormone signaling or receptor function are not supported. PMID- 17704187 TI - Mechanical ventilation with 40% oxygen reduces pulmonary expression of genes that regulate lung development and impairs alveolar septation in newborn mice. AB - Mechanical ventilation with 40% oxygen reduces pulmonary expression of genes that regulate lung development and impairs alveolar septation in newborn mice. Am J Physiol Lung Cell Mol Physiol 293: , 2007. First published August 17, 2007; - Mechanical ventilation (MV) with O(2)-rich gas offers life-saving treatment for extremely premature infants with respiratory failure but often leads to neonatal chronic lung disease (CLD), characterized by defective formation of alveoli and blood vessels in the developing lung. We discovered that MV of 2- to 4-day-old mice with 40% O(2) for 8 h, compared with unventilated control pups, reduced lung expression of genes that regulate lung septation and angiogenesis (VEGF-A and its receptor, VEGF-R2; PDGF-A; and tenascin-C). MV with air for 8 h yielded similar results for PDGF-A and tenascin-C but did not alter lung mRNA expression of VEGF or VEGF-R2. MV of 4- to 6-day-old mice with 40% O(2) for 24 h reduced lung protein abundance of VEGF-A, VEGF-R2, PDGF-A, and tenascin-C and resulted in lung structural abnormalities consistent with evolving CLD. After MV with 40% O(2) for 24 h, lung volume was similar to unventilated controls, whereas distal air space size, assessed morphometrically, was greater in lungs of ventilated pups, indicative of impaired septation. Immunostaining for vimentin, which is expressed in myofibroblasts, was reduced in distal lung after 24 h of MV with 40% O(2). These molecular, cellular, and structural changes occurred without detectable lung inflammation as evaluated by histology and assays for proinflammatory cytokines, myeloperoxidase activity, and water content in lung. Thus lengthy MV of newborn mice with O(2)-rich gas reduces lung expression of genes and proteins that are critical for normal lung growth and development. These changes yielded lung structural defects similar to those observed in evolving CLD. PMID- 17704185 TI - Kinetic mechanism of the Ca2+-dependent switch-on and switch-off of cardiac troponin in myofibrils. AB - The kinetics of Ca(2+)-dependent conformational changes of human cardiac troponin (cTn) were studied on isolated cTn and within the sarcomeric environment of myofibrils. Human cTnC was selectively labeled on cysteine 84 with N-((2 (iodoacetoxy)ethyl)-N-methyl)amino-7-nitrobenz-2-oxa-1,3-diazole and reconstituted with cTnI and cTnT to the cTn complex, which was incorporated into guinea pig cardiac myofibrils. These exchanged myofibrils, or the isolated cTn, were rapidly mixed in a stopped-flow apparatus with different [Ca(2+)] or the Ca(2+)-buffer 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid to determine the kinetics of the switch-on or switch-off, respectively, of cTn. Activation of myofibrils with high [Ca(2+)] (pCa 4.6) induced a biphasic fluorescence increase with rate constants of >2000 s(-1) and approximately 330 s( 1), respectively. At low [Ca(2+)] (pCa 6.6), the slower rate was reduced to approximately 25 s(-1), but was still approximately 50-fold higher than the rate constant of Ca(2+)-induced myofibrillar force development measured in a mechanical setup. Decreasing [Ca(2+)] from pCa 5.0-7.9 induced a fluorescence decay with a rate constant of 39 s(-1), which was approximately fivefold faster than force relaxation. Modeling the data indicates two sequentially coupled conformational changes of cTnC in myofibrils: 1), rapid Ca(2+)-binding (k(B) approximately 120 microM(-1) s(-1)) and dissociation (k(D) approximately 550 s( 1)); and 2), slower switch-on (k(on) = 390s(-1)) and switch-off (k(off) = 36s( 1)) kinetics. At high [Ca(2+)], approximately 90% of cTnC is switched on. Both switch-on and switch-off kinetics of incorporated cTn were around fourfold faster than those of isolated cTn. In conclusion, the switch kinetics of cTn are sensitively changed by its structural integration in the sarcomere and directly rate-limit neither cardiac myofibrillar contraction nor relaxation. PMID- 17704188 TI - Caveolins and intracellular calcium regulation in human airway smooth muscle. AB - Regulation of intracellular Ca(2+) concentration ([Ca(2+)](i)) is a key factor in airway smooth muscle (ASM) tone. In vascular smooth muscle, specialized membrane microdomains (caveolae) expressing the scaffolding protein caveolin-1 are thought to facilitate cellular signal transduction. In human ASM cells, we tested the hypothesis that caveolae mediate Ca(2+) responses to agonist stimulation. Fluorescence immunocytochemistry with confocal microscopy, as well as Western blot analysis, was used to determine that agonist receptors (M(3) muscarinic, bradykinin, and histamine) and store-operated Ca(2+) entry (SOCE)-regulatory mechanisms colocalize with caveolin-1. Although caveolin-2 coexpressed with caveolin-1, caveolin-3 was absent. In fura 2-loaded ASM cells, [Ca(2+)](i) responses to 1 microM ACh, 10 microM histamine, and 10 nM bradykinin, as well as SOCE, were attenuated (each to a different extent) after disruption of caveolae by the cholesterol-chelating drug methyl-beta-cyclodextrin. Transfection of ASM cells with 50 nM caveolin-1 small interfering RNA significantly weakened caveolin 1 expression and blunted [Ca(2+)](i) responses to bradykinin and histamine, as well as SOCE, but the response to ACh was less intense. These results indicate that caveolae are present in ASM and that caveolin-1 contributes to regulation of [Ca(2+)](i) responses to agonist. PMID- 17704189 TI - Constitutive NADPH oxidase and increased mitochondrial respiratory chain activity regulate chemokine gene expression. AB - Alveolar macrophages, which generate high levels of reactive oxygen species, especially O(2)(*-), are involved in the recruitment of neutrophils to sites of inflammation and injury in the lung, and the generation of chemotactic proteins triggers this cellular recruitment. In this study, we asked whether O(2)(*-) generation in alveolar macrophages had a role in the expression of chemokines. Specifically, we hypothesized that O(2)(*-) generation is necessary for chemokine expression in alveolar macrophages after TNF-alpha stimulation. We found that alveolar macrophages have high constitutive NADPH oxidase activity that was not increased by TNF-alpha, but TNF-alpha increased the activity of the mitochondrial respiratory chain. In addition, the mitochondrial respiratory chain increased O(2)(*-) generation if the NADPH oxidase was inhibited. O(2)(*-) generation was necessary for macrophage inflammatory protein-2 (MIP-2) gene expression, because inhibition of NADPH oxidase or the mitochondrial respiratory chain or overexpression of Cu,Zn-superoxide dismutase significantly inhibited expression of MIP-2. TNF-alpha activated the ERK MAP kinase, and ERK activity was essential for chemokine gene expression. In addition, overexpression of the MEK1-->ERK pathway significantly increased IL-8 expression, and a small interfering RNA to the NADPH oxidase inhibited ERK- and TNF-alpha-induced chemokine expression. Collectively, these results suggest that in alveolar macrophages, O(2)(*-) generation mediates chemokine expression after TNF-alpha stimulation in an ERK dependent manner. PMID- 17704190 TI - Effect of PEEP on induced constriction is enhanced in decorin-deficient mice. AB - Decorin (Dcn), a small leucine-rich proteoglycan, is present in the extracellular matrix of the airways and lung tissues, contributes to lung mechanical properties, and its deposition is altered in asthma. The effect of Dcn deficiency on airway parenchymal interdependence was examined during induced bronchoconstriction. Studies were performed in C57Bl/6 mice in which the Dcn gene was disrupted by targeted deletion (Dcn(-/-)) and in wild-type controls (Dcn(+/+)). Mice were mechanically ventilated, and respiratory system impedance was measured during in vivo ventilation at positive end-expiratory pressure (PEEP) = 2 and 10 cmH(2)0, before and after aerosol delivery of methacholine (MCh). Length vs. tension curves in isolated tracheal rings were measured in vitro. Dcn distribution in +/+ mice airways was characterized by immunofluorescence; differences in collagen structure in Dcn(+/+) and Dcn(-/-) mouse lungs was examined by electron microscopy. MCh caused similar increases in airway resistance (Raw) and tissue elastance (H) in Dcn(+/+) and Dcn(-/-) mice. During MCh-induced constriction, increasing PEEP caused a decrease in Raw that was greater in Dcn(-/-) mice and a decrease in H in Dcn(-/-) mice only. Tracheal ring compliance was greater in Dcn (-/-) mice. Imaging studies showed that Dcn was deposited primarily in the airway adventitial layer in Dcn(+/+) mice; in Dcn( /-) mice, collagen had an irregular appearance, especially in the lung periphery. These results show that lack of Dcn alters the normal interaction between airways and lung parenchyma; in asthma, changes in Dcn could potentially contribute to abnormal airway physiology. PMID- 17704191 TI - The cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling. AB - We have recently reported that in bone the cannabinoid CB1 receptor is present in sympathetic terminals. Here we show that traumatic brain injury (TBI), which in humans enhances peripheral osteogenesis and fracture healing, acutely stimulates bone formation in a distant skeletal site. At this site we demonstrate i) a high level of the main endocannabinoid, 2-arachidonoylglycerol (2-AG), and expression of diacylglycerol lipases, enzymes essential for 2-AG synthesis; ii) that the TBI induced increase in bone formation is preceded by elevation of the 2-AG and a decrease in norepinephrine (NE) levels. The TBI stimulation of bone formation was absent in CB1-null mice. In wild-type animals it could be mimicked, including the suppression of NE levels, by 2-AG administration. The TBI- and 2-AG-induced stimulation of osteogenesis was restrained by the beta-adrenergic receptor agonist isoproterenol. NE from sympathetic terminals is known to tonically inhibit bone formation by activating osteoblastic beta2-adrenergic receptors. The present findings further demonstrate that the sympathetic control of bone formation is regulated through 2-AG activation of prejunctional CB1. Elevation of bone 2-AG apparently suppresses NE release from bone sympathetic terminals, thus alleviating the inhibition of bone formation. The involvement of osteoblastic CB2 signaling in this process is minimal, if any. PMID- 17704192 TI - Molecular basis of the redox regulation of SUMO proteases: a protective mechanism of intermolecular disulfide linkage against irreversible sulfhydryl oxidation. AB - Sumoylation has emerged as an indispensable post-translational modification that modulates the functions of a broad spectrum of proteins. Recent studies have demonstrated that reactive oxygen species influence the equilibrium of sumoylation-desumoylation. We show herein that H2O2 induces formation of an intermolecular disulfide linkage of human SUMO protease SENP1 via the active-site Cys 603 and a unique residue Cys 613. Such reversible modification confers a higher recovery of enzyme activity, which is also observed in yeast Ulp1, but not in human SENP2, suggesting its protective role against irreversible sulfhydryl oxidation. In vivo formation of a disulfide-linked dimer of SENP1 is also detected in cultured cells in response to oxidative stress. The modifications are further elucidated by the crystal structures of Ulp1 with the catalytic cysteine oxidized to sulfenic, sulfinic, and sulfonic acids. Our findings suggest that, in addition to SUMO conjugating enzymes, SUMO proteases may act as redox sensors and effectors modulating the desumoylation pathway and specific cellular responses to oxidative stress. PMID- 17704193 TI - Beta-tubulin cofactor D and ARL2 take part in apical junctional complex disassembly and abrogate epithelial structure. AB - In epithelial cells, the apical junctional complex (AJC), composed of tight junctions (TJs) and adherens junctions (AJs), maintains cell-surface polarity by forming a fence that prevents lateral movement and diffusion of proteins and lipids between the apical and basolateral PM and holds the epithelial monolayer intact through cell-cell contacts. Disassembly of this complex is a prime event in development and cell transformation. Maintenance of the AJC has been shown to involve mainly the actin cytoskeleton. Recent findings also point to the involvement of the microtubule (MT) system. Here we show the first evidence that in polarized epithelial MDCK cells, ARF-like protein 2 (ARL2) and beta-tubulin cofactor D, known to be involved in MT dynamics, have a role in disassembly of the AJC followed by cell dissociation from the epithelial monolayer, which is not dependent on MT depolymerization. In addition, we show that beta-tubulin cofactor D is partially localized to the lateral PM through its 15 C-terminal amino acids and intact MTs. ARL2 inhibited beta-tubulin cofactor D-dependent cell dissociation from the monolayer and AJC disassembly. To our knowledge, this is the first evidence that beta-tubulin cofactor D plays a role in cells independent of its presumed role in folding tubulin heterodimers. We conclude that ARL2 and beta-tubulin cofactor D participate in AJC disassembly and epithelial depolarization. PMID- 17704194 TI - Training and other predictors of personal protective equipment use in Australian grain farmers using pesticides. AB - OBJECTIVES: To investigate patterns of use of personal protective equipment (PPE) to reduce pesticide exposure in a sample of Australian farmers and also to assess the influence of possible predictive factors. METHODS: A cross-sectional survey of 1102 farmers recruited through the Victorian Farmers Federation (VFF) was conducted. A written questionnaire was filled out by participants at VFF meetings attended by a visiting research assistant. Participants answered questions about frequency of pesticide use and PPE items they usually used when doing two different pesticide-related tasks, mixing and application, of each of four classes of pesticides. They also answered questions about personal characteristics, farm characteristics, farming activities, career and health. RESULTS: Nearly all surveyed farmers had ever used pesticides, and over 87% had used Herbicides or Animal Health Products in the previous 12 months. Non-use of PPE was frequently reported, with up to 10-40% of farmers routinely using no PPE at all when using pesticides. Across all pesticide classes, PPE use was higher for pesticide mixing than for application. In multivariate analyses PPE use appeared to be most strongly associated with younger age and farm chemical training. CONCLUSIONS: PPE use across all pesticide classes was poor, indicating the possibility of clinically significant pesticide exposure in many farmers. Given that PPE use was found to be associated with farm chemical training, the authors suggest that training is likely to be an important intervention for reducing farmers' pesticide exposure. Poor uptake of farm chemical training by farmers and the aging farming workforce are causes for concern in the light of these findings. PMID- 17704196 TI - Comparisons of self-reported and register data on sickness absence among public employees in Sweden. AB - AIM: Self-reported assessments of sickness absence are often performed in epidemiological studies. The objective of this study was to compare the number of sick-leave days according to self-reported data over 12 months with data from the employer's register for the same period. An additional aim was to ascertain whether the self-reported information and the recorded data would show equivalent associations with self-reported general health. METHODS: The study was based on a cohort of 4869 municipal employees in Sweden, about 80% women, who answered a questionnaire in 2001-2. The responses provided by the employees included information on number of sick-leave days and self-rated health. Data on sick leave days, occupation and age were derived from the employers' computerised registers. The questionnaire information on sick-leave days was compared with the corresponding information retrieved from the employer register by means of calculating sensitivity and specificity, using the employers' data as the "gold standard". RESULTS: The annual number of sick-leave days was lower according to the self-reported information than to the register data. For women the agreement between the two sickness absence measures for no sick-leave days, 1-7 days and >/=28 days were 74%, 72% and 67%, respectively. The sensitivity of questionnaire versus register information regarding any self-reported sick-leave day was 91% and the specificity was 74%. Sensitivity and specificity for sickness absence >/=28 days were 67% and 98%, respectively. The results for men were similar to those for women. Self-reported and recorded sickness absence were both associated with self-rated health. The odds ratios were 7.27 and 8.25, for subjects with >/=28 recorded and self-reported number of sick-leave days respectively, compared to subjects with no sickness absence. CONCLUSIONS: Good agreement was found between self-reported and register information on sickness absence. Self-reported data on sickness absence may be useful in common epidemiological applications. PMID- 17704195 TI - Experimental exposure to wood smoke: effects on airway inflammation and oxidative stress. AB - BACKGROUND: Particulate air pollution affects cardiovascular and pulmonary disease and mortality. A main hypothesis about the mechanisms involved is that particles induce inflammation in lower airways, systemic inflammation and oxidative stress. OBJECTIVES: To examine whether short-term exposure to wood smoke in healthy subjects affects markers of pulmonary inflammation and oxidative stress. METHODS: 13 subjects were exposed first to clean air and then to wood smoke in a chamber during 4-hour sessions, 1 week apart. The mass concentrations of fine particles at wood smoke exposure were 240-280 mug/m(3), and number concentrations were 95 000-180 000/cm(3), about half of the particles being ultrafine (<100 nm). Blood and breath samples were taken before and at various intervals after exposure to wood smoke and clean air and examined for exhaled nitric oxide and Clara cell protein in serum and urine, and malondialdehyde in exhaled breath condensate. RESULTS: Exposure to wood smoke increased alveolar nitric oxide 3 hours post-exposure while malondialdehyde levels in breath condensate were higher both immediately after and 20 hours after exposure. Serum Clara cell protein was increased 20 hours after exposure. CONCLUSIONS: Wood smoke at levels that can be found in smoky indoor environments caused an inflammatory response and signs of increased oxidative stress in the respiratory tract, especially in the lower airways. PMID- 17704197 TI - Cancer risk after cessation of asbestos exposure: a cohort study of Italian asbestos cement workers. AB - OBJECTIVES: We aimed to study mortality for asbestos related diseases and the incidence of mesothelioma in a cohort of Italian asbestos cement workers after cessation of asbestos exposure. METHODS: The Eternit factory operated from 1907 to 1986. The cohort included 3434 subjects active in 1950 or hired in 1950-86, ascertained from company records, without selections. Local reference rates were used for both mortality and mesothelioma incidence. RESULTS: Mortality was increased in both sexes for all causes (overall 1809 observed (obs) vs 1312.3 expected (exp); p<0.01), pleural (135 obs vs 3.6 exp; p<0.01) and peritoneal (52 vs 1.9; p<0.01) malignancies and lung cancer (249 vs 103.1; p<0.01). In women, ovarian (9 vs 4.0; p<0.05) and uterine (15 vs 5.8; p<0.01) malignancies were also in excess. No statistically significant increase was found for laryngeal cancer (16 obs vs 12.2 exp). In Poisson regression analyses, the RR of death from pleural neoplasm linearly increased with duration of exposure, while it showed a curvilinear increase with latency and time since cessation of exposure. RR for peritoneal neoplasm continued to increase by latency, duration and time since cessation of exposure. RR for lung cancer showed a reduction after 15 years since cessation of exposure and levelled off after 40 years of latency. CONCLUSION: This study of a cohort of asbestos exposed workers with very long follow-up confirmed the reduction in risk of death from lung cancer after the end of exposure. It also suggested a reduction in risk for pleural mesothelioma with over 40 years of latency, while risk for peritoneal mesothelioma showed a continuing increase. PMID- 17704198 TI - The precautionary principle: in action for public health. PMID- 17704199 TI - Problems in applying the precautionary principle to public health. PMID- 17704200 TI - The IARC Monographs: a resource for precaution and prevention. PMID- 17704201 TI - The reactionary principle: inaction for public health. PMID- 17704202 TI - The precautionary principle in the context of multiple risks. PMID- 17704204 TI - Reply to the recent article by Boffetta et al. [28(5):913 915] on attribution of cancer to the environment. PMID- 17704203 TI - Selecting appropriate study designs to address specific research questions in occupational epidemiology. AB - Various epidemiological study designs are available to investigate illness and injury risks related to workplace exposures. The choice of study design to address a particular research question will be guided by the nature of the health outcome under study, its presumed relation to workplace exposures, and feasibility constraints. This review summarises the relative advantages and limitations of conventional study designs including cohort studies, cross sectional studies, repeated measures studies, case-control (industry- and community-based) studies, and more recently developed variants of the nested case control DESIGN: case-cohort and case-crossover studies. PMID- 17704205 TI - Inducible NO synthase dependent S-nitrosylation and activation of arginase1 contribute to age-related endothelial dysfunction. AB - Endothelial function is impaired in aging because of a decrease in NO bioavailability. This may be, in part, attributable to increased arginase activity, which reciprocally regulates NO synthase (NOS) by competing for the common substrate, L-arginine. However, the high Km of arginase (>1 mmol/L) compared with NOS (2 to 20 micromol/L) seemingly makes direct competition for substrate unlikely. One of the mechanisms by which NO exerts its effects is by posttranslational modification through S-nitrosylation of protein cysteines. We tested the hypothesis that arginase1 activity is modulated by this mechanism, which serves to alter its substrate affinity, allowing competition with NOS for L arginine. We demonstrate that arginase1 activity is altered by S-nitrosylation, both in vitro and ex vivo. Furthermore, using site-directed mutagenesis we demonstrate that 2 cysteine residues (C168 and C303) are able to undergo nitrosylation. S-Nitrosylation of C303 stabilizes the arginase1 trimer and reduces its Km value 6-fold. Finally, arginase1 nitrosylation is increased (and thus its Km decreased) in blood vessels from aging rats, likely contributing to impaired NO bioavailability and endothelial dysfunction. This is mediated by inducible NOS, which is expressed in the aging endothelium. These findings suggest that S-nitrosylated arginase1 can compete with NOS for L-arginine and contribute to endothelial dysfunction in the aging cardiovascular system. PMID- 17704206 TI - Differential regulation of endothelial cell permeability by cGMP via phosphodiesterases 2 and 3. AB - Endothelial barrier dysfunction leading to increased permeability and vascular leakage is an underlying cause of several pathological conditions, including edema and sepsis. Whereas cAMP has been shown to decrease endothelial permeability, the role of cGMP is controversial. Endothelial cells express cGMP inhibited phosphodiesterase (PDE)3A and cGMP-stimulated PDE2A. Thus we hypothesized that the effect of cGMP on endothelial permeability is dependent on the concentration of cGMP present and on the relative expression levels of PDE2A and PDE3A. When cAMP synthesis was slightly elevated with a submaximal concentration of 7-deacetyl-7-(O-[N-methylpiperazino]-gamma-butyryl) dihydrochloride-forskolin (MPB-forskolin), we found that low doses of either atrial natriuretic peptide (ANP) or NO donors potentiated the inhibitory effects of MPB-forskolin on thrombin-induced permeability. However, this inhibitory effect of forskolin was reversed at higher doses of ANP or NO. These data suggest that cGMP at lower concentrations inhibits PDE3A and thereby increases a local pool of cAMP, whereas higher concentrations cGMP activates PDE2A, reversing the effect. Inhibitors of PDE3A mimicked the effect of low-dose ANP on thrombin induced permeability, and inhibition of PDE2A reversed the stimulation of permeability seen with higher doses of ANP. Finally, increasing PDE2A expression with tumor necrosis factor-alpha reversed the inhibition of permeability caused by low doses of ANP. As predicted, the effect of tumor necrosis factor-alpha on permeability was reversed by a PDE2A inhibitor. These findings suggest that the effect of increasing concentrations of cGMP on endothelial permeability is biphasic, which, in large part, is attributable to the relative amounts of PDE2A and PDE3A in endothelial cells. PMID- 17704207 TI - Spatial distribution of fibrosis governs fibrillation wave dynamics in the posterior left atrium during heart failure. AB - Heart failure (HF) commonly results in atrial fibrillation (AF) and fibrosis, but how the distribution of fibrosis impacts AF dynamics has not been studied. HF was induced in sheep by ventricular tachypacing (220 bpm, 6 to 7 weeks). Optical mapping (Di-4-ANEPPS, 300 frames/sec) of the posterior left atrial (PLA) endocardium was performed during sustained AF (burst pacing) in Langendorff perfused HF (n=7, 4 micromol/L acetylcholine; n=3, no acetylcholine) and control (n=6) hearts. PLA breakthroughs were the most frequent activation pattern in both groups (72.0+/-4.6 and 90.2+/-2.7%, HF and control, respectively). However, unlike control, HF breakthroughs preferentially occurred at the PLAs periphery near the pulmonary vein ostia, and their beat-to-beat variability was greater than control (1.93+/-0.14 versus 1.47+/-0.07 changes/[beats/sec], respectively, P<0.05). On histological analysis (picrosirius red), the area of diffuse fibrosis was larger in HF (23.4+/-0.4%) than control (14.1+/-0.6%; P<0.001, n=4). Also the number and size of fibrous patches were significantly larger and their location was more peripheral in HF than control. Computer simulations using 2-dimensional human atrial models with structural and ionic remodeling as in HF demonstrated that changes in AF activation frequency and dynamics were controlled by the interaction of electrical waves with clusters of fibrotic patches of various sizes and individual pulmonary vein ostia. During AF in failing hearts, heterogeneous spatial distribution of fibrosis at the PLA governs AF dynamics and fractionation. PMID- 17704208 TI - Regulation of tetrahydrobiopterin biosynthesis by shear stress. AB - An essential cofactor for the endothelial NO synthase is tetrahydrobiopterin (H4B). In the present study, we show that in human endothelial cells, laminar shear stress dramatically increases H4B levels and enzymatic activity of GTP cyclohydrolase (GTPCH)-1, the first step of H4B biosynthesis. In contrast, protein levels of GTPCH-1 were not affected by shear. Shear did not change protein expression or activity of the downstream enzymes 6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase and decreased protein levels of the salvage enzyme dihydrofolate reductase. Oscillatory shear only modestly affected H4B levels and GPTCH-1 activity. We also demonstrate that laminar, but not oscillatory shear stress, stimulates phosphorylation of GTPCH-1 on serine 81 and that this is mediated by the alpha prime (alpha') subunit of casein kinase 2. The increase in H4B caused by shear is essential in allowing proper function of endothelial NO synthase because GPTCH-1 blockade with 2,4-diamino-6 hydroxypyrimidine during shear inhibited dimer formation of endothelial NO synthase, increased endothelial cell superoxide production, and prevented the increase in NO production caused by shear. Thus, shear stress not only increases endothelial NO synthase levels but also stimulates production of H4B by markedly enhancing GTPCH-1 activity via casein kinase 2-dependent phosphorylation on serine 81. These findings illustrate a new function of casein kinase 2 in the endothelium and provide insight into regulation of GTPCH-1 activity. PMID- 17704209 TI - Oxidized phospholipids induce phenotypic switching of vascular smooth muscle cells in vivo and in vitro. AB - Atherosclerosis is a vascular disease characterized by lipid deposition and inflammation within the arterial wall. Oxidized phospholipids (oxPLs), such as 1 palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) and its constituents 1-palmytoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) are concentrated within atherosclerotic lesions and are known to be potent proinflammatory mediators. Phenotypic switching of smooth muscle cells (SMCs) plays a critical role in the development, progression, and end-stage clinical consequences of atherosclerosis, yet little is known regarding the effects of specific oxPLs on SMC phenotype. The present studies were focused on determining whether oxPLs regulate expression of SMC differentiation marker genes and the molecular mechanisms involved. Results showed that POVPC and PGPC induced profound suppression of smooth muscle (SM) alpha-actin and SM myosin heavy chain expression while simultaneously increasing expression of MCP-1, MCP-3, and cytolysin. OxPLs also induced nuclear translocation of Kruppel-like transcription factor 4 (KLF4), a known repressor of SMC marker genes. siRNA targeting of KLF4 nearly blocked POVPC-induced suppression of SMC marker genes, and myocardin. POVPC-induced repression of SMC marker genes was also significantly attenuated in KLF4 knockout SMCs. Taken together, these results suggest a novel role for oxPLs in phenotypic modulation of SMCs and indicate that these effects are dependent on the transcription factor, KLF4. These results may have important novel implications for the mechanisms by which oxPLs contribute to the pathogenesis of atherosclerosis. PMID- 17704210 TI - Intra-sarcoplasmic reticulum free [Ca2+] and buffering in arrhythmogenic failing rabbit heart. AB - Smaller Ca2+ transients and systolic dysfunction in heart failure (HF) can be largely explained by reduced total sarcoplasmic reticulum (SR) Ca2+ content ([Ca]SRT). However, it is unknown whether low [Ca]SRT is manifest as reduced: (1) intra-SR free [Ca2+] ([Ca2+]SR), (2) intra-SR Ca2+ buffering, or (3) SR volume (as percentage of cell volume). Here we assess these possibilities in a well characterized rabbit model of nonischemic HF. In HF versus control myocytes, diastolic [Ca2+]SR is similar at 0.1-Hz stimulation, but the increase in both [Ca2+]SR and [Ca]SRT as frequency increases to 1 Hz is blunted in HF. Direct measurement of intra-SR Ca2+ buffering (by simultaneous [Ca2+]SR and [Ca]SRT measurement) showed no change in HF. Diastolic [Ca]SRT changes paralleled [Ca2+]SR, suggesting that SR volume is not appreciably altered in HF. Thus, reduced [Ca]SRT in HF is associated with comparably reduced [Ca2+]SR. Fractional [Ca2+]SR depletion increased progressively with stimulation frequency in control but was blunted in HF (consistent with the blunted force-frequency relationship in HF). By studying a range of [Ca2+]SR, analysis showed that for a given [Ca]SR, fractional SR Ca2+ release was actually higher in HF. For both control and HF myocytes, SR Ca2+ release terminated when [Ca2+]SR dropped to 0.3 to 0.5 mmol/L during systole, consistent with a role for declining [Ca2+]SR in the dynamic shutoff of SR Ca2+ release. We conclude that low total SR Ca2+ content in HF, and reduced SR Ca2+ release, is attributable to reduced [Ca2+]SR, not to alterations in SR volume or Ca2+ buffering capacity. PMID- 17704211 TI - Coronary vessel development is dependent on the type III transforming growth factor beta receptor. AB - Transforming growth factor (TGF)beta receptor III (TGFbetaR3), or beta-glycan, binds all 3 TGFbeta ligands and inhibin with high affinity but lacks the serine/threonine kinase domain found in the type I and type II receptors (TGFbetaR1, TGFbetaR2). TGFbetaR3 facilitates signaling via TGFbetaR1/TGFbetaR2 but also has been suggested to play a unique and nonredundant role in TGFbeta signaling. Targeted deletion of Tgfbr3 revealed a requirement for Tgfbr3 during development of the coronary vessels. Coronary vasculogenesis is significantly impaired in null mice, with few vessels evident and numerous, persistent blood islands found throughout the epicardium. Tgfbr3-null mice die at embryonic day 14.5, the time when functional coronary vasculature is required for embryo viability. However, in null mice nascent coronary vessels attach to the aorta, form 2 coronary ostia, and initiate smooth muscle recruitment by embryonic day 14. Analysis of earlier developmental stages revealed defects in the epicardium. At embryonic day 13.5, these defects include an irregular and hypercellular epicardium with abundant subepicardial mesenchyme and a thin compact zone myocardium. Tgfbr3-null mice also displayed other defects in coronary development, including dysmorphic and distended vessels along the atrioventricular groove and subepicardial hemorrhage. In null mice, vessels throughout the yolk sac and embryo form and recruit smooth muscle in a pattern indistinguishable from heterozygous or wild-type littermates. These data demonstrate a requirement for Tgfbr3 during coronary vessel development that is essential for embryonic viability. PMID- 17704212 TI - Loss of the alpha7 integrin promotes extracellular signal-regulated kinase activation and altered vascular remodeling. AB - Vascular smooth muscle cell (VSMC) proliferation and migration are underlying factors in the development and progression of cardiovascular disease. Studies have shown that altered expression of vascular integrins and extracellular matrix proteins may contribute to the vascular remodeling observed after arterial injury and during disease. We have recently shown that loss of the alpha7beta1 integrin results in VSMC hyperplasia. To investigate the cellular mechanisms underlying this phenotype, we have examined changes in cell signaling pathways associated with VSMC proliferation. Several studies have demonstrated the mitogen-activated protein kinase signaling pathway is activated in response to vascular injury and disease. In this study, we show that loss of the alpha7 integrin in VSMCs results in activation of the extracellular signal-regulated kinase and translocation of the activated kinase to the nucleus. Forced expression of the alpha7 integrin or use of the mitogen-activated protein kinase kinase 1 inhibitor U0126 in alpha7 integrin-deficient VSMCs suppressed extracellular signal-regulated kinase activation and restored the differentiated phenotype to alpha7 integrin-null cells in a manner dependent on Ras signaling. Alpha7 integrin-null mice displayed profound vascular remodeling in response to injury with pronounced neointimal formation and reduced vascular compliance. These findings demonstrate that the alpha7beta1 integrin negatively regulates extracellular signal-regulated kinase activation and suggests an important role for this integrin as part of a signaling complex regulating VSMC phenotype switching. PMID- 17704213 TI - A WD40 domain cyclophilin interacts with histone H3 and functions in gene repression and organogenesis in Arabidopsis. AB - Chromatin-based silencing provides a crucial mechanism for the regulation of gene expression. We have identified a WD40 domain cyclophilin, CYCLOPHILIN71 (CYP71), which functions in gene repression and organogenesis in Arabidopsis thaliana. Disruption of CYP71 resulted in ectopic activation of homeotic genes that regulate meristem development. The cyp71 mutant plants displayed dramatic defects, including reduced apical meristem activity, delayed and abnormal lateral organ formation, and arrested root growth. CYP71 was associated with the chromatin of target gene loci and physically interacted with histone H3. The cyp71 mutant showed reduced methylation of H3K27 at target loci, consistent with the derepression of these genes in the mutant. As CYP71 has close homologs in eukaryotes ranging from fission yeast to human, we propose that it serves as a highly conserved histone remodeling factor involved in chromatin-based gene silencing in eukaryotic organisms. PMID- 17704214 TI - Auxin synthesized by the YUCCA flavin monooxygenases is essential for embryogenesis and leaf formation in Arabidopsis. AB - Auxin plays a key role in embryogenesis and seedling development, but the auxin sources for the two processes are not defined. Here, we demonstrate that auxin synthesized by the YUCCA (YUC) flavin monooxygenases is essential for the establishment of the basal body region during embryogenesis and the formation of embryonic and postembryonic organs. Both YUC1 and YUC4 are expressed in discrete groups of cells throughout embryogenesis, and their expression patterns overlap with those of YUC10 and YUC11 during embryogenesis. The quadruple mutants of yuc1 yuc4 yuc10 yuc11 fail to develop a hypocotyl and a root meristem, a phenotype similar to those of mp and tir1 afb1 afb2 afb3 auxin signaling mutants. We further show that YUC genes play an essential role in the formation of rosette leaves by analyzing combinations of yuc mutants and the polar auxin transport mutants pin1 and aux1. Disruption of YUC1, YUC4, or PIN1 alone does not abolish leaf formation, but the triple mutant yuc1 yuc4 pin1 fails to form leaves and flowers. Furthermore, disruption of auxin influx carrier AUX1 in the quadruple mutant yuc1 yuc2 yuc4 yuc6, but not in wild-type background, phenocopies yuc1 yuc4 pin1, demonstrating that auxin influx is required for plant leaf and flower development. Our data demonstrate that auxin synthesized by the YUC flavin monooxygenases is an essential auxin source for Arabidopsis thaliana embryogenesis and postembryonic organ formation. PMID- 17704215 TI - Magnaporthe grisea cutinase2 mediates appressorium differentiation and host penetration and is required for full virulence. AB - The rice blast fungus Magnaporthe grisea infects its host by forming a specialized infection structure, the appressorium, on the plant leaf. The enormous turgor pressure generated within the appressorium drives the emerging penetration peg forcefully through the plant cuticle. Hitherto, the involvement of cutinase(s) in this process has remained unproven. We identified a specific M. grisea cutinase, CUT2, whose expression is dramatically upregulated during appressorium maturation and penetration. The cut2 mutant has reduced extracellular cutin-degrading and Ser esterase activity, when grown on cutin as the sole carbon source, compared with the wild-type strain. The cut2 mutant strain is severely less pathogenic than the wild type or complemented cut2/CUT2 strain on rice (Oryza sativa) and barley (Hordeum vulgare). It displays reduced conidiation and anomalous germling morphology, forming multiple elongated germ tubes and aberrant appressoria on inductive surfaces. We show that Cut2 mediates the formation of the penetration peg but does not play a role in spore or appressorium adhesion, or in appressorial turgor generation. Morphological and pathogenicity defects in the cut2 mutant are fully restored with exogenous application of synthetic cutin monomers, cAMP, 3-isobutyl-1-methylxanthine, and diacylglycerol (DAG). We propose that Cut2 is an upstream activator of cAMP/protein kinase A and DAG/protein kinase C signaling pathways that direct appressorium formation and infectious growth in M. grisea. Cut2 is therefore required for surface sensing leading to correct germling differentiation, penetration, and full virulence in this model fungus. PMID- 17704216 TI - MicroRNA-mediated regulation of stomatal development in Arabidopsis. AB - The proper number and distribution of stomata are essential for the efficient exchange of gases between the atmosphere and the aerial parts of plants. We show that the density and development of stomatal complexes on the epidermis of Arabidopsis thaliana leaves depend, in part, on the microRNA-mediated regulation of Agamous-like16 (AGL16), which is a member of the MADS box protein family. AGL16 mRNA is targeted for sequence-specific degradation by miR824, a recently evolved microRNA conserved in the Brassicaceae and encoded at a single genetic locus. Primary stomatal complexes can give rise to higher-order complexes derived from satellite meristemoids. Expression of a miR824-resistant AGL16 mRNA, but not the wild-type AGL16 mRNA, in transgenic plants increased the incidence of stomata in higher-order complexes. By contrast, reduced expression of AGL16 mRNA in the agl16-1 deficiency mutant and in transgenic lines overexpressing miR824 decreased the incidence of stomata in higher-order complexes. These findings and the nonoverlapping patterns of AGL16 mRNA and miR824 localization led us to propose that the miR824/AGL16 pathway functions in the satellite meristemoid lineage of stomatal development. PMID- 17704217 TI - Induction of RpoS degradation by the two-component system regulator RstA in Salmonella enterica. AB - Bacterial survival in diverse and changing environments relies on the accurate interplay between different regulatory pathways, which determine the design of an adequate adaptive response. The proper outcome depends on a precise gene expression profile generated from the finely tuned and concerted action of transcriptional factors of distinct regulatory hierarchies. Salmonella enterica serovar Typhimurium harbors multiple regulatory systems that are crucial for the bacterium to cope with harsh extra- and intracellular environments. In this work, we found that the expression of Salmonella RstA, a response regulator from the two-component system family, was able to downregulate the expression of three RpoS-controlled genes (narZ, spvA, and bapA). Furthermore, this downregulation was achieved by a reduction in RpoS cellular levels. The alternative sigma factor RpoS is critical for bacterial endurance under the most-stressful conditions, including stationary-phase entrance and host adaptation. Accordingly, RpoS cellular levels are tightly controlled by complex transcriptional, translational, and posttranslational mechanisms. The analysis of each regulatory step revealed that in Salmonella, RstA expression was able to promote RpoS degradation independently of the MviA-ClpXP proteolytic pathway. Additionally, we show that RstA is involved in modulating Salmonella biofilm formation. The fact that the RpoS-modulated genes affected by RstA expression have previously been demonstrated to contribute to Salmonella pathogenic traits, which include biofilm forming capacity, suggests that under yet unknown conditions, RstA may function as a control point of RpoS-dependent pathways that govern Salmonella virulence. PMID- 17704218 TI - The extension of the fourth transmembrane helix of the sensor kinase KdpD of Escherichia coli is involved in sensing. AB - The KdpD sensor kinase and the KdpE response regulator control expression of the kdpFABC operon coding for the KdpFABC high-affinity K+ transport system of Escherichia coli. In search of a distinct part of the input domain of KdpD which is solely responsible for K+ sensing, sequences of kdpD encoding the transmembrane region and adjacent N-terminal and C-terminal extensions were subjected to random mutagenesis. Nine KdpD derivatives were identified that had lost tight regulation of kdpFABC expression. They all carried single amino acid replacements located in a region encompassing the fourth transmembrane helix and the adjacent arginine cluster of KdpD. All mutants exhibited high levels of kdpFABC expression regardless of the external K+ concentration. However, 3- to 14 fold induction was observed under extreme K+-limiting conditions and in response to an osmotic upshift when sucrose was used as an osmolyte. These KdpD derivatives were characterized by a reduced phosphatase activity in comparison to the autokinase activity in vitro, which explains constitutive expression. Whereas for wild-type KdpD the autokinase activity and also, in turn, the phosphotransfer activity to KdpE were inhibited by increasing concentrations of K+, both activities were unaffected in the KdpD derivatives. These data clearly show that the extension of the fourth transmembrane helix encompassing the arginine cluster is mainly involved in sensing both K+ limitation and osmotic upshift, which may not be separated mechanistically. PMID- 17704219 TI - The circadian clock-related gene pex regulates a negative cis element in the kaiA promoter region. AB - In the cyanobacterium Synechococcus sp. strain PCC 7942, a circadian clock related gene, pex, was identified as the gene prolonging the period of the clock. A PadR domain, which is a newly classified transcription factor domain, and the X ray crystal structure of the Pex protein suggest a role for Pex in transcriptional regulation in the circadian system. However, the regulatory target of the Pex protein is unknown. To determine the role of Pex, we monitored bioluminescence rhythms that reported the expression activity of the kaiA gene or the kaiBC operon in pex deficiency, pex constitutive expression, and the wild type genotype. The expression of kaiA in the pex-deficient or constitutive expression genotype was 7 or 1/7 times that of the wild type, respectively, suggesting that kaiA is the target of negative regulation by Pex. In contrast, the expression of the kaiBC gene in the two pex-related genotypes was the same as that in the wild type, suggesting that Pex specifically regulates kaiA expression. We used primer extension analysis to map the transcription start site for the kaiA gene 66 bp upstream of the translation start codon. Mapping with deletion and base pair substitution of the kaiA upstream region revealed that a 5 bp sequence in this region was essential for the regulation of kaiA. The repression or constitutive expression of the kaiA transgene caused the prolongation or shortening of the circadian period, respectively, suggesting that the Pex protein changes the period via the negative regulation of kaiA. PMID- 17704221 TI - The motors powering A-motility in Myxococcus xanthus are distributed along the cell body. AB - Two models have been proposed to explain the adventurous gliding motility of Myxococcus xanthus: (i) polar secretion of slime and (ii) an unknown motor that uses cell surface adhesion complexes that form periodic attachments along the cell length. Gliding movements of the leading poles of cephalexin-treated filamentous cells were observed but not equivalent movements of the lagging poles. This demonstrates that the adventurous-motility motors are not confined to the rear of the cell. PMID- 17704220 TI - The NtcA-regulated amtB gene is necessary for full methylammonium uptake activity in the cyanobacterium Synechococcus elongatus. AB - The Amt proteins constitute a ubiquitous family of transmembrane ammonia channels that permit the net uptake of ammonium by cells. In many organisms, there is more than one amt gene, and these genes are subjected to nitrogen control. The mature Amt protein is a homo- or heterooligomer of three Amt subunits. We previously characterized an amt1 gene in the unicellular cyanobacterium Synechococcus elongatus strain PCC 7942. In this work, we describe the presence in this organism of a second amt gene, amtB, which encodes a protein more similar to the bacterial AmtB proteins than to any other characterized cyanobacterial Amt protein. The expression of amtB took place in response to nitrogen step-down, required the NtcA transcription factor, and occurred parallel to the expression of amt1. However, the transcript levels of amtB measured after 2 h of nitrogen deprivation were about 100-fold lower than those of amt1. An S. elongatus amtB insertional mutant exhibited an activity for uptake of [14C]methylammonium that was about 55% of that observed in the wild type, but inactivation of amtB had no noticeable effect on the uptake of ammonium when it was supplied at a concentration of 100 microM or more. Because an S. elongatus amt1 mutant is essentially devoid of [14C]methylammonium uptake activity, the mature Amt transporter is functional in the absence of AmtB subunits but not in the absence of Amt1 subunits. However, the S. elongatus amtB mutant could not concentrate [14C]methylammonium within the cells to the same extent as the wild type. Therefore, AmtB is necessary for full methylammonium uptake activity in S. elongatus. PMID- 17704223 TI - Inferring the evolutionary history of vibrios by means of multilocus sequence analysis. AB - We performed the first broad study aiming at the reconstruction of the evolutionary history of vibrios by means of multilocus sequence analysis of nine genes. Overall, 14 distinct clades were recognized using the SplitsTree decomposition method. Some of these clades may correspond to families, e.g., the clades Salinivibrio and Photobacteria, while other clades, e.g., Splendidus and Harveyi, correspond to genera. The common ancestor of all vibrios was estimated to have been present 600 million years ago. We can define species of vibrios as groups of strains that share >95% gene sequence similarity and >99.4% amino acid identity based on the eight protein-coding housekeeping genes. The gene sequence data were used to refine the standard online electronic taxonomic scheme for vibrios (http://www.taxvibrio.lncc.br). PMID- 17704222 TI - Changes in nucleoid morphology and origin localization upon inhibition or alteration of the actin homolog, MreB, of Vibrio cholerae. AB - MreB is an actin homolog required for the morphogenesis of most rod-shaped bacteria and for other functions, including chromosome segregation. In Caulobacter crescentus and Escherichia coli, the protein seems to play a role in the segregation of sister origins, but its role in Bacillus subtilis chromosome segregation is less clear. To help clarify its role in segregation, we have here studied the protein in Vibrio cholerae, whose chromosome I segregates like the one in C. crescentus and whose chromosome II like the one in E. coli or B. subtilis. The properties of Vibrio MreB were similar to those of its homologs in other bacteria in that it formed dynamic helical filaments, was essential for viability, and was inhibited by the drug A22. Wild-type (WT) cells exposed to A22 became spherical and larger. The nucleoids enlarged correspondingly, and the origin positions for both the chromosomes no longer followed any fixed pattern. However, the sister origins separated, unlike the situation in other bacteria. In mutants isolated as A22 resistant, the nucleoids in some cases appeared compacted even when the cell shape was nearly normal. In these cells, the origins of chromosome I were at the distal edges of the nucleoid but not all the way to the poles where they normally reside. The sister origins of chromosome II also separated less. Thus, it appears that the inhibition or alteration of Vibrio MreB can affect both the nucleoid morphology and origin localization. PMID- 17704224 TI - Influence of the hydrodynamic environment on quorum sensing in Pseudomonas aeruginosa biofilms. AB - We provide experimental and modeling evidence that the hydrodynamic environment can impact quorum sensing (QS) in a Pseudomonas aeruginosa biofilm. The amount of biofilm biomass required for full QS induction of the population increased as the flow rate increased. PMID- 17704227 TI - Proteomic characterization of the Rhodobacter sphaeroides 2.4.1 photosynthetic membrane: identification of new proteins. AB - The Rhodobacter sphaeroides intracytoplasmic membrane (ICM) is an inducible membrane that is dedicated to the major events of bacterial photosynthesis, including harvesting light energy, separating primary charges, and transporting electrons. In this study, multichromatographic methods coupled with Fourier transform ion cyclotron resonance mass spectrometry, combined with subcellular fractionation, was used to test the hypothesis that the photosynthetic membrane of R. sphaeroides 2.4.1 contains a significant number of heretofore unidentified proteins in addition to the integral membrane pigment-protein complexes, including light-harvesting complexes 1 and 2, the photochemical reaction center, and the cytochrome bc(1) complex described previously. Purified ICM vesicles are shown to be enriched in several abundant, newly identified membrane proteins, including a protein of unknown function (AffyChip designation RSP1760) and a possible alkane hydroxylase (RSP1467). When the genes encoding these proteins are mutated, specific photosynthetic phenotypes are noted, illustrating the potential new insights into solar energy utilization to be gained by this proteomic blueprint of the ICM. In addition, proteins necessary for other cellular functions, such as ATP synthesis, respiration, solute transport, protein translocation, and other physiological processes, were also identified to be in association with the ICM. This study is the first to provide a more global view of the protein composition of a photosynthetic membrane from any source. This protein blueprint also provides insights into potential mechanisms for the assembly of the pigment-protein complexes of the photosynthetic apparatus, the formation of the lipid bilayer that houses these integral membrane proteins, and the possible functional interactions of ICM proteins with activities that reside in domains outside this specialized bioenergetic membrane. PMID- 17704225 TI - Decoration of Pasteurella multocida lipopolysaccharide with phosphocholine is important for virulence. AB - Phosphocholine (PCho) is an important substituent of surface structures expressed by a number of bacterial pathogens. Its role in virulence has been investigated in several species, in which it has been shown to play a role in bacterial adhesion to mucosal surfaces, in resistance to antimicrobial peptides, or in sensitivity to complement-mediated killing. The lipopolysaccharide (LPS) structure of Pasteurella multocida strain Pm70, whose genome sequence is known, has recently been determined and does not contain PCho. However, LPS structures from the closely related, virulent P. multocida strains VP161 and X-73 were shown to contain PCho on their terminal galactose sugar residues. To determine if PCho was involved in the virulence of P. multocida, we used subtractive hybridization of the VP161 genome against the Pm70 genome to identify a four-gene locus (designated pcgDABC) which we show is required for the addition of the PCho residues to LPS. The proteins predicted to be encoded by pcgABC showed identity to proteins involved in choline uptake, phosphorylation, and nucleotide sugar activation of PCho. We constructed a P. multocida VP161 pcgC mutant and demonstrated that this strain produces LPS that lacks PCho on the terminal galactose residues. This pcgC mutant displayed reduced in vivo growth in a chicken infection model and was more sensitive to the chicken antimicrobial peptide fowlicidin-1 than the wild-type P. multocida strain. PMID- 17704226 TI - Glyceraldehyde-3-phosphate ferredoxin oxidoreductase from Methanococcus maripaludis. AB - The genome sequence of the non-sugar-assimilating mesophile Methanococcus maripaludis contains three genes encoding enzymes: a nonphosphorylating NADP(+) dependent glyceraldehyde-3-phosphate dehydrogenase (GAPN), glyceraldehyde-3 phosphate dehydrogenase (GAPDH), and glyceraldehyde-3-phosphate ferredoxin oxidoreductase (GAPOR); all these enzymes are potentially capable of catalyzing glyceraldehyde-3-phosphate (G3P) metabolism. GAPOR, whose homologs have been found mainly in archaea, catalyzes the reduction of ferredoxin coupled with oxidation of G3P. GAPOR has previously been isolated and characterized only from a sugar-assimilating hyperthermophile, Pyrococcus furiosus (GAPOR(Pf)), and contains the rare metal tungsten as an irreplaceable cofactor. Active recombinant M. maripaludis GAPOR (GAPOR(Mm)) was purified from Escherichia coli grown in minimal medium containing 100 muM sodium molybdate. In contrast, GAPOR(Mm) obtained from cells grown in medium containing tungsten (W) and W and molybdenum (Mo) or in medium without added W and Mo did not display any activity. Activity and transcript analysis of putative G3P-metabolizing enzymes and corresponding genes were performed with M. maripaludis cultured under autotrophic conditions in chemically defined medium. The activity of GAPOR(Mm) was constitutive throughout the culture period and exceeded that of GAPDH at all time points. As GAPDH activity was detected in only the gluconeogenic direction and GAPN activity was completely absent, only GAPOR(Mm) catalyzes oxidation of G3P in M. maripaludis. Recombinant GAPOR(Mm) is posttranscriptionally regulated as it exhibits pronounced and irreversible substrate inhibition and is completely inhibited by 1 muM ATP. With support from flux balance analysis, it is concluded that the major physiological role of GAPOR(Mm) in M. maripaludis most likely involves only nonoptimal growth conditions. PMID- 17704228 TI - The sbcDC locus mediates repression of type 5 capsule production as part of the SOS response in Staphylococcus aureus. AB - Most strains of Staphylococcus aureus produce one type of capsular polysaccharide that belongs to either type 5 or type 8. The production of these capsules has been shown to be regulated by various regulators. Here we report that the sbcD and sbcC genes are involved in the repression of type 5 capsule production. Chromosomal deletions in the sbcDC genes resulted in increased capsule promoter activity, capsule gene transcripts, and capsule production. The survival rates of the sbcDC deletion mutant were reduced upon UV irradiation compared to those for the wild-type strain Newman, suggesting that the genes are involved in DNA repair in S. aureus. The two genes were organized as an operon and were expressed very early in the exponential growth phase. A subinhibitory concentration of ciprofloxacin or mitomycin C induced sbcDC transcription but repressed the capsule promoter activity, suggesting that the sbcDC genes and the capsule genes are part of the SOS regulon. By reporter gene fusion and Northern blotting, we found that sbcDC regulated capsule by downregulating arl and mgr. Further genetic studies indicate that sbcDC functions upstream of arl and mgr in capsule regulation. Collectively, our results indicate that sbcDC, upon the SOS response, represses type 5 capsule production through an arl-mgr pathway. To our knowledge, this is the first demonstration that an SbcDC homolog was involved in transcriptional regulation. PMID- 17704229 TI - Diversity of bacteriocins and activity spectrum in Streptococcus pneumoniae. AB - The production of bacteriocins can be favorable for colonization of the host by eliminating other bacterial species that share the same environment. In Streptococcus pneumoniae, the pnc (blp) locus encoding putative bacteriocins, immunity, and export proteins is controlled by a two-component system similar to the comCDE system required for the induction of genetic competence. A detailed comparison of the pnc clusters of four genetically distinct isolates confirmed the great plasticity of this locus and documented several repeat sequences. Members of the multiple-antibiotic-resistant Spain23F-1 clone, one member of the Spain9V-3 clone, sensitive 23F strain 2306, and the TIGR4 strain produced bactericidal substances active against other gram-positive bacteria and in some cases against S. pneumoniae as well. However, other strains did not show activity against the indicator strains despite the presence of a bacteriocin cluster, indicating that other factors are required for bacteriocin activity. Analysis of strain 2306 and mutant derivatives of this strain confirmed that bacteriocin production was dependent on the two-component regulatory system and genes involved in bacteriocin transport and processing. At least one other bacteriocin gene, pncE, is located elsewhere on the chromosome and might contribute to the bacteriocin activity of this strain. PMID- 17704230 TI - Dual regulation role of GH3.5 in salicylic acid and auxin signaling during Arabidopsis-Pseudomonas syringae interaction. AB - Salicylic acid (SA) plays a central role in plant disease resistance, and emerging evidence indicates that auxin, an essential plant hormone in regulating plant growth and development, is involved in plant disease susceptibility. GH3.5, a member of the GH3 family of early auxin-responsive genes in Arabidopsis (Arabidopsis thaliana), encodes a protein possessing in vitro adenylation activity on both indole-3-acetic acid (IAA) and SA. Here, we show that GH3.5 acts as a bifunctional modulator in both SA and auxin signaling during pathogen infection. Overexpression of the GH3.5 gene in an activation-tagged mutant gh3.5 1D led to elevated accumulation of SA and increased expression of PR-1 in local and systemic tissues in response to avirulent pathogens. In contrast, two T-DNA insertional mutations of GH3.5 partially compromised the systemic acquired resistance associated with diminished PR-1 expression in systemic tissues. The gh3.5-1D mutant also accumulated high levels of free IAA after pathogen infection and impaired different resistance-gene-mediated resistance, which was also observed in the GH3.6 activation-tagged mutant dfl1-D that impacted the auxin pathway, indicating an important role of GH3.5/GH3.6 in disease susceptibility. Furthermore, microarray analysis showed that the SA and auxin pathways were simultaneously augmented in gh3.5-1D after infection with an avirulent pathogen. The SA pathway was amplified by GH3.5 through inducing SA-responsive genes and basal defense components, whereas the auxin pathway was derepressed through up regulating IAA biosynthesis and down-regulating auxin repressor genes. Taken together, our data reveal novel regulatory functions of GH3.5 in the plant pathogen interaction. PMID- 17704231 TI - Yeast-plant coupled vector system for identification of nuclear proteins. AB - Nuclear proteins are involved in many critical biological processes within plant cells and, therefore, are in the focus of studies that usually begin with demonstrating that the protein of interest indeed exhibits nuclear localization. Thus, studies of plant nuclear proteins would be facilitated by a convenient experimental system for identification of proteins that are actively imported into the cell nucleus and visualization of their nuclear accumulation in vivo. To this end, we developed a system of vectors that allows screening for cDNAs coding for nuclear proteins in a simple genetic assay in yeast cells, and verification of nuclear accumulation in planta following one-step transfer and autofluorescent tagging of the identified clones into a multiple cloning site-compatible and reading frame-compatible plant expression vector. In a recommended third experimental step, the plant expression cassette containing the identified clone can be transferred, also by a one-step cloning, into a binary multigene expression vector for transient or stable coexpression with any other proteins. PMID- 17704233 TI - Genetic and molecular regulation by DELLA proteins of trichome development in Arabidopsis. AB - Gibberellins (GA) are known to influence phase change in Arabidopsis (Arabidopsis thaliana) as well as the development of trichomes, which are faithful epidermal markers of shoot maturation. They modulate these developmental programs in part by antagonizing DELLA repressors of growth, GIBBERELLIC ACID INSENSITIVE (GAI) and REPRESSOR OF ga1-3 (RGA). In this study, we have probed the relative roles played by RGA, GAI, and two homologs, RGA-LIKE1 (RGL1) and RGL2, in these processes and investigated molecular mechanisms through which they influence epidermal differentiation. We found that the DELLAs act collectively to regulate trichome initiation on all aerial organs and that the onset of their activity is accompanied by the repression of most genes known to regulate trichome production. These effects are consistent with the results of genetic analysis, which conclusively place theses genes downstream of the DELLAs. We find that repression of trichome regulatory genes is rapid, but involves an indirect, rather than a direct, molecular mechanism, which requires de novo protein synthesis. DELLA activity also influences postinitiation events and we show that GAI is a major repressor of trichome branching, a role in which it is antagonized by RGL1 and RGL2. Finally, we report that, in contrast to most other effects, the repression by GA applications of flower trichome initiation is not dependent on RGA, GAI, RGL1, or RGL2. In summary, our data show that DELLA proteins are central to trichome development in Arabidopsis and that their effect can be largely explained by their transcriptional influence on trichome initiation activators. PMID- 17704232 TI - Golgi regeneration after brefeldin A treatment in BY-2 cells entails stack enlargement and cisternal growth followed by division. AB - Brefeldin A (BFA) treatment stops secretion and leads to the resorption of much of the Golgi apparatus into the endoplasmic reticulum. This effect is reversible upon washing out the drug, providing a situation for studying Golgi biogenesis. In this investigation Golgi regeneration in synchronized tobacco BY-2 cells was followed by electron microscopy and by the immunofluorescence detection of ARF1, which localizes to the rims of Golgi cisternae and serves as an indicator of COPI vesiculation. Beginning as clusters of vesicles that are COPI positive, mini Golgi stacks first become recognizable 60 min after BFA washout. They continue to increase in terms of numbers and length of cisternae for a further 90 min before overshooting the size of control Golgi stacks. As a result, increasing numbers of dividing Golgi stacks were observed 120 min after BFA washout. BFA-regeneration experiments performed on cells treated with BFA (10 microg mL(-1)) for only short periods (30-45 min) showed that the formation of ER-Golgi hybrid structures, once initiated by BFA treatment, is an irreversible process, the further incorporation of Golgi membranes into the ER continuing during a subsequent drug washout. Application of the protein kinase A inhibitor H-89, which effectively blocks the reassembly of the Golgi apparatus in mammalian cells, also prevented stack regeneration in BY-2 cells, but only at very high, almost toxic concentrations (>200 microm). Our data suggest that under normal conditions mitosis-related Golgi stack duplication may likely occur via cisternal growth followed by fission. PMID- 17704234 TI - Heat suppresses activation of an auxin-responsive promoter in cultured guard cell protoplasts of tree tobacco. AB - Cultured guard cell protoplasts (GCP) of tree tobacco (Nicotiana glauca) comprise a novel system for investigating the cell signaling mechanisms that lead to acquired thermotolerance and thermoinhibition. At 32 degrees C in a medium containing an auxin (1-naphthaleneacetic acid [NAA]) and a cytokinin (6 benzylaminopurine), GCP expand, regenerate cell walls, dedifferentiate, and divide. At 38 degrees C, GCP acquire thermotolerance within 24 h, but their expansion is limited and they neither regenerate walls nor reenter the cell cycle. These putative indicators of auxin insensitivity led us to hypothesize that heat suppresses induction of auxin-regulated genes in GCP. Protoplasts were transformed with BA-mgfp5-ER, in which the BA auxin-responsive promoter regulates transcription of mgfp5-ER encoding thermostable green fluorescent protein (GFP) or with a similar 35S-cauliflower mosaic virus constitutive promoter construct. Heat suppressed NAA-mediated activation of BA. After 21 h at 32 degrees C in media with NAA, 49.0% +/- 3.9% of BA-mgfp5-ER transformants strongly expressed GFP; expression percentages were similar to those of 35S-mgfp5-ER transformants at 32 degrees C or 38 degrees C. After 21 h at 38 degrees C in media with NAA, 7.9% +/- 1.6% of BA-mgfp5-ER transformants weakly expressed GFP, similar to GCP cultured at 32 degrees C in media lacking NAA. Expression at 38 degrees C was not increased by incubating for 48 h or increasing NAA concentrations 20-fold. After 9 to 12 h at 38 degrees C, BA was no longer activated when cells were transferred to 32 degrees C. Heat-stressed cells accumulate reactive oxygen species, and hydrogen peroxide (H(2)O(2)) suppresses auxin-responsive promoter activation in Arabidopsis (Arabidopsis thaliana) mesophyll protoplasts. H(2)O(2) did not suppress BA activation at 32 degrees C, nor did superoxide and H(2)O(2) scavengers prevent BA suppression at 38 degrees C. PMID- 17704235 TI - AtHIPM, an ortholog of the apple HrpN-interacting protein, is a negative regulator of plant growth and mediates the growth-enhancing effect of HrpN in Arabidopsis. AB - HrpN (harpin) protein is critical to the virulence of the fire blight pathogen Erwinia amylovora in host plants like apple (Malus x domestica). Moreover, exogenous treatment of Arabidopsis (Arabidopsis thaliana), a nonhost plant, with partially purified HrpN enhances growth. To address the bases of the effects of HrpN in disease, we sought a HrpN-interacting protein(s) in apple, using a yeast two-hybrid assay. A single positive clone, designated HIPM (HrpN-interacting protein from Malus), was found. HIPM, a 6.5-kD protein, interacted with HrpN in yeast and in vitro. Deletion analysis showed that the N-terminal 198 of 403 amino acids of HrpN are required for interaction with HIPM. HIPM orthologs were found in Arabidopsis (AtHIPM) and rice (Oryza sativa; OsHIPM). HrpN also interacted with AtHIPM in yeast and in vitro. In silico analyses revealed that the three plant proteins contain putative signal peptides and putative transmembrane domains. We showed that both HIPM and AtHIPM have functional signal peptides, and green fluorescent protein-tagged HIPM and AtHIPM associated, in clusters, with plasma membranes. Both HIPM and AtHIPM are expressed constitutively; however, they are expressed more strongly in apple and Arabidopsis flowers than in leaves and stems. The size of AtHIPM knockout mutant plants of Arabidopsis was slightly larger than the wild-type plants. Interestingly, the knockout mutant did not exhibit enhanced plant growth in response to treatment with HrpN. Overexpression of AtHIPM conversely resulted in smaller plants. These results indicate that AtHIPM functions as a negative regulator of plant growth and mediates enhanced growth that results from treatment with HrpN. PMID- 17704236 TI - Transcriptional profiling of high pigment-2dg tomato mutant links early fruit plastid biogenesis with its overproduction of phytonutrients. AB - Phenotypes of the tomato (Solanum lycopersicum) high pigment-2(dg) (hp-2(dg)) and hp-2(j) mutants are caused by lesions in the gene encoding DEETIOLATED1, a negative regulator of light signaling. Homozygous hp-2(dg) and hp-2(j) plants display a plethora of distinctive developmental and metabolic phenotypes in comparison to their normal isogenic counterparts. These mutants are, however, best known for the increased levels of carotenoids, primarily lycopene, and other plastid-accumulating functional metabolites. In this study we analyzed the transcriptional alterations in mature-green, breaker, and early red fruits of hp 2(dg)/hp-2(dg) plants in relation to their normal counterparts using microarray technology. Results show that a large portion of the genes that are affected by hp-2(dg) mutation display a tendency for up- rather than down-regulation. Ontology assignment of these differentially regulated transcripts revealed a consistent up-regulation of transcripts related to chloroplast biogenesis and photosynthesis in hp-2(dg) mutants throughout fruit ripening. A tendency of up regulation was also observed in structural genes involved in phytonutrient biosynthesis. However, this up-regulation was not as consistent, positioning plastid biogenesis as an important determinant of phytonutrient overproduction in hp-2(dg) and possibly other hp mutant fruits. Microscopic observations revealed a highly significant increase in chloroplast size and number in pericarp cells of mature-green hp-2(dg)/hp-2(dg) and hp-2(j)/hp-2(j) fruits in comparison to their normal counterparts. This increase could be observed from early stages of fruit development. Therefore, the molecular trigger that drives phytonutrient overproduction in hp-2(dg) and hp-2(j) mutant fruits should be initially traced at these early stages. PMID- 17704237 TI - From Avicennia to Zizania: seed recalcitrance in perspective. AB - BACKGROUND: Considered only in terms of tolerance of, or sensitivity to, desiccation (which is an oversimplification), orthodox seeds are those which tolerate dehydration and are storable in this condition, while highly recalcitrant seeds are damaged by loss of only a small proportion of water and are unstorable for practical purposes. Between these extremes, however, there may be a gradation of the responses to dehydration--and also to other factors- suggesting perhaps that seed behaviour might be best considered as constituting a continuum subtended by extreme orthodoxy and the highest degree of recalcitrance. As the characteristics of seeds of an increasing number of species are elucidated, non-orthodox seed behaviour is emerging as considerably more commonplace--and its basis far more complex--than previously suspected. SCOPE: Whatever the post-harvest responses of seeds of individual species may be, they are the outcome of the properties of pre-shedding development, and a full understanding of the subtleties of various degrees of non-orthodox behaviour must await the identification of, and interaction among, all the factors conferring extreme orthodoxy. Appreciation of the phenomenon of recalcitrance is confounded by intra- and interseasonal variability across species, as well as within individual species. However, recent evidence suggests that provenance is a pivotal factor in determining the degree of recalcitrant behaviour exhibited by seeds of individual species. Non-orthodox--and, in particular, recalcitrant--seed behaviour is not merely a matter of desiccation sensitivity: the primary basis is that the seeds are actively metabolic when they are shed, in contrast to orthodox types which are quiescent. This affects all aspects of the handling and storage of recalcitrant seeds. In the short to medium term, recalcitrant seeds should be stored in as hydrated a condition as when they are shed, and at the lowest temperature not diminishing vigour or viability. Such hydrated storage has attendant problems of fungal proliferation which, unless minimized, will inevitably and significantly affect seed quality. The life span of seeds in hydrated storage even under the best conditions is variable among species, but is curtailed (days to months), and various approaches attempting to extend non orthodox seed longevity are discussed. Conservation of the genetic resources by means other than seed storage is then briefly considered, with detail on the potential for, and difficulties with, cryostorage highlighted. CONCLUSIONS: There appears to be little taxonomic relationship among species exhibiting the phenomenon of seed recalcitrance, suggesting that it is a derived trait, with tolerance having been lost a number of times. Although recalcitrant seededness is best represented in the mesic tropics, particularly among rainforest climax species, it does occur in cooler, drier and markedly seasonal habitats. The selective advantages of the trait are considered. PMID- 17704238 TI - A century of B chromosomes in plants: so what? AB - BACKGROUND: Supernumerary B chromosomes (Bs) are a major source of intraspecific variation in nuclear DNA amounts in numerous species of plants. They favour large genomes, and create polymorphisms for DNA variation in natural populations. By studying Bs we can gain useful knowledge about the organization, function and evolution of genomes. There are also significant biological questions concerning the origin and structural organization of Bs, and the way in which these selfish elements can establish themselves by exploiting the replicative machinery of their host genome nucleus. SCOPE: It is a sine qua non that Bs originate from the A chromosomes, in a variety of ways. We can study their modes of drive and ask how it is that chromosomes which apparently lack genes can have control over their own drive process which leads to their survival in natural populations. Molecular cytogenetic studies are opening up new avenues of investigation. Population equilibria for B frequencies are determined by a balance between accumulation and harmful effects. Bs are also subject to meiotic loss due to polysomy and to elimination at meiosis as univalents. These balancing forces can be seen in the context of host/parasite interaction, based on a dissection of the genetic elements in both As and Bs (in maize) which interact to bring about a stable equilibrium, at least for a snapshot in time. CONCLUSIONS: Aside from their intrinsic enigmatic properties, B chromosomes make useful experimental tools to study genome organization. Thus far they have not been exploited for their applications, other than through the use of A-B translocations used for gene mapping in maize; but there are opportunities to use them to modulate the frequency and distribution of recombination, to diploidize allopolyploids, to study centromeres and to be developed as plant artificial chromosomes; given that they can be structurally modified and their inheritance stabilized. PMID- 17704239 TI - Clinical applications of PET in brain tumors. AB - Malignant gliomas and metastatic tumors are the most common brain tumors. Neuroimaging plays a significant role clinically. In low-grade tumors, neuroimaging is needed to evaluate recurrent disease and to monitor anaplastic transformation into high-grade tumors. In high-grade and metastatic tumors, the imaging challenge is to distinguish between recurrent tumor and treatment-induced changes such as radiation necrosis. The current clinical gold standard, MRI, provides superior structural detail but poor specificity in identifying viable tumors in brain treated with surgery, radiation, or chemotherapy. (18)F-FDG PET identifies anaplastic transformation and has prognostic value. The sensitivity and specificity of (18)F-FDG in evaluating recurrent tumor and treatment-induced changes can be improved significantly by co-registration with MRI and potentially by delayed imaging 3-8 h after injection. Amino acid PET tracers are more sensitive than (18)F-FDG in imaging recurrent tumors and in particular recurrent low-grade tumors. They are also promising in differentiating between recurrent tumors and treatment-induced changes. PMID- 17704240 TI - microPET-based biodistribution of quantum dots in living mice. AB - This study evaluates the quantitative biodistribution of commercially available CdSe quantum dots (QD) in mice. METHODS: (64)Cu-Labeled 800- or 525-nm emission wavelength QD (21- or 12-nm diameter), with or without 2,000 MW (molecular weight) polyethylene glycol (PEG), were injected intravenously into mice (5.55 MBq/25 pmol QD) and studied using well counting or by serial microPET and region of-interest analysis. RESULTS: Both methods show rapid uptake by the liver (27.4 38.9 %ID/g) (%ID/g is percentage injected dose per gram tissue) and spleen (8.0 12.4 %ID/g). Size has no influence on biodistribution within the range tested here. Pegylated QD have slightly slower uptake into liver and spleen (6 vs. 2 min) and show additional low-level bone uptake (6.5-6.9 %ID/g). No evidence of clearance from these organs was observed. CONCLUSION: Rapid reticuloendothelial system clearance of QD will require modification of QD for optimal utility in imaging living subjects. Formal quantitative biodistribution/imaging studies will be helpful in studying many types of nanoparticles, including quantum dots. PMID- 17704242 TI - Role of 99mTc-octreotide acetate scintigraphy in suspected lung cancer compared with 18F-FDG dual-head coincidence imaging. AB - The aim of this study was to evaluate the clinical value of tomographic (99m)Tc octreotide acetate (hereafter, (99m)Tc-octreotide) scintigraphy in the detection of patients with suspected lung cancer in comparison with that of (18)F-FDG dual head coincidence imaging (DHC). METHODS: Forty-four consecutive patients with suspected pulmonary neoplasms underwent tomographic (99m)Tc-octreotide scintigraphy and (18)F-FDG coincidence imaging using the same gantry. The region of interest was drawn on the entire primary lesion. The tumor-to-normal tissue tracer values for both (99m)Tc-octreotide and (18)F-FDG were determined using region of interests and expressed as T/N(r) and T/N(m), respectively. Final diagnosis was confirmed by histopathologic analysis or clinical follow-up. RESULTS: Thirty-one of the 44 patients had lung cancer-6 with small cell lung cancer (SCLC) and 25 with non-small cell lung cancer (NSCLC). Thirteen of the 44 patients had benign lung lesions. The sensitivity, specificity, positive predictive value, and negative predictive value of (99m)Tc-octreotide were 100%, 75.7%, 90.1%, and 100%, respectively, and of (18)F-FDG DHC were 100%, 46.1%, 83.8%, and 100%, respectively. In the 31 patients with malignant tumors, all 38 abnormal lymph nodes in 20 patients showed abnormal high focal uptake of (18)F FDG; only 7 patients with 10 regional lymph adenopathies showed moderate uptake of (99m)Tc-octreotide. Thirteen patients with 39 distant sites of abnormal uptake visualized (imaging stage IV) with (99m)Tc-octreotide included 2 patients with brain metastases, 6 patients with pleural invasion and multiple bone metastasis, 2 patients with contralateral internal lung metastasis and pleural invasion, and 3 patients with only multiple bone metastasis. The final diagnosis was confirmed by histopathology or clinical follow-up. CONCLUSION: The sensitivity of (99m)Tc octreotide for the detection of lung cancer at the primary lesion was comparable with that of (18)F-FDG coincidence imaging. Tomographic (99m)Tc-octreotide scintigraphy had lower sensitivity for the detection of hilar and mediastinal lymph node metastasis compared with that of (18)F-FDG coincidence PET, but it had high sensitivity for the detection of remote metastatic lesions. However, because of the small population, further investigation is necessary. PMID- 17704241 TI - Influence of chelate conjugation on a newly identified tumor-targeting peptide. AB - The transfer of peptide sequences identified by screening of phage-displayed libraries to clinical application is often difficult. This study investigated whether coupling of a new peptide, FROP-1, to the chelator 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) resulted in structural restriction and, consequently, improved binding and stability. METHODS: The peptide FROP-1 was coupled to the chelator DOTA and labeled with (111)In. The structural changes caused by the addition of the chelator were determined by circular dichroism. The properties of this modified peptide were investigated in in vitro binding assays and monitored for kinetics, competition, and internalization as well as serum stability. A cell-type binding profile was established and the in vivo biodistribution was evaluated in a nude mouse model. RESULTS: When compared with the free peptide without chelator, FROPDOTA revealed different cellular uptake kinetics, reaching a maximum at 2 h in vitro. The cells completely accumulated the tracer, and competition experiments revealed that 99.4% (FRO82-2 cells), 98.6% (MCF-7 cells), or 99.3% (average for 3 primary head and neck tumor cell lines) of tracer accumulation could be suppressed, revealing the specificity of this process. The internalization kinetics determined in MCF-7 cells supported this finding: After an incubation time of 180 min, the major fraction of FROPDOTA was trapped intracellularly. Serum stability experiments revealed an increase in stability due to the chelator, with a half-life of 71 min. Circular dichroism measurements indicated a fixed alpha-helix structure of FROPDOTA representing a strong change in secondary structure. In competition binding experiments, the binding constant (K(D)) to FRO82-2 cells was determined to be 494 nM. Despite this avid binding affinity, the binding kinetics were found to be too slow to induce an uptake in vivo before clearance. Consequently, the biodistribution revealed a rapid renal and hepatobiliary clearance, with blood levels dropping from 5.48 +/- 0.26 %ID/g (percentage injected dose per gram) 5 min after injection to 0.77 +/- 0.15 %ID/g at 135 min after injection. CONCLUSION: This study revealed that peptides that are identified by display techniques may be underrated. Careful alteration of their structure will permit going beyond the possibilities that the limited pool of naturally occurring peptides provide for tumor targeting. PMID- 17704243 TI - Validation of an extracerebral reference region approach for the quantification of brain nicotinic acetylcholine receptors in squirrel monkeys with PET and 2-18F fluoro-A-85380. AB - The aim of the present study was to explore the applicability of an extracerebral reference region for the quantification of cerebral receptors with PET. METHODS: Male squirrel monkeys underwent quantitative PET studies of cerebral nicotinic acetylcholine receptors (nAChRs) with 2-(18)F-fluoro-A-85380 (2-FA). Data from dynamic PET scans were analyzed with various compartment- and non-compartment based models, including a simplified reference tissue model (SRTM). Nondisplaceable volume-of-distribution (VDnd) values were determined in regions of interest after the blockade of 2-FA-specific binding by nicotine infusion. Binding potential values, estimated with the cerebellum and muscle as reference regions, were compared and the reproducibility of measurements was determined. RESULTS: One- and 2-tissue-compartment modeling and linear graphic analysis provided similar total volume-of-distribution (VD(T)) values for each studied region. VD(T) values were high in the thalamus, intermediate in the cortex and midbrain, and low in the cerebellum and muscle, consistent with the distribution pattern of nAChR containing alpha(4) and beta(2) receptor subunits (alpha(4)beta(2)*). The administration of nicotine at 2 mg/kg/d via an osmotic pump resulted in a nearly complete saturation of 2-FA-specific binding and led to very small changes in volumes of distribution in the cerebellum and muscle (-9% +/- 4% [mean +/- SEM] and 0% +/- 6%, respectively), suggesting limited specific binding of the radioligand in these areas. VD(T) measured in muscle in 15 monkeys was reasonably constant (3.0 +/- 0.2, with a coefficient of variation of 8%). VDnd in studied brain regions exceeded VD(T) in muscles by a factor of 1.3. With this factor and with muscle as a reference region, BP* values calculated for studied brain regions with the SRTM were in good agreement with those obtained with the cerebellum as a reference region. Significant correlations were observed between BP* values estimated with these 2 approaches. The reproducibilities of BP* measurements obtained with the 2 methods were comparable, with coefficients of variation of less than 11% and 13% for the thalamus and the cortex, respectively. CONCLUSION: These results suggest that the accurate quantification of nAChRs can be performed with 2-FA and a reference region outside the brain, providing a novel approach for the quantification of brain receptors when no suitable cerebral reference region is available. PMID- 17704244 TI - Detection of secondary thalamic degeneration after cortical infarction using cis 4-18F-fluoro-D-proline. AB - The amino acid cis-4-(18)F-fluoro-D-proline (D-cis-(18)F-FPro) exhibits preferential uptake in the brain compared with its L-isomer, but the clinical potential of the tracer is as yet unknown. In this study we explored the cerebral uptake of D-cis-(18)F-FPro in rats with focal cortical infarctions. METHODS: Focal cortical infarctions were induced in different areas of the cortex of 20 Fisher CDF rats by photothrombosis (PT). At variable time points after PT (1 d to 4 wk), the rats were injected intravenously with D-cis-(18)F-FPro. For comparison, 12 rats were injected simultaneously with (3)H-deoxyglucose ((3)H DG), 3 rats were injected with (3)H-methyl-L-methionine ((3)H-MET), and 2 rats were injected with (3)H-PK11195. Within 2 h after injection of the tracers, coronal cryosections of the brains were produced and evaluated by dual-tracer autoradiography. Lesion-to-brain ratios (L/B ratios) were calculated by dividing the maximal uptake in areas with increased tracer uptake by the mean uptake in normal brain tissue. Histologic slices were stained by toluidine blue and by immunostainings for glial fibrillary acidic protein (GFAP), CD68 for macrophages, and CD11b for microglia. RESULTS: Prominent uptake of D-cis-(18)F-FPro was found in ipsilateral thalamic nuclei (TN) and partially in the corpus striatum starting at 3 d after infarction with increasing L/B ratios up to 4 wk (mean L/B ratio +/- SD, 6.7 +/- 3.5). The involved TN varied with the site of the cortical lesion corresponding to their thalamocortical projections connecting them with their specific target region in the cerebral cortex. The TN were positive for CD11b and GFAP from day 7 onward, whereas uptake of (3)H-DG, (3)H-MET, and (3)H-PK11195 and immunostaining for CD68 were similar to that of normal brain. Furthermore, increased uptake of D-cis-(18)F-FPro was found in the area of the cortical infarctions (mean L/B ratio +/- SD, 12.1 +/- 8.1). From day 5 onward, the pattern of uptake was congruent with that of immunostaining for CD11b and CD68 but was different from that of GFAP. CONCLUSION: D-cis-(18)F-FPro appears to be a sensitive PET tracer for detection of secondary degeneration of TN after cortical injury. The uptake mechanisms of D-cis-(18)F-FPro remain to be elucidated, but the relationship to microglial activation suggests a diagnostic potential in various brain diseases. PMID- 17704245 TI - Application of 99mTc-pertechnetate scintigraphy to microvascular autologous transplantation of the submandibular gland in patients with severe keratoconjunctivitis sicca. AB - Our objective was to evaluate the role of (99m)Tc-pertechnetate scintigraphy on microvascular autologous transplantation of the submandibular gland in patients with severe keratoconjunctivitis sicca (KCS). METHODS: (99m)Tc-Pertechnetate scintigraphy was performed on 106 patients with severe KCS. The patients were examined before surgery and at 1 wk and 3 mo afterward using a standardized protocol that included static scintigrams, time-activity curves, and delayed scintigrams to check the function and secretion of the major salivary glands. The scintigraphic findings were assessed visually. When possible, the scintigraphic findings were compared with the clinical appearance of the transplanted gland. RESULTS: The function of all 4 major salivary glands was almost completely lost in 10 patients, indicating that these patients were not suitable for transplantation. The other 96 patients were treated by autologous transplantation of the submandibular gland. In 14 patients, the function of the major salivary glands was below normal. One patient's scintigram, obtained on the second day after surgery, showed no uptake of (99m)Tc-pertechnetate in the transplanted gland. Surgical exploration showed embolism of the artery of the transplanted gland. Scintigraphy was performed 1 wk after surgery in 90 patients. There was no uptake of (99m)Tc-pertechnetate in the temporal region in 8 patients, indicating that the glands were not revascularized. Scintigraphy showed obvious uptake of (99m)Tc-pertechnetate in the temporal region of the other 82 patients, indicating that the transplanted glands were viable. At more than 3 mo after surgery, scintigraphy was again performed on 30 patients. Scintigraphy after a 120-min delay showed that (99m)Tc-pertechnetate drained into the orbit through the duct of the transplanted gland in 26 patients. However, no secretion into the orbit was found in 4 patients, indicating obstruction of the duct. CONCLUSION: Scintigraphy plays an important role in microvascular autologous transplantation of the submandibular gland in patients with severe KCS. Scintigraphy can be used to select patients and donor glands, to evaluate the viability of the graft, and to check the patency of Wharton's duct of the transplanted gland. PMID- 17704246 TI - A transfectant mosaic xenograft model for evaluation of targeted radiotherapy in combination with gene therapy in vivo. AB - For gene therapy to be efficacious in the treatment of cancer, therapeutic transgenes must be limited in their expression to tumor cells and must be expressed at sufficiently high transcriptional levels. Moreover, the inadequacy of gene delivery must be overcome by induction of toxicity to neighboring nontargeted cells. Combining targeted radionuclide therapy with gene therapy using human telomerase promoters has shown promise in these respects, and the efficacy of this scheme has been assessed in vitro using transfectant mosaic tumor spheroids. To enable the evaluation of targeted radiotherapy combined with gene transfer in vivo, we have developed a transfectant mosaic xenograft (TMX) model. METHODS: Human telomerase promoters were used to drive expression of the noradrenaline transporter (NAT) transgene in 2 human cell lines (UVW and EJ138). Promoter activity was assessed in xenografts in nude mice by determination of the uptake of the radiopharmaceutical (131)I-metaiodobenzylguanidine ((131)I-MIBG) and by measurement of tumor growth. The efficacy of (131)I-MIBG treatment was also assessed in TMXs to determine the delay in growth of tumors composed of various proportions of NAT-expressing cells-a likely clinical scenario after gene delivery in vivo. RESULTS: In terms of induction of the capacity for active uptake of (131)I-MIBG and the resultant inhibition of tumor growth in vivo, both telomerase promoters (hTR and hTERT) were similar in potency to the CMV (cytomegalovirus) promoter as controlling elements for the expression of the NAT transgene. In TMXs derived from UVW and EJ138 cells, (131)I-MIBG uptake was proportional to NAT gene expression (r(s) = 0.910, P < 0.001 for UVW; r(s) = 0.971, P < 0.001 for EJ138). Inhibition of the growth of these tumors correlated with the fraction of NAT-transfected cells (r(s) = 0.910, P < 0.001 for UVW; r(s) = 0.971, P < 0.001 for EJ138), and substantial tumor growth delay was observed when 5% of the xenograft was composed of NAT-positive cells. CONCLUSION: TMXs constitute a suitable model to measure the efficacy of cancer gene therapy strategies when <100% of the tumor mass can be targeted to express the therapeutic transgene. PMID- 17704248 TI - Performance measurement of the microPET focus 120 scanner. AB - The microPET Focus 120 scanner is a third-generation animal PET scanner dedicated to rodent imaging. Here, we report the results of scanner performance testing. METHODS: A (68)Ge point source was used to measure energy resolution, which was determined for each crystal and averaged. Spatial resolution was measured using a (22)Na point source with a nominal size of 0.25 mm at the system center and various off-center positions. Absolute sensitivity without attenuation was determined by extrapolating the data measured using an (18)F line source and multiple layers of absorbers. Scatter fraction and counting rate performance were measured using 2 different cylindric phantoms simulating rat and mouse bodies. Sensitivity, scatter fraction, and noise equivalent counting rate (NECR) experiments were repeated under 4 different conditions (energy window, 250 approximately 750 keV or 350 approximately 650 keV; coincidence window, 6 or 10 ns). A performance phantom with hot-rod inserts of various sizes was scanned, and several animal studies were also performed. RESULTS: Energy resolution at a 511 keV photopeak was 18.3% on average. Radial, tangential, and axial resolution of images reconstructed with the Fourier rebinning (FORE) and filtered backprojection (FBP) algorithms were 1.18 (radial), 1.13 (tangential), and 1.45 mm full width at half maximum (FWHM) (axial) at center and 2.35 (radial), 1.66 (tangential), and 2.00 mm FWHM (axial) at a radial offset of 2 cm. Absolute sensitivities at transaxial and axial centers were 7.0% (250 approximately 750 keV, 10 ns), 6.7% (250 approximately 750 keV, 6 ns), 4.0% (350 approximately 650 keV, 10 ns), and 3.8% (350 approximately 650 keV, 6 ns). Scatter fractions were 15.9% (mouse phantom) and 35.0% (rat phantom) for 250 approximately 750 keV and 6 ns. Peak NECR was 869 kcps at 3,242 kBq/mL (mouse phantom) and 228 kcps at 290 kBq/mL (rat phantom) at 250 approximately 750 keV and 6 ns. Hot-rod inserts of 1.6-mm diameter were clearly identified, and animal studies illustrated the feasibility of this system for studies of whole rodents and mid-sized animal brains. CONCLUSION: The results of this independent field test showed the improved physical characteristics of the F120 scanner over the previous microPET series systems. This system will be useful for imaging studies on small rodents and brains of larger animals. PMID- 17704247 TI - Doxorubicin enhances the expression of transgene under control of the CMV promoter in anaplastic thyroid carcinoma cells. AB - We investigated the effect of doxorubicin on transgene expression and evaluated the mechanism of enhanced transgene expression by doxorubicin in transfected human anaplastic thyroid cancer cells (ARO cells). METHODS: ARO cells were transfected with plasmid vectors or adenoviral vectors expressing human sodium/iodide symporter (hNIS) or luciferase (Luc) under the control of cytomegalovirus (CMV) promoter. After treating transfected and control ARO cells with doxorubicin, iodide uptake assay and luciferase assay were performed. Reversed-phase polymerase chain reaction analysis for hNIS and Western blot analysis for IkappaB protein were executed. Electrophoretic mobility-shift assay (EMSA) was performed to evaluate nuclear factor-kappaB (NF-kappaB) binding activity induced by doxorubicin. Scintigraphic and bioluminescent images were acquired and quantitated before and after doxorubicin in a tumor-bearing mouse model. RESULTS: Radioiodide uptake in ARO cells transfected with the NIS gene under the CMV promoter was remarkably enhanced by doxorubicin, and this corresponded to a significant increase in NIS messenger RNA. In addition, luciferase gene upregulation by doxorubicin was also observed in luciferase gene transfected ARO cells. These results were verified by in vivo imaging in a tumor bearing mouse model. Moreover, transgene expressional enhancement by doxorubicin was observed after transfecting ARO cells with adenoviral vector or plasmid vector, when transgenes were under the control of a CMV promoter. In addition, NF kappaB, activated by doxorubicin, induced transgene transcription under the control of the CMV promoter, which possesses an NF-kappaB binding site. CONCLUSION: These findings indicate that doxorubicin enhances transgene expression under the control of the CMV promoter and that doxorubicin might be used as an adjuvant to radioiodine therapy by NIS gene transfer in anaplastic thyroid carcinoma. PMID- 17704250 TI - Early prediction of response to chemotherapy and survival in malignant pleural mesothelioma using a novel semiautomated 3-dimensional volume-based analysis of serial 18F-FDG PET scans. AB - The aim of chemotherapy for mesothelioma is to palliate symptoms and improve survival. Measuring response using CT is challenging because of the circumferential tumor growth pattern. This study aims to evaluate the role of serial (18)F-FDG PET in the assessment of response to chemotherapy in patients with mesothelioma. METHODS: Patients were prospectively recruited and underwent both (18)F-FDG PET and conventional radiological response assessment before and after 1 cycle of chemotherapy. Quantitative volume-based (18)F-FDG PET analysis was performed to obtain the total glycolytic volume (TGV) of the tumor. Survival outcomes were measured. RESULTS: Twenty-three patients were suitable for both radiological and (18)F-FDG PET analysis, of whom 20 had CT measurable disease. After 1 cycle of chemotherapy, 7 patients attained a partial response and 13 had stable disease on CT assessment by modified RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In the 7 patients with radiological partial response, the median TGV on quantitative PET analysis fell to 30% of baseline (range, 11% 71%). After 1 cycle of chemotherapy, Cox regression analysis demonstrated a statistically significant relationship between a fall in TGV and improved patient survival (P = 0.015). Neither a reduction in the maximum standardized uptake value (P = 0.097) nor CT (P = 0.131) demonstrated a statistically significant association with patient survival. CONCLUSION: Semiquantitative (18)F-FDG PET using the volume-based parameter of TGV is feasible in mesothelioma and may predict response to chemotherapy and patient survival after 1 cycle of treatment. Therefore, metabolic imaging has the potential to improve the care of patients receiving chemotherapy for mesothelioma by the early identification of responding patients. This technology may also be useful in the assessment of new systemic treatments for mesothelioma. PMID- 17704249 TI - microPET of tumor integrin alphavbeta3 expression using 18F-labeled PEGylated tetrameric RGD peptide (18F-FPRGD4). AB - In vivo imaging of alpha(v)beta(3) expression has important diagnostic and therapeutic applications. Multimeric cyclic RGD peptides are capable of improving the integrin alpha(v)beta(3)-binding affinity due to the polyvalency effect. Here we report an example of (18)F-labeled tetrameric RGD peptide for PET of alpha(v)beta(3) expression in both xenograft and spontaneous tumor models. METHODS: The tetrameric RGD peptide E{E[c(RGDyK)](2)}(2) was derived with amino 3,6,9-trioxaundecanoic acid (mini-PEG; PEG is poly(ethylene glycol)) linker through the glutamate alpha-amino group. NH(2)-mini-PEG-E{E[c(RGDyK)](2)}(2) (PRGD4) was labeled with (18)F via the N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB) prosthetic group. The receptor-binding characteristics of the tetrameric RGD peptide tracer (18)F-FPRGD4 were evaluated in vitro by a cell binding assay and in vivo by quantitative microPET imaging studies. RESULTS: The decay-corrected radiochemical yield for (18)F-FPRGD4 was about 15%, with a total reaction time of 180 min starting from (18)F-F(-). The PEGylation had minimal effect on integrin-binding affinity of the RGD peptide. (18)F-FPRGD4 has significantly higher tumor uptake compared with monomeric and dimeric RGD peptide tracer analogs. The receptor specificity of (18)F-FPRGD4 in vivo was confirmed by effective blocking of the uptake in both tumors and normal organs or tissues with excess c(RGDyK). CONCLUSION: The tetrameric RGD peptide tracer (18)F-FPRGD4 possessing high integrin-binding affinity and favorable biokinetics is a promising tracer for PET of integrin alpha(v)beta(3) expression in cancer and other angiogenesis related diseases. PMID- 17704251 TI - Diagnosis of diffuse and localized arrhythmogenic right ventricular dysplasia by gated blood-pool SPECT. AB - This study aimed to assess the ability of global and local systolic parameters measured with gated blood-pool SPECT (GBPS) to diagnose and characterize the severity of diffuse or localized arrhythmogenic right ventricular dysplasia (ARVD). METHODS: Fifty-nine subjects with symptomatic ventricular arrhythmias were prospectively included in the study. With the International Society and Federation of Cardiology criteria for ARVD as a gold standard, these subjects were classified as subjects without ARVD (21 control subjects) and patients with localized ARVD (16 patients) or diffuse ARVD (22 patients). Right ventricular volumes, right ventricular ejection fractions (EF), the SD of local EF (sigma EF), and the SD of the local times of end systole (sigma-TES) were computed from GBPS data and compared among the groups in the study population. RESULTS: sigma EF did not differ between control subjects and patients with diffuse or localized ARVD. Right ventricular EF and volumes differed between patients with diffuse ARVD and control subjects, with similar areas under the receiver-operating characteristic curves, but right ventricular EF and volumes failed to differentiate patients with localized ARVD. In contrast, sigma-TES differed between patients with diffuse or localized ARVD and control subjects. Regression analysis showed that the systolic parameter most strongly associated with the diagnosis of ARVD was sigma-TES. The probabilities of a randomly chosen patient in the diffuse ARVD group and of a randomly chosen patient in the localized ARVD group having sigma-TES values greater than that of a randomly chosen control subject were 98.5% and 96.7%, respectively. For the diagnosis of localized ARVD, a threshold of 80 ms for sigma-TES corresponded to sensitivity, specificity, and positive and negative predictive values of 100%, 81%, 80%, and 100%, respectively. CONCLUSION: With GBPS, both diffuse ARVD and localized ARVD can be accurately diagnosed by computing sigma-TES for all of the pixels on the surface of the right ventricle. PMID- 17704252 TI - Validation of a standardized normalization template for statistical parametric mapping analysis of 123I-FP-CIT images. AB - (123)I-FP-CIT ((123)I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4 iodophenyl)nortropane) is a SPECT dopamine transporter (DAT) tracer that probes dopaminergic cell loss in Parkinson's disease (PD). Quantification of (123)I-FP CIT images is performed at equilibrium using a ratio (BR) of specific (striatal) to nonspecific (occipital) uptake with values obtained from regions of interest drawn manually over these structures. Statistical parametric mapping (SPM) is a fully automated voxel-based statistical approach that has great potential in the context of DAT imaging. However, the accuracy of the spatial normalization provided by SPM has not been validated for (123)I-FP-CIT images. Our first aim was to create an (123)I-FP-CIT template that does not require the acquisition of patient-specific MRI and to validate the spatial normalization procedure. Next, we hypothesized that this customized template could be used by different SPECT centers without affecting the outcomes of imaging analyses. METHODS: The spatial normalization to the customized template created with SPM (template A1) was validated using (123)I-FP-CIT images obtained from 6 subjects with essential tremor (ET) with normal DAT status and 6 PD patients. Variability in BR values due to the normalization was evaluated using striatal volume of interest (VOI). To determine whether different SPECT centers could use a unique (123)I-FP-CIT template, we generated 3 other (123)I-FP-CIT templates using different subjects and image-processing schemes. The interchangeability of these templates was assessed using (a) putamen BR values analyzed with the intraclass correlation coefficient (ICC) and the Bland-Altman graphical analysis, and (b) SPM analysis comparing the results of group comparisons-that is, ET versus PD, obtained after normalization to each of the 4 templates. RESULTS: There was no significant difference between pre- and post-normalization striatal BR values in our study. The mean variability calculated with putamen VOI values after normalization to each template was <10%, with the lowest ICC of 98%. Intergroup analyses performed with VOI and SPM approaches provided similar results independently of the template used. CONCLUSION: SPM normalization was accurate even in subjects with low striatal (123)I-FP-CIT uptake, making it a promising approach for automatic analysis of (123)I-FP-CIT images using a single customized template at different centers. PMID- 17704253 TI - Epidermal growth factor receptor inhibition modulates the nuclear localization and cytotoxicity of the Auger electron emitting radiopharmaceutical 111In-DTPA human epidermal growth factor. AB - (111)In-DTPA-human epidermal growth factor ((111)In-DTPA-hEGF [DTPA is diethylenetriaminepentaacetic acid]) is an Auger electron-emitting radiopharmaceutical that targets EGF receptor (EGFR)-positive cancer. The purpose of this study was to determine the effect of EGFR inhibition by gefitinib on the internalization, nuclear translocation, and cytotoxicity of (111)In-DTPA-hEGF in EGFR-overexpressing MDA-MB-468 human breast cancer cells. METHODS: Western blot analysis was used to determine the optimum concentration of gefitinib to abolish EGFR activation. Internalization and nuclear translocation of fluorescein isothiocyanate-labeled hEGF were evaluated by confocal microscopy in MDA-MB-468 cells (1.3 x 10(6) EGFRs/cell) in the presence or absence of 1 microM gefitinib. The proportion of radioactivity partitioning into the cytoplasm and nucleus of MDA-MB-468 cells after incubation with (111)In-DTPA-hEGF for 24 h at 37 degrees C in the presence or absence of 1 microM gefitinib was measured by cell fractionation. DNA double-strand breaks caused by (111)In were quantified using the gamma-H2AX assay, and radiation-absorbed doses were estimated. Clonogenic survival assays were used to measure the cytotoxicity of (111)In-DTPA-hEGF alone or in combination with gefitinib. RESULTS: Gefitinib (1 microM) completely abolished EGFR phosphorylation in MDA-MB-468 cells. Internalization and nuclear translocation of fluorescein isothiocyanate-labeled EGF were not diminished in gefitinib-treated cells compared with controls. The proportion of internalized (111)In that localized in the nucleus was statistically significantly greater when (111)In-DTPA-hEGF was combined with gefitinib compared with (111)In-DTPA hEGF alone (mean +/- SD: 26.0% +/- 5.5% vs. 14.6% +/- 4.0%, respectively; P < 0.05). Induction of gamma-H2AX foci was greater in MDA-MB-468 cells that were treated with (111)In-DTPA-hEGF (250 ng/mL, 1.5 MBq/mL) plus gefitinib (1 microM ) compared with those treated with (111)In-DTPA-hEGF alone (mean +/- SD: 35 +/- 4 vs. 24 +/- 5 foci per nucleus, respectively). In clonogenic assays, a significant reduction in the surviving fraction was observed when (111)In-DTPA-hEGF (5 ng/mL, 6 MBq/microg) was combined with gefitinib (1 microM ) compared with (111)In-DTPA hEGF alone (42.9% +/- 5.7% vs. 22.9% +/- 3.6%, respectively; P < 0.01). CONCLUSION: The efficacy of (111)In-DTPA-hEGF depends on internalization and nuclear uptake of the radionuclide. Nuclear uptake, DNA damage, and cytotoxicity are enhanced when (111)In-DTPA-hEGF is combined with gefitinib. These results suggest a potential therapeutic role for peptide receptor radionuclide therapy in combination with tyrosine kinase inhibitors. PMID- 17704254 TI - Ground squirrels use an infrared signal to deter rattlesnake predation. AB - The evolution of communicative signals involves a major hurdle; signals need to effectively stimulate the sensory systems of their targets. Therefore, sensory specializations of target animals are important sources of selection on signal structure. Here we report the discovery of an animal signal that uses a previously unknown communicative modality, infrared radiation or "radiant heat," which capitalizes on the infrared sensory capabilities of the signal's target. California ground squirrels (Spermophilus beecheyi) add an infrared component to their snake-directed tail-flagging signals when confronting infrared-sensitive rattlesnakes (Crotalus oreganus), but tail flag without augmenting infrared emission when confronting infrared-insensitive gopher snakes (Pituophis melanoleucus). Experimental playbacks with a biorobotic squirrel model reveal this signal's communicative function. When the infrared component was added to the tail flagging display of the robotic models, rattlesnakes exhibited a greater shift from predatory to defensive behavior than during control trials in which tail flagging included no infrared component. These findings provide exceptionally strong support for the hypothesis that the sensory systems of signal targets should, in general, channel the evolution of signal structure. Furthermore, the discovery of previously undescribed signaling modalities such as infrared radiation should encourage us to overcome our own human-centered sensory biases and more fully examine the form and diversity of signals in the repertoires of many animal species. PMID- 17704255 TI - Heteroresistance to penicillin in Streptococcus pneumoniae. AB - Heteroresistance to beta-lactam antibiotics has been mainly described for staphylococci, for which it complicates diagnostic procedures and therapeutic success. This study investigated whether heteroresistance to penicillin exists in Streptococcus pneumoniae. Population analysis profile (PAP) showed the presence of subpopulations with higher penicillin resistance in four of nine clinical pneumococcal strains obtained from a local surveillance program (representing the multiresistant clones ST179, ST276, and ST344) and in seven of 16 reference strains (representing the international clones Spain(23F)-1, Spain(9V)-3, Spain(14)-5, Hungary(19A)-6, South Africa(19A)-13, Taiwan(23F)-15, and Finland(6B)-12). Heteroresistant strains had penicillin minimal inhibitory concentrations (MICs) (for the majority of cells) in the intermediate- to high level range (0.19-2.0 mug/ml). PAP curves suggested the presence of subpopulations also for the highly penicillin-resistant strains Taiwan(19F)-14, Poland(23F)-16, CSR(19A)-11, and CSR(14)-10. PAP of bacterial subpopulations with higher penicillin resistance showed a shift toward higher penicillin-resistance levels, which reverted upon multiple passages on antibiotic-free media. Convergence to a homotypic resistance phenotype did not occur. Comparison of two strains of clone ST179 showed a correlation between the heteroresistant phenotype and a higher-penicillin MIC and a greater number of altered penicillin-binding proteins (PBP1a, -2b, and -2x), respectively. Therefore, heteroresistance to penicillin occurs in international multiresistant clones of S. pneumoniae. Pneumococci may use heteroresistance to penicillin as a tool during their evolution to high penicillin resistance, because it gives the bacteria an opportunity to explore growth in the presence of antibiotics before acquisition of resistance genes. PMID- 17704257 TI - Diploid apomicts of the Boechera holboellii complex display large-scale chromosome substitutions and aberrant chromosomes. AB - We conducted a cytogenetic study of sexual lines of Boechera stricta and Boechera holboellii (2n = 14) and seven diploid apomictic accessions of their interspecific hybrid Boechera divaricarpa and B. holboellii (2n = 14 or 15). By studying chromosome morphology, rDNA repeats, genome painting, male meiosis, pollen morphology, and flow-cytometry seed screens, we revealed an unexpected plethora of chromosome forms, pairing behavior, and hybrid composition in all apomictic lines. Genome painting demonstrated that the apomicts are alloploid with variable numbers of B. stricta and B. holboellii-like chromosomes. We assume that large-scale homeologous chromosome substitutions took place in the apomictic hybrids that resulted from recurrent diploid-polyploid transitions through restitutional meiosis and polyploidy-diploid transitions through reductional meiosis. A second peculiarity was the presence of a largely heterochromatic chromosome (Het) in all apomictic accessions (2n = 14 and 15) and an additional smaller chromosome (Del) in the aneuploids (2n = 15). Both chromosomes share repetitive pericentromere repeats with those from the sexual B. stricta, suggesting that they originated from this species. Pairing and behavior at meiosis I of the Het share features with both Y and B chromosomes and suggest that the Del arose from a translocation event or homeologous recombination between a B. holboellii (or related taxon) and a B. stricta chromosome. Based on its presence exclusively in apomictic accessions, we propose that the Het chromosome plays a role in the genetic control of apomixis. PMID- 17704256 TI - Serendipitous backyard hybridization and the origin of crops. AB - Backyard gardens, dump heaps, and kitchen middens are thought to have provided important venues for early crop domestication via generation of hybrids between otherwise isolated plant species. However, this process has rarely been demonstrated empirically. For the majority of polyploid crops, it remains uncertain to what extent hybridization and polyploidization preceded domestication or were precipitated by human activities. Using archaeological, ethnobotanical, geographical, and genetic data, we investigate the extent and significance of predomestication cultivation, backyard sympatry, and spontaneous hybridization for the Mimosoid legume tree Leucaena, which is used as a food crop throughout south-central Mexico. We show that predomestication cultivation was widespread, involved numerous independent transitions from the wild to cultivation, and resulted in extensive artificial sympatry of 2-6 species locally and 13 species in total. Using chloroplast and rapidly evolving nuclear-encoded DNA sequences, we demonstrate that hybridization in Leucaena has been extensive and complex, spawning a diverse set of novel hybrids as a result of juxtaposition of species in cultivation. The scale and complexity of hybridization in Leucaena is significantly greater than that documented for any other Mexican plant domesticates so far. However, there are striking parallels between Leucaena and the other major Mexican perennial domesticates Agave and Opuntia, which show very similar domestication via backyard hybridization pathways. Our results suggest that backyard hybridization has played a central role in Mesoamerican crop domestication and demonstrate that the simple step of bringing species together in cultivation can provide a potent trigger for domestication. PMID- 17704258 TI - A diapause pathway underlies the gyne phenotype in Polistes wasps, revealing an evolutionary route to caste-containing insect societies. AB - Colonies of social wasps, ants, and bees are characterized by the production of two phenotypes of female offspring, workers that remain at their natal nest and nonworkers that are potential colony reproductives of the next generation. The phenotype difference includes morphology and is fixed during larval development in ants, honey bees, and some social wasps, all of which represent an advanced state of sociality. Paper wasps (Polistes) lack morphological castes and are thought to more closely resemble an ancestral state of sociality wherein the phenotype difference between workers and nonworkers is established only during adult life. We address an alternative hypothesis: a bias toward the potential reproductive (gyne) phenotype among Polistes female offspring occurs during larval development and is based on a facultatively expressed ancestral life history trait: diapause. We show that two signatures of diapause (extended maturation time and enhanced synthesis and sequestration of a hexameric storage protein) characterize the development of gyne offspring in Polistes metricus. Hexameric storage proteins are implicated in silencing juvenile hormone signaling, which is a prerequisite for diapause. Diverging hexamerin protein dynamics driven by changes in larval provisioning levels thereby provide one possible mechanism that can cause an adaptive shift in phenotype bias during the Polistes colony cycle. This ontogenetic basis for alternative female phenotypes in Polistes challenges the view that workers and gynes represent behavior options equally available to every female offspring, and it exemplifies how social insect castes can evolve from casteless lineages. PMID- 17704259 TI - Structural insights into the interaction of the evolutionarily conserved ZPR1 domain tandem with eukaryotic EF1A, receptors, and SMN complexes. AB - Eukaryotic genomes encode a zinc finger protein (ZPR1) with tandem ZPR1 domains. In response to growth stimuli, ZPR1 assembles into complexes with eukaryotic translation elongation factor 1A (eEF1A) and the survival motor neurons protein. To gain insight into the structural mechanisms underlying the essential function of ZPR1 in diverse organisms, we determined the crystal structure of a ZPR1 domain tandem and characterized the interaction with eEF1A. The ZPR1 domain consists of an elongation initiation factor 2-like zinc finger and a double stranded beta helix with a helical hairpin insertion. ZPR1 binds preferentially to GDP-bound eEF1A but does not directly influence the kinetics of nucleotide exchange or GTP hydrolysis. However, ZPR1 efficiently displaces the exchange factor eEF1Balpha from preformed nucleotide-free complexes, suggesting that it may function as a negative regulator of eEF1A activation. Structure-based mutational and complementation analyses reveal a conserved binding epitope for eEF1A that is required for normal cell growth, proliferation, and cell cycle progression. Structural differences between the ZPR1 domains contribute to the observed functional divergence and provide evidence for distinct modalities of interaction with eEF1A and survival motor neuron complexes. PMID- 17704261 TI - My approach to and thoughts on the typing of ovarian carcinomas. AB - Ovarian carcinomas of epithelial type comprise a heterogeneous group of neoplasms, each with a different underlying pathogenesis and natural behaviour. Accurate classification of ovarian carcinomas is important since each type may be associated with a different behaviour, natural history and outcome. Precise classification is also critical to determine whether alternative therapeutic strategies are appropriate for different tumour types. Previous studies have shown significant interobserver variation in the typing of ovarian carcinomas. There are several areas where there are particular difficulties; these include the distinction between high-grade serous and endometrioid adenocarcinomas and the distinction between a true clear cell carcinoma and clear cell areas within other adenocarcinomas. This review details my approach to the typing of ovarian carcinomas. Morphological assessment, which remains the mainstay in diagnosis, can be supplemented by immunohistochemistry which, for example, is useful in the distinction between serous carcinomas (WT1 positive) and other carcinomas (generally WT1 negative). In recent years, there has been emerging new information regarding the major underlying molecular events in several types of ovarian carcinoma. This has resulted in the acceptance that there are two distinct types of ovarian serous carcinoma. These are termed low-grade and high grade serous carcinoma, but represent two distinct tumour types rather than low grade and high-grade variants of the same neoplasm. The integration of clinical, morphological and molecular data has resulted in a more precise classification of ovarian carcinomas and has resulted in the proposal for a broad dualistic pathway of ovarian epithelial carcinogenesis with, in general, low-grade type 1 tumours evolving from benign and borderline neoplasms through a well-defined adenoma carcinoma sequence, and high-grade type 2 neoplasms arising from an, as yet, undefined precursor lesion. PMID- 17704260 TI - Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome. AB - Cardio-facio-cutaneous (CFC) syndrome, Noonan syndrome (NS), and Costello syndrome (CS) are clinically related developmental disorders that have been recently linked to mutations in the RAS/MEK/ERK signalling pathway. This study was a mutation analysis of the KRAS, BRAF, MEK1 and MEK2 genes in a total of 130 patients (40 patients with a clinical diagnosis of CFC, 20 patients without HRAS mutations from the French Costello family support group, and 70 patients with NS without PTPN11 or SOS1 mutations). BRAF mutations were found in 14/40 (35%) patients with CFC and 8/20 (40%) HRAS-negative patients with CS. KRAS mutations were found in 1/40 (2.5%) patients with CFC, 2/20 (10%) HRAS-negative patients with CS and 4/70 patients with NS (5.7%). MEK1 mutations were found in 4/40 patients with CFC (10%), 4/20 (20%) HRAS-negative patients with CS and 3/70 (4.3%) patients with NS, and MEK2 mutations in 4/40 (10%) patients with CFC. Analysis of the major phenotypic features suggests significant clinical overlap between CS and CFC. The phenotype associated with MEK mutations seems less severe, and is compatible with normal mental development. Features considered distinctive for CS were also found to be associated with BRAF or MEK mutations. Because of its particular cancer risk, the term "Costello syndrome" should only be used for patients with proven HRAS mutation. These results confirm that KRAS is a minor contributor to NS and show that MEK is involved in some cases of NS, demonstrating a phenotypic continuum between the clinical entities. Although some associated features appear to be characteristic of a specific gene, no simple rule exists to distinguish NS from CFC easily. PMID- 17704262 TI - p53 protein expression and genetic mutation in two primary cell types in pulmonary sclerosing haemangioma. AB - AIMS: To investigate the significance of p53 protein expression and genetic mutations in two primary cell types in pulmonary sclerosing haemangioma (PSH). METHODS: p53 protein expression in polygonal cells and cuboidal cells in 19 patients with PSH was detected using immunohistochemistry. The two major cell types were captured using laser capture microdissection technology. Mutations in the p53 gene (exons 5-8) were examined using single-stranded conformation polymorphism and DNA sequencing analysis. RESULTS: p53 protein expression and gene mutations were observed in 15.8% (3/19) of cases. In these cases, p53 protein was expressed in the nucleus of both cell types, with higher expression levels and mutation rates in polygonal cells than in surface cuboidal cells. Two cases showed mutation only in the polygonal cells, while one case showed double (separate) mutations in both the polygonal and cuboidal cells. CONCLUSIONS: p53 mutation was exhibited in PSH. The mutation rate in polygonal cells was higher than that in surface cuboidal cells. PMID- 17704263 TI - The squamous variant of eccrine porocarcinoma: a clinicopathological study of 21 cases. AB - AIM: Squamous differentiation in eccrine porocarcinoma (EPC) is an unusual phenomenon that has rarely been reported in the literature. This study describes the clinical and pathological findings in a series of 21 cases of EPC showing extensive squamous differentiation. METHODS: The H&E-stained sections, epithelial membrane antigen and carcinoembryonic antigen immunohistochemical stains were reviewed for each case. The following variables were examined: age, gender, race, site and size of the EPC. The prevalence of other cutaneous lesions and/or underlying systemic disease was also documented. RESULTS: There was an almost equal gender distribution. Mean age was 61.5 years and the average tumour size was 46.5 mm. An inordinately large number (10/21, 48%) of EPCs occurred in black patients. The tumours were located at various sites with the extremities predominating (10/19, 53%). Seven patients developed other sun-induced skin tumours, three patients were renal transplant recipients, and two patients were HIV-positive, one of whom also suffered from albinism. Six of the 11 patients in whom follow-up was available had an adverse outcome: local recurrence developed in one patient, one patient developed nodal metastases, and one patient experienced both local recurrence and nodal metastases, and of the three patients who died of disease, two developed distant metastases. CONCLUSION: The findings suggest a possible role for ultraviolet radiation and chronic immunosuppression in the induction of malignant squamous differentiation in a subset of EPCs. Further reports on this histological variant of EPC are required to determine whether a pathogenetic link does indeed exist or whether these tumours simply represent a unique variant of squamous cell carcinoma with divergent acrosyringial differentiation. PMID- 17704264 TI - Calcification in breast lesions: pathologists' perspective. AB - Evaluation of calcification in breast lesions is a major assessment criterion for breast mammography. The morphology and distribution of the calcification are related to the histology of the lesions. Radiologically, calcifications can be divided into: benign; intermediate concern; and higher probability of malignancy according to the morphology. Different pathological entities may give rise to different calcifications. Fibrocystic changes may give rise to milk of calcium or teacup type calcification, or small calcifications occurring in a cluster. Fibroadenoma may be associated with large popcorn like calcifications, and sclerosing adenosis may have fine, punctate or granular calcifications. Fat necrosis may give rise to egg shell calcification. Precursor malignant lesions give rise to benign to indeterminate type calcifications, and may occasionally be associated with malignant type calcifications. For malignant lesions, ductal carcinoma in situ and invasive duct carcinoma may be associated with large irregular, rod or V shaped, pleomorphic or branching type calcifications that follow the distribution of the duct. Furthermore, analysis of the characteristics of the calcifications may help to predict the tumour size and grade, and presence of invasion. PMID- 17704265 TI - Subtypes of the plasmid-encoded serine protease EspP in Shiga toxin-producing Escherichia coli: distribution, secretion, and proteolytic activity. AB - We investigated the prevalence, distribution, and structure of espP in Shiga toxin-producing Escherichia coli (STEC) and assessed the secretion and proteolytic activity of the encoded autotransporter protein EspP (extracellular serine protease, plasmid encoded). espP was identified in 56 of 107 different STEC serotypes. Sequencing of a 3,747-bp region of the 3,900-bp espP gene distinguished four alleles (espPalpha, espPbeta, espPgamma, and espPdelta), with 99.9%, 99.2%, 95.3%, and 95.1% homology, respectively, to espP of E. coli O157:H7 strain EDL933. The espPbeta, espPgamma, and espPdelta genes contained unique insertions and/or clustered point mutations that enabled allele-specific PCRs; these demonstrated the presence of espPalpha, espPbeta, espPgamma, and espPdelta in STEC isolates belonging to 17, 16, 15, and 8 serotypes, respectively. Among four subtypes of EspP encoded by these alleles, EspPalpha (produced by enterohemorrhagic E. coli [EHEC] O157:H7 and the major non-O157 EHEC serotypes) and EspPgamma cleaved pepsin A, human coagulation factor V, and an oligopeptide alanine-alanine-proline-leucine-para-nitroaniline, whereas EspPbeta and EspPdelta either were not secreted or were proteolytically inactive. The lack of proteolysis correlated with point mutations near the active serine protease site. We conclude that espP is widely distributed among STEC strains and displays genetic heterogeneity, which can be used for subtyping and which affects EspP activity. The presence of proteolytically active EspP in EHEC serogroups O157, O26, O111, and O145, which are bona fide human pathogens, suggests that EspP might play a role as an EHEC virulence factor. PMID- 17704266 TI - Influence of lactic acid bacteria on longevity of Caenorhabditis elegans and host defense against salmonella enterica serovar enteritidis. AB - This study aimed to develop a convenient model to investigate the senescence of host defenses and the influence of food and nutrition. A small soil nematode, Caenorhabditis elegans, was grown for 3 days from hatching on a lawn of Escherichia coli OP50 as the normal food source, and subsequently some of the nematodes were fed lactic acid bacteria (LAB). The life spans of worms fed LAB were significantly longer than the life spans of those fed OP50. To investigate the effect of age on host defenses, 3- to 7-day-old worms fed OP50 were transferred onto a lawn of Salmonella enterica serovar Enteritidis for infection. The nematodes died over the course of several days, and the accumulation of salmonella in the intestinal lumen suggested that the worms were infected. The 7 day-old worms showed a higher death rate during the 5 days after infection than nematodes infected at the age of 3 days; no clear difference was observed when the worms were exposed to OP50. We then investigated whether the LAB could exert probiotic effects on the worms' host defenses and improve life span. Seven-day old nematodes fed LAB from the age of 3 days were more resistant to salmonella than worms fed OP50 until they were infected with salmonella. This study clearly showed that LAB can enhance the host defense of C. elegans and prolong life span. The nematode appears to be an appropriate model for screening useful probiotic strains or dietetic antiaging substances. PMID- 17704267 TI - Multilocus sequence typing of Lactobacillus casei reveals a clonal population structure with low levels of homologous recombination. AB - Robust genotyping methods for Lactobacillus casei are needed for strain tracking and collection management, as well as for population biology research. A collection of 52 strains initially labeled L. casei or Lactobacillus paracasei was first subjected to rplB gene sequencing together with reference strains of Lactobacillus zeae, Lactobacillus rhamnosus, and other species. Phylogenetic analysis showed that all 52 strains belonged to a single compact L. casei-L. paracasei sequence cluster, together with strain CIP107868 (= ATCC 334) but clearly distinct from L. rhamnosus and from a cluster with L. zeae and CIP103137(T) (= ATCC 393(T)). The strains were genotyped using amplified fragment length polymorphism, multilocus sequence typing based on internal portions of the seven housekeeping genes fusA, ileS, lepA, leuS, pyrG, recA, and recG, and tandem repeat variation (multilocus variable-number tandem repeats analysis [MLVA] using nine loci). Very high concordance was found between the three methods. Although amounts of nucleotide variation were low for the seven genes (pi ranging from 0.0038 to 0.0109), 3 to 12 alleles were distinguished, resulting in 31 sequence types. One sequence type (ST1) was frequent (17 strains), but most others were represented by a single strain. Attempts to subtype ST1 strains by MLVA, ribotyping, clustered regularly interspaced short palindromic repeat characterization, and single nucleotide repeat variation were unsuccessful. We found clear evidence for homologous recombination during the diversification of L. casei clones, including a putative intragenic import of DNA into one strain. Nucleotides were estimated to change four times more frequently by recombination than by mutation. However, statistical congruence between individual gene trees was retained, indicating that recombination is not frequent enough to disrupt the phylogenetic signal. The developed multilocus sequence typing scheme should be useful for future studies of L. casei strain diversity and evolution. PMID- 17704268 TI - Changes in Listeria monocytogenes membrane fluidity in response to temperature stress. AB - Listeria monocytogenes is a food-borne pathogen that has been implicated in many outbreaks associated with ready-to-eat products. Listeria adjusts to various stresses by adjusting its membrane fluidity, increasing the uptake of osmoprotectants and cryoprotectants, and activating the sigma(B) stress factor. The present work examines the regulation of membrane fluidity through direct measurement based on fluorescent anisotropy. The membrane fluidities of L. monocytogenes Scott A, NR30, wt10403S, and cld1 cells cultured at 15 and 30 degrees C were measured at 15 and 30 degrees C. The membrane of the cold sensitive mutant (cld1) was more rigid than the membranes of the other strains when grown at 30 degrees C, but when grown at 15 degrees C, it was able to adjust its membrane to approach the rigidity of the other strains. The difference in rigidities, as determined at 15 and 30 degrees C, was greater in liposomes than in whole cells. The rates of fluidity adjustment and times required for whole cells to adjust to a different temperature were similar among strains but different from those of liposomes. This suggests that the cells had a mechanism for homeoviscous adaptation that was absent in liposomes. PMID- 17704269 TI - The termite group I phylum is highly diverse and widespread in the environment. AB - The bacterial candidate phylum Termite Group I (TG-1) presently consists mostly of "Endomicrobia," which are endosymbionts of flagellate protists occurring exclusively in the hindguts of termites and wood-feeding cockroaches. Here, we show that public databases contain many, mostly undocumented 16S rRNA gene sequences from other habitats that are affiliated with the TG-1 phylum but are only distantly related to "Endomicrobia." Phylogenetic analysis of the expanded data set revealed several diverse and deeply branching lineages comprising clones from many different habitats. In addition, we designed specific primers to explore the diversity and environmental distribution of bacteria in the TG-1 phylum. PMID- 17704270 TI - Comparative transcriptome analysis of Listeria monocytogenes strains of the two major lineages reveals differences in virulence, cell wall, and stress response. AB - Listeria monocytogenes is a food-borne, opportunistic, bacterial pathogen causing a wide spectrum of diseases, including meningitis, septicemia, abortion, and gastroenteritis, in humans and animals. Among the 13 L. monocytogenes serovars described, human listeriosis is mostly associated with strains of serovars 4b, 1/2b, and 1/2a. Within the species L. monocytogenes, three phylogenetic lineages are described. Serovar 1/2a belongs to phylogenetic lineage I, while serovars 4b and 1/2b group in phylogenetic lineage II. To explore the role of gene expression in the adaptation of L. monocytogenes strains of these two major lineages to different environments, as well as in virulence, we performed whole-genome expression profiling of six L. monocytogenes isolates of serovars 4b, 1/2b, and 1/2a of distinct origins, using a newly constructed Listeria multigenome DNA array. Comparison of the global gene expression profiles revealed differences among strains. The expression profiles of two strains having distinct 50% lethal doses, as assessed in the mouse model, were further analyzed. Gene ontology term enrichment analysis of the differentially expressed genes identified differences in protein-, nucleic acid-, carbon metabolism-, and virulence-related gene expression. Comparison of the expression profiles of the core genomes of all strains revealed differences between the two lineages with respect to cell wall synthesis, the stress-related sigma B regulon and virulence-related genes. These findings suggest different patterns of interaction with host cells and the environment, key factors for host colonization and survival in the environment. PMID- 17704271 TI - Effects of heavy fuel oil on the bacterial community structure of a pristine microbial mat. AB - The effects of petroleum contamination on the bacterial community of a pristine microbial mat from Salins-de-Giraud (Camargue, France) have been investigated. Mats were maintained as microcosms and contaminated with no. 2 fuel oil from the wreck of the Erika. The evolution of the complex bacterial community was monitored by combining analyses based on 16S rRNA genes and their transcripts. 16S rRNA gene-based terminal restriction fragment length polymorphism (T-RFLP) analyses clearly showed the effects of the heavy fuel oil after 60 days of incubation. At the end of the experiment, the initial community structure was recovered, illustrating the resilience of this microbial ecosystem. In addition, the responses of the metabolically active bacterial community were evaluated by T RFLP and clone library analyses based on 16S rRNA. Immediately after the heavy fuel oil was added to the microcosms, the structure of the active bacterial community was modified, indicating a rapid microbial mat response. Members of the Gammaproteobacteria were initially dominant in the contaminated microcosms. Pseudomonas and Acinetobacter were the main genera representative of this class. After 90 days of incubation, the Gammaproteobacteria were superseded by "Bacilli" and Alphaproteobacteria. This study shows the major changes that occur in the microbial mat community at different time periods following contamination. At the conclusion of the experiment, the RNA approach also demonstrated the resilience of the microbial mat community in resisting environmental stress resulting from oil pollution. PMID- 17704272 TI - Influence of antibiotic selection on genetic composition of Escherichia coli populations from conventional and organic dairy farms. AB - The widespread agricultural use of antimicrobials has long been considered a crucial influence on the prevalence of resistant genes and bacterial strains. It has been suggested that antibiotic applications in agricultural settings are a driving force for the development of antimicrobial resistance, and epidemiologic evidence supports the view that there is a direct link between resistant human pathogens, retail produce, farm animals, and farm environments. Despite such concerns, little is understood about the population processes underlying the emergence and spread of antibiotic resistance and the reversibility of resistance when antibiotic selective pressure is removed. In this study, hierarchical log linear modeling was used to assess the association between farm type (conventional versus organic), age of cattle (calf versus cow), bacterial phenotype (resistant versus susceptible), and the genetic composition of Escherichia coli populations (E. coli Reference Collection [ECOR] phylogroup A, B1, B2, or D) among 678 susceptible and resistant strains from a previously published study of 60 matched dairy farms (30 conventional and 30 organic) in Wisconsin. The analysis provides evidence for clonal resistance (ampicillin resistance) and genetic hitchhiking (tetracycline resistance [Tet(r)]), estimated the rate of compositional change from conventional farming to organic farming (mean, 8 years; range, 3 to 15 years), and discovered a significant association between low multidrug resistance, organic farms, and strains of the numerically dominant phylogroup B1. These data suggest that organic farming practices not only change the frequency of resistant strains but also impact the overall population genetic composition of the resident E. coli flora. In addition, the results support the hypothesis that the current prevalence of Tet(r) loci on dairy farms has little to do with the use of this antibiotic. PMID- 17704273 TI - Identification of genes that confer sediment fitness to Desulfovibrio desulfuricans G20. AB - Signature-tagged mutants of Desulfovibrio desulfuricans G20 were screened, and 97 genes crucial for sediment fitness were identified. These genes belong to functional categories including signal transduction, binding and transport, insertion elements, and others. Mutants with mutations in genes encoding proteins involved in amino acid biosynthesis, hydrogenase activity, and DNA repair were further characterized. PMID- 17704275 TI - The diversity of coliphages and coliforms in horse feces reveals a complex pattern of ecological interactions. AB - The diversity of coliphages and indigenous coliform strains (ICSs) simultaneously present in horse feces was investigated by culture-based and molecular methods. The richness of coliforms (as estimated by the Chao1 method) is about 1,000 individual ICSs distinguishable by genomic fingerprinting present in a single sample of feces. This unexpectedly high value indicates that some factor limits the competition of coliform bacteria in the horse gut microbial system. In contrast, the diversity of phages active against any selected ICS is generally limited to one to three viral genotypes present in the sample. The sensitivities of different ICSs to simultaneously present coliphages overlap only slightly; the phages isolated from the same sample on different ICSs are usually unrelated. As a result, the titers of phages in fecal extract as determined for different Escherichia coli strains and ICSs may differ by several orders of magnitude. Summarizing all the data, we propose that coliphage infection may provide a selection pressure that maintains the high level of coliform diversity, restricting the possibility of a few best competitors outgrowing other ICSs. We also observed high-magnitude temporal variations of coliphage titers as determined using an E. coli C600 test culture in the same animal during a 16-day period of monitoring. No correlation with total coliform count was observed. These results are in good agreement with our hypothesis. PMID- 17704274 TI - Mtx toxins synergize Bacillus sphaericus and Cry11Aa against susceptible and insecticide-resistant Culex quinquefasciatus larvae. AB - Two mosquitocidal toxins (Mtx) of Bacillus sphaericus, which are produced during vegetative growth, were investigated for their potential to increase toxicity and reduce the expression of insecticide resistance through their interactions with other mosquitocidal proteins. Mtx-1 and Mtx-2 were fused with glutathione S transferase and produced in Escherichia coli, after which lyophilized powders of these fusions were assayed against Culex quinquefasciatus larvae. Both Mtx proteins showed a high level of activity against susceptible C. quinquefasciatus mosquitoes, with 50% lethal concentrations (LC(50)) of Mtx-1 and Mtx-2 of 0.246 and 4.13 microg/ml, respectively. The LC(50)s were 0.406 to 0.430 microg/ml when Mtx-1 or Mtx-2 was mixed with B. sphaericus, and synergy improved activity and reduced resistance levels. When the proteins were combined with a recombinant Bacillus thuringiensis strain that produces Cry11Aa, the mixtures were highly active against Cry11A-resistant larvae and resistance was also reduced. The mixture of two Mtx toxins and B. sphaericus was 10 times more active against susceptible mosquitoes than B. sphaericus alone, demonstrating the influence of relatively low concentrations of these toxins. These results show that, similar to Cyt toxins from B. thuringiensis subsp. israelensis, Mtx toxins can increase the toxicity of other mosquitocidal proteins and may be useful for both increasing the activity of commercial bacterial larvicides and managing potential resistance to these substances among mosquito populations. PMID- 17704276 TI - Combined imaging of bacteria and oxygen in biofilms. AB - Transparent sensors for microscopic O(2) imaging were developed by spin coating an ultrathin (<1- to 2-microm) layer of a luminescent O(2) indicator onto coverslips. The sensors showed (i) an ideal Stern-Volmer quenching behavior of the luminescence lifetime towards O(2) levels, (ii) homogeneous measuring characteristics over the sensor surface, and (iii) a linear decline of luminescence lifetime with increasing temperature. When a batch of such coverslip sensors has been characterized, their use is thus essentially calibration free at a known temperature. The sensors are easy to use in flow chambers and other growth devices used in microbiology. We present the first application for combined imaging of O(2) and bacteria in a biofilm flow chamber mounted on a microscope equipped with a spinning-disk confocal unit and a luminescence lifetime camera system. PMID- 17704277 TI - Effect of biotic and abiotic factors on in vitro proliferation, encystment, and excystment of Pfiesteria piscicida. AB - Pfiesteria spp. are mixotrophic armored dinoflagellates populating the Atlantic coastal waters of the United States. They have been a focus of intense research due to their reported association with several fish mortality events. We have now used a clonal culture of Pfiesteria piscicida and several new environmental isolates to describe growth characteristics, feeding, and factors contributing to the encystment and germination of the organism in both laboratory and environmental samples. We also discuss applied methods of detection of the different morphological forms of Pfiesteria in environmental samples. In summary, Pfiesteria, when grown with its algal prey, Rhodomonas sp., presents a typical growth curve with lag, exponential, and stationary phases, followed by encystment. The doubling time in exponential phase is about 12 h. The profiles of proliferation under a standard light cycle and in the dark were similar, although the peak cell densities were markedly lower when cells were grown in the dark. The addition of urea, chicken manure, and soil extracts did not enhance Pfiesteria proliferation, but crude unfiltered spent aquarium water did. Under conditions of food deprivation or cold (4 degrees C), Pfiesteria readily formed harvestable cysts that were further analyzed by PCR and scanning electron microscopy. The germination of Pfiesteria cysts in environmental sediment was enhanced by the presence of live fish: dinospores could be detected 13 to 15 days earlier and reached 5- to 10-times-higher peak cell densities with live fish than with artificial seawater or f/2 medium alone. The addition of ammonia, urea, nitrate, phosphate, or surprisingly, spent fish aquarium water had no effect. PMID- 17704278 TI - Mutagenesis of the "leucine gate" to explore the basis of catalytic versatility in soluble methane monooxygenase. AB - Soluble methane monooxygenase (sMMO) from methane-oxidizing bacteria is a multicomponent nonheme oxygenase that naturally oxidizes methane to methanol and can also cooxidize a wide range of adventitious substrates, including mono- and diaromatic hydrocarbons. Leucine 110, at the mouth of the active site in the alpha subunit of the hydroxylase component of sMMO, has been suggested to act as a gate to control the access of substrates to the active site. Previous crystallography of the wild-type sMMO has indicated at least two conformations of the enzyme that have the "leucine gate" open to different extents, and mutagenesis of homologous enzymes has indicated a role for this residue in the control of substrate range and regioselectivity with aromatic substrates. By further refinement of the system for homologous expression of sMMO that we developed previously, we have been able to prepare a range of site-directed mutations at position 110 in the alpha subunit of sMMO. All the mutants (with Gly, Cys, Arg, and Tyr, respectively, at this position) showed relaxations of regioselectivity compared to the wild type with monoaromatic substrates and biphenyl, including the appearance of new products arising from hydroxylation at the 2- and 3- positions on the benzene ring. Mutants with the larger Arg and Trp residues at position 110 also showed shifts in regioselectivity during naphthalene hydroxylation from the 2- to the 1- position. No evidence that mutagenesis of Leu 110 could allow very large substrates to enter the active site was found, however, since the mutants (like the wild type) were inactive toward the triaromatic hydrocarbons anthracene and phenanthrene. Thus, our results indicate that the "leucine gate" in sMMO is more important in controlling the precision of regioselectivity than the sizes of substrates that can enter the active site. PMID- 17704279 TI - Effect of biofilm formation by Pseudoalteromonas spongiae on induction of larval settlement of the polychaete Hydroides elegans. AB - The effects of culture conditions and chloramphenicol treatment on the induction of the marine bacterium Pseudoalteromonas spongiae to larval settlement of Hydroides elegans were investigated. The results showed that P. spongiae cells grown in the medium containing both yeast extract and peptone (YP-grown P. spongiae) was highly inductive to larval settlement, whereas P. spongiae cells grown in the medium containing only peptone (P-grown P. spongiae) or YP-grown P. spongiae cells treated with chloramphenicol at the onset of biofilm development (YPC-grown P. spongiae) did not induce larval settlement. Analysis of biofilm formation, biofilm structure, and the surface protein profile indicated that only the induction-capable YP-grown P. spongiae formed a well-developed biofilm, while the P-grown P. spongiae and the YPC-grown P. spongiae did not. We report here for the first time that bacterial biofilm formation was associated with its induction of larval settlement. PMID- 17704281 TI - Calgary seeks help to identify E. coli source. PMID- 17704280 TI - Microbial composition and structure of aerobic granular sewage biofilms. AB - Aerobic activated sludge granules are dense, spherical biofilms which can strongly improve purification efficiency and sludge settling in wastewater treatment processes. In this study, the structure and development of different granule types were analyzed. Biofilm samples originated from lab-scale sequencing batch reactors which were operated with malthouse, brewery, and artificial wastewater. Scanning electron microscopy, light microscopy, and confocal laser scanning microscopy together with fluorescence in situ hybridization (FISH) allowed insights into the structure of these biofilms. Microscopic observation revealed that granules consist of bacteria, extracellular polymeric substances (EPS), protozoa and, in some cases, fungi. The biofilm development, starting from an activated sludge floc up to a mature granule, follows three phases. During phase 1, stalked ciliated protozoa of the subclass Peritrichia, e.g., Epistylis spp., settle on activated sludge flocs and build tree-like colonies. The stalks are subsequently colonized by bacteria. During phase 2, the ciliates become completely overgrown by bacteria and die. Thereby, the cellular remnants of ciliates act like a backbone for granule formation. During phase 3, smooth, compact granules are formed which serve as a new substratum for unstalked ciliate swarmers settling on granule surfaces. These mature granules comprise a dense core zone containing bacterial cells and EPS and a loosely structured fringe zone consisting of either ciliates and bacteria or fungi and bacteria. Since granules can grow to a size of up to several millimeters in diameter, we developed and applied a modified FISH protocol for the study of cryosectioned biofilms. This protocol allows the simultaneous detection of bacteria, ciliates, and fungi in and on granules. PMID- 17704282 TI - Comparison of the BD GeneOhm VanR assay to culture for identification of vancomycin-resistant enterococci in rectal and stool specimens. AB - Active screening for vancomycin-resistant enterococci (VRE) in rectal and stool specimens has been recommended to limit the spread of antimicrobial resistance within certain high-risk populations. Directly from 502 rectal swabs and stool specimens, we evaluated the diagnostic performance of the BD GeneOhm VanR assay (BD GeneOhm, San Diego, CA), a rapid real-time PCR test that detects the presence of vanA and/or vanB genes. The VanR assay was compared to culture consisting of both bile-esculin-azide agar with 6 mug/ml vancomycin (BEAV agar) (BD Diagnostics, Sparks, MD) and BEAV broth with 8 mug/ml vancomycin (Hardy Diagnostics, Santa Maria, CA). Enterococci were identified to the species level using standard biochemical tests and a Phoenix automated microbiology system (BD Diagnostics, Sparks, MD). The susceptibility of the enterococci to vancomycin and teicoplanin was determined using an Etest (AB Biodisk, Solna, Sweden). VRE were initially isolated from 147 cultures, and the VanR assay detected 142 of the 147 positive cultures for a sensitivity of 96.6%. The specificity was 87.0% (309/355) largely due to false positives seen with the vanB portion of the assay. The sensitivity when testing rectal swabs was 98.3%, and the sensitivity for stool samples was 95.4% (P = 0.643). The specificity of rectal swabs was comparable to that of the stool specimens (87.5% and 86.5%, respectively). When used only to detect VanA resistance, the VanR assay was 94.4% (136/144) sensitive and 96.4% (345/358) specific, with positive and negative predictive values of 91.3% and 97.7%, respectively. In summary, the BD GeneOhm VanR assay is a good screening test for VRE in our population of predominantly vanA-colonized patients. However, patient samples testing only vanB positive should be confirmed by another method for the presence of VRE. PMID- 17704283 TI - Severe gastroenteritis and hypovolemic shock caused by Grimontia (Vibrio) hollisae infection. AB - Vibrio hollisae is a halophilic species that was recently reclassified as Grimontia hollisae. This organism is known to cause moderate to severe cases of gastroenteritis. We report a case of an individual who suffered a more severe form of this disease, presenting with profound hypotension and acute renal failure, secondary to hypovolemic shock. PMID- 17704284 TI - Impairment of sympathetic baroreceptor reflexes in obese Zucker rats. AB - Adult obese Zucker rats (OZRs) have elevated sympathetic vasomotor tone and arterial pressure (AP) with blunted baroreflex-mediated changes in heart rate (HR) compared with adult lean Zucker rats (LZRs). The present study examined whether compromised cardiac baroreflexes are indicative of attenuated sympathetic responses. In addition, because juvenile OZRs have a normal mean AP, we determined whether baroreflexes are fully functional prior to hypertension. At 13 wk, adult OZRs had an elevated baseline mean AP compared with LZRs (137 +/- 3 vs. 123 +/- 5 mmHg, P < 0.05) under urethane anesthesia. Phenylephrine-induced increases in AP evoked smaller inhibitions of splanchnic sympathetic nerve activity (SNA) and HR in OZRs compared with LZRs. In addition, sympathoexcitatory responses to nitroprusside-induced hypotension were also blunted in OZRs. Sigmoid analysis revealed a decreased gain, a higher mean AP at the midpoint of the curve (AP(50)), and a reduced range of changes in SNA in OZRs. In contrast, at 7 wk of age, although juvenile OZRs weighed more than LZRs (313 +/- 13 vs. 204 +/- 4 g, P < 0.05), mean AP was comparable in both groups (122 +/- 5 vs. 121 +/- 4 mmHg, not significant). In these rats, rapid changes in AP evoked comparable changes in SNA and HR in OZRs and LZRs. Sigmoid analysis revealed that, although the gain of the reflex was blunted in OZRs (P < 0.05), the mean AP(50) and range of changes in SNA were comparable in OZRs and LZRs. Together, these data indicate that in adult OZRs, sympathetic responses to acute changes in AP are smaller than those observed in adult LZRs and that impairment of baroreceptor reflexes in OZR is not limited to the regulation of HR but extends to sympathetic vasomotor control. In addition, most of these deficits in baroreflex control of SNA develop in adulthood long after the onset of obesity and when other deficits in cardiovascular regulation are present. PMID- 17704285 TI - Intravascular pressure and diameter profile of the utero-ovarian resistance artery network: estrous cycle-dependent modulation of resistance artery tone. AB - Blood flow to the ovary varies dramatically in both magnitude and distribution throughout the estrous cycle to meet the hormonal and metabolic demands of the ovarian parenchyma as it cyclically develops and regresses. Several vascular components appear to be critical to vascular regulation of the ovary. As a first step in resolving the role of the resistance arteries and their paired veins in regulating ovarian blood flow and transvascular exchange, we characterized the architecture and intravascular pressure profile of the utero-ovarian resistance artery network in an in vivo preparation of the ovary of the anesthetized Golden hamster. We also investigated estrous cycle-dependent changes in resistance artery tone. The right ovary and the cranial aspect of the uterus in 26 female hamsters were exposed for microcirculatory observations. Estrous-cycle phase was determined in each animal before experimentation. The utero-ovarian vascular architecture was determined and resistance artery diameters were measured in each animal by video microscopy. Servo-null intravascular pressure measurements were made throughout the uteroovarian arterial network in 11 of the animals. Architectural data showed a complex anastomotic network jointly supplying the uterus and ovary. Resistance arteries showed a high degree of coiling and close apposition to veins, maximizing countercurrent-exchange capabilities. Arterial pressure dropped below 60% of systemic arterial pressure before the arteries entered the ovary. Both the ovarian artery and the uterine artery, which jointly feed the ovary, showed cycle day-dependent changes in diameter. Arterial diameters were smallest on the day following ovulation, during the brief luteal phase of the hamster. The data show that resistance arteries comprise a critical part of a complex network designed for intimate local communication and control and suggest that these arteries may play an important role in regulating ovarian blood flow in an estrous cycle-specific manner. PMID- 17704287 TI - Genomic modulation of mitochondrial respiratory genes in the hypertrophied heart reflects adaptive changes in mitochondrial and contractile function. AB - We hypothesized the coordinate induction of mitochondrial regulatory genes in the hypertrophied right ventricle to sustain mitochondrial respiratory capacity and contractile function in response to increased load. Wistar rats were exposed to hypobaric hypoxia (11% O(2)) or normoxia for 2 wk. Cardiac contractile and mitochondrial respiratory function were separately assessed for the right and left ventricles. Transcript levels of several mitochondrial regulators were measured. A robust hypertrophic response was observed in the right (but not left) ventricle in response to hypobaric hypoxia. Mitochondrial O(2) consumption was increased in the right ventricle, while proton leak was reduced vs. normoxic controls. Citrate synthase activity and mitochondrial DNA content were significantly increased in the hypertrophied right ventricle, suggesting higher mitochondrial number. Transcript levels of nuclear respiratory factor-1, peroxisome proliferator-activated receptor-gamma-coactivator-1alpha, cytochrome oxidase (COX) subunit II, and uncoupling protein-2 (UCP2) were coordinately induced in the hypertrophied right ventricle following hypoxia. UCP3 transcript levels were significantly reduced in the hypertrophied right ventricle vs. normoxic controls. Exposure to chronic hypobaric hypoxia had no significant effects on left ventricular mitochondrial respiration or contractile function. However, COXIV and UCP2 gene expression were increased in the left ventricle in response to chronic hypobaric hypoxia. In summary, we found coordinate induction of several genes regulating mitochondrial function and higher mitochondrial number in a model of physiological right ventricular hypertrophy, linking the efficiency of mitochondrial oxidative phosphorylation and respiratory function to sustained contractile function in response to the increased load. PMID- 17704286 TI - The cardioprotection of the late phase of ischemic preconditioning is enhanced by postconditioning via a COX-2-mediated mechanism in conscious rats. AB - The present study sought to determine whether the combination of late preconditioning (PC) with postconditioning enhances the reduction in infarct size. Chronically instrumented rats were assigned to a 45-min (subset 1) or 60 min (subset 2) coronary occlusion followed by 24 h of reperfusion. In each subset, rats received no further intervention (control) or were preconditioned 24 h before occlusion (PC), postconditioned at the onset of reperfusion following occlusion, or preconditioned and postconditioned without (PC + postconditioning) or with the COX-2 inhibitor celecoxib (3 mg/kg ip; PC + postconditioning + celecoxib) 10 min before postconditioning. Myocardial cyclooxygenase-2 (COX-2) protein expression and COX-2 activity (assessed as myocardial levels of PGE(2)) were measured 6 min after reperfusion in an additional five groups (control, PC, postconditioning, PC + postconditioning, and PC + postconditioning + celecoxib) subjected to a 45-min occlusion. PC alone reduced infarct size after a 45-min occlusion but not after a 60-min occlusion. Postconditioning alone did not reduce infarct size in either setting. However, the combination of late PC and postconditioning resulted in a robust infarct-sparing effect in both settings, suggesting additive cardioprotection. Celecoxib completely abrogated the infarct sparing effect of the combined interventions in both settings. Late PC increased COX-2 protein expression and PGE(2) content. PGE(2) content (but not COX-2 protein) was further increased by the combination of both interventions, suggesting that postconditioning increases the activity of COX-2 induced by late PC. In conclusion, the combination of late PC and postconditioning produces additive protection, likely due to a postconditioning-induced enhancement of COX 2 activity. PMID- 17704288 TI - Role of maximum rate of depolarization in predicting action potential duration during ventricular fibrillation. AB - During ventricular fibrillation (VF) only 39% of the variation in action potential duration (APD) is accounted for by the previous diastolic interval [DI((n-1))], i.e., restitution, and the previous APD [APD((n-1))], i.e., memory. We tested the hypothesis that a characteristic of the AP upstroke, the maximum rate of depolarization (V(max)), also helps account for its APD. A floating microelectrode was used to make transmembrane recordings at 16,000 samples/s from the anterior left ventricular wall during four 20-s episodes of VF in each of six pigs. V(max), time from V(max) to 60% repolarization (APD(60)), and DI were calculated throughout all episodes. Stepwise linear regression was used to determine how well each APD(60) (APD(60n)) was predicted by V(max) of that AP, the four previous DIs (n-1, n - 2, n - 3, n - 4), and the three previous APD(60)s (n-1, n - 2, n - 3). V(max) entered in the regression equation significantly more often (86% of VF episodes) than either APD((n-1)) (47% of episodes) or DI((n-1)) (58% of episodes). When these three variables entered first or second, their coefficients were almost always positive, consistent with a longer APD associated with 1) a larger V(max), 2) a longer APD((n-1)), and 3) a longer DI((n-1)). R(2) of the regression for all entered variables was 0.51 +/- 0.01 (mean +/- SD). During the first 20 s of VF in swine, V(max) is a more important determinant of APD than the previous DI (restitution) or the previous APD (memory). All variables together account for only one-half of APD variation during VF. PMID- 17704289 TI - A role for ICAM-1 in maintenance of leukocyte-endothelial cell rolling interactions in inflamed arterioles. AB - A key endothelial receptor in leukocyte-endothelial cell (EC) interactions is ICAM-1. ICAM-1 is constitutively expressed at low levels on vascular ECs, and its levels significantly increase following stimulation with many proinflammatory agents. This study provides evidence that in inflamed arterioles of anesthetized mice (65 mg/kg ip Nembutal), ICAM-1 mediates leukocyte rolling, in contrast to its expected role of mediating firm adhesion in venules. The number of leukocytes rolling on arteriolar ECs is decreased in ICAM-1 knockout (KO) compared with wild type (WT) mice (KO, 6.0 +/- 0.9; WT, 12.0 +/- 1.0 leukocytes/40 s; P < 0.05), whereas the leukocyte-rolling number in venules remains unaffected (KO, 5.6 +/- 0.9; WT, 7.0 +/- 0.7 leukocytes/40 s; n = 13-15 sites). We also show that the fraction of leukocytes that is rolling on arteriolar ECs does so with a higher characteristic velocity (>70 microm/s), and, furthermore, that the distance over which rolling contacts with the arteriolar wall are maintained is ICAM-1 dependent. In ICAM-1 KO animals or in WT mice in the presence of ICAM-1-blocking antibody, leukocytes rolled significantly shorter distances over the sampled 200 microm vessel length compared with WT (68 +/- 6.7 and 55 +/- 9.4 vs. 85 +/- 12.9% total, respectively, n = 4 sites, P < 0.05). We also found evidence that in ICAM 1 KO mice, a significant fraction of leukocyte rolling and adhesive interactions with arteriolar ECs could be accounted for by upregulation of another adhesion molecule, VCAM-1, providing an important illustration of how expression of related proteins can be altered following genetic ablatement of a target molecule (in this case ICAM-1). PMID- 17704290 TI - Monophasic action potentials generated by bidomain modeling as a tool for detecting cardiac repolarization times. AB - Unipolar electrograms (EGs) and hybrid (or unorthodox or unipolar) monophasic action potentials (HMAPs) are currently the only proposed extracellular electrical recording techniques for obtaining cardiac recovery maps with high spatial resolution in exposed and isolated hearts. Estimates of the repolarization times from the HMAP downstroke phase have been the subject of recent controversies. The goal of this paper is to computationally address the controversies concerning the HMAP information content, in particular the reliability of estimating the repolarization time from the HMAP downstroke phase. Three-dimensional numerical simulations were performed by using the anisotropic bidomain model with a region of short action potential durations. EGs, transmembrane action potentials (TAPs), and HMAPs elicited by an epicardial stimulation close or away from a permanently depolarized site were computed. The repolarization time was computed as the moment of EG fastest upstroke (RT(eg)) during the T wave, of HMAP fastest downstroke (RT(HMAP)), and of TAP fastest downstroke (RT(tap)). The latter was taken as the gold standard for repolarization time. We also compared the times (RT90(HMAP), RT90(tap)) when the HMAP and TAP first reach 90% of their resting value during the downstroke. For all explored sites, the HMAP downstroke closely followed the TAP downstroke, which is the expression of local repolarization activity. Results show that HMAP and TAP markers are highly correlated, and both markers RT(HMAP) and RT(eg) (RT90(HMAP)) are reliable estimates of the TAP reference marker RT(tap) (RT90(tap)). Therefore, the downstroke phase of the HMAP contains valuable information for assessing repolarization times. PMID- 17704291 TI - Mismatch between uniform increase in cardiac glucose uptake and regional contractile dysfunction in pacing-induced heart failure. AB - Increased glucose utilization and regional differences in contractile function are well-known alterations of the failing heart and play an important pathophysiological role. We tested whether, similar to functional derangement, changes in glucose uptake develop following a regional pattern. Heart failure was induced in 13 chronically instrumented minipigs by pacing the left ventricular (LV) free wall at 180 beats/min for 3 wk. Regional changes in contractile function and stress were assessed by magnetic resonance imaging, whereas regional flow and glucose uptake were measured by positron emission tomography utilizing, respectively, the radiotracers [(13)N]ammonia and (18)F-deoxyglucose. In heart failure, LV end-diastolic pressure was 20 +/- 4 mmHg, and ejection fraction was 35 +/- 4% (all P < 0.05 vs. control). Sustained pacing-induced dyssynchronous LV activation caused a more pronounced decrease in LV systolic thickening (7.45 +/- 3.42 vs. 30.62 +/- 8.73%, P < 0.05) and circumferential shortening (-4.62 +/- 1.0 vs. -7.33 +/- 1.2%, P < 0.05) in the anterior/anterior-lateral region (pacing site) compared with the inferoseptal region (opposite site). Conversely, flow was reduced significantly by approximately 32% compared with control and was lower in the opposite site region. Despite these nonhomogeneous alterations, regional end systolic wall stress was uniformly increased by 60% in the failing LV. Similar to wall stress, glucose uptake markedly increased vs. control (0.24 +/- 0.004 vs. 0.07 +/- 0.01 micromol x min(-1) x g(-1), P < 0.05), with no significant regional differences. In conclusion, high-frequency pacing of the LV free wall causes a dyssynchronous pattern of contraction that leads to progressive cardiac failure with a marked mismatch between increased glucose uptake and regional contractile dysfunction. PMID- 17704292 TI - Do vasoregulatory mechanisms in exercising human muscle compensate for changes in arterial perfusion pressure? AB - We tested the hypothesis that vasoregulatory mechanisms completely counteract the effects of sudden changes in arterial perfusion pressure on exercising muscle blood flow. Twelve healthy young subjects (7 female, 5 male) lay supine and performed rhythmic isometric handgrip contractions (2 s contraction/ 2 s relaxation 30% maximal voluntary contraction). Forearm blood flow (FBF; echo and Doppler ultrasound), mean arterial blood pressure (arterial tonometry), and heart rate (ECG) were measured. Moving the arm between above the heart (AH) and below the heart (BH) level during contraction in steady-state exercise achieved sudden approximately 30 mmHg changes in forearm arterial perfusion pressure (FAPP). We analyzed cardiac cycles during relaxation (FBF(relax)). In an AH-to-BH transition, FBF(relax) increased immediately, in excess of the increase in FAPP (approximately 69% vs. approximately 41%). This was accounted for by pressure related distension of forearm resistance vasculature [forearm vascular conductance (FVC(relax)) increased by approximately 19%]. FVC(relax) was restored by the second relaxation. Continued slow decreases in FVC(relax) stabilized by 2 min without restoring FBF(relax). In a BH-to-AH transition, FBF(relax) decreased immediately, in excess of the decrease in FAPP (approximately 37% vs. approximately 29%). FVC(relax) decreased by approximately 14%, suggesting pressure-related passive recoil of resistance vessels. The pattern of FVC(relax) was similar to that in the AH-to-BH transition, and FBF(relax) was not restored. These data support rapid myogenic regulation of vascular conductance in exercising human muscle but incomplete flow restoration via slower-acting mechanisms. Local arterial perfusion pressure is an important determinant of steady-state blood flow in the exercising human forearm. PMID- 17704293 TI - Prediction of atherosclerotic plaque ruptures with high-frequency ultrasound imaging and serum inflammatory markers. AB - Atherosclerotic plaque rupture and thrombosis are the main causes of acute coronary syndrome. In the present study, we investigated whether ultrasound imaging and inflammatory parameters are predictive of plaque rupture in a newly established animal model. We developed a rabbit model for plaque rupture by locally delivering recombinant p53 adenovirus to plaques in rabbits fed a high cholesterol diet for 10 wk, and plaque rupture was triggered using Chinese Russell's viper venom and histamine. We found that 81.1% of rabbits transfected with p53 (n = 37) had the ruptured plaques, which was significantly higher than results in rabbits transfected with the control vector (26.3%, n = 38; P < 0.001). Among measured biomarkers, high-sensitive C-reactive protein, soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1 were significantly different between rabbits with and without ruptured plaques. Using high-frequency duplex and intravascular ultrasound imaging techniques, we obtained a list of parameters. With the multivariate logistic regression model, we identified that plaque eccentric index, plaque area, high-sensitive C-reactive protein, and corrected integrated backscatter intensity were significant predictors of plaque rupture, with odds ratios of 7.056 [95% confidence interval (CI): 1.958, approximately 25.430], 1.942 (95% CI: 1.058, approximately 3.564), 1.025 (95% CI: 1.007, approximately 1.043), and 0.856 (95% CI: 0.775, approximately 0.946), respectively. Localized p53 overexpression technique induces plaque rupture, and the combined measurement of ultrasound and biochemical markers is a valuable tool in predicting plaque rupture. PMID- 17704294 TI - Inhibition of HIV replication by the plasminogen activator is dependent on vitronectin-mediated cell adhesion. AB - Urokinase-type plasminogen activator (uPA), an inducer of macrophage adhesion, inhibits HIV-1 expression in PMA-stimulated, chronically infected U1 cells. We investigated whether uPA-dependent cell adhesion played a role in uPA-dependent inhibition of HIV-1 replication in these cells. Monocyte-derived macrophages (MDM) were generated from monocytes of HIV-infected individuals or from cells of seronegative donors infected acutely in vitro. U1 cells were stimulated in the presence or absence of uPA in standard tissue culture (TC) plates, allowing firm cell adhesion or ultra-low adhesion (ULA) plates. Moreover, U1 cells were also maintained in the presence or absence of vitronectin (VN)-containing sera or serum from VN(-/-) mice. Virus production was evaluated by RT activity in culture supernatants, whereas cell adhesion was by crystal violet staining and optical microscopy. uPA inhibited HIV replication in MDM and PMA-stimulated U1 cells in TC plates but not in ULA plates. uPA failed to inhibit HIV expression in U1 cells stimulated with IL-6, which induces virus expression but not cell adhesion in TC plates. VN, known to bind to the uPA/uPA receptor complex, was crucial for these adhesion-dependent, inhibitory effects of uPA on HIV expression, in that they were not observed in TC plates in the presence of VN(-/-) mouse serum. HIV production in control cell cultures was increased significantly in ULA versus TC plates, indicating that macrophage cell adhesion per se curtails HIV replication. In conclusion, uPA inhibits HIV-1 replication in macrophages via up-regulation of cell adhesion to the substrate mediated by VN. PMID- 17704295 TI - A role for TNF in limiting the duration of CTL effector phase and magnitude of CD8 T cell memory. AB - It is known that TNF-alpha (TNF) exerts distinct tissue-protective or destructive effects in the pathogenesis of T cell-dependent immunopathology, depending on the context and amount of cytokine produced. To better understand the cellular mechanisms underlying the regulation of T cells by TNF, we have analyzed the role of TNF in regulating various facets of the antigen-specific CD8 T cell response to lymphocytic choriomeningitis virus (LCMV) in mice. We show that expansion and differentiation of virus-specific effector CD8 T cells and LCMV clearance are not dependent on TNF. Instead, we demonstrate that TNF limits the duration of the effector phase of the CD8 T cell response by regulating apoptosis and not proliferation of effector cells in vivo. We further show that attenuation of effector cell apoptosis induced by TNF deficiency led to a substantial increase in the number of virus-specific memory CD8 T cells without affecting their function. The enhancement in the number of memory CD8 T cells in TNF-deficient (TNF-/-) mice was not associated with up-regulation of IL-7Ralpha or Bcl-2 in effector cells, which indicated that TNF might limit differentiation of memory cells from IL-7R(lo) effector cells. Collectively, these data are strongly suggestive of a role for TNF in down-regulating CD8 T cell responses and the establishment of CD8 T cell memory during an acute viral infection. These findings further our understanding of the regulation of CD8 T cell homeostasis and have implications in vaccine development and clinical use of anti-TNF therapies to treat T cell-dependent, inflammatory disorders. PMID- 17704296 TI - A hCXCR1 transgenic mouse model containing a conditional color-switching system for imaging of hCXCL8/IL-8 functions in vivo. AB - To address the functions of human CXCL8 (hCXCL8)/IL-8 through hCXCR1 in vivo, we have developed a humanized, transgenic mouse for hCXCR1. This mouse line is versatile and allows for a variety of functional analyses using bioimaging, including Cre/loxP-mediated, tissue-specific hCXCR1 expression in a spatiotemporal manner; a color-switching mechanism, which uses spectrum complementary, genetically encoded green and red fluorescence markers to label the hCXCR1-expressing cells [enhanced GFP (eGFP)] against the background [monomeric red fluorescent protein (mRFP)]; a bioluminescent marker, which is present in the hCXCR1-expressing cells; and an exogenous cell surface marker (eGFP moiety) in the hCXCR1-expressing cells, which facilitates identification, isolation, and targeting of these cells. The established, transgenic founder line RCLG3A (TG(+)) expresses only mRFP and does so ubiquitously. When the RCLG3A mice are crossed with the tamoxifen-inducible, whole-tissue Cre mice (ROSA26 Cre/Esr(+/-)), administration of tamoxifen induces whole-body hCXCR1 expression and color-switching. When RCLG3A mice are crossed with thymocyte-specific Cre mice (Lck-Cre(+/+)), the hCXCR1 expression and color-switching are restricted in a lineage-specific manner. This mouse line can be used to understand the functions of hCXCL-8 in vivo. In addition, our approach and vectors can be used to establish other tissue-specific, transgenic mice in conjunction with multifunctional cell markers, which facilitate cell imaging, tracing, and manipulation in vivo. PMID- 17704297 TI - The association of ICAM-1 Exon 6 (E469K) but not of ICAM-1 Exon 4 (G241R) and PECAM-1 Exon 3 (L125V) polymorphisms with the development of differentiation syndrome in acute promyelocytic leukemia. AB - The use of all trans-retinoic acid (ATRA) is the basis of treatment of acute promyelocytic leukemia (APL) and represents the paradigm of differentiation therapy. In general, ATRA is well-tolerated but may be associated with a potentially lethal side-effect, referred to as retinoic acid or differentiation syndrome (DS). The cellular and molecular mechanisms of DS are poorly understood and involve changes in the adhesive qualities and cytokine secretion of leukemic cells during ATRA-induced differentiation. As leukocyte extravasation is a key event in DS pathogenesis, we analyzed the association between the polymorphisms at Exon 4 (G241R) and Exon 6 (E469K) of ICAM-1 and Exon 3 (L125V) of PECAM-1 genes with DS development in APL patients treated with ATRA and anthracyclines. DS was diagnosed in 23/127 (18.1%) APL patients at an average of 11.5 days after the start of ATRA. All patients presented respiratory distress associated with increased ground-glass opacity in chest radiographies. Other accompanying symptoms were: fever not attributable to infection (65.2%), generalized edema (37.5%), weight gain (37.5%), and impairment of renal function (8.6%). We detected an association between development of DS and the AA genotype at Codon 469 of ICAM-1 (odds ratio of 3.5; 95% confidence interval: 1.2-10.2). Conversely, no significant association was detected between G241R or L125V polymorphisms at Exon 4 of ICAM-1 and Exon 3 of PECAM-1, respectively. Our results suggest that susceptibility to DS in APL patients may be influenced by genetic variation in adhesion molecule loci. PMID- 17704298 TI - S 26948: a new specific peroxisome proliferator activated receptor gamma modulator with potent antidiabetes and antiatherogenic effects. AB - OBJECTIVE: Rosiglitazone displays powerful antidiabetes benefits but is associated with increased body weight and adipogenesis. Keeping in mind the concept of selective peroxisome proliferator-activated receptor (PPAR)gamma modulator, the aim of this study was to characterize the properties of a new PPARgamma ligand, S 26948, with special attention in body-weight gain. RESEARCH DESIGN AND METHODS: We used transient transfection and binding assays to characterized the binding characteristics of S 26948 and GST pull-down experiments to investigate its pattern of coactivator recruitment compared with rosiglitazone. We also assessed its adipogenic capacity in vitro using the 3T3 F442A cell line and its in vivo effects in ob/ob mice (for antidiabetes and antiobesity properties), as well as the homozygous human apolipoprotein E2 knocking mice (E2-KI) (for antiatherogenic capacity). RESULTS: S 26948 displayed pharmacological features of a high selective ligand for PPARgamma with low potency in promoting adipocyte differentiation. It also displayed a different coactivator recruitment profile compared with rosiglitazone, being unable to recruit DRIP205 or PPARgamma coactivator-1 alpha. In vivo experiments showed that S 26948 was as efficient in ameliorating glucose and lipid homeostasis as rosiglitazone, but it did not increase body and white adipose tissue weights and improved lipid oxidation in liver. In addition, S 26948 represented one of the few molecules of the PPARgamma ligand class able to decrease atherosclerotic lesions. CONCLUSIONS: These findings establish S 26948 as a selective PPARgamma ligand with distinctive coactivator recruitment and gene expression profile, reduced adipogenic effect, and improved biological responses in vivo. PMID- 17704300 TI - Inflammation and endothelial activation is evident at birth in offspring of mothers with type 1 diabetes. AB - OBJECTIVE: Offspring of mothers with diabetes are at risk of obesity and glucose intolerance in later life. In adults, markers of subclinical inflammation (C reactive protein [CRP] and interleukin [IL]-6) and endothelial activation (intracellular adhesion molecule [ICAM]-1) are associated with obesity and higher risk for incident type 2 diabetes. We examined whether these biomarkers were elevated at birth in offspring of type 1 diabetic mothers (OT1DM). RESEARCH DESIGN AND METHODS: Umbilical cord plasma CRP, IL-6, and ICAM-1 were measured in 139 OT1DM and 48 control offspring, with analysis relative to fetal lipids and hormonal axes. RESULTS: OT1DM had higher median (interquartile range) CRP (OT1DM 0.17 mg/l [0.13-0.22] vs. control subjects 0.14 mg/l [0.12-0.17], P < 0.001) and ICAM-1 (OT1DM 180 ng/ml [151-202] vs. control subjects 166 ng/ml [145-187], P = 0.047). IL-6 was not different after necessary adjustment for mode of delivery. Birth weight was unrelated to inflammatory indexes; however, leptin was correlated with CRP (control subjects r = 0.33, P = 0.02; OT1DM r = 0.41, P < 0.001) and with IL-6 (r = 0.23, P < 0.01) and ICAM-1 (r = 0.29, P < 0.001) in OT1DM. In OT1DM, CRP correlated with maternal glycemic control (A1C at 35-40 weeks; r = 0.28, P = 0.01). In multivariate analysis, leptin was a determinant of CRP (P < 0.001), ICAM-1 (P = 0.003), and IL-6 (P = 0.02) in OT1DM. Inflammatory measures demonstrated positive relationships with triglycerides in OT1DM (CRP, IL 6, and ICAM-1 P < 0.05) and control subjects (ICAM-1 P = 0.001). CONCLUSIONS: Inflammatory markers are increased in OT1DM and are related to measures of fetal adiposity, particularly leptin, and maternal glycemia. Subclinical inflammation is a novel component of the diabetic intrauterine environment and should be considered a potential etiological mechanism for in utero programming of disease. PMID- 17704301 TI - Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin-resistant subjects. AB - OBJECTIVE: The objective of this study is to quantitate expression of genes possibly contributing to insulin resistance and fat deposition in the human liver. RESEARCH DESIGN AND METHODS: A total of 24 subjects who had varying amounts of histologically determined fat in the liver ranging from normal (n = 8) to steatosis due to a nonalcoholic fatty liver (NAFL) (n = 16) were studied. The mRNA concentrations of 21 candidate genes associated with fatty acid metabolism, inflammation, and insulin sensitivity were quantitated in liver biopsies using real-time PCR. In addition, the subjects were characterized with respect to body composition and circulating markers of insulin sensitivity. RESULTS: The following genes were significantly upregulated in NAFL: peroxisome proliferator activated receptor (PPAR) gamma 2 (2.8-fold), the monocyte-attracting chemokine CCL2 (monocyte chemoattractant protein [MCP]-1, 1.8-fold), and four genes associated with fatty acid metabolism (acyl-CoA synthetase long-chain family member 4 [ACSL4] [2.8-fold], fatty acid binding protein [FABP]4 [3.9-fold], FABP5 [2.5-fold], and lipoprotein lipase [LPL] [3.6-fold]). PPARgamma coactivator 1 (PGC1) was significantly lower in subjects with NAFL than in those without. Genes significantly associated with obesity included nine genes: plasminogen activator inhibitor 1, PPARgamma, PPARdelta, MCP-1, CCL3 (macrophage inflammatory protein [MIP]-1 alpha), PPAR gamma 2, carnitine palmitoyltransferase (CPT1A), FABP4, and FABP5. The following parameters were associated with liver fat independent of obesity: serum adiponectin, insulin, C-peptide, and HDL cholesterol concentrations and the mRNA concentrations of MCP-1, MIP-1 alpha, ACSL4, FABP4, FABP5, and LPL. CONCLUSIONS: Genes involved in fatty acid partitioning and binding, lipolysis, and monocyte/macrophage recruitment and inflammation are overexpressed in the human fatty liver. PMID- 17704302 TI - High glucose attenuates protein S-nitrosylation in endothelial cells: role of oxidative stress. AB - OBJECTIVE: Hyperglycemia-induced endothelial dysfunction, via a defect of nitric oxide (NO) bioactivity and overproduction of superoxide, is regarded as one of the most significant events contributing to the vascular lesions associated with diabetes. However, the mechanisms underlying such hyperglycemic injury remain undefined. We hypothesized that alterations in cellular protein S-nitrosylation may contribute to hyperglycemia-induced endothelial dysfunction. RESEARCH DESIGN AND METHODS: We exposed endothelial cells to high glucose in the presence and absence of reactive oxygen species inhibitors and used the biotin switch assay to analyze the alteration in the global pattern of protein S-nitrosylation compared with cells cultured under normal glucose conditions. We identified endogenous S nitrosylated proteins by mass spectrometry and/or immunoblotting with specific antibodies. RESULTS: High-glucose treatment induced a significant reduction of endogenous S-nitrosylated proteins that include endothelial NO synthase, beta actin, vinculin, diacylglycerol kinase-alpha, GRP78, extracellular signal regulated kinase 1, and transcription factor nuclear factor-kappaB (NF-kappaB). Interestingly, these changes were completely reversed by inhibition of superoxide production, suggesting a key role for oxidative stress in the regulation of S nitrosylation under hyperglycemic conditions. In addition, we found that in parallel with the restoration of decreased S-nitrosylation of NF-kappaB, high glucose-induced NF-kappaB activation was blocked by the superoxide inhibitors. CONCLUSIONS: The alterations in protein S-nitrosylation may underlie the adverse effect of hyperglycemia on the vasculature, such as endothelial dysfunction and the development of diabetic vascular complications. PMID- 17704303 TI - Switching of the core transcription machinery during myogenesis. AB - Transcriptional mechanisms that govern cellular differentiation typically include sequence-specific DNA-binding proteins and chromatin-modifying activities. These regulatory factors are assumed necessary and sufficient to drive both divergent programs of proliferation and terminal differentiation. By contrast, potential contributions of the basal transcriptional apparatus to orchestrate cell-specific gene expression have been poorly explored. In order to probe alternative mechanisms that control differentiation, we have assessed the fate of the core promoter recognition complex, TFIID, during skeletal myogenesis. Here we report that differentiation of myoblast to myotubes involves the disruption of the canonical holo-TFIID and replacement by a novel TRF3/TAF3 (TBP-related factor 3/TATA-binding protein-associated factor 3) complex. This required switching of core promoter complexes provides organisms a simple yet effective means to selectively turn on one transcriptional program while silencing many others. Although this drastic but parsimonious transcriptional switch had previously escaped our attention, it may represent a more general mechanism for regulating cell type-specific terminal differentiation. PMID- 17704305 TI - Pseudocalcification on chest CT scan. AB - Liquid ventilation with perfluorocarbons is used in severe respiratory failure that cannot be managed by conventional methods. Very little is known about the use of liquid ventilation in paediatric patients with respiratory failure and there are no reports describing the distribution and excretion of perfluorocarbons in paediatric patients with severe respiratory failure. The aim of this report is to highlight the prolonged retention of perfluorocarbons in a paediatric patient, mimicking pulmonary calcification and misleading the interpretation of the chest CT scan. A 10-year-old girl was admitted to our intensive care unit with severe respiratory failure due to miliary tuberculosis. Extracorporeal membrane oxygenation (ECMO) was used to support gas exchange and partial liquid ventilation (PLV) with perfluorodecalin was used to aid in oxygenation, lavage the lungs and clear thick secretions. The patient developed a pneumothorax (fluorothorax) on the next day and PLV was discontinued. Multiple bronchoalveolar lavages were performed to clear thick secretions. With no improvement in lung function over the next month a CT scan of the chest was performed. This revealed extensive pulmonary fibrosis and multiple high attenuation lesions suggestive of pulmonary calcification. To exclude perfluorodecalin as the cause for high attenuation lesions, a sample of perfluorodecalin was scanned to estimate the Hounsfield unit density, which was similar to the density of high attenuation lesions on chest CT scan. High-density opacification should be interpreted with caution, especially following liquid ventilation. PMID- 17704306 TI - Granulocytic sarcoma manifested as a parametrial mass mimicking a haemorrhagic abscess: a case report with CT and MR findings. AB - Granulocytic sarcoma is a neoplasm arising from myeloid precursor cells and frequently accompanies leukaemia and myeloproliferative disorders. Granulocytic sarcoma can arise anywhere, and it frequently involves bones, perineural tissues and lymph nodes. However, granulocytic sarcoma in the female genital organs is uncommon, and it is extremely rare that it presents as an adnexal or parametrial mass. We report here the CT and MR findings in a case of granulocytic sarcoma that manifested as a uterine cervical and parametrial mass mimicking a haemorrhagic abscess in a 50-year-old woman with chronic myelogenous leukaemia. PMID- 17704304 TI - A Rap GTPase interactor, RADIL, mediates migration of neural crest precursors. AB - The neural crest (NC) is a highly motile cell population that gives rise to multiple tissue lineages during vertebrate embryogenesis. Here, we identify a novel effector of the small GTPase Rap, called RADIL, and show that it is required for cell adhesion and migration. Knockdown of radil in the zebrafish model results in multiple defects in NC-derived lineages such as cartilage, pigment cells, and enteric neurons. We specifically show that these defects are primarily due to the diminished migratory capacity of NC cells. The identification of RADIL as a regulator of NC migration defines a role for the Rap pathway in this process. PMID- 17704307 TI - Primary localized amyloidosis manifested as supraclavicular and mediastinal lymphadenopathy. AB - Thoracic involvement of amyloidosis is relatively rare, but mediastinal lymphadenopathy in the absence of pulmonary parenchymal involvement is extremely rare. The case presented here is of a previously healthy elderly woman who developed a palpable mass in the right supraclavicular area. The chest CT scan showed extensive, contiguous and homogeneous low attenuated lymphadenopathy with stippled calcification in the right supraclavicular area and mediastinum. Amyloidosis was confirmed histopathologically on a biopsy specimen from a right supraclavicular lymph node. Because there were no other sites found to be affected by amyloidosis and there was no underlying chronic disease, we made a final diagnosis of primary localized amyloidosis involving only the supraclavicular and mediastinal lymph nodes. PMID- 17704308 TI - A viable secondary intra-abdominal pregnancy resulting from rupture of uterine scar: role of MRI. AB - Pre-natal diagnosis of intra-abdominal pregnancy is difficult. Ultrasound has been the frontline modality to date; however, it gives a diagnostic error of 50 90% and its use is disappointing. In recent years, MRI has emerged as an appealing imaging modality. With its good soft tissue contrast and non-ionizing property, it acts as a means of definitive non-invasive assessment before surgical intervention when ultrasound is inconclusive. PMID- 17704310 TI - Fibrosing mediastinitis manifesting as thoracic prevertebral thin band-like mass on MRI and PET-CT. AB - To our knowledge, no report exists of a posterior mediastinal thin band-like mass as a manifestation of fibrosing mediastinitis. A man showed right pleural effusion on chest radiograph. On CT, there was a band-like mass on thoracic prevertebral area. MRI demonstrated the enhancing longitudinal band-like mass all along the vertebrae on coronal and sagittal scans. It was hypermetabolic on PET CT and there was another hot mass in the presacral area. Additional pelvic MRI showed presacral mass with aortic encasement. Biopsy specimen was consistent with fibrosing mediastinitis. We report a case of fibrosing mediastinitis of posterior mediastinum manifesting as thoracic prevertebral band-like mass and discontiguous presacral, periaortic mass studied with CT, MRI and PET-CT. PMID- 17704309 TI - Congenital cystic eye: features on MRI. AB - Congenital cystic eye is a rare cause of cystic orbital lesion. The condition is recognized at birth as a large orbital mass in place of a normal eye. Only 29 cases have been reported previously. We report a case of unilateral congenital cystic eye with multiple brain anomalies in the form of agenesis of corpus callosum and grey matter heterotopias. In this case report we highlight the MRI features of this entity, which have not been described previously in the literature. PMID- 17704311 TI - Nasopharyngeal liposarcoma MRI imaging features and a review of the literature. AB - We present a case of liposarcoma in a 37-year-old female with a chronic history of nasal stuffiness. MR imaging revealed a fatty lesion in the nasopharynx. Subsequent tissue sampling and histopathology demonstrated features consistent with a liposarcoma. PMID- 17704312 TI - Endovascular therapy for a profunda femoris artery aneurysm which ruptured following intravenous thrombolysis. AB - Arterial aneurysms are a relative contraindication for systemic thrombolytic therapy due to the risk of rupture. This case report describes rupture of a rare profunda artery aneurysm (PFAA) following systemic thrombolysis for myocardial infarction. Subsequent imaging and endovascular management of this rare complication is presented with a brief discussion. PMID- 17704313 TI - Duplication of the extrahepatic bile duct with anomalous union of the pancreaticobiliary ductal system revealed by MR cholangiopancreatography. AB - MR cholangiopancreatography (MRCP) is a valuable, non-invasive tool for accurate examination of the biliary system. We report a case in which MRCP played a critical role in the diagnosis of a duplication of the extrahepatic bile duct with anomalous union of the pancreaticobiliary ductal system in a patient with hilar cholangiocarcinoma. This variant of a duplication of the extrahepatic biliary system has not been described previously in the literature. PMID- 17704314 TI - Display considerations for hospital-wide viewing of soft copy images. AB - Digital imaging is progressively replacing film for the acquisition and display of diagnostic images in modern health care. Specifications for the devices used for the soft copy display of images are not currently well defined, nor are the requirements for optimal set-up and quality assurance. This paper considers the current situation and presents potential hospital-wide solutions for the outstanding issues. PMID- 17704315 TI - A comparative study of thoracic radiation doses from 64-slice cardiac CT. AB - The goal of this study was to measure radiation doses for 64-slice cardiac CT angiography studies and to study the dose-savings features of these CT scanners. This was done using various phantoms. These radiation doses were compared with those from typical helical body CT scans, fluoroscopy cardiac catheterization studies and mammography examinations. Radiation measurements were made with a CT ionization detector and a solid state dosimeter. A GE 64-slice Lightspeed VCT and a Siemens Somatom Sensation 64 CT were used to scan a standard 32 cm acrylic phantom and an anthropomorphic phantom. Data were collected in axial and various gated cardiac helical modes. Organ doses and the effective doses were calculated from the measurements. In gated CT cardiac mode with the 32 cm acrylic phantom, the measured radiation doses per study were generally three to seven times greater than those from typical body helical CT examinations; the range depended upon selectable scan parameters. With the anatomical phantom, the surface doses in the anteroposterior (AP) plane were typically 20-60% higher than those measured using the 32 cm phantom. The lateral surface doses were -4% to +15%. These results can be attributed to the shorter AP dimension and the air in the lungs. The CT skin entrance radiation doses were 80-90% less than diagnostic cardiac catheterization studies, and organ doses were similar. Because 64-slice cardiac gated CT uses pitches equal to 0.20-0.27 and high mAs values, the patient radiation doses are appreciably higher than in routine body CT examinations. The female breast, which could receive a radiation dose 10-30 times that received from mammography screening, is an organ of particular concern. PMID- 17704316 TI - Dose reduction and its influence on diagnostic accuracy and radiation risk in digital mammography: an observer performance study using an anthropomorphic breast phantom. AB - This study aimed to investigate the effect of dose reduction on diagnostic accuracy and radiation risk in digital mammography. Simulated masses and microcalcifications were positioned in an anthropomorphic breast phantom. Thirty digital images, 14 with lesions, 16 without, were acquired of the phantom using a Mammomat Novation (Siemens, Erlangen, Germany) at each of three dose levels. These corresponded to 100%, 50% and 30% of the normally used average glandular dose (AGD; 1.3 mGy for a standard breast). Eight observers interpreted the 90 unprocessed images in a free response study, and the data were analysed with the jackknife free response receiver operating characteristic (JAFROC) method. Observer performance was assessed using the JAFROC figure of merit (FOM). The benefit of radiation risk reduction was estimated based on several risk models. There was no statistically significant difference in performance, as described by the FOM, between the 100% and the 50% dose levels. However, the FOMs for both the 100% and the 50% dose were significantly different from the corresponding quantity for the 30% dose level (F-statistic = 4.95, p-value = 0.01). A dose reduction of 50% would result in three to nine fewer breast cancer fatalities per 100,000 women undergoing annual screening from the age of 40 to 49 years. The results of the study indicate a possibility of reducing the dose to the breast to half the dose level currently used. This has to be confirmed in clinical studies, and possible differences depending on lesion type should be examined further. PMID- 17704317 TI - Gadoteridol for MR imaging of lymphatic vessels in lymphoedematous patients: initial experience after intracutaneous injection. AB - The aim of this study was to evaluate the feasibility of gadoteridol in visualizing lymphatic vessels of lymphoedematous patients after intracutaneous injection. 20 lower extremities in 10 lymphoedematous patients were examined. Gadoteridol (9 ml) was subdivided into five portions and injected intracutaneously into the dorsal aspect of each foot. For MRI, a three dimensional spoiled gradient echo sequence was performed. No complications were observed during or after intracutaneous injection of gadoteridol. The lymphoedema was bilateral in seven and unilateral in three of the examined patients. Contrast enhancement of gadoteridol was detected in lymphatic vessels at the level of the lower leg in 17 lower extremities (85%). Enhancing lymphatic vessels of the upper leg were observed in 11 lower extremities (55%). Furthermore, gadoteridol enhanced 10 out of 20 inguinal lymph node groups (50%). No external iliac lymph nodes were observed in any of the patients. Regions of dermal backflow, indicating proximal lymphatic obstruction, were seen in 13 lower extremities (65%). As soon as 15 min after gadoteridol injection, accompanying venous enhancement was detected in all lower extremities (100%). MRI of lymphatic vessels in lymphoedematous patients is safe and feasible after intracutaneous injection of gadoteridol if the diagnosis of lymphoedema necessitates a better definition for optimal therapeutic planning or an objective, diagnostic baseline is required. The proposed technique represents a minimally invasive imaging method of identifying anatomical and physiological derangements in lymphatic vessels. PMID- 17704318 TI - Stability of linear and macrocyclic gadolinium based contrast agents. PMID- 17704319 TI - "Stability" of gadolinium chelates. PMID- 17704320 TI - Groin mass in pregnancy. PMID- 17704321 TI - Oxidative stress signalling: a potential mediator of tumour necrosis factor alpha induced genomic instability in primary vascular endothelial cells. AB - Studying the potential role of tumour necrosis factor (TNF)alpha in the initiation of genomic instability is necessary to understand whether TNFalpha can serve as a signalling mediator of radiation-induced genomic instability in non irradiated bystander cells. In this study, we examined whether TNFalpha could initiate processes through oxidative stress signalling that lead to DNA damage and genomic instability in primary vascular endothelium. In these cells, low linear energy transfer (LET) radiation (0.1-2 Gy) induced the secretion of TNFalpha into the culture medium. When added ectopically, TNFalpha at concentrations ranging from 0.1 ng ml(-1) to 10 ng ml(-1) increased (twofold to threefold) intracellular oxidative stress. Next, to examine whether TNFalpha induces genetic damage, cells were treated with TNFalpha for 5 h and analysed immediately using the single cell gel electrophoresis assay or after 3 days, 12 days and 20 days using solid stain chromosomal analysis. Cells exposed to 0.1 Gy, 1 Gy or 2 Gy or treated with 100 microM H2O2 were used as positive controls. The results showed that TNFalpha as low as 0.1 ng ml(-1) could initiate increased DNA damage compared with untreated controls. When examined in the progeny cells after several generations, the chromosomal instability appeared to be carried over even after day 12 and day 20. The increased genetic damage is inhibited in cells that are pre-incubated with the antioxidant enzyme catalase, the antioxidant N-acetyl L-cysteine or the metal chelator pyrrolidine dithiocarbamate. These results clearly indicate that TNFalpha at concentrations at which no cytotoxicity is observed could induce genetic damage through free radical generation, which could, in turn, lead to the delayed events associated with genomic instability. PMID- 17704322 TI - The genetic basis of tissue responses to ionizing radiation. AB - The response of mammalian cells to ionizing radiation can be directly influenced by genetics, and mouse strains can be identified that differ in their cellular radiosensitivity. The C57BL/6 radiation resistant and DBA/2 radiation susceptible mouse strains were utilized to aid the elucidation of the mechanisms involved in the early response to ionizing radiation. Investigation of the p53 pathway revealed differences in the expression and activity of p53 and its downstream targets between these mouse strains. The radiation resistant C57BL/6 strain showed an early p53 response and preferentially upregulated pro-apoptotic Bax, whereas the radiation sensitive DBA/2 strain exhibited a later, more prolonged p53 response and a greater expression of the cyclin dependent kinase inhibitor p21. These two mouse strains also showed significantly different levels of splenic radiation-induced apoptosis, the radiation resistant C57BL/6 scoring twofold more apoptotic cells than its radiation sensitive counterpart. These data provided a quantitative endpoint for an apoptosis genetic linkage analysis. The preliminary results of the linkage analysis indicated that three distinct loci may be involved in driving the different apoptosis phenotypes exhibited by the mouse strains. Moreover, we ascertained whether the mechanisms involved in the response to ionizing radiation may work in a tissue-specific fashion. In the linkage analysis, comparison of apoptosis scores in the colon and small intestine with data from the spleen showed little correlation suggesting that levels of apoptosis are tissue-specific. Tissue-specificity in the colon and small intestine was further illustrated by work with a 2D gel electrophoresis system. This revealed different patterns of p53 phosphorylation between the intestinal tissues both before and after exposure to ionizing radiation. The data discussed here will aid our understanding of the genes and mechanisms involved in radiation responses. PMID- 17704323 TI - Oxidative damage pathways in relation to normal tissue injury. AB - Given the increasing population of long-term cancer survivors, the need to mitigate or treat late effects has emerged as a primary area of radiation biology research. Once thought to be irreversible, radiation-induced late effects are now viewed as dynamic multicellular interactions between multiple cell types within a particular program that can be modulated. The molecular, cellular and biochemical pathways responsible for radiation-induced late morbidity remain ill-defined. This review provides data in support of the hypothesis that these late effects are driven, in part, by a chronic oxidative stress. Irradiating late responding normal tissues leads to chronic increases in reactive oxygen/reactive nitrogen oxide species that serve as intracellular signaling species to alter cell function/phenotype, resulting in chronic inflammation, organ dysfunction, and ultimate fibrosis and/or necrosis. Furthermore, we hypothesize that the effectiveness of renin-angiotensin system blockers in preventing or mitigating the severity of radiation-induced late effects reflects, in part, inhibition of reactive oxygen species generation and the resultant chronic oxidative stress. These findings provide a robust rationale for anti-inflammatory-based interventional therapies in the treatment of late normal tissue injury. PMID- 17704324 TI - Rho/ROCK pathway as a molecular target for modulation of intestinal radiation induced toxicity. AB - More than half of cancer patients are treated with radiation therapy. Despite its high therapeutic index, radiation therapy can cause disabling injuries to normal tissues, especially in long-term survivors. Thus, one of the great challenges of modern radiation therapy is to increase tolerance of normal tissue to ionizing radiation in order to improve the quality of life of cancer survivors and/or enhance local control using dose escalation. The physiopathological aspects of normal tissue toxicity have been widely explored; however, none of these descriptive findings has led to the development of effective therapeutic strategies. Several empirical treatments have also been used in clinical trials (superoxide dismutase, pentoxifylline-tocopherol); however, the results are still controversial, and their mechanisms of action have not been clearly defined. The recent development of high-throughput biological approaches will contribute greatly to the characterization of the molecular pathways associated with normal tissue toxicity and the identification of specific and effective molecular targets for therapeutic interventions using already known or new pharmacological compounds. In this paper, we will discuss recent advances made in the characterization of one of the most serious complications of radiation therapy, late intestinal toxicity, using molecular profiling. We will focus on the involvement of the Rho/ROCK pathway in the development and maintenance of late radiation enteropathy. The role of the Rho/ROCK pathway in tissue response to radiation injury will be reviewed, as well as therapeutic perspectives. PMID- 17704325 TI - Neuroimmune interactions: potential target for mitigating or treating intestinal radiation injury. AB - Intestinal radiation injury is characterized by breakdown of the epithelial barrier and mucosal inflammation. In addition to replicative and apoptotic cell death, radiation also induces changes in cellular function, as well as alterations secondary to tissue injury. The recognition of these "non-cytocidal" radiation effects has enhanced the understanding of normal tissue radiation toxicity, thus allowing an integrated systems biology-based approach to modulating radiation responses and providing a mechanistic rationale for interventions to mitigate or treat radiation injuries. The enteric nervous system regulates intestinal motility, blood flow and enterocyte function. The enteric nervous system also plays a central role in maintaining the physiological state of the intestinal mucosa and in coordinating inflammatory and fibroproliferative processes. The afferent component of the enteric nervous system, in addition to relaying sensory information, also exerts important effector functions and contributes critically to preserving mucosal integrity. Interactions between afferent nerves, mast cells as well as other cells of the resident mucosal immune system serve to maintain mucosal homeostasis and to ensure an appropriate response to injury. Notably, enteric sensory neurons regulate the activation threshold of mast cells by secreting substance P, calcitonin gene-related peptide and other neuropeptides, whereas mast cells signal to enteric nerves by the release of histamine, nerve growth factor and other mediators. This article reviews how enteric neurons interact with mast cells and other immune cells to regulate the intestinal radiation response and how these interactions may be modified to mitigate intestinal radiation toxicity. These data are not only applicable to radiation therapy, but also to intestinal injury in a radiological terrorism scenario. PMID- 17704326 TI - Human mesenchymal stem cells home specifically to radiation-injured tissues in a non-obese diabetes/severe combined immunodeficiency mouse model. AB - The therapeutic potential of bone marrow-derived human mesenchymal stem cells (hMSC) has recently been brought into the spotlights of many fields of research. One possible application of the approach is the repair of tissue injuries related to side effects of radiotherapy. The first challenge in cell therapy is to assess the quality of the cell and the ability to retain their differentiation potential during the expansion process. Efficient delivery to the sites of intended action is also necessary. We addressed both challenges using hMSC cultured and then infused to non-obese diabetes/severe combined immunodeficiency (NOD/SCID) mice submitted to total body irradiation. Furthermore, we tested the impact of additional abdominal irradiation superimposed to total body irradiation (TBI), as a model of local therapeutic irradiation. Our results showed that the hMSC used for transplant have been expanded without significant loss in their differentiation capacities. After transplantation into adult unconditioned mice, hMSC not only migrate in bone marrow but also into other tissues. Total body irradiation increased hMSC implantation in bone marrow and muscle and further led to engraftment in brain, heart and liver. Local irradiation in addition to TBI, increased homing of injected cells to the injured tissues and to other tissues outside the local irradiation field. Morphological recovery of irradiated tissues after MSC transplantation and/or differentiation of MSC into specific organ cell types needs to be investigated. This study suggests that using the potential of hMSC to home to various organs in response to tissue injuries might be a strategy to repair the radiation-induced damages. PMID- 17704327 TI - Target cell frequency is a genetically determined risk factor in radiation leukaemogenesis. AB - Whole body exposure to ionizing radiation increases the risk of radiation-induced acute myeloid leukaemia (r-AML). r-AML is the result of the accumulation of mutations in a single haemopoietic stem cell, so risk is therefore a function of the number of mutations required to transform the stem cell and the mutation rate. There is a genetic component to the risk of AML within the general population, and low penetrance variant alleles encoding DNA repair enzymes have been genetically implicated in therapy-related AML susceptibility. However, what is largely ignored is that target cell number, which defines the number of genomes at risk from DNA damaging agents, is also part of the equation that defines risk. We will review the evidence from genetic studies of inbred mouse models that target cell frequency is a risk factor in radiation leukaemogenesis. Inbred mouse strains that differ in their susceptibility to radiation-induced r AML and thymic lymphoma (r-TL), spontaneous TL and pristane-induced plasmacytoma (PCT) have been exploited to identify susceptibility loci. The target cell in AML is the haemopoietic stem cell, whereas TLs and PCT arise from more mature lymphoid progenitor cells. Inbred mice also differ significantly in all aspects of haemopoiesis, and these differences have been used to identify quantitative trait loci (QTL) that determine the frequency of specific haemopoietic stem, progenitor or mature blood cells. The co-localization of QTL that determine risk and target cell frequency in all three haemopoietic malignancies is strong evidence that target cell frequency is a risk factor in radiation leukaemogenesis. PMID- 17704328 TI - Reconstruction of doses from ionizing radiation using fluorescence in situ hybridization techniques. AB - This paper reviews cytogenetic methods of biological dosimetry. The most reliable indicator of exposure to ionizing radiation is the observation of dicentrics in human peripheral lymphocytes. The major disadvantage is that dicentrics cannot be used for exposures that occur many years prior to blood sampling. In such cases, translocations are the aberrations of choice, and recent developments in their measurement using fluorescence in situ hybridization techniques are highlighted. PMID- 17704329 TI - The early and initiation processes of radiation-induced bystander effects involved in the induction of DNA double strand breaks in non-irradiated cultures. AB - The initiation and the early process of bystander response induced by low dose alpha-particle irradiation are very important for understanding the mechanisms underlying the bystander response. Using a 1 cGy alpha-particle to irradiate 50% of the area of a rectangular mylar dish, time-dependent DNA double strand breaks (DSBs) were induced shortly after irradiation in AG1522 cells, located either in the irradiated area or in the non-irradiated bystander area, reaching a maximum 30 min post irradiation. Medium transfer experiments showed that the conditioned medium harvested from the irradiated culture induced excessive DNA DSBs in the medium recipient cells, and the DSB-inducing ability of the medium showed was time-dependent. The medium transfer results indicated that the soluble bystander signalling molecule(s) had been generated very soon (probably less than 2.5 min) after irradiation and exist continuously to 30 min although the production of signalling molecule(s) decreased after 10 min post irradiation. Pre-treatment with dimethyl sulphoxide (DMSO) eliminated the DNA DSB-inducing ability of the conditioned medium, as well as the formation of excessive DNA DSBs in both irradiated and non-irradiated bystander areas, indicating that reactive oxygen/nitrogen species etc. might be involved in these processes. PMID- 17704330 TI - Reperfusion syndrome: cellular mechanisms of microvascular dysfunction and potential therapeutic strategies. AB - Reperfusion injury is the paradoxical and complex phenomenon of exacerbation of cellular dysfunction and increase in cell death after the restoration of blood flow to previously ischemic tissues. It involves biochemical and cellular changes causing oxidant production and complement activation, which culminates in an inflammatory response, mediated by neutrophil and platelet cell interactions with the endothelium and among the cells themselves. The mounted inflammatory response has both local and systemic manifestations. Despite improvements in imaging, interventional techniques, and pharmacological agents, morbidity from reperfusion remains high. Extensive research has furthered the understanding of the various pathophysiological mechanisms involved and the development of potential therapeutic strategies. Preconditioning has emerged as a powerful method of ameliorating ischemia reperfusion injury to the myocardium and in transplant surgery. More recently, postconditioning has been shown to provide a therapeutic counter to vasoocclusive emergencies. More research and well-designed trials are needed to bridge the gap between experimental evidence and clinical implementation. PMID- 17704331 TI - Impact of endoluminal treatment on small abdominal aortic aneurysm: aneurysm sac regression and secondary interventions with 5 years of follow-up. AB - Does early repair of small abdominal aortic aneurysms (AAAs) lead to faster aneurysm sac regression or less secondary intervention? Computed tomography scans and reconstructions from M2S of all patients undergoing endovascular AAA repair at our institution from 1996 to 2006 were retrospectively reviewed. A small aneurysm is defined as an aneurysm sac to renal diameter ratio of less than 2. There were 374 patients with endovascular AAA repair that had complete imaging studies. There were 75 patients (20%) with small AAAs; of those, 19 patients (25.3%) had endoleak compared with 108 patients (36.1%) with a large aneurysm ( P = .1). Over a mean follow-up time of 42 months (range, 1-109), 11 small AAAs (14.7%) had secondary interventions compared with 58 (19.4%) of the large AAAs (P = .41). Small AAAs at 5 years had a 2.5% volume sac regression but a 3.0% increase in diameter. Those with a large aneurysm had a slight increase in sac volume and diameter at 1 month (3.3%, 1.4%) and then steadily decreased to -13.4% and -8.8% at 5 years. Patients with Endologix (Endologix Inc., Irvine, Calif) devices have the most regression when compared with patients with AneuRx (Medtronic Inc., Minneapolis, Minn) and Talent (Medtronic Inc., Minneapolis, Minn) devices. Early endovascular intervention in small AAAs does not result in faster aneurysm sac regression or secondary intervention. Aneurysm sac regression is significantly affected by endoleak, aneurysm size, and device used. PMID- 17704332 TI - Midterm results of endovascular infrarenal abdominal aortic aneurysm repair in high-risk patients. AB - Short-term and midterm clinical outcomes after endovascular repair of abdominal aortic aneurysms (AAAs) have been well documented. Evaluation of longer term outcomes is now possible. Here we describe our initial 100 high-risk patients treated with endovascular aneurysm repair (EVAR), all with a minimum of 5 years of follow-up. A retrospective review of prospectively recorded data in a departmental database was undertaken for the first 100 consecutive EVAR patients with a minimum of 5 years (range, 60-105 months) of follow-up performed between December 1997 and June 2001. Information was obtained from surgical follow-up visits and family doctors' offices. Endovascular repair of AAA in high-risk patients can be achieved with acceptably low postoperative mortality and morbidity. Longer term results in this high-risk cohort suggest that EVAR is effective in preventing aneurysm-related deaths at 5 years and beyond. All late mortalities were due to patients' comorbid diseases. PMID- 17704333 TI - Remote superficial femoral artery endarterectomy: early results for TASC D lesions in patients with severe ischemia. AB - Endovascular treatment for Transatlantic Inter-Society Consensus (TASC) D lesions of the superficial femoral artery has been disappointing. This has been attributed to a bulking atheromatous plaque. Debulking the superficial femoral artery allows for a larger lumen, whereas covering the lumen with an endograft provides in-line flow. We evaluated the intermediate results of remote superficial femoral artery endarterectomy with covered endograft placement in 18 patients. Patient demographic, vascular laboratory, and preoperative data were gathered retrospectively. The procedure was technically successful in all the patients. The mean age was 62.2 +/- 9.9 years. Ankle brachial index improved from 0.35 +/- 0.1 to 0.86 +/- 0.1. The cumulative 12-month primary patency was 42.2%, whereas assisted primary or secondary patency was 70.8%. Five endografts occluded within the 12 months. Two of those patients underwent subsequent femoral-to-below knee bypass, whereas 2 had major amputations. Remote superficial femoral artery endarterectomy can be reasonably offered if an autogenous conduit is not available for revascularization of the superficial femoral artery. PMID- 17704334 TI - Computed tomography angiography to evaluate thoracic outlet neurovascular compression. AB - The objective was to evaluate the efficacy of computed tomography angiography with upper extremity hyperabduction to diagnose thoracic outlet syndrome. Over 5 years, 21 patients were treated surgically for neurogenic symptoms of thoracic outlet syndrome. For patients whose diagnosis was unclear after history and physical examination, adjunctive tests (duplex, magnetic resonance angiography, or computed tomography angiography) were performed to help establish the diagnosis. Five of the 6 computed tomography angiograms were positive. The sixth computed tomography was deemed to be an incomplete study. With mean follow-up of 9.4 months, 95% (n = 19) of patients with a positive hyperabduction test on physical examination were free of symptoms postoperatively. All patients with a positive computed tomography angiogram, with their neurovascular compression localized to the thoracic outlet, had successful operative decompression. Computed tomography angiogram with abduction of the arm can be used as an adjunct to confirm the diagnosis of neurovascular compression and then predict successful operative decompression. PMID- 17704335 TI - Platelet activation in bypass surgery for critical limb ischemia. AB - Platelet activation contributes to graft occlusion after bypass surgery. This study investigated platelet activation status before, during, and after bypass. Blood was taken preoperatively from patients undergoing femoro-popliteal bypass and at incision, after dissection, after ischemia, after reperfusion, 24 hours after surgery, and almost 2 years after bypass (and given aspirin or warfarin). Platelet aggregation was measured using a turbidimetric method and platelet activation with flow cytometry. Statistical analysis was performed using Mann Whitney U and Wilcoxon's tests. Resting platelet activation was similar between controls and patients undergoing bypass. Platelet activation decreased at incision but remained highly reactive. Platelet aggregation increased after dissection and the ischemic phase but significantly decreased after reperfusion. Platelet aggregation and activation were increased at 24 hours and subsequently after bypass. Platelets in critical limb ischemia exist in the primed state and become activated by minimum stimuli. Increased platelet activation occurs after bypass grafting for critical limb ischemia despite adjunctive therapy. PMID- 17704336 TI - Decreased antioxidant vitamin concentration may be a risk factor for recurrent carotid stenosis. AB - Carotid endarterectomy has been found to be associated with a transient increase in systemic oxidative stress, and this has been shown to be a predictor of restenosis. The aim of this study was to determine the incidence of early recurrent stenosis and investigate a possible role of oxidative stress in its development by measuring the concentration of antioxidant vitamins. Patients undergoing carotid endarterectomy between August 2001 and February 2003 were included in the study. A preoperative blood sample was analyzed for antioxidant vitamin concentrations. All patients were followed up by duplex scans 3 and 12 months postoperatively. Ninety-three patients (101 carotid endarterectomies) were recruited. Nine arteries had developed restenosis by 12 months. Those patients who developed recurrent stenosis had significantly lower vitamin C concentrations (19.10 +/- 3.69 vs 30.11 +/- 19.10, P = .02) than those who did not. This study suggests that low antioxidant vitamin levels may predispose to early restenosis after carotid endarterectomy. PMID- 17704337 TI - Intraoperative coil embolization reduces transplant nephrectomy transfusion requirement. AB - Transplant nephrectomy for failed renal transplants can be challenging. Patients often have numerous comorbidities, and the procedure may be associated with considerable blood loss. This study was performed to determine if intraoperative coil embolization of the transplant renal artery reduces blood loss associated with transplant nephrectomy. Data were collected retrospectively on 13 consecutive transplant nephrectomies performed immediately following coil embolization and compared with the 13 most recently performed consecutive transplant nephrectomies without coil embolization. The groups were compared for operative time, estimated blood loss, and transfusion requirements. Mean age was 45 in both groups. There were no major complications in either group. Operative times were not significantly different, although open operative time was reduced in the embolization group (113 vs 96 minutes). Estimated blood loss was 465 mL versus 198 mL (P = .035); packed red blood cell requirements during the operation and subsequent 48 hours were 1.85 units versus 0.31 units (P = .008) and during the operation and subsequent hospital stay were 2.3 units versus 0.69 units (P = .027) in the nonembolized group and embolized group, respectively. Intraoperative embolization of the transplant renal artery immediately prior to surgery facilitates transplant nephrectomy by significantly reducing intraoperative blood loss and transfusion requirements while slightly reducing open operative time. PMID- 17704338 TI - Effect of folic acid and vitamins B6 and B12 on microcirculatory vasoreactivity in patients with hyperhomocysteinemia. AB - OBJECTIVE: Hyperhomocysteinemia (HHcy) has been identified as an independent risk factor for atherosclerotic vascular disease. The effect of high-dose folic acid or combination vitamin therapy for the treatment of HHcy on the microcirculation is unknown. The purpose of this study was to evaluate the effect of a combination of folic acid, vitamin B6, and vitamin B12 on endothelium-dependent and endothelium-independent vasoreactivity in patientswith HHcy. METHODS: Baseline cutaneous microvascular vasoreactivity was measured in 20 patients with HHcy and 18 patients with normohomocysteinemia (NHcy). Laser Doppler scan imaging before and after iontophoresis of 1% acetylcholine chloride (endothelium-dependent response) and 1% sodium nitroprusside (endothelium-independent response) was performed for the measurement of forearm skin vasodilatation. Patients were then treated with 10 mg folic acid, 100 mg vitamin B6, and 1 mg vitamin B12 orally once a day for 6 months. Follow-up fasting serum homocysteine and cutaneous Laser Doppler scan imaging before and after iontophoresis were performed at 1, 2, 3, and 6 months. Statistical analysis was performed using Fisher's exact test, paired t test, and Wilcoxon matched-pairs signed-ranks test, with significance set at P < .05. RESULTS: The HHcy group was older than the NHcy group (70.89 +/- 1.95 vs 61.78 +/- 2.73 years, P = .02). Otherwise the groups were similar in terms of race, tobacco use, comorbid diseases, and serum lipoproteins. Over the 6 month period, fasting serum homocysteine levels decreased significantly in both the NHcy group (10.40 +/- 0.59 micromol/L vs 8.97 +/- 0.84 micromol/L, P = .01) and the HHcy group (19.80 +/- 1.06 micromol/L vs 13.40 +/- 0.86 micromol/L, P = .0002). There were no statistically significant changes in endothelium independent vasoreactivity (voltage change from baseline) in either group. Endothelium-independent vasore activity decreased over the 6-month period in the HHcy group (0.20 +/- 0.04 V vs 0.11 +/- 0.03 V, P = .03). Subanalysis of HHcy with diabetes or age greater than 65 years both showed worsening trends in endothelium-independent vasoreactivity (P = .05 for both groups). There were no statistically significant changes in endothelium-independent vasoreactivity in the NHcy group. CONCLUSIONS: High doses of folic acid and vitamins B6 and B12 lower fasting serum homocysteine levels in patients with HHcy. Older and diabetic patients with HHcy tend to do worse possibly because of long-term fixed microvascular insult secondary to multiple sustained comorbidities. PMID- 17704339 TI - Arterial occlusion after repetitive angio-seal device closure. PMID- 17704340 TI - Adjunctive uses of the radial artery for emergency infrapopliteal bypass in patients presenting with acute limb-threatening ischemia. AB - Although the radial artery has proven to be a reliable conduit for arterial bypass procedures in cardiac surgery, its use in lower extremity revascularization has been limited due to its length. In patients who have undergone multiple cardiovascular procedures, venous conduit options can be limited, and infrapopliteal bypass with prosthesis has been shown to yield poor patency rates. In this report, the authors describe 3 different uses of the radial artery in patients with acute limb-threatening ischemia in the redo setting, which resulted in limb salvage. PMID- 17704341 TI - Ureteral perigraft fistula. AB - Ureteral injury following aortic surgery occurs in less than 1% of all cases. Ureteral-arterial fistulae rarely occur in the current literature and only in case reports. This case involves a suspected ureteral aortic graft fistula presenting with acute hematuria with distant history of redo aortic bifemoral graft for aortoenteric fistula. Cystoscopy with retrograde pyelogram was performed and demonstrated what appeared to be a fistula between the left ureter and the aortic graft with a proximal hydroureter and hydronephrosis. After a detailed review of the films, we diagnosed a more benign ureteral perigraft fistula. Multidisciplinary management including urology and vascular surgery suggested conservative management. However, the patient later required more definitive therapy for his illness. This case demonstrates a ureteral perigraft fistula and displays how it appears radiographically. Here we present our experience with this new radiological diagnosis. PMID- 17704342 TI - Endovascular repair of cervical aortic arch aneurysm. AB - Cervical aortic arch (CAA) is a rare congenital anomaly of the aortic arch. Rarely, CAA is associated with aneurysm of the arch and great vessels. A 32-year old male patient, previously in good health, presented with 2 weeks of severe chest pain. Radiographic evaluation revealed a CAA with aneurysmal dilation of the distal aortic arch. The aneurysm extended into the left subclavian artery. There was also marked angulation just distal to the aneurysmal portion. The aneurysmal arch and subclavian artery were repaired using a thoracic aortic endograft. An open axillary-to-axillary bypass was performed, and the left axillary artery was ligated proximally. This restored perfusion to the left upper extremity and effectively excluded the aneurysm sac. Immediately postoperatively, the patient's chest pain resolved, and he has remained symptom free. To the authors' knowledge, this is the first reported repair of a cervical arch aneurysm by endovascular technique. PMID- 17704343 TI - Autologous great saphenous vein tailored graft to replace an infected prosthetic graft in the groin. AB - The authors propose a technique using the autologous great saphenous vein to replace an infected prosthetic limb graft at the groin. The whole great saphenous vein is incised longitudinally and divided into 2 approximately equal segments, which are sewn side to side. The longitudinal edges of the resulting great saphenous vein are then joined and anastomosed side to side to form a conduit, whose caliber is twice the original vein's diameter. The authors have used this technique to replace 1 limb of a prosthetic aortofemoral bypass infected at the groin. After 5 years, the new venous conduit is patent, with no recurrent infection, dilation, or aneurysmal degeneration. If validated by further experiences, this might be an attractive alternative to restoring flow through clean tissue planes using extra-anatomic bypass or the femoral vein in the infected fields. PMID- 17704344 TI - Hypercoagulable state due to alcohol-paracetamol syndrome producing acute limb ischemia. AB - The authors describe a man with alcohol-paracetamol syndrome and hepatic failure who presented with acute arterial thrombosis of the left limb. The patient has jaundice, increased serum transaminase levels, and significant coagulopathy, with elevated international normalized ratio and prolonged prothrombin time. A transient hypercoagulable state due to liver failure is documented, characterized by acquired deficiencies of antithrombin III, protein C, and protein S. Laboratory and molecular testing for inherited hypercoagulable disorders during the follow-up period is positive for increased levels of factor VIII. The patient undergoes successful thrombectomy and receives intensive symptomatic and causal treatment, resulting in complete recovery. The patient is discharged 20 days after admission on a regimen of acenocoumarol. PMID- 17704345 TI - Changes in vigorous physical activity and incident diabetes in male runners. AB - OBJECTIVE: We examined the relationship between changes in reported vigorous exercise and self-reported physician-diagnosed diabetes in 25,988 active men. RESEARCH DESIGN AND METHODS: The dose-response relationship between changes in reported vigorous exercise (running distance, change in kilometers per week) and self-reported physician-diagnosed diabetes was followed prospectively for 7.8 +/- 1.8 years (means +/- SD). RESULTS: Logistic regression analyses showed that the log odds for diabetes declined significantly in relation to men's change in running distance (coefficient +/- SE: -0.012 +/- 0.004, P < 0.01), which remained significant when adjusted for BMI (-0.018 +/- 0.003, P < 0.0001). The decline in the log odds for diabetes was related to the distance run at the end of follow-up when adjusted for baseline distance, with (-0.024 +/- 0.005, P < 0.0001) or without (-0.027 +/- 0.005, P < 0.0001) adjustment for BMI. Baseline distance was unrelated to diabetes incidence when adjusted for the distance at the end of follow-up. Compared with men who ran < 8 km/week at the end of follow-up, incidence rates in those who ran > or = 8 km/week were 95% lower between 35 and 44 years of age (P < 0.0001), 92% lower between 45 and 54 (P < 0.0001), 87% lower between 55 and 64 (P < 0.0001), and 46% lower between 65 and 75 (P = 0.30). For the subset of 6,208 men who maintained the same running distance during follow-up (+/-5 km/week), the log odds for diabetes declined with weekly distance run ( 0.024 +/- 0.010, P = 0.02) but not when adjusted for BMI (-0.005 +/- 0.010, P = 0.65). CONCLUSIONS: Vigorous exercise significantly reduces diabetes incidence, due in part to the prevention of age-related weight gain and in part to other exercise effects. PMID- 17704346 TI - Plasma asymmetric dimethylarginine (ADMA) is associated with retinopathy in type 2 diabetes. PMID- 17704347 TI - Dehydroepiandrosterone administration counteracts oxidative imbalance and advanced glycation end product formation in type 2 diabetic patients. AB - OBJECTIVE: Dehydroepiandrosterone (DHEA) has been shown to prevent oxidative stress in several in vivo and in vitro models. This study aimed to evaluate the effects of DHEA administration on oxidative stress, pentosidine concentration, and tumor necrosis factor (TNF)-alpha/TNF-alpha receptor system activity in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Twenty patients were enrolled in the study and randomly assigned to the DHEA (n = 10) or placebo (n = 10) group. Twenty healthy sex- and age-matched subjects with normal glucose levels served as control subjects. DHEA was given as a single daily dose of 50 mg for 12 weeks. RESULTS: Oxidative stress parameters were significantly higher in diabetic patients versus control subjects. Pentosidine levels, as well as soluble TNF receptor (sTNF-R)I and sTNF-RII, were also higher in diabetic patients. After DHEA, plasma levels of reactive oxygen species and hydroxynonenal dropped by 53 and 47%, respectively, whereas the nonenzymatic antioxidants glutathione and vitamin E increased (+38 and +76%, respectively). The same changes in oxidative parameters were detected in peripheral blood mononuclear cells (PBMCs). DHEA treatment also induced a marked decrease of pentosidine plasma concentration in diabetic patients (-50%). Moreover, the TNF-alpha/TNF-alpha receptor system was shown to be less activated after DHEA treatment, in both plasma and PBMCs. CONCLUSIONS: Data indicate that DHEA treatment ameliorates the oxidative imbalance induced by hyperglycemia, downregulates the TNF-alpha/TNF-alpha receptor system, and prevents advanced glycation end product formation, suggesting a beneficial effect on the onset and/or progression of chronic complications in type 2 diabetic patients. PMID- 17704349 TI - Lower somatostatin expression is an early event in diabetic retinopathy and is associated with retinal neurodegeneration. AB - OBJECTIVE: To test the hypothesis that a reduction of somatostatin (SST) in the retina exists in patients without clinically detectable diabetic retinopathy and that it is associated with retinal neurodegeneration. RESEARCH DESIGN AND METHODS: Human diabetic postmortem eyes (n = 10) without clinically detectable retinopathy were compared with eyes (n = 10) from nondiabetic donors. SST mRNA (RT-PCR) and SST-28 immunoreactivity (confocal laser) were measured separately in neuroretina and retinal pigment epithelium (RPE). In addition, SST-28 (radioimmunoassay) was measured in the vitreous fluid. Glial fibrillar acidic protein (GFAP) was assessed by immunofluorescence and Western blot. Apoptotic cells were quantified using transferase-mediated dUTP nick-end labeling. RESULTS: A higher expression of SST was detected in RPE than neuroretina in both groups. SST mRNA levels and SST-28 immunoreactivity were significantly lower in both RPE and the neuroretina from diabetic donors compared with nondiabetic donors. These results were in agreement with those obtained by measuring SST-28 in the vitreous fluid of the same donors. Increased GFAP and a higher degree of apoptosis were observed in diabetic retinas compared with nondiabetic retinas. These changes were most evident in patients with the higher deficit of SST. CONCLUSIONS: Underproduction of SST is an early event in the eyes of diabetic patients and is associated with glial activation and neural death. In addition, our results suggest that RPE is an important source of SST in the human eye. The possible role of the lower production of SST in the pathogenesis of diabetic retinopathy requires further investigation. PMID- 17704350 TI - The knowledge translation paradigm: historical, philosophical, and practice perspectives. PMID- 17704348 TI - Insulin resistance, metabolic syndrome, and subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis (MESA). AB - OBJECTIVE: To investigate the association of insulin resistance and clinically defined metabolic syndrome (MetS) with subclinical atherosclerosis and examine whether these relationships vary by race/ethnicity or sex. RESEARCH DESIGN AND METHODS: Subclinical atherosclerosis was assessed by coronary artery calcium (CAC) and carotid intima-medial thickness (IMT) in 5,810 participants without diabetes in the Multi-Ethnic Study of Atherosclerosis, a cohort of adults aged 45 84 years without prior cardiovascular disease (CVD). Fasting insulin and glucose were utilized to estimate insulin resistance by the homeostasis model assessment of insulin resistance (HOMA-IR) index, and the revised National Cholesterol Education Program definition of MetS was utilized. Multivariable linear or relative risk regression was used to analyze the association between HOMA-IR and subclinical atherosclerosis and assess its independence from MetS components. RESULTS: HOMA-IR was associated with increased IMT after adjustment for demographics (age, site, and education), smoking, education, and LDL cholesterol in each ethnic group, except Hispanic subjects, and in both men and women. After further adjusting for nonglucose MetS components, HOMA-IR was not associated with increased IMT. Subjects in the highest quintile of HOMA-IR had an elevated prevalence of CAC in each ethnic group and both sexes, after adjustment for demographics, smoking, and LDL but not after further adjustment for nonglucose MetS components. Among those with detectable CAC, there was no significant relationship between HOMA-IR and the amount of CAC. CONCLUSIONS: Although HOMA-IR was associated with increased subclinical atherosclerosis, the association was not independent of the risk factors that comprise MetS. Determination of HOMA-IR is unlikely to contribute to improved determination of risk of subclinical CVD. PMID- 17704351 TI - Closing evidence to practice gaps in emergency care: the Australian experience. AB - The National Institute of Clinical Studies (NICS) was established in 2000 by the Australian government to improve health care by closing evidence-practice gaps. Improving emergency care through use of evidence is a priority area of work for NICS. This article describes the NICS Emergency Care Program and the current application of a "Community of Practice" to support emergency clinicians to implement best practices research. This approach combines aspects of evidence implementation science, quality improvement techniques, and knowledge management within a social network model to provide a mechanism for rapid sharing of explicit and tacit knowledge. Through the Community of Practice, the clinical community guides the priorities for the Emergency Care Program and is actively engaged in the development and implementation of initiatives. PMID- 17704352 TI - A standardized approach to performing the action research arm test. AB - The study of stroke and its treatment in human subjects requires accurate measurement of behavioral status. Arm motor deficits are among the most common sequelae after stroke. The Action Research Arm Test (ARAT) is a reliable, valid measure of arm motor status after stroke. This test has established value for characterizing clinical state and for measuring spontaneous and therapy-induced recovery; however, sufficient details have not been previously published to allow for performance of this scale in a standardized manner over time and across sites. Such an approach to ARAT scoring would likely reduce variance between investigators and sites. This report therefore includes a manual that provides a highly detailed and standardized approach for assigning ARAT scores. Intrarater reliability and interrater reliability, as well as validity, with this approach were measured and are excellent. The ARAT, when performed in a standardized manner, is a useful tool for assessment of arm motor deficits after stroke. PMID- 17704353 TI - Development of advanced-type multi-functional electronic personal dosemeter. AB - An advanced-type small, light, multi-functional electronic personal dosemeter has been developed using silicon semiconductor radiation detectors for dose management of workers at nuclear power plants and accelerator facilities. This dosemeter is 62 x 82 x 27 mm(3) in size and approximately 130 g in weight, which is capable of measuring personal gamma ray and neutron dose equivalents, Hp(10), simultaneously. The neutron dose equivalent can be obtained using two types of silicon semiconductors: a slow-neutron sensor (<1 MeV) and a fast-neutron sensor (>1 MeV). The slow neutron sensor is a 10 x 10 mm(2) p-type silicon on which a natural boron layer is deposited around an aluminium electrode. The fast neutron sensor is also a 10 x 10 mm(2) p-type silicon crystal on which an amorphous silicon hydride is deposited. The neutron energy response corresponding to the fluence-to-dose-equivalent conversion coefficient given by ICRP Publication 74 has been evaluated using a monoenergetic neutron source from 250 keV to 15 MeV at the Fast Neutron Laboratory of Tohoku University. As the result, the Hp(10) response to neutrons in the energy range of 250 keV and 4.4 MeV within +/-50% difference has been obtained. PMID- 17704354 TI - Mitochondrially targeted effects of berberine [Natural Yellow 18, 5,6-dihydro 9,10-dimethoxybenzo(g)-1,3-benzodioxolo(5,6-a) quinolizinium] on K1735-M2 mouse melanoma cells: comparison with direct effects on isolated mitochondrial fractions. AB - Berberine [Natural Yellow 18, 5,6-dihydro-9,10-dimethoxybenzo(g)-1,3 benzodioxolo(5,6-a)quinolizinium] is an alkaloid present in plant extracts and has a history of use in traditional Chinese and Native American medicine. Because of its ability to arrest the cell cycle and cause apoptosis of several malignant cell lines, it has received attention as a potential anticancer therapeutic agent. Previous studies suggest that mitochondria may be an important target of berberine, but relatively little is known about the extent or molecular mechanisms of berberine-mitochondrial interactions. The objective of the present work was to investigate the interaction of berberine with mitochondria, both in situ and in isolated mitochondrial fractions. The data show that berberine is selectively accumulated by mitochondria, which is accompanied by arrest of cell proliferation, mitochondrial fragmentation and depolarization, oxidative stress, and a decrease in ATP levels. Electron microscopy of berberine-treated cells shows a reduction in mitochondria-like structures, accompanied by a decrease in mitochondrial DNA copy number. Isolated mitochondrial fractions treated with berberine had slower mitochondrial respiration, especially when complex I substrates were used, and increased complex I-dependent oxidative stress. It is also demonstrated for the first time that berberine stimulates the mitochondrial permeability transition. Direct effects on ATPase activity were not detected. The present work demonstrates a number of previously unknown alterations of mitochondrial physiology induced by berberine, a potential chemotherapeutic agent, although it also suggests that high doses of berberine should not be used without a proper toxicology assessment. PMID- 17704355 TI - Ethanol sensitivity of GABAergic currents in cerebellar granule neurons is not increased by a single amino acid change (R100Q) in the alpha6 GABAA receptor subunit. AB - Cerebellar granule neurons (CGNs) extrasynaptically express GABA(A) receptors containing alpha(6)beta(x)delta subunits, which mediate tonic inhibitory currents. Although it has been shown that the function of these receptors is potently and directly enhanced by ethanol, this finding has not been reproducible across different laboratories. In outbred Sprague-Dawley rats, a naturally occurring arginine (R) to glutamine (Q) mutation in position 100 of the alpha(6) subunit was reported to increase the ethanol sensitivity of these receptors. However, we did not detect an action of this mutation in selectively bred rats (alcohol-tolerant and alcohol-nontolerant). Consequently, we reexamined the effect of the mutation on ethanol sensitivity in Sprague-Dawley rats. Using patch clamp electrophysiological techniques in cerebellar vermis parasagittal slices, we found that 25 mM ethanol increases the tonic current amplitude, tonic current noise, and spontaneous inhibitory postsynaptic current (sIPSC) frequency to a similar extent in alpha(6)-100R/100R and alpha(6)-100Q/100Q CGNs. Exposure to 80 mM ethanol increased the tonic current amplitude to a significantly greater extent in alpha(6)-100R/100R than in alpha(6)-100Q/100Q CGNs; however, the effects of 80 mM ethanol on the tonic current noise and sIPSC frequency were not significantly different between these groups. In the presence of tetrodo-toxin, a non-N-methyl-d-aspartate receptor antagonist, exogenous GABA, and a GABA transporter inhibitor, neither 8 nor 40 mM ethanol consistently affected tonic current amplitude or noise in alpha(6)-100R/100R or alpha(6)-100Q/100Q CGNs. Thus, the alpha(6)-R100Q GABA(A) receptor subunit polymorphism does not in-crease the acute ethanol sensitivity of extrasynaptic receptors, lending further support to the hypothesis that ethanol modulates these currents indirectly via a presynaptic mechanism. PMID- 17704357 TI - Gadolinium-enhanced MR imaging and nephrogenic systemic fibrosis: retrospective study of a renal replacement therapy cohort. AB - PURPOSE: To retrospectively compare the frequency of administration and cumulative dose of gadolinium-based contrast agent in dialysis-dependent patients who did and those who did not develop nephrogenic systemic fibrosis. MATERIALS AND METHODS: The ethics committees granted exempt status for this study and also waived the need for informed consent. A retrospective analysis was performed of all adult patients undergoing dialysis in the west of Scotland between January 1, 2000, and July 1, 2006. Diagnoses of nephrogenic systemic fibrosis, episodes of gadolinium-enhanced magnetic resonance (MR) imaging, and cumulative doses of gadolinium-based contrast agent were recorded. Outcomes were analyzed by means of parametric and nonparametric testing. RESULTS: Fourteen of 1826 patients had a diagnosis of nephrogenic systemic fibrosis. Mortality was similar for affected and nonaffected patients. Thirteen (93%) of 14 patients with nephrogenic systemic fibrosis had undergone gadolinium-enhanced MR imaging compared with 408 (22.5%) of 1812 nonaffected patients (P<.001). Patients with nephrogenic systemic fibrosis received a higher median cumulative dose of gadodiamide (0.39 vs 0.23 mmol per kilogram of body weight, P=.008) and underwent more gadolinium-enhanced MR imaging than their nonaffected gadolinium-exposed counterparts. CONCLUSION: The data support a positive association between gadolinium-based contrast agent administration and development of nephrogenic systemic fibrosis in the established renal failure population; in addition, there is a positive association between cumulative dose of gadodiamide used and dosing events. PMID- 17704356 TI - Cyclooxygenase inhibition limits blood-brain barrier disruption following intracerebral injection of tumor necrosis factor-alpha in the rat. AB - Increased permeability of the blood-brain barrier (BBB) is important in neurological disorders. Neuroinflammation is associated with increased BBB breakdown and brain injury. Tumor necrosis factor (TNF)-alpha is involved in BBB injury and edema formation through a mechanism involving matrix metalloproteinase (MMP) up-regulation. There is emerging evidence indicating that cyclooxygenase (COX) inhibition limits BBB disruption following ischemic stroke and bacterial meningitis, but the mechanisms involved are not known. We used intracerebral injection of TNF-alpha to study the effect of COX inhibition on TNF-alpha-induced BBB breakdown, MMP expression/activity, and oxidative stress. BBB disruption was evaluated by the uptake of (14)C-sucrose into the brain and by magnetic resonance imaging utilizing gadolinium-diethylenetriaminepentaacetic acid as a paramagnetic contrast agent. Using selective inhibitors of each COX isoform, we found that COX 1 activity is more important than COX-2 in BBB opening. TNF-alpha induced a significant up-regulation of gelatinase B (MMP-9), stromelysin-1 (MMP-3), and COX 2. In addition, TNF-alpha significantly depleted glutathione as compared with saline. Indomethacin (10 mg/kg i.p.), an inhibitor of COX-1 and COX-2, reduced BBB damage at 24 h. Indomethacin significantly attenuated MMP-9 and MMP-3 expression and activation and prevented the loss of endogenous radical scavenging capacity following intracerebral injection of TNF-alpha. Our results show for the first time that BBB disruption during neuroinflammation can be significantly reduced by administration of COX inhibitors. Modulation of COX in brain injury by COX inhibitors or agents modulating prostaglandin E(2) formation/signaling may be useful in clinical settings associated with BBB disruption. PMID- 17704358 TI - Neurocognitive function in same-sex twins following focal radiation for medulloblastoma. AB - Increased neurotoxicity and poor long-term neurocognitive outcome of preschool children treated for brain tumors have led to innovative therapeutic strategies in order to delay or avoid the use of craniospinal radiation and to improve survival. Because these protocols are relatively new, few data exist regarding cognitive outcome. We conducted a twin case-control study to investigate neurocognitive and behavioral outcome in a preschool patient who was 16 months old at diagnosis of medulloblastoma and was treated with surgery, chemotherapy, stem cell transplant, and focal radiation to the tumor bed. Stability and change over two assessments were compared for the patient and her nonaffected twin for standardized measures of cognitive function and experimental measures of parent child interaction, social competence, and goal-directed play. A striking finding was improvement in intelligence, receptive language, and visual-motor functioning in the affected twin from 12 months to 24 months after treatment. Improvement in ratings of parent-child interaction and social competence for the affected twin was also evident. These findings are notable compared with the potentially devastating impact of craniospinal tumor, and this study is among the first to document the relative benefit of focal radiation in sparing cognitive function, albeit in a single case study. PMID- 17704359 TI - Functional VEGF and VEGF receptors are expressed in human medulloblastomas. AB - Vascular endothelial growth factor (VEGF) is one of the key regulators of tumor neoangiogenesis. It acts through two types of high-affinity tyrosine kinase receptors (VEGF receptor-1 [VEGFR-1]/fms-related tyrosine kinase 1 [Flt-1] and VEGFR-2/kinase domain receptor [KDR]) expressed on endothelial cells. VEGFRs have also been detected on cancer cells, suggesting a possible autocrine effect of VEGF on their growth. We studied the expression of VEGF, VEGFR-1, and VEGFR-2 in human medulloblastoma cell lines (DAOY, D283Med, and D341Med) and investigated the possible autocrine mechanisms of VEGF on medulloblastoma cell proliferation. Reverse transcriptase PCR analysis showed the presence of VEGF and VEGFR mRNAs in all cell lines studied. Of the three VEGF isoforms, VEGF(121) and VEGF(189) were detected by Western blot analysis in all three medulloblastoma cell lines, whereas VEGF(165) was identified only in DAOY cells. Medulloblastoma cell lines expressed both VEGFR-1 and VEGFR-2. We also demonstrated expression of VEGF and its receptors in medulloblastoma tumor specimens. Exogenous VEGFR-2 inhibitor reduced the VEGF-dependent cell proliferation of DAOY and D283Med cells. In DAOY cells, VEGF(165) induced phosphorylation of VEGFR-2/KDR and of downstream proteins in the signal transduction pathway. These data suggest a possible autocrine role for VEGF in medulloblastoma growth. Targeting VEGF signaling may represent a new therapeutic option in the treatment of medulloblastoma. PMID- 17704360 TI - DNA repair after irradiation in glioma cells and normal human astrocytes. AB - We examined DNA damage responses and repair in four human glioma cell lines (A7, U87, T98G, and U373) and normal human astrocytes (NHAs) after clinically relevant radiation doses to establish whether we could identify differences among them that might suggest new approaches to selective radiosensitization. We used phosphorylation of histone H2AX visualized by immunocytochemistry to assess DNA double-strand break (DSB) formation and resolution. Fluorescence immunocytochemistry was used to visualize and quantify repair foci. Western blotting was used to quantify repair protein levels in the different cell lines before and after irradiation and during different cell cycle phases. Mitotic labeling was used to measure cell cycle parameters after irradiation. We found that the glioma cell lines repaired DSBs more slowly and less effectively than did NHAs in the clinically relevant dose range, as assessed by induction and resolution of H2AX phosphorylation, and this was most marked in the three TP53 mutated cell lines (T98G, A7, and U373). The glioma cells also expressed relatively high repair-protein levels compared with NHAs that were not altered by irradiation. High levels of the repair protein Rad51 in these cells persisted throughout the cell cycle, and a marked increase in Rad51 foci formation, which was not restricted to cells in G2/S phase, occurred at early time points after irradiation. TP53-mutated glioma cell lines demonstrated a very prominent dose responsive G2 checkpoint and were sensitized to radiation by caffeine, which inhibits G2/S phase checkpoint activation. In conclusion, DNA repair events differed in these four glioma cell lines compared with NHAs. In particular, the three TP53-mutated glioma cell lines exhibited markedly increased Rad51 protein levels and marked, dose-dependent Rad51 foci formation after low radiation doses. This suggests that agents that disrupt Rad51-dependent repair or prevent G2 checkpoint activation may selectively sensitize these cells. PMID- 17704361 TI - Visual outcome of a cohort of children with neurofibromatosis type 1 and optic pathway glioma followed by a pediatric neuro-oncology program. AB - We evaluated the visual outcome of a cohort of children with neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG) treated according to standardized therapeutic guidelines. The study population consisted of all consecutive patients with NF1 and OPG referred to a specialized pediatric neuro-oncology program between 1994 and 2004. Treatment was instituted only in cases of progressive disease or clinical deterioration. Treatment modalities were chemotherapy (based on vincristine/carboplatin) for children younger than 5 years and radiotherapy for all others. Ten boys and 10 girls (seven with a positive family history) entered the trial (median age at diagnosis of OPG, 29 months). At a median follow-up time of 78 months, seven patients had been treated with chemotherapy only, four with radiotherapy, and four with chemotherapy plus radiotherapy. Five patients were observed only. Currently, 18 are alive and two have died. Eight patients were treated for progressive visual loss in the face of stable disease, five for tumor volume increase without visual deterioration, and two for symptomatic tumor volume increase. At referral, six children had a visual acuity (VA) of < 30% in both eyes; eight children had 100% VA bilaterally. At referral, the visual field (VF) could be assessed in three children: One had VF loss in both eyes, one had VF loss in one eye, and one had normal VF. At last follow-up, eight children had VA < 20% in both eyes; only two children had 100% VA in both eyes. Among 11 children who had some visual function, three had VF loss in one eye and three in both eyes, and five had an intact VF. Contrast and color sensitivity were abnormal in seven and six patients, respectively. Thirteen children fell into the WHO hypovision category. In summary, among the 15 children treated, one had a definitive and two a mild improvement in VA. In conclusion, the visual outcome of this selected cohort of NF1 patients with OPG is unsatisfactory. A critical reappraisal of the therapeutic strategy adopted is needed. PMID- 17704362 TI - Early recurrences in histologically benign/grade I meningiomas are associated with large tumors and coexistence of monosomy 14 and del(1p36) in the ancestral tumor cell clone. AB - Tumor recurrence is the major clinical complication in meningiomas, and its prediction in histologically benign/grade I tumors remains a challenge. In this study, we analyzed the prognostic value of specific chromosomal abnormalities and the genetic heterogeneity of the tumor, together with other clinicobiological disease features, for predicting early relapses in histologically benign/grade I meningiomas. A total of 149 consecutive histologically benign/grade I meningiomas in patients who underwent complete tumor resection were prospectively analyzed. Using interphase fluorescence in situ hybridization, we studied the prognostic impact of the abnormalities detected for 11 different chromosomes, together with other relevant clinicobiological and histopathological characteristics of the disease, on recurrence-free survival (RFS) at 2.5, 5, and 10 years. From the prognostic point of view, losses of chromosomes 9, 10, 14, and 18 and del(1p36) were associated with a shorter RFS at 2.5, 5, and 10 years. Similarly, histologically benign/grade I meningiomas showing coexistence of monosomy 14 and del(1p36) in the ancestral tumor cell clone displayed a higher frequency of early relapses. In fact, coexistence of -14 and del(1p36) in the ancestral tumor cell clone, together with tumor size, represented the best combination of independent prognostic factors for the identification of those patients with a high risk of an early relapse. Our results indicate that patients with large histologically benign/grade I meningiomas carrying monosomy 14 and del(1p36) in their ancestral tumor cell clone have a high probability of relapsing early after diagnostic surgery. These findings suggest the need for closer follow-up in this small group of patients. PMID- 17704365 TI - The well-being of poultry in production. PMID- 17704363 TI - Synovial sarcoma of the sellar region. AB - Primary sarcomas of the sellar region are uncommon, although a wide variety have been reported. To date, no cases of primary synovial sarcoma have been described as occurring at this site. We report an immunohistochemically and molecular genetically confirmed primary synovial sarcoma involving the sellar/parasellar region and cavernous sinus in an adult male. Subtotal resection and radiosurgery proved to be efficacious. The spectrum of primary sellar region sarcomas is summarized. PMID- 17704364 TI - Glioblastoma multiforme after stereotactic radiotherapy for acoustic neuroma: case report and review of the literature. AB - Indications for the use of radiotherapy in the management of a variety of benign intracranial neoplastic and nonneoplastic pathologies are increasing. Although the short-term risks are minimal, the long-term risks of radiation-induced de novo secondary neoplasms or malignant progression of the primary benign tumor need to be considered. There are currently 19 reported cases of tumors linked with stereotactic radiotherapy/radiosurgery, to which we add our second institutional experience of a patient who succumbed to a glioblastoma multiforme (GBM) after stereotactic radiotherapy for an acoustic neuroma (AN). Review of these 20 cases revealed 10 de novo secondary tumors, of which eight were malignant, with six being malignant gliomas. The majority of the cases (14 of 20) involved AN, with most being in patients with neurofibromatosis-2 (NF2; 8 of 14), reflecting the large numbers and long-term use of radiotherapy for AN. Accelerated growth of the primary benign AN, some 2 to 6 years after focused radiotherapy, was found in six of eight NF2 patients, with pathological verification of a malignant nerve sheath tumor documented in most. The exact carcinogenic risk after radiotherapy is unknown but likely extremely low. However, the risk is not zero and requires discussion with the patient, with specific consideration in young patients and those with a cancer predisposition. PMID- 17704366 TI - Effects of genetic selection on behavioral profiles of Single Comb White Leghorn hens through two production cycles. AB - Four layer genetic stocks consisting of 3 Ottawa control strains (5, 7, and 10) and a commercial laying stock (CCS) were utilized to evaluate potential changes in behavioral profiles due to the effects of genetic selection through 2 production cycles. The Ottawa strains were started as random bred strains from the crosses of several popular commercial layers in 1950, 1959, and 1972, and the commercial strain used herein was from calendar year 1993, and its ancestors were involved in the formation of all of the random bred strains. The behavior study utilized 2 replicates from each strain that contained 4 cages, 6 hens/cage, for a total of 192 hens. Behavioral observations were recorded on 2 consecutive days beginning at 22 wk of age and every 28 d thereafter during the first production cycle, the molt period, and the second production cycle through 90 wk of age and periodic feather and Hansen's test scores recorded. Behavior profiles were similar between the control strains and the CCS, indicating that long-term genetic selection by commercial egg-type breeding firms to enhance production parameters has had no impact on laying strain behavior patterns. Appetitive behaviors were not affected by strain. During the molt, hens had reduced (P < 0.05) feeding and drinking frequencies in comparison with those observed during the first and second cycles. The data indicated that hens pecked inedible objects at a greater (P < 0.0001) frequency during the first cycle and molt than during the second cycle. Fearfulness scores were only influenced by production phase with the molt having the highest (P < 0.01) score of 3.46. Strain or production phase did not influence the frequency of aggressive and submissive acts. PMID- 17704367 TI - Molt performance and bone density of cortical, medullary, and cancellous bone in laying hens during feed restriction or alfalfa-based feed molt. AB - A study was conducted to evaluate the effects of alfalfa-based molt diets on molting performance and bone qualities. A total of 36 Single Comb White Leghorn hens were used for the study. There were 6 treatments: pretrial control (PC), fully fed (FF), feed withdrawal (FW), 90% alfalfa:10% layer ration (A90), 80% alfalfa:20% layer ration (A80), and 70% alfalfa:30% layer ration (A70). For the PC treatment, hens were euthanized by CO(2) gas, and bones were collected before molt was initiated. At the end of the 9-d molt period, hens were euthanized, and femurs and tibias were collected to evaluate bone qualities by peripheral quantitative computed tomography, mechanical testing, and conventional ash weights. The hens fed alfalfa-based molt diets and FW stopped laying eggs within 5 d after molt started, and all hens in these groups had reduced ovary weights compared with those of the FF hens. In the FW and A90 groups, total femur volumetric bone mineral densities (vBMD) at the midshaft were significantly lower, but those of the A80 and A70 groups were not significantly different from the values for the PC and FF hens. In cortical bone density, the midshaft tibial vBMD were significantly higher for FF and A70 hens than for PC hens. The medullary bone densities at the midshaft femur or tibia of the FW, A90, A80, and A70 hens were reduced compared with those of the PC hens. Femur cancellous densities at the distal femur for the FW and A90 hens were significantly reduced compared with those of the PC and FF hens. The FW, A80, and A70 hens yielded significantly higher elastic moduli, and the A80 hens had higher ultimate stress compared with the PC hens, suggesting that the mechanical integrity of the midshaft bone was maintained even though the medullary vBMD was reduced. These results suggest that alfalfa-based molt diets exhibit molt performance similar to FW, that medullary and cancellous bones are labile bone compartments during molting, and that alfalfa-based molt diets may be beneficial to maintain the mechanical properties of bones during molt. PMID- 17704368 TI - The effects of different bill-trimming methods on the well-being of Pekin ducks. AB - Pekin ducks are often bill-trimmed to prevent feather pecking and cannibalism, but this practice has been criticized because of the resulting potential for acute and chronic pain. The goal of this experiment was to compare 2 different bill-trimming methods, hot blade trimming with cautery (TRIM) and cautery only (tip-searing; SEAR), on the behavior, bill morphology, and weight gain of Pekin ducks. Ducklings (n = 192, 96 per sex) were trimmed at the hatchery and assigned to 12 floor pens (3.66 x0.91 m) by treatment. Behavior was evaluated by scan sampling, and plumage condition was scored using a 0 to 3 scoring system. Thirty six ducks were randomly euthanized at 3 and 6 wk of age, and their bills were collected for examination. Following fixation and decalcification, the bills were embedded in paraffin wax and sectioned longitudinally. Alternate sections were stained with hematoxylin and eosin and Masson's trichrome for the connective tissues, and with Bielschowsky's silver impregnation, Bodian's staining, and Holmes' staining for the nerve fibers. Trimmed ducks engaged in fewer bill related behaviors and rested more than untrimmed ducks (NOTRIM) during the first 2 wk posttrim. Ducks in the SEAR and NOTRIM groups showed similar patterns of weight gain, but those in the TRIM group had a lower rate of gain than ducks in the SEAR group during the first week posttrim and had a lower rate of gain than those in the NOTRIM group for 2 wk posttrim. Feather scores of ducks in the NOTRIM group were significantly worse than those in the TRIM or SEAR group by 18 d, and scores continued to deteriorate at a greater rate than those of trimmed ducks throughout the study. Both trimming methods caused connective tissue proliferation in the bill stumps, but the TRIM method caused thicker scar tissue than the SEAR method. No neuromas were found with either trimming method, but there were more nerve fibers in bill stumps of the SEAR ducks than the TRIM ducks. These results suggest that acute pain is associated with both trimming methods, but that SEAR may be a preferable method, causing less check in weight gain and fewer bill morphological changes while still being effective in minimizing feather pecking damage. PMID- 17704369 TI - Spatial shifts in microbial population structure within poultry litter associated with physicochemical properties. AB - Microbial populations within poultry litter have been largely ignored with the exception of potential human or livestock pathogens. A better understanding of the community structure and identity of the microbial populations within poultry litter could aid in the development of management practices that would reduce populations responsible for toxic air emissions and pathogen incidence. In this study, poultry litter air and physical properties were correlated to shifts in microbial community structure as analyzed by principal component analysis (PCA) and measured by denaturing gradient gel electrophoresis (DGGE). Litter samples were taken in a 36-point grid pattern at 5 m across and 12 m down a 146 m x 12.8 m chicken house. At each sample point, physical parameters such as litter moisture, pH, air and litter temperature, and relative humidity were recorded, and samples were taken for molecular analysis. The DGGE analysis showed that the banding pattern of samples from the back and water/feeder areas of poultry house were distinct from those of samples from other areas. There were distinct clusters of banding patterns corresponding to the front, middle front, middle back, back, and waterer/feeder areas. The PCA analysis showed similar cluster patterns, but with more distinct separation of the front and midhouse samples. The PCA analysis also showed that moisture content and litter temperature (accounting for 51.5 and 31.5% of the separation of samples, respectively) play a major role in spatial diversity of microbial community in the poultry house. Based on analysis of DGGE fingerprints and cloned DGGE band sequences, there appear to be differences in the types of microorganisms over the length of the house, which correspond to differences in the physical properties of the litter. PMID- 17704370 TI - Motor incoordination, intracranial fat bodies, and breeding strategy in Crested ducks (Anas platyrhynchos f.d.). AB - Some Crested ducks (CR) are burdened with an intracranial fat body that, depending on the size and location, may lead to varying degrees of motor incoordination. A behavioral test is proposed that helps to identify those CR individuals bearing the problematical fat body. The test consists of putting the ducks on their backs and measuring the time required to right themselves. This was repeated 13 times per animal, and means were calculated. The minimum time required was 0.5 s, and the maximum was 62.6 s. Individuals that show motor incoordination need more time than ducks without such problems (14.3 s in contrast to 1.2 s) and exhibit a larger intracranial fat body. Ducks used for breeding should require no more than approximately 1 to 2 s to right themselves. In an allometric comparison with 3 other domestic duck breeds, CR show a significantly smaller brain; specifically, the cerebellum, tegmentum, apicale hyperpallium, and olfactory bulb are reduced. The relationship between fat body and these structures was discussed. PMID- 17704371 TI - Performance assessment of broiler chickens given mushroom extract alone or in combination with probiotics. AB - A study was conducted to evaluate the effect of combined Shiitake mushroom (Lentinus edodes) extract with probiotics (PrimaLac) on the growth and health of broiler chickens. In trial 1, 540 d-of-hatch chicks were randomly assigned to 6 treatment groups, replicated 3 times, with 15 males and 15 females per pen for 3 wk. Dietary probiotics and mushroom treatments were as follows: 1) control feed + ad libitum tap water; 2) control feed + skip-a-day mushroom water; 3) control feed + ad libitum mushroom water; 4) probiotic feed + ad libitum tap water; 5) probiotic feed + skip-a-day mushroom water; 6) probiotic feed + ad libitum mushroom water. Body weight gain, feed consumption and efficiency, mortality, bursa, liver, and spleen relative weights of chicks were taken. In trial 2, the performance of broilers 3 to 7 wk withdrawn from the mushroom extract was evaluated along with the comparative level of fecal biofidobacteria in the control and mushroom extract treatment (trt). Mortality, weight gain, feed consumption and efficiency, carcass yield, fat pads, bursa weights and fecal bifidobacteria were measured in trial 2. In trial 1, significant differences (P < 0.05) in female weight gain (trt 4-0.62 vs. trt 1-0.54 kg) and male spleen weights were observed. In trial 2, significant differences were observed in male weight gain (trt 2-2.40 vs. trt 4-1.12 kg), male and female fat pads, male bursa weights (trt 3-0.15 vs. trt 6-0.39), female carcass yield percentage (trt 1-77.8 vs. trt 4-66.4), and feed consumption and efficiency. Body weights were severely depressed in the male broilers receiving the probiotics feed in treatments 4, 5, and 6, but not in the female broilers. These results indicate that performance differences in gender occur with additives during different grow-out periods, and mushroom extract promotes bifidobacteria growth in broiler chickens after 4 wk of withdrawal. It appears that probiotics and mushroom extract offered no combination potential for weight gain, which was compromised in this study, but possible health-enhanced attributes. PMID- 17704372 TI - Dam line and sire line effects on turkey embryo survival and thyroid hormone concentrations at the plateau stage in oxygen consumption. AB - Inheritance of embryo thyroid function was measured in lines of turkeys. Two lines that had been selected for either increased egg production (E) or increased 16-wk BW (F) and their respective randombred controls (i.e., RBC1 and RBC2) were examined. Reciprocal crosses of dams and sires from each selected line and its randombred control were made to estimate sire line and dam line effects. Orthogonal contrasts were used to determine if the differences found were due to the presence of additive, nonadditive, or maternal, sex-linked, or both, gene effects. With the data involved, sex-linkage and maternal effects could not be separated. Embryo survival was measured for all lines and their reciprocal crosses. Crossing the RBC1 sire and E dam also resulted in better embryo survival and lower death losses at pipping than for the other cross- or purelines. Reciprocal crosses of the F and RBC2 lines showed better total embryo survival, and they survived pipping better than the F or RBC2 purelines. Thyroxine (T(4)) and triiodothyronine (T(3)) concentrations differed between the reciprocal crosses at external pipping, but the effects were inconsistent for the 2 data sets. Reciprocal tests indicated that maternal, sex-linked, or both, effects were present for T(3) concentrations at internal pipping in the E and RBC1 lines and at external pipping for the F and RBC2 lines. Reciprocal effects were significant for T(4) at internal pipping for both data sets. The RBC1 sire embryos had significantly higher T(3):T(4) ratios than the E line sire embryos at internal and external pipping, and the pureline RBC1 embryos had consistently higher ratios than the pureline E embryos. The differences for the T(3):T(4) ratios between these 2 lines at internal pipping, external pipping, and hatch appeared to be consistently additive in nature, although significant nonadditive or heterotic effects were present for the ratio at external pipping. Similar effects on the T(3):T(4) ratio were observed for the F and RBC2 lines at external pipping. PMID- 17704373 TI - Association of Spot14alpha gene polymorphisms with body weight in the chicken. AB - In mammals, thyroid hormone responsive Spot14 (THRSP) is a small acidic protein that responds to thyroid hormone stimulation and, therefore, is thought to play a role in growth. The current study was designed to investigate the associations of Spot14alpha gene polymorphisms on chicken growth and body composition traits. The Northeast Agricultural University Resource Population (NEAURP) was used in the present study. The NEAURP was established by crossing broiler sires, derived from Northeast Agricultural University broiler lines divergently selected for abdominal fat content, with Baier layer dams, a local Chinese breed. The F(1) birds were intercrossed to produce the F(2) population. Body weight and body composition traits were measured in the F(2) population. Polymorphisms of the gene were detected between parental lines by DNA sequencing. Primers were designed according to the chicken Spot14alpha gene (AY568628). The PCR-RFLP and PCR-length polymorphisms methods were then developed to genotype polymorphisms in the NEAURP. The A213C and 9 bp insertion-deletion of the Spot14alpha gene in the F(2) population was found to be associated with BW, which implied that Spot14alpha gene or a tightly linked gene had an important effect on growth in the chicken. PMID- 17704374 TI - A method for discriminating a Japanese brand of chicken, the Hinai-jidori, using microsatellite markers. AB - The Hinai-dori is a native breed of chicken from the Akita Prefecture in Japan. A cross between the Hinai-dori and Rhode Island Red breeds has been commercialized as the Hinai-jidori chicken, one of the most popular brands of chicken in Japan. Here, a method of discriminating between the Hinai-jidori and other chickens is described. Individuals (555) of the Hinai-dori breed were analyzed by using 37 microsatellite markers on the Z chromosome. Fourteen of the marker loci (ABR1003, ADL0250, ABR0241, ABR0311, ABR1004, ABR1013, ABR0633, ABR1005, ABR0089, ABR1007, ABR1001, ABR1009, ABR1010, and ABR1011) were fixed in the Hinai-dori breed. So, the Hinai-jidori chicken, F(1) of the Hinai-dori breed, must have at least one of the alleles with all fixed loci. When these alleles on 14 loci from the Hinai dori breed were not detected in meat samples, it would be judged that the samples were not the Hinai-jidori chicken. Thus, the use of these 14 microsatellite markers provides a practical method of accurately discriminating the Hinai-jidori chicken from other chickens on the market. PMID- 17704375 TI - Chronic toxicity of fumonisins in turkeys. AB - Fumonisins are mycotoxins that are found worldwide. They are mainly produced by Fusarium verticillioides during its development on corn. The main toxic effects of these molecules have been well characterized in poultry in the case of acute exposure, but the subclinical and economic effects of chronic exposure are less known. Whereas the latest European recommendations suggest that maximal levels of fumonisins in corn could reach 60 mg/kg and the maximal contamination of poultry feeds could reach 20 mg/kg, no study is available at this level in turkeys. The aim of the present work was thus to characterize the effects of exposure to fumonisins (concentrations of 0, 5, 10, and 20 mg of fumonisin B1 + fumonisin B2/kg of feed) on feed consumption and growth in turkeys over a period of 9 wk. Main biochemical parameters of the liver and alteration of sphingolipid metabolism were investigated in plasma, liver, and kidney. The main results showed no effect on feed consumption and growth in exposed turkeys. Moreover, no effect was observed on the weight of tissues and markers of liver injury. By contrast, a disruption of sphingolipid metabolism was clear at a level of exposure of 10 and 20 mg of fumonisin B1 + fumonisin B2 mg/kg of feed. Both hepatic and kidney concentrations of sphinganine increased gradually throughout the exposure period. These results reveal that disruption of sphingolipid metabolism is an early and sensitive biomarker of fumonisins exposure in turkeys; the consequences on these alterations remain to be established. PMID- 17704376 TI - Effect of single or combined climatic and hygienic stress on natural and specific humoral immune competence in four layer lines. AB - Effects of long-term climatic stress (heat exposure), short-term hygienic stress [lipopolysaccharide (LPS)], or a combination of both challenges on the immune competence of 4 layer lines was investigated. The lines were earlier characterized for natural humoral immune competence and survival rate. Eighty hens per line were randomly divided over 2 identical climate chambers and exposed to a constant high temperature (32 degrees C) or a control temperature (21 degrees C) for 23 d. Half of the hens housed in each chamber were i.v. injected with LPS at d 1 after the start of the heat stress period. Within each of the treatment groups, half of the hens were s.c. immunized with human serum albumin (HuSA) at d 2 after the start of the heat stress period to measure specific antibody (Ab) titers to HuSA. The effect of heat, LPS, or a combined challenge on specific Ab titers to HuSA, natural Ab titers to keyhole limpet hemocyanin or HuSA (in hens that were not immunized with HuSA), and activity of the classical and alternative complement pathways were investigated. Heat stress enhanced specific and natural immune responses. Administration of LPS enhanced natural immune responses but decreased specific immune responses. The lack of interaction between heat stress and LPS administration, except for natural Ab titers to HuSA, suggest that these were 2 independent stressors. The lines had a similar response pattern but differed in the response level. Neither natural humoral immune competence nor survival rate, for which the lines had been characterized, was indicative of the specific and natural immune response to different stressors. Lipopolysaccharide and heat stress initiated sequential responses over time, with an earlier effect of short-term LPS exposure (within the first and second week) and a later effect of long-term heat exposure (within the second and third week). These data suggest that LPS and heat stress affect the natural and specific immune competence of laying hens. PMID- 17704377 TI - Ability of bacteriophages isolated from different sources to reduce Salmonella enterica serovar enteritidis in vitro and in vivo. AB - Salmonella enterica serovar Enteritidis-lysing bacteriophages isolated from poultry or human sewage sources were used to reduce Salmonella Enteritidis in vitro and in experimentally infected chicks. Cocktails of 4 different bacteriophages obtained from commercial broiler houses (CB4O) and 45 bacteriophages from a municipal wastewater treatment plant (WT45O) were evaluated. In experiment 1, an in vitro crop assay was conducted with selected bacteriophage concentrations (10(5) to 10(9) pfu/mL) to determine ability to reduce Salmonella Enteritidis in the simulated crop environment. Following 2 h at 37 degrees C, CB4O or WT45O reduced Salmonella Enteritidis recovery by 1.5 or 5 log, respectively, as compared with control. However, CB4O did not affect total SE recovery after 6 h, whereas WT45O resulted in up to a 6-log reduction of Salmonella Enteritidis. In experiment 2, day-of-hatch chicks were challenged orally with 3 x 10(3) cfu/chick Salmonella Enteritidis and treated cloacally with 1 x 10(9) WT45O pfu/chick 1 h postchallenge. One hour later, chicks were treated or not with a commercially available probiotic (Floramax-B11). Both treatments significantly reduced Salmonella Enteritidis recovery from cecal tonsils at 24 h following vent lip application as compared with controls, but no additive effect was observed with the combination of bacteriophages and probiotic. In experiment 3, day-of-hatch chicks were challenged orally with 9 x 10(3) cfu/chick Salmonella Enteritidis and treated via oral gavage with 1 x 10(8) CB4O pfu/chick, 1.2 x 10(8) WT45O pfu/chick, or a combination of both, 1 h postchallenge. All treatments significantly reduced Salmonella Enteritidis recovered from cecal tonsils at 24 h as compared with untreated controls, but no significant differences were observed at 48 h following treatment. These data suggest that some bacteriophages can be efficacious in reducing SE colonization in poultry during a short period, but with the bacteriophages and methods presently tested, persistent reductions were not observed. PMID- 17704378 TI - Purification of immunoglobulins from chicken sera by thiophilic gel chromatography. AB - Immunoglobulin Y is different from most of the other immunoglobulins because it does not bind protein A or protein G. Thiophilic gel chromatography has been successfully used to purify IgY from chicken egg yolk, but the technology has not previously been used to purify IgY from serum. In this research note, we describe the optimization of T-gel chromatography for purification of IgY from serum. Data are provided on the recovery and purity of IgY obtained using potassium sulfate buffers of different concentrations. Decreasing the strength of potassium sulfate buffer from 0.5 to 0.3 M did not alter the amount of IgY recovered but increased the purity. Using 0.3 M potassium sulphate, we recovered approximately 63.7% of the serum Ig as almost pure IgY. PMID- 17704379 TI - Ultrastructural observations on effects of infectious bronchitis virus in eggshell-forming regions of the oviduct of the commercial laying hen. AB - The pathogenesis of 2 strains of infectious bronchitis virus (T and N1/88 strains) was studied in the eggshell-forming regions of the oviduct of commercial laying hens. There were no external shell deformities, except for paler shells. There was no decline in egg production in either of the infected groups. One hen from the N1/88-infected group and 2 hens from the T-infected group were out of lay. The light, scanning, and transmission electron microscopic changes in infected shell-forming regions of the oviduct were compared with the control oviducts at different egg positions. The ultrastructural finding revealed that the extent of cytopathology in the isthmus was greater than in the tubular shell gland and shell gland pouch. The T strain of infectious bronchitis virus was more pathogenic compared with the N1/88 strain. Severe cytopathology was recorded in the shell-forming region of hens that were out of production, and virus particles were observed in hens that had stopped laying. Virus particles were recorded in the dilated rough endoplasmic reticulum and Golgi complex of the isthmus, tubular shell gland, and shell gland pouch of all 3 hens that had stopped laying. Although a decrease in egg production and deterioration in eggshell quality were not observed in this trial, cessation of egg production in a small number of hens could be due to severe cytopathology in the eggshell-forming regions of the oviduct. PMID- 17704380 TI - Effect of dietary Rhodobacter capsulatus on cholesterol concentration and fatty acid composition in broiler meat. AB - The study was designed to investigate the effects of dietary Rhodobacter capsulatus on cholesterol concentration and fatty acid composition in broiler meat. A total of 45 two-week-old male broiler chicks were randomly assigned into 3 treatment groups and fed ad libitum diets supplemented with 0 (control), 0.02, and 0.04% R. capsulatus for a 6-wk feeding period. The results of this study revealed that the supplementation of 0.04% R. capsulatus in diet reduced (P < 0.05) cholesterol and triglyceride concentrations in broiler meat. The concentrations (expressed as a percentage of total fatty acids) of oleic acid (18:1), linoleic acid (18:2), and linolenic (18:3) acid in thigh muscle and breast muscle were higher (P < 0.05) in the broilers fed the 0.04% R. capsulatus supplemented diet than in the broilers fed the control diet. The ratio of unsaturated fatty acids to saturated fatty acids was greater (P < 0.05) in both muscles of broilers fed the 0.04% R. capsulatus supplemented diet than the control diet. In addition, the concentrations of serum cholesterol and triglyceride, and hepatic cholesterol and triglyceride were also reduced (P < 0.05) by dietary R. capsulatus. Compared with the control diet, the 0.04% R. capsulatus supplemented diet reduced (P < 0.05) the ratio of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol. Moreover, the supplementation of R. capsulatus in broiler diets did not show any adverse effect on production performance. Therefore, these results conclude that the application of R. capsulatus into diet may be feasible to reduce cholesterol concentration and improve the ratio of unsaturated fatty acids to saturated fatty acids in broiler meat. PMID- 17704381 TI - The effect of different feed restriction programs on reproductive performance, efficiency, frame size, and uniformity in broiler breeder hens. AB - Two experiments were conducted to determine the effect of feed restriction programs on breeder reproductive performance. In experiment 1, every day (ED), skip-a-day (SK), 4-3, and 5-2 programs were compared. Diets did not differ, and feed intake was identical in all groups. Four hundred twenty pullets were reared on each program. At 21 wk, 80 breeders from each program were individually housed to record performance parameters. Body weight and frame size were larger in ED pullets than SK, 4-3, or 5-2 despite equal intakes. Hens fed ED reached sexual maturity at a younger age than other groups. Hens fed ED also produced more total and settable eggs than SK hens. Egg weight was heavier in 5-2 hens than in ED with 4-3 and SK intermediate. Efficiency of feed utilization was best in ED hens. In experiment 2 the same programs were tested, but pullets were reared to reach equal BW. One hundred seventy-five pullets were reared on each program, of which 60 were housed. Feed intake was greater for SK, 4-3, and 5-2 than ED pullets to reach the same BW. Frame size did not differ, indicating that BW was the cause of differences in experiment 1. In experiment 2, differences in performance were attenuated but not eliminated by feeding to reach equal BW, suggesting that metabolic factors aside from BW are altered by feeding programs. The 5-2 produced larger eggs than ED with the trend among programs being identical to that in experiment 1. These results suggest that metabolic changes such as increased lipogenesis or alterations in body composition may result in larger eggs in feeding programs that include off-feed days. Mortality, fertility, and hatchability were not affected by feeding programs in either experiment. Body composition analysis indicated the importance of total lean protein mass as a threshold for the onset of sexual maturity. Programs like SK are less efficient than ED and may result in reduced performance. PMID- 17704383 TI - Effect of age and method on ileal endogenous amino acid flow in turkey poults. AB - Ileal endogenous amino acid (IEAA) flow in turkey poults was determined at 2 experimental locations on d 5, 15, and 21 posthatch using 3 methods, namely a N free diet (NFD), a highly digestible protein (casein), and the regression method, obtained by regressing IEAA flow against dietary casein levels. The diets were semipurified and contained 0, 50, 100, or 150 g of casein/kg of diet as the sole source of dietary protein. Each diet was fed for 5 d to 6 replicate cages of 30 (d 5), 10 (d 15), or 8 (d 21) birds per cage. There was no interaction between locations and age or locations and diet, so the data from both locations were pooled. Ileal endogenous amino acid flow on d 5 (NFD method) was higher (P < 0.05) than on d 15 or 21. Ileal endogenous amino acid flow estimated from the NFD and the regression methods was different on d 5 (P < 0.05), but there were no differences in IEAA flow for most of the amino acids on d 15 and 21. Increasing the level of casein resulted in a linear (P < 0.05) increase in IEAA flow. The amino acids with the lowest flow were Trp and Met, whereas Glu had the greatest flow. The results obtained from this study indicate that data generated across laboratories were repeatable. The results also suggest that about twice as much amino acids of endogenous origin are found in the digesta of poults on d 5 relative to d 21. Also, as poults age, there is a decrease in IEAA flow from d 5 to 15, but flows from d 15 to 21 are not different. These observations suggest that apparent digestibility coefficients for poults on d 5 and d 15 or 21 could be significantly influenced by the level of endogenous amino acids, more so on d 5. PMID- 17704382 TI - The effect of supplemental glutamine on growth performance, development of the gastrointestinal tract, and humoral immune response of broilers. AB - Two experiments were conducted to evaluate the effect of supplemental Gln on growth performance, development of the gastrointestinal tract, and humoral immune response of broilers. Immediately after hatch 6 replicate pens of 6 chicks were randomly assigned to 1 of 7 (experiment 1) or 5 (experiment 2) dietary treatments for 21 d. On d 4, 7, 14, and 21, twelve chicks per treatment (2 chicks/pen) were killed for thymus, spleen, bursa, duodenum, jejunum, ileum, bile, and blood sample collections and weights. In experiment 1, the effect of 1 or 4% Gln addition to the feed, water, or both was compared with a corn-soybean meal (SBM) control diet. All diets were formulated to be isocaloric and isonitrogenous. Weight gain improved significantly (P < 0.05) when chicks were fed diets with 1% Gln as compared with chicks fed the control diet (11% average improvement). The addition of 4% Gln to the diet or water depressed (P < 0.05) growth performance. Based on the results from experiment 1, 1% Gln supplementation to the diet was determined to be ample and most practical. Thus in experiment 2, diets supplemented with 1% Gln were fed for 4, 7, 14, or 21 d after which time chicks were fed the corn-SBM control diet until the experiment was terminated at 21 d. Weight gain improved significantly (P < 0.05) when chicks were fed diets supplemented with 1% Gln throughout the 21-d study. In both experiments, chicks fed diets supplemented with 1% Gln for 21 d had higher concentrations of bile, intestinal, and sera IgA and sera IgG (P < 0.05). Chicks fed diets with 1% Gln had heavier intestinal relative weights and longer intestinal villi (P < 0.05) as compared with the chicks fed the corn-SBM diet. Our results indicate that the addition of 1% Gln to the diet of broiler chicks improves growth performance and may stimulate development of the gastrointestinal tract and humoral immune response. PMID- 17704384 TI - Effect of polysavone (alfalfa extract) on abdominal fat deposition and immunity in broiler chickens. AB - Two hundred 1-day-old male commercial Arbor Acres broiler birds were randomly distributed to a control group and a polysavone group (5 replicates of 20 birds each) to investigate the influence of polysavone, a natural extract from alfalfa, on abdominal fat deposition and immunity in broiler chickens. Birds in the control group were supplied with a basal diet, and 0.06% polysavone was added to the basal diet of birds in the polysavone group. Body weight and feed consumption for each replicate were recorded weekly. At 3, 4, 5, and 6 wk of age, 4 birds from each replicate were randomly selected for blood and organ sampling. Polysavone had no significant effect on feed intake, BW, or feed:gain ratio in the experimental period, and it decreased the abdominal fat weights at 5 and 6 wk of age. Polysavone improved (P <0.05) the relative thymus and spleen weights at 6 wk of age and the bursa weights at 4 and 5 wk of age compared with the control group. At 4 and 6 wk of age, the proliferation of T and B lymphocytes in the polysavone group was significantly greater (P <0.05) than that in the control group. When birds were 4 and 5 wk of age, polysavone resulted in a significant increase (P <0.05) in serum anti-Newcastle disease virus hemagglutination inhibition antibody titer. These results showed that polysavone may decrease abdominal fat deposition and enhance immunity without an adverse effect on the performance of broiler chickens. PMID- 17704385 TI - Further investigations on the role of diet-induced thermogenesis in the regulation of feed intake in chickens: comparison of adult cockerels of lines selected for high or low residual feed intake. AB - The main objective of this study was to investigate the role of diet-induced thermogenesis (DIT) in feed intake regulation in cockerels selected for high (R+) or low (R-) residual feed intake. The selection criterion was defined as the difference between observed feed intake and feed intake predicted by regression between feed intake and BW, BW gain, and egg mass production. Furthermore, the effect of genotype on postprandial oxidation of U-(13)C(6)-glucose, decarboxylation of 1-(13)C(1)-Leu, and key metabolites and hormones was analyzed. Thirty 24-wk-old cockerels of both lines were kept in battery cages under standard conditions on a commercial diet. Three cockerels per genotype were examined twice weekly from wk 30 through 34 in open-circuit respiratory cells. After adaptation, cockerels were feed deprived for 24 h and heat production was measured. During the subsequent 7-h refeeding period, DIT and feed intake, as well as glucose oxidation and Leu decarboxylation were assessed by using breath tests. Blood samples were collected after fasting and refeeding. Finally, 10 animals per genotype were killed to record abdominal fat weight. Body composition of 6 different chickens per genotype was determined by using dual-energy x-ray absorptiometry. During feed deprivation, the R+ cockerels had a significantly higher heat production than their R- counterparts, which was even more pronounced during refeeding. Consequently, the R+ cockerels had a significantly increased DIT and a higher feed intake than the R- cockerels. Thus, no evidence of a feedback effect of DIT on feed intake was observed. The oxidation of U-(13)C(6) glucose was significantly higher in the R+ cockerels, confirming their higher respiratory quotient values and the augmented fat deposition in the R- chickens, as assessed by abdominal fat weight and dual-energy x-ray absorptiometry measurements. No significant genotype effect on 1-(13)C(1)-Leu decarboxylation was observed, despite increased circulating uric acid levels in the R+ chickens. Genotype did not influence plasma levels of triglycerides, free fatty acids, glucose, triiodothyronine, or thyroxine after refeeding, whereas plasma leptin levels were significantly higher in the R+ cockerels. PMID- 17704386 TI - Comparison of broiler performance when fed diets containing grain from second generation insect-protected and glyphosate-tolerant, conventional control or commercial reference corn. AB - Two 42-d floor pen studies were conducted to compare broiler (Ross x Ross 308) performance and carcass measurements when broilers were fed diets containing grain from either second-generation lepidopteran insect-protected corn (MON 89034; study 1) or second-generation lepidopteran combined with second-generation corn rootworm-protected and glyphosate-tolerant corn (MON 89034 x MON 88017; study 2) with those of diets containing corn grain from the conventional control and 4 conventional corn hybrids. In both studies, broilers were fed starter diets (approximately 55%, wt/wt, corn grain) from d 0 to 21 and grower-finisher diets (approximately 59%, wt/wt, corn grain) from d 21 to 42. Each study used a randomized complete block design with 6 dietary treatments assigned randomly within 5 blocks of 12 pens each (6 male and 6 female) and 10 pens per treatment group (5 male and 5 female). In study 1 (MON 89034), no treatment differences were detected among dietary treatments for feed intake, weight gain, or any measured carcass parameter. A significant difference was noted for adjusted feed conversion between MON 89034 and control birds; however, no differences were detected in individual treatment comparisons between the MON 89034 and 3 of the 4 commercial corn diets. In study 2 (MON 89034 x MON 88017), no treatment differences were observed for feed intake and most carcass parameters. When significant treatment differences were detected, no differences were observed between MON 89034 x MON 88017, its control, and 2 or more of the commercial corn diets. In each study, comparison of all parameters measured showed no differences between birds fed the test diet and the population of birds fed the control and 4 commercial corn diets. In conclusion, the test diets were nutritionally equivalent to diets containing the control and corn grain from commercial hybrids. PMID- 17704387 TI - Dietary nitrogen intake regulates hepatic malic enzyme messenger ribonucleic acid expression. AB - Increased dietary protein intake rapidly (3 h) decreases malic enzyme and increases hepatic histidase mRNA expression. Experiments were conducted to determine the role that individual dispensable amino acids and nonprotein N sources might have in regulating the activity of these enzymes and to determine if the addition of a N supplement to a practical broiler diet during the entire rearing period would reduce abdominal fat accumulation in broilers. Broiler chicks were fed a basal diet containing 22% protein or this diet supplemented with 9.5% l-Glu, 5% Gly, 6% l-Ala, 5.08% ammonium bicarbonate, or 4.25% dibasic ammonium phosphate for 24 h. Each of the dietary supplements added 0.90% total N to the diet. Hepatic malic enzyme mRNA expression was significantly (P < 0.05) depressed in chicks fed any of the supplemented diets compared with chicks fed the basal diet. Histidase mRNA expression, however, was only significantly increased in the chicks fed the basal diet supplemented with Gly. Broilers fed practical corn-soybean meal starter and developer diets supplemented with 2.3, 4.7, or 9.5% Glu from 0 to 40 d of age had significantly smaller abdominal fat pads relative to BW than broilers fed the unsupplemented corn-soybean meal diets. Feeding the Glu supplements, however, reduced the overall BW gain of broilers by 100 to 150 g compared with broilers fed the unsupplemented diets. The results suggest that hepatic mRNA expression of malic enzyme may be regulated by total dietary N intake, whereas hepatic mRNA expression of histidase may be regulated by specific amino acids. PMID- 17704388 TI - Comparison of broiler performance and carcass parameters when fed diets containing combined trait insect-protected and glyphosate-tolerant corn (MON 89034 x NK603), control, or conventional reference corn. AB - A 42-d floor pen study was conducted to compare broiler (Ross x Ross 308) performance and carcass measurements when fed diets containing lepidopteran protected corn combined with glyphosate-tolerant corn (MON 89034 x NK603) with those of broilers fed diets containing corn grain from the conventional control (similar genetic background to the test corn) and 6 conventional corn hybrids. It has been found that MON 89034 produces the Cry1A.105 and Cry2Ab2 insecticidal proteins that protect corn plants from feeding damage caused by European corn borer (Ostrinia nubilalis) and other lepidopteran insect pests. In addition, NK603 produces the 5-enolpyruvylshikimate-3-phosphate synthase protein from Agrobacterium sp. strain CP4 (CP4 EPSPS), which confers tolerance to glyphosate, the active ingredient in Roundup agricultural herbicides. The traditional breeding of plants that express the individual traits produced MON 89034 x NK603. Broilers were fed starter diets (approximately 57% wt/wt corn grain) from d 0 to 21 and grower-finisher diets (approximately 59% wt/wt corn grain) from d 21 to 42. The study utilized a randomized complete block design with 8 dietary treatments assigned randomly within 5 blocks of 16 pens each (8 male and 8 female) with 10 birds per pen. There were 10 pens per treatment group (5 male and 5 female). Weight at d 0 and 42, feed intake, feed conversion, and all measured carcass and meat quality parameters were not different (P > 0.05) for birds fed MON 89034 x NK603 and control corn diets. In addition, comparisons of the MON 89034 x NK603 diet to the population of the control and 6 reference corn diets showed no difference (P > 0.05) in any performance, carcass, or meat quality parameter measured. In conclusion, the diets containing MON 89034 x NK603 were nutritionally equivalent to diets containing the control or conventional reference corn grain when fed to broilers. PMID- 17704389 TI - Effect of excess methionine and methionine hydroxy analogue on growth performance and plasma homocysteine of growing Pekin ducks. AB - One experiment was conducted to study the effect of excess dl-methionine (DLM) and dl-2-hydroxy-4-methylthiobutanoic acid free acid (dl-HMB-FA) on duck growth. One-day-old male white Pekin ducklings were fed common starter diets from hatch to 21 d of age and then fed the experimental diets from 21 to 42 d of age. Three hundred twenty 21-d-old birds were allotted to 40 raised wire-floor pens with 8 birds per pen according to similar pen weight. There were 5 dietary treatments that included a methionine-adequate control diet and control diets supplemented with 2 levels of dry DLM (1 or 2%) or 2 equimolar levels of liquid dl-HMB-FA (1.13 or 2.26%). Each dietary treatment was replicated 8 times. At 42 d of age, weight gain, feed intake, and gain/feed were measured and plasma was collected to analyze homocysteine. Compared with ducks fed control diets, excess DLM or dl-HMB FA supplementation reduced weight gain and feed intake of birds significantly. However, on the equimolar basis, at 1 or 2% supplemental methionine activity, dl HMB-FA was less growth-depressing than DLM. According to the growth response to excess methionine, the tolerable upper limit of dietary methionine for growing ducks may be less than 1.38% when the methionine level of the control diet (0.38%) was considered. On the other hand, plasma homocysteine was elevated markedly when 2% DLM or 2.26% dl-HMB-FA was added to control diets, but plasma homocysteine of ducks fed 2.26% dl-HMB-FA supplemented diets was lower significantly than birds fed equimolar DLM-supplemented diets, which indicated the toxicity of excess methionine sources and less toxicity of dl-HMB-FA relative to DLM. PMID- 17704390 TI - Investigation of feather follicle development in embryonic geese. AB - In the present study, the process of feather follicle formation in the Zi goose, a Chinese indigenous breed, was investigated during various stages of embryonic development by using a modified histological processing method. The results showed that the feather placodes evolved initially at embryonic day (E) 12 on the spinal feather tract, emerging as symmetrical structures. Sequentially, the buds elongated from E14 to E16 with anterior-posterior and proximal-distal asymmetries, and invaginated to form the primary feather follicles, which were identified to develop the contour feathers or remiges. The remarkable observation at this stage was the formation of the feather follicle wall, which was understood to be the result of the epidermis surrounding the base and further invaginating into the dermis. With the differentiation of the barbule plates, the various types of feathers were determined. We proved that the secondary feather follicles simply had radially symmetrical barb ridges, with much smaller diameters than the primary follicles, and that they developed only downy feathers. The primary and secondary follicles evolved independently of each other and formed ranks in a linear fashion. Moreover, quantitative measurements of the densities of both follicles confirmed that the density of the primary follicles sharply reached the maximum at E18, and then decreased gradually. Coincidentally, the secondary follicles started to increase from the age of E18, and up to E26 the density of the secondary follicles exceeded that of the primary follicles. Each of the primary feather follicles was richly encircled with muscles, which pointed to a quadrangularly arranged network in the dermis. The present work lays the foundation for further study of the cellular and molecular mechanisms of feather follicle morphogenesis in geese. PMID- 17704391 TI - The isoflavonoid daidzein attenuates the oxidative damage induced by polychlorinated biphenyls on cultured chicken testicular cells. AB - The soy isoflavonoid daidzein (DAI) is one of the most abundant phenolic compounds in the human diet and in animal feedstuffs. Daidzein possesses a wide spectrum of physiological and pharmacological functions related to human health. The aim of this study was to evaluate the effect of DAI on oxidative damage induced by a potential carcinogen, polychlorinated biphenyl. Testicular cells were dispersed from 18-d-old chicken embryos and exposed to DAI alone or in combination with a mixture of polychlorinated biphenyls, Aroclor 1254 (A1254), in culture. Oxidative damage was estimated by measuring the lipid peroxidation and superoxide dismutase activities and glutathione content. Results showed that DAI (10 microg/mL) increased germ cell numbers, which were inhibited by cotreatment with the estrogen receptor antagonist tamoxifen at 0.1 microg/mL. Exposure to A1254 (10 microg/mL) reduced superoxide dismutase activity and glutathione content but increased lipid peroxidation significantly. However, simultaneous supplementation with 10 microg/mL of DAI restored these parameters. The above results indicated that DAI may exert weak estrogenic activity, and more important, that DAI may display an antioxidant effect to prevent oxidative damage induced by the oxidant A1254. PMID- 17704392 TI - Ontogeny of the cloacal gland in male Japanese quail classified in a T-maze. AB - Broiler chicks that traverse a T-maze quickly to reinstate contact with their companions (HP, high performers) are known to grow faster, are more social, and have a reduced plasma corticosterone response to acute stress than slower chicks (LP, low performers). High-performing quail from a line selected for reduced rather than exaggerated (high-stress) adrenocortical stress responsiveness also show enhanced female reproductive performance when compared with LP-high-stress quail. Herein, time courses of male sexual development were evaluated in genetically unremarkable quail that were categorized at 2 d of age as HP or LP in the T-maze. Body weight, cloacal gland volume (CVOL), proportion of individuals that produced cloacal gland foam, intensity of foam production, and CVOL relative to BW (RCVOL) were determined weekly from 4 to 10 wk of age, and again at 22 wk, along with absolute and BW-adjusted testes weight. Although CVOL and RCVOL were initially similar in both T-maze groups, both variables were greater (P < 0.05) in HP than in LP quail between 6 and 10 wk of age. High-performing birds also showed a trend (P < 0.1) of greater cloacal gland foam than their LP counterparts from 5 to 7 wk. From 8 wk on, all birds were in foam production. Intensity of foam production results generally mimicked those found for CVOL and RCVOL. Body weights were higher (P < 0.05) in HP than LP quail from 5 to 7 wk. No T-maze group differences were found in any of the variables at 22 wk of age. The results suggest that rapid negotiation of the T-maze is associated with accelerated growth and puberty in male quail, although the enhanced reproductive development of HP males does not remain extant in aged adults. PMID- 17704393 TI - The effect of glypican-1 glycosaminoglycan chains on turkey myogenic satellite cell proliferation, differentiation, and fibroblast growth factor 2 responsiveness. AB - The glypicans are a family of cell-surface heparan sulfate proteoglycans consisting of a core protein covalently attached with glycosaminoglycans (GAG). Only glypican-1 is expressed in skeletal muscle and increases in expression during myoblast differentiation. Previous studies have suggested that glypican-1 influences fibroblast growth factor 2 (FGF2) signaling pathway by its heparan sulfate chains. Fibroblast growth factor 2 is a potent stimulator of muscle cell proliferation and an intense inhibitor of differentiation. To investigate the functional contribution of each GAG chain attachment site, a turkey glypican-1 full length cDNA (1,650 bp, Gen-Bank accession number AY551002) was cloned into the pCMS-EGFP vector and mutated at 2 or all 3 potential GAG attachment sites at Ser(483), Ser(485), and Ser(487) to obtain 1-chain and no-chain mutants, respectively. The unmutated glypican-1, 1-chain, and no-chain mutants, and the pCMS-EGFP vector without an insert were transfected into turkey myogenic satellite cells. The transfected cell cultures were assayed for cell proliferation, differentiation, and FGF2 responsiveness. The overexpression of glypican-1 increased FGF2 responsiveness during proliferation compared with the 1 chain, no-chain mutants, and the pCMS-EGFP vector without an insert, but there was no significant interaction between FGF2 and glypican-1. The overexpression of glypican-1 also increased differentiation but did not affect proliferation when compared with the 1-chain, no-chain mutants, and the pCMS-EGFP vector without an insert. To support the overexpression data, glypican-1 expression was reduced using a small interfering RNA against turkey glypican-1. Inhibition of glypican-1 expression decreased myogenic satellite cell proliferation, differentiation, and FGF2 responsiveness during proliferation. These data indicate that glypican-1 function requires the GAG chain attachment sites for myogenic satellite cell FGF2 responsiveness during proliferation and to affect the process of differentiation. PMID- 17704394 TI - Feeding turkeys a highly digestible supplement during preslaughter feed withdrawal. AB - Standard commercial practice is to deny poultry access to feed 8 to 12 h prior to slaughter. Occasionally a flock of turkeys is marketed at several ages, and starvation can occur for birds that are not shipped. For this project multiple marketed female turkeys were fed a special diet (nutritive supplement) during the preslaughter feed withdrawal period to reduce live weight loss, bird stress, and grazing on manure. Three trials were conducted at the Nova Scotia Agricultural College using 60 female turkey poults for each of 8 pens for each trial. The birds were separated into 8 pens with 20 birds from half of the pens shipped at 63 d of age and all remaining birds shipped 1 wk later. Prior to shipping, feed was withdrawn, with half the pens receiving the supplement. The pens that had received supplement at 63 d of age received it again a week later along with half the pens not previously marketed. The supplement was only consumed in a significant quantity when it was new to the birds (~10 g/kg of bird). The carcass yield, based on the live weight before the conventional feed withdrawal period, was improved for birds that consumed the supplement. Microbiological profiles of the crops revealed that although the total number aerobic bacteria was not affected, birds ingesting the supplement had fewer Escherichia coli and coliforms present. Breast meat samples collected at 15 min postmortem and 24 h postmortem and measured for pH were not found to be different between the treatments. Because birds would only consume the supplement on the first exposure, this supplement is only effective for reducing live weight loss and microbial load of the crop in an all-in all-out management situation. PMID- 17704395 TI - Control of microorganisms and reduction of biogenic amines in chicken breast and thigh by irradiation and organic acids. AB - The effect of irradiation or organic acid treatment of raw chicken breast and thigh meat to control inoculated microorganisms and the production of biogenic amines (BA) was studied. Bacillus cereus, Enterobacter cloacae, and Alcaligenes faecalis were selected and inoculated into raw ground chicken breast and thigh meat at approximately 10(7) cfu/g. The samples were irradiated at 0, 0.5, 1, and 2 kGy or mixed with a 0.2 M solution of acetic, citric, or lactic acid (1 mL for 10 g of meat sample) for 24 h at 4 degrees C. Viable cell counts and BA contents were determined. Irradiation was effective in reducing the inoculated bacteria: 0.5 kGy achieved approximately a 2-log reduction, and no viable cells were detected at a dose of 2 kGy. In contrast, only up to a 1-log reduction was achieved by organic acid treatment except for citric acid, which achieved approximately a 3-log reduction of E. cloacae. Both the irradiation and organic acid treatment of raw chicken breast and thigh reduced the BA content, but the rate of BA reduction differed by inoculated organism and treatment (irradiation or organic acid). Although irradiation was an excellent method for controlling inoculated microorganisms, the content of BA produced was similar to that of the organic acid treatment of raw chicken breast and thigh meat. PMID- 17704396 TI - Effect of flock size on dioxin levels in eggs from chickens kept outside. AB - To decrease dioxin uptake by the general population the European Union (EU) has set limits to the dioxin content of many foodstuffs including eggs. Eggs from free foraging chickens are known to have a higher dioxin content compared with confined laying hens, and the question is whether these eggs can adhere to current EU regulations. The aim of the study was to investigate parameters that are involved in the contamination of eggs from chickens raised under organic conditions. Samples from 34 organic farms including soil and earthworm samples were collected between September and December of the year 2003. Dioxin levels were assayed by gas chromatography-mass spectrometry. Various parameters were collected by on farm interviews. Egg dioxin content varied between 0.4 and 8.1 pg of toxic equivalents (TEQ)/g of egg fat with a mean of 2.2 pg of TEQ/g of egg fat. Nine out of 34 farms exceeded the EU limit of 3 pg of TEQ/g of egg fat. In addition, dioxin-like polychlorinated biphenyls (DL-PCB) were measured, and 8 samples exceeded the limit for the sum of dioxins and DL-PCB. Overall, egg samples from 10 farms were noncompliant with the dioxin or total TEQ limits. No statistically significant relation could be observed between egg dioxin levels and the concentration observed in soil or earthworms. A statistically significant association was observed between flock size and egg dioxin and DL-PCB content. This effect is most likely attributable to the fact that flock size is related to the time chickens spend outside. Restricting outdoor run use on one of the farms resulted in a decrease of the egg dioxin content to a level that was within the EU limits. This demonstrates that the most likely contamination source is the soil or soil organisms but that the behavior of the hens determines the extent of the contamination. Following the completion of this study, a dioxin monitoring protocol has been set up in the Netherlands to prevent marketing of eggs with raised dioxin levels. PMID- 17704398 TI - Total recall. PMID- 17704397 TI - Comment on report from Schaser and coworkers. PMID- 17704399 TI - Predicting outcomes in prostate cancer: how many more nomograms do we need? PMID- 17704400 TI - The Titanic and the Iceberg: prostate proton therapy and health care economics. PMID- 17704401 TI - The sound and the fury: financial conflicts of interest in oncology. PMID- 17704402 TI - Ovarian cancer, CA-125 addiction, and informed confusion: much ado about less. PMID- 17704403 TI - End points in advanced colon cancer clinical trials: a review and proposal. PMID- 17704404 TI - A nomogram predicting 10-year life expectancy in candidates for radical prostatectomy or radiotherapy for prostate cancer. AB - PURPOSE: Candidates for definitive therapy for localized prostate cancer (PCa) should have life expectancy (LE) in excess of 10 years. However, LE estimation is difficult. To circumvent this problem, we developed a nomogram predicting 10-year LE for patients treated with either radical prostatectomy (RP) or external-beam radiation therapy (EBRT) and compared it with an existing tool. PATIENTS AND METHODS: Between 1989 and 2000, 9,131 men were treated with either RP (n = 5,955) or EBRT (n = 3,176), without any secondary therapy and all deaths were considered unrelated to PCa. Age and Charlson comorbidity index (CCI) predicted 10-year LE in Cox regression models. We used 200 bootstrap resamples to internally validate the nomogram. RESULTS: Median age was 66 years, median CCI was 1, median follow up was 5.9 years and median actuarial survival was 13.8 years. Advanced age (P < .001), elevated CCI score (P < .001) and treatment type (EBRT v RP, P < .001) were independent predictors of poor 10 year LE. The nomogram predicting 10 year LE after either RP or EBRT was 84.3% accurate in split sample validation and was 2.9% (P = .007) more accurate than the existing tool. A cutoff of 70% or less was 84% accurate in identifying men who did not survive beyond 10 years. CONCLUSION: Our nomogram can accurately identify those individuals who do not have sufficient LE to warrant definitive PCa treatment and can help optimizing therapy decision making. PMID- 17704405 TI - Assessing individual risk for prostate cancer. AB - PURPOSE: To construct a clinical nomogram instrument to estimate individual risk for having prostate cancer (PC) for patients undergoing prostate specific antigen (PSA) screening, using all risk factors known for PC. PATIENTS AND METHODS: We conducted a cross-sectional study of 3,108 men who underwent a prostate biopsy, including a subset of 408 volunteers with normal PSA levels. Factors including age, family history of PC (FHPC), ethnicity, urinary symptoms, PSA, free:total PSA ratio, and digital rectal examination (DRE) were incorporated in the model. A nomogram was constructed to assess risk for any and high-grade PC (Gleason score >or= 7). RESULTS: Of the 3,108 men, 1,304 (42.0%) were found to have PC. Among the 408 men with a normal PSA (< 4.0 ng/mL), 99 (24.3%) had PC. All risk factors were important predictors for PC by multivariate analysis (P, .01 to .0001). The area under the curve (AUC) for the nomogram in predicting cancer, which included age, ethnicity, FHPC, urinary symptoms, free:total PSA ratio, PSA, and DRE, was 0.74 (95% CI, 0.71 to 0.81) and 0.77 (95% CI, 0.74 to 0.81) for high-grade cancer. This was significantly greater than the AUC that considered using the conventional screening method of PSA and DRE only (0.62; 95% CI, 0.58 to 0.66 for any cancer; 0.69; 95% CI, 0.65 to 0.73 for high-grade cancer). From receiver operating characteristic analysis, risk factors including age, ethnicity, FHPC, symptoms, and free:total PSA ratio contributed significantly more predictive information than PSA and DRE. CONCLUSION: In a PC screening program, it is important to consider age, family history of PC, ethnicity, urinary voiding symptoms, and free:total PSA ratio, in addition to PSA and DRE. PMID- 17704406 TI - Disparities in treatment and outcome for renal cell cancer among older black and white patients. AB - PURPOSE: Black patients with renal cell cancer have shorter survival compared with their white counterparts, but the causes for this disparity are unclear. To elucidate reasons for this inequality, we examined differences in treatment and survival between black and white patients. PATIENTS AND METHODS: A retrospective cohort study was conducted using data from the linked Surveillance, Epidemiology and End Results (SEER) cancer registry and Medicare databases. Participants included 964 black and 10,482 white patients age >or= 65 years who were enrolled into Medicare and diagnosed with renal cell cancer between 1986 and 1999. Information on surgical treatment was ascertained from both databases, whereas data regarding coexisting illness and survival was obtained from the Medicare database. RESULTS: The percentage of black patients receiving nephrectomy treatment was significantly lower compared with whites (61.2% v 70.4%; P < .0001). After adjustment for age, sex, median income, cancer stage, tumor size, and comorbidity index, blacks were less likely to undergo nephrectomy treatment compared with whites (risk ratio = 0.93; 95% CI, 0.90 to 0.96). Overall survival was worse for blacks than whites even after adjustment for demographic and cancer prognostic factors (hazard ratio [HR] = 1.16; 95% CI, 1.07 to 1.25); however, additional adjustment for comorbidity index and nephrectomy treatment reduced the disparity substantially (HR = 1.00; 95% CI, 0.93 to 1.09). CONCLUSION: This study indicates that the lower survival rate among blacks compared with whites with renal cell cancer can be explained largely by the increased number of comorbid health conditions and the lower rate of surgical treatment among black patients. PMID- 17704407 TI - Combination of polymorphisms from genes related to estrogen metabolism and risk of prostate cancers: the hidden face of estrogens. AB - PURPOSE: The association between common functional polymorphisms from the CYP17, CYP19, CYP1B1, and COMT genes involved in the estrogen metabolism and the risk of prostate carcinoma was evaluated. PATIENTS AND METHODS: The study investigated 1,983 white French men (1,101 patients with prostate cancer and 882 healthy controls) aged between 40 and 98 years. The different alleles and genotypes were analyzed according to case-control status, aggressiveness pattern of the tumors, age at onset, and family history of cancers. RESULTS: The VV (high activity) genotype of the V432L polymorphism from CYP1B1 (odds ratio [OR] = 1.36; 95% CI, 1.03 to 1.79; P = .031), and the long allele (> 175 bp) of the TTTA repeat from CYP19 (OR, 1.26; 95% CI, 1.08 to 1.47; P = .003) were significantly associated with the risk of prostate cancer. An additive effect was observed when we combined the two at-risk alleles (OR = 1.63; 95% CI, 1.24 to 2.13; P < .001). The association was stronger for the CYP1B1 VV genotype (OR = 1.55; 95% CI, 1.13 to 2.13; P = .007) among the group of patients with highly aggressive disease. Stratification by age at onset showed that the associations of CYP1B1 and CYP19 variants were largely confined to the younger prostate cancer patients. CONCLUSION: This association between polymorphisms from genes related to estrogen metabolism and prostate cancer risk suggest new clinical considerations in the management of prostate cancer: the development of new prevention trials based on genetic profiling and the evaluation of specific inhibitors involving the estrogen pathways. PMID- 17704408 TI - Is proton beam therapy cost effective in the treatment of adenocarcinoma of the prostate? AB - PURPOSE: New treatments are introduced routinely into clinical practice without rigorous economic analysis. The specific aim of this study was to examine the cost effectiveness of proton beam radiation compared with current state-of-the art therapy in the treatment of patients with prostate cancer. MATERIALS AND METHODS: A Markov model was informed with cost, freedom from biochemical failure (FFBF), and utility data obtained from the literature and from patient interviews to compare the cost effectiveness of 91.8 cobalt gray equivalent (CGE) delivered with proton beam versus 81 CGE delivered with intensity-modulated radiation therapy (IMRT). The length of how many years the model was run, patient's age, probability of FFBF after treatment with proton beam therapy and IMRT, utility of patients treated with salvage hormone therapy, and treatment cost were tested in sensitivity analyses. RESULTS: Analysis at 15 years resulted in an expected mean cost of proton beam therapy and IMRT of $63,511 and $36,808, and $64,989 and $39,355 for a 70-year-old and 60-year-old man respectively, with quality-adjusted survival of 8.54 and 8.12 and 9.91 and 9.45 quality-adjusted life-years (QALY), respectively. The incremental cost effectiveness ratio was calculated to be $63,578/QALY for a 70-year-old man and $55,726/QALY for a 60-year-old man. CONCLUSION: Even when based on the unproven assumption that protons will permit a 10-Gy escalation of prostate dose compared with IMRT photons, proton beam therapy is not cost effective for most patients with prostate cancer using the commonly accepted standard of $50,000/QALY. Consideration should be given to limiting the number of proton facilities to allow comprehensive evaluation of this modality. PMID- 17704409 TI - Frequency, type, and monetary value of financial conflicts of interest in cancer clinical research. AB - PURPOSE: Using data from American Society of Clinical Oncology (ASCO) Annual Meetings, we determined the frequency, type, and monetary value of researchers' financial interests. METHODS: Financial disclosures for the 2004 (3,529 abstracts and 25,416 authors) and 2005 (3,556 abstracts and 26,181 authors) ASCO Annual Meetings were categorized into four groups: no author with a financial interest, research funding only, employment and leadership positions only, or at least one author with a personal financial interest. Interests were stratified by monetary value and other factors. RESULTS: In 2004 and 2005, 23% of abstracts had one or more authors with a personal financial interest. More than 75% of all personal financial interests were valued at less than $10,000. More than 90% of financial interests of more than $100,000 were employment related. Fewer than 3.5% of authors with personal financial interests had interests valued at more than $100,000. Overall, 6.3% (2004) and 2.9% (2005) of abstracts only had research funding, whereas 7.3% (2004) and 6.9% (2005) had only commercial employment. In 2005, 60% of plenary sessions compared with 23.1% in general poster sessions and 17.3% for publish-only abstracts reported financial ties. Personal financial interests were more common among US authors compared with non-US authors (9.2% v 4.2%). CONCLUSION: About one fourth of abstracts at ASCO Annual Meetings have an author with a personal financial interest. Most personal financial interests are valued at less than $10,000 per year, whereas a majority valued at more than $100,000 are related to employees of commercial entities. PMID- 17704410 TI - An early signal of CA-125 progression for ovarian cancer patients receiving maintenance treatment after complete clinical response to primary therapy. AB - PURPOSE: For ovarian cancer patients receiving maintenance treatment after complete clinical response to primary therapy, we tested the predictive value of the following early signal of progressive disease (EPD) criterion based on serum CA-125: for patients with CA-125 nadir or= 20 U/mL serves as an early signal of CA-125 progression; for patients with nadir more than 10 U/mL, a value >or= 2x nadir that is confirmed predicts progression. PATIENTS AND METHODS The EPD criterion was tested on Southwest Oncology Group trial 9701/Gynecologic Oncology Group trial 178 patients (n = 288) and compared with Gynecologic Cancer Intergroup criterion. RESULTS: For 204 patients with known progressive disease, the progression date was predated by EPD by 1.0 cm residual disease had an increased risk of recurrence (HR = 1.96; 95% CI, 1.70 to 2.26; and HR = 2.36; 95% CI, 2.04 to 2.73, respectively) and death (HR = 2.11; 95% CI, 1.78 to 2.49; P < .001; and HR = 2.47; 95% CI, 2.09 to 2.92, respectively). CONCLUSION: Age, PS, tumor histology, and residual tumor volume were independent predictors of prognosis in patients with stage III EOC. These data can be used to identify patients with poor prognosis and to design future tailored randomized clinical trials. PMID- 17704412 TI - Role of human papillomavirus genotype in prognosis of early-stage cervical cancer undergoing primary surgery. AB - PURPOSE: Our aim was to evaluate the prognostic significance of human papillomavirus (HPV) genotype in early-stage cervical carcinoma primarily treated with surgery in a large tertiary referral medical center. PATIENTS AND METHODS: Consecutive patients who underwent primary surgery for invasive cervical carcinoma of International Federation of Gynecology and Obstetrics (FIGO) stage I to IIA between 1993 and 2000 were retrospectively reviewed. Polymerase chain reaction (PCR) using a general primer set followed by reverse-blot detection of 38 types of HPV DNA in a single reaction was performed for genotyping. E6 type specific PCR was performed to validate multiple types. RESULTS: A total of 1,067 eligible patients were analyzed. HPV DNA sequences were detected in 95.1% of the specimens, among which 9.6% contained multiple types. HPV 16 was detected in 63.8% of the samples, and HPV 18 was detected in 16.5% of the samples. The median follow-up time of surviving patients was 77 months. By multivariate analysis, FIGO stage, lymph node metastasis, depth of cervical stromal invasion, grade of differentiation, and HPV 18 positivity were significantly related to cancer relapse. FIGO stage II, deep stromal invasion, parametrial extension, HPV 18 positivity, and age older than 45 years were significant predictors for death. Using the seven selected variables from either recurrence-free or overall survival analysis, death-predicting (P < .0001) and relapse-predicting (P < .0001) models classifying three risk groups (low, intermediate, and high risk) were constructed and endorsed by internal validation. CONCLUSION: The independent prognostic value of HPV genotype is confirmed in this study. The prognostic models could be useful in counseling patients and stratifying patients in future clinical trials. PMID- 17704413 TI - Noninvasive evaluation of late anthracycline cardiac toxicity in childhood cancer survivors. AB - PURPOSEl: Childhood cancer survivors treated with anthracyclines and cardiac radiation are at risk for late-onset cardiotoxicity. The purpose of this study was to delineate the relationship between clinical factors and abnormalities of noninvasive cardiac testing (NICT). PATIENTS AND METHODS: Participants were recruited from a long-term follow-up clinic. Study measures comprised physical examination, laboratory evaluation, echocardiogram, and ECG. Mean fractional shortening (FS) and afterload were compared for survivors who did (at risk [AR]) and did not (no risk [NR]) receive potentially cardiotoxic modalities, and with values expected for comparable age- and sex-matched controls. RESULTS: The 278 study participants (mean age, 18.1 years; median age, 16.8 years; range, 7.5 to 39.7 years) included 223 survivors AR for cardiotoxicity after treatment with anthracyclines (median dose +/- standard deviation [SD], 202 +/- 109 mg/m(2)) and/or cardiac radiation. Mean FS (+/- SD) was lower for AR (0.33 +/- 0.06) compared with NR survivors (0.36 +/- 0.05; P = .004) and normative controls (0.36 +/- 0.04; P < .001). Mean afterload (+/- SD) was higher for AR (58 +/- 21 g/cm(2)) compared with NR survivors (46 +/- 15 g/cm(2); P < .001) and normative controls (48 +/- 13 g/cm(2); P < .001). The distribution of FS and afterload among NR survivors did not differ from that of controls. After adjustment for age group at diagnosis and time since completion of therapy, anthracycline dose predicted decline in distribution of FS (P < .001) and increase in distribution of afterload (P < .001). Treatment with anthracycline doses >or= 100 mg/m(2) increased the risk of abnormal NICT; survivors who received >or= 270 mg/m(2) had a 4.5-fold excess risk of abnormal NICT (95% CI, 2.1 to 9.6) compared with controls. CONCLUSION: Childhood cancer survivors treated with anthracycline doses >or= 270 mg/m(2) are at greatest risk for abnormalities of FS and afterload. PMID- 17704414 TI - High incidence of cetuximab-related infusion reactions in Tennessee and North Carolina and the association with atopic history. AB - PURPOSE: To confirm the anecdotal observation that patients in North Carolina (NC) and Tennessee (TN) treated with cetuximab experience hypersensitivity reactions (HSR) at a much higher rate than are reported nationally and internationally ( 15% of patients) were diarrhea, nausea, rash, palmar-plantar erythrodysesthesia, mucositis, vomiting, and stomatitis. There were four confirmed responses (one complete response and three partial responses). The pharmacokinetics (area under the curve and maximum concentration) of lapatinib, capecitabine and its metabolites, fluorouracil, and alpha-fluoro-beta-alanine, were not meaningfully altered by coadministration. CONCLUSION: Lapatinib and capecitabine administered on a 3-week schedule were well tolerated, and no pharmacokinetic interaction was observed. Clinical activity was observed in patients with previously treated, advanced solid malignancies. PMID- 17704423 TI - Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1. AB - PURPOSE: This randomized, 2 x 2 factorial study compared a semimonthly regimen (fluorouracil [FU] and leucovorin [LV] semi-monthly is LV5FU2) with a monthly regimen of FU and LV (mFU/LV) as well as 24 weeks versus 36 weeks of each regimen as adjuvant treatment of stage II and III colon cancer. PATIENTS AND METHODS: LV5FU2 was administered semimonthly for 2 days as racemate (dl) or levogyre (l-; 200 or 100 mg/m(2)) as a 2-hour infusion, followed by 400 mg/m(2) FU bolus and a 600-mg/m(2) FU 22-hour continuous infusion. FU and LV were administered monthly (mFU/LV) for 5 days as dl- or l-LV 15-minute infusion, followed by a 400 mg/m(2) FU 15-minute infusion. The primary end point was disease-free survival (DFS). RESULTS: Between September 1996 and November 1999, 905 patients with stage II (43%) and III (57%) colon cancer were enrolled. The median follow-up was 6 years. There was no statistically significant difference between mFU/LV and LV5FU2 in terms of DFS (150 v 148 events; hazard ratio [HR],1.01; 95% CI, 0.806 to 1.269; P = .94) and overall survival (OS; 104 v 103 events; HR,1.02; 95% CI, 0.77 to 1.34; P = .91). No statistical difference was observed between 24 or 36 weeks of chemotherapy. Median survival from metastatic relapse was 24 months. The survival of patients with metastatic relapse (n = 243) was significantly longer for patients with a longer time from random assignment to relapse (< 1, 1 to 2, >or= 2 years; log-rank test for trend P, .0497). CONCLUSION: DFS and OS were not statistically different between treatment groups and treatment durations. These data confirm the value of LV5FU2 as control arm in the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer and Pan European Trials in Adjuvant Colon Cancer studies. PMID- 17704425 TI - Ototoxicity in a randomized phase III trial of intra-arterial compared with intravenous cisplatin chemoradiation in patients with locally advanced head and neck cancer. AB - PURPOSE: Cisplatin concomitantly administered with radiotherapy is increasingly used in locally advanced head and neck squamous cell carcinoma. We aimed to compare the incidence of hearing loss between patients treated with intra arterial high-dose cisplatin chemoradiation with sodium thiosulfate (CRT-IA) and intravenous high-dose cisplatin chemoradiation without sodium thiosulfate (CRT IV). PATIENTS AND METHODS: We conducted a prospective analysis of hearing thresholds at low and (ultra-) high frequencies obtained before, during, and after treatment in 158 patients. Patients were randomly assigned for either CRT IA (150 mg/m(2), four courses) with sodium thiosulfate cisplatin neutralization or CRT-IV (100 mg/m(2), three courses) without rescue. All patients received concomitant radiation therapy (RT; 70 Gy). RESULTS: CRT-IA resulted in approximately 10% less hearing loss at frequencies vital for speech perception, compared with CRT-IV (P < .001). In CRT-IA, fewer ears qualified for hearing aids (36% v 49%; P = .03). However, in both treatment arms, the incidence expressed in National Cancer Institute Common Terminology Criteria of Adverse Events (version 3) did not deviate (P > .14). Age, cumulative cisplatin dose, cumulative RT dose, and the considered frequency area determine the degree of hearing loss (P < .001). Cisplatin induced increasing hearing loss of 24% to 60% with increasing frequencies. RT induced hearing loss at speech frequencies of 9% to 12%. CONCLUSION: Depending on the criteria used to assess hearing loss due to treatment, differences in ototoxicity between CRT-IA and CRT-IV were found in favor of CRT-IA. It is desirable to specify hearing loss criteria toward frequencies vital for speech perception, and to refine grading scales to reveal subtle and clinically relevant dissimilarities in ototoxicity between different treatment protocols. PMID- 17704426 TI - Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. AB - PURPOSE: To determine the efficacy and safety of single-agent sorafenib in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) and nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: In this single-arm phase II trial, oral continuous sorafenib was administered in 28-day cycles. Patients had 120 mmol/day. Total sodium removal correlated with total body water, ECW, and ICW (p < 0.001, p < 0.001, p < 0.025, respectively), as well as with height and weight (p < 0.06, p < 0.01 respectively). On multivariate analysis, only ultrafiltration volume and urine volume were significantly associated with total sodium removal (r(2) = 0.67, p < 0.0001 for both). There was also a correlation between sodium removal and urea nitrogen appearance (r(2) = 0.31, p < 0.001), with urea nitrogen appearance in turn being closely correlated with ICW (p < 0.001). Volume Status: The ECW/ICW ratio was 0.88 +/- 0.17, which was not significantly different to that found in hemodialysis patients without clinical evidence of fluid overload, either predialysis (0.96 +/ 0.16) or postdialysis (0.92 +/- 0.16); p = 0.07 and 0.36 respectively. Blood Pressure: Mean +/- standard deviation systolic blood pressure (BP) was 111.9 +/- 18.2 mmHg and diastolic BP was 63.3 +/- 11.9 mmHg, with only 4 (7%) patients having a systolic BP > 140 mmHg and 1 (2%) having a diastolic BP > 80 mmHg. Median number of antihypertensives was 1 per day. Blood pressure control and ECW/ICW ratio were similar in those with sodium removal >120 mmol/day compared to those with sodium removal < or =120 mmol/day (p = 0.39 for SBP, p = 0.70 for diastolic BP, p = 0.24 for ECW/ICW). CONCLUSIONS: We have shown that good blood pressure and volume control is achievable in a large contemporary APD population with liberal use of icodextrin and avoidance of long daytime glucose-based dwells. Neither low nor high sodium removal was associated with more frequent hypertension or volume expansion. PMID- 17704446 TI - A simple method to prevent peritoneal dialysis catheter tip migration. AB - BACKGROUND: We report here a one-stitch fixation method that prevents catheter tip migration during implantation of the double-cuffed straight Tenckhoff catheter. METHODS: From July 2003 to September 2005, 38 patients with end-stage renal disease underwent implantation of the double-cuff straight Tenckhoff catheter for peritoneal dialysis by this method. RESULTS: No patient had catheter tip migration out of the true pelvis. No patient had pericatheter dialysate leakage or developed incisional hernia. Two patients (5.3%) experienced exit-site infection during the 2- and 5-month follow-up and they recovered well after wound care. Three patients (7.9%) developed peritonitis during the 3-day and 2- and 6 month follow-up; the conditions were controlled after antibiotic care. One patient (2.6%) experienced mechanical catheter obstruction during the 10-day follow-up due to omental wrapping; surgical revision was necessitated. CONCLUSIONS: We believe that the method is an easy, safe, and effective technique for preventing catheter tip migration. PMID- 17704447 TI - Does previous abdominal surgery increase postoperative complication rates in continuous ambulatory peritoneal dialysis? AB - BACKGROUND: This study was to compare the postoperative complication rates of continuous ambulatory peritoneal dialysis (CAPD) catheter insertion via open technique between two groups of patients, those with and those without a history of previous abdominal surgery. METHODS: A review was carried out in 122 patients over a 2-year period. The patients were divided into two groups: those with and those without previous lower abdominal surgery. All patient records were retrospectively analyzed until the time of catheter failure or to current time if alive and receiving CAPD. Patient characteristics, operative factors, and postoperative complications were recorded. RESULTS: Postoperative complications were reported as catheter malfunction in 16 patients and CAPD-related peritonitis in 36 patients. The complication rates in the group of patients with previous abdominal surgery were 16.7% catheter malfunction and 33.3% CAPD-related peritonitis. In patients without previous lower abdominal surgery, a catheter malfunction rate of 12.5% and a peritonitis rate of 28.8% were seen. The operation time in patients with previous abdominal surgery was longer than that in patients without previous abdominal surgery. However, no statistically significant difference in postoperative complication rates was detected between patients with and patients without previous lower abdominal surgery. CONCLUSION: CAPD remains a reliable modality in the treatment of end-stage renal disease and does not increase postoperative complications in patients with previous abdominal surgery. PMID- 17704448 TI - Risks and outcomes of peritonitis after flexible colonoscopy in CAPD patients. AB - OBJECTIVE: The ISPD 2005 guidelines for peritonitis recommend antibiotic prophylaxis for patients undergoing colonoscopy with polypectomy while on continuous ambulatory peritoneal dialysis (CAPD) but there is little literature to support this recommendation. This study aimed to look into the risks and outcomes of peritonitis after colonoscopy in CAPD patients. PATIENTS AND METHODS: All records of flexible colonoscopy performed on our CAPD patients from January 1994 to January 2006 were retrieved. Demographic and clinical data, use of antibiotics before colonoscopy, endoscopic findings, procedure performed, and peritonitis data were analyzed. RESULTS: 77 CAPD patients underwent 97 colonoscopies. No peritonitis developed in the 18 cases where antibiotics were given before colonoscopy. Among those without antibiotic prophylaxis, 4 episodes of peritonitis occurred within 24 hours after the procedure and 1 occurred 5 days later. All responded to intraperitoneal antibiotics. Colonic biopsy and polypectomy were not associated with more peritonitis (2 in 41 with biopsy vs 3 in 38 without biopsy, p = 0.67; 1 in 30 with polypectomy vs 4 in 49 without polypectomy, p = 0.64). CONCLUSION: The risk of peritonitis after colonoscopy without antibiotic prophylaxis was 6.3%. All peritonitis episodes responded to intraperitoneal antibiotics. Colonic biopsy or polypectomy did not appear to increase the risk of peritonitis. Although statistically not significant when compared with patients without antibiotic prophylaxis, we observed no peritonitis after colonoscopy in patients that were given antibiotics for prophylactic purposes or for other reasons. The efficacy of prophylactic antibiotics would be better defined by large randomized trials. PMID- 17704449 TI - A quarter of a century of adult peritoneal dialysis-related peritonitis at an Australian medical center. AB - BACKGROUND: Peritonitis remains one of the major complications of peritoneal dialysis (PD) and results in reduced technique survival and increased patient morbidity and mortality. METHODS: We prospectively recorded comprehensive data on all episodes of PD peritonitis over a 25-year period, including organisms isolated and antibiotic sensitivities. Data on 1588 PD patient-years with 2073 episodes of peritonitis were analyzed; 2089 organisms were isolated in 608 patients. Peritoneal dialysis technique and patient survival were also recorded. RESULTS: There was a significant decline over the years in the incidence of peritonitis, from 6.5 to 0.35 episodes/patient-year, with the decline in the post twin-bag era from 2.3 to 0.47 (p < 0.001) due primarily to a decrease in gram positive organisms. The most common isolates (68.9%) were gram-positive organisms; gram-negative organisms comprised 26.8% and fungi 4.1%. Coagulase negative staphylococci were the most common pathogen isolated (35.3%). Culture negative peritonitis was seen in 13.4% of episodes. CONCLUSION: This is the largest series of PD peritonitis reported, demonstrating a dramatic reduction over a 25-year period and also detailing the changing trends of organisms isolated in association with improved technique and patient survival. Although rates have improved, peritonitis remains a major complication and further research needs to be done to improve both PD technique and patient survival. PMID- 17704450 TI - Effects of peritoneal resting on peritoneal fluid transport kinetics. AB - BACKGROUND: Peritoneal resting has been used to restore peritoneal ultrafiltration capacity in peritoneal dialysis patients. Therefore, in the present study, we made a detailed investigation on the effects of peritoneal resting on peritoneal fluid transport characteristics in patients on continuous ambulatory peritoneal dialysis (CAPD). METHODS: A temporary transfer to daytime ambulatory peritoneal dialysis with a nocturnal "empty belly" was applied to let the peritoneal membrane rest overnight in patients with poor ultrafiltration capacity. All included patients were asked to record appropriately their dialysis exchanges for the assessment of peritoneal fluid transport characteristics, which were evaluated before and after peritoneal resting. RESULTS: Seven CAPD patients were included in the present study. There was a significant improvement in peritoneal ultrafiltration capacity as assessed by ultrafiltration volume per gram of glucose load. Patients' daily glucose exposure and dialysate-to-plasma ratio of creatinine were significantly decreased after peritoneal resting. The peritoneal fluid absorption rate was also significantly decreased after peritoneal resting: 1.011 +/- 0.4484 versus 0.625 +/- 0.3833 mL/minute. CONCLUSION: The present study suggests that peritoneal resting can improve CAPD patients' ultrafiltration capacity and decrease the use of hypertonic dialysis solution. The improved ultrafiltration capacity by peritoneal resting was due to decreased membrane solute transport rate and decreased peritoneal fluid absorption rate. PMID- 17704451 TI - Effects of Smad7 overexpression on peritoneal inflammation in a rat peritoneal dialysis model. AB - OBJECTIVE: Transforming growth factor-beta (TGF-beta) has been shown to play a role in peritoneal complications due to long-term peritoneal dialysis (PD). In this study, we examined the effects of the TGF-beta signaling pathway on peritoneal inflammation associated with PD in rats by over-expressing Smad7, an inhibitor of TGF-beta/Smad signaling. METHODS: Peritoneal inflammation was induced in male Sprague-Dawley rats by intraperitoneal injections of 4.25% glucose dialysate (100 mg/kg body weight) daily for 4 weeks, with the addition of lipopolysaccharides (0.6 mg/kg body weight) on days 8, 10, 12, 22, 24, and 26. Peritoneal Smad7 gene transfer was achieved using an ultrasound microbubble mediated, doxycycline regulated, Smad7-expressing plasmid on day 0 and day 14 after initiation of PD. An empty vector was used as control. All rats were sacrificed after 4 weeks of PD. Peritoneal inflammatory response, including infiltration of total leukocytes (OX-1 positive) and macrophages (ED-1 positive) and expression of interleukin (IL)-1beta and tumor necrosis factor-alpha (TNF alpha), was examined by immunofluorescence and RT-PCR. RESULTS: After PD, peritoneal inflammation developed in control animals, as demonstrated by an increase in the number of OX-1-positive and ED-1-positive cells and upregulation of IL-1beta and TNF-alpha mRNA and protein expression. In contrast, in animals treated with Smad7 gene transfer, IL-1beta and TNF-alpha expression and OX-1 positive and ED-1-positive cell infiltration were significantly inhibited. Furthermore, prevention of peritoneal inflammation by overexpression of Smad7 was associated with inhibition of phosphorylation of Smad2/3, a downstream of the TGF beta signaling pathway, as well as TGF-beta1 expression. CONCLUSION: Overexpression of Smad7 suppresses peritoneal inflammation induced by high glucose and lipopolysaccharides. The ability of Smad7 gene transfer to inhibit peritoneal inflammation indicates that targeting TGF-beta/Smad signaling may represent a new therapeutic strategy for the treatment of peritoneal complications associated with PD. PMID- 17704452 TI - Patients with chronic kidney disease stages 3 and 4 demand survival information on dialysis. PMID- 17704453 TI - Appendicitis in a CAPD patient: a diagnostic challenge. PMID- 17704454 TI - Depression, nutritional status, and serum cytokines in peritoneal dialysis patients: is there a relationship? PMID- 17704455 TI - Successful treatment of Alcaligenes xylosoxidans in automated peritoneal dialysis related peritonitis. PMID- 17704457 TI - Memories of childhood sexual abuse: narrative analyses of types, experiences, and processes of remembering. AB - The study explored types of memory for childhood sexual abuse (CSA) in a clinical sample of 30 women and identified factors that led some women (n = 24) to report recovered memories. Questionnaires produced three types of memory: always (n = 6), recovered (n = 14), both (n = 10); however, analysis of narrative data also revealed the use of language that could not be categorized into discrete types. Recovered memories were linked to three categories of experience (cumulative reactions, atypical reactions, and atypical experiences). Subcategories identified specific contexts associated with those experiences. Findings suggest that further research is needed on the phenomenology of memory experiences using language derived from CSA survivors and a better understanding of the long-term process of interpretations of key experiences that result in reports of recovered memories. PMID- 17704456 TI - Icodextrin-associated sterile peritonitis: a recent outbreak in Turkey. PMID- 17704458 TI - Intimate partner violence, relationship status, and protective orders: does "living in sin" entail a different experience? AB - The legal status of women's intimate relationships may allow for different experiences with intimate partner violence (IPV) and the protections received from the criminal justice system. There has been limited research examining differences in IPV and protective orders for women in marital and cohabiting intimate relationships. This study examines differences in experiences with IPV and factors related to protective orders: stipulations, violations, and perceived efficacy in a sample of married (n = 392) and cohabiting (n = 307) women with protective orders. Results suggest (a) married and cohabiting women are significantly different on a number of demographic characteristics; however, after controlling for these demographic differences, (b) married and cohabiting women's experiences with IPV are similar in almost all dimensions, except with the psychological tactic of degradation; and (c) married and cohabiting women receive similar protective order stipulations, experience similar rates of violations, and have the same overall perceptions of safety, freedom, and effectiveness pertaining to the domestic violence order. Implications for policy are discussed. PMID- 17704459 TI - Females' reasons for their physical aggression in dating relationships. AB - Approximately 32% of dating college females reported that they engaged in physical aggression against their partners and that they engaged in acts of physical aggression more often than their male partners engaged in aggression against them. However, the females also reported that their male partners attempted to force them to engage in oral sex more often than the females engaged in such coercive behavior. Based on both open-ended and closed responses, the primary reasons given for engaging in physical aggression were anger at the partner and poor communication. Females who reported physical aggression in their relationships were less satisfied with their relationships, and both psychological and physical aggression were negatively correlated with positive feelings about the partners. PMID- 17704460 TI - A nine-year follow-up study on the predictive validity of the Self-Appraisal Questionnaire for predicting violent and nonviolent recidivism. AB - The effectiveness of the Self-Appraisal Questionnaire (SAQ) in providing estimates for predicting violent and nonviolent recidivism over a 9-year period is examined. The SAQ is a quantitative risk/need instrument consisting of 72 items that compose eight subscales. There were 657 federally sentenced Canadian male offenders who completed the SAQ prior to their release and were followed up for 9 years (108 months) at 4-month intervals. Consistent with previous predictive studies, the results presented here demonstrate that the SAQ has adequate predictive validity. PMID- 17704462 TI - Relationships among abuse characteristics, coping strategies, and abused women's psychological health: a path model. AB - We examined relationships between abuse, coping, and psychological health among 143 women who had experienced abuse in adult relationships. Measures included characteristics of the abuse, problem-focused and emotion-focused coping, Sense of Coherence, and four measures of psychological wellbeing--the SF-36 Mental Component Scale, the General Health Questionnaire, Center for Epidemiologic Studies Depression scale, and a measure of perceived negative effects of the abuse. Problem-focused coping was not related to psychological health, and the influence of emotion-focused coping on psychological health was indirect. Sense of coherence had significant direct effects on psychological health. Both emotion focused coping and sense of coherence were related to aspects of the abusive experience. The concept of sense of coherence has parallels with the recently proposed concept of meaning-focused coping, and the data suggest that finding meaning in adverse events such as abuse is associated with better psychological well-being. PMID- 17704461 TI - Onset of conduct disorder, use of delinquent subsistence strategies, and street victimization among homeless and runaway adolescents in the Midwest. AB - This study examines the effects of childhood-onset conduct disorder on later antisocial behavior and street victimization among a group of homeless and runaway adolescents. Four hundred twenty-eight homeless and runaway youth were interviewed directly on the streets and in shelters from four Midwestern states. Key findings include the following. First, compared with those who exhibit adolescent-onset conduct disorder, youth with childhood onset are more likely to engage in a series of antisocial behaviors such as use of sexual and nonsexual survival strategies. Second, youth with childhood-onset conduct disorder are more likely to experience violent victimization; this association, however, is mostly through an intervening process such as engagement in deviant survival strategies. PMID- 17704463 TI - Changes in coping following treatment for child molesters. AB - Relapse prevention theory assumes that specific coping skills deficits contribute to sexual reoffending. Recent research suggests that the general coping style of sexual offenders is also ineffective. In this study changes were examined in specific and general coping deficits following a treatment program that incorporated specific skills training as well as modifying general styles. Treated incarcerated child molesters were compared to a group of incarcerated child molesters on a waiting list for treatment. Groups completed various measures aimed at identifying coping strategies used in specific high-risk situations and general coping styles. Compared to the waiting list group, treated child molesters identified more effective coping strategies in specific high-risk situations. Changes are noted in their general coping styles with an increase in the endorsement of task-focused strategies and social diversion strategies. No changes in their endorsement of ineffective strategies such as emotion-focused or distraction strategies occurred. Implications for treatment are discussed. PMID- 17704464 TI - Exploring the link between pet abuse and controlling behaviors in violent relationships. AB - Domestic violence is not as simple as one partner physically harming another. Instead, it consists of a complex range of controlling behaviors including physical, emotional, sexual, and economic maltreatment as well as isolation, male privilege, blaming, intimidation, threats, and minimizing/denying behaviors. In addition to the controlling behaviors reported by women seeking shelter from violent relationships, a growing body of research indicates some individuals who abuse their intimate partner also abuse their pets. This study explores these connections using reports of 1,283 female pet owners seeking refuge from their male batterer in a domestic violence shelter. Findings indicate that batterers who also abuse their pet (a) use more forms of violence and (b) demonstrate greater use of controlling behaviors than batterers who do not abuse their pets. Likewise, positive correlations are found between specific controlling behaviors and cruelty to pets. Implications for practice and future research are discussed. PMID- 17704465 TI - Recovery characteristics following maintenance of anaesthesia with sevoflurane or isoflurane in dogs premedicated with acepromazine. AB - A standard anaesthetic protocol was used to anaesthetise 40 dogs for intravenous urography and a retrograde urethrogram or vaginourethrogram. The dogs were allocated by blocked randomisation to receive either isoflurane or sevoflurane for maintenance of anaesthesia after they had been premedicated with acepromazine and pethidine, and anaesthesia induced with propofol. An observer who was unaware of which agent had been used assessed ataxia 30 and 60 minutes after discontinuation of administration of the anaesthetic and assigned an overall recovery score. No complications occurred during anaesthesia of either group of dogs. The scores for ataxia were significantly lower after 60 minutes than after 30 minutes, but there was no significant difference between the groups. The quality of recovery was significantly better in the dogs that received sevoflurane than in those that received isoflurane, but the recovery times were similar. PMID- 17704466 TI - One-step method for catheterising the jugular vein of cats to enable repeated blood sampling. AB - A one-step method for catheterising the jugular vein of cats for taking multiple blood samples was developed, with the aid of radiography, to determine an appropriate internal catheter length for adult cats. The effects of multiple blood sampling and heparin flushes on the cats' haematocrit and blood total solids were also assessed. Seven healthy adult cats were used. A total of 128 of 132 (97 per cent) blood samples were collected successfully through a 19 G, 30.5 cm catheter introduced as a central venous catheter and maintained in place during two periods of 48 hours. The haematocrit and total solids were significantly decreased in all the cats, but no clinically significant blood loss or coagulation disorders were observed. PMID- 17704467 TI - Ultrasonographic imaging of loggerhead sea turtles (Caretta caretta). AB - Twenty live and five dead juvenile and subadult loggerhead sea turtles were examined ultrasonographically. Ten soft tissue areas of the integument were used as acoustic windows: cervical-dorsal and cervical-ventral, left and right cervicobrachial, left and right axillary, left and right prefemoral and left and right postfemoral windows. Anatomical cross-sections were performed on the dead turtles to provide reference data. The fourth and fifth cervical vertebrae, the spinal cord, and the venous sinuses of the external jugular vein were clearly visible through the cervical-dorsal acoustic window, and the oesophagus and the heart were imaged through the cervical-ventral acoustic window. The stomach was more frequently visible through the left axillary acoustic window. The liver could be imaged through both sides, but the right axillary acoustic window was better for visualising the gall bladder. The large and small intestines and the kidneys were visible through the right and left prefemoral acoustic windows; the kidneys were easily identified by their intense vasculature. PMID- 17704469 TI - Anaesthesia of a Siamang monkey (Hylobates syndactylus) for the surgical correction of a hand injury. PMID- 17704468 TI - Incidence of infection and premature crimp failure after repair of cranial cruciate ligament-deficient stifles in 110 dogs. PMID- 17704470 TI - Akabane viral encephalitis in calves in South Korea. PMID- 17704471 TI - Mechanical evaluation of a thermoplastic casting material. PMID- 17704472 TI - Heart lesions following accidental electrocution of dairy cattle. PMID- 17704473 TI - Control of bovine TB. PMID- 17704474 TI - Disease in wild animals. PMID- 17704475 TI - BSE terminology. PMID- 17704476 TI - Seasonal rise in permethrin 'spot-on' poisoning in cats. PMID- 17704478 TI - Conventional open repair of descending thoracic aortic aneurysms. AB - Conventional open reconstruction of the descending thoracic aorta is a safe and effective therapy for the management of aneurysms and is the standard by which all other therapies should be compared. Advances in surgical techniques, circulation management, neurocerebral protection, anesthesia, and postoperative management have contributed to significant reductions in morbidity and mortality over the past 50 years. More recently, endovascular stent grafting has begun to supplant conventional open repair based on its ease of performance and a perception of reduced morbidity and mortality. In reality, when carefully compared, differences in primary outcomes (mortality, stroke rate, and paraplegia) between open repair and endovascular repair are not so clear, and the long-term durability of endovascular repairs is not yet known. Open descending thoracic aortic repair still has an important role in the management of descending thoracic aortic disease in the current era. PMID- 17704479 TI - Commentary on "Conventional open repair of descending thoracic aortic aneurysms". PMID- 17704480 TI - Mid-term results of a multicenter study of thoracic endovascular aneurysm repair versus open repair. AB - Three thoracic endograft devices have concluded their phase II trials for release in the United States. The Gore TAG endoprosthesis (W. L. Gore and Associates, Flagstaff, Ariz) was the first to enter clinical trials for the treatment of thoracic aortic aneurysms, confirming its safety and efficacy as well as its short-term advantages over open surgical repair. In March 2005, it became the first endograft to gain United States Food and Drug Administration approval for general use. Follow-up in the Gore TAG pivotal trial demonstrates that aneurysm related mortality is improved compared with open surgical repair, with similar overall mortality and reintervention rates. PMID- 17704481 TI - Commentary on "Mid-term results of a multicenter study of thoracic endovascular aneurysm repair versus open repair". PMID- 17704482 TI - Role of endovascular therapies in the management of diverse thoracic aortic pathology. AB - Stent grafts are currently indicated for treatment of chronic aneurysmal disease of the descending thoracic aorta. At most centers of excellence, this technique has become the preferred treatment modality for this pathologic process. Many centers are also reporting excellent outcomes using a variety of debranching procedures to expand the anatomic limits of therapeutic intervention. These debranching procedures enable proximal extension of stent grafts into the transverse aortic arch and similarly enable distal extension into the visceral portion of the abdominal aorta. Thoracic aortic disease, however, is not limited to aneurysmal pathology. In our experience, at least half of all patients with major thoracic aortic pathology will have nonaneurysmal disease processes. Frequently, these patients are high-risk candidates for the performance of open surgical intervention. The reduced procedural morbidity and mortality observed with thoracic endovascular aortic repair when compared with open surgical intervention have catalyzed the investigation of stent grafts in the management of nonaneurysmal pathologic processes. This therapy has been successfully applied to a variety of diverse thoracic aortic pathologies, including aortic dissection, aortic transection, penetrating atherosclerotic ulcers, embolic lesions, and aortic coarctation. The focus of this article is on the latter 3 of these pathologies. PMID- 17704483 TI - Commentary on "Role of endovascular therapies in the management of diverse thoracic aortic pathology". PMID- 17704484 TI - Complicated acute type B dissection and endovascular repair: indications and pitfalls. AB - In light of the morbidity and mortality associated with open repair of complicated acute type B dissection, endoluminal approaches provide an attractive option; however, the challenges of accurate placement within an angulated arch, size of the delivery system, and uncertainty regarding long-term durability have been cited as reasons for caution. This review examines the current literature regarding acute type B dissection and details the methods and potential pitfalls in endovascular management of these complex pathologies. PMID- 17704485 TI - Commentary on "Complicated acute type B dissection and endovascular repair: indications and pitfalls". PMID- 17704486 TI - Stent graft management of stable, uncomplicated type B aortic dissection. AB - Aortic dissection has an incidence of 2.6 to 3.5 per 100,000 person years. Although the traditional approach has focused on surgical and medical intervention, several studies demonstrate the efficacy of endovascular repair for aortic dissection. Bolstered by a high technical success rate and improved morbidity and mortality relative to its surgical counterpart, endovascular repair has become a first-line treatment for complicated type B aortic dissection. The debate over the optimal approach to uncomplicated type B dissection is more contentious. The consensus remains in support of medical therapy tailored for tight control of hypertension. The poor long-term results of this regimen, with up to 50% mortality at 5 years, have shifted attention to endovascular stent grafting as an alternative. This article reviews the latest research on uncomplicated type B dissection and its treatment, concentrating on endovascular technique, anatomic considerations, timing of intervention, and outcomes. Early research indicates endovascular stent grafting is a promising modality for these patients. PMID- 17704487 TI - Commentary on "Stent graft management of stable, uncomplicated type B aortic dissection". PMID- 17704488 TI - Hybrid interventions for the treatment of the complex aortic arch. AB - Open surgical replacement of the ascending and arch aorta is a formidable operation that requires extracorporeal circulation and hypothermic circulatory arrest, and may be associated with increased morbidity and mortality. In recent years, endoluminal graft therapy has been increasingly applied to the treatment of thoracic aortic pathologies with decreased morbidity, mortality, and risk of paraplegia. The hybrid approach combines various extra-anatomic debranching procedures with endoluminal graft therapy, providing a less invasive approach for the management of various complex thoracic arch pathologies without the morbidity and mortality associated with hypothermic circulatory arrest. This article reviews the hybrid approach for the management of various complex aortic arch pathologies. PMID- 17704489 TI - Commentary on "Hybrid interventions for the treatment of the complex aortic arch". PMID- 17704490 TI - Endovascular repair of the aortic arch. AB - The aortic arch is a challenging site for endovascular repair. The proximal implantation site is often wide, angulated, conical, and limited in length by the presence of vital branches to the head and arms. The only way to lengthen the implantation site without risking stroke is to provide an alternative source of inflow through endovascular or extravascular bypass. The complexity and stroke risk of branched stent-graft implantation increases exponentially with each additional branch. In our opinion, the safest strategy is to limit the stent graft to a single side branch. This bifurcated stent graft requires multiple bypass grafts in the neck but avoids median sternotomy and partial aortic clamping. Stent-graft implantation through the carotid or innominate artery provides a short, straight route to the proximal ascending aorta and ensures simple accurate placement of the innominate limb. In our experience, the primary limitation has been the anatomy of the ascending thoracic aorta, which may be too short or too wide. Previously created coronary bypass grafts (if patent) may also prevent proximal stent-graft implantation. The bypass grafts and route of access through the neck and groin are created using standard surgical techniques. Both components of the stent graft are implanted during brief periods of cardiac standstill. The tip of the bifurcated stent-graft delivery system is introduced over a curved guidewire into the left ventricle. Otherwise, the endovascular techniques of bifurcated arch repair are essentially those of bifurcated abdominal aortic repair. Despite high flows and wide-diameter components, current experience has shown bifurcated stent grafts of this type to be stable with follow-up over 3 years. PMID- 17704492 TI - Commentary on: Redgrave JNE, Lovett JK, Gallagher PJ, et al. Histological assessment of 526 symptomatic carotid plaques in relation to the nature and timing of ischemic symptoms: the Oxford Plaque Study. Circulation. 2006; 113:2320 2328. AB - Available at http://circ.ahajournals.org/cgi/content/abstract/CIRCULATIONAHA.105.589044v1. PMID- 17704491 TI - Commentary on "Endovascular repair of the aortic arch". PMID- 17704493 TI - Commentary on: Menegaux F, Tresallet C, Kieffer E, Bodin L, Thabut D, Rouby J-J. Aggressive management of nonocclusive ischemic colitis following aortic reconstruction. Arch Surg. 2006;141:678-682. AB - Available at http://archsurg.ama-assn.org/cgi/content/abstract/141/7/678. PMID- 17704494 TI - Commentary on: Klein WM, van der Graaf Y, Seegers J, et al. Dutch Iliac Stent Trial: long-term results in patients randomized for primary or selective stent placement. Radiology. 2006;238:734-744. AB - PURPOSE: To determine long-term results of the prospective Dutch Iliac Stent Trial. MATERIALS AND METHODS: The study protocol was approved by local institutional review boards. All patients gave written informed consent. Two hundred seventy-nine patients (201 men, 78 women; mean age, 58 years) with iliac artery disease were randomly assigned to undergo primary stent placement (143 patients) or percutaneous transluminal angioplasty (PTA) with selective stent placement in cases in which the residual mean pressure gradient was greater than 10 mm Hg across the treated site (136 patients). Before and at 3, 12, and 24 months and 5-8 years after treatment, all patients underwent assessment, which included duplex ultrasonography (US), ankle-brachial index (ABI) measurement, Fontaine classification of symptoms, and completion of the Rand 36-Item Health survey for quality-of-life assessment. Treatment was considered successful for symptoms if symptoms increased at least one Fontaine grade, for ABI if ABI increased more than 0.10, for patency if peak systolic velocity ratio at duplex US was less than 2.5, and for quality of life if the RAND 36-Item Health Survey score increased more than 15 points. Effects of both treatments on symptoms, quality of life, patency, and ABI were compared by using survival analyses. RESULTS: Patients who underwent PTA and selective stent placement had better improvement of symptoms (hazard ratio [HR], 0.8; 95% confidence limits [CLs]: 0.6, 1.0) than did patients treated with primary stent placement, whereas ABI (HR, 0.9; 95% CLs: 0.7, 1.3), iliac patency (HR, 1.3; 95% CLs: 0.8, 2.1), and score for quality of life for nine survey dimensions did not support a difference between treatment groups. CONCLUSION: Patients treated with PTA and selective stent placement in the iliac artery had a better outcome for symptomatic success compared with patients treated with primary stent placement, whereas data about iliac patency, ABI, and quality of life did not support a difference between groups. PMID- 17704495 TI - Commentary on: Clark DJ, Lessio S, O'Donoghue M, Tsalamandris C, Schainfeld R, Rosenfield R. Mechanisms and predictors of carotid artery restenosis: a serial intravascular ultrasound study. J Am Coll Cardiol. 2006;47:2390-2396. AB - Available at http://content.onlinejacc.org/cgi/content/short/47/12/2390?rss=1. PMID- 17704496 TI - Commentary on: Mas JL, Chatellier G, Beyssen B, et al. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med. 2006;355:1660-1671. AB - BACKGROUND: Carotid stenting is less invasive than endarterectomy, but it is unclear whether it is as safe in patients with symptomatic carotid-artery stenosis. METHODS: We conducted a multicenter, randomized, non-inferiority trial to compare stenting with endarterectomy in patients with a symptomatic carotid stenosis of at least 60%. The primary end point was the incidence of any stroke or death within 30 days after treatment. RESULTS: The trial was stopped prematurely after the inclusion of 527 patients for reasons of both safety and futility. The 30-day incidence of any stroke or death was 3.9% after endarterectomy (95% confidence interval [CI], 2.0-7.2) and 9.6% after stenting (95% CI, 6.4-14.0); the relative risk of any stroke or death after stenting as compared with endarterectomy was 2.5 (95% CI, 1.2-5.1). The 30-day incidence of disabling stroke or death was 1.5% after endarterectomy (95% CI, 0.5-4.2) and 3.4% after stenting (95% CI, 1.7-6.7); the relative risk was 2.2 (95% CI, 0.7 7.2). At 6 months, the incidence of any stroke or death was 6.1% after endarterectomy and 11.7% after stenting (P = .02). There were more major local complications after stenting and more systemic complications (mainly pulmonary) after endarterectomy, but the differences were not significant. Cranial-nerve injury was more common after endarterectomy than after stenting. CONCLUSIONS: In this study of patients with symptomatic carotid stenosis of 60% or more, the rates of death and stroke at 1 and 6 months were lower with endarterectomy than with stenting. PMID- 17704497 TI - Neonatal abstinence syndrome and cerebral infarction following maternal codeine use during pregnancy. AB - Neonatal withdrawal from maternal drugs and medications is common in some NICUs. Codeine-containing cough preparations given to pregnant mothers have been identified as a cause of neonatal abstinence syndrome. However, many women do not consider prescription cough syrups when asked about drug use. Maternal medication or illicit drug use has been identified as a cause of perinatal arterial stroke. Since codeine is an opiate with similar pharmacodynamic effects to morphine, it is reasonable to investigate if maternal codeine use has effects on the fetus that are similar to other opiates. The authors present 2 cases of newborn infants with perinatal arterial stroke that may have been associated with in utero exposure to codeine. Physicians should ask about maternal medication use, including codeine-containing cough preparations, when evaluating newborn infants with evidence of cerebral infarction. PMID- 17704498 TI - Bilingual child. PMID- 17704500 TI - Plant nitrogen dynamics and nitrogen-use strategies under altered nitrogen seasonality and competition. AB - BACKGROUND AND AIMS: Numerous studies have examined the effects of climatic factors on the distribution of C(3) and C(4) grasses in various regions throughout the world, but the role of seasonal fluctuations in temperature, precipitation and soil N availability in regulating growth and competition of these two functional types is still not well understood. This report is about the effects of seasonality of soil N availability and competition on plant N dynamics and N-use strategies of one C(3) (Leymus chinensis) and one C(4) (Chloris virgata) grass species. METHODS: Leymus chinensis and C. virgata, two grass species native to the temperate steppe in northern China, were planted in a monoculture and a mixture under three different N seasonal availabilities: an average model (AM) with N evenly distributed over the growing season; a one-peak model (OM) with more N in summer than in spring and autumn; and a two-peak model (TM) with more N in spring and autumn than in summer. KEY RESULTS: The results showed that the altered N seasonality changed plant N concentration, with the highest value of L. chinensis under the OM treatment and C. virgata under the TM treatment, respectively. N seasonality also affected plant N content, N productivity and N-resorption efficiency and proficiency in both the C(3) and C(4) species. Interspecific competition influenced N-use and resorption efficiency in both the C(3) and C(4) species, with higher N-use and resorption efficiency in the mixture than in monoculture. The C(4) grass had higher N-use efficiency than the C(3) grass due to its higher N productivity, irrespective of the N treatment or competition. CONCLUSIONS: The observations suggest that N-use strategies in the C(3) and C(4) species used in the study were closely related to seasonal dynamics of N supply and competition. N seasonality might be involved in the growth and temporal niche separation between C(3) and C(4) species observed in the natural ecosystems. PMID- 17704501 TI - Evaluation of a new questionnaire for the presurgical diagnosis of bladder endometriosis. AB - BACKGROUND: The main objective was to evaluate the diagnostic accuracy of a new questionnaire for the presurgical diagnosis of bladder endometriosis in patients with a high suspicion index for this disease. METHODS: We included all patients of age <40 years undergoing laparoscopy or laparotomy for chronic pelvic pain. We partially modified the American Urologic Association Symptom Index with the aim of identifying bladder endometriosis among 157 women undergoing surgery for chronic pelvic pain. All patients underwent preoperative ultrasonography; selected patients, with suspected bladder endometriosis, underwent computed tomography and cystoscopy. The physicians performing both the preoperative evaluation and surgery were blinded to the questionnaires' results. RESULTS: A total of 127 (81%) patients had pelvic endometriosis, 14 (8.9%) had bladder endometriosis. The questionnaires' score for patients with and without bladder endometriosis was 21 +/- 8.7 and 4.6 +/- 5.7, respectively (P < 0.0001). The area under the receiver operating characteristic curve was 0.951. With a cut-off of 9, sensitivity was 93% and specificity 88%. CONCLUSIONS: The questionnaire proved to be effective in identifying bladder endometriosis, allowing a proper diagnostic work-up and surgical treatment, and minimizing the risk of recurrence. In this primary referral centre for endometriosis the prevalence of the disease was high therefore it may achieve a lower diagnostic accuracy when evaluated on a population of women with a lower prevalence of bladder endometriosis. PMID- 17704502 TI - Workplace characterisation in mixed neutron-gamma fields, specific requirements and available methods at high-energy accelerators. AB - A good knowledge of the radiation field present outside the shielding of high energy particle accelerators is very important to be able to select the type of detectors (active and/or passive) to be employed for area monitoring and the type of personal dosemeter required for estimating the doses received by individuals. Around high-energy electron and proton accelerators the radiation field is usually dominated by neutrons and photons, with minor contributions from other charged particles. Under certain circumstances, muon radiation in the forward beam direction may also be present. Neutron dosimetry and spectrometry are of primary importance to characterise the radiation field and thus to correctly evaluate personnel exposure. Starting from the beam parameters important for radiation monitoring, the paper first briefly reviews the stray radiation fields encountered around high-energy accelerators and then addresses the relevant techniques employed for their monitoring. Recent developments to increase the response of neutron measuring devices beyond 10-20 MeV are illustrated. Instruments should be correctly calibrated either in reference monoenergetic radiation fields or in a field similar to the field in which they are used (workplace calibration). The importance of the instrument calibration is discussed and available neutron calibration facilities are briefly reviewed. PMID- 17704504 TI - Comparison of patient doses in interventional radiology procedures performed in two large hospitals in Greece. AB - Purpose of the study was to determine patient doses in the most common interventional radiology (IR) procedures performed in two large Greek hospitals. A total of 164 patients who underwent 4 types of IR procedures were studied. Fluoroscopy time, total exposure time, number of frames, number of runs, radiation field size, and cumulative dose-area product (DAP) were recorded. The median DAP values for carotid arteriography and lower limb arteriography were 66 and 123 Gy cm2 for hospital 'A' and 21 and 49 Gy cm2 for hospital 'B'. For the cerebral arteriographies performed in hospital 'A', the median DAP was 116 Gy cm2, while for the hepatic embolizations performed in hospital 'B', it was 104 Gy cm2. The DAP values observed in hospital 'A' for carotid arteriography and lower limb arteriography were almost three times than those of hospital 'B'. From the data analysis, it is evident that dose optimization in hospital 'A' should be pursued through revision of the techniques used. PMID- 17704503 TI - In vitro dissolution study of plutonium in aerosol particles from the Mayak PA: a tool for individualised dose estimates. AB - Chronic inhalation of Pu particles during Mayak processing is a potential concern for workers. Of the many particle properties that affect individualised dose estimates, particle solubility in lung fluids can be most important. This study compares in vitro dissolution rates of several plutonium industrial compounds present at different stages of the Mayak processing cycle using three different solvents. The results are then used to develop values of absorption parameters for individual dose assessments. In this study, the dissolution rates of nitrate, oxide and mixed plutonium aerosols were determined using a serum ultrafiltrate stimulant (SUF), phagolysosomal simulant fluid and Ringer's solution, all using a static system. According to the results obtained with SUF, Pu nitrate is absorbed into the blood to a larger extent than predicted using model parameters currently applied for Mayak workers. Absorption into the blood of 21.5 vs. 3% of deposited nuclide as current model predicts results in underestimation of systemic burden and overestimation of the lung dose. These data are being used to provide improved retrospective dose assessments for inhaled plutonium aerosols. PMID- 17704505 TI - Preliminary evaluations of the undesirable patient dose from a BNCT treatment at the ENEA-TAPIRO reactor. AB - Boron neutron capture therapy (BNCT) is an experimental technique for the treatment of certain kinds of tumors. Research in BNCT is performed utilizing both thermal and epithermal neutron beams. Epithermal neutrons (0.4 eV-10 keV) penetrate more deeply into tissue and are thus used in non-superficial clinical applications such as the brain glioma. In the last few years, the fast reactor TAPIRO (ENEA-Casaccia Rome) has been employed as a neutron source for research into BNCT applications. Recently, an 'epithermal therapeutic column' has been designed and its construction has been completed. The Monte Carlo code MCNPX was employed to optimize the design of the column and to evaluate the dose profiles and the therapeutic parameters in the cranium of the anthropomorphic phantom ADAM. In the same context, some preliminary evaluations of the undesirable doses to the patient were performed with MCNPX. A hermaphrodite phantom derived from ADAM and EVA was employed to evaluate the energy deposition in some organs during a standard BNCT treatment. The total dose consists of the contributions from the primary neutron beam, the neutron interactions with boron and the neutron induced photons generated in the epithermal column structures and in the patient's tissues. The paper summarizes the computational procedure and provides a general dosimetric framework of the patient radiological protection aspects related to a BNCT treatment scenario at the TAPIRO reactor. PMID- 17704506 TI - Nanodosimetric measurements and calculations in a neutron therapy beam. AB - A comparison of calculated and measured values of the dose mean lineal energy (y(D)) for the former neutron therapy beam at Louvain-la-Neuve is reported. The measurements were made with wall-less tissue-equivalent proportional counters using the variance-covariance method and simulating spheres with diameters between 10 nm and 15 microm. The calculated y(D)-values were obtained from simulated energy distributions of neutrons and charged particles inside an A-150 phantom and from published y(D)-values for mono-energetic ions. The energy distributions of charged particles up to oxygen were determined with the SHIELD HIT code using an MCNPX simulated neutron spectrum as an input. The mono energetic ion y(D)-values in the range 3-100 nm were taken from track-structure simulations in water vapour done with PITS/KURBUC. The large influence on the dose mean lineal energy from the light ion (A > 4) absorbed dose fraction, may explain an observed difference between experiment and calculation. The latter being larger than earlier reported result. Below 50 nm, the experimental values increase while the calculated decrease. PMID- 17704507 TI - IRSN methodological guide to conducting workplace studies in compliance with French regulations. AB - Under French regulations governing radiation protection of workers, dosimetric workplace studies are mandatory. However, their practical implementation is not described. IRSN has developed a guide to help stakeholders in the radiological protection of workers conduct such studies. It proposes a general methodology applicable to most cases and 'workplace sheets', which apply this methodology to specific occupational settings. At present, two sheets are available: conventional radiology and interventional radiology. PMID- 17704508 TI - Sequence-based bioinformatic prediction and QUASEP identify genomic imprinting of the KCNK9 potassium channel gene in mouse and human. AB - Genomic imprinting is the epigenetic marking of gene subsets resulting in monoallelic or predominant expression of one of the two parental alleles according to their parental origin. We describe the systematic experimental verification of a prioritized 16 candidate imprinted gene set predicted by sequence-based bioinformatic analyses. We used Quantification of Allele-Specific Expression by Pyrosequencing (QUASEP) and discovered maternal-specific imprinted expression of the Kcnk9 gene as well as strain-dependent preferential expression of the Rarres1 gene in E11.5 (C57BL/6 x Cast/Ei)F1 and informative (C57BL/6 x Cast/Ei) x C57BL/6 backcross mouse embryos. For the remaining 14 candidate imprinted genes, we observed biallelic expression. In adult mouse tissues, we found that Kcnk9 expression was restricted to the brain and also was maternal specific. QUASEP analysis of informative human fetal brain samples further demonstrated maternal-specific imprinted expression of the human KCNK9 orthologue. The CpG islands associated with the mouse and human Kcnk9/KCNK9 genes were not differentially methylated, but strongly hypomethylated. Thus, we speculate that mouse Kcnk9 imprinting may be regulated by the maternal germline differentially methylated region in Peg13, an imprinted non-coding RNA gene in close proximity to Kcnk9 on distal mouse chromosome 15. Our data have major implications for the proposed role of Kcnk9 in neurodevelopment, apoptosis and tumourigenesis, as well as for the efficiency of sequence-based bioinformatic predictions of novel imprinted genes. PMID- 17704510 TI - Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity. AB - Huntington's disease is caused by an expanded polyglutamine tract in huntingtin protein, leading to accumulation of huntingtin in the nuclei of striatal neurons. The 18 amino-acid amino-terminus of huntingtin is an amphipathic alpha helical membrane-binding domain that can reversibly target to vesicles and the endoplasmic reticulum (ER). The association of huntingtin to the ER is affected by ER stress. A single point mutation in huntingtin 1-18 predicted to disrupt this helical structure displayed striking phenotypes of complete inhibition of polyglutamine-mediated aggregation, increased huntingtin nuclear accumulation and greatly increased mutant huntingtin toxicity in a striatal-derived mouse cell line. Huntingtin vesicular interaction mediated by 1-18 is specific to late endosomes and autophagic vesicles. We propose that huntingtin has a normal biological function as an ER-associated protein that can translocate to the nucleus and back out in response to ER stress or other events. The increased nuclear entry of mutant huntingtin due to loss of ER-targeting results in increased toxicity. PMID- 17704509 TI - Isolation and characterization of the Drosophila ubiquilin ortholog dUbqln: in vivo interaction with early-onset Alzheimer disease genes. AB - UBQLN1 variants have been associated with increased risk for late-onset Alzheimer's disease (AD). We produced transgenic Drosophila models that either silence (by RNAi) or overexpress the Drosophila ortholog of human UBQLN1, dUbqln. Silencing of dUbqln in the central nervous system led to age-dependent neurodegeneration and shortened lifespan. Silencing of dUbqln in the wing led to wing vein loss that could be partially rescued by mutant rhomboid (rho), a known component of epidermal growth factor receptor signaling pathway. Conversely, overexpression of dUbqln promoted ecotopic wing veins. Overexpression of dUbqln in the eye rescued a small, rough eye phenotype induced by overexpression of Drosophila presenilin (dPsn), and also rescuing dPsn-induced malformations in bristles. In contrast, RNAi silencing of dUbqln enhanced the retinal degenerative defect induced by overexpression of dPsn. Finally, co-overexpression of dUbqln and the human amyloid precursor protein (APP) in the eye significantly reduced the levels of full-length APP and its C-terminal fragment. Collectively, these data support in vivo functional interaction between UBQLN1 and the AD-associated genes, presenilin and APP, and provide further clues regarding the potential role of UBQLN1 in AD pathogenesis. PMID- 17704511 TI - A Gne knockout mouse expressing human GNE D176V mutation develops features similar to distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy. AB - Distal myopathy with rimmed vacuoles (DMRV) or hereditary inclusion body myopathy (hIBM) is an early adult-onset distal myopathy caused by mutations in the UDP-N acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene which encodes for a bifunctional enzyme involved in sialic acid biosynthesis. It is pathologically characterized by the presence of rimmed vacuoles (RVs), especially in atrophic fibers, which also occasionally contain congophilic materials that are immunoreactive to beta-amyloid, lysosomal proteins, ubiquitin and tau proteins. To elucidate the pathomechanism of this myopathy and to explore treatment options, we generated a mouse model of DMRV/hIBM. We knocked out the Gne gene in mice but this resulted in embryonic lethality. We therefore generated a transgenic mouse that expressed the human GNE D176V mutation, which is one of the most prevalent mutations among Japanese DMRV patients, and crossed this with Gne(+/-) mice to obtain Gne(-/-)hGNED176V-Tg. Interestingly, these mice exhibit marked hyposialylation in serum, muscle and other organs. Reduction in motor performance in these mice can only be seen from 30 weeks of age. A compelling finding is the development of beta-amyloid deposition in myofibers by 32 weeks, which clearly precedes RV formation at 42 weeks. These results show that the Gne( /-)hGNED176V-Tg mouse mimics the clinical, histopathological and biochemical features of DMRV/hIBM, making it useful for understanding the pathomechanism of this myopathy and for employing different strategies for therapy. Our findings underscore the notion that hyposialylation plays an important role in the pathomechanism of DMRV/hIBM. PMID- 17704512 TI - Investigation of conditions involved in the susceptibility of the dermatophyte Trichophyton rubrum to photodynamic treatment. AB - BACKGROUND: Photodynamic treatment (PDT) refers to a treatment with light activated agents (photosensitizers) in combination with visible light and molecular oxygen. Recently, we have demonstrated that the porphyrins, 5,10,15 tris(4-methylpyridinium)-20-phenyl-[21H,23H]-porphine trichloride (Sylsens B) and deuteroporphyrin monomethylester (DP mme) are excellent photosensitizers to be used against Trichophyton rubrum both in vitro and ex vivo. OBJECTIVES AND METHODS: The objective of this study was to investigate the key factors involved in PDT efficacy of both photosensitizers in an ex vivo situation during different fungal growth stages using a recently developed ex vivo model. The study focused on the influence of pH and ion strength of incubation media, photochemical properties of the photosensitizers (spectra and singlet oxygen production), and the effect of several scavengers of reactive oxygen species (sodium azide, histidine, mannitol) and phenylmethylsulphonylfluoride (keratinase inhibitor) on the PDT efficacy. RESULTS AND CONCLUSIONS: The results show that an optimal pH and low concentrations of calcium are crucial for a selective binding of Sylsens B to the fungus, leading to an increased PDT efficacy. This selective binding to T. rubrum cannot be accomplished for DP mme. It can be concluded that the prerequisite for successful treatment is a use of a low molarity solution of pH 5, supplemented with a chelating agent and a keratinase activity-repressing agent. Under these conditions, PDT with Sylsens B inactivates, initially via singlet oxygen, effectively the fungus in different fungal growth stages. PMID- 17704513 TI - Decreased susceptibility of Candida albicans to azole antifungals: a complication of long-term treatment in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients. AB - BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS1) is an autosomal recessive disease exceptionally common in Finland. Most patients have chronic oral candidiasis from early childhood and this infection has been shown to be carcinogenic. Hence, patients receive repeated treatment and prophylactic courses of antifungals throughout life. In Finland, 92 patients have been diagnosed with APECED and 66 of them are currently alive. Our aim was to study the effect of long-term azole treatment on the candidal colonization of APECED patients and the influence on antifungal susceptibilities. METHODS: We evaluated the culture reports from 1994 to 2004 of 56 APECED patients followed in Helsinki University Central Hospital. Candida albicans strains of all 11 patients initially reported resistant (n = 27) and 12 patients reported susceptible (n = 16) to fluconazole were re-analysed for their susceptibility to fluconazole. Antifungal usage was analysed up to 30 years back. RESULTS: A total of 162 fungal cultures had been performed. Of these, 75% had been reported positive for Candida and 63% for C. albicans. Eleven patients (31.4%) had been reported to harbour at least once a C. albicans strain resistant to fluconazole. Re-analysis of the stored C. albicans strains originally reported to be resistant to fluconazole revealed a mean MIC of 19.5 mg/L. CONCLUSIONS: Multiple courses (>6) of fluconazole annually and low dose prophylaxis are major risk factors for persistent colonization with C. albicans with decreased susceptibility in APECED patients. PMID- 17704514 TI - Diffusion of ertapenem into bone and synovial tissues. AB - OBJECTIVES: The degree of penetration of an antibiotic into the infected site is an important criterion for therapeutic success. Ertapenem is a new carbapenem, exhibiting activity against most Gram-positive and Gram-negative aerobic and anaerobic bacteria commonly recovered from community-acquired infections. However, no studies concerning its diffusion into bone and synovial tissue are available. Our objective was to quantify ertapenem bone and synovial tissue penetration and to compare our data with the MIC(90)s for causative pathogens. PATIENTS AND METHODS: In an open-label study, 18 patients who were undergoing elective total hip replacement received a single, parenteral, 1 g dose of ertapenem. One serum, one cortical and cancellous bone and one synovial tissue sample was collected per patient a median [interquartile range (IQR)] of 1.6 (1.5 1.7), 12.4 (11.9-13.1) or 23.8 h (22.6-25.2) later and analysed by HPLC. RESULTS: The median (IQR) serum concentrations of ertapenem were 70.1 (56.1-75.9), 10.0 (9.1-11.2) and 2.6 mg/L (2.3-3.0), respectively, at the different time points. The median (IQR) cancellous bone tissue concentrations were 13.2 (10.2-14.8), 1.9 (1.7-2.1) and 0.6 microg/g (0.4-0.6) at the different time points, corresponding to a median (IQR) tissue/serum penetration ratio of 0.19 (0.18-0.23). The median (IQR) cortical bone tissue concentrations were 8.0 (6.5-9.5), 1.3 (1.2-1.3) and 0.3 microg/g (0.3-0.4) at the different time points, corresponding to a median (IQR) tissue/serum penetration ratio of 0.13 (0.12-0.14). The median (IQR) synovial tissue concentrations were 26.2 microg/g (22.7-28.4), 4.0 mg/L (3.7-4.4) and 1.0 mg/L (0.9-1.2) at the different time points, corresponding to a median (IQR) tissue/serum penetration ratio of 0.41 (0.39-0.42). CONCLUSIONS: The concentrations after an ertapenem 1 g dose achieved in cancellous and cortical bone tissue and in synovial tissue were greater than the MIC(90)s for most aerobic organisms for 24 h, and for 12 to 24 h for anaerobic bacteria in healthy volunteers undergoing total hip replacement. PMID- 17704515 TI - Macrolide-resistant Campylobacter: the meat of the matter. AB - The use of macrolide antibiotics in food animals has the potential to select for macrolide-resistant strains of resident bacterial flora. This may include the animal pathogens that are the intended targets of macrolide antibiotic intervention and Campylobacter, common inhabitants of the intestinal tract of food animals that are zoonotic pathogens in man. Such Campylobacter strains are not only resistant to the macrolide antibiotics used in food animals, e.g. tylosin, tilmicosin and tulathromycin, but to the macrolide antibiotics used in human medicine, e.g. erythromycin, azithromycin and clarithromycin, as well. Retail meat is a possible source of Campylobacter and persons consuming the meat derived from macrolide-treated food animals could acquire infections due to macrolide-resistant strains of this organism. Erythromycin is sometimes used to treat human cases of campylobacteriosis and those infected with animal-derived macrolide-resistant Campylobacter may not respond to treatment. The actual risk to human health from the use of macrolide antibiotics in food animals has been difficult to determine because of a lack of information about the macrolide resistant Campylobacter found on the farm and in the clinic. Recently, however, a plethora of new information has become available on this topic. This review discusses what is currently known about the selection of macrolide-resistant Campylobacter in food animals, the prevalence of macrolide-resistant Campylobacter on retail meat, the prevalence of animal-derived macrolide resistant Campylobacter in the clinic and the human health consequences associated with macrolide-resistant Campylobacter infection. This work will emphasize the comprehensive body of data generated in Denmark and the US as part of government-sponsored research studies over the last 10 years. These scientific findings may allow informed decisions to be made in the future about how macrolide antibiotics should be used in food animals while still safeguarding human health. PMID- 17704516 TI - The carbohydrate-binding plant lectins and the non-peptidic antibiotic pradimicin A target the glycans of the coronavirus envelope glycoproteins. AB - OBJECTIVES: Many enveloped viruses carry carbohydrate-containing proteins on their surface. These glycoproteins are key to the infection process as they are mediators of the receptor binding and membrane fusion of the virion with the host cell. Therefore, they are attractive therapeutic targets for the development of novel antiviral therapies. Recently, carbohydrate-binding agents (CBA) were shown to possess antiviral activity towards coronaviruses. The current study further elucidates the inhibitory mode of action of CBA. METHODS: Different strains of two coronaviruses, mouse hepatitis virus and feline infectious peritonitis virus, were exposed to CBA: the plant lectins Galanthus nivalis agglutinin, Hippeastrum hybrid agglutinin and Urtica dioica agglutinin (UDA) and the non-peptidic mannose binding antibiotic pradimicin A. RESULTS AND CONCLUSIONS: Our results indicate that CBA target the two glycosylated envelope glycoproteins, the spike (S) and membrane (M) protein, of mouse hepatitis virus and feline infectious peritonitis virus. Furthermore, CBA did not inhibit virus-cell attachment, but rather affected virus entry at a post-binding stage. The sensitivity of coronaviruses towards CBA was shown to be dependent on the processing of the N-linked carbohydrates. Inhibition of mannosidases in host cells rendered the progeny viruses more sensitive to the mannose-binding agents and even to the N acetylglucosamine-binding UDA. In addition, inhibition of coronaviruses was shown to be dependent on the cell-type used to grow the virus stocks. All together, these results show that CBA exhibit promising capabilities to inhibit coronavirus infections. PMID- 17704517 TI - Determination of disc breakpoints and evaluation of Etests for tigecycline susceptibility testing by the BSAC method. AB - BACKGROUND: Tigecycline has been recently licensed in Europe for intra-abdominal and complicated skin and soft tissue infections. We determined zone breakpoints for use with 15 microg tigecycline discs and evaluated Etests for the routine determination of tigecycline susceptibility by BSAC methods. METHODS: Disc zones for 2236 isolates and MICs by Etest for 531 isolates were compared with MICs obtained by the BSAC agar dilution method. RESULTS: Based on error minimization, we propose zone breakpoints for 15 microg tigecycline discs as follows: alpha/beta-haemolytic streptococci, S > or = 25 mm, R < or = 19 mm; Acinetobacter spp. and Enterobacteriaceae, S > or = 24 mm, R < or = 19 mm; Enterococcus spp., S > or = 21 mm, R < or = 20 mm; Haemophilus spp., S > or = 28 mm, R < or = 27; Streptococcus pneumoniae, S > or = 24 mm, R < or = 23 mm; and staphylococci, S > or = 26 mm, R < or = 25 mm. These criteria gave overall false resistance rates of < or =0.8% and false susceptibility rates of < or =0.7%. Tigecycline Etests, used on Iso-Sensitest agar, gave MICs within one doubling dilution of those by agar dilution in 97% of cases. Categorization agreement was good for isolates with borderline susceptibility or resistance-a group where Etests are likely to be used in order to verify disc-based results. MICs for highly susceptible alpha haemolytic streptococci were underestimated by Etest, but this seems unlikely to be significant. CONCLUSIONS: Disc breakpoints corresponding to BSAC MIC breakpoints were defined for 15 microg tigecycline discs and have been adopted by the BSAC. Tigecycline Etest gave results in good agreement with agar dilution. PMID- 17704518 TI - CCAAT/enhancer-binding protein delta (C/EBPdelta) maintains amelogenin expression in the absence of C/EBPalpha in vivo. AB - C/EBPalpha is implicated to regulate mouse amelogenin gene expression during tooth enamel formation in vitro. Because enamel formation occurs during postnatal development and C/EBPalpha-deficient mice die at birth, we used the Cre/loxP recombination system to characterize amelogenin expression in C/EBPalpha conditional knock-out mice. Mice carrying the Cre transgene under the control of the human keratin-14 promoter show robust Cre expression in the ameloblast cell lineage. Mating between mice bearing the floxed C/EBPalpha allele with keratin-14 Cre mice generate C/EBPalpha conditional knock-out mice. Real-time PCR analysis shows that removal of one C/EBPalpha allele from the molar enamel epithelial organ of 3-day postnatal mice results in dramatic decrease in endogenous C/EBPalpha mRNA levels and coordinately altered amelogenin mRNA abundance. Conditional deletion of both C/EBPalpha alleles further diminishes C/EBPalpha mRNA levels; however, rather than ablating amelogenin expression, we observe wild type amelogenin mRNA abundance levels. We examined C/EBPbeta and nuclear factor YA expression, two transcription factors that had previously been shown to modestly participate in amelogenin expression, in vitro but found no significant changes in either of their mRNA abundance levels comparing conditional knock-out mice with wild-type counterparts. Although the abundance of C/EBPdelta is also unchanged in C/EBPalpha conditional knock-out mice, in vitro we find that C/EBPdelta activates the mouse amelogenin promoter and synergistically cooperates with nuclear factor Y, suggesting that C/EBPdelta can functionally substitute for C/EBPalpha to produce an enamel matrix competent to direct biomineralization. PMID- 17704519 TI - High levels of NK cells in the peripheral blood of patients affected with anti phospholipid syndrome and recurrent spontaneous abortion: a potential new hypothesis. AB - OBJECTIVES: No data regarding phenotypic assets of circulating lymphocytes in anti-phospholipid syndrome (APS) are reported in the literature. Role of anti phospholipid antibodies (aPL) in recurrent spontaneous abortion (RSA) remains uncertain, while natural killer (NK)-cells are involved in RSA pathogenesis. In this study, patients affected with APS without RSA, APS with RSA and RSA without aPL were studied for NK-cell subpopulation to evaluate its role in abortive events typical of APS. METHODS: NK-cell levels in peripheral blood of APS patients without RSA (n = 28) and in APS-RSA patients (n = 25) were evaluated by means of flow cytofluorimetry. NK-cells levels were evaluated also in RSA without aPL associated with either endocrine (n = 86), anatomic (n = 30) or idiopathic (n = 77) conditions and in 42 healthy women. RESULTS: High NK levels were found in 14/25 (56%) APS-RSA patients. Among these patients, all except one aborted before the 10th gestational week (GW), while among the remaining patients all except one aborted after the 10th GW. NK mean levels were significantly higher in APS-RSA than in all the other conditions studied, including healthy subjects, except idiopathic RSA. CONCLUSIONS: Our results demonstrate that the numbers and proportions of NK-cells are significantly higher in patients with RSA with APS than in APS without RSA. Increased numbers of NK-cells correlate with reduced gestational age at abortion in patients with APS-RSA. These data lead to a hypothesis that NK-cells contribute to the development of RSA in patients with APS. NK-cells might precipitate damage initiated by aPL or they might cause pathology in RSA independent of aPL. PMID- 17704520 TI - Muscular dystrophy mimicking refractory idiopathic inflammatory myositis: a trio of cases. PMID- 17704522 TI - The predictive value of creatine kinase, EMG and MRI in diagnosing muscle disease. PMID- 17704521 TI - Prevalence and associations of hypertension and its control in patients with rheumatoid arthritis. AB - OBJECTIVES: Rheumatoid arthritis (RA) associates with excessive cardiovascular morbidity and mortality. Hypertension (HT) contributes significantly to the development of cardiovascular disease (CVD). Little is known about the factors that influence blood pressure (BP) in patients with RA. In this study, we assessed the prevalence of HT in a secondary care cohort of RA patients, and aimed to identify factors associated with its presence and inadequate control. METHODS: A total of 400 consecutive RA patients were studied. HT was defined as systolic BP >/=140 mmHg and/or diastolic BP >/=90 mmHg or current use of antihypertensive drugs. The association of HT with several demographic and RA related factors, comorbidities and drugs was evaluated using logistic regression. RESULTS: HT was present in 282 (70.5%) patients. Of those, 171 (60.6%) received anti-hypertensive therapy, but 111 (39.4%) remained undiagnosed. Of those treated, only 37/171 (21.8%) were optimally controlled. Multivariable logistic regression revealed age (OR = 1.054, CI: 1.02 to 1.07, P = 0.001), body mass index [BMI (OR = 1.06, CI: 1.003-1.121, P = 0.038)] and prednisolone use (OR = 2.39, CI: 1.02-5.6, P = 0.045) to be independently associated with the presence of HT. BMI (OR = 1.11, CI: 1.02-1.21, P = 0.002) and the presence of CVD (OR = 4.01, CI: 1.27-12.69, P = 0.018) associated with uncontrolled HT. CONCLUSIONS: HT is highly prevalent in RA, under-diagnosed particularly in the young, and under treated particularly in old RA patients with CVD. RA patients receiving steroids should be specifically targeted for screening and treatment; those with any cardiovascular comorbidity may require particularly aggressive monitoring and treatment strategies. PMID- 17704523 TI - Reaching the parts that are hard to reach: expanding the scope of professional education in anaesthesia. PMID- 17704524 TI - Muscle relaxation and depth of anaesthesia: where is the missing link? PMID- 17704525 TI - An object-based frame of reference within the human pulvinar. AB - The pulvinar nucleus of the thalamus is massively interconnected to cortical areas which translate spatial visual information into coordinate systems defined by multiple reference frames [Grieve et al. (The primate pulvinar nuclei: vision and action. Trends in Neurosciences 2000; 23(1): 35-39)]. Here we report the first evidence that spatial coding in the pulvinar is defined by an object-based frame. We evaluated the efficiency of spatial coding in two patients with damage to spatial maps within the pulvinar. Patients located targets within a 2 x 2 (up/down x left/right) search array, which was itself located within a 2 x 2 retinotopic space. For both patients, spatial deficits were defined in both a retinotopic and an object-based frame. For example, targets in the contralesional side of the array were poorly localized whether the array appeared in contra or ipsilesional retinotopic space. We conclude that spatial processing bias following pulvinar damage can be defined by coordinate systems based on both object-based and retinotopic spaces. PMID- 17704527 TI - Evidence for cortical reorganization of language in patients with hippocampal sclerosis. AB - Naming is mediated by perisylvian cortex in the left (language-dominant) hemisphere, and thus, left anterior temporal lobe resection for pharmacologically intractable temporal lobe epilepsy (TLE) carries risk for post-operative naming decline. Interestingly, this risk is lower in patients with hippocampal sclerosis (HS) relative to those without HS (non-HS). Although the hippocampus has traditionally been considered a critical structure for memory, without contribution to naming, this pattern might implicate direct hippocampal naming involvement. On the other hand, critical naming sites have been found in anterior, lateral temporal (i.e. extra-hippocampal) neocortex, the region typically removed with 'standard' TLE resection. We, therefore, speculated that the relative preservation of naming in post-operative HS patients might reflect cortical reorganization of language to areas outside this region. Using pre resection electrical stimulation mapping, we compared the topography of auditory and visual naming sites in 12 patients with HS and 12 patients without structural brain pathology. Consistent with previous work, non-HS patients exhibited post operative naming decline, whereas HS patients did not. As hypothesized, HS patients had proportionally fewer overall naming sites in anterior temporal cortex, the region typically removed with standard anterior temporal resection, whereas non-HS patients exhibited a more even distribution of naming sites in anterior and posterior temporal regions (P = 0.03). Although both groups exhibited the previously reported pattern of auditory naming sites anterior to visual naming sites, auditory naming sites had a significantly more posterior distribution in HS patients (P = 0.02). Additionally, non-HS patients exhibited a greater proportion of visual naming sites above the superior temporal sulcus, whereas visual naming sites in HS patients were scattered across superior and inferior temporal cortex. Results suggest that preserved naming ability in HS patients following anterior temporal resection might be attributable, at least in part, to intrahemispheric reorganization of language in response to the likely, early development of sclerosis in the medial temporal region. Furthermore, their more posterior distribution of naming sites is consistent with the more anterior propagation of EEG discharges in TLE. These results hold theoretical implications regarding the role of the dominant hippocampus in determining the cortical representation of semantic and lexical information, and raise questions regarding the specific roles of medial and lateral temporal cortex in targeted word retrieval. The different patterns of naming areas identified in patients with and without HS may also carry clinical implications, potentially improving efficiency during the time-constrained process of stimulation mapping. PMID- 17704526 TI - FDG-PET improves accuracy in distinguishing frontotemporal dementia and Alzheimer's disease. AB - Distinguishing Alzheimer's disease (AD) and frontotemporal dementia (FTD) currently relies on a clinical history and examination, but positron emission tomography with [(18)F] fluorodeoxyglucose (FDG-PET) shows different patterns of hypometabolism in these disorders that might aid differential diagnosis. Six dementia experts with variable FDG-PET experience made independent, forced choice, diagnostic decisions in 45 patients with pathologically confirmed AD (n = 31) or FTD (n = 14) using five separate methods: (1) review of clinical summaries, (2) a diagnostic checklist alone, (3) summary and checklist, (4) transaxial FDG-PET scans and (5) FDG-PET stereotactic surface projection (SSP) metabolic and statistical maps. In addition, we evaluated the effect of the sequential review of a clinical summary followed by SSP. Visual interpretation of SSP images was superior to clinical assessment and had the best inter-rater reliability (mean kappa = 0.78) and diagnostic accuracy (89.6%). It also had the highest specificity (97.6%) and sensitivity (86%), and positive likelihood ratio for FTD (36.5). The addition of FDG-PET to clinical summaries increased diagnostic accuracy and confidence for both AD and FTD. It was particularly helpful when raters were uncertain in their clinical diagnosis. Visual interpretation of FDG-PET after brief training is more reliable and accurate in distinguishing FTD from AD than clinical methods alone. FDG-PET adds important information that appropriately increases diagnostic confidence, even among experienced dementia specialists. PMID- 17704528 TI - The 2-sample problem for failure rates depending on a continuous mark: an application to vaccine efficacy. AB - The efficacy of an HIV vaccine to prevent infection is likely to depend on the genetic variation of the exposing virus. This paper addresses the problem of using data on the HIV sequences that infect vaccine efficacy trial participants to (1) test for vaccine efficacy more powerfully than procedures that ignore the sequence data and (2) evaluate the dependence of vaccine efficacy on the divergence of infecting HIV strains from the HIV strain that is contained in the vaccine. Because hundreds of amino acid sites in each HIV genome are sequenced, it is natural to treat the genetic divergence as a continuous mark variable that accompanies each failure (infection) time. Problems (1) and (2) can then be approached by testing whether the ratio of the mark-specific hazard functions for the vaccine and placebo groups is unity or independent of the mark. We develop nonparametric and semiparametric tests for these null hypotheses and nonparametric techniques for estimating the mark-specific relative risks. The asymptotic properties of the procedures are established. In addition, the methods are studied in simulations and are applied to HIV genetic sequence data collected in the first HIV vaccine efficacy trial. PMID- 17704529 TI - Elicitor-induced cytoskeletal rearrangement relates to vacuolar dynamics and execution of cell death: in vivo imaging of hypersensitive cell death in tobacco BY-2 cells. AB - Disintegration of the vacuolar membrane (VM) has been proposed to be a crucial event in various types of programmed cell death (PCD) in plants. However, its regulatory mechanisms are mostly unknown. To obtain new insights on the regulation of VM disintegration during hypersensitive cell death, we investigated the structural dynamics and permeability of the VM, as well as cytoskeletal reorganization during PCD in tobacco BY-2 cells induced by a proteinaceous elicitor, cryptogein. From sequential observations, we have identified the following remarkable events during PCD. Stage 1: bulb-like VM structures appear within the vacuolar lumen and the cortical microtubules are disrupted, while the cortical actin microfilaments are bundled. Simultaneously, transvacuolar strands including endoplasmic microtubules and actin microfilaments are gradually disrupted and the nucleus moves from the center to the periphery of the cell. Stage 2: cortical actin microfilament bundles and complex bulb-like VM structures disappear. The structure of the large central vacuole becomes simpler, and small spherical vacuoles appear. Stage 3: the VM is disintegrated and a fluorescent dye, BCECF, leaks out of the vacuoles just prior to PCD. Application of an actin polymerization inhibitor facilitates both the disappearance of bulb-like vacuolar membrane structures and induction of cell death. These results suggest that the elicitor-induced reorganization of actin microfilaments is involved in the regulation of hypersensitive cell death via modification of the vacuolar structure to induce VM disintegration. PMID- 17704530 TI - Hygiene and waste management in UK hospitals: are self-reported compliance scores always valid? PMID- 17704531 TI - Alcohol drinking and breast cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population. AB - BACKGROUND: We reviewed epidemiological studies on alcohol drinking and breast cancer among the Japanese population. This report is one among a series of articles by our research group evaluating the existing evidence concerning the association between health-related lifestyles and cancer. METHODS: Original data were obtained from MEDLINE searches using PubMed or from searches of the Ichushi database, complemented with manual searches. Evaluation of associations was based on the strength of evidence and the magnitude of association, together with biological plausibility as previously evaluated by the International Agency for Research on Cancer. RESULTS: Three cohort studies and eight case-control studies were identified. There were inconsistent results regarding alcohol drinking and breast cancer risk among cohort studies. A significant positive association was observed in one, but another showed nonsignificant inverse association. Out of the eight case-control studies, two studies showed a significantly increased risk among women who drink daily and who had higher intake of alcohol, respectively. Experimental studies have supported the biological plausibility of a positive association between alcohol drinking and breast cancer risk. CONCLUSION: We conclude that epidemiologic evidence on the association between alcohol drinking and breast cancer risk remains insufficient in terms of both the number and methodological quality of studies among the Japanese population. PMID- 17704532 TI - Neoadjuvant, surgery and adjuvant chemotherapy without radiation for esophageal cancer. AB - BACKGROUND: A phase II trial to evaluate neoadjuvant (NAD), surgery and adjuvant (AD) combination chemotherapy without radiation therapy (RT) for patients with esophageal adenocarcinoma staged with endoscopic ultrasound and CT as T3N1 was carried out. METHODS: Thirty-three eligible patients were enrolled. NAD therapy was administered in two 49-day cycles and included cisplatin, floxuridine, paclitaxel and leucovorin. Esophageal resection was performed followed by AD therapy. RESULTS: Thirty-three patients initiated NAD therapy; 10 experienced grade 3 and 4 toxicities, which included leucopenia, fatigue, nausea, diarrhea and stomatitis. Additionally, 16 patients experienced grade 1 and 2 hematologic and non-hematologic toxicities. Fifteen patients were down-staged, of whom five were T2, seven were T1, and three had nodal disease with no evidence of residual cancer in the esophageal bed. Fifteen patients remained T3, and two showed progressive disease. Thirty-two patients proceeded to surgery and 30 were resected. Although all resected patients were eligible for AD therapy, 15 did not receive it either because of patient refusal or surgeon recommendation. Fifteen patients received AD therapy: nine who had remained T3 and six who had down staged. Three patients experienced grade 3 and 4 toxicities similar to those in NAD therapy. Six patients had grade 1 and 2 toxicities. Kaplan-Meier estimates of overall survival at 1, 3 and 5 years were 73% (95% CI: 58-88%), 52% (95% CI: 34 69%) and 29% (95% CI: 13-45%), respectively. Median survival was 42 months. CONCLUSION: Deletion of RT may safely allow for more aggressive chemotherapy and increase chances of survival. The results need to be confirmed in a randomized phase II or larger phase III trial. PMID- 17704533 TI - Inter-observer variations in FDG-PET interpretation for cancer screening. AB - BACKGROUND: Diagnostic guidelines for the use of 2-(fluorine 18) fluoro-2 deoxy-D glucose (FDG)-positron emission tomography (PET) in cancer screening have yet to be established. We assessed inter-observer variability in screening FDG-PET. METHODS: Subjects comprised 40 individuals who underwent FDG-PET and computed tomography (CT) for cancer screening. To assess various patterns of FDG uptakes, three subsets of the cases were selected: 'Cancer', 15 cases with cancer; 'Not malignant', 15 cases with suspected cancer by FDG-PET who were confirmed as cancer-free; and 'Normal', 10 cases without remarkable FDG uptake who were confirmed as cancer-free. A total of 68 lesions made up of malignancy (n = 18), benign (n = 21), and physiological FDG uptake (n = 29) were interpreted by six physicians. Each observer reviewed each case three times. Step 1 involved interpretation of PET images alone, Step 2 involved side-by-side reading of PET and CT images, and Step 3 involved re-evaluation of findings with the results of other screening tests. We assessed inter-observer agreement for each step. RESULTS: Inter-observer agreement for all lesions at each step was moderate, compared to fair agreement for 'Normal' subjects. Inter-observer agreement of 'Cancer' and 'Not malignant' subjects in Step 1 were better than those in Step 2 and 3; however, the differences were not statistically significant. CONCLUSION: The interpretation of FDG-PET is adequately reproducible, while that of 'Normal' subjects is less reproducible. Improvement of inter-observer variability in assessing physiological FDG uptakes requires universal reporting criteria in FDG PET. Correlative interpretation of PET, CT and other information may require standardization in subjects with suspected cancer by FDG-PET. PMID- 17704534 TI - Alcohol drinking and total cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population. AB - BACKGROUND: We conducted a systematic review of epidemiological evidence to evaluate the association between alcohol drinking and total cancer risk among the Japanese population. METHODS: Original data were obtained from MEDLINE searches using PubMed or from searches of the Ichushi database, complemented with manual searches. Evaluation of associations was based on the strength of evidence and the magnitude of association, together with biological plausibility as previously evaluated by the International Agency of Research on Cancer. RESULTS: Of eight cohort studies identified, six studies, three of which included women, were subjected to evaluation. In men, all six studies showed a weak to moderate positive association between alcohol drinking and total cancer risk. While light drinking had little effect on total cancer risk, heavy drinking of more than 46 69 g of alcohol per day contributed to total cancer risk for most of these Japanese populations. However, no association was reported in women in any of the three studies. CONCLUSION: We conclude that there is convincing evidence that alcohol drinking increases the risk of total cancer in the Japanese population, specifically among heavy drinking men. PMID- 17704535 TI - Hepatitis G virus infection in patients with hepatocellular carcinoma in Recife, Brazil. AB - The evidence of a higher incidence of hepatitis G virus (HGV) infection among patients with hepatocellular carcinoma (HCC) and the relatively high prevalence of patients with primary liver carcinoma without apparent risk factors in our country motivated the present study, the objective of which was to determine the frequency of HGV-ribonucleic acid (RNA) in a series of patients with HCC. The diagnosis of HCC was established based on alpha-fetoprotein levels (>400 ng/ml), a compatible image and/or biopsy of the hepatic nodules. Markers of hepatitis B virus (HBV) (HBsAg and anti-HBc), hepatitis C virus (HCV) (anti-HCV) and HGV (HGV RNA) were investigated using MEIA and RT-PCR (reverse transcriptase polymerase chain reaction). There were 32 patients evaluated, including 20 males (63%), with a mean age of 58 years. Twenty-eight (88%) patients were cirrhotic (Child-Pugh: A = 8 patients, B = 14, and C = 6) and 50% reported alcohol consumption. Serological hepatitis markers were detected in 26 (81%) patients, including HBV in 19 (59%), HCV in 12 (38%) and HGV in 9 (28%). Only one (3%) patient was positive for HGV alone. The prevalence of HGV in blood donors from the same region is 10%. The findings suggest that, despite the frequent detection of HGV markers in patients with HCC, isolated infection with this agent does not seem to be a relevant factor in the etiology of this carcinoma. PMID- 17704536 TI - Expression of oncofetal fibronectin mRNA in thyroid anaplastic carcinoma. AB - BACKGROUND: Oncofetal fibronectin (onfFN) is a fetal protein, the expression of which is observed in papillary thyroid carcinomas but not in follicular tumors or in normal thyroid. Its expression in anaplastic thyroid carcinoma (ATC), however, has not been clarified, since only a few cases had been examined in previous studies. METHODS: We examined the expression levels of onfFN mRNA in ATC tissues and cell lines derived from ATC by real-time quantitative reverse transcription polymerase chain reaction (PCR) and in situ hybridization. RESULTS: Increased expression of onfFN mRNA was observed in all cases of ATC regardless of the type of accompanying differentiated carcinoma and five of six ATC cell lines. Furthermore, expression of onfFN mRNA was observed in the majority of ATC cells in all six tissues examined by in situ hybridization. CONCLUSION: These results confirm that expression of onfFN mRNA characterizes not only papillary thyroid carcinoma but also ATC. onfFN mRNA or protein may be a useful marker to identify anaplastic carcinoma cells and may be considered as an optimistic target in molecular-based therapy of ATC. PMID- 17704537 TI - Prevention of cachexia-like syndrome development and reduction of tumor progression in inhibin-deficient mice following administration of a chimeric activin receptor type II-murine Fc protein. AB - Inhibin is a secreted tumor suppressor, and inhibin alpha null mice develop gonadal sex cord-stromal tumors with 100% penetrance at an early age. Inhibin deficient mice die of a severe wasting syndrome due to increased activin signaling through activin receptor type II. The current study was designed to assess the in vivo effects of an activin antagonist, a chimeric activin receptor type II fused to the Fc region of a murine IgG2a (ActRII-mFc), administered transiently to the inhibin-deficient mice. Results showed that the severe weight loss was prevented in the ActRII-mFc-treated mice, FSH levels were reduced, and an extended life span was observed for these mice compared with phosphate buffered saline-treated controls. Although ActRII-mFc treatment did not seem to prevent the formation of gonadal tumors, tumors were smaller in the majority of experimentally treated mice and were characterized by the presence of variable numbers and sizes of cysts in contrast to the solid hemorrhagic tumors that typically developed in the controls. Moreover, the ActRII-mFc-treated mice were less anemic, and their livers and stomachs were histologically normal. In summary, this study demonstrated that in vivo administration of the activin antagonist, ActRII-mFc, not only prevents the cachexia-like symptoms in the inhibin-deficient mouse model, but also reduces tumor progression. These results support an essential role of activins in the cachexia-like syndrome development and implicate activins as growth-promoting factors in gonadal tumor progression. The current findings have potential implications in the design of new drugs or strategies for the treatment of ovarian and testicular tumors and other conditions where ligands signal through ActRII. PMID- 17704538 TI - Progress in research and development on hybrid rice: a super-domesticate in China. AB - BACKGROUND: China has been successful in breeding hybrid rice strains, but is now facing challenges to develop new hybrids with high-yielding potential, better grain quality, and tolerance to biotic and abiotic stresses. This paper reviews the most significant advances in hybrid rice breeding in China, and presents a recent study on fine-mapping quantitative trait loci (QTLs) for yield traits. SCOPE: By exploiting new types of male sterility, hybrid rice production in China has become more diversified. The use of inter-subspecies crosses has made an additional contribution to broadening the genetic diversity of hybrid rice and played an important role in the breeding of super rice hybrids in China. With the development and application of indica-inclined and japonica-inclined parental lines, new rice hybrids with super high-yielding potential have been developed and are being grown on a large scale. DNA markers for subspecies differentiation have been identified and applied, and marker-assisted selection performed for the development of restorer lines carrying disease resistance genes. The genetic basis of heterosis in highly heterotic hybrids has been studied, but data from these studies are insufficient to draw sound conclusions. In a QTL study using stepwise residual heterozygous lines, two linked intervals harbouring QTLs for yield traits were resolved, one of which was delimited to a 125-kb region. CONCLUSIONS: Advances in rice genomic research have shed new light on the genetic study and germplasm utilization in rice. Molecular marker-assisted selection is a powerful tool to increase breeding efficiency, but much work remains to be done before this technique can be extended from major genes to QTLs. PMID- 17704539 TI - Genomic screening for artificial selection during domestication and improvement in maize. AB - BACKGROUND: Artificial selection results in phenotypic evolution. Maize (Zea mays L. ssp. mays) was domesticated from its wild progenitor teosinte (Zea mays subspecies parviglumis) through a single domestication event in southern Mexico between 6000 and 9000 years ago. This domestication event resulted in the original maize landrace varieties. The landraces provided the genetic material for modern plant breeders to select improved varieties and inbred lines by enhancing traits controlling agricultural productivity and performance. Artificial selection during domestication and crop improvement involved selection of specific alleles at genes controlling key morphological and agronomic traits, resulting in reduced genetic diversity relative to unselected genes. SCOPE: This review is a summary of research on the identification and characterization by population genetics approaches of genes affected by artificial selection in maize. CONCLUSIONS: Analysis of DNA sequence diversity at a large number of genes in a sample of teosintes and maize inbred lines indicated that approx. 2 % of maize genes exhibit evidence of artificial selection. The remaining genes give evidence of a population bottleneck associated with domestication and crop improvement. In a second study to efficiently identify selected genes, the genes with zero sequence diversity in maize inbreds were chosen as potential targets of selection and sequenced in diverse maize landraces and teosintes, resulting in about half of candidate genes exhibiting evidence for artificial selection. Extended gene sequencing demonstrated a low false-positive rate in the approach. The selected genes have functions consistent with agronomic selection for plant growth, nutritional quality and maturity. Large-scale screening for artificial selection allows identification of genes of potential agronomic importance even when gene function and the phenotype of interest are unknown. These approaches should also be applicable to other domesticated species if specific demographic conditions during domestication exist. PMID- 17704541 TI - Interacting proteins dictate function of the minimal START domain phosphatidylcholine transfer protein/StarD2. AB - The Star (steroidogenic acute regulatory protein)-related transfer (START) domain superfamily is characterized by a distinctive lipid-binding motif. START domains typically reside in multidomain proteins, suggesting their function as lipid sensors that trigger biological activities. Phosphatidylcholine transfer protein (PC-TP, also known as StarD2) is an example of a START domain minimal protein that consists only of the lipid-binding motif. PC-TP, which binds phosphatidylcholine exclusively, is expressed during embryonic development and in several tissues of the adult mouse, including liver. Although it catalyzes the intermembrane exchange of phosphatidylcholines in vitro, this activity does not appear to explain the various metabolic alterations observed in mice lacking PC TP. Here we demonstrate that PC-TP function may be mediated via interacting proteins. Yeast two-hybrid screening using libraries prepared from mouse liver and embryo identified Them2 (thioesterase superfamily member 2) and the homeodomain transcription factor Pax3 (paired box gene 3), respectively, as PC-TP interacting proteins. These were notable because the START domain superfamily contains multidomain proteins in which the START domain coexists with thioesterase domains in mammals and with homeodomain transcription factors in plants. Interactions were verified in pulldown assays, and colocalization with PC TP was confirmed within tissues and intracellularly. The acyl-CoA thioesterase activity of purified recombinant Them2 was markedly enhanced by recombinant PC TP. In tissue culture, PC-TP coactivated the transcriptional activity of Pax3. These findings suggest that PC-TP functions as a phosphatidylcholine-sensing molecule that engages in diverse regulatory activities that depend upon the cellular expression of distinct interacting proteins. PMID- 17704540 TI - Analysis of glycan polymers produced by peptidoglycan glycosyltransferases. AB - Bacterial cells are surrounded by a cross-linked polymer called peptidoglycan, the integrity of which is necessary for cell survival. The carbohydrate chains that form the backbone of peptidoglycan are made by peptidoglycan glycosyltransferases (PGTs), highly conserved membrane-bound enzymes that are thought to be excellent targets for the development of new antibacterials. Although structural information on these enzymes recently became available, their mechanism is not well understood because of a dearth of methods to monitor PGT activity. Here we describe a direct, sensitive, and quantitative SDS-PAGE method to analyze PGT reactions. We apply this method to characterize the substrate specificity and product length profile for two different PGT domains, PBP1A from Aquifex aeolicus and PBP1A from Escherichia coli. We show that both disaccharide and tetrasaccharide diphospholipids (Lipid II and Lipid IV) serve as substrates for these PGTs, but the product distributions differ significantly depending on which substrate is used as the starting material. Reactions using the disaccharide substrate are more processive and yield much longer glycan products than reactions using the tetrasaccharide substrate. We also show that the SDS PAGE method can be applied to provide information on the roles of invariant residues in catalysis. A comprehensive mutational analysis shows that the biggest contributor to turnover of 14 mutated residues is an invariant glutamate located in the center of the active site cleft. The assay and results described provide new information about the process by which PGTs assemble bacterial cell walls. PMID- 17704542 TI - Topology inversion of SecG is essential for cytosolic SecA-dependent stimulation of protein translocation. AB - SecG, a subunit of the protein translocon, undergoes a cycle of topology inversion. To further examine the role of this topology inversion, we analyzed the activity of membrane vesicles carrying a SecG-PhoA fusion protein (SecG-PhoA inverted membrane vesicles (IMVs)). In the absence of externally added SecA, SecG PhoA IMVs were as active in protein translocation as SecG(+) IMVs per SecA. Consistent with this observation, insertion of membrane-bound SecA into SecG-PhoA IMVs was normally observed. On the other hand, externally added SecA did not affect the activity of SecG-PhoA IMVs, but it caused >10-fold stimulation of the translocation activity of SecG(+) IMVs, indicating that the topology inversion of SecG, which cannot occur in SecG-PhoA IMVs, is essential for cytosolic SecA dependent stimulation of protein translocation. SecG-PhoA IMVs generated a 46-kDa fragment of SecA upon trypsin treatment. The accumulation of this membrane inserted SecA in the SecG-PhoA IMVs was responsible for the loss of the soluble SecA-dependent stimulation. Moreover, fixation of the inverted SecG topology was found to be dependent on soluble SecA. The dual functions of SecG in protein translocation will be discussed. PMID- 17704544 TI - Mental Health Programme in the 11th Five Year Plan. PMID- 17704543 TI - Risk of cardiovascular events among women with high normal blood pressure or blood pressure progression: prospective cohort study. AB - OBJECTIVE: To compare cardiovascular risk among women with high normal blood pressure (130-9/85-9 mm Hg) against those with normal blood pressure (120-9/75-84 mm Hg) and those with baseline hypertension. DESIGN: Prospective cohort study. SETTING: Women's health study, United States. PARTICIPANTS: 39 322 initially healthy women classified into four categories according to self reported baseline blood pressure and followed for a median of 10.2 years. MAIN OUTCOME MEASURES: Time to cardiovascular death, myocardial infarction, or stroke (major cardiovascular event-primary end point); progression to hypertension. RESULTS: 982 (2.5%) women developed a major cardiovascular event, and 8686 (30.1%) women without baseline hypertension progressed to hypertension. The age adjusted event rate for the primary end point was 1.6/1000 person years among women with normal blood pressure, 2.9/1000 person years among those with high normal blood pressure, and 4.3/1000 person years among those with baseline hypertension. Compared with women with high normal blood pressure (reference group), those with normal blood pressure had a lower risk of a major cardiovascular event (adjusted hazard ratio 0.61, 95% confidence interval 0.48 to 0.76) and of incident hypertension (0.42, 0.40 to 0.44). The hazard ratio for a major cardiovascular event in women with baseline hypertension was 1.30 (1.08 to 1.57). Women who progressed to hypertension (reference group) during the first 48 months of the study had a higher cardiovascular risk than those who remained normotensive (adjusted hazard ratio 0.64, 0.50 to 0.81). Women with high normal blood pressure at baseline who progressed to hypertension (reference group) had similar outcome rates to women with baseline hypertension (adjusted hazard ratio 1.17, 0.88 to 1.55). CONCLUSION: The cardiovascular risk of women with high normal blood pressure is higher than that of women with normal blood pressure. The cardiovascular risk of women who progress to hypertension is increased shortly after a diagnosis of hypertension has been made. TRIAL REGISTRATION: Clinical trials NCT00000479 [ClinicalTrials.gov]. PMID- 17704545 TI - Nitric oxide in health & diseases. PMID- 17704546 TI - Vascular endothelial growth factor (VEGF) & tumour angiogenesis. PMID- 17704547 TI - GB virus C/hepatitis G virus--its role in human disease redefined? PMID- 17704549 TI - Activation of inducible nitric oxide synthase by Kagamjuaguiem in peritoneal macrophages in mice. AB - BACKGROUND & OBJECTIVE: A Korean herbal formula Kagamjuaguiem (KJE) has been used for the purpose of the tumour therapy. However, its mechanism of action is not clear. Nitric oxide (NO) as a potent macrophage-derived effector molecule against a variety of tumours has received increasing attention. In this study, using mouse peritoneal macrophages, we have examined the mechanism by which KJE regulates NO production. METHODS: Peritoneal macrophages were cultured with recombinant interferon-gamma (gammaIFN-gamma) for 6 h. The cells were then stimulated with various concentrations of KJE. NO synthesis in cell cultures was measured by Griess method, and inducible NOS expression was measured by western blotting. The amount of tumour necrosis factor-alpha (TNF-alpha) secreted by the cell was measured by a modified enzymelinked immunosorbent assay. RESULTS: When KJE was used in combination with gammaIFN-gamma there was a marked co-operative induction of NO production. However, KJE had no effect on NO production by itself. The increased production of NO from rIFN-gamma plus KJE-stimulated cells was almost completely inhibited by pre-treatment with pyrrolidine dithiocarbamate, an inhibitor of nuclear factor kappa B (NF-kappaB). Further, treatment of peritoneal macrophages with rIFN-gamma plus KJE caused a significant increase in TNF-alpha production. INTERPRETATION & CONCLUSION: Our findings demonstrate that KJE increases the production of NO and TNF-alpha by rIFN-gamma primed macrophages and suggest that NF-kappaB plays a critical role in mediating these effects of KJE. PMID- 17704548 TI - Neural mechanism of rapid eye movement sleep generation with reference to REM-OFF neurons in locus coeruleus. AB - The noradrenergic (NA-ergic) rapid eye movement (REM)-OFF neurons in locus coeruleus (LC) and cholinergic REM-ON neurons in laterodorsal/pedunculopontine tegmentum show a reciprocal firing pattern. The REM-ON neurons fire during REM sleep whereas REM-OFF neurons stop firing during REM sleep. The cessation of firing of REM-OFF neurons is a pre-requisite for the generation of REM sleep and non-cessation of those neurons result in REM sleep loss that is characterized by symptoms like loss of memory retention, irritation, hypersexuality, etc. There is an intricate interplay between the REM-OFF and REM-ON neurons for REM sleep regulation. Acetylcholine from REM-ON neurons excites the GABA-ergic interneurons in the LC that in turn inhibit the REM-OFF neurons. The cessation of firing of REM-OFF neurons withdraws the inhibition from the REM-ON neurons, and facilitates the excitation of these neurons resulting in the initiation of REM sleep. GABA modulates the generation of REM sleep in pedunculopontine tegmentum (PPT) by acting pre-synaptically on the NA-ergic terminals that synapse on the REM-ON neurons whereas in LC it modulates the maintenance of REM sleep by acting post synaptically on REM-OFF neurons. The activity of REM sleep related neurons is modulated by wakefulness (midbrain reticular formation/ascending reticular activating system) and sleep inducing (caudal brainstem/medullary reticular formation) areas. Thus, during wakefulness the wake-active neurons keep on firing that excites the REM-OFF neurons, which in turn keeps the REMON neurons inhibited; therefore, during wakefulness REM sleep episodes are not expressed. Additionally, the wakefulness inducing area keeps the REM-ON neurons inhibited. In contrast, the sleep inducing area excites the REM-ON neurons. Thus, the wakefulness inducing area excites and inhibits the REM-OFF and REM-ON neurons, respectively, while the sleep inducing area excites the REM-ON neurons that facilitate the generation of REM sleep. PMID- 17704550 TI - Relation of serum vascular endothelial growth factor as an angiogenesis biomarker with nitric oxide & urokinase-type plasminogen activator in breast cancer patients. AB - BACKGROUND & OBJECTIVE: The primary mediator of angiogenesis is vascular endothelial growth factor (VEGF). It is well documented that angiogenic activity in human cancer depends on nitric oxide (NO) levels in tissues. Additionally, urokinase type plasminogen activator (u-PA) plays a role in cell adhesion and migration. Serum VEGF and its relationship between NO and u-PA concentrations are poorly reported in breast cancer patients. The aim of this study was to investigate the relationship between serum levels of VEGF and NO and u-PA in patients with breast cancer. METHODS: Serum concentrations of VEGF, NO and u-PA were measured in groups of pre-operative breast cancer patients without metastasis (n=20), post-operative breast cancer patients without metastasis (four wk after the operation, n=20), breast cancer patients with metastasis (n=23), patients with benign breast disease (n=11) and healthy female controls (n=20). RESULTS: There was no difference in serum concentrations of VEGF, NO and u-PA between controls and patients with benign breast disease. Serum VEGF, NO and u-PA concentrations were significantly higher in pre-operative breast cancer patients than in controls and in patients with benign breast diseases (P<0.01). Post operative breast cancer patients without metastasis had significantly lower serum VEGF and u-PA concentrations than the pre-operative patients (P<0.01). In breast cancer patients with metastasis, serum VEGF, and u-PA were significantly higher than post-operative nonmetastatic patients (P<0.01). Serum VEGF concentrations were positively correlated with serum uPA in all of the patients groups (r=0.886, P<0.01). Serum VEGF levels were positively correlated with serum NO levels in breast cancer patients with metastasis (r= 0.386, P<0.05). INTERPRETATION & CONCLUSION: Our results demonstrated that the angiogenic activity was increased in patients with breast cancer. Elevated VEGF levels as an angiogenesis marker may be associated with uPA. VEGF, NO and uPA seem to be associated with the angiogenetic and metastatic process of breast cancer. PMID- 17704551 TI - Occurrence & nucleotide sequence analysis of hepatitis G virus in patients with acute viral hepatitis & fulminant hepatitis. AB - BACKGROUND & OBJECTIVE: Association of hepatitis G virus (HGV) with acute viral hepatitis (AVH) and fulminant hepatitis (FH) is not clearly understood. This study was designed to asses the occurrence of HGV infection and its relationship with other hepatotropic viruses in patients with FH and AVH and also to determine the nucleotide sequence of HGV isolates. METHODS: The study included 100 patients of FH and 125 of AVH on the basis of clinical examination, liver function test and serology for hepatitis A, B, C and E virus. HGV RNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) and direct sequencing for 4 randomly selected samples followed by phylogenetic analysis. RESULTS: Of the 100 patients with FH, 30 were negative for hepatitis viruses A, B, C and E by serology (non A-non E) while 60 were negative in the AVH group. In the non A-non E hepatitis group, HGV was positive in 16.66 per cent (5/30) cases of FH, 10 per cent (6/60) cases of AVH and 6 per cent (6/100) of healthy controls. The difference in HGV seropositivity between FH and AVH patients was statistically not significant compared to healthy controls, while HBV and HCV infections were significant. The four isolates sequenced seemed to be of same type and close to Chinese strain of HGV (Y13755.1 Y13756.1 Y15407, and U67782) on phylogeny. INTERPRETATION & CONCLUSION: In HGV infection was not found to be clinically significant as well as nonpathogenic in the patients of FH and AVH and appeared to be an innocent bystander in the course of the disease. The four sequenced HGV isolates showed close pairing with Chinese strains. PMID- 17704553 TI - Urine levels of rifampicin & isoniazid in asymptomatic HIV-positive individuals. AB - BACKGROUND & OBJECTIVE: AIDS and its associated gastrointestinal complications may impair the absorption of anti-tuberculosis (TB) drugs. Impaired absorption of anti-TB drugs could lead to low drug exposure, which might contribute to acquired drug resistance and reduced effectiveness of anti-TB treatment. The aim of this study was to obtain information on the status of absorption of rifampicin (RMP) and isoniazid (INH) in asymptomatic HIV- positive individuals, who are less immunocompromised. The D-xylose absorption test was also carried out to assess the absorptive capacity of intestive. METHODS: The absorption of RMP, INH and D xylose was studied in 15 asymptomatic HIV-positive individuals with CD4 cell counts>350 cells/mm3 and 16 healthy volunteers, after oral administration of single doses of RMP (450 mg), INH (300 mg) and D-xylose (5 g). Urine was collected up to 8 h after drug administration. Percentage dose of the drugs and their metabolites and D-xylose excreted in urine were calculated. RESULTS: A significant reduction in the urinary excretion of INH and D-xylose in HIV positive persons compared to healthy volunteers was observed. The per cent dose of RMP and its metabolite, desacetyl RMP was also lower in HIV-positive persons compared to healthy volunteers, but this difference was not statistically significant. INTERPRETATION & CONCLUSION: Decreased urinary excretion of D-xylose and INH are suggestive of intestinal malabsorption in HIV-positive individuals. HIV infection could cause malabsorption of anti-TB drugs even at an early stage of the disease. The clinical implications of these findings need to be confirmed in larger studies. PMID- 17704552 TI - Cassia occidentalis poisoning as the probable cause of hepatomyoencephalopathy in children in western Uttar Pradesh. AB - BACKGROUND & OBJECTIVE: Recurrent annual outbreaks of acute encephalopathy illness affecting young children have been reported for several years in many districts of western Uttar Pradesh (UP). Our earlier investigations over three consecutive years (2002-2005) proved that these outbreaks were due to a fatal multi-system disease (hepatomyoencephalopathy syndrome) probably caused by some phytotoxin and not due to viral encephalitis as believed so far. We conducted a case-control study to investigate the risk, if any, from various environmental factors and also to identify the putative toxic plant responsible for development of this syndrome. METHODS: Eighteen cases with acute hepatomyoencephalopathy syndrome admitted in 2005 in a secondary care paediatric hospital of Bijnor district of western UP were included in the study. Three age-matched controls were selected for each case. A semi-structured questionnaire was developed and applied to all 18 cases and 54 controls. All interviews were conducted within one week of discharge or death of each case. Quantitative data were analyzed using the relevant established statistical tests. RESULTS: Parents of 8 (44.4%) cases gave a definite history of their children eating beans of Cassia occidentalis weed before falling ill, compared with 3 (5.6% controls), the odds ratio being 12.9 (95% CI 2.6-88.8, P<0.001). History of pica was the other associated factor with the disease, odds ratio 5.20 (95% CI 1.4-19.5, P<0.01). No other factor was found significantly associated with the disease. INTERPRETATION & CONCLUSION: Consumption of C. occidentalis beans probably caused these outbreaks, described earlier as hepatomyoencephalopathy syndrome. Public education has the potential to prevent future outbreaks. PMID- 17704554 TI - Ultrastructural analysis of slime positive & slime negative Staphylococcus epidermidis isolates in infectious keratitis. AB - BACKGROUND & OBJECTIVE: Slime is a major determinant of Staphylococcus epidermidis adherence. The established methods of laboratory detection of slime production by this organism i.e., Christensen's tube method and congo red agar plate method, can both yield inconclusive and/or intermediate results. We, therefore tried to find out electronmicroscopically the localization of slime in relation to the bacterial cell wall and look for the effect, if any of the slime location on the staphylococcal adherence as well as on the quantum of slime production. METHODS: A total of 132 coagulase negative staphylococci from cases of infectious keratitis were identified as S. epidermidis following the recommended protocol. Slime was detected both by Christensen's tube method and congo red agar plate method. Antibiotic sensitivity testing was performed by standardized disc diffusion method. Adherence of the organisms to artificial surfaces was determined by a quantitative method and transmission electron microscopy was carried out by the conventional techniques. RESULTS: Of the total 132 isolates, 57 (43.2%) were slime positive and 75 (56.8%) were slime negative. Twenty seven (47.4%) of the 57 slime producing organisms were multi drug resistant as compared to only 12 (16%) of 75 nonslime-producing organisms (P<0.001). A majority i.e., 45 (78.9%) of 57 adherent organisms were slime producers as against 12 (16%) of 75 nonadherent organisms. Electron microscopic study revealed a thick viscid layer of slime anchoring to the bacterial cell wall, especially in adherent organisms and those yielding positive slime test. Some of the organisms showed loose nonadherent slime and those were mostly nonadherent to artificial surfaces. INTERPRETATION & CONCLUSION: Slime and multi drug resistance were the important virulence factors of S. epidermidis in bacterial keratitis. It was the adherent slime (i.e., slime in intimate association with the bacterial cell wall as shown by electron microscopy) only, which was responsible for resistance to multiple antibiotics and for the adhesion phenomenon observed in the quantitative slime test. PMID- 17704555 TI - Occurrence, significance & molecular epidemiology of cholera outbreaks in West Bengal. AB - BACKGROUND & OBJECTIVE: Diarrhoeal disease outbreaks are causes of major public health emergencies in India. We carried out investigation of two cholera outbreaks, for identification, antimicrobial susceptibility testing, phage typing and molecular characterization of isolated Vibrio cholerae O1, and to suggest prevention and control measures. METHODS: A total of 22 rectal swabs and 20 stool samples were collected from the two outbreak sites. The V. cholerae isolates were serotyped and antimicrobial susceptibility determined. Pulsed- field gel electrophoresis (PFGE) was performed to identify the clonality of the V. cholerae strains which elucidated better understanding of the epidemiology of the cholera outbreaks. RESULTS: Both the outbreaks were caused by V. cholerae O1 (one was caused by serotype Ogawa and the other by serotype Inaba). Clinically the cases presented with profuse watery diarrhoea and dehydration. All the tested V. cholerae isolates were sensitive to tetracycline, gentamycin and azithromycin but resistance for ampicillin, co-trimoxazole, nalidixic acid, and furazolidone. PFGE pattern of the isolates from the two outbreaks revealed that they were clonal in origin. Stoppage of the source of water contamination and chlorination of drinking water resulted in terminating the two outbreaks. INTERPRETATION & CONCLUSION: The two diarrhoeal outbreaks were caused by V. cholerae O1 (Inaba/Ogawa). Such outbreaks are frequently seen in cholera endemic areas in many parts of the world. Vaccination is an attractive disease (cholera) prevention strategy although long-term measures like improvement of sanitation and personal hygiene, and provision of safe water supply are important, but require time and are expensive. PMID- 17704556 TI - Audiological findings in cleft palate patients attending speech camp. AB - BACKGROUND & OBJECTIVE: Hearing impairment is one of the associated problems seen particularly in children with cleft palate rather than cleft lip alone. This has received very little attention in the area of cleft care although research shows that hearing impairment affects language development The present study was carried not to find out the type and pattern of audiogram in cases attending a speech camp, average degree of hearing loss and its relation to the side of cleft, and the acoustic immittance findings and its relation to the otological evaluation. The parental awareness about the hearing problem was also assessed. METHODS: The study was conducted on cleft palate patients attending a speech camp. In all, there were 43 patients (19 males and 24 females) in the age range of 3-22 yr. All had undergone audiological assessment, speech and language evaluation, and otological evaluation using standard procedures. RESULTS: Hearing loss was seen in 38 (88.38%) patients. It was the first audiological assessments they ever had. The average pure tone Thresholds revealed a reverse-ski pattern with a wide air-bone gap. The degree of hearing loss ranged from 25 to 68 dB indicating that untreated otitis media resulted in moderate to moderately severe degree of hearing loss. The immittance findings supported the extent of extracranial complications identified on otoscopic examination. There were more patients with unilateral cleft of the left side with greater hearing loss in the ear alongside the cleft. INTERPRETATION & CONCLUSION: Hearing loss is prevalent in more than three-fourths of the patients attending the speech camp. There is a need for early identification and intervention of middle ear effusion for all cleft palate cases. PMID- 17704557 TI - Paraoxonase (PON1) activity in north west Indian Punjabis with coronary artery disease & type 2 diabetes mellitus. AB - BACKGROUND & OBJECTIVE: Paraoxonase (PON1), an arylesterase is associated with high density lipoprotein cholesterol (HDL-C). PON1 prevents low density lipo protein cholesterol (LDL-C) from peroxidation and can also hydrolyze lipid peroxides, thereby providing protection against atherosclerosis and coronary artery disease (CAD). The incidence of CAD is known to be high in north western Indian Punjabis. Though many factors may play a role in its pathogenesis, low PON1 activity could be an independent risk factor. We carried out this study to determine PON1 activity in north-west Indian Punjabi patients with CAD with and without type 2 diabetes mellitus and compared with healthy individuals. METHODS: A total of 120 patients with angiographically proven CAD (57 with and 63 without type II diabetes mellitus) and 19 healthy controls were studied for plasma PON1 activity and lipid variables. Comparison was undertaken between CAD patients and healthy controls and between CAD patients with and without type II DM. RESULTS: Significantly lower plasma PON1 activity (P<0.05) along with lower HDL-C (P<0.001) and higher LDL-C (P<0.05) levels were observed in CAD patients as compared to healthy controls. On univariate analysis of variance after adjusting for age and sex, no significant difference could be observed between PON1 activity and age and sex. On discriminant analysis, no clear cut-off could be observed in PON1 activity between patients CAD and controls. Similarly between CAD with and without patients type II diabetes mellitus, there was no significant difference in PON1 activity and lipids. INTERPRETATION & CONCLUSION: The low plasma PON1 activity irrespective of being diabetic may be an independent risk factor for CAD in north-western Indian Punjabi population. Similar studies involving larger samples in different ethnic groups in India need to be done to find out the role of PON1 activity in CAD. PMID- 17704558 TI - Urgent need of experimental model for Indian childhood cirrhosis. PMID- 17704559 TI - Renal function in male rats concurrently exposed to nicotine & ethanol. PMID- 17704560 TI - HemoCue haemoglobin systems--a clarification. PMID- 17704561 TI - Separating model optimization and model validation in statistical cross validation as applied to crystallography. AB - Statistical cross-validation has become an integral part of the model-refinement process in macromolecular crystallography. However, the test set of reflections, for which the free R value is calculated, is used both to optimize the parameterization of the structure model and to validate the model itself. This practice could introduce bias and diminish the value of R(free) as an independent check of model quality. It is proposed here that by introducing a dormant hold out set of reflections, any problems with such bias can be avoided. This procedure requires only a small modification of the standard cross-validation protocol. PMID- 17704562 TI - Quality of protein crystal structures. AB - The genomics era has seen the propagation of numerous databases containing easily accessible data that are routinely used by investigators to interpret results and generate new ideas. Most investigators consider data extracted from scientific databases to be error-free. However, data generated by all experimental techniques contain errors and some, including the coordinates in the Protein Data Bank (PDB), also integrate the subjective interpretations of experimentalists. This paper explores the determinants of protein structure quality metrics used routinely by protein crystallographers. These metrics are available for most structures in the database, including the R factor, R(free), real-space correlation coefficient, Ramachandran violations etc. All structures in the PDB were analyzed for their overall quality based on nine different quality metrics. Multivariate statistical analysis revealed that while technological improvements have increased the number of structures determined, the overall quality of structures has remained constant. The quality of structures deposited by structural genomics initiatives are generally better than the quality of structures from individual investigator laboratories. The most striking result is the association between structure quality and the journal in which the structure was first published. The worst offenders are the apparently high-impact general science journals. The rush to publish high-impact work in the competitive atmosphere may have led to the proliferation of poor-quality structures. PMID- 17704563 TI - Photoreduction of the active site of the metalloprotein putidaredoxin by synchrotron radiation. AB - X-ray damage to protein crystals is often assessed on the basis of the degradation of diffraction intensity, yet this measure is not sensitive to the rapid changes that occur at photosensitive groups such as the active sites of metalloproteins. Here, X-ray absorption spectroscopy is used to study the X-ray dose-dependent photoreduction of crystals of the [Fe(2)S(2)]-containing metalloprotein putidaredoxin. A dramatic decrease in the rate of photoreduction is observed in crystals cryocooled with liquid helium at 40 K compared with those cooled with liquid nitrogen at 110 K. Whereas structural changes consistent with cluster reduction occur in the active site of the crystal measured at 110 K, no such changes occur in the crystal measured at 40 K, even after an eightfold increase in dose. When the structural results from extended X-ray absorption fine structure measurements are compared with those obtained by crystallography on this and similar proteins, it is apparent that X-ray-induced photoreduction has had an impact on the crystallographic data and subsequent structure solutions. These results strongly indicate the importance of using liquid-helium-based cooling for metalloprotein crystallography in order to avoid the subtle yet important changes that can take place at the metalloprotein active sites when liquid-nitrogen-based cooling is used. The study also illustrates the need for direct measurement of the redox states of the metals, through X-ray absorption spectroscopy, simultaneously with the crystallographic measurements. PMID- 17704564 TI - Production of Slit2 LRR domains in mammalian cells for structural studies and the structure of human Slit2 domain 3. AB - Slit2 and Roundabout 1 (Robo1) provide a key ligand-receptor interaction for the navigation of commissural neurons during the development of the central nervous system. Slit2 is a large multidomain protein containing an unusual domain organization of four tandem leucine-rich repeat (LRR) domains at its N-terminus. These domains are well known to mediate protein-protein interactions; indeed, the Robo1-binding region has been mapped to the concave face of the second LRR domain. It has also been shown that the fourth LRR domain may mediate Slit dimerization and that both the first and second domains can bind heparin. Thus, while roles have been ascribed for three of the LRR domains, there is still no known role for the third domain. Each of the four LRR domains from human Slit2 have now been successfully expressed in milligram quantities using expression in mammalian cells. Here, the crystallization of the second and third LRR domains and the structure of the third LRR domain are presented. This is the first structure of an LRR domain from human Slit2, which has an extra repeat compared with the Drosophila homologue. It is proposed that a highly conserved patch of surface residues on the concave face may mediate any protein-protein interactions involving this LRR domain, a result that will be useful in guiding further studies on Slit2. PMID- 17704565 TI - The structure of apo tryptophanase from Escherichia coli reveals a wide-open conformation. AB - The crystal structure of apo tryptophanase from Escherichia coli (space group F222, unit-cell parameters a = 118.4, b = 120.1, c = 171.2 A) was determined at 1.9 A resolution using the molecular-replacement method and refined to an R factor of 20.3% (R(free) = 23.2%). The structure revealed a significant shift in the relative orientation of the domains compared with both the holo form of Proteus vulgaris tryptophanase and with another crystal structure of apo E. coli tryptophanase, reflecting the internal flexibility of the molecule. Domain shifts were previously observed in tryptophanase and in the closely related enzyme tyrosine phenol-lyase, with the holo form found in an open conformation and the apo form in either an open or a closed conformation. Here, a wide-open conformation of the apo form of tryptophanase is reported. A conformational change is also observed in loop 297-303. The structure contains a hydrated Mg(2+) at the cation-binding site and a Cl(-) ion at the subunit interface. The enzyme activity depends on the nature of the bound cation, with smaller ions serving as inhibitors. It is hypothesized that this effect arises from variations of the coordination geometry of the bound cation. PMID- 17704566 TI - Structural studies of a bifunctional inhibitor of neprilysin and DPP-IV. AB - Neutral endopeptidase (NEP) is the major enzyme involved in the metabolic inactivation of a number of bioactive peptides including the enkephalins, substance P, endothelin, bradykinin and atrial natriuretic factor, as well as the incretin hormone glucagon-like peptide 1 (GLP-1), which is a potent stimulator of insulin secretion. The activity of GLP-1 is also rapidly abolished by the serine protease dipeptidyl peptidase IV (DPP-IV), which led to an elevated interest in inhibitors of this enzyme for the treatment of type II diabetes. A dual NEP/DPP IV inhibitor concept is proposed, offering an alternative strategy for the treatment of type 2 diabetes. Here, the synthesis and crystal structures of the soluble extracellular domain of human NEP (residues 52-749) complexed with the NEP, competitive and potent dual NEP/DPP-IV inhibitor MCB3937 are described. PMID- 17704567 TI - Structure of GES-1 at atomic resolution: insights into the evolution of carbapenamase activity in the class A extended-spectrum beta-lactamases. AB - The structure of the class A extended-spectrum beta-lactamase GES-1 from Klebsiella pneumoniae has been determined to 1.1 A resolution. GES-1 has the characteristic active-site disulfide bond of the carbapenemase family of beta lactamases and has a structure that is very similar to those of other known carbapenemases, including NMC-A, SME-1 and KPC-2. Most residues implicated in the catalytic mechanism of this class of enzyme are present in the GES-1 active site, including Ser70, which forms a covalent bond with the carbonyl C atom of the beta lactam ring of the substrate during the formation of an acyl-enzyme intermediate, Glu166, which is implicated as both the acylation and deacylation base, and Lys73, which is also implicated as the acylation base. A water molecule crucial to catalysis is observed in an identical location as in other class A beta lactamases, interacting with the side chains of Ser70 and Glu166. One important residue, Asn170, also normally a ligand for the hydrolytic water, is missing from the GES-1 active site. This residue is a glycine in GES-1 and the enzyme is unable to hydrolyze imipenem. This points to this residue as being critically important in the hydrolysis of this class of beta-lactam substrate. This is further supported by flexible-docking studies of imipenem with in silico generated Gly170Asn and Gly170Ser mutant GES-1 enzymes designed to mimic the active sites of imipenem-hydrolyzing point mutants GES-2 and GES-5. PMID- 17704568 TI - An unusual case of pseudo-merohedral twinning in orthorhombic crystals of Dicer. AB - The crystal structure of the enzyme Dicer from Giardia intestinalis was solved to 3.3 A resolution by MAD using crystals belonging to space group P2(1)2(1)2 [Macrae et al. (2006), Science, 311, 195-198]. These crystals were derived from crystals that diffracted X-rays to 3.0 A resolution but were refractory to structure determination because they were twinned. It is shown here that the original Dicer crystals represent an unusual case of perfect pseudo-merohedral twinning of orthorhombic crystals. Before the twinning problem was overcome, it was possible to calculate a low-resolution electron-density map in space group P4(1) that was used to build a partial molecular model. Experimental phases were sufficient to identify heavy-atom sites that indicated space-group inconsistency, leading to identification of the true space group. This information guided the search for different crystallization conditions that yielded untwinned crystals and ultimately a fully interpretable electron-density map. PMID- 17704569 TI - The effect of deuteration on protein structure: a high-resolution comparison of hydrogenous and perdeuterated haloalkane dehalogenase. AB - Haloalkane dehalogenase from Xanthobacter autotrophicus (XaDHL) was overexpressed under different isotopic conditions to produce fully hydrogenous (h-XaDHL) and perdeuterated (d-XaDHL) enzyme forms. Deuterium atoms at labile positions were allowed to back-exchange during purification and hydrogenous solutions were used for crystallization. Optimal crystals of h-XaDHL and d-XaDHL were obtained under different pH conditions (pH 6.0 and 4.6, respectively) but had similar P2(1)2(1)2 unit cells. X-ray diffraction data were refined to 1.53 A (h-XaDHL) and 1.55 A (d XaDHL) with excellent overall statistics. The conformations of h-XaDHL and d XaDHL are similar, with slightly altered surface regions because of different packing environments, and h-XaDHL is found to have a more hydrophobic core than d XaDHL. The active site of h-XaDHL is similar to those of previously determined structures, but the active site of d-XaDHL unexpectedly has some crucial differences. Asp124, the primary nucleophile in the hydrolysis of haloalkane substrates, is displaced from its position in h-XaDHL and rotates to form a hydrogen bond with His289. As a consequence, the water molecule proposed to function as the nucleophile in the next catalytic step is excluded from the active site. This is the first observation of this unusual active-site configuration, which is obtained as a result of perdeuteration that decreases the hydrophobicity of the enzyme, therefore shifting the optimal pH of crystallization. This d-XaDHL structure is likely to represent the termination state of the catalytic reaction and provides an explanation for the acid inhibition of XaDHL. These results underline the importance of carefully verifying the assumption that isotopic substitution does not produce significant structural changes in protein structures. PMID- 17704570 TI - Microscale vapour diffusion for protein crystallization. AB - The development of new crystallization platforms via the application of high throughput technologies has delivered a plethora of crystallization plates suitable for robot-driven and manual setups. However, practically all these plates (except for microfluidic channel chips) are based on a very similar design and well (precipitant):drop (protein) volume ratios. A new type of crystallization plate (microplate) has therefore been developed and tested that still employs the classical vapour-diffusion technique but minimizes the precipitant well volume to 1.2 microl for a 150 nl protein drop setup. This enables a very significant saving on the total bulk of the crystallization screen, hence allowing the application of new, rare and expensive solutions in automated crystallization-screening procedures. Additionally, owing to the very low drop:well volume ratio, the new microplate can significantly accelerate the equilibrium time necessary for crystal nucleation and growth, in many cases shortening the high-throughput crystallization screening process to a few hours. PMID- 17704571 TI - Effect of a sodium ion on the dehydration-induced phase transition of monoclinic lysozyme crystals. AB - A monoclinic lysozyme crystal grown in NaCl solution was transformed into a new monoclinic crystal form by controlled dehydration. This crystal-to-crystal phase transition was accompanied by 20-40% solvent loss and the transformed crystal diffracted to prominently high resolution. The structures of the native and transformed crystals were determined at 1.4 and 1.15 A resolution, respectively. In the native crystal a sodium ion was bound to the loop region Ser60-Asn74; however, it was released in the transformed crystal and a water molecule occupied this position. In the transformed crystal a sodium ion was bound to the carboxyl group of Asp52, a catalytic residue. The same structural change was observed in the phase transition of a crystal soaked in a saturated NaCl solution. In contrast, a crystal soaked in 10% NaCl solution was transformed in a shorter time with a smaller loss of solvent and the structure of the sodium-binding site was conserved in the transformed crystal. The high concentration of NaCl is likely to stabilize the crystal structure against dehydration by forming salt linkages between protein molecules. This suggests that the sodium ion in the crystal regulates not only the structural change of the loop region Ser60-Asn74 but also the molecular rearrangement caused by dehydration. PMID- 17704572 TI - Rapid shape determination of tissue transglutaminase using high-throughput computing. AB - Small-angle X-ray scattering can be used to determine the molecular shape of macromolecules in solution which are otherwise refractory to conventional high resolution studies. DAMMIN and GASBOR are applications that utilize ab initio methods to build models of proteins using simulated annealing; both DAMMIN and GASBOR have to be run numerous times on the same input data to generate the most likely protein shape. Condor is a specialized workload-management system for PC computation-intensive tasks. Using Condor, DAMMIN and GASBOR can be run a number of times simultaneously on the same input data, allowing the shape of proteins to be determined in a fraction of the time it would have taken to have run DAMMIN and GASBOR sequentially. The main advantage of this approach is that it allows quicker data processing; therefore, results are obtained promptly and without undue delay. Tissue transglutaminase is a multidomain enzyme that catalyses the formation of isopeptide bonds between polypeptide chains. This reaction requires the enzyme to undergo a series of conformational changes that are not well understood in order to allow the sequential interaction with the two substrate proteins and their subsequent release when cross-linked. Condor was applied to determine the solution shape of tissue transglutaminase in a rapid fashion. Eventually, the next step will be to move towards online analysis at synchrotron sources by developing a graphical user interface that will enable remote access, allowing users to submit jobs to Condor whilst at synchrotrons. PMID- 17704573 TI - Using barium ions for heavy-atom derivatization and phasing of xylanase II from Trichoderma longibrachiatum. AB - This paper describes the use of barium chloride to produce a heavy-atom derivative of xylanase II crystals from Trichoderma longibrachiatum, which was obtained either by cocrystallization or soaking. SAD phasing led to interpretable electron-density maps that allowed unambiguous chain tracing. In the best case, with a data set collected at 9.5 keV, 88% of the residues were built, with 83% of the side chains assigned. The barium ions are found to mainly interact with main chain carbonyl groups and water molecules. It is suggested that barium ions could also be used as a potential anomalous scatterer in the quick cryosoaking procedure for phasing. PMID- 17704574 TI - MARS in acute-on-chronic liver failure. PMID- 17704575 TI - Pre-transplant optimization by Molecular Adsorbent Recirculating System in patients with severely decompensated chronic liver disease. AB - BACKGROUND: The outcome of liver transplantation (LT) is influenced by the recipient's clinical condition. In a retrospective observational study, we evaluated the role of pre-LT Molecular Adsorbent Recirculating System (MARS) treatment in improving the clinical status and thereby the outcome of patients with chronic liver disease and severe hepatic decompensation. METHODS: Between March 2002 and September 2006, 70 patients with end-stage chronic liver disease underwent living-donor LT (LDLT). Of these, 9 (13%) patients with severely decompensated liver function (serum bilirubin> 350 micromol/L [20 mg/dL] and/or hepatic encephalopathy > or = grade 2) received pre-LT MARS treatment. RESULTS: The median MELD score was 33 (range, 26-47). A median of 2 (range, 1-6) sessions (8 hour/session) of MARS dialysis was performed per patient. MARS treatment was associated with reduction in serum bilirubin, creatinine and ammonia levels and no procedure-related complications. CONCLUSION: Pre-LT MARS is well tolerated and results in reduction of jaundice and improvement in renal function and may be useful in the management of patients with severe hepatic decompensation. PMID- 17704576 TI - Primary mesenteric venous thrombosis: a study from western India. AB - INTRODUCTION: The prevalence and clinical spectrum of mesenteric venous thrombosis (MVT) in India is largely unknown. METHODS: We retrospectively re viewed the case records of patients with primary mesenteric venous thrombosis seen over a 10-year period and retrieved information on clinical picture, underlying hypercoagulable states and outcome. RESULTS: The 28 cases (mean age 41.2 [SD 10.2] years; 19 male) included 13 with acute MVT, 10 with subacute MVT and 5 with chronic MVT. Ten patients had past thromboembolic events (multiple events in five); four patients had isolated superior mesenteric vein involvement and 14 had multiple vessel involvement. Hypercoagulable state was identified in 17 patients, with multiple etiologies in 7 patients. Pre-operative diagnosis was made in all patients. Ten patients needed surgical management; the rest were managed medically initially, but 2 required surgery on follow up. Seven patients died during a follow up of up to 10 years, with in-hospital mortality during index admission in six. CONCLUSIONS: Most of the patients with MVT have multiple intra-abdominal vessel involvement and underlying hypercoagulable state. The policy of early treatment with anticoagulation in all and surgical treatment as per need, achieves low mortality. PMID- 17704578 TI - Non-diarrheal celiac disease: a report of 31 cases from northern India. AB - BACKGROUND AND AIMS: Non-diarrheal presentation of celiac disease (CD) is being increasingly recognized. Data on this form of CD from India are limited. METHODS: Consecutive patients with CD presenting to a tertiary referral center in northern India over a 3-year period were studied, with special emphasis on non-diarrheal celiac disease (NDCD). Diagnosis was based on the presence of autoantibodies typical of CD (IgA anti-tissue transglutaminase antibodies and/ or IgA endomysial antibodies), abnormal duodenal biopsy and response to gluten-free diet (GFD). Clinical, hematological and histological responses were assessed over a one-year period after instituting GFD. RESULTS: Of 86 patients with CD, 31 (16 children, 15 adult) had NDCD. Mean (SD) age of these children (12 boys) and adults (4 male) was 10.2 (4.2) y and 35.3 (12.0) y, respectively. Failure to thrive was the most common (11/16) presentation in children, as was refractory anemia in adults (10/15). Malabsorption was found in 8 adults (54%) and 10 children (64%) with NCCD. The duration from onset of symptoms to diagnosis was 2.9 (1.5) y in children and 3.3 (0.3) y in adults. There was significant improvement in body weight (children--baseline 18.9 [5.8] Kg, follow up 27.4 [12.4] Kg; adults- baseline 47.6 [18.2] Kg, follow up 54.9 [5.1] Kg) and hemoglobin (children--8.1 [2.0] g/dL to 11.2 [1.4] g/dL; adults--7.3 [2.3] g/dL to 9.7 [1.7] g/dL) in both groups after one year of GFD; duodenal biopsy also improved, with a majority of patients attaining normal to IIIa Marsh grading. Five adults and all children had evidence of metabolic bone disease at presentation, which did not revert completely with GFD. Eight adults and nine children showed dietary transgression 6 weeks after starting GFD. CONCLUSION: NDCD ac-counted for nearly one-third of all cases with CD at our center, with 'failure to thrive' and refractory anemia being the most common presentations in children and adults, respectively. PMID- 17704577 TI - Role of oxidative stress in lansoprazole-mediated gastric and hepatic protection in Wistar rats. AB - BACKGROUND AND AIM: Lansoprazole, a benzimidazole derivative, is a widely-used proton-pump inhibitor. In addition, it has been reported to have an independent gastroprotective action. Since free radicals and antioxidant mechanisms appear to counter-act tissue-related injury, we studied the effect of lansoprazole on oxidative stress in acid-ethanol gastric injury. As this drug is metabolized in the liver, we also studied its effect on the liver. METHODS: Wistar rats were divided into three groups: control group, group I (vehicle treatment) and group II (lansoprazole treatment for eight days). In all the groups, injury was induced by ethanol-HCl administration. The effect of lansoprazole on free-radical generation and various antioxidants, e.g. superoxide dismutase (SOD), catalase, reduced glutathione (GSH), glutathione-s-transferase (GST) and glutathione reductase was evaluated in the gastric mucosal and liver homogenates. RESULTS: Ethanol-HCl administration initiated injury as shown by increase in malondialdehyde (MDA) levels in both gastric mucosa and liver. There was an increase in SOD and GST activity and a decrease in catalase, glutathione reductase and GSH in the gastric mucosa. In liver, ethanol-HCl administration decreased the activity of SOD, catalase and GSH and increased GST activity. Lansoprazole pretreatment led to decrease in the levels of MDA and increase in SOD, catalase, GSH, glutathione reductase and GST in both the gastric mucosa and liver. CONCLUSIONS: Lansoprazole has a protective action on gastric mucosa and the liver. This protection is mediated by a decrease in oxidative stress and a concomitant in-crease in antioxidants. PMID- 17704579 TI - Profile of colonic polyps in a southern Indian population. AB - BACKGROUND: In Western countries, colonic polyps are usually adenomatous in nature, are evenly distributed along the entire colon in asymptomatic per-sons and show a left-sided predominance in symptomatic patients. There is dearth of such literature from India. METHODS: We retrospectively analyzed reports of colonoscopies done in our institution during the period 2001 to 2005. Clinical features, colonoscopic description and histologic findings of all patients with polyps were noted. Association of the degree of dysplasia with the size, site and type of polyps and the person's age was assessed. RESULTS: Polyps were seen in 124 (5.1%) of 2412 complete colonoscopies. Mean age of patients with polyps was 58.1 (SD 19.9) years; ninety were men. A majority of polyps (92%) were located in the left colon. They were adenomatous in 99 (79.8%), juvenile in 12 (9.8%), hyperplastic in 11 (8.8 %), inflammatory in 1 (0.8%) and Peutz-Jegher's polyp in 1 (0.8%). Dysplasia was severe in large (>2 cm) polyps compared to small (< 1 cm) ones (p< 0.001). Age of patient and location of polyp had no association with degree of dysplasia. CONCLUSIONS: In southern Indian adults, most colonic polyps are adenomatous and are in the left colon. Large polyps are associated with severe dysplasia. PMID- 17704580 TI - Pain, jaundice and lump in a middle-aged man. PMID- 17704581 TI - Preoperative demonstration of broncho-esophageal fistula by multidetector computed tomography. PMID- 17704582 TI - Butachlor-induced acute toxic hepatitis. AB - Butachlor is a highly effective herbicidal substance widely used by farmers. We report a 60-year-old man with exfoliative dermatitis, jaundice, increase in liver enzymes and eosinophilia one day after accidental dermal exposure to butachlor toxin. The diagnostic workup showed no other cause and liver histology was consistent with substance-induced toxic hepatitis. Within two weeks of conservative therapy, his liver function tests returned to normal. PMID- 17704583 TI - Eosinophilic pancreatitis with pseudocyst. AB - Eosinophilic pancreatitis is a rare entity in patients having underlying systemic manifestations such as peripheral eosinophilia, elevated serum IgE levels and/ or eosinophilic infiltrates in other organs, including the gastrointestinal tract. We report a 38-year-old woman with peripheral eosinophilia in association with acute pancreatitis, pancreatic ascites and pseudocyst. PMID- 17704584 TI - Primary neuroendocrine carcinoma presenting as mesenteric cyst. AB - Primary neuroendocrine carcinoma occurring in the mesentery is extremely rare. Surgical resection is the best treatment modality, with a chance of cure. We present a 65-year-old man with large mesenteric cyst and absence of bowel involvement. Histology showed a well-differentiated neuroendocrine tumor. PMID- 17704585 TI - Vesicoperitoneal fistula--an unusual cause of tense ascites. AB - We report a 55-year-old man who developed tense ascites due to vesicoperitoneal fistula. He had undergone surgery 32 years ago for excision of an infected urachal cyst, the tract and the umbilicus. PMID- 17704586 TI - Intraductal papillary mucinous neoplasm in tropical chronic pancreatitis. AB - We report a 56-year-old man with chronic calcifying pancreatitis of the tropics (tropical calcific pancreatitis) who had been asymptomatic and on follow up developed a pancreatic mass that was identified as intraductal papillary mucinous neoplasm. He has been asymptomatic after distal pancreatectomy. PMID- 17704587 TI - Spontaneous regression of patent omphalo-mesenteric duct. AB - We report a one-month-old male child with a patent omphalo-mesenteric duct that regressed spontaneously in the neonatal period and resulted in a Meckel's diverticulum. PMID- 17704588 TI - Retrogastric interposition of colon: differential diagnosis for gastric pseudo tumor. PMID- 17704589 TI - Mechanical bowel preparation in elective colo-rectal surgery: a practice to purge or promote? PMID- 17704591 TI - What is the true prevalence of glucagonoma? PMID- 17704590 TI - Anterior route reconstruction after transhiatal esophagectomy is comparable with posterior route reconstruction. PMID- 17704592 TI - Combined garlic-omeprazole versus standard quadruple therapy for eradication of Helicobacter pylori infection. PMID- 17704593 TI - FDG-avid thyroid incidentaloma in advanced gastrointestinal stromal tumor: metachronous dual primaries. PMID- 17704595 TI - Hemorrhoids banding with bands prepared from Foley's catheter. PMID- 17704594 TI - Polymyositis during pegylated alpha-interferon ribavirin therapy for chronic hepatitis. PMID- 17704596 TI - How to intubate ileum easier. PMID- 17704597 TI - Association of Ehlers-Danlos syndrome and solitary rectal ulcer syndrome. PMID- 17704598 TI - Coexistence of chronic calcific pancreatitis and celiac disease. PMID- 17704599 TI - Splenic rupture as complication of colonoscopy. PMID- 17704601 TI - Salivary chromogranin A as a measure of stress response to noise. AB - Effects of noise on the secretion of salivary chromogranin A (CgA), which is considered to be a substitute measure of catecholamines, were investigated in a laboratory experiment. This study included 20 male subjects with normal hearing; their ages ranged from 21 to 24 years. Prior to the experiment, the subjects were asked to answer a questionnaire containing the 28-item General Health Questionnaire (GHQ-28) and Weinstein's noise sensitivity scale. White noise at 90 dB was presented to the subjects for 15 min with 15-minute-rest periods before and after noise exposure. It was shown that salivary CgA levels increased significantly during noise exposure and decreased immediately after it (Friedman's test, p = 0.001, two tailed). This result suggests that salivary CgA can be used to measure the stress response to noise. Furthermore, individual differences in the change in salivary CgA levels were discussed in relation to the subjective responses of the participants to the questionnaire. Some subjects showed prolonged elevation in the salivary CgA levels and the others showed immediate recovery or no effects. These individual differences correlated with the score on the somatic symptoms in GHQ-28; this implies that the score on the somatic symptoms in GHQ-28 could be a measure of physiological sensitivity to noise. PMID- 17704600 TI - An estimation of annoyance due to various public modes of transport in Delhi. AB - Measurements of noise levels associated with different types of vehicles plying the roads in Delhi were made. From the data, noise level indices L(10) , L(90) and Leq were determined. In addition, spectra of noise for different vehicles at 1- octave band frequencies were also obtained. The time-averaged noise spectra reveal that the noise intensities are significantly higher in the frequency range of 0.5 kHz to 2 kHz for all types of vehicles. Perceived noise levels (PNdB) and the total noisiness measured on NOY scale indicate that rural transport vehicles (RTVs) are most annoying, followed by buses, auto-rickshaws and taxis. PMID- 17704603 TI - Clinical diagnosis of metabolic syndrome 1. Metabolic syndrome and insulin resistance. PMID- 17704602 TI - Effects of industrial solvents on hearing and balance: a review. AB - Industrial hearing loss has generally been associated with noise exposure, but there is a growing awareness that industrial solvents can have an adverse effect on the auditory and vestibular systems in man. Both animal experiments and human studies point to an ototoxic effect of industrial solvents, as well as some central auditory and vestibular disturbances. This review examines the research from the last four decades in an attempt to get an overview of the available evidence. Research shows that industrial solvents are ototoxic in rats. The majority of the solvents studied cause a loss of auditory sensitivity in the mid frequencies in rats, affecting outer hair cells in the order OHC 3 > OHC 2 > OHC 1 . Inner hair cells are generally unaffected. Spiral ganglion cells are most vulnerable to trichloroethylene. Simultaneous exposure to solvents and noise results in a synergistic effect; the pattern of trauma mirrors that due to solvent exposure rather than noise, but is more enhanced. There is a critical level when synergy occurs. The effects of solvents on the vestibular system are neurotoxic and influence the vestibulo-oculomotor system in both animals and humans; humans also present with problems in postural sway. There is a strong suggestion from human studies that solvents are ototoxic in man, but findings show that both the peripheral and central auditory pathways can be affected. Hearing losses can be in the high frequency region or can affect a wider range of frequencies. Hearing loss and balance disturbances can occur at levels below permitted levels of exposure. The synergistic effect of combined exposure to solvents and noise has also been noted in humans, resulting in greater hearing losses than would be expected from exposure to noise and solvents alone. The findings from both human and animal studies indicate that exposure to industrial solvents or to industrial solvents and noise can have an adverse effect on hearing and balance. The implications for industry and hearing conservation are far reaching. PMID- 17704604 TI - Clinical diagnosis of metabolic syndrome 2. Lipotoxicity as a mechanism of the metabolic syndrome. PMID- 17704605 TI - Clinical diagnosis of metabolic syndrome 3. Diagnostic criteria for metabolic syndrome in Japan and its clinical significance. PMID- 17704606 TI - Clinical diagnosis of metabolic syndrome 4. Therapy for metabolic syndrome. PMID- 17704607 TI - Clinical pathology and treatment of renin-angiotensin system 1. Usefulness of blocking of the renin-angiotensin system in treatment of chronic heart failure. PMID- 17704608 TI - Clinical pathology and treatment of renin-angiotensin system 2. Chronic kidney disease and the renin-angiotensin system. PMID- 17704609 TI - Clinical pathology and treatment of renin-angiotensin system 3. Atherosclerosis and the renin-angiotensin system. PMID- 17704610 TI - Clinical pathology and treatment of renin-angiotensin system 4. Renin-angiotensin system and insulin resistance. PMID- 17704611 TI - Treatment of inflammatory immunologic disease 1. Leukocytapheresis for inflammatory immunologic disease (tentative). PMID- 17704612 TI - Treatment of inflammatory immunologic disease 2. Anti-cytokine therapies in inflammatory bowel disease. PMID- 17704613 TI - Treatment of inflammatory immunologic disease 3. Anti-TNF therapy in rheumatoid arthritis. PMID- 17704614 TI - Treatment of inflammatory immunologic disease 4. B cell targeting therapy using the anti-CD20 antibody rituximab in inflammatory autoimmune diseases. PMID- 17704615 TI - Focal dural arteriovenous fistula (DAVF) presenting with progressive cognitive impairment including amnesia and alexia. AB - A 75-year-old woman with a dural arteriovenous fistula (DAVF) presented with progressive cognitive impairment including amnesia and alexia. Neuroradiological studies showed a relatively confined DAVF lesion in the left temporal lobe. The patient did not have a history of trauma and did not complain of headache or tinnitus. Amnesia and alexia dramatically improved upon treatment of the DAVF, and this was associated with attenuation of an abnormal MRI signal in the left temporal lobe. The results suggest that gradually impaired cerebral circulation due to focal venous hypertensive encephalopathy localized to the left temporal lobe and resulting from a DAVF could be involved in slowly progressive amnesia and alexia. The case also shows that an intracranial DAVF may present as a variety of neurological symptoms, depending on its localization, size and clinical stage. PMID- 17704617 TI - Clinical impact of metabolic syndrome by modified NCEP-ATPIII criteria on carotid atherosclerosis in Japanese adults. AB - AIM: The present study aimed to clarify the clinical impact of modified NCEP-ATP III criteria for metabolic syndrome (MS) and Framingham Risk Score (FRS) on carotid atherosclerosis in 615 Japanese adults (319 men and 296 women) including 307 with type 2 diabetes. METHODS: Waist circumference was the only component from the original NCEP-ATP III criteria based on Japanese criteria. The intima medial thickness (IMT) and stiffness parameter beta of the carotid artery were measured by ultrasound. RESULTS: Both IMT and stiffness parameter beta were significantly increased with the number of coexisting components of MS, and higher in subjects with MS than in those without MS (all Ps < 0.0001). In a logistic regression analysis with each component of MS as independent factors, hyperglycemia and hypertension had the highest odds ratio for progressors of IMT and stiffness parameter beta , respectively. Univariate odds ratios of MS for both IMT and stiffness parameter beta were comparable with that of an increase of 10% in 10-year coronary heart disease (CHD) risk by FRS (CHD risk/ 10%) but inferior to CHD risk by FRS >/= 20%. CONCLUSION: The modified NCEP-ATP III criteria for MS revealed an additive predictive impact on carotid atherosclerosis but no superiority to FRS. PMID- 17704616 TI - Small dense low-density lipoprotein cholesterol is a useful marker of metabolic syndrome in patients with coronary artery disease. AB - AIM: An evaluation of the relation between small dense low-density lipoprotein cholesterol (sd-LDL-C) levels measured by the heparin-magnesium precipitation method and metabolic syndrome (MetS). METHODS: We have prospectively measured sd LDL-C levels by the heparin-magnesium precipitation method in 112 Japanese patients (male/female=80/32) with coronary artery disease (CAD) who received percutaneous coronary intervention (PCI). Patients were diagnosed with MetS according to modified Japanese criteria. RESULTS: A total of 36 patients (32%) met the criteria for MetS. Sd-LDL-C levels were significantly higher in the MetS group than non-MetS group (20.7 +/- 1.5 mg/dL vs. 17.1 +/- 1.0 mg/dL, p=0.042), especially among patients without lipid-lowering therapy (26.4 +/- 2.6 mg/dL vs. 17.5 +/- 1.5 mg/dL, p= 0.0034). Sd-LDL-C levels gradually increased with the number of components used to define MetS (0; 14.5 +/- 1.8 mg/dL, 1; 16.5 +/- 1.8 mg/dL, 2; 16.7 +/- 1.3 mg/dL, 3; 19.3 +/- 1.7 mg/dL, 4; 23.1 +/- 2.1 mg/dL, 5; 40.0 mg/dL, p=0.0071). High-sensitivity C-reactive protein (hs-CRP) levels were significantly higher in the patients with MetS (1.09 +/- 0.17 mg/L vs. 0.67 +/- 0.09 mg/L, p=0.0204). CONCLUSION: The sd-LDL-C level measured by the heparin magnesium precipitation method is a useful marker of MetS in Japanese patients with CAD. PMID- 17704618 TI - Identification of ISG12b as a putative interferon-inducible adipocytokine which is highly expressed in white adipose tissue. AB - AIM: A number of adipocytokines have been suggested to be involved in the disruption of glucose metabolism, and also in the development of various diabetic complications. We attempted to identify and analyze additional adipocytokines, to better understanding the roles of adipocytes and adipocytokines. METHODS: An oligo-capping signal sequence trap, developed in our laboratory for screening the cDNAs of secretory proteins, was used to sreen cDNAs expressed in mouse white adipose tissue. Profiles of the genes identified in mice and cultured cells were further investigated by northern blotting and luciferase assay. RESULTS: A cDNA fragment of interferon-stimulated gene 12b (ISG12b) was obtained in the search. A northern blot analysis revealed ISG12b to be highly expressed in white adipose tissue. Interferon alpha (IFNalpha) was shown to induce ISG12b expression in the adipose tissue of BL6 mice in vivo, and also in a 3T3-L1 preadipocyte cell line in vitro. The level of ISG12b was higher in mature adipocytes than in preadipocytes. A promoter analysis demonstrated that the 369bp upstream from the transcription initiation site of ISG12b mRNA contain strong promoter activity, and the interferon-stimulated response elements (ISREs) were not present within the 5593bp upstream region. CONCLUSION: ISG12b is an additional candidate for a adipocytokine induced to express in adipose tissue by interferon. PMID- 17704619 TI - Polymorphisms of apolipoprotein e and methylenetetrahydrofolate reductase in the Japanese population. AB - AIM: The aim of this study is to analyze the effect of apolipoprotein E (apo E) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms on serum lipid and homocysteine levels in the general Japanese population. METHODS: We analyzed the polymorphisms in individuals randomly selected from among participants of Serum Lipid Survey 2000. RESULTS: The frequency of the epsilon2, epsilon3, and epsilon4 alleles of APOE was 4.2, 85.3, and 10.5%, respectively. Individuals with the genotype epsilon4/epsilon4 had the highest total and low-density lipoprotein (LDL) cholesterol levels, while those with epsilon2/epsilon2 had the lowest. Individuals with the epsilon2/epsilon2 and epsilon2/epsilon4 genotypes had higher remnant-like particles (RLP)-cholesterol levels than those with epsilon2epsilon3, epsilon3epsilon3, and epsilon3epsilon4. There was a trend for individuals with the epsilon2/epsilon4 and epsilon2/epsilon2 genotypes to have higher triglyceride levels, although the difference was not significant. The presence of the T allele in a MTHFR polymorphism (C667T) was associated with higher homocysteine levels, which is more prominent in men than in women. CONCLUSION: Thus in our large-scale analysis we have shown that RLP-cholesterol is better associated with, APOE genotype than triglyceride and the effect of the T allele on MTHFR polymorphism (C667T) homocysteine levels is more prominent in men than in women among Japanese. PMID- 17704620 TI - Physiological significance of cyclic changes in room temperature around dusk and dawn for circadian rhythms of core and skin temperature, urinary 6 hydroxymelatonin sulfate, and waking sensation just after rising. AB - The present study investigated whether room temperature (T(a)) cycles around dusk and dawn could influence the circadian rhythm of rectal temperature (T(core)), urinary 6-hydroxymelatonin sulfate during nocturnal sleep, and subjective assessments of sleep in humans. Six female and two male students served as participants. Two different T(a) conditions, cyclic and constant, were established. Two kinds of room temperature were provided to subjects: cyclic T(a) (gradual decrease from 27 degrees C to 24 degrees C between 1800 and 2200 h and gradual increase from 24 degrees C to 27 degrees C between 0300 and 0700 h) and constant T(a) (27 degrees C over 24 h). At cyclic T(a), the circadian nadir of T(core) rhythm was significantly advanced, while T(core) was significantly lower from 2300 to 0200 h and significantly higher from 0600 to 1000 h. The nocturnal concentration of 6-hydroxymelatonin sulfate in the urine during sleep was significantly higher during cyclic T(a). Waking sensation just after rising was significantly better with cyclic T(a). (Skin temperatures in the extremities T(a)) were significantly higher with cyclic T(a) especially during the evening and night. Our results suggest that gradual change of room temperature in the evening and early morning is important in terms of sleep promotion and fresh awakening. It seems probable that mankind has been evolved to have deeper sleep under the influence of cyclic T(a) around dusk and dawn. PMID- 17704621 TI - Changes over four years in body composition and oxygen uptake of young adult males after university graduation. AB - Lifestyle changes and challenges following university graduation often present a sharp contrast to the relatively free and basically pleasant university life enjoyed by the typical college student. Adaptation to a new work environment, relocation to a new community, concerns of marriage and family, personal finances, including income and budgeting (automobile and mortgage payments, savings, etc.), and adjustment to independent living result in an unfamiliar schedule of duties, often too sedentary in nature. The aim of this study was to analyse the changes observed in young working professionals by comparing selected body composition estimates, and physiological working capacity variables at the time of university graduation and four years later. Anthropometric and functional cardio-respiratory exercise test data were collected in 26 physically active (but non-athletic) volunteer males at the time of their university graduation in 2000 and 4 years later in 2004. By the end of this four-year period body weight, body mass index (BMI), the sum of 5 skinfold thicknesses, and relative body fat content increased significantly. Both mean BMI and weight-related body fat content were within the categorized risk range at the time of the second data collection. Parallel with unfavourable changes in body composition, peak minute ventilation, aerobic power, oxygen pulse, and maximum treadmill running distance had decreased significantly during this time. We attributed the significant changes observed mainly to the dramatically changed lifestyle. The subjects could not maintain their previous level of habitual physical activity. PMID- 17704622 TI - Potentiation of knee extensor contraction by antagonist conditioning contraction at several intensities. AB - The purpose of this study was to examine the effect of graded conditioning contractions of the antagonist knee flexor muscles on the output characteristics of knee extensor muscles in healthy humans. Eight male university students performed maximum isometric contractions of knee extensors, preceded by isometric conditioning contractions of the antagonist knee flexors. The developed force and electromyographic (EMG) amplitudes of the knee extensors after the conditioning contraction were measured and compared with those of simple knee extension without conditioning. The forces of the conditioning flexor contraction were set at three levels: low (20% of maximum voluntary contraction: MVC), moderate (60% of MVC), and high (100% of MVC). The EMG amplitudes of the vastus medialis, vastus lateralis, and rectus femoris muscle were recorded and the root mean square amplitudes were calculated. The strongest enhancement of the extension force was obtained by moderate intensity conditioning contraction (108.95+/-1.87% of simple knee extension), although high intensity conditioning also induced a significant increase (105.41+/-2.69%). Low intensity conditioning did not cause a significant enhancement of the contraction force (103.17+/-2.99%). Similarly, the EMG amplitudes were significantly increased by moderate and/or high conditioning. These results suggest that antagonist conditioning contraction of moderate intensities is sufficient and may be optimal to potentiate knee extensor contraction. PMID- 17704623 TI - Perception of foot temperature in young women with cold constitution: analysis of skin temperature and warm and cold sensation thresholds. AB - To examine the disease state of cold constitution, physiological measurements of the foot were conducted by investigating thermal sensations under an environmental condition of 25 degrees C-26 degrees C (neutral temperature) in 29 young women with and without cold constitution. The subjects were classified into 3 groups according to their experiences with cold constitution: cold constitution, intermediate, and normal groups. Foot skin temperature was measured by thermography. Thermal sensations were measured on the dorsum of the left foot using a thermal stimulator. Cold and warm spots on the dorsum of the right foot were ascertained. Thermal stimulation was delivered by a copper probe. No significant differences in foot skin temperature among these 3 groups were identified as measured in a laboratory under neutral temperature conditions. However, the mean warm sensation threshold was +6.3+/-1.09 degrees C (mean+/-SEM) for the cold constitution group (n=14), +3.4+/-2.10 degrees C (mean+/-SEM) for the intermediate group (n=7), and -0.25+/-1.96 degrees C (mean+/-SEM) for the normal group (n=6). The difference was significant between the cold constitution and normal groups. No significant differences among the 3 groups were found in the cold sensation threshold. This may be attributable to the distribution of thermal receptors and to chronically reduced blood flow in subcutaneous tissues, where the skin temperature receptors responsible for temperature sensation are located. PMID- 17704624 TI - Pedometer-determined physical activity among obese and non-obese 8- to 12-year old Saudi schoolboys. AB - Physical activity levels were measured in obese and non-obese 8- to 12- year-old schoolboys (n=296). Anthropometric measures included weight, height, body mass index (BMI), triceps and subscapular skinfolds, predicted fat percentage, fat mass (FM), fat-free mass (FFM), FM index (FMI), and FFM index (FFMI). Physical activity was assessed using an electronic pedometer for three continuous weekdays. Boys were divided into active and inactive groups based on daily accumulation of pedometer counts above or below 13,000 steps. Obesity was defined as body fat content that equals or exceeds 25% of body weight. The international age- and gender-specific child BMI cut-off points were also used to define overweight and obesity. Estimated fat content for the whole sample averaged 23.3+/-9.7%. More than 37% of the boys were classified as obese. The mean step counts were about 13,489+/-5,791 steps per day (range: 335-29,169 steps). Over 71% of the boys accumulated 10,000 steps or more per day. Based on BMI standards, mean step counts for the obese group (10,602+/-4,800 steps/day) were significantly (p=0.004) lower than in the normal group (14,271+/-5,576 steps/day). Based on fat percentage, obese boys also accumulated significantly (p=0.009) lower numbers of steps per day (12,682+/-5,236) than did non-obese boys (14,915+/-5,643). Further, there were significant differences (p<0.05) between active and inactive boys in weight, BMI, triceps and subscapular skinfolds, fat percentage, FMI, and flexibility. It is concluded that the prevalence of obesity and inactivity among Saudi boys aged 8-12 years was high. Active boys exhibited significantly lower body fat percentage and BMI than inactive peers. Obese boys, on the other hand, were significantly less active than non-obese boys. Increased prevalence of obesity and physical inactivity among Saudi children is a major public health concern. PMID- 17704625 TI - An electromyographic study of human gait both in water and on dry ground. AB - The purpose of the present study was to define the degree of muscular activation while walking in water in order to aid rehabilitation therapists in their choice of exercises for daily clinical practice in aquatherapy. This study compares the electromyographic (EMG) activity of the rectus femoris, the soleus of the right lower limb and the contra-lateral lumbar erector spinae, during gait in water and on dry ground. The study was carried out on a group of seven healthy female subjects without past rachidian pathology. EMG recordings in water were taken with immersion to the umbilicus at "comfortable" speed. A total of five recordings were made at this speed, in water and on dry ground, with a one-minute rest between recordings. Integrated EMG results, averaged on eight gait cycles, show, for all the subjects, more erector spinae activity in water than on the ground (p<0.01). Soleus activity is greater during gait on dry ground for the whole group (p<0.01). For four subjects, the electromyographic (EMG) activity of the rectus femoris over the entire cycle is greater than that exhibited on dry ground. In the two experimental situations, no differences have been found either on amplitudinal peaks or on the shape of the patterns. The speed and gait cycle length are reduced in water (60% and 25%). Walking in water at an umbilical level increases the activity of the erector spinae and activates the rectus femoris to levels near to or higher than walking on dry ground. These data should be taken into account by the physiotherapist when designing a rehabilitation programme. PMID- 17704626 TI - Determination of hand surface area by sex and body shape using alginate. AB - Hand surface area (HSA) has been utilized for burned skin area estimation in burn therapy, heat exchange in thermal physiology, exposure assessment in occupational toxicology, and the development of manual equipment/ protective gloves in ergonomics. The purpose of this study was to determine the hand surface area to the total body surface area (BSA) and derive a formula for estimating HSA. Thirty four Korean males (20-60 years old; 158.5-187.5 cm in height; 48.5-103.1 kg in body weight) and thirty-one Korean females (20-63 years old; 140.6-173.1 cm; 36.8 106.1 kg) participated as subjects. The HSA and BSA of 65 subjects were directly measured using alginate. The measurements showed 1) the surface area of the hand had a mean of 448 (371-540) cm(2) for males, and 392 (297-482) cm(2) for females. 2) The hand as a percentage of the total body surface area for males and females was 2.5% and 2.4% respectively, showing no significant difference. 3) The hand as a percentage of BSA by body shape was 2.5% for the lean group and 2.3% for overweight people (p=0.001). 4) When estimating the surface area of a hand, formulae based on hand length or hand circumference were more valid than formulae based on height and body weight. We obtained the following formula for estimating HSA: Estimated HSA(cm(2))=1.219 Hand length(cm) x Hand circumference(cm). PMID- 17704627 TI - Postural control adaptability to floor oscillation in the elderly. AB - We established a method to evaluate postural control adaptability, applying it to 341 subjects, aged 18-29 years (young subjects) and 50-79 years, in order to investigate the influences of age and gender on adaptability. Subjects stood with eyes closed on a force plate fixed to a floor oscillator, which was sinusoidally oscillated in the anteroposterior direction with 0.5 Hz frequency and 2.5 cm amplitude. Five trials of 1-minute oscillation were conducted, with a short rest between trials. The mean speed of fluctuation of the center of foot pressure (CFP), as detected by the force plate, was calculated as an index of postural steadiness. Mean CFP speed decreased significantly in all age groups with trial repetition. The adaptability capability of elderly subjects was categorized as "good," "moderate," or "poor," as evaluated against a standard value, based on the variation of the regression of mean CFP speed between the 1st and 5th trials in young subjects. Results showed that the magnitude of reduction in the mean speed, with practice, was linearly related to the initial mean speed. We found a general decline in adaptability, and increase in initial mean speed, in subjects aged 60 years and older, with no gender difference detected in any age group. The proportion of subjects exhibiting moderate and poor adaptability increased gradually with age. In conclusion, age, but not gender, appears to affect adaptation of postural sway with short-term practice, although some elderly subjects maintain postural sway velocity and adaptability capabilities similar to those of young subjects. PMID- 17704628 TI - Metabolic equivalents during scooter exercise. AB - The purpose of this study was to determine the metabolic equivalents (METs) for scooter exercise (riding a scooter, scootering) and to examine the energy expenditure and the heart rate response, so that the results can be used in health promotion activities. Eighteen young adults (10 males and 8 females) participated in scootering on a treadmill at three different speeds for six minutes each. Before, during, and after the exercise, pulmonary ventilation, oxygen uptake (VO(2)), carbon dioxide product, respiratory exchange ratio (R), and heart rate (HR) were measured. These measurements kept steady states from the 3rd to 6th minute of each different speed session. The MET values acquired during scootering at 80 m.min(-1), 110 m.min(-1), and 140 m.min(-1) were 3.9, 4.3, and 5.0, respectively. Calculated using VO(2) (ml.kg(-1).min(-1))x[4.0+R], the energy consumption for scootering at each speed was 67.0+/-10.6, 73.3+/-10.2, and 84.8+/ 7.9 cal.kg(-1).min(-1), respectively. The regression equation between scootering speed (X, m.min(-1)) and VO(2) (Y, ml.kg(-1).min(-1)) is Y=0.062X+8.655, and the regression equation between HR (X, beats.min(-1)) and VO(2)reserve (Y, %) is Y=0.458X-11.264. These equations can be applied to both females and males. Thus, scootering at 80 to 140 m.min(-1) might not be sufficient to improve the cardiorespiratory fitness of young male adults similar to the participants, but it may contribute many healthy benefits to most female adults and even male adults, and improve their health and fitness at the faster speeds. PMID- 17704629 TI - Anthropometry and body composition in soccer and volleyball players in West Bengal, India. AB - 50 sedentary males and 128 sports persons (volleyball=82, soccer=46) of 20-24 years were selected from West Bengal, India, to evaluate and compare their anthropometry and body composition. Skinfolds, girth measurements, body fat percentage (%fat), and endomorphy were significantly higher among sedentary individuals, but lean body mass (LBM) and mesomorphy were significantly (p<0.001) higher among the sports persons. Soccer and volleyball players were found to be ectomorphic mesomorph, whereas sedentary subjects were endomorphic mesomorph. The soccer and volleyball players had higher %fat with lower body height and body mass than their overseas counterparts. %fat exhibited a significant correlation with body mass index (BMI) and thus prediction equations for %fat from BMI were computed in each group. The present data will serve as a reference standard for the anthropometry and body composition of Indian soccer and volleyball players and the prediction norms for %fat will help to provide a first-hand impression of body composition in the studied population. PMID- 17704630 TI - Prospect of manufacturing and design based on physiological polymorphism. AB - Modern manufacturing and design should satisfy not only the requirements of high cost performance but also of the user. Besides that, the social environment which surrounds manufacturing is rapidly changing depending on new technologies. To create future products with user satisfaction, the effective use of human physiological data is essential. This is where knowledge of physiological anthropology can be applied. Physiological anthropologists have been pointing out a limit to the interpretation of the physiological data based on its average value. They have begun to notice that the physiological functions of humans show various types according to the blended effect of heredity and the surroundings. Adequate consideration of physiological polymorphism is indispensable to accomplish manufacturing that is well devised for human. In this study the concept of manufacturing and design based on physiological polymorphism is expressed. The target and the methodology for new manufacturing are discussed in seven fields, that is, welfare equipment, clothes, artificial tissue, sporting gear, furniture, building materials, and human interface. Through the above discussion, a procedure to achieve manufacturing and design based on physiological polymorphism is proposed. PMID- 17704631 TI - Relationships between body fat measured by DXA and subcutaneous adipose tissue thickness measured by Lipometer in adults. AB - The aim of this study was to examine the relationships between body fat measured by DXA and subcutaneous adipose tissue layers (SAT-layers) measured by LIPOMETER in adult males (n=28) and females (n=53). Body height and mass were measured and BMI was calculated (kg/m2). Measurements of the thicknesses of SAT-layers by LIPOMETER were performed at 15 original body sites. Body composition was measured using DXA. Total body fat % measured by DXA was highly dependent on the SAT layers in the upper back and inner thigh in males (87.1%, R(2)x100) and the lateral chest, biceps, and calf in females (78.5%, R(2)x100). There were gender differences in trunk fat mass and right hand and leg fat mass calculation using specific SAT-layers. In conclusion, our results indicate that there are close relationships between SAT-layers and body fat measured by DXA. However, there are big differences between genders. PMID- 17704632 TI - Rhamnolipid-dependent spreading growth of Pseudomonas aeruginosa on a high-agar medium: marked enhancement under CO2-rich anaerobic conditions. AB - Anaerobiosis of Pseudomonas aeruginosa in infected organs is now gaining attention as a unique physiological feature. After anaerobic cultivation of P. aeruginosa wild type strain PAO1 T, we noticed an unexpectedly expanding colony on a 1.5% agar medium. The basic factors involved in this spreading growth were investigated by growing the PAO1 T strain and its isogenic mutants on a Davis high-agar minimal synthetic medium under various experimental conditions. The most promotive environment for this spreading growth was an O(2)-depleted 8% CO(2) condition. From mutational analysis of this spreading growth, flagella and type IV pili were shown to be ancillary factors for this bacterial activity. On the other hand, a rhamnolipid-deficient rhlA mutant TR failed to exhibit spreading growth on a high-agar medium. Complementation of the gene defect of the mutant TR with a plasmid carrying the rhlAB operon resulted in the restoration of the spreading growth. In addition, an external supply of rhamnolipid or other surfactants (surfactin from Bacillus subtilis or artificial product Tween 80) also restored the spreading growth of the mutant TR. Such activity of surfactants on bacterial spreading on a hard-agar medium was unique to P. aeruginosa under CO(2)-rich anaerobic conditions. PMID- 17704633 TI - Microbiological and immunological features of oral candidiasis. AB - Candida albicans(C. albicans) is the major infectious agent of oral candidiasis, and both innate immunity and cell-mediated immune response participate in the control of the fungal infections. The aim of this study was to correlate the clinical forms of oral candidiasis with the number of colony forming units (CFU) of C. albicans in saliva and to characterize T cell response in patients with oral candidiasis. Participants included 75 subjects: 36 with lesions of candidiasis and 39 without lesions of oral candidiasis. A 2-ml sample of saliva was collected from all subjects for microbiological analysis. Cytokine levels were determined by ELISA in supernatants of peripheral blood mononuclear cells of 25 patients with oral candidiasis, after in vitro stimulation with C. albicans antigens. In 48% of patients, no association was observed with denture use. C. albicans was detected in the saliva of 91.7% of patients with oral candidiasis, and there was an association between the number of CFU and the presence of oral lesions. A type Th1 immune response was observed in supernatants of peripheral blood mononuclear cells stimulated with C. albicans antigens. In contrast, IL-5 and IL-10 levels were very low or undetectable. Together, this study shows an association between clinical forms of oral candidiasis and the number of colonies of C. albicans in saliva, and that a systemic immune response characterized by the production of TNF-alpha and IFN-gamma is observed in patients with oral candidiasis. PMID- 17704634 TI - Identification and characterization of a dextranase gene of Streptococcus criceti. AB - The dextranase gene, dex, was identified in Streptococcus criceti strain E49 by degenerate PCR and sequenced completely by the gene-walking method. A sequence of 3,960 nucleotides was determined. The dex gene encodes a 1,200-amino acid protein, which has a calculated molecular mass of 128,129.91 and pI of 4.15 and is predicted to be a cell-surface protein. The deduced amino acid sequence of dex showed homology to S. downei dextranase (63.9% identity). Phylogenetic analysis revealed the similarity of the deduced amino acid sequence of dextranases in S. criceti, S. sobrinus, and S. downei. A recombinant form of the protein with six histidine residues tagged in the C-terminus was partially purified and showed dextranase activity on blue-dextran sodium dodecyl sulfate-polyacrylamide gel electrophoresis (BD-SDSPAGE) followed by renaturation. We also detected dextranase activity in S. criceti cell extracts and culture supernatant by renatured BD-SDS-PAGE, whereas no dextranase activity of the cells was observed on blue-dextran brain heart infusion (BD-BHI) agar plates. Furthermore, PCR-based mutations of dextranase indicated that a deletion mutant of the C-terminal region could hydrolyze blue dextrans and that the D453E mutation, W793L mutation, and double mutations (W793L and deletion of the C-terminal region) resulted in a loss of dextranase activity. These findings suggest that Asp-453 and Trp-793 residues of S. criceti dextranase are critical to the enzyme's activity. PMID- 17704635 TI - Evaluation of repetitive extragenic palindromic-PCR for discrimination of fecal Escherichia coli from humans, and different domestic- and wild-animals. AB - The objective of this study was to investigate the potential of repetitive extragenic palindromic anchored polymerase chain reaction (rep-PCR) in differentiating fecal Escherichia coli isolates of human, domestic- and wild animal origin that might be used as a molecular tool to identify the possible source(s) of fecal pollution of source water. A total of 625 fecal E. coli isolates of human, 3 domestic- (cow, dog and horse) and 7 wild-animal (black bear, coyote, elk, marmot, mule deer, raccoon and wolf) species were characterized by rep-PCR DNA fingerprinting technique coupled with BOX A1R primer and discriminant analysis. Discriminant analysis of rep-PCR DNA fingerprints of fecal E. coli isolates from 11 host sources revealed an average rate of correct classification of 79.89%, and 84.6%, 83.8%, 83.3%, 82.5%, 81.6%, 80.8%, 79.8%, 79.3%, 77.4%, 73.2% and 63.6% of elk, human, marmot, mule deer, cow, coyote, raccoon, horse, dog, wolf and black bear fecal E. coli isolates were assigned to the correct host source. These results suggest that rep-PCR DNA fingerprinting procedures can be used as a source tracking tool for detection of human- as well as animal-derived fecal contamination of water. PMID- 17704636 TI - Adjuvant effect of CpG-oligodeoxynucleotide in anti-fungal chemotherapy against fatal infection with Cryptococcus neoformans in mice. AB - Cryptococcal meningoencephalitis is a life-threatening infectious disease in immunocompromised patients. Unmethylated CpG-oligodeoxynucleotides (CpG-ODN) protects hosts in a mouse model. In the present study, we tested the adjuvant effect of CpG-ODN in anti-fungal chemotherapy. Administration of either fluconazole (FLCZ) or CpG-ODN was effective in extending survival, accelerating clearance of fungi and preventing disseminated infection. Combination of both agents provided more beneficial effect than either agent alone. Cytokine balance in the infected lungs was biased to Th1-type response by CpGODN, while FLCZ did not further promote. These results suggest that CpG-ODN is a promising adjuvant in chemotherapy against this infection. PMID- 17704637 TI - Metascardovia criceti Gen. Nov., Sp. Nov., from hamster dental plaque. AB - A novel microorganism, Metascardovia criceti gen. nov., sp. nov., was isolated from dental plaque of golden hamsters fed with a high-carbohydrate diet. The three isolated strains, OMB104, OMB105, and OMB107, were Gram-positive, facultative anaerobic rods that lacked catalase activity. Analyses of the partial 16S rRNA and heat-shock protein 60 (HSP60) gene sequences of these isolates indicated that they belonged to the family Bifidobacteriaceae. However, in contrast to Bifidobacterium, one of the genera under this family, these isolates grew under aerobic conditions, and the DNA G + C contents were lower (53 mol%) than those of Bifidobacterium. On the basis of phylogenetic analyses using phenotypic characterization, and partial 16S rRNA and HSP60 gene sequences data, we propose a novel taxa, Metascardovia criceti for OMB105(T) (type strain=JCM 13493(T)=DSM 17774(T)) for this newly described isolate. PMID- 17704638 TI - HLA-DRB1*0410-restricted recognition of XAGE-1b37-48 peptide by CD4 T cells. AB - XAGE-1b belongs to cancer/testis (CT) antigens, and has been shown to be expressed frequently in lung cancers and to elicit an antibody response in patients with XAGE-1b-expressing tumors. In this study, we investigated an XAGE 1b peptide recognized by CD4 T cells. CD4 T cells were purified from PBMC of a healthy donor and stimulated with pooled 25-mer peptides overlapped with 15 amino acids spanning the entire XAGE-1b protein. The generation of XAGE-1b-specific CD4 T cells was shown by IFNgamma secretion assay. A CD4 T cell clone OHD1 was obtained by limiting dilution. OHD1 recognized two overlapping peptides, XAGE1 b(33-49) and XAGE-1b(37-52), by ELISPOT assay. A peptide XAGE-1b(38-46) which was included in both XAGE-1b(33-49) and XAGE-1b(37-52) was predicted to be a DRB1*0410-restricted 9-mer peptide by a computer-based program. We identified the 12-mer peptide XAGE-1b(37-48) as a new XAGE-1b epitope restricted to HLA DRB1*0410. PMID- 17704639 TI - Photoactivated ethidium monoazide directly cleaves bacterial DNA and is applied to PCR for discrimination of live and dead bacteria. AB - Ethidium monoazide (EMA) is a DNA intercalating agent and a eukaryotic topoisomerase II poison. We found that EMA treatment and subsequent visible light irradiation (photoactivation or photolysis) shows a bactericidal effect, hence the mechanism was analyzed. When bacterial cells were treated with more than 10 microg/ml of EMA for 1 hr plus photoactivation for 20 min, cleavage of bacterial DNA was confirmed by agarose gel electrophoresis and electron microscopic studies. The cleavage of chromosomal DNA was seen when it was treated in vitro with EMA and photolysis, which showed that the cleavage directly took place without the assistance of DNA gyrase/topoisomerase IV and the DNA repair enzymes of bacteria. It was also verified, by using negatively supercoiled pBR322 DNA, that medium/high concentrations of EMA (1 to 100 microg/ml) led to breaks of double-stranded DNA and that low concentrations of EMA (10 to 100 ng/ml) generated a single-stranded break. EMA is known to easily penetrate dead but not live bacteria. After treatment of 10 microg/ml of EMA for 30 min and photoactivation for 5 min, EMA cleaved the DNA of dead but not live Klebsiella oxytoca. When the cleaved DNA was used for templates in PCR targeting 16S rDNA, PCR product from the dead bacteria was completely suppressed. We demonstrated that EMA and photolysis directly cleaved bacterial DNA and are effective tools for discriminating live from dead bacteria by PCR. PMID- 17704640 TI - Enhancement of Legionella pneumophila culture isolation from microenvironments by macrophage infectivity potentiator (mip) gene-specific nested polymerase chain reaction. AB - The combination of a Legionella pneumophila culture isolation technique and macrophage infectivity potentiator (mip) gene-specific nested polymerase chain reaction (PCR) is pivotal for effective routine use in an environmental water system laboratory. Detection of Legionella organisms in 169 environmental samples was performed by using modified buffered charcoal yeast extract (MBCYE) agar for conventional culture. Nested PCR specific for L. pneumophila was performed using boiled genomic DNA extracts from filtered and Chelex 100-treated water samples, or by using silica-gel membrane spin column-eluted DNA from concentrated pond, canal and river samples. Overall, the nested PCR was twelvefold more sensitive than the culture method. The target amplicons (471 basepairs) of all 4 biochemically characterized L. pneumophila isolates were sequenced. They had homology at the DNA and protein levels to 3' proximity of the mip-coding gene of L. pneumophila deposited in genome databases. EcoRI- or KpnI-digested PCR fragments with expected sizes were also confirmed in all 52 PCR-positive samples that were isolated from cooling towers and condenser drains. Viable but nonculturable L. pneumophila might have been present in 48 PCR-positive samples. This study demonstrates that detection of the genetically stable mip gene by nested PCR with a modified process of water sample preparation can be rapidly and effectively used to enhance isolation of the L. pneumophila taxon from microenvironments. PMID- 17704641 TI - Breast cancer metastasis in a human bone NOD/SCID mouse model. AB - A major dilemma facing patients with breast cancer is how to decide between over treating indolent tumors and failing to adequately treat aggressive, potentially lethal cancers. Determination of the metastatic potential of a patient's breast cancer would clearly help guide those treatment decisions. Breast cancer commonly spreads to bone in 70% of women with advanced disease. However, the mechanism of bone metastasis is not well understood. One possibility is that the microenvironment within bone marrow, highly rich in growth factors and cytokines, is suitable for the proliferation of breast cancer cells. In this study, we developed a method for implanting human bone in NOD/SCID mice and show that the human bone implants are viable for more than 20 weeks. This human bone NOD/SCID mouse model provides an opportunity to functionally characterize human breast cancer cell behavior in an in vivo human microenvironment. Several breast tumor cell lines have been shown to grow in the human-bone-NOD/SCID model system, however each line has a different functional profile. Here we show that cotransplantation of GFP-MDA-MB-231 breast cancer cells with morcellized human bone allows for tissue specific metastasis to an initially tumor free bone implant. Furthermore, metastasis of breast tumor cells to implanted tumor-free human bone was seen when patient bone containing a metastatic breast tumor was implanted in the host mouse. With this model, we can distinguish between primary invasive breast tumors with and without bone metastatic potential. PMID- 17704642 TI - Inhibition of melanoma by ultrasound-microbubble-aided drug delivery suggests membrane permeabilization. AB - Ultrasound exposure-induced cavitation has been shown to accentuate cell membrane permeability, thus promoting effective drug delivery into cells, a technique that can be enhanced in the presence of microbubbles (MB). Here we applied this method as a treatment for malignant melanoma of the eyelid. The incidence of malignant melanoma in ophthalmology is relatively high, but its treatment is cosmetically difficult. A greater in vitro growth suppression of B-16 melanoma cells was achieved using ultrasound and MB in combination with the anticancer drug bleomycin than when a more concentrated dose of bleomycin alone was applied to the cell culture. Moreover, this effect was enhanced in an in vivo tumor model created by injecting B-16 melanoma cells into the lower eyelids of SCID mice. The antitumor effect of bleomycin was observed at a lower dose (0.5 mg/ ml) when the treatment was used in conjunction with ultrasound. The effect was further enhanced when MB were included, with tumor shrinkage occurring at bleomycin levels of 0.06 mg/ml. These results show that ultrasound and MB promote efficient bleomycin uptake by cells, and that the technique is a potentially useful drug delivery method. PMID- 17704643 TI - Coregulators in adipogenesis: what could we learn from the SRC (p160) coactivator family? AB - Strong epidemiological studies clearly show that reduction in body fat content decreases the risk for many clinical conditions including diabetes, hypertension, coronary atherosclerotic heart disease and some forms of cancer. Therefore, detailed understanding of the mechanisms underlying how fat pads expand appears crucial. Extensive studies already identified a cohort of transcription factors involved in adipocyte differentiation but the fine interrelationship between the myriads of cellular and molecular events occurring during this complex biological process is far from being completely understood. Since the cloning of the first coregulator, the impact of those molecules has dramatically increased. In this review, we will summarize the emerging impact of coregulators on energy balance with a specific interest for fat formation. Emphasis will be given to the coactivators of the SRC (p160) family. PMID- 17704644 TI - The ubiquitin E3 ligase Cbl-b in T cells tolerance and tumor immunity. AB - The implication of the immune system in tumor surveillance is proven and widely accepted. However, anti-cancer immunotherapy is still difficult due to insufficient activation, immune suppression and tolerance induction. The ubiquitin E3 ligase Cbl-b, is a member of the Cbl (casitas B-lineage lymphoma) protein family and was identified as a key dominant "tolerogenic" factor in T cells that directly regulates T-cell activation by controlling activation thresholds and the requirement for co-stimulation. Intriguingly, Cbl-b deficient mice spontaneously reject a variety of cancers including spontaneous solid tumors and hematopoietic malignancies. Mechanistically, modulation of Cbl-b in T cells controls activation of tumor-reactive cytotoxic T cells in vivo and might circumvent several limitations of T cell immunotherapy. Therefore manipulation of Cbl-b might provide us with a unique opportunity for future immune treatment of human disorders such as autoimmunity, chronic viral infections, or cancer. PMID- 17704645 TI - Domain architectures of the Scm3p protein provide insights into centromere function and evolution. AB - Recently, Scm3p has been shown to be a nonhistone component of centromeric chromatin that binds stoichiometrically to CenH3-H4 histones, and to be required for the assembly of kinetochores in Saccharomyces cerevisiae. Scm3p is conserved across fungi, and displays a remarkable variation in protein size, ranging from approximately 200 amino acids in S. cerevisiae to approximately 1300 amino acids in Neurospora crassa. This is primarily due a variable C-terminal segment that is linked to a conserved N-terminal, CenH3-interacting domain. We have discovered that the extended C-terminal region of Scm3p is strikingly characterized by lineage-specific fusions of single or multiple predicted DNA-binding domains different versions of the MYB and C2H2 zinc finger domains, AT-hooks, and a novel cysteine-rich metal-chelating cluster that are absent from the small versions of Scm3. Instead, S. cerevisiae point centromeres are recognized by components of the CBF3 DNA binding complex, which are conserved amongst close relatives of budding yeast, but are correspondingly absent from more distant fungi that possess regional centromeres. Hence, the C-terminal DNA binding motifs found in large Scm3p proteins may, along with CenH3, serve as a key epigenetic signal by recognizing and accommodating the lineage-specific diversity of centromere DNA in course of evolution. PMID- 17704646 TI - Import of nuclear DNA-encoded RNAs into mitochondria and mitochondrial translation. AB - Targeting nuclear DNA-encoded tRNA into mitochondria is a quasi-ubiquitous process, found in a variety of species, although the mechanisms of this pathway seem to differ from one system to another. In all cases reported, this import concerns small non-coding RNAs and the vast majority of imported RNAs are transfer RNAs. If was commonly assumed that the main criterion to presume a tRNA to be imported is the absence of the corresponding gene in mitochondrial genome, in some cases the imported species seemed redundant in the organelle. By studying one of such "abnormal" situation in yeast S. cerevisiae, we discovered an original mechanism of conditional regulation of mitochondrial translation exploiting the RNA import pathway. Here, we provide an outline of the current state of RNA import in yeast and discuss the possible impact of the newly described mechanism of translational adaptation. PMID- 17704647 TI - The IKK inhibitor BMS-345541 affects multiple mitotic cell cycle transitions. AB - The IkappaB kinase (IKK) complex controls processes such as inflammation, immune responses, cell survival and the proliferation of both normal and tumor cells. By activating NFkappaB, the IKK complex contributes to G1/S transition and first evidence has been presented that IKKalpha also regulates entry into mitosis. At what stage IKK is required and whether IKK also contributes to progression through mitosis and cytokinesis, however, has not yet been determined. In this study, we use BMS-345541, a potent allosteric small molecule inhibitor of IKK, to inhibit IKK specifically during G2 and during mitosis. We show that BMS-345541 affects several mitotic cell cycle transitions, including mitotic entry, prometaphase to anaphase progression and cytokinesis. Adding BMS-345541 to the cells released from arrest in S-phase blocked the activation of Aurora A, B and C, Cdk1 activation and histone H3 phosphorylation. Additionally, treatment of the mitotic cells with BMS-345541 resulted in precocious cyclin B1 and securin degradation, defective chromosome separation and improper cytokinesis. BMS-345541 was also found to override the spindle checkpoint in nocodazole-arrested cells. In vitro kinase assays using BMS-345541 indicate that these effects are not primarily due to a direct inhibitory effect of BMS-345541 on mitotic kinases such as Cdk1, Aurora A or B, Plk1 or NEK2. This study points towards a new potential role of IKK in cell cycle progression. Since deregulation of the cell cycle is one of the hallmarks of tumor formation and progression, the newly discovered level of BMS-345541 function could be useful for cell cycle control studies and may provide valuable clues for the design of future therapeutics. PMID- 17704648 TI - Src kinase inhibitors induce apoptosis and mediate cell cycle arrest in lymphoma cells. AB - Src kinases are involved in multiple cellular contexts such as proliferation, adhesion, tumor invasiveness, angiogenesis, cell cycle control and apoptosis. We here demonstrate that three newly developed dual selective Src/Abl kinase inhibitors (SrcK-I) (AZM559756, AZD0530 and AZD0424) are able to induce apoptosis and cell cycle arrest in BCR-ABL, c-KIT and platelet-derived growth factor negative lymphoma cell lines. Treatment of DOHH-2, WSU-NHL, Raji, Karpas-299, HUT78 and Jurkat cells with SrcK-I revealed that the tested substances were effective on these parameters in the cell lines DOHH-2 and WSU-NHL, whereas the other tested cell lines remained unaffected. Phosphorylation of Lyn and in particular Lck were affected most heavily by treatment with the SrcK-I. Extrinsic as well as intrinsic apoptosis pathways were activated and elicited unique expressional patterns of apoptosis-relevant proteins such as downregulation of survivin, Bcl-XL and c-FLIP. Protein levels of c-abl were downregulated and Akt phosphorylation was decreased by treatment with SrcK-I. Basal expression levels of c-Myc were notably lower in sensitive cell lines as compared with nonsensitive cell lines, possibly providing an explanation for sensitivity versus resistance against these novel substances. This study provides the first basis for establishing novel SrcK-I as weapons in the arsenal against lymphoma cells. PMID- 17704649 TI - Structure-antileukemic activity relationship study of B- and D-ring modified and nonmodified steroidal esters of 4-methyl-3-N,N-bis(2-chloroethyl)amino benzoic acid: a comparative study. AB - This study was designed as a rational continuation of our research regarding the functional requirements essential for the antileukemic activity of compounds comprising an alkylating moiety and a modified steroid. The steroidal esteric derivatives of 4-methyl-3-N,N-bis(2-chloroethyl)amino benzoic acid were tested on leukemias P388 and L1210 in vivo and in normal human lymphocytes in vitro. Among them the B-lactamic steroidal esters proved more potent antileukemic agents than the 7-oxidized and those with a simple B-ring, but not more effective inducers of DNA damage and cell cycle arrest in vitro. We speculate that these results indicate a different mechanism of action induced by the lactamized B steroidal ring, in comparison to the 7-keto or the D-lactamic groups, which involves the interaction of the -NHCO- moiety with cellularcomponents essential for tumor growth. 4-Methyl-3-N,N-bis(2-chloroethyl)amino benzoic acid proved a more proper module for the B-lactams than chlorambucil and phenyl acetic acid's nitrogen mustard probably because the esteric bond is less cleaved by the esterases, resulting in an increased concentration of the drug in the vinicity of the target site essential for an antineoplasmatic response. PMID- 17704650 TI - Differential regulation of thrombospondin-1 expression and antiangiogenesis of ECV304 cells by trichostatin A and helixor A. AB - Trichostatin A and helixor A increased thrombospondin-1 expression by ECV304 cells at both mRNA and protein levels by transcriptional activation through the enhancement of tsp-1 promoter activity. The induction of thrombospondin-1 by these agents potently reduced ECV 304 cell migration and capillary-like tube formation on Matrigel; these findings were confirmed by the neutralization of thrombospondin-1 using a specific antibody. In the presence of exogenous vascular endothelial growth factor, however, these agents had a different effect on the vascular endothelial growth factor-induced tube formation; trichostatin A remarkably inhibited tube formation regardless of the presence of exogenous vascular endothelial growth factor, whereas helixor A reduced it to 70-80% of the control level. Interestingly, when the helixor A-generated conditioned media were concentrated three-fold and the endogenous vascular endothelial growth factor was removed, tube formation was remarkably inhibited compared with the effect of three-fold concentrated conditioned media that had endogenous vascular endothelial growth factor. Additionally, in media with endogenous vascular endothelial growth factor that were concentrated five-fold, tube formation was markedly blocked regardless of the presence of exogenous or endogenous vascular endothelial growth factor. Thus, our results indicate that trichostatin A-induced or helixor A-induced antiangiogenesis is mediated by both agents; increased, absolute and relative levels of thrombospondin-1 to the vascular endothelial growth factor level are critical in angiogenesis. PMID- 17704651 TI - Reversal effect of BM-cyclin 1 on multidrug resistance in C-A120 cells. AB - In this study, multidrug-resistant human epidermoid C-A120 cells and the sensitive parental KB cells were used as experimental models. BM-cyclin 1, a traditional antimycoplasma drug, was tested to explore the reversal effect of multidrug resistance and its mechanisms in these cell lines. The MTT analysis showed that BM-cyclin 1 could reverse multidrug resistance effectively in C-A120 cells; the sensitivity of C-A120 cells to adriamycin, etoposide and cisplatin was enhanced by 6.0, 8.2 and 1.7 times, respectively. Immunoblotting analysis and reverse transcription-polymerase chain reaction were used to study the BM-cyclin 1-induced changes in topoisomerase IIalpha. The results showed that the expression of topoisomerase IIalpha in treated C-A120 cells increased significantly. Topoisomerase II catalytic activity increased by 30% compared with the untreated cells, as measured by decatenation of kinetopolast DNA. Immunoblotting analysis also indicated the transcription factor levels of specificity: those of protein 1 (Sp1) and nuclear factor-YA increased after treatment with BM-cyclin 1, whereas the mRNA and protein expression of multidrug resistance protein 2 was significantly downregulated. These results demonstrated that BM-cyclin 1 could effectively reverse the multidrug resistance of C-A120 cells by increasing the expression of topoisomerase IIalpha and by suppressing the expression of multidrug resistance protein 2, strongly suggesting that BM cyclin 1 is a potential multidrug resistance reversal agent. PMID- 17704652 TI - Cudraflavanone A purified from Cudrania tricuspidata induces apoptotic cell death of human leukemia U937 cells, at least in part, through the inhibition of DNA topoisomerase I and protein kinase C activity. AB - A chloroform extract of the root bark of Cudrania tricuspidata showed an inhibitory effect on mammalian DNA topoisomerase I. The topoisomerase I inhibitory compound was purified and identified as 2S-2',5,7-trihydroxy-4',5' (2,2-dimethylchromeno)-6-prenyl flavanone (cudraflavanone A). Cudraflavanone A was shown to inhibit the activity of topoisomerase I with approximately 0.4 mmol/l 50% inhibitory concentration. A concentration of 6 micromol/l cudraflavanone A caused a 50% growth inhibition of human cancer cell U937. Cudraflavanone A-induced cell death was characterized by the cleavage of poly(ADP ribose) polymerase and pro-caspase-3. Furthermore, cudraflavanone A induced the fragmentation of DNA into multiples of 180 bp (an apoptotic DNA ladder), indicating that the inhibitor triggered apoptosis. This induction of apoptosis by cudraflavanone A was also confirmed using flow-cytometry analysis. In addition, this compound inhibited protein kinase C activity with approximately 150 micromol/l 50% inhibitory concentration. Taken together, these results suggest that cudraflavanone A may function by inhibiting oncogenic disease, at least in part, through the inhibition of protein kinase C and topoisomerase I activity. PMID- 17704653 TI - Imatinib mesylate reduces rituximab-induced tumor-growth inhibition in vivo on Epstein-Barr virus-associated human B-cell lymphoma. AB - We have reported earlier an increase of tumor-growth inhibition following chemotherapy combined with concomitant administration of imatinib mesylate. Conversely, the combination of imatinib and rituximab has been reported in very few cases of patients and remains controversial. To explore this particular combination of targeted therapies, we therefore investigated the in-vivo impact of rituximab plus imatinib on B-cell lymphoproliferation. Combination of the tyrosine kinase inhibitor imatinib mesylate (STI571) and the anti-CD20 monoclonal antibody rituximab was evaluated on an Epstein-Barr virus-associated B-cell lymphoproliferative disorder xenografted into severe combined immunodeficient or Rag2/gammac-/- (B-, T- and NK-) mice. Using severe combined immunodeficient mice, we found that STI571 diminished the efficacy of rituximab to inhibit tumor growth in vivo. Using alymphoid Rag2/gammac-/- mice, we showed that the effect of STI571 was not dependent on the presence of natural killer cells. In contrast, serum complement administered after STI571 treatment reversed this inhibitory effect. Finally, using nonimmunodeficient mice, we observed an in-vivo decrease of CD4 positive T-cells and mature B-cell lymphocytes after imatinib administration. We found that STI571 decreased the in-vivo efficacy of rituximab via serum protein components that could influence complement-dependent cytotoxicity. In contrast, this effect was not dependent on the presence of natural killer cells. PMID- 17704654 TI - Synthesis of 1,1,2-triphenylethylenes and their antiproliferative effect on human cancer cell lines. AB - Tamoxifen analogs (1-3) and 1,1,2-triphenylethylenes (4-7) have been synthesized by the McMurry coupling reaction. Their antiproliferative effects on MCF-7 human breast-cancer cells, HO-8910 human ovarian-carcinoma cells, and (HL)-60 human promyelocytic-leukemia cells were studied by use of the colorimetric MTT assay or sulphorhodamine B assay. Compounds 2 and 3 exhibited significantly higher antiproliferative activity on all the three cell lines, and compound 6 exhibited a remarkably higher antiproliferative activity on HO-8910 and human peripheral blood HL-60 cell lines, than did tamoxifen. Structure-activity relationship analysis demonstrates that the methoxyl group on the 2-phenyl ring contributes critically to the activity. PMID- 17704655 TI - Changes in the protein spectrum of mitochondria isolated from hydroxycamptothecin treated hepatoma cells. AB - As one of the most potent topoisomerase inhibitors, hydroxycamptothecin is more active and less toxic than conventional camptothecin. Recently, we found that hydroxycamptothecin can induce cell apoptosis via the mitochondrial pathway. This study was designed to investigate the mitochondrial protein profile in HCPT treated cells using high-accuracy and high-sensitivity protein-identification technology. Of the 39 mitochondrial protein spots investigated, 25 displayed elevated and 14 suppressed abundance in hydroxycamptothecin-treated cells. The 25 spots were identified by mass spectrometry and they included proteins involved in many essential cellular functions. The potential role of these proteins in hydroxycamptothecin-mediated apoptosis is also discussed. This study has produced a short list of mitochondrial proteins that might hold the key to the mechanism by which hydroxycamptothecin induces mitochondrial dysfunction and cell apoptosis. It has laid the foundation for further elucidating the role of hydroxycamptothecin during apoptosis. Successful applications of multiple techniques including two-dimensional gel electrophoresis, matrix-assisted laser desorption ionization time-of-flight mass spectrometry and Western blot analysis have demonstrated that proteomic analyses provide appropriate approaches for understanding of the roles of anticancer drugs. PMID- 17704656 TI - 5-Bromo-2-deoxyuridine activates DNA damage signalling responses and induces a senescence-like phenotype in p16-null lung cancer cells. AB - 5-Bromo-2-deoxyuridine (BrdU) is a thymidine analogue that is incorporated into replicating DNA. Although originally designed as a chemotherapeutic agent, sublethal concentrations of BrdU have long been known to alter the growth and phenotype of a wide range of cell types. Mechanisms underlying these BrdU mediated effects remain unknown, however. We have characterized the effects of BrdU on A549 lung cancer cells by examining DNA damage responses, cell cycle effects and phenotypic changes. A549 cells express wild-type p53, but are p16 null. Sublethal concentrations of BrdU evoke a DNA damage response in these cells that involves the activation of Chk1, Chk2 and p53. Increased numbers of enlarged nuclei and multinucleated cells are evident in the treated populations. Cell cycle inhibition occurs, resulting in reduced proliferation and accumulation of cells in the S, G2/M and G0 phases. BrdU induces an early inhibition of p21 expression that coincides with nuclear localization of proliferating cell nuclear antigen. Subsequently, p21 levels increase, whereas proliferating cell nuclear antigen levels decrease compared with control cells. Upregulation of p27 and p57 expression also occurs. By day 7 of exposure to BrdU, treated cells acquire a senescent-like phenotype with an increase in cell size, granularity and beta galactosidase activity. We conclude that BrdU induces a DNA damage response in A549 cells, which results in reduced proliferation mitotic exit and phenotypic changes that resemble senescence. PMID- 17704657 TI - In-vitro antiproliferative activities and kinase inhibitory potencies of glycosyl isoindigo derivatives. AB - In the course of studies on the preparation of potential kinase inhibitors, we were interested in the synthesis of diversely substituted glycosyl-isoindigo derivatives. To get an insight into the effect of the substitution pattern of the isoindigo aromatic and carbohydrate moieties on the biological activities and to identify the cellular target(s) involved in the in-vitro antiproliferative activity of these derivatives, their inhibitory activities toward a panel of 10 different kinases were examined. The best inhibitory activities were found toward cyclin-dependent kinase 2/cyclin A. Molecular modelling experiments were carried out to investigate the binding interactions between the active site of cyclin dependent kinase 2 and the lead compound of this series. PMID- 17704658 TI - Effects of celecoxib on the reversal of multidrug resistance in human gastric carcinoma by downregulation of the expression and activity of P-glycoprotein. AB - We investigated the effects of celecoxib on the cell proliferation and the expression and activity of P-glycoprotein in the human gastric carcinoma multidrug resistance sublines SGC7901/adriamycin and SGC7901/vincristine. The cell proliferation was measured by [3H]thymidine incorporation assay and MTT test. The expression of the multidrug resistant gene (MDR1) was detected by real time quantitative reverse transcription-polymerase chain reaction. P-glycoprotein was measured by Western blot analysis. The intracellular rhodamine 123 accumulation was analyzed by flow cytometry to evaluate the activity of P glycoprotein. After treatment with celecoxib, the proliferation inhibitions of SGC7901 cell line and the SGC7901/adriamycin and SGC7901/vincristine sublines increased linearly in a positive dose-dependent pattern in both the [3H]thymidine incorporation assay and in the MTT test. The IC50 value of the MDR1/GAPDH ratio was 5.50 x 10(-6) mol/l in SGC7901/adriamycin and 3.89 x 10(-6) mol/l in SGC7901/vincristine. P-glycoprotein expression levels in the two multidrug resistance sublines treated with celecoxib were significantly lower than those in control groups, 0.28 vs. 0.71 in the SGC7901/adriamycin subline and 0.21 vs. 0.83 in the SGC7901/vincristine subline, respectively, P<0.05. After treatment with celecoxib, intracellular rhodamine 123 accumulation in the SGC7901/adriamycin and SGC7901/vincristine sublines increased positively in a dose-dependent pattern (P<0.05), and reached more than 50% of that in the SGC7901 cell line at the concentration of 1 x 10(-4) mol/l of celecoxib. In conclusion, celecoxib could inhibit proliferation of multidrug resistance in gastric carcinoma sublines. The reversal of multidrug resistance was caused by downregulation of the expression and activity of P-glycoprotein. The results may suggest a new way to reverse P glycoprotein-dependent multidrug resistance in human gastric carcinoma. PMID- 17704659 TI - Cardiac safety and antitumoral activity of a new nitric oxide derivative of pegylated epirubicin in mice. AB - The use of epirubicin is limited by the risk of a dilatory congestive heart failure that develops as a consequence of induction of a mitochondrial-dependent cardiomyocyte apoptosis. In a previous in-vitro study, we have provided evidence that a new formulation of pegylated epirubicin- bearing moieties that release nitric oxide, named BP-747, exerted a potent antitumoral activity against a colon cancer cell line, which was completely devoid of cytotoxic activity against cardiomyocytes. The aim of this study was to investigate the antitumoral and cardiotoxic profile of BP-747 in Caco-2 and SKOV-2 tumor-bearing mice. Epirubicin induced cardiomyopathy was detected by clinical (survival, weight loss), anatomical (heart weight loss) and biochemical evaluations (measurement of serum troponin and creatine phosphokinase levels). The antitumoral activity was investigated by the measurement of tumor diameters and weight. In comparison with free epirubicin and pegylated epirubicin, BP-747 showed more potent antineoplastic effects, as demonstrated by the 95% reduction of tumor volume. Moreover, while administration of epirubicin and pegylated epirubicin resulted in the development of a severe anthracycline cardiomyopathy, BP-747-treated mice were virtually devoid of clinical and biochemical signs of cardiotoxicity. The present data provide evidence that addition of a nitric oxide-releasing moiety to pegylated epirubicin confers a new and unique cytotoxic profile to the drug. PMID- 17704660 TI - A prospective randomized controlled trial of tumour chemosensitivity assay directed chemotherapy versus physician's choice in patients with recurrent platinum-resistant ovarian cancer. AB - The primary aim of this randomized trial was to determine response rate and progression-free survival following chemotherapy in patients with platinum resistant recurrent ovarian cancer, who had been treated according to an ATP based tumour chemosensitivity assay in comparison with physician's choice. A total of 180 patients were randomized to assay-directed therapy (n=94) or physician's-choice chemotherapy (n=86). Median follow-up at analysis was 18 months. Response was assessable in 147 patients: 31.5% achieved a partial or complete response in the physician's-choice group compared with 40.5% in the assay-directed group (26 versus 31% by intention-to-treat analysis respectively). Intention-to-treat analysis showed a median progression-free survival of 93 days in the physician's-choice group and 104 days in the assay-directed group (hazard ratio 0.8, 95% confidence interval 0.59-1.10, not significant). No difference was seen in overall survival between the groups, although 12/39 (41%) of patients who crossed over from the physician's-choice arm obtained a response. Increased use of combination therapy was seen in the physician's-choice arm during the study as a result of the observed effects of assay-directed therapy in patients. Patients entering the physician's-choice arm of the study during the first year did significantly worse than those who entered in the subsequent years (hazard ratio 0.44, 95% confidence interval 0.2-0.9, P<0.03). This small randomized clinical trial has documented a trend towards improved response and progression-free survival for assay-directed treatment. Chemosensitivity testing might provide useful information in some patients with ovarian cancer, although a larger trial is required to confirm this. The ATP-based tumour chemosensitivity assay remains an investigational method in this condition. PMID- 17704661 TI - A phase II trial of modified FOLFOX as first-line chemotherapy in advanced colorectal cancer. AB - The objective was to evaluate the efficacy and toxicity of leucovorin plus 5 fluorouracil combined with oxaliplatin (modified FOLFOX regimen) every 2 weeks on previously untreated advanced colorectal cancer patients in the Chinese population. Fifty-one inpatients were enrolled to receive 85 mg/m oxaliplatin intravenously over a 2- h period on day 1, together with 400 mg/m2 leucovorin over 2- h, followed by a 46-h infusion of 5-fluorouracil at 2600 mg/m2 every 2 weeks. Treatment was given until progression or unmanageable toxicity ensued. In all, 51 patients received three or more oxaliplatin doses and a median of nine treatment cycles (range 3-16 cycles). Of the 51 eligible patients, two complete responses and 22 partial responses were observed for an overall response rate of 47.0% (95% confidence interval 35-64%). Median progression-free survival was 7.7 months (95% confidence interval 6.8-8.6) and median overall survival was 15.0 months (95% confidence interval 13.1-16.9). Toxicities were mild: five patients (9.8%) reported grade 3-4 neutropenia, 33 patients (64.8%) experienced grade 1-3 neurotoxicity and only six patients (11.8%) experienced grade 3 neurotoxicity. The leucovorin plus 5-fluorouracil combined with oxaliplatin (modified FOLFOX) regimen is active and well tolerated in patients with previously untreated advanced colorectal cancer in the Chinese population. PMID- 17704662 TI - Severe lung and skin toxicity during treatment with gemcitabine and erlotinib for metastatic pancreatic cancer. AB - Gemcitabine in combination with the oral epidermal growth factor receptor tyrosine kinase inhibitor erlotinib is a new treatment option for patients with advanced pancreatic cancer. The nonhematological side effects of this regimen mainly include diarrhea and skin rash. For each of these drugs, gemcitabine and erlotinib, lung toxicities have been described previously. In this report, we present the first case of a nonlung cancer patient experiencing not only acne like skin toxicity, but subsequently also severe interstitial lung disease during therapy with gemcitabine and erlotinib. Both therapeutic agents were suspected as a possible cause of this adverse event. An interaction between gemcitabine and erlotinib might have also contributed to the pathogenesis of this pulmonary toxicity. Treatment with high-dose steroids was, however, very effective in our patient and a complete recovery appeared within a few days. Thus, pulmonary side effects should be regarded carefully in pancreatic cancer patients receiving palliative therapy with gemcitabine and erlotinib. PMID- 17704663 TI - Abstracts of the 12th Biennial Meeting of the European Behavioural Pharmacology Society, Tubingen, 2007. PMID- 17704667 TI - A mobility protocol for critically ill adults. AB - Although the complications of immobility are well-described in the literature, critically ill patients are often subjected to prolonged periods of bed rest. Nurses, by virtue of their expertise in preventing iatrogenic complications, are in an ideal position to prevent the adverse outcomes associated with immobility. This article describes how nurses can use a mobility protocol to increase the activity of critically ill patients in a timely manner that may prevent the infirmity and suffering that is caused by unnecessarily long periods of bed rest. PMID- 17704670 TI - Should we allow children to visit ill parents in intensive care units? Your responses. AB - Should children be allowed to visit ill parents in the intensive care unit? This question was posed in the November/December 2006 issue of Dimensions of Critical Care Nurses. The responses of readers are presented in this article. PMID- 17704669 TI - An overview of pulmonary embolism. AB - Unfortunately, acute pulmonary embolism is still a far too common occurrence. Fortunately, with prompt recognition, diagnosis, and treatment, mortality can be reduced. This article provides an overview of risk factors, diagnostic studies, and treatment of patients with acute pulmonary embolism in the critical care setting. PMID- 17704672 TI - Serving as an expert witness. AB - Sometimes nurses are asked to serve as expert witnesses in litigation cases. This article provides a brief overview of the role of the expert witness as well as the positive and negative aspects of the role. The article concludes with a list of tips for the nurse expert witness. PMID- 17704674 TI - Cultural differences with end-of-life care in the critical care unit. AB - Critical care nurses are providing healthcare for an increasingly multicultural population. This ever-increasing diversity in cultures and subcultures presents a challenge to nurses who want to provide culturally competent care. It is common for patients and families to face difficult decisions about end-of-life care in critical care units, and minority cultures do not always believe in the Westerner's core values of patient autonomy and self-determination. Knowledge of these cultural differences is fundamental if critical care nurses wish to provide appropriate and culturally competent information regarding end-of-life decisions. PMID- 17704678 TI - Intensive care patients' evaluations of the informed consent process. AB - This study examines the informed consent process from the perspective of intensive care patients. Using the largest single-method database of patient derived information in the United States, we systematically outlined and tested several key factors that influence patient evaluations of the intensive care unit (ICU) informed consent process. Measures of information, understanding, and decision-making involvement were found to predict overall patient satisfaction and patient loyalty intentions. Specific actions supportive of ICU informed consent, such as giving patients information on advance directives, patient's rights, and organ donation, resulted in significantly higher patient evaluation scores with large effect sizes. This research suggests that the effectiveness of the informed consent process in the ICU from the patient's perspective can be measured and evaluated and that ICU patients place a high value on the elements of the informed consent process. PMID- 17704676 TI - Distressing situations in the intensive care unit: a descriptive study of nurses' responses. AB - Moral distress is a significant stressor for nurses in critical care. Feeling that they are doing the "right thing" is important to nurses, and situations of moral distress can make them question their work. The purpose of this study was to describe critical care nurses' levels of moral distress, the effects of that distress on their personal and professional lives, and nurses' coping strategies. The study consisted of open-ended questions to elicit qualitatively the nurses' feelings about moral distress and a quantitative measure of the degree of distress caused by certain types of situations. The questionnaires were then analyzed to assess the nurses' opinions regarding moral distress, how their self perceived job performance is affected, and what coping methods they use to deal with moral distress. The most frequently encountered moral distress situations involved critically ill patients whose families wished to continue aggressive treatment when it probably would not benefit the patient in the end. PMID- 17704682 TI - A closing word: national licensure for nurses. PMID- 17704683 TI - Timing of cryptococcal immune reconstitution inflammatory syndrome after antiretroviral therapy in patients with AIDS and cryptococcal meningitis. PMID- 17704684 TI - Proteinuria and endothelial dysfunction in stable HIV-infected patients. A pilot study. PMID- 17704686 TI - Quality of life after starting highly active antiretroviral therapy for chronic HIV-1 infection at different CD4 cell counts. PMID- 17704685 TI - Safety of switching to nevirapine-based highly active antiretroviral therapy at elevated CD4 cell counts in a resource-constrained setting. PMID- 17704687 TI - Increases in noninjection methamphetamine use in men who have sex with men, men who do not have sex with men, and Latino men diagnosed with AIDS in Los Angeles County, 2000 through 2004. PMID- 17704688 TI - Conspiracy beliefs and trust in information about HIV/AIDS among minority men who have sex with men. PMID- 17704690 TI - The HIV-coinfected patient: managing viral hepatitis. PMID- 17704691 TI - Diagnosis and management of cirrhosis in coinfected patients. AB - HIV coinfection is associated with faster progression of liver disease resulting from hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Thus, liver complications have become a major cause of illness and death in coinfected patients. Controlling HIV through highly active antiretroviral therapy may slow disease progression to nearly the rate of HIV-negative persons. Several antiretroviral regimens have been associated with drug-induced liver injury, however, which is more common in patients coinfected with hepatitis B or C. After development of cirrhosis and decompensation, survival is shorter in coinfected patients. Diagnosis and management of cirrhosis should be the same for coinfected and monoinfected HBV/HCV patients. The main complications of cirrhosis are ascites, spontaneous bacterial peritonitis, bleeding esophageal varices, hepatic encephalopathy, the hepatorenal syndrome, and hepatocellular carcinoma. Liver transplantation is feasible in patients with HIV infection, and early evaluation for this option is crucial because of the accelerated course of complications in HIV coinfection. PMID- 17704692 TI - Hepatitis C in the HIV-infected patient. AB - Hepatitis C virus (HCV) coinfection in the presence of HIV raises several challenging issues for the treating clinician. Some evidence indicates that concomitant HIV infection alters HCV virology in ways that are relevant for treatment. Pegylated interferon plus ribavirin is the recommended therapy for HCV in HIV-infected patients. Proportionately fewer HIV/HCV-coinfected patients achieve a sustained virologic response (SVR) compared with those infected with HCV alone. Possible reasons for this include higher levels of HCV viremia and inadequate ribavirin exposure. Strategies under study for optimizing therapeutic response include weight-based ribavirin dosing, use of growth factors to avoid dose reduction, and longer duration of therapy. Aggressive management of adverse effects to avoid dose reduction or treatment discontinuation is also crucial. An integrated multidisciplinary team, including a psychiatrist and addictions specialist, can increase the proportion of HIV/HCV-coinfected patients eligible for treatment. Investigational options exist for patients who relapse after treatment is discontinued and for those with a partial virologic response. Promising therapies that are under development include protease and polymerase inhibitors. PMID- 17704693 TI - Hepatitis B in the HIV-coinfected patient. AB - HIV and hepatitis B virus (HBV) infection share transmission patterns and risk factors; therefore, it is not surprising that the prevalence of chronic HBV infection is elevated among HIV-infected persons. HBV does not significantly affect the course of HIV disease, but HIV does alter the course of HBV. HIV infected persons are less likely to clear acute HBV infection spontaneously, and HIV/HBV-coinfected persons face a higher risk of liver-related death than those monoinfected with either virus. The immune restoration associated with highly active antiretroviral therapy (HAART) can improve control of HBV replication but can also lead to increased immune-mediated liver injury. On balance, use of HAART before severe immunosuppression develops may be beneficial. Still, the complexity of HBV, HIV, and HAART interactions must be evaluated for each individual. There is a dearth of high-quality evidence about management of coinfected patients. A recent consensus conference has issued recommendations. HBV DNA thresholds for starting anti-HBV therapy are the same in coinfected and HBV-monoinfected patients. Continuing drugs with anti-HBV activity is important, because stopping such therapy has been associated with HBV reactivation. Development of resistance is a risk with the long-term maintenance therapy required in most patients. PMID- 17704696 TI - Use of a hydroxyapatite-coated stem in patients with Dorr Type C femoral bone. AB - Type C bone, as described by Dorr, exhibits both cellular and structural compromise, which presents a challenge for fixation of a total hip arthroplasty (THA). We evaluated the performance of the Omnifit HA stem, a hydroxyapatite coated titanium alloy stem, by retrospectively reviewing the clinical and radiographic data of 15 patients with femoral Type C bone who received the stem during primary THA between 1991 and 1994. The patients were followed a minimum of 9 years (mean, 11.5 years; range, 9-14 years). The average age at surgery was 54 years and the average body mass index was 28. Eight of the patients were men. The median Harris hip score was 94.5 points. Radiographically, two independent reviewers identified all patients as Type C bone. The average canal to calcar isthmus ratio was 0.74 (range, 0.65-0.95). At most recent followup, four patients demonstrated proximal osteolysis. Using plain radiography we detected no patients with distal osteolysis or subsidence. At 9 to 14 years, the stem has performed well in a selected series of patients with poor bone quality and the outcomes compare favorably with previously reported findings using this design of stem in other bone types. These results support the decision to use a hydroxyapatite coated stem in patients with Type C bone. PMID- 17704697 TI - Time to revision of primary THA is shorter for specialists than nonspecialists. AB - We asked if there was a shorter time to revision, and different indications for revision, for primary total hip arthroplasties performed in the community by general orthopaedic surgeons (nonspecialists) as compared with primary total hip arthroplasties performed by specialists. We retrospectively reviewed 560 revision total hip arthroplasties performed in 486 patients from 1998 to 2006 at our tertiary referral center. One hundred ninety revisions from the community (nonspecialists cohort) and 109 revisions for which the primary arthroplasty was performed by the specialists (specialist cohort) at our center met the criteria for inclusion. These cohorts were analyzed by the time to revision and the indications for revision. Our findings were that the specialists had a shorter mean time to revision (8.3 years versus 10.1 years). This result may reflect a greater concern by specialists over the potential complications of osteolysis as reflected by the finding that the indication for surgery was more often aseptic loosening for the nonspecialists (57.9% versus 12.8%) and osteolysis for the specialists (61.5% versus 15.8%). As a result of possible selection bias in cases referred by the non-specialists, the indications for revision may not represent the modes of failure for arthroplasties performed by nonspecialists. PMID- 17704702 TI - Surgical management of facial neuromas: lessons learned. AB - OBJECTIVE: Primary tumors of the facial nerve are rare, representing 1% of all intrapetrous lesions. We analyzed the management and surgical outcomes of 16 patients with multisegment facial neuromas treated at our institution during a 16 year period. STUDY DESIGN: A retrospective chart review. SETTING: Tertiary referral center. PATIENTS: All patients included in the study had surgical management of their facial neuroma. There were 9 women and 7 men. The mean age was 46 years, with a mean follow-up period of 3 years. INTERVENTION: Surgical excision (n = 15) or decompression (n = 1) of facial neuroma. MAIN OUTCOME MEASURES: Tumor location, presenting symptoms, hearing outcomes, and facial function. RESULTS: Thirteen (81%) patients had facial paresis as their presenting symptom. Unilateral hearing loss was present in 9 (56%) patients. Most tumors (n = 15) involved multiple segments of the facial nerve and ranged in size from 1.5 to 7 cm. Fifteen (94%) patients had the tumor completely excised, and 1 (6%) patient underwent needle decompression of the cystic component of the tumor. The geniculate ganglion was the most commonly involved (11 patients, 69%) segment of the nerve, followed by the labyrinthine and tympanic segments. Despite multiple types of reconstructive options used, the best recovery of facial function was a House-Brackmann Grade III in 12 patients. CONCLUSION: Treatment of facial neuromas depends on the extent of tumor, degree of facial paresis, and hearing function. We advocate complete resection of tumor when facial palsy exists. Patients with normal facial function and hearing may be advised on a more conservative treatment option such as radiologic observation, drainage of any cystic component of the tumor for histologic diagnosis, and/or bony decompression of the tumor. PMID- 17704703 TI - Relevance of the A1555G Mutation in the 12S rRNA Gene for Hearing Impairment in Austria. AB - OBJECTIVE:: To analyze the prevalence and importance of the maternally inherited A1555G mutation in the 12S rRNA gene in the Austrian population. STUDY DESIGN:: Investigation for mutations of genetically affected familial and sporadic cases of hearing impairment (HI), including analyses of audiometric data. SETTING:: Teaching hospital, tertiary referral center. PATIENTS:: Forty-five familial and 77 sporadic cases of nonsyndromic HI in an Austrian Caucasian ethnic group. MAIN OUTCOME MEASURE(S):: Pure-tone audiometric data and screening by restriction fragment length polymorphism analysis after exclusion of GJB2 (Connexin 26) caused hearing loss. RESULTS:: In the investigated hearing-impaired population, the mutation A1555G in the mitochondrial 12S rRNA gene was not detected. CONCLUSION:: The A1555G mutation in the mitochondrial DNA 12S rRNA is not a major cause of HI in the Austrian Caucasian population. PMID- 17704704 TI - Vibration-Induced Nystagmus as an Office Procedure for the Diagnosis of Superior Semicircular Canal Dehiscence. AB - OBJECTIVE:: To describe nystagmus induced by cranial vibration in a case series of 8 patients with superior semicircular canal dehiscence. DESIGN:: Consecutive case series review. SETTING:: Tertiary vestibular center. PATIENTS:: Eight consecutive patients with computed tomographic confirmed superior semicircular canal dehiscence syndrome observed in the last 24 months. PROCEDURE:: Vertex, bilateral mastoid, and bilateral suboccipital cranial vibration were performed using 100 Hz. Vibration for 10 to 15 seconds on patients in the seated position during office evaluation for vestibular complaints. Nystagmus was monitored by infrared video oculography with digital recording. RESULTS:: All patients demonstrated distinct torsional/vertical vibration-induced nystagmus. Maximal recorded slow-phase velocity was 20 degrees/s. This was observed best with suboccipital vibration on the side of the dehiscence. CONCLUSION:: Vibration induced torsional/vertical nystagmus, observed best with ipsilateral suboccipital cranial vibration in the seated position, seems to be a sensitive screening test in the office setting for the presence of superior semicircular canal dehiscence. PMID- 17704705 TI - MRI Scanners and the Stapes Prosthesis. AB - OBJECTIVE:: Physicians and patients alike have concerns regarding exposing in vivo implanted metal stapes prostheses to magnetic resonance imaging (MRI) scanners. As MRI scanners become more powerful, the possibility for stapes prosthesis displacement due to ferromagnetic forces increases. It is hypothesized that some metal stapes prostheses may be exposed to powerful MRI scanners without leading to potential adversities for patients. STUDY DESIGN:: Literature review, retrospective case review, and physician survey. SETTINGS:: Tertiary care, University Medical Center. MATERIALS AND METHODS:: A review of the medical literature,a retrospective case review, and a clinical survey were performed. RESULTS:: In the history of stapes prostheses, 1 adverse patient outcome was causally substantiated when a defective stapes prosthesis was exposed to an MRI field. Otherwise, a review of the literature on experiments investigating stapes prostheses and MRI fields revealed a lack of any adverse clinical reports. In addition, 2 physician's surveys revealed no other cases of symptoms or damage to the ears of patients with stapes prostheses that had been exposed to an MRI scanner. CONCLUSION:: All patients with a metallic stapes prosthesis may be sent to the MRI scanner, with the exception of 1 specific defective prosthesis type. The exception is a 1987 accidental mismanufacture of several lots of McGee pistons with a magnetic alloy. Patients with these specifically identified lots of McGee pistons should go to a computed tomographic scanner or be reimplanted with another prosthesis if MRI scans are mandatory. It would be advisable for manufacturers to use nonferromagnetic metals such as titanium for production of future stapes prostheses. PMID- 17704706 TI - Novel therapy for hearing loss: delivery of insulin-like growth factor 1 to the cochlea using gelatin hydrogel. AB - HYPOTHESIS: Local application of recombinant human insulin-like growth factor 1 (rhIGF-1) via a biodegradable hydrogel after onset of noise-induced hearing loss (NIHL) can attenuate functional and histologic damage. BACKGROUND: The biodegradable gelatin hydrogel makes a complex with drugs by static electric charges and releases drugs by degradation of gelatin polymers. We previously demonstrated the efficacy of local rhIGF-1 application via hydrogels before noise exposure for prevention of NIHL. METHODS: First, we used an enzyme-linked immunosorbent assay to measure human IGF-1 concentrations in the cochlear fluid after placing a hydrogel containing rhIGF-1 onto the round window membrane of guinea pigs. Second, the functionality and the histology of guinea pig cochleae treated with local rhIGF-1 application at different concentrations after noise exposure were examined. Control animals were treated with a hydrogel immersed in physiologic saline alone. RESULTS: The results revealed sustained delivery of rhIGF-1 into the cochlear fluid via the hydrogel. The measurement of auditory brainstem responses demonstrated that local rhIGF-1 treatment significantly reduced the threshold elevation from noise. Histologic analysis exhibited increased survival of outer hair cells by local rhIGF-1 application through the hydrogel. CONCLUSION: These findings indicate that local rhIGF-1 treatment via gelatin hydrogels is effective for treatment of NIHL. PMID- 17704709 TI - Effects of Ciprofloxacin/Dexamethasone and Ofloxacin on Tympanic Membrane Perforation Healing. AB - HYPOTHESIS:: Exposure to ciprofloxacin/dexamethasone, but not ofloxacin, prolongs tympanic membrane (TM) healing. BACKGROUND:: Exposure to hydrocortisone has been shown to delay TM wound healing. No published studies have compared the effects of ciprofloxacin/dexamethasone and ofloxacin on TM healing. METHODS:: Noninfected TM perforations were created in 30 rats. The rats were split into three groups, and ciprofloxacin/dexamethasone, ofloxacin, or isotonic sodium chloride solution drops were instilled for 8 days. Tympanic membrane healing was analyzed at specified intervals using photographic documentation verified by a blinded observer. RESULTS:: The isotonic sodium chloride solution control and ofloxacin exposed TMs healed at similar rates. There was a statistically significant delay in TM healing in the ciprofloxacin-/dexamethasone-exposed TMs by postoperative Day 10. However, all TM perforations were healed by postoperative Day 20. CONCLUSION:: Ciprofloxacin/dexamethasone delays healing of experimental TM perforations, but the brief exposure in this study did not cause persistent perforations. PMID- 17704717 TI - Cyclin D1 expression and histopathologic features in vestibular schwannomas. AB - OBJECTIVE: To evaluate cyclin D1 expression in vestibular schwannoma and its relationship with histologic, clinical, and radiologic features. PATIENTS: Twenty one patients with histologically confirmed vestibular schwannoma. INTERVENTION: Immunohistochemistry analysis was performed with anticyclin D1. Histopathologic features studied included Antoni pattern and nuclear and stromal degenerative changes. Clinical charts, audiometric data, and magnetic resonance imaging characteristics were reviewed. MAIN OUTCOME MEASURES: Cyclin D1 expression and its association with histologic, clinical, and radiologic findings. RESULTS: Cyclin D1 expression was found in 52% of cases. Cyclin D1 expression was more frequent in right-sided tumors (p = 0.02) and in tumors with nuclear degenerative changes (p < 0.0001). Patients with negative cyclin D1 expression had longer duration of deafness (p = 0.02) and higher 2,000-Hz hearing thresholds (p = 0.04) than cyclin D1+ patients. CONCLUSION: Cyclin D1 expression, present in nearly half of the cases, may play a role in the development of these tumors. Further studies are needed to fully understand the contributions of histopathologic and immunohistochemical factors to vestibular schwannoma biological activity. PMID- 17704718 TI - Immediate Efficacy of the Canalith Repositioning Procedure for the Treatment of Benign Paroxysmal Positional Vertigo. AB - OBJECTIVE:: To study the immediate efficacy of the canalith repositioning procedure (CRP) in the treatment of benign paroxysmal positional vertigo. PATIENTS:: Thirty-four patients with benign paroxysmal positional vertigo. INTERVENTION:: Eighteen patients were treated with CRP (CRP group); 16 control patients did not receive CRP treatment (non-CRP group). MAIN OUTCOME MEASURES: We compared the success rates of the CRP and non-CRP groups. The treatment was considered successful if it prevented vertigo and dizziness. Patients were evaluated 3 times: immediately posttreatment (the day after the first visit), in the short term (1 wk after treatment), and in the midterm (1 mo after treatment) RESULTS:: Successful outcomes occurred in 12 patients (67%) from the CRP group and in 1 patient (6%) from the non-CRP group as immediate results (p < 0.001), 13 (72%) and 4 patients (25%) in the short term, respectively, (p = 0.007), and 16 (89%) and 14 patients (88%) in the midterm, respectively, (p > 0.05). Among patients in the CRP group who did not report immediate success, 1 patient (6%) reported success after 1 week (short term), and 4 patients (67%) had successful outcomes after 1 month (midterm). CONCLUSION:: The immediate efficacy of CRP supported the canalolithiasis theory. The prognosis of patients with immediate unsuccessful results with CRP was somewhat worse than that for patients without CRP treatment. PMID- 17704721 TI - The High-Frequency/Acceleration Head Heave Test in Detecting Otolith Diseases. AB - OBJECTIVE:: To investigate whether transient, high-acceleration interaural head heaves (translational vestibulo-ocular reflex [tVOR]) could aid in the diagnosis of otolith diseases. STUDY DESIGN:: Prospective cohort study. SETTING:: Tertiary referral center. PATIENTS:: Thirteen patients with symptoms suggestive of otolith diseases and 10 age-matched controls. INTERVENTIONS:: Patients underwent a clinical otoneurologic examination and standard laboratory audiovestibular evaluation, including audiometry, electronystagmography with bithermal caloric, Halmagyi-Curthoys head thrust test with search coils, and vestibular-evoked myogenic potential. All subjects underwent subjective visual vertical (SVV) and tVOR testings. MAIN OUTCOME MEASURES:: Sensitivity (ratio of peak eye to peak head velocities) and velocity gain (ratio of actual to ideal peak eye velocities). RESULTS:: Five of 13 patients showed no abnormality in any tests. Of the remaining 8, 3 (38%) had reduced tVOR responses, whereas 1 (13%) had abnormal SVV. Sensitivity and velocity gains were symmetrically reduced in 2 patients, who had symptoms for 8 and 24 months. A third patient, symptomatic for 7 weeks, had asymmetric reduction of tVOR responses and a deviated SVV. CONCLUSION:: Both head heave and SVV tests detect acute, asymmetric otolith diseases. Subjective visual vertical test relies on imbalance of utricular tone and may not detect bilateral symmetric diseases or partial diseases with central compensation. Our preliminary data in a small group of patients show that measuring the tVOR in a higher and more physiologic range of frequencies may serve as useful adjunct to detect acute and chronic otolith dysfunction and seems to be superior to the SVV in detecting bilateral symmetric or asymmetric otolith diseases. PMID- 17704722 TI - Clinical and Diagnostic Characterization of Canal Dehiscence Syndrome: A Great Otologic Mimicker. AB - OBJECTIVE:: To identify otologic and audiologic characteristics of superior (and posterior) semicircular canal dehiscence (SCD). STUDY DESIGN:: Retrospective case review. SETTING:: Tertiary referral center. PATIENTS:: Sixty-five adult patients were evaluated for SCD; 26 of 65 (35 ears) had dehiscence. INTERVENTION(S):: Otologic examination, high-resolution computerized tomography (CT), air and bone audiometry, tympanometry, acoustic reflex, and vestibular evoked myogenic potential (VEMP). MAIN OUTCOME MEASURE(S):: Imaging demonstrating canal dehiscence, preferentially including Poschel and Stenvers reconstructions. Audiologic findings of pseudoconductive loss, intact ipsilateral stapedial reflex, and abnormally low VEMP thresholds. RESULTS:: The most common presenting complaints were autophony of voice and a "blocked ear" (94%), mimicking patulous eustachian tube, including relief with Valsalva or supine position (50%), but without autophony of nasal breathing. Pseudoconductive loss was found in 86% of dehiscence ears, and 60% (21 of 35) of these ears had better than 0-dB-hearing loss bone conduction thresholds at 250 and/or 500 Hz. Acoustic reflex was present in 89%. Assuming CT as the criterion standard, VEMP resulted in 91.4% sensitivity and 95.8% specificity. One false-positive CT, with abnormal VEMP, resulted in surgical explorations negative for superior SCD but positive for posterior SCD. CONCLUSION:: Semicircular canal dehiscence may present with various symptoms such as autophony, ear blockage, and dizziness/vertigo. A combination of high resolution CT and audiologic testing is recommended for diagnosis. Low-frequency conductive loss with better than 0 dB hearing level (HL) bone conduction threshold and normal tympanometry, with intact acoustic reflexes, are audiologic signs of SCD. Vestibular evoked myogenic potential is highly sensitive and specific for SCD, possibly better than CT. PMID- 17704723 TI - Does packing the eustachian tube impact cerebrospinal fluid rhinorrhea rates in translabyrinthine vestibular schwannoma resections? AB - OBJECTIVE: To calculate cerebrospinal fluid (CSF) leak rates for translabyrinthine (TL), middle cranial fossa (MCF), and retrosigmoid/suboccipital (SO) craniotomies performed for removal of vestibular schwannoma (VS) and analyze whether packing the eustachian tube (ET) in TL VS resections impacts CSF rhinorrhea rates. STUDY DESIGN: Retrospective. SETTING: Tertiary care center. METHODS: Chart review. RESULTS: Three hundred fifty-nine VS resections were reviewed in 356 patients ranging from 10 to 86 years of age. Two hundred thirty one TL, 70 MCF, 53 SO, and 5 combined TL/SO procedures were analyzed. Total CSF leak rates (incisional, otorrhea, and rhinorrhea) were 14.2% for TL, 11.4% for MCF, and 13.2% for SO approaches. Differences in overall CSF leak rates were not statistically significant. For those who underwent TL craniotomies, 2 groups of patients were identified based on whether their ETs were packed during surgery. In 1 group, the incus was removed, the aditus enlarged, the ET packed, and the middle ear filled with muscle. In the second group, the aditus, epitympanum and middle ear were packed without removing the incus, and the ET was not packed. Of 148 patients who had their ET packed, 12 developed CSF rhinorrhea (8.1%). The CSF rhinorrhea rate for patients who did not have ET packing was 5.9% (3 of 51 patients). This difference was not statistically significant (p = 0.80). When Proplast was used to pack the ET (121 patients), the CSF rhinorrhea rate was 5.8%. Unfortunately, this material extruded in 4 of 121 patients (3.3%) and presented clinically as delayed purulent otorrhea. CONCLUSION: Cerebrospinal fluid leak rates were similar in patients undergoing TL, SO, and MCF approaches, and CSF rhinorrhea was not decreased by ET packing. Patients whose ETs are packed with Proplast are at risk for extrusion and otorrhea years after their initial VS resection. PMID- 17704730 TI - Early organ-specific endothelial activation during hemorrhagic shock and resuscitation. AB - Multiple organ dysfunction syndrome (MODS) is a complication of hemorrhagic shock (HS) and related to high morbidity and mortality. Interaction of activated neutrophils and endothelial cells is considered to play a prominent role in the pathophysiology of MODS. Insight in the nature and molecular basis of endothelial cell activation during HS can assist in identifying new rational targets for early therapeutic intervention. In this study, we examined the kinetics and organ specificity of endothelial cell activation in a mouse model of HS. Anesthetized male mice were subjected to controlled hemorrhage to a MAP of 30 mmHg. Mice were killed after 15, 30, 60, or 90 min of HS. After 90 min of hemorrhagic shock, a group of mice was resuscitated with 6% hydroxyethyl starch 130/0.4. Untreated mice and sham shock mice that underwent instrumentation and 90 min of anesthesia without shock served as controls. Gene expression levels of inflammatory endothelial cell activation (P-selectin, E-selectin, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1) and hypoxia-responsive genes (vascular endothelial growth factor and hypoxia-inducible factor 1alpha) were quantified in kidney, liver, lung, brain, and heart tissue by quantitative reverse-transcription-polymerase chain reaction. Furthermore, we examined a selection of these genes with regard to protein expression and localization using immunohistochemical analysis. Induction of inflammatory genes occurred early during HS and already before resuscitation. Expression of adhesion molecules was significantly induced in all organs, albeit to a different extent depending on the organ. Endothelial genes CD31 and VE-cadherin, which function in endothelial cell homeostasis and integrity, were not affected during the shock phase except for VE-cadherin in the liver, which showed increased mRNA levels. The rapid inflammatory activation was not paralleled by induction of hypoxia-responsive genes. This study demonstrated the occurrence of early and organ-specific endothelial cell activation during hemorrhagic shock, as presented by induced expression of inflammatory genes. This implies that early therapeutic intervention at the microvascular level may be a rational strategy to attenuate MODS. PMID- 17704732 TI - Hemorrhage progressively disturbs interalveolar perfusion in the lungs of rats. AB - Acute hemorrhage is often followed by devastating lung injury. However, why blood loss should lead to lung injury is not known. One possibility is that hemorrhage rapidly disturbs the distribution of microvascular perfusion at the alveolar level, which may be a triggering event for subsequent injury. We showed previously that a 30% blood loss in rats caused significant maldistribution of interalveolar perfusion within 45 min (J Trauma 60:158, 2006). In this report, we describe results of further exploration of this phenomenon. We wanted to know if perfusion distribution was disturbed at 15 min, when vascular pressures were significantly reduced by the blood loss, compared with those at 45 min, when the pressures had returned substantially toward normal. We hemorrhaged rats by removing 30% of their blood volume. We quantified interalveolar perfusion distribution by statistically analyzing the trapping patterns of 4-microm diameter fluorescent latex particles infused into the pulmonary circulation 15 (red particles) and 45 min (green particles) after blood removal. We used confocal fluorescence microscopy to digitally image the trapping patterns in sections of the air-dried lungs and used pattern analysis to quantify the patterns in tissue image volumes that ranged from 1,300 alveoli to less than 1 alveolus. LogDI, a measure of perfusion maldistribution, increased from 1.00 +/- 0.15 at 15 min after blood loss to 1.62 +/- 0.24 at 45 min (P < 0.001). These values were 0.86 +/- 0.22 (15 min) and 1.12 +/- 0.24 (45 min) in control rats (P = 0.03). Hemorrhage caused the green (45 min)-to-red (15 min) particle distance to decrease from 35.9 +/- 6.5 to 28.0 +/- 5.1 microm (P = 0.024) and the red-to green particle distance to remain unchanged (30.2 +/- 5.7 microm [red]; 31.5 +/- 10.0 microm [green] [n.s.]). We conclude that hemorrhage caused a progressive increase in interalveolar perfusion maldistribution over 45 min that did not correspond to reduced arterial pressures or altered blood gases. Our particle distance measurements led us to further conclude that this maldistribution occurred in areas that were perfused at 15 min rather than in previously unperfused areas . PMID- 17704733 TI - Toll-like receptor 4 contributes to microvascular inflammation and barrier dysfunction in thermal injury. AB - Systemic and microvascular inflammation plays a key role in the development of multiple organ failure after infection, sepsis, and traumatic injury. Toll-like receptors (TLRs) regulate host responses to pathogens and sterile, injury associated inflammatory responses. We investigated whether TLR-4 contributes to microvascular dysfunction during thermal injury in vivo in anesthetized wild-type or TLR-4 (-/-) mice receiving either a 25% total body surface area full-thickness scald burn or sham treatment on the dorsal skin. Using intravital microscopy, we assessed the hemodynamics and leukocyte dynamics in the mesenteric microvasculature as representative of the splanchnic microcirculation at a site remote from the burn wound. The transvascular flux of fluorescein isothiocyanate albumin across mesenteric venules was measured as an indicator of microvascular permeability. Furthermore, cultured microvascular endothelial cell models were used to evaluate the endothelial-specific mechanisms involved in TLR-4-mediated barrier dysfunction. The results showed significantly elevated microvascular permeability in wild-type mice after burn, whereas this response was markedly attenuated in TLR-4 (-/-) mice. Burn injury also increased leukocyte adhesion in mesenteric venules of wild-type mice, and a blunted leukocyte response was seen in the TLR-4 mice. Treatment of endothelial cell monolayers with burn plasma induced a rapid reduction in the transendothelial electrical resistance measured by electric cell-substrate impedance sensing, indicative of endothelial cell-cell adhesive barrier dysfunction. Reducing expression of TLR-4 with siRNA treatment attenuated this response. Taken together, these data indicate that TLR-4 plays an important role in microvascular leakage and leukocyte adhesion under the inflammatory condition associated with nonseptic thermal injury. PMID- 17704735 TI - Effect of 17beta-estradiol on signal transduction pathways and secondary damage in experimental spinal cord trauma. AB - Because studies have shown that 17beta-estradiol (E2) produces anti-inflammatory effects after various adverse circulatory conditions, we examined whether administration of E2 before spinal cord injury (SCI) has any salutary effects in reducing SCI. Spinal cord injury was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. To gain a better insight into the mechanism of action of the anti-inflammatory effects of E2, the following end points of the inflammatory process were evaluated: (1) spinal cord inflammation and tissue injury (histological score); (2) neutrophil infiltration (myeloperoxidase activity); (3) expression of iNOS, nitrotyrosine, and COX-2; (4) apoptosis (terminal deoxynucleotidyltransferase-mediated UTP end labeling staining and Bax and Bcl-2 expression); and (5) tissue TNF-alpha, IL-6, IL-1beta, and monocyte chemoattractant protein 1 levels. In another set of experiments, the pretreatment or posttreatment with E2 significantly ameliorates the recovery of limb function (evaluated by motor recovery score). To elucidate whether the protective effects of E2 were mediated via the estrogen receptors, we investigated the effect of an estrogen receptor antagonist, ICI 182,780, on the protective effects of E2. ICI 182,780 (500 microg/kg, s.c., 1 h before treatment with E2) significantly antagonized the effect of the E2 and abolished the protective effect against SCI. Taken together, our results clearly demonstrate that administration of E2 before SCI reduces the development of inflammation and tissue injury associated with spinal cord trauma. PMID- 17704736 TI - Molecular profiling and genomic microarrays in prostate cancer. AB - In the present review article a global approach regarding the usefulness of genomic microarrays in prostate cancer management, is attempted. Cancer is a multistep process of mutations in key regulatory genes and epigenetic alterations that result in loss of balanced gene expression. A complete knowledge of the interaction between the genetic variability of the neoformation (tumor profiling) and the genetic variability of the host (inherited genome profiling), will be able to determine the better strategy against the cancer and the less toxicity for the patient. Alterations in the sequence of the hormone binding domain of the androgen receptor as well as mutations in some genes, determine radioresistance and resistance or sensitivity to some chemotherapeutic drugs. New therapies using monoclonal antibodies directed against specific extracellular binding domains of some receptors are based on molecular alterations observed in tumors. PMID- 17704737 TI - Identification of new DNA markers of endometrial cancer in patients from the Ukrainian population. AB - AIM: To identify clinically significant molecular markers of endometrial cancer. MATERIALS AND METHODS: Cancer and normal endometrial tissue samples from 20 patients of the Gynecology Clinic of Odessa State Medical University (Odessa, Ukraine) with confirmed endometrial cancer were compared for SSR and ISSR polymorphisms. Identified polymorphic fragments from anonymous genome regions situated between microsatellite repeats underwent direct DNA sequencing; analysis of their homology to sequences from human genome database has been performed. RESULTS: No significant variability for the microsatellite loci adjacent to the E2F1, BAX, TCF7L2, C-MYC, WNT1, FES, DCC, P27, THRA, APC, CYP19 and P53 genes was detected. Search for new molecular markers of endometrial cancer within anonymous DNA sequences located between microsatellite repeats revealed 100 bp and 174 bp polymorphic fragments. These fragments were detected correspondingly in 60% and 35% of patients. 100 bp fragment appeared to be homologous to a region within the NFKB gene, 174 bp fragment - to a sequence within the DDR1 gene. CONCLUSIONS: NFKB1 and DDR1 genes may be regarded as potential markers for some types of endometrial cancer. This is a first report about possible association of these genes with endometrial cancer. PMID- 17704738 TI - Plasmid encoding matrix protein of vesicular stomatitis viruses as an antitumor agent inhibiting rat glioma growth in situ. AB - AIM: Oncolytic effect of vesicular stomatitis virus (VSV) has been proved previously. Aim of the study is to investigate glioma inhibition effect of Matrix (M) protein of VSV in situ. MATERIALS AND METHODS: A recombinant plasmid encoding VSV M protein (PM) was genetically engineered, and then transfected into cultured C6 gliomas cells in vitro. C6 transfected with Liposome-encapsulated PM (LEPM) was implanted intracranially for tumorigenicity study. In treatment experiment, rats were sequentially established intracranial gliomas with wild-typed C6 cells, and accepted LEPM injection intravenously. Possible mechanism of M protein was studied by using Hoechst staining, PI-stained flow cytometric analysis, TUNEL staining and CD31 staining. RESULTS: M protein can induce generous gliomas lysis in vitro. None of the rats implanted with LEPM-treated cells developed any significant tumors, whereas all rats in control group developed tumors. In treatment experiment, smaller tumor volume and prolonged survival time was found in the LEPM-treated group. Histological studies revealed that possible mechanism were apoptosis and anti-angiogenesis. CONCLUSION: VSV-M protein can inhibit gliomas growth in vitro and in situ, which indicates such a potential novel biotherapeutic strategy for glioma treatment. PMID- 17704740 TI - Experimental study of the efficacy of combined use of cancer vaccine and interferon. AB - AIM: To study in in vivo model the efficacy of combined scheme of administration of cancer vaccine (CV) and interferon (IFN). MATERIALS AND METHODS: Lewis lung carcinoma (LLC) was transplanted to male C57Bl mice. For treatment, CV prepared from LLC cells with the use of cytotoxic lectins of B. subtilis B-7025, and preparation of murine IFN-alpha were used. Therapeutic effect was evaluated by measurement of tumor volume and analysis of average life span (ALS) of treated animals. Immunologic study included determination of antitumor cytotoxicity of T lymphocytes (CTL) and natural killer (NK) cells by radiometric method, functional activity of peritoneal macrophages (MP) - by colorimetric test with nitroazole blue, and evaluation of titers of tumor necrosis factor (TNF) and interleukins-1 and -2 (IL-1, 2). RESULTS: It has been shown that the use of IFN preparation significantly elevated efficacy of vaccine therapy of solid form of LLC: duration of latent period of tumor growth elevated by 25%, ALS - by 28%, index of tumor growth inhibition - by 35-40%. Upon combined use of CV and IFN, significant activation of the cells - effectors of nonspecific immune defense (MP), and specific one (CTL) was observed. CONCLUSION: The obtained results evidence on perspectiveness of the development of combined schemes of administration of CV and IFN for elevation of the efficacy of vaccine therapy. PMID- 17704739 TI - Antitumor activity of polyphenolic extract of Ichnocarpus frutescens. AB - AIM: Phytochemical and dietary antioxidants are known to decrease the risk of many diseases such as cancer and cardiovascular diseases. In this study polyphenolic extract (PPE) of leaves of Ichnocarpus frutescens was evaluated for antitumor activity in vivo. MATERIALS AND METHODS: Murine Ehrlich ascites carcinoma (EAC) model was used to assess PPE antitumor activity in vivo. PPE cytotoxicity was determined in vitro in U-937 monocytoid leukemia and K-562 erythroleukemia cell lines. PPE also have been assessed for the free radical scavenging activity against superoxide and nitric oxide radicals. Acute oral toxicity was performed by acute toxic classic method. The total phenolics content was quantified by the Folin-Ciocalteu method. RESULTS: Results of in vivo study showed a significant decrease in tumor volume, viable tumor cell count and a significant increase of life span in the PPE treated group compared to untreated one: the life span of PPE treated animals increased by 53.41% (50 mg PPE/kg) and 73.95% (100 mg PPE/kg). PPE (5, 10 and 20 microg/mL) effectively inhibits in vitro proliferation of U-937 and K-562 cell lines. PPE exhibited pronounced radical scavenging activity with an inhibitory concentration (IC(50)) value of 167.46 microg/mL and 158.52 microg/mL against superoxide and nitric oxide radicals, respectively. CONCLUSION: PPE of Ichnocarpus frutescens possesses strong free radical scavenging activity and anti-tumor activity in vitro and in vivo. PMID- 17704741 TI - Effects of ethyl-esterization, chain-lengths, unsaturation degrees, and hyperthermia on carcinostatic effect of omega-hydroxylated fatty acids. AB - AIM: To evaluate promotive effect of hyperthermia on the carcinostatic activity of synthesized omega-hydroxy fatty acids (omega HFAs) and their ethylesters agaist Ehrlich ascites tumor (EAT) cells. METHODS: EAT cells were cultured with either omegaHFAs or their ethylester derivatives in a water bath at either 37 degrees C or 42 degrees C for 30 min, followed by incubation in a CO2 incubator for 20 or 72 h. Mitochond-rial dehydrogenase-based WST-1 assay and trypan blue dye exclusion assay were then conducted after incubation. Morphological changes were observed by scanning electron microscopy (SEM). RESULTS: Omega-HFA having a saturated 16-carbon straight-chain (omega H16:0) was the most carcinostatic (at 37 degrees C - viability level: 60.0%; at 42 degrees C - 49.6% (WST-1)) among saturated and unsaturated omegaHFAs with 12, 15 or 16 carbon atoms, when administrated to EAT cells at 100 microM for 20 h. Carcinostatic activity was markedly enhanced by ethyl-esterization of saturated fatty acids, such as omegaH16:0 (at 37 degrees C - 42.3%; at 42 degrees C - 11.2%, ibid) and omegaH15:0 (at 37 degrees C - 74.6%; at 42 degrees C - 25.3%, ibid), and their unsaturated counterparts were extremely effective only in combination with hyperthermia. Prolongation of the incubation period to 72 h at the same concentration increased appreciably their carcinostatic effect (omega H16:0 ethylesther: 1.3%; omegaH15:0 ethylesther: 8.0%). These values were also supported by dye exclusion assay. The carcinostatic activity enhanced more markedly by hyperthermia (1.2%; 2.1%, ibid). SEM shows that omegaH16:0 ethylester exposed EAT cells underwent extensive injury, such as deformation of cell structure or disappearance of microvilli. CONCLUSIONS: omega H16:0 ethylester possesses high carcinostatic activity in vitro in combination with hyperthermia and may be utilized as potent anticancer therapeutic agent. PMID- 17704742 TI - Thromboelastographic profiles as a tool for thrombotic risk in digestive tract cancer. AB - BACKGROUND: Quantification of the magnitude of thrombotic risk associated with malignancy and with anti-cancer therapy is indispensable to use anticoagulant drugs which selectively interfere with haemostatic mechanisms protecting patients from venous thromboembolism (VTE) and probably from tumor progression. However, none of activation coagulation markers has any predictive value for the occurrence of the thrombotic events in one individual patient. Current clotting methods can't reveal the overall dynamic clot formation; in contrast thromboelastographic methods specifically assess overall coagulation kinetics and its strength in whole blood. AIM: Objective of study was to evaluate if the activation of coagulation as eventually revealed by ROTEM thromboelastometry could assess an hypercoagulable state in surgical neoplastic patients. PATIENTS AND METHODS: Fifty consecutive patients with carcinoma of the digestive tract in preoperative period (23 M, 27 F aging 61.5 (45-79 years) and 147 healthy subjects (71 M, 76 F) were studied. A recent thromboelastometric method based on thrombelastography after Hartert was employed. Measurements were performed on ROTEM Coagulation Analyzer. The continuous coagulation data from 50 min course were transformed into dynamic velocity profiles of WB clot formation. RESULTS: Standard parameters (CT, CFT, MCF) of cancer patients were similar to controls. CT (in cancer patients): females 50 s (38.3-58.7), males 50 s (42-71.2) vs 51 s (42-59), p = 0.1210 / 53 s (42-74.8), p = 0.1975 (in controls). CFT (in cancer patients): females 72 s (32- 92.4), males 80 s (50.2- 128.7) vs 78 s (62-100), p = 0.0128 / 80 s (59-124.4), p = 0.9384 (in controls). MCF (in cancer patients): females 70 mm (59.9-82.5), males 63 mm (56-73.7) vs 69 mm (59-95.8), p = 0.9911 / 69 mm (53.6-90), p = 0.0135 (in controls). Females showed a higher MaxVel when compared to males. The MaxVel was increased in cancer patients: females 19 mm /100 s (14.3-49.5) males 18 mm / 100 s (11-27) vs 15 mm 100 s (11.8-22), p < 0.001 / 13 mm / 100 s (10-21.8), p < 0.001 in controls. The t-MaxVel was shortened in cancer patients: females 65s (48.6-112.8), males 81s (50.1-135.9) vs 115s (56.8-166), p < 0.001 / 115 s (59.8-180.8), p = 0.0002 in controls. The AUC was increased in cancer patients: females 6451 mm 100(5511-8148), males 5984 mm 100 (5119-6899) vs 5778 mm 100 (4998-6655), p < 0.001 / 5662 mm 100 (4704-6385), p = 0.0105. CONCLUSION: Unlike other assays measuring variations in a single component during coagulation, the thrombelastographic method records a profile of real-time continuous WB clot formation, and may provide extensive informations on haemostasis in neoplastic patients before surgery. PMID- 17704743 TI - Molecular cytogenetic aberrations in patients with multiple myeloma studied by interphase fluorescence in situ hybridization. AB - BACKGROUND: Multiple myeloma (MM) is an incurable hematological disorder characterized by the accumulation of malignant plasma cells within the bone marrow (BM). The clinical heterogeneity of MM is dictated by the cytogenetic aberrations present in the clonal plasma cells (PCs). Cytogenetic studies in MM are hampered by the hypoproliferative nature of plasma cells in MM. Therefore, fluorescence in situ hybridization (FISH) analysis combined with magnetic activated cell sorting (MACS) is an attractive alternative for evaluation of numerical and structural chromosomal changes in MM. METHODS: Interphase FISH studies with three different specific probes for the regions containing 13q14.3(D13S319), 14q32(IGHC/IGHV) and 1q12(CEP1) were performed in 48 MM patients. Interphase FISH studies with LSI IGH/CCND1, LSI IGH/FGFR3, and LSI IGH/MAF probes were used to detect t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16)(q32;q23) in patients with 14q32 rearrangement. RESULTS: Molecular cytogenetic aberrations were found in 40 (83.3%) of the 48 MM patients. 13 patients (27.1%) simultaneously had 13q deletion/monosomy 13[del(13q14)], illegitimate IGH rearrangement and chromosome 1 abnormality. Del (13q14) was detected in 21 cases (43.7%), and illegitimate IGH rearrangements in 29 (60.4%) including 6 with t (11;14) and 5 with t(4;14). None of 9 patients with illegitimate IGH rearrangements and without t(11;14) or t(4;14) we detected had t(14;16)(q32;q23). 24 of the 48 MM patients (50%) had chromosome 1 abnormalities. Among 21 patients with del (13q14), 15 patients had Amp1q12;16 had IgH rearrangements. Whereas, among 27 cases without del (13q14), 8 had Amp1q12; 13 had IgH rearrangements. There was a strong association between del(13q14) and Amp1q12 ( = 8.26, p < 0.01), and between del (13q14) and IgH rearrangement ( = 3.88, p < 0.05). CONCLUSION: 13q deletion/monosomy 13, IGH rearrangement and chromosome 1 abnormality are frequent in MM. They are not randomly distributed, but strongly interconnected. Interphase FISH technique combined with MACS using CD138-specific antibody is a highly sensitive technique at detecting molecular cytogenetic aberrations in MM. PMID- 17704744 TI - Survivin expression in ovarian cancer. AB - AIM: To examine the expression of survivin in benign ovarian tumors, ovarian carcinomas of different stages. METHODS: We screened the expression of survivin mRNA by reverse transcription polymerase chain reaction in 114 ovarian tissue samples. Quantitative real-time PCR was used to estimate survivin mRNA levels in the samples with positive survivin expression. RESULTS: No survivin mRNA was expressed in all normal ovarian specimens, while it appeared in 73% of ovarian carcinomas, 47% of borderline ovarian carcinomas and 19% of benign ovarian tumors. The survivin mRNA expression rate was positively associated with clinical stage (P = 0.026) and differentiation grade (P = 0.049). There was notably statistically significant difference in the survivin mRNA expression rate dependent on different histological types (serous, mucinous, endometrioid, P = 0.008), but not - dependent on lymph node metastasis (P = 0.921) and ascites (P = 0.87). In tissues with positive expression of survivin, we also found that mean survivin mRNA expression levels were higher in ovarian carcinomas than that in benign ovarian tumors and borderline ovarian carcinoma tissues (P < 0.001). Among ovarian carcinomas, the high survivin mRNA expression levels correlated with the clinical stages, differentiation grade, lymph node metastasis, but not - with ascites and histological type. CONCLUSION: Our study suggest that survivin is associated with progression of ovarian carcinoma. PMID- 17704745 TI - Combined antiproliferative activity of imatinib mesylate (STI-571) with radiation or cisplatin in vitro. AB - Little is known about the interaction of novel anticancer drugs with other treatment modalities. THE AIM of this study was to examine the effect of combining imatinib mesylate (STI-571) with radiation or cisplatin on the survival of two human solid tumor cell lines - SKNMC cells derived from Ewing sarcoma and breast cancer MCF-7 cells. METHODS: Cell proliferation was determined using the sulphorodamine B cytotoxicity assay. Cell cycle analysis was performed with flow cytometry. Apoptosis was determined using a commercial cell death ELISA plus kit. Phosphorylated AKT, which has been suggested to be involved in radiation resistance, was detected by Western blot analysis. RESULTS: Exposure of SKNMC cells to STI-571 resulted in a dose-dependent antiproliferative effect and a decrease in phosphorylated AKT expression. There was no evidence of apoptosis. The combination of STI-571 with radiation or cisplatin had an additive antiproliferative effect in SKNMC cells (60% reduction in cell number). A similar effect was observed in human MCF-7 breast cancer cells. CONCLUSION: STI-571 improves the outcome of cisplatin or irradiation treatment in vitro. AKT pathway may play a role in the additive effect of STI-571 and irradiation. PMID- 17704746 TI - Serum levels of sFas and sFasL during chemotherapy of lung cancer. AB - THE AIM of this study was to assess the clinical usefulness of determination of soluble Fas (sFas) and soluble Fas Ligand (sFasL) during chemotherapy of lung cancer. METHODS: The study included 80 patients (69 males; 11 females; mean age 64 years; 48 with non-small cell lung cancer-NSCLC, 32 with small cell lung cancer-SCLC). The control group consisted of 15 healthy volunteers. The peripheral blood samples were taken before and after 4 cycles of chemotherapy. sFas and sFasL levels were assessed by Elisa method. RESULTS: The serum sFas and sFasL levels observed at the end of the chemotherapy were higher in all patients with lung cancer compared to healthy volunteers. The levels of sFas and sFasL were higher after chemotherapy than before therapy. The levels of sFasL were significantly higher in SCLC patients than in NSCLC ones. There were no significant differences in serum sFasL levels in relation to clinical stage of lung cancer. After chemotherapy the levels of sFas were higher in patients with metastases. There were no significant differences in serum sFasL levels in relation to response to therapy. At the end of the therapy the serum levels of sFas were higher in Partial Response group than in Progressed patients. Before chemotherapy the levels of sFas were higher in Progressive Disease group than in No Change one. The levels of sFas observed after chemotherapy were higher in Partial Response group than in No Change one. CONCLUSION: Determination of serum sFas and sFasL levels can be useful in clinical practice, but their practical significance needs further studies. PMID- 17704747 TI - Autogeneic rna-electroporated CD40-ligand activated b-cells from hepatocellular carcinoma patients induce CD8+ T-cell responses ex vivo. AB - Since dendritic cells (DCs) constitute only 0.1-0.5% of human peripheral blood mononuclear cells (PBMCs), and generation of DCs from monocytes or stem cells is difficult and expensive, we choose B-lymphocytes as an alternative, cost effective source of antigen presenting cells (APC). AIM: To induce specific CTLs response ex vivo by CD40L activated B-cells (CD40-B) transfected with hepatocellular carcinoma (HCC) total RNA. METHODS: To induce CD40-B PBMCs of patients with HCC were isolated by Ficoll technique and cultured in RMPI 1640 supplemented with 10% fetal calf serum (FCS), sCD40L (2 microg/ml), recombinant human interleukin-4 (IL-4) (4 ng/ml). The expression of CD80 and CD86 was evaluated by flow cytometry. The level of interleukin-12 (IL-12) produced by cultured B-lymphocytes was measured using enzyme-linked immunosorbent assay (ELISA). HCC patient's T-lymphocytes were obtained from PBMCs cultured in RMPI 1640 supplemented with 10% FCS, 2 ng/mL IL-4 and 10 ng/ml IL-7. CD40-B transfected with tumor total RNA isolated from HCC cells were used to induce specific CTL proliferation. The level of IFN-gamma was measured using ELISA and the expression of CD8 was determined by FCAS. Specific cytotoxicity was measured using MTT method. RESULTS: The results show that the activated B-lymphocytes were easily expandable and formed large clones, and a high expression of CD80/CD86 and a high IL-12 secretion by CD40-B was registered. CD40-B transfected with tumor total RNA can induce CTLs to express CD8 and generate IFN-gamma at high levels. Compared to the control group, the specific cytotoxicity of CTLs was up regulated. CONCLUSION: These findings demonstrate that CD40-B-cells electroporated with total RNA derived from carcinoma cells can be used as alternative APC for the induction of antigen-specific CD8(+) T-cell responses, which might be used in HCC immunotherapy. PMID- 17704748 TI - Intensive cyclic chemotherapy and transplantation of autologous peripheral blood progenitor cells (PBPC) or whole blood in high-risk breast cancer - follow up at 10 years. AB - AIM: The main aim of our paper is to contribute to objectification of currently widely discussed results of overall survival (OS), disease free survival (DFS) and time from relapse to tumor progression (TTP) in women with breast cancer. METHODS: Forty consecutive patients fulfilling the eligibility criteria were admitted to the study. Fifty-six women were included in the control group. All patients received 6 cycles of adjuvant intensive cyclic combined chemotherapy with epirubicin 150 mg/m(2) and cyclophosphamide 1250 mg/m(2) (EC) applied each 14 days. To overcome haematological toxicity transplantations of autologous peripheral blood progenitor cells (PBPCs) or whole blood enriched of PBPC were used. RESULTS: We found statistically significant difference in OS regardless of the stage of the disease to the benefit of women treated by intensive cyclic EC chemotherapy when compared with the control group. In evaluation of DFS no statistically significant difference was found in survival between the control group and the group with all stages of the disease. TTP in women without relation to the stage was statistically significantly longer than in the control group. CONCLUSION: In our study intensive cyclic EC chemotherapy did not show better curative effect when compared with conventional dosage chemotherapy. PMID- 17704749 TI - The effect of electromagnetic field and local inductive hyperthermia on nonlinear dynamics of the growth of transplanted animal tumors. AB - AIM: To examine the effects of electromagnetic field with amplified magnetic component and local inductive hyperthermia (IH) on nonlinear dynamics of the growth of animal tumors. MATERIALS AND METHODS: Guerin carcinoma, Lewis lung carcinoma, sarcoma 45, Walker 256 carcinosarcoma and Pliss lymphosarcoma were studied. The animal tumors were exposed inside of loop aerial, 3 cm in diameter locally for 30 min. Parameters of electromagnetic irradiation (EI): frequency 40 MHz, magnetic intensity 72 A/m, electric intensity 200 V/m and the output power 50 W. The temperature measured by immersion of thermocouple inside the center of the tumor didn't exceed 38.5-39.5 degrees C. Nonlinear dynamics of the growth of animal tumors was analyzed by autocatalytic equation. The heterogeneity of ultrasonic image of the tumor was analyzed by Moran spatial autocorrelation. RESULTS: The strongest inhibition effect under the influence of EI was in Pliss lymphosarcoma and sarcoma 45. The growth stimulation of animal tumors after EI was recorded in Walker 256 carcinosarcoma. The use of mild IH increased the blood flow in the tumor of Guerin carcinoma. CONCLUSION: These results are important for clinical application because they testify the necessity of optimization of schemes for local EI during anticancer neoadjuvant therapy with the use of drugs or magnetic nanoparticles. The use of mild IH as a basis for the monotherapy of malignant tumors is not expedient. PMID- 17704751 TI - Skin deep: report from the annual meeting of the British Society for Investigative Dermatology. PMID- 17704750 TI - A phyllodes tumor of the urinary bladder in a rat. AB - AIM: The aim of this short communication was to describe a case of phyllodes tumor of the urinary bladder discovered in a female Fisher 344 rat that died during an experimental protocol to induce and study urothelial lesions by N-butyl N-(4-hydroxybutyl) nitrosamine (BBN). METHODOLOGY: From a group of several female rats exposed to BBN via drinking water over the course of 20 weeks, one animal died. At necropsy, a solid mass was identified in the urinary bladder lumen, with a diameter of 0.8 x 0.7 cm. This tumor was processed for histopathological examination and Feulgen coloration. RESULTS: Microscopically, the mass in the bladder was observed to be a phyllodes tumor. DNA content measured by image analysis of a Feulgen-stained section of the tumor and stroma cells displayed diploid DNA content in both components of the tumor. CONCLUSION: This is the first reported phyllodes tumor in a rat's urinary bladder. The exact prognosis and histogenesis of phyllodes tumors of the urinary bladder remains to be determined by the accumulation of data from additional cases. PMID- 17704752 TI - Radio-responsive TRAIL gene therapy for malignant gliomas. PMID- 17704753 TI - Reversal of drug resistance of hepatocellular carcinoma cells by adenoviral delivery of anti-ABCC2 antisense constructs. AB - Human cancers are characterized by a high degree of drug resistance. The multidrug resistance transporters MDR1-P-glycoprotein (ABCB1) and ABCC2 (MRP2) are expressed in a variety of human cancers, including hepatocellular carcinoma (HCC). The ABCC2 gene encodes a membrane protein involved in the ATP-dependent transport of conjugates of lipophilic substances. In this study we analyzed the effect of an ABCC2 antisense construct on the chemosensitization of HepG2 cells. Adenoviral vectors were constructed to allow an efficient expression of anti ABCC2 antisense constructs. The effective target sequence comprised nucleotides 2543-2942 of the human ABCC2 cDNA. Adenoviral delivery of the ABCC2 antisense construct resulted in a reduced IC(50) for doxorubicin (12-fold), vincristine (50 fold), cisplatin (25-fold) and etoposide (VP-16) (25-fold). The adenoviral delivery of the ABCC2 antisense construct was so efficient that chemosensitization of HepG2 cells could even be demonstrated in mass cell cultures without a selection of transduced cells for single ABCC2 antisense expressing HCC cell clones. After transfection of the ABCC2 antisense-expressing construct, HepG2 cells had significantly reduced ABCC2 mRNA and ABCC2 protein levels. Transduction of the ABCC2 antisense-expressing construct into HepG2 cells resulted in the accumulation of the high-affinity ABCC2 substrate Fluo-3. HepG2 tumors stably transfected with an anti-ABCC2 antisense construct regressed significantly in nude mice upon vincristine treatment. In addition, significant tumor regression was also observed when adenovirus-expressing anti-ABCC2 antisense construct was directly injected into HepG2 tumors in nude mice. Our study demonstrates the specific reversal of ABCC2-related drug resistance in adenovirus-transduced HepG2 cells and in HepG2 tumors in nude mice expressing this ABCC2 antisense construct. PMID- 17704754 TI - Coexpression of Flt3 ligand and GM-CSF genes modulates immune responses induced by HER2/neu DNA vaccine. AB - DNA vaccine and dendritic cells (DCs)-based vaccine have emerged as promising strategies for cancer immunotherapy. Fms-like tyrosine kinase 3-ligand (Flt3L) and granulocyte-macrophage-colony-stimulating factor (GM-CSF) have been exploited for the expansion of DC. It was reported previously that combination of plasmid encoding GM-CSF with HER2/neu DNA vaccine induced predominantly CD4(+) T-cell mediated antitumor immune response. In this study, we investigated the modulation of immune responses by murine Flt3L and GM-CSF, which acted as genetic adjuvants in the forms of bicistronic (pFLAG) and monocistronic (pFL and pGM) plasmids for HER2/neu DNA vaccine (pN-neu). Coexpression of Flt3L and GM-CSF significantly enhanced maturation and antigen-presentation abilities of splenic DC. Increased numbers of infiltrating DC at the immunization site, higher interferon-gamma production, and enhanced cytolytic activities by splenocytes were prominent in mice vaccinated with pN-neu in conjunction with pFLAG. Importantly, a potent CD8(+) T-cell-mediated antitumor immunity against bladder tumors naturally overexpressing HER2/neu was induced in the vaccinated mice. Collectively, our results indicate that murine Flt3L and GM-CSF genes coexpressed by a bicistronic plasmid modulate the class of immune responses and may be superior to those codelivered by two separate monocistronic plasmids as the genetic adjuvants for HER2/neu DNA vaccine. PMID- 17704755 TI - A phase I trial of intravenous infusion of ONYX-015 and enbrel in solid tumor patients. AB - ONYX-015 is an attenuated chimeric human group C adenovirus, which preferentially replicates in and lyses tumor cells that are p53 negative. The purpose of this phase I, dose-escalation study was to determine the safety and feasibility of intravenous infusion with ONYX-015 in combination with enbrel in patients with advanced carcinoma. Enbrel is a recombinant dimer of human tumor-necrosis factor (TNF)-alpha receptor, previously shown to reduce the level of functional TNF. Nine patients, three in each cohort received multiple cycles of ONYX-015 infusion (1 x 10(10), 1 x 10(11) and 1 x 10(12) vp weekly for 4 weeks/cycle) in addition to subcutaneous enbrel (only during cycle 1) injections per FDA-indicated dosing. Of the nine patients, four had stable disease. No significant adverse events were attributed to the experimental regimen, confirming that enbrel can be safely administered along with oncolytic virotherapy. Two of the three patients in cohort 3 had detectable viral DNA at days 3 and 8 post-ONYX-015 infusion. Their detectable circulating viral DNA was markedly higher during cycle 1 (with enbrel coadministration) as compared with cycle 2 (without enbrel) at the same time points. Area under the curve determinations indicate a marked higher level of TNF alpha induction and accelerated clearance at cycle 2 in the absence of enbrel. Further assessment is recommended. PMID- 17704756 TI - Loss of heterozygosity identifies genetic changes in chronic myeloid disorders, including myeloproliferative disorders, myelodysplastic syndromes and chronic myelomonocytic leukemia. AB - This study evaluates changes in genetic loci of chronic myeloid disorders using loss of heterozygosity (LOH) techniques. We present the combined results of three experiments. First, examination of a panel of genetic loci in groups of myeloproliferative disorders was evaluated. The second experiment involved microdissection of megakaryocytes from myeloproliferative disorders and comparison of their genetic changes to surrounding neoplastic marrow elements. Finally, we compared results of LOH studies of myeloproliferative disorders to those of myelodysplastic syndromes and chronic myelomonocytic leukemia. A total of 41 bone marrow biopsies were evaluated. Twenty-seven were myeloproliferative disorders (11 chronic idiopathic myelofibrosis, 11 essential thrombocythemia, 5 polycythemia vera). The remaining cases consisted of myelodysplastic syndromes (total=5; RAEB-1=2; RAEB-2=2; MDS, not otherwise specified=1) and chronic myelomonocytic leukemia (n=8). The abnormalities in myeloproliferative disorders were distributed as follows: D7S2554-4/14 (5/14); D8S263-4/15 (5/15); D9S157-5/15 (5/15); D9S161-7/17 (6/17); D13S319-5/14 (4/14); TP53-5/16 (5/16); D20S108-4/15 (4/15). In 75% cases diagnosed as essential thrombocythemia (6/8), both cases of polycythemia vera (2/2), and 29% cases of chronic idiopathic myelofibrosis (2/7), there were genetic differences between the megakaryocytes and the surrounding marrow. These results suggest that in some cases, megakaryocytes have different clonal abnormalities than surrounding hematopoietic tissue. The genetic profiles of myeloproliferative disorders had several differences from those of myelodysplastic syndromes. Although different from both, chronic myelomonocytic leukemia appeared more similar to myeloproliferative disorders using these techniques. PMID- 17704757 TI - Reversible tetracycline staining of adult dentition in the treatment of chronic blepharitis. PMID- 17704758 TI - Bilateral Group A streptococcal endogenous endophthalmitis following routine gynaecological surgery. PMID- 17704759 TI - Characteristics of and risk factors for contact lens-related microbial keratitis in a tertiary referral hospital. AB - AIM: A retrospective case-control study was conducted at a tertiary referral hospital to determine the characteristics of and risk factors for contact lens (CL) related presumed microbial keratitis. METHODS: Two hundred and ninety-one cases of presumed microbial keratitis were retrospectively identified over a 2 year period. Records were reviewed for a history of CL wear and, where identified, CL, demographic, and clinical data were collected. Lens wearing controls (n=186) were identified by a community telephone survey. Multiple logistic regression estimated risk factors for infection and vision loss. RESULTS: Ninety-nine (34%) new cases of presumed microbial keratitis were associated with CL wear. Overnight soft CL use was associated with an increased risk of infection compared to daily disposable CL wear (odds ratio (OR): 8.03, 95% confidence interval (CI): 1.82-35.46). Compared with older CL wearers, 15-24 year olds had a 3.5 times greater risk of infection (OR, 95% CI: 1.7-7.4). Of the 84 cases with available data, 24 (29%) lost two or more lines of best-corrected visual acuity. Delaying treatment by 49-72 h had a 4.5 times (OR, 95% CI: 1.4 14.9) greater risk of visual loss compared to seeking treatment early. Of the 99 cases of infection, 88 were scraped and 78% (69/88) of these returned a positive culture. Gram-positive bacteria were the predominant causative organisms. CONCLUSION: Overnight use of CL and youth carry a greater risk of infection. Practitioners should reinforce the importance of proper CL care at all times, and early presentation following the onset of symptoms. PMID- 17704760 TI - Peripheral corneal ulceration as a complication of silicon punctal plug: a case report. PMID- 17704761 TI - Enzymatic vitreolysis with recombinant microplasminogen and tissue plasminogen activator. AB - PURPOSE: To generate microplasmin (microPlm) using recombinant microplasminogen (microPlg) and recombinant tissue plasminogen activator (rt-PA) before intravitreous injection and to investigate the efficacy of microPlm in inducing posterior vitreous detachment (PVD). METHODS: Forty-eight female or male New Zealand white rabbits were randomized into three groups. Recombinant human microPlg was incubated with rt-PA with a 200:1 molar ratio at 37 degrees C for 40 min. The right eyes of groups 1, 2, and 3, were injected with 0.5, 1.0, and 1.5 U microPlm in 0.1 ml respectively, and 0.1 ml balanced salt solution (BSS) was injected into the left eye as controls. Scanning electron microscopy (SEM), gross specimen examination, B-ultrasonography and optical coherence tomography (OCT) were performed to detect vitreoretinal interface. RESULTS: Over eighty percent of recombinant human microPlg could be activated to active microPlm by rt-PA after 40 min incubation. Complete PVD was found at vitreous posterior pole of microPlm treated eyes without morphological change of retina. Complete PVD of 25, 75, and 87.5% rabbit eyes was induced by 0.5, 1.0 and 1.5 U recombinant microPlm respectively on day 1. The remnants of vitreous cortex at the posterior pole were dependent on the concentration of microPlm. Among the four approaches for detecting PVD, SEM, gross specimen examination, and B-ultrasonography were more effective methods than OCT. CONCLUSION: Intravitreous injection of 1.5 U microPlm can effectively induce complete PVD in rabbit eyes on day 1 without morphological change of retina. PMID- 17704762 TI - Mechanism of chloride interaction with neurotransmitter:sodium symporters. AB - Neurotransmitter:sodium symporters (NSS) have a critical role in regulating neurotransmission and are targets for psychostimulants, anti-depressants and other drugs. Whereas the non-homologous glutamate transporters mediate chloride conductance, in the eukaryotic NSS chloride is transported together with the neurotransmitter. In contrast, transport by the bacterial NSS family members LeuT, Tyt1 and TnaT is chloride independent. The crystal structure of LeuT reveals an occluded binding pocket containing leucine and two sodium ions, and is highly relevant for the neurotransmitter transporters. However, the precise role of chloride in neurotransmitter transport and the location of its binding site remain elusive. Here we show that introduction of a negatively charged amino acid at or near one of the two putative sodium-binding sites of the GABA (gamma aminobutyric acid) transporter GAT-1 from rat brain (also called SLC6A1) renders both net flux and exchange of GABA largely chloride independent. In contrast to wild-type GAT-1, a marked stimulation of the rate of net flux, but not of exchange, was observed when the internal pH was lowered. Equivalent mutations introduced in the mouse GABA transporter GAT4 (SLC6A11) and the human dopamine transporter DAT (SLC6A3) also result in chloride-independent transport, whereas the reciprocal mutations in LeuT and Tyt1 render substrate binding and/or uptake by these bacterial NSS chloride dependent. Our data indicate that the negative charge, provided either by chloride or by the transporter itself, is required during binding and translocation of the neurotransmitter, probably to counterbalance the charge of the co-transported sodium ions. PMID- 17704763 TI - ZEITLUPE is a circadian photoreceptor stabilized by GIGANTEA in blue light. AB - The circadian clock is essential for coordinating the proper phasing of many important cellular processes. Robust cycling of key clock elements is required to maintain strong circadian oscillations of these clock-controlled outputs. Rhythmic expression of the Arabidopsis thaliana F-box protein ZEITLUPE (ZTL) is necessary to sustain a normal circadian period by controlling the proteasome dependent degradation of a central clock protein, TIMING OF CAB EXPRESSION 1 (TOC1). ZTL messenger RNA is constitutively expressed, but ZTL protein levels oscillate with a threefold change in amplitude through an unknown mechanism. Here we show that GIGANTEA (GI) is essential to establish and sustain oscillations of ZTL by a direct protein-protein interaction. GI, a large plant-specific protein with a previously undefined molecular role, stabilizes ZTL in vivo. Furthermore, the ZTL-GI interaction is strongly and specifically enhanced by blue light, through the amino-terminal flavin-binding LIGHT, OXYGEN OR VOLTAGE (LOV) domain of ZTL. Mutations within this domain greatly diminish ZTL-GI interactions, leading to strongly reduced ZTL levels. Notably, a C82A mutation in the LOV domain, implicated in the flavin-dependent photochemistry, eliminates blue-light enhanced binding of GI to ZTL. These data establish ZTL as a blue-light photoreceptor, which facilitates its own stability through a blue-light-enhanced GI interaction. Because the regulation of GI transcription is clock-controlled, consequent GI protein cycling confers a post-translational rhythm on ZTL protein. This mechanism of establishing and sustaining robust oscillations of ZTL results in the high-amplitude TOC1 rhythms necessary for proper clock function. PMID- 17704764 TI - Enzymatic capture of an extrahelical thymine in the search for uracil in DNA. AB - The enzyme uracil DNA glycosylase (UNG) excises unwanted uracil bases in the genome using an extrahelical base recognition mechanism. Efficient removal of uracil is essential for prevention of C-to-T transition mutations arising from cytosine deamination, cytotoxic U*A pairs arising from incorporation of dUTP in DNA, and for increasing immunoglobulin gene diversity during the acquired immune response. A central event in all of these UNG-mediated processes is the singling out of rare U*A or U*G base pairs in a background of approximately 10(9) T*A or C*G base pairs in the human genome. Here we establish for the human and Escherichia coli enzymes that discrimination of thymine and uracil is initiated by thermally induced opening of T*A and U*A base pairs and not by active participation of the enzyme. Thus, base-pair dynamics has a critical role in the genome-wide search for uracil, and may be involved in initial damage recognition by other DNA repair glycosylases. PMID- 17704765 TI - High-frequency generation of viable mice from engineered bi-maternal embryos. AB - Mammalian development to adulthood typically requires both maternal and paternal genomes, because genomic imprinting places stringent limitations on mammalian development, strictly precluding parthenogenesis. Here we report the generation of bi-maternal embryos that develop at a high success rate equivalent to the rate obtained with in vitro fertilization of normal embryos. These bi-maternal mice developed into viable and fertile female adults. The bi-maternal embryos, distinct from parthenogenetic or gynogenetic conceptuses, were produced by the construction of oocytes from fully grown oocytes and nongrowing oocytes that contain double deletions in the H19 differentially methylated region (DMR) and the Dlk1-Dio3 intergenic germline-derived DMR. The results provide conclusive evidence that imprinted genes regulated by these two paternally methylated imprinting-control regions are the only paternal barrier that prevents the normal development of bi-maternal mouse fetuses to term. PMID- 17704767 TI - Toll-like receptors modulate adult hippocampal neurogenesis. AB - Neurogenesis - the formation of new neurons in the adult brain - is considered to be one of the mechanisms by which the brain maintains its lifelong plasticity in response to extrinsic and intrinsic changes. The mechanisms underlying the regulation of neurogenesis are largely unknown. Here, we show that Toll-like receptors (TLRs), a family of highly conserved pattern-recognizing receptors involved in neural system development in Drosophila and innate immune activity in mammals, regulate adult hippocampal neurogenesis. We show that TLR2 and TLR4 are found on adult neural stem/progenitor cells (NPCs) and have distinct and opposing functions in NPC proliferation and differentiation both in vitro and in vivo. TLR2 deficiency in mice impaired hippocampal neurogenesis, whereas the absence of TLR4 resulted in enhanced proliferation and neuronal differentiation. In vitro studies further indicated that TLR2 and TLR4 directly modulated self-renewal and the cell-fate decision of NPCs. The activation of TLRs on the NPCs was mediated via MyD88 and induced PKCalpha/beta-dependent activation of the NF-kappaB signalling pathway. Thus, our study identified TLRs as players in adult neurogenesis and emphasizes their specified and diverse role in cell renewal. PMID- 17704766 TI - Comparative analysis of the complete genome sequence of the plant growth promoting bacterium Bacillus amyloliquefaciens FZB42. AB - Bacillus amyloliquefaciens FZB42 is a Gram-positive, plant-associated bacterium, which stimulates plant growth and produces secondary metabolites that suppress soil-borne plant pathogens. Its 3,918-kb genome, containing an estimated 3,693 protein-coding sequences, lacks extended phage insertions, which occur ubiquitously in the closely related Bacillus subtilis 168 genome. The B. amyloliquefaciens FZB42 genome reveals an unexpected potential to produce secondary metabolites, including the polyketides bacillaene and difficidin. More than 8.5% of the genome is devoted to synthesizing antibiotics and siderophores by pathways not involving ribosomes. Besides five gene clusters, known from B. subtilis to mediate nonribosomal synthesis of secondary metabolites, we identified four giant gene clusters absent in B. subtilis 168. The pks2 gene cluster encodes the components to synthesize the macrolactin core skeleton. PMID- 17704768 TI - The F-box protein Fbl10 is a novel transcriptional repressor of c-Jun. AB - c-Jun is a component of the heterodimeric transcription factor AP-1 that is rapidly activated in response to ultraviolet light (UV). In unstressed cells, c Jun activity is negatively regulated by transcriptional repressor complexes. Here we show that the F-box protein Fbl10/JHDM1B interacts with c-Jun and represses c Jun-mediated transcription. Chromatin-immunoprecipitation assays demonstrate that Fbl10 is present at the c-jun promoter, and that c-Jun is required for the recruitment of Fbl10. Fbl10 binds to the unmethylated CpG sequences in the c-jun promoter through the CxxC zinc finger and tethers transcriptional repressor complexes. Suppression of Fbl10 expression by RNA interference (RNAi) induces transcription of c-jun and other c-Jun-target genes, and causes an aberrant cell cycle progression and increased UV-induced cell death. Furthermore, Fbl10 protein and messenger RNA are downregulated in response to UV in an inverse correlation with c-Jun. Taken together, our results demonstrate that Fbl10 is a key regulator of c-Jun function. PMID- 17704769 TI - Genome-wide analysis identifies a general requirement for polarity proteins in endocytic traffic. AB - In a genome-wide RNA-mediated interference screen for genes required in membrane traffic - including endocytic uptake, recycling from endosomes to the plasma membrane, and secretion - we identified 168 candidate endocytosis regulators and 100 candidate secretion regulators. Many of these candidates are highly conserved among metazoans but have not been previously implicated in these processes. Among the positives from the screen, we identified PAR-3, PAR-6, PKC-3 and CDC-42, proteins that are well known for their importance in the generation of embryonic and epithelial-cell polarity. Further analysis showed that endocytic transport in Caenorhabditis elegans coelomocytes and human HeLa cells was also compromised after perturbation of CDC-42/Cdc42 or PAR-6/Par6 function, indicating a general requirement for these proteins in regulating endocytic traffic. Consistent with these results, we found that tagged CDC-42/Cdc42 is enriched on recycling endosomes in C. elegans and mammalian cells, suggesting a direct function in the regulation of transport. PMID- 17704770 TI - S-nitrosylation of microtubule-associated protein 1B mediates nitric-oxide induced axon retraction. AB - Treatment of cultured vertebrate neurons with nitric oxide leads to growth-cone collapse, axon retraction and the reconfiguration of axonal microtubules. We show that the light chain of microtubule-associated protein (MAP) 1B is a substrate for S-nitrosylation in vivo, in cultured cells and in vitro. S-nitrosylation occurs at Cys 2457 in the COOH terminus. Nitrosylation of MAP1B leads to enhanced interaction with microtubules and correlates with the inhibition of neuroblastoma cell differentiation. We further show, in dorsal root ganglion neurons, that MAP1B is necessary for neuronal nitric oxide synthase control of growth-cone size, growth-cone collapse and axon retraction. These results reveal an S nitrosylation-dependent signal-transduction pathway that is involved in regulation of the axonal cytoskeleton and identify MAP1B as a major component of this pathway. We propose that MAP1B acts by inhibiting a microtubule- and dynein based mechanism that normally prevents axon retraction. PMID- 17704771 TI - A new family of ATP-dependent oligomerization-macrocyclization biocatalysts. AB - Oligomerization and macrocyclization reactions are key steps in the biosynthesis of many bioactive natural products. Important macrocycles include the antibiotic daptomycin (1; ref. 1), the immunosuppressant FK-506 (2; ref. 2), the anthelmintic avermectin B1a (3; ref. 3) and the insecticide spinosyn A (4; ref. 4); important oligomeric macrocycles include the siderophores enterobactin (5; ref. 5) and desferrioxamine E (6; ref. 6). Biosynthetic oligomerization and macrocyclization reactions typically involve covalently tethered intermediates and are catalyzed by thioesterase domains of polyketide synthase and nonribosomal peptide synthetase multienzymes. Here we report that the purified recombinant desferrioxamine siderophore synthetase DesD from Streptomyces coelicolor M145 catalyzes ATP-dependent trimerization-macrocyclization of a chemically synthesized 10-aminocarboxylic acid substrate via noncovalently bound intermediates. DesD is dissimilar to other known synthetase families but is similar to other enzymes known or proposed to be required for the biosynthesis of omega-aminocarboxylic acid-derived cyclodimeric siderophores. This suggests that DesD is the first biochemically characterized member of a new family of oligomerizing and macrocyclizing synthetases. PMID- 17704772 TI - Enzymatic total synthesis of enterocin polyketides. AB - Polyketides are clinically important natural products that often require elaborate organic syntheses owing to their complex chemical structures. Here we report the multienzyme total synthesis of the Streptomyces maritimus enterocin and wailupemycin bacteriostatic agents in a single reaction vessel from simple benzoate and malonate substrates. To our knowledge, our results represent the first in vitro assembly of a complete type II polyketide synthase enzymatic pathway to natural products. PMID- 17704773 TI - Terrequinone A biosynthesis through L-tryptophan oxidation, dimerization and bisprenylation. AB - The antitumor fungal metabolite terrequinone A, identified in extracts of Aspergillus sp., is biosynthesized by the five-gene cluster tdiA-tdiE. In this work, we have overproduced all five proteins (TdiA-TdiE) in the bacterial host Escherichia coli, fully reconstituting the biosynthesis of terrequinone A. This pathway involves aminotransferase activity, head-to-tail dimerization and bisprenylation of the scaffold to yield the benzoquinone natural product. We have established that TdiD is a pyridoxal-5'-phosphate-dependent L-tryptophan aminotransferase that generates indolepyruvate for an unusual nonoxidative coupling by the tridomain nonribosomal peptide synthetase TdiA. TdiC, an NADH dependent quinone reductase, generates the nucleophilic hydroquinone for two distinct rounds of prenylation by the single prenyltransferase TdiB. TdiE is required to shunt the benzoquinone away from an off-pathway monoprenylated species by an as yet unknown mechanism. Overall, we have biochemically characterized the complete biosynthetic pathway to terrequinone A, highlighting the nonoxidative dimerization pathway and the unique asymmetric prenylation involved in its maturation. PMID- 17704774 TI - Nicotinic control of axon excitability regulates thalamocortical transmission. AB - The thalamocortical pathway, a bundle of myelinated axons that arises from thalamic relay neurons, carries sensory information to the neocortex. Because axon excitation is an obligatory step in the relay of information from the thalamus to the cortex, it represents a potential point of control. We now show that, in adult mice, the activation of nicotinic acetylcholine receptors (nAChRs) in the initial portion of the auditory thalamocortical pathway modulates thalamocortical transmission of information by regulating axon excitability. Exogenous nicotine enhanced the probability and synchrony of evoked action potential discharges along thalamocortical axons in vitro, but had little effect on synaptic release mechanisms. In vivo, the blockade of nAChRs in the thalamocortical pathway reduced sound-evoked cortical responses, especially those evoked by sounds near the acoustic threshold. These data indicate that endogenous acetylcholine activates nAChRs in the thalamocortical pathway to lower the threshold for thalamocortical transmission and to increase the magnitude of sensory-evoked cortical responses. Our results show that a neurotransmitter can modulate sensory processing by regulating conduction along myelinated thalamocortical axons. PMID- 17704775 TI - A functional circuitry for edge-induced brightness perception. AB - The identification of visual contours and surfaces is central to visual scene segmentation. One view of image construction argues that object contours are first identified and then surfaces are filled in. Although there are psychophysical and single-unit data to suggest that the filling-in view is correct, the underlying circuitry is unknown. Here we examine specific spike timing relationships between border and surface responses in cat visual cortical areas 17 and 18. With both real and illusory (Cornsweet) brightness contrast stimuli, we found a border-to-surface shift in the relative timing of spike activity. This shift was absent when borders were absent and could be reversed with relocation of the stimulus border, indicating that the direction of information flow is highly dependent on stimulus conditions. Furthermore, this effect was seen predominantly in 17-18, and not 17-17, interactions. These results demonstrate a border-to-surface mechanism at early stages of visual processing and emphasize the importance of interareal circuitry in vision. PMID- 17704776 TI - Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. AB - We report germline loss-of-function mutations in SPRED1 in a newly identified autosomal dominant human disorder. SPRED1 is a member of the SPROUTY/SPRED family of proteins that act as negative regulators of RAS->RAF interaction and mitogen activated protein kinase (MAPK) signaling. The clinical features of the reported disorder resemble those of neurofibromatosis type 1 and consist of multiple cafe au-lait spots, axillary freckling and macrocephaly. Melanocytes from a cafe-au lait spot showed, in addition to the germline SPRED1 mutation, an acquired somatic mutation in the wild-type SPRED1 allele, indicating that complete SPRED1 inactivation is needed to generate a cafe-au-lait spot in this syndrome. This disorder is yet another member of the recently characterized group of phenotypically overlapping syndromes caused by mutations in the genes encoding key components of the RAS-MAPK pathway. To our knowledge, this is the first report of mutations in the SPRY (SPROUTY)/SPRED family of genes in human disease. PMID- 17704777 TI - Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2. AB - We have identified a recurrent de novo pericentromeric deletion in 16p11.2-p12.2 in four individuals with developmental disabilities by microarray-based comparative genomic hybridization analysis. The identification of common clinical features in these four individuals along with the characterization of complex segmental duplications flanking the deletion regions suggests that nonallelic homologous recombination mediated these rearrangements and that deletions in 16p11.2-p12.2 constitute a previously undescribed syndrome. PMID- 17704779 TI - Tensile ductility and necking of metallic glass. AB - Metallic glasses have a very high strength, hardness and elastic limit. However, they rarely show tensile ductility at room temperature and are considered quasi brittle materials. Although these amorphous metals are capable of shear flow, severe plastic instability sets in at the onset of plastic deformation, which seems to be exclusively localized in extremely narrow shear bands approximately 10 nm in thickness. Using in situ tensile tests in a transmission electron microscope, we demonstrate radically different deformation behaviour for monolithic metallic-glass samples with dimensions of the order of 100 nm. Large tensile ductility in the range of 23-45% was observed, including significant uniform elongation and extensive necking or stable growth of the shear offset. This large plasticity in small-volume metallic-glass samples did not result from the branching/deflection of shear bands or nanocrystallization. These observations suggest that metallic glasses can plastically deform in a manner similar to their crystalline counterparts, via homogeneous and inhomogeneous flow without catastrophic failure. The sample-size effect discovered has implications for the application of metallic glasses in thin films and micro-devices, as well as for understanding the fundamental mechanical response of amorphous metals. PMID- 17704781 TI - Tailoring properties and functionalities of metal nanoparticles through crystallinity engineering. AB - Metal nanoparticles (NPs) with size comparable to their electron mean free path possess unusual properties and functionalities, serving as model systems to explore quantum and classical coupling interactions as well as building blocks of practical applications. Although advances in strategies for synthesizing metal NPs have enabled control of size, composition and shape, the requirement that defects are simultaneously controlled, to ensure essential perfect nanocrystallinity for physics modelling as well as device optimization, is a potentially more significant issue, but has posed substantial technological challenges. Here we report that crystallinity of monodisperse silver NPs can be well controlled by judicious choice of functional groups of molecular precursors, thus facilitating investigation of their scope for versatile applications. We demonstrate how nanoscale chemical transformation, electron-phonon interactions and nanomechanical properties are modified by nanocrystallinity. Lastly, we find that performance of NP-based molecular sensing devices can be optimized with significant improvement of figure of merit if perfect single-crystalline NPs are applied. Our approach represents a versatile synthetic route for other metal nanomaterials with unprecedented control of their structure, creating a rational pathway for understanding and manipulating nanoscale chemical and physical processes as well as technological applications of metal NPs. PMID- 17704778 TI - Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. AB - Nonsense-mediated mRNA decay (NMD) is of universal biological significance. It has emerged as an important global RNA, DNA and translation regulatory pathway. By systematically sequencing 737 genes (annotated in the Vertebrate Genome Annotation database) on the human X chromosome in 250 families with X-linked mental retardation, we identified mutations in the UPF3 regulator of nonsense transcripts homolog B (yeast) (UPF3B) leading to protein truncations in three families: two with the Lujan-Fryns phenotype and one with the FG phenotype. We also identified a missense mutation in another family with nonsyndromic mental retardation. Three mutations lead to the introduction of a premature termination codon and subsequent NMD of mutant UPF3B mRNA. Protein blot analysis using lymphoblastoid cell lines from affected individuals showed an absence of the UPF3B protein in two families. The UPF3B protein is an important component of the NMD surveillance machinery. Our results directly implicate abnormalities of NMD in human disease and suggest at least partial redundancy of NMD pathways. PMID- 17704780 TI - In vivo imaging of hydrogen peroxide with chemiluminescent nanoparticles. AB - The overproduction of hydrogen peroxide is implicated in the development of numerous diseases and there is currently great interest in developing contrast agents that can image hydrogen peroxide in vivo. In this report, we demonstrate that nanoparticles formulated from peroxalate esters and fluorescent dyes can image hydrogen peroxide in vivo with high specificity and sensitivity. The peroxalate nanoparticles image hydrogen peroxide by undergoing a three-component chemiluminescent reaction between hydrogen peroxide, peroxalate esters and fluorescent dyes. The peroxalate nanoparticles have several attractive properties for in vivo imaging, such as tunable wavelength emission (460-630 nm), nanomolar sensitivity for hydrogen peroxide and excellent specificity for hydrogen peroxide over other reactive oxygen species. The peroxalate nanoparticles were capable of imaging hydrogen peroxide in the peritoneal cavity of mice during a lipopolysaccharide-induced inflammatory response. We anticipate numerous applications of peroxalate nanoparticles for in vivo imaging of hydrogen peroxide, given their high specificity and sensitivity and deep-tissue-imaging capability. PMID- 17704782 TI - Highly efficient somatic-mutation identification using Escherichia coli mismatch repair detection. AB - The discovery of somatic mutations in cancer tissue is extremely laborious, time consuming and costly. In an evaluation comparing mismatch repair detection (MRD) against Sanger sequencing for somatic-mutation detection, we found that MRD had a specificity of 96% and a sensitivity of 92%. Our results showed that MRD is a robust and cost-effective alternative to Sanger sequencing for identifying somatic mutations in human tumors. PMID- 17704783 TI - Microfluidics for in vivo imaging of neuronal and behavioral activity in Caenorhabditis elegans. AB - The nematode C. elegans is an excellent model organism for studying behavior at the neuronal level. Because of the organism's small size, it is challenging to deliver stimuli to C. elegans and monitor neuronal activity in a controlled environment. To address this problem, we developed two microfluidic chips, the 'behavior' chip and the 'olfactory' chip for imaging of neuronal and behavioral responses in C. elegans. We used the behavior chip to correlate the activity of AVA command interneurons with the worm locomotion pattern. We used the olfactory chip to record responses from ASH sensory neurons exposed to high-osmotic strength stimulus. Observation of neuronal responses in these devices revealed previously unknown properties of AVA and ASH neurons. The use of these chips can be extended to correlate the activity of sensory neurons, interneurons and motor neurons with the worm's behavior. PMID- 17704784 TI - CD8+ T lymphocytes protective against malaria liver stages are primed in skin draining lymph nodes. AB - The success of immunization with irradiated sporozoites is unparalleled among the current vaccination approaches against malaria, but its mechanistic underpinnings have yet to be fully elucidated. Using a model mimicking natural infection by Plasmodium yoelii, we delineated early events governing the development of protective CD8(+) T-cell responses to the circumsporozoite protein. We demonstrate that dendritic cells in cutaneous lymph nodes prime the first cohort of CD8(+) T cells after an infectious mosquito bite. Ablation of these lymphoid sites greatly impairs subsequent development of protective immunity. Activated CD8(+) T cells then travel to systemic sites, including the liver, in a sphingosine-1-phosphate (S1P)-dependent fashion. These effector cells, however, no longer require bone marrow-derived antigen-presenting cells for protection; instead, they recognize antigen on parenchymal cells-presumably parasitized hepatocytes. Therefore, we report an unexpected dichotomy in the tissue restriction of host responses during the development and execution of protective immunity to Plasmodium. PMID- 17704785 TI - Lack of Fas antagonism by Met in human fatty liver disease. AB - Hepatocytes in fatty livers are hypersensitive to apoptosis and undergo escalated apoptotic activity via death receptor-mediated pathways, particularly that of Fas FasL, causing hepatic injury that can eventually proceed to cirrhosis and end stage liver disease. Here we report that the hepatocyte growth factor receptor, Met, plays an important part in preventing Fas-mediated apoptosis of hepatocytes by sequestering Fas. We also show that Fas antagonism by Met is abrogated in human fatty liver disease (FLD). Through structure-function studies, we found that a YLGA amino-acid motif located near the extracellular N terminus of the Met alpha-subunit is necessary and sufficient to specifically bind the extracellular portion of Fas and to act as a potent FasL antagonist and inhibitor of Fas trimerization. Using mouse models of FLD, we show that synthetic YLGA peptide tempers hepatocyte apoptosis and liver damage and therefore has therapeutic potential. PMID- 17704786 TI - Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. AB - Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen-specific T-cell immunity that involves secretion of the high-mobility group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death. PMID- 17704787 TI - Sustained complete remission of refractory enteropathy-type T-cell lymphoma following reduced-intensity unrelated cord blood transplantation. PMID- 17704788 TI - Rhinovirus as a cause of fatal lower respiratory tract infection in adult stem cell transplantation patients: a report of two cases. PMID- 17704789 TI - Hair follicle: a reliable source of recipient origin after allogeneic hematopoietic stem cell transplantation. AB - Blood, buccal swab and hair follicles are among the most commonly used sources for forensic science, parentage testing and personal identification. A total of 29 patients who have had a sustained engraftment from 15 months to 21.5 years after allogeneic hematopoietic stem cell transplantation (HSCT) without rejection, relapse or chronic GVHD involving oral mucosa were enrolled for a chimerism study. PCR-amplified short tandem repeat analyses were conducted per patient every 3 months for at least three consecutive times. The results for blood were all donor type except one who had a mixed chimerism, 14.5 years after receiving a transplant for lymphoma. As for buccal swab, mixed chimerism ranging from 10 to 96% donor origin was noted for 28 recipients except the one who had mixed chimerism of blood and retained total recipient type. In contrast, hair follicles were 100% recipient type for the entire group. It is concluded that the hair follicle is devoid of adult stem cell plasticity and may serve as a reliable source of recipient's origin when pre-transplant DNA fingerprinting or reference DNA is not available for people who have successfully received allogeneic HSCT while in need of a personal identification. PMID- 17704790 TI - Autologous stem cell transplantation for refractory Langerhans' cell histiocytosis. PMID- 17704791 TI - Health status and quality of life in long-term survivors of childhood leukaemia: the impact of haematopoietic stem cell transplantation. AB - We compared late side effects and quality of life (QoL) in 430 survivors of childhood acute leukaemia based on whether they had undergone haematopoietic cell transplantation (n=142) or not (n=288). Mean age was 18.2 years and mean follow up duration was 11.9 years. Multivariate logistic regression analyses were performed to compare the risk of each type of late effect in the two groups. Based on age, VSP-A or SF36 questionnaires were used to assess QoL. For each QoL dimension, multiple linear regression was done to construct models of association with the treatment group. Transplanted patients experienced more side effects, including height growth failure, gonadal dysfunction, hypothyroidism and cataract. Children and adolescents in the two treatment groups reported similar QoL levels for almost all dimensions except a better perception of school work by young transplanted children and more difficulties in relating to the medical staff for transplanted adolescents. In adults, two differences in physical domain of QoL were detected but the calculated effect sizes were less than 0.2 in each case, suggesting an uncertain clinical significance. In spite of a higher risk of physical adverse events in the transplanted group, very few clinically significant differences in QoL are detectable. PMID- 17704792 TI - Interleukin-7 induced facilitation of immunological reconstitution of sublethally irradiated mice following treatment with alloreactive spleen cells in a murine model of B-cell leukemia/lymphoma (BCL1). AB - Interleukin-7 (IL-7) plays a key role in maturation and function of both T and B cells. We investigate the potential use of recombinant human IL-7 for facilitation of graft-versus-leukemia (GVL) effects mediated by T cells following transplantation in a murine model. Administration of IL-7 in vivo to allogeneic transplanted mice improved disease-free survival: 67% of mice treated with IL-7 remained alive and disease free for more than 60 days, in comparison to 17% of the controls (P<0.05). Similar results were obtained when C57BL/6 spleen cells sensitized against irradiated B-cell leukemia (BCL(1)) cells in the presence of IL-7 were transplanted to F(1) mice, followed by IL-7 treatment in vivo. Of the BALB/c mice that received spleen cells from F(1) mice treated with IL-7 following transplantation of C57BL/6 spleen cells sensitized with irradiated BCL(1) in the presence of IL-7, only 29% developed leukemia, as compared to 79% in the control group (P<0.05). Mice treated with IL-7 showed increased splenic and thymic cellularity and improved T cell-dependent proliferative responses compared to the controls (P<0.05). IL-7 may provide a novel tool to enhance immune reconstitution following transplantation of mismatched stem cells and for enhancement of GVL effects mediated by alloreactive lymphocytes. PMID- 17704793 TI - Failure to achieve a threshold dose of CD34+ CD110+ progenitor cells in the graft predicts delayed platelet engraftment after autologous stem cell transplantation. AB - In this study, we retrospectively analysed the utility of CD110 expression on CD34(+) cells as a predictor of delayed platelet transfusion independence in 39 patients who underwent autologous peripheral blood stem cell transplantation. Absolute CD34(+) cells and CD34(+) subsets expressing CD110 were enumerated using flow cytometry. Of the 39 patients, 7 required 21 days or more to achieve platelet transfusion independence. Six of the seven patients received a dose of CD34(+)CD110(+) cells below 6.0 x 10(4)/kg while 30 of 32 patients who achieved platelet transfusion independence in <21 days received a dose of CD34(+)CD110(+) cells >6.0 x 10(4)/kg (P<0.001). Patients with delayed platelet engraftment received a median dose of 5.2 x 10(4) CD34(+)CD110(+) cells/kg compared with a median dose of 16.4 x 10(4) cells/kg for those engrafting within 21 days (P=0.003). Further analysis showed that >6.0 x 10(4) CD34(+)CD110(+) cells/kg was highly sensitive (93.8%) and highly specific (85.7%) for achieving platelet transfusion independence within 21 days. Delay in platelet transfusion independence translated into an increased requirement for platelet transfusion (median 6 vs 2 transfusions, P<0.0001). The dose of CD34(+)/CD110(+) cells/kg infused at time of transplantation appears to be an important factor identifying patients at risk of delayed platelet engraftment. PMID- 17704794 TI - Disappearance of pre-existing high HHV-6 DNA load in blood after allogeneic SCT. PMID- 17704795 TI - Pilot study of a multimodal intervention: mixed-type exercise and psychoeducation in patients undergoing allogeneic stem cell transplantation. AB - Substantial physical and functional deconditioning and diminished psychological wellbeing are all potential adverse effects of allogeneic stem cell transplantation (allo-HSCT). The aim of this study was to evaluate the feasibility, safety and benefits (physical and functional capacity) of a 4-6 week supervised and structured mixed-type exercise, progressive relaxation and psychoeducation programme in patients undergoing allo-HSCT. Nineteen patients were randomized to an intervention or a conventional care group (CC) and were tested for physical and functional capacity before admission and upon hospital discharge. In all, 14 patients completed all study requirements (74%) and no adverse reactions that could be attributed to the intervention were observed. At the time of discharge, the intervention group showed significant improvements in several muscle strength scores as compared to the CC group; chest press (P=0.023), leg extension (P=0.007) and isometric right knee flexor (P=0.033). The intervention proved feasible, safe and well tolerated in this small sample of patients undergoing allo-HSCT. An intervention of this type may be a useful strategy for maintaining or improving muscle strength, and minimizing loss of physical and functional capacity in patients undergoing allo-HSCT. PMID- 17704796 TI - Clonal gammopathies following alemtuzumab-based reduced intensity conditioning haematopoietic stem cell transplantation: association with chronic graft-versus host disease and improved overall survival. AB - The presence of clonal gammopathies (CG) has been reported following both conventional myeloablative and autologous haematopoietic stem cell transplantation (HSCT). We monitored the occurrence of CG in a cohort of patients with myeloid malignancies receiving FBC (fludarabine-busulphan-alemtuzumab)-based reduced intensity conditioned (RIC) HSCT, and assessed its correlation with infections, graft-versus-host disease (GvHD) and survival. Serial serum protein electrophoresis was analysed in a total of 138 patients and CG were detected in 49 patients (36%). The predominant Ig isotype was IgG (82%). There was no difference in the incidence of viral infections between patient groups. However, patients with gammopathies were more likely to have had prior chronic GvHD (OR 2.7, 95% CI 1.3-5.5, P<0.001). On multivariate analysis, the only factors that were found to influence overall survival (OS) were presence of gammopathies, which was associated with an improved OS (OR 0.35 95% CI 0.14-0.86, P=0.02) as well as disease stage, patients with advanced disease having a higher risk of death (OR 2.20 95% CI 1.18-4.11, P=0.02). Disease stage was the only variable that influenced relapse incidence on multivariate analysis (OR 4.22 95% CI 1.82 9.78, P<0.01). Clonal gammopathies are a frequent but benign occurrence following alemtuzumab-based RIC HSCT, and their appearance may define a group of patients with a favourable overall outcome. PMID- 17704797 TI - Has stem cell transplantation come of age in the treatment of sickle cell disease? AB - Currently, hematopoietic SCT (HCT) is the only intervention that can restore normal hematopoiesis to provide a 'cure' in sickle cell disease. Yet, this treatment modality is used sparsely-a total of less than 400 transplants are reported in the Center for International Blood and Marrow Transplant Research database despite 70,000 afflicted in the United States; 88% of transplants are from HLA-matched sibling donors and 84% are <16 years of age at transplant. Overall survival at 3 years is over 90% after HCT in the young but 62% in adult HCT recipients due to increased disease and transplant-related morbidity. The decision and timing of HCT is a dilemma for physicians and families due to the need to consider HCT before severe organ damage in a disease that is generally not fatal in children with adequate supportive care. From the transplant physician's perspective, however, advances in the ability to identify well matched donors, supportive care and promising conditioning regimens with low toxicity and transplant complications support the development of new HCT trials for sickle cell disease as the risk/benefit ratio can be balanced better. With the recognition of new predictors of early mortality, the anticipation of extensive and expensive life-long medical support, and the poor quality of life despite medical care, the scales tip in favor of HCT. This is prime time for the development of careful unrelated donor HCT trials for sickle cell disease. Research efforts targeting HCT will need to be directed at seeking safe and effective transplant methods applicable to all patients who might derive benefit. PMID- 17704798 TI - Cellular functions of 14-3-3 zeta in apoptosis and cell adhesion emphasize its oncogenic character. AB - 14-3-3 proteins are relevant to cancer biology as they are key regulators of major cellular processes such as proliferation, differentiation, senescence and apoptosis. So far, the sigma isoform (14-3-3sigma) has most directly been implicated in carcinogenesis and was recognized as a tumour-suppressor gene. The other six members of the mammalian 14-3-3 gene family likely behave as oncogenes, although direct evidence supporting this view is largely circumstantial. In this report, we show that knockdown of 14-3-3zeta induces at least two isoform specific phenotypes that are consistent with a potential oncogenic activity during tumorigenesis. Firstly, downregulation of 14-3-3zeta sensitized cells to stress-induced apoptosis and JNK/p38 signalling and secondly, it enforced cell cell contacts and expression of adhesion proteins. Apparently, the zeta isoform restrains both cell adhesion and the cellular propensity for apoptosis, two activities that are also restrained during carcinogenesis. The assumption that 14 3-3zeta has oncogenic properties was substantiated with a web-based meta-analysis (Oncomine), revealing that 14-3-3zeta is overexpressed in various types of carcinomas. As the highly conserved human 14-3-3 gene family encodes proteins with either tumour-promoting or tumour-suppressing activities, we infer that the cellular balance between the various 14-3-3 isoforms is crucial for the proper functioning of cells. PMID- 17704799 TI - The ternary complex factor Net/Elk-3 participates in the transcriptional response to hypoxia and regulates HIF-1 alpha. AB - The ternary complex factor Net/Elk3 is downregulated in hypoxia and participates in the induction by hypoxia of several genes, including c-fos, vascular endothelial growth factor and egr-1. However, the global role of Net in hypoxia remains to be elucidated. We have identified, in a large-scale analysis of RNA expression using microarrays, more than 370 genes that are regulated by Net in hypoxia. In order to gain insights into the role of Net in hypoxia, we have analysed in parallel the genes regulated by HIF-1alpha, the classical factor involved in the response to hypoxia. We identified about 190 genes that are regulated by HIF-1alpha in hypoxia. Surprisingly, when we compare the genes induced by hypoxia that require either Net or HIF-1alpha, the majority are the same (75%), suggesting that the functions of both factors are closely linked. Interestingly, in hypoxia, Net regulates the expression of several genes known to control HIF-1alpha stability, including PHD2, PHD3 and Siah2, suggesting that Net regulates the stability of HIF-1alpha. We found that inhibition of Net by RNAi leads to decreased HIF-1alpha expression at the protein level in hypoxia. These results indicate that Net participates in the transcriptional response to hypoxia by regulation of HIF-1alpha protein stability. PMID- 17704800 TI - An N-Myc truncation analogous to c-Myc-S induces cell proliferation independently of transactivation but dependent on Myc homology box II. AB - Myc promotes both normal cell proliferation and oncogenic transformation through the activation and repression of target genes. The c-Myc-S protein is a truncated form of c-Myc that is produced in some cells from translation initiation at an internal AUG codon. We report that c-Myc-S and a similar truncated form of N MycWT can fully rescue the proliferation defect in myc-null fibroblasts, but rescue is dependent on the highly conserved Myc homology box II (MBII). Global gene expression studies show that the N-Myc equivalent of c-Myc-S is defective for virtually all transcriptional activation of Myc target genes but remains active for the majority of transcriptional repression. Repression by Myc-S is dependent on MBII, but it does not bind to several known nuclear cofactors. These data suggest that repression by Myc involves recruitment of a novel MBII dependent cofactor. PMID- 17704801 TI - BRE is an antiapoptotic protein in vivo and overexpressed in human hepatocellular carcinoma. AB - BRE binds to the cytoplasmic domains of tumor necrosis factor receptor-1 and Fas, and in cell lines can attenuate death receptor-initiated apoptosis by inhibiting t-BID-induced activation of the mitochondrial apoptotic pathway. Overexpression of BRE by transfection can also attenuate intrinsic apoptosis and promote growth of the transfected Lewis lung carcinoma line in mice. There is, however, a complete lack of in vivo data about the protein. Here, we report that by using our BRE-specific monoclonal antibody on the immunohistochemistry of 123 specimens of human hepatocellular carcinoma (HCC), significant differences in BRE expression levels between the paired tumoral and non-tumoral regions (P<2.2e-16) were found. Marked overexpression of BRE was detected in majority of the tumors, whereas most non-tumoral regions expressed the same low level of the protein as in normal livers. To investigate whether BRE overexpression could promote cell survival in vivo, liver-specific transgenic BRE mice were generated and found to be significantly resistant to Fas-mediated lethal hepatic apoptosis. The transgenic model also revealed post-transcriptional regulation of Bre level in the liver, which was not observed in HCC and non-HCC cell lines. Indeed, all cell lines analysed express high levels of BRE. In conclusion, BRE is antiapoptotic in vivo, and may promote tumorigenesis when overexpressed. PMID- 17704802 TI - Angiopoietin-2 decreases vascular endothelial growth factor expression by modulating HIF-1 alpha levels in gliomas. AB - Angiogenesis is thought to depend on a perfectly coordinated balance between endogenous-positive and negative regulatory factors. Of these factors, the vascular endothelial growth factor (VEGF) and angiopoietins (Angs) seem to play an essential role. Recently, we reported the expression of the Ang-natural receptor, Tie2, in neoplastic astrocytic cells within gliomas. Because of the VEGF/Ang2 functional partnership together with the presence of Tie2 in gliomas, we hypothesized a role of Ang2 on the modulation of VEGF levels in these tumors. We examined the effect of Ang2 on VEGF expression in a panel of glioma cells, which showed that Ang2 inhibited VEGF expression at both mRNA and protein levels in Tie2-expressing cells, but not in Tie2-negative cells. VEGF promoter analysis showed that Ang2 regulated VEGF expression at the transcriptional level in relation to a decrease in HIF-1alpha expression and HIF-DNA-binding activity. Tie2 silencing by siRNA rescued the Ang2-mediated downmodulation of VEGF, suggesting an essential role for Tie2 in this regulatory loop. To our knowledge, this is the first report on the role of Ang2/Tie2 in the regulation of HIF 1alpha/VEGF expression, providing additional evidence of the intrinsic coordination that occurs among these factors during angiogenesis. PMID- 17704803 TI - Zebrafish pten genes have overlapping and non-redundant functions in tumorigenesis and embryonic development. AB - In human cancer, PTEN (Phosphatase and TENsin homolog on chromosome 10, also referred to as MMAC1 and TEP1) is a frequently mutated tumor suppressor gene. We have used the zebrafish as a model to investigate the role of Pten in embryonic development and tumorigenesis. The zebrafish genome encodes two pten genes, ptena and ptenb. Here, we report that both Pten gene products from zebrafish are functional. Target-selected inactivation of ptena and ptenb revealed that Ptena and Ptenb have redundant functions in embryonic development, in that ptena-/- and ptenb-/- mutants did not show embryonic phenotypes. Homozygous single mutants survived as adults and they were viable and fertile. Double homozygous ptena-/ ptenb-/- mutants died at 5 days post fertilization with pleiotropic defects. These defects were rescued by treatment with the phosphatidylinositol-3-kinase inhibitor, LY294002. Double homozygous embryos showed enhanced cellular proliferation. In addition, cell survival was dramatically enhanced in embryos that lack functional Pten upon gamma-irradiation. Surprisingly, adult ptenb-/- zebrafish developed ocular tumors later in life, despite the expression of ptena in adult eyes. We conclude that whereas Ptena and Ptenb have redundant functions in embryonic development, they apparently do not have completely overlapping functions later in life. These pten mutant zebrafish represent a unique model to screen for genetic and/or chemical suppressors of Pten loss-of-function. PMID- 17704804 TI - The apoptosis-inducing effect of gastrin on colorectal cancer cells relates to an increased IEX-1 expression mediating NF-kappa B inhibition. AB - Addressing the puzzling role of amidated gastrin(17) (G17) and the gastrin/CCKB/CCK2 receptor in colorectal carcinogenesis, we analysed potential candidate genes involved in G17-dependent NF-kappaB inhibition and apoptosis. The colorectal carcinoma cell line Colo320 overexpressing the wild-type CCK2 receptor (Colo320wt) underwent G17-induced apoptosis along with suppressed NF-kappaB activation and decreased expression of the antiapoptotic NF-kappaB target genes cIAP1 and cIAP2, whereas G17 was without effect on Colo320 cells expressing a CCK2 receptor bearing a loss of function mutation (Colo320mut). Gene microarray analysis revealed an elevated expression of the stress response gene IEX-1 in G17 treated Colo320wt but not Colo320mut cells. Quantitative real-time PCR and conventional RT-PCR confirmed this G17-dependent increase of IEX-1 expression in Colo320wt cells. If these cells were subjected to IEX-1 knockdown by small interfering RNA transfection, the apoptosis-inducing effect of G17 was abolished. Moreover, tumor necrosis factor alpha (TNFalpha)- or 5-FU-induced apoptosis that is greatly enhanced by G17 treatment in Colo320wt cells was prevented if IEX-1 expression was repressed. Under these conditions of blocked IEX-1 expression, the NF-kappaB activity remained unaffected by G17, in particular in Colo320wt cells co-treated with TNFalpha and also the suppressive effect of G17 on cIAP1 and cIAP2 expression was not observed anymore if IEX-1 expression was blocked. Conversely, IEX-1 overexpression in Colo320mut cells caused an increase of basal and TNFalpha- or 5-FU-induced apoptosis, an effect not further triggered by G17 treatment. Using a xenograft tumor model in severe combined immune deficiency mice, we could show that experimental systemic hypergastrinemia induced by the administration of omeprazole led to enhanced apoptosis as well as to a marked increase of IEX-1 expression in Colo320wt tumors, but not in Colo320mut tumors. These observations indicate that the proapoptotic effect of G17 on human colon cancer cells expressing the wild-type CCK2 receptor is mediated by IEX-1, which modulates NF-kappaB-dependent antiapoptotic protection and thereby exerts tumor suppressive potential. PMID- 17704805 TI - HPV-16 E5 oncoprotein upregulates lipid raft components caveolin-1 and ganglioside GM1 at the plasma membrane of cervical cells. AB - High-risk human papillomaviruses (HPVs), especially HPV-16, play a primary role in the pathogenesis of cervical cancer. HPV-16 encodes the E5, E6 and E7 oncoproteins. Although the biological functions of E5 are poorly understood, recent studies indicate that its expression correlates with papillomavirus oncogenicity. In this study we demonstrate that the HPV-16 E5 oncoprotein increases plasma membrane expression of caveolin-1, which is a constituent of lipid rafts and regulator of cell signaling, and that this phenotype is mediated by the C-terminal 10 amino acids of E5. Moreover, E5 (but not mutant E5) induces a 23- to 40-fold increase in the lipid raft component, ganglioside GM1, on the cell surface and mediates a dramatic increase in caveolin-1/GM1 association. Since gangliosides strongly inhibit cytotoxic T lymphocytes, block immune synapse formation and are expressed at high levels on the surface of many tumor cells, our results suggest a potential mechanism for immune evasion by the papillomaviruses. Additionally, surface gangliosides are known to enhance proliferative signaling by the epidermal growth factor (EGF) receptor, providing a possible mechanistic basis for observations that EGF signaling is enhanced in E5-expressing cells. Finally, the upregulation of caveolin-1 and ganglioside GM1 at the plasma membrane of E5-expressing cervical cells provides potential new therapeutic targets and diagnostic markers for high-risk HPV infections. PMID- 17704806 TI - Phosphorylation by Akt disables the anti-oncogenic activity of YB-1. AB - The Y box-binding protein 1 (YB-1) is a DNA/RNA-binding protein that regulates mRNA transcription and translation. It is a major component of free messenger ribonucleoprotein particles and, at higher concentrations, blocks protein synthesis. In chicken embryo fibroblasts, overexpression of YB-1 confers a specific resistance to oncogenic cellular transformation by phosphoinositide 3 kinase (PI3K) or Akt/PKB. Recent studies have identified YB-1 as a direct substrate of Akt. The functional significance of Akt-mediated phosphorylation remains largely unknown. We generated YB-1 mutants in the Akt phosphorylation consensus sequence to explore the effect of phosphorylated YB-1 in PI3K-induced transformation. In contrast to wild-type YB-1, the phosphomimetic S99E mutant no longer interferes with cellular transformation. This mutant has reduced affinity for the cap of mRNAs and fails to inhibit cap-dependent translation. The data suggest that phosphorylation by Akt disables the inhibitory activity of YB-1 and thereby enhances the translation of transcripts that are necessary for oncogenesis. Overexpression of wild-type YB-1 overrides inactivation by Akt and maintains inhibition of protein synthesis and resistance to transformation. PMID- 17704807 TI - Telomere attrition induces a DNA double-strand break damage signal that reactivates p53 transcription in HTLV-I leukemic cells. AB - Persistent inhibition of telomerase induces a severe telomere shortening in human T-cell leukemia virus type-1-infected cells which signals a DNA double-strand break damage response, formation of telomere dysfunction-induced foci and activates the ATM pathway. In turn, activation of ATM and its downstream effectors led to an increased phosphorylation and acetylation on specific residues of p53 known to be involved in transcriptional activation. Disruption of Mdm2-p53 complexes coupled with increased proteasomal degradation of MDMX further enhanced reactivation of p53 transcription, ultimately leading to senescence of tumor cells. Induction of senescence in these T-cells was associated with an increased expression of p21, p16 and activation of GSK3beta. Our results support the cancer-aging model and demonstrate that the halt of aging in cancer cells can be reversed through reactivation of p53. PMID- 17704808 TI - Astrocyte elevated gene-1 activates cell survival pathways through PI3K-Akt signaling. AB - Astrocyte elevated gene-1 (AEG-1) displays oncogenic properties. Its expression is elevated in diverse neoplastic states and it cooperates with Ha-ras to promote cellular transformation. Overexpression of AEG-1 augments invasion and anchorage independent growth of transformed cells, while AEG-1 siRNA inhibits Ha-ras mediated colony formation, supporting a potential functional role in tumorigenesis. Additionally, oncogenic Ha-ras induces AEG-1 expression through the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. In the present study, we investigated whether AEG-1 could induce serum-independent cell growth, another property of oncogenes. Overexpression of AEG-1 inhibited serum starvation induced apoptosis through activation of PI3K-Akt signaling, one of the effector pathways induced by activated Ras. AEG-1 also affected the phosphorylation state of Akt substrates that are implicated in apoptosis suppression, including glycogen synthase kinase 3beta, c-Myc, murine double minute 2, p53, p21/mda-6 and Bad. Additionally, AEG-1 blocked the activity of serum starvation-induced caspases. Taken together, these observations provide evidence that AEG-1 is an oncogene cooperating with Ha-ras as well as functioning as a downstream target gene of Ha-ras and may perform a central role in Ha-ras-mediated carcinogenesis. Activation of survival pathways may be one mechanism by which AEG-1 exerts its oncogenic properties. PMID- 17704810 TI - Development of GABA innervation in the cerebral and cerebellar cortices. AB - In many areas of the vertebrate brain, such as the cerebral and cerebellar cortices, neural circuits rely on inhibition mediated by GABA (gamma-aminobutyric acid) to shape the spatiotemporal patterns of electrical signalling. The richness and subtlety of inhibition are achieved by diverse classes of interneurons that are endowed with distinct physiological properties. In addition, the axons of interneurons display highly characteristic and class-specific geometry and innervation patterns, and thereby distribute their output to discrete spatial domains, cell types and subcellular compartments in neural networks. The cellular and molecular mechanisms that specify and modify inhibitory innervation patterns are only just beginning to be understood. PMID- 17704809 TI - Functional characterization of TIP60 sumoylation in UV-irradiated DNA damage response. AB - The histone acetyltransferase TIP60 regulates the DNA damage response following genotoxic stress by acetylating histone and remodeling chromatin. However, the molecular mechanisms underlying the TIP60-dependent response to UV-induced DNA damage remain poorly understood. To systematically analyse proteins that regulate TIP60 activity in response to UV irradiation, we performed a proteomic analysis of proteins selectively bound to TIP60 in response to UV irradiation using mass spectrometry and identified a novel regulatory mechanism by which TIP60 orchestrates transcriptional activation of p53-dependent checkpoint response in UV-irradiated cells. The initial step of this pathway involves UV-induced association of TIP60 with SUMO-conjugation enzymes and site-specific sumoylation of TIP60 at lysines 430 and 451 via Ubc9. This sumoylation initiates the relocation of TIP60 from nucleoplasm to the promyelocytic leukemia body, which is essential for the UV-irradiated DNA damage repair response via a p53-dependent pathway. Significantly, inhibition of TIP60 sumoylation by overexpression of non sumoylatable mutant abrogates the p53-dependent DNA damage response, demonstrating the importance of TIP60 sumoylation in response to UV irradiation. Our biochemical characterization demonstrated that the sumoylation of TIP60 augments its acetyltransferase activity in vitro and in vivo. Thus, this study shed new light on the function and regulation of TIP60 activity in UV-irradiated DNA damage response. PMID- 17704811 TI - Long-term synaptic plasticity in hippocampal interneurons. AB - Rapid memory formation relies, at least in part, on long-term potentiation (LTP) of excitatory synapses. Inhibitory interneurons of the hippocampus, which are essential for information processing, have recently been found to exhibit not one, but two forms of LTP. One form resembles LTP that occurs in pyramidal neurons, which depends on N-methyl-D-aspartate receptors and is triggered by coincident pre- and postsynaptic activity. The other depends on Ca2+ influx through glutamate receptors that preferentially open when the postsynaptic neuron is at rest. Here we review these contrasting forms of LTP and describe how they are mirrored by two forms of long-term depression. We further discuss how the remarkable plasticity of glutamatergic synapses on interneurons greatly enhances the computational capacity of the cortical microcircuit. PMID- 17704812 TI - Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. AB - The majority of functional neuroscience studies have focused on the brain's response to a task or stimulus. However, the brain is very active even in the absence of explicit input or output. In this Article we review recent studies examining spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal of functional magnetic resonance imaging as a potentially important and revealing manifestation of spontaneous neuronal activity. Although several challenges remain, these studies have provided insight into the intrinsic functional architecture of the brain, variability in behaviour and potential physiological correlates of neurological and psychiatric disease. PMID- 17704813 TI - The effect of neurodegenerative diseases on the subventricular zone. AB - During brain development, one of the most important structures is the subventricular zone (SVZ), from which most neurons are generated. In adulthood the SVZ maintains a pool of progenitor cells that continuously replace neurons in the olfactory bulb. Neurodegenerative diseases induce a substantial upregulation or downregulation of SVZ progenitor cell proliferation, depending on the type of disorder. Far from being a dormant layer, the SVZ responds to neurodegenerative disease in a way that makes it a potential target for therapeutic intervention. PMID- 17704814 TI - Can neuroscience be integrated into the DSM-V? AB - To date, the diagnosis of mental disorders has been based on clinical observation, specifically: the identification of symptoms that tend to cluster together, the timing of the symptoms' appearance, and their tendency to resolve, recur or become chronic. The Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Disease, the manuals that specify these diagnoses and the criteria for making them, are currently undergoing revision. It is thus timely to ask whether neuroscience has progressed to the point that the next editions of these manuals can usefully incorporate information about brain structure and function. PMID- 17704815 TI - Crystal structure of human DGCR8 core. AB - A complex of Drosha with DGCR8 (or its homolog Pasha) cleaves primary microRNA (pri-miRNA) substrates into precursor miRNA and initiates the microRNA maturation process. Drosha provides the catalytic site for this cleavage, whereas DGCR8 or Pasha provides a frame for anchoring substrate pri-miRNAs. To clarify the molecular basis underlying recognition of pri-miRNA by DGCR8 and Pasha, we determined the crystal structure of the human DGCR8 core (DGCR8S, residues 493 720). In the structure, the two double-stranded RNA-binding domains (dsRBDs) are arranged with pseudo two-fold symmetry and are tightly packed against the C terminal helix. The H2 helix in each dsRBD is important for recognition of pri miRNA substrates. This structure, together with fluorescent resonance energy transfer and mutational analyses, suggests that the DGCR8 core recognizes pri miRNA in two possible orientations. We propose a model for DGCR8's recognition of pri-miRNA. PMID- 17704817 TI - An iron-sulfur domain of the eukaryotic primase is essential for RNA primer synthesis. AB - Primases synthesize the RNA primers that are necessary for replication of the parental DNA strands. Here we report that the heterodimeric archaeal/eukaryotic primase is an iron-sulfur (Fe-S) protein. Binding of the Fe-S cluster is mediated by an evolutionarily conserved domain at the C terminus of the large subunit. We further show that the Fe-S domain is essential to the unique ability of the eukaryotic primase to start DNA replication. PMID- 17704816 TI - Release of autoinhibition of ASEF by APC leads to CDC42 activation and tumor suppression. AB - Autoinhibition of the Rho guanine nucleotide exchange factor ASEF is relieved by interaction with the APC tumor suppressor. Here we show that binding of the armadillo repeats of APC to a 'core APC-binding' (CAB) motif within ASEF, or truncation of the SH3 domain of ASEF, relieves autoinhibition, allowing the specific activation of CDC42. Structural determination of autoinhibited ASEF reveals that the SH3 domain forms an extensive interface with the catalytic DH and PH domains to obstruct binding and activation of CDC42, and the CAB motif is positioned adjacent to the SH3 domain to facilitate activation by APC. In colorectal cancer cell lines, full-length, but not truncated, APC activates CDC42 in an ASEF-dependent manner to suppress anchorage-independent growth. We therefore propose a model in which ASEF acts as a tumor suppressor when activated by APC and inactivation of ASEF by mutation or APC truncation promotes tumorigenesis. PMID- 17704818 TI - Molecular basis of messenger RNA recognition by the specific bacterial repressing clamp RsmA/CsrA. AB - Proteins of the RsmA/CsrA family are global translational regulators in many bacterial species. We have determined the solution structure of a complex formed between the RsmE protein, a member of this family from Pseudomonas fluorescens, and a target RNA encompassing the ribosome-binding site of the hcnA gene. The RsmE homodimer with its two RNA-binding sites makes optimal contact with an 5' A/UCANGGANGU/A-3' sequence in the mRNA. When tightly gripped by RsmE, the ANGGAN core folds into a loop, favoring the formation of a 3-base-pair stem by flanking nucleotides. We validated these findings by in vivo and in vitro mutational analyses. The structure of the complex explains well how, by sequestering the Shine-Dalgarno sequence, the RsmA/CsrA proteins repress translation. PMID- 17704819 TI - Endocannabinoid metabolism and uptake: novel targets for neuropathic and inflammatory pain. AB - Cannabinoid CB1 and CB2 receptors are located at key sites involved in the relaying and processing of noxious inputs. Both CB1 and CB2 receptor agonists have analgesic effects in a range of models of inflammatory and neuropathic pain. Importantly, clinical trials of cannabis-based medicines indicate that the pre clinical effects of cannabinoid agonists may translate into therapeutic potential in humans. One of the areas of concern with this pharmacological approach is that CB1 receptors have a widespread distribution in the brain and that global activation of CB1 receptors is associated with adverse side effects. Studies of the endogenous cannabinoids (endocannabinoids) have demonstrated that they are present in most tissues and that in some pain states, such as neuropathic pain, levels of endocannabinoids are elevated at key sites involved in pain processing. An alternative approach that can be used to harness the potential therapeutic effects of cannabinoids is to maximise the effects of the endocannabinoids, the actions of which are terminated by re-uptake and metabolism by various enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL) and cyclooxygenase type 2 (COX2). Preventing the metabolism, or uptake, of endocannabinoids elevates levels of these lipid compounds in tissue and produces behavioural analgesia in models of acute pain. Herein we review recent studies of the effects of inhibition of metabolism of endocannabinoids versus uptake of endocannabinoids on nociceptive processing in models of inflammatory and neuropathic pain. PMID- 17704820 TI - Novel approaches to developing new antibiotics for bacterial infections. AB - Antibiotics are an essential part of modern medicine. The emergence of antibiotic resistant mutants among bacteria is seemingly inevitable, and results, within a few decades, in decreased efficacy and withdrawal of the antibiotic from widespread usage. The traditional answer to this problem has been to introduce new antibiotics that kill the resistant mutants. Unfortunately, after more than 50 years of success, the pharmaceutical industry is now producing too few antibiotics, particularly against Gram-negative organisms, to replace antibiotics that are no longer effective for many types of infection. This paper reviews possible new ways to discover novel antibiotics. The genomics route has proven to be target rich, but has not led to the introduction of a marketed antibiotic as yet. Non-culturable bacteria may be an alternative source of new antibiotics. Bacteriophages have been shown to be antibacterial in animals, and may find use in specific infectious diseases. Developing new antibiotics that target non multiplying bacteria is another approach that may lead to drugs that reduce the emergence of antibiotic resistance and increase patient compliance by shortening the duration of antibiotic therapy. These new discovery routes have given rise to compounds that are in preclinical development, but, with one exception, have not yet entered clinical trials. For the time being, the majority of new antibiotics that reach the marketplace are likely to be structural analogues of existing families of antibiotics or new compounds, both natural and non-natural which are screened in a conventional way against live multiplying bacteria. PMID- 17704821 TI - Characterization of 4-(2-hydroxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p fluorobenzamido]ethyl]piperazine (p-DMPPF) as a new potent 5-HT1A antagonist. AB - BACKGROUND AND PURPOSE: The identification of potent and selective radioligands for the mapping of 5-HT receptors is interesting both for clinical and experimental research. The aim of this study was to compare the potency of a new putative 5-HT(1A) receptor antagonist, p-DMPPF, (4-(2-hydroxyphenyl)-1-[2'-[N (2''-pyridinyl)-p-fluorobenzamido]ethyl]piperazine) with that of the well-known 5 HT(1A) antagonists, WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N (2-pyridinyl) cyclohexanecarboxamide) and its fluorobenzoyl analogue, p-MPPF (4 (2-methoxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-fluorobenzamido]ethyl]piperazine). EXPERIMENTAL APPROACH: Single cell extracellular recordings of dorsal raphe (DR) neurones were performed in rat brain slices. The potency of each compound at antagonizing the effect of the 5-HT(1A) agonist, 8-OH-DPAT [8-hydroxy-2-(di-n propylamino)-tetraline], was quantified using the Schild equation. The pharmacological profile of p-DMPPF was defined using competition binding assays. KEY RESULTS: Consistently with a 5-HT(1A) receptor antagonist profile, incubation of slices with an equimolar (10 nM) concentration of each compound markedly reduced the inhibitory effect of 8-OH-DPAT on the firing rate of DR neurones, causing a significant rightward shift in its concentration-response curve. The rank order of potency of the antagonists was WAY-100635>p-DMPPF>or=p-MPPF. The sensitivity of DR neurones to the inhibitory effect of 8-OH-DPAT was found to be heterogeneous. The binding experiments demonstrated that p-DMPPF is highly selective for 5-HT(1A) receptors, with a K(i) value of 7 nM on these receptors. CONCLUSIONS AND IMPLICATIONS: The potency of the new compound, p-DMPPF, as a 5 HT(1A) antagonist is similar to that of p-MPPF in our electrophysiological assay. Its selectivity towards 5-HT(1A) receptors makes it a good candidate for clinical development. PMID- 17704822 TI - Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability. AB - BACKGROUND AND PURPOSE: The present study addressed the effects of the investigational PDE4 inhibitor roflumilast on leukocyte-endothelial cell interactions and endothelial permeability in vivo and in vitro. EXPERIMENTAL APPROACH: In vivo, intravital video-microscopy was used to determine effects of roflumilast p.o. on leukocyte-endothelial cell interactions and microvascular permeability in rat mesenteric venules. In vitro, the effects of roflumilast N oxide, the active metabolite of roflumilast in humans, and other PDE4 inhibitors on neutrophil adhesion to tumour necrosis factor alpha (TNFalpha)-activated human umbilical vein endothelial cells (HUVEC), E-selectin expression and thrombin induced endothelial permeability was evaluated. Flow cytometry was used to determine the effect of roflumilast on N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced CD11b upregulation on human neutrophils. KEY RESULTS: In vivo, roflumilast, given 1 h before lipopolysaccharide (LPS), dose-dependently reduced leukocyte-endothelial cell interactions in rat mesenteric postcapillary venules. It also diminished histamine-induced microvascular permeability. Immunohistochemical analyses revealed that roflumilast prevented LPS-induced endothelial P- and E-selectin expression. In vitro, roflumilast N-oxide concentration-dependently suppressed neutrophil adhesion to TNFalpha-activated HUVEC and CD11b expression on fMLP-stimulated neutrophils. It also reduced TNFalpha-induced E-selectin expression on HUVEC, when PDE3 activity was blocked. HUVEC permeability elicited by thrombin was concentration-dependently suppressed by roflumilast N-oxide. While roflumilast N-oxide was as potent as roflumilast at inhibiting stimulated endothelial cell and neutrophil functions, both compounds were significantly more potent than the structurally unrelated PDE4 inhibitors, rolipram or cilomilast. CONCLUSIONS AND IMPLICATIONS: These findings further support earlier observations on the inhibition of inflammatory cell influx and protein extravasation by roflumilast in vivo. PMID- 17704824 TI - Cannabinoids go nuclear: evidence for activation of peroxisome proliferator activated receptors. AB - Cannabinoids act at two classical cannabinoid receptors (CB1 and CB2), a 7TM orphan receptor and the transmitter-gated channel transient receptor potential vanilloid type-1 receptor. Recent evidence also points to cannabinoids acting at members of the nuclear receptor family, peroxisome proliferator-activated receptors (PPARs, with three subtypes alpha, beta (delta) and gamma), which regulate cell differentiation and lipid metabolism. Much evidence now suggests that endocannabinoids are natural activators of PPAR alpha. Oleoylethanolamide regulates feeding and body weight, stimulates fat utilization and has neuroprotective effects mediated through activation of PPAR alpha. Similarly, palmitoylethanolamide regulates feeding and lipid metabolism and has anti inflammatory properties mediated by PPAR alpha. Other endocannabinoids that activate PPAR alpha include anandamide, virodhamine and noladin. Some (but not all) endocannabinoids also activate PPAR gamma; anandamide and 2 arachidonoylglycerol have anti-inflammatory properties mediated by PPAR gamma. Similarly, ajulemic acid, a structural analogue of a metabolite of Delta(9) tetrahydrocannabinol (THC), causes anti-inflammatory effects in vivo through PPAR gamma. THC also activates PPAR gamma, leading to a time-dependent vasorelaxation in isolated arteries. Other cannabinoids which activate PPAR gamma include N arachidonoyl-dopamine, HU210, WIN55212-2 and CP55940. In contrast, little research has been carried out on the effects of cannabinoids at PPAR delta. In this newly emerging area, a number of research questions remain unanswered; for example, why do cannabinoids activate some isoforms and not others? How much of the chronic effects of cannabinoids are through activation of nuclear receptors? And importantly, do cannabinoids confer the same neuro- and cardioprotective benefits as other PPAR alpha and PPAR gamma agonists? This review will summarize the published literature implicating cannabinoid-mediated PPAR effects and discuss the implications thereof. PMID- 17704823 TI - Role and regulation of acylethanolamides in energy balance: focus on adipocytes and beta-cells. AB - The endocannabinoid, arachidonoylethanolamide (AEA), and the peroxisome proliferator-activated receptor (PPAR)-alpha ligand, oleylethanolamide (OEA) produce opposite effects on lipogenesis. The regulation of OEA and its anti inflammatory congener, palmitoylethanolamide (PEA), in adipocytes and pancreatic beta-cells has not been investigated. We report here the results of studies on acylethanolamide regulation in these cells during obesity and hyperglycaemia, and provide an overview of acylethanolamide role in metabolic control. We analysed by liquid chromatography-mass spectrometry OEA and PEA levels in: 1) mouse 3T3F442A adipocytes during insulin-induced differentiation, 2) rat insulinoma RIN m5F beta cells kept in 'low' or 'high' glucose, 3) adipose tissue and pancreas of mice with high fat diet-induced obesity (DIO), and 4) in visceral fat or blood of obese or type 2 diabetes (T2D) patients. In adipocytes, OEA levels remain unchanged during differentiation, whereas those of PEA decrease significantly, and are under the negative control of both leptin and PPAR-gamma. PEA is significantly downregulated in subcutaneous adipose tissue of DIO mice. In RIN m5F insulinoma beta-cells, OEA and PEA levels are inhibited by 'very high' glucose, this effect being enhanced by insulin, whereas in cells kept for 24 h in 'high' glucose, they are stimulated by both glucose and insulin. Elevated OEA and PEA levels are found in the blood of T2D patients. Reduced PEA levels in hypertrophic adipocytes might play a role in obesity-related pro-inflammatory states. In beta-cells and human blood, OEA and PEA are down- or up-regulated under conditions of transient or chronic hyperglycaemia, respectively. PMID- 17704826 TI - Endocannabinoids and the haematological system. AB - Endocannabinoids are blood borne and may also be secreted by the endothelium. Accordingly, there has been interest in the interactions between (endo)cannabinoids and blood cells. There is certainly evidence that (endo)cannabinoids may promote platelet activation, indicating that they may be thrombogenic. Platelets are involved both in the metabolism and release of endocannabinoids, and so it is possible that their circulating levels may be regulated by platelets. This process is altered in disease states such that platelet-derived endocannabinoids contribute towards hypotension in cardiovascular shock. Not only may endocannabinoids regulate platelet function and possibly lead to thrombogenesis, but they may also influence haematopoiesis. Given these emerging roles, the aim of this review is to examine the interactions between cannabinoids and blood. PMID- 17704827 TI - The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects. AB - BACKGROUND AND PURPOSE: Atypical cannabinoids are thought to cause vasodilatation through an as-yet unidentified 'CBx' receptor. Recent reports suggest GPR55 is an atypical cannabinoid receptor, making it a candidate for the vasodilator 'CBx' receptor. The purpose of the present study was to test the hypothesis that human recombinant GPR55 is activated by atypical cannabinoids and mediates vasodilator responses to these agents. EXPERIMENTAL APPROACH: Human recombinant GPR55 was expressed in HEK293T cells and specific GTPgammaS activity was monitored as an index of receptor activation. In GPR55-deficient and wild-type littermate control mice, in vivo blood pressure measurement and isolated resistance artery myography were used to determine GPR55 dependence of atypical cannabinoid-induced haemodynamic and vasodilator responses. KEY RESULTS: Atypical cannabinoids O-1602 and abnormal cannabidiol both stimulated GPR55-dependent GTPgammaS activity (EC50 approximately 2 nM), whereas the CB1 and CB2-selective agonist WIN 55,212-2 showed no effect in GPR55-expressing HEK293T cell membranes. Baseline mean arterial pressure and heart rate were not different between WT and GPR55 KO mice. The blood pressure-lowering response to abnormal cannabidiol was not different between WT and KO mice (WT 20+/-2%, KO 26+/-5% change from baseline), nor was the vasodilator response to abnormal cannabidiol in isolated mesenteric arteries (IC50 approximately 3 micro M for WT and KO). The abnormal cannabidiol vasodilator response was antagonized equivalently by O-1918 in both strains. CONCLUSIONS: These results demonstrate that while GPR55 is activated by atypical cannabinoids, it does not appear to mediate the vasodilator effects of these agents. PMID- 17704828 TI - The molecular mechanism of the inhibition by licofelone of the biosynthesis of 5 lipoxygenase products. AB - BACKGROUND AND PURPOSE: Licofelone is a dual inhibitor of the cyclooxygenase and 5-lipoxygenase (5-LO) pathway, and has been developed for the treatment of inflammatory diseases. Here, we investigated the molecular mechanisms underlying the inhibition by licofelone of the formation of 5-LO products. EXPERIMENTAL APPROACH: The efficacy of licofelone to inhibit the formation of 5-LO products was analysed in human isolated polymorphonuclear leukocytes (PMNL) or transfected HeLa cells, as well as in cell-free assays using respective cell homogenates or purified recombinant 5-LO. Moreover, the effects of licofelone on the subcellular redistribution of 5-LO were studied. KEY RESULTS: Licofelone potently blocked synthesis of 5-LO products in Ca(2+)-ionophore-activated PMNL (IC(50)=1.7 microM) but was a weak inhibitor of 5-LO activity in cell-free assays (IC(50)>>10 microM). The structures of licofelone and MK-886, an inhibitor of the 5-LO activating protein (FLAP), were superimposable. The potencies of both licofelone and MK-886 in ionophore-activated PMNL were impaired upon increasing the concentration of arachidonic acid, or under conditions where 5-LO product formation was evoked by genotoxic, oxidative or hyperosmotic stress. Furthermore, licofelone prevented nuclear redistribution of 5-LO in ionophore-activated PMNL, as had been observed for FLAP inhibitors. Finally, licofelone as well as MK-886 caused only moderate inhibition of the synthesis of 5-LO products in HeLa cells, unless FLAP was co-transfected. CONCLUSIONS AND IMPLICATIONS: Our data suggest that the potent inhibition of the biosynthesis of 5-LO products by licofelone requires an intact cellular environment and appears to be due to interference with FLAP. PMID- 17704825 TI - GPR55 and the vascular receptors for cannabinoids. AB - CB1 and CB2 receptors mediate most responses to cannabinoids but not some of the cardiovascular actions of endocannabinoids such as anandamide and virodhamine, or those of some synthetic agents, like abnormal cannabidiol (abn-cbd). These agents induce vasorelaxation which is antagonised by rimonabant but only at high concentrations relative to those required to block CB1 receptors. Vasorelaxation to anandamide is sensitive to Pertussis toxin (though that to abn-cbd is not), and so is thought to be mediated by a G protein-coupled receptor through Gi/o. An orphan receptor, GPR55, apparently a cannabinoid receptor, is activated by abn cbd, but is not the receptor mediating vasorelaxation to this agent, as the response persists in vessels from GPR55 knockout mice. However, the activity of anandamide in GPR55 knockout mice is not yet reported and so the role of GPR55 as a cannabinoid receptor mediating vascular responses has yet to be finalised. PMID- 17704834 TI - H(1) and H(2) receptors in the locus ceruleus are involved in the intracerebroventricular histamine-induced carotid sinus baroreceptor reflex resetting in rats. AB - Objective To investigate the role of H(1) and H(2) receptors in the locus ceruleus (LC) in carotid sinus baroreceptor reflex (CSR) resetting induced by intracerebroventricular (i.c.v.) injection of histamine (HA). Methods The left and right carotid sinus regions were isolated from the systemic circulation in 18 male Sprague-Dawley rats anesthetized with pentobarbital sodium. The intracarotid sinus pressure (ISP) was altered in a stepwise manner in vivo. ISP-mean arterial pressure (MAP) relationship curve and its characteristic parameters were constructed by fitting to the logistic function with five parameters. The changes in CSR performance induced by i.c.v. HA and the effects of pretreatment with H(1) or H(2) receptors selective antagonist, chlorpheniramine (CHL) or cimetidine (CIM) into the LC, on the responses of CSR to HA were examined. Results I.c.v. HA (100 ng in 5 mu l) significantly shifted the ISP-MAP relationship curve upwards (P < 0.05) and obviously decreased the value of the reflex parameters such as MAP range and maximum gain (P < 0.05), but increased the threshold pressure, saturation pressure and ISP at maximum gain (P < 0.05). The pretreatment with CHL (0.5 mu g in 1 mu l) or CIM (1.5 mu g in 1 mu l) into the LC could obviously attenuate the changes mentioned above in CSR performance induced by HA, but the alleviative effect of CIM was less remarkable than that of CHL (P < 0.05). Respective microinjection of CHL or CIM alone into the LC with the corresponding dose and volume did not change CSR performance significantly (P > 0.05). Conclusion Intracerebroventricular administration of HA results in a rapid resetting of CSR and a decrease in reflex sensitivity, and the responses of CSR to HA may be mediated, at least in part, by H(1) and H(2) receptors activities in the LC, especially by H(1) receptors. Moreover, the effects of the central HA on CSR might be related to a histaminergic descending pathway from the hypothalamus to LC. PMID- 17704833 TI - Vesicular glutamate transporter-immunoreactivities in the vestibular nuclear complex of rat. AB - Objective Aims to delineate the distribution profile of three isoforms of vesicular glutamate transporter (VGluT), viz. VGluT1-3, and their cellular localization within vestibular nuclear complex (VNC). Methods Brain sections from normal Sprague-Dawley rats were processed immunohistochemically for VGluT detection, employing avidin-biotinylated peroxidase complex method with 3-3' diaminobenzidine (DAB) as chromogen. Results The whole VNC expressed all of the three transporters that were observed to be localized to the fiber endings. Compared with VGluT1 and VGluT3, VGluT2 demonstrated a relatively homogeneous distribution, with much higher density in VNC. VGluT3 displayed the highest density in lateral vestibular nucleus and group X, contrasting with the sparse immunostained puncta within vestibular medial and inferior nuclei. Conclusion Glutamtatergic pathways participate in the processing of vestibular signals within VNC mainly through the re-uptake of glutamate into synaptic vesicles by VGluT1 and 2, whereas VGluT3 may play a similar role mainly in areas other than medial and inferior nuclei of VNC. PMID- 17704832 TI - Immunohistochemical investigation of voltage-gated potassium channel-interacting protein 1 in normal rat brain and Pentylenettrazole-induced seizures. AB - Objective To explore the possible role of voltage-gated potassium channel interacting protein 1 (KChIP1) in the pathogenesis of epilepsy. Methods Sprague Dawley female adult rats were treated with pentylenettrazole (PTZ) to develop acute and chronic epilepsy models. The approximate coronal sections of normal and epilepsy rat brain were processed for immunohistochemistry. Double-labeling confocal microscopy was used to determine the coexistence of KChIP1 and gamma aminobutyric acid (GABA). Results KChIP1 was expressed abundantly throughout adult rat brain. KChIP1 is highly co-localize with GABA transmitter in hippocampus and cerebral cortex. In the acute PTZ-induced convulsive rats, the number of KChIP1-postive cells was significantly increased especially in the regions of CA1 and CA3 (P < 0.05); whereas the chronic PTZ-induced convulsive rats were found no changes. The number of GABA-labeled and co-labeled neurons in the hippocampus appeared to have no significant alteration responding to the epilepsy-genesis treatments. Conclusion KChIP1 might be involved in the PTZ induced epileptogenesis process as a regulator to neuronal excitability through influencing the properties of potassium channels. KChIP1 is preferentially expressed in GABAergic neurons, but its changes did not couple with GABA in the epileptic models. PMID- 17704835 TI - Activation of ERK1/2 in spinal cord contributes to the development of acute cystic pain in rabbits. AB - Objective To investigate the role of activated extracellular signal-regulated kinase 1/2 (ERK1/2) in spinal cord in the development of cystic pain in rabbit. Methods We observed the relationship between the activation of ERK1/2 in spinal cord and nociceptive behaviors, as well as the effect of U0126, a mitogen activated protein kinase (MEK, upstream protein of ERK1/2) inhibitor, on cystic pain in rabbits by behavioral test, immunohistochemistry and western blot analysis. Results After injecting 0.5 ml formalin into gallbladder, the behaviors such as grasping of the cheek and licking of the abdomen increased in 30 min, with a significant increase in pERK1/2 expression in the spinal cord, as well as the pERK1/2 immunoreactive cells located in laminae V-VII and X of the dorsal horn and ventral horn of T6 spinal cord. Administration of U0126 (100 - 400 mu g/kg body weight, i.v., 10 min before instillation of formalin) could attenuated nociceptive behaviors dose-dependently, but could not restrain the nociceptive behaviors completely even at the maximal efficient dose of 400 mu g/kg body weight. Conclusion Activated ERK1/2 in the spinal cord at least partly participates in the development of acute inflammatory cystic pain induced by formalin in rabbits. PMID- 17704830 TI - New insights into human prostacyclin receptor structure and function through natural and synthetic mutations of transmembrane charged residues. AB - BACKGROUND AND PURPOSE: The human prostacyclin receptor (hIP), a G-protein coupled receptor (GPCR) expressed mainly on platelets and vascular smooth muscle cells, plays important protective roles in the cardiovascular system. We hypothesized that significant insights could be gained into the structure and function of the hIP through mutagenesis of its energetically unfavourably located transmembrane charged residues. EXPERIMENTAL APPROACH: Within its putative transmembrane helices fourteen hydrophilic residues, both unique and conserved across GPCRs, were systematically mutated to assess for effects on receptor structure and function. KEY RESULTS: Mutations of ten of the fourteen charged residues to alanine exhibited defective binding and/or activation. Key potential interactions were identified between 6 core residues; E116(3.49)-R117(3.50) (salt bridge TMIII), D274(7.35)-R279(7.40) (salt bridge TMVII), and D60(2.50) D288(7.49) (H-bond network TMII-TMVII). Further detailed investigation of E116(3.49) (TMIII) with mutation to a glutamine showed a 2.6-fold increase in agonist-independent basal activity. This increase in activity accounts for a proportion ( approximately 13%) of full agonist induced activation. We further characterized two novel naturally occurring human mutations, R77(2.33)C and R279(7.40)C recently identified in a 1455 human genomic DNA sample screen. The R77(2.33)C variant appeared to exclusively affect expression, while the R279(7.40)C variant, exhibited considerable deficiencies in both agonist binding and activation. CONCLUSIONS AND IMPLICATIONS: Transmembrane charged residues play important roles in maintaining the hIP binding pocket and ensuring normal activation. The critical nature of these charged residues and the presence of naturally occurring mutations have important implications in the rational design of prostacyclin agonists for treating cardiovascular disease. PMID- 17704836 TI - Beneficial effects of BV2 cell on proliferation and neuron-differentiating of mesenchymal stem cells in the circumstance of injured PC12 cell supernatant. AB - Objective The microglias is the representative of immune cells in the brain. It plays dual roles of both repairing and damaging in injured nervous system, and works as an inevitable component of the circumstance of injured neurons. This study was aiming at the effects of the microglias on the biological activities of mesenchymal stem cells (MSCs) in the circumstance of injured neurons. Methods MSCs were obtained by primary culture. We adopted PC12 cells (PC12) and BV2 cells (BV2) to substitute for neurons and microglias, respectively. PC12 were injured by aged Abeta(1-40) and the supernatant of the injured PC12 was used to set up the circumstance of injured neurons. Transwells were used for co-culture of BV2 and MSCs, which allowed the independent detection of cells after co-culture. Immunofluorescence was used to identify MSCs and neuron-differentiating cells with CD44 and neuron specific enolase (NSE) staining, respectively. MTT assay was adopted to measure the proliferation. Results In the circumstance of both BV2 presence and injured PC12 supernatant incubation, either the proliferation or the differentiation of MSCs reached the highest, which seemed to be contradictory, but we gave our explanations. With the BV2 co-culture, the proliferation of MSCs tend to be higher, but the neuron-differentiating MSCs were similar to those incubated without BV2 co-culture either in normal or injured in PC12 supernatant. With the incubation of injured PC12 supernatant, the neuron-differentiating cells were significantly higher than that of control (P < 0.05). Conclusion In the circumstance of injured neurons, microlgias tend to promote the MSCs proliferation. Although not helpful in neuron-differentiating, microglias did not exert any negative effect either. PMID- 17704831 TI - Characterization of the vasorelaxant mechanisms of the endocannabinoid anandamide in rat aorta. AB - BACKGROUND AND PURPOSE: Studies in isolated preparations of vascular tissue (mainly resistance vessels) provide evidence that anandamide exerts vasorelaxation. The aim of the present work was to further characterize the mechanisms involved in the vascular response induced by anandamide in a conduit vessel, rat aorta. EXPERIMENTAL APPROACH: Isometric tension changes in response to a cumulative concentration-response curve of anandamide (1 nM-100 micro M) were recorded in aortic rings from male Wistar rats. The involvement of a number of factors in this relaxation was investigated including endothelium-derived vasorelaxant products, cannabinoid and vanilloid receptors (transient potential vanilloid receptor-1 (TRPV1)), release of calcitonin gene-related peptide (CGRP), anandamide metabolism and the membrane transporter for anandamide. KEY RESULTS: Anandamide caused a significant concentration-dependent vasorelaxation in rat aorta. This vasorelaxation was significantly inhibited by Pertussis toxin, by a non-CB1/non-CB2 cannabinoid receptor antagonist, by endothelial denudation, by inhibition of nitric oxide synthesis or inhibition of prostanoid synthesis via cyclooxygenase-2 (COX-2), by blockade of prostaglandin receptors EP4 and by a fatty acid amino hydrolase inhibitor. Antagonists for CB1, CB2, TRPV1 or CGRP receptors, an inhibitor of the release of endothelium-derived hyperpolarizing factor, and an inhibitor of anandamide transport did not modify the vascular response to anandamide. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate, for the first time, the involvement of the non-CB1/non-CB2 cannabinoid receptor and an anandamide-arachidonic acid-COX-2 derived metabolite (which acts on EP4 receptors) in the endothelial vasorelaxation caused by anandamide in rat aorta. PMID- 17704837 TI - Priming stimulation modifies synaptic plasticity in the perforant path of hippocampal slice in rat. AB - Objective The potential of all central nervous system synapses to exhibit long term potentiation (LTP) or long term depression (LTD) is subject to modulation by prior synaptic activity, a higher-order form of plasticity that has been termed metaplasticity. This study is designed to examine the plasticity and metaplasticity in the lateral perforant path of rat. Methods Field potential was measured with different priming and conditioning stimulation protocols. Results Ten-hertz priming, which does not affect basal synaptic transmission, caused a dramatic reduction in subsequent LTP at lateral perforant path synapses in vitro, and the reduced LTP lasted for at least 2 h. The LTD was unaffected. The reduction of LTP in the lateral perforant path was also readily induced by applying priming antidromically at the mossy fibers. Conclusion Priming with 10 Hz, which is within a frequency range observed during physiological activity, can cause potent, long-lasting inhibition of LTP, but not LTD. This form of metaplasticity adds a layer of complexity to the activity-dependent modification of synapses within the dentate gyrus. PMID- 17704829 TI - Alkylation of prohibitin by cyclohexylphenyl-chloroethyl urea on an aspartyl residue is associated with cell cycle G(1) arrest in B16 cells. AB - BACKGROUND AND PURPOSE: Phenyl-chloroethyl ureas (CEUs) are a class of anticancer drugs that mainly react with proteins. Two molecules of this family, cyclohexylphenyl-chloroethyl urea (CCEU) and iodophenyl-chloroethyl urea (ICEU) induced G(1)/S and G(2)/M cell cycle blocks, respectively. We hypothesised that these observations were linked to a differential protein alkylation pattern. EXPERIMENTAL APPROACH: Proteins from B16 cells incubated with [(14)C-urea]-CCEU and [(125)I]-ICEU were compared by 2D-analyses followed by MALDI-TOF identification of modified proteins and characterisation of the CCEU binding. Protein expression was investigated by Western blot analyses and cell cycle data were obtained by flow cytometry. KEY RESULTS: Several proteins (PDIA1, PDIA3, PDIA6, TRX, VDAC2) were alkylated by both ICEU and CCEU but beta-tubulin and prohibitin (PHB) were specifically alkylated by either ICEU or CCEU respectively. Specific alkylation of these two proteins might explain the observed difference in B16 cell cycle arrest in G(2) and G(1) phases respectively. Mass spectrometry studies on the alkylated prohibitin localised the modified peptide and identified Asp-40 as the target for CCEU. This alkylation induced an increased cellular content of PHB that should contribute to the accumulation of cells in G(1) phase. CONCLUSIONS AND IMPLICATIONS: This study reinforces our findings that CEUs alkylate proteins through an ester linkage with an acidic amino acid and shows that PHB alkylation contributes to G(1)/S arrest in CCEU treated B16 cells. Modification of PHB status and/or activity is an open route for new cancer therapeutics. PMID- 17704838 TI - The role of DJ-1 in the pathogenesis of Parkinson's disease. AB - Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder characterized clinically by bradykinesia, rigidity, tremor, gait dysfunction, and postural instability. Several genes have been identified for monogenic disorders that variably resemble Parkinson's disease. Here, we focus on PARK7, a gene relates to an autosomal recessive form of early-onset Parkinsonism and encodes a protein named DJ-1. Though the exact role of DJ-1 needs to be elucidated, it is generally thought to be functioned as a molecular chaperone and an oxidative sensor (or antioxidative factor). We will review the protective role of DJ-1 to prevent dopaminergic neurons in the substantia nigra pars compacta (SNpc) from degeneration and how its dysfunction would lead to neurodegeneration. PMID- 17704839 TI - Visual functional changes during acute elevation of intraocular pressure. AB - Glaucoma is closely related to elevation of intraocular pressure (IOP). Many studies have done on the effect of chronic elevation of IOP on the retina and optic nerve, but less attention was paid to the effect of acute elevated IOP. Here we briefly review experimental studies on functional changes of the visual system from the retina to the visual cortex under acute elevated IOP condition, which is similar to that of acute primary angle-closure glaucoma. PMID- 17704840 TI - The role of synphilin-1 in the pathogenesis of Parkinson's disease. AB - Parkinson's disease (PD) is one of the commonest neurodegenerative disorders characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the appearance of Lewy bodies (LBs), whose cytoplasmic inclusions are highly enriched with ubiquitin, synphilin-1, alpha-synuclein and parkin. Synphilin-1 is an alpha-synuclein-binding protein and a major component of LBs. It is widely accepted that synphilin-1 is involved in the pathogenic process of PD. This review will provide an overall view of the role of synphilin-1 in the pathogenesis of Parkinson's disease and the latest findings in this field. PMID- 17704841 TI - Repeated morphine treatment influences operant and spatial learning differentially. AB - OBJECTIVE: To investigate whether repeated morphine exposure or prolonged withdrawal could influence operant and spatial learning differentially. METHODS: Animals were chronically treated with morphine or subjected to morphine withdrawal. Then, they were subjected to two kinds of learning: operant conditioning and spatial learning. RESULTS: The acquisition of both simple appetitive and cued operant learning was impaired after repeated morphine treatment. Withdrawal for 5 weeks alleviated the impairments. Single morphine exposure disrupted the retrieval of operant memory but had no effect on rats after 5-week withdrawal. Contrarily, neither chronic morphine exposure nor 5-week withdrawal influenced spatial learning task of the Morris water maze. Nevertheless, the retrieval of spatial memory was impaired by repeated morphine exposure but not by 5-week withdrawal. CONCLUSION: These observations suggest that repeated morphine exposure can influence different types of learning at different aspects, implicating that the formation of opiate addiction may usurp memory mechanisms differentially. PMID- 17704843 TI - Growth enhancement effect of BzATP on primary cultured astrocytes from rat brain. AB - OBJECTIVE: To explore whether BzATP could promote the growth of primary cultured astrocytes (AS) of rat and its possible mechanism, and whether TGF-beta1 was involved in the event. METHODS: The primary cultured ASs were derived from new born Sprague-Dawley rats. Glial fibrillary acidic protein (GFAP) immunofluorescent staining was used to check the purity of cultured AS. Morphometry was used to detect the changes of AS. The proliferation index of AS was detected by BrdU incorporation assay. Western blot was used to detect the changes of GFAP under different conditions. Changes of TGF-beta1 gene transcription were detected by RT-PCR. ELISA was utilized to detect the variation of TGF-beta1 protein in the supernate. RESULTS: The purity of primary cultured AS reached 99%. BzATP promoted the hypertrophy of AS including the elongation of AS processes and the enlargement of cell bodies, BzATP also promoted the expression of GFAP in existence of Ca2+, but had no effect on cell proliferation. BzATP increased the transcription of TGF-beta1 mRNA and the release of TGF-beta1 protein in existence of Ca2+. TGF-beta1 neutralizing antibody partially inhibited the expression of GFAP induced by BzATP, but had no effect on AS proliferation and cell morphology. CONCLUSION: BzATP enhanced the hypertrophy of primary cultured AS, increased the expression of GFAP partially through TGF-beta1. Mechanisms of the enhancement of AS growth induced by BzATP other than TGF-beta1 pathway remain to be elucidated. PMID- 17704842 TI - Effect of water restrictions on the physiological parameters, psychological behavior and brain c-Fos expression in rats. AB - OBJECTIVE: In order to characterize the feature of stress response induced by stressor with both physical and psychological natures, the effects of water restriction performed in different experimental modes on the physiological parameters, psychological behavioral manifestations and brain c-Fos expressions were observed and compared. METHODS: Fifty-eight male Wistar rats were used and randomly divided into three experimental groups (n = 18 for each) and a control group (n = 4). In control group, the rats were allowed to access drinking water freely at all experimental period. In the experimental groups the water supply to the rats was restricted. In timed water supply (TW) group, the water was supplied twice a day, 10 min for each in fixed hours every day. In empty bottle-served (EB) and water-restricted (WR) groups, the water was served only once a day for 10 min, either in the early morning or evening, and in the other time point scheduled for water supply only an empty bottle without water was provided in the EB group and nothing was given in the WR group. The quantities of drank water and eaten food, weight-gaining, and behavior score were observed every day. The serum level of corticosterone was assayed and the rats were sacrificed with fixative perfusion of 3 d, 7 d or 14 d, respectively, following water restriction (n = 6 for each time point in each group). The brain c-Fos expressions were examined with immunohistochemical method. RESULTS: The slow down of weight-gaining, rise of serum corticosterone level, occurrence of psychological behavioral manifestations of unpeaceful restlessness such as exploring and attacking, enhance of c-Fos expression in the subfornical organ (SFO), median preoptic nucleus (MnPO), area postrema (AP), hypothalamic paraventricular nucleus (PVN), supraoptic nucleus (SON), medial (MeA) and central (CeA) amygdaloid nucleus and ventrolateral septum (LSV) were noticed in both EB and WR groups, except the nucleus of solitary tract (NTS) in which the Fos expression was decreased. The changes of Fos expression in most of nuclei in EB group began at day 3, at least persisted till day 7, and backed down at day 14, while in WR group, similar changes started at day 7 and reached its peak at day 14. In TW group, only the concentration of corticosterone at day 7 was slightly increased and the rest indexes observed were unchanged. CONCLUSION: The results indicate that water restriction induces physical as well as psychological stress responses. And the water restrictions experimentally executed in different modes result in different manifestations of behavioral response and brain immediately early gene expression in discrete brain nuclei/regions. PMID- 17704844 TI - Mechanism of over-activation in direct pathway mediated by dopamine D1 receptor in rats with levodopa-induced dyskinesia. AB - OBJECTIVE: To study the changes of prodynorphin (PDyn) gene expression and dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) phosphorylation in rats with levodopa-induced dyskinesia (LID), and to explore the mechanism of over-activation in direct pathway mediated by dopamine D1 receptor. METHODS: Parkinson's disease (PD) rats were received levodopa (10 mg/kg, i.p.) for 28 d to get the LID rats. According to the behavior scale, LID rats were divided into mild (n = 8) and severe (n = 16) groups. On day 29, 8 rats in severe LID group were given an acute intraperitoneal injection of MK-801 (0.1 mg/kg) 15 min before levodopa treatment (MK-801 group, n = 8). The normal rats received same course and dosage of levodopa as the control group (n = 8). Hybridization in situ was used to measure the expression of PDyn mRNA in striatum. Protein and mRNA levels of total DARPP-32 and phospho-Thr-34 DARPP-32 level were measured by immunoblotting and RT-PCR, respectively. RESULTS: The levels of PDyn mRNA and phospho-Thr-34 DARPP-32 increased significantly in LID rats compared with control rats (P < 0.01), and they also increased markedly in severe LID group compared with mild group (P < 0.01). CONCLUSION: Phospho-Thr-34 DARPP-32 level was increased in LID rats, which contributed to the over-activation of direct pathway mediated by dopamine D1 receptor. PMID- 17704845 TI - Electroencephalogram and evoked potential parameters examined in Chinese mild head injury patients for forensic medicine. AB - OBJECTIVE: To evaluate the usefulness of quantitative electroencephalogram (QEEG), flash visual evoked potential (F-VEP) and auditory brainstem responses (ABR) as indicators of general neurological status. METHODS: Comparison was conducted on healthy controls (n = 30) and patients with brain concussion (n = 60) within 24 h after traumatic brain injury. Follow-up study of patient group was completed with the same standard paradigm 3 months later. All participants were recorded in multi-modality related potential testing in both early and late concussion at the same clinical setting. Glasgow coma scale, CT scanning, and physical examinations of neuro-psychological function, optic and auditory nervous system were performed before electroencephalogram (EEG) and evoked potential (EEG EP) testing. Any participants showed abnormal changes of clinical examinations were excluded from the study. Average power of frequency spectrum and power ratios were selected for QEEG testing, and latency and amplitude of F-VEP and ABR were recorded. RESULTS: Between patients and normal controls, the results indicated: (1) Highly significance (P < 0.01) in average power of alpha1 and power ratios of theta/alpha1, theta/alpha2, alpha1/alpha2 of EEG recording; (2) N70-P100 amplitude of F-VEP in significant difference at early brain concussion; and (3) apparent prolongation of I-III inter-peak latency of ABR appeared in some individuals at early stage after concussion. The follow-up study showed that some patients with concussion were also afflicted with characteristic changes of EEG components for both increments of alpha1 average power and theta/alpha2 power ratio after 3 months recording. CONCLUSION: EEG testing has been shown to be more effective and sensitive than evoked potential tests alone on detecting functional state of patients with mild traumatic brain injury (MTBI). Increments of alpha1 average power and theta/alpha2 power ratio are the sensitive EEG parameters to determining early concussion and evaluating outcome of post-concussion symptoms (PCS). Follow-up study associated with persistent PCS may be consistent with the postulate of substantial biological, rather than psychological origin. The study suggests that combination of EEG and EP parameters can contribute to the evaluation of brain function as a whole for clinical and forensic applications. PMID- 17704846 TI - Inflammatory mechanism in ischemic neuronal injury. AB - Inflammation has been implicated as a secondary mechanism underlying neuronal injury induced by ischemia. A variety of experimental models, including thromboembolic stroke, focal and global ischemia, have been used to evaluate contributions of inflammation to neuronal damage. The vasculature endothelium promotes inflammation through upregulation of adhesion molecules such as intercellular adhesion molecule (ICAM), E-selectin, and P-selectin that bind to circulating leukocytes and facilitate migration of leukocytes into the central nervous system (CNS). Once being in the CNS, leukocytes produce cytotoxic molecules that promote cell death. The response of macrophages and microglia to injury may either be beneficial by scavenging necrotic debris or be detrimental by facilitating cell death of neurons that would otherwise recover. While many studies have tested these hypotheses, the significance of inflammation in stroke models is inconclusive. This review summarizes data regarding roles of cell adhesion molecules, astrocytes, microglia and leukocytes in stroke. PMID- 17704847 TI - Nogo, a star protein in reticulon family. AB - Nogo is widely expressed in higher vertebrate animals. Nogo gene gives rise to multiple isoforms. All the subtypes of Nogo proteins are characterized by a 200 amino-acid C-terminal domain, including two long hydrophobic sequences. Biological functions of Nogo include inhibition of neurite growth from the cell surface via specific receptors, intracellular trafficking, cell division and apoptosis. Here, we briefly review the elementary structure, taxonomic distribution and tissue expression of Nogo, summarize recent discoveries about localization of Nogo and mechanism of action, and discuss the possible functions of Nogo. PMID- 17704848 TI - Neuroprotective effects of receptor imidazoline 2 and its endogenous ligand agmatine. AB - Receptor imidazoline 2 (I2) is one of the imidazoline receptors with high affinity for [3H]-idazoxan. Receptor I2, being classified into I(2A) and I(2B) subtypes, is mainly localized to the outer membrane of mitochondria in liver, kidney and brain. Receptor I2, displaying high similarity of sequence with monoamine oxidase-B (MAO-B), is structurally related to MAO-B, but the I2 imidazoline binding site (I2BS) with ligand is distinct from the catalytic site of MAO-B. Agmatine is the endogenous ligand of receptor I2. Accumulating evidence have revealed that the activation of receptors I2 may produce neuroprotective effects by increasing expression of glial fibrillary acidic protein (GFAP) in astrocytes, inhibiting activity of MAO, reducing calcium overload in cells. Agmatine exerts neuroprotection against ischemia-hypoxia, injury, glutamate induced neurotoxicity by activating imidazoline receptors, blocking N-methyl-D aspartate (NMDA) receptor, inhibiting all isoforms of nitric oxide synthase (NOS), and selectively blocking the voltage-gated calcium channels (VGCC). It would be expected that agmatine is one of the potential neuroprotective agents. PMID- 17704849 TI - Effects of glucocorticoids on apoptosis and clearance of apoptotic cells. AB - The glucocorticoid (GC) drugs are one of the most commonly prescribed and effective anti-inflammatory agents used for the treatment of many inflammatory disorders through their ability to attenuate phlogistic responses. The glucocorticoid receptor (GCR) primarily mediates GC actions via activation or repression of gene expression. GCs directly induce the expression of proteins displaying anti-inflammatory activities. However, the likely predominant effect of GCs is the repression of multiple inflammatory genes that invariably are overexpressed during nonresolving chronic inflammation. Although most GC actions are mediated through regulation of transcription, rapid nongenomic actions have also been reported. In addition, GCs modulate inflammatory cell survival, inducing apoptosis in immature thymocytes and eosinophils, while delaying constitutive neutrophil apoptosis. Importantly, GCs promote noninflammatory phagocytosis of apoptotic cell targets, a process important for the successful resolution of inflammation. Here, the effects and mechanisms of action of GC on inflammatory cell apoptosis and phagocytosis will be discussed. PMID- 17704850 TI - Swimming and persons with mild persistant asthma. AB - The aim of our study was to analyze the effect of recreational swimming on lung function and bronchial hyperresponsiveness (BHR) in patients with mild persistent asthma. This study included 65 patients with mild persistent asthma, who were divided into two groups: experimental group A (n = 45) and control group B (n = 20). Patients from both groups were treated with low doses of inhaled corticosteroids (ICS) and short-acting beta2 agonists salbutamol as needed. Our program for patients in group A was combined asthma education with swimming (twice a week on a 1-h basis for the following 6 months). At the end of the study, in Group A, we found a statistically significant increase of lung function parameters FEV1 (forced expiratory volume in 1 sec) (3.55 vs. 3.65) (p < 0.01), FVC (forced vital capacity) (4.27 vs. 4.37) (p < 0.05), PEF (peak expiratory flow) (7.08 vs. 7.46) (p < 0.01), and statistically significant decrease of BHR (PD20 0.58 vs. 2.01) (p < 0.001). In Group B, there was a statistically significant improvement of FEV1 3.29 vs. 3.33 (p < 0.05) and although FVC, FEV1/FVC, and PEF were improved, it was not significant. When Groups A and B were compared at the end of the study, there was a statistically significant difference of FVC (4.01 vs. 4.37), FEV1 (3.33 vs. 3.55), PEF (6.79 vs.7.46), and variability (p < 0.001), and statistically significantly decreased BHR in Group A (2.01 vs. 1.75) (p < 0.001). Engagement of patients with mild persistent asthma in recreational swimming in nonchlorinated pools, combined with regular medical treatment and education, leads to better improvement of their parameters of lung function and also to more significant decrease of their airway hyperresponsiveness compared to patients treated with traditional medicine. PMID- 17704851 TI - Gastric signet-ring cell carcinoma: unilateral lower extremity lymphoedema as the presenting feature. PMID- 17704852 TI - Syncytin and cancer cell fusions. PMID- 17704853 TI - Effect of lime, humic acid and moisture regime on the availability of zinc in Alfisol. AB - Lime and humic acid application can play an important role in the availability of zinc in paddy soils. We conducted laboratory incubation experiments on a rice growing soil (Alfisol) to determine the effect of lime, humic acid and different moisture regimes on the availability of Zn. Addition of half doses of liming material (powdered lime stone) recorded highest values of DTPA-Zn followed by no lime and 100% of lime requirement throughout the incubation period. With the progress of incubation, DTPA-Zn increased slightly during the first week and then decreased thereafter. The highest DTPA-extractable Zn content of 2.85 mg/kg was found in the treatment Zn10 L1/2 at 7 days of incubation, showing 17.3 % increase in DTPA-Zn content over its corresponding treatment of Zn alone (Zn10L0). The DTPA-Zn concentration increased with the application of humic acid compared with no humic acid throughout 35 days of the incubation period and the peak value obtained was 3.12 mg/kg in the treatment Zn10 HA2 at 14 days after incubation, showing 50 % increase in Zn content over its corresponding treatment of Zn alone (Zn10HA0). The application of 0.2% humic acid compared with 0.1% resulted in greater increase in DTPA-Zn concentration in soil application. During the 35 days of incubation, highest values of DTPA-Zn were recorded in soil maintained at saturated compared to water logged conditions. However, under alternate wetting and drying condition the DTPA-Zn content gradually decreased up to 21 days and thereafter increased slowly. PMID- 17704854 TI - Proteoglycan biosynthesis during chondrogenic differentiation of mesenchymal stem cells. AB - Mesenchymal stem cells are multipotent progenitor cells that can differentiate into the chondrogenic lineage. To date, only limited knowledge about the formation and remodeling of the cartilaginous extracellular matrix is available. We recently analyzed the coordinated expression of proteins involved in the biosynthesis of proteoglycans and collagens, the two major components of cartilage matrix, to understand matrix formation and to provide potential tools to improve the quality of tissue-engineered cartilage. PMID- 17704855 TI - A comprehensive review of quality of life (QOL) research in Hong Kong. AB - Published quality of life (QOL) studies in Hong Kong indexed in the major databases were reviewed. Several observations are highlighted from this review. First, most of the published studies were empirical studies involving data collection. Second, there are more micro studies utilizing individual QOL indices than macro studies using societal indicators. Third, most studies addressed personal well-being, followed by studies on family well-being and societal well being. Fourth, the studies were predominantly quantitative in nature. Fifth, most of the studies were based on adults and comparatively fewer studies were based on children and adolescents. Sixth, most studies were based on populations with special needs, followed by studies based on the general population, helping professionals, and caregivers. Seventh, most studies used measures of QOL rather than developed QOL measures. Finally, QOL data in Hong Kong were seldom compared with those in other places. The gaps on QOL studies in Hong Kong and future research directions are discussed. PMID- 17704856 TI - Non-traditional management of the neurogenic bladder: tissue engineering and neuromodulation. AB - Patients with spina bifida and a neurogenic bladder have traditionally been managed with clean intermittent catheterization and pharmacotherapy in order to treat abnormal bladder wall dynamics, protect the upper urinary tract from damage, and achieve urinary continence. However, some patients will fail this therapy and require surgical reconstruction in the form of bladder augmentation surgery using reconfigured intestine or stomach to increase the bladder capacity while reducing the internal storage pressure. Despite functional success of bladder augmentation in achieving a low pressure reservoir, there are several associated complications of this operation and patients do not have the ability to volitionally void. For these reasons, alternative treatments have been sought. Two exciting alternative approaches that are currently being investigated are tissue engineering and neuromodulation. Tissue engineering aims to create new bladder tissue for replacement purposes with both "seeded" and "unseeded" technology. Advances in the fields of nanotechnology and stem cell biology have further enhanced these tissue engineering technologies. Neuromodulation therapies directly address the root of the problem in patients with spina bifida and a neurogenic bladder, namely the abnormal relationship between the nerves and the bladder wall. These therapies include transurethral bladder electrostimulation, sacral neuromodulation, and neurosurgical techniques such as selective sacral rhizotomy and artificial somatic-autonomic reflex pathway construction. This review will discuss both tissue engineering techniques and neuromodulation therapies in more detail including rationale, experimental data, current status of clinical application, and future direction. PMID- 17704858 TI - Morphological and phylogenetic analysis of Anabaenopsis abijatae and Anabaenopsis elenkinii (nostocales, cyanobacteria) from tropical inland water bodies. AB - Anabaenopsis spp. are heterocytous cyanobacteria commonly found in tropical, subtropical, and temperate water bodies. So far, the knowledge about the phylogeny of this genus is poor. Therefore, we have isolated 15 Anabaenopsis spp. strains from Kenyan and Mexican alkaline and saline water bodies and from a Ugandan freshwater body and studied the morphology and phylogeny in a polyphasic approach. Morphologically, the investigated strains could be discriminated in two groups. One group was containing six Anabaenopsis abijatae and A. cf. abijatae strains with up to more than 500 vegetative cells in one filament, mostly single intercalary heterocyte formation, and the ability to branch out. The other group comprised nine strains of Anabaenopsis elenkinii with short filaments with up to 38 vegetative cells, intercalary heterocytes in pairs, and no ability to branch out. The morphological differences were reflected in the two distinct clusters, which were found in the phylogenetic trees of 16S rDNA and PC-IGS. While the high 16S rDNA similarity values > 97.5% found between all investigated A. abijatae and A. elenkinii strains support the assignment of these two species to one single genus, the morphological differences and the low similarity values (< 87.3) found in PC-IGS sequences between the two clusters indicate two separate genera. A close morphological and phylogenetic relationship was found for A. abijatae and Anabaenopsis (Cyanospira) rippkae. PMID- 17704857 TI - Related factors of urge, stress, mixed urinary incontinence and overactive bladder in reproductive age women in Tabriz, Iran: a cross-sectional study. AB - Urinary incontinence remains a pressing problem, particularly for women. So this study was conducted to assess risk factors for stress, urge, mixed urinary incontinence and overactive bladder (OVB). Three hundred and thirty women aged 15 49, non-pregnant, non-breastfeeding who were referred to gynecologic clinics were surveyed. A questionnaire was used to collect data. Women with no symptoms related to urinary incontinence (UI) and OVB served as the reference group. The risk of all types of UI and OVB increased with constipation. Posterior pelvic organ prolapse was associated with stress and urge incontinence. Vaginal delivery was a predictor of stress, urge and mixed incontinence. BMI and PID were predictors of OVB. Pelvic muscle strength was a predictor of stress incontinence. Vaginal length was associated with mixed incontinence. Optimal weight gain, having a healthy lifestyle, treatment of constipation and pelvic organ prolapse, and improving pelvic floor muscle strength can be suggested as preventive measures against UI and OVB. Pelvic measurement can be included in evaluation of UI. PMID- 17704861 TI - Videolaparoscopic appendectomy: the current outlook. PMID- 17704859 TI - Ideal manipulation angle and instrument length in hand-assisted laparoscopic surgery. AB - BACKGROUND: This study aimed to investigate the impact of manipulation angles and instrument length on task performance and muscle workload in hand-assisted laparoscopic surgery. METHODS: The standard task was to close a 5-cm enterotomy of porcine small bowel inside a hand-assisted laparoscopic trainer. Surgeons were instructed to place the sutures 3 to 5 mm apart and from the enterotomy edge. Ten surgeons participated in each experiment. In the first experiment, each surgeon performed one task for each of the following manipulation angles: 45 degrees , 60 degrees , 75 degrees , and 90 degrees . In the second experiment, each surgeon performed two sessions of three tasks using either standard-length (330 mm) or short (250 mm) needle holders in the external hand. Outcome measures were execution time (s), placement error score (mm deviation from exact placement), leaking pressure (mmHg), and muscle workload by upper extremities as measured by integrated electromyography (mV s). RESULTS: In the first experiments, the mean execution time was significantly longer with 90 degrees angles than with 45 degrees and 60 degrees manipulation angles (1,074.9 vs 715.9 s and 657.9 s with p < 0.05 and p < 0.01, respectively). The 90 degrees manipulation angle had the greatest muscle workload by the deltoid and trapezius of the extracorporeal and intracorporeal limbs and the extracorporeal dominant arm extensor and flexor groups. In the second experiment, the short instruments had a shorter mean execution time than the standard-length instrument (572.05 vs 618.75 s; p < 0.01). There was less muscle workload with the short than with the standard length instrument by the extracorporeal dominant forearm extensor and flexor muscle groups and the deltoid of extracorporeal dominant and intracorporeal limbs. There were no significant differences in leaking pressure or placement error score between the different manipulation angles and instrument lengths. CONCLUSION: The best ergonomic setup in hand-assisted laparoscopic surgery entails a manipulation angle of 45 degrees to 60 degrees and use of an instrument with a shorter shaft than standard laparoscopic length. PMID- 17704862 TI - Disappointing results with a 5 cm calibrating device for laparoscopic vertical banded gastroplasty. AB - BACKGROUND: The gastric outlet represents a critical point of laparoscopic vertical banded gastroplasty (LVBG): the diameter and the material used to calibrate the gastric outlet are essential for long-term success. We present the results of our initial clinical experience with the Proring band, a new calibrating device specifically designed to calibrate LVBG outlet. METHODS: Between February and April 2004, 13 LVBG were performed using the Proring band. There were 12 women and one man; their mean age was 44 years; mean preoperative weight was 118.8 kg; mean body mass index (BMI) was 44.4 kg/m(2). RESULTS: The immediate postoperative course was uneventful in all cases. In the follow-up 10 patients out of 13 (76.9%) presented a sudden or progressive food intolerance. Five patients were immediately reoperated by laparoscopic approach and five underwent endoscopic dilatation with initial clinical improvement; early recurrence of symptoms despite further dilatations occurred in four out of five cases. These four patients were then reoperated. Therefore a total of nine (69.2%) patients underwent a laparoscopic reoperation with Proring band removal and its replacement with a polypropylene band. In seven cases an intraoperative endoscopic dilatation was associated with the laparoscopic procedure. Outcome was successful in all cases, with discharge after two days. CONCLUSION: The results of our experience using the Proring band are unsatisfactory, showing 76.9% with outlet stenosis and 69.2% with reoperations. These data compare negatively with our previous experience on more than 900 VBG procedures using polypropylene mesh. PMID- 17704863 TI - Laparoscopic cholecystectomy for severe acute cholecystitis. A meta-analysis of results. AB - OBJECTIVE: The aim of this review was to evaluate surgical outcomes of laparoscopic cholecystectomy for gangrenous and empyematous acute cholecystitis defined as severe acute cholecystitis. BACKGROUND: It is not known to what extent surgical outcomes of laparoscopic cholecystectomy for severe acute cholecystitis differ from those for the nonsevere acute form, making it questionable whether urgent laparoscopic cholecystectomy is the best approach even in severe acute cases. METHODS: Literature searches were conducted to identify: (1) comparative studies which reported laparoscopic surgical outcomes separately for severe acute and nonsevere acute cholecystitis; (2) studies comparing such an approach with open cholecystectomy, subtotal laparoscopic cholecystectomy or cholecystostomy in severe acute cholecystitis. Results were pooled by standard meta-analytic techniques. RESULTS: Seven studies with a total of 1,408 patients undergoing laparoscopic cholecystectomy were found. The risks of conversion (RR 3.2, 95% CI 2.5 to 4.2) and overall postoperative complications (RR 1.6, 95% CI 1.2-2.2) were significantly higher in severe acute cholecystitis with respect to the nonsevere acute forms. However, no difference was detected as regards to local postoperative complications. No studies comparing open cholecystectomy or cholecystostomy with urgent laparoscopy were found. CONCLUSION: A lower feasibility of laparoscopic cholecystectomy has been found for severe cholecystitis. A lower threshold of conversion is recommended since this may allow to reduce local postoperative complications. Literature data lack valuable comparative studies with other treatment modalities, which therefore need to be investigated. PMID- 17704864 TI - Is laparoscopic adrenalectomy safe and effective for adrenal masses larger than 7 cm? AB - BACKGROUND: Laparoscopic adrenalectomy (LA) has become the gold standard treatment for small (less than 6 cm) adrenal masses. However, the role of LA for large-volume (more than 6 cm) masses has not been well defined. Our aim was to evaluate, retrospectively, the outcome of LA for adrenal lesions larger than 7 cm. PATIENTS AND METHODS: 18 consecutive laparoscopic adrenalectomies were performed from 1996 to 2005 on patients with adrenal lesions larger than 7 cm. RESULTS: The mean tumor size was 8.3 cm (range 7-13 cm), the mean operative time was 137 min, the mean blood loss was 182 mL (range 100-550 mL), the rate of intraoperative complications was 16%, and in three cases we switched from laparoscopic procedure to open surgery. CONCLUSIONS: LA for adrenal masses larger than 7 cm is a safe and feasible technique, offering successful outcome in terms of intraoperative and postoperative morbidity, hospital stay and cosmesis for patients; it seems to replicate open surgical oncological principles demonstrating similar outcomes as survival rate and recurrence rate, when adrenal cortical carcinoma were treated. The main contraindication for this approach is the evidence, radiologically and intraoperatively, of local infiltration of periadrenal tissue. PMID- 17704865 TI - Videothoracoscopic thymectomy for nonthymomatous myasthenia gravis: results of 90 patients. AB - BACKGROUND: Videothoracoscopic thymectomy is an alternative surgical procedure for patients with nonthymomatous myasthenia gravis. The aim of this study is to present our experience and to analyze the factors contributing to the operative morbidity. METHODS: Ninety myasthenia gravis patients were operated through right sided videothoracoscopy from June 2002 to September 2006. Prospective data recording was performed. Surgeon-related conversion to open surgery, length of the operation, chest tube duration time, duration of hospital stay, amount of drainage, pain score, and complications were evaluated. Factors contributing to longer operation time and longer postoperative stay were studied. RESULTS: The mean length of chest tube duration and postoperative hospital stay was 26.7 +/- 18.6 hours and 2.2 days +/- 1.1 days respectively. Visual analogue scale (VAS) values for pain evaluation were 2.0 +/- 1.4. Surgeon-related open conversion occured in two patients (2.2%). Body mass index (BMI) was the sole significant factor for longer operation time. (23.04 +/- 2.93 versus 25.61 +/- 2.70 (p = 0.001). The amount of pyridostigmine was the only significant factor for longer hospital stay (213.3 +/- 101.5 mg versus 270. 0 +/- 122.6 mg (p = 0.044). CONCLUSIONS: This study demonstrates the right-sided videothoracoscopy is a safe procedure. The only contributing factors were: BMI >25.61 for longer operation time, and pyridostigmine level >270 mg for duration of postoperative stay. PMID- 17704866 TI - Intermittent pneumatic sequential compression of the lower extremities restores the cerebral oxygen saturation during laparoscopic cholecystectomy. AB - BACKGROUND: Pneumoperitoneum causes intracranial pressure elevation and blood stasis at lower extremities. This study investigates cerebral oxygen saturation changes during laparoscopy and the effects of intermittent sequential compression (ISC) of the lower extremities in patients during elective laparoscopic cholecystectomy. PATIENTS AND METHOD: Sixty patients were randomly divided into two groups according to the application of ISC to the lower extremities. Group I served as control group whereas ISC was applied to group II. Cerebral oxygen saturation, peripheral blood oxygen saturation, heart rate, mean blood pressure, and associated changes have been recorded during the operation. RESULTS: Peripheral blood oxygen saturation and mean blood pressure values did not change significantly after pneumoperitoneum. Cerebral oxygen saturation levels of the group II patients were higher in than the group I patients and the difference between the groups was statistically significant (p = 0.0001). The difference became more prominent following the 35(th) minute of the operation. Mean heart rate of the patients in group II was lower than the patients in group I and the difference was also statistically significant (p = 0.0001). CONCLUSION: In this study, it was found that the decrease in cerebral oxygen saturation was recovered with ISC application. This simple and reliable technique helps to restore cerebral oxygen saturation levels while increasing blood return from the lower extremities. PMID- 17704868 TI - Laparoscopic training on Thiel human cadavers: a model to teach advanced laparoscopic procedures. AB - BACKGROUND: Nowadays, the laparoscopic approach represents the gold standard for a wide range of various basic and advanced procedures. To reduce the learning curve in advanced laparoscopic surgery, the search for new teaching tools is of utmost importance. Our experiences with a new teaching tool to train advanced laparoscopic procedures are reported. METHODS: Hands-on training courses in colon, hernia, bariatric and vascular surgery using Thiel human cadavers (THCs) were organised by the Swiss Association of Laparoscopic and Thoracoscopic Surgery (SALTS). The courses were held by consultant surgeons expert in the field of minimal invasive surgery (MIS). At the end of each course, data was collected using a standardised, anonymous questionnaire using a Likert scale (1 = strongly disagree; 2 = disagree; 3 = neither agree nor disagree; 4 = agree; 5 = strongly agree). Data are presented as mean +/- standard deviation (SD), percentages (%) or total number (n), if indicated. RESULTS: From January 2005 to May 2006, six courses (colon = 2; hernia = 2; bariatric = 1; vascular = 1) were organized with a total of 33 participants (31 consultant surgeons; two senior residents). The authenticity of tissue colour, tissue consistency and operative tactility, respectively, were stated for the courses as follows: colon (mean: 4.4/4.2/4.2), hernia (mean: 4.3/4.2/4.0), bariatric (mean: 4.5/4.8/4.3) and vascular (mean: 2.8/2.8/2.6) courses. A high mean overall satisfaction with the courses (colon: 4.0; hernia: 4.2; bariatric: 5.0 and vascular surgery: 4.1) was also observed. All participants of the colon, bariatric, hernia and vascular courses will recommend the courses to other surgeons. CONCLUSION: Training on THCs might be an excellent additional model to teach advanced bariatric, hernia and colon surgery. However, an important issue that remains to be defined is which training model (THC, anesthetized animals, virtual computer training, etc.) is the most appropriate for the curriculum of the skill or procedure that is being trained. PMID- 17704867 TI - Stent implantation as a treatment option in patients with thoracic anastomotic leaks after esophagectomy. AB - BACKGROUND: In patients with esophagectomy and gastric pull up for esophageal carcinoma anastomotic leaks are a well-known complication and a major cause of morbidity and mortality. OBJECTIVE: We evaluated stent implantation as a treatment option in patients with thoracic anastomotic leaks after esophagectomy. METHODS: 269 patients with esophageal cancer (adenocarcinoma n = 212, squamous cell carcinoma n = 57) had undergone esophagectomy and gastric pull up with an intrathoracic anastomosis between January 1998 and December 2005. A thoracic anastomotic leak was clinically and endoscopically proven in 12 patients (4.5%). Endoscopic insertion of a self-expanding covered metal stent at the site of the anastomotic leak was performed in 10 patients; two patients were treated with fibrin glue. RESULTS: Stents were successfully placed in all patients without complications. In all but one patient (n = 9) radiological examination showed complete closure of the leakage. In one patient the stent was endoscopically corrected and complete closure could be achieved thereafter. The stent could be removed after six weeks in five patients. Stent migration occurred in four patients. In all but one patient (n = 7) definitive leak occlusion was achieved. Two patients died during their hospital stayfor reasons not related to the stent placement. CONCLUSION: Stent implantation in patients with thoracic anastomotic leaks after esophagectomy is an easily available and effective treatment option with low morbidity, but stent migration does occur. PMID- 17704869 TI - The effects of preoperative rofecoxib, metoclopramide, dexamethasone, and ondansetron on postoperative pain and nausea in patients undergoing elective laparoscopic cholecystectomy. AB - BACKGROUND: No trial to date has evaluated the combined effect of preoperative Rofecoxib, Metoclopramide, Dexamethasone, and Ondansetron on postoperative pain and nausea in patients undergoing laparoscopic cholecystectomy (LC). METHODS: A prospective randomized double-blinded placebo-controlled trial was conducted on patients undergoing elective LC. The patients in the intervention group received Rofecoxib 25 mg PO. Additionally the study group received Metoclopramide 10 mg and Dexamethasone 4 mg; and Ondansetron 4 mg intravenously. Pain and nausea were rated preoperatively, on arrival at the postanesthesia care unit (PACU), at points until discharge, and at 24 hours. RESULTS: 97 patients were in the control group, and 108 received intervention. The intervention group had a smaller proportion of men (10% vs. 23%; p < 0.015). There were differences in: length of stay (LOS) until discharge criteria met (12.88 vs. 9.85 hours, p = 0.0006), pain rating on arrival to floor (3.55 vs. 2.48, p = 0.003); highest pain rating (4.38 vs. 3.56, p = 0.032), highest nausea rating (2.99 vs. 1.47, p = 0.001), worst nausea since discharge (2.58 vs. 1.26, p = 0.005), and the use of postoperative anti-emetics in women (64% vs. 37.1%, p = 0.001). CONCLUSIONS: The use of this preoperative regimen resulted in decreased LOS, maximum pain, and nausea ratings. Patients in the intervention group required less postoperative anti-emetics. PMID- 17704870 TI - Effects of experience on force perception threshold in minimally invasive surgery. AB - BACKGROUND: Distorted haptic feedback by the surgical instrumentation is a major problem in minimally invasive surgery (MIS). Friction force generated by the rubber seal in the trocars masks the haptic information needed to perceive the properties and structure of the target tissue, resulting in an increased haptic perception threshold in naive subjects. This can lead to over application of forces in surgery. OBJECTIVE: This paper examines the effect of surgical experience on the psychophysics of force perception and force application efficiency in MIS. METHOD: A controlled experiment was conducted using a mixed design, with friction and vision as independent within-subjects factors, experience as a between-subjects factor, and applied force and detection time as dependent measures. Fourteen subjects (eight novices and six experienced surgeons) performed a simulated tissue probing task. Performance data were recorded by a custom-built force-sensing system. RESULTS: When friction was present, higher thresholds and longer detection times were observed for both experienced and inexperienced subjects. In all cases, experienced surgeons applied a greater force than novices, but were quicker to detect contact with tissue, resulting in higher force application efficiency. CONCLUSION: Surgeons seem to have adapted to the higher threshold in haptic perception by reacting faster, even while applying more force to the tissue, keeping within the limits of safety. PMID- 17704871 TI - Completely transvaginal NOTES cholecystectomy using magnetically anchored instruments. AB - INTRODUCTION: Natural orifice translumenal endoscopic surgery (NOTES) is an evolving field and suitable instruments are lacking. The purpose of this study was to perform transvaginal cholecystectomies using instruments incorporated into a magnetic anchoring and guidance system (MAGS). METHODS: Non-survival procedures were conducted in pigs (n = 4). Through a vaginotomy created under direct vision, a rigid access port was inserted into the peritoneal cavity and used to maintain a CO(2) pneumoperitoneum. MAGS instruments were deployed through the port and held in place on the peritoneal surface using magnetic coupling via an external handheld magnet which was optionally exchanged for an 18 ga percutaneous threaded needle anchor; instruments included a tissue retractor (a clip-fixated magnet or flexible graspers) and a cautery dissector. A gastroscope was used for visualization. RESULTS: The first two procedures ended prematurely due to instrumentation shortcomings and inadvertent magnetic coupling between instruments; one case required a laparoscopic rescue. Three new forms of instrumentation were developed: (1) a longer access port (50 cm) which provided easier deployment of instruments and suitable reach, (2) a more robust cauterizer with a longer, more rigid, pneumatically deployed tip with better reach and sufficient torque to allow blunt dissection, and (3) a more versatile tissue retractor with bidirectional dual flexible graspers which provided excellent cephalad fundus retraction and inferiolateral infundibulum retraction. With these modifications, 100% of the cholecystectomy was completed in the third and fourth animals using only a NOTES/MAGS approach. Retrieval of the tissue retractor resulted in a rectal injury in the third animal but further procedural modifications resulted in a successful procedure in the fourth animal with no complications. CONCLUSIONS: While still under development with more refinements needed, completely transvaginal cholecystectomy using MAGS instruments is feasible. By offering triangulation and rigidity, MAGS may facilitate a NOTES approach while alleviating shortcomings of a flexible platform. PMID- 17704872 TI - Laparoscopic colectomy for apparently benign colorectal neoplasia: A word of caution. AB - PURPOSE: Endoscopically unresectable apparently benign colorectal polyps are considered by some surgeons as ideal for their early laparoscopic colectomy experience. Our hypotheses were: (1) a substantial fraction of patients undergoing laparoscopic colectomy for apparently benign colorectal neoplasia will have adenocarcinoma on final pathology; and (2) in our practice, we perform an adequate laparoscopic oncological resection for apparently benign polyps as evidenced by margin status and nodal retrieval. METHODS: Data from a consecutive series of patients undergoing laparoscopic colectomy (on an intention-to-treat basis) for endoscopically unresectable neoplasms with benign preoperative histology were retrieved from a prospective database and supplemented by chart review. RESULTS: The study population consisted of 63 patients (mean age 67, mean body mass index 29). Two out of 63 cases (3%) were converted to laparotomy because of extensive adhesions (n = 1) and equipment failure (n = 1). Colectomy type: right/transverse (n = 49, 78%); left/anterior resection (n = 10, 16%); subtotal (n = 4, 6%). Invasive adenocarcinoma was found on histological analysis of the colectomy specimen in 14 out of 63 cases (22%), standard error of the proportion 0.052. Staging of the 14 cancers were I (n = 6, 43%), II (n = 3, 21%), III ( = 4, 29%), and IV (n = 1, 7%). The median nodal harvest was 12 and all resection margins were free of neoplasm. Neither dysplasia on endoscopic biopsy nor lesion diameter was predictive of adenocarcinoma. Eight out of 23 (35%) patients with dysplasia on endoscopic biopsy had adenocarcinoma on final pathology versus 6/40 (15%) with no dysplasia (p = 0.114, Fisher's exact test). Mean diameter of benign tumors was 3.2 cm (range 0.5-10.0cm) versus 3.9cm (range 1.5-7.5cm) for adenocarcinomas (p = 0.189, t - test). CONCLUSION: A substantial fraction of endoscopically unresectable colorectal neoplasms with benign histology on initial biopsy will harbor invasive adenocarcinoma, some of advanced stage. This finding supports the practice of performing oncological resection for all patients with endoscopically unresectable neoplasms of the colorectum. The inexperienced laparoscopic colectomist should approach these cases with caution. PMID- 17704873 TI - Robotic-assisted placement of a hepatic artery infusion catheter for regional chemotherapy. AB - Hepatic arterial infusion chemotherapy can be of value to patients with metastatic liver disease from colorectal cancer. Arterial infusion therapy requires surgical placement of a catheter into the gastroduodenal artery connected to a subcutaneous infusion pump or port, a procedure involving major abdominal surgery. Placement of chemotherapy infusion catheters by conventional laparoscopic techniques has been described, but is a technically challenging procedure. The purpose of this report is to introduce a new, minimally invasive approach for hepatic artery catheter placement using the DaVinci robotic system with the potential to minimize surgical trauma, pain, and hospital stay, and to render this minimal access procedure more feasible and widely applicable. PMID- 17704874 TI - The usefulness of preoperative colonoscopic tattooing using a saline test injection method with prepackaged sterile India ink for localization in laparoscopic colorectal surgery. AB - BACKGROUND: Laparoscopic surgery for colorectal neoplasm requires precise tumor localization. The authors have assessed the safety and efficacy of colonoscopic tattooing using a saline test injection method with prepackaged sterile India ink for tumor localization in laparoscopic colorectal surgery. METHODS: Between July 2004 and January 2007, 63 patients underwent colonoscopic tattooing using prepackaged sterile India ink before laparoscopic surgery of colorectal tumors. Patient medical records and operation videos were retrospectively assessed. RESULTS: Tattoos were visualized intraoperatively in 62 (98.4%) of the 63 patients, and colorectal tumors were accurately localized in 61 patients (96.8%). In one patient, the tattoo could not be detected, whereas in another patient, it was visualized but the serosal surface of the rectosigmoid colon was stained diffusely. Both of these patients underwent intraoperative colonoscopy. Localized leakages of ink were identified in six patients (9.5%) during surgery. However, five of these patients had no symptoms, and the sixth patient, who underwent polypectomy and tattooing simultaneously, felt mild chilling without fever or abdominal pain. CONCLUSIONS: Preoperative colonoscopic tattooing using a saline test injection method with prepackaged sterile India ink is a safe and effective method for tumor localization in laparoscopic colorectal surgery. PMID- 17704875 TI - Antireflux surgery for patients with end-stage lung disease before and after lung transplantation. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is prevalent among patients with end-stage lung disease (ESLD). This disease can lead to microaspiration and may be a risk factor for lung damage before and after transplantation. A fundoplication is the best way to stop reflux, but little is known about the safety of elective antireflux surgery for patients with ESLD. This study aimed to report the safety of laparoscopic fundoplication for patients with ESLD and GERD before or after lung transplantation. METHODS: Between January 1997 and January 2007, 305 patients were listed for lung transplantation, and 189 patients underwent the procedure. In 2003, routine esophageal studies were added to the pretransplantation evaluation. After the authors' initial experience, gastric emptying studies were added as well. RESULTS: A total of 35 patients with GERD or delayed gastric emptying were referred for surgical intervention. A laparoscopic fundoplication was performed for 32 patients (27 total and 5 partial). For three patients, a pyloroplasty also was performed. Two patients had a pyloroplasty without fundoplication. Of the 35 operations, 15 were performed before and 20 after transplantation. Gastric emptying of solids or liquids was delayed in 12 (92%) of 13 posttransplantation studies and 3 (60%) of 5 pretransplantation studies. All operations were completed laparoscopically, and 33 patients recovered uneventfully (94%). The median hospital length of stay was 2 days (range, 1-34 days) for the patients admitted to undergo elective operations. Hospitalization was not prolonged for the three patients who had fundoplications immediately after transplantation. CONCLUSIONS: The results of this study show that laparoscopic antireflux surgery can be performed safely by an experienced multidisciplinary team for selected patients with ESLD before or after lung transplantation, and that gastric emptying is frequently abnormal and should be objectively measured in ESLD patients. PMID- 17704876 TI - Day case emergency laparoscopic appendectomy. AB - BACKGROUND: Laparoscopic appendectomy (LA) is associated with a shorter hospital stay and fewer complications than conventional open appendectomy (OA). This study aimed to examine the safety and efficacy of day case emergency LA. METHODS: The records of patients undergoing emergency LA under the care of two laparoscopic surgeons over a 3-year period (Februrary 2003 to February 2006) were reviewed to examine hospital length of stay (LOS), complications, histology, grade of the operating surgeon, and time required to perform the procedure. RESULTS: A total of 104 patients (median age, 25 years; range, 11-72 years; 58 men) underwent LA, with 9 and 66 patients discharged in 8 and 24 hours, respectively (median LOS 22 hours: range 6-170 hours). One patient underwent conversion to OA. Histologically, 86 patients had appendicitis and 18 had normal appendices with another pathology present. The median operative time was 35 min (range, 20-80 min). The complications included three wound infections and two pelvic abscesses not requiring further operative intervention. CONCLUSION: Day case emergency LA is safe and effective for treating selected patients. PMID- 17704879 TI - Multimedia article. Laparoscopic repair of a perforated marginal ulcer 2 years after gastric bypass. AB - The authors present the case of a 43-year-old women who underwent a laparoscopic gastric bypass in 2003 for morbid obesity. They report that 2 years later, she had maintained significant weight loss, but had developed acute abdominal pain, followed by nausea and emesis. In the emergency room, she had diffuse tenderness, tachycardia, and leukocytosis. After initial resuscitation, a computed tomography was performed, which showed free air above the liver and thickened small bowel loops. She was brought emergently to the operating room for laparoscopy. At surgery, turbid fluid and inflamed small bowel loops were seen. A perforated marginal ulcer was discovered in the Roux limb, approximately 2 cm distal to the gastrojejunal anastomosis. The perforation was oversewn primarily and patched with omentum. The repair was tested by intraoperative endoscopy. A gastrostomy tube also was placed within the gastric remnant for enteral access. The patient did extremely well postoperatively, and had an uneventful postoperative course. She was discharged on postoperative day 4. The gastrostomy tube was removed at 1 month, and at this writing, she remains well since surgery. An upper endoscopy at 2 months was completely normal, and the Helicobacter pylori test results were negative. The gastric pouch had not significantly enlarged since initial surgery, as indicated by both endoscopy and barium study. Marginal ulcer is reported to be 0.6% to 16% after laparoscopic gastric bypass. Etiologies include gastrogastric fistula, excessively large gastric pouch containing antral mucosa, H. pylori infection, nonsteroidal antiinflammatory use, and smoking. Unfortunately, none of these applied to the reported patient. Because her exact etiology remains unknown, she at this writing continues to receive proton pump inhibitor therapy. PMID- 17704877 TI - Comparison of robot-assisted laparoscopic adrenalectomy with traditional laparoscopic adrenalectomy - 1 year follow-up. AB - BACKGROUND: Laparoscopic adrenalectomy offers distinct benefits to patients and has now become the gold standard for the removal of adrenal lesions. Nonetheless, the procedure poses a challenge for surgeons in regards to the maneuverability of instruments, the two-dimensional operating field and the counterintuitive movements. This study reports our experience using the Zeus robotic surgical system in laparoscopic adrenalectomy compared with traditional laparoscopic adrenalectomy. PATIENTS AND METHODS: From January 2003 to February 2005, a total of 12 patients were prospectively enrolled to receive robot-assisted laparoscopic adrenalectomy (RALA) or traditional laparoscopic adrenalectomy (TLA). The time necessary for robotic setup and operation was recorded, as well as complications, technical problems, postoperative hospital stay, morbidity, and mortality. RESULTS: Five RALA procedures and seven TLA were successfully completed. There was no significant difference between the groups in terms of age, body mass index, and tumor size. Resection times were longer in the RALA group (168.0 +/- 30.7 min vs. 131.4 +/- 29.0 min, p = 0.05). There were no perioperative complications. There was neither postoperative mortality nor morbidity at the time of discharge and during one year follow-up. CONCLUSIONS: RALA is as safe and technically feasible as TLA, It provides a real benefit for the surgeon with the three dimensional view, a comfortable sitting position, the elimination of the surgeon's tremor, and increased degrees of freedom of the operative instruments compared with TLA. However, patient outcomes and operative costs should be evaluated further. PMID- 17704878 TI - Laparoscopic liver resection for hepatocellular carcinoma. AB - BACKGROUND: Single, small hepatocarcinomas (HCC) are still an indication for partial liver resection in patients ineligible for transplantation. Anatomical resections are recommended for oncological reasons. The mini-invasive approach of laparoscopy should minimize hepatic and parietal injury, thereby decreasing the risk of liver failure and ascites. However, the oncological results of this approach and its presumed benefits remain undemonstrated. We evaluated the short- and midterm results of laparoscopic liver resections for HCC. METHODS: Between 1999 and 2006, we performed 32 laparoscopic liver resections for HCC. Mean tumor size was 3.8 +/- 2 cm and the mean age of the patients was 65 +/- 11 years. Twenty-two patients had cirrhosis (21 Child A and one Child C). Operative and postoperative results were analyzed, together with recurrence and survival rates. RESULTS: We carried out 13 unisegmentectomies, nine bisegmentectomies, one trisegmentectomy, two right hepatectomies, one left hepatectomy, and six atypical resections. The duration of the operation was 231 +/- 101 minutes. Conversion to laparotomy was required in three patients (9%), none in emergency situations. Mean blood loss was 461 ml, with five patients (15.6%) requiring blood transfusion. The mean surgical margin was 10.4 mm. One cirrhotic patient (Child C) underwent surgery for a partially ruptured tumor and died of liver failure. Two patients had ascites and no transient liver failure occurred in the other 19 cirrhotic patients. Mean hospital stay was 7.1 days. During a mean follow-up of 26 months, 10 patients (31%) presented recurrence within the liver. None of the patients had peritoneal carcinomatosis or trocar site recurrence. Three-year overall and disease-free survival rates were 71.9% and 54.5%, respectively. CONCLUSIONS: Laparoscopic liver resection for HCC is feasible and well tolerated. Midterm survival and recurrence rates are similar to those after laparotomy. PMID- 17704880 TI - Self-expandable metallic stents for malignant biliary obstruction with an anomalous pancreaticobiliary junction. AB - BACKGROUND: Anomalous pancreaticobiliary junction (APBJ) is associated with pancreaticobiliary cancer. Limited data are available on endoscopic biliary drainage for unresectable malignant biliary obstruction with APBJ. This study evaluated the efficacy and safety of self-expandable metallic stents (EMSs) for the management of malignant biliary obstruction with APBJ. METHODS: Between 1993 and 2005, 324 patients with unresectable malignant biliary obstruction underwent insertion of an EMS. Six of these patients with concomitant APBJ constituted the subjects of this study. Early (30 days after EMS insertion) stent-related complications and stent patency were evaluated in these six patients. RESULTS: The cause of biliary obstruction was gallbladder cancer in four patients and pancreatic cancer in two patients. Uncovered EMSs were inserted across the common channel without performance of a biliary sphincterotomy. The diameter of the uncovered EMS used was based on the diameter of the common channel. For all six patients, endoscopic biliary drainage was successful, and their jaundice subsided steadily. None of the six patients experienced early complications, including acute pancreatitis. The mean stent related complication-free period was 163 days. Stent occlusion caused by tumor ingrowth occurred in two patients. Acute cholangitis and cholecystitis were observed in one patient each. CONCLUSIONS: Uncovered EMSs are effective for palliation of unresectable malignant biliary obstruction in patients who have APBJ without increasing the risk of stent-related early complications. PMID- 17704881 TI - Midline versus nonmidline laparoscopic incisional hernioplasty: a comparative study. AB - BACKGROUND: Nonmidline incisional hernia is a surgical problem of major interest, but to date, little information on this problem is available. This study aimed to analyze the results of nonmidline laparoscopic incisional hernioplasty in a multidisciplinary abdominal wall unit over the past 10 years. METHODS: This prospective study examined a series of 199 patients undergoing surgery for incisional hernia via the laparoscopic approach: 146 midline and 53 nonmidline. A comparative analysis compared midline and nonmidline defects, and a descriptive analysis compared four nonmidline types: 18 lumbar, 11 subcostal, 14 inguinal, and 10 lateral. Clinical and follow-up parameters were assessed during a mean follow-up period of 64 months (range, 12-120 months). RESULTS: The nonmidline incisional hernias were significantly larger, involved more preoperative pain, and required a longer hospital stay than the midline incisional hernias (p < 0.001). Also, the intraoperative complications and the consumption of analgesics were more frequent in the nonmidline group (p < 0.05). The postoperative morbidity and recurrence rates were similar in the two groups. No statistical differences were noted between the four types of nonmidline incisional hernias. The most common nonmidline type was lumbar hernia (34%). Hematomas (17%) predominated in the inguinal types, and pain predominated in the lumbar types. Two early recurrences were diagnosed for poor mesh placement: one subcostal and one lumbar. CONCLUSIONS: Laparoscopic incisional hernioplasty can be applied to nonmidline defects with the same rates of morbidity and recurrence as for patients with midline defects. The four types of nonmidline defects seem to have their own evolutionary characteristics. PMID- 17704882 TI - Endoscopic submucosal dissection used for treating early neoplasia of the foregut using a combination of knives. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) has emerged as a novel technique for achieving en bloc resection for early esophageal or gastric carcinoma limited to the mucosa. The authors report their experience with a combination of various devices to treat early neoplasia of the foregut using the ESD technique. METHODS: In this prospective case series, ESD was performed for early esophageal or gastric carcinoma limited to the mucosa. These lesions were staged by endoscopic ultrasonography before resection. Magnifying endoscopy and chromoendoscopy were used to locate the tumor and define the margin. The resection was accomplished with submucosal dissection using the insulated tip knife, the hook knife, and the triangular tip knife. The resected specimen was examined systematically for the lateral and deep margins. RESULTS: From January 2004 to March 2006, ESD was performed to manage 30 cases of early gastric or esophageal carcinoma. For 29 of these patients, R0 resection was successfully achieved. The mean operating time was 84.6 min. One patient experienced reactionary hemorrhage 12 h after resection, which was controlled endoscopically. There was no perforation. Most of the circumferential mucosal incisions were performed using the insulated tip knife (76.6%), whereas submucosal dissection was accomplished with a combination of various knives. One of the specimens showed involvement of the lateral margin, whereas another patient had two areas of new early gastric cancer 6 months after the initial procedure. These patients received salvage laparoscopically assisted gastrectomy. CONCLUSIONS: Endoscopic submucosal dissection to manage early neoplasia of the foregut can be achieved safely and effectively with a combination of knives. PMID- 17704883 TI - Hand-assisted versus laparoscopic-assisted colorectal surgery: Practice patterns and clinical outcomes in a minimally-invasive colorectal practice. AB - INTRODUCTION: Laparoscopic assisted (LA) colectomy has significant patient benefits but is technically challenging. Hand-assisted laparoscopic surgery (HALS) allows tactile feedback because the surgeon's hand assists in retraction and dissection. This may decrease the technical difficulty and shorten the learning curve associated with performing laparoscopic colectomy. We investigated the patient selection and short-term clinical outcomes of HALS and LA since the introduction of HALS to our minimally invasive colorectal practice. METHODS: Prospectively collected data on 258 patients undergoing HALS (n = 109) or LA colectomy (n = 149) during a calendar year (2004) were analyzed. Patient and disease characteristics, operative parameters, and perioperative outcomes were compared. RESULTS: HALS patients were similar to LA patients in age (51 vs. 54 yrs), gender (56 vs. 52% male), body mass index (26 vs. 26 kg/m2), comorbidities (84 vs. 85% with one or more), and diagnosis (83 vs. 80% benign), but differed in incidence of previous surgery (49 vs. 30%; P = 0.008). A significantly greater proportion of HALS patients underwent complex procedures and extensive resections. Conversion rates (15 vs. 11%, P = 0.44), intraoperative complications (4 vs. 1%, P = 0.17), 30-day morbidity (18 vs. 11%, P = 0.12) and surgical reinterventions (2 vs. 1%, P = 0.58) did not differ. Recovery measured by days to flatus was not different [mean (standard deviation) 3(2) vs. 3(2) days, P = 0.26], however HALS patients had longer operative times [276(96) vs. 211(107) minutes P < 0.0001] and 1 day longer stay in hospital [6(3) vs. 5 (3) days, P = 0.0009)]. CONCLUSIONS: Patients undergoing HALS underwent more-complex procedures than LA patients but retained the short-term benefits associated with LA colectomy. HALS facilitates expansion of a minimally invasive colectomy practice to include more challenging procedures while maintaining short-term patient benefits. PMID- 17704884 TI - Nissen versus Toupet fundoplication: results of a randomized and multicenter trial. AB - BACKGROUND: Laparoscopic Toupet fundoplication (TF) is reported to be as effective as Nissen (NF), but to be associated with fewer unfavorable postoperative side-effects. This study evaluates the one- and three-year clinical outcome of 140 randomized patients after a laparoscopic NF or TF. PATIENTS AND METHODS: Inclusion criteria included patients over 16 years old with complications of gastro-oesophageal reflux disease (GORD) and persistence or recurrence of symptoms after three months of treatment. Subjects with a previous history of gastric surgery or repeated fundoplication, brachy-oesophagus or severe abnormal manometry results were excluded. Seventy-seven NF and 63 TF were performed. The severity of symptoms was assessed before and after the procedure. RESULTS: One hundred and twenty-one of the 140 patients after one year, and 118 after three years, were evaluated and no statistically significant clinical difference was observed. The level of satisfaction concerning the outcome of the operation remained high after one or three years regardless of the type of fundoplication performed. CONCLUSIONS: Functional complications after NF are not avoided with TF. PMID- 17704885 TI - Evaluation of needle-knife precut papillotomy after unsuccessful biliary cannulation, especially with regard to postoperative anatomic factors. AB - BACKGROUND: Biliary cannulation is the first step in therapeutic endoscopic retrograde cholangiopancreatography. This study aimed to evaluate unsuccessful cases of biliary cannulation in which the standard procedure was changed to a needle-knife precut papillotomy (NKPP), with particular attention given to postoperative anatomic factors. METHODS: Between October 2002 and February 2006, a total of 501 consecutive patients with an intact duodenal papilla were retrospectively investigated. After biliary cannulation using standard maneuvers was unsuccessful within 20 min, NKPP was performed in 80 cases (16%). The clinical backgrounds for difficult biliary cannulation were compared between patients who had standard maneuvers (n = 421, 84%) and those who underwent NKPP. RESULTS: For 76 difficult cannulation cases (95%), successful cannulation after NKPP was accomplished, and the total success rate reached 99% (497/501). Multivariate analysis indicated that female gender (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.34-3.79), left lobe hypertrophy after hepatectomy (OR, 6.25; 95% CI, 2.52-15.54), history of Billroth I reconstruction after gastrectomy (OR, 7.49; 95% CI, 2.55-22.02), and malignant biliary stricture (OR, 2.31; 95% CI, 1.21- 4.41) were significant risk factors associated with unsuccessful standard procedures used for biliary cannulation. Complications after NKPP were observed in nine cases (11%), all of which were pancreatitis. CONCLUSIONS: Difficult biliary cannulation was strongly associated with postoperative anatomic factors. In these situations, early introduction of NKPP should be recommended if the conventional biliary cannulation promises to be difficult. PMID- 17704886 TI - Laparoscopic treatment of type 2 diabetes mellitus for patients with a body mass index less than 35. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a common disease with numerous complications. Bariatric surgery is an efficient procedure for controlling T2DM in morbidly obese patients. In T2DM, the incretin effect is either greatly impaired or absent. This study aimed to evaluate the preliminary results from interposing a segment of ileum into the proximal jejunum associated with a sleeve or diverted sleeve gastrectomy to control T2DM in patients with a body mass index (BMI) less than 35 kg/m(2). METHODS: For this study, 39 patients (16 women and 23 men) underwent two laparoscopic procedures comprising different combinations of ileal interposition into the proximal jejunum via a sleeve or diverted sleeve gastrectomy. The mean age of these patients was 50.3 years (range, 36-66 years). The mean BMI was 30.1 kg/m(2) (range, 23.4-34.9 kg/m(2)). All the patients had a diagnosis of T2DM that had persisted for at least 3 years and evidence of stable treatment with oral hypoglycemic agents or insulin for at least 12 months. The mean duration of T2DM was 9.3 years (range, 3-22 years). RESULTS: The mean operative time was 185 min, and the median hospital stay was 4.3 days. Four major complications occurred in the short term (30-days), and the mortality rate was 2.6%. The mean postoperative follow-up period was 7 months (range, 4-16 months), and the mean percentage of weight loss was 22%. The mean postoperative BMI was 24.9 kg/m(2) (range, 18.9-31.7 kg/m(2)). An adequate glycemic control was achieved for 86.9% of the patients, and 13.1% had important improvement. The patients whose glycemia was not normalized were using a single oral hypoglycemic agent. No patient needed insulin therapy postoperatively. All the patients except experienced normalization of their cholesterol levels. Targeted triglycerides levels were achieved by 71% of the patients, and hypertension was controlled for 95.8%. CONCLUSIONS: The laparoscopic ileal interposition via either a sleeve gastrectomy or diverted sleeve gastrectomy seems to be a promising procedure for the control of T2DM and the metabolic syndrome. A longer follow-up period is needed. PMID- 17704887 TI - The usefulness of chromoendoscopy with methylene blue in Barrett's metaplasia and early esophageal carcinoma. AB - BACKGROUND: Barrett's esophagus is a condition that is premalignant for adenocarcinoma of the esophagus and the esophagogastric junction. Early detection of Barrett's metaplasia and dysplasia is very important to decrease the mortality and morbidity from esophageal adenocarcinoma cancer. This study aimed to evaluate the effectiveness of methylene blue-targeted biopsies in the differential diagnosis of intestinal metaplasia, dysplasia, and superficial esophageal carcinoma. METHODS: A total of 109 patients (43 women and 66 men; average age, 62.32 +/- 10.61 years; range, 33-82 years) were enrolled for the study. Four groups were designed before endoscopic examinations. The patients for these groups were selected at the conventional endoscopy, and then chromoendoscopy was performed. The esophagus was stained with methylene blue, after which six biopsies were taken from stained and unstained areas. RESULTS: Conventional and chromoendoscopic assessments were compared with histopathologic examination. The sensitivity of chromoendoscopy for Barrett's epithelium was superior to that of conventional endoscopy (p < 0.05). However, there was no statistical difference between the two methods in the diagnosis of esophagitis or esophageal carcinoma (p > 0.05). Stained biopsies were superior to unstained biopsies in terms of sensitivity for Barrett's epithelium and esophageal carcinoma (p < 0.001). CONCLUSION: Chromoendoscopy is useful for delineating Barrett's epithelium and for indicating the correct location for securing biopsies where dysplasia or early esophageal cancer is suspected. PMID- 17704889 TI - Virtual reality training for endoscopic surgery: voluntary or obligatory? AB - INTRODUCTION: Virtual reality (VR) simulators have been developed to train basic endoscopic surgical skills outside of the operating room. An important issue is how to create optimal conditions for integration of these types of simulators into the surgical training curriculum. The willingness of surgical residents to train these skills on a voluntary basis was surveyed. METHODS: Twenty-one surgical residents were given unrestricted access to a VR simulator for a period of four months. After this period, a competitive element was introduced to enhance individual training time spent on the simulator. The overall end-scores for individual residents were announced periodically to the full surgical department, and the winner was awarded a prize. RESULTS: In the first four months of study, only two of the 21 residents (10%) trained on the simulator, for a total time span of 163 minutes. After introducing the competitive element the number of trainees increased to seven residents (33%). The amount of training time spent on the simulator increased to 738 minutes. CONCLUSIONS: Free unlimited access to a VR simulator for training basic endoscopic skills, without any form of obligation or assessment, did not motivate surgical residents to use the simulator. Introducing a competitive element for enhancing training time had only a marginal effect. The acquisition of expensive devices to train basic psychomotor skills for endoscopic surgery is probably only effective when it is an integrated and mandatory part of the surgical curriculum. PMID- 17704890 TI - Expandable metal stent placement for benign colorectal obstruction: outcomes for 23 cases. AB - BACKGROUND: Self-expanding metal stents (SEMS) are an established treatment for palliation of malignant colorectal strictures and as a bridge to surgery for acute malignant colonic obstruction. Patients with benign colonic strictures may benefit from stent placement, but little data exist for this indication. METHODS: All cases of colonic stent placement identified from a prospectively collected gastrointestinal database from April 1999 to August 2006 were reviewed. During the study period, 23 patients with benign obstructive disease underwent endoscopic SEMS placement. The etiologies of the stricture were diverticular/inflammatory (n = 16), postsurgical anastomotic (n = 3), radiation induced (n = 3), and Crohn's (n = 1) disease. All strictures were located in the left colon. Five patients had an associated colonic fistula. Uncovered Enteral Wallstents or Ultraflex Precision Colonic stents (Boston Scientific) were endoscopically placed in all but one patient. RESULTS: Stent placement was technically successful for all 23 patients, and obstruction was relieved for 22 patients (95%). Major complications occurred in 38% of the patients including migration (n = 2), reobstruction (n = 4), and perforation (n = 2). Of these major complications, 87% occurred after 7 days. Four patients did not undergo an operation. Of the 19 patients who underwent planned surgical resection, 16 were successfully decompressed and converted from an emergent operation to an elective one with a median time to surgical resection of 12 days (range, 2 days to 18 months). Surgery was delayed more than 30 days after stent placement for six of these patients. Of the 19 patients who underwent a colectomy, 8 (42%) did not need a stoma after stent insertion. CONCLUSIONS: SEMS can effectively decompress high-grade, benign colonic obstruction, thereby allowing elective surgery. The use of SEMS can offer medium-term symptom relief for benign colorectal strictures, but this approach is associated with a high rate of delayed complications. Thus, if elective surgery is planned, data from this small study suggest that it should be performed within 7 days of stent placement. PMID- 17704888 TI - Effect of types of resection and manipulation on trocar site contamination after laparoscopic colectomy: An experimental study in rats with intraluminal radiotracer application. AB - BACKGROUND: The etiology and incidence of port-site metastases after laparoscopic surgery for colorectal cancer remain unknown. The purpose of this experimental study was to detect and quantify the amount of contamination at the port-site by means of a method utilizing radiolabelled colloid particles following extra- or intracorporeal laporoscopic resection of cecum. METHODS: Prior to experimental surgery, we obtained a high concentration of luminal colonic radiotracer activity by per anum application of sulphur colloid molecules labelled with Tc-99m pertechnetate. In three main groups of rats, we either resected a portion of cecum extracorporeally or intracorporeally, or did no resection. Each main group was further divided into two subgroups, in which the manipulations were either autraumatic or traumatic. We excised trocar sites as 2 cm doughnuts after completion of the surgical procedure. We used gamma camera imaging to quantify the amount of radioactive contamination at trocar sites. The background corrected trocar site activity for each rat was calculated. Activities exceeding the maximum background activity were accepted as trocar site contamination. RESULTS: We detected an overall incidence of contamination in 44% of rats. This rate were 71% and 17% in traumatic and atraumatic subgroups. The resection itself increased the rate and intensity of contamination, as well (p = 0.04). The most intensive contamination was detected in the intracorporeal resection with traumatic manipulation subgroup (p = 0.0007). CONCLUSIONS: Both the presence of resection and manipulative trauma seemed to be increasing the rate and intensity of the radioactive activity at the trocar site. When traumatic manipulatiun was exercised, the contamination was so intense that the type of resection did not differ. We concluded that our scintigraphic method would be useful in the intraoperative detection of port site contamination by the tumor cells, and that surgeons would take some preventive measures to prevent future port-site metastases. PMID- 17704892 TI - Functional proteomics to identify critical proteins in signal transduction pathways. AB - Reversible protein phosphorylation plays a crucial role in the regulation of signaling pathways that control various biological responses, such as cell growth, differentiation, invasion, metastasis and apoptosis. Proteomics is a powerful research approach for fully monitoring global molecular responses to the activation of signal transduction pathways. Identification of different phosphoproteins and their phosphorylation sites by functional proteomics provides informational insights into signaling pathways triggered by all kinds of factors. This review summarizes how functional proteomics can be used to answer specific questions related to signal transduction systems of interest. By examining our own example on identifying the novel phosphoproteins in signaling pathways activated by EB virus-encoded latent membrane protein 1 (LMP1), we demonstrated a functional proteomic strategy to elucidate the molecular activity of phosphorylated annexin A2 in LMP1 signaling pathway. Functional profiling of signaling pathways is promising for the identification of novel targets for drug discovery and for the understanding of disease pathogenesis. PMID- 17704891 TI - A suitable animal model for laparoscopic hepatic resection training. AB - BACKGROUND: There is a growing interest in using laparoscopy for hepatic resection. However, structured training is lacking in part because of the lack of an ideal animal training model. We sought to identify an animal model whose liver anatomy significantly resembled that of the human liver and to assess the feasibility of learning laparoscopic hepatic inflow and outflow dissection and parenchyma transection on this model. METHODS: The inflow and outflow structures of the sheep liver were demonstrated via surgical dissection and contrast studies. Laparoscopic left major hepatic resections were performed. RESULTS: The portal hepatis of all 12 sheep (8 for anatomic study and 4 for laparoscopic hepatic resection) resembled that of human livers. The portal vein (PV) was located posteriorly; the common hepatic artery (CHA) and the common bile duct (CBD) were located anterior medially and anterior laterally with respect to the portal hepatis. The main PV bifurcated into a short right and a long left PV. The extrahepatic right PV then bifurcated into right posterior and anterior sectoral PV. The CBD and CHA bifurcated into left and right systems. The cystic duct originated from the right hepatic duct. The cystic artery originated from the right HA in 11/12 animals. The left hepatic vein drained directly into the inferior vena cava (IVC). The middle and the right hepatic veins formed a short common channel before entering the IVC. Multiple venous tributaries drained directly into IVC. Familiarity with sheep liver anatomy allowed laparoscopic left hepatic lobe (left medial and lateral segments) resection to be performed with accuracy and preservation of the middle hepatic vein. CONCLUSIONS: The surgical anatomy of sheep liver resembled that of human liver. Laparoscopic major hepatic resection can be performed with accuracy using this information. Sheep is therefore an ideal animal model for advanced surgical training in laparoscopic hepatic resection. PMID- 17704893 TI - High-throughput capillary electrophoresis method for plasma cysteinylglycine measurement: evidences for a clinical application. AB - Increased levels in plasma homocysteine and cysteine, and more recently, decreased levels in cysteinylglycine have been indicated as a risk factor for vascular diseases. Most assays focused their attention only on homocysteine determination and when also other thiols were measured, analytical times drastically increased. By modifying our previous method for thiols detection, we set up a rapid capillary electrophoresis method for the selective quantification of plasma cysteinylglycine, cutting the analysis time of about 50%. Samples were treated with tri-n-butylphosphine as reducing agent, proteins were precipitated with trichloroacetic acid and released thiols were successively derivatized by the selective thiol laser-induced fluorescence-labeling agent 5 iodoacetamidofluorescein and separated by capillary electrophoresis. A baseline separation between peaks was obtained in about 2 min using 3 mmol/L sodium phosphate/2.5 mmol/L boric acid as electrolyte solution with 75 mmol/L N-methyl-D glucamine at pH 11.25 in a 47 cm long capillary with a cartridge temperature of 45 degrees C. The method application was checked by measuring plasma Cys-Gly levels in a group of patients affected by retinal vein occlusion (RVO), an important cause of visual loss in the elderly. The low levels of Cys-Gly found in the RVO patients suggest that these small thiols may have importance in the disease development. PMID- 17704894 TI - Bicarbonate is a stimulus in the inter-species induced sporulation of strict anaerobic Syntrophomonas erecta subsp. sporosyntropha. AB - Previously Syntrophomonas species had been described as the bacteria those did not form spores, however, in our previous studies, a newly isolated S. erecta subsp. sporosyntropha JCM13344(T) was found to form spores in the co-culture with methanogens, while not in mono-culture or in co-culture with sulfate reducer. In this study, we examined the sporulation stimulus conferred by methanogens in the co-culture. By reducing bicarbonate in mono-culture and sulfate-reducing co culture, we could induce S. erecta subsp. sporosyntropha JCM13344(T) to form spores, so that bicarbonate at lower concentration was determined as another stimulus for sporulation. Based on the substrate degradation by strain JCM13344(T) in different concentration of bicarbonate vs at different pHs, it was suggested that bicarbonate could stimulate the sporulation by mediating a nutrient deprivation but not pH drop. To further confirm the sporulation potential of this group of bacteria, spo0A fragments were amplified from strain JCM13344(T) as well as all the recognized Syntrophomonas species, confirming that they were members of the spore-forming group. Since sporulation is a kind of response of spore-forming bacteria to environmental stresses, the observation in this work implies that stresses can be created even between the mutual beneficial partners, in this case, inducing sporulation. PMID- 17704895 TI - Electroacupuncture alters the expression of genes associated with lipid metabolism and immune reaction in liver of hypercholesterolemia mice. AB - Acupuncture or electroacupuncture (EA) is effective in treating various metabolism disorders. Previously we found that EA at the acupoint, Fenglong (ST40), had the cholesterol-lowering effect and regulated genes expression in liver of hypercholesterolemia mice (M Li and YZ Zhang, Int J Mol Med 2007, 19: 617-629). To explain gene expression associated with EA, suppression subtractive hybridization (SSH), combined with targeted display (TD), was used and 26 up regulated and 24 down-regulated genes with known functions were identified in hypercholesterolemia mice liver, some of which are involved in key reactions of lipid metabolism and immune reaction. Promoting lipid metabolism and suppressing inflammation via modulating mRNA expression may be the mechanism of EA inducing modulation of cholesterol concentrations. PMID- 17704896 TI - The alkaline solution to the emergence of life: energy, entropy and early evolution. AB - The Earth agglomerates and heats. Convection cells within the planetary interior expedite the cooling process. Volcanoes evolve steam, carbon dioxide, sulfur dioxide and pyrophosphate. An acidulous Hadean ocean condenses from the carbon dioxide atmosphere. Dusts and stratospheric sulfurous smogs absorb a proportion of the Sun's rays. The cooled ocean leaks into the stressed crust and also convects. High temperature acid springs, coupled to magmatic plumes and spreading centers, emit iron, manganese, zinc, cobalt and nickel ions to the ocean. Away from the spreading centers cooler alkaline spring waters emanate from the ocean floor. These bear hydrogen, formate, ammonia, hydrosulfide and minor methane thiol. The thermal potential begins to be dissipated but the chemical potential is dammed. The exhaling alkaline solutions are frustrated in their further attempt to mix thoroughly with their oceanic source by the spontaneous precipitation of biomorphic barriers of colloidal iron compounds and other minerals. It is here we surmise that organic molecules are synthesized, filtered, concentrated and adsorbed, while acetate and methane--separate products of the precursor to the reductive acetyl-coenzyme-A pathway-are exhaled as waste. Reactions in mineral compartments produce acetate, amino acids, and the components of nucleosides. Short peptides, condensed from the simple amino acids, sequester 'ready-made' iron sulfide clusters to form protoferredoxins, and also bind phosphates. Nucleotides are assembled from amino acids, simple phosphates carbon dioxide and ribose phosphate upon nanocrystalline mineral surfaces. The side chains of particular amino acids register to fitting nucleotide triplet clefts. Keyed in, the amino acids are polymerized, through acid-base catalysis, to alpha chains. Peptides, the tenuous outer-most filaments of the nanocrysts, continually peel away from bound RNA. The polymers are concentrated at cooler regions of the mineral compartments through thermophoresis. RNA is reproduced through a convective polymerase chain reaction operating between 40 and 100 degrees C. The coded peptides produce true ferredoxins, the ubiquitous proteins with the longest evolutionary pedigree. They take over the role of catalyst and electron transfer agent from the iron sulfides. Other iron-nickel sulfide clusters, sequestered now by cysteine residues as CO-dehydrogenase and acetyl coenzyme-A synthase, promote further chemosynthesis and support the hatchery--the electrochemical reactor--from which they sprang. Reactions and interactions fall into step as further pathways are negotiated. This hydrothermal circuitry offers a continuous supply of material and chemical energy, as well as electricity and proticity at a potential appropriate for the onset of life in the dark, a rapidly emerging kinetic structure born to persist, evolve and generate entropy while the sun shines. PMID- 17704899 TI - [Diagnosis-related groups. Safeguarding and distribution of revenues from the perspective of anaesthesiology]. AB - After 30 years of belt-tightening in the health care system and the mandatory implementation of the German diagnosis-related groups (DRG) system in 2004, the cost pressure on German hospitals has increased again. Cases break even only if prime costs fall below DRG revenues. On the one hand it is required from hospitals that prime costs are evaluated in terms of effectiveness, but on the other hand they have to allow for generation of adequate revenues and performance oriented distribution of profits. This article first presents the political background of the German DRG system and then systematically assesses the different types of reimbursement. Aspects in the field of anaesthesia which are relevant to the generation of adequate revenues are: documentation of intraoperatively occurring diagnoses, documentation of intraoperative procedures, the grouper function "complicating procedure", the demographic attribute "hours on mechanical ventilation" and the issue of supplemental revenues. Following comments on the generation of adequate revenues, the alternative means of internal budgeting, the German DRG case-costing and the percentage of sales method, are discussed. The present contribution is intended to assist readers in the prevailing discussion about economic awareness of the health care market. PMID- 17704897 TI - A role for Haemophilus ducreyi Cu,ZnSOD in resistance to heme toxicity. AB - The Cu,Zn superoxide dismutase (Cu,ZnSOD) from Haemophilus ducreyi is the only enzyme of this class which binds a heme molecule at its dimer interface. To explore the role of the enzyme in this heme-obligate bacterium, a sodC mutant was created by insertional inactivation. No difference in growth rate was observed during heme limitation. In contrast, under heme rich conditions growth of the sodC mutant was impaired compared to the wild type strain. This growth defect was abolished by supplementation of exogenous catalase. Genetic complementation of the sodC mutant in trans demonstrated that the enzymatic property or the heme binding activity of the protein could repair the growth defect of the sodC mutant. These results indicate that Cu,ZnSOD protects Haemophilus ducreyi from heme toxicity. PMID- 17704900 TI - [A 64-year-old female patient with recurring hypoglycaemia. Difficult aspects of diagnosis]. AB - Insulinomas are the most common pancreatic islet cell tumours and are characterised by uncontrolled insulin secretion even in the presence of hypoglycaemia. Diagnosis is usually made by the detection of endogenous hyperinsulinism over a period of fasting. We report the case of a patient with insulinoma without hyperinsulinaemia. A secretion and overexpression of split insulin has to be discussed. The diagnosis was made by endoscopic ultrasound guided fine-needle aspiration and the immunohistochemical detection of chromogranine. In conclusion, the present report demonstrates that insulinomas should be considered and searched for in every case of hypoglycaemia, even when associated with normal insulin levels. It also confirms the essential role of endoscopic ultrasonography in the diagnosis of insulin-secreting tumors. PMID- 17704902 TI - [A 65-year-old female patient with breast cancer accompanied by thrombocytopenia and hyperfibrinolysis]. AB - Tumor diseases can be accompanied by paraneoplastic syndromes. Low platelet counts and hyperfibrinolysis led to the diagnosis of recurrent breast cancer in this case. A tumour disease with disturbed hemostasis caused by both plasmatic coagulation and thrombocytopenia has not yet been reported. PMID- 17704901 TI - [Electrotherapy of cardiac failure]. AB - Intracardiac conduction disturbances, mostly manifested as a left bundle branch block (LBBB), are common findings in cardiac failure and associated with a poor prognosis. LBBB is a marker of disease progression and also leads to worsened cardiac hemodynamics by dyssynchronous contraction that can accelerate progression of the underlying disease. Cardiac resynchronization therapy (CRT) can reduce the negative effects of these disturbances leading to improvement in hemodynamics and long-term improvement in cardiopulmonary exercise tolerance, reduction of left ventricular volumes and functional mitral regurgitation. Prospective multicenter studies, such as the CARE-HF and COMPANION trials have demonstrated reduced mortality with CRT or combined treatment with defibrillator capability (CRT-D). Thus, CRT has been adopted in the current guidelines of cardiology societies. Nevertheless, there are a number of open issues with CRT, such as the high number of non-responders or the value of CRT in patients with atrial fibrillation, narrow QRS complex and mild cardiac failure or asymptomatic left ventricular dysfunction. In addition, the question whether every CRT patient needs a device with defibrillating capabilities is not fully resolved, at least for patients with dilative cardiomyopathy. PMID- 17704903 TI - Primary immune surveillance: some like it hot. AB - The thermal element of fever has been found to be beneficial in models of infectious disease. The contributions of fever-range temperatures to the efficacy of the adaptive immune response have only begun to be delineated. There is accumulating evidence that fever-range thermal stress bolsters primary immune surveillance of lymph nodes and Peyer patches by augmenting lymphocyte extravasation across specialized vessels termed high endothelial venules. Molecular mechanisms have recently come to light by which the thermal component of fever alone may promote lymphocyte trafficking, and thereby the probability of mounting a defense against microbial infection. Acquired knowledge of the molecular changes associated with thermal stress may allow for the development of novel therapies for a variety of disease processes. PMID- 17704904 TI - ENPP1 K121Q polymorphism and obesity, hyperglycaemia and type 2 diabetes in the prospective DESIR Study. AB - AIMS/HYPOTHESIS: We assessed the predictive value of ectonucleotide pyrophosphatase/phosphodiesterase 1 gene (ENPP1) SNPs with regard to the risk of developing obesity and/or type 2 diabetes in a large French general population. METHODS: We genotyped the ENPP1 SNPs K121Q (rs1044498), IVS20delT-11 (rs1799774) and A/G+1044TGA (rs7754561) in 5,153 middle-aged participants of the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort. RESULTS: At baseline, the K121Q polymorphism was not associated either with BMI (p = 0.98) or with class I obesity (odds ratio [OR] 0.99, p = 0.81), but showed a borderline association with class II obesity (OR 1.65, p = 0.02). The K121Q variant was not associated with any trait during the 9-year follow-up. Pooled analyses both at baseline and at follow-up failed to show any association with hyperglycaemia (OR 1.08, p = 0.28) or type 2 diabetes (OR 1.15, p = 0.38). However, we did show an association of the Q121 allele with the risk of hyperglycaemia (OR 1.45, p = 0.001; n = 265) and type 2 diabetes (OR 1.65, p = 0.01; n = 103) in participants reporting a family history of type 2 diabetes. These results did not remain significant after a Bonferroni correction. The IVS20delT-11 and A/G+1044TGA polymorphisms and the three-allele risk haplotype (K121Q, IVS20delT-11 and A- >G+1044TGA [QdelTG]) were not associated with any trait, either at baseline or at follow-up. CONCLUSIONS/INTERPRETATION: In a general French population we did not find an association of the QdelTG risk haplotype with adult obesity and type 2 diabetes. We detected nominal evidence of association between the K121Q polymorphism and both severe adult obesity at baseline and the risk of hyperglycaemia or type 2 diabetes in participants with a family history of type 2 diabetes in pooled analyses both at baseline and follow-up. PMID- 17704905 TI - An adenylate kinase is involved in KATP channel regulation of mouse pancreatic beta cells. AB - AIMS/HYPOTHESIS: In a previous study, we demonstrated that a creatine kinase (CK) modulates K(ATP) channel activity in pancreatic beta cells. To explore phosphotransfer signalling pathways in more detail, we examined whether K(ATP) channel regulation in beta cells is determined by a metabolic interaction between adenylate kinase (AK) and CK. METHODS: Single channel activity was measured with the patch-clamp technique in the inside-out (i/o) and open-cell attached (oca) configuration. RESULTS: The ATP sensitivity of K(ATP) channels was higher in i/o patches than in permeabilised beta cells (oca). One reason for this observation could be that the local ATP:ADP ratio in the proximity of the channels is determined by factors not active in i/o patches. AMP (0.1 mmol/l) clearly increased open channel probability in the presence of ATP (0.125 mmol/l) in permeabilised cells but not in excised patches. This suggests that AK-catalysed ADP production in the vicinity of the channels is involved in K(ATP) channel regulation. The observation that the stimulatory effect of AMP on K(ATP) channels was prevented by the AK inhibitor P (1),P (5)-di(adenosine-5')pentaphosphate (Ap(5)A; 20 micromol/l) and abolished in the presence of the non-metabolisable ATP analogue adenosine 5'-(beta,gamma-imido)triphosphate tetralithium salt (AMP PNP; 0.12 mmol/l) strengthens this idea. In beta cells from AK1 knockout mice, the effect of AMP was less pronounced, though not completely suppressed. The increase in K(ATP) channel activity induced by AMP in the presence of ATP was outweighed by phosphocreatine (1 mmol/l). We suggest that this is due to an elevation of the ATP concentration by CK. CONCLUSIONS/INTERPRETATION: We propose that phosphotransfer events mediated by AK and CK play an important role in determining the effective concentrations of ATP and ADP in the microenvironment of pancreatic beta cell K(ATP) channels. Thus, these enzymes determine the open probability of K(ATP) channels and eventually the actual rate of insulin secretion. PMID- 17704907 TI - [Management of isolated subscapularis tendon tears]. AB - Isolated subscapularis tendon tears are rare and often of traumatic origin. Despite specific clinical tests and exact radiological tools (ultrasound, magnetic resonance imaging), these tendon ruptures are often overlooked. For restoration of normal biomechanical joint function, immediate operative reconstruction is recommended. Tears of the upper subscapularis and partial articular-side tendon can be safely managed arthroscopically. The biceps tendon is often involved, and adequate treatment with tenotomy or tenodesis must be given to prevent postoperative pain. Complete subscapularis tendon avulsions should be reconstructed with an open repair technique. Immediate surgical management provides better results than delayed repair. PMID- 17704909 TI - MRI features of Lyme arthritis of the hips. AB - Diagnosing Lyme arthritis without a history of travel to endemic regions or erythema migrans can be a challenge. Radiographic and ultrasonographic findings are nonspecific for the diagnosis of Lyme arthritis. We present the MRI features of Lyme disease of the hip in a 4-year-old boy who presented with hip pain and was found to have Lyme disease by Western blot. Our findings include bilateral hip effusions and synovial enhancement, normal bone marrow signal intensity without enhancement, minimal adjacent muscular and soft-tissue edema, and bilateral inguinal lymph nodes measuring up to 1 cm. PMID- 17704908 TI - Proprioceptive deficits of the lower limb following anterior cruciate ligament deficiency affect whole body steering control. AB - The role of lower limb proprioception in the steering control of locomotion is still unclear. The purpose of the current study was to determine whether steering control is altered in individuals with reduced lower limb proprioception. Anterior cruciate ligament deficiency (ACLD) results in a decrease in proprioceptive information from the injured knee joint (Barrack et al. 1989). Therefore the whole body kinematics were recorded for eight unilateral ACLD individuals and eight CONTROL individuals during the descent of a 20 degrees incline ramp followed by either a redirection using a side or cross cutting maneuver or a continuation straight ahead. Onset of head and trunk yaw, mediolateral displacement of a weighted center of mass (COM(HT)) and mediolateral displacement of the swing foot were analyzed to evaluate differences in the steering control. Timing analyses revealed that ACLD individuals delayed the reorientation of body segments compared to CONTROL individuals. In addition, ACLD did not use a typical steering synergy where the head leads whole body reorientation; rather ACLD individuals reoriented the head, trunk and COM(HT) in the new direction at the same time. These results suggest that when lower limb proprioceptive information is reduced, the central nervous system (CNS) may delay whole body reorientation to the new travel direction, perhaps in order to integrate existing sensory information (vision, vestibular and proprioception) with the reduced information from the injured knee joint. This control strategy is maintained when visual information is present or reduced in a low light environment. Additionally, the CNS may move the head and trunk segments as, effectively, one segment to decrease the number of degrees of freedom that must be controlled and increase whole body stability during the turning task. PMID- 17704906 TI - [How to treat massive rotator cuff tears]. AB - The treatment of massive rotator cuff tears must be adapted to the patient's individual needs and preoperative parameters to achieve the best outcome. First, the shoulder surgeon has to determine whether a direct transosseous repair is possible. If there is not enough remaining tissue, the tissue is atrophic, and the tendon stump can be reduced only with great tension, one can use a margin convergence technique for partial closure, perform a biceps tendoplasty, or perform local tendon transfers with the subscapularis or infraspinatus muscle. If the defect cannot be sufficiently closed, elderly patients with low demands can be treated with tubercleplasty/subacromial decompression, whereas patients younger than 60 years with higher demands should receive muscle and tendon transfers. A balanced posterosuperior defect can be reconstructed by a deltoid muscle transfer, in contrast to an unbalanced one, which is best treated with an active transfer of the latissimus dorsi muscle and tendon. Anterosuperior defects can be addressed by a pectoralis muscle transfer. If the humeral head is superiorly migrated, if signs of osteoarthritis are present, and if the patient is older than 70 years, a reverse prosthesis can be implanted as a salvage procedure. PMID- 17704910 TI - Percutaneous vertebroplasty for eosinophilic granuloma of the cervical spine in a child. AB - We report a case of eosinophilic granuloma at the fourth cervical vertebra in a 10-year-old girl presenting with a 1-month history of cervical pain and stiffness. This lesion was histologically diagnosed by needle biopsy and then treated by percutaneous vertebroplasty. After the procedure, the cervical pain and stiffness resolved rapidly. The height of the vertebral body remained stable without further collapse over a 6-month follow-up period. PMID- 17704912 TI - Bilateral duplication of the internal auditory canal. AB - Duplication of the internal auditory canal is an extremely rare temporal bone anomaly that is believed to result from aplasia or hypoplasia of the vestibulocochlear nerve. We report bilateral duplication of the internal auditory canal in a 28-month-old boy with developmental delay and sensorineural hearing loss. PMID- 17704911 TI - Fucosidosis: MRI and MRS findings. AB - Fucosidosis is a rare, autosomal recessive lysosomal storage disease in which fucose-containing glycolipids, glycoproteins, and oligosaccharides accumulate in tissues as a consequence of alpha-L: -fucosidase enzyme deficiency. We present the MR imaging findings of diffuse white-matter hyperintensity and pallidal curvilinear streak hyperintensity in a 6-year-old Caucasian girl with a diagnosis of fucosidosis based on cDNA isolated from skin fibroblasts. This report also includes the MRS findings of a decreased N-acetylaspartate/choline ratio together with an abnormal peak at 3.8 ppm which expand the knowledge of the neuroradiological spectrum of this rare disease. PMID- 17704913 TI - Cranial ultrasound and chronological changes in molybdenum cofactor deficiency. AB - Molybdenum cofactor is essential for the function of three human enzymes: sulphite oxidase, xanthine dehydrogenase, and aldehyde oxidase. Molybdenum cofactor deficiency is a rare autosomal recessively inherited disease. Disturbed development and damage to the brain may occur as a result of accumulation of toxic levels of sulphite. The CT and MRI findings include severe early brain abnormalities and have been widely reported, but the cranial US imaging findings have seldom been reported. We report a chronological series of cranial US images obtained from an affected infant that show the rapid development of cerebral atrophy, calcifications and white matter cysts. Our report supports the utility of cranial US, a noninvasive bed-side technique, in the detection and follow-up of these rapidly changing lesions. PMID- 17704914 TI - Percutaneous management of tumoral biliary obstruction in children. AB - BACKGROUND: There is limited experience of percutaneous biliary interventions in children although they are safe and effective procedures. OBJECTIVE: To evaluate the efficacy and safety of percutaneous management of tumoral biliary obstruction in children. MATERIALS AND METHODS: Percutaneous biliary interventions were performed in eight children (six boys, two girls) with a mean age of 10.5 years (range 4-17 years). The interventions included percutaneous biliary drainage (five patients), percutaneous biliary drainage and placement of a self-expanding metallic stent (two patients), and percutaneous cholecystostomy (one patient). All patients had signs of obstructive jaundice and two had cholangitis. RESULTS: All procedures were successful. No procedure-related mortality was observed. Bilirubin levels returned to normal in four of the eight patients. Findings of cholangitis resolved in the two affected patients after the procedure and antibiotic treatment. Two patients underwent surgery after percutaneous biliary drainage procedures. A self-expanding metallic stent was placed in two patients with malignancy and the stents remained patent until death. CONCLUSION: Percutaneous biliary interventions can be performed safely for the management of tumoral biliary obstruction in children. PMID- 17704916 TI - Recent advances using green and red fluorescent protein variants. AB - Fluorescent proteins have proven to be excellent tools for live-cell imaging. In addition to green fluorescent protein (GFP) and its variants, recent progress has led to the development of monomeric red fluorescent proteins (mRFPs) that show improved properties with respect to maturation, brightness, and the monomeric state. This review considers green and red spectral variants, their paired use for live-cell imaging in vivo, in vitro, and in fluorescence resonance energy transfer (FRET) studies, in addition to other recent "two-color" advances including photoswitching and bimolecular fluorescence complementation (BiFC). It will be seen that green and red fluorescent proteins now exist with nearly ideal properties for dual-color microscopy and FRET. PMID- 17704915 TI - Properties, production, and applications of camelid single-domain antibody fragments. AB - Camelids produce functional antibodies devoid of light chains of which the single N-terminal domain is fully capable of antigen binding. These single-domain antibody fragments (VHHs or Nanobodies) have several advantages for biotechnological applications. They are well expressed in microorganisms and have a high stability and solubility. Furthermore, they are well suited for construction of larger molecules and selection systems such as phage, yeast, or ribosome display. This minireview offers an overview of (1) their properties as compared to conventional antibodies, (2) their production in microorganisms, with a focus on yeasts, and (3) their therapeutic applications. PMID- 17704917 TI - Functional analysis of the pBC1 replicon from Bifidobacterium catenulatum L48. AB - To determine the minimal replicon of pBC1 (a 2.5-kb cryptic plasmid of Bifidobacterium catenulatum L48) and to check the functionality of its identified open reading frames (ORFs) and surrounding sequences, different segments of pBC1 were amplified by polymerase chain reaction (PCR) and cloned into pBif, a replication probe vector for bifidobacteria. The largest fragment tested in this manner encompassed most of the pBC1 sequence, while the shortest just included the repB gene and its immediate upstream sequences. Derivatives were all shown to allow replication in bifidobacteria. Surprisingly, both the transformation frequency and segregational stability in the absence of antibiotic selection decreased with reducing plasmid length. The relative copy number of the constructs (ranging from around 3 to 23 copies per chromosome equivalent, as compared to 30 copies for the original pBC1) was shown to be strain dependent and to decrease with reducing plasmid length. These results suggest that, although not essential, the copG-like and orfX-like genes of pBC1 play important roles in pBC1 replication. Interruption of repB produced a construct incapable of replicating in bifidobacteria. The analysis of pBC1 will allow its use in the construction of general and specific cloning vectors. PMID- 17704918 TI - Biological aspects of bone, cartilage and tendon regeneration. PMID- 17704919 TI - Semi-algebraic optimization of temperature compensation in a general switch-type negative feedback model of circadian clocks. AB - Temperature compensation is an essential property of circadian oscillators which enables them to act as physiological clocks. We have analyzed the temperature compensating behavior of a generalized transcriptional-translational negative feedback oscillator with a hard hysteretic switch and rate constants with an Arrhenius-type temperature dependence. These oscillations can be considered as the result of a lowpass filtering operator acting on a train of rectangular pulses. Such a signal-processing viewpoint makes it possible to express, in a semi-algebraic manner, the period length, the oscillator's control (sensitivity) coefficients, and the first and second-order derivatives of the period temperature relationship. We have used the semi-algebraic approach to investigate a 3-dimensional Goodwin-type representation of the oscillator, where local optimization for temperature compensation has been considered. In the local optimization, activation energies are found, which lead to a zero first order derivative and to a closest-to-zero second order derivative at a given reference temperature. We find that the major contribution to temperature compensation over an extended temperature range is given by the (local) zero first order derivative, while only minor contributions to temperature compensation are given by an optimized second order derivative. In biological terms this could be interpreted to relate to a circadian clock mechanism which during evolution is being optimized for a certain but relative narrow (habitat) temperature range. PMID- 17704920 TI - Iloprost infusion does not reduce oxidative stress in systemic sclerosis. AB - Systemic sclerosis is a connective tissue disease in which oxidative stress represents an important player among the complex pathogenetic mechanisms of the disease. Iloprost, an analogue of natural prostacyclin, is used in systemic sclerosis for the treatment of severe Raynaud's phenomenon and ischemic ulcers. There is a clear evidence that iloprost attenuates oxidative damage induced by ischemia-reperfusion phenomena. The aim of this study is to evaluate the effect of iloprost on oxidative status in ten patients with systemic sclerosis by measuring urinary levels of 8-isoprostaglandin-F(2alpha), a member of F(2) isoprostanes. We found that systemic sclerosis patients cyclically treated with iloprost showed increased urinary level of 8-isoprostaglandin-F(2alpha )in comparison with healthy subjects; urinary 8-isoprostaglandin-F(2alpha) did not diminish soon after the iloprost infusion as well as 3, 15 and 30 days after the drug administration. Unlike experimental studies, in vivo the strong vasodilator effect of iloprost infusion did not reduce oxidative status. PMID- 17704922 TI - The protective effects of trimetazidine on testicular ischemia and reperfusion injury in rats. AB - This study was designed to investigate the protective effect of trimetazidine [TMZ; 1-(2, 3, 4-trimethhoxibenzyl)-piperazine dihydrochloride], as an antioxidant agent, on torsion-detorsion-induced biochemical and histopathological changes in experimental testicular ischemia/reperfusion injury in rats. Twenty seven male Wistar rats weighing 180-220 g were divided into five groups: control (C, n = 4), sham-operated (S, n = 4), ischemia (I, n = 6), ischemia-reperfusion (I/R, n = 6) and ischemia-reperfusion + trimetazidine (I/R + TMZ; n = 7). Control rats were used for basal normal values. In group I, 2 h torsion of the left testis was performed. In I/R and I/R + TMZ groups, following 2 h of torsion, 4 h detorsion of the testis was performed. In ischemia and I/R groups, physiologic saline was administered orally for 7 days, and the rats in I/R + TMZ group were pretreated orally with 5 mg/kg day TMZ for 7 days before inducing ischemia. At the end of each experiment, ipsilateral orchiectomies were performed for the tissue levels of malondialdehyde (MDA), glutathione peroxidase (GPx) enzyme activities and histopathological examinations in all groups. MDA levels were significantly reduced and GPx enzyme activities were significantly increased in testes in I/R+TMZ pretreated group compared to group I and I/R. The mean seminiferous tubular diameter (MSTD) and Johnsen's score were significantly better in I/R+TMZ group than groups I and I/R. Pretreatment with TMZ decreased germ cell apoptosis and caspase-3 expression in the ischemic testis. The present results show that TMZ has a protective activity in the testicular injury caused by I/R, and provide the first evidence of the role of TMZ for the prevention of I/R-induced testicular injury. PMID- 17704921 TI - [Primary vitrectomy with intraocular antibiotic application in postoperative endophthalmitis]. AB - PURPOSE: Pars plana vitrectomy with intravitreal antibiotic application is an established procedure for treating postoperative endophthalmitis. The presented study analyzes our own results with this treatment as well as the role of adjuvant systemic steroid treatment. METHOD: We analyzed the data of 34 consecutive patients with postoperative endophthalmitis from January 2000 to March 2006. Thirty-two patients underwent vitrectomy and intravitreal application of antibiotics, and two patients received intravitreal antibiotics only. All patients received intravitreal dexamethasone and systemic antibiotics, and 12 patients received the systemic treatment with prednisolone. The effect of vitrectomy with respect to final visual acuity and the rate of postoperative complications were analyzed. The vitreous was microbiologically examined. Postoperative follow-up time ranged from 2 weeks to 24 months. RESULTS: Endophthalmitis followed cataract surgery with intraocular lens implantation in 30 patients (89%) and followed pars plana vitrectomy in four patients (11%). Positive cultures were obtained in 19 (56%) patients. Visual acuity improved in 31 (91%) patients. At their final examinations, 27 (79%) patients had gained visual acuity of 0.05 or better. CONCLUSIONS: CONCLUSION: Immediate vitrectomy in combination with intraocular antibiotics and steroid administration resulted in preservation of ambulatory vision in most of the patients. Systemic postoperative therapy with steroids seems to be associated with better final visual acuity. PMID- 17704924 TI - Genetic alterations of APC, K-ras, p53, MSI, and MAGE in Korean colorectal cancer patients. AB - BACKGROUND AND AIM: Colorectal cancer (CRC) is one of the most rapidly increasing cancers in Korea, but no comprehensive analysis has been performed to speculate the genetic basis of CRC development. We investigated the presence of adenomatous polyposis coli gene (APC), Kirsten-ras (K-ras), p53, microsatellite instability (MSI), and melanoma antigen gene (MAGE) alterations in CRC and correlated the results obtained with clinical data. MATERIALS AND METHODS: We collected 78 cancer tissues from CRC patients. Genetic analyses were performed on APC, K-ras, p53, and MSI (BAT 25 and BAT 26), and in addition, MAGE expression was tested by reverse transcription polymerase chain reaction. Correlations between genetic markers and clinical factors were analyzed after reviewing medical records. RESULT: The positive rates for alterations of APC, K-ras, p53, MSI, and MAGE in 78 tissue samples were 33.3, 29.5, 34.6, 9.0, and 68.4%, respectively. Mutations were frequently detected in codons 1291 and 1450 of APC, in codon 12 of K-ras and in codons 248, 282, and 176 of p53. APC mutations were frequently noted in early stage cancer, whereas MSI was observed in right-sided and multiple cancers. No associations were found between the presence of alterations in APC, K-ras, p53, MSI, and MAGE. INTERPRETATION: In Koreans, positive rates of alterations in APC and p53 were slightly lower than those of APC and p53 in Caucasians, and the genetic alterations including MAGE expression are involved in 92.1% of CRCs. The lack of multiple mutations and of a relation between mutation rates and clinical stage suggest that genetic alterations might have independent influences on CRC development in Koreans. PMID- 17704923 TI - "Fast-track" rehabilitation for elective colonic surgery in Germany--prospective observational data from a multi-centre quality assurance programme. AB - BACKGROUND: The results of "Fast-track" colonic surgery in an unselected population outside of specialised units has been unknown yet. MATERIALS AND METHODS: Data from 24 German hospitals performing "Fast-track" rehabilitation as the standard peri-operative care for patients undergoing elective colonic resection were collected in a prospective multi-centre study conducted between April 2005 and September 2006 to evaluate local and general morbidity. RESULTS: One thousand and forty-seven patients undergoing elective "fast-track" colonic resection were included. Compliance to essential parts of "fast-track" rehabilitation was high (epidural analgesia 86,6%, early oral feeding and mobilisation on the day of surgery 85.5 and 85.4%). Surgical morbidity was observed in 148 patients (14.1%) and general morbidity in 95 patients (9.1%), while mortality was 0.8%. Predefined discharge criteria were met within 5 (1-83) days after surgery, but because of economical restraints in the German DRG system, patients were discharged only after 8 (3-83) days. Re-admission rate was 3.9%. CONCLUSION: "Fast-track" rehabilitation for elective colonic resection was safe and feasible in German hospitals of all sizes and yielded a low general morbidity and re-admission rate. Post-operative recovery was enhanced, but discharge from hospital was delayed because of economical reasons. PMID- 17704925 TI - Long-term efficacy of preoperative radiotherapy for locally advanced low rectal cancer. AB - BACKGROUND AND AIMS: The purpose of this study was to assess the long-term efficacy of preoperative radiotherapy for locally advanced low rectal cancer. MATERIALS AND METHODS: Between April 1990 and June 2005, all patients who underwent surgery for low rectal cancer with a pretreatment diagnosis of T3 or resectable T4 without distant metastasis were enrolled. The total dose of radiation was 45 Gy. Patients with a partial or complete response were defined as radiotherapy responders (RT-R) and the others as radiotherapy non-responders (RT NR). Patients who did not receive radiotherapy were termed the non-radiotherapy group (NRT). The endpoint of this study was overall survival and local and/or distant metastasis. RESULTS: There were 24 patients in RT-R, 26 in RT-NR, and 40 in NRT. Gastrointestinal complications were commonly observed in all groups. RT-R had a significantly higher incidence of genitourinary complications. Five-year overall survival rate was 79.6% in RT-R, 58.9% in RT-NR, and 58.8% in NRT. The difference was significant in favor of RT-R over the others (P=0.015, 0.024, respectively). Five-year local recurrence-free survival rate was 100% in RT-R, 81.5% in RT-NR, and 74.9% in NRT. RT-R had significantly improved local control compared with the others (P=0.034, 0.021, respectively). Five-year distant metastasis-free survival was not statistically different among all groups. CONCLUSIONS: Survival benefit of preoperative radiotherapy was limited to responders. Considering the increased risk of adverse effects, identification of predictors of radiosensitivity is required in order to provide the most suitable treatment for individual patients. PMID- 17704927 TI - [International classification of functioning, disability and health and its significance for rheumatology]. AB - The international classification of functioning, disability and health (ICF) has been developed by the World Health Organization (WHO) to describe health and handicaps in more detail in order to allow better classification and registration. The ICF comprises the disease, structure, functioning, activity and participation as well as corresponding factors related to the individual and the environment. By this means an integrated concept and assessment of biologic, individual and social aspects of health is attained. The ICF represents an essential addition to the international classification of diagnoses (ICD) and procedures (OPS). The ICF consists of two interelated parts. The first part that describes functioning and disability contains two components: one related to the body (functioning and structure) and one related to activity and participation. The second part describes the context factors (related to the environment and the individual). Body functions are the physical and mental functions of the organism. Body structures are the anatomically defined parts of the body. Activity describes how a task is solved or how an action can be performed and participation is the way in which an individual is involved in the environment and society. The ICF categories make the classification of all aspects of functioning and health in individuals easier and independent of diseases or specific assessment instruments. However, since there are more than 1,400 categories, the ICF cannot be used in daily practice in this form. Therefore, attempts are made to identify those parts of the ICF that are relevant for specific patients, situations and disease states or activities. These are the so called ICF core sets. This article attempts to give an overview on the ICF, to provide an insight into recent work on the ICF related to musculoskeletal and rheumatic diseases and, finally, to describe how an ICF core set for patients with acute arthritis was made possible by means of a successful multicenter cooperative effort. PMID- 17704929 TI - EMAP-II antibody detects both proEMAP/p43 and mature EMAP-II molecules. PMID- 17704926 TI - Optimizing electrode implantation in sacral nerve stimulation--an anatomical cadaver study controlled by a laparoscopic camera. AB - BACKGROUND AND AIM: Sacral nerve stimulation is the therapy of choice in patients with neurogenic faecal and urine incontinence, constipation and some pelvic pain syndromes. The aim of this study is to determine the best insertion angles of the electrode under laparoscopic visualization of the sacral nerves. MATERIALS AND METHODS: Five fresh cadaver pelvises were dissected through an anterior approach of the presacral space, exposing the ventral sacral roots. Needles and electrodes were inserted into the S3 foramen. Both right and left sides were used, with the traditional percutaneous procedure. The validation was done by a laparoscopic camera controlling the position of the needle and electrode on the nerve. The angles were assessed with a goniometer and were confirmed in two living patients. RESULTS: The mean angle of insertion in the sagittal plane was 62.9+/-3 degrees (range, 59-70). In the axial plane, the mean angle for the left side was 91.7+/ 13.5 degrees (range, 80-110) and 83.2+/-7.7 degrees for the right side (range, 75 95). These angles resulted in the optimal placement of the leads along the S3 sacral root, in all these cases. CONCLUSIONS: This study allows direct visualization during the placement of the needle and electrode, thus permitting accurate calculations of the best angle of approach during the surgical procedure in sacral nerve stimulation. These objective findings attempt to standardize this technique, which is often performed with the aid of intra-operative fluoroscopy but still leaving a lot to chance. These insertion angles should help to find more consistent and reproducible results and thus improved outcome in patients. PMID- 17704930 TI - The effect of high and low pressure pulsatile lavage on soft tissue and cortical blood flow: a canine segmental humerus fracture model. AB - OBJECTIVE: To determine the effect of high pressure pulsatile lavage (HPPL) and low pressure pulsatile lavage (LPPL) on cortical and soft tissue blood flow in a canine humerus segmental fracture model. DESIGN: Midshaft humeral osteotomies to create a 2-cm segment of diaphyseal bone were performed on bilateral canine humeri. Each osteotomy site was irrigated using either high pressure (n = 6) or low pressure (n = 5) pulsatile lavage prior to stabilization with a 5-mm steinman pin. Perfusion of cortical bone, periosteum, and biceps muscle was measured using Laser Doppler Flowmetry during four intraoperative intervals: pre-osteotomy, post osteotomy, post-lavage, and post-nailing. RESULTS: Following osteotomy, a significant drop occurred in cortical perfusion (HPPL P = 0.049, LPPL P = 0.021) and in periosteal flow (HPPL P = 0.019, LPPL P = 0.012). Following irrigation there was no significant decrease in blood flow in either group for muscle (HPPL P = 0.249, LPPL P = 0.41), periosteum (HPPL P = 0.381, LPPL P = 0.402), or cortex (HPPL P = 0.398, LPPL P = 0.352) measurements. There was no significant difference between irrigation groups in post-lavage perfusion values for muscle (P = 0.326), periosteum (P = 0.452), and cortex (P = 0.464). Cortical perfusion decreased significantly post-nailing (HPPL P = 0.027, LPPL P = 0.047). Measurements did not differ significantly between groups at any other time interval. CONCLUSION: Although previous work has demonstrated an association between HPPL and detrimental structural changes in bone, this study demonstrates that HPPL does not adversely affect cortical or soft tissue blood flow acutely. Further, LPPL offers no acute benefit to cortical or soft tissue perfusion. PMID- 17704931 TI - Construction of novel in vitro epithelioid cell granuloma model from mouse macrophage cell line. AB - There have been several attempts to make granuloma model to clarify the mechanism of granulomatous diseases like sarcoidosis. However, a unique in vitro model that generates multinucleated giant cell (MGC) through epithelioid cells resembled to human granuloma, has not yet been clearly established. In this study, the generation of granuloma model that forms MGC via epithelioid cells from the mouse macrophage cell line was investigated. A RAW 246.7 mouse macrophage cell line was cultured with lipopolysaccharide (LPS) and concanavalin A (Con A) in various concentrations either alone or both. We found that separate treatment of LPS and Con A induced around 35 and 20% MGC respectively whereas cotreatment of these chemicals drastically accelerated granuloma formation rate and it was around 80%. The highest fusion index (MGC formation rate) was observed at days 7. A gradual increase of tumor necrosis factor alpha (TNF-alpha) production in the culture supernatant was analyzed by enzyme-linked immunosorbent assay (ELISA). And the neutralization of the elevated level of TNF-alpha production by its monoclonal antibody leads to significant decrease of MGC formation. Interestingly, we found that the RAW cells were changed into spindle cells, which morphologically resembled to epithelioid cells and eventually MGC was formed from these spindle cells. Our in vitro granuloma model appeared to be similar with in vivo epithelioid cell granulomas like sarcoidosis. Thus, our model would be useful as in vitro epithelioid granuloma model for analyzing the mechanisms and screening the effective drugs of granulomatous diseases in future. PMID- 17704932 TI - Treatment of an acute salivary fistula after parotid surgery: botulinum toxin type A injection as primary treatment. AB - A salivary fistula is a relatively uncommon but troublesome complication after parotid surgery. Most cases are self-limiting and respond well to conservative therapy (compression dressings). However, this treatment may require weeks before its effect becomes evident. We present the first report of direct administration of botulinum toxin type A as an effective primary treatment for an acute salivary fistula after parotid surgery, in the absence of other, more conservative treatment. A 47-year-old man with a 7-day history of sore throat was found to have a parapharyngeal tumor originating from the deep lobe of the parotid gland. He underwent tumor removal via a trans-paroticocervical approach. However, on postoperative day 7, the patient was noted to have massive salivary discharge from the surgical incision during a meal. We administered a transcutaneous botulinum toxin type A injection without a pressure dressing. One day after the injection, the salivary discharge from the incision line disappeared completely and there was no evidence of recurrent sialorrhea in the 6 months following the procedure. This report suggests that the injection of botulinum toxin type A is a highly effective and relatively safe primary method of treatment for an acute postparotidectomy salivary fistula, and not merely an alternative to more conservative therapy. PMID- 17704934 TI - Comment on "Mortality from cardiovascular diseases in the German uranium miners cohort study, 1946-1998" by Kreuzer M, Kreisheimer M, Kandel M, Schnelzer M, Tschense A, Grosche B (2006) Radiat Environ Biophys 45:159-166. PMID- 17704935 TI - Modelling of effects due to chronic exposure of a fish population to ionizing radiation. AB - A dynamic model was developed for description of radiation effects in an isolated fish population chronically exposed at different dose rates. The induced effects were predicted based on damage created by the radiation, recovery by means of repair mechanisms, and natural growth of the population. Three types of radiation effects (umbrella endpoints) were simulated--decrease of population size, decrease of reproductive capacity, and effects on the morbidity of the population. The influence of ecological interactions on the irradiated fish population was simulated using the combined action of radiation and parasite infestation as an example (ecological interaction "host-parasite"). The model calculations demonstrate that influence of ecological interactions can considerably aggravate the effects of radiation to an exposed population. It was concluded that development of standards for wildlife protection against ionizing radiation requires consideration of possible ecological interactions and to take into account the ecological effects of radiation. PMID- 17704936 TI - Reduction of iatrogenic RPE lesions in AMD patients: evidence for wound healing? AB - PURPOSE: Our purpose was to study retinal pigment epithelium (RPE) wound healing in patients with age-related macular degeneration (AMD). PATIENTS AND METHODS: Abrasive debridement of nasal RPE was performed with a metal cannula during pars plana vitrectomy for foveal choroidal neovascularization (CNV) membrane excision combined with simultaneous autologous RPE transplantation. Fundus autofluorescence, fluorescein angiography images, and red-free pictures were taken initially within 1-2 weeks postoperatively, subsequently in 2-week intervals until 3 months, monthly until 6 months, and every 3 months thereafter. The borders of these lesions were measured; areas were calculated and compared using ArchiCad Software. Fourteen eyes of 14 patients suffering from AMD were included (nine women and four men, mean age 75.6 years +/-6.6 years). RESULTS: Six of 14 (42.9 %) patients showed a reduction of the RPE debrided area. The size of these lesions reduced 5.6-20% within 2 postoperative months compared with their size at first examination (from a mean of 13.7 mm2 +/- 7.2 at baseline to a mean of 12.8 mm2 +/- 6.7 at 2 months postoperatively). No further reduction of the lesions was seen after the 2 months. In eight cases, borders of the RPE debrided areas stayed stable during observation time. CONCLUSIONS: Wound healing of abrasively debrided RPE monolayer defects in patients with AMD occurs to a certain extent in nearly half of the cases. This process seems to stop after 2 months. PMID- 17704937 TI - Complement factor H variant Y402H and basal laminar deposits in exudative age related macular degeneration. AB - BACKGROUND: Complement factor H (CFH) polymorphism Y402H has been shown to be significantly associated with age-related macular degeneration (AMD). Furthermore, histopathological studies in AMD have implicated basal laminar deposits (BLD) in the development of choroidal neovascularization (CNV) membranes. The purpose of this study was to correlate CFH staining in BLD with the CFH genotype at the tyrosine 402 histidine (Y402H) polymorphism. PATIENTS AND METHODS: During macular translocation, 21 angiographically confirmed CNV membranes were extracted in 21 patients. The specimens were analysed histologically for BLD. The presence of CFH, complement proteins, and vitronectin was determined by immunohistochemistry. Finally, the CFH Y402H genotype was established by direct sequencing analysis. RESULTS: Histological examination demonstrated BLD in all of the excised CNV membranes. By immunostaining CFH was detected in the peripheral aspect at the inner and outer surface of BLD, which colocalized with other proteins of the complement cascade (C3, C5b-9). Similarly, vitronectin was detected in all of the BLD investigated. Four patients were noncarriers of CFH Y402H polymorphism, nine patients were heterozygous and eight patients homozygous for the CFH Y402H polymorphism. CONCLUSIONS: BLD are composed of different complement factors (factor H, C3, C5b-9) and extracellular matrix proteins such as vitronectin. The prevalence of homozygous carriers in regard to CFH Y402H polymorphism, which is suspicious for AMD, might be associated with increased secretion of vitronectin in response to dysregulation of the complement cascade. PMID- 17704938 TI - Occult tumor cells in lymph nodes as a predictor for tumor relapse in pancreatic adenocarcinoma. AB - BACKGROUND AND AIMS: Occurrence of tumor relapse is frequent in patients with pancreatic cancer despite the absence of residual tumor detectable at primary surgery and in histopathological examination. Therefore, it has to be assumed that current tumor staging procedures fail to identify minimal amounts of disseminated tumor cells, which might be precursors of subsequent metastatic relapse. The aim of this study was to assess the prognostic impact of minimal tumor cell spread detected in lymph nodes classified as "tumor-free" in routine histopathologic evaluation. MATERIALS AND METHODS: A total of 154 "tumor-free" lymph nodes from 59 patients with pancreatic cancer who underwent intentionally curative tumor resection were examined by immunohistochemistry for disseminated tumor cells. RESULTS: Fifty (32.5%) of the "tumor-free" lymph nodes obtained from 36 (61%) patients displayed disseminated tumor cells. Multivariate survival analysis revealed that the presence of disseminated tumor cells in "tumor-free" lymph nodes is an independent prognostic factor for both a significantly reduced relapse-free survival (p = 0.03) and overall survival (p = 0.02). CONCLUSIONS: The frequent occurrence and prognostic impact of immunohistochemically identifiable disseminated tumor cells in lymph nodes of patients with operable pancreatic cancer supports the need for a refined staging system of excised lymph nodes, which should include immunohistochemical examination. PMID- 17704939 TI - Restitution analysis of alternans and its relationship to arrhythmogenicity in hypokalaemic Langendorff-perfused murine hearts. AB - Alternans and arrhythmogenicity were studied in hypokalaemic (3.0 mM K(+)) Langendorff-perfused murine hearts paced at high rates. Epicardial and endocardial monophasic action potentials were recorded and durations quantified at 90% repolarization. Alternans and arrhythmia occurred in hypokalaemic, but not normokalaemic (5.2 mM K(+)) hearts (P<0.01): this was prevented by treatment with lidocaine (10 microM, P<0.01). Fourier analysis then confirmed transition from monomorphic to polymorphic waveforms for the first time in the murine heart. Alternans and arrhythmia were associated with increases in the slopes of restitution curves, obtained for the first time in the murine heart, while the anti-arrhythmic effect of lidocaine was associated with decreased slopes. Thus, hypokalaemia significantly increased (P<0.05) maximal gradients (from 0.55+/-0.14 to 2.35+/-0.67 in the epicardium and from 0.67+/-0.13 to 1.87 +/-0.28 in the endocardium) and critical diastolic intervals (DIs) at which gradients equalled unity (from -2.14+/-0.52 ms to 50.93+/-14.45 ms in the epicardium and from 8.14+/ 1.49 ms to 44.64+/-5 ms in the endocardium). While treatment of normokalaemic hearts with lidocaine had no significant effect (P>0.05) on either maximal gradients (0.78+/-0.27 in the epicardium and 0.83+/-0.45 in the endocardium) or critical DIs (6.06+/-2.10 ms and 7.04+/-3.82 ms in the endocardium), treatment of hypokalaemic hearts with lidocaine reduced (P<0.05) both these parameters (1.05+/ 0.30 in the epicardium and 0.89+/-0.36 in the endocardium and 30.38+/-8.88 ms in the epicardium and 31.65+/-4.78 ms in the endocardium, respectively). We thus demonstrate that alternans contributes a dynamic component to arrhythmic substrate during hypokalaemia, that restitution may furnish an underlying mechanism and that these phenomena are abolished by lidocaine, both recapitulating and clarifying clinical findings. PMID- 17704940 TI - Identification of a protein kinase gene associated with pistillody, homeotic transformation of stamens into pistil-like structures, in alloplasmic wheat. AB - Homeotic transformation of stamens into pistil-like structures (called pistillody) has been reported in cytoplasmic substitution (alloplasmic) lines of bread wheat (Triticum aestivum) having the cytoplasm of a wild relative species, Aegilops crassa. Our previous studies indicated that pistillody is caused by alterations of the class B MADS-box gene expression pattern associated with mitochondrial gene(s) in the Ae. crassa cytoplasm. To elucidate the nuclear gene involved in the cross-talk between pistillody-related mitochondrial gene(s) and nuclear homeotic genes, we performed cDNA subtraction analysis using cDNAs derived from young spikes of a pistillody line and a normal line. As a result, we identified a protein kinase gene, WPPK1 (wheat pistillody-related protein kinase 1), which is upregulated in the young spikes of the pistillody line. RT-PCR analysis indicated that WPPK1 is strongly expressed in pistils and pistil-like stamens in the pistillody line, suggesting that it is involved in the formation of pistil-like stamens as well as pistils. The full-length cDNA sequence for WPPK1 showed high similarity with a flowering plant PVPK-1 protein kinase, and phylogenetic analysis indicated that it is a member of AGC group protein kinases. Furthermore, a phosphorylation assay indicated that it has protein kinase activity. In situ hybridization analysis revealed that WPPK1 is expressed in developing pistils and pistil-like stamens as well as in their primordia. These indicate that in the alloplasmic line, WPPK1 plays a role in formation and development of pistil-like stamens. PMID- 17704942 TI - Thyroid follicular carcinoma-like renal tumor: a case report with morphologic, immunophenotypic, cytogenetic, and scintigraphic studies. AB - In this report, a rare renal tumor that morphologically resembles a thyroid follicular carcinoma is described. To date, this subtype has not been integrated into a known form of renal carcinoma. A 29-year-old female patient without relevant family or social history underwent nephrectomy because of a renal tumor measuring 5 cm by the largest diameter. The macroscopically white-yellow tumor showed follicular structures with abundant eosinophilic colloidal material and focal papillary differentiation by light microscopy. Immunohistochemically, the tumor cells stained positively for cytokeratin (CK-7, CK-20, CAM 5.2) and vimentin. CD-10, CD-117, thyroid transcription factor-1, and thyreoglobulin remained completely negative. Chromosomal losses of 1, 3, 7, 9p21, 12, 17, and X were detected by fluorescence in situ hybridization. Scintigraphs showed an inconspicuous thyroid gland and no extrathyroidal pathological accumulations, making metastatic spread to the kidney highly unlikely. To our knowledge, this is the second fully documented case of a thyroid follicular carcinoma-like renal tumor. This uncommon variant is important to keep in mind to prevent unnecessary or inappropriate treatment. PMID- 17704941 TI - Conserved relationship between FtsZ and peptidoglycan in the cyanelles of Cyanophora paradoxa similar to that in bacterial cell division. AB - Cyanelles of the biflagellate protist Cyanophora paradoxa have retained the peptidoglycan layer, which is critical for division, as indicated by the inhibitory effects of beta-lactam antibiotics. An FtsZ ring is formed at the division site during cyanelle division. We used immunofluorescence microscopy to observe the process of FtsZ ring formation, which is expected to lead cyanelle division, and demonstrated that an FtsZ arc and a split FtsZ ring emerge during the early and late stages of cyanelle division, respectively. We used an anti FtsZ antibody to observe cyanelle FtsZ rings. We observed bright, ring-shaped fluorescence of FtsZ in cyanelles. Cyanelles were kidney-shaped shortly after division. Fluorescence indicated that FtsZ did not surround the division plane at an early stage of division, but rather formed an FtsZ arc localized at the constriction site. The constriction spread around the cyanelle, which gradually became dumbbell shaped. After the envelope's invagination, the ring split parallel to the cyanelle division plane without disappearing. Treatment of C. paradoxa cells with ampicillin, a beta-lactam antibiotic, resulted in spherical cyanelles with an FtsZ arc or ring on the division plane. Transmission electron microscopy of the ampicillin-treated cyanelle envelope membrane revealed that the surface was not smooth. Thus, the inhibition of peptidoglycan synthesis by ampicillin causes the inhibition of septum formation and a marked delay in constriction development. The formation of the FtsZ arc and FtsZ ring is the earliest sign of cyanelle division, followed by constriction and septum formation. PMID- 17704943 TI - Mucinous carcinoma of thyroid gland. Report of a primary and a metastatic mucinous tumour from ovarian adenocarcinoma with immunohistochemical study and review of literature. AB - Mucinous carcinoma of the thyroid gland is an uncommon tumour that from the histological point of view, resembles mucinous carcinoma of others sites. Although a mucinous appearance has sometimes been reported in association with cases of typical thyroid carcinoma, true mucinous carcinoma is exceptionally rare. We describe two cases of thyroid tumours with mucinous differentiation studied with immunohistochemistry. Both cases disclosed a similar histological appearance, with small nests and sheets of malignant epithelial cells associated with extensive extracellular mucin that substituted and entrapped the follicular parenchyma of the thyroid. Thyroglobulin and focally thyroid transcription factor (TTF) 1 were positive in one case. From these findings, we classified this tumour as primary mucinous thyroid carcinoma. Thyroglobulin and TTF-1 were negative in tumour cells of second case; on the contrary, positivity to the carcinoembryonic antigen and CA-125 was strong and generalized. However, successfully, the patient presented ascites associated to right ovarian mass. In this case, thyroid tumour represents the first clinical sign of an ovarian mucinous adenocarcinoma, and it has not been previously described in literature. Both patients died after few months to diagnosis. In conclusion, primary and secondary mucinous carcinoma are rare and unusual tumours of the thyroid gland that can be a cause of pitfall in differential diagnosis. In these cases, for a correct diagnosis, a complete clinical history, restricted histological criteria and immunohistochemical panel are necessary. PMID- 17704944 TI - Serological assessment of synthetic peptides of Campylobacter jejuni NCTC11168 FlaA protein using antibodies against multiple serotypes. AB - The flagellum of Campylobacter jejuni is not only responsible for initiating colonization of the gastrointestinal tract of host animals but is also a major antigen that induces protective immune responses. However, protection is limited to the homologous strain and the ability to protect against multiple serotypes has yet to be determined. In this study, we have shown that FlaA is an immunodominant protein on NCTC11168 CJ1 flagella and we mapped the immunoreactive epitopes on the protein by probing a series of overlapping synthetic peptides spanning the entire sequence with sera against multiple C. jejuni serotypes. Amino acid residues 176-205 (P8), 376-405 (P16) and 501-530 (P21) were immunodominant and cross-reactive. The mucosal IgA in the intestinal secretions of CJ1-infected birds reacted significantly with peptides P16 and P21 indicating that the specificity of the mucosal response is different from the systemic response. Antisera raised against formalin-killed CJ1 cells and purified flagellin showed positive reactivity with a subset of peptides identified by antisera against live C. jejuni. This study provides insight into the specificity of the host immune responses to the FlaA protein of C. jejuni and suggests that these sequences merit further testing for their immunogenicity and potential as subunit vaccine candidates for multiple serotypes. PMID- 17704946 TI - A 15-year-old girl with a large pericardial effusion. AB - Pericarditis is a rare manifestation of tuberculosis and can be fatal. We describe a 15-year-old girl admitted for a large pericardial effusion. Subxiphoid pericardial biopsy was performed. Biopsy samples were positive for M. tuberculosis DNA by PCR, which confirmed the diagnosis of tuberculous pericarditis. PMID- 17704945 TI - Ocular findings in children with a microdeletion in chromosome 22q11.2. AB - A microdeletion in chromosome 22q11.2 is one of the most frequent genetic syndromes. The phenotypic manifestations vary widely, which has led to its initial description as apparently different clinical entities, such as the velocardiofacial syndrome (VCFS) and DiGeorge syndrome. Characteristic features include cleft palate, conotruncal heart malformations, thymus hypoplasia, hypoparathyroidism, a characteristic facial phenotype and learning difficulties. Ocular abnormalities are frequently seen in this patient population. We describe the ophthalmological findings in 36 children between the age of 3 and 14 years with a microdeletion in chromosome 22q11.2. They underwent a full ophthalmological examination with assessment of visual acuity, eye position and motility, stereoscopic vision, biomicroscopic examination, refraction and fundoscopy. If necessary amblyopia treatment was started and follow-up was planned. The presence of a cardiovascular malformation was noted. In conclusion, refractive errors, strabismus, amblyopia and structural ocular abnormalities are frequently encountered in children with a microdeletion in chromosome 22q11.2. Ophthalmological examination at a young age and refractive correction in those children is warranted. On the other hand, ocular findings can give a clue to the diagnosis of del 22q11.2. PMID- 17704949 TI - Immuno-localization of vesicular acetylcholine transporter in mouse taste cells and adjacent nerve fibers: indication of acetylcholine release. AB - Acetylcholine (ACh) is well established as a neurotransmitter and/or neuromodulator in various organs. Previously, it has been shown by Ogura (J Neurophysiol 87:2643-2649, 2002) that in both physiological and immunohistochemical studies the muscarinic acetylcholine (ACh) receptor is present in taste receptor cells. However, it has not been determined if ACh is released locally from taste receptor cells and/or surrounding nerve fibers. In this study we investigated the sites of ACh release in mouse taste tissue using the antisera against vesicular ACh transporter (VAChT), a key element of ACh containing vesicles. Our data show that VAChT-immunoreactivity is present in many taste receptor cells, including cells expressing the transient receptor potential channel M5 (TRPM5). In taste cells, VAChT-immunoreactivity was colocalized with the immunoreactivity to choline-acetyltransferase (ChAT), which synthesizes ACh. Additionally, enhanced green fluorescent protein (eGFP) was detected in the taste cells of BAC-transgenic mice, in which eGFP was placed under the control of endogenous ChAT transcriptional regulatory elements (ChAT(BAC)-eGFP mice). Furthermore, many ChAT-immunolabeled taste cells also reacted to an antibody against the vesicle-associated membrane protein synaptobrevin-2. These data suggest that ACh-containing vesicles are present in taste receptor cells and ACh release from taste cells may play a role in autocrine and/or paracrine cell-to cell communication. In addition, certain nerve fibers surrounding or within taste buds were immunoreactive for the VAChT antibody. Some of these fibers were also immunolabeled with antibody against calcitonin gene-related peptide (CGRP), a marker for trigeminal peptidergic fibers. Thus, functions of taste receptor cells could be modulated by trigeminal fibers via ACh release as well. PMID- 17704947 TI - Enhancement of erbB2 and erbB3 expression during oral oncogenesis in diabetic rats. AB - PURPOSE: The expression of erbB2 and erbB3 receptors was investigated in an experimental model of chemically induced oral carcinogenesis in normal and diabetic (type I) Sprague-Dawley rats. METHODS: Thirteen diabetic and twelve normal rats developed precancerous and cancerous lesions after 4-nitroquinoline-N oxide treatment, while six diabetic and six normal animals were used as controls. Sections of biopsies from all animals were classified histologically in the following categories: normal mucosa, hyperplasia, dysplasia, early invasion, well and moderately-differentiated squamous cell carcinoma. Each section was studied immunohistochemically using monoclonal antibodies against erbB2 and erbB3 proteins and six representative histological regions in each section were analysed. RESULTS: The erbB2 was expressed at very low levels in normal rats, while in diabetic animals its expression was significantly increased during early invasion (P = 0.04). The erbB3 expression was significantly elevated in well differentiated carcinoma in normal animals (P = 0.01), while in diabetic animals it was significantly increased during oral mucosal hyperplasia and dysplasia (P = 0.03 and 0.0007, respectively). The comparison of erbB2 expression between diabetic and normal rats revealed significant differences in all stages except for the tumor stage of moderately differentiated carcinoma (P = 0.01, 0.00001, 0.00001, 0.003, and 0.00001). In regard to erbB3 expression, significant differences between diabetic and normal rats existed only in normal, non cancerous and precancerous stages (P = 0.007, 0.0001, 0.0003). CONCLUSIONS: It seems that diabetes enhances the expression of both erbB2 and erbB3 in certain stages of oral oncogenesis possibly resulting in promotion of cell proliferation and inhibition of apoptosis. PMID- 17704950 TI - The mouse pubic symphysis as a remodeling system: morphometrical analysis of proliferation and cell death during pregnancy, partus and postpartum. AB - Marked changes in mice pubic symphysis occur by the end of pregnancy. Tissue remodeling involves a dynamic balance between cell proliferation and programmed cell death as well as changes in the extracellular matrix components. Therefore, it is important to consider both of these cellular behaviors when investigating the mechanism that regulates interpubic tissue remodeling, growth during late pregnancy and partus ensuring involution during the postpartum period. Proliferating and programmed death cells were identified by immunohistochemistry (proliferating cell nuclear antigen and TUNEL detection, respectively) and the rates at which these processes occurred were determined by morphometric analysis. The results demonstrated that cellular proliferation was intense during the period of ligament formation, from D15 to D18, thereafter abruptly declining on D19. From parturition (D19) onwards, an ever-increasing decline in the cellular proliferation levels could be observed. The quantitative analyses of cellular death showed opposite results when compared to cellular proliferation. During early pregnancy the cycle of cellular renovation was clearly proliferative and during late mouse pregnancy the cycle was directed by programmed cellular death. Although the high levels of cellular death during postpartum involution could be shown by the TUNEL-positive cells, we were unable to observed picnotic nucleus at the light microscopy. PMID- 17704948 TI - Characterization of Taenia solium cysticerci microsomal glutathione S-transferase activity. AB - Glutathione S-transferase activity has been shown to be associated with the microsomal fraction of Taenia solium. Electron microscopy and subcellular enzyme markers indicate the purity of the microsomal fraction that contains the glutathione S-transferase activity. T. solium microsomes were solubilized under conditions used to solubilize integral microsomal proteins. This procedure proved necessary to obtain enzymatic activity. To characterize this parasite enzyme activity, several substrates and inhibitors were used. The optimum activity for microsomal glutathione S-transferase was found to be pH 6.6, with a specific enzyme activity of 0.9, 0.1, 0.067, 0.03, and 0.05 micromol min(-1) mg(-1) with the substrates 1-chloro-2,4-dinitrobenzene (CDNB), 1,2-dichloro-4-nitrobenzene, 4 hydroxynonenal, 2,4-hexadienal, and trans-2-nonenal, respectively. No activity of glutathione peroxidase was observed. T. solium microsomes had an appKm (GSH)=0.161 microM, appKm (CDNB)=14.5 microM, and appVmax of 0.15 and 27.9 micromol min(-1) mg(-1) for GSH and CDNB, respectively. T. solium microsomes were inhibited by several glutathione S-transferase enzyme inhibitors, and it was possible to establish a simple inhibition system as well as corresponding Ki's for each inhibitor. These results indicate that the T. solium microsomal glutathione S-transferase is different from the parasite cytoplasmic enzymes that catalyze similar reactions. PMID- 17704951 TI - Test of local adaptation to biotic interactions and soil abiotic conditions in the ant-tended Chamaecrista fasciculata (Fabaceae). AB - Few previous studies have assessed the role of herbivores and the third trophic level in the evolution of local adaptation in plants. The overall objectives of this study were to determine (1) whether local adaptation is present in the ant defended plant, Chamaecrista fasciculata, and (2) the contribution of ant-plant herbivore interactions and soil source to such adaptation. We used three C. fasciculata populations and performed both a field and a greenhouse experiment. The first involved reciprocally transplanting C. fasciculata seedlings from each population-source to each site, and subsequently applying one of three treatments to one-third of the seedlings of each population-source at each site: control, reduced ant density and reduced folivory. The greenhouse experiment involved reciprocal transplants of population-sources with soil sources to test for a soil source effect on flower production and local adaptation to soil conditions. Field results showed that ant and herbivore treatments reduced ant density (increasing folivory) and herbivore damage relative to controls, respectively; however, these manipulations did not impact C. fasciculata reproduction or the likelihood of survival. In contrast, greenhouse results showed that soil source significantly affected flower production. Overall, plants in both experiments, regardless of population-source, always had higher reproductive output at one specific site. Native populations did not outperform nonnative ones, causing us to reject the hypothesis of local adaptation. The absence of treatment effects on plant reproduction and the likelihood of survival suggest a limited effect of ants and folivores on C. fasciculata fitness and local adaptation during the study year. Temporally inconsistent effects of biotic forces across years, coupled with the young age of populations, relative proximity of populations and possible counter effects of seed predators may reduce the likelihood of local adaptation in the populations studied. PMID- 17704952 TI - Renal involvement and hypocomplementemia in a patient with acute hemorrhagic edema of infancy. AB - Acute hemorrhagic edema of infancy (AHEI) is a cutaneous leukocytoclastic vasculitis that affects children under 2 years of age and is clinically characterized by fever, extensive tender edema and large purpuric lesions that involve mainly the face, ears and limbs. AHEI typically exhibits an acute onset, with a short benign course followed by spontaneous and complete recovery. Visceral involvement is usually absent, and laboratory studies reveal no specific abnormalities. The pathogenic mechanisms underlying the development of AHEI remain unknown. We describe a patient with AHEI exhibiting transient renal involvement and hypocomplementemia. A 19-month-old Japanese boy was admitted to our hospital with a 2-day history of fever and purpura affecting his face, right ear and legs, and a 1-day history of painful edema of the right side of his face and his right lower leg. Laboratory studies revealed microscopic hematuria, proteinuria and hypocomplementemia affecting C4, C1q and CH50. A clinical diagnosis of AHEI was made, and the patient made a rapid and completely recovery without any specific therapy. We suggest that activation of the classical pathway of complement might be one of the pathogenic mechanisms underlying the development of AHEI. PMID- 17704954 TI - Intravenous iron treatment in paediatric chronic kidney disease patients not on erythropoietin. AB - Intravenous (i.v.) iron treatment reduces erythropoietin (EPO) dose in paediatric haemodialysis patients. The efficacy in paediatric nonhaemodialysis patients is less well established. i.v. iron is routinely given in our institution to these patients, including some who have not started EPO. The effect of this strategy was examined. Patients with chronic kidney disease (CKD) or peritoneal dialysis (PD) not on EPO were identified. Case notes were reviewed for haemoglobin (Hb), red cell and iron indices for 6 months before and at least 3 months after i.v. iron. Five patients were identified. Mean age was 13.3 years and mean i.v. iron (Venofer) dose = 3.1 mg/kg. Median number of doses = 7 (range 3-10). Hb increased significantly after i.v. iron from 11.4 +/- 0.7 to 12.8 +/- 1.3 g/dl (p = 0.02). Mean cell volume increased from 87.7+/-3.4 to 90.1 +/- 3.7 fl (p = 0.01), and mean cell Hb remained unchanged: 29.2 +/- 1.2 to 29.7 +/- 1.0 pg (p = 0.12). Absolute and percentage reticulocyte count remained unchanged. There was no change in iron indices: ferritin 55.1 +/- 31.3 to 97.3 +/- 46.5 ng/ml (p = 0.3), iron 18.9 +/- 6.9 to 18.1 +/- 4.2 micromol/l (p = 0.7), transferrin 1.9 +/- 1.6 to 2.0 +/- 0.1 g/l (p = 1.0), transferrin saturation 35.7 +/- 8.1 to 40.3 +/- 18.0% (p = 0.5). i.v. iron slightly improved Hb levels in five paediatric CKD and PD patients not receiving EPO. This strategy may delay the need for EPO treatment and deserves further evaluation. PMID- 17704955 TI - Evaluation of a tablet PC technology to screen and educate oncology patients. AB - STUDY GOAL: The aim of the study was to evaluate The Patient Assessment, Care and Education (PACE) System-an electronic patient symptom screening and reporting system for oncology. Specifically, the study determined provider and patient opinions of The PACE System and documented evidence as to whether symptom assessment rates increased after this system was implemented. MATERIALS AND METHODS: Ninety-two providers (i.e., physicians, nurse practitioners, and physician assistants) at 16 community oncology clinics were surveyed about their experiences with The PACE System. In addition, 100 patients at two community oncology clinics were surveyed about their perceptions of The PACE System. Finally, at two oncology clinics, 100 patient charts were abstracted in the year before implementation of The PACE System, and 100 patient charts were abstracted in the year after its implementation to evaluate changes in symptom assessment rates. MAIN RESULTS: Providers seemed to value the system. In particular, they reported that the screening and reporting system helped them to identify, track, and document the patients' most important symptoms. The patient survey indicated that the majority of patients at the two sites found the system easy to use and generally helpful and would recommend it to others. The chart review indicated that assessment rates for depression, fatigue, and pain increased after The PACE System was implemented. CONCLUSIONS: The PACE System appears to be a promising approach to addressing the widespread problem of under-identification and under treatment of symptoms in patients receiving cancer treatment. PMID- 17704953 TI - The influence of urinary flow rate in children on excretion of markers used for assessment of renal damage: albumin, gamma-glutamyl transpeptidase, N-acetyl-beta D -glucosaminidase, and alpha1-microglobulin. AB - The aim of the present study was to examine the influence of urinary flow rate on markers of renal function in children. A sub-study of the New England Children's Amalgam Trial collected 82 pairs of urine samples from children aged 10-16 years: a timed overnight collection and a spot daytime sample collected the following day. These samples were analyzed for albumin, gamma-glutamyl transpeptidase (gamma-GT), N-acetyl-beta-D-glucosaminidase (NAG), alpha1-microglobulin (A1M), and creatinine concentration. Regression analysis was used to model the effect of urinary flow rate in the timed overnight samples. A paired t-test compared concentrations and creatinine-corrected renal markers between overnight and daytime samples. Albumin, gamma-GT, NAG, and A1M excretion rates increased significantly with urinary flow rate. Their corresponding creatinine-corrected markers did not vary significantly with urinary flow rate, but the creatinine corrected excretions of albumin, gamma-GT, and NAG were significantly higher in daytime samples than in overnight samples, with the same (non-significant) trend for A1M. The influence of urinary flow rate on creatinine-corrected markers of renal function was markedly less than its influence on excretion rates. Therefore, the use of creatinine-corrected markers seems to be a good choice in practice, with the caveat that daytime and overnight samples are not comparable. PMID- 17704956 TI - Hybrid density functional theory with a specific reaction parameter: hydrogen abstraction reaction of difluoromethane by the hydroxyl radical. AB - Accurate potential energy surfaces for the OH + CH2F2 --> H2O + CHF2 reaction are constructed using hybrid and hybrid meta density functional theory methods (mPW1PW91, B1B95, and mPW1B95) with specific reaction parameters in conjunction with the 6-31 + G(d,p) basis set. The accuracy of a surface is examined by comparing the calculated rate constants with the experimental ones. The rate constants are calculated over the temperature range 200-1,500 K using variational transition state theory with multidimensional tunneling contributions. The hybrid density functional theory methods with specific-reaction-parameter Hartree-Fock exchange contributions (39.2-41.0% for mPW1PW91, 41.0-42.2% for B1B95, and 44.9 46.3% for mPW1B95, respectively) provide accurate rate constants over an extended temperature range. The classical barrier height for the hydrogen abstraction reaction on these potential energy surfaces is determined to be 5.0-5.3 kcal mol( 1), and the best estimate value is 5.14 kcal mol(-1). PMID- 17704958 TI - Imaging features of a cecal lipoma as a lead point for colo-colonic intussusception. AB - Intussusception is a rare occurrence in the adult population with most of the cases seen during the childhood period. Compared with the pediatric intussusceptions, there is more often an underlying cause in adults. Lipoma as a lead point for colonic intussusception is rare. Ultrasound may be helpful in the diagnosis, but computed tomography is more reliably used for differential diagnosis. An adult patient with colo-colonic intussusception diganosed with ultrasound and confirmed with computed tomography is presented. PMID- 17704957 TI - PVOD suggested by MDCT and clinical findings in a pregnant woman. AB - Pulmonary hypertension secondary to pulmonary venoocclusive disease (PVOD) is increasingly recognized (Wagenvoort, Chest 69:82-86, [20]; Scully et al., N Engl J Med 308:823-834, [21]). The clinical presentation is usually progressive pulmonary hypertension. It should be kept in mind when there is pulmonary arterial hypertension, pulmonary edema, and a normal pulmonary artery wedge pressure. Importance of diagnosing this condition is to protect patient from fatal pulmonary edema when using prostacyclins that are effective for treatment of primary pulmonary hypertension. Herein, we present multidetector computed tomography findings of PVOD in a pregnant woman that presented with pulmonary hypertension. PMID- 17704959 TI - Visual marking and change detection. AB - The preview benefit from prior exposure of response-irrelevant (distracter) objects in visual search has been accounted for in terms of top-down inhibition (i.e. visual marking), bottom-up abrupt onset capture, or asynchrony-dependent perceptual segregation. We assess the relative contribution of abrupt onset and visual marking in a paradigm combining visual search with a visual working memory task. We investigated time-based selection of multiple objects for storage in visual working memory, using a change detection paradigm (Luck and Vogel in Nature 390:279-281, 1997) with distracter preview. We varied preview exposure (short vs. long), in a series of three experiments. The contribution of asynchrony-related perceptual segregation was assessed across experiments by varying the complexity of the stimuli (colored squares, oriented bars and oriented T-shapes) and the type of change detection (color or orientation), resulting in different levels of perceptual segregation between visual elements. The results suggest that bottom-up abrupt onset, visual marking and perceptual segregation factors co-operate in time-based selection for storage in visual working memory. PMID- 17704962 TI - [Dear colleagues]. PMID- 17704960 TI - Effects of dehydroepiandrosterone (DHEA) on hepatic lipid metabolism parameters and lipogenic gene mRNA expression in broiler chickens. AB - The aim of the present study was to identify the effects of dehydroepiandrosterone (DHEA) on hepatic lipid metabolism parameters and lipogenic gene mRNA expression in broiler chickens. A total of 72 1-day-old broiler chicks received a common basal diet with DHEA added at either 0 (control), 5 or 20 mg/kg feed. In the present study, the hepatic triglyceride (TG) concentration was significantly lower in male and female broilers that had bed administered DHEA than in control birds. In contrast, DHEA administration caused a marked rise in the hepatic non-esterified fatty acid (NEFA) concentration in both male and female broilers and also increased lipase (HL) activity in male broilers, while in female birds, no significant differences were observed in HL activity. The expression of peroxisome proliferators-activated receptor alpha (PPARalpha) and carnitine palmitoyl transferase I (CPTI) mRNA was decidedly enhanced following treatment with DHEA, and a similar tendency was also observed in the expression of acyl-Coenzyme A oxidase 1 (ACOX1). However, no significant differences were observed in the expression of either sterol regulatory element binding protein-1c (SREBP-1c) or acetyl CoA carboxylase (ACC) mRNA, except for a decline in the expression of ACC in females treated with 5 mg DHEA/kg. Numerous peroxisomes without a core and an increased number of peroxisomes were evident during morphological observations of broiler livers, in animals that had been treated with DHEA. Overall, the results of the present study indicated that DHEA accelerated lipid catabolism by direct regulation of hepatic lipid metabolism and by induction of relevant gene expression. PMID- 17704965 TI - Intrauterine programming of bone. Part 2: alteration of skeletal structure. AB - Osteoporosis is believed to be partly programmed in utero. Rat dams were given a low protein diet during pregnancy, and offspring were studied at different ages. Old aged rats showed site-specific strength differences. In utero nutrition has consequences in later life. INTRODUCTION: Epidemiological studies suggest skeletal growth is programmed during intrauterine and early postnatal life. We hypothesize that age-related decrease in bone mass has, in part, a fetal origin and investigated this using a rat model of maternal protein insufficiency. METHODS: Dams received either 18% w/w (control) or w/w 9% (low protein) diet during pregnancy, and the offspring were studied at selected time points (4, 8, 12, 16, 20, 47, 75 weeks). RESULTS: Using micro-CT, we found that at 75 weeks of age female offspring from mothers fed a restricted protein diet during pregnancy had femoral heads with thinner, less dense trabeculae, femoral necks with closer packed trabeculae, vertebrae with thicker, denser trabeculae and midshaft tibiae with denser cortical bone. Mechanical testing showed the femoral heads and midshaft tibiae to be structurally weaker, whereas the femoral necks and vertebrae were structurally stronger. CONCLUSIONS: Offspring from mothers fed a restricted protein diet during pregnancy displayed significant differences in bone structure and density at various sites. These differences result in altered bone characteristics indicative of significantly altered bone turnover. These results further support the need to understand the key role of the nutritional environment in early development on programming of skeletal development and consequences in later life. PMID- 17704966 TI - Prevailing attitude amongst current senior intercounty hurlers to head and facial protection: a pilot study. AB - BACKGROUND: Head and facial injury is a major cause of morbidity associated with the game of hurling. Yet, little is known about either players' experience of these injuries and their prevention with safety devices. AIMS: To survey the attitude of some of the country's senior intercounty players towards the use of protective head and facial devices and their experience of injuries relating to the head and face. METHODS: A questionnaire-based study. Player attitude to the use of protective devices will be reported here. RESULTS: Forty-five players completed the survey. Thirty-two (71%) players currently wear helmets with 28 (87.5%) of these also wearing faceguards. Twenty-four (75%) players have been injured despite wearing a helmet and/or faceguard. Thirteen (40.6%) players expressed frustration with helmet performance. CONCLUSIONS: Injury is an unavoidable feature of hurling. To this end perhaps more should be done to involve players in overall apparatus design and safety. PMID- 17704968 TI - Laparoscopic resection for colorectal cancer in Japan. AB - The first laparoscopic surgery for colorectal cancer in Japan was reported in 1992. In the early phase, many cases were indicated for early cancer. The number of operations has been increasing year by year, and now even some advanced cases undergo laparoscopic surgery. According to questionnaires administered in 2003 by the Japan Society for Endoscopic Surgery, more than half of 3,892 cases were indicated for advanced cancer. In 2004, the 60th biannual meeting of the Japanese Society for Cancer of the Colon and Rectum took up "the current status of laparoscopic resection for colorectal cancer" as one of the main topics of the meeting, and conducted a questionnaire survey of the member's opinions to laparoscopic resection for colorectal cancer prior to the meeting. It was revealed that at least ninety institutes had already performed a laparoscopic resection for colorectal cancer. In order to evaluate the feasibility of laparoscopic resection for colorectal cancer, a randomized control study comparing laparoscopic and open resection of colorectal cancer was started in 2004. This study is scheduled to collect 818 cases. The characteristic of this study was to enroll only advanced cancer cases. The primary endpoint is the survival, while the secondary end points are disease-free survival, early postoperative course, adverse events and conversion to open surgery. As more surgeons perform laparoscopic colorectal surgery, the importance for education and credentialing has been discussed. The Japan Society for Endoscopic Surgery started a system to qualify the surgeon's technique for endoscopic and laparoscopic surgery in 2004. One hundred and three surgeons took the examination for laparoscopic colorectal surgery in 2004, and 43 passed. PMID- 17704967 TI - Development of a pluripotent ES-like cell line from Asian sea bass (Lates calcarifer)--an oviparous stem cell line mimicking viviparous ES cells. AB - We report a pluripotent embryonic stem cell-like cell line designated as SBES from blastula stage embryos of Asian sea bass (Lates calcarifer), which is an economically important cultivable and edible marine fish species in India. The SBES cells were cultured at 28 degrees C in Leibovitz L-15 medium supplemented with 20% fetal bovine serum without a feeder layer. The ES-like cells were round or polygonal and grew exponentially in culture. The SBES cells exhibited an intense alkaline phosphatase activity and expression of transcription factor Oct 4. The undifferentiated state of these cells was maintained at low seeding densities and the cells formed embryoid bodies when seeded in bacteriological plates. On treatment with all-trans retinoic acid, these cells differentiated into neuron-like cells, muscle cells, and beating cardiomyocytes, indicating their pluripotency. This embryonic ES-like cell line derived from an oviparous fish blastula conserved several peculiar features of viviparous mammalian embryonic stem cell lines. The present study highlights the importance and potential of piscine ES-like cell line for stem cell research without evoking ethical issues and invasive interventions sparing mammalian embryos. PMID- 17704970 TI - On the long-term fitness of cells in periodically switching environments. AB - Because all the cell populations are capable of making switches between different genetic expression states in response to the environmental change, Thattai and van Oudenaarden (Genetics 167, 523-530, 2004) have raised a very interesting question: In a constantly fluctuating environment, which type of cell population (heterogeneous or homogeneous) is fitter in the long term? This problem is very important to development and evolution biology. We thus take an extensive analysis about how the cell population evolves in a periodically switching environment either with symmetrical time-span or asymmetrical time-span. A complete picture of the phase diagrams for both cases is obtained. Furthermore, we find that the systems with time-dependent cellular transitions all collapse to the same set of dynamical equations with the modified parameters. Furthermore, we also explain in detail how the fitness problem bears much resemblance to the phenomenon, stochastic resonance, in physical sciences. Our results could be helpful for the biologists to design artificial evolution experiments and unveil the mystery of development and evolution. PMID- 17704969 TI - Does infliximab influence surgical morbidity of ileal pouch-anal anastomosis in patients with ulcerative colitis? AB - PURPOSE: Since infliximab has been approved for treatment of patients with refractory ulcerative colitis, surgeons will be increasingly faced with operating on patients who have failed therapy with this potent immunosuppressant. This study was designed to compare short-term complications in patients with ulcerative colitis who were treated with and without infliximab before colectomy. METHODS: The charts of patients undergoing ileal pouch-anal anastomosis or subtotal colectomy for refractory ulcerative colitis during the five-year period ending October 2005 were reviewed. Postoperative medical and surgical complications were assessed. RESULTS: Seventeen patients had failed infliximab treatment and 134 patients were never treated with infliximab. Ileal pouch-anal anastomosis was performed in 112 patients (74 percent) and subtotal colectomy in 39 patients (36 percent). There were no deaths. Postoperative complications were observed in 43 patients (28 percent), with no significant difference observed between infliximab-treated (37 percent) and infliximab-untreated patients (27 percent). Of 61 patients (40 percent) treated with preoperative cyclosporine A, 5 patients also had been treated with infliximab. The infliximab and cyclosporine A treated patient group had an 80 percent complication rate, significantly higher than the 29 percent complication rate noted in the cyclosporine A only-treated group (P = 0.04). CONCLUSIONS: Although preoperative treatment with infliximab alone does not significantly increase the incidence of postoperative complications, using both inflixiamb and cyclosporine A before colectomy in refractory ulcerative colitis is associated with high surgical morbidity. PMID- 17704971 TI - Case fatality proportion. AB - A precise definition of case fatality proportion for compartmental disease transmission models with disease induced mortality rate is given. This is applied in classical epidemic modeling frameworks to models with multiple infectious stages, with multi-groups, with spatial patches, and with age of infection. It is shown that the case fatality proportion is the sum over all stages of the product of the probability of dying from the disease at a given stage and the probability of surviving to that stage. The derived expressions for case fatality can be used to estimate the disease induced death rates from more readily available data. PMID- 17704972 TI - [Phytodrugs--phytotherapy]. PMID- 17704973 TI - [New developments in hypericum extracts: data on efficacy and interactions]. AB - The recent clinical studies on hypericum extract support the present indications for its use in mild to moderate depression and depressive episodes. The effectiveness is superior to placebo and comparable with synthetic antidepressive drugs. The rate of unwanted events is explicitly lower and their severity in general only mild. A further indication for hypericum could be somatoform disorders, but further clinical studies are recommended. The main compound responsible for interactions is presumably hyperforin, but further ingredients could contribute according to the specific composition of the particular extract. PMID- 17704974 TI - Ginkgo biloba (EGb 761) in arteriosclerosis prophylaxis. AB - The prevention or deceleration of atherogenesis is one of the most significant anti-aging objectives since this is a matter of avoidance of myocardial infarction and stroke. To approach this prophylactic aim, phytochemical nutrition counteracting peroxidation of blood lipids based on their scavenger qualities for reactive oxygen species (ROS) can possibly serve. For example, oxidized LDL particles are highly atherogenic. Against this background, we investigated in a pilot study the effect of Ginkgo biloba (EGb 761: Rokan novo), the free oxygen radical scavenging properties of which are well-documented, on the atherosclerotic nanoplaque formation in cardiovascular high-risk patients. In eight patients who had undergone an aortocoronary bypass operation, the reduction of atherosclerotic nanoplaque formation amounted to 11.9 +/- 2.5% (p < 0.0078) and of nanoplaque size to 24.4 +/- 8.1% (p < 0.0234), respectively, after a 2 month therapy with Ginkgo biloba extract (EGb 761, 2 x 120 mg daily, Rokan novo, Spitzner Arzneimittel, Ettlingen, Germany). Additionally, superoxide dismutase (SOD) activity was upregulated by 15.7 +/- 7.0% (p < 0.0391), the quotient oxLDL/LDL lowered by 17.0 +/- 5.5% (p < 0.0234) and lipoprotein(a) concentration decreased by 23.4 +/- 7.9% (p < 0.0234) in the patients' blood after the 2-month medication regimen. The concentration of the vasodilating substances cAMP and cGMP was augmented by 37.5 +/- 9.1% (p < 0.0078) and 27.7 +/- 8.3% (p < 0.0156), respectively. A multimodal regression analysis reveals a basis for a mechanistic explanation of nanoplaque reduction under ginkgo treatment. The atherosclerosis inhibiting effect is due to an upregulation in the body's own radical scavenging enzymes and an attenuation of the risk factors oxLDL/LDL and Lp(a). Furthermore, the significant increase in the vasodilator cAMP and cGMP concentration powerfully supports the maintenance of an open bypass. PMID- 17704975 TI - Effects of Ginkgo biloba extract EGb 761 on neuropsychiatric symptoms of dementia: findings from a randomised controlled trial. AB - In a randomised, double-blind, 22-week trial 400 patients with dementia associated with neuropsychiatric features were treated with Ginkgo biloba extract EGb 761 (240 mg/day) or placebo. Patients with probable Alzheimer's disease, possible Alzheimer's disease with cerebrovascular disease or vascular dementia were eligible if they scored 9 to 23 on the SKT cognitive test battery and at least 5 on the Neuropsychiatric Inventory (NPI). EGb 761 was significantly superior to placebo with respect to the primary (SKT test battery) and all secondary outcome variables. The mean composite score (frequency x severity) and the mean caregiver distress score of the NPI dropped from 21.3 to 14.7 and 13.5 to 8.7, respectively, in the EGb 761-treated patients, but increased from 21.6 to 24.1 and 13.4 to 13.9, respectively, under placebo (p < 0.001). The largest drug placebo differences in favour of EGb 761 were found for apathy/indifference, anxiety, irritability/lability, depression/dysphoria and sleep/nighttime behaviour. PMID- 17704977 TI - [Time and again it hits the little ones: herbal therapy for childhood diarrhea]. AB - Acute diarrhea is amongst the most common childhood illnesses. Of paramount importance is an oral rehydration with glucose-electrolyte solutions. A number of herbal therapies are available to shorten the duration of the diarrhea and to alleviate the unpleasant symptoms. Although herbal preparations are generally well tolerated, only a few have been tested on children and adjusted to their needs. Various therapies for diarrhea in childhood are highlighted with regard to the clinical trials with children, and their user-friendliness. PMID- 17704976 TI - [STW 5/Iberogast: multi-target-action for treatment of functional dyspepsia and irritable bowel syndrome]. AB - Functional gastro-intestinal diseases such as functional dyspepsia and irritable bowel syndrome are a therapeutic challenge, as they are not only characterized by a multitude of symptoms, some of them with severe consequences for affected patients, but are also caused by a multitude of factors. The clinical efficacy of the therapeutics STW 5/Iberogast in these diseases has been proven in a number of randomized prospective clinical studies. Several preclinical studies suggest that its efficacy could be due to its complex composition of nine standardized herbal extracts, which act differently on multiple sites. This principle, which is quite popular in clinical medicine, was introduced as a multi-target therapy for functional bowel disorders. Components of STW 5/Iberogast reduce gastro intestinal hypersensitivity and act spasmolytic on spastic, tonicising on atonic gastro-intestinal muscle. In addition a stimulating effect on reduced mucus secretion, an inhibitory effect on enhanced gastric acid secretion and an anti inflammatory effect have been shown. These effects could explain the clinical efficacy of STW5/Iberogast in a large range of symptoms. PMID- 17704979 TI - Saffron in phytotherapy: pharmacology and clinical uses. AB - Saffron (stigmata of Crocus sativus L.) has been used for medicinal purposes for millennia. Throughout history, uses against cancer and depressive mood can regularly be identified. These applications have also been in the focus of modern research. Promising and selective anti-cancer effects have been observed in vitro and in vivo, but not yet in clinical trials. Antidepressant effects were found in vivo and in clinical pilot studies. Saffron extracts thus have the potential to make a major contribution to rational phytotherapy. PMID- 17704978 TI - Achillea millefolium L. s.l. revisited: recent findings confirm the traditional use. AB - Yarrow (Achillea millefolium L. s.l.) is traditionally used in the treatment of inflammatory and spasmodic gastro-intestinal disorders, hepato-biliary complaints and inflammation. Now we could show that the flavonoids mediated the antispasmodic properties of yarrow, whereas the dicaffeoylquinic acids caused the choleretic effects. Moreover, we observed an in vitro-inhibition of human neutrophil elastase, a protease involved in the inflammatory process, by extracts and fractions from yarrow, which suggests additional mechanisms of antiphlogistic action. The presented results confirm the traditional use of yarrow. PMID- 17704980 TI - [Inhibitors of alpha-amylase from plants--a possibility to treat diabetes mellitus type II by phytotherapy?]. AB - Antidiabetics of plant origin are in common use. A proof of their effectiveness or their mode of action is often missing. The aim of this work was to review the knowledge about inhibitors of alpha-amylase from plants and to comment on the use in anti-diabetic treatment. Herbal alpha-amylase inhibitors are rarely described in the literature, nevertheless they have the ability to lower postprandial blood glucose level and should be used in the supplementary treatment of diabetes. Important constituents for the inhibitory activity against alpha-amylase are mainly polyphenolic compounds. There is a need for further clinical studies to establish a rational therapy with traditional herbal preparations, especially for the leaves from the blueberry, tamarind, lemon balm and rosemary, the hulls from white kidney beans or green tea extract. PMID- 17704982 TI - [Pelargonium sidoides-extract (EPs 7630): registration confirms efficacy and safety]. AB - For centuries the roots of Pelargonium sidoides DC have been used in South African ethno-medicine for the treatment of respiratory diseases. In Germany, a medicinal product containing a special extract of this substance is among the group of self-medication products most widely bought at chemist's shops. In December 2005, the Federal Institute for Drugs and Medical Devices (BfArM, Bonn) approved a new license for its use as a drug. The following review focuses on the current pharmacological, toxicological and clinical data covering the efficacy and innocuousness of this drug when administered for the treatment of acute bronchitis. PMID- 17704981 TI - Cranberry juice-- a well-characterized folk-remedy against bacterial urinary tract infection. AB - Cranberry (Vaccinium macrocarpon) is a North-American folk remedy for treating and preventing infection. Research has identified an anti-adhesive mechanism of cranberry-proanthocyanidins that inhibit docking of bacteria on tissues "in vitro". This efficacy mechanism can be traced in the patient's urine following oral intake of cranberry juice. The efficacy of cranberry juice and extracts as a prophylactic agent against recurrent urinary infections is well documented in women. The anti-adhesion effect of cranberry-proanthocyandins can also be applied for treatment of other common diseases of bacterial pathogenesis, e.g. Helicobacter pylori-associated gastritis and dental caries/periodontal disease. PMID- 17704984 TI - Phytodolor--effects and efficacy of a herbal medicine. AB - Herbal antirheumatics are successfully used in painful inflammatory or degenerative rheumatic diseases. One of these herbal medicines is Phytodolor (STW 1), a fixed combination of extracts from aspen leaves and bark (Populus tremula), common ash bark (Fraxinus excelsior), and golden rod herb (Solidago virgaurea). Its effects as well as those of its components have been verified in experimental and human pharmacological investigations. The mode of action of STW 1 includes antiinflammatory, antioedematous, antioxidative and analgesic properties, and it is considered to be broader than that of synthetic antirheumatics. Open clinical studies and randomised, placebo- or verum-controlled double-blind trials, performed in different subtypes of rheumatic diseases, confirm the pharmacological evidence of efficacy, such as by reducing the intake of non steroidal antiinflammatory drugs (NSAIDs). STW 1 has a high drug safety. CONCLUSION: Phytodolor (STW 1) is a reasonable alternative to NSAIDs and to cyclooxygenase(COX)-2-inhibitors such as rofecoxib. PMID- 17704983 TI - [Management of capecitabine-induced hand-foot syndrome by local phytotherapy]. AB - The so-called hand-foot syndrome (HFS) is a dose-limiting side effect with only rare therapeutic options in cancer patients treated with capecitabine (Xeloda). Depending on the intensity of the skin reaction dose reduction, interruption or even the break-off of capecitabine therapy is necessary. We therefore try to describe a new and promising alternative treatment of the hand-foot syndrome, a local therapy with a mixture of herbal medicinal products mainly consisting of hand- and foot baths, and present the promising results of this treatment modality observed in 11 consecutive patients. PMID- 17704985 TI - Willow bark extract: the contribution of polyphenols to the overall effect. AB - The efficacy of willow bark extract in the treatment of painful mobility disorders, such as back pain and arthritis, has been attributed to the content of salicin and its derivatives as pro-drugs of salicylates. However, based on clinical experience and the evidence of experimental pharmacological studies, the fraction of total salicin cannot satisfactorily explain the clinical efficacy of willow bark. In addition, salicins and their metabolites lack the acetylating potential of ASA and must therefore possess a different mechanism of action. A detailed pharmacological screening of the aqueous willow bark extract STW 33-I addressed the question of the identification of fractions contributing to the overall effect. All in vivo and in vitro models studied pointed to relevant contributions of the fraction of polyphenols and flavonoids. The single compounds or their combinations responsible for the effect remain to be elucidated. PMID- 17704986 TI - [Herb-drugs interactions]. AB - Herbal therapeutics are increasingly associated with herb drug interactions. The vast majority of the purported cases is unsubstantiated and misinterpreted. Pharmacological and clinical studies should only be demanded in cases of reliable evidence. First steps to be taken by manufacturers of herbal drugs should be in vitro studies with metabolizing systems like CYP and P-gp. Manufacturers of drugs that are metabolized by modulated systems should be requested to conduct drug specific interaction studies as necessary. PMID- 17704988 TI - Placebo controlled continuation treatment with Hypericum extract WS 5570 after recovery from a mild or moderate depressive episode. AB - Patients suffering from an acute episode of mild to moderate major depression and who had been treated successfully with Hypericum perforatum extract WS 5570 in doses of 600 mg/day or 1200 mg/day or with placebo for 6 weeks in a multi-centre, double-blind, randomized clinical trial, were asked to take part in a continuation treatment. Those participants with a HAMD total score decrease > or =50% during acute treatment were eligible for 4 months of double-blind continuation treatment with the same dose regimen. In total, 69, 68 and 24 (WS 5570 600 mg/day, 1200 mg/day and placebo) patients entered continuation treatment. Both WS 5570 groups showed an additional slight decrease of the HAMD total score by 0.8 (600 mg WS 5570/day) and 0.4 (1200 mg WS 5570/day) points during treatment phase, while patients in the placebo group deteriorated by 2.1 points. The incidence of adverse events was low in all therapy groups. PMID- 17704987 TI - St. John's wort: role of active compounds for its mechanism of action and efficacy. AB - St. John's wort (Hypericum perforatum L., SJW) contains numerous compounds with documented biological activity. Constituents that have stimulated the most interest include the naphthodianthrones hypericin and pseudohypericin, a broad range of flavonoids, and the phloroglucinols hyperforin and adhyperforin. According to the actual state of scientific knowledge the total extract has to be considered as the active substance. Although there are some open questions, the bulk of data suggests that several groups of active compounds are contributing to the antidepressant efficacy of the plant extract. PMID- 17704989 TI - Scientific evidence for a fixed extract combination (Ze 91019) from valerian and hops traditionally used as a sleep-inducing aid. AB - Valerian and hops are traditionally used as sleep-inducing aids. Alertness reduces gradually with the prolongation of wakefulness through the release of endogenous adenosine in the frontal basal cortex. Valerian has an adenosine-like action and supports the readiness to fall asleep. The control of the sleep-wake rhythm induces sleep when the time-related interaction is operating properly. The control is closely related to endogenous melatonin secretion. Hops act in a similar way to melatonin. Therefore, the efficacy of a valerian and hops combination in sleep disorder can scientifically be explained. PMID- 17704990 TI - Features of limb fractures: a review of epidemiology from a Japanese perspective. PMID- 17704991 TI - Oxygen tension is an important mediator of the transformation of osteoblasts to osteocytes. AB - Osteocytes are derived from osteoblasts, but reside in the mineralized bone matrix under hypoxic conditions. Osteocyte-like cells show higher expression of ORP150, which is induced by hypoxia, than osteoblast-like cells. Accordingly, we hypothesized that the oxygen tension may regulate the transformation of osteoblasts to osteocytes. MC3T3-E1 cells and calvariae from 4-day-old mice were cultured under normoxic (20% O(2)) or hypoxic (5% O(2)) conditions. To investigate osteoblastic differentiation and tranformation to osteocytes, alizarin red staining was done and the expression of various factors was assessed. Hypoxic culture promoted the increased synthesis of mineralized matrix by MC3T3-E1 cells. Alkaline phosphatase activity was initially increased during hypoxic culture, but decreased during osteogenesis. Osteocalcin production was also increased by hypoxic culture, but decreased after mineralization. Furthermore, expression of Dmp1, Mepe, Fgf23, and Cx43, which are osteocyte specific or osteocyte-predominant proteins, by MC3T3-E1 cells was greater under hypoxic than under normoxic conditions. In mouse calvarial cultures, the number of cells in the bone matrix and cells expressing Dmp1 and Mepe were increased by hypoxia. In MC3T3-E1 cell cultures, ORP150 expression was only detected in the mineralized nodules under normoxic conditions, while its expression was diffuse under hypoxic conditions, suggesting that the nodules were hypoxic zones even in normoxic cultures. These findings suggest that a low oxygen tension promotes osteoblastic differentiation and subsequent transformation to osteocytes. PMID- 17704992 TI - Effects of IL-23 and IL-27 on osteoblasts and osteoclasts: inhibitory effects on osteoclast differentiation. AB - Interleukin (IL)-23 and IL-27 are IL-6/IL-12 family members that play a role in the regulation of T helper 1 cell differentiation. Cytokines are known to be involved in the bone remodeling process, although the effects of IL-23 and IL-27 have not been clarified. In this study, we examined the possible roles of these cytokines on osteoblast phenotypes and osteoclastogenesis. We found that IL-27 induced signal transducers and activators of transcription 3 activation in osteoblasts. However, neither IL-23 nor IL-27 showed any significant effects on alkaline phosphatase activity, receptor activator of nuclear factor kappaB ligand (RANKL) expression, mRNA expression such as alkaline phosphatase type I procollagen, or the proliferation of osteoblasts. Osteoclastogenesis from bone marrow cells induced by soluble RANKL was partially inhibited by IL-23 and IL-27 with reduced multinucleated cell numbers, but these interleukins did not affect the proliferation of osteoclast progenitor cells. These results indicate that IL 23 and IL-27 could partly modify cell fusion or the survival of multinucleated osteoclasts. On the other hand, partially purified T cells, which are activated by 2 microg/ml anti-CD3 antibody, completely inhibited osteoclastogenesis by M CSF/RANKL. On using T cells activated with 0.2 microg/ml anti-CD3 antibody, in which osteoclastogenesis was partially inhibited, the interleukins had additive effects for inhibiting osteoclastogenesis. Although the consequences of phosphorylated signals in osteoblasts have not been identified, IL-23 and IL-27, partly and indirectly through activated T cells, inhibited osteoclastogenesis, indicating that these interleukins may protect against bone destructive autoimmune disorders. PMID- 17704994 TI - Effects on the bones of vanadyl acetylacetonate by oral administration: a comparison study in diabetic rats. AB - Oral delivery, rather than parenteral administration, would be beneficial for treating diabetic mellitus owing to the need for a long-term regimen. The objectives of this study were to evaluate oral delivery tolerance and the effects on the bone of accumulated vanadium following the long-term administration of vanadyl acetylacetonate (VAC). Normal and diabetic rats were intragastrically administered VAC at a dose of 3 mg vanadium/kg body weight once daily for 35 consecutive days. VAC did not cause any obvious signs of diarrhea, any changes in kidney or liver, or deaths in any group. The phosphate levels in the bone were slightly increased, and the calcium levels in the bone were not obviously changed as compared with those of the rat group not receiving VAC. After administration of VAC, the decreased ultimate strength, trabecular thickness, mineral apposition rate, and plasma osteocalcin in diabetic rats were either improved or normalized, but reduced bone mineral density (BMD) in diabetic rats was not improved. None of the parameters evaluated in normal rats were altered. The results indicate that the oral VAC is tolerated and benefits the diabetic osteopathy of rats, but seems not to influence the bone of normal rats. They also suggest that VAC improves diabetes-related bone disorders, primarily by improving the diabetic state. PMID- 17704993 TI - Expression of cytokines IL-4, IL-12, IL-15, IL-18, and IFNgamma and modulation by different growth factors in cultured human osteoblast-like cells. AB - The antigenic phenotype of cultured human osteoblast-like cells, their ability to phagocytose particles of different nature and size, and their capacity to stimulate allogeneic T cells suggest that they are related to other cell populations with which they may also have immunological functions in common. The objective of this study was to investigate the intracytoplasmatic presence of cytokines and their modulation by different biomolecules. Immunocytochemistry and flow cytometry were used to study the expression of IL-4, IL-12, IL-15, IL-18, and IFNgamma cytokines. To investigate whether FGF, TGF, PDGF, IL-1, and IFNgamma modulate expression of these cytokines in cultured human osteoblast-like cells we used flow cytometry. IL-4, IL-12, IL-15, IL-18, and IFNgamma cytokines were expressed by all the cultured human osteoblast-like cells studied. Treatment with FGF and TGFbeta1 reduced the percentage expression and fluorescence intensity of the cytokines. PDGF treatment enhanced their fluorescence intensity but did not modify their expression. IL-1 treatment produced a small reduction in expression and fluorescence intensity of IL-12 and IL-15, but did not produce major changes in the expression of IL-4, IL-18, or IFNgamma. IFNgamma markedly increased the fluorescence intensity of the cytokines. The results indicate that human osteoblast-like cells may perform immunological functions (e.g., synthesizing cytokines with immune regulator function) that can be modulated by different biomolecules related to bone tissue and/or immune response. PMID- 17704995 TI - Factors affecting long-term compliance of osteoporotic patients with bisphosphonate treatment and QOL assessment in actual practice: alendronate and risedronate. AB - The aim of our study was to examine compliance with a daily dose of 5 mg alendronate (ALN) and 2.5 mg risedronate (RDN) in actual practice, and to determine the causes of noncompliance through a questionnaire. In addition, we studied the quality of life (QOL) of patients through another disease-related questionnaire. The overall compliance rate remained at approximately 40% one year after the initial dose. The rates did not differ significantly between the ALN group (783 patients) and the RDN group (491 patients). The compliances in the female group and the rheumatism group were better than in the male group and the nonrheumatism group. From the questionnaire, 36% of noncompliant patients showed adverse effects (AEs), and the other noncompliant patients stopped the medication in spite of having no AEs. A logistic regression analysis of factors that might have affected long-term compliance included AEs, an understanding of the disease, the method of ingestion, visiting medical facilities, the shape of the tablet, the cost of the drug, and the explanation of the doctor or pharmacist. This analysis showed that noncompliance occurred mainly due to AEs, the inconvenience of visiting a medical facility, unusual methods of ingestion, and a poor understanding of the disease. According to the results of the questionnaire for QOL assessment, the patients who continued the medication for more than 1 year had improved scores for pain in both the ALN and RDN groups. Osteoporotic treatment needs long-term patient compliance. To improve compliance, it is very important that doctors and pharmacists ensure that patients understand the purpose of this therapy. PMID- 17704996 TI - Association analysis of the polymorphisms of the VDR gene with bone mineral density and the occurrence of fractures. AB - Associations of the FokI, BsmI, ApaI, and TaqI polymorphisms of the vitamin D receptor (VDR) gene with the bone mineral density (BMD) of the lumbar part of the spinal column (BMD LS) and the neck of the femur (BMD FN), and with the occurrence of fractures, were studied using the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis on DNA isolated from peripheral blood of 239 women and 40 men from the region of western Poland. Three polymorphisms of the 3' end of the VDR gene (BsmI, ApaI, TaqI) indicated a strong linkage disequilibrium. Association analysis of the VDR gene FokI polymorphism with BMD LS showed a dose effect of allele f. The association of the bAT haplotype of the BsmI, ApaI, and TaqI polymorphisms of the VDR gene with BMD FN was statistically significant. The association of the ApaI polymorphism with the occurrence of fractures was observed. Associations were also observed between the occurrence of fractures and the baT haplotypes of the VDR gene. PMID- 17704997 TI - Genetic association of a polymorphism of the cAMP-responsive element binding protein-binding protein with steroid-induced osteonecrosis after kidney transplantation. AB - Nontraumatic osteonecrosis (ON) of the femoral head is known to be one of the major complications after organ transplantations. Although the precise mechanism is still uncertain, the administration of glucocorticoid (GC) has been considered to play an important role in the occurrence of ON. To elucidate the genetic factors involved in this pathogenesis, we analyzed single nucleotide polymorphisms (SNP) in the genes for the GC receptor (GR), CYP3A4, cAMP responsive element binding protein-binding protein (CBP), and nuclear receptor co activator 2 (NCoA2). Among the patients examined, A/G alleles of the CBP gene were demonstrated in 32.4% of those with ON, but in only 14.6% of those without ON (P = 0.018). No relationships were observed between the SNPs of GR, CYP3A4, and NCoA2 genes and the occurrence of ON. These results indicate that the genetic polymorphism of the CBP, which is one of the essential factors exerting the biological effects of GC, may affect susceptibility to steroid-induced ON in patients after renal transplantation. PMID- 17704998 TI - Relationship between body composition and bone mineral density in women with and without osteoporosis: relative contribution of lean and fat mass. AB - To assess the relationship of total fat mass (TFM) and total lean mass (TLM) with bone mineral density (BMD) and bone mineral content (BMC), we studied 770 postmenopausal white women after total body measurements by dual-energy X-ray absorptiometry. Height-independent bone mineral density (HIBMD) was also tested. The effects of TFM and TLM on the dependent variables HIBMD, BMD, and BMC were assessed by the univariate general linear model (UGLM). Age, age at menopause, height, and bone area were entered in the models as controlling variables when appropriate. In the total population, TLM and TFM were associated with BMD, BMC, and HIBMD (P < 0.001). Taking the T-score cut-off as -2.5, women without (463) and with (307) osteoporosis were then tested separately. In nonosteoporotic women, TLM was significantly associated with BMD, BMC, and HIBMD (P < 0.001), while TFM was not. In osteoporotic women, both TLM and TFM were associated with BMD to the same extent (P < 0.05), but not with HIBMD. Women without osteoporosis were then tested according to whether their TFM/TLM fraction was less than or greater than 1. In those with TFM/TLM less than 1, both TLM (P < 0.001) and TFM (P < 0.01), tested separately, were associated with BMD and BMC, but not with HIBMD. When TLM and TFM were tested at the same time and assessed by the same UGLM, only TLM (P < 0.001) still affected these three bone parameters. In women with TFM/TLM greater than 1, testing the body components both separately and at the same time and using the UGLM showed that TFM affected both BMC and BMD (P < 0.05), while TLM did not. In conclusion, our data indicate that both TFM and TLM affect bone density, with different physiological/pathological conditions modulating this relationship. PMID- 17704999 TI - Pelvic insufficiency fracture associated with severe suppression of bone turnover by alendronate therapy. PMID- 17705000 TI - Dosimetric properties of a flattening filter-free 6-MV photon beam: a Monte Carlo study. AB - PURPOSE: The dosimetric features of an unflattened 6-MV photon beam of an Elekta SL-25 linac was calculated by the Monte Carlo (MC) method. MATERIAL AND METHODS: The head of the Elekta SL-25 linac was simulated using the MCNP4C MC code. The accuracy of the model was evaluated using measured dosimetric features, including depth dose values and dose profiles in a water phantom. The flattening filter was then removed, and beam dosimetric properties were calculated by the MC method and compared with those of the flattened photon beam. RESULTS: Our results showed a significant (twofold) increase in the dose rate for all field sizes. Also, the photon beam spectra for an unflattened beam were softer, which led to a steeper reduction in depth doses. The decrease in the out-of-field dose and increase in the contamination electrons and a buildup region dose were the other consequences of removing the flattening filter. CONCLUSION: Our study revealed that, for recent radiotherapy techniques, the use of multileaf collimators for beam shaping removing the flattening filter could offer some advantages, including an increased dose rate and decreased out-of-field dose. PMID- 17705001 TI - Preprocedural MR imaging for percutaneous vertebroplasty: special interest in contrast enhancement. AB - PURPOSE: The success of percutaneous vertebroplasty (PVP) depends greatly on preprocedural evaluation of the patients. The purpose of this study was to evaluate the efficacy of preprocedural magnetic resonance imaging (MRI) for the indications of PVP. MATERIALS AND METHODS: A retrospective review of 122 osteoporotic compression fractures in 63 patients who underwent preprocedural gadolinium-enhanced MRI and PVP was performed. Based on the extent of contrast enhancement on preprocedural MRI, each case was classified into one of two groups: group 1, which represented more than 50% of the vertebral body enhanced; and group 2, which represented less than 50% of the vertebral body enhanced. The most enhancing level was evaluated in multilevel PVP sessions. We evaluated the difference of pre- and postprocedural pain scales between groups 1 and 2 using Mann-Whitney's U-test. RESULTS: There was a trend toward higher preoperative pain score in group 1, but it was not statistically significant (P = 0.0537). In addition, the postoperative pain score in group 2 was significantly higher than that in group 1 (P = 0.0007). The difference between the pre- and postoperative pain scores was significantly higher in group 1 than in group 2 (P = 0.0001). CONCLUSION: Contrast enhancement on MRI indicates a painful lesion and extensive contrast enhancement predicts better pain relief after PVP. PMID- 17705002 TI - Comparison of urethral diameters for calculating the urethral dose after permanent prostate brachytherapy. AB - PURPOSE: No studies have yet evaluated the effects of a dosimetric analysis for different urethral volumes. We therefore evaluated the effects of a dosimetric analysis to determine the different urethral volumes. METHODS: This study was based on computed tomography/magnetic resonance imaging (CT/MRI) combined findings in 30 patients who had undergone prostate brachytherapy. Postimplant CT/MRI scans were performed 30 days after the implant. The urethra was contoured based on its diameter (8, 6, 4, 2, and 0 mm). The total urethral volume-in cubic centimeters [UrV150/200(cc)] and percent (UrV150%/200%), of the urethra receiving 150% or 200% of the prescribed dose-and the doses (UrD90/30/5) in Grays to 90%, 30%, and 5% of the urethral volume were measured based on the urethral diameters. RESULTS: The UrV150(cc) and UrD30 were statistically different between the of 8-, 6-, 4-, 2-, and 0-mm diameters, whereas the UrD5 was statistically different only between the 8-, 6-, and 4-mm diameters. Especially for UrD5, there was an approximately 40-Gy difference between the mean values for the 8- and 0-mm diameters. CONCLUSION: We recommend that the urethra should be contoured as a 4- to 6-mm diameter circle or one side of a triangle of 5-7 mm. By standardizing the urethral diameter, the urethral dose will be less affected by the total urethral volume. PMID- 17705003 TI - Spasm induced by protection balloon during carotid artery stenting. AB - PURPOSE: The PercuSurge system is a distal balloon embolic protection device used for carotid artery stenting (CAS). We performed a retrospective study on the prognosis and clinical effects of spasms induced by the PercuSurge GuardWire system (PercuSurge-induced spasm). MATERIALS AND METHODS: We performed CAS in 118 carotid stenoses using the PercuSurge system. Of the 118 procedures, 31 (26.3%) of the patients experienced PercuSurge-induced spasm, and all underwent postoperative follow-up studies by cerebral angiography and antiplatelet treatment. RESULTS: On follow-up angiograms obtained a mean of 5.2 months (range 3-10 months) after CAS, all 31 PercuSurge-induced spasms had disappeared, and no delayed stenosis was found at the sites where the spasms had occurred. No ischemic events due to the spasms occurred during a mean follow-up of 13 months (range 3-32 months). CONCLUSION: In the hands of physicians experienced in endovascular surgery, CAS using the PercuSurge system is a safe method with which to treat patients with carotid stenosis. Our study demonstrated that PercuSurge induced spasms had no morphological or clinical adverse effects. PMID- 17705005 TI - Magnetic resonance imaging findings of endometrioid adenocarcinoma of the ovary. AB - PURPOSE: We assessed magnetic resonance imaging (MRI) features and clinical characteristics of ovarian endometrioid adenocarcinoma. MATERIALS AND METHODS: A total of 31 patients with 39 surgically proven ovarian endometrioid adenocarcinomas were analyzed retrospectively. Histologically, 13 lesions in 12 patients arose from proven endometriomas (group A), and 26 lesions in 19 patients did not coexist with endometrioma (group B). The morphological pattern of the lesion on MRI was classified as a solid or a cystic type: A solid type was defined as a solid component occupying more than half of the lesion; and a cystic type was a cystic lesion with one or more mural nodules. RESULTS: Altogether, 11 lesions in group A were the cystic type on MRI, whereas 24 lesions in group B were the solid type (P < 0.0001). Among the 11 cystic-type lesions in group A, the cysts of 5 lesions were hypointense on T1-weighted images, and the cysts of 6 lesions were hyperintense on T1- and T2-weighted images without "shading." The nuclear grade was higher (P = 0.0028) and the clinical stage more advanced (P = 0.0018) in group B compared to group A. CONCLUSION: MRI of ovarian endometrioid adenocarcinomas revealed two types: a solid type and a cystic type. The lesions arising from endometriomas tended to be the cystic type on MRI and have a good prognosis. Preexisting endometrioma in this entity rarely showed "shading" on T2 weighted images. PMID- 17705006 TI - Extraskeletal mesenchymal chondrosarcoma of the cervical meninx. AB - We report a case of recurrent mesenchymal chondrosarcoma in the cervical paravertebral region that was diagnosed preoperatively by imaging studies. The tumor showed findings of a well-differentiated cartilaginous tumor with a characteristic pattern of calcifications on computed tomography (CT). However, it appeared as a soft tissue sarcoma of lower intensity than common cartilaginous tumors on T2-weighted magnetic resonance imaging (MRI). This discrepancy between CT and MRI was well correlated with pathological findings of mesenchymal chondrosarcoma and suggested this entity. PMID- 17705004 TI - Comparing size evaluation methods for acoustic neuroma after stereotactic radiosurgery. AB - PURPOSE: Acoustic neuroma tumor size may be evaluated using several methods. Here we investigate the variations among measuring techniques. MATERIALS AND METHODS: A retrospective analysis of pre- and posttreatment magnetic resonance (MR) scans was performed on 15 acoustic neuroma patients with a history of stereotactic radiosurgery who had been followed for more than 2 years. Tumor size was measured on each MR scan using three methods, where the extracanalicular (EX) and intracanalicular (IN) portions were measured separately. We collected data on the largest diameter (M1), the square root of the product of the maximum anteroposterior and mediolateral diameter (M2), and the average for the maximum anteroposterior, mediolateral, and superoinferior diameters (M3). Size differences between follow-up MR scans separated by more than 2 years were calculated for each method, and we evaluated whether the tumors progressed, remained stable, or regressed. RESULTS: A total of 154 follow-up pairs of EX and 115 follow-up pairs of IN showed a statistically significant difference for the number of each category among the three methods (P = 0.03, P < 0.01, respectively). The greatest category agreement was observed between the M2 and M3 methods. CONCLUSION: A significant difference between the tumor size measuring methods was observed. To strengthen specificity when evaluating tumor size difference, a measuring method using two or more parameters is recommended. PMID- 17705007 TI - Cerebral hemorrhage with angiographic extravasation immediately after carotid artery stenting. AB - Recognizing cerebral hyperperfusion syndrome with intracerebral hemorrhage following carotid artery stenting is critical because the mortality rate is high. This type of hemorrhage usually arises from within several hours to a few days after the procedure. Here we describe a putaminal hemorrhage with extravasation during angiography that developed immediately after carotid artery stenting. A search of the literature revealed only one other similar case report. The etiology of the intracerebral hemorrhage immediately after carotid stenting might be analogous to that of hypertensive hemorrhage. PMID- 17705010 TI - Assessment of cardiac function in patients with heart disease by quantitative gated myocardial perfusion SPECT. AB - OBJECTIVE: We examined the cardiac function of patients who underwent Tc-99m sestamibi quantitative gated myocardial single photon emission computed tomography with 16-framing data acquisition between January 1, 2004 and March 31, 2006 for an evaluation of suspected or known heart disease in our hospital. METHODS: In 192 patients aged >or=40 years, the left ventricular (LV) systolic function [parameter: ejection fraction (EF)] and diastolic function [first third filling fraction (1/3FF), peak filling rate (PFR), and time-to-peak filling (TPF)] were estimated by volume curve analysis. In 51 (age >or=60 years) of 192 patients, brachial-ankle pulse wave velocity (baPWV) was also measured. RESULTS: The correlation between diastolic parameters PFR and 1/3FF was mild (r = 0.28, P < 0.001). On the basis of EF and PFR, 192 patients were divided into four groups: P (preserved LV function), Q (isolated systolic dysfunction, EF < 50%), R (isolated diastolic dysfunction, PFR < 1.8 EDV/s), and S (both dysfunctions). The numbers of patients in P, Q, R, and S groups were 94 (49.0%), 7 (3.6%), 31 (16.1%), and 60 (31.3%), respectively. The 1/3FF correlated weakly but significantly with age (r = -0.16, P < 0.05). The TPF also correlated weakly with age (r = 0.25, P < 0.01), but EF did not. The baPWV, an indicator of cardiovascular stiffness, correlated inversely with 1/3FF (r = -0.59, P < 0.001) or correlated positively with TPF (r = 0.45, P < 0.001), but not with EF. CONCLUSIONS: Our study suggests that cardiovascular stiffness associated with increased baPWV may contribute to the occurrence of diastolic dysfunction in elderly patients. PMID- 17705009 TI - Improvement in image quality of noncontrast head images in multidetector-row CT by volume helical scanning with a three-dimensional denoising filter. AB - PURPOSE: The aim of this study was to improve the contrast-to-noise ratio on noncontrast head computed tomography (CT) images, which are crucial for assessing patients with acute ischemic stroke. We applied a technique combining volume helical scanning with a three-dimensional (3D) denoising filter. MATERIALS AND METHODS: We scanned phantoms for low-contrast resolutions and helical/cone-beam artifacts as well as stroke patients using a 16-row multidetector-row CT (MDCT) unit. Volume helical scans with 1-mm collimation and nonhelical scans with 8-mm thickness were performed. From the 1-mm thick volume data, 8-mm thick contiguous images were generated before and after applying a 3D denoising filter. RESULTS: On images stacked from volume data, the contrast-to-noise ratio was significantly improved by the 3D denoising filter and was nearly the same as that on nonhelical images. On stacked volume images, artifacts due to the cone beam and the helical scan were increased with larger helical pitches, but bone-related streak artifacts in the posterior fossa and underneath the calvarium were reduced when compared with nonhelical images. CONCLUSION: Volume helical scan with a 3D denoising filter effectively improves image quality in noncontrast head MDCT images. PMID- 17705008 TI - Omental pseudocyst. AB - Diagnostic image features of the omental cyst remain to be fully understood because of its rarity. We present here a case of omental cyst in a 29-year-old man involving several diagnostic image features. Contrasted computed tomography showed thin ring-like enhancement, and angiography revealed the feeding arteries that branched from the right gastroepiploic artery. The cyst was excised surgically, and the final pathological diagnosis was an omental pseudocyst. PMID- 17705011 TI - Diffuse and diffuse-plus-focal uptake in the thyroid gland identified by using FDG-PET: prevalence of thyroid cancer and Hashimoto's thyroiditis. AB - OBJECTIVE: To investigate and evaluate the prevalence of incidental thyroid diffuse and diffuse-plus-focal fluorine-18 fluorodeoxyglucose (FDG) uptake in healthy subjects who underwent cancer screening on positron emission tomography (PET) scan, and also to evaluate the prevalence of thyroid cancer and Hashimoto's thyroiditis. METHODS: We carried out a retrospective review of 1626 subjects who underwent PET scanning at our institution. Diffuse uptake was defined as FDG uptake in the whole thyroid gland, whereas diffuse-plus-focal uptake was defined as a thyroid lesion with both diffuse uptake and focal FDG uptake. The maximum standardized uptake value of the thyroid lesions was recorded and reviewed. In each selected subject with positive thyroid FDG uptake, serum thyroid-stimulating hormone, thyroid hormone, and thyroid antibodies were measured. Fine needle aspiration cytology was performed on patients with a definite nodule using ultrasonography. RESULTS: Twenty-nine subjects (1.78%) were identified as having either diffuse FDG uptake (n = 25, 1.53%) or diffuse-plus-focal FDG uptake (n = 4, 0.24%). All subjects with diffuse FDG uptake were diagnosed as having Hashimoto's thyroiditis. In 1 of the 25 subjects with diffuse FDG uptake and two of the four with diffuse-plus-focal FDG uptake, histopathologic diagnosis showed papillary thyroid carcinoma associated with Hashimoto's thyroiditis. However, PET scan did not detect papillary carcinoma associated with Hashimoto's thyroiditis in one of the three subjects. CONCLUSIONS: Our results suggest that although diffuse FDG uptake usually indicates Hashimoto's thyroiditis, the risk of thyroid cancer must be recognized in both diffuse FDG uptake and diffuse-plus-focal FDG uptake on PET scan. PMID- 17705012 TI - Comparison of MET-PET and FDG-PET for differentiation between benign lesions and lung cancer in pneumoconiosis. AB - OBJECTIVE: The aim of this study was to evaluate and compare the ability of C-11 methionine (MET) and F-18 fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) to diagnose lung cancer in patients with pneumoconiosis. METHODS: Twenty-six subjects underwent both whole-body MET-PET and FDG-PET on the same day. The first group was a lung cancer group, which consisted of 15 patients, and included those with pneumoconiosis with increased nodules (13 cases), hemoptysis (1 case), and positive sputum cytology (1 case). The second group was a no malignancy control group, consisting of 11 patients with pneumoconiosis. RESULTS: Significant correlations between nodule size and the maximum standardized uptake value (SUV(max)) of the two PET tracers were observed in the control group. The larger the nodule size, the greater were the amounts of these tracers accumulated (MET: r = 0.771, P < 0.0001; FDG: r = 0.903, P < 0.0001). The SUV(max) of MET was significantly lower than that of FDG in the pneumoconiotic nodules (P < 0.0001). Lung cancer was found in 5 of 19 nodules (two with adenocarcinoma, one with squamous cell carcinoma, one with small cell carcinoma, and one with large cell carcinoma) in the first group. As for nodules equal to or less than 3 cm in diameter, the SUV(max) of MET was significantly higher in the lung cancer than in the pneumoconiotic nodules, with 3.48 +/- 1.18 (mean +/- SE) for the lung cancer and 1.48 +/- 0.08 for the pneumoconiotic nodules (P < 0.01), similar to the SUV(max) of FDG, with 7.12 +/- 2.36 and 2.85 +/- 0.24 (P < 0.05), respectively. On the basis of the criteria for the control group, FDG and MET identified lung cancer with sensitivities of 60% and 80%, specificities of 100% and 93%, accuracies of 90% and 90%, positive predictive values of 100% and 80%, and negative predictive values of 88% and 93%, respectively. CONCLUSIONS: Our results indicate that nodules with an intense uptake of MET and FDG relative to their size should be carefully observed because of a high risk for lung cancer. PMID- 17705013 TI - Suppressing bladder artifacts in bone SPECT of the pelvis. AB - OBJECTIVE: Bladder-filling reconstruction artifacts have a detrimental effect on the image quality of pelvic bone single photon emission computed tomography (SPECT). Using a simple protocol consisting of forced diuresis coupled with intravenous (IV) hydration, this study was undertaken to obtain an artifact-free pelvic SPECT after discarding the residual urinary activity. METHODS: Thirty patients were enrolled. In group I, pelvic SPECT was performed directly after normal void, whereas in group II, SPECT was preceded by IV injection of 0.5 mg/kg furosemide (maximum 40 mg) coupled with IV infusion of 500 cc of physiologic saline. Bladder-filling reconstruction artifacts were analyzed in group I patients, who had their images reconstructed using both filtered backprojection and iterative algorithms, both qualitatively and quantitatively by means of regions of interest (ROIs) drawn around the artifact-bearing bone areas as well as the corresponding contralateral sites. For group II patients, besides visual analysis, ROIs were placed over the sites corresponding to those of the group I patients. In every patient, total counts of each ROI were normalized to a reference ROI placed over the sacrum, and a ratio was created. RESULTS: Using filtered backprojection, two forms of artifacts were identified in group I patients: first, a streak pattern that extended to the sacro-iliac joint in nine (60%) patients, the hip joint in five (33%), the superior pubic rami in four (27%), the sacrum in three (20%), and the ischium in one (6%); second, a count loss subtype which extended to the hip joints in nine (60%) patients. Corresponding values after iterative reconstruction were two (13%) for the sacro iliac joint, three (20%) for the hip joint, one (6%) for the superior pubic ramus, and one (6%) for the sacrum. In five (33%) patients, residual count loss artifacts were still identifiable after iterative reconstruction. However in group II, no such effects were observed because the bladder activity reached near background level in 14 (93%) of 15 patients after three successive voids with a 3.5-fold decrease in the mean value of total bladder count in comparison with group I patients. A statistically significant difference was found between artifact- and non-artifact-harboring ROIs in group I whichever the method used for reconstruction, whereas the values of right and left hemi-pelvis ROIs/sacrum in group II were almost identical. CONCLUSIONS: Forced diuresis coupled with parenteral hydration facilitates the acquisition of an artifact-free pelvic SPECT. Especially for clinical questions that focus on femoral heads and pubic bones, applying the aforementioned protocol may improve the diagnostic accuracy of pelvic bone SPECT. PMID- 17705014 TI - Physiological FDG uptake in the ovaries after hysterectomy. AB - OBJECTIVE: It is known that focal 18F-fluorodeoxyglucose (FDG) uptake is physiologically seen in the ovaries and uterus of premenopausal women in correlation with the menstrual cycle, which may cause false-positive diagnoses on the images of FDG positron emission tomography (PET). The objective of this study was to clarify whether women of reproductive age after hysterectomy whose ovaries were preserved, also showed physiological ovarian FDG uptake. METHODS: We reviewed 26 women after hysterectomy (age 51.1 +/- 5.0 years), who underwent annual cancer screening, including FDG-PET and pelvic magnetic resonance (MR) imaging, three times. RESULTS: Seven women (age 45.9 +/- 5.8 years, range 34-52 years) had at least one ovary, showing changes in its appearance including the size and number of follicles on MR images each year, which suggested that the ovary was functioning. Four of the seven women showed focal FDG uptake (standardized uptake value 4.2 +/- 1.1) that corresponded to the normal ovaries on five PET examinations. Another group of 19 women (age 53.1 +/- 3.1 years, range 47-59 years) who had small ovaries without changes on MR images each year did not show FDG uptake in the ovaries. CONCLUSIONS: Physiological FDG uptake observed in the ovaries of women of reproductive age even after hysterectomy is reasonably common. As it is not easy to determine the hormonal cycle in these women, it is essential to correlate focal FDG uptake in the pelvis with anatomical and morphological findings on MR images to avoid false-positive diagnoses. PMID- 17705017 TI - Metastasis of the gastrointestinal tract: FDG-PET imaging. AB - We assess the usefulness of F-18-fluoro-deoxyglucose (FDG) positron emission tomography (PET) in the evaluation of gastrointestinal metastases. Four cases (five lesions) in which metastases from three lung cancers and one malignant fibrous histiocytoma (MFH) of the femur were found in the gastrointestinal tract were reviewed (men/women 3 : 1, age 63-78 years, mean 72 years). The five lesions were duodenal, jejunal metastasis, and two stomach metastases from lung carcinoma, and rectal metastasis from MFH of the femur. FDG-PET was unable to detect small masses, but it was able to detect unforeseen lesions such as gastrointestinal metastases because FDG-PET is a whole-body scan in a single operation examination. FDG-PET imaging provided valuable information for the diagnosis of gastrointestinal metastasis. PMID- 17705015 TI - Effects of smoking on the lung accumulation of [11C]McN5652. AB - OBJECTIVE: The lung is one of the key organs for determining the distribution of drugs in the human body. Various factors influence the accumulation of drugs. In this study, we investigated the effects of smoking on drug distribution to the lung using radiolabeled drugs. METHODS: We measured the lung uptake of [11C](+)McN5652, a radioligand for serotonin transporter (5-HTT), and inactive enantiomer [11C](-)McN5652 in 19 healthy men (12 nonsmokers and 7 smokers) using positron emission tomography. Pretreatment study was performed by the administration of clomipramine (50 mg), a potent 5-HTT inhibitor. RESULTS: The mean lung uptake of [11C](+)McN5652 and [11C](-)McN5652 was significantly higher in smokers than in nonsmokers. The lung uptake of [11C](+)McN5652 decreased after pretreatment with clomipramine, whereas that of [11C](-)McN5652 was not affected by clomipramine. CONCLUSIONS: Lung uptake of [11C](-)McN5652 was influenced by smoking, possibly because the probable nonspecific binding accumulation was changed as [11C](-)McN5652 was reported to have negligible affinity to 5-HTT. Smoking might be one of the important factors when distribution of radioligands is considered. PMID- 17705016 TI - Mapping of central dopamine synthesis in man, using positron emission tomography with L-[beta-11C]DOPA. AB - OBJECTIVE: To estimate the presynaptic function of the central dopaminergic system, positron emission tomography measurement of the endogenous dopamine synthesis rate was performed with L-[beta-11C]DOPA. In the present study, we developed a simple method for calculating an indicator of the dopamine synthesis rate with L-[beta-11C]DOPA on a voxel-by-voxel basis for parametric mapping. METHODS: After intravenous injection of L-[beta-11C]DOPA, dynamic scanning was performed on ten healthy men for 89 min. The dopamine synthesis ratio was calculated on a voxel-by-voxel basis as the ratio of the area under the time activity curves of brain regions to the reference brain region, that is, occipital cortex. The overall uptake rate constant as an indicator of dopamine synthesis was also calculated by kinetic and graphical analyses. RESULTS: The dopamine synthesis ratio calculated by the present method was in good agreement with the indicators of dopamine synthesis calculated by kinetic and graphical analyses, although a systemic underestimation was observed, especially when the integration interval was set in the early phase of the scan duration. In particular, underestimations were prominent in brain regions with relatively lower influx rate constant K1. CONCLUSIONS: By this method, regional dopamine synthesis could be estimated on a voxel-by-voxel basis. This method does not need an arterial input function and should prove to be useful for clinical research. PMID- 17705018 TI - Airway complication occurring during radioiodine treatment for Graves' disease. AB - Airway complications rarely occur in 131I radioiodine therapy for Graves' disease. This study presents two cases in which 131I therapy caused this acute complication. The patients complained of the symptom 6 h and 33 h after administration of 131I. A histamine H1 receptor antagonist and hydrocortisone rapidly resolved symptoms in both cases. These two cases remind physicians that 131I therapy for Graves' disease may cause potentially life-threatening complications. PMID- 17705019 TI - Massive inguinoscrotal herniation of the bladder with ureter: incidental demonstration on bone scan. AB - Inguinoscrotal herniation of the bladder is a rare clinical entity. The condition is often diagnosed incidentally or during the course of surgical repair of inguinal hernias. In a smaller number of cases, bladder hernia can be seen during nuclear medicine studies. We report a rare case of massive inguinoscrotal bladder herniation with ureter, causing urinary stasis on bone scintigraphy. PMID- 17705020 TI - A 18F-FDG-positive, 67Ga-negative, and transferrin receptor expression-negative patient with diffuse large B-cell lymphoma. AB - We recently experienced a case with uveitis suffering from fever of unknown origin suspected of being caused by sarcoidosis. Chest computed tomography showed right supraclavicular, bilateral mediastinal, and right hilar lymphadenopathy, and intensive abnormal uptake of 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) was observed on positron emission tomography with 18F-FDG (FDG-PET). On the other hand, 67Ga scintigraphy showed almost no abnormal findings. Histopathological examination revealed the lesion to be a diffuse large B-cell lymphoma (DLBCL), namely, an aggressive non-Hodgkin lymphoma from a right supraclavicular lymph node biopsy specimen. Additional immunohistochemical analysis showed the negative expression of transferrin receptor (TfR) on the formalin-fixed paraffin-embedded specimen. Although DLBCL is generally considered to be a 67Ga-avid tumor, it does not always have a large number of TfRs and that leads to a discrepancy between the 67Ga scintigraphy and FDG-PET findings. FDG-PET should be more appropriate for the initial staging of DLBCL than 67Ga scintigraphy, whereas 67Ga scintigraphy might be able to provide additional information including prognostic factors and to support strategies that target TfR for cancer therapy. PMID- 17705021 TI - Natural hybridization between Phlomis lycia D. Don x P. bourgaei Boiss., (Lamiaceae) revealed by RAPD markers. AB - Randomly Amplified Polymorphic DNA markers (RAPD) were used to assess the hybrid identity of individuals sampled as Phlomis x termessi Davis. Out of 95 primers screened, 11 primers produced reproducible amplification patterns used for discrimination of P. x termessi and their parents. Eleven primers produced 81 bands. Forty two percent of the RAPD bands existed in parents. Of the 54 bands found in P. lycia, 19 were found only in this species and 7 of these were monomorphic. Similarly, of 57 RAPD bands observed in P. bourgaei, 18 were found only in P. bourgaei and 6 of these were monomorphic. Among hybrid individuals, 35 of the 73 markers were monomorphic. Fifteen of these existed in individual parents showing that parents were homozygous for these markers. Of the 35 monomorphic bands observed among hybrid individuals, 5 were present in the samples of one of the parents and completely absent from the samples of the other; therefore, additive inheritance is indicated. Of the 5 additive bands, 1 was inherited from P. bourgaei and 4 were inherited from P. lycia. Among 38 polymorhic markers observed in hybrid individuals, 9 were new and hybrid specific. Pollen fertility was also investigated. Mean pollen fertility for P. lycia and P. bourgaei was 93% and 97% respectively. However, mean pollen fertility for hybrids was 65% (+/-10.5). PMID- 17705022 TI - Influence of weight on the content of trace metals in tissues of Mytilus galloprovincialis (Lamarck, 1819): a forecast model. AB - Fifty seven samples of Mytilus galloprovincialis (Lamarck, 1819) collected along the breakwater barriers of Fano (station 1) and Pesaro (station 2), Adriatic Sea, Marche Region, central Italy, were analyzed by atomic absorption spectrometry and Cd, Cu, Pb and Zn concentrations in the soft tissues were measured. The aims of this work were the statistical analysis of Cd-weight, Cu-weight, Pb-weight, Zn weight relationships, and the building of a tendency function that allows assessing with a good approximation the concentrations of a metal in different weight organisms. In Mytilus galloprovincialis the content of Cd proportionally grew with the weight and therefore its concentration was independent from this factor; while the concentration of Pb decreased as the weight increased. In both cases the accuracy of multiple regression models improved considering the variable 'site', while the same approach appeared not reliable for Cu and Zn, that were two essential metals. Our results showed that a tendency function was reliable, solid and able to predict to a very satisfying extent the concentration of non-physiological metals, like Cd and Pb; while it did not show a good approximation with real Cu and Zn contents. PMID- 17705023 TI - Serum S100B levels in X-linked adrenoleukodystrophy and Gaucher disease. AB - S100B, a small acidic protein, is a member of a multigenic family of calcium modulated proteins. It is mainly produced by astrocytes and the secreted protein, depending on its concentration, can exert either trophic or toxic effects. In humans increased S100B levels have been detected in brain trauma and ischaemia, and neurodegenerative, neurometabolic, inflammatory and psychiatric disease. Serum S100B concentrations have been used as markers of brain disease. In the present study S100B serum levels were determined in patients with the neuroinflammatory disease X-linked adrenoleukodystrophy (X-ALD) and in patients with both the acute neuronopathic (type II) and the non-neuronopathic (type I) types of Gaucher disease (GD). Sixteen X-ALD patients (10 with the childhood, 4 with the adult cerebral forms, 2 asymptomatic) and 22 Gaucher disease patients (19 type I, 3 type II) were studied. No statistically significant differences were observed between the X-ALD (median 0.13 microg/L, p=0.191) or Gaucher type I patients (median 0.07 microg/L, p=0.095) and controls of similar age (median 0.10 microg/L, n=22). Serum S100B levels of type II Gaucher disease patients were also within the normal for their age range (patients 0.2, 0.22, 0.65; control median 0.81 microg/L, n=44). Lack of clinical symptoms and/or MRI findings in X-ALD patients was not associated with lower S100B values. Our results indicate that serum S100B levels cannot serve as peripheral marker in the evaluation of brain disease in X-ALD and GD. PMID- 17705024 TI - Three successful pregnancies through dietary management of fructose-1,6 bisphosphatase deficiency. AB - Fructose-1,6-bisphosphatase (FBPase) deficiency (OMIM 229700) has been characterized as the cause of life-threatening hypoglycaemia and lactic acidaemia following prolonged fasting. The patient, an adult African-American woman, presented during the second trimester of her first pregnancy with recurrent episodes of lactic acidaemia and hypoglycaemia. She had recently been admitted to a nearby intensive care unit after presentation with profound hypoglycaemia and lactic acidosis, and was found to be pregnant. The history was remarkable for approximately 30 hospitalizations for hypoglycaemia and acidosis. She had previously undergone liver biopsy at another centre and was diagnosed with a 'glycogen storage disease', although no enzyme testing had been done for confirmation. Based on clinical symptoms, a diagnosis of FBPase deficiency was accomplished through gene sequencing, which revealed homozygosity for a panethnic, common mutation, 960/961insG in exon 7. The availability of mutation testing facilitated the confirmation of FBPase deficiency in this patient, obviating liver biopsy for enzyme activity confirmation. The patient underwent three successful pregnancies by strict compliance with dietary management, including nocturnal uncooked cornstarch to manage hypoglycaemia. The pregnancies were complicated by mild gestational diabetes, increased cornstarch requirements, and hypoglycaemia at the time of discharge from the hospital. The three infants had normal birth weights and experienced no complications during the neonatal period. The patient subsequently developed sensorineural hearing loss and early onset cognitive impairment, despite compliance with the monitoring and treatment of hypoglycaemia. The experience with multiple pregnancies in this FBPase deficient patient provides insight into the management of hypoglycaemia in inherited disorders of gluconeogenesis. PMID- 17705025 TI - High frequency of missense mutations in glycogen storage disease type VI. AB - Deficiency of liver glycogen phosphorylase in glycogen storage disease (GSD) type VI results in a reduced ability to mobilize glucose from glycogen. Six mutations of the PYGL gene, which encodes the liver isoform of the enzyme, have been identified in the literature. We have characterized eight patients from seven families with GSD type VI and identified 11 novel PYGL gene defects. The majority of the mutations were missense, resulting in the substitution of highly conserved residues. These could be grouped into those that were predicted to affect substrate binding (p.V456M, p.E673K, p.S675L, p.S675T), pyridoxal phosphate binding (p.R491C, p.K681T), or activation of glycogen phosphorylase (p.Q13P) or that had an unknown effect (p.N632I and p.D634H). Two mutations were predicted to result in null alleles, p.R399X and [c.1964_1969inv6;c.1969+1_+4delGTAC]. Only 7 of the 23 (30%) reported PYGL alleles carry nonsense, splice site or frameshift mutations compared to 68-80% of affected alleles of the highly homologous muscle glycogen phosphorylase gene, PYGM, that underlie McArdle disease. There was heterogeneity in the clinical symptoms observed in affected individuals. These varied from hepatomegaly and subclinical hypoglycaemia, to severe hepatomegaly with recurrent severe hypoglycaemia and postprandial lactic acidosis. We conclude that deficiency of liver glycogen phosphorylase is predominantly the result of missense mutations affecting enzyme activity. There are no common mutations and the severity of clinical symptoms varies significantly. PMID- 17705026 TI - Geneticization and bioethics: advancing debate and research. AB - In the present paper, we focus on the role that the concept of geneticization has played in the discussion about health care, bioethics and society. The concept is discussed and examples from the evolving discourse about geneticization are critically analyzed. The relationship between geneticization, medicalization and biomedicalization is described, emphasizing how debates about the latter concepts can inspire future research on geneticization. It is shown how recurrent themes from the media coverage of genetics portray typical traits of geneticization and thus contribute to the process. We look at examples of small-scale studies from the literature where geneticization of medical practice has been demonstrated. Methodological disputes about the relevance of empirical evidence for the geneticization thesis and the normative status of the concept are discussed. We consider arguments to the effect that ideas from mainstream bioethics have facilitated geneticization by emphasizing individualistic notions of autonomy and responsibility while ignoring the role of genetics in the wider social context. It is shown how a concept like geneticization, which can be used to draw the attention of philosophers, social scientists and others to challenges that tend to be neglected by mainstream bioethics, also has the potential to move people's attention away from other pertinent issues. This may happen if researchers become preoccupied with the transformative effects of genetics, and we argue that a wider reading of geneticization should inspire critical analysis of the sociocultural preconditions under which genetics is currently evolving. PMID- 17705027 TI - Endostatin gene therapy enhances the efficacy of paclitaxel to suppress breast cancers and metastases in mice. AB - Chemotherapy combined with antiangiogenic therapy is more effective than chemotherapy alone. The aim of this study was to investigate whether endostatin, a potent anti-angiogenic agent, could enhance the efficacy of paclitaxel to combat breast cancer. An expression plasmid encoding mouse endostatin (End pcDNA3.1) was constructed, which produced intense expression of endostatin and inhibited angiogenesis in the chorioallantoic membrane assay. 4T1 breast tumors were established in BALB/c mice by subcutaneous injection of 1 x 10(5) 4T1 cells. The End-pcDNA3.1 plasmid diluted in the transfection reagent FuGENE was injected into the tumors (around 100 mm(2)), and paclitaxel was injected i.p. into the mice. Endostatin gene therapy synergized with paclitaxel in suppressing the growth of 4T1 tumors and their metastasis to the lung and liver. Both endostatin and paclitaxel inhibited tumor angiogenesis and induced cell apoptosis. Despite the finding that endostatin was superior to paclitaxel at inhibiting tumor angiogenesis, paclitaxel was nevertheless more effective at inducing tumor apoptosis. The combination of paclitaxel and endostatin was more effective in suppressing tumor growth, metastases, angiogenesis, and inducing apoptosis than the respective monotherapies. The combinational therapy with endostatin and paclitaxel warrants future investigation as a therapeutic strategy to combat breast cancer. PMID- 17705028 TI - Predicting the solubility of the anti-cancer agent docetaxel in small molecule excipients using computational methods. AB - PURPOSE: To develop an in silico model that provides an accurate prediction of the relative solubility of the lipophilic anticancer agent docetaxel in various excipients. MATERIALS AND METHODS: The in silico solubility of docetaxel in the excipients was estimated by means of the solubility (delta) and Flory-Huggins interaction (chi (FH)) parameters. The delta values of docetaxel and excipients were calculated using semi-empirical methods and molecular dynamics (MD) simulations. Cerius(2) software and COMPASS force-field were employed for the MD simulations. The chi (FH) values for the binary mixtures of docetaxel and excipient were also estimated by MD simulations. RESULTS: The values obtained from the MD simulations for the solubility of docetaxel in the various excipients were in good agreement with the experimentally determined values. The simulated values for solubility of docetaxel in tributyrin, tricaproin and vitamin E were within 2 to 6% of the experimental values. MD simulations predicted docetaxel to be insoluble in beta-caryophyllene and this result correlated well with experimental studies. CONCLUSIONS: The MD model proved to be a reliable tool for selecting suitable excipients for the solubilization of docetaxel. PMID- 17705030 TI - Living with hereditary non-polyposis colorectal cancer; experiences from and impact of genetic testing. AB - Hereditary non-polyposis colorectal cancer (HNPCC) is one of our most common cancer syndromes and an increasing number of individuals live in families with verified hereditary cancer. We conducted an interview study to explore experiences from and perceived impact on life after genetic testing for HNPCC. Three major themes emerged: reactions and emotions, family relations and implications for life. Among the reactions described were suspecting heredity, feelings of guilt, the importance of experiential knowledge, and coping strategies. The impact on family relations was related to perceived responsibility for conveying information, encountering different reactions among family members, and difficulties in communication and relations. The implications described included uncertainty, adaptation, new choices and changes in life, family planning issues, and experiences of surveillance programs. We suggest that the themes and sub-themes identified should be taken into account during genetic counselling in order to facilitate the spread of information and to prepare family members for the impact on life that knowledge about hereditary cancer may have. PMID- 17705031 TI - Caraparu virus (group C Orthobunyavirus): sequencing and phylogenetic analysis based on the conserved region 3 of the RNA polymerase gene. AB - Here, for the first time, we report the nucleotide sequence of Caraparu virus (CARV) L segment and the analysis of the RNA polymerase region 3 encoded by this segment. The 1,404 bp nucleotide sequence shares the highest identity with Bunyamwera, La Crosse, Oropouche, and Akabane virus sequences. The amino acid sequence was deduced and aligned with sequences from members of the Bunyaviridae family and used for phylogenetic analysis. The CARV clustered in the Orthobunyavirus genus. The premotif A and motifs A-E are present in the region 3 of the Bunyaviridae family, were also conserved in CARV L protein, as well as other conserved regions among Orthobunyavirus genus. PMID- 17705032 TI - The relationship between alcohol consumption and unprotected sex among known HIV discordant couples in Rwanda and Zambia. AB - Although alcohol abuse is highly prevalent in many countries in sub-Saharan Africa, little is known about the relationship between alcohol consumption and risky sexual behavior in these settings. An understanding of this relationship is particularly important given the high prevalence of HIV that exists in many of these countries. This study analyzes data collected from members of cohabiting HIV-discordant couples regarding alcohol consumption and self-reported condom use. After controlling for demographic and socioeconomic co-factors, alcohol use by male partners of HIV-discordant couples was associated with self-reported unprotected sex at follow-up. Counseling about alcohol use should be part of HIV testing and counseling programs, particularly among those found to be HIV positive. PMID- 17705033 TI - The use of rectal douches among HIV-uninfected and infected men who have unprotected receptive anal intercourse: implications for rectal microbicides. AB - Although some rectal douches result in surface epithelium loss and potential increase of HIV transmission, men who have sex with men (MSM) continue to use them. We describe the prevalence of this practice among MSM engaging in unprotected receptive anal intercourse (URAI) in risky circumstances. A multiethnic sample with overrepresentation of HIV-negative MSM who had URAI in the previous year was recruited exclusively through the Internet. Participants were 105 MSM (78 HIV-negative, 27 HIV-positive). A total of 53% of HIV-negative and 96% of HIV-positive men douched in preparation for sex, most of them frequently or always, mainly for hygienic purposes. 27% of HIV-negative and 44% of HIV-positive douched after sex, partly believing douching protected from infections. Douching practices started around age 25. Regression analyses found the association between HIV status and douching occasions persisted after controlling for demographic characteristics and number of URAI occasions. Rectal douching in preparation for sex is common among men who practice URAI. This population could benefit from alternatives to condoms, such as rectal microbicides. Given the popularity of pre-coital douching and its frequency, a harmless rectal douche that could deliver a rectal microbicide could have great acceptability. PMID- 17705034 TI - Increased HIV risk associated with criminal justice involvement among men on methadone. AB - This paper examines the relationship between HIV risk and criminal justice involvement among a random sample of 356 men enrolled in methadone maintenance treatment programs in New York City. Bivariate and logistic regression analyses were performed to estimate the associations between measures of criminal justice involvement and participant HIV risk, controlling for socio-demographic variables. A lifetime history of incarceration was significantly associated with being HIV positive (Adjusted OR=5.08). Recent arrest was associated with unprotected vaginal sex and having multiple female sexual partners. Sex trading was associated with both arrest and incarceration, and the strongest association was found between selling sex and recent incarceration (Adjusted OR=5.69). Results suggest that recent criminal justice involvement among men with substance abuse histories is associated with increased HIV risk behaviors. Findings underscore the need for targeted HIV prevention efforts for men on methadone with a recent history of arrest or incarceration. PMID- 17705035 TI - Assessing social preparedness for antiretroviral therapy in a generalized AIDS epidemic: a diffusion of innovations approach. AB - Researchers conducted focus groups in the Eastern Cape Province of South Africa concerning AIDS and treatment options. Constituent groups included adults aged 25 45, HIV/AIDS caregivers, HIV-positive adults, nurses, rural elders, teenagers, and traditional healers. This pilot work aimed to gather early evidence on perceptions about the government's rollout of antiretroviral treatment (ART), identify potential barriers to success, and inform a subsequent pilot survey. Diffusion of innovations theory was used to interpret the data and helped identify potential obstacles to the ART rollout. AIDS stigma and a weakened healthcare system were negatively impacting the program. There was a lack of accurate knowledge about HIV/AIDS and antiretroviral treatment, with wide disparities among groups. Many people were not convinced that antiretroviral treatment is superior to other treatments, and a few people were afraid it was poisonous. There was no evidence that people were aware of the long-term difficulties of adherence to the regimen. PMID- 17705036 TI - Automatic prospective registration of high-resolution trabecular bone images of the tibia. AB - Magnetic Resonance Imaging (MRI) longitudinal studies conducted to assess changes in tibia bone quality impose strict requirements on the reproducibility of the prescribed region acquired. Registration, the process of aligning two images, is commonly performed on the images after acquisition. However, techniques to improve image registration precision by adjusting scanning parameters prospectively, prior to image acquisition, would be preferred. We have adapted an automatic prospective mutual information based registration algorithm to a MRI longitudinal study of trabecular bone of the tibia and compared it to a post-scan manual registration. Qualitatively, image alignment due to the prospective registration is shown in 2D subtraction images and 3D surface renderings. Quantitatively, the registration performance is demonstrated by calculating the sum of the squares of the subtraction images. Results show that the sum of the squares is lower for the follow up images with prospective registration by an average of 19.37% +/- 0.07 compared to follow up images with post-scan manual registration. Our study found no significant difference between the trabecular bone structure parameters calculated from the post-scan manual registration and the prospective registration images (p > 0.05). All coefficient of variation values for all trabecular bone structure parameters were within a 2-4.5% range which are within values previously reported in the literature. Results suggest that this algorithm is robust enough to be used in different musculoskeletal imaging applications including the hip as well as the tibia. PMID- 17705037 TI - Management of lignite fly ash for improving soil fertility and crop productivity. AB - Lignite fly ash (LFA), being alkaline and endowed with excellent pozzolanic properties, a silt loam texture, and plant nutrients, has the potential to improve soil quality and productivity. Long-term field trials with groundnut, maize, and sun hemp were carried out to study the effect of LFA on growth and yield. Before crop I was sown, LFA was applied at various doses with and without press mud (an organic waste from the sugar industry, used as an amendment and source of nutrients). LFA with and without press mud was also applied before crops III and V were cultivated. Chemical fertilizer, along with gypsum, humic acid, and biofertilizer, was applied in all treatments, including the control. With one-time and repeat applications of LFA (with and without press mud), yield increased significantly (7.0-89.0%) in relation to the control crop. The press mud enhanced the yield (3.0-15.0%) with different LFA applications. The highest yield LFA dose was 200 t/ha for one-time and repeat applications, the maximum yield being with crop III (combination treatment). One-time and repeat application of LFA (alone and in combination with press mud) improved soil quality and the nutrient content of the produce. The highest dose of LFA (200 t/ha) with and without press mud showed the best residual effects (eco-friendly increases in the yield of succeeding crops). Some increase in trace- and heavy metal contents and in the level of gamma-emitters in soil and crop produce, but well within permissible limits, was observed. Thus, LFA can be used on a large scale to boost soil fertility and productivity with no adverse effects on the soil or crops, which may solve the problem of bulk disposal of fly ash in an eco friendly manner. PMID- 17705038 TI - Dams, floodplain land use, and riparian forest conservation in the semiarid Upper Colorado River Basin, USA. AB - Land and water resource development can independently eliminate riparian plant communities, including Fremont cottonwood forest (CF), a major contributor to ecosystem structure and functioning in semiarid portions of the American Southwest. We tested whether floodplain development was linked to river regulation in the Upper Colorado River Basin (UCRB) by relating the extent of five developed land-cover categories as well as CF and other natural vegetation to catchment reservoir capacity, changes in total annual and annual peak discharge, and overall level of mainstem hydrologic alteration (small, moderate, or large) in 26 fourth-order subbasins. We also asked whether CF appeared to be in jeopardy at a regional level. We classified 51% of the 57,000 ha of alluvial floodplain examined along >2600 km of mainstem rivers as CF and 36% as developed. The proportion developed was unrelated to the level of mainstem hydrologic alteration. The proportion classified as CF was also independent of the level of hydrologic alteration, a result we attribute to confounding effects from development, the presence of time lags, and contrasting effects from flow alteration in different subbasins. Most CF (68% by area) had a sparse canopy (50% canopy cover occupied <1% of the floodplain in 15 subbasins. We suggest that CF extent in the UCRB will decline markedly in the future, when the old trees on floodplains now disconnected from the river die and large areas change from CF to non-CF categories. Attention at a basinwide scale to the multiple factors affecting cottonwood patch dynamics is needed to assure conservation of these riparian forests. PMID- 17705039 TI - Landholder profiling and typologies for natural resource-management policy and program support: potential and constraints. AB - The use of landholder typologies to aid the development, implementation, and monitoring natural-resource management (NRM) policies and programs has increased considerably during the past decade. This article explores the potential for using such typologies for a variety of NRM and rural and regional development applications. Review of typology use further suggests that there is potential to refine the way that typologies are developed and applied to better aid NRM, farming systems analyses, and rural and regional development. Before typologies will be adopted more widely, a number of theoretical and methodologic issues must be addressed. These include the following questions: (1) Which criteria and methods should or can be used to classify landholders? (2) How should studies across spatial and temporal scales be integrated? (3) How should multiple and single industry studies be integrated to gain the most value from research? We argue that quantitative research techniques are well suited to provide an underlying structure for landholder typologies, and qualitative research techniques are useful for developing understanding of the nature of variation within and between landholder types. We argued further that because of the potential utility and breadth for the application of landholder typologies, a nested set of landholder typologies could be developed that are coordinated at the national, regional, and local geographic levels, with repeated measures used to track the evolution with time of landholder practices, management values, and socioeconomic characteristics. PMID- 17705040 TI - Glycolitic enzymes are targets of oxidation in aged human frontal cortex and oxidative damage of these proteins is increased in progressive supranuclear palsy. AB - Progressive supranuclear palsy (PSP) is a neurodegenerative disorder pathologically characterized by neuronal loss and gliosis mainly in specific subcortical nuclei, but also in the cerebral cortex. In addition to neuron loss, hyperphosphorylated tau deposition is found in neurons, astrocytes and coiled bodies. Limited studies have shown that certain oxidative products are increased in the PSP brain. The present study examines oxidative damage in the frontal cortex in 7 PSP compared with 8 age-matched controls. Western blotting of the frontal cortex showed increased 4-hydroxy-2-nonenal (HNE)-immunoreactive bands between 40 and 50 kDa in PSP cases. Bi-dimensional gel electrophoresis and Western blotting, together with mass spectometry, were used to identify HNE modified proteins. Oxidized phosphoglycerate kinase 1 (PGK-1) and fructose bisphosphate aldolase A (aldolase A) were identified in all cases and 4 of 7 PSP cases, respectively. In contrast, PGK-1 and aldolase A were oxidized in 3 of 8 controls. Immunohistochemistry revealed the localization of aldolase A in neurons and astrocytes, and PGK-1 mainly in astrocytes. These findings show that PGK-1 and aldolase A are targets of oxidation in the frontal cortex in the aged human cerebral cortex and that oxidative damage of these proteins is markedly increased in the frontal cortex in PSP. PMID- 17705041 TI - Subacute hemicorporal parkinsonism in 5 patients with infarcts of the basal ganglia. AB - In 1929, Critchley introduced the term "vascular parkinsonism" (VP), which has been the subject of considerable controversy in neurology. Parkinsonism does not appear to be a frequent consequence of striatal infarcts, although unilateral parkinsonism has been reported as an acute or subacute onset syndrome following strategic infarcts in the striatum. Previous 123-I ioflupane SPECT (DaTSCAN) studies involving radioisotope labeling of the dopamine transporter protein at presynaptic level in patients with IPD (idiopathic Parkinson's disease) have found this technique to be highly sensitive in exploring the nigrostriatal pathway. Previous studies of VP with DatSCAN have been inconclusive. The present study correlates clinical data (unilateral parkinsonism following contralateral lenticular infarction), and radiological (CT/MRI) and functional neuroimaging findings (DatSCAN) in 5 patients with CT/MRI criteria for striatal infarcts. Finally, in 2 of these patients a diagnosis of IPD was made because of the follow up of clinical signs and pathological DaTSCAN findings not concordant with the size and location of the vascular lesion. PMID- 17705042 TI - Crohn's disease of the terminal ileum: a cheap diagnosis. AB - BACKGROUND: A 29-year-old man was admitted with a 7-day history of progressive non-specific abdominal pain that progressed to small bowel obstruction following ingestion of a 20-pence coin 4-months previously. Colonoscopic retrieval was unsuccessful. A subsequent laparotomy revealed a chronically inflamed thickened terminal ileum with mesenteric fat encroachment necessitating a right hemicolectomy. Histopathological analysis confirmed Crohn's disease with impaction of the 20-pence coin in a distal terminal ileum stricture near the ileo caecal valve. LEARNING POINT: Gastrointestinal foreign body retention should alert the clinician to the presence of an undiagnosed bowel abnormality. Furthermore, failed endoscopic retrieval should be considered as a marker for potential underlying gastrointestinal pathology and a requirement for operative intervention. CONCLUSION: This case describes a rare presentation of Crohn's disease and highlights the need to consider underlying gastrointestinal pathology in patients presenting with a deteriorating clinical condition in the presence of an incidental foreign body. PMID- 17705043 TI - New method for 3D parametric visualization of contrast-enhanced pulmonary perfusion MRI data. AB - Three-dimensional (3D) dynamic contrast-enhanced magnetic resonance imaging (3D DCE-MRI) has been proposed for the assessment of regional perfusion. The aim of this work was the implementation of an algorithm for a 3D parametric visualization of lung perfusion using different cutting planes and volume rendering. Our implementation was based on 3D DCE-MRI data of the lungs of five patients and five healthy volunteers. Using the indicator dilution theory, the regional perfusion parameters, tissue blood flow, blood volume and mean transit time were calculated. Due to the required temporal resolution, the volume elements of dynamic MR data sets show a reduced spatial resolution in the z direction. Therefore, perfusion parameter volumes were interpolated. Linear interpolation and a combination of linear and nearest-neighbor interpolation were evaluated. Additionally, ray tracing was applied for 3D visualization. The linear interpolation algorithm caused interpolation errors at the lung borders. Using the combined interpolation, visualization of perfusion information in arbitrary cutting planes and in 3D using volume rendering was possible. This facilitated the localization of perfusion deficits compared with the coronal orientated source data. The 3D visualization of perfusion parameters using a combined interpolation algorithm is feasible. Further studies are required to evaluate the additional benefit from the 3D visualization. PMID- 17705045 TI - Laparoscopic assisted endorectal pull-through with posterior sagittal approach to the repair of postoperative rectourethral and rectovaginal fistula. AB - Rectourethral or rectovaginal fistula is a troublesome complication after anorectal surgery. The pelvic and perineal dissection may be difficult because of severe fibrosis adhesion around the fistula. The authors applied a novel technique: a combined laparoscopic assisted abdominal and posterior sagittal approach (PSA) to perform the redo surgery. Three boys and two girls (3-13 years old): case 1 had rectovaginal fistula after rectal dialation and modified Swenson's procedure; case 2 had rectovestibular fistula after twice perineal anorectoplasty; case 3 had rectourethral fistula after twice anorectoplasty; case 4 was imperforate anus with Hirschsprung's disease and rectourethral fistula that had been misdiagnosed; case 5 had rectourethral fistula after abdominoperineoanoplasty and Mollard procedure and posterior sagittal anorectoplasty. Laparoscopic assisted abdominal dissection was done first to mobilize the colon as far as the mid pelvis, and the normal colon was marked with a suture. The lower pelvic dissection was performed through the posterior sagittal route, the proximal rectum was mobilized and servered, the distal rectum was left undisected, endorectal mucosectomy with electric ablation was performed, then the fistula was closed from inside the rectum, and the stump of the colon was pulled through the rectum, the stump and the dentate line were anastomosed extraanally. Colostomy was done in case 2 and case 5. The postoperative follow-up showed no recurrent fistula, and all patients had attained normal voluntary bowel actions, but one child had infrequent minor soiling. Laparoscopic assisted endorectal pull-through of the intact colon can offer precise dissection, minimal abdominal injure, and spare troublesome mobilization of the fistula, and can prevent the recurrent of fistula. Posterior sagittal approach provides a direct repair of the fistula and anastomosis. PMID- 17705044 TI - Virtual autopsy using imaging: bridging radiologic and forensic sciences. A review of the Virtopsy and similar projects. AB - The transdisciplinary research project Virtopsy is dedicated to implementing modern imaging techniques into forensic medicine and pathology in order to augment current examination techniques or even to offer alternative methods. Our project relies on three pillars: three-dimensional (3D) surface scanning for the documentation of body surfaces, and both multislice computed tomography (MSCT) and magnetic resonance imaging (MRI) to visualise the internal body. Three dimensional surface scanning has delivered remarkable results in the past in the 3D documentation of patterned injuries and of objects of forensic interest as well as whole crime scenes. Imaging of the interior of corpses is performed using MSCT and/or MRI. MRI, in addition, is also well suited to the examination of surviving victims of assault, especially choking, and helps visualise internal injuries not seen at external examination of the victim. Apart from the accuracy and three-dimensionality that conventional documentations lack, these techniques allow for the re-examination of the corpse and the crime scene even decades later, after burial of the corpse and liberation of the crime scene. We believe that this virtual, non-invasive or minimally invasive approach will improve forensic medicine in the near future. PMID- 17705046 TI - The use of CalciumOrange-5N as a specific marker of mitochondrial Ca2+ in mouse skeletal muscle fibers. AB - We report the use of the fluorescent dye CalciumOrange-5N (CaOr-5N) as a specific mitochondria Ca(2+) marker in enzymatically dissociated mouse FBD muscle fibers. Using laser scanning confocal microscopy and the dyes Mitotracker Green (MTG), di 8-ANEPPS and endoplasmic reticulum tracker green (ERTG), we determined the relative position of mitochondria, transverse tubules and sarcoplasmic reticulum in the sarcomere. Comparison with electron micrographies showed that mitochondria are mostly present at both sides of Z lines and near the triads located at the A I band border. CaOr-5N fluorescence was mainly distributed in mitochondria, highly co-localised with MTG and basically excluded from the A band space. ERTG localised mostly between the two t-tubules present in each sarcomere. We studied the effect of the protonophore FCCP using CaOr-5N to measure mitochondrial Ca(2+) and JC-1 dye to measure mitochondria inner membrane potential (DeltaPsi(m)). After FCCP treatment, the CaOr-5N fluorescence diminished by about 33% in 80 s, while JC-1 fluorescence diminished by 36% in 200 s. Our results show the loss of Ca(2+) from mitochondria when DeltaPsi(m) is depolarised and demonstrate the usefulness of CaOr-5N to mark mitochondrial [Ca(2+)](m). PMID- 17705047 TI - Fracture risk associated with parkinsonism and anti-Parkinson drugs. AB - We studied fracture risk associated with parkinsonism (including Parkinson's disease) and drugs used to treat these conditions in a case-control study. Cases were all subjects with any fracture during the year 2000 (n = 124,655). For each case, three controls (n = 373,962) matched on age and gender were randomly drawn from the background population. Exposure was a diagnosis of parkinsonism or use of anticholinergic drugs, levodopa alone or in combination with carbidopa, and/or catechol-O-methyl transferase (COMT) inhibitors, dopamine agonists, or monoamine oxidase B (MAO-B) inhibitors and a number of other confounders. Parkinsonism was associated with a crude odds ratio (OR) of any fracture of 2.2 (95% confidence interval [95% CI] 2.0-2.5) and an adjusted OR of 1.2 (95% CI 1.0-1.4), the risk being higher especially in males younger than 75 years. Levodopa was associated with an increased overall fracture risk and an increased risk of hip fractures in high doses. Dopamine agonists, anticholinergic drugs, and MAO-B inhibitors were not associated with increased fracture risk except for hip fractures at high doses for MAO-B inhibitors and hip fractures at median doses for dopamine agonists. Neuroleptics were associated with increased risk of fractures in almost all skeletal sites and doses. In conclusion, parkinsonism was associated with increased risk of fractures, especially among males younger than 75 years, and the risk was significantly attenuated upon adjustment for confounders. Use of neuroleptics and, to some degree, levodopa was associated with increased risk of fractures. PMID- 17705048 TI - Adenosine inhibition of lipopolysaccharide-induced interleukin-6 secretion by the osteoblastic cell line MG-63. AB - Adenosine is known to inhibit inflammatory responses in many cell systems via a family of purine receptors termed "P1." The P1 family consists of the adenosine receptors (ADORA) of subtypes A(1), A(2a), A(2b), and A(3). In order to assess whether adenosine has anti-inflammatory actions in osteoblastic cells, we investigated its effects on lipopolysaccharide (LPS)-induced interleukin 6 (IL-6) release in an in vitro inflammatory functional response model. We showed that the osteoblastic cell line MG-63 expresses ADORA(1), A(2a), and A(2b) but not A(3). Treatment of MG-63 cells with adenosine and pharmacological ADORA agonist 5'-N ethylcarboxamidoadenosine or 2-[4-(2-p-carboxyethyl)phenylamino]-5'-N ethylcarboxamidoadenosine (CGS21680) inhibits LPS-induced IL-6 release. This inhibition was protein kinase A (PKA)-dependent and mimicked by treatment with the adenylate cyclase activator forskolin. Treatment of MG-63 with the ADORA(2a) specific antagonist ZM241385 partially reversed the inhibitory effects of ADORA stimulation on LPS-induced IL-6 release. Overall, these data suggest that ADORA(2a) is involved in the regulation of LPS-induced IL-6 release, thus illustrating a regulatory role for adenosine receptors in the control of inflammation and potentially osteoclastogenesis and bone resorption. PMID- 17705049 TI - Marfan-like skeletal phenotype in the tight skin (Tsk) mouse. AB - Tight skin (Tsk) is an autosomal dominant mutation located on mouse chromosome 2 and is associated with an intragenic duplication of the fibrillin 1 (Fbn1) gene. Mutant mice (Tsk/+) display a tightness of skin in the interscapular region, lung emphysema, myocardial hypertrophy, skeletal overgrowth, and kyphosis. It is hypothesized in this study that in Tsk mice the mutation in Fbn1 alters bone cell metabolism. A detailed study of the Tsk skeletal phenotype revealed that Tsk mice have significantly longer femurs and axial skeleton as well as vertebral abnormalities. Cortical and trabecular bone volumes were significantly decreased in Tsk femurs from 2- and 4-month-old mice (13% and 39%, respectively) as well as trabecular thickness, number, connectivity, and surface area. These skeletal differences were also associated with a reduction in bone mineral density in mutant mice. Expression of the osteoblast-specific genes Col1a1, BSP and OC was examined in marrow stromal cell cultures at various time points. A decrease in the rate of maturation of the Tsk cells was indicated by a delay in the appearance of OC expression. These initial experiments demonstrated a significant role of the fibrillin 1 protein in the extracellular matrix of bone cells. PMID- 17705050 TI - Fuzzy logic structure analysis of trabecular bone of the calcaneus to estimate proximal femur fracture load and discriminate subjects with and without vertebral fractures using high-resolution magnetic resonance imaging at 1.5 T and 3 T. AB - Newly developed fuzzy logic-derived structural parameters were used to characterize trabecular bone architecture in high-resolution magnetic resonance imaging (HR-MRI) of human cadaver calcaneus specimens. These parameters were compared to standard histomorphological structural measures and analyzed concerning performance in discriminating vertebral fracture status and estimating proximal femur fracture load. Sets of 60 sagittal 1.5 T and 3.0 T HR-MRI images of the calcaneus were obtained in 39 cadavers using a fast gradient recalled echo sequence. Structural parameters equivalent to bone histomorphometry and fuzzy logic-derived parameters were calculated using two chosen regions of interest. Calcaneal, spine, and hip bone mineral density (BMD) measurements were also obtained. Fracture status of the thoracic and lumbar spine was assessed on lateral radiographs. Finally, mechanical strength testing of the proximal femur was performed. Diagnostic performance in discriminating vertebral fracture status and estimating femoral fracture load was calculated using regression analyses, two-tailed t-tests of significance, and receiver operating characteristic (ROC) analyses. Significant correlations were obtained at both field strengths between all structural and fuzzy logic parameters (r up to 0.92). Correlations between histomorphological or fuzzy logic parameters and calcaneal BMD were mostly significant (r up to 0.78). ROC analyses demonstrated that standard structural parameters were able to differentiate persons with and without vertebral fractures (area under the curve [A(Z)] up to 0.73). However, none of the parameters obtained in the 1.5-T images and none of the fuzzy logic parameters discriminated persons with and without vertebral fractures. Significant correlations were found between fuzzy or structural parameters and femoral fracture load. Using multiple regression analysis, none of the structural or fuzzy parameters were found to add discriminative value to BMD alone. In summary significant correlations were obtained at both field strengths between all structural and fuzzy logic parameters. However, fuzzy logic-based calcaneal parameters were not well suited for vertebral fracture discrimination. Although significant correlations were found between fuzzy or structural parameters and femoral fracture load, multiple regression analysis showed limited improvement for estimating femoral failure load in addition to femoral BMD alone. Local femoral measurements are still needed to estimate femoral bone strength. Overall, parameters obtained at 3.0 T performed better than those at 1.5 T. PMID- 17705052 TI - Value of transthoracic echocardiography in therapy regimens evaluation in pulmonary embolism. AB - BACKGROUND: Acute pulmonary embolism (APE) causes right ventricular dysfunction (RVD). APE patients with and without RVD can benefit from thrombolytic therapy or anticoagulants. In this study, we assessed the changes of right ventricular (RV) function on transthoracic echocardiography (TTE) after different therapy strategies among a broad spectrum of APE. METHODS: The present prospective randomized trial included 520 APE patients from 41 hospitals in China between June 2002 and November 2004. Patients were divided into two groups at presentation: group I (major APE)--52 patients with hemodynamic instability and 198 normotensive patients with RVD; group II (minor APE)--270 normotensive patients without RVD. The patients in group I were randomly divided into four subgroups according to different thrombolytic regimens: A--urokinase 12 h subgroup; B--urokinase 2 h subgroup; C--recombinant tissue-type plasminogen activator (rtPA) 50 mg subgroup and D--rtPA 100 mg subgroup; Different anticoagulants were randomly assigned to patients in group II: NA--heparin subgroup; NB--nadroparin subgroup. TTE were performed before the therapy, and 24 h, 14 days and 3 months after the therapy, respectively. RESULTS: Mean age was 57.4 +/- 14.1 years and 323 patients (62.1%) were male. The indexes of RV function on TTE in group I were significantly improved compared with those in group II at each point (P < 0.05) and SPAP decreased after anticoagulants administration in group II. However, there was no difference among thrombolytic subgroups in group I and between the two anticoagulants subgroups in group II. The presence of RVD was much lower (34.0% vs. 100%, P < 0.001) 24 h after thrombolytic therapies than that before the therapy in group I, which documented that thrombolytic agents early reversed RVD in major APE patients. Even 3 months after the therapy, TRPG and SPAP were still higher in group I than those in group II. CONCLUSIONS: TTE documented the identical effect of thrombolytic regimen of urokinase 12 h, urokinase 2 h, rtPA 50 mg and rtPA 100 mg in major APE which suggest rtPA 100 mg can supersede rtPA 50 mg in these patients. Heparin produced the similar results compared with nadroparin in minor APE. TTE can monitor the effect DC3 NAK of thrombolysis early and identify the patients with persistent pulmonary hypertension which possibly develop chronic thromboembolic pulmonary hypertension. Therefore, it can facilitate the management of APE. PMID- 17705053 TI - Role of mean platelet volume in triagging acute coronary syndromes. AB - BACKGROUND: Acute coronary syndromes, characterized by the rupture of unstable plaque and the subsequent thrombotic process involving platelets, have been increasing in relative frequency. The central role of platelet activation has long been noticed in this pathophysiology; hence, many therapies have been directed against it. In this study, we have aimed to search prospectively the value of mean platelet volume (MPV), which is a simple and accurate measure of the functional status of platelets, in patients hospitalized with diagnosis of acute coronary syndromes (ACS). MATERIALS AND METHODS: A total of 216 consecutive patients (156 male, 60 female) hospitalized with the diagnosis of non-ST segment elevation (NSTE) ACS within the first 24 h of their chest pain were enrolled. One hundred and twenty patients, matched according to sex and age, with stable coronary heart disease (CHD) (85 male, 35 female) were enrolled as a control group. Patients were classified into two group: those with unstable angina (USAP, n = 105) and those with non-ST segment elevation myocardial infarction (NSTEMI, n = 111). RESULTS: MPVs were 10.4 +/- 0.6 fL, 10 +/- 0.7 fL, 8.9 +/- 0.7 fL consecutively for NSTEMI, USAP and stable CHD with significant differences. Patients with ischemic attacks in the first day of hospitalization accompanied by >0.05 mV ST segment shift had significantly higher MPV compared to those without such attacks (P = 0.001). Multivariable logistic regression analysis yielded that MPV (P = 0.016), platelet count (P < 0.001), and the presence of >0.05 mV ST segment depression at admission (P = 0.002) were independent predictors of development of NSTEMI in patients presenting with NSTE ACS. CONCLUSION: In patients presenting with NSTE ACS, higher MPV, though there are overlaps among subgroups, indicates not only more risk of having NSTEMI but also ischemic complications. PMID- 17705054 TI - Synthesis and characterization of arginine-glycine-aspartic peptides conjugated poly(lactic acid-co-L-lysine) diblock copolymer. AB - A biodegradable Copolymer of poly(lactic acid-co-lysine)(PLA-PLL) was synthesized by a modified method and novel Arginine-Glycine-Aspartic (RGD) peptides were chemical conjugated to the primary epsilon-amine groups of lysine components in four steps: I to prepare the monomer of 3-(Nepsilon-benzoxycarbonyl-L-lysine)-6-L methyl-2,5-morpholinedione; II to prepare diblock copolymer poly(lactic acid-co (Z)-L-lysine) (PLA-PLL(Z)) by ring-opening polymerization of monomer and L,L lactide with stannous octoate as initiator; III to prepare diblock copolymer PLA PLL by deprotected the copolymer PLA-PLL(Z) in HBr/HoAc solution; IV the reaction between RGD and the primary epsilon-amine groups of the PLA-PLL. The structure of PLA-PLL-RGD and its precursors were conformed by FTIR-Raman and 1H NMR. Low weight average molecular weight (9,200 g/mol) of the PLA-PLL was obtained and its PDI is 1.33 determined by GPC. The PLA-PLL contained 2.1 mol% lysine groups as determined by 1H NMR using the lysine protecting group's phenyl protons. Therefore, the novel RGD-grafted diblock copolymer is expected to find application in drug carriers for tumor therapy or non-viral DNA carriers for gene therapy. PMID- 17705051 TI - Possible involvement of different connexin43 domains in plasma membrane permeabilization induced by ischemia-reperfusion. AB - In vitro and in vivo studies support the involvement of connexin 43-based cell cell channels and hemichannels in cell death propagation induced by ischemia reperfusion. In this context, open connexin hemichannels in the plasma membrane have been proposed to act as accelerators of cell death. Progress on the mechanisms underlying the cell permeabilization induced by ischemia-reperfusion reveals the involvement of several factors leading to an augmented open probability and increased number of hemichannels on the cell surface. While open probability can be increased by a reduction in extracellular concentration of divalent cations and changes in covalent modifications of connexin 43 (oxidation and phosphorylation), increase in number of hemichannels requires an elevation of the intracellular free Ca(2+) concentration. Reversal of connexin 43 redox changes and membrane permeabilization can be induced by intracellular, but not extracellular, reducing agents, suggesting a cytoplasmic localization of the redox sensor(s). In agreement, hemichannels formed by connexin 45, which lacks cytoplasmic cysteines, or by connexin 43 with its C-terminal domain truncated to remove its cysteines are insensitive to reducing agents. Although further studies are required for a precise localization of the redox sensor of connexin 43 hemichannels, modulation of the redox potential is proposed as a target for the design of pharmacological tools to reduce cell death induced by ischemia reperfusion in connexin 43-expressing cells. PMID- 17705056 TI - Immune evaluation of biomaterials in TNF-alpha and IL-1beta at mRNA level. AB - OBJECTIVE: To examine biomaterial biocompatibility and improve current methods of immunological evaluation TNF-alpha and IL1-beta were used as indicators at mRNA levels. METHODS: Rat peritoneal macrophages were stimulated with different biomaterials and expression of TNF-alpha and IL1-beta was measured by RT-PCR and compared within different groups. RESULTS: Macrophages that were stimulated with PTFE produced significantly more TNF-alpha and IL1-beta than unstimulated macrophages (p < 0.001). The PLGA, NPG, beta-TCP, and CPC groups also induced moderate TNF-alpha and IL1-beta expression (p < 0.01). CONCLUSIONS: TNF-alpha and IL1-beta are sensitive indicators of immune stimulation that can help to monitor the levels of cellular activation induced by different biomaterials. Our findings showed that beta-TCP and CPC had a good biocompability, and CPC was the most biocompatible of all the biomaterials tested. While PTFE and NPG still had side effect because of producing pro-inflammatory cytokines in vitro once implanted. PMID- 17705055 TI - Poly(2-hydroxyethyl methacrylate) emboli with increased haemostatic effect for correction of haemorrhage of complex origin in endovascular surgery of children. AB - Poly(2-hydroxyethyl methacrylate) (PHEMA) embolization particles with enhanced haemostatic properties were prepared by bulk or suspension polymerisation of 2 hydroxyethyl methacrylate (HEMA) followed by particle soaking in ethamsylate solution. The particles accelerated thrombus formation as evidenced by blood analysis of rabbits with implanted emboli. Usefulness of both spherical and cylindrical PHEMA particles with enhanced haemostatic effect was demonstrated on the embolization of arterial anastomosis, fistulas of the lower extremity and abdominal cavity, haemangioma and arteriovenous malformation of the head of several children. PMID- 17705057 TI - Mariner-like elements in Rhynchosciara americana (Sciaridae) genome: molecular and cytological aspects. AB - Two mariner-like elements, Ramar1 and Ramar2, are described in the genome of Rhynchosciara americana, whose nucleotide consensus sequences were derived from multiple defective copies containing deletions, frame shifts and stop codons. Ramar1 contains several conserved amino acid blocks which were identified, including a specific D,D(34)D signature motif. Ramar2 is a defective mariner-like element, which contains a deletion overlapping in most of the internal region of the transposase ORF while its extremities remain intact. Predicted transposase sequences demonstrated that Ramar1 and Ramar2 phylogenetically present high identity to mariner-like elements of mauritiana subfamily. Southern blot analysis indicated that Ramar1 is widely represented in the genome of Rhynchosciara americana. In situ hybridizations showed Ramar1 localized in several chromosome regions, mainly in pericentromeric heterochromatin and their boundaries, while Ramar2 appeared as a single band in chromosome A. PMID- 17705059 TI - Molecular cytogenetics and characterization of a ZZ/ZW sex chromosome system in Triportheus nematurus (Characiformes, Characidae). AB - Chromosomes of Triportheus nematurus, a fish species from family Characidae, were analyzed in order to establish the conventional karyotype, location of C-band positive heterochromatin, Ag-NORs, GC- and AT-rich sites, and mapping of 18S and 5S rDNA with fluorescence in situ hybridization (FISH). The diploid number found was 2n = 52 chromosomes in both males and females. However, the females presented a pair of differentiated heteromorphic chromosomes, characterizing a ZZ/ZW sex chromosome system. The Z chromosome was metacentric and the largest one in the karyotype, bearing C-positive heterochromatin at pericentromeric and telomeric regions. The W chromosome was middle-sized submetacentric, appearing mostly heterochromatic after C-banding and presenting heterogeneous heterochromatin composed of GC- and AT-rich regions revealed by fluorochrome staining. Ag-NORs were also GC-rich and surrounded by heterochromatic regions, being located at the secondary constriction on the short arms of the second chromosome pair, in agreement with 18S rDNA sites detected with FISH. The 18S and 5S rDNA were aligned in tandem, representing an uncommon situation in fishes. The results obtained reinforce the basal condition of the ZZ/ZW sex system in the genus Triportheus, probably arisen prior to speciation in the group. PMID- 17705058 TI - Maternal inheritance, epigenetics and the evolution of polyandry. AB - Growing evidence indicates that females actively engage in polyandry either to avoid genetic incompatibility or to bias paternity in favor of genetically superior males. Despite empirical support for the intrinsic male quality hypothesis, the maintenance of variation in male fitness remains a conundrum for traditional "good genes" models of sexual selection. Here, we discuss two mechanisms of non-Mendelian inheritance, maternal inheritance of mitochondria and epigenetic regulation of gene expression, which may explain the persistence of variation in male fitness traits important in post-copulatory sexual selection. The inability of males to transmit mitochondria precludes any direct evolutionary response to selection on mitochondrial mutations that reduce or enhance male fitness. Consequently, mitochondrial-based variation in sperm traits is likely to persist, even in the face of intense sperm competition. Indeed, mitochondrial nucleotide substitutions, deletions and insertions are now known to be a primary cause of low sperm count and poor sperm motility in humans. Paradoxically, in the field of sexual selection, female-limited response to selection has been largely overlooked. Similarly, the contribution of epigenetics (e.g., DNA methylation, histone modifications and non-coding RNAs) to heritable variation in male fitness has received little attention from evolutionary theorists. Unlike DNA sequence based variation, epigenetic variation can be strongly influenced by environmental and stochastic effects experienced during the lifetime of an individual. Remarkably, in some cases, acquired epigenetic changes can be stably transmitted to offspring. A recent study indicates that sperm exhibit particularly high levels of epigenetic variation both within and between individuals. We suggest that such epigenetic variation may have important implications for post copulatory sexual selection and may account for recent findings linking sperm competitive ability to offspring fitness. PMID- 17705060 TI - Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study. AB - RATIONALE: The majority of volumetric magnetic resonance imaging (MRI) studies of the hippocampus in patients with bipolar disorder (BD) show no differences in hippocampal volume between patients and healthy controls. Significant variability, however, exists in the medication status of patients included in these studies. In particular, treatment with lithium may exert long-term effects on hippocampal volume, influencing cognitive outcomes in BD patients. OBJECTIVES: To our knowledge, no longitudinal volumetric study has been performed in patients with BD, which would allow for an examination of whether lithium therapy used to treat BD can exert a long-term effect on hippocampal volume. MATERIALS AND METHODS: We examined the effects of lithium on hippocampal volumes and recollective memory performance over a period of 2 to 4 years in 12 patients with BD who had never received pharmacotherapy before lithium initiation. RESULTS: We found bilateral increases in volume of the hippocampus over time. We also found some evidence of improvement in verbal memory performance over the 4-year measurement period as assessed by the California Verbal Learning Test. CONCLUSIONS: Consistent with preclinical literature supporting the neuroprotective effects of lithium, long-term treatment is associated with preservation of recollective memory function and increased hippocampal size in vivo. PMID- 17705062 TI - Sterile surgical technique for shunt placement reduces the shunt infection rate in children: preliminary analysis of a prospective protocol in 115 consecutive procedures. AB - OBJECTIVE: The objective of this study was to evaluate whether the rigid application of a sterile protocol for shunt placement was applicable on a routine basis and allowed the reduction of shunt infections (SI) in children. MATERIALS AND METHODS: Since 2001, a rigid sterile protocol for shunt placement in children using neither antibiotic-impregnated catheters nor laminar airflow was prospectively applied at Erasme Hospital, Brussels, Belgium. For assessing the protocol efficacy before continuation, we preliminarily analyzed the results of the first 100 operated children (43 females, 57 males, 49 aged <12 months; 115 consecutive shunt placement/revision procedures). All procedures were performed by the same senior surgeon, one assistant, one circulating nurse, one anesthesiologist. The sterile protocol was rigidly imposed to these four staff members: uniformed surgical technique; limited implant and skin edge manipulation; minimized human circulation in the room; scheduling surgery as first morning operation; avoiding postoperative cerebrospinal fluid (CSF) leak; double gloving; procedures of less than 30-min duration; systemic antibiotics prophylaxis. We analyzed separately: (1) children carrying an increased risk of SI (n = 38) due to preoperative external ventricular drainage, CSF leak, meningitis, glucocorticoids, chemotherapy; (2) children aged <12 months; (3) procedures for shunt revision. RESULTS: Errors in protocol application were recorded in 71/115 procedures. They were mainly done by non-surgical staff, decreased with time and were medically justified in some young children. Surprisingly, no SI occurred (follow-up, 4 to 70 months). One child developed an appendicitis with peritonitis (Streptococcus faecalis) after 6 months. No SI was found. After peritonitis was cured, shunt reinsertion was uneventful. CONCLUSION: These preliminary results suggest that a uniform and drastic sterile surgical technique for shunt placement: (1) can be rigidly applied on a routine basis; (2) can lower the early SI rate below 1%; (3) might have a stronger impact to reduce SI than using antibiotic-impregnated catheters and optimizing the operative environment such as using laminar airflow and reducing the non-surgical staff. This last issue will be evaluated further in the present ongoing protocol. PMID- 17705061 TI - The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats. AB - RATIONALE AND OBJECTIVES: Yohimbine is an alpha-2 adrenoreceptor antagonist that provokes stress- and anxiety-like responses in both humans and laboratory animals. In rats, yohimbine increases operant alcohol self-administration and reinstates alcohol seeking. In this study, we assess whether these effects of yohimbine are attenuated by systemic injections of the corticotrotropin-releasing factor 1 (CRF1) receptor antagonist antalarmin. MATERIALS AND METHODS: In Exp. 1, we trained rats to lever press for alcohol solutions (12% w/v, 1 h/day) over several weeks; during training, the response requirement was increased from a fixed-ratio-1 (FR-1) to a fixed-ratio-3 (FR-3) reinforcement schedule. We then tested the effect of antalarmin (10 or 20 mg/kg) on yohimbine (1.25 mg/kg) induced increases in operant alcohol self-administration (FR-3 reinforcement schedule). Subsequently, we assessed the effect of antalarmin on yohimbine induced increases in plasma corticosterone levels in the previously self administering rats. In Exp. 2, we trained the rats to self-administer alcohol as in Exp. 1, and after extinction of the alcohol-reinforced lever responding over 13 days, we tested antalarmin's effect on yohimbine-induced reinstatement of alcohol seeking. RESULTS: Yohimbine increased operant alcohol self-administration and reinstated alcohol seeking after extinction. These effects of yohimbine were attenuated by antalarmin. Antalarmin injections in the absence of yohimbine had no effect on either operant alcohol self-administration or extinction responding. Antalarmin had no effect on yohimbine-induced corticosterone release in alcohol experienced rats. CONCLUSIONS: These results suggest that extrahypothalamic CRF1 receptors are involved in the effect of yohimbine on operant alcohol self administration and on relapse to alcohol seeking and support the notion that CRF1 receptor antagonists should be considered in alcohol addiction treatment. PMID- 17705063 TI - Modulation of gene expression of three Cryptosporidium parvum ATP-binding cassette transporters in response to drug treatment. AB - We studied three ATP-binding cassette (ABC) transporters (cgd1_1350, cgd7_4510, and cgd7_4520) of Cryptosporidium parvum that were identified to share a high level of homology with nucleotide binding domains of other parasitic ABC transporters and therefore could be potential candidates of efflux of drugs and/or contribute to the intrinsic resistance to chemotherapy observed of this parasite. Partial characterization and expression analysis of three C. parvum ABC transporters was determined by standard semi-quantitative real-time polymerase chain reaction. Expression of mRNA of the three ABC transporters was detected at different time points in infected cell cultures over the 48-h period, corresponding to the development of the sexual and asexual stages of the parasite. To determine if these three transporters were modulated in response to drug treatment, infected HCT 8 cells were then incubated for 48 h with different concentrations of paromomycin and a single concentration of cyclosporin A. Our results indicated that treatment by paromomycin resulted in approximately five to eightfold upregulation of cgd1_1350 transcript and about threefold of upregulation of Cgd7_4510 transcript levels. Cyclosporin A had a similar upregulating effect on cgd1_1350 and cgd7_4510 RNA levels: fivefold and 2.6-fold, respectively. On the contrary, drug treatment had little effect on cgd7_4520 transcript levels. Therefore, two of these transporters may be of value as tools for the study and the rational drug design of specific inhibitors to counteract C. parvum's intrinsic drug resistance. PMID- 17705064 TI - Lung cancer in individuals less than 50 years of age. AB - The aim of this study was to compare the epidemiologic, clinical, and laboratory characteristics and survival rates of younger and older patients with lung cancer. We studied 1340 patients who were histopathologically diagnosed as having lung cancer from 1990 to 2005. Based on prior reports, we defined "younger" as individuals less than 50 years old. The patients were classified into two groups: <50 years (the younger group) and >/=50 years (the older group). Of the 1340 patients, 179 (13.4%) were in the younger group and 1161 were in the older group. In the younger group, exposure to occupational risk factors was a risk factor for lung cancer, while in the older group, smoking was a risk factor. At the time of diagnosis, chest pain was more common in the younger group, while in the older group, cough, dyspnea, and hilar enlargement on chest X-ray were more frequent. The incidence of adenocarcinoma and small-cell carcinoma was greater in the younger group, while squamous cell carcinoma was more common in the older group. Metastasis rates were significantly different between the two age groups: 52.0% of the younger group presented with stage IV disease compared with 43.5% of the older group. Although fewer younger than older patients were not able to receive or rejected anticancer therapy, the overall survival was similar in both groups. These data indicate that lung cancer had different etiopathogenetic characteristics in younger patients, which may have clinical implications. By planning preventive measures based on these characteristics, more efficient use of resources can be achieved. PMID- 17705065 TI - Combined vaginal-laparoscopic-abdominal approach for the surgical treatment of rectovaginal endometriosis with bowel resection: a comparison of this new technique with various established approaches by laparoscopy and laparotomy. AB - BACKGROUND: A new combined vaginal-laparoscopic-abdominal approach for rectovaginal endometriosis allows intraoperative digital bowel palpation to assess bowel infiltration and prevents unnecessary bowel resections. This technique was compared to various established approaches where bowel resection was indicated by clinical symptoms and imaging results only. METHODS: Patients operated for rectovaginal endometriosis with endometriotic bowel involvement between March 2002 and April 2006 at the gynecological department Charite, Berlin, Germany were included. Bowel involvement was suspected by clinical symptoms, clinical examination, and/or results of imaging techniques. The study group (SG) was operated by the combined vaginal-laparoscopic-abdominal approach (n = 30) and the control group (CG) (n = 18) by laparoscopy (n = 4), laparotomy (n = 3), laparoscopy followed by laparotomy for bowel resection (n = 8) or laparoscopy followed by vaginal bowel resection (n = 3). In all cases histopathology was performed. RESULTS: The study group and the control group were comparable regarding age, body mass index, symptoms, American Society for Reproductive Medicine (ASRM) classification, colorectal operative procedures, operating times, length of the resected bowel specimen, and concomitant surgical procedures. However, only in the CG were protective stomas required (p = 0.047). There were significantly less complications in the SG (p = 0.027). No patient experienced leakage of anastomosis. Bowel involvement by endometriosis was confirmed by histopathology in the SG in all cases whereas in the CG only in 16/18 (88.9%) cases. Hospitalization time was significantly shorter in the SG. Rehospitalizations were necessary only in the CG to repair one rectovaginal fistula and to reverse three stomas. CONCLUSIONS: With the presented technique of a combined vaginal-laparoscopic-abdominal surgical procedure for rectovaginal endometriosis, we showed that the complication rate, rehospitalization rate, and hospitalization time were significantly lower than in the patients of the CG. Furthermore, the combined vaginal-laparoscopic-abdominal technique allowed better evaluation of the invasiveness of the endometriotic lesion and avoided unnecessary bowel surgery. PMID- 17705066 TI - Laparoscopic adrenalectomy: lessons learned from an initial series of 100 patients. AB - BACKGROUND: Laparoscopic adrenalectomy is considered the gold standard for the surgical treatment of adrenal disorders in most centers. This study analyzes the authors' experience using the lateral intraperitoneal approach with the first 100 patients. In addition to analyzing the authors' experience, this article aims to contrast it with some published series as an internal quality control. METHODS: In a 10-year period, 138 laparoscopic adrenalectomies were performed for 100 patients. Demographics, surgical results, complications, and long-term outcomes were analyzed. RESULTS: The participants comprised 69 women and 31 men with a mean age of 37 years. The procedures included 24 right, 38 left, and 38 bilateral adrenalectomies. The indications for surgery were Cushing's disease for 33 patients, pheochromocytoma (4 bilateral) for 23 patients, Cushing's syndrome for 18 patients, Conn's syndrome for 16 patients, and incidentaloma for 10 patients. Five procedures were converted to open surgery. Two patients with pheochromocytoma required intraoperative blood transfusion. The mean operative time was 174 min for unilateral adrenalectomies and 302 min for the bilateral procedures. The mean hospital stay was 5 days. Surgical morbidity included an abdominal wall hematoma, a small pneumothorax, and intraabominal bleeding in one patient that required reexploration. There were three operative mortalities not related to the technique. The long-term results showed control of hypercortisolism in all the patients with Cushing's disease and 82% of the patients with pheochromocytoma. Most of the patients with Conn's syndrome (91.4%) became normotensive after surgery. CONCLUSIONS: Laparoscopic adrenalectomy is safe and effective. The complications are mild, and mortality is related more to the patient's condition than to the surgical technique. PMID- 17705067 TI - Perioperative results of 214 laparoscopic adrenalectomies by anterior transperitoneal approach. AB - BACKGROUND: The present study attempts to evaluate the perioperative results of the anterior approached laparoscopic adrenalectomy (LA) in a large cohort of patients, and report the advantages and disadvantages of this route. METHODS: 204 patients, 125 female and 79 male with a mean age 52.8 years (range, 19-75 years), underwent LA by the anterior transperitoneal approach from 1994 to 2005 in our institution. There were 100 right and 114 left LAs. Ten patients underwent bilateral LA. Associated surgical procedures were performed in 17 cases. During the same period 47 LAs had been performed by different approaches (flank and submesocolic). RESULTS: Mean operative time was 80 minutes for right (40-150), 109 minutes for left (64-300) and 194 minutes for bilateral adrenalectomy. Intraoperative major complications were observed in six patients. Mortality occurred in one diabetic patient who was converted to open surgery because of a colonic perforation and subsequently developed a Candida sepsis in the postoperative course. The mean size of lesion removed was 6.2 cm (1.5-12 cm). Oral intake started within 24 hours and the mean hospital stay was 2.5 days (1-8 days). Histology results were as follows: nonsecreting adenoma 65, Cushing's adenoma 58, Conn's adenoma 53, pheochromocytoma 24, metastases 9, myelolipoma 3, adrenogenital syndrome 1, carcinoma 1. CONCLUSIONS: LA by anterior transperitoneal approach is safe and effective in our experience, despite the inherent limitation that this was not a prospective randomized study. The main advantage of this route is early ligature of the adrenal vein on both sides, enabling the performance of associated surgical procedures and bilateral adrenalectomy. PMID- 17705068 TI - Feasibility of radical sigmoid colectomy performed as natural orifice translumenal endoscopic surgery (NOTES) using transanal endoscopic microsurgery. AB - BACKGROUND: Natural orifice translumenal endoscopic surgery (NOTES), a recent development in the field of minimally invasive surgery, may offer advantages over open and laparoscopic surgery. Most investigations to date have focused on small end-organ resections, and none have described en bloc regional lymphadenectomy. This study aimed to describe a method of anal transcolonic sigmoid colon resection. METHODS: A fresh frozen then thawed cadaver model was used. Three male human cadavers were subjected to transanal sigmoid colon mobilization, high vascular ligation, en bloc lymphadenectomy, and stapled end-to-end anastomosis performed by a single operator using transanal endoscopic microsurgery instrumentation. RESULTS: The findings showed that NOTES sigmoid colon resection with en bloc lymphadenectomy and primary anastomosis can be performed successfully. The critical steps of the procedure were (1) luminal suture occlusion of the sigmoid colon, (2) transrectal bowel division, (3) entry through the mesorectum into the presacral space, (4) en bloc mobilization of the sigmoid colon mesentery off of the retroperitoneum, (5) high ligation of the superior hemorrhoidal artery, (6) transanal delivery of the intact sigmoid colon specimen, (7) extracorporeal division of the colon, and (8) creation of a stapled end-to end colorectal anastomosis. Postprocedure laparotomy confirmed adequate lymphadenectomy and anastomosis with no untoward events. CONCLUSIONS: It is possible to complete the critical steps of a NOTES sigmoid resection, en bloc lymphadenectomy, primary anastomosis, and retrieval of an intact specimen without any incisions using transanal endoscopic microsurgery instrumentation. PMID- 17705069 TI - Scarless endoscopic surgery: NOTES or TUES. PMID- 17705070 TI - A full review of port-closure techniques. PMID- 17705072 TI - Reoperation for marginal ulceration. PMID- 17705071 TI - Gastric banding: conversion to sleeve, bypass, or DS. AB - A review of conversions of gastric banding for obesity to Roux-en-Y gastric bypass, gastric sleeve, or duodenal switch attempts to determine which revisional procedure best enhances weight loss. Indications for these conversions are multiple and include hardware problems, motility problems, and miscellaneous like inadequate weight loss. Analysis of band conversions to band of 193 patients, and bands to gastric bypass in 214 patients reveals better weight loss with the latter strategy. Smaller cohorts of patients who underwent a biliopancreatic diversion or simply a sleeve gastrectomy are too small to conclude on their efficacy. Prospective randomized trials are needed to determine which revisional procedure is best in the setting of inadequate weight loss of excessive weight regain after gastric adjustable banding for severe obesity. PMID- 17705073 TI - Reoperative bariatric surgery. PMID- 17705074 TI - A novel three-dimensional dynamic anorectal ultrasonography technique (echodefecography) to assess obstructed defecation, a comparison with defecography. AB - AIM: To test the effectiveness of echodefecography, the dynamic 3D anorectal ultrasonography technique -(EDF). To assess women with obstructed defecation (OD), as compared with conventional defecography (DF). METHODS: A prospective study was carried out with 30 women with OD symptoms, the mean validated Wexner constipation score was 14 (range 7-25) and the mean age 47.7 years. All patients were submitted to DF followed by EDF and the results compared. RESULTS: Six patients were normal at DF and five were normal at EDF. Defecography identified grade I rectocele in five patients (average size: 1.8 cm), grade II in seven (average size: 2.9 cm) and grade III in 12 (average size: 4.6 cm). Different sizes of anorectocele were also observed at EDF and quantified according to DF classification (grade I: 1.3 cm). Significant differences were observed between anorectocele sizes (p < 0.05) and between normal patients and grade I (p < 0.001). The level of agreement between the techniques was high (kappa = 0.902), with only one normal case wrongly identified as anorectocele III at EDF. Rectal intussusception was identified in five patients at DF; EDF confirmed these cases and revealed seven others, demonstrating moderate agreement (kappa = 0.462). Anismus was identified in nine patients in DF and in eight in EDF (kappa = 0.901). CONCLUSION: Echodefecography may be used as an alternative method to assess patients with OD as it has been shown to detect the same anorectal dysfunctions observed in DF. It is minimally invasive, well tolerated, inexpensive, avoids exposure to radiation, and clearly demonstrates all the anatomic structures involved with defecation. PMID- 17705075 TI - Laparoscopy-assisted distal gastrectomy with D1+beta compared with D1+alpha lymph node dissection. AB - BACKGROUND: Laparoscopy-assisted distal gastrectomy (LADG) with D1+beta lymph node dissection has become the most popular treatment for early gastric cancer in Asian countries. However, the same clinical advantages with this procedure as with LADG with D1+alpha lymph node dissection has not been shown. The aim of this study was to compare the outcome of LADG with D1+beta to that of LADG with D1+alpha lymph node dissection. METHODS: During the period June 2002 through June 2006, LADG with D1+alpha lymph node dissection was performed in 54 patients, and LADG with D1+beta lymph node dissection was performed in 42 patients. Surgical findings, clinicopathological data, postoperative course, complications, nutritional status, and blood analysis findings were compared between the two groups. Differences were analyzed with Mann-Whitney U test and chi-square test. RESULTS: Patients in the two groups were comparable with respect to age, sex, body mass index, and stage and pathological characteristics of gastric cancer. A significantly greater number of N2 lymph nodes were harvested by D1+beta lymph node dissection than by D1+alpha dissection (5.9 vs. 2.7, P < 0.01). However, no significances in the total number of retrieved lymph nodes (24.7 vs. 22.2) or perigastric lymph nodes dissected (18.9 vs. 19.4) were identified between the D1+beta and D1+alpha groups. There was also no significant difference between the D1+alpha and D1+beta groups with respect to operation time, blood loss, complication rate, time to first walking, first flatus, first eating, and first defecation, frequency of analgesics given, volume of food intake on postoperative day 7, weight loss, and postoperative hospital stay. Blood analysis showed there were no significant differences in white blood cell count, granulocyte count, lymphocyte count, levels of C-reactive protein, and serum albumin. CONCLUSIONS: The short-term outcome of LADG with D1+beta lymph node dissection is comparable to that of LADG with D1+alpha lymph node dissection. According to the oncological requirements, we can apply this operation as a minimally invasive surgery. PMID- 17705076 TI - Clinical outcome of the laparoscopic surgery for stage II and III colorectal cancer. AB - BACKGROUND: Laparoscopic colorectal cancer surgery has become widely accepted recently. However, the oncological validity of this surgery has not yet been well analyzed, especially for advanced cancer. The aim of this study is to assess the clinical outcome of laparoscopic surgery for stage II/III colorectal cancer in our hospital. PATIENTS AND METHODS: Between June 1999 and August 2006, 321 patients underwent laparoscopic colorectal cancer surgery in our hospital; of those 121 cases whose pathological findings revealed stage II/III were included in this study. Among these cases, we assessed a short-term outcome and a medium term outcome in terms of survival evaluation. RESULTS: The male:female ratio was 73:48, and mean age of patients was 62.4 years. Thirteen tumors were located in the cecum, 29 in the ascending colon, five in the transverse colon, one in the descending colon, 43 in the sigmoid colon, and 30 in the rectum. Average duration of operation was 184 minutes, and mean estimated blood loss was 53.5 ml. Five patients (4.1%) were converted to open procedures. No intraoperative complication was observed but eight complications (6.6%) occurred postoperatively. Forty-two cases were classified as stage II, 62 as stage IIIA /B, and 17 as stage IIIC. Five patients died of cancer relapse (4.1%), and 18 cases had recurrence of disease (14.9%), to date. No port-site recurrence was detected. Overall five-year survival was 95.7% in stage II, 84.1% in stage IIIA/B, 70.0% in stage IIIC. Meanwhile disease-free five-year survival was 75.6% in stage II, 80.1% in stage IIIA/B, and 66.8% in stage IIIC. No significant difference was observed between stages, in terms of either overall or disease-free survival. CONCLUSION: Although further evaluation is required, laparoscopic surgery for stage II/III colorectal cancer is safe and would be an oncologically adequate procedure. PMID- 17705078 TI - Retracting and seeking movements during laparoscopic goal-oriented movements. Is the shortest path length optimal? AB - AIMS: Minimally invasive surgery (MIS) requires a high degree of eye-hand coordination from the surgeon. To facilitate the learning process, objective assessment systems based on analysis of the instruments' motion are being developed. To investigate the influence of performance on motion characteristics, we examined goal-oriented movements in a box trainer. In general, goal-oriented movements consist of a retracting and a seeking phase, and are, however, not performed via the shortest path length. Therefore, we hypothesized that the shortest path is not an optimal concept in MIS. METHODS: Participants were divided into three groups (experts, residents, and novices). Each participant performed a number of one-hand positioning tasks in a box trainer. Movements of the instrument were recorded with the TrEndo tracking system. The movement from point A to B was divided into two phases: A-M (retracting) and M-B (seeking). Normalized path lengths (given in %) of the two phases were compared. RESULTS: Thirty eight participants contributed. For the retracting phase, we found no significant difference between experts [median (range) %: 152 (129-178)], residents [164 (126-250)], and novices [168 (136-268)]. In the seeking phase, we find a significant difference (<0.001) between experts [180 (172-247)], residents [201 (163-287)], and novices [290 (244-469)]. Moreover, within each group, a significant difference between retracting and seeking phases was observed. CONCLUSIONS: Goal-oriented movements in MIS can be split into two phases: retracting and seeking. Novices are less effective than experts and residents in the seeking phase. Therefore, the seeking phase is characteristic of performance differences. Furthermore, the retracting phase is essential, because it improves safety by avoiding intermediate tissue contact. Therefore, the shortest path length, as presently used during the assessment of basic MIS skills, may be not a proper concept for analyzing optimal movements and, therefore, needs to be revised. PMID- 17705079 TI - Microdialysis monitoring for evaluation of the influence exerted by pneumoperitoneum on the kidney: an experimental study. AB - BACKGROUND: Laparoscopic donor nephrectomy has become the first choice for living donor kidney transplantation, offering advantages over open donor nephrectomy. This study aimed to evaluate kidney tissue metabolism during and after pneumoperitoneum using a microdialysis technique. METHODS: Eight pigs underwent laparotomy and implantation of two microdialysis catheters: one in the cortex and one in the medulla of the left kidney. After laparotomy, the abdominal wall was closed, and pneumoperitoneum was induced with a constant standard pressure of 16 to 18 mmHg for 4 h, followed by rapid desufflation. In microdialysis samples collected from intrarenal catheters, markers of ischemia (glucose, lactate, pyruvate, and lactate-pyruvate ratio) and the marker of cell membrane injury (glycerol) were monitored. RESULTS: There were no changes in glucose, lactate, or pyruvate level before, during, or after pneumoperitoneum, either in the cortex or in the medulla. Additionally, the calculated lactate-pyruvate ratio did not show signs of ischemia during or after pneumoperitoneum. However, with regard to the marker of cell injury, glycerol increased in the medulla after decompression from 22.57 +/- 3.76 to 35.67 +/- 5.43 mmol/l (p < 0.01). This release of glycerol in the medulla was significantly higher than in the cortex (area under the curve [AUC], 22.18 +/- 4.87 vs 34.79 +/- 7.88 mmol/l; p < 0.01). CONCLUSIONS: The pattern of metabolic changes monitored in the kidney during and after pneumoperitoneum indicates some kind of cell injury predominant in the medulla without any signs of kidney ischemia. This nonischemic injury could be related to hyperperfusion of the kidney after decompression or injury to cells attributable to mechanical cell expansion at the point of rapid decompression. PMID- 17705077 TI - The value of laparoscopic liver surgery for solid benign hepatic tumors. AB - BACKGROUND: Laparoscopic liver resection (LLR) has gained wide acceptance for various liver resection procedures, mainly for benign diseases. However, only small series have been reported from a few selected centers. METHODS: Between January 2001 and January 2006, a total of 629 liver resections were performed at our institution. The indication was solid benign liver tumor in 56 (8.9%) patients. LLR was performed in 20 (35.7%) cases. Data from the LLR group were compared with those from a consecutive control group undergoing open liver surgery (OS) for similar indications in a matched-pair analysis during the same period. The pairs were matched as closely as possible for age, gender, American Society of Anesthesiologists (ASA) score, indication for resection, and type and location of the lesions. The endpoint was to investigate overall morbidity and outcome. RESULTS: All patients but one are alive and well after a mean follow-up of 35 months (range 10-60 months). Conversion laparotomy was required in two out of 20 (10%) cases for uncontrolled bleeding (one requiring temporary hemodialysis). LLR was characterized by faster time to first oral intake and shorter hospital stay compared to OS (p = 0.001 and 0.008, respectively). Incisional hernias (25%) were only recorded in the OS (p = 0.047 vs. LLR). Overall morbidity was 45% in OS versus 20% in LLR (p = 0.3). CONCLUSIONS: LLR significantly reduced time to oral intake, hospital stay, and incisional hernias compared to OS. Bleeding is a major risk and should be carefully considered when resecting benign tumors. In the hands of expert surgeons, LLR may become the gold standard for the resection of benign liver tumors located in the anterior and lateral sectors and for minor hepatic resections. PMID- 17705080 TI - Laparoscopic total proctocolectomy with ileal pouch anal anastomosis for ulcerative colitis and familial adenomatous polyposis: initial experience in Mexico. AB - BACKGROUND: Since the introduction of laparoscopic colectomy in 1991, experience in laparoscopic bowel surgery has gradually increased. Several reports from specialized centers have demonstrated that laparoscopic colorectal resections are feasible and safe, providing an acceptable alternative to laparotomy for a variety of diseases. Some studies have shown the feasibility, safety, and good functional outcome of the minimally invasive procedures for ulcerative colitis (UC) and familial adenomatous polyposis (FAP). No known studies have investigated laparoscopic proctocolectomy in Mexico. This report aims to describe the first laparoscopic proctocolectomies with ileal pouch anal anastomosis (IPAA) performed at the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMNSZ). METHODS: All the patients in the authors' institution who underwent a one- or two-stage laparoscopic total proctocolectomy with IPAA between June 2005 and December 2006 were included in the study. All the operations were performed by the same surgeon, who had already completed the learning curve for colorectal laparoscopic procedures. RESULTS: For the study, 10 patients underwent a laparoscopic proctocolectomy with IPAA by a single surgeon. Eight of the patients underwent a one-stage procedure, whereas two patients with severe colitis underwent a two-step procedure. All the cases were managed with a diverting loop ileostomy. Six patients underwent a standard double-stapled IPAA anastomosis, and two patients with FAP underwent a mucosectomy with a manual IPAA anastomosis. The mean operative time was 187 min, and the mean blood loss was 46 ml. There were two postoperative complications. One patient presented with an early small bowel obstruction due to an internal hernia, which required reoperation. The other complication was a wound infection. The mean return to oral intake was 1.5 days, and the mean length of hospital stay was 3.4 days. CONCLUSION: Although this was not a comparative study and although sample size imposed limitations, with this preliminary data, we conclude that the laparoscopic approach to UC and FAP at our institution is safe, feasible, and effective. However, to achieve the benefits in postoperative outcome, this procedure should be performed only by experienced laparoscopic surgeons. PMID- 17705081 TI - Endoscopic harvest of saphenous vein: a lesson learned from 1,348 cases. AB - BACKGROUND: Endoscopic harvest of saphenous vein is a relatively new technique developed to minimize the wound and postoperative complications. This technique has gained patients' acceptance and become popular in cardiac surgical practices. Because most centers have limited experience with this approach, the authors summarize the clinical profiles of patients undergoing endoscopic vessel harvest (EVH). METHODS: Between March 2001 and August 2006, 1,348 patients (945 men and 403 women) with a mean age of 67.2 years (range, 28-89 years) underwent EVH of saphenous vein for coronary artery bypass surgery, peripheral artery reconstruction, and miscellaneous conditions. The EVH technique was performed using the Vasoview system (Guidant, Menlo Park, CA, USA) under the assistance of carbon dioxide (CO(2)) insufflation. RESULTS: Technical success was achieved in 98.6% of the cases. Two saphenous veins were discarded because of obvious vein injury. The mean harvest time was 45 min: 68 min for the first 50 cases and 23 min for the last 200 cases. Nearly all the patients (98%) had saphenous vein harvested only from the thighs, whereas only 1.5% of the patients had saphenous vein harvested from the legs. Postoperative wound complications were experienced by 61 patients including 25 tract hematomas, 19 wound dehiscences or poor healing, 16 wound infections, and 1 overlying skin necrosis. Overall, 13 subsequent revisions were required for these complications. Detectable air embolisms occurred for 143 patients and numbness in the saphenous nerve territory for 169 patients. CONCLUSION: The findings showed EVH of saphenous vein to be a valid alternative to open saphenectomy, providing excellent surgical results. Therefore, EVH should be considered as the standard of care for saphenous vein harvest. PMID- 17705082 TI - Randomized clinical trial comparing radially expanding trocars with conventional cutting trocars for the effects on pain after laparoscopic cholecystectomy. AB - BACKGROUND: Trocar incisions are important sources of pain the first days after laparoscopic cholecystectomy. Radially expanding trocars may cause less pain than conventional cutting trocars. METHODS: In a patient- and observer-blinded trial, 80 patients were randomized to undergo laparoscopic cholecystectomy using either radially expanding trocars (radial group) or conventional cutting trocars (cutting group). Two 10-mm and two 5-mm trocars were used in both treatment groups. All the patients received standardized anesthetic and analgesic treatment. The primary outcome was incisional pain. Pain was registered during mobilization using a visual analog scale (VAS) and a verbal rating scale (VRS) before and 6 h after the operation, and at postoperative days 1 and 2. The needs for a fascial incision to retract the gallbladder, active surgical hemostasis, and supplementary requirements of opioids during the hospital stay were registered. In addition, 2 days after the operation, the incidence and severity of suggilations at the trocar incisions were measured. RESULTS: Data from 77 patients were available for statistical analysis. In the radial group, 23 patients needed fascial incision for gallbladder retraction compared with 11 patients in the cutting group (p = 0.006). No significant intergroup differences in VAS or VRS pain scores or any other variable were found. CONCLUSIONS: The use of radially expanding trocars has no effect on incisional pain after laparoscopic cholecystectomy. PMID- 17705083 TI - Isobaric gasless laparoscopy versus minilaparotomy in uterine myomectomy: a randomized trial. AB - BACKGROUND: Isobaric gasless laparoscopy and minilaparotomy have been used as more recent minimally invasive approaches to myomectomy. This randomized trial aimed to compare the surgical and immediate postoperative outcomes for myomectomy performed by isobaric gasless laparoscopy with those for minilaparotomy. METHODS: A total of 100 patients with symptomatic uterine myomas requiring myomectomy were randomly allocated to the gasless laparoscopy group or the minilaparotomy group. The randomization procedure was based on a computer-generated list. The primary outcome was a comparison of the discharge times between the two procedures. A power calculation verified that more than 26 patients for each group was necessary to detect a difference of more than 24 h in discharge time with an alpha error level of 5% and a beta error of 80%. Continuous outcome variables were analyzed using the Student's t-test. Discrete variables were analyzed with the chi-square test or Fisher's exact test. A p value less than 0.05 was considered statistically significant. RESULTS: The mean discharge time was longer for minilaparotomy than for gasless laparoscopy (98.4 +/- 1.4 vs 52.8 +/- 1.6 h; p < 0.001). Gasless laparoscopy resulted in shorter times for canalization (21.6 +/- 1.1 vs 32 +/- 1.3 h; p < 0.05) and surgery (79.5 +/- 25.1 vs 103.5 +/- 24.9 min; p < 0.001). The intraoperative blood loss was less with gasless laparoscopy (154.2 +/- 1.2 vs 188.6 +/- 1.3 ml; p < 0.001). No intraoperative complications occurred, and no case was returned to the theater in either group. No conversion to standard laparotomy was necessary. CONCLUSIONS: Isobaric gasless laparoscopy and minilaparotomy can be suitable options for uterine myomectomy. Several surgical and immediate postoperative outcomes were significantly better in the gasless laparoscopy group than in the minilaparotomy group. However, further controlled prospective studies are required to confirm the results. PMID- 17705084 TI - Mesh migration into the esophageal wall after mesh hiatoplasty: comparison of two alloplastic materials. AB - BACKGROUND: Hiatal mesh implantation in the operative treatment of gastroesophageal reflux disease has become an increasing therapy option. Besides clinical results little is known about histological changes in the esophageal wall. METHODS: Two different meshes [polypropylene (PP), Prolene; polypropylene polyglecaprone 25 composite (PP-PG), Ultrapro] were placed on the diaphragm circular the esophagus of 20 female rabbits. After three months a swallow with iodine water-soluble contrast medium for functional analysis was performed. After the animals were sacrificed, histopathological evaluation of the foreign-body reaction, the localization of the mesh relating to the esophageal wall was analyzed. RESULTS: Sixteen rabbits survived the complete observation period of three months. After three months distinctive mesh shrinkage was observed in all animals and meshes had lost up to 50% of their original size before implantation. We found a delayed passage of the fluid into the stomach in all operated animals. There was a significant increased diameter of the outer ring of granulomas in the PP group (76.5 +/- 8.0) compared to the PP-PG group (64 +/- 8.5; p = 0.002). However, we found a mesh migration into the esophageal wall in six out of seven animals (PP) and five out of nine animals (PP-PG), respectively. CONCLUSION: Experimental data suggest that more knowledge is necessary to assess the optimal size, structure, and position of prosthetic materials for mesh hiatoplasty. The indication for mesh implantation in the hiatal region should be carried out very carefully. PMID- 17705085 TI - Short and long term results of the laparoscopic Heller-Dor myotomy. The influence of age and previous conservative therapies. AB - AIMS: To evaluate the long-term outcome and quality of life (QoL) data, and to assess the potential influence of age and different conservative procedures on laparoscopic surgery. BACKGROUND: Current therapies for achalasia can palliate dysphagia, but other symptoms may persist, making it difficult to quantify and compare. To understand if they could influence results, we analyzed short- and long-term results and correlated them to age and previous conservative treatments using a specific QoL test. METHODS: Functional examinations (endoscopy, 24-hr pH manometry, upper GI X-rays) and the gastrointestinal quality of life index (GIQLI) were used before and after a laparoscopic Heller-Dor myotomy. Data were analyzed by the Mann-Whitney U test, Wilcoxon signed rank test, and Spearman's rho coefficient for bivariate correlations (p < 0.05). RESULTS: From January 1996 to January 2004, 31 consecutive patients out of 35 diagnosed with achalasia, in clinical stages I-III, were operated on by laparoscopy . Two groups were identified using the break point of 70 years of age, (20 younger and 15 older) and two subgroups according to the conservative therapy performed (20, none; 15, some). Patients underwent a clinical manometry evaluation at six and 12 months, and then yearly, and pH-metry at six, 24, and 60 months. In 78% of patients dysphagia disappeared and the incidence of reflux was 13%. Age and previous treatments did not influence surgical outcome. Patients completed a GIQLI questionnaire before surgery, six months after surgery, and then yearly (for five years). The median preoperative GIQLI score was 78 (range 38-109) out of a theoretical maximum score of 144. At a median follow-up of 49 months (range 24-72 months), the score had significantly improved to 115 (range 71-140). There was no significant statistical difference between the groups. CONCLUSIONS: Laparoscopic Heller-Dor myotomy is an effective palliation for achalasia; the long-term outcome is not significantly affected by preoperative conservative treatments or by the age of the patients. The GIQLI questionnaire is a reliable instrument to compare the impact of achalasia symptoms on health-related QoL before and after surgery. PMID- 17705086 TI - Laparoscopic versus open liver resection for hepatocellular carcinoma in patients with histologically proven cirrhosis: short- and middle-term results. AB - BACKGROUND: Liver surgery, especially for cirrhotic patients, is one of the last areas of resistance to progress in laparoscopic surgery. This study compares the postoperative results and the 2-year patient outcomes between laparoscopic and open resection for hepatocellular carcinoma in patients with histologically proven cirrhosis. METHODS: From May 2000 to October 2004, 23 consecutive cirrhotic patients who underwent laparoscopic hepatectomy (LH) for HCC were compared in a retrospective analysis with a historic group of 23 patients who underwent open hepatectomy (OH). The two groups were well matched for age, gender, American Society of Anesthesiology (ASA) class, tumor location and size, type of liver resection, and severity of cirrhosis. The selection criteria for both groups specified a small (size < 5 cm), exophytic, or subcapsular tumor located in the left or peripheral right segments of the liver (II-VI segments, Couinaud); a well-compensated cirrhosis (Child-Pugh A); and an ASA score lower than 3. In the LH group, 15 subsegmentectomies, 3 segmentectomies, and 5 left lateral sectionectomies were performed, as compared with 12 subsegmentectomies, 5 segmentectomies, and 6 left lateral sectionectomies in the OH group. RESULTS: One patient in the LH group (4.3%) underwent conversion to laparotomy for inadequate exposition. The mean operative time was statistically longer for the LH group (LH, 148 min; OH, 125 min; p = 0.016), whereas blood transfusions (LH, 0%; OH, 17.3%; p = 0.036), Pringle maneuver (LH, 0%; OH, 21.73%; p = 0.017), mean hospital stay (LH, 8.3 days; OH, 12 days; p = 0.047), and postoperative complications (LH, 13%; OH, 47.8%; p = 0.010) were significantly greater in OH group. There was no statistically significant difference in mortality and 2-year survival rates between the two groups. CONCLUSION: This study shows that LH for HCC in properly selected cirrhotic patients results in fewer early postoperative complications and a shorter hospital stay than the traditional OH. The 2-year survival rate was the same for LH and OH. PMID- 17705087 TI - Experienced surgeons can do more than one thing at a time: effect of distraction on performance of a simple laparoscopic and cognitive task by experienced and novice surgeons. AB - BACKGROUND: While operating, surgeons are required to make cognitive decisions and often are interrupted to attend to questions from other members of the health care team. Technical automatization may be achieved by experienced surgeons such that these distractions have little effect on performance of either the surgical or the cognitive task. This study assessed the effect of adding a distracting cognitive task on performance of a basic laparoscopic skill by novice and experienced surgeons. METHODS: In this study, 31 novice (medical students in postgraduate years [PGYs] 1-2) and 9 experienced (fellows/attendants and PGYs 4 5) laparoscopic surgeons practiced the Fundamentals of Laparoscopic Surgery (FLS) laparoscopic peg transfer task until their scores stabilized. The mean normalized score after five repetitions then was recorded. The subjects also were tested on the number of mathematical addition questions they could answer in 1 min. This was repeated five times, with the mean number of questions attempted and the accuracy (% correct) recorded. The laparoscopic and addition tasks then were performed concurrently five times. Data, presented as mean +/- standard deviation, were analyzed using Student's t-test. A p value less than 0.05 was considered statistically significant. RESULTS: After practice to stable peg transfer performance, the baseline peg transfer score was higher in the experienced group (98 +/- 6 vs 87 +/- 12; p < 0.01). There were no baseline differences between the groups in the number of math questions attempted in 1 min (10 +/- 2 vs 9 +/- 2; p = 0.55) or the number of correct answers (9 +/- 3 vs 8 +/ 3; p = 0.36). The comparison of baseline performance and dual-task performance showed that the experienced surgeons had no decline in peg transfer score (98 +/- 6 vs 97 +/- 6; p = 0.48), number of questions attempted in 1 min (10 +/- 2 vs 9 +/- 3; p = 0.32), or number of correct answers (9 +/- 3 vs 8 +/- 3; p = 0.46). In contrast, dual-tasking among the novices was associated with a decrease in the number of questions attempted (9 +/- 2 vs 8 +/- 2; p < 0.01) and the number of correct answers (8 +/- 3 vs 7 +/- 2; p = 0.02), and with no change in the peg transfer score (87 +/- 12 vs 88 +/- 8; p = 0.38) compared with baseline. CONCLUSIONS: Distraction significantly decreased a novice's ability to process cognitively based math problems, whereas there was no effect on experienced subjects. This occurred despite the fact that the novice group had practiced to high-level peg transfer scores at baseline. This suggests that the experienced surgeons had achieved automatization of the peg transfer basic surgical skill to a level that cognitive distraction did not affect performance of either task. The experienced surgeons were able to attend equally to both tasks, whereas the novices attended to the surgical task at the expense of some aspects of cognitive task performance. PMID- 17705088 TI - Postoperative hypoesthesia and pain: qualitative assessment after open and laparoscopic inguinal hernia repair. AB - BACKGROUND: Chronic pain is an important outcome variable after inguinal hernia repair that is generally not assessed by objective methods. The aim of this study was to objectively investigate chronic pain and hypoesthesia after inguinal hernia repair using three types of operation: open suture, open mesh, and laparoscopic. METHODS: A total of 96 patients were included in the study with a median follow-up of 4.7 years. Open suture repair was performed in 40 patients (group A), open mesh repair in 20 patients (group B), and laparoscopic repair in 36 patients (group C). Hypoesthesia and pain were assessed using von Frey monofilaments. Quality of life was investigated with Short Form 36. RESULTS: Pain occurring at least once a week was found in 7 (17.5%) patients of group A, in 5 (25%) patients of group B, and in 6 (16.6%) patients of group C. Area and intensity of hyposensibility were increased significantly after open nonmesh and mesh repair compared to those after laparoscopy (p = 0.01). Hyposensibility in patients who had laparoscopic hernia repair was significantly associated with postoperative pain (p = 0.03). Type of postoperative pain was somatic in 19 (61%), neuropathic in 9 (29%), and visceral in 3 (10%) patients without significant differences between the three groups. CONCLUSIONS: The incidence of hypoesthesia in patients who had laparoscopic hernia repair is significantly lower than in those who had open hernia repair. Hypoesthesia after laparoscopic but not after open repair is significantly associated with postoperative pain. Von Frey monofilaments are important tools for the assessment of inguinal hypoesthesia and pain in patients who had inguinal hernia repair allowing quantitative and qualitative comparison between various surgical techniques. PMID- 17705089 TI - A phase II study of gemcitabine and capecitabine in advanced cholangiocarcinoma and carcinoma of the gallbladder: a single-institution prospective study. AB - AIM: To determine the clinical benefit response (CBR), time to tumor progression (TTP), overall survival, and effect on quality of life (QOL) of gemcitabine and capecitabine in patients with advanced biliary cancer. METHODS: Gemcitabine (1000 mg/m2 i.v. over 30 minutes on days 1 and 8) and capecitabine (650 mg/m2 orally twice daily for 14 days) were administered and repeated every 21 days. All patients completed the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire and Pancreatic Cancer Module (EORTC QLQ-C30 PAN 26) questionnaire on day 1 of each cycle. Cumulative QOL scores were calculated. The two-stage design required 17 patients to evaluate the confirmed response at nine weeks. RESULTS: Twelve patients with a median age of 54 years were enrolled. A median of eight cycles per patient were completed. With a median follow-up of 18.2 months, the CBR (two partial response and five stable disease) was 58% [95% confidence interval (CI) 28-85%]. Four out of seven patients with CBR had no decline in QOL with chemotherapy. The probability of survival at one year was 0.58. Median TTP and overall survival were 9.0 and 14.0 months, respectively. Nine patients had grade 3 or 4 toxicities. There were no treatment related deaths. CONCLUSIONS: Gemcitabine and capecitabine at this dose and schedule are well tolerated and effective and may offer clinical benefit and maintain QOL in patients with advanced biliary cancer. This regimen merits further investigation in the neoadjuvant setting. PMID- 17705090 TI - DCIS of the breast: a look towards discovery and advancements in the field. PMID- 17705091 TI - Outcome of posthepatectomy-missing colorectal liver metastases after complete response to chemotherapy: impact of adjuvant intra-arterial hepatic oxaliplatin. AB - BACKGROUND: Dramatic responses to chemotherapy are occurring more and more frequently in patients with multiple colorectal liver metastases (LMs), leading to resection. In a few patients, some LMs vanish on imaging studies, remain undetected during hepatectomy, and are left in place, which defines the "missing LMs." The aim of our study was to assess the long-term outcome of such "missing LMs." PATIENTS: Between January 1999 and June 2004, among 228 patients treated for colorectal LMs, missing LMs were observed in 16 patients. All the patients were operated within 4 weeks of imaging. Hepatic arterial infusion (HAI) with oxaliplatin was administrated in 12 patients (75%): seven before hepatectomy and five after. RESULTS: Overall, 69 missing LMs were diagnosed and left in place. Among the persistent LMs resected, a complete pathological response was significantly more often observed in the group with preoperative HAI (6 of 7), than in the group without (2 of 9, P < .02). With a mean follow-up of 51 months (24-90), missing LMs did not reappear in 10 patients (62%). Adjuvant HAI was significantly correlated with the definitive eradication of missing LMs (P < .01), as it was not a complete pathological response. The overall 3-year survival rate of these highly selected 16 patients was 94%. CONCLUSION: Colorectal LMs under chemotherapy that vanish on high-quality imaging studies, remain undetected during hepatectomy, and are left in place, are definitively cured in 62% of cases. This excellent result seems to be due to the administration of adjuvant hepatic arterial infusion of chemotherapy and should stimulate new investigations. PMID- 17705092 TI - A phase-II clinical trial of laparoscopy-assisted distal gastrectomy with D2 lymph node dissection for gastric cancer patients. AB - OBJECTIVES: This study was conducted to determine whether laparoscopy-assisted distal gastrectomy (LADG) with complete D2 lymph node dissection for gastric cancer is a safe and effective surgical option. METHODS: During an 8-month period, 64 patients, who were diagnosed preoperatively as having T1-2, N0-1 or M0 gastric cancer, were prospectively enrolled to undergo LADG with D2 lymph node dissection; two surgeons with experience of over 50 cases of laparoscopic gastrectomy performed the procedures. The compliance rate, defined as cases with no more than one missing lymph node station according to the Japanese Research Society of Gastric Cancer (JRSGC) lymph node grouping, for the open gastrectomy with D2 lymph node dissection was 66.0% in a pilot study and was used for calculations of sample size. Compliance rate and other surgical outcomes, including the number of retrieved lymph nodes from each lymph node station, morbidities, mortalities and conversion rate, were analyzed. RESULTS: The compliance rate was 67.2% and was similar to that of open distal gastrectomy reported in the pilot study. The mean number of retrieved lymph nodes was 50.1 (range 20-100). The most frequently missed lymph node station was no. 5 (31.2%) followed by no. 3 (25.0%). There were no missed lymph nodes at stations no. 6 and 9. The complication rate was 3.1% (2/66); there were two conversions (3.0%) and no mortalities. CONCLUSIONS: The current study suggests that LADG with D2 lymph node dissection is oncologically feasible, and phase-III clinical trials will be needed. PMID- 17705093 TI - Isolation and identification of a non-haemagglutinating strain of rabbit hemorrhagic disease virus from China and sequence analysis for the VP60 Gene. AB - A variant strain of rabbit hemorrhagic disease virus, designated "whn-1", was isolated and identified in China. The virus lacked haemagglutinating activity at 25, 37 and 4 degrees C, respectively, and gave negative results in the HAT after two passages in experimentally infected rabbits, but gave positive results in Agar Diffusion Reaction (ADR) and Counter Immunoelectrophoresis (CIE). Using electron microscopy, negatively stained particles of the RHDV isolate showed that the virions was approximately 35 nm in diameter. The capsid protein VP60 gene of whn-1 strain was cloned into pMD18-T vector by RT-PCR assays and sequenced. The obtained VP60 gene sequence has been submitted to GenBank with the accession number: DQ069280. The whole VP60 gene of whn-1 was 1740 nt in size and encodes 579 aa. Alignment with other 16 strains of RHDV in the world, including such "RHDVa" strains as France 99-05, France-Reu-00, Germany-Triptis and ChinaTP, in addition to RCV and EBHSV, showed that the homology of RHDV strains were 90.0 98.0% for nucleotide sequence, 94.3-99.0% for amino acid sequence, respectively. The results indicated that the sequences of VP60 gene of different RHDV isolates, including non-haemagglutinating whn-1 strain and low-haemagglutinating Rainham strain, were relatively highly homologous, and the major variant amino acid were located within region C (301-328 aa) and region E(344-434 aa), which were specific to "RHDVa" strains. Moreover, the molecular characterisation of VP60 protein of RHDV whn-1 strain, such as Hydrophilicity plot, Flexible regions, Antigenic index, etc., were compared with reference RHDV strains of Spanish AST/89, France-99-5 and UK-Rainham in this article. From the experiment, it's concluded that, the "whn-1" strain is probably an antigenic variant of "RHDVa", and the 3 amino acids of Phe (304), Ala (305), Ser (309), and 5 amino acids of Gly (359), Asn (365), Ala (369), Ala (370), Asn (386), located in P2 region in the VP60 protein, probably played an important role in the haemagglutination activity. PMID- 17705094 TI - Moving from fact to policy: housing is HIV prevention and health care. AB - A growing body of empirical evidence shows strong correlations between improved housing status and reduced HIV risk behaviors, improved access to health care for persons living with HIV/AIDS, and better health outcomes. These findings support the provision of housing assistance for low-income persons living with HIV/AIDS: as a basic human right; as a necessary component of systems to enable individuals to manage their HIV/AIDS care and treatment; and as an exciting new tool to end the AIDS crisis in America by reducing the number of new HIV infections. This paper provides a public policy framework for consideration of the research reported in this special issue of AIDS and Behavior, and offers suggestions for using research to move policy and practice towards a true public health response to the housing needs of persons at risk for or living with HIV/AIDS. PMID- 17705095 TI - Men who have sex with transgender women: challenges to category-based HIV prevention. AB - Although transgender women are acknowledged as a priority population for HIV prevention, there is little knowledge on men who have sex with transgender women (MSTGWs). MSTGWs challenge conventional sexual orientation categories in public health and HIV prevention research, and warrant increased attention from the public health community. This paper used qualitative techniques to analyze how MSTGWs describe their sexual orientation identities, and to explore the correspondence between men's identities and sexual behaviors with transgender women. We conducted in-depth semi-structured individual interviews with 46 MSTGWs in San Francisco. We observed a diversity in the ways participants identified and explained their sexual orientation, and found no consistent patterns between how men described their sexual orientation identity versus their sexual behavior and attraction to transgender women. Findings from this qualitative study question the utility of category-based approaches to HIV prevention with MSTGWs and offer insights into developing HIV interventions for these men. PMID- 17705096 TI - HIV illness representation as a predictor of self-care management and health outcomes: a multi-site, cross-cultural study. AB - Research has shown that the perceptions that form the cognitive representation of an illness (illness representation) are fundamental to how persons cope with illness. This study examined the relationship of illness representation of HIV with self-care behavior and health outcomes. Data were collected at 16 sites in the United States, Taiwan, Norway, Puerto Rico and Colombia via survey. HIV seropositive participants (n = 1,217, 31% female, 38% African-American/Black, 10% Asian/Pacific Islander and 26% White/Anglo) completed measures of illness representation based on the commonly accepted five-component structure: identity, time-line, consequences, cause, and cure/controllability (Weinman et al. 1996, Psychology and Health, 11, 431-445). Linear regression analyses were conducted to investigate relationships among illness representation, self-care behaviors and quality-of-life outcomes. Components of illness representation were associated with self-care and health outcomes, indicating that the cognitive representation of HIV has consequences for effective illness management. For example, perception that there is little that can be done to control HIV was significantly associated with fewer and less effective self-care activities (F = 12.86, P < .001) and poorer health function in the domain of quality-of-life (F = 13.89, P < .001). The concept of illness representation provides a useful framework for understanding HIV symptom management and may be useful in directing development of effective patient-centered interventions. PMID- 17705097 TI - Inflammation, depression and dementia: are they connected? AB - Chronic inflammation is now considered to be central to the pathogenesis not only of such medical disorders as cardiovascular disease, multiple sclerosis, diabetes and cancer but also of major depression. If chronic inflammatory changes are a common feature of depression, this could predispose depressed patients to neurodegenerative changes in later life. Indeed there is now clinical evidence that depression is a common antecedent of Alzheimer's disease and may be an early manifestation of dementia before the cognitive declines becomes apparent. This review summarises the evidence that links chronic low grade inflammation with changes in brain structure that could precipitate neurodegenerative changes associated with Alzheimer's disease and other dementias. For example, neuronal loss is a common feature of major depression and dementia. It is hypothesised that the progress from depression to dementia could result from the activation of macrophages in the blood, and microglia in the brain, that release pro inflammatory cytokines. Such cytokines stimulate a cascade of inflammatory changes (such as an increase in prostaglandin E2, nitric oxide in addition to more pro-inflammatory cytokines) and a hypersecretion of cortisol. The latter steroid inhibits protein synthesis thereby reducing the synthesis of neurotrophic factors and preventing reairto damages neuronal networks. In addition, neurotoxic end products of the tryptophan-kynurenine pathway, such as quinolinic acid, accumulate in astrocytes and neurons in both depression and dementia. Thus increased neurodegeneration, reduced neuroprotection and neuronal repair are common pathological features of major depression and dementia. Such changes may help to explain why major depression is a frequent prelude to dementia in later life. PMID- 17705098 TI - The role of emotion regulation in the treatment of child anxiety disorders. AB - In this review, we examine the role of emotion regulation in the treatment of children with anxiety disorders. Cognitive-behavioral therapy (CBT) has been shown to "work" for children with anxiety disorders and it has been categorized as an evidence-based treatment. However, most studies have shown that the treatment is effective for about 60-70% of children, leaving the remaining children symptomatic and oftentimes with persisting psychological disorders. Of importance, it has also been shown that many children with anxiety disorders demonstrate poor emotion regulation skills. Despite these findings, little attention has been directed toward incorporating emotion regulation strategies into these relatively effective cognitive-behavioral treatments. It is possible that CBT programs do not work as well for a portion of children because their emotion regulation deficits, if present, are not being targeted sufficiently. In this review, it is suggested that adding an emotion regulation component could increase treatment efficacy. In addition, strategies aimed at improving emotion regulation at the individual level and at the family level are introduced. Details of how improved emotion regulation skills could be beneficial in bringing about change are discussed. Finally, issues of measurement and the clinical implications for research and practice are considered. PMID- 17705100 TI - Loss of a preterm infant: psychological aspects in parents. AB - QUESTIONS UNDER STUDY: The unexpected death of a preterm infant is an extremely painful situation for parents. Despite a number of quantitative studies, little is known about parents' inner experience. The aim of this study was to gather more in-depth information about what preoccupies parents in this situation of suffering, thus leading to a deeper understanding of their dealing with the stressful event and enabling more adequate support to be provided by professionals. 10 mothers and 9 fathers, who had lost their extremely premature infant born between 24 and 26 weeks of gestation were invited for a semi structured interview and retrospectively asked about their emotional, cognitive, physical and social experience at three different points in time (time of hospitalisation, 6 months and 3.5-6.5 years after the loss). The interviews were analysed by method of qualitative context analysis. RESULTS: The loss of a preterm infant is an extremely intense experience for parents resulting in a rollercoaster of emotions and perceptions as well as relevant effects on the social network. The strain of this situation notwithstanding, parents also experience positive aspects, eg, feelings of closeness to their infant, comforting thoughts or help from their social network. Although still mourning the loss of their baby, most parents have overcome the tragic event. CONCLUSIONS: Most parents seem to have the psychological strength to overcome the traumatic experience of losing their premature infant and are able to face life normally again. Professionals can play an important role in supporting them. Some parents require additional help to overcome the loss. PMID- 17705099 TI - Bronchial hyper-responsiveness and exhaled nitric oxide in chronic obstructive pulmonary disease. AB - Several lung diseases including asthma and chronic obstructive pulmonary disease (COPD) involve chronic inflammation of the airways. Therefore, there is great interest in non-invasive methods assessing airway inflammation. Measurement of bronchial hyper-responsiveness (BHR) and exhaled nitric oxide (NO) are such indirect markers of airway inflammation. Additional information about severity of disease, prognosis and possible response to anti-inflammatory treatment with inhaled corticosteroids can be gained by these methods. However, they are not yet established in assessing patients with COPD in clinical routine. BHR has long been recognised as a hallmark of asthma. Less is known about prevalence and clinical relevance of BHR in the general population and in COPD patients. Longitudinal studies have shown that BHR in healthy persons is a risk factor for development of respiratory symptoms, asthma and COPD. BHR has also been shown to increase the detrimental effect of cigarette smoke and is associated with a decline in lung function. Furthermore, studies indicate that the presence of BHR is a prognostic factor in COPD. Increased BHR to histamine has been shown to be a predictor for mortality in COPD patients. Based on current guidelines, treatment of patients with severe COPD (GOLD stage III and IV) and regular exacerbations includes therapy with inhaled corticosteroids. Inhaled corticosteroids have been shown to reduce frequency of exacerbations but they have not been shown to modify long-term decline in FEV1. However, one small study found that BHR to inhaled mannitol could possibly predict responsiveness to inhaled corticosteroids in patients with moderately severe COPD and identify a subgroup of patients that is likely to benefit from this treatment. Exhaled NO has been shown to correlate with other inflammatory markers and to be elevated in asthma. In COPD patients, data is inconsistent. However, measuring exhaled NO may have a role in the identification of patients with severe, unstable COPD who were shown to have higher NO levels compared to patients with stable COPD. This suggests that exhaled NO might be a method to assess and monitor disease activity in COPD. Possible explanations for the contradictory results are different measurement techniques of exhaled NO and different smoking histories of patients in various studies. Smoking has been found to be a confounding factor by reducing NO levels significantly, an effect which might counteract the potentially increased exhaled NO due to airway inflammation. In conclusion, measuring BHR and exhaled NO in patients with COPD might provide additional information about disease severity, prognosis and possible response to anti-inflammatory medical treatment. However, to establish these methods in clinical routine in COPD patients, more data is clearly needed. PMID- 17705101 TI - Clinical recognition and treatment of atrial ectopic tachycardia in newborns. AB - QUESTIONS: Atrial ectopic tachycardia (AET) may be difficult to diagnose in neonates and treatment can be complex especially in case of severe heart failure. This study addresses the clinical recognition and drug therapy of AET in neonates. METHODS: Retrospective chart and database review of neonates diagnosed with AET between 1994 and 2002. RESULTS: AET was diagnosed in 19 neonates at a median age of 18 days (range 0-64). A paroxysmal AET pattern was seen in 10 and a permanent in 9 patients. Tachycardia in the foetal or neonatal period indicated an arrhythmia in 8 patients while 11 showed non-specific symptoms. Severely depressed ventricular dysfunction was observed in 2 patients necessitating cardiovascular resuscitation in 1. The mean maximum paroxysmal AET rate was 213 bpm (range 178-227). For permanent AET, the median mean heart rate was 169 bpm (153-185) and the mean maximum heart rate was 212 bpm (range 196-274). Antiarrhythmic class Ic and III drugs alone or as combination therapy controlled AET in all 18 treated neonates and ventricular dysfunctions resolved. Proarrhythmic drug side effects were seen in 1 patient under propafenone therapy. CONCLUSIONS: AET in neonates is frequently recognised as paroxysmal or permanent tachycardia. Symptoms are often non-specific even though neonates and infants may develop severe ventricular dysfunction. A high degree of awareness is mandatory for neonatologists, paediatricians and primary care physicians to recognise AET in neonates. Class Ic and III antiarrhythmic drugs are effective in the treatment of neonatal AET. Monitoring for proarrhythmic drug side effects is mandatory. PMID- 17705102 TI - Successful use of activated recombinant factor VII in life threatening bleeding after thoracic surgery. AB - We present three patients in whom life-threatening haemorrhage following lung resection was successfully managed using activated recombinant factor VII (NovoSeven). In one case, activated recombinant factor VII was the only therapy administered to manage bleeding, and in the two remaining cases, activated recombinant factor VII was administered after patients failed to respond to conventional therapy. All patients demonstrated effective haemostasis and improved coagulation parameters as a result of treatment with activated recombinant factor VII. Our experience with the clinical use of rFVIIa suggests that this agent may provide effective hemostasis following lifethreatening postoperative bleeding after major thoracic surgery. Despite these favorable results, randomized, placebo - controlled trials are needed to identify optimal treatment strategy, patient selection, and safety of treatment in patients with massive bleeding following major thoracic surgery. PMID- 17705103 TI - Complement inhibition by anti-C5 antibodies--from bench to bedside and back again. AB - The complement system is an important part of the innate immune system with pro inflammatory and regulatory functions. Although many experimental studies have demonstrated that complement inhibition might be advantageous in a number of different human diseases, complement inhibition is still not part of the clinical treatment routine. With blocking antibodies against complement C5 a new generation of therapeutic complement inhibitors has now been investigated in some human diseases. This review gives an overview on the new complement inhibitors and the results obtained in clinical studies thus far. PMID- 17705105 TI - Dietary intake and physical activity of normal weight and overweight 6 to 14 year old Swiss children. AB - PRINCIPLES AND QUESTIONS UNDER STUDY: The prevalence of overweight is increasing in Swiss children, and they are at increased risk for hypertension and insulin resistance. Better understanding of how food intakes and activity patterns differ between overweight and normal weight children is needed to develop intervention strategies to control childhood adiposity. The aim of the study was therefore to compare nutrient intake, dietary patterns and physical activity in overweight and normal weight children in Switzerland. METHODS: The subjects were healthy 6 to 14 year-old normal weight and overweight children (n=74 and n=68 respectively). Dietary intakes were assessed during three home visits with two 24-hour recalls and one 1-day food record. Questionnaires on physical activity and social background were completed. RESULTS: The carbohydrate and fat contents of the diet as a percent of energy did not differ comparing normal and overweight children, but the percentage of protein was significantly higher in overweight children. Intakes of energy, carbohydrates and fat were not significantly correlated with body mass index (BMI) standard deviation scores (SDS) after controlling for age, gender and total energy (for carbohydrates and fat). However, protein intake significantly predicted BMI-SDS after controlling for age, gender and total energy. Similarly, meat intake predicted BMI-SDS after controlling for age, gender and total energy, but none of the other analysed food groups were predictors. Time spent watching television and time spent in organised sports activity were significantly correlated with BMI-SDS. The educational level of mothers of overweight children was significantly lower than of mothers of normal weight children. CONCLUSION: Intakes of fat and saturated fat in Swiss children are 20% and 50% higher, respectively than recommended intakes. Higher protein intake, higher intake of meat and more hours spent watching TV and playing computer games are associated with overweight in primary school-aged Swiss children. PMID- 17705104 TI - Interferon and ribavirin with or without amantadine for interferon non-responders with chronic hepatitis C. A randomized, controlled pilot study. AB - BACKGROUND/AIMS: Treatment options for interferon-non-responders (INF-NR) with chronic hepatitis C are limited. Our aim was to compare efficacy and tolerability of an interferon-alfa-2a (INF), ribavirin (RIBA) and amantadine (AMA) combination with those of an INF and RIBA combination. METHODS: 30 patients with biopsy proven chronic hepatitis C were randomised to INFRIBA-AMA or INF-RIBA, stratified according to genotype (1/4 versus 2/3) and presence or absence of cirrhosis. They were treated with INF 6 million units subcutaneously daily for the first four weeks, RIBA (>or=75 kg 1200 mg, <75 kg 1000 mg) with or without AMA 200 mg daily. If serum hepatitis C RNA was undetectable after 28 days, therapy was continued for a total of 48 weeks and INF was reduced to 6 million units thrice weekly (tiw). After stopping therapy all patients were followed up for six months. RESULTS: The end of treatment response was 25% (4/16) after INF-RIBA-AMA and 29% (4/14) after INF-RIBA, and a sustained virologic response (SVR) was observed in 19% (3/16) in the triple therapy group compared to 14% (2/14) in the double therapy group, with a similar safety and tolerability profile. CONCLUSION: Although similarly tolerated triple combination with INF, RIBA and AMA does not seem to offer relevant efficacy advantages over double combination with INF and RIBA in INF non-responders with chronic hepatitis C. PMID- 17705106 TI - Obesity is associated with increased serum TSH level, independent of thyroid function. AB - OBJECTIVE: To reinvestigate the relationship between circulating TSH levels and adiposity in a cohort of obese people, who have normal thyroid function. METHODS: Retrospective cross-sectional analysis was carried out on 226 euthyroid obese or overweight female patients. Thirty-nine female lean and euthyroid subjects (BMI<25 kg/m2) were included in the study group. TSH, free thyroxine (FT4), free triiodothyronine (FT3), fasting plasma levels of insulin and glucose, homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and insulin secretion (HOMA-b cell), body weight, height, body mass index (BMI) and waist circumference were assessed. RESULTS: Serum TSH levels were higher in the obese than in the lean subjects. In the study group (lean and obese subjects), there was a significant positive correlation between serum TSH and body weight (r=0.231, p<0.001), BMI (r=0.270, p<0.001), waist circumference (r=0.219, p=0.001), fasting insulin (r=0.201, p=0.002) and HOMA-IR (r=0.201, p=0.002); there was no correlation between serum FT4 and any of the parameters. A multivariate linear regression analysis revealed that only BMI (p=0.012, 95% CI=0.01-0.08) contributed significantly to the variance of TSH. CONCLUSIONS: This study strongly supports existing, but contradictory evidence that serum TSH levels are positively correlated with the degree of obesity and some of its metabolic consequences in overweight people with normal thyroid function. PMID- 17705107 TI - The endothelium and genetics in pulmonary arterial hypertension. AB - There have been tremendous progresses in research and improvement in therapeutic options for pulmonary arterial hypertension (PAH) and other types of pulmonary hypertension (PH) over the last 15 years. PAH and other PH have been shown to present similar histopathologic changes and therefore, do not indicate lung biopsies for a specific diagnosis. This may be due to shared physiopathologic mechanisms, involving initially endothelial alterations, leading to three main changes: vasoconstrictive phenomena, growth factor releases, leading to small vessel remodelling and to thrombotic phenomena. Genetic polymorphisms have been discovered in two genes of the transforming growth factor family (the bone morphogenetic protein receptor II and the activin receptor-like kinase) and one in the serotonin transporter gene. The genetic findings are not yet applicable for genetic counselling, but the physiopathologic discoveries have allowed major therapeutic progresses. PMID- 17705108 TI - First delivery of healthy offspring after freezing and thawing of oocytes in Switzerland. AB - The interest in long-term storage of uninseminated oocytes through cryopreservation has seen a recent upsurge, because it provides the potential to assist young women to postpone childbirth after having overcome a malignant disease or delaying childbirth until after management of a professional career. The low fertilisation rate of frozen/thawed oocytes in earlier feasibility trials can now be improved by using intracytoplasmic sperm injection (ICSI) for assisting the penetration of the spermatozoon through the oocyte's hardened zona pellucida. Another reason for the reported low success rates of oocyte cryopreservation in earlier studies may have been the low developmental potential of spare oocytes, which were available for experimental cryopreservation. Oocytes retrieved from supernumerary follicles in women treated with gonadotropins for ovulation induction and intrauterine insemination can be used for the optimisation of cryostorage of uninseminated oocytes. We intended to investigate to what extent the well-established and successful cryopreservation protocols for pronucleate oocytes are also applicable for the cryopreservation of uninseminated oocytes. We herewith report the first successful pregnancy and delivery of frozen/thawed oocytes in Switzerland, which were inseminated with ICSI. In unbiased treatment groups the freezing and thawing of uninseminated oocytes and pronucleate oocytes give comparable results, if the additional manipulation during ICSI was taken into account. PMID- 17705109 TI - Work-related behaviour and experience patterns of physicians compared to other professions. AB - OBJECTIVES: To identify health risk factors and resources of physicians in comparison with other professions. METHODS: Data of cross-sectional mail surveys conducted among German physicians (n = 344), teachers (n = 5169), policemen (n = 851), prison officers (n = 3653), and starting entrepreneurs (n = 632) were analysed regarding eleven health-relevant dimensions and four behaviour patterns examined by the questionnaire "Work-Related Behaviour and Experience Pattern (AVEM)". RESULTS: Only 17% of the physicians showed healthy behaviour and experience patterns. With 43%, they scored highest in terms of reduced working motivation. Together with the teachers, they also had the highest scores for resignation and burnout (27%). Satisfaction with life and work as well as social support showed medium scores. Starting entrepreneurs showed the healthiest patterns (45%), but also the highest risk pattern for overexertion (38%). CONCLUSIONS: It was possible to identify clear risk patterns for profession related psychosocial symptoms and impairments. The high scores for reduced working motivation demonstrate the need for interventions to improve organisation of health care and individual coping strategies. PMID- 17705110 TI - Impact of tonsillectomy on quality of life in adults with chronic tonsillitis. AB - OBJECTIVES: Tonsillectomy is one of the most frequently performed surgical procedures. Nevertheless there is less known about the impact of this procedure on Health-Related Quality of life (HRQOL). The two different most common used surgical techniques are "cold" (CT) and "hot" (HT) tonsillectomy. The aim of this study was to measure patients' HRQOL-benefit after adult tonsillectomy with the indication of chronic tonsillitis and to compare HT and CT. METHODS: The Glasgow Benefit Inventory (GBI) was used to quantify the health benefit of CT and HT retrospectively in 600 patients aged 16 years and older. RESULTS: 227 of the patients returned the completed surveys. Mean total GBI score was 15.8 (18 SD, 13.2-18.4 CI) for CT and 11.6 (15 SD, 7-16.3 CI) for HT (p = 0.214). Patients reported an improvement in HRQOL in all GBI subscales. We could not find a significant difference in reported HRQOL benefit between HT and CT. CONCLUSION: Adult tonsillectomy, HT as well as CT, for the indication of chronic tonsillitis provides an improvement in HRQOL. This positive impact of tonsillectomy in patients with chronic tonsillitis should be considered in the clinical decision making process for tonsillectomy. PMID- 17705111 TI - Does a negative D-dimer test rule out aortic dissection? PMID- 17705112 TI - Digital mammography screening: average glandular dose and first performance parameters. AB - PURPOSE: The Radiation Protection Commission demanded structured implementation of digital mammography screening in Germany. The main requirements were the installation of digital reference centers and separate evaluation of the fully digitized screening units. Digital mammography screening must meet the quality standards of the European guidelines and must be compared to analog screening results. We analyzed early surrogate indicators of effective screening and dosage levels for the first German digital screening unit in a routine setting after the first half of the initial screening round. MATERIALS AND METHODS: We used three digital mammography screening units (one full-field digital scanner [DR] and two computed radiography systems [CR]). Each system has been proven to fulfill the requirements of the National and European guidelines. The radiation exposure levels, the medical workflow and the histological results were documented in a central electronic screening record. RESULTS: In the first year 11,413 women were screened (participation rate 57.5 %). The parenchymal dosages for the three mammographic X-ray systems, averaged for the different breast sizes, were 0.7 (DR), 1.3 (CR), 1.5 (CR) mGy. 7 % of the screened women needed to undergo further examinations. The total number of screen-detected cancers was 129 (detection rate 1.1 %). 21 % of the carcinomas were classified as ductal carcinomas in situ, 40 % of the invasive carcinomas had a histological size 70 bpm. Images were reconstructed in 10 % increments from 10 - 100 % of the RR interval. Two blinded experienced observers independently calculated Agatston (AS), calcium mass (MS) and volume scores (VS) for every reconstructed image series. The results were compared to similar studies for 16-slice CT scanners. RESULTS: The mean values and mean coefficients of variation among all patients were as follows: AS, 397 +/- 829, 109 % MS, 88 +/- 225, 154 % VS, 335 +/ 669, 100 %. Regarding the reconstruction intervals, the mean coefficients of variation were as follows: 107 % (AS), 97 % (VS), 116 % (MS). No specific image reconstruction interval with statistically significant lower variability for each score could be identified. High inter-observer agreement was achieved (K = 0.98). With statistical significance (p < 0.05) 10/30 patients (pts) were able to be allocated to more than one risk group (RG): 6 pts = 2 RG; 3 pts = 3 RG; 1 pts = 4 RG. The scores for 5/30 patients were zero for at least one reconstruction interval, but further reconstructions revealed calcifications. The number of patients assignable to different risk groups was significantly lower compared to published data using a 16-slice scanner (p < 0.05). CONCLUSION: Coronary calcium scores determined using a 64-slice scanner display a wide range of variability depending on the image reconstruction interval as already described for 16-slice CT scanners. However, compared to previous studies, our data indicate that this vendor's generation of scanners reduces the influence of score variations on the risk stratification. PMID- 17705117 TI - [High-resolution MRI for the quantitative evaluation of subendocardial and subepicardial perfusion under pharmacological stress and at rest]. AB - PURPOSE: MR stress perfusion imaging of the heart allows the quantification of myocardial perfusion and the evaluation of myocardial perfusion reserve (MPR) and the ratio of subendocardial to subepicardial perfusion at rest and under adenosine stress. The aim of this study was to evaluate a high-resolution GRAPPA sequence for quantitative MR first pass perfusion imaging in healthy volunteers. MATERIALS AND METHODS: First pass stress and rest perfusion studies were performed on 10 healthy volunteers using a 1.5 T MR scanner with a multislice SR TrueFISP first pass perfusion sequence with a GRAPPA algorithm (acceleration factor 3) in prebolus technique and an image resolution of 1.8 x 1.8 mm. For the comparison group, we examined 12 different healthy volunteers with a standard first pass perfusion SR-TrueFISP sequence using a resolution of 2.7 x 3.3 mm. Myocardial contours were manually delineated followed by an automatic division of the myocardium into two rings with an equal thickness for the subendo- and subepicardial layer. Eight sectors per slice were evaluated using contamination and baseline correction. RESULTS: Using the GRAPPA sequence, the ratio of subendo to subepimyocardial perfusion was 1.18 +/- 0.32 for the examination at rest. Under pharmacologically induced stress, the ratio was 1.08 +/- 0.27. For the standard sequence the ratio was 1.15 +/- 0.28 at rest and 1.11 +/- 0.33 under stress. For the high resolution sequence higher mean values for the subendo- to subepimyocardial ratio were obtained with comparable standard deviations. The difference between the sequences was not significant. CONCLUSION: The evaluation of subendomyocardial and subepimyocardial perfusion is feasible with a high resolution first pass perfusion sequence. The use of a higher resolution to avoid systematic error leads to increased image noise. However, no relevant reduction in the quantitative perfusion values under stress and at rest was able to be depicted. PMID- 17705118 TI - [Transjugular intrahepatic portosystemic shunt: evaluation of the impact of the stent's configuration on the patency rate]. AB - PURPOSE: To evaluate the impact of the configuration of the stent on the patency rate after transjugular intrahepatic portosystemic shunt with a self-expanding stent. MATERIALS AND METHODS: In total, 80 patients (60 male, 20 female; mean age 56 +/- 9.6, range 37 - 81) with a transjugular intrahepatic portosystemic shunt were evaluated. The primary technical success rate, interventional revision rate, and mean patency rate according to Kaplan-Meier were calculated. The angle of deviation of the blood flow at the portal venous inflow and central venous outflow were measured on projected angiograms (valid cases, n = 78). The following five angle groups were established: 1. portal venous inflow, 2. central venous outflow, 3. maximum, angle, 4. minimum angle, and 5. sum of both angles in the shunt system. Within each group, the Mann-Whitney Test and after dichotomic partition using the median Pearson's Chi-Square Test and Fisher's Exact Test were carried out to prove the dependency of the patency on the stent's configuration. RESULTS: The primary technical success rate was 93 %, the interventional revision rate was 28 %, and the mean patency rate was 17.5 months. The mean/standard deviation/median angle were as follows: 1. portal venous inflow 66.5 degrees / 19.2 degrees / 65 degrees , 2. central venous outflow 43.7 degrees / 14.0 degrees / 40 degrees , 3. maximum angle 69.1 degrees / 16.3 degrees / 65 degrees , 4. minimum angle 40.6 degrees / 13.3 degrees / 40 degrees , and 5. sum of both angles 110.2 degrees / 21.8 degrees / 110 degrees . The 2-sided values of significance in the Mann-Whitney Test/Chi-Square Test/Exact-Fisher Test were as follows: 1. portal venous inflow 0.112 / 0.066 / 0.083, 2. central venous outflow 0.960 / 0.919 / 1.000, 3. maximum angle 0.151 / 0.042 / 0.056, 4. minimum angle 0.578 / 0.622 / 0.632, and 5. sum of both angles 0.104 / 0.111 / 0.140. CONCLUSION: The shunt's patency rate when using a self-expanding stent is not dependent on the stent's configuration regarding the deviation of the blood flow at the portal venous inflow and central venous outflow, and the maximum, minimum and total deviation in the shunt. PMID- 17705119 TI - [Splenosis: the heterotopic autotransplantation of splenic tissue]. PMID- 17705121 TI - [Thrombosed aneurysm of the vena cava inferior]. PMID- 17705120 TI - [Metastatic follicular thyroid carcinoma imitates glomus jugulare tumor]. PMID- 17705129 TI - Modulation of dendritic cell differentiation and function by YopJ of Yersinia pestis. AB - Yersinia pestis evades immune responses in part by injecting into host immune cells several effector proteins called Yersinia outer proteins (Yops) that impair cellular function. This has been best characterized in the innate effector cells, but much less so for cells involved in adaptive immune responses. Dendritic cells (DC) sit at the crossroads between innate and adaptive immunity, and can function to initiate or inhibit adaptive immune responses. Although Y. pestis can target and inactivate DC, the mechanism responsible for this remains unclear. We have found that injection of Y. pestis YopJ into DC progenitors disrupts key signal transduction pathways and interferes with DC differentiation and subsequent function. YopJ injection prevents up-regulation of the NF-kappaB transcription factor Rel B and inhibits MAPK/ERK activation--both having key roles in DC differentiation. Furthermore, YopJ injection prevents costimulatory ligand up regulation, LPS-induced cytokine expression, and yields differentiated DC with diminished capability to induce T cell proliferation and IFN-gamma induction. By modulating DC function through YopJ-mediated disruption of signaling pathways during progenitor to DC differentiation, Yersinia may interfere with the adaptive responses necessary to clear the infection as well as establish a tolerant immune environment that leads to chronic infection/carrier state in the surviving host. PMID- 17705130 TI - Vaccination with plasmacytoid dendritic cells induces protection against infection with Leishmania major in mice. AB - DC-based vaccination against Leishmania major induces a parasite-specific Th1 response and long-lasting protective immunity in susceptible mice. Since distinct DC subsets have been proposed to direct the predominant development of either Th1 or Th2 cells, we analyzed the capability of plasmacytoid DC (pDC) to induce protection and elicit a Th1 response against L. major. Pulsing with L. major lysate induced the activation and maturation of semi-mature murine pDC that had been isolated from the spleen, as indicated by up-regulation of the co stimulatory molecules CD86 and CD80, but did not enhance the level of IFN-alpha secretion by pDC. Vaccination of susceptible mice with L. major lysate-pulsed pDC induced highly effective T cell-mediated immunity against subsequent infection with L. major parasites. Surprisingly, the protection was not accompanied by a polarized Th1 cytokine profile. Co-activation of pDC with CpG-containing oligodeoxynucleotides, which has been shown to be critical for activating the protective potential of myeloid DC, was not required for the protective effect of L. major antigen-pulsed pDC. These findings demonstrate that antigen-loaded pDC are able to induce T cell-mediated protection against a parasite disease and that experimental leishmaniasis is a suitable model to elucidate the mechanisms underlying DC-based vaccination against infections. PMID- 17705131 TI - Nod1 and Nod2 induce CCL5/RANTES through the NF-kappaB pathway. AB - The Nod-like receptor proteins Nod1 and Nod2 participate in innate immune responses against bacteria through intracellular detection of peptidoglycan, a component of bacterial cell wall. Recent evidence has demonstrated that Nod1 stimulates the release of chemokines that attract neutrophils at the site of infection, such as CXCL8/IL-8 in humans, and CXCL1/keratinocyte-derived chemokine and CXCL2/MIP-2 in mice. We aimed to determine whether Nod proteins could trigger the release of CCL5/RANTES, a chemokine known to attract a number of immune cells, but not neutrophils. Our results demonstrate that activation of both Nod1 and Nod2 results in substantial secretion of CCL5 by murine macrophages. Moreover, in vivo, the intraperitoneal injection of murine Nod1 or Nod2 agonists resulted in a rapid secretion of CCL5 into the bloodstream. We also observed that Nod-dependent secretion of CCL5 did not correlate with the induction of the interferon-beta pathway, a major signaling cascade for the activation of CCL5 by viruses. In contrast, we identified a key role of the NF-kappaB pathway in Nod dependent stimulation of the CCL5 promoter. Together, these results identify a novel target downstream of Nod1 and Nod2, which is likely to play a key role in orchestrating the global Nod-dependent immune defense during bacterial infections. PMID- 17705132 TI - Transcriptional control of human T-BET expression: the role of Sp1. AB - Murine T-bet (T-box expressed in T cells) is a master regulator of IFN-gamma gene expression in NK and T cells. T-bet also plays a critical role in autoimmunity, asthma and other diseases. However, cis elements or trans factors responsible for regulating T-bet expression remain largely unknown. Here, we report on our discovery of six Sp1-binding sites within the proximal human T-BET promoter that are highly conserved among mammalian species. Electrophoretic mobility shift assays demonstrate a physical association between Sp1 and the proximal T-BET promoter with a direct dose response between Sp1 expression and T-BET promoter activity. Ectopic overexpression of Sp1 also enhanced T-BET expression and cytokine-induced IFN-gamma secretion in NK cells and T cells. Mithramycin A, which blocks the binding of Sp1 to the T-BET promoter, diminished both T-BET expression and IFN-gamma protein production in monokine-stimulated primary human NK cells. Collectively, our results suggest that Sp1 is a positive transcriptional regulator of T-BET. As T-BET and IFN-gamma are critically important in inflammation, infection, and cancer, targeting Sp1, possibly with mithramycin A, may be useful for preventing and/or treating diseases associated with aberrant T-BET or IFN-gamma expression. PMID- 17705133 TI - Protein kinase C delta is a critical regulator of CD1d-mediated antigen presentation. AB - We have recently demonstrated that the p38 and ERK1/2 MAP kinases play reciprocal roles in the control of CD1d-mediated antigen presentation. Although the use of specific inhibitors for these pathways clearly had an effect, the effects were not complete, leading to speculations that additional pathways were involved. Here, we show that inhibiting protein kinase C delta (PKCdelta) substantially impairs antigen presentation by murine CD1d1 to NKT cells. This effect was accompanied by marked changes in the intracellular localization of CD1d. Expression of a dominant-negative mutant of PKCdelta in CD1d(+) cells resulted in nearly undetectable endogenous antigen presentation, substantially impaired CD1d recycling, a decrease in MAPK activation, and a decrease in the ability to present low (but not high) concentrations of alpha-galactosylceramide at the cell surface. These data strongly suggest that PKCdelta is a critical regulator of CD1d-mediated antigen presentation and is involved in multiple steps of the process. PMID- 17705134 TI - NF-kappaB p50 and p65 subunits control intestinal homeostasis. AB - Mice which lack the p50 subunit of NF-kappaB and are heterozygous for the p65 subunit (3X mice), are exquisitely sensitive to LPS-induced shock. Here, we demonstrate that prior to becoming moribund, 3X mice challenged with LPS develop a profound enteropathy. The enteropathy is characterized by defects in intestinal barrier function, increased epithelial apoptosis, and deregulated intestinal cytokine gene expression. The defect that sensitizes 3X mice to LPS-induced enteropathy is located within the innate immune compartment, as LPS induced similar findings in 3X mice lacking lymphocytes (3X/RAG). TNF-alpha depletion ameliorated the ability of LPS to induce pathology and TNF-alpha was able to independently induce similar findings, suggesting that TNF-alpha plays a critical role in the development of LPS-induced pathology in these mice. These data highlight that NF-kappaB subunits have essential functions in regulating intestinal homeostasis during acute inflammation. PMID- 17705135 TI - beta-Defensins chemoattract macrophages and mast cells but not lymphocytes and dendritic cells: CCR6 is not involved. AB - beta-Defensins are natural peptide antibiotics whose immunomodulatory functions are poorly understood. In the present study, macrophages were found to migrate to human beta-defensins (HBD)-1 to -4 using Galpha(i) proteins as well as MAPK ERK, p38 and JNK as signal transducers. In addition, mast cells responded to HBD-1 to 4 with calcium fluxes as well as chemotaxis, which increased upon stimulation with IgE plus antigen or ionomycin. In contrast, human beta-defensins were unable to induce migration of memory lymphocytes and dendritic cells (DC). Similar to HBD, the murine beta-defensin (mBD)-8 mobilized macrophages and lacked the ability to recruit memory T cells. These findings were unexpected as CCR6 on memory T cells and DC has been previously observed to be a receptor for human beta-defensins. In support of our findings, however, RBL-2H3 as well as 300.19 cells stably expressing CCR6 proved to be unresponsive to HBD-2 and -3. Intriguingly, our observation of a PKC-independent homologous desensitization between HBD-1 to -4 suggests a common receptor for HBD. In summary, chemoattraction of macrophages and mast cells is evolutionary conserved within the beta-defensin family despite a considerable sequence variation and distinct antimicrobial activities. However, CCR6 is not a functional receptor for beta defensins. PMID- 17705136 TI - Identification and isolation of murine antigen-reactive T cells according to CD154 expression. AB - T helper (Th) cells are central regulators of adaptive immune responses. However, the detection of the small number of Th cells specific for a particular antigen or pathogen is still a major challenge. CD154 was recently introduced as a marker for antigen-specific Th cells. To date, this technology was not applicable for mice - arguably the most important immunological model system. CD154 is difficult to detect due to its rapid removal from the cell surface upon binding to CD40 during antigen-specific activation by APC. We present an efficient strategy to block the degradation of murine CD154 by combined use of antibodies against CD40 and CD154. This strategy makes CD154 easily accessible for surface staining, which allows isolation and expansion of rare antigen specific T cells. Importantly, CD154 identified all specific T cells in strongly Th1- or Th2 polarized immune responses against pathogens like Salmonella typhimurium and Heligmosomoides polygyrus, independent of their potential to produce cytokines. We demonstrate that CD154 can in fact be used as a reliable marker for antigen specific CD4 T cells in mice, offering a unique option to analyze, isolate and rapidly expand the entire pool of Th-cells generated during a physiological T cell response in vivo. PMID- 17705137 TI - Bim regulates BCR-induced entry of B cells into the cell cycle. AB - BH3-only Bcl-2 homologs are key regulators of the intrinsic apoptotic pathway. In particular, Bim, is critical for mediating apoptosis of hematopoietic cells including B cells. While studies using Bcl-2 Tg mice have defined an important role for Bcl-2 in cell cycle control, the role of BH3-only proteins is less clear. Using Bim KO mice, we show that Bim is required for B cells to enter the cell cycle normally. Bim KO B cells had reduced cell division compared to WT B cells in response to BCR, TLR3 or TLR4 signaling, whereas Bim deficiency did not affect TLR9-induced B cell division. Cell cycle progression in BCR- and LPS stimulated Bim KO B cells was blocked at the G0-G1 stage. BCR-induced p130 degradation and pRb hyperphosphorylation on Ser807/811, which are critical for G1 entry, were reduced in Bim KO compared to WT B cells. Likewise, BCR-induced p27(Kip1) degradation was decreased in Bim KO compared to WT B cells. These defects in BCR-induced cell cycle entry correlated with a proximal defect in BCR mediated intracellular calcium release in Bim KO B cells. Our results suggest that the balance of pro- and anti-apoptotic Bcl-2 family proteins is critical for controlling both cell cycle progression and apoptosis in B cells. PMID- 17705140 TI - Antiobesity properties of two African plants (Afromomum meleguetta and Spilanthes acmella) by pancreatic lipase inhibition. AB - Ethanol extracts of seeds of Afromomum meleguetta and flower buds of Splilanthes acmella presented pancreatic lipase inhibitory activities in a concentration related manner under in vitro conditions. The two plants were extracted with 70% ethanol by sonication, fractionated on silica gel and tested at concentrations in the range 0.75-2.0 mg/mL. Lipase inhibitory activities of 90% and 40% were observed in A. meleguetta and S. acmella, respectively. The two plants have potentials as candidates for weight reduction and obesity control. PMID- 17705138 TI - Extensive HLA class I allele promiscuity among viral CTL epitopes. AB - Promiscuous binding of T helper epitopes to MHC class II molecules has been well established, but few examples of promiscuous class I-restricted epitopes exist. To address the extent of promiscuity of HLA class I peptides, responses to 242 well-defined viral epitopes were tested in 100 subjects regardless of the individuals' HLA type. Surprisingly, half of all detected responses were seen in the absence of the originally reported restricting HLA class I allele, and only 3% of epitopes were recognized exclusively in the presence of their original allele. Functional assays confirmed the frequent recognition of HLA class I restricted T cell epitopes on several alternative alleles across HLA class I supertypes and encoded on different class I loci. These data have significant implications for the understanding of MHC class I-restricted antigen presentation and vaccine development. PMID- 17705139 TI - Monitoring of fluoroquinolone residual levels in chicken eggs by microbiological assay and confirmation by liquid chromatography. AB - The primary objective of this study was to develop a simple, rapid, and efficient method for the simultaneous determination of four fluoroquinolone residues, ciprofloxacin (CFX), danofloxacin (DFX), enrofloxacin (EFX) and norfloxacin (NFX), in chicken eggs. The samples were first monitored by microbiological assay using Escherichia coli as the reference organism, and were then quantified using HPLC with a fluorescence detector. Egg samples were extracted by the liquid-phase extraction process, and the analytes were analyzed via an ODS column using a mixture of acetonitrile and 0.4% phosphoric acid-0.4% triethylamine (15: 85, v/v) as a mobile phase (pH=2) without purification. The calibration curves were linear (r2>or=0.999) over a concentration range of 0.1-1.0 microg/mL. The majority of the mean recoveries at four different fortification levels, 0.1, 0.2, 0.5 and 1.0 ppm, ranged from 73.7+/-7.2% to 87.1+/-12.7%, and the repeatability (as the relative standard deviation) from three repetitive determinations of recovery was between 1.03 and 18.83%. The calculated limit of quantitation (LOQ) was 9 ppb for CFX, EFX and NFX and 0.6 ppb for DFX. Both the bioassay and HPLC methods were applied to 120 total egg samples collected from the six major cities in the Republic of Korea. The bioassay, showed that two samples were positive (i.e contained inhibiting substances). On the other hand, the results of HPLC only identified and quantified the residues of enrofloxacin (from 0.43 to 1.02 ppm) in three samples out of 120. We concluded that the bioassay can be used as a routine screening method for the presence of fluoroquinolones in chicken eggs, which can be confirmed and quantified using LC. PMID- 17705141 TI - Hepatoprotective effect of leaf extracts of Andrographis lineata nees on liver damage caused by carbon tetrachloride in rats. AB - The present study was conducted to evaluate the hepatoprotective effect of Andrographis lineata (Acanthaceae) extracts in carbon tetrachloride-induced liver injury in rats. Male Wistar rats with chronic liver damage, induced by subcutaneous injection of 50% v/v carbon tetrachloride in liquid paraffin at a dose of 3 mL/kg on alternate days for a period of 4 weeks, were treated with methanol and aqueous extracts of A. lineata orally at a dose of 845 mg/kg/day. The biochemical parameters such as serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, serum bilirubin and alkaline phosphatase were estimated to assess the liver function. Histopathological studies of the liver were also carried out to confirm the biochemical changes. Histopathological examinations of liver tissue corroborated well with the biochemical changes. The activities of extracts were comparable to a standard drug. Hepatic steatosis, hydropic degeneration and necrosis were observed in the carbon tetrachloride treated group, while these were completely absent in the standard and extract treated groups. A. lineata extracts exhibited hepatoprotective action against carbon tetrachloride-induced liver injury. The present investigation established pharmacological evidence to support the folklore claim that it is used traditionally as a hepatoprotective agent. PMID- 17705142 TI - Antiplasmodial compounds from Cassia siamea stem bark extract. AB - Cassia siamea L. (Fabaceae) was identified from the southwest Nigerian ethnobotany as a remedy for febrile illness. This led to the bioassay-guided fractionation of stem bark of the plant extract, using the parasite lactate dehydrogenase assay and multi-resistant strain of Plasmodium falciparum (K1) for assessing the in vitro antimalarial activity. Emodin and lupeol were isolated from the ethyl acetate fraction by a combination of chromatographic techniques. The structures of the compounds were determined by spectroscopy, co-spotting with authentic samples and comparison with literature data. Both compounds were found to be the active principles responsible for the antiplasmodial property with IC(50) values of 5 microg/mL, respectively. PMID- 17705143 TI - Restoration of the immune functions in aged mice by supplementation with a new herbal composition, HemoHIM. AB - The effect of a new herbal composition, HemoHIM, on immune functions was examined in aged mice, in which various immune responses had been impaired. The composition HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of three edible herbs, Angelica Radix, Cnidium Rhizoma and Paeonia Radix. Supplementation to the aged mice with HemoHIM restored the proliferative response and cytokine production of splenocytes with a response to ConA. Also, HemoHIM recovered the NK cell activity which had been impaired in the aged mice. Meanwhile aging is known to reduce the Th1-like function, but not the Th2-like function, resulting in a Th1/Th2 imbalance. HemoHIM restored the Th1/Th2 balance in the aged mice through enhanced IFN-gamma and IgG2a production, and conversely a reduced IL-4 and IgG1 production. It was found that one factor for the Th1/Th2 imbalance in the aged mice was a lower production of IL-12p70. However, HemoHIM restored the IL-12p70 production in the aged mice. These results suggested that HemoHIM was effective for the restoration of impaired immune functions of the aged mice and therefore could be a good recommendation for immune restoration in elderly humans. PMID- 17705145 TI - In vitro anti-Helicobacter pylori activity of diallyl sulphides and protocatechuic acid. AB - The in vitro inhibitory effects of diallyl disulphide (DADS), diallyl trisulphide (DAT), roselle calyx extract and protocatechuic acid (PA) on the growth of Helicobacter pylori (15 susceptible, 11 clarithromycin-resistant and 9 metronidazole-resistant strains) were studied. The inhibition zone was determined after each agent had been heated at 25, 60, 100 degrees C for 60 min. The minimal inhibitory concentration (MIC) of each agent was determined by the tube dilution assay. The results showed that heat treatment did not affect the anti-H. pylori activity of DADS, DAT, roselle calyx extract and PA, and the MIC values of these agents against test H. pylori strains were in the range 8-64 mg/L. The time-kill study assay for DAT and PA at 1x MIC was monitored in Muller Hinton broth supplemented with 10% horse blood or mice stomach homogenate. Both DAT and PA inhibited the growth of all test H. pylori in broth and mice stomach homogenate (p < 0.05); however, the inhibitory effects of these two agents were less in mice stomach homogenate than in broth (p < 0.05). DAT at 4, 6, 8, 10, 12, 14 mg/L and PA at 8, 16, 24, 32, 40, 48 mg/L were used for urease activity assay. These two agents significantly reduced urease activity of test H. pylori strains (p < 0.05), in which DAT and PA at 1x MIC reduced the urease activity of H. pylori to 70% and 40%, respectively. These agents, based on their lower MIC values and heat tolerance, might be useful in the prevention or therapy of H. pylori. PMID- 17705144 TI - Schizandrin reverses memory impairment in rats. AB - The present study investigated the effect of schizandrin, a component of the fruit of Schizandra chinesis Baill (Fructus Schizandrae), on memory impairment in rats. Scopolamine (0.5 mg/kg, i.p.), a non-selective muscarinic receptor antagonist, markedly impaired spatial memory in an eight-arm radial maze. A higher dose of scopolamine (3 mg/kg, i.p.) also impaired the passive avoidance response. Schizandrin (1 and 10 mg/kg, p.o.) significantly reversed the scopolamine-induced impairment of spatial memory. Similarly, schizandrin (1 mg/kg, p.o.) significantly reversed the scopolamine-induced impairment of the passive avoidance response. Moreover, in mice, schizandrin (1 and 10 mg/kg, p.o.) enhanced tremors induced by oxotremorine, a muscarinic M(1) receptor agonist. Taken together these findings suggest that schizandrin reverses scopolamine induced memory impairment, in part, by enhancing cholinergic function, and that schizandrin might be useful for treating memory deficits. PMID- 17705146 TI - Theanine prevents memory impairment induced by repeated cerebral ischemia in rats. AB - The present study investigated the neuroprotective effect of gamma glutamylethylamide (theanine), a component Japanese green tea (Camellia sinensis), on memory impairment induced by twice-repeated cerebral ischemia in rats. Theanine was injected i.p. immediately after the first occlusion. Theanine (0.3 and 1 mg/kg) significantly prevented the impairment of spatial memory in rats subjected to repeated cerebral ischemia, 7 days after the second reperfusion. Moreover, theanine (1 mg/kg) significantly inhibited the decrease in the number of surviving cells in the hippocampal CA1 field in the same rats. These results suggest that theanine prevents memory impairment induced by repeated cerebral ischemia, in part by protecting against neuronal cell death, and that it might be useful for preventing cerebrovascular disease. PMID- 17705147 TI - Growth inhibitory effect of ethyl acetate-soluble fraction of Cynara cardunculus L. in leukemia cells involves cell cycle arrest, cytochrome c release and activation of caspases. AB - An extract of artichoke Cynara cardunculus L. (CCE) has been shown to exhibit antioxidant and antigenotoxic properties. In this study, the ability of CCE to inhibit the growth of L1210 and HL-60 leukemia cells was studied. Treatment of leukemia cells with a variety of concentrations of CCE (500-2500 microg/microL) for 24 h resulted in dose-dependent inhibition of leukemia cell growth. The cell growth inhibition was accompanied by G(0)/G(1) cell cycle arrest and by a loss of cells in S phase. Futhermore, apoptosis detected as a sub-G(0) cell population and apoptotic DNA fragmentation was observed. More detailed analyses of apoptosis induced by CCE in HL-60 cells revealed that apoptosis progressed through the caspase-9/-3 pathway, as release of cytochrome c, caspase-9/-3 activations and specific proteolytic cleavage of poly(ADP-ribose) polymerase. Taken together, the results suggest that CCE exerts an antiproliferative activity on leukemia cells and induces apoptosis of these cells through a mitochondrial/caspase dependent pathway. PMID- 17705148 TI - Antioxidant and neurosedative properties of polyphenols and iridoids from Lippia alba. AB - The neurosedative and antioxidative properties of some major compounds isolated from a citral chemotype of Lippia alba were investigated. Binding assays were performed on two CNS inhibitory targets: benzodiazepine and GABA(A) receptors. The most active compound was luteolin-7-diglucuronide, with half maximal inhibitory concentrations (IC(50)) of 101 and 40 microm, respectively. Fifteen compounds isolated from Lippia alba were tested for their radical scavenging capacities against DPPH. Four of the major compounds (verbascoside, calceolarioside E, luteolin-7-diglucuronide and theveside) were also tested for their antioxidant activity against superoxide radical-anion in cell-free (hypoxanthine-xanthine oxidase) and cellular (PMA-stimulated neutrophil granulocytes) systems. PMID- 17705149 TI - Dehydrogenation reaction for Na-O-H system: a first-principles study. AB - The crystal structures, electronic, dielectric, and vibrational properties of NaH, Na(2)O and NaOH are systematically investigated by first-principles calculations and the quasiharmonic approximation. The phonon dispersion relations and the phonon density of states of the phases and their thermodynamic functions including the heat capacity, the vibrational enthalpy, and the vibrational entropy are calculated using a direct force-constant method. Based on these results, the dehydrogenation reaction, NaH+NaOH-->H(2)+Na(2)O, is predicted to take place at 528 K, which is in agreement with the experimental observed value. PMID- 17705150 TI - Editorial--Individuation through socialization. PMID- 17705151 TI - The development of thermally assisted particle manipulation and thermal nanointeraction studies as a means of investigating drug-polymer interactions. AB - This investigation outlines the development of two novel techniques, thermally assisted particle manipulation and thermal nanointeraction studies, to examine the interaction between materials during heating. Dispersions of paracetamol in polyethylene glycol 6000 were prepared and studied using microthermal analysis in a range of modes. The localised thermomechanical analysis (L-TMA) responses showed intermediate responses compared to the pure materials. Thermally assisted particle manipulation was used to place a single particle of PEG on the paracetamol surface and the assembly analyzed using L-TMA as a function of position, with the intermediate response seen at the interface between the two materials. Thermal nanointeraction studies, whereby nanosampled PEG was heated in the immediate proximity of the paracetamol, indicated that the process was kinetically controlled and could be interpreted in terms of the molten PEG influencing the apparent melting of the paracetamol. Near-field photothermal IR was used to identify the nature of the material on the probe tip; we provide the first quantitative evaluation of the amount sampled when carrying out thermally assisted nanosampling (circa 500 fg). The investigation has therefore demonstrated that these methods maybe used as a novel approach to studying thermal interactions between pharmaceutical materials. PMID- 17705152 TI - The interaction of heparin/polyanions with bovine, porcine, and human growth hormone. AB - The interaction of polyanions with proteins is of potential pharmaceutical and cellular significance. A partial thermodynamic description of the interaction of four representative polyanions with human, bovine, and porcine growth hormone is described. A heparin bead-binding assay confirms all growth hormones bind to heparin but to varying extents. Moderate-binding constants and high ratios of bound protein to the more extended polyanions, heparin, and dextran sulfate were measured by isothermal titration calorimetry and dynamic light scattering. The binding constants and ratio of protein bound to ligand were significantly smaller for the low molecular weight polyanions phytic acid and sucrose octasulfate (SOS). The effect of polyanion binding on the bovine, porcine, and human growth hormone's (hGH) structural and colloidal stability was also explored. Heparin and dextran sulfate inhibit porcine somatotropin (pST) and bovine somatotropin (bST) aggregation to the greatest extent, as compared to phytic acid and SOS, while decreasing secondary and tertiary structural stability as measured by the temperature dependence of their circular dichroism and intrinsic fluorescence. Somewhat surprisingly, the polyanions do not appear to affect the structure or stability of hGH. The potential biological significance of growth hormone polyanion interactions is discussed. PMID- 17705153 TI - On the volume of distribution at steady state and its relationship with two compartmental models. AB - The volume of distribution at steady state is considered to be one of the primary pharmacokinetic measurements obtained from in vivo experiments. This quantity is quite commonly calculated using moments of the observed concentration curve, the process being referred to as noncompartmental analysis. In this paper the underlying assumptions of noncompartmental analysis are analysed with regard to the observed behaviour of models with two compartments: one of which has elimination from the central compartment, the other from the peripheral tissue compartment. This is in order to clarify the relationship between volume of distribution and clearance. It is shown that these two models are indistinguishable from measurements in blood. Furthermore relationships between the parameter values for the two models are given so that they produce the same observed profile. Expressions are derived in a novel way that relates the volume of distribution to these model rate constants. The definitions of clearance and volume of distribution at steady state are investigated using several different mathematical techniques, demonstrating the consistency of the derived expressions. It is shown, in a manner that the authors believe is a new approach, that when the assumption of central elimination does not apply, noncompartmental analysis will under estimate the volume of distribution, whereas clearance remains unchanged. This is compared quantitatively with respect to the volume predicted where central elimination holds, and is a result of an extended mean residence time. PMID- 17705154 TI - The origin of trisomy 22: evidence for acrocentric chromosome-specific patterns of nondisjunction. AB - Trisomy 22 is one of the most common trisomies in clinically recognized pregnancies, yet relatively little is known about the origin of nondisjunction for chromosome 22. Accordingly, we initiated studies to investigate the origin of the extra chromosome in 130 trisomy 22 cases. Our results indicate that the majority of trisomy 22 errors (>96%) arise during oogenesis with most of these errors ( approximately 90%) occurring during the first meiotic division. As with other trisomies, failure to recombine contributed to nondisjunction of chromosome 22. Taken together with data available for other trisomies, our results suggest patterns of nondisjunction that are shared among the acrocentric, but not all nonacrocentric, chromosomes. PMID- 17705155 TI - Poly(vinylidene fluoride)-graft-poly(N-vinyl-2-pyrrolidone) copolymers prepared via a RAFT-mediated process and their use in antifouling and antibacterial membranes. AB - PNVP-g-PVDF copolymers were synthesized and used to produce microfiltration membranes. The pore size and distribution varied with the grafting concentration and the density of graft points. A significant decrease of the amounts of adsorbed BSA indicated improved antifouling properties of PVDF. The MF membranes were further functionalized via surface-initiated block copolymerization with DMAEMA to obtain (PVDF-g-PNVP)-b-PDMAEMA MF membranes. Quaternization of the tertiary amine groups of the PDMAEMA brushes gave rise to a high concentration of quaternary ammonium salt on the membrane surfaces. The bactericidal effect of the QAS-functionalized membranes on E. coli was also demonstrated and discussed. PMID- 17705156 TI - Chromosomal heteromorphisms may help for the diagnosis of uniparental disomy (UPD): a case report. PMID- 17705157 TI - Understanding and predicting bed humidity in fluidized bed granulation. AB - Bed humidity is a critical parameter that needs to be controlled in a fluidized bed granulation to ensure reliability. To predict and control the bed humidity during the fluidized bed granulation process, a simple model based on the mass conservation of moisture was developed. The moisture mass balance model quantitatively simulates the effects of spray rate, binder solution concentration, airflow rate, inlet air temperature, and dew point on the bed humidity. The model was validated by a series of granulations performed in different scale granulators including Glatt GPCG-1, GPCG-15, and GPCG-60. Good agreement was observed between the theoretical prediction and the measured loss on drying (LOD). The model developed in the current work enables us to choose the appropriate parameters for the fluidized bed granulation and can be used as a valuable tool in process scaling-up. PMID- 17705158 TI - Biological rhythms: a neglected factor of variability in pharmacokinetic studies. AB - Biological rhythms may influence drug response (chronopharmacology) and some chronopharmacological studies have underlined the influence of time of day on drug pharmacodynamics and pharmacokinetics. The aim of the present review is to underline how biological rhythms may interfere with drug kinetics and to try to underline when, how, and why taking into account the moment of administration of a drug. Many physiological factors, possibly implicated in different steps of the fate of drugs in the organism (e.g., absorption, distribution, metabolism, and elimination) vary along the 24 h scale. Taking into account biological rhythms in kinetic studies, should be indicated when the concerned drug will be used in a chronobiological disease (e.g., asthma, cancer, depression, hypertension, gastrointestinal diseases, rheumatisms), etc. In case of a drug characterised by a high inter- and intra-variability, a narrow therapeutic range or when the drug will be further used following a once-a-day formulation. It is of importance to rigorously control factors which are known to influence pharmacokinetic processes in chronokinetic studies. Time of day has to be regarded as an additional variable to influence the kinetics of a drug. PMID- 17705159 TI - Gelatin-stabilised microemulsion-based organogels facilitates percutaneous penetration of Cyclosporin A in vitro and dermal pharmacokinetics in vivo. AB - Gelatin-stabilised microemulsion-based organogels (MBGs) are very useful in transdermal and topical delivery of hydrophobic drugs because of their lipophilic nature. MBGs systems possessing a potentially improved skin bioavailability of Cyclosporin A were designed and explored for some characteristics. The release characteristics of drug from MBGs were studied according to drug concentration. As the concentration of drug increased, the release of drug from gel increased, showing concentration dependency. Percutaneous penetration studies using rat skin in vitro showed that the deposition of Cyclosporin A was significantly improved by MBGs compared to the control. We also evaluated the therapeutic advantage of dermal administration of Cyclosporin A in rat model. Local (subcutaneous and skin), systemic concentrations and organ distribution (liver and kidney) were evaluated serially following topical and oral application of the drug. In rat dermal applied with the MBGs containing Cyclosporin A, the deposition of the drug into skin and subcutaneous fat was, respectively, almost 55- and 3-fold higher than the concentrations compared with oral administration. Systemic distribution in blood, liver and kidney was much lower following topical than following oral administration. With high local concentrations and minimal distribution to other organs via the circulation, topical applied MBGs loaded with Cyclosporin A might deliver maximal therapeutic effect to local tissue while avoiding the side effects seen with systemic therapy. The histopathological findings revealed that the new MBGs vehicle was a safe vehicle for topical drug delivery systems. PMID- 17705161 TI - Resiniferatoxin and botulinum toxin type A for treatment of lower urinary tract symptoms. AB - Resiniferatoxin (RTX) and botulinum toxin subtype A (BTX-A) are increasingly viewed as potential treatments for lower urinary tract symptoms (LUTS) refractory to conventional therapy. RTX, a capsaicin analogue devoid of severe pungent properties, acts by desensitizing the transient receptor potential vanilloid type 1 (TRPV1) receptor and inactivating C-fibers. BTX-A cleaves soluble N ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in afferent and efferent nerve endings, therefore impeding the fusion of synaptic vesicles with the neuronal membrane necessary for the release of neurotransmitters. In patients with neurogenic and idiopathic detrusor overactivity, RTX and BTX-A have been shown to increase the volume to first detrusor contraction, increase bladder capacity, and improve urinary incontinence and quality of life. Recent data also suggest a role for these neurotoxins in treating urgency, the primary symptom in overactive bladder (OAB) syndrome. Furthermore, experimental data strongly support the use of both neurotoxins in the treatment of pain and frequency in patients with interstitial cystitis/painful bladder syndrome (IC/PBS), although the results from available clinical trials for this use are still inconclusive. In spite of promising results overall, it should be made clear that the administration of these neurotoxins is still considered an experimental procedure and that more clinical studies are necessary before a license for their use will be issued by health authorities. PMID- 17705160 TI - Neuromuscular electrical stimulation and the treatment of lower urinary tract dysfunction in multiple sclerosis--a double blind, placebo controlled, randomised clinical trial. AB - AIMS: Lower urinary tract dysfunction affects up to 75% of the multiple sclerosis population. Results from our recent Pilot Study (McClurg et al., 2006) indicated that a combined programme of pelvic floor muscle training, electromyography biofeedback and neuromuscular electrical stimulation modalities may alleviate some of the distressing symptoms within this population. This clinical trial aimed to evaluate further the efficacy of these interventions and to establish the benefit of neuromuscular electrical stimulation above and beyond that of EMG biofeedback and pelvic floor muscle training. METHODS: 74 multiple sclerosis patients who presented with lower urinary tract dysfunction were randomly allocated to one of two groups - Group 1 received Pelvic Floor Muscle Training, Electromyography Biofeedback and Placebo Neuromuscular Electrical Stimulation (n=37), and Group 2 which received Pelvic Floor Muscle Training, Electromyography Biofeedback, and Active Neuromuscular Electrical Stimulation (n=37). Treatment was for nine weeks with outcome measures recorded at weeks 0, 9, 16 and 24. The Primary Outcome Measure was the number of leakage episodes. Within group analysis was by Paired Samples t-test. Group differences were analysed using Repeated Measures Analysis of Variance and Post-hoc tests were used to determine the significance of differences between Groups at each time point. RESULTS: The mean number of incontinence episodes were reduced in Group 2 by 85% (p=0.001) whereas in Group 1 a lesser reduction of 47% (p=0.001) was observed. However, there was a statistically superior benefit in Group 2 when compared to Group 1 (p=0.0028). This superior benefit was evident in all other outcome measures. CONCLUSIONS: The addition of Active Neuromuscular Electrical Stimulation to a programme of Pelvic Floor Muscle Training and Electromyography Biofeedback should be considered as a first-line option in alleviating some of the symptoms of lower urinary tract dysfunction associated with multiple sclerosis. PMID- 17705162 TI - Parameterization of azole-bridged dinuclear platinum anticancer drugs via a QM/MM force matching procedure. AB - Azole-bridged diplatinum compounds are promising new anticancer drugs designed to induce small distortions upon DNA alkylation, able to circumvent resistance problems of existing platinum drugs. Hybrid quantum classical (QM/MM) molecular dynamics (MD) simulations of different azole-bridged platinum drugs have recently revealed the nature of the local deformations at the DNA binding site. However, the description of global slow converging rearrangements cannot be addressed by QM/MM MD due to the short time scale accessible. Extensive classical MD simulations are therefore mandatory to describe accurately the structural distortions in the DNA double helix. This issue is now addressed by developing a new set of accurate force field parameters of the platinated moiety via a recently proposed force matching procedure of the classical forces to ab initio forces obtained from QM/MM trajectories. The accuracy of our force field parameters is validated by comparison of structural properties from classical MD and hybrid QM/MM simulations. The structural characteristics of the Pt-lesion are well reproduced during classical MD compared with QM/MM simulations and available experimental data. The global distortions in the DNA duplex upon binding of dinuclear Pt-compounds are very small and rather opposite to those induced by cisplatin. Thus, the force match approach significantly extends the potentialities of molecular simulations in the study of anticancer drugs and of the interactions with their biological targets. PMID- 17705163 TI - Theoretical study of the reactions CF3CH2OCHF2 + OH/Cl and its product radicals and parent ether(CH3CH2OCH3) with OH. AB - A dual-level direct dynamic method is employed to study the reaction mechanisms of CF3CH2OCHF2 (HFE-245fa2; HFE-245mf) with the OH radicals and Cl atoms. Two hydrogen abstraction channels and two displacement processes are found for each reaction. For further study, the reaction mechanisms of its products (CF3CH2OCF2 and CF3CHOCHF2) and parent ether CH3CH2OCH3 with OH radical are investigated theoretically. The geometries and frequencies of all the stationary points and the minimum energy paths (MEPs) are calculated at the B3LYP/6-311G(d,p) level. The energetic information along the MEPs is further refined at the G3(MP2) level of theory. For reactions CF3CH2OCHF2 + OH/Cl, the calculation indicates that the hydrogen abstraction from --CH2-- group is the dominant reaction channel, and the displacement processes may be negligible because of the high barriers. The standard enthalpies of formation for the reactant CF3CH2OCHF2, and two products CF3CH2OCHF2 and CF3CHOCHF2 are evaluated via group-balanced isodesmic reactions. The rate constants of reactions CF3CH2OCHF2 + OH/Cl and CH3CH2OCH3 + OH are estimated by using the variational transition state theory over a wide range of temperature (200-2000 K). The agreement between the theoretical and experimental rate constants is good in the measured temperature range. From the comparison between the rate constants of the reactions CF3CH2OCHF2 and CH3CH2OCH3 with OH, it is shown that the fluorine substitution decreases the reactivity of the C--H bond. PMID- 17705164 TI - Computational chemistry approach for the early detection of drug-induced idiosyncratic liver toxicity. AB - Idiosyncratic drug toxicity (IDT), considered as a toxic host-dependent event, with an apparent lack of dose response relationship, is usually not predictable from early phases of clinical trials, representing a particularly confounding complication in drug development. Albeit a rare event (usually <1/5000), IDT is often life threatening and is one of the major reasons new drugs never reach the market or are withdrawn post marketing. Computational methodologies, like the computer-based approach proposed in the present study, can play an important role in addressing IDT in early drug discovery. We report for the first time a systematic evaluation of classification models to predict idiosyncratic hepatotoxicity based on linear discriminant analysis (LDA), artificial neural networks (ANN), and machine learning algorithms (OneR) in conjunction with a 3D molecular structure representation and feature selection methods. These modeling techniques (LDA, feature selection to prevent over-fitting and multicollinearity, ANN to capture nonlinear relationships in the data, as well as the simple OneR classifier) were found to produce QSTR models with satisfactory internal cross validation statistics and predictivity on an external subset of chemicals. More specifically, the models reached values of accuracy/sensitivity/specificity over 84%/78%/90%, respectively in the training series along with predictivity values ranging from ca. 78 to 86% of correctly classified drugs. An LDA-based desirability analysis was carried out in order to select the levels of the predictor variables needed to trigger the more desirable drug, i.e. the drug with lower potential for idiosyncratic hepatotoxicity. Finally, two external test sets were used to evaluate the ability of the models in discriminating toxic from nontoxic structurally and pharmacologically related drugs and the ability of the best model (LDA) in detecting potential idiosyncratic hepatotoxic drugs, respectively. The computational approach proposed here can be considered as a useful tool in early IDT prognosis. PMID- 17705165 TI - Polymorphism and drug selected mutations of reverse transcriptase gene in 102 HIV 1 infected patients living in China. AB - Few data are available for genotypic patterns within human immunodeficiency virus 1 (HIV-1) reverse transcriptase (RT) in drug-naive patients and RT inhibitor (RTI) treated patients in China. This study aimed at characterizing the polymorphism of RT HIV-1 in the absence of drug treatment and to identify known and unknown mutations emerging under RTI selective pressure. The HIV-1 RT gene from 21 drug-naive patients and 81 RTI treated patients from three provinces in China was analyzed. Most patients (>80%) received a triple regimen including stavudine (d4T) plus didanosine (ddI) and nevirapine (NVP), or d4T plus lamivudine (3TC) and efavirenz (EFV), or zidovudine (AZT) +ddI + NVP. In untreated patients, four highly polymorphic positions were found (122, 200, 207, and 211). In treated patients, two patterns of resistance associated mutations (RAMs) were observed: (1) K65R (9.8%), L74V (7.4%), M184V (7.4%), Q151M (5%), and thymidine analogue mutations (TAMs) (9.3%) including T215Y (5.5%), in patients who underwent ddI + d4T + NVP. (2) T215Y (23%), M184V (20%), and TAMs (15.4%) in patients receiving d4T + 3TC + EFV. In all cases, a high prevalence of non nucleoside RTIs (NNRTI) RAMs (41.9%) was found. Four RTI suspected new RAMs were described at position 142, 221, 224, and 228. An association between H221Y and L228H/R with Y181C was noted. These data highlight the predominant spread of NNRTI RAM in China, depict the specific genotypic pattern of RTI selected mutations in China, and suggest the association of newly described mutations with RTI therapy. PMID- 17705166 TI - Molecular epidemiology of HIV-1 in Santa Catarina State confirms increases of subtype C in Southern Brazil. AB - Recent studies have demonstrated an increased prevalence of human immunodeficiency virus type 1 (HIV-1) subtype C in southern Brazil. Although Santa Catarina State (SC) is located in this area and presents one of the country's highest incidences of HIV/AIDS, knowledge on the molecular epidemiology of HIV-1 in such State is lacking. The aim of this study was to investigate the HIV-1 molecular diversity and epidemiological profile of HIV-1-infected patients from SC. DNA samples were PCR amplified and HIV-1 subtypes were determined using both env and gag genes by direct sequencing. Phylogenetic analyses revealed that 48% were subtype C and 23% were subtype B. Possible recombinant forms were observed for both B/C (23%) and B/F (6%) subtypes. Our results, for the first time, identifies HIV-1 subtype C as a major clade circulating in SC and contributes to the understanding of HIV epidemics in the country by confirming the epidemic spread of the HIV-1 subtype C in southern Brazil. PMID- 17705167 TI - High diversity of HHV-8 molecular subtypes in the Amazon region of Brazil: evidence of an ancient human infection. AB - The present study describes the molecular epidemiology of Human herpesvirus 8 (HHV-8) among four Indian tribes (Kararao, Arara Laranjal, Tiriyo, and Zo'e) of the Amazon region of Brazil and a group of HIV-1-infected subjects from the urban population of Belem, Para. Infection was characterized by the presence of antibodies using ELISA (measuring antibodies to ORF59, ORF65, K8.1A, K8.1B, and ORF73), and molecular assays (gene amplification of the regions ORF26 and the variable region VR1). Antibodies to HHV-8 were detected in 66 samples of the 221 Brazilian Amerindians, namely, 6 (25%) in the Kararao, 18 (19.6%) in the Arara Laranjal, 24 (42.9%) in the Tiriyo, and 18 (36.7%) in the Zo'e. Among the 477 HIV 1-infected subjects, antibodies to HHV-8 were present in 74 (15.5%) persons. The ORF26 region was amplified in seven samples, one of the Arara Laranjal, one of the Tiriyo, two of the Zo'e, and three of the HIV-1-infected group. Subtyping of HHV-8 described a high multiplicity of molecular subtypes, including C (Zo'e), E (Tiriyo), and B (HIV-1 infected). Serological results confirm the high prevalence of HHV-8 among Amerindians and the presence of three subtypes in the Amazon region of Brazil, including a unique subtype, which favors the idea of HHV-8 as an ancient human infection within this particular geographical region. PMID- 17705168 TI - High prevalence of amantadine-resistance influenza a (H3N2) in six prefectures, Japan, in the 2005-2006 season. AB - Substantial increase in amantadine-resistant influenza A (H3N2) was reported in Asia and North America in 2005. In this study the frequency and genetic characteristics of amantadine-resistant influenza A, circulated in Japan in 2005 2006 season, were investigated. Isolates were tested by amantadine susceptibility test (TCID(50)/0.2 ml method), and sequencing of the M2 gene to identify mutations that confer resistance. Additionally, the hemagglutinin (HA) and neuraminidase (NA) genes of the viruses were examined. In total, 415 influenza A isolates from six prefectures were screened, and 231 (65.3%) of 354 influenza A (H3N2) were amantadine-resistant, with a serine to asparagine (S31N) change in the M2 gene. However, none of 61 A (H1N1) isolates were resistant. In addition, genetic analyses of the HA gene showed all amantadine-resistant viruses clustered in one (named clade N), possessing specific double mutations at 193, serine to phenylalanine (S193F), and at 225, asparatic acid to asparagine (D225N), and sensitive viruses belonged to another group (clade S). The clinical presentations at the clinical visit did not differ between patients shedding clade N virus and those shedding clade S virus. None of the patients had received previous treatment with amantadine. The results indicate an unusually high prevalence and wide circulation of the amantadine-resistance influenza A (H3N2) in Japan in the 2005-2006 season. These strains had the characteristic double mutations in the HA, in addition to the M2 mutation responsive for resistance. Antiviral resistance monitoring should be intensified and maintained for rapid feedback into treatment strategies, and selection of alternative therapeutic agents. PMID- 17705169 TI - Neuraminidase inhibitor resistance in influenza viruses. AB - Zanamivir and oseltamivir, the currently marketed influenza virus neuraminidase inhibitors (NAIs), are prescribed for the treatment and prophylaxis of influenza and are being stockpiled for pandemic influenza. Oseltamivir resistance has been reported in up to 2% of patients in clinical trials of oseltamivir and in up to 18% of treated children. There are also reports in at least three patients treated with oseltamivir for influenza A (H5N1) infections. At this stage, there are no reports of resistance occurring to zanamivir in immunocompetent patients. Zanamivir and oseltamivir bind differently at the neuraminidase catalytic site and this contributes to different drug resistance profiles. The magnitude and duration of NAI concentrations at the site of infection are also expected to be important factors and are determined by route and timing of drug administration, dose, and pharmacokinetic differences between patients. In addition, the type, strain, and virulence of the influenza strain and the nature of the immune response all appear to play a role in determining the likelihood of drug resistance arising. The clinical significance of a particular NAI-resistant isolate from a patient is often not clear but virus viability and transmissibility are clearly important characteristics. Early initiation of NAI treatment in suspected cases of influenza is important for maximizing efficacy and minimizing the risk of drug resistance. Higher NAI doses and longer periods of treatment may be required for patients with influenza A (H5N1) infections but further work is needed in this area. PMID- 17705170 TI - Frequent detection of cell-associated HIV-1 RNA in patients with plasma viral load <50 copies/ml. AB - Despite prolonged undetectable plasma viral load some HIV-1 infected patients have been reported to develop resistance-associated mutations leading to treatment failure. The mechanisms for this phenomenon and the point of origin for residual viral evolution are still not elucidated. In order to quantify cell associated HIV-1 RNA in patients with different levels of plasma viremia paired cell-associated HIV-1 RNA loads and plasma viral loads were determined. Weak inverse correlation between these parameters and the amounts of CD4(+) T cells was observed, whereas there was no correlation between viral loads and CD8(+) T cells or CD14(+) monocytes, respectively. In a subset of patients, cell associated and plasma HIV-1 env V3 sequences were analyzed. Plasma viral load and the amount of cell-associated HIV-RNA correlated strongly. However, in 62.3% of patients with undetectable plasma viral load cell-associated HIV-RNA could be detected. Analyses of HIV-RNA in plasma and blood cells showed identical sequences in 4/19 patients, whereas the majority of patients had differing HIV-1 RNA sequences in plasma and cells, respectively. In summary, this study shows that residual viral replication in peripheral blood still occurs in the majority of patients with undetectable plasma viral load. Since these replication events could lead to ongoing viral evolution it should be considered to optimize antiretroviral therapy in order to minimize the development of drug resistance. PMID- 17705171 TI - Development of nonsurfactant cyclodextrin nanoparticles loaded with anticancer drug paclitaxel. AB - In the current formulation of clinical use paclitaxel (PCX) is associated with solubilizers that may produce severe side effects. In this study, PCX was complexed to an amphiphilic cyclodextrin (CD), 6-O-CAPRO-beta-CD, capable of forming nanoparticles spontaneously in order to mask its physicochemical properties via the formation of inclusion complexes of the drug with amphiphilic CD before the nanoparticle is formed. Complexes have been characterized with various techniques such as (1)H NMR, Fourier Transform Infrared (FTIR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) confirming the formation of inclusion complex between PCX and 6-O-CAPRO-beta-CD. Nanospheres and nanocapsules were prepared directly from the preformed PCX/6-O CAPRO-beta-CD inclusion complex by the nanoprecipitation technique, showing a size from 150 to 250 nm for nanospheres and from 500 to 500 nm for nanocapsules. Zeta potentials of the nanospheres and nanocapsules indicate stable colloidal dispersions within the range of -18 to -39 mV. A 12-month physical stability was demonstrated for blank nanoparticles. PCX encapsulation was high with three-fold increase in loading when nanoparticles are prepared directly from preformed inclusion complexes of the drug with 6-O-CAPRO-beta-CD. In vitro liberation profiles of PCX from CD nanoparticles show a prolonged release profile for this drug up to 12 h for nanospheres and 24 h for nanocapsules. PMID- 17705173 TI - Seroreactivity to Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) latent nuclear antigen in AIDS-associated Kaposi's sarcoma patients depends on CD4+ T-cell count. AB - In AIDS/Kaposi's sarcoma (KS) patients, the sensitivity of immunofluorescence assays for detecting antibodies against latent nuclear antigen ranges from 52% to 93%. However, in classic and African KS, sensitivities above 90% have been reported systematically. This study evaluates whether CD4+ T-cell count affects seroreactivity to KSHV LANA and to lytic antigens in AIDS/KS patients. Kaposi's sarcoma-associated herpesvirus (KSHV) latent (IFA-LANA) and lytic (IFA-Lytic and ORF65/K8.1 EIA) antibodies were screened in 184 consecutive samples taken from 36 AIDS/KS patients grouped according to their CD4+ counts as follows: <100 (group A), 100-300 (group B), and >300 (group C) cells/mm(3). At enrollment, the immunofluorescence assay for the detection of antibodies against latent nuclear antigen (IFA-LANA) was positive in 3/11(27.2%) group A patients, in 10/11 (90.9%) group B patients, and in 14/14 (100%) group C patients (P < 0.01). Seropositivity to lytic antigens did not differ according to CD4+ T-cell count. Considering IFA Lytic and ORF65/K8.1 EIA, seropositivity for lytic antigens was 100% in all three patient groups. In patients whose CD4+ count improved during follow-up, IFA-LANA seroconversion occurred; unstable counts resulted in a decrease in LANA antibody titers while the persistence of high counts resulted in unchanged, elevated antibody titers. In conclusion, LANA seroreactivity in AIDS/KS patients, as assessed by an immunofluorescence assay, depends on CD4+ T-cell count, rendering this evaluation important in the interpretation of seroepidemiological studies of KSHV infection in AIDS patients. To evaluate future serological tests based on latency-associated antigens, the selection of sera from KS patients with CD4+ cell count >300 cells/mm(3) as a positive gold standard is recommended. PMID- 17705172 TI - Diverse genotypes of Kaposi's sarcoma associated herpesvirus (KSHV) identified in infant blood infections in African childhood-KS and HIV/AIDS endemic region. AB - Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) has been associated with several neoplasias, including childhood endemic Kaposi's sarcoma (KS). It is possible that strain genotypes could contribute to the differences in regional presentation (mainly sub-Saharan Africa), childhood infection, lack of male sex bias, distinct disseminated forms and rapid fatality observed for childhood endemic KS. Early studies, at the advent of the HIV/AIDS epidemic, identified only the K1-A5 genotype in childhood KS biopsies as well as blood of a few HIV positive and negative febrile infants in Zambia, a highly endemic region. This current enlarged study analyses blood infections of 200 hospitalized infants (6 34 months age) with symptoms of fever as well as upper respiratory tract infection, diarrhoea, rash or rhinitis. KSHV and HIV viraemia and were prevalent in this group, 22% and 39%, respectively. Multiple markers at both variable ends of the genome (K1, K12, and K14.1/K15) were examined, showing diverse previously adult-linked genotypes (K1 A2, A5, B, C3, D, with K12 B1 and B2 plus K14.1/K15 P or M) detected in both HIV positive and negative infants, demonstrating little restriction on KSHV genotypes for infant/childhood transmission in a childhood endemic KS endemic region. This supports the interpretation that the acquisition of childhood KSHV infections and subsequent development of KS are due to additional co-factors. PMID- 17705174 TI - Environmental contamination with rhinovirus and transfer to fingers of healthy individuals by daily life activity. AB - Rhinovirus infection may be acquired by inoculation of virus on fingertips to conjunctiva or nose (self-inoculation). The virus contaminating the fingertips may come from hand contact with someone with a cold or from virus in mucus on environmental surfaces. This study was designed to assess rhinovirus contamination of surfaces by adults with colds and rhinovirus transfer from surfaces to fingertips during normal daily activities. Fifteen adults with natural rhinovirus colds stayed overnight in a local hotel. Ten touched sites in each room were tested for rhinovirus RNA using RT-PCR. Transfer to fingertips of five subjects was examined by drying 10 microl of virus-containing mucus from each subject onto light switches, telephone dial buttons and telephone handsets. After an interval of 1 or 18 hr the subject flipped the light switch, pressed the button, held the handset. Fingertip rinses were tested for virus. Thirty five percent of the 150 environmental sites in the rooms were contaminated. Common virus-positive sites were door handles, pens, light switches, TV remote controls, faucets, and telephones. Rhinovirus was transferred from surfaces to fingertips in 18/30 (60%) trials 1 hr after contamination and in 10/30 (33%) of trials 18 hr (overnight) after contamination. Adults with colds commonly contaminate environmental surfaces with rhinovirus; virus on surfaces can be transferred to a fingertip during normal daily activities. PMID- 17705175 TI - Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: a report from the Children's Oncology Group. AB - BACKGROUND: Effective chemotherapy is lacking for most types of central nervous system (CNS) tumors in children. Temozolomide, an agent with activity against adult brain tumors, was investigated in children and adolescents with recurrent CNS tumors. METHODS: Temozolomide was administered orally as monthly 5-day courses at doses of 200 mg/m(2)/d (patients with no prior craniospinal irradiation [CSI]) or 180 mg/m(2)/d (prior CSI). Patients with a complete (CR) or partial (PR) response or stable disease (SD) could continue temozolomide for up to 12 cycles. RESULTS: The cohort comprised 122 patients, including 113 with CNS tumors. Median age was 11 years (range, 1-23 years). Among 104 evaluable patients with CNS tumors, 5 PRs and 1 CR were observed. PRs occurred in 1 of 23 evaluable patients with high-grade astrocytoma, 1 of 21 with low-grade astrocytoma, and 3 of 25 with medulloblastoma/primitive neuroectodermal tumor (PNET). The CR occurred in an additional patient with medulloblastoma/PNET. No responses were observed in patients with ependymoma, brain-stem glioma, or other CNS tumors. Notably, 41% of patients with low-grade astrocytoma had SD through 12 courses. The most frequent toxicities were grade 3 or 4 neutropenia (19%) and thrombocytopenia (25%); nonhematologic toxicity was infrequent. CONCLUSIONS: Although overall objective responses were limited, further exploration of temozolomide may be warranted in children with medulloblastoma and other PNETs, or in patients with low-grade astrocytoma, perhaps in a setting of less pretreatment than the patients in the current study, or in the context of multiagent therapy. PMID- 17705176 TI - Clinical management and outcome of papillary and follicular (differentiated) thyroid cancer presenting with distant metastasis at diagnosis. AB - BACKGROUND: Differentiated thyroid cancer has a good prognosis and only rarely presents with distant metastasis at diagnosis. The clinical outcome of this presentation was assessed with respect to survival and factors that may determine prognosis. METHODS: A retrospective review was undertaken of patients with stage M1 differentiated thyroid cancer at presentation (n = 49), referred from 1980 2000 at a single institution. RESULTS: The median age was 68 (range, 17-90), with 69% females. The initial site(s) of metastasis were lung only, 45%, bone only, 39%, other single site, 4%, and multiple sites, 12%. HISTOLOGY: papillary, 51%, follicular, 49%. Initial treatment(s) included: thyroidectomy, 82%, radioactive iodine (RAI), 88%, excision of metastasis, 29%, radiotherapy, 47%, and chemotherapy, 6%. With a median follow-up time of 3.5 years, 25 patients are alive (51%) and 24 died (49%), with 3-year and 5-year actuarial survivals of 69% and 50%, respectively. Only a minority of patients (4/25, 16%) had no clinical evidence of disease at last follow-up. Most deaths (17/24, 71%) were due to progressive cancer. Prognosis was associated with age, site of metastasis, histology, and iodine avidity of the metastasis. Patients aged 45 years (P = .001). The 3 year survival for lung only versus bone only metastasis was 77% versus 56% (P = .02); for papillary versus follicular carcinoma, 75% versus 62% (P = .006); for iodine-avid disease (n = 29) versus not avid (n = 14), 82% versus 57% (P = .02), respectively. In multivariate analysis after adjusting for age, only histology and iodine avidity remained significant for survival. The hazard ratio for follicular histology was 3.7 (95% confidence interval [CI], 1.1-12.1, P = .03), and for tumors not avid for iodine, 3.4 (95% CI, 1.2-9.2, P = .02). CONCLUSIONS: The data support the aggressive management of patients presenting with stage M1 thyroid cancer, with thyroidectomy and RAI. Complete clinical eradication of disease was rarely seen, and 50% of patients survived for more than 5 years. Young patients with papillary tumors and/or iodine-avid disease have an even better prognosis. PMID- 17705177 TI - Management of blood pressure after acute ischemic stroke: An evidence-based guide for the hospitalist. AB - Hospitalists are frequently called upon to manage blood pressure after acute ischemic stroke. A review of both post infarction cerebral perfusion physiology and the data from randomized trials of antihypertensive therapy is necessary to explain why consensus guidelines for blood pressure management after stroke differ from those of other hypertensive emergencies. The peri-infarct penumbra is the central concept in understanding post ischemic cerebral perfusion. This area of impaired cerebral blood flow is dependent on mean arterial blood pressure and acute reduction of blood pressure may expand the area of infarction. Review of clinical trials fails to show benefit from reduction of blood pressure after ischemic stroke and current guidelines suggest antihypertensive therapy be employed if the systemic blood pressure is greater than 180/105 mmHg after tPA is employed, or 220/120 mmHg when tPA is not used. Induced hypertension remains a promising but unproven therapy in the acute setting, but the evidence for long term control of blood pressure to less than 140/80 mmHG for secondary prevention of stroke is strong. Adherence to guidelines is poor but it is recognized that current evidence is limited by a lack of trials in which blood pressure is titrated to a pre-specified goal, as is common in clinical practice. PMID- 17705178 TI - Signal transducer and activator of transcription-6 (STAT6) is a constitutively expressed survival factor in human prostate cancer. AB - BACKGROUND: Signal transducer and activator of transcription (STAT)-6 is a member of the STAT family of latent transcription factors. In this investigation, we examined STAT6 expression in clinical prostate cancer tissue specimen and determined its role in prostate cell proliferation and migration. METHODS: STAT6 expression in cell lines and tissues was analyzed by RT-PCR, IHC and/or immunoblot analyses. Down-regulation of STAT6 expression was achieved by STAT6 siRNA and its effect on cell migration and apoptosis was measured. RESULTS: STAT6 is highly expressed in the fibromuscular stroma of prostate cancer specimens. STAT6 is also expressed in the malignant epithelial layer and prostate intraepithelial neoplasia (PIN). STAT6 expression was significantly correlated with high histological grades of prostate cancer as well as with tumor size. Our data indicate deregulated STAT6 mRNA and protein expression in prostate cancer cells with high levels in the non-cancerous HPV 18C-1 and cancerous DU145 cell lines and low levels in PC3 and LNCaP cells. Phosphorylated STAT6 was expressed in all three cancer cell lines DU145, PC3, and LNCaP. Down-regulation of STAT6 using siRNA leads to the induction of early apoptosis in DU145 cells and inhibits migration of these cells. Significant reduction in cell viability and transcriptional down-regulation of the anti-apoptotic protein Bcl-X(L) was observed followed by STAT6 down-regulation in DU145 cells. Interestingly STAT6 also regulates transcription of 15-lipoxygenase-1 gene in DU145 cells. CONCLUSIONS: Our data suggest that STAT6 is a survival factor in prostate cancer and regulates the genetic transcriptional program that is responsible for prostate cancer progression. PMID- 17705179 TI - Prevalence and characterization of enteric adenoviruses in the South of Ireland. AB - Enteric adenoviruses have been shown to be a substantial cause of pediatric gastroenteritis in various parts of the world, and are considered to be the second most common cause of viral gastroenteritis, next to rotavirus in young children. Genetic characterization of 95 adenovirus isolates obtained from patients with acute gastroenteritis between 2002 and 2007 from the southern regions of Ireland, were characterized by PCR analysis, restriction endonuclease (RE) analysis and sequencing analysis. All isolates were found to be of adenovirus type 41 origin. Genetic analysis of seven hypervariable regions (HVRs) located within the hexon gene has revealed a high level of amino acid sequence homology in samples over the course of this study, with a very close relationship to the D22 genome type. The D22 genome type has been detected in several other countries, thus suggesting Irish isolates have common genome types with other stains worldwide. This is the first such study undertaken in the south of Ireland, to type and genetically characterize adenoviral gastroenteritis isolates, and has revealed a high level of conservation within the isolated analyzed. PMID- 17705180 TI - Tula and Puumala hantavirus NSs ORFs are functional and the products inhibit activation of the interferon-beta promoter. AB - The S RNA genome segment of hantaviruses carried by Arvicolinae and Sigmodontinae rodents encodes the nucleocapsid (N) protein and has an overlapping (+1) open reading frame (ORF) for a putative nonstructural protein (NSs). The aim of this study was to determine whether the ORF is functional. A protein corresponding to the predicted size of Tula virus (TULV) NSs was detected using coupled in vitro transcription and translation from a cloned S segment cDNA, and a protein corresponding to the predicted size of Puumala virus (PUUV) NSs was detected in infected cells by Western blotting with an anti-peptide serum. The activities of the interferon beta (IFN-beta) promoter, and nuclear factor kappa B (NF-kappaB)- and interferon regulatory factor-3 (IRF-3) responsive promoters, were inhibited in COS-7 cells transiently expressing TULV or PUUV NSs. Also IFN-beta mRNA levels in IFN-competent MRC5 cells either infected with TULV or transiently expressing NSs were decreased. These data demonstrate that Tula and Puumala hantaviruses have a functional NSs ORF. The findings may explain why the NSs ORF has been preserved in the genome of most hantaviruses during their long evolution and why hantavirus-infected cells secrete relatively low levels of IFNs. PMID- 17705181 TI - Development and evaluation of a real-time PCR assay for rapid identification and semi-quantitation of measles virus. AB - A real-time PCR assay for measles virus was designed and validated using clinical samples including oral fluids, sera, urines, throat swabs, blood samples, and nasopharyngeal aspirates. The test was specific for measles virus, with a slightly higher sensitivity compared to the conventional nested PCR. Calculation of viral genome number in these samples, by comparison with a standard curve prepared from dilutions of cloned measles virus H gene, indicated that, overall, serum samples tended to have a lower viral load than oral fluid samples, and that the viral load decreased with increasing time after onset of symptoms. The real time PCR is considered to be a sensitive and specific alternative to the conventional measles PCR, especially in situations where early and rapid diagnosis are important. PMID- 17705182 TI - Respiratory syncytial virus protects against the subsequent development of Japanese cedar pollen-induced allergic responses. AB - Respiratory syncytial virus (RSV) infection has been hypothesized to be a risk factor for the development of allergy and asthma, but epidemiologic studies in humans still remain inconclusive. The association between RSV infection and allergic diseases may be dependent on atopic background and previous history of RSV infection. In this study, the influence of the timing of RSV infection on the development of Japanese cedar pollen (JCP)-induced allergic responses was examined. BALB/c mice were intranasally infected with RSV before or after sensitization to JCP. Production of cytokines in the culture fluid of lung parenchyma cells and the level of antigen-specific antibodies in the serum were determined. It became clear that JCP was a strong inducer for the elicitation of Th2-type responses, characterized by production of interleukin (IL)-4 and IL-5 in the lung and JCP-specific IgE antibody in the serum. RSV infection, however, suppressed JCP-induced allergic responses by decreasing the production of Th2 like cytokines and Th2-type antibodies. This phenomenon was observed more clearly in the groups that were infected with RSV, 2 weeks or 2 days before sensitization to JCP. The inhibitory mechanism of RSV infection seems to be due to RSV-induced Th1 type dominant environment, which down-regulated the Th2-type responses subsequently induced by allergen sensitization. On the other hand, JCP inoculation altered RSV-induced immune responses to shift from Th1- to Th2-type dominance, by inhibiting RSV-induced Th1-like cytokine production. These data provide evidence that under a certain condition, RSV infection may play a protective role in JCP-induced allergic responses. PMID- 17705183 TI - Amino acid substitutions in the VP7 protein of human rotavirus G3 isolated in China, Russia, Thailand, and Vietnam during 2001-2004. AB - The distribution of rotavirus G-types in the world appears to be changing, especially with the emergence of G3 and G9 in many countries. Sequence analysis of the VP7 gene was performed on the 27 human G3 rotavirus strains isolated in China, Russia, Thailand, and Vietnam during 2001-2004. All the strains studied were clustered into the same branch of the phylogenetic tree. The comparison of the G3 deduced amino acid sequences between the studied Chinese strains and the strains circulating in China during 1986-1992 showed a wide range of amino acid substitutions (up to 13 amino acids in the VP7 antigenic regions). The two considerable changes both from aspartic acid to asparagine were located at positions 96 in antigenic region A and 213 in antigenic region C. Those amino acid substitutions of the Chinese G3 strains might involve in the emergence of G3 rotavirus in China during 2001-2003. PMID- 17705184 TI - RANKL/OPG/TRAIL plasma levels and bone mass loss evaluation in antiretroviral naive HIV-1-positive men. AB - Osteopenia and osteoporosis are common in HIV-1-infected individuals and represent a challenge in clinical and therapeutic management. This report investigated osteopenia/osteoporosis in a group of 31 antiretroviral naive HIV-1 positive men and the role of specific molecules belonging to TNF and the TNF receptor family in HIV-1-related bone mass loss. Osteoprotegerin (OPG), the receptor activator of NF-kappab-ligand (RANKL), and the TNF-related apoptosis inducing ligand (TRAIL) were significantly increased in the plasma of antiretroviral naive HIV-1-positive patients compared to a control group of healthy blood donors. In addition, TRAIL and RANKL plasma concentrations were positively correlated to HIV-1-RNA viral load. Measurement of bone mineral density in 20 out of 31 HIV-1-positive subjects disclosed osteopenia/osteoporosis in 40% of these patients. The antiretroviral naive HIV-1-positive subjects with low bone mineral density had a decreased plasma OPG/RANKL ratio and a plasma RANKL concentration >500 pg/ml. Together, these data indicate that plasma concentrations of specific factors involved in bone homeostasis were increased during HIV-1 infection and that RANKL and OPG/RANKL ratio deregulation may be involved in osteopenia/osteoporosis occurring in antiretroviral naive HIV-1 individuals. PMID- 17705185 TI - Predictors and kinetics of occult hepatitis B virus infection in HIV-infected persons. AB - It has been proposed that occult hepatitis B virus (HBV) infection, defined as detectable HBV-DNA in serum with undetectable surface antigen (HBsAg(-)), is associated with raised transaminases in HIV-infected persons. The aim of this study was to determine the prevalence of occult HBV infection in two independent cohorts, and investigate its predictors, association with alanine aminotransferase (ALT) levels and response to antiretroviral therapy. Sera from HBsAg(-) persons with core antibody (anti-HBc(+)) were tested by real-time PCR. Overall, 5.2% of patients were HBsAg(+) and 39% HBsAg(-)/anti-HBc(+). The prevalence of occult HBV infection was 48/343 (14.0%; 95% CI 10.7-18.1%), and 27/196 (13.8%) and 21/147 (14.3%) in the two cohorts. Median HBV-DNA load was 342 (51-147,500) and 60 (25-33,850) copies/ml respectively. HBV-DNA detection was associated with absence of surface antibody (anti-HBs), but not with CD4 or ALT levels. Among 11 HBV-DNA(+) persons who started antiretroviral therapy containing lamivudine or lamivudine/tenofovir, HBV-DNA was repeatedly undetectable over median 19 (3-43) months. However, HBV-DNA detection was intermittent among drug naive persons. Occult HBV infection is common in HBsAg(-)/anti-HBc(+) HIV infected patients and predicted by undetectable anti-HBs. The intermittent nature of HBV-DNA detection poses a diagnostic challenge, but no association is observed with ALT levels. PMID- 17705187 TI - Proteomic analysis of hepatitis B surface antigen positive transgenic mouse liver and decrease of cyclophilin A. AB - The small, 22-nm spherical particles associated with hepatitis B infection are composed of hepatitis B surface antigen (HBsAg) and usually outnumber the virions by a ratio of 10(2) or 10(3). To study the interactions and pathogenesis between liver cells and the expression of HBsAg, global protein profiles were compared by two dimensional gel-based differential proteomics between the livers of a lineage of HBsAg positive transgenic mice and their HBsAg negative control siblings. A total of 93 proteins were identified in the HBV transgenic mice. Around 45% of these differentially expressed proteins were enzymes associated with metabolism, suggesting that the processing of lipids, carbohydrates and certain amino acids were up- or down-regulated. Among these proteins, cyclophilin A (CypA), the major target for the potent immunosuppressive drug cyclosporin A, was found decreased in HBsAg positive transgenic mouse liver and in a stable cell line expressing HBsAg when compared to their controls. The decrease of intracellular CypA was accompanied by an increased secretion of this protein into the supernatant of HBsAg positive cells. Possible implications of HBsAg expression and the intracellular decrease of CypA are discussed. PMID- 17705186 TI - Loss of hepatitis B surface antigen from the serum of patients with chronic hepatitis treated with lamivudine. AB - Although loss of hepatitis B e antigen (HBeAg) from the serum is sought by treatment with lamivudine, clearance of hepatitis B surface antigen (HBsAg) is the eventual goal of any antiviral therapy. In a single hepatology center in the Metropolitan Tokyo, 486 patients with chronic hepatitis B were followed up for longer than 3 years after they started treatment with lamivudine. HBsAg disappeared from the serum in 17 (3.5%). Age >or=50 years and low HBsAg levels (hemagglutination titer or=50 years at the start of lamivudine was the only factor predicting the loss of HBsAg (hazard ratio: 2.96 [95% confidence interval: 1.14-7.68], P = 0.028). By the method of Kaplan-Meier performed on the 486 patients, the loss of HBsAg was estimated to occur in 3% and 13% of patients, respectively, who had received lamivudine therapy for 5 and 10 years. These results indicate that loss of HBsAg occurs in a minority (3.5%) of patients with chronic hepatitis B who receive lamivudine therapy and more frequently in those with lower HBsAg titers and older ages at the start of treatment. PMID- 17705188 TI - The membrane protein of SARS-CoV suppresses NF-kappaB activation. AB - Severe acute respiratory syndrome coronavirus (SARS-CoV) infects many organs, such as lung, liver, and immune organs and causes life-threatening atypical pneumonia, SARS causes high morbidity and mortality rates. The molecular mechanism of SARS pathogenesis remains elusive. Inflammatory stimuli can activate IkappaB kinase (IKK) signalsome and subsequently the nuclear factor kappa B (NF kappaB), which influences gene expression of cyclooxygenase-2 (Cox-2) along with other transcription factors. In this work, we found that the membrane (M) protein of SARS-CoV physically interacted with IKKbeta using a co-immunoprecipitation assay (IPA). Expression of M suppressed tumor necrosis factor alpha (TNF-alpha) induced NF-kappaB activation using a luciferase reporter assay. Further investigation showed M protein suppressed Cox-2 expression using a luciferase reporter gene assay, RT-PCR and Western blot analysis. The carboxyl terminal of M protein was sufficient for the M protein function. Together, these results indicate that SARS-CoV M suppresses NF-kappaB activity probably through a direct interaction with IKKbeta, resulting in lower Cox-2 expression. Suppression of NF kappaB activity and Cox-2 expression may contribute to SARS pathogenesis. PMID- 17705190 TI - Molecular and cellular determinants of cell-to-cell transmission of HCV in vitro. AB - It was reported previously that HCV can be transmitted from persistently infected human bone-marrow-derived B-lymphoblastoid cells (TO.FE(HCV)) to human hepatoma cells by cell-to-cell contact. The present study confirms and characterize further such type of HCV infection in vitro. TO.FE(HCV) cells were co-cultured with 2.2.15 hepatoma cells, that are not susceptible to cell-free infection by sera containing HCV of 1b genotype. By this co-cultivation system it was demonstrated that HCV transmission to recipient cells requires de novo virus RNA replication. Several factors may favor HCV-transmission, evidence is provided that TO.FE(HCV) cells were able to select HCV-quasispecies. 5'-UTR and core sequence analysis revealed differences in the HCV-quasispecies composition in serum inoculum and in infected TO.FE B-cells at 4 months post-inoculation. It is considered that the latter may be more successful in replicating HCV in vitro and used to express surface molecules which may be involved in cell-to-cell contact. In TO.FE(HCV) cells replicate distinct, or few close related, HCV-variants correlated with those of serum inoculum. Comparative analysis of tetra-spans and integrins expression undertaken by cytofluorimetry displayed higher level of expression for TO.FE cells in comparison to other human bone-marrow-derived B cell lines. Overall, the observed persistent in vitro HCV replication is mediated by a continuous cell-to-cell reinfection that may be favored by selection of viral variants and expression of molecules involved in cell adhesion. These observations may provide an explanation for the establishment of HCV infection, the occurrence of chronic infection and HCV-related lymphoproliferative diseases. PMID- 17705189 TI - Interferon-induced prolonged biochemical response reduces hepatocarcinogenesis in hepatitis C virus infection. AB - The aim of this study was to elucidate indicator of interferon (IFN) therapy for reducing hepatocellular carcinoma (HCC) in chronic hepatitis C patients without eradicating hepatitis C virus (HCV) RNA during IFN therapy. Inclusion criteria were biopsy-proven chronic hepatitis or liver cirrhosis, IFN period for more than 1.5 years and persistently positive HCV-RNA during IFN therapy. Two hundred thirty-six patients satisfied above criteria were treated with IFN for 1.5-5 years (median 1.8 years, mean 2 years). Mean age was 55.1 years and male was 145 (61%). Eighty-one (34%) patients had severe fibrosis of the liver. These patients were prospectively monitored about HCC after the termination of IFN therapy. We regarded biochemical response (BR) as normalization of serum aminotransferase and alpha-fetoprotein for more than 1 year during IFN therapy. Cumulative rate of development of HCC after the termination of IFN therapy was 9.1% at 5th year and 26.5% at 10th year. Cox proportional analysis showed that HCC development after the termination of IFN therapy occurred when histological staging was advanced (P < 0.0001) and BR was not achieved (P = 0.009), age was >60 years (P = 0.026). The relative risk of HCC development in patients with BR was 0.36 compared with patients without BR. The attainment of BR during IFN therapy is effective in reducing hepatocarcinogenesis for patients with chronic HCV infection. PMID- 17705191 TI - Serum proteomics with SELDI-TOF-MS in congenital human cytomegalovirus hepatitis. AB - Human cytomegalovirus (HCMV) is a widespread pathogen, the most common congenital viral infection, and the leading cause of infant hepatitis syndrome. In this study, serum samples were collected from 20 HCMV-infected infants with hepatitis and 25 controls. Of the 25 infants in the control group, 5 were infected with HCMV but without hepatitis, 10 had hepatitis but no HCMV infection, and 10 were healthy. Proteomic expression in the serum was detected by WCX2 chips and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS), to identify serum protein biomarkers in infants with hepatitis syndrome resulting from HCMV. Fifteen protein peaks were distinctly different among the four groups in the mass range from 2,000 to 20,000 Da. Of these 15 peaks, 4 at 4,349.8, 5,808.7, 7,935.6, and 8,885.9 Da were significantly different between the congenital HCMV-infected infants with hepatitis and the controls. Five peaks were distinctly up-regulated in the infants with HCMV infection (3,266.8, 5,638.5, 5,909.1, 7,771.4, and 15,835.6 Da) compared to those without HCMV infection. Two proteins at 4,600.1 and 5,704.3 were up-regulated in infants with HMCV infection but no hepatitis. Four protein peaks were markedly different (7,567.0, 13,744.8, 15,100.7, and 15,915.0 Da) between the infants with hepatitis and the other controls. Comparison of the differentially expressed proteins' properties with those available on an international database suggest that specific serum proteins such as the augmenter of liver regeneration, pre-albumin, and haptoglobin closely related to liver function, and cytokines such as beta defensins 31 and 8, and macrophage-derived chemokine, among others, are involved in HMCV infection and the pathogenesis of HMCV-induced hepatitis in infants. PMID- 17705192 TI - Dengue neurovirulence in mice: identification of molecular signatures in the E and NS3 helicase domains. AB - Recent observations indicate that the clinical profile of dengue virus (DENV) infection is changing, and that neurological manifestations are becoming frequent. The neuro pathogenesis of dengue, and the contribution of viral and host factors to the disease are not well understood. To define the amino acid substitutions in DENV potentially implicated in the acquisition of a neurovirulent phenotype we used a murine model to characterize two neuroadapted strains of DENV-1, FGA/NA a5c (previously obtained), and FGA/NA P6 (recently obtained). Only three amino acid substitutions were identified in the neurovirulent strains, mapping to the E and NS3 helicase domains. These mutations enhanced the ability of neuroadapted viral strains to replicate in the CNS of infected mice, causing extensive damage with leptomeningitis and encephalitis. PMID- 17705193 TI - Do G protein-coupled receptors expressed in human lingual epithelium interact with HPV11? AB - Human papillomaviruses infect epithelia but little is known about the nature of cell surface receptors interacting with the viral particles. It has been proposed that glycosaminoglycans and integrins may be involved in the attachment process. In the present study, the putative interactions of virus-like particles of human papillomavirus type 11 (HPV11), which present a tropism for nasopharyngeal epithelia, with olfactory and taste receptors expressed in the human lingual epithelium were studied. The L1 protein of HPV11 was produced in insect cells. The presence of L1 virus-like particles was analyzed by ELISA using monoclonal antibodies specific for full-size particles and by electron microscopy. Using immunofluorescence, it was observed that virus-like particles interacted with taste buds from murine tongue, with the tagged human olfactory receptor hJCG5 expressed in HEK-293 but not with the tagged taste receptor hT2R4. This therefore suggests that hJCG5 may be involved in the adsorption process of HPV11 to lingual epithelium serving as a so-called "adsorption-adhesive molecule." PMID- 17705194 TI - Institutional factors and HIV/AIDS, TB and Malaria. AB - This paper outlines the principal institutional factors affecting the slow progress in reaching agreed targets in Africa regarding the prevention and control of HIV/AIDS, TB and Malaria. It focuses on three key factors: political analysis, strategic business approach and international inputs. Most of the analyses tend to look at the technical aspects of disease prevention and control, of political analysis there is a marked absence. Yet, we know that wider contextual or macro factors such as power and political decision making can make or break a programme. Many senior managers in public sector institutions are preoccupied with day-to-day work. Successful businesses in the private sector have some things in common with each other. Outstanding leadership, a strategic and action orientated culture, highly focused on comparative strengths on priorities and quality being some of the key ones. Adopting such successful business characteristics might make the difference to public institutions. The move to results based institutions by focussing on outputs and outcomes is for the better. However, we still need to rigorously examine the quality of inputs that the increasing availability of funds is being used on. This is especially so in relation to needing a better balance between aid for health services and that for institutional and health systems development. In addition, technical advisers from development partners need to work more across a ministry of health on institutional and management change to have a greater impact on achieving targets. PMID- 17705195 TI - ERK1/2 and p38 MAP kinases control prion protein fragment 90-231-induced astrocyte proliferation and microglia activation. AB - Astrogliosis and microglial activation are a common feature during prion diseases, causing the release of chemoattractant and proinflammatory factors as well as reactive free radicals, involved in neuronal degeneration. The recombinant protease-resistant domain of the prion protein (PrP90-231) displays in vitro neurotoxic properties when refolded in a beta-sheet-rich conformer. Here, we report that PrP90-231 induces the secretion of several cytokines, chemokines, and nitric oxide (NO) release, in both type I astrocytes and microglial cells. PrP90-231 elicited in both cell types the activation of ERK1/2 MAP kinase that displays, in astrocytes, a rapid kinetics and a proliferative response. Conversely, in microglia, PrP90-231-dependent MAP kinase activation was delayed and long lasting, inducing functional activation and growth arrest. In microglial cells, NO release, dependent on the expression of the inducible NO synthase (iNOS), and the secretion of the chemokine CCL5 were Ca(2+) dependent and under the control of the MAP kinases ERK1/2 and p38: ERK1/2 inhibition, using PD98059, reduced iNOS expression, while p38 blockade by PD169316 inhibited CCL5 release. In summary, we demonstrate that glial cells are activated by extracellular misfolded PrP90-231 resulting in a proliferative/secretive response of astrocytes and functional activation of microglia, both dependent on MAP kinase activation. In particular, in microglia, PrP90-231 activated a complex signalling cascade involved in the regulation of NO and chemokine release. These data argue in favor of a causal role for misfolded prion protein in sustaining glial activation and, possibly, glia-mediated neuronal death. PMID- 17705196 TI - Crb1 is a determinant of retinal apical Muller glia cell features. AB - Mutations in the human Crumbs homologue-1 (CRB1) gene cause retinal blinding diseases, such as Leber congenital amaurosis and retinitis pigmentosa. In the previous studies we have shown that Crb1 resides in retinal Muller glia cells and that loss of Crb1 results in retinal degeneration (particularly in the inferior temporal quadrant of the mouse eye). Degeneration is increased by exposure to white light. Here, we studied the role of light and aging to gain a better understanding of the factors involved in the progress of retinal disease. Our data reveal that light is neither sufficient nor required to induce retinal disorganization and degeneration in young Crb1(-/-) mutant mice, suggesting that it rather modulates the retinal phenotype. Gene expression profiling showed that expression of five genes is altered in light-exposed Crb1(-/-) mutant retinas. Three of the five genes are involved in chromosome stabilization (Pituitary tumor transforming gene 1 or Pttg1, Establishment of cohesion 1 homolog 1 or Esco1, and a gene similar to histone H2B). In aged retinas, degeneration of photoreceptors, inner retinal neurons, and retinal pigment epithelium was practically limited to the inferior temporal quadrant. Loss of Crb1 in Muller glia cells resulted in an irregular number and size of their apical villi. We propose that Crb1 is required to regulate number and size of these Muller glia cell villi. The subsequent loss of retinal integrity resulted in neovascularization, in which blood vessels of the choroid protruded into the neural retina. PMID- 17705197 TI - Dose intensity and hematologic toxicity in older cancer patients receiving systemic chemotherapy. AB - BACKGROUND: This prospective study was undertaken to evaluate patient and treatment characteristics that contribute to hematologic toxicity in older cancer patients. METHODS: A nationwide study of 115 community oncology practices was conducted between 2002 and 2005 with data collected on 976 patients who had received chemotherapy for common malignancies, including lung cancer, colorectal cancer, breast cancer, ovarian cancer, genitourinary cancer, and lymphoma. Primary outcomes included severe neutropenia (SN) and febrile neutropenia (FN). Secondary outcomes included delivered relative dose intensity (RDI) <85%, dose delays > or =15% days, and reductions > or =15%. RESULTS: Approximately 50% of both patients with early-stage disease and patients with advanced-stage disease received an actual RDI <85%, and this rate reached 60% in the oldest group (aged >80 years). Increasing age was associated with lower actual RDI (P = .030) and averaged 87.5% across all elderly age groups. A decreasing trend in SN or FN events occurred with increasing age (P for trend = .039), with the majority of initial neutropenic events occurring in Cycle 1 for all age groups. Among the patients who received an actual RDI > OR =85%, there was no significant difference in SN or FN by age group or disease stage. Independent risk factors for the development of SN or FN included cancer type, planned RDI > or =85%, body surface area < or =2m(2), anthracycline- or platinum-based regimens, previous chemotherapy, elevated blood urea nitrogen, and alkaline phosphatase. Neutropenic complications decreased significantly with primary colony-stimulating factor (CSF) prophylaxis (coefficient of determination [R(2)] = 0.260; c-statistic = 0.782). CONCLUSIONS: Among cancer patients aged > or =70 years, 50% of whom received relatively full-dose chemotherapy, increasing age alone did not increase the risk of hematologic toxicity. PMID- 17705198 TI - Myelin-associated glycoprotein reduces axonal branching and enhances functional recovery after sciatic nerve transection in rats. AB - The mature peripheral nervous system (PNS) generally shows better regeneration of injured axons as opposed to the central nervous system (CNS). However, complete functional recovery is rarely achieved even in the PNS although morphologically good axonal regeneration often occurs. This mainly results from aberrant reinnervation due to extensive branching of cut axons with consequent failure of synchronized movements of the muscles. Myelin-associated glycoprotein (MAG), a well-characterized molecule existing both in the CNS and PNS myelin, is considered to be a potent inhibitor of axonal regeneration especially in the CNS. In the present study, we investigated whether MAG has any effects not only on axonal elongation, but also on axonal branching. We show herein that MAG minimized branching of the peripheral axons both in vitro and in vivo via activation of RhoA. Furthermore, after sciatic nerve transection in rats, focal and temporary application of MAG to the lesion dramatically enhanced the functional recovery. Using double retrograde labeling and preoperative/postoperative labeling of spinal neurons, reduced hyperinnervation and improved accuracy of target reinnervation was confirmed, respectively. In conclusion, as MAG significantly improves the quality of axonal regeneration, it can be used as a new therapeutic approach for peripheral nerve repair with possible focal and temporary application. PMID- 17705199 TI - Notch signaling modulates the activation of microglial cells. AB - The Notch signaling pathway plays a crucial role in specifying cellular fate in metazoan development by regulating communication between adjacent cells. Correlative studies suggested an involvement of Notch in hematopoietic cell development. Here, we report that the Notch pathway is expressed and active in microglial cells. During inflammatory activation, the transcription of the Notch down-stream effector Hes1 is downregulated. When Notch1 transcription in microglia is inhibited, an upregulation of the expression of pro-inflammatory cytokines is observed. Notch stimulation in activated microglia, using a soluble form of its ligand Jagged1, induces a decrease in pro-inflammatory cytokines secretion and nitric oxide production as well as an increase in phagocytic activity. Notch-stimulation is accompanied by an increase in the rate of STAT3 phosphorylation and nuclear translocation. Our results show that the Notch pathway plays an important role in the control of inflammatory reactions in the CNS. PMID- 17705201 TI - Up to seven-component adducts by unprecedented multiple alkyne and carbonyl insertions in the metal-carbon bond of chromium alkoxy alkynyl carbene complexes. AB - Chromium alkoxy alkynyl Fischer carbene complexes react with symmetrical internal alkynes to form new and different organometallic species, which result from consecutive insertions of several alkyne units and carbonyl groups into the metal carbon bond. The insertion sequence can be controlled and, by slight modification of the reaction conditions, it can be directed to the preparation of either seven or five-component adducts. Three molecules of alkyne, two carbonyl groups, the carbene ligand and the chromium metal moiety partake in the creation of seven new carbon-carbon bonds and two five-membered carbocycles in the first case while four new carbon-carbon bonds, a sigma Cr--C(sp(2)) bond and a cyclopentadienyl moiety are built in the second case. Evidence that five-component chromium complexes are intermediates in the formation of seven-component adducts is provided; they are also able to insert a unit of a different internal alkyne which confers more diversity to the seven-component adducts. The presence of the sigma Cr--C(sp(2)) bond has also been exploited to develop the synthesis of both cyclopentene-fused and novel spiro-cyclopentenones as well as symmetrical biscyclopentenones. Finally, the isolation of six-component adducts, when tolane was employed as the initial alkyne, provides further support to the proposed mechanism. PMID- 17705200 TI - Decreased estradiol release from astrocytes contributes to the neurodegeneration in a mouse model of Niemann-Pick disease type C. AB - Niemann-Pick disease type C (NPC) is a deadly neurodegenerative disease often caused by mutation in a gene called NPC1, which results in the accumulation of unesterified cholesterol and glycosphingolipids in the endosomal-lysosomal system. Most studies on the mechanisms of neurodegeneration in NPC have focused on neurons. However, the possibility also exists that NPC1 affects neuronal functions indirectly by acting on other cells that are intimately interacting with neurons. In this study, using a heterotypic neuron-glia coculture system, we found that wild-type neurons cultured on a layer of NPC1-/- astrocytes showed decreased neurite growth compared with those cultured on wild-type astrocytes. RT PCR and immunohistochemical assessments showed significantly lower expression of neurosteroid enzymes and StAR (steroidogenic acute regulatory protein) in NPC1-/- astrocyte cultures than in wild-type cultures. Furthermore, a reduced level of estradiol was measured from both astrocyte culture medium and whole brains from NPC1-/- mice. Administration of 17beta-estradiol to neonatal NPC1-/- mice significantly delayed the onset of neurological symptoms, increased Purkinje cell survival, and extended the animals' life span. Our findings suggest that astrocyte dysfunction contributes to the neurodegeneration of NPC and estradiol treatment may be useful in ameliorating progression of the disease. PMID- 17705202 TI - Indium-mediated selective introduction of a 1,3-butadien-2-yl group at the C4 position in 2-azetidinones and application of 1,3-diene-tethered 2-azetidinones in the Diels-Alder reaction. AB - The reaction of 4-acetoxy-2-azetidinones with organoindium reagents generated in situ from indium and 1,4-dibromo-2-butyne in the presence of LiCl in DMF selectively produced 2-azetidinones which contain a 1,3-butadienyl-2-yl group at the C4-position in good yields. The Diels-Alder reaction of 4-[(1-methylene)prop 2-enyl]-2-azetidinones with a variety of dienophiles provided 2-azetidinones with valuable functional-group-substituted six-membered rings at the C4-position in good yields. PMID- 17705203 TI - Positional assembly of enzymes in polymersome nanoreactors for cascade reactions. PMID- 17705204 TI - Saccharin inhibits carbonic anhydrases: possible explanation for its unpleasant metallic aftertaste. PMID- 17705205 TI - Proline-modified DNA as catalyst of the aldol reaction. PMID- 17705206 TI - Surface noncovalent bonding for rational design of hierarchical molecular self assemblies. PMID- 17705207 TI - Dynamic kinetic resolution allows a highly enantioselective synthesis of cis alpha-aminocycloalkanols by ruthenium-catalyzed asymmetric hydrogenation. PMID- 17705208 TI - Thermoluminescence originating from the singlet excited state of 1,4 diarylcyclohexane-1,4-diyls: a potentially general strategy for the observation of short-lived biradicals. PMID- 17705209 TI - Carbene activation of P4 and subsequent derivatization. PMID- 17705211 TI - Provider response to insulin-induced hypoglycemia in hospitalized patients. AB - BACKGROUND: Risk of hypoglycemia is a major barrier to the implementation of tight blood glucose (BG) control in hospitalized patients. The objective of this study was to evaluate the changes in diabetes treatment after an episode of hypoglycemia. METHODS: The study was a retrospective data analysis of patients who received 50% dextrose for an episode of hypoglycemia. Data on immediate and subsequent changes in the antidiabetic medications the patients received were collected and evaluated by 2 diabetes specialists. RESULTS: Data from 52 patients were included in the study. Mean BG at the time of dextrose administration was 52.1 +/- 9.3 mg/dL (range 31-68). Mean BG during the 24 hours before the hypoglycemic episode was 137.5 +/- 57.0 mg/dL (range 63-287). Insulin dose was held at the time of the hypoglycemic episode in all 52 patients. Diabetes specialists agreed with this decision 100% of the time. Changes were subsequently made in the treatment of only 21 patients (40%), and diabetes specialists agreed with the changes made for 11 of these patients (52%). Thirty-one patients (60%) received no changes in treatment, and diabetes specialists agreed with that decision for 10 patients (32%). CONCLUSIONS: Provider response in making treatment changes after an episode of hypoglycemia is suboptimal. Standardized protocols to make changes in diabetes treatment after an episode of hypoglycemia need to be tested. PMID- 17705210 TI - Consequences of missed opportunities. PMID- 17705212 TI - Endoscopic laser surgery in severe second-trimester twin-twin transfusion syndrome: a three-year experience from a Latin American center. AB - OBJECTIVE: In order to assess the outcome of pregnancies complicated by severe second trimester twin-twin transfusion syndrome (TTTS) undergoing treatment with endoscopic laser surgery, we reviewed our experience following the implementation of an institutional fetal surgery program. METHODS: Patients presenting with monochorionic-diamniotic twin pregnancies complicated by severe TTTS before 26 weeks of gestation were offered endoscopic laser surgery to coagulate placental vascular anastomoses. Using regional anesthesia and guided by real-time sonography, anastomoses were identified and selectively coagulated. At the end of the procedure, amniodrainage was performed to restore normal amniotic fluid volume. Follow-up and delivery were carried out at the referring institutions. Six-month follow-up was performed in all cases. RESULTS: During a 3-year period from September 2003 to December 2006, 33 consecutive cases of severe TTTS were operated on at a median gestational age of 21 weeks (range 17-25). Nine (27.3%) cases were classified as stage II, 21 (63.6%) as stage III, and three (9.1%) as stage IV. The placenta was anterior or predominantly anterior in 15 (45.5%) of the cases. Overall, both twins were born alive in 16 (48.5%) cases, only one twin was born alive in 11 (33.3%), and neither was born alive in the remaining six (18.2%). Therefore, 81.8% (27 of 33) of the pregnancies resulted in at least one liveborn infant. Among them, the mean gestational age at delivery was 32 weeks (range 23-38) and the mean birthweight of the liveborn infants was 1591 g (range 350-3800). Thirty-four infants survived the perinatal period, yielding an overall perinatal survival rate of 51.5%, with 75.8% (25 of 33) of the pregnancies resulting in at least one perinatal survivor. All neonatal deaths were associated with extreme prematurity. CONCLUSIONS: This preliminary experience suggests that selective laser coagulation appears to be a good treatment option in cases of monochorionic twin pregnancies complicated by severe TTTS. However, technical skills and adequate equipment are required for implementing a fetal surgery program. Auditing outcomes during the learning curve would help in identifying potential problems. PMID- 17705213 TI - Early prenatal diagnosis of ICF syndrome by mutation detection. PMID- 17705214 TI - Applying quantitative methods for detecting new drug safety signals in pharmacovigilance national database. AB - OBJECTIVES: To applies three different methods of signal detection to the registered adverse events in Iranian Pharmacovigilance database over the period of 1998-2005. METHODS: All adverse drug reactions (ADRs) reported to Iranian Pharmacovigilance Center (IPC) from March 1998 through January 2005, were used for the analysis. The data were analysed based on three different signal detection methods including reporting odds ratios (RORs), information component (IC) and proportional reporting ratios (PRRs). The signals detected were categorised based on the number of reports per drug-adverse event combination, severity of the event and labelled or unlabelled ADRs. RESULTS: During the study period, 6353 cases of ADR reports describing 11 130 reactions were received by IPC. The dataset involved 4975 drug-adverse event combinations. The count of drug event combinations was 1, 2 and 3 or more for 3470, 726 and 779 combinations, respectively. According to PRRs, there were 2838, 872 and 488 drug-event combinations known as a signal for the pairs with the reporting frequency of 1, 2 and 3 reports, respectively. The results of estimating RORs showed that 2722, 862 and 481 drug-adverse event combinations were detected to be signal for the pairs with the reporting frequency of 1, 2 and 3 reports, respectively, while measuring IC and IC-2SD detected 1120, 378 and 235 for the same reporting frequencies. Diclofenac-induced paralysis and tramadol-induced severe reactions were the most important signals. CONCLUSION: Applying quantitative signal detection methods to the database of national pharmacovigilance centres is necessary to early detection of drug safety alerts. PMID- 17705215 TI - Suppurative complications and upper airway obstruction in infectious mononucleosis. PMID- 17705216 TI - Spontaneous pneumomediastinum. PMID- 17705217 TI - Inpatient hyperglycemia. PMID- 17705218 TI - Steroid hyperglycemia. PMID- 17705220 TI - Are numbers special? Comparing the generation of verbal materials from ordered categories (months) to numbers and other categories (animals) in an fMRI study. AB - Months, days of the week, and numbers differ from other verbal concepts because they are ordered in a sequence, whereas no order is imposed on members of other categories, such as animals or tools. Recent studies suggest that numbers activate a representation of their quantity within the intraparietal sulcus (IPS) automatically, that is, in tasks that do not require the processing of quantity. It is unclear, however, whether ordered verbal materials in general and not only numbers activate the IPS in such tasks. In the present functional magnetic resonance imaging study word generation of months, numbers, and animals were compared. Word generation of numbers and nonnumerical materials from an ordered category (months) activated the IPS more strongly than generating items from a not-ordered category such as animals or the verbal control conditions. An ROI analysis of three subregions within the anterior IPS revealed that the most anterior and lateral of these regions, human intraparietal area hIP2, shows a greater sensitivity to ordered materials than the other two areas, hIP1 and hIP3. Interestingly, no difference in activation was observed within the IPS between numbers and months suggesting that the activation of the IPS might not be modulated by the additional quantity information carried by numbers. PMID- 17705222 TI - RE: a rebuttal: secret ties to industry and conflicting interests in cancer research. PMID- 17705219 TI - Region-of-interest-based analysis with application of cortical thickness variation of left planum temporale in schizophrenia and psychotic bipolar disorder. AB - In neuroimaging studies, spatial normalization and multivariate testing are central problems in characterizing group variation of functions (e.g., cortical thickness, curvature, functional response) in an atlas coordinate system across clinical populations. We present a region-of-interest (ROI)-based analysis framework for detecting such a group variation. This framework includes two main techniques: ROI-based registration via large deformation diffeomorphic metric surface mapping and a multivariate testing using a Gaussian random field (GRF) model on the cortical surface constructed by the eigenfunctions of the Laplace Beltramioperator. We compared our GRF statistical model with a pointwise hypothesis testing approach, whose P-value is corrected using false discovery rate or random field theory at several smoothness scales. As an illustration, we applied this framework to a clinical study of the cortical thickness of the left planum temporale (PT) in subjects with psychotic bipolar disorder, schizophrenia, and healthy comparison controls. Our results show that the anterior portion of the left PT is thinner in the psychotic bipolar and schizophrenic groups than in the healthy control group, and the posterior portion of the left PT shows the reversal finding. Moreover, there may be a greater thickness variation in the left PT in psychotic bipolar patients when compared with that in schizophrenic patients. PMID- 17705221 TI - Mechanisms of protection by the betaine-homocysteine methyltransferase/betaine system in HepG2 cells and primary mouse hepatocytes. AB - Betaine-homocysteine methyltransferase (BHMT) regulates homocysteine levels in the liver. We previously reported that the alteration of BHMT is associated with alcoholic liver steatosis and injury. In this study, we tested whether BHMT protects hepatocytes from homocysteine-induced injury and lipid accumulation. Both BHMT transfectants of HepG2 cells and primary mouse hepatocytes with suppressed BHMT were generated. Comparisons were made between the cell models with respect to their response to homocysteine treatments. Homocysteine metabolism was impaired in HepG2 cells, and the expression of BHMT in HepG2 cells ameliorated the impairment and stabilized the levels of intracellular homocysteine after the addition of exogenous homocysteine. BHMT expression inhibited homocysteine-induced glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and homocysteine-induced cell death. A betaine treatment protected primary mouse hepatocytes from a homocysteine-induced increase in GRP78 and cell death but not a tunicamycin-induced increase. Homocysteine induced greater CHOP expression (2.7-fold) in BHMT small interfering RNA (siRNA)-transfected cells than in a control (1.9-fold). Homocysteine-induced cell death was increased by 40% in the siRNA-treated cells in comparison with the control. Apolipoprotein B (apoB) expression was higher and triglycerides and cholesterol were lower in HepG2 expressing BHMT. In primary mouse hepatocytes, homocysteine induced the accumulation of triglycerides and cholesterol, which was reduced in the presence of betaine. Betaine partially reduced homocysteine induced sterol regulatory element binding protein 1 expression in HepG2 cells and increased S-adenosylmethionine in primary mouse hepatocytes. CONCLUSION: The BHMT/betaine system directly protects hepatocytes from homocysteine-induced injury but not tunicamycin-induced injury, including an endoplasmic reticulum stress response, lipid accumulation, and cell death. This system also exhibits a more generalized effect on liver lipids by inducing ApoB expression and increasing S-adenosylmethionine/S-adenosylhomocysteine. PMID- 17705223 TI - Ontogeny of conspecific and heterospecific alarm call recognition in wild Verreaux's sifakas (Propithecus verreauxi verreauxi). AB - The production of vocalizations in nonhuman primates is predominantly innate, whereas learning influences the usage and comprehension of vocalizations. In this study, I examined the development of alarm call recognition in free-ranging infant Verreaux's sifakas. Specifically, I investigated their ability to recognize conspecific alarm calls as well as those of sympatric redfronted lemurs (Eulemur fulvus rufus) in Kirindy forest, western Madagascar. Both species have functionally referential alarm calls for aerial predators and give general alarm calls for both aerial and general predators and also other kinds of threats, such as intergroup encounters with conspecifics. I conducted playback experiments with members of two birth cohorts (nine and ten individuals) to determine the age at which infant Verreaux's sifakas discriminate between conspecific alarm calls, heterospecific alarm calls, and non-alarm vocalizations (parrot song). Most 3-4 months old infants fled toward adults after hearing any playback stimuli, whereas 4-5-month-old infants did so only after presentation of alarm calls. Moreover, all infants of these age classes showed a longer latency to flee after the parrot song indicating their emerging ability to discriminate between alarm calls and non-alarm stimuli. At an age of about 6 months, infants switched from fleeing toward adults to performing adult-like escape responses after presentation of conspecific and heterospecific alarm calls. Thus, the ability to discriminate between alarm from non-alarm stimuli precedes the appearance of adult-like responses. The transition to adult-like escape behavior was coincident with the physical independence of infants from their mothers. PMID- 17705224 TI - Unemployment and aggression: the moderating role of self-awareness on the effect of unemployment on aggression. AB - In February 2005, the unemployment rate in Germany surpassed the 10% mark. Derived from the revised version of the frustration-aggression hypothesis [Berkowitz, 1989], the present studies investigated the association between unemployment and aggression, as well as the moderating role of the self in this context. Because previous research on unemployment and aggression has been plagued by the cause-and-effect issue, the present research employed both an experimental and a correlational field approach. Three studies revealed that participants who expected to be unemployed after their degree (Studies 1 and 3), or who were currently unemployed (Study 2), reported stronger aggressive inclinations than participants who expected not to be unemployed or who were not unemployed at the time of data collection. However, this aggression-eliciting effect of expected or real unemployment only occurred for participants with low self-awareness. Participants who could actualize their self prior to reporting on aggression were not differently affected by different expectations or states of unemployment. PMID- 17705225 TI - Ethanolic fermentation of hydrolysates from ammonia fiber expansion (AFEX) treated corn stover and distillers grain without detoxification and external nutrient supplementation. AB - External nutrient supplementation and detoxification of hydrolysate significantly increase the production cost of cellulosic ethanol. In this study, we investigated the feasibility of fermenting cellulosic hydrolysates without washing, detoxification or external nutrient supplementation using ethanologens Escherichia coli KO11 and the adapted strain ML01 at low initial cell density (16 mg dry weight/L). The cellulosic hydrolysates were derived from enzymatically digested ammonia fiber expansion (AFEX)-treated corn stover and dry distiller's grain and solubles (DDGS) at high solids loading (18% by weight). The adaptation was achieved through selective evolution of KO11 on hydrolysate from AFEX-treated corn stover. All cellulosic hydrolysates tested (36-52 g/L glucose) were fermentable. Regardless of strains, metabolic ethanol yields were near the theoretical limit (0.51 g ethanol/g consumed sugar). Volumetric ethanol productivity of 1.2 g/h/L was achieved in fermentation on DDGS hydrolysate and DDGS improved the fermentability of hydrolysate from corn stover. However, enzymatic hydrolysis and xylose utilization during fermentation were the bottlenecks for ethanol production from corn stover at these experimental conditions. In conclusion, fermentation under the baseline conditions was feasible. Utilization of nutrient-rich feedstocks such as DDGS in fermentation can replace expensive media supplementation. PMID- 17705226 TI - Enhancement of PCB degradation by Burkholderia xenovorans LB400 in biphasic systems by manipulating culture conditions. AB - Two-phase partitioning bioreactors (TPPBs) can be used to biodegrade environmental contaminants after their extraction from soil. TPPBs are typically stirred tank bioreactors containing an aqueous phase hosting the degrading microorganism and an immiscible, non-toxic and non-bioavailable organic phase functioning as a reservoir for hydrophobic compounds. Biodegradation of these compounds in the aqueous phase results in thermodynamic disequilibrium and partitioning of additional compounds from the organic phase into the aqueous phase. This self-regulated process can allow the delivery of large amounts of hydrophobic substances to degrading microorganisms. This paper explores the reactor conditions under which the polychlorinated biphenyl (PCB) degrader Burkholderia xenovorans LB400 can degrade significant amounts of the PCB mixture Aroclor(R) 1242. Aroclor(R) degradation was found to stall after approximately 40 h if no carbon source other than PCBs was available in the reactor. Sodium pyruvate was found to be a suitable carbon source to maintain microbial activity against PCBs and to function as a substrate for additional cell growth. Both biphenyl (while required during the inoculum preparation) and glucose had a negative effect during the Aroclor(R) degradation phase. Initial Aroclor(R) 1242 degradation rates in the presence of pyruvate were high (6.2 mg L(-1) h(-1)) and 85% of an equivalent concentration of 100 mg Aroclor(R) 1242 per L aqueous phase could be degraded in 48 h, which suggest that solvent extraction of PCBs from soil followed by their biodegradation in TPPBs might be a feasible remediation option. PMID- 17705227 TI - CFD simulation of non-Newtonian fluid flow in anaerobic digesters. AB - A general mathematical model that predicts the flow fields in a mixed-flow anaerobic digester was developed. In this model, the liquid manure was assumed to be a non-Newtonian fluid, and the flow governed by the continuity, momentum, and k-epsilon standard turbulence equations, and non-Newtonian power law model. The commercial computational fluid dynamics (CFD) software, Fluent, was applied to simulate the flow fields of lab-scale, scale-up, and pilot-scale anaerobic digesters. The simulation results were validated against the experimental data from literature. The flow patterns were qualitatively compared for Newtonian and non-Newtonian fluids flow in a lab-scale digester. Numerical simulations were performed to predict the flow fields in scale-up and pilot-scale anaerobic digesters with different water pump power inputs and different total solid concentration (TS) in the liquid manure. The optimal power inputs were determined for the pilot-scale anaerobic digester. Some measures for reducing dead and low velocity zones were proposed based upon the CFD simulation results. PMID- 17705228 TI - Purification of equine IgG using membrane based enhanced hybrid bioseparation technique: a potential method for manufacturing hyperimmune antibody. AB - Hyperimmune equine IgG is widely used as antivenom and anti-rabies agents. This article discusses a membrane based enhanced hybrid bioseparation technique for efficient and scalable purification of equine immunoglobulin G (IgG) from horse serum. This technique is an improved version of a standard hybrid bioseparation technique developed within our group earlier for fractionation of human plasma proteins (Ghosh. 2004. J Membr Sci 237: 109-117). In the presence of a high antichaotropic salt concentration, equine IgG is selectively and reversibly captured within a stirred cell membrane module from horse serum, partly due to precipitation and microfiltration, and partly due to hydrophobic interaction based membrane adsorption, while the impurities are washed out from the device. The reversibly sequestered IgG is then released by lowering the salt concentration which favor both dissolution of the precipitated IgG and desorption of the membrane bound IgG. The enhanced hybrid bioseparation technique improves the IgG recovery from the membrane module by switching from a stirring to non stirring mode during the IgG release phase. It also reduces membrane fouling by an appropriate pH switch. The effects of operating conditions on equine IgG capture were first systematically studied. The enhanced hybrid bioseparation technique was followed by an ultrafiltration step to remove ammonium sulfate and low molecular weight impurities. The equine IgG purity obtained under optimized conditions was 88% and its recovery was over 90%, both being significantly higher than corresponding values obtained using currently used purification techniques. PMID- 17705229 TI - Primitive versus derived traits in the developmental program of the vertebrate head: views from cyclostome developmental studies. AB - Evolution can be viewed as a series of changes in the developmental program along the phylogenetic tree. To better understand the early evolution of the vertebrate skull, we can use the embryos of the cyclostome species as models. By comparing the cyclostome developmental patterns with those of gnathostomes, it becomes possible to distinguish the primitive and derived parts of the developmental program as taxon-specific traits. These traits are often recognizable as developmental constraints that define taxa by biasing the developmental trajectories within a certain limited range, resulting in morphological homologies in adults. These developmental constraints are distributed on the phylogenetic tree like the morphological character states of adult animals and are associated with specific regions of the tree. From this perspective, we emphasize the importance of considering gene expression and embryonic anatomy as the mechanistic bases that can result in homologous or nonhomologous morphological patterns at later developmental stages. Taking the acquisition of the jaw and trabecula cranii as examples, we demonstrate that a set of embryonic features can be coupled or decoupled during evolution and development. When they are coupled, they exert an ancestral developmental constraint that results in homologous morphological patterns, and when they are decoupled, the ancestral constraints tend to be abandoned, generating a new body plan. The heterotopy behind the specification of the oral domain is an example of decoupling, based on shifted tissue interactions. We also stress the importance of "developmental burden" in determining the sequential order of changes through evolution. PMID- 17705230 TI - SELDI protein profiling of dunning R-3327 derived cell lines: identification of molecular markers of prostate cancer progression. AB - BACKGROUND: We recently demonstrated the protein expression profiling of Dunning rat tumor cell lines of varying metastatic potential (G (0%), AT-1 ( approximately 20%), and MLL (100%)) using SELDI-TOF-MS. As a parallel effort, we have been pursuing the identification of the protein(s) comprising the individual discriminatory "peaks" and evaluating their utility as potential biomarkers for prostate cancer progression. METHODS: To identify the observed SELDI-TOF-MS m/z (mass/charge) values with discriminatory expression between different sublines, we employed a combination of chemical pre-fractionation, liquid chromatography, gel electrophoresis and tandem mass spectroscopy. Identified proteins were then verified by immuno-assay and Western analysis. RESULTS: A 17.5 K m/z SELDI-TOF-MS peak was found to retain discriminatory value in each of two separate study-sets with an increased expression in the metastatic MLL line. Sequence identification and subsequent immunoassays verified that Histone H2B is the observed 17.5 K m/z SELDI peak. SELDI-based immuno-assay and Western Blotting revealed that Histone H2B is specifically over-expressed in metastatic MLL lines. CONCLUSIONS: SELDI TOF MS analysis of the Dunning prostate cancer cell lines confirmed the consistent overexpression of a 17.5 K m/z peak in metastatic MLL subline. The 17.5 kDa protein from MLL has been isolated and identified as Histone H2B. PMID- 17705231 TI - Monoclonal anti-A antibody removal by synthetic A antigen immobilized on specific antibody filters. AB - Removal of blood group anti-A and anti-B antibodies can prevent hyperacute organ rejection in ABO-incompatible transplantation. We are developing an extracorporeal-specific antibody filter (SAF) as an immunoadsorption device for direct removal of ABO blood group antibodies from whole blood, without the need for plasma separation and plasma exchange. A hollow fiber-based small scale SAF (mini-SAF) device was fabricated and synthetic A antigen, Atrisaccharide (Atri) conjugated to activated polyacrylic acid, was immobilized on the fiber lumen surface. Monoclonal antibody anti-A IgM were specifically removed up to 70% of initial antibodies using mini-SAF device. The monoclonal anti-A capture experiments on mini-SAF indicated that antibody removal relative to the initial concentration is independent of inlet concentration in the beginning; however, as the surface starts saturating with bound antibodies, removal becomes dependent on inlet concentration. No significant effect of flow rate on removal rate was observed. The radial diffusion and axial convection-based mathematical model developed for unsteady state antibody removal was in good agreement with the experimental data and showed that the antibody removal rate can be maximized by increasing the antibody-binding capacity of the SAF. PMID- 17705232 TI - Lentiviruses inefficiently incorporate human parainfluenza type 3 envelope proteins. AB - We have previously shown that the envelope glycoproteins of human parainfluenza type 3 (HPIV3), F and HN, are able to pseudotype lentiviruses, but the titers of these viruses are too low for use in clinical gene transfer. In this study we investigated the cause of these low titers. We compared the mRNA and protein expression levels of HN and F in transfected cells and in cells infected with wild-type HPIV3. Transfected cells contained similar levels of HN and F cytosolic mRNA, but fewer cell-surface HN and F proteins (3.8- and 1.3-fold less, respectively), than cells infected with wild-type HPIV3. To increase expression of HN in transfected cells, we codon-optimized HN and used it to transfect lentivirus producer cells. Cell surface expression of HN, as well as the amount of HN incorporated into virus particles, increased two- to threefold. Virus titers increased 1.2- to 6.4-fold, and the transduction efficiency of polarized MDCK cells via their apical surfaces increased 1.4-fold. Interestingly, even though codon optimization improved the expression levels of HN and virus titers, we found that HPIV3 pseudotyped viruses contained about 14-fold fewer envelope proteins than lentiviruses pseudotyped with the amphotropic envelope protein. Taken together, our findings suggest that titers are low, not because virus producer cells express levels of HPIV3 envelope proteins that are too low, but because too few of these proteins are incorporated by the lentiviruses for them to be able to efficiently transduce cells. PMID- 17705233 TI - Simultaneous estimation of chlorophyll a and lipid contents in microalgae by three-color analysis. AB - A method of rapid determination of chlorophyll a and lipid contents of microalgae based on colorimetric analysis of the digital images of the microalgae is proposed. The color variation of microalgae during cultivation is evaluated by the brightness of the three primary colors (red, green, and blue). The brightness values of the three primary colors are modeled as two linear correlation functions (RGB model) for microalgal chlorophyll a and lipid contents, respectively. The chlorophyll a and lipid contents predicted by the proposed model are compared with that determined by the standard methods. The good agreement of the model predictions with experimental results is demonstrated with a squared correlation coefficient (R(2)) of 0.99 for chlorophyll a and lipid. The reliability of the RGB model was verified in real cultivations of the microalgae in a photobioreactor. Growth dynamics, contents of chlorophyll a and lipid corresponded very well with previously reported studies. PMID- 17705234 TI - Production of cell-enclosing hollow-core agarose microcapsules via jetting in water-immiscible liquid paraffin and formation of embryoid body-like spherical tissues from mouse ES cells enclosed within these microcapsules. AB - We developed agarose microcapsules with a single hollow core templated by alginate microparticles using a jet-technique. We extruded an agarose aqueous solution containing suspended alginate microparticles into a coflowing stream of liquid paraffin and controlled the diameter of the agarose microparticles by changing the flow rate of the liquid paraffin. Subsequent degradation of the inner alginate microparticles using alginate lyase resulted in the hollow-core structure. We successfully obtained agarose microcapsules with 20-50 microm of agarose gel layer thickness and hollow cores ranging in diameter from ca. 50 to 450 microm. Using alginate microparticles of ca. 150 microm in diameter and enclosing feline kidney cells, we were able to create cell-enclosing agarose microcapsules with a hollow core of ca. 150 microm in diameter. The cells in these microcapsules grew much faster than those in alginate microparticles. In addition, we enclosed mouse embryonic stem cells in agarose microcapsules. The embryonic stem cells began to self-aggregate in the core just after encapsulation, and subsequently grew and formed embryoid body-like spherical tissues in the hollow core of the microcapsules. These results show that our novel microcapsule production technique and the resultant microcapsules have potential for tissue engineering, cell therapy and biopharmaceutical applications. PMID- 17705235 TI - Preconceptional and prenatal screening for fragile X syndrome: experience with 40,000 tests. AB - OBJECTIVES: To determine the carrier frequency of fragile X syndrome, and the rate of expansion from premutation (PM) carrier to full mutation (FM) fetus. METHODS: Results were analyzed on women with no family history of fragile X syndrome, or who were PM/FM carriers, who were tested between January 1994 and June 2004. PM was defined 55-199 repeats, FM above 200. RESULTS: Out of 40 079 women screened, 5 FM and 255 PM carriers were detected. There was no significant difference in carrier frequency between those with versus those without family history of mental retardation or developmental abnormalities: 1 in 128 (28/3596) versus 1 in 157 (232/36 483). However, the median of repeats differed significantly: 58 and 66 repeats, respectively, (P < 0.0001). Invasive prenatal diagnosis was carried out in 370 pregnancies (7 FM and 363 PM). Thirty FM fetuses were detected. There was a lower expansion rate in cases without a family history: 10% (17/169 PMs) compared to 50% (11/22 PMs) in those with a history, but this could be accounted for by the difference in allele size. CONCLUSION: There is now sufficient information on screening parameters and prenatal diagnosis of fragile X syndrome to offer testing to women of reproductive age. PMID- 17705236 TI - Prenatal detection of Pierre Robin sequence with deletion Xp and additional trisomy 14q by telomere screening. PMID- 17705237 TI - Predictive blood group genetics in hemolytic disease of the fetus and newborn: a 10-year review of a laboratory evaluation of amniotic fluid-derived DNA. AB - OBJECTIVE: To identify the types of requests, the patterns of testing, and the error rates associated with the genetic identification of fetuses at risk for immune-mediated hemolytic disease. METHOD: Retrospective review of the laboratory information system for all fetal blood group genotyping tests performed at Mount Sinai Hospital, Toronto, Canada from January 1997 to December 2006. RESULTS: Amniotic fluid-derived DNA, from 220 women (243 pregnancies), was tested for one or more antigens (279 tests) when the father was heterozygous for the inferred blood group antigen or was unavailable. The PCR amplification failure rate of amniotic fluid-derived DNA was 5.0%. When the father was considered hemizygous for RHD or was not available, the fetus was positive in 68.6% and 72.7% of cases, respectively. Two amniotic fluid-derived DNA KEL1 SSP-PCR results did not correlate with the result determined from cultured amniocyte DNA. CONCLUSIONS: Paternal RHD hemizygosity may be overestimated. Thus, we recommend that RHD zygosity be established by molecular analysis of the RHD breakpoint. Cultured amniocytes should be reserved for testing if the amniotic fluid-derived DNA is inconclusive due to PCR amplification failure. We use PCR-RFLP genotyping methods for RHCE*E/RHCE*e (Rh E/e), KEL1/KEL2 (K/k), FYA/FYB (Fy(a/b)), and JKA/JKB (Jk(a/b)). PMID- 17705238 TI - Extremely rare case of cephalothoracopagus characterized by differences of external genitalia. PMID- 17705239 TI - Editorial: assessing the safety of dietary supplements. PMID- 17705240 TI - Impact of Society of Hospital Medicine workshops on hospitalists' knowledge and perceptions of health care-associated infections and antimicrobial resistance. AB - BACKGROUND: Health care-associated infections and antimicrobial resistance threaten the safety of hospitalized patients. New prevention strategies are necessary to address these problems. In response, the Society of Hospital Medicine (SHM) in collaboration with the Centers for Disease Control and Prevention developed and conducted workshops to educate hospitalists about conducting quality improvement programs to address antimicrobial resistance and health care-associated infections in hospitalized patients. METHODS: SHM collected and analyzed data from pretests and posttests administered to physicians who attended SHM workshops in 2005 in 1 of 3 major cities: Denver, Colorado; Boston, Massachusetts; or Portland, Oregon. RESULTS: A total of 69 SHM members attended the workshops, and 50 completed both a pretest and a posttest. Scores on the knowledge-based questions increased significantly from pretest to posttest (x = 48% vs. 63%, P < .0001); however, perceptions of the problem of antimicrobial resistance did not change. Most participants (85%) rated the quality of the workshop as "very good" or "excellent" and rated the workshop sessions as "useful" (x = 3.9 on a 5.0 scale). CONCLUSIONS: Hospitalists who attended the SHM workshop increased their knowledge of health care-associated infections, antimicrobial resistance, and quality improvement programs related to these issues. Similar workshops should be considered in efforts to prevent health care-associated infections and antimicrobial resistance. PMID- 17705241 TI - Epigallocatechin-3-Gallate suppresses early stage, but not late stage prostate cancer in TRAMP mice: mechanisms of action. AB - BACKGROUND: Prostate cancer (PCa) is the second leading cause of cancer-related death in men in the United States. Many men have implemented purported chemopreventive agents into their daily diet in an attempt to delay the early onset of a PCa. Green tea polyphenols, one such agent, has been shown to be chemopreventive in skin, breast, and prostate cancers. We hypothesized that Epigallocatechin-3-Gallate (EGCG), the major polyphenol found in green tea, will exert its chemopreventive effect in the prostate via regulation of sex steroid receptor, growth factor-signaling, and inflammatory pathways. METHODS: Five-week old male TRAMP (Transgenic Adenocarcinoma Mouse Prostate) offspring were fed AIN 76A diet and 0.06% EGCG in tap water. Animals were sacrificed at 28 weeks of age and the entire prostates were scored histopathologically. In addition, animals were sacrificed at 12 weeks of age and ventral (VP) and dorsolateral (DLP) prostates were removed for histopathological evaluation and immunoblot analyses or ELISA. RESULTS: EGCG, inhibited early but not late stage PCa in the current study. In the VP, EGCG significantly reduced cell proliferation, induced apoptosis, and decreased androgen receptor (AR), insulin-like growth factor-1 (IGF-1), IGF-1 receptor (IGF-1R), phospho-extracellular signal-regulated kinases 1 and 2 (phospho-ERKs 1 and 2), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). CONCLUSIONS: The attenuation of the AR, the down regulation of potent growth factor IGF-1, modulation of inflammation biomarkers, and decrease in the MAPK signaling may contribute to the reduction in cell proliferation and induction of apoptosis and hence provide a biochemical basis for EGCG suppressing PCa without toxicity. PMID- 17705242 TI - A prospective randomized trial comparing contrast-enhanced targeted versus systematic ultrasound guided biopsies: impact on prostate cancer detection. AB - BACKGROUND: We performed a prospective randomized trial comparing 5 contrast enhanced color Doppler (CECD) ultrasound (US) targeted biopsy cores to 10 gray scale US guided systematic biopsy (SB) cores to determine the impact on the cancer detection rate. METHODS: We prospectively randomized 100 prostate specific antigen (PSA) screening volunteers with an elevated PSA (> or =1.25 ng/ml and free-to-total PSA < 18%) to undergo contrast-enhanced targeted or SB. Contrast enhanced targeted biopsies with a limited number of five cores were performed into hypervascular areas of the peripheral zone (PZ) during administration of the US contrast agent SonoVue (Bracco, Italy). A subjective grading of the vascularity from 0 to 3 was used: grade 0, no color signal; 1, low density; 2, medium density; and 3, high density of color signals. Ten SBs were obtained in a standard spatial distribution. Cancer detection rates were compared in the groups. RESULTS: Cancer was detected in 16/50 subjects (32%) by targeted biopsy, and in 13/50 patients (26%) with SB. The cancer detection rate was significantly better for the targeted approach (P < 0.04, McNemar). The detection rate for targeted biopsy cores (15.6% or 39/250 cores) was significantly better than for SB cores (6.8% or 34/500 cores, P < 0.001, McNemar). CONCLUSIONS: CECD targeted biopsy detected more cancers than SB with a reduced number of biopsy cores. PMID- 17705244 TI - Production of plant sesquiterpenes in Saccharomyces cerevisiae: effect of ERG9 repression on sesquiterpene biosynthesis. AB - The yeast Saccharomyces cerevisiae was chosen as a microbial host for heterologous biosynthesis of three different plant sesquiterpenes, namely valencene, cubebol, and patchoulol. The volatility and low solubility of the sesquiterpenes were major practical problems for quantification of the excreted sesquiterpenes. In situ separation of sesquiterpenes in a two-phase fermentation using dodecane as the secondary phase was therefore performed in order to enable quantitative evaluation of different strains. In order to enhance the availability of the precursor for synthesis of sesquiterpenes, farnesyl diphosphate (FPP), the ERG9 gene which is responsible for conversion of FPP to squalene was downregulated by replacing the native ERG9 promoter with the regulatable MET3 promoter combined with addition of 2 mM methionine to the medium. This strategy led to a reduced ergosterol content of the cells and accumulation of FPP derived compounds like target sesquiterpenes and farnesol. Adjustment of the methionine level during fermentations prevented relieving MET3 promoter repression and resulted in further improved sesquiterpene production. Thus, the final titer of patchoulol and farnesol in the ERG9 downregulated strain reached 16.9 and 20.2 mg/L, respectively. The results obtained in this study revealed the great potential of yeast as a cell factory for production of sesquiterpenes. PMID- 17705243 TI - Serum PSA half-life as a predictor of survival for hormone-refractory prostate cancer patients: modelization using a standardized set of response criteria. AB - OBJECTIVE: Changes of serum prostate-specific antigen (PSA) during chemotherapy have been validated as a marker of response for hormone-refractory prostate cancer (HRPC) patients. We retrospectively established new response criteria to assess the risk of death. METHODS: Two hundred fifty-six chemonaive HRPC patients treated with chemotherapy were included in the analysis. According to PSA half life (HL) dynamics, three response categories were defined: responders (R), late progressors (LP) and initial-progressors (IP), that were compared with Working Group (WG) criteria. PSA HL time to failure (TTF) and overall survival (OS) were estimated and compared between HT categories. Multivariate regression analysis was performed to isolate the impact on OS of these response categories. A new predictor of survival, delta-time PSA interval (DeltaT) was described. RESULTS: PSA HL categories were strongly related with WG criteria (P = 0.0001). PSA HL TTF differed among PSA HL categories: 4.2, 2.3, and 0.9 months for R, LP, and IP patients, respectively, and their respective median OS were 27, 19.7, and 12.3 months (P = 0.0001). For DeltaT > or = 3 versus <3 months, median OS significantly differed: 24.9 months versus 13.2 months (P = 0.0001). CONCLUSIONS: PSA HL dynamics during chemotherapy were able to accurately predict survival, earlier than WG-defined progression criteria. This criterion should be prospectively evaluated in randomized trials for HRPC patients in order to better estimate the risk of death. PMID- 17705245 TI - Silicate mineral dissolution during heap bioleaching. AB - Silicate minerals are present in association with metal sulfides in ores and their dissolution occurs when the sulfide minerals are bioleached in heaps for metal recovery. It has previously been suggested that silicate mineral dissolution can affect mineral bioleaching by acid consumption, release of trace elements, and increasing the viscosity of the leach solution. In this study, the effect of silicates present in three separate samples in conjunction with chalcopyrite and a complex multi-metal sulfide ore on heap bioleaching was evaluated in column bioreactors. Fe(2+) oxidation was inhibited in columns containing chalcopyrite samples A and C that leached 1.79 and 1.11 mM fluoride, respectively but not in sample B that contained 0.14 mM fluoride. Microbial Fe(2+) oxidation inhibition experiments containing elevated fluoride concentrations and measurements of fluoride release from the chalcopyrite ores supported that inhibition of Fe(2+) oxidation during column leaching of two of the chalcopyrite ores was due to fluoride toxicity. Column bioleaching of the complex sulfide ore was carried out at various temperatures (7-50 degrees C) and pH values (1.5-3.0). Column leaching at pH 1.5 and 2.0 resulted in increased acid consumption rates and silicate dissolution such that it became difficult to filter the leach solutions and for the leach liquor to percolate through the column. However, column temperature (at pH 2.5) only had a minor effect on the acid consumption and silicate dissolution rates. This study demonstrates the potential negative impact of silicate mineral dissolution on heap bioleaching by microbial inhibition and liquid flow. PMID- 17705246 TI - A novel small-diameter vascular graft: in vivo behavior of biodegradable three layered tubular scaffolds. AB - Small-diameter vascular grafts are potential substitutes for damaged vessels in patients, but most biodegradable grafts available now are not strong enough. The present study examined the burst strength, radial compliance, suture retention strength for a novel biodegradable tubular scaffold and investigated its behavior in vivo. The tubular scaffold (6-mm i.d., 4 cm long) has three layers including porous polylacticglycolic- acid in both inner and outer layers, a compact polyurethanes layer in midst. Bone marrow stromal cells (bMSCs) were seeded on the scaffolds and cultured for 7 days in vitro to construct tissue engineered vascular grafts which were then implanted in canine abdominal aorta. After 1, 3, 6, 12 and 24 weeks, the grafts were retrieved and evaluated histologically, angiographically and immunohistochemically. The biodegradable tubular scaffolds showed wall thickness of 0.295 mm to 0.432 mm; radial compliance of 3.80%/100 mmHg approximately 0.57%/100 mmHg, burst strength of 160 kPa approximately 183 kPa, and suture retention strength of 1959 N/cm(2) approximately 3228N/cm(2). The implanted grafts were fully patent without any signs of dilation or obstruction after 3 months' implantation. Scanning electron microscopy revealed a confluence endothelial cell layer spreading on the inner surface of the grafts. Immunohistochemistry of the retrieved grafts showed that vWF-stainin, alphaSMA staining were positive in the inner and medium layer respectively. Masson's trichrome staining showed that amount of collagen fibers existed in the grafts wall. Overall, these novel three-layered scaffolds exhibited favourable mechanical strength, long term patency and good remodeling in vivo. PMID- 17705247 TI - Extension of the MST continuum solvation model to the RM1 semiempirical Hamiltonian. AB - The need to simulate large-sized molecules or to deal with large series of compounds is a challenging topic in computational chemistry, which has stimulated the development of accurate semiempirical methods, such as the recently reported Recife Model 1 (RM1; J Comput Chem 2006, 27, 1101). Even though RM1 may prove to be of value simply due to the enhanced quantitative accuracy in gas phase, it is unclear how the new parameters optimized for RM1 affect the suitability of this semiempirical Hamiltonian to study chemical processes in condensed phases. To address this question, we report the parametrization of the MST/RM1 continuum model for neutral solutes in water, octanol, chloroform and carbon tetrachloride, and for ions in water. The results are used to discuss the transferability of the solvation parameters implemented in previous MST/AM1 and MST/PM3 models. PMID- 17705248 TI - Culture requirements of prostatic epithelial cell lines for acinar morphogenesis and lumen formation in vitro: role of extracellular calcium. AB - BACKGROUND: Three-dimensional (3D) culture of benign prostatic epithelial cell lines can recapitulate acinar morphogenesis in vitro, but the broad applicability of this approach has not been described. The present studies examine the culture conditions important for prostatic acinar morphogenesis in vitro and the role of extracellular calcium in this process. METHODS: With optimized culture conditions, RWPE-1, pRNS-1-1, PZ-HPV-7, PNT1A, BPH-1, and PrEC were analyzed for their ability to undergo acinar morphogenesis in 3D culture and by immunoblotting. RWPE-1 cells were further examined for the effects of calcium on morphology, E-cadherin membrane localization and multicellular layering in 2D culture and for acinar morphogenesis, luminal apoptosis, and luminal filling in 3D. RESULTS: Cell lines grown in low-calcium medium have the ability to form acinar structures with lumens, which correlates with E-cadherin expression, but low calcium is not required for this process. Adding CaCl(2) to the medium strongly inhibits lumen formation, luminal apoptosis and induces luminal filling, and luminal filling is blocked by an interfering antibody. CONCLUSIONS: Optimized medium composition allows nearly all seeded RWPE-1 cells to undergo acinar morphogenesis, forming consistent structures representative of normal adult prostate glands. Low-calcium-containing medium appears selective for cells capable of undergoing acinar morphogenesis in vitro, and branching and luminal space within the acini are strongly influenced by extracellular calcium levels, likely through the actions of E-cadherin. These results provide important information about a relevant in vitro model with which to study prostate development and carcinogenesis and highlight the importance of extracellular calcium in regulating 3D morphology. PMID- 17705249 TI - Bismuth dimercaptopropanol (BisBAL) inhibits the expression of extracellular polysaccharides and proteins by Brevundimonas diminuta: implications for membrane microfiltration. AB - A 2:1 molar ratio preparation of bismuth with a lipophilic dithiol (3-dimercapto 1-propanol, BAL) significantly reduced extracellular polymeric substances (EPS) expression by Brevundimonas diminuta in suspended cultures at levels just below the minimum inhibitory concentration (MIC). Total polysaccharides and proteins secreted by B. diminuta decreased by approximately 95% over a 5-day period when exposed to the bismuth-BAL chelate (BisBAL) at near MIC (12 microM). Fourier transform infrared spectroscopy (FTIR) suggested that a possible mechanism of biofilm disruption by BisBAL is the inhibition of carbohydrate O-acetylation. FTIR also revealed extensive homology between EPS samples with and without BisBAL treatment, with proteins, polysaccharides, and peptides varying predominantly only in the amount expressed. EPS secretion decreased following BisBAL treatment as verified by atomic force microscopy and scanning electron microscopy. Without BisBAL treatment, a slime-like EPS matrix secreted by B. diminuta resulted in biofouling and inefficient hydrodynamic backwashing of microfiltration membranes. PMID- 17705250 TI - Redox control bioreactor: a unique biological water processor. AB - The redox control bioreactor (RCB) is a new hollow fiber membrane bioreactor (HFMBR) design in which oxygen and hydrogen gases are provided simultaneously through separate arrays of juxtaposed hollow fiber (HF) membranes. This study applied the RCB for completely autotrophic conversion of ammonia to N(2) through nitrification with O(2) and denitrification using hydrogen as an electron donor (i.e., autohydrogentrophic denitrification). The hypothesis of this research was that efficient biofilm utilization of O(2) and H(2) at respective HFs would limit transport of these gases to bulk fluid, thereby enabling completely autotrophic ammonia conversion to N(2) through the co-occurrence of ammonia oxidation (O(2) HF biofilms) and autohydrogenotrophic denitrification (H(2)-HF biofilms). A prototype RCB was fabricated and operated for 215 days on a synthetic, organic free feedstream containing 217 mg L(-1) NH(4)(+)-N. When O(2) and H(2) were simultaneously supplied, the RCB achieved a steady NH(4)(+)-N removal flux of 5.8 g m(-2) day(-1) normalized to O(2)-HF surface area with a concomitant removal flux of 4.4 g m(-2) day(-1) (NO(3)(-))+NO(2)(-))-N based on H(2)-HF surface area. The significance of H(2) supply was confirmed by an increase in effluent NO(3)(-) N when H(2) supply was discontinued and a decline in NO(3)(-)-N when H(2) supply was restarted. Increases in H(2) pressure caused decreased ammonia utilization, suggesting that excess H(2) interfered with nitrification. Microprobe profiling across radial transects revealed significant gradients in dissolved O(2) on spatial scales of 1 mm or less. Physiological and molecular analysis of biofilms confirmed that structurally and functionally distinct biofilms developed on adjacent, juxtaposed fibers. PMID- 17705252 TI - A single glucose derivative suitable for gas chromatography/mass spectrometry and gas chromatography/combustion/isotope ratio mass spectrometry. AB - The incorporation of stable isotopes improves the assessment of glucose metabolism and, with some researchers using two tracers, (2)H-glucose assessed by gas chromatography/mass spectrometry (GC/MS) and (13)C-glucose by gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS), a common derivative for both is advantageous. The most commonly used derivatives for GC/MS are inappropriate for GC/C/IRMS as additional functional groups dilute the label. We therefore considered the suitability of six derivatives for both GC/MS and GC/C/IRMS. Glucose alkylboronates were prepared by adding the appropriate alkylboronic acid (butyl- or methylboronic acid) in pyridine to desiccated glucose. The derivatisation was completed by reacting this with either (a) acetic anhydride or trifluoroacetic anhydride (acetate derivatives) or (b) bis(trimethylsilyl)trifluoroacetamide BSTFA (TMS derivatives). All six derivatives were assessed using GC/MS and (13)C GC/C/IRMS. Neither TMS derivative exhibited any signal intensity in the molecular ion, although a M-15 ion showed good agreement between experimental and theoretical data and, whilst still low in intensity, could be suitable for isotope work. Similarly, none of the acetate derivatives showed any intensity at the molecular ion although three key fragmentation series were identified. The most attractive sequence, initiated by the loss of 1,2 cyclic boronate, resulted in the main fragment ion of interest, m/z 240, corresponding to the fluorinated methylboronate derivate. Minimal carbon and hydrogen atoms are added to this derivative making it an excellent choice for stable isotope work, while proving suitable for analysis by both GC/MS and GC/C/IRMS. PMID- 17705251 TI - Fed-batch cultivation of the marine bacterium Sulfitobacter pontiacus using immobilized substrate and purification of sulfite oxidase by application of membrane adsorber technology. AB - Sulfitobacter pontiacus, a gram-negative heterotrophic bacterium isolated from the Black Sea is well known to produce a soluble AMP-independent sulfite oxidase (sulfite: acceptor oxidoreductase) of high activity. Such an enzyme can be of great help in establishing biosensor systems for detection of sulfite in food and beverages considering the high sensitivity of biosensors and the increasing demand for such biosensor devices. For obtaining efficient amounts of the enzyme, an induction of its biosynthesis by supplementing sufficient concentrations of sodium sulfite to the fermentation broth is required. Owing to the fact that a high initial concentration of sodium sulfite decreases dramatically the enzyme expression, different fed-batch strategies can be applied to circumvent such inhibition or repression of the enzyme respectively. By the use of sulfite species immobilized in polyvinyl alcohol gels, an approach to the controlled and continuous feeding of sulfite to the cultivation media could be established to diminish inhibitory concentrations. Furthermore, the purification of the enzyme is described by using membrane adsorber technology. PMID- 17705253 TI - A multiresidue method for the determination of 109 pesticides in rice using the Quick Easy Cheap Effective Rugged and Safe (QuEChERS) sample preparation method and gas chromatography/mass spectrometry with temperature control and vacuum concentration. AB - A rapid, specific and sensitive multiresidue method based on the Quick Easy Cheap Effective Rugged and Safe (QuEChERS) sample preparation method and gas chromatography with mass spectrometric detection by selected ion monitoring (GC/MS-SIM) has been developed for the routine analysis of 109 pesticides in rice. The method uses one quantification ion and two identification ions. Temperature control during sample preparation helps improve the recovery of thermally labile pesticides such as captan. The method was validated by the analysis of samples spiked at 0.025-0.150 mg/kg in rice matrix. The recoveries of all pesticides were between 80% and 115% with a relative standard deviation of less than 15%. The limit of quantitation (LOQ) for most compounds met the maximum residue limits (MRLs) for pesticides in rice in Korea. PMID- 17705254 TI - Using high-concentration trypsin-immobilized magnetic nanoparticles for rapid in situ protein digestion at elevated temperature. AB - We describe an innovative approach - using a high concentration of trypsin modified magnetic nanoparticles (TMNPs) - for the rapid and efficient digestion of proteins at elevated temperature. The required digestion time could be reduced to less than 10 s. After digestion, the TMNPs were collected magnetically from the sample solution for reuse and the digested peptides were characterized using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Protein digestion was optimized when using the TMNPs (5 microg/microL) at 57 degrees C; a significantly high peptide coverage was achieved for protein identification (e.g., 98% for lysozyme). Although a high concentration of TMNPs was used for digestion, the short digestion time led to much lower amounts of trypsin peptides being produced through self-digestion. As a result, interference in the mass spectrometric detection of the peptide ions was reduced significantly. PMID- 17705255 TI - Improvement of the duty cycle of an orthogonal acceleration time-of-flight mass spectrometer using ion gates. AB - A method to control the duty cycle of a time-of-flight mass spectrometer is described. The method relies on one or more ion gates placed in the beam path that have the function to transmit or stop the beam. These ion gates can switch from the open state to the closed state in tens of nanoseconds and effectively select portions of the mass range. The method is useful in circumstances where recording the complete mass spectrum is not an essential requirement, for example, in the analysis of known compounds where sensitivity and speed of operation are more important. It will be of benefit for applications in separation sciences with techniques involving fast chromatographic separations, where hundreds of mass spectra may be required per second. In such circumstances analytical identification may require only a limited number of masses (or mass regions) to be continuously monitored. Improvement of the duty cycle is particularly important for orthogonal-acceleration time-of-flight (oa-TOF) mass spectrometry instruments whose performance suffers from a low duty cycle. The duty cycle is not a constant for an instrument design but is a mass-dependent function and is least for smaller masses. The method described here is capable of raising the duty cycle to 100%. A theory is developed for one or more ion gate arrangements, for both linear- and reflectron-TOF systems. For a two-gate system the relationship between the positions of the first and second gates is described by a '2/3 rule'. Experimental results are shown for one-gate and two-gate operation, both in linear and in reflectron modes of operation, on an oa-TOF system built in-house. PMID- 17705256 TI - Development of a simple and reliable accurate mass liquid chromatography/electrospray ionization mass spectrometry method for high resolution accurate mass determinations of new drug entities on a triple quadrupole mass spectrometer. AB - Accurate mass measurements are used to determine the elemental composition and formulae of molecules to confirm their identity or to assist in their characterization. Currently, the most widely used techniques for measuring exact masses employ magnetic sector instruments, Fourier transform ion cyclotron resonance mass spectrometers and lower resolution instruments such as time-of flight (TOF) and quadrupole-TOF. This paper reports the accurate mass measurement using a triple quadrupole mass spectrometer. Indeed, the recently introduced triple quadrupole mass spectrometer, with unique enhanced mass-resolution capability, has demonstrated simple data acquisition methods and requires few experiments to measure exact masses with accuracy and determines elemental compositions of both protonated and deprotonated molecules. All the accurate mass measurements were performed using both positive and negative electrospray ionization in enhanced mass-resolution mode (peak width of 0.1 Th FWMH). Several new drug entities were investigated as simulated unknowns and analyzed by means of an accurate mass liquid chromatography/electrospray ionization mass spectrometry (AM-LC/ESI-MS) method. The accurate mass measurements resulted in only one proposed elemental composition for all tested compounds, using reasonable elemental limits and mass tolerance for the calculation. Moreover, all the experimentally determined accurate mass measurements gave satisfactory results in terms of accuracy (lower than 5 ppm). PMID- 17705257 TI - Studies of iridoid glycosides using liquid chromatography/electrospray ionization tandem mass spectrometry. AB - Fragmentation pathways of five iridoid glycosides have been studied by using electrospray ionization multi-stage tandem mass spectrometry (ESI-MS(n)). The first-stage MS data of the five iridoid glycosides were compared. The MS spectra showed that the adduct ions of iridoid glycosides and the formate anion were diagnostic ions to distinguish iridoid glycosides with a carboxyl group at the C 4 position or an ester group at the C-4 position. The MS fragmentation pathways of the five iridoid glycosides were also studied. Analyzing the product ion spectra of iridoid glycosides, some neutral losses were observed, such as H(2)O, CO(2) and glucose residues, which were very useful for the identification of the functional groups in the structures of iridoid glycosides. Furthermore, specific loss of one molecule of methyl 3-oxopropanoate or 3-oxopropanic acid was firstly discussed, which corresponded to the isomerization of the hemiacetal group in the structure of iridoid aglycone. According to the fragmentation mechanisms and HPLC/MS(n) data, the structures of five iridoid glycosides in a crude extract of Gardenia jasminoisdes fruit have been identified. Three compounds were compared with standards and the other two were identified as shanzhiside and genipin gentibioside by their MS(n) data without standard compounds. In order to further validate the veracity of the deduction, genipin gentiobioside was isolated from the extract of Gardenia jasminoisdes fruit using Purification Factory and was further identified by C- and H-NMR. PMID- 17705258 TI - Normalization of measured stable isotopic compositions to isotope reference scales--a review. AB - In stable isotope ratio mass spectrometry (IRMS), the stable isotopic composition of samples is measured relative to the isotopic composition of a working gas. This measured isotopic composition must be converted and reported on the respective international stable isotope reference scale for the accurate interlaboratory comparison of results. This data conversion procedure, commonly called normalization, is the first set of calculations done by the users. In this paper, we present a discussion and mathematical formulation of several existing routinely used normalization procedures. These conversion procedures include: single-point anchoring (versus working gas and certified reference standard), modified single-point normalization, linear shift between the measured and the true isotopic composition of two certified reference standards, two-point and multi-point linear normalization methods. Mathematically, the modified single point, two-point, and multi-point normalization methods are essentially the same. By utilizing laboratory analytical data, the accuracy of the various normalization methods (given by the difference between the true and the normalized isotopic composition) has been compared. Our computations suggest that single-point anchoring produces normalization errors that exceed the maximum total uncertainties (e.g. 0.1 per thousand for delta(13)C) often reported in the literature, and, therefore, that it must not be used for routinely anchoring stable isotope measurement results to the appropriate international scales. However, any normalization method using two or more certified reference standards produces a smaller normalization error provided that the isotopic composition of the standards brackets the isotopic composition of unknown samples. PMID- 17705259 TI - Novel screening assay for antioxidant protection against peroxyl radical-induced loss of protein function. AB - Oxidative damage to proteins, implicated amongst other in the etiology and progression of Parkinson's disease (PD) and Alzheimer's disease (AD), results in the loss of specific biological protein function. A simple, sensitive, and cost effective fluorimetric test to assess the antioxidant capacity of new chemical entities to protect proteins from loss of activity caused by reactive oxygen species (ROS) was developed using alkaline phosphatase (ALP) as model protein. Protein oxidation was induced by 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AAPH) and the decrease in catalytic activity of ALP to hydrolyze 4-methylumbelliferyl phosphate (4-MUP) to fluorescent 4-methylumbelliferone (4 MU) was monitored as a marker of protein degradation. According to their capacity to protect ALP from peroxyl radical-induced activity loss, ten reference antioxidants were divided into three classes, namely efficient (pIC(50) > 5 for quercetin, chlorogenic acid, caffeic acid, mangiferin, and resveratrol), intermediate (4 < pIC(50) < or = 5 for melatonin, trolox, and ascorbic acid), and poor antioxidants (pIC(50) < 4 for glutathione and D-mannitol). Multifunctional drugs, having the ability to interact with several disease-related targets are of interest in PD. Therefore, the capacity of three catechol-O-methyltransferase (COMT) inhibitors, entacapone, nitecapone, and tolcapone to protect ALP from oxidative damage was also investigated and found to be very similar to the most potent reference antioxidants. PMID- 17705260 TI - Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9. AB - Apoptosis of hepatocytes results in the development of liver fibrosis, but the molecular signals mediating this are poorly understood. Degradation and modification of nuclear DNA is a central feature of apoptosis, and DNA from apoptotic mammalian cells is known to activate immune cells via Toll-like receptor 9 (TLR9). We tested if DNA from apoptotic hepatocytes can induce hepatic stellate cell (HSC) differentiation. Our data show that apoptotic hepatocyte DNA and cytidine-phosphate-guanosine oligonucleotides induced up-regulation of transforming growth factor beta1 and collagen 1 messenger RNA both in the human HSC line LX-2 and in primary mouse HSCs. These effects were opposed by TLR9 antagonists. We have recently shown that adenosine inhibits HSC chemotaxis, and we now show that apoptotic hepatocyte DNA also inhibits platelet-derived growth factor (PDGF)-mediated HSC chemotaxis. Inhibition of HSC chemotaxis by PDGF was blocked by TLR9 antagonists, and was absent in primary HSCs from mice deficient in TLR9 or the TLR adaptor molecule MyD88. Stimulation of TLR9 on HSCs blocked signaling by the PDGF signaling molecule inositol 1,4,5-triphosphate and reduced PDGF-mediated increase in cytosolic Ca(2+). CONCLUSION: DNA from apoptotic hepatocytes acts as an important mediator of HSC differentiation by (1) providing a stop signal to mobile HSCs when they have reached an area of apoptosing hepatocytes and (2) inducing a stationary phenotype-associated up-regulation of collagen production. PMID- 17705261 TI - Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumor cells but not in most normal cells and has therefore been proposed as a promising antitumor agent. Recent experiments suggested that isolated primary human hepatocytes but not monkey liver cells are susceptible to certain TRAIL agonists, raising concerns about the use of TRAIL in cancer treatment. Whether TRAIL indeed exerts hepatotoxicity in vivo and how this is influenced by chemotherapeutic drugs or liver disease are completely unknown. Employing different forms of recombinant TRAIL, we found that the cytokine can induce proapoptotic caspase activity in isolated human hepatocytes. However in marked contrast, these different TRAIL preparations induced little or no cytotoxicity when incubated with tissue explants of fresh healthy liver, an experimental model that may more faithfully mimic the in vivo situation. In healthy liver, TRAIL induced apoptosis only when combined with histone deacetylase inhibitors. Strikingly, however, TRAIL alone triggered massive apoptosis accompanied by caspase activation in tissue explants from patients with liver steatosis or hepatitis C viral infection. This enhanced sensitivity of diseased liver was associated with an increased expression of TRAIL receptors and up-regulation of proapoptotic Bcl-2 proteins. CONCLUSION: These results suggest that clinical trials should be performed with great caution when TRAIL is combined with chemotherapy or administered to patients with inflammatory liver diseases. PMID- 17705262 TI - Intranuclear rod myopathy: molecular pathogenesis and mechanisms of weakness. AB - OBJECTIVE: Mutations in the alpha-skeletal actin gene (ACTA1) result in a variety of inherited muscle disorders characterized by different pathologies and variable clinical phenotypes. Mutations at Val163 in ACTA1 result in pure intranuclear rod myopathy; however, the molecular mechanisms by which mutations at Val163 lead to intranuclear rod formation and muscle weakness are unknown. METHODS AND RESULTS: We investigated the effects of the Val163Met mutation in ACTA1 in tissue culture and Drosophila models, and in patient muscle. In cultured cells, the mutant actin tends to aggregate rather than incorporate into cytoplasmic microfilaments, and it affects the dynamics of wild-type actin, causing it to accumulate with the mutant actin in the nucleus. In Drosophila, the Val163Met mutation severely disrupts the structure of the muscle sarcomere. The intranuclear aggregates in patient muscle biopsies impact on nuclear structure and sequester normal Z-disc associated proteins within the nucleus; however, the sarcomeric structure is relatively well preserved, with evidence of active regeneration. By mass spectrometry, the levels of mutant protein are markedly reduced in patient muscle compared with control. INTERPRETATION: Data from our tissue culture and Drosophila models show that the Val163Met mutation in alpha-skeletal actin can affect the dynamics of other actin isoforms and severely disrupt sarcomeric structure, processes that can contribute to muscle weakness. However, in human muscle, there is evidence of regeneration, and the mutant protein tends to aggregate rather than incorporate into cytoplasmic microfilaments in cells. These are likely compensatory processes that ameliorate the effects of the mutant actin and contribute to the milder clinical and pathological disease phenotype. PMID- 17705263 TI - Viral load in hepatitis B e antigen-negative carriers with normal aminotransferase level. PMID- 17705264 TI - Signal transducer and activator of transcription 3 signaling within hepatocytes attenuates systemic inflammatory response and lethality in septic mice. AB - Sepsis is an infection-induced syndrome with systemic inflammatory response leading to multiorgan failure and occasionally death. During this process, signal transducer and activator of transcription 3 (STAT3) is activated in the liver, but the significance of this molecule has not been established. We generated hepatocyte-specific STAT3-deficient mice (L-STAT3 KO) and examined the susceptibility of these mice to cecal ligation and puncture-induced peritonitis, a well-established septic model. L-STAT3 KO mice showed significantly higher mortality and produced lesser amounts of various acute phase proteins than control littermates. Although blood bacterial infection did not differ between L STAT3 KO mice and control mice, the former showed deterioration of the systemic inflammatory response as evidenced by a significant increase in various cytokines such as tumor necrosis factor alpha, IFN-gamma, IL-6, IL-10, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1beta. A similar hyperinflammatory response was observed in another septic model caused by lipopolysaccharide (LPS) injection. In vitro analysis revealed that soluble substances derived from hepatocytes and dependent on STAT3 were critical for suppression of cytokine production from LPS-stimulated macrophage and splenocytes. CONCLUSION: STAT3 activation in hepatocytes can attenuate a systemic hyperinflammatory response and lethality in sepsis, in part by suppressing immune cell overactivation, implying a critical role of hepatocyte STAT3 signaling in maintaining host homeostasis. PMID- 17705265 TI - Hepatitis C treatment, subcutaneous naltrexone implants, and methadone maintenance treatment. PMID- 17705266 TI - Diagnostic accuracy of the aspartate aminotransferase-to-platelet ratio index for the prediction of hepatitis C-related fibrosis: a systematic review. AB - The development of noninvasive markers of liver fibrosis is a clinical and research priority. The aspartate aminotransferase-to-platelet ratio index (APRI) is a promising tool with limited expense and widespread availability. Our objective was to systematically review the performance of the APRI in hepatitis C virus (HCV)-infected patients. Random effects meta-analyses and areas under summary receiver operating characteristic curves (AUC) were examined to characterize APRI accuracy for significant fibrosis (stages 2-4) and cirrhosis. In 22 studies (n = 4,266), the summary AUCs of the APRI for significant fibrosis and cirrhosis were 0.76 [95% confidence interval (CI), 0.74-0.79] and 0.82 (95%CI, 0.79-0.86), respectively. For significant fibrosis, an APRI threshold of 0.5 was 81% sensitive and 50% specific. At a 40% prevalence of significant fibrosis, this threshold had a negative predictive value (NPV) of 80%, but could reduce the necessity of liver biopsy by only 35%. For cirrhosis, a threshold of 1.0 was 76% sensitive and 71% specific. At a 15% cirrhosis prevalence, the NPV of this threshold was 91%. Higher APRI thresholds had suboptimal positive predictive values except in settings with a high prevalence of cirrhosis. APRI accuracy was not affected by the prevalence of advanced fibrosis, or study and biopsy quality. However, the accuracy for cirrhosis was greater in studies including human immunodeficiency virus (HIV)/HCV-co-infected patients. CONCLUSION: The major strength of the APRI is the exclusion of significant HCV-related fibrosis. Future studies of novel markers should demonstrate improved accuracy and cost effectiveness compared with this economical and widely available index. PMID- 17705268 TI - Are aromatic carbon donor hydrogen bonds linear in proteins? AB - Proteins fold and maintain structure through the collective contributions of a large number of weak, noncovalent interactions. The hydrogen bond is one important category of forces that acts on very short distances. As our knowledge of protein structure continues to expand, we are beginning to appreciate the role that weak carbon-donor hydrogen bonds play in structure and function. One property that differentiates hydrogen bonds from other packing forces is propensity for forming a linear donor-hydrogen-acceptor orientation. To ascertain if carbon-donor hydrogen bonds are able to direct acceptor linearity, we surveyed the geometry of interactions specifically involving aromatic sidechain ring carbons in a data set of high resolution protein structures. We found that while donor-acceptor distances for most carbon donor hydrogen bonds were tighter than expected for van der Waals packing, only the carbons of histidine showed a significant bias for linear geometry. By categorizing histidines in the data set into charged and neutral sidechains, we found only the charged subset of histidines participated in linear interactions. B3LYP/6-31G**++ level optimizations of imidazole and indole-water interactions at various fixed angles demonstrates a clear orientation dependence of hydrogen bonding capacity for both charged and neutral sidechains. We suggest that while all aromatic carbons can participate in hydrogen bonding, only charged histidines are able to overcome protein packing forces and enforce linear interactions. The implications for protein modeling and design are discussed. PMID- 17705267 TI - Ectopic expression and dynamics of TPM1alpha and TPM1kappa in myofibrils of avian myotubes. AB - From the four known vertebrate tropomyosin genes (designated TPM1, TPM2, TPM3, and TPM4) over 20 isoforms can be generated. The predominant TPM1 isoform, TPM1alpha, is specifically expressed in both skeletal and cardiac muscles. A newly discovered alternatively spliced isoform, TPM1kappa, containing exon 2a instead of exon 2b contained in TPM1alpha, was found to be cardiac specific and developmentally regulated. In this work, we transfected quail skeletal muscle cells with green fluorescent proteins (GFP) coupled to chicken TPM1alpha and chicken TPM1kappa and compared their localizations in premyofibrils and mature myofibrils. We used the technique of fluorescence recovery after photobleaching (FRAP) to compare the dynamics of TPM1alpha and TPM1kappa in myotubes. TPM1alpha and TPM1kappa incorporated into premyofibrils, nascent myofibrils, and mature myofibrils of quail myotubes in identical patterns. The two tropomyosin isoforms have a higher exchange rate in premyofibrils than in mature myofibrils. F-actin and muscle tropomyosin are present in the same fibers at all three stages of myofibrillogenesis (premyofibrils, nascent myofibrils, mature myofibrils). In contrast, the tropomyosin-binding molecule nebulin is not present in the initial premyofibrils. Nebulin is gradually added during myofibrillogenesis, becoming fully localized in striated patterns by the mature myofibril stage. A model of thin filament formation is proposed to explain the increased stability of tropomyosin in mature myofibrils. These experiments are supportive of a maturing thin filament and stepwise model of myofibrillogenesis (premyofibrils to nascent myofibrils to mature myofibrils), and are inconsistent with models that postulate the immediate appearance of fully formed thin filaments or myofibrils. PMID- 17705269 TI - Crystal structure and putative function of small Toprim domain-containing protein from Bacillus stearothermophilus. AB - The crystal structure of the Midwest Center for Structural Genomics target APC35832, a 14.7-kDa cytosolic protein from Bacillus stearothermophilus, has been determined at 1.3 A resolution by the single anomalous diffraction method from a mercury soaked crystal. The APC35832 protein is a representative of large group of bacterial and archeal proteins entirely consisting of the Toprim (topoisomerase-primase) domain. This domain is found in the catalytic centers of many enzymes catalyzing phosphodiester bond formation or cleavage, but the function of small Toprim domain proteins remains unknown. Consistent with the sequence analysis, the APC35832 structure shows a conserved Toprim fold, with a central 4-stranded parallel beta-sheet surrounded by four alpha-helixes. Comparison of the APC35832 structure with its closest structural homolog, the catalytic core of bacteriophage T7 primase, revealed structural conservation of a metal binding site and isothermal titration calorimetry indicates that APC35832 binds Mg2+ with a sub-millimolar dissociation constant (K(d)). The APC35832-Mg2+ complex structure was determined at 1.65 A and reveals the role of conserved acidic residues in Mg2+ ion coordination. The structural similarities to other Toprim domain containing proteins and potential function and substrates of APC35832 are discussed in this article. PMID- 17705270 TI - Identification and functional characterization of the bile acid transport proteins in non-mammalian ileum and mammalian liver. AB - It has been proposed that intracellular carrier proteins mediate active transport of the bile acids within hepatocytes and ileocytes, during the enterohepatic circulation. In mammalian species only ileal bile acid binding proteins have been so far identified, while liver cytosolic carriers have never been found. On the contrary, in non-mammalian vertebrates, only liver, and not ileal, bile acid binding proteins were reported. The aim of the present work is to find the missing cytosolic transport proteins. A bioinformatic search allowed us to identify a non-mammalian putative bile acid binding protein in the chicken ileum (cI-BABP), which we recombinantly expressed and purified. The protein exhibits the capability, tested by in vitro NMR experiments, of binding bile acids. Furthermore, strong NMR evidence reported that the human liver fatty acid binding protein (hL-FABP) can also bind bile acids. Taken together, these data strongly suggest that both cI-BABP and hL-FABP have a bile acid binding function in the two organisms, and support a previous hypothesis on the role of hL-FABP in regulating bile acid metabolism and determining bile acid pool size. PMID- 17705271 TI - Quantifying the relationship of protein burying depth and sequence. AB - Protein burying depth (BD) is a structural descriptor that is exploited not only to find whether a residue is exposed or buried, but also to determine how deep a residue is buried. The widely used solvent accessible surface area is mainly focusing on the study of protein surface residues, while protein BD can provide more detailed information about the arrangement of buried residues, which may be used to study protein deep level structure and the formation of protein folding nucleus. In this work, we analyse the relationship of protein BD and sequences, and describe it by nonlinear functions estimated by support vector machines. We examine the functions by crossvalidation tests and find strong correlation between residue BD and local sequence environment. By further taking account the size of the molecule where a residue is located, we find that the correlation coefficient between predicted and observed depths improves from 0.60 to 0.65. Moreover, nearly half of the deepest 10% residues in a protein sequence can be correctly predicted. Our study suggests that a residue's burying extent is able to be predicted, to some degree, by itself and its local neighbouring residues. The methods used to estimate the sequence-depth functions are expected to become more useful in the investigation of protein structures and folding mechanism. PMID- 17705273 TI - New tools and expanded data analysis capabilities at the Protein Structure Prediction Center. AB - We outline the main tasks performed by the Protein Structure Prediction Center in support of the CASP7 experiment and provide a brief review of the major measures used in the automatic evaluation of predictions. We describe in more detail the software developed to facilitate analysis of modeling success over and beyond the available templates and the adopted Java-based tool enabling visualization of multiple structural superpositions between target and several models/templates. We also give an overview of the CASP infrastructure provided by the Center and discuss the organization of the results web pages available through http://predictioncenter.org. PMID- 17705272 TI - The crystal structure of the effector-binding domain of the trehalose repressor TreR from Bacillus subtilis 168 reveals a unique quarternary assembly. PMID- 17705274 TI - A model for the assembly of nicotinic receptors based on subunit-subunit interactions. AB - Neuronal ion-channels are complex multimeric proteins. Within a given family, the variability of their pharmacological responses depends on subunit composition and subunit arrangement. We report here that protein assembly in the pentameric nicotinic acetylcholine receptor family, the best characterized of all neuronal receptors, can be predicted using information derived from homology modeled surface to surface subunit interactions based on the atomic structure of a snail acetylcholine-binding protein. An empirical assembly model is able to establish both subunit stoichiometry and subunit arrangement of known neuronal and muscle nicotinic receptors. This contribution to the understanding of nicotinic receptor assembly and variability might be extended to other types of ion-channels. PMID- 17705275 TI - Cooperative symmetric to asymmetric conformational transition of the apo-form of scavenger decapping enzyme revealed by simulations. AB - Decapping is a central step in eukaryotic mRNA turnover and in gene expression regulation. The human scavenger decapping enzyme, DcpS, catalyses cap hydrolysis following mRNA degradation. DcpS is a dimeric enzyme, with two active sites. Crystal structures suggest that DcpS must undergo significant conformational changes upon ligand binding, but the mechanism of this transition is unknown. Here, we report two long timescale (20 ns) molecular dynamics simulations of the apo-form of DcpS. The dimer is observed to undergo a strikingly cooperative motion, with one active site closing while the other opens. The amplitude of the conformational change is 6-21 A and the apparent timescale is 4-13 ns. These findings indicate that the crystallographically observed symmetric conformation of apo-form of DcpS is only a minor conformation in solution. The simulations also show that active sites are structurally connected via the domain-swapped dimer structure of the N-terminal domain, even in the absence of a bound ligand. These findings suggest a functional reason for the enzyme existing as a dimer, and may be widely relevant, also for other dimeric proteins. PMID- 17705276 TI - Analysis of TASSER-based CASP7 protein structure prediction results. AB - An improved TASSER (Threading/ASSEmbly/Refinement) methodology is applied to predict the tertiary structure for all CASP7 targets. TASSER employs template identification by threading, followed by tertiary structure assembly by rearranging continuous template fragments, where conformational space is searched via Parallel Hyperbolic Monte Carlo sampling with an optimized force-field that includes knowledge-based statistical potentials and restraints derived from threading templates. The final models are selected by clustering structures from the low temperature replicas. Improvements in TASSER over CASP6 involve use of better templates from 3D-jury applied to three threading programs, PROSPECTOR_3, SP(3), and SPARKS, and a fragment comparison method for better model ranking. For targets with no reliable templates, a variant of TASSER (chunk-TASSER) is also applied with potentials and restraints extracted from ab initio folded supersecondary chunks of the target to build full-length models. For all 124 CASP targets/domains, the average root-mean-square-deviation (RMSD) from native and alignment coverage of the best initial threading models from 3D-jury are 6.2 A and 93%, respectively. Following TASSER reassembly, the average RMSD of the best model in the template aligned region decreases to 4.9 A and the average TM-score increases from 0.617 for the template to 0.678 for the best full-length model. Based on target difficulty, the average TM-scores of the final model to native are 0.904, 0.671, and 0.307 for high-accuracy template-based modeling, template based modeling, and free modeling targets/domains, respectively. For the more difficult targets, TASSER with modest human intervention performed better in comparison to its server counterpart, MetaTASSER, which used a limited time simulation. PMID- 17705277 TI - Pancreatic and duodenal homeobox gene 1 induces hepatic dedifferentiation by suppressing the expression of CCAAT/enhancer-binding protein beta. AB - It is believed that adult tissues in mammals lack the plasticity needed to assume new developmental fates because of the absence of efficient pathways of dedifferentiation. However, the well-documented ability of the transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) to activate pancreatic lineage development and insulin production following ectopic expression in liver suggests a surprising degree of residual plasticity in adult liver cells. This study seeks a mechanistic explanation for the capacity of PDX-1 to endow liver cells with pancreatic characteristics and function. We demonstrate that PDX-1, previously shown to play an essential role in normal pancreatic organogenesis and pancreatic beta-cell function and to possess the potential to activate multiple pancreatic markers in liver, can also direct hepatic dedifferentiation. PDX-1 represses the adult hepatic repertoire of gene expression and activates the expression of the immature hepatic marker alpha-fetoprotein. We present evidence indicating that PDX-1 triggers hepatic dedifferentiation by repressing the key hepatic transcription factor CCAAT/enhancer-binding protein beta. Hepatic dedifferentiation is necessary though not sufficient for the activation of the mature pancreatic repertoire in liver. CONCLUSION: Our study suggests a dual role for PDX-1 in liver: inducing hepatic dedifferentiation and activating the pancreatic lineage. The identification of dedifferentiation signals may promote the capacity to endow mature tissues in mammals with the plasticity needed for acquiring novel developmental fates and functions to be implemented in the field of regenerative medicine. PMID- 17705279 TI - Microvascular breast reconstruction pedicle thrombosis: how long can we wait? AB - Re-exploration plays a key role in salvaging vascularly compromised free flaps. A retrospective review of 290 free flaps in breast reconstruction was performed to determine whether the time delay between thrombosis detection and surgical re exploration had any effect on flap salvage. Overall flap success was 97.6%. Postoperative thrombosis requiring re-exploration was documented in 6.2% cases. Fifty-five percent of take-back flaps were salvaged and 45% were lost. The median time between detection of flap compromise to surgical incision was 128 min in our saved flaps, and 228 min in the lost flap group. Our preliminary data suggests that re-exploration within 188 min may improve flap salvage. PMID- 17705280 TI - A new type of magnification system in free microvascular tissue transfer: Varioscope M5. AB - Free microvascular tissue transfers have become today a key instrument for the surgical treatment of wide loss of tissue. These procedures can provide definitive treatment in a single operation but they are expensive and require specialized practitioners. The operating microscope traditionally has provided this requirement; our study is focusing on the prospect of using a new visual system-Varioscope M5-in the reconstructive microsurgery field. Varioscope M5 (Life Optics, Vienna, Austria) has been employed in 21 microvascular anastomoses, where different free flaps were used in head and neck reconstruction. The necessity to operate in a different department, not provided with an operating microscope, brought along the idea of exploring an alternative procedure to classical visualization systems. Specific advantages such as reduced cost, freedom of movement, autofocus, minimal upkeep, a variable range of magnification from 2x to 9x are some of the reasons that convinced the authors to use this new type of magnification system. Increasing interest in microsurgery magnification highlights the need for further technical development in that field. We consider Varioscope M5 a future mean of anastomotic magnification in most free-tissue transfers with specific characteristics that combine the microscope and loupe philosophies. PMID- 17705278 TI - Novel structural and functional findings of the ehFLN protein from Entamoeba histolytica. AB - The ehFLN protein (previously known as EhABP-120) is the first filamin to be identified in the parasitic protozoan Entamoeba histolytica. Filamins are a family of cross-linking actin-binding proteins that organize filamentous actin in networks and stress fibers. It has been reported that filamins of different organisms directly interact with more than 30 cellular proteins and some PPIs. The biochemical consequences of such interactions may have either positive or negative effects on the cross-linking function. Besides, filamins form a link between cytoskeleton and plasma membrane. In this work, the ehFLN protein was biochemically characterized; amoebae filamin was found to associate with both PA and PI(3)P in vitro, new lipid targets for a member of the filamins. By molecular modeling analysis and protein-lipid overlay assays, K-609, 709, and 710 were determined to be essential for the PA-ehFLN1 complex stability. Also, the integrity of the 4th repeat of ehFLN is essential to keep interaction with the PI(3)P. Transfected trophozoites that overexpressed the d100, d50NH(2), and d50COOH regions of ehFLN1 displayed both increased motility and chemotactic response to TYI-S-33 media. Together, these results suggest that short regions of ehFLN are involved in signaling events that, in cooperation with phosphatidic acid, EhPLD2 and EhPI3K, could promote cell motility. PMID- 17705281 TI - A novel model of portal vein transplantation in mice using two-cuff technique. AB - Allogeneic portal vein (PV) grafts have been widely used for vascular reconstruction in the aggressive biliary-pancreatic surgery and partial liver transplantation. We developed a novel PV transplantation model aimed at studying the pathologic alteration of the grafts and further managements. The PV graft was implanted orthotopically into the recipient using two-cuff technique. A total of 80 PV transplants have been performed, and the overall survival rate for the recipients was 91.3% (73/80). Mice were randomly separated into isografts group, allografts group, and allografts group treated with CTLA4-Ig. PV grafts were harvested on the 1st, 2nd, 4th, and 8th postoperative week. The isografts remained intact vascular structure, and the allografts developed marked rejection with significant increase in wall thickness (95 +/- 19 microm vs. 49 +/- 7 microm; P < 0.01) and decrease in lumen area (1.9 +/- 1.1 x 10(4) microm(2) vs. 7.7 +/- 3.1 x 10(4) microm(2); P < 0.01) on the 4th week. In the CTLA4-Ig treated group, the vascular thickness and lumen area were significantly improved when compared with the untreated allografts (wall-thickness: 53 +/- 3 microm vs. 95 +/ 19 microm, P < 0.01; lumen area: 8.8 +/- 2.4 x 10(4) microm(2) vs. 1.9 +/- 1.1 x 10(4) microm(2), P < 0.01) on the 4th week. In conclusion, the PV transplantation model in mice using two-cuff technique is a feasible procedure with a high survival rate. The PV allografts responded well to the CTLA4-Ig therapy in our preliminary research by the model. PMID- 17705282 TI - Management and functional outcomes of combined injuries of flexor tendons, nerves, and vessels at the wrist. AB - A retrospective review of 42 patients with spaghetti wrist lacerations operated on by the author between June 1997 and May 2005 was completed. A total of 31 males and 11 females, average age of 17.1 years (range, 2-40 years), sustained spaghetti wrist injuries. The most frequent mechanisms of injury were accidental glass lacerations (55%), knife wounds (24%), and electrical saw injuries (11%). An average of 9.16 structures was injured, including 6.95 tendons, 1.4 nerves, and 0.8 arteries. The most frequently injured structures were median nerve (83%), flexor digitorum superficialis 2-4 tendons (81%), flexor digitorum profundus 2-4 tendons (66%), ulnar nerve and ulnar artery (57%), and flexor pollicis longus (40%). Combined flexor carpi ulnaris, ulnar nerve, and ulnar artery (ulnar triad) injuries occurred in 31%, while combined median nerve, palmaris longus, and flexor carpi radialis injuries (radial triad) occurred in 43%. Simultaneous injuries of both median and ulnar nerves occurred in 40.5%. Simultaneous injuries of both ulnar and radial arteries occurred in 14%. Neither artery was injured in 30.9%. Follow-up has ranged from 1 to 8 years, with an average of 46 months. Only four patients have been completely lost to follow-up. Range of motion of all involved digits (tendon function) was excellent in 34 patients, good in 3 patients, and poor in only 1 patient. Opposition was excellent in 31 patients, good in 5 patients, and poor in 2 patients. Intrinsic muscle recovery was subjectively reported to be excellent in 29 patients, good in 7, and fair to poor in 2 patients. Minor deformity (partial clawing) was reported in 4 patients and 1 patient has major deformity (total clawing). Sensory recovery was reported, excellent in 32 patients, good in 5 patients, and fair in only 1 patient. PMID- 17705283 TI - Anatomic study and clinical application of distally-based neuro-myocutaneous compound flaps in the leg. AB - OBJECTIVE: Anatomical study on the anastomosis between the neurovascular axis and the musculocutaneous perforators in leg. The distally-based neuron-myocutaneous flap was used for repairing special patients with soft tissue defect in foot and ankle. METHODS: Systematical observation was carried out on 30 injected lower legs about the anastomosis between the neurovascular axis and the musculocutaneous perforators, and we summarized the clinical experiences from February 2004 on 12 cases using distally-based neuron-myocutaneous flap for repairing special patients with soft tissue defect in foot and ankle. RESULTS: The neuron-vessels of sural nerve anastomosed permanently with the musculocutaneous perforators of medial and lateral head of gastrocnemius. There were two to three anastomoses found, respectively. The medial anastomotic branches were found larger in caliber than the lateral ones. The spatium intermuscular branches of the posterior tibial artery gave off their junior branches and anastomosed with the vessels in or out of the soleus muscle. There were two to three muscular branches perforated out of the soleus muscle, with mean caliber 0.5 +/- 0.2 mm and accompanying with one to two veins. The neuron vessels of the superficial fibular nerve gave off alone its course two to three muscular branches to the long extensor muscle digits and the long fibular muscle, and one to two fasciocutaneous to the skin. The diameter of the muscular branches was 0.4 +/- 0.2 mm in average. Accounting for the operating models in the 12 cases, we had distally-based sural neuron-myocutaneous flap in 7 cases, saphenous neuron-myocutaneous flap in 4 cases, and superficial fibular neuron-myocutaneous flap in 1 case. All these cases were followed up at least for 2-6 months and had the significant results of nice limb's shape and cured osteomyelitis. CONCLUSION: Distally-based neuro-myocutaneous flap in leg can live with reliable blood circulation. These flaps offer excellent donor sites for repairing special the soft tissue defect in foot and ankle. PMID- 17705285 TI - Concentration decrease of nitric oxide in the postischemic muscle is not only caused by the generation of O2-. AB - Reperfusion of ischemic skeletal muscle is associated with an alteration of the concentrations of O(2) (-) and NO. In this study, the influence of epigallocatechin-3-gallate (EGCG), a known radical scavenger, on the balance of O(2) (-) and NO has been measured online in the skeletal muscle of Wistar rats. The hind limb of 14 male rats had been exposed to ischemic stress for 2 h. Seven rats received an infusion of 1.5 micromol EGCG/kg 5 min before reperfusion. O(2) (-), NO, and temperature were measured during reperfusion. The concentration of O(2) (-) declined under the influence of EGCG from 156.5 to 72.2 nmol/l (P = 0.01). The level of NO was found to decrease; this decrease was not significantly changed by EGCG (-175 nmol/l vs. - 227 nmol/l; P = 0.33). Thus the different superoxide concentrations did not correspond to different levels of NO, and the interaction of both radicals is not the only reason for the concentration decrease of NO in the reperfusion period. We conclude that EGCG protects skeletal muscle from I/R-injury without influencing the NO concentration profile to a large extent. PMID- 17705287 TI - Evaluation of drug precipitation of solubility-enhancing liquid formulations using milligram quantities of a new molecular entity (NME). AB - A precipitation screening method using a 96-well microtiter plate was developed to evaluate in vitro drug precipitation kinetics of liquid formulations for poorly water-soluble compounds, using milligram quantities of compounds and milliliter volumes of biorelevant media. By using this method we identified three formulations showing distinct in vitro precipitation kinetics (fast, slow, and no precipitation) for a model new molecular entity (JNJ-25894934). The in vitro precipitation profiles in simulated intestinal fluid (SIF), fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF) were compared with those measured by a USP dissolution method, and with in vivo absorption at the fasted and fed states in canine pharmacokinetic (PK) studies. The precipitation kinetics of all three formulations in the initial hours measured by the screening method correlated to those determined by the USP method (R(2) = 0.96). The PK results showed that the fast-precipitation formulation had the lowest bioavailability. However, a similar bioavailability was observed for the slow- and no-precipitation formulations. The oral bioavailability of JNJ-25894934 at the fed state was also significantly higher than that at the fasted state for all three formulations (p < 0.05). In addition, the in vitro precipitation profiles in FeSSIF correlated better with in vivo absorption than those in SIF and FaSSIF. PMID- 17705288 TI - Pharmacokinetic-pharmacodynamic modeling and simulation for in vivo bactericidal effect in murine infection model. AB - A pharmacokinetic (PK)/pharmacodynamic (PD) modeling strategy to simulate in vivo bactericidal effects for three carbapenem antibiotics, doripenem (DRPM), meropenem (MEPM)/cilastatin (CS), and imipenem (IPM)/CS, against a Pseudomonas aeruginosa (P. aeruginosa) strain is proposed. The PD model we have already developed to explain in vitro time-kill profiles was modified to incorporate the growth rate, bactericidal activities, and PK profiles in murine lung infection models. Plasma concentration data and bacterial time-kill data for each antibiotic consist of six and eight time points, respectively, at one dose regimen (four or five mouse/point). In vivo time-kill curves could be well simulated for each antibiotic by the PK/PD model. Simulated bacterial counts at 24 h and PK/PD indices derived from total drug concentrations (time above the minimum inhibitory concentration (MIC) (T > MIC), C(max)/MIC, and AUC/MIC) for various dose regimens were examined for MEPM/CS and IPM/CS. Simulated bacterial counts correlated only with T > MIC (correlation coefficient: 0.951 for MEPM/CS, 0.982 for IPM/CS) and T > MIC values to achieve a bacteriostatic effect and a 2 log killing effect for both antibiotics were estimated to be approximately 15 and 20%, respectively, which are similar to previously reported results. These findings suggested that the proposed PK/PD model is a good tool for predicting in vivo bactericidal effects. PMID- 17705286 TI - Phosphatidylserine containing liposomes reduce immunogenicity of recombinant human factor VIII (rFVIII) in a murine model of hemophilia A. AB - Factor VIII (FVIII) is a multidomain protein that is deficient in hemophilia A, a clinically important bleeding disorder. Replacement therapy using recombinant human FVIII (rFVIII) is the main therapy. However, approximately 15-30% of patients develop inhibitory antibodies that neutralize rFVIII activity. Antibodies to epitopes in C2 domain, which is involved in FVIII binding to phospholipids, are highly prevalent. Here, we investigated the effect of phosphatidylserine (PS)-containing liposomes, which bind to C2 domain with high affinity and specificity, upon the immunogenicity of rFVIII. Circular dichroism studies showed that PS-containing liposomes interfered with aggregation of rFVIII. Immunogenicity of free- versus liposomal-rFVIII was evaluated in a murine model of hemophilia A. Animals treated with s.c. injections of liposomal-rFVIII had lower total- and inhibitory titers, compared to animals treated with rFVIII alone. Antigen processing by proteolytic enzymes was reduced in the presence of liposomes. Animals treated with s.c. injections of liposomal-rFVIII showed a significant increase in rFVIII plasma concentration compared to animals that received rFVIII alone. Based on these studies, we hypothesize that specific molecular interactions between PS-containing bilayers and rFVIII may provide a basis for designing lipidic complexes that improve the stability, reduce the immunogenicity of rFVIII formulations, and permit administration by s.c. route. PMID- 17705289 TI - G protein betagamma subunits interact with alphabeta- and gamma-tubulin and play a role in microtubule assembly in PC12 cells. AB - The betagamma subunit of G proteins (Gbetagamma) is known to transfer signals from cell surface receptors to intracellular effector molecules. Recent results suggest that Gbetagamma also interacts with microtubules and is involved in the regulation of the mitotic spindle. In the current study, the anti-microtubular drug nocodazole was employed to investigate the mechanism by which Gbetagamma interacts with tubulin and its possible implications in microtubule assembly in cultured PC12 cells. Nocodazole-induced depolymerization of microtubules drastically inhibited the interaction between Gbetagamma and tubulin. Gbetagamma was preferentially bound to microtubules and treatment with nocodazole suggested that the dissociation of Gbetagamma from microtubules is an early step in the depolymerization process. When microtubules were allowed to recover after removal of nocodazole, the tubulin-Gbetagamma interaction was restored. Unlike Gbetagamma, however, the interaction between tubulin and the alpha subunit of the Gs protein (Gsalpha) was not inhibited by nocodazole, indicating that the inhibition of tubulin-Gbetagamma interactions during microtubule depolymerization is selective. We found that Gbetagamma also interacts with gamma-tubulin, colocalizes with gamma-tubulin in centrosomes, and co-sediments in centrosomal fractions. The interaction between Gbetagamma and gamma-tubulin was unaffected by nocodazole, suggesting that the Gbetagamma-gamma-tubulin interaction is not dependent on assembled microtubules. Taken together, our results suggest that Gbetagamma may play an important and definitive role in microtubule assembly and/or stability. We propose that betagamma-microtubule interaction is an important step for G protein-mediated cell activation. These results may also provide new insights into the mechanism of action of anti-microtubule drugs. PMID- 17705290 TI - Proteomic identification of biomarkers in the cerebrospinal fluid in a rat model of nigrostriatal dopaminergic degeneration. AB - We have performed proteomic analysis in the cerebrospinal fluid in an animal model of Parkinson's disease induced by axotomy of the medial forebrain bundle. In this model, the degeneration of dopaminergic neurons was completed in 14 days, with a loss of about 50% dopaminergic neurons in the substantia nigra and a loss of more than 80% dopamine terminals in the striatum, with a similar diminution of dopamine levels in both structures. Proteins were separated by 2D electrophoresis and identified by matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF). We found significant increases of haptoglobin and transthyretin along with a decrease of Apo E concentrations in the cerebrospinal fluid of axotomized animals. Changes for haptoglobin and transthyretin were further confirmed in cerebrospinal fluid and plasma by Western blotting. These results suggest that monitoring plasma levels of these signals appears to be a promising biological marker of neuronal degeneration of the nigrostriatal dopaminergic system. PMID- 17705291 TI - Alpha-synuclein and its role in metal binding: relevance to Parkinson's disease. AB - Parkinson's disease and some other neurodegenerative disorders are associated with a protein that can aggregate and form fibrils called alpha-synuclein. Like many other proteins associated with neurodegenerative disorders, this protein has no known function, and the mechanism by which it could cause diseases is poorly defined. It was recently suggested that it binds copper. This review assesses what is known about alpha-synuclein and its interaction with metals. PMID- 17705292 TI - Decreased nicotinic receptors and cognitive deficit in rats intracerebroventricularly injected with beta-amyloid peptide(1-42) and fed a high cholesterol diet. AB - To investigate whether the changes in nicotinic receptors (nAChRs) and in learning and memory associated with Alzheimer's disease (AD) are influenced by both beta-amyloid peptide (Abeta) and cholesterol in vivo, we examined the effects of intracerebroventricular injection of Abeta(1-42) and/or a high cholesterol diet on brain levels of nAChRs and learning and memory in rats. The levels of nAChR subunit proteins and the corresponding mRNA were measured by Western blotting and RT-PCR, respectively; and learning and memory were evaluated with the Morris Water Maze examination. Injection of Abeta(1-42) resulted in deposition of this peptide, activation of astrocytes, decreased levels of the alpha7 and alpha4 protein subunits of the nAChR, and elevated expression of alpha7 mRNA, as well as impaired learning and spatial memory. A high-cholesterol diet activated astrocytes and, more importantly, potentiated the toxic effects of Abeta on nAChR subunit levels and on learning and memory. These findings may be highly relevant to the mechanisms underlying the cognitive deficits associated with AD. PMID- 17705293 TI - Loss of synapses in the entorhinal-dentate gyrus pathway following repeated induction of electroshock seizures in the rat. AB - The goal of this study was to answer the question of whether repeated administration of electroconvulsive shock (ECS) seizures causes structural changes in the entorhinal-dentate projection system, whose neurons are known to be particularly vulnerable to seizure activity. Adult rats were administered six ECS seizures, the first five of which were spaced by 24-hr intervals, whereas the last two were only 2 hr apart. Stereological approaches were employed to compare the total neuronal and synaptic numbers in sham- and ECS-treated rats. Golgi stained material was used to analyze dendritic arborizations of the dentate gyrus granule cells. Treatment with ECS produced loss of neurons in the entorhinal layer III and in the hilus of the dentate gyrus. The number of neurons in the entorhinal layer II, which provides the major source of dentate afferents, and in the granular layer of the dentate gyrus, known to receive entorhinal projections, remained unchanged. Despite this, the number of synapses established between the entorhinal layer II neurons and their targets, dentate granule cells, was reduced in ECS-treated rats. In addition, administration of ECS seizures produced atrophic changes in the dendritic arbors of dentate granule cells. The total volumes of entorhinal layers II, III, and V-VI were also found to be reduced in ECS-treated rats. By showing that treatment with ECS leads to partial disconnection of the entorhinal cortex and dentate gyrus, these findings shed new light on cellular processes that may underlie structural and functional brain changes induced by brief, generalized seizures. PMID- 17705294 TI - Non-native protein aggregation kinetics. AB - Experimental kinetics of non-native protein aggregation are of practical importance in that they help dictate viable processing, formulation, and storage conditions for biotechnology products, and appear to play a role in determining the onset of a number of diseases. Fundamentally, aggregation kinetics provide insights into the identity of key intermediates in the process, and quantitative tests of available models of aggregation. Although aggregation kinetics often display seemingly disparate behaviors across different proteins and sample conditions, this review illustrates how many of these can be understood within a general framework that treats aggregation as a multi-stage process, and how most available kinetic models of aggregation can be grouped hierarchically in terms of which stage(s) they include. This provides an aid for workers seeking a mechanistic interpretation of in vitro aggregation kinetics, for discriminating among competing models, and in designing experiments to assess in vitro protein stability. Limitations and the utility of purely kinetic approaches to studying aggregation, clarifications of common misperceptions regarding experimental aggregation kinetics, and some outstanding challenges in the field are briefly discussed. PMID- 17705295 TI - Bile duct destruction by 4,4'-diaminodiphenylmethane does not block the small hepatocyte-like progenitor cell response in retrorsine-exposed rats. AB - Liver regeneration after surgical partial hepatectomy (PH) in retrorsine-exposed rats is accomplished through the outgrowth and expansion of small hepatocyte-like progenitor cells (SHPCs). The cells of origin for SHPCs and their tissue niche have not been identified. Nevertheless, some investigators have suggested that SHPCs may represent an intermediate or transitional cell type between oval cells and mature hepatocytes, rather than a distinct progenitor cell population. We investigated this possibility through the targeted elimination of oval cell proliferation secondary to bile duct destruction in retrorsine-exposed rats treated with 4,4'-diaminodiphenylmethane (DAPM). Fischer 344 rats were treated with 2 doses (30 mg/kg body weight) retrorsine (at 6 and 8 weeks of age) followed by PH 5 weeks later. Twenty-four hours before PH, select animals were given a single dose of DAPM (50 mg/kg). Treatment of rats with DAPM produced severe bile duct damage but did not block liver regeneration. Oval cells were never seen in the livers of DAPM-treated retrorsine-exposed rats after PH. Rather, liver regeneration in these rats was mediated by the proliferation of SHPCs, and the cellular response was indistinguishable from that observed in retrorsine-exposed rats after PH. SHPC clusters emerge 1 to 3 days post-PH, expand through 21 days post-PH, with normalization of the liver occurring by the end of the experimental interval. CONCLUSION: These results provide direct evidence that SHPC-mediated liver regeneration does not require oval cell activation or proliferation. In addition, these results provide strong evidence that SHPCs are not the progeny of oval cells but represent a distinct population of liver progenitor cells. PMID- 17705297 TI - The impact of ethnicity on the natural history of autoimmune hepatitis. AB - The impact of ethnicity on the natural history of autoimmune hepatitis (AIH) has not been well characterized. The aim of this study was to assess the natural history of AIH in blacks in comparison with others (nonblacks). This was a 10 year (June 1996 to June 2006) retrospective analysis of patients with AIH from a single tertiary care center. The diagnosis of AIH was defined by the criteria established by the International Autoimmune Hepatitis Club. A poor outcome was defined as liver failure at presentation, failure to achieve remission, need for liver transplantation, and/or death. One hundred one patients with AIH were eligible for the study. Black patients were more likely to have cirrhosis (56.7% versus 37.5%, P = 0.061), have liver failure at the initial presentation (37.8% versus 9.3%, P = 0.001), and be referred for liver transplantation (51.3% versus 23.4%, P = 0.004). The overall mortality was also significantly higher in black patients (24.3% versus 6.2%, P = 0.009). Compared with nonblacks, blacks had more advanced hepatic fibrosis (3.6 +/- 2.7 versus 2.1 +/- 2.4, P = 0.013). A Kaplan Meier analysis showed that the probability of developing a poor outcome was significantly higher in blacks (P = 0.003). Independent predictors of poor outcome were black ethnicity, the presence of cirrhosis, and the fibrosis stage at presentation. Black males were the group most likely to have a poor outcome (85.7%). CONCLUSION: Blacks, especially black men with AIH, have more aggressive disease at the initial presentation, are less likely to respond to conventional immunosuppression, and have a worse outcome than nonblacks. PMID- 17705296 TI - Efficient generation of human hepatocytes by the intrahepatic delivery of clonal human mesenchymal stem cells in fetal sheep. AB - Alternative methods to whole liver transplantation require a suitable cell that can be expanded to obtain sufficient numbers required for successful transplantation while maintaining the ability to differentiate into hepatocytes. Mesenchymal stem cells (MSCs) possess several advantageous characteristics for cell-based therapy and have been shown to be able to differentiate into hepatocytes. Thus, we investigated whether the intrahepatic delivery of human MSCs is a safe and effective method for generating human hepatocytes and whether the route of administration influences the levels of donor-derived hepatocytes and their pattern of distribution throughout the parenchyma of the recipient's liver. Human clonally derived MSCs were transplanted by an intraperitoneal (n = 6) or intrahepatic (n = 6) route into preimmune fetal sheep. The animals were analyzed 56-70 days after transplantation by immunohistochemistry, enzyme-linked immunosorbent assay, and flow cytometry. The intrahepatic injection of human MSCs was safe and resulted in more efficient generation of hepatocytes (12.5% +/- 3.5% versus 2.6% +/- 0.4%). The animals that received an intrahepatic injection exhibited a widespread distribution of hepatocytes throughout the liver parenchyma, whereas an intraperitoneal injection resulted in a preferential periportal distribution of human hepatocytes that produced higher amounts of albumin. Furthermore, hepatocytes were generated from MSCs without the need to first migrate/lodge to the bone marrow and give rise to hematopoietic cells. CONCLUSION: Our studies provide evidence that MSCs are a valuable source of cells for liver repair and regeneration and that, by the alteration of the site of injection, the generation of hepatocytes occurs in different hepatic zones, suggesting that a combined transplantation approach may be necessary to successfully repopulate the liver with these cells. PMID- 17705300 TI - Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome. AB - Meckel-Gruber syndrome (MKS) is an autosomal recessive, lethal multisystemic disorder characterized by meningooccipital encephalocele, cystic kidney dysplasia, hepatobiliary ductal plate malformation, and postaxial polydactyly. Recently, genes for MKS1 and MKS3 were identified, putting MKS on the list of ciliary disorders (ciliopathies). By positional cloning in a distantly related multiplex family, we mapped a novel locus for MKS to a 3-Mb interval on 12q21. Sequencing of the CEP290 gene located in the minimal critical region showed a homozygous 1-bp deletion supposed to lead to loss of function of the encoded centrosomal protein CEP290/nephrocystin-6. CEP290 is thought to be involved in chromosome segregation and localizes to cilia, centrosomes, and the nucleus. Subsequent analysis of another consanguineous multiplex family revealed homozygous haplotypes and the same frameshift mutation. Our findings add to the increasing body of evidence that ciliopathies can cause a broad spectrum of disease phenotypes, and pleiotropic effects of CEP290 mutations range from single organ involvement with isolated Leber congenital amaurosis to Joubert syndrome and lethal early embryonic multisystemic malformations in Meckel-Gruber syndrome. We compiled clinical and genetic data of all patients with CEP290 mutations described so far. No clear-cut genotype-phenotype correlations were apparent as almost all mutations are nonsense, frameshift, or splice-site changes and scattered throughout the gene irrespective of the patients' phenotypes. Conclusively, other factors than the type and location of CEP290 mutations may underlie phenotypic variability. PMID- 17705298 TI - Association of reduced extracellular brain ammonia, lactate, and intracranial pressure in pigs with acute liver failure. AB - We previously demonstrated in pigs with acute liver failure (ALF) that albumin dialysis using the molecular adsorbents recirculating system (MARS) attenuated a rise in intracranial pressure (ICP). This was independent of changes in arterial ammonia, cerebral blood flow and inflammation, allowing alternative hypotheses to be tested. The aims of the present study were to determine whether changes in cerebral extracellular ammonia, lactate, glutamine, glutamate, and energy metabolites were associated with the beneficial effects of MARS on ICP. Three randomized groups [sham, ALF (induced by portacaval anastomosis and hepatic artery ligation), and ALF+MARS] were studied over a 6-hour period with a 4-hour MARS treatment given beginning 2 hours after devascularization. Using cerebral microdialysis, the ALF-induced increase in extracellular brain ammonia, lactate, and glutamate was significantly attenuated in the ALF+MARS group as well as the increases in extracellular lactate/pyruvate and lactate/glucose ratios. The percent change in extracellular brain ammonia correlated with the percent change in ICP (r(2) = 0.511). Increases in brain lactate dehydrogenase activity and mitochondrial complex activity for complex IV were found in ALF compared with those in the sham, which was unaffected by MARS treatment. Brain oxygen consumption did not differ among the study groups. CONCLUSION: The observation that brain oxygen consumption and mitochondrial complex enzyme activity changed in parallel in both ALF- and MARS-treated animals indicates that the attenuation of increased extracellular brain ammonia (and extracellular brain glutamate) in the MARS-treated animals reduces energy demand and increases supply, resulting in attenuation of increased extracellular brain lactate. The mechanism of how MARS reduces extracellular brain ammonia requires further investigation. PMID- 17705304 TI - Development and evolution of the vertebrate mesoderm. PMID- 17705305 TI - Regulation of adult intestinal epithelial stem cell development by thyroid hormone during Xenopus laevis metamorphosis. AB - During amphibian metamorphosis, most or all of the larval intestinal epithelial cells undergo apoptosis. In contrast, stem cells of yet-unknown origin actively proliferate and, under the influence of the connective tissue, differentiate into the adult epithelium analogous to the mammalian counterpart. Thus, amphibian intestinal remodeling is useful for studying the stem cell niche, the clarification of which is urgently needed for regenerative therapies. This review highlights the molecular aspects of the niche using the Xenopus laevis intestine as a model. Because amphibian metamorphosis is completely controlled by thyroid hormone (TH), the analysis of TH response genes serves as a powerful means for clarifying its molecular mechanisms. Although functional analysis of the genes is still on the way, recent progresses in organ culture and transgenic studies have gradually uncovered important roles of cell-cell and cell-extracellular matrix interactions through stromelysin-3 and sonic hedgehog/bone morphogenetic protein 4 signaling pathway in the epithelial stem cell development. PMID- 17705307 TI - Multicomponent dynamic covalent assembly of a rhombicuboctahedral nanocapsule. AB - Molecular container compounds have a range of potential applications in chemical and biological sciences, most notably as nanoreactors, drug delivery devices, and storage materials. We report a highly efficient dynamic covalent chemistry approach for the synthesis of covalent rhombicuboctahedral nanocapsule 1 from 14 square- and triangular-shaped molecular components. The nanocapsule is obtained in a one-pot reaction in high yield and high purity, and has a solvodynamic diameter of 3.9 nm. In our approach, six formyl cavitands and eight 1,3,5-tris(p aminophenyl)benzene molecules are assembled into a molecular rhombicuboctahedron through twenty four newly formed dynamic imine bonds. Binding studies show that 1 encapsulates tetraalkylammonium salts in toluene. We also discuss the growth mechanism of this nanocapsule. PMID- 17705306 TI - The role of FoxC1 in early Xenopus development. AB - FoxC1 is an important transcription factor in vertebrate development since its mutation in humans results in Axenfeld-Rieger syndrome. In the mouse, disturbance of its function causes congenital hydrocephalus and abnormalities in the development of various mesodermal derivatives. In this report, we provide one mechanistic basis for the requirement for FoxC1 in vertebrate development. We find that, in Xenopus laevis embryos, FoxC1 expression is regulated by the maternal T-box transcription factor VegT, via the nodal sub-family of TGFbeta signaling transducers. We show that at the late neurula to early tailbud stage, FoxC1 depletion causes the down-regulation of adhesion molecules, EP and E cadherin, as well as members of the Ephrin/EphR signaling families in the mesoderm germ layer resulting in the loss of adhesion and apoptosis of mesodermal cells. PMID- 17705308 TI - Synthesis, conformational studies, binding assessment and liposome insertion of a thioether-bridged mimetic of the antigen GM3 ganglioside lactone. PMID- 17705309 TI - Keratanase II-catalyzed synthesis of keratan sulfate oligomers by using sugar oxazolines as transition-state analogue substrate monomers: a novel insight into the enzymatic catalysis mechanism. AB - Keratan sulfate (KS) oligomers with well-defined structures were synthesized by keratanase II (KSase II)-catalyzed transglycosylation. N-Acetyllactosamine [Galbeta(1-->4)GlcNAc; LacNAc] oxazoline derivatives with sulfate groups at the C 6 (1 a) and both the C-6 and the C-6' (1 b) were prepared as transition-state analogue substrate monomers for KSase II. Monomer 1 a was effectively oligomerized by the enzyme under weak alkaline conditions, to give alternating 6 sulfated KS oligomers (2 a) in good yields, and with total control of regioselectivity and stereochemistry. KSase II also recognized 1 b, which provided fully 6-sulfated KS oligomers (2 b) in good yields under similar conditions. Nonsulfated LacNAc oxazoline was difficult to oligomerize enzymatically. These results imply that the catalysis mechanism of KSase II involves a sugar oxazolinium ion that requires the 6-sulfate group in the GlcNAc residue not only in hydrolysis of KS chains, but also in oligomerization of oxazoline monomers. This is the first report of KSase II-catalyzed transglycosylation to form beta(1-->3)-glycosidic bond through a substrate assisted mechanism. PMID- 17705310 TI - Differential selectivity of natural and synthetic aminoglycosides towards the eukaryotic and prokaryotic decoding A sites. AB - The lack of absolute prokaryotic selectivity of natural antibiotics is widespread and is a significant clinical problem. The use of this disadvantage of aminoglycoside antibiotics for the possible treatment of human genetic diseases is extremely challenging. Here, we have used a combination of biochemical and structural analysis to compare and contrast the molecular mechanisms of action and the structure-activity relationships of a new synthetic aminoglycoside, NB33, and a structurally similar natural aminoglycoside apramycin. The data presented herein demonstrate the general molecular principles that determine the decreased selectivity of apramycin for the prokaryotic decoding site, and the increased selectivity of NB33 for the eukaryotic decoding site. These results are therefore extremely beneficial for further research on both the design of new aminoglycoside-based antibiotics with diminished deleterious effects on humans, as well as the design of new aminoglycoside-based structures that selectively target the eukaryotic ribosome. PMID- 17705311 TI - Bi2WO6 nano- and microstructures: shape control and associated visible-light driven photocatalytic activities. AB - The shape-controlled synthesis of nano- and microstructured materials has opened up new possibilities to improve their physical and chemical properties. In this work, new types of Bi(2)WO(6) with complex morphologies, namely, flowerlike, tyre and helixlike, and platelike shapes, have been controllably synthesized by a facile hydrothermal process. The benefits of the present work also stem from the first report on the transformation of Bi(2)WO(6) from three-dimensional (3D) flowerlike superstructures to 2D platelike structures, and on the formation of tyre- and helixlike Bi(2)WO(6) superstructures. UV/Vis absorption spectra show that the optical properties of Bi(2)WO(6) samples are relevant to their size and shape. More importantly, the photocatalytic activities of Bi(2)WO(6) nano- and microstructures are strongly dependent on their shape, size, and structure for the degradation of Rhodamine B (RhB) under visible-light irradiation. The reasons for the differences in the photocatalytic activities of these Bi(2)WO(6) nano- and microstructures are further investigated. PMID- 17705312 TI - Cell apoptosis control using BMP4 and noggin embedded in a polyelectrolyte multilayer film. AB - Programmed cell death (apoptosis) is a genetically regulated process of cell elimination essential during development. During development, programmed cell death is involved in the specific shaping of organs, in the elimination of cells having achieved their program, and in regulating the number of cells to differentiate. Tooth development includes these three aspects and was used here as a model to study the control of apoptosis. Bone morphogenetic proteins (BMPs) are currently considered as playing a major role in signaling apoptosis. This apoptosis could be stopped by treatments with a BMP antagonist ("Noggin"). We selected a model system made by a layer-by-layer approach using poly-L-glutamic acid (PlGA) and poly-L-lysine (PlL) films into which BMP4 and/or Noggin have been embedded. Our results indicate that in situ control of apoptosis during tooth differentiation mediated by both BMP4 and Noggin embedded in a polyelectrolyte multilayer film is possible. We show here for the first time that in the presence of BMP4 and Noggin embedded in a multilayered film, we can induce or inhibit cell death in tooth differentiation, and conserve their biological effects. PMID- 17705313 TI - Why semiconducting single-walled carbon nanotubes are separated from their metallic counterparts. AB - The separation of single-walled carbon nanotubes (SWNTs) according to their electronic structure has attracted much recent attention. In many cases, metallic SWNTs are separated from semiconducting SWNTs and enriched in the supernatant due to stronger interaction between metallic SWNTs and adsorbates. However, the inverse separation of semiconducting from metallic SWNTs is often observed. In this computational study, the underlying mechanism is elucidated by density functional theory. We show that the shape of an aromatic molecule, the degree of hybridization between a molecule and a SWNT, and the oxidative state of SWNTs can affect the type of enriched SWNTs. In principle, one can control the type of enriched SWNTs by selecting a structurally compatible aromatic molecule or changing the hole concentration of the SWNTs. PMID- 17705314 TI - Dielectrophoretic manipulation and real-time electrical detection of single nanowire bridges in aqueous saline solutions. AB - Dielectrophoretic manipulation of nanoscale materials is typically performed in nonionic, highly insulating solvents. However, biomolecular recognition processes, such as DNA hybridization and protein binding, typically operate in highly conducting, aqueous saline solutions. Here, we report investigations of the manipulation and real-time detection of individual nanowires bridging microelectrode gaps in saline solutions. Measurements of the electrode impedance versus frequency show a crossover in behavior at a critical frequency that is dependent on the ionic strength. We demonstrate that by operating above this critical frequency, it is possible to use dielectrophoresis to manipulate nanowires across electrode gaps in saline solutions. By using electrical ground planes and nulling schemes to reduce the background currents, we further demonstrate the ability to electrically detect bridging and unbridging events of individual nanowires in saline solutions. The ability to both manipulate and detect bridging events with electrical signals provides a pathway toward automated assembly of nanoscale devices that incorporate biomolecular recognition elements. PMID- 17705315 TI - Specific integrin labeling in living cells using functionalized nanocrystals. AB - We present an integrin labeling method using functionalized quantum dots (QDs). Cyclic Arg-Gly-Asp (RGD) peptides and a biotin-streptavidin linkage are used to specifically couple individual QDs to integrins of living cells. The spacer distance between the RGD sequence and the QD surface is a crucial parameter to ensure specific binding to individual alpha(v)beta(3) integrins of osteoblast cells. Despite blinking, the position of single QDs is tracked with nanometer precision and localized diffusive behavior is observed. We show that blinking events do not prevent the acquisition of quantitative parameters from the QD trajectories. PMID- 17705318 TI - DNA shadow nanolithography. PMID- 17705317 TI - Nanomechanical investigation of Mo6S9-x Ix nanowire bundles. PMID- 17705316 TI - Nanorod heterostructures showing photoinduced charge separation. AB - Size- and shape-dependent property modifications of semiconductor nanocrystals have been a subject of intense interest because of their potential for future engineering devices. The bandgap and related optical-property tuning of these materials are mainly governed by the nature of their band edges. In addition, fusing one type of nanocrystal over another enables further control of material properties that are dependent on the relative alignments of their energy levels. On a molecular scale, the synthesis of supramolecular compounds has inspired advances in theories for photoinduced charge transfer. Heterostructured nanocrystals potentially provide a nanoscale analog of such systems. A method for preparing heterostructured nanocrystals of complex morphologies showing photoinduced charge separation is presented. It is shown that the energy and lifetime of the charge-transfer photoluminescence band can be tuned by changing the relative alignment of band edges in CdSe/CdTe heterostructure nanorods. The long-lived charge transfer states in these type II semiconductors may make them attractive for photovoltaic applications. PMID- 17705320 TI - Design of binaphthyl-modified symmetrical chiral phase-transfer catalysts: substituent effect of 4,4',6,6'-positions of binaphthyl rings in the asymmetric alkylation of a glycine derivative. AB - A series of symmetrical chiral phase-transfer catalysts with 4,4',6,6' tetrasubstituted binaphthyl units have been designed, and these aryl- and trialkylsilyl-substituted phase-transfer catalysts, which included a highly fluorinated catalyst, were prepared. The chiral efficiency of these chiral phase transfer catalysts was investigated in the asymmetric alkylation of tert butylglycinate-benzophenone Schiff base under mild phase-transfer conditions, and the eminent substituent effect of the 4,4',6,6'-positions of the binaphthyl units on enantioselection was observed. In particular, the OctMe2Si-substituted catalyst was found to be highly efficient for the phase-transfer alkylation of tert-butylglycinate-benzophenone Schiff base with various alkyl halides, including sec-alkyl halides. The highly fluorinated catalyst was also utilized as a recyclable chiral phase-transfer catalyst by simple extraction with fluorous solvents. PMID- 17705319 TI - Fragment docking to S100 proteins reveals a wide diversity of weak interaction sites. AB - The S100 protein family is a highly conserved group of Ca(2+)-binding proteins that belong to the EF-hand type and are considered potential drug targets. In the present study we focused our attention on two members of the family: S100A13 and S100B; the former is involved in the nonclassical protein release of two proangiogenic polypeptides FGF-1 and IL-1alpha that are involved in inflammatory processes, whereas S100B is known to interact with the C-terminal domain of the intracellular tumor suppressor p53 and promote cancer development. We screened, using waterLOGSY NMR experiments, 430 molecules of a generic fragment library and we identified different hits for each protein. The subset of fragments interacting with S100B has very few members in common with the subset interacting with S100A13. From the (15)N-HSQC NMR spectra of the proteins in the presence of those hits the chemical shift differences Deltadelta(HN) were calculated, and the main regions of surface interaction were identified. A relatively large variety of interaction regions for various ligands were identified for the two proteins, including known or suggested protein-protein interaction sites. PMID- 17705321 TI - Intracellular hydrogelation of small molecules inhibits bacterial growth. PMID- 17705322 TI - Rapid patterning of cells and cell co-cultures on surfaces with spatial and temporal control through centrifugation. PMID- 17705323 TI - Multiple FID acquisition of complementary HMBC data. PMID- 17705325 TI - Stringing oxo-centered trinuclear [MnIII3O] units into single-chain magnets with formate or azide linkers. PMID- 17705324 TI - Cleavage agents for soluble oligomers of amyloid beta peptides. PMID- 17705326 TI - Fluorescent sensors for the detection of chemical warfare agents. AB - Along with biological and nuclear threats, chemical warfare agents are some of the most feared weapons of mass destruction. Compared to nuclear weapons they are relatively easy to access and deploy, which makes them in some aspects a greater threat to national and global security. A particularly hazardous class of chemical warfare agents are the nerve agents. Their rapid and severe effects on human health originate in their ability to block the function of acetylcholinesterase, an enzyme that is vital to the central nervous system. This article outlines recent activities regarding the development of molecular sensors that can visualize the presence of nerve agents (and related pesticides) through changes of their fluorescence properties. Three different sensing principles are discussed: enzyme-based sensors, chemically reactive sensors, and supramolecular sensors. Typical examples are presented for each class and different fluorescent sensors for the detection of chemical warfare agents are summarized and compared. PMID- 17705327 TI - The unexpected versatility of P(4)S(3) as a building block in polymeric copper halide networks: 2,3-P, 1,2,3-P and all-P coordination. AB - Layering solutions of P(4)S(3) in CH(2)Cl(2) with solutions of CuCl or CuI in CH(3)CN gives the coordination polymers (P(4)S(3))(3)(CuCl)(7) (1), (P(4)S(3))(2)(CuCl)(3) (2), (P(4)S(3))(CuI) (3) and (P(4)S(3))(CuI)(3) (4), respectively, after slow diffusion. The yellow compounds were characterised by elemental analysis, (31)P magic-angle spinning (MAS) NMR spectroscopy and single crystal X-ray crystallography. The solid-state structures demonstrate the unexpected ligand versatility of the P(4)S(3) molecule, which interacts through two, three, or even all of the phosphorus atoms with copper according to the nature of the copper halide. Compound 1 has a three-dimensional network in which linear and cylindrical infinite CuCl subunits coexist with diatomic CuCl building blocks. For the first time, all four P atoms of the P(4)S(3) cage are involved in coordination with metal atoms. The 3D structure of 2 contains stacks of P(4)S(3) that are interconnected by slightly undulated and planar [CuCl](n) ribbons. Compound 3 is a one-dimensional polymer composed of alternating (CuI)(2) rings and P(4)S(3) bridges. The structure of 4 consists of undulated [CuI](n) layers in which the P(4)S(3) cage functions as a bridge within the layer, as well as a spacer between the layers. The (31)P MAS NMR spectra obtained are in good agreement with the solid-state structures obtained crystallographically. Thus, analytically pure 3 and 4 show singlet peaks that correspond to uncoordinated P and quartets owing to coupling with (63)Cu and (65)Cu, respectively, whereas that of 1 contains quartets according to all-P coordination. The spectrum of 2 was obtained from a sample that still contained 40 % of 1. PMID- 17705328 TI - An ionically driven molecular IMPLICATION gate operating in fluorescence mode. AB - An asymmetrically core-extended boron-dipyrromethene (BDP) dye was equipped with two electron-donating macrocyclic binding units with different metal ion preferences to operate as an ionically driven molecular IMPLICATION gate. A Na(+) responsive tetraoxa-aza crown ether (R(2)) was integrated into the extended pi system of the BDP chromophore to trigger strong intramolecular charge transfer (ICT(2)) fluorescence and guarantee cation-induced spectral shifts in absorption. A dithia-oxa-aza crown (R(1)) that responds to Ag(+) was attached to the meso position of BDP in an electronically decoupled fashion to independently control a second ICT(1) process of a quenching nature. The bifunctional molecule is designed in such a way that in the absence of both inputs, ICT(1) does not compete with ICT(2) and a high fluorescence output is obtained (In(A)=In(B)=0- >Out=1). Accordingly, binding of only Ag(+) at R(1) (In(A)=1, In(B)=0) as well as complexation of both receptors (In(A)=In(B)=1) also yields Out=1. Only for the case in which Na(+) is bound at R(2) and R(1) is in its free state does quenching occur, which is the distinguishing characteristic for the In(A)=0 and In(B)=1- >Out=0 state that is required for a logic IMPLICATION gate and Boolean operations such as IF-THEN or NOT. PMID- 17705329 TI - Organocatalytic asymmetric Mannich reactions with N-Boc and N-Cbz protected alpha amido sulfones (Boc: tert-butoxycarbonyl, Cbz: benzyloxycarbonyl). AB - Different malonates and beta-ketoesters can react with N-tert-butoxycarbonyl- (N Boc) and N-benzyloxycarbonyl- (N-Cbz) protected alpha-amido sulfones in an organocatalytic asymmetric Mannich-type reaction. The reaction makes use of a simple and easily obtained phase-transfer catalyst and proceeds under very mild and user-friendly conditions. The optimised protocol avoids the preparation and the isolation of the relatively unstable N-Boc and N-Cbz imines that are generated in situ from the bench-stable alpha-amido sulfones. The corresponding Mannich bases are generally obtained in good yields and enantioselectivities, and can be readily transformed into key compounds, such as optically active beta3 amino acids in one easy step. Enantioenriched N-Boc and N-Cbz protected beta amino acids that are suitable for peptide synthesis are also available from the Mannich adducts through simple manipulations. Control experiments showed the dual role of the enolate-catalyst ion pair in this reaction, as well as the crucial role of the presence of water to achieve high enantioselectivities. PMID- 17705330 TI - Going to extremes: "super" armed glycosyl donors in glycosylation chemistry. AB - This concept article gives an overview of stereoelectronic effects in monosaccharide systems and how these can be used to dramatically enhance the reactivity of glycosyl donors in oligosaccharide synthesis. PMID- 17705332 TI - Guest editors' introduction. PMID- 17705331 TI - Calorimetric investigation of phosphorylated and non-phosphorylated peptide ligand binding to the human Grb7-SH2 domain. AB - Grb7 is a member of the Grb7 family of proteins, which also includes Grb10 and Grb14. All three proteins have been found to be overexpressed in certain cancers and cancer cell lines. In particular, Grb7 (along with the receptor tyrosine kinase erbB2) is overexpressed in 20-30% of breast cancers. In general, growth factor receptor bound (Grb) proteins bind to activated membrane-bound receptor tyrosine kinases (RTKs; e.g., the epidermal growth factor receptor, EGFR) through their Src homology 2 (SH2) domains. In particular, Grb7 binds to erbB2 (a.k.a. EGFR2) and may be involved in cell signaling pathways that promote the formation of metastases and inflammatory responses. In previous studies, we reported the solution structure and the backbone relaxation behavior of the Grb7-SH2/erbB2 peptide complex. In this study, isothermal titration calorimetry studies have been completed by measuring the thermodynamic binding parameters of several phosphorylated and non-phosphorylated peptides representative of natural Grb7 receptor ligands as well as ligands developed through combinatorial peptide screening methods. The entirety of these calorimetric studies is interpreted in an effort to describe the specific ligand binding characteristics of the Grb7 protein. PMID- 17705333 TI - Measuring health polarization with self-assessed health data. AB - This paper proposes an axiomatic foundation for new measures of polarization that can be applied to ordinal distributions such as self-assessed health (SAH) data. This is an improvement over the existing measures of polarization that can be used only for cardinal variables. The new measures of polarization avoid one difficulty that the related measures for evaluating health inequalities face. Indeed, inequality measures are mean based, and since only cardinal variables have a mean, SAH has to be cardinalized to compute a mean, which can then be used to calculate an inequality measure. In contrast, the new polarization measures are median based and hence do not require to impose cardinal scaling on the categories. After deriving the properties of these new polarization measures, we provide an empirical illustration using data from the British Household Panel Survey that demonstrates that SAH polarization is also a relevant question on empirical grounds, and that the polarization measures are adequate to evaluate polarization phenomena whereas inequality measures are not adequate in these cases. PMID- 17705334 TI - Effects of youth, price, and audience size on alcohol advertising in magazines. AB - In this paper, we study the effects of youth readership, price of advertisements, and audience size on alcohol advertising in 35 major magazines. The regressions also account for readership demographics (adult reader age, income, gender, race), magazine characteristics (newsstand sales, number of annual issues), and type of beverage (beer, wine, spirits). Using count data models, the results indicate significant effects for price, audience size, and adult demographics, but fail to support claims that alcohol advertisers target adolescent readers. PMID- 17705338 TI - Multiple stable isotope (18O, 13C, 15N and 34S) analysis of human hair to identify the recent migrants in a rural community in SW England. AB - Relationships between recent migration and hair delta(18)O values were examined for 40 people living in a rural community in SW England. The isotopic contents of 35 'local' hair samples were compared with those of 5 recently arrived individuals (from Australia, Canada, Chile, Germany and the USA). The hair delta(18)O values of these 'visitors' were +7.9 (Omaha, USA), +11.2 (Jena, Germany), +12.1 (Osorno, Chile), +12.6 (Montreal, Canada) and +14.3 per thousand (Adelaide, Australia). The hair value for the USA visitor (+7.9 per thousand) fell outside the range for the 33 local adult residents, +10.5 to +14.3 per thousand (+12.7 +/- 0.8 per thousand). Hair delta(18)O values did not identify the individuals from Adelaide, Montreal and Osorno as 'visitors', but hair delta(13)C or delta(34)S data did. Combining the hair delta(18)O, delta(13)C and delta(34)S values using principal components analysis (two components explained 89% of the overall variation among the 40 subjects) helped to more clearly distinguish European from non-European individuals, indicating the existence of global overall isotope (geo-origin) relationships. PMID- 17705339 TI - Identification of beta-sitosterol, stigmasterol and ergosterin in A. roxburghii using supercritical fluid extraction followed by liquid chromatography/atmospheric pressure chemical ionization ion trap mass spectrometry. AB - beta-Sitosterol and stigmasterol are the most common phytosterols in traditional Chinese medicine. They have been proved to have many important bioactivities. To the best of our knowledge, this is the first report that beta-sitosterol, stigmasterol and ergosterol coexisting in A. roxburghii herbs can be simultaneously extracted by a supercritical fluid extraction (SFE) procedure; then a simple high-performance liquid chromatography/atmospheric pressure chemical ionization ion trap mass spectrometry (HPLC/APCI/MS) method was developed for simultaneous identification and determination of these three compounds. The ion trap MS/MS detector was equipped with an atmospheric pressure chemical ionization source operating in the positive ion mode, APCI(+). The linear responses were obtained in the concentration range of 0.50-150 microg/mL (r = 0.9999) for ergosterol, 5-400 microg/mL (r = 0.9999) for stigmasterol, and 10-2000 microg/mL (r = 0.9998) for beta-sitosterol. An orthogonal L(9) (3(3)) test design was employed for optimization of the SFE process. Under the optimized conditions, i.e. pressure of 25 mPa, temperature of 45 degrees C and ethanol as modifier, the concentrations of sterols in the extract were found to be 2.89% (g/g) for beta-sitosterol, 3.56% (g/g) for stigmasterol and 2.96% (g/g) for ergosterin. The SFE method was also compared with a previously developed Soxhlet extraction. The SFE method produced higher yields of sterols than that of the Soxhlet extraction. The proposed method has been successfully used for identification and quantitation of beta-sitosterol, stigmasterol and ergosterin in a real A. roxburghii sample. PMID- 17705340 TI - Systematic epitope analysis of the p26 EIAV core protein. AB - The major core protein of equine infectious anemia virus (EIAV), p26, is one of the primary immunogenic structural proteins during a persistent infection of horses and is highly conserved among antigenically variants of viral isolates. In order to investigate its immune profile in more detail for a better diagnostic, an epitope mapping was carried out by means of two libraries of overlapping peptide fragments prepared by simultaneous and parallel SPPS on derivatized cellulose membranes (SPOT synthesis). Polyclonal equine sera from infected horses were used for the biological assay. Particularly two promising continuous epitopes (NAMRHL and MYACRD) were localized on the C-terminal extreme of p26, region 194-222. A cyclic synthetic fragment of 29 amino acid residues containing the identified epitopes was designed and studied. A significant conformational change towards a helical structure was observed when the peptide was cyclized by a bridge between Cys198 and Cys218. This observation correlated with an improvement of its ability to be recognized by specific antibodies in an EIA (Enzyme-linked Immunosorbent assay). These results suggest that the conformationally restricted synthetic antigen adequately mimics the native structure of this region of p26 core protein. PMID- 17705341 TI - Styryl-based compounds as potential in vivo imaging agents for beta-amyloid plaques. AB - A group of styryl-based neutral compounds has been synthesized in this study for potential use as in vivo imaging agents for beta-amyloid plaques. Of 56 candidates, 14 compounds were found to label beta-amyloid plaques well on Alzheimer's disease (AD) human brain sections in vitro. The binding affinity to beta-amyloid fibrils was then determined by measuring the change in fluorescence intensity. Interestingly, we found that a class of quinaldine-styryl scaffold compounds displays specific binding to beta-amyloid fibrils. A representative compound, STB-8, was used in ex vivo and in vivo imaging experiments on an AD transgenic mouse model and demonstrated excellent blood-brain barrier (BBB) permeability and specific staining of the AD beta-amyloid plaques. PMID- 17705343 TI - Profiling RNA polymerase-promoter interaction by using ssDNA-dsDNA probe on a surface addressable microarray. PMID- 17705344 TI - Diffusivity fractionations of H2(16)O/H2(17)O and H2(16)O/H2(18)O in air and their implications for isotope hydrology. AB - We have determined the isotope effects of (17)O and (18)O substitution of (16)O in H(2)O on molecular diffusivities of water vapor in air by the use of evaporation experiments. The derived diffusion fractionation coefficients (17)alpha(diff) and (18)alpha(diff) are 1.0146 +/- 0.0002 and 1.0283 +/- 0.0003, respectively. We also determined, for the first time, the ratio ln((17)alpha(diff))/ln((18)alpha(diff)) as 0.5185 +/- 0.0002. This ratio, which is in excellent agreement with the theoretical value of 0.5184, is significantly smaller than the ratio in vapor-liquid equilibrium (0.529). We show how this new experimental information gives rise to (17)O excess in meteoric water, and how it can be applied in isotope hydrology. PMID- 17705345 TI - Monitoring and evaluation of dechlorination processes using compound-specific chlorine isotope analysis. AB - A simple, quick and sensitive method for the compound-specific stable chlorine isotope analysis of chlorinated solvents by conventional quadrupole gas chromatography/mass spectrometry (GC/MS) is presented. With this method, compound specific stable chlorine isotope ratios of typical chlorinated solvents like tetrachloroethene (PCE) and trichloroethene (TCE) can be determined quantitatively within 30 min by direct injection. The chlorine isotope ratios of target substances are calculated from the peak areas of several selected molecular ions and fragment ions of the substances, using a set of unique mathematical equations. The precision of the method was demonstrated through reproducibility tests. An internal precision of +/-0.4 per thousand to +/-1.1 per thousand was obtained when analyzing PCE and TCE in the 10-1000 pmol range. The validity of the method was further demonstrated by determining the chlorine isotopic fractionation factor during the reductive dechlorination of TCE in a batch experiment using zero-valent iron. The chlorine isotopic fractionation factor was calculated as 0.9976 +/- 0.0011 with a correlation coefficient of 0.9469 (n = 38). The high correlation coefficient indicates that compound specific stable chlorine isotope analysis can be performed with sufficient accuracy using conventional quadrupole GC/MS when significant fractionation takes place during a reaction. For the first time, the chlorine isotope fractionation factor of TCE during an abiotic anaerobic dechlorination process was determined using quadrupole GC/MS, without offline sample preparation. PMID- 17705346 TI - Routine hydrogen isotope measurement of cellulose nitrate by high-temperature pyrolysis--reference materials and precision. AB - The determination of isotope ratios of non-exchangeable hydrogen in tree-ring cellulose is commonly based on the nitration of wood cellulose followed by online high-temperature pyrolysis and isotope ratio mass spectrometry measurement of cellulose nitrate samples. The application of this method requires a proper calibration using appropriate reference materials whose delta(2)H values have been reliably normalized to the V-SMOW/SLAP scale. In our study, we achieve this normalization by a direct alternating measurement of reference waters (V-SMOW and SLAP) and three cellulose nitrates chosen as reference materials. For that purpose, both water and solid organic samples are introduced into the pyrolysis reactor by silver capsule injection. The analytical precision of the water measurement using the capsule method is +/-1.5 per thousand. The hydrogen isotopic composition of three cellulose nitrate standards measured ranges from 106.7 to -53.9 per thousand. The standard deviation of the calculated means from five measurement periods of those standards is better than 1 per thousand. Twenty four different measurements of the hydrogen isotope composition of cellulose nitrate were evaluated in order to assess the precision of the described method. We obtained an analytical precision of +/-3.0 per thousand as representative for the 95% confidence interval applicable for routine measurements of cellulose nitrate samples. Evidence was found for significant differences in the behavior of cellulose nitrate and PE foil during the pyrolitic conversion that emphasizes the need for a proper calibration of the routine measurements. This calibration can only be successful if the reference materials used have a very similar chemical composition and undergo the same preparation procedure as the samples. PMID- 17705347 TI - Peptide Fragment Ion Analyser (PFIA): a simple and versatile tool for the interpretation of tandem mass spectrometric data and de novo sequencing of peptides. AB - The software Peptide Fragment Ion Analyser (PFIA) aids in the analysis and interpretation of tandem mass spectrometric data of peptides. The software package has been designed to facilitate the analysis of product ions derived from acyclic and cyclic peptide natural products that possess unusual amino acid residues and are heavily post-translationally modified. The software consists of two programmes: (a) PFIA-I lists the amino acid compositions and their corresponding product ion types for 'a queried m/z value' (z = +1) and (b) PFIA II displays fragmentation pattern diagram(s) and lists all sequence-specific product ion types for the protonated adduct of 'a queried sequence'. The unique feature of PFIA-II is its ability to handle cyclic peptides. The two programmes used in combination can prove helpful for deriving peak assignments in the de novo sequencing of novel peptides. PMID- 17705348 TI - Testing logistic regression coefficients with clustered data and few positive outcomes. AB - Applications frequently involve logistic regression analysis with clustered data where there are few positive outcomes in some of the independent variable categories. For example, an application is given here that analyzes the association of asthma with various demographic variables and risk factors using data from the third National Health and Nutrition Examination Survey, a weighted multi stage cluster sample. Although there are 742 asthma cases in all (out of 18,395 individuals), for one of the categories of one of the independent variables there are only 25 asthma cases (out of 695 individuals). Generalized Wald and score hypothesis tests, which use appropriate cluster-level variance estimators, and a bootstrap hypothesis test have been proposed for testing logistic regression coefficients with cluster samples. When there are few positive outcomes, simulations presented in this paper show that these tests can sometimes have either inflated or very conservative levels. A simulation-based method is proposed for testing logistic regression coefficients with cluster samples when there are few positive outcomes. This testing methodology is shown to compare favorably with the generalized Wald and score tests and the bootstrap hypothesis test in terms of maintaining nominal levels. The proposed method is also useful when testing goodness-of-fit of logistic regression models using deciles-of-risk tables. PMID- 17705351 TI - Finding the transition state of quasi-barrierless reactions by a growing string method for newton trajectories: application to the dissociation of methylenecyclopropene and cyclopropane. AB - A method for finding a transition state (TS) between a reactant minimum and a quasi-flat, high dissociation plateau on the potential energy surface is described. The method is based on the search of a growing string (GS) along reaction pathways defined by different Newton trajectories (NT). Searches with the GS-NT method always make it possible to identify the TS region because monotonically increasing NTs cross at the TS or, if not monotonically increasing, possess turning points that are located in the TS region. The GS-NT method is applied to quasi-barrierless and truly barrierless chemical reactions. Examples are the dissociation of methylenecyclopropene to acetylene and vinylidene, for which a small barrier far out in the exit channel is found, and the cycloaddition of singlet methylene and ethene, which is barrierless for a broad reaction channel with Cs-symmetry reminiscent of a mountain cirque formed by a glacier. PMID- 17705349 TI - A phase I multiple dose, dose escalation study of cG250 monoclonal antibody in patients with advanced renal cell carcinoma. AB - The chimeric monoclonal antibody cG250 recognises the G250/CAIX/MN antigen found on 95% of clear cell renal cell carcinomas (RCCs). We performed a phase I clinical trial to evaluate the safety, blood pharmacokinetics (PK), and biodistribution of repeated doses of cG250. The primary endpoint was toxicity. Secondary endpoints were cG250 biodistribution and PK; measurement of human anti chimeric-antibodies (HACA); and tumour response rates. Eligible patients had unresectable or metastatic clear cell RCC. Doses of 5, 10, 25, or 50 mg/m(2) were given weekly by intravenous infusion for six weeks. Three patients were treated at each dose level. Trace (131)I-labelled cG250 was administered on weeks 1 and 5. Thirteen patients participated and were evaluable. One patient developed brain metastases and was replaced. No grade 3 or 4 toxicities and no dose-limiting toxicity occurred. One patient died due to progressive disease within 30 days of receiving the study drug. One patient developed HACA during the second six-week cycle. PK analysis showed mean whole body and blood alpha and beta half-lives of cG250 of 18.99 +/- 6.84 and 180.19 +/- 86.68 hours, respectively. All patients had cG250 tumour localization by gamma camera imaging in week 1 and 5. One patient had a complete response, nine patients had stable disease, and three had progressive disease. One patient received 11 six-week cycles of treatment with no toxicity or HACA. In conclusion, repeated intravenous doses of up to 50 mg/m(2) of cG250 are safe. Furthermore cG250 has a long half-life and targets clear cell RCC effectively. PMID- 17705352 TI - Experimental and theoretical electron density study of a highly twisted polycyclic aromatic hydrocarbon: 4-methyl-[4]helicene. AB - Helicenes are molecules of considerable interest in view of their aromaticity which persists despite a marked departure from planarity and because of the extreme potency of some of their metabolites as tumor and mutation promoters. In this study, the electron density of 4-methyl-[4]helicene (or 4 methylbenzo[c]phenanthrene) is studied topologically with an emphasis on the fjord region since this region is where metabolic activation is initiated. The molecule consists of four fused aromatic rings that assume a twisted geometry. This geometry brings two hydrogen atoms into close proximity in the fjord region of the molecule accompanied by the appearance of an intramolecular C Hdelta+...delta+H-C bond path (an interaction termed hydrogen-hydrogen or H- H bonding to distinguish it from dihydrogen bonding from which it is qualitatively distinct). In addition to the intramolecular H-H interaction, a number of intermolecular interactions are shown to be involved in the packing of this molecule in the crystalline state. The effect of the nonplanarity of the molecule on the local aromaticity of each ring is also discussed. PMID- 17705350 TI - A pilot study of monoclonal antibody cG250 and low dose subcutaneous IL-2 in patients with advanced renal cell carcinoma. AB - The chimeric monoclonal antibody cG250 recognizes the CAIX/MN antigen. cG250 induces antibody-dependent cellular cytotoxicity (ADCC) responses in vitro that can be enhanced by IL-2. We studied the effects of adding daily low-dose subcutaneous IL-2 to cG250 for treatment of clear cell renal cell carcinoma (RCC). The primary endpoints of the trial were toxicity and immunological effects (human anti-chimeric antibodies [HACA], ADCC, natural killer [NK] and lymphokine activated killer cell [LAK] activity); secondary endpoints were cG250 biodistribution and pharmacokinetics (PK) and tumour response rates. Eligible patients had unresectable metastatic or locally advanced clear cell RCC with measurable or evaluable disease. Nine patients were treated with six doses of cG250 (10 mg/m(2)/week, first and fifth doses trace-labelled with (131)I), and 1.25 x 10(6) IU/m(2)/day IL-2 for six weeks. Treatment was generally well tolerated with no adverse events attributable to cG250. Two patients required a 50% dose reduction of IL-2 due to toxicity. No HACA was detected. (131)I-labeled cG250 showed excellent targeting of tumour deposits. (131)I cG250 PK: T(1/2)alpha 20.16 +/- 6.59 h, T(1/2)beta 126.21 +/- 34.04 h, CL 39.67 +/- 23.06 mL/h, Cmax 5.12 +/- 0.86 microg/mL, V(1) 3.88 +/- 1.05 L. IL-2 did not affect cG250 PK. A trend for increased percentage of circulating CD3-/CD16+CD56+ NK cells was observed. Some patients showed enhanced ADCC or LAK activity. No antitumour responses were observed. In conclusion, weekly cG250 with daily low-dose subcutaneous IL-2 is well tolerated. IL-2 does not influence cG250 biodistribution or increase HACA. PMID- 17705353 TI - Infrared multiphoton dissociation spectra as a probe of ion molecule reaction mechanism: the formation of the protonated water dimer via sequential bimolecular reactions with 1,1,3,3-tetrafluorodimethyl ether. AB - The gas-phase ion-molecule reactions of 1,1,3,3-tetrafluorodimethyl ether and water have been examined using Fourier transform ion cyclotron resonance mass spectrometry, infrared multiphoton dissociation (IRMPD) spectroscopy, and ab initio molecular orbital calculations. This reaction sequence leads to the efficient bimolecular production of the proton-bound dimer of water (H5O2+). Evidence for the dominant mechanistic pathway involving the reaction of CF2H O=CHF+, an ion of m/z 99, with water is presented. The primary channel occurs via nucleophilic attack of water on the ion of m/z 99 (CF2H-O=CHF+), to lose formyl fluoride and yield-protonated difluoromethanol (m/z 69). Association of a second water molecule with protonated difluoromethanol generates a reactive intermediate that decomposes via a 1,4-elimination to release hydrogen fluoride and yield the proton-bound dimer of water and formyl fluoride (m/z 67). Last, the elimination of formyl fluoride occurs by the association of a third water molecule to produce H5O2+ (m/z 37). The most probable isomeric forms of the ions with m/z 99 and 69 were found using IRMPD spectroscopy and electronic structure theory calculations. Thermochemical information for reactant, transition state, and product species was obtained using MP2(full)/6-311+G**//6-31G* level of theory. PMID- 17705354 TI - Deprotonation of 1,2-dialkylpyridinium ions: a DFT study of reactivity and site selectivity. AB - A site-selectivity model, based on the Fukui function as a local reactivity descriptor, has been applied to 1,2-disubstituted pyridinium ions incorporating two competing sites of similar reactivity, i.e., 1-methylene and 2-methylene, which may undergo deprotonation depending on the nature of substituent present on these moieties. Applicability of the local HSAB rule, in context with the Li Evans' generalized HSAB principle suggesting the hard-hard interactions to be controlled by minimum Fukui function, has been illustrated. Global and local reactivity descriptors have been computed by carrying out DFT calculations at B3LYP/6-31++G** level using Mulliken and NPA methods for charge analysis. A comparison with the calculated deprotonation energies involving two sites indicates that the observed site selectivity in differently substituted pyridinium ions is better explained by the Li-Evans rule of minimum Fukui function for hard-hard interactions. PMID- 17705355 TI - Electron super-rich radicals in the gas phase. A neutralization-reionization mass spectrometric and ab initio/RRKM study of diaminohydroxymethyl and triaminomethyl radicals. AB - Diaminohydroxymethyl (1) and triaminomethyl (2) radicals were generated by femtosecond collisional electron transfer to their corresponding cations (1+ and 2+, respectively) and characterized by neutralization-reionization mass spectrometry and ab initio/RRKM calculations at correlated levels of theory up to CCSD(T)/aug-cc-pVTZ. Ion 1+ was generated by gas-phase protonation of urea which was predicted to occur preferentially at the carbonyl oxygen with the 298 K proton affinity that was calculated as PA = 875 kJ mol-1. Upon formation, radical 1 gains vibrational excitation through Franck-Condon effects and rapidly dissociates by loss of a hydrogen atom, so that no survivor ions are observed after reionization. Two conformers of 1, syn-1 and anti-1, were found computationally as local energy minima that interconverted rapidly by inversion at one of the amine groups with a <7 kJ mol-1 barrier. The lowest energy dissociation of radical 1 was loss of the hydroxyl hydrogen atom from anti-1 with ETS = 65 kJ mol-1. The other dissociation pathways of 1 were a hydroxyl hydrogen migration to an amine group followed by dissociation to H2N-C=O* and NH3. Ion 2+ was generated by protonation of gas-phase guanidine with a PA = 985 kJ mol-1. Electron transfer to 2+ was accompanied by large Franck-Condon effects that caused complete dissociation of radical 2 by loss of an H atom on the experimental time scale of 4 mus. Radicals 1 and 2 were calculated to have extremely low ionization energies, 4.75 and 4.29 eV, respectively, which belong to the lowest among organic molecules and bracket the ionization energy of atomic potassium (4.34 eV). The stabilities of amino group containing methyl radicals, *CH2NH2, *CH(NH2)2, and 2, were calculated from isodesmic hydrogen atom exchange with methane. The pi-donating NH2 groups were found to increase the stability of the substituted methyl radicals, but the stabilities did not correlate with the radical ionization energies. PMID- 17705356 TI - Computational study of the release of H2 from ammonia borane dimer (BH3NH3)2 and its ion pair isomers. AB - High-level electronic structure calculations have been used to map out the relevant portions of the potential energy surfaces for the release of H2 from dimers of ammonia borane, BH3NH3 (AB). Using the correlation-consistent aug-cc pVTZ basis set at the second-order perturbation MP2 level, geometries of stationary points were optimized. Relative energies were computed at these points using coupled-cluster CCSD(T) theory with the correlation-consistent basis sets at least up to the aug-cc-pVTZ level and in some cases extrapolated to the complete basis set limit. The results show that there are a number of possible dimers involving different types of hydrogen-bonded interactions. The most stable gaseous phase (AB)2 dimer results from a head-to-tail cyclic conformation and is stabilized by 14.0 kcal/mol with respect to two AB monomers. (AB)2 can generate one or two H2 molecules via several direct pathways with energy barriers ranging from 44 to 50 kcal/mol. The diammoniate of diborane ion pair isomer, [BH4 ][NH3BH2NH3+] (DADB), is 10.6 kcal/mol less stable than (AB)2 and can be formed from two AB monomers by overcoming an energy barrier of approximately 26 kcal/mol. DADB can also be generated from successive additions of two NH3 molecules to B2H6 and from condensation of AB with separated BH3 and NH3 molecules. The pathway for H2 elimination from DADB is characterized by a smaller energy barrier of 20.1 kcal/mol. The alternative ion pair [NH4+][BH3NH2BH3-] is calculated to be 16.4 kcal/mol above (AB)2 and undergoes H2 release with an energy barrier of 17.7 kcal/mol. H2 elimination from both ion pair isomers yields the chain BH3NH2BH2NH3 as product. Our results suggest that the neutral dimer will play a minor role in the release of H2 from ammonia borane, with a dominant role from the ion pairs as observed experimentally in ionic liquids and the solid state. PMID- 17705357 TI - Chemical kinetics of reactions in the unfrozen solution of ice. AB - Some reactions are accelerated in ice compared to aqueous solution at higher temperatures. Accelerated reactions in ice take place mainly due to the freeze concentration effect of solutes in an unfrozen solution at temperatures higher than the eutectic point of the solution. Pincock was the first to report an acceleration model for reactions in ice,1 which successfully simulated experimental results. We propose here a modified version of the model for reactions in ice. The new model includes the total molar change involved in reactions in ice. Furthermore, we explain why many reactions are not accelerated in ice. The acceleration of reactions can be observed in the cases of (i) second- or higher-order reactions, (ii) low concentrations, and (iii) reactions with a small activation energy. Reactions with a buffer solution or additives in order to adjust ion strength, zero- or first-order reactions, or reactions containing high reactant concentrations are not accelerated by freezing. We conclude that the acceleration of reactions in the unfrozen solution of ice is not an abnormal phenomenon. PMID- 17705358 TI - Multichannel reaction of C2Cl3 + O2 studied by time-resolved Fourier transform infrared emission spectroscopy. AB - The multichannel reaction of the C(2)Cl(3) radical with O(2) has been studied thoroughly by step-scan time-resolved Fourier transform infrared emission spectroscopy. Vibrationally excited products of Cl(2)CO, CO, and CO(2) are observed and three major reaction channels forming respectively ClCO + Cl(2)CO, CO + CCl(3)O, and CO(2) + CCl(3) are identified. The vibrational state distribution of the product CO is derived from the spectral fitting, and the nascent average vibrational energy of CO is determined to be 59.9 kJ/mol. A surprisal analysis is applied to evaluate the vibrational energy disposal, which reveals that the experimentally measured CO vibrational energy is much more than that predicted by statistical model. Combining previous ab initio calculation results, the nonstatistical dynamics and mechanism are characterized to be barrierless addition-elimination via short-lived reaction intermediates including the peroxy intermediate C(2)Cl(3)OO* and a crucial three-member-ring COO intermediate. PMID- 17705359 TI - Synthesis and in vivo evaluation of fluorine-18 and iodine-123 labeled 2beta carbo(2-fluoroethoxy)-3beta-(4'-((Z)-2-iodoethenyl)phenyl)nortropane as a candidate serotonin transporter imaging agent. AB - 2Beta-carbo(2-fluoroethoxy)-3beta-(4'-((Z)-2-iodoethenyl)phenyl)nortropane (betaFEpZIENT, 1) was synthesized as a serotonin transporter (SERT) imaging agent for both positron emission tomography (PET) and single photon emission computerized tomography (SPECT). The binding affinity of 1 to human monoamine transporters showed a high affinity for the SERT (Ki = 0.08 nM) with respect to the dopamine transporter (DAT) (Ki = 13 nM) and the norepinephrine transporter (NET) (Ki = 28 nM). In vivo biodistribution and blocking studies performed in male rats demonstrated that [123I]1 was selective and specific for SERT. In vivo microPET brain imaging studies in an anesthetized monkey with [18F]1 showed high uptake in the diencephalon and brainstem with peak uptake achieved at 120 min. A chase study with (R,S)-citalopram.HBr displaced [18F]1 radioactivity from all SERT-rich brain regions. A chase study with the DAT ligand 2beta-carbophenoxy 3beta-(4-chlorophenyl)tropane (9, RTI-113) failed to displace [18F]1, indicating that [18F]1 is specific to the SERT. The in vivo evaluation of [18F]1 indicates that this radiotracer is a good candidate for mapping and quantifying CNS SERT. PMID- 17705360 TI - Structure-based optimization of protein tyrosine phosphatase 1B inhibitors: from the active site to the second phosphotyrosine binding site. AB - Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin and leptin receptor pathways and thus an attractive therapeutic target for diabetes and obesity. Starting with a high micromolar lead compound, structure based optimization of novel PTP1B inhibitors by extension of the molecule from the enzyme active site into the second phosphotyrosine binding site is described. Medicinal chemistry, guided by X-ray complex structure and molecular modeling, has yielded low nanomolar PTP1B inhibitors in an efficient manner. Compounds from this chemical series were found to be actively transported into hepatocytes. This active uptake into target tissues could be one of the possible avenues to overcome the poor membrane permeability of PTP1B inhibitors. PMID- 17705361 TI - Toward the development of prophylactic and therapeutic human papillomavirus type 16 lipopeptide vaccines. AB - Four lipid-core peptide systems were synthesized using stepwise solid-phase peptide synthesis, incorporating a sequence from the human papillomavirus type-16 (HPV-16) E7 protein (E744-62), for the purpose of developing vaccines against HPV 16 associated cervical cancer. d-Mannose was conjugated to the vaccine in order to investigate whether the targeting of dendritic cell mannose receptors would improve vaccine efficacy. The ability of the vaccines to clear or reduce the size of HPV-16 associated tumors was assessed in C57BL/6 (H-2b) mice using the TC-1 HPV-16 tumor model. Overall, significant reductions in the size of TC-1 tumors were observed in the mouse model, with the conjugation of mannose to these vaccines demonstrated to clear or reduce the size of TC-1 tumors to a greater extent than non-mannose-containing vaccines (37 out of 40 versus 21 out of 30 tumors cleared, respectively). PMID- 17705363 TI - Prediction of protein-protein interaction inhibitors by chemoinformatics and machine learning methods. AB - We describe a collection of structurally diverse inhibitors of protein-protein interactions (PPIs). This collection is compared against the FDA drug database and a subset of the ZINC database by machine learning methods which rely on classical QSAR descriptors. We obtain a decision tree that contains three descriptors. Of particular importance is a constitutional descriptor related to molecular shape and size. Validation of the decision tree by various procedures indicates that it does not result from chance correlations and has predictive value. We conclude that constitutional descriptors may be valuable tools in the preselection of potential PPI inhibitors from compound databases. PMID- 17705362 TI - Synthesis and characterization of nonsteroidal glucocorticoid receptor modulators for multiple myeloma. AB - Structure-activity relationship studies centered around 3'-substituted (Z)-5-(2' (thienylmethylidene))1,2-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5H chromeno[3,4-f]quinolines are described. A series of highly potent and efficacious selective glucocorticoid receptor modulators were identified with in vitro activity comparable to dexamethasone. In vivo evaluation of these compounds utilizing a 28 day mouse tumor xenograft model demonstrated efficacy equal to dexamethasone in the reduction of tumor volume. PMID- 17705365 TI - Synthesis and electrochemistry of new Rh-centered and conjuncto rhodium carbonyl clusters. X-ray structure of [NEt(4)](3)[Rh(15)(CO)(27)], [NEt(4)](3)[Rh(15)(CO)(25)(MeCN)(2)] x 2MeCN, and [NEt(4)](3)[Rh(17)(CO)(37)]. AB - A reinvestigation of the redox chemistry of [Rh7(CO)16]3- resulted in the finding of new alternative syntheses for a series of previously reported Rh-centered carbonyl clusters, i.e., [H4-nRh14(CO)25]n- (n = 3 and 4) and [Rh17(CO)30]3-, as well as new species such as a different isomer of [Rh15(CO)27]3-, the carbonyl substituted [Rh15(CO)25(MeCN)2]3-, and the conjuncto [Rh17(CO)37]3- clusters. All of the above clusters are suggested to derive from oxidation of [Rh7(CO)16]3- with H+, arising from dissociation either of [M(H2O)n]2+ aquo complexes or nonoxidizing acids. The nature of the previously reported species has been confirmed by IR, electrospray ionization mass spectrometry, and complete X-ray diffraction studies. Only the molecular structures of the new clusters are reported in some details. The ready conversion of [Rh7(CO)16]3- in [HRh14(CO)25]3 upon oxidation has been confirmed by electrochemical techniques. In addition, electrochemical studies point out that the close-packed [H3Rh13(CO)24]2- dianion undergoes a reversible monoelectronic reduction followed by an irreversible reduction. The irreversibility of the second reduction is probably a consequence of H2 elimination from a purported [H3Rh13(CO)24]4- species. Conversely, the body centered-cubic [HRh14(CO)25]3- and [Rh15(CO)27]3- trianions display several well defined redox changes with features of electrochemical reversibility, even at low scan rate. The major conclusion of this work is that mild experimental conditions and a tailored oxidizing reagent may enable more selective conversion of [Rh7(CO)16]3- into a higher-nuclearity rhodium carbonyl cluster. It is also shown that isonuclear Rh clusters may display isomeric metal frameworks [i.e., [Rh15(CO)27]3-], as well as almost identical metal frames stabilized by a different number of carbonyl groups [i.e., [Rh15(CO)27]3- and [Rh15(CO)30]3-]. Other isonuclear Rh clusters stabilized by a different number of CO ligands more expectedly exhibit completely different metal geometries [i.e., [Rh17(CO)30]3- and [Rh17(CO)37]3-]. The first pair of isonuclear and isoskeletal clusters is particularly astonishing in that [Rh15(CO)30]3- features six valence electrons more than [Rh15(CO)27]3-. Finally, the electrochemical studies seem to suggest that interstitial Rh atoms are less effective than Ni and Pt interstitial atoms in promoting redox properties and inducing molecular capacitor behavior in carbonyl clusters. PMID- 17705364 TI - A copper(II) ion-selective on-off-type fluoroionophore based on zinc porphyrin dipyridylamino. AB - A new copper(II) fluorescent sensor 5,10,15,20-tetra((p-N,N-bis(2 pyridyl)amino)phenyl)porphyrin zinc (1) has been designed and synthesized by the Ullmann-type condensation of bromoporphyrin zinc with 2,2'-dipyridylamine (dpa) under copper powder as a catalyst as well as with K2CO3 as the base in a DMF solution. It consists of two separately functional moieties: the zinc porphyrin performs as a fluorophore, and the dpa-linked-to-zinc porphyrin acts as a selected binding site for metal ions. It displays a high selectivity and antidisturbance for the Cu2+ ion among the metal ions examined (Na+, Mg2+, Cr3+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Ag+, Zn2+, Cd2+, Hg2+, and Fe3+) and exhibits fluorescence quenching upon the binding of the Cu2+ ion with an "on-off"-type fluoroionophoric switching property. The detection limit is found to be 3.3 x 10( 7) M (3s blank) for Cu2+ ion in methanol solution, and its fluorescence can be revived by the addition of EDTA disodium solution. The design strategy and remarkable photophysical properties of sensor 1 help to extend the development of fluorescent sensors for metal ions. PMID- 17705366 TI - Synthesis and structure of a molecular barium Aminebis(phenolate) and its application as an initiator for ring-opening polymerization of cyclic esters. AB - The synthesis and structural characterization of an unusual trinuclear barium aminebis(phenolate) complex are reported along with its application as an initiator for the ring-opening polymerization of epsilon-caprolactone and L lactide. PMID- 17705367 TI - New fluorescent chemosensors for heavy metal ions based on functionalized pendant arm derivatives of 7-anthracenylmethyl-1,4,10-trioxa-7,13-diazacyclopentadecane. AB - Two new ligands 7-anthracenylmethyl-13-methylpyridyl-1,4,10-trioxa-7,13 diazacyclopentadecane (L4) and 7-anthracenylmethyl-13-(2,2-dimethyl-2 hydroxyethyl)-1,4,10-trioxa-7,13-diazacyclopentadecane (L(5)) have been synthesized and characterized. Both derive from 7-anthracenylmethyl-1,4,10-trioxa 7,13-diazacyclopentadecane (L(3)) and differ for having a differently functionalized pendant arm covalently attached to the remaining secondary nitrogen donor of the macrocyclic framework. The protonation and coordination behavior of L(4), L(5), and the unbranched L(3) with metal ions have been studied in MeCN/H2O (1:1 v/v, 298.1 K, I = 0.1 M) using potentiometric methods. The crystal structures of L(3), [(H2L(3))(HL(3))](ClO4)3, and the complex [CdL(3)(NO3)2] have been determined by single-crystal X-ray methods. The fluorescent behavior of L(3)-L(5) in the presence of Cu(II), Zn(II), Cd(II), Hg(II), and Pb(II) has been studied as a function of pH in MeCN/H2O (1:1 v/v). The presence of Cu(II), Hg(II), or Pb(II) does not affect the fluorescent behavior observed for the three free ligands upon changing the pH. Interestingly, the fluorescent emission of L(3) and L(5) is selectively enhanced only in the presence of Cd(II) at basic pH. The same effect is observed for L4 in the presence of Cd(II) or Zn(II) at about pH 7. PMID- 17705368 TI - Lanthanide complexes of the chiral hexaaza macrocycle and its meso-type isomer: solvent-controlled helicity inversion. AB - Lanthanide(III) complexes of the enantiopure chiral hexaaza tetraamine macrocycle L, 2(R),7(R),18(R),23(R)-1,8,15,17,24,31-hexaazatricyclo[25.3.1.1.0.0] dotriaconta-10,12,14,26,28,30-hexaene, as well as of its meso-type 2(R),7(R),18(S),23(S)-isomeric macrocycle L1, have been synthesized and characterized by spectroscopic methods. The 2D NMR spectra confirm the identity of these complexes and indicate C2 symmetry of the [LnL]3+ and Cs symmetry of the [LnL1]3+ complexes. The crystal structures of the [PrL(NO3)(H2O)2](NO3)2, [EuL(NO3)(H2O)2](NO3)2, [DyL(NO3)2]2[Dy(NO3)5] x 5CH3CN, [YbL(NO3)2]2[Yb(NO3)5] x 5CH3CN, [YbL(H2O)2](NO3)3 x H2O, and [EuL1(NO3)(H2O)2]0.52[EuL1(NO3)2]0.48(NO3)1.52 x 0.48H2O complexes have been determined by single-crystal X-ray diffraction. In all complexes, the lanthanide(III) ions are coordinated by six nitrogen atoms of the macrocycle L or L1, but for each type of complex, the conformation of the macrocycle and the axial ligation are different. The crystallographic, NMR, and CD data show that the [YbL]3+ complex exists in two stable forms. Both forms of the Yb(III) complex have been isolated, and their interconversion was studied in various solvents. The two forms of [YbL]3+ complex correspond to two diastereomers of ligand L, which differ in the sense of the helical twist and the configuration at the stereogenic amine nitrogen atoms. In one of the stereoisomers, the macrocycle L of (RRRR) configuration at the stereogenic cyclohexane carbon atoms adopts the (RSRS) configuration at the amine nitrogen atoms, while in the other stereoisomer, the macrocycle L of (RRRR) configuration at the stereogenic cyclohexane carbon atoms adopts the (SSSS) configuration at the amine nitrogen atoms. The (RRRR)(RSRS) isomer is quantitatively converting to the (RRRR)(SSSS) isomer in water solution, while the reverse process is observed for an acetonitrile solution, thus representing the rare case of helicity inversion controlled by the solvent. PMID- 17705369 TI - Unusual iron(II) and cobalt(II) complexes derived from monodentate arylamido ligands. AB - The coordination chemistry of the N-substituted arylamido ligands [N(R)(C6H3R'2 2,6)] [R = SiMe3, R' = Me (L1); R = CH2But, R' = Pri (L2)] toward FeII and CoII ions was studied. The monoamido complexes [M(L1)(Cl)(tmeda)] [M = Fe (1), Co (2)] react readily with MeLi, affording the mononuclear, paramagnetic iron(II) and cobalt(II) methyl-arylamido complexes [M(L1)(Me)(tmeda)] [M = Fe (3), Co (4)]. Treatment of 2:1 [Li(L2)(THF)2]/FeCl2 affords the unusual two-coordinate iron(II) bis(arylamide) [Fe(L2)2] (5). PMID- 17705370 TI - Modulating Electronic Coupling Using O- and S-donor Linkers. AB - Structures of compounds having two dimolybdenum units Mo2(DAniF)3+ (DAniF = N,N' di-p-anisylformamidinate) connected by unsubstituted oxamidate (1) and dithiooxamidate (2) linkers are isomorphous, and the cores of the molecules are planar because of two intramolecular hydrogen bonds within the linkers. Molecular mechanics calculations show a barrier of rotation along the C-C bond of approximately 10 kcal x mol(-1), which suggests that planar conformations are also expected in solution. Changing the two oxygen atoms in the linker of 1 to sulfur atoms results in a significant enhancement of the electronic coupling between the dimetal units (Delta(E1/2) = 204 mV for 1 and 407 mV for 2). The electronic spectrum of 2 shows an intense low energy (600 nm) metal-to-ligand charge transfer (MLCT) band, whereas that for 1 shows only a weak absorption band at 460 nm. DFT calculations on models 1' and 2', in which the anisyl groups were replaced by hydrogen atoms, show that the energy of the pi* orbital of the linker is much lower for 2'. This allows dpi-ddelta interactions from the electrons in the delta orbitals of the Mo2 unit to the sulfur atom that in turn facilitates an electron hopping pathway. PMID- 17705371 TI - Carbon-sulfur bond formation via alkene addition to an oxidized ruthenium thiolate. AB - Bulk oxidation of [Ru(DPPBT)3], 1b, (DPPBT = 2-diphenylphosphinobenzenethiolate) in the presence of ethylene yields [(ethane-1,2-diylbis(thio-2,1 phenylene)diphenylphosphine) ruthenium(II)] hexafluorophosphate, [2a]PF6, from the addition of the alkene across cis sulfur sites. During oxidation, the absorption bands of 1b at 540, 797, and 1041 nm decrease in intensity. The resulting complex [2a]+ displays a single redox couple at +804 mV. The +ESI-MS of [2a]+ shows a parent ion peak at m/z = 1009.1013, and the 31P NMR spectrum displays chemical shift values of delta(1) = 61.0, delta(2) = 40.3, and delta(3) = 37.5 with coupling constants of J(12) approximately J(13) approximately 30 Hz and J(23) = 304 Hz. Oxidation of [2a]+ by one electron at a holding potential of +1000 mV yields [(ethane-1,2-diylbis(thio-2,1-phenylene)diphenyl phosphine)ruthenium(III)] hexafluorophosphate, [2b][PF6]2. The EPR of [2b][PF6]2 displays a rhombic signal with g(1) = 2.09, g(2) = 2.04, and g(3) = 2.03. Oxidation of 1b in the presence of alkenes including 1-hexene, styrene, cyclohexene, and norbornene yields products similar to [2a]+. Each of these products was further oxidized to an analogue of [2b]2+. Complex [2a]+ was also prepared, as the bromide salt, from [PPN][Ru(DPPBT)3] (PPN [1a]; PPN = bis(triphenylphosphoranylidene)ammonium) and 1,2-dibromoethane. The complex [2a]Br crystallizes as thin yellow plates in the monoclinic space group P21/c with unit cell dimensions of a = 10.2565(9) A, b = 13.2338(12) A, c = 38.325(3) A, and beta = 93.3960(10) degrees. PMID- 17705372 TI - Preparation of stable and metastable coordination compounds: insight into the structural, thermodynamic, and kinetic aspects of the formation of coordination polymers. AB - The reaction of ZnI2 and pyrimidine in acetonitrile results in the formation of the 1:2 compound ZnI2(pyrimidine)2 (1), which consists of discrete tetrahedral building blocks. Slow heating of 1 at 1 degrees C/min leads to its transformation into the ligand-deficient intermediate 1:1 compound ZnI2(pyrimidine) (3), which upon further heating decomposes into the most ligand-deficient 2:1 compound (ZnI2)2(pyrimidine) (4). In contrast, the 2:3 compound (ZnI2)2(pyrimidine)3 (2) is formed as an intermediate by decomposing 1 using a faster heating rate of 8 degrees C/min. Compound 2 consists of oligomeric units in which each ZnI2 unit is coordinated by two iodine atoms and one bridging and one terminal pyrimidine ligand. The crystal structure of compound 3 is built up of ZnI2 units, which are connected by the ligands into chains. For the thermal transformation of 1 into 3 via 2 as the intermediate, a smooth reaction pathway is found in the crystal structure, for which only small translational and rotational changes are needed. The metastable solvated compound (ZnI2)(pyrimidine)(acetonitrile)0.25 (5) consisting of (ZnI2)4(pyrimidine)4 rings is obtained by quenching the reaction of ZnI2 and pyrimidine in acetonitrile using an antisolvent. On heating, 5 decomposes into a new polymorphic 1:1 compound 6, which consists of (ZnI2)(pyrimidine) chains. On further heating, 6 transforms into a third polymorphic 1:1 compound 7, which consists of (ZnI2)3(pyrimidine)3 rings, and finally into the 1:1 compound 3. Solvent-mediated conversion experiments reveal that compounds 1-4 are thermodynamically stable, whereas compounds 5-7 are metastable. Time-dependent crystallization experiments unambiguously show that compound 7 is formed by kinetic control and transforms within minutes into compound 6, which finally transforms into 3. Compound 3 represents the thermodynamically most stable 1:1 modification, whereas compounds 6 and 7 are metastable. The different compounds obtained by thermal decomposition and by crystallization from solution represent a snapshot of the species in solution and thus provide insight into the formation of coordination compounds. PMID- 17705373 TI - Cyclic Se6 and helical infinity1[Sex] as neutral ligands in the new compounds PdBr2Se6 and PdCl2Se8. AB - PdBr2Se6 and PdCl2Se8 are two new compounds with cyclic Se6 coordinated to PdBr2 molecules and one-dimensional helical Sex chains coordinated to PdCl2 molecules. PdBr2Se6 is a black solid with a crystal structure similar, but not equal, to PdCl2Se6. It crystallizes in the space group P1 with the lattice constants a = 4.3946(8) A, b = 7.605(1) A, c = 7.992(2) A, alpha = 66.15(2) degrees , beta = 86.44(2) degrees , gamma = 80.90(2) degrees , and Z = 1 and can be handled in air like the deep red PdCl2Se8 which crystallizes in the orthorhombic space group Pbca with the lattice constants a = 9.609(2) A, b = 8.958(2) A, c = 13.799(3) A, and Z = 4. In PdBr2Se6, two cyclic Se6 molecules (chair conformation) are directly coordinated to Pd atoms, forming Pd(Se6)2Br2 groups. These are connected to one-dimensional chains via trans-standing Se atoms. In PdCl2Se8, the selenium substructure consists of helical chains with every fifth Se atom directly coordinated to the Pd atom of a PdCl2 group. Each PdCl2 group on the other hand connects two neighboring Sex helices. The type of Sex helix found for this compound is unique and differs from all other ones reported up to now including elemental alpha-Se. A reproducible twinning observed for PdBr2Se6 crystals in the course of the X-ray single-crystal investigations is checked by transmission electron microscopy in connection with details of the atomic arrangement. The Raman spectra of PdBr2Se6 and PdCl2Se8 are compared to Raman data of elemental Se modifications and give significant support for the Se6 and helical Sex to be neutral molecules. A discussion of the results of thermal analyses gives clear evidence that cyclic Se6 and helical Sex are considerably stabilized by bonding to the PdX2 molecules because the melting temperatures of the composite materials are significantly higher than the ones of the respective elemental modifications. PMID- 17705375 TI - Coordination complexes of the dimethyl-thio-phosphonium cation and ligand exchange. AB - The quantitative exchange of a 4-(dimethylamino)pyridine ligand on the dimethyl thio-phosphonium cation by Me3P demonstrates the coordinative nature of the N-P and P-P bond and diversifies a fundamentally important new direction in the coordination chemistry of phosphorus as an acceptor. PMID- 17705374 TI - Nickel-based oxyphosphide superconductor with a layered crystal structure, LaNiOP. AB - A layered oxyphosphide, LaNiOP, was synthesized by solid-state reactions. This crystal was confirmed to have a layered structure composed of an alternating stack of (La(3+)O(2-))(+) and (Ni(2+)P(3-))(-). We found that the resulting LaNiOP shows a superconducting transition at approximately 3 K. This material exhibited metallic conduction and Pauli paramagnetism in the temperature range of 4-300 K. The resistivity sharply dropped to zero and the magnetic susceptibility became negative at <4 K, indicating that a superconducting transition occurs. The volume fraction of the superconducting phase estimated from the diamagnetic susceptibility reached approximately 40 vol % at 1.8 K, substantiating that LaNiOP is a bulk superconductor. PMID- 17705376 TI - Vibrational recognition of adsorption sites for CO on platinum and platinum ruthenium surfaces. AB - We have studied the vibrational properties of CO adsorbed on platinum and platinum-ruthenium surfaces using density-functional perturbation theory within the Perdew-Burke-Ernzerhof generalized-gradient approximation. The calculated C-O stretching frequencies are found to be in excellent agreement with spectroscopic measurements. The frequency shifts that take place when the surface is covered with ruthenium monolayers are also correctly predicted. This agreement for both shifts and absolute vibrational frequencies is made more remarkable by the frequent failure of local and semilocal exchange-correlation functionals in predicting the stability of the different adsorption sites for CO on transition metal surfaces. We have investigated the chemical origin of the C-O frequency shifts introducing an orbital-resolved analysis of the force and frequency density of states, and assessed the effect of donation and backdonation on the CO vibrational frequency using a GGA+molecular U approach. These findings rationalize and establish the accuracy of density-functional calculations in predicting absolute vibrational frequencies, notwithstanding the failure in determining relative adsorption energies, in the strong chemisorption regime. PMID- 17705377 TI - Transparent CoAl2O4 hybrid nano pigment by organic ligand-assisted supercritical water. AB - Transparent types of inorganic pigments are important as they can be used in a variety of applications, such as metallic finishing, contrast enhancing luminescent pigments, high-end optical filters, and so on. Currently, the difficulty in producing monodisperse and stable binary metal oxide nano pigments at low temperature hampers the applicability and realization of transparent blue nano pigments. Here, for the first time, we report organic ligand capped CoAl2O4 hybrid transparent nano pigment, which has a particle size less than 8 nm with well-stabilized single nanocrystals, using organic ligand-assisted supercritical water as the reaction medium. The organic ligand capping could effectively inhibit the particle growth and also control the size of nanocrystals. This helps to diminish the scattering effect of the nano blue pigment, realizing a transparent cobalt blue nano pigment without any postheat treatment. PMID- 17705378 TI - Synthesis and structure of pentaorganostannate having five carbon substituents. PMID- 17705379 TI - Direct observation of electrocatalytic synergy. PMID- 17705380 TI - Ion motion in conjugated polyelectrolyte electron transporting layers. PMID- 17705381 TI - Bronsted/Lewis acid synergy in dealuminated HY zeolite: a combined solid-state NMR and theoretical calculation study. AB - The Bronsted/Lewis acid synergy in dealuminated HY zeolite has been studied using solid-state NMR and density function theory (DFT) calculation. The 1H double quantum magic-angle spinning (DQ-MAS) NMR results have revealed, for the first time, the detailed spatial proximities of Lewis and Bronsted acid sites. The results from 13C NMR of adsorbed acetone as well as DFT calculation demonstrated that the Bronsted/Lewis acid synergy considerably enhanced the Bronsted acid strength of dealuminated HY zeolite. Two types of Bronsted acid sites (with enhanced acidity) in close proximity to extra-framework aluminum (EFAL) species were identified in the dealuminated HY zeolite. The NMR and DFT calculation results further revealed the detailed structures of EFAL species and the mechanism of Bronsted/Lewis acid synergy. Extra-framework Al(OH)3 and Al(OH)2+ species in the supercage cage and Al(OH)2+ species in the sodalite cage are the preferred Lewis acid sites. Moreover, it is the coordination of the EFAL species to the oxygen atom nearest the framework aluminum that leads to the enhanced acidity of dealuminated HY zeolite though there is no direct interaction (such as the hydrogen-bonding) between the EFAL species and the Bronsted acid sites. All these findings are expected to be important in understanding the roles of Lewis acid and its synergy with the Bronsted acid in numerous zeolite-mediated hydrocarbon reactions. PMID- 17705382 TI - Nitrosonium complexes of resorc[4]arenes: spectral, kinetic, and theoretical studies. AB - Resorc[4]arene octamethyl ethers 1-3, when treated with NOBF4 salt in chloroform, form very stable 1:1 nitrosonium (NO+) complexes, which are deeply colored. The complexation process is reversible, and the complexes dissociate and bleach upon addition of methanol or water, to give the starting macrocycles. Resorc[4]arenes 1 and 2 are in the same cone conformation, but with different side-chains, whereas 3 possesses a different conformation (chair), while bearing the same side chain as 2. Kinetic and spectral UV-visible analysis revealed that NO+ interacts with resorc[4]arenes 1 and 2 both outside and inside their basket, leading to complexes with two absorption patterns growing at different rates, one featuring high-energy bands (HEB) within the near-UV zone, and the other one low-energy bands (LEB), attributed to charge-transfer interactions, within the visible range. The presence of ester carbonyl groups in 2 strongly drives the NO+ cation outside the resorcarene. Resorc[4]arene 3 showed a spectral pattern pointing out a clear involvement of the ester moieties in the NO+ entrapping, beside the formation of significant charge-transfer interactions. 1H NMR spectroscopy and molecular modeling clearly supported these findings. PMID- 17705383 TI - Human telomeric DNA forms parallel-stranded intramolecular G-quadruplex in K+ solution under molecular crowding condition. AB - The G-rich strand of human telomeric DNA can fold into a four-stranded structure called G-quadruplex and inhibit telomerase activity that is expressed in 85-90% tumor cells. For this reason, telomere quadruplex is emerging as a potential therapeutic target for cancer. Information on the structure of the quadruplex in the physiological environment is important for structure-based drug design targeting the quadruplex. Recent studies have raised significant controversy regarding the exact structure of the quadruplex formed by human telomeric DNA in a physiological relevant environment. Studies on the crystal prepared in K+ solution revealed a distinct propeller-shaped parallel-stranded conformation. However, many later works failed to confirm such structure in physiological K+ solution but rather led to the identification of a different hybrid-type mixed parallel/antiparallel quadruplex. Here we demonstrate that human telomere DNA adopts a parallel-stranded conformation in physiological K+ solution under molecular crowding conditions created by PEG. At the concentration of 40% (w/v), PEG induced complete structural conversion to a parallel-stranded G-quadruplex. We also show that the quadruplex formed under such a condition has unusual stability and significant negative impact on telomerase processivity. Since the environment inside cells is molecularly crowded, our results obtained under the cell mimicking condition suggest that the parallel-stranded quadruplex may be the more favored structure under physiological conditions, and drug design targeting the human telomeric quadruplex should take this into consideration. PMID- 17705384 TI - Using measurements of anchoring energies of liquid crystals on surfaces to quantify proteins captured by immobilized ligands. AB - We describe a simple optical method that employs measurement of the interaction energy of a liquid crystal (LC) with a surface (the so-called anchoring energy) to report proteins captured on surfaces through specific interactions with immobilized binding groups. To define the sensitivity and dynamic range of the response of the LC, we covalently immobilized a tyrosine-containing, 13-residue peptide sequence (Y1173) from the epidermal growth factor receptor/kinase (EGFR) at which autophosphorylation takes place and to which the adapter protein Shc binds. We determined that, on peptide-decorated (Y1173 or pY1173, where pY1173 is the corresponding phosphopeptide) surfaces incubated against anti-phosphotyrosine antibody, the anchoring energy of the LC decreased systematically from 4.4 to 1.4 microJ/m2 (with SEM=0.3 microJ/m2 for n=5) as the antibody concentration increased from 10 pM to 100 nM. Over the same range of antibody concentrations in solution and densities of immobilized peptides, independent ellipsometric measurements were not sufficiently sensitive to report the captured antibody (ellipsometric thicknesses were <0.1 nm). These results, when combined with control experiments reported in this article, provide the first demonstration of the use of anchoring energy measurements of LCs to report proteins captured by immobilized ligands on surfaces. The sensitivity and dynamic range of the methodology suggest that it may offer the basis of a simple yet broadly useful principle for reporting the interactions between proteins and other biomolecules that underlie complex and poorly understood chemical and biological events. PMID- 17705385 TI - Trace level cyclic voltammetry facilitated by single-walled carbon nanotube network electrodes. PMID- 17705386 TI - Guest-specific function of a flexible undulating channel in a 7,7,8,8-tetracyano p-quinodimethane dimer-based porous coordination polymer. PMID- 17705387 TI - Dynamic extension-contraction motion in supramolecular springs. PMID- 17705389 TI - Interflap distances in HIV-1 protease determined by pulsed EPR measurements. PMID- 17705390 TI - Expanding the structural diversity of self-assembling dendrons and supramolecular dendrimers via complex building blocks. AB - The design and synthesis of the first examples of AB4 and AB5 dendritic building blocks with complex architecture are reported. Structural and retrostructural analysis of supramolecular dendrimers self-assembled from hybrid dendrons based on different combinations of AB4 and AB5 building blocks with AB2 and AB3 benzyl ether dendrons demonstrated that none of these new hybrid dendrons exhibit the previously encountered conformations of libraries of benzyl ether dendrons. These hybrid dendrons enabled the discovery of some highly unusual tapered and conical dendrons generated by the intramolecular back-folding of their repeat units and of their apex. The new back-folded tapered dendrons have double thickness and self-assemble into pine-tree-like columns exhibiting a long-range 7/2 helical order. The back-folded conical dendrons self-assemble into spherical dendrimers. Non-back-folded truncated conical dendrons were also discovered. They self assemble into spherical dendrimers with a less densely packed center. The discovery of dendrons displaying a novel crown-like conformation is also reported. Crown-like dendrons self-assemble into long-range 5/1 helical pyramidal columns. The long-range 7/2 and 5/1 helical structures were established by applying, for the first time, the helical diffraction theory to the analysis of X ray patterns obtained from oriented fibers of supramolecular dendrimers. PMID- 17705392 TI - Nonenzymatic oxidative steps accompanying action of the cytochrome P450 enzymes StaP and RebP in the biosynthesis of staurosporine and rebeccamycin. PMID- 17705394 TI - Ruthenium-catalyzed cross-metathesis between diallylsilanes and electron deficient olefins. AB - Diallysilanes can be selectively coupled with electron-deficient olefins under cross-metathesis (CM) conditions using the Hoveyda-Grubbs catalyst to produce mono- and/or bis-CM compounds in good yield. The formation of the mono- and the bis-CM compounds depends on the nature of the electron-deficient olefin. PMID- 17705391 TI - Oligomeric electrolyte as a multifunctional gelator. PMID- 17705395 TI - A concise synthesis of the Pennsylvania Green fluorophore and labeling of intracellular targets with O6-benzylguanine derivatives. AB - We report improved syntheses of the Pennsylvania Green and 4-carboxy-Pennsylvania Green fluorophores; the latter compound was prepared from methyl 4-iodo-3 methylbenzoate in a three-pot process (32% overall yield). Chinese hamster ovary cells expressing O6-alkylguanine-DNA alkyltransferase fusion proteins were treated with Pennsylvania Green and Oregon Green linked to O6-benzylguanine (SNAP Tag substrates). Analysis of living cells by confocal microscopy revealed that Pennsylvania Green derivatives exhibit substantially higher cell permeability than analogous Oregon Green-derived molecular probes. PMID- 17705396 TI - Lewis base activation of Lewis acids: development of a Lewis base catalyzed selenolactonization. AB - The concept of Lewis base activation of Lewis acids has been applied to the selenolactonization reaction. Through the use of substoichiometric amounts of Lewis bases with "soft" donor atoms (S, Se, P) significant rate enhancements over the background reaction are seen. Preliminary mechanistic investigations have revealed the resting state of the catalyst as well as the significance of a weak Bronsted acid promoter. PMID- 17705397 TI - A water-soluble "switching on" fluorescent chemosensor of selectivity to Cd2+. AB - Compound 1, a new fluorescent chemosensor signaling via significantly enhanced fluorescence when bound with cation analytes, was synthesized and characterized. This fluorescent chemosensor exhibits its selectivity to Cd2+ among a series of cations in HEPES buffer solution. Its in vitro sensitivity to Cd2+ was demonstrated in the HK-2 cell line with use of confocal microscopy. The mechanistic selectivity and sensitivity of compound 1 to Cd2+ was discussed on the basis of fluorescence, 1H NMR, and mass spectroscopic results. PMID- 17705398 TI - Intermolecular radical carboaminohydroxylation of olefins with aryl diazonium salts and TEMPO. AB - Highly reactive aryl radicals can selectively be reacted with a broad variety of activated and nonactivated olefinic substrates in the presence of nitroxyl radicals. Direct recombination of the aryl radical and the nitroxide as well as telomerization of the olefin is successfully suppressed by the reaction conditions. PMID- 17705399 TI - Simultaneous LC/MS/MS determination of thiols and disulfides in urine samples based on differential labeling with ferrocene-based maleimides. AB - A method for the simultaneous determination of a series of thiols and disulfides in urine samples has been developed based on the sequential labeling of free and bound thiol functionalities with two ferrocene-based maleimide reagents. The sample is first exposed to N-(2-ferroceneethyl)maleimide, thus leading to the derivatization of free thiol groups in the sample. After quantitative reaction and subsequent reduction of the disulfide-bound thiols by tris(2 carboxyethyl)phosphine, the newly formed thiol functionalities are reacted with ferrocenecarboxylic acid-(2-maleimidoyl)ethylamide. The reaction products are determined by LC/MS/MS in the multiple reaction mode, and precursor ion scan as well as neutral loss scan is applied to detect unknown further thiols. The method was successfully applied to the analysis of free and disulfide-bound thiols in urine samples. Limits of detection are 30 to 110 nM, and the linear range comprises two decades of concentration, thus covering the relevant concentration range of thiols in urine samples. The thiol and disulfide concentrations were referred to the creatinine content to compensate for different sample volumes. As some calibration standards for the disulfides are not commercially available, they were synthesized in an electrochemical flow-through cell. This allowed the synthesis of hetero- and homodimeric disulfides. PMID- 17705400 TI - Direct visualization of the binding of c-Myc/Max heterodimeric b-HLH-LZ to E-box sequences on the hTERT promoter. AB - Myc and Max belong to the b-HLH-LZ family of transcription factors. Heterodimerization between Myc and Max or homodimerization of Max allows these proteins to bind their cognate DNA sequence known as the E-box (CACGTG). Recent evidence has suggested that the c-Myc/Max heterodimeric b-HLH-LZ could interact to form a head-to-tail dimer of dimers and induce complex topologies such as loops in promoters containing more than one E-box sequence. In an attempt to shed light on this hypothesis, the interaction between the heterodimeric b-HLH-LZ of c Myc/Max and a fragment of the hTERT promoter containing two E-box sequences was studied by atomic force microscopy. Specific binding events were observed at both E-box sites with equal probabilities. In accordance with previous results obtained by EMSA, we observed that the specific binding of the c-Myc/Max b-HLH-LZ bends the promoter. However no looping could be observed in a wide range of concentration encompassing the Ka (association constant) of the putative tetramer and the Ka for the specific binding of the heterodimer. In contrast, experiments performed with a mandatory c-Myc/Max b-HLH-LZ tetramer incubated with the hTERT promoter fragment allowed for the visualization of loops and cross-linked DNA strands originating from specific binding. Altogether, our results indicate that the c-Myc/Max b-HLH-LZ dimer binds specifically and equally to both E-box sites of the hTERT promoter and induces a significant bending of the promoter and that the suggested oligomerization of the c-Myc/Max heterodimeric b-HLH-LZ, if existing, is most likely too weak to induce the formation of a loop in a promoter. PMID- 17705401 TI - Unphosphorylated rhabdoviridae phosphoproteins form elongated dimers in solution. AB - The phosphoprotein (P) is an essential component of the replication machinery of rabies virus (RV) and vesicular stomatitis virus (VSV), and the oligomerization of P, potentially controlled by phosphorylation, is required for its function. Up to now the stoichiometry of phosphoprotein oligomers has been controversial. Size exclusion chromatography combined with detection by multiangle laser light scattering shows that the recombinant unphosphorylated phosphoproteins from VSV and from RV exist as dimers in solution. Hydrodynamic analysis indicates that the dimers are highly asymmetric, with a Stokes radius of 4.8-5.3 nm and a frictional ratio larger than 1.7. Small-angle neutron scattering experiments confirm the dimeric state and the asymmetry of the structure and yield a radius of gyration of about 5.3 nm and a cross-sectional radius of gyration of about 1.6-1.8 nm. Similar hydrodynamic properties and molecular dimensions were obtained with a variant of VSV phosphoprotein in which Ser60 and Thr62 are substituted by Asp residues and which has been reported previously to mimic phosphorylation by inducing oligomerization and activating transcription. Here, we show that this mutant also forms a dimer with hydrodynamic properties and molecular dimensions similar to those of the wild type protein. However, incubation at 30 degrees C for several hours induced self-assembly of both wild type and mutant proteins, leading to the formation of irregular filamentous structures. PMID- 17705402 TI - Unusual regioselectivity and active site topology of human cytochrome P450 2J2. AB - The oxidation of six derivatives of terfenadone by recombinant human CYP2J2 (CYP = cytochrome P450) was studied by high-performance liquid chromatography coupled to mass spectrometry (MS) using tandem MS techniques and by 1H NMR spectroscopy. CYP2J2 exhibited a surprising regioselectivity in favor of the hydroxylation of the substrate terminal chain at the weakly reactive homobenzylic position. In contrast, hydroxylation of the same substrates by CYP3A4 mainly occurred on the most chemically reactive sites of the substrates (N-oxidation and benzylic hydroxylation). A 3D homology model of CYP2J2 was constructed using recently published structures of CYP2A6, CYP2B4, CYP2C8, CYP2C9, and CYP2D6 as templates. In contrast with other CYP2 structures, it revealed an active site cavity with a severely restricted access of substrates to the heme through a narrow hydrophobic channel. Dynamic docking of terfenadone derivatives in the CYP2J2 active site allowed one to interpret the unexpected regioselectivity of the hydroxylation of these substrates by CYP2J2, which is mainly based on this restricted access to the iron. The structural features that have been found to be important for recognition of substrates or inhibitors by CYP2J2 were also interpreted on the basis of CYP2J2-substrate interactions in this model. PMID- 17705403 TI - Curcumin is a modulator of bilayer material properties. AB - Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is the major bioactive compound in turmeric (Curcuma longa) with antioxidant, antiinflammatory, anticarcinogenic, and antimutagenic effects. At low muM concentrations, curcumin modulates many structurally and functionally unrelated proteins, including membrane proteins. Because the cell membranes' lipid bilayer serves as a gate-keeper and regulator of many cell functions, we explored whether curcumin modifies general bilayer properties using channels formed by gramicidin A (gA). gA channels form when two monomers from opposing monolayers associate to form a conducting dimer with a hydrophobic length that is less than the bilayer hydrophobic thickness; gA channel formation thus causes a local bilayer thinning. The energetic cost of this bilayer deformation alters the gA monomer <--> dimer equilibrium, which makes the channels' appearance rate and lifetime sensitive to changes in bilayer material properties, and the gA channels become probes for changes in bilayer properties. Curcumin decreases bilayer stiffness, increasing both gA channel lifetimes and appearance rates, meaning that the energetic cost of the gA-induced bilayer deformation is reduced. These results show that curcumin may exert some of its effects on a diverse range of membrane proteins through a bilayer-mediated mechanism. PMID- 17705404 TI - Heterogeneous environment of the S-H group of Cys966 near the flavin chromophore in the LOV2 domain of Adiantum neochrome1. AB - The primary photochemistry of the blue-light sensor protein, phototropin, is adduct formation between the C4a atom of the flavin mononucleotide (FMN) chromophore and a nearby, reactive cysteine (Cys966), following decay of the triplet excited state of FMN. The distance between the C4a position of FMN and the sulfur atom of Cys966 is 4.2 A in the LOV2 domain of Adiantum neochrome 1 (neo1-LOV2), a fusion protein of phototropin containing the phytochrome chromophoric domain. We previously reported the presence of an unreactive fraction in neo1-LOV2 at low temperatures, which presumably originated from the heterogeneous environment of Cys966 [Iwata, T., Nozaki, D., Tokutomi, S., Kagawa, T., Wada, M., and Kandori, H. (2003) Biochemistry 42, 8183-8191]. The present study showed that (i) 28% forms an adduct at 77 K (state I), (ii) 50% forms an adduct at 150 K but not at 77 K (state II), and (iii) 22% does not form an adduct at 150 K (state III). By Fourier transform infrared (FTIR) spectroscopy, we observed the S-H stretching frequencies at 2570 and 2562 cm-1 for state I and at 2563 cm-1 for state II, suggesting that the microenvironment of the S-H group of Cys966 determines the reactivity at low temperatures. Adduct formation is more efficient for state I than for states II and III. Molecular dynamics simulation strongly suggests that the observed multiple structures originate from the isomeric forms of Cys966. We thus concluded that there are multiple local structures of FMN and cysteine in neo1-LOV2, each of which is thermally converted by protein fluctuation at physiological temperatures. PMID- 17705405 TI - Growth and surface properties of boehmite nanofibers and nanotubes at low temperatures using a hydrothermal synthesis route. AB - The growth of boehmite nanostructures at low temperature using a soft chemistry route with and without (PEO) surfactant is presented. Remarkably long boehmite 1D nanotubes/nanofibers were formed within a significantly short time by changing the reaction mechanism of aluminum hydroxide. By using the PEO surfactant as a templating agent, boehmite nanotubes up to 170 nm in length with internal and external diameters of 2-5 and 3-7 nm, respectively, were formed at 100 degrees C. A slightly higher temperature (120 degrees C) resulted in the formation of lath like nanofibers with an average length of 250 nm. Using the cationic surfactant CTAB, nanotubes rather than nanofibers were formed at 120 degrees C. Without surfactant, nanotubes counted for around 20% of the entire sample. A regular interval supply of fresh boehmite precipitate resulted in a larger crystallite size distribution of nanotubes. The morphology of nanotubes was more uniform in samples without the regular addition of aluminum hydroxide. Moreover, for the same hydrothermal time, the final nanotubes for nanomaterials without a regular interval supply of fresh aluminum hydroxide precipitate were longer than those with a regular aluminum hydroxide precipitate supply, which is in contrast to previously published results. Higher Al/PEO concentrations resulted in the formation of shorter nanotubes. A detailed characterization and mechanism are presented. PMID- 17705407 TI - Universal and scaling behavior at the proximity of the solid to the deformable air-water interface. AB - The scaling descriptions of the deformation of the air-water interface due to van der Waals attractive forces induced by a paraboloid shaped solid as well as of the force vs distance behavior are systematically discussed theoretically and experimentally. It is demonstrated that the force-distance curves at the proximity of the solid to the air-water interface without contact satisfy a simple and universal scaling law, which can be useful to help study various systems involved in the deformable interface. Moreover, an analytical solution to the E-L differential equation governing the deformation of the water surface profile is obtained from the scaling relation, and the two length scales that quantitatively evaluate the lateral and longitudinal deformation of the air-water interface respectively are hence determined. PMID- 17705406 TI - Surface modification of nanoclays by catalytically active transition metal ions. AB - A unique class of nanoclays was prepared by modification of pristine clays or organoclays (Cloisite C20A) with transition metal ions (TMIs). The composition, structure, morphology and thermal properties of TMI-modified nanoclays were investigated by atomic absorption spectroscopy (AAS), elemental analysis (EA), scanning electron microscopy (SEM), small-angle X-ray scattering (SAXS), wide angle X-ray diffraction (WAXD), thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray absorption near-edge structure (XANES) spectroscopy. The content of TMIs in modified clays was found to be close to the limiting value of ion exchange capacity. SEM and X-ray results confirmed that TMIs were located between the mineral layers instead of being adsorbed on the surface of clay particles. TGA results indicated that the TMI treatment of organoclays could significantly increase the thermal stability, which was more pronounced in air than in nitrogen. Temperature-resolved SAXS measurements revealed that the presence of TMIs increased the onset temperature of structural degradation. The higher thermal stability of TMI-modified organoclays can be attributed to the change in the thermal degradation mechanism, resulting in a decrease in the yield of volatile products and the formation of char facilitated by the presence of catalytically active TMIs. PMID- 17705408 TI - Methods for generation of spatial gradients in concentration of monomeric surfactants and micelles in microfluidic systems. AB - We report methods suitable for use in microfluidic systems that permit the generation and manipulation of spatial gradients in concentrations of monomeric surfactants and micelles within aqueous solutions. The methods involve the use of the redox-active surfactant, (11-ferrocenylundecyl)trimethyl-ammonium bromide (FTMA) and build from past studies that have established that FTMA exhibits a critical micelle concentration of 0.1 mM (in 0.1 M Li2SO4), whereas oxidized FTMA remains dispersed in a monomeric state up to concentrations of at least 30 mM. Following the application of potentials of 0 V (vs Ag|AgCl; cathode) and +0.3 V (vs Ag|AgCl; anode) to electrodes separated by distances of 25-116 microm, we measured steady state currents of equal magnitude to be passed at each electrode within 1-20 s of the onset of the application of the potentials. We used dynamic light scattering and surface tension measurements to determine that oxidized and reduced FTMA do not measurably interact in solution and thus interpret the steady state currents, measured as a function of the concentration of FTMA added to the system and distance between the electrodes, within the framework of a simple model that assumes fast electrode kinetics, local micelle-monomer equilibrium within the bulk solution, and transport by diffusion only (no migration). Comparison of experimental measurements and model predictions reveals good overall agreement, consistent with the presence of one-dimensional gradients in concentrations of monomeric FTMA and micelles of FTMA in solution between the electrodes. The nature of the gradients can be manipulated by the potentials applied to the electrodes and can be used to achieve spatially localized populations of micelles in the system. PMID- 17705409 TI - Synthesis of positively charged silver nanoparticles via photoreduction of AgNO3 in branched polyethyleneimine/HEPES solutions. AB - Branched polyethyleneimine (BPEI) and 4-(2-hydroxyethyl)-1 piperazineethanesulfonic acid (HEPES) were used collaboratively to reduce silver nitrate under UV irradiation for the synthesis of positively charged silver nanoparticles. The effects of molar ratio of the ingredients and the molecular weight of BPEI on the particle size and distribution were investigated. The mechanism for the reduction of Ag+ ions in the BPEI/HEPES mixtures entails oxidative cleavage of BPEI chains that results in the formation of positively charged BPEI fragments enriched with amide groups as well as in the production of formaldehyde, which serves as a reducing agent for Ag+ ions. The resultant silver nanoparticles are positively charged due to protonation of surface amino groups. Importantly, these positively charged Ag nanoparticles demonstrate superior SERS activity over negatively charged citrate reduced Ag nanoparticles for the detection of thiocyanate and perchlorate ions; therefore, they are promising candidates for sensing and detection of a variety of negatively charged analytes in aqueous solutions using surface-enhanced Raman spectroscopy (SERS). PMID- 17705410 TI - Tuning the electron affinity and secondary electron emission of diamond (100) surfaces by Diels-Alder reaction. AB - The tuning of electron affinity and secondary electron emission on diamond (100) surfaces due to cycloaddition with 1,3-butadiene is investigated by photoemission experiments and density functional theory (DFT) calculations. A significant reduction in electron affinity up to 0.7 eV and enhancement of secondary electron emission were observed after 1,3-butadiene adsorption. The lowering of vacuum level via 1,3-butadiene adsorption is supported by DFT calculations. The C-H bonds in the covalently bonded organics on diamond contribute to the enhanced secondary electron emission and reduced electron affinity in a mechanism similar to that of C-H bonds on hydrogenated diamond surfaces. This combination of strong secondary emission and low electron affinity by the organic functionalization of diamond has potential applications in diamond-based molecular electronic devices. PMID- 17705411 TI - AFM imaging of immobilized fibronectin: does the surface conjugation scheme affect the protein orientation/conformation? AB - Covalent grafting of biomolecules could potentially improve the biocompatibility of materials. However, these molecules have to be grafted in an active conformation to play their biological roles. The present work aims at verifying if the surface conjugation scheme of fibronectin (FN) affects the protein orientation/conformation and activity. FN was grafted onto plasma-treated fused silica using two different crosslinkers, glutaric anhydride (GA) or sulfosuccinimidyl 4-(p-maleimidophenyl)butyrate (SMPB). Fused silica was chosen as a model surface material because it presents a roughness well below the dimensions of FN, therefore allowing AFM analyses with appropriate depth resolution. Cell adhesion assays were performed to evaluate the bioactivity of grafted FN. Cell adhesion was found to be higher on GA-FN than on SMPB-FN. Since FN-radiolabeling assays allowed us to rule out a surface concentration effect (approximately 80 ng/cm2 of FN on both crosslinkers), it was hypothesized that FN adopted a more active conformation when grafted via GA. In this context, the FN conformation on both crosslinkers was investigated through AFM and contact angle analyses. Before FN grafting, GA- and SMPB-modified surfaces had a similar water contact angle, topography, and roughness. However, water contact angles of GA-FN and SMPB-FN surfaces clearly show differences in surface hydrophilicity, therefore indicating a dependence of protein organization toward the conjugation strategy. Furthermore, AFM results demonstrated that surface topography and roughness of both FN-conjugated surfaces were significantly different. Distribution analysis of FN height and diameter confirmed this observation as the protein dimensions were significantly larger on GA than SMPB. This study confirmed that the covalent immobilization scheme of biomolecules influences their conformation and, hence, their activity. Consequently, selecting the appropriate conjugation strategy is of paramount importance in retaining molecule bioactivity. PMID- 17705412 TI - Creation of mammalian single- and double-stranded DNA surfaces: a real-time QCM-D study. AB - The quartz crystal microbalance with dissipation monitoring (QCM-D) is an excellent method for studying the creation of DNA-based surfaces and films. Previous studies have used QCM-D to focus on the construction of DNA surfaces composed of short synthetic DNA oligomers or plasmid DNA. Here, we have used QCM D to monitor the creation of genomic single- and double-stranded calf thymus DNA surfaces on a polycation adsorbed to a SiO2 support. We have successfully monitored the hybridization between the ssDNA surfaces and their complementary strands in solution and have also shown that DNA multilayer formation can be observed using denatured calf thymus DNA. We have furthermore established that the ssDNA and dsDNA surfaces show different binding characteristics to ethidium bromide, a common dsDNA intercalator, demonstrating the potential use of such surfaces to identify possible DNA ligands. PMID- 17705414 TI - Biotinylated anisomycin: a comparison of classical and "click" chemistry approaches. AB - Two approaches to the synthesis of biotinylated derivatives of the stress activated protein kinase (SAPK) pathway activator anisomycin have been investigated. Attachment of the biotin moiety to the central core was achieved either through the use of a classical displacement reaction on alpha-halo carbonyl derivatives of biotin or through a copper(I)-catalyzed 1,3-dipolar Huisgen cycloaddition ("click") coupling of biotinylated azides to propargyl marked analogues of anisomycin. In each case, the resultant N-linked molecular probes were found to be active in SAPK pathway immunoblot assays, while their O linked counterparts were inactive. However, in sharp contrast to the classical coupling approach which results in low coupling yields, the aqueous "click" coupling process was found to deliver high yields of biotinylated probes, making it the conjugation method of choice. A survey of the available methods for the addition of a propargyl marker onto a range of chemical functionalities strongly suggests that this copper(I)-catalyzed 1,3-dipolar Huisgen cycloaddition approach to biotinylation may be generally applied. PMID- 17705413 TI - Reaction of the indole group with malondialdehyde: application for the derivatization of tryptophan residues in peptides. AB - A method for the selective modification of tryptophan residues based on the reaction of malondialdehyde with the indole nitrogen of the tryptophan side chain at acidic conditions is presented. The condensation reaction is quantitative and leads to a substituted acrolein moiety with a remaining reactive aldehyde group. As is shown, this group can be further converted to a hydrazone using hydrazide compounds, but if hydrazine or phenylhydrazine are used, release of the free indole group is observed upon cleavage of the substitution. Alternatively, secondary amines such as pyrrolidine may also act as cleavage reagents. This general reaction scheme has been adapted and optimized for the derivatization of tryptophan-containing peptides and small N-heterocyclic compounds. It serves as the basis of a reversible tagging scheme for Trp-peptides or molecules of interest carrying indole structures as it allows the specific attachment and removal of a reactive group that may be used for a variety of purposes such as affinity tagging. PMID- 17705415 TI - Comparative in vitro and in vivo studies on long-wavelength photosensitizers derived from bacteriopurpurinimide and Bacteriochlorin p6: fused imide ring enhances the in vivo PDT efficacy. AB - In situ conversion of bacteriochlorophyll-a, present in Rhodobacter sphaeroides (Rb. sphaeroides) gave bacteriopurpurin-18 in modest yield, which in a sequence of reactions was converted into two series of bacteriochlorins: bacteriopurpurinimide and bacteriopurpurin p6 with and without a fused imide ring system, respectively. To determine the effect of overall lipophilicity in photosensitizing efficacy, these bacteriochlorins were independently reacted with HBr gas and subsequently treated with various alkyl alcohols to afford the corresponding alkyl ether derivatives as diastereomeric mixtures (the R- and S isomers were obtained in almost equal ratios). Between the two series of bacteriochlorins, the bacteriopurpurinimides containing a fused imide ring system were found to be more effective in vivo (C3H mice bearing RIF tumors). To investigate the effect of the presence of the chiral center at position 3 of the most effective purpurinimide 9 [3(1'-heptyloxy)ethyl-3-deacetyl-bacteriopurpurin 18-N-hexylimide propyl ester], the acetyl group was replaced with a hydroxymethyl substituent and converted into 3(1'-decyloxy)methyl-3-deacetyl-purpurin-18-N hexylimide methyl ester 26 with a similar lipophilicity. Interestingly, compared to 26, the bacteriopurpurinimide 9 was found to be more effective, suggesting that the chiral center at position 3 certainly plays an important role in photosensitizing activity. Among a series of alkyl ether analogues, between the PDT efficacy and the lipophilicity (log P and log D) calculated by computational methods (PALLAS program), a parabolic relationship was observed to some extent. However, it was limited to a particular series, e.g., compounds with similar log P values between bacteriopurpurinimides and bacteriochlorin e6 did not produce similar in vivo efficacy. As expected, within a series, a linear relationship was observed between the log P values and the HPLC retention times of the photosensitizers. Some of the mitochondrial localized photosensitizers showed a significant peripheral benzodiazepine binding (PBR) affinity. However, limited correlation between PBR binding affinity and in vivo PDT efficacy was observed. Compared to the naturally occurring bacteriochlorophyll-a, the bacteriopurpurinimides with fused imide ring system showed higher in vitro/in vivo stability. In contrast to methyl pyropheophorbide-a, the ester functionalities in bacteriopurpurinimide did not convert into the corresponding carboxylic acid by the enzyme esterases. PMID- 17705417 TI - Proteomic analysis of peripheral blood mononuclear cells: selective protein processing observed in patients with rheumatoid arthritis. AB - In a comparative proteome analysis of peripheral blood mononuclear cells (PBMCs), we analyzed 130 two-dimensional gels obtained from 33 healthy control individuals and 32 patients diagnosed with rheumatoid arthritis (RA). We found 16 protein spots that are deregulated in patients with RA and, using peptide mass fingerprinting and Western blot analyses, identified these spots as belonging to 9 distinct proteins. A hierarchical clustering procedure organizes the study subjects into two main clusters based on the expression of these 16 protein spots, one that contains mostly healthy control individuals and the other mostly RA patients. The majority of the proteins differentially expressed in RA patients when compared with healthy controls can be detected as protein fragments in PBMCs obtained from RA patients. This set of deregulated proteins includes several factors that have been shown to be autoantigens in autoimmune diseases. PMID- 17705416 TI - Osteotropic Peptide that differentiates functional domains of the skeleton. AB - HPMA copolymer-d-aspartic acid octapeptide (D-Asp8) conjugates have been found to target the entire skeleton after systemic administration. In a recent study using the ovariectomized rat model of osteoporosis, we surprisingly discovered that D Asp8 would favorably recognize resorption sites in skeletal tissues, while another bone-targeting moiety, alendronate (ALN), directs the delivery system to both formation and resorption sites. Atomic force microscopy (AFM) analyses reveal that ALN has a stronger binding force to hydroxyapatite (HA) than D-Asp8. In vitro HA binding studies indicate that D-Asp8 is more sensitive to change of HA crystallinity than ALN. Because the bone apatite in the newly formed bone (formation sites) usually has lower crystallinity than the resorption sites (mainly mature bone), we believe that the favorable recognition of D-Asp8 to the bone resorption sites could be attributed to its relatively weak binding to apatite, when compared to bisphosphonates, and the different levels of crystallinity of bone apatite at different functional domains of the skeleton. PMID- 17705419 TI - Formation of ferroelectric domains observed in simulation of droplets of dipolar particles. AB - In this work it is shown that domains of ordered dipoles are formed in large droplets made from dipolar particles provided that the dipole-dipole interaction between nearest neighbors is larger than the thermal energy. The size of the domains grows almost linearly with the size of the droplets for droplets containing 1000-30 000 particles. The largest domains occupy around 25-35% of the droplet volume. The total dipole moment of a domain is of the order of 3-10% of the maximum dipole moment possible if all dipoles in the domain were parallel. The finding offers an explanation to the observation that different boundary conditions yield different long-range order for dipolar liquids and challenges the present view of a short-range dipolar order in polar solvents. PMID- 17705418 TI - Diversifying the solid state and lyotropic phase behavior of nonionic urea-based surfactants. AB - The solid state and lyotropic phase behavior of 10 new nonionic urea-based surfactants has been characterized. The strong homo-urea interaction, which can prevent urea surfactants from forming lyotropic liquid crystalline phases, has been ameliorated through the use of isoprenoid hydrocarbon tails such as phytanyl (3,7,11,15-tetramethyl-hexadecyl) and hexahydrofarnesyl (3,7,11-trimethyl dodecyl) or the oleyl chain (cis-octadec-9-enyl). Additionally, the urea head group was modified by attaching either a hydroxy alkyl (short chain alcohol) moiety to one of the nitrogens of the urea or by effectively "doubling" the urea head group by replacing it with a biuret head group. The solid state phase behavior, including the liquid crystal-isotropic liquid, polymorphic, and glass transitions, is interpreted in terms of molecular geometries and probable hydrogen-bonding interactions. Four of the modified urea surfactants displayed ordered lyotropic liquid crystalline phases that were stable in excess water at both room and physiological temperatures, namely, 1-(2-hydroxyethyl)-1-oleyl urea (oleyl 1,1-HEU) with a 1D lamellar phase (Lalpha), 1-(2-hydroxyethyl)-3-phytanyl urea (Phyt 1,3-HEU) with a 2D inverse hexagonal phase (HII), and 1-(2 hydroxyethyl)-1-phytanyl urea (Phyt 1,1-HEU) and 1-(2-hydroxyethyl)-3 hexahydrofarnesyl urea (Hfarn 1,3-HEU) with a 3D bicontinuous cubic phase (QII). Phyt 1,1-HEU exhibited rich mesomorphism (QII1, QII2, Lalpha, LU, and HII), as did one other surfactant, oleyl 1,3-HEU (QII1, QII2, Lalpha, LU, and HII), in the study group. LU is an unusual phase which is mobile and isotropic but possesses shear birefringence, and has been very tentatively assigned as an inverse sponge phase. Three other surfactants exhibited a single lyotropic liquid crystalline phase, either Lalpha or HII, at temperatures >50 degrees C. The 10 new surfactants are compared with other recently reported nonionic urea surfactants. Structure-property correlations are examined for this novel group of self assembling amphiphiles. PMID- 17705420 TI - Glass transition line in C60: a mode-coupling/molecular-dynamics study. AB - We report a study of the mode-coupling theory (MCT) glass transition line for the Girifalco model of C60 fullerene. The equilibrium static structure factor of the model, the only required input for the MCT calculations, is provided by molecular dynamics simulations. The glass transition line develops inside the metastable liquid-solid coexistence region and extends down in temperature, terminating on the liquid side of the metastable portion of the liquid-vapor binodal. The vitrification locus does not show re-entrant behavior. A comparison with previous computer simulation estimates of the location of the glass line suggests that the theory accurately reproduces the shape of the arrest line in the density temperature plane. The theoretical HNC and MHNC structure factors (and consequently the corresponding MCT glass line) compare well with the numerical counterpart. Our results confirm the conclusion drawn in previous works about the existence of a glassy phase for the fullerene model at issue. PMID- 17705421 TI - On the possibility that cyclodextrins' chiral cavities can be available on AOT n heptane reverse micelles. A UV-visible and induced circular dichroism study. AB - The formation of reverse micelles (RMs) of sodium 1,4-bis(2 ethylhexyl)sulfosuccinate (AOT) in n-heptane including two different beta cyclodextrin (beta-CD) derivatives (hydroxypropyl-beta-CD, hp-beta-CD, and decenyl succinyl-beta-CD, Mod-beta-CD) is reported. Both cyclodextrins can be incorporated into AOT RMs in different zones within the aggregate, while beta-CD cannot. Using UV-vis and induced circular dichroism (ICD) spectroscopy and different achiral molecular probes (some azo dyes, p-nitroaniline and ferrocene), it was possible to determine that Mod-beta-CD is located with its cavity at the oil side of the AOT RM interface, while for hp-beta-CD the cavity is inside the RM water pool. Among the molecular probes used, methyl orange (MO) was the only one which gave the ICD signal when dissolved in the AOT RMs with hp-beta-CD, so a detailed study of MO behavior in homogeneous media was also performed to compare with the microheterogeneous media. The solvatochromic behavior of the dye depends not only on the polarity of the media but also on other specific solvent properties. A Kamlet-Taft analysis shows that the MO absorption spectrum shifts to longer wavelength with an increase in the solvent polarity-polarizability (pi*) and the hydrogen donor ability (alpha) of the medium. MO appears to be almost 3 times more sensitive to the pi* parameter than to the alpha parameter. In addition, from the MO absorption spectral changes with the hp-beta-CD concentration, the association equilibrium constants in pure water (K11W) and inside the RMs (K11RM) were computed. The results show that K11W is almost 10 times larger than the value inside the RMs. The latter can be explained considering that MO resides anchored to the RM interface through hydrogen bond interaction with the hydration bound water. This study shows for the first time that the cyclodextrin chiral cavity is available for a guest in an organic medium such as the RMs; therefore, we have created a potentially powerful nanoreactor with two different confined regions in the same aggregate: the polar core of the RMs and the chiral hydrophobic cavity of cyclodextrin. PMID- 17705422 TI - Gas-phase methylation of [60]fullerene. AB - Direct methylation of [60]fullerene via a gas-phase reaction in a CH4/H2 atmosphere was performed using a modified hot filament chemical vapor deposition method. Pressures were varied from 10 to 60 mbar and the substrate was maintained at 690 degrees C. High-resolution matrix-assisted laser desorption ionization (MALDI) mass spectrometry analysis showed signals corresponding to C60H18 2n(H,CH3)n. Collision-induced dissociation experiments confirmed a maximum of 18 ligands possible to the [60]fullerene cage. PMID- 17705423 TI - Weibull mixture model for modeling nonisothermal kinetics of thermally stimulated solid-state reactions: application to simulated and real kinetic conversion data. AB - The possibility of applying Weibull mixture model for the fitting of the nonisothermal kinetic conversion data has been investigated. It has been found that the kinetic conversion data at different heating rates can be successfully described by one or the linear combination of few Weibull distribution functions. Several simulated and real kinetic conversion traces have been analyzed. An optimal fitting of the kinetic conversion data has been obtained by a mixture of Weibull distribution functions. The results obtained have shown that the obtained conversion curves calculated by the model proposed in this paper are in agreement with the raw kinetic conversion data. PMID- 17705424 TI - Electric field effects on absorption and fluorescence spectra of trimethylsilyl- and trimethylsilylethynyl-substituted compounds of pyrene in a PMMA film. AB - External electric field effects on absorption and fluorescence spectra of 1,3,6,8 tetrakis(trimethylsilyl)pyrene and 1,3,6,8-tetrakis(trimethylsilylethynyl)pyrene (TMSPy and TMS(E)Py, respectively) have been examined in a poly(methyl methacrylate) (PMMA) film at various concentrations at various temperatures. TMS(E)Py preferentially forms an aggregate in a PMMA film, as the concentration increases, indicating that the acetylenic groups enhance the pi-pi interactions between pyrene molecules. The change in molecular polarizability following excitation has been determined both for the monomer and for the aggregate, based on the electroabsorption spectra. The change in molecular polarizability following emission has also been determined in both compounds, based on the electrofluorescence spectra. TMSPy exhibits two excimer fluorescence emissions at high concentrations which are ascribed to the partially overlapping excimer and the sandwich-type excimer, respectively, besides the monomer fluorescence emitted from the locally excited state. The sandwich-type excimer fluorescence as well as monomer fluorescence is quenched by an electric field, whereas the fluorescence of the partially overlapping excimer is enhanced by an electric field. Excimer fluorescence of TMS(E)Py, which arises from the sandwich-type excimer, is quenched by an electric field at any temperature. Only one species of the partially overlapping excimer is confirmed in TMSPy, while no partially overlapping excimer is confirmed in TMS(E)Py. PMID- 17705425 TI - Side-chain conformation of the M2 transmembrane peptide proton channel of influenza a virus from 19F solid-state NMR. AB - The M2 transmembrane peptide (M2TMP) of the influenza A virus forms a tetrameric helical bundle that acts as a proton-selective channel important in the viral life cycle. The side-chain conformation of the peptide is largely unknown and is important for elucidating the proton-conducting mechanism and the channel stability. Using a 19F spin diffusion NMR technique called CODEX, we have measured the oligomeric states and interhelical side chain-side chain 19F-19F distances at several residues using singly fluorinated M2TMP bound to DMPC bilayers. 19F CODEX data at a key residue of the proton channel, Trp41, confirm the tetrameric state of the peptide and yield a nearest-neighbor interhelical distance of approximately 11 A under both neutral and acidic pH. Since the helix orientation is precisely known from previous 15N NMR experiments and the backbone channel diameter has a narrow allowed range, this 19F distance constrains the Trp41 side-chain conformation to t90 (chi1 approximately 180 degrees , chi2 approximately 90 degrees ). This Trp41 rotamer, combined with a previously measured 15N-13C distance between His37 and Trp411, suggests that the His37 rotamer is t-160. The implication of the proposed (His37, Trp41) rotamers to the gating mechanism of the M2 proton channel is discussed. Binding of the antiviral drug amantadine to the peptide does not affect the F-F distance at Trp41. Interhelical 19F-19F distances are also measured at residues 27 and 38, each mutated to 4-19F-Phe. For V27F-M2TMP, the 19F-19F distances suggest a mixture of dimers and tetramers, whereas the L38F-M2TMP data indicate two tetramers of different sizes, suggesting side chain conformational heterogeneity at this lipid facing residue. This work shows that 19F spin diffusion NMR is a valuable tool for determining long-range intermolecular distances that shed light on the mechanism of action and conformational heterogeneity of membrane protein oligomers. PMID- 17705426 TI - Mannosylated poly(ethylene oxide)-b-poly(epsilon-caprolactone) diblock copolymers: synthesis, characterization, and interaction with a bacterial lectin. AB - A novel bioeliminable amphiphilic poly(ethylene oxide)-b-poly(epsilon caprolactone) (PEO-b-PCL) diblock copolymer end-capped by a mannose residue was synthesized by sequential controlled polymerization of ethylene oxide and epsilon caprolactone, followed by the coupling of a reactive mannose derivative to the PEO chain end. The anionic polymerization of ethylene oxide was first initiated by potassium 2-dimethylaminoethanolate. The ring-opening polymerization of epsilon-caprolactone was then initiated by the omega-hydroxy end-group of PEO previously converted into an Al alkoxide. Finally, the saccharidic end-group was attached by quaternization of the tertiary amine alpha-end-group of the PEO-b-PCL with a brominated mannose derivative. The copolymer was fully characterized in terms of chemical composition and purity by high-resolution NMR spectroscopy and size exclusion chromatography. Furthermore, measurements with a pendant drop tensiometer showed that both the mannosylated copolymer and the non-mannosylated counterpart significantly decreased the dichloromethane/water interfacial tension. Moreover, these amphiphilic copolymers formed monodisperse spherical micelles in water with an average diameter of approximately 11 nm as measured by dynamic light scattering and cryo-transmission electron microscopy. The availability of mannose as a specific recognition site at the surface of the micelles was proved by isothermal titration microcalorimetry (ITC), using the BclA lectin (from Burkholderia cenocepacia), which interacts selectively with alpha-D-mannopyranoside derivatives. The thermodynamic parameters of the lectin/mannose interaction were extracted from the ITC data. These colloidal systems have great potential for drug targeting and vaccine delivery systems. PMID- 17705427 TI - In situ observation of spherical DNA assembly in water and the controlled release of bound dyes. AB - Three strands of 30-mer oligodeoxyribonucleotides (ODNs) were designed to form three-way junctions that possess self-complementary sticky ends. The morphology of self-assembled ODNs in water was observed in situ by confocal laser scanning fluorescence microscopy. The three-way junctions self-assembled into spherical assemblies, in accordance with transmission and scanning electron microscopy. The size of nucleospheres was in the range of several tens of nanometers to micrometers, which varied depending on the concentration of ODNs and added salts. Fluorescence images of spherical ODN assemblies suggested that the nucleospheres possess multiwalled structures. The fluorescence of sodium 1-anilinonaphthalene-8 sulfonate in the presence of nucleospheres revealed that the interior of nucleospheres possesses polarity corresponding to that between methanol and ethanol. A dye-inclusion experiment showed that cationic and even anionic dyes were adsorbed to the interior of the nucleospheres. The dye-included nucleospheres released dyes by thermal dissociation or digestion of the constituent ODNs. PMID- 17705428 TI - Temperature-dependent changes in hydrogen bonds in cellulose Ialpha studied by infrared spectroscopy in combination with perturbation-correlation moving-window two-dimensional correlation spectroscopy: comparison with cellulose Ibeta. AB - Our recent IR study demonstrated that hydrogen-bond structure in cellulose Ibeta drastically changes around 220 degrees C (Watanabe et al. Biomacromolecules 2006, 7, 3164). In the present study, temperature-dependent IR spectra of cellulose Ialpha from 30 to 260 degrees C were analyzed by use of perturbation-correlation moving-window two-dimensional correlation spectroscopy. It was observed that as in the case of cellulose Ibeta abrupt changes in the hydrogen-bond structure occur around 220 degrees C in cellulose Ialpha. It was also revealed that although weakly hydrogen-bonded OH groups in Ibeta are stable below 230 degrees C thermal oxidation of those in Ialpha is accelerated around 220 degrees C. In this way, the present study has clarified a difference between the thermal behavior of Ialpha and that of Ibeta at the functional group level. Our result suggests that the drastic change in the hydrogen-bond structure around 220 degrees C makes cellulose Ialpha much more unstable than Ibeta. PMID- 17705429 TI - Partially O-alkylated thiacalix[4]arenes: synthesis, molecular and crystal structures, conformational behavior. AB - NMR spectroscopy, X-ray diffraction analysis, and quantum chemical calculations were used for conformational behavior study of partially alkylated thiacalix[4]arenes bearing methyl (1), ethyl (2), or propyl (3) groups at the lower rim. The conformational properties are governed by two basic effects: (i) stabilization by intramolecular hydrogen bonds, and (ii) sterical requirements of the alkoxy groups at the lower rim. While the monosubstituted derivatives 1a and 3a adopt the cone conformation in solution, distally disubstituted compounds 1b, 1'b, 2b, 2'b, 3b, and 3'b exhibit several interesting conformational features. They prefer pinched cone conformation in solution, and, except for 3'b, they form also 1,2-alternate conformation, which is flexible and undergoes rather fast transition between two identical structures. The crystal structures of the compounds 1b, 2b, 2'b, and 3b revealed yet quite rare 1,2-alternate conformation forming molecular channels held together by pi-pi interactions. Different channels-with hexagonal symmetry, 0.26 nm wide-are formed in the crystal structure of the pinched cone conformation of 3b. An uncommon hydrogen bonding pattern was found in dimethoxy and dipropoxy derivatives 1'b and 3'b that adopt distorted cone conformations in crystal. Trialkoxy-substituted compounds 1c and 3c adopt the partial cone conformation in solution. A higher mobility of methyl derivative 1c enables also existence of the cone conformer. PMID- 17705430 TI - On the synthesis of protopine alkaloids. AB - For the synthesis of protopine alkaloids, we studied a reaction sequence based on a ring enlargement of indeno[2,1-a][3]benzazepines by a singlet oxygen oxygenation, followed by conversion of an amide carbonyl group of the resultant 10-membered keto-lactam to a methylene group, which is the last step for completion of the synthesis. The key substances, indeno[2,1-a][3]benzazepines, were prepared by Bischler-Napieralski cyclization of alkoxy-substituted 1-(2 bromobenzyl)-3-benzazepin-2-ones. Steric effects of the substituents in this synthesis were examined. PMID- 17705432 TI - Synthesis of helicenes utilizing palladium-catalyzed double C-H arylation reaction. AB - [5]- and [6]helicenes were synthesized in moderate to good yields from Z,Z bis(bromostilbene)s by palladium-catalyzed double C-H arylation reaction. This method can be applied to the syntheses of helicenes possessing electron-deficient substituents. PMID- 17705431 TI - An easy stereoselective access to beta,gamma-aziridino alpha-amino ester derivatives via mannich reaction of benzophenone imines of glycine esters with N sulfonyl alpha-chloroaldimines. AB - Mannich-type addition of benzophenone imine glycinates across newly synthesized N (p-toluenesulfonyl) alpha-chloroaldimines afforded gamma-chloro-alpha,beta diamino ester derivatives with moderate diastereoselectivity as separable mixtures of anti and syn diastereomers. The gamma-chloro-alpha,beta-diamino esters were efficiently cyclized under basic conditions to the corresponding beta,gamma-aziridino alpha-amino ester derivatives, representing a new class of conformationally constrained heterocyclic alpha,beta-diamino acid derivatives. The relative configuration of the aziridines was determined via X-ray diffraction analysis. Mechanisms and intermediate transition states to explain the stereochemical outcome of the Mannich reaction with different substrates or under different conditions are proposed. The synthetic importance of the beta,gamma aziridino alpha-amino ester derivatives is demonstrated by their conversion into the corresponding Boc-protected derivatives and ring opening reactions to alpha,beta-diamino esters and a gamma-amino alpha,beta-unsaturated amino ester. PMID- 17705433 TI - Synthesis of 1-arylmethyl-2-(2-cyanoethyl)aziridines and their rearrangement into novel 2-(aminomethyl)cyclopropanecarbonitriles. AB - 1-Arylmethyl-2-(bromomethyl)aziridines were transformed into novel 2-(2 cyanoethyl)aziridines upon treatment with alpha-lithiated trimethylsilylacetonitrile in THF in an efficient and straightforward approach. The latter aziridines underwent ring opening by reaction with benzyl bromide in acetonitrile, affording 5-amino-4-bromopentanenitriles through a regiospecific ring opening of intermediate aziridinium salts by bromide. Further elaboration of these gamma-bromonitriles resulted in the synthesis of novel 2-[N,N bis(arylmethyl)aminomethyl]cyclopropanecarbonitriles in high yields by means of a 1,3-cyclization protocol upon treatment with KOtBu in THF. PMID- 17705434 TI - Biomimetic superhydrophobic surfaces: multiscale approach. AB - Micro- and macrodroplet evaporation and condensation upon micropatterned superhydrophobic surfaces built of flattop pillars are investigated with the use of an environmental scanning electron microscope. It is shown that the contact angle hysteresis depends upon both kinetic effects at the triple line and adhesion hysteresis (inherently present even at a smooth surface) and that the magnitude of the two contributions is comparable. The transition between the composite (Cassie) and wetted (Wenzel) states is a linear effect with the microdroplet radius proportional to the pitch over pillar diameter. It is shown that wetting of a superhydrophobic surface is a multiscale phenomenon that involves three scale lengths. Although the contact angle is the macroscale parameter, the contact angle hysteresis and the Cassie--Wenzel transition cannot be determined from the macroscale equations and are governed by micro- and nanoscale effects. PMID- 17705435 TI - Novel bioinorganic nanostructures based on mesolamellar intercalation or single molecule wrapping of DNA using organoclay building blocks. AB - Nanosheets or nanoclusters of aminopropyl-functionalized magnesium phyllosilicate (AMP) were prepared in water by exfoliation and used as structural building blocks for the preparation of DNA-based hybrid nanostructures in the form of ordered mesolamellar nanocomposites or highly elongated nanowires, respectively. The former consisted of alternating layers of single sheets of AMP interspaced with intercalated monolayers of intact double-stranded DNA molecules of relatively short length ( approximately 700 base pairs) that were accessible to small molecules such as ethidium bromide. In contrast, the nanowires comprised isolated micrometer-long molecules of lambda-DNA or plasmid DNA that were sheathed in an ultrathin organoclay layer and which were either protected from or remained accessible to endonuclease-mediated clipping depending on the extent of biomolecule wrapping. Both types of hybrid nanostructures showed a marked increase in the DNA melting (denaturation) temperature, indicating significant thermal stabilization of the confined biomolecules. Our results suggest that nanoscale building blocks derived from organically modified inorganic clays could be useful agents for enhancing the chemical, thermal, and mechanical stability of isolated molecules or ensembles of DNA. Such constructs should have increased potential as functional components in bionanotechnology and nonviral gene transfection. PMID- 17705436 TI - A complete scheme for creating predefined networks of individual carbon nanotubes. AB - We describe and demonstrate a method of creating arrays of patterned, individual, single-walled carbon nanotubes, including the spectroscopic mapping of the array. The process consists of creating networks of nanotubes suspended between silicon pillars, which are then transferred onto other substrates by an innovative process of direct stamping. Raman spectroscopy is used to spatially map and assign the specific properties of the suspended network prior to transfer. This method provides a simple and inexpensive means for deriving nanoscale devices utilizing individually assigned carbon nanotubes in a robust and non-surface specific technique. PMID- 17705437 TI - Effect of cold storage and packaging material on the major aroma components of sweet cream butter. AB - The major aroma compounds of commercial sweet cream AA butter quarters were analyzed by GC-olfactometry and GC-MS combined with dynamic headspace analysis (DHA) and solvent-assisted flavor evaporation (SAFE). In addition, the effect of long-term storage (0, 6, and 12 months) and type of wrapping material (wax parchment paper vs foil) on the aroma components and sensory properties of these butters kept under refrigerated (4 degrees C) and frozen (-20 degrees C) storage was evaluated. The most intense compounds in the aroma of pasteurized AA butter were butanoic acid, delta-octalactone, delta-decalactone, 1-octen-3-one, 2-acetyl 1-pyrroline, dimethyl trisulfide, and diacetyl. The intensities of lipid oxidation volatiles and methyl ketones increased as a function of storage time. Refrigerated storage caused greater flavor deterioration compared with frozen storage. The intensity and relative abundance of styrene increased as a function of time of storage at refrigeration temperature. Butter kept frozen for 12 months exhibited lower styrene levels and a flavor profile more similar to that of fresh butter compared to butter refrigerated for 12 months. Foil wrapping material performed better than wax parchment paper in preventing styrene migration into butter and in minimizing the formation of lipid oxidation and hydroxyl acid products that contribute to the loss of fresh butter flavor. PMID- 17705438 TI - Screening of iron bioavailability patterns in eight bean (Phaseolus vulgaris L.) genotypes using the Caco-2 cell in vitro model. AB - The common bean ( Phaseolus vulgaris) is an important staple plant food in the diets of people of Latin America, East Africa,and other regions of the developing world. It is also a major source of dietary iron. The primary goal of this research was to use an in vitro digestion/Caco-2 model to study iron bioavailability in eight genotypes (three Mesoamerican and five Andean) that represent the diversity of grain types in this crop. Complementing this goal, we measured the distribution of both iron and phytate in different bean grain tissues (cotyledon, seed coats, and embryos). Seed coats were confirmed to be the exclusive tissue containing polyphenols. The removal of the seed coat and associated polyphenols improved Caco-2 iron bioavailability, and significant differences were observed between genotypes. The addition of ascorbate enhanced iron bioavailability and exposed additional differences in Fe availability among the genotypes. These results indicate that iron accumulation and in vitro iron bioavailability vary among bean genotypes and that polyphenols had greater inhibitory effects on Caco-2 iron bioavailability as compared to phytate. PMID- 17705439 TI - Dietary fiber content and associated antioxidant compounds in Roselle flower (Hibiscus sabdariffa L.) beverage. AB - The beverage of Hibiscus sabdariffa flowers is widely consumed in Mexico. Polyphenols contained in plant foods are frequently associated with dietary fiber. The aim of this work is to quantify the dietary fiber, associated polyphenols, and antioxidant capacity of the Roselle flower and the beverage traditionally prepared from it and its contribution to the Mexican diet. Roselle flower contained dietary fiber as the largest component (33.9%) and was rich in phenolic compounds (6.13%). Soluble dietary fiber was 0.66 g/L in beverage, and 66% of total extractable polyphenols contained in Roselle flower passed to the beverage and showed an antioxidant capacity of 335 micromoL trolox equivalents/100 mL beverage measured by ABTS. These data suggest that Roselle flower beverage intake in the Mexican diet may contribute around 166 and 165 mg/per serving to the intake of dietary fiber and polyphenols, respectively. The health benefits from consumption of Hibiscus beverage could be of considerable benefit to the whole population. PMID- 17705440 TI - Synthesis, characterization, and gene delivery of poly-L-lysine octa(3 aminopropyl)silsesquioxane dendrimers: nanoglobular drug carriers with precisely defined molecular architectures. AB - Macromolecules with defined nanosizes--nanoglobules--were synthesized and characterized as novel drug carriers with precise molecular architectures. Poly-L lysine dendrimers with a cubic octa(3-aminopropyl)silsesquioxane (OAS) core, (L lysine 8-OAS, (L-lysine) 16-(L-lysine) 8-OAS, (L-lysine) 32-(L-lysine) 16-(L lysine) 8-OAS, and (L-lysine) 64-(L-lysine) 32-(L-lysine) 16-(L-lysine) 8-OAS, were divergently synthesized by solution phase peptide chemistry in good yield and purity. Matrix-assisted laser desorption time of flight (MALDI-TOF) mass spectrometry showed complete substitution of the surface amino groups of lower generation dendrimers during synthesis, as well as precisely defined molecular architectures of the nanoglobules. The structures of the nanoglobules were further characterized by (1)H- and (13)C-NMR and 2D-NMR (correlation spectroscopy (COSY) and pulsed-field-gradient heteronuclear multiple quantum correlation (gHMQC)) spectroscopy. The (1)H-NMR spectroscopy revealed that the nanoglobules had a relatively rigid molecular architecture. Cytotoxicity studies showed that these nanoglobules exhibited a size-dependent toxicity, but it was much lower than that of linear poly-L-lysine. Preliminary in vitro nucleic acid delivery studies have shown that these globular dendrimers can efficiently deliver plasmid DNA to MDA-MB-231 cells. These nanoglobules hold much promise as safe drug carriers with precisely defined molecular architecture. PMID- 17705441 TI - Targeted therapy of breast and gynecological cancers with cytotoxic analogues of peptide hormones. AB - Gynecological cancers such as breast, ovarian, and endometrial carcinoma express receptors for luteinizing hormone-releasing hormone (LHRH), bombesin/gastrin releasing peptide (BN/GRP), and somatostatin (SST). These tumors are therefore suitable candidates for targeted therapy with cytotoxic hybrid molecules consisting of a cytotoxic radical and a peptide hormone analogue as a carrier. These compounds have been shown to be more active and less toxic in vivo than nontargeted chemotherapy in models of various human cancers which express the respective receptors. The current review summarizes experimental and clinical findings with cytotoxic peptide hormone analogues of LHRH (AN-152 [AEZS 108], AN 207), BN/GRP (AN-215), and SST (AN-238) in breast, ovarian, and endometrial cancers. PMID- 17705442 TI - Surfactant-polymer nanoparticles overcome P-glycoprotein-mediated drug efflux. AB - Nanoparticles enhance the therapeutic efficacy of an encapsulated drug by increasing and sustaining the delivery of the drug inside the cell. We have previously demonstrated that Aerosol OT (AOT)-alginate nanoparticles, a novel formulation developed recently in our laboratory, significantly enhance the therapeutic efficacy of encapsulated drugs like doxorubicin in drug-sensitive tumor cells. The purpose of this study is to evaluate the drug delivery potential of AOT-alginate nanoparticles in drug-resistant cells overexpressing the drug efflux transporter, P-glycoprotein (P-gp). AOT-alginate nanoparticles were formulated using an emulsion-cross-linking process. Rhodamine 123 and doxorubicin were used as model P-gp substrates. Cytotoxicity of nanoparticle-encapsulated doxorubicin and kinetics of nanoparticle-mediated cellular drug delivery were evaluated in both drug-sensitive and -resistant cell lines. AOT-alginate nanoparticles enhanced the cytotoxicity of doxorubicin significantly in drug resistant cells. The enhancement in cytotoxicity with nanoparticles was sustained over a period of 10 days. Uptake studies with rhodamine-loaded nanoparticles indicated that nanoparticles significantly increased the level of drug accumulation in resistant cells at nanoparticle doses higher than 200 microg/mL. Blank nanoparticles also improved rhodamine accumulation in drug-resistant cells in a dose-dependent manner. Nanoparticle-mediated enhancement in rhodamine accumulation was not because of membrane permeabilization. Fluorescence microscopy studies demonstrated that nanoparticle-encapsulated doxorubicin was predominantly localized in the perinuclear vesicles and to a lesser extent in the nucleus, whereas free doxorubicin accumulated mainly in peripheral endocytic vesicles. Inhibition of P-gp-mediated rhodamine efflux with AOT-alginate nanoparticles was confirmed in primary brain microvessel endothelial cells. In conclusion, an AOT-alginate nanoparticle system enhanced the cellular delivery and therapeutic efficacy of P-gp substrates in P-gp-overexpressing cells. PMID- 17705443 TI - One-pot synthesis of quinoline-based tetracycles by a tandem three-component reaction. AB - A practical one-pot synthetic strategy for the efficient synthesis of a range of structurally interesting and bioactive quinoline-based tetracycles has been developed. A key step in the synthesis is a tandem three-component reaction of heteroaromatic amine, methyl 2-formylbenzoate and (t)butyl isonitrile, followed by TFA-mediated lactamization via intramolecular aminolysis of an adjacent ester. Results related to a kinase-panel screening for several selected compounds are also discussed in this article. PMID- 17705444 TI - Targeted cancer therapy: conferring specificity to cytotoxic drugs. AB - The therapeutic activity of most anticancer drugs in clinical use is limited by their general toxicity to proliferating cells, including some normal cells. Although, chemists continue to develop novel cytotoxic agents with unique mechanisms of action, many of these compounds still lack tumor selectivity and have not been therapeutically useful. Monoclonal antibodies that bind to specific markers on the surface of tumor cells offer an alternative therapy that is tumor specific and thus less toxic. Although highly selective, very few monoclonal antibodies are therapeutically useful since they only display modest cell killing activity. The linkage of monoclonal antibodies to highly cytotoxic drugs can be viewed as a means of (a) conferring higher tumor selectivity to cytotoxic drugs that are too toxic to be used on their own or (b) conferring cell killing power to monoclonal antibodies that are tumor-specific but not sufficiently cytotoxic. This Account provides a brief history of the development of antibody-drug conjugates and shows how the lessons learned from the first generation of conjugates has guided the development of more effective antitumor agents. The three components of antibody-drug conjugates, that is, the monoclonal anitbody, the cytotoxic drug, and the linker connecting the drug to the antibody, have been methodically studied and optimized. The antimitotic drug maytansine was chosen for use in the targeted delivery approach because of its high in vitro potency. Analogues of maytansine bearing a disulfide substituent that allowed linkage to monoclonal antibodies via disulfide bonds were prepared. These analogues retain the high potency of the parent drug. The stability of the disulfide link in antibody-maytansinoid conjugates was varied by introduction of methyl substituents on the carbon atoms geminal to the disulfide link. The optimized disulfide linker was stable in circulation in vivo. The circulation half-life of the cytotoxic drug was increased from just a few hours for the unconjugated drug to several days for the conjugate. Upon binding of the conjugate to the tumor cell, internalization and lysosomal processing released the potent cytotoxic agent inside the cell. These conjugates displayed high target-specific cytotoxicity in vitro. The antitumor activity of these targeted agents was superior to that of the antibodies alone or the standard anticancer drugs in human tumor xenograft models. Several conjugates from this new class of tumor targeted anticancer agents are currrently undergoing clinical evaluation. The progress made in the targeted delivery approach and initial clinical results opens the door to the future development of highly potent drugs that were too toxic on their own to be therapeutically useful. PMID- 17705445 TI - Solvation, solute rotation and vibration relaxation, and electron-transfer reactions in room-temperature ionic liquids. AB - A brief account of recent simulation and theoretical model studies of various solution-phase processes in room-temperature ionic liquids is given. These include structure and dynamics of equilibrium and nonequilibrium solvation, solute rotation and vibrational energy relaxation, and free energetics and dynamics of unimolecular electron-transfer reactions. Special attention is paid to both the aspects shared by and the contrasts with polar solvents under normal conditions. A brief comparison with available experiments is also made. PMID- 17705446 TI - Asymmetric hydrogenation using monodentate phosphoramidite ligands. AB - Monodentate phosphoramidites are excellent ligands for Rh-catalyzed asymmetric hydrogenations of substituted olefins. Enantioselectivities between 95 and 99% were obtained in the asymmetric hydrogenation of protected alpha- and beta dehydroamino acids and esters, itaconic acid and esters, aromatic enamides, aromatic enol esters, aromatic and aliphatic enol carbamates, and alpha substituted cinnamic acids. An iridium catalyst Ir(L*)(COD)Cl was developed that contains only a single bulky phosphoramidite based on 3,3'-disubstituted BINOL or bisphenol as a chiral ligand. With this catalyst, acetylated dehydroamino acid esters could be hydrogenated with very good enantioselectivity. Most reactions have turnover frequencies of 250-1600 h (-1), depending upon the hydrogen pressure. The enantioselectivity is unaffected by the pressure over a wide range. Because of their modularity and easy synthesis, parallel ligand synthesis is possible. Results obtained with these library ligands deviate only slightly from those obtained with purified ligands. Using this instant ligand library protocol, DSM has developed catalysts for industrial processes. These MonoPhos ligands are currently used in production for pharmaceutical intermediates by DSM. It is possible to use catalysts based on a mixture of two different monodentate ligands, such as two different monodentate phosphoramidites or one phosphoramidite and one achiral phosphine ligand. Dependent upon the substrate, the "mixed" catalyst may lead to higher enantioselectivity and rate than the "homocatalysts". PMID- 17705447 TI - Indirect determination of sulfide at ultratrace levels in natural waters by flow injection on-line sorption in a knotted reactor coupled with hydride generation atomic fluorescence spectrometry. AB - A simple and sensitive nonchromatographic approach for indirect determination of sulfide at ultratrace levels in natural waters based on its selective precipitation with Hg2+ on the inner wall of a knotted reactor (KR) was developed for flow injection on-line sorption coupled with hydride generation atomic fluorescence spectrometry (HG-AFS). With the Hg2+ pH kept at 2.0, the HgS precipitation was formed in the KR after a reaction time of 120 s. A 10% (v/v) HCl was introduced to elute the remnant inorganic mercury and to merge with the KBH4 solution (0.05% m/v) for HG-AFS detection. Under the optimal experimental conditions, the sample throughputs were 20 h(-1). The detection limit was found to be 0.05 microg L(-1), and the relative standard deviation (RSD, n = 11) for determination of 2.0 microg L(-1) sulfide was 3.3%. The developed method was successfully applied to the determination of sulfide in a variety of natural water samples and wastewater samples with the gas-phase separation and sorption apparatus. PMID- 17705449 TI - Differentially ligand-functionalized microcantilever arrays for metal ion identification and sensing. AB - A microcantilever array sensor with cantilevers differentially functionalized with self-assembled monolayers (SAMs) of thiolated ligands is prepared by simultaneous capillary coating. This array is described for the detection of metal ions including Li+, Cs+, Cu2+, Co2+, Fe3+, and Al3+. Binding of the charged metal cations to the surface of the microcantilever sensors produces surface stress that causes bending of the cantilevers that is detected as tip deflection using an array of vertical cavity surface emitting lasers and a position sensitive detector. Optimization studies of the nanostructured dealloyed surface were performed for SAMs based on their response to Cu2+ cations. Sensor performance experiments demonstrate good sensitivity toward metal ions, with limits of detection as low as 10(-8) molar. A multiplex capillary coating method for cantilever array creation is demonstrated and validated based on surface enhanced Raman spectra obtained from adjacent cantilevers that were functionalized with different thiolated SAMs. The cantilever array coated with a range of thiolated ligands was exposed to the group of metal ions. The response characteristics of each metal ion show substantial diversity, varying not only in response magnitude, but response kinetics. A pattern recognition algorithm based on a combination of independent component analysis and support vector machines was able to validate that the sensor array response profiles produced enough information content that metal ions could be reliably classified with probabilities as high as 89%. PMID- 17705450 TI - Photophoretic velocimetry for colloid characterization and separation in a cross flow setup. AB - We introduce photophoretic velocimetry as a new technique for characterization of particulate matter on the basis of optical particle properties. Complementary to well-established techniques, we could show that, by measuring the photophoretic velocity of the single particles, it is possible to distinguish particles of different sizes as well as particles of one size but different refractive indices. The difference in photophoretic migration of particles can be applied to the separation of particles. Polystyrene, melamine, and SiO2 microparticles (0.3 10 mum) suspended in purified water were used as test samples for validation of a cross-flow setup. The particles were pushed perpendicular to a uniform, pulsation free fluid flow by a focused He-Ne laser (lambda = 633 nm, P = 47 mW, I(max) = 14.0 kW cm(-2)) providing a well-defined Gaussian-shaped flux distribution. The migration behavior was observed by means of a video camera system, and the velocities and displacements were calculated by using an adapted particle imaging velocimetry code as an approach to automatic characterization. The photophoretic displacement depends on both flow conditions and particle properties and can be applied for separation means. PMID- 17705448 TI - Photoderivatized polymer thin films at quartz crystal microbalance surfaces: sensors for carbohydrate-protein interactions. AB - Photoderivatized polymer-coated gold surfaces have been developed following a perfluorophenylazide-based double ligation strategy. Gold-plated quartz crystal microbalance (QCM) crystals were initially covalently functionalized with a monolayer of poly(ethylene glycol) (PEG), using photo- or thermolytic nitrene formation and insertion. The polymer surfaces were subsequently used as substrates for photoinsertion of carbohydrate-derivatized photoprobes, yielding different recognition motifs for selective protein binding. The resulting robust and biocompatible sensor surfaces were applied to a flow-through QCM instrument for monitoring lectin-carbohydrate interactions in real time. The results clearly show the predicted lectin selectivity, demonstrating the applicability of the approach. PMID- 17705451 TI - Identification of inorganic improvised explosive devices by analysis of postblast residues using portable capillary electrophoresis instrumentation and indirect photometric detection with a light-emitting diode. AB - A commercial portable capillary electrophoresis (CE) instrument has been used to separate inorganic anions and cations found in postblast residues from improvised explosive devices (IEDs) of the type used frequently in terrorism attacks. The purpose of this analysis was to identify the type of explosive used. The CE instrument was modified for use with an in-house miniaturized light-emitting diode (LED) detector to enable sensitive indirect photometric detection to be employed for the detection of 15 anions (acetate, benzoate, carbonate, chlorate, chloride, chlorite, cyanate, fluoride, nitrate, nitrite, perchlorate, phosphate, sulfate, thiocyanate, thiosulfate) and 12 cations (ammonium, monomethylammonium, ethylammonium, potassium, sodium, barium, strontium, magnesium, manganese, calcium, zinc, lead) as the target analytes. These ions are known to be present in postblast residues from inorganic IEDs constructed from ammonium nitrate/fuel oil mixtures, black powder, and chlorate/perchlorate/sugar mixtures. For the analysis of cations, a blue LED (470 nm) was used in conjunction with the highly absorbing cationic dye, chrysoidine (absorption maximum at 453 nm). A nonaqueous background electrolyte comprising 10 mM chrysoidine in methanol was found to give greatly improved baseline stability in comparison to aqueous electrolytes due to the increased solubility of chrysoidine and its decreased adsorption onto the capillary wall. Glacial acetic acid (0.7% v/v) was added to ensure chrysoidine was protonated and to enhance separation selectivity by means of complexation with transition metal ions. The 12 target cations were separated in less than 9.5 min with detection limits of 0.11-2.30 mg/L (calculated at a signal-to-noise ratio of 3). The anions separation system utilized a UV LED (370 nm) in conjunction with an aqueous chromate electrolyte (absorption maximum at 371 nm) consisting of 10 mM chromium(VI) oxide and 10 mM sodium chromate, buffered with 40 mM tris(hydroxymethyl)aminomethane at pH 8.05. All 15 target anions were baseline separated in less than 9 min with limits of detection ranging from 0.24 to 1.15 mg/L (calculated at a signal-to-noise ratio of 3). Use of the portable instrumentation in the field was demonstrated by analyzing postblast residues in a mobile laboratory immediately after detonation of the explosive devices. Profiling the ionic composition of the inorganic IEDs allowed identification of the chemicals used in their construction. PMID- 17705453 TI - Electronic structures and bonding of CeF: a frozen-core four-component relativistic configuration interaction study. AB - We study the electronic structure of the ground and several low-lying states of the CeF molecule using Dirac-Fock-Roothaan (DFR) and four-component relativistic single and double excitation configuration interaction (SDCI) calculations in the reduced frozen-core approximation (RFCA). The ground state and two low-lying excited states are calculated to have (4f)1(5d)1(6s)1 configurations with Omega = 3.5, 4.5, and 3.5, and the resulting excitation energies, T0, are, respectively, 0.319 and 0.518 eV. The experimental configurations for these states are the same, although the experimental T0 values are approximately 0.3 eV smaller than those calculated. Experimentally, the red-degraded band was observed to be 2.181 eV above the ground state, having the configuration (4f)1(5d)1(6p)1 with Omega = 4.5. The calculation for this state gives 2.197 eV and configuration (4f)1.0(5d)1.7(6p)0.3 with Omega = 4.5. We found that Omega, Re, and nu(1-0) obtained by CI agree well with experiment. Bonding between the Ce and the F is highly ionic. The 4f, 5d, and 6s valence electrons are localized at the Ce+ ion, because they are attracted by the Ce4+ ion core, and are excluded from the bonding region because of the electronic cloud around the negatively charged fluoride anion. The bonding in the ground and excited states of the CeF molecule is significantly influenced by the 6s and 5d electron distributions between the Ce and the F. PMID- 17705452 TI - Stability of virtual air walls on micropallet arrays. AB - Arrays of micropallets have been used to pattern adherent cells as well to sort mixtures of cells. These artificial surfaces are composed of micrometer-sized, SU 8 structures formed on a hydrophobic glass surface. Successful application of these arrays requires stable Cassie-Baxter wetting by aqueous biological solutions. This paper systematically studies the factors governing the stability of Cassie-Baxter wetting on the arrays, including the surface properties of the array components as well as the physical and chemical properties of the wetting solutions. To establish stable Cassie-Baxter wetting with water, the surface of the array must be coated with a perfluoroalkylsilane of sufficient hydrophobicity, and the roughness of array must be greater than 1.6. Additionally, long-term stability of the Cassie-Baxter wetting depends on the properties of the wetting solutions, including the surface tension (>40 mM/m), salt concentration (>10 mM), and protein concentration (<5 mg/mL) of the wetting liquid. Under optimal conditions, Cassie-Baxter wetting of the micropallet array is stable for up to 1 month in the presence of tissue culture medium containing fetal calf serum. These experimental results provide critical information regarding the stability and endurance of the virtual air walls when the micropallet arrays are used as a bioanalytical tool. PMID- 17705454 TI - Effects of microsolvation on the adenine-uracil base pair and its radical anion: adenine-uracil mono- and dihydrates. AB - Microhydration effects upon the adenine-uracil (AU) base pair and its radical anion have been investigated by explicitly considering various structures of their mono- and dihydrates at the B3LYP/DZP++ level of theory. For the neutral AU base pair, 5 structures were found for the monohydrate and 14 structures for the dihydrate. In the lowest-energy structures of the neutral mono- and dihydrates, one and two water molecules bind to the AU base pair through a cyclic hydrogen bond via the N(9)-H and N(3) atoms of the adenine moiety, while the lowest-lying anionic mono- and dihydrates have a water molecule which is involved in noncyclic hydrogen bonding via the O4 atom of the uracil unit. Both the vertical detachment energy (VDE) and adiabatic electron affinity (AEA) of the AU base pair are predicted to increase upon hydration. While the VDE and AEA of the unhydrated AU pair are 0.96 and 0.40 eV, respectively, the corresponding predictions for the lowest-lying anionic dihydrates are 1.36 and 0.75 eV, respectively. Because uracil has a greater electron affinity than adenine, an excess electron attached to the AU base pair occupies the pi* orbital of the uracil moiety. When the uracil moiety participates in hydrogen bonding as a hydrogen bond acceptor (e.g., the N(6)-H(6a)...O(4) hydrogen bond between the adenine and uracil bases and the O(w)-H(w)...N and O(w)-H(w)...O hydrogen bonds between the AU pair and the water molecules), the transfer of the negative charge density from the uracil moiety to either the adenine or water molecules efficiently stabilizes the system. In addition, anionic structures which have C-H...O(w) contacts are energetically more favorable than those with N-H...O(w) hydrogen bonds, because the C-H...O(w) contacts do not allow the unfavorable electron density donation from the water to the uracil moiety. This delocalization effect makes the energetic ordering for the anionic hydrates very different from that for the corresponding neutrals. PMID- 17705455 TI - Total oxidation of methanol on Cu(110): a density functional theory study. AB - The partial and total oxidation of methanol on clean and oxygen-precovered Cu(110) has been studied by periodic density functional theory calculations within the generalized gradient approximation. Reaction paths including the geometry and the energetics of several reaction intermediates and the activation barriers between them have been determined, thus creating a complete scheme for methanol oxidation on copper. The calculations demonstrate that the specific structure of oxygen on copper plays an important role in both the partial and the total oxidation of methanol. For lower oxygen concentrations on the surface, the partial oxidation of methanol to formaldehyde is promoted by the presence of oxygen on the surface through the removal of hydrogen in the form of water, which prevents the recombinative desorption of methanol. At larger oxygen concentrations, the presence of isolated oxygen atoms reduces the C-H bond breaking barrier of adsorbed methoxy considerably, thus accelerating the formation of formaldehyde. Furthermore, oxygen also promotes the formation of dioxymethylene from formaldehyde, which then easily decays to formate. Formate is the most stable reaction intermediate in the total oxidation. Thus the formate decomposition represents the rate-limiting step in the total oxidation of methanol on copper. PMID- 17705456 TI - Molecular dynamics analysis of interfacial structures and sum frequency generation spectra of aqueous hydrogen halide solutions. AB - Molecular dynamics simulation for gas/liquid interfaces of aqueous hydrochloric (HCl) and hydroiodic (HI) acid solutions is performed to calculate and analyze their sum frequency generation (SFG) spectra. The present MD simulation supports the strong preference of hydronium ions at the topmost surface layer and a consequent formation of ionic double layers by the hydronium and halide ions near the interface. Accordingly, the orientational order of surface water in the double layers is reversed in the acid solutions from that in the salt (NaCl or NaI). The calculated SFG spectra of the O-H stretching region reproduce the experimental spectra of ssp and sps polarizations well. In the ssp spectra, the strong enhancement in the hydrogen-bonding region for the acid solutions is elucidated by two mechanisms, ordered orientation of water in the double layer and symmetric OH stretching of the surface hydronium ions. In the sps spectra, reversed orientation of surface water is evidenced in the spectral line shapes, which are quite different from those of the salt solutions. PMID- 17705457 TI - Visible absorption spectrum of the CH3CO radical. AB - The visible absorption spectrum of the acetyl radical, CH(3)CO, was measured between 490 and 660 nm at 298 K using cavity ring-down spectroscopy. Gas-phase CH(3)CO radicals were produced using several methods including: (1) 248 nm pulsed laser photolysis of acetone (CH(3)C(O)CH(3)), methyl ethyl ketone (MEK, CH(3)C(O)CH(2)CH(3)), and biacetyl (CH(3)C(O)C(O)CH(3)), (2) Cl + CH(3)C(O)H --> CH(3)C(O) + HCl with Cl atoms produced via pulsed laser photolysis or in a discharge flow tube, and (3) OH + CH(3)C(O)H --> CH(3)CO + H(2)O with two different pulsed laser photolysis sources of OH radicals. The CH(3)CO absorption spectrum was assigned on the basis of the consistency of the spectra obtained from the different CH(3)CO sources and agreement of the measured rate coefficients for the reaction of the absorbing species with O(2) and O(3) with literature values for the CH(3)CO + O(2) + M and CH(3)CO + O(3) reactions. The CH(3)CO absorption spectrum between 490 and 660 nm has a broad peak centered near 535 nm and shows no discernible structure. The absorption cross section of CH(3)CO at 532 nm was measured to be (1.1 +/- 0.2) x 10(-19) cm(2) molecule(-1) (base e). PMID- 17705458 TI - Magnetic resonance energies of heterocyclic conjugated molecules. AB - Magnetic resonance energy (MRE), derived from ring-current diamagnetic susceptibility, can be interpreted as a kind of aromatic stabilization energy. For polycyclic conjugated hydrocarbons, this quantity correlates well with topological resonance energy (TRE). MREs for typical heterocyclic conjugated molecules were then calculated and analyzed. It was found that even for heterocycles MRE highly correlates with TRE. Thus, the MRE concept has been firmly established as a reliable indicator of aromaticity, which mediates magnetic criteria of aromaticity with energetic ones. The conformity of heterocycles to the rule of topological charge stabilization can be checked using not only TRE but also MRE. PMID- 17705459 TI - External electric field effects on absorption, fluorescence, and phosphorescence spectra of diphenylpolyynes in a polymer film. AB - External electric field effects on absorption, fluorescence, and phosphorescence spectra of a series of unsubstituted diphenylpolyynes have been examined in a PMMA film. The analysis of the electroabsorption spectra indicates that the shorter diphenylpolyynes exhibit only the change in molecular polarizability, whereas the longer ones exhibit the change both in dipole moment and in molecular polarizability following absorption. The finding of the change in dipole moment following absorption of centrosymmetric diphenylpolyynes is interpreted in terms of the symmetry distortion upon doping a polymer film. When the external electric field is applied, the fluorescence yield is reduced and enhanced, respectively, in diphenylacetylene and diphenyloctatetrayne, indicating that the rate of the nonradiative process from the fluorescence state is accelerated in diphenylacetylene and decelerated in diphenyloctatetrayne by an external electric field. All of the diphenylpolyynes used in the present study exhibit the change in molecular polarizability following the phosphorescence process. PMID- 17705460 TI - Two-photon excited fluorescence of nitrogen-vacancy centers in proton-irradiated type Ib diamond. AB - Two-photon fluorescence spectroscopy of negatively charged nitrogen-vacancy [(N V)-] centers in type Ib diamond single crystals have been studied with a picosecond (7.5 ps) mode-locked Nd:YVO(4) laser operating at 1064 nm. The (N-V)- centers were produced by radiation damage of diamond using a 3 MeV proton beam, followed by thermal annealing at 800 degrees C. Prior to the irradiation treatment, infrared spectroscopy of the C-N vibrational modes at 1344 cm(-1) suggested a nitrogen content of 109 +/- 10 ppm. Irradiation and annealing of the specimen led to the emergence of a new absorption band peaking at approximately 560 nm. From a measurement of the integrated absorption intensity of the sharp zero-phonon line (637 nm) at liquid nitrogen temperature, we determined a (N-V)- density of (4.5 +/- 1.1) x 10(18) centers/cm3 (or 25 +/- 6 ppm) for the substrate irradiated at a dose of 1 x 1016) H(+)/cm(2). Such a high defect density allowed us to observe two-photon excited fluorescence and measure the corresponding fluorescence decay time. No significant difference in the spectral feature and fluorescence lifetime was observed between one-photon and two-photon excitations. Assuming that the fluorescence quantum yields are the same for both processes, a two-photon absorption cross section of sigma(TPA) = (0.45 +/- 0.23) x 10(-50) cm(4).s/photon at 1064 nm was determined for the (N-V)- center based on its one photon absorption cross section of sigma(OPA) = (3.1 +/- 0.8) x 10(-17) cm2 at 532 nm. The material is highly photostable and shows no sign of photobleaching even under continuous two-photon excitation at a peak power density of 3 GW/cm(2) for 5 min. PMID- 17705461 TI - The reactions of O(3P) with terminal alkenes: the H2CO channel via 3,2 H-atom shift. AB - The step-scan time-resolved FTIR emission spectroscopy is used to characterize systematically the H(2)CO channel for the reactions of O((3)P) with various alkenes. IR emission bands due to the products of CO, CO(2), and H(2)CO have been observed in the spectra. H(2)CO is identified to be the primary reaction product whereas CO and CO(2) are secondary reaction products of O((3)P) with alkenes. A general trend is observed in which the fraction yield of the H(2)CO product increases substantially as the reactant alkene varies from C(2)H(4), C(3)H(6), 1 C(4)H(8), iso-C(4)H(8), to 1-C(5)H(10). The formation mechanism of the H(2)CO is therefore elucidated to arise from a 3,2 H-atom shift followed by breaking of the C(1)-C(2) bond in the initially formed energized diradical RCH(2)CHCH(2)O*. The 3,2 H-atom shift may become the dominant process with the more rapid delocalization of the energy when the hydrocarbon chain of the alkene molecule is lengthened. PMID- 17705462 TI - Synthesis and biological evaluation of imidazoquinoxalinones, imidazole analogues of pyrroloiminoquinone marine natural products. AB - This report describes the synthesis and biological activity of imidazoquinoxalines, benzimidazole-based analogues of indole-based pyrroloiminoquinone marine natural products. Our analogues consist of series 1, which possesses the ethylene tether and extended amidine feature found in the pyrroloiminoquinone natural products, and series 2, which also has the ethylene tether but with an electrostatically stabilized iminoquinone rather than a resonance stabilized iminoquinone (i.e., extended amidine). The biological properties of series 1 analogues, bearing electron-rich side chain rings (indole and phenol), display cytostatic and cytotoxic properties similar to that of the pyrroloiminoquinone natural products. In contrast, COMPARE analysis suggests that analogues bearing benzyl and phenethyl side chains possess a different cytotoxicity mechanism. Hollow fiber assays of analogs of 1 indicate promising antitumor activity and acceptable levels of toxicity. One analogue of 2 is active only against breast cancer cell lines, but the cellular target is as yet unknown. PMID- 17705463 TI - Ontology aided modeling of organic reaction mechanisms with flexible and fragment based XML markup procedures. AB - The mechanism models for primary organic reactions encoding the structural fragments undergoing substitution, addition, elimination, and rearrangements are developed. In the proposed models, each and every structural component of mechanistic pathways is represented with flexible and fragment based markup technique in XML syntax. A significant feature of the system is the encoding of the electron movements along with the other components like charges, partial charges, half bonded species, lone pair electrons, free radicals, reaction arrows, etc. needed for a complete representation of reaction mechanism. The rendering of reaction schemes described with the proposed methodology is achieved with a concise XML extension language interoperating with the structure markup. The reaction scheme is visualized as 2D graphics in a browser by converting them into SVG documents enabling the desired layouts normally perceived by the chemists conventionally. An automatic representation of the complex patterns of the reaction mechanism is achieved by reusing the knowledge in chemical ontologies and developing artificial intelligence components in terms of axioms. PMID- 17705465 TI - Improving the performance of self-organizing maps via growing representations. AB - Self-organizing maps (SOMs) are a type of artificial neural network that through training can produce simplified representations of large, high dimensional data sets. These representations are typically used for visualization, classification, and clustering and have been successfully applied to a variety of problems in the pharmaceutical and bioinformatics domains. SOMs in these domains have generally been restricted to static sets of nodes connected in either a grid or hexagonal connectivity and planar or toroidal topologies. We investigate the impact of connectivity and topology on SOM performance, and experiments were performed on fixed and growing SOMs. Three synthetic and two relevant data sets from the chemistry domain were used for evaluation, and performance was assessed on the basis of topological and quantization errors after equivalent training periods. Although we found that all SOMs were roughly comparable at quantizing a data space, there was wide variation in the ability to capture its underlying structure, and growing SOMs consistently outperformed their static counterparts in regards to topological errors. Additionally, one growing SOM, the Neural Gas, was found to be far more capable of capturing details of a target data space, finding lower dimensional relationships hidden within higher dimensional representations. PMID- 17705464 TI - DrugScoreRNA--knowledge-based scoring function to predict RNA-ligand interactions. AB - There is growing interest in RNA as a drug target due to its widespread involvement in biological processes. To exploit the power of structure-based drug design approaches, novel scoring and docking tools need to be developed that can efficiently and reliably predict binding modes and binding affinities of RNA ligands. We report for the first time the development of a knowledge-based scoring function to predict RNA-ligand interactions (DrugScoreRNA). Based on the formalism of the DrugScore approach, distance-dependent pair potentials are derived from 670 crystallographically determined nucleic acid-ligand and -protein complexes. These potentials display quantitative differences compared to those of DrugScore (derived from protein-ligand complexes) and DrugScoreCSD (derived from small-molecule crystal data). When used as an objective function for docking 31 RNA-ligand complexes, DrugScoreRNA generates "good" binding geometries (rmsd (root mean-square deviation) < 2 A) in 42% of all cases on the first scoring rank. This is an improvement of 44% to 120% when compared to DrugScore, DrugScoreCSD, and an RNA-adapted AutoDock scoring function. Encouragingly, good docking results are also obtained for a subset of 20 NMR structures not contained in the knowledge-base to derive the potentials. This clearly demonstrates the robustness of the potentials. Binding free energy landscapes generated by DrugScoreRNA show a pronounced funnel shape in almost 3/4 of all cases, indicating the reduced steepness of the knowledge-based potentials. Docking with DrugScoreRNA can thus be expected to converge fast to the global minimum. Finally, binding affinities were predicted for 15 RNA-ligand complexes with DrugScoreRNA. A fair correlation between experimental and computed values is found (RS = 0.61), which suffices to distinguish weak from strong binders, as is required in virtual screening applications. DrugScoreRNA again shows superior predictive power when compared to DrugScore, DrugScoreCSD, and an RNA-adapted AutoDock scoring function. PMID- 17705467 TI - A CASPT2 study of the electronic spectrum of hexacyanoosmate(III). AB - CASPT2 calculations reveal that the ligand field splitting parameter Delta(o) of [Os(CN)6]3- is much higher than previously proposed values of +/-38,000 cm(-1). In line with the expected increase down a transition-metal group, Delta(o) is found to be +/-55,000 cm(-1), excluding the possible appearance of ligand field transitions in the UV-vis spectrum. Instead, the calculations confirm that the observed spectrum arises from the three lowest symmetry-allowed ligand-to-metal charge-transfer (LMCT) excitations. Spin-orbit coupling in the ground state is found to be about 4350 cm(-1), leading to a spin-orbit coupling constant zeta of +/-2900 cm(-1). Spin-orbit coupling in the 2T(1u) LMCT states is found not to be negligible, contrary to previous belief. PMID- 17705468 TI - Analysis of uranium azide and nitride complexes by atmospheric pressure chemical ionization mass spectrometry. AB - Atmospheric pressure chemical ionization mass spectrometry (APCI-MS) has been used to characterize the air-sensitive paramagnetic organouranium azide and nitride complexes [(C5Me5)2UN3(mu-N3)]3 and [(C5Me5)U(mu-I)2]3N, respectively. The trimetallic complex [(C5Me5)U(mu-I)2]3E had been identified by X-ray crystallography, but the data did not definitively identify E as N3- versus O2- or (OH)-, a common problem in heavy-element nitride complexes involving metals with variable oxidation states. A comparison of the 250 degrees C APCI-MS spectra of products made from NaN3 and Na15NNN showed mixed [M]+ and [M + H]+ envelopes at expected ion intensities for the 14N and 15N isotopomers. A compilation of U C(C5Me5) and U-I bond distance data for U3+ and U4+ is also reported that shows that the ranges for the two oxidation states have significant overlap. PMID- 17705469 TI - Radical (NO) and nonradical (N(2)O) reagents convert a ruthenium(IV) nitride to the same nitrosyl complex. AB - The ruthenium(IV) nitride complex (PNP)RuN (PNP = (tBu2PCH2-SiMe2)2N-) reacts rapidly with 2NO to form (PNP)Ru(NO) and N2O, via no detectable intermediate. The linear nitrosyl complex has a planar structure. In a slower reaction, (PNP)RuN reacts with N2O by O-atom transfer (established by 15N labeling) to give the same nitrosyl complex and N2. Density functional theory (B3LYP) calculations show both reactions to be very thermodynamically favorable. Analysis of possible intermediates in each reaction shows that radical (PNP)RuN(NO) has much spin density on nitride N (hence, N2-), while one 2 + 3 metallacycle, (PNP)RuN3O, has the wrong connectivity to form a product. Instead, an intermediate with a doubly bent N2O (hence, a two-electron reduced N-nitrosoimide form) brings the O atom in proximity to the nitride N on the path to a product. PMID- 17705470 TI - The solventless syntheses of unique PbS nanowires of X-shaped cross sections and the cooperative effects of ethylenediamine and a second salt. AB - Unique PbS nanowires with x-shaped cross sections, with diameters in the range of 300-800 nm with an average of 598 nm (sigma = +/-21.7% ), and lengths of up to several tens of micrometers, have been made by a solventless method. Such nanowires show high adsorptivities of the PbS nanooctahedra, which can be washed off by ultrasound. The suitable precursor is obtained from a Pb(NO3)2/octanoate/ethylenediamine/dodecanethiol molar ratio of 1:2:1:1.6, and the PbS nanowires are produced by the thermolysis of such precursors at 280 degrees C for 1 hour. The X-ray diffraction, scanning electron microscopy, and transmission electron microscopy characterizations of the products and the keys of the morphological control have been reported. For the formation of such products, two cooperative effects are found to be crucial, the roles of ethylenediamine and a second salt, lead octanonate. PMID- 17705471 TI - Germanium phthalocyanine, GePc, and the reduced complexes SiPc(pyridine)(2) and GePc(pyridine)(2) containing antiaromatic pi-electron circuits. AB - The reaction of GeCl2(dioxane) with K2Pc(DMF)4 yields germanium phthalocyanine, GePc. GePc dissolves in pyridine to form GePc(py)2. The 1H NMR spectrum of GePc(py)2 and nucleus-independent chemical shift (NICS) calculations on GePc(NMe3)2 both show the presence of a strong paratropic ring current. That ring current, along with the bond-length alternation in the crystal structure of GePc(tBuPy)2, indicates the presence of an antiaromatic pi-electron circuit in GePc(py)2. SiPc(py)2 was synthesized, and its electronic structure is similar to that of GePc(py)2. PMID- 17705473 TI - Crystal structure of a cerium(IV) bis(phosphate) derivative. PMID- 17705472 TI - Characterization of polymorphs and solid-state reactions for paramagnetic systems by 13C solid-state NMR and ab initio calculations. PMID- 17705474 TI - Specificity of acyl transfer from 2-mercaptobenzamide thioesters to the HIV-1 nucleocapsid protein. AB - The HIV-1 nucleocapsid protein (NCp7) is a small, highly conserved protein with two zinc-binding domains that are essential for the protein's function. Molecules that bind to and inactivate NCp7 are currently being evaluated as new antiviral drugs. In particular, derivatives based on a 2-mercaptobenzamide thioester template have been shown to specifically eject zinc from the C-terminal zinc binding domain (ZD2) of NCp7 via acyl transfer from the thioester to a cysteine sulfur. In this study, mutational analysis of the NCp7 amino acid sequence has been used to investigate the specificity of the interaction between ZD2 and a 2 mercaptobenzamide thioester compound using UV-vis spectroscopy and mass spectrometry to monitor the rate of metal ejection from NCp7 mutant peptides and sites of acylation, respectively. We were able to extend the previously reported mechanism of action of these thioester compounds to include a secondary S to N intramolecular acyl transfer that occurs after the primary acyl transfer from the thioester to a cysteine side chain in the protein. Structural models of the thioester/ZD2 complex were then examined to identify the most likely binding orientation. We determined that position x+1 (where x is Cys36) needs to be an aromatic residue for reactivity and a hydrogen-bond donor in position x+9 is important for optimal reactivity. A basic residue (lysine or arginine) is required at position x+2 for the correct fold, while a lysine residue is needed for reactivity involving S to N acyl transfer. We report highly specific interactions between 2-mercaptobenzamide thioester compounds and NCp7 that offer a structural basis for refining and designing new antiretroviral therapeutics, directed toward a target that is resistant to viral mutation. PMID- 17705475 TI - Modeling [Fe-Fe] hydrogenase: evidence for bridging carbonyl and distal iron coordination vacancy in an electrocatalytically competent proton reduction by an iron thiolate assembly that operates through Fe(0)-Fe(II) levels. AB - IR spectroelectrochemistry of Fe4{Me(CH2S)3}2(CO)8 (4Fe6S) in the nu(CO) region shows that the neutral and anion forms have all their CO groups terminally bound to the Fe atoms; however, for the dianion there is a switch of the coordination mode of at least one of the CO groups. The available structural and nu(CO) spectra are closely reproduced by density-functional theory calculations. The calculated structure of 4Fe6S2- closely mirrors that of the diiron subsite of the [Fe-Fe] hydrogenase H cluster with a bridging CO group and an open coordination site on the outer Fe atom of pairs of dithiolate-bridged Fe0FeII subunits connected by two bridging thiolates. Geometry optimization based on the all terminal CO isomer of 4Fe6S2- does not give a stable structure but reveals a second-order saddle point ca. 11.53 kcal mol(-1) higher in energy than the CO bridged form. Spectroelectrochemical studies of electrocatalytic proton reduction by 4Fe6S show that slow turnover from the primary reduction process (E1/2'=-0.71 V vs Ag/AgCl) involves rate-limiting protonation of 4Fe6S- followed by reduction to H:4Fe6S-. Rapid electrocatalytic proton reduction is obtained at potentials sufficient to access 4Fe6S2-, where the rate of dihydrogen elimination from the FeIIFeII core of 4Fe6S is ca. 500 times faster than that from the FeIFeI core of Fe2(mu-S(CH2)3S)(CO)6. The dramatically increased rate of electrocatalysis obtained from 4Fe6S over all previously identified model compounds appears to be related to the features uniquely common between it and the H-cluster, namely, that turnover involves the same formal redox states of the diiron unit (FeIFeII and Fe0FeII), the presence of an open site on the outer Fe atom of the Fe0FeII unit, and the thiolate-bridge to a second one-electron redox unit. PMID- 17705476 TI - Conformational adaptation and selective adatom capturing of tetrapyridyl porphyrin molecules on a copper (111) surface. AB - We present a combined low-temperature scanning tunneling microscopy and near-edge X-ray adsorption fine structure study on the interaction of tetrapyridyl porphyrin (TPyP) molecules with a Cu(111) surface. A novel approach using data from complementary experimental techniques and charge density calculations allows us to determine the adsorption geometry of TPyP on Cu(111). The molecules are centered on "bridge" sites of the substrate lattice and exhibit a strong deformation involving a saddle-shaped macrocycle distortion as well as considerable rotation and tilting of the meso-substituents. We propose a bonding mechanism based on the pyridyl-surface interaction, which mediates the molecular deformation upon adsorption. Accordingly, a functionalization by pyridyl groups opens up pathways to control the anchoring of large organic molecules on metal surfaces and tune their conformational state. Furthermore, we demonstrate that the affinity of the terminal groups for metal centers permits the selective capture of individual iron atoms at low temperature. PMID- 17705477 TI - Encapsidation of nanoparticles by red clover necrotic mosaic virus. AB - Icosahedral virus capsids demonstrate a high degree of selectivity in packaging cognate nucleic acid genome components during virion assembly. The 36 nm icosahedral plant virus Red clover necrotic mosaic virus (RCNMV) packages its two genomic ssRNAs via a specific capsid protein (CP) genomic RNA interaction. A 20 nucleotide hairpin structure within the genomic RNA-2 hybridizes with RNA-1 to form a bimolecular complex, which is the origin of assembly (OAS) in RCNMV that selectively recruits and orients CP subunits initiating virion assembly. In this Article, an oligonucleotide mimic of the OAS sequence was attached to Au, CoFe2O4, and CdSe nanoparticles ranging from 3 to 15 nm, followed by addition of RNA-1 to form a synthetic OAS to direct the virion-like assembly by RCNMV CP. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) measurements were consistent with the formation of virus-like particles (VLPs) comparable in size to native RCNMV. Attempts to encapsidate nanoparticles with diameters larger than 17 nm did not result in well-formed viral capsids. These results are consistent with the presence of a 17 nm cavity in native RCNMV. Covalent linkage of the OAS to nanoparticles directs RNA-dependent encapsidation and demonstrates that foreign cargo can be packaged into RCNMV virions. The flexibility of the RCNMV CP to encapsidate different materials, as long as it is within encapsidation constraint, is a critical factor to be considered as a drug delivery and diagnostic vehicle in biomedical applications. PMID- 17705478 TI - Residual dipolar couplings by off-magic-angle spinning in solid-state nuclear magnetic resonance spectroscopy. PMID- 17705479 TI - Design of cationic conjugated polyelectrolytes for DNA concentration determination. AB - Cationic conjugated polyelectrolytes poly110 and poly120 were designed, synthesized, and characterized with the anticipation of function in the determination of double-stranded DNA concentration [dsDNA]. Their structures contain a pi-delocalized optically active backbone composed of phenylene-fluorene segments copolymerized with 2,1,3-benzothiadiazole (BT) units and charged pendant groups that allow excellent solubility in water. The subscript in poly1x refers to the molar percent of BT units in the chain. Addition of dsDNA to poly110 or poly120 results in a change in the color of emission from blue to green. These spectral changes can be treated to obtain the parameter delta, which can be used to generate calibration curves that indicate [dsDNA]. Analysis of photoluminescence spectra reveals that dsDNA addition gives rise to more efficient FRET from blue emitting segments to the BT sites, an increase in the BT emission quantum yield, and partial quenching of the phenylene-fluorene segments. Studies were also carried out to maximize the range of [dsDNA] determination. We find that by combining the response from two different initial concentrations of poly110, it is possible to generate calibration curves that respond with a difference in [dsDNA] of over 7 orders of magnitude. PMID- 17705480 TI - Phosphate-mediated arginine insertion into lipid membranes and pore formation by a cationic membrane peptide from solid-state NMR. AB - The insertion of charged amino acid residues into the hydrophobic part of lipid bilayers is energetically unfavorable yet found in many cationic membrane peptides and protein domains. To understand the mechanism of this translocation, we measured the (13)C-(31)P distances for an Arg-rich beta-hairpin antimicrobial peptide, PG-1, in the lipid membrane using solid-state NMR. Four residues, including two Arg's, scattered through the peptide were chosen for the distance measurements. Surprisingly, all residues show short distances to the lipid (31)P: 4.0-6.5 A in anionic POPE/POPG membranes and 6.5-8.0 A in zwitterionic POPC membranes. The shortest distance of 4.0 A, found for a guanidinium Czeta at the beta-turn, suggests N-H...O-P hydrogen bond formation. Torsion angle measurements of the two Arg's quantitatively confirm that the peptide adopts a beta-hairpin conformation in the lipid bilayer, and gel-phase 1H spin diffusion from water to the peptide indicates that PG-1 remains transmembrane in the gel phase of the membrane. For this transmembrane beta-hairpin peptide to have short (13)C-(31)P distances for multiple residues in the molecule, some phosphate groups must be embedded in the hydrophobic part of the membrane, with the local (31)P plane parallel to the beta-strand. This provides direct evidence for toroidal pores, where some lipid molecules change their orientation to merge the two monolayers. We propose that the driving force for this toroidal pore formation is guanidinium phosphate complexation, where the cationic Arg residues drag the anionic phosphate groups along as they insert into the hydrophobic part of the membrane. This phosphate-mediated translocation of guanidinium ions may underlie the activity of other Arg-rich antimocrobial peptides and may be common among cationic membrane proteins. PMID- 17705481 TI - Tangential ligand-induced strain in icosahedral Au13. PMID- 17705482 TI - Buffer-assisted proton-coupled electron transfer in a model rhenium-tyrosine complex. AB - The mechanism for tyrosyl radical generation in the [Re(P-Y)(phen)(CO)3]PF6 complex is investigated with a multistate continuum theory for proton-coupled electron transfer (PCET) reactions. Both water and the phosphate buffer are considered as potential proton acceptors. The calculations indicate that the model in which the proton acceptor is the phosphate buffer species HPO(4)2- can successfully reproduce the experimentally observed pH dependence of the overall rate and H/D kinetic isotope effect, whereas the model in which the proton acceptor is water is not physically reasonable for this system. The phosphate buffer species HPO4(2-) is favored over water as the proton acceptor in part because the proton donor-acceptor distance is approximately 0.2 A smaller for the phosphate acceptor due to its negative charge. The physical quantities impacting the overall rate constant, including the reorganization energies, reaction free energies, activation free energies, and vibronic couplings for the various pairs of reactant/product vibronic states, are analyzed for both hydrogen and deuterium transfer. The dominant contribution to the rate arises from nonadiabatic transitions between the ground reactant vibronic state and the third product vibronic state for hydrogen transfer and the fourth product vibronic state for deuterium transfer. These contributions dominate over contributions from lower product states because of the larger vibronic coupling, which arises from the greater overlap between the reactant and product vibrational wave functions. These calculations provide insight into the fundamental mechanism of tyrosyl radical generation, which plays an important role in a wide range of biologically important processes. PMID- 17705483 TI - The lanthanide contraction revisited. AB - A complete, isostructural series of complexes with La-Lu (except Pm) with the ligand TREN-1,2-HOIQO has been synthesized and structurally characterized by means of single-crystal X-ray analysis. All complexes are 1D-polymeric species in the solid state, with the lanthanide being in an eight-coordinate, distorted trigonal-dodecahedral environment with a donor set of eight unique oxygen atoms. This series constitutes the first complete set of isostructural complexes from La Lu (without Pm) with a ligand of denticity greater than two. The geometric arrangement of the chelating moieties slightly deviates across the lanthanide series, as analyzed by a shape parameter metric based on the comparison of the dihedral angles along all edges of the coordination polyhedron. The apparent lanthanide contraction in the individual Ln-O bond lengths deviates considerably from the expected quadratic decrease that was found previously in a number of complexes with ligands of low denticity. The sum of all bond lengths around the trivalent metal cation, however, is more regular, showing an almost ideal quadratic behavior across the entire series. The quadratic nature of the lanthanide contraction is derived theoretically from Slater's model for the calculation of ionic radii. In addition, the sum of all distances along the edges of the coordination polyhedron show exactly the same quadratic dependence as the Ln-X bond lengths. The universal validity of this coordination sphere contraction, concomitant with the quadratic decrease in Ln-X bond lengths, was confirmed by reexamination of four other, previously published series of lanthanide complexes. Owing to the importance of multidentate ligands for the chelation of rare-earth metals, this result provides a significant advance for the prediction and rationalization of the geometric features of the corresponding lanthanide complexes, with great potential impact for all aspects of lanthanide coordination. PMID- 17705484 TI - Modular total chemical synthesis of a human immunodeficiency virus type 1 protease. AB - As part of our ongoing studies of the human immunodeficiency virus type 1 (HIV-1) protease enzyme, we set out to develop a modular chemical synthesis of the protein from multiple peptide segments. Our initial attempts were frustrated by the insolubility of intermediate peptide products. To overcome this problem, we designed a synthetic strategy combining the solubility-enhancing properties of C terminal (Arg)n tags and the biological phenomenon of autoprocessing of the Gag Pol polyprotein that occurs during maturation of the HIV-1 virus in vivo. Synthesis of a 119-residue peptide chain containing 10 residues of the reverse transcriptase (RT) open reading frame plus an (Arg)(10) tag at the C-terminus was straightforward by native chemical ligation followed by conversion of the Cys residues to Ala by Raney nickel desulfurization. The product polypeptide itself completed the final synthetic step by removing the C-terminal modification under folding conditions, to give the mature 99-residue polypeptide. High-purity homodimeric HIV-1 protease protein was obtained in excellent yield and had full enzymatic activity; the structure of the synthetic enzyme was confirmed by X-ray crystallography to a resolution of 1.07 A. This efficient modular synthesis by a biomimetic autoprocessing strategy will enable the facile synthesis of unique chemical analogues of the HIV-1 protease to further elucidate the molecular basis of enzyme catalysis. PMID- 17705485 TI - High-enthalpy hydrogen adsorption in cation-exchanged variants of the microporous metal-organic framework Mn3[(Mn4Cl)3(BTT)8(CH3OH)10]2. AB - Exchange of the guest Mn2+ ions in Mn3[(Mn4Cl)3(BTT)8(CH3OH)10]2 (1-Mn2+; BTT=1,3,5-benzenetristetrazolate) with selected cations results in the formation of isostructural framework compounds 1-M (M=Li+, Cu+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+). Similar to the parent compound, the new microporous materials are stable to desolvation and exhibit a high H2 storage capacity, ranging from 2.00 to 2.29 wt % at 77 K and 900 torr. Measurements of the isosteric heat of adsorption at zero coverage reveal a difference of 2 kJ/mol between the weakest and strongest H2-binding materials, which is attributed to variations in the strength of interaction between H2 molecules and unsaturated metal centers within each framework. The Co2+-exchanged compound, 1-Co2+, exhibits an initial enthalpy of adsorption of 10.5 kJ/mol, the highest yet observed for a microporous metal organic framework. PMID- 17705486 TI - Quantitative analysis of carbohydrate-protein interactions using glycan microarrays: determination of surface and solution dissociation constants. AB - Carbohydrate-protein interactions on surface and in solution were quantitatively measured by a glycan microarray. Assessing carbohydrate affinities is typically difficult due to weak affinities and limited sources of structurally complex glycans. We described here a sensitive, high-throughput, and convenient glycan microarray technology for the simultaneous determination of a wide variety of parameters in a single experiment using small amounts of materials. Assay systems based on this technology were developed to analyze multivalent interactions and determine the surface dissociation constant (KD,surf) for surface-coated mannose derivatives with mannose binding lectins and antibodies. Competition experiments that employed monovalent ligands in solution yielded KD and Ki values in solution similar to equilibrium binding constants obtained in titration microcalorimetry and surface plasmon resonance experiments. PMID- 17705487 TI - Topotactic oxidative and reductive control of the structures and properties of layered manganese oxychalcogenides. AB - Topotactic modification, by both oxidation and reduction, of the composition, structures, and magnetic properties of the layered oxychalcogenides Sr4Mn3O7.5Cu2Ch2 (Ch=S, Se) is described. These Mn3+ compounds are composed of alternating perovskite-type strontium manganese oxide slabs separated by anti fluorite-type copper chalcogenide layers and are intrinsically oxide deficient in the central layer of the perovskite slabs. The systems are unusual examples of perovskite-related compounds that may topotactically be both oxidized by fluorination and reduced by deintercalation of oxygen from the oxide-deficient part of the structure. The compounds exhibit antiferromagnetic ordering of the manganese magnetic moments in the outer layers of the perovskite slabs, while the other moments, in the central layers, exhibit spin-glass-like behavior. Fluorination has the effect of increasing the antiferromagnetic ordering temperature and the size of the ordered moment, whereas reduction destroys magnetic long-range order by introducing chemical disorder which leads to both further disorder and frustration of the magnetic interactions in the manganese oxide slab. PMID- 17705488 TI - An oxidosqualene cyclase makes numerous products by diverse mechanisms: a challenge to prevailing concepts of triterpene biosynthesis. AB - The genome of the model plant Arabidopsis thaliana encodes 13 oxidosqualene cyclases, 9 of which have been characterized by heterologous expression in yeast. Here we describe another cyclase, baruol synthase (BARS1), which makes baruol (90%) and 22 minor products (0.02-3% each). This represents as many triterpenes as have been reported for all other Arabidopsis cyclases combined. By accessing an extraordinary repertoire of mechanistic pathways, BARS1 makes numerous skeletal types and deprotonates the carbocation intermediates at 14 different sites around rings A, B, C, D, and E. This undercurrent of structural and mechanistic diversity in a superficially accurate enzyme is incompatible with prevailing concepts of triterpene biosynthesis, which posit tight control over the mechanistic pathway through cation-pi interactions, with a single proton acceptor in a hydrophobic active site. Our findings suggest that mechanistic diversity is the default for triterpene biosynthesis and that product accuracy results from exclusion of alternative pathways. PMID- 17705489 TI - Detection and memory of nonracemic molecules by a racemic host polymer film. PMID- 17705490 TI - Unraveling solvent-driven equilibria between alpha- and 3(10)-helices through an integrated spin labeling and computational approach. AB - In this work we present an effective and flexible computational approach, which is the result of an ongoing development in our groups, allowing the complete a priori simulation of the ESR spectra of complex systems in solution. The usefulness and reliability of the method are demonstrated on the very demanding playground represented by the tuning of the equilibrium between 3(10)- and alpha helices of polypeptides by different solvents. The starting point is the good agreement between computed and X-ray diffraction structures for the 3(10)-helix adopted by the double spin-labelled heptapeptide Fmoc-(Aib-Aib-TOAC)2-Aib-OMe. Next, density functional computations, including dispersion interactions and bulk solvent effects, suggest another energy minimum corresponding to an alpha-helix in polar solvents, which, eventually, becomes the most stable structure. Computation of magnetic and diffusion tensors provides the basic ingredients for the building of complete spectra by methods rooted in the Stochastic Liouville Equation (SLE). The remarkable agreement between computed and experimental spectra at different temperatures allowed us to identify helical structures in the various solvents. The generality of the computational strategy and its implementation in effective and user-friendly computer codes pave the route toward systematic applications in the field of biomolecules and other complex systems. PMID- 17705491 TI - C-H bond activation by hyperconjugation with Al-C bonds and by chelating coordination of the hydride ion. AB - On treating di(tert-butyl)butadiyne with dimethylaluminum hydride under different reaction conditions two unprecedented organoelement compounds, containing cationic carbon atoms stable in solution at room temperature, were obtained. A vinyl cation (2) in which the cationic carbon atom is part of a C=C double bond was produced from 3 equiv of the hydride, whereas a large excess of the hydride yielded an aliphatic carbocation (3) by complete hydroalumination of all C-C multiple bonds. Each compound is zwitterionic with the hydride counterion effectively coordinated in a chelating manner by two strongly Lewis acidic aluminum atoms. In agreement with quantum-chemical calculations the C-H bond activation and the stabilization of the cationic species are further supported by a strong hyperconjugation with Al-C single bonds. This considerably diminishes the effective positive charge at the respective cationic carbon atoms. PMID- 17705492 TI - Probing the cross-beta core structure of amyloid fibrils by hydrogen-deuterium exchange deep ultraviolet resonance Raman spectroscopy. PMID- 17705493 TI - [2+2] cycloaddition reactions with a tungsten-stabilized 2H-phenol. PMID- 17705495 TI - Dehydrogenative coupling of 4-substituted pyridines catalyzed by diruthenium complexes. PMID- 17705494 TI - Genetic engineering of the heme pocket in human serum albumin: modulation of O2 binding of iron protoporphyrin IX by variation of distal amino acids. AB - Complexing an iron protoporphyrin IX into a genetically engineered heme pocket of recombinant human serum albumin (rHSA) generates an artificial hemoprotein, which can bind O2 in much the same way as hemoglobin (Hb). We previously demonstrated a pair of mutations that are required to enable the prosthetic heme group to bind O2 reversibly: (i) Ile-142-->His, which is axially coordinated to the central Fe2+ ion of the heme, and (ii) Tyr-161-->Phe or Leu, which makes the sixth coordinate position available for ligand interactions [I142H/Y161F (HF) or I142H/Y161L (HL)]. Here we describe additional new mutations designed to manipulate the architecture of the heme pocket in rHSA-heme complexes by specifically altering distal amino acids. We show that introduction of a third mutation on the distal side of the heme (at position Leu-185, Leu-182, or Arg 186) can modulate the O2 binding equilibrium. The coordination structures and ligand (O2 and CO) binding properties of nine rHSA(triple mutant)-heme complexes have been physicochemically and kinetically characterized. Several substitutions were severely detrimental to O2 binding: for example, Gln-185, His-185, and His 182 all generated a weak six-coordinate heme, while the rHSA(HF/R186H)-heme complex possessed a typical bis-histidyl hemochrome that was immediately autoxidized by O2. In marked contrast, HSA(HL/L185N)-heme showed very high O2 binding affinity (P1/2O2 1 Torr, 22 degrees C), which is 18-fold greater than that of the original double mutant rHSA(HL)-heme and very close to the affinities exhibited by myoglobin and the high-affinity form of Hb. Introduction of Asn at position 185 enhances O2 binding primarily by reducing the O2 dissociation rate constant. Replacement of polar Arg-186 with Leu or Phe increased the hydrophobicity of the distal environment, yielded a complex with reduced O2 binding affinity (P1/2O2 9-10 Torr, 22 degrees C), which nevertheless is almost the same as that of human red blood cells and therefore better tuned to a role in O2 transport. PMID- 17705496 TI - Multiparameter fluorescence spectroscopy of single quantum dot-dye FRET hybrids. PMID- 17705497 TI - Engineering a monomeric miniature protein. PMID- 17705498 TI - High-affinity pyrophosphate receptor by a synergistic effect between metal coordination and hydrogen bonding in water. AB - We have developed the tightest binding PPi receptor reported to date by a combination of metal coordination and hydrogen bonding interaction in water. PMID- 17705499 TI - Carbon networks based on benzocyclynes. 6. synthesis of graphyne substructures via directed alkyne metathesis. AB - Intramolecular ring closing alkyne metathesis afforded the graphyne biscyclyne (3) in high macrocyclization yield and good overall yield. This methodology also furnished the tris[12]cyclyne 4, which contains the longest linear diphenylacetylene conjugation pathway for any graphyne substructure based on the tribenzo[12]cyclyne core. PMID- 17705500 TI - Enhancing regiocontrol in carboaluminations of terminal alkynes. Application to the one-pot synthesis of coenzyme Q10. AB - Two new "generations" of methodological advances are reported for the Negishi carboalumination of terminal alkynes. Use of simple, inexpensive additives that alter the Al-Zr complex formed between Me(3)Al and Cp(2)ZrCl(2) give rise to an especially effective reagent mix that results in virtually complete control of regiochemistry upon carboalumination of 1-alkynes. One timely application to coenzyme Q10 is highlighted. Regioisomers from subsequent coupling, which would otherwise be very difficult to separate, are avoided. PMID- 17705501 TI - Palladium-catalyzed silylation of aryl chlorides with hexamethyldisilane. AB - A method for the palladium-catalyzed silylation of aryl chlorides has been developed. The method affords desired product in good yield, is tolerant of a variety of functional groups, and provides access to a wide variety of aryltrimethylsilanes from commercially available aryl chlorides. Additionally, a one-pot procedure that converts aryl chlorides into aryl iodides has been developed. PMID- 17705503 TI - Interrupted nazarov reactions using dichlorocyclopropanes: a novel mode of arene trapping. AB - 2-Siloxy-2-alkenyl-1,1-dichlorocyclopropanes with aryl-terminated side chains undergo silver-assisted electrocyclic opening/Nazarov cyclization. The resulting 2-siloxycyclopentenyl cations are intercepted by the pendant arenes to furnish tricyclic adducts in moderate to good yields. In cases where the arene trap was tethered through the cyclopropane unit, a new mode of trapping occurred to generate unique bridged carbon frameworks. PMID- 17705502 TI - Enantioselective reductive coupling of 1,3-enynes to glyoxalates mediated by hydrogen: asymmetric synthesis of beta,gamma-unsaturated alpha-hydroxy esters. AB - Catalytic hydrogenation of 1,3-enynes 1a-8a in the presence of ethyl glyoxalate at ambient pressure and temperature using a rhodium catalyst modified by (R)-(3,5 tBu-4-MeOPh)-MeO-BIPHEP results in highly regio- and enantioselective reductive coupling to furnish the corresponding alpha-hydroxy esters 1b-8b. As demonstrated by the elaboration of alpha-hydroxy ester 1b, the terminal and internal olefin moieties embodied by the diene side chain are subject to selective manipulation, one over the other. PMID- 17705504 TI - Total syntheses of brominated marine sponge alkaloids. AB - Total syntheses of six brominated marine sponge bis(indole) alkaloids of the hamacanthin, spongotine, and topsentin classes are described. Retrosynthetic analysis shows that their structures all include the 1-(6'-bromoindol-3'-yl)-1,2 diaminoethane unit 13a. This key moiety has been prepared from brominated indolic N-hydroxylamine 5b via synthetic intermediate 8b. PMID- 17705505 TI - Two syntheses of (-)-kainic acid via highly stereoselective zinc-ene cyclizations. AB - Two concise, high-yielding syntheses of enantioenriched (-)-kainic acid are presented. Both routes feature a Pd-catalyzed Zn-ene cyclization that proceeds with complete diastereoselectivity. The key step can be carried out on a multigram scale, and the overall yields are among the highest to date for this marine alkaloid. PMID- 17705506 TI - Recombinant synthesis of hyaluronan by Agrobacterium sp. AB - Hyaluronan (HA) is a sugar polymer of a repeating disaccharide, beta1-3 D-N acetylglucosamine (GlcNAc) beta1-4 D-glucuronic acid (GlcA). It finds applications in numerous biomedical procedures such as ophthalmic surgery and osteoarthritis treatment. Until recently, the only commercial sources were extraction of rooster combs and from fermentation of pathogenic Streptococcus. In this work, we demonstrate that metabolic engineering strategies enable the recombinant synthesis of hyaluronan in a safe microorganism. Agrobacterium sp. ATCC 31749 is a commercial production strain for a food polymer, Curdlan. A broad host range expression vector was successfully developed to express the 3 kb HA synthase gene from Pasteurella multocida, along with a kfiD gene encoding UDP glucose dehydrogenase from Escherichia coli K5 strain. Coexpression of these two heterologous enzymes enables Agrobacterium to produce HA. Hyaluronan was accumulated up to 0.3 g/L in shaker flask cultivation. The molecular weight of the polymer from various Agrobacterium strains is in the range of 0.7-2 MD. To our knowledge, this is the first successful recombinant hyaluronan synthesis in a Gram-negative bacterium that naturally produces a food product. The ease of genetic modifications provides future opportunities to tailor properties of polymers for specific applications. PMID- 17705508 TI - TgCRND8 amyloid precursor protein transgenic mice exhibit an altered gamma secretase processing and an aggressive, additive amyloid pathology subject to immunotherapeutic modulation. AB - We investigated the morphology and biochemistry of the amyloid-beta (Abeta) peptides produced in TgCRND8 Tg mice carrying combined amyloid precursor protein (APP) Swedish (K670M/N671L) and Indiana (V717F) mutations. Histological analyses employing amyloid-specific staining and electron microscopy revealed that the TgCRND8 Tg mice produce an aggressive pathology, evident as early as 3 months of age, that is a composite of core plaques and peculiar floccular diffuse parenchymal deposits. The Abeta peptides were purified using combined FPLC-HPLC, Western blots, and immunoprecipitation methods and characterized by MALDI TOF/SELDI-TOF mass spectrometry. The C-terminal APP peptides, assessed by Western blot experiments and mass spectrometry, suggested an alteration in the order of secretase processing, yielding a C-terminal fragment pattern that is substantially different from that observed in sporadic Alzheimer's disease (AD). This modified processing pattern generated longer Abeta peptides, as well as those ending at residues 40/42/43, which may partially explain the early onset and destructive nature of familial AD caused by APP mutations. Despite an aggressive pathology that extended to the cerebellum and white matter, these animals tolerated the presence of an imposing amount of Abeta load. Abeta immunization resulted in an impressive 7-fold reduction in the number of amyloid core plaques and, as previously demonstrated, a significant memory recovery. However, given the phylogenetic distance and the differences in APP processing and Abeta chemistry between Tg mice and AD, caution should be applied in projecting mouse therapeutic interventions onto human subjects. PMID- 17705507 TI - Cytotoxic ribonucleases: the dichotomy of Coulombic forces. AB - Cells tightly regulate their contents. Still, nonspecific Coulombic interactions between cationic molecules and anionic membrane components can lead to adventitious endocytosis. Here, we characterize this process in a natural system. To do so, we create variants of human pancreatic ribonuclease (RNase 1) that differ in net molecular charge. By conjugating a small-molecule latent fluorophore to these variants and using flow cytometry, we are able to determine the kinetic mechanism for RNase 1 internalization into live human cells. We find that internalization increases with solution concentration and is not saturable. Internalization also increases with time to a steady-state level, which varies linearly with molecular charge. In contrast, the rate constant for internalization (t1/2 = 2 h) is independent of charge. We conclude that internalization involves an extracellular equilibrium complex between the cationic proteins and abundant anionic cell-surface molecules, followed by rate limiting internalization. The enhanced internalization of more cationic variants of RNase 1 is, however, countered by their increased affinity for the cytosolic ribonuclease inhibitor protein, which is anionic. Thus, Coulombic forces mediate extracellular and intracellular equilibria in a dichotomous manner that both endangers cells and defends them from the potentially lethal enzymatic activity of ribonucleases. PMID- 17705510 TI - Silver hierarchical bowl-like array: synthesis, superhydrophobicity, and optical properties. AB - We present a facile synthetic route to a silver bowl-like array film with hierarchical structures on glass substrate using the colloidal monolayer as a template. In these special hierarchical structures, microstructures were provided by a colloidal template of polystyrene latex spheres and nanostructures resulting from the thermal decomposition of silver acetate. These structures were chemically modified with 1-hexadecanethiol, and a corresponding self-assembled monolayer (SAM) was formed on their surfaces. Due to the lotus leaf-like morphology with hierarchical micro/nanostructures, the film displayed an extraordinary superhydrophobicity after chemical modification. Water contact angle and sliding angle were 169 degrees and 3 degrees (the weight of water droplets: 3 mg), respectively. Additionally, its optical property has also been investigated. This structure could be used in microfluidic devices, optical devices, and biological science. PMID- 17705509 TI - Binding of TPX2 to Aurora A alters substrate and inhibitor interactions. AB - The Aurora kinases are a family of serine/threonine kinases involved in mitosis. The expression of AurA is ubiquitous and cell cycle regulated. It is overexpressed in many tumor types, including breast, colon, and ovarian. TPX2 is a binding partner and activator of AurA. A fragment of TPX2 (residues 1-43) has been shown to be sufficient for binding, kinase activation, and protection from dephosphorylation. We have shown that the addition of TPX2(1-43) increases the catalytic efficiency of AurA. While TPX2 binding has no effect on the turnover number of AurA and does not change the reaction mechanism (characterized here to be a rapid equilibrium random mechanism), it increases the binding affinity of both ATP and a peptide substrate. We have also demonstrated differences in the inhibitor structure-activity relationship (SAR) in the presence or absence of TPX2(1-43). To better understand the differential SAR, we carried out computer modeling studies to gain insight into the effect of TPX2 on the binding interactions between AurA and inhibitors. Our working hypothesis is that TPX2 binding decreases the size and accessibility of a hydrophobic pocket, adjacent to the ATP site, to inhibitors. PMID- 17705511 TI - Resolving the coupled effects of hydrodynamics and DLVO forces on colloid attachment in porous media. AB - Transport of colloidal particles in porous media is governed by the rate at which the colloids strike and stick to collector surfaces. Classic filtration theory has considered the influence of system hydrodynamics on determining the rate at which colloids strike collector surfaces, but has neglected the influence of hydrodynamic forces in the calculation of the collision efficiency. Computational simulations based on the sphere-in-cell model were conducted that considered the influence of hydrodynamic and Derjaguin-Landau-Verwey-Overbeek (DLVO) forces on colloid attachment to collectors of various shape and size. Our analysis indicated that hydrodynamic and DLVO forces and collector shape and size significantly influenced the colloid collision efficiency. Colloid attachment was only possible on regions of the collector where the torque from hydrodynamic shear acting on colloids adjacent to collector surfaces was less than the adhesive (DLVO) torque that resists detachment. The fraction of the collector surface area on which attachment was possible increased with solution ionic strength, collector size, and decreasing flow velocity. Simulations demonstrated that quantitative evaluation of colloid transport through porous media will require nontraditional approaches that account for hydrodynamic and DLVO forces as well as collector shape and size. PMID- 17705512 TI - Deciphering the role of hydrogen bonding in enhancing pDNA-polycation interactions. AB - There is considerable interest in the binding and condensation of DNA with polycations to form polyplexes because of their possible application to cellular nucleic acid delivery. This work focuses on studying the binding of plasmid DNA (pDNA) with a series of poly(glycoamidoamine)s (PGAAs) that have previously been shown to deliver pDNA in vitro in an efficient and nontoxic manner. Herein, we examine the PGAA-pDNA binding energetics, binding-linked protonation, and electrostatic contribution to the free energy with isothermal titration calorimetry (ITC). The size and charge of the polyplexes at various ITC injection points were then investigated by light scattering and zeta-potential measurements to provide comprehensive insight into the formation of these polyplexes. An analysis of the calorimetric data revealed a three-step process consisting of two different endothermic contributions followed by the condensation/aggregation of polyplexes. The strength of binding and the point of charge neutralization were found to be dependent upon the hydroxyl stereochemistry of the carbohydrate moiety within each polymer repeat unit. Circular dichroism spectra reveal that the PGAAs induce pDNA secondary structure changes upon binding, which suggest a direct interaction between the polymers and the DNA base pairs. Infrared spectroscopy experiments confirmed both base pair and phosphate group interactions and, more specifically, showed that the stronger-binding PGAAs had more pronounced interactions at both sites. Thus, we conclude that the mechanism of poly(glycoamidoamine)-pDNA binding is most likely a combination of electrostatics and hydrogen bonding in which long-range Coulombic forces initiate the attraction and hydroxyl groups in the carbohydrate comonomer, depending on their stereochemistry, further enhance the association through hydrogen bonding to the DNA base pairs. PMID- 17705513 TI - Decoupling of the liquid response of a superhydrophobic quartz crystal microbalance. AB - Recent reports using particle image velocimetry and cone-and-plate rheometers have suggested that a simple Newtonian liquid flowing across a superhydrophobic surface demonstrates a finite slip length. Slippage on a superhydrophobic surface indicates that the combination of topography and hydrophobicity may have consequences for the coupling at the solid--liquid interface observed using the high-frequency shear-mode oscillation of a quartz crystal microbalance (QCM). In this work, we report on the response of a 5 MHz QCM possessing a superhydrophobic surface to immersion in water--glycerol mixtures. QCM surfaces were prepared with a layer of SU-8 photoresist and lithographically patterned to produce square arrays of 5 mum diameter circular cross-section posts spaced 10 microm center-to center and with heights of 5, 10, 15, and 18 microm. Non-patterned layers were also created for comparison, and both non-hydrophobized and chemically hydrophobized surfaces were investigated. Contact angle measurements confirmed that the hydrophobized post surfaces were superhydrophobic. QCM measurements in water before and after applying pressure to force a Cassie-Baxter (non penetrating) to Wenzel (penetrating) conversion of state showed a larger frequency decrease and higher dissipation in the Wenzel state. QCM resonance spectra were fitted to a Butterworth-van Dyke model for the full range of water glycerol mixtures from pure water to (nominally) pure glycerol, thus providing data on both energy storage and dissipation. The data obtained for the post surfaces show a variety of types of behavior, indicating the importance of the surface chemistry in determining the response of the quartz crystal resonance, particularly on topographically structured surfaces; data for hydrophobized post surfaces imply a decoupling of the surface oscillation from the mixtures. In the case of the 15 microm tall hydrophobized post surfaces, crystal resonance spectra become narrower as the viscosity-density product increases, which is contrary to the usual behavior. In the most extreme case of the 18 microm tall hydrophobized post surfaces, both the frequency decrease and bandwidth increase of the resonance spectra are significantly lower than that predicted by the Kanazawa and Gordon model, thus implying a decoupling of the oscillating surface from the liquid, which can be interpreted as interfacial slip. PMID- 17705514 TI - Iron/iron oxide nanoparticle sequestration of catalytic metal impurities from aqueous media and organic reaction products. AB - A host of transition metal ions (Co2+, Cu2+, Ni2+, RuX+, RhX+, Pd2+, Ag+, and Pt4+) were sequestered from aqueous media upon exposure to FexOy@Fe nanoparticles. Concentrations were lowered from approximately 100 ppm to below 40 ppb. This technique was extended to the removal of catalytic ions from the products of a "Click" cycloaddition and a Heck coupling in organic solvents. Residual metal concentrations in organic reaction products matched or exceeded pharmaceutical standards. PMID- 17705515 TI - Microwave-Assisted Coating of PMMA beads by silver nanoparticles. AB - Microwave (MW) irradiation was found to be a new technique for coating silver nanoparticles with an average size of approximately 31 nm onto the surface of poly(methyl methacrylate) PMMA beads (3 mm diameter). The microwave polyol reduction was carried out under an argon atmosphere. Silver nanoparticles were obtained by the MW irradiation of a solution mixture containing silver nitrate (or silver acetate), poly(ethylene glycol), ethanol, water, and 24 wt % aqueous ammonia for 5 min in the presence of PMMA beads, yielding a PMMA-nanosilver composite. By controlling the atmosphere and reaction conditions, we could achieve the deposition of silver nanoparticles onto the surface of poly(methyl methacrylate) and vary the amount of the silver anchored to the surface. The resulting silver-deposited PMMA samples were characterized using X-ray diffraction, transmission electron microscopy, energy-dispersive X-ray analysis, high-resolution scanning electron microscopy, X-ray photoelectron spectroscopy, and volumetric titration with potassium thiocyanate (KSCN) according to the Folgard method. PMID- 17705516 TI - Influence of applied potential on the impedance of alkanethiol SAMs. AB - Self-assembled monolayers are generally considered to behave as dielectric layers with a capacitance that is dependent on the monolayer thickness and the relative permittivity that is determined by the hydrocarbon tail. We show that the impedance response of alkanethiol-modified gold surfaces can be modeled as a parallel network consisting of the capacitance and resistance of the monolayer over a wide potential range. At potentials positive to -0.3 V (Ag/AgCl), the monolayer resistance is greater than 10(6) Omega cm2; however, at more negative potentials, the monolayer resistance decreases exponentially with potential with an inverse slope of about 250 mV. Over the same potential range, the monolayer capacitance is independent of potential. Although the same behavior is observed on ultrasmooth, template-stripped gold, the resistance at any potential is larger than for evaporated gold. The progressive increase in permeability of the monolayer is associated with an increase in electric field at potentials negative to the potential of zero charge. PMID- 17705517 TI - Role of the spacer stereochemistry on the structure of solid-supported gemini surfactants aggregates. AB - Energy dispersive X-ray diffraction was applied to investigate the role of the spacer stereochemistry on the structure of the solid supported aggregates of three stereoisomeric cationic gemini surfactants, 2,3-dimethoxy-1,4-bis-(N hexadecyl-N,N-dimethylammonio)butane dibromide. Solid-supported Gemini surfactant aggregates self-assemble into highly interdigitated multibilayer stacks. Structural properties, such as the bilayer thickness, the headgroup size, the thickness of the hydrophobic core, and the size of the interbilayer water region, were derived from electron density profiles. Results show that the stereochemistry of the spacer controls the structural properties of the solid supported interfacial aggregates. PMID- 17705518 TI - Ultrafast infrared heating laser pulse-induced micellization kinetics of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) in water. AB - The heating-induced micellization of poly(ethylene oxide)-b-poly(propylene oxide) b-poly(ethylene oxide) (Pluronic PE10300) triblock copolymer chains was studied by ultrasensitive differential scanning calorimetry, laser light scattering, and fluorescence spectrometry with a fluorescent probe, 8-anilino-1 naphthalenesulfonic acid ammonium salt. The critical micellization temperatures obtained from the three methods are similar. The micellization kinetics was studied in terms of changes in the fluorescence and Rayleigh scattering intensities after an ultrafast infrared heating laser pulse (approximately 10 ns) induced temperature jump. The increases in the fluorescence and Rayleigh scattering intensities in the millisecond range can be well described by a single exponential equation, corresponding to the incorporation of individual triblock copolymer chains (unimers) into large spherical micelles. The increase in copolymer concentration or the initial solution temperature decreases the characteristic transition time. In general, the fluorescence measurement has a better signal-to-noise ratio but leads to a transition time that is slightly shorter than that from the corresponding Rayleigh scattering measurement for a given copolymer solution. PMID- 17705519 TI - An in situ study of the adsorption behavior of functionalized particles on self assembled monolayers via different chemical interactions. AB - The formation of particle monolayers by convective assembly was studied in situ with three different kinds of particle-surface interactions: adsorption onto native surfaces, with additional electrostatic interactions, and with supramolecular host-guest interactions. In the first case carboxylate functionalized polystyrene (PS-COOH) particles were assembled onto native silicon oxide surfaces, in the second PS-COOH onto protonated amino-functionalized (NH3+) self-assembled monolayers (SAMs), and in the third beta-CD-functionalized polystyrene (PS-CD) particles onto beta-CD SAMs with pre-adsorbed ferrocenyl functionalized dendrimers. The adsorption and desorption behaviors of particles onto and from these surfaces were observed in situ on a horizontal deposition setup, and the packing density and order of the adsorbed particle lattices were compared. The desorption behavior of particles from surfaces was evaluated by reducing the temperature below the dew point, thus initiating water condensation. Particle lattices on native oxide surfaces formed the best hexagonal close packed (hcp) order and could be easily desorbed by reducing the temperature to below the dew point. The electrostatically modified assembly resulted in densely packed, but disordered particle lattices. The specificity and selectivity of the supramolecular assembly process were optimized by the use of ferrocenyl functionalized dendrimers of low generation and by the introduction of competitive interaction by native beta-CD molecules during the assembly. The fine tuned supramolecularly formed particle lattices were nearly hcp packed. Both electrostatically and supramolecularly formed lattices of particles were strongly attached to the surfaces and could not be removed by condensation. PMID- 17705520 TI - Selective assembly and guiding of actomyosin using carbon nanotube network monolayer patterns. AB - We report a new method for the selective assembly and guiding of actomyosin using carbon nanotube patterns. In this method, monolayer patterns of the single-walled carbon nanotube (swCNT) network were prepared via the self-limiting mechanism during the directed assembly process, and they were used to block the adsorption of both myosin and actin filaments on specific substrate regions. The swCNT network patterns were also used as an efficient barrier for the guiding experiments of actomyosin. This is the first result showing that inorganic nanostructures such as carbon nanotubes can be used to control the adsorption and activity of actomyosin. This strategy is advantageous over previous methods because it does not require complicated biomolecular linking processes and nonbiological nanostructures are usually more stable than biomolecular linkers. PMID- 17705521 TI - SANS study of polymer-linked droplets. AB - We report experimental results obtained from SANS on microemulsion droplets connected by a telechelic polymer. Thanks to its ability to anchor droplets through its short stickers, the addition of this polymer leads to the formation of transient aggregates. Measurements were performed on samples at low surfactant content in such a way that the droplets appear to be isolated with a separation distance longer than the end-to-end distance of the polymer. The locally spherical structure of the micelles is unchanged in size upon polymer addition whereas the large rise in scattered intensity at low Q is due to the induced effective attractive interaction between droplets. The fitting model that we propose allows a quantitative description of the bridging effect. PMID- 17705522 TI - Comparative profiling of serum glycoproteome by sequential purification of glycoproteins and 2-nitrobenzensulfenyl (NBS) stable isotope labeling: a new approach for the novel biomarker discovery for cancer. AB - The recent progress in various proteomic technologies allows us to screen serum biomarker including carbohydrate antigens. However, only a limited number of proteins could be detected by current conventional methods such as shotgun proteomics, primarily because of the enormous concentration distribution of serum proteins and peptides. To circumvent this difficulty and isolate potential cancer specific biomarkers for diagnosis and treatment, we established a new screening system consisting of the sequential steps of (1) immunodepletion of 6 high abundance proteins, (2) targeted enrichment of glycoproteins by lectin column chromatography, and (3) the quantitative proteome analysis using 12C6- or 13C6 NBS (2-nitrobenzenesulfenyl) stable isotope labeling followed by MALDI-QIT-TOF mass spectrometric analysis. Through this systematic analysis for five serum samples derived from patients with lung adenocarcinoma, we identified as candidate biomarkers 34 serum glycoproteins that revealed significant difference in alpha1,6-fucosylation level between lung cancer and healthy control, clearly demonstrating that the carbohydrate-focused proteomics could allow for the detection of serum components with cancer-specific features. In addition, we developed a more simplified and practical technique, mass spectrometry-based glycan structure analysis and lectin blotting, in order to validate glycan structure of candidate biomarkers that could be applicable in clinical use. Our new glycoproteomic strategy will provide highly sensitive and quantitative profiling of specific glycan structures on multiple proteins, which should be useful for serum biomarker discovery. PMID- 17705523 TI - Evaluation of tubulointerstitial lesions' severity in patients with glomerulonephritides: an NMR-based metabonomic study. AB - An 1H NMR-based metabonomic approach was used to investigate the correlation of histopathologically assessed tubulointerstitial lesions with the urinary metabolite profile in 77 patients with glomerulonephritides submitted to renal biopsy. The presence of renal damage was predicted with a sensitivity of 96% and a specificity of 99%. Patients with mild, moderate, and severe tubulointerstitial lesions were progressively differentiated from the healthy individuals in the Orthogonal Signal Correction Partial Least-Squares-Discriminant Analysis (OSC/PLS DA) models with a statistically significant separation between those with mild and with severe lesions. The onset of the tubulointerstitial lesions is characterized by decreased excretion of citrate, hippurate, glycine, and creatinine, whereas further deterioration is followed by glycosuria, selective aminoaciduria, total depletion of citrate and hippurate, and gradual increase in the excretion of lactate, acetate, and trimethylamine-N-oxide. NMR-based metabonomic urinalysis could contribute to the early evaluation of the severity of the renal damage and possibly to the monitoring of kidney function. PMID- 17705524 TI - Hard (Beta-)keratins in the epidermis of reptiles: composition, sequence, and molecular organization. AB - Beta-keratins form the hard corneous material of reptilian scales. In the present review, the distribution and molecular characteristics of beta-keratins in reptiles are presented. In lepidosaurians immunoreactive, protein bands at 12-18 kDa are generally present with less frequent proteins at higher molecular weight. In chelonians, bands at 13-18 and 22-24 kDa are detected. In crocodilians, bands at 14-20 kDa and weaker bands at 30-32 kDa are seen. Protein bands above 25 kDa are probably polymerized beta-keratins or aggregates. Two-dimensional gel electrophoresis shows that beta-keratins are mainly basic and that acidic-neutral keratins may derive from post-translational modifications. Beta-keratins comprise glycine-proline-rich and cystein-proline-rich proteins of 13-19 kDa. Beta-keratin genes may or may not contain introns and are present in multiple copies with a linear organization as in avian beta-keratin genes. Despite amino acid differences toward N- and C-terminals all beta-keratins share high homology in their central, beta-folded region of 20 amino acids, indicated as core-box. This region is implicated in the formation of beta-keratin filaments of scales, claws, and feathers. The homology of the core-box suggests that these proteins evolved from a progenitor sequence present in the stem of reptiles. Beta-keratins have diversified in their amino acid sequences producing secondary (and tertiary) conformations that suited them for their mechanical role in scales. In birds, a small beta-keratin has allowed the formation of feathers. It is suggested that beta-keratins represent the reptilian counterpart of keratin associated or matrix proteins present in mammalian hairs, claws, and horns. PMID- 17705525 TI - Selective modification of Trp19 in beta-lactoglobulin by a new diazo fluorescence probe. AB - To obtain the local information on the tryptophan domain in a protein, the design and synthesis of a new fluorescent probe, 1,7-bis(4-hydroxy-3-methoxyphenyl)-4 diazo-1,6-heptadiene-3,5-dione, is reported for the selective modification of tryptophan residues. The probe comprises a curcumin fluorophore and a diazo labeling group, whose spectroscopic properties are characterized. The diazo group may be catalytically degraded by transition metal complexes such as Rh2(OAc)4, generating an active rhodium carbenoid intermediate, which can react selectively with tryptophan residues. By the use of the carbene's intermolecular reactions, the tryptophan residue (Trp19) of beta-lactoglobulin may be modified with the diazo curcumin probe. Furthermore, slight secondary but larger tertiary structural changes are detected after Trp19 is modified, and the Trp19 modification produces a great effect on the binding of 8-anilino-1 naphthalenesulfonic acid and retinol. These results indicate that the Trp19 residue plays an essential role in the structure and stability of beta lactoglobulin, and the specific modification of this residue may have a potential use in further elucidating the relationship between the structure and function of the protein. PMID- 17705526 TI - Molecular dynamics simulations of charged dendrimers: low-to-intermediate half generation PAMAMs. AB - We have performed atomistic molecular dynamics simulations of PAMAM dendrimers of generations 0.5, 1.5, 2.5, 3.5, and 4.5. The simulated systems comprise the charged dendrimer and its counterions embedded in a dielectric continuum (i.e., without explicit solvent). Structural properties of these dendrimers, like the radius of gyration, the principal moments of inertia, and the segment density profiles, were evaluated from the simulations. The average radius of gyration obtained for the intermediate half-generations 2.5, 3.5, and 4.5 follows the same scaling law that was previously inferred from simulations of full-generation PAMAMs, Rg approximately M1/3, and is characteristic of space-filling objects. The low half-generations 0.5 and 1.5 deviate, however, to greater Rg values. The shape of the smaller dendrimers is approximately that of a prolate ellipsoid, which becomes more spherical for higher generations. The segment density profiles show features identical to those obtained in other simulations of flexible-chain dendrimers, like dendron-backfolding. Two slightly different configurations, in terms of size and shape, were identified for generation 2.5. The radial distributions of counterions extracted from the simulations compare well with the solutions of Poisson-Boltzmann cell model, and the dendrimer's effective charge was estimated using the Bjerrum criterion. The influence of electrostatic interactions in the dendrimer's conformation due to repulsion between the charged end-groups and its relation to counterion effects is discussed for the several generations simulated. The form factors calculated from the simulations are compared with the model of a homogeneous ellipsoid of revolution. The overall results are in agreement with the previously established morphological transition of PAMAM dendrimers toward a more spherical and compact conformation above generations 3 or 4. PMID- 17705528 TI - Molecular dynamics simulations of polycarbonate doped with Lemke chromophores. AB - In the search for optimal electro-optical modulating materials we report in this work molecular dynamics simulations of polycarbonate doped with Lemke chromophores which is a promising candidate system for materials with such functionality. The simulations cover the electric field poling effects on the chromophore order at a temperature above the glass transition temperature (Tg) of the material, the cooling procedure from liquid state to the glass state in the presence of the poling field, and the back relaxation of the system after removal of the field. Our study shows that electric field poling results in a higher chromophore order and that the order is also maintained during the cooling procedure with the poling field applied. In the liquid state, the applied poling field has little effect on the structure of the material. However, after the cooling procedure, the structure changes significantly because the polymer matrix tends to become closely packed. Our study thus indicates that for the bulk material, the structure of the host matrix is very important in determining the performance of the material. PMID- 17705529 TI - A hybrid approach for microscopic properties and self-assembly of dendrimers between two hard walls. AB - Dendrimers are of interest in a number of applications and theoretical studies due to their interesting and complex architectures. We use a hybrid approach to investigate the microstructure of hard dendrimers and self-assembly of diblock dendrimers confined between two hard walls. In the hybrid approach, a single chain Monte Carlo simulation is used to evaluate the ideal-gas contribution of the Helmholtz energy and a density functional theory is employed to calculate the excess Helmholtz energy. In our calculations, a coarse-grained model is used to represent the dendrimers of generations 1-4. The effects of generation and bulk packing fraction on the microscopic properties of the hard dendrimers are explored. With the increase of generations, the complexity of the dendritic architecture increases. Accordingly, the depletion effect becomes stronger with the generation at etabulk = 0.1. Furthermore, it is found that the more complex the molecular architecture and the higher the molecular stiffness, the smaller is the partitioning coefficient of confined dendrimers. In addition, we also investigate the effects of the width of the slit and the interaction (epsilon*AA) between hydrophilic segments on the self-assembly of diblock dendrimers in the slit. With the increase of epsilon*AA, we observe that the curves of average packing fraction of the dendrimers in the slit exist an abrupt jump, which corresponds to the first-order phase transition from a disordered state to a lamellar ordered structure. In the slit of H = 11sigma, it is at epsilon*AA = 8 rather than epsilon*AA = 10 or epsilon*AA = 12 that the minimum critical bulk packing fraction appears. This observation is distinctively different from the case of self-assembly of rod-like molecules in the slit, where the critical bulk concentration increases with the decrease of the head-head interaction linearly. PMID- 17705527 TI - Steady state and time-resolved fluorescence investigation of the specific binding of two chlorin derivatives with human serum albumin. AB - The specific binding of two model drugs for photodynamic therapy, namely chlorin p6 and purpurin 18 in the vicinity of Sudlow's Site I of HSA has been investigated by monitoring the intrinsic fluorescence of single tryptophanyl residue and by competitive binding with warfarin. The distance from the tryptophanyl residue has been ascertained by FRET from Trp to the chlorins and has been found to indicate a binding to Sudlow's Site I. The principal driving force for the interaction is found to be the hydrophobic effect. The main mechanism of protein fluorescence quenching was static. Time-resolved fluorescence results of competitive binding with warfarin are found to confirm that they bind to the warfarin binding site. PMID- 17705530 TI - Energetics of ion transport in a peptide nanotube. AB - Ion channels constitute an important family of integral membrane proteins responsible for the regulation of ion transport across the cell membrane. Yet, the underlying energetics of the permeation events and how the latter are modulated by the environment, specifically near the mouth of the pore, remain only partially characterized. Here, a synthetic membrane channel formed by cyclic peptides of alternated d- and l-hydrophobic alpha-amino acids was considered. The free energy delineating the translocation of a sodium ion was measured along the conduction pathway by means of molecular dynamics simulations. The free-energy profiles that underly the permeation of the open-ended tubular structure are shown to not only depend on the characteristics of the latter but also inherently on the location of the mouth of the synthetic channel with respect to the membrane surface. PMID- 17705531 TI - Fibrinogen-catecholamine interaction as observed by NMR and Fourier transform infrared spectroscopy. AB - In this work, the interactions between the main catecholamines-epinephrine and norepinephrine-and fibrinogen were investigated by NMR and Fourier transform infrared spectroscopies. The two hormones were found to interact with fibrinogen and to affect the protein secondary structure to a different extent. In particular, the protein selectively binds epinephrine at both the basal and stress concentrations, while it shows a weak nonspecific interaction with norepinephrine. The interaction with the stress level of epinephrine leads to drastic protein conformational changes, whereas norepinephrine does not affect fibrinogen secondary structure, even at stress concentration. PMID- 17705532 TI - Adhesion and viability of two enterococcal strains on covalently grafted chitosan and chitosan/kappa-carrageenan multilayers. AB - Chitosans are natural aminopolysaccharides, whose low cytotoxicity suggests their potential use for nonadhesive, antibacterial coatings on biomaterials implant surfaces. Here, the antiadhesive behavior and ability to kill bacteria upon adhesion ("contact killing") of chitosan coatings were evaluated for two strains of Enterococcus faecalis, isolated from clogged biliary stents. Chitosan coatings covalently grafted or applied as chitosan/kappa-carrageenan multilayers were characterized by ellipsometry, scanning force microscopy (SFM), X-ray photoelectron spectroscopy (XPS), and electrokinetic measurements. Decreases in initial bacterial deposition rates and the number of bacteria adhering in a more advanced state of the adhesion process were observed on both types of modified surfaces, with more pronounced effects on highly hydrated multilayers. Adhesion of negatively charged enterococci was slightly enhanced on chitosan-terminated multilayers, but antibacterial effect was absent on kappa-carrageenan-terminated multilayers. Thus, the efficacy of multilayers remains an interesting interplay between the promoting effect of cationically charged groups on adhesion of negatively charged bacteria and, on the other hand, their antibacterial effects. PMID- 17705533 TI - Comparison of benzene, nitrobenzene, and dinitrobenzene 2-arylsulfenylpyrroles. AB - The effectiveness of the 2,4-dinitrobenzenesulfenyl and 4-nitrobenzenesulfenyl groups as masking and directing groups at the 2-position of pyrrole has been investigated and compared to that of 2-phenylthiopyrrole. The presence of the nitro group(s) enhances stability of the corresponding pyrrole toward acid and does not significantly decrease the ability of the pyrrolic unit to undergo electrophilic aromatic substitution reactions in the form of formylation, nitration, and condensation with aldehydes. The synthetic utility of 2-(2,4 dinitrobenzenesulfenyl)pyrrole was demonstrated through the synthesis of meso substituted dipyrromethanes. The sulfoxides 2-(2,4-dinitrobenzenesulfinyl)pyrrole and 2-(4-nitrobenzenesulfinyl)pyrrole underwent neither formylation nor nitration, and the increasing presence of nitro groups within the moiety at the 2 position resulted in decreased stability under acidic conditions. PMID- 17705534 TI - Wedelolides A and B: novel sesquiterpene delta-lactones, (9R)-eudesman-9,12 olides, from Wedelia trilobata. AB - Two new sesquiterpene lactones, wedelolides A (1) and B (2), were isolated by bioassay-guided fractionation from the leaves of Wedelia trilobata, together with known trilobolides 6-O-isobutyrate (3) and 6-O-methacrylate (4). The compounds 1 and 2 were the first examples of an unprecedented framework: a novel sesquiterpene delta-lactone, (9R)-eudesman-9,12-olide. The structures of the antimalarial wedelolides A (1) and B (2) were determined on the basis of MS and 2D NMR spectral analysis. The absolute configuration of eight carbon stereocenters of compounds 1 and 2 was determined to be 1S,4S,5S,6R,7S,8S,9R,10S by mean of auxiliary chiral MTPA derivatives. PMID- 17705535 TI - Preparation of polyfunctional aryl azides from aryl triazenes. A new synthesis of ellipticine, 9-methoxyellipticine, isoellipticine, and 7 carbethoxyisoellipticine. AB - The preparation of polyfunctional aryl azides by the reaction of aryl triazenes with NaN3 in the presence of KHSO4 or BF3.OEt2/TFA (trifluoroacetic acid) has been described. A variety of functional groups (halides, esters, ketones, nitriles, aldehydes, and boronic esters) are tolerated under the Lewis acidic conditions. By using this methodology, the potent antitumor agents, ellipticine and 9-methoxyellipticine, have been synthesized. In addition, isoellipticine and a related derivative, 7-carbethoxyisoellipticine, were also prepared. PMID- 17705536 TI - Superacidic activation of quinoline and isoquinoline; their reactions with cyclohexane and benzene(1). AB - Quinoline (1) and isoquinoline (2), upon activation by strong acids, lead to intermediate N,C-diprotonated dications, which are involved in reactions with weak nucleophiles. Thus, 1 and 2 undergo selective ionic hydrogenation with cyclohexane in CF3SO3H-SbF5, HBr-AlBr3-CH2Br2, or HCl-AlCl3-CH2Cl2 acid systems to give their 5,6,7,8-tetrahydro derivatives. They also readily condense with benzene in the presence of HBr-AlBr3 or HCl-AlCl3 to provide 5,6,7,8-tetrahydro 5,7-diphenylquinoline (10) and 5,6,7,8-tetrahydro-6,8-diphenylisoquinoline (12), respectively. PMID- 17705537 TI - A new series of 3-alkyl phosphate derivatives of 4,5,6,7-tetrahydro-1-D-ribityl 1H-pyrazolo[3,4-d]pyrimidinedione as inhibitors of lumazine synthase: design, synthesis, and evaluation. AB - Lumazine synthase catalyzes the penultimate step in the biosynthesis of riboflavin. A homologous series of three pyrazolopyrimidine analogues of a hypothetical intermediate in the lumazine synthase-catalyzed reaction were synthesized and evaluated as lumazine synthase inhibitors. The key steps of the synthesis were C-5 deprotonation of 4-chloro-2,6-dimethoxypyrimidine, acylation of the resulting anion, and conversion of the product to a pyrazolopyrimidine with hydrazine. Alkylation of the pyrazolopyrimidine with a substituted ribityl iodide and deprotection of the ribityl chain afforded the final set of three products. All three compounds were extremely potent inhibitors of the lumazine synthases of Mycobacterium tuberculosis, Magnaporthe grisea, Candida albicans, and Schizosaccharomyces pombe lumazine synthase, with inhibition constants in the low nanomolar to subnanomolar range. Molecular modeling of one of the homologues bound to Mycobacterium tuberculosis lumazine synthase suggests that both the hypothetical intermediate in the lumazine synthase-catalyzed reaction pathway and the metabolically stable analogues bind similarly. PMID- 17705538 TI - Ir-catalyzed allylic amination/ring-closing metathesis: a new route to enantioselective synthesis of cyclic beta-amino alcohol derivatives. AB - Ir-catalyzed allylic aminations of (E)-4-benzyloxy-2-butenyl methyl carbonate with benzylamine using Feringa's (Sa,Sc,Sc)-phosphoramidite as a chiral ligand afforded linear-aminated achiral product N,O-dibenzyl-4-amino-2-buten-1-ol regioselectively (linear/branched = >99/1), whereas the (E)-5-benzyloxy-2 pentenyl methyl carbonate showed completely opposite regioselectivity (linear/branched = >1/99) and afforded the optically active (3R)-N,O-dibenzylated 3-amino-1-penten-5-ol with very high enantioselectivity (96% ee), which was used as a key intermediate for the effective synthesis of various cyclic beta-amino alcohol derivatives through ring-closing metathesis in high yields. PMID- 17705539 TI - Regioselective transformation of octaethylporphyrin into a phytoporphyrin analogue. AB - An octaethylporphyrin derivative, 1, possessing an exo-five-membered ring fused at the 13- and 15-positions was oxidized by osmium tetroxide to give two isomeric chlorins, 3 and 5, possessing beta,beta'-dihydroxy groups at the A- and C-rings, respectively. Single dehydration of 2,3-dihydroxychlorin 3 gave a mixture of 2- and 3-(1-hydroxyethyl)porphyrins 7, while that of 12,13-dihydroxychlorin 5 resulted in the sole formation of 131-hydroxyporphyrin 9. The latter was modified smoothly to the phytoporphyrin analogue 2, whose molecular skeleton was similar to that of naturally occurring chlorophylls possessing a 131-oxo group fixed on an exo-five-membered ring. PMID- 17705540 TI - Convergency and divergency as strategic elements in total synthesis: the total synthesis of (-)-drupacine and the formal total synthesis of (+/-)-cephalotaxine, (-)-cephalotaxine, and (+)-cephalotaxine. AB - A concise route toward the syntheses of (-)-drupacine and (+)- and (-) cephalotaxine has been developed. The syntheses rely on Pd(II)-catalyzed aerobic oxidative heterocyclization chemistry, which was employed to rapidly construct an important spirocyclic amine intermediate. A dynamic beta-elimination/conjugate addition process was strategically applied to complete the first asymmetric total synthesis of (-)-drupacine. PMID- 17705541 TI - Synthetic model of the phosphate binding protein: solid-state structure and solution-phase anion binding properties of a large oligopyrrolic macrocycle. AB - The macrocyclic receptors 4-6 were synthesized via the anion-templated condensation of appropriately chosen dialdehyde and diamine building blocks. Whereas all three products could be obtained directly via the appropriate choice of reaction conditions, the larger [3+3] product, 6, which incorporates three of each precursor subunit, could also be obtained conveniently via an indirect procedure involving ring expansion of the smaller [2+2] macrocycle 4. As detailed earlier (Sessler, J. L.; Katayev, E. A.; Pantos, G. D.; Reshetova, M. D.; Khrustalev, V. N.; Lynch, V. M.; Ustynyuk, Y. A. Angew. Chem. 2005, 117, 7552 7556; Angew. Chem., Int. Ed. 2005, 44, 7386-7390), this ring expansion occurs under thermodynamic control in the presence of HSO4- and H2PO4- anions in acetonitrile solution and serves to effect the conversion of 4 to 6. An analysis of the X-ray crystal structure of complex 6H22+.HPO42- revealed a strong resemblance to the active site of the phosphate binding protein (PBP) with similar structural analogies being drawn between the active site of the sulfate binding protein (SBP) and the corresponding hydrogensulfate anion complex. In both cases, the anions are bound in a 1:1 fashion in the solid state through a complementary hydrogen bond network involving both the receptor 6 and the anions. UV-vis spectroscopic titrations provide support for the conclusion that macrocycle 6 binds the hydrogensulfate and dihydrogenphosphate anion (studied as the corresponding tetrabutylammonium salts) with high selectivity and affinity in acetonitrile (log Ka for the first binding interaction approaching 7), albeit with different receptor-to-anion binding stoichiometries (1:1 vs 1:3 for HSO4- and H2PO4-, respectively). PMID- 17705542 TI - An efficient de novo synthesis of partially reduced phenanthrenes through C-C insertion. AB - An efficient and novel approach to the synthesis of highly congested 3-alkyl-, 4 alkyl-, 3-aryl-, 3,4-dialkyl-, 4-alkyl-3-aryl-, and 3,4-diaryl-9,10-dihydro-1-sec aminophenanthrene-2-carbonitriles has been delineated through the base-catalyzed ring transformation of 5,6-dihydro-2-oxo-4-sec-amino-2H-benzo[h]chromene-3 carbonitrile by carbanion derived in situ from various ketones in moderate to good yields. 9,10-Dihydrophenanthrenes with and without substituent in the bay region are efficiently and regioselectively synthesized by using propanal and acetyltrimethylsilane as a source of carbanion. Even the synthesis of bisphenanthrenes has been achieved by the ring transformation of 5,6-dihydro-2 oxo-4-sec-amino-2H-benzo[h]chromene-3-carbonitrile by 2-acetylphenanthrene in moderate yield. Highly substituted 3-amino-1-sec-amino-5,6-dihydrophenanthrene 2,4-dicarbonitriles have also been prepared from the reaction of 2 oxobenzo[h]chromene and malononitrile. PMID- 17705543 TI - Conversion of nocathiacin I to nocathiacin acid by a mild and selective cleavage of dehydroalanine. AB - Thiazolyl peptide antibiotic nocathiacin I (1) was converted to nocathiacin acid (4) in high yield by treatment with trifluoroacetic anhydride and pyridine in THF at room temperature. Two equipotent water-soluble amide analogues of nocathiacin I were readily prepared from this important and versatile carboxylic acid intermediate under mild peptide coupling conditions. The present method is useful for chemical derivatization of complex natural products that contain C-terminal dehydroalanine. PMID- 17705544 TI - General and efficient route for the synthesis of 3,4-disubstituted coumarins via Pd-catalyzed site-selective cross-coupling reactions. AB - Palladium-catalyzed site-selective cross-coupling reactions of 3-bromo-4 trifloxycoumarin or 3-bromo-4-tosyloxycoumarin provide an efficient and facile route for the synthesis of 3,4-disubstituted coumarins, which include 3,4 diarylcoumarins, 3-amino-4-arylcoumarins, and 3-aryl-4-aminocoumarins. The order of reactivity of the (pseudo)halide substituents in the coumarins was found to be 4-OTf > 3-Br > 4-OTs. PMID- 17705545 TI - Use of deuterium labeling studies to determine the stereochemical outcome of palladium migrations during an asymmetric intermolecular Heck reaction. AB - A series of deuterium labeling experiments showed that Pd migrations during an intermolecular asymmetric Heck reaction between phenyl triflate and various deuterated 2,3-dihydrofurans (2b, 2c, 2d, 2e) occurs exclusively by either syn 1,2-dyotropic shifts or a syn-chain-walking mechanism; no evidence was observed to support anti-1,2-dyotropic shifts or anti-beta-H Pd eliminations during the formation of 6 and 7. PMID- 17705546 TI - Biocatalytic microcontact printing. AB - Immobilized biocatalytic lithography is presented as an application of soft lithography. In traditional microcontact printing, diffusion limits resolution of pattern transfer. By using an immobilized catalyst, the lateral resolution of microcontact printing would depend only on the length and flexibility of the tether (<2 nm) as opposed to diffusion (>100 nm). In the work, exonuclease reversibly immobilized on a relief-patterned stamp is used to ablate ssDNA monolayers Percent of ablation was determined via confocal fluorescence microscopy to be approximately 70%. PMID- 17705547 TI - N-heterocyclic carbene catalyzed aza-Morita-Baylis-Hillman reaction of cyclic enones with N-tosylarylimines. AB - N-Heterocyclic carbenes (NHCs) prove to be efficient catalysts for the aza-Morita Baylis-Hillman (aza-MBH) reaction of cyclopent-2-en-1-one or cyclohex-2-en-1-one with a variety of N-tosylarylimines to give the aza-MBH adduct in high yields. Crossover experiments show NHC can add to N-tosylarylimines in a reversible manner, which allows the addition of NHC to cyclic enones and thus catalyzes the aza-Mortia-Baylis-Hillman reaction. PMID- 17705548 TI - Voltage and length-dependent phase diagram of the electronic transport in carbon nanotubes. AB - In this work, we report experimental data on the evolution of the resistance with applied voltage in nonsuspended single-walled carbon nanotubes (SWNTs) of lengths ranging from 100 nm up to 6 microm. At low bias, the differential resistance as a function of length is well described by a linear fitting. At high biases, this magnitude first saturates and then decreases for nanotubes longer than 1 microm. We also present Monte Carlo numerical simulations for the one-dimensional Boltzmann's equation, describing how the electrons propagate along the tube and how they interact with acoustic and optical phonons. Our theoretical results show a remarkable agreement with the experimental differential resistance, allowing us to give a detailed description of the electron distribution function and the chemical potential along the nanotube. Finally, we present experimental results on the transition from Anderson localization at low bias to high diffusive regime at high bias in defected SWNTs. This result is combined with those of defect-free SWNTs to present a general landscape of the electronic transport in carbon nanotubes. PMID- 17705550 TI - Near-static dielectric polarization of individual carbon nanotubes. AB - Low-frequency dielectric responses of carbon nanotubes are important for their manipulation, separation, and electronic applications. Here we report the first experimental measurement of near-dc polarization of individual carbon nanotubes by using modified scanning force microscopy techniques. The transverse polarizability of carbon nanotubes is equivalent to solid cylindrical media with a dielectric constant of about 10, irrespective of tube diameter and chirality. The longitudinal polarization is also observed and used to distinguish metallic from semiconducting nanotubes. PMID- 17705549 TI - RF response of single-walled carbon nanotubes. AB - We present for the first time an in-depth study of the RF response of a single walled carbon nanotube (SWCNT) rope. Our novel electrode design, based on a tapered coplanar approach, allows for single tube measurements well into the GHz regime, minimizing substrate-related parasitics. From the analysis of the S parameters, the ac transport mechanism in the range 30 kHz to 6 GHz is established. This work is an essential prerequisite for the fabrication of high speed devices based on bundles of nanowires or low-dimensional structures. PMID- 17705551 TI - Convergence of quantum dot barcodes with microfluidics and signal processing for multiplexed high-throughput infectious disease diagnostics. AB - Through the convergence of nano- and microtechnologies (quantum dots and microfluidics), we have created a diagnostic system capable of multiplexed, high throughput analysis of infectious agents in human serum samples. We demonstrate, as a proof-of-concept, the ability to detect serum biomarkers of the most globally prevalent blood-borne infectious diseases (i.e., hepatitis B, hepatitis C, and HIV) with low sample volume (<100 microL), rapidity (<1 h), and 50 times greater sensitivity than that of currently available FDA-approved methods. We further show precision for detecting multiple biomarkers simultaneously in serum with minimal cross-reactivity. This device could be further developed into a portable handheld point-of-care diagnostic system, which would represent a major advance in detecting, monitoring, treating, and preventing infectious disease spread in the developed and developing worlds. PMID- 17705552 TI - Controlling DNA capture and propagation through artificial nanopores. AB - Electrophorescing biopolymers across nanopores modulates the ionic current through the pore, revealing the polymer's diameter, length, and conformation. The rapidity of polymer translocation ( approximately 30,000 bp/ms) in this geometry greatly limits the information that can be obtained for each base. Here we show that the translocation speed of lambda-DNA through artificial nanopores can be reduced using optical tweezers. DNAs coupled to optically trapped beads were presented to nanopores. DNAs initially placed up to several micrometers from the pore could be captured. Subsequently, the optical tweezers reduced translocation speeds to 150 bp/ms, about 200-fold slower than free DNA. Moreover, the optical tweezers allowed us to "floss" single polymers back and forth through the pore. The combination of controlled sample presentation, greatly slowed translocation speeds, and repeated electrophoresis of single DNAs removes several barriers to using artificial nanopores for sequencing, haplotyping, and characterization of protein-DNA interactions. PMID- 17705553 TI - 3-Amino-4-(2-((4-[18F]fluorobenzyl)methylamino)methylphenylsulfanyl)benzonitrile, an F-18 fluorobenzyl analogue of DASB: synthesis, in vitro binding, and in vivo biodistribution studies. AB - 3-amino-4-(2[11C]methylaminomethylphenylsulfanyl)benzonitrile (C-11 DASB) exhibits excellent in vitro and in vivo properties toward the serotonin transporter. If labeled with a longer physical half-life radioisotope, this ligand could be more attractive to research groups lacking an on-site cyclotron or lacking C-11 synthesis capabilities. We produce p-[18F]fluorobenzyl iodide on a routine basis to synthesize several neuroimaging agents. Therefore, it was straightforward for us to substitute the DASB precursor with this prosthetic group and assess its biological properties. We designed a different synthesis strategy to obtain the DASB precursor (desmethyl DASB). Herein we report an efficient and facile synthetic route that provides higher chemical yields of 3 amino-4-(2-aminomethylphenylsulfanyl)benzonitrile and related analogues. In addition, we report our results from incorporating p-[18F]fluorobenzyl iodide in DASB precursor and its affect on the in vitro and in vivo biological properties of the DASB. PMID- 17705554 TI - Avidin-biotin-PEG-CPA complexes as potential EPR-directed therapeutic protein carriers: preparation and characterization. AB - Bovine carboxypeptidase A (CPA) conjugated with biotinylated poly(ethylene glycol) (PEG) has been synthesized and characterized in terms of stoichiometry and half-life of the avidin-biotin-PEG(s)-CPA complex. The half-lives for dissociation are 3.34 days for the avidin-biotin-PEG(3400)-CPA 1:1 complex, 3.65 days for the avidin-biotin-PEG(5000)-CPA 1:1 complex, 3.91 days for the avidin biotin-PEG(3400)-CPA-PEG(2000) 1:1 complex, and 2.74 days for the avidin-biotin PEG(5000)-CPA-PEG(2000) 1:1 complex. The slow dissociation demonstrates the stability of complexes using a PEGylated biotin terminus as a linker with avidin. The stoichiometry of the biotin-PEGylated CPA with avidin was determined by the 2,6-ANS method, and the results are consistent with measurements of the stoichiometry using size exclusion chromatography. The stoichiometries are 1:2 for the avidin-biotin-PEG(3400)-CPA complex and the avidin-biotin-PEG(3400)-CPA PEG(2000) complex, 1:1 for the avidin-biotin-PEG(5000)-CPA complex, and 1:4 for the avidin-biotin-PEG(5000)-CPA-PEG(2000) complex. These findings stress both the importance of the length of a PEG chain as an appropriate spacer between the biotin terminus and a functional group, and the great potential of the avidin biotin-PEGylated-protein complex as a therapeutic protein delivery system for solid tumor prodrug targeting. PMID- 17705555 TI - Chemical imaging with combined fast-scan cyclic voltammetry-scanning electrochemical microscopy. AB - Fast-scan cyclic voltammetry (FSCV) is applied to the tip of a scanning electrochemical microscope (SECM) for imaging the distribution of chemical species near a substrate. This approach was used to image the diffusion layer of both a large substrate electrode (3-mm-diameter glassy carbon) and a microelectrode substrate (10-microm-diameter Pt). Additionally, oxygen depletion near living cells was measured and correlated to respiratory activity. Finally, oxygen and hydrogen peroxide were simultaneously detected during the oxidative burst of a zymosan-stimulated macrophage cell. These results demonstrate the utility of FSCV-SECM for chemical imaging when conditions are chosen such that feedback interactions with the substrate are minimal. PMID- 17705556 TI - Characterization of oligo- and polysialic acids by MALDI-TOF-MS. AB - Oligo- and polysialic acids (oligo/polySia) are characterized by a high diversity in nature due to the different types of sialic acids linked to each other and glycosidic linkages involved. Considering the methods that are presently available for analysis of oligo/polySia chains, only fluorometric anion-exchange high-performance liquid chromatography (HPLC) analysis, fluorometric C7/C9 detection, and western blotting are applicable to small amounts of material. Here we describe an alternative technique using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry after on-target lactonization to characterize different sialic acid polymers. The MS-based method allows a rapid, highly sensitive, and unambiguous identification of native as well as fluorescently labeled sialic acid polymers without the need of standard substances due to exact mass determination. PolySia chains with at least 100 sialic moieties are easily detectable, and in addition, potential modifications of hydroxyl groups by, for instance, acetyl residues can be precisely registered. Based on different lactonization characteristics, alpha2-8- and alpha2-9-linked oligo/polySia can be distinguished. Furthermore, this method can be combined with fluorometric derivatization and HPLC separation. PMID- 17705557 TI - Importance of partially unfolded conformations for Mg(2+)-induced folding of RNA tertiary structure: structural models and free energies of Mg2+ interactions. AB - RNA molecules in monovalent salt solutions generally adopt a set of partially folded conformations containing only secondary structure, the intermediate or I state. Addition of Mg2+ strongly stabilizes the native tertiary structure (N state) relative to the I state. In this paper, a combination of experimental and computational approaches is used to estimate the free energy of the interaction of Mg2+ with partially folded I state RNAs and to consider the possibility that Mg2+ favors "compaction" of the I state to a set of conformations with a higher average charge density. A sequence variant with a drastically destabilized tertiary structure was used as a mimic of I state RNA; as measured by small-angle X-ray scattering, it adopted a progressively more compact conformation over a wide Mg2+ concentration range. Average free energies of the interaction of Mg2+ with the I state mimic were obtained by a fluorescence titration method. To interpret these experimental data further, we generated molecular models of the I state and used them in calculations with the nonlinear Poisson-Boltzmann equation to estimate the change in Mg2+-RNA interaction free energy as the average I state dimensions decrease from expanded to compact. The same models were also used to reproduce quantitatively the experimental difference in excess Mg2+ between N and I states. On the basis of these experiments and calculations, I state compaction appears to enhance Mg2+-I state interaction free energies by 10-20%, but this enhancement is at most 5% of the overall Mg2+-associated stabilization free energy for this rRNA fragment. PMID- 17705558 TI - Dynamics of membrane protein/amphipol association studied by Forster resonance energy transfer: implications for in vitro studies of amphipol-stabilized membrane proteins. AB - Amphipols (APols) are short amphipathic polymers that can substitute for detergents to keep membrane proteins (MPs) water-soluble while stabilizing them biochemically. We have examined the factors that determine the size and dispersity of MP/APol complexes and studied the dynamics of the association, taking as a model system the transmembrane domain of Escherichia coli outer membrane protein A (tOmpA) trapped by A8-35, a polyacrylate-based APol. Molecular sieving indicates that the solution properties of the APol largely determine those of tOmpA/APol complexes. Achieving monodispersity depends on using amphipols that themselves form monodisperse particles, on working in neutral or basic solutions, and on the presence of free APols. In order to investigate the role of the latter, a fluorescently labeled version of A8-35 has been synthesized. Forster resonance energy transfer measurements show that extensive dilution of tOmpA/A8-35 particles into an APol-free medium does not entail any detectable desorption of A8-35, even after extended periods of time (hours-days). The fluorescent APol, on the other hand, readily exchanges for other surfactants, be they detergent or unlabeled APol. These findings are discussed in the contexts of sample optimization for MP solution studies and of APol-mediated MP functionalization. PMID- 17705559 TI - Can modern anesthesia practice harm the developing brain? PMID- 17705560 TI - Challenges in international pediatric pharmacology: a milestone meeting in Shanghai. PMID- 17705561 TI - Insights into early treatment of mild asthma: do inhaled corticosteroids make a difference? AB - Approaches to the management of moderate-to-severe persistent asthma in both children and adults are widely accepted but the treatment of mild persistent asthma remains controversial because of the lack of agreement on what constitutes mild asthma and whether regular treatment is required at all. Recent evidence indicates that 'mild asthma' may not be as benign a condition as was widely believed and should be treated to improve asthma control and to prevent the significant burden of exacerbation and progression of disease. This is supported by compelling evidence from histologic and clinical studies that have attributed irreversible pathologic and functional airway changes to consequences of persistent airway inflammation and under-treated asthma. This article focuses on the rationale of early treatment of mild persistent asthma, and discusses the various findings from the largest randomized, early-intervention trial with inhaled corticosteroids as regular treatment in patients with asthma of recent onset--the START (inhaled Steroid Treatment As Regular Therapy in early asthma) study. A brief review of the background of the natural history of asthma, the findings from key longitudinal epidemiologic studies on disease progression in children and adults, and the effect of inhaled corticosteroids on this progression are included, to provide further insight into the impact of early treatment on asthma management guidelines. PMID- 17705562 TI - Social anxiety disorder in children and adolescents: epidemiology, diagnosis, and treatment. AB - Social anxiety disorder (SOC) is characterized by marked and persistent fear of one or more social performance situations in which the person is exposed to unfamiliar people or to possible scrutiny. The person fears that she or he might act in a way that will be humiliating or embarrassing. Children and adolescents with this disorder often have great impairment in their academic performance, social skills, peer relationships, and family life. Early diagnosis is vital. Primary care providers are in a unique situation to first diagnose and treat SOC in children and adolescents. There is evidence of successful pharmacologic and psychosocial treatment in pediatric SOC. Serotonin reuptake inhibitors, which are considered first-line medications for SOC, have shown promising results in open label and double-blind trials. Studies have demonstrated that psychosocial treatments, specifically cognitive-behavioral therapy and group therapy, are efficacious in pediatric SOC. There is some evidence that the use of combination therapy, both pharmacology and psychosocial treatment, is beneficial in the management of pediatric SOC. PMID- 17705563 TI - Management of childhood malignant peripheral nerve sheath tumor. AB - Malignant peripheral nerve sheath tumor (MPNST) is rare, but is one of the most frequent non-rhabdomyosarcoma soft-tissue sarcomas in the pediatric population. These tumors occur most frequently at axial sites and are characterized by local aggressiveness and a propensity to metastasize. They are often associated with neurofibromatosis type 1 (NF-1): the lifetime risk of patients with NF-1 developing MPNST has been estimated at 8-13%, compared with 0.001% in the general population. Because of the rarity of this tumor, little information is available on its clinical management, particularly in the pediatric age group. In a recent report on the clinical findings and treatment outcomes from a large number of children and adolescents with MPNST in an Italian and German series, less satisfactory overall outcomes than those for other pediatric sarcomas were described. Therefore, the approach to the treatment of patients with MPNST should be aggressive and risk adapted, and is necessarily complex. Patients should be referred to selected institutions with adequate experience in treating soft tissue sarcomas, and with the multidisciplinary skills for enrolling patients in clinical trials. Surgical resection represents the mainstay of treatment, while the role of adjuvant treatment is not yet clear. Post-operative radiotherapy seems to have a role in improving local control, although the potential morbidity of irradiation should be taken into account, particularly when treating children. Although lack of local control is the major cause of treatment failure, MPNST may give rise to distant metastases. These tumors are usually considered as having uncertain chemosensitivity, but recent evidence suggests that there may be a role for chemotherapy in patients with a high-grade histology. For the near future, our hopes lie in the development of novel tailored therapies directed specifically against the molecular targets of the neoplastic cells: soft-tissue sarcomas seem particularly promising candidates for targeted therapy. PMID- 17705565 TI - Establishing causality in pediatric adverse drug reactions: use of the Naranjo probability scale. AB - Carbamazepine hypersensitivity syndrome is a rare, life-threatening condition. Its diagnosis is critical to avoid future exposure to aromatic anticonvulsants. Pediatricians rarely use a systematic approach to establish the cause of drug reactions in the clinical setting. We describe the use of the Naranjo adverse drug reaction probability scale to establish causality in three cases of suspected anticonvulsant hypersensitivity syndrome with the aim of introducing clinicians to this effective tool. Our analysis reveals that this method is useful, but also highlights potential areas for its improvement. PMID- 17705564 TI - Atypical antipsychotics in children with pervasive developmental disorders. AB - The treatment of pervasive developmental disorders (PDDs) is a challenging task, which should include behavioral therapy modifications as well as pharmacologic therapy. There has been a lack of data on using medications in children with PDDs until recent years. Within the last 10 years, an increase in clinical research has attempted to provide efficacy and safety data to support the use of medications in children with PDDs. Double-blinded and open-label research of atypical antipsychotics has been of particular focus. Evidence shows that atypical antipsychotics (AAs) may be useful in treating certain symptoms associated with PDDs, such as aggression, irritability, and self-injurious behavior. This article reviews the literature regarding the use of AAs in children with PDDs. Of the AAs, risperidone has the largest amount of evidence with five published double-blinded, placebo-controlled trials and nine open-label trials. These risperidone trials have consistently shown improvements in aggression, irritability, self-injurious behavior, temper tantrums, and quickly changing moods associated with autistic disorder and other PDDs. Data for the other AAs are limited, but ziprasidone and aripiprazole appear to be promising treatment options. Based on clinical trials, olanzapine and quetiapine have shown minimal clinical benefit and a high incidence of weight gain and sedation. It should be noted that all AAs do have a risk of metabolic syndrome, and patients should be monitored appropriately while receiving these medications. Overall, AAs can be beneficial in alleviating behavioral symptoms, and should be considered an appropriate therapeutic option, as part of a comprehensive treatment strategy, for children with PDD. PMID- 17705566 TI - Intravenous busulfan: in the conditioning treatment of pediatric patients prior to hematopoietic stem cell transplantation. AB - An intravenous formulation of busulfan, a cytotoxic bifunctional alkylating agent, has been developed to replace oral busulfan as a conditioning treatment prior to hematopoietic stem cell transplantation (HSCT) in pediatric patients. Doses of intravenous busulfan based on actual bodyweight, but not age, reduce inter- and intraindividual variability in exposure. In a study of intravenous busulfan as a conditioning treatment prior to allogeneic or autologous HSCT, the majority of pediatric patients, who received one of five bodyweight-based doses, achieved busulfan area under the plasma concentration-time curve (AUC) values within the targeted therapeutic range. Although mean busulfan clearance values were highly variable between bodyweight strata, exposure was not affected, with no significant differences between bodyweight groups in mean AUC values. The achievement of therapeutic AUC values with intravenous busulfan resulted in a high rate of sustained engraftment, low transplant-related mortality, and promising survival outcomes post-transplant. Intravenous busulfan was considered to be well tolerated, in the particular context of HSCT, and no failure of HSCT due to organ toxicity was reported. Nonhematologic adverse events commonly associated with busulfan conditioning regimens were frequent, but generally of mild to moderate severity. The intravenous busulfan regimen was frequently associated with elevated liver enzymes, but hepatic veno-occlusive disease (HVOD) was infrequent, of mild to moderate severity, and resolved within 10 days of diagnosis. Unlike oral busulfan, intravenous busulfan does not appear to be associated with severe HVOD or death due to organ toxicity. PMID- 17705568 TI - Regression or reduction in progression of atherosclerosis, and avoidance of coronary events, with lovastatin in patients with or at high risk of cardiovascular disease: a review. AB - HMG-CoA reductase inhibitors (statins) are the drugs of first choice for treating hypercholesterolaemia in order to prevent or slow the progression of coronary heart disease (CHD). Statins generally reduce the risk of CHD morbidity or mortality by about 30%. Lovastatin is effective in lowering plasma total cholesterol and low-density lipoprotein cholesterol levels, and is widely prescribed for both the primary and secondary prevention of CHD. In the major AFCAPS/TexCAPS primary prevention study of 6605 middle-aged or elderly men and women without symptomatic cardiovascular disease and with only moderately elevated serum lipids, treatment with lovastatin 20-40 mg once daily for a mean of 5.2 years significantly (p < 0.001) reduced the incidence of a first acute major cardiac event by 37% compared with placebo. In the smaller ACAPS study of 919 men and women who were asymptomatic for cardiovascular disease, but with evidence of early atherosclerosis, treatment with lovastatin for 3 years significantly (p = 0.001) slowed or reversed atherosclerosis compared with placebo, as measured by changes in the intimal-medial thickness of carotid arteries on B-mode ultrasound. Three randomised, controlled, secondary prevention trials have demonstrated that in patients with coronary artery disease, treatment with lovastatin 20-80 mg/day alone or in combination with colestipol for 2-2.5 years reduced the severity of stenosis and/or slowed or reversed the progression of atherosclerosis, as assessed by angiography. In the FATS study, the severity of stenosis after 2.5 years in recipients of lovastatin plus colestipol was reduced by 2.8% compared with placebo, while the frequency of lesion progression was halved and the frequency of lesion regression was tripled. Treatment with lovastatin for 2.2 years in the MARS study significantly reduced the mean percent diameter stenosis compared with placebo (p = 0.005) in patients with more severe stenosis, and also significantly (p = 0.002) reduced the mean global change score (indicating less progression). In the CCAIT study, lovastatin therapy for 2 years significantly improved coronary change scores (p < 0.01) and significantly reduced the incidence of new lesions (p = 0.001) compared with placebo. Across the primary and secondary prevention studies, lovastatin was shown to be similarly effective in women, the elderly, smokers and in subjects with hypertension, hypercholesterolaemia or type 2 diabetes mellitus. Therefore, the available data demonstrate that lovastatin provides significant lipid-modifying efficacy, slows progression or causes regression of atherosclerosis, and protects against acute cardiac events, in both those with and those without symptomatic CHD. PMID- 17705569 TI - Absorption of fentanyl from fentanyl buccal tablet in cancer patients with or without oral mucositis: a pilot study. AB - BACKGROUND AND OBJECTIVES: Patients with cancer, particularly those undergoing chemotherapy or radiotherapy, may develop oral mucositis. This is the first study to investigate the absorption profile of fentanyl buccal tablet (FBT) - an effervescent formulation of fentanyl indicated for the management of breakthrough pain in opioid-tolerant cancer patients - in patients with or without oral mucositis. METHODS: In this open-label study, patients with or without oral mucositis self-administered a single 200 microg dose of FBT by placing the tablet between the upper gum and cheek above a molar tooth. Venous blood samples for measurement of plasma fentanyl concentrations were collected at regular intervals up to 8 hours following FBT administration. Parameters of interest included maximum plasma concentration (C(max)), time to reach C(max) (t(max)), area under the plasma concentration-time curve from time zero to 8 hours (AUC(8)), and AUC from time zero to the median t(max) (AUC(tmax)(')). Adverse events were monitored throughout the study. Oral mucosal examinations and measurements of vital signs were performed at intervals up to 8 hours following FBT administration. RESULTS: Sixteen patients, 8 with and 8 without oral mucositis, received FBT and completed the study. The severity of oral mucositis was mild in the patients exhibiting this condition. Median C(max) values were comparable: 1.14 ng/mL (range 0.26-2.69 ng/mL) in patients with mucositis, and 1.21 ng/mL (range 0.21-2.34 ng/mL) in patients without mucositis. The t(max) was not significantly different in the two groups: median t(max) was 25.0 min (range 15-45 min) in patients with mucositis and 22.5 min (range 10-121 min) in patients without mucositis. Median AUC(tmax') values were 0.17 ng . h/mL (range 0.04-0.52 ng . h/mL) in patients with mucositis, and 0.20 ng . h/mL (range 0.00-0.65 ng . h/mL) in patients without mucositis. The corresponding AUC(8) values were 2.05 ng . h/mL (range 1.16-3.83 ng . h/mL) and 1.55 ng . h/mL (range 0.74-3.07 ng . h/mL), respectively. FBT was generally well tolerated in this small group. No application site adverse events or changes in oral mucosal assessments were reported. CONCLUSION: The absorption profile of a single dose of FBT 200 microg was similar in patients with or without mild oral mucositis. The compound was generally well tolerated. PMID- 17705570 TI - Quinapril for treatment of hypertension in Turkey: dose titration and diuretic combination treatment strategies. AB - BACKGROUND AND OBJECTIVE: Recently the PatenT (Prevalence, awareness, treatment and control of hypertension in Turkey) study showed that while the prevalence of hypertension in Turkey is high, effective control of BP is infrequently achieved. This study investigated the efficacy and safety of quinapril (as monotherapy or in combination with hydrochlorothiazide [HCTZ]) for achieving BP control (target <140/90 mm Hg) in Turkish subjects with mild to moderate hypertension. METHODS: Two-hundred male and female outpatients aged 19-65 years with mild to moderate hypertension (stage I or II, Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure 7 guidelines) entered this 12 week, open-label study. All subjects received quinapril 20 mg/day for 6 weeks. If BP targets were achieved at week 6, responders were maintained on 20 mg/day; if BP targets were not achieved, non-responders were randomised to quinapril 40 mg/day or quinapril 20 mg/day + HCTZ 12.5 mg/day for the remainder of the study. RESULTS: After 6 weeks, 63% of subjects achieved BP targets, and 82% of week-6 responders who continued on quinapril 20 mg/day maintained BP targets at week 12. Of the non-responders, 50% and 52% randomised to quinapril 40 mg/day or quinapril 20 mg/day + HCTZ 12.5 mg/day, respectively, went on to achieve BP targets by week 12. Safety was not compromised with increased dosages or use of combination therapy. CONCLUSION: Quinapril was an effective and safe treatment for achieving and maintaining recommended BP targets in this sample population. These findings will provide clinicians in Turkey with valuable data on the use of quinapril for effective control and management of hypertension. PMID- 17705571 TI - Antihypertensive efficacy and safety of manidipine versus amlodipine in elderly subjects with isolated systolic hypertension: MAISH study. AB - BACKGROUND AND OBJECTIVE: Isolated systolic hypertension (ISH) affects 10-20% of the elderly population and is strongly related to the risk of cardiovascular events. Elevated systolic BP values are primarily caused by reduced large vessel compliance with a consequent increase in total peripheral resistance. Vasodilating drugs, such as calcium channel antagonists, have proven to be effective in controlling ISH in elderly patients. This study set out to compare the antihypertensive efficacy and safety of two different calcium channel antagonists, manidipine and amlodipine, administered once daily in elderly subjects with ISH. METHODS: In a European, randomised, double-blind, multicentre, parallel-group study, after a 2-week placebo run-in period, 195 patients aged >or=60 years with ISH received manidipine 10-20 mg once daily or amlodipine 5-10 mg once daily. Chlortalidone 25mg once daily could be added to the high dose of test drug in the event of insufficient antihypertensive control. The primary efficacy parameter was the proportion of patients with a reduction in office sitting systolic BP (SBP) >or=15 mm Hg, measured at trough, at the final visit. Secondary efficacy parameters included: the proportion of patients with a normal sitting SBP value (<140 mm Hg) at the final visit; a change from baseline to the final visit in mean office trough sitting SBP; a change from baseline to the final visit in the cardiovascular risk score as measured by the INDANA (INdividual Data ANalysis of Antihypertensive intervention trials) project score; the proportion of patients with at least a two-point reduction in the cardiovascular risk score; the percentage of patients requiring upward dose titration and diuretic add-on treatment and the investigator's final judgement. Safety and tolerability evaluations were based on adverse events, ECG and laboratory tests, and clinically relevant reports of abnormalities. RESULTS: In the intention-to-treat population (n = 189), 76% and 72% of patients in the manidipine and amlodipine groups, respectively, had a reduction in sitting SBP of >or=15 mm Hg (p-value not significant for between-group comparison). The percentage of patients with a normal sitting SBP value was 52% in the manidipine group and 51% in the amlodipine group (p-value not significant for between-group comparison). Sitting SBP reductions at the end of treatment were -19.5 +/- 11.8 mm Hg in patients receiving manidipine and -18.4 +/- 11.1 mm Hg in patients receiving amlodipine. Both treatments induced a small reduction in cardiovascular risk score, with 45% of patients in both treatment groups having a two-point reduction in the final score. At the final visit, approximately half of the patients in both treatment groups were still being treated with the low dose of one of the test drugs (manidipine 10mg or amlodipine 5mg). Chlortalidone was added to the high dose of test drugs in 7% and 11% of patients in the amlodipine and manidipine groups, respectively. Both drugs were well tolerated, with a higher incidence of oedema in the amlodipine group (9% vs 4%). No clinically relevant changes in heart rate were induced by either treatment. CONCLUSION: In elderly patients with ISH, treatment with manidipine for 12 weeks was well tolerated and effective and the antihypertensive effects obtained with manidipine were the same as those obtained with amlodipine. PMID- 17705572 TI - Cost-effectiveness analysis of ziprasidone versus haloperidol in sequential intramuscular/oral treatment of exacerbation of schizophrenia: economic subanalysis of the ZIMO trial. AB - OBJECTIVE: This study aimed to assess the cost effectiveness of ziprasidone versus haloperidol in sequential intramuscular (IM)/oral treatment of patients with exacerbation of schizophrenia in Spain. METHODS: A cost-effectiveness analysis from the hospital perspective was performed. Length of stay, study medication and use of concomitant drugs were calculated using data from the ZIMO trial. The effectiveness of treatment was determined by the percentage of responders (reduction in baseline Brief Psychiatric Rating Scale [BPRS] negative symptoms subscale >or=30%). Economic assessment included estimation of mean (95% CI) total costs, cost per responder and the incremental cost-effectiveness ratio (ICER) per additional responder. The economic uncertainty level was controlled by resampling and calculation of cost-effectiveness acceptability curves. RESULTS: A total of 325 patients (ziprasidone n = 255, haloperidol n = 70) were included in this economic subanalysis. Ziprasidone showed a significantly higher responder rate compared with haloperidol (71% vs 56%, respectively; p = 0.023). Mean total costs were euro3582 (95% CI 3226, 3937) for ziprasidone and euro2953 (95% CI 2471, 3436) for haloperidol (p = 0.039), mainly due to a higher ziprasidone acquisition cost. However, costs per responder were lower with ziprasidone (euro5045 [95% CI 4211, 6020]) than with haloperidol (euro5302 [95% CI 3666, 7791], with a cost per additional responder (ICER) for ziprasidone of euro4095 (95% CI -130, 22 231). The acceptability curve showed an ICER cut-off value of euro13 891 at the 95% cost-effectiveness probability level for >or=30% reduction in BPRS negative symptoms. CONCLUSIONS: Compared with haloperidol, ziprasidone was significantly better at controlling psychotic negative symptoms in acute psychoses. The extra cost of ziprasidone was offset by a higher effectiveness rate, yielding a lower cost per responder. In light of the social benefit (less family burden and greater restoration of productivity), the incremental cost per additional responder with sequential IM/oral ziprasidone should be considered cost effective in patients with exacerbation of schizophrenia in Spain. PMID- 17705574 TI - Resource utilisation and time commitment associated with correction of anaemia in cancer patients using epoetin alfa. PMID- 17705573 TI - Lipid-modifying therapy and attainment of cholesterol goals in Hungary: the return on expenditure achieved for lipid therapy (REALITY) study. AB - BACKGROUND AND OBJECTIVE: Cardiovascular disease is a leading cause of death in Eastern Europe. Few studies on cholesterol goal achievement have been conducted in Hungarian clinical settings. This study set out to evaluate lipid-modifying therapy practices and their effects on total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) goal attainment in Hungarian patients with coronary heart disease (CHD), CHD risk equivalents, or >or=2 coronary risk factors. METHODS: This multicentre observational study involved patients receiving lipid-modifying therapy who were under the care of general practitioners (n = 300) or specialists (n = 140). Physician questionnaires were used to collect data on baseline patient characteristics, including laboratory parameters. Using validated cardiovascular risk assessment measures, patients were stratified into high-risk (10-year absolute coronary risk >20%; n = 367) and lower risk groups (n = 73). Cholesterol goals were TC <4.5 mmol/L (<175 mg/dL) and LDL-C <2.5 mmol/L (<100 mg/dL) for the high-risk group and TC <5.0 mmol/L (<193 mg/dL) and LDL-C <3.0 mmol/L (<117 mg/dL) for those at lower risk. RESULTS: Among 440 patients (n = 312 with CHD or CHD risk equivalents), 374 (85%) were initiated on HMG-CoA reductase inhibitors (statin monotherapy), 44 (10%) received fibric acid derivatives and 22 (5%) received combination regimens. Although >50% of patients needed >35% TC lowering to reach goal, <10% of patients received high or very high potency lipid-modifying regimens or combination regimens initially. A total of 116 (26.4%) patients achieved their TC goals after >/=1 year of treatment, including 27.9% of patients with CHD/risk equivalents and 22.7% of those with risk factors only. Sixty-six (15%) patients achieved goal on initial lipid-modifying regimens, while a further 50 (11.4%) achieved goal following treatment changes, including upward dosage adjustments. CONCLUSION: Approximately 74% of Hungarian patients receiving lipid-modifying therapy in our study did not achieve cholesterol goals. The proportion of patients realising their TC goals was higher in those treated by specialists but still did not exceed one-third. PMID- 17705575 TI - Predicting the risk of cardiovascular disease: where does lipoprotein-associated phospholipase A(2) fit in? AB - Although an atherogenic lipoprotein phenotype has been well recognized as an important predictor of cardiovascular disease, recent studies have demonstrated a number of additional lipid-related markers as emerging biomarkers to identify patients at risk for future coronary heart disease. Among them, lipoprotein associated phospholipase A(2) (Lp-PLA(2)), seems to be a promising candidate that might be added to the clinical armamentarium for improved prediction of cardiovascular disease in the future. Of particular note, Lp-PLA(2) is the only enzyme that cleaves oxidized low-density lipoprotein (oxLDL) in the subendothelial space, with further generation of proinflammatory mediators such as lysophosphatidylcholine (LysoPC) and oxidized fatty acid (oxFA), thereby probably linking two important features of atherogenesis, namely oxidation of LDL and local inflammatory processes within the atherosclerotic plaque. This overview aims to summarize our current knowledge based on observations from recent experimental and clinical studies. Emphasis has been put on potential pathophysiological mechanisms of action and on the clinical relevance of Lp PLA(2) in a wide variety of clinical settings, including apparently healthy individuals, patients with stable angina or acute coronary syndromes, after myocardial infarction, and with subclinical disease. Although a growing body of evidence from epidemiological and clinical studies suggests that Lp-PLA(2) may represent an independent and clinically relevant long-term risk marker for coronary heart disease and, probably, also for stroke, the role of this enzyme in the setting of the acute coronary syndrome remains to be established. PMID- 17705576 TI - Lipoprotein-associated phospholipase A(2) : review of its role as a marker and a potential participant in coronary endothelial dysfunction. AB - The role of inflammation in atherosclerosis continues to emerge. Lipoprotein associated phospholipase A(2) (Lp-PLA(2)), a novel plasma biomarker, circulates in the blood bound mainly to low-density lipoprotein (LDL) and promotes vascular inflammation. Several epidemiological studies have shown that circulating levels of Lp-PLA(2) are an independent risk factor for cardiovascular events. Recent studies demonstrate that Lp-PLA(2) is also associated with endothelial dysfunction and early atherosclerosis. This review provides an overview of these studies, suggests plausible mechanisms for the association between endothelial dysfunction and Lp-PLA(2), and highlights future potential therapies. PMID- 17705578 TI - Comparison of FISH and quantitative RT-PCR for the diagnosis and follow-up of BCR ABL-positive leukemias. AB - BACKGROUND: For Philadelphia chromosome positive (Ph+) leukemias (chronic myelogenous leukemia [CML], acute lymphoblastic leukemia [ALL], and rare other leukemias), both allogeneic transplantation and treatment with tyrosine kinase inhibitors offer chances of molecular remission (the molecular marker being consistently undetectable). Molecular remission is defined as a reduction in the quantification of BCR-ABL transcripts to an undetectable level by molecular diagnostic methods, and is considered as a surrogate marker for cure or long-term disease control. The molecular diagnostic methods including fluorescence in situ hybridization (FISH) and quantitative reverse transcription-polymerase chain reaction (QRT-PCR) are more sensitive than classical cytogenetic analysis for the detection of BCR-ABL positive cells. QRT-PCR, due to its superior sensitivity, is considered the gold standard for the follow-up of Ph+ leukemias treated with imatinib. AIM: The objective of our study was to compare the diagnostic and clinical usefulness of FISH and QRT-PCR at different timepoints for Ph+ leukemias. PATIENTS AND METHODS: We investigated 23 unselected patients with Ph+ CML (n = 21) or Ph+ ALL (n = 2) at 77 different timepoints in a comparative study with both FISH and QRT-PCR using commercially available reagents in a routine laboratory. RESULTS: Our study demonstrated a good correlation of QRT-PCR with FISH in detecting the BCR-ABL fusion gene among patients with CML or ALL (coefficient of correlation = 0.77493, p < 0.0001, using Spearman's correlation procedure). All newly diagnosed or untreated cases were positive with both methods. Lower coefficients of correlation were found when FISH and QRT-PCR were correlated with the white blood cell count (WBC). An overall concordance of FISH and QRT-PCR (being either negative or positive in both tests) was found in 65 cases (84.4%) and a discrepancy identified in 12 cases (15.6%). CONCLUSIONS: We confirm that QRT-PCR allows precise measurement of low levels of BCR-ABL transcripts and can serve as a sensitive indicator for minimal residual disease. In addition, we demonstrate in most cases a good correlation of QRT-PCR with FISH in detecting the BCR-ABL fusion gene among patients with CML or Ph+ ALL. FISH is not suitable for monitoring minimal residual disease. PMID- 17705577 TI - Biomarkers of lymphatic function and disease: state of the art and future directions. AB - Substantial advances have accrued over the last decade in the identification of the processes that contribute to lymphatic vascular development in health and disease. Identification of distinct regulatory milestones, from a variety of genetic models, has led to a stepwise chronology of lymphatic development. Several molecular species have been identified as important tissue biomarkers of lymphatic development and function. At present, vascular endothelial growth factor receptor (VEGFR)-3/VEGF-C/VEGF-D signaling has proven useful in the identification of clinical lymphatic metastatic potential and the assessment of cancer prognosis. Similar biomarkers, to be utilized as surrogates for the assessment of inherited and acquired diseases of the lymphatic circulation, are actively sought, and will represent a signal advance in biomedical investigation. PMID- 17705579 TI - T-cell function monitoring in stable renal transplant patients treated with sirolimus monotherapy. AB - BACKGROUND: Sirolimus is an agent with lymphocyte-specific features similar to those of calcineurin inhibitors but with a different mechanism of action and safety profile. To optimize the use of sirolimus-based immunosuppression, further investigation of appropriate pharmacokinetic (sirolimus exposure) and pharmacodynamic (sirolimus T-cell immunomodulator effect) monitoring is required to determine personalized target concentrations. AIM: The main objective of the study was to evaluate the feasibility and reproducibility of combined pharmacokinetic and pharmacodynamic monitoring and to apply biomarkers of immunosuppression in stable kidney transplant recipients receiving sirolimus monotherapy. METHODS: Fourteen renal transplant patients treated with sirolimus monotherapy (median 2 years) were included in this study. Pharmacokinetic and pharmacodynamic parameters were evaluated in each patient three times: at inclusion in the study (day 1), then again at 3 and 6 months. RESULTS: The median sirolimus concentration was 11.5 ng/mL. CD4+ T-cell adenosine triphosphate (ATP) concentrations (150 ng/mL) and interleukin (IL)-10 production (50.9 ng/mL) were significantly lower in treated patients than in healthy controls (n = 95) [301 ng/mL; 278 ng/mL, respectively]. Median inhibition of T-cell proliferation was 60% (31-96%) in treated patients. Interferon-gamma and transforming growth factor beta production was found to be similar to those in the healthy controls. Our results suggest an association between low ATP and IL-10 concentrations and the presence of infection. CONCLUSIONS: The sequential measurement of these biomarkers in stable renal transplant recipients treated with monotherapy could be useful to evaluate the biological effect of sirolimus in each patient and to establish personalized therapy taking into account the individual response to the drug. PMID- 17705580 TI - Tumor necrosis factor-alpha gene polymorphism correlates with cardiovascular disease in patients with end-stage renal disease. AB - BACKGROUND AND OBJECTIVE: Tumor necrosis factor-alpha (TNFalpha) is a potent proinflammatory cytokine. Through its effects on lipid metabolism and endothelial function, TNFalpha is involved in cardiovascular disease (CVD). We have studied two polymorphisms in the promoter region of the TNFalpha gene (TNF -308G/A and TNF -238G/A) in end-stage renal disease (ESRD) patients with and without CVD. The aim was to assess the association of these polymorphisms with ESRD and cardiovascular comorbidity in hemodialyzed patients. METHODS: A total of 603 patients with ESRD treated with hemodialysis (382 patients with CVD) and 325 healthy control subjects were genotyped for the TNF -308G/A and TNF -238G/A ploymorphisms by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) procedure. RESULTS: The A allele of the TNF -308 polymorphism was more frequent in the ESRD group than in control individuals. The odds ratio (OR) for the risk allele was 2.05 (95% CI 1.48, 2.84). In the subgroup of ESRD patients with CVD, the OR was 5.76 (95% CI 3.67, 9.03) relative to ESRD patients without CVD. There was no association observed between the TNF -238 polymorphism and renal failure or CVD in ESRD patients. CONCLUSION: Our results demonstrate for the first time that the A allele of the TNF -308 polymorphism is associated with CVD in hemodialyzed ESRD patients. If confirmed in prospective studies, it may be a predictor of increased susceptibility to CVD in these patients. PMID- 17705581 TI - The simple classification of multiple cancer types using a small number of significant genes. AB - BACKGROUND AND OBJECTIVE: The problems involved in the classification of cancers have recently received a great deal of attention in the context of DNA microarrays. We propose a simple procedure for classifying or predicting the cancer types of test samples when multiple cancer types and many genes are present. METHOD: The procedure sequentially combines a gene-sort algorithm and a predictive likelihood-based classifier. Genes that have homogeneous patterns of expression measurements across cancer types are of limited interest. Therefore, this algorithm orders genes on the basis of strong heterogeneous patterns. The proposed classifier then selects the first few genes, which are sufficient to classify most training samples correctly via cross validation. Test samples were classified using only the selected genes. RESULTS AND CONCLUSION: This predictive likelihood-based classifier performs well and is simple to understand. Empirical examination revealed good classification accuracy using relatively few genes. PMID- 17705582 TI - Total energy evaluation in the Strutinsky shell correction method. AB - We analyze the total energy evaluation in the Strutinsky shell correction method (SCM) of Ullmo et al. [Phys. Rev. B 63, 125339 (2001)], where a series expansion of the total energy is developed based on perturbation theory. In agreement with Yannouleas and Landman [Phys. Rev. B 48, 8376 (1993)], we also identify the first order SCM result to be the Harris functional [Phys. Rev. B 31, 1770 (1985)]. Further, we find that the second-order correction of the SCM turns out to be the second-order error of the Harris functional, which involves the a priori unknown exact Kohn-Sham (KS) density, rho(KS)(r). Interestingly, the approximation of rho(KS)(r) by rho(out)(r), the output density of the SCM calculation, in the evaluation of the second-order correction leads to the Hohenberg-Kohn-Sham functional. By invoking an auxiliary system in the framework of orbital-free density functional theory, Ullmo et al. designed a scheme to approximate rho(KS)(r), but with several drawbacks. An alternative is designed to utilize the optimal density from a high-quality density mixing method to approximate rho(KS)(r). Our new scheme allows more accurate and complex kinetic energy density functionals and nonlocal pseudopotentials to be employed in the SCM. The efficiency of our new scheme is demonstrated in atomistic calculations on the cubic diamond Si and face-centered-cubic Ag systems. PMID- 17705583 TI - Correction to constrained coupled cluster doubles models based on the second coupled cluster central moment. AB - We develop a correction for the coupled cluster version of the perfect pairing (PP) model. The correction is based on finding modified values of the PP amplitudes such that the second coupled cluster central moment defined in the space of all valence single and double substitutions vanishes and, subject to this constraint, minimizing the deviation between the modified and unmodified PP amplitudes with respect to a chosen metric. We discuss how this correction can be generalized to other constrained doubles models, such as local correlation and active-space models. While the correction is not strictly size consistent and retains some of the deficiencies of the PP model, numerical results indicate that much of the missing active-space coupled cluster singles and doubles correlation energy is recovered. PMID- 17705584 TI - Nonadiabatic couplings from time-dependent density functional theory: formulation in the Casida formalism and practical scheme within modified linear response. AB - We present an efficient method to compute nonadiabatic couplings (NACs) between the electronically ground and excited states of molecules, within the framework of time-dependent density functional theory (TDDFT) in frequency domain. Based on the comparison of dynamic polarizability formulated both in the many-body wave function form and the Casida formalism, a rigorous expression is established for NACs, which is similar to the calculation of oscillator strength in the Casida formalism. The adiabatic local density approximation (ALDA) gives results in reasonable accuracy as long as the conical intersection (ci) is not approached too closely, while its performance quickly degrades near the ci point. This behavior is consistent with the real-time TDDFT calculation. Through the use of modified linear response theory together with the ground-state-component separation scheme, the performance of ALDA can be greatly improved, not only in the vicinity of ci but also for Rydberg transitions and charge-transfer excitations. Several calculation examples, including the quantization of NACs from the Jahn-Teller effect in the H3 system, have been given to show that TDDFT can efficiently give NACs with an accuracy comparable to that of wave-function based methods. PMID- 17705585 TI - Basis set convergence of post-CCSD contributions to molecular atomization energies. AB - Basis set convergence of correlation effects on molecular atomization energies beyond the coupled cluster with singles and doubles (CCSD) approximation has been studied near the one-particle basis set limit. Quasiperturbative connected triple excitations, (T), converge more rapidly than L(-3) (where L is the highest angular momentum represented in the basis set), while higher-order connected triples, T3-(T), converge more slowly--empirically, proportional to L(-5/2). Quasiperturbative connected quadruple excitations, (Q), converge smoothly as proportional to L(-3) starting with the cc-pVTZ basis set, while the cc-pVDZ basis set causes overshooting of the contribution in highly polar systems. Higher order connected quadruples display only weak, but somewhat erratic, basis set dependence. Connected quintuple excitations converge very rapidly with the basis set, to the point where even an unpolarized double-zeta basis set yields useful numbers. In cases where fully iterative coupled cluster up to connected quintuples (CCSDTQ5) calculations are not an option, CCSDTQ(5) (i.e., coupled cluster up to connected quadruples plus a quasiperturbative connected quintuples correction) cannot be relied upon in the presence of significant nondynamical correlation, whereas CCSDTQ(5)(Lambda) represents a viable alternative. Connected quadruples corrections to the core-valence contribution are thermochemically significant in some systems. We propose an additional variant of W4 theory [A. Karton et al., J. Chem. Phys. 125, 144108 (2006)], denoted W4.4 theory, which is shown to yield a rms deviation from experimental atomization energies (active thermochemical tables, ATcT) of only 0.05 kcal/mol for systems for which ATcT values are available. We conclude that "3sigma H+HCO via the singlet (S0) and triplet (T1) surfaces. AB - We have explored the photodissociation dynamics of the reaction H(2)CO+hnu- >H+HCO in the range of 810-2600 cm(-1) above the reaction threshold. Supersonically cooled formaldehyde was excited into selected J(Ka,Kc) rotational states of six vibrational levels (1(1)4(1), 5(1), 2(2)6(1), 2(2)4(3), 2(3)4(1), and 2(4)4(1)) in the A((1)A2) state. The laser induced fluorescence spectra of the nascent HCO fragment provided detailed product state distributions. When formaldehyde was excited into the low-lying levels 1(1)4(1), 5(1), and 2(2)6(1), at E(avail)<1120 cm(-1), the product state distribution can be modeled qualitatively by phase space theory. These dynamics are interpreted as arising from a reaction path on the barrierless S0 surface. When the initial states 2(2)4(3) and 2(3)4(1) were excited (E(avail)=1120-1500 cm(-1)), a second type of product state distribution appeared. This second distribution peaked sharply at low N, Ka and was severely truncated in comparison with those obtained from the lower lying states. At the even higher energy of 2(4)4(1) (E(avail) approximately 2600 cm(-1)) the sharply peaked distribution appears to be dominant. We attribute this change in dynamics to the opening up of the triplet channel to produce HCO. The theoretical height of the barrier on the T1 surface lies between 1700 and 2100 cm(-1) and so we consider the triplet reaction to proceed via tunneling at the intermediate energies and proceed over the barrier at the higher energies. Considerable population was observed in the excited (0,0,1) state for all initial H(2)CO states that lie above the appearance energy. Rotational populations in the (0,0,1) state dropped more rapidly with (N,Ka) than did the equivalent populations in (0,0,0). This indicates that, although individual rotational states are highly populated in (0,0,1), the total v3=1 population might not be so large. Specific population was also measured in the almost isoenergetic Kc and J states. No consistent population preference was found for either asymmetry or spin-rotation component. PMID- 17705592 TI - Intramolecular vibrational energy redistribution from a high frequency mode in the presence of an internal rotor: classical thick-layer diffusion and quantum localization. AB - We study the effect of an internal rotor on the classical and quantum intramolecular vibrational energy redistribution (IVR) dynamics of a model system with three degrees of freedom. The system is based on a Hamiltonian proposed by Martens and Reinhardt [J. Chem. Phys. 93, 5621 (1990)] to study IVR in the excited electronic state of para-fluorotoluene. We explicitly construct the state space and show, confirming the mechanism proposed by Martens and Reinhardt, that an excited high frequency mode relaxes via diffusion along a thick layer of chaos created by the low frequency-rotor interactions. However, the corresponding quantum dynamics exhibits no appreciable relaxation of the high frequency mode. We attribute the quantum suppression of the classical thick-layer diffusion to the rotor selection rules and, possibly, dynamical localization effects. PMID- 17705593 TI - Car-Parrinello and path integral molecular dynamics study of the hydrogen bond in the chloroacetic acid dimer system. AB - We have studied the double proton transfer (DPT) reaction in the cyclic dimer of chloroacetic acid using both classical and path integral Car-Parrinello molecular dynamics. We also attempt to quantify the errors in the potential energy surface that arise from the use of a pure density functional. In the classical dynamics a clear reaction mechanism can be identified, where asynchronized DPT arises due to coupling between the O-H stretching oscillator and several low energy intermolecular vibrational modes. This mechanism is considerably altered when quantum tunneling is permitted in the simulation. The introduction of path integrals leads to considerable changes in the thermally averaged molecular geometry, leading to shorter and more centered hydrogen bond linkages. PMID- 17705594 TI - Tuning electronic eigenvalues of benzene via doping. AB - Using variable atomic numbers within molecular grand-canonical ensemble theory, the highest occupied Kohn-Sham eigenvalue of isoelectronic benzene derivatives is tuned. The performed transmutational changes correspond to the iterative doping with boron and nitrogen. The molecular Fukui function proves to be a reliable index in order to predict the changes in the highest occupied molecular orbital eigenvalue due to doping. PMID- 17705595 TI - Photofragment slice imaging studies of pyrrole and the Xe...pyrrole cluster. AB - The photolysis of pyrrole has been studied in a molecular beam at wavelengths of 250, 240, and 193.3 nm, using two different carrier gases, He and Xe. A broad bimodal distribution of H-atom fragment velocities has been observed at all wavelengths. Near threshold at both 240 and 250 nm, sharp features have been observed in the fast part of the H-atom distribution. Under appropriate molecular beam conditions, the entire H-atom loss signal from the photolysis of pyrrole at both 240 and 250 nm (including the sharp features) disappear when using Xe as opposed to He as the carrier gas. We attribute this phenomenon to cluster formation between Xe and pyrrole, and this assumption is supported by the observation of resonance enhanced multiphoton ionization spectra for the (Xe...pyrrole) cluster followed by photofragmentation of the nascent cation cluster. Ab initio calculations are presented for the ground states of the neutral and cationic (Xe...pyrrole) clusters as a means of understanding their structural and energetic properties. PMID- 17705596 TI - Experimental and theoretical study of the pyrrole cluster photochemistry: closing the pisigma* dissociation pathway by complexation. AB - Photolysis of size selected pyrrole clusters has been investigated and compared to the photolysis of an isolated pyrrole molecule. Experimentally, size distributions of different mean cluster sizes (n=3 and n>>5) have been prepared in supersonic expansions and the clusters were photolyzed at 243 and 193 nm. The kinetic energy distributions of the H photofragments have been measured. The distributions exhibit a bimodal character with fast and slow H-fragment peaks similar to the spectra of the bare molecule. However, with increasing cluster size the slow component gains intensity with respect to the fast one. A similar effect is observed with increasing the excitation energy from 243 to 193 nm. Theoretical calculations at the CASSCF/CASPT2 level have been performed for bare and complexed pyrroles (pyrrole is complexed with an argon atom and with another pyrrole unit). Combination of theoretical and experimental approaches leads to the conclusion that the direct dissociative pathway along the pisigma* potential energy surface in the N-H stretch coordinate is closed by the presence of the solvent molecule. This pathway is an important channel leading to the fast H atoms in the dissociation of the bare molecule. The solvent molecule influences significantly the electronic structure in the Rydberg-type pisigma* state while it has little influence on the valence states. The slow channel is mostly populated by the out-of-plane deformation mode which is also not influenced by solvation. We have also studied other possible reaction channels in pyrrole clusters (hydrogen transfer, dimerization). The present study shows that more insight into the bulk behavior of biologically relevant molecules can be gained from cluster studies. PMID- 17705597 TI - Photodissociation of S atom containing amino acid chromophores. AB - Photodissociation of 3-(methylthio)propylamine and cysteamine, the chromophores of S atom containing amino acid methionine and cysteine, respectively, was studied separately in a molecular beam at 193 nm using multimass ion imaging techniques. Four dissociation channels were observed for 3 (methylthio)propylamine, including (1) CH(3)SCH(2)CH(2)CH(2)NH(2)- >CH(3)SCH(2)CH(2)CH(2)NH+H, (2) CH(3)SCH(2)CH(2)CH(2)NH(2)- >CH(3)+SCH(2)CH(2)CH(2)NH(2), (3) CH(3)SCH(2)CH(2)CH(2)NH(2)- >CH(3)S+CH(2)CH(2)CH(2)NH(2), and (4) CH(3)SCH(2)CH(2)CH(2)NH(2)- >CH(3)SCH(2)+CH(2)CH(2)NH(2). Two dissociation channels were observed from cysteamine, including (5) HSCH(2)CH(2)NH(2)-->HS+CH(2)CH(2)NH(2) and (6) HSCH(2)CH(2)NH(2)-->HSCH(2)+CH(2)NH(2). The photofragment translational energy distributions suggest that reaction (1) and parts of the reactions (2), (3), (5) occur on the repulsive excited states. However, reaction (4), (6) occur only after the internal conversion to the electronic ground state. Since the dissociation from an excited state with a repulsive potential energy surface is very fast, it would not be quenched completely even in the condensed phase. Our results indicate that reactions following dissociation may play an important role in the UV photochemistry of S atom containing amino acid chromophores in the condensed phase. A comparison with the potential energy surface from ab initio calculations and branching ratios from RRKM calculations was made. PMID- 17705598 TI - Chemiluminescent reaction of Ba(3P) with N2O at hyperthermal collision energies: rotational alignment of the BaO(A 1Sigma+) product. AB - The chemiluminescent reaction Ba(6s6p (3)P)+N(2)O was studied at an average collision energy of 1.56 eV in a beam-gas arrangement. Ba((3)P) was produced by laser ablation of barium, which resulted in a broad collision energy distribution extending up to approximately 5.7 eV. A series of experiments was made to extract the Ba((3)P) contribution to chemiluminescence from that corresponding to Ba 6s(2) (1)S0 and 6s5d (3)D, which are the other two most populated states in the atomic beam. The fully dispersed polarized chemiluminescence spectra at 400-600 nm from the title reaction were recorded and assigned to a BaO molecule excited in the A (1)Sigma+ level. In addition, the average and wavelength-resolved degrees of polarization associated to the parallel BaO(A (1)Sigma+-->X (1)Sigma+) emission are reported. The analysis of the average polarization degree show that the BaO(A (1)Sigma+) product is significantly aligned, suggesting that the reaction mechanism is predominantly direct. The product rotational alignment was found to depend markedly on the emission wavelength, which revealed a negative correlation with the BaO(A (1)Sigma+) product vibrational state. On the basis of experimental and theoretical investigations on the reactions of N(2)O with both the (1)S0, (3)D, and (1)P1 states of Ba and the lighter group 2 atoms, it is suggested that the Ba((3)P) reaction involves a charge transfer at relatively short reagent separations and that restricted collision geometries at the highest velocity components of the broad distribution are necessary to rationalize the data. PMID- 17705599 TI - Probing molecular symmetry effects in the ionization of N2 and O2 by intense laser fields. AB - High-resolution electron spectroscopy is used to explore the role played by molecular symmetry in determining the morphology of the energy spectra of electrons ejected when N2 and O2 are irradiated by intense laser fields. In O2, the low-energy part of the electron spectrum is curtailed due to the destructive interference brought about by the antibonding nature of the O2 valence orbital. The high-energy tail of the spectrum is also suppressed by virtue of electron rescattering being of little consequence in O2. In contrast, in N2, which has a bonding valence orbital, the electron dynamics follow the pattern that has been established for atomic ionization in strong optical fields. PMID- 17705600 TI - Ligand field photofragmentation spectroscopy of [Ag(L)N]2+ complexes in the gas phase: experiment and theory. AB - Experiments have been undertaken to record photofragmentation spectra from a series of [Ag(L)N]2+ complexes in the gas phase. Spectra have been obtained for silver(II) complexed with the ligands (L): acetone, 2-pentanone, methyl-vinyl ketone, pyridine, and 4-methyl pyridine (4-picoline) with N in the range of 4-7. A second series of experiments using 1,1,1,3-fluoroacetone, acetonitrile, and CO2 as ligands failed to show any evidence of photofragmentation. Interpretation of the experimental data has come from time-dependent density functional theory (TDDFT), which very successfully accounts for trends in the spectra in terms of subtle differences in the properties of the ligands. Taking a sample of three ligands, acetone, pyridine, and acetonitrile, the calculations show all the spectral transitions to involve ligand-to-metal charge transfer, and that wavelength differences (or lack of spectra) arise from small changes in the energies of the molecular orbitals concerned. The calculations account for an absence in the spectra of any effects due to Jahn-Teller distortion, and they also reveal structural differences between complexes where the coordinating atom is either oxygen or nitrogen that have implications for the stability of silver(II) compounds. Where possible, comparisons have also been made with the physical properties of condensed phase silver(II) complexes. PMID- 17705601 TI - OOCO+ cation I: characterization of its isomers and lowest electronic states. AB - Accurate ab initio calculations are performed in order to investigate the stable isomers of OOCO+ and its electronic states at both the molecular and asymptotic regions. These calculations are done using large basis sets and configuration interaction methods. Our theoretical computations predict the presence of four stable forms: A global minimum where a weakly bound charge transfer complex (OOOC+) may be found. Few tenths of cm(-1) above in energy, the OOCO+ very weakly bound isomer is predicted. At 1.75 eV above OOCO+, a strongly bound centrosymmetric isomer (c-CO3+) is located. For energies >8 eV, a third isomer of C(2v) symmetry is found where one oxygen is in the center. The one-dimensional potential energy surface cuts of these electronic states reveal the existence of shallow potential wells for OOCO+ and OOOC+ and of deep potential wells for the two other forms, where electronically excited molecules can be formed at least transiently. Finally, the electronic states of each isomer should interact by spin-orbit, vibronic, Renner-Teller, and Jahn-Teller couplings in competition with isomerization processes converting one form to another. PMID- 17705602 TI - OOCO+ cation. II. Its role during the atmospheric ion-molecule reactions. AB - For the charge transfer and vibrational and electronic deexcitations between O2/O2+ + CO+/CO, O/O+ + CO2+/CO2, and C/C+ + O3+/O3, multistep reaction pathways are discussed in light of the theoretical data of this and previous paper together with close comparison with the experimental observations. Our calculations show that these pathways involve both the long range and molecular region ranges of the potential energy surfaces of the electronic states of the stable isomers of OOCO+ and mostly those of the weakly bound charge transfer complex OOCO+. The couplings between these electronic states such as vibronic, Renner-Teller, Jahn-Teller, and spin orbit are viewed to play crucial roles here. Moreover, the initial orientation of the reactants, in the entrance channels, strongly influences the reaction mechanisms undertaken. We propose for the first time a mechanism for the widely experimentally studied spin-forbidden exothermic O+((4)S(u))+CO2(X (1)Sigmag+)-->O2+(X (2)Pi(g))+CO(X (1)Sigma+) reaction where the O turns around the OCO molecule. PMID- 17705603 TI - Temperature dependence of negative ion lifetimes. AB - The autodetachment lifetimes of SF6-* and C6F6-* ions formed by charge transfer in K(np)/SF6, C6F6 collisions are measured as a function of target temperature over the range of approximately 300-600 K with the aid of time-of-flight techniques and a Penning ion trap. At room temperature only formation of long lived SF6 -* ions with lifetimes tau >or similar to 1 ms is seen. As the temperature is increased the lifetime of these long-lived ions is reduced, some having lifetimes as short as approximately 0.4 ms. The appearance of a short lived, tau O+OH(v',j') reaction on three potential energy surfaces. AB - We report state-to-state and total reaction probabilities for J=0 and total reaction probabilities for J=2 and 4 for the title reaction, both for ground state and initially rovibrationally excited reactants. The results for three different potential energy surfaces are compared and contrasted. The potential energy surfaces employed are the DMBE IV surface by Pastrana et al. [J. Phys. Chem. 94, 8073 (1990)], the surface by Troe and Ushakov (TU) [J. Chem. Phys. 115, 3621 (2001)], and the new XXZLG ab initio surface by Xu et al. [J. Chem. Phys. 122, 244305 (2005)]. Our results show that the total reaction probabilities from both the TU and XXZLG surfaces are much smaller in magnitude for collision energies above 1.2 eV compared to the DMBE IV surface. The three surfaces also show different behavior with regards to the effect of initial state excitation. The reactivity is increased on the XXZLG and the TU surfaces and decreased on the DMBE IV surface. Vibrational and rotational product state distributions for the XXZLG and the DMBE IV surface show different behaviors for both types of distributions. Our results show that for energies above 1.25 eV the dynamics on the DMBE IV surface are not statistical. However, there is also evidence that the dynamics on the XXZLG surface are not purely statistical for energies above the onset of the first excited product vibrational state v'=1. The magnitude of the total reaction probability is decreased for J>0 for the DMBE IV and the XXZLG surfaces for ground-state reactants. However, for initially rovibrationally excited reactants, the total reaction probability does not decrease as expected for both surfaces. As a result the total cross section averaged over all Boltzmann accessible rotational states may well be larger than the cross section reported in the literature for j=1. PMID- 17705604 TI - Quantum energy flow and the kinetics of water shuttling between hydrogen bonding sites on trans-formanilide. AB - A potential energy surface for trans-formanilide (TFA)-H2O is calculated and applied to study energy flow in the complex as well as the kinetics of water shuttling between hydrogen bonding sites on TFA. In addition to the previously identified H2O-TFA(C[Double Bond]O) and H2O-TFA(NH) minima, with the water monomer bound to the C[Double Bond]O and NH groups, respectively, the new surface reveals a second local minimum with the water bound to the C[Double Bond]O group, and which lies energetically 310 cm(-1) above the previously identified H2O TFA(C[Double Bond]O) global minimum. On this surface, the energy barrier for water shuttling from H2O-TFA(C[Double Bond]O) global minimum to H2O-TFA(N-H) is 984 cm(-1), consistent with the experimental bounds of 796 and 988 cm(-1) [J. R. Clarkson et al. Science 307, 1443 (2005)]. The ergodicity threshold of TFA is calculated to be 1450 cm(-1); for the TFA-H2O complex, the coupling to the water molecule is found to lower the ergodicity threshold to below the isomerization barrier. Energy transfer between the activated complex and the vibrational modes of TFA is calculated to be sufficiently rapid that the Rice-Ramsperger-Kassel Marcus (RRKM) theory does not overestimate the rate of water shuttling. The possibility that the rate constant for water shuttling is higher than the RRKM theory estimate is discussed in light of the relatively high energy of the ergodicity threshold calculated for TFA. PMID- 17705606 TI - Influence of thermostats and carrier gas on simulations of nucleation. AB - We investigate the influence of carrier gas and thermostat on molecular dynamics (MD) simulations of nucleation. The task of keeping the temperature constant in MD simulations is not trivial and an inefficient thermalization may have a strong influence on the results. Different thermostating mechanisms have been proposed and used in the past. In particular, we analyze the efficiency of velocity rescaling, Nose-Hoover, and a carrier gas (mimicking the experimental situation) by extensive MD simulations. Since nucleation is highly sensitive to temperature, one would expect that small variations in temperature might lead to differences in nucleation rates of up to several orders of magnitude. Surprisingly, the results indicate that the choice of the thermostating method in a simulation does not have--at least in the case of Lennard-Jones argon--a very significant influence on the nucleation rate. These findings are interpreted in the context of the classical theory of Feder et al. [Adv. Phys. 15, 111 (1966)] by analyzing the temperature distribution of the nucleating clusters. We find that the distribution of cluster temperatures is non-Gaussian and that subcritically sized clusters are colder while postcritically sized clusters are warmer than the bath temperature. However, the average temperature of all clusters is found to be always higher than the bath temperature. PMID- 17705607 TI - A diagrammatic formulation of the kinetic theory of fluctuations in equilibrium classical fluids. VI. Binary collision approximations for the memory function for self-correlation functions. AB - We use computer simulation results for a dense Lennard-Jones fluid for a range of temperatures to test the accuracy of various binary collision approximations for the memory function for density fluctuations in liquids. The approximations tested include the moderate density approximation of the generalized Boltzmann Enskog memory function (MGBE) of Mazenko and Yip [Statistical Mechanics. Part B. Time-Dependent Processes, edited by B. J. Berne (Plenum, New York, 1977)], the binary collision approximation (BCA) and the short time approximation (STA) of Ranganathan and Andersen [J. Chem. Phys. 121, 1243 (2004); J. Phys. Chem. 109, 21437 (2005)] and various other approximations we derived by using diagrammatic methods. The tests are of two types. The first is a comparison of the correlation functions predicted by each approximate memory function with the simulation results, especially for the self-longitudinal current correlation (SLCC) function. The second is a direct comparison of each approximate memory function with a memory function numerically extracted from the correlation function data. The MGBE memory function is accurate at short times but decays to zero too slowly and gives a poor description of the correlation function at intermediate times. The BCA is exact at zero time, but it predicts a correlation function that diverges at long times. The STA gives a reasonable description of the SLCC but does not predict the correct temperature dependence of the negative dip in the function that is associated with caging at low temperatures. None of the other binary collision approximations is a systematic improvement on the STA. The extracted memory functions have a rapidly decaying short time part, much like the STA, and a much smaller, more slowly decaying part of the type predicted by a mode coupling theory. Theories that use mode coupling commonly include a binary collision term in the memory function but do not discuss in detail the nature of that term. It is clear from the present work that the short time part of the memory function has a behavior associated with brief binary repulsive collisions, such as those described by the STA. Collisions that include attractive as well as repulsive interactions, such as those of the MGBE, have a much longer duration, and theories that include them have memory functions that decay to zero much too slowly to provide a good first approximation of the correlation function. This leads us to speculate that the memory function for density fluctuations can be usefully regarded as a sum of at least three parts: a contribution from repulsive binary collisions (the STA or something similar to it), another short time part that is related to all the other interactions (but whose nature is not understood), and a longer time slowly decaying part that describes caging (of the type predicted by the mode coupling theory). PMID- 17705608 TI - Instability and pattern formation in reaction-diffusion systems: a higher order analysis. AB - We analyze the condition for instability and pattern formation in reaction diffusion systems beyond the usual linear regime. The approach is based on taking into account perturbations of higher orders. Our analysis reveals that nonlinearity present in the system can be instrumental in determining the stability of a system, even to the extent of destabilizing one in a linearly stable parameter regime. The analysis is also successful to account for the observed effect of additive noise in modifying the instability threshold of a system. The analytical study is corroborated by numerical simulation in a standard reaction-diffusion system. PMID- 17705609 TI - Synchrotron x-ray studies of molecular liquid SnI4. AB - Synchrotron x-ray diffraction measurements were performed on liquid SnI4 up to a scattering vector of 25 A(-1), utilizing a horizontal two-axis diffractometer installed at the SPring-8 bending magnet beam line BL04B2 in Japan. An effective method based on the maximum entropy method was devised to transform the measured total structure factor to the reduced radial distribution function. The reliability of the density estimation is discussed. PMID- 17705610 TI - Interrelation between cluster formation time, cluster growth probability, and nucleation rate. AB - Approximate expressions are derived for the mean time tau for formation of a cluster of n molecules in nucleation of single-component phases. The derivation elucidates the interrelation between tau, the cluster growth probability P, and the stationary nucleation rate. The extraction of both tau(n) and P(n) data from individual cluster growth curves obtained in experiments or simulations is discussed. It is shown that the analysis of tau(n) data allows a model independent determination of the nucleus size, the Zeldovich factor, the stationary nucleation rate, the frequency with which molecules are attached to the nucleus, and the difference between the works to form the nucleus and the smallest "cluster" of one molecule. PMID- 17705611 TI - Fourier transform infrared observation of the nu1(sigma) mode of linear CoC3 trapped in solid Ar. AB - Fourier transform infrared (FTIR) and density functional theory (DFT) isotopic studies on cobalt-carbon species have resulted in the detection of linear CoC3. Dual laser ablation of carbon and cobalt rods, followed by trapping the products in solid Ar at approximately 10 K, produced the CoC3 chain. FTIR measurements of 13C isotopic shifts are in good agreement with the predictions of DFT calculations using the B3LYP and BPW91 functionals and the 6-311+G(3df) basis set, confirming the assignment of the nu1(sigma) fundamental of linear CoC3 at 1918.2 cm(-1). PMID- 17705612 TI - Regarding convergence curve of virial expansion for the Lennard-Jones system. AB - We calculate the convergence curve of the virial expansion for a Lennard-Jones system in the density-temperature plane using the approximate method based on the density expansion of the Ornstein-Zernike equation and the condition of thermodynamic consistency [J. Chem. Phys. 106, 6095 (1997)]. At subcritical temperatures, this curve is close to the binodal. At supercritical temperatures, the curve does not coincide with the freezing curve. In the latter case, the densities along the convergence line are distinctly smaller than the densities corresponding to the condensed state. PMID- 17705613 TI - Theoretical study on the sound absorption of electrolytic solutions. II. Assignments of relaxations. AB - The theory on the ultrasonic absorption spectrum of electrolytic solutions recently proposed by us is applied to the model system that resembles to the aqueous solution of MgSO4. The charges on ions are reduced to +/-1.5e in order to obtain the equilibrium structure by the integral equation theory. The theory reproduces the existence of two relaxations around 100 kHz and 1 GHz. The physical origin of the relaxation is analyzed based on the theoretical expression. The slower relaxation is shown to originate in the formation of contact ion pair, in harmony with the conventional assignment. The amplitude of this relaxation agrees with the experimental one fairly well. The absorption cross section is a weakly increasing function of the concentration of the salt in theory, whereas it depends little on the concentration in experiment, which is ascribed to the weaker association of the pair in the theory. The deviation from the Debye relaxation is found for the faster process, and the concentration dependence is small. The analysis shows that this relaxation stems from the coupling between the pressure and the long-range concentration fluctuation, and the concentration independence and the non-Debye relaxation are explained based on the theoretical analysis. In particular, the theory demonstrates that this process has the t(-3/2) tail in the time domain, which is confirmed by numerical calculation. The deviation of the theoretical relaxation amplitude from the experimental one is elucidated in terms of the theoretical expression of the coefficient. PMID- 17705615 TI - The formation of vibrationally excited HD from atomic recombination on cold graphite surfaces. AB - HD molecules formed in v"=3 and v"=4 have been detected by laser spectroscopy when a cold (15 K) graphite surface is irradiated with H and D atoms. Population of the v"=3, J"=0-6 and v"=4, J"=0-6 levels has been detected and the average rotational temperatures of the nascent HD were determined. These results are compared with previous data collected for the formation of HD in v"=1 and 2 under similar conditions. This comparison indicates that the nascent HD flux increases with increasing vibrational quantum number for v"=1-4. PMID- 17705614 TI - Hydration free energies of monovalent ions in transferable intermolecular potential four point fluctuating charge water: an assessment of simulation methodology and force field performance and transferability. AB - Hydration free energies of nonpolarizable monovalent atomic ions in transferable intermolecular potential four point fluctuating charge (TIP4P-FQ) are computed using several commonly employed ion-water force fields including two complete model sets recently developed for use with the simple water model with four sites and Drude polarizability and TIP4P water models. A simulation methodology is presented which incorporates a number of finite-system free energy corrections within the context of constant pressure molecular dynamics simulations employing the Ewald method and periodic boundary conditions. The agreement of the computed free energies and solvation structures with previously reported results for these models in finite droplet systems indicates good transferability of ion force fields from these water models to TIP4Q-FQ even when ion polarizability is neglected. To assess the performance of the ion models in TIP4P-FQ, we compare with consensus values for single-ion hydration free energies arising from recently improved cluster-pair estimates and a reevaluation of commonly cited, experimentally derived single-ion hydration free energies; we couple the observed consistency of these energies with a justification of the cluster-pair approximation in assigning single-ion hydration free energies to advocate the use of these consensus energies as a benchmark set in the parametrization of future ion force fields. PMID- 17705617 TI - Contact instability of thin elastic films on patterned substrates. AB - The free surface of a soft elastic film becomes unstable and forms an isotropic labyrinth pattern when a rigid flat plate is brought into adhesive contact with the film. These patterns have a characteristic wavelength, lambda approximately 3H, where H is the film thickness. We show that these random structures can be ordered, modulated, and aligned by depositing the elastic film (cross-linked polydimethylsiloxane) on a patterned substrate and by bringing the free surface of the film in increasing adhesive contact with a flat stamp. Interestingly, the influence of the substrate "bleeds" through the film to its free surface. It becomes possible to generate complex two-dimensional ordered structures such as an array of femtoliter beakers even by using a simple one-dimensional stripe patterned substrate when the instability wavelength, lambda approximately 3H, nearly matches the substrate pattern periodicity. The free surface morphology is modulated in situ by merely varying the stamp-surface separation distance. The free surface structures originating from the elastic contact instability can also be made permanent by the UV-ozone induced oxidation and stiffening. PMID- 17705616 TI - Magnetic studies of a syn-anti triatomic carboxylate-bridging chainlike copper(II) complex exhibiting ferromagnetic exchange. AB - The magnetic properties of triatomic syn-anti carboxylate bridging copper(II) complex, {[Cu(2,2'-bipydine)(maleate)].2H2O}infinity (complex 1), were investigated experimentally and theoretically, suggesting weak ferromagnetic intrachain interaction. The magnetic data were analyzed and interpreted in terms of Heisenberg chain model corrected by a mean molecular field. Fitting parameters obtained for J, g, and zJ' are 3.14 cm(-1), 2.08, and -0.13, respectively. Density functional theory with generalized gradient approximation was applied to calculate the electronic structure and spin distribution of the present complex. The structural and electronic factors controlling the magnetic interactions were also determined. Ferromagnetic intrachain interactions through triatomic syn-anti carboxylate bridge result from nonplanarity of the bridging network, the exchange pathway involving both the sigma and pi orbitals of the carboxylate bridge and the spin delocalization of each magnetic orbital on the atoms of the carboxylate bridge from the copper(II) centers. PMID- 17705618 TI - Line and boundary tensions on approach to the wetting transition. AB - A mean-field density-functional model often used in the past in the study of line and boundary tensions at wetting and prewetting transitions is reanalyzed by extensive numerical calculations, approaching the wetting transition much more closely than had previously been possible. The results are what are now believed to be definitive for the model. They include strong numerical evidence for the presence of the logarithmic factors predicted by theory both in the mode of approach of the prewetting line to the triple-point line at the point of the first-order wetting transition and in the line tension itself on approach to that point. It is also demonstrated with convincing numerical precision that the boundary tension on the prewetting line and the line tension on the triple-point line have a common limiting value at the wetting transition, again as predicted by theory. As a by product of the calculations, in the model's symmetric three phase state, far from wetting, it is found that certain properties of the model's line tension and densities are almost surely given by simple numbers arising from the symmetries, but proving that these are exact for the model remains a challenge to analytical theory. PMID- 17705619 TI - Interlayer water molecules in vanadium pentoxide hydrate. IX. Anisotropic translational diffusion leading to anisotropic ac conductivity. AB - The anisotropy of the dynamic properties of interlayer water molecules along the a and b axes of vanadium pentoxide hydrate, orthorhombic V2O5.nH2O, was studied using quasielastic neutron scattering (QENS) in relation to the anisotropy of the ac conductivity. The QENS spectra were analyzed using a stretched exponential function and a Lorentzian function. Both methods showed that the double-layer water molecules along the b axis are more mobile than those along the a axis. The difference in mobility between the two axes is more pronounced using a Lorentzian function analysis. These facts suggest that the diffusion coefficient of water molecules along the b axis is larger than that along the a axis, which is closely related to the ac conductivity originating from proton hopping. The anisotropy of the dynamic motion of water molecules can be attributed to the shorter b-axis length (b=3.60 A), with respect to the longer and less regular repetition of the atomic arrangements along the a axis (42.34 A). PMID- 17705620 TI - Effects of coverage on the structures, energetics, and electronics of oxygen adsorption on RuO2(110). AB - Plane-wave supercell DFT calculations within the PW91 generalized gradient approximation are used to examine the influence of oxygen coverage on the structure, energetics, and electronics of the RuO2(110) surface. Filling of O(br) and O(cus) sites is exothermic with respect to molecular O2 at all coverages and causes changes in local Ru electronic structure consistent with the changing metal coordination. By fitting the surface energies of a large number of surface configurations to a two-body interaction model, an O atom is calculated to be bound by 2.55 eV within a filled O(br) row and by 0.98 eV along an otherwise vacant O(cus) row. Lateral interactions modify these binding energies by up to 20%. O(cus)-O(cus) interactions are repulsive and diminish binding energy with increasing O(cus) filling. Due to the favorable relief of local strain, O(br) O(br) interactions are attractive and favor filling of neighbor br sites. These interaction effects are relatively modest in absolute magnitude but are large enough to influence the ability of the RuO2(110) surface to promote oxidation of relatively weak reductants, such as NO and C2H4. PMID- 17705621 TI - Role of chain stiffness on the conformation of single polyelectrolytes in salt solutions. AB - Conformation of single polyelectrolytes in tetravalent salt solutions is investigated under the framework of a coarse-grained model, using Langevin dynamics simulations. The chain size, studied by the radius of gyration, shows three different variational behaviors with salt concentration, depending on the chain stiffness. According to the size variations, polyelectrolytes of fixed chain length are classified into three categories: (1) flexible chain, for which the variation shows a curve similar to a tilted L, (2) semiflexible chain, whose curve resembles U, and (3) rigid chain, for which the curve is a straight line. The wormlike chain model with persistence length predicted by the Odijk-Skolnick Fixman theory is found to be able to qualitatively describe the end-to-end distance at low salt concentration not only for semiflexible and rigid chains but also for flexible chain. In a low salt region, a flexible polyelectrolyte extends more significantly than a semiflexible chain, in reference of the size of their uncharged counterparts, and in a high salt region, regardless of chain stiffness, a chain attains a dimension comparable to that of its neutral polymer. The chain stiffness influences both the local and the global chain structures. A flexible chain exhibits a zigzagged local structure in the presence of salt ions, and the condensed structure is a disordered, random globule. A semiflexible chain is locally smooth, and the condensed structure is orderly packed, taking a form such as hairpin or toroid. Moreover, the chain stiffness can also affect the nature of the coil-globule transition. The transition occurred in a discrete manner for semiflexible chain, whereas it occurred in a continuous way for flexible chain. This discrete feature happened not only at low salt concentration when a semiflexible chain collapsed but also at high salt concentration when the collapsed chain is reexpanded. At the end, the effects of chain stiffness and salt concentration on the conformation of single polyelectrolytes are summarized in a schematic state diagram. PMID- 17705622 TI - Modeling of polyethylene and poly (L-lactide) polymer blends and diblock copolymer: chain length and volume fraction effects on structural arrangement. AB - Dissipative particle dynamics (DPD), a mesoscopic simulation approach, has been used to investigate the chain length effect on the structural property of the immiscible polyethylene (PE)/poly(L-lactide) (PLLA) polymer in a polymer blend and in a system with their diblock copolymer. In this work, the interaction parameter in DPD simulation, related to the Flory-Huggins interaction parameter chi, is estimated by the calculation of mixing energy for each pair of components in molecular dynamics simulation. The immiscibility property of PE and PLLA polymers induces the phase separation and exhibits different architectures at different volume fractions. In order to observe the structural property, the radius of gyration is used to observe the detailed arrangement of the polymer chains. It shows that the structure arrangement of a polymer chain is dependent on the phase structure and has a significantly different structural arrangement character for the very short chains in the homopolymer and copolymers. The chain length effect on the degree of stretching or extension of polymers has also been observed. As the chain length increases, the chain exhibits more stretching behavior at lamellae, perforated lamellae, and cylindrical configurations, whereas the chain exhibits a similar degree of stretching or extension at the cluster configuration. PMID- 17705623 TI - New theoretical considerations in polymer rheology: elastic breakdown of chain entanglement network. AB - Recent experimental evidence has motivated us to present a set of new theoretical considerations and to provide a rationale for interpreting the intriguing flow phenomena observed in entangled polymer solutions and melts [P. Tapadia and S. Q. Wang, Phys. Rev. Lett. 96, 016001 (2006); 96, 196001 (2006); S. Q. Wang et al., ibid. 97, 187801 (2006)]. Three forces have been recognized to play important roles in controlling the response of a strained entanglement network. During flow, an intermolecular locking force f(iml) arises and causes conformational deformation in each load-bearing strand between entanglements. The chain deformation builds up a retractive force f(retract) within each strand. Chain entanglement prevails in quiescence because a given chain prefers to stay interpenetrating into other chains within its pervaded volume so as to enjoy maximum conformational entropy. Since each strand of length l(ent) has entropy equal to k(B)T, the disentanglement criterion is given by f(retract)>f(ent) approximately k(B)Tl(ent) in the case of interrupted deformation. This condition identifies f(ent) as a cohesive force. Imbalance among these forces causes elastic breakdown of the entanglement network. For example, an entangled polymer yields during continuous deformation when the declining f(iml) cannot sustain the elevated f(retract). This opposite trend of the two forces is at the core of the physics governing a "cohesive" breakdown at the yield point (i.e., the stress overshoot) in startup flow. Identifying the yield point as the point of force imbalance, we can also rationalize the recently observed striking scaling behavior associated with the yield point in continuous deformation of both shear and extension. PMID- 17705624 TI - Elastic coefficient of a single polymer chain by using Brownian dynamics analysis. AB - The elastic coefficient of a single polystyrene chain has been experimentally evaluated by using Brownian dynamics analysis. The Brownian motion of the chain is probed using a particle trapped by optical tweezers with a negligibly small spring constant. The displacement of the particle due to Brownian motion is measured by an interferometer assembled using the same laser beam as the optical tweezers. Two methods are employed for Brownian dynamics analysis: (1) the analysis of the time course of the displacement of the particle and (2) the fitting of the power spectrum of Brownian motion with a Lorentzian. The elastic constant of a polystyrene chain in dichloromethane at 21 degrees C is estimated to be 6.4 x 10(-6) and 1.1 x 10(-5) N/m when methods (1) and (2) are employed, respectively. The elastic constant obtained by approximating the polystyrene chain to a freely jointed chain is in agreement with the experimentally evaluated elastic constant. PMID- 17705625 TI - Annealed importance sampling of peptides. AB - Annealed importance sampling assigns equilibrium weights to a nonequilibrium sample that was generated by a simulated annealing protocol [R. M. Neal, Stat. Comput. 11, 125 (2001)]. The weights may then be used to calculate equilibrium averages, and also serve as an "adiabatic signature" of the chosen cooling schedule. In this paper we demonstrate the method on the 50-atom dileucine peptide and an alanine 5-mer, showing that equilibrium distributions are attained for manageable cooling schedules. For dileucine, as naively implemented here, the method is modestly more efficient than constant temperature simulation. The alanine application demonstrates the success of the method when there is little overlap between the high (unfolded) and low (folded) temperature distributions. The method is worth considering whenever any simulated heating or cooling is performed (as is often done at the beginning of a simulation project or during a NMR structure calculation), as it is simple to implement and requires minimal additional computational expense. Furthermore, the naive implementation presented here can be improved. PMID- 17705627 TI - Hard/soft-acid/base principle and the reaction AhBs+AsBh-->AhBh+AsBs. PMID- 17705626 TI - Dynamics of trehalose molecules in confined solutions. AB - The dynamics of trehalose molecules in aqueous solutions confined in silica gel have been studied by quasielastic neutron scattering (QENS). Small-angle neutron scattering measurements confirmed the absence of both sugar clustering and matrix deformation of the gels, indicating that the results obtained are representative of homogeneous trehalose solutions confined in a uniform matrix. The pore size in the gel is estimated to be 18 nm, comparable to the distances in cell membranes. For the QENS measurements, the gel was prepared from D2O in order to accentuate the scattering from the trehalose. Values for the translational diffusion constant and effective jump distance were derived from model fits to the scattering function. Comparison with QENS and NMR results in the literature for bulk trehalose shows that confinement on a length scale of 18 nm has no significant effect on the translational diffusion of trehalose molecules. PMID- 17705628 TI - Comment on "Electronic structure of C60 on Au(887)" [J. Chem. Phys. 125, 144719 (2006)]. PMID- 17705629 TI - A high-power laser-driven source of sub-nanosecond soft X-ray pulses for single shot radiobiology experiments. AB - A large-scale, double-stream gas puff target has been illuminated by sub-kJ, near infrared (NIR) focused laser pulses at the PALS facility (Prague Asterix Laser System) to produce high-energy pulses of soft X rays from hot, dense plasma. The double-puff arrangement ensures high gas density and conversion efficiency from NIR to X rays approaching that typical for solid targets. In addition, its major advantage over solid targets is that it is free of debris and has substantially suppressed charged-particle emission. The X-ray emission characteristics of the source were determined for a range of gases that included krypton, xenon, N(2), CO and N(2)-CO. A demonstrated application of the xenon-based source is a single shot damage induction to plasmid DNA. The yields of single-strand breaks (SSBs) and double-strand breaks (DSBs) were determined as a function of energy fluence adjusted by varying distance of sample from the source and thickness of aluminum filters. PMID- 17705630 TI - Involvement of DNA polymerase beta in repair of ionizing radiation damage as measured by in vitro plasmid assays. AB - Characteristic of damage introduced in DNA by ionizing radiation is the induction of a wide range of lesions. Single-strand breaks (SSBs) and base damages outnumber double-strand breaks (DSBs). If unrepaired, these lesions can lead to DSBs and increased mutagenesis. XRCC1 and DNA polymerase beta (polbeta) are thought to be critical elements in the repair of these SSBs and base damages. XRCC1-deficient cells display a radiosensitive phenotype, while proliferating polbeta-deficient cells are not more radiosensitive. We have recently shown that cells deficient in polbeta display increased radiosensitivity when confluent. In addition, cells expressing a dominant negative to polbeta have been found to be radiosensitized. Here we show that repair of radiation-induced lesions is inhibited in extracts with altered polbeta or XRCC1 status, as measured by an in vitro repair assay employing irradiated plasmid DNA. Extracts from XRCC1 deficient cells showed a dramatically reduced capacity to repair ionizing radiation-induced DNA damage. Extracts deficient in polbeta or containing a dominant negative to polbeta also showed reduced repair of radiation-induced SSBs. Irradiated repaired plasmid DNA showed increased incorporation of radioactive nucleotides, indicating use of an alternative long-patch repair pathway. These data show a deficiency in repair of ionizing radiation damage in extracts from cells deficient or altered in polbeta activity, implying that increased radiosensitivity resulted from radiation damage repair deficiencies. PMID- 17705631 TI - Growth laws in cancer: implications for radiotherapy. AB - Comparing the conventional Gompertz tumor growth law (GL) with the "Universal" law (UL), which has recently been proposed and applied to cancer, we have investigated the implications of the growth laws for various radiotherapy regimens. According to the GL, the surviving tumor cell fraction could be reduced ad libitum, independent of the initial tumor mass, simply by increasing the number of treatments. In contrast, if tumor growth dynamics follows the Universal scaling law, there is a lower limit of the surviving fraction that cannot be reduced further regardless of the total number of treatments. This finding can explain the so-called tumor size effect and re-emphasizes the importance of early diagnosis because it implies that radiotherapy may be successful provided that the tumor mass at treatment onset is rather small. Taken together with our previous work, the implications of these findings include revisiting standard radiotherapy regimens and treatment protocols overall. PMID- 17705633 TI - Comparative biokinetics of trivalent radionuclides with similar ionic dimensions: promethium-147, curium-242 and americium-241. AB - Data on the distribution and redistribution patterns in the laboratory rat of three trivalent elements with a similar ionic radius have been compared. This showed that these distributions for the two ions with the same ionic radius (111 pm), i.e., those of promethium (a lanthanoid) and curium (an actinoid), were indistinguishable and that americium, with a slightly larger ion size (111.5 pm), behaved similarly. The results are consistent with the suggestion that ion size is the only important factor controlling the deposition and redistribution patterns of trivalent lanthanoids and actinoids in rats. The result is important because it suggests that the same radiological protection dosimetry models should be used for trivalent actinoids and lanthanoids, that human volunteer data generated for lanthanoid isotopes can be used to predict the behavior of actinoids with the same ion size, and that appropriate pairs of beta-particle emitting lanthanoid and alpha-particle-emitting actinoids could be used to study the relative toxicity of alpha and beta particles in experimental animals. PMID- 17705632 TI - Peptide-induced inflammatory increase in vascular permeability improves photosensitizer delivery and intersubject photodynamic treatment efficacy. AB - Photodynamic therapy (PDT) treatment can exhibit high intersubject variability due to the inherent differences in drug delivery within the tissue to be treated. In this study, the increased perfusion of the lipid-associated photosensitizer verteporfin was studied using substance P, a peptide known to increase vascular permeability. The transvascular permeability coefficient was quantified before and after administration of substance P, and the mean value increased from 0.026 to 0.043 microm/s with the induced inflammation. Correspondingly, there was a 40 50% increase in uptake of verteporfin in the tumor parenchyma in tumors injected with substance P compared to those without. This increased drug uptake resulted in a modest increase in tumor doubling time from 4 days with regular PDT to 6.2 days with substance P and PDT. There was also a significant reduction in the interindividual variability in with substance P plus PDT from 64% to 13%. The resulting treatment was therefore more effective and there was less variability in dose between subjects. PMID- 17705634 TI - A nested case-control study of lung cancer risk and ionizing radiation exposure at the portsmouth naval shipyard. AB - Results have been inconsistent between studies of lung cancer risk and ionizing radiation exposures among workers at the Portsmouth Naval Shipyard (PNS). The purpose of this nested case-control study was to evaluate the relationship between lung cancer risk and external ionizing radiation exposure while adjusting for potential confounders that included gender, radiation monitoring status, smoking habit surrogates (socioeconomic status and birth cohort), welding fumes and asbestos. By incidence density sampling, we age-matched 3,291 controls selected from a cohort of 37,853 civilian workers employed at PNS between 1952 and 1992 with 1,097 lung cancer deaths from among the same cohort. Analyses using conditional logistic regression were conducted in various model forms: log-linear (main), linear excess relative risk (ERR), and categorical. Lung cancer risk was positively associated with occupational dose (OR = 1.02 at 10 mSv; 95% CI 0.99- 1.04) but flattened after the inclusion of work-related medical X-ray doses (OR = 1.00; 95% CI 0.98-1.03) in multivariate analyses. Similar risk estimates were observed in the linear ERR model at 10 mSv of cumulative exposure with a 15-year lag. PMID- 17705636 TI - The time dependence of bystander responses induced by iron-ion radiation in normal human skin fibroblasts. AB - Although bystander effects have been shown for some high-LET radiations, few studies have been done on bystander effects induced by heavy-ion radiation. In this study, using a Transwell insert co-culture system, we have demonstrated that irradiation with 1 GeV/nucleon iron ions can induce medium-mediated bystander effects in normal AG01522 human fibroblasts. When irradiated and unirradiated bystander cells were combined in shared medium immediately after irradiation, a two- to threefold increase in the percentage of bystander cells with gamma-H2AX foci occurred as early as 1 h after irradiation and lasted at least 24 h. There was a twofold increase in the formation of micronuclei in bystander cells when they were co-cultured with irradiated cells immediately or 1 or 3 h after irradiation, but there was no bystander effect when the cells were co-cultured 6 h or later after irradiation. In addition, bystander micronucleus formation was observed even when the bystander cells were co-cultured with irradiated cells for only 1 h. This indicates that the crucial signaling to bystander cells from irradiated cells occurs shortly after irradiation. Moreover, both gamma-H2AX focus formation and micronucleus formation in bystander cells were inhibited by the ROS scavengers SOD or catalase or the NO scavenger PTIO. This suggests that ROS and NO play important roles in the initiation of bystander effects. The results with iron ions were similar to those with X rays, suggesting that the bystander responses in this system are independent of LET. PMID- 17705635 TI - A comparative evaluation of EPR and OxyLite oximetry using a random sampling of pO(2) in a murine tumor. AB - Methods currently available for the measurement of oxygen concentrations (oximetry) in viable tissues differ widely from each other in their methodological basis and applicability. The goal of this study was to compare two novel methods, particulate-based electron paramagnetic resonance (EPR) and OxyLite oximetry, in an experimental tumor model. EPR oximetry uses implantable paramagnetic particulates, whereas OxyLite uses fluorescent probes affixed on a fiber-optic cable. C3H mice were transplanted with radiation-induced fibrosarcoma (RIF-1) tumors in their hind limbs. Lithium phthalocyanine (LiPc) microcrystals were used as EPR probes. The pO(2) measurements were taken from random locations at a depth of approximately 3 mm within the tumor either immediately or 48 h after implantation of LiPc. Both methods revealed significant hypoxia in the tumor. However, there were striking differences between the EPR and OxyLite readings. The differences were attributed to the volume of tissue under examination and the effect of needle invasion at the site of measurement. This study recognizes the unique benefits of EPR oximetry in terms of robustness, repeatability and minimal invasiveness. PMID- 17705637 TI - Biological response to nonuniform distributions of (210)Po in multicellular clusters. AB - Radionuclides are distributed nonuniformly in tissue. The present work examined the impact of nonuniformities at the multicellular level on the lethal effects of (210)Po. A three-dimensional (3D) tissue culture model was used wherein V79 cells were labeled with (210)Po-citrate and mixed with unlabeled cells, and multicellular clusters were formed by centrifugation. The labeled cells were located randomly in the cluster to achieve a uniform distribution of radioactivity at the macroscopic level that was nonuniform at the multicellular level. The clusters were maintained at 10.5 degrees C for 72 h to allow alpha particle decays to accumulate and then dismantled, and the cells were seeded for colony formation. Unlike typical survival curves for alpha particles, two component exponential dose-response curves were observed for all three labeling conditions. Furthermore, the slopes of the survival curves for 100, 10 and 1% labeling were different. Neither the mean cluster absorbed dose nor a semi empirical multicellular dosimetry approach could accurately predict the lethal effects of (210)Po-citrate. PMID- 17705638 TI - Transcriptomic profile of Arabidopsis rosette leaves during the reproductive stage after exposure to ionizing radiation. AB - We attempted to obtain a transcriptomic profile of ionizing radiation-responsive genes in Arabidopsis plants using Affymetrix ATH1 whole-genome microarrays. The Arabidopsis plants were irradiated with 200 Gy gamma rays at the early reproduction stage, 33 days after sowing. Rosette leaves were harvested during the postirradiation period from 36 to 49 days after sowing and used for the microarray analysis. The most remarkable changes in the genome-wide expression were observed at 42 days after sowing (9 days after the irradiation). We identified 2165 genes as gamma-ray inducible and 1735 genes as gamma-ray repressible. These numbers of affected genes were almost two to seven times higher than those at other times. In a comparison of the control and irradiated groups, we also identified 354 differentially expressed genes as significant by applying Welch's t test and fold change analysis. The gene ontology analysis showed that radiation up-regulated defense/ stress responses but down-regulated rhythm/growth responses. Specific expression patterns of 10 genes for antioxidant enzymes, photosynthesis or chlorophyll synthesis after irradiation were also obtained using real-time quantitative PCR analysis. We discuss physiological and genetic alterations in the antioxidative defense system, photosynthesis and chlorophyll metabolism after irradiation at the reproductive stage. PMID- 17705641 TI - In memoriam Victor P Bond (1920-2007). PMID- 17705639 TI - On the chemical yield of base lesions, strand breaks, and clustered damage generated in plasmid DNA by the direct effect of X rays. AB - The purpose of this study was to determine the yield of DNA base damages, deoxyribose damage, and clustered lesions due to the direct effects of ionizing radiation and to compare these with the yield of DNA trapped radicals measured previously in the same pUC18 plasmid. The plasmids were prepared as films hydrated in the range 2.5 < Gamma < 22.5 mol water/mol nucleotide. Single-strand breaks (SSBs) and double-strand breaks (DSBs) were detected by agarose gel electrophoresis. Specific types of base lesions were converted into SSBs and DSBs using the base-excision repair enzymes endonuclease III (Nth) and formamidopyrimidine-DNA glycosylase (Fpg). The yield of base damage detected by this method displayed a strikingly different dependence on the level of hydration (Gamma) compared with that for the yield of DNA trapped radicals; the former decreased by 3.2 times as Gamma was varied from 2.5 to 22.5 and the later increased by 2.4 times over the same range. To explain this divergence, we propose that SSB yields produced in plasmid DNA by the direct effect cannot be analyzed properly with a Poisson process that assumes an average of one strand break per plasmid and neglects the possibility of a single track producing multiple SSBs within a plasmid. The yields of DSBs, on the other hand, are consistent with changes in free radical trapping as a function of hydration. Consequently, the composition of these clusters could be quantified. Deoxyribose damage on each of the two opposing strands occurs with a yield of 3.5 +/- 0.5 nmol/J for fully hydrated pUC18, comparable to the yield of 4.1 +/- 0.9 nmol/J for DSBs derived from opposed damages in which at least one of the sites is a damaged base. PMID- 17705640 TI - Mechanisms of direct radiation damage in DNA, based on a study of the yields of base damage, deoxyribose damage, and trapped radicals in d(GCACGCGTGC)(2). AB - Dose-response curves were measured for the formation of direct-type DNA products in X-irradiated d(GCACGCGTGC)(2)prepared as dry films and as crystalline powders. Damage to deoxyribose (dRib) was assessed by HPLC measurements of strand break products containing 3' or 5' terminal phosphate and free base release. Base damage was measured using GC/ MS after acid hydrolysis and trimethylsilylation. The yield of trappable radicals was measured at 4 K by EPR of films X-irradiated at 4 K. With exception of those used for EPR, all samples were X-irradiated at room temperature. There was no measurable difference between working under oxygen or under nitrogen. The chemical yields (in units of nmol/J) for trapped radicals, free base release, 8-oxoGua, 8-oxoAde, diHUra and diHThy were G(total)(fr) = 618 +/- 60, G(fbr) = 93 +/- 8, G(8-oxoGua) = 111 +/- 62, G(8-oxoAde) = 4 +/- 3, G(diHUra) = 127 +/- 160, and G(diHThy) = 39 +/- 60, respectively. The yields were determined and the dose-response curves explained by a mechanistic model consisting of three reaction pathways: (1) trappable-radical single-track, (2) trappable-radical multiple-track, and (3) molecular. If the base content is projected from the decamer's GC:AT ratio of 4:1 to a ratio of 1:1, the percentage of the total measured damage (349 nmol/J) would partition as follows: 20 +/- 16% 8-oxoGua, 3 +/- 3% 8-oxoAde, 28 +/- 46% diHThy, 23 +/- 32% diHUra, and 27 +/- 17% dRib damage. With a cautionary note regarding large standard deviations, the projected yield of total damage is higher in CG-rich DNA because C combined with G is more prone to damage than A combined with T, the ratio of base damage to deoxyribose damage is approximately 3:1, the yield of diHUra is comparable to the yield of diHThy, and the yield of 8-oxoAde is not negligible. While the quantity and quality of the data fall short of proving the hypothesized model, the model provides an explanation for the dose-response curves of the more prevalent end products and provides a means of measuring their chemical yields, i.e., their rate of formation at zero dose. Therefore, we believe that this comprehensive analytical approach, combined with the mechanistic model, will prove important in predicting risk due to exposure to low doses and low dose rates of ionizing radiation. PMID- 17705642 TI - Carcinogenicity study of 217 Hz pulsed 900 MHz electromagnetic fields in Pim1 transgenic mice. AB - In an 18-month carcinogenicity study, Pim1 transgenic mice were exposed to pulsed 900 MHz (pulse width: 0.577 ms; pulse repetition rate: 217 Hz) radiofrequency (RF) radiation at a whole-body specific absorption rate (SAR) of 0.5, 1.4 or 4.0 W/kg [uncertainty (k = 2): 2.6 dB; lifetime variation (k = 1): 1.2 dB]. A total of 500 mice, 50 per sex per group, were exposed, sham-exposed or used as cage controls. The experiment was an extension of a previously published study in female Pim1 transgenic mice conducted by Repacholi et al. (Radiat. Res. 147, 631 640, 1997) that reported a significant increase in lymphomas after exposure to the same 900 MHz RF signal. Animals were exposed for 1 h/day, 7 days/week in plastic tubes similar to those used in inhalation studies to obtain well-defined uniform exposure. The study was conducted blind. The highest exposure level (4 W/kg) used in this study resulted in organ-averaged SARs that are above the peak spatial SAR limits allowed by the ICNIRP (International Commission on Non ionizing Radiation Protection) standard for environmental exposures. The whole body average was about three times greater than the highest average SAR reported in the earlier study by Repacholi et al. The results of this study do not suggest any effect of 217 Hz-pulsed RF-radiation exposure (pulse width: 0.577 ms) on the incidence of tumors at any site, and thus the findings of Repacholi et al. were not confirmed. Overall, the study shows no effect of RF radiation under the conditions used on the incidence of any neoplastic or non-neoplastic lesion, and thus the study does not provide evidence that RF radiation possesses carcinogenic potential. PMID- 17705644 TI - Differential resistance to copper and mine drainage in Daphnia longispina: relationship with allozyme genotypes. AB - Differential resistance to metal pollution in Daphnia longispina populations was reported in previous studies. In this work, we tried to determine if variation in polymorphic enzymes, often referred as being under metal selection, were related with differences in resistance to acute single- and mixed-metal exposure. Allozyme genotype of 20 putatively polymorphic enzymes, 48-h median lethal concentration (LC50) for copper, and median lethal time (LT50) for a 3% dilution of acid mine drainage (AMD) were determined for 24 lineages of D. longispina. The copper LC50s ranged from 29.3 to 226 microg/L, and the AMD LT50s ranged from 48 min to 25 h and 29 min, with a strong correlation between both end points. Five distinct multilocus genotypes were identified based on polymorphisms in glucose-6 phosphate isomerase, lactate dehydrogenase, malate dehydrogenase, nicotinamide adenine dinucleotide phosphate (NADP+), phosphoglucomutase, and peroxidase. No differences were found in average genotype sensitivity for both toxicity end points or in genotype frequencies between the resistant- and sensitive-lineage groups. The results obtained indicate that allozyme genotype is not associated with increased resistance to acute metal stress in D. longispina. PMID- 17705645 TI - Tamoxifen protects against 17alpha-ethynylestradiol-induced liver damage and the development of urogenital papillae in the rainbow darter (Etheostoma caeruleum). AB - Juvenile rainbow darters (Etheostoma caeruleum) were exposed to nominal concentrations of 20 to 1,000 ng/L of 17alpha-ethynylestradiol (EE2) at 120 d posthatch and in a subsequent experiment to 200 ng/L of EE2 with 2.0 to 20,000 ng/L of tamoxifen (TMX) at 150 d posthatch to determine the threshold of estrogen induced morphological and histological changes in a sexually dimorphic benthic fish species ecologically relevant to southern Minnesota (USA). 17Alpha ethynylestradiol induced female-associated urogenital papillae in males at 200 ng/L, enlargement and development of fibrosis in male testes, enlargement of ovary and oocyte size in females, and large fatty inclusions in the liver of both sexes. Exposure to 1,000 ng/L of EE2 caused gross hypertrophy of the liver and kidneys and high mortalities, predominantly in male fish. A low incidence of ovotestes found in all treatment groups was unaffected by EE2, which may be unusual to this species or a response to unknown water contaminants present during the hatching or early development of the darters. Gonadosomatic index was not altered for either sex by any treatment. A TMX level equal to or less than that of EE2 decreased fat accumulation in the liver in both sexes, and a TMX level greater than that of EE2 appeared to prevent urogenital papilla in males. Tamoxifen did not significantly alter fibrosis caused by EE2 in testes. It appears that the presence of TMX in the environment can mask many signs of estrogen exposure, including secondary sexual characteristics, hypertrophy of ovaries and testes, and fatty infiltration of organs. Ovotestes did not prove to be a good indicator of estrogen exposure at this late stage of juvenile darter development. PMID- 17705646 TI - Ecological health assessments based on whole effluent toxicity tests and the index of biological integrity in temperate streams influenced by wastewater treatment plant effluents. AB - Whole effluent toxicity (WET) tests and ecosystem health assessments, based on test guidelines of U.S. Environmental Protection Agency (U.S. EPA) and index of biological integrity (IBI), were conducted on various streams located in Youngsan River watershed, Korea. The WET tests showed that about 33 and 82% of wastewater treatment plants (WWTPs) exhibited significant toxicity to Daphnia magna and Selenastrum capricornutum, respectively. Small WWTPs with low discharge volumes contributed less than 1% to the total stream toxicity. Fish community compositions and trophic guild analysis showed that the diversity index was greater in the control than in impacted streams, and the proportion of omnivore species was less in the control. Also, ecosystem health assessments, based on the IBI, showed distinct differences between the control and impacted sites of WWTPs. Model values of the IBI, based on 12 stream data sets, averaged 28, which is judged as a fair to poor condition according to the U.S. EPA criteria. The mean IBI in the control sites was 42, indicating good stream condition, whereas the impacted sites was scored 21, indicating poor condition. Overall, WET tests and ecosystem health assessments suggested the WWTP effluents had evident toxic effects on the biota, and impacted the species compositions and trophic guilds, resulting in degradation of the stream ecosystem health. PMID- 17705647 TI - Laboratory culturing and selection for increased resistance to cadmium reduce genetic variation in the least killifish, Heterandria formosa. AB - Populations exposed to environmental contaminants can undergo intense selection pressures, which in turn can lead to a loss of genetic variation. We assessed this loss of genetic variation in the least killifish Heterandria formosa for laboratory populations that had undergone eight generations of selection for an increased resistance to cadmium. Using microsatellite markers, we compared genetic variation between three selection and three control laboratory populations and between these laboratory populations and the source population. Heterozygosity was lower in each selection population than it was in its paired control population, with this difference being statistically significant in two of the three comparisons. This is evidence that adaptation to environmental contaminants can result in an overall loss of genetic variation. Furthermore, the laboratory populations had much lower heterozygosity than did the source population. The latter loss of genetic variation, probably a result of random drift, did not prevent the laboratory populations from showing a strong response to the selection for cadmium resistance. The loss of genetic variation resulting from maintaining populations in the laboratory demonstrates that it is important to maintain a large population size for such populations and that the potential for loss of genetic variation in laboratory populations is taken into consideration in ecotoxicology when extrapolating from laboratory to natural populations. PMID- 17705648 TI - Competitive binding comparison of endocrine-disrupting compounds to recombinant androgen receptor from fathead minnow, rainbow trout, and human. AB - Typically, in vitro hazard assessments for the identification of endocrine disrupting compounds (EDCs), including those outlined in the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) Tier 1 Screening protocols, utilize mammalian receptors. Evidence, however, exists that fish sex steroid hormone receptors differ from mammalian receptors both structurally and in their binding affinities for some steroids and environmental chemicals. Most of the binding studies to date have been conducted using cytosolic preparations from various tissues. In the present study, we compare competitive binding of a set of compounds to full-length recombinant rainbow trout androgen receptor alpha (rtAR), fathead minnow androgen receptor (fhAR), and human androgen receptor (hAR), each expressed in COS cells. Saturation binding and subsequent Scatchard analysis using [3H]R1881, a high-affinity synthetic androgen, revealed an equilibrium dissociation constant (Kd) of 0.11 nM for the rtAR, 1.8 nM for the fhAR, and 0.84 nM for the hAR. Compounds, including endogenous and synthetic steroids, known mammalian antiandrogens, and environmental compounds, were tested for competitive binding to each of the three receptors. Overall, agreement existed across receptors as to binding versus nonbinding for all compounds tested in this study. Minor differences, however, were found in the relative order of binding of the compounds to the individual receptors. Studies such as these will facilitate the identification of EDCs that may differentially affect specific species and aid in the development and support of future risk assessment protocols. PMID- 17705649 TI - Bayesian multimodel inference for dose-response studies. AB - Statistical inference in dose-response studies is model-based: The analyst posits a mathematical model of the relation between exposure and response, estimates parameters of the model, and reports conclusions conditional on the model. Such analyses rarely include any accounting for the uncertainties associated with model selection. The Bayesian inferential system provides a convenient framework for model selection and multimodel inference. In this paper we briefly describe the Bayesian paradigm and Bayesian multimodel inference. We then present a family of models for multinomial dose-response data and apply Bayesian multimodel inferential methods to the analysis of data on the reproductive success of American kestrels (Falco sparveriuss) exposed to various sublethal dietary concentrations of methylmercury. PMID- 17705650 TI - Supercritical carbon dioxide extraction as a predictor of polycyclic aromatic hydrocarbon bioaccumulation and toxicity by earthworms in manufactured-gas plant site soils. AB - The toxicity and uptake of polycyclic aromatic hydrocarbons (PAHs) by earthworms were measured in soil samples collected from manufactured-gas plant sites having a wide range in PAH concentrations (170-42,000 mg/kg) and soil characteristics. Samples varied from vegetated soils to pure lampblack soot and had total organic carbon contents ranging from 3 to 87%. The biota-soil accumulation factors (BSAFs) observed for individual PAHs in field-collected earthworms (Aporrectodea caliginosa) were up to 50-fold lower than the BSAFs predicted using equilibrium partitioning theory. Acute toxicity to the earthworm Eisenia fetida was unrelated to total PAH concentration: Mortality was not observed in some soils having high concentrations of total PAHs (>42,000 mg/kg), whereas 100% mortality was observed in other soils having much lower concentrations of total PAHs (1,520 mg/kg). Instead, toxicity appeared to be related to the rapidly released fraction of PAHs determined by mild supercritical CO2 extraction (SFE). The results demonstrate that soils having approximately 16,000 mg rapidly released total PAH/kg organic carbon can be acutely toxic to earthworms and that the concentration of PAHs in soil that is rapidly released by SFE can estimate toxicity to soil invertebrates. PMID- 17705651 TI - An algal toxicity database of organic toxicants derived by a closed-system technique. AB - The current study presents the toxicity data of 90 organic compounds with various modes of actions to Pseudokirchneriella subcapitata. The assessment was conducted using a closed-system technique, and a biomass-type end point based on the cell density was employed. The above toxicity data were compared with test results from ciliate (Tetrahymena pyriformis), water flea (Daphnia magna), fish (Pimephales promelas), and luminescent bacteria (Photobacterium phosphoreum). Satisfactory correlation relationships between toxicity data from algae and other aquatic organisms were found (r2 = 0.66-0.82). Pseudokirchneriella subcapitata revealed considerably higher sensitivity to organic toxicants compared with other organisms. Benzenes, aldehydes, and alkanes also were highly selective to the test alga. In addition, the results show that conventional algal batch tests tend to underestimate the toxicity of organic compounds, except in the case of 4 chlorophenol. Toxicity observed from the closed-system test is approximately 2- to 380-fold higher than that estimated by conventional batch tests. Such a phenomenon can be found in nearly all organic compounds, regardless of the chemical's Henry's law constant. In the risk assessment of chemicals, following the European Union's practice, approximately 30% (7 of 23) of the cases may result in a more strict classification when the batch test is replaced by the closed-system test. More effort therefore is needed to revise the algal toxicity database using the closed-system test method. PMID- 17705652 TI - Chemical reactivation and aging kinetics of organophosphorus-inhibited cholinesterases from two earthworm species. AB - An in vitro study was conducted to evaluate the ability of pyridine-2-aldoxime methochloride (2-PAM) to recover organophosphorus (OP)-inhibited cholinesterase (ChE) activity of two earthworm species (Eisenia fetida and Lumbricus terrestris). After inhibition of ChE activity by OP pesticides, an alkyl group may be released from the OP-ChE complex. This reaction is termed aging, and the esterase cannot be reactivated either spontaneously or by the action of reactivating agents, such as 2-PAM. We also examined the aging kinetics of OP inhibited ChE activity to evaluate the suitability of 2-PAM reactivation methodology for field monitoring. A 2-PAM concentration of 5 x 10(-4) M was enough to reactivate the OP-inhibited ChE activity after 60 min of incubation at 25 degrees C. Chemical reactivation kinetics followed an exponential rise to a maximum of 70 to 80% of normal enzyme activity when ChEs were inhibited with methyl paraoxon or dichlorvos and up to 60% for the chlorpyrifos-inhibited ChE of E. fetida. The aging rates (ka) of the inhibited ChEs were strongly affected by the OP type, and these rates decreased for both earthworm species in the following order: Methyl paraoxon (ka = 0.023-0.033/h) > dichlorvos (ka = 0.008 0.009/h) > chlorpyrifos oxon (ka = 0.003-0.006/h). In particular, chlorpyrifos inhibited ChE activity of L. terrestris aged slowly (median aging time, 190 h), which means that chemical reactivation of esterase activity with 2-PAM seems feasible one week after exposure to OP pesticides. We conclude that reactivation of earthworm ChE activity by treatment with 2-PAM is a complementary and specific methodology for assessing exposure to OP pesticides. PMID- 17705653 TI - Prediction of lethal/effective concentration/dose in the presence of multiple auxiliary covariates and components of variance. AB - Predictors of the percentile lethal/effective concentration/dose are commonly used measures of efficacy and toxicity. Typically such quantal-response predictors (e.g., the exposure required to kill 50% of some population) are estimated from simple bioassays wherein organisms are exposed to a gradient of several concentrations of a single agent. The toxicity of an agent may be influenced by auxiliary covariates, however, and more complicated experimental designs may introduce multiple variance components. Prediction methods lag examples of those cases. A conventional two-stage approach consists of multiple bivariate predictions of, say, medial lethal concentration followed by regression of those predictions on the auxiliary covariates. We propose a more effective and parsimonious class of generalized nonlinear mixed-effects models for prediction of lethal/effective dose/ concentration from auxiliary covariates. We demonstrate examples using data from a study regarding the effects of pH and additions of variable quantities 2',5'-dichloro-4'-nitrosalicylanilide (niclosamide) on the toxicity of 3-trifluoromethyl-4-nitrophenol to larval sea lamprey (Petromyzon marinus). The new models yielded unbiased predictions and root-mean-squared errors (RMSEs) of prediction for the exposure required to kill 50 and 99.9% of some population that were 29 to 82% smaller, respectively, than those from the conventional two-stage procedure. The model class is flexible and easily implemented using commonly available software. PMID- 17705654 TI - Comparison of short-term chronic and chronic silver toxicity to fathead minnows in unamended and sodium chloride-amended waters. AB - The chronic (early life stage [ELS]) and short-term chronic (STC) toxicity of silver (as silver nitrate) to fathead minnows (FHM) was determined concurrently in flow-through exposures (33 volume additions/d). Paired ELS (approximately 30 d) and STC (7 d) studies were conducted with and without the addition of 60 mg/L Cl (as NaCl). The paired studies in unamended water were later repeated using standard flow conditions (9 volume additions/d). The purpose of the paired studies was to determine if short-term chronic endpoints can be used to predict effects in ELS studies. For each experiment, a "split-chamber" design (organisms were held in a common exposure chamber) allowed the direct comparison between short-term and chronic exposures. It appeared that the chronic toxicity of silver was mitigated to some extent by NaCl addition. The maximum acceptable toxicant concentration for growth in the ELS study was 0.53 microg dissolved Ag/L under standard flow conditions. Early life stage and STC endpoints in all three studies typically agreed within a factor of two. Whole-body sodium and silver concentrations measured in individual fathead minnows during these studies showed an increase in silver body burdens and a decrease in sodium concentration. These results indicate that the STC study could be used as a surrogate test to estimate chronic toxicity and that the mechanism of chronic silver toxicity may be the same as for acute toxicity. PMID- 17705655 TI - Orally administered bisphenol a in rainbow trout (Oncorhynchus mykiss): estrogenicity, metabolism, and retention. AB - The estrogenic effect of orally administered bisphenol A (BPA) was investigated in a rainbow trout (Oncorhynchus mykiss) test system. Bisphenol A was administered orally to sexually immature rainbow trout every second day for up to 12 d in doses between 1.8 and 258 mg/kg every second day (/2d). Plasma vitellogenin was measured before and during the exposures, and the concentrations of BPA in plasma, liver, and muscle and the plasma concentrations of BPA glucuronic acid (BPAGA) were determined at the end of the experiments. Increases in average plasma vitellogenin levels were seen at oral exposure to 24 mg BPA/kg/2d; the most sensitive fish responded to 9.3 mg/kg/2d. At day 12, the 10, 50, and 90% effective doses for increase in vitellogenin synthesis were 13, 19, and 25 mg/kg/2d, respectively. Bisphenol A could be detected in liver, muscle, and plasma at the end of the exposure, generally in increasing concentrations with increasing doses; liver concentrations generally were higher than muscle concentrations. Four to five hours after the last feeding of doses between 3.6 and 24 mg BPA/kg, plasma BPA concentrations ranged between 400 and 1,200 nM, whereas BPAGA concentrations were between 2- and 10-fold higher. The difference between BPA and BPAGA concentrations increased with increasing BPA dose. Bisphenol A showed little tendency to bioaccumulate in rainbow trout; less than 1% of the total amount of BPA administered orally at doses between 1.8 and 258 mg/ kg/2d over the 10- or 12-d experimental period was retained in muscle and liver at 5 or 24 h after the end of the experiments. PMID- 17705656 TI - Enantioselective acetylcholinesterase inhibition of the organophosphorous insecticides profenofos, fonofos, and crotoxyphos. AB - A large number of organophosphorous insecticides (OPs) are chiral compounds, and yet enantioselectivity in their environmental fate and effects is rarely addressed. In the present study, we isolated individual enantiomers of three OPs, profenofos, fonofos, and crotoxyphos, and evaluated enantioselectivity in their inhibition of acetylcholinesterase (AChE). Acetylcholinesterase inhibition by the enantiomers and racemates was determined in vivo in the aquatic invertebrate Daphnia magna and in Japanese medaka (Oryzias latipes) as well as in vitro with electric eel (Electrophorus electricus) and human recombinant AChEs. The overall results showed variable sensitivity between AChE enzymes from different species as well as variable magnitude of enantioselectivity in enzyme inhibition. The (-) enantiomer of profenofos was 4.3- to 8.5-fold more inhibitory to AChE in vivo, whereas (-)-fonofos was 2.3- to 29-fold more potent than the corresponding (+) enantiomer. The (+)-enantiomer of crotoxyphos was 1.1- to 11-fold more inhibitory to AChE than the (-)-enantiomer. In contrast, the in vitro results showed (+) profenofos to be 2.6- to 71.8-fold more inhibitory than the (-)-enantiomer and ( )-crotoxyphos to be 1.6- to 1.9-fold more active than the (+)-enantiomer. The reversed direction of enantioselectivity observed between the in vivo and in vitro assays suggests enantioselectivity within toxicodynamic processes such as uptake, biotransformation, or elimination. Findings from the present study provide evidence of enantioselectivity in the AChE inhibition of chiral OPs in nontarget organisms and indicate the need to consider enantiomers individually when assessing environmental risk of these chiral pesticides. PMID- 17705657 TI - The sorptive capacity of animal protein. AB - Partition coefficients that are used to predict concentrations of hydrophobic organic chemicals in biota (e.g., the bioconcentration factor) often assume that the sorptive capacity of an organism or tissue is adequately represented by its lipid content. In lean organisms and tissues, however, theory suggests that partitioning may be strongly influenced by the sorptive capacity of nonlipid materials, such as protein. Little is known about the sorptive capacity of proteins for hydrophobic organic chemicals, and methods to include proteins in bioaccumulation models do not exist. Here, we present a compilation and meta analysis of published data to estimate the relative sorptive capacities of animal proteins and lipids for neutral organic chemicals. We found that the estimated sorptive capacity of protein in solid animal tissues ranged from around 1 to 10% that of lipid for compounds with a log octanol/water partition coefficient (K(OW)) of greater than two. The sorptive capacity of blood protein (albumin) appeared to be substantially higher than this, especially for low-K(OW) chemicals. For modeling purposes, we recommend estimating the sorptive capacity of animal protein as 5% that of lipid. According to this estimate, the sorptive capacity of an animal or tissue will be dominated by the contribution from protein if the lipid content makes up less than 5% of the dry-weight organic content. In such situations, a consideration of the sorptive capacity of nonlipid constituents, such as protein, will permit more accurate predictions of chemical accumulation and distribution. PMID- 17705658 TI - Recovery of cholinesterase activity in the earthworm Eisenia fetida Savigny following exposure to chlorpyrifos. AB - Organophosphorus (OP) insecticides inhibit cholinesterase activity, an essential process in the nervous system of most animals. Re-establishment of active enzymes is slow and depends on elimination of the insecticide from the body followed by two lengthy processes: Reactivation and/or biosynthesis of new enzymes. Earthworms (Eisenia fetida) were exposed to either clean or chlorpyrifos containing (240 mg/kg) soil for 48 h. After transfer to clean soil, we monitored two cholinesterases (E1 and E2) and chlorpyrifos content of the earthworms for 12 weeks. After 14 to 21 d of recovery, the exposed and control worms were indistinguishable in terms of appearance and behavior. Chemical analysis showed a rapid elimination of chlorpyrifos from the earthworms, with only minor levels detected after one week. The activities of E1 and E2 were measured spectrophotometrically in whole specimen homogenates using acetylthiocholine as the substrate. Carbaryl, which selectively inhibits E1, was used to discriminate the enzyme activities. Mean +/- standard error of mean of E1 and E2 activity in the controls immediately after exposure were 1.57 +/- 0.18 nanokatal (nkat)/mg protein (n = 3) and 0.95 +/- 0.07 nkat/mg protein, respectively, and 0.48 +/- 0.07 nkat/mg and 0.45 +/- 0.06 nkat/mg, respectively, in exposed worms. After three weeks, E1 had regained an activity comparable to the controls, whereas E2 remained depressed throughout the 12-week monitoring period. The non- or late recovery of E2 makes this enzyme a potential biomarker candidate for previous OP insecticide exposure in Eisenia fetida, provided the protocol for measurements is improved and standardized. PMID- 17705659 TI - Availability of polychlorinated biphenyls in field-contaminated sediment. AB - Two chemical approaches, Tenax extraction and matrix solid phase microextraction (matrix-SPME), were evaluated as surrogates to estimate bioavailability of polychlorinated biphenyls (PCBs) from field-contaminated sediment. Aroclor 1254 was the primary contaminant found in sediment from Crab Orchard Lake in Marion, Illinois, USA, and a total of 18 PCB congeners were selected for study. Bioaccumulation was determined by exposing the freshwater oligochaete, Lumbriculus variegatus, to the sediment for 28 d. Differences in the rapidly desorbing fraction of PCBs and fraction desorbed within 6 h, defined by Tenax extraction, accounted for 39 and 31% of the differences among biota-sediment accumulation factor values, respectively. A better relationship (r2 = 0.95) was found between the oligochaete PCB body residues and the concentration of PCBs in the rapidly desorbing fraction of sediment. The degree of chlorination and planarity of the PCB congeners affected both desorption and bioaccumulation. The higher chlorine substituted and planar PCBs showed less chemical and biological availability, due to their stronger sorption to sediment, compared to the lower chlorinated and nonplanar PCBs. Accumulation of PCBs by L. variegatus correlated well (r2 = 0.88) with matrix-SPME fiber concentrations. The ratio of measured body residue to estimated body residue from the pore water concentration measured by matrix-SPME ranged from 0.4 to 1.3 with an average of 0.9. Overall, both Tenax and matrix-SPME approaches were useful surrogates of bioaccumulation for a field contaminated sediment. PMID- 17705660 TI - 3-Methyl-4-nitrophenol metabolism by uridine diphosphate glucuronosyltransferase and sulfotransferase in liver microsomes of mice, rats, and Japanese quail (Coturnix japonica). AB - 3-Methyl-4-nitrophenol (PNMC) is a component of diesel exhaust particles and one of the major breakdown products of the insecticide fenitrothion. This chemical has a high potential for reproductive toxicity in Japanese quail (Coturnix japonica) and rats. Because PNMC inhaled by the body is metabolized by uridine diphosphate glucuronosyltransferase (UGT) and sulfotransferase, we investigated these enzyme activities in the hepatic microsomes and cytosols of quail (as a model of wild birds) and compared these activities with those of rats and mice as models of ecological and human risk assessment. The maximum velocity of the UGT for PNMC in quail was 12.7 nmol/min/mg, which was one third and one fourth those of rats and mice, respectively. The Michaelis-Menten constant of UGT for PNMC in quail was 0.29 mM, which was 1.3- and 1.8-fold higher than that in mice and rats, respectively, but not significantly different. In accordance with these results, UGT activities for PNMC were lowest in quail, with those in mice and rats being 4.4- and 2.7-fold higher, respectively. Sulfotransferase activity for PNMC was considerably less than that of UGT in all animals, including quail; no significant differences in the activities were found among mice, rats, and quail. These results suggest that glucuronidation may be involved primarily in PNMC elimination from wild birds as well as mammals and that the UGT activity in quail is less than that in the rodents. PMID- 17705662 TI - Determinants of variability in acute to chronic toxicity ratios for aquatic invertebrates and fish. AB - Variability in acute to chronic ratios (ACRs; median lethal or effect concentration divided by chronic value) has been of continuing interest in aquatic toxicology because of the reliance on ACRs to estimate chronic toxicity for chemicals and species with known acute toxicity data but with limited or no information for chronic toxicity. To investigate the variability and significant differences in ACRs, an extensive data set was compiled of 456 same-species pairs of acute and maximum acceptable toxicant concentrations for metals, narcotics, pesticides, and other organic chemicals. The overall median value for 456 aquatic invertebrate and fish ACRs analyzed in the present study was 8.3, with a 16,000 fold range in values (1.1-18,550) and a 32-fold range in 10th and 90th percentile values (2.5-79.5). Median ACRs for taxa, ambient habitat media, chronic test end point, and chemical mode of action (MOA)/class categories generally were similar but, in some cases, extremely variable (ranges of 1 to >10,000). No significant differences (p G and 276G>T of the adiponectin gene and 62G>A and -180C>G of the resistin gene in patients with obesity (OB), anorexia nervosa (AN) and in control healthy normal-weight women (NW) and to study the influence of particular genotypes on serum concentrations of these hormones and on insulin sensitivity. Serum adiponectin, resistin, tumor necrosis factor alpha (TNF-alpha), insulin, cholesterol, glycated hemoglobin (HbA1c) and blood glucose levels were measured in 77 patients with OB, 28 with AN and 38 NW. DNA analysis was carried out by polymerase chain reaction with restriction analysis of PCR product. The presence of SNP ADP+276 G>T allele was accompanied by higher cholesterol levels in AN patients, higher adiponectin concentrations in OB patients and lower HbA1c levels in NW. SNP of the resistin gene 62G>A was associated with lower HbA1c in NW and higher cholesterol concentrations in OB group. The carriers of the minor G allele in the position -180 of the resistin gene within AN group had significantly higher BMI relative to non-carriers. We conclude that polymorphisms in adiponectin and resistin genes can contribute to metabolic phenotype of patients with obesity and anorexia nervosa. PMID- 17705673 TI - Lipoprotein lipase activity determined in vivo is lower in carriers of apolipoprotein A-V gene variants 19W and -1131C. AB - The apolipoprotein A-V (apo A-V) plays an important role in regulation of triglyceride (TG) concentration in serum. To better understand how apo A-V affects triglyceridemia and glucoregulation, the lipoprotein lipase (LPL) activity was determined using intravenous fat tolerance test (IVFTT) and oral glucose tolerance test (oGTT) was performed in carriers of apolipoprotein A-V gene (APOAV) variants known to be associated with increased triglyceridemia. Twelve carriers of 19W variant, 16 carriers of -1131C variant, 1 combined heterozygote and 16 control subjects homozygous for wild type variants (19S/ 1131T) were selected from a population sample and matched with respect to body mass index and age. The APOAV variants carriers had increased TG, very low density lipoprotein-TG, and apo B concentrations (p < 0.05). The LPL activity evaluated as k(2) rate constant for clearance of Intralipid was 14 % lower in APOAV variants carriers. The depression of nonesterified fatty acids (NEFA) concentration after glucose load was delayed in APOAV variants carriers in spite of the same insulinemia and glycemia. Our results suggest that variants of APOAV combined with increased triglyceridemia are associated with lower LPL activity in vivo and with disturbances of regulation of NEFA concentration after glucose load. PMID- 17705674 TI - Family history of diabetes mellitus determines insulin sensitivity and beta cell function in polycystic ovary syndrome. AB - OBJECTIVE: To examine the impact of family history of diabetes mellitus 2 (DM 2) on insulin sensitivity and secretion in lean women with polycystic ovary syndrome (PCOS). Thirteen healthy women (C), 14 PCOS without family history of DM 2 (FH-) and 8 PCOS with family history of DM 2 (FH+) were examined using euglycemic hyperinsulinemic clamp and an arginine secretion test (insulin and glucagon at fasting glycemia (AIR(FG) and AGR(FG)) and at hyperglycemia (AIR(14) and AGR(14)). FH+ women were more insulin resistant than FH- with lower insulin sensitivity index corrected per lean body mass (p 0.05). They had significantly higher triglycerides (p 0.05) and lower HDL-cholesterol (p 0.05) than C or FH- women. Concerning insulin secretion, AIR(FG) was increased in FH+ women comparing FH- women (p 0.05). Disposition indices derived from AIR(FG) or AIR(14) and insulin sensitivity index did not differ between FH+ or FH-. Thus, women with PCOS with the concomitant family history of DM 2 have lower insulin sensitivity than healthy control women. Insulin resistance observed in these women with PCOS is compensated by increased insulin secretion. PMID- 17705675 TI - Influence of gemfibrozil on sulfate transport in human erythrocytes during the oxygenation-deoxygenation cycle. AB - The effects of gemfibrozil (GFZ), an antihyperlipidemic agent, on the anionic transport of the human red blood cells (RBC) during the oxygenation-deoxygenation cycle were examined. Gemfibrozil clearly plays a role in the modulation of the anionic flux in erythrocytes; in fact it causes a strong increment of anions transport when the RBCs are in the high-oxygenation state (HOS). Such an effect is remarkably reduced in the low-oxygenation state (LOS). With the aim of identifying the dynamics of fibrate action, this effect has been investigated also in human ghost and chicken erythrocytes. These latter, in fact, are known to possess a B3 (anion transporter or Band 3) modified at the cytoplasmic domain (cdb3) which plays a significant role in the metabolic modulation of red blood cells. The results were analyzed taking into account the well-known interactions between fibrates and both conformational states of hemoglobin i.e. the T state (deoxy-conformation) and the R state (oxy-conformation). The effect of gemfibrozil on anionic influx appears to be due to a wide interaction involving a "multimeric" Hb-GFZ-cdb3 macromolecular complex. PMID- 17705677 TI - Depressed cardiac contractility and its postnatal development in rats after chemical sympathectomy. AB - The contribution of the sympathetic innervation to the postnatal development of cardiac contractility remains unclear. In this study, the postnatal maturation of cardiac contractility was compared in control rats and rats after chemical sympathectomy. The chemical sympathectomy was induced by administration of 6 hydroxydopamine to newborn rats. At days 20, 40 and 60 of postnatal life, the contractile parameters and concentrations of sympathetic neurotransmitters were measured in both right and left ventricles. In rats with chemical sympathectomy, concentrations of norepinephrine were reduced almost completely in both ventricles at all time points. The contractility of the left ventricle papillary muscles was substantially decreased at all time points. In contrast, the contractility of the right ventricle papillary muscles was decreased only transiently, showing a recovery at day 60 regardless of the permanently decreased concentration of norepinephrine. The concentration of neuropeptide Y, another neurotransmitter present in sympathetic nerves, showed the same developmental trend as contractility: permanent reduction in the left ventricle, transient reduction with a recovery at day 60 in the right ventricle. The data indicate that the sympathetic nervous system plays an important role in the postnatal development of cardiac contractility and neuropeptide Y may contribute to this effect. PMID- 17705676 TI - Oral administration of polyphenolic compounds from cognac decreases ADP-induced platelet aggregation and reduces chronotropic effect of isoprenaline in rats. AB - This study sought to evaluate whether consumption of polyphenol extract from Cognac (CPC) modulates platelet activation and cardiovascular reactivity in rats. Male Wistar rats were treated daily for 4 weeks by intra-gastric gavage receiving CPC at 80 mg/kg/day or vehicle (5 % glucose). Platelet adhesion and aggregation in response to different activators were assessed. Cardiac and vascular reactivity in response to various agonists as well as NO measurement by electron paramagnetic resonance technique were investigated in isolated heart and thoracic aorta. Oral administration of CPC decreased platelet aggregation induced by ADP but not by collagen. CPC did not affect adhesion to collagen. The chronotropic but not the inotropic response to isoprenaline was reduced without alteration of NO production in hearts from CPC-treated rats. CPC treatment did not affect ex vivo relaxation to acetylcholine nor NO content of rat aorta. CPC did not significantly alter the response to phenylephrine in aorta despite the participation of endothelial vasoconstrictor products. In summary, chronic treatment with CPC has no impact on ex vivo vascular and cardiac reactivity; however, it reduced heart work and platelet aggregation. These data suggest the existence of compounds in Cognac that may decrease the risk of coronary thrombosis and protect against some cardiac diseases. PMID- 17705678 TI - Evidences of apoptosis during the early phases of soleus muscle atrophy in hindlimb suspended mice. AB - The purpose of this study was to investigate the occurrence and time-course of apoptosis in soleus skeletal muscle during the first 48 hours of unloading. Fifty Charles River mice were randomly divided into five groups (n=10 each) according to the time of hindlimb suspension (HS). Mice were suspended for 0 (Control), 6 (6HS), 12 (12HS), 24 (24HS), and 48 hours (48HS). Soleus muscle atrophy was confirmed by a significant decrease of 20 % in muscle-wet weight and of 5 % in the ratio protein concentration/muscle wet-weight observed after 48 hours of unloading. The apoptotic index, the AIF (apoptosis-inducing factor) and p53 expression presented their uppermost value (304 %, 241 % and 246 %, respectively) at 24HS, and were preceded by the highest activity of caspase-3 and -8 at 12HS (170 % and 218 %, respectively) and of Bax/Bcl-2 content at 6HS (160 %). There were no marked ultrastructural alterations until 24 hours of simulated weightlessness. Lysosomal autophagic activity and infiltration of phagocytic cells were observed at 24HS and 48HS and might have contributed to the degenerative changes noticed in both groups. Though not consistently supported by morphological evidences, the biochemical parameters sustain the concept that the occurrence of apoptosis parallels the soleus atrophic response in its early phase. PMID- 17705679 TI - Lidocaine suppresses subthreshold oscillations by inhibiting persistent Na(+) current in injured dorsal root ganglion neurons. AB - The aim of this study was to determine the effect and mechanism of low concentration of lidocaine on subthreshold membrane potential oscillations (SMPO) and burst discharges in chronically compressed dorsal root ganglion (DRG) neurons. DRG neurons were isolated by enzymatic dissociation method. SMPO, burst discharges and single spike were elicited by whole cell patch-clamp technique in current clamp mode. Persistent Na(+) current (I(NaP)) and transient Na(+) current (I(NaT)) were elicited in voltage clamp mode. The results showed that SMPO was suppressed and burst discharges were eliminated by tetrodotoxin (TTX, 0.2 micromol/l) in current clamp mode, I(NaP) was blocked by 0.2 micromol/l TTX in voltage clamp mode. SMPO, burst discharges and I(NaP) were also suppressed by low concentration of lidocaine (10 micromol/l) respectively. However, single spike and I(NaT) could only be blocked by high concentration of lidocaine (5 mmol/l). From these results, it is suggested that I(NaP) mediates the generation of SMPO in injured DRG neurons. Low concentration of lidocaine (10 micromol/l) suppresses SMPO by selectively inhibiting I(NaP), but not I(NaT), in chronically compressed DRG neurons. PMID- 17705680 TI - Effect of hindlimb unweighting on expression of hypoxia-inducible factor-1alpha vascular endothelial growth factor, angiopoietin, and their receptors in mouse skeletal muscle. AB - Hindlimb unweighting (HU) leads to capillary regression in skeletal muscle. However, the molecular mechanism(s) remains to be elucidated. To gain insight into the regulation of this process, we investigated gene expression of hypoxia inducible factor-1alpha (HIF-1alpha)vascular endothelial growth factor (VEGF), angiopoietin, and their receptors in the atrophied muscle induced by HU. The hindlimbs of mice were unweighted by tail-suspension and then the gastrocnemius muscles were isolated after 10 days. To assess the capillary distribution, the capillary endothelium in frozen transverse sections was identified by staining for alkaline phosphatase. The mRNA levels were analyzed using a real-time reverse transcription-polymerase chain reaction. After 10 days of HU, the number of capillaries around a muscle fiber was significantly decreased by 19.5 %, suggesting that capillary regression appears to occur. The expression of HIF 1alpha ?was significantly down-regulated after 10 days of HU. The expression of VEGF remained unchanged, whereas those of Flt-1, KDR/Flk-1, and neuropilin-1 were significantly down-regulated, suggesting that VEGF signaling through these receptors would be attenuated. The expression of angiopoietin-1, and -2, as well as their receptor, Tie-2 were also significantly down-regulated, suggesting that angiopoietin-1 signaling through Tie-2 would be attenuated. These findings suggest that alterations in expression of VEGF, angiopoietins, and their receptors may be associated with capillary regression after HU. PMID- 17705681 TI - The relationship between glycemia, insulin and oxidative stress in hereditary hypertriglyceridemic rat. AB - The aim of this study was to determine the effects of insulin infusion on oxidative stress induced by acute changes in glycemia in non-stressed hereditary hypertriglyceridemic rats (hHTG) and Wistar (control) rats. Rats were treated with glucose and either insulin or normal saline infusion for 3 hours followed by 90 min of hyperglycemic (12 mmol/l) and 90 min of euglycemic (6 mmol/l) clamp. Levels of total glutathione (GSH), oxidized glutathione (GSSG) and total antioxidant capacity (AOC) were determined to assess oxidative stress. In steady states of each clamp, glucose infusion rate (GIR) was calculated for evaluation of insulin sensitivity. GIR (mg.kg(-1).min(-1)) was significantly lower in hHTG in comparison with Wistar rats; 25.46 (23.41 - 28.45) vs. 36.30 (27.49 - 50.42) on glycemia 6 mmol/l and 57.18 (50.78 - 60.63) vs. 68.00 (63.61 - 85.92) on glycemia 12 mmol/l. GSH/GSSG ratios were significantly higher in hHTG rats at basal conditions. Further results showed that, unlike in Wistar rats, insulin infusion significantly increases GSH/GSSG ratios in hHTG rats: 10.02 (9.90 - 11.42) vs. 6.01 (5.83 - 6.43) on glycemia 6 mmol/l and 7.42 (7.15 - 7.89) vs. 6.16 (5.74 - 7.05) on glycemia 12 mmol/l. Insulin infusion thus positively influences GSH/GSSG ratio and that way reduces intracellular oxidative stress in insulin-resistant animals. PMID- 17705682 TI - Grounded cognition. AB - Grounded cognition rejects traditional views that cognition is computation on amodal symbols in a modular system, independent of the brain's modal systems for perception, action, and introspection. Instead, grounded cognition proposes that modal simulations, bodily states, and situated action underlie cognition. Accumulating behavioral and neural evidence supporting this view is reviewed from research on perception, memory, knowledge, language, thought, social cognition, and development. Theories of grounded cognition are also reviewed, as are origins of the area and common misperceptions of it. Theoretical, empirical, and methodological issues are raised whose future treatment is likely to affect the growth and impact of grounded cognition. PMID- 17705683 TI - Visual perception and the statistical properties of natural scenes. AB - The environments in which we live and the tasks we must perform to survive and reproduce have shaped the design of our perceptual systems through evolution and experience. Therefore, direct measurement of the statistical regularities in natural environments (scenes) has great potential value for advancing our understanding of visual perception. This review begins with a general discussion of the natural scene statistics approach, of the different kinds of statistics that can be measured, and of some existing measurement techniques. This is followed by a summary of the natural scene statistics measured over the past 20 years. Finally, there is a summary of the hypotheses, models, and experiments that have emerged from the analysis of natural scene statistics. PMID- 17705684 TI - Complement regulatory genes and hemolytic uremic syndromes. AB - Hemolytic uremic syndrome is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. It is one of a group of conditions termed the thrombotic microangiopathies, which are characterized by prominent endothelial cell injury. It may be diarrheal-associated or atypical (aHUS). Evidence for a pathogenic role of the alternative pathway of complement was first suggested in 1974. Mutations in the complement regulatory proteins factor H, membrane cofactor protein (CD46), and factor I predispose to aHUS development. Mutations of the activating components factor B and complement C3 have also been reported. Penetrance is approximately 50%, suggesting other genetic and environmental modifiers are needed for disease expression. Identification of mutations is important owing to differences in mortality, renal survival, and outcome of renal transplantation. Current treatment is plasma infusion/exchange, but complement inhibitor therapy provides hope for the future. PMID- 17705685 TI - Nicotinic acid: pharmacological effects and mechanisms of action. AB - Pharmacological doses of nicotinic acid induce a profound change in the plasma levels of various lipids and lipoproteins. The ability of nicotinic acid to strongly increase the plasma concentration of high-density lipoprotein (HDL) cholesterol has in recent years led to an increased interest in the pharmacological potential of nicotinic acid. There is increasing evidence that nicotinic acid alone or in addition to LDL cholesterol-lowering drugs can reduce the progression of atherosclerosis and reduce the risk of cardiovascular events. The clinical use of nicotinic acid is, however, hindered by harmless but unpleasant side effects, especially by a strong cutaneous vasodilation called flushing. The recent discovery of the G protein-coupled receptor GPR109A (HM74A or PUMA-G) as a receptor for nicotinic acid has allowed for better understanding of the mechanisms underlying the metabolic and vascular effects of nicotinic acid. On the basis of recent progress in understanding the pharmacological effects of nicotinic acid, new strategies are in development to better exploit the pharmacological potential of nicotinic acid. New drugs acting via the nicotinic acid receptor or related receptors, as well as new co-medications that suppress unwanted effects of nicotinic acid, will most likely be introduced as new therapeutic options in the treatment of dyslipidemia and the prevention of cardiovascular diseases. PMID- 17705686 TI - The Medtronic Minimed Gold continuous glucose monitoring system: an effective means to discover hypo- and hyperglycemia in children under 7 years of age. AB - BACKGROUND: The glycemic patterns of children less than 7 years with type 1 diabetes have not been well studied using continuous glucose monitoring. Our goal was to assess the incidence of hypoglycemia as well as postprandial glycemic patterns in this age group utilizing continuous glucose monitoring. METHODS: Nineteen children used the Medtronic MiniMed (Northridge, CA) CGMS System Gold on three to seven occasions over approximately 6 months. RESULTS: Nineteen children (nine girls and 10 boys; mean age 4.8 +/- 1.4 years, range 1.6-6.8 years) used the CGMS 102 times, providing 434 days of data; 79% of days were optimal based on CGMS Solutions software version 3.0. Mild hypoglycemia (glucose or=2 mg/dL/min following 50% of breakfasts. Children with hemoglobin A1c levels >or=8% had higher postprandial glucose concentrations. There was no significant advantage of continuous subcutaneous insulin infusion therapy over multiple daily injection therapy in decreasing postprandial hyperglycemia. CONCLUSIONS: CGMS tracings from young children with diabetes demonstrate frequent mild nocturnal hypoglycemia and significant postprandial hyperglycemia, with a rapid rise in glucose following the meal. The most rapid rate of rise and the most severe postprandial hyperglycemia occurred after breakfast. PMID- 17705687 TI - The incretin mimetic exenatide as a monotherapy in patients with type 2 diabetes. AB - BACKGROUND: Exenatide is an adjunctive therapy for type 2 diabetes, and preliminary evidence suggests that its glucoregulatory effects may be similar in the absence of oral therapy. METHODS: Study A was a randomized, double-blind, placebo-controlled study of 99 patients with type 2 diabetes that received either 10 microg twice-daily, 10 microg once-daily, or 20 microg once-daily exenatide or placebo for 28 days in the absence of background pharmacotherapy. Study B was an open-label extension of a short-term study of 127 patients with type 2 diabetes treated with metformin or diet and exercise. Patients received exenatide 5 microg twice-daily for 4 weeks followed by 10 microg for 26 weeks. Subjects treated with metformin continued oral therapy. RESULTS: Monotherapeutic treatment with 10 microg of exenatide twice-daily for 28 days resulted in significant mean reductions in glycosylated hemoglobin (A1C) of -0.4 +/- 0.1% and fasting plasma glucose of -36.1 +/- 11.0 mg/dL compared to increases of +0.2 +/- 0.1% and +11.0 +/- 12.7 mg/dL with placebo. Self-monitored blood glucose profiles showed significant mean reductions in daily blood glucose concentrations in exenatide treated patients compared to placebo. Exenatide treatment for 30 weeks in an open label extension study resulted in similar mean reductions from baseline in A1C and body weight in patients treated with diet and exercise alone (-1.0 +/- 0.2% and -4.3 +/- 1.3 kg, respectively) as those treated on a background of metformin (-0.9 +/- 0.1% and -3.7 +/- 0.5 kg, respectively). In both studies, the most frequent adverse events were gastrointestinal and predominantly mild to moderate in intensity. Incidence of mild-to-moderate hypoglycemia was low, with no severe hypoglycemia. CONCLUSIONS: Exenatide twice-daily monotherapy resulted in glycemic improvements and reductions in body weight comparable to that of exenatide combination therapy with metformin in patients with type 2 diabetes. PMID- 17705688 TI - Clinical validation of a new control-oriented model of insulin and glucose dynamics in subjects with type 1 diabetes. AB - BACKGROUND: The development of an artificial pancreas requires an accurate representation of diabetes pathophysiology to create effective and safe control systems for automatic insulin infusion regulation. The aim of the present study is the assessment of a previously developed mathematical model of insulin and glucose metabolism in type 1 diabetes and the evaluation of its effectiveness for the development and testing of control algorithms. METHODS: Based on the already existing "minimal model" a new mathematical model was developed composed of glucose and insulin submodels. The glucose model includes the representation of peripheral uptake, hepatic uptake and release, and renal clearance. The insulin model describes the kinetics of exogenous insulin injected either subcutaneously or intravenously. The estimation of insulin sensitivity allows the model to personalize parameters to each subject. Data sets from two different clinical trials were used here for model validation through simulation studies. The first set had subcutaneous insulin injection, while the second set had intravenous insulin injection. The root mean square error between simulated and real blood glucose profiles (G(rms)) and the Clarke error grid analysis were used to evaluate the system efficacy. RESULTS: Results from our study demonstrated the model's capability in identifying individual characteristics even under different experimental conditions. This was reflected by an effective simulation as indicated by G(rms), and clinical acceptability by the Clarke error grid analysis, in both clinical data series. CONCLUSIONS: Simulation results confirmed the capacity of the model to faithfully represent the glucose-insulin relationship in type 1 diabetes in different circumstances. PMID- 17705689 TI - Continuous subcutaneous insulin infusion attenuated glycemic instability in preschool children with type 1 diabetes mellitus. AB - BACKGROUND/AIMS: Continuous subcutaneous insulin infusion (CSII) is believed to decrease glycemic instability and hypoglycemia while increasing quality of life compared to insulin injection regimens. To evaluate indices of glycemic control and impact on quality of life, we studied a group of preschool children with type 1 diabetes mellitus (DM) on CSII. METHODS: Fourteen patients (eight girls and six boys) 3.9 +/- 0.8 years old with DM duration of 2.0 +/- 0.8 years were transitioned from flexible multiple daily insulin (FMDI) (pre-meal aspart and bedtime glargine) to CSII. Patients were evaluated with hemoglobin A(1c) (HbA(1c)) and continuous glucose monitoring quarterly for 1 year. Mean blood glucose (MBG), mean amplitude of glycemic excursion (MAGE), and hypoglycemic events (blood glucose <60 mg/dL) were determined. Patients' parents completed quality of life [TNO-AZL Preschool Children Quality of Life (TAPQoL)] questionnaires for their children at baseline and 1.0 year. RESULTS: The total daily insulin and the bolus:basal ratio did not change during CSII (0.72 +/- 0.21 vs. 0.74 +/- 0.16 U/kg/day and 2.1 +/- 0.61 vs. 2.40 +/- 0.58 U/kg/day, respectively). There was no change in HbA(1c) (8.0 +/- 0.50% vs. 7.8 +/- 0.40%) or frequency of hypoglycemia (moderate, 92.3 vs. 73.1 events/100 patient-years; severe, 22.5 vs. 17.5 events/100 patient-years). The MBG (213 +/- 94 vs. 185 +/- 79 mg/dL) and frequency (1.9 +/- 1.6 vs. 2.1 +/- 2.2) and duration (nocturnal, 135 +/- 141 vs. 120 +/- 103 min; total, 267 +/- 222 vs. 189 +/- 148 min) of hypoglycemic events did not decrease, whereas MAGE was reduced on CSII (210 +/- 31 vs. 168 +/- 22 mg/dL, P < 0.005). The quality of life subscales on the TAPQoL questionnaire did not change on CSII. CONCLUSIONS: CSII improved glycemic instability without reducing HbA(1c) or frequency and duration of hypoglycemic events and altering the parent's perception of his or her child's quality of life. CSII improves glycemic instability and is an effective alternative to FMDI therapy in young children with type 1 DM. PMID- 17705690 TI - Peripheral leptin levels in narcoleptic patients. AB - BACKGROUND: Narcolepsy is a severe sleep disorder that in most patients is characterized by the deficiency of central orexin. Clinically, narcolepsy is associated with obesity. Currently, there is a literature controversy about the potential alteration of leptin levels in narcoleptic patients. Theoretically, diminished leptin levels could partially contribute to the observed overweight of patients. Two studies have reported decreased leptin levels, whereas a larger, recent study failed to detect differences between patients and controls. METHODS: To help settle the controversy, we have measured peripheral leptin levels in 42 narcoleptic patients and in 31 body mass index-matched controls. RESULTS: No significant differences in leptin levels between the groups were observed. Mean leptin levels were 16.0 +/- 14.9 ng/mL in the narcoleptic men and 30.4 +/- 17.8 ng/mL in the narcoleptic women. The corresponding values for the controls were 21.2 +/- 17.0 ng/mL (P = 0.49, men) and 33.9 +/- 16.9 ng/mL (P = 0.31, women). In addition, no correlation was found between leptin levels and clinical symptomatology in the narcoleptic patients. CONCLUSIONS: Taken together, the data argue against a major deterioration of leptin secretion in narcoleptic patients. PMID- 17705691 TI - Decreased core temperature and increased beta(3)-adrenergic sensitivity in diabetes-prone BB rats. AB - BACKGROUND: Diabetes-prone (DP) congenic DR.lyp/lyp BioBreeding (BB) rats all develop Type 1 diabetes between 50 and 81 days of age, while DR.lyp/+ or DR.+/+ BB rats are diabetes resistant (DR). The DP rats display reduced weight gain prior to developing hyperglycemia, implying that metabolic events may precede diabetes onset. We tested the hypothesis that temperature measurements could serve as a physiological marker for the impending onset of hyperglycemia. METHODS: Prior to the onset of hyperglycemia, brain, lower back, and intrascapular brown adipose tissue temperatures were analyzed by thermal signature analysis, which measures infrared emission from tissues. A thermocoupled rectal probe measured core temperature. In addition we performed a beta(3)-adrenergic receptor challenge test with the beta(3)-adrenergic receptor agonist BRL37344. RESULTS: DP rats displayed lower core temperature than DR rats prior to the onset of hyperglycemia. No temperature difference was detected in brain, lower back, or intrascapular brown adipose tissue between DP and DR rats. The beta(3)-adrenergic challenge showed that the rate of temperature increase after administration of BRL37344 was significantly higher (0.005 +/- 0.002 degrees C/min) in DP than in DR rats (P = 0.044). CONCLUSIONS: These studies reveal that the prediabetic DP rats fail to maintain core temperature and that they display increased sensitivity to heat production induced by a beta(3) adrenergic receptor agonist. These studies suggest that body temperature as a measure of metabolic dysregulation is altered in the prediabetic DP rat prior to the onset of hyperglycemia. PMID- 17705692 TI - The impact of non-model-related variability on blood glucose prediction. AB - BACKGROUND: Physiological models are frequently used to predict blood glucose values from insulin and meal data of people with diabetes. Obviously, errors in the input data used result in prediction errors. A more complex problem is that no model may include all factors influencing the blood glucose level in any given situation. We have analyzed the influence of five parameters on prediction accuracy with respect to the time horizon. METHODS: A physiological model, consisting of an insulin model, a meal model, and a glucose metabolism model in combination with a Monte Carlo simulation, was used for this investigation. It was used to examine the change in blood glucose following the intake of carbohydrate and insulin. The intra-individual variability, which was studied, included pharmacokinetic variability of insulin aspart and estimation error of carbohydrate intake, as well as the accuracy of blood glucose meters and insulin pens. RESULTS: Simulations showed how the coefficient of variance for the different model compartments changes over time. For average people with diabetes the inaccuracies of blood glucose meters and carbohydrate estimates contribute to more than half of the variance. CONCLUSION: We showed how blood glucose prediction is severely affected by the inaccuracy in the input variables. Metabolic fluctuations, causing variability in insulin dynamics, also display important effects, but these are difficult to change. The inaccuracy of carbohydrate counting and the use of blood glucose meters appear to be the two main sources of error, which can be reduced through better patient education. PMID- 17705693 TI - Comparison of oral insulin spray and subcutaneous regular insulin at mealtime in type 1 diabetes. AB - BACKGROUND: The aim of this study was to compare the glucose pharmacodynamics after oral spray insulin (Oral-lyn , Generex Biotechnology, Toronto, ON, Canada) and subcutaneous (sc) injection of regular insulin in 10 subjects with type 1 diabetes mellitus (T1DM). METHODS: Basal therapy was twice-daily insulin glargine. Preprandial (30 min) regular insulin was given for 3 days, followed by 9 days of Oral-lyn, eight to 12 puffs immediately pre- and postprandially. Adjustments for glycemia were made using standard snacks and additional regular insulin or Oral-lyn. Peripheral glucose measurements were self-monitored in duplicate. Serum concentrations of fructosamine and hemoglobin A1c (HbA1c) were determined at the start and the end of the study period. RESULTS: Average glucose concentrations (in mmol/L) for the 3-day regular insulin and 9-day Oral-lyn periods, respectively, were: pre-breakfast (B), 5.06 and 3.89; 1-h post-B, 8.39 and 7.67; post-B, 6.00 and 6.33; pre-lunch (L), 5.50 and 4.72; 1-h post-L, 7.83 and 7.89; 2-h post-L, 5.89 and 6.33; pre-dinner (D), 5.61 and 5.17; 1-h post-D, 7.22 and 7.83; and 2-h post-D, 6.11 and 6.67. Areas under the curve for both treatments were not significantly different (P = 0.6875). Fructosamine (mean +/- SD, 338.7 +/- 77.4 micromol/L and 321.7 +/- 63.4 micromol/L), and HbA1c (mean +/- SD, 7.5 +/- 1.5% and 7.2 +/- 1.2%) did not change significantly. CONCLUSIONS: Regular insulin and Oral-lyn had similar glucodynamic effects in subjects with T1DM receiving twice-daily insulin analogue as baseline therapy. Intensive monitoring and timely corrections with additional snacks, additional sc regular insulin, or Oral-lyn puffs resulted in appropriate glycemic control as assessed by individual daily glycemic responses and, especially, normal preprandial glycemia. Protein glycation decreased, but not significantly. PMID- 17705694 TI - The effect of rosiglitazone on orthostatic tolerance during heat exposure in individuals with type II diabetes. AB - BACKGROUND AND METHODS: Twenty-two subjects with type II diabetes and 30 control subjects participated in a 1-year study to examine the effect of rosiglitazone on heart rate variability at rest and the blood pressure, heart rate, and blood flow changes during a change in body position from horizontal to the 45 degrees head up position. To assess nerve damage, latency was measured for sensory nerves in the foot. RESULTS: The results of the experiments showed that subjects with diabetes had an approximate 50% impairment in sural, medial, and lateral plantar nerve latency. After 1 year of administration of rosiglitazone, there was improvement by about 50% in sural, medial, and lateral nerve plantar latency. The changes in blood flow in the subject with diabetes was less than half that of control subjects, during tilting from the horizontal to the vertical position. Heart rate variability was less during tilt, and the blood pressure change was significantly greater in subjects with diabetes than control subjects (P < 0.01). After administration of rosiglitazone for 1 year, the changes in blood flow, blood pressure, and heart rate, while improving by about half, were not equal to those of age matched controls (P < 0.01). CONCLUSIONS: The results of the experiments indicate that the insulin sensitizer rosiglitazone cannot reverse all of the damage associated with diabetes to the autonomic nervous system, but much can be reversed. PMID- 17705695 TI - Effects of pioglitazone in combination with metformin or a sulfonylurea compared to a fixed-dose combination of metformin and glibenclamide in patients with type 2 diabetes. AB - BACKGROUND: This study was designed to compare the effectiveness of co administration of pioglitazone with metformin or a sulfonylurea (SU), with a fixed-dose combination of metformin and glibenclamide on glycemic control and beta-cell function in patients with type 2 diabetes. METHODS: Patients (n = 250) treated with metformin (3 months and with glycosylated hemoglobin (HbA(1c)) between 7.5% and 11% inclusive were randomized to receive either pioglitazone (15-30 mg/day) as add-on therapy to metformin or an SU or a fixed-dose combination of metformin (400 mg) and glibenclamide (2.5 mg) (up to three tablets per day) for 6 months. HbA(1c) and fasting plasma glucose (FPG) were measured at baseline and 2, 4, and 6 months. C peptide levels were measured at baseline and 6 months, and post-challenge glucose and insulin responses were measured. RESULTS: After 6 months, pioglitazone-based and fixed-dose metformin + glibenclamide resulted in similar reductions in HbA(1c) (-1.11% vs. -1.29%, respectively; P = 0.192) and FPG (-2.13 vs. -1.81 mmol/L, respectively; P = 0.370). Patients treated with pioglitazone for 6 months had significantly reduced C-peptide levels compared with baseline (-0.09 nmol/L, P = 0.001), while patients receiving fixed-dose metformin + glibenclamide combination had slightly increased C-peptide levels (+0.04 nmol/L, P = 0.08). Pioglitazone treatment also improved post-challenge insulin responses. CONCLUSIONS: Co-administration of pioglitazone with metformin or an SU is an effective alternative to fixed-dose metformin + glibenclamide combination for patients with type 2 diabetes. The complementary effects of pioglitazone with either metformin or an SU may also have the potential to preserve beta-cell function and delay the progression of type 2 diabetes. PMID- 17705696 TI - Clinical studies of exposure to perchlorate in the United States. AB - Perchlorate is a competitive inhibitor of the sodium/iodine symporter, decreasing the active transport of iodine into the thyroid. It was used as an antithyroid drug in the treatment of hyperthyroidism in the 1950s and 1960s but was discontinued because of the occasional occurrence of aplastic anemia. More recently, lower doses of perchlorate have been used successfully in the treatment of iodine-induced hyperthyroidism. There has been concern that naturally occurring perchlorate and industrial contamination of water supplies with perchlorate might pose a health hazard by inducing or aggravating underlying thyroid dysfunction. In a series of studies in normal volunteers, administration of perchlorate from 2 weeks to 6 months and in perchlorate production workers exposed intermittently to high levels of perchlorate for years, no abnormalities of circulating thyroid hormones, thyroid-stimulating hormone, thyroglobulin, or ultrasound evaluation of thyroid structure were observed even though the thyroid (123)I uptake was decreased in some studies. Further studies of the effects of perchlorate on thyroid function in normal volunteers will now be difficult to carry out due to the adverse publicity that perchlorate and the studies on its effect have received. PMID- 17705697 TI - A fast method to detect cell surface expression of thyrotropin receptor (TSHr): the microchip flow cytometry analysis. AB - Loss-of-function mutations of the thyrotropin receptor (TSHr) may be responsible for congenital hypothyroidism or isolated hyperthyreotropinemia. To study cell surface expression of inactivating TSHr mutations detected in patients with isolated hyperthyreotropinemia (L252P, Q8fsX62, P27T, E34K, R46P, D403N, W488R, and M527T), we used the Agilent 2100 bioanalyzer to perform microchip flow cytometry analysis. The previously described TSHr inactivating mutation T477I was used as control. The level of receptor expression in COS-7 cells transfected with the T477I measured by binding assay was four times lower with respect to the wild type TSHr. The very low expression of T477I was confirmed by fluorescence activated cell sorting (FACS) analysis and by microchip flow cytometry analysis, suggesting that this method can be a reliable system to measure receptor cell surface expression. Other inactivating TSHr mutations were expressed in COS-7 cells for binding studies, FACS analysis, and microchip flow cytometry analysis. Binding studies showed that L252P, Q8fsX62, P27T, E34K, R46P, D403N, W488R, and M527T mutants had a low expression at the cell surface, as demonstrated by Bmax values. Data obtained by binding studies were in good agreement with data obtained by FACS analysis and microchip flow cytometry analysis. In conclusion, the low number of cells required for analysis and the ease of use make the microchip flow cytometry analysis a very reliable and favorable system to study cell surface expression of TSHr mutations. PMID- 17705698 TI - Vaccination with polymerase chain reaction-generated linear expression cassettes protects mice against lethal influenza A challenge. AB - The feasibility of a linear expression cassette (LEC)-based influenza A DNA vaccine was demonstrated in mice, using a lethal dose (LD90) of a mouse-adapted A/Hong Kong/8/68 (H3N2) influenza strain. LECs expressing hemagglutinin (HA) from either the homotypic H3N2 or the heterotypic H1N1 (A/Puerto Rico/8/34) influenza virus were produced by polymerase chain reaction and either phosphodiester- or phosphorothioate-modified oligonucleotide primers. Survival subsequent to lethal viral challenge was used as a primary end point; weight loss was the secondary end point. Survival and weight loss data showed that protection can be achieved in mice with 50 microg of phosphate-buffered saline-formulated LEC DNA or 2 microg of Vaxfectin-formulated LEC DNA. Survival correlated with neutralizing antibody titers (hemagglutination inhibition, HAI); titers obtained after vaccination with LEC were equivalent to those obtained with HA (H3N2) plasmid DNA control. Vaccination with heterotypic H1 HA-LEC DNA provided no protection against viral challenge. PMID- 17705699 TI - Metabolomic applications to neuroscience: more challenges than chances? PMID- 17705702 TI - Peptide fragmentation and phospho-site detection. PMID- 17705703 TI - Alternative profiling platform based on MELDI and its applicability in clinical proteomics. AB - The presence of numerous proteomics data and their results in literature reveal the importance and influence of proteins and peptides on human cell cycle. For instance, the proteomic profiling of biological samples, such as serum, plasma or cells, and their organelles, carried out by surface-enhanced laser desorption/ionization mass spectrometry, has led to the discovery of numerous key proteins involved in many biological disease processes. However, questions still remain regarding the reproducibility, bioinformatic artifacts and cross validations of such experimental set-ups. The authors have developed a material based approach, termed material-enhanced laser desorption/ionization mass spectrometry (MELDI-MS), to facilitate and improve the robustness of large-scale proteomic experiments. MELDI-MS includes a fully automated protein-profiling platform, from sample preparation and analysis to data processing involving state of-the-art methods, which can be further improved. Multiplexed protein pattern analysis, based on material morphology, physical characteristics and chemical functionalities provides a multitude of protein patterns and allows prostate cancer samples to be distinguished from non-prostate cancer samples. Furthermore, MELDI-MS enables not only the analysis of protein signatures, but also the identification of potential discriminating peaks via capillary liquid chromatography mass spectrometry. The optimized MELDI approach offers a complete proteomics platform with improved sensitivity, selectivity and short sample preparation times. PMID- 17705704 TI - Methodology development for predicting subcellular localization and other attributes of proteins. AB - Facing the explosion of newly generated protein sequences in the postgenomic age, we are challenged to develop computational methods for the fast and accurate identification of their subcellular localization and other attributes. This review summarizes recent methodology developments, with a focus on artificial neural networks, the statistical learning and support vector machine, the fuzzy logic-based algorithm and the evidence-theory-based algorithm, as well as the ensemble classifier approach. Meanwhile, an outline of the use of different descriptors for protein samples is given. In addition, a series of web servers established recently based on various ensemble classifiers are also briefly introduced. PMID- 17705705 TI - Histone proteomics and the epigenetic regulation of nucleosome mobility. AB - Chromatin structure plays a vital role in the transmission of heritable gene expression patterns. The recent application of mass spectrometry to histone biology provides several striking insights into chromatin regulation. The continuing identification of new histone post-translational modifications is revolutionizing the ways in which we think about how access to genomic DNA is controlled. While post-translational modifications of the flexible histone tails continue to be an active area of investigation, the recent discovery of multiple modifications in the structured globular domains of histones provides new insights into how the nucleosome works. Recent experiments underscore the importance of a subgroup of these modifications: those that regulate histone-DNA interactions on the lateral surface of the nucleosome. This information highlights an emerging new paradigm in chromatin control, that of the epigenetic regulation of nucleosome mobility. PMID- 17705707 TI - Functional proteomics in histone research and epigenetics. AB - Post-translational modifications of histones comprise an important part of epigenetic gene regulation. Mass spectrometry and immunochemical techniques are currently the methods of choice for identification and quantitation of known and novel histone modifications. While peptide-centric mass spectrometry is a well established tool for identification and quantification of histone modifications, recent technological advances have allowed discrete modification patterns to be assessed on intact histones. Chromatin immunoprecipitation assays (ChIP and ChIP on-chip) are currently gaining tremendous popularity and are used to explore gene specific patterns of histone modifications on a genomic scale. In this review, we introduce the basic concepts and recent developments of mass spectrometry, as well as immunochemical techniques and their applications in the analysis of histone modifications. PMID- 17705706 TI - Transfected cell microarrays: an efficient tool for high-throughput functional analysis. AB - Transfected cell microarrays are considered to be a breakthrough methodology for high-throughput and high-content functional genomics. Here, recent advances in the cell microarray field are reviewed, along with its potential to increase the speed of determining gene function. These advances, combined with an increasing number and diversity of gene perturbing systems, such as RNAi and ectopic gene expression, provide tools for expanding our understanding of biology at the systems level. PMID- 17705708 TI - High-throughput antibody microarrays for quantitative proteomic analysis. AB - The antibody microarray is an intrinsically robust and quantitative system that delivers high-throughput and parallel measurements on particular sets of known proteins. It has become an important proteomics research tool, complementary to the conventional unbiased separation-based and mass spectrometry-based approaches. This review summarizes the technical aspects of production and the application for quantitative proteomic analysis with an emphasis on disease proteomics, especially the identification of biomarkers. Quality control, data analysis methods and the challenges for quantitative assays are also discussed. PMID- 17705709 TI - Recent advances in protein profiling of tissues and tissue fluids. AB - Creating protein profiles of tissues and tissue fluids, which contain secreted proteins and peptides released from various cells, is critical for biomarker discovery as well as drug and vaccine target selection. It is extremely difficult to obtain pure samples from tissues or tissue fluids, however, and identification of complex protein mixtures is still a challenge for mass spectrometry analysis. Here, we summarize recent advances in techniques for extracting proteins from tissues for mass spectrometry profiling and imaging. We also introduce a novel technique using a capillary ultrafiltration (CUF) probe to enable in vivo collection of proteins from the tissue microenvironment. The CUF probe technique is compared with existing sampling techniques, including perfusion, saline wash, fine-needle aspiration and microdialysis. In this review, we also highlight quantitative mass spectrometric proteomic approaches with, and without, stable isotope labels. Advances in quantitative proteomics will significantly improve protein profiling of tissue and tissue fluid samples collected by CUF probes. PMID- 17705710 TI - Human saliva proteome analysis and disease biomarker discovery. AB - Human saliva is an attractive body fluid for disease diagnosis and prognosis because saliva testing is simple, safe, low-cost and noninvasive. Comprehensive analysis and identification of the proteomic content in human whole and ductal saliva will not only contribute to the understanding of oral health and disease pathogenesis, but also form a foundation for the discovery of saliva protein biomarkers for human disease detection. In this article, we have summarized the proteomic technologies for comprehensive identification of proteins in human whole and ductal saliva. We have also discussed potential quantitative proteomic approaches to the discovery of saliva protein biomarkers for human oral and systemic diseases. With the fast development of mass spectrometry and proteomic technologies, we are enthusiastic that saliva protein biomarkers will be developed for clinical diagnosis and prognosis of human diseases in the future. PMID- 17705711 TI - CNS proteomes in alcohol and drug abuse and dependence. AB - Drugs of abuse, including alcohol, can induce dependency formation and/or brain damage in brain regions important for cognition. 'High-throughput' approaches, such as cDNA microarray and proteomics, allow the analysis of global expression profiles of genes and proteins. These technologies have recently been applied to human brain tissue from patients with psychiatric illnesses, including substance abuse/dependence and appropriate animal models to help understand the causes and secondary effects of these complex disorders. Although these types of studies have been limited in number and by proteomics techniques that are still in their infancy, several interesting hypotheses have been proposed. Focusing on CNS proteomics, we aim to review and update current knowledge in this rapidly advancing area. PMID- 17705712 TI - Biochips and other microtechnologies for physiomics. AB - This paper presents a review of microtechnologies relevant to applications in cellular physiology, including biochips, electrochemical sensors and optrodic sensing techniques. Microelectrodes have been the main tools for measuring cellular electrophysiology, oxygen, nitric oxide, neurotransmitters, pH and various ions. Optical fiber sensing methods, such as indicator-based optrodes, with fluorescence lifetime measurement, are now emerging as viable alternatives to electroanalytical chemistry. These new optrode techniques are possible because of recent advances in the optoelectronics industry and are comparably easier to miniaturize, have faster response times, do not consume the analyte and have lower operational costs. This review serves as a summary and predicts future trends for both electrochemical and optical luminescence lifetime sensing as components in lab-on-a-chip devices for physiological sensing. PMID- 17705713 TI - Nanobiotechnology: quantum dots in bioimaging. AB - Many biological systems, including protein complexes, are natural nanostructures. To better understand these structures and to monitor them in real time, it is becoming increasingly important to develop nanometer-scale signaling markers. Single-molecule methods will play a major role in elucidating the role of all proteins and their mutual interactions in a given organism. Fluorescent semiconductor nanocrystals, known as quantum dots, have several advantages of optical and chemical features over the traditional fluorescent labels. These features make them desirable for long-term stability and simultaneous detection of multiple signals. Here, we review current approaches to developing a biological application for quantum dots. PMID- 17705714 TI - Advancing signaling networks through proteomics. AB - Healthful physiology can be distinguished from unhealthful physiology by focusing upon how a given signal transduction pathway is shifted as a function of disease. In order to distinguish between pathways that contribute to normal versus disease biology, it is necessary to identify components that comprise a protein module. The development of methods that target such differences is essential for the identification, development and validation of biomarkers that can improve the quality of diagnoses and treatment of disease. This review discusses the use of proteomic methods that integrate cell biology, mass spectrometry and bioinformatics, in relation to the analyses of protein signaling modules that are subject to differential phosphorylation. We examine how these methods can be used to distinguish abnormal from normal physiology. PMID- 17705716 TI - NOTES: the hybrid technique. AB - INTRODUCTION: Natural orifice translumenal endoscopic surgery (NOTES) has gained much interest by minimal invasive surgeons and gastroenterologists. Performing abdominal operations without any abdominal wall incisions may offer all the advantages of minimally invasive surgery (MIS) and eliminate the complications associated with these wounds. The NOTES technique is rapidly being developed, but one of the major issues involved in the procedure that has to be addressed prior to implementation is in obtaining adequate spatial orientation. OBJECTIVE: The aim of this study was to combine the standard laparoscopic vision together with the endoscopic surgery procedure in order to acquire an independent satisfactory vision source. MATERIALS AND METHODS: The hybrid technique was performed in 6 porcine animal models. Among the procedures performed were tubal ligation, liver biopsies, oophorectomy, and cholecystectomy. All procedures were performed under general anesthesia, and all animals were euthanized at the termination of the procedure. RESULTS: The laparoscopic vision offers substantial advantages over the endoscopic vision. Spatial orientation is achieved in the same manner and quality as in MIS, and furthermore, the laparoscopic vision increases the safety of the NOTES procedure. CONCLUSIONS: The hybrid technique offers a superior vision source independent to the working endoscope. It may be an interim technique for developing NOTES until a novel imaging device will be available, or serve as the final solution for acquiring an adequate vision for this approach. PMID- 17705715 TI - Laparoscopic enucleation of pancreatic insulinomas. AB - Insulinomas are rare endocrine pancreatic tumors whose incidence has been increasing in recent years owing to early detection by clinical and radiologic, such as remote neural monitoring, computed tomography (CT), and ultrasound (US) findings. The classical treatment consists of open surgical resection, which is associated with relative morbidity and mortality rates. The aim of this paper was to present 5 patients who were diagnosed with pancreatic insulinomas that were treated by laparoscopic resection. Five (5) patients, ranging from 14 to 45 years and presenting with classical Whipple Triad, had lesions ranging from 1.5 to 2.5 cm by CT (body and tail of the pancreas), which were subsequently diagnosed as insulinomas. An ecoendoscopy showed no combined lesions. They were treated by a laparoscopic resection. Glicemic levels were controlled during surgery with an expected glucose rise. All patients had an uneventfull recovery. The mean length of follow-up is 14 months. The laparoscopic resection of pancreatic insulinomas is a reliable procedure for superficial lesions in the body and tail of the pancreas. PMID- 17705717 TI - Assessment of construct validity of a virtual reality laparoscopy simulator. AB - BACKGROUND: The aim of this study was to assess whether virtual reality (VR) can discriminate between the skills of novices and intermediate-level laparoscopic surgical trainees (construct validity), and whether the simulator assessment correlates with an expert's evaluation of performance. METHODS: Three hundred and seven (307) participants of the 19th-22nd Davos International Gastrointestinal Surgery Workshops performed the clip-and-cut task on the Xitact LS 500 VR simulator (Xitact S.A., Morges, Switzerland). According to their previous experience in laparoscopic surgery, participants were assigned to the basic course (BC) or the intermediate course (IC). Objective performance parameters recorded by the simulator were compared to the standardized assessment by the course instructors during laparoscopic pelvitrainer and conventional surgery exercises. RESULTS: IC participants performed significantly better on the VR simulator than BC participants for the task completion time as well as the economy of movement of the right instrument, not the left instrument. Participants with maximum scores in the pelvitrainer cholecystectomy task performed the VR trial significantly faster, compared to those who scored less. In the conventional surgery task, a significant difference between those who scored the maximum and those who scored less was found not only for task completion time, but also for economy of movement of the right instrument. CONCLUSIONS: VR simulation provides a valid assessment of psychomotor skills and some basic aspects of spatial skills in laparoscopic surgery. Furthermore, VR allows discrimination between trainees with different levels of experience in laparoscopic surgery establishing construct validity for the Xitact LS 500 clip and-cut task. Virtual reality may become the gold standard to assess and monitor surgical skills in laparoscopic surgery. PMID- 17705718 TI - Risk factors influencing conversion of laparoscopic to open cholecystectomy. AB - BACKGROUND: Conversion of laparoscopic to open cholecystectomy is required in certain cases for the safe completion of the operation. Some factors contribute more to the need for conversion. METHODS: Over a 13-year period, the laparoscopic cholecystectomy procedure was attempted in 1263 patients whose mean age was 54 years and 28% being male. The conversion was necessary in 98 cases whose mean age was 60 years, with 42% being male. All data were studied retrospectively. Six factors were examined statistically for a possible correlation with the conversion rate, as well as the trend of it over time. RESULTS: The main reason for conversion was the unclear anatomy owing to previous inflammation, followed by bleeding and choledocholithiasis suspicion, gallbladder carcinoma, bile duct injury, or spilled gallstones. The overall conversion rate was 7.75%. It was significantly increased in males (11.6%) and the elderly (12.4 %), gallbladder inflammation (29%), and morbid obesity (50%). Conversion rate did not change significantly in the first half period (8.1%) of the study, the second half period (7.6%), in patients with diabetes mellitus (6.7%), or hematological disorders (6%). CONCLUSIONS: The risk for the conversion of laparoscopic cholecystectomy increases significantly in males, the elderly, obese patients, and when inflammation is present. This observation remains unchanged over time. Diabetes mellitus and hematologic disorders do not predispose in a higher risk for conversion. PMID- 17705719 TI - Effect of carbon dioxide pneumoperitoneum on liver function following laparoscopic cholecystectomy. AB - BACKGROUND: It has been noted that following a laparoscopic cholecystectomy (LC), liver function parameters were disturbed. The causes of this disturbance are still controversial. PATIENTS AND METHODS: The serum levels of eight parameters of liver function were measured both before and 24 hours after surgery in 142 consecutive patients who underwent LC, 23 patients who underwent open cholecystectomy (OC), and in 25 patients who underwent a conventional hernial repair. The same anesthetic protocol was applied to all patients in the various groups and in the case of LC; the intra-abdominal pressure was maintained at 12 mmHg of CO2. RESULTS: Twenty-four (24) hours after surgery, there was a statistically significant change of all the eight parameters studied, except alkaline phosphatase in patients who underwent LC, whereas there were only 3 patients from the OC group who had changes of alanine aminotransferase and aspartite aminotransferase and 2 patients who had raised levels of direct bilirubin, and no changes were observed among those who had conventional hernial repair. We found that 83% of the patients showed more than a 100% increase in at least one parameter, 43% showed an increase in two or more parameters, and 23% showed an increase in three or more parameters. We also observed a significant drop of total proteins and albumin levels in all patients who had LC. CONCLUSIONS: It appears that the pneumoperitoneum plays a major role in these changes. Although these changes of liver function were of no clinical relevance in healthy patients, the safety of the procedure must nonetheless be assessed in those with underlying liver diseases. PMID- 17705720 TI - Impact of fellowship training in initiating a laparoscopic donor nephrectomy program. AB - OBJECTIVES: Laparoscopic donor nephrectomy (LDN) is the current standard of care, but remains a challenging procedure. A urologist at our center performed 6 months of standard and hand-assisted laparoscopic nephrectomy (HALN) fellowship (46 cases, 30 as surgeon). He subsequently performed 30 HAL renal surgeries prior to initiating our hand-assisted laparoscopic donor nephrectomy (HALDN) program. METHODS: We reviewed the intra- and postoperative outcomes of the first 20 HALDNs performed at our center. We examined demographics, estimated blood loss (EBL), operative time, complications, change in hemoglobin and creatinine, length of hospital stay, warm ischemic time, and recipient outcome. RESULTS: Twenty (20) patients underwent HALDN between November 2003 and December 2005. The mean operative time was 277 minutes. EBL averaged 176 mL. An expected rise in creatinine of 0.1-0.8 mg/dL occurred in all patients. One (1) patient had a splenic abrasion and was transfused intraoperatively. Two (2) patients' courses were complicated by ileus. The remaining patients were discharged on postoperative days 2-6. There were no other complications. Warm ischemia time averaged 3.7 minutes. Two (2) recipients experienced acute or delayed rejection episodes, requiring increased immunosuppression. One (1) recipient had good renal function until he developed sepsis 3 months later and died. All recipients were discharged with functioning grafts, and there have been no ureteral strictures. CONCLUSIONS: Six (6) months of laparoscopic nephrectomy training plus a 30-case HAL/LRN surgical experience sufficiently prepares a surgeon to initiate a HALDN program. Even at a lower volume transplant center, positive operative results and long-term graft outcomes can be achieved. PMID- 17705721 TI - Validation assessment of the Chinese (Taiwan) version of the Gastrointestinal Quality of Life Index for patients with symptomatic gallstone disease. AB - BACKGROUND: Symptomatic gallstone is one of the most common diseases in Taiwan. The aim of this study was to develop a Mandarin Chinese outcomes measure for the assessment on quality of life among gallstone patients. MATERIALS AND METHODS: The Gastrointestinal Quality of Life Index (GIQLI) is a valid, disease-specific measure for the evaluation of health status and treatment effectiveness for adults with chronic gastrointestinal condition. The GIQLI was translated into Mandarin Chinese using a parallel model. The Chinese (Taiwan) version of the GIQLI (CGIQLI) was administered to 102 patients with symptomatic gallstone disease in a prospective manner; the CGIQLI then was validated according to established criteria for reliability, validity, and longitudinal sensitivity. RESULTS: The CGIQLI demonstrates good test-retest reliability (r = 0.92, P = 0.001) and internal consistency (Cronbach's alpha = 0.92). The CGIQLI significantly correlates with the Mandarin Chinese (Taiwan) version of the generic 36-Item Short-Form Health Survey (SF-36). The standardized response mean for the CGIQLI total score is 0.96, indicating excellent sensitivity to clinical change in the study group. CONCLUSION: This validation study demonstrated that the performance characteristics of the CGIQLI are equivalent to the English version, the GIQLI. This study demonstrates that the CGIQLI is a valid tool to evaluate adults with chronic gastrointestinal problems among the Chinese-speaking population. PMID- 17705722 TI - Incorporation of hand-assisted laparoscopic nephrectomy into an academic training program: an assessment of the utility of a 3-month minifellowship. AB - INTRODUCTION: The aim of this study was to assess the amount of training necessary for a midcareer urologic surgeon to incorporate hand-assisted laparoscopic (HAL) renal surgery into an academic practice. MATERIALS AND METHODS: A urologist (JAB) without laparoscopic surgical experience in his fifth year of practice completed a 3-month minifellowship at a high-volume center primarily to learn HAL nephrectomy (HALN), during which he performed 15 HALNs (and 2 HAL nephroureterectomies) and assisted during 5 HALNs. Surgical outcomes and resident surgical participation on nephrectomy cases at the home medical center during the 6 months prior to (phase 1) and after (phase 2) the fellowship were evaluated. RESULTS: During phase 1, 12 open nephrectomies were performed in a mean operative time of 265 (10-387) minutes. During phase 2, 16 HALNs were initiated and 2 (13%) combined cases were converted to open at the discretion of general surgeon. The mean operative time was 288 (226-355) minutes. Ten (10) and 5 patients from each cohort had concomitant procedures performed. The mean tumor size was 8.7 (2-15) and 7.1 (2.5-15) cm. Three (3) patients from each cohort were anemic preoperatively (hemoglobin < or =10 mg/dL). Ten (10) (83%) and 4 (25%) patients from each cohort received transfusions. There were 3 and 2 intraoperative and postoperative cohort complications, respectively. Residents were the operative surgeon on all cohort 1 and two thirds of cohort 2 cases. Chief residents completed the entirety of their third and fourth HALNs, respectively. CONCLUSIONS: A 3-month fellowship is an effective tool for a midcareer urologist to rapidly gain significant HALN experience. Twenty-two (22) cases (17 as surgeon) allowed for the immediate incorporation of this procedure into a complex academic practice without any interruption of residency training. PMID- 17705723 TI - Laparoscopic gastric bypass for morbid obesity decreases bodily pain, improves physical functioning, and mental and general health in women. AB - INTRODUCTION: Surgery is an effective long-term therapeutic option for morbid obese patients. Although bariatric surgery's amelioration of medical ailments is well established, its nonphysical benefits have not been as well documented. METHODS: Women who had undergone laparoscopic gastric bypass between August 2003 and May 2005 were provided with an SF-36 1 month before surgery, as well as 1, 3, 6, 9, 12, 15, and 18 months after surgery. Those women who completed three surveys were included in this study. Scores were summed for each of six areas analyzed: physical function, physical role limitations, emotional role limitations, bodily pain, mental health, and general health. The results of the preoperative and the last postoperative surveys were compared using Wilcoxon's signed-rank test. RESULTS: Of 91 women considered for this study, 40 (44%) completed at least three postoperative surveys. For bodily pain, physical function, physical role limitations, mental health, and general health, median postoperative exceeded median preoperative scores (P < 0.004 for each analysis); for emotional role limitations, the median postoperative score was the same as the median preoperative score. CONCLUSIONS: In women, gastric bypass for morbid obesity decreases bodily pain and physical role limitations, and improves physical functioning as well as mental and general health. The positive impact of laparoscopic gastric bypass is thus validated by the SF-36 questionnaire. PMID- 17705725 TI - Port-site recurrence after laparoscopy-assisted gastrectomy: report of the first case. AB - In advanced gastric cancer, laparoscopic management has been associated with trocar-site recurrence, even though laparoscopy-assisted gastrectomies have reported positive results to treat early-stage gastric cancer in the world. There are no reports of port-site recurrence after laparoscopic gastrectomy in the literature. In this paper, we present a case report of advanced gastric cancer with port-site recurrence 12 month after the initial operation. A wide excision of this recurrence was performed. Otherwise, the evaluation of metastasis in other sites remained negative at 18 months after the original operation. The laparoscopic surgeon should be aware of trocar-site recurrence when dealing with advanced gastric cancer. PMID- 17705724 TI - Portal vein thrombosis after laparoscopic splenectomy in benign hematologic diseases. AB - INTRODUCTION: Portal vein thrombosis is an unfrequent, but potentially deadly, complication of the laparoscopic splenectomy procedure. The laparoscopic approach has shortened the duration of hospital stay; portal vein thrombosis may appear after the patient has left the hospital, determining a later diagnosis. Because of the mild, nonspecific symptoms, the diagnosis can even be missed and only achieved when chronic complications take place. OBJECTIVES: In this study, we aimed to determine the appearance of portal vein thrombosis in a consecutive series of patients who underwent laparoscopic splenectomy by performing a contrast-enhanced computed tomography (CT) scan postoperatively. MATERIALS AND METHODS: A transversal study was established, performing in 2005 a contrast enhanced CT scan on 20 patients who underwent laparoscopic splenectomy between 1999 and 2005 at Ramon y Cajal University Hospital (Madrid, Spain). The presence of thrombosis in the splenoportomesenteric axis was investigated. RESULTS: Two (2) cases (10%) of portal vein thrombosis were detected: 1 symptomatic case, 7 days after surgery, was treated with anticoagulation, resulting in the disappearance of the thrombus in a new CT scan 6 months later; the second case was asymptomatic and was discovered during the performance of this study. CONCLUSIONS: The contrast-enhanced CT scan shows the best accuracy for the diagnosis of portal vein thrombosis, and it must be performed when any clinical manifestation appear; also, it must still be determined if a contrast-enhanced CT scan should be systematically performed in high-risk thromboembolic patients. An ultrasound Doppler may present many diagnostic errors. It is probably advisable to prolong the antithromboembolic prophylaxis. PMID- 17705726 TI - A classical technique applied to laparoscopic rectal cancer surgery: transillumination of the inferior mesenteric root and its tributaries. AB - One of the major concerns associated with current techniques of laparoscopic rectal resections is the accurate, safe identification of the inferior mesenteric root and its tributaries, especially in patients with thickened, fatty mesentery. The classical technique of transillumination was applied successfully by the use of two telescopes, each with a different light source in laparoscopic rectal procedures. Therefore, this approach can decrease conversion and morbidity rates during the learning curve. PMID- 17705727 TI - Laparoscopic D3 lymph node dissection with preservation of the superior rectal artery for the treatment of proximal sigmoid and descending colon cancer. AB - In this paper we report a technique for laparoscopic lymph node (LN) dissection for descending and proximal sigmoid colon cancer with the preservation of the superior rectal artery (SRA) to maintain the blood supply to the distal sigmoid colon. Five (5) cases were included from November 2004 to March 2005. For D3 LN dissection, the root of inferior mesenteric artery was exposed with ultrasonic cutting and coagulating surgical device to avoid bleeding. The arterial wall was then exposed with a spatula-type electric cautery down to the left colic artery (LCA). The LCA was then clipped and cut while preserving the SRA. The inferior mesenteric vein was divided at the caudal side of the LCA and prior to joining to the splenic vein. All cases underwent a LN dissection laparoscopically. There were no cases of complications originating from the LN dissection. Although long term outcomes should be investigated, our results indicate that this is a safe, applicable method. PMID- 17705728 TI - A novel technique for the treatment of a symptomatic giant colonic lipoma. AB - Submucosal lipomas are usually harmless neoplasms arising from submucosal adipocytes. They are found most commonly in the colon, but may develop in any part of the gastrointestinal tract. Most colonic lipomas are asymptomatic and need no treatment, whereas larger ones (>2 cm) may present with abdominal pain, changes in bowel habits, rectal bleeding, and intussusception or prolapse. The literature on the endoscopic resection of colonic lipomas is limited owing to the increased risk of colonic perforation. In this paper, we describe a novel technique for the treatment of colonic obstruction resulting from a giant lipoma by placing two large clips at the narrow base of the lipoma and performing multiple cuttings on the mucosa covering the fatty tissue by using a needle-knife to facilitate the fat's discharge into the colon's lumen. Our case showed that the endoclipping of semi- or pedunculated large colonic lipomas not amenable for endoloop ligation and associated with cuttings of the mucosa covering the fat is a promising new technique, which avoids the risk of perforation or bleeding of the snare cautery, especially in high-risk patients. PMID- 17705729 TI - A simple technique for wedge biopsy of the liver during laparoscopic surgery. AB - A simple technique for wedge biopsy of the liver, which can be performed concomitantly with laparoscopic surgery, is described in this paper. For this technique, the edge of the liver is clamped with two standard laparoscopic bowel graspers at an approximately 90-degree angle to create a wedge of hepatic tissue for biopsy. A pair of endoscopic scissors is used to excise the specimen between the graspers. The cutting surface of the liver is then coagulated with a monopolar device. This technique is rapid, safe and inexpensive, and requires no specific instruments and/or devices. PMID- 17705730 TI - Results of teenaged bariatric patients performed in an adult program. AB - BACKGROUND: Morbid obesity is a growing epidemic among adolescents. Bariatric surgery has proven to be the only long-term effective method in treating morbidly obese adults for over a decade. The laparoscopic approach has become a popular option. This study tested the hypothesis that laparoscopic Roux-en-Y gastric bypass is a feasible option in teenaged patients with good results through an adult bariatric program. METHODS: All patients under the age of 20 at the time of surgery were included in this study. Each patient had undergone a laparoscopic Roux-en-Y gastric bypass. Charts were reviewed for preoperative evaluation, operative time, complications, and length of hospital stay. Percentage of excess body weight lost (%EBWL) was calculated at the follow-up. RESULTS: Of the 202 patients who underwent a laparoscopic gastric bypass procedure at our institution, 5 (2%) were teenagers. The mean age was 18 years (range, 17-19). The mean height was 69 inches (range, 61-75). Average weight was 323 lbs (range, 227 394). The mean preoperative body mass index was 48 kg/m2 (range, 44-56). All patients had medical and psychological clearance prior to surgery. Mean operative time was 150 minutes (range, 130-172). There were no complications in this subset of patients. All 5 patients were discharged on postoperative day 2. Follow-up ranged from 17.8 to 44.8 months. The mean %EBWL was 77% (range, 58%-88%). CONCLUSIONS: The laparoscopic gastric bypass procedure is technically feasible in teenaged patients, with excellent results even when performed in an adult bariatric program. Long-term data will be needed to determine its role in the treatment of morbidly obese adolescents. PMID- 17705731 TI - Appendicectomy for simple appendicitis: video-assisted or intracorporeal? AB - BACKGROUND: We reviewed our experience with laparoscopic appendicectomy (LA) to compare the video-assisted and intracorporeal approaches. MATERIALS AND METHODS: One hundred and sixty-one (161) patients undergoing LA for simple appendicitis were considered. The procedure was video-assisted with an extracorporeal appendicectomy in 74 cases operated on during the first 5 years of our experience (group A), whereas it was entirely intracorporeal in the subsequent 87 (group B). In the latter group, the dissection of the mesoappendix was accomplished by using titanium clips in 38 cases, with monopolar coagulation in 42 and other devices in 7. The base of the appendix was closed by using endoloops in 11 patients and a stapler in 76. In all the intracorporeal LAs, the appendix was delivered through a port site. A very low position of the two accessory ports was adopted in 34 group B patients. RESULTS: No difference in outcome was found between the two groups, except in operating time (48 vs. 29 minutes) and length of hospital stay (3 vs. 1 day). The complication rate was not statistically different among the various techniques used in group B to divide the mesoappendix and to close the base of the appendix. The cost of disposable instruments for intracorporeal LA was 3- to 6 folds higher than for the extracorporeal one. An extremely low position of the ports did not interfere with the procedure in any case. CONCLUSIONS: LA for simple appendicitis can be performed safely with many techniques. The intracorporeal procedure allows for a shorter operating time, but can dramatically increase the costs of the disposable instruments that are required. PMID- 17705732 TI - Laparoscopic gastrostomy in children with congenital heart disease. AB - AIM: The aim of this study was to study the type and frequency of complications and change in weight after a laparoscopic gastrostomy procedure in 31 children with congenital heart disease, comparing patient groups of children with univentricular and biventricular circulation, and with completed and uncompleted cardiac surgery. METHODS: The method used was that of a retrospective study of all 31 children with congenital heart disease who underwent a laparoscopic gastrostomy at our center from 1995 to 2004. MAIN OUTCOME MEASURES: Postoperative complications and body weight changes during follow-up were the main outcome measures used in this study. RESULTS: Minor stoma-related problems were common in both groups. Two severe complications requiring an operative intervention occurred in the univentricular circulation group. Weight was normal at birth, low at the time of the gastrostomy procedure, and did not catch up completely during the follow-up period of a mean of 20 months. There were no significant differences regarding mean weight gain between the groups. CONCLUSIONS: The complication rate after the laparoscopic gastrostomy procedure was higher in our patient group, compared to previously studied children with various diseases. Comparisons regarding mean weight gain between the groups showed no significant differences. The mean weight gain was low, suggesting that the energy expenditure in this patient group of children with severe congenital heart disease may be even higher than previously assumed. PMID- 17705733 TI - Intestinal malrotation with midgut volvulus presenting as acute abdomen in children: value of diagnostic and therapeutic laparoscopy. AB - INTRODUCTION: Intestinal malrotation is a developmental anomaly of intestinal fixation and rotation caused by a disruption in the normal embryologic development of the bowel. Normal rotation takes place around the superior mesenteric artery. Incomplete rotation and midgut volvulus is the commonest type of anomaly. Intestinal obstruction is the commonest presentation in symptomatic cases. PATIENTS AND METHODS: Between 2000 and 2006, 73 children with acute abdomen underwent a diagnostic laparoscopy procedure. In this paper, we report 7 cases (9.5%) of midgut malrotation with volvulus and acute abdomen. Age range was between 7 and 12 years; there were 4 females and 3 males. They all presented with features of intestinal obstruction. A diagnosis of malrotation was established in only 1 patient, whereas the other 6 were diagnosed on laparoscopy. A laparoscopic Ladd's procedure was successfully performed for all cases. There were no postoperative complications. DISCUSSION: Intestinal malrotation occurs at a rate of 1 in 500 live births. The Ladd's procedure is the operation of choice. In 1995, the first report of laparoscopic surgery for malrotation was published. Since then, many studies were reported. Laparoscopy is a well-established diagnostic and treatment modality for this condition, even in the presence of volvulus. CONCLUSIONS: Our study shows the diagnostic value of laparoscopy in acute abdomen in children. The other advantages include less postoperative pain, a better cosmesis, especially in children, early return of bowel movement, and early discharge. PMID- 17705734 TI - A financial analysis of pediatric laparoscopic versus open fundoplication. AB - INTRODUCTION: Laparoscopic fundoplication (LF) is rapidly replacing open fundoplication (OF) for correcting symptomatic gastroesophageal reflux (GER) in infants and children. In this study, we compared various clinical and financial parameters to determine if one technique is superior. METHODS: With Institutional Review Board approval, charts and charge data for 50 consecutive patients undergoing elective LF or OF were reviewed in 2003 and 2004 (n = 100). Clinical variables evaluated included gender, age, weight, length of stay (LOS), operating time (OT), and time to initial (IF) and full (FF) feedings. Financial charges that were reviewed included anesthesia, central supply and sterilization, equipment, operating suite, hospital room and board, pharmacy, and total charges. RESULTS: The groups were equally matched in relation to gender, age, and weight. The table below illustrates the statistically significant differences (P < 0.05) between the groups. Favoring LNF LOS (1.2 vs. 2.9 days) IF (7.3 vs. 27.9 hours) FF (21.8 vs. 42.9 hours) Equipment ($1,006 vs. $1,609) Hospital Room ($1,290 vs. $2,847) Pharmacy ($180 vs. $461), Favoring OF OT (77 vs. 91 minutes) Anesthesia ($389 vs. $475) Central Supply and Sterilization ($1,367 vs. $2,515) Operating Suite ($4,058 vs. $5,142) Total charges were similar (LF, $11,449; OF, $11,632). CONCLUSIONS: Interestingly, although there were statistical differences in every charge category, total charges for LF and OF did not differ significantly. Thus, traditionally higher expenses from longer OT for LF seem to be offset by financial benefits, such as shorter LOS, reduced discomfort as evidenced by lower narcotic charges, and earlier IF/FF. PMID- 17705736 TI - Improving tactile sensation in minimally invasive pediatric surgery. AB - PURPOSE: The aim of this study was to investigate factors that impact tactile sensation during minimally invasive pediatric surgery. METHODS: Three different 3 mm Maryland laparoscopic instruments were tested with and without the resistance of a trocar (Ethicon 3-mm): Jarit (24-cm shaft, 113 g), Storz (30-cm shaft, 62 g), and an ultra-light prototype (24-cm shaft, 5 g). Experiments were conducted in a custom-designed laparoscopic simulator that directs instruments at fixed angles toward a central target. Surgeons were instructed to insert the instruments into the simulator and make contact with the target with as little force as possible. Instantaneous pressure measurements on the target were measured and recorded every 0.0001 seconds. The differences between impact pressures were compared with a paired, two-tailed, Student's t test. RESULTS: Twenty-seven (27) surgeons participated in the study. The ultra-light prototype had significantly lower impact pressures than the Storz instrument at all angles both with a trocar (P < 0.05) and without a trocar (P < 0.001). The ultra-light prototype had significantly lower impact pressures than the Jarit instrument at all angles in the absence of a trocar (P < 0.001), but with a trocar in place the only significant difference was at 5 degrees (P < 0.001). The presence of the trocar on the ultra-light prototype had a negative impact on tactile sensation that was statistically significant (P < 0.01). CONCLUSIONS: The presence of a trocar negatively impacted the surgeon's tactile sensation. Decreasing instrument mass by 10- to 20 fold did make a statistically significant improvement in tactile sensation. PMID- 17705735 TI - New primary management for appendiceal masses in children: laparoscopic drainage. AB - PURPOSE: The management of appendiceal masses (AM) in children remains controversial. In this study, we evaluated primary laparoscopic drainage (PLD) for efficacy. METHODS: Eleven (11) consecutive cases of AM (mean age, 8.1 +/- 2.8 years) treated between 2000 and 2004 were the subjects for this study. All had PLD on presentation. If the appendix was seen easily seen after PLD, a laparoscopic appendectomy (LA) was also performed. RESULTS: Eight (8) patients underwent PLD alone (LD group) and 3 underwent PLD and LA (LDLA group). In the LD group, the mean operating time was 87.9 +/- 23.2 minutes, oral feeding was commenced after a mean of 2.3 +/- 0.8 days, patients became afebrile within 4.3 +/- 3.1 days, intravenous antibiotics were ceased after 5.3 +/- 3.1 days, C reactive protein normalized within 13.6 +/- 4.2 days, drains were removed within 4.0 +/- 1.3 days, and hospital stay ranged from 7 to 15 days. There were no intra or postoperative complications related to the PLD procedure. Interval LA was performed 6.8 +/- 5.8 months after PLD in 6 of 8 LD group patients and was not performed in the remaining 2 owing to parental refusal. In the LDLA group, operating time ranged from 125 to 150 minutes, and oral feeding commenced 4, 5, and 5 days after LA, respectively. One (1) patient developed an adhesive bowel obstruction after LA, which resolved with conservative therapy; in the remaining 2, there were no complications. All 11 patients are well after a mean follow-up period of 3.7 +/- 1.0 years. A histologic examination of the excised appendices showed mild to severe inflammation. CONCLUSIONS: We recommend that PLD be adopted for the primary management of appendiceal masses, as it would appear to be simple, safe, and effective. PMID- 17705737 TI - Balloon-assisted single-port thoracoscopic debridement in children with thoracic empyema. AB - PURPOSE: In this study, we evaluated the results of a balloon-aided single-port thoracoscopic debridement of late-stage thoracic empyema in children. PATIENTS AND METHODS: We retrospectively reviewed age, gender, duration of prehospital illness, physical findings, surgical interventions, and the morbidity in 12 children with late-stage parapneumonic empyema. The diagnosis of pleural effusion was confirmed by a thoracocentesis before thoracoscopy. A balloon connected to a 12 F feeding tube was inserted into the thoracic cavity and inflated with air before the enterance of the thoracoscope. By this maneuver, a cavity was formed just under the enterance point. Thereafter, a routine debridement and chest irrigation was performed by thoracoscopy. Only one port was inserted in all but 1 patient, and the telescope was used as a dissecting tool. A thorax tube was inserted through the port site at the end of the procedure and left for the drainage. RESULTS: The main symptoms of the patients were dyspnea, cough, and fever. The empyema was located on the right hemithorax in 5 patients and on the left side in 7 patients. A second port was necessary to enhance the dissection in 1 case. The chest tube was removed within 3-30 days (median, 11 days) after the surgical approach. No complication directly related to the procedure was seen. The only problems postoperatively were a self-limited and spontaneously resolved bronchopleural fistula in 4 patients, and we had to perform an additional thoracoscopy to resolve the remaining intrapleural adhesions in 1 child. CONCLUSIONS: Thoracoscopic debridement in patients with late-stage thoracic empyema may be very beneficial, and this treatment method may provide any further thoracotomy. A balloon inflated in the thoracic cavity may achieve a wider field of vision for thorascopic surgery, and single-port thoracoscopy is sufficient and safe for the dissection. PMID- 17705738 TI - Bleeding jejunal Dieulafoy pseudopolyp: capsule endoscopic detection and laparoscopic-assisted resection. AB - In this paper, we report a case of bleeding solitary jejunal Dieulafoy pseudopolyp that was detected on capsule endoscopy and treated with a laparoscopic-assisted transumbilical polypectomy procedure. This case illustrates an innovative, tailored application of minimal invasive techniques in the management of a relatively uncommon lesion. To our knowledge, this is the first case report of the combination of capsule endoscopy and laparoscopic-assisted transumbilical resection for a bleeding jejunal Dieulafoy pseudopolyp in children. PMID- 17705739 TI - Laparoscopy-assisted gastropexy for gastric volvulus in a child with situs inversus, asplenia, and major cardiac anomaly. AB - AIM: The aim of this study was to report on laparoscopy-assisted gastropexy in a child with situs inversus, asplenia, and major cardiac anomaly. CASE: A 15-month old boy presented with a sudden onset of epigastralgia, nonbilious vomiting, and severe abdominal distention. After a nasogastric tube decompression of the stomach, symptoms resolved and an upper gastrointestinal contrast study confirmed situs inversus and asplenia. Computed tomography showed hepatic symmetry. Major cardiac anomalies (e.g., single atrium, single ventricle, common atrioventricular valve, and pulmonary atresia) were also present and had been treated elsewhere by a Blalock-Taussig shunt operation, the Glenn procedure, and pulmonary artery plasty. To prevent recurrent gastric volvulus, an anterior gastropexy procedure was performed laparoscopically. The patient's weight at the time of surgery was 8.1 kg, and the operating time was 65 minutes. Cardiopulmonary status was stable during insufflation and throughout the laparoscopic procedure. Postoperative recovery was uneventful, and the patient was allowed oral fluids 1 day after surgery and an unrestricted diet on day 2. A Fontan procedure was performed 18 months later, and our patient is now 6 years old and well--with no recurrence of gastrointestinal symptoms. CONCLUSION: This is the first report about the successful application of laparoscopy for performing a gastropexy procedure in a child with gastric volvulus, situs inversus, major cardiac anomaly, and asplenia. PMID- 17705740 TI - Retroiliac double ureters in duplex system: incidental retroperitoneoscopic diagnosis. AB - Retroiliac ureter is a rare congenital anomaly. In this paper, we present a case in which retroiliac double ureters were incidentally found during a retroperitoneoscopic nephroureterectomy procedure in a 5-year-old boy with dysplastic right kidney in duplex system and ureterocele. Ureters were both in the retroiliac artery position. The nephroureterectomy procedure was completed retroperitoneoscopically. After a literature review, this case appeared to be the first report of retroiliac double ureters in a duplex system. PMID- 17705741 TI - Laparoscopic leak-free technique for the treatment of choledochal cysts. AB - OBJECTIVE: The aim of this report was to present our experience with a modified surgical technique designed for the treatment of choledochal cysts (CC) in children. MATERIALS AND METHODS: Between June 2004 and February 2005, we operated on 6 patients with a diagnosis of type I CC by means of a "leak-free" technique that consists of a transient complete sealing of the hepatic duct for the duration of the dissection, and a single- or double laparoscopic running suture to build the end-to-side hepatico-jejuno anastomosis. There were 4 females and 2 males, whose age ranged between 45 days and 7 years (median, 45 months). All cases were performed with three trocars plus the scope, and two or three percutaneous stay-stitches to retract the liver. The end-to-side hepatico-jejuno anastomoses were done with 5.0 or 6.0 PDS. We left no drains. RESULTS: The mean operative time was 335 minutes, and mean postoperative time to oral feeding was 44 hours. The mean hospital stay was 6 days (range, 5-10). No postoperative biliary leak was observed. A cosmetic result was excellent in all patients. In the follow-up (mean, 12 months), all patients were asymptomatic, had no intrahepatic biliary tree dilation, and had normal liver function tests. CONCLUSIONS: Based on the results of our series, we think that the laparoscopic approach is suitable for these patients, but some surgical details should be followed to lower the complication rate. First, a temporary closure of the hepatic duct to prevent bile spillage during the dissection is important for keeping the area clean and thus reducing the operative time. Second, the use of a running suture for the hepatico-jejunostomy, even though it may be technically challenging, should always be attempted to avoid postoperative bile leaks in these high-flow anastomoses. PMID- 17705747 TI - Laparoscopic pyeloplasty: status and review of literature. AB - The ideal treatment for ureteropelvic junction (UPJ) obstruction should have the highest success rate, enable treatment of all types of obstruction, allow removal coexisting renal stones, and be minimally invasive. Open pyeloplasty offers all these features except the last (minimal invasiveness), whereas endourology techniques guarantee only the last one. Different techniques of pyeloplasty can be applied laparoscopically, although the best results are seen with dismembered pyeloplasty (Anderson-Hynes technique). Various methods of tissue approximation have been devised to avoid the difficult-to-master, time-consuming conventional suturing technique. Laparoscopic (antegrade) stenting is preferred by some surgeons, but we consider retrograde stenting is superior, as this rules out the presence of associated distal-ureteral obstruction. The transperitoneal approach has the advantages of a larger working space and readily identifiable anatomic landmarks. However, access to the renal pelvis requires considerable mobilization and retraction of the overlying loops of bowel. The retroperitoneal approach has the perceived disadvantage of a somewhat limited working space and absence of readily identifiable intra-abdominal anatomic structures such as the liver and spleen. However, the retroperitoneal approach has the advantage of greater familiarity, better detection of crossing vessels, direct and rapid access to the UPJ, and less risk of ileus. The robot-assisted technique has made suturing easier and may allow expansion of advanced laparoscopic procedures to surgeons without expertise in advanced laparoscopic surgery. The optimal length of follow up after pyeloplasty is still unclear. Although most failures occur within the first 2 years, failures continue to appear after 5 and 10 years. PMID- 17705748 TI - Jacques de Vaucanson: the father of simulation. AB - BACKGROUND: Jacques de Vaucanson's accomplishments are remarkable from almost every standpoint. His appreciation of human anatomy allowed him to formalize and discuss at the Royal Academie of Churgeons the first surgery/anatomy trainer. METHODS: Works on the history of automata are replete with descriptions of de Vaucanson's creations. I sought to better understand this intriguing individual and his mechanical accomplishments in light of current interest in surgical simulators and skill enhancement. RESULTS: de Vaucanson is known to have built at least three highly sophisticated automated robotic devices. His first robot was constructed in 1735: a life-sized flutist that could play 12 melodies. The fingers moved by levers, and a bellow-like device piped air into the robot's mouth. His second robot, another musician, could play 20 melodies. His third automaton became the most famous, a mechanical duck. The duck consisted of a gold plated copper exterior with more than a thousand moving parts, including a gastrointestinal system. Voltaire would quip that France now had as its glorious mascot a golden creature that was famous for its excrement. Lastly, de Vaucanson created another musical automaton that could play 20 melodies. CONCLUSIONS: de Vaucanson worked with famed surgeon La Cat and in 1741 gave a talk to the Academy of Art on "Constructing an automaton figure which will imitate in its movements animal functions, the circulation of blood, respiration, digestion, the combination of muscles, tendons, nerves, etc." The Academy's minutes recorded "this ingenious machine, which will represent a human anatomy lesson." Add to de Vaucanson's list of accomplishments as devising, albeit not producing, the first anatomic simulator. PMID- 17705749 TI - Effectiveness of noncontrast computed tomography in evaluation of residual stones after percutaneous nephrolithotomy. AB - PURPOSE: We prospectively compared the sensitivity of antegrade pyelography (AGP), plain film radiography (KUB film), and noncontrast thin-slice abdominal CT for detecting residual stones after percutaneous nephrolithotomy (PCNL). PATIENTS AND METHODS: We prospectively evaluated 50 patients (53 renal units) who underwent PCNL for radiopaque renal pelvic stones with noncontrast abdominal CT 1 month postoperatively. We compared the number and size of residual fragments, as determined by immediate postoperative AGP and 1-month KUB film and CT scan. RESULTS: Stone-free rates according to AGP, KUB film, and noncontrast CT were 73.6% (39/53), 62.3% (33/53), and 20.8% (11/53), respectively. However, if clinically insignificant residual fragments are included in the success rates, these rates increased to 84.9% (45/53), 83.0% (44/53), and 41.5% (22/53), respectively. Of the 22 patients in whom residual stones were detected by CT but not by KUB film, 10 (45.5%) had stones >4 mm in diameter on CT, with a mean size of 7.4 mm. The sensitivity for the detection of residual fragments was 47.6% for KUB films as judged by noncontrast CT. After CT, seven patients received extracorporeal shockwave lithotripsy for residual stones. CONCLUSIONS: Noncontrast thin-slice abdominal CT was the most accurate imaging method to determine the stone-free rate after PCNL. Noncontrast abdominal CT gives accurate information for selecting patients who may benefit from additional treatment and for planning follow-up. PMID- 17705751 TI - Need for ancillary procedures among patients undergoing tubeless percutaneous renal surgery for nephrolithiasis. AB - PURPOSE: We routinely perform percutaneous nephrolithotomy (PCNL) without the use of nephrostomy tubes. We examined the need for secondary surgery for the treatment of residual stones in patients who underwent both tubeless surgery and PCNL with tube placement. PATIENTS AND METHODS: We retrospectively reviewed the charts of 180 patients who underwent 186 percutaneous nephrolithotomies. Among them, 125 patients had tubeless surgery, and 61 had nephrostomy tubes. We compared the need for ancillary surgical procedures for residual stone disease in the two groups. RESULTS: A total of 99 patients (79%) without tubes and 25 (41%) of those with tubes were stone free after surgery. A total of 45 ancillary procedures were performed for residual stone disease, with 15% of the tubeless and 43% of the patients with tubes requiring a second procedure. Extracorporeal shockwave lithotripsy (SWL) was the most common ancillary procedure. CONCLUSIONS: Patients who are eligible for tubeless PCNL are unlikely to need a secondary procedure, and residual stones can most often be treated with SWL. Patients who required nephrostomy tubes had more complicated disease and a greater need for subsequent surgery. PMID- 17705750 TI - Single-center review of fluoroscopy-guided percutaneous nephrostomy performed by urologic surgeons. AB - PURPOSE: To review the success rate and complications of radiologically guided percutaneous nephrostomies (PCNs) performed by urologists and compare the complication rates with the standards recommended by the Society of Interventional Radiology (SIR) and the American College of Radiology (ACR). PATIENTS AND METHODS: From January 1996 to December 2005, 667 patients had 765 PCNs performed by three urologists, with 74 patients having simultaneous bilateral PCNs. The mean age of the patients was 29 years (range 8 months-95 years). The medical records were reviewed for underlying diseases, success rate, and complications of PCN; and the results were assessed in comparison with recommendations made by SIR and ACR. RESULTS: The PCN was successful in 742 renal units (97%). A total of 26 of the 667 patients (3.89%) had major complications: 12 (1.79%) had sepsis, 10 (1.49%) had hemorrhage sufficient to necessitate transfusion, 1 (0.14%) had pleural injury that was managed conservatively, and another patient had a vascular complication necessitating nephrectomy. None of the patients had bowel transgression. Minor complications occurred in 61 patients (9.1%): urinary-tract infection in 17, PCN tube dislodgement in 11, catheter obstruction by clot or debris in 12, urine leakage around the PCN site in 8, and loss of the PCN catheter in 13. CONCLUSION: Percutaneous nephrostomy is a relatively safe, minimally invasive, and effective procedure with a low rate of morbidity. Our overall results in term of success rate and major complications are within the threshold limits set by the SIR and ACR. Hence, trained urologists can produce results similar to those of interventional radiologists. Learning of PCN should be mandatory in the training curriculum for all urology residents. PMID- 17705752 TI - Safety of the Veress needle in pediatric laparoscopy. AB - PURPOSE: To better establish the complication rate with the Veress needle technique for establishing a pneumoperitoneum in pediatric laparoscopy. PATIENTS AND METHODS: We reviewed all pediatric laparoscopy cases performed by a single surgeon from 1996 to 2003. There were 257 patients ranging in age from 4 months to 19 years. Infraumbilical placement of the Veress needle was used to create a pneumoperitoneum. All instances of preperitoneal insufflation, vessel/viscus injury, and forced conversion to open surgery were recorded. The length of time required to establish pneumoperitoneum was reported in the last 139 patients. RESULTS: The average length of time required to gain access to the peritoneum was <2 minutes. Of these procedures, 138 were performed for nonpalpable undescended testicles, 101 for varicoceles, 13 for duplication anomalies, and 5 for intersex disorders. There were 18 cases (7.0%) of preperitoneal insufflation. No cases resulted in vessel/visceral injury, conversion to open surgery, conversion to use of the Hassan trocar technique, or inability to complete the procedure because of complications in establishing a pneumoperitoneum. In all cases of preperitoneal insufflation, proper access was achieved by pulling the needle out and reinserting it at a different angle, with pneumoperitoneum being achieved easily in each case. CONCLUSION: The use of the Veress needle to establish pneumoperitoneum in children of all ages is safe, fast, and efficacious. PMID- 17705753 TI - Effects of proximal and distal ends of double-J ureteral stent position on postprocedural symptoms and quality of life: a randomized clinical trial. AB - PURPOSE: To evaluate the effect of the position of the proximal and distal ends of Double-J ureteral stents on postprocedural flank pain, lower urinary-tract symptoms, and quality of life. PATIENTS AND METHODS: The study included 120 patients who required unilateral Double-J ureteral stents for various indications. They were randomized into two equal groups. Group 1 had longer stents, with the proximal end in the upper calix and the distal end crossing the midline of the bladder. Group 2 had proper stent length with the proximal end in the pelvis and the lower end just beyond the vesicoureteral junction. Patients answered a questionnaire regarding flank pain, dysuria, and urgency as well as quality of life after 1 week of stenting. RESULTS: Forty patients (67%) of group 1 and 43 (72%) of group 2 had mild flank pain, especially during urination. There was no significant difference in the degree of flank pain in the two groups. Moderate to severe dysuria was reported by 53 patients (88%) in group 1 and 11 patients (18%) in group 2 (P < 0.001). Moderate to severe urgency was reported by 48 patients (80%) in group 1 and in 14 (23%) in group 2 (P < 0.001). A worse quality of life was reported by patients in group 1, among whom moderate to severe bother was noted by 51 (85%) compared with group 2, in which moderate to severe bother was reported by only 13 patients (22%) (P < 0.001). CONCLUSION: Ureteral stents are associated with flank pain and lower urinary-tract symptoms. The flank pain was not affected by the length of stent. Urgency and dysuria as well as a worse quality of life were significantly more common in the patients who had longer stents. PMID- 17705754 TI - Small changes in operative time can yield discrete increases in operating room throughput. AB - BACKGROUND AND PURPOSE: Operating room throughput is influenced by the efficiency of the perioperative process (for nonoperative time) and by the surgeon (for operative time). Operative time is thought not to be easily amenable to deliberate reductions. We tested the hypothesis that gradual improvements in operative time had allowed one surgeon to perform additional cases during scheduled hours. MATERIALS AND METHODS: The surgeon had been working in both a high-throughput and a conventional operating room for more than 1 year prior to the study. During the studied interval, we applied statistical process control analysis to time data for the surgeon performing full days of complex laparoscopic operations. Separate analyses were conducted for the conventional and high-throughput operating rooms. The average operative time for each day and the number of cases per day were plotted against sequential days for each environment. RESULTS: Midway through the studied interval, there was a discrete 17-minute drop in operative time in both the high-throughput and the conventional environment. Throughput increased from two cases per day to three per day in the high-throughput environment. The average end time for the three-case days was 17:15 (range 16:04-18:32). Longer average operative and nonoperative times in the conventional rooms precluded performing three complex cases during regular work hours. CONCLUSION: There was a sudden, rather than a gradual, reduction of operative time leading to extra cases being performed. This coincided with (1) the surgeon being assigned a new fellow and (2) administrative commitment to finish three cases per day. Our original hypothesis was negated, but other controllable causes for changes in surgical throughput were identified. PMID- 17705755 TI - Nephron-sparing surgery and percutaneous biopsies in renal-cell carcinoma: a global impression among endourologists. AB - BACKGROUND AND PURPOSE: On the one hand, nephron-sparing surgery (NSS) in small renal tumors is a safe and effective alternative to radical nephrectomy. On the other hand, the role of preoperative percutaneous needle biopsies (PNB) remains controversial. The purpose of this study was to evaluate the global current use of NSS in the treatment of renal-cell carcinoma (RCC) and the use of PNB among endourologists. MATERIALS AND METHODS: One thousand questionnaires were distributed during the 23rd World Congress of Endourology and SWL. Six questions regarding NSS and two questions regarding PNB were presented. Two hundred twenty two questionnaires were returned. RESULTS: Of the respondents, 86.6% perform NSS for small renal tumors, whereas 13.4% perform only radical nephrectomies; 7.5% will consider NSS only in patients with a solitary kidney, and 0.5% will never consider NSS. The techniques for NSS, in descending order of preference, are partial nephrectomy, enucleation, cryoablation, radiofrequency ablation, and high intensity focused ultrasound. The mean and maximum diameter of the tumor in patients with a normal contralateral kidney for which the urologists perform NSS is 4.0 cm. For a centrally located tumor, NSS is an option for 27.2% of the respondents. Regarding PNB in patients with suspicion of RCC, 55.9% of respondents never obtain renal biopsies in the preoperative assessment and 41.8% obtain them only in rare cases. The majority (90%) prefer histologic over cytologic biopsies. CONCLUSIONS: Nephron-sparing surgery is evolving to a global worldwide standard treatment for small renal tumors. Percutaneous needle biopsy remains a highly debated procedure. PMID- 17705756 TI - Original dissecting balloon for retroperitoneal laparoscopy: cost-effective alternative to commercially available device. AB - BACKGROUND AND PURPOSE: Creation of an optimal retroperitoneal space is of pivotal importance in laparoscopic retroperitoneal surgery. The aim of this study was to examine the balloon dissecting technique developed at our institution, comparing the costs of our device with that of a commercially available balloon retroperitoneal expander. PATIENTS AND METHODS: Twenty patients scheduled to undergo retroperitoneoscopic surgery were randomly divided in two groups. In group 1, retroperitoneal dilation was performed with the commercially available balloon expander. In group 2, we employed our balloon dilator created with two middle finger of No. 8 powder-free surgical gloves tied to a nondisposable 11-mm trocar and filled with 600 mL of saline employing two 60-mL syringes simultaneously. Subjective evaluation of the created space was performed blindly in both groups. Economic evaluation included the costs of the disposable materials and of the time required for dilation. RESULTS: In all cases, the dilation was considered good. In group 1, the median time required to dilate the retroperitoneal space was 3.15 minutes, whereas in group 2, the median time required was 1.16 minutes, and the time required to dissect the retroperitoneal space was 4.41 minutes (total 5.57 minutes). Considering the costs of the disposable material, the overall costs of creating the retroperitoneal space was 141.95 euro in group 1 and 60.27 euro in group 2 (P < 0.005). CONCLUSION: The original dissecting balloon employed at our institution is easy and fast and offers a valid option for the proper dissection of the retroperitoneal space. Moreover, it was revealed to be cost-effective compared with the commercially available device. PMID- 17705757 TI - Ureteroscopic treatment of upper-tract urothelial lesions: a novel technique. AB - We describe a simple and effective method of using a stone-extraction basket and electrocautery to treat pedunculated renal-pelvic neoplasms ureteroscopically. This technique may make it easier to obtain tissue from the urothelium and reduce operative times. PMID- 17705758 TI - Pilot experience with transhepatic percutaneous renal cryoablation. AB - BACKGROUND AND PURPOSE: Percutaneous renal cryoablation has been shown to be a feasible therapeutic option for small renal tumors. Despite advances in equipment design and imaging capabilities, tumor location can present challenges to the percutaneous approach. We present our pilot experience with transhepatic percutaneous cryoablation of right upper-pole renal tumors. PATIENTS AND METHODS: Three patients aged 75 to 87 years with American Society of Anesthesiologists scores of III or IV underwent transhepatic percutaneous cryoablation between November 2005 and February 2006. Tumor size ranged from 2 to 5 cm. Cryoprobe placement was guided by CT imaging, and two freeze-thaw cycles were used. Additionally, 60-second freeze-thaw cycles were used to assist with hemostasis in the transhepatic tract. RESULTS: The procedure was completed percutaneously in all cases with the patient under conscious sedation. The procedure time ranged from 67 to 167 minutes. Postoperative pain was managed with minimal use of nonnarcotic oral medications. Although one patient developed a moderate perinephric hematoma and required a blood transfusion, no hepatic complications were manifest. Local treatment failure was evident in one patient with a 5-cm mass showing enhancement at follow-up imaging. CONCLUSIONS: Transhepatic access for percutaneous cryoablation of renal tumors is feasible. Limitations include tumor size, as larger tumors may introduce prohibitive risks. PMID- 17705759 TI - Successful conservative management of colorenal fistula after percutaneous cryoablation of renal-cell carcinoma. AB - BACKGROUND: Cryoablation is an increasingly utilized treatment for renal-cell carcinoma. We describe the first reported case of colorenal fistula resulting from percutaneous renal cryoablation. CASE REPORT: A 63-year-old man with hematuria was found to have an enhancing renal mass that was treated with percutaneous CT-guided cryoablation. Two months later, he presented with lower urinary-tract symptoms, and CT imaging revealed a colorenal fistula at the ablation site. Ureteral stent placement resulted in resolution of the fistula. CONCLUSIONS: Contrary to previously reported animal and clinical studies, our case report demonstrates that it is possible to incur serious harm to the renal collecting system as a result of percutaneous renal cryoablation. In stable patients, an attempt at conservative management of a fistula should precede extensive reconstructive efforts. PMID- 17705760 TI - Transitional-cell carcinoma recurrence rate after nephroureterectomy in patients who undergo open excision of bladder cuff v transurethral incision of the ureteral orifice. AB - BACKGROUND AND PURPOSE: The gold standard treatment for upper-tract transitional cell carcinoma is radical nephroureterectomy, but management of the distal ureter is not standardized. Two treatment options to detach the distal ureter are open cystotomy (OC) and excision of a bladder cuff or transurethral incision of the ureteral orifice (TUIUO). We compared the clinico-pathologic outcomes of these two techniques. PATIENTS AND METHODS: Hospital records were reviewed on all 51 patients who had undergone open or laparoscopic nephroureterectomy at our institution between 1 January 1990 and 30 June 2005. Patient demographics, intraoperative parameters, and pathology data were collected. The mean follow-up was 23.2 months (range 4.5-75 months) and 22.1 months (range 1-50 months) for the OC and TUIUO groups, respectively. There were no significant differences in sex, age at operation, American Society Anesthesiologists risk score, previous transitional-cell tumors, pathologic tumor grade and stage, or metastatic disease status in the two groups. RESULTS: Five patients had an unplanned incomplete ureterectomy. The bladder recurrence rates were similar in the OC group (22.2%; 6/27) and the TUIUO group (26.3%; 5/19). There were no pelvic recurrences in either group. Four of the five patients who had an incomplete ureterectomy had tumor recurrences, three in the form of metastatic disease. CONCLUSION: Management of the distal ureter by TUIUO in appropriate patients offers the same rate of bladder recurrence as OC. Incomplete ureterectomy results in a significantly higher rate of recurrence, often associated with the development of metastatic disease. PMID- 17705761 TI - Retroperitoneoscopic radical nephrectomy for renal-cell carcinoma during twin pregnancy. AB - Renal-cell carcinoma (RCC) is rarely reported during pregnancy. Both the open and the laparoscopic approach to nephrectomy have been used effectively and safely in pregnant patients with RCC. We report a unique case of a 52-year-old woman found to have RCC during twin gestation who was treated with retroperitoneoscopic radical nephrectomy, one of the first such cases managed by this approach. PMID- 17705762 TI - Pediatric laparoscopic pyeloplasty in a referral center: lessons learned. AB - PURPOSE: We present our first-year experience with pediatric transperitoneal laparoscopic dismembered pyeloplasty (TLDP) in a large referral center. PATIENTS AND METHODS: A chart review was conducted in 27 consecutive children (M:F 23:4) aged 4 to 17 years (mean 9.7 years) with ureteropelvic junction obstruction who underwent TLDP (21 on the left, 6 on the right) in 2005. The key steps implemented to facilitate and streamline this procedure were: (1) clamping the Foley catheter before surgery to distend the renal pelvis and facilitate the transmesenteric approach; (2) stabilizing the renal pelvis with a traction suture; (3) performing the dismembered pyeloplasty using a modified double-armed suture; and (4) placing the ureteral stent percutaneously antegrade before completing the anastomosis. Operative time, hospital stay, complications, and follow-up radiologic studies were reviewed. RESULTS: The TLDP was performed with no open conversions. Crossing vessels and horseshoe kidney were present in 8 patients and 2 patients, respectively. The mean operative time was 221 minutes. Stent insertion was successful in all but one patient. Postoperative pain management was successful in all 27 patients. There were 4 postoperative complications (14.8%) consisting of prolonged leakage in two, obstruction in one, and obstruction with pyelonephritis in one. These last two complications occurred early in our experience and were treated successfully by percutaneous nephrostomy with subsequent retrograde endopyelotomy. The average hospital stay was 2.1 days (range 1-4 days). Radiologic studies 8 to 20 months after removal of the Double-J stents showed reduction of the degree of hydronephrosis in all patients. CONCLUSION: Our 1-year experience with TLDP gave us the opportunity to implement key steps to establish a standardized technique for this procedure. Although the follow-up period was short, most complications occurred early in this series, demonstrating that a learning curve is inevitable. PMID- 17705763 TI - Endoureterotomy for treatment of primary obstructive megaureter in children. AB - PURPOSE: To describe a new approach to the treatment of primary obstructive megaureter (POMU) using endoscopic endoureterotomy. The results obtained with this technique are reviewed with long-term follow-up. PATIENTS AND METHODS: A total of 47 children (mean age 3.7 years) with 52 POMU units and a history of failed conservative management underwent endoureterotomy of obstructed juxtavesical and intramural ureter. A 3F Double-J ureteral stent was introduced up to the obstructed segment of ureter. Then a zebra catheter was inserted into the affected ureter beside the stent, followed by a neonatal-size ureteroscope. Following delineation of the length of the narrowed portion of the ureter, a guidewire with a plastic sheath replaced the zebra catheter. A longitudinal incision was made through the detrusor muscle at the 6 o'clock position, leaving the bladder adventitia untouched. The Double-J stent was left in place, while its distal tip was fixed by long nylon suture and single knot to the external genitalia to permit easy removal 1 week after the procedure. RESULTS: With a mean follow-up of 39 months (range 14-62 months), no leakage, ureteral-orifice obstruction, or reflux was observed. The postoperative success rate was 90% (47 of 52 ureters), defined as resolution or decrease in hydroureteronephrosis and improvement or stability of renal function determined by renal scan. In 37 ureterorenal units (71%), there was complete resolution of hydroureteronephrosis. CONCLUSIONS: On the basis of previous studies demonstrating the value of endoureterotomy with stenting for the treatment of benign ureteral strictures in adults, we developed a modified endoscopic approach for the treatment of POMU and applied this technique in meticulously selected cases. Our results showed that this approach is a valid option for the treatment of children with POMU. PMID- 17705764 TI - Simultaneous bilateral robot-assisted dismembered pyeloplasties for bilateral ureteropelvic junction obstruction: technique and literature review. AB - BACKGROUND AND PURPOSE: Simultaneous bilateral laparoscopic renal operations are technically difficult and not often performed. We present our technique of bilateral simultaneous robot-assisted pyeloplasties for bilateral ureteropelvic junction (UPJ) obstruction, review the literature, and discuss the advantages of robot assistance in such cases. METHODS: A 19-year-old man with bilateral congenital UPJ obstruction underwent bilateral simultaneous robotic pyeloplasties at our center. A transperitoneal approach was used with the patient in the lateral decubitus position and with repositioning and redraping between sides. A total of five ports was used: three in the midline, which were used for both sides, and an additional port in the iliac fossa on each side. Three arms of a four-arm da Vinci Surgical System (Intuitive Surgical, Sunnyvale, CA) were used with four instruments. Antegrade 6F Double-J stents were placed on both sides. RESULTS: The procedure was completed in a total surgical time of 305 minutes. This included 30 minutes for robot docking/instrument error and 145 and 130 minutes of operating time for the right and left sides, respectively. The blood loss was <30 mL. There were five adverse haptic events: two incorrect suture placements and three suture breakages during knot-tying. The patient developed subcutaneous emphysema on the chest wall that resolved in 6 hours. He was allowed oral intake 6 hours after surgery, ambulated after 14 hours, and was discharged after 38 hours. CONCLUSIONS: Robotic assistance allows complex bilateral reconstructive laparoscopic operations to be performed in one session. PMID- 17705765 TI - Comparison of intraoperative parameters and perioperative complications of retroperitoneal and transperitoneal approaches to laparoscopic partial nephrectomy: support for a retroperitoneal approach in selected patients. AB - BACKGROUND AND PURPOSE: Retroperitoneal laparoscopy (RP) may have some intrinsic advantages over transperitoneal laparoscopy (TP) in certain patients undergoing partial nephrectomy. We reviewed our experience with RP and TP partial nephrectomy to identify differences in intraoperative and postoperative parameters. PATIENTS AND METHODS: The records of 72 patients (45 TP, 27 RP) undergoing laparoscopic partial nephrectomy without hand assistance between January 2003 and August 2005 were reviewed. The two groups were similar demographically; tumors were smaller in RP patients (2.1 v 2.7 cm; P = 0.03), and the RP approach was used more frequently on right kidneys (70.4% v 37.8%; P = 0.01). RESULTS: The operative time (mean 160 v 192 minutes; P = 0.008) and length of stay (LOS; median 1.0 days [range 1-10 days] v 2.0 days [range 1-64 days]; P = 0.001) were shorter in RP patients. Rates of collecting system entry (22% v 38%), positive-margin rate (0% v 6.7%; P = 0.29), and complications (19% v 22%; P = 0.77) were similar in RP and TP patients. Hemorrhage was the most common complication in both groups. Bowel-related complications occurred in three TP patients, but in no RP patients. Overall, the median estimated blood loss (EBL) was lower in RP patients (100 mL [range 25-3500 mL] v 225 mL [range 25-1900 mL]; P = 0.06). Among patients with complications, EBL was similar in both groups (median 325 mL [50-1500 mL] v 200 mL [50-3500 mL] for RP and TP; P = 0.86). CONCLUSIONS: The RP approach reduces operative time, LOS, and some types of complications without compromising the quality of tumor resection. Complications in the retroperitoneal space are not associated with higher EBL. Anatomic considerations and surgeon experience may improve outcomes. PMID- 17705766 TI - Unilateral pulmonary edema after laparoscopic donor nephrectomy: report of two cases. AB - Unilateral pulmonary edema of the dependent lung presented after laparoscopic living-donor nephrectomy in two patients. Treatment with O(2) supplementation and diuretics resulted in relief of symptoms and radiographic improvement. The presumed causes of this previously unreported complication of laparoscopic living donor nephrectomy include prolonged lateral decubitus positioning and high fluid requirements. PMID- 17705767 TI - Embolization of renal-artery pseudoaneurysm after laparoscopic partial nephrectomy for angiomyolipoma: case report and literature review. AB - BACKGROUND: Renal-artery pseudoaneurysm (RAP) is a well-described complication of trauma or percutaneous urologic procedures. Delayed bleeding from an RAP is rare after partial nephrectomy. CASE REPORT: We present a 49-year-old woman who, 24 days after undergoing a laparoscopic right partial nephrectomy for a mesophytic 2.5-cm tumor, developed gross hematuria. Prompt CT imaging, followed by therapeutic angio-embolization of a third-order segmental renal artery with coils, treated the pseudoaneurysm successfully. CONCLUSIONS: Renal-artery pseudoaneurysm is a rare, potentially life-threatening, condition that often is difficult to diagnose and requires a high index of clinical suspicion. Early use of selective angio-embolization minimizes morbidity and maximizes renal conservation. The etiology, diagnosis, and management are discussed. PMID- 17705768 TI - Ureteral quadruplication associated with ureteral cyst and massive vesicoureteral reflux treated by laparoscopic nephroureterectomy. AB - BACKGROUND AND PURPOSE: Ureteral quadruplication is an extremely unusual developmental abnormality. We present the eighth reported case but the first to be associated with a ureteral cyst, with massive vesicoureteral reflux that was treated with laparoscopic nephroureterectomy. CASE REPORT: A 3-year-old boy was evaluated for recurrent urinary-tract infection. Massive left-sided vesicoureteral reflux associated with incomplete ureteral triplication was identified. A DMSA scan disclosed impaired function of this kidney. An uneventful total laparoscopic nephroureterectomy was performed at which a fourth atresic ureter was identified. All the four proximal ureters opened into a large ureteral cyst, and a distal monoureter opened into the bladder. CONCLUSION: The patient recovered fully and was asymptomatic 6 months postoperatively. PMID- 17705769 TI - Laparoscopic partial cystectomy with endo-GIA stapling device in bladder diverticular carcinoma. AB - BACKGROUND AND PURPOSE: The incidence of bladder diverticular carcinoma is low, ranging from 0.8% to 10%. Traditionally, treatment consisted of open surgical excision or transurethral resection. More recently, laparoscopic surgery has become widely accepted. We report here a case of bladder diverticular carcinoma treated with laparoscopic partial cystectomy. CASE REPORT: A 56-year-old man presented with gross hematuria and was found to have transitional-cell carcinoma in a bladder diverticulum. We performed transurethral resection of the tumors and laparoscopic partial cystectomy. A 45-mm Endo-GIA stapler (U.S. Surgical Corp., Norwalk, CT) was used for direct resection of the diverticular tissue, and the specimen was removed en bloc. Suture of the seromuscular layer was performed with the intracorporeal knotting technique. Lymph-node dissection also was performed. At 3-month follow-up, it was noted that there was tumor recurrence that was not at the original diverticular site, and transurethral resection was carried out. After 1 year, cystoscopy and CT scans showed neither recurrence nor metastasis. No encrustation or erosion was induced by the staples. CONCLUSION: Laparoscopic partial cystectomy can be an alternative treatment for bladder diverticular carcinoma. PMID- 17705770 TI - Robot-assisted excision of seminal vesicle cyst associated with ipsilateral renal agenesis. AB - Seminal vesicle cysts associated with other genitourologic abnormalities are rare. We describe the first known robot-assisted excision of a cystic seminal vesicle associated with ipsilateral renal agenesis in a symptomatic pediatric patient. The patient was discharged home on postoperative day 1 and remains symptom free after 9 months' follow-up. Operative time, blood loss, and hospital stay were comparable to those of published series of conventional laparoscopy. PMID- 17705771 TI - In-vivo evaluation of flow characteristics of novel metal ureteral stent. AB - PURPOSE: To characterize the flow of a novel ureteral stent composed of a nickel cobalt-chromium-molybde-num alloy and compare it with flow in a standard ureteral stent. MATERIALS AND METHODS: Six 6F Resonance stents and six 6F standard Black Beauty ureteral stents were placed in six Yucatan minipigs, with each pig serving as its own control. Flow assessment was performed on all stents via a nephrostomy tube delivering a standard rate of 0.9% saline at 35 cm H(2)O. Flow studies on the standard stents encompassed extraluminal (i.e., lumen of stent occluded with a guidewire), intraluminal (i.e., ureter secured to stent with a constricting suture), and combined (i.e., open lumen without constricting suture) flow. In the Resonance stent, only combined and intraluminal flow could be addressed, as there is no access to the lumen of this stent. RESULTS: With the Resonance stent, intraluminal flow was much greater than combined flow, with mean values of 5.15 mL/min and 2.50 mL/min, respectively (P = 0.057; SD = 7.73). Intraluminal flow was similar to combined flow in the 6F standard stent, with mean values of 7.34 mL/min and 7.30 mL/min, respectively (P = 0.88; SD = 1.76). The standard stent had significantly greater combined flow than the Resonance stent (P = 0.023) but not intraluminal flow (P = 0.247). Of note, whereas it was possible to occlude the 6F standard stent completely with a ureteral ligature (i.e., no guidewire placed in the lumen), it was not possible to occlude the Resonance stent regardless of how tightly the suture was tied. CONCLUSION: The Resonance metal alloy stent provides less overall flow than a standard stent. However, under circumstances of extrinsic ureteral compression sufficient to occlude a standard stent (e.g., extrinsic compression plus an internal guidewire), the metal stent continues to provide satisfactory drainage. PMID- 17705772 TI - Proportional analysis of pig kidney arterial segments: differences from the human kidney. AB - PURPOSE: To present a systematic study and a proportional analysis of the arterial segments of the pig kidney. MATERIALS AND METHODS: Sixty-one three dimensional endocasts of the arterial segments of pig kidneys were studied. Each segment was injected with a resin of a different color. Cavalieri's principle was used to calculate the volume of each renal segment, and these results were compared with the results from the point-counting planimetry method used on photographs of pig-kidney surfaces. RESULTS: Two to five renal segments were observed. Division into two segments, a cranial and a caudal, was the most common (42.62%). The renal volume ranged from 101 to 173 cm(3) (mean 130.85 cm(3)). The cranial segment was present in 39 of the 57 casts (68.42%). It presented the greatest median value of proportional area (50.00%) and also the greatest maximum value of proportional area, accounting for as much as 74.04% of the total kidney area. The ventral segment, which was found in 20 of the 57 casts (35.09%), presented the lowest median value of proportional area (13.87%) and showed the most variation in area (coefficient of variation 72.89%). There was no significant statistical difference between the segmental areas as evaluated by Cavalieri's principle and by the point-counting planimetry method. CONCLUSIONS: The distribution and size of the renal-arterial segments in pigs are not similar to those of the human kidneys. Therefore, this information must be taken into account by practitioners of urologic training or ablation using pigs as the animal model, as the structure of the porcine arterial segments cannot be transposed to humans. PMID- 17705773 TI - Newly developed mini-endoscope for diagnosis and follow-up of orthotopic bladder transitional-cell carcinoma in vivo. AB - BACKGROUND AND PURPOSE: Orthotopic models of bladder transitional-cell carcinoma (TCC) are indispensable to the development of new intravesical agents for the treatment of non-muscle-invasive disease. Visual inspection of induced tumors and normal urothelium is of crucial interest when evaluating growth patterns and the potential effects of instillation therapies. The aim of our study was to test the practicability of a newly developed mini-endoscope in terms of the benefit and reproducibility of repeated diagnostic cystoscopy in a rat model, thus mimicking standard procedures in patients. MATERIALS AND METHODS: The study group consisted of 24 Foxn(rnu) athymic nude rats. In 18 animals, a suspension of the human TCC cell line UMUC-3 was instilled into the urinary bladder after trypsinization. Six animals underwent bladder trypsinization only and served as a control group. Follow-up cystoscopy was performed weekly. A newly developed semirigid mini endoscope (Karl Storz, Tuttlingen, Germany), 0.89 mm in diameter, was used. RESULTS: In total, 213 cystoscopies were performed. Each animal underwent at least seven procedures at weekly intervals over a period of 2 months. All tumors were detected by the mini-endoscope within 14 days of tumor-cell implantation. Cystoscopy provided visibility of the entire lower urinary tract (LUT), with the smallest detectable lesion being 0.5 mm in diameter. The regularly performed cystoscopy was tolerated without any significant procedure-related morphologic alterations in the LUT. CONCLUSIONS: The new mini-endoscope constitutes a practicable and reliable tool for diagnosis and regular follow-up cystoscopy in rats. This instrument can contribute to the preclinical development of experimental intravesical antitumor agents when used for regular evaluations of morphologic drug effects in vivo. PMID- 17705774 TI - Re: Borin JF, Melamud O, Clayman RV. Initial experience with full-length metal stent to relieve malignant ureteral obstruction. J Endourol 2006;20:300-304. PMID- 17705779 TI - Agent-based model of genotype editing. AB - Evolutionary algorithms rarely deal with ontogenetic, non-inherited alteration of genetic information because they are based on a direct genotype-phenotype mapping. In contrast, several processes have been discovered in nature which alter genetic information encoded in DNA before it is translated into amino-acid chains. Ontogenetically altered genetic information is not inherited but extensively used in regulation and development of phenotypes, giving organisms the ability to, in a sense, re-program their genotypes according to environmental cues. An example of post-transcriptional alteration of gene-encoding sequences is the process of RNA Editing. Here we introduce a novel Agent-based model of genotype editing and a computational study of its evolutionary performance in static and dynamic environments. This model builds on our previous Genetic Algorithm with Editing, but presents a fundamentally novel architecture in which coding and non-coding genetic components are allowed to co-evolve. Our goals are: (1) to study the role of RNA Editing regulation in the evolutionary process, (2) to understand how genotype editing leads to a different, and novel evolutionary search algorithm, and (3) the conditions under which genotype editing improves the optimization performance of traditional evolutionary algorithms. We show that genotype editing allows evolving agents to perform better in several classes of fitness functions, both in static and dynamic environments. We also present evidence that the indirect genotype/phenotype mapping resulting from genotype editing leads to a better exploration/exploitation compromise of the search process. Therefore, we show that our biologically-inspired model of genotype editing can be used to both facilitate understanding of the evolutionary role of RNA regulation based on genotype editing in biology, and advance the current state of research in Evolutionary Computation. PMID- 17705780 TI - Covariant genetic dynamics. AB - We present a covariant form for the dynamics of a canonical GA of arbitrary cardinality, showing how each genetic operator can be uniquely represented by a mathematical object - a tensor - that transforms simply under a general linear coordinate transformation. For mutation and recombination these tensors can be written as tensor products of the analogous tensors for one-bit strings thus giving a greatly simplified formulation of the dynamics. We analyze the three most well known coordinate systems -- string, Walsh and Building Block - discussing their relative advantages and disadvantages with respect to the different operators, showing how one may transform from one to the other, and that the associated coordinate transformation matrices can be written as a tensor product of the corresponding one-bit matrices. We also show that in the Building Block basis the dynamical equations for all Building Blocks can be generated from the equation for the most fine-grained block (string) by a certain projection ("zapping"). PMID- 17705781 TI - Crossover and evolutionary stability in the prisoner's dilemma. AB - We examine the role played by crossover in a series of genetic algorithm-based evolutionary simulations of the iterated prisoner's dilemma. The simulations are characterized by extended periods of stability, during which evolutionarily meta stable strategies remain more or less fixed in the population, interrupted by transient, unstable episodes triggered by the appearance of adaptively targeted predators. This leads to a global evolutionary pattern whereby the population shifts from one of a few evolutionarily metastable strategies to another to evade emerging predator strategies. While crossover is not particularly helpful in producing better average scores, it markedly enhances overall evolutionary stability. We show that crossover achieves this by (1) impeding the appearance and spread of targeted predator strategies during stable phases, and (2) greatly reducing the duration of unstable epochs, presumably by efficient recombination of building blocks to rediscover prior metastable strategies. We also speculate that during stable phases, crossover's operation on the persistently heterogeneous gene pool enhances the survival of useful building blocks, thus sustaining long-range temporal correlations in the evolving population. Empirical support for this conjecture is found in the extended tails of probability distribution functions for stable phase lifetimes. PMID- 17705782 TI - A new approach of data clustering using a flock of agents. AB - This paper presents a new bio-inspired algorithm (FClust) that dynamically creates and visualizes groups of data. This algorithm uses the concepts of a flock of agents that move together in a complex manner with simple local rules. Each agent represents one data. The agents move together in a 2D environment with the aim of creating homogeneous groups of data. These groups are visualized in real time, and help the domain expert to understand the underlying structure of the data set, like for example a realistic number of classes, clusters of similar data, isolated data. We also present several extensions of this algorithm, which reduce its computational cost, and make use of a 3D display. This algorithm is then tested on artificial and real-world data, and a heuristic algorithm is used to evaluate the relevance of the obtained partitioning. PMID- 17705783 TI - A graph-based evolutionary algorithm: Genetic Network Programming (GNP) and its extension using reinforcement learning. AB - This paper proposes a graph-based evolutionary algorithm called Genetic Network Programming (GNP). Our goal is to develop GNP, which can deal with dynamic environments efficiently and effectively, based on the distinguished expression ability of the graph (network) structure. The characteristics of GNP are as follows. 1) GNP programs are composed of a number of nodes which execute simple judgment/processing, and these nodes are connected by directed links to each other. 2) The graph structure enables GNP to re-use nodes, thus the structure can be very compact. 3) The node transition of GNP is executed according to its node connections without any terminal nodes, thus the past history of the node transition affects the current node to be used and this characteristic works as an implicit memory function. These structural characteristics are useful for dealing with dynamic environments. Furthermore, we propose an extended algorithm, "GNP with Reinforcement Learning (GNPRL)" which combines evolution and reinforcement learning in order to create effective graph structures and obtain better results in dynamic environments. In this paper, we applied GNP to the problem of determining agents' behavior to evaluate its effectiveness. Tileworld was used as the simulation environment. The results show some advantages for GNP over conventional methods. PMID- 17705784 TI - Fortilin binds Ca2+ and blocks Ca2+-dependent apoptosis in vivo. AB - Fortilin, a 172-amino-acid polypeptide present both in the cytosol and nucleus, possesses potent anti-apoptotic activity. Although fortilin is known to bind Ca2+, the biochemistry and biological significance of such an interaction remains unknown. In the present study we report that fortilin must bind Ca2+ in order to protect cells against Ca2+-dependent apoptosis. Using a standard Ca2+-overlay assay, we first validated that full-length fortilin binds Ca2+ and showed that the N-terminus (amino acids 1-72) is required for its Ca2+-binding. We then used flow dialysis and CD spectropolarimetry assays to demonstrate that fortilin binds Ca2+ with a dissociation constant (Kd) of approx. 10 mM and that the binding of fortilin to Ca2+ induces a significant change in the secondary structure of fortilin. In order to evaluate the impact of the binding of fortilin to Ca2+ in vivo, we measured intracellular Ca2+ levels upon thapsigargin challenge and found that the lack of fortilin in the cell results in the exaggerated elevation of intracellular Ca2+ in the cell. We then tested various point mutants of fortilin for their Ca2+ binding and identified fortilin(E58A/E60A) to be a double-point mutant of fortilin lacking the ability of Ca2+-binding. We then found that wild type fortilin, but not fortilin(E58A/E60A), protected cells against thapsigargin induced apoptosis, suggesting that the binding of fortilin to Ca2+ is required for fortilin to protect cells against Ca2+-dependent apoptosis. Together, these results suggest that fortilin is an intracellular Ca2+ scavenger, protecting cells against Ca2+-dependent apoptosis by binding and sequestering Ca2+ from the downstream Ca2+-dependent apoptotic pathways. PMID- 17705785 TI - Intracellular localization of human Ins(1,3,4,5,6)P5 2-kinase. AB - InsP6 is an intracellular signal with several proposed functions that is synthesized by IP5K [Ins(1,3,4,5,6)P5 2-kinase]. In the present study, we overexpressed EGFP (enhanced green fluorescent protein)-IP5K fusion proteins in NRK (normal rat kidney), COS7 and H1299 cells. The results indicate that there is spatial microheterogeneity in the intracellular localization of IP5K that could also be confirmed for the endogenous enzyme. This may facilitate changes in InsP6 levels at its sites of action. For example, overexpressed IP5K showed a structured organization within the nucleus. The kinase was preferentially localized in euchromatin and nucleoli, and co-localized with mRNA. In the cytoplasm, the overexpressed IP5K showed locally high concentrations in discrete foci. The latter were attributed to stress granules by using mRNA, PABP [poly(A) binding protein] and TIAR (TIA-1-related protein) as markers. The incidence of stress granules, in which IP5K remained highly concentrated, was further increased by puromycin treatment. Using FRAP (fluorescence recovery after photobleaching) we established that IP5K was actively transported into the nucleus. By site-directed mutagenesis we identified a nuclear import signal and a peptide segment mediating the nuclear export of IP5K. PMID- 17705786 TI - A stress-induced rice (Oryza sativa L.) beta-glucosidase represents a new subfamily of glycosyl hydrolase family 5 containing a fascin-like domain. AB - GH5BG, the cDNA for a stress-induced GH5 (glycosyl hydrolase family 5) beta glucosidase, was cloned from rice (Oryza sativa L.) seedlings. The GH5BG cDNA encodes a 510-amino-acid precursor protein that comprises 19 amino acids of prepeptide and 491 amino acids of mature protein. The protein was predicted to be extracellular. The mature protein is a member of a plant-specific subgroup of the GH5 exoglucanase subfamily that contains two major domains, a beta-1,3 exoglucanase-like domain and a fascin-like domain that is not commonly found in plant enzymes. The GH5BG mRNA is highly expressed in the shoot during germination and in leaf sheaths of mature plants. The GH5BG was up-regulated in response to salt stress, submergence stress, methyl jasmonate and abscisic acid in rice seedlings. A GUS (glucuronidase) reporter tagged at the C-terminus of GH5BG was found to be secreted to the apoplast when expressed in onion (Allium cepa) cells. A thioredoxin fusion protein produced from the GH5BG cDNA in Escherichia coli hydrolysed various pNP (p-nitrophenyl) glycosides, including beta-D-glucoside, alpha-L-arabinoside, beta-D-fucoside, beta-D-galactoside, beta-D-xyloside and beta-D-cellobioside, as well as beta-(1,4)-linked glucose oligosaccharides and beta-(1,3)-linked disaccharide (laminaribiose). The catalytic efficiency (kcat/K(m)) for hydrolysis of beta-(1,4)-linked oligosaccharides by the enzyme remained constant as the DP (degree of polymerization) increased from 3 to 5. This substrate specificity is significantly different from fungal GH5 exoglucanases, such as the exo-beta-(1,3)-glucanase of the yeast Candida albicans, which may correlate with a marked reduction in a loop that makes up the active-site wall in the Candida enzyme. PMID- 17705788 TI - Expression of functional human (pro)renin receptor in silkworm (Bombyx mori) larvae using BmMNPV bacmid. AB - The circulating RA (renin-angiotensin) system is essential for the regulation of blood pressure and electrolyte balance. Recently, plasma prorenin has been reported to significantly increase its level in diabetes and to be possibly non proteolytically activated by binding to the PRR [(pro)renin receptor] on the cell membrane reported in several tissues during circulation. Although many pathological aspects have been researched, there is a lack of sufficient information on the biochemical structure and biological function of this hPRR (human PRR) because of the difficulty in increasing hPRR expression. In the present study, GFP(uv)-hPRR (hPRR fused with green fluorescence protein when excited with long-wave UV light) was successfully expressed by using BmMNPV (Bombyx mori multiple nucleopolyhedrovirus) bacmid DNA in silkworm (Bombyx mori) larvae. Some of the hPRR was expressed in the haemolymph of silkworm larvae and some of the hPRR was located in the fat body of silkworm larvae. The binding ability of hPRR expressed in the haemolymph and fat body with renin or prorenin was analysed by ELISA and surface plasmon resonance using a biosensor respectively. These binding assays suggest that the expressed hPRR has a functional bioactivity. hPRR preparation in silkworm larvae would, therefore, be useful for biochemical and biomedical researches related to PRR. PMID- 17705787 TI - The NHB1 (N-terminal homology box 1) sequence in transcription factor Nrf1 is required to anchor it to the endoplasmic reticulum and also to enable its asparagine-glycosylation. AB - Nrf1 (nuclear factor-erythroid 2 p45 subunit-related factor 1) is negatively controlled by its NTD (N-terminal domain) that lies between amino acids 1 and 124. This domain contains a leucine-rich sequence, called NHB1 (N-terminal homology box 1; residues 11-30), which tethers Nrf1 to the ER (endoplasmic reticulum). Electrophoresis resolved Nrf1 into two major bands of approx. 95 and 120 kDa. The 120-kDa Nrf1 form represents a glycosylated protein that was present exclusively in the ER and was converted into a substantially smaller polypeptide upon digestion with either peptide:N-glycosidase F or endoglycosidase H. By contrast, the 95-kDa Nrf1 form did not appear to be glycosylated and was present primarily in the nucleus. NHB1 and its adjacent residues conform to the classic tripartite signal peptide sequence, comprising n-, h- and c-regions. The h-region (residues 11-22), but neither the n-region (residues 1-10) nor the c-region (residues 23-30), is required to direct Nrf1 to the ER. Targeting Nrf1 to the ER is necessary to generate the 120-kDa glycosylated protein. The n-region and c region are required for correct membrane orientation of Nrf1, as deletion of residues 2-10 or 23-30 greatly increased its association with the ER and the extent to which it was glycosylated. The NHB1 does not contain a signal peptidase cleavage site, indicating that it serves as an ER anchor sequence. Wild-type Nrf1 is glycosylated through its Asn/Ser/Thr-rich domain, between amino acids 296 and 403, and this modification was not observed in an Nrf1(Delta299-400) mutant. Glycosylation of Nrf1 was not necessary to retain it in the ER. PMID- 17705789 TI - Oxygen sensing and hypoxia-induced responses. AB - Low cellular oxygenation (hypoxia) represents a significant threat to the viability of affected tissues. Multicellular organisms have evolved a highly conserved signalling pathway that directs many of the changes in gene expression that underpin physiological oxygen homoeostasis. Oxygen-sensing enzymes in this pathway control the activity of the HIF (hypoxia-inducible factor) transcription factor by the direct incorporation of molecular oxygen into the post translational hydroxylation of specific residues. This represents the canonical hypoxia signalling pathway which regulates a plethora of genes involved in adaptation to hypoxia. The HIF hydroxylases have been identified in other biological contexts, consistent with the possibility that they have other substrates. Furthermore, several intracellular proteins have been demonstrated, directly or indirectly, to be hydroxylated, although the protein hydroxylases responsible have yet to be identified. This chapter will summarize what is currently known about the canonical HIF hydroxylase signalling pathway and will speculate on the existence of other oxygen-sensing enzymes and the role they may play in signalling hypoxia through other pathways. PMID- 17705790 TI - Mitochondrial oxygen sensing: regulation of hypoxia-inducible factor by mitochondrial generated reactive oxygen species. AB - Decreased oxygen availability (hypoxia) promotes physiological processes such as energy metabolism, angiogenesis, cell proliferation and cell viability through the transcription factor HIF (hypoxia-inducible factor). Activation of HIF can also promote pathophysiological processes such as cancer and pulmonary hypertension. The mechanism(s) by which hypoxia activates HIF are the subject of intensive research. In this chapter we outline the model in which mitochondria regulate the stability of HIF through the increased production of ROS (reactive oxygen species) during hypoxia. PMID- 17705791 TI - Nitric oxide and hypoxia. AB - NO (nitric oxide) can affect mitochondrial function by interacting with the cytochrome c oxidase (complex IV) of the electron transport chain in a manner that is reversible and in competition with oxygen. Concentrations of NO too low to inhibit respiration can trigger cell defence response mechanisms involving reactive oxygen species and various signalling molecules such as nuclear factor kappaB and AMP kinase. Inhibition of mitochondrial respiration by NO at low oxygen concentrations can cause so-called metabolic hypoxia and divert oxygen towards other oxygen-dependent systems. Such a diversion reactivates prolyl hydroxylases and thus accounts for the prevention by NO of the stabilization of hypoxia-inducible transcription factor. In certain circumstances NO interacts with superoxide radical to form peroxynitrite, which can affect the action of key enzymes, such as mitochondrial complex I, by S-nitrosation. This chapter discusses the physiological and pathophysiological implications of the interactions of NO with the cytochrome c oxidase. PMID- 17705792 TI - Sensing hypoxia in the carotid body: from stimulus to response. AB - The carotid body is a peripheral sensory organ that can transduce modest falls in the arterial PO(2) (partial pressure of oxygen) into a neural signal that provides the afferent limb of a set of stereotypic cardiorespiratory reflexes that are graded according to the intensity of the stimulus. The stimulus sensed is tissue PO(2) and this can be estimated to be around 50 mmHg during arterial normoxia, falling to between 10-40 mmHg during hypoxia. The chemoafferent hypoxia stimulus-response curve is exponential, rising in discharge frequency with falling PO(2), and with no absolute threshold apparent in hyperoxia. Although the oxygen sensor has not been definitely identified, it is believed to reside within type I cells of the carotid body, and presently two major hypotheses have been put forward to account for the sensing mechanism. The first relies upon alterations in the cell energy status that is sensed by the cytosolic enzyme AMPK (AMP-activated protein kinase) subsequent to hypoxia-induced increases in the cellular AMP/ATP ratio during hypoxia. AMPK is localized close to the plasma membrane and its activation can inhibit both large conductance, calcium-activated potassium (BK) and background, TASK-like potassium channels, inducing membrane depolarization, voltage-gated calcium entry and neurosecretion of a range of transmitter and modulator substances, including catecholamines, ATP and acetylcholine. The alternative hypothesis considers a role for haemoxygenase-2, which uses oxygen as a substrate and may act to gate an associated BK channel through the action of its products, carbon monoxide and possibly haem. It is likely however, that these and other hypotheses of oxygen transduction are not mutually exclusive and that each plays a role, via its own particular sensitivity, in shaping the full response of this organ between hyperoxia and anoxia. PMID- 17705793 TI - Hypoxic pulmonary vasoconstriction. AB - HPV (hypoxic pulmonary vasoconstriction) is the critical and distinguishing characteristic of the arteries that feed the lung. In marked contrast, systemic arteries dilate in response to hypoxia to meet the metabolic demands of the tissues they supply. Physiologically, HPV contributes to ventilation-perfusion matching in the lung by diverting blood flow to oxygen-rich areas. However, when alveolar hypoxia is global, as in diseases such as emphysema and cystic fibrosis, HPV leads to HPH (hypoxic pulmonary hypertension) and right heart failure. HPV is driven by the intrinsic response to hypoxia of two different cell types, namely the pulmonary arterial smooth muscle and endothelial cells. These are representatives of a group of specialized cells, commonly referred to as oxygen sensing cells, which are defined by their acute sensitivity to relatively small changes in PO(2) and have evolved to monitor oxygen supply and alter respiratory and circulatory function, as well as the capacity of the blood to transport oxygen. Upon exposure to hypoxia, mitochondrial oxidative phosphorylation is inhibited in all such cells and this, in part, mediates cell activation. In the case of pulmonary arteries, constriction is triggered via: (i) calcium release from the smooth muscle sarcoplasmic reticulum and consequent store-depletion activated calcium entry into the smooth muscle cells and, (ii) the modulation of transmitter release from the pulmonary artery endothelium, which leads to further constriction of the smooth muscle by increasing the sensitivity of the contractile apparatus to calcium. PMID- 17705794 TI - Oxygen sensing by ion channels. AB - The ability to sense and react to changes in environmental oxygen levels is crucial to the survival of all aerobic life forms. In mammals, specialized tissues have evolved which can sense and rapidly respond to an acute reduction in oxygen and central to this ability in many is dynamic modulation of ion channels by hypoxia. The most widely studied oxygen-sensitive ion channels are potassium channels but oxygen sensing by members of both the calcium and sodium channel families has also been demonstrated. This chapter will focus on mechanisms of physiological oxygen sensing by ion channels, with particular emphasis on potassium channel function, and will highlight some of the consensuses and controversies within the field. Where data are available, this chapter will also make use of information gleaned from heterologous expression of recombinant proteins in an attempt to consolidate what we know currently about the molecular mechanisms of acute oxygen sensing by ion channels. PMID- 17705795 TI - Cellular mechanisms associated with intermittent hypoxia. AB - Hypoxia, i.e. decreased availability of oxygen occurs under many different circumstances and can be either continuous or intermittent. Continuous hypoxia such as that experienced during periods of high altitude leads to physiological adaptations, whereas chronic IH (intermittent hypoxia) associated with sleep disordered breathing manifested as recurrent apneas leads to morbidity. The purpose of the present chapter is to highlight recent findings on cellular responses to IH. Studies on cell culture models of IH revealed that for a given duration and intensity, IH is more potent than continuous hypoxia in evoking transcriptional activation. IH activates HIF-1 (hypoxia-inducible factor-1), the immediate early gene c-fos, activator protein-1, nuclear factor kappaB and cAMP response-element-binding protein. Physiological studies showed that HIF-1 plays an important role in chronic IH-induced autonomic abnormalities in mice. IH affects expression of proteins associated with neuronal survival and apoptosis, as well as post-translational modifications of proteins resulting in increased biological activity. Comparisons between continuous hypoxia and IH revealed notable differences in the kinetics of protein kinase activation, type of protein kinase being activated and the downstream targets of protein kinases. IH increases ROS (reactive oxygen species) generation both in cell culture and in intact animals, and ROS-mediated signalling mechanisms contribute to cellular and systemic responses to IH. Future studies utilizing genomic and proteomic approaches may provide important clues to the mechanisms by which IH leads to morbidity as opposed to continuous hypoxia-induced adaptations. Cellular mechanisms associated with IH (other than recurrent apneas) such as repetitive, brief ascents to altitude, however, remain to be studied. PMID- 17705796 TI - Vascular adaptations to hypoxia: molecular and cellular mechanisms regulating vascular tone. AB - Several molecular and cellular adaptive mechanisms to hypoxia exist within the vasculature. Many of these processes involve oxygen sensing which is transduced into mediators of vasoconstriction in the pulmonary circulation and vasodilation in the systemic circulation. A variety of oxygen-responsive pathways, such as HIF (hypoxia-inducible factor)-1 and HOs (haem oxygenases), contribute to the overall adaptive process during hypoxia and are currently an area of intense research. Generation of ROS (reactive oxygen species) may also differentially regulate vascular tone in these circulations. Potential candidates underlying the divergent responses between the systemic and pulmonary circulations may include Nox (NADPH oxidase)-derived ROS and mitochondrial-derived ROS. In addition to alterations in ROS production governing vascular tone in the hypoxic setting, other vascular adaptations are likely to be involved. HPV (hypoxic pulmonary vasoconstriction) and CH (chronic hypoxia)-induced alterations in cellular proliferation, ionic conductances and changes in the contractile apparatus sensitivity to calcium, all occur as adaptive processes within the vasculature. PMID- 17705797 TI - The AMP-activated protein kinase: more than an energy sensor. AB - The AMPK (AMP-activated protein kinase) is a highly conserved eukaryotic protein serine/threonine kinase. It mediates a nutrient signalling pathway that senses cellular energy status and was appropriately called the fuel gauge of the cell. At the cellular level, AMPK controls energy homoeostasis by switching on catabolic ATP-generating pathways, while switching off anabolic ATP-consuming processes. Its effect on energy balance extends to whole-body energy homoeostasis, because, in the hypothalamus, it integrates nutritional and hormonal signals that control food intake and body weight. The interest in AMPK also stems from the demonstration of its insulin-independent stimulation of glucose transport in skeletal muscle during exercise. Moreover, the potential importance of AMPK in metabolic diseases is supported by the notion that AMPK mediates the anti-diabetic action of biguanides and thiazolidinediones and that it might be involved in the metabolic syndrome. Finally, the more recent demonstration that AMPK activation could occur independently of changes in cellular energy status, suggests that AMPK action extends to the control of non metabolic functions. PMID- 17705798 TI - Hypoxia in the central nervous system. AB - The brain, as a very high energy consumer, is completely reliant on molecular oxygen but because oxygen is dangerous due to toxicity [1], there are mechanisms which allow the brain to exist under low oxygen conditions when 'idling' but increase oxygen delivery when activated. This situation means that the brain can respond naturally to mild hypoxia with acute and chronic adaptive mechanisms. These mechanisms involve systemic and central metabolic and vascular processes that are mediated by hypoxia-inducible factor (HIF)-1. HIF-1-mediated cerebral angiogenesis is completed within 3 weeks of exposure onset and is reversible over the same time frame if normoxia is restored. Hypoxic acclimatizing responses may be significantly impaired with aging and metabolic or vascular disease. PMID- 17705799 TI - Hypoxia and Alzheimer's disease. AB - Numerous cardiorespiratory disorders result in persistent systemic hypoxia, or at worst (as a consequence of stroke) deprive the brain of oxygen completely for a period of time. Patients suffering from such conditions are much more susceptible to the development of dementias such as AD (Alzheimer's disease). Until recently, the cellular and molecular basis for the predisposition to AD by systemic hypoxia has been completely unknown. However, emerging evidence suggests that pathological cellular remodelling caused by chronic hypoxia shows striking similarities to those observed in the central nervous system as a consequence of AD. Furthermore, prolonged hypoxia can induce formation of Abetas (amyloid beta peptides), the primary neurotoxic elements of AD, which accumulate over years to form the extracellular plaques that are the hallmark feature of the disease. Hypoxia can lead to paradoxical increases in mitochondrial ROS (reactive oxygen species) generation upstream of Abeta formation. The downstream consequences of prolonged hypoxia include remodelling of functional expression of voltage-gated calcium channels and disturbance of intracellular calcium homoeostasis via disrupted calcium buffering and inhibition of calcium extrusion mechanisms. These effects can be mimicked by application of exogenous Abeta and, crucially, appear to depend on Abeta formation. Current knowledge supports the concept that prevention of the deleterious effects of hypoxia may prove beneficial in slowing or preventing the onset of AD. PMID- 17705800 TI - Hypoxia in cancer cell metabolism and pH regulation. AB - At a molecular level, hypoxia induces the stabilization and activation of the alpha-subunit of an alpha/beta heterodimeric transcription factor, appropriately termed HIF (hypoxia-inducible factor). Hypoxia is encountered, in particular, in tumour tissues, as a result of an insufficient and defective vasculature present in a highly proliferative tumour mass. In this context the active HIF heterodimer binds to and induces a panel of genes that lead to modification in a vast range of cellular functions that allow cancer cells to not only survive but to continue to proliferate and metastasize. Therefore HIF plays a key role in tumorigenesis, tumour development and metastasis, and its expression in solid tumours is associated with a poor patient outcome. Among the many genes induced by HIF are genes responsible for glucose transport and glucose metabolism. The products of these genes allow cells to adapt to cycles of hypoxic stress by maintaining a level of ATP sufficient for survival and proliferation. Whereas normal cells metabolize glucose through a cytoplasmic- and mitochondrial-dependent pathway, cancer cells preferentially use a cytoplasmic, glycolytic pathway that leads to an increased acid load due, in part, to the high level of production of lactic acid. This metabolic predilection of cancer cells is primarily dependent directly on the HIF activity but also indirectly through changes in the activity of tumour suppressors and oncogenes. A better understanding of HIF-dependent metabolism and pH regulation in cancer cells should lead to further development of diagnostic tools and novel therapeutics that will bring benefit to cancer patients. PMID- 17705801 TI - RNA-interference-mediated Cdc42 silencing down-regulates phosphorylation of STAT3 and suppresses growth in human bladder-cancer cells. AB - Cdc42 (cell division cycle 42), a member of Rho GTPases, is involved in cell transformation, proliferation, survival, invasion and metastasis of human cancer cells. Here, RNAi (RNA interference)-mediated gene silencing was used to investigate the roles of Cdc42 and to assess its therapeutic potential in human bladder cancer. The results showed that Cdc42 silencing resulted in a marked reduction of Cdc42 mRNA and protein expression and a significant inhibition of cell proliferation from G(0)/G(1)- to S-phase in two (EJ and T24) human bladder cancer cell lines. Moreover, RNAi-mediated inhibition of Cdc42 induced apoptosis of EJ cells 96 h after transfection. In addition, we found that silencing of Cdc42 could down-regulate the level of phosphorylated STAT3 (signal transducer and activator of transcription 3), but did not influence the level of total STAT3 in the two bladder-cancer cell lines. These results suggest that RNAi-mediated Cdc42 silencing may be a novel approach for gene therapy of bladder cancer. PMID- 17705803 TI - Recent advances and future directions in research on testicular germ cell cancer. PMID- 17705804 TI - Testicular cancer trends as 'whistle blowers' of testicular developmental problems in populations. AB - Recently a worldwide rise in the incidence of testicular germ cell cancer (TGCC) has been repeatedly reported. The changing disease pattern may signal that other testicular problems may also be increasing. We have reviewed recent research progress, in particular evidence gathered in the Nordic countries, which shows strong associations between testicular cancer, undescended testis, hypospadias, poor testicular development and function, and male infertility. These studies have led us to suggest the existence of a testicular dysgenesis syndrome (TDS), of which TGCC, undescended testis, hypospadias/disorders of sex differentiation and male fertility problems may be symptoms with varying penetration. In spite of their fetal origin, most of the TDS symptoms, including TGCC and poor semen quality, can only be diagnosed in adulthood. Data from a Danish-Finnish research collaboration strongly suggest that trends in TGCC rates of a population may be 'whistle blowers' of other reproductive health problems. As cancer registries are often of excellent quality - in contrast to registries for congenital abnormalities - health authorities should consider an increase in TGCC as a warning that other reproductive health problems may also be rising. PMID- 17705805 TI - Susceptibility alleles for testicular germ cell tumour: a review. AB - Family history is among the strongest and most consistent of the risk factors for testicular germ cell tumour (TGCT). Brothers of affected cases have an 8- to10 fold relative risk and fathers/sons have a risk between four and sixfold. The familial relative risk of TGCT is higher than for most other cancer types, which rarely exceeds four. The high relative risk suggests that inherited susceptibility to TGCT may account for a substantial fraction of TGCT cases. The search for TGCT susceptibility genes has proven difficult and a recent genome wide linkage study for TGCT susceptibility loci demonstrated no statistically significant regions of linkage with all LOD scores less than two. Moreover, a previous report of linkage to a region on Xq27 was not replicated. The results from genetic linkage analysis demonstrate that TGCT susceptibility is likely to be due to several genes, each with a modest effect on disease risk. The Y chromosome, which cannot be analysed by genetic linkage, carries a number of testis- and germ cell-specific genes. We recently demonstrated that a deletion on the Y chromosome known as 'gr/gr' is a rare, low-penetrance allele that is associated with susceptibility to TGCT. Based on the evidence from the linkage search the 'gr/gr' deletion represents one of possibly many TGCT susceptibility alleles, and new and emerging technologies will be employed in future work to identify these genes. PMID- 17705806 TI - Do all patients with bilateral testis cancer have a hereditary predisposition? AB - An international study has demonstrated that patients with bilateral testicular cancer are significantly more likely to have brothers with testis cancer than those with unilateral disease. This, together with other evidence, implies that patients with bilateral disease are likely to carry a predisposing genotype. But is it the great majority of them which is thus predisposed? We show that if as few as half of these patients have the predisposing genotype, its penetrance would have to be 80%, causing 38% of resulting cases to be bilateral. Evidence from the International Testis Cancer Linkage Consortium shows that the proportion of familial cases with bilateral disease is much lower. It is likely that at least the majority of cases of bilateral testis cancer arise as a result of a predisposing genotype. PMID- 17705807 TI - Why human extragonadal germ cell tumours occur in the midline of the body: old concepts, new perspectives. AB - Hypotheses on the origin and distribution of extragonadal germ cell tumours (GCTs) and teratomas are briefly reviewed and revisited in the light of (i) new developments in the classification of GCTs, (ii) data on genomic imprinting of these neoplasms and (iii) the recent finding that germ cells can be derived from mouse and human embryonal stem (ES) cells. Only the Type I (infantile teratomas/yolk sac tumours) and Type II GCTs (seminomatous tumours and non seminomas) occur in the gonads and extragonadal localizations. The data on genomic imprinting lend support to the hypothesis that they are derived from germ cells. These precursor cells could have differentiated from ES cells in extragonadal localizations. Their distribution along the midline of the body is still best explained by the migration of primitive germ cells during development. The narrower distribution of the Type II than the Type I GCTs is probably due to the more strict conditions for survival and proliferation of primordial germ cells (PGCs)/gonocytes from which the Type II tumours originate, when compared with the precursor cells of Type I tumours, probably primitive germ cells closer to the ES cell. The known niches in which the Type II tumours develop have in common that they contain feeder cells expressing stem cell factor (SCF) - the ligand for the SCF receptor c-KIT, involved in proliferation and survival of PGCs/gonocytes - and contain GBY including the gene TSPY. PMID- 17705808 TI - JKT-1 is not a human seminoma cell line. AB - The JKT-1 cell line has been used in multiple independent studies as a representative model of human testicular seminoma. However, no cell line for this specific tumour type has been independently confirmed previously; and therefore, the seminomatous origin of JKT-1 must be proven. The genetic constitution of the JKT-1 cells was determined using flow cytometry and spectral karyotyping, as well as array comparative genomic hybridization and fluorescent in situ hybridization. Marker profiling, predominantly based on differentially expressed proteins during normal germ cell development, was performed by immunohistochemistry and Western blot analyses. Moreover, genome wide affymetrix mRNA expression and profiling of 157 microRNAs was performed, and the status of genomic imprinting was determined. A germ cell origin of the JKT-1 cells was in line with genomic imprinting status and marker profile (including positive staining for several cancer-testis antigens). However, the supposed primary tumour, from which the cell line was derived, being indeed a classical seminoma, was molecularly proven not to be the origin of the cell line. The characteristic chromosomal anomalies of seminoma, e.g. gain of the short arm of chromosome 12, as well as the informative marker profile (positive staining for OCT3/4, NANOG, among others) were absent in the various JKT-1 cell lines investigated, irrespective of where the cells were cultured. All results indicate that the JKT-1 cell line is not representative of human seminoma. Although it can originate from an early germ cell, a non-germ cell derivation cannot be excluded. PMID- 17705809 TI - Inhibition of tyrosine kinases PDGFR and C-Kit by imatinib mesylate interferes with postnatal testicular development in the rat. AB - The tyrosine kinase receptor c-kit and its interaction with the ligand, stem cell factor (SCF), play an essential role in the developing testis. C-kit is important for the development of the Leydig cells and for the migration, proliferation and survival of spermatogonia. Platelet-derived growth factor (PDGF) and its tyrosine kinase receptor (PDGFR) are important for the development of Leydig cells and myoid cells. The chemotherapeutic agent, imatinib mesylate (STI571, Glivec; Novartis) inhibits both of these tyrosine kinase receptors. Three-day treatment of immature male rats (SD) with imatinib (150 mg/kg) on postnatal days 5-7 delayed the formation of germ-line stem cell pool, reduced proliferation of type A spermatogonia and induced germ cell apoptosis. PDGFR-mediated proliferation of mesenchymal myoid precursors was also decreased and the length of the seminiferous cord was reduced. However, at the age of 11 weeks the exposed animals had normal epididymal sperm counts, whereas plasma levels of luteinizing hormone and follicle stimulating hormone were significantly increased. Imatinib serves as a good tool to study postnatal formation of the male germ-line stem cell pool and factors determining the final testicular size. As development of the human testis is controlled by the same mechanisms, further studies with primate and human models are needed to explore whether imatinib affects the testis in children as well. PMID- 17705810 TI - The transforming growth factor-beta superfamily in early spermatogenesis: potential relevance to testicular dysgenesis. AB - Regulated transforming growth factor-beta (TGFbeta) superfamily signalling is an integral part of normal testicular development and the processes that enable the production of fertile sperm. Through shared utilization of receptors, signal transduction components and inhibitors, many ligands in this family exhibit functional overlaps; this facet of their function is critical to understand because these ligands are often co-expressed and, hence, they may compete with or compensate for one another, depending on the specific cellular context. This review describes particular germ cell maturation steps governed by bone morphogenetic proteins, glial cell line-derived neurotrophic factor and activins, focusing on data predominantly from rodent studies that implicate activin and other family members in modulation of gonocyte and spermatogonial stem cell development. We also review knowledge of the TGFbeta superfamily signalling components in the human testis, exploring their potential impact on the processes associated with disrupted gonocyte development and an enhanced risk of testicular cancer. PMID- 17705811 TI - Epigenetic transgenerational toxicology and germ cell disease. AB - The ability of an environmental exposure (i.e. endocrine disruptor) during sex determination to reprogramme the male germline and promote an epigenetic transgenerational disease phenotype suggests that environmental factors and compounds may permanently alter the germline epigenome. This epigenetic transgenerational phenomenon will be discussed with respect to adult-onset germline disease (e.g. testicular cancer). A thorough literature review is not provided, rather a perspective is provided on how this epigenetic transgenerational toxicology should be considered in germ cell disease and testicular cancer. PMID- 17705812 TI - Current approaches for detection of carcinoma in situ testis. AB - Testicular germ cell tumours have a favourable prognosis if detected early, but are potentially lethal in a subset of patients. Multi-modality treatment is often necessary, thus the preferable time of diagnosis is at the pre-invasive, but unfortunately often asymptomatic precursor stage of carcinoma in situ (CIS). This review describes current possible approaches for the detection of CIS. At present, an open testicular biopsy is the only definitive way of establishing the presence of CIS. The tissue section should be of an adequate size, be properly fixed, and evaluation be supported by at least one solid immunohistochemical marker, for example PLAP, OCT-3/4 or AP-2gamma. Determination of who should be offered testicular biopsies is based on clinical and ultrasonic examination along with the evaluation of risk factors. A surgical biopsy is an invasive procedure with potential complications, although rare. Therefore, a noninvasive and equally reliable method is needed. Testicular ultrasound is risk-free, painless and at present the only noninvasive method of aid for andrologists when CIS is suspected. The presence of testicular microlithiasis is, in some cases, indicative of pre-malignant changes, especially in males with additional risk factors. Promising results have recently been obtained with a novel noninvasive detection method based on immunocytological AP-2gamma-staining of CIS cells in semen. This method could be a supporting method in andrology centres where careful follow-up is possible. In conclusion, one difficulty is to determine in which males CIS should be suspected; secondly, there does not as yet exist an optimal noninvasive method of diagnosis that is more acceptable than an open surgical biopsy. PMID- 17705813 TI - Testicular carcinoma in situ in subfertile Danish men. AB - Carcinoma in situ (CIS) testis is the precursor stage for the majority of testicular germ cell tumours (TGCT). Infertility is one of the conditions known to predispose to TGCT, but based on scarce existing data, the prevalence of CIS in this risk group was estimated at only approximately 1%. To establish more objective data, we investigated retrospectively the prevalence of CIS based on testicular biopsies performed in a well-defined group of subfertile males. We included 453 patients who had testicular biopsies performed for infertility reasons during 1995-2005 at the Copenhagen University Hospital (Rigshospitalet). Biopsies were evaluated by two experienced observers independently. CIS was detected in 10 individuals, of whom three had bilateral CIS, corresponding to a prevalence of 2.2% (95% CI 1.1-4.0%). This is greater than the estimated risk of 0.45% for the age- and birth cohort-matched general Danish population. All patients with CIS testis had severe oligozoospermia ( .05). CONCLUSION: Prolonged, self-paced use of a standard computer interface does not put older persons at a risk of upper limb complaints or reduce functional health in older adults. PMID- 17705832 TI - High performance microbiological transformation of L-tyrosine to L-dopa by Yarrowia lipolytica NRRL-143. AB - BACKGROUND: The 3,4-dihydroxy phenyl L-alanine (L-dopa) is a drug of choice for Parkinson's disease, controlling changes in energy metabolism enzymes of the myocardium following neurogenic injury. Aspergillus oryzae is commonly used for L dopa production; however, potential improvements in ease of handling, growth rate and environmental impact have led to an interest in exploiting alternative yeasts. The two important elements required for L-dopa production are intracellular tyrosinases (thus pre-grown yeast cells are required for the transformation of L-tyrosine to L-dopa) and L-ascorbate, which acts as a reducing agent. RESULTS: Pre-grown cells of Yarrowia lipolytica NRRL-143 were used for the microbiological transformation of L-tyrosine to L-dopa. Different diatomite concentrations (0.5-3.0 mg/ml) were added to the acidic (pH 3.5) reaction mixture. Maximum L-dopa biosynthesis (2.96 mg/ml L-dopa from 2.68 mg/ml L tyrosine) was obtained when 2.0 mg/ml diatomite was added 15 min after the start of the reaction. After optimizing reaction time (30 min), and yeast cell concentration (2.5 mg/ml), an overall 12.5 fold higher L-dopa production rate was observed when compared to the control. Significant enhancements in Yp/s, Qs and qs over the control were observed. CONCLUSION: Diatomite (2.0 mg/ml) addition 15 min after reaction commencement improved microbiological transformation of L tyrosine to L-dopa (3.48 mg/ml; p < or = 0.05) by Y. lipolytica NRRL-143. A 35% higher substrate conversion rate was achieved when compared to the control. PMID- 17705834 TI - Identification of novel proteins affected by rotenone in mitochondria of dopaminergic cells. AB - BACKGROUND: Many studies have shown that mitochondrial dysfunction, complex I inhibition in particular, is involved in the pathogenesis of Parkinson's disease (PD). Rotenone, a specific inhibitor of mitochondrial complex I, has been shown to produce neurodegeneration in rats as well as in many cellular models that closely resemble PD. However, the mechanisms through which complex I dysfunction might produce neurotoxicity are as yet unknown. A comprehensive analysis of the mitochondrial protein expression profile affected by rotenone can provide important insight into the role of mitochondrial dysfunction in PD. RESULTS: Here, we present our findings using a recently developed proteomic technology called SILAC (stable isotope labeling by amino acids in cell culture) combined with polyacrylamide gel electrophoresis and liquid chromatography-tandem mass spectrometry to compare the mitochondrial protein profiles of MES cells (a dopaminergic cell line) exposed to rotenone versus control. We identified 1722 proteins, 950 of which are already designated as mitochondrial proteins based on database search. Among these 950 mitochondrial proteins, 110 displayed significant changes in relative abundance after rotenone treatment. Five of these selected proteins were further validated for their cellular location and/or treatment effect of rotenone. Among them, two were confirmed by confocal microscopy for mitochondrial localization and three were confirmed by Western blotting (WB) for their regulation by rotenone. CONCLUSION: Our findings represent the first report of these mitochondrial proteins affected by rotenone; further characterization of these proteins may shed more light on PD pathogenesis. PMID- 17705835 TI - The impact of maternal experience of violence and common mental disorders on neonatal outcomes: a survey of adolescent mothers in Sao Paulo, Brazil. AB - BACKGROUND: Both violence and depression during pregnancy have been linked to adverse neonatal outcomes, particularly low birth weight. The aim of this study was to investigate the independent and interactive effects of these maternal exposures upon neonatal outcomes among pregnant adolescents in a disadvantaged population from Sao Paulo, Brazil. METHODS: 930 consecutive pregnant teenagers, admitted for delivery were recruited. Violence was assessed using the Californian Perinatal Assessment. Mental illness was measured using the Composite International Diagnostic Interview (CIDI). Apgar scores of newborns were estimated and their weight measured. RESULTS: 21.9% of mothers reported lifetime violence (2% during pregnancy) and 24.3% had a common mental disorder in the past 12 months. The exposures were correlated and each was associated with low education. Lifetime violence was strongly associated with Common Mental Disorders. Violence during pregnancy (PR = 2.59(1.05-6.40) and threat of physical violence (PR = 1.86(1.03-3.35) and any common mental disorders (PR = 2.09 (1.21 3.63) (as well as depression, anxiety and PTSD separately) were independently associated with low birth weight. CONCLUSION: Efforts to improve neonatal outcomes in low income countries may be neglecting two important independent, but correlated risk factors: maternal experience of violence and common mental disorder. PMID- 17705836 TI - Information from the Internet and the doctor-patient relationship: the patient perspective--a qualitative study. AB - BACKGROUND: Both doctors and patients may perceive the Internet as a potential challenge to existing therapeutic relationships. Here we examine patients' views of the effect of the Internet on their relationship with doctors. METHODS: We ran 8 disease specific focus groups of between 2 and 8 respondents comprising adult patients with diabetes mellitus, ischaemic heart disease or hepatitis C. RESULTS: Data are presented on (i) the perceived benefits and (ii) limitations of the Internet in the context of the doctor-patient relationship, (iii) views on sharing information with doctors, and (iv) the potential of the Internet for the future. Information from the Internet was particularly valued in relation to experiential knowledge. CONCLUSION: Despite evidence of increasing patient activism in seeking information and the potential to challenge the position of the doctor, the accounts here do not in any way suggest a desire to disrupt the existing balance of power, or roles, in the consultation. Patients appear to see the Internet as an additional resource to support existing and valued relationships with their doctors. Doctors therefore need not feel challenged or threatened when patients bring health information from the Internet to a consultation, rather they should see it as an attempt on the part of the patient to work with the doctor and respond positively. PMID- 17705837 TI - Computational modeling of protein mutant stability: analysis and optimization of statistical potentials and structural features reveal insights into prediction model development. AB - BACKGROUND: Understanding and predicting protein stability upon point mutations has wide-spread importance in molecular biology. Several prediction models have been developed in the past with various algorithms. Statistical potentials are one of the widely used algorithms for the prediction of changes in stability upon point mutations. Although the methods provide flexibility and the capability to develop an accurate and reliable prediction model, it can be achieved only by the right selection of the structural factors and optimization of their parameters for the statistical potentials. In this work, we have selected five atom classification systems and compared their efficiency for the development of amino acid atom potentials. Additionally, torsion angle potentials have been optimized to include the orientation of amino acids in such a way that altered backbone conformation in different secondary structural regions can be included for the prediction model. This study also elaborates the importance of classifying the mutations according to their solvent accessibility and secondary structure specificity. The prediction efficiency has been calculated individually for the mutations in different secondary structural regions and compared. RESULTS: Results show that, in addition to using an advanced atom description, stepwise regression and selection of atoms are necessary to avoid the redundancy in atom distribution and improve the reliability of the prediction model validation. Comparing to other atom classification models, Melo-Feytmans model shows better prediction efficiency by giving a high correlation of 0.85 between experimental and theoretical Delta Delta G with 84.06% of the mutations correctly predicted out of 1538 mutations. The theoretical Delta Delta G values for the mutations in partially buried beta-strands generated by the structural training dataset from PISCES gave a correlation of 0.84 without performing the Gaussian apodization of the torsion angle distribution. After the Gaussian apodization, the correlation increased to 0.92 and prediction accuracy increased from 80% to 88.89% respectively. CONCLUSION: These findings were useful for the optimization of the Melo-Feytmans atom classification system and implementing them to develop the statistical potentials. It was also significant that the prediction efficiency of mutations in the partially buried beta-strands improves with the help of Gaussian apodization of the torsion angle distribution. All these comparisons and optimization techniques demonstrate their advantages as well as the restrictions for the development of the prediction model. These findings will be quite helpful not only for the protein stability prediction, but also for various structure solutions in future. PMID- 17705838 TI - High mortality during tuberculosis treatment does not indicate long diagnostic delays in Vietnam: a cohort study. AB - BACKGROUND: Delay in tuberculosis diagnosis and treatment initiation may increase disease severity and mortality. In evaluations of tuberculosis control programmes high fatality rates during tuberculosis treatment, are used as an indicator of long delays in low HIV-prevalence settings. However, data for this presumed association between delay and fatality are lacking. We assessed the association between diagnostic delay and mortality of new smear-positive pulmonary tuberculosis patients in Vietnam. METHODS: Follow-up of a patient cohort included in a survey of diagnostic delay in 70 randomly selected districts. Data on diagnosis and treatment were extracted from routine registers. Patients who had died during the course of treatment were compared to those with reported cure, completed treatment or failure (survivors). RESULTS: Complete data were available for 1881/2093 (89.9%) patients, of whom 82 (4.4%) had died. Fatality was 4.5% for patients with < or = 4 weeks delay, 5.0% for 5- < or = 8 weeks delay (aOR 1.11, 95%CI 0.67-1.84) and 3.2% for > 9 weeks delay (aOR 0.69, 95%CI 0.37-1.30). Fatality tended to decline with increasing delay but this was not significant. Fatality was not associated with median diagnostic delay at district level (Spearman's rho = -0.08, P = 0.5). CONCLUSION: Diagnostic delay is not associated with treatment mortality in Vietnam at individual nor district level, suggesting that high case fatality should not be used as an indicator of long diagnostic delay in national tuberculosis programmes. PMID- 17705839 TI - Genomic mapping of Suppressor of Hairy-wing binding sites in Drosophila. AB - BACKGROUND: Insulator elements are proposed to play a key role in the organization of the regulatory architecture of the genome. In Drosophila, one of the best studied is the gypsy retrotransposon insulator, which is bound by the Suppressor of Hairy-wing (Su [Hw]) transcriptional regulator. Immunolocalization studies suggest that there are several hundred Su(Hw) sites in the genome, but few of these endogenous Su(Hw) binding sites have been identified. RESULTS: We used chromatin immunopurification with genomic microarray analysis to identify in vivo Su(Hw) binding sites across the 3 megabase Adh region. We find 60 sites, and these enabled the construction of a robust new Su(Hw) binding site consensus. In contrast to the gypsy insulator, which contains tightly clustered Su(Hw) binding sites, endogenous sites generally occur as isolated sites. These endogenous sites have three key features. In contrast to most analyses of DNA-binding protein specificity, we find that strong matches to the binding consensus are good predictors of binding site occupancy. Examination of occupancy in different tissues and developmental stages reveals that most Su(Hw) sites, if not all, are constitutively occupied, and these isolated Su(Hw) sites are generally highly conserved. Analysis of transcript levels in su(Hw) mutants indicate widespread and general changes in gene expression. Importantly, the vast majority of genes with altered expression are not associated with clustering of Su(Hw) binding sites, emphasizing the functional relevance of isolated sites. CONCLUSION: Taken together, our in vivo binding and gene expression data support a role for the Su(Hw) protein in maintaining a constant genomic architecture. PMID- 17705840 TI - Atypical antipsychotics in bipolar disorder: systematic review of randomised trials. AB - BACKGROUND: Atypical antipsychotics are increasingly used for treatment of mental illnesses like schizophrenia and bipolar disorder, and considered to have fewer extrapyramidal effects than older antipsychotics. METHODS: We examined efficacy in randomised trials of bipolar disorder where the presenting episode was either depression, or manic/mixed, comparing atypical antipsychotic with placebo or active comparator, examined withdrawals for any cause, or due to lack of efficacy or adverse events, and combined all phases for adverse event analysis. Studies were found through systematic search (PubMed, EMBASE, Cochrane Library), and data combined for analysis where there was clinical homogeneity, with a special reference to trial duration. RESULTS: In five trials (2,206 patients) participants presented with a depressive episode, and in 25 trials (6,174 patients) the presenting episode was manic or mixed. In 8-week studies presenting with depression, quetiapine and olanzapine produced significantly better rates of response and symptomatic remission than placebo, with NNTs of 5-6, but more adverse event withdrawals (NNH 12). With mania or mixed presentation atypical antipsychotics produced significantly better rates of response and symptomatic remission than placebo, with NNTs of about 5 up to six weeks, and 4 at 6-12 weeks, but more adverse event withdrawals (NNH of about 22) in studies of 6-12 weeks. In comparisons with established treatments, atypical antipsychotics had similar efficacy, but significantly fewer adverse event withdrawals (NNT to prevent one withdrawal about 10). In maintenance trials atypical antipsychotics had significantly fewer relapses to depression or mania than placebo or active comparator. In placebo-controlled trials, atypical antipsychotics were associated with higher rates of weight gain of >or=7% (mainly olanzapine trials), somnolence, and extrapyramidal symptoms. In active controlled trials, atypical antipsychotics were associated with lower rates of extrapyramidal symptoms, but higher rates of weight gain and somnolence. CONCLUSION: Atypical antipsychotics are effective in treating both phases of bipolar disorder compared with placebo, and as effective as established drug therapies. Atypical antipsychotics produce fewer extrapyramidal symptoms, but weight gain is more common (with olanzapine). There is insufficient data confidently to distinguish between different atypical antipsychotics. PMID- 17705841 TI - Causes of stigma and discrimination associated with tuberculosis in Nepal: a qualitative study. AB - BACKGROUND: Tuberculosis (TB) is a major cause of death. The condition is highly stigmatised, with considerable discrimination towards sufferers. Although there have been several studies assessing the extent of such discrimination, there is little published research explicitly investigating the causes of the stigma and discrimination associated with TB. The objectives of our research were therefore to take the first steps towards determining the causes of discrimination associated with TB. METHODS: Data collection was performed in Kathmandu, Nepal. Thirty four in-depth interviews were performed with TB patients, family members of patients, and members of the community. RESULTS: Causes of self-discrimination identified included fear of transmitting TB, and avoiding gossip and potential discrimination. Causes of discrimination by members of the general public included: fear of a perceived risk of infection; perceived links between TB and other causes of discrimination, particularly poverty and low caste; perceived links between TB and disreputable behaviour; and perceptions that TB was a divine punishment. Furthermore, some patients felt they were discriminated against by health workers CONCLUSION: A comprehensive package of interventions, tailored to the local context, will be needed to address the multiple causes of discrimination identified: basic population-wide health education is unlikely to be effective. PMID- 17705842 TI - Large-scale polymorphism of heterochromatic repeats in the DNA of Arabidopsis thaliana. AB - BACKGROUND: The composition of the individual eukaryote's genome and its variation within a species remain poorly defined. Even for a sequenced genome such as that of the model plant Arabidopsis thaliana accession Col-0, the large arrays of heterochromatic repeats are incompletely sequenced, with gaps of uncertain size persisting in them. RESULTS: Using geographically separate populations of A. thaliana, we assayed variation in the heterochromatic repeat arrays using two independent methods and identified significant polymorphism among them, with variation by as much as a factor of two in the centromeric 180 bp repeat, in the 45S rDNA arrays and in the Athila retroelements. In the accession with highest genome size as measured by flow cytometry, Loh-0, we found more than a two-fold increase in 5S RNA gene copies relative to Col-0; results from fluorescence in situ hybridization with 5S probes were consistent with the existence of size polymorphism between Loh-0 and Col-0 at the 5S loci. Comparative genomic hybridization results of Loh-0 and Col-0 did not support contiguous variation in copy number of protein-coding genes on the scale needed to explain their observed genome size difference. We developed a computational data model to test whether the variation we measured in the repeat fractions could account for the different genome sizes determined with flow cytometry, and found that this proposed relationship could account for about 50% of the variance in genome size among the accessions. CONCLUSION: Our analyses are consistent with substantial repeat number polymorphism for 5S and 45S ribosomal genes among accession of A. thaliana. Differences are also suggested for centromeric and pericentromeric repeats. Our analysis also points to the difficulties in measuring the repeated fraction of the genome and suggests that independent validation of genome size should be sought in addition to flow cytometric measurements. PMID- 17705844 TI - Cell-to-cell spread and massive vacuole formation after Cryptococcus neoformans infection of murine macrophages. AB - BACKGROUND: The interaction between macrophages and Cryptococcus neoformans (Cn) is critical for containing dissemination of this pathogenic yeast. However, Cn can either lyse macrophages or escape from within them through a process known as phagosomal extrusion. Both events result in live extracellular yeasts capable of reproducing and disseminating in the extracellular milieu. Another method of exiting the intracellular confines of cells is through host cell-to-cell transfer of the pathogen, and this commonly occurs with the human immuno-deficiency virus (HIV) and CD4+ T cells and macrophages. In this report we have used time-lapse imaging to determine if this occurs with Cn. RESULTS: Live imaging of Cryptococcus neoformans interactions with murine macrophages revealed cell-to cell spread of yeast cells from infected donor cells to uninfected cells. Although this phenomenon was relatively rare its occurrence documents a new capacity for this pathogen to infect adjacent cells without exiting the intracellular space. Cell-to-cell spread appeared to be an actin-dependent process. In addition, we noted that cryptococcal phagosomal extrusion was followed by the formation of massive vacuoles suggesting that intracellular residence is accompanied by long lasting damage to host cells. CONCLUSION: C. neoformans can escape the intracellular confines of macrophages in an actin dependent manner by cell-to-cell transfer of the yeast leading to infection of adjacent cells. In addition, complete extrusion of internalized Cn cells can lead to the formation of a massive vacuole which may be a sign of damage to the host macrophage. These observations document new outcomes for the interaction of C. neoformans with host cells that provide precedents for cell biological effects that may contribute to the pathogenesis of cryptococcal infections. PMID- 17705845 TI - Thiamine diphosphate adenylyl transferase from E. coli: functional characterization of the enzyme synthesizing adenosine thiamine triphosphate. AB - BACKGROUND: We have recently identified a new thiamine derivative, adenosine thiamine triphosphate (AThTP), in E. coli. In intact bacteria, this nucleotide is synthesized only in the absence of a metabolizable carbon source and quickly disappears as soon as the cells receive a carbon source such as glucose. Thus, we hypothesized that AThTP may be a signal produced in response to carbon starvation. RESULTS: Here we show that, in bacterial extracts, the biosynthesis of AThTP is carried out from thiamine diphosphate (ThDP) and ADP or ATP by a soluble high molecular mass nucleotidyl transferase. We partially purified this enzyme and characterized some of its functional properties. The enzyme activity had an absolute requirement for divalent metal ions, such as Mn2+ or Mg2+, as well as for a heat-stable soluble activator present in bacterial extracts. The enzyme has a pH optimum of 6.5-7.0 and a high Km for ThDP (5 mM), suggesting that, in vivo, the rate of AThTP synthesis is proportional to the free ThDP concentration. When ADP was used as the variable substrate at a fixed ThDP concentration, a sigmoid curve was obtained, with a Hill coefficient of 2.1 and an S0.5 value of 0.08 mM. The specificity of the AThTP synthesizing enzyme with respect to nucleotide substrate is restricted to ATP/ADP, and only ThDP can serve as the second substrate of the reaction. We tentatively named this enzyme ThDP adenylyl transferase (EC 2.7.7.65). CONCLUSION: This is the first demonstration of an enzyme activity transferring a nucleotidyl group on thiamine diphosphate to produce AThTP. The existence of a mechanism for the enzymatic synthesis of this compound is in agreement with the hypothesis of a non-cofactor role for thiamine derivatives in living cells. PMID- 17705843 TI - Diagnostic stability among chronic patients with functional psychoses: an epidemiological and clinical study. AB - BACKGROUND: Diagnostic stability and illness course of chronic non-organic psychoses are complex phenomena and only few risk factors or predictors are known that can be used reliably. This study investigates the diagnostic stability during the entire course of illness in patients with non-organic psychoses and attempts to identify non-psychopathological risk factors or predictors. METHOD: 100 patients with functional psychosis were initially characterised using the Operational Criteria Checklist for Psychotic Illness and Affective Illness (OPCRIT), medical records and health registers. To study the stability of diagnoses (i.e. shifts per time), we used registry data to define four measures of diagnostic variation that were subsequently examined in relation to four possible measures of time (i.e. observation periods or hospitalisation events). Afterwards, we identified putative co-variables and predictors of the best measures of diagnostic stability. RESULTS: All four measures of diagnostic variation are very strongly associated with numbers-of-hospitalisations and less so with duration-of-illness, duration-of-hospitalisation and with year-of-first admission. The four measures of diagnostic variation corrected for numbers-of hospitalisations were therefore used to study the diagnostic stability. Conventional predictors of illness course - e.g. age-of-onset and premorbid functioning - are not significantly associated with stability. Only somatic comorbidity is significantly associated with two measures of stability, while family-history-of-psychiatric-illness and global-assessment-of-functioning (GAF) scale score show a trend. However, the traditional variables age-of-first admission, civil-status, first-diagnosis-being-schizophrenia and somatic comorbidity are able to explain two-fifth of the variation in numbers-of hospitalisations. CONCLUSION: Diagnostic stability is closely linked with the contact between patient and the healthcare system. This could very likely be due to fluctuation of disease manifestation over time or presence of co-morbid psychiatric illness in combination with rigid diagnostic criteria that are unable to capture the multiple psychopathologies of the functional psychoses that results in differential diagnoses and therefore diagnostic instability. Not surprisingly, somatic-comorbidity was found to be a predictor of diagnostic variation thereby being a non-psychiatric confounder. PMID- 17705846 TI - Extensive parallelism in protein evolution. AB - BACKGROUND: Independently evolving lineages mostly accumulate different changes, which leads to their gradual divergence. However, parallel accumulation of identical changes is also common, especially in traits with only a small number of possible states. RESULTS: We characterize parallelism in evolution of coding sequences in three four-species sets of genomes of mammals, Drosophila, and yeasts. Each such set contains two independent evolutionary paths, which we call paths I and II. An amino acid replacement which occurred along path I also occurs along path II with the probability 50-80% of that expected under selective neutrality. Thus, the per site rate of parallel evolution of proteins is several times higher than their average rate of evolution, but still lower than the rate of evolution of neutral sequences. This deficit may be caused by changes in the fitness landscape, leading to a replacement being possible along path I but not along path II. However, constant, weak selection assumed by the nearly neutral model of evolution appears to be a more likely explanation. Then, the average coefficient of selection associated with an amino acid replacement, in the units of the effective population size, must exceed approximately 0.4, and the fraction of effectively neutral replacements must be below approximately 30%. At a majority of evolvable amino acid sites, only a relatively small number of different amino acids is permitted. CONCLUSION: High, but below-neutral, rates of parallel amino acid replacements suggest that a majority of amino acid replacements that occur in evolution are subject to weak, but non-trivial, selection, as predicted by Ohta's nearly-neutral theory. PMID- 17705847 TI - Global transcription profiling reveals differential responses to chronic nitrogen stress and putative nitrogen regulatory components in Arabidopsis. AB - BACKGROUND: A large quantity of nitrogen (N) fertilizer is used for crop production to achieve high yields at a significant economic and environmental cost. Efforts have been directed to understanding the molecular basis of plant responses to N and identifying N-responsive genes in order to manipulate their expression, thus enabling plants to use N more efficiently. No studies have yet delineated these responses at the transcriptional level when plants are grown under chronic N stress and the understanding of regulatory elements involved in N response is very limited. RESULTS: To further our understanding of the response of plants to varying N levels, a growth system was developed where N was the growth-limiting factor. An Arabidopsis whole genome microarray was used to evaluate global gene expression under different N conditions. Differentially expressed genes under mild or severe chronic N stress were identified. Mild N stress triggered only a small set of genes significantly different at the transcriptional level, which are largely involved in various stress responses. Plant responses were much more pronounced under severe N stress, involving a large number of genes in many different biological processes. Differentially expressed genes were also identified in response to short- and long-term N availability increases. Putative N regulatory elements were determined along with several previously known motifs involved in the responses to N and carbon availability as well as plant stress. CONCLUSION: Differentially expressed genes identified provide additional insights into the coordination of the complex N responses of plants and the components of the N response mechanism. Putative N regulatory elements were identified to reveal possible new components of the regulatory network for plant N responses. A better understanding of the complex regulatory network for plant N responses will help lead to strategies to improve N use efficiency. PMID- 17705848 TI - Recovery of visual fields in brain-lesioned patients by reaction perimetry treatment. AB - BACKGROUND: The efficacy of treatment in hemianopic patients to restore missing vision is controversial. So far, successful techniques require laborious stimulus presentation or restrict improvements to selected visual field areas. Due to the large number of brain-damaged patients suffering from visual field defects, there is a need for an efficient automated treatment of the total visual field. METHODS: A customized treatment was developed for the reaction perimeter, permitting a time-saving adaptive-stimulus presentation under conditions of maximum attention. Twenty hemianopic patients, without visual neglect, were treated twice weekly for an average of 8.2 months starting 24.2 months after the insult. Each treatment session averaged 45 min in duration. RESULTS: In 17 out of 20 patients a significant and stable increase of the visual field size (average 11.3 degrees +/- 8.1) was observed as well as improvement of the detection rate in the defective visual field (average 18.6% +/- 13.5). A two-factor cluster analysis demonstrated that binocular treatment was in general more effective in augmenting the visual detection rate than monocular. Four out of five patients with a visual field increase larger than 10 degrees suffered from hemorrhage, whereas all seven patients with an increase of 5 degrees or less suffered from infarction. Most patients reported that visual field restoration correlated with improvement of visual-related activities of daily living. CONCLUSION: Rehabilitation treatment with the Lubeck Reaction Perimeter is a new and efficient method to restore part of the visual field in hemianopia. Since successful transfer of treatment effects to the occluded eye is achieved under monocular treatment conditions, it is hypothesized that the damaged visual cortex itself is the structure in which recovery takes place. PMID- 17705849 TI - PPARalpha L162V underlies variation in serum triglycerides and subcutaneous fat volume in young males. AB - BACKGROUND: Of the five sub-phenotypes defining metabolic syndrome, all are known to have strong genetic components (typically 50-80% of population variation). Studies defining genetic predispositions have typically focused on older populations with metabolic syndrome and/or type 2 diabetes. We hypothesized that the study of younger populations would mitigate many confounding variables, and allow us to better define genetic predisposition loci for metabolic syndrome. METHODS: We studied 610 young adult volunteers (average age 24 yrs) for metabolic syndrome markers, and volumetric MRI of upper arm muscle, bone, and fat pre- and post-unilateral resistance training. RESULTS: We found the PPARalpha L162V polymorphism to be a strong determinant of serum triglyceride levels in young White males, where carriers of the V allele showed 78% increase in triglycerides relative to L homozygotes (LL = 116 +/- 11 mg/dL, LV = 208 +/- 30 mg/dL; p = 0.004). Men with the V allele showed lower HDL (LL = 42 +/- 1 mg/dL, LV = 34 +/- 2 mg/dL; p = 0.001), but women did not. Subcutaneous fat volume was higher in males carrying the V allele, however, exercise training increased fat volume of the untrained arm in V carriers, while LL genotypes significantly decreased in fat volume (LL = -1,707 +/- 21 mm3, LV = 17,617 +/- 58 mm3 ; p = 0.002), indicating a systemic effect of the V allele on adiposity after unilateral training. Our study suggests that the primary effect of PPARalpha L162V is on serum triglycerides, with downstream effects on adiposity and response to training. CONCLUSION: Our results on association of PPARalpha and triglycerides in males showed a much larger effect of the V allele than previously reported in older and less healthy populations. Specifically, we showed the V allele to increase triglycerides by 78% (p = 0.004), and this single polymorphism accounted for 3.8% of all variation in serum triglycerides in males (p = 0.0037). PMID- 17705850 TI - The pathogen recognition sensor, NOD2, is variably expressed in patients with pulmonary tuberculosis. AB - BACKGROUND: NOD2, an intracellular pathogen recognition sensor, modulates innate defences to muropeptides derived from various bacterial species, including Mycobacterium tuberculosis (MTB). Experimentally, NOD2 attenuates two key putative mycobactericidal mechanisms. TNF-alpha synthesis is markedly reduced in MTB-antigen stimulated-mononuclear cells expressing mutant NOD2 proteins. NOD2 agonists also induce resistance to apoptosis, and may thus facilitate the survival of MTB in infected macrophages. To further define a role for NOD2 in disease pathogenesis, we analysed NOD2 transcriptional responses in pulmonary leucocytes and mononuclear cells harvested from patients with pulmonary tuberculosis (PTB). METHODS: We analysed NOD2 mRNA expression by real-time polymerase chain-reaction in alveolar lavage cells obtained from 15 patients with pulmonary tuberculosis and their matched controls. We compared NOD2 transcriptional responses, in peripheral leucocytes, before and after anti tuberculous treatment in 10 patients. In vitro, we measured NOD2 mRNA levels in MTB-antigen stimulated-mononuclear cells. RESULTS: No significant differences in NOD2 transcriptional responses were detected in patients and controls. In some patients, however, NOD2 expression was markedly increased and correlated with toll-like-receptor 2 and 4 expression. In whole blood, NOD2 mRNA levels increased significantly after completion of anti-tuberculosis treatment. NOD2 expression levels did not change significantly in mononuclear cells stimulated with mycobacterial antigens in vitro. CONCLUSION: There are no characteristic NOD2 transcriptional responses in PTB. Nonetheless, the increased levels of NOD2 expression in some patients with severe tuberculosis, and the increases in expression levels within peripheral leucocytes following treatment merit further studies in selected patient and control populations. PMID- 17705851 TI - Genetic effects on coat colour in cattle: dilution of eumelanin and phaeomelanin pigments in an F2-Backcross Charolais x Holstein population. AB - BACKGROUND: In cattle, the gene coding for the melanocortin receptor 1 (MC1R) is known to be the main regulator of the switch between the two coat colour pigments: eumelanin (black pigment) and phaeomelanin (red pigment). Some breeds, such as Charolais and Simmental, exhibit a lightening of the original pigment over the whole body. The dilution mutation in Charolais (Dc) is responsible for the white coat colour of this breed. Using an F2-Backcross Charolais x Holstein population which includes animals with both pigment backgrounds, we present a linkage mapping study of the Charolais dilution locus. RESULTS: A Charolais x Holstein crossbred population was investigated for genetic effects on coat colour dilution. Three different traits representing the dilution of the phaeomelanin, eumelanin, and non-pigment-specific dilution were defined. Highly significant genome-wide associations were detected on chromosome 5 for the three traits analysed in the marker interval [ETH10-DIK5248]. The SILV gene was examined as the strongest positional and functional candidate gene. A previously reported non synonymous mutation in exon 1 of this gene, SILV c.64A>G, was associated with the coat colour dilution phenotype in this resource population. Although some discrepancies were identified between this mutation and the dilution phenotype, no convincing recombination events were found between the SILV c.64A>G mutation and the Dc locus. Further analysis identified a region on chromosome 28 influencing the variation in pigment intensity for a given coat colour category. CONCLUSION: The present study has identified a region on bovine chromosome 5 that harbours the major locus responsible for the dilution of the eumelanin and phaeomelanin seen in Charolais crossbred cattle. In this study, no convincing evidence was found to exclude SILV c.64A>G as the causative mutation for the Charolais dilution phenotype, although other genetic effects may influence the coat colour variation in the population studied. A region on chromosome 28 influences the intensity of pigment within coat colour categories, and therefore may include a modifier of the Dc locus. A candidate gene for this effect, LYST, was identified. PMID- 17705852 TI - Physicians' attitudes about artificial feeding in older patients with severe cognitive impairment in Japan: a qualitative study. AB - BACKGROUND: The question of whether to withhold artificial nutrition and hydration (ANH) from severely cognitively impaired older adults has remained nearly unexplored in Japan, where provision of ANH is considered standard care. The objective of this study was to identify and analyze factors related to the decision to provide ANH through percutaneous endoscopic gastrostomy (PEG) in older Japanese adults with severe cognitive impairment. METHODS: Retrospective, in-depth interviews with thirty physicians experienced in the care of older, bed ridden, non-communicative patients with severe cognitive impairment. Interview content included questions about factors influencing the decision to provide or withhold ANH, concerns and dilemmas concerning ANH and the choice of PEG feeding as an ANH method. The process of data collection and analysis followed the Grounded Theory approach. RESULTS: Data analysis identified five factors that influence Japanese physicians' decision to provide ANH through PEG tubes: (1) the national health insurance system that allows elderly patients to become long-term hospital in-patients; (2) legal barriers with regard to limiting treatment, including the risk of prosecution; (3) emotional barriers, especially abhorrence of death by 'starvation'; (4) cultural values that promote family-oriented end-of life decision making; and (5) reimbursement-related factors involved in the choice of PEG. However, a small number of physicians did offer patients' families the option of withholding ANH. These physicians shared certain characteristics, such as a different perception of ANH and repeated communication with families concerning end-of-life care. These qualities were found to reduce some of the effects of the factors that favor provision of ANH. CONCLUSION: The framework of Japan's medical-legal system unintentionally provides many physicians an incentive to routinely offer ANH for this patient group through PEG tubes. It seems apparent that end-of-life education should be provided to medical providers in Japan to change the automatic assumption that ANH must be provided. PMID- 17705853 TI - Healthcare in schizophrenia: effectiveness and progress of a redesigned care network. AB - BACKGROUND: The aim of this study was designed to investigate the care effectiveness of different healthcare models for schizophrenic patients and the impact of it on caregivers. METHODS: Sample cases were randomly selected from southern Taiwan, 257 patients in redesigned care network, including a general hospital, a chronic ward, 10 outpatient clinics, and multialternative community programs, was compared to 247 patients in other traditional healthcare provider that were utilized as the control group. The quality of life (QOL) questionnaire and the Chinese health questionnaire (CHQ) were used. RESULTS: The controls had longer duration of illness (p = 0.001) and were older (p = 0.004). The average resource utilization in the study group (US$ 2737/year, per case) was higher than the control group (US$ 2041) (t = 7.91, p < 0.001). For the study group, the average length of stay was shorter, but the admission rate was higher. The QOL of the patients in the study group was better than that of the controls (p = 0.01). The family burden of the study group was lower (p = 0.035) and the score of general health questionnaire higher (p = 0.019). CONCLUSION: We found that patients in the redesigned care network had a better QOL, lower family burden, decreased days of hospital stay, higher medical resource utilization and less frequent admission to a hospital, and the caregivers had better mental health. Although the costs were higher, the continued care network was more helpful in providing comprehensive mental illness services. PMID- 17705854 TI - Characterization of novel transforming growth factor-beta type I receptors found in malignant pleural effusion tumor cells. AB - BACKGROUND: Tumors expressing a transforming growth factor-beta type I receptor (T beta RI) mutant with sequence deletions in a nine-alanine (9A) stretch of the signal peptide are reported to be highly associated with disease progression. Expression of this mutant could interfere with endogenous TGFbeta signaling in the cell. However, little is known about the importance of the remaining part of the signal peptide on the cellular function of T beta RI. RESULTS: We cloned and identified four new in-frame deletion variants of T beta RI, designated DM1 to DM4, in pleural effusion-derived tumor cells. Intriguingly, DM1 and DM2, with a small region truncated in the putative signal peptide of T beta RI, had a serious defect in their protein expression compared with that of the wild-type receptor. Using serial deletion mutagenesis, we characterized a region encoded by nucleotides 16-51 as a key element controlling T beta RI protein expression. Consistently, both DM1 and DM2 have this peptide deleted. Experiments using cycloheximde and MG132 further confirmed its indispensable role for the protein stability of T beta RI. In contrast, truncation of the 9A-stretch itself or a region downstream to the stretch barely affected T beta RI expression. However, variants lacking a region C-terminal to the stretch completely lost their capability to conduct TGFbeta-induced transcriptional activation. Intriguingly, expression of DM3 in a cell sensitive to TGFbeta made it significantly refractory to TGFbeta-mediated growth inhibition. The effect of DM3 was to ablate the apoptotic event induced by TGFbeta. CONCLUSION: We identified four new transcript variants of T beta RI in malignant effusion tumor cells and characterized two key elements controlling its protein stability and transcriptional activation. Expression of one of variants bestowed cancer cells with a growth advantage in the presence of TGFbeta. These results highlight the potential roles of some naturally occurring T beta RI variants on the promotion of tumor malignancy. PMID- 17705855 TI - FishNet: an online database of zebrafish anatomy. AB - BACKGROUND: Over the last two decades, zebrafish have been established as a genetically versatile model system for investigating many different aspects of vertebrate developmental biology. With the credentials of zebrafish as a developmental model now well recognized, the emerging new opportunity is the wider application of zebrafish biology to aspects of human disease modelling. This rapidly increasing use of zebrafish as a model for human disease has necessarily generated interest in the anatomy of later developmental phases such as the larval, juvenile, and adult stages, during which many of the key aspects of organ morphogenesis and maturation take place. Anatomical resources and references that encompass these stages are non-existent in zebrafish and there is therefore an urgent need to understand how different organ systems and anatomical structures develop throughout the life of the fish. RESULTS: To overcome this deficit we have utilized the technique of optical projection tomography to produce three-dimensional (3D) models of larval fish. In order to view and display these models we have created FishNet http://www.fishnet.org.au, an interactive reference of zebrafish anatomy spanning the range of zebrafish development from 24 h until adulthood. CONCLUSION: FishNet contains more than 36,000 images of larval zebrafish, with more than 1,500 of these being annotated. The 3D models can be manipulated on screen or virtually sectioned. This resource represents the first complete embryo to adult atlas for any species in 3D. PMID- 17705857 TI - Intensive insulin therapy in the medical ICU--not so sweet? PMID- 17705856 TI - Temporal dynamics of selective attention and conflict resolution during cross dimensional Go-NoGo decisions. AB - BACKGROUND: Decision-making is a fundamental capacity which is crucial to many higher-order psychological functions. We recorded event-related potentials (ERPs) during a visual target-identification task that required go-nogo choices. Targets were identified on the basis of cross-dimensional conjunctions of particular colors and forms. Color discriminability was manipulated in three conditions to determine the effects of color distinctiveness on component processes of decision making. RESULTS: Target identification was accompanied by the emergence of prefrontal P2a and P3b. Selection negativity (SN) revealed that target-compatible features captured attention more than target-incompatible features, suggesting that intra-dimensional attentional capture was goal-contingent. No changes of cross-dimensional selection priorities were measurable when color discriminability was altered. Peak latencies of the color-related SN provided a chronometric measure of the duration of attention-related neural processing. ERPs recorded over the frontocentral scalp (N2c, P3a) revealed that color-overlap distractors, more than form-overlap distractors, required additional late selection. The need for additional response selection induced by color-overlap distractors was severely reduced when color discriminability decreased. CONCLUSION: We propose a simple model of cross-dimensional perceptual decision making. The temporal synchrony of separate color-related and form-related choices determines whether or not distractor processing includes post-perceptual stages. ERP measures contribute to a comprehensive explanation of the temporal dynamics of component processes of perceptual decision-making. PMID- 17705858 TI - CHEK2 1100delC is prevalent in Swedish early onset familial breast cancer. AB - BACKGROUND: A truncating variant, 1100delC, in check point-kinase CHEK2, has been identified as a risk factor for familial and sporadic breast cancer. The prevalence in healthy non-breast cancer cases is low and varies between populations. METHODS: We analyzed the prevalence of CHEK2 1100delC in 763 breast cancer patients with a defined family history and 760 controls from the Stockholm region. The breast cancer patients originated from; a population-based cohort (n = 452) and from a familial cancer clinic (n = 311), the detailed family history was known in both groups. RESULTS: The variant was found in 2.9% of the familial cases from the population-based cohort and in 1.9% from the familial cancer clinic. In total 2.2% of the patients with a family history of breast cancer carried the variant compared to 0.7% of the controls (p = 0.03). There was no increased prevalence in sporadic patients (0.3%). The variant was most frequent in young familial patients (5.1% of cases /=3%). The median follow-up was 71.5 months (range, 6-138 months). The 5-year overall survival (OS) and disease free survival (DFS) rates was 84% and 74%, respectively. Lymph node involvement, tumor size more than 2 cm, high nuclear grade and estrogen receptor negativity were found to be associated with poorer DFS and OS rates. On subgroup analysis, however, the 5 year OS rate was significantly higher in the low TLI-group than in the high TLI group in patients with stage I disease (100% vs 76%, p = 0.05). CONCLUSION: Our findings suggest that the prognostic significance of TLI appears to be limited to early breast cancer that might help to distinguish patients who need more aggressive adjuvant treatment. PMID- 17705876 TI - In silico characterization of immunogenic epitopes presented by HLA-Cw*0401. AB - BACKGROUND: HLA-C locus products are poorly understood in part due to their low expression at the cell surface. Recent data indicate that these molecules serve as major restriction elements for human immunodeficiency virus type 1 (HIV-1) cytotoxic T lymphocyte (CTL) epitopes. We report here a structure-based technique for the prediction of peptides binding to Cw*0401. The models were rigorously trained, tested and validated using experimentally verified Cw*0401 binding and non-binding peptides obtained from biochemical studies. A new scoring scheme facilitates the identification of immunological hot spots within antigens, based on the sum of predicted binding energies of the top four binders within a window of 30 amino acids. RESULTS: High predictivity is achieved when tested on the training (r(2) = 0.88, s = 3.56 kJ/mol, q(2) = 0.84, s(press) = 5.18 kJ/mol) and test (A(ROC) = 0.93) datasets. Characterization of the predicted Cw*0401 binding sequences indicate that amino acids at key anchor positions share common physico chemical properties which correlate well with existing experimental studies. CONCLUSION: The analysis of predicted Cw*0401-binding peptides showed that anchor residues may not be restrictive and the Cw*0401 binding pockets may possibly accommodate a wide variety of peptides with common physico-chemical properties. The potential Cw*0401-specific T-cell epitope repertoires for HIV-1 p24(gag) and gp160(gag) glycoproteins are well distributed throughout both glycoproteins, with thirteen and nine immunological hot spots for HIV-1 p24(gag) and gp160(gag) glycoproteins respectively. These findings provide new insights into HLA-C peptide selectivity, indicating that pre-selection of candidate HLA-C peptides may occur at the TAP level, prior to peptide loading in the endoplasmic reticulum. PMID- 17705878 TI - Nasogastric tube incidents and the use of the 'whoosh test'. PMID- 17705877 TI - An integrative in silico approach for discovering candidates for drug-targetable protein-protein interactions in interactome data. AB - BACKGROUND: Protein-protein interactions (PPIs) are challenging but attractive targets for small chemical drugs. Whole PPIs, called the 'interactome', have been emerged in several organisms, including human, based on the recent development of high-throughput screening (HTS) technologies. Individual PPIs have been targeted by small drug-like chemicals (SDCs), however, interactome data have not been fully utilized for exploring drug targets due to the lack of comprehensive methodology for utilizing these data. Here we propose an integrative in silico approach for discovering candidates for drug-targetable PPIs in interactome data. RESULTS: Our novel in silico screening system comprises three independent assessment procedures: i) detection of protein domains responsible for PPIs, ii) finding SDC-binding pockets on protein surfaces, and iii) evaluating similarities in the assignment of Gene Ontology (GO) terms between specific partner proteins. We discovered six candidates for drug-targetable PPIs by applying our in silico approach to original human PPI data composed of 770 binary interactions produced by our HTS yeast two-hybrid (HTS-Y2H) assays. Among them, we further examined two candidates, RXRA/NRIP1 and CDK2/CDKN1A, with respect to their biological roles, PPI network around each candidate, and tertiary structures of the interacting domains. CONCLUSION: An integrative in silico approach for discovering candidates for drug-targetable PPIs was applied to original human PPIs data. The system excludes false positive interactions and selects reliable PPIs as drug targets. Its effectiveness was demonstrated by the discovery of the six promising candidate target PPIs. Inhibition or stabilization of the two interactions may have potential therapeutic effects against human diseases. PMID- 17705879 TI - Corticosteroids to prevent postextubation upper airway obstruction: the evidence mounts. AB - Intubation of the airway can lead to laryngotracheal injury, resulting in extubation failure from upper airway obstruction (UAO). A number of factors can help to identify patients who are at greatest risk for postextubation UAO. Three randomized controlled trials demonstrate that prophylactic corticosteroids decrease the risk for postextubation UAO and probably the need for re-intubation. PMID- 17705881 TI - Inflammation and breast cancer. Inflammatory component of mammary carcinogenesis in ErbB2 transgenic mice. AB - This review addresses genes differentially expressed in the mammary gland transcriptome during the progression of mammary carcinogenesis in BALB/c mice that are transgenic for the rat neu (ERBB2, or HER-2/neu) oncogene (BALB-neuT664V E mice). The Ingenuity knowledge database was used to characterize four functional association networks whose hub genes are directly linked to inflammation (specifically, the genes encoding IL-1beta, tumour necrosis factor, interferon-gamma, and monocyte chemoattractant protein-1/CC chemokine ligand-2) and are increasingly expressed during such progression. In silico meta-analysis in a human breast cancer dataset suggests that proinflammatory activation in the mammary glands of these mice reflects a general pattern of human breast cancer. PMID- 17705880 TI - Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. AB - Recent insights into the molecular and cellular mechanisms underlying cancer development have revealed that immune cells functionally regulate epithelial cancer development and progression. Moreover, accumulated clinical and experimental data indicate that the outcome of an immune response toward an evolving breast neoplasm is largely determined by the type of immune response elicited. Acute tumor-directed immune responses involving cytolytic T lymphocytes appear to protect against tumor development, whereas immune responses involving chronic activation of humoral immunity, infiltration by Th2 cells, and protumor polarized innate inflammatory cells result in the promotion of tumor development and disease progression. Herein we review this body of literature and summarize important new findings revealing the paradoxical role of innate and adaptive leukocytes as regulators of breast carcinogenesis. PMID- 17705882 TI - Amping up estrogen receptors in breast cancer. AB - This article highlights a recent study by Holst et al. in Nature Genetics that finds estrogen receptor-alpha (ER-alpha) amplification in early benign lesions and more advanced invasive carcinomas of the breast, and discusses the potential implications to our present understanding of the role of ER-alpha in breast tumorigenesis. PMID- 17705884 TI - Powell's Pearls: John Braxton Hicks, MD (1823-1897). PMID- 17705885 TI - Female reproductive issues following bariatric surgery. AB - One in 3 adult American women is obese. Almost half of the approximately 100,000 bariatric surgeries performed in 2004 were on reproductive-aged women. Anatomic and physiologic changes resulting from such surgery may have significant clinical implications for preconception, pregnancy, and postpartum care. This review summarizes these issues and the available related literature, and offers guidelines for care of these patients. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to recall that bariatric surgery has many anatomic and physiologic changes that potentially will affect future pregnancies, and state that attention to these physiologic changes and attention to potential nutritional deficiencies significantly improves the chances of a good pregnancy outcome. PMID- 17705886 TI - Periodontal disease and pregnancy outcomes: state-of-the-science. AB - To examine the existing evidence on the relationship between periodontal disease and adverse pregnancy outcomes, we conducted a systematic review of studies published up to December 2006. Studies published in full text were identified by searching computerized databases (e.g., MEDLINE, EMBASE). A meta-analysis was performed to pool the effect size of the clinical trials. Forty-four studies were identified (26 case-control studies, 13 cohort studies, and 5 controlled trials). The studies focused on preterm low birth weight, low birth weight, preterm birth, birth weight by gestational age, miscarriage or pregnancy loss, preeclampsia, and gestational diabetes mellitus. Of the chosen studies, 29 suggested an association between periodontal disease and increased risk of adverse pregnancy outcome (odds ratios [ORs] ranging from 1.10 to 20.0) and 15 found no evidence of an association (ORs ranging from 0.78 to 2.54). A meta-analysis of the clinical trials suggested that oral prophylaxis and periodontal treatment may reduce the rate of preterm low birth weight (pooled risk ratio (RR): 0.53, 95% confidence interval [CI]: 0.30-0.95, P < 0.05), but did not significantly reduce the rates of preterm birth (pooled RR: 0.79, 95% CI: 0.55-1.11, P > 0.05) or low birth weight (pooled RR: 0.86, 95% CI: 0.58%1.29, P > 0.05). The authors conclude that periodontal disease may be associated with increased risk of adverse pregnancy outcomes. More methodologically rigorous studies are needed in this field. Currently, there is insufficient evidence to support the provision of periodontal treatment during pregnancy for the purpose of reducing adverse pregnancy outcomes. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to state that the published literature is not vigorous to clinically link periodontal disease and/or its treatment to specific adverse pregnancy outcomes, and explain that more rigorous studies with world-wide agreed-upon definitions are particularly needed before periodontal disease treatment can be recommended. PMID- 17705887 TI - Endometriosis and genetic polymorphisms. AB - Endometriosis is a benign gynecological disease with an unclear pathophysiology characterized by ectopic endometrium causing endometrium-like inflammatory lesions outside the uterine cavity. Recently, a number of studies have investigated genetic polymorphisms as a possible factor contributing to the development of endometriosis. In this review, we have summarized current data regarding genes with nucleotide polymorphisms investigated with regard to endometriosis. We searched PubMed for publications on endometriosis and polymorphism and found 108 publications between January 1979 and September 2005. These were classified according to the type of genetic polymorphism investigated and whether the result favored or did not favor association with endometriosis. We found a strikingly large amount of conflicting results. About 50% of the reviewed studies demonstrated positive correlations between different polymorphisms and endometriosis. This relation is most clearly seen in groups 1 (cytokines and inflammation), 2 (steroid-synthesizing enzymes and detoxifying enzymes and receptors), 4 (estradiol metabolism), 5 (other enzymes and metabolic systems), and 7 (adhesion molecules and matrix enzymes). Group 8 (apoptosis, cellcycle regulation, and oncogenes) seemed to be negatively correlated with the disease, whereas group 3 (hormone receptors), 6 (growth factor systems), and especially 9 (human leukocyte antigen system components) showed a relatively strong correlation. The review indicates that polymorphisms may have a limited value in assessing possible development of endometriosis. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to recall the complexity of attempting to link endometriosis to single nucleotide polymorphisms (SNPs), explain that the literature is varied on results and recommendations and is population specific, and state that there are some SNP relationships that are clinically stronger than others. PMID- 17705883 TI - Clinical review: Prevention and therapy of vasospasm in subarachnoid hemorrhage. AB - Vasospasm is one of the leading causes of morbidity and mortality following aneurysmal subarachnoid hemorrhage (SAH). Radiographic vasospasm usually develops between 5 and 15 days after the initial hemorrhage, and is associated with clinically apparent delayed ischemic neurological deficits (DID) in one-third of patients. The pathophysiology of this reversible vasculopathy is not fully understood but appears to involve structural changes and biochemical alterations at the levels of the vascular endothelium and smooth muscle cells. Blood in the subarachnoid space is believed to trigger these changes. In addition, cerebral perfusion may be concurrently impaired by hypovolemia and impaired cerebral autoregulatory function. The combined effects of these processes can lead to reduction in cerebral blood flow so severe as to cause ischemia leading to infarction. Diagnosis is made by some combination of clinical, cerebral angiographic, and transcranial doppler ultrasonographic factors. Nimodipine, a calcium channel antagonist, is so far the only available therapy with proven benefit for reducing the impact of DID. Aggressive therapy combining hemodynamic augmentation, transluminal balloon angioplasty, and intra-arterial infusion of vasodilator drugs is, to varying degrees, usually implemented. A panoply of drugs, with different mechanisms of action, has been studied in SAH related vasospasm. Currently, the most promising are magnesium sulfate, 3-hydroxy-3 methylglutaryl-CoA reductase inhibitors, nitric oxide donors and endothelin-1 antagonists. This paper reviews established and emerging therapies for vasospasm. PMID- 17705888 TI - Diagnosis, management and prevention of ventilator-associated pneumonia in the UK. AB - BACKGROUND AND OBJECTIVE: Ventilator-associated pneumonia is a nosocomial infection that occurs in patients receiving mechanical ventilation for >48 h. Many aspects of its diagnosis, treatment and management are controversial. We used a postal questionnaire to survey current practice within the UK. METHODS: Questionnaire study of 207 general intensive care units in the UK. RESULTS: The response rate was 77.3%. Regarding diagnosis, 30% of units obtained specimens from the lungs invasively, while the remainder relied on tracheal aspirates. In only 28.2% of units using tracheal aspirates were results reported in a quantitative manner. A clinical suspicion of ventilator-associated pneumonia would lead to the administration of empirical antibiotic therapy in the majority of units (77.2%), opinion being almost equally divided on whether this should be mono (49.1%) or combination therapy (50.9%). Although most units received regular microbiology feedback (90.5%), the involvement of a microbiologist in the antibiotic decision-making process was variable. Antibiotics were continued for a median of 7 days (inter-quartile range 5-8.5, range 2-14 days). Compliance with the principal methods of ventilator-associated pneumonia prevention was good. CONCLUSION: There is widespread variation in the methods used for the diagnosis of ventilator-associated pneumonia within the UK. The majority of units rely on non-quantitative analysis of tracheal aspirates. This technique has a high percentage of false-positives, and suggests widespread over utilization of antibiotics. However, most agree that antibiotics should be given empirically when there is a clinical suspicion of ventilator-associated pneumonia. The widespread introduction of 'ventilator bundles' appears to have ensured that most units actively take measures to prevent ventilator-associated pneumonia. PMID- 17705889 TI - Dietary arachidonic acid: harmful, harmless or helpful? PMID- 17705890 TI - Plant sterols beyond low-density lipoprotein-cholesterol. PMID- 17705891 TI - Dietary, physiological, genetic and pathological influences on postprandial lipid metabolism. AB - Most of diurnal time is spent in a postprandial state due to successive meal intakes during the day. As long as the meals contain enough fat, a transient increase in triacylglycerolaemia and a change in lipoprotein pattern occurs. The extent and kinetics of such postprandial changes are highly variable and are modulated by numerous factors. This review focuses on factors affecting postprandial lipoprotein metabolism and genes, their variability and their relationship with intermediate phenotypes and risk of CHD. Postprandial lipoprotein metabolism is modulated by background dietary pattern as well as meal composition (fat amount and type, carbohydrate, protein, fibre, alcohol) and several lifestyle conditions (physical activity, tobacco use), physiological factors (age, gender, menopausal status) and pathological conditions (obesity, insulin resistance, diabetes mellitus). The roles of many genes have been explored in order to establish the possible implications of their variability in lipid metabolism and CHD risk. The postprandial lipid response has been shown to be modified by polymorphisms within the genes for apo A-I, A-IV, A-V, E, B, C-I and C-III, lipoprotein lipase, hepatic lipase, fatty acid binding and transport proteins, microsomal triglyceride transfer protein and scavenger receptor class B type I. Overall, the variability in postprandial response is important and complex, and the interactions between nutrients or dietary or meal compositions and gene variants need further investigation. The extent of present knowledge and needs for future studies are discussed in light of ongoing developments in nutrigenetics. PMID- 17705892 TI - Consumer understanding of nutrition and health claims: sources of evidence. AB - Provided that they are scientifically substantiated, nutrition and health (NH) claims linked to food products can help consumers make well-informed food choices. The new European legislation on NH claims made on foods entered into force on 19 January 2007. The law sets out conditions for their use, establishes a system for their scientific evaluation, and will create European lists of authorised claims. An important aspect of this proposed legislation is that it states, in article 5.2, 'the use of nutrition and health claims shall only be permitted if the average consumer can be expected to understand the beneficial effects expressed in the claim'. The present review examines consumer understanding of NH claims from a consumer science perspective. It focuses on the type of data and information that could be needed to provide evidence that the average consumer adequately understands a particular NH claim. After exploring several different methodologies, it proposes a case-specific approach using a stepwise procedure for assessing consumer understanding of a NH claim. PMID- 17705893 TI - Expression of circadian clock genes in retinal dopaminergic cells. AB - The mammalian neural retina contains single or multiple intrinsic circadian oscillators that can be directly entrained by light cycles. Dopaminergic amacrine (DA) cells represent an especially interesting candidate as a site of the retinal oscillator because of the crucial role of dopamine in light adaptation, and the widespread distribution of dopamine receptors in the retina. We hereby show by single-cell, end-point RT-PCR that retinal DA cells contain the transcripts for six core components of the circadian clock: Bmal1, Clock, Cry1, Cry2, Per1, and Per2. Rod photoreceptors represented a negative control, because they did not appear to contain clock transcripts. We finally confirmed that DA cells contain the protein encoded by the Bmal1 gene by comparing immunostaining of the nuclei of DA cells in the retinas of wildtype and Bmal1-/- mice. It is therefore likely that DA cells contain a circadian clock that anticipates predictable variations in retinal illumination. PMID- 17705894 TI - Benign schwannoma in paranasal sinuses: a clinico-pathological study of five cases, emphasising diagnostic difficulties. AB - OBJECTIVES: To highlight the difficulty in making a correct diagnosis of benign schwannoma in the paranasal region, to raise awareness of this rare condition, and to suggest the most appropriate treatment. METHOD: Retrieval of cases retrospectively from archives of the histopathology department of a major UK cancer centre with central review of all cases. RESULTS: Five cases were identified since 1990 and clinical and pathological features are summarised. Median follow up of patients was 8.1 years. Radiological appearances of local bone invasion and histological features of tumour unencapsulation and hypercellularity could give the mistaken impression of malignant disease and lead to unnecessary over-treatment. CONCLUSION: Central pathological review and clinical awareness is required. Although local recurrence can occur, the prognosis is excellent. The treatment of choice is local excision. Radiotherapy can be considered, but in most cases it would incur unnecessary morbidity. PMID- 17705895 TI - Relationship between tuberculous otomastoiditis and tuberculous meningitis. AB - OBJECTIVE: The aim of this study was to determine the correlation between tuberculous meningitis and tuberculous otomastoiditis. MATERIALS AND METHODS: Meningeal involvement sites were investigated by magnetic resonance imaging in 32 patients (21 males, 11 females) who had previously been diagnosed with tuberculous meningitis. Clinical and laboratory findings and responses to anti tuberculous treatment were evaluated, and the presence of concomitant tuberculous otomastoiditis was also investigated. RESULTS: The meningeal involvement site was unilateral (in the sylvian fissure and the perimesencephalic cistern) in 28 patients (87.5 per cent), and bilateral and widespread in four patients (12.5 per cent). Tuberculous otomastoiditis was found in 11 of the patients with tuberculous meningitis (34.3 per cent). Otomastoiditis was on the same side as the meningeal involvement in nine of these 11 patients. Bilateral otomastoiditis with meningeal involvement was observed in two patients. CONCLUSIONS: Tuberculous meningitis is frequently accompanied by otomastoiditis, although the exact causal relationship between the two conditions is unclear. Since meningitis is a serious clinical condition, concomitant otomastoiditis generally remains unrecognised. Tuberculosis should be considered in the differential diagnosis of patients with otitis or otomastoiditis who do not respond to antibiotic therapy. PMID- 17705896 TI - Sensitive, stimulating caregiving predicts cognitive and behavioral resilience in neurodevelopmentally at-risk infants. AB - Although neurodevelopmental impairment is a risk factor for poor cognitive and behavioral outcomes, associations between early and later functioning are only moderate in magnitude, and it is likely that other factors intervene to modify this trajectory. The current study tested the hypothesis that sensitive, stimulating caregiving would promote positive behavioral and cognitive outcomes among children who were at risk based on the results of a neurodevelopmental screener and a temperament inventory. The sample comprised 1,720 infants and toddlers from the National Survey of Child and Adolescent Well-Being, a longitudinal study of children who were involved with child welfare services. Children were first assessed between 3 and 24 months of age and subsequently 18 months later. Children who experienced improvements in the amount of sensitive, stimulating caregiving they received had positive cognitive and behavioral outcomes 18 months later, despite early levels of neurodevelopmental risk. The association between changes in caregiving quality and changes in children's functioning was stronger for children who were removed from the care of their biological parents before the follow-up assessment than for children who remained in the care of biological parents, suggesting a causal role for caregiving quality on children's outcomes. PMID- 17705897 TI - Vagal tone as a resilience factor in children with prenatal cocaine exposure. AB - Studies have investigated the potential effects of prenatal cocaine exposure (CE) on children's development. However, few studies have examined predictors of resilient outcomes in this population. We examined vagal tone (VT) as a resilience factor in prenatal CE. Utilizing data from the Maternal Lifestyle Study, a cumulative risk index was derived for children with and without prenatal CE. Presence of CE and other prenatal drugs was summed with postnatal risks in infancy to yield a 15-item risk index. Preschool cognitive outcomes, problem behaviors, and adaptive behaviors were measured. VT was assessed during an infant exam at 1 month and toy exploration at 36 months. We included children with complete physiologic data (217 CE, 333 non-CE). Children were classified as having consistently high, consistently low, or fluctuating VT at 1 and 36 months. Children were also classified as high versus low risk. High-risk children had lower IQ scores, more problem behaviors, and lower ratings of adaptive behaviors than low-risk children. A significant risk by VT-stability interaction indicated that for high-risk children, those with stable low VT had higher ratings of adaptive behaviors at 36 months. This is consistent with theory linking reduced VT during tasks to adaptive regulation and indicates that such regulatory functioning may serve as a protective factor in prenatal CE. PMID- 17705898 TI - Biological, behavioral, and relational levels of resilience in the context of risk for early childhood behavior problems. AB - Longitudinal growth patterns of internalizing and externalizing behavior problems were examined in a community sample of 441 children across the ages of 2 to 5 using hierarchical linear modeling. Contextual risk was measured using five indicators (socioeconomic status, marital status, number of siblings, parent stress, parent psychopathology), and three levels of child resilience (biological, behavioral, and relational) were also assessed. Results indicate that a general pattern of decline in both types of behavior problems was observed for the entire sample across time, although considerable individual variability in this pattern was observed. Children's externalizing and internalizing behavior at age 5 was predicted by the level of risk at age 2. All three child resilience factors were also predictive of externalizing and internalizing behaviors at age 5. In the prediction of the slope of problem behavior over time, risk status interacted with both temperamental fearlessness and a mutually responsive orientation with the mother to predict the decline in externalizing and internalizing problem behavior. Results underscore the complex interactions of risk and multiple levels of resilience that are implicated in the maintenance of problem behavior over time. They highlight the importance of considering whether expected resilience factors operate similarly across different levels of risk. PMID- 17705900 TI - Behavioral inhibition and anxiety disorders: multiple levels of a resilience process. AB - Behavioral inhibition is reported to be one of the most stable temperamental characteristics in childhood. However, there is also evidence for discontinuity of this trait, with infants and toddlers who were extremely inhibited displaying less withdrawn social behavior as school-age children or adolescents. There are many possible explanations for the discontinuity in this temperament over time. They include the development of adaptive attention and regulatory skills, the influence of particular styles of parenting or caregiving contexts, and individual characteristics of the child such as their level of approach withdrawal motivation or their gender. These discontinuous trajectories of behaviorally inhibited children and the factors that form them are discussed as examples of the resilience process. PMID- 17705901 TI - Risk factors and resilience in the developing world: one of many lessons to learn. AB - This article summarizes the results of an intervention study with approximately 4,000 Zambian children, in which risk of helminth infection and related health problems were ameliorated with medication and micronutrient and vitamin supplementation. The results of this intervention were tracked with a newly developed cognitive assessment battery for Zambian school children in Grades 3-7. The quantification of cognitive functioning manifested after the intervention indicated treatment-related improvements in the cognitive skill of following instructions. This skill is fundamental to success in school. It constitutes an important indicator of resilience in overcoming difficulties related to growing up and being educated under the pressure of the multiple risk factors characteristic of the developing world. PMID- 17705899 TI - Familial and temperamental predictors of resilience in children at risk for conduct disorder and depression. AB - In this study, we evaluated predictors of resilience among 8- to 12-year-old children recruited from primarily low socioeconomic status neighborhoods, 117 of whom suffered from clinical levels of conduct problems and/or depression, and 63 of whom suffered from no significant symptoms. Tests of interactions were conducted between (a) paternal antisocial behavior and maternal depression and (b) several physiological indices of child temperament and emotionality in predicting (c) children's conduct problems and depression. Both internalizing and externalizing outcomes among children were associated specifically with maternal melancholic depression, and not with nonmelancholic depression. In addition, low levels of respiratory sinus arrhythmia (RSA) among children conferred significant risk for depression, regardless of maternal melancholia, whereas high RSA offered partial protection. Furthermore, high levels of maternal melancholia conferred significant risk for child depression, regardless of paternal antisocial behavior, whereas low levels of maternal melancholia offered partial protection. Finally, low levels of electrodermal responding (EDR) conferred significant risk for conduct problems, regardless of paternal antisocial behavior, whereas high EDR offered partial protection. None of the identified protective factors offered complete immunity from psychopathology. These findings underscore the complexity of resilience and resilience-related processes, and suggest several potential avenues for future longitudinal research. PMID- 17705902 TI - Genotype and neuropsychological response inhibition as resilience promoters for attention-deficit/hyperactivity disorder, oppositional defiant disorder, and conduct disorder under conditions of psychosocial adversity. AB - Whereas child personality, IQ, and family factors have been identified as enabling a resilient response to psychosocial adversity, more direct biological resilience factors have been less well delineated. This is particularly so for child attention-deficit/hyperactivity disorder (ADHD), which has received less attention from a resilience perspective than have associated externalizing disorders. Children from two independent samples were classified as resilient if they avoided developing ADHD, oppositional defiant disorder (ODD), or conduct disorder (CD) in the face of family adversity. Two protective factors were examined for their potential relevance to prefrontal brain development: neuropsychological response inhibition, as assessed by the Stop task, and a composite catecholamine genotype risk score. Resilient children were characterized in both samples by more effective response inhibition, although the effect in the second sample was very small. Genotype was measured in Sample 1, and a composite high risk genotype index was developed by summing presence of risk across markers on three genes expressed in prefrontal cortex: dopamine transporter, dopamine D4 receptor, and noradrenergic alpha-2 receptor. Genotype was a reliable resilience indicator against development of ADHD and CD, but not ODD, in the face of psychosocial adversity. Results illustrate potential neurobiological protective factors related to development of prefrontal cortex that may enable children to avoid developing ADHD and CD in the presence of psychosocial adversity. PMID- 17705904 TI - Emotion and resilience: a multilevel investigation of hemispheric electroencephalogram asymmetry and emotion regulation in maltreated and nonmaltreated children. AB - The current study was a multilevel investigation of resilience, emotion regulation, and hemispheric electroencephalogram (EEG) asymmetry in a sample of maltreated and nonmaltreated school age children. It was predicted that the positive emotionality and increased emotion regulatory ability associated with resilient functioning would be associated with relatively greater left frontal EEG activity. The study also investigated differences in pathways to resilience between maltreated and nonmaltreated children. The findings indicated that EEG asymmetry across central cortical regions distinguished between resilient and nonresilient children, with greater left hemisphere activity characterizing those who were resilient. In addition, nonmaltreated children showed greater left hemisphere EEG activity across parietal cortical regions. There was also a significant interaction between resilience, maltreatment status, and gender for asymmetry at anterior frontal electrodes, where nonmaltreated resilient females had greater relative left frontal activity compared to more right frontal activity exhibited by resilient maltreated females. An observational measure of emotion regulation significantly contributed to the prediction of resilience in the maltreated and nonmaltreated children, but EEG asymmetry in central cortical regions independently predicted resilience only in the maltreated group. The findings are discussed in terms of their meaning for the development of resilient functioning. PMID- 17705903 TI - Personality, adrenal steroid hormones, and resilience in maltreated children: a multilevel perspective. AB - In this multilevel investigation, resilience in adaptive functioning among maltreated and nonmaltreated low-income children (N = 677) was examined in relation to the regulation of two stress-responsive adrenal steroid hormones, cortisol and dehydroepiandrosterone (DHEA), as well as the personality constructs of ego resiliency and ego control. Maltreatment status was not related to differences in average levels of morning or afternoon cortisol or DHEA. However, lower morning cortisol was related to higher resilient functioning, but only in nonmaltreated children. In contrast, among physically abused children, high morning cortisol was related to higher resilient functioning. Morning and afternoon DHEA was negatively related to resilient functioning. Although diurnal change in cortisol was not related to resilience, for DHEA, maltreated children with high resilience showed an atypical rise in DHEA from morning to afternoon. Morning and afternoon cortisol/DHEA ratios were positively related to resilient functioning, but did not interact with maltreatment status. Ego resiliency and ego control strongly differentiated maltreated and nonmaltreated children, and the personality variables were substantially predictive of resilience. When considered together, demonstrated effects of personality, cortisol, and DHEA maintained independent contributions in predicting resilience among high-risk youth. PMID- 17705905 TI - Resilience among children and adolescents at risk for depression: Mediation and moderation across social and neurobiological contexts. AB - This article offers a multilevel perspective on resilience to depression, with a focus on interactions among social and neurobehavioral systems involved in emotional reactivity and regulation. We discuss models of cross-contextual mediation and moderation by which the social context influences or modifies the effects of resilience processes at the biological level, or the biological context influences or modifies the effects of resilience processes at the social level. We highlight the socialization of emotion regulation as a candidate process contributing to resilience against depression at the social context level. We discuss several factors and their interactions across levels-including genetic factors, stress reactivity, positive affect, neural systems of reward, and sleep-as candidate processes contributing to resilience against depression at the neurobehavioral level. We then present some preliminary supportive findings from two studies of children and adolescents at high risk for depression. Study 1 shows that elevated neighborhood level adversity has the potential to constrain or limit the benefits of protective factors at other levels. Study 2 indicates that ease and quickness in falling asleep and a greater amount of time in deep Stage 4 sleep may be protective against the development of depressive disorders for children. The paper concludes with a discussion of clinical implications of this approach. PMID- 17705906 TI - Do cognitive, physiological, and psychosocial risk and promotive factors predict desistance from delinquency in males? AB - Relatively few studies have examined cognitive, physiological, and psychosocial promotive and risk factors that can be linked to desistance from delinquency in community samples. This paper reports on a sample of boys first studied at age 7 and then followed up yearly to age 20. Around age 16, most of the boys received a range of cognitive tests; at that time, information regarding their resting heart rate and skin conductance activity in response to aversive stimuli was also collected. Several psychosocial and two cognitive measures distinguished delinquents from nondelinquents around age 16. Among the promotive factors associated with low delinquency were good housing quality, low community crime (parent and youth report), verbal IQ, delayed verbal memory, and sustained attention. Predictive analyses discriminating between desisters and persisters in delinquency between ages 17 and 20 showed that all of the significant predictors were either child or peer risk factors. None of the cognitive, physiological, parenting, or community factors significantly predicted desistance from delinquency. In addition, no promotive factors were significantly related to desistance. The final set of analyses compared persisters, desisters, and nondelinquents in terms of their adult adjustment. Desisters were similar to persisters in that desisters continued to display serious problems in anxiety, failure to graduate from high school, no post high school education, being a nonstudent and unemployed, daily cigarette use, and weekly marijuana use. Desisters scored low on depression and weekly heavy drinking and in these respects were indistinguishable from nondelinquents and better off than persisters. PMID- 17705907 TI - Psychobiological mechanisms of resilience: relevance to prevention and treatment of stress-related psychopathology. AB - Resilience refers to the ability to successfully adapt to stressors, maintaining psychological well-being in the face of adversity. Recent years have seen a great deal of research into the neurobiological and psychological factors and mechanisms that characterize resilient individuals. This article draws from that research to outline some of the most important contributors to resilience. The authors hope that by contributing to a growing understanding of the genetic, developmental, neurobiological, and psychological underpinnings of resilience, researchers and clinicians in the field will move closer toward the goal of identifying and treating individuals at risk for developing posttraumatic psychopathology. PMID- 17705908 TI - Resilience in developing systems: progress and promise as the fourth wave rises. AB - Perspectives based on the first three waves of resilience research are discussed with the goal of informing the fourth wave of work, which is characterized by a focus on multilevel analysis and the dynamics of adaptation and change. Resilience is defined as a broad systems construct, referring to the capacity of dynamic systems to withstand or recover from significant disturbances. As the systems perspective on resilience builds strength and technologies of measuring and analyzing multiple levels of functioning and their interactions improve, it is becoming feasible to study gene-environment interactions, the development of adaptive systems and their role in resilience, and to conduct experiments to foster resilience or reprogram the fundamental adaptive systems that protect development in the context of adversity. Hot spots for future research to study and integrate multiple levels of analysis are delineated on the basis of evidence gleaned from the first waves of resilience research. PMID- 17705910 TI - Somatosensory processes subserving perception and action. AB - The functions of the somatosensory system are multiple. We use tactile input to localize and experience the various qualities of touch, and proprioceptive information to determine the position of different parts of the body with respect to each other, which provides fundamental information for action. Further, tactile exploration of the characteristics of external objects can result in conscious perceptual experience and stimulus or object recognition. Neuroanatomical studies suggest parallel processing as well as serial processing within the cerebral somatosensory system that reflect these separate functions, with one processing stream terminating in the posterior parietal cortex (PPC), and the other terminating in the insula. We suggest that, analogously to the organisation of the visual system, somatosensory processing for the guidance of action can be dissociated from the processing that leads to perception and memory. In addition, we find a second division between tactile information processing about external targets in service of object recognition and tactile information processing related to the body itself. We suggest the posterior parietal cortex subserves both perception and action, whereas the insula principally subserves perceptual recognition and learning. PMID- 17705909 TI - Maximizing resilience through diverse levels of inquiry: Prevailing paradigms, possibilities, and priorities for the future. AB - The study of resilience has two core characteristics: it is fundamentally applied in nature, seeking to use scientific knowledge to maximize well-being among those at risk, and it draws on expertise from diverse scientific disciplines. Recent advances in biological processes have confirmed the profound deleterious effects of harsh caregiving environments, thereby underscoring the importance of early interventions. What remains to be established at this time is the degree to which insights on particular biological processes (e.g., involving specific brain regions, genes, or hormones) will be applied in the near future to achieve substantial reductions in mental health disparities. Aside from biology, resilience developmental researchers would do well to draw upon relevant evidence from other behavioral sciences as well, notably anthropology as well as family, counseling, and social psychology. Scientists working with adults and with children must remain vigilant to the advances and missteps in each others' work, always ensuring caution in conveying messages about the "innateness" of resilience or its prevalence across different subgroups. Our future research agenda must prioritize reducing abuse and neglect in close relationships; deriving the "critical ingredients" in effective interventions and going to scale with these; working collaboratively to refine theory on the construct; and responsibly, proactively disseminating what we have learned about the nature, limits, and antecedents of resilient adaptation across diverse at-risk groups. PMID- 17705936 TI - Automatic contrast: evidence that automatic comparison with the social self affects evaluative responses. AB - The aim of the present research was to investigate whether unconsciously presented affective information may cause opposite evaluative responses depending on what social category the information originates from. We argue that automatic comparison processes between the self and the unconscious affective information produce this evaluative contrast effect. Consistent with research on automatic behaviour, we propose that when an intergroup context is activated, an automatic comparison to the social self may determine the automatic evaluative responses, at least for highly visible categories (e.g. sex, ethnicity). Contrary to previous research on evaluative priming, we predict automatic contrastive responses to affective information originating from an outgroup category such that the evaluative response to neutral targets is opposite to the valence of the suboptimal primes. Two studies using different intergroup contexts provide support for our hypotheses. PMID- 17705937 TI - A classification of handedness using the Annett Hand Preference Questionnaire. AB - The Annett Hand Preference Questionnaire (AHPQ) was administered to a sample of 352 randomly selected individuals from the general community to examine the reproducibility of its handedness classification and to evaluate its model-based reliability and convergent validity. Latent class analysis showed that the eight categories of hand preferences could not be justified on statistical grounds. Instead, three broad handedness classes adequately accommodated the variety of handedness patterns: 'consistent right' (66.0%), 'consistent left' (9.8%) and 'inconsistent or mixed' (24.2%). Confirmatory factor analysis not only showed that the AHPQ is reliable and has solid convergent validity, but also the measurement properties of the AHPQ could be further improved by eliminating a few items from the scale. The implications of these findings are discussed, and it is suggested that questionnaire requires modification, possibly by replacing obsolete items such as 'sweeping' and 'shovelling' with modern manual activities, such as 'typing SMS messages' and 'using a remote control'. PMID- 17705938 TI - Children's recognition of time in the causes and cures of physical and emotional reactions to illnesses and injuries. AB - The present set of studies examined children's and college students' recognition of the role of time in the manifestation of causes and cures for illnesses and injuries. In Study 1, participants ranging from 4-year-olds through college students were presented with biological, moral, psychological, and irrelevant causes for illness symptoms and were asked how much time elapsed between the cause and the symptom. They were also asked if medicine would make the person feel better and if so how much time elapsed between taking the medicine and feeling better. Study 2 replicated Study 1 with 4- and 5-year-olds. Study 3 examined whether 4- and 5-year-olds and college students could differentiate between physical and emotional reactions to illnesses and injuries, with regard to time course. Overall, young children underestimate how long it takes for illness symptoms to emerge (expecting them to result right away following exposure to contamination). Nonetheless, children generated longer timelines for biological cures than biological causes. Moreover, 4- and 5-year-olds expect physical and emotional reactions to follow different time courses. These results suggest that young children have a nascent expectation that biological events are distinct from non-biological events, in how they unfold over time. PMID- 17705939 TI - The role of effort in influencing the effect of anxiety on performance: testing the conflicting predictions of processing efficiency theory and the conscious processing hypothesis. AB - The aim of this study was to test the conflicting predictions of processing efficiency theory (PET) and the conscious processing hypothesis (CPH) regarding effort's role in influencing the effects of anxiety on a golf putting task. Mid handicap golfers made a series of putts to target holes under two counterbalanced conditions designed to manipulate the level of anxiety experienced. The effort exerted on each putting task was assessed though self-report, psychophysiological (heart rate variability) and behavioural (pre-putt time and glances at the target) measures. Performance was assessed by putting error. Results were generally more supportive of the predictions of PET rather than the CPH as performance was maintained for some performers despite increased state anxiety and a reduction in processing efficiency. The findings of this study support previous research suggesting that both theories offer useful theoretical frameworks for examining the relationship between anxiety and performance in sport. PMID- 17705940 TI - Application of the theory of planned behaviour to the prediction of objectively assessed breaking of posted speed limits. AB - In two studies the Theory of Planned Behaviour (TPB) including moral norms, anticipated regret and past behaviour was applied to predicting intention to exceed the posted speed limit across different roads and objectively assessed speeding behaviour. All measures except behaviour were taken by self-report questionnaires referring to different driving scenarios. The behaviour measures were based on performance in a simulator (Study 1) or unobtrusive on-road speed camera assessment taken without driver awareness (Study 2) across roads with varying posted speed limits. Results are reported averaged across road types in both studies. In Study 1 (N=83), 82% of the variance in intentions to speed was explained, with attitudes, subjective norms, perceived behavioural control (PBC), moral norms, anticipated regret and past behaviour being significant predictors. A total of 35% of the variance in speed as assessed on a driving simulator was accounted for with intentions, PBC, moral norms and previous accidents being significant predictors. In Study 2 (N=303), 76% of the variance in intentions to speed was explained with attitudes, moral norms, anticipated regret and past behaviour being significant predictors. A total of 17% of the variance in speed as assessed on-road was accounted for with intentions and moral norms being significant. Practical implications of the findings for road safety are discussed. PMID- 17705941 TI - Individual and gender differences in 'good' and 'first-class' undergraduate degree performance. AB - Corroborating recent findings elsewhere, women within a large undergraduate sample at the University of Sussex achieved a greater proportion of 'good' (first or upper-second-class) degrees than did their male counterparts. This female advantage disappeared when statistically controlling for the trait openness to experience and for study-related behaviour whilst at university (i.e. attending seminars and completing 'non-contributory' assignments). Contrary to robust findings previously obtained elsewhere, only slight and unreliable evidence was found that men at Sussex obtained a greater proportion of first-class degrees than did women. Moreover, differences favouring either gender were unreliable across the subjects of study. Indeed, 'subject gaps' often appeared more pronounced than 'gender gaps', where present. We conclude that emphasis should be shifted away from research on gender differences per se in favour of recent approaches that more directly explore reasons for successful undergraduate performance. However, to the extent that subject choice is an important determinant of degree performance, gender differences in subject choice will continue to be an important area of research. PMID- 17705942 TI - Effects of contextual cues in recall and recognition memory: the misinformation effect reconsidered. AB - Research in semantic word list-learning paradigms suggests that presentation modality during encoding may influence word recognition at test. Given these findings, it is argued that some previous misinformation effect research might contain methodologies which are problematic. Misleading information groups typically receive erroneous information in written narratives, which may be further impeded by written tests. Results may therefore be explained by misinformation or encoding specificity. In two experiments, participants received restated, neutral, and misleading post-event information through auditory or written modalities. Participants' recognition and recall of critical details about the source event were tested. In a recognition test using the standard testing procedure, there were no condition differences for post-event information presented via an auditory modality. However, for post-event information presented in the text modality, recognition performance was more accurate for restated information relative to neutral information, which in-turn was better than the misled condition. Using the modified testing procedure, the differences were again limited to the text condition. Better performance was evident in the restated condition relative to the average of the neutral and the misled conditions, and there was no difference in performance between the neutral and the misled conditions. Using a recall test, however, there was no effect of modality. Memory was significantly better for restated information than for the average of the neutral and the misled conditions and poorer in the misled condition relative to the neutral condition. Results are discussed in terms of the effects of contextual cues at test, and methodological and interpretational limitations associated with previous research. PMID- 17705943 TI - Age of acquisition effects in reading Chinese: evidence in favour of the arbitrary mapping hypothesis. AB - Two experiments explored the locus of the age of acquisition (AoA) effects in the processing of Chinese characters and tested the arbitrary mapping hypothesis of AoA effects. In Experiment 1, AoA and predictability from orthography to pronunciation of Chinese characters were manipulated in a naming task. Results showed a larger AoA effect for characters from low-predictive families than for characters from high-predictive families. In Experiment 2, AoA and predictability from orthography to meaning were manipulated in a semantic category judgment task. Results showed a larger AoA effect for characters from low-predictive families than for characters from high-predictive families. In summary, the two experiments provided empirical support for the arbitrary mapping hypothesis to explain AoA effects. PMID- 17705944 TI - Emotional memory and perception of emotional faces in patients suffering from depersonalization disorder. AB - Previous work has shown that patients with depersonalization disorder (DPD) have reduced physiological responses to emotional stimuli, which may be related to subjective emotional numbing. This study investigated two aspects of affective processing in 13 patients with DPD according to the DSM-IV criteria and healthy controls: the perception of emotional facial expressions (anger, disgust, fear, happiness, sadness, and surprise) and memory for emotional stimuli. Results revealed a specific lack of sensitivity to facial expression of anger in patients, but normal enhancement of memory for peripheral aspects of arousing emotional material. The results are consistent with altered processing of threat related stimuli but intact consolidation processes, at least when the stimuli involved are potently arousing. PMID- 17705946 TI - How can we reduce TB deaths? PMID- 17705945 TI - Safety and efficacy of intravenous N-acetylcysteine for acetaminophen overdose: analysis of the Hunter Area Toxicology Service (HATS) database. AB - BACKGROUND: Acetaminophen (N-acetyl-p-aminophenyl; APAP) is the leading drug used in self-poisoning and frequently causes hepatotoxicity, including acute liver failure. OBJECTIVE: To provide descriptive data on the safety and efficacy of intravenous N-acetylcysteine (IV-NAC) in the treatment of APAP toxicity, based on information in the Hunter Area Toxicology Service (HATS) database involving residents of the Greater Newcastle Area of New South Wales, Australia. METHODS: This was a retrospective analysis of all APAP overdoses from January 1987 to January 2003. Data were collected prospectively according to a published protocol and included patient characteristics, exposures to APAP and other potential toxins, treatments, and outcomes. Primary safety/tolerability endpoints included the mortality rate and incidence of adverse drug reactions, while efficacy endpoints included alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. RESULTS: Of 1749 patients, 399 (22.8%) were treated with IV-NAC. Of these, 37 (9.3%) had an adverse drug reaction to IV-NAC, of which seven (1.8% of total) were anaphylactoid. There were five deaths in hospital (mortality rate = 0.3%), including two attributed to APAP (0.1%) and none to IV-NAC. Of 64 patients who were treated with IV-NAC within 8 hours after APAP ingestion and had available ALT/AST data, two (3.1%) developed hepatotoxicity (AST/ALT > 1000 IU/L) compared with 32 (25%) of 128 patients receiving IV-NAC > 8 hours after APAP ingestion (p = 0.0002). A total of 26 patients (15.6%) receiving IV-NAC treatment within 8 hours after APAP ingestion had hospitalization stays > 48 hours compared with 70 (33.3%) receiving IV-NAC > 8 hours after ingestion (p < 0.0001). CONCLUSIONS: For patients with APAP overdose seen in the HATS database of New South Wales, Australia, in-hospital death was infrequent (< 1%) and hepatotoxicity was significantly less likely when IV-NAC was administered within 8 hours after APAP ingestion compared with longer intervals (p < 0.01). As a descriptive retrospective database analysis, this study could not exclude certain sources of bias, including temporal changes over the 16-year course of data collection in the use of IV-NAC and low ascertainment of mild, self-limiting reactions to IV-NAC. PMID- 17705947 TI - Recurrent tuberculosis and its risk factors: adequately treated patients are still at high risk. AB - Recurrent tuberculosis (TB) poses significant threats, including drug resistance, to TB control programs. However, recurrence and its causes, particularly in the era of epidemic human immunodeficiency virus (HIV), have not been well described. We systematically searched published material for studies reporting on recurrent TB following completion of standard treatment regimens to provide data on the issue. A total of 32 studies were reviewed. Among controlled trials, the overall recurrence rates (per 100,000 person-years) were respectively 3,010 (95%CI 2,230 3,970) and 2,290 (95%CI 1,730-2,940) at 6 and 12 months after treatment completion. Recurrence rates were higher among observational studies compared to controlled trials and in countries with high versus low background TB incidence. TB recurrence (%) was higher among HIV-infected (6.7, 95%CI 5.9-7.6) than non-HIV infected individuals (3.3, 95%CI 2.8-3.9). Factors independently associated with recurrence in the literature included residual cavitation, greater area of involved lung tissue, positive sputum culture at 2 months of treatment and HIV infection. Among those with HIV infection, recurrent TB was associated with a low initial CD(4) count and receiving less than 37 weeks of anti-tuberculosis treatment. We argue that adequately treated patients are still at high risk for recurrent disease and should be considered in case-finding strategies. Moreover, those with multiple risk factors may benefit from modification of standard treatment. PMID- 17705948 TI - Providing and monitoring quality service for smoking cessation in tuberculosis care. AB - All tobacco smokers should be identified and provided with a smoking cessation intervention (SCI) during tuberculosis (TB) treatment. To ensure that this occurs, the intervention process should be recorded and monitored. Monitoring is the best guarantee that care is standardised and offered equitably to all patients. It allows for evaluation of processes and outcomes so that population needs can be identified and appropriate techniques added or updated. In this article we propose steps for brief intervention as a part of the monitoring process, using model forms and suggested procedures for filling them in. The suggested forms are a modified TB treatment card that includes information about tobacco use, an SCI patient card to be added to the patient's TB treatment folder, SCI registers and SCI quarterly report forms and a tobacco use questionnaire for evaluation of services. PMID- 17705949 TI - Does antiretroviral treatment reduce case fatality among HIV-positive patients with tuberculosis in Malawi? AB - SETTING: Thyolo district, Malawi. OBJECTIVES: To report on 1) case fatality among human immunodeficiency virus (HIV) positive tuberculosis (TB) patients while on anti-tuberculosis treatment and 2) whether antiretroviral treatment (ART) initiated during the continuation phase of TB treatment reduces case fatality. DESIGN: Retrospective cohort analysis. METHODS: Comparative analysis of treatment outcomes for TB patients registered between January and December 2004. RESULTS: Of 983 newly registered TB patients receiving diagnostic HIV testing, 658 (67%) were HIV-positive. A total of 132 (20%) patients died during the 8-month course of anti-tuberculosis treatment, of whom 82 (62%) died within the first 2 months of treatment when ART was not provided (cumulative incidence 3.0, 95%CI 2.5-3.6 per 100 person-years). A total of 576 TB patients started the continuation phase of anti-tuberculosis treatment, 180 (31%) of whom were started on ART. The case fatality rate per 100 person-years was not significantly different for patients on ART (1.0, 95%CI 0.6-1.7) and those without ART (1.2, 95%CI 0.9-1.7, adjusted hazard ratio 0.86, 95%CI 0.4-1.6, P = 0.6) CONCLUSIONS: ART provided in the continuation phase of TB treatment does not have a significant impact on reducing case fatality. Reasons for this and possible measures to reduce high case fatality in the initial phase of TB treatment are discussed. PMID- 17705950 TI - Micronutrient supplements and mortality of HIV-infected adults with pulmonary TB: a controlled clinical trial. AB - SETTING: Zomba and Blantyre, Malawi, Africa. OBJECTIVES: To determine whether daily micronutrient supplementation reduces the mortality of human immunodeficiency virus (HIV) infected adults with pulmonary tuberculosis (TB). DESIGN: A randomised, controlled clinical trial of micronutrient supplementation for HIV-positive and HIV-negative adults with pulmonary TB. Participants were enrolled at the commencement of chemotherapy for sputum smear-positive pulmonary TB and followed up for 24 months. RESULTS: A total of 829 HIV-positive and 573 HIV-negative adults were enrolled. During follow-up, 328 HIV-positive and 17 HIV negative participants died. The proportion of HIV-positive participants who died in the micronutrient and placebo groups was 38.7% and 40.4%, respectively (P = 0.49). Micronutrient supplementation did not reduce mortality (hazard ratio [HR] 0.93, 95%CI 0.75-1.15) among HIV-positive adults. CONCLUSIONS: Micronutrient supplementation at the doses used in this study does not reduce mortality in HIV positive adults with pulmonary TB in Malawi. PMID- 17705951 TI - Molecular investigation of recurrent tuberculosis in patients from Rwanda. AB - SETTING: Pulmonary tuberculosis (TB) patients enrolled in four provinces of Rwanda. OBJECTIVE: To determine the cause of recurrent TB. DESIGN: Serial Mycobacterium tuberculosis isolates obtained from patients with recurrent TB from January 2002 to September 2005 were genotyped by spoligotyping and mycobacterial interspersed repetitive unit-variable number of tandem repeat (MIRU-VNTR) typing. Drug resistance was determined by phenotypic susceptibility testing and sequencing of rpoB, katG, inhA and embB genes. RESULTS: Among 710 culture positive TB patients enrolled in the study, initial drug susceptibility testing results were available for 638. Sixty-nine of these had multidrug-resistant (MDR) TB and 569 were non-MDR-TB. Among the MDR-TB patients, 22 had follow-up isolates after cure (n = 12) or chronic infection (n = 10). The DNA patterns of sequential isolates from 4 of the 12 previously cured MDR-TB patients were different, indicating re-infection. DNA patterns of isolates from the remaining 8 previously cured and 10 chronic MDR-TB patients were identical, suggesting reactivation and treatment failure, respectively. Among the non-MDR-TB patients, disease recurrence was observed in one case; this was determined to be due to reactivation after initial mixed infection. CONCLUSION: These results document a high treatment failure/reactivation rate for MDR-TB and suggest that re-infection within 2 years may not be a common cause of recurrent TB in this setting. PMID- 17705952 TI - Adverse drug reactions associated with first-line anti-tuberculosis drug regimens. AB - BACKGROUND: Standard treatment of active tuberculosis (TB) consists of isoniazid (INH), rifampin (RMP), pyrazinamide (PZA) and ethambutol (EMB). Although this regimen is effective in treating active TB, it is associated with many adverse drug reactions (ADRs) and poses a significant challenge to completion of treatment. OBJECTIVES: To examine the incidence of major ADRs and risk factors associated with first-line anti-tuberculosis medications. METHODS: This study evaluated patients receiving treatment for active TB from a population-based database (2000-2005). The nature of the ADRs, likelihood of association with the study medications and severity were evaluated. RESULTS: A total of 1061 patients received treatment, of whom 318 (30%) had at least one major ADR. The overall incidence of all major ADRs was 7.3 events per 100 person-months (95%CI 7.2-7.5): 23.3 (95%CI 23.0-23.7) when on all four first-line drugs, 13.6 (95%CI 13.3-14.0) when on RMP, INH and PZA, and 2.4 (95%CI 2.3-2.6) when on INH and RMP. Adjusted hazard ratio (HR) revealed that combination regimens containing PZA, females, subjects aged 35-59 and >or=60 years, baseline aspartate aminotransferase >or=80 U/l and drug resistance were associated with any major event. CONCLUSIONS: First line anti-tuberculosis drugs are associated with significant ADRs. There are several risk factors associated with the development of ADRs, including exposure to regimens containing PZA. PMID- 17705953 TI - Accuracy of classification of notified tuberculosis cases in Taiwan. AB - SETTING: Tuberculosis (TB) suspects and cases reported in 2003 in Taiwan. OBJECTIVES: To evaluate the accuracy of the classification of notified TB cases in Taiwan. DESIGN: A list of all TB cases reported in 2003 in Taiwan was obtained from the Taiwan Center for Disease Control, along with their classification. TB cases residing in Taipei City were investigated by consulting their medical charts. RESULTS: Of 1,973 patients, 782 (39.6%) were bacteriologically confirmed, 1,024 (52%) were not bacteriologically confirmed (indeterminate) and 167 (9%) were not TB cases (in whom non-tuberculosis mycobacteria [NTM] was isolated). Of the 1,973 cases, 1,716 (87%) had been treated with anti-tuberculosis drugs, while 257 (13%) had not been treated. Of the 782 bacteriologically confirmed cases, 68 (8.7%) were misclassified as non-notifiable (32 [4.1%] had their diagnosis changed by a clinician and 36 [4.6%] by administrative coding). Of the 167 cases in whom NTM were isolated, 72 (43.1%) were misclassified as TB cases. Of the 257 untreated suspects, 31 (12.1%) did not have any evidence of TB (20 indeterminate and 11 NTM cases) and were questionably classified as newly diagnosed cases. CONCLUSION: There was substantial misclassification of notified TB cases in Taiwan. PMID- 17705954 TI - Notification of patients with tuberculosis detected in the private sector, Tehran, Iran. AB - OBJECTIVE: To determine the case notification rate of patients with tuberculosis (TB) detected by private laboratories, in Tehran, Iran. STUDY DESIGN: Cross sectional study. METHOD: All confirmed TB cases among suspected cases referred to private laboratories for acid-fast bacilli (AFB) examination in 2002-2003 were enrolled in the study. All AFB-positive cases were followed up for notification to the Iranian Ministry of Health (MOH) National Tuberculosis Programme (NTP). RESULTS: Of the total number of cases referred to private laboratories, 646 AFB positive cases were followed up. Of these, 317 (49.1%) cases were female and 328 (50.8%) were male; the mean age was 52.2 years (SD +/- 21.7). Patients were contacted either at their residence or by telephone: 82 were found to be registered with the MOH while 564 (87.3%) could not be traced. A positive correlation was detected between physician advice for patient referral to health centres and case registration by the MOH (Fisher's Exact test 0.000). CONCLUSION: The private sector in Tehran plays a significant role in TB detection, but there are major gaps in the collaboration between the private and public health systems. PMID- 17705956 TI - Impact of mass media on knowledge about tuberculosis control among homemakers in Delhi. AB - SETTING: Homes in Delhi, India. OBJECTIVE: To study the reach of mass media campaigns and their impact on awareness about tuberculosis (TB) control among homemakers/housewives. DESIGN: A community-based cross-sectional survey among homemakers residing in Delhi for more than 6 months. RESULTS: Of a total of 920 women interviewed, about 74.2% had seen specific TB-related health messages in one or more of the mass media. The maximum number of subjects could recall having seen billboards or television campaigns. The percentage of respondents who had correct information about various aspects of the disease was higher among those who had seen TB campaigns on any of the mass media. The effectiveness of radio and newsprint in communicating TB messages was found to be more limited than that of television and billboards. CONCLUSION: The mass media can be effective in getting messages about TB across to the community of women who are homemakers, especially in developing countries. In view of our findings, it may be recommended that television and billboards be used as tools for reaching out to them with specific campaigns regarding TB control, and that the use of these media should be strengthened further. PMID- 17705955 TI - Evaluation of post-treatment health-related quality of life (HRQoL) among tuberculosis patients. AB - BACKGROUND: Health-related quality of life (HRQoL) measures the impact of a disease by assessing the health status of patients. OBJECTIVE: To assess the HRQoL of tuberculosis (TB) patients one year after treatment completion. METHODS: Patients registered under the TB control programme from July 2002 to June 2003 in a TB Unit in south India were interviewed one year after successful completion of treatment. Data on HRQoL were collected using the SF-36 questionnaire, which covers physical, mental and social well-being components. Data on economic well being were also collected. Scores were given for all domains. RESULT: Of 436 TB patients interviewed, the mean scores for social, physical, mental and economic well-being were respectively 84, 74, 68 and 62 on a scale of 100. The well-being scores were significantly related to age, sex, education, employment and persistent symptoms. There was a significant association between economic and social well-being. CONCLUSION: This study suggests that the HRQoL of TB patients one year after successful completion of treatment under the TB control programme was normal for most of the domains studied and was associated with age, literacy and employment, income, smoking, alcoholism and persistence of symptoms. PMID- 17705957 TI - Evaluation of a rapid culture method on liquid Bio FM (BIO-RAD) medium for the isolation of mycobacteria. AB - SETTING: The search continues for a simple, rapid culture system for the isolation of Mycobacterium tuberculosis in low-income countries. Bio FM (BIO-RAD) medium is an enriched 7H9 medium optimised for the growth of mycobacteria and contains a chromogenic indicator. OBJECTIVE: To evaluate the detection rate and time to detection of mycobacteria using the Bio FM system in comparison with the Lowenstein-Jensen (LJ) medium method routinely used in our laboratory. MATERIALS AND METHODS: A total of 270 pulmonary and 178 extra-pulmonary samples were cultured in parallel on Bio FM and LJ media. The mycobacterial detection rate and time were compared. RESULTS: The mycobacteria detection rate on Bio FM and LJ were not significantly different (respectively 97.9% and 93.15%, P > 0.05). The growth of M. tuberculosis was faster on Bio FM (mean 12.42 days [3-41] vs. 20.7 [10-48] days for LJ, P < 10(-6)). CONCLUSION: In our study, the culture method on liquid Bio FM medium was faster, but the detection rate was not better than with solid LJ medium. PMID- 17705958 TI - Rapid detection of Mycobacterium tuberculosis from sputum specimens using the FASTPlaqueTB test. AB - OBJECTIVES: To determine the performance of the FASTPlaqueTB test, based on bacteriophage amplification technology, by comparison with the BACTEC 460 TB culture system, the Lowenstein-Jensen (LJ) medium culture method and Ziehl Neelsen (ZN) staining. METHODS: Of 400 sputum specimens studied in our laboratory, 19 were excluded due to contaminant growth. The FASTPlaqueTB test was performed according to the manufacturer's instructions. RESULTS: Only 42 of the 381 specimens examined were positive on at least one test: 30 were positive with ZN staining, 34 with LJ medium, 36 with the FASTPlaqueTB test and 39 with BACTEC 460 TB. The combination of BACTEC 460 TB and LJ medium culture was considered the gold standard. The sensitivity and specificity were 70.7% and 99.7% for ZN staining, 87.8% and 100% for the FASTPlaqueTB test, 82.9% and 100% for LJ, and 95.1% and 100% for BACTEC 460 TB. CONCLUSIONS: The FASTPlaqueTB test is useful in the rapid diagnosis of TB. PMID- 17705959 TI - Risk factors for recurrence of haemoptysis following bronchial artery embolisation for life-threatening haemoptysis. AB - SETTING: Life-threatening haemoptysis is a frequent and often fatal complication in areas with a high prevalence of tuberculosis (TB). Bronchial artery embolisation remains the standard initial treatment. Subsequent curative measures, such as surgical resection of the focus of haemorrhage, are generally recommended to prevent recurrence, but risk-based selection criteria have not been established. OBJECTIVES: To identify risk factors for the recurrence of haemoptysis following embolisation. DESIGN: Baseline characteristics were obtained from consecutive patients with life-threatening haemoptysis who were successfully embolised and followed up for at least 12 months. RESULTS: Recurrence of haemoptysis was observed in 47% and was associated with increased mortality compared to patients without recurrence (31% vs. 10%, P = 0.021). Patients with recurrence experienced residual mild haemoptysis beyond the first week after embolisation (odds ratio [OR] 7.2), received blood transfusions (OR 5.3) or presented with an aspergilloma (OR 5.1). Conversely, the presence of active TB amenable to treatment (OR 0.3) protected patients from these events. Radiographic or angiographic appearance did not predict recurrence. CONCLUSIONS: Recurrence of haemoptysis following embolisation for life-threatening haemoptysis is common and is associated with high mortality. The results of this study can contribute to the risk assessment of these patients and guide decisions regarding the urgency of definitive therapy. PMID- 17705960 TI - Smoking habits and beliefs of future physicians of Pakistan. AB - OBJECTIVE: To assess the habits, knowledge and attitudes towards smoking among Pakistani medical students. METHODS: A cross-sectional study was conducted from March 2004 to July 2005 at three medical colleges using a World Health Organization (WHO) questionnaire. A total of 1,029 medical students participated in the study. RESULTS: The prevalence of smoking was found to be 11.2%. Smoking was more prevalent among males, hostel residents and first year medical students. Almost half of the smokers had tried to quit smoking. A family member or a friend was considered to be the most likely person to help quit smoking. The majority believed that passive smoking was harmful to health and were generally supportive of legislative measures to reduce tobacco use, such as the restriction of smoking in public places and the prohibition of sale of tobacco to children. Lesser but significant numbers thought that there should be a complete ban on smoking advertisements and that the price of tobacco products should be increased. CONCLUSION: The study shows a high prevalence of tobacco use in future physicians in spite of adequate knowledge about and a satisfactory attitude towards smoking. PMID- 17705961 TI - Factors associated with frequent emergency room attendance by asthma patients in Palestine. AB - SETTING: The emergency room (ER) of Alia Governmental Hospital in Hebron city, in the southern part of the West Bank. OBJECTIVE: To investigate the role of asthma severity, health services utilisation and medication use in frequent ER attendance for asthmatics in Palestine. DESIGN: A cross-sectional study using a previously developed questionnaire. RESULTS: Of 121 asthma patients, 73.5% were frequent ER attendees during the previous year, with a mean 6.7 visits (standard error 0.75). Moderate/severe asthma and hospital admissions in the previous year due to asthma were the strongest predictors for frequent attendees (adjusted OR [aOR] 6.92, 95%CI 2.44-19.62 and 11.16, 95%CI 4.37-28, respectively). Frequent attendees reported more difficulties in using asthma inhalers compared to one time ER attendees (aOR 2.49, 95%CI 1.04-5.99). Inhaled short-acting beta(2) agonists were reported to be used regularly, on most days, by frequent attendees (>or=1 canister/month) compared to one-time attendees (aOR 4.4, 95%CI 1.28-15 and 4.05, 95%CI 1.33-12, respectively). CONCLUSIONS: Lack of proper use of inhalers and an over-reliance on reliever therapy contributes to asthma morbidity in Palestine. We recommend an intervention programme at the professional and patient levels. PMID- 17705962 TI - A survey on the referral of tuberculosis patients at the National Tuberculosis Institute, Yemen. AB - The study aims to determine whether the tuberculosis (TB) patients referred from the National Tuberculosis Institute (NTI), Sana'a City, actually present themselves, are registered and initiate treatment at the health facilities to which they are referred. In 2004, 591 smear-positive TB cases were diagnosed, 481 cases were referred back to health centres, 75 cases were registered at the NTI and 35 cases could not be retrieved. Among the 481 referred cases, 427 cases actually presented themselves and were registered at the health centres (88.8%). The average number of days between the day of referral and that of registration was 2.5 days (median 1 day). PMID- 17705963 TI - Pulmonary tuberculosis presenting with pancytopaenia, haemophagocytosis and foamy histiocytes in an infant. PMID- 17705964 TI - Obstructive sleep apnoea in India: what the mind does not think, the eyes do not see. PMID- 17705965 TI - What is the best strategy for treating TB-HIV co-infected patients with HAART and rifampicin without saquinavir? PMID- 17705966 TI - False-positive tuberculin reactions due to non-tuberculous mycobacterial infections. PMID- 17705967 TI - Low serum concentrations of anti-tuberculosis agents: do they matter? PMID- 17705968 TI - Exposure to cold and respiratory tract infections. AB - There is a constant increase in hospitalizations and mortality during winter months; cardiovascular diseases as well as respiratory infections are responsible for a large proportion of this added morbidity and mortality. Exposure to cold has often been associated with increased incidence and severity of respiratory tract infections. The data available suggest that exposure to cold, either through exposure to low environmental temperatures or during induced hypothermia, increases the risk of developing upper and lower respiratory tract infections and dying from them; in addition, the longer the duration of exposure the higher the risk of infection. Although not all studies agree, most of the available evidence from laboratory and clinical studies suggests that inhaled cold air, cooling of the body surface and cold stress induced by lowering the core body temperature cause pathophysiological responses such as vasoconstriction in the respiratory tract mucosa and suppression of immune responses, which are responsible for increased susceptibility to infections. The general public and public health authorities should therefore keep this in mind and take appropriate measures to prevent increases in morbidity and mortality during winter due to respiratory infections. PMID- 17705969 TI - Edith Maas Lincoln and the treatment of latent tuberculous infection. PMID- 17705970 TI - Critical appraisal of current recommendations and practices for tuberculosis sputum smear microscopy. AB - This report is the consensus-based, agreed position of the participants in a workshop for experts in sputum smear microscopy organised in August 2005 by the International Union Against Tuberculosis and Lung Disease (The Union), and as such reflects their views, but not necessarily those of their respective organisations. The group reviewed current practices in sputum smear microscopy for tuberculosis (TB) and suggests considering certain changes in standard guidelines for the sputum collection strategy and the definition of sputum smear positive TB. The Ziehl-Neelsen staining guidelines need to incorporate a wider error margin for widespread application under field conditions. Quality assurance is of utmost importance, and needs more commitment from National Tuberculosis Programmes and other health authorities. In particular, allocation of sufficient resources for rechecking and integration of laboratory supervision must be ensured. Countries must make better investments in the purchase of high quality microscopes and laboratory supplies. To address the human resource crisis, personnel without specific laboratory schooling can, in principle, be trained to respond to immediate needs for TB diagnostic microscopy services. Periodic reporting on acid-fast smear examinations is highly desirable for regular monitoring and a more balanced provision of supplies. PMID- 17705971 TI - Reducing the number of sputum samples examined and thresholds for positivity: an opportunity to optimise smear microscopy. AB - SETTING: Urban health clinic, Nairobi. OBJECTIVE: To evaluate the impact on tuberculosis (TB) case detection and laboratory workload of reducing the number of sputum smears examined and thresholds for diagnosing positive smears and positive cases. DESIGN: In this prospective study, three Ziehl-Neelsen stained sputum smears from consecutive pulmonary TB suspects were examined blind. The standard approach (A), > or = 2 positive smears out of 3, using a cut-off of 10 acid-fast bacilli (AFB)/100 high-power fields (HPF), was compared with approaches B, > or = 2 positive smears (> or = 4 AFB/100 HPF) out of 3, one of which is > or = 10 AFB/100 HPF; C, > or = 2 positive smears (> or = 4 AFB/100 HPF) out of 3; D, > or = 1 positive smear (> or = 10 AFB/100 HPF) out of 2; and E, > or = 1 positive smear (> or = 4 AFB/100 HPF) out of 2. The microscopy gold standard was detection of at least one positive smear (> or = 4 AFB/100 HPF) out of 3. RESULTS: Among 644 TB suspects, the alternative approaches detected from 114 (17.7%) (approach B) to 123 cases (19.1%) (approach E) compared to 105 cases (16.3%) for approach A (P < 0.005). Sensitivity ranged between 82.0% (105/128) for A and 96.1% (123/128) for E. The single positive smear approaches reduced the number of smears by 36% compared to approach A. CONCLUSION: Reducing the number of specimens and the positivity threshold to define a positive case increased the sensitivity of microscopy and reduced laboratory workload. PMID- 17705972 TI - Sputum smear-positive tuberculosis: empiric evidence challenges the need for confirmatory smears. AB - OBJECTIVE: To determine the frequency of single scanty or positive sputum smear results and its impact on the surveillance definition of sputum smear-positive tuberculosis (TB). SETTING: Moldova, Mongolia, Uganda and Zimbabwe. METHODS: A representative sample of laboratories was selected in each country. Data were double-entered and discordances resolved by rechecking the register. RESULTS: The dataset comprised 128808 examinees with valid information from 23 laboratories in Moldova, all 31 in Mongolia, 30 in Uganda and 23 in Zimbabwe, each covering at least one calendar year. The reason for the examination was diagnostic for 89362, of which 15.2% (n = 13577) were defined as laboratory cases with at least one bacillus on at least one examination. Cases were confirmed by another examination in 72.6% (n = 9861). Of the 9014 cases who had a full set of three examinations, confirmation was obtained in 92.4% (n = 8325). CONCLUSION: One quarter of laboratory cases had no confirmatory result, almost entirely attributable to not examining another specimen. The current definition of sputum smear-positive TB requires two positive smears or one positive smear result plus more complex confirmatory evidence. Accepting a single positive examination as sufficient for the definition would greatly increase the sensitivity of the surveillance definition without sacrificing its specificity. PMID- 17705973 TI - Ethambutol in paediatric tuberculosis: aspects of ethambutol serum concentration, efficacy and toxicity in children. AB - SETTING: Ethambutol (EMB) is used as a fourth drug in paediatric anti tuberculosis treatment. In current recommendations the dosage of EMB is calculated per kg body weight. OBJECTIVE: To present two studies investigating an appropriate EMB dosage in children, and observational data on its toxicity and efficacy. DESIGN: EMB serum levels in children of different age groups were determined after single oral administration of EMB alone as well as after EMB combined with rifampicin, and optimal dosages were established. The efficacy and toxicity of these EMB dosages were examined retrospectively. RESULTS: EMB serum levels were lower than those expected in adults receiving a similar oral dose, due to different pharmacokinetics and pharmacodynamics in childhood. Thereafter, children were treated with EMB doses calculated by body surface (867 mg/m2). Ocular toxicity occurred in 0.7% of cases and relapses in 0.8%. CONCLUSION: Current recommended EMB dosages in childhood tuberculosis lead to subtherapeutic serum levels. It appears to be more valid to calculate the EMB dosage on the basis of body surface rather than body weight, leading to higher dosages especially in younger children. With these dosages, therapeutic serum levels are reached in all age groups, leading to a high efficacy of anti-tuberculosis treatment without increased ocular toxicity. PMID- 17705974 TI - Low serum concentrations of anti-tuberculosis drugs and determinants of their serum levels. AB - SETTING: Low serum concentrations of anti-tuberculosis drugs have occasionally been associated with treatment failure. OBJECTIVE: To determine the prevalence of low serum concentrations of anti-tuberculosis drugs and to identify the determinants of drug concentrations. DESIGN: Venous blood was obtained 2 h after drug ingestion, and serum levels of isoniazid (INH), rifampicin (RMP), ethambutol (EMB), pyrazinamide (PZA), acetyl INH and 25-desacetyl RMP were analysed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Patients with human immunodeficiency virus co-infection and gastrointestinal disease or diarrhoea were excluded. RESULTS: Among 69 enrolled TB patients, the prevalence of a low 2 h serum concentration of at least one anti-tuberculosis drug was 46.4%. Prevalences of a low concentration of INH, RMP, EMB or PZA were 15.2%, 23.5%, 22.4% and 4.5%, respectively. By multivariate linear regression analysis, the serum concentrations of INH, RMP and PZA were positively associated with dose per kg of body weight (P < 0.05). Moreover, INH concentration was associated with acetyl INH/INH ratio (beta = -8.588, P < 0.001) and EMB concentration was associated with calculated creatinine clearance (beta = -0.025, P < 0.001). CONCLUSION: Low concentrations of anti-tuberculosis drugs are common, and although the clinical significance of low concentrations remains uncertain, it may be necessary to optimise drug doses by therapeutic drug monitoring, especially in patients with an inadequate clinical response to chemotherapy. PMID- 17705976 TI - Multicentre evaluation of an automated BACTEC 960 system for susceptibility testing of Mycobacterium tuberculosis. AB - SETTING: Three mycobacteria reference laboratories in the south-eastern part of Brazil. OBJECTIVE: To evaluate the automated Mycobacteria Growth Indicator Tube (MGIT) for drug susceptibility testing of Mycobacterium tuberculosis. DESIGN: Performance of the automated BACTEC MGIT 960 (M960) system for testing M. tuberculosis susceptibility to streptomycin (SM), isoniazid (INH), rifampicin (RMP) and ethambutol (EMB) was evaluated with 95 clinical isolates and compared to the results of the radiometric BACTEC 460TB (B460) system, the proportion method (PM), and the resistance ratio method (RRM). Judicial susceptibility profiles of 88 isolates were defined based on two or more concordant results among B460, PM and RRM, and used as a reference for comparison with M960 results. RESULTS: Agreement rates between M960 and conventional methods were 95.2% with B460, 96.6% with the PM and 93.4% with the RRM. The lowest agreement rates were obtained for SM with the RRM and for EMB with B460. When comparing M960 with judicial susceptibility profiles, the agreement rate was 97.9%. The agreement rates obtained for INH and RMP were 99.2% and for SM and EMB they were 96.2% and 96.9%, respectively. The mean time to reporting the M960 results was 6.9 days. CONCLUSION: M960 offers great improvements when compared to the proportion and resistance ratio methods and would benefit patient treatment. PMID- 17705975 TI - The role of surgery and fluoroquinolones in the treatment of multidrug-resistant tuberculosis. AB - SETTING: Although modern tuberculosis treatment relies on chemotherapy, surgery is accepted as adjuvant treatment for multidrug-resistant tuberculosis (MDR-TB). OBJECTIVE: To evaluate the effect of resectional surgery and fluoroquinolones on long-term treatment success and survival in a large group of MDR-TB cases. DESIGN: A total of 252 patients with MDR-TB were included in this retrospective cohort study. Multiple logistic regression was used to determine independent predictive factors for long-term treatment success, and survival analyses were done based on different treatment approaches with or without surgery. RESULTS: The mean age of the study cohort was 37.9 +/- 12.5 years; 204 (80%) were males. Long-term treatment success was associated with resistance to fewer drugs, female sex, younger age and limited disease. Sixty-six patients (26.2%) had undergone resectional surgery after 2-16 months of treatment. The highest long-term treatment success and survival rates were achieved in patients who both received fluoroquinolones and underwent surgery (P = 0.001 vs. other groups). CONCLUSION: Although the treatment success rate was higher in patients treated with surgery and fluoroquinolones compared to other groups, an additional significant benefit from surgery could not be demonstrated. Larger scale studies are needed to clarify this issue. PMID- 17705978 TI - Selected biological and behavioural risk factors associated with pulmonary tuberculosis. AB - OBJECTIVES: To measure the independent association of risk factors age, sex, smoking and alcoholism with pulmonary tuberculosis (TB) in terms of prevalence odds ratio (POR). METHOD: A community-based cross-sectional survey was conducted from June 2001 to December 2003. A total of 93945 individuals aged > or = 15 years selected from a random sample of villages in a district from South India were screened for pulmonary TB by chest symptoms and chest X-ray (MMR). Two sputum samples were collected (one spot and one early morning) from patients with chest symptoms and those with abnormal X-rays for examination by microscopy for acid-fast bacilli and by culture for Mycobacterium tuberculosis. Bacillary cases are bacteriologically positive cases diagnosed by either sputum smear or culture examination. In addition, data on exposure to tobacco smoking and alcohol consumption were collected from the male population only. All females were considered non-smokers and non-alcoholics. RESULTS: A total of 429 bacteriologically positive cases were detected during the survey. The adjusted PORs (with 95%CI) for age, sex, smoking and alcoholism were 3.3 (2.7-4.1), 2.5 (1.9-3.3), 2.1 (1.7-2.7) and 1.5 (1.2-2.0), respectively. CONCLUSION: Risk factors such as age, sex, smoking and alcoholism are independently associated with pulmonary TB. Risk factors age and sex show a stronger association than smoking and alcoholism. PMID- 17705977 TI - Tuberculosis in European cities: establishment of a patient monitoring system over 10 years in Paris, France. AB - BACKGROUND: Tuberculosis (TB) is a persistent public health problem in European cities. France has been unable to report on treatment outcomes until now, and it is not known whether the World Health Organization (WHO) target cure rate of 85% has been met. METHODS: All patients placed under treatment in four hospitals and five out-patient Social Medical Centres in Paris were followed up between 1996 and 2005. Patient monitoring and evaluation were performed using a new software programme, TB-INFO. RESULTS: In a cohort of 1127 patients, 76% had pulmonary TB, of whom 39% were smear-positive, 81% were foreign-born and 9.3% were human immunodeficiency virus positive. At the end of the follow-up, 16% were cured and 54% had completed treatment. Among the 1118 non-multidrug-resistant patients, these percentages were 17% and 46%, respectively, for smear-positive pulmonary patients. Some patients died (1.9%) or failed treatment (0.1%), but many more defaulted (20.5%) as they interrupted treatment (1.5%), were lost to follow-up (19.5%) or were transferred out (7.9%). CONCLUSIONS: This 10-year follow-up of TB patients, managed with TB-INFO software, shows that a patient monitoring system can be implemented in France, providing essential information. Treatment success in this cohort of patients was far below the WHO target. PMID- 17705979 TI - Increasing TB case detection through intensive referral of TB suspects by village doctors to county TB dispensaries. AB - OBJECTIVE: To explore new approaches to increase the detection of tuberculosis cases (TB). DESIGN: Thirty counties participated in the study. Patients with TB symptoms were surveyed and referred by trained village doctors to county dispensaries, designated township health centres or general hospitals for free sputum examination. TB patients and suspects notified by general hospitals were traced by TB staff if they defaulted during the transfer. RESULTS: A total of 12,091 new smear-positive TB cases were detected. The registration rate of new smear-positives increased from 36.2 per 100,000 population before the project to 49.9/100,000 after the project, and the case detection rate under the DOTS strategy reached 86%. Of 43,464 registered TB suspects, 15,363 (35.3%) were referred by village and hospital doctors. The referral rate increased significantly (P < 0.01). Of the 15,363 referred patients, 3870 were diagnosed as new smear-positive TB cases. Among three different microscopy centres, there was a statistically significant difference in the sputum examination rates of TB suspects and in the smear-positive rates among the suspects examined. The follow up rate was 70.9%, but the follow-up success rate was only 33.1%. CONCLUSIONS: Intensive referral of patients with TB symptoms by village doctors to TB dispensaries is an effective way of increasing detection. At the same time, incentives are necessary for patients and village doctors. PMID- 17705980 TI - The epidemiology of HIV-associated tuberculosis in rural Cambodia. AB - SETTING: Banteay Meanchey Province, Cambodia. OBJECTIVE: The World Health Organization recommends human immunodeficiency virus (HIV) testing for all tuberculosis (TB) patients and TB screening for all HIV-infected persons in countries with a TB-HIV syndemic. We sought to determine whether evidence supports implementing these recommendations in South-East Asia. DESIGN: We conducted a cross-sectional survey and retrospective cohort study of patients newly diagnosed with HIV or TB from October 2003 to February 2005 to identify risk factors for HIV infection and TB, and for death during TB treatment. RESULTS: HIV infection was diagnosed in 216/574 (38%) TB patients. TB disease was found in 124/450 (24%) HIV-infected persons. No sub-groups of patients had a low risk of HIV infection or TB. Of 180 TB patients with HIV infection and a recorded treatment outcome, 49 (27%) died compared to 17/357 (5%) without HIV infection (relative risk [RR] 5.2, 95% confidence interval [CI] 3.1-8.7). HIV-infected TB patients with smear-negative pulmonary disease died less frequently than those with smear-positive pulmonary disease (RR 0.39, 95%CI 0.16-0.93). CONCLUSIONS: No sub-groups of patients had low risk for HIV infection or TB, and mortality among HIV-infected TB patients was high. These data justify using the WHO global TB-HIV recommendations in South-East Asia. Urgent interventions are needed to reduce the high mortality rate in HIV-infected TB patients. PMID- 17705981 TI - Tuberculin skin test size and risk of tuberculosis development: a large population-based study in contacts. AB - SETTING: Contacts of tuberculosis (TB) cases identified from eight Provincial databases in British Columbia, Canada, between 1990 and 2000. OBJECTIVE: To assess the risk of developing TB based on tuberculin skin test (TST) sizes in contacts of TB cases who did not receive treatment for latent TB infection. DESIGN: Retrospective, population-based cohort study with a 12-year follow-up. RESULTS: Among 26,542 contacts, 180 individuals developed TB (TB rate 678/100,000). Household contacts with a TST size 0-4 mm had a TB rate of 1014/100,000, those with 5-9 mm a TB rate of 2162/100,000 and those with 10-14 mm a rate of 4478/100,000. Children aged 0-10 years with 0-4 mm had a TB rate of 806/100,000, those with 5-9 mm a TB rate of 5556/100,000 and those with 10-14 mm a rate of 42,424/100,000. Immunosuppressed contacts with TST sizes 0-4 mm had a TB rate of 630/100,000, those with 5-9 mm a TB rate of 1923/100,000, and those with 10-14 mm a rate of 1770/100,000. CONCLUSIONS: TB rates were high for all TST sizes in household contacts, 0-10 year old contacts and immunosuppressed contacts. These contacts may benefit from treatment for latent TB infection, regardless of the size of their TST. PMID- 17705982 TI - Waning of the specific interferon-gamma response after years of tuberculosis infection. AB - HYPOTHESIS: Memory T-cell responses to specific antigens wane over time in subjects with tuberculosis (TB) infection. SETTING: Accumulated evidence indicates that QuantiFERON-TB Gold (QFT-G), a specific whole-blood interferon gamma (IFN-gamma) based assay, can detect recent TB infections with superior sensitivity and specificity. OBJECTIVE: We applied this technique to the adult population of a Japanese community to determine its epidemiological usefulness. METHOD: A total of 1559 subjects attending periodic health screening volunteered to participate in the study. RESULTS: The QFT-G positive rates were 3.1% for those aged 40-49 years, 5.9% for those aged 50-59 and 9.8% for those aged 60-69. The expected infection prevalence estimated by the authors from a series of studies was 11.1%, 29.6% and 53.1% for those aged 40-49, 50-59 and 60-69 years, respectively. This wide gap between the expected and observed positivity suggests that the IFN-gamma response waned substantially with time after infection. Those with X-rays suggestive of old TB lesions exhibited positivity rates well below 100%. CONCLUSION: The specific IFN-gamma response may wane considerably with time after infection. Longitudinal studies are required to investigate long-term dynamics of cell-mediated immunity in infected donors. PMID- 17705983 TI - Chronic obstructive pulmonary disease is missed in asthmatics in specialty care in Trinidad, West Indies. AB - SETTING: Underdiagnosis of chronic obstructive pulmonary disease (COPD) in asthmatics attending specialty care in Trinidad, West Indies. OBJECTIVE: To determine the prevalence of COPD in diagnosed asthmatics receiving specialty respiratory care. DESIGN: In a cross-sectional study, 258 asthmatics were screened for lung function measures to examine forced expiratory volume after 1 second (FEV1), forced vital capacity (FVC) and post-bronchodilator FEV1/FVC (COPD was defined as FEV1/FVC < 70%). RESULTS: Of 165 patients evaluated (response rate 64.0%), 53 (32.1%, 95%CI 25.0-39.2) had a study diagnosis of COPD and a mean FEV1/FVC of 60.12 +/- 1.2. Proportionally, more males had COPD (50.9%) than asthma (24.1%, P < 0.001). Patients with COPD were 10 years older than asthmatics (P < 0.001). Persons with asthma who smoked were more likely to have COPD (56.0%) (OR 3.26, 95%CI 1.36-7.80, P = 0.006). In both sexes, FEV1/FVC was lower among older people (P < 0.001), with a greater effect (OR 2.75, 95%CI 1.00-7.56, P < 0.01) seen among men in this cross-sectional study. CONCLUSIONS: One third of diagnosed asthmatics in specialty care also have COPD. Lung function was lower among older persons. Early spirometric evaluation of elderly asthmatics who smoke can determine the presence of COPD and facilitate appropriate management. PMID- 17705984 TI - Tobacco policies in Austria during the Third Reich. AB - BACKGROUND: The anti-smoking stance taken by Adolf Hitler, coupled with Nazi support for research on smoking and lung cancer and campaigns to discourage smoking, have encouraged pro-smoking groups to equate tobacco control activities with totalitarianism. Previous work has described the situation in Germany. OBJECTIVE: To examine the situation in Austria, also part of the Reich after 1938. DESIGN: Iterative analysis of documents and reports about the situation in Austria in the 1930s and 1940s, supplemented by a review of Reich legal ordinances, party newspapers, health behaviour guidelines issued by Nazi party organisations and interviews with expert informants. RESULTS: In contrast to the situation in Germany where, albeit to a much lesser degree than is commonly believed, some anti-smoking policies were adopted, the Nazi authorities in Austria made almost no attempt to discourage smoking and the Austrian tobacco company worked closely with the Nazi authorities to ensure that supplies were maintained. CONCLUSION: Especially when looked at in the Austrian context, the much-cited link between anti-smoking policies and Nazism is a gross over simplification. This purported link should not be used to justify the continued failure to act effectively against smoking in Germany and Austria. PMID- 17705985 TI - The prevalence of tuberculosis in different economic strata: a community survey from South India. AB - A cross-sectional socio-economic survey to assess the standard of living index (SLI) of a rural population in South India was undertaken along with a tuberculosis (TB) prevalence survey during 2004-2006. Of 32,780 households, the SLI was low, medium and high in 22%, 36% and 42%, and TB prevalence was 343, 169 and 92 per 100,000 population, respectively, a significant decrease in trend (P < 0.001); 57% of the TB patients had a low SLI and the prevalence of TB was higher amongst the landless (P < 0.001), those living below the poverty line (P < 0.01) and in katcha houses (P < 0.001), suggesting that TB disproportionately affects those with a low SLI. PMID- 17705987 TI - Aging influences multiple indices of oxidative stress in the heart of the Fischer 344/NNia x Brown Norway/BiNia rat. AB - We report the influence of aging on multiple markers of oxidative-nitrosative stress in the heart of adult (6-month), aged (30-month) and very aged (36-month) Fischer 344/NNiaHSd x Brown Norway/BiNia (F344/NXBN) rats. Compared to adult (6 month) hearts, indices of oxidative (superoxide anion [O2*-], 4-hydroxy-2-nonenal [4-HNE]) and nitrosative (protein nitrotyrosylation) stress were 34.1 +/- 28.1%, 186 +/- 28.1% and 94 +/- 5.8% higher, respectively, in 36-month hearts and these findings were highly correlated with increases in left ventricular wall thickness (r > 0.669; r > 0.710 and P < 0.01, respectively). Regression analysis showed that increases in cardiac oxidative-nitrosative stress with aging were significantly correlated with changes in the expression and/or regulation of proteins involved in transcriptional (NF-kappaB) activities, signaling (mitogen activated protein kinases along with Src), apoptotic (Bcl-2, Traf-2), and cellular stress (HSPs). These results suggest that the aging F344/NXBN heart may be highly suited for unraveling the molecular events that lead to age-associated alterations in cardiac oxidative stress. PMID- 17705988 TI - Growth on ethanol results in co-ordinated Saccharomyces cerevisiae response to inactivation of genes encoding superoxide dismutases. AB - Superoxide dismutase (SOD) is an essential enzyme protecting cells against oxidative stress. However, its specific role under different conditions is not clear. To study the possible role of SOD in the cell during respiration, Saccharomyces cerevisiae single and double mutants with inactivated SOD1 and/or SOD2 genes growing on ethanol as an energy and carbon source were used. Activities of antioxidant and associated enzymes as well as the level of protein carbonyls were measured. SOD activity was significantly higher in a Mn-SOD deficient strain than that in the wild-type parental strain, but significantly lower in a Cu, Zn-SOD mutant. A strong positive correlation between SOD and catalase activities (R(2) = 0.99) shows possible protection of catalase by SOD from inactivation in vivo and/or decrease in catalase activity because of lower H(2)O(2) formation in the mutant cells. SOD deficiency resulted in a malate dehydrogenase activity increase, whereas glucose-6-phosphate dehydrogenase (G6PDH) activity was lower in SOD-deficient strains. Linear and non-linear positive correlations between SOD and isocitrate dehydrogenase activities are discussed. No changes in the activity of glutathione reductase and protein carbonyl levels support the idea that SOD-deficient cells are not exposed to strong oxidative stress during exponential growth of yeast cultures on ethanol. PMID- 17705989 TI - Effects of MCI-186 upon neutrophil-derived active oxygens. AB - Reactions of 3-methyl-1-phenyl-2-pyrazoline-5-one (MCI-186) with hypochlorous acid and superoxide were analysed by spectrophotometry and mass spectrometry. The results were applied to the neutrophil system to evaluate the scavenging activity of neutrophil-derived active oxygen species by MCI-186. MCI-186 reacted rapidly with hypochlorous acid (1 x 10(6) M(-1)s(-1)) to form a chlorinated intermediate, followed by a slow conversion to a new spectrum. MCI-186 consumed 3 moles of hypochlorous acid and did not react with superoxide. The newly synthesized fluorescence probes, 2-[6-(4'-amino)-phenoxy-3H-xanthen-3-on-9-yl]benzoic acid (APF) and 2-[6-(4'-hydroxy)phenoxy-3H-anthen-3-on-9-yl]benzoic acid (HPF) successfully detected neutrophil-derived active oxygens (Setsukinai K, Urano Y, Kakinuma K, Majima HJ, Nagano T. Development of novel fluorescence probes that can reliably detect reactive oxygen species and distinguish specific species. J Biol Chem 2003; 278: 3170-3175). The rate constants for the reaction of hypochlorous acid with MCI-186 and fluorescence probes was in the order of MCI 186 > APF > HPF. Fluorescence due to the oxidation of APF and HPF was observed with the stimulated neutrophils. The result that the intensity from APF oxidation was higher than that from HPF oxidation is compatible with reports that APF selectively reacts with hypochlorous acid. Fluorescence due to oxidation of both APF and HPF decreased when the reactions were carried out in the presence of a fluorescence probe and MCI-186 in a dose-dependent manner. These results indicate that MCI-186 effectively scavenges neutrophil-derived hypochlorous acid and other active oxygens. PMID- 17705990 TI - Time course and attenuation of ischaemia-reperfusion induced oxidative injury by propofol in human renal transplantation. AB - Ischaemia-reperfusion injury resulting from interruption and restoration of blood flow might be related to free radical mediated oxidative stress and inflammation, and subsequently to post-surgery related complications. We studied the impact of renal transplantation on oxidative stress and inflammation by measuring F(2) isoprostanes and prostaglandin F(2alpha), respectively, during transplantation and post-surgery. Additionally, due to earlier observations, two dissimilar anaesthetic agents (thiopentone and propofol) were compared to determine their antioxidative capacity rather than their anaesthetic properties. Blood samples were collected before, post-intubation, immediately, 30, 60,120, 240 min, and 12 and 24 h after reperfusion. Oxidative stress and inflammatory response were detected by measuring 8-iso-PGF(2alpha) (a major F(2)-isoprostane and a biomarker of oxidative stress) and 15-keto-dihydro-PGF(2alpha) (a major metabolite of PGF(2alpha) and a biomarker of COX-mediated inflammatory response), respectively. Reperfusion of the transplanted graft significantly increased plasma levels of 8 iso-PGF(2alpha). PGF(2alpha) metabolite levels, although elevated, did not reach statistical significance. In addition, significantly lower levels of 8-iso PGF(2a) were observed in the propofol group compared to the thiopentone group. Together, these findings underline an augmented oxidative stress activity following an inflammatory response after human renal transplantation. Furthermore, propofol a well-known anaesthetic, counteracted oxidative stress by lowering the formation of a major F(2)-isoprostane. PMID- 17705992 TI - Standardized criterion to analyze and directly compare various materials and models for peripheral nerve regeneration. AB - Progress in understanding conditions for optimal peripheral nerve regeneration has been stunted due to lack of standardization of experimental conditions and assays. In this paper we review the large database that has been generated using the Lundborg nerve chamber model and compare various theories for their ability to explain the experimental data. Data were normalized based on systematic use of the critical axon elongation, the gap length at which the probability of axon reconnection between the stumps is just 50%. Use of this criterion has led to a rank-ordering of devices or treatments and has led, in turn, to conclusions about the conditions that facilitate regeneration. Experimental configurations that have maximized facilitation of peripheral nerve regeneration are those in which the tube wall comprised degradable polymers, including collagen and certain synthetic biodegradable polymers, and was cell-permeable rather than protein permeable. Tube fillings that showed very high regenerative activity were suspensions of Schwann cells, a solution either of acidic or basic fibroblast growth factor, insoluble ECM substrates rather than solutions or gels, polyamide filaments oriented along the tube axis and highly porous, insoluble analogs of the ECM with specific structure and controlled degradation rate. It is suggested that the data are best explained by postulating that the quality of regeneration depends on two critical processes. The first is compression of stumps and regenerating nerve by a thick myofibroblast layer that surrounds these tissues and blocks synthesis of a nerve of large diameter (pressure cuff theory). The second is synthesis of linear columns of Schwann cells that serve as tracks for axon elongation (basement membrane microtube theory). It is concluded that experimental configurations that show high regenerative activity suppress the first process while facilitating the second. PMID- 17705993 TI - Biomimetic materials replicating Schwann cell topography enhance neuronal adhesion and neurite alignment in vitro. AB - It is well established that Schwann cells (SCs) promote and enhance axon guidance and nerve regeneration by providing multiple cues, including extracellular matrix, cell surface molecules, neurotrophic factors and cellular topography. Which of the elements of the complex environment associated with SCs provides the essential information for directed nerve growth is unclear, because, until now, it has been impossible to investigate their contributions individually. Our development of biomimetic materials that replicate the micro- and nanoscale topography of SCs has allowed us to investigate for the first time the role of cellular topography in directing nerve growth. Dorsal root ganglion (DRG) neurons were cultured on flat poly(dimethyl siloxane) (PDMS) and on PDMS replicas with protruding SC topography. Image analysis showed that more neurons adhered to the replicas than to the flat substrates, and that neurite growth on the replicas followed the underlying SC pattern. Neuronal alignment was dependent on cell density. Live SCs derived from the DRG also grew along the replica SC pattern. These results suggest that the combination of micro- and nanoscale topographical cues provided by SCs can influence nerve growth and point toward design parameters for future nerve guidance channels. PMID- 17705994 TI - Effects of collagen 1, fibronectin, laminin and hyaluronic acid concentration in multi-component gels on neurite extension. AB - Recovery after peripheral nerve injury remains a significant challenge. Extracellular matrix proteins and hydrogels of extracellular matrix components have been shown to improve regeneration in peripheral nerve entubulation models, especially over long distances. The chemical properties, ligand identity and density, and mechanical properties of the hydrogel can affect neurite extension. However, the importance of combinatorial effects between different components in co-gels of several extracellular matrix components is unclear. In this study, we investigated neurite extension from explanted dorsal root ganglia cultured within co-gels made from laminin, fibronectin, collagen 1 and hyaluronic acid. Laminin had a strong, dose-dependent effect on both neurite length and outgrowth. Fibronectin was slightly, but generally not significantly, inhibitory to neurite extension. The concentration of collagen 1 and hyaluronic acid did not have significant effects on neurite extension. The combinatorial effects among the four components were additive rather than synergistic. A co-gel made with 1.5 mg/ml collagen 1 and 1.5 mg/ml laminin was optimum in this study, resulting in an average neurite length of 1532 +/- 91 microm versus 976 +/- 32 microm for controls, and an increase in overall volume outgrowth (reflecting neurite length and branching) of 85.9+/-9.3% over controls. This co-gel provides a mechanically stable scaffold with high ligand density and biochemical affinity. The results of this study support the use of co-gels of laminin and collagen 1 for promoting regeneration in peripheral nerve injuries and suggest that interactions among hydrogel components are not significant. PMID- 17705995 TI - Directed growth and differentiation of stem cells towards neural cell fates using soluble and surface-mediated cues. AB - Stem and progenitor cells are helping researchers understand the complex process of mammalian development and also show great promise in treating diseases that are unresponsive to standard therapies. The potential for embryonic stem cells to differentiate into any cell in the body is their great benefit but avoiding co culture with animal cells and efficiently narrowing cell fate to a single cell type remains challenging. Adult progenitor cells have a more restricted cell fate, but have the potential for use in autologous cell therapies and avoid the ethical issues surrounding the derivation of embryonic stem cell lines. While progress is encouraging, there is much work to be done in directing cells to specific lineages before stem and progenitor cells can be commonly used in clinical settings. This review discusses current techniques used for investigation of the growth and differentiation of stem and progenitor cells, with a focus on neural cell fates. PMID- 17705996 TI - Photopolymerized poly(ethylene glycol)/poly(L-lysine) hydrogels for the delivery of neural progenitor cells. AB - Neural progenitor cells (NPCs) have shown promise in a number of models of disease and injury, but for these cells to be safe and effective, they must be directed to differentiate appropriately following transplantation. We have developed a photopolymerized hydrogel composed of macromers of poly(ethylene glycol) (PEG) bound to poly(L-lysine) (PLL) that supports NPC survival and directs differentiation. Green fluorescent protein (GFP) positive NPCs were encapsulated in these gels and demonstrated survival up to 17 days. When encapsulated in the gels at a photoinitiator concentration of 5.0 mg/ml, few NPCs (0.5 +/- 0.25%) demonstrated apoptosis. Furthermore, 55 +/- 6% of the NPCs cultured within the gels in epidermal growth factor (EGF) containing media differentiated into a mature neuronal cell type (neurofilament 200 positive) while the remainder 44 +/- 8% were undifferentiated (nestin positive). A small percentage, 1 +/- 0.4%, expressed the astrocytic marker glial acidic fibrilary protein. Photopolymerized PEG/PLL gels promote the survival and direct the differentiation of NPCs, making this system a promising delivery vehicle for NPCs in the treatment of injuries and diseases of the central nervous system. PMID- 17705997 TI - Retinal prostheses: current challenges and future outlook. AB - Blindness from retinal diseases, including age-related macular degeneration (AMD) and retinitis pigmentosa (RP), usually causes a significant decline in quality of life for affected patients. Currently there is no cure for these conditions. However, over the last decade, several groups have been developing retinal prostheses which hopefully will provide some degree of improved visual function to these patients. Several such devices are now in clinical trials. Unfortunately, the possibility of electrode or tissue damage limits excitation schemes to those that may be employed with electrodes that have relatively low charge densities. Further, the excitation thresholds that have been required to achieve vision to date, in general, are relatively high. This may result in part from poor apposition between neurons and the stimulating electrodes and is confounded by the effects of the photoreceptor loss, which initiates other pathology in the surviving retinal tissue. The combination of these and other factors imposes a restriction on the pixel density that can be used for devices that actively deliver electrical stimulation to the retina. The resultant use of devices with relatively low pixel densities presumably will limit the degree of visual resolution that can be obtained with these devices. Further increases in pixel density, and therefore increased visual acuity, will necessitate either improved electrode-tissue biocompatibility or lower stimulation thresholds. To meet this challenge, innovations in materials and devices have been proposed. Here, we review the types of retinal prostheses investigated, the extent of their current biocompatibility and future improvements designed to surmount these limitations. PMID- 17705998 TI - Fabrication and evaluation of conductive elastomer electrodes for neural stimulation. AB - This study explored the feasibility of applying nanocomposites derived from conducting organic polymers and silicone elastomers to fabricate electrodes for neural stimulation. A novel combination of nanoparticulate polypyrrole polymerized within a processable elastomeric silicone host polymer was evaluated in vitro and in vivo. The electrical properties of the elastomeric conductors were strongly dependent on their composition, and mixtures were identified that provided high and stable conductivity. Methods were developed for incorporating conductive polymer-siloxane co-polymer nanocomposite and silicone insulating polymers into thin-layered structures for simple single-poled electrode fabrication. In vitro testing revealed that the materials were stable under continuous pulsing for at least 10 days. Single contact prototype nerve cuff electrodes were fabricated and device functionality was demonstrated in vivo following acute implantation. The results of this study demonstrate the feasibility of conductive elastomers for peripheral nerve stimulating electrodes. Matching the mechanical properties of cuff electrode to those of the underlying neural tissue is expected to improve the long-term tissue response to the presence of the electrode. PMID- 17705999 TI - Electrochemical fabrication of conducting polymer poly(3,4 ethylenedioxythiophene) (PEDOT) nanofibrils on microfabricated neural prosthetic devices. AB - This paper describes methods for electrochemically polymerizing conducting polymer poly(3,4-dioxyethylenethiophene) (PEDOT) nanofibrils on microfabricated neural prosthetic devices from aqueous solutions containing polyacrylic acid (PAA). These fibrils have characteristic sizes ranging from 100 to 1000 nm in diameter, depending on the concentration, molecular weight of PAA and thickness of the film. The PEDOT nanofibril-coated electrodes have significantly lower electrical impedance due to their higher effective surface area. We propose a mechanism of nanofibril formation involving locally anisotropic variations in EDOT monomer transport and PEDOT film growth due to segregation of the PAA counter-ions. This deposition method provides an improvement in the electrical properties by increasing the effective surface area of the electrodes, while still maintaining the overall small electrode size. It is also opens up new reliable and reproducible strategies for the direct electrochemical polymerization of conducting polymer nanofibrils on a variety of electrodes. PMID- 17706000 TI - Development of astroglial cells in patterned neuronal cultures. AB - The purpose of this work was to study the development of astroglial cells in patterned neuronal cultures. Hippocampal neurons, derived from embryonic stage (E18) rats and cultured in serum-free Neurobasal/B27 medium, grew to follow patterns of poly(D-lysine) created by micro-contact printing. The growth of the astroglial cells and the co-localization of neurons and astroglial cells were measured for up to one month using fluorescence immunostaining of neurons and astroglial cells. Neurons grew to form square patterns within 2 weeks, while astroglia only started to emerge in the same period. Astroglial cells continued to proliferate for a month following a general growth curve. Over 90% of the astroglial cell area co-localized with neurons (within 2 mum) at an early stage of astroglial development (13 DIV). Over the remaining period, astroglial cells proliferated and the co-localization was 80%. Hence, in these culture conditions astroglial cells develop 2-3 weeks later than neurons but remain highly co localized with neurons. PMID- 17706001 TI - Attention to internal face features in unfamiliar face matching. AB - Accurate matching of unfamiliar faces is vital in security and forensic applications, yet previous research has suggested that humans often perform poorly when matching unfamiliar faces. Hairstyle and facial hair can strongly influence unfamiliar face matching but are potentially unreliable cues. This study investigated whether increased attention to the more stable internal face features of eyes, nose, and mouth was associated with more accurate face-matching performance. Forty-three first-year psychology students decided whether two simultaneously presented faces were of the same person or not. The faces were displayed for either 2 or 6 seconds, and had either similar or dissimilar hairstyles. The level of attention to internal features was measured by the proportion of fixation time spent on the internal face features and the sensitivity of discrimination to changes in external feature similarity. Increased attention to internal features was associated with increased discrimination in the 2-second display-time condition, but no significant relationship was found in the 6-second condition. Individual differences in eye movements were highly stable across the experimental conditions. PMID- 17706002 TI - Economic analysis of a multicentre, randomised, phase III trial comparing FOLFOXIRI with FOLFIRI in patients with metastatic colorectal cancer in Greece. AB - INTRODUCTION: An economic evaluation of the irinotecan, leucovorin, 5 fluorouracil (FOLFIRI) combination versus the irinotecan, oxaliplatin, leucovorin, 5-fluorouracil (FOLFOXIRI) regimen in patients with metastatic colorectal cancer was performed in the context of a randomised phase III study. METHODS: The trial did not find any differences in efficacy and, therefore, a cost-minimisation analysis was undertaken. Treatment cost accounts for the administration of first and second line chemotherapy, for concomitant medications, for laboratory and other examinations and hospitalisations due to treatment side effects. Unit prices used reflect 2006 and are common among NHS hospitals in Greece. RESULTS: The mean total cost of therapy in the FOLFOXIRI group (18,344 euros, 95% CI: 16,951 euros-19,776 euros), was significantly higher than the FOLFIRI group (12,201 euros, 95% CI: 11,011 euros-13,427 euros). Mean chemotherapy cost of the FOLFOXIRI group (9016 euros; 95% CI: 8338 euros-9669 euros) was significantly higher than that of the FOLFIRI group (4830 euros; 95% CI: 4435 euros-5231 euros). The next largest component of cost involves second line drugs, where the average cost per patient was 3306 euros (95% CI: 2479 euros 4237 euros) in the FOLFIRI group and 3996 euros (95% CI: 3196 euros-4892 euros) in the FOLFOXIRI group. The cost of hospitalisations was 1814 euros (95% CI: 1672 euros-1954 euros) in the first group and 2663 euros (95% CI: 2469 euros-2859 euros) in the second. The rest of the components represent a small part of the total cost and there are no differences in the two groups. CONCLUSION: The combination of irinotecan, leucovorin, 5-fluorouracil has the same effectiveness as the combination of irinotecan, oxaliplatin, leucovorin, 5-fluorouracil in patients with metastatic colorectal cancer, nonetheless it is associated with a much lower overall treatment cost and it should be the preferred treatment regimen in this context. PMID- 17706003 TI - A prospective, multicentre, open-label study of aripiprazole in the management of patients with schizophrenia in psychiatric practice in Europe: Broad Effectiveness Trial with Aripiprazole in Europe (EU-BETA). AB - OBJECTIVE: To examine the effectiveness of aripiprazole in schizophrenia in a naturalistic setting in 14 European countries. METHODS: This multicentre, open label study of aripiprazole evaluated outpatients with schizophrenia for whom a medication switch was clinically reasonable or antipsychotic initiation was required. Patients (n = 833) were randomized in a 4:1 ratio to aripiprazole (recommended starting dose 15 mg/day, permitted adjustment 10-30 mg/day) (n = 680) or another antipsychotic (safety control [SC] group) (n = 153) for 8 weeks. The control group received an antipsychotic different to their recent pre-study medication. The primary effectiveness measure was the Clinical Global Impression Improvement (CGI - I) score of aripiprazole-treated patients at Week 8 (last observation carried forward [LOCF]). Patients' and caregivers' medication preference was assessed using the Preference of Medication (POM) questionnaire. The Investigator Assessment Questionnaire (IAQ) was used to record investigators' assessments of their patients' responses to the study antipsychotic. Adverse events (AEs) were recorded. RESULTS: At endpoint (Week 8, LOCF), the mean CGI - I score of 3.16 (95% confidence interval, [CI]: 3.04, 3.28) demonstrated the effectiveness of aripiprazole. At endpoint, 43% of aripiprazole-treated patients showed a response (CGI - I score = 1/2). Aripiprazole was rated as slightly or much better than previous antipsychotic at endpoint by 68% of patients and 65% of caregivers. The mean CGI - I score (Week 8, LOCF) for the SC group was 3.37 (95% CI: 3.14, 3.60). No major differences in the occurrence of AEs were noted between aripiprazole- and SC-treated patients. LIMITATIONS: As this is an open-label design, there may have been a bias. Secondly, the study was not powered to show differences between treatment groups and no statistical comparisons were planned. Thirdly, 8 weeks is too short to evaluate long-term effectiveness. CONCLUSIONS: Aripiprazole was effective, well tolerated and well accepted by patients and caregivers in this naturalistic study. PMID- 17706004 TI - Darifenacin treatment of patients >or= 65 years with overactive bladder: results of a randomized, controlled, 12-week trial. AB - BACKGROUND: Overactive bladder (OAB) increases in prevalence with advancing age. This study specifically investigated patients >or= 65 years, evaluating the efficacy, tolerability, safety and quality of life (QoL) outcomes from darifenacin treatment. METHODS: Patients (n = 400, mean age 72 years) with OAB were randomized (2:1) to receive 12 weeks of double-blind treatment with darifenacin (7.5 mg once daily for 2 weeks, then optional titration to 15 mg daily) or placebo (with sham titration). Efficacy, tolerability and safety were assessed from patient diary data, adverse events and discontinuations and QoL outcomes using specific questionnaires. RESULTS: Mean urgency urinary incontinence episodes (UUIEs) decreased significantly from baseline to Week 12 with both darifenacin (-88.6%) and placebo (-77.9%; p > 0.05), with 70% and 58% patients responding with >or= 50% reductions, respectively (p = 0.021). This was accompanied by significant differences between groups in reductions in micturition frequency (-25.3% with darifenacin vs. -18.5% placebo; p < 0.01). QoL assessments revealed significant improvements with darifenacin versus placebo at Week 12 in OAB-q, Patient Perception of Bladder Condition, and patient and physician assessments of treatment benefit (all p < 0.001). The most commonly reported adverse events were dry mouth and constipation. CONCLUSIONS: This study demonstrated that marked improvements in OAB symptoms can be achieved in patients >or= 65 years, with significant treatment differences in responder rates, micturition frequency and QoL. Reduction in UUIEs may not be the optimal endpoint in this population, whereas QoL appears to be a sensitive and relevant patient oriented measure of treatment effect. PMID- 17706005 TI - Cloning and expression of an antigenic domain of a major surface protein (Nc-p43) of Neospora caninum. AB - Neospora caninum is an obligate intracellular protozoan that can infect domestic and wild canids, as well as ruminants and equines. It was described in 1988 as causing neuromuscular alterations and death in dogs. Recently, N. caninum has been the focus of considerable attention for its large impact on the dairy industry, given the economic losses related to breeding failures and to a decrease in productivity. ELISA diagnosis of neosporosis has not been widely used in Brazil, mostly because of the assay's cost, and thus the distribution of the disease in the country is not well known. In order to evaluate its ability to react with sera from infected animals from the state of Mato Grosso do Sul, an antigenic determinant domain of a major surface protein (Nc-p43) was produced. The antigenic domain, located in the distal 2/3 region of the C-terminus, was amplified by polymerase chain reaction. The DNA fragments were cloned into pet100/D-TOPO vectors. The recombinant plasmids were transformed into Escherichia coli of the BL21 Star (DE3) strain and induced to express the fused fragment of Nc-p43 as a 29-kDa protein that, when assayed with bovine Neospora-positive serum from a regional sample, was sensitive for identification by immunoblotting. This Nc-p43 fragment may be of use in additional studies targeted at diagnosing N. caninum infection and at evaluating the immunoprotection conferred by the protein fragment to animal hosts. PMID- 17706006 TI - In vitro evaluation of the disinfection efficacy on Eimeria tenella unsporulated oocysts isolated from broilers. AB - The objective of this study was to evaluate in vitro the action of eight chemical principles by disinfection efficacy (DE) of Eimeria tenella oocysts. Disinfection efficacy was evaluated by either destruction or sporulation inhibition of the oocysts. Eight treatments were performed: T1 (Glutaraldehyde 42.5 g + Benzalkonium Chloride 7.5 g); T2 (Benzalkonium chloride + quaternary ammonium salt); T3 (formol 37% + Sodium Dodecylbenzene Sulfonate 12%); T4 (sodium hypochlorite 2%); T5 (Orthodichlorobenzene 60% + Xylene 30%); T6 (Polyoctyl polyamino ethyl glycine + Polyoxyethylene alkylphenol ether + Sodium Chloride); T7 (Chloramine T) and finally T8 (free iodine 2.25% + Phosphoric acid 15 g). The control test was carried out with distilled water (T9). The best DE were observed, respectively, in T3 (79.49%), T5 (75.60%) and T4 (65.56%) treatments. PMID- 17706007 TI - Hypnozoites of Cystoisospora Frankel, 1977 (Apicomplexa: Cystoisosporinae) in Mongolian gerbil lymph nodes and their transmission to cats free of coccidia. AB - Nine Mongolian gerbils (Meriones unguiculatus) were fed with 5.6 x 10(5) Cystoisospora sporulated oocysts orally. After 28 days post inoculation (DPI) four animals were euthanized, and their mesenteric lymph nodes were removed and they were submitted to peptic digestion technique and samples of them were submitted to transmission electron microscopy for hypnozoites identification. From lymph nodes digestion 4 x 10(2) hypnozoites/mL were obtained. Morphologically they were banana or stick form in shape, and measured 18.17 (15.09-20.02) in length by 6.21 (5.48-7.06) microm in width. In the same experiment, at 6 DAI, five gerbils were posted and liver, mesenteric lymph nodes and spleen were removed from each animal and were homogenized before given to three cats free of coccidia. All visceras used individually in each cat were capable to induce infection of species, C. felis and C. rivolta. PMID- 17706008 TI - [Trichostrongylus colubriformis larvae recovery from different Brachiaria decumbens and Panicum maximum strata]. AB - The purpose of the experiment was to evaluate infective Trichostrongylus colubriformis larvae vertical migration in two forage grass species. Experimental modules formed by eight plots, established with Brachiaria decumbens cv. Australian and Panicum maximum cv. Aruana, were used in the study, totaling four plots for each grass species. Each plot was divided into six 30 x 30 cm subplots. Larval migration was evaluated in the four seasons of the year, in different plant strata (0-7, 7-14, 14-21, 21-28 and above 28 cm). Four feces deposits were made, one in each season of the year, in the middle of 30-cm tall forage. The feces were collected from the forage ten days after each feces deposit in the experimental subplots. Grass height was measured in each of the strata immediately before the collections. The forage of the different strata was cut from an area measuring 10-cm in radius. The feces were collected manually from the subplots. There was a grass species and grass stratum interaction in the deposit made in autumn (P<0.05). During that season, most of the larvae were recovered from the Brachiaria grass base; meanwhile, at the forage apex, the biggest average was registered in the aruana grass. Infective larvae (L3) recovery was similar among the different strata during spring. In springtime, the biggest L3 recovery occurred at the 21-28 cm stratum from both forage species. No L3 was recovered from any of the No L3 was recovered from any of the grass strata during winter and summer. Study results show that migration of T. colubriformis larvae was more influenced by weather conditions than by forage species. PMID- 17706009 TI - Eimeria auritanensis n. sp. and E. gambai Carini, 1938 (Apicomplexa: Eimeriidae) from the opossum Didelphis aurita Wied-Newied, 1826 (Marsupialia: Didelphidae) from southeastern Brazil. AB - Two eimerid species are described from the opossum Didelphis aurita from southeastern Brazil. Eimeria auritanensis n. sp. sporulated oocysts spherical to subspherical (31.55 +/- 1.56 by 29.55 +/- 1.40 microm), shape index 1.07; oocyst wall double layered 2.10 +/- 0.27 microm thick, outer yellowish and strongly ornamented having a prominently mammillated surphace; inner layer smooth and brownish. There is no micropyle or oocyst residuum, but one or two polar granules are present. Sporocysts ovoid (13.20 +/- 1.64 by 10.41 +/- 1.10microm) with a faint Stieda's body and residuum composed of granules and spherules. Eimeria gambai Carini, 1938 sporulated oocysts ovoid to subspherical (26.54 +/- 1.7 by 24.82 +/- 1.85 microm), shape index 1.07; oocyst wall double layered 2.10 +/- 0.27 microm thick, outer colorless to pale yellow entirely pitted, while inner layer smooth dark yellow to pale brow. Micropyle and residual bodies absent, polar granules present. Sporocysts ovoid 12.49 +/- 1.75 by 9.32 +/- 1.01 microm. Stieda body present and round. Sporocysts residuum composed of many granules and spherules. PMID- 17706010 TI - [Insecticide effects of natural amides from Piper and of the synthetic derivative tetrahydropiperine on Lucilia cuprina (Diptera: Calliphoridae) and Musca domestica (Diptera: Muscidae)]. AB - The insecticide activity of piperine, cinamoil amide, and tetrahydropiperine against Lucilia cuprina and Musca domestica adults were conducted at the Federal Rural University of Rio de Janeiro. Chemicals were topically applied on thoracic areas of the flies and the toxicity was determined after 24 and 48 hr post treatment and LD50 were calculated using Probit Analysis. Tetrahydropiperine (THP amide) was the only substance which demonstrated insecticide activity against both species of flies. LD50 against L. cuprina and M. domestica were 16.25 and 7.65 microg/fly, respectively, after 24 hr of treatment. Similar results were observed after 48 hr post treatment because the LD50's were 18.03 and 6.57 microg/fly, respectively. Males of L. cuprina were more resistant to tetrahydropiperine than females. However females of M. domestica were more resistant to the insecticide than males. PMID- 17706011 TI - [Anatomic regions of major occurrence of Cysticercus bovis in bovines under federal inspection at slaughterhouse in the municipality of Sao Jose dos Pinhais, State of Parana from July to December, 2000]. AB - The purpose of this work was to determine the most common anatomic location of bovine cysticercosis, as well as its number per animal. To accomplish these objectives a number of 26,633 bovines from the slaughterhouse Argus Ltd., SIF 1710, located at Sao Jose dos Pinhais in the State of Parana, Brazil, were examined from July to December 2000. The results demonstrated that the head's muscles were infected with a rate of 57.77%, and the cardiac muscles 39.65%, totalizing 97.42% of the infected sites. According to the classification concerning viability, the occurrence of metacestode was 66.97% nonviable (dead) and 33.02% viable (alive). From the Cysticercus alive, 81% of them were located in the head's muscles and 17% in the heart; whereas from those dead, 52.11% were located in the heart's muscles and 47.88% in the hea's one. Of the total of carcasses positives for Cysticercus bovis, 94% of them were infected by only one cyst and 6% by multiple cysts. All the viable cysts were submitted to the morphologic identification being verified that 100% of the parasites were C. bovis. PMID- 17706012 TI - [Differentiation of the species of Eimeria parasite of sheep by the use of linear regression and morphologic algorithms]. AB - With the aims to evaluate the use of the linear regression analysis as a technique to detect interespecifc morphometric differences and to develop algorithms for differentiating oocysts from the Eimeria species, fecal samples of Santa Ines sheep, has been used. Empiric algorithms have been developed based on quantitative and qualitative data from the oocysts morphology. The linear regression of the length and width of the oocysts has been tested. There was no significant difference among the measures from the oocysts of the species E. bakuensis, E. faurei and E. ovinoidalis in lambs and in adults. From the five polar cap provided species, E. ahsata was differentiated from E. intricata and from E. bakuensis based on the straight lines angular coefficient. Concerning the species that do not present polar cap, E. parva and E. pallida were more subject to confusion. Even so, with the application of the algorithm, it was possible to cluster them into different strips. The efficiency presented by the algorithm for gathering these species was 77% and 64%, respectively. Regarding to the species with polar cap, the lowest efficiency presented by the algorithm was to cluster E. bakuensis, though it was above 50%. PMID- 17706013 TI - [Bovine parasitic otitis due to rhabditiform nematodes in Gyr cows from the State of Rio de Janeiro, Brazil]. AB - The aim of this report was to describe the occurrence of the bovine parasitic otitis caused by rhabditiform nematodes in Gyr cows breed from the State of Rio de Janeiro, Brazil. Eighty six Gyr cows, from the same farm, presenting clinical otitis, were examined for the presence of rhabditiform nematodes with the aid of a swab. All the animals were positive for rhabditiform nematodes in both ear cannals. PMID- 17706014 TI - [Parasitism by Amblyomma triste in domestic cat]. AB - Amblyomma triste is an ixodidae, ectoparasite of several mammals' species, with occurrence reported in Argentina, Brazil, Colombia, Ecuador, Peru, Uruguay and Venezuela. The aim of this work was to register the parasitism by A. triste in domestic cat (Felis catus) in Rio Grande do Sul state, Brazil. PMID- 17706015 TI - Larvals of Terranova sp. (Nematoda: Anisakidae) parasitic in Plagioscion squamosissimus (Perciformes: Sciaenidae) from Araguaia River, State of Tocantins, Brazil. AB - During the study of the metazoan parasites of fishes from Araguaia River, municipality of Araguatins (05 degrees 39'S, 48 degrees 07'W), State of Tocantins, Brazil, a third stage larvae of an undescribed species of Terranova were collected from the mesenteries of Plagioscion squamosissimus. These larvae were characterized to present large size, excretory pore situated near of the base of ventrolateral lips, presence of short intestinal caecum dorsal to oesophagus, ventriculus less than seven times as long as wide and absence of mucron. This is the first record and description of larval of species of Terranova parasitic in South American freshwater fishes. PMID- 17706017 TI - HER-2 tissue expression correlated with serum levels in breast cancer patients. AB - We explored the relationship between circulating HER-2 extracellular domain and tissue HER-2 status in a group of 42 postmenopausal breast cancer patients. All patients were examined before adjuvant chemotherapy or other adjuvant treatment. Serum levels were measured by BAYER Advia Centaur System, Golden, CO (the cut-off level was in our conditions considered at 12 ng/ml). Tissue expression was assayed with the DAKO HercepTest, North America, Inc, Carpinteria, CA. Our findings that serum levels are in consonance with tissue expression could be important in metastatic breast cancer, when it is impossible to get a new tumour sample and establish the actual HER-2 status, which may be different from the primary tumour. Although we know that serum HER-2 concentration cannot be substituted for IHC or FISH, we have observed a statistically significant correlation between serum level concentration and tissue HER-2 status. PMID- 17706016 TI - Murine homodimeric adhesion/growth-regulatory galectins-1, -2 and -7: comparative profiling of gene/ promoter sequences by database mining, of expression by RT PCR/immunohistochemistry and of contact sites for carbohydrate ligands by computational chemistry. AB - Following the detection of individual members of the family of galectins it is an obvious challenge to define the extent of functional overlap/divergence among these proteins. As a step to address this issue a comparative profiling has been started in the mouse as a model organism, combining sequence analysis, expression patterns and structural features in the cases of the homodimeric galectins-1, -2 and -7. Close relationship was apparent at the level of global gene organization. Scrutiny of the proximal promoter regions for putative transcription-factor binding sites by two search algorithms uncovered qualitative and quantitative differences with potential to influence the combinatorial functionality of regulatory sequences. RT-PCR mapping with samples from an array of 17 organs revealed significant differences, separating rather ubiquitous gene expression of galectin-1 from the more restricted individual patterns of galectins-2 and -7. Using specific antisera obtained by affinity depletion including stringent controls to ascertain lack of cross-reactivity these results were corroborated at the level of galectin localization in fixed tissue sections. Nuclear presence was seen in the case of galectin-1. In addition to nonidentical expression profiles the mapping of the carbohydrate recognition domains of galectins-1 and -7 by homology modelling and docking of naturally occurring complex tetra- and pentasaccharides disclosed a series of sequence deviations which may underlie disparate affinities for cell surface glycans/glycomimetic peptides. In view of applicability the presented data can serve as useful reference to delineate changes with respect to disease and in genetically engineered models. To enable more general conclusions on the galectin network it is warranted to further pursue this combined approach within this lectin family. PMID- 17706018 TI - The influence of endothelin-A receptor gene polymorphism on the progression of autosomal dominant polycystic kidney disease and IgA nephropathy. AB - ADPKD is the most common hereditary renal disease. IGAN is a mesangial proliferative glomerulonephritis characterized by diffuse mesangial deposition of immunoglobulin A. ET-1 has been suggested to be a major disease-promoting factor in renal diseases. The vasoconstrictor effect of ET-1 is mediated by the ET-A receptor. We have investigated the influence of C/T polymorphism in exon 8 of the EDNRA gene. A total number of 193 patients (87 males, 106 females) with ADPKD entered into this study. Patients were divided into three groups: 1. 47 pts with ESRD later than in 63 years (slow progressors), 2. 49 pts with ESRD before 45 (rapid progressors) and 3. 97 pts with ESRD between 45-63 years. Moreover, we examined a group of 153 pts with histologically proven IGAN (116 males, 37 females). Pts were divided into two groups: 1. 79 pts with ERSD during 5 years of the study (IGAN rapid progressors) and 2. 74 patients with normal renal function (IGAN slow progressors). As a control group we used 100 genetically unrelated healthy subjects. The distribution of C/T polymorphism did not significantly differ between rapid and slow progressors of ADPKD and IGAN. The comparison of ESRD ages showed that CC females with ADPKD failed significantly later than CT heterozygotes: CC (57.4 +/- 8.1 years), CT (53.0 +/- 9.1 years) and TT (54.5 +/- 6.4years) (t-test, P = 0.018). To conclude, the CC genotype could be protective in ADPKD females. This genotype was described to be associated with lower pulse pressure. PMID- 17706019 TI - Apolipoprotein E gene polymorphism in the Mongolian population. AB - Apolipoprotein E plays a key role in the regulation of lipid metabolism. ApoE function is determined by the presence of three common alleles (epsilon2, epsilon3, epsilon4). The apo epsilon3 allele is the most prevalent, apo epsilon2 is associated with dysbetalipoproteinaemia, and apo epsilon4 is frequently associated with an increased risk for cardiovascular and Alzheimer's diseases. Mongolian population has a high rate of cardiovascular mortality and morbidity and there might be genetic susceptibility of the population to cardiovascular disease. The aim of our study was to establish the frequency of apoE genotypes in 744 Mongolian subjects and to compare the results with findings from other Asian populations. The apo E sequence was amplified using polymerase chain reaction and apo E genotyping was performed by restriction enzyme cleavage with CfoI. The relative apoE allele frequencies were epsilon2 = 3.7%, epsilon3 = 80.8%, and epsilon4 = 15.5%, the genotype frequencies were epsilon2/epsilon2 = 0% (N = 0), epsilon2/epsilon3 = 5.7% (N = 42), epsilon2/epsilon4 = 1.7% (N = 13), epsilon3/epsilon3 = 65.3% (N = 486), epsilon3/epsilon4 = 25.4% (N = 189), epsilon4/epsilon4 = 1.9% (N = 14); the occurrence of the risk epsilon4 allele in Mongolia is among the highest in Asia. The high frequency of the apo epsilon4 allele may increase the susceptibility of Mongolian population to cardiovascular diseases. PMID- 17706020 TI - Risedronate has no adverse effects on mouse haematopoiesis. AB - Bisphosphonates are commonly used for treatment of osteoporosis. They inhibit osteoclast activity and thus bone resorption. It was shown that they also affect some other cell types including tumour and endothelial cells. The effects of risedronate on bone marrow microenvironment were not studied yet. As endothelial cells are integral part of bone marrow microenvironment, it is important to know whether prolonged administration of bisphosphonates does not affect haematopoietic stem cells and bone marrow haematopoiesis. We fed mice two weeks with risedronate. We found no effect of risedronate treatment on bone marrow stem cells using the method of congenic bone marrow repopulation. Risedronate administration in the dose which is considered to be comparable to a dose of risedronate used for treatment of osteoporosis in women seems to be safe in terms of effects on mouse haematopoiesis. PMID- 17706021 TI - The spectrum and types of adverse side effects to biological immune modulators: a proposal for new classification. AB - In recent years, a growing number of biological agents such as cytokines, monoclonal antibodies and fusion proteins have become available for the treatment of various autoimmune, neoplastic, cardiovascular, infectious, allergic, and other conditions. Their introduction has resulted in marked clinical improvements for many patients. Nevertheless, a variety of adverse side effects have been observed with these agents. Based on the special features of biological agents a new classification of these side effects of biological agents is proposed- related but clearly distinct from the classification of side effects observed with chemicals and drugs. This classification differentiates five distinct types, namely clinical reactions due to high cytokine levels (type alpha), hypersensitivity due to an immune reaction against the biological agents (type beta), immune or cytokine imbalance syndromes (type gamma), symptoms due to cross reactivity (type delta), and symptoms not directly affecting the immune system (type epsilon). This classification could help to better deal with the clinical features of these side effects, to identify possible individual and general risk factors and to direct research in this novel area of medicine. PMID- 17706022 TI - [Current research on diagnosis and treatment of neonatal hypoxic-ischemic encephalopathy]. PMID- 17706023 TI - [A preliminary study on diagnosis and grading of hypoxic-ischemic brain damage of premature infants]. AB - OBJECTIVE: Hypoxic-ischemic brain damage (HIBD) occurs frequently in premature infants, resulting death or neurological sequela in some survivors. Up to now, however, there are no diagnostic criteria for this disease. The aim of this study was to explore the diagnostic criteria and the grading principle for HIBD of premature infants. METHODS: The clinical data of 453 premature infants who were diagnosed with HIBD based on the diagnostic criteria for HIBD of term infants, including medical history, clinical manifestations, laboratory results and imaging findings, were studied retrospectively. RESULTS: A preliminary diagnostic criteria for HIBD of premature infants was propounded based on clinical and pathologic features of brain damage of premature infants. Of the 453 premature infants, 346 (76%) matched the diagnostic criteria. Of the 346 cases, PaO2 (42.21 +/- 8.33 mmHg) and /or SaO2 (68.49 +/- 5.19%) decreased in 208 patients and the BE value (-10.86 +/-3.41 mmol/L) decreased in 138 patients. The sensitivity and specificity of cranial computer tomography for the diagnosis of HIBD in premature infants was 100% and 17.8%, respectively. Cranial ultrasound displayed a sensitivity of 87.9% and specificity of 100% for the diagnosis of HIBD in premature infants. CONCLUSIONS: The diagnostic criteria used for HIBD for term infants is not suitable for premature infants. This study puts forward the reference diagnostic criteria of premature HIBD as following: 1) evidence of hypoxia; 2) neurological symptoms and signs; 3) imaging findings: severe brain edema, germinal matrix intraventricular hemorrhage (GMH-IVH), periventricular leukomalacia (PVL), or brain infarction, and/or the resistance index (RI) > 0.75 or < 0.55 showed by cranial ultrasound; 4) Brain damage caused by infection, electrolyte disturbance and congenital metabolic disease was excluded. The grading principle of premature HIBD is proposed as follows: MILD HIBD when cranial ultrasound shows grade I-II of GMH-IVH or PVL, and SEVERE HIBD when cranial ultrasound shows grade III-IV of GMH-IVH or PVL. PMID- 17706024 TI - [Risk factors for intracranial hemorrhage in very low birth weight infants]. AB - OBJECTIVE: To study the risk factors for intracranial hemorrhage in very low birth weight infants. METHODS: Data from 169 very low birth weight (VLBW) infants (birth weight 1000-1500 g; gestational age 23-36 weeks) were studied retrospectively. Twenty-nine perinatal and postnatal factors were analyzed by Crosstabs Test with SPSS 12.0. A logistic regression analysis was used to identify the risk factors associated with the development of intracranial hemorrhage. RESULTS: Multivariate logistic analysis revealed that rupture of membranes (OR=0.146, 95%CI=0.22-0.964, P < 0.05), 1-minute Apgar score < or = 7 (OR=0.112, 95%CI=0.21-0.591, P < 0.01), pulmonary surfactant therapy (OR=0.110, 95%CI=0.24-0.504, P < 0.01), mechanical ventilation therapy (OR =0.076, 95%CI=0.009-0.668, P < 0.05), mechanical ventilation duration > 72 hrs(OR=0.053, 95%CI=0.007-0.410, P < 0.01), prothrombin time > 20 seconds (OR=4.186, 95%CI=1.606-10.923, P < 0.01), pH value on day 1 of life < 7.25 (OR=0.421, 95%CI=0.179-0.995, P < 0.05) and hyponatremia on day 1 (OR= 0.27, 95%CI=0.077 0.940, P < 0.05) or 2 (OR=2.480, 95%CI=1.053-5.838, P < 0.05) of life were risk factors for intracranial hemorrhage. CONCLUSIONS: 1-minute Apgar score < or =7 and mechanical ventilation treatment were leading risk factors for intracranial hemorrhage, followed by abnormal coagulation and electrolytes related to perinatal asphyxia in VLBW infants. These findings can be used to improve the surveillance and prophylaxis measures in VLBW infants at high risk. PMID- 17706025 TI - [Effect of ventricle injection of Nogo-A antibody on neuronal regeneration following hypoxic-ischemic brain damage in the neonatal rat]. AB - OBJECTIVE: Nogo-A antibody IN-1 can neutralize Nogo-A, a neurite growth inhibitory protein, promoting axonal regeneration following lesions of the central nervous system (CNS) in adult rats. This study aimed to examine the effect of ventricle injection of Nogo-A antibody on neuronal regeneration in neonatal rats following hypoxic-ischemic brain damage (HIBD). METHODS: A model of neonatal HIBD was prepared by the ligation of the left common carotid artery, followed by 8% hypoxia exposure. Forty HIBD rats were randomly given a ventricle injection of 10 microL Nogo-A antibody IN-1 (IN-1 group) or 10 microL artificial cerebrospinal fluid (artificial CSF group) (n=20 each). Another 20 neonatal rats were sham-operated, without hypoxia-ischemia, and were used as the controls. The levels of Nogo-A and GAP-43 protein in the brain were measured by immunohistochemistry. RESULTS: The number of immunohistory positive cells of Nogo A in the brain in the IN-1 group (28.61+/-1.70) was obviously less than that in the artificial CSF (39.52 +/-1.40) and the sham-operated groups (32.78 +/- 1.87) (both P < 0.01). There were significant differences in the Nogo-A protein expression between the artificial CSF and the sham-operated groups (P < 0.01). The GAP-43 protein expression in the IN-1 group (31.14 +/- 1.88) was noticeably higher than that in the artificial CSF group (27.73 +/- 1.43 ) (P < 0.01). Both the IN-1 and the artificial CSF groups showed lower GAP-43 protein levels than the sham-operated groups (33.64 +/- 1.24) (both P < 0.01). CONCLUSIONS: Nogo-A antibody can reduce the expression of Nogo-A protein in the brain and thus promote neuronal regeneration in neonatal rats following HIBD. An increased GAP 43 protein expression in the brain after Nogo-A antibody administration shows an enhanced neuronal regeneration in the neonatal rats following HIBD. PMID- 17706026 TI - [Effect of cerebral mild hypothermia on cerebral mitochondrial ATPase activity in neonatal rats with hypoxic-ischemic brain damage]. AB - OBJECTIVE: To study the effect of cerebral mild hypothermia on cerebral mitochondrial ATPase activities in neonatal rats with hypoxic-ischemic brain damage (HIBD). METHODS: Eighty-four seven-day-old Wistar rats were randomly assigned into four groups: sham-operated normothermic, sham-operated mild hypothermic, HIBD normothermic and HIBD mild hypothemic. HIBD was induced by left common carotid artery ligation, followed by 8% hypoxia exposure. At each time interval of 2, 6, and 12 hrs post-hypoxia-ischemia (HI), 7 rats were sacrificed and the brain tissues were sampled for detecting the activities of mitochondrial Na+K+ATPase and Ca2+ATPase. RESULTS: The activities of mitochondrial Ca2+ATPase decreased significantly in the two HIBD groups compared with those of the two sham-operated groups at 2, 6, and 12 hrs post-HI. The HIBD mild hypothemic group had higher mitochondrial Ca2+ATPase activities compared with the HIBD normothermic group at 2, 6, and 12 hrs post-HI (5.25 +/- 0.61 micromol/mgPr.h vs 3.17 +/- 0.81 micromol/mgPr.h 4.59 +/- 0.81 micromol/mgPr.h vs 2.26 +/- 0.53 micromol/mgPr.h4.61 +/- 0.62 micromol/mgPr.h vs 1.31 +/- 0.78 micromol/mgPr.H, respectively) (P < 0.01). The activities of mitochondrial Na+K+ATPase decreased significantly in the two HIBD groups compared with those of the two sham-operated groups at 6 and 12 hrs post-HI. A significant difference was observed in the mitochondrial Na+K+ATPase activities between the HIBD mild hypothemic and HIBD normothermic groups at 6 and 12 hrs post-HI (5.25 +/- 0.66 micromol/mg Pr.h vs 3.76 +/- 0.78 micromol/mgPr.h, 4.74 +/- 0.80 micromol/mgPr.h vs 3.12 +/- 0.53 micromol/mgPr.h; P < 0.01). CONCLUSIONS: Mild hypothermia following HIBD inhibits the decline in cerebral mitochondrial Ca2+ and Na+K+ ATPase activities in neonatal rats, thus providing protective effects against HIBD. PMID- 17706027 TI - [Effect of hyperbaric oxygen therapy administered at different time on white matter damage following hypoxic-ischemic brain damage in neonatal rats]. AB - OBJECTIVE: A recent study has suggested that hyperbaric oxygen (HBO) therapy administered within 3 hrs following hypoxic-ischemic brain damage (HIBD) may alleviate brain white matter damage (WMD) in neonatal rats. However it is unclear whether a delayed HBO therapy (more than 3 hrs following HIBD) has neuroprotective effects in neonatal rats. This study aimed to explore the effect of HBO therapy administered at different time points following HIBD on WMD in neonatal rats. METHODS: The HIBD model was prepared according to the Rice Vannucci procedure in 7-day-old Sprague-Dawley rats. HBO therapy was administered at 3, 6, 12, 24 or 72 hrs after HIBD, once daily for consecutive 7 days. T-maze test, the foot-fault test and the radial arm maze test were performed after 14 days of HIBD. Myelin basic protein (MBP) in the callositas and corpora striata was examined by immunohistochemical method 28 days after HIBD. RESULTS: The rats receiving HBO therapy at 3, 6 and 12 hrs after HIBD performed significantly better in the T-maze test, the radial arm maze test and the foot-fault test than the untreated HIBD rats. There were no significant differences in the behavioral test results between the HBO-treated groups administered HBO at 24 and 72 hrs after HIBD and the untreated HIBD group. The MBP expression in the HBO-treated groups treated within 12 hrs after HIBD was significantly higher than that in the untreated HIBD group (P < 0.05). When the HBO therapeutic window was delayed to 24 hrs after HIBD, there were no significant differences in the MBP expression between the HBO-treated and the untreated HIBD groups. CONCLUSIONS: HBO therapy administered within 12 hrs following HIBD can alleviate brain WMD in neonatal rats, but the efficacy of HBO therapy administered 24 hrs after HIBD does not appear to be satisfactory. PMID- 17706028 TI - [Roles of glutamate receptor 2 and cellular free calcium in the pathogenesis of periventricular leukomalacia]. AB - OBJECTIVE: To study the expression of the AMPA receptor subunit glutamate receptor 2 (GluR2) and the cellular free calcium concentration in the white matter of neonatal rats with periventricular leukomalacia (PVL) and their roles in the pathogenesis of PVL. METHODS: A PVL model was prepared by unilateral carotid artery ligation (UCL) followed by exposure to 6% oxygen for 4 hrs in 2 day-old rats. The neonatal rats performed a sham operation, without hypoxia ischemia (HI), were used as the control group. At 12, 24, 48 and 72 hrs of HI, the expressions of GluR2 mRNA and protein in the white matter were detected using real time quantitative PCR and Western blot respectively. Spectrophotofluorimetry and Fura 2/AM were used to detect the cellular free calcium concentration. RESULTS: The expressions of GluR2 mRNA and protein in the white matter were significantly reduced in the PVL group at 24 hrs of HI, and remained at lower expressions until 72 hrs of HI compared with the control group (P < 0.05). The cellular free calcium concentrations increased significantly in the PVL group at 12 hrs of HI, and remained at higher levels until 72 hrs of HI compared with the control group (P < 0.05). CONCLUSIONS: The expressions of GluR2 mRNA and protein in the white matter decreased whereas the cellular free calcium concentration increased in neonatal rats with PVL. The decreased expression of GluR2 might lead to the overloading of cellular calcium in the white matter, which may cause neuronal damage and death. PMID- 17706029 TI - [Expression of P75NTR protein and RhoA mRNA in the brain of neonatal rats with white matter damage]. AB - OBJECTIVE: Recent studies have indicated that the signal pathway of NgR-P75NTR- RhoA plays a key role in nerve injury and remodeling, but its exact mechanism and the role of the downstream molecule RhoA regulated by P75NTR remain unclear in hypoxia-ischemia (HI) neonatal animals. The present study was designed to assess the expression of P75NTR protein and RhoA mRNA in neonatal white matter and to investigate their relationship in newborn rats with white matter damage (WMD). METHODS: The rat WMD model was established by the ligation of right common carotid artery, followed by 6% hypoxia exposure for 4 hrs. The control group was sham-operated, without HI treatment. The histological changes of brain tissue were observed under light and electron microscopes. Expression of P75NTR protein and RhoA mRNA in the brain white matter after 12, 24, 48 and 72 hrs and 7 days of HI were detected by RT-PCR and immunohistochemistry, respectively. RESULTS: Periventricular white matter damage was observed by 48 hrs of HI. Expression of P75NTR protein increased in the striatum and callosum zones at 12 hrs, peaked at 48 hrs, and remained at a higher level than control until 72 hrs of HI in the WMD group (P < 0.01). After 7 days of HI expression of P75NTR protein was no longer statistically different from controls. The RhoA mRNA was higher in the WMD group for the first 72 hrs and then declined to control values. CONCLUSIONS: Increased P75NTR protein might mediate apoptosis of nerve cells and inhibit the regeneration of neuron axons. The subsequent decline back to control value may be correlated with the aggregation of necrosis of nerve cells after HI. The patterns of RhoA mRNA expression were consistent with those of P75NTR protein, suggesting that the increased P75NTR level may promote RhoA mRNA expression. PMID- 17706030 TI - [Expression of ephrin-B3 mRNA and cellular apoptosis in the brain of neonatal rats with periventricular leukomalacia]. AB - OBJECTIVE: To study the changes of ephrin-B3 mRNA expression and cellular apoptosis in the brain of neonatal rats with periventricular leukomalacia (PVL) and to explore the possible role of ephrin-B3 in the pathogenesis of PVL. METHODS: Two-day-old SD rats were randomly assigned to two groups: PVL and control. PVL model was prepared by right common carotid artery ligation followed by 4-hr 6% oxygen exposure. The control group, without ligation of the artery and hypoxia treatment, was sham operated. The rats were then sacrificed and brain tissues were collected at 0, 8, 24, 48 and 72 hrs and at 7 days of hypoxic ischemia (HI). Hematoxylin and eosin staining was used for pathologic studies. Real time RT-PCR was applied to detect brain ephrin-B3 mRNA expression. DAPI staining was applied to detect neuronal apoptosis. RESULTS: The brain ephrin-B3 mRNA expression increased significantly in the PVL group at 8, 24, 48 and 72 hrs and at 7 days of HI compared with that of the control group (P < 0.05). The apoptotic cells in the brain of the PVL group were significantly more than that of the control group at 8, 24, 48 and 72 hrs of HI (P < 0.05). CONCLUSIONS: ephrin-B3 mRNA expression and cellular apoptosis in the brain increased significantly in neonatal rats with PVL, which suggests that ephrin-B3 may participate in the pathogenesis of PVL in neonatal rats. PMID- 17706031 TI - [Effects of calcium and calmodulin dependent kinase against hypoxic neuronal injury]. AB - OBJECTIVE: To study the effects of calcium and calmodulin dependent kinase against hypoxic neuronal injury and its possible mechanisms. METHODS: Embryonic cortical neurons of 17-day pregnant embryo Sprague-Dawley rats were cultured in vitro and the cultured neurons were randomly allocated into different groups that exposed to hypoxia or hypoxia +calcium channel antagonist. Nimodipine and MK-801 were used to block the L-voltage sensitive calcium channel and NMDA receptor respectively before hypoxia. The methyl thiazolyl tetrazolium (MTT) method was used to determine the cell viability. Fluo-4AM, an intracellular calcium indictor, was used to detect the changes of intracellular calcium after hypoxia. The expressions of CaMKII and CaMKIV were detected by Western blot. RESULTS: The cell viability of the nimodipine or MK-801-treated groups was significantly higher than that of the untreated hypoxia group. The intracellular calcium level of the nimodipine-treated group decreased rapidly after hypoxia. Compared to nimodipine treatment, MK-801 treatment could inhibit hypoxia-induced calcium influx for a longer time. Nimodipine treatment decreased the CaMKII expression while MK-801 treatment decreased the CaMKIV expression. CONCLUSIONS: Nimodipine and MK-801 protect neurons from hypoxic injury possibly by the inhibition of CaMKII and CaMKIV expressions respectively. PMID- 17706032 TI - [Treatment of periventricular leukomalacia in preterm infants]. PMID- 17706033 TI - [Imaging diagnosis of white matter damage in preterm infants]. PMID- 17706034 TI - Clinical features and growth hormone receptor gene mutations of patients with Laron syndrome from a Chinese family. AB - Laron syndrome is an autosomal recessive disorder caused by defects of growth hormone receptor (GHR) gene. It is characterized by severe postnatal growth retardation and characteristic facial features as well as high circulating levels of growth hormone (GH) and low levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3). This report described the clinical features and GHR gene mutations in 2 siblings with Laron syndrome in a Chinese family. Their heights and weights were in the normal range at birth, but the growth was retarded after birth. When they presented to the clinic, the heights of the boy (8 years old) and his sister (11 years old) were 80.0 cm (-8.2 SDS) and 96.6 cm (-6.8 SDS) respectively. They had typical appearance features of Laron syndrome such as short stature and obesity, with protruding forehead, saddle nose, large eyes, sparse and thin silky hair and high-pitched voice. They had higher basal serum GH levels and lower serum levels of IGF-I, IGFBP-3 and growth hormone binding protein (GHBP) than normal controls. The peak serum GH level after colonidine and insulin stimulations in the boy was over 350 ng/mL. After one-year rhGH treatment, the boy's height increased from 80.0 cm to 83.3 cm. The gene mutation analysis revealed that two patients had same homozygous mutation of S65H (TCA -->CCA) in exon 4, which is a novel gene mutation. It was concluded that a definite diagnosis of Laron syndrome can be made based on characteristic appearance features and serum levels of GH, IGF-I, IGFBP-3 and GHBP. The S65H mutation might be the cause of Laron syndrome in the two patients. PMID- 17706035 TI - [Juvenile psoriatic arthritis]. AB - A case of juvenile psoriatic arthritis in a 12 year-old boy was reported. The patient had a history of one and half a year of bilateral heel pain, followed by pain in the right knee and ankle and right hip joint. He developed psoriatic lesions affecting his nails and skin. He had increased erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) contents. Human leukocyte antigen (HLA) B27 was detected but serum rheumatoid factor was not in the patient. A skin biopsy revealed psoriasis and ultrasonography demonstrated synovitis in right knee and ankle. Juvenile psoriatic arthritis was diagnosed based on his physical, laboratory and skin biopsy findings. A treatment with nonsteroidal anti inflammatory drugs and sulfasalazine produced no effect. Leflunomide in conjunction with anti-TNF biologic agents (Etanercept) was administered, followed by symptomatic improvement 2 weeks later. PMID- 17706036 TI - [Efficacy of low-dose heparin and prostaglandin E1 in the prevention of hepatic veno-occlusive disease after allogenic hematopoietic stem cell transplantation in children with beta-thalassemia major]. AB - OBJECTIVE: Hepatic veno-occlusive disease (HVOD) is one of the most serious complications after allogenic hematopoietic stem cell transplantation (allo-SCT). Endothelial injury, leading to deposition of coagulation factors in the terminal hepatic venules, is believed to the key event in the pathogenesis of HVOD. This study was designed to explore the efficacy of low-dose heparin and prostaglandin E1 (PGE1) in the prevention of HVOD after allo-SCT in children with beta thalassemia major. METHODS: Forty-three children with beta-thalassemia major received allo-SCT. For the prevention of HVOD, 23 of the 43 patients received low dose heparin (100 IU/kg.d) and also received PGE1 (7.2 microg/kg x d) by continuous intravenous infusion (study group) from the beginning of conditioning treatment to the 30th day after allo-SCT. Patients who received continuous infusions of PGE1 (7.2 microg/kg x d) alone were used as the control group (n=20). RESULTS: HVOD occurred in 6 patients (26.1%) in the study group (3 mild, 3 moderate). Twelve patients in the control group had HVOD (60.0%) (3 mild, 3 moderate, 6 severe)(P < 0.05). In the study group, 5 cases of HVOD were treated successfully and one died from other complications. Of the 12 cases of HVOD in the control group, 10 patients were treated successfully and two patients died from HVOD. There were no obvious drug adverse effects in the two groups. CONCLUSIONS: Low-dose heparin and PGE1 is more effective than PGE1 alone for the prevention of HVOD after allo-SCT. PMID- 17706038 TI - [Clinical features and prognosis of advanced neuroblastoma in children]. AB - OBJECTIVE: To investigate the clinical features, treatment modalities and the prognosis of advanced neuroblastoma in children. METHODS: The medical records of 63 children with stage III or IV neuroblastoma from January 1996 to December 2005 were retrospectively reviewed. Sixty patients were treated by tumor resection and (or) chemotherapy and (or) radiation. Fourteen out of the 60 patients received another autologous peripheral blood stem cell transplantation. RESULTS: Of the 63 patients with advanced neuroblastoma, the male/female ratio was 2.7:1 and the median age at diagnosis was 4 years old. Most of the initial symptoms included pyrexia, abdominal pain, abdominal mass, and leg or articular pain. Primary tumor sites were adrenal (38%), retroperitoneal (35%), mediastinal (17%), pelvic (6%) and cervical (2%). The sites of metastasis at diagnosis included local (41%) and (or) distant (37%) lymph nodes, bone marrow (60%), bone (46%) and liver (16%). The median survival time of the 63 patients was 32.7 months. The 2-year survival rate was 44.3%. Statistical analysis demonstrated that unfavorable survival prognostic factors were the following: age > 1 year at diagnosis (P < 0.05); serum neuro-specific enolase > 100 mg/L (P < 0.05); serum lactic dehydrogenase > 1500 U/L (P < 0.01); serum ferritin >150 mg/L (P < 0.05). The overall survival period of the patients was prolonged through total resection of the primary tumor (P < 0.05). Intensive chemotherapy in combination with autologous peripheral blood stem cell transplantation could also result in a prolonged overall survival period (P < 0.01). CONCLUSIONS: Neuroblastoma with advanced stages often presents with various clinical manifestations and has a poor prognosis. It is beneficial to improve the prognosis of neuroblastoma through an early diagnosis and a comprehensive therapy including total resection of the primary tumor, autologous peripheral blood stem cell transplantation and intensive chemotherapy. PMID- 17706037 TI - [Changes of inflammation-associated factors in children with Mycoplasma pneomoniaepneumonia and concomitant systemic inflammatory response syndrome]. AB - OBJECTIVE: To study the relationship between the changes of inflammation associated factors, C-reactive protein (CRP), procalcitonin (PCT), erythrocyte sedimentation rate (ESR), white blood cell (WBC) and neutrophils, and the severity in children with Mycoplasma pneomoniae pneumonia (MPP). METHODS: Ninety two children with acute MPP consisting of 52 cases with concomitant systemic inflammation response syndrome (SIRS) and 40 cases without SIRS were enrolled in this study. The 52 cases with concomitant SIRS were classified into two groups based on the severity of SIRS: mild SIRS (n=25) and severe SIRS (n=27). CRP, PCT, ESR and WBC count and the percentage of neutrophils (NE%) were detected on admission and one week after anti-inflammation treatment. RESULTS: All of patients showed increased serum CRP contents at admission. The serum CRP contents were the highest in the severe SIRS group, followed by the mild SIRS and non-SIRS groups on admission (P < 0.05 or 0.01). The serum CRP contents were reduced in all of patients after 1-week treatment. The severe SIRS group still demonstrated higher serum CRP contents than the non-SIRS and the mild SIRS groups (P < 0.01). The severe SIRS group had increased serum PCT contents on admission, which were significantly higher than those of the mild SIRS and non-SIRS groups (P < 0.01). After 1-week treatment, the serum PCT contents were reduced in the severe SIRS group but remained higher than in the mild SIRS and non-SIRS groups (P < 0.01). ESR increased significantly in the severe SIRS group than in the mild SIRS and non-SIRS groups on admission (P < 0.01). One-week treatment did not significantly decrease ESR in all three groups. The WBC count and NE% in the mild and severe SIRS groups were significantly higher than in the non-SIRS group and the severe SIRS group had higher WBC count and NE% than the mild SIRS group on admission (P < 0.05). The WBC count and NE% decreased after 1-week treatment in the mild and severe SIRS groups (P < 0.05). One inflammation-associated factor (only CRP) increase was predominant in the non-SIRS group (65%), 2 factors increase in the mild SIRS group (56%), and three or more factors increase in the severe SIRS group (70.4%). CONCLUSIONS: The detection of inflammation-associated factors, CRP, PCT, ESR, WBC and neutrophils, are valuable to the evaluation of severity in MPP. PMID- 17706039 TI - [Decreased active oxygen metabolism in neutrophils of preterm infants]. AB - OBJECTIVE: To investigate the influence of neonatal maturity on active oxygen metabolism in neutrophils and possible causes of a high susceptibility to bacterial infection in preterm infants. METHODS: Thirty-five preterm infants born at a gestation age of 26-32 weeks (< or =32 weeks group, n=15) and at 33-36 weeks (> 32 weeks group, n=20) and 23 full-term infants (control group) were enrolled in this study. The samples of whole cord blood from the two preterm groups and the control group were stimulated in vitro with live bacteria,Staphylococcus aureus ( S. aureus) and Escherichia coli (E. coli) and stained with hydroethedine, an indicator of superoxide. The percentage of neutrophils which produced superoxide and the mean fluorescence intensity for superoxide production were measured by flow cytometry. The incidence of bacterial infection during hospital stay was compared between the two preterm groups. RESULTS: Under S. aureus or E. coli stimulation, the percentage of neutrophils which produced superoxide in the < or =32 weeks group was significantly lower than that of the > 32 weeks group and the control group (P < 0.01). The percentage of neutrophils which produced superoxide was closely related to gestational age in preterm infants ( y=2.66 x, P < 0.01).There were no significant differences in the blood level of superoxide production in neutrophils among the three groups. The incidence of bacterial infection during hospital stay in the < or =32 weeks group (40%) was significantly higher than that the > 32 weeks group (10%) (P < 0.05). CONCLUSIONS: The capability of active oxygen metabolism in neutrophils was significantly related to the gestational age in preterm infants. The decreased capability of active oxygen metabolism might be contributed to a higher susceptibility to bacterial infection in preterm infants. PMID- 17706040 TI - [Molecular analysis of beta-thalassemia intermedia in Guangdong Province]. AB - OBJECTIVE: To determine the molecular defects of beta-thalassemia intermedia in Guangdong Province and to provide basis for gene diagnosis and gene therapy of this disorder. METHODS: DNA analysis of the alpha, beta and gamma globin genes was performed in 18 children with beta-thalassemia intermedia from Guangdong Province using polymerase chain reaction (PCR), microarray technique, Southern blot and direct sequencing. RESULTS: Of the 18 patients,one was identified as the homozygote of TATA box-28 (A-->G) change, one as the homozygote of betaE26 (G- >A) mutation, ten as compound heterozygotes of TATA box- 28 (A-->G) mutation with other beta-globin mutations, two as compound heterozygotes of betaE26 (G-->A ) mutation with other beta globin mutations, and four as double heterozygotes for beta globin and alpha globin mutations including -SEA and -alpha(4.2). CONCLUSIONS: The molecular defects of beta- thalassemia intermedia in Guangdong Province were highly heterogeneous and its spectrum was different from the reports from other provinces of China. PMID- 17706041 TI - [IgE level of cord blood in neonates with meconium-stained amniotic fluid]. AB - OBJECTIVE: To study the effects of meconium-stained amniotic fluid on the cord blood IgE level in neonates. METHODS: A total of 404 neonates with meconium stained amniotic fluid who were born by cesarean delivery between August 2003 and August 2005 (meconium-stained group) and 256 neonates with normal amniotic fluid delivered by cesarean (control group) were enrolled in this study. The meconium stained group consisted of 80 cases of mild, 62 cases of moderate and 262 cases of severe meconium-stained amniotic fluid. The cord blood IgE level was measured using ELISA. RESULTS: The cord blood IgE level in the meconium-stained group was statistically higher than that in the control group (t = 4.03, P < 0.01). There were significant differences between the mild and severe meconium-stained subgroups and the control group for the cord blood IgE level (F=4.28, P < 0.01). The cord blood IgE level in neonates with premature rupture of the membrane between the meconium-stained and the control groups was statistically different. Sexes, gestational age, birth weight and birth order were not associated with the IgE level of cord blood. CONCLUSIONS: The cord blood IgE levels in neonates with meconium-stained amniotic fluid increase. Premature rupture of the membranes may be associated with an increase of cord blood IgE level. PMID- 17706042 TI - [Pattern of electrogastrogram in healthy neonates]. AB - OBJECTIVE: To investigate the electrogastrogram (EGG) characteristics of healthy neonates. METHODS: Twenty healthy neonates born at 37-39 weeks of gestation (11 males and 9 females, Apagar's score 9.3 +/- 0.4) were enrolled in this study. EGG recordings were performed for half an hour pre- and postprandially at an interval of a week from birth until age 4 weeks. The EEG variables measured included the percentage of normal gastric rhythm, the percentage of tachygastria and bradygastria, the fed-to-fasting ratio of the EEG dominant power, as well as the EEG dominant frequency and its instability coefficient. The paired sample t test (95% CI) was used to compare the recordings. RESULTS: Between birth and age 28 days, the percentage of normal gastric rhythm ranged from 38.2 +/- 4.9% to 39.7 +/- 3.5% of recorded time, tachygastria was observed in the range of 23.7 +/- 5.4% to 23.5 +/- 4.3% of recorded time, and bradygastria was shown to be in the range of 38.1 +/- 5.5% to 36.8 +/- 3.9% of recorded time in the 20 neonates before meal. Statistically significant differences were not seen in neonates with different ages as well as during pre- and postprandial periods. The EEG dominant frequency of neonates before meal was 2.38 +/- 0.5, 2.43 +/- 0.2, 2.54 +/- 0.3, 2.57 +/- 0.2 and 2.59 +/- 0.1 cpm at birth and at postnatal age of 7, 14, 21 and 28 days respectively. There were no significant differences in the dominant frequency and the coefficient of instability of the dominant frequency during pre and postprandial periods. The EEG dominant frequency at postnatal age of 14, 21 and 28 days during pre- and postprandial periods was significantly higher than that at birth and at postnatal age of 7 days (P < 0.05). The coefficient of instability of the dominant frequency at postnatal age of 21 and 28 days was significantly lower than that at birth and at postnatal age of 7 and 14 days (P < 0.05). There were no statistically significant differences in the fed-to-fasting ratio of EGG dominant power in neonates with different ages. CONCLUSIONS: The pattern of electrical activity in the normal neonatal stomach appears to be different from that demonstrated in adults and children. The percentage of normal gastric rhythm is lower, and tachygastria and bradygastria are more frequently seen. The EEG dominant frequency increases with postnatal age in neonates. PMID- 17706043 TI - [Relationship between Helicobacter pylori infection and Henoch-Schonlein purpura with gastrointestinal involvement in children]. AB - OBJECTIVE: To study the relationship of Helicobacter pylori (H. pylori) infection with the development and relapse of Henoch-Schonlein purpura (HSP) with gastrointestinal involvement in children. METHODS: Thirty-six HSP children with gastrointestinal manifestations and 16 of 32 HSP children without gastrointestinal involvement underwent gastroscopy and rapid urease test for H. pylori detection. Thirty healthy children served as the control group. All of the patients received 14C urea breath test and serum H. pylori antibody detections. H. pylori infection was definited when two of detection approaches demonstrated positive. RESULTS: Twenty-one of 36 HSP patients with gastrointestinal manifestations were confirmed with H. pylori infection (58.3%). Of them, the relapsed patients had an H. pylori positive rate of 81.3% (13/16), which was significantly higher than that of the newly diagnosed patients (45.0%, 9/20) (chi(2)=4.49, P < 0.05). Nine of 32 HSP patients without gastrointestinal manifestations were confirmed with H. pylori infection (28.1%); 2 of 30 healthy children showed H. pylori positive (6.7%, 2/30). There was a significant difference in the H. pylori positive rate among the three groups (chi(2)=14.7, P < 0.01). CONCLUSIONS: H.pylori infection may be associated with the development and relapse of HSP with gastrointestinal involvement in children. PMID- 17706045 TI - [Expression of mRNA of vascular endothelial growth factor in a rat model of hyperoxia-induced retinopathy]. AB - OBJECTIVE: To examine the expression of mRNA of vascular endothelial growth factor (VEGF) in a rat model of hyperoxia-induced retinopathy and to investigate the role of VEGF in the process of neovascularization in retinopathy. METHODS: One hundred fifty one-day-old neonatal Sprague-Dawley rats were randomly divided into hyperoxia-induced retinopathy and normal control groups. The rats in the retinopathy group were exposed to (80 +/- 2)% oxygen for 7 days and then replaced by room air. The rats in the control group were exposed to room air all the time of the experiment. The morphologic changes of retinal vessels were estimated by observing the vascular pattern in adenosine diphosphate ase (ADPase) stained retina flat mounts. The newborn vessels were quantified by haematoxylin and eosin staining. Reversal transcription-polymerase chain reaction (RT-PCR) was used to detect the VEGF mRNA expression. RESULTS: In the retinopathy group at 7 days of age, most of central radial vessels became constricted and blocked, and central perfusion decreased obviously. After switching to room air exposure for 7 days (14 days of age), noticeable retinal neovascularization appeared. The expression of VEGF mRNA in the retinopathy group at 7 days of hyperoxia exposure was noticeably lower than in the control group, and increased gradually after switching to room air exposure. At 9 and 14 days of age, the expression of VEGF mRNA in the retinopathy group was noticeably higher than in the control group. The expression of retinal VEGF mRNA in the retinopathy group increased before neovascularization occurred, and decreased with regression of new vessels. CONCLUSIONS: Hyperoxia exposure may decrease the transcription of VEGF mRNA and the growth of retinal blood vessels. The relative hypoxia after hyperxia withdrawal can up-regulate the transcription of VEGF mRNA, resulting in a significant retinal neovascularization. The abnormal expression of VEGF in the retina may play an important role in the development of neovascularization in retinopathy. PMID- 17706046 TI - [Effect of bifidobacteria on ileum intercellular adhesion molecule-1 expression in young rats with endotoxin-induced intestinal damage]. AB - OBJECTIVE: To investigate the effects of bifidobacteria on malondialdehyde (MDA) content and intercellular adhesion molecule-1 (ICAM-1) expression in serum and ileum tissues of young rats with endotoxin-induced intestinal damage, and possible protective mechanisms of bifidobacteria on intestines. METHODS: Eigteen day-old Wistar rats were randomly administered with normal saline (NS), lipopolysaccharide (LPS, 5 mg/kg) or LPS + bifidobacteria. Bifidobacteria (0.5 mL, twice a day) was intragastrically administrated 7 days prior to LPS injection until the end of the experiment. MDA contents in serum and ileum were detected by the TBA method. Expression of ICAM-1 protein and mRNA were evaluated by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) after 2, 6, 24 and 72 hrs of LPS injection. RESULTS: The serum and ileum MDA contents in the untreated LPS group increased significantly and reached a peak at 6 hrs of LPS injection when compared with the NS control group (ileum: 99.88 +/- 12.62 nmol/mg prot vs 84.25+/-12.96 nmol/mg prot, P < 0.05; serum: 1.67 +/- 0.30 nmol/mL vs 1.13 +/- 0.20 nmol/mL, P < 0.05). The MDA contents in ileum (92.75 +/- 9.28 nmol/mg prot) and serum (1.17 +/- 0.23 nmol/mL) in the bifidobacteria treated group at 6 hrs of LPS injection were significantly lower than in the LPS group (P < 0.05). The expression of ICAM-1 protein in the untreated LPS group remarkably increased at 6, 12, 24 and 72 hrs of LPS injection when compared with the NS control group (P < 0.01). The bifidobacteria-treated group displayed lower ICAM-1 protein levels than the untreated LPS group at 72 hrs of LPS injection (P < 0.01). The ICAM-1 mRNA expression in the untreated LPS group significantly increased at 2 hrs of LPS injection when compared with the NS control group (P < 0.01). The ICAM-1 mRNA expression in the bifidobacteria-treated group began to decrease at 2 hrs of LPS injection and was reduced again at 24 hrs after experiencing increase at 6 and 12 hrs of LPS injection when compared with the untreated LPS group (P < 0.01). CONCLUSIONS: The serum and ileum MDA contents and the expression of ICAM-1 protein and mRNA increased in young rats with endotoxin induced intestinal damage. Bifidobacteria supplementation can decrease MDA contents and inhibit ICAM-1 expressions, thus providing protections for intestines. PMID- 17706047 TI - [Primary idiopathic chylopericardium: report of 9 cases]. PMID- 17706048 TI - [Extend-spectrum beta-lactamas-producing Klebsilla pneumoniae infection in preterm infants: clinical analysis of 7 cases]. PMID- 17706049 TI - [Investigation on birth defects in 8285 perinatal infants]. PMID- 17706050 TI - [Etiology of long-time vomiting in pediatric patients]. PMID- 17706051 TI - [Cerebellar cognitive affective syndrome in pediatric patients: clinical analysis of 13 cases]. PMID- 17706052 TI - [Immunoproliferative small intestinal disease: a case report and literature review]. PMID- 17706053 TI - [Progress on diagnosis and therapy of childhood acute pancreatitis]. PMID- 17706054 TI - [Research progress on psychological and behavioral aspects of adolescents with Turner syndrome]. PMID- 17706055 TI - [Protracted and chronic diarrhea in children: current trends]. PMID- 17706056 TI - [An overview of the 12th annual conference of Hong Kong Society of Pediatric Neurology and Development]. PMID- 17706057 TI - [IgA nephropathy: modulation of progression by vitamin E, tonsillectomy, steroid and cytotoxic]. PMID- 17706058 TI - [Diagnosis and treatment of Crohn's disease in children: 10 years' clinical experience]. AB - OBJECTIVE: To enhance our understanding of pediatric Crohn's disease and improve diagnostic accuracy and therapeutic efficacy by characterizing the clinical picture and reviewing 10 years' clinical experience in diagnosis and treatment. METHODS: Nine cases with active Crohn's disease diagnosed between 1996 and 2005, including 8 males and 1 female, aged 6 - 13 years, were reviewed. Clinical, radiologic, endoscopic and histological data as well as therapeutic results were analized. RESULTS: The mean interval from the onset of symptoms to the diagnosis was 10 months. The sites of involvement were both the small intestine and colon in 6, small intestine only in 3. Abdominal pain and diarrhea were the two most common gastrointestinal symptoms. The main extraintestinal manifestations were weight loss in 7, hypoalbuminemia in 5, mild anemia in 5, fever in 4 and hypocalcemia in 2. All the patients had undergone colonoscopy, and the findings included ulcerations, segmental lesions, cobblestone appearance, pseudopolyps and perianal abnormalities. Capsule endoscopic examination in one patient demonstrated the segmental distribution with typical longitudinal cleft-like ulcers and cobblestone appearance. Gastrointestinal barium meal X-ray examination was performed in 7 patients, the main findings were segmental strictures and abnormal mucosa. Histological examination of biopsy specimens mainly showed nonspecific chronic inflammation. Non-caseating granulomas were identifiable in 2 cases. Although there were many macroscopic and microscopic features supporting the diagnosis of Crohn's disease, no epithelioid granuloma could be found in surgical specimens of two patients. Treatment was given up by parents of 2 patients after the diagnosis was established. All the other 7 patients were treated with 5-acetylsalicylic acid, antibiotics and nutritional support during the acute phase. Corticosteroids were used in two patients. Long-term remission was achieved and maintained in 3 children, and in one of them medication could be discontinued and had no signs of disease activity at the end of the follow-up. CONCLUSIONS: Children and adolescents presenting with Crohn's disease commonly have weight loss and nutritional impairment, which may provide clues to the diagnosis. Appropriate formulation and higher dosage of 5-acetylsalicylic acid [30-50 mg/(kg x d)] may be effective in inducing and maintaining remission in pediatric Crohn's disease. PMID- 17706059 TI - [Efficacy and safety of reduced osmolarity oral rehydration salts in treatment of dehydration in children with acute diarrhea--a multicenter, randomized, double blind clinical trial]. AB - OBJECTIVE: To assess the efficacy and safety of reduced osmolarity oral rehydration salts (ROORS) in treatment of mild to moderate dehydration caused by acute diarrhea in children. METHODS: A multicenter, randomized, double-blind, positive drug controlled clinical trial was conducted in 125 cases aged 1 to 17 years. These children with acute diarrhea and signs of dehydration were randomly assigned to receive either ROORS (trial group, n = 62) or oral rehydration salts II (ORS II) (control group, n = 63). The volume of intravenous infusion were recorded. The improvements of systemic symtoms and signs, diarrhea, dehydration and total scores were compared between the two groups. The adverse events and changes of electrolyte and other laboratory tests during treatment were also observed and analyzed. RESULTS: The overall effective rates in trial group and control group were 96.8% and 96.8%, respectively. The recovery of systemic symptoms, dehydration signs and diarrhea occurred in 96%, 97% and 78% patients in trial groups, and 96%, 98% and 85% patients in control group. The scores of symptoms and signs in both groups decreased significantly after treatment. All the above parameters and the number of cases who needed intravenous infusion (41 vs. 39) were not statistically different between two groups. However, the average volume of intravenously infused fluids in trial group was (450.98 +/- 183.07) ml, 24.5% less than that in the control group (597.30 +/- 343.37) ml (P < 0.05). The mean serum Na(+) concentration elevated from (137.48 +/- 4.55) mmol/L to (139.52 +/- 3.25) mmol/L (P < 0.01) in control group after treatment, but the change was not statistically significant in trail group. Serum K(+), Cl(-), HCO(3)(-) and other laboratory result did not change significantly after treatment. The total scores in both groups decreased obviously after treatment, but no significant difference was demonstrated between two groups (P > 0.05). A case in trial group had mild abdominal distention and recovered spontaneously. CONCLUSION: ROORS was shown to be effective and safe in the treatment of mild and moderate dehydration induced by acute diarrhea. Compared to ORS II, ROORS could decrease the intravenous supplement of fluid and lower the risk of hypernatremia. PMID- 17706061 TI - [Summary of national symposium on pediatric chronic diarrhea in 2006]. PMID- 17706060 TI - [Analysis of risk factors for diarrhea in breast fed infants]. AB - OBJECTIVE: To analyze possible risk factors for diarrhea in breast fed infants and provide evidences for prevention and treatment of diarrhea, reducing allergic and other diseases in infants and for renewing the definition of "physiological diarrhea". METHODS: Totally 334 infants (207 boys and 127 girls, mean age 3.0 +/- 0.4 months) who were solely breast fed and seen between August 2004 and June 2006 at the outpatient clinic of the Department of Pediatrics, the 3rd Hospital of Peking University were enrolled in this study. The following information concerning parental and the infants' possible risk factors was obtained through a questionnaire that included parents' age, education, smoking, alcohol consumption, weight, height, maternal pregnancy weight, weight gain and health status during pregnancy and family history of hypersensitivity, family history of digestive tract disease, diet of mother in lactation, the infants' age, height, weight, head circumference, chest circumference, rash, eczema, diet, vomiting, abdominal distention, and blubber. The levels of PGE(2), fat and lactose in breast milk, serum allergen and skin prick test were performed in all the 334 infants. Logistic regression analysis was performed by using the software SPSS 10.0. RESULTS: Maternal smoking (OR = 2.3), hypersensitivity (OR = 2.7), family history of hypersensitivity (OR = 2.8), diet of mother included seafood (OR = 1.8), egg (OR = 2.3) and peanut (OR = 2.0), infants' eczema (OR = 2.9), blubber (OR = 2.7), high level of PGE(2) (OR = 2.4) and fat in breast milk (OR = 3.0), serum allergen positive (OR = 4.0), positive skin prick test (OR = 2.7) were the risk factors for diarrhea in breast fed infants (P < 0.05). CONCLUSIONS: Diarrhea in breast fed infants is not a simple physiologic process. It may be associated with many factors and the underlying mechanism remains to be clarified via further studies. PMID- 17706062 TI - [Prevalence of chronic headache in Shanghai children and adolescents: a questionnaire-based study]. AB - OBJECTIVE: To explore the prevalence and characteristics of chronic headache in children and adolescents in Shanghai and to collect messages concerning the impact and compliance of medication for migraine. METHODS: A population-based questionnaire study was conducted among subjects 6 - 15 years of age sampled from primary and junior high schools in Shanghai and the subjects were followed up. RESULTS: (1) The prevalence: 8701 (88.6%) out of 9857 pupils responded to the questionnaire; 17% of the respondents had headache and in 86.4% of them the reason of headache was unknown. The prevalence of chronic headache in Shanghai children and adolescents was 7.8%, there was no significant difference between both genders (chi(2) = 0.010, P > 0.05). (2) The prevalence of chronic headache increased with age, the incidence was higher in boys before 12 years of age, while higher in girls after 12 years of age. (3) Characteristics of chronic headache: the proportion of unilateral, bilateral and headache of unknown site was similar; in most of the cases headache was localized in the temple (35.2%) and forehead region (25.6%), the duration of headache was short, always accompanied by gastrointestinal symptoms. Half of the patients reported that the headache had affected their study and daily life. (4) The status of using health care facilities: 24% of the students sought medical assistance during their headache episodes and among them only 30.9% took medicine. (5) Over-fatigue (51.4%), followed by insufficient sleep (40.4%), emotional changes (38.5%) were the main aggravating factors. The headache was also associated with positive family history and stress in studying. CONCLUSIONS: Headache is a common complaints of children, affecting the patients' study and daily life. But many patients with headache were not treated properly, therefore, the medical and educational sectors and the society should pay more attention to this problem. PMID- 17706063 TI - [Effect of external retinoic acid on Tbx1 gene during zebrafish embryogenesis]. AB - OBJECTIVE: DiGeorge/del22q11 syndrome is one of the most common genetic causes of outflow tract and aortic arch defects in human. DiGeorge/del22q11 is thought to involve an embryonic defect restricted to the pharyngeal arches and the corresponding pharyngeal pouches. Previous studies have evidenced that retinoic acid (RA) signaling is definitely indispensable for the development of the pharyngeal arches. Tbx1, one of the T-box containing genes, is proved to be the most attractive candidate gene for DiGeorge/del22q11 syndrome. However, the interaction between RA and Tbx1 has not been fully investigated. Exploring the interaction will contribute to discover the molecular pathways disrupted in DiGeorge/del22q11 syndrome, and will also be essential for understanding genetic basis for congenital heart disease. It now seems possible that genes and molecular pathways disrupted in DiGeorge syndrome will also account for some isolated cases of congenital heart disease. Accordingly, the present study aimed to extensively study the effects of external RA on the cardiac development and Tbx1 expression during zebrafish embryogenesis. METHODS: The chemical genetics approach was applied by treating zebrafish embryos with 5 x 10(-8) mol/L RA and 10(-7) mol/L RA at 12.5 hour post fertilization (hpf). The expression patterns of Tbx1 were monitored by whole-mount in situ hybridization and quantitative real time RT-PCR, respectively. RESULTS: The zebrafish embryos treated with 5 x 10(-8) mol/L RA and 10(-7) mol/L RA for 1.5 h at 12.5 hpf exhibited selective defects of abnormal heart tube. The results of whole-mount in situ hybridization with Tbx1 RNA probe showed that Tbx1 was expressed in cardiac region, pharyngeal arches and otic vesicle during zebrafish embryogenesis. RA treatment led to a distinct spatio-temporal expression pattern for Tbx1 from that in wild type embryo. The real-time PCR analysis showed that Tbx1 expression levels were markedly reduced by RA treatment. Tbx1 expression in the pharyngeal arches and heart were obviously down regulated compared to the wild type embryos. In contrast to 5 x 10(-8) mol/L RA-treated groups, 10(-7) mol/L RA caused a more severe effect on the Tbx1 expression level. CONCLUSION: These results suggested that there was a genetic link between RA and Tbx1 during development of zebrafish embryo. RA could produce an altered Tbx1 expression pattern in zebrafish. RA may regulate the Tbx1 expression in a dose-dependant manner. RA could represent a major epigenetic factor to cause abnormal expression of Tbx1, secondarily, disrupt the pharyngeal arch and heart development. PMID- 17706064 TI - [Clinical and pathological manifestations of Chinese childhood patients with primary IgA nephropathy: a national collaborative study of 33 hospitals]. AB - OBJECTIVE: Primary IgA nephropathy (IgAN) is characterized by a highly variable course ranging from a totally benign condition to rapidly progressive renal failure. About 30% of children with IgAN will eventually have end-stage renal failure after 20 years from onset. A nation-wide survey was conducted and data of hospitalized children (younger than 14 years old) with IgAN during the period of 1995 to 2004 were analyzed. The aim was to investigate the clinical and pathological characteristics, treatment and outcome of the hospitalized children with IgAN. METHODS: Questionnaires concerning children with IgAN were designed by the Subspecialty Group of Nephrology, Chinese Society of Pediatrics and distributed to the doctors of 33 hospitals in China. The criterion of IgAN was prominent and diffuse IgA deposition and to a lesser extent, other immunoglobulins in the glomerular mesangium and/or capillary loops, and purpura nephritis, lupus nephritis and hepatic disease were excluded. The data were collected and analyzed. RESULTS: From January 1, 1995 to December 31, 2004, 1349 hospitalized children were diagnosed as IgAN. The cases of childhood IgAN accounted for 1.37% of the hospitalized cases with urologic-kidney diseases and 11.18% of those who underwent renal biopsies. Complete records were available for 1203 patients. The male to female ratio was 2.07:1. Both the median ages at the disease onset and diagnosis were 9.0 years. The median duration from onset to diagnosis of IgAN was 4 months; 55.94% of patients had predisposing causes, especially infection. Recurrent macroscopic hematuria was the most common clinical manifestation (41.15%), followed by nephritic syndrome (23.77%) and hematuria and proteinuria (20.78%). Subclass III (41.40%) and II (28.51%) were the most common histologic types. The main type of immunofluorescence examination was IgA deposition (34.50%). The intensity of IgA deposition in patients with hematuria and proteinuria and in acute rapidly progressive nephritis was the strongest (+++). There was no unified treatment scheme. Some patients were treated with corticosteroids and immunosuppressants, and 69.24% of the patients with IgAN showed clinical improvement, 10.39% remained unchanged, and 2 cases presented deterioration. The rate of follow-up was 23.35%, the mean duration of follow-up was 24.4 months. CONCLUSION: The mean age of onset of the primary childhood IgAN was after 6 years. Hematuria was the most common clinical manifestation. Subclass III and II were the most common histologic type. There was no unified treatment scheme. The rate of follow-up was lower and the rate of lost follow-up was high. It is necessary to establish a normalized management, treatment and follow-up system for childhood IgAN in China. PMID- 17706065 TI - [Effects of fosinopril on proliferation and secretion of extracellular matrix of rat glomerular mesangial cell]. AB - OBJECTIVE: To observe the effects of fosinopril (FOS) on proliferation and secretion of extracellular matrix of rat glomerular mesangial cell induced by LPS. METHODS: In vitro culture method for glomerular mesangial cells (GMC) of rat was established and passages 3 - 10 of the cells were used in the experiment after identification. The experiment included the following 5 groups: control group (Ctrl), LPS group (LPS), high, medium and low dose FOS groups (FOS1, FOS2 and FOS3 groups, respectively). GMC proliferation was detected by methyl thiazolyl tetrazolium (MTT) incorporation method at 24 and 48 h; the changes of laminin (LN), fibronectin (FN) and ColIV protein secretion was detected by the enzyme-linked immunosorbent assay (ELISA). The changes of LNbeta(2) mRNA expression was detected by semi-quantitative real-time RT-PCR. RESULTS: (1) LPS could induce the mesangial cell proliferation, FOS inhibited this effect of proliferation induced by LPS. (2) Mesangial cells could secrete some extracellular matrix (ECM) protein in normal culture medium, mesangial cell secreted ECM protein was significantly higher in LPS group than that in Ctrl group (P < 0.01), but significantly lower in all FOS groups than that in LPS group (P < 0.01). (3) Mesangial cell could express LNbeta(2) mRNA in normal culture medium, LNbeta(2) mRNA expression was significantly higher in LPS group than that in Ctrl group at all time points, but was significantly lower in FOS group than that in LPS group. CONCLUSIONS: LPS could induce increased secretion of the ECM, including LN, FN, ColIV; FOS could inhibit the secretion of ECM in GMC in a dose-dependent manner at mRNA and protein levels. PMID- 17706066 TI - [Expression of transcription factors T-bet/GATA-3 mRNA and its effect on Tc1/Tc2 balance in asthmatic children]. AB - OBJECTIVE: In contrast to CD(4)(+) helper T-lymphocytes (T(H)), little is known about the transcriptional regulation of CD(8)(+) cytotoxic T-lymphocytes (Tc) and its role in the pathogenesis of asthma is unclear. This study was conducted to investigate the effect of T-bet and GATA-3 mRNA expression on profiles of type 1 and type 2 cytotoxic T lymphocytes in asthmatic children. METHOD: Totally 38 asthmatic children, including acute attack group composed of 20 cases (age 3 - 13 years, mean 6.2 +/- 2.9), remission group with 18 cases (age 3 - 12 years, mean 6.1 +/- 2.5) and 20 healthy control children (age 3 - 12, 6.9 +/- 2.7) were recruited in this study from Sep. 2005 to Mar. 2006. The mRNA expression of T-bet and GATA-3 in the peripheral blood mononuclear cells were detected by using semi quantitative PCR and Tc1, Tc2 cell numbers by flow cytometry analysis system. RESULT: T-bet mRNA in asthmatic children was lower than that in control group and lower in attack stage than in remission stage (0.14 +/- 0.04, 0.21 +/- 0.03, 0.28 +/- 0.03, P < 0.05). In contrast, GATA-3 mRNA was higher in asthmatic children than in control group and higher in attack stage than in remission stage (0.49 +/ 0.09, 0.44 +/- 0.08, 0.37 +/- 0.04, P < 0.05). It was shown that Tc1 percentage was lower in asthmatic children than those of control group and lower in attack stage than those of remission stage (6.6 +/- 2.4, 14.2 +/- 4.3, 31.2 +/- 3.8, P < 0.05). Tc2 percentage in asthmatic children was higher than that of control group and higher in attack stage than that of remission stage (10.0 +/- 4.2, 5.4 +/- 2.2, 3.5 +/- 1.1, P < 0.05). Spearman correlation analysis revealed that T-bet mRNA was positively correlated with Tc1 percentage (r = 0.704) and negatively correlated with Tc2 percentage (r = -0.629). GATA3 mRNA was negatively correlated with Tc1 percentage (r = -0.612) and positively correlated with Tc2 percentage (r = 0.673). The T-bet/GATA-3 mRNA ratio was positively correlated with Tc1 percentage (r = 0.731) and Tc1/Tc2 (r = 0.773), while negatively correlated with Tc2 percentage (r = -0.642). CONCLUSION: The imbalance of T-bet/GATA-3 mRNA expression is closely correlated with skewed Tc2 dominance in asthmatic children. PMID- 17706069 TI - [Lovastatin induction of the redundant gene: implications for therapy of X-linked adrenoleukodystrophy]. PMID- 17706068 TI - [Expression of multidrug resistance protein in normal immature rat brain induced by anti-epileptic drugs]. PMID- 17706067 TI - [Role of external signal regulated kinase signal transduction pathway in airway remodeling of rats with asthma and regulation by glucocorticoids]. AB - OBJECTIVE: Airway remodeling in asthma makes treatment of asthma very difficult, and study of its pathogenesis becomes very important. The present study aimed to explore the role of external signal regulated kinase (ERK) signal transduction pathway in airway remodeling in rats asthma model and regulatory effects of glucocorticoids on ERK signal transduction pathway and airway remodeling. METHODS: Totally 80 male Sprague-Dawlay rats (6-8 weeks old, weighing about 120 g) were randomly divided into control groups (30 rats), asthma groups (30 rats) and treated groups [including a group intervened with dexamethasone (DM group) and budesonide (BUD group), each had 10 rats]. The rats were sensitized for inducing asthma by intraperitoneal injection of ovalbumin and Al (OH)(3) and were repeatedly exposed to aerosolized ovalbumin for 4, 8, or 12 weeks [respectively called 4, 8 or 12 wk asthma group (A4, A8 or A12 group), each had 10 rats]; and correspondingly control rats were intraperitoneally injected with 0.9% NaCl, then were repeatedly exposed to 0.9% NaCl for 4, 8, or 12 weeks [respectively called 4, 8 or 12 wk control group (C4, C8 or C12 group), each had 10 rats]; DM group rats were repeatedly exposed to aerosolized ovalbumin for 8 wk, and BUD group rats for 12 wk. Total bronchial wall thickness (Wat) and smooth muscle thickness (Wam) were measured by an image analysis system. Concentrations of PDGF-AB in serum were measured by sandwich ELISA. Phospho-ERK (P-ERK) and c-Fos were detected by immunohistochemical technique; lung tissue extracts were analyzed for phosphorylation of ERK by Western blotting. RESULTS: Wat and Wam in all asthma groups were significantly higher than those in corresponding control groups (P < 0.01, respectively), those of the treated groups were significantly lower than asthma groups (P < 0.01). The concentrations of PDGF-AB in serum of asthma groups [(228 +/- 18) pg/ml, (293 +/- 77) pg/ml, (225 +/- 66) pg/ml for A4, A8, A12 groups, respectively] were all significantly higher than those of the control groups [(160 +/- 14) pg/ml, (165 +/- 29) pg/ml and (164 +/- 27) pg/ml for C4, C8, C12 group, respectively] (P < 0.01 or P < 0.05); the value of DM group [(157 +/- 46) pg/ml] was significantly lower than that of the group A8 (P < 0.01), no significant difference was found when the values of BUD group [(208 +/- 40) pg/ml] was compared with that of A12 group (P > 0.05). Mean absorbance values (by immunohistochemistry) of P-ERK and c-Fos in asthma groups were significantly higher than those in corresponding control groups (P < 0.01, respectively), DM group had a significantly lower value than group A8 (P < 0.01), BUD group had a significantly lower value than group A12 (P < 0.01); absorbance (by Western blot) of P-ERK in A4, A8, A12 group was significantly higher than that in C4 and C8 group, the value of DM group was significantly lower than that of group A8 (P < 0.01), and that of BUD group (1.8 +/- 0.2) was significantly lower than that of group A12 (P < 0.01). CONCLUSION: Asthmatic rats have higher concentrations of PDGF-AB in serum and phosphorylation of ERK and c-Fos; glucocorticoids inhibit phosphorylation of ERK and c-Fos in asthmatic rats, and to some extent also inhibit Wat and Wam. PMID- 17706070 TI - [Changes of thrombomodulin in rats with pulmonary hypertension induced by monocrotaline]. PMID- 17706071 TI - [Clinical feature and etiological analysis of 33 cases with cervical lymphadenopathy in children]. PMID- 17706072 TI - [Analysis of gastric bilirubin absorbance values and gastric pH monitoring in children with primary duodenogastric reflux]. PMID- 17706073 TI - [Comparative study on intervention and surgical procedures for treatment of congenital heart disease]. PMID- 17706074 TI - [Streptococcal toxic shock syndrome: report of 2 cases]. PMID- 17706075 TI - [Alagille syndrome in 5 Chinese children]. PMID- 17706076 TI - [Two cases of tubulointerstitial nephritis and uveitis syndrome in children]. PMID- 17706077 TI - [Twin cases with methylmalonic aciduria and homocysteinemia]. PMID- 17706078 TI - [Glutaric aciduria type II resembling Rett syndrome in a case]. PMID- 17706079 TI - [Disseminated infection with bacille Calmette-Guerin vaccine in an infant with severe combined immunodeficiency]. PMID- 17706080 TI - [Lymphoproliferative disease occurred after unrelated umbilical cord blood transplantation]. PMID- 17706081 TI - [Hoarseness as the initial manifestation of Bartter syndrome in a case]. PMID- 17706082 TI - [Immunization in children with kidney diseases]. PMID- 17706083 TI - [More attention should be paid to the application of newly disciplines such as bioinformatics in the ophthalmic research in China]. AB - After giving a broad overview of the ophthalmic research in China, we find that the research in ophthalmology is making good progress and has reached the top level in most fields in the world since the 21(st) century. However, the lack of original and interdisciplinary research is one of the reasons, which leads to the obvious discrepancy between our country and the developed countries. In order to improve the level of the ophthalmic research and narrow the gaps between China and the developed countries, the researchers focused on the ophthalmic research should create more original results through inputting, digesting, absorbing and melting the research results in other disciplinary and new technology. With the era of "omics", the complicated problems in life science can not be solved by the single disciplinary. A turning point will be brought to the ophthalmic research by the interdisciplinary such as bioinformatics and system biology, which will accelerate the change of thinking mode and research methods in ophthalmology. PMID- 17706084 TI - [Construction of bicistronic lentiviral vectors carrying HSV-tk and EGFP gene]. AB - OBJECTIVE: To construct CMV-mediated Lentiviral vectors coexpressing EGFP and HSV tk gene in order to establish a novel lentiviral vector platform for the suicide gene therapy of eye disease. METHODS: The restriction endonuclease and T4 DNA ligase were used to construct the vector plasmid. HSV-tk fragments from pcDNA3 HSV-tk were cloned into the site of lenti-internal ribosomal entry site (IRES) EGFP to construct the bicistronic lenti-HSV-tk-EGFP vector. Human embryonic kidney 293T cells were co-transfected with the lentiviral vector (three plasmids) by calcium phosphate DNA precipitation. HLEC, HXO-Rb(44), SH-SY-5Y and Hela cells were transfected with viral production and the expression of EGFP was examined under fluorescent microscope after transfection. The expression of HSV-tk and EGFP was examined by RT-PCR. RESULTS: Lentivirus mediated stable integration and efficient expression of EGFP and TK genes in the cells tested. Coexpression of HSV-tk and EGFP in HLECs mediated by lentiviral vectors was confirmed by the result of RT-PCR. The transfection efficiency for HLECs was about 100% at MOI = 100, and kept the same level for at least 6 months. CONCLUSION: The bicistronic lentiviral vector platform carrying HSV-tk-EGFP is an efficient and stable gene transfer vector, it might be used for suicide genes therapy in the treatment some eye disease. PMID- 17706085 TI - [The effects of caspase-3 in apoptosis of cultured retinal microvascular pericytes induced by advanced glycation end products]. AB - OBJECTIVE: One of the earliest changes observed in the development of diabetic retinopathy (DR) is the selective loss of pericytes and acellular capillaries. We tested the hypothesis that advanced glycation end products (AGE) might be involved in the disappearance of retinal pericytes by apoptosis and further investigated the activity and effect of caspase-3 at the same time. METHODS: Cultured bovine retinal microvascular pericytes (BRPs) were exposed to various concentrations of advanced glycation end products-bovine serum albumin (AGE, 0.47, 1.88, 7.50 micromol/L) for 4 days. We assayed the degree of pericytes apoptosis by fluorescence activated cell sorting, and further measured the caspase-3 activity and the effect of selective caspase-3 inhibitor Z-DEVD-fmk on apoptosis and the of ratio Bcl-2/Bax expression. RESULTS: The results showed that AGE could induce significantly the apoptosis of BRPs in a dose-dependent manner compared with controls (r = 0.867, P < 0.01), associated with an increase in intracellular caspase-3 activity. Selective caspase-3 inhibitor Z-DEVD-fmk inhibited pericyte apoptosis induced by AGE. CONCLUSION: These data suggest that the pericyte loss in DR involves an apoptotic process, and that activation of caspase-3 are associated with apoptotic process, which can provide new therapeutic perspectives in diabetic retinopathy. PMID- 17706086 TI - [Changes of tight junction protein and GFAP in the retina of experimental diabetic rats and their relationship with blood aqueous barrier]. AB - OBJECTIVE: To investigate the changes of vascular endothelial cell tight junction protein (occludin) and glial cell morphology as well as their relationship with blood-retinal barrier (BRB) in the retina of diabetic rats. METHODS: The distribution of occludin and GFAP were explored by immunofluorescence histochemical studies in the retina of streptozotocin (STZ)-diabetic rats and age matched control rats. Evans blue was used to evaluate the impairment of BRB. RESULTS: GFAP immunoreactivity was limited to ganglion cell layer and nerve fiber layer in the control retina. GFAP immunoreactivity was significantly increased in ganglion cell layer and nerve fiber layer in one month diabetic rats. GFAP positive Muller cells were increased in three months and six months diabetic rats. Occludin immunoreactivity progressively decreased in three months and six months diabetic rats but not in the one month diabetic rats. Evans blue injection showed a progressive impairment of BRB. CONCLUSIONS: Astrocytes activation in the early stage of diabetes plays an important role in the maintaining of the BRB function. But the activation of Muller cells in the later stage destroyed the BRB eventually. These changes are consistent with the concept that BRB changes caused by altered glial-endothelial cell interactions contributes to the occurrence of diabetic retinopathy. PMID- 17706087 TI - [The analysis of healthy adult male lens fibers proteome using tandem mass spectrometry]. AB - OBJECTIVE: To establish the method for studying the proteome of the lens fibers of healthy adult male in order to provide a tool for further analysis of cataract related protein using reverse tandem mass spectrometry. METHODS: Lens fibers proteins were separated and analyzed using sodium dodecyl sulfate polyacrylamide gel electrophoresis followed by RPLC-MS/MS (SDS-PAGE-RPLC/MS/MS). The experiment was repeated three times. The tandem mass spectra of positive results were quality controlled by SEQUEST/AMASS softwares which were based on high abundance ion matching rate, continuity of matched ions and randomnicity score proteins were identified based on 2-hit criteria with reliability over 98% for each peptide. RESULTS: Total 60 lens fibers proteins were identified at least twice in three experiments. Among these proteins, 22 were identified in previous lens proteome study. CONCLUSION: The results in this study provided preliminary data on the composition of crystallin in the lens fibers of healthy adult male. The results can be used as a reference for future studies to detect the changes of human lens proteins during aging and cataract formation. Combination of SDS-PAGE and RPLC/MS/MS is a quick and simple method, it may be useful for large scale analysis of clinical samples. PMID- 17706088 TI - [Study of binocular function in early stage after implantation of multifocal intraocular lens]. AB - OBJECTIVE: To evaluate binocular function in the early stage after implantation of multifocal intraocular lens. METHODS: Three weeks postoperatively, simultaneous perception, fusion, near and far-distance stereoacuity, visual acuity and visual symptoms were observed in 31 cases (46 eyes) with multifocal intraocular lens implantation (MIOL) [MIOL group, in which 16 cases with unilateral implantation (Ms) and 15 cases with bilateral implantation (Md)] and 32 cases (47 eyes) with single-focal intraocular lens implantation (SIOL) [SIOL group, in which 17 cases with unilateral implantation (Ss) and 15 cases with bilateral implantation (Sd)]. RESULTS: All patients obtained simultaneous perception and fusion sense, there was no significantly statistical difference between these two group (P > 0.05). Foveal far-distance stereoacuity was established in 38.7% cases among MIOL group (12/31) and 40.6% in SIOL group (13/32), with no statistically significant difference between these two groups (P > 0.05). Foveal near-distance stereoacuity was established in 41.9% MIOL cases (13/31) and in 15.6% SIOL group (5/32), the difference was statistically significant (P < 0.05). Foveal near and far-distance stereoacuity of either Ms and Md or Ss and Sd revealed no significantly statistical difference (P > 0.05). Two patients (6.5%) with MIOL in only one eye complained glare at night, others were satisfied. The stereopsis visual performance such as the quality of vision during eating, up-and-down stairs was improved in MIOL group [80.6% (25/31)] and in SIOL group [56.2% (18/32)], the difference was statistically significant (P < 0.05). CONCLUSIONS: There is a complete recovery of binocular vision in the early post-operative stage of MIOL implantation as compared with the normal value of aged people. Foveal near and far-distance stereoacuity after bilateral and unilateral implantation of either MIOL or SIOL revealed no statistically significant difference. Foveal near-distance stereopsis acuity of MIOL group was improved more quickly than that of SIOL group. MIOL has distinct advantage in providing whole-distance visual acuity and stereoacuity. PMID- 17706089 TI - [Characteristics of ophthalmic symptoms in the 278 patients with human immunodeficiency virus]. AB - OBJECTIVE: To investigate the characteristics of ophthalmic symptoms of patients with human immunodeficiency virus (HIV) and to provide reference for early diagnosis and treatment of HIV. METHODS: The clinical data of 278 patients with HIV, including ophthalmic symptoms and general condition collected from September 2002 to July 2004, were analyzed retrospectively. These patients were from the Central African Republic. RESULTS: Among the 278 patients with HIV, 102 had pathologic changes in the eyes and were accompanied with chronic dissipative symptoms and decreased CD4 cell counts. The pathogen of 278 patients with HIV at the initial reception were airway infection (n = 87, 31.3%), digestive tract infection (n = 65, 23.4%), skin symptoms (n = 55, 19.8%), multiple organ failure (n = 51, 18.4%) and ophthalmic symptoms (n = 20, 7.2%). Ophthalmic symptoms manifested as opportunistic infection and sarcoma formation, such as HIV retinopathy, chronic uveitis, external ophthalmoplegia, ocular herpes, and Kaposi's sarcoma in the eyelid. HIV-related retinopathy was not specific, which manifested as retinal hemorrhage, cotton wool spots, vascular occlusion, retinal necrosis, retinal detachment and ocular nerve atrophy. CONCLUSIONS: Many kinds of ophthalmic symptoms might appear in patients with HIV. Severe retinopathy and uveitis are the main causes of ablepsia. Because of neglecting the ophthalmic symptoms in the early stage, many HIV patients suffer from decreased visual acuity, which may severely affect the quality of their lives. Consequently, ophthalmologists should pay more attention to patients in the early stage of HIV. PMID- 17706090 TI - [A study on the association of apolipoprotein E genotypes with primary open-angle glaucoma and primary angle-closure glaucoma in northeast of China]. AB - OBJECTIVE: To analysis the association of apolipoprotein E (APOE) genotype with primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) in northeast of China. METHOD: The polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) technique were used to detect the distribution of genotype and gene frequency of APOE alleles in 36 patients with POAG, 69 with PACG and 57 healthy subjects as control. RESULTS: The frequency of APOE epsilon 3/epsilon 4 genotype in POAG group (41.7%)and epsilon 2/epsilon 4 in PACG group (43.5%) was significantly (P < 0.05) higher than that in control group (14.0% and 21.1%, respectively). The frequency of APOE epsilon 4 allele in both of POAG (37.5%) and PACG group (39.2%) was significantly (P < 0.05) higher than that in control group (17.5%), whereas the frequency of APOE epsilon 2 allele in POAG group (8.3%) was significantly (P < 0.05) lower than that in control group (15.8%). CONCLUSION: APOE epsilon 4 allele may be a latent risk factor in the development of primary glaucoma, but APOE epsilon 2 allele may play a protective role in POAG and warrant further investigation. PMID- 17706091 TI - [Modified viscocanalostomy for the surgical treatment with primary open angle glaucoma]. AB - OBJECTIVE: To compare the clinical outcome of trabeculectomy with viscocanalostomy in patients with primary open angle glaucoma (POAG). METHODS: 100 patients (100 eyes) with uncontrolled POAG were randomly assigned to either trabeculectomy group (50 eyes) or viscocanalostomy (VCO) group (50 eyes) and followed up for average 28 months. Intraocular pressure (IOP) was measured with a non-contact Topcon CT80 tonometer. RESULTS: At 1 month after operation, IOP was (11.22 +/- 4.34) and (12.35 +/- 3.79) mmHg (1 mmHg = 0.133 kPa, n = 50) in the eyes undergoing VCO or trabeculectomy surgery, respectively. The complete success rate (IOP < 21 mmHg without antiglaucoma medications) was 98.0% in both groups. There was no significant difference in IOP and complete success rate between both groups. At 12 months, IOP in VCO group was significantly (P < 0.05) lower (14.50 +/- 3.22) than that in trabeculectomy group (16.58 +/- 4.73) mmHg, while the complete success rate in VCO group (87.5%) was significantly higher (P < 0.05) than that in trabeculectomy group (70.0%). The early transient complications such as shallow anterior chamber and encysted blebs were significantly (P < 0.01) more common in trabeculectomy group than in VCO group. CONCLUSIONS: VCO appears to have long term advantages over trabeculectomy in terms of complete success rate, IOP control, and less early transient postoperative complications in POAG. PMID- 17706092 TI - [Morphologic characteristics and formation of adhesion complex of cultured rabbit limbal epithelium on amniotic membrane in vitro]. AB - OBJECTIVE: To investigate the morphologic characteristics and the formation of adhesion complex formation of cultured rabbit limbal epithelium on amniotic membrane in vitro. METHODS: The limbal explants (size: 2 mm x 2 mm) were taken from 15 rabbits and were treated with 1.2 U/ml dispase II at 37 degrees C in 5% CO(2) incubator for 20 min, then, cultured on amniotic membrane in vitro for 4 weeks. It was cultured in culture medium during the first two weeks, and then cultured as airlifted culture in the following two weeks. Transmission electronmicroscope (TEM) was performed weekly, the AE-5 immunohistochemical staining, PAS staining and HE staining were performed at the end of fourth week. RESULTS: It took 2 weeks for the cultured limbal epithelium to cover the whole amniotic membrane. Immunocytochemical studies showed that cultured limbal epithelium was positive for keratin 3 and negative for PAS staining. HE staining showed that the morphologic characteristics of cultured limbal epithelium were similar to normal rabbit corneal epithelium. The adhesion complex formation didn't appear on 7th day and 14th day. Early stage of adhesion complex formation appeared on 21st day, and without significant change until 28th day. CONCLUSIONS: The morphologic characteristics of cultured limbal epithelium on amniotic membrane in vitro are similar to normal rabbit corneal epithelium. Only early stage of adhesion complex is formed as compare to the normal adhesion complex of rabbit. PMID- 17706093 TI - [Experimental study on the effects of hydrogen peroxide on caveolin in human lens epithelial cells]. AB - OBJECTIVE: To observe the expression and distribution of caveolin and phosphorylated caveolin-1 in human lens epithelial cells (HLECs) under H(2)O(2) treatment. METHODS: HLECs (SRA01/04) were exposed to different concentrations of H(2)O(2) for different periods of time. The distribution of caveolin and phosphorylated caveolin-1 in H(2)O(2) treated cells was observed by laser scanning confocal microscopy and fluorescence microscopy. Western blot was conducted to analyze the protein expression alterations of caveolin and caveolin 1 phosphorylation. RESULTS: HLECs contained abundant caveolin. Immunofluorescence image of caveolin in cytoplasm increased significantly in H(2)O(2) treated cells. One hour after H(2)O(2) treatment, the cells membranes began to break, whereas the immunofluorescence image of caveolin could still be observed. Caveolin-1 was phosphorylated on tyrosine 14 in HLECs after stimulation with H(2)O(2). Western blot analysis revealed that caveolin protein level was down regulated under H(2)O(2) stress. CONCLUSIONS: The caveolin is redistributed and the caveolae is destroyed in HLECs when stimulated by H(2)O(2). And the caveolin expression also down regulated by H(2)O(2) stimulation. Caveolae and caveolin are likely to play an important role in the HLECs. PMID- 17706094 TI - [Xenogenic corneal acellular matrix as carrier for reconstruction of biological cornea epithelium-scaffold-endothelium compound]. AB - OBJECTIVE: To investigate the method and feasibility of constructing biological cornea by culturing corneal epithelial and endothelial cells on the scaffold of xenogenic corneal acellular matrix (XCAM) in vitro. METHODS: Porcine cornea was prepared as XCAM by application of detergent 1% Triton X-100 and freeze-drying process. After the carrier has rehydrated, rabbit epithelial and endothelial cells were seeded on each side of XCAM. After 2 weeks of culture, the reconstructed tissue of epithelium-scaffold-endothelium compound was examined by histological studies by HE staining and scanning electron microscope (SEM). The epithelium was examined by immunohistochemical studies using antibodies to cytokeratin (CK3), and the endothelium was stained with trypan blue and alizarin red. RESULTS: Reconstructed biological cornea was composed of epithelium, acellular stroma and endothelium. Four to five layers of stratified flat cells were formed on the surface of XCAM, which were stained positively by CK3. Continuous monolayer cells located on the endothelial side, which were alive and showed honeycomb-like shape via dual staining with trypan blue and alizarin red, cells arranged tightly. Under SEM, epithelial cells showed several layers with the morphology of flat and spindle cells alternatively, endothelial cells showed polygonal shape with microvillus over the surface. CONCLUSIONS: The biological corneal tissue reconstructed in vitro possessed three layers: the epithelium, scaffold and the endothelium. XCAM provides ideal surface for corneal epithelial and endothelial cells' adhesion and proliferation, it is desired to be used as scaffold for reconstruction of cornea in vitro. PMID- 17706095 TI - [Effects of trabeculectomy combined with amniotic membrane and extracellular matrix of conjunctiva on filtering bleb in rabbits eyes]. AB - OBJECTIVE: To investigate the effect of trabeculectomy combined with amniotic membrane and extracellular matrix (ECM) of conjunctiva on filtering bleb in rabbits. METHODS: Glaucoma was induced by injecting alpha-chymotrypsin into the posterior chamber of rabbit eyes. 27 rabbits were randomly divided into the following three groups: group (1) trabeculectomy alone as control; group (2) trabeculectomy combined with amniotic membrane transplantation; group (3) trabeculectomy combined with extracellular matrix (ECM) transplantation. IOPs were measured by a Schiotz tonometer and filtering bleb observed under a microscopy and electric microscopy at day 1, 7, 14, 21, 28, 35, 42, 56 after surgery. RESULTS: Compared with pre-operation, the IOP in the control group (group 1) was reduced from (34.59 +/- 4.44) mm Hg (1 mm Hg = 0.133 kPa) to (11.31 +/- 2.76) mm Hg, (19.20 +/- 5.27) mm Hg, (21.17 +/- 4.36) mm Hg, (22.22 +/- 1.39) mm Hg, (23.90 +/- 1.97) mm Hg, (23.67 +/- 1.73) mm Hg, respectively, after surgery. In the group 2, the IOP was decreased from (34.38 +/- 4.21) mm Hg to (10.48 +/- 2.45) mm Hg, (12.80 +/- 3.41) mm Hg, (13.50 +/- 2.25) mm Hg, (16.17 +/ 1.73) mm Hg, (17.22 +/- 1.32) mm Hg, (16.71 +/- 1.52) mm Hg, respectively. In the group 3, the IOP was decreased from (34.66 +/- 4.49) mm Hg to (10.94 +/- 2.75) mm Hg, (11.29 +/- 2.40) mm Hg, (13.93 +/- 3.55) mm Hg, (15.63 +/- 3.54) mm Hg, (15.70 +/- 2.44) mm Hg, (15.12 +/- 3.65) mm Hg, respectively, at day 1, 7, 14, 28, 42, 56, post-operatively. IOPs in the group 2 and 3 were significantly (P < 0.01) lower than that in the control group (group 1) at post-operative day 7, 14, 28, 42, 56. However, there was no IOP difference between the group 2 and 3 post-operatively at any time. Morphologically, the filtering blebs were flatded at day 28 in the group 1, while were normal in the group 2 and 3 at day 56. Less scar formation of filtering blebs was observed in group 2 and 3 compared with group 1. CONCLUSIONS: Trabeculectomy combined with the application of amniotic membrane or conjunctiva ECM can improve filtering bleb function and reduce scar formation that lead to a better IOP control after surgery. PMID- 17706107 TI - [Research advances of proteome on ophthalmology]. AB - The investigation of proteome can not only show the rules of vital movement, but also play an important role to illuminate the mechanism of genesis and development on certain diseases and that may find a new way to treat those. Using the compare analysis of proteome of physiology and pathology of individual, we can find the specific protein molecule of those diseases, provide identification markers of the diseases for early diagnosis, and point out the molecule target of the new drugs. Here we reviewed the applications of proteomic in the field of ophthalmologic research. PMID- 17706108 TI - [Anticardiolipin antibodies and ocular diseases]. AB - Anticardiolipin antibodies are a group of autoantibodies. It has been found that these antibodies were associated with thrombosis, recurrent spontaneous abortions and thrombocytopenia. This paper reviews the latest findings about the epidemiology, the mechanism for immunopathology, main systemic features, ocular features, diagnosis, differential diagnosis, prevention and treatment of anticardiolipin antibodies syndrome. PMID- 17706109 TI - [Trend in diagnosis and therapy of breast cancer]. PMID- 17706110 TI - [Problems in the diagnosis of thyroid papillary and follicular carcinoma]. PMID- 17706111 TI - [Evaluation of efficacy of stereoscopic location and whole serial sections of margin status in breast conservation therapy specimens]. AB - OBJECTIVE: To evaluate the efficacy of different methods in pathologic assessment of margin status in breast conservation therapy specimens. METHODS: Assessment of margin status in breast conservation therapy specimens by stereoscopic location and whole serial sections (SLWS) and selective margin sections (SMS) was compared. The margin status was evaluated with intraoperative frozen sections either by SLWS (145 cases) or SMS (79 cases). On the other hand, with formalin fixed specimens, the margin status of 84 cases was assessed by SLWS and that of another 226 cases by SMS. Follow-up data of all patients were analyzed. RESULTS: The rate of detection of positive margin by SLWS (24.1%, 35/145) was significantly higher than that by SMS (6.3%, 5/79) during frozen section setting. Similarly, the rate of detection of positive margin by SLWS (34.5%, 29/84) was also higher than that by SMS (12.0%, 27/226) when applied in formalin-fixed specimens. The duration of follow-up ranged from 2 to 46 months. None of the patients with margin status assessed by SLWS developed local recurrence. This was in contrast to 3 cases with tumor recurrence (6 months, 15 months and 28 months after the operation respectively) in SMS group. CONCLUSIONS: Assessment of margin status by SLWS in breast conservation therapy specimens can reduce the chance of missing underlying minute foci of margin involvement and help to localize the exact site of positive margin. It thus reduces the overall risk of local recurrence and the need of a second operation. PMID- 17706112 TI - [Diagnosis and prognosis study of breast carcinoma with micropapillary component]. AB - OBJECTIVE: To study the diagnostic criteria, clinicopathologic characteristics and prognosis of invasive micropapillary carcinoma (IMPC) of breast. METHODS: All cases of breast carcinoma diagnosed during the period from 1989 to 2001 were retrospectively reviewed. One hundred examples with IMPC component, according to the 2003 World Health Organization classification of breast tumors, were identified. The clinicopathologic features and follow-up data of these cases were analyzed. RESULTS: Amongst the 100 cases of IMPC studied, 69% (69/100) had evidence of lymphovascular invasion. The incidence of regional lymph node metastasis was 84.8% (84/99). Follow-up information was available in 98 patients (mean of follow-up duration = 60.1 months). Eleven patients (11.2%) had local recurrence within a mean of 26.4 months after the operation, while 38 patients (38.8%) had distant metastases within a mean of 36.0 months. Thirty-six patients (36.7%) died of the disease. The overall 5-year survival rate was 59% and the 10 year survival rate was 48%. Univariate and multivariate analysis showed that the prognosis of patients was adversely affected by the presence of lymphovascular invasion and family history of breast cancer. On the other hand, tamoxifen therapy and adjuvant chemotherapy improved survival. CONCLUSIONS: Breast carcinoma with IMPC component is associated with poor prognosis, despites the relative proportion of this architectural pattern. The overall prognosis is related to the presence of lymphovascular invasion and family history of breast cancer. Hormonal therapy and individualized chemotherapy can improve the survival rate. PMID- 17706113 TI - [Prognostic significance of clinicopathologic parameters in gastrointestinal stromal tumor: a study of 156 cases]. AB - OBJECTIVE: To evaluate the prognostic significance of various clinicopathologic parameters in gastrointestinal stromal tumor (GIST), and to study the frequency of c-kit exon 11 mutations in this tumor. METHODS: One hundred and fifty-six cases of gastric or small intestinal GIST were retrieved from the archival files of the Department of Pathology, Chinese PLA General Hospital. The clinical features, site of occurrence, tumor diameter, mitotic index, coagulative tumor necrosis, and risk grade were studied and analyzed statistically. Tumor DNA was extracted and c-kit exon 11 was amplified. Upon detection by denaturing high performance liquid chromatography, the amplified exon 11 was sequenced. RESULTS: For the 83 cases of gastric GIST studied, the mean age of patients was 55.4 years. Follow-up information was available in 62 cases, with 17 cases having local recurrence or distant metastasis. The 5-year survival rate was 66.5% +/- 17.1%. For the 73 cases of small intestinal GIST studied, the mean age of patients was 50.6 years. Follow-up information was available in 43 cases, with 22 cases having local recurrence or distant metastasis. The 5-year survival rate was 61.8% +/- 18.3%. In general, for gastric GIST, age younger than 50 years (P = 0.046), advanced clinical stage (P = 0.0001), large tumor size (P = 0.0001), high mitotic index (P = 0.0001), presence of coagulative tumor necrosis (P = 0.0001), and high risk grade (P = 0.004) were associated with lower survival rate. COX hazard proportional model revealed that advanced clinical stage (P = 0.001), large tumor size (P = 0.001), high mitotic index (P = 0.002) and high risk grade (P = 0.018) indicated worse prognosi. For small intestinal GIST, advanced clinical stage (P = 0.010) and presence of coagulative tumor necrosis (P = 0.036) were associated with lower survival rate. Advanced clinical stage was an independent prognostic factor. A total of 25 cases harbored c-kit mutations. The frequency of c-kit mutations was 32% and 22.5% for gastric and small intestinal GIST respectively. For gastric GIST, c-kit mutations occurred mainly in patients older than 50 years. In contrast, c-kit mutations in small intestinal GIST occurred in the age group of 40 to 49 years. CONCLUSIONS: For gastric GIST, advanced clinical stage, tumor diameter, mitotic index and risk grade are the main prognostic indicators. For small intestinal GIST, advanced clinical stage and presence of coagulative tumor necrosis indicate poor prognosis. In general, small intestinal GIST is more frequently associated with metastasis and tumor relapse than gastric GIST. The occurrence of c-kit mutations also correlates with age of patients. PMID- 17706114 TI - [Littoral cell angioma of spleen: a clinicopathologic study of 17 cases]. AB - OBJECTIVE: To study the clinicopathologic features and immunophenotype of splenic littoral cell angioma. METHODS: The clinical features, radiologic findings and histopathology of 17 cases of splenic littoral cell angioma were retrospectively reviewed. Immunohistochemical study was carried out on paraffin-embedded tissues, using normal spleen, cases of congestive splenomegaly and cavernous hemangioma as controls. RESULTS: All the 17 cases had similar clinical manifestations and radiologic findings. There was mild to moderate splenomegaly, with solitary or multifocal space-occupying lesions. Hepatic cysts were observed in 5 of the 17 cases. One case was also accompanied by serous cystadenoma of ovary. Gross examination revealed enlarged spleen containing single or multiple tan-colored nodules which ranged from 0.2 cm to 6.0 cm in diameter. Histologically, the lesions consisted of anastomosing vascular channels, sometimes with papillary or cavernous appearance. Two types of component cells were identified. A population of smaller cells lined the vascular channels, while another population of larger cells often floated in the vascular lumen. Both cell populations showed little cytologic atypia. Immunohistochemical study demonstrated that the smaller cells of all cases were positive for CD31 and polyclonal factor VIII-related antigen. They were negative for CD34, histiocytic markers and S-100 protein. CD8 and CD21 were expressed in 1 and 1 of the 17 cases respectively. On the other hand, the larger cells expressed histiocytic markers, including CD68 (KP1 and PG-M1), CD163 and lysozyme. There was also focal positivity for CD31. The staining for CD34, monocolonal factor VIII-related antigen and S-100 protein was negative. The immunophenotype of splenic littoral cell angioma was different from that of the controls. CONCLUSIONS: Littoral cell angioma is a benign condition, likely secondary to hemodynamic disturbance in spleen. The littoral cells become hyperplastic and anastomose, resulting in a hemangioma-like growth associated with histiocytic reaction. Attention to the characteristic histopathologic findings and immunophenotype are crucial for diagnosis. PMID- 17706115 TI - [Renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusions: a study of 11 cases and review of literature]. AB - OBJECTIVE: To study the clinicopathologic features, differential diagnosis and prognosis of renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusions. METHODS: The histopathologic findings and immunophenotype of 11 cases of renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusions were studied. Follow-up data (ranged from 10 to 112 months) were also analyzed. RESULTS: There were a total of 7 females and 4 males. The age of patients ranged from 8 to 26 years (mean = 16.3 years). The diameter of the tumors varied from 2.5 to 6.0 cm. Histologically, two morphologic patterns were seen. The first pattern consisted of alveolar, papillary or nested architecture. The tumor cells contained voluminous, clear to eosinophilic cytoplasm, distinct cell borders, vesicular chromatin, and prominent nucleoli. Psammoma bodies were frequently found and could be abundant. In contrast, the second pattern was composed of nested and compact architecture. The tumor cells possessed less abundant cytoplasm and inconspicuous nucleoli. Few psammoma bodies were detected. Immunohistochemical study showed that all cases strongly expressed TFE3, CD10 and P504s. Variable positivity for pan-cytokeratin, epithelial membrane antigen and vimentin was also noted. None of them expressed CK7, Ksp-cadherin and CD117. CONCLUSIONS: Renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusions is a newly described but rarely encountered subtype of renal cell carcinoma. Pathologic diagnosis can be established when taken age of the patients, histopathologic findings and immunoreactivity for TFE3 protein into consideration. PMID- 17706117 TI - [Promoter methylation and mRNA expression of WT1 gene in MCF10 breast cancer model]. AB - OBJECTIVE: To investigate the role of WT1 gene in breast carcinogenesis by analyses of the promoter methylation status and mRNA expression of WT1 gene in MCF10 model system of breast cancer progression. METHODS: Methylation specific PCR and sodium bisufite genomic sequencing were employed to detect methylation status of WT1 promoter in normal breast tissue, traditional breast cancer cell line MCF7 and MCF10 model series, including MCF10A (breast hyperplastic cell line, non-tumorigenic), MCF10AT (pre-malignant cell line, forming slowly progressing hyper and dysplastic lesions), MCF10DCIS.com (breast ductal carcinoma in situ cell line, forming ductal carcinoma in situ), and three invasive cell lines with metastatic potential (MCF10CA1a, MCF10CA1d, and MCF10CA1h). Real time reverse transcription PCR assay was used to determine the mRNA expression levels of WT1 in various cell lines. RESULTS: Hypermethylation of WT1 promoter was identified in MCF7 and all MCF10 model cell lines (MCF10A, MCF10AT, MCF10DCIS.com, MCF10CA1a, MCF10CA1d, and MCF10CA1h). Unexpectedly, an increased expression of WT1 mRNA was found in all MCF10 cell lines and MCF7 comparing with normal breast tissue [folds of overexpression: 3.23 (MCF10A), 1.94 (MCF10AT), 4.20 (MCF10CA1a), 1.53 (MCF10CA1d), 4.20 (MCF10CA1h), 4.35 (MCF10DCIS) and 28.69 (MCF7)]. CONCLUSIONS: Promoter methylation does not silence the mRNA expression of WT1 during the development of breast cancer. Overexpression of WT1 occurs in the early stages of breast cancer development, suggesting its role as an oncogene rather than a tumor suppressor gene. PMID- 17706118 TI - [Study on morphological and immunophenotypic features of renal cell carcinoma with sarcomatoid differentiation]. PMID- 17706116 TI - [CD147 and matrix metallo-proteinase (MMP) 2 and MMP9 expression in multidrug resistant breast cancer cells treated with P-glycoprotein substrate drugs]. AB - OBJECTIVE: To investigate effects of P-glycoprotein (gp) substrate drugs on the expression of CD147 and MMP2 and 9 in multidrug resistant breast cancer cells. METHODS: MDR human breast cancer cell line, MCF7/AdrR, and its sensitive parental line, MCF7, were treated with various concentrations of P-gp substrate drugs, including paclitoxel and vincristine, and P-gp nonsubstrate drugs, bleomycin, in serum-free media. At the end of the treatment, expressions of CD147 and MMP2 and 9 were determined by real-time PCR and western blot. RESULTS: Increased expressions of CD147 and MMP2 and 9 were observed in multidrug resistant cancer cells compared with their parental MCF7 cells. After treatment with bleomycin, the expression of CD147 and MMP2 and 9 in both MCF7 and MCF7/AdrR cells remained unchanged (P > 0.05). However, treatment with paclitoxel and vincristine resulted in a remarkable over-expression of CD147 and MMP2 and 9 at both transcription and protein levels in MCF7/AdrR cell line (P < 0.05), while MCF7 cells failed to show similar response. CONCLUSIONS: P-gp substrate drugs can greatly upregulate the expression of CD147 and MMP2 and 9 in multidrug resistant breast cancer cells, therefore enhancing the tumor metastatic capability. PMID- 17706119 TI - [Expression of macrophage migration inhibitory factor, p53 and CD34 in ovarian carcinoma]. PMID- 17706120 TI - [Study of dehydroepiandrosterone retarding atherosclerosis of high cholesterol fed rabbits]. PMID- 17706121 TI - [Experimental study on the carcinogenic effects of sterigmatocystin in new born BALB/c mice]. PMID- 17706122 TI - [Recent advances on lymphangiogenesis and lymphatic metastasis]. PMID- 17706123 TI - [Myxofibrosarcoma and low-grade fibromyxoid sarcoma]. PMID- 17706124 TI - [Using DQ-gelatin in situ zymography to detect gelatinolytic activity]. PMID- 17706125 TI - [Fluorescence in situ hybridization in paraffin-embedded tissue of synovial sarcoma]. PMID- 17706126 TI - [Intermediate trophoblastic tumor in omentum]. PMID- 17706128 TI - [Clinicopathologic features of large-cell calcifying Sertoli cell tumor of the testis]. PMID- 17706129 TI - [Sclerosing hemangioma with lymph node metastasis: report of a case]. PMID- 17706130 TI - [Primary leiomyosarcoma of tibia: report of a case]. PMID- 17706131 TI - [Diagnosis and treatment of inflammatory myofibroblastic tumor with malignant transformation]. PMID- 17706132 TI - [The importance of close crosstalk between clinicians and pathologists]. PMID- 17706134 TI - [Atypical adenomatous hyperplasia of lung: clinicopathologic study of 8 cases and review of literature]. AB - OBJECTIVE: To study the clinicopathologic and immunohistochemical features of atypical adenomatous hyperplasia (AAH) of lung. METHODS: Eight cases of AAH of lung were studied by light microscopy and immunohistochemical staining for p16, thyroid transcription factor-1 (TTF-1), Ki-67, p53, epidermal growth factor receptor (EGFR) and c-erbB-2. RESULTS: The mean age of the patients was 52 years. The male-to-female ratio was 1:3. Two patients were chronic smokers. The clinical symptoms were relatively non-specific. Three patients had past history of non pulmonary tumors, while 4 patients had lung adenocarcinoma. CT scan revealed solitary or multifocal hyperdense opacities. Histologically, the lesions ranged from 1 mm to 6 mm in size. Two cases were solitary and 6 cases were multifocal. All were of high-grade lesions. Associated low-grade component was noted in 3 cases. There was no evidence of local recurrence or disease progression in the 7 patients with post-operative follow-up information available (mean duration of follow up = 23 months). Four patients had received chemotherapy as well. Immunohistochemical study showed variable positivity for p16 (5/8), TTF-1 (5/8), Ki-67 (with proliferation index ranging from 1% to 10%), p53 (1/8) and EGFR (1/8). The staining for c-erbB-2 was negative (0/8). Four cases of AAH were associated with pulmonary adenocarcinoma. The adenocarcinoma cells were diffusely positive for TTF-1 (4/4), variably positive for p16 (2/4), Ki-67 (with proliferation index ranging from 2% to 40%), p53 (1/4) and EGFR (3/4), and negative for c-erbB-2 (0/4). CONCLUSIONS: AAH of lung is associated with pulmonary adenocarcinoma. Diagnosis of AAH requires correlation with CT findings and pathologic examination. PMID- 17706135 TI - [Distinction between lymphoma-like lesions and lymphoma of uterine cervix: a clinicopathologic study of 26 cases]. AB - OBJECTIVE: To study the clinicopathologic features and differential diagnosis of lymphoma-like lesions and lymphoma of uterine cervix. METHODS: Clinical data and hematoxylin and eosin-stained slides of 10 cases of lymphoma-like lesion and 16 cases of lymphoma of uterine cervix were reviewed. Immunohistochemical study for B- and T-cell markers and light chains (kappa, lambda) were performed on paraffin sections. The rearrangement status of immunoglobulin heavy chain (IgH) gene was analyzed with semi-nested polymerase chain reaction in 4 cases lymphoma-like lesion and 4 cases of lymphoma of uterine cervix. RESULTS: The age of patients with lymphoma-like lesion ranged from 24 to 54 years (medium = 43 years). The lesion generally presented with cervical erosion or polyp. Microscopically, it is characterized by focal or diffuse superficial infiltration of immunoblast-like large B cells intermingled with a polymorphic population of inflammatory cells, including plasma cells, eosinophils and neutrophils. Maturation of the transformed large B cells was also noticed. On the other hand, the age of the patients with lymphoma of uterine cervix varied from 28 to 78 years (medium = 58 years). Cervical mass or diffuse enlargement of cervix were the commonest clinical findings. The cases included 12 examples of diffuse large B-cell lymphoma and 4 examples of follicular lymphoma. The former was characterized by a diffuse monomorphic population of large atypical lymphoid cells, while neoplastic follicles were identified in the latter. Neither polymorphic inflammatory infiltrates nor maturation phenomenon was found. The immunostaining for kappa and lambda light chains was inconclusive. Molecular study showed clonal rearrangement of IgH gene in all cases of cervical lymphoma, as well as 2 cases of lymphoma like lesion. CONCLUSIONS: The distinction between lymphoma-like lesion and lymphoma of uterine cervix depends primarily on the clinical and histopathologic features. Assay for rearrangement of IgH gene may be helpful in differential diagnosis, though monoclonality can be detected in some benign lesions as well. PMID- 17706136 TI - [Perivascular epithelioid cell tumor of uterus: report of 5 cases and literature review]. AB - OBJECTIVE: To study the pathologic features, diagnosis, differential diagnosis and biologic behavior of uterine perivascular epithelioid tumor. METHODS: Five cases of uterine perivascular epithelioid cell tumor were studied by light microscopy and immunohistochemistry. Follow-up information was reviewed. RESULTS: All the five tumors were composed by clear or eosinophilic cells arranged in nests and cords, associated with abundant small vessels and hyalinization in the stroma. Immunohistochemically, the tumor cells demonstrated positive staining for melanocytic markers (HMB45 and/or Melan-A), desmin and smooth muscle actin. The staining for cytokeratin and CD10 was negative. All the patients followed for a certain period are still alive, with no evidence of disease recurrence. CONCLUSIONS: Perivascular epithelioid cell tumor is a rare mesenchymal tumor of uterus, with distinctive histologic and immunohistochemical features. It should be distinguished from clear cell carcinoma and epithelioid leiomyoma of uterus. Positivity for melanocytic markers (especially HMB45) plays an important role in the diagnosis of this tumor. In general, the tumor is categorized as benign, with uncertain malignant potential and malignant. PMID- 17706138 TI - [Functional aspects of protease-activated receptor 1 in promoting metastasis of lung cancer]. AB - OBJECTIVE: To study the functional aspects of protease-activated receptor 1 (PAR 1) gene involved in tumor metastasis. METHODS: Two human lung giant cell carcinoma cell lines PLA801C (low metastasis potential) and PLA801D (high metastasis potential) were chosen as in-vitro human cancer model systems. Sense and anti-sense expression constructs of PAR-1 gene (pC/PAR1s and pC/PAR1as) were transfected into PLA-801C and PLA-801D cells by lipofection. PAR-1 expression was determined by RT-PCR and western blot analysis. MTT growth, flow cytometry analysis, fibronectin adhesion, and matrigel invasion assays were used to study the effect of PAR-1 expression on the proliferation, adhesion, and invasion of the transfected cells. RESULTS: Appropriate up-regulation or down-regulation of protein expression of PAR-1 was observed in both transfected cell lines (PLA801C and PLA801D) to express PAR-1s or PAR-1as, respectively. Expression of the sense PAR-1 markedly increased cellular proliferation, adhesion and invasion of PLA 801C cells. In contrast, anti-sense PAR-1 significantly inhibited cell growth, adhesion and invasion capabilities, along with cell arrest at G0/G1 phase of the PLA-801D cells. CONCLUSIONS: Successful up- and down- regulation of expression of PAR-1 can be achieved by in-vitro transfection of sense and antisense PAR-1 constructs. PAR-1 may enhance metastasis of lung cancer through its regulation of cellular proliferation, adhesion and invasion. Down-regulation of expression of PAR-1 may provide a new therapeutic strategy against lung carcinoma. PMID- 17706137 TI - [Implications of lung interstitial dendritic cells of mice in multiple organ dysfunction syndrome]. AB - OBJECTIVE: To explore the role of lung interstitial dendritic cells in immunodissonance and organ injury in multiple organ dysfunction syndrome (MODS). METHODS: Animal model of MODS was established by injecting zymosan into the peritoneal cavity of C57BL/6 mice. The mice were randomly divided into groups of normal, 3 - 6 hours, 12 - 48 hours, 5 - 7 days, 10 - 12 days post injection. Pathological changes of lung and interstitial dendritic cells were studied by light and transmission electron microscope. Immunohistochemistry, RT-PCR and flow cytometry analyses were used to document status of biomarkers, including specific surface markers (CD205 and CD11c), costimulatory molecules (CD80 and CD86), SLC and its receptor CCR7 in lung, CD4+ and CD8+ T lymphocyte subtypes in peripheral blood. RESULTS: At early stage of injury, interstitial dendritic cells showed an increase in proliferation with expression of low level of CD80 and CD86. In contrast, the expression of SLC and its receptor CCR7 in lung were increased. The ratio of CD4+/CD8+ declined in peripheral blood. At the stage of SIRS, interstitial dendritic cells continued to proliferate with high expressions of CD80 and CD86. SLC and CCR7 in lung also increased. The ratio of CD4+/CD8+ declined markedly in peripheral blood. At the MODS stage, interstitial dendritic cells further proliferated, but the expression of CD80 and CD86 declined to a very low level. Although the level of SLC increased consistently, the level of CCR7 continued to decrease, along with a markedly decreased CD4+/CD8+ ratio in peripheral blood. CONCLUSIONS: Alterations of lung interstitial dendritic cells are likely to influence the course of immunological dysfunction of MODS. The level of CCR7 may serve as an indicator of the migration activity of interstitial dendritic cells and systemic immune response. PMID- 17706139 TI - [Effects of AKT protein kinase activation on biologic behavior of diffuse large B cell lymphoma cells]. AB - OBJECTIVE: To observe the status of AKT and phospho-AKT (pAKT) in three diffuse large B cell lymphoma (DLBCL) cell lines, and to investigate the effects of AKT activation on biologic behavior of DLBCL cells. METHODS: Three DLBCL cell lines, ly1, ly8 and ly10 were maintained in 10% FBS or serum free culture medium. The expression of AKT and status of pAKT were detected by Western blotting. LY294002, an inhibitor of PI3K, was used to suppress the level of pAKT. Flow cytometry combined with PI staining, AnnexinV-FITC assay and Brdu incorporation assay were used to analyze the parameters of the cell cycle, apoptosis and proliferation respectively. RESULTS: There was constitutive activation of AKT in three DLBCL cell lines and the levels of pAKT were altered in the different environments. In 10% FBS culture medium, pAKT was higher than that in serum free culture medium in ly8 and ly10, however, pAKT in ly1 maintained in serum free culture medium was mildly higher than that in 10% FBS culture medium. When the cell lines ly1, ly8, ly10 were maintained in 10% FBS culture medium, the inhibitor LY294002 suppressed the level of pAKT efficiently in three DLBCL cell lines. The percentage of cells at S phase and the proliferation index were significantly decreased (P < 0.05) without an increase of apoptosis (P > 0.05). CONCLUSIONS: Activation of AKT may play an important role in the development of DLBCL. It is closely related to the control of cell cycle and proliferation, but is not associated with apoptosis. LY294002 can inhibit cell growth by decreasing the levels of pAKT in DLBCL cell lines. PMID- 17706140 TI - [Biological implication of PTEN gene expression in human gastric cancer and related molecular mechanisms]. AB - OBJECTIVE: To study the role of PTEN gene involved in the biological behavior of human gastric carcinoma cells and underlying molecular mechanisms. METHODS: Gastric carcinoma cell line, SGC7901, was transfected with plasmid PBP-PTEN and stable high PTEN expression clones were selected by Western blot and cell immunohistochemistry screening. Cell proliferation rate and apoptosis index of transfected cells were investigated by growth curve analysis, colony-formation assay and flow cytometry (FCM). Expressions of vascular endothelial growth factor (VEGF), matrix metalloprotease-2 (MMP-2) and MMP-9 proteins in cell culture supernatant and cytoplasm were determined by ELISA, gelatin zymogram, Western blot and cell immunohistochemistry. RESULTS: Stable clone with high level expression of PTEN was successfully established (PTEN-SGC7901). Cell doubling time of PTEN-SGC7901 was longer than that of the control cells (P < 0.05). The size and colony-forming efficiency of PTEN-SGC7901 cells deceased compared with those of the control. The relative colony-inhibition efficiency of PTEN-SGC7901 to SGC7901 (naive untransfected) and PBP-SGC7901 (control vector transfected) cells were 69.8% and 64.8%, respectively. PTEN-SGC7901 clone had more cells at G1 phase (P < 0.05) compared with that of the control. However, the apoptosis index did not show significant differences among the three groups (P > 0.05). There were significantly less VEGF and MMP-9 protein expressions in the PTEN-SGC7901 culture supernatant and cytoplasm (P < 0.05). In contrast, the MMP-2 expression among three cell groups had no significant difference (P > 0.05). CONCLUSIONS: PTEN expression suppresses the growth and proliferation of gastric carcinoma cell SGC7901, possibly through an inhibition of the expressions of VEGF and MMP-9. PMID- 17706141 TI - [The nuclear localization of Y-box binding protein-1 correlates with P glycoprotein expression in diffuse large B cell lymphoma]. PMID- 17706142 TI - [The expression of vascular endothelial growth factor C, ETS-1, microvessal density, and microlymphaticdensity and their clinicopathologic in colorectal carcinoma]. PMID- 17706143 TI - [Sarcoidosis and tuberculosis]. PMID- 17706144 TI - [Clinicopathological characteristic of lymphomatoid granulomatosis]. PMID- 17706145 TI - [Recent advances of hemangioendothelioma (borderline vascular tumors)]. PMID- 17706146 TI - [Distinguishing blood vessels from lymphatics using double immunohistochemical staining for CD34 and D2 - 40]. PMID- 17706149 TI - [Pulmonary alveolar microlithiasis: report of a case]. PMID- 17706150 TI - [Intraduct papilloma of breast with sebaceous metaplasia: report of a case]. PMID- 17706151 TI - [Pleomorphic adenoma with extensive lipometaplasia in the parotid gland: report of two cases]. PMID- 17706152 TI - [Renal clear cell carcinoma associated with pelvis hemangioma and adrenal cortical adenoma: report of a case]. PMID- 17706153 TI - [Cervical symmetric lipomatosis: report of a case]. PMID- 17706154 TI - [Primary cardiac lymphoma of non-Hodgkin's lymphoma located in the right atrium: report of a case]. PMID- 17706155 TI - [Glomangiomyoma of thigh: a case report]. PMID- 17706158 TI - Recognizing the toxicity of "nontoxic" drugs employed in the management of malignant disease. PMID- 17706159 TI - Characterization of tumor specimens for a targeted therapy in metastatic renal cell carcinoma patients. PMID- 17706160 TI - Pentostatin, cyclophosphamide, and rituximab show significant clinical activity in patients with previously untreated chronic lymphocytic leukemia. PMID- 17706161 TI - Diagnosis and treatment of acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL), characterized by a translocation between the promyelocytic leukemia gene (PML) on chromosome 15 and the retinoic acid receptor alpha (RARalpha) gene on chromosome 17, has become a model for targeted treatment of cancer. Advances in our understanding of the fundamental biology of this disease have led to the development of tools for diagnosis, monitoring of minimal residual disease, and detection of early relapse. Differentiation therapy with all-trans retinoic acid in combination with chemotherapy has significantly improved survival in patients with APL. Moreover, arsenic trioxide, which induces differentiation and apoptosis of APL cells, has become standard treatment for relapsed disease, and its role in the treatment of newly diagnosed APL is under active investigation. The lessons learned from APL have broad applications to other forms of leukemia and to cancer in general, whereby molecularly targeted therapy is directed to specifically defined subgroups. PMID- 17706162 TI - Chronic lymphocytic leukemia: biology and current treatment. AB - There has been considerable recent progress in understanding of the biology of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). These accomplishments have been accompanied by progressive improvement in the management of CLL and its complications. This review summarizes these changes and provides guidelines for a comprehensive approach to patient care. PMID- 17706163 TI - New treatments for chronic lymphocytic leukemia. AB - An enhanced understanding of the important pathways governing chronic lymphocytic leukemia (CLL) cell survival and the critical role played by the microenvironment in the pathogenesis of the disease has brought new opportunities for drug development in CLL. Several new targets have been identified, and novel agents are under intense investigation in clinical trials. Some of these agents are already demonstrating promising anti-CLL activity on their own, whereas others hold promise in combination with existing therapeutic options. As the use of monoclonal antibodies for chemoimmunotherapy becomes standard clinical practice, the future holds promise for concurrent targeting of the tumor cell as well as its microenvironment. PMID- 17706165 TI - Therapy-related acute myelogenous leukemia and myelodysplastic syndrome. AB - Therapy-related acute myelogenous leukemia and myelodysplastic syndrome (t AML/MDS) are increasing in prevalence with aging of the population and improved survival of patients treated with chemotherapy or radiotherapy for other malignancies. Research focused on the pathogenesis of t-AML/MDS will provide insight into the pathogenesis of de novo AML/MDS. Participation in clinical trials should be encouraged for this patient population because results with available treatment options are clearly suboptimal. PMID- 17706164 TI - The role of DNA repair in chronic lymphocytic leukemia pathogenesis and chemotherapy resistance. AB - Front-line therapy for chronic lymphocytic leukemia (CLL) with alkylating agents is associated with low rates of complete remission and no improvement in overall survival. The ability of CLL cells to efficiently repair alkylator-induced damage to DNA might explain this lack of response. Novel strategies that inhibit DNA repair, such as combinations of alkylating agents, purine nucleoside analogues, and immunotherapy, have produced durable clinical and molecular remission in both untreated and relapsed CLL. This review evaluates the contribution of DNA repair processes in the development of resistance to chemotherapy and the impact of therapies that exploit the DNA repair capacity of CLL cells to therapeutic advantage. PMID- 17706166 TI - Rituximab maintenance in indolent lymphoma: indications and controversies. AB - Over the past few years it has been shown in previously untreated and relapsed/refractory follicular lymphoma that rituximab maintenance has a clear clinical benefit after induction with rituximab plus chemotherapy, chemotherapy alone, or rituximab monotherapy. However, the optimal dose, schedule, and duration of rituximab maintenance therapy still need to be established. The important issue of maintenance treatment versus retreatment upon relapse is the topic of the ongoing large randomized phase III Rituximab Extended Schedule or Retreatment Trial (RESORT). Current data indicate that rituximab maintenance can be safely administered for up to 2 years, although assessment of long-term safety requires longer follow-up. PMID- 17706167 TI - Update on HIV lymphoma. AB - In industrialized nations people infected with HIV remain at increased risk for malignancies despite highly active antiretroviral therapy. In these countries, lymphoma is the most common HIV-associated malignancy. This review summarizes progress from January 2005 to February 2007. The majority of investigation has been in diffuse large B cell lymphoma, with infusional therapy remaining promising but cumbersome. Rituximab likely improves complete response rates, and, possibly overall survival, but is likely associated with increased infections in a subset of patients with very low CD4 counts. Biologic insights have been attained in the spectrum of HIV-associated non-Hodgkin's lymphoma, Hodgkin's lymphoma, and virologic coinfections. Overall, the outcome for non-Hodgkin's lymphoma and Hodgkin's lymphoma in the setting of HIV continues to improve as insights into the pathophysiology and treatment advance. PMID- 17706168 TI - Mantle cell lymphoma: evolving novel options. AB - Mantle cell lymphoma (MCL) represents only 6% of non-Hodgkin's lymphoma but is one of the most active fields of clinical investigation. Front-line therapy appears to benefit from intensification either through high-dose therapy with stem cell transplant consolidation or dose-intense chemotherapy with hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and rituximab. Unfortunately, no standard therapy has been defined, and most patients eventually relapse. An impressive number of novel agents are currently being tested, the bulk of which are biologic agents or targeted therapies. Bortezomib is the first in class of proteasome inhibitors and the first new agent to be approved in relapsed/refractory MCL. Other small molecules have shown encouraging activity, including mTOR and Bcl-2 inhibitors, novel antibodies, and new cytotoxic agents. Future trials will also benefit from new molecular approaches through pharmacogenomics. PMID- 17706169 TI - Unusual histologic and clinical variants of melanoma: implications for therapy. AB - Unusual histologic variants of melanoma may be problematic to the histopathologist. Several of these variants are sufficiently rare that their biologic behavior remains obscure. As identification of some of these melanoma subtypes has specific implications for the therapeutic approach, and as some may mimic other forms of epithelial or mesenchymal neoplasia, their recognition is key to patient management. PMID- 17706172 TI - Review of osmotic pressure driven release of proteins from monolithic devices. AB - Protein therapeutics are a rapidly growing drug class, with sales in 2004 in the area of $US 34 billion. They are presently administered primarily by injection, although there is increasing recognition that many proteins would benefit from long-term, localized delivery. Such delivery represents a significant challenge due principally to protein stability concerns. Polymeric delivery systems which rely on osmotic pressure driven drug release may prove to be an effective formulation approach. This paper reviews the evolution of osmotic pressure drug release from polymers, with an emphasis on their potential for protein delivery. It is concluded that osmotic pressure driven release is promising for protein delivery, but there is still a need for in vivo demonstration of protein stability and delivery efficacy. PMID- 17706171 TI - Multidisciplinary management of special melanoma situations: oligometastatic disease and bulky nodal sites. AB - Potentially resectable, advanced stage melanoma in the form of extensive palpable adenopathy or limited systemic metastases presents a significant challenge but also offers the prospect of long-term disease control. Although surgical resection is the mainstay of therapy, involvement of a multidisciplinary team is required for optimal management of these special situations. These patients need to be evaluated preoperatively by the team, discussed at a multidisciplinary conference, and treated by experienced physicians with access to the full spectrum of modern surgical and oncologic therapy. Surgical resection is generally extensive and may require en bloc resection of important anatomic structures. Adjuvant radiation or systemic therapy is required in many patients to help achieve durable regional and systemic control of disease. In addition, novel therapies, such as neoadjuvant chemotherapy, targeted therapies, or investigational intralesional therapies, may ultimately play a role in the management of these difficult clinical situations and require further evaluation, as preliminary studies show some encouraging results. PMID- 17706170 TI - Management of metastatic melanoma patients with brain metastases. AB - Brain metastases seem to be an almost inevitable complication in patients with metastatic melanoma. Except for the rare patients who can undergo successful surgical resection of brain metastases, current management strategies do not appear adequate and result in a poor outcome (median survival, 2-4 months). In recent small series, stereotactic radiosurgery or gamma-knife treatment has suggested improvement in local control compared with whole brain radiation therapy. We have recently shown prolonged survival (11.1 months) using a multimodality treatment approach in 44 sequential patients with melanoma brain metastases. A subsequent study demonstrated that the outcome of biochemotherapy for metastatic melanoma is not affected by the presence or absence of brain metastases. Our results suggest that the outcome of patients with melanoma brain metastases can be improved using a multidisciplinary management strategy. PMID- 17706173 TI - Phase I study with an autologous tumor cell vaccine for locally advanced or metastatic prostate cancer. AB - PURPOSE: To attempt the isolation and primary culture of prostate tumor cells, to use the cultured cells for active immunotherapy, and to evaluate the safety and efficacy in a Phase I clinical trial. MATERIALS AND METHODS: Tumor fragments were collected from 50 patients with prostate-specific antigen (PSA) > or = 10 ng/mL, < or = cT2 PCa who underwent radical retropubic prostatectomy (RRP) and 6 patients with metastatic PCa who underwent transurethral resection of the prostate (TURP). Cultured tumor cells were incubated with IFN-fi, irradiated, and cryopreserved. Seven vaccine inoculations were performed into > or = pT3 and/or N+ patients, and M+ patients, with the first two doses admixed with Bacille Calmette-Guerin (BCG). Follow-up was performed with measurement of delayed-type hypersensitivity (DTH) reactions, PSA and hemato-chemical tests, and bone scans. RESULTS: No cell culture was obtained in the TURP group. Cell culture and vaccine production were obtained in 37 cases (74%) in the RRP group. Eleven > or = pT3 and/or N+ patients were vaccinated. Toxicity was generally limited to the inoculation sites. DTH reactions > or = 10 mm were observed in 2 patients and > or = 5 mm in 6 patients. Two patients had a decrease in PSA levels after vaccine administration. CONCLUSIONS: The autologous cell vaccine is safe and seems to induce a positive immune cellular response. Primary cell culture and vaccine production can be obtained for most RRP patients, but not for TURP patients using our method. There seems to be some influence of the vaccine in PSA evolution after RRP. PMID- 17706175 TI - Design and synthesis of new rofecoxib analogs as selective cyclooxygenase-2 (COX 2) inhibitors: replacement of the methanesulfonyl pharmacophore by a N acetylsulfonamido bioisostere. AB - PURPOSE: A group of 3,4-diaryl- 2(5H)furanones were synthesized to determine whether a N-acetylsulfonamido (SO2NHCOCH3) moiety could be used as a bioisosteric replacement for the traditional sulfonamide (SO2NH2) and methanesulfonyl (SO2CH3) COX-2 pharmacophores. METHODS: In vitro COX-1 and COX-2 isozyme inhibition studies were carried out to acquire structure activity relationship data with respect to the point of attachment of the Nacetylsulfonamide moiety at the para and metapositions of the C-4 phenyl ring in conjunction with a variety of substituents (H, F, Cl, Me, OMe) at the para position of the C-3 phenyl ring. RESULTS: COX-1 and COX-2 inhibition studies showed that all compounds were selective inhibitors of COX-2 since no inhibition of COX-1 was observed at a concentration of 100 microM. The relative COX-2 potency, and COX-2 selectivity index, profiles for the C-4 para acetamidophenyl compounds, with respect to the C 3 phenyl parasubstituent was H > F > Cl. The point of attachment of the SO2NHCOCH3 substituent on the C-4 phenyl ring was a determinant of COX-2 potency, and COX-2 selectivity, where the relative activity profile was para acetylsulfonamido > meta acetylsulfonamido. 4-[4-(NAcetylsulfonamido) phenyl]-3 phenyl-2(5H)furanone was identified as a more potent (IC50 = 0.32 microM), and selective (S.I. > 313), COX-2 inhibitor than the parent reference compound rofecoxib (IC50 = 0.43 microM, S.I. > 232). CONCLUSIONS: The SO2NHCOCH3 moiety i) is a novel COX-2 pharmacophore that also has the potential to serve as a prodrug moiety to the traditional SO2NH2 COX-2 pharmacophore, and ii) it could serve as a useful COX-2 pharmacophore to study the structure-function relationship of the COX-2 isozyme in view of its potential to acetylate the NH2 moiety of amino acid residues such as Gln192 or Arg513 that line the pocket of the secondary COX-2 binding site. PMID- 17706174 TI - Functionalized N(2-oxyiminoethyl) piperazinyl quinolones as new cytotoxic agents. AB - PURPOSE: The prokaryotic type II topoisomerases (DNA gyrase and topoisomerase IV) and the eukaryotic type II topoisomerases represent the cellular targets for quinolone antibacterial agents and a wide variety of anticancer drugs, respectively. In view of the mechanistic similarities and sequence homologies exhibited by the two enzymes, tentative efforts to selectively shift from an antibacterial to an antitumoral activity was made by synthesizing a series of functionalized N-(2-oxyiminoethyl)piperazinyl quinolones, in which the C-7 piperazine ring of antibacterial quinolones, ciprofloxacin and norfloxacin, is attached by a certain N-[2-(furan-2-yl)-2-oxyiminoethyl] and N-[2-(thiophen-2-yl) 2-oxyiminoethyl] moieties. Thus, as part of a continuing search for potential anticancer drug candidates in the N-substituted piperazinyl quinolones series, the cytotoxicity evaluation of functionalized N-(2-oxyiminoethyl) piperazinyl quinolones was our interest. METHODS: The growth inhibitory activities of synthesized N-[2-(furan-2-yl)-2-oxyiminoethyl] and N-[2-(thiophen-2-yl)-2 oxyiminoethyl] piperazinyl quinolones were determined against seven cancer cell lines using an in vitro cell culture system (MTT assay). RESULTS: Preliminary screening showed that some of N-(2-oxyiminoethyl) piperazinyl quinolone analogs containing O-benzyl group displayed in vitro cytotoxic activity comparable or higher than reference drug etoposide. CONCLUSIONS: These studies demonstrate that introduction of O-benzylmoiety on oxime group of N-(2-oxyimino) piperazinyl quinolone series changes the biological profile of piperazinyl quinolones from antibacterial to cytotoxic activity. As can be deduced from these data, O-benzyl functionalized N-(2-oxyiminoethyl) piperazinyl quinolones have excellent potential as a new class of cytotoxic agents. PMID- 17706176 TI - Use of a simulated annealing algorithm to fit compartmental models with an application to fractal pharmacokinetics. AB - Increasingly, fractals are being incorporated into pharmacokinetic models to describe transport and chemical kinetic processes occurring in confined and heterogeneous spaces. However, fractal compartmental models lead to differential equations with power-law time-dependent kinetic rate coefficients that currently are not accommodated by common commercial software programs. This paper describes a parameter optimization method for fitting individual pharmacokinetic curves based on a simulated annealing (SA) algorithm, which always converged towards the global minimum and was independent of the initial parameter values and parameter bounds. In a comparison using a classical compartmental model, similar fits by the Gauss-Newton and Nelder-Mead simplex algorithms required stringent initial estimates and ranges for the model parameters. The SA algorithm is ideal for fitting a wide variety of pharmacokinetic models to clinical data, especially those for which there is weak prior knowledge of the parameter values, such as the fractal models. PMID- 17706177 TI - Molecular imaging agents for clinical positron emission tomography in oncology other than fluorodeoxyglucose (FDG): applications, limitations and potential. AB - Recent efforts in radiopharmaceutical design for positron emission tomography (PET) imaging in clinical oncology have provided a library of tracers that have the potential to contribute to individualizing cancer patient management. These tracers can provide PET images that reveal aspects of the fundamental underlying biochemistry in the tumor before and during treatment. For a number of these PET tracers the cellular processing has been well described and they are now generally referred to as molecular imaging agents. Despite their recognized value in clinical oncology these tracers have not yet obtained widespread acceptance and are not generally available at centers performing PET scans. There are a number of barriers and challenges to the widespread use of these PET tracers that include; a limited clinical demand, challenges presented by the chemistry and formulation for clinical acceptability, the short physical half life of the PET radionuclides, regulatory issues and the overall costs associated with PET radiopharmaceutical production. In addition the interpretation of the PET images requires a clear understanding of the biochemical processes involved at the cellular level. A concerted effort is required among stakeholders including clinicians, scientists, industry and governmental agencies if the potential of these agents in clinical oncology is to be realized. PMID- 17706178 TI - Imaging of tumor hypoxia with [124I]IAZA in comparison with [18F]FMISO and [18F]FAZA--first small animal PET results. AB - PURPOSE: This study was performed to compare the 2-nitroimidazole derivatives [124I]IAZA, [18F]FAZA and well known [18F]FMISO in visualization of tumor hypoxia in a mouse model of human cancer using small animal PET. METHODS: PET imaging of female Balb/c nude mice bearing A431 tumors on a Phillips Mosaic small animal PET scanner was performed 3 h p.i. for all three tracers. Mice injected with [124I]IAZA were scanned again after 24 h and 48 h. In addition to the mice breathing air, in the case of [18F]FAZA and [124I]IAZA a second group of mice for each tracer was kept in an atmosphere of carbogen gas (5% of CO2 + 95 % of O2; from 1 h before to 3 h after injection) to evaluate the oxygenation dependency on uptake (all experiments n = 4). After the final PET scan animals were sacrificed and biodistribution was studied. RESULTS: Mice injected with [18F]FAZA displayed significantly higher tumor-to background (T/B) ratios (5.19 +/- 0.73) compared to those injected with [18F]FMISO (3.98 +/- 0.66; P $lt; 0.05) or [124I]IAZA (2.06 +/- 0.26; P $lt; 0.001) 3 h p.i. Carbogen breathing mice showed lower ratios ([18F]FAZA: 4.06 +/- 0.59; [124I]IAZA: 2.02 +/- 0.36). The T/B ratios increased for [124I]IAZA with time (24 h: 3.83 +/- 0.61; 48 h: 4.20 +/- 0.80), but after these late time points the absolute whole body activity was very low, as could be seen from the biodistribution data (< 0.1 %ID/g for each investigated organ) and ratios were still lower than for [18F]FAZA 3 h p.i. Due to de-iodination uptake in thyroid was high. Biodistribution data were in good agreement with the PET results. CONCLUSIONS: [18F]FAZA showed superior biokinetics compared to [18F]FMISO and [124I]IAZA in this study. Imaging at later time points that are not possible with the short lived 18F labeled tracers resulted in no advantage for [124I]IAZA, i. e. tumor to normal tissue ratios could not be improved. PMID- 17706179 TI - A novel and efficient synthesis of [2-11C]5-fluorouracil for prognosis of cancer chemotherapy. AB - PURPOSE: In order to facilitate the use of the PET-based Strauss test for 5-FU sensitivity, a rapid and facile synthesis of [2-11C]5-fluorouracil ([2-11C]5-FU), based on = [11C]phosgene ([11C]COCl2), is reported. METHOD: The key intermediate (E)-beta- benzoylamino-Alpha-fluoroacrylamide (1) and [11C]phosgene was submitted to cyclocondensation to give [2-11C]5-fluorouracil. RESULTS: [2-11C]5 Fluorouracil was synthesized in 17 min with high (25%) radiochemical yield. CONCLUSION: The present study provides a rapid, simple, and efficient synthesis of [2-11C]5-FU, that would serve as a useful prognostic PET tracer for 5-FU chemotherapy. PMID- 17706180 TI - Poly(D,L-lactic-co-glycolic acid) microsphere delivery of adenovirus for vaccination. AB - PURPOSE: To study the effect of encapsulation of recombinant adenovirus type 5 encoding Beta-galactosidase (Ad5-Betagal) in poly (D,Llactic-co-glycolic acid) (PLGA) microspheres on viral delivery to professional antigen presenting cells (APCs) in vitro, viral dissemination in vivo, and induction of protective immune responses in vivo. METHODS: PLGA microspheres containing Ad5-alphagal were prepared by a double emulsion solvent evaporation method. Encapsulation efficiency, in vitro release profile, in vitro cellular uptake and in vivo biodistribution of Ad5-alphagal loaded PLGA microspheres were determined using 125I-labeled Ad5-alphagal (125I-Ad5-alphagal). To evaluate the potential of PLGA microsphere delivery of Ad-alphagal for induction of antigen specific immune responses in vivo, Balb/c mice were immunized with the subcutaneous injection of the formulations then splenocytes of the immunized mice were assayed for cytotoxic T lymphocyte (CTL) activity against a variety of target cells in a 51Cr release assay. Anti-alphagal antibody responses were assessed in the sera of the immunized mice by enzyme linked immunosorbent assay (ELISA). The effect of encapsulated Ad5-alphagal immunization on protection against a tumor challenge was tested in a murine artificial metastatic lung tumor model with alphagalexpressing tumor cells, CT26.CL25. RESULTS: PLGA microspheres encapsulated Ad5-alphagal with 24.8 +/- 1.4 % encapsulation efficiency and 11.4 +/- 3.6 % of the encapsulated virus retained the functional activity. In vitro release study showed slow release (15% in 11 days) of the virus from the microspheres. PLGA microsphere delivery of Ad5-alphagal resulted in enhanced uptake of the virus by APCs with an increase in the transgene expression in vitro. Administration of the virus in the encapsulated form resulted in substantially decreased viral dissemination to remote organs and tissues as compared to the free virus. Encapsulated virus were capable of eliciting antigen specific CTL as well as antibody responses against alphagal and induced protective immune responses against lethal tumor challenge at a significantly lower infectious viral dose as compared to the free virus. CONCLUSION: PLGA microsphere with Ad5-alphagal enhances the delivery of virus to APCs with reduced viral dissemination in other organs and induces protective antigen specific immune responses against viral encoded transgene. PMID- 17706181 TI - Development and validation of a sensitive and specific HPLC assay of cladribine for pharmacokinetics studies in rats. AB - PURPOSE: To develop and validate a sensitive and specific HPLC assay for cladribine (CdA) in plasma for pharmacokinetic studies in rats. METHODS: CdA and the internal standard AZT were purchased from Sigma-Aldrich Chem. The HPLC system consisted of a Shimadzu LC-9A pump, a 3 im, 250 x 2.0 mm I.D. high speed C18 column (Jupitertrade mark), preceded by a 5 im 4 4 mm I.D. C18 guard column (Licrocarttrade mark), an Agilent Model 1050 UV-VIS detector and a 3395 Integrator. The mobile phase was made up of 0.01M KH2PO4 (pH 5): methanol: acetonitrile 90:5:5). The system was operated at ambient temperature with a flow rate of 0.3 mL/min, and UV wavelength at 265 nm, and an operating pressure of ca. 1.56 kpsi. Extraction of cladribine and AZT from plasma was achieved by solid phase extraction using 100 mg/mL C18 SPE columns Extra-septrade mark). The assay was validated for sensitivity, precision, specificity and application for pharmacokinetic study in rats. RESULTS: Under these conditions, the average retention times of CdA and AZT were 13.5 and 21 min, respectively, and recoveries were between 80 - 95%. Standard curve constructed from plasma standards was linear from 0.1 ug/mL to 1 ug/mL with regression coefficient (r2) 0.99 or greater. Sensitivity assessed by on column injection was < 1 ng. Using a 50-uL plasma sample size, the mean intra assay variations 0.1 ug/mL were 7%, and inter assay variations over a period of 3 months for 5 separate batches were less than 20%. The assay was used to study a single dose pharmacokinetic study of CdA in rats after a 2 mg/kg subcutaneous injection. CONCLUSION: The described HPLC assay has adequate sensitivity and specificity to study pharmacokinetics of CdA in rats, and could be adapted also to clinical pharmacokinetic studies. PMID- 17706182 TI - Synthesis, transportability and hypoxiaselective binding of 1-beta-D-(5-Deoxy-5 fluororibofuranosyl)-2-nitroimidazole (beta-5-FAZR), a configurational isomer of the clinical hypoxia marker, FAZA. AB - PURPOSE: Cellular uptake of most azomycin-based radiosensitizers depends on perfusion and diffusion, rather than on active transport. In medical imaging using radioisotopically labeled azomycin nucleosides, image contrast depends on rapid diffusion from normoxic tissues and rapid renal clearance from the central compartment. [18F]FAZA [1-alpha-D-(5-deoxy-18F]fluoroarabinofuranosyl)-2 nitroimidazole], an azomycin nucleoside currently under clinical evaluation as a marker of tissue hypoxia in medical centers world wide, provides high contrast but its uptake is diffusion dependent and therefore low. 1-D-(5-Fluoro-5 deoxyribofuranosyl)-2-nitroimidazole 6 (beta-5-FAZR), a Beta-ribose analog of FAZA, has now been developed to exploit transport across cell membranes to improve absolute uptake in hypoxic regions and high contrast. METHODS: Beta-5 FAZR was synthesized by classical sugar base coupling followed by regioselective fluorination. In radiosensitization of hypoxic and normoxic to 60Co x-rays was determined relative to known radiosensitizers. The relative abilities of five human nucleoside transporters (hENT1/2, hCNT1/2/3 to bind the radiosensitizers were determined by quantifying their inhibition of uridine transport by recombinant transporters produced in yeast. RESULTS: Beta-5-FAZR was synthesized in 44 percent yield. Beta-5-FAZR had moderate radiosensitization effect on human HCT116/100 colorectal carcinoma (OER 1.8). Beta-5-FAZR was a weak inhibitor of uridine transport relative to nonfluorinated 1-beta-D-(ribofuranosyl)-2 nitroimidazole (beta-AZR). CONCLUSION: Facile synthesis of beta-5-FAZR was achieved and its activity as a radiosensitizer was confirmed. Substitution of C-5 hydroxyl by fluorine in the ribose moiety greatly reduced interaction with hENT1/2 and hCNT1/2 and moderately reduced interaction with hCNT3 relative to thymidine and beta-AZR. PMID- 17706183 TI - Characterization of a cyclodextrinoligonucleotide complex by capillary electrophoresis using laser-induced fluorescence. AB - PURPOSE: Cyclodextrins (CDs) have been identified as a viable alternative to viral vectors for use in therapeutic applications. Here, the stability of the complex formed between the a multiply charged, cationic, fully substituted heptakis-(6-amino-2-galactosyl)cyclodextrin (BCDX12) with a multiply charged 12 mer hexachlorofluorescein tagged arabinopolynucleotide (Hex-PAH) have been evaluated. METHODS: The stability of complexes of Hex-PAH and BCD-X12 was studied with respect to mole ratio (1:1, 1:2, and 1:5 Hex-PAH:BCD-X12), pH, buffer concentration, temperature, and agitation using capillary electrophoresis with laser induced fluorescence detection (CE/LIF). Two neutral CDs and an additional cationic CD were also tested under the same analytical conditions to determine their ability to form complexes. RESULTS: Hex-PAH:BCDX12 complexes at mole ratios of 1:2 were stable in 10 mM (160 mM total borate concentration) sodium tetraborate buffer at pH 7.5 and at temperatures of 4 degrees C and 25 degrees C over 48 hours. However, the Hex-PAH:BCD-X12 complex was less stable at 37 degrees C and at higher buffer concentrations and pH values. Strong vortex mixing prior to analysis was found to disrupt the complex. Of the four CDs tested for their ability to complex with Hex-PAH, only BCDX12 formed stable complexes with Hex-PAH under the test conditions. CONCLUSIONS: Capillary electrophoresis was found to be well suited to test the stability of cyclodextrin-nucleotide complexes. CE/LIF indicated that only a single Hex- PAH:BCD-X12 complex was formed at all formulation ratios, and that the complexes were electrophoretically identical to each other, and increasing the molar ratio beyond 1:2 did not contribute measurably to complex stability. Storage temperature and agitation conditions were found to influence complex stability. Since no stable complexes were formed with neutral cyclodextrins, the results support the hypothesis of a 'charge associated' complex rather than an inclusion complex, although inclusion complexes cannot be excluded on the basis of these studies. PMID- 17706184 TI - Repeated treatment with N-methyl-d-aspartate antagonists in neonatal, but not adult, rats causes long-term deficits of radial-arm maze learning. AB - Brain glutamatergic system is involved in synaptic plasticity as a base for learning and neural development. This study investigated the effects of neonatal and adult chronic antagonism of N-methyl-d-aspartate (NMDA) receptors, a subtype of glutamate receptors, on learning and/or memory. Rats were trained in the radial-maze learning, which is known as a measure of spatial working memory capacities, in adulthood after neonatal or adult repeated treatment of MK-801 (dizocilpine; 5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine), a non-competitive antagonist, or neonatal repeated treatment of CGS 19755 (cis-4 phosphonomethyl-2-piperadine carboxilic acid), a competitive antagonist. Neonatal repeated treatment of MK-801 or CGS 19755 markedly impaired the radial-arm maze learning. In addition, the treatment altered activities differently in the radial maze and in the open-field. On the other hand, adult repeated treatment with MK 801 affected neither the radial-maze learning nor activities. Results suggest that chronic blockade of NMDA receptors in a neonatal stage may produce long lasting deteriorative effects on spatial working memory in adulthood. PMID- 17706186 TI - A computational study of conflict-monitoring at two levels of processing: reaction time distributional analyses and hemodynamic responses. AB - The conflict-monitoring hypothesis of cognitive control proposes that response conflict is higher in incongruent conditions compared to congruent or neutral conditions and that increases in conflict lead to increased control on subsequent trials. A neurocomputational model is used to address data on reaction time distributions and hemodynamic responses in a flanker task with neutral (N), congruent (CO), stimulus-incongruent (SI), and response-incongruent (RI) trials, allowing investigation of stimulus- and response-conflict. A computational study is presented in which the conflict-signal is (a) computed at every level of processing (response, stimulus) and is (b) used to modulate the input in the same trial. Results show that the models capture (1) the profile of distributional plots seen in the behavioral literature and (2) the patterns of hemodynamic responses seen in the neuroimaging literature. Based on the simulations it is suggested that the prefrontal cortex processes response-conflict and that the parietal cortex processes stimulus-conflict. PMID- 17706185 TI - Systemic administration of a proteasome inhibitor does not cause nigrostriatal dopamine degeneration. AB - Proteasomal dysfunction has been suggested to contribute to the degeneration of nigrostriatal dopamine neurons in Parkinson's disease. A recent study reported that systemic treatment of rats with the proteasome inhibitor Z-lle-Glu(OtBu)-Ala Leu-al (PSI) causes a slowly progressive degeneration of nigrostriatal dopamine neurons, the presence of inclusion bodies in dopamine neurons, and motor impairment. We examined in vitro and in vivo the effects of PSI on nigrostriatal dopamine neurons. Mass spectrometric analysis was employed to verify the authenticity of the PSI compound. PSI was non-specifically toxic to neurons in ventral mesencephalic organotypic slice cultures, indicating that impairment of proteasome function in vitro is toxic. Moreover, systemic administration of PSI transiently decreased brain proteasome activity. Systemic treatment of rats with PSI did not, however, result in any biochemical or anatomical evidence of lesions of nigrostriatal dopamine neurons, nor were any changes in locomotor activity observed. These data suggest that systemic administration of proteasome inhibitors to normal adult rats does not reliably cause an animal model of parkinsonism. PMID- 17706188 TI - Haptoglobin phenotype and risk of cervical neoplasia: a case-control study. AB - BACKGROUND: Haptoglobin is an acute-phase glycoprotein that influences host response to infections and tumours. The haptoglobin locus is polymorphic with 2 classes of alleles (Hp(1) and Hp(2)) yielding 3 phenotypes: Hp1-1, Hp2-2, and Hp2 1 with structurally and functionally distinct protein products, suggesting that haptoglobin polymorphism may influence susceptibility to infections and cancers. METHODS: We examined the relation between haptoglobin phenotype and high-grade cervical intraepithelial neoplasia (CIN) in a hospital-based case-control study. Cases (n = 307) were women with biopsy-confirmed CIN-2 or CIN-3. Controls (n = 358) were a random sample of women with normal cytology. The PGMY polymerase chain reaction and reverse line blot methods were used for HPV detection and genotyping. Haptoglobin phenotype was determined by polyacrylamide gel electrophoresis. RESULTS: Among controls, phenotype distribution corresponded to allele frequencies of 0.39 for Hp(1) and 0.61 for Hp(2) with no significant deviation from the Hardy-Weinberg equilibrium (p=0.66). With all women included in the analysis, the Hp1-1 phenotype was associated with increased risk of CIN (OR contrasting Hp1-1 vs. Hp2-2 = 1.0; 95% CI: 0.6-1.5). However, in analyses restricted to HPV-positive participants, the Hp1-1 phenotype was associated with 2.7-fold (95% CI: 1.0-7.2) higher risk of CIN. CONCLUSIONS: If confirmed, these findings indicate an increased risk of CIN among women with the Hp1-1 phenotype. PMID- 17706187 TI - Natural killer cell receptor expression in patients with severe and recurrent Herpes simplex virus-1 (HSV-1) infections. AB - Herpes simplex virus-1 (HSV-1) is an important human pathogen which in a minority of people causes severe infections. In immunocompetent hosts the infection is self limiting. However, a small minority of people have frequent attacks. As NK cells have been implicated in host protection against HSV-1, the aim of this study was to compare NK cell receptor expression in healthy controls and in patients suffering from recurrent HSV-1 reactivations using monoclonal antibodies against NK cell receptors and 3 colour flow cytometry. Eighteen patients were recruited into the study and the results were compared to a control group. The results obtained showed that overall there was no statistical difference between patient and control groups in the expression of the NK cell receptors. There were however, individuals in the patient group (in particular, two members of one family) with significantly reduced level of activating receptors compared to the control group. PMID- 17706189 TI - Glutathione status in the blood and tissues of patients with virus-originated hepatocellular carcinoma. AB - OBJECTIVES: Glutathione status can be regarded as the redox status for many diseases. This study was performed to investigate the glutathione status in virus originated hepatocellular carcinoma (HCC). DESIGN AND METHODS: The blood and tissue samples were obtained from 24 patients. Blood samples were also obtained from 137 controls for comparison. RESULTS: The GSH level and the ratios of GSH/GSSG and GSH/total glutathione of the blood samples from the patients were significantly lower than those of the controls, while the GSSG values were significantly higher. Meanwhile, levels of GSH and total glutathione, as well as the ratios of GSH/GSSH and GSH/total glutathione, were significantly decreased, whereas GSSG levels were significantly higher, in the HCC tissues than those of the adjacent cancer-free tissues. CONCLUSIONS: Glutathione status in the HCC suggested that the antioxidant system is severely impaired, supporting a consistent role of the free radical cytotoxicity in the pathophysiology of the disease. PMID- 17706190 TI - Scalp hair as a biomarker in environmental and occupational mercury exposed populations: suitable or not? AB - Hair is a well-established and widely used matrix for measuring mercury exposure of an individual. Although a variety of washing procedures to remove external mercury contamination have been proposed, no standardized procedures are available yet. In this study, different washing reagents like l-cysteine (Cys), 2 mercaptoethanol (ME), and disodium diaminoethanetetra acetate (EDTA) were used to find out if it is possible to remove mercury contamination from human scalp hair spiked with HgCl2 solutions at different concentrations. It was found that the external mercury contamination could not be fully washed off even using reagents with high affinity to mercury like l-cysteine and ME. However, for the well pulverized CRM hair samples some of the endogenous mercury was washed off. It suggests that hair is not a suitable biomarker for evaluation of total mercury exposure especially in people like mercury miners or gold miners/burners associated with serious external Hg exposure. However, hair still can be used as an indicator for methyl mercury exposure because, generally, there is almost no exogenous contamination of methyl mercury in hair. PMID- 17706191 TI - Monitoring of PCDD/Fs in a mountain forest by means of active and passive sampling. AB - Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F) are sampled and investigated in a forested area in Middle-Europe. The campaigns, consisting in active and passive samplings, were conducted in the Bavarian and Bohemian Forest at four sites chosen for their similar soil and forest stand characteristics. Passive sampling was conducted using both semi-permeable membrane devices (SPMDs) and needles of well-exposed dominant spruce trees. Active air sampling was also performed at one site with a low volume air sampler. Correlations were performed to identify relationships and trends of PCDD/F. Lower chlorinated PCDD/F are accumulated in SPMDs, needles collected all compounds among homologues and their PCDD/F pattern is close to that of active sampling. Results of the analysed compounds obtained with the different sampling methods served as a basis for the establishment of advantages and disadvantages of the sampling tools applied and their possible optimisation. PMID- 17706192 TI - Amitriptyline affects histamine-N-methyltransferase and diamine oxidase activity in rats and guinea pigs. AB - Histamine participates in numerous physiological and patophysiological processes. Drugs which interfere with the histamine actions are antagonists and agonists of histamine receptors. Histamine degrading enzymes as a possible target for modifying histamine action have so far not been extensively studied. Therefore we examined in vivo and in vitro effects of amitriptyline on two histamine degrading enzymes - diamine oxidase and histamine-N-methyltransferase. We were interested in the in vivo effects of amitriptyline on the diamine oxidase release into guinea pig plasma after heparin stimulation and in effects on the activity and gene expression of both histamine degrading enzymes in different guinea pig tissues. Amitriptyline's in vitro effects on the diamine oxidase and histamine-N methyltransferase activities were measured in guinea pig and also in rat. Enzyme activities were determined with the radiometric micro-assay. The results showed that amitriptyline in vivo changed the profile of the heparin-induced diamine oxidase release, which could be due to changes in at least three processes: diamine oxidase release into plasma, protein synthesis and enzyme activity at the molecular level. Amitriptyline in some tissues (lung and spleen) amplified the mRNA expression of histamine degrading enzymes. Furthermore, the activities of these enzymes were increased in most examined tissues of amitriptyline treated guinea pigs. In vitro studies indicate that amitriptyline differently affects diamine oxidase and histamine-N-methyltransferase in two different rodent species, guinea pig and rat. Our study proved that amitriptyline enhances the histamine degrading processes in guinea pig, what might importantly contribute to lower histamine levels. PMID- 17706193 TI - Inhibition of estrogen receptor beta-mediated human telomerase reverse transcriptase gene transcription via the suppression of mitogen-activated protein kinase signaling plays an important role in 15-deoxy-Delta(12,14)-prostaglandin J(2)-induced apoptosis in cancer cells. AB - The nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) gamma plays a role in cancer development in addition to its role in glucose metabolism. The natural ligand of PPAR-gamma, namely, 15-deoxy-Delta(12,14) prostaglandin J(2) (15d-PGJ(2)), has been shown to possess antineoplastic activity in cancer cells. However, the mechanism underlying its antineoplastic activity remains to be elucidated. Inhibition of the expression of human telomerase reverse transcriptase (hTERT), a major determinant of telomerase activity, reportedly induces rapid apoptosis in cancer cells. In this study, we investigated the effect of 15d-PGJ(2) on hTERT expression. We found that 15d PGJ(2) induced apoptosis in the MIAPaCa-2 pancreatic cancer cells and dose dependently decreased hTERT mRNA and protein expression. Down-regulation of hTERT expression by hTERT-specific small inhibitory RNA also induced apoptosis. Furthermore, 15d-PGJ(2) attenuated the DNA binding of estrogen receptor (ER). MIAPaCa-2 expressed only ERbeta, and although its expression did not decrease due to 15d-PGJ(2), its phosphorylation was suppressed. Additionally, a mitogen activated protein kinase (MAPK) kinase inhibitor decreased ERbeta phosphorylation, and 15d-PGJ(2) attenuated MAPK activity. We conclude that hTERT down-regulation by 15d-PGJ(2) plays an important role in the proapoptotic property of the latter. Furthermore, 15d-PGJ(2) inhibits ERbeta-mediated hTERT gene transcription by suppressing ERbeta phosphorylation via the inhibition of MAP kinase signaling. PMID- 17706195 TI - Protein malnutrition differentially alters the number of glutamic acid decarboxylase-67 interneurons in dentate gyrus and CA1-3 subfields of the dorsal hippocampus. AB - In 30- and 90-day-old rats, using immunohistochemistry for glutamic acid decarboxylase 67 (GAD-67), we have tested whether malnutrition during different periods of hippocampal development produces deleterious effects on the population of GABA neurons in the dentate gyrus (DG) and cornu Ammonis (CA1-3) of the dorsal hippocampus. Animals were under one of four nutritional conditions: well nourished controls (Con), prenatal protein malnourished (PreM), postnatal protein malnourished (PostM), and chronic protein malnourished (ChroM). We found that the number of GAD-67-positive (GAD-67+) interneurons was higher in the DG than in the CA1-3 areas of both Con and malnourished groups. Regarding the DG, the number of GAD-67+ interneurons was increased in PreM and PostM and decreased in ChroM at 30 days. At 90 days of age the number of GAD-67+ interneurons was increased in PostM and ChroM and remained unchanged in PreM. With respect to CA1-3, the number of labeled interneurons was decreased in PostM and ChroM at 30 days of age, but no change was found in PreM. At 90 days no changes in the number of these interneurons were found in any of the groups. These observations suggest that 1) the cell death program starting point is delayed in DG GAD-67+ interneurons, and 2) protein malnutrition differentially affects GAD-67+ interneuron development throughout the dorsal hippocampus. Thus, these changes in the number of GAD-67+ interneurons may partly explain the alterations in modulation of dentate granule cell excitability, as well as in the emotional, motivational, and memory disturbances commonly observed in malnourished rats. PMID- 17706194 TI - Central role of alpha9 acetylcholine receptor in coordinating keratinocyte adhesion and motility at the initiation of epithelialization. AB - Epithelialization, a major component of wound healing, depends on keratinocyte adhesion and migration. Initiation of migration relies upon the ability of keratinocytes to free themselves from neighboring cells and basement membrane. The local cytotransmitter acetylcholine (ACh) controls keratinocyte adhesion and locomotion through different classes of ACh receptors (AChR). In this study, we explored signaling pathways downstream of the alpha9 AChR subtype that had been shown to control cell shape and cytoplasm mobility. Inactivation of alpha9 signaling by pharmacologic antagonism and RNA interference in keratinocyte cultures and null mutation in knockout mice delayed wound re-epithelialization in vitro and in vivo, respectively, and diminished the extent of colony scattering and cell outgrowth from the megacolony. Although keratinocytes at the leading edge elongated, produced filopodia and moved out, most of them remained anchored to the substrate by long cytoplasmic processes that stretched during their migration instead of retracting the uropod. Since the velocity of keratinocyte migration was not altered, we investigated the role of alpha9 in assembly/disassembly of the cell-cell and cell-matrix adhesion complexes. Stimulation of alpha9 upregulated in a time-dependent fashion phosphorylation of the adhesion molecules comprising focal adhesions (FAK, paxillin) and intercellular junctions (beta-catenin, desmoglein 3) as well as cytokeratins. Stimulation of alpha9 was associated with activation of phospholipase C, Src, EGF receptor kinase, protein kinase C, Rac and Rho, whereas inhibition of this receptor interfered with phosphorylation of adhesion and cytoskeletal proteins, and also altered cell-cell cohesion. We conclude that signaling through alpha9 AChR is critical for completion of the very early stages of epithelialization. By activating alpha9 AChR, ACh can control the dynamics and strength of cell-cell cohesion, disabling of a trailing uropod and disassembly and reassembly of focal adhesions, thus facilitating crawling locomotion. PMID- 17706196 TI - Sensorimotor deficits associated with brain tumor progression and tumor-induced brain plasticity mechanisms. AB - The objective of this study was to investigate functional deficits and reactive peri-tumoral brain plasticity events in glioma-bearing rats. 9L gliosarcoma cells were implanted into the forelimb region of the sensorimotor cortex in Fischer rats. Control animals underwent the same operation without tumor implantation. Sensitive tests for detecting sensorimotor dysfunction, including forelimb-use asymmetry, somatosensory asymmetry, and vibrissae-evoked forelimb placing tests, were conducted. We found that tumor-bearing animals exhibited significant composite behavioral deficits on day 14 post-tumor injection compared to surgical controls. With the assistance of magnetic resonance imaging, we demonstrated a significant correlation between tumor volume and magnitude of somatosensory asymmetry, indicating that the somatosensory asymmetry test can provide an effective and efficient means to measure and predict tumor progression. Histopathological assessments were performed after the rats were sacrificed 14 days following tumor implantation. Immunostaining revealed that densities of microtubule-associated protein 2, glial fibrillary acid protein, von Willebrand factor, and synaptophysin were all significantly upregulated in the peri-tumoral area, compared to the corresponding region in surgical controls, suggesting synaptic plasticity, astrocyte activation and angiogenesis in response to tumor insult. Understanding the behavioral and bystander cellular events associated with tumor progression may lead to improved evaluation and development of new brain tumor treatments that promote, or at least do not interfere with, functional adaptation. PMID- 17706197 TI - Deletion of the MTO2 gene related to tRNA modification causes a failure in mitochondrial RNA metabolism in the yeast Saccharomyces cerevisiae. AB - We report here the characterization of the yeast mto2 null mutants carrying wild type mitochondrial DNA or 15S rRNA C1049G allele. The amounts of mitochondrial tRNA(Lys), tRNA(Glu), tRNA(Gln), tRNA(Leu), tRNA(Gly) and tRNA(Met) were markedly decreased but those of tRNA(Arg) and tRNA(His) were not affected in mto2 strains. The mto2 strains exhibited significant reduction in the aminoacylation of tRNA(Lys), tRNA(Leu) but almost no effect in those of tRNA(His). Interestingly, the strain carrying the C1049G allele exhibited an impairment of aminoacylation of those tRNAs. Furthermore, the steady-state levels of mitochondrial mRNA CYTB, COX1, COX2, COX3, and ATP6 were markedly decreased in mto2 strains. These data strongly indicate that unmodified tRNA caused by the deletion of MTO2 caused the instability of mitochondrial tRNAs and mRNAs and impairment of aminoacylation of tRNAs. PMID- 17706198 TI - Evidence for the formation of start aggregates as an initial stage of protein aggregation. AB - The kinetics of thermal aggregation of glycogen phosphorylase b and glyceraldehyde 3-phosphate dehydrogenase from rabbit skeletal muscles were studied using dynamic light scattering. Use of high concentrations of the enzymes (1-3 mg/ml) provided a simultaneous registration of the native enzyme forms and protein aggregates. It was shown that initially registered aggregates (start aggregates) were large-sized particles. The hydrodynamic radius of the start aggregates was about 100 nm. The intermediate states between the native enzyme forms and start aggregates were not detected. The initial increase in the light scattering intensity is connected with accumulation of the start aggregates, the size of the latter remaining unchanged. From a certain moment in time aggregates of higher order, formed as a result of sticking of the start aggregates, make a major contribution to the enhancement of the light scattering intensity. PMID- 17706199 TI - Enhanced sialylation of EPO by overexpression of UDP-GlcNAc 2-epimerase/ManAc kinase containing a sialuria mutation in CHO cells. AB - Sialylation (e.g. expression of sialic acid) plays a crucial role for function and stability of most glycoproteins. The key enzyme for the biosynthesis of sialic acid is the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine-kinase (GNE). Mutations in the binding site of the feedback inhibitor CMP-sialic acid of the GNE leads to sialuria, a disease in which patients produce sialic acid in gram scale. Here, we report on the use in biotechnology of sialuria-mutated GNE. Expression of the sialuria-mutated GNE in CHO-cells leads to increased sialylation of recombinant expressed erythropoietin (EPO). Our data show that sialuria-mutated-GNE over-expressing cells are the perfect platform to express highly sialylated therapeutic proteins, such as EPO. PMID- 17706200 TI - The antioxidative function of eicosapentaenoic acid in a marine bacterium, Shewanella marinintestina IK-1. AB - When the eicosapentaenoic acid (EPA)-deficient mutant strain IK-1Delta8 of the marine EPA-producing Shewanella marinintestina IK-1 was treated with various concentrations of hydrogen peroxide (H(2)O(2)), its colony-forming ability decreased more than that of the wild type. Protein carbonylation, induced by treating cells with 0.01 mM H(2)O(2) under bacteriostatic conditions, was enhanced only in cells lacking EPA. The amount of cells recovered from the cultures was decreased more significantly by the presence of H(2)O(2) for cells lacking EPA than for those producing EPA. Treatment of the cells with 0.1 mM H(2)O(2) resulted in much lower intracellular concentrations of H(2)O(2) being consistently detected in cells with EPA than in those without EPA. These results suggest that cellular EPA can directly protect cells against oxidative damage by shielding the entry of exogenously added H(2)O(2) in S. marinintestina IK-1. PMID- 17706201 TI - The GluCre-ROSA26EYFP mouse: a new model for easy identification of living pancreatic alpha-cells. AB - The control of glucagon secretion by pancreatic alpha-cells is poorly understood, largely because of the difficulty to recognize living alpha-cells. We describe a new mouse model, referred to as GluCre-ROSA26EYFP (or GYY), allowing easy alpha cell identification because of specific expression of EYFP. GYY mice displayed normal glycemic control during a fasting/refeeding test or intraperitoneal insulin injection. Glucagon secretion by isolated islets was normally inhibited by glucose and stimulated by adrenaline. [Ca(2+)](c) responses to arginine, adrenaline, diazoxide and tolbutamide, were similar in GYY and control mice. Hence, this new mouse model is a reliable and powerful tool to specifically study alpha-cells. PMID- 17706202 TI - Estrogen receptor alpha gene polymorphisms are associated with idiopathic premature ovarian failure. AB - OBJECTIVE: To assess the role of hormone receptor/binding protein variants in genetic predisposition to premature ovarian failure (POF). DESIGN: Case-control study. SETTING: Academic. PATIENT(S): Fifty-five POF patients, 107 control women from the general population, and 27 control women who had proven fertility after age 37. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Allele distributions in cases and controls were assessed for genetic association. RESULT(S): Allele distributions of polymorphisms at the androgen receptor (AR) gene, estrogen receptor beta (ESR2) gene, sex hormone-binding globulin (SHBG) gene, and FSH receptor (FSHR) gene did not differ between patients and controls. At a repeat in a promoter of the estrogen receptor alpha(ESR1) gene, POF patients had fewer (<18) short repeat alleles than did controls (P=.004 vs. combined controls). Genotypes consisting of two short alleles were found in 36.4% of control women but only 5.5% of POF patients (P<.0001 vs. combined controls). The ESR1 repeat may confer risk for POF in a simple dominant manner in which carriers of a long repeat have a relative risk of 9.7 (95% CI = 2.6 - 35.6). CONCLUSION(S): Polymorphisms at the ESR1 gene are associated with POF in this patient population, while those in AR, ESR2, SHBG, and FSHR showed no association. Further studies are necessary to confirm these findings in larger patient samples and to identify the specific predisposing lesion. PMID- 17706204 TI - Human parthenogenetic blastocysts derived from noninseminated cryopreserved human oocytes. AB - OBJECTIVE: To report on the development of human parthenogenetic blastocysts and an in vitro attachment that was generated from noninseminated cryopreserved human oocytes for the first time. DESIGN: Prospective study. SETTING: Department of reproductive medicine in a medical institute in Buenos Aires, Argentina. PATIENT(S): Five healthy fertile donors. INTERVENTION(S): Artificial activation of noninseminated cryopreserved human oocytes after thawing, parthenote culture, and their in vitro attachment. MAIN OUTCOME MEASURE(S): Survival rate, activation rate, cleavage rate, and blastocyst formation. RESULT(S): Thirty-six of 38 cryopreserved noninseminated oocytes survived after thawing (survival rate, 94.7%). Thirty-one of 36 oocytes showed one pronucleus (activation rate, 86.1%). Thirty of 31 cleaved (cleavage rate, 96.8%). Five of 30 showed cavitation (blastocyst rate, 16.7%). CONCLUSION(S): Noninseminated cryopreserved human oocytes showed a high survival rate after thawing. They responded very satisfactorily to artificial activation, which was followed by a high rate of parthenogenetic embryos, which can develop into blastocysts. In the future, these could be a new source for development of human parthenogenetic stem cells. PMID- 17706203 TI - Circulating levels of cytokines during pregnancy: thrombopoietin is elevated in miscarriage. AB - OBJECTIVE: To evaluate the hypothesis that cytokine levels are associated with miscarriage risk using serum samples collected before report of miscarriage. DESIGN: A nested case-control study. SETTING: Biospecimens from the multisite Collaborative Perinatal Project, University of Florida, laboratory assessment of interleukin (IL)-1 receptor antagonist, IL-1beta, IL-4, IL-6, interferon (IFN) gamma, tumor necrosis factor (TNF)-alpha, thrombopoietin (TPO), and granulocyte colony-stimulating factor (G-CSF). PATIENT(S): Cases of miscarriage (n = 439) were matched to controls (n = 373) by gestational age at sample collection. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Miscarriage. RESULT(S): Increased risk of miscarriage was associated with elevated TPO (adjusted odds ratio [OR] 1.16, 95% confidence interval [CI] 1.00-1.36) and decreased G-CSF (adjusted OR 0.78, 95% CI 0.64-0.95). When analysis was restricted to samples collected more than 35 days before miscarriage, the effect of G-CSF was not observed (adjusted OR 0.96, 95% CI 0.72-1.28), whereas increased risk related to higher TPO remained. CONCLUSION(S): Circulating levels of TPO may be associated with increased risk of miscarriage. PMID- 17706205 TI - Subfertile couples' negative experiences with intrauterine insemination care. AB - OBJECTIVE: To identify subfertile couples' experiences with specific aspects of intrauterine insemination (IUI) care and to determine which patient and hospital characteristics affect their experiences. DESIGN: Cross-sectional survey with written questionnaires. SETTING: One large tertiary hospital and nine medium sized hospitals, including both teaching and nonteaching centers, in the southeast of the Netherlands. PATIENT(S): One thousand seventy-nine subfertile couples who underwent IUI treatment between April 2000 and August 2002. RESULT(S): The response rate was 71%. Many subfertile couples have had negative experiences with IUI care, particularly regarding the doctor's attitude and coordination of care. Among several patient and hospital characteristics that significantly predicted these negative experiences, the main predictors were no ongoing pregnancy and high education level. CONCLUSION(S): From the perspective of subfertile couples, several aspects of IUI care are in serious need of improvement, particularly care aspects regarding the doctor's attitude and coordination of care. These findings are an important incentive for developing tailored interventions that address the reported deficits in IUI care to meet subfertile couples' needs better. PMID- 17706206 TI - Circulating and cellular adiponectin in polycystic ovary syndrome: relationship to glucose tolerance and insulin action. AB - OBJECTIVE: To evaluate serum adiponectin levels and organization into multimers in women with polycystic ovary syndrome (PCOS) and assess relationships between adiponectin, glucose tolerance, and insulin resistance. DESIGN: In vivo and in vitro study. SETTING: Outpatient clinic at university and Veterans hospitals in the United States and university laboratory. PATIENT(S): Thirty-one obese women with PCOS and six age- and body mass index (BMI)-matched normal cycling control subjects. INTERVENTION(S): All subjects studied in the fasting state. MAIN OUTCOME MEASURE(S): A 75-g oral glucose tolerance test (OGTT), hyperinsulinemic/euglycemic clamp, circulating adiponectin levels, adipocyte adiponectin content, and organization of adiponectin into multimeric forms. RESULT(S): Whole body insulin action (glucose disposal rate, 5.61 +/- 2.90 vs. 8.79 +/- 0.81 mg/kg/min, PCOS and control) and adiponectin levels (9.5 +/- 0.7 7 vs. 17.4 +/- 1 microg/mL, PCOS vs. control) were significantly reduced in the subjects with PCOS. There were significant correlations between glucose tolerance, insulin action, and circulating adiponectin levels in all subjects. The content of adiponectin protein was reduced in subcutaneous adipocytes from subjects with PCOS (252 +/- 31 vs. 388 +/- 58 arbitrary units/10 microg protein). Subjects with PCOS had less of their circulating adiponectin organized into high molecular weight (HMW) multimeric complexes. Glucose-intolerant subjects with PCOS also had less intracellular HMW adiponectin. CONCLUSION(S): Both circulating adiponectin levels and the portion present as the most active HMW form are reduced in PCOS, with differences related to the degree of glucose intolerance and insulin resistance. PMID- 17706208 TI - Panel of markers can accurately predict endometriosis in a subset of patients. AB - OBJECTIVE: To evaluate whether a combination of putative markers of inflammation and CA-125 could serve as a multiple-marker screening test for endometriosis in a heterogeneous population of patients. DESIGN: Case-control evaluation of a diagnostic test. SETTING: University medical center. PATIENT(S): Consenting women of reproductive age undergoing laparoscopy for indications of pain, infertility, elective tubal ligation, tubal reanastomosis, or other benign indications. INTERVENTION(S): Diagnostic laparoscopy and peripheral venipuncture. MAIN OUTCOME MEASURE(S): Serum concentrations of interleukin-6, tumor necrosis factor-alpha, macrophage migration inhibitory factor, macrophage chemotactic protein-1, interferon-gamma, leptin, and CA-125 measured by using ELISA assays; surgical staging of endometriosis. RESULT(S): Concentrations of the seven markers were compared between the 63 women with surgically confirmed stage II-IV endometriosis and 78 women who were surgically confirmed to be free of endometriosis. The individual diagnostic performance of each of the markers, based on receiver operating characteristic curves, was poor. When combinations of markers were evaluated by using classification tree analysis, a three-marker panel of CA-125, macrophage chemotactic protein-1, and leptin could diagnose 51% of subjects as to the presence of endometriosis with 89% accuracy. A four-marker panel of CA-125, macrophage chemotactic protein-1, leptin, and macrophage migration inhibitory factor could diagnose 48% of subjects with 93% accuracy. The remaining subjects would have no definitive diagnosis on the basis of the algorithm and would need to undergo standard evaluation. CONCLUSION(S): This large study evaluates the combined use of putative serum markers for the diagnosis of endometriosis, rather than the use of each singly. Using the serum concentration of four markers in a two-tiered decision rule, nearly half of the subjects in this population would have been diagnosed (and could have avoided surgery) with 93% accuracy. PMID- 17706207 TI - Increased frequency of human leukocyte antigen-E inhibitory receptor CD94/NKG2A expressing peritoneal natural killer cells in patients with endometriosis. AB - OBJECTIVE: To analyze the frequency of peritoneal natural killer (NK) cells expressing the human leukocyte antigen (HLA)-E receptor CD94/NKG2A in patients with endometriosis. DESIGN: Case-control study. SETTING: University hospital. PATIENT(S): Stage III and stage IV endometriosis, according to the revised American Society for Reproductive Medicine classification, was laparoscopically and histologically confirmed in 11 and 9 patients, respectively; 13 subjects without endometriosis were selected for the control group. INTERVENTION(S): Collection of peripheral venous blood, peritoneal fluid, endometriotic tissue, and normal endometrium in subjects undergoing laparoscopy. MAIN OUTCOME MEASURE(S): Surface expression levels of CD94/NKG2A and CD94/NKG2C were detected by three-color cytofluorometric analysis. Semiquantitative HLA-E messenger RNA expression analysis was performed in endometriotic lesions and in eutopic endometrium. NK cell-mediated cytotoxic activity toward HLA-E positive target, DT360 cell line, was also determined. RESULT(S): In women with endometriosis, the percentage of CD94/NKG2A-positive peritoneal NK cells was significantly higher than in the control group. The CD94/NKG2A ligand, HLA-E, was detected at high levels in endometriotic tissue as messenger RNA transcript. Target cells bearing HLA-E were resistant to NK cell-mediated lysis in a CD94/NKG2A-dependent manner. CONCLUSION(S): Increased expression of CD94/NKG2A in peritoneal NK cells may mediate the resistance of endometriotic tissue to NK cell-mediated lysis, thus contributing to the progression of the disease. PMID- 17706209 TI - Use of the levonorgestrel-releasing intrauterine system in breast cancer patients. AB - OBJECTIVE: To study the recurrence of breast cancer among patients who were using the levonorgestrel-releasing intrauterine system (LNG IUS). DESIGN: A retrospective, controlled cohort analysis. SETTING: Six Belgian hospitals. PATIENT(S): We identified 79 breast cancer patients who used the LNG IUS, and we selected a control group of 120 patients with no history of LNG IUS use and who were closely matched for age at diagnosis, tumor stage, tumor grade, and treatment modalities. Two subgroups were identified: [1] breast cancer patients who continued using the LNG IUS after diagnosis and [2] breast cancer patients who began using an LNG IUS after treatment for breast cancer. INTERVENTION(S): Patient's data were collected and survival analysis was performed. MAIN OUTCOME MEASURE(S): Breast cancer recurrence rate. RESULT(S): There was a recurrence rate of 21.5% (17/79) among LNG IUS users and of 16.6% (20/120) among the control group (adjusted hazard ratio, 1.86; 95% confidence interval, 0.86-4.00; no statistically significant difference). Subgroup analysis showed that women using the LNG IUS (n = 38) at the time of breast cancer diagnosis (and who continued its use) had a statistically significantly increased risk of recurrence (adjusted hazard ratio, 3.39; 95% confidence interval, 1.01-11.35) compared with patients in the control group. There was 47.4% (18/38) nodal involvement in this subgroup, and all patients who recurred had metastatic disease. CONCLUSION(S): Overall, we did not find an increased risk of breast cancer recurrence associated with use of the LNG-IUS. However, in a subgroup analysis of women who developed breast cancer while using an LNG IUS and who continued to use the LNG IUS, we found a higher risk of recurrence of borderline statistical significance. Additional research is needed to confirm or refute these findings. PMID- 17706210 TI - Assisted reproductive technologies (ART) in Canada: 2004 results from the Canadian ART Register. AB - OBJECTIVE: To present the results of assisted reproductive technology (ART) cycles performed in 2004 in Canada. This is the fourth annual report of Canadian ART outcomes. DESIGN: Prospective cohort study. SETTING: Twenty-six of 26 ART centers in Canada. PATIENT(S): Couples undergoing ART treatment in Canada during 2004. INTERVENTION(S): Assisted reproductive technology treatments, including IVF, intracytoplasmic sperm injection (ICSI), frozen embryo transfer, and oocyte donation. MAIN OUTCOME MEASURE(S): Clinical pregnancy, live birth, and multiple birth rates. RESULT(S): A total of 11,068 ART cycles was reported to the Canadian ART Register. There were 7,874 IVF/ICSI cycles that used the woman's own oocytes. Per cycle started, the clinical pregnancy rate was 31.7% (37.8% per embryo transfer procedure), and the live birth rate was 24.2%; the multiple birth rate per delivery was 27.8%, with a triplet birth rate of 1.5%. In vitro fertilization was performed in 42% of cycles, and ICSI, in 58%, with similar pregnancy rates. There were 365 IVF/ICSI cycles that used donor oocytes. The clinical pregnancy rate was 44.9%, and the live birth rate was 33.7%; the multiple birth rate was 32.5%, with a triplet birth rate of 4.3%. There were 2,431 frozen embryo transfer cycles that used the woman's own oocytes. The clinical pregnancy rate was 22.8% and the live birth rate was 16.5%; the multiple birth rate was 26.0%, with a triplet birth rate of 1.0%. There were 398 cycles of various other ART types, including 87 cycles involving gestational carriers. CONCLUSION(S): For 2004, the Canadian ART Register achieved 100% voluntary participation from Canadian ART centers for the second consecutive year. Clinical pregnancy and live birth rates were higher and multiple birth rates were lower in 2004 than in previous years. PMID- 17706211 TI - Fertility services for human immunodeficiency virus-positive patients: provider policy, practice, and perspectives. AB - OBJECTIVE: To examine demand for, and access to, fertility services for HIV positive patients in the United States. DESIGN: An electronic survey. SETTING: The URL for the Web-based survey was e-mailed to those surveyed. PATIENT(S): The 916 members of the Society of Reproductive Endocrinology and Infertility of the American Society of Reproductive Medicine. MAIN OUTCOME MEASURE(S): Policy and practice in evaluation and treatment of HIV-positive and HIV-serodiscordant couples who desire conception, demand for services, and perceived barriers to providing these services. RESULT(S): The response rate was 22%. Forty percent of respondents reported policies. Fifty-one percent reported requests. Sixty-four percent reported offering treatment to HIV-serodiscordant couples, and 57% reported offering treatment to HIV-positive couples. Treatments most frequently offered to HIV-serodiscordant male-positive couples were reproductive surgery (50%), ovulation induction (46%), and intracytoplasmic sperm injection (45%). Twenty-nine percent of those offering treatment test-washed specimens for HIV. Factors limiting care included the following: low volume of requests (45%), concern for child welfare (37%), no laboratory policy (32%), and legal risk (32%). CONCLUSION(S): Patients who are HIV-positive are seeking fertility services in the United States. The small demand is a major limiting factor to provision of services. There is a lack of global application of current American Society of Reproductive Medicine guidelines. Provider education is needed to ensure that the safest reproductive services are offered to HIV-positive patients. Legal reform is imperative to improve access to reproductive services for the HIV-positive population. PMID- 17706212 TI - Hysteroscopic treatment of atypical polypoid adenomyoma diagnosed incidentally in a young infertile woman. AB - OBJECTIVE: To describe the conservative treatment of an atypical polypoid adenomyoma (APA) in a young infertile patient using a modification of the technique previously reported for the conservative treatment of stage IA endometrial cancer. DESIGN: Case report. SETTING: Department of Gynaecology and Obstetrics and Pathophysiology of Human Reproduction of the University of Naples "Federico II." PATIENT(S): A 35-year-old woman diagnosed incidentally with an APA during routine investigation for primary infertility. INTERVENTION(S): Conservative resectoscopic treatment using a four-step technique in which each step is characterized by a pathological analysis: the removal of the APA (step 1), the removal of endometrium adjacent to the APA (step 2), the removal of the myometrium underlying the APA (step 3), and multiple random endometrial biopsies (step 4). MAIN OUTCOME MEASURE(S): Complete resection of the APA and ruling out of any malignancy. RESULT(S): The conservative surgery was effective as histological examination of all specimens confirmed an APA confined to the endometrium without any other premalignant or malignant lesion. Transvaginal ultrasound and office hysteroscopy with target biopsies at 1 and 6 months after surgery were negative for atypia and malignancy. CONCLUSION(S): Our technique under a close, intermittent postoperative surveillance might represent a good therapeutic option for those women with APA who wish to preserve their fertility as well as for those at high medical risk for hysterectomy. PMID- 17706213 TI - Antenatal mood and fetal attachment after assisted conception. AB - OBJECTIVE: Australian women conceiving with ART are at fourfold risk of admission to early parenting treatment programs compared with those conceiving spontaneously. This study aimed to identify prevalence and determinants of antenatal mood disturbance and other risks for early parenting difficulties after assisted conception. DESIGN: A prospective longitudinal investigation from conception to 18 months postpartum using telephone interviews and self-report questionnaires. SETTING: Melbourne IVF and Royal Women's Hospital Reproductive Services, Victoria, Australia. PATIENT(S): A consecutive cohort of English speaking women with ultrasound-confirmed ART-conceived pregnancies. MAIN OUTCOME MEASURE(S): Standardized psychometric measures of mood, quality of marital relationship, mother-to-fetus emotional attachment, and personality. INTERVENTION(S): None. RESULT(S): Of the 288 women with confirmed pregnancies, 239 were contactable, and 183 (77%) were recruited, 95% of whom completed both early and late pregnancy assessments. Participants were socioeconomically advantaged, had very good pregnancy health, exceptional marital relationships, normal personality styles, and intense affectionate attachment to the fetus. Very few (<5%) had clinically significant mood disturbance in late pregnancy. CONCLUSION(S): There were low rates of antenatal mood disturbance and other risk factors for postpartum depression. Pregnancy and motherhood might be idealized after ART conception, and preparation for the realities of infant care might then be insufficient. PMID- 17706214 TI - Increased achondroplasia mutation frequency with advanced age and evidence for G1138A mosaicism in human testis biopsies. AB - OBJECTIVE: To evaluate the influence of aging on the achondroplasia mutation rate in the male germline. DESIGN: Studies in sperm and testis biopsy DNA according to donor's age. SETTING: University teaching hospital. PATIENT(S): Seventeen donors aged 30 to 65 years for sperm collection and 14 deceased donors aged 53 to 95 years for testis biopsies, all with normal stature. INTERVENTION(S): Testes were obtained from 14 deceased donors, and sperm was obtained from 17 patients who requested ART. MAIN OUTCOME MEASURE(S): Real-time polymerase chain reaction quantification of the G1138A mutation in sperm and testis biopsies. RESULT(S): The rate of G1138A mutation did not significantly vary with age in sperm, whereas in testis biopsies it increased markedly past the age of 70 years. Moreover, and for the first time, a mosaic for this mutation was detected in the testis of three subjects who were >80 years of age. CONCLUSION(S): These findings could contribute to providing a molecular explanation for the increased incidence of achondroplastic offspring with advanced paternal age. PMID- 17706215 TI - Diagnostic criteria for polycystic ovary syndrome in Taiwanese Chinese women: comparison between Rotterdam 2003 and NIH 1990. AB - Roughly 61% of patients diagnosed with polycystic ovary syndrome (PCOS) using the 2003 Rotterdam criteria fulfilled the 1990 National Institutes of Health (NIH) criteria. Patients meeting the 1990 NIH diagnostic criteria have more severe clinical and biochemical PCOS symptoms than those who did not. PMID- 17706216 TI - Molecular cloning and sequence analysis of multiple cDNA variants for thyroid stimulating hormone beta subunit (TSHbeta) in the fathead minnow (Pimephales promelas). AB - We cloned and sequenced full-length cDNAs encoding the beta subunit of thyroid stimulating hormone (TSHbeta) from the pituitary of fathead minnow (Pimephales promelas) using 5'- and 3'-rapid amplification of cDNA ends (RACE). Three cDNA variants for TSHbeta with lengths of 1184-, 1093-, and 818-bp were identified. The cDNA variant of 1184-bp included 453-bp of open-reading frame and 610-bp of 3' UTR followed by a poly(A)site. This cDNA encodes 150 amino acids including a 19 residue signal peptide and a mature TSHbeta protein of 131 residues with sequence identities of 97-53% to other fishes and 42-39% to mammals. The 1093-bp cDNA variant was identical to the 1184-bp variant in the open-reading frame, but contained a deletion of 40-bp in the 3' UTR. The 818-bp cDNA variant, however, contained 498-bp of open-reading frame followed by 227-bp of 3' UTR and a poly(A)site. The deduced amino acid sequence for this cDNA variant showed 99.2% homology with the 1184- and 1093-bp variants of TSHbeta, but a single deletion of 332-bp nucleotides spanning the predicted stop codon and 3' UTR resulted in a deduced amino acid sequence with 15 additional residues on the C terminus. The presence of this 818-bp cDNA variant in the pituitary was further confirmed by PCR using primers developed to the 5' and 3' UTR. PCR and Southern blot analyses of genomic DNA suggested only one gene for TSHbeta. Sequencing of this gene revealed a hairpin loop structure of approximately 300-bp located in the 3' UTR and corresponding to the region of the 332-bp deletion in the 818-bp transcript. PMID- 17706217 TI - Comparative genomics of leucine-rich repeats containing G protein-coupled receptors and their ligands. AB - Leucine-rich repeats containing G protein-coupled receptors (LGRs) constitute a unique cluster of transmembrane proteins sharing a large leucine-rich extracellular domain for hormone binding. In mammals, LGRs steer important developmental, metabolic and reproductive processes as receptors for glycoprotein hormones and insulin/relaxin-related proteins. In insects, a receptor structurally related to human LGRs mediates the activity of the neurohormone bursicon thereby regulating wing expansion behaviour and remodelling of the newly synthesized exoskeleton. In the past decade, novel insights into the molecular evolution of LGR encoding genes accumulated rapidly due to comparative genome analyses indicating that the endocrine LGR signalling system likely emerged before the radiation of metazoan phyla and expanded throughout evolution. Here, we present a short survey on the evolution of LGRs and the hormones they interact with. PMID- 17706218 TI - Robust integral variable structure controller and pulse-width pulse-frequency modulated input shaper design for flexible spacecraft with mismatched uncertainty/disturbance. AB - This paper presents a dual-stage control system design method for the flexible spacecraft attitude maneuvering control by use of on-off thrusters and active vibration control by input shaper. In this design approach, attitude control system and vibration suppression were designed separately using lower order model. As a stepping stone, an integral variable structure controller with the assumption of knowing the upper bounds of the mismatched lumped perturbation has been designed which ensures exponential convergence of attitude angle and angular velocity in the presence of bounded uncertainty/disturbances. To reconstruct estimates of the system states for use in a full information variable structure control law, an asymptotic variable structure observer is also employed. In addition, the thruster output is modulated in pulse-width pulse-frequency so that the output profile is similar to the continuous control histories. For actively suppressing the induced vibration, the input shaping technique is used to modify the existing command so that less vibration will be caused by the command itself, which only requires information about the vibration frequency and damping of the closed-loop system. The rationale behind this hybrid control scheme is that the integral variable structure controller can achieve good precision pointing, even in the presence of uncertainties/disturbances, whereas the shaped input attenuator is applied to actively suppress the undesirable vibrations excited by the rapid maneuvers. Simulation results for the spacecraft model show precise attitude control and vibration suppression. PMID- 17706219 TI - Controller tuning via performance maps. AB - While there are a number of visual methods common to the design and analysis of dynamic systems, they tend to be specific to their application and limited in the amount of information which they yield. This paper explores a visualization technique, titled the performance map, which is derived from the Julia set commonly used in the visualization of iterative chaos. Performance maps are generated via digital computation, and require a minimum of a priori knowledge of the system under evaluation. By the use of colour-coding, these images convey a wealth of information to the informed user about dynamic behaviours of a system that may be hidden from all but the expert analyst. Application to the tuning of PI controllers is presented. User friendly software makes the application to tuning easy and allows the user to visually inspect any number of potential solutions. The software will be made available upon request. PMID- 17706220 TI - Liver injuries--improved results with a formal protocol including angiography. AB - OBJECTIVE: We hypothesised that a formal treatment protocol for liver injuries including angiography would increase the non-operative management (NOM) rate and would be efficient as an adjunct to damage control surgery. METHODS: During the 4 year period from 1 August 2000, a total of 138 adult patients with liver injuries were admitted to the largest trauma centre in Norway and prospectively included in the institutional trauma registry. On 1 August 2002, a protocol mandating angiography in all NOM patients with OIS grades 3-5 liver injuries and after packing of the liver was implemented. All patients admitted during the subsequent 2-year period (group 2) were compared with the previous 2 years as historic controls (group 1). RESULTS: Fifty-five patients were included in group 1 and 59 in group 2. The groups were statistically comparable, both with a mean ISS of 31. Patients selected for NOM increased from 28 (51%) to 45 (76%) (p<0.05), without increasing failure rate, liver-related complications, mortality or transfusion rate. Angiography was performed in 26 patients in group 2 (44%). Only nine patients underwent embolisation (35%), and five of these were in the NOM group. Angiography was negative in the eight NOM stable patients with OIS grade 3 injury. CONCLUSION: The implementation of a formal NOM protocol decreased total laparotomy rate and seemed to improve patient outcome without jeopardising patient safety. Surprisingly few of the patients undergoing angiography required embolisation. Angiography is not indicated in stable OIS grade 3 liver injuries, and the protocol in our institution has been adjusted accordingly. AE seems to be a valuable adjunct to DCS with packing of liver injuries. PMID- 17706221 TI - Investigating the dynamics of nurse migration in early career: a longitudinal questionnaire survey of variation in regional retention of diploma qualifiers in England. AB - BACKGROUND: Increasing mobility of healthcare professionals has led to concerns that certain countries or regions are depleted of sufficient staff to meet healthcare needs. In formulating appropriate strategies to ensure better retention locally, human resource managers are hindered by lack of information about migration patterns. PURPOSE AND AIMS: Purposes included studying movement of diploma nurses qualifying in England and contributing to literature on developing methods for obtaining migration data. Specific aims ascertained: regional variation in retention of locally trained nurses; associations between nurses' profile and retention in training region; and impact on each region of inter-regional movement of nurses. METHOD: Questionnaires sent to a nationally representative cohort of adult branch nurses at qualification (n=1596) and at subsequent intervals thereafter provided data on all employment and other activities and geographical location of each. Event histories constructed from chart data were used to analyse length of retention in region of training and movements between regions. Retention was operationalised through developing the construct 'engagement with nursing'. RESULTS: Older entrants and those with children were more likely to nurse in their training region than younger and childless counterparts. Regions differed in retention of locally trained nurses and in the impact on their diplomate workforce of inter-regional movement. Regional variations were insufficiently explained by differences in nurses' profiles; hence influences of regional characteristics were also considered. CONCLUSION: Retention strategies should include maintaining the policy of recruiting greater diversity of entrants, particularly mature entrants and those who have children. In developing local strategies, each region needs: information about retention of different components of their workforce; and an understanding of how regional characteristics can facilitate or constrain retention. National and international workforce organisations need to plan how best to obtain accurate and comparable nurse migration data. PMID- 17706223 TI - Interleukin-10 concentration and coronary heart disease (CHD) event risk in the estrogen replacement and atherosclerosis (ERA) study. AB - Interleukin-10 (IL-10) is a cytokine with pleiotropic properties. Limited biochemical and clinical evidence suggest a link between IL-10 and coronary heart disease (CHD). However, more data are needed to clarify the relationship between IL-10 and risk for CHD events. METHODS: The present study was a secondary analysis of the estrogen replacement and atherosclerosis (ERA) trial, a randomized clinical trial that examined the effects of hormone replacement therapy on post-menopausal women with known coronary atherosclerosis. IL-10 concentration, measured at baseline, was treated as both a continuous and categorical variable. Cox proportional hazards models were used to compute hazard ratios as estimates of relative risk for CHD events. RESULTS: There were 71 events over an average 3.2 year follow-up. Incident rates were higher for individuals with IL-10 concentrations equal to or greater than the median level (1.04 pg/mL) compared to those individuals below the median level (30% versus 18.5%, p=0.02). The cumulative incidence of CHD events was significantly greater in individuals with IL-10 concentrations >or=1.04 pg/mL (p=0.01). A one standard deviation increase in baseline IL-10 concentration was associated with a 34% greater risk of a CHD event (HR 1.34 [1.06-1.68], p=0.01). This elevated risk was not altered by interleukin-6, C-reactive protein, or additional cardiovascular risk factors. IL-10 concentration and risk for CHD events was most pronounced in diabetics (HR 2.4 [1.46-3.83], p=0.0005). CONCLUSION: In the ERA trial, elevated IL-10 concentration was associated with an increased risk for future cardiovascular events in post-menopausal women with established coronary atherosclerosis. Further study of the relationship between IL-10 and the pathogenesis and progression of atherosclerosis and cardiovascular events is warranted. PMID- 17706224 TI - Up-regulation of thromboxane A2 receptor expression by lipid soluble smoking particles through post-transcriptional mechanisms. AB - Atherosclerosis is a key factor in vascular disease, and cigarette smoking is a well-known risk factor that may induce an inflammatory response and enhance plaque formation in arteries. Thromboxane (Tx) is one key inflammatory mediator involved in the pathogenesis of cardiovascular disease. The present study was designed to test if lipid soluble smoking particles (DSP) enhance TxA(2) receptor (TP) expression in rat mesenteric arteries, and if intracellular mitogen activated protein kinase (MAPK) pathways play a role. Organ culture of rat mesenteric arteries in the presence of DSP (0.2 microl/ml for 24h) resulted in markedly elevated contractile responses to the Tx analog U46619, compared with the control DMSO. There was no increase in TP receptor mRNA expression, while the protein expression was significantly enhanced. This up-regulation was not affected by a general transcriptional inhibitor actinomycin D, but was almost completely abolished by cycloheximide, a general translational inhibitor. Dexamethasone, a glucocorticoid, manifested a potent inhibitory effect as well. These results suggest that the up-regulation of TP receptor occurs via post transcriptional events, and mainly translation. This is supported by experiments with specific inhibitors for c-Jun-NH(2)-terminal kinase (SP600125), extracellular signal-regulated kinase 1 and 2 (PD98059 and U0126) and p38 (SB203580) that had no inhibitory effect on the up-regulation of TP receptors. Collectively, the results show that MAPK pathways are not involved in TP receptor up-regulation. Study on TP receptor mRNA stability showed that during organ culture, the TP receptor mRNA was stable in both DMSO and DSP group, but the latter elicited a tendency to stabilize the TP receptor mRNA at higher level. Thus, post-transcriptional mechanisms are responsible for the up-regulation of TP receptor by DSP, in which enhanced translation is the major cause of the elevated protein expression and the enhanced contraction. PMID- 17706222 TI - Acetylation of the Entamoeba histone H4 N-terminal domain is influenced by short chain fatty acids that enter trophozoites in a pH-dependent manner. AB - Treatment of higher eukaryotic cells with short-chain fatty acids (SCFA) such as butyrate causes decreased levels of histone deacetylase (HDAC) activity and hyperacetylation of histones, and thereby affects gene expression, cell growth and differentiation. Entamoeba parasites encounter high levels of SCFA in the host colon, and in vitro these compounds allow trophozoite stage parasites to multiply but prevent their differentiation into infectious cysts. The Entamoeba invadens IP-1 histone H4 protein has an unusual number of lysines in its N terminus, and these become hyperacetylated in trophozoites exposed to the HDAC inhibitors trichostatin A (TSA) or HC-toxin, but not in trophozoites exposed to butyrate. We have now found that several other commonly studied isolates of Entamoeba parasites also have an extended set of histone H4 acetylation sites that become hyperacetylated in response to TSA, but hypoacetylated in response to butyrate, suggesting an unusual sensitivity of this parasite's histone modifying enzymes to SCFA. Butyrate was found to enter trophozoites in a pH-dependent manner consistent with diffusive entry of the un-ionised form of the fatty acid into the amoebae. Transit of the Entamoeba organism through areas of the host intestine with distinct pH and SCFA concentrations would therefore result in very different levels of SCFA within the parasite. Entamoeba appears to have acquired unique alterations of its histone acetylation mechanism that may allow for its growth in the presence of varying amounts of the bacterial fermentation products. PMID- 17706225 TI - Head and neck anthropometry, vertebral geometry and neck strength in height matched men and women. AB - Women have an increased incidence of whiplash injury and neck pain compared to men. Physical and numerical models represent one avenue to explore and potentially explain these gender differences, but a valid model of the female neck does not yet exist. A fundamental question in the development of a female neck model is whether female necks are simply scaled versions of male necks, or whether there are significant inter-gender geometrical differences. The goal of this study was to quantify differences in head and neck geometry and neck strength in pairs of male and female subjects matched for standing height and neck length. Based on 14 matched pairs of men and women, we found that most head and neck anthropometric parameters were significantly smaller in females compared to males. Moreover, gender differences in a number of neck anthropometry parameters (an average of 9-16% smaller in females) were larger than differences in head anthropometry parameters (an average of 3-6% smaller in females). Female vertebrae between C3 and C7 were significantly smaller than male vertebrae in the anterior-posterior dimension (p < 0.012) but not in the medial-lateral dimension (p > 0.07). Female necks were also significantly weaker than male necks (32% weaker in flexion and 20% weaker in extension; p < 0.001), and these strength differences corresponded well to those predicted solely from the observed geometric differences. These results demonstrate that male and female necks are not geometrically similar and indicate that a female-specific model will be necessary to study gender differences in neck-related disorders. PMID- 17706226 TI - Compression testing of very soft biological tissues using semi-confined configuration--a word of caution. AB - We analyse semi-confined (i.e. using no-slip boundary conditions) compression experiment of very soft tissue sample using finite element method. We show that the assumption that the planes perpendicular to the direction of the applied force remain plane during the experiments is not satisfied for compression levels lower than previously stated in Miller [2005. Method for testing very soft biological tissues in compression. Journal of Biomechanics 38, 153-158]. Therefore, we recommend that the parameters for constitutive models of very soft tissues be determined by fitting a solution of the finite element models of the experimental set-up to the measurements obtained using semi-confined compression experiments. PMID- 17706227 TI - Vertebral end-plate fractures as a result of high rate pressure loading in the nucleus of the young adult porcine spine. AB - In a healthy spine, end-plate fractures occur from excessive pressurization of the intervening nucleus. Younger spines are most susceptible to such type of injury due to the highly hydraulic nature of their intervertebral discs. The purpose of this paper was to confirm this fracture mechanism of the healthy spine through the pressurization of the nucleus in the absence of external compressive loading. Sixteen functional porcine spine units were dissected and both injection and pressure transducer needles were inserted into the nucleus of the intervertebral disc. Hydraulic fluid was rapidly injected into the nucleus until failure occurred. Peak pressure and rate of pressure development were monitored. Spine units were dissected to determine the type and location of fracture. Fifteen of the 16 spine units fractured (the remaining unit had a degenerated disc). Of the 15 fractures, 13 occurred at the posterior margin of the end-plate along the lines of the growth plates. A slightly exponential relationship was found between peak pressure and its rate of development (R(2) = 0.544). Also, in each of the growth-plate fractured specimens, nuclear material was forcefully emitted, during fracture, from the intervertebral disc into the vertebral foramen. The posterior end-plate fractures produced here are similar to those often seen in young adult humans. This provides insight into a mechanism of fracture development through pressurization of the nucleus that might be seen in older adolescents and younger adults during athletic events or mild trauma. PMID- 17706228 TI - Reliable simulations of the human proximal femur by high-order finite element analysis validated by experimental observations. AB - BACKGROUND: The mechanical response of patient-specific bone to various load conditions is of major clinical importance in orthopedics. Herein we enhance the methods presented in Yosibash et al. [2007. A CT-based high-order finite element analysis of the human proximal femur compared to in-vitro experiments. ASME Journal of Biomechanical Engineering 129(3), 297-309.] for the reliable simulations of the human proximal femur by high-order finite elements (FEs) and validate the simulations by experimental observations. METHOD OF APPROACH: A fresh-frozen human femur was scanned by quantitative computed tomography (QCT) and thereafter loaded (in vitro experiments) by a quasi-static force of up to 1250 N. QCT scans were manipulated to generate a high-order FE bone model with distinct cortical and trabecular regions having inhomogeneous isotropic elastic properties with Young's modulus represented by continuous spatial functions. Sensitivity analyses were performed to quantify parameters that mostly influence the mechanical response. FE results were compared to displacements and strains measured in the experiments. RESULTS: Young moduli correlated to QCT Hounsfield Units by relations in Keyak and Falkinstein [2003. Comparison of in situ and in vitro CT scan-based finite element model predictions of proximal femoral fracture load. Medical Engineering and Physics 25, 781-787.] were found to provide predictions that match the experimental results closely. Excellent agreement was found for both the displacements and strains. The presented study demonstrates that reliable and validated high-order patient-specific FE simulations of human femurs based on QCT data are achievable for clinical computer-aided decision making. PMID- 17706229 TI - Application of mechanoregulatory models to simulate peri-implant tissue formation in an in vivo bone chamber. AB - Several mechanoregulatory tissue differentiation models have been proposed over the last decade. Corroboration of these models by comparison with experimental data is necessary to determine their predictive power. So far, models have been applied with various success rates to different experimental set-ups investigating mainly secondary fracture healing. In this study, the mechanoregulatory models are applied to simulate the implant osseointegration process in a repeated sampling in vivo bone chamber, placed in a rabbit tibia. This bone chamber provides a mechanically isolated environment to study tissue differentiation around titanium implants loaded in a controlled manner. For the purpose of this study, bone formation around loaded cylindrical and screw-shaped implants was investigated. Histologically, no differences were found between the two implant geometries for the global amount of bone formation in the entire chamber. However, a significantly larger amount of bone-to-implant contact was observed for the screw-shaped implant compared to the cylindrical implant. In the simulations, a larger amount of bone was also predicted to be in contact with the screw-shaped implant. However, other experimental observations could not be predicted. The simulation results showed a distribution of cartilage, fibrous tissue and (im)mature bone, depending on the mechanoregulatory model that was applied. In reality, no cartilage was observed. Adaptations to the differentiation models did not lead to a better correlation between experimentally observed and numerically predicted tissue distribution patterns. The hypothesis that the existing mechanoregulatory models were able to predict the patterns of tissue formation in the in vivo bone chamber could not be fully sustained. PMID- 17706230 TI - Development of a stir bar sorptive extraction and thermal desorption-gas chromatography-mass spectrometry method for the simultaneous determination of several persistent organic pollutants in water samples. AB - Stir bar sorptive extraction (SBSE) and thermal desorption followed by capillary gas chromatography coupled to mass spectrometry (SBSE-TD-GC-MS) was applied to the simultaneous determination of ultra-traces of 16 polycyclic aromatic hydrocarbons (PAHs), 12 polychlorinated biphenyls (PCBs), 6 phthalate esters (PEs) and 3 nonylphenols (NPs) in water samples. The parameters that could affect the sorption-desorption efficiency were studied. A Plackett-Burman design was used for the screening of the main effects of the experimental parameters related to the desorption step (desorption time, desorption temperature, desorption flow, cryo-focusing temperature and vent pressure). Afterwards, two central composite designs were used to find the optimal process settings for the extraction and desorption steps. The best analytical compromise conditions for the simultaneous determination of analytes from spiked water samples were found to be: sample volume (20 mL), sodium chloride addition (30%), methanol addition (20%), desorption time (10 min), desorption temperature (300 degrees C), desorption flow (23 mL min(-1)), cryo-focusing temperature (-50 degrees C) and vent pressure (7 psi). Remarkable recovery, repeatability and reproducibility were attained. Furthermore, excellent linearities (r(2) = 0.959-0.999) and low detection limits (0.1-10 ng L(-1)) were also achieved for the congeners studied. The proposed methodology was applied for the simultaneous determination of PAHs, PCBs, PEs and NPs in sea and estuarine waters. The influence of humic acids on the recovery was also studied. PMID- 17706231 TI - Magnesium oxide microspheres as a packing material for the separation of basic compounds in normal-phase liquid chromatography. AB - Uniform monodisperse magnesium oxide microspheres with a high surface area have been prepared by a facile seed-induced precipitation. By characterizing these particles with scanning electron microscopy and N(2) physisorption techniques, the results demonstrate that these magnesium oxide microspheres have an average particle diameter of 9.5 microm, a specific surface area of 211.7 m(2)g(-1), a total pore volume of 0.76 mL g(-1), and an average pore diameter of 143 A. The chromatographic properties of these microspheres have been investigated in normal phase mode for the separation of various basic compounds including aniline, quinoline, and pyridine derivatives. In contrast to conventional silica, the magnesium oxide particles exhibit unique selectivity and retention property for the separation of the tested basic compounds, and these microspheres are promising as an alternative new packing material for high-performance liquid chromatography. PMID- 17706232 TI - A direct and fast method to monitor lipid oxidation progress in model fatty acid methyl esters by high-performance size-exclusion chromatography. AB - A new method based on high-performance size-exclusion chromatography (HPSEC) is proposed to quantitate primary and secondary oxidation compounds in model fatty acid methyl esters (FAMEs). The method consists on simply injecting an aliquot sample in HPSEC, without preliminary isolation procedures neither addition of standard internal. Four groups of compounds can be quantified, namely, unoxidised FAME, oxidised FAME monomers including hydroperoxides, FAME dimers and FAME polymers. Results showed high repeatability and sensitivity, and substantial advantages versus determination of residual substrate by gas-liquid chromatography. Applicability of the method is shown through selected data obtained by numerous oxidation experiments on pure FAME, mainly methyl linoleate, at ambient and moderate temperatures. PMID- 17706234 TI - Gellan beads as a transparent media for protein immobilization and affinity capture. AB - Gellan gum beads are presented as a novel substrate for protein immobilization and immobilized protein activity measurements. The optical transparency of the gellan beads down to 200 nm provides a method for direct quantitation of the amount of protein immobilized onto the beads. The ability to utilize these beads in a non-aqueous activation step allowed for a fourfold increase in the amount of protein immobilized, and this method was used to immobilize Protein A onto gellan beads at a final yield of 1.42+/-0.07 mg of Protein A/g of beads. The optical transparency also allowed for detection of the activity of the immobilized Protein A simply by measuring the absorbance of the beads following capture of rabbit IgG. This activity measurement method was compared with a traditional method utilizing the amount of protein remaining in solution after the IgG capture step. The traditional method yielded an activity measurement of 10.9+/ 0.2 mg IgG/mg of Protein A, while the absorbance method showed an activity of only 7.5+/-0.3 mg IgG/mg of Protein A. The difference can be explained by the more direct measurement used in the absorbance method. The optical transparency of the beads was also evaluated in a fluorescence based IgG capture experiment, showing that detection of fluorescent IgG captured on the beads was possible with no interference from the beads. PMID- 17706235 TI - Electrosorption-enhanced solid-phase microextraction using activated carbon fiber for determination of aniline in water. AB - Electrosorption-enhanced solid-phase microextraction (EE-SPME) based on activated carbon fiber (ACF) was developed for determination of aniline in aqueous solution. A porous ACF, served as working electrode in electrosorption procedure, was prepared and attached to a commercial manual SPME device. Parameters affecting the adsorption efficiency were investigated. Under optimized condition, which was 400 mV electrosorption potential, 0.01 M Na(2)SO(4) electrolyte, pH 7, and electrosorption at 40 degrees C for 10 min, the method exhibited wide linear range (0.1-100 microg L(-1), R(2)=0.9980), good repeatability of adsorption (RSD 6.15%, n=6), and low detection limit (0.02 microg L(-1)). The feasibility of the method was evaluated by analyzing lake water spiked with aniline. Comparison was made with direct immersion (DI) ACF-SPME without electrosorption enhancement. The proposed procedure was demonstrated to be a simple, fast, sensitive sample preparation method for determination of aniline in water samples. PMID- 17706236 TI - On relationships between surfactant type and globular proteins interactions in solution. AB - The binding of sodium perfluorooctanoate (C8FONa), sodium octanoate (C8HONa), lithium perfluorooctanoate (C8FOLi), and sodium dodecanoate (C12HONa) onto myoglobin, ovalbumin, and catalase in water has been characterized using electrophoretic mobility. The tendency of the protein-surfactant complexes to change their charge in the order catalase < ovalbumin < myoglobin was observed which was related to the contents of alpha-helices in the proteins. alpha-Helices are more hydrophobic than beta-sheets. The effect of surfactant on the zeta potentials follows C8HONa < C8FONa < C8FOLi < C12HONa for catalase and ovalbumin; and C8HONa < C8FOLi < C8FONa < C12HONa for myoglobin. The numbers of binding sites on the proteins were determined from the observed increases of the zeta potential as a function of surfactant concentration in the regions where the binding was a consequence of the hydrophobic effect. The Gibbs energies of binding of the surfactants onto the proteins were evaluated. For all systems, Gibbs energies are negative and large at low concentrations (where binding to the high energy sites takes place) and become less negative at higher ones. This fact suggests a saturation process. Changes in Gibbs energies with the different proteins and surfactants under study have been found to follow same sequence than that found for the charge. The role of hydrophobic interactions in these systems has been demonstrated to be the predominant. PMID- 17706237 TI - Treatment of methyl orange by calcined layered double hydroxides in aqueous solution: adsorption property and kinetic studies. AB - Adsorption of a weak acid dye, methyl orange (MO) by calcined layered double hydroxides (LDO) with Zn/Al molar ratio of 3:1 was investigated. In the light of so called "memory effect," LDO was found to recover their original layered structure in the presence of appropriate anions, after adsorption part of MO(-) and CO(2-)(3) (come from air) intercalated into the interlayer of LDH which had been supported by XRD and ICP. The results of adsorption experiments indicate that the maximum capacity of MO at equilibrium (Q(e)) and percentage of adsorption (eta%) with a fixed adsorbent dose of 0.5 g L(-1) were found to be 181.9 mg g(-1) and 90.95%, respectively, when MO concentration, temperature, pH and equilibrium time were 100 mg L(-1), 298 K, 6.0 and 120 min, respectively. The isotherms showed that the adsorption of MO by Zn/Al-LDO was both consistent with Langmuir and Freundlich equations. The adsorption process was spontaneous and endothermic in nature and followed pseudo-second-order kinetic model. The calculated value of E(a) was found to be 77.1 kJ mol(-1), which suggests that the process of adsorption of methyl orange is controlled by the rate of reaction rather than diffusion. The possible mechanism for MO adsorption has also been presumed. In addition, the competitive anions on adsorption and the regeneration of Zn/Al-LDO have also been investigated. PMID- 17706238 TI - Friction and adsorption of aqueous polyoxyethylene (Tween) surfactants at hydrophobic surfaces. AB - The nanotribological responses of a series of nonionic polyoxyethylene surfactants (Tween 20, Tween 40, Tween 60, and Tween 80) were investigated after they were adsorbed from aqueous solution onto atomically smooth hydrophobic substrates. The hydrophobic surfaces were composed of a condensed monolayer of octadecyltriethoxysilane (OTE; contact angle theta>110 degrees ). The nanorheological measurements were performed using a modified surface forces apparatus after coating atomically smooth mica with these OTE monolayers, while adsorption measurements were performed using phase-modulated ellipsometry on silicon wafers coated with these same monolayers. The minimum surface-surface separation observed under high load in friction studies agreed quantitatively with the thickness obtained from ellipsometry. For Tweens 20, 40, and 60, the thickness of the adsorbed film increases with increasing alkyl chain length. Systematic investigations of the nanorheological response showed that there is a "solid-like" elastic response from confined surfactant layers, which is the case for the smallest separations to separations up to slightly larger than twice the adsorbed film thickness. In kinetic friction, these confined layers are characterized by a shear stress of approximately 3 MPa with minimal dependence on shear rate. The magnitude of the sliding shear stress is the same as the apparent yield stress at approximately 3 MPa; it is independent of alkyl chain length within the Tween family of surfactants and corresponds to a nominal friction coefficient of mu approximately 1. A similar friction coefficient is observed for boundary lubrication on the macroscopic scale in a tribometer utilizing hydrophobic surfaces and mu approximately 1.1 for Tweens 20, 40, and 60. These results suggest that while Tween molecules adsorb onto hydrophobic surfaces to form a robust separating layer, the lubricating properties of these layers are dominated by a highly dissipative slip plane, the same for all alkyl chain lengths. PMID- 17706239 TI - Adsorption and viscoelastic properties of fractionated mucin (BSM) and bovine serum albumin (BSA) studied with quartz crystal microbalance (QCM-D). AB - The adsorption profile and viscoelastic properties of bovine submaxillary gland mucin (BSM) and bovine serum albumin (BSA), extracted from a commercial mucin preparation, adsorbing to polystyrene surfaces has been studied using quartz crystal microbalance with dissipation monitoring (QCM-D). A significant difference in the adsorption properties of the different proteins was detected; with the BSA adsorbing in a flat rigid layer whilst the mucin adsorbed in a diffuse, highly viscoelastic layer. Subsequent addition of BSA to the preadsorbed mucin layer resulted in stiffening of the protein layer which was attributed to complexation of the mucin by BSA. In contrast, a preadsorbed layer of BSA prevented mucin adsorption altogether. Combined mixtures of mucin and BSA in well defined ratios revealed intermediate properties between the two separate protein species which varied systematically with the protein ratios. The results shed light on the synergistic effects of complexation of lower molecular weight biomolecular species with mucin. The possibility to selectively control protein uptake and tailor the physical properties of the adsorbed layer makes mucin an attractive option for application in biomaterial coatings. PMID- 17706240 TI - Preparation of SiO2@polystyrene@polypyrrole sandwich composites and hollow polypyrrole capsules with movable SiO2 spheres inside. AB - In this paper, we describe a flexible method for preparing conducting building blocks: SiO2@polystyrene@polypyrrole sandwich multilayer composites and hollow polypyrrole (PPy) capsules with movable SiO2 spheres inside. First, SiO2@polystyrene (PS) core/shell composites were synthesized, and then SiO2@PS@PPy sandwich multilayer composites were prepared by chemical polymerization of pyrrole monomer on the surface of SiO2@PS composites. Furthermore, hollow polypyrrole capsules with movable SiO2 spheres inside were obtained after removal of the middle PS layer. The diameter of sandwich multilayer composites could easily be controlled by adjusting the dosage of pyrrole monomer. The conductivities of composites increased with the increase of PPy content. After the insulating PS layer was selectively etched, the conductivities of hollow capsules with movable SiO2 spheres inside were much higher than those of the corresponding sandwich multilayer composites. PMID- 17706241 TI - Quartz resonator signatures under Newtonian liquid loading for initial instrument check. AB - The quartz crystal microbalance (QCM) has been increasingly utilized in the monitoring of the deposition of thin macromolecular films. Studies in the deposition of polymers, biomaterials, and interfacial reactions under electrochemical environment are some of the conditions for the study of these material and deposition properties at a lipid interface. Numerous studies have shown the difficulties in configuring an experimental setup for the QCM such that the recorded data reflect only the behavior of the quartz crystal and its load, and not some artifact. Such artifacts for use in liquids include mounting stress, surface properties such as hydrophobicity, surface roughness coupling to loading liquids, influence of compressional waves, and even problems with the electronic circuitry including the neglect of the quartz capacitance and the hysteretic effects of electronic components. It is thought useful to obtain a simple test by which the user could make a quick initial assessment of the instrument's performance. When a smooth quartz crystal resonator is immersed from air into a Newtonian liquid, the resonance and loss characteristics of the QCM are changed. A minimum of two experimental parameters is needed to characterize these changes. One of the changes is that of the resonant frequency. The second is characterized by either a change in the equivalent circuit resistance (DeltaR) or a change in the resonance dissipation (DeltaD). Two combinations of these observables, in terms of either Deltaf and DeltaR or Deltaf and DeltaD, which we define as Newtonian signatures of S(1) and S(2), are calculated to have fixed values and to be independent of the harmonic and of the physical values of the Newtonian liquid. We have experimentally determined the values of S(1) and S(2) using three different QCM systems. These are the standard oscillator, the network analyzer, and the QCM dissipation instrument. To test the sensitivity of these signatures to surface roughness, which is potential experimental artifact, we determined the values of S(1) and S(2) for roughened crystals and found that these signatures do reflect that experimental condition. Moreover, these results were qualitatively in accord with the roughness scaling factor described by Martin. PMID- 17706242 TI - IGC studies of binary cationic surfactant mixtures. AB - Inverse gas chromatography (IGC) has been used to measure the interaction parameter between two twin-tailed cationic surfactants. Didodecyldimethylammonium (DDAB) and dioctadecyldimethylammonium (DODAB) bromides and their mixtures were used as stationary phases. IGC and DSC techniques have been used for the determination of the temperature zone of working. The activity coefficients at infinite dilution (on a mole fraction basis) were calculated for eleven probe solutes on each pure surfactant column. Values of interaction parameter between surfactants obtained at four weight fractions of the mixtures and at five temperatures are positive and suggested that the interactions is more unfavourable with the increment of DODAB concentration in the mixture. The results are interpreted on the basis of partial miscibility between DDAB and DODAB. PMID- 17706243 TI - Lymphangiosarcoma in a cat. AB - This report describes a 5-year-old female cat with lymphangiosarcoma arising within the dermis and subcutis of the caudal mammary region. The mass presented as a large, poorly demarcated and fluctuant swelling with bruising of the overlying skin. Histopathologically, the dermis and subcutis in the affected region were diffusely oedematous, haemorrhagic, and infiltrated by plump spindle cells that formed irregular vascular clefts and cavernous channels. Neoplastic cells were aligned in one or more layers along oedematous collagenous trabeculae. The vascular clefts and channels contained only a few or no erythrocytes. The neoplastic cells had moderate to marked nuclear pleomorphism and prominent nucleoli. Lymphocytes and plasma cells were scattered throughout the neoplasm and the adjacent soft tissues. Immunohistochemical labelling revealed the neoplastic cells to express vimentin, factor VIII-related antigen and the lymphatic endothelial cell marker PROX-1, but the cells did not express cytokeratin. The nuclei of many neoplastic cells expressed the proliferation marker Ki67. These histopathological and immunohistochemical findings confirmed the diagnosis of lymphangiosarcoma. This is the first report describing the usefulness of expression of PROX-1 for differentiating between angiosarcoma of lymphatic and vascular origin in cats. PMID- 17706244 TI - A simplified and reliable assay for complex I in human blood lymphocytes. AB - Complex I activity of the mitochondrial respiratory chain is difficult to measure in blood lymphocytes because of the limited access of substrates to the enzyme complex in these cells. The results of the present study show that permeabilization of human blood lymphocytes in the presence of protease inhibitors by three cycles of freeze-thawing enables reproducible detection of the rotenone-sensitive complex I activity. To that end, the water-soluble coenzyme Q(10) analogue CoQ(1) and a relatively high concentration of blood lymphocytes were combined in small quartz cuvettes so that the amount of blood needed for this assay remained low. The relationship between the initial rate of NADH oxidation by complex I and the protein concentration was quasi-linear. The fractional inhibition of the total NADH:CoQ(1) oxidoreductase by a saturating concentration of rotenone decreased sharply at CoQ(1) concentrations higher than 20 muM, which is indicative, but does not prove the involvement of a second CoQ(1) binding site at complex I. Since the present complex I assay requires only a small amount of blood, the functionality of this important respiratory chain complex can be assessed in an easy and reliable manner not only in adult patients but also in children suspected to have a mitochondrial disease. PMID- 17706245 TI - The role of N-beta-alanyldopamine synthase in the innate immune response of two insects. AB - Insects trigger a multifaceted innate immune response to fight microbial infections. We show that in the yellow mealworm, Tenebrio molitor, septic injuries induce the synthesis of N-beta-alanyldopamine (NBAD), which is known as the main sclerotization precursor of insect brown cuticles. We demonstrate that NBAD synthase is induced in the epidermis of the mealworm and of the Medfly, Ceratitis capitata, by infection with Escherichia coli. Our results indicate that synthesis of NBAD seems to be a novel component of the overall innate immune response in insects. PMID- 17706246 TI - Non-canonical Wnt signaling enhances differentiation of Sca1+/c-kit+ adipose derived murine stromal vascular cells into spontaneously beating cardiac myocytes. AB - Recent reports have described a stem cell population termed stromal vascular cells (SVCs) derived from the stromal vascular fraction of adipose tissue, which are capable of intrinsic differentiation into spontaneously beating cardiomyocytes in vitro. The objective of this study was to further define the cardiac lineage differentiation potential of SVCs in vitro and to establish methods for enriching SVC-derived beating cardiac myocytes. SVCs were isolated from the stromal vascular fraction of murine adipose tissue. Cells were cultured in methylcellulose-based murine stem cell media. Analysis of SVC-derived beating myocytes included Western blot and calcium imaging. Enrichment of acutely isolated SVCs was carried out using antibody-tagged magnetic nanoparticles, and pharmacologic manipulation of Wnt and cytokine signaling. Under initial media conditions, spontaneously beating SVCs expressed both cardiac developmental and adult protein isoforms. Functionally, this specialized population can spontaneously contract and pace under field stimulation and shows the presence of coordinated calcium transients. Importantly, this study provides evidence for two independent mechanisms of enriching the cardiac differentiation of SVCs. First, this study shows that differentiation of SVCs into cardiac myocytes is augmented by non-canonical Wnt agonists, canonical Wnt antagonists, and cytokines. Second, SVCs capable of cardiac lineage differentiation can be enriched by selection for stem cell-specific membrane markers Sca1 and c-kit. Adipose-derived SVCs are a unique population of stem cells that show evidence of cardiac lineage development making them a potential source for stem cell-based cardiac regeneration studies. PMID- 17706247 TI - Interplay between network structures, regulatory modes and sensing mechanisms of transcription factors in the transcriptional regulatory network of E. coli. AB - Though the bacterial transcription regulation apparatus is distinct in terms of several structural and functional features from its eukaryotic counterpart, the gross structure of the transcription regulatory network (TRN) is believed to be similar in both superkingdoms. Here, we explore the fine structure of the bacterial TRN and the underlying "co-regulatory network" (CRN) to show that despite the superficial similarities to the TRN of the eukaryotic model organism yeast, the bacterial networks display entirely different organizational principles. In particular unlike in eukaryotes, hubs of the bacterial networks are both global regulators and integrators of diverse disparate transcriptional responses. These and other organizational differences might correlate with the fundamental differences in gene and promoter organization in the two superkingdoms, especially the presence of operons and regulons in bacteria. Further we explored to find the interplay, if any, between network structures, mode of regulatory interactions and signal sensing of transcription factors (TFs) in shaping up the bacterial transcriptional regulatory responses. For this purpose, we first classified TFs according to their regulatory mode (activator, repressor or dual regulator) and sensory mechanism (one-component systems responding to internal or external signals, TFs from two-component systems and chromosomal structure modifying TFs) in the bacterial model organism Escherichia coli and then we studied the overall evolutionary optimization of network structures. The incorporation of TFs in different hierarchical elements of the TRN appears to involve on a multi-dimensional selection process depending on regulatory and sensory modes of TFs in motifs, co-regulatory associations between TFs of different functional classes and transcript half-lives. As a result it appears to have generated circuits that allow intricately regulated physiological state changes. We identified the biological significance of most of these optimizations, which can be further used as the basis to explore similar controls in other bacteria. We also show that, though on the larger evolutionary scale, unrelated TFs have evolved to become hubs, within lineages like gamma proteobacteria there is strong tendency to retain hubs, as well as certain higher order network modules that have emerged through lineage specific paralog duplications. PMID- 17706249 TI - Electrophysiological features in patients and presymptomatic relatives with spinocerebellar ataxia type 2. AB - Motor and sensitive nerve conduction studies, visual (VEP), brainstem auditory (BAEP) and somatosensory (SSEP) evoked potentials in 82 patients with spinocerebellar ataxia type 2 (SCA2), 62 presymptomatics relatives and 80 controls, correlating it with CAG repeat, disease duration and ataxia score were assessed. All the groups showed differences in the amplitude of sensory action potentials in median and sural nerves. Sural amplitude was negatively correlated with disease duration and ataxia score. Differences among patients and controls in the mean latency and conduction velocity of sensory action potentials were found. Abnormal morphology and replicability of SSEPs and BSAEPs were found in patients and presymptomatics. Moreover, consistent increase in latencies of P40 component of SSEPs, III and V peaks and I-III interpeak of BSAEPs was found in patients. A positive correlation was found between latency of III and V waves, I III and III-V interpeak latencies of BSAEPs and disease duration. CAG repeat and electrophysiological markers assessed were not correlative. Electrophysiological alterations in the SCA2 appeared in presymptomatic stages. These alterations are consistent markers which could be used to evaluate the progression of the disease. PMID- 17706250 TI - Serum S100B is a useful surrogate marker for long-term outcomes in photochemically-induced thrombotic stroke rat models. AB - In recent years, serum S100B has been used as a secondary endpoint in some clinical trials, in which serum S100B has successfully indicated the benefits or harm done by the tested agents. Compared to clinical stroke studies, few experimental stroke studies report using serum S100B as a surrogate marker for estimating the long-term effects of neuroprotectants. This study sought to observe serum S100B kinetics in PIT stroke models and to clarify the association between serum S100B and both final infarct volumes and long-term neurological outcomes. Furthermore, to demonstrate that early elevations in serum S100B reflect successful neuroprotective treatment, a pharmacological study was performed with a non-competitive NMDA glutamate receptor antagonist, MK-801. Serum S100B levels were significantly elevated after PIT stroke, reaching peak values 48 h after the onset and declining thereafter. Single measurements of serum S100B as early as 48 h after PIT stroke correlated significantly with final infarct volumes and long-term neurological outcomes. Elevated serum S100B was significantly attenuated by MK-801, correlating significantly with long-term beneficial effects of MK-801 on infarct volumes and neurological outcomes. Our results showed that single measurements of serum S100B 48 h after PIT stroke would serve as an early and simple surrogate marker for long-term evaluation of histological and neurological outcomes in PIT stroke rat models. PMID- 17706248 TI - Molecular basis of tropomyosin binding to tropomodulin, an actin-capping protein. AB - The tropomodulin (Tmod) family of proteins that cap the pointed, slow-growing end of actin filaments require tropomyosin (TM) for optimal function. Earlier studies identified two regions in Tmod1 that bind the N terminus of TM, though the ability of different isoforms to bind the two sites is controversial. We used model peptides to determine the affinity and define the specificity of the highly conserved N termini of three short, non-muscle TMs (alpha, gamma, delta-TM) for the two Tmod1 binding sites using circular dichroism spectroscopy, native gel electrophoresis, and chemical crosslinking. All TM peptides have high affinity for the second Tmod1 binding site (within residues 109-144; alpha-TM, 2.5 nM; gamma-TM, delta-TM, 40-90 nM), but differ >100-fold for the first site (residues 1-38; alpha-TM, 90 nM; undetectable at 10 microM, gamma-TM, delta-TM). Residue 14 (R in alpha; Q in gamma and delta) and, to a lesser extent, residue 4 (S in alpha; T in gamma and delta) are primarily responsible for the differences. The functional consequence of the sequence differences is reflected in more effective inhibition of actin filament elongation by full-length alpha-TMs than gamma-TM in the presence of Tmod1. The binding sites of the two Tmod1 peptides on a model TM peptide differ, as defined by comparing (15)N,(1)H HSQC spectra of a (15)N labeled model TM peptide in both the absence and presence of Tmod1 peptide. The NMR and CD studies show that there is an increase in alpha-helix upon Tmod1-TM complex formation, indicating that intrinsically disordered regions of the two proteins become ordered upon binding. A model proposed for the binding of Tmod to actin and TM at the pointed end of the filament shows how the Tmod-TM accentuates the asymmetry of the pointed end and suggests how subtle differences among TM isoforms may modulate actin filament dynamics. PMID- 17706251 TI - Air--sea gaseous exchange of PCB at the Venice lagoon (Italy). AB - Water bodies are important storage media for persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and this function is increased in coastal regions because their inputs are higher than those to the open sea. The air-water interface is extensively involved with the global cycling of PCBs because it is the place where they accumulate due to depositional processes and where they may be emitted by gaseous exchange. In this work the parallel collection of air, microlayer and sub-superficial water samples was performed in July 2005 at a site in the Venice lagoon to evaluate the summer gaseous flux of PCBs. The total concentration of PCBs (sum of 118 congeners) in air varies from 87 to 273 pg m(-3), whereas in the operationally defined dissolved phase of microlayer and sub-superficial water samples it varies from 159 to 391 pg L(-1). No significant enrichment of dissolved PCB into the microlayer has been observed, although a preferential accumulation of most hydrophobic congeners occurs. Due to this behaviour, we believe that the modified two-layer model was the most suitable approach for the evaluation of the flux at the air-sea interface, because it takes into account the influence of the microlayer. From its application it appears that PCB volatilize from the lagoon waters with a net flux varying from 58 to 195 ng m(-2)d(-1) (uncertainty: +/-50-64%) due to the strong influence of wind speed. This flux is greater than those reported in the literature for the atmospheric deposition and rivers input and reveals that PCB are actively emitted from the Venice lagoon in summer months. PMID- 17706252 TI - Model-based estimation of the link between the daily survival probability and a time-varying covariate, application to mosquitofish survival data. AB - The survival probability in a group of individuals may evolve in time due to the influence of a time-varying covariate. In this paper we present a model-based approach allowing the estimation of the functional link between the survival probability and a time-varying covariate when data are grouped and time-period censored. The approach is based on an underlying model consisting in non stationary Markov processes and describing the survival of individuals. The underlying model is aggregated in time and at the group level to handle the group structure of data and the censoring. The aggregation yields a generalized non linear mixed model. Then, a Bayesian procedure allows the estimation of the model parameters and the description of the link between the survival probability and the time-varying covariate. This approach is applied in order to explore the relationship between the daily survival probability of mosquitofish (Gambusia holbrooki) and their time-varying lengths (small mosquitofish die with a higher rate than large ones because they are more affected by predation, cannibalism and environmental stress). PMID- 17706253 TI - Plasma sphingomyelin is not associated with microvascular changes in the retina. PMID- 17706255 TI - Solving a mental rotation task in congenital hemiparesis: motor imagery versus visual imagery. AB - A recent study showed that motor imagery was compromised after right congenital hemiparesis. In that study, posture of the displayed stimuli and the actual posture of the hand making the response were incongruent. Ample evidence exists that such an incongruency may negatively influence laterality judgements in a mental rotation task. In the present study, three participant groups (controls, left hemiparesis, right hemiparesis [all n=11]) performed a mental rotation task in which posture of the displayed hand and the responding hand were congruent. A small amount of errors were made and linear relations between reaction times and rotation angles of the stimuli were found for all groups, suggesting intact motor imagery. However, reaction times for the participants with hemiparesis were consistently slower compared to controls and no asymmetry in responding between the affected and less-affected hand was found, suggesting a visual imagery strategy. Collectively, these results suggest that the ability to mentally rotate stimuli is still intact in right hemiparesis. The results are discussed in relation to two strategies that may have been used to solve the task: visual imagery and motor imagery. PMID- 17706256 TI - Lexical-semantic inhibitory mechanisms in Parkinson's disease as a function of subthalamic stimulation. AB - Inhibitory control may be affected by Parkinson's disease (PD) due to impairment within the non-motor basal ganglia-thalamocortical circuits. The present study aimed to identify the effects of chronic stimulation of the subthalamic nucleus (STN) on lexical-semantic inhibitory control. Eighteen participants with PD who had undergone surgery for deep brain stimulation (DBS) of the STN, completed a picture-word interference (PWI) task and the Hayling test in on and off stimulation conditions. The results of PD participants were compared with 21 non neurologically impaired control participants. PD participants performed no differently from controls on the PWI task, and no significant differences between on and off stimulation conditions were revealed, therefore suggesting that PD participants are not impaired in lexical-semantic interference control. In contrast, in the off stimulation condition, PD participants had significantly delayed reaction times and increased errors on the inhibition section of the Hayling test compared with the STN stimulation condition and control participants. These results suggest that PD patients are impaired in aspects of inhibitory control that are dependent on behavioural inhibition (such as the suppression of prepotent responses) and selection from competing alternatives without the presence of external cues. Furthermore, STN stimulation acts to restore these behavioural inhibitory processes. PMID- 17706257 TI - Hypertension, urbanization, social and spatial disparities: a cross-sectional population-based survey in a West African urban environment (Ouagadougou, Burkina Faso). AB - Data show that hypertension has become a public health problem in developing countries. Many studies have reported social disparities among the affected populations, but few of them pointed out spatial disparities within towns. We aimed to show that hypertension could be a good indicator of the medical change that occurs unequally in towns. A cross-sectional survey was done in April and October 2004 in Ouagadougou, Burkina Faso, among 2087 adults over 35 years old in different kinds of urban areas. Social and demographic data were collected and blood pressure was measured. Prevalence of hypertension was 40.2%. Age, body mass index, level of equipment, absence of community integration, absence of occupation, duration of residence over 20 years, protein-rich diet and absence of physical activity were identified as risk factors, but there were social and spatial disparities according to location of housing (parcelled-out or non parcelled-out areas) and to integration within the town. The high rate of hypertension found in Ouagadougou and the heterogeneity of the risk within the population highlights that social and spatial risk factors have to be taken into account for the prevention of the non-transmissible diseases in countries in full process of urbanization and medical change. PMID- 17706254 TI - Input-specific plasticity at excitatory synapses mediated by endocannabinoids in the dentate gyrus. AB - Endocannabinoids (eCBs) mediate transient and long-lasting synaptic plasticity in several brain structures. In the dentate gyrus, activation of the type 1 cannabinoid receptor (CB1R) by exogenous ligands reportedly depresses excitatory synaptic transmission. However, direct evidence of eCB signaling at excitatory synapses in this region has been lacking. Here, we demonstrate that eCB release can be induced by a brief postsynaptic depolarization of dentate granule cells (DGCs), which potently and transiently suppresses glutamatergic inputs from mossy cell interneurons (MCs) but not from entorhinal cortex via the lateral and medial perforant paths. This input-specific depolarization-induced suppression of excitation (DSE) is calcium-dependent and can be modulated by agonists of cholinergic and group I metabotropic glutamate receptors. Inhibiting the synthesis of 2-arachidonoyl glycerol (2-AG), one of the most abundant eCBs in the brain, by diacyglycerol lipase (DGL) does not abolish DSE. Moreover, preventing the breakdown of anandamide, the other main eCB, does not potentiate DSE. Thus, eCB signaling underlying DSE in the dentate does not require DGL activity and is unlikely to be mediated by anandamide. Finally, we find that manipulations known to induce eCB-LTD at other central synapses do not trigger LTD at MCF-DGC synapses. PMID- 17706258 TI - Potential impact of nanotechnology on the control of infectious diseases. AB - Nanotechnology encompasses those technologies used to fabricate materials, including sphere, cubic and needle-like nanoscaled particles (approximately 5 100nm), and near-nanoscaled devices (up to micrometres). In comparison, mycoplasma are approximately 200nm in length, and a nanometre is 10(-9) of a metre. The field of nanotechnology is experiencing rapid growth, with many and diverse potential applications being explored in the biomedical field, including the control of infectious diseases. Nanotechnology not only has the potential to offer improvements to current approaches for immunisation, drug design and delivery, diagnostics and cross-infection control, but is also unexpectedly delivering many new tools and capabilities. PMID- 17706259 TI - Dengue outbreak in Karachi, Pakistan, 2006: experience at a tertiary care center. AB - This is the first report of the largest epidemic of dengue hemorrhagic fever (DHF) virus infection (2006) with IgM-confirmed cases from Karachi, Pakistan. Medical records of 172 IgM-positive patients were reviewed retrospectively for demographic, clinical and laboratory data. Patients were categorized into dengue fever (DF) and DHF according to the WHO severity grading scale. The mean+/-SD age of the patients was 25.9+/-12.8 years, 55.8% were males and the hemoconcentration was recorded in a small number of patients [10 (7.0%)]. Male gender [odds ratio (OR)=14.7, P=0.003), positive history of vomiting (OR=4.3, P=0.047), thrombocytopenia at presentation (OR=225.2, P<0.001) and monocytosis (OR=5.8, P=0.030) were independently associated with DHF, but not with DF. Five cases (2.9%) had a fatal outcome, with a male-to-female ratio of 1:4. Three were from a pediatric group (<15 years). Pulmonary hemorrhages, disseminated intravascular coagulation and cerebral edema preceded death in these patients. The results have highlighted significant findings, such as adult susceptibility to DHF, pronounced abdominal symptoms and lack of hemoconcentration at time of presentation in the study population. These findings may play an important role in the case definitions of future studies from this part of the world. PMID- 17706260 TI - Gene expression profiling reveals underlying molecular mechanisms of the early stages of tamoxifen-induced rat hepatocarcinogenesis. AB - Tamoxifen is a widely used anti-estrogenic drug for chemotherapy and, more recently, for the chemoprevention of breast cancer. Despite the indisputable benefits of tamoxifen in preventing the occurrence and re-occurrence of breast cancer, the use of tamoxifen has been shown to induce non-alcoholic steatohepatitis, which is a life-threatening fatty liver disease with a risk of progression to cirrhosis and hepatocellular carcinoma. In recent years, the high throughput microarray technology for large-scale analysis of gene expression has become a powerful tool for increasing the understanding of the molecular mechanisms of carcinogenesis and for identifying new biomarkers with diagnostic and predictive values. In the present study, we used the high-throughput microarray technology to determine the gene expression profiles in the liver during early stages of tamoxifen-induced rat hepatocarcinogenesis. Female Fisher 344 rats were fed a 420 ppm tamoxifen containing diet for 12 or 24 weeks, and gene expression profiles were determined in liver of control and tamoxifen exposed rats. The results indicate that early stages of tamoxifen-induced liver carcinogenesis are characterized by alterations in several major cellular pathways, specifically those involved in the tamoxifen metabolism, lipid metabolism, cell cycle signaling, and apoptosis/cell proliferation control. One of the most prominent changes during early stages of tamoxifen-induced hepatocarcinogenesis is dysregulation of signaling pathways in cell cycle progression from the G(1) to S phase, evidenced by the progressive and sustained increase in expression of the Pdgfc, Calb3, Ets1, and Ccnd1 genes accompanied by the elevated level of the PI3K, p-PI3K, Akt1/2, Akt3, and cyclin B, D1, and D3 proteins. The early appearance of these alterations suggests their importance in the mechanism of neoplastic cell transformation induced by tamoxifen. PMID- 17706262 TI - Genomic characterization of equine coronavirus. AB - The complete genome sequence of the first equine coronavirus (ECoV) isolate, NC99 strain was accomplished by directly sequencing 11 overlapping fragments which were RT-PCR amplified from viral RNA. The ECoV genome is 30,992 nucleotides in length, excluding the polyA tail. Analysis of the sequence identified 11 open reading frames which encode two replicase polyproteins, five structural proteins (hemagglutinin esterase, spike, envelope, membrane, and nucleocapsid) and four accessory proteins (NS2, p4.7, p12.7, and I). The two replicase polyproteins are predicted to be proteolytically processed by three virus-encoded proteases into 16 non-structural proteins (nsp1-16). The ECoV nsp3 protein had considerable amino acid deletions and insertions compared to the nsp3 proteins of bovine coronavirus, human coronavirus OC43, and porcine hemagglutinating encephalomyelitis virus, three group 2 coronaviruses phylogenetically most closely related to ECoV. The structure of subgenomic mRNAs was analyzed by Northern blot analysis and sequencing of the leader-body junction in each sg mRNA. PMID- 17706261 TI - Characterization of replication defects induced by mutations in the basic domain and C-terminus of HIV-1 matrix. AB - Extensive mutagenesis has defined distinct functional domains in the HIV-1 matrix domain (MA). In an attempt to more clearly define functions of regions of MA which affect viral entry, we analyzed mutations in the N-terminal basic and the C terminal helical domains. Deletions of 8-10 amino acid residues of the C-terminal fifth helix of MA resulted in viruses that were only mildly defective in infectivity and fusion. The defect exhibited by these mutations could largely be attributed to a reduction in levels of viral envelope incorporated into mature virions. Truncation of the gp41 cytoplasmic tail (gp41CT) could rescue the phenotype of one of these mutants. In contrast, mutations of multiple basic residues in the N-terminus of MA were severely defective in both infectivity and fusion. While these mutations induce severe envelope incorporation defects, they also result in virus crippled at a post-entry step, since truncation of the gp41CT could not rescue the infectivity defect. PMID- 17706263 TI - Influence of ionic surfactants on the flocculation and sorption of palladium and mercury in the aquatic environment. AB - The influence of sub-micellar concentrations of an anionic surfactant (sodium dodecyl sulphate; SDS) and a cationic surfactant (hexadecyl trimethylammonium bromide; HDTMA) on the aquatic behaviour of the strongly complexing metals, Pd(II) and Hg(II), has been investigated. In river water, flocculation of organic complexes of metal was suppressed by SDS but accentuated by HDTMA, effects that are consistent with electrostatic and hydrophobic interactions between ionic surfactants and natural polyelectrolytes. In sea water, flocculation of metal complexes was enhanced by both surfactants because of the shielding and salting effects of inorganic ions on these interactions. Particle surface modification engendered by sorbed surfactant strongly influenced the sorption of Pd and Hg to estuarine particles. Thus, hydrophobically bound SDS enhances the negative charge at the particle surface and favours specific sorption of metal, while specifically sorbed HDTMA enhances the solvency of the particle surface, favouring non-specific sorption of metal complexes. Given the relatively short environmental half-life of SDS, its impacts on strongly complexing metals are predicted to be localised. However, greater stability of HDTMA suggests that its effects on such metals, including enhanced flocculation and sorption, are likely to be more pervasive. PMID- 17706264 TI - Fine-pore aeration diffusers: accelerated membrane ageing studies. AB - Polymeric membranes are widely used in aeration systems for biological treatment. These membranes may degrade over time and are sensitive to fouling and scaling. Membrane degradation is reflected in a decline in operating performance and higher headloss, resulting in increased energy costs. Mechanical property parameters, such as membrane hardness, Young's modulus, and orifice creep, were used to characterize the performance of membranes over time in operation and to predict their failure. Used diffusers from municipal wastewater treatment plants were collected and tested for efficiency and headloss, and then dissected to facilitate measurements of Young's modulus, hardness, and orifice creep. Higher degree of membrane fouling corresponded consistently with larger orifice creep. A lab-scale membrane ageing simulation was performed with polyurethane and four different ethylene-propylene-diene (EPDM) membrane diffusers by subjecting them to chemical ageing cycles and periodic testing. The results confirmed full-scale plant results and showed the superiority of orifice creep over Young's modulus and hardness in predicting diffuser deterioration. PMID- 17706265 TI - DBPs removal in GAC filter-adsorber. AB - A rapid sand filter and granular activated carbon filter-adsorber (GAC FA) were compared in terms of dissolved organic carbon (DOC) and disinfection by-products (DBPs) removal. A water treatment plant (WTP) that had a high ammonia concentration and DOC in raw water, which, in turn, led to a high concentration of DBPs because of a high dose of pre-chlorination, was investigated. To remove DBPs and DOC simultaneously, a conventional rapid sand filter had been retrofitted to a GAC FA at the Buyeo WTP in Korea. The overall removal efficiency of DBPs and DOC was higher in the GAC FA than in the sand filter, as expected. Breakthrough of trihalomethanes (THMs) was noticed after 3 months of GAC FA operation, and then removal of THMs was minimal (<10%). On the other hand, the removal efficiency of five haloacetic acids (HAA(5)) in the GAC FA was better than that of THMs, though adsorption of HAA(5) decreased rapidly after 3.5 months of GAC FA operation. And then, gradual improvement (>90%) in HAA(5) removal efficiency was again observed, which could be attributed to biodegradation. At the early stage of GAC FA operation, HAA(5) removal was largely due to physical adsorption, but later on biodegradation appeared to prevail. Biodegradation of HAA(5) was significantly influenced by water temperature. Similar turbidity removal was noticed in both filters, while better manganese removal was confirmed in the sand filter rather than in the GAC FA. PMID- 17706266 TI - Plasticizers and their degradation products in the process streams of a large urban physicochemical sewage treatment plant. AB - The plasticizers bis (2-ethylhexyl) phthalate (BEHP), bis (2-ethylhexyl) terephthalate (BEHTP) and bis (2-ethylhexyl) adipate (BEHA) were found in significant quantities in the influents, process streams, treated effluent and solid residues of a large physicochemical treatment plant in Montreal, Canada. Of these plasticizers, BEHA was the most abundant in the influent but most was removed during primary treatment. Evidence indicated that significant biodegradation occurred within the sewers and during treatment resulting in the formation of three biodegradation products that had been reported in earlier laboratory studies; namely, 2-ethylhexanol, 2-ethylhexanal and 2-ethylhexanoic acid. Significantly greater concentrations of 2-ethylhexanal were found in process streams than had been reported in earlier laboratory work. This was attributed to the fact that there were fewer opportunities for losses of this volatile compound over the course of wastewater treatment. The plasticizers were removed from the aqueous phase to varying degrees during treatment, with most ending up in the solid residues. All three metabolites and the parent plasticizers were observed in the effluent and most were found in the solids that were analyzed. Results suggest that the treatment plant does not effectively remove plasticizers from the influent and represents a significant source of these compounds and their degradation products in the environment. PMID- 17706267 TI - Removal of antibiotics from wastewater by sewage treatment facilities in Hong Kong and Shenzhen, China. AB - Concentrations of nine antibiotics [erythromycin-H(2)O (ERY-H(2)O); trimethoprim (TMP); tetracycline (TET); norfloxacin (NOR); penicillin G (PEN G); penicillin V (PEN V); cefalexin (CLX); cefotaxim (CTX); and cefazolin (CFZ)] were measured in influent and effluent samples from four sewage treatment plants (STPs) in Hong Kong as well as in influent samples from one STP in Shenzhen. Levels of PEN V and CFZ were below method detection limits in all of the samples analyzed. CLX concentrations were the highest in most of the Hong Kong samples, ranging from 670 to 2900 ng/L and 240 to 1800 ng/L in influent and effluent samples, respectively, but CLX was not detected in the samples from Shenzhen. Comparatively lower concentrations were observed for ERY-H(2)O (470-810 ng/L) and TET (96-1300 ng/L) in the influent samples from all STPs in Hong Kong. CTX was found to be the dominant antibiotic in the Shenzhen STP influents with a mean concentration of 1100 ng/L, but occurred at lower concentrations in Hong Kong sewage. These results likely reflect regional variations in the prescription and use patterns of antibiotics between Hong Kong and Shenzhen. Antibiotic removal efficiencies depended on their chemical properties and the wastewater treatment processes used. In general, relatively higher removal efficiencies were observed for NOR (5-78%) and TET (7-73%), which are readily adsorbed to particulate matter, while lower removal efficiencies were observed for ERY-H(2)O (9-19%), which is relatively persistent in the environment. Antibiotics were removed more efficiently at Hong Kong STPs employing secondary treatment processes compared with those using primary treatment only. Concentrations of NOR measured in effluents from STPs in Hong Kong were lower than the predicted no-effect concentration of 8000 ng/L determined in a previous study. Therefore, concentrations of antibiotics measured in this preliminary study would be unlikely to cause adverse effects on microorganisms used in wastewater treatment processes at the sampled STPs. PMID- 17706268 TI - Selection of anionic exchange resins for removal of natural organic matter (NOM) fractions. AB - Early elimination of natural organic matter (NOM) by ion exchange (IEX) in water treatment is expected to improve subsequent water treatment processes and the final drinking water quality. Nine anionic exchange resins were investigated to remove NOM and specific NOM fractions determined by liquid chromatography in combination with organic carbon detection (LC-OCD) and fluorescence excitation emission matrices (EEM). Breakthrough of NOM was predicted by model calculations using Freundlich isotherms and IEX rate experiments. The time to breakthrough varied from 4 to 38 days. Removal of specific NOM fractions proved to vary considerably for the different types of IEX resins, ranging from 1% to almost 60%. The removal of NOM fractions, specifically humic substances, increased with an increase in water content of the investigated IEX resins and with a decrease in resin size. The best-performing IEX resins consisted of the smallest resins and/or those with the highest water content. The worst-performing IEX resins reflected the highest exchanging capacities and the lowest water contents. PMID- 17706269 TI - Age and biostratigraphic significance of the Punung Rainforest Fauna, East Java, Indonesia, and implications for Pongo and Homo. AB - The Punung Fauna is a key component in the biostratigraphic sequence of Java. It represents the most significant faunal turnover on the island in the last 1.5 million years, when Stegodon and other archaic mammal species characteristic of earlier Faunal stages were replaced by a fully modern fauna that included rainforest-dependent species such as Pongo pygmaeus (orangutan). Here, we report the first numerical ages for the Punung Fauna obtained by luminescence and uranium-series dating of the fossil-bearing deposits and associated flowstones. The Punung Fauna contained in the dated breccia is of early Last Interglacial age (between 128+/-15 and 118+/-3 ka). This result has implications for the age of the preceding Ngandong Fauna, including Homo erectus remains found in the Ngandong Terrace, and for the timing of Homo sapiens arrival in Southeast Asia, in view of claims for a modern human tooth associated with the Punung breccia. PMID- 17706270 TI - Life history theory and dental development in four species of catarrhine primates. AB - Dental development was reconstructed in several individuals representing four species of catarrhine primates--Symphalangus syndactylus, Hylobates lar, Semnopithecus entellus priam, and Papio hamadryas--using the techniques of dental histology. Bar charts assumed to represent species-typical dental development were constructed from these data and estimated ages at first and third molar emergence were plotted on them along with ages at weaning, menarche, and first reproduction from the literature. The estimated age at first molar emergence appears to occur at weaning in the siamang, lar gibbon, and langur, and just after weaning in the baboon. Age at menarche and first reproduction occur earlier relative to dental development in both cercopithecoids than in the hylobatids, suggesting that early reproduction may be a derived trait in cercopithecoids. The results are examined in the context of life history theory. PMID- 17706271 TI - The effects of body proportions on thermoregulation: an experimental assessment of Allen's rule. AB - Numerous studies have discussed the influence of thermoregulation on hominin body shape concluding, in accordance with Allen's rule, that the presence of relatively short limbs on both extant as well as extinct hominin populations offers an advantage for survival in cold climates by reducing the limb's surface area to volume ratio. Moreover, it has been suggested that shortening the distal limb segment compared to the proximal limb segment may play a larger role in thermoregulation due to a greater relative surface area of the shank. If longer limbs result in greater heat dissipation, we should see higher resting metabolic rates (RMR) in longer-limbed individuals when temperature conditions fall, since the resting rate will need to replace the lost heat. We collected resting oxygen consumption on volunteer human subjects to assess the correlation between RMR and lower limb length in human subjects, as well as to reexamine the prediction that shortening the distal segment would have a larger effect on heat loss and, thus, RMR than the shortening of the proximal segment. Total lower limb length exhibits a statistically significant relationship with resting metabolic rate (p<0.001; R(2)=0.794). While this supports the hypothesis that as limb length increases, resting metabolic rate increases, it also appears that thigh length, rather than the length of the shank, drives this relationship. The results of the present study confirm the widely-held expectation of Allen's rule, that short limbs reduce the metabolic cost of maintaining body temperature, while long limbs result in greater heat dissipation regardless of the effect of mass. The present results suggest that the shorter limbs of Neandertals, despite being energetically disadvantageous while walking, would indeed have been advantageous for thermoregulation. PMID- 17706272 TI - Preoperative serum CA125 in surgical stage 1 epithelial ovarian cancer. PMID- 17706273 TI - Means of transportation to work and overweight and obesity: a population-based study in southern Sweden. AB - OBJECTIVES: To investigate the association between means of transportation to work and overweight+obesity and obesity. METHODS: The 2004 public health survey in Skane is a cross-sectional postal questionnaire study of the population aged 18-80 with a 59% response rate including 16,705 employed participants. RESULTS: Forty-six percent of men and 26.6% of women were overweight (BMI 25.0-29.9); 11.6% of men and 10.3% of women were obese (BMI 30.0-); 18.2% of men and 25.9% of women bicycled and/or walked to work and 10.4% and 16.2% used public transportation, respectively. In contrast, 68.3% of men and 55.8% of women went to work by car. The odds ratios of overweight+obesity among persons who walked or bicycled were significantly lower and remained 0.62 (95% CI 0.51-0.76) among men and 0.79 (95% CI 0.67-0.94) among women in the models including all confounders compared to the car driving reference category. The odds ratios of obesity were initially significantly lower among both men and women who walked or bicycled, but in the final models only among women. The odds ratios of overweight+obesity as well as obesity were also lower among men using public transportation. CONCLUSIONS: Walking and bicycling to work are significantly negatively associated with overweight+obesity and, to some extent, obesity. Public transportation is significantly negatively associated with overweight+obesity and obesity among men. PMID- 17706274 TI - Stress assignment in aphasia: word and non-word reading and non-word repetition. AB - This paper investigates stress assignment in Dutch aphasic patients in non-word repetition, as well as in real-word and non-word reading. Performance on the non word reading task was similar for the aphasic patients and the control group, as mainly regular stress was assigned to the targets. However, there were group differences on the real-word reading and non-word repetition tasks. Unlike the non-brain-damaged group, the patients showed a strong regularization tendency in their repetition of irregular patterns. The patients' stress error patterns suggest an impairment in retention or retrieval of targets with irregular stress patterns. Limited verbal short-term memory is proposed as a possible underlying cause for the stress difficulties. PMID- 17706275 TI - Targeting base excision repair to improve cancer therapies. AB - Most commonly used cancer therapies, particularly ionizing radiation and certain classes of cytotoxic chemotherapies, cause cell death by damaging DNA. Base excision repair (BER) is the major system responsible for the removal of corrupt DNA bases and repair of DNA single strand breaks generated spontaneously and induced by exogenous DNA damaging factors such as certain cancer therapies. In this review, the physico-chemical properties of the proteins involved in BER are discussed with particular emphasis on molecular mechanisms coordinating repair processes. The aim of this review is to apply extensive knowledge that currently exists regarding the biochemical mechanisms involved in human BER to the molecular biology of current therapies for cancer. It is anticipated that the application of this knowledge will translate into the development of novel effective therapies for improving existing treatments such as radiation therapy and oxaliplatin chemotherapy. PMID- 17706276 TI - In vitro study of edge-strength of provisional polymer-based crown and fixed partial denture materials. AB - OBJECTIVES: To evaluate in vitro the edge-strength of polymer-based provisional crown and fixed partial denture materials at increasing distances from an edge. METHODS: Three dimethacrylate-based provisional crown and fixed partial denture materials (Protemp 3 Garant, Luxatemp, and fast set Temphase) and one monomethacrylate-based one (Trim) were selected. Seven disk-shaped specimens of 12mm in diameter and 2.5mm in thickness for each material were fabricated and stored at 37 degrees C and 80% relative humidity for 1 month. The edge-strength was measured by using a CK 10 testing machine at a distance of 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, and 1.0mm from the edge of the specimen. All experiments were carried out in triplicate at each distance at 23+/-1 degrees C. The data were statistically analyzed using one-way ANOVA and the multiple comparison Scheffe test at the significance level of 0.05. RESULTS: Trim showed severe deformation without chipping during loading at all distances. Protemp 3 Garant showed indentation at over 0.8mm from the edge, and for Luxatemp and fast set Temphase over 0.6mm from the edge without chipping. At 0.5mm from the edge, the highest values (2073.7N) were displayed by Protemp 3 Garant, approximately three times those of fast set Temphase (767.3N) and Luxatemp (697.0N) (p<0.05). The strengths of fast set Temphase and Luxatemp were not significantly different (p>0.05). Linear regression between the distance from the edge to 0.7mm and strength values of Protemp 3 Garant produced a correlation coefficient, R=0.99. SIGNIFICANCE: The dimethacrylate-based provisional materials tested were stronger in edge-strength than the monomethacrylate-based one which showed severe deformation without fracture. PMID- 17706277 TI - Enhanced fibronectin adsorption on carbon nanotube/poly(carbonate) urethane: independent role of surface nano-roughness and associated surface energy. AB - The contribution of nanoscale surface roughness on the adsorption of one key cell adhesive protein, fibronectin, on carbon nanotube/poly(carbonate) urethane composites of different surface energies was evaluated. Systematic control of various surface energies by creating different nanosurface roughness features was performed by mixing two promising biomaterials: multi-wall carbon nanotubes and poly(carbonate) urethane. High ratios of carbon nanotubes coated with poly(carbonate) urethane provided for greater hydrophilic surfaces because of higher nanosurface roughness although pure carbon nanotube surfaces were extremely hydrophobic. Fabrication methods followed in this study generated various homogenous nanosurface roughness values (ranging from 2 to 20nm root mean square (RMS) AFM roughness). With the aid of such nanosurface roughness values in composites, a model was developed that linearly correlated nanosurface roughness and associated nanosurface energy to fibronectin adsorption. Specifically, independent contributions of surface chemistry (70%) and surface nano-roughness (30%) were found to mediate fibronectin adsorption. The results of the present study showed why carbon nanotube/poly(carbonate) urethane composites enhance cellular functions and tissue growth by delineating the importance of their physical nano-roughness on promoting the adsorption of a protein well known to be critical for mediating the adhesion of anchorage-dependent cells. PMID- 17706278 TI - Phenotypic dichotomies in the foreign body reaction. AB - To better understand the relationship between macrophage/foreign body giant cell adhesion and activation on surface-modified biomaterials, quantitative assessment of adherent cell density (cells per mm(2)) and cytokine production (pgs per mL) were determined by ELISA. Further analysis to identify cellular activation was carried out by normalizing the cytokine concentration data to provide a measure of cellular activation. This method of analysis demonstrated that hydrophobic surfaces provided statistically significantly greater adherent cell densities than hydrophilic/neutral surfaces. However, when cell activation parameters were determined by normalization to the adherent cell density, the hydrophilic/neutral surfaces demonstrated statistically significantly greater levels of activation and production of IL-10, IL-1beta, IL-6, IL-8, and MIP-1beta. With increasing time, production of the anti-inflammatory cytokine IL-10 increased, whereas IL 1beta, IL-6, and IL-8 decreased and MIP-1beta was relatively constant over the culture time period. This observed dichotomy or disparity between adhesion and activation may be related to surface-induced adherent cell apoptosis. Further evaluation of macrophage activation on biomaterial surfaces indicated that an apparent phenotypic switch in macrophage phenotype occurred over the course of the in vitro culture. Analysis of cytokine/chemokine profiles with surface modified biomaterials revealed similarities between the classically activated macrophages and the biomaterial-adherent macrophages early (day 3) in culture, while at later timepoints the biomaterial-adherent macrophages produced profiles similar to alternatively activated macrophages. Classically activated macrophages are those commonly activated by lipopolysaccharide (LPS) or interferon-gamma (IFN gamma) and alternatively activated macrophages are those activated by IL-4/IL-13 or IL-10. Surface modification of biomaterials offer an opportunity to control cellular activation and cytokine profiles in the phenotypic switch, and may provide a means by which macrophages can be induced to regulate particular secretory proteins that direct inflammation, the foreign body reaction, wound healing, and ultimately biocompatibility. PMID- 17706281 TI - Copper deficiency with increased hematogones mimicking refractory anemia with excess blasts. AB - We describe a 19-year-old male patient with a previous diagnosis of familial Mediterranean fever (FMF), nephrotic syndrome and secondary amyloidosis, who presented with anemia and leukopenia. The bone marrow assessments showed dysplastic precursors including vacuolated myeloid and erythroid precursors and increased proportion of immature cells up to 19%. The patient received erythropoietin and G-CSF for myelodysplastic syndrome (MDS). No response was observed. During his evaluations copper deficiency was detected. One month after oral copper replacement, the peripheral blood counts and bone marrow findings became completely normalized. An evaluation to identify the cause of copper deficiency, revealed intestinal amyloidosis. Based on our experience we recommend serum copper determination in the diagnostic workup of MDS in patients with comorbidities. PMID- 17706279 TI - Fetuin-A gene expression, synthesis and release in primary human hepatocytes cultured in a galactosylated membrane bioreactor. AB - This paper reports on human hepatocytes cultured in a galactosylated membrane bioreactor in order to explore the modulation of the effects of a pro inflammatory cytokine, Interleukin-6 (IL-6) on the liver cells at molecular level. In particular the role of IL-6 on gene expression and production of a glycoprotein, fetuin-A produced by hepatocytes, was investigated by culturing hepatocytes in the membrane bioreactor, both in the absence and presence of IL-6 (300 pg/ml). IL-6 modulated the fetuin-A gene expression, synthesis and release by primary human hepatocytes cultured in the bioreactor. A 75% IL-6-induced reduction of fetuin-A concentration in the medium was associated with a 60% increase of C-reactive protein in the same samples. Real-time-PCR demonstrated an 8-fold IL-6-induced reduction of fetuin-A gene expression. These results demonstrate that the hepatocyte galactosylated membrane bioreactor is a valuable tool to study IL-6 effects and gave evidence, for the first time, that IL-6 down regulates the gene expression and synthesis of fetuin-A by primary human hepatocytes. The human hepatocyte bioreactor behaves like the in vivo liver, reproducing the same hepatic acute-phase response that occurs during the inflammatory process. PMID- 17706280 TI - Oxygen tension directs the differentiation pathway of human cytotrophoblast cells. AB - During placental development, human cytotrophoblast cells can differentiate to either villous syncytiotrophoblast cells or invasive extravillous trophoblast cells. We hypothesize that oxygen tension plays a critical role in determining the pathway of cytotrophoblast differentiation. A highly purified preparation of cytotrophoblast cells from human third trimester placenta was cultured for 5 days in either 20% or 1% oxygen tension. The cells incubated at 20% oxygen formed a syncytium as determined by immunohistochemistry using an anti-desmosomal protein antibody that identifies cell membranes. In addition, the mRNA was markedly induced for syncytin, a glycoprotein shown to be essential for syncytiotrophoblast formation, and for human placental lactogen (hPL), which is a specific marker for syncytiotrophoblast cells. In contrast, the cell incubated at 1% oxygen tension did not fuse by morphologic analysis and did not express syncytin or hPL mRNA. However, these cells expressed abundant amounts of HLA-G, a specific marker for extravillous trophoblast cells, which was not seen in cells incubated at 20% oxygen tension. These results suggest that low oxygen tension directs differentiation along the extravillous trophoblast cell pathway while greater oxygen tension directs differentiation along the villous trophoblast cell pathway. PMID- 17706282 TI - Thrombospondin-1 (TSP-1) and Survivin (S) expression in non-Hogkin's lymphomas. AB - Survivin (S) is a member of inhibitor of apoptosis family (IAP) and is expressed in the majority of malignant tumors but undetectable in normal differentiated adult tissues. S is an encouraging target for cancer therapy. TSP-1 is a multifunctional protein regulating cell growth, motility and apoptosis in both physiological and pathological conditions. The role of TSP-1 in cancer progression remains controversial. We aimed to determine the pathogenetic and prognostic role of TSP-1 and S in non-Hodgkin's lymphomas (NHL). S and TSP-1 expressions were looked for in 177 cases with NHL. S was found to be positive in 94 of the cases (53%). TSP-1 was found to be positive in 31 of the cases (17.5%). There was a strong association between S and TSP-1 and also aggressive histology with S and TSP-1. The overall survival (OS) times were longer in cases without S expression than cases with S expression (p=0.0514). Although the OS was shorter in TSP-1 expressing cases as compared with TSP-1 (-) cases, difference was not significant (p=0.2428). In conclusion, S and TSP-1 expressions were detected in 53 and 17.5% of the cases with NHL, and are associated with aggressive histology and shorter OS. PMID- 17706283 TI - Mesenchymal stem cells from JAK2(V617F) mutant patients with primary myelofibrosis do not harbor JAK2 mutant allele. PMID- 17706284 TI - Tuberculosis as a zoonosis from a veterinary perspective. AB - Tuberculosis is an important disease among many zoonoses, because both Mycobacterium tuberculosis and Mycobacterium bovis, which are the major causes of tuberculosis, are highly pathogenic, infect many animal species and thus are likely to be the source of infection in humans. In particular, monkeys are highly susceptible to these bacteria and are important spreaders. Recently, two outbreaks of M. tuberculosis occurred in four different kinds of monkeys and humans were also infected with the disease in Japan. In zoos, tuberculosis was reported not only in monkeys, but also in several different kinds of animals, including elephants. Pets such as dogs and cats are believed to be generally less susceptible to M. tuberculosis, but in this article we introduce a case of infection from man to dog by close contact. Japan is one of the few countries that have been able to control M. bovis infection. In other countries, however, cases of bovine tuberculosis and human M. bovis infection have been reported, and thus further attention is still required in the future. PMID- 17706285 TI - The association between acculturation and needle sharing among Puerto Rican injection drug users. AB - BACKGROUND: Base-line data from a community-based HIV outreach effort serving Puerto Rican injection drug users (IDUs) in Massachusetts identified that approximately half of their clients were born on the mainland and half on the island. METHODS: Logistic regression methods examined the relationship between place of birth, primary language spoken, primary residence of family and needle sharing for a sample of 200 Puerto Rican IDUs residing in Massachusetts. Focus groups were used to interpret quantitative findings. RESULTS: A logistic regression model indicated that Puerto Rican IDUs born on mainland USA were 2.1 times more likely to share needles than IDUs born in Puerto Rico, after controlling for gender, age, education, drug overdose, incarceration history and psychiatric status. Also, Puerto Rican IDUs who were older had overdosed on drugs in the past year, had been incarcerated in their lifetime, and were homeless were significantly more likely to report having shared needles in the past 6 months compared to their counterparts. Focus group interviews with Puerto Rican outreach workers and individuals in recovery suggested that differences in needle sharing by mainland versus island born IDUs may be due to cultural differences in interpretation of the interview questions. IMPLICATIONS: Researchers examining HIV risk behaviors among culturally diverse substance abusers need to conduct more mixed-method studies to identify if different cultural groups understand quantitative measures differently. Incarceration may be a significant risk factor in the continued spread of HIV among IDUs and expanded HIV prevention efforts need to be developed that specifically target this high-risk group. PMID- 17706286 TI - Research, policy and practice in work and mental health: a multi-disciplinary discussion. PMID- 17706287 TI - Reproducibility of peripapillary retinal nerve fiber thickness measurements with stratus OCT in glaucomatous eyes. AB - PURPOSE: To determine the reproducibility of Stratus OCT peripapillary retinal nerve fiber layer (RNFL) measurements in glaucomatous eyes. DESIGN: Experimental study. PARTICIPANTS: Fifty-one stable glaucoma patients with a range of severity. METHODS: Peripapillary RNFL thickness was measured using the Standard and Fast scan protocols of Stratus optical coherence tomography (OCT) 3 times on the same day to determine intrasession variability and on 5 different days within a 2 month period to determine intersession variability. The same instrument was used by the same operator for all scans. MAIN OUTCOME MEASURES: Intraclass correlation coefficient (ICC), coefficient of variation (COV), and test-retest variability. RESULTS: For mean RNFL thickness, the intrasession and intersession ICCs for the Standard and Fast scans were 0.98 and 0.96, respectively. The COV ranged from 3.8% to 5.2%. Test-retest variability was approximately 7 microm between sessions, most of which can be attributed to the approximate 5-microm variability within each session. For quadrants, the ICC was 0.9 or higher and the COV was under 10% except nasally. Test-retest variability for quadrant measurements ranged from 6 to 16 microm. For clock hours, test-retest variability approached 20 microm between sessions in some sectors. In general, the ICC was lower in the nasal region than elsewhere. Variability was greater the smaller the area over which RNFL thickness was determined. Intrasession variability was not a predictor of intersession variability in individual subjects (P Standard = 0.72, P Fast = 0.28). There was no relationship between variability and mean RNFL thickness (P Standard = 0.28, P Fast = 0.93). CONCLUSIONS: The reproducibility of Stratus OCT for RNFL thickness is sufficiently good to be useful clinically as a measure of glaucoma progression. When comparing 2 mean RNFL values on different days in the same eye, an 8-microm decrease in thickness might be accepted as within normal limits of test-retest variability with 95% tolerance. For quadrants and clock hour sectors, variability is higher, and more detailed calculations are necessary. PMID- 17706289 TI - Trends in Salmonella enterica serotypes isolated from human, food, animal, and environment in Tunisia, 1994-2004. AB - OBJECTIVE: The present study was conducted to investigate, for the first time in Tunisia, the current trends in Salmonella enterica serotypes in Tunisia (human, food, animal, and environment) which would help to improve the control and prevention of Salmonella infections. METHODS: Data from 1994 to 2004 from the National Centre of Enteropathogenic Bacteria - Pasteur Institute - Tunis, were analysed a total of 16,214 Salmonella isolates that were reported from all over Tunisia and serotyped according to the Kauffman-White scheme. Statistical analysis was done by SPSS v.11.5 software. RESULTS: The isolation rate was decreasing in the human and food categories only. The top three frequently isolated serotypes during the 11-years were: Enteritidis (25.5%), Anatum (14%), and Corvallis (13.2%), indicating Tunisia as an endemic area for these serotypes. Among human isolates, Enteritidis was the most common serotype, accounting for 24% of all isolates. Among nonhuman isolates, Anatum (28%), Enteritidis (69%), and Corvallis (17.3%) were reported as the first common serotypes for food, animal and environmental samples, respectively. Percentage of Salmonella isolates demonstrated a marked pattern of seasonality, increasing in the warm spring months for human, food and animal isolates. Except for environmental isolates which increased in the spring season. Human salmonellosis outbreak by serotypes Mbandaka, Livingstone, and Typhi Vi+ had been reported during the years: 1997, 1999, 2002 and 2004. CONCLUSION: Importance of enhancing the Salmonella surveillance system not only in Tunisia but also in the neighboring countries, and the need to get a better monitoring of trends in serotypes over time which would provide information about emerging serotypes and about the efficacy of prevention and control measures. PMID- 17706288 TI - Comparison of visual acuity in macular degeneration patients measured with snellen and early treatment diabetic retinopathy study charts. AB - PURPOSE: To compare the measurements of visual acuity (VA) results measured with Snellen and Early Treatment Diabetic Retinopathy Study (ETDRS) charts in eyes with and without age-related macular degeneration (AMD). DESIGN: Cross-sectional study. PARTICIPANTS: One hundred four participants (190 eyes) selected from a university retina practice; 80 participants (142 eyes) had some degree of AMD. METHODS: Visual acuity was measured in each patient using standard procedure with both Snellen and ETDRS charts in random order. Statistical analysis of the results was performed. MAIN OUTCOME MEASURES: Difference in VA measured by both charts in logarithm of minimal angle of resolution (logMAR) notations. RESULTS: Overall, the mean Snellen VA was 0.78 logMAR (= 20/120), and the mean ETDRS VA in the same eye was 0.54 logMAR (= 20/70; P<0.001). In the low vision group (<20/200), represented by patients with AMD, the average difference in number of lines was considerably larger than in the good vision range (>20/30). On average, 20/200 on Snellen was 20/95 on ETDRS (>3 lines difference), and 20/30 on Snellen was 20/25 on ETDRS (<1 line difference). CONCLUSION: Our results show poor agreement between the Snellen and ETDRS charts, and it was more pronounced in the group with poor vision. The ETDRS measurements yielded better VA, particularly in participants with vision <20/200 (representing more advanced AMD patients). We suggest taking these findings into consideration when comparing outcomes in clinical practices (which typically measure VA using standard Snellen charts) with outcomes from clinical trials (which typically measure VA using ETDRS charts). PMID- 17706290 TI - Vision and precision reaching in 15-month-old infants. AB - Visual information about the location of the hand in space plays a key role in many theories of the development of reaching. Empirical data casts doubt on this assumption, although vision of the hand is clearly used by adults. The current study investigated the role of vision in 15-month-olds' reaching, manipulating both the precision demands of the task and the level of visual information available. Infants reached for both large and small objects, presented with visual feedback of the target and hand (full lighting), or with visual feedback of only the target object (glowing object in the dark). In contrast to findings with younger infants, 15-month-olds' reaches were sensitive to changes in precision demands and visual feedback, reflecting corrective movements that become necessary as reaching tasks become more challenging. Furthermore, these kinematic alterations are similar to those seen in adults, suggesting that visual guidance may become more important over the course of development, as infants engage in increasingly higher precision tasks. PMID- 17706292 TI - High-resolution EEG techniques for brain-computer interface applications. AB - High-resolution electroencephalographic (HREEG) techniques allow estimation of cortical activity based on non-invasive scalp potential measurements, using appropriate models of volume conduction and of neuroelectrical sources. In this study we propose an application of this body of technologies, originally developed to obtain functional images of the brain's electrical activity, in the context of brain-computer interfaces (BCI). Our working hypothesis predicted that, since HREEG pre-processing removes spatial correlation introduced by current conduction in the head structures, by providing the BCI with waveforms that are mostly due to the unmixed activity of a small cortical region, a more reliable classification would be obtained, at least when the activity to detect has a limited generator, which is the case in motor related tasks. HREEG techniques employed in this study rely on (i) individual head models derived from anatomical magnetic resonance images, (ii) distributed source model, composed of a layer of current dipoles, geometrically constrained to the cortical mantle, (iii) depth-weighted minimum L(2)-norm constraint and Tikhonov regularization for linear inverse problem solution and (iv) estimation of electrical activity in cortical regions of interest corresponding to relevant Brodmann areas. Six subjects were trained to learn self modulation of sensorimotor EEG rhythms, related to the imagination of limb movements. Off-line EEG data was used to estimate waveforms of cortical activity (cortical current density, CCD) on selected regions of interest. CCD waveforms were fed into the BCI computational pipeline as an alternative to raw EEG signals; spectral features are evaluated through statistical tests (r(2) analysis), to quantify their reliability for BCI control. These results are compared, within subjects, to analogous results obtained without HREEG techniques. The processing procedure was designed in such a way that computations could be split into a setup phase (which includes most of the computational burden) and the actual EEG processing phase, which was limited to a single matrix multiplication. This separation allowed to make the procedure suitable for on-line utilization, and a pilot experiment was performed. Results show that lateralization of electrical activity, which is expected to be contralateral to the imagined movement, is more evident on the estimated CCDs than in the scalp potentials. CCDs produce a pattern of relevant spectral features that is more spatially focused, and has a higher statistical significance (EEG: 0.20+/-0.114 S.D.; CCD: 0.55+/-0.16 S.D.; p=10(-5)). A pilot experiment showed that a trained subject could utilize voluntary modulation of estimated CCDs for accurate (eight targets) on-line control of a cursor. This study showed that it is practically feasible to utilize HREEG techniques for on line operation of a BCI system; off-line analysis suggests that accuracy of BCI control is enhanced by the proposed method. PMID- 17706294 TI - Further analysis of anti-human leukocyte mAbs with reactivity to equine leukocytes by two-colour flow cytometry and immunohistochemistry. AB - We have reported on the reactivity of anti-human CD molecules with equine leukocytes by single-colour flow cytometry (this issue). The objectives of this additional study were to test for the reliability of the results obtained, and to obtain further information on the positive populations of lymphocytes. Two-colour flow cytometry and immunohistochemistry were performed, using many of the positive mAbs and a few questionable ones from the first part of the study. All mAbs analysed by two-colour flow cytometry could be confirmed to their previous designation as "positive" or "questionable". Most of the mAbs tested were effective in immunohistochemistry, supporting previous results. Examples of positive results will be presented and limitations of the study will be discussed briefly. PMID- 17706293 TI - A DNA vaccine against dolphin morbillivirus is immunogenic in bottlenose dolphins. AB - The immunization of exotic species presents considerable challenges. Nevertheless, for facilities like zoos, animal parks, government facilities and non-profit conservation groups, the protection of valuable and endangered species from infectious disease is a growing concern. The rationale for immunization in these species parallels that for human and companion animals; to decrease the incidence of disease. The U.S. Navy Marine Mammal Program, in collaboration with industry and academic partners, has developed and evaluated a DNA vaccine targeting a marine viral pathogen - dolphin morbillivirus (DMV). The DMV vaccine consists of the fusion (F) and hemagglutinin (H) genes of DMV. Vaccine constructs (pVR-DMV-F and pVR-DMV-H) were evaluated for expression in vitro and then for immunogenicity in mice. Injection protocols were designed for application in Atlantic bottlenose dolphins (Tursiops truncatus) to balance vaccine effectiveness with clinical utility. Six dolphins were inoculated, four animals received both pDMV-F and pDMV-H and two animals received a mock vaccine (vector alone). All animals received an inoculation week 0, followed by two booster injections weeks 8 and 14. Vaccine-specific immune responses were documented in all four vaccinated animals. To our knowledge, this is the first report of pathogen-specific immunogenicity to a DNA vaccine in an aquatic mammal species. PMID- 17706295 TI - Polymorphism of Toll-like receptor 9 (TLR9) gene in sheep. AB - Bacterial and synthetic DNA containing unmethylated CpG dinucleotides in particular sequence contexts, activates the vertebrate immune system through Toll like receptor 9 (TLR9). In this study, we use PCR-single-strand conformational polymorphism (PCR-SSCP) analysis to investigate genetic variation in a key region of the ovine TLR9 gene. Three novel SSCP patterns, representing three different sequences, were identified. Either one or two different sequences were detected in individual sheep and all the sequences identified shared high homology to the TLR9 sequences from a variety of species, suggesting that these sequences represent allelic variants of the ovine TLR9 gene. Four single nucleotide polymorphisms (SNPs) were detected in the region amplified and two of them were non-synonymous substitutions that would result in amino acid changes. Variation detected here might have an impact on the structure and/or function of TLR9 and hence affect the immune response to pathogens. PMID- 17706297 TI - Grisel's syndrome in otolaryngology: a systematic review. AB - AIMS: to assess etiology, treatment and outcome of Grisel's syndrome. METHODS: A Medline search was performed using the terms Grisel's syndrome, spontaneous atlantoaxial subluxation, head, neck, ear, nose and throat. A systematic review of the literature was performed. Case series of both adult and pediatric cases were included. Only papers focusing on true non-traumatic atlantoaxial subluxation were included. RESULTS: Seventy-one papers have been published from 1950 to 2006. Forty-eight of these fulfilled our inclusion criteria, totaling 103 patients for review. The main causes of Grisel's syndrome were infection (48%) and post-adenotonsillectomy (31%). Less common causes included other postoperative cases such as pharyngoplasty and ear operations. Neurosurgical consultation was paramount in all cases. In the majority of cases conservative management in the form of bedrest, antibiotics, muscle relaxants, traction and collar was effective; in a few cases only surgery in the form of arthrodesis was deemed necessary. Morbidity was significant in those cases where diagnosis was delayed, with the most devastating consequence a permanent neurological deficit in one case. CONCLUSIONS: Grisel's syndrome is a rare but dangerous complication that can go unnoticed in its early phase and can be a major cause of morbidity and mortality following infection or head and neck procedures/interventions. Early recognition of any cervical complication following routine otolaryngological operations together with early neurosurgical consultation is mandatory to prevent devastating consequences. PMID- 17706298 TI - Development of a dipstick immunoassay to detect nucleopolyhedroviruses in Douglas fir tussock moth larvae. AB - In this paper, we describe the development of a novel field detection system for the identification of Orgyia pseudotsugata nucleopolyhedrovirus (OpNPV) and OpNPV infections in Douglas-fir tussock moth (O. pseudotsugata) (DFTM) larvae, utilizing antibodies in a dipstick immunoassay. The dipstick method is sensitive to a minimum of 10ng of extracted virus protein, or approximately 1070 virus occlusion bodies, and is sufficiently sensitive to detect OpNPV infections in DFTM prior to mortality. Additionally, the method can be used to unambiguously detect virus in infected larvae without purification of the test sample. This research provides a novel tool for on-site assessment of the incidence of OpNPV in field populations of DFTM, and has the potential to improve the biological control of the DFTM by facilitating on-site pest management decisions. PMID- 17706296 TI - Immune responses of swine inoculated with a recombinant fowlpox virus co expressing P12A and 3C of FMDV and swine IL-18. AB - Two recombinant fowlpox viruses (rFPV-P1 and rFPV-IL18-2AP12A) containing foot and-mouth disease virus (FMDV) capsid polypeptide, 3C coding regions of O/NY00 were evaluated to determine their abilities to induce humoral and cellular responses in the presence or absence of swine IL-18 as genetic adjuvant. The ability to protect swine against homologous virus challenge was examined. All swine were given booster vaccinations at 21 days after the initial inoculation and were challenged 10 days after the booster vaccination. Control groups were inoculated with wild-type fowlpox virus (wtFPV). All animals vaccinated with rFPV P12A and rFPV-IL18-P12A developed specific anti-FMDV ELISA antibody and neutralizing antibody and T-lymphocyte proliferation was observed. Cellular immune function was evaluated via examination of IFN-gamma production in swine peripheral blood serum. The results demonstrate the potential viability of a fowlpox virus-based recombinant vaccine in the control and prevention of FMDV infections. PMID- 17706300 TI - Coronary-subclavian steal syndrome: an usual cause of refractory unstable angina. AB - A 73 year old woman, with previous history of coronary artery bypass grafting, was admitted for refractory unstable angina. The angiography revealed a significant stenosis of the ostium of the left subclavian artery. The patient underwent successful stenting of the subclavian artery and remained symptom free until hospital discharge a few days later. PMID- 17706299 TI - JBP2, a SWI2/SNF2-like protein, regulates de novo telomeric DNA glycosylation in bloodstream form Trypanosoma brucei. AB - Synthesis of the modified thymine base, beta-d-glucosyl-hydroxymethyluracil or J, within telomeric DNA of Trypanosoma brucei correlates with the bloodstream form specific epigenetic silencing of telomeric variant surface glycoprotein genes involved in antigenic variation. In order to analyze the function of base J in the regulation of antigenic variation, we are characterizing the regulatory mechanism of J biosynthesis. We have recently proposed a model in which chromatin remodeling by a SWI2/SNF2-like protein (JBP2) regulates the developmental and de novo site-specific localization of J synthesis within bloodstream form trypanosome DNA. Consistent with this model, we now show that JBP2 (-/-) bloodstream form trypanosomes contain five-fold less base J and are unable to stimulate de novo J synthesis in newly generated telomeric arrays. PMID- 17706301 TI - Surgical vs. percutaneous atrial septal defect closure: Remote effects on left ventricular diastolic function. AB - While surgical closure used to be the only treatment for atrial septal defects (ASD), recently, placement of an occluding device has become the treatment of choice for this condition. We sought to study the remote effects of surgical vs. device ASD closure on the indices of left ventricular diastolic function. Forty patients--16 after device and 19 after surgical closure--were evaluated at least 1 year after the procedure. Mitral inflow and tissue Doppler indices were studied. The results were compared to those of 65 control subjects. The early mitral inflow velocities E were higher in controls and E/A ratios were different among all 3 groups. Late diastolic A' TDI velocities were higher in both device and surgical group patients and more different from the controls in surgical than in device group. It appears that surgical ASD closure alters left ventricular diastolic indices more significantly than device ASD closure. PMID- 17706302 TI - Transient left apical ballooning syndrome--the need for a common terminology? A reply. AB - The apical ballooning syndrome, called also transient left ventricular apical ballooning syndrome or Tako-tsubo cardiomyopathy is a new syndrome that mimics acute myocardial infarction. The authors comment the statement of Dr Parodi who recommended a new denomination of neuromediated myocardial stunning. According to many different denominations of the syndrome and over 25 years history of research on it, the authors recommended a name of "transient left ventricular ballooning syndrome (TLVBS)" and pursued to goal a new expert consensus. PMID- 17706303 TI - Cerebral infarction in an adult patient with right ventricular hypertrabeculation/noncompaction. AB - Ventricular hypertrabeculation/noncompaction (VHT) is a rare congenital anomaly, and usually involves the left ventricle (LVHT), with the right ventricle (RVHT) being infrequently involved. Clinical manifestations are highly variable, ranging from no symptoms to disabling congestive heart failure, arrhythmias, systemic thromboemboli and sudden death. We report a case of right ventricular hypertrabeculation/noncompaction (RVHT) presenting as cerebral infarction. PMID- 17706291 TI - "Listening" and "talking" to neurons: implications of immune activation for pain control and increasing the efficacy of opioids. AB - It is recently become clear that activated immune cells and immune-like glial cells can dramatically alter neuronal function. By increasing neuronal excitability, these non-neuronal cells are now implicated in the creation and maintenance of pathological pain, such as occurs in response to peripheral nerve injury. Such effects are exerted at multiple sites along the pain pathway, including at peripheral nerves, dorsal root ganglia, and spinal cord. In addition, activated glial cells are now recognized as disrupting the pain suppressive effects of opioid drugs and contributing to opioid tolerance and opioid dependence/withdrawal. While this review focuses on regulation of pain and opioid actions, such immune-neuronal interactions are broad in their implications. Such changes in neuronal function would be expected to occur wherever immune-derived substances come in close contact with neurons. PMID- 17706304 TI - Safety and efficacy of granulocyte colony-stimulating factor for patients with recent myocardial infarction: a meta-analysis. PMID- 17706305 TI - Progressive intrapulmonary shunting in a child after bidirectional Glenn operation only resolved after total cavopulmonary completion. AB - We report on a girl with progressive intrapulmonary shunting after bidirectional Glenn (BDG) operation and resolution of these microscopic fistulas after completion to total cavopulmonary connection (TCPC). PMID- 17706306 TI - Evaluation of source displacement and dose--volume changes after permanent prostate brachytherapy with stranded seeds. AB - BACKGROUND AND PURPOSE: The aim of the study was to analyze source displacements and dose-volume changes in the first month after a permanent implant. MATERIALS AND METHODS: In 51 consecutive patients, CT scans were performed at the postoperative day (day 1) and one month (day 30) after an (125)I implant with stranded seeds. Seed positions were determined relative to pelvic bones for five seeds at the base and five seeds at the apex for each patient (n=510) and compared. To verify these results, treatment margins (TM=distance of prescription isodose to prostate) and displacements of the prostate surface (anterior/posterior/right/left/superior/inferior) relative to pelvic bones were measured. RESULTS: Seed positions have moved significantly between day 1 and 30 in the posterior (mean 1.0mm; p<0.001) and inferior (mean 3.8mm; p<0.001) directions. TM increased particularly at the posterior (mean 2.2mm; p<0.001) and apical (median 3.0mm; p<0.001) prostate contour with decreasing oedema. With a stable apex position and a mean inward posterior surface displacement of 1.1mm (p<0.001) relative to pelvic bones, seed displacements could be well correlated with prescription isodose displacements (Pearson correlation coefficients >or=0.81; p<0.001). CONCLUSIONS: Both changes of prostate volume and seed displacements need to be considered to explain dosimetric changes after permanent prostate brachytherapy. PMID- 17706307 TI - Guidelines for target volume definition in post-operative radiotherapy for prostate cancer, on behalf of the EORTC Radiation Oncology Group. AB - The appropriate application of 3-D conformal radiotherapy, intensity modulated radiotherapy or image guided radiotherapy for patients undergoing post-operative radiotherapy for prostate cancer requires a standardisation of the target volume definition and delineation as well as standardisation of the clinical quality assurance procedures. Recommendations for this are presented on behalf of the European Organisation for Research and Treatment of Cancer (EORTC) Radiation Oncology Group and in addition to the already published guidelines for radiotherapy as the primary treatment. PMID- 17706308 TI - Significant reduction of acute toxicity following pelvic irradiation with helical tomotherapy in patients with localized prostate cancer. AB - PURPOSE: To assess and quantify the possible benefit deriving from IMRT with Helical Tomotherapy (HTT) delivery to the pelvic nodal area in patients with prostate cancer in terms of reduction of acute and late toxicities. METHODS AND MATERIALS: Thirty-five patients candidate to radical or postoperative RT on whole pelvis (WPRT) were treated with HTT, while receiving a concomitant boost to the prostate or the prostatic bed (median 74.2 and 72 Gy, respectively) within a moderately hypofractionated (28-33 fractions; median HTT duration 44 days) regimen. Median and mean doses to whole pelvis were 52 and 54 Gy, respectively. One of the major goals of planning optimisation was to minimize the dose received by the intestinal cavity (IC) outside the nodal PTV. RESULTS: HTT resulted to be very efficient in sparing the IC even at dose levels below 30-35 Gy and guaranteed a significant sparing of bladder and rectum even at intermediate-low doses (V20-V40). No acute Grade 3 RTOG toxicity was recorded. Eighteen G1 and two G2 GU acute toxicities, 13 G1 upper GI acute toxicities, 8 G1 and 1 G2 acute proctitis were observed; no patient experienced G2 upper GI toxicity. After a median FU of 11.5 months (>10 in 18 patients) one case of late G3 GU toxicity was reported in one post-prostatectomy treated patient; no G2 late rectal bleeding or other GI toxicity was recorded. CONCLUSIONS: WPRT with HTT resulted in a very low incidence of acute Grade 2 and in the disappearance of acute Grade 3 toxicities. PMID- 17706309 TI - Set-up errors due to endorectal balloon positioning in intensity modulated radiation therapy for prostate cancer. AB - PURPOSE: To investigate the set-up errors and deformation associated with daily placement of endorectal balloons in prostate radiotherapy. MATERIALS AND METHODS: Endorectal balloons were placed daily in 20 prostate cancer patients undergoing radiotherapy. Electronic portal images (EPIs) were collected weekly from anterior posterior (AP) and lateral views. The EPIs were compared with digitally reconstructed radiographs from computed tomography scans obtained during pretreatment period to estimate displacements. The interfraction deformation of balloon was estimated with variations in diameter in three orthogonal directions throughout the treatment course. RESULTS: A total of 154 EPIs were evaluated. The mean displacements of balloon relative to bony landmark were 1.8mm in superior inferior (SI), 1.3mm in AP, and 0.1mm in left-right (LR) directions. The systematic errors in SI, AP, and LR directions were 3.3mm, 4.9 mm, and 4.0mm, respectively. The random (interfraction) displacements, relative to either bony landmarks or treatment isocenter, were larger in SI direction (4.5mm and 4.5mm), than in AP (3.9 mm and 4.4mm) and LR directions (3.0mm and 3.0mm). The random errors of treatment isocenter to bony landmark were 2.3mm, 3.2mm, and 2.6mm in SI, AP, and LR directions, respectively. Over the treatment course, balloon deformations of 2.8mm, 2.5mm, and 2.6mm occurred in SI, AP, and LR directions, respectively. The coefficient of variance of deformation was 7.9%, 4.9%, and 4.9% in these directions. CONCLUSIONS: Larger interfractional displacement and the most prominent interfractional deformation of endorectal balloon were both in SI direction. PMID- 17706310 TI - A special device (double-hole belly board) and optimal radiation technique to reduce testicular radiation exposure in radiotherapy of rectal cancer. AB - PURPOSE: Patients with rectal cancer are treated in prone position on a belly board to reduce the volume of irradiated small bowel. With this technique the testes obtain radiation doses, which often result in partial or complete impairment of the spermatogenesis and a dose-dependent decrease of testosterone levels. We developed a double-hole belly board (DHBB) and evaluated its potential to reduce testicular dose. METHODS AND MATERIALS: In nine consecutive male patients (3 very low tumor localisations [inguinal RT], 3 low [RT perineum], 3 high [lower border ischial tuberosities]) CT scans were performed on a conventional single-hole belly board (SHBB) and on a DHBB. Dose-volume histograms of the testes were analysed for both belly boards and for different treatment techniques (3-field and 4-field). RESULTS: To reduce testicular dose in high tumors, positioning on DHBB was most effective (V(1.5Gy) 20-30% vs. 60% for SHBB, V(4Gy) 7% vs. 35%). In low tumors, a 3-field technique reduced high testicular doses (V(14Gy) 0-6% vs. 28-34% for 4-fields). In very low tumors a combination of DHBB and 3-fields led to a decrease of high dose exposure (V(33Gy) 0% vs. 24 78%). CONCLUSION: In male patients with rectal cancer the use of a DHBB and a 3 field technique is recommended to reduce testicular radiation exposure. PMID- 17706311 TI - Cardiac defense: from attention to action. AB - The concept of defense relates to the idea that organisms react physiologically to the presence of danger or threat in order to protect themselves from potential injury or death. This article reviews the literature on cardiac defense, a specific defense reaction that has a long tradition in psychophysiological research. The review begins with a brief analysis of the two traditional approaches to understand this autonomic response: the cognitive -- linked to Pavlov, Sokolov, and Graham's work on sensory reflexes -- and the motivational -- linked to Cannon and Selye's work on the concepts of activation and stress. Then, the classic model of cardiac defense and its basic assumptions concerning differentiation from other cardiac reflexes -- namely orienting and startle -- are presented. A critical analysis of these assumptions follows centered on evidence from a systematic research of the cardiac response to intense acoustic stimulation. Finally, an integrative model of cardiac defense is presented which emphasizes the dynamic nature of this defense reaction - characterized by a complex pattern of heart rate changes with accelerative and decelerative components, with sympathethic and parasympathetic influences, and with both attentional and motivational significance - providing a new framework in which the two opposite traditional approaches can be reconciled. PMID- 17706313 TI - Estimating mycotoxin contents of Fusarium-damaged winter wheat kernels. AB - Winter wheat (Triticum aestivum L., cultivars Ritmo and Dekan) grain was sampled in Northern Germany between 2001 and 2006. Kernels damaged by fungi of the genus Fusarium were separated from sound grain by visual assessment. Samples containing 0%, 20%, 40%, 60%, 80% and 100% of Fusarium-damaged kernels were compiled and analyzed for the Fusarium type B trichothecenes deoxynivalenol (DON, 2001-2006), nivalenol (NIV, 2006), 3-acetyl-deoxynivalenol (3AcDON, 2006) and 15-acetyl deoxynivalenol (15AcDON, 2006). The relationship between mycotoxin contents and the percentage of Fusarium-damaged kernels was calculated for each lot of grain. Apart from one exception, relationships between the percentage of Fusarium damaged kernels and NIV, 3AcDON or 15AcDON were non-significant. In contrast, close relationships between the percentage of Fusarium-damaged kernels and the DON content were observed (r(2)=0.93-0.99). The y-axis intercepts were not significantly different from zero, but the DON content of the damaged kernels varied by a factor of 11.59 between years and by a factor of 1.87 between cultivars. Fusarium-damaged kernels contained between 0.21 and 2.39 microg DON kernel(-1). The overall average DON content of a Fusarium-damaged wheat kernel was 1.29 +/- 0.11 microg. The DON content of diseased kernels was affected by environment and wheat genotype but not by genotype x environment interaction. On average, Fusarium-damaged kernels contained 9.7-fold more DON than 15AcDON, 19.5 fold more DON than NIV, and 26.9-fold more DON than 3AcDON. 3AcDON and 15AcDON contents per wheat kernel were not significantly different between cultivars. On average, 4.27% of Fusarium-damaged kernels were sufficient to reach the 1.25 mg DON kg(-1) grain limit for unprocessed cereals in the EU. Given the low percentages of Fusarium-damaged kernels that are equivalent to current legal DON limits, grading accuracies >96% would be needed when using automatic grading systems for separating sound from damaged kernels. PMID- 17706315 TI - Phylogenetic characterization of porcine circovirus type 2 in PMWS and PDNS Korean pigs between 1999 and 2006. AB - Porcine circovirus type 2 (PCV2) has been associated with several disease outcomes in swine, primarily postweaning multisystemic wasting syndrome (PMWS) and porcine dermatitis nephropathy syndrome (PDNS). Over an 8-year period (1999 2006), we detected 36 PCV2 strains from PMWS and PDNS cases. Complete genes of the detected PCV2 strains were sequenced and analyzed. The sequences encoding a putative capsid protein, ORF2, of 233 PCV2 strains, isolated in Korea and throughout the world, could be divided into two groups (1 and 2) by phylogenetic tree analysis and multiple alignments of nucleotide sequences. Group 1 has the sequence CCCCG/TC and group 2 has the sequence AAAATC at nucleotides 262-267 of ORF2. Group 1 has PR/L and 2 has KI at amino-acid positions 88-89 of ORF2. Of the 233 PCV2 strains, 153 (65.7%) were placed in group 1 and 80 (34.4%) were in group 2 by phylogenetic characterization analysis using CLUSTER X 1.83, Puzzle 5.2, and PHYLIP 3.66 software package. Geographical analysis showed that PCV2 strains detected from the Netherlands, Thailand, and the United Kingdom were included in group 1. In contrast, PCV2 isolates from Japan, Canada, Spain, Taiwan, and South Africa belonged to group 2. Both groups were found in isolates from Korea, France, Hungary, Austria, Germany, Brazil, and the United States. Pathogenic analysis showed that PCV2 isolates from healthy pigs and from PDNS cases also fell into the two groups. PCV2 isolates from PMWS cases induced by PCV2 alone also fell into both groups. PMID- 17706314 TI - Parallel microfluidic networks for studying cellular response to chemical modulation. AB - A microfluidic chip featuring parallel gradient-generating networks etched on glass plate was designed and fabricated. The dam and weir structures were fabricated to facilitate cell positioning and seeding, respectively. The microchip contains five gradient generators and 30 cell chambers where the resulted concentration gradients of drugs are delivered to stimulate the on-chip cultured cells. This microfluidics exploits the advantage of lab-on-a-chip technology by integrating the generation of drug concentration gradients and a series of cell operations including seeding, culture, stimulation and staining into a chip. Steady parallel concentration gradients were generated by flowing two fluids in each network. The microchip described above was applied in studying the role of reduced glutathione (GSH) in MCF-7 cells' chemotherapy sensitivity. The parental breast cancer cell line, MCF-7 and the derived adriamycin resistant cell line MCF-7(adm) were treated with concentration gradients of arsenic trioxide (ATO) and N-acetyl cysteine (NAC) for GSH modulation, followed by exposure to adriamycin. The intracellular GSH level and cell viability were assessed by fluorescence image analysis. GSH levels of both cell lines were down regulated upon ATO treatment and up-regulated upon NAC treatment. For both cell lines, suppression of intracellular GSH by treatment with ATO has been shown to increase chemotherapy sensitivity; conversely, elevation of intracellular GSH by treatment with NAC leads to increased drug resistance. The results indicated that high intracellular GSH level has negative effect on chemotherapy sensitivity, while depletion of cellular GSH may serve as an effective way to improve chemotherapy sensitivity. The integrated microfluidic chip is able to perform multiparametric pharmacological profiling with easy operation, thus, holds great potential for extrapolation to the high-content drug screening. PMID- 17706317 TI - Social inequality in health: dichotomy or gradient? A comparative study of problematizations in national public health programmes. AB - Recent public health programmes from four countries: Denmark, England, Norway, and Sweden, are studied to analyse how social inequality in health is described, explained and suggested to be tackled, i.e., the problematization or the discursive process whereby the issue is framed and made accessible to political action. Social inequality in health is defined in these programmes both as a disadvantaged minority with major health problems, in contrast to the rest of the population, i.e., as a dichotomy; and as a gradient in which health problems are seen as increasing with lower social class or educational level. The causes of health inequality are identified as behaviour, social relations and underlying social structures. Policies aimed at reducing health inequality can be characterized as either in accordance with a residual welfare state model, targeting the disadvantaged, or a universal model, addressing the whole population. All countries have policies that are mixtures of these problematizations, but with some systematic differences between the countries. In this field England resembles the Scandinavian countries, as much as they resemble each other dispelling the idea of a Nordic or Scandinavian welfare state model. PMID- 17706312 TI - Evidence for a distributed hierarchy of action representation in the brain. AB - Complex human behavior is organized around temporally distal outcomes. Behavioral studies based on tasks such as normal prehension, multi-step object use and imitation establish the existence of relative hierarchies of motor control. The retrieval errors in apraxia also support the notion of a hierarchical model for representing action in the brain. In this review, three functional brain imaging studies of action observation using the method of repetition suppression are used to identify a putative neural architecture that supports action understanding at the level of kinematics, object centered goals and ultimately, motor outcomes. These results, based on observation, may match a similar functional-anatomic hierarchy for action planning and execution. If this is true, then the findings support a functional-anatomic model that is distributed across a set of interconnected brain areas that are differentially recruited for different aspects of goal-oriented behavior, rather than a homogeneous mirror neuron system for organizing and understanding all behavior. PMID- 17706318 TI - Model-based assessment of insulin sensitivity of glucose disposal and endogenous glucose production from double-tracer oral glucose tolerance test. AB - A new mathematical model of short-term glucose regulation by insulin is proposed to exploit the oral glucose tolerance test (OGTT), which is commonly used for clinical diagnosis of glucose intolerance and diabetes. Contributions of endogenous and exogenous sources to measured plasma glucose concentrations have been separated by means of additional oral administration and constant intravenous infusion of glucose labeled with two different tracers. Twelve type 2 diabetic patients (7 males and 5 females) and 10 control subjects (5 males and 5 females) with normal glucose tolerance and matched body mass index (BMI) participated in this study. Blood samples for measurement of concentrations/activity of unlabeled and double-tracer glucose and insulin were collected every 15 min for 3 h following the oral glucose load. A minimal model combined with non-linear mixed-effects population parameter estimation has been devised to characterize group-average and between-patient variability of: (i) gastrointestinal glucose absorption; (ii) endogenous glucose production (EGP), and (iii) glucose disposal rate. Results indicate that insulin-independent glucose clearance does not vary significantly with gender or diabetic state and that the latter strongly affects, as expected, insulin-dependent clearance (insulin sensitivity). Inhibition of EGP, interpreted in terms of variations from basal of insulin concentrations, does not appear to be affected by diabetes but rather by BMI, i.e. by the degree of obesity. This study supports the utility of a minimal modelling approach, combined with population parameter estimation, to characterize glucose absorption, production and disposition during double-tracer OGTT experiments. The model provides a means for planning further experiments to validate the new hypothesis on the influence of individual factors, such as BMI and diabetes, on glucose appearance and disappearance, and for designing new simplified clinical tests. PMID- 17706319 TI - Fast collision detection based on nose augmentation virtual surgery. AB - Collision detection is the key technology in nose augmentation surgery simulation system, which can avoid incorrect intersection between bones and the implant model. In this paper, we present a sphere-tree-based hierarchical collision detection algorithm (STHCD) for surgery simulation. Each model is represented as a clustered hierarchy of sphere tree (CHST). Graphics processing unit (GPU)-based occlusion queries were used for fast collision culling between massive models. Furthermore, we are able to generate these hierarchies and perform collision queries using out-of-core techniques on all triangulated models. Experimental results show that STHCD performs real-time collision detection between massive bones and implant models, consisting of millions of triangles at interactive rates on a commodity PC. PMID- 17706320 TI - Tumour cell expression of C4.4A, a structural homologue of the urokinase receptor, correlates with poor prognosis in non-small cell lung cancer. AB - PURPOSE: C4.4A expression has been implicated in human cancer progression. This protein is a structural homologue of the urokinase receptor, uPAR, which constitutes a well-established prognostic marker in various human cancers. Nonetheless, little is known about the prognostic significance of C4.4A expression. In the present study, we therefore explored the possible association between C4.4A expression and prognosis in patients with non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Tissue sections from 108 NSCLC patients were subjected to immunohistochemical staining using a polyclonal antibody that specifically recognises human C4.4A. Staining frequency and intensity was scored semiquantitatively and grouped into cancers with high and low expression of C4.4A. Kaplan-Meier survival curves were generated to evaluate the significance of C4.4A expression in prognosis of NSCLC patients. RESULTS: High C4.4A expression was observed in 42% of the NSCLC specimens analysed, and this correlates with overall survival (p = 0.012). A remarkably strong correlation was noted between high expression of C4.4A in pulmonary adenocarcinoma and survival (p < 0.0001). Multivariate Cox regression analysis shows that high C4.4A expression is an independent predictor of poor disease outcome in NSCLC (risk ratio, 1.42; 95% confidence interval, 1.09-1.86; p = 0.009). Although histological type is not a predictor of outcome in NSCLC, high C4.4A expression in adenocarcinoma is nevertheless a very strong predictor of poor disease outcome (risk ratio, 1.62; 95% confidence interval, 1.24-2.09; p = 0.001). CONCLUSIONS: High tumour cell C4.4A expression is associated with shorter survival for NSCLC patients. Patients with pulmonary adenocarcinoma have a particularly poor prognosis if this histological type is combined with high tumour cell C4.4A expression. PMID- 17706321 TI - The solitary lymphomatous papule, nodule, or tumor. AB - BACKGROUND: Lymphoma and reactive lymphoid infiltrates presenting as solitary lesion pose a diagnostic and prognostic dilemma for the clinician. OBJECTIVE: We sought to review prognosis and treatment of suggestive solitary lymphoma lesions. METHODS: A retrospective chart review was conducted in 27 patients who presented with a single solitary lesion suggestive of lymphoma at a cancer center. RESULTS: Eighteen of 27 patients' (66.7%) lesions were diagnosed as lymphoma by histology and the remainder was classified as reactive lymphoid infiltrates. Only one patient's lymphoma was systemic at presentation and one progressed later. In all, 23 patients (85.2%) subsequently experienced prolonged, complete remissions. The treatments used varied from none or conservative to chemotherapy, with the more aggressive treatments directed especially against lymphomas or recurrent diseases. LIMITATIONS: This study is limited by the number of patients and follow up duration (average 36.8 months, range 3-133 months). CONCLUSION: Patients presenting with a solitary lesion suggestive of lymphoma and negative staging work-up results generally have a good prognosis. Excellent prognosis is usually expected for benign lesions. PMID- 17706322 TI - Are patients with psoriasis undertreated? Results of National Psoriasis Foundation survey. AB - OBJECTIVE: We sought to assess whether patients with psoriasis with moderate or severe disease are being treated with systemic therapy. METHODS: Participants were identified from a random sample of the National Psoriasis Foundation contact database who were 18 years and older, with severe psoriasis (>10% body surface area) and moderate psoriasis (3%-10% body surface area); respondents with psoriatic arthritis were excluded. RESULTS: In all, 1657 respondents with psoriasis completed the survey (28% severe, 41% moderate). A total of 39% of respondents with severe psoriasis and 37% with moderate psoriasis were not currently receiving any treatment. Among respondents currently receiving therapy, only 43% of respondents with severe psoriasis received either traditional systemic therapy, biologic therapy, or phototherapy. LIMITATIONS: Respondents were from the National Psoriasis Foundation contact database and reported their current severity, which may be affected by their treatment. Body surface area as a measure of patient-reported severity has not been validated but has been used in several published studies. CONCLUSIONS: Almost 40% of respondents with psoriasis were currently not receiving treatment. For respondents with severe psoriasis, 26% were treated with systemic therapy, phototherapy, or both; 39% were not in treatment; and 35% were treated with topical therapy alone. PMID- 17706323 TI - Effects of streptozotocin-induced diabetes on the uterine adrenergic nerve function in pregnant rats. A superfusion study. AB - Pregnancy-induced diabetes mellitus poses one of the greatest challenges in obstetrical practice. The direct action of diabetes on the myometrial adrenergic functions has not been completely characterized. Accordingly, the present study relates to the impact of experimentally induced diabetes on the presynaptic functions of the rat uterus in relation to gestational age. Experiments were carried out on non-pregnant, early-pregnant (day 7), middle-pregnant (day 14) and late-pregnant (day 21) animals. Diabetes was induced with streptozotocin (60 mg/kg, i.v.) in virgin female or early-pregnant animals (on day 2 for the day 7 experiments and on day 5 for the experiments on the middle and late-pregnant animals). Myometrial samples were utilized for superfusion experiments. After saturation, [3H]noradrenaline perfusate fractions were collected and electric field stimulation was applied to determine the amount of transmitter liberated. Additionally, the total uptake capacity of each sample was assayed. Experimental diabetes decreases the transmitter uptake capacity both in virgin rats and at all stages of pregnancy. In early pregnancy (on day 7), this limitation in uptake is obvious as early as 5 days after the induction of diabetes. In non-pregnant animals, the electrically stimulated transmitter release is inhibited substantially, a similar decrease being observed only at mid-pregnancy (day 14). The present superfusion study proves that experimental diabetes depresses the presynaptic adrenergic functions (both the transmitter uptake and the stimulated release) in the myometrium of the rat. Since the effect of diabetes on the uptake capacity can be detected earlier than for generally accepted markers of peripheral neuropathies, superfusion can be suggested as a sensitive and reliable approach for investigations of hyperglycaemia-related functional deteriorations. We speculate that diabetes-induced functional deterioration of the adrenergic nerves could partially explain the anomalies of the reproductive functions found in diabetic patients if a similar mechanism is operative in humans. PMID- 17706324 TI - Molecular determinants of Pb2+ interaction with NMDA receptor channels. AB - Lead (Pb2+) is a potent neurotoxin that acts as a non-competitive, voltage independent antagonist of the NMDA receptor (NR) channel. Pb2+ action partially overlaps with that of zinc (Zn2+), but precise coincidence with Zn2+ binding site is debated. We investigated the site of Pb2+ interaction in NR channels expressed in Xenopus laevis oocytes from the clones zeta1, epsilon1 or epsilon2 and mutated epsilon1 or epsilon2 forms. For each epsilon subunit we chose two mutations that have been identified as 'strong mutations' for Zn2+ binding and examined the effect of Pb2+ on channels that contained those mutations. In epsilon1-containing channels, mutations D102A and H128A caused a decrease of Pb2+ inhibition with a 10-fold (D102A) and four-fold (H128A) shift of IC50. In epsilon2-containing channels, the most effective mutation in removing Pb2+ inhibition was H127A, with a five-fold increase of IC50, while D101A was virtually ineffective. Other mutations, D104A, T103A, and T233A, were less effective. The double mutation D101AH127A, while reducing Zn2+ inhibition by nearly nine-fold, caused a minor (less than two-fold) shift in Pb2+ IC50. Competition experiments showed that increasing doses of Zn2+ reduced the apparent affinity for Pb2+ in epsilon1 containing receptors, but not in epsilon2-containing receptors. In addition the effect of Pb2+ on epsilon2-containing channels was additive with that of ifenprodil, with no competition for the site. Although none of the mutations that we have tested abolished the block by Pb2+, our results indicate that the action of this toxic metal on NR channels is more dependent on the receptor composition than previously thought, because Zn2+ is able to displace Pb2+ from its binding site in epsilon1-containing channels, but not in epsilon2-containing channels. PMID- 17706325 TI - Schiff base transition metal complexes as novel inhibitors of xanthine oxidase. AB - Twenty transition metal complexes with Schiff bases were evaluated for their inhibitory activities on xanthine oxidase (XO), of which 11 were newly synthesized and characterized by X-ray single crystal diffraction. It was found that 9 of the 20 complexes showed potent inhibitory activities against XO near to the standard inhibitor allopurinol. The cadmium(II) complex (8) had the most potent inhibitory activity with the IC(50) value of 2.16 microM. Relationships between the structures and the activities showed that the ligands and the metal ions influenced the inhibitory activities. The XO inhibition of the Schiff base metal complexes most probably resulted from their direct interactions with the enzymes "in the whole complex form". These results demonstrated that the Schiff base transition metal complexes could be potential selective XO inhibitors. PMID- 17706327 TI - Assessing undergraduate nursing students in clinical practice: do preceptors use assessment strategies? AB - Health care organisations such as the World Health Organisation (WHO) and An Bord Altranais (ABA, The Irish Nursing Registration Board) demand higher standards of new graduate nurses than heretofore. This is in conjunction with the implementation of degree programmes for undergraduate nurse education. These organisations stipulate that graduates must be well-educated, accountable, and can demonstrate the skills of a safe, caring and competent decision-making practitioner. The Bachelor of Science (BSc) four-year degree programme for undergraduate nurse education was introduced in Ireland in 2002, and is provided in universities and colleges of higher education throughout The Republic of Ireland. During the implementation process, each university and college of higher education developed a range of assessment strategies to clinically assess students. Preceptor nurses were subsequently assigned the responsibility of clinically assessing students, a remit previously undertaken by Clinical Ward/Unit Nurse Managers. Preceptors are qualified nurses, working in clinical units who are specially prepared to support BSc students during clinical placements. The purpose of this study was to explore to what extent preceptor nurses use the devised assessment strategies to clinically assess BSc students in one university in The Republic of Ireland. Data were collected by using a questionnaire distributed to all known preceptors in General, Psychiatric and Intellectual Disability nursing, during year four of the first cycle of the BSc programme. Findings from this descriptive study revealed that many preceptors were inexperienced, did not fully comprehend the assessment process and were not applying all of the recommended assessment strategies when assessing students in clinical practice. In light of these findings suggestions are made in the context of further research, management and education. PMID- 17706326 TI - Synthesis and in vivo anti-mutagenic activity of novel melatonin derivatives. AB - Extensive literature suggests that melatonin play a role against the degenerative effect of central neurotoxins by its acting as free radical scavenger. This study aimed at evaluation of the anti-mutagenic activity of novel synthesized indole derivatives 2, 4a, and 8 in albino male mice in comparison with the parent melatonin. Efficacy of melatonin and its derivatives to influence cyclophosphamide (CP)-induced genotoxicity was tested using micronuclei (MN) formation in the bone marrow cells and determination of DNA, RNA and protein levels as well as cholinesterase and peroxidase activities in several organs of male mice. Following intragastrical injection of melatonin or one of its derivatives daily for 1 week, CP was given intraperitoneally, i.p., as a single dose of 25mg/kg BW. Pyridazin-4-yl thiadiazoloindole derivative 8, diaminothiophen-5-yl thiadiazoloindole derivative 4a and melatonin were significantly able to reduce the number of micronucleated polychromatic erythrocytes (MnPCEs) in the bone marrow cells induced by CP (P<0.0001, P<0.001, P<0.01, respectively). However, reduction of MN formation in the bone marrow cells was not significant when thiadiazoloindole derivative 2 was administered (P=0.14). Examination of the protective effect of melatonin and its derivatives on the levels of DNA, RNA and protein as well as enzyme activities showed that compound 8 had the ability to inhibit the clastogenic effect of CP in several organs of male mice. These findings suggest that compounds 4a, 8 and melatonin were able to reduce the mutagenicity effect of CP in male mice. The ability of compounds 4a, 8 and melatonin to reduce CP-related genotoxicity is possibly attributed to their antioxidant activity. PMID- 17706328 TI - Influence of fipronil compounds and rice-cultivation land-use intensity on macroinvertebrate communities in streams of southwestern Louisiana, USA. AB - Laboratory tests of fipronil and its degradation products have revealed acute lethal toxicity at very low concentrations (LC50) of <0.5 microg/L to selected aquatic macroinvertebrates. In streams draining basins with intensive rice cultivation in southwestern Louisiana, USA, concentrations of fipronil compounds were an order of magnitude larger than the LC50. The abundance (rho=-0.64; p=0.015) and taxa richness (r2=0.515, p<0.005) of macroinvertebrate communities declined significantly with increases in concentrations of fipronil compounds and rice-cultivation land-use intensity. Macroinvertebrate community tolerance scores increased linearly (r2=0.442, p<0.005) with increases in the percentage of rice cultivation in the basins, indicating increasingly degraded stream conditions. Similarly, macroinvertebrate community-tolerance scores increased rapidly as fipronil concentrations approached about 1 microg/L. Pesticide toxicity index determinations indicated that aquatic macroinvertebrates respond to a gradient of fipronil compounds in water although stream size and habitat cannot be ruled out as contributing influences. PMID- 17706329 TI - Comparison of regression coefficient and GIS-based methodologies for regional estimates of forest soil carbon stocks. AB - Estimates of forest soil organic carbon (SOC) have applications in carbon science, soil quality studies, carbon sequestration technologies, and carbon trading. Forest SOC has been modeled using a regression coefficient methodology that applies mean SOC densities (mass/area) to broad forest regions. A higher resolution model is based on an approach that employs a geographic information system (GIS) with soil databases and satellite-derived landcover images. Despite this advancement, the regression approach remains the basis of current state and federal level greenhouse gas inventories. Both approaches are analyzed in detail for Wisconsin forest soils from 1983 to 2001, applying rigorous error-fixing algorithms to soil databases. Resulting SOC stock estimates are 20% larger when determined using the GIS method rather than the regression approach. Average annual rates of increase in SOC stocks are 3.6 and 1.0 million metric tons of carbon per year for the GIS and regression approaches respectively. PMID- 17706331 TI - Understanding and representing 'place' in health research: a relational approach. AB - Epidemiology, sociology, and geography have been successful in re-establishing interest in the role of place in shaping health and health inequalities. However, some of the relevant empirical research has relied on rather conventional conceptions of space and place and focused on isolating the "independent" contribution of place-level and individual-level factors. This approach may have resulted in an underestimate of the contribution of 'place' to disease risk. In this paper we argue the case for extensive (quantitative) as well as intensive (qualitative) empirical, as well as theoretical, research on health variation that incorporates 'relational', views of space and place. Specifically, we argue that research in place and health should avoid the false dualism of context and composition by recognising that there is a mutually reinforcing and reciprocal relationship between people and place. We explore in the discussion how these theoretical perspectives are beginning to influence empirical research. We argue that these approaches to understanding how place relates to health are important in order to deliver effective, 'contextually sensitive' policy interventions. PMID- 17706330 TI - Disappearing acts: the social networks of formerly homeless individuals with co occurring disorders. AB - Studies of the social lives of men and women living with co-occurring disorders (substance abuse and serious mental illness) suggest that social networks critically influence recovery. In this paper, we examine some of the reasons that the social networks of individuals with co-occurring disorders are small, and the impact of small networks for this population. Using a social capital framework with cross-case analysis, we analyze 72 in-depth qualitative interviews with 39 formerly homeless mentally ill men and women who were substance abusers. All were participants in the New York Services Study (NYSS), a federally funded study of mentally ill adults in New York City. The patterns suggest that networks shrunk because (1) social network members died prematurely, (2) study participants withdrew or pushed others away, and (3) friends and family members faced so many obstacles of their own that they could not provide resources for the study participants. We suggest that as networks diminished, some participants responded by attempting to rebuild their networks, even if the networks provided negative social capital, and others isolated themselves socially to escape the pressures and disappointments of interaction. PMID- 17706332 TI - Sympathetic arousal to a vestibular stressor in high and low hostile men. AB - The aim of the present experiment was to extend the literature on hostility and a cerebral systems based model of sympathetic arousal to a vestibular-based stress. Several authors have concluded that autonomic stress reactivity in high hostile individuals must be interpersonally based, whereas healthy vestibular system functioning does not depend on interpersonal features. Utilizing a vestibular activation paradigm, skin conductance levels of 15 high hostile and 15 low hostile men were recorded after brief passive rotation about the vertical neuroaxis. It was expected that hostile individuals would exhibit higher skin conductance levels after rotation compared with low hostile individuals. The results confirmed expectations of heightened sympathetic tone among high hostiles subsequent to vestibular stress. Overall, the findings are interpreted to support a cerebral model of frontal region capacity limitation for regulation of vestibular stress that is independent of psychosocial mechanisms. PMID- 17706333 TI - Hemispheric asymmetries for temporal information processing: transient detection versus sustained monitoring. AB - This study investigated functional differences in the processing of visual temporal information between the left and right hemispheres (LH and RH). Participants indicated whether or not a checkerboard pattern contained a temporal gap lasting between 10 and 40 ms. When the stimulus contained a temporal signal (i.e. a gap), responses were more accurate for the right visual field-left hemisphere (RVF-LH) than for the left visual field-right hemisphere (LVF-RH). This RVF-LH advantage was larger for the shorter gap durations (Experiments 1 and 2), suggesting that the LH has finer temporal resolution than the RH, and is efficient for transient detection. In contrast, for noise trials (i.e. trial without temporal signals), there was a LVF-RH advantage. This LVF-RH advantage was observed when the entire stimulus duration was long (240 ms, Experiment 1), but was eliminated when the duration was short (120 ms, Experiment 2). In Experiment 3, where the gap was placed toward the end of the stimulus presentation, a LVF-RH advantage was found for noise trials whereas the RVF-LH advantage was eliminated for signal trials. It is likely that participants needed to monitor the stimulus for a longer period of time when the gap was absent (i.e. noise trials) or was placed toward the end of the presentation. The RH may therefore be more efficient in the sustained monitoring of visual temporal information whereas the LH is more efficient for transient detection. PMID- 17706334 TI - Development of a home cage locomotor tracking system capable of detecting the stimulant and sedative properties of drugs in rats. AB - The advent of automated locomotor activity methodologies has been extremely useful in removing the subjectivity and bias out of measuring this parameter in rodents. However, many of these behavioural studies are still conducted in novel environments, rather than in ones that the animals are familiar with, such as their home cage. The purpose of the present series of experiments was to develop an automated home cage tracking (HCT) profile using EthoVision software and assessing the acute effects of stimulant (amphetamine and methamphetamine, 0-5 mg/kg, sc) and sedative (diazepam, 0-20 mg/kg, sc and chlordiazepoxide, 0-50 mg/kg sc) drugs in this apparatus. Young adult male Sprague-Dawley rats were used, and the home cage locomotor activity was recorded for 11-60 min following administration (n=4 per group). For amphetamine and methamphetamine, a dose dependent increase in home cage activity was evident for both drugs, with a plateau, followed by reduction at higher doses. Methamphetamine was more potent, whereas amphetamine produced greater maximal responses. Both diazepam and chlordiazepoxide dose-dependently reduced locomotor activity, with diazepam exhibiting a greater potency and having stronger sedative effects than chlordiazepoxide. Three doses of each drug were selected at the 31-40 min time period following administration, and compared to open field responses. Diazepam, chlordiazepoxide and amphetamine did not produce significant changes in the open field, whilst methamphetamine produced a significant increase in the 2.5 mg/kg group. In conclusion, these studies have successfully developed a sensitive HCT methodology that has been validated using drugs with stimulant and sedative properties in the same test conditions, with relatively small numbers of animals required to produce statistically significant results. It has proven superior to the open field investigations in allowing dose-response effects to be observed over a relatively short observation period (i.e. 10 min) for both stimulants and sedatives. In addition, the HCT system can determine differences in potency and efficacy between drugs of a similar chemical class. PMID- 17706336 TI - GSTM1 and GSTT1 polymorphism influences protection against induced oxidative DNA damage by quercetin and ascorbic acid in human lymphocytes in vitro. AB - Antioxidants are of major importance in the protection against cellular oxidative damage caused by endogenous as well as exogenous free radicals. This study aims to establish the impact of genetic polymorphisms in GSTM1 and GSTT1, which encode for enzymatic antioxidative defence, on H(2)O(2)-induced oxidative DNA damage and on the effectiveness of quercetin and ascorbic acid in preventing this induced damage in human lymphocytes. Lymphocytes from 12 healthy volunteers were pre incubated either with 10 microM of quercetin or with 10 microM of ascorbic acid, and exposed to 25 microM H(2)O(2) for 1h. The induction of oxidative DNA damage was quantified using the Comet assay. Genotyping of these 12 subjects showed that six individuals were GSTM1+ and six were GSTM1-; eight were GSTT1+ and four GSTT1 . RESULTS: Baseline levels of oxidative DNA damage did not differ between GSTM1 or GSTT1 variants and their respective wild types. Also with respect to ex vivo induced levels of oxidative DNA damage, no significant difference was seen between variants and wild types of both genotypes. The protection against H(2)O(2)-induced oxidative DNA damage by quercetin was significantly higher in GSTT1 wild types than in GSTT1 variants (57% and 9% decrease, respectively; p=0.01); furthermore, GSTT1 wild types were protected against induced oxidative DNA damage by ascorbic acid pre-incubation while GSTT1 variants showed an increase of damage (16% decrease vs. 91% increase; p=0.01). For GSTM1 variants and wild types, observed differences in protective effects of quercetin or ascorbic acid were not statistically significant. Overall, quercetin proves to be better in protecting human lymphocytes in vitro against oxidative DNA damage upon H(2)O(2) challenge than ascorbic acid. PMID- 17706335 TI - Low-activity allele of Catechol-O-Methyltransferase (COMTL) is associated with increased lateral ventricles in patients with first episode non-affective psychosis. AB - BACKGROUND: Structural brain anomalies are present at early phases of psychosis. The objective was to examine the impact of Catechol-O-Methyltransferase (COMT) gene variations on brain morphology in first-episode non-affective psychosis. We hypothesized that the low activity-COMT (COMT(L)) allele would be associated with the presence of structural brain changes as assessed by quantitative magnetic resonance imaging (MRI). METHODS: Fifty-two males and 23 females underwent COMT genotyping and MRI. Patients were categorized into three genetic subgroups: COMT(H/H), COMT(L/H) and COMT(L/L). MRI data were analyzed using BRAINS2. Global and lobar volumes of grey matter (GM) and cerebrospinal fluid (CSF) were compared among the three groups after controlling for total intracranial volume and age of illness onset. RESULTS: COMT(L) carriers showed a significant enlargement of the lateral ventricles (F = 7.13, p = 0.009), right lateral ventricle (F = 5.99, p = 0.017) and left lateral ventricle (F = 6.22, p = 0.015). No other significant differences in any of the brain structures were found among subgroups. CONCLUSIONS: Our findings suggest that genetic variations of COMT can contribute to the enlargement of the lateral ventricles described in early phases of non affective psychosis. PMID- 17706337 TI - Adhesion molecules changes at 20 gestation weeks in pregnancies complicated by preeclampsia. AB - OBJECTIVES: To examine soluble E-selectin, L-selectin, P-selectin, ICAM-1, and VCAM-1 levels in normotensive and preeclamptic pregnancies. To determine cut-offs useful for preeclampsia early detection. STUDY DESIGN: A cohort of nulliparous women was recruited at family medicine clinics in Mexico City. Preeclampsia developed in 75 patients; 125 normotensive controls were matched. Adhesion molecules were assessed in serum obtained at 20 gestation weeks and in third trimester pregnancies. Predictive values and odds ratios for preeclampsia development were calculated with the 20 gestation week results. Threshold values were selected based on ROC curves values. RESULTS: In women with subsequent preeclampsia, sL-selectin and sVCAM-1 concentrations were significantly lower, whereas sE-selectin, sP-selectin and sICAM-1 levels were significantly higher, compared with controls at mid-pregnancy (p<0.05). The odds ratio for low sL selectin was 25.6 (95% CI, 8.9-73.5; cut-off, 1414 ng/ml). The sensitivity, specificity, and positive and negative predictive values of low sL-selectin for preeclampsia development were 84, 90, 39, and 98%, respectively, whereas its sensitivity, specificity, and positive and negative predictive values for severe preeclampsia development (cut-off, 1210 ng/ml) were 100, 98, 60, and 100%, respectively. CONCLUSIONS: Early enhanced activation of endothelial cells, platelets and leukocytes seem to be present in preeclamptic patients, especially in those that develop severe preeclampsia. Low sL-selectin levels at 20 gestation weeks may be an indicator of preeclampsia development. PMID- 17706338 TI - A busy cell--endoplasmic reticulum stress in the pancreatic beta-cell. AB - The pancreatic beta-cell senses nutrients, neurotransmitters and hormones in the circulating blood. The unique function of the cell is to integrate all these ambient signals into an appropriate insulin secretory rate in order to maintain normal glucose homeostasis. A prerequisite for adequate insulin secretion is proper biosynthesis of the hormone. The rate of biosynthesis needs to be regulated in order to compensate for rapid fluctuations in secretory rate. The synthesis of insulin includes transcription of its gene to mRNA, translation of mRNA into preproinsulin, and processing of preproinsulin via proinsulin into mature insulin. It also involves the induction of additional components of the secretory pathway to support processing, transport and exocytosis of insulin granules. The endoplasmic reticulum (ER) is the cell organelle playing a paramount role in these processes. A functional ER is crucial to all eukaryotic cells, but especially important in a professional hormone-secreting cell like the beta-cell. This essay will describe the phenomenon of ER stress in pancreatic beta-cells with special focus on its involvement in the regulation of beta-cell survival and death. The involvement of some ER stress components in the regulation of insulin biosynthesis and secretion will be discussed, along with a short description of the ER stress response (also known as the unfolded protein response). PMID- 17706339 TI - Surgery of intracranial aneurysms previously treated endovascularly. AB - OBJECTIVE: To perform a retrospective study on the patients who underwent aneurysmal surgery following endovascular treatment. PATIENTS AND METHODS: We performed a retrospective study on eight patients who underwent aneurysmal surgery following endovascular treatment (-attempts) with gugliemi detachable coils (GDCs). The indications for surgery, surgical techniques and clinical outcomes were analyzed. RESULTS: The indications for surgical treatment after GDC coiling of aneurysm were classified into three groups. First group: surgery of incompletely coiled aneurysms (n=4). Second group: surgery of mass effect on the neural structures due to coil compaction or rebleeding (n=2). Third group: surgery of vascular complications after endovascular procedure due to parent artery occlusion or thrombus propagation from aneurysm (n=2). Aneurysm obliterations could be performed in all cases confirmed by postoperative angiography. Six patients had an excellent outcome and returned to their profession. Patient's visual acuity was improved. One individual experienced right hemiparesis (grade IV/V) and hemihypesthesia. CONCLUSIONS: Microsurgical clipping is rarely necessary for previously coiled aneurysms. Surgical treatment is uncommonly required when an acute complication arises during endovascular treatment, or when there is a dynamic change of a residual aneurysm configuration over time that is considered to be insecure. PMID- 17706340 TI - A novel electrochemical alkylation of aniline with methanol over Zn/Cu salts modified kaolin. AB - A novel liquid phase alkylation of aniline with methanol over Zn/Cu salts modified kaolin assisted with a pair of porous carbon electrode in slurry-bed reactor under constant current intensity, room temperature and atmospheric pressure was reported. The Zn/Cu salts modified kaolin catalysts were synthesized and characterized by infrared spectrometer (IR), powder X-ray diffraction (XRD) and scanning electron microscopy (SEM), which showed that the transition metals were completely supported on kaolin's structure and formed a pored one. The effect parameters, such as initial pH, electrolysis time, metal ratio with kaolin and salts composition in this electrochemical catalytic system, were studied. The procedure was inspected by ultraviolet-visible spectrum (UV-vis), and the product distribution was detected by gas chromatography/mass spectrometry (GC/MS). In addition, a possible reaction mechanism was also proposed. PMID- 17706341 TI - Effect of cooling rate and basicity during vitrification of fly ash. Part 2. On the chemical stability and acid resistance of slags. AB - The object of this study is to investigate how the cooling rate and the basicity during the vitrification process govern the chemical stability and acid resistance of slags. In this experiment, the incineration fly ashes with various basicities were vitrified at 1450 degrees C and cooled down by air cooling and water quenching, respectively. The amorphous volume fractions (AVF) in slags were estimated by X-ray diffraction analysis with the addition of an internal standard. Scanning electron microscopy was applied to qualitatively examine the microstructures of the original and the acid-immersed slags. It was verified that the addition of SiO(2) and water quenching both significantly affected the crystalline characteristics of the slag. When the basicity was >0.990, the AVF of slags was approximately equal regardless of the cooling rate. When the basicity was <0.674, water quenching greatly enhanced the formation of glassy amorphous phase and the immobilization of metals in slags. In contrast, a lower basicity (<0.511) is required if one wants to vitrify fly ash into slags and cool it down by air. As a whole, the glassy amorphous structure presented better chemical resistance than the crystalline structure to decomposition by an acid. PMID- 17706342 TI - Effluent from drug manufactures contains extremely high levels of pharmaceuticals. AB - It is generally accepted that the main route for human pharmaceuticals to the aquatic environment is via sewage treatment plants receiving wastewater from households and hospitals. We have analysed pharmaceuticals in the effluent from a wastewater treatment plant serving about 90 bulk drug manufacturers in Patancheru, near Hyderabad, India--a major production site of generic drugs for the world market. The samples contained by far the highest levels of pharmaceuticals reported in any effluent. The high levels of several broad spectrum antibiotics raise concerns about resistance development. The concentration of the most abundant drug, ciprofloxacin (up to 31,000 microg/L) exceeds levels toxic to some bacteria by over 1000-fold. The results from the present study call for an increased focus on the potential release of active pharmaceutical ingredients from production facilities in different regions. PMID- 17706343 TI - A comparative study on Pb2+, Zn2+ and Cd2+ sorption onto zirconium phosphate supported by a cation exchanger. AB - In the present study, a novel hybrid sorbent ZrP-001 was prepared by loading zirconium phosphate (ZrP) onto a strongly acidic cation exchanger D-001. Sorption behavior of Pb(2+), Zn(2+), and Cd(2+) onto ZrP-001 was experimentally examined by comparing with the host exchanger D-001. ZrP-001 was characterized by scanning electron micrograph (SEM), X-ray diffraction (XRD), thermogravimetric analysis (TGA), pH-titration and pore size distribution analysis. Sorption of the heavy metals onto ZrP-001 was found to be pH-dependent due to the ion exchange mechanism. Compared to D-001, a smaller pore size of ZrP-001 due to the ZrP dispersion consequently resulted in a lower sorption rate. Competitive effect of Ca(2+) on sorption of heavy metals onto ZrP-001 and D-001 was compared to elucidate sorption preference of the hybrid sorbent towards heavy metals. More favorable sorption of ZrP-001 than D-001 was observed for all the three metals and their sorption preference onto ZrP-001 followed the order Pb(2+)>>Zn(2+) approximately Cd(2+). Fixed-bed sorption results and its efficient regeneration property further demonstrated that ZrP-001 is a potential candidate for removing heavy metals from contaminated water. PMID- 17706344 TI - Removal of phosphate from aqueous solutions and sewage using natural and surface modified coir pith. AB - Iron impregnated coir pith (CP-Fe-I) can be effectively used for the removal of phosphate from aqueous streams and sewage. Iron impregnation on natural coir pith was carried out by drop by drop addition method. The effect of various factors such as pH, initial concentration of phosphate, contact time and adsorbent dose on phosphate adsorption was studied by batch technique. The pH at 3.0 favored the maximum adsorption of phosphate from aqueous solutions. The effect of pH on phosphate adsorption was explained by pH(zpc), phosphate speciation in solution and affinity of anions towards the adsorbent sites. A comparative study of the adsorption of phosphate using CP-Fe-I and CP (coir pith) was made and results show that the former one is five to six times more effective than the latter. Kinetic studies revealed that the adsorption process followed a pseudo-second order kinetic model. Adsorption followed Langmuir isotherm model. Column studies were conducted to examine the utility of the investigated adsorbent for the removal of phosphate from continuously flowing aqueous solutions. PMID- 17706345 TI - Electrocoagulation of cutting oil emulsions using aluminium plate electrodes. AB - The treatment of very concentrated oil-water emulsions by electrocoagulation (EC) was experimentally investigated as a pre-treatment step prior to a membrane process. The oil-water emulsion was prepared from a cutting mineral oil B22 currently used for drilling and machining operations. The electrocoagulation progress was followed by the measurement of COD, turbidity and pH in a batch process with recirculation of the liquid. This study is mainly focused on the effects of operating parameters such as initial pH, current density, oil concentration and recirculation rate, on the de-emulsification efficiency. Kinetic curves showed that the EC process exhibits two phases: a "reactive phase" during which the COD and the turbidity removals increase with electrolysis, and a stationary phase for which further aluminium dissolution is useless in the pollution abatement. The results showed that the treatment efficiency increases with increasing current density, but decreases with oil concentration. It appears that treatment of the considered cutting oil is completed through dissolution of around 10mgAl/g oil, with a slight positive effect of the liquid flow rate. Best results are also obtained with initial pH near 7. PMID- 17706346 TI - Determination of adsorption entropies on solid surfaces by reversed-flow gas chromatography. AB - The reversed-flow gas chromatography (RF-GC) method has been applied to measure the time separation of adsorption entropies and their probability density functions, when acetic and formic acid vapors, responsible for artifacts degradation inside museums, are adsorbed on various heterogeneous surfaces. The solid materials studied were Penteli marble and solid metals (lead, copper and iron), which are commonly used for the construction of the artifacts. Physicochemical measurements were performed at various temperatures in the range 353-473 K, the surface coverage theta being also calculated over time. A new mathematical model, based on well known equations was used in order to extract the above quantities. PMID- 17706347 TI - Simultaneous removal of perchlorate and arsenate by ion-exchange media modified with nanostructured iron (hydr)oxide. AB - Hybrid ion-exchange (HIX) media for simultaneous removal of arsenate and perchlorate were prepared by impregnation of non-crystalline iron (hydr)oxide nanoparticles onto strong base ion-exchange (IX) resins using two different chemical treatment techniques. In situ precipitation of Fe(III) (M treatment) resulted in the formation of sphere-like clusters of nanomaterials with diameters of approximately 5nm, while KMnO4/Fe(II) treatments yielded rod-like nanomaterials with diameters of 10-50nm inside the pores of the media. The iron content of most HIX media was >10% of dry weight. The HIX media prepared via the M treatment method consistently exhibited greater arsenate adsorption capacity. The fitted Freundlich adsorption intensity parameters (q=K x C(E)(1/n)) for arsenate (1/n<0.6) indicated favorable adsorption trends. The K values ranged between 2.5 and 34.7mgAs/gdry resin and were generally higher for the M treated media in comparison to the permanganate treated media. The separation factors for perchlorate over chloride (alpha(Cl-)(ClO4-)) for the HIX media were lower than its untreated counterparts. The HIX prepared via the M treatment, had higher alpha(Cl-)(ClO4-) than the HIX obtained by the KMnO(4)/Fe(II) treatments suggesting that permanganate may adversely impact the ion-exchange base media. Short bed adsorber (SBA) tests demonstrated that the mass transport kinetics for both ions are adequately rapid to permit simultaneous removal using HIX media in a fixed bed reactor. PMID- 17706348 TI - Treatment of metal cyanide bearing wastewater by simultaneous adsorption and biodegradation (SAB). AB - This paper presents process review and comparative study of biodegradation and adsorption alone with simultaneous adsorption and biodegradation (SAB) process using Pseudomonas fluorescens. Ferrocyanide solution was used for all studies with initial CN(-) concentrations of 50, 100, 200 and 300mg/L, and initial pH of 6. Pseudomonas fluorescens used ferrocyanide as sole source of nitrogen and biodegradation efficiency was observed as 96.4, 94.1, 86.2 and 69.3%, respectively after 60h of agitation. Whereas in adsorption process with granular activated carbon (GAC) as adsorbent, CN(-) removal efficiency was found to be 85.6, 80.1, 70.2 and 50.2%, respectively. But in SAB process the removal efficiency could be more than 70% for all concentrations only at 36h of agitation and achieved removal efficiency of 99.9% for 50 and 100mgCN(-)/L. It was found that SAB process is more effective than biodegradation and adsorption alone. PMID- 17706349 TI - Accumulation of polycyclic aromatic hydrocarbons and heavy metals in lettuce grown in the soils contaminated with long-term wastewater irrigation. AB - Accumulation of polycyclic aromatic hydrocarbons (PAHs) and heavy metals (HMs) by crop plants from contaminated soils may pose health risks. A greenhouse pot experiment using lettuce (Lactuca satuva L.) as a representative vegetable was conducted to assess the concentrations of PAHs and HMs in vegetables grown in wastewater-contaminated soils. The concentrations of total PAHs were ranged from 1.5 to 3.4 mg kg(-1) in the contaminated soils, while 1.2 mg kg(-1) in the reference soil. Linear regression analyses showed that the relationships between soil and shoot PAH concentrations were stronger for LMW-PAHs (R(2) between 0.51 and 0.92) than for HMW-PAHs (R(2) 0.02 and 0.60), suggesting that translocation for LMW-PAHs is faster than HMW-PAHs. Furthermore, the data imply that root uptake was the main pathway for HMW-PAHs accumulation. The plant shoots were also highly contaminated with HMs, particularly Cd (0.4-0.9 mg kg(-1)), Cr (3.4-4.1 mg kg(-1)), Ni (11.7-15.1 mg kg(-1)) and Pb (2.3-5.3 mg kg(-1)), and exceed the guidance limits set by State Environmental Protection Administration (SEPA), China and the World Health Organization (WHO). This study highlights the potential health risks associated with cultivation and consumption of leafy vegetables on wastewater-contaminated soils. PMID- 17706350 TI - Effect of EDTA on divalent metal adsorption onto grape stalk and exhausted coffee wastes. AB - In the present work, two industrial vegetable wastes, grape stalk, coming from a wine producer, and exhausted coffee, coming from a soluble coffee manufacturer, have been investigated for the removal of Cu(II) and Ni(II) from aqueous solutions in presence and in absence of the strongly complexing agent EDTA. Effects of pH and metal-EDTA molar ratio, kinetics as a function of sorbent concentration, and sorption equilibrium for both metals onto both sorbents were evaluated in batch experiments. Metal uptake was dependent of pH, reaching a maximum from pH around 5.5. EDTA was found to dramatically reduce metal adsorption, reaching total uptake inhibition for both metals onto both sorbents at equimolar metal:ligand concentrations. Kinetic results were successfully modelled by means of the pseudo second order model. Langmuir and Freundlich models were used to describe the sorption equilibrium data. Grape stalk showed the best performance for Cu(II) and Ni(II) removal in presence and in absence of EDTA, despite exhausted coffee appears as less sensitive to the presence of complexing agent. The performance of Cu(II) and Ni(II) sorption onto grape stalk in a continuous flow process was evaluated. In solutions containing EDTA, an initial metal concentration in the outlet flow corresponding to the complexed metal fraction was observed from the beginning of the process. A high metal recovery yield (>97%) was achieved by feeding the metal-loaded column with 0.05 M HCl. PMID- 17706351 TI - Dechlorinating ability of TCE-fed microcosms with different electron donors. AB - The main objective of the work presented herein is to assess the effect of different electron donors (butyric acid and methanol) on the dechlorinating activity of two microbial cultures where active methanogenic populations are present, in an effort to evaluate the importance of the electron donor selection process. The ability of each anaerobic culture to dechlorinate TCE, when enriched with either butyric acid or methanol, was verified based on the results of gas chromatography. In addition, the fluorescent in situ hybridization (FISH) and the polymerase chain reaction (PCR) methods gave positive results for the presence of Dehalococcoides spp. According to results of the batch tests conducted in this study, it appears that the selection of the electron donor for stimulating TCE dechlorination depends on microbial culture composition; therefore, the decision on the appropriate electron donor should be based on site-specific microcosm studies. PMID- 17706352 TI - TiO2 hydrosols with high activity for photocatalytic degradation of formaldehyde in a gaseous phase. AB - Two types of TiO2 hydrosols (TOSO and HTO) were prepared from titanium sulfate (TiOSO4) and metatitanic acid (H2TiO3) by a chemical precipitation-peptization method, respectively. The prepared hydrosols were characterized by means of X-ray diffraction, particle size distribution, scanning electron microscopy, UV-vis spectroscopy, Fourier transform infrared spectroscopy, Brunauer-Emmett-Teller and Barret-Joyner-Halender methods. The results showed that the TiO2 hydrosols with an anatase crystal structure had smaller particle sizes, higher surface areas, larger pore volume, and higher transparence than Degussa P-25 suspension. The photocatalytic activity of the TiO2 hydrosols was evaluated for formaldehyde degradation under UVA illumination in a gaseous phase. The results demonstrated that the photocatalytic activity with the catalyst loading of 2mgcm(-2) was ranked as an order of HTO>TOSO>P-25. The photocatalytic activity was further studied using the HTO catalyst under different experimental conditions. The results showed that catalyst loading, relative humidity, and initial concentration could influence the efficiency of HCHO photocatalytic degradation. It was found that a catalyst loading of more than 2mgcm(-2) and a relative humidity of 55% were two essential conditions for achieving the best performance under these experimental conditions. The repeated experiments indicated that the HTO catalyst was reasonably stable and could be repeatedly used for the HCHO oxidation under UVA irradiation. This investigation would be helpful to promote the application of TiO2 photocatalytic technique for indoor air purification. PMID- 17706353 TI - Comments on "Comparison of reductive dechlorination of p-chlorophenol using Fe(0) and nanosized Fe(0)" by R. Cheng, et al. [J. Hazard. Mater. 144 (2007) 334]. PMID- 17706354 TI - Decolouration of industrial azo dyes by crude laccase from Trametes hirsuta. AB - The decolouration of several azo dyes, commonly used in the leather industry, by crude laccase obtained from Trametes hirsuta cultivation was assessed. Among the six dyes studied four showed a decolouration percentage higher than 50% in 4h, whereas the other two showed more resistance to degradation. These results show the ability of laccase towards different dye structures as well as its enormous potential for the decolouration of recalcitrant azo dyes. PMID- 17706355 TI - Long-term study of dendritic spines from hippocampal CA1 pyramidal cells, after neuroprotective melatonin treatment following global cerebral ischemia in rats. AB - Melatonin reduces pyramidal neuronal death in the hippocampus and prevents the impairment of place learning and memory in the Morris water maze, otherwise occurring following global cerebral ischemia. The cytoarchitectonic characteristics of the hippocampal CA1 remaining pyramidal neurons in brains of rats submitted 120 days earlier to acute global cerebral ischemia (15-min four vessel occlusion, and melatonin 10mg/(kg h 6h), i.v. or vehicle administration) were compared to those of intact control rats in order to gain information concerning the neural substrate underlying preservation of hippocampal functioning. Hippocampi were processed according to a modification of the Golgi method. Dendritic bifurcations from pyramidal neurons in both the oriens-alveus and the striatum radiatum; as well as spine density and proportions of thin, stubby, mushroom-shaped, wide, ramified, and double spines in a 50 microm length segment of an oblique dendrite branching from the apical dendrite of the hippocampal CA1 remaining pyramidal neurons were evaluated. No impregnated CA1 pyramidal neurons were found in the ischemic-vehicle-treated rats. CA1 pyramidal neurons from ischemic-melatonin-treated rats showed stick-like and less ramified dendrites than those seen in intact control neurons. In addition, lesser density of spines, lower proportional density of thin spines, and higher proportional density of mushroom spines were counted in ischemic-melatonin-treated animals than those in the sinuously branched dendrites of the intact control group. These cytoarchitectural arrangements seem to be compatible with place learning and memory functions long after ischemia and melatonin neuroprotection. PMID- 17706356 TI - Lipid components in the detergent-resistant membrane microdomain (DRM) obtained from the synaptic plasma membrane of rat brain. AB - Lateral association of sphingolipids and cholesterol is considered to form membrane microdomains such as "lipid rafts" obtainable as a detergent-resistant membrane microdomain (DRM) fraction after solubilization with a non-ionic detergent and density gradient centrifugation. Since not only sphinogolipids and cholesterol, but also functional lipids such as phosphatidylinositol 4,5 bisphosphate (PIP(2)) are reported to be localized in DRM prepared from several cultured cells, this domain is considered to be a platform mediating lipid signaling. Although PIP(2) is considered to have pivotal roles in the nervous system, little information is available on the localization of PIP(2) in the DRM within the synaptic plasma membrane (SPM) obtained from matured rat brains. In this study, in order to know the localization of PIP(2) in SPM-derived DRM, we measured the amount of PIP(2) in SPM and SPM-derived DRM, by the thin-layer chromatography blotting method, using a GST-fusion protein of the pleckstrin homology domain of phospholipase Cdelta1 as a PIP(2) binding probe. About 10% of the PIP(2) in SPM was recovered in DRM. In contrast, over 40% recovery was observed for the membrane cholesterol and sphingomyelin, and about 30% recovery was observed for phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine in the DRM were detected using the thin-layer chromatography method. Since the recovery of proteins in DRM was about 10%, the result indicates that there occurs no enrichment of PIP(2) in DRM prepared from SPM. PMID- 17706357 TI - Expression of PGE2 EP3 receptor subtypes in the mouse preoptic region. AB - Inflammatory-induced fever is dependent on prostaglandin E(2) (PGE(2)) binding to its EP(3) receptor in the thermoregulatory region of the hypothalamus, but it is not known which EP(3) receptor isoform(s) that is/are involved. We identified the EP(3) receptor expression in the mouse preoptic region by in situ hybridization and isolated the corresponding area by laser capture microdissection. Real-time RT-PCR analysis of microdissected tissue revealed a predominant expression of the EP(3alpha) isoform, but there was also considerable expression of EP(3gamma), corresponding to approximately 15% of total EP(3) receptor expression, whereas EP(3beta) was sparsely expressed. This distribution was not changed by immune challenge induced by peripheral administration of LPS, indicating that EP(3) receptor splicing and distribution is not activity dependent. Considering that EP(3alpha) and EP(3gamma) are associated with inhibitory and stimulatory G proteins, respectively, the present data demonstrate that the PGE(2) response of the target neurons is intricately regulated. PMID- 17706358 TI - Endosomal abnormalities related to amyloid precursor protein in cholesterol treated cerebral cortex neuronal cells derived from trisomy 16 mice, an animal model of Down syndrome. AB - The CNh and CTb cell lines are derived from the cerebral cortex of normal and trisomy 16 mice, an animal model of human trisomy 21, Down syndrome (DS), and represent in vitro models to study cellular events associated with the human condition. Amyloid precursor protein (APP) plays an important role in the development of neuropathology associated with DS and cholesterol in the amyloidogenic processing of APP. There is also increasing evidence of alterations in the recycling pathway of the early endosome compartment in nervous tissue from DS. In the present study, we report endosomal abnormalities related to amyloid precursor protein in cholesterol-treated CTb cells. Colocalization studies revealed the presence of APP-derived products in early endosomal compartments in both cell lines. Using internalization and immunoprecipitation techniques, differential effects were observed between the normal and trisomic cell lines when treated with cholesterol. Internalization experiments showed that the CTb cell line accumulates internalized APP in intracellular compartments for longer periods of time when compared to the CNh cell line. Immunoprecipitation revealed a differential interaction between the trafficking-related protein Rab4 and APP in the neuronal cell lines CNh and CTb. The present study suggests a putative mechanism by which overexpressed APP accumulates in intracellular compartments related to the endosomal trafficking pathway in individuals with DS, and highlights the usefulness of the CTb cell line as a model to study altered APP metabolism related to this genetic condition. PMID- 17706359 TI - Prevalence of anti-Toxoplasma gondii and anti-Neospora caninum antibodies in goats slaughtered in the public slaughterhouse of Patos city, Paraiba State, Northeast region of Brazil. AB - The prevalence of anti-Toxoplasma gondii and anti-Neospora caninum antibodies was investigated in goats slaughtered in the public slaughterhouse of Patos, State of Paraiba, Northeast region of Brazil, and possible associations between sex of the animals and antibody prevalence were verified. Three-hundred six blood samples from goats collected before slaughter by jugular venopuncture were used. For the serologic diagnosis of T. gondii and N. caninum, the indirect fluorescent antibody test (IFAT) with cut-off values 64 and 50, respectively, was carried out. The prevalence of anti-T. gondii antibodies was 24.5% [95% CI=19.8-29.7%] with titers ranging from 64 to 4096, and anti-N. caninum antibodies was 3.3% (95% CI=1.6-5.9%) with titers ranging from 50 to 400. There were no associations between sex of animals and prevalence of anti-T. gondii and anti-N. caninum antibodies. PMID- 17706360 TI - Taenia saginata in Europe. AB - In spite of the EU directives that regulate meat inspection for bovine cysticercosis, Taenia saginata is still present in Europe and causes economic losses due to condemnation, refrigeration and downgrading of infected carcasses. The main reasons for this persistence include the low sensitivity of current meat inspection protocols, the dissemination and survival of eggs in the environment and cattle husbandry systems, which allow grazing on pastures and drinking from water streams. It is assumed that water streams and surface water are potentially contaminated with T. saginata eggs. Furthermore, current wastewater management not only fails to halt, but rather contributes to the dissemination of eggs in the environment. Here, the authors discuss an integrated approach for control of this food-borne zoonosis, as well as the potential use of serological methods as a way of improving detection of bovine cysticercosis. PMID- 17706361 TI - Elderly burn prevention: a novel epidemiological approach. AB - OBJECTIVE: To develop burn prevention strategies for the elderly population in Hong Kong using a novel epidemiological approach. METHODS: Medical records of all patients aged 60 or above who were admitted to our hospital in a 6-year period were reviewed and demographic data, injury characteristics, details of management and outcome were obtained. Selected interviews were undertaken to determine the exact mechanisms of injury and further details of the medical and social background. RESULTS: Fifty-nine elderly patients were identified from the medical records with under half (42%) aged 75 and above. Male to female ratio was 1:1.68. Three-quarters of the injuries occurred at home, principally in the kitchen and bathroom. Two-thirds of the burns were scalds. Forty-eight percent of the admitted patients had surgery. Thirty-seven patients (or next of kin) were interviewed further. Of the subgroup only 12% had received appropriate first aid and 27% had treatment delayed for over 24 h before seeking medical help. The majority of patients had little or no formal education and one quarter were living alone. CONCLUSION: We identified common scenarios of elderly burns which could be used to focus prevention strategies. PMID- 17706362 TI - Pruritus in patients with small burn injuries. AB - OBJECTIVE: To document incidence of pruritus and the presence of predisposing factors after small burns and their (subjective) impact on daily life. METHODS: Retrospective study interviewing all patients treated in an outpatient burn clinic during 2004. Patients were contacted by phone and questioned on aspects of the burn and the presence, intensity and impact of pruritus. Predisposing factors for pruritus were analysed by multivariate logistic regression analysis. RESULTS: Eighty-five percent of the 318 outpatients consented to the interview. Median total burned surface area (TBSA) was 2% (interquartile range of 1-4%). Thirty five percent of patients recalled moderate pruritus, 14% severe pruritus. Impact on daily life was reported in 42% of patients suffering from moderate pruritus and 92% of patients suffering from severe pruritus. A multi variant logistic regression model based on baseline parameters (TBSA, age and anatomical region burned) only predicted 16.8% of experienced pruritus. CONCLUSION: Recovery from small burns is associated with a high incidence of pruritus, which has substantial impact on daily life. It is difficult to identify patients at risk at the time of injury, as baseline demographic and injury related parameters only play a minor role. Future studies are needed to assess the effect of prevention and treatment and to define predictors for the incidence of pruritus. PMID- 17706363 TI - Use of "rescue burns" as another term of expression in certain situations of burns. PMID- 17706364 TI - Retinal influences induce bidirectional changes in the kinetics of N-methyl-D aspartate receptor-mediated responses in striate cortex cells during postnatal development. AB - Development of the visual callosal projection in rodents goes through an early critical period, from postnatal day (P) 4 to P6, during which retinal input specifies the blueprint for normal topographic connections, and a subsequent period of progressive pathway maturation that is largely complete by the time the eyes open, around P13. This study tests the hypothesis that these developmental stages correlate with age-related changes in the kinetics of synaptic responses mediated by the N-methyl-D-aspartate subclass of glutamate receptors (NMDARs). We used an in vitro slice preparation to perform whole-cell recordings from retrogradely-labeled visual callosal cells, as well from cortical cells with unknown projections. We analyzed age-related changes in the decay time constant of evoked as well as spontaneous excitatory postsynaptic currents mediated by N methyl-D-aspartate subclass of glutamate receptors (NMDAR-EPSCs) in slices from normal pups and pups enucleated at different postnatal ages. In normal pups we found that the decay time constant of NMDAR-EPSCs increases starting at about P6 and decreases by about P13. In contrast, these changes were not observed in rats enucleated at birth. However, by delaying the age at which enucleation was performed we found that the presence of the eyes until P6, but not until P4, is sufficient for inducing slow NMDAR-EPSC kinetics during the second postnatal week, as observed in normal pups. These results provide evidence that the eyes exert a bidirectional effect on the kinetics of NMDARs: during a P4-P6 critical period, retinal influences induce processes that slow down the kinetics of NMDAR EPSCs, while, near the age of eye opening, retinal input induces a sudden acceleration of NMDAR-EPSC kinetics. These findings suggest that the retinally driven processes that specify normal callosal topography during the P4-P6 time window also induce an increase in the decay time constant of NMDAR-EPSCs. This increase in response kinetics may play an important role in the maturation of cortical topographic maps after P6. Using ifenprodil, a noncompetitive NR2B selective blocker, we obtained evidence that although NR1/NR2B diheteromeric receptors contribute to evoked synaptic responses in both normal and enucleated animals, they are not primarily responsible for either the age-related changes in the kinetics of NMDAR-mediated responses, or the effects that bilateral enucleation has on the kinetics of NMDAR-EPSCs. PMID- 17706365 TI - The p75 neurotrophin receptor is essential for neuronal cell survival and improvement of functional recovery after spinal cord injury. AB - The mechanisms initiating post-spinal cord injury (SCI) apoptotic cell death remain incompletely understood. The p75 neurotrophin receptor (p75(NTR)) has been shown to exert both pro-survival and pro-apoptotic effects on neural cells in vitro. While a previous study had shown that there is decreased oligodendrocyte apoptosis distal to a clean partial transection injury of the cord in mice with nonfunctional p75(NTR), most human spinal cord injuries do not involve partial transections but are rather due to compression/contusion injuries with significant perilesional ischemia. Therefore, we sought to examine the role of the p75(NTR) in a clinically relevant clip compression model of SCI in p75 null mice with an exon III mutation. Mice with a functional p75(NTR) had increased caspase-9 activation at 3 days after SCI in comparison to the functionally deficient p75(NTR) mice. However, at 7 days following SCI there was no difference in the activation of the effector caspases (caspase-3 and caspase-6) at the spinal cord lesion. Moreover, at 7 days after injury, there was increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end (TUNEL) positive cell death at the injury site in the functionally deficient p75(NTR) mice. Using double labeling with TUNEL and cell specific markers we showed that the absence of p75(NTR) function increased the extent of neuronal but not oligodendroglial cell death at the injury site. This selective loss of neuronal cells after SCI was confirmed with a decrease in levels of microtubule-associated protein 2 in the p75 null mice. Furthermore, the wild-type animals had dramatically improved survival and enhanced locomotor recovery at 8 weeks after SCI when compared with the p75(NTR) null mice. Also at 8 weeks, there were significantly more neurons present at the injury site of wild-type mice when compared with p75 null mice. We conclude that the p75(NTR) receptor is integral to neuronal cell survival and endogenous reparative mechanisms after compressive/contusive SCI. PMID- 17706368 TI - The hegemony of empiricism: the opportunity for theoretical science in medicine. AB - Partly spurred by the rapid emergence of discovery tools, empirical science founded on experimental validation now dominates academic funding, publishing, and recognition while forums for theoretical science have been marginalized. Although this hegemony of empiricism instills useful discipline to the scientific process, it also limits the pace of science to sensor innovation and renders the ontogeny of scientific knowledge path-dependent, concealing potential discontinuities in intellectual trajectories. Theoretical science, founded on intuition, inspiration, and abstraction, can complement empirical science by creating disruptive paradigms that facilitate detection of spurious results and frame new hypotheses. For example, framing the compendium of human diseases as varying manifestations of buffer dysfunctions - insufficient or maladaptive responses to stress - portends new insights into disease mechanisms and treatments. As a specific incarnation of this theory, the "trauma hypothesis" suggests that the coordinated regulation of inflammation, coagulation, vasoconstriction, and fluid retention that evolved as a prehistoric adaptation to predatory stress and environmental injury conspires in modern times to produce acute coronary syndromes, heart failure, renal dysfunction, stroke, and pulmonary embolism. The theory also exposes the paradigmatic flaw behind the half-century detour perfecting balloon-deployed endovascular interventions. As the basis of buffer acquisition shifts from genetic to cognitive, phenoptosis - the theory that adaptive programmed death of organisms yields opportunity to successors - is rendered maladaptive, as an extended lifespan permits more efficient trait acquisition compared with life-death recycling. While forestalling death is a largely unfruitful medical game of "whack-a-mole" today, the recognition that aging and death may be programmed adaptations suggests they may also be amenable to systemic reprogramming. Epitomizing this opportunity are tumor cells, which reprogram themselves to escape their apoptotic fate and assume indefinite persistence. The prevalence and resilience of these cancer cells, and their ability to withstand the protean assaults of toxins, poisons, radiation, and host defenses, presage the potential robustness of life when appropriately programmed. Paradoxical medicine and dynamic range management may represent initial strategies to reprogram the neuroendocrine stress axes to modulate lifespan at the organism level, and many other strategies are anticipated. The key to theoretical science is original insight, but the prevailing pressure to conform to medicine's educational and practice standards dis-incentivizes independent thinking. A scientific future is envisioned when the commoditization of experimental science will enable its outsourcing, liberating health scientists from the tyranny of empiricism to engage in a more balanced process of discovery infused with theoretical considerations. PMID- 17706367 TI - Neonatally born granule cells numerically dominate adult mice dentate gyrus. AB - Hippocampal granule cells (GCs) are continuously generated in the subgranular zone of the dentate gyrus (DG) and functionally incorporated to dentate neural circuits even in adulthood. This raises a question about the fate of neonatally born GCs in adult DG. Do they exist until adulthood or are they largely superseded by adult-born GCs? To investigate this question, we examined the contributions of postnatally born GCs to the adult mouse DG. C57BL/6 mice were grouped in three different postnatal (P) ages (group 1: P0, group 2: P7, and group 3: P35) and received a daily bromodeoxyuridine (BrdU) injection for three consecutive days (P0/1/2, P7/8/9, and P35/36/37, respectively) to label dividing cells. At 6 months old, hippocampal sections were prepared from the animals and immunostained with anti-BrdU antibody and an antibody against the homeobox prospero-like protein Prox1, a marker of GCs. We defined BrdU- and Prox1-double positive cells as newborn GCs and analyzed their density and distribution in the granule cell layer (gcl), revealing that newborn GCs of each group still existed 6 months after BrdU injections and that the density of GCs born during P0-2 (group 1) was significantly higher compared with the other groups. Although the density of newborn GCs in the each group did not differ between male and female, the radial distribution of them in gcl showed some differences, that is, male newborn GCs localized toward the molecular layer compared with female ones in group 1, while to the hilus in group 2. These results suggest that GCs born in early postnatal days numerically dominate adult DG and that there exist sex differences in GC localizations which depend on the time when they were born. PMID- 17706369 TI - Identifying newly diagnosed Hispanic cancer patients who use a physician with a Spanish-language practice, for studies of quality of cancer treatment. AB - BACKGROUND: Language barriers may affect cancer treatment choices among U.S. Hispanic-Latino patients newly diagnosed with cancer. This study examined use of a physician with a Spanish-language practice (SLP) by Hispanic patients diagnosed with a cancer reported to a population-based cancer registry. METHODS: Data on all 1,874 Connecticut Hispanic patients diagnosed with cancer in 1999-2002 were obtained from the Connecticut Tumor Registry, including the follow-up physician (FUP) responsible for the patient's medical care around the time of cancer diagnosis. FUPs were compared to a list of Spanish surnames (SS) to identify potential Hispanic ethnicity. A statewide database from a survey of licensed physicians was used to identify SLPs. For the two most common cancers (breast and prostate), SLP was examined in relation to radiotherapy after breast-conserving surgery (202 patients) and for prostate cancer (207 patients). RESULTS: The 1,874 patients had 829 different FUPs, of whom 783 had information on SLP; only 37 FUPs had a SS but 269 had a SLP. Of the 1,727 Hispanic patients with known FUP, only 3.5% had a SS FUP, while 36.8% had a FUP with a SLP. Having a FUP with a SLP was statistically significantly associated with receipt of radiotherapy for breast cancer but not for prostate cancer. CONCLUSION: This methodology should be explored in states with larger Hispanic populations, and future efforts should include efforts to obtain data on other cancer treatments (e.g., chemotherapy and hormone therapy). PMID- 17706366 TI - Noradrenergic agonist administration into the central nucleus of the amygdala increases the tail-flick latency in lightly anesthetized rats. AB - The amygdala is a medial forebrain structure with an established role in nociceptive modulation, including the expression of stress-induced hypoalgesia (SIH). Projections from the locus coeruleus increase levels of noradrenaline in the amygdala during acute stress. alpha(2)-Noradrenergic receptor agonists have significant clinical utility as analgesic agents. We therefore hypothesized that alpha(2)-noradrenergic activation of the amygdala may result in behaviorally measurable hypoalgesia. Lightly anesthetized rats underwent microinjection of the alpha(2)-noradrenergic agonist clonidine into the amygdala and intermittent measurement of thermal nociception using the tail-flick latency (TFL). Bilateral microinjection of clonidine into the central nucleus of the amygdala (CeA) resulted in a significant, dose-dependent increase in TFL. This effect was blocked by systemic pre-treatment with the alpha(2)-antagonist yohimbine or by local pre-injection of the alpha(2)-antagonist idazoxan but not by local pre injection of the alpha(1)-antagonist WB-4101. When injected alone, no antagonist resulted in a significant change in TFL compared with baseline. Clonidine injection into the amygdala but outside the CeA, including the basolateral nucleus of the amygdala, did not significantly alter TFL. These results demonstrate that anatomically and pharmacologically specific activation of alpha(2)-receptors in the CeA in lightly anesthetized rats results in behaviorally measurable antinociception. PMID- 17706371 TI - Solitary obsession or menage a trois, but cooperative breeding is never a two party game. PMID- 17706370 TI - Variability of total flavonoids in Crataegus--factor evaluation for the monitored production of industrial starting material. AB - European Hawthorn species (Crataegus spp.) are traditionally used for their demonstrated cardioprotective benefits. Most products are based on the compendial leaf and flower drug (LFD), which is standardised on the total flavonoid content (TF). In order to reduce variability associated with the wild plant origin and to ease product standardisation, we set out to develop a sustainable source of high quality raw material. Firstly, the LFD of wild trees in Germany was screened in terms of TF content (spectrophotometric analysis, calculated as hyperoside) according to the current pharmacopoeia requirements. Secondly, eleven high value provenances were selected, propagated, cultivated and the grafted clones were reanalysed. Thirdly, major environmental and sourcing influences were assessed: the year of harvest, the growing location, exposure to sunlight, the harvest time and the portion of leaf, flower and wood within the LFD. We found the TF in LFD of 150 wild grown Crataegus ranged between 0.28% and 1.92% (average 1.15%). Pure single styled Crataegus monogyna and hybrid trees represented the major portion (57%) of all screened trees. The hybrids with mainly two-styled flowers (pure Crataegus laevigata and hybrids) showed slightly higher TF values. The selected clones proved to maintain a high TF profile in cultivation, although superiority was attenuated when not only O-glycosides, but also C-glycosides were covered by the assay. Environmental influence surpassed in part the genetic variation of the selection in this study. In conclusion, cultivated high performance trees under central European conditions produced LFD exceeding the Pharmacopoeia standards. Careful monitoring of production--particularly in terms of the harvest time and actual LFD location and composition--has decisive impact to guarantee consistent high TF values. PMID- 17706372 TI - Cooperation theory of cooperative breeding. PMID- 17706373 TI - Cooperation-The role of past and present. PMID- 17706374 TI - Association between improvement in depression, reduced benzodiazepine (BDZ) abuse, and increased psychotropic medication use in methadone maintenance treatment (MMT) patients. AB - We had evaluated the depressive symptoms severity of 75 former heroin addicts in methadone maintenance treatment (MMT) using the 21-item Hamilton rating scale for depression (21-HAM-D) and re-assessed 63 of them 1.6+/-0.3 years later. The second mean 21-HAM-D score was lower than the first (11.8+/-8.4 versus 17.4+/ 6.2, p<0.0005). Benzodiazepine (BDZ) abuse was lower although not significantly (p=0.06) during the month preceding the second analysis (32/63, 50.8%) than the month preceding the first one (40/63, 63.5%). Psychotropic medication usage was higher at the second assessment than at the first one (50/63, 79.4% versus 27/63, 42.9%, p<0.0005). 21-HAM-D score reduced significantly over time among 13 "no psychotropic medication" patients (13.5+/-6.3 versus 6.8+/-6.8, p=0.005) and in 27 who started medication following the first assessment (19.3+/-3.8 versus 11.0+/-8.4, p<0.0005), but not in those who were already taking any medication before the first assessment (17.7+/-7.0 versus 15.0+/-8.0, p=n.s). 21-HAM-D score reduced in all BDZ groups but scores were still highest in the 32 patients who continued BDZ abuse (19.4+/-5.6 versus 15.2+/-7.7) followed by 14 who stopped it (16.8+/-6.4 versus 9.6+/-9.1) and were lowest in 17 patients who never abused BDZ (14.2+/-5.2 versus 7.2+/-6.4) (repeated measured, time and group effect, each p<0.0005). Predictors for being depressed at follow-up were pre-existing depression only. Stopping BDZ abuse and starting psychotropic treatment was associated with a reduction of depressive symptoms among MMT patients. PMID- 17706376 TI - Repetitive DNA, molecular cytogenetics and genome organization in the King scallop (Pecten maximus). AB - We studied the structure, organization and relationship of repetitive DNA sequences in the genome of the scallop, Pecten maximus, a bivalve that is important both commercially and in marine ecology. Recombinant DNA libraries were constructed after partial digestion of genomic DNA from scallop with PstI and ApaI restriction enzymes. Clones containing repetitive DNA were selected by hybridisation to labelled DNA from scallop, oyster and mussel; colonies showing strong hybridisation only to scallop were selected for analysis and sequencing. Six non-homologous tandemly repeated sequences were identified in the sequences, and Southern hybridisation with all repeat families to genomic DNA digests showed characteristic ladders of hybridised bands. Three families had monomer lengths around 40 bp while three had repeats characteristic of the length wrapping around one (170 bp), or two (326 bp) nucleosomes. In situ hybridisation to interphase nuclei showed each family had characteristic numbers of clusters indicating contrasting arrangements. Two of the repeats had unusual repetitions of bases within their sequence, which may relate to the nature of microsatellites reported in bivalves. The study of these rapidly evolving sequences is valuable to understand an important source of genomic diversity, has the potential to provide useful markers for population studies and gives a route to identify mechanisms of DNA sequence evolution. PMID- 17706377 TI - Molecular characterization of the herpes simplex virus 1 (HSV-1) homologues, UL25 to UL30, in duck enteritis virus (DEV). AB - A 16.6-kilo-base pair (kb) sequence was amplified from the duck enteritis virus (DEV) clone-03 strain genome using 'targeted gene walking polymerase chain reaction (PCR)'. Seven complete open reading frames (ORFs) were predicted, and designated herpes simplex virus 1 (HSV-1) homologues, unique long (UL) 25, UL26, UL26.5, UL27, UL28, UL29, and UL30. Sequence analysis revealed that the arrangement of seven genes in DEV clone-03 strain was collinear to that from HSV 1. In addition, mRNA transcription orientation was identical to the HSV-1 genes. While UL25, UL26, and UL26.5 shared the same poly A signal, the UL27 and UL28 genes overlapped by 211bp nucleotides and shared the same 3' transcription terminus. UL26.5, an in-frame ORF of UL26, was co-terminal with UL26 at its 3' end. We predicted that the gene arrangement in the unique long segment of the DEV clone-03 was identical to that in HSV-1, particularly in the region from UL25 to UL30 gene. Phylogenetic trees of the putative proteins encoded by these seven genes showed that UL27, UL28, and UL30 had a close evolutionary relationship with the Mardivirus, however, the other four proteins exhibited close relationships with the Simplexvirus or Varicellovirus, indicating that the DEV clone-03 should be placed into a single cluster within the subfamily Alphaherpesvirinae. PMID- 17706375 TI - The alcohol use disorder and associated disabilities interview schedule-IV (AUDADIS-IV): reliability of new psychiatric diagnostic modules and risk factors in a general population sample. AB - This study presents test-retest reliability statistics and information on internal consistency for new diagnostic modules and risk factors for alcohol, drug, and psychiatric disorders from the Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV (AUDADIS-IV). Test-retest statistics were derived from a random sample of 1899 adults selected from 34,653 respondents who participated in the 2004-2005 Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Internal consistency of continuous scales was assessed using the entire Wave 2 NESARC. Both test and retest interviews were conducted face-to-face. Test-retest and internal consistency results for diagnoses and symptom scales associated with posttraumatic stress disorder, attention-deficit/hyperactivity disorder, and borderline, narcissistic, and schizotypal personality disorders were predominantly good (kappa>0.63; ICC>0.69; alpha>0.75) and reliability for risk factor measures fell within the good to excellent range (intraclass correlations=0.50-0.94; alpha=0.64-0.90). The high degree of reliability found in this study suggests that new AUDADIS-IV diagnostic measures can be useful tools in research settings. The availability of highly reliable measures of risk factors for alcohol, drug, and psychiatric disorders will contribute to the validity of conclusions drawn from future research in the domains of substance use disorder and psychiatric epidemiology. PMID- 17706378 TI - Two herpesviruses associated with disease in wild Atlantic loggerhead sea turtles (Caretta caretta). AB - Herpesviruses are associated with lung-eye-trachea disease and gray patch disease in maricultured green turtles (Chelonia mydas) and with fibropapillomatosis in wild sea turtles of several species. With the exception fibropapillomatosis, no other diseases of wild sea turtles of any species have been associated with herpesviral infection. In the present study, six necropsied Atlantic loggerhead sea turtles (Caretta caretta) had gross and histological evidence of viral infection, including oral, respiratory, cutaneous, and genital lesions characterized by necrosis, ulceration, syncytial cell formation, and intranuclear inclusion bodies. Nested polymerase chain reaction targeting a conserved region of the herpesvirus DNA-dependent-DNA polymerase gene yielded two unique herpesviral sequences referred to as loggerhead genital-respiratory herpesvirus and loggerhead orocutaneous herpesvirus. Phylogenetic analyses indicate that these viruses are related to and are monophyletic with other chelonian herpesviruses within the subfamily alpha-herpesvirinae. We propose the genus Chelonivirus for this monophyletic group of chelonian herpesviruses. PMID- 17706379 TI - The NS3 proteins of global strains of bluetongue virus evolve into regional topotypes through negative (purifying) selection. AB - Comparison of the deduced amino acid sequences of the genes (S10) encoding the NS3 protein of 137 strains of bluetongue virus (BTV) from Africa, the Americas, Asia, Australia and the Mediterranean Basin showed limited variation. Common to all NS3 sequences were potential glycosylation sites at amino acid residues 63 and 150 and a cysteine at residue 137, whereas a cysteine at residue 181 was not conserved. The PPXY and PS/TAP late-domain motifs were conserved in all but three of the viruses. Phylogenetic analyses of these same sequences yielded two principal clades that grouped the viruses irrespective of their serotype or year of isolation (1900-2003). All viruses from Asia and Australia were grouped in one clade, whereas those from the other regions were present in both clades. Each clade segregated into distinct subclades that included viruses from single or multiple regions, and the S10 genes of some field viruses were identical to those of live-attenuated BTV vaccines. There was no evidence of positive selection on the S10 gene as assessed by reconstruction of ancestral codon states on the phylogeny, rather the functional constraints of the NS3 protein are expressed through substantial negative (purifying) selection. PMID- 17706380 TI - From Haemobartonella to hemoplasma: molecular methods provide new insights. AB - Hemotropic mycoplasmas (aka hemoplasmas) are the causative agents of infectious anemia in numerous mammalian species. Originally known as Haemobartonella and Eperythrozoon species, these organisms have been reclassified within the genus Mycoplasma. The development of new molecular assays has expanded our knowledge of this heterogeneous group of agents and allowed us to study their epidemiology and pathogenesis. The present review summarizes recently gained insights into feline hemotropic mycoplasmas, formerly known as Haemobartonella felis. Besides the two initially identified feline hemoplasma species, Mycoplasma haemofelis and Candidatus Mycoplasma haemominutum, we discovered a third novel hemoplasma in a Swiss pet cat; preliminary results suggest that the pathogenic potential of the latter agent depends on cofactors. In applying PCR-based assays, feline hemoplasma infections have been documented in domestic cats and wild felids worldwide. Differences between the three hemoplasmas in regard to response to antibiotic treatment and establishment of a carrier status have been reported. Additionally, besides an ostensible vector-borne transmission, direct transmission by aggressive interaction of cats or interspecies transmission might play a role in the epidemiology of these organisms. Based on a potential vector borne and interspecies transmission, a zoonotic potential of hemoplasmas should be further investigated. PMID- 17706382 TI - A repeatability assessment of sows mated 4-6 days after weaning in breeding herds. AB - The objectives of this study were to investigate the associations of weaning-to first-mating interval (WMI) groups with reproductive performance, to determine the repeatability and the correlation coefficients in WMI groups between consecutive parities, and to investigate factors associated with the proportion of sows having WMI 4-6 days. This study was conducted using 55,690 parity records of 11,991 sows born during 1999 in 94 herds. Five groups of WMI were formed: 0-3, 4-6, 7-20, 21-27, and > or =28 days. The correlation and the repeatability of the WMI groups were determined using correlation analysis and variance component analysis. Mixed-effects models were used to analyze the associations of WMI groups with reproductive performance, and the associations of parity, lactation length (LL), and nursing piglets with the proportion of sows having WMI 4-6 days. The overall proportion of the WMI 4-6 days was 82.3%. Sows with WMI 4-6 days had the highest farrowing rate, and had more pigs born alive than those with WMI 7-20 days (P<0.01). At each farrowed parity, sows with WMI 4-6 days had higher parity at removal than those with WMI 7-20 days (P<0.01). The repeatability of the WMI groups was low (0.08), and the correlation coefficients of WMI groups between consecutive parities were also low (0.10< or = r< or =0.18; P<0.01). More than 85.9% of sows with WMI 4-6 days were mated on 4-6 days postweaning at subsequent parity. Meanwhile, 65.8-83.9% of sows with WMI 0-3 or > or =7 days were also mated on 4-6 days postweaning at subsequent parity. Additionally, sows with parity > or =2, LL 24-28 days, and 9-10 nursing piglets were more likely to have WMI 4-6 days (P<0.01). In conclusion, sows having any WMI were more likely to be mated on 4-6 days postweaning at subsequent parity, and sows mated on 4-6 days had higher reproductive performance and higher longevity. Increased LL may increase the proportion of sows having WMI 4-6 days. PMID- 17706381 TI - Genotype 3 hepatitis E has been widespread in pig farms of Shanghai suburbs. AB - Hepatitis E virus (HEV) genotype 3 was first identified in swine raised on a Shanghai suburban pig farm in late 2006. To accurately determine the prevalence of HEV infections among Shanghai pig farms, 426 pig fecal samples were collected from 37 pig farms located in all 10 Shanghai suburban districts and tested for the presence of HEV RNA using RT-PCR. Genetic analysis based on an amplified 150 bp ORF2 fragment revealed 111 samples to be HEV positive, and the prevalence of HEV infection within the different districts varied between 0 and 41.7%. Thirty two samples were sequenced, and phylogenetic analysis indicated that 10 isolates belonged to HEV genotype 4 and were most closely related to 3 human and 2 swine HEV strains, all of which had originally been isolated from Asian countries including Japan and China. The remaining 22 isolates belonged to genotype 3 and were most closely related to a strain of swine HEV, US-SW, isolated from pigs in the United States. Our data indicated that genotype 3 HEV was widespread among suburban Shanghai pig farms although further study is required to determine the source and zoonotic nature of the virus. PMID- 17706383 TI - Preparation and characteristic of vinorelbine bitartrate-loaded solid lipid nanoparticles. AB - A hydrophilic and temperature-induced degradation drug, vinorelbine bitartrate (VB)-loaded solid lipid nanoparticles (SLNs) were prepared by a cold homogenization technique. The physicochemical properties of the SLNs, with various lipid composition, drug content and altered homogenizing times, were investigated. The mean particle size of the SLNs ranged from 150 to 350 nm. The enhancement of lecithin content in lipid matrix resulted in smaller particle of SLNs. The atomic force microscopy (AFM) images displayed that the shape of the SLNs was irregular sphere with smooth surface. The drug entrapment efficiency (EE) could be improved with the increasing of lecithin or oleic acid content in lipid matrix, and reduced with the added amount of drug. The highest EE and drug loading capacity (DL) could reach up to 80 and 6.6%, respectively. The studies of drug release showed that the drug release could last for 48 h, and the rate was delayed by the addition of lecithin or oleic acid in the formulations. The physical stability experiment indicated that the SLNs were stable for 2 months under room temperature. Moreover, the cellular cytotoxicity of VB against MCF-7 cells could be improved by the entrapment of SLNs. PMID- 17706384 TI - Calotropis procera latex affords protection against carbon tetrachloride induced hepatotoxicity in rats. AB - In the present study, latex of Calotropis procera possessing potent antioxidant and anti-inflammatory properties was evaluated for its hepatoprotective effect against carbon tetrachloride (CCl(4)) induced hepatotoxicity in rats. Subcutaneous injection of CCl(4,) administered twice a week, produced a marked elevation in the serum levels of aspartate transaminase (AST), alanine transaminase (ALT) and tumor necrosis factor alpha (TNF-alpha). Histological analysis of the liver of these rats revealed marked necro-inflammatory changes that were associated with increase in the levels of TBARS, PGE(2) and catalase and decrease in the levels of glutathione (GSH), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Daily oral administration of aqueous suspension of dried latex (DL) of Calotropis procera at 5, 50 and 100mg/kg doses produced a dose-dependent reduction in the serum levels of liver enzymes and inflammatory mediators and attenuated the necro-inflammatory changes in the liver. The DL treatment also normalized various biochemical parameters of oxidative stress. Our study shows that the antioxidant and anti-inflammatory effects of DL and silymarin were comparable and suggests that DL could be used as a hepatoprotective agent. PMID- 17706385 TI - Effects of methanolic extract of Asparagus pubescens root on sexual behavior and pituitary hormone secretion on Wistar rats during pregnancy and lactation. AB - We investigated the effect of methanolic extract of Asparagus pubescens root on sexual behavior and on pituitary hormone secretion during pregnancy and lactation on Wistar rats. Different doses (0.25, 0.5, 1.0 and 1.5g/kg) of the extract, given in a single bolus dose or in four (divided) daily injections (0.0625, 0.125, 0.25 and 0.375 mg/(kg day)), inhibited sexual behavior when given to proestrous females in a dose-dependent manner, with the high doses (1.0-1.5g/kg) inhibiting significantly the lordosis quotient. All treated females showed aggressive behavior towards the males to a similar extent irrespective of dose. Fertilization rate, pregnancy, delivery and litter size were normal. Birth weight and growth rates of the pups were also unaffected indicating no deleterious effects of extract on offspring development. The extract had significant effects on preovulatory luteinizing hormone (LH), prolactin (PRL) and progesterone (P4) release. Divided doses of 1.0 and 1.5g/kg significantly decreased preovulatory LH, PRL and P4 release. Administration of 0.5 or 1.5g/kg in bolus dose, produced significant inhibition of preovulatory LH and PRL while 1.5g/kg had no effect. Progesterone was not modified while 1.0g/kg dose caused a decrease in GH. 0.25g/kg produced a paradoxical increase in preovulatory PRL secretion, also seen on day 4 of pregnancy. During pregnancy, both dose regimens were effective in inhibiting the afternoon peaks in prolactin secretion at all dose levels with the exception of 0.25g/kg. There were no effects on the second half of pregnancy or on the suckling-induced PRL release on day 3 postpartum. Circulating GH was scarcely affected on day 3 postpartum. All the results taken together, indicate that the contraceptive effects of the extract may be exerted through interference with neural mechanisms that control preovulatory hormone release and sexual behavior. PMID- 17706386 TI - Flavonoid-rich fraction of Maytenus ilicifolia Mart. ex. Reiss protects the gastric mucosa of rodents through inhibition of both H+,K+ -ATPase activity and formation of nitric oxide. AB - Maytenus ilicifolia Mart. ex. Reissek (Celastraceae), a medicinal plant known in Brazil as "espinheira-santa" is commonly used to treat gastric disorders. The effect of the flavonoid-rich fraction separated from the leaves was evaluated for its gastroprotective properties and the mechanism(s) involved in this activity. Intraperitoneal administration of the flavonoid-rich fraction potently protected rats from experimentally induced chronic (ED(50)=79 mg/kg) and acute gastric lesions by ethanol (ED(50)=25mg/kg) and indomethacin (ED(50)=4 mg/kg) without altering the decreased amount of cytoprotective glutathione and mucus amount in the injured gastric mucosa. A potent reduction of gastric acid hypersecretion (ED(50)=7 mg/kg, i.p.) was accompanied by a reduction of nitric oxide release (ED(50)=1.6 mg/kg, i.p.) in the gastric secretion of 2h pylorus ligated rats which suggests an important role for nitric oxide-dependent mechanisms. Inhibition of gastric acid secretion in vivo was correlated with the in vitro inhibition of rabbit gastric H(+),K(+)-ATPase activity (IC(50)=41 microg/mL). Chemical investigation of the fraction showed galactitol (25%), epicatechin (3.1%) and catechin (2%) as the majoritary components. Collectively, the results show that the flavonoid-rich fraction of Maytenus ilicifolia potently protects animals from gastric lesions with high potency through inhibition of gastric acid secretion. PMID- 17706388 TI - Natural aging, expression of fibrosis-related genes and collagen deposition in rat lung. AB - Aging lung is characterized by morpho-structural modifications, including progressive fibrosis, that lead to an altered function. Here we provide a comprehensive description of lung collagen expression and metabolism during natural aging of rats. Peribronchial collagen increased significantly in the oldest animals (p=0.05 2- vs. 6- and 19-month-old rats), as a consequence of Collagen-I and Collagen-III (COL-I, COL-III) protein accumulation (p<0.05 in 6-, 12- and 19-month-old rats versus the youngest). No changes in fibronectin (FN) protein expression and in COL-III and transforming grow factor beta-1 (TGFbeta-1) mRNA expression were observed. Conversely the transcription activity of the COL-I gene was overexpressed in the oldest animals (p<0.05). In the aged rats, the activity of lung matrix metalloproteinases (MMP), MMP-1 and MMP-2, dropped significantly (p<0.05), whilst MMP-9 levels were slightly decreased. These changes were associated with a concomitant increase of tissue inhibitors of MMP (TIMP-1 and TIMP-2). All together, these results suggest that, during natural aging, collagen accumulation in the lung and its progressive fibrosis are mainly due to a reduced proteolytic activity of MMP, in which TIMP-1 and -2 seem to be the major regulating factors. PMID- 17706387 TI - Age-related decline in actomyosin structure and function. AB - This review focuses on the role of changes in the contractile proteins actin and myosin in age-related deterioration of skeletal muscle function. Functional and structural changes in contractile proteins have been determined indirectly from specific force and unloaded shortening velocity of permeabilized muscle fibers, and were detected directly from site-directed spectroscopy in muscle fibers and from biochemical analysis of purified actin and myosin. Contractile proteins from aged and young muscle differ in (a) myosin and actomyosin ATPase activities, (b) structural states of myosin in contracting muscle, (c) the state of oxidative modifications. The extent of age-related physiological and molecular changes is dependent on the studied animal, the animal's age, and the type of muscle. Therefore, understanding the aging process requires systematic, multidisciplinary studies on physiological, biochemical, structural, and chemical changes in specific muscles. PMID- 17706389 TI - Endovascular stent-graft treatment of thoracic aortic syndromes: a 7-year experience. AB - Thoracic aortic diseases (TAD) are relatively frequent conditions associated with high mortality. Recently, several reports have demonstrated the safety and efficacy of endovascular stent-graft (EVG) placement for TAD as an alternative to open surgery. We report our experience in management of thoracic aortic syndrome on 56 consecutive patients with TAD that underwent endovascular stent-graft repair. MDCT angiography was used in all patients to provide preprocedure evaluation and measurements. In particular it is necessary to evaluate the proximal and distal landing zones of the stent-graft. All EVGs in our series were placed successfully. Conversion to open surgery was never required. Six patients (10.7%) died early after the stent-graft deployment. During follow-up four more patients died. The endoleak rate was 16.7% (no. 10 pt). We did not observe any case of paraplegia. The present study shows the efficacy of EVG in the long-term follow-up, with an overall survival of 82.1%, which is comparable to that reported in recent studies. In conclusion this technique is emerging as an alternative approach in the treatment of TAD because this approach offers a less invasive therapeutic option to standard surgical techniques, even in patients who have associated diseases that make them poor surgical candidates. PMID- 17706390 TI - Isolation and structural identification of an impurity in fluconazole bulk drug substance. AB - Four impurities in fluconazole API sample obtained from a recently proposed synthetic process were detected by HPLC. One of the impurities was unknown having not been reported previously. This less polar unknown impurity was isolated from the crude sample of fluconazole bulk drug using semi-preparative HPLC. Structure of impurity was elucidated as 2-(2-(dimethylamino)-4-fluorophenyl)-1,3-di(3H 1,2,4-triazol-1-yl)propan-2-ol by using NMR spectroscopy(1H, 13C, 19F, 1H-1H, 1H 13C, HMBC and nOe) and mass spectrometry. The formation and synthesis of the impurity was discussed. PMID- 17706391 TI - Comparison of liquid chromatographic methods with direct detection for the analysis of gentamicin. AB - Several liquid chromatographic (LC) methods have been described for the analysis of gentamicin. LC combined with pulsed electrochemical detection (LC-PED) or evaporative light scattering detection (LC-ELSD) was found to be the most suitable technique. A first method, previously developed by Adams et al. used a poly(styrene-divinyl benzene) stationary phase with a mobile phase containing sodium sulphate, sodium-1-octanesulphonate, tetrahydrofuran, 0.2M phosphate buffer (pH 3) and water. However, the polymer columns show low efficiency, which also leads to poor sensitivity. So, recently the use of newer conventional C18 columns was further investigated. Improved separation was obtained using a Supelcosil LC-18-DB column with an adapted mobile phase. Another method derived from a company method was checked by using a Gemini column and a mobile phase containing an aqueous solution of trifluoroacetic acid (TFA) and pentafluoropropionic acid (PFPA) adjusted to pH 2.6 with sodium hydroxide (NaOH). This method was transferred to ELSD by replacing the non-volatile NaOH with volatile ammonium hydroxide solution. A volatile method, which was originally developed for ELSD using an aqueous solution of 50mM TFA and gradient elution with methanol, was also combined with PED. In this study, these methods were compared with regard to their selectivity, sensitivity and ease of use. PMID- 17706392 TI - An HPLC method for the simultaneous determination of neurotoxic dipyridyl isomers in human plasma. AB - Several studies on dipyridyl isomers have suggested that they are neurotoxic and that chronic exposure to these compounds could be a potential human health hazard. A reversed phase HPLC method was developed for the simultaneous quantitation of 2,2'-dipyridyl and its four positional isomers, 2,3'-, 2,4'-, 3,4'- and 4,4'-dipyridyl in human plasma. Plasma samples were basified, extracted with 1-chlorobutane, evaporated, the residue reconstituted in mobile phase, and an aliquot part was analyzed by HPLC. Chromatographic separations were performed on a C(18) reversed phase Sunfire column eluted with a mobile phase composed of potassium phosphate (pH 3.5; 25 mM)-acetonitrile (80:20, v/v). Isomers were separated with good resolution, and quantification was determined utilizing an internal standard of quinoxaline. The method has been validated over a range from 30 to 2000 ng/ml with correlation coefficients higher than 0.995. Extraction recoveries for the dipyridyl isomers averaged from 65 to 92%. Limit of detection and limit of quantitation for the dipyridyl isomers ranged from 15 to 70 ng/ml and 30 to 90 ng/ml, respectively. The inter- and intra-day variation did not exceed 7% with an accuracy range of 96-102%. The described analytical method was successfully utilized for the determination of dipyridyl isomers in human plasma and suggested the need for more routine monitoring of tobacco smokers and other individuals who are involuntarily exposed to environmental source of dipyridyl isomers. PMID- 17706393 TI - LC-MS/MS method for the simultaneous determination of icariin and its major metabolites in rat plasma. AB - A rapid and sensitive method using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) was developed and validated for the simultaneous quantitative determination of icariin and its two major metabolites, icariside I and icariside II in rat plasma. The analytes were extracted by liquid-liquid extraction with ethyl acetate after internal standard (daidzein) spiked. The separation was performed by a ZORBAX SB-C(18) column (3.5 microm, 2.1 mm x 100 mm) and a C(18) guard column (5 microm, 4.0 mm x 2.0mm) with an isocratic mobile phase consisting of acetonitrile-water-formic acid (50:50:0.05, v/v/v) at a flow rate of 0.25 mL/min. The Agilent G6410A triple quadrupole LC-MS system was operated under the multiple reaction monitoring (MRM) mode using the electrospray ionization technique in positive mode. The nominal retention times for icariin, icariside I, icariside II and daidzein were 1.21, 1.88, 2.34 and 1.35 min, respectively. The lower limits of quantification (LLOQ) of icariin, icariside I and icariside II of the method were 1.0, 0.5 and 0.5 ng/mL, respectively. The method was linear for icariin and its metabolites with correlation coefficients >0.995 for all analytes. The intra-day and inter-day accuracy and precision of the assay were less than 12.5%. This method has been applied successfully to a pharmacokinetic study involving the intragastric administration of icariin to rats. PMID- 17706394 TI - Alkaloid profiling in crude and processed Strychnos nux-vomica seeds by matrix assisted laser desorption/ionization-time of flight mass spectrometry. AB - Direct analysis of alkaloids in the tissues of crude and processed Strychnos nux vomica seeds by MALDI-TOFMS was described. The alkaloid profiles of the herb drugs were obtained without the need of complicated sample preparation to avoid potential damage or change of the active components. Seed tissues that were optimally sliced to a thickness of 10-20 microm from the crude and processed Strychnos nux-vomica seeds as well as various parts of tissue such as endosperm and epidermis were analyzed on MALDI target plate after the matrix was directly applied onto the tissue surface. The obtained alkaloid profiles provided valuable information for the differentiation of crude and processed Strychnos nux-vomica seeds and for the explanation of the significantly different toxicity. Experimental results indicated that the direct MALDI-TOFMS analysis allowed rapid screening of the alkaloid components in Strychnos nux-vomica seeds. PMID- 17706395 TI - Laccase production at reactor scale by filamentous fungi. AB - Laccases have received much attention from researchers during the past decades due to their broad substrate specificity and to the fact that they use molecular oxygen as the final electron acceptor instead of hydrogen peroxide as used by peroxidases. This makes laccases highly interesting for a wide variety of processes, such as textile dye decolouration, pulp bleaching, effluent detoxification, biosensors and bioremediation. The successful application of laccases to the above-mentioned processes requires the production of large quantities of enzyme at low cost. Filamentous fungi are able to produce laccases in high amounts, however, an efficient production system at bioreactor scale is still lacking. This is mainly due to the fact that laccase production by wild type strains of filamentous fungi is linked to secondary metabolism, which implies that the following drawbacks must be overcome: uncontrolled fungal growth, the formation of polysaccharides around mycelia and the secretion of certain compounds (i.e. proteases) that inactivate laccases. This review summarizes the current status of laccase production by wild-type strains of filamentous fungi at the bioreactor scale. PMID- 17706397 TI - [Hyperbaric oxygen therapy as an adjunctive treatment for acute mediastinitis due to oesophageal perforation: a case report]. AB - In spite of antibiotic treatment, of progress of resuscitation and surgery, acute posterior mediastinitis remains associated to a high mortality. We report a case of man with posterior mediastinitis by performing of the cervical oesophagus. While his state remained still with the classic treatment, the contribution of the hyperbaric oxygen therapy quickly improved his state. This therapeutics in addition in the usual treatment could improve the survival in this affection. PMID- 17706396 TI - Developmental effects of SSRIs: lessons learned from animal studies. AB - Selective serotonin reuptake inhibitors (SSRIs) are utilized in the treatment of depression in pregnant and lactating women. SSRIs may be passed to the fetus through the placenta and the neonate through breastfeeding, potentially exposing them to SSRIs during peri- and postnatal development. However, the long-term effects of this SSRI exposure are still largely unknown. The simplicity and genetic amenability of model organisms provides a critical experimental advantage compared to studies with humans. This review will assess the current research done in animals that sheds light on the role of serotonin during development and the possible effects of SSRIs. Experimental studies in rodents show that administration of SSRIs during a key developmental window creates changes in brain circuitry and maladaptive behaviors that persist into adulthood. Similar changes result from the inhibition of the serotonin transporter or monoamine oxidase, implicating these two regulators of serotonin signaling in developmental changes. Understanding the role of serotonin in brain development is critical to identifying the possible effects of SSRI exposure. PMID- 17706398 TI - Cytochrome P450IA1 polymorphisms along with PM(10) exposure contribute to the risk of birth weight reduction. AB - We explored the effects of particulate matter <10 microm (PM(10)) exposure along with CYP1A1 polymorphisms of MspI (T6235C) and NcoI (Ile462Val) on reduced birth weight (BW). A prospective cohort study was done with women who delivered from 2001 to 2004 at Ewha Womans University Hospital, Seoul, Korea. We compared the estimated least squares means of BW in the generalized linear model, after adjusting for controlling factors. High PM(10) exposure at the 90th percentile level and above during the 1st trimester conferred a significant risk for reduced BW, compared with low PM(10) exposure below the 90th percentile level. The effect of high PM(10) exposure during the 1st trimester of pregnancy compared with low PM(10) exposure was greater for women with MspI TC/CC and NcoI IleVal/ValVal genotypes than for those with MspI TT and NcoI IleIle genotypes. In conclusion, high PM(10) exposure during the 1st trimester increased the risk for reduced BW in concert with MspI TC/CC and NcoI IleVal/ValVal genotypes in Korean women. PMID- 17706399 TI - 3D planar reformation of vascular central axis surface with biconvex slab. AB - Curved multi-planar reformation (curved MPR) is one of the commonly used vascular visualization methods in clinics. It re-samples and visualizes the vascular central axis surface (VCAS), which is a curved surface passing through the vascular central axis (VCA) or vessel centerline. The rotation of the VCAS along the VCA generates a set of 2D images. In this paper, we introduce a 3D curved MPR method, VCAS planar reformation (VPR) by a convex hull, called a biconvex slab. The entire vessel is enclosed within a biconvex slab and rendered in one image by volume rendering, such as MIP or X-ray. The method is applied to computed tomographic angiography (CTA) data sets. The resulting image is clear and free from obstruction by bones and other adjacent organs. PMID- 17706400 TI - Encapsulated Bifidobacteria reduced bacterial translocation in rats following hemorrhagic shock and resuscitation. AB - OBJECTIVE: The aim of the present study was to determine the effects of peroral encapsulated Bifidobacteria on intestinal microflora, bacterial translocation (BT), plasma endotoxin, and ileal villi injury in a rat model of hemorrhagic shock. METHODS: Sprague-Dawley rats were fed daily with three different diet supplements: phosphate buffered saline, Bifidobacteria (10(9) colon-forming units/day), or microencapsulated Bifidobacteria (10(9) colony-forming units/day). After 7 d of treatment, rats were anesthetized for hemorrhagic or sham shock. Then a laparotomy was performed to determine microbiological analysis of cecal content, BT to mesenteric lymph nodes, plasma endotoxin, and terminal ileal villous damage. RESULTS: In the hemorrhagic-shock model, rats pretreated with Bifidobacteria showed decreases in total aerobes in cecum, magnitude of total aerobes to BT, levels of plasma endotoxin, and percentage of ileal villous damage when compared with rats treated with phosphate buffered saline. Encapsulated Bifidobacteria induced greater decreases than intact Bifidobacteria in this model, except for no difference in percentage of ileal villous damage between the two groups. In addition, the incidence of BT was decreased in hemorrhagic rats pretreated with Bifidobacteria compared with control. However, the magnitude of total anaerobes and Bifidobacteria BT were similar among hemorrhagic-shocked rats receiving three different supplements. CONCLUSION: Bifidobacteria can be useful in preventing BT in hemorrhagic-shocked rats, and encapsulated Bifidobacteria can augment this effect further. Peroral administration of Bifidobacteria may be a favorable strategy to prevent sepsis and multiple organ dysfunction syndrome in hemorrhagic shock. PMID- 17706401 TI - Epileptic seizures are temporally interdependent under certain conditions. AB - PURPOSE: The possibility that seizures may be intercorrelated has not been sufficiently investigated. A handful of studies, the majority based on patient seizure diaries, provide disparate results: some claim that seizures are serially correlated and others that they are random events. This study investigates the effect that a seizure may have on the time of occurrence and severity of subsequent ones in subjects undergoing invasive surgical evaluation. METHODS: The Savit-Green statistic, a measure of time series lag dependency, was applied to seizure sequences derived from the ECoGs of 26 epilepsy surgery candidates. Seizure onset times, intensities and durations were obtained using a validated seizure detection algorithm, and from these, inter-seizure intervals (ISI) and severities were computed and their lag dependencies were compared to suitably randomized and amplitude-scaled linear surrogate sets. RESULTS: The null hypothesis (seizures are uncorrelated) was rejected (p<0.05) for ISI in 12/26 subjects and for seizure severity in 13/26. The temporal correlations spanned up to three preceding seizures and were nonlinear in 7/12 subjects for ISI and in 8/13 for severity. An important finding is that dependencies may be related to the frequency of seizures in the sample. CONCLUSIONS: This study demonstrates that under certain conditions, there are linear and nonlinear seizure dependencies of low order and at small time scales (minutes to hours), for ISI and seizure severity. This observation has important implications for studies of seizure predictability, which de facto treat seizures as independent occurrences. Given the study subjects' conditions, it is not clear if the dependencies reflect innate brain dynamics, drug withdrawal, local trauma or a combination of these. PMID- 17706402 TI - Challenges in Brucella bacteraemia. AB - Brucella possesses unique historical, epidemiological, phylogenetic and pathogenetic characteristics that constantly reinforce the pathogen's place at the epicentre of scientific interest. One such unique characteristic is the significance of bacteraemia in the course of the disease. Bacteraemia in brucellosis may be periodically present, of limited practical diagnostic importance, and of doubtful significance as an index of bacteriological cure. On the other hand, recognition of bacteraemia augments prognosis, typing and biotyping (and thus further research). Recent advances in molecular diagnosis with the help of real time polymerase chain reaction (rtPCR) have shown that bacteraemia in brucellosis may persist, at culture non-detectable levels, for protracted periods even after apparent clinical cure. This raises important issues for future research, implying that the pathogen may actually be non eradicable. PMID- 17706403 TI - Cosmesis, late sequelae and local control after breast-conserving therapy: influence of type of tumour bed boost and adjuvant chemotherapy. AB - AIMS: To study the influence of various factors affecting cosmetic outcome and late sequelae in a large cohort of women treated with breast-conserving therapy. MATERIALS AND METHODS: Between 1980 and 2000, 1022 pathological stage I/II breast cancer patients underwent breast-conserving therapy. On the basis of the type of tumour bed boost they received after whole breast radiotherapy, these women were assigned to three groups: (A) low dose rate (LDR) brachytherapy of 15-20 Gy (n=383); (B) high dose rate (HDR) brachytherapy of 10 Gy (optimised) in a single fraction (n=153); (C) electron beam 15 Gy/six fractions (n=460). Systemic adjuvant therapy was given to 757 women, of whom 570 received adjuvant chemotherapy. RESULTS: Cosmesis at the last follow-up was good or excellent in 77% of women. Post-radiation worsening of cosmesis was observed in 11.5% of women and was similar in the three boost groups. Moderate to severe late breast sequelae were observed in 22% of women in group B, which was significantly higher than the 12% in group A (P=0.002) and 9% in group C (P=0.0001). The actuarial 5 year local control rate was 91% and was 90, 92 and 93% in groups A, B and C, respectively. Tumour size (P=0.049) and adjuvant chemotherapy (P=0.04) were the significant factors affecting cosmetic outcome on univariate analysis. On multivariate analysis, adjuvant chemotherapy was the only factor leading to worsening in the cosmetic outcome, with P=0.03 (hazard ratio 1.65 [95% confidence interval 1.05-2.59]). CONCLUSION: The type of tumour bed boost did not have a significant effect on the worsening of cosmetic outcome. However, there were significantly more late breast sequelae in women treated with single fraction HDR implants. Chemotherapy had an adverse effect on the cosmetic outcome, but the late breast sequelae and local control rates were comparable. PMID- 17706404 TI - Target volume definition for head and neck intensity modulated radiotherapy: pre clinical evaluation of PARSPORT trial guidelines. AB - AIMS: There is considerable controversy surrounding target volume definition for parotid-sparing intensity modulated radiotherapy (IMRT) for head and neck cancer. The aim of this study was to evaluate the dosimetric and radiobiological predictors of outcome anticipated by application of the detailed target volume definition guidelines agreed for the UK multicentre randomised controlled trial of parotid-sparing IMRT (PARSPORT). MATERIALS AND METHODS: Five patients eligible for the study were delineated using the trial guidelines. Following the protocol, plans were produced to treat these volumes with three-dimensional radiotherapy (control arm) and IMRT aimed to spare dose to the contralateral parotid gland (experimental arm). Dosimetric comparisons were made between plans, and normal tissue complication probability (NTCP) modelling for salivary glands was carried out. RESULTS: Doses delivered to the planning target volumes (PTV) were similar with each technique, although IMRT produced more homogeneous irradiation of the PTV. Mean doses to the contralateral parotid gland were 22.4+/-1.7 Gy with the IMRT plans vs 60.0+/-7.2 Gy with three-dimensional radiotherapy, P=0.0003. Calculated contralateral parotid gland NTCP values for grade 2 xerostomia were 20 22% for IMRT and 98-100% for three-dimensional radiotherapy (P<0.0001). CONCLUSION: Pre-clinical evaluation of the PARSPORT trial target volume definition guidelines provides theoretical support for a significant reduction in xerostomia rates. These data await confirmation from the clinical trial results. PMID- 17706405 TI - Improving adjuvant chemotherapy in breast cancer -- can we get more for less with TACT2? PMID- 17706406 TI - Carbonic anhydrase IX expression and outcome after radiotherapy for muscle invasive bladder cancer. AB - AIMS: Carbonic anhydrase IX (CA IX) expression has been described as an endogenous marker of hypoxia in solid neoplasms. Furthermore, CA IX expression has been associated with an aggressive phenotype and resistance to radiotherapy. We assessed the prognostic significance of CA IX expression in patients with muscle-invasive bladder cancer treated with radiotherapy. MATERIALS AND METHODS: A standard immunohistochemistry technique was used to show CA IX expression in 110 muscle-invasive bladder tumours treated with radiotherapy. Clinicopathological data were obtained from medical case notes. RESULTS: CA IX immunostaining was detected in 89 ( approximately 81%) patients. Staining was predominantly membranous, with areas of concurrent cytoplasmic and nuclear staining and was abundant in luminal and perinecrotic areas. No significant correlation was shown between the overall CA IX status and the initial response to radiotherapy, 5-year bladder cancer-specific survival or the time to local recurrence. CONCLUSIONS: The distribution of CA IX expression in paraffin embedded tissue sections seen in this series is consistent with previous studies in bladder cancer, but does not provide significant prognostic information with respect to the response to radiotherapy at 3 months and disease-specific survival after radical radiotherapy. PMID- 17706407 TI - A long-term survivor with pulmonary large-cell neuroendocrine carcinoma. AB - Pulmonary large-cell neuroendocrine carcinoma (LCNEC) has been characterized by highly aggressive behavior, with early spread to both regional lymph nodes and distant sites and a rapidly fatal course. In fact, no reports have described an advanced pulmonary LCNEC patient who has had long-term survival. A patient with large-sized pulmonary LCNEC, who is free of disease 11 years after surgery and postoperative chemotherapy, was reported. PMID- 17706409 TI - Role of NT-proBNP and 6MWD in chronic thromboembolic pulmonary hypertension. AB - BACKGROUND: This study aims to evaluate the role of NT-proBNP and six minute walking distance (6MWD) in the pre- and post-operative assessment of subjects undergoing pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Subjects undergoing PEA between August 2004 and July 2006 were assessed at baseline and 3 months post-operatively with resting haemodynamics, NT-proBNP and 6MWD. RESULTS: A number of 111 subjects underwent surgery, of which 102 were included. 15 subjects died before their 3 month assessment. Non-survivors had significantly worse preoperative NT-proBNP and 6MWD (4728 pg/mL vs 1863 pg/mL, p=0.001, 182.4 m vs 263.5 m, p=0.001). Taking pre operative cut-off values of 1200 pg/mL for NT-proBNP and 345 m for 6MWD, both tests had high negative predictive value for predicting mortality (97.3% and 100%, respectively). Amongst survivors, peri-operative changes in NT-proBNP and 6MWD correlated with changes in total pulmonary resistance (TPR) (r=0.49, p<0.001 and r=-0.46, p<0.001). Post-operatively, both NT-proBNP and 6MWD also correlated with mPAP (r=0.65, p<0.001 and r=-0.50, p<0.001) and PVR (r=0.63, p<0.001 and r= 0.47, p<0.001). The ability of NT-proBNP to predict persistent pulmonary hypertension was significantly confounded by age, but not gender, BMI or renal function. CONCLUSIONS: Pre-operative evaluation with NT-proBNP and 6MWD helps risk-stratify patients prior to PEA. Post-operatively, both markers correlate with changes in disease burden and right ventricular function. These results suggest that both NT-proBNP and 6MWD offer effective 'bedside' tools for the long term follow up of patients with CTEPH. PMID- 17706408 TI - Prevention of bacterial meningitis: an overview of Cochrane systematic reviews. AB - Acute bacterial meningitis (ABM) is an acute inflammation of leptomeninges caused by bacteria, and has a case fatality rate of 10-30%. Prevention strategies, such as vaccination and prophylactic antibiotics, can prevent ABM and have substantial public health impact by reducing the disease burden associated with it. The aim of this paper is to summarize the main findings from Cochrane systematic reviews that have considered the evidence for measures to prevent ABM. We assessed the evidence available in the Cochrane Library. We found five Cochrane reviews focused on the prevention of ABM; three with use of vaccination and two with prophylactic antibiotics. Polysaccharide serogroup A vaccine is strongly protective for the first year, against serogroup A meningococcal meningitis in adults and children over 5 years of age. Meningococcal serogroup C conjugate (MCC) vaccine is safe and effective in infants. Haemophilus influenzae type b (Hib) vaccine is safe and effective against Hib-invasive disease at all ages. Ceftriaxone, rifampicin and ciprofloxacin are the most effective prophylactic antibiotics against Neisseria meningitidis. There is sufficient evidence to use polysaccharide serogroup A vaccine to prevent serogroup A meningococcal meningitis, MCC conjugate vaccines to prevent meningococcal C meningitis and Hib conjugate vaccine to prevent Hib infections. More studies are needed to evaluate the effects of Hib conjugate vaccine on mortality. Further, studies are required to compare the relative effectiveness of ceftriaxone, ciprofloxacin and rifampicin in chemoprophylaxis against meningococcal infection. PMID- 17706411 TI - A plant growth promoting rhizobacterium, Paenibacillus polymyxa strain GBR-1, suppresses root-knot nematode. AB - Exposure of root-knot nematode, Meloidogyne incognita to various concentrations (5-100%) of culture filtrate of Paenibacillus polymyxa GBR-1 under in vitro conditions significantly reduced egg hatch and caused substantial mortality of its juveniles. The increase in the exposure durations of juveniles to culture filtrate and its concentrations increased the mortality rate. Similarly, higher concentrations increased its inhibitory effect on egg hatch. In higher concentrations (25-100%) egg hatch was inhibited by 84-91% after 2 days of exposures as compared to control in sterile distilled water. Application of various concentrations of culture filtrate extract or bacterial suspension of P. polymyxa GBR-1 into potting soil infested with 2000 J2 of M. incognita, reduced the root galling and nematode populations and increased tomato plant growth and root-mass production compared with untreated control (P< or = 0.05). The beneficial effect of P. polymyxa GBR-1 into potted soil increased exponentially with the increase in dose concentrations. Root gall index was reduced from 4.8 to 1.4 and 1.8 when potting soil was treated with 10% concentrations of culture filtrate extract and bacterial suspension, respectively, compared with untreated control. Application of bacterial suspension of P. polymyxa GBR-1 into potted soil at 3 day pre-inoculation of nematode was the most effective followed by simultaneously and at 2 days post-inoculation; as root galling was reduced by 62.5%, 58.3% and 50.0%, respectively, compared with untreated control. PMID- 17706410 TI - From chills to chilis: mechanisms for thermosensation and chemesthesis via thermoTRPs. AB - Six highly temperature-sensitive ion channels of the transient receptor potential (TRP) family have been implicated to mediate temperature sensation. These channels, expressed in sensory neurons innervating the skin or the skin itself, are active at specific temperatures ranging from noxious cold to burning heat. In addition to temperature sensation thermoTRPs are the receptors of a growing number of environmental chemicals (chemesthesis). Recent studies have provided some striking new insights into the molecular mechanism of thermal and chemical activation of these biological thermometers. PMID- 17706412 TI - Anionic surfactants in treated sewage and sludges: risk assessment to aquatic and terrestrial environments. AB - Compared to low concentrations of anionic surfactants (AS) in activated sludge process effluents (ASP) (<0.2 mg/L), upflow anaerobic sludge blanket-polishing pond (UASB-PP) effluents were found to contain very high concentrations of AS (>3.5 mg/L). AS (or linear alkylbenzen sulfonate, LAS) removals >99% have been found for ASP while in case of UASB-PP it was found to be < or = 30%. AS concentrations averaged 7347 and 1452 mg/kg dry wt. in wet UASB and dried sludges, respectively. Treated sewage from UASB based sewage treatment plants (STPs) when discharged to aquatic ecosystems are likely to generate substantial risk. Post-treatment using 1-1.6d detention, anaerobic, non-algal polishing ponds was found ineffective. Need of utilizing an aerobic method of post-treatment of UASB effluent in place of an anaerobic one has been emphasized. Natural drying of UASB sludges on sludge drying beds (SDBs) under aerobic conditions results in reduction of adsorbed AS by around 80%. Application of UASB sludges on SDBs was found simple, economical and effective. While disposal of treated UASB effluent may cause risk to aquatic ecosystems, use of dried UASB sludges is not likely to cause risk to terrestrial ecosystems. PMID- 17706413 TI - Comparative studies of products produced from four different biomass samples via deoxy-liquefaction. AB - The objective of this study is to investigate the distribution of products, i.e. gas, liquid oil and char from four different biomass samples (legume straw, corn stalk, cotton stalk and wheat straw) and analysis of the oil for the differences in the hydrocarbon composition with respect to the materials by deoxygenate liquefaction (abbr. deoxy-liquefaction). GC/MS was used to analyze the gas and oil components. According to the similarity of the natural petroleum and bio petroleum, a new standard for bio-petroleum was established in this paper. The striking characteristic of the bio-petroleum was H/C>1.5, oxygen content <6% and the HHV>40 MJ/kg, containing mainly alkanes, cycloalkanes and aromatic hydrocarbons. In this paper, only the oil produced from legume straw and corn stalk could be called bio-petroleum. The oil derived from different samples contained almost the same compounds, while the relative content varied based on the different content of the main biomass components (lignin and holocellulose). The gaseous products were carbon dioxide, carbon monoxide, methane and hydrogen. In addition, small amount of ethylene, ethane and propane was also observed in gas. The major gas product was carbon dioxide (81.29-86.33%) for all samples. PMID- 17706414 TI - Uncertainty of preset-order kinetic equations in description of biosorption data. AB - This study investigated uncertainty encountered in description of biosorption data by preset-order kinetic equations. It was shown that for a given set of biosorption data, the kinetic equations with the preset-order of first to fourth can all provide equally good fittings to the experimental data, indicated by comparable values of correlation coefficients (R). In the sense of chemistry, the reaction order of a biosorption process must be experimentally determined rather than preset to a fixed value. In this case, a generalized kinetic equation was proposed without any constrain on the reaction order. In order to statistically evaluate the curve fittings of biosorption data by various kinetic equations, a concept of the relative goodness of curve fitting was developed. Compared to all the preset-order kinetic equations studied, the generalized equation can offer the best prediction for experimental data obtained in various biosorption experiments. PMID- 17706415 TI - Antioxidant properties of methanol extract and its solvent fractions obtained from selected Indian red seaweeds. AB - In vitro antioxidant activities of three selected Indian red seaweeds - viz., Euchema kappaphycus, Gracilaria edulis and Acanthophora spicifera were evaluated. Total phenolic content and reducing power of crude methanol extract were determined. The antioxidant activities of total methanol extract and five different solvent fractions (viz., petroleum ether (PE), ethyl acetate (EA), dichloromethane (DCM), butanol (BuOH) and aqueous) were also evaluated. EA fraction of A. spicifera exhibited higher total antioxidant activity (32.01 mg ascorbic acid equivalent/g extract) among all the fractions. Higher phenolic content (16.26 mg gallic acid equivalent/g extract) was noticed in PE fraction of G. edulis. Reducing power of crude methanol extract increased with increasing concentration of the extract. Reducing power and hydroxyl radical scavenging activity of E. kappaphycus were higher compared to standard antioxidant (alpha tocopherol). The total phenol content of all the seaweeds was significantly different (P<0.05). In vitro antioxidant activities of methanol extracts of all the three seaweeds exhibited dose dependency; and increased with increasing concentration of the extract. PMID- 17706416 TI - In vitro studies of eggplant (Solanum melongena) phenolics as inhibitors of key enzymes relevant for type 2 diabetes and hypertension. AB - National Diabetes Education Program of NIH, Mayo Clinic and American Diabetes Association recommend eggplant-based diet as a choice for management of type 2 diabetes. The rationale for this suggestion is the high fiber and low soluble carbohydrate content of eggplant. We propose that a more physiologically relevant explanation lies in the phenolic-linked antioxidant activity and alpha glucosidase inhibitory potential of eggplant which could reduce hyperglycemia induced pathogenesis. Results from this study indicate that phenolic-enriched extracts of eggplant with moderate free radical scavenging-linked antioxidant activity had high alpha-glucosidase inhibitory activity and in specific cases moderate to high angiotensin I-converting enzyme (ACE) inhibitory activity. Inhibition of these enzymes provide a strong biochemical basis for management of type 2 diabetes by controlling glucose absorption and reducing associated hypertension, respectively. This phenolic antioxidant-enriched dietary strategy also has the potential to reduce hyperglycemia-induced pathogenesis linked to cellular oxidation stress. These results provide strong rationale for further animal and clinical studies. PMID- 17706417 TI - Production of ethanol from soybean hull hydrolysate by osmotolerant Candida guilliermondii NRRL Y-2075. AB - In this research, we studied the use of soybean hull hydrolysate (SHH) as a substrate for ethanol and xylitol production using an osmotolerant strain of Candida guilliermondii. The best acid hydrolysis of soybean hull achieved a recovery of 85 and 62% of xylose and mannose, respectively. Among detoxification treatments, activated charcoal 10% (w/v) showed the best results. Kinetic parameters obtained from the cultivation on four-fold concentrated SHH have shown that the osmotic pressure of this medium is higher than that supported by most osmophilic yeasts, revealing the osmotolerant characteristic of C. guilliermondii NRRL Y-2075. When cultivations were carried out on two times concentrated SHH, we obtained high yields of ethanol production, showing the prospect of SHH as a candidate for this biofuel production. Although xylose was present in high concentrations, no xylitol was produced, probably due to the presence of furfural acting as external electron acceptor or some varying cofactor preference of xylose reductase in this yeast strain. PMID- 17706419 TI - Development of alcoholic and malolactic fermentations in highly acidic and phenolic apple musts. AB - This work reports the influence of the high acidity and high phenolic content in apple musts on the development of alcoholic and malolactic fermentations and on the final chemical and microbiological composition of the ciders. Four different musts were obtained by pressing several varieties and proportions of cider apples from the Basque Country (Northern Spain). Specially acidic and phenolic varieties were selected. Three musts were obtained in experimental stations and the fourth one, in a cider factory following usual procedures. The evolution of these musts was monitored during five months by measuring 18 parameters throughout eight samplings. In the most acidic of the three experimental musts, yeasts were added to complete the alcoholic fermentation. In the rest of the musts, alcoholic and malolactic fermentations took place spontaneously due to natural microflora and no chemical was added to control these processes. Malolactic fermentation (MLF) finished before alcoholic fermentation in the three tanks obtained in experimental stations, even in the most acidic and phenolic one (pH 3.18, 1.78 g tannic acid/l). After four months, these ciders maintained low levels of lactic acid bacteria (10(4)CFU/ml) and low content of acetic acid (<0.60 g/l). Both fermentations began simultaneously in the must obtained in the cider factory, but MLF finished 10 days after alcoholic fermentation. Subsequently, this must maintained a high population of lactic acid bacteria (>10(6)CFU/ml), causing a higher production of acetic acid (>1.00 g/l) than in the other ciders. These results show the possible advantages of MLF finishing before alcoholic fermentation. PMID- 17706418 TI - Adsorption of Cu(II), Cd(II), and Pb(II) from aqueous single metal solutions by cellulose and mercerized cellulose chemically modified with succinic anhydride. AB - This work describes the preparation of new chelating material from mercerized cellulose. The first part treats the chemical modification of non-mercerized cellulose (cell 1) and mercerized cellulose (cell 2) with succinic anhydride. Mass percent gains (mpg) and degree of succinylation (DS) of cell 3 (from cell 1) and cell 4 (from cell 2) were calculated. Cell 4 in relation to cell 3 exhibited an increase in mpg and in the concentration of carboxylic functions of 68.9% and 2.8 mmol/g, respectively. Cells 5 and 6 were obtained by treatment of cells 3 and 4 with bicarbonate solution to release the carboxylate functions and characterized by FTIR. The second part compares the adsorption capacity of cells 5 and 6 for Cu2+, Cd2+, and Pb2+ ions in an aqueous single metal solution. Adsorption isotherms were developed using Langmuir model. Cell 6 in relation to cell 5 exhibited an increase in Qmax for Cu2+ (30.4 mg/g), Cd2+ (86.0 mg/g) and Pb2+ (205.9 mg/g). PMID- 17706420 TI - Use of rice husk for the adsorption of congo red from aqueous solution in column mode. AB - A continuous fixed bed study was carried out by using rice husk as a biosorbent for the removal of congo red (CR) from aqueous solution. The effects of important factors, such as the value of initial pH, existing salt, the flow rate, the influent concentration of CR and bed depth, were studied. Data confirmed that the breakthrough curves were dependent on flow rate, initial dye concentration and bed depth. Thomas, Adams-Bohart, and Yoon-Nelson models were applied to experimental data to predict the breakthrough curves using non-linear regression and to determine the characteristic parameters of the column useful for process design, while bed depth/service time analysis (BDST) model was used to express the effect of bed depth on breakthrough curves. The results showed that Thomas model was found suitable for the normal description of breakthrough curve at the experimental condition, while Adams-Bohart model was only for a initial part of dynamic behavior of the rice husk column. The data were in good agreement with BDST model. It was concluded that the rice husk column can remove CR from solution. PMID- 17706421 TI - Studies of optimum conditions for covalent immobilization of Candida rugosa lipase on poly(gamma-glutamic acid) by RSM. AB - Poly(gamma-glutamic acid) (gamma-PGA) is a material of polymer. Immobilization of Candida rugosa lipase (Lipase AY-30) by covalent binding on gamma-PGA led to a markedly improved performance of the enzyme. Response surface methodology (RSM) and 3-level-3-factor fractional factorial design were employed to evaluate the effects of immobilization parameters, such as immobilization time (2-6h), immobilization temperature (0-26 degrees C), and enzyme/support ratio (0.1-0.5, w/w). Based on the analysis of ridge max, the optimum immobilization conditions were as follows: immobilization time 2.3h, immobilization temperature 13.3 degrees C, and enzyme/support ratio 0.41 (w/w); the highest lipase activity obtained was 1196 U/mg-protein. PMID- 17706422 TI - Combustion characteristics of different parts of corn straw and NO formation in a fixed bed. AB - Experiments with five samples of corn straw were carried out on a one-dimensional bench combustion test rig. The bed temperature distribution and the mass loss of fuel and gas components such as O2, CO, CO2 and NO were measured in the bed. The combustion of corn straw occurred in two stages, ignition front propagation and char oxidation. The average burning rate increased with an increase in the primary air flow until a critical point was reached, beyond which a further increase in the primary air flow resulted in a decreased burning rate. The mean concentration of NO reached a minimum value and then increased with increased primary air flow. The time taken for the drying front to reach the bottom of the bed was 800 s, 700 s, and 500 s; the temperatures in the high bed temperature zones were 900-935 degrees C, 800-850 degrees C and 700-743 degrees C; and the maximum concentrations of NO were 725 ppmv, 1287 ppmv, and 2730 ppmv, for whole corn stalks, hollow corn stalks and flaked corn stalks, respectively. The maximum concentrations of CO and NO were quite different between samples. There was only one peak in the distribution of NO concentration for sample B, but there were two peaks for whole corn stalks and sample A. PMID- 17706423 TI - Effect of carbon sources and shock loading on the removal of chlorophenols in sequential anaerobic-aerobic reactors. AB - The effect of carbon sources and shock loadings have been studied using two sets of sequential upflow anaerobic sludge blanket (UASB) and rotating biological contactor (RBC) reactors viz., UASB-I followed by RBC-I and UASB-II followed by RBC-II for the removal of two different priority pollutants, 2-CP and 2,4-DCP present in simulated wastewaters. Sodium formate, sodium propionate, glucose and methanol were used separately as four different carbon sources in the feed as co substrate. Methanol was found to be the best carbon source for UASB reactors showing 95% 2-CP and 81.1% 2,4-DCP removals. The carbon sources formate and propionate were not found suitable in UASB reactors as only 22.6-46.8% 2-CP and 41.9-42.8% 2,4-DCP removals were observed. With glucose as carbon source 93.7% 2 CP and 79.6% 2,4-DCP removals were observed in UASB reactors. For all the four carbon sources more than 97.6% 2-CP and 99.7% 2,4-DCP removals were observed in sequential reactors. Although all the four carbon sources could not serve as good carbon source for UASB reactor alone but could be successfully used by the sequential reactors for the removal of chlorophenols. The Performance of sequential reactors was also evaluated at five different chlorophenolic shock loadings. During shock loading study the concentration of chlorophenols in the wastewaters was increased to 45, 60, 75, 90 and 105 mg/l as compared to the normal feed containing 30 mg/l 2-CP or 2,4-DCP. During shock loading study complete removal of 2-CP and more than 99.6% removal of 2,4-DCP was observed in sequential reactors. Sequential reactors successfully withstood all the shock loadings and produced high quality effluents. PMID- 17706424 TI - Synthesis of neuroprotective cyclopentenone prostaglandin analogs: suppression of manganese-induced apoptosis of PC12 cells. AB - The synthesis and evaluation for anti- and proapoptotic properties of cyclopentenone prostaglandin analogs are described. Novel J-type analogs of NEPP11 with a cross-conjugated cyclopentadienone moiety and a lipophilic omega side chain suppressed manganese ion-induced apoptosis of PC12 cells at comparable levels to NEPP11, while monoenone derivatives were inactive. The proapoptotic activities of J-type analogs were much lower than that of NEPP11. Natural 15 deoxy-Delta(12,14)-PGJ(2) and Delta(7)-PGA(1) methyl ester were highly toxic, inducing apoptosis at lower concentrations. PMID- 17706425 TI - Immunology and breast cancer: therapeutic cancer vaccines. AB - Cancer immunosurveillance is a process that results from activity of recognition and destruction of cancer cells by innate and adaptive immune effector cells and molecules. Cancer cells can avoid immunosurveillance through the immunoselection, that is the development of poorly immunogenic tumor-cell variants, and through subversion of the immune system (also known as immunosubversion). Identification of tumor antigens (Ags) that can be recognized by immune effector cells has opened the perspective of developing therapeutic vaccines in the field of breast cancer. Breast cancer vaccines can induce immunogenic response against tumors weakly immunogenic; usually have a good tolerance and safety profile and can induce a long-term immune memory, critical to prevent efficiently tumor recurrence. Several studies evaluating breast cancer vaccines have been performed in patients with extended metastatic breast cancer, usually refractory to other standard treatments so that clinical efficacy was difficult to achieve. Significant immune responses against tumor Ags induced upon vaccinations were described to several tumor Ag vaccines. A better understanding of the relation between innate and adaptive immune responses, of the immune escape mechanisms employed by tumor cells and acknowledgment of the importance of both cell mediated and humoral adaptive immunity for the control of tumor growth are necessary for leading to a more comprehensive immunotherapeutic approach in breast cancer. PMID- 17706426 TI - Level of knowledge articulated by intensive care nurses and clinical decision making. PMID- 17706427 TI - Cyclodextrin-based aggregates and characterization by microscopy. AB - Cyclodextrin-based aggregates have been widely investigated with microscopies such as STM, AFM, SEM, TEM, and fluorescent microscopy to obtain the direct morphology and structure of samples. In the present review, we discuss various types of cyclodextrin aggregates, that is, native and modified cyclodextrins, inclusion complexes and their aggregates of cyclodextrins, cyclodextrin rotaxanes and polyrotaxanes, cyclodextrin nanotubes and their secondary assembly, and other high-order aggregates of cyclodextrins. Especially, we focus on the use of microscopy to characterize above aggregates. The application of modern microscopy tools promotes the investigation on cyclodextrins. PMID- 17706428 TI - Altered calcium homeostasis in motor neurons following AMPA receptor but not voltage-dependent calcium channels' activation in a genetic model of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disease characterized by a substantial loss of motor neurons in the spinal cord, brain stem and motor cortex. By combining electrophysiological recordings with imaging techniques, clearance/buffering capacity of cultured spinal cord motor neurons after a calcium accumulation has been analyzed in response to AMPA receptors' (AMPARs') activation and to depolarizing stimuli in a genetic mouse model of ALS (G93A). Our studies demonstrate that the amplitude of the calcium signal in response to AMPARs' or voltage-dependent calcium channels' activation is not significantly different in controls and G93A motor neurons. On the contrary, in G93A motor neurons, the [Ca(2+)](i) recovery to basal level is significantly slower compared to control neurons following AMPARs but not voltage dependent calcium channels' activation. This difference was not observed in G93A cultured cortical neurons. This observation is the first to indicate a specific alteration of the calcium clearance linked to AMPA receptors' activation in G93A motor neurons and the involvement of AMPA receptor regulatory proteins controlling both AMPA receptor functionality and the sequence of events connected to them. PMID- 17706429 TI - Gene and protein expression of galectin-3 and galectin-9 in experimental pneumococcal meningitis. AB - Inflammation of the subarachnoid and ventricular space contributes to the development of brain damage i.e. cortical necrosis and hippocampal apoptosis in pneumococcal meningitis (PM). Galectin-3 and -9 are known pro-inflammatory mediators and regulators of apoptosis. Here, the gene and protein expression profile for both galectins was assessed in the disease progression of PM. The mRNA of Lgals3 and Lgals9 increased continuously in the cortex and in the hippocampus from 22 h to 44 h after infection. At 44 h after infection, mRNA levels of Lgals9 in the hippocampus were 7-fold and those of Lgals3 were 30-fold higher than in uninfected controls (P<0.01). Galectin-9 protein did not change, but galectin-3 significantly increased in cortex and hippocampus with the duration of PM. Galectin-3 was localized to polymorphonuclear neutrophils, microglia, monocytes and macrophages, suggesting an involvement of galectin-3 in the neuroinflammatory processes leading to brain damage in PM. PMID- 17706430 TI - The management of patients with uterine sarcoma: a debated clinical challenge. AB - Uterine sarcomas include a heterogeneous group of rare tumours that usually have an aggressive clinical behaviour and a poor prognosis. Total abdominal hysterectomy and bilateral salpingo-oophorectomy represents the standard surgical treatment. Pelvic and/or para-aortic lymphadenectomy is indicated for carcinosarcoma, but not for leiomyosarcoma and undifferentiated endometrial sarcoma. Some recent data on low numbers of patients with low-grade endometrial stromal sarcoma appear to show an incidence of nodal involvement higher than previously expected, thus suggesting a role for lymphadenectomy in this malignancy. Carcinosarcoma also requires a comprehensive surgical peritoneal staging. Postoperative treatment of uterine sarcomas has been long debated. Adjuvant pelvic radiotherapy appears to improve local control without any significant impact on overall survival. There is little evidence in the literature supporting the use of adjuvant chemotherapy in any gynaecological sarcomas except for carcinosarcomas. However, uterine sarcomas have a high tendency to develop distant recurrences, and recent data on adjuvant chemotherapy in soft tissue sarcomas are promising. As for the drugs to be used, it is worth noting that in a Swiss study, the combination of ifosfamide (IFO) and doxorubicin (DOX) obtained similar response rates in advanced gynaecological sarcomas and in advanced soft tissue sarcomas of other sites. In our decision-making scheme for early-stage disease, patients with leiomyosarcoma or undifferentiated endometrial sarcoma should receive adjuvant doxorubicin/epidoxorubicin (EPIDX)+ifosfamide, and those with carcinosarcoma should be treated with adjuvant cisplatin (CDDP) based chemotherapy. The same drug regimens are used for the treatment of advanced disease. Sequential pelvic radiotherapy following chemotherapy could be delivered to selected cases. Recurrent disease often requires the integration of different therapeutic modalities, but no curative option is currently available with the possible exception of surgery for lung metastases and hormone therapy with or without debulking surgery for recurrent low-grade endometrial stromal sarcoma. Patients should be encouraged to enter clinical trials designed to identify new active drugs for these malignancies. PMID- 17706432 TI - Signal and noise characteristics of SSFP FMRI: a comparison with GRE at multiple field strengths. AB - Recent work has proposed the use of steady-state free precession (SSFP) as an alternative to the conventional methods for obtaining functional MRI (FMRI) data. The contrast mechanism in SSFP is likely to be related to conventional FMRI signals, but the details of the signal changes may differ in important ways. Functional contrast in SSFP has been proposed to result from several different mechanisms, which are likely to contribute in varying degrees depending on the specific parameters used in the experiment. In particular, the signal dynamics are likely to differ depending on whether the sequence is configured to scan in the SSFP transition band or passband. This work describes experiments that explore the source of SSFP FMRI signal changes by comparing SSFP data to conventional gradient-recalled echo (GRE) data. Data were acquired at a range of magnetic field strengths and repetition times, for both transition band and passband methods. The signal properties of SSFP and GRE differ significantly, confirming a different source of functional contrast in SSFP. In addition, the temporal noise properties are significantly different, with important implications for SSFP FMRI sequence optimisation. PMID- 17706433 TI - Prestimulus oscillations predict visual perception performance between and within subjects. AB - In the present study, the electrophysiological correlates of perceiving shortly presented visual stimuli are examined. In particular, we investigated the differences in the prestimulus EEG between subjects who were able to discriminate between four shortly presented stimuli (Perceivers) and subjects who were not (Non-Perceivers). Additionally, we investigated the differences between the subjects perceived and unperceived trials. The results show that Perceivers exhibited lower prestimulus alpha power than Non-Perceivers. Analysis of the prestimulus EEG between perceived and unperceived trials revealed that the perception of a stimulus is related to low phase coupling in the alpha frequency range (8-12 Hz) and high phase coupling in the beta and gamma frequency range (20 45 Hz). Single trial analyses showed that perception performance can be predicted by phase coupling in the alpha, beta and gamma frequency range. The findings indicate that synchronous oscillations in the alpha frequency band inhibit the perception of shortly presented stimuli whereas synchrony in higher frequency ranges (>20 Hz) enhances visual perception. We conclude that alpha, beta and gamma oscillations indicate the attentional state of a subject and thus are able to predict perception performance on a single trial basis. PMID- 17706434 TI - Validation of in vitro probabilistic tractography. AB - Diffusion weighted imaging (DWI) and tractography allow the non-invasive study of anatomical brain connectivity. However, a gold standard for validating tractography of complex connections is lacking. Using the porcine brain as a highly gyrated brain model, we quantitatively and qualitatively assessed the anatomical validity and reproducibility of in vitro multi-fiber probabilistic tractography against two invasive tracers: the histochemically detectable biotinylated dextran amine and manganese enhanced magnetic resonance imaging. Post mortem DWI was used to ensure that most of the sources known to degrade the anatomical accuracy of in vivo DWI did not influence the tracking results. We demonstrate that probabilistic tractography reliably detected specific pathways. Moreover, the applied model allowed identification of the limitations that are likely to appear in many of the current tractography methods. Nevertheless, we conclude that DWI tractography can be a precise tool in studying anatomical brain connectivity. PMID- 17706435 TI - The involvement of ipsilateral temporoparietal cortex in tactile pattern working memory as reflected in beta event-related desynchronization. AB - Cortical oscillatory activity in various frequency bands has been shown to reflect working memory processes operating on visual and auditory stimulus information. Here we use magnetoencephalography to investigate cortical oscillatory activity related to working memory for tactile patterns. Right-handed subjects made same-different judgements on two dot patterns sequentially applied with a 3-s delay to the right middle fingertip. Spectral analysis revealed beta desynchronization (17+/-2.5 Hz) at contralateral postcentral and ipsilateral temporoparietal regions preceding and during the presentation of both tactile stimuli as well as during the early and late delay periods. Whereas contralateral beta desynchronization preceding tactile stimulation may reflect anticipation of incoming stimuli, ipsilateral beta desynchronization may underlie working memory maintenance of tactile patterns. The later hypothesis is supported by a significant positive correlation between subjects' performance and the amplitude of ipsilateral beta desynchronization 800 ms to 500 ms before the onset of the second pattern stimulus. Thus, our results suggest that ipsilateral temporoparietal cortex contributes to the maintenance of tactile pattern information in working memory. PMID- 17706437 TI - Oral cysticercosis: case report. AB - Frequent in developing countries, cysticercosis is a parasitic infection that rarely involves the mouth. This study reports a case of oral cysticercosis in a 13-year-old female patient who had an asymptomatic nodule in the right labial mucosa. An excisional biopsy was carried out and the histopathologic examination revealed a cystic space containing a Taenia solium larva. PMID- 17706436 TI - Large cemento-ossifying fibroma of the maxilla causing proptosis: a case report. AB - Cemento-ossifying fibromas form a part of the spectrum of fibro-osseous lesions of the jaws and are considered benign but locally aggressive tumors. This report presents a 31-year-old female patient with a large cemento-ossifying fibroma of the maxilla, expanding into the orbit and causing proptosis. The report also discusses the surgical management of this lesion with successful preservation of optic nerve function and normal vision. PMID- 17706438 TI - Preparation of the coronal and middle third of oval root canals with a rotary or an oscillating system. AB - OBJECTIVES: To comparatively evaluate the preparation of oval root canals with a rotary or an oscillating system. STUDY DESIGN: The middle and coronal parts of 55 extracted permanent teeth with oval canals were prepared using FlexMaster (FM) rotary NiTi instruments and EndoEze AET (EE) stainless steel oscillating instruments. Pre- and postoperative images of cross-sections were superimposed to identify shifts in the center and to assess the percentage of untreated regions. In addition, the middle segment was investigated by scanning electron microscope (SEM) to determine debris and smear layer removal. RESULTS: The systems did not significantly differ in the shifts of the canal centers in the middle part of the root. Only a few of the preparations yielded an excellent result with no uninstrumented canal wall left. The SEM investigation demonstrated poor results for both systems regarding debris and smear layer removal, but no significant differences could be observed. CONCLUSIONS: Neither FM nor EE was capable of completely preparing oval root canals. PMID- 17706439 TI - Endodontic treatment outcome: effect of the permanent restoration. AB - OBJECTIVE: To investigate the relationship between the presence of the coronal restoration and endodontic treatment success or failure. METHODS: This study comprised 200 endodontically treated teeth with 441 roots. Follow-up examination was conducted 4 +/- 0.5 years after completion of endodontic treatment. Outcome criteria were modified from Strindberg. RESULTS: Teeth/roots restored with permanent coronal restoration (casting or filling) had a higher success rate (80%) than teeth/roots not restored (60%; P < .01) in the analysis of aggregate data. However, the results of stratified analysis on key confounding factor (preoperative periapical diagnosis) showed that there is no significant association between the presence of permanent restoration and endodontic outcome. Teeth with preoperative apical periodontitis were less likely to be restored with a crown (23.9%) than teeth without apical periodontitis (76.1%; P < .01). Anterior teeth were more likely to be restored with a filling and sooner than the posterior teeth. These associations suggest a treatment selection bias. CONCLUSIONS: Stratified analysis on the key confounding factor reveals that endodontic outcome is driven by the presence of preoperative root canal infection (apical periodontitis). Lack of stratification on key confounding factors inaccurately suggests that presence of permanent restoration contributes to the success of endodontic treatment in the aggregate analysis of grouped data. The choice to restore the tooth as well as the choice and timing of permanent restoration may be the result of a bias in treatment selection. Stratified analysis on key confounding factors is the key to valid analysis and accurate results. PMID- 17706440 TI - Injection pain of the inferior alveolar nerve block in patients with irreversible pulpitis. AB - OBJECTIVE: The purpose of this retrospective analysis was to determine the pain associated with needle insertion, placement, and solution deposition for the conventional inferior alveolar nerve (IAN) block in patients with irreversible pulpitis. STUDY DESIGN: One hundred two emergency patients with irreversible pulpitis received IAN block injections using 2% lidocaine with 1:100,000 epinephrine. The patients recorded pain of the 3 injection stages on a Heft Parker visual analog scale (VAS). RESULTS: Moderate-to-severe pain may occur 57% to 89% of the time with the IAN block. Needle placement was significantly more painful than needle insertion for men and significantly more painful than either insertion or deposition for women (P < .03). There was no statistical difference between the pain for men or women with respect to needle insertion, placement, or deposition pain (P > .05). Deposition of 0.2 to 0.4 mL anesthetic during placement did not significantly reduce placement pain for either gender (P = .753). CONCLUSION: In conclusion, 57% to 89% of patients presenting with irreversible pulpitis have the potential for moderate to severe pain with the IAN block. PMID- 17706441 TI - Mechanisms of root canal sealers cytotoxicity on osteoblastic cell line MC3T3-E1. AB - OBJECTIVE: The cytotoxic mechanisms of root canal sealers (Sealapex, AH26, and N2 Universal) were studied in vitro with MC3T3-E1 osteoblastic cells. STUDY DESIGN: MC3T3-E1 cells were cotreated with root canal sealers and antioxidants, and concentrations of intracellular glutathione (GSH) and reactive oxygen species (ROS) were measured. DNA fragmentation was observed after treatment with the sealers. RESULTS: N-Acetylcysteine (NAC) prevented N2 Universal- and AH26-induced cytotoxicities. However, ascorbic acid and Trolox did not affect the cytotoxicity of the sealers. N2 Universal and AH26 significantly decreased the GSH pool within a 3-hour treatment period. Unlike GSH levels, the ROS levels were not altered by the sealers. Cytotoxicity of Sealapex was not affected by NAC, and there were no changes of GSH/glutathione disulfide levels in cells treated with Sealapex. CONCLUSION: Cytotoxicities of N2 Universal and AH26 are caused by an intracellular GSH depletion without a burst of ROS. Sealapex may cause cytotoxicity in a way different from N2 Universal and AH26. PMID- 17706442 TI - Melorheostosis: report of two cases affecting the jaw. AB - Melorheostosis is a rare sclerosing bone dysplasia that is characterized by a localized, diffuse thickening of the cortical bone. This condition usually affects the appendicular skeleton and associated soft tissue and rarely affects the craniofacial complex. The etiology of this condition is obscure. Diagnosis of melorheostosis relies on clinical, radiographic, and histological correlation. Only 8 cases of melorheostosis involving the craniofacial complex have been reported. We report 2 new cases of isolated melorheostosis involving the maxilla and mandible, together with differential diagnostic considerations. To our knowledge, involvement of the maxilla only has not been previously reported. PMID- 17706443 TI - Oral leiomyosarcomas: report of two cases with immunohistochemical profile. AB - Leiomyosarcoma of the oral cavity is a very rare tumor associated with aggressive clinical behavior and low survival. In this paper, we report 2 cases of leiomyosarcoma, affecting the gingival mucosa of a 54-year-old female and the maxillary bone of a 63-year-old male. Histologically, the tumors were composed of variably oriented fascicles of spindle-shaped cells with cigar-shaped nuclei and eosinophilic cytoplasm. The lesions were treated by surgical resection. Immunoreactivity to anti-vimentin, anti-smooth muscle actin, anti-desmin, anti laminin, and anti-muscle-specific actin antibodies were found; conversely, the tumor cells were negative for anti-S100 and AE1/AE3 proteins. This report emphasizes the role of immunohistochemical study for correct diagnosis of leiomyosarcoma. PMID- 17706444 TI - Identification and characterization of a temperature-sensitive R268H mutation in the human succinyl-CoA:3-ketoacid CoA transferase (SCOT) gene. AB - Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency causes episodic ketoacidosis. We encountered a case of siblings in South Africa in whom a novel homozygous mutation (R268H) was found in genomic DNA. Mutant SCOT protein was very faintly detected in their fibroblasts using immunoblot analysis. Transient expression analysis of R268H mutant cDNA at 37 degrees C revealed that the R268H mutant protein was clearly detected, as much as 50% wild-type, together with 40% residual SCOT activities, hence R268H was first regarded as not being a disease causing mutation. Since no other mutation was identified, R268H mutation was re evaluated by further transient expression analysis. Accumulation of the R268H mutant protein was revealed to be strongly temperature dependent; residual SCOT activities were calculated to be 59.7%, 34%, and 4%, respectively, in expression at 30 degrees C, 37 degrees C, and 40 degrees C in SV40-transformed fibroblasts of GS01(a homozygote of S283X). SCOT activity of the R268H protein was more vulnerable than the wild-type to heat treatment at 50 degrees C. These results indicated that the R268H mutant protein was clearly more unstable than the wild type in a temperature-sensitive manner. Furthermore, an analysis of the three dimensional structure of SCOT showed that the R268H mutation was expected to break a conserved salt bridge between R268 and D52, which would be expected to lead to decreased stability of the protein. Hence we finally concluded that the R268H mutation is a disease-causing one. The stability of mutant protein in transient expression analysis does not always reflect the condition in patients' fibroblasts. PMID- 17706446 TI - Prevalence of Cryptosporidium, Giardia and Isospora species infections in pet cats with clinical signs of gastrointestinal disease. AB - This study reports the prevalence of Cryptosporidium, Giardia and Isospora species in cats showing signs of gastrointestinal disease. Records from a United Kingdom commercial diagnostic laboratory between December 2003 and December 2005 were reviewed. Of 1355 cats, Cryptosporidium species oocysts were found in 13 cats (1%), Giardia species trophozoites in 74 (6%), and Isospora felis oocysts in 46 (3%). In a second group of 48 cats, prevalence of Giardia species was 15% using an immunoassay for detection of antigen compared to 4% detected with microscopy. Prevalence of Giardia (9%) and Isospora (9%) species was higher in cats less than 6 months old. Gender and breed did not affect prevalence. There was a trend for Cryptosporidium and Isospora species infections to be detected in late autumn and early winter. Regional differences in prevalence were not detected. None of these organisms show a characteristic pattern of clinical signs. This study demonstrates that enteric protozoal infection is common in domestic cats showing signs of alimentary disease. PMID- 17706445 TI - A novel complex deletion-insertion mutation mediated by Alu repetitive elements leads to lipoprotein lipase deficiency. AB - Lipoprotein lipase (LPL) deficiency is a rare autosomal recessive inherited disorder, characterized by marked hypertriglyceridemia, eruptive xanthoma, hepatosplenomegaly, recurrent attacks of pancreatitis, and markedly low or absent LPL activity in postheparin plasma. A majority of LPL deficient patients have been reported to have point mutations in the LPL gene; however, we find a complex deletion-insertion mutation by Alu elements, mobile retrotransposons, in a patient with LPL deficiency. This patient suffered from acute pancreatitis, showed chylomicronemia and lacked detectable LPL activity or mass in her postheparin plasma. Southern blot analysis and long-range PCR of the patient's DNA demonstrated a 2.2-kb deletion encompassing exon 2. Sequence analysis revealed (1) a 2.3-kb deletion between an AT-rich region adjacent to an Alu element in intron 1 and another Alu element in intron 2; (2) an insertion of approximately 150bp 5'-truncated Alu sequence with a poly (A) tail at the deletion point. The inserted sequence belongs to Alu Yb9, the youngest subfamily of Alu elements. The deletion occurred at the consensus cleavage site (3'-A|TTTT 5') without target site duplication. These findings indicated that Alu retrotransposition caused the complex deletion-insertion. The patient was homozygous for this complex mutation, which eliminates exon 2 and leads to LPL deficiency. To our knowledge, the patient is the first case with LPL deficiency due to a complex deletion-insertion mediated by Alu repetitive elements. PMID- 17706447 TI - Tick toxicity in cats caused by Ixodes species in Australia: a review of published literature. AB - Tick toxicity in cats caused by Ixodes holocyclus and related species is a common medical condition on the east coast of Australia. Intoxication typically causes a flaccid ascending neuromuscular paralysis and clinical signs can include anxiety, dysphonia, hind limb weakness and/or ataxia, pupillary dilation, respiratory signs and possible bladder voiding dysfunction. Diagnosis is made with a combination of appropriate clinical signs and visualisation of tick(s) on a thorough body search. Cases are classified clinically using a scoring system, which grades neuromuscular weakness and respiratory compromise. The mainstays of treatment are tick removal, administration of tick antitoxin serum and intensive supportive care. Given a prompt and appropriate management regimen, prognosis is good, according to available literature. Most of the literature concerning tick toxicity in cats is anecdotal in nature and an evidence-based review of what is known of this condition has not previously been published. PMID- 17706448 TI - HIV morbidity and mortality in Jamaica: analysis of national surveillance data, 1993--2005. AB - OBJECTIVES: Pre-antiretroviral therapy (ART) HIV-related survival and timing of HIV identification have not been reported from the Caribbean. Using Jamaican national surveillance data, we estimated overall, AIDS-free, and AIDS survival, identified factors influencing HIV-related mortality, and examined factors associated with late HIV/AIDS identification. METHODS: The Jamaican HIV/AIDS tracking system (HATS) national surveillance data included timing of first positive HIV test, stage at identification, date of AIDS diagnosis, and death. We estimated overall and AIDS-free survival by initial stage, using a proportional hazard model to identify factors associated with worse survival, and logistic regression to examine factors related to later case identification. RESULTS: Of 10674 reported HIV cases, 48% were asymptomatic, 14% symptomatic, and 38% first reported with AIDS. Five-year AIDS-free survival was 77% for asymptomatic persons and 63% for symptomatic. Median survival after AIDS diagnosis was 1.02 years. Age, number of opportunistic diseases, and initial stage were strongly associated with mortality. Older age, drug use, and sex with a commercial sex worker were associated with later identification. CONCLUSIONS: In the pre-ART era, over one third of HIV-infected persons in Jamaica were first identified with advanced disease. This highlights the need for earlier diagnosis as ART programs roll out in the Caribbean. PMID- 17706449 TI - Efficacy of thalidomide in systemic onset juvenile rheumatoid arthritis. AB - Thalidomide is an immunomodulating agent which reverses many of the cytokine disturbances seen in systemic onset juvenile idiopathic arthritis (SoJIA) with inadequate response to other treatments. We report 3 cases of recalcitrant SoJIA which improved dramatically after treatment with thalidomide. PATIENTS: Three children aged 9, 8, and 6 years diagnosed with SoJIA treated with conventional therapy including NSAIDs, corticosteroids, methotrexate and etanercept failed to respond fully and their condition worsened. Thalidomide was begun based on two previous reports showing its efficacy in recalcitrant SoJIA. RESULTS: Thalidomide produced successful remission of the disease in all 3 patients according to the preliminary criteria for inactive disease and clinical remission of JIA. CONCLUSION: Thalidomide may be a viable, alternative corticoid-sparing therapy in patients with recalcitrant, multidrug-resistant SoJIA. PMID- 17706450 TI - [Sentinel node biopsy in invasive breast cancer in 2007]. AB - Sentinel lymph node (SN) biopsy for breast cancer has been introduced in the mid 1990s and it has now been performed on thousands of patients. This procedure has been rapidly adopted around the world by surgical specialists in clinical practice as a diagnostic procedure instead of the axillary lymph node dissection. The diffusion of the SN mapping in routine must be careful by respecting some principles of methodology and especially of training, in order to maintain its irreversible development. However, the advent of this mini-invasive technique revealed new questions, which the concept of the SN procedure raises: can we increase the current indications? Could axillary lymph node dissection be avoided in patients with metastatic SN? What is the morbidity of the biopsy of the SN? Which is the prognostic value of micrometastatis discovered by the diffusion of the ultra-stadification of the SNs? The GS procedure is a diagnostic method the reliability of which is now on accepted in its usual indications (tumours in place, small size breast tumour without palpable adenopathy). The value of the axillary dissection after metastatic SN is the subject of debates and controversies although axillary dissection remains recommended. So the use of scores or predictive nomograms is currently developed to select the patients being able not to justify of complementary axillary dissection, and seems promising. PMID- 17706451 TI - Sonochemical degradation of various monocyclic aromatic compounds: relation between hydrophobicities of organic compounds and the decomposition rates. AB - Various aromatic compounds, i.e., nitrobenzene, aniline, phenol, benzoic acid, salicylic acid, 2-chlorophenol, 4-chlorophenol, styrene, chlorobenzene, toluene, ethylbenzene and n-propylbenzene were decomposed under identical ultrasonic irradiation conditions. The relationships between the initial rates of degradation of these aromatic compounds and their physicochemical parameters were systematically investigated. It was revealed that some correlations between the degradation rates and parameters of volatility, Henry's law constant and vapor pressure, were observed only in the limited high range of parameters. It was suggested that the Henry's law constant and vapor pressure had influenced on the rate of degradation for some of the tested aromatic compounds. In contrast, better correlations between the initial rates of degradation and hydrophobic parameters, water solubility and LogP (water-octanol partition coefficient), were observed over the wide range of chosen parameters. These results meant that the hydrophobicity of the compounds significantly affected their accumulation at the gas-liquid interface of the bubbles and it was the most important factor for the sonochemical degradation of aromatic compounds. In particular, for the sonolysis of water-insoluble organic compounds, LogP was found to be the representative parameter for understanding the hydrophobic properties of water-insoluble compounds. PMID- 17706452 TI - Chondroitin sulfate and heparan sulfate-containing proteoglycans are both partners and targets of basic fibroblast growth factor-mediated proliferation in human metastatic melanoma cell lines. AB - Basic fibroblast growth factor (FGF-2) and its respective tyrosine kinase receptors, form an autocrine loop that affects human melanoma growth and metastasis. The aim of the present study was to examine the possible participation of various glycosaminoglycans, i.e. chondroitin sulfate, dermatan sulfate and heparin on basal and FGF-2-induced growth of WM9 and M5 human metastatic melanoma cells. Exogenous glycosaminoglycans mildly inhibited WM9 cell's proliferation, which was abolished by FGF-2. Treatment with the specific inhibitor of the glycosaminoglycan sulfation, sodium chlorate, demonstrated that endogenous glycosaminoglycan/proteoglycan production is required for both basal and stimulated by FGF-2 proliferation of these cells. Heparin capably restored their growth, and unexpectedly exogenous chondroitin sulfate to WM9 and both chondroitin sulfate and dermatan sulfate to M5 cells allowed FGF-2 mitogenic stimulation. Furthermore, in WM9 cells the degradation of membrane-bound chondroitin/dermatan sulfate stimulates basal growth and even enhances FGF-2 stimulation. The specific tyrosine kinase inhibitor, genistein completely blocked the effects of FGF-2 and glycosaminoglycans on melanoma proliferation whereas the use of the neutralizing antibody for FGF-2 showed that the mitogenic effect of chondroitin sulfate involves the interaction of FGF-2 with its receptors. Both the amounts of chondroitin/dermatan/heparan sulfate and their sulfation levels differed between the cell lines and were distinctly modulated by FGF-2. In this study, we show that chondroitin/dermatan sulfate-containing proteoglycans, likely in cooperation with heparan sulfate, participate in metastatic melanoma cell FGF 2-induced mitogenic response, which represents a novel finding and establishes the central role of sulfated glycosaminoglycans on melanoma growth. PMID- 17706453 TI - Convergence of the NF-kappaB and IRF pathways in the regulation of the innate antiviral response. AB - The type I interferon (IFN) alpha and beta promoters have been a leading paradigm of virus-activated transcriptional regulation for more than two decades, and have contributed substantially to our understanding of virus-inducible gene regulation, the coordinated activities of NF-kappaB and IRF transcription factors, the temporal and spatial recruitment of co-activators to the enhanceosome, and signaling pathways that trigger the innate antiviral response. In 2003, the ISICR Milstein Award was presented to John Hiscott of McGill University and Tom Maniatis of Harvard University for their ongoing research describing the mechanisms of regulation of type 1 interferon genes and specifically for the identification of key signaling kinases involved in phosphorylation of the transcription factors IRF-3 and IRF-7. The specific roles played by IRFs and the IKK-related kinases TBK1 and IKKvarepsilon are now recognized within the broader framework of TLR and RIG-I signaling pathways. This review summarizes the unique features of the IKK-related kinases and offers a summary of recent advances in the regulation of the early host response to virus infection. PMID- 17706454 TI - Infrared and ab initio studies of conducting molecules: 2,5-diamino-3,6-dichloro 1,4-benzoquinone. AB - 2,5-Diamino-3,6-dichloro-1,4-benzoquinone has been synthesized by modifying the procedure reported in literature. Its IR spectrum has been recorded in the solid phase in the range 4000-400cm(-1). Ab initio calculations have been performed using Gaussian '03 program to compute optimized geometry, harmonic vibrational frequencies along with intensities in IR and Raman spectra and atomic charges at RHF/6-31+G*, B3LYP/6-31+G* and B3LYP/6-311++G** levels. To make vibrational analysis Gaussian View software was used. The optimized molecular structure is found to possess C2h point group symmetry. The observed IR frequencies have been assigned to different modes taking C2h molecular symmetry with the help of pictorial view of normal modes. From the magnitude of the observed frequencies corresponding to the NH2 stretching motions an indication of H-bonding is noticed. From geometrical parameters of the molecule it appears that two parallel sets of conjugated strands are formed in this molecule providing a route to conduct charges. The N-H bonds facing towards chlorine atoms are found to be shorter than those facing towards oxygen atoms indicating the presence of H bonding between hydrogen atom of an NH2 group and carbonyl (quinoid) oxygen atom. PMID- 17706455 TI - Ruthenium(II) complexes of 2-benzoylpyridine-derived thiosemicarbazones with cytotoxic activity against human tumor cell lines. AB - Reaction of [RuCl(3)(dppb)H(2)O] (dppb=1,4 bis(diphenylphospine)butane) with 2 benzoylpyridine thiosemicarbazone (H2Bz4DH) and its N(4)-methyl (H2Bz4M) and N(4) phehyl (H2Bz4Ph) derivatives gave [RuCl(dppb)(H2Bz4DH)]Cl (1), [RuCl(dppb)(H2Bz4M)]Cl (2) and [RuCl(dppb)(H2Bz4Ph)]Cl (3). The cytotoxic activity of the studied compounds was tested against the MCF-7, TK-10 and UACC-62 human tumor cell lines. The precursor [RuCl(3)(dppb)H(2)O] exhibits cytocidal activity against the tree cell lines. H2BzDH, H2Bz4M, and [RuCl(dppb)(H2Bz4M)]Cl (2) show a selective cytocidal effect against the UACC-62 cell line which makes them the most promising compounds. PMID- 17706456 TI - Spin probe ESR studies of dynamics of single walled carbon nanotubes. AB - The highly sensitive technique of spin-probe Electron Spin Resonance (ESR) has been used to study dynamics of carbon nanotubes. The ESR signals were recorded for the nitroxide free radical TEMPO in carbon nanotubes from 5 to 300 K. The onset of the fast dynamics of the probe molecule was indicated by appearance of a narrow triplet at 230 K. The ESR measurements were also done on TEMPO in methanol for the comparative studies in the same temperature range, and in the latter observations, no change in spectra was seen around 230 K. The results indicate the occurrence of a change in the dynamics of carbon nanotubes around this temperature. PMID- 17706457 TI - A newly reported human polyomavirus, KI virus, is present in the respiratory tract of Australian children. AB - BACKGROUND: Recently, Allander and co-workers reported the discovery of a new human polyomavirus, KI virus, in respiratory secretions from patients with acute respiratory tract infection (ARTI). OBJECTIVE: We examined 951 respiratory samples collected in Queensland, Australia, between November 2002 and August 2003 from patients with respiratory infection, for the presence of the KI virus. RESULTS: Twenty-four (2.5%) samples were positive for KI virus with 20 (83%) of these from children younger than 5 years. In six (25%) patients KI was co detected with another virus. Full genome sequencing of three isolates shows a high degree of conservation between the Queensland isolates and the original isolates reported from Swedish patients. CONCLUSIONS: The newly described KI polyomavirus may commonly be found in the respiratory tract of patients with ARTI, particularly children, and results indicate that the virus has global presence. PMID- 17706458 TI - Structural requirements for uptake and recognition of CpG oligonucleotides. AB - Recognition of infectious danger by innate immune cells is a fundamental requirement to directly combat infections and to activate the adaptive immune response of T and B cells. Pathogen-associated molecular patterns (PAMPs) play a fundamental role in this process. PAMPs are sensed by pattern recognition receptors, among which the Toll-like receptors (TLRs) play an important role. Within the TLR ligands, bacterial CpG DNA is peculiar. CpG DNA is recognized by TLR9 and harbors the outstanding propensity to induce a milieu that favors activation of Th1-dominated immune responses. This is mainly due to activation of dendritic cells and subpopulations, thereby inducing an intense interferon and IL 12 response. Therefore, CpG DNA has become a promising candidate for constructing new vaccines as well as for induction of immune responses in cancer and allergy. CpG DNA can be synthesized with high purity, defined base composition and various chemical modifications. We aimed to understand the structural requirements for cellular uptake and activation of CpG DNA, which will improve our means to enhance the intrinsic activity of CpG for therapeutic use. We show that sequence modifications can be utilized to enhance cellular uptake, and that chemical substitutions can confer new qualities to synthetic CpG DNA. Additionally, we propose a model of CpG DNA recognition which occurs by sensing partial duplex forms instead of single-stranded DNA. Moreover, we provide evidence that the propensity of CpG DNA to induce high amounts of IL-12 is due to its unique ability to trigger epigenetic modifications of the IL-12p40 promoter, including acetylation and nucleosomal remodeling. Hence, CpG DNA represents a new and promising class of adjuvant for vaccination. PMID- 17706459 TI - The reliability of physiological and performance measures during simulated team sport running on a non-motorised treadmill. AB - The aim of this study was to determine the reliability of a non-motorised treadmill team-sport simulation for measuring physiological responses and performance demands of team sports. Following familiarisation, 11 team-sport athletes completed a peak sprinting speed assessment followed by a 30-min team sport simulation on the non-motorised treadmill, on three occasions, 5 days apart. Several performance (total distance, distance covered during each speed category, total work, high-intensity activity, mean maximal sprinting speed and power) and physiological variables (V(O)(2), heart rate and blood measures) were measured. A one-way analysis of variance and ratio limits of agreement were used to compare the results from each trial. Significant differences were established in total sprint distance and high-intensity activity between trials 1-2 and trials 1-3 and 3-s mean maximal sprinting speed for trials 1-3 (p<0.05). No other significant differences were identified. Moderate to high intraclass correlation coefficients (i.e., >0.8) were identified in 11 of the 18 physiological and performance variables measured. Ratio limits of agreement for total distance covered and total work performed during the team-sport simulation were 0.99 (*//1.05) and 0.97 (*//1.09), respectively. Largest measurement error was shown in post-exercise blood lactate concentration with a coefficient of variation of 17.6%. All other measures showed low coefficients of variation of < or = 10%. These results show that the non-motorised treadmill team-sport simulation provides a reliable tool for assessing and monitoring physiological and performance demands of team-sport activity. We recommend the inclusion of two familiarisation sessions prior to testing. PMID- 17706460 TI - How do aerial freestyler skiers land on their feet? A situated analysis of athletes' activity related to new forms of acrobatic performance. AB - Based on the course-of-action theory, this study performed a situated analysis of three elite aerial freestyle skiers' activity. Data were collected by observation, videotaping and self-confrontation interviews retrospectively build the athletes' activity. The analysis identified units of action, thought, and feelings and described their relationships during each leap. Comparisons of the different courses of action revealed six components of freestyle skiers' activity: (1) pick up speed in the descent, (2) manage the curve of the tremplin, (3) take-off, (4) manage the exit of the tremplin, (5) perform rotations, and (6) organize the landing. This study revealed the dynamic and situated property of acrobatic activity. As the leap unfolded, the athletes step-by-step enhanced their knowledge of what was occurring and what they would have to do to perform their best and land on their feet. Points of convergence and divergence with other acrobatic performances are discussed. PMID- 17706461 TI - The motivation of children to play an active video game. AB - The purpose of this pilot study was to evaluate the effect of a weekly multiplayer class on the motivation of children aged 9-12 years to play an interactive dance simulation video game (IDSVG) at home over a period of 12 weeks. A sample of 27 children was randomly assigned to (1) a home group instructed to play the IDSVG at home; (2) a multiplayer group instructed to play the IDSVG at home and to participate in a weekly IDSVG multiplayer class. Participants were asked to play the IDSVG as often as they liked and report the playing time daily on a calendar for a 12-week period. Motivation to play was assessed by the playing duration of IDSVG in minutes and the dropout during the study. Mean age of the 16 children who completed the study was 10.6+/-0.8 years. During the 12-week intervention period, the multiplayer group played approximately twice as many minutes (901min) as the home group (376min, p=0.13). Dropout was significantly (p=0.02) lower in the multiplayer group (15%) than in the home group (64%). Our findings suggest that multiplayer classes may increase children's motivation to play interactive dance simulation video games. PMID- 17706462 TI - The effect of participation in Ramadan on substrate selection during submaximal cycling exercise. AB - This study was undertaken to investigate whether or not substrate selection during exercise is altered with participation in Ramadan, and whether or not this alteration is influenced by exercise intensity. Eight men (21-41 years) exercised on an electronically braked cycle ergometer at three 10-min workloads (45, 60 and 75% VO(2peak)): (1) the week before Ramadan; (2) the end of the first week of Ramadan and (3) the final week of Ramadan. Four subjects were unable to complete the final 10-min (75% VO(2peak)) workload during Ramadan. During the two lower workloads, exercise RER significantly decreased during Ramadan (p<0.01) and there was a significant effect of Ramadan on the increase in RER with increased workload (p=0.041). Post hoc contrasts revealed only that RER during exercise at the end of the first week was significantly lower (p<0.01) than pre-Ramadan. Rate of lipid oxidation increased from 0.18gmin(-1)+/-0.22 to 0.31gmin(-1)+/-0.28 by the first week of Ramadan (p<0.01), the effect reversed by the final week (0.23gmin(-1)+/-0.22) (p=0.02). Although body weight declined during Ramadan (from 71.1kg+/-6.9 to 69.8kg+/-7.3, p=0.02), percentage body fat, measured via underwater weighing, did not change. In conclusion, daily fasting during Ramadan induces changes in substrate selection during submaximal exercise within 1 week, but these changes are moderated with continued daily fasting. However, changes in anthropometric variables reflect a net energy deficit during Ramadan which may have mediated the observed increased lipid oxidation during submaximal exercise. PMID- 17706463 TI - Established B16 tumors are rejected following treatment with GM-CSF-secreting tumor cell immunotherapy in combination with anti-4-1BB mAb. AB - Immunization with irradiated tumor cells engineered to secrete granulocyte macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific and long lasting anti-tumor immunity in clinical and preclinical settings. Efforts to further increase immunotherapy efficacy with immune-modulatory agents are under evaluation. Based on the immune-modulatory properties of 4-1BB (CD137), it has been postulated that agonistic 4-1BB antibodies may add additional anti-tumor efficacy to GM-CSF-secreting tumor cell immunotherapy. The combination of GM-CSF secreting tumor cell immunotherapy and anti-4-1BB monoclonal antibody (mAb) treatment resulted in rejection of established tumors in the B16 melanoma model. These anti-tumor effects correlated with persistent tumor-specific CD8(+) T cell responses. In addition, early tumor infiltration of functional CD8(+) T cells and a greater expansion of antigen-specific memory T cells were found in mice treated with the combination therapy. In summary, an agonistic anti-4-1BB mAb combined with GM-CSF-secreting tumor cell immunotherapy may provide a novel and potent treatment strategy for patients with cancer. PMID- 17706466 TI - The influence of polycaprolactone coating on the internalization and cytotoxicity of gold nanoparticles. AB - The interaction between mesoscopic colloids and cells is largely dependent on the particle size and surface properties. Under a mild reaction condition, gold particles with an average diameter of approximately 100 nm were prepared by incubating poly(dimethylsiloxane) film in HAuCl4/acetic acid solution. The particles were then transferred into a polycaprolactone (PCL) film by thermal pressing. Bare and PCL-coated particles were obtained by control over the extent of rinsing. The bare and PCL-coated gold particles were co-cultured with ECV-304 cells to examine the particle internalization and their influence on the cell morphology and cytotoxicity. Transmission electron microcopy observed the subcellular distribution of the gold particles, which were found in the cell compartments (endosomes or lysosomes), cytoplasm, nucleic envelope, and even nucleus regardless of the existence of PCL coating. However, scanning electron microscopy and beta-tubulin staining revealed a significant change in terms of the cell morphology and cytoskeleton caused by the bare gold particles. Higher cytotoxicity was also determined for the bare gold particles. By contrast, no significant difference of the cell morphology and cytoskeleton change was caused by the PCL-coated gold particles, which have also shown lower cytotoxicity. PMID- 17706465 TI - Epothilone D, a microtubule-stabilizing compound, inhibits neointimal hyperplasia after rat carotid artery injury by cell cycle arrest via regulation of G1 checkpoint proteins. AB - Epothilone D (Epo-D) is a paclitaxel-like microtubule-stabilizing agent that was isolated from the myxobacterium Sorangium cellulosum. Although Epo-D can inhibit proliferation in multiple tumor cell lines, the effect of Epo-D on neointimal hyperplasia after angioplasty has not been reported. The aim of the present study was to investigate the effects of Epo-D on neointimal hyperplasia using an in vivo rat carotid artery injury model. We demonstrated that local Epo-D treatment significantly reduced neointimal hyperplasia after in vivo rat carotid artery injury, and Epo-D potently inhibited DNA synthesis, cell cycle progression and cell proliferation after FBS- and PDGF-BB-stimulation; PDGF-BB has been identified as the most potent growth factor for stimulating the proliferation of activated rat aortic smooth muscle cells (RASMCs). To clarify the specific effects of Epo-D on cell cycle machinery, we examined its effects on cyclin dependent kinase (CDK)2, CDK4, cyclin E, p27, and retinoblastoma (Rb) proteins as cell cycle-related proteins in cellular lysates from PDGF-BB-stimulated RASMCs. Epo-D treatment significantly decreased the level of CDK2 protein, but did not change the levels of CDK4 and cyclin E proteins. Furthermore, Epo-D inhibited the phosphorylation of Rb, a key regulator of the G1 to S phase transition in the cell cycle. These findings suggest that Epo-D may regulate the cell cycle G1 checkpoint proteins as its major molecular mechanism for inhibiting neointimal hyperplasia after in vivo rat carotid artery injury. PMID- 17706467 TI - Xenopus galectin-VIa shows highly specific expression in cement glands and is regulated by canonical Wnt signaling. AB - Anterior-posterior neural patterning of Xenopus embryo is determined during gastrulation and then followed by differentiation of neural structures including brain and eye. The cement gland is a mucus-secreting neural organ located in the anterior end of the neural plate. This study analyzed expression patterns of Xenopus galectin-VIa (Xgalectin-VIa) by whole-mount in situ hybridization, and found highly restricted expression of this gene in the cement gland region. These patterns were similar to those of XAG-1 and XCG, known cement gland-specific genes. In addition, Xgalectin-VIa was expressed in the dorsal edge of eye vesicles, the otic vesicle, and in part of the hatching gland at the tadpole stage. Although the spatial expression pattern was similar, the temporal expression of Xgalectin-VIa differed from that of XAG-1 and XCG. RT-PCR analysis showed only weak Xgalectin-VIa expression in early neurula embryos, whereas both XAG-1 and CGS were strongly expressed at that stage. We also showed that Xgalectin-VIa expression is repressed by enhancement of Wnt signaling and increased by its inhibition. Furthermore, Xgalectin-VIa expression was activated by neural-gene inducer Xotx2, as is the case for XAG-1 and CGS. Together, these results indicated that Xgalectin-VIa possesses different features from other cement gland genes and is a novel and useful marker of the cement gland in developing embryos. PMID- 17706469 TI - Does chronic mountain sickness (CMS) have perinatal origins? AB - Chronic mountain sickness (CMS) occurs in approximately 10% of male high-altitude residents. It is characterized by hypoventilation and hypoxemia but its underlying cause remains unknown. We hypothesized that CMS' origins reside in exaggerated perinatal hypoxia that serves, in turn, to impair the development of pulmonary structure and/or respiratory control. As a preliminary test, we asked if birth weights were low and other signs of perinatal hypoxia were present in 12 young men with excessive erythrocytosis (EE, Hb>or=18.3g/dL), a condition thought to be a preclinical phase of CMS. Their birth weights were uniformly low (2571+/ 243g) and all but one demonstrated perinatal hypoxia as manifested either by being small for their gestational age (SGA, 8%), preterm (67%), born to a preeclamptic (PE) mother (50%), or diagnosed with neonatal hypoxia (83%). Impaired growth in utero has been shown to raise susceptibility to adult disease; these are the first data to demonstrate a possible influence of reduced fetal growth and/or exaggerated perinatal hypoxia on increasing the susceptibility to CMS. Future studies, with more detailed testing in larger samples of control as well as EE subjects, with longitudinal follow-up, are required to determine the role of perinatal hypoxia in the development of CMS. PMID- 17706468 TI - ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain. AB - The genetic disease ataxia telangiectasia (AT) results from mutations in the ataxia telangiectasia mutated (ATM) gene. AT patients develop a progressive degeneration of cerebellar Purkinje neurons. Surprisingly, while ATM plays a criticial role in the cellular reponse to DNA damage, previous studies have localized ATM to the cytoplasm of rodent and human Purkinje neurons. Here we show that ATM is primarily localized to the nucleus in cerebellar Purkinje neurons in postmortem human brain tissue samples, although some light cytoplasmic ATM staining was also observed. No ATM staining was observed in brain tissue samples from AT patients, verifying the specificity of the antibody. We also found that antibodies against components of the Mre11/Rad50/Nbs1 (MRN) complex showed strong staining in Purkinje cell nuclei. However, while ATM is present in both the nucleoplasm and nucleolus, MRN proteins are excluded from the nucleolus. We also observed very high levels of topoisomerase 1 (TOP1) in the nucleus, and specifically the nucleolus, of human Purkinje neurons. Our results have direct implications for understanding the mechanisms of neurodegeneration in AT and AT like disorder. PMID- 17706471 TI - Determination of vancomycin in serum by liquid chromatography-high resolution full scan mass spectrometry. AB - A liquid chromatography-mass spectrometry (LC-MS) method was developed for the analysis of vancomycin (VCM) in human serum. The method was based on full scan data with extracted ions for the accurate masses of VCM and the atenolol internal standard obtained by Fourier transform MS. VCM was extracted from serum using strong cation exchange (SCX) solid phase extraction (SPE). The method was found to be linear in the range 0.05-10 microg/ml, which was adequate for quantification of VCM in serum samples, with a limit of quantification (LOQ) of 0.005 microg/ml and a limit of detection (LOD) of 0.001 microg/ml. Intra-day precision (n=5) was +/-3.5%, +/-2.5%, +/-0.7% at 0.05, 0.5 and 5 microg/ml, respectively. Inter-day precision (n=5) was +/-7.6%, +/-6.4%, +/-3.9% at 0.05, 0.5 and 5 microg/ml, respectively. The process efficiency for VCM was in the range 89.2-98.1% with the recovery for the atenolol internal standard (IS) being 97.3%. The method was used to determine VCM levels in patients during peri operative infusion of the drug, which was found to result in drug levels within the required therapeutic window. PMID- 17706470 TI - Quantitative analysis of monofluoroacetate in biological samples by high performance liquid chromatography using fluorescence labeling with 9 chloromethylanthracene. AB - A rapid and sensitive RP-HPLC method with fluorescence detection has been developed for the quantitative analysis of trace amounts of monofluoroacetate (MFA) in biological samples as serum, food and meat. 9-Chloromethylanthracene (9 CMA) is used as the fluorescence labeling reagent. Samples were extracted and reacted with 9-chloromethylanthracene together with tetrabutylammonium bromide as catalyst at 80 degrees C for 50 min to give a new fluorescent derivative as 9 methyleneanthracene monofluoroacetate (MA-MFA). The resulting MA-MFA was characterized with IR, (1)H NMR, (13)C NMR and MS. Chromatography separation is performed on an Agilent Hypersil ODS column with a fluorescent detector employed with the excitation and emission wavelengths as 256 nm and 412 nm, respectively. Optimal conditions for derivatization, fluorescence detection and chromatographic separation have been established. The novel method yields a good linear relationship when the MFA concentration in serum within 1 and 250 ng/mL (r=0.9988). The detection limit (signal-to-noise ratio=3 with 2 microL injected) was 0.25 ng/mL. The practical applicability of this method was demonstrated by quantitative determination of MFA-Na in a blood sample from a person who had ingested the poison. PMID- 17706472 TI - Expression of human BK ion channels in Sf9 cells, their purification using metal affinity chromatography, and functional reconstitution into planar lipid bilayers. AB - This report describes a procedure for purification of large conductance calcium activated potassium (BK, maxi-K) channels using immobilised metal affinity chromatography (IMAC) under non-denaturing conditions. An amino-terminal histidine fusion tag was added to hSlo, the human BK channel, and expressed in Sf9 insect cells. Following IMAC purification and production of proteoliposomes, protein function was assessed electrophysiologically in planar bilayer lipid membranes. Single channel openings had conductances of 250-300 pS and were inhibited by paxilline, demonstrating that the BK channels remained functional following IMAC purification. This method to obtain functional human ion channels will be useful in assays to screen potential pharmaceuticals. PMID- 17706473 TI - Quantification of darunavir (TMC114) in human plasma by high-performance liquid chromatography with ultra-violet detection. AB - A precise and accurate high-performance liquid chromatography (HPLC) method with UV detection has been developed and validated for darunavir, a peptidic protease inhibitor. An internal standard, methylclonazepam, was added to 100 microL of plasma before a solid-phase extraction on C18 Bond Elut column. The eluted solutions were evaporated to dryness and reconstituted with 100 microL of mobile phase before being injected in the chromatographic system. The separation was performed on a C8 column using an acetonitrile and ultrapure water mixture (40:60, v/v) as mobile phase. All compounds were detected at a wavelength of 266 nm. The method was linear and validated over a concentration range of 0.25 20mg/L. The within-day precision, ranged from 3.0 to 7.9%, while the within-day accuracy ranged from -11.4 to 0.5%. The between day precision and accuracy were respectively less than 13.7 and -11.4%. The mean recovery was 75.7% for darunavir and 66.7% for methylclonazepam. This method provides a useful tool for therapeutic drug monitoring in HIV patients. PMID- 17706474 TI - Speeding up coeliac disease diagnosis in the developing countries. AB - BACKGROUND: Anti-transglutaminase antibodies are highly predictive markers of active coeliac disease. Because limited facilities are available for routine use of anti-transglutaminase antibodies assays in developing countries, a simple, economical immunological test would represent a great step forward in the screening of coeliac disease. AIM: We determined the prevalence of coeliac disease in two different populations living in an urban area and in a sub-urban impoverished area of Recife (Brazil), using two rapid tests based on detection of anti-transglutaminase antibodies in serum and in one drop of whole blood. METHODS: Whole-blood and serum samples from 1074 individuals were analysed by the two rapid tests; 580 subjects were university students and 494 subjects were coming from sub-urban impoverished areas, characterized by the endemic presence of filariasis. The positive subjects were evaluated by anti-tranglutaminase enzyme linked immunosorbent assay (ELISA) assay, the coeliac disease-related HLA DQ2/8 and intestinal biopsy. RESULTS: Both rapid assays were positive in 25/1074 subjects, but only 9/25 (4/4 in urban areas, specificity 100%; 5/21 in poor areas, specificity 76%) were confirmed positive by ELISA assay. The nine subjects testing positive for HLA DQ2 and the intestinal biopsy showed the typical coeliac disease lesions (coeliac disease-prevalence: 0.84%, 9/1074); seven coeliacs were asymptomatic and two presented recurrent abdominal pain. CONCLUSIONS: The rapid assays were accurate in finding new coeliacs at a remarkably low cost. We are convinced that this new way of testing for coeliac disease can be successfully used by non-specialized personnel in daily practice in developing countries. PMID- 17706475 TI - Intrauterine fetal transfusions in the management of fetal anemia and fetal thrombocytopenia. AB - During the past 40 years, rhesus alloimmunization has gone from being one of the major causes of perinatal mortality to an almost eradicated disease. The unraveling of the pathophysiology, the development of reliable diagnostic tools, a very effective prophylaxis program, and for those (nowadays rare) cases slipping through the prevention system the availability of treatment by intrauterine blood transfusions, together constitute one of the great triumphs in modern medicine. Although Rh-D alloimmunization remains the most common indication for fetal blood transfusion therapy, an increasing percentage of these procedures is used to treat other causes of fetal anemia such as Kell alloimmunization and parvovirus B19 infection. Apart from transfusing blood, the same technique can be used to transfuse platelets to thrombocytopenic fetuses. This chapter describes the technique of fetal transfusion, and reviews the current management of fetal anemia and fetal thrombocytopenia. PMID- 17706476 TI - Caesareans and authoritative knowledge. PMID- 17706477 TI - Osteoporosis in children and adolescents. AB - In recent years, the issue of low bone density in children and adolescents has attracted much attention. The classical definition of osteoporosis should be valid at any age, yet its practical applicability to children and adolescents remains a matter of debate and there is no consensus on a diagnosis based solely on the BMD value. The clinical relevance of uncomplicated low bone density in the young and its long-term consequences remain difficult to evaluate and there is only preliminary evidence that the BMD value is a predictor of fracture risk in growing subjects. Moreover, the interpretation of densitometric data in the young is difficult because the "normal" BMD values to be used for comparison are continuously changing with age, and in addition, depend on several variables, such as gender, body size, pubertal stage, skeletal maturation and ethnicity. Although Z-score values below -2 are generally considered a serious warning, most bone specialists make a diagnosis of osteoporosis in children and adolescents only in the presence of low BMD and at least one fragility fracture. The scope of this review is limited to presenting a picture of the available knowledge. The literature on fractures will be presented in detail, since fractures are one of the key elements in the debate. There are countless papers on fractures in childhood and adolescence, but very few of them attempt to identify fragility fractures, and still fewer develop the concept of osteoporosis in the young in relation to fractures. The different forms of primary and secondary osteoporosis, the more technical aspects of bone densitometry in pediatrics, and the delicate issue of treatment will be discussed only briefly. PMID- 17706478 TI - Sample size requirements for bone density precision assessments and effect on patient categorization: a Monte Carlo simulation study. AB - A sample size of 30 degrees of freedom (df) for bone mineral density (BMD) precision studies may be insufficient for reliably categorizing change. Monte Carlo simulation was used to evaluate the effect of precision study sample size on identifying change in clinical patients. Least significant change (LSC) from 198 spine and 193 total hip scan-pairs was used to categorize change for 1420 patients undergoing BMD monitoring. Relative to this reference change fraction (RCF), LSC limits were identified that gave specified deviations from the RCF ( 25% to +25%). Confidence limits (95% and 80%) for these LSC values (5 to 500 df) were estimated using 'bootstrap' samplings. A sample size providing 140 df is needed to avoid overdetecting spine change by 5% and 150 df to avoid underdetecting spine change by 5% with 95% confidence limits. A sample size of 30 df resulted in up to a 12.5% overdetection and 10.0% underdetection of spine or hip change based upon 95% confidence limits. In conclusion, assessing the effect of precision study sample size on classifying change in monitored patients is an important element of the precision assessment that is neglected in current recommendations. Sample sizes larger than 30 df are required if low levels of categorization error are to be achieved. PMID- 17706479 TI - Pure esophageal atresia with normal outer appearance: case report. AB - Isolated esophageal atresia is characterized by a long segment between the 2 esophageal pouches. This article presents a case of pure esophageal atresia with a 1-cm-long segment at the midportion without discontinuity that resembled the subtype II3 according to the Kluth atlas. Resection of the atretic segment and primary anastomosis were performed successfully. PMID- 17706480 TI - Bilateral cystic adrenal neuroblastoma with cystic metastasis in the liver. AB - A 2 1/2-month-old infant presented with a massive hepatomegaly. Ultrasound and computerized tomography showed a large cystic lesion in the right adrenal, small cysts in the left adrenal, and multiple cystic liver metastases. The right adrenal cyst, on excision, turned out to be a cystic neuroblastoma with hemorrhage. On follow-up, the cysts in the left adrenal and the liver metastases are regressing. PMID- 17706481 TI - Burkitt lymphoma presenting as colonic ischemia and overwhelming sepsis. AB - Lymphomas may occasionally present as acute surgical emergencies in children, most commonly because of obstruction, intussusception, or direct bowel invasion. We present the case of a 14-year-old adolescent boy who presented with septic shock and was found to have necrosis of the cecum because of a Burkitt lymphoma. The cause of the ischemia appeared to be mesenteric infiltration and subsequent vascular compromise of the bowel. We discuss the management of this patient and present a review of the literature. PMID- 17706482 TI - A large struma ovarii tumor removed via laparoscopy in a 16-year-old adolescent. AB - Struma ovarii is rare ovarian tumor that is characterized by the presence of at least 50% thyroid tissue on histologic examination. This usually benign neoplasm is predominantly found in women between the ages of 40 and 60 years and infrequently in the pediatric age group. In the foregoing report, we present an unusual case of a large struma ovarii in a 16-year-old adolescent girl with abdominal pain and increasing abdominal girth. Removal of the mass was achieved via a laparoscopic approach. We conclude that the diagnosis of struma ovarii should be considered in adolescent girls presenting with large cystic ovarian masses and that a laparoscopic approach to management is the treatment of choice. PMID- 17706483 TI - Resection of giant liver adenoma in a 17-year-old adolescent boy using venovenous bypass, total hepatic vascular isolation, and in situ cooling. AB - Giant liver adenomas are rare pediatric tumors. Hepatocellular adenomas account for approximately 2% to 4% of all pediatric liver tumors. We present the case of a biopsy-proven 21 x 20.5 x 10.5-cm hepatocellular adenoma in a 17-year-old adolescent boy resected using venovenous bypass and total hepatic isolation. Hepatic adenomas of this size are historically treated with orthotopic liver transplantation. Resection of a massive centrally located giant liver adenoma using total hepatic vascular isolation and venovenous bypass with in situ hepatic cooling and is not previously reported. By combining these techniques, we were able to defer the risks of orthotopic liver transplantation and life-long immunosuppression for our patient. The patient's recovery was uncomplicated and hepatic regeneration was excellent. At 9 months' follow-up, the patient reported enjoying an athletic adolescent life-style with no evidence of recurrence. PMID- 17706484 TI - Continuous hyperthermic peritoneal perfusion for desmoplastic small round cell tumor. AB - Desmoplastic small round cell tumor (DSRCT) is a rare disease of children, adolescents, and young adults that begins and spreads on the peritoneal surfaces. Desmoplastic small round cell tumor usually presents with diffuse abdominal metastatic disease similar in gross appearance to carcinomatosis. To date, very aggressive treatment programs have yielded dismal outcomes. Here we present 2 cases of DSRCT that were treated with aggressive surgical excision followed by intraoperative continuous hyperthermic peritoneal perfusion using cisplatin. These are the first pediatric case reports of DSRCT being treated with continuous hyperthermic peritoneal perfusion, a procedure usually used in treatment of adult carcinomatosis. PMID- 17706485 TI - Tinea capitis: no incision nor excision. AB - Tinea capitis is a fungal infection of the scalp and hair shaft that mainly affects prepubescent children. Its clinical aspects range from a mild noninflammatory infection resembling seborrheic dermatitis to a highly inflammatory swelling reaction (kerion). We report the cases of 2 children who underwent surgical treatment of their kerions under general anesthesia. One lesion had been incised and the other excised. This inappropriate treatment made conservative treatment after surgery more difficult. We recommend that abscesslike lesions on the scalps of children be carefully investigated by surgeons and dermatologists to determine whether they are the result of a dermatophytic infection in order that the appropriate conservative treatment can be initiated. PMID- 17706486 TI - Segmental liver resection in a child using intraoperative ultrasound-guided radiofrequency energy. AB - Segmental surgical liver resection is still considered the only potentially curative option for patients with resectable liver tumors. Intraoperative bleeding may be a dangerous complication even in an expert's hands. A bloodless technique of radiofrequency (RF)-assisted segmental liver resection was performed in a 9-year-old girl with a mycobacterial spindle cell pseudotumor of the liver. Under intraoperative ultrasound guidance, the liver parenchyma was coagulated along the marked resection plane by a single "cooled-tip" RF electrode and then divided with a surgical knife. A nearly bloodless resection of the parenchyma was achieved within 25 minutes. The patient was discharged on the fifth postoperative day without complications. My early experience shows that RF-assisted liver resection offers a valuable additional option for bloodless removal of liver tumors in pediatric age. PMID- 17706487 TI - Gastroschisis associated with cleft lip and palate. AB - Gastroschisis is a common congenital abdominal wall defect. Rarely, it is associated with extraabdominal midline congenital anomalies. Oral clefts are the commonest craniofacial congenital midline defects. They can be associated with other midline defects like omphalocele. We believe these are the first 3 case reports of gastroschisis and cleft palate occurring in the same patient. PMID- 17706488 TI - Clinical significance of the confluence of the cystic duct in patients with anomalous arrangement of the pancreaticobiliary duct. AB - BACKGROUND/PURPOSE: In anomalous arrangement of the pancreaticobiliary duct (AAPBD), there is anatomical diversity of the cystic duct. In this study, we evaluated the influence of the level of insertion of the cystic duct into the extrahepatic bile duct on the pathophysiology of AAPBD. METHODS: Thirty-two children with AAPBD were examined using cholangiopancreatography. If the cystic duct entered the hepatic duct at the lower middle point of the extrahepatic bile duct, it was defined as low confluence; otherwise, it was considered as high confluence. Clinical details and radiological variables were compared between these 2 groups. RESULTS: Low confluence was noted in 8 of the 32 patients. Seven of the 8 had fusiform-type or nondilatation-type choledochus, and the cystic-type was significantly less frequent than in the high-confluence group. The diameter of the common bile duct was significantly smaller and the main pancreatic duct was significantly greater than in the high-confluence group. Pancreatitis was more common and biliopancreatic reflux on computed tomography combined with intravenous infusion cholangiography was more often seen in the low-confluence group than in the high-confluence group. CONCLUSIONS: Bile juice could regurgitate into the pancreatic duct via the low confluence of the cystic duct, resulting in severe pancreatitis in patients with AAPBD. PMID- 17706489 TI - Kasai portoenterostomy: 12-year experience with a novel adjuvant therapy regimen. AB - AIM: The role of adjuvant therapy with corticosteroids and choleretics after Kasai portoenterostomy for biliary atresia (BA) remains uncertain. Experience with a novel postoperative adjuvant therapy regimen is reported. METHODS: Between 1994 and 2006, 71 infants with BA were referred. Four died from uncorrectable congenital heart disease/cardiorespiratory failure without undergoing portoenterostomy, 7 underwent primary liver transplantation (3 referred > or = 19 weeks of age), and 60 underwent portoenterostomy at a median of 51 (10-104) days. Of these, 55 (92%) had type 3 BA and 6 had the BA splenic malformation syndrome. Fifty (83%) received the following adjuvant therapy beginning on postoperative day 5: oral dexamethasone 0.3 mg/kg bd for 5 days, 0.2 mg/kg bd for 5 days, and 0.1 mg/kg bd for 5 days together with oral ursodeoxycholic acid 5 mg/kg bd and phenobarbitone 5 mg/kg nocte, both of which were continued for 1 year. All infants received routine perioperative prophylactic antibiotics. RESULTS: Overall, 42 of 60 (70%) infants cleared their jaundice (bilirubin < 20 micromol/L): 38 of 50 (76%) with the dexamethasone/ursodeoxycholic acid regimen compared with 4 of 10 (40%) not receiving this adjuvant treatment. There were 4 late deaths after portoenterostomy: 2 from associated congenital disorders and 2 after liver transplantation. Of the remaining 56 children, 39 (70%) are currently alive with their native liver at a median follow-up of 3.3 years and 17 are alive after liver transplantation. Surgical complications occurred in 3 after portoenterostomy: adhesive bowel obstruction (2) and an anastomotic leak. One infant had gastrointestinal bleeding that may have been related to dexamethasone, but this resolved with ranitidine. There were no perioperative septic complications. CONCLUSION: In this series, adjuvant postoperative treatment with a short course of oral dexamethasone and longer-term ursodeoxycholic acid significantly improved the outcome after Kasai portoenterostomy. PMID- 17706490 TI - Problems during and after pregnancy in female patients with biliary atresia. AB - BACKGROUND/PURPOSE: Advances in the management for biliary atresia (BA) have improved the prognosis and has greatly increased the number of long-term survivors. Even the long-term survivors, however, still face some problems. This retrospective review was performed to assess pregnancy-associated issues in long term survivors after surgery for BA. MATERIALS AND METHODS: Of 55 patients with BA surviving for 16 years or more without liver transplantation, 9 patients have experienced pregnancy and delivery. Clinical courses, the outcome of pregnancy and delivery, and current statuses were retrospectively evaluated from their clinical records. RESULTS: The study revealed 14 pregnancies and 11 deliveries. Before pregnancy, no patient showed visible jaundice, but 6 patients had some complications such as episodes of cholangitis and portal hypertension. Two of the patients had both conditions and 2 others developed visible jaundice after pregnancy. One intrauterine fetal death occurred. CONCLUSIONS: Our retrospective review suggests that the previously mentioned conditions can be risk factor for cholangitis and gastrointestinal bleeding during or after pregnancy but are not considered to be contraindications for pregnancy and delivery. Complications can occur with pregnancy even during the normal course. Thus, careful observation is recommended. PMID- 17706491 TI - Is there a safe advantage in performing outpatient laparoscopic cholecystectomy in children? AB - BACKGROUND: Laparoscopic cholecystectomy, the standard procedure for removing the sick gallbladder of children, is generally performed leaving the child overnight in the hospital. PURPOSE: This study aimed to determine if there is a safe advantage in performing laparoscopic cholecystectomy as an outpatient procedure while setting the clinical parameters for those who will benefit from in-hospital stay. METHODS: Thirty-five patients were selected for the study and were divided into group A, if the outpatient procedure was done, and group B, if the child was left overnight in the hospital. Retrospective review of medical charts was performed. Statistical significance was defined as P < .05. RESULTS: Group A consisted of 13 patients and group B of 22 patients. All patients in group A left the hospital the same day of surgery. Distribution by age and sex in the groups was not statistically different. Preoperative symptoms of vomiting were statistically significantly higher in group B. Presence of an associated medical condition was higher in the in-hospital patients. Concomitant procedures, blood loss estimates, and duration of surgery showed no statistical difference. No child was readmitted after release from the hospital. Pre-, intra-, and postoperative pain management were the same in all patients. Mean postoperative stay and medical charges were statistically significant between the groups. CONCLUSIONS: Laparoscopic cholecystectomy can safely be done as an outpatient procedure. Children with a complicated gallbladder disease process or associated medical condition benefit from an overnight stay. Perioperative pain management is crucial in all cases. Reduced hospital stay and medical charges are significant advantages in performing laparoscopic cholecystectomy as an outpatient procedure. PMID- 17706492 TI - Partial internal biliary diversion through a cholecystojejunocolonic anastomosis- a novel surgical approach for patients with progressive familial intrahepatic cholestasis: a preliminary report. AB - BACKGROUND/PURPOSE: The purpose of the study was to describe the initial experience with a novel approach to the surgical treatment of progressive familial intrahepatic cholestasis (PFIC), avoiding the creation of a permanent stoma. METHODS: Two teenaged patients, aged 15 and 17 years, underwent partial internal biliary diversion to treat uncontrollable pruritus associated with PFIC. The surgical technique involved the creation of an isolated jejunal conduit, anastomosed proximally in a terminolateral fashion to the gallbladder and distally to the ascending colon. This operation combines the advantages of partially diverting the biliary flow from the enterohepatic cycle, avoiding an external biliary fistula. In one of the patients, this technique was used as a primary procedure, whereas in the other, a previous partial external diversion was converted to an internal diversion. RESULTS: Both patients had complete resolution of their pruritus and normalization of hepatic laboratory tests. One of the patients developed a mild choleretic diarrhea that can be controlled with eventual use of cholestyramine. No complications were observed related to this operation. CONCLUSIONS: Biliary diversion appears to be a very attractive surgical option for the treatment of PFIC in children with a normal gallbladder. Long-term follow-up is necessary to evaluate late results and eventual complications of this approach. PMID- 17706493 TI - Outcomes of fundoplication in children with cystic fibrosis. AB - PURPOSE: Children with cystic fibrosis (CF) have a high prevalence of gastroesophageal reflux disease (GERD). As GERD is associated with chronic respiratory symptoms and feeding problems, fundoplication is often performed in children with CF. Although the outcomes of fundoplication have been described across diverse pediatric groups, there is no published experience with CF. METHODS: The records of 25 children with CF who underwent fundoplication in our center were reviewed. Data on symptoms and diagnostic testing results as well as on complications related to fundoplication were collected. Nutritional parameters and pulmonary function were compared before and after fundoplication. RESULTS: There was no mortality associated with fundoplication, but 12% had complications that required a subsequent surgical procedure. Whereas 28% were able to discontinue their antireflux medications, 48% developed symptoms of recurrent GERD. Overall, there was no change in body mass index, body mass index percentile, or the slope of forced expiratory volume in 1 second (FEV1) after fundoplication. Children who had an FEV1 of less than 60% predicted at the time of fundoplication exhibited an improvement in FEV1 slope compared to those with FEV1 of 60% or more (+5.3% vs -8.6% per year, P = .004). CONCLUSION: The complication rate of fundoplication is similar to what has been reported in large series in children without CF. There is a high rate of recurrent GERD and little apparent benefit for either nutritional or pulmonary outcomes. The observed difference on FEV1 slope, in those with moderate-severe vs mild lung disease, highlights the need to thoroughly evaluate the role of fundoplication in children with CF. PMID- 17706494 TI - Predictors of outcome in patients with congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation. AB - BACKGROUND: The role of extracorporeal membrane oxygenation (ECMO) in patients with congenital diaphragmatic hernia is still evolving. The use of ECMO is invasive with potential complications during instrumentation for cannulation and heparinization. There are no reliable predictors of outcome in patients requiring ECMO. We aimed to identify (a) the factors that could predict outcome and (b) the incidence and relation of complications during ECMO to outcome. METHODS: "Pre" ECMO (age, sex, birth weight, blood gasses, and ventilator settings) and "on" ECMO variables (mode of ECMO, use of nitric oxide, surfactant, liquid ventilation, inotropes, timing of repair, and complications on ECMO) were analyzed to identify predictors of outcome. RESULTS: Fifty-two patients were included. The overall survival was 58%. Mean duration of ECMO (181 +/- 120 vs 317 +/- 156 hours, P = .001), use of nitric oxide (6 vs 10, P = .049), and renal complications (4 vs 14; P < .001) differed between survivors and nonsurvivors. The survival of patients requiring ECMO support for more than 2 weeks is significantly lower than that of patients requiring ECMO support for less than 2 weeks (18% vs 68%, P = .005). Multiple logistic regression revealed ECMO duration of 2 weeks or more and renal complications to be associated with mortality. CONCLUSION: No pre-ECMO variable could be identified as predictor of mortality. Prolonged duration of ECMO and renal complications on ECMO were independently associated with mortality. PMID- 17706495 TI - Characteristics of congenital cystic adenomatoid malformations associated with nonimmune hydrops and outcome. AB - BACKGROUND/PURPOSE: In fetuses with congenital cystic adenomatoid malformations of the lung (CCAMs), hydrops fetalis and large masses are associated with poor outcomes. This study attempts to (1) determine sonographic features (in addition to large size) that correlate with hydrops and (2) characterize the features that correlate with outcome among hydropic fetuses. METHOD: Charts and sonograms of fetuses with large, unilateral CCAMs were retrospectively reviewed. Mass features evaluated included laterality, macrocystic/microcystic, cystic/solid predominance, degree of mediastinal shift, retrocardiac component, diaphragm eversion, polyhydramnios, and mass-thorax ratio (MTR). Features of hydrops included degree of ascites, scalp and integumentary edema, pleural/pericardial effusion, and placentomegaly. RESULTS: Thirty-six fetuses with large CCAMs were studied: 27 with and 9 without hydrops. Three sonographic features were significantly associated with hydrops: MTR of at least 0.56, cystic predominance of mass, and eversion of hemidiaphragm. Of 27 fetuses with hydrops, 10 (37%) demonstrated all 3 features compared with none in those without hydrops (P = .04). All 9 nonhydropic fetuses were expectantly managed, and 100% survived. In the hydropic group, none of the expectantly managed fetuses survived, and 10 (43%) of the 21 fetuses who underwent fetal intervention survived. CONCLUSION: Three features of large CCAMs were significantly associated with hydrops: MTR, cystic predominance, and diaphragm eversion. Identification of these features will allow clinicians to accurately predict which fetuses may warrant closer follow-up and possible treatment. PMID- 17706496 TI - Thoracoscopic division of vascular rings in infants and children. AB - OBJECTIVE: Traditionally vascular rings in infants and children are treated through an open thoracotomy. Recently, thoracoscopic surgery has been used for these complex procedures. This study reports our early experience with thoracoscopic division of vascular rings and evaluates the efficacy and safety of this approach. MATERIAL AND METHODS: Patients who underwent thoracoscopic division of vascular rings at King Khalid University Hospital, Riyadh, Saudi Arabia, from December 2004 to January 2006 are included. Their data were carefully analyzed looking at demographics, clinical presentation, diagnostic modality, type of the anomaly, operative details, complications, and outcome. RESULTS: A total of 9 patients underwent thoracoscopic division of vascular rings. Age at surgery ranged between 2 and 108 months (mean, 24 months). Weight varied between 5.3 and 32 kg (mean, 10.3 kg). All patients were symptomatic. Computed tomographic scan was diagnostic and accurately defined the type of anomaly in all the patients. Four patients had a right aortic arch with an aberrant left subclavian artery and left ductus/ligamentum arteriosum, 2 had double aortic arches, and 3 had a right aberrant subclavian artery. One patient developed right-sided pneumothorax on the contralateral site, and another one developed apnea 12 hours after surgery, requiring mechanical ventilation. There was no mortality. Operative time ranged between 50 and 145 minutes, the mean being 107 minutes. The average hospital stay was 4 days. Five patients had their preoperative symptoms completely resolved, and the rest are showing steady improvement. The average follow-up period is 6 months. CONCLUSION: Our early experience indicates that thoracoscopic division of vascular rings is safe and effective. Because it takes away the need for thoracotomy, it is likely that it can result in less postoperative pain and rapid convalescence. It also prevents the ill effects of thoracotomy and gives good cosmetic results. PMID- 17706497 TI - Minimal access approach to jejunal atresia. AB - AIM: Jejunal atresia (JA) is a common cause of intestinal obstruction in the newborn. It is corrected by small bowel tapering/excision and end-to-end enteroenterostomy, performed through a transverse laparotomy incision. It has excellent result with minimal morbidity and mortality. This incision can be reduced to a circumumbilical type as has been described for hypertrophic pyloric stenosis. MATERIALS: Sixteen neonates, aged 1 to 8 days, underwent JA repair via this approach over a 3-year period. RESULT: The small bowel is easily accessible through this approach in all but 1 case, where a suspected colonic atresia, combined with JA, necessitated an extension to classical incision. Thirteen patients had an uneventful recovery; 2 cases required revision for anastomotic strictures, which was done through the same incision. Postoperative follow-up at 6 months showed well-healed skin incisions that were hardly visible and integrating well with the natural umbilical fold. CONCLUSION: Circumumbilical incision permits an adequate approach to correction of JA. It has minimal complications and a superior cosmesis compared to the classical approach. PMID- 17706498 TI - Effect of probiotics on intestinal regrowth and bacterial translocation after massive small bowel resection in a rat. AB - BACKGROUND/PURPOSE: Because of their ability to inhibit intestinal bacterial overgrowth, probiotics (PROs) have been advocated for the treatment of patients with short bowel syndrome (SBS). This study was conducted to determine the effect of PROs on bacterial translocation and intestinal regrowth after massive small bowel resection in a rat. METHODS: Male Sprague-Dawley rats were divided into 3 experimental groups: sham rats underwent bowel transection and reanastomosis, SBS rats underwent 75% small bowel resection, and SBS-PRO rats underwent bowel resection and were treated with a PRO given in drinking water from day 4 through 14. Intestinal structural changes (bowel circumference, overall bowel and mucosal weight, mucosal DNA and protein, villus height and crypt depth, enterocyte proliferation and enterocyte apoptosis) and bacterial translocation (BT) to mesenteric lymph nodes, liver, portal blood, and peripheral blood were determined on day 15 after operation. RESULTS: Sham rats exhibited a 20% BT to the mesenteric lymph nodes (level I), liver (level II), and blood (level III). Short bowel syndrome rats demonstrated a 100% BT to lymph nodes (level I) and liver (level II) and 40% translocation to peripheral blood (level III). Treatment with PROs resulted in a significant decrease in BT to all 3 target organs and decreased enterocyte apoptosis compared with SBS-untreated animals. Short bowel syndrome rats showed a significant increase (vs sham) in jejunal and ileal bowel and mucosal weight, mucosal DNA and protein, villus height, and crypt depth. Short bowel syndrome rats also had a greater proliferation index and apoptotic index in both jejunum and ileum compared with sham animals. SBS-PRO rats showed a significant increase (vs SBS rats) in crypt depth in ileum and a mild decrease in apoptotic index in jejunum and ileum, compared with SBS-untreated animals. CONCLUSIONS: In a rat model of SBS, PROs decrease BT through mechanisms which maybe dependent on intestinal mucosal integrity. PMID- 17706499 TI - Nutrition assessment in children with short bowel syndrome weaned off parenteral nutrition: a long-term follow-up study. AB - PURPOSE: The purpose of the study was to assess long-term growth and nutrition status of children with neonatal short bowel syndrome (SBS) after weaning off parenteral nutrition (PN). METHODS: Eight children with neonatal SBS weaned from PN therapy for more than 2 years were studied. Medical records were reviewed; anthropometric measurements and blood test (hemoglobin, albumin and prealbumin, immunoglobulin, electrolytes, trace elements, and fat-soluble vitamins) were assayed during follow-up. RESULTS: Anthropometric measurements, weight for age, and height for age were normal in all children; one child was found to be overweight according to weight for height z score. No children were found to have anemia, although one presented with macrocytosis and another had microcytosis. Low serum concentrations of zinc in 3 cases and iron in 1 case were detected. Immunoglobulin levels of all children were within the reference value. Low plasma levels of vitamin A in 2 cases, vitamin E in 4 cases, and beta-carotene in 2 cases were found; one of them had obviously low levels of the 3 fat-soluble vitamins. CONCLUSION: Children with SBS are still at risk for different nutrient malabsorption even after weaning off PN for a long time. Therefore, they need long-term, regular monitoring and intensive nutritional care to prevent various nutrient deficiencies. PMID- 17706500 TI - The influence of rejection on graft motility after intestinal transplantation in swine: the possibility of using this method for the real-time monitoring of acute cellular rejection. AB - BACKGROUND: We have previously reported that rejected allografts show dysmotility, which can be detected by real-time monitoring in swine. We examined the correlation between the motility and the mucosal histology to detect rejection at an early stage by real-time monitoring. METHODS: Intestinal transplantation was performed orthotopically using FK506. The distal segment of the allograft measuring about 20 cm was isolated and exteriorized as "Thiry Vella" stoma for biopsies. Strain-gage force transducers were attached on a graft for the real-time monitoring of graft motility. The pigs without intestinal transplantation were used as controls (C). The rejection was classified into 4 groups based on the histologic findings: nonrejection, mild rejection, moderate rejection, and severe rejection. Migrating motor complex (MMC) phase 3 was estimated by the following parameters: duration, amplitude, interval, motility index, velocity, and frequency of the propagation. RESULTS: In the nonrejection group, all parameters were almost the same as in C group. In contrast, in the moderate rejection and severe rejection groups, most of the parameters were significantly lower than those in the C group. In the mild rejection group, the contractility of the MMC was not significantly altered, but the frequency of the propagation decreased significantly. CONCLUSIONS: The graft motility detected by the real-time strain-gage method correlated closely to the grade of mucosal histology. This method is therefore considered to be useful for detecting rejection at an early stage by examining the frequency of MMC propagation. PMID- 17706502 TI - Novel action of epidermal growth factor on caspase 3 and its potential as a chemotherapeutic adjunct for neuroblastoma. AB - PURPOSE: We previously reported that epidermal growth factor (EGF) induced cleaved caspase 3 expression and apoptosis in human neuroblastoma cells. We hypothesized that EGF upregulates total caspase 3 expression, thereby enhancing the cytotoxic potency of chemotherapeutic agents. METHODS: Wild-type (WT) and doxorubicin-resistant (Dox-R) SK-N-SH neuroblastoma cells were incubated with EGF 0 to 250 ng/mL for 24 hours or with 5 ng/mL for 0 to 5 days, and total caspase 3 expression and transcription were determined by immunoblots and reverse transcription and polymerase chain reaction, respectively. Cell proliferation was determined after EGF (5 ng/mL) incubation for 1 to 5 days. Cells incubated with EGF (5 ng/mL) for 24 hours before doxorubicin treatment were used to determine the effect of EGF on cell replication and cleaved caspase 3 expression. RESULTS: Wild-type and Dox-R cells had maximal total caspase 3 expression after incubation with EGF (5 ng/mL) for 3 and 5 days, respectively, and a corresponding increase in DNA transcription. Treating the cells with or without EGF (5 ng/mL) resulted in similar replication rate. However, cell death was increased by EGF pretreatment and doxorubicin when compared with that by doxorubicin alone (WT, 53% +/- 8%; Dox-R, 44% +/- 9%; P < .05). Cleaved caspase 3 expression was upregulated when cell death was increased. CONCLUSION: Epidermal growth factor upregulates the expression and transcription of total caspase 3 in WT and Dox-R cells in a concentration- and time-dependent manner. Epidermal growth factor pretreatment augments the cytotoxic effect of doxorubicin. PMID- 17706501 TI - Posttraumatic small bowel obstruction in children. AB - BACKGROUND: The diagnosis of intestinal injuries in children after blunt abdominal trauma can be difficult and delayed. Most children who suffer blunt abdominal trauma are managed nonoperatively, making the diagnosis of intestinal injuries more difficult. We sought to gain information about children who develop intestinal obstruction after blunt abdominal trauma by reviewing our experience. METHODS: Review of records from a pediatric tertiary care center over an 11.5 year period revealed 5 patients who developed small bowel obstruction after blunt trauma to the abdomen. The details of these patients were studied. RESULTS: All patients were previously managed nonoperatively for blunt abdominal trauma. Intestinal obstruction developed 2 weeks to 1 year (median, 21 days) after the trauma. Abdominal x-ray, computerized tomography scan, or barium meal studies were used to establish the diagnosis. The pathology was either a stricture, an old perforation, or adhesions causing the intestinal obstruction. Laparotomy with resection and anastomosis was curative. CONCLUSIONS: Posttraumatic small bowel obstruction is a clinical entity that needs to be watched for in all patients managed nonoperatively for blunt abdominal trauma. PMID- 17706503 TI - In vitro induction of immune responses to shared tumor-associated antigens in rhabdomyosarcoma. AB - PURPOSE: Currently, novel therapies to improve survival of patients with rhabdomyosarcoma (RMS) are being investigated. One of the new approaches involves immunotherapy using tumor-specific T-lymphocytes. An effective prolonged immune mediated response against tumor cells is dependent upon the response of helper T lymphocytes (HTLs) to tumor-associated antigens in the presence of histocompatibility lymphocyte antigen surface proteins. METHODS: Rhabdomyosarcoma tumor lysate-pulsed human dendritic cells were used to stimulate HTL precursors (naive CD4+ T-cells) in vitro. After 3 rounds of antigen stimulation with antigen presenting cells, the T-cells were tested for reactivity (T-cell proliferation assays) against a large panel of tumor lysate-pulsed autologous antigen presenting cells. RESULTS: Using peripheral blood mononuclear cells from normal naive donors, we have been able to generate HTL clones that recognize and proliferate to multiple tumor cell lines. The HTLs were induced using lysate from a single alveolar RMS tumor cell line (RMS13). The clones generated recognized all of the alveolar RMS cell lines (RMS13, Rh18, Rh28, Rh30, and Rh41), prostate cancer cell lines (LNCAP and LAPC4), melanoma cell lines (Mel 624 and G361), and breast cancer cell line (SKBR3). Helper T-lymphocytes recognition was also confirmed by interferon-gamma production. The clones did not recognize colon, lymphoma, ovarian carcinoma, ERMS or Epstein-Barr virus (EBV) transformed B cells. This recognition was histocompatibility lymphocyte antigen class II restricted and was not an allogeneic response. CONCLUSION: The results of this work demonstrate that HTLs, exposed to RMS lysate, are able to recognize and respond to a broad range of tumor types suggesting that a common antigen exist among these different tumors. These findings suggest novel treatment strategies for patients with RMS using tumor lysate to induce antitumor immune responses. PMID- 17706504 TI - Chronic pain after childhood groin hernia repair. AB - BACKGROUND: In contrast to the well-described 10% risk of chronic pain affecting daily activities after adult groin hernia repair, chronic pain after childhood groin hernia repair has never been investigated. Studies of other childhood surgery before the age of 3 months suggest a risk of increased pain responsiveness later in life, but its potential relationship to chronic pain in adult life is unknown. METHODS: This was a nationwide detailed questionnaire study of chronic groin pain in adults having surgery for a groin hernia repair before the age of 5 years (n = 1075). RESULTS: The response rate was 63.3%. In the 651 patients available for analysis, pain from the operated groin was reported by 88 (13.5%) patients whereof 13 (2.0%) patients reported frequent and moderate or severe pain. Pain occurred primarily when exercising sports or other leisure activities. Patients operated on before the age of 3 months (n = 122) did not report groin pain more often or with higher intensity than other patients did. CONCLUSIONS: Groin pain in adult patients operated on for a groin hernia in childhood is uncommon and usually mild and occurs in relation to physical activity. Operation before the age of 3 months does not increase the risk of chronic pain. PMID- 17706505 TI - Postoperative pyloric stenosis in the newborn: a forgotten problem. AB - PURPOSE: Postoperative vomiting in newborns is a common finding usually attributed to the original surgery. We report 10 newborns whose postoperative course was complicated by pyloric stenosis. METHODS: We reviewed the charts of all newborns who had pyloric stenosis diagnosed after a major abdominothoracic operation over the past 30 years (1973-2003) at a single children's hospital. RESULTS: Ten cases of pyloric stenosis were diagnosed in postoperative newborns (esophageal atresia [3], small bowel atresia [2], diaphragmatic hernia, fetus-in fetu, imperforate anus, lung biopsy, malrotation [1]). Their mean gestational age was 36 weeks, birth weight was 3.2 kg, and age at newborn operation was 2 days. Their postoperative feeds started on the sixth day (mean), and the pyloric stenosis vomiting started on the 14th day. It took a mean of 12 days to make the diagnosis of pyloric stenosis, and this was done entirely by diagnostic imaging. Mean age at pyloromyotomy was 3 1/2 weeks. A new incision was used in 7 patients. Postoperative feedings started on the first day; all did well. There were 3 complications (bowel obstruction), all requiring operation. CONCLUSION: Unfortunately, this review offers no specific insight or novel advice to help the readership think about the diagnosis in such a postoperative setting. PMID- 17706506 TI - Indications for excision of nevi and melanoma diagnosed in a pediatric surgical unit. AB - BACKGROUND/PURPOSE: Childhood melanoma is rare but increasing in incidence. Its management relies on early diagnosis. The purpose of this study is to discuss surgical indications of nevi and diagnosis of melanoma in a pediatric surgical unit. METHODS: Data relative to the patients who underwent removal of nevi in our pediatric surgical unit from 1999 to 2005 were reviewed to identify indications, histology, and melanoma occurrence. RESULTS: The most frequent indication was atypical nevus. Compound nevus was the most common finding, followed by congenital and Spitz nevi. Melanoma was diagnosed in 3 excised nevi, and in 1 case it occurred as a metastatic disease. CONCLUSIONS: Our data showed a pattern of indications for surgery similar to that described in the literature, with a high detection rate of melanoma, nonetheless showing that some rare conditions may delay diagnosis. PMID- 17706507 TI - Stability of prevalence rates of anorectal malformations in the Alberta Congenital Anomalies Surveillance System 1990-2004. AB - BACKGROUND/PURPOSE: Anorectal malformations appeared to be increasing in the province of Alberta, Canada. To assess whether this was a significant trend, with the possibility of these having a teratogenic origin, we examined the frequency of anorectal malformations over a 15-year period. METHODS: We examined the records of the Alberta Congenital Anomaly Surveillance System, which is a semiactive surveillance system using the British Paediatric Association and the Royal College of Paediatrics and Child Health expansions of the International Classification of Diseases-Ninth Revision and the International Classification of Diseases-10th Revision. RESULTS: The overall rate was 1/2162 (4.63/10,000 total births) with a marked male predominance (1.7:1). Approximately two thirds of the 273 cases had 1 or more malformations. CONCLUSION: Although there was an increasing trend in the rate from 1999 especially for the multiples, this was not significant. In view of the advances in syndrome identification and molecular diagnostics, consideration should be given to a detailed review of the family history and appropriate testing not only for multiple cases but also for isolated ones. PMID- 17706508 TI - Anal ultraslow waves and high anal pressure in childhood: a clinical condition mimicking Hirschsprung disease. AB - PURPOSE: Anal ultraslow waves (USWs) have been described in several clinical conditions closely related to chronic constipation associated with high anal pressure; however, USW-related clinical manifestations in childhood are poorly understood. The purpose of this study is to elucidate the clinical relevance of USWs in childhood. METHODS: Manometric recordings of 118 cases including 70 children with constipation and 16 patients with Hirschsprung disease were analyzed. RESULTS: Ultraslow waves were seen in 4 of 70 children with constipation. None of the controls or patients with Hirschsprung disease exhibited USWs. The 4 patients comprised 2 infants with marked abdominal distension mimicking Hirschsprung disease and 2 children (aged 4 and 8 years) with intractable constipation accompanying hemorrhoid or anal fissure. The manometric findings of the USW-positive patients showed a markedly high anal resting pressure and high frequency of slow waves compared to controls, patients with constipation not accompanied by USWs or patients with Hirschsprung disease. CONCLUSION: Children with USWs exhibit symptoms mimicking Hirschsprung disease in infants and chronic intractable constipation in older children. In manometric studies of children, more attention should be paid not only to rectoanal reflex, but also USWs. PMID- 17706509 TI - Early adult outcome of the Duhamel procedure for left-sided Hirschsprung disease- a prospective serial assessment study. AB - PURPOSE: To assess both early adult functional outcome and change in long-term functional outcome over time after the Duhamel procedure (DP) for left-sided Hirschsprung disease (HSCR). METHODS: The study population consisted of 78 children (aged 19.9 +/- 3.6 years) who previously underwent objective outcome assessment after DP was performed for HSCR during the period of 1980 to 1991. Inclusion criteria were previous evaluation of functional outcome and either rectosigmoid or left-sided HSCR. Outcome measures were assessed twice within the cohort, in 1997 and in 2005. The primary outcome measure was the Rintala (J Ped Surg. 1995;30:491-494) functional outcome score (FOS; maximum, 20). Controls consisted of 20 age-matched healthy children. Satisfactory functional score was defined as an FOS at or above the 10th percentile of controls (FOS, > or = 17). Secondary outcome measures were the operation failure rate (defined by requirement for a stoma or major reoperative surgery), and enterocolitis rates (defined by intention to treat). Consecutive outcome scores were compared by paired t test. Data were expressed as mean +/- SD, and P < .05 was considered significant. RESULTS: Operation failure occurred in 9 (11.5%) of 78. Consecutive FOSs were obtained in 40 (57%) of 69. A satisfactory functional score was observed in 23 (58%) of 40 adults as opposed to 33 (47%) of 70 children 8 years previously (P = .02). Satisfactory outcome (defined by satisfactory functional score and lack of enterostomy or major revision pull-through procedure) was observed in 23 (47%) of 49. Previously, this figure was 34 (44%) of 78. Individual paired FOSs showed a significant improvement with time (1997: 14.9 +/- 4.1; 2005: 16.4 +/- 2.8; P = .02). CONCLUSIONS: At early adult follow-up, the operation failure rate has not changed from that of the same cohort 8 years earlier. However, a significant improvement in individual FOSs was demonstrated. PMID- 17706510 TI - The structural characteristics and expression of neuropeptides in the esophagus of patients with congenital esophageal atresia and tracheoesophageal fistula. AB - PURPOSE: The aim of this study was to investigate the structural characteristics and the expression of a group of neuropeptides in the esophagus of patients with congenital esophageal atresia and tracheoesophageal fistula (EA-TEF), as well to elucidate the roles of these neuropeptides in the pathogenesis of postoperative incoordination of esophagus after successful surgical repair of EA-TEF. METHODS: Twenty-four specimens from distal tracheoesophageal fistulas of patients with EA TEF (EA-TEF group) and 10 esophageal specimens from neonates who died of nonesophageal diseases (control group) were studied. All of the specimens were subjected to routine pathologic study, ultrastructural observation, and immunohistochemical staining for neuron-specific enolase, substance P, vasoactive intestinal polypeptide, and nitric oxide synthase. RESULTS: In the EA-TEF group, mitochondria were distributed along the membrane of smooth muscle cell, whereas mitochondria in the control group were distributed along the karyotheca of the smooth muscle cells. The ratio of granulated vesicles to clear vesicles in the varicosity of the intramuscular motor nerve ending of the EA-TEF group (0.520 +/- 0.137) was much higher than that in the control group (0.192 +/- 0.020, P < .05). The percentages of specimens shown to have positive expression of neuron-specific enolase and substance P in the EA-TEF group (20.8% and 12.5%, respectively) were significantly lower than those in the control group (90% and 80% respectively, P < .05). The percentages of specimens shown to have positive expression of vasoactive intestinal polypeptide and nitric oxide synthase in the EA-TEF group (83.3% and 75%, respectively) were significantly higher than that in the control group (30% and 10% respectively, P < .05). CONCLUSION: Imbalance of neurotransmitters excretion in nerve vesicle, abnormal intrinsic dysplasia of nerve plexus and increased expression of certain neuropeptides were the main characteristics of esophagus with abnormal intrinsic innervation, which may be responsible for the postoperative esophageal dysfunction of EA-TEF. PMID- 17706511 TI - Nonoperative treatment of acute appendicitis in children. AB - BACKGROUND/PURPOSE: Appendicitis is considered by many surgeons to be a surgical emergency for which necessary to avoid perforation of the appendix. Although it has also been treated nonoperatively using antibiotic therapy, experience in such treatment in children with acute appendicitis (AA) is extremely limited. In addition, previous studies on nonoperative treatment (NT) showed it to be a cause of morbidity and mortality. The authors hold that not all appendicitis cases respond to NT because only some of the cases recover. In the present study, 16 of 95 cases with AA were selected for NT according to physical and ultrasound examinations. The clinical and ultrasonographic findings of the cases are presented. METHODS: The medical records of all children with appendicitis treated between August 2003 and March 2006 were retrospectively reviewed. Patients who had history of abdominal pain for less than 24 hours with localized abdominal tenderness and hemodynamic stability underwent NT. Children were treated with parenteral antibiotics (ampicillin with sulbactam, 100 mg x kg(-1) x 24 h(-1), divided into 3 doses daily, and ornidasole, 20 mg x kg(-1) x 24 h(-1), divided into 2 doses daily), intravenous fluid, and nothing by mouth for at least 48 hours. RESULTS: A total of 136 patients with appendicitis were treated. Of the cases, 95 (70%) were AA, and 41 (30%) had perforated appendicitis. Sixteen (16.8%) cases of AA were selected for NT (12 boys and 4 girls; age range, 5-13 years; mean age, 9 years). The mean anteroposterior diameter of the appendix at the presentation was 7.11 +/- 1.01 mm (range, 6-9.5 mm). Ultrasound examination was repeated after 48 hours of treatment. The mean diameter of the appendix was 4.64 +/- 0.82 mm (range, 3.6-6.8 mm). The difference was statistically significant (t = 9.63, P < .0001). Nonoperative treatment was successful in 15 (93.7%) of the 16 patients. CONCLUSION: Hyperplasia of the appendiceal lymphoid follicle frequently causes luminal obstruction. Antibiotic therapy probably causes regression of lymphoid hyperplasia because of suppression of bacterial infection and prevents ischemia and bacterial invasion in the early stage of appendicitis. We found that some of the patients who had a history of abdominal pain for less than 24 hours with localized abdominal tenderness and hemodynamic stability could be treated nonoperatively. PMID- 17706512 TI - The combined effects of balloon valvuloplasty and surgical weight loss in treatment of aortic stenosis. AB - We report a case of a patient with a congenitally bicuspid aortic valve and extreme obesity who developed severe aortic stenosis. She dramatically improved after the combined use of balloon valvuloplasty and Roux en Y gastric bypass. Gastric bypass surgery has promise for patients with congenital cardiac disease whose treatment is complicated by extreme obesity. PMID- 17706513 TI - Concurrent imperforate hymen, transverse vaginal septum, and unicornuate uterus: a case report. AB - A 14-year-old premenarcheal adolescent girl presented with lower abdominal discomfort and urine retention. After clinical and imaging examination, an imperforate hymen and a large hematocolpos along the upper part of the vagina was diagnosed. Incision of the imperforate hymen did not lead to drainage of blood or fluid. A complete transverse vaginal septum in the middle third of the vagina was identified and when incised drained approximately 200 mL of a dense brownish fluid. Laparoscopy showed a small unicornuate uterus, confirmed by hysteroscopy. This is the first case in the literature of concurrent imperforate hymen, transverse complete vaginal septum, and unicornuate uterus, and it highlights the potential of a multifactorial embryologic genetic etiology. PMID- 17706514 TI - A case of portal vein thrombosis after laparoscopy-assisted splenectomy and cholecystectomy in a child. AB - We report the case of an 8-year-old boy with a red cell membrane disorder who developed, soon after undergoing laparoscopic cholecystectomy and splenectomy, complete thrombosis of the right branch and a partial occlusion of the left branch of the portal vein. The child was affected by a right hemiparesis because of a hypoxic-ischemic disorder that occurred in the first hours of life and was heterozygous for the methylenetetrahydrofolate reductase gene mutation 677C-T. Intravenous heparin and aspirin were initiated on postoperative day 7. Heparin treatment was switched to the subcutaneous route after the first 24 hours. The symptoms subsided 3 days after the beginning of treatment, whereas complete resolution of portal vein thrombosis was observed 2 months later. A review of the literature is reported, and the possible pathogenetic mechanisms underlying portal vein thrombosis are discussed. PMID- 17706516 TI - Short-segment Hirschsprung's disease, cat eye syndrome, and anorectal malformation: a unique association. AB - The association of Hirschsprung's disease (HD) and anorectal malformations has been reported in 2.3% to 3.4% cases. Only 2 cases have previously been published where cat eye syndrome was associated with long (but not short) segment HD. Here, we report a case where there appears to be an association among short segment HD, cat eye syndrome, and anorectal malformation, which has not previously been identified. An abnormality in chromosome 22 may be involved in the development of this association. PMID- 17706515 TI - Carney's triad: a 16-year follow-up. AB - We report a female teenager who presented with a gastrointestinal stromal tumor of the stomach and a paraganglioneuroma. She later developed a pulmonary chondroma, fulfilling the requirements of Carney's triad. This patient demonstrates the course of the disease, which included severe emotional symptoms. She died, at 30 years of age, 16 years after the onset of disease, riddled with metastases. Many patients with Carney's triad survive for many years, but we can not predict the prognosis in any patient. During her lifetime, the patient had considerable emotional suffering, perhaps because of her disease. PMID- 17706517 TI - Splenic cyst in a wandering spleen: laparoscopic treatment with preservation of splenic function. AB - BACKGROUND: Wandering spleen and splenic cyst are rare benign congenital conditions that can both cause severe complications related to torsion or trauma. CASE REPORT: A 14-year-old girl presented a mobile 10-cm-long abdominal mass in the left lower quadrant associated with mild abdominal pain. The diagnosis of an 8-cm-long nonparasitic cyst in a wandering spleen was confirmed by computerized tomography and negative serum indirect hemagglutination titer for hydatid disease. Laparoscopic unroofing of the cyst and splenopexy in a vycril mesh was performed. RESULTS: No problems were encountered during laparoscopic surgery. Postoperative course was uneventful, and at a 1-year follow-up, the spleen is viable and maintains a normal position in the phrenorenal angle. CONCLUSIONS: In the child, treatment of wandering spleen associated with a cyst should aim at the prevention of vascular accidents and at conservation of the spleen. We achieved these goals with unroofing and splenopexy through laparoscopic surgery. PMID- 17706518 TI - Episodic painless hematuria of unusual etiology--a case report and review of literature. AB - We present the case of an 11-year-old girl with hereditary hemorrhagic telangiectasia who presented with recurrent macroscopic hematuria secondary to bladder vascular abnormalities. This case illustrates the importance of taking a detailed clinical and family history and cystoscopic examination at the time of active hematuria in cases where recurrent hematuria persists and no other cause is identified. PMID- 17706519 TI - Familial adenomatous polyposis. PMID- 17706521 TI - Management of rotation abnormalities in children with heterotaxia. PMID- 17706523 TI - Gastrobronchial fistula after toothbrush ingestion. PMID- 17706525 TI - Comment on pediatric anorectal impalement with bladder rupture. PMID- 17706526 TI - Staging of lung cancer. AB - Imaging techniques play a vital role in the diagnosis, staging, and follow-up of patients who have lung cancer. For this purpose, PET has become an important adjunct to conventional imaging techniques such as chest radiography, CT, ultrasonography, and MR imaging. The ability of PET to differentiate the metabolic properties of tissues allows more accurate assessment of undetermined lung lesions, mediastinal lymph nodes, or extrathoracic abnormalities, tumor response after induction treatment, and detection of disease recurrence. PMID- 17706527 TI - Impact of PET on radiation therapy planning in lung cancer. AB - The superiority of PET imaging to structural imaging in many cancers is rapidly transforming the practice of radiotherapy planning, especially in lung cancer. Although most lung cancers are potentially treatable with radiation therapy, only patients who have truly locoregionally confined disease can be cured by this modality. PET improves selection for high-dose radiation therapy by excluding many patients who have incurable distant metastasis or extensive locoregional spread. In those patients suitable for definitive treatment, PET can help shape the treatment fields to avoid geographic miss and minimize unnecessary irradiation of normal tissues. PET will allow for more accurately targeted dose escalation studies in the future and could potentially lead to better long-term survival. PMID- 17706528 TI - PET versus PET/CT dual-modality imaging in evaluation of lung cancer. AB - Non-small cell lung cancer (NSCLC) accounts for approximately 80% of bronchogenic malignancies. The choice of therapy options, including surgery, radiation therapy, and chemotherapy-used alone or in combination-is based on the tumor stage. Consequently, the accurate determination of tumor size, potential infiltration of adjacent structures, mediastinal lymph node involvement, and the detection of distant metastases are of central importance. The purpose of this article is to summarize the accuracy of dual-modality FDG-PET/CT imaging in staging of NSCLC as compared with FDG-PET alone, and with FDG-PET as well as CT read side by side. Furthermore, an optimized PET/CT protocol for patients who have lung cancer is outlined. PMID- 17706529 TI - F-18 fluorodeoxyglucose-positron emission tomography imaging for primary breast cancer and loco-regional staging. AB - Breast cancer is the most common female malignancy in Western countries. The limitations of mammography, ultrasound and MRI do not allow reliable identification of primary breast cancer at early stages. Functional breast imaging with positron emission tomography (PET) and F-18 fluorodeoxyglucose (FDG) enables the visualization of increased glucose metabolism of breast cancer. However, despite the successful identification of primary breast cancer, FDG-PET provides a low sensitivity to detect small tumors. Therefore, FDG-PET does not allow screening of asymptomatic women and cannot be used to exclude breast cancer in patients with suspicious breast masses or abnormal mammography. FDG-PET is a powerful tool for staging of breast cancer patients, but does not detect micrometastases and small tumor infiltrated lymph nodes. Nevertheless, in patients with locally advanced breast cancer, PET accurately determines the extent of disease, particularly the loco-regional lymph node status. Advances in technology, for example the development of dedicated breast imaging devices such as positron emission mammography, hold promise to improve the detection of primary tumors in the future. PMID- 17706530 TI - Diagnosis of recurrent and metastatic disease using f-18 fluorodeoxyglucose positron emission tomography in breast cancer. AB - One of the major strengths of F-18 fluorodeoxyglucose-positron emission tomography (FDG-PET) in breast cancer imaging is in the evaluation of patients who have suspected loco-regional recurrence or distant metastasis. In general, FDG-PET is more sensitive than conventional imaging for the detection of recurrent disease. Because of its ability to more accurately stage patients who have advanced breast cancer, FDG-PET has a significant impact on choice of treatment and management in this patient group. PMID- 17706531 TI - Detection of bone metastases in breast cancer by positron emission tomography. AB - Positron emission tomography (PET) is able to demonstrate changes in the metabolism of malignant tumors and metastases before they become visible on anatomical imaging. The skeleton is the most common site of distant metastases of breast cancer. There is convincing evidence that FDG-PET is more sensitive in detecting osteolytic metastases than bone scintigraphy, whereas bone scintigraphy is more sensitive in detecting osteoblastic metastases. Because both types of metastases can occur in breast cancer, bone scintigraphy and FDG-PET should be considered as complementary and can currently be regarded as standard of care for staging in breast cancer patients, whereas the decision to use F-18 fluoride PET should be made individually for each patient, depending on the expected change of therapy management. PMID- 17706532 TI - Normal and abnormal patterns of 18F-fluorodeoxyglucose PET/CT in lymphoma. AB - In spite of the high performance of 18F-fluorodeoxyglucose (FDG) PET for the evaluation of lymphoma, inherent limitations of this modality underscore the additional value of PET/CT as an important tool in the assessment of this disease. Accumulating data on the use of PET/CT in lymphoma indicate the contribution of hybrid imaging to improved interpretation accuracy of PET using FDG and CT. Knowledge of the normal and abnormal patterns of FDG-PET/CT imaging and their variability in patients with lymphoma is important to provide a comprehensive clinically significant interpretation that has an impact on patient management and potentially on outcome. PMID- 17706533 TI - PET and PET/CT in management of the lymphomas. AB - Within recent years, F-18 fluorodeoxyglucose (FDG) PET has become the most important nuclear medicine and radiology imaging modality in the management of lymphoma. FDG-PET detects more disease sites and involved organs than conventional staging procedures, including CT, and has a large influence on staging. FDG-PET performed during and after therapy seems to provide considerable prognostic information. The impact on patient outcome is not clear, however, because no controlled trials have yet been conducted and follow-up periods are generally short. PMID- 17706534 TI - Fluorine-18 fluorodeoxyglucose PET/CT patterns of extranodal involvement in patients with Non-Hodgkin lymphoma and Hodgkin's disease. AB - Lymphoma may originate in extranodal sites. Extranodal lymphoma may also be secondary to and accompany nodal disease. Fluorine-18 fluorodeoxyglucose (18F FDG) imaging has an essential role in the staging of lymphoma, in monitoring the response to therapy, and in detection of recurrence. The introduction of 18F-FDG PET/CT hybrid imaging allows for accurate localization of disease and may be specifically beneficial for the detection of unexpected extranodal sites of disease or exclusion of disease in the presence of nonspecific extranodal CT findings. Accurate staging and localization often dictate the appropriate treatment strategy in patients with lymphoma. Therefore, at any stage in the course of the disease, the potential presence of extranodal disease should be considered when interpreting 18F-FDG PET/CT studies in patients with non-Hodgkin lymphoma and Hodgkin's disease. PMID- 17706535 TI - Critical role of 18F-labeled fluorodeoxyglucose PET in the management of patients with arthroplasty. AB - The most frequent complications after arthroplasty are aseptic loosening and infection. It is often difficult to differentiate aseptic loosening from infection. The management of these two distinct clinical identities is quite different, however. Treatment of aseptic loosening usually requires one-step revision surgery, whereas treatment of infection requires antimicrobial therapy for an extended period before inserting a new prosthesis. Infection associated with arthroplasty is a serious complication and should be treated adequately before proceeding with a surgical intervention. PET with 18F-labeled fluorodeoxyglucose (FDG) has been proposed as an accurate technique for evaluating painful arthroplasty. This review addresses the applications of FDG PET in such clinical settings. In addition, the potential of PET in the assessing the viability of bone grafts in revision arthroplasty is discussed. PMID- 17706536 TI - Nonprosthesis orthopedic applications of (18)F fluoro-2-deoxy-D-glucose PET in the detection of osteomyelitis. AB - This article describes the impact of [(18)F]2-fluoro-2-deoxy-D-glucose (FDG) PET in the diagnosis of non-prosthesis-related orthopedic infections and inflammation. FDG-PET has an excellent sensitivity in the detection of osteomyelitis (OM). Early data indicate that FDG-PET may be more specific than MRI in diagnosing OM. The role of the combination of FDG and PET-CT in the diagnosis of OM is likely to be determined as this combination is used on a routine basis. Early data from studies in rheumatoid arthritis indicate that FDG PET is highly accurate in early diagnosis and that it provides results comparable to the most advanced conventional techniques. PMID- 17706537 TI - [(18)F]fluorodeoxyglucose PET in large vessel vasculitis. AB - [(18)F]fluorodeoxyglucose (FDG) PET is a noninvasive metabolic imaging modality based on the regional distribution of [18F]FDG that is highly effective in assessing the activity and extent of giant cell arteritis and Takayasu's arteritis, respectively. Metabolic imaging using [18F]FDG-PET has been shown to identify more affected vascular regions than morphologic imaging with MRI in both diseases. The visual grading of vascular [18F]FDG uptake helps to discriminate arteritis from atherosclerosis and therefore provides high specificity. High sensitivity is attained by scanning during the active inflammatory phase. Thus, [18F]FDG-PET has the potential to develop into a valuable tool in the diagnostic workup of giant cell arteritis and Takayasu's arteritis. PMID- 17706538 TI - Reprint of "Chronic toxicity of silver nitrate to Ceriodaphnia dubia and Daphnia magna, and potential mitigating factors". AB - We investigated the chronic toxicity of Ag, as silver nitrate, using two freshwater aquatic cladoceran species, Ceriodaphnia dubia and Daphnia magna, to generate data for the development of a chronic ambient water quality criterion for Ag. Preliminary studies with C. dubia showed variable results which were related to the equilibration time between food and silver. Follow-up testing was conducted using a 3 h equilibration time, which stabilized dissolved Ag concentrations and the toxicity of Ag(+). Results with C. dubia conducted individually (1 per cup, n=10) and in mass (30 per chamber, n=2) gave similar results once similar standardized equilibration times were used. The maximum acceptable toxicant concentration (MATC) of Ag to C. dubia and D. magna was 9.61 and 3.00 microg dissolved Ag/L, respectively. The chronic toxicity of Ag(+) to C. dubia was also evaluated in the presence of: (1) dissolved organic carbon (DOC) and (2) sulfide. The addition of DOC (0.4 mg/L) resulted in a approximately 50% decrease in toxicity while the addition of sulfide (75.4 nM) deceased toxicity by 42%. Whole-body Ag concentration in D. magna was positively correlated with increased levels of Ag exposure, however; we observed a non-statistical decrease in whole-body Na levels, an estimator of sodium homeostasis. PMID- 17706539 TI - New Court guidance on repackaging of parallel traded products. PMID- 17706540 TI - Memo to the FDA and ICH: appeal for in vivo drug target identification and target pharmacokinetics Recommendations for improved procedures and requirements. AB - This memorandum is addressed to members of regulatory agencies, as well as managers of pharmaceutical companies. Pharmacokineticists and toxicologists may consider this proposal, weigh its merits, and provide input for implementation. Experience from academic research and ADME experiments during drug development has prompted this appeal for improved drug target recognition. Similar demands have been made repeatedly in the literature. Such efforts are not new, but a renewed urgency has come from comparing results obtained with methods of different resolution and sensitivity, namely high-resolution receptor microscopic autoradiography compared and viewed in parallel to conventional low-resolution 'cut-and-count' radioassays and whole body autoradiography. Conflicting results reveal astounding deficiencies of current ADME approaches. False negatives and false positives of favored 'expedient' procedures allow drugs to reach the market with misleading and inaccurate information about the total drug effect. PMID- 17706541 TI - Drug metabolism in the paediatric population and in the elderly. AB - This review focuses on one of the key factors accounting for differences in drug/metabolite exposure in paediatric and elderly subjects compared with that of the adult population, that is, differences in drug metabolism (both qualitative and quantitative) and in particular differences due to changes in the activity and/or concentration of drug metabolizing enzymes. Important differences have been found in the paediatric population compared with adults for both phase I (e.g. CYP3A7 versus CYP3A4 and CYP1A2, reductive and hydrolytic enzymes) and phase II (e.g. glucuronosyltransferases) enzymes. In the elderly, some phase I enzymes (e.g. esterases) appear to be impaired. From the information collected thus far, it would appear that phase II reactions, though sometimes decreased, are not extensively affected by old age. PMID- 17706542 TI - Seeding drug discovery: integrating telomerase cancer biology and cellular senescence to uncover new therapeutic opportunities in targeting cancer stem cells. AB - Telomerase activation is a hallmark of cancer. Advancement of telomerase as a therapeutic drug target has paved the way for translational opportunities in the related fields of senescence and cancer stem cells. Here, lessons may be learnt that can be applied to drug discovery, particularly with regard to the need to appreciate the relationships between telomerase, senescence and cancer stem cells. When considered as a time line to clinical trial, targeting of telomerase is leading the way to clinical proof-of-concept, with senescence and the cancer stem cell phenotype driving research concepts vital to maintaining a clinical development pipeline. PMID- 17706543 TI - A new paradigm for protein kinase inhibition: blocking phosphorylation without directly targeting ATP binding. AB - Protein kinases are now recognised as an important class of drug targets. Whilst many protein kinase inhibitors directly interact with the ATP-binding site, Gleevec is a notable example from a new class of allosteric inhibitors that alter protein kinase conformation to block productive ATP binding. Recently, kinase inhibitors with different mechanisms of action have also been described. Some of these are allosteric inhibitors that alter kinase conformation and prevent protein substrate binding. Other inhibitors directly compete with protein substrate binding. These inhibitors promise exciting therapeutic opportunities by exploiting new mechanisms of action and may thus allow greater specificity in protein kinase inhibition with fewer off-target side effects. PMID- 17706544 TI - Strategies to support drug discovery through integration of systems and data. AB - Much progress has been made over the past several years to provide technologies for the integration of drug discovery software applications and the underlying data bits. Integration at the application layer has focused primarily on developing and delivering applications that support specific workflows within the drug discovery arena. A fine balance between creating behemoth applications and providing business value must be maintained. Heterogeneous data sources have typically been integrated at the data level in an effort to provide a more holistic view of the data packages supporting key decision points. This review will highlight past attempts, current status, and potential future directions for systems and data integration strategies in support of drug discovery efforts. PMID- 17706545 TI - Insight into the structural determinants for selective inhibition of matrix metalloproteinases. AB - The matrix metalloproteinase (MMP) family has been a pharmaceutical target for over 20 years. Despite massive research and development efforts, only one MMP inhibitor (Periostat) has been approved by the FDA for the treatment of periodontal disease. Possible reasons for the low success rate of MMP inhibitors in the clinic include unwanted side effects caused by their lack of selectivity, poor oral bioavailability and decreased potency in vivo. We review how three dimensional structures (3D) of MMP inhibitor complexes as well as the inhibition profile of compounds screened on MMP can be used to guide the optimization of selectivity of MMP inhibitors. Analysis of MMP 3D structures provides a ranking of their pockets on the basis of opportunities for selective interactions. One can use inhibition data to build pharmacophore or quantitative structure-activity models (QSAR) for virtual screening of libraries of novel MMP inhibitors. Combining protein- and ligand-based approaches, we conclude that targeting a single pocket is not always sufficient to achieve the desired selectivity profile. Finally, we also outline novel series of selective MMP inhibitors that exploit differences in the intrinsic flexibility of the catalytic domain to form selective interactions with a given MMP. PMID- 17706546 TI - ELN implementation challenges. AB - Electronic Laboratory Notebooks are becoming foundation platforms within many pharmaceutical companies because of the benefits that they offer to both the business and the scientists alike. Implementing an ELN within an established organisation presents challenges for the project team, both in terms of managing the impact on the scientists and the technical requirements for integration and data management. Implementation of a commercial ELN is not exempt from such challenges, and working with a third party supplier offers both advantages and additional challenges. PMID- 17706547 TI - Inorganic hollow nanoparticles and nanotubes in nanomedicine Part 1. Drug/gene delivery applications. AB - Recent cytotoxicity studies on carbon nanotubes have shown that the biocompatibility of nanomaterial might be determined mainly by surface functionalization, rather than by size, shape, and material. Although the cytotoxicity for individual inorganic hollow nanomaterials should be extensively tested in vitro and in vivo, potential safety concerns about the use of inorganic nanomaterials in biomedical applications could be alleviated with proper surface treatment. Inorganic hollow nanoparticles and nanotubes have attracted great interest in nanomedicine because of the generic transporting ability of porous material and a wide range of functionality that arises from their unique optical, electrical, and physical properties. In this review, we describe recent developments of hollow and porous inorganic nanomaterials in nanomedicine, especially for drug/gene delivery. PMID- 17706549 TI - Identification of drugs that interact with herbs in drug development. AB - To date, several clinically important drugs have been identified that interact with commonly used herbs. These drugs include (among others) warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus and irinotecan. Importantly, many of these drugs have very narrow therapeutic indices. Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). Because drug-herb interactions can significantly affect circulating levels of drug and, hence, alter the clinical outcome, the identification of drugs that interact with commonly used herbal medicines has important implications in drug development. In silico, in vitro, animal and human studies are often used to identify drug interactions with herbs. We propose that drug-herb and herb-CYP interaction studies should be incorporated into drug development. PMID- 17706548 TI - Inorganic hollow nanoparticles and nanotubes in nanomedicine Part 2: Imaging, diagnostic, and therapeutic applications. AB - Inorganic nanoparticles, such as carbon nanotubes, quantum dots and gold nanoshells, have been adopted for biomedical use, due to their unique optical and physical properties. Compared to conventional materials, inorganic nanomaterials have several advantages such as simple preparative processes and precise control over their shape, composition and size. In addition, inorganic porous nanomaterials are fundamentally advantageous for developing multifunctional nanomaterials, due to their distinctive inner and outer surfaces. In this review, we describe recent developments of hollow and porous inorganic nanomaterials in nanomedicine, especially for imaging/diagnosis and photothermal therapy. PMID- 17706550 TI - Immunogenicity of protein therapeutics and the interplay between tolerance and antibody responses. AB - Patients can mount sustained immune responses to protein therapeutics with the production of neutralizing antibodies (NAbs) that can compromise efficacy or safety of these drugs. Dendritic cells (DCs) are required for immunoglobulin (Ig) isotype switching and the production of IgG, a process involving presentation of MHC class II binding epitopes to helper T cells (CD4+ T cells) and subsequent B cell activation. DCs, CD4+ T cells and MHC class II binding epitopes are also involved in self-tolerance. While many assay formats are available for reliable antibody detection, the complex in vivo interplay between immunogenicity and tolerance hinders accurate pre-clinical predictions of protein drug immunogenicity to humans. PMID- 17706551 TI - Epilepsy and HIV--a dangerous combination. PMID- 17706552 TI - A first therapy for Niemann-Pick C. PMID- 17706553 TI - Drugs for vascular dementia. PMID- 17706554 TI - Is homocysteine a causal and treatable risk factor for stroke? PMID- 17706555 TI - The fragile benefit of BENEFIT. PMID- 17706556 TI - The first steps towards gene therapy for Parkinson's disease. PMID- 17706557 TI - Unexplained cerebral vasculitis and stroke: keep Lyme neuroborreliosis in mind. PMID- 17706559 TI - A next-generation Alzheimer's centre for Madrid. PMID- 17706560 TI - Profile: Karen Roos: treating neuroinfections in Indiana. PMID- 17706561 TI - Women in neurology. PMID- 17706563 TI - Development of new antiepileptic drugs: challenges, incentives, and recent advances. AB - Despite the introduction of many second-generation antiepileptic drugs (AEDs) in the past 15 years, a third of patients with epilepsy remain refractory to available treatments, and newer and more effective therapies are needed. Although our understanding of the mechanisms of drug resistance is fragmented, novel AED targets have been identified, and models of refractory epilepsy have been developed that can help to select candidate compounds for development. There are more than 20 compounds with potential antiepileptic activity in various stages of clinical development, and for many of these promising clinical trial results are already available. Several incentives justify further investment into the discovery of newer and more effective AEDs. Moreover, developments in clinical trial methodology enable easier completion of proof-of-concept studies, earlier definition of the therapeutic potential of candidate compounds, and more efficient completion of trials for various epilepsy indications. PMID- 17706564 TI - The spectrum of neuromyelitis optica. AB - Neuromyelitis optica (also known as Devic's disease) is an idiopathic, severe, demyelinating disease of the central nervous system that preferentially affects the optic nerve and spinal cord. Neuromyelitis optica has a worldwide distribution, poor prognosis, and has long been thought of as a variant of multiple sclerosis; however, clinical, laboratory, immunological, and pathological characteristics that distinguish it from multiple sclerosis are now recognised. The presence of a highly specific serum autoantibody marker (NMO-IgG) further differentiates neuromyelitis optica from multiple sclerosis and has helped to define a neuromyelitis optica spectrum of disorders. NMO-IgG reacts with the water channel aquaporin 4. Data suggest that autoantibodies to aquaporin 4 derived from peripheral B cells cause the activation of complement, inflammatory demyelination, and necrosis that is seen in neuromyelitis optica. The knowledge gained from further assessment of the exact role of NMO-IgG in the pathogenesis of neuromyelitis optica will provide a foundation for rational therapeutic trials for this rapidly disabling disease. PMID- 17706565 TI - Comparison of endovascular and surgical treatments for intracranial aneurysms: an evidence-based review. AB - Intracranial aneurysms can be treated with endovascular or surgical techniques. We provide an objective comparison of these treatments, using data from single centre studies, multicentre studies with and without independent outcome ascertainment, and randomised clinical trials. We compared the outcomes of patients who were candidates for endovascular treatment, surgical treatment, or both. In patients with ruptured intracranial aneurysms, rates of aneurysm obliteration were higher, and need for second treatment was lower, after surgery than after endovascular treatment. However, in observational studies and randomised trials, outcome at discharge, at 2-6 months, and at 1 year, and later survival, were all better after endovascular treatment than after surgery. The results suggest that the higher rates of incomplete obliteration and retreatment after endovascular treatment do not affect patients' clinical outcome. In observational studies of patients with unruptured intracranial aneurysms, discharge outcomes were better and hospital costs were lower after endovascular treatment than after surgery. These patients showed no difference between the two treatments in 1-year outcomes and later rebleeding, although few data were available for this comparison. PMID- 17706566 TI - Fibrotic heart-valve reactions to dopamine-agonist treatment in Parkinson's disease. AB - BACKGROUND: Retroperitoneal and pleuropulmonary fibrosis are well known but rare complications of the treatment of Parkinson's disease with ergolinic dopamine agonists; however, until now, these complications have not substantially affected the routine clinical use of these drugs. The occurrence of restrictive valvular heart disease during treatment with pergolide and cabergoline caused concern about the safety of dopamine agonists in Parkinson's disease. Specifically, there is uncertainty whether fibrotic cardiac valvulopathy is due to exposure to these two ergolinic dopamine agonists or whether the abnormality is reversible. Changes in the heart valves can incur additional disability and worsen the clinical disorders of Parkinson's disease. RECENT DEVELOPMENTS: Population studies of patients with Parkinson's disease compared with non-parkinsonian controls have reported that pergolide and cabergoline have a similar risk of inducing fibrotic changes in cardiac valve leaflets. The fibrotic changes cause thickening, retraction, and stiffening of valves, which result in incomplete leaflet coaptation and clinically significant regurgitation, and have necessitated surgical valve replacement in some patients. Pergolide and cabergoline have high affinity for the 5-HT(2B) serotonin receptors, which are expressed in heart valves and might mediate mitogenesis and, in turn, the proliferation of fibroblasts. When analysed together, current population studies of similar designs and doses report 102 patients on cabergoline, 245 patients on pergolide, 181 patients on non-ergot agonists (pramipexole and ropinirole), and 177 non parkinsonian controls. The frequency of moderate-to-severe regurgitation in at least one heart valve was higher in patients receiving cabergoline or pergolide than in patients taking non-ergot agonists or controls, and the incidence of new onset valvulopathy was high in patients taking the ergot-derived drugs. WHERE NEXT?: Because of the routine prescription of pergolide and cabergoline, the switching of patients to different treatment regimens might be difficult. Moreover, whether the fibrotic changes are reversible is unknown. Finally, these adverse events do not occur in all patients, and no susceptibility factors are known. Prospective studies will assess the full effect of these abnormalities and help establish whether and when mitral valve tenting area abnormalities become clinically relevant during chronic treatment. The exact pathway leading to valvulopathy is unknown, although agonism of 5-HT(2B) receptors in the heart is implicated as a mediator in the process. Other ergolinic dopamine agonists, such as lisuride, and non-ergot dopamine agonists are devoid of 5-HT(2B) agonistic activity; therefore, their use might not induce fibrotic changes in heart valves. However, further prospective studies are needed. Such studies should also clarify the clinical relevance of mild-to-moderate echocardiographic changes and their natural history. Because of the clinical consequences of the adverse reactions, we suggest that affinity for 5-HT(2B) receptors is routinely tested in future drugs, in the laboratory or in animals, before they are given to patients. PMID- 17706567 TI - Homocysteine-lowering therapy: a role in stroke prevention? AB - On the basis of the results of several recent clinical trials, many researchers have concluded that vitamin therapy designed to lower total homocysteine concentrations is not effective in reducing the risk of cardiovascular events. However, whereas almost all myocardial infarctions are due to plaque rupture, stroke has many more pathophysiological mechanisms, and thrombosis-which is increased by raised total homocysteine concentrations-has an important role in many of these processes. Thus, stroke and myocardial infarction could respond differently to vitamin therapy. A detailed assessment of the results of the recent HOPE-2 trial and a reanalysis of the VISP trial restricted to patients capable of responding to vitamin therapy suggest that higher doses of vitamin B12 and perhaps new approaches to lowering total homocysteine besides routine vitamin therapy with folate, vitamin B6, and vitamin B12 could reduce the risk of stroke. Thus, therapy to lower homocysteine could still help to prevent stroke, if not other vascular outcomes. PMID- 17706569 TI - Letter from the President of APDS. PMID- 17706568 TI - July. PMID- 17706570 TI - Case-based multimedia program enhances the maturation of surgical residents regarding the concepts of professionalism. AB - INTRODUCTION: The Accreditation Council for Graduate Medical Education (ACGME) has mandated that surgical residencies incorporate formal curricula in each of the 6 competencies, including professionalism. A questionnaire study was developed by the authors that aimed (1) to measure the ability of surgical residents to define components of professionalism, (2) to evaluate the efficacy of the American College of Surgeons (ACS) case-based scenarios in teaching concepts of professionalism, and (3) to determine whether postgraduate level correlates with the ability to articulate the meaning of professionalism. METHODS: Surgical residents (n = 47) were matched for PG level and were administered a questionnaire that assessed their ability to articulate concepts of professionalism after either (1) watching the ACS case-based DVD, (2) reading the ACS "Code of Professional Conduct," or (3) neither. Blinded faculty rated responses according to a scoring scale. Data were analyzed statistically to assess differences. RESULTS: Residents who watched the ACS DVD scored higher than those who did not (p = 0.096). Junior and senior residents (PG 2-5) who watched the DVD were more likely to score above the mean than interns (p = 0.095). In contrast to interns, where no differences were observed, among junior and senior residents, the proportion of participants who scored above the mean was higher in the ACS DVD group (p = 0.009). CONCLUSIONS: Surgical residents at all levels were successful in defining components of professionalism. With increased postgraduate level, they matured in their ability to extract concepts of professionalism from the multimedia case-based educational tool. The ACS DVD enhanced the comfort of residents in recognizing challenges to professionalism. PMID- 17706571 TI - Training physicians for combat casualty care on the modern battlefield. AB - INTRODUCTION: Trauma training among nonsurgical physicians in the military is highly variable in amount and quality. However, all deployed military physicians, regardless of specialty, are expected to provide combat casualty care. The goal was to assess the effectiveness of an intense modular trauma refresher course for nonsurgical physicians deploying to a combat zone. METHODS: All graduating nonsurgical residents participated in this 2.5-day course, consisting of 4 modules: (1) didactic session; (2) simulation with interactive human surgical simulators; (3) case presentations and triage scenarios from Iraq/Afghanistan with associated skill stations; and (4) live tissue surgical procedure laboratory. Competency tests, surveys, and after action comments were reviewed and compared before and after course completion. RESULTS: Between May 2005 and April 2007, 60 physicians participated in the course. By specialties, there were 32 internists, 16 pediatricians, 7 general practitioners, 4 obstetricians/gynecologists, and 1 "other" nonsurgical physician represented. Precourse and postcourse tests were administered to 31 of 60 participants. The mean test scores improved from 76% to 96% upon completion of the course (p < 0.01). Additionally, self-perceived confidence levels in handling battlefield casualties from questionnaires based on Likert scale responses (1 = not confident, 5 = confident) improved from an average of 2.3 before the course to 3.9 upon completion of the course (p < 0.01). CONCLUSION: All military physicians must be prepared to manage combat casualties. This hybrid training model may be an effective method to prepare nonsurgeons to deal with battle injuries. This course significantly improved the knowledge and confidence among primary care physicians. PMID- 17706572 TI - Do men and women use the same criteria in selecting a general surgery residency program? Results of a 20-year study in a non-university program. AB - BACKGROUND: To assess applicant preferences in general surgery program selection, we surveyed current and former residents of our non-university general surgery residency program over the last 20 years, with particular emphasis on male and female selection preferences. METHODS: Surveys were distributed to current and former categorical residents. Respondents were asked to rate 25 residency criteria using a Likert scale. Responses by males and females were compared using the Mann-Whitney U-test. Results are reported as mean scores, with p-values indicating statistical significance of trends toward higher scores. RESULTS: Of 50 former (76% male, 24% female) and 18 current residents (56% male, 44% female), 56 responded (38 male, 18 female), for an overall response rate of 82%. For both male and female respondents, the top 4 selection criteria by mean average score were identical: variety and number of cases, friendly training environment, camaraderie among residents, and quality of relationships with attendings. Selection criteria that received significantly higher scores among women were camaraderie among residents, the number of female residents, and the number of female attendings (p < 0.05). For men, a suburban location, compensation and benefits, and the reputation of the program director received significantly higher scores (p < 0.05). Gender-related selection preference was most marked for the number of female residents (mean, 2.4 for women vs 1.3 for men) and the number of female attendings (mean, 2.3 for women vs 1.4 for men). These 2 criteria, however, were ranked 20th and 21st (of the 25), respectively, by the female respondents. CONCLUSIONS: The most important selection criteria, regardless of gender, relate to operative experience, training environment, and quality relationships. Gender-based preferences seem to play only a minor role in general surgery program selection. PMID- 17706573 TI - Abdominal compartment syndrome. PMID- 17706574 TI - Bloodless surgery in a Jehovah's Witness patient with a 12.7-kg uterine leiomyosarcoma. AB - INTRODUCTION: Bloodless surgery aims to optimize outcomes in patients undergoing surgical procedures who wish to avoid allogeneic transfusion. Using a series of interventions and management strategies related to this goal, patients who were previously considered extremely high risk or inoperable without a blood transfusion can now undergo complex surgical procedures with acceptable outcomes. The techniques of bloodless surgery have been incorporated in order to care for a patient with a large uterine sarcoma with involvement and invasion into adjacent organs. CASE: A 52-year-old female Jehovah's Witness patient refusing allogeneic blood transfusion presented to the gynecologic oncology division with a 40-cm pelvic mass and anemia. She was enrolled into the bloodless surgery program at the authors' institution and subsequently underwent surgical resection of a 12.7 kg uterine leiomyosarcoma. Although her intraoperative course was significant for severe anemia with a hemoglobin of 2.5 g/dl and her postoperative course required long-term hospitalization, the patient regained full function to her preoperative performance status. CONCLUSIONS: Bloodless surgery in patients with a potential for large-volume intraoperative blood loss requires a well-organized systematic, multidisciplinary approach to achieve the best possible outcome. PMID- 17706576 TI - Nonoperative management of bronchial injury in a 21-month-old child. AB - Bronchial laceration is an uncommon complication of blunt trauma in children. Treatment of bronchial laceration has involved thoracotomy with primary repair of the bronchial injury or nonoperative management with tube thoracostomy. We report a 21-month-old boy who sustained a large tear of the right upper lobe bronchus after an automobile/pedestrian accident in whom nonoperative management resulted in a favorable outcome. The relevant literature is reviewed, and an algorithm for management is proposed. PMID- 17706575 TI - Late pancreaticojejunostomy stent migration and hepatic abscess after Whipple procedure. AB - A previously unreported late complication of a transanastomotic stent across a pancreaticotojejunostomy is described. The stent migrated distally into the jejunal lumen, through the biliary anastomis into the bile duct and proximally into the liver where it served as a nidus for infection with abscess formation. A percutaneous transhepatic interventional radiologic approach both drained the abscess and pushed the stent out of the liver and biliary tree and into the bowel, with complete recovery. The decision by the surgeon to use a stent in these patients is discussed, and the complications associated with stenting a pancreaticojejunostomy are reviewed. PMID- 17706577 TI - Postcholecystectomy biliary symptoms. AB - Patients with postcholecystectomy biliary symptoms beyond their original surgery present a diagnostic challenge for the practicing surgeon. The diagnostic algorithm is the same as in an initial episode and should rule out nonbiliary causes of right upper quadrant pain. If biliary causes are suspected, the most common diagnosis is retained common bile duct stones.(1) Among the less common diagnoses, congenital anomalies of the biliary system must also be considered. Anatomical variants are well described in medical literature and must be anticipated by the general surgeon. Here the course and imaging of 2 different patients with postcholecystectomy biliary symptoms are presented followed by a discussion of several etiologies that could cause these symptoms. These cases are presented to remind the general surgeon of the wide variety of presentations possible with biliary disease. In these situations, knowledge of a patient's surgical history can lead to confusion when attempting to make an accurate diagnosis. A prepared surgeon can help shed light on a case complicated by inconsistencies between imaging studies and patient history. PMID- 17706578 TI - Juvenile papillomatosis and breast cancer. PMID- 17706580 TI - Organizing a regional ARCS. PMID- 17706579 TI - Review of tracheo-esophageal fistula associated with endotracheal intubation. AB - Tracheo-esophageal fistula (TEF) formation is a rare complication of either endotracheal intubation or tracheostomy. This complication is generally thought to be iatrogenic and occurs in less than 1% of patients. High-volume, low pressure cuffs have made TEFs an infrequent occurrence; however, it still poses as a potential life-threatening condition. Evaluation and close monitoring of endotracheal tube (ETT) cuff pressures is an area of significance commonly overlooked and/or underemphasized by surgical residents. To illustrate and review this clinical problem, a case of an iatrogenic TEF as a consequence of excessive endotracheal cuff pressures is reported. PMID- 17706581 TI - Origami. PMID- 17706582 TI - Kinetics of reactions catalyzed by enzymes in solutions of surfactants. AB - The effect of surfactants, both in water-in-oil microemulsions (hydrated reverse micelles) and aqueous solutions upon enzymatic processes is reviewed, with special emphasis on the effect of the surfactant upon the kinetic parameters of the process. Differences and similarities between processes taking place in aqueous and organic solvents are highlighted, and the main models currently employed to interpret the results are briefly discussed. PMID- 17706583 TI - Risk factors for the development of cataract requiring surgery in uveitis associated with juvenile idiopathic arthritis. AB - PURPOSE: To identify the possible risk factors for the development of cataract requiring surgery in children with juvenile idiopathic arthritis (JIA)-associated uveitis. DESIGN: Retrospective cohort study. METHODS: Data of 53 children with JIA-associated uveitis, of whom 27 had undergone cataract extraction (CE), were obtained. The main outcome measure, the interval between the onset of uveitis and the first CE (U-CE interval), was examined in relation to clinical and ophthalmologic characteristics and treatment strategies before CE. RESULTS: A shorter U-CE interval was found for children with posterior synechia vs those without posterior synechia (hazard ratio [HR], 3.57; 95% confidence interval [CI], 1.33 to 10.00). No significant difference was found for children in whom the uveitis was the first manifestation of JIA vs those in whom arthritis was the first manifestation of JIA (HR, 1.59; 95% CI, 0.63 to 4.00) and children treated with periocular corticosteroid injections vs those not treated with periocular corticosteroid injections (HR, 3.23; 95% CI, 0.95 to 11.11). Children treated with methotrexate (MTX) had a longer U-CE interval than children not treated with MTX (HR, 0.29; 95% CI, 0.10 to 0.87). CONCLUSIONS: The risk factor for development of early cataract requiring surgery in children with JIA-associated uveitis is the presence of posterior synechia at the time of diagnosis of uveitis. However, early treatment with MTX is associated with a mean delay in the development of cataract requiring surgery of 3.5 years. PMID- 17706584 TI - A tag-based approach for high-throughput analysis of CCWGG methylation. AB - Non-CpG methylation occurring in the context of CNG sequences is found in plants at a large number of genomic loci. However, there is still little information available about non-CpG methylation in mammals. Efficient methods that would allow detection of scarcely localized methylated sites in small quantities of DNA are required to elucidate the biological role of non-CpG methylation in both plants and animals. In this study, we tested a new whole genome approach to identify sites of CCWGG methylation (W is A or T), a particular case of CNG methylation, in genomic DNA. This technique is based on digestion of DNAs with methylation-sensitive restriction endonucleases EcoRII-C and AjnI. Short DNAs flanking methylated CCWGG sites (tags) are selectively purified and assembled in tandem arrays of up to nine tags. This allows high-throughput sequencing of tags, identification of flanking regions, and their exact positions in the genome. In this study, we tested specificity and efficiency of the approach. PMID- 17706585 TI - Cloud point formation based on mixed micelle in the presence of electrolyte for extraction, preconcentration, and spectrophotometric determination of trace amounts of hydrazine in water and biological samples. AB - A cloud point extraction process using mixed micelle of the anionic surfactant sodium dodecyl sulfate and the nonionic surfactant Triton X-114 to extract hydrazine from aqueous solutions was investigated. The method is based on the condensation reaction of hydrazine with p-(dimethylamino)benzaldehyde, azine formation, and mixed micelle-mediated extraction of azine in the presence of NaCl electrolyte as an inducing phase separation. An azine product was concentrated in surfactant-rich phase after separation. The optimal extraction and reaction conditions (e.g., surfactant, reagent and electrolyte concentrations, and centrifuge time) were studied and the analytical characteristics of the method (e.g., limit of detection, linear range, preconcentration, and improvement factors) were obtained. Linearity was obeyed in the range of 0.50-110ngml(-1) of hydrazine and the detection limit of the method is 0.08ngml(-1). The interference effect of some cations, anions, and organic compounds was also tested. The method was successfully applied to the determination of hydrazine in water and biological samples. PMID- 17706586 TI - A continuous fluorometric assay for the assessment of MazF ribonuclease activity. AB - Plasmids maintain themselves in their bacterial host through several different mechanisms, one of which involves the synthesis of plasmid-encoded toxin and antitoxin proteins. When the plasmid is present, the antitoxin binds to and neutralizes the toxin. If a plasmid-free daughter cell arises, however, the labile antitoxin is degraded (and not replenished) and the toxin kills the cell from within. These toxin-antitoxin (TA) systems thereby function as postsegregational killing systems, and the disruption of the TA interaction represents an intriguing antibacterial strategy. It was recently discovered that the genes for one particular TA system, MazEF, are ubiquitous on plasmids isolated from clinical vancomycin-resistant enterococci (VRE) strains. Thus, it appears that small molecule disruptors of the MazEF interaction have potential as antibacterial agents. The MazF toxin protein is known to be a ribonuclease. Unfortunately, traditional methods for the assessment of MazF activity rely on the use of radiolabeled substrates followed by analysis with polyacrylamide gel electrophoresis. This article describes a simple and convenient continuous assay for the assessment of MazF activity. The assay uses an oligonucleotide with a fluorophore on the 5' end and a quencher on the 3' end, and processing of this substrate by MazF results in a large increase in the fluorescence signal. Through this assay, we have for the first time determined K(M) and V(max) values for this enzyme and have also found that MazF is not inhibited by standard ribonuclease inhibitors. This assay will be useful to those interested in the biochemistry of the MazF family of toxins and the disruption of MazE/MazF. PMID- 17706588 TI - Involvement of CaM kinase II in gonadotropin-releasing hormone-induced activation of MAP kinase in cultured hypothalamic neurons. AB - Gonadotropin-releasing hormone (GnRH) is secreted from hypothalamic GnRH neurons. There is accumulating evidence that GnRH neurons have GnRH receptors and that the autocrine action of GnRH activates MAP kinase. In this study, we found that KN93, an inhibitor of Ca(2+)/calmodulin-dependent protein kinases (CaM kinases), inhibited the GnRH-induced activation of MAP kinase in immortalized GnRH neurons (GT1-7 cells). Immunoblot analysis indicated that the CaM kinase IIdelta2 isoform (CaM kinase IIdelta2) and synapsin I were expressed in GT1-7 cells. GnRH treatment rapidly increased phosphorylation of synapsin I at serine 603, a specific phosphorylation site for CaM kinase II, suggesting that GnRH treatment rapidly activated CaM kinase IIdelta2. In addition, when we stably overexpressed CaM kinase IIdelta2 in GT1-7 cells, the activation of MAP kinase was strongly enhanced. These results suggest that CaM kinase IIdelta2 was involved in the GnRH induced activation of MAP kinase in GT1-7 cells. PMID- 17706587 TI - Rapid determination of enzyme kinetics from fluorescence: overcoming the inner filter effect. AB - Fluorescence change is convenient for monitoring enzyme kinetics. Unfortunately, it loses linearity as the absorbance of the fluorescent substrate increases with concentration. When the sum of absorbance at excitation and emission wavelengths exceeds 0.08, this inner filtering effect (IFE) alters apparent initial velocities, K(m), and k(cat). The IFE distortion of apparent initial velocities can be corrected without doing fluorophore dilution assays. Using the substrate's extinction coefficients at excitation and emission wavelengths, the inner filter effect can be modeled during curve fitting for more accurate Michaelis-Menten parameters. A faster and simpler approach is to derive k(cat) and K(m) from progress curves. Strategies to obtain reliable and reproducible estimates of k(cat) and K(m) from only two or three progress curves are illustrated using matrix metalloproteinase 12 and alkaline phosphatase. Accurate estimates of concentration of enzyme-active sites and specificity constant k(cat)/K(m) (from one progress curve with [S]< or =50%. Serum resistin was moderately but significantly correlated with age (r=0.139; p=0.001), high-sensitivity C-reactive protein (hsCRP; r=0.228; p<0.001) and decreasing renal function (r=0.240; p<0.001). However, there was no significant difference of serum resistin between patients with CAD and those in whom angiography did not show CAD (4.5 [3.1-5.8] vs. 4.3 [3.4-5.3] ng/ml; p=0.545) and between patients with > or =50% coronary narrowings and those without such lesions (4.5 [3.2-5.9] vs. 4.3 [3.1-5.5] ng/ml; p=0.265). Prospectively, Cox regression analyses neither indicated an association between serum resistin and major coronary events nor between serum resistin and cumulative vascular events. CONCLUSIONS: Among coronary patients serum resistin is significantly correlated with hsCRP, age and decreasing renal function but resistin is neither associated with the presence of significant coronary stenoses nor with the incidence of future vascular events. PMID- 17706626 TI - Quantitative and qualitative evaluation of plasma and urine alpha1-microglobulin in healthy donors and patients with different haemolytic disorders and haemochromatosis. AB - BACKGROUND: The haem-binding protein alpha(1)-microglobulin (alpha(1)m) is involved in protection against oxidative damage induced by extracellular haem/haemoglobin. A carboxy-terminally truncated form of alpha(1)m (t-alpha(1)m), formed by reactions with haemoglobin, degrades haem into a yellow-brown chromophore linked to the protein. The aim of this work was to investigate if t alpha(1)m is present in urine from a large cohort and if urinary and plasma alpha(1)m/t-alpha(1)m concentrations are changed in patients with haemolytic disorders and haemochromatosis. METHODS: Urine and blood from patients (n=20) and a control group (n=22) were investigated for alpha(1)m and t-alpha(1)m by gel electrophoresis, Western blotting and radioimmunoassay. Data were compared to clinical chemistry data and medical records. RESULTS: Two thirds of all studied subjects displayed t-alpha(1)m in urine but the t-alpha(1)m/alpha(1)m ratio was not increased in patients. Instead, significantly elevated ratios were found in females compared to males. Patients with intravascular or extravascular haemolysis showed higher alpha(1)m, albumin and beta(2)-microglobulin/creatinine ratios in urine indicating glomerulo-tubular dysfunction. CONCLUSIONS: The demonstration of t-alpha(1)m in urine of this cohort may be of importance in quantitative clinical chemistry. Whilst impaired kidney function due to intravascular haemolysis is well-known to occur, it is an unexpected finding in a group of patients with extravascular haemolysis. PMID- 17706627 TI - Lactase persistence/non-persistence variants, C/T_13910 and G/A_22018, as a diagnostic tool for lactose intolerance in IBS patients. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a symptom-based disorder characterized by abdominal pain related to altered bowel habit. We evaluated the predictive power of 2 genetic markers of hypolactasia, C/T_13910 and G/A_22018, in IBS patients with and without lactose intolerance in order to gain insight into the role of lactose intolerance in IBS. METHODS: Seventy five patients (59F/16M, mean age: 49.6+/-14.2 years) with an IBS diagnosis based on Rome II criteria and 272 healthy individuals, where 74 (58F/16M, 54.1+/-10.9 years) were matched-controls, were evaluated. IBS and healthy individuals were genotyped for the C/T_13910 and G/A_22018 polymorphisms nearby the lactase-phlorizin hydrolase gene. Hydrogen breath test (HBT) with gas chromatography was performed in IBS patients to assess for lactose intolerance. RESULTS: Of the 75 IBS patients, 28 (37%) were defined as lactose intolerants. The grade/severity of symptoms after an oral lactose load were positively correlated to the expiratory H2 excretion (P<0.001). Alleles and genotypes frequencies from C/T_13910 and G/A_22018 were not significantly different between IBS patients and control individuals (P>0.05;NS). Presence of the C and G allele were positively associated with a higher expiratory hydrogen excretion and more intense gastrointestinal symptoms (P<0.001). Considering these polymorphisms as a diagnostic test for lactose intolerance in IBS patients, presence of the CC and GG genotypes were estimated to have, a sensitivity of 100% and 96%, respectively; and a specificity of 83% and 79%, positive predictive value of 76% and 73%, and negative predictive value of 100% and 97%. CONCLUSIONS: In IBS patients, genotyping of C/T_13910 and G/A_22018 polymorphisms predicts gastrointestinal symptoms after lactose ingestion and are a diagnostic tool for lactose intolerance. PMID- 17706628 TI - Long-term stability of endogenous B-type natriuretic peptide during storage at 20 degrees C for later measurement with Biosite Triage assay. AB - OBJECTIVE: To evaluate the long-term stability of B-type natriuretic peptide (BNP) in frozen samples at -20 degrees C. DESIGN AND METHODS: During a health and nutrition survey of a representative sample of the adult population of Porto, Portugal, blood samples were collected in EDTA tubes. Aliquots of plasma were frozen at -20 degrees C until measurement. Subjects with cardiac structural or functional abnormalities or renal dysfunction were excluded. BNP was assessed using a commercial immunofluorescence assay (Triage BNP Test) as a continuous variable (n=340) and in four subgroups selected according to different storage periods: < or =1 month (n=35), 6-12 months (n=80), 20-24 months (n=18) and > or =36 months (n=21). RESULTS: Age- and sex-adjusted BNP values, analyzed as a continuous variable, decreased significantly over time of storage. When we stratified in four intervals of storage time, the median BNP value (25th-75th percentile, p value) was: 22.6 pg/mL (8.9-76.2, reference group) for < or =1 month, 19.8 pg/mL (9.5-48.4, p=0.055) for 6-12 months, 15.3 pg/mL (7.5-35.0, p=0.037) for 20-24 months, and 2.5 pg/mL (2.5-10.5, p<0.001) for > or =36 months. CONCLUSIONS: BNP is stable at -20 degrees C for 1 year, without protease inhibitors. PMID- 17706629 TI - An approach to the characterization of serum low-molecular weight proteins/peptides in liver injury using SELDI-TOF MS and factor analysis. AB - OBJECTIVES: The objective of this work was to investigate if the application of factor analysis to the SELDI-TOF MS data could contribute to the characterization of the serum low-molecular weight proteins/peptides in liver injury. DESIGN AND METHODS: Distinguished SELDI-TOF mass spectral peaks of the liver injury group were identified by comparing with those of the control group. Factor analysis was introduced to classify these peaks into different groups, assignable to the possible underlying factors. Based on original mass spectral plot, loading and current medical knowledge, the common characteristics of the peaks in same group were revealed and the underlying factors were tentatively defined. RESULTS: The SELDI profiles of liver injury group exhibit 43 discriminating peaks from the control group. Factor analysis extracted 4 common factors, which were the cholestasis, coagulation, attenuation and 9292 factors. And a plausible interpretation for some undetermined peaks was proposed. CONCLUSION: The application of factor analysis to SELDI-TOF MS data extracted valuable information out of complex and high-dimensional mass spectra data. PMID- 17706630 TI - Applicability of adaptive noise cancellation to fetal heart rate detection using photoplethysmography. AB - In this paper, an approach based on adaptive noise cancellation (ANC) is evaluated for extraction of the fetal heart rate using photoplethysmographic signals from the maternal abdomen. A simple optical model is proposed in which the maternal and fetal blood pulsations result in emulated signals where the lower SNR limit (fetal to maternal) is -25dB. It is shown that a recursive least squares algorithm is capable of extracting the peaks of the fetal PPG from these signals, for typical values of maternal and fetal tissues. PMID- 17706631 TI - Insulin is imprinted in the placenta of the marsupial, Macropus eugenii. AB - Therian mammals (marsupials and eutherians) rely on a placenta for embryo survival. All mammals have a yolk sac, but while both chorio-allantoic and chorio vitelline (yolk sac) placentation can occur, most marsupials only develop a yolk sac placenta. Insulin (INS) is unusual in that it is the only gene that is imprinted exclusively in the yolk sac placenta. Marsupials, therefore, provide a unique opportunity to examine the conservation of INS imprinting in mammalian yolk sac placentation. Marsupial INS was cloned and its imprint status in the yolk sac placenta of the tammar wallaby, Macropus eugenii, examined. In two informative individuals of the eight that showed imprinting, INS was paternally expressed. INS protein was restricted to the yolk sac endoderm, while insulin receptor, IR, protein was additionally expressed in the trophoblast. INS protein increased during late gestation up to 2 days before birth, but was low the day before and on the day of birth. The conservation of imprinted expression of insulin in the yolk sac placenta of divergent mammalian species suggests that it is of critical importance in the yolk sac placenta. The restriction of imprinting to the yolk sac suggests that imprinting of INS evolved in the chorio-vitelline placenta independently of other tissues in the therian ancestor of marsupials and eutherians. PMID- 17706632 TI - Combinations of WOX activities regulate tissue proliferation during Arabidopsis embryonic development. AB - Tissue growth as the result of cell division is an essential part of embryonic development. Previous studies have shown that STIMPY (STIP)/WOX9, a homeodomain transcription factor of the Arabidopsis thaliana WOX family, is required for maintaining cell division and preventing premature differentiation in emerging seedlings. Here we present evidence that STIP performs similar functions during embryogenesis. Complete loss of STIP activity results in early embryonic arrest, most likely due to a failure in cell division. STIMPY-LIKE (STPL)/WOX8, a close homolog of STIP in Arabidopsis, also positively regulates early embryonic growth and can replace STIP function when expressed under the STIP promoter. STPL shares redundant functions with a more distantly related member of the WOX family, WOX2, in regulating embryonic apical patterning. These findings show that combinatorial action of WOX transcription factors is essential for Arabidopsis embryonic development. PMID- 17706633 TI - Glutathione level after long-term occupational elemental mercury exposure. AB - Many in vitro and in vivo studies have elucidated the interaction of inorganic mercury (Hg) and glutathione. However, human studies are limited. In this study, we investigated the potential effects of remote long-term intermittent occupational elemental Hg vapour (Hg degrees ) exposure on erythrocyte glutathione levels and some antioxidative enzyme activities in ex-mercury miners in the period after exposure. The study included 49 ex-mercury miners divided into subgroups of 28 still active, Hg degrees -not-exposed miners and 21 elderly retired miners, and 41 controls, age-matched to the miners subgroup. The control workers were taken from "mercury-free works". Reduced glutathione (GSH) and oxidized disulphide glutathione (GSSG) concentrations in haemolysed erythrocytes were determined by capillary electrophoresis, while total glutathione (total GSH) and the GSH/GSSG ratio were calculated from the determined values. Catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) activities in erythrocytes were measured using commercially available reagent kits, while urine Hg (U-Hg) concentrations were determined by cold vapour atomic absorption (CVAAS). No correlation of present U-Hg levels, GSH, GSSG, and antioxidative enzymes with remote occupational biological exposure indices were found. The mean CAT activity in miners and retired miners was significantly higher (p<0.05) than in the controls. No differences in mean GPx activity among the three groups were found, whereas the mean GR activity was significantly higher (p<0.05) in miners than in retired miners. The mean concentrations of GSH (mmol/g Hb) in miners (13.03+/-3.71) were significantly higher (p<0.05) than in the control group (11.68+/-2.66). No differences in mean total GSH, GSSG levels, and GSH/GSSG ratio between miners and controls were found. A positive correlation between GSSG and present U-Hg excretion (r=0.41, p=0.001) in the whole group of ex-mercury miners was observed. The significantly lower GSH level (p<0.05) determined in the group of retired miners (9.64+/-1.45) seems to be age-related (r= -0.39, p=0.001). Thus, the moderate but significantly increased GSH level, GR and CAT activity in erythrocytes in the subgroup of miners observed in the period after exposure to Hg degrees could be an inductive and additive response to maintain the balance between GSH and antioxidative enzymes in interaction with the Hg body burden accumulated during remote occupational exposure, which does not represent a severely increased oxidative stress. PMID- 17706634 TI - Spatial and temporal variations in silver contamination and toxicity in San Francisco Bay. AB - Although San Francisco Bay has a "Golden Gate", it may be argued that it is the "Silver Estuary". For at one time the Bay was reported to have the highest levels of silver in its sediments and biota, along with the only accurately measured values of silver in solution, of any estuarine system. Since then others have argued that silver contamination is higher elsewhere (e.g., New York Bight, Florida Bay, Galveston Bay) in a peculiar form of pollution machismo, while silver contamination has measurably declined in sediments, biota, and surface waters of the Bay over the past two to three decades. Documentation of those systemic temporal declines has been possible because of long-term, ongoing monitoring programs, using rigorous trace metal clean sampling and analytical techniques, of the United States Geological Survey and San Francisco Bay Regional Monitoring Program that are summarized in this report. However, recent toxicity studies with macro-invertebrates in the Bay have indicated that silver may still be adversely affecting the health of the estuarine system, and other studies have indicated that silver concentrations in the Bay may be increasing due to new industrial inputs and/or the diagenetic remobilization of silver from historically contaminated sediments being re-exposed to overlying surface waters and benthos. Consequently, the Bay may not be ready to relinquish its title as the "Silver Estuary". PMID- 17706636 TI - The endocannabinoids anandamide and 2-arachidonoylglycerol inhibit cholinergic contractility in the human colon. AB - The effects of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) were determined on cholinergic contractility in strips of human colonic longitudinal muscle and circular muscle in vitro, in the presence of nitric oxide synthase blockade with N-nitro-l-arginine (10(-4) M). Anandamide and 2-AG inhibited longitudinal muscle and circular muscle contractile responses to acetylcholine (10(-9)-10(-4) M) in a concentration-dependent manner. This was unaltered following pretreatment with the cannabinoid CB(1) receptor-selective antagonist AM251 (10(-7) M), however in isolation AM251 elicited a significant rightward shift in the potency of acetylcholine-evoked contraction in both longitudinal muscle and circular muscle preparations. Pretreatment with an inhibitor of anandamide catabolism, arachidonoyl trifluoromethyl ketone (10(-5) M), alone caused a significant decrease in the potency of acetylcholine-evoked contraction in both longitudinal and circular muscle, but had no significant additional effect on the anandamide-induced (10(-5) M) suppression of contraction. Pretreatment with the cannabinoid CB(2) receptor inverse agonist JTE 907 (10(-6) M) neither influenced the potency of acetylcholine-evoked contraction alone nor prevented the potency shift in acetylcholine-evoked contraction in the presence of anandamide (10(-5) M). The findings of the present study indicate that the endocannabinoids anandamide and 2-arachidonoylglycerol suppress colonic cholinergic contractility via a non conventional cannabinoid or non-cannabinoid receptor-mediated pathway. Cholinergic contraction may be tonically modulated by endocannabinoids and/or products of arachidonate metabolism unrelated to endocannabinoid production. The extent of anandamide metabolism is not sufficient to influence the functional effects of its exogenous administration in human colonic tissue in vitro. PMID- 17706635 TI - Effect of hyperhomocysteinemia on cardiovascular risk factors and initiation of atherosclerosis in Wistar rats. AB - Hyperhomocysteinemia is considered an independent risk factor for atherosclerosis. The present study was designed to assess the effect of high level of serum homocysteine on other cardiovascular risk factors and markers in rats and to study its mode of action in initiating atherosclerosis. To address this issue, four different doses of methionine (0.1 g/kg, 0.25 g/kg, 0.5 g/kg, 1 g/kg) were orally administered to four groups (Group II, III, IV, V respectively) of rats (6 rats in each group) for a period of 8 weeks to get different level of homocysteine in serum. Group I was administered with saline and served as control. Our results revealed that the level of Total cholesterol, Triglyceride, and Oxidized low-density lipoproteins increased significantly with the increase in the level of serum homocysteine. The levels of Resistin, C-reactive protein and cysteinyl-leukotrienes were found to be significantly high in Group IV (P<0.001 vs Group I) and Group V (P<0.001 vs Group I) at 8 weeks. Total antioxidant capacity and nitrite/nitrate level in serum showed negative correlation with the increased dose of methionine. The mRNA expression and the enzyme activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase significantly increased only in livers of rats of Group V. Furthermore, high mRNA expression of P2 receptors and caveolin were found in aorta of rats administered with high dose of methionine (Group IV and V at 8 weeks). Data obtained from in vitro effect of homocysteine on isolated aortic arch also showed induction in P2 receptors and caveolin with the increase in the concentration of homocysteine. These findings collectively suggest that hyperhomocysteinemia initiates atherosclerosis by modulating the cholesterol biosynthesis and by significantly inducing the level of other cardiovascular risk factors and markers, which play important role in initiating atherosclerosis. PMID- 17706637 TI - Involvement of ERK signaling in halofuginone-driven inhibition of fibroblast ability to contract collagen lattices. AB - Halofuginone, an alkaloid isolated from the plant Dichroa febrifuga, has been shown to be a potent inhibitor of tissue fibrosis. We herein demonstrate that, at concentrations below 10(-7) M, halofuginone does not affect the cell cycle but efficiently induces extracellular signal-regulated kinases(1,2) (ERK(1,2)), p38 and Jun NH2-terminal kinases(1,2) (JNK(1,2)) phosphorylation. In addition, at these non cytotoxic concentrations, halofuginone diminishes the capacity of fibroblasts to contract mechanically unloaded collagen lattices, an effect that is specifically blocked by the ERK inhibitors PD98059 and U0126, not by inhibitors of the JNK or p38 pathways. These data thus indicate that the inhibitory effect of halofuginone on fibroblast contractile activity, a key function for wound healing implicated in the development of tissue fibrosis, is an ERK-mediated mechanism. PMID- 17706638 TI - Cytoprotective and immunomodulating properties of piperine on murine splenocytes: an in vitro study. AB - Piper longum Linn. and Piper nigrum Linn. are conventionally used as immuno enhancers in Indian system of traditional medicine. The underlying mechanism remains unknown. The present study was therefore, undertaken to delineate the role of piperine (major alkaloid) in cadmium (Cd) induced immuno-compromised murine splenocytes. The various biological determinants such as oxidative stress markers (reactive oxygen species and GSH), Bcl-2 protein expression, mitochondrial membrane potential, caspase-3 activity, DNA damage, splenic B and T cell population, blastogenesis and cytokines (Interleukin-2 and gamma-Interferon) were measured to ascertain its cell protective potential. Cadmium induces apoptosis at 6 h onwards. The oxidative stress markers markedly alter prior to a decline in mitochondrial membrane potential, caspase-3 activation and DNA degradation The splenic cell population was observed to change only at 18 h and the release of two cytokines was affected at 72 h. Addition of piperine in various concentrations (1, 10 and 50 microg/ml) ameliorated the above events. The highest dose of piperine could completely abrogate the toxic manifestations of cadmium and the splenic cells behaved similar to control cells. The reported free radical scavenging property of piperine and its antioxidant potential could be responsible for the modulation of intracellular oxidative stress signals. These in turn appear to mitigate the apoptotic pathway and other cellular responses altered by cadmium. The findings strongly indicate the anti-oxidative, anti apoptotic and chemo-protective ability of piperine in blastogenesis, cytokine release and restoration of splenic cell population and is suggestive of its therapeutic usefulness in immuno-compromised situations. PMID- 17706640 TI - Keratinocyte growth factor-transfection-stimulated adhesion of colorectal cancer cells to extracellular matrices. AB - The keratinocyte growth factor (KGF) regulates cell growth and behavior in an autocrine or paracrine manner. In colorectal cancer tissues, KGF is expressed in tumor cells and adjacent stromal fibroblasts. We have constructed a KGF-gene transfected cell line (HCT15-KGF) from a colorectal cancer cell line, HCT-15, that expresses the KGF receptor, and studied the effects of KGF on cell behavior, particularly growth and adhesion to extracellular matrices (ECMs). The amount of KGF secreted from HCT15-KGF was significantly higher than that from a mock transfected cell line (HCT15-MOCK). The modes of growth of these cell lines were similar. The degree of adhesion of HCT15-KGF to ECMs, including type-IV collagen and fibronectin was higher than that of HCT15-MOCK. The expressions of integrins in both cell lines were not significantly different. However, extracellular regulated kinase-1 and -2 (ERK1/2) phosphorylation and focal adhesion kinase (FAK) expression that regulate the adhesive functions of integrin families were enhanced in HCT15-KGF. U0126, an inhibitor of the ERK upstream regulator MEK, attenuated the adhesion and spreading of HCT15-KGF cells to type-IV collagen. These results indicate that KGF enhances the adhesion of colorectal cancer cells to type-IV collagen through ERK and FAK signaling pathways. PMID- 17706639 TI - Antiarrhythmic effect of newly synthesized compound 44Bu on model of aconitine induced arrhythmia -- compared to lidocaine. AB - The antiarrhythmic action of the newly developed compound 44Bu (an original compound that was synthesized at our Faculty of Pharmacy) was tested on a model of aconitine-induced arrhythmia and compared with the effect of lidocaine. Both tested substances were administered either as therapeutic or prophylactic agents. 44Bu was highly effective in reducing the occurrence of ventricular fibrillation from 94% to 8% by therapeutic administration, and to 0% by prophylactic administration. The overall mortality rate was significantly reduced by 44Bu from 100% to 25% in the case of therapeutic administration, and to 0% in the case of prophylactic administration. In contrast, there was not any significant difference between therapeutic and prophylactic administration of lidocaine. The occurrence of ventricular fibrillation dropped from 94% to 50% with therapeutic administration, and to 67% with prophylactic administration of lidocaine. The overall mortality rate was significantly reduced from 100% to 63% and to 67%, respectively. We conclude that the 44Bu compound is a highly effective agent in suppressing aconitine-induced arrhythmias. The antiarrhythmic effect of 44Bu was significantly more evident in comparison with lidocaine, particularly in the case of its prophylactic administration. PMID- 17706641 TI - CXCR4 chemokine receptor engagement modifies integrin dependent adhesion of renal carcinoma cells. AB - The mechanisms leading to renal cell carcinoma (RCC) metastasis are incompletely understood. Although evidence shows that the chemokine receptor CXCR4 and its ligand CXCL12 may regulate tumor dissemination, their role in RCC is not clearly defined. We examined CXCR4 expression and functionality on RCC cell lines, and explored CXCL12-triggered tumor adhesion to human endothelium (HUVEC) or extracellular matrix proteins. Functional CXCR4 was expressed on A498 tumor cells, enabling them to migrate towards a CXCL12 gradient. CXCR4 engagement by CXCL12 induced elevated cell adhesion to HUVEC, to immobilized fibronectin, laminin or collagen. Anti-CXCR4 antibodies or CXCR4 knock down by siRNA applied prior to CXCL12 stimulation impaired CXCL12-triggered tumor adhesion. However, blocking CXCR4 subsequent to CXCL12 stimulation did not. This pointed to an indirect control of tumor cell adhesion by CXCR4. In fact, CXCR4 engagement by CXCL12 also induced alterations of receptors of the integrin family, notably alpha3, alpha5, beta1 and beta3 subunits, and blocking beta1 integrins with a function-blocking antibody prevented CXCL12-induced A498 adhesion. Focal adhesion kinase (total and activated) and integrin-linked kinase significantly increased in CXCL12-treated A498 cells, accompanied by a distinct up-regulation of ERK1/2, JNK and p38 phosphorylation. Therefore, CXCR4 may be crucial in controlling adhesion of A498 cells via cross talking with integrin receptors. These data show that CXCR4 receptors contribute to RCC dissemination and may provide a novel link between CXCR4 chemokine receptor expression and integrin triggered RCC adhesion to the vascular wall and subendothelial matrix components. PMID- 17706642 TI - Chronic phencyclidine administration reduces the expression and editing of specific glutamate receptors in rat prefrontal cortex. AB - Phencyclidine (PCP) induces a form of psychosis that mimics naturally occurring schizophrenia in the most relevant domains of the psychopathology. In this report, we investigated the effect of chronic treatment with PCP on expression and RNA editing of alpha-amino-propionic acid (AMPA) and kainate (KA) glutamate receptor (GluR), in the rat prefrontal cortex and the hippocampus. We found that chronic, but not acute, PCP treatment decreased GluRs expression in the rat prefrontal cortex but not in the hippocampus. In particular, the mRNA coding for GluR2 and GluR3 subunits were reduced by 50%, whereas those coding for KA GluR5 and GluR6 were decreased by 30%. In addition, we observed a decrease of the editing levels of the R/G site in the flop form of both GluR2 and GluR3 and a significant increase in the editing level of GluR6 Q/R site. The variation in the editing level of the R/G sites suggests that chronic PCP treatment induced the formation of glutamate receptor subunits with slower resensitization kinetics and, with respect to kainate receptors, an increase in the Q/R editing level might generate receptor channels with a lower permeability to cations. Combining all the data, it can be inferred that the PCP treatment induced a specific and site-selective reduction of glutamatergic neurotransmission in the prefrontal cortex but not in the hippocampus. PMID- 17706608 TI - Glutamatergic substrates of drug addiction and alcoholism. AB - The past two decades have witnessed a dramatic accumulation of evidence indicating that the excitatory amino acid glutamate plays an important role in drug addiction and alcoholism. The purpose of this review is to summarize findings on glutamatergic substrates of addiction, surveying data from both human and animal studies. The effects of various drugs of abuse on glutamatergic neurotransmission are discussed, as are the effects of pharmacological or genetic manipulation of various components of glutamate transmission on drug reinforcement, conditioned reward, extinction, and relapse-like behavior. In addition, glutamatergic agents that are currently in use or are undergoing testing in clinical trials for the treatment of addiction are discussed, including acamprosate, N-acetylcysteine, modafinil, topiramate, lamotrigine, gabapentin and memantine. All drugs of abuse appear to modulate glutamatergic transmission, albeit by different mechanisms, and this modulation of glutamate transmission is believed to result in long-lasting neuroplastic changes in the brain that may contribute to the perseveration of drug-seeking behavior and drug associated memories. In general, attenuation of glutamatergic transmission reduces drug reward, reinforcement, and relapse-like behavior. On the other hand, potentiation of glutamatergic transmission appears to facilitate the extinction of drug-seeking behavior. However, attempts at identifying genetic polymorphisms in components of glutamate transmission in humans have yielded only a limited number of candidate genes that may serve as risk factors for the development of addiction. Nonetheless, manipulation of glutamatergic neurotransmission appears to be a promising avenue of research in developing improved therapeutic agents for the treatment of drug addiction and alcoholism. PMID- 17706644 TI - Human-based studies on alpha-synuclein deposition and relationship to Parkinson's disease symptoms. AB - This article reviews the current knowledge on alpha-synuclein and its cellular locations in studies using human brain tissue. Alterations in the conformation and distribution of alpha-synuclein are examined in Parkinson's disease and the relationship between clinical symptoms and pathology explored. alpha-Synuclein as a molecular chaperone has several isoforms and is known to have different environment-dependent conformations. Processing methods for studying human brain tissue significantly impact on the conformational type of alpha-synuclein analysed, and antibody species used for the in situ detection of alpha-synuclein give variable results depending on the epitope visualised. Human studies show that alpha-synuclein is not isolated to neurons, but is also found in glia, making the interpretation of studies using brain tissue homogenates less clearly related to neurons. These methodological issues impact significantly on our understanding of the form, location, and therefore function of alpha-synuclein in normal human brain tissue. There are less methodological issues regarding highly aggregated alpha-synuclein found in the major hallmark of Parkinson's disease, the Lewy body. However, it remains unclear whether these alpha-synuclein inclusions are harmful to host neurons or provide protection. Several correlations exist between the clinical symptoms of Parkinson's disease and the distribution of Lewy pathology, the strongest being the association between limbic and cortical Lewy bodies and well-formed visual hallucinations. Further correlation studies in prospectively-followed patients and, perhaps more importantly, controls are required in order to determine normal versus pathologic alpha-synuclein and how to detect such differences in clinical situations. PMID- 17706645 TI - Galectin-1 regulates neurogenesis in the subventricular zone and promotes functional recovery after stroke. AB - Galectin-1 (Gal-1) has recently been identified as a key molecule that plays important roles in the regulation of neural progenitor cell proliferation in two neurogenic regions: the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone of the hippocampal dentate gyrus. To test the hypothesis that Gal-1 contributes to adult neurogenesis after focal ischemia, we studied the temporal profile of endogenous Gal-1 expression and the effects of human recombinant Gal-1 on neurogenesis and neurological functions in an experimental focal ischemic model. In the normal brain, Gal-1 expression was observed only in the SVZ. In the ischemic brain, Gal-1 expression was markedly upregulated in the SVZ and the area of selective neuronal death around the infarct in the striatum. The temporal profile of Gal-1 expression was correlated with that of neural progenitor cell proliferation in the SVZ of the ischemic hemisphere. Double labeling studies revealed that Gal-1 was localized predominantly in both reactive astrocytes and SVZ astrocytes. Administration of Gal-1, which is known to have carbohydrate-binding ability, into the lateral ventricle increased neurogenesis in the ipsilateral SVZ and improved sensorimotor dysfunction after focal ischemia. By contrast, blockade of Gal-1 in the SVZ by the administration of anti Gal-1 neutralizing antibody strongly inhibited neurogenesis and diminished neurological function. These results suggest that Gal-1 is one of the principal regulators of adult SVZ neurogenesis through its carbohydrate-binding ability and provide evidence that Gal-1 protein has a role in the improvement of sensorimotor function after stroke. PMID- 17706643 TI - Molecular/genetic manipulation of extrinsic axon guidance factors for CNS repair and regeneration. AB - During development, guidance molecules play a key role in the formation of complex circuits required for neural functions. With the cessation of development, this exuberant growth process slows and stabilizes, and inhibitory molecules expressed by glia prevent initial attempts for axonal regeneration. In this review, we discuss the expression patterns and relative contribution of several guidance molecules on the regenerative process. Injury to the immature CNS or species capable of regenerating exhibit a complete or partial recapitulation of their developmental guidance patterns, whereas similar injuries to adult mammals results in altered expression that acts to further hinder regeneration. Manipulations of guidance molecules after injury have been used to control detrimental effects of axon sprouting and target regenerating axons within the spinal cord. PMID- 17706647 TI - Brugia pahangi: in vivo tissue migration of early L3 alters gene expression. AB - Events occurring during early filarial nematode migrations are central to parasite establishment but rarely studied. Brugia pahangi larvae injected intradermal (ID) into the hind limb of the gerbil (Meriones unguiculatus) can be recovered from the popliteal lymph node (POP) at 3 days post-infection (DPI). They have been designated migrating larvae (IDL3). Alternatively, L3 recovered at 3DPI from the peritoneal cavity (IPL3) do not migrate. Subtracted cDNA libraries using IDL3 and IPL3 revealed distinct gene profiles between IDL3 and IPL3. Troponin-c was significantly upregulated in IDL3, while Cathepsin L was significantly increased in IPL3. Differences in mRNA levels were also observed with these and other genes between IDL3, IPL3 and L3 isolated from mosquitoes (VL3). These data suggest that migratory activity, exposure to potentially different host environments and/or host location may be important external factors in influencing larval gene expression. PMID- 17706648 TI - P-glycoprotein models of the apo and ATP-bound states based on homology with Sav1866 and MalK. AB - We exploit the biochemical and sequence similarity between Staphylococcus aureus Sav1866 and P-glycoprotein to develop a homology model of P-glycoprotein representing an ATP-bound state, which captures the major features of the low resolution EM structure and is consistent with cysteine mutagenesis studies. Using insights from the MalK crystal structures and BtuCD simulations, we model two nucleotide-free conformations. Conformational changes are characterized by pincering rigid-body rotations of the nucleotide-binding domains, inducing transmembrane domain reorganizations which correspond to the two lowest frequency normal modes of the protein. These conformations (see supplementary material) may characterize some of the major steps in the nucleotide catalytic cycle. PMID- 17706650 TI - Double lamellae in trabecular osteons: towards a new method for age estimation by bone microscopy. AB - The study of anatomical ageing has a dual purpose in biological anthropology. On the one hand, it can provide insights into age associated changes in the body and thus widen the understanding of human senescence; and on the other hand it can provide means of estimation of age at death. This paper explores normal ageing in the pattern of remodelling of trabecular bone in humans. The material consists of necropsies of bone from the ilium of 25 males. A 1 cm2 prism extending from the outer to the inner surface of the iliac bone was removed from men who had died with no clinical signs of diseases, which would usually affect bone structure and metabolism. The samples were cut, and studied by light microscopy at a magnification of 100 x. New trabecular bone is formed in disk-shaped osteons with a clear double lamellar structure. In each sample, the number of double lamellae in a mean of 21 complete osteons was counted. The mean number of lamellae was taken as the measurement of interest. The log of the mean counts was found to regress linearly and with no evidence for heteroscedacity on age. The correlation between the two was high and negative (r=-0.83, p<0.001). The material is too limited to provide a useful basis for age estimation as such, but the study demonstrates the potential for palaeodemographic application of the method. PMID- 17706651 TI - Comparative study of decay ratios of disturbance-rejection magnitude optimum method for PI controllers. AB - One of the key time-domain closed-loop performance requirements is the closed loop response decay ratio. In this paper, the decay ratios of the disturbance rejection magnitude optimum (DRMO) tuning method [Vrancic D, Strmcnik S, Kocijan J. Improving disturbance rejection of PI controllers by means of the magnitude optimum method. ISA Trans 2004; 43: 73-84; Vrancic D, Strmcnik S. Achieving optimal disturbance rejection by using the magnitude optimum method. In: Pre prints of the CSCC'99 conference. 1999. p. 3401-6] are analyzed and compared to decay ratios of two other modern tuning methods, i.e. the Kappa-Tau tuning method (based on time-domain step-response characteristics) [Astrom KJ, Hogglund T. PID controllers: Theory, design, and tuning. 2nd ed. Instrument Society of America; 1995] and the non-convex optimization tuning method (based on frequency response) [Panagopoulos H, Astrom KJ, Hagglund T. Design of PI controllers based on non convex optimization. Automatica 1998; 34: 585-601; Panagopoulos H, Astrom KJ, Hagglund T. Design of PID controllers based on constrained optimisation. IEE Proc Control Theory Appl 2002; 149 (1): 32-40]. It is shown that the DRMO method results in such a closed-loop response that the decay ratio is within a relatively narrow interval when compared to the other two methods. PMID- 17706646 TI - Leishmania chagasi: homogenous metacyclic promastigotes isolated by buoyant density are highly virulent in a mouse model. AB - Homogenous metacyclic promastigotes of Leishmania chagasi were isolated by buoyant density from in vitro heterogeneous cultures and used for biochemical characterization of isoforms of the major surface protease (MSP). Compared to stationary phase promastigotes, metacyclic cells had three times more MSP, produced 3-fold higher parasite loads in a mouse model in vivo, and were more resistant to complement-mediated lysis in vitro. These metacyclic L. chagasi expressed both the virulence-associated 59-kDa, and the constitutively expressed 63-kDa, isoforms of MSP. PMID- 17706649 TI - The zebrafish erythropoietin: functional identification and biochemical characterization. AB - In the present study, the zebrafish epo cDNA was cloned. The encoded protein displays 90%, 55% and 32% identity to the Epo from carp, fugu and human, respectively. Through RT-PCR, the expression of zepo mRNA was mainly in the heart and liver. In the COS-1 cell transfection experiments, the recombinant zEpo-HA protein was efficiently secreted into the culture medium as a glycoprotein and the carbohydrate moiety can be cleaved by the treatment of peptide-N-glycosidase F (PNGase F). Using the morpholino approach, we showed that zepo morphants displayed severe anemia leading to high mortality during development. Such an effect can be significantly rescued by zepo RNA. Furthermore, in the absence of functional zEpo, the expression of specific markers for adult globin genes, such as alphaA1- and betaA1-globin, but not the embryonic betae1-globin, was affected. PMID- 17706652 TI - Observer-based monitoring of heat exchangers. AB - The goal of this work is to provide a method for monitoring performance degradation in counter-flow double-pipe heat exchangers. The overall heat transfer coefficient is estimated by an adaptive observer and monitored in order to infer when the heat exchanger needs preventive or corrective maintenance. A simplified mathematical model is used to synthesize the adaptive observer and a more complex model is used for simulation. The reliability of the proposed method was demonstrated via numerical simulations and laboratory experiments with a bench-scale pilot plant. PMID- 17706653 TI - Characteristics of polytrauma patients between 1992 and 2002: what is changing? AB - OBJECTIVE: To analyse the characteristics of polytrauma patients and the quality and progress of treatment regimens by an evaluation of a trauma population. METHODS: The study included all polytrauma patients treated between 1992 and 2002 at a level 1 trauma centre. Data of 501 cases were collected prospectively and analysed retrospectively. The analysis included the demographic data, injury severity, preclinical haemodynamics, intubation rates, incidences of multiorgan failure and adult respiratory distress syndrome, and mortality. RESULTS: Per year of the study, the average age of patients increased by 0.748 years. Preclinical intubation rates also increased and the number of cases of primary shock decreased. The Injury Severity Score fell on average by 0.59 points per year. There was a significant decrease in multiorgan failure and adult respiratory distress syndrome. The mortality rate remained constant. CONCLUSIONS: Protracted time of initial rescue, early intubation and good preclinical treatment lead to a reduction of complications during intensive care. The increasing number of elderly patients results in persistently high mortality even with decreasing injury severity. PMID- 17706654 TI - The use of recombinant activated factor VII in trauma patients: Experience from the Australian and New Zealand haemostasis registry. AB - BACKGROUND: There is increasing use of rFVIIa (eptagog alpha, Novoseven) in injured patients with critical bleeding. The role of rFVIIa is not defined in this group of patients. Registries provide an opportunity to review the patients, reported response and adverse events for rFVIIa. AIM: To determine the pattern of use, reported response and adverse events in patients receiving rFVIIa following injury using the Australian and New Zealand Haemostasis Registry (ANZHR). METHODS: The ANZHR (commenced May 2005) collects data from 53 hospitals on all patients receiving rFVIIa in those hospitals. RESULTS: Of 695 cases in the registry, 108 patients from 19 hospitals were submitted with a primary trauma diagnosis. Most (88) patients received one 90microg/kg dose of rFVIIa. There was a significant reduction in the use of all blood products following rFVIIa (p<0.001) and rFVIIa was thought to have decreased or stopped bleeding in 59% of cases. There was wide variation in the timing of rFVIIa use. There were two adverse events that were considered possibly linked and a total of three thromboembolic events. Following multivariate analysis, pH provided the best model of response to rFVIIa. Patients with a pH<7.05 were significantly less likely to respond (OR=0.3, 95% CI=0.0-0.3). Only two patients would fit the criteria for the present prospective study of rFVIIA in trauma patients. CONCLUSION: The best approach to managing critical bleeding in trauma patients is not agreed. The role of rFVIIa will only be clarified if there is a standardised approach to fluid management and transfusion of blood products. The registry allows tracking of current practice, outcomes and adverse events and will complement present phase 2 and 3 trials. PMID- 17706655 TI - Estimation of hand forces and propelling efficiency during front crawl swimming with hand paddles. AB - The aim of the study was to investigate possible modifications caused by hand paddles in the relative contribution of the lift and drag forces of the hand and in the propelling efficiency, during front crawl swimming. Eight female swimmers swam 25 m with maximal intensity without paddles, with small (116 cm(2)) and with large paddles (268 cm(2)). Four cameras operating at 60 Hz were used to record the images and the Ariel Performance Analysis System was used for the digitisation. The results showed that, although during swimming with hand paddles the hand's velocity decreased, the greater propulsive area of the hand paddle caused an increase in the drag, lift, resultant and effective forces of the hand. However, the relative contribution of lift and drag forces on swimming propulsion was not modified, nor was the direction of the resultant force. Hand paddles also increased the propelling efficiency, the stroke length and the swimming velocity, mainly because of the larger propulsive areas of the hand in comparison with free swimming. However, the significant decrease of the stroke rate, might argue the effectiveness of hand paddle training, particularly when large paddles are used in front crawl swimming. PMID- 17706656 TI - Image-based RSA: Roentgen stereophotogrammetric analysis based on 2D-3D image registration. AB - Image-based Roentgen stereophotogrammetric analysis (IBRSA) integrates 2D-3D image registration and conventional RSA. Instead of radiopaque RSA bone markers, IBRSA uses 3D CT data, from which digitally reconstructed radiographs (DRRs) are generated. Using 2D-3D image registration, the 3D pose of the CT is iteratively adjusted such that the generated DRRs resemble the 2D RSA images as closely as possible, according to an image matching metric. Effectively, by registering all 2D follow-up moments to the same 3D CT, the CT volume functions as common ground. In two experiments, using RSA and using a micromanipulator as gold standard, IBRSA has been validated on cadaveric and sawbone scapula radiographs, and good matching results have been achieved. The accuracy was: |mu |< 0.083 mm for translations and |mu| < 0.023 degrees for rotations. The precision sigma in x-, y , and z-direction was 0.090, 0.077, and 0.220 mm for translations and 0.155 degrees , 0.243 degrees , and 0.074 degrees for rotations. Our results show that the accuracy and precision of in vitro IBRSA, performed under ideal laboratory conditions, are lower than in vitro standard RSA but higher than in vivo standard RSA. Because IBRSA does not require radiopaque markers, it adds functionality to the RSA method by opening new directions and possibilities for research, such as dynamic analyses using fluoroscopy on subjects without markers and computer navigation applications. PMID- 17706657 TI - Diametral compression of non-circular diaphyseal bone sections. AB - Many research endeavors involve strength testing of long bones, frequently using whole-bone four-point bending models. Recently, diametral compression of short sections has been used to quantify local mechanical parameters and effects of treatment, but testing of biologically derived samples entails a number of added complications, such as the non-circularity of bone sections, ambiguity of load orientation during testing, thickness variation in a section, and size and shape variation between sections in a single sample. In order to quantify the effects of these confounding factors, finite element diametral compression models of a number of bone sections were compared with simplified circular and elliptical sections. Each anatomic section was tested in all rotationally stable load configurations. A high degree of correlation was observed between the anatomic sections and their circular and elliptic analogs, indicating that meaningful comparisons may be made between bone sections of disparate geometry. The aspect ratio and shape of the bone sections did not have a significant impact on the maximum in-plane principal stresses, whereas stresses were strongly dependant on the mean thickness and spatial thickness variation. Some variation due to load orientation was observed. These results indicate that diametral ring compression testing of anatomic sections can be used effectively to measure structural and material parameters of long bones, and that anatomic variation can be successfully accommodated. The ability to use diametral compression testing should allow researchers to obtain many more samples from each specimen than whole-bone bending without the difficulty of extracting solid core or dog-bone samples. PMID- 17706658 TI - Optimization of stir bar sorptive extraction applied to the determination of pesticides in vinegars. AB - Stir bar sorptive extraction (SBSE) has been evaluated for analysing pesticides in vinegar. The extraction analytical conditions have been optimised using a two level factorial design expanded further to a central composite design. After optimization, the proposed analytical conditions are: sample volume 40 mL, sampling time 150 min, and stirring speed 1000 rpm. On the basis of the results, it was decided not to add NaCl. The SBSE procedure developed shows detection limits and linear ranges adequate for analysing this type of compound, giving recoveries close to 100%. The repeatability and reproducibility values obtained were lower than 18 and 23%, respectively. The method was applied to a variety of commercial vinegars. SBSE is a very simple, solvent-free, and fast technique with high sensitivities. PMID- 17706659 TI - Understanding and design of existing and future chromatographic support formats. AB - The present contribution reviews the use of alternative support formats as a means to surpass the chromatographic performance of the packed bed of spheres. First, a number of idealized structures are considered to obtain a general insight in how the performance of a chromatographic support depends on its shape and size, using the isocratic peak-capacity generation speed as the main performance indicator. Using this criterion, it is found that the packing density or, equivalently, the external porosity, is the most important of all geometrical shape factors. Depending on whether the sample consists of weakly or strongly retained components, the optimal external porosity can be expected to vary between 60% and a value near 100%. The optimal exploitation of a high external porosity, however, also requires overall shrinkage of the domain size, towards and into the sub-micron range. With the current fabrication technologies, this requirement seems difficult to achieve. In the presence of a lower limit on the characteristic support size, each range of desired plate numbers or peak capacities has its own optimal external porosity, ranging from a very low value (high packing density) for high speed, small peak capacity applications, to very high external porosities (low packing density) for applications requiring a very large peak capacity. Subsequently, the obtained theoretical insights are used to review and discuss the past and current research on alternative support formats. Finally, a number of emerging micro- and nano-fabrication technologies are introduced and their potential for the future production of supports with improved shape and homogeneity is discussed. PMID- 17706660 TI - Use of an alternative scale-down approach to predict and extend hydroxyapatite column lifetimes. AB - Ceramic hydroxyapatite (CHT) chromatography offers unique selectivity for protein purification. However, columns composed of CHT, a crystalline form of calcium phosphate, often suffer from short column lifetimes, particularly under acidic operating conditions. In this paper, CHT was used under slightly acidic conditions (pH 6) for the production scale purification of a recombinant protein. Under these conditions, the packing quality of production scale CHT columns (45 cm diameter) degraded after 5-10 cycles of operation. This was not reproduced using a conventional scale-down chromatography model, in which a constant column bed height was maintained across scales. Thus, an alternative scale-down model was developed to better predict the lifetime of large scale CHT columns. The alternative approach, which utilized a constant column diameter-to-height aspect ratio, was able to predict column failure that approximated that of the manufacturing scale column. The alternative scale-down approach was then used to test alternate buffer formulations that significantly improved the CHT column lifetime. Screening studies, which assessed the effects of mobile phase pH and composition on the dissolution (weight loss) of CHT, were used to identify the alternative mobile phase formulations. Results from the study showed that slight changes to the existing mobile phase compositions significantly increased the column lifetime, from approximately 10 cycles to approximately 65 cycles of use, without altering the purification of the recombinant protein. The alternative scale-down model, together with relatively rapid mobile phase screening studies, provides a practical approach for predicting and optimizing the useful lifetime of CHT columns for large scale applications. PMID- 17706661 TI - Analysis of gin essential oil mixtures by multidimensional and one-dimensional gas chromatography/mass spectrometry with spectral deconvolution. AB - The composition of essential oils and their mixtures used to formulate gin is usually too complex to separate all sample components by standard capillary gas chromatography (GC). In particular, minor constituents that possess important organoleptic properties can be masked by co-elution with major sample components. A solution is provided that combines gas chromatography/mass spectrometry (GC/MS) with "interactive" spectral deconvolution software. Sequential two-dimensional (2D) GC/MS is used to produce a target compound library, with orthogonal GC-GC providing the separation power required to obtain peak retention times and the corresponding mass spectra needed for the deconvolution database. The combination of these two techniques, mass spectral deconvolution and automated sequential 2D GC/MS, offers a very effective synergy for both identifying key constituents that determine the perception of flavor and aroma and the quality control needed to analyze mixtures of complex essential oils. PMID- 17706662 TI - A modified enzyme-linked immunosorbent assay adapted for immunodetection of low amounts of water-insoluble proteins. AB - A mixture of thiourea, urea and CHAPS (TUC) is an excellent solvent compatible with isoelectrofocusing (IEF) separation of water-insoluble protein extracts, and their subsequent two-dimensional gel electrophoresis is an important step in proteomic studies. The main aim of this work was to quantify extremely low amounts of water-insoluble proteins contained, for instance, in samples collected in bio-aerosol samplers. High CHAPS concentrations solubilize many proteins. However, enzyme-linked immunosorbent assay (ELISA), which is the most popular immunodetection method of quantifying antigens, is unfortunately not compatible with these high CHAPS concentrations and with the low protein concentrations of TUC extracts. The most common mixture used to solubilize these proteins contains 2 mol l(-1) thiourea, 7 mol l(-1) urea and 5% w/v CHAPS. This paper shows that these components inhibit the adsorption and/or recognition of proteins on microtitration plates, preventing antigen quantification under classic ELISA conditions. We have tried several solvents (ethanol, isopropanol, acetonitrile and trichloroacetic acid) to make the TUC-soluble proteins stick to the ELISA plates, and ethanol was shown to be the most appropriate. In this study, we have defined a new ELISA protocol allowing rapid and sensitive detection of low concentrations (60-500 ng ml(-1)) of water-insoluble proteins extracted with high concentrations of TUC. PMID- 17706663 TI - Nutritional ecology of a parasitic wasp: food source affects gustatory response, metabolic utilization, and survivorship. AB - The success of biological control is partly mediated by the longevity and reproductive success of beneficial insects. Availability of nectar and honeydew can improve the nutrition of parasitic insects, and thereby increase their longevity and realized fecundity. The egg parasitoid, Anaphes iole, showed strong gustatory perception of trehalulose, a carbohydrate found in homopteran honeydew. Chromatographic analysis demonstrated that enzymatic hydrolysis of sucrose, a common nectar sugar, proceeded at a faster rate than that of melezitose, a sugar common in aphid honeydew. A long-term bioassay showed that longevity was greater at 20 degrees C than at 27 degrees C, and at both temperatures survival was generally greatest for wasps provisioned with the three major nectar sugars, sucrose, glucose, and fructose. Patterns of food acceptance and utilization showed that A. iole accepted and utilized a broad range of sugars found in nature, including those found in nectar as well as honeydew. Glucose, fructose, and several oligosaccharides composed of these monosaccharide units appear to be more suitable for A. iole than other sugars tested. Evidence suggests that individual fitness benefits afforded by food sources are important for a time limited parasitoid, and that continued investigations on the interface between nutrition and biological control are warranted for A. iole. PMID- 17706664 TI - Function of multiple sperm-storage organs in female damselflies (Ischnura senegalensis): difference in amount of ejaculate stored, sperm loss, and priority in fertilization. AB - We studied changes in the number of sperm within two kinds of female sperm storage organ in the damselfly Ischnura senegalensis (Odonata: Coenagrionidae): the bursa copulatrix and the spermatheca. We counted the number of sperm within each storage organ and tested their viability after a single copulation in female damselflies kept for seven days with and without oviposition. We also counted sperm and tested their viability in females that underwent an interrupted second copulation after the sperm-removal stage, and after subsequent oviposition. Our results showed that the bursa copulatrix and spermatheca have different sperm storage roles. Immediately after copulation, most eggs appear to have been fertilized with bursal sperm, which were positioned near the fertilization point. By seven days after copulation, a greater proportion of spermathecal sperm were used for fertilization, as the number of bursal sperm had decreased. We hypothesize that female damselflies use the spermatheca for long-term storage and the bursa copulatrix for short-term storage: bursal sperm are more likely to be used for fertilization but may have a higher risk of mortality due to sperm removal by a competing male and/or sperm expelling by the female, whereas spermathecal sperm are safer but will be used for fertilization only after their release from the spermatheca. PMID- 17706665 TI - Pheromonal communication involved in courtship behavior in Diptera. AB - Sex pheromones are known for many dipteran species and play an important role in courtship behavior, together with visual, tactile, acoustic and other factors. Pheromones for a number of dipterans have been recently identified. This survey covers a number of species in all the families that have been studied. The review discusses diverse courtship behaviors in Diptera, with a special focus on the sex pheromones involved. In the Nematocera suborder, pheromones are volatile components, which act at a distance. They are derived from short-chain alkanes with acetoxy groups (Cecidomyidae) or terpenes (Psychodidae). In the Cyclorrhapha, pheromones may be volatile, derived from alkanes (Tephritidae) or terpenes (Agromyzidae), or non-volatile, unsaturated or methyl-branched hydrocarbons, which act by contact (the other subgenera). The behavioral roles and regulation of these pheromones are described, and their importance in species recognition is discussed. PMID- 17706666 TI - A putative protein translation inhibitory factor encoded by Cotesia plutellae bracovirus suppresses host hemocyte-spreading behavior. AB - An endoparasitoid, Cotesia plutellae (Hymenoptera: Braconidae), possesses a mutualistic bracovirus (CpBV), which plays significant roles in the parasitized host, Plutella xylostella (Lepidoptera: Plutellidae). CpBV15beta, a viral gene encoded by CpBV, is expressed at early and late parasitization periods, suggesting that it functions to manipulate the physiology of the parasitized host. This paper reports a physiological function of CpBV15beta as an immunosuppressive agent. The effect of CpBV15beta on cellular immunity was analyzed by assessing hemocyte-spreading behavior. Parasitization by C. plutellae caused altered behavior of hemocytes of P. xylostella, in which the hemocytes were not able to attach and spread on glass slides. CpBV15beta was expressed in Sf9 cells using a baculovirus expression system and purified from the culture media. When hemocytes of nonparasitized P. xylostella were incubated with purified CpBV15beta protein, spreading behavior was impaired in a dose-dependent manner at low micro-molar range. This inhibitory effect of CpBV15beta could also be demonstrated on hemocytes of a non-natural host, Spodoptera exigua. CpBV15beta protein significantly inhibited F-actin growth of hemocytes in response to an insect cytokine. Similarly, cycloheximide, a eukaryotic translation inhibitor, strongly inhibited the spreading behavior and F-actin growth of P. xylostella hemocytes. Under in vitro condition, hemocytes of nonparasitized P. xylostella released proteins into the surrounding medium. Upon incubation of hemocytes with either CpBV15beta or cycloheximide, their ability to release protein molecules was markedly inhibited. This study suggests that CpBV15beta suppresses hemocyte behavior by inhibiting protein translation. PMID- 17706667 TI - Crystal structures of hydrogenase maturation protein HypE in the Apo and ATP bound forms. AB - The hydrogenase maturation protein HypE serves an essential function in the biosynthesis of the nitrile group, which is subsequently coordinated to Fe as CN( ) ligands in [Ni-Fe] hydrogenase. Here, we present the crystal structures of HypE from Desulfovibrio vulgaris Hildenborough in the presence and in the absence of ATP at a resolution of 2.0 A and 2.6 A, respectively. Comparison of the apo structure with the ATP-bound structure reveals that binding ATP causes an induced fit movement of the N-terminal portion, but does not entail an overall structural change. The residue Cys341 at the C terminus, whose thiol group is supposed to be carbamoylated before the nitrile group synthesis, is completely buried within the protein and is located in the vicinity of the gamma-phosphate group of the bound ATP. This suggests that the catalytic reaction occurs in this configuration but that a conformational change is required for the carbamoylation of Cys341. A glutamate residue is found close to the thiol group as well, which is suggestive of deprotonation of the carbamoyl group at the beginning of the reactions. PMID- 17706668 TI - Structural requirements for nucleocapsid protein-mediated dimerization of avian leukosis virus RNA. AB - The avian leukosis virus (ALV) belongs to the alpha group of retroviruses that are widespread in nature. The 5'-untranslated region of ALV genome contains the L3 element that is important for virus infectivity and the formation of an unstable RNA dimer in vitro. The L3 sequence is predicted to fold into a long stem-loop structure with two internal loops and an apical one. Phylogenetic analysis predicts that the L3 stem-loop is conserved in alpharetroviruses. Furthermore, a significant selection mechanism maintains a palindrome in the apical loop. The nucleocapsid protein of the alpharetroviruses (NCp12) is required for RNA dimer formation and replication in vivo. It is not known whether L3 can be an NCp12-mediated RNA dimerization site able to bind NCp12 with high affinity. Here, we report that NCp12 chaperones formation of a stable ALV RNA dimer through L3. To investigate the NCp12-mediated L3 dimerization reaction, we performed site-directed mutagenesis, gel retardation and heterodimerization assays and analysis of thermostability of dimeric RNAs. We show that the affinity of NCp12 for L3 is lower than its affinity for the microPsi RNA packaging signal. Results show that conservation of a long stem-loop structure and a loop-loop interaction are not required for NCp12-mediated L3 dimerization. We show that the L3 apical stem-loop is sufficient to form an extended duplex and the whole stem loop L3 cannot be converted by NCp12 into a duplex extending throughout L3. Three dimensional modelling of the stable L3 dimer supports the notion that the extended duplex may represent the minimal dimer linkage structure found in the genomic RNA. PMID- 17706669 TI - Four new crystal structures of Tk-subtilisin in unautoprocessed, autoprocessed and mature forms: insight into structural changes during maturation. AB - Subtilisin from the hyperthermophilic archaeon Thermococcus kodakaraensis (Tk subtilisin) is matured from Pro-Tk-subtilisin upon autoprocessing and degradation of the propeptide. The crystal structures of the autoprocessed and mature forms of Tk-subtilisin were determined at 1.89 A and 1.70 A resolution, respectively. Comparison of these structures with that of unautoprocessed Pro-Tk-subtilisin indicates that the structure of Tk-subtilisin is not seriously changed during maturation. However, one unique Ca(2+)-binding site (Ca-7) is identified in these structures. In addition, the N-terminal region of the mature domain (Gly70 Pro82), which binds tightly to the main body in the unautoprocessed form, is disordered and mostly truncated in the autoprocessed and mature forms, respectively. Interestingly, this site is formed also in the unautoprocessed form when its crystals are soaked with 10 mM CaCl(2), as revealed by the 1.87 A structure. Along with the formation of this site, the N-terminal region (Leu75 Thr80) is disordered, with the scissile peptide bond contacting with the active site. These results indicate that the calcium ion binds weakly to the Ca-7 site in the unautoprocessed form, but is trapped upon autoprocessing. We propose that the Ca-7 site is required to promote the autoprocessing reaction by stabilizing the autoprocessed form, in which the new N terminus of the mature domain is structurally disordered. Furthermore, the crystal structure of the Tk propeptide:S324A-subtilisin complex, which was formed by the addition of separately expressed proteins, was determined at 1.65 A resolution. This structure is virtually identical with that of the autoprocessed form, indicating that the interaction between the two domains is highly intensive and specific. PMID- 17706670 TI - prlF and yhaV encode a new toxin-antitoxin system in Escherichia coli. AB - Toxin-antitoxin systems consist of a stable toxin, frequently with endonuclease activity, and a small, labile antitoxin, which sequesters the toxin into an inactive complex. Under unfavorable conditions, the antitoxin is degraded, leading to activation of the toxin and resulting in growth arrest, possibly also in bacterial programmed cell death. Correspondingly, these systems are generally viewed as agents of the stress response in prokaryotes. Here we show that prlF and yhaV encode a novel toxin-antitoxin system in Escherichia coli. YhaV, a ribonuclease of the RelE superfamily, causes reversible bacteriostasis that is counteracted by PrlF, a swapped-hairpin transcription factor homologous to MazE. The two proteins form a tight, hexameric complex, which binds with high specificity to a conserved sequence in the promoter region of the prlF-yhaV operon. As homologs of MazE and RelE, respectively, PrlF and YhaV provide an evolutionary connection between the two best-characterized toxin-antitoxin systems in E. coli, mazEF and relEB. PMID- 17706672 TI - Specificity of familial transmission of anxiety and comorbid disorders. AB - This study examines the specificity and impact of comorbid disorders in probands on the familial transmission of panic and social anxiety disorders. It employs a contemporary family study design with 225 probands (with and without panic and social anxiety disorders) sampled from outpatient clinics and the local community. Their 1053 adult first-degree relatives were assessed for lifetime disorders, based on best estimate diagnoses derived from semi-structured psychiatric diagnostic interviews (Schedule for Affective Disorders and Schizophrenia), multi-informant family history information, and medical records. Generalized estimating equations were used to examine the familial aggregation of panic and social anxiety disorders, and the contributions of comorbid disorders. Results show specificity of familial aggregation of both panic disorder and social anxiety in probands and relatives (i.e., panic odds ratio=3.7, 95%CI 1.5 9.3; social anxiety odds ratio=1.8, 95%CI 1.1-2.9) after controlling for comorbid disorders. There was no contribution of common comorbid disorders (depression, alcoholism, generalized anxiety disorder and agoraphobia) in probands on the familial aggregation of either disorder. These findings confirm prior studies of specificity of familial transmission of panic and social anxiety disorders, and demonstrate that the association between these disorders in probands is not attributable to comorbid mood, anxiety or substance use disorders. Therefore, despite the high magnitude of co-occurrence of panic disorder and social anxiety, there may be distinct etiologic factors underlying each disorder. These findings have implications for studies of the etiology, genetics, and treatment of these disorders. PMID- 17706671 TI - Declarative and procedural memory consolidation during sleep in patients with borderline personality disorder. AB - Borderline personality disorder (BPD) is characterized by changes in subjective and objective measures of sleep quality. As recent findings point to the importance of sleep in memory consolidation, sleep-related memory consolidation was investigated in 15 female BPD patients (mean age 26.1+/-6.1 years) and 15 female healthy controls (mean age 25.6+/-6.8 years). Before and after the study night, declarative and procedural memory performance was tested by a paired associate list and a mirror tracing task. Subjective sleep quality was assessed by a sleep questionnaire, objective sleep quality was measured by a portable sleep recording device. During the study night the restorative value of sleep was significantly reduced in BPD patients (p<0.001), while objective sleep quality showed a trend for longer REM sleep duration (p=0.054). No significant differences were found regarding overnight performance improvement in the declarative and procedural memory tasks. Present findings suggest that declarative and procedural memory consolidation during sleep is intact in BPD patients. PMID- 17706673 TI - Effect of enteral versus parenteral nutrition on LPS-induced sepsis in a rat model. AB - BACKGROUND: The purpose of the present study was to determine whether total enteral nutrition (TEN) or total parenteral nutrition (TPN) differ in their modulation of ghrelin production and cardiac dysfunction induced by lipopolysaccharide (LPS). MATERIALS AND METHODS: Vascular catheters or gastrostomy tubes were surgically placed into rats who received isocaloric parenteral or enteral nutrition postoperatively. After 7 d, the rats were injected intravenously with LPS (2.5 mg/kg). Serum ghrelin levels were determined by enzyme-linked immunosorbent assay and myocardiac function was assessed via the Langendorff isolated heart technique. RESULTS: Before and after the administration of LPS, TEN was found to be more effective at increasing the plasma ghrelin levels than TPN. After LPS administration, left-ventricular developed pressure decreased in animals receiving TPN when compared with animals receiving TEN. Animals receiving TPN also had significant reductions in their maximal rates of increase (+dp/dt max) and decrease (-dp/dt max) in left ventricular pressure when compared with animals receiving TEN (unpaired t-test, P < 0.05). Upon reperfusion after 30 min of ischemia, the left ventricular resting tension decreased in animals receiving TPN compared with animals receiving TEN. Thereafter, left-ventricular developed pressure, +dp/dt max, and -dp/dt max decreased in the TEN recipients in comparison to the TPN-receiving animals. CONCLUSIONS: We conclude that TEN more effectively increases plasma ghrelin levels than TPN. The maintenance of higher ghrelin levels in TEN-fed rats is associated with maintaining cardiac function during LPS-induced septic shock. PMID- 17706674 TI - Endothelial Bmp4 is induced during arterial remodeling: effects on smooth muscle cell migration and proliferation. AB - BACKGROUND: Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta superfamily of proteins that have multiple functional roles in mammalian development. A role for BMP4 in adult vascular remodeling has recently been suggested. We evaluated the expression of Bmp4 during neointimal lesion development in vivo. MATERIALS AND METHODS: Heterozygous Bmp4(lacZ/+) mice were used to evaluate in vivo Bmp4 expression after carotid ligation. beta galactosidase (beta-gal) activity was evaluated in histological sections 1 to 14 d after carotid ligation and this was compared with control carotid arteries. The effects of recombinant human (rh) BMP4 on smooth muscle cell (SMC) migration and proliferation were evaluated using a rat aortic SMC line. We next assessed the effects of BMP4 signaling by over-expressing a constitutively active BMP receptor (BMPR-IA/Alk-3) using adenovirus-mediated gene transfer. SMC proliferation, migration, and apoptosis were evaluated in adenovirus transfected cells. RESULTS: Ligated carotid arteries expressed endothelium-specific beta-gal staining after 1 d. Staining intensity increased at both 3 d and 1 wk after ligation and remained stable at 2 weeks while no beta-gal staining was observed in control vessels. Endothelial-specific expression of beta-galactosidase was confirmed through positive staining for PECAM-1. When human recombinant BMP4 was added to cultured SMCs, it inhibited migration but did not affect cultured SMC proliferation. SMCs infected with adenovirus encoding for the active BMP receptor Alk-3 demonstrated dose-dependent receptor expression. Alk-3 over-expressing cells showed a dose dependent decrease in proliferation and migration but no effect on apoptosis. CONCLUSIONS: These results demonstrate that endothelial Bmp4 expression is upregulated after carotid ligation in vivo, and furthermore, that activating the BMP signaling cascade results in decreased SMC proliferation and migration. This suggests that BMPs may counterbalance the effect of mitogen up-regulation observed during the development of neointimal hyperplasia. PMID- 17706676 TI - Sleep under extreme environments: effects of heat and cold exposure, altitude, hyperbaric pressure and microgravity in space. AB - Human sleep is sensitive to the individual's environment. The present review examines current knowledge of human sleep patterns under different environments: heat exposure, cold exposure, altitude, high pressure and microgravity in space. Heat exposure has two effects. In people living in temperate conditions, moderate heat loads (hot bath, sauna) prior to sleep provoke a delayed reaction across time (diachronic reaction) whereby slow-wave sleep (SWS) augments in the following night (neurogenic adaptive pathway). Melanoids and Caucasians living in the Sahel dry tropical climate experience diachronic increases in SWS throughout seasonal acclimatization. Such increases are greater during the hot season, being further enhanced after daytime exercise. On the contrary, when subjects are acutely exposed to heat, diachronic decreases in total sleep time and SWS occur, being often accompanied by synchronic (concomitant) diminution in REM sleep. Stress hormones increase. Nocturnal cold exposure provokes a synchronic decrease in REM sleep along with an activation of stress hormones (synchronic somatic reaction). SWS remains undisturbed as it still occurs at the beginning of the night before nocturnal body cooling. Altitude and high pressure are deleterious to sleep, especially in non-acclimatized individuals. In their controlled environment, astronauts can sleep well in microgravity. Exercise-induced sleep changes help to understand environmental effects on sleep: well-tolerated environmental strains may improve sleep through a neurogenic adaptive pathway; when this "central" adaptive pathway is overloaded or bypassed, diachronic and synchronic sleep disruptions occur. PMID- 17706675 TI - Association of visual hallucinations with reduction of MIBG cardiac uptake in Parkinson's disease. AB - BACKGROUND: Postganglionic cardiac sympathetic denervation is evident in patients with Parkinson's disease (PD) and iodine-123 metaiodobenzylguanidine ((123)I MIBG) cardiac scintigraphy has proven to be a useful tool for diagnosis of PD. OBJECTIVE: To elucidate the factors associated with severity of cardiac sympathetic nerve dysfunction in PD patients. METHODS: We investigated 95 PD patients hospitalized in the Department of Neurology at Tottori University Hospital. (123)I-MIBG cardiac scintigraphy was performed on each patient and the early and delayed heart to mediastinum (H/M) ratios and washout rate (WR) of (123)I-MIBG cardiac scintigraphy were calculated. Independent predictive variables for parameters of (123)I-MIBG cardiac scintigraphy were analyzed by multivariate regression analysis. RESULTS: Multivariate regression analysis revealed that the presence of visual hallucinations (VH) and the patient's age at the time of evaluation independently predicted the early or delayed H/M ratio. Analysis of covariance, adjusted for the age of the patients as covariates, revealed that the early and delayed H/M ratios of PD patients with VH but no dementia, as well as PD patients with dementia were significantly lower than the ratios in PD patients with no VH or dementia. CONCLUSION: Cardiac sympathetic dysfunction may be associated with the presence of VH in PD patients. PMID- 17706677 TI - Neurological course of long-term surviving patients with SCLC and anti-Hu syndrome. AB - Patients with small-cell lung cancer (SCLC) have a poor prognosis with a three year survival rate of 4%. Our report concerns three patients with histologically proven SCLC and anti-Hu associated paraneoplastic neurological syndrome who have survived for 11 in two cases and 16 years respectively. The patients showed progressive deterioration which was only partly beneficially modulated by steroid therapy or tumor treatment, even in the cases with complete tumor remission. PMID- 17706678 TI - Endovascular cooling in a patient with neuroleptic malignant syndrome. AB - We report a case of severe neuroleptic malignant syndrome with hyperthermia, rhabdomyolysis and hepatic failure where we applied endovascular cooling in order to reverse hyperthermia. After rapid normalization of core temperature at 37.5 degrees C, the patient's condition improved and CK levels dropped. However, upon withdrawl of endovascular temperature control there was a relapse. This is the first case where endovascular cooling was applied successfully in neuroleptic malignant syndrome. PMID- 17706679 TI - Interactive effects of builders and exploiters on environmental quality and the outcome of competition between the two. AB - The implications of spatial and temporal structure for the maintenance of mutualism, altruism, and niche construction or ecosystem engineering have been explored by many theoretical models. Part of what these models have shown is that organisms that give up some amount of potential short-term gain in order to improve the quality of their environment can, in a variety of scenarios, persist in the face of more exploitative competitors if structure in environmental quality allows the former to preferentially benefit from their investments. The models presented here consider the additional implications of interactions between competitors in their effects on their environment (recently documented in multiple systems). Relative to when competitor types were additive, synergistic effects promoted coexistence and antagonistic effects promoted founder effects (but favored the less exploitative type when both had equal initial frequencies). Spatial and temporal patterns of patch quality and occupancy also differed markedly between scenarios, even where all three scenarios generated the same qualitative outcome. These models show that understanding both the scale over which organisms affect their environment and the degree to which organisms interact in such effects are important for interpreting patterns in environmental quality, predicting the effects of organism-environment feedback on competition, and explaining the persistence of mutualistic traits. PMID- 17706680 TI - Cost minimization of ribosomal frameshifts. AB - Properties of mRNA leading regions that modulate protein synthesis are little known (besides effects of their secondary structure). Here I explore how coding properties of leading regions may account for their disparate efficiencies. Trinucleotides that form off frame stop codons decrease costs of ribosomal slippages during protein synthesis: protein activity (as a proxy of gene expression, and as measured in experiments using artificial variants of 5' leading sequences of beta galactosidase in Escherichia coli) increases proportionally to the number of stop motifs in any frame in the 5' leading region. This suggests that stop codons in the 5' leading region, upstream of the recognized coding sequence, terminate eventual translations that sometimes start before ribosomes reach the mRNA's recognized start codon, increasing efficiency. This hypothesis is confirmed by further analyses: mRNAs with 5' leading regions containing in the same frame a start preceding a stop codon (in any frame) produce less enzymatic activity than those with the stop preceding the start. Hence coding properties, in addition to other properties, such as the secondary structure of the 5' leading region, regulate translation. This experimentally (a) confirms that within coding regions, off frame stops increase protein synthesis efficiency by early stopping frameshifted translation; (b) suggests that this occurs for all frames also in 5' leading regions and that (c) several alternative start codons that function at different probabilities should routinely be considered for all genes in the region of the recognized initiation codon. An unknown number of short peptides might be translated from coding and non-coding regions of RNAs. PMID- 17706681 TI - Associative learning in biochemical networks. AB - It has been recently suggested that there are likely generic features characterizing the emergence of systems constructed from the self-organization of self-replicating agents acting under one or more selection pressures. Therefore, structures and behaviors at one length scale may be used to infer analogous structures and behaviors at other length scales. Motivated by this suggestion, we seek to characterize various "animate" behaviors in biochemical networks, and the influence that these behaviors have on genomic evolution. Specifically, in this paper, we develop a simple, chemostat-based model illustrating how a process analogous to associative learning can occur in a biochemical network. Associative learning is a form of learning whereby a system "learns" to associate two stimuli with one another. Associative learning, also known as conditioning, is believed to be a powerful learning process at work in the brain (associative learning is essentially "learning by analogy"). In our model, two types of replicating molecules, denoted as A and B, are present in some initial concentration in the chemostat. Molecules A and B are stimulated to replicate by some growth factors, denoted as G(A) and G(B), respectively. It is also assumed that A and B can covalently link, and that the conjugated molecule can be stimulated by either the G(A) or G(B) growth factors (and can be degraded). We show that, if the chemostat is stimulated by both growth factors for a certain time, followed by a time gap during which the chemostat is not stimulated at all, and if the chemostat is then stimulated again by only one of the growth factors, then there will be a transient increase in the number of molecules activated by the other growth factor. Therefore, the chemostat bears the imprint of earlier, simultaneous stimulation with both growth factors, which is indicative of associative learning. It is interesting to note that the dynamics of our model is consistent with certain aspects of Pavlov's original series of conditioning experiments in dogs. We discuss how associative learning can potentially be performed in vitro within RNA, DNA, or peptide networks. We also describe how such a mechanism could be involved in genomic evolution, and suggest relevant bioinformatics studies that could potentially resolve these issues. PMID- 17706682 TI - Rhythms of high-grade block in an ionic model of a strand of regionally ischemic ventricular muscle. AB - Electrical alternans, a beat-to-beat alternation in the electrocardiogram or electrogram, is frequently seen during the first few minutes of acute myocardial ischemia, and is often immediately followed by malignant cardiac arrhythmias such as ventricular tachycardia and ventricular fibrillation. As ischemia progresses, higher-order periodic rhythms (e.g., period-4) can replace the period-2 alternans rhythm. This is also seen in modelling work on a two-dimensional (2-D) sheet of regionally ischemic ventricular muscle. In addition, in the experimental work, ventricular arrhythmias are overwhelmingly seen only after the higher-order rhythms arise. We investigate an ionic model of a strand of ischemic ventricular muscle, constructed as a 3-cm-long 1-D cable with a centrally located 1-cm-long segment exposed to an elevated extracellular potassium concentration ([K(+)](o)). As [K(+)](o) is raised in this "ischemic segment" to represent one major effect of ongoing ischemia, the sequence of rhythms {1:1-->2:2 (alternans)-->2:1} is seen. With further increase in [K(+)](o), one sees higher-order periodic 2N:M rhythms {2:1-->4:2-->4:1-->6:2-->6:1-->8:2-->8:1}. In a 2N:M cycle, only M of the 2N action potentials generated at the proximal end of the cable successfully traverse the ischemic segment, with the remaining ones being blocked within the ischemic segment. Finally, there is a transition to complete block {8:1-->2:0- >1:0} (in an n:0 rhythm, all action potentials die out within the ischemic segment). Changing the length of the ischemic segment results in different rhythms and transitions being seen: e.g., when the ischemic segment is 2 cm long, the period-6 rhythms are not seen; when it is 0.5 cm long, there is a 3:1 rhythm interposed between the 2:1 and 1:0 rhythms. We discuss the relevance of our results to the experimental observations on the higher-order rhythms that presage reentrant ischemic ventricular arrhythmias. PMID- 17706683 TI - A model of bubble growth leading to xylem conduit embolism. AB - The dynamics of a gas bubble inside a water conduit after a cavitation event was modeled. A distinction was made between a typical angiosperm conduit with a homogeneous pit membrane and a typical gymnosperm conduit with a torus-margo pit membrane structure. For conduits with torus-margo type pits pit membrane deflection was also modeled and pit aspiration, the displacement of the pit membrane to the low pressure side of the pit chamber, was found to be possible while the emboli was still small. Concurrent with pit aspiration, the high resistance to water flow out of the conduit through the cell walls or aspirated pits will make the embolism process slow. In case of no pit aspiration and always for conduits with homogeneous pit membranes, embolism growth is more rapid but still much slower than bubble growth in bulk water under similar water tension. The time needed for the embolism to fill a whole conduit was found to be dependent on pit and cell wall conductance, conduit radius, xylem water tension, pressure rise in adjacent conduits due to water freed from the embolising conduit, and the rigidity and structure of the pits in the case of margo-torus type pit membrane. The water pressure in the conduit hosting the bubble was found to occur almost immediately after bubble induction inside a conduit, creating a sudden tension release in the conduit, which can be detected by acoustic and ultra-acoustic monitoring of xylem cavitation. PMID- 17706699 TI - Urological radiographic manifestations of the Ehlers-Danlos syndrome. PMID- 17706700 TI - Mesothelioma of the tunica vaginalis. PMID- 17706701 TI - Laparoscopic pyeloplasty in the pediatric patient: hand sewn anastomosis versus robotic assisted anastomosis--is there a difference? AB - PURPOSE: The most difficult portion of laparoscopic pyeloplasty is the intracorporeal suturing involved in the anastomosis. We identified whether there is a difference in outcomes between a laparoscopic hand sewn anastomosis and a robotic assisted anastomosis. MATERIALS AND METHODS: We studied 29 patients who underwent pyeloplasty in the last 30 months, including a robotic assisted procedure in 15, a laparoscopic procedure in 12 and an aborted procedure in 2. RESULTS: Followup was 10 to 122 weeks (average 41). All surgeries except 1 were deemed successful by resolution of hydronephrosis on ultrasound and symptomatic criteria. Intraoperative time for robotic assisted pyeloplasty was 150 to 290 minutes (average +/- SD 223.1 +/- 46.5). Laparoscopic time was 200 to 285 minutes (average 236.5 +/- 24.1). CONCLUSIONS: Robotic assisted and laparoscopic anastomosis produced similar outcomes in pediatric patients who underwent pyeloplasty. Overall operative times did not vary significantly between the 2 procedures. There appeared to be no quantifiable benefits between the 2 procedures. PMID- 17706702 TI - Postpubertal urodynamic and upper urinary tract changes in children with conservatively treated myelomeningocele. AB - PURPOSE: We examined the urodynamic and upper urinary tract changes in children with myelomeningocele treated conservatively through puberty at our institution between 1980 and 2006. MATERIALS AND METHODS: A total of 40 patients were exclusively treated conservatively with or without anticholinergics and/or clean intermittent catheterization through puberty at our institution. The records of 37 patients (17 males and 20 females) were available for review and constituted the subject matter for our study. The neurological lesion was sacral in 4 patients, lumbosacral in 5, thoracic in 12 and lumbar in 16. Clinical evaluations, radiological imaging studies of the upper urinary tract and urodynamic studies were repeated every 6 to 12 months. Data were collected and comparisons were made with respect to prepubertal (age 10 years) and postpubertal (15) continence status, urodynamic parameters and upper urinary tract changes. Children spontaneously achieving urinary continence postpubertally were examined in a similar fashion as a separate subgroup. Continence was defined as a dry interval of 4 hours or more. RESULTS: Of the 26 patients with urinary incontinence before puberty 12 (2 males and 10 females, 45%, p <0.003) achieved continence following puberty. Hydronephrosis remained stable in 4 patients, improved in 3 and was new onset in 3 (p >0.05). Vesicoureteral reflux persisted in 1 patient, resolved in 4 and was new onset in 1 (p >0.05). Total cystometric bladder capacity, maximum detrusor pressure and detrusor leak point pressure all increased significantly after puberty, from 277 +/- 82 to 487 +/- 140 ml, 45 +/- 17 to 54 +/- 20 cm H(2)O and 49 +/- 16 to 59 +/- 21 cm H2O, respectively. In patients achieving urinary continence following puberty total cystometric bladder capacity increased significantly from 284 +/- 58 to 473 +/- 93 ml (p <0.005). Maximum detrusor pressure and detrusor leak point pressure showed insignificant changes after puberty, increasing from 45 +/- 11 to 47 +/- 16 cm H2O and from 46 +/- 11 to 55 +/- 21 cm H2O, respectively. CONCLUSIONS: This study demonstrates that total cystometric bladder capacity, maximum detrusor pressure and detrusor leak point pressure increase significantly in patients with myelomeningocele following puberty. The increase in bladder capacity could be attributed to increasing bladder outlet resistance resulting from prostate gland enlargement in males and estrogenization in females. A significant number of patients spontaneously achieve continence at puberty, and continence becomes more likely when increased total cystometric bladder capacity is not associated with an increase in maximum detrusor pressure. Finally, no significant postpubertal upper urinary tract deterioration was observed in our series. PMID- 17706703 TI - Radiographic changes following excisional tapering and reimplantation of megaureters in childhood: long-term outcome in 46 renal units. AB - PURPOSE: Despite the routine use of renal ultrasonography to document progressive improvement in hydronephrosis following ureteral tailoring and reimplantation of megaureters, there have been few reports characterizing the serial radiographic changes to be expected following this procedure. We evaluated the radiographic outcomes following surgical repair of megaureters at single institution, and assessed potential preoperative factors for predicting outcome. MATERIALS AND METHODS: We conducted a retrospective analysis of all patients who underwent surgical correction of clinically significant megaureters at our center between 1996 and 2003. Demographic data, indications for surgery, and preoperative and postoperative radiographic imaging data were recorded. RESULTS: A total of 46 megaureters (39 patients) were tapered and reimplanted. Average patient age at surgery was 4.0 years (range 5 months to 19 years). Indications for surgery included recurrent or breakthrough urinary tract infections, decreased renal function and increased hydroureteronephrosis. Mean followup was 3.9 years (range 4 months to 7 years). Postoperative voiding studies showed vesicoureteral reflux in 3 reimplanted ureters (7%). There was no evidence of obstruction on postoperative nuclear renal scans in any patient. Renal ultrasonography revealed improvement or resolution of hydroureteronephrosis in 29 reimplanted units (63%). In general, male patients, those operated on at a younger age and those with a lower preoperative grade of hydronephrosis were most likely to demonstrate improvement or resolution of hydronephrosis. The best results were seen in ectopic megaureters, followed in decreasing order by refluxing megaureters, megaureters associated with ureteroceles and primary obstructive megaureters. CONCLUSIONS: Despite functional improvement on postoperative radiographic imaging, it is not uncommon to see persistent hydroureteronephrosis following excisional tapering and reimplantation of megaureters in childhood. PMID- 17706704 TI - Endoscopic treatment of vesicoureteral reflux associated with paraureteral diverticula in children. AB - PURPOSE: Paraureteral or Hutch diverticula are congenital bladder diverticula that occur at or adjacent to the ureteral hiatus and are associated with vesicoureteral reflux in the majority of cases. Surgical treatment has traditionally been ureteral reimplantation with or without diverticulectomy. We present our experience with endoscopic treatment of vesicoureteral reflux associated with paraureteral diverticula. MATERIALS AND METHODS: Of 745 patients undergoing endoscopic treatment for vesicoureteral reflux between 2002 and 2006, 17 (2.3%) had paraureteral diverticula located at the refluxing ureter. The hydrodistention implantation technique was used and dextranomer/hyaluronic acid copolymer was used as bulking material. Success was defined as vesicoureteral reflux grade 0 on postoperative voiding cystourethrogram at 1 to 3 months after a single treatment. RESULTS: A total of 20 refluxing ureters with associated paraureteral diverticula were treated in 17 patients. Of the cases 14 were unilateral and 3 were bilateral. Reflux was grade I in 6 patients, grade II in 4, grade III in 8, grade IV in 1 and grade V in 1. A mean of 1.2 ml bulking agent was injected per ureter. Overall success was 81% (13 of 16 patients) after a single injection. Success per vesicoureteral reflux grade was 100% (6 of 6 patients) for grade I, 100% (3 of 3) for grade II, 63% (5 of 8) for grade III, 100% (1 of 1) for grade IV and 100% (1 of 1) for grade V. Endoscopic treatment failed in 3 patients. Multivariate analysis identified large diverticular size and high bulking agent volume as predictors of treatment failure. Age, reflux grade and the presence of unilateral vs bilateral paraureteral diverticula did not impact outcome. CONCLUSIONS: Endoscopic injection of dextranomer/hyaluronic acid copolymer is an excellent choice for the treatment of vesicoureteral reflux associated with paraureteral diverticula because it has a high success rate and avoids open surgery. PMID- 17706705 TI - Evidence of variation by race in the timing of surgery for correction of pediatric ureteropelvic junction obstruction. AB - PURPOSE: We used a national pediatric database to investigate the association of patient race with timing of surgery for ureteropelvic junction obstruction. MATERIALS AND METHODS: The Kids' Inpatient Database is a national database containing 5.5 million pediatric hospitalizations (patients younger than 21 years) during the years 2000 to 2003. We used International Classification of Disease-9 codes to identify patients undergoing pyeloplasty, and investigated patient and hospital factors associated with timing of surgery using multivariable linear and mixed models. RESULTS: A total of 2,989 patients underwent pyeloplasty. Mean patient age was 72.3 months (median 36). Of the patients 69.3% were male and 66.0% were white. White patients were significantly older than nonwhite patients (82.3 vs 52.8 months, p <0.0001). The proportion of patients undergoing surgery during the first 12 months of life also varied by race (31.3% among white vs 46.9% among nonwhite patients, p <0.0001). Other factors associated with younger age included male gender (p = 0.0002), hospital volume and teaching status (p <0.0001), and Medicaid insurance (p <0.0001). Socioeconomic status at the zip code level was not associated with timing of surgery. Using a multivariable mixed model to adjust for all variables, including random effects of individual hospitals, nonwhite race was still associated with earlier surgery (p = <0.0001). CONCLUSIONS: This study confirms that nonwhite patients undergo pyeloplasty an average of more than 2.5 years earlier than white patients (even after adjusting for insurance status and other factors). Future research should elucidate the clinical factors that influence surgical decision making in ureteropelvic junction obstruction, including socioeconomic and cultural factors among families and providers, as well as possible biological differences between racial groups in the natural history of ureteropelvic junction obstruction. PMID- 17706706 TI - The effect of obesity on treatment efficacy in children with nocturnal enuresis and voiding dysfunction. AB - PURPOSE: Obesity continues to be a leading public health concern in the United States. Our previous studies have suggested that there is a high rate of obesity in children with dysfunctional voiding, especially nocturnal enuresis. We investigated the correlation between body mass index and the efficacy of treatment in obese patients. MATERIALS AND METHODS: We evaluated retrospectively records from patients seen with a diagnosis of nocturnal enuresis or dysfunctional voiding between January 2004 and July 2005. Bladder and bowel symptoms and urinary diary data were evaluated, and body mass index percentile was determined. Response to treatment was evaluated and correlated with body mass index percentile. RESULTS: We evaluated 250 children, of whom 96 (38%) had nocturnal enuresis and 154 (62%) had dysfunctional voiding. Body mass index was normal in about half of the patients, and half were above the 85th percentile for body mass index. Patients with a body mass index above the 85th percentile had a reduced response to therapy. After treatment patients with a normal body mass index had a lower nocturnal accident frequency than those above the 85th percentile. Similarly, in those with voiding dysfunction the response rate was 65% in association with a normal body mass index vs 35% with a high body mass index. Furthermore, patients with a normal body mass index had a significantly higher rate of completing a urinary diary compared to those with a high body mass index. CONCLUSIONS: Obesity correlates with a lower voiding diary completion rate and lower efficacy of treatment in children with nocturnal enuresis or dysfunctional voiding. PMID- 17706708 TI - Decision making during laparoscopic orchiopexy for intra-abdominal testes near the internal ring. AB - PURPOSE: We studied whether testicular proximity to the ipsilateral internal ring or ability to reach the contralateral ring predicted the likelihood that laparoscopic orchiopexy would deliver an intra-abdominal testis to the dependent scrotum. MATERIALS AND METHODS: Records of patients undergoing laparoscopic orchiopexy for testes within 2 cm of the internal ring were reviewed. Factors considered included patient age, mobility of the testis to the contralateral ring, intraoperative positioning in the upper vs lower scrotum, and postoperative findings of testicular viability and location. RESULTS: Of 46 testes treated with laparoscopic orchiopexy 20 reached the low scrotum. The remaining 26 testes only reached the upper scrotum. Of these testes 14 were fixed to the most distal aspect of the scrotum that they would reach, while 12 were managed by vessel transection with 1-stage orchiopexy to the low scrotum in 10 and the upper scrotum in 2. Patient age at surgery, location within 2 cm of the internal ring and mobility to the contralateral ring did not predict ability of laparoscopic orchiopexy to bring the testis to the low scrotum. Followup was available in 42 testes at a mean of 6.8 months (range 1 to 25), with 25 (60%) in the low scrotum, 6 (14%) in the upper scrotum, 6 (14%) showing atrophy and 5 (12%) reoperated on for a position at or above the upper margin of the scrotum. CONCLUSIONS: Factors evaluated did not indicate the likelihood that laparoscopic orchiopexy would result in a testis in the dependent scrotum. It is unclear whether a testis only reaching the upper scrotum should be fixed with vessels intact, or undergo 1 stage Fowler-Stephens orchiopexy to attempt to reach the low scrotum. PMID- 17706707 TI - Comparative analysis of tubularized incised plate versus onlay island flap urethroplasty for penoscrotal hypospadias. AB - PURPOSE: Despite being the dominant technique for repair of distal hypospadias, application of the tubularized incised plate approach for penoscrotal hypospadias remains controversial. We report our experience with severe hypospadias, comparing tubularized incised plate to transverse island flap onlay urethroplasty. MATERIALS AND METHODS: We retrospectively reviewed consecutive patients with penoscrotal hypospadias presenting between 1998 and 2006. Based on surgeon preference 35 children underwent tubularized incised plate and 40 underwent onlay urethroplasty. Penoscrotal transposition and degree of ventral curvature, type of ventral curvature repair, complication rate, postoperative uroflowmetry pattern in toilet trained patients and number of reoperations were compared between the 2 groups. RESULTS: Mean patient age at surgery was 17 months (range 9 to 91) for tubularized incised plate urethroplasty and 17.8 months (10 to 58) for the onlay procedure. Urethroplasty was performed over an 8Fr catheter in all patients. With mean followups of 30 months (range 6 to 74) and 38.8 months (16 to 80) the overall complication rates were 60% and 45% for the tubularized incised plate and onlay procedures, respectively. Fistula occurred in 15 patients and repair breakdown in 3 patients (total 51.4%) treated with tubularized incised plate repair, compared to 8 and 2 patients, respectively (25%), treated with onlay repair (p = 0.01). Fistula location also differed significantly between the 2 groups, with proximal fistulas occurring in 11 of 15 tubularized incised plate repairs (73.3%) vs 2 of 8 onlay repairs (25%, p = 0.02). Recurrent ventral curvature was more frequent after onlay urethroplasty (5.7% vs 12.5%, not significant). At a mean age of 5.1 years a plateau uroflow curve (vs normal bell curve) was observed in 16 of 24 children (66.7%) who underwent tubularized incised plate repair and in 7 of 21 (33.3%) who underwent onlay repair (p <0.01). CONCLUSIONS: In this series the overall complication rate was similar for tubularized incised plate and onlay urethroplasty. Despite similar urethroplasty calibers, the uroflow curves and fistula positions in patients undergoing tubularized incised plate repair suggest that the neourethra distal to the fistula may be relatively narrow, creating flow resistance and leading to proximal fistula. Longer followup and close monitoring are needed before embracing one approach over the other. PMID- 17706709 TI - Prepubertal orchiopexy for cryptorchidism may be associated with lower risk of testicular cancer. AB - PURPOSE: Current indications for orchiopexy are to decrease the risk of infertility and to facilitate testicular self-examination. Although the increased risk of germ cell cancer in cryptorchid testes is undisputed, it is unclear whether orchiopexy affects the natural history of testis cancer development. We hypothesize that early orchiopexy is protective against subsequent development of testicular germ cell cancer. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of the literature. Studies pertaining to cryptorchidism and testicular cancer risk were retrieved by searching MEDLINE, BIOSIS and the Cochrane Library, using cryptorchidism as a keyword, combined with treatment, orchiopexy, testis and cancer. For data extraction exposure was dichotomized to orchiopexy before or after age 10 to 11 years, while outcome was defined as the development of testicular germ cell cancer. Summary risk measures were calculated using the random effects model. RESULTS: Four studies met our criteria. Review of all studies revealed an increased risk of testicular cancer if orchiopexy was delayed until after age 10 to 11 years or was never performed. Odds ratios ranged from 2.9 to 32.0. Meta-analysis showed that testicular cancer was nearly 6 times more likely (OR 5.8 [1.8, 19.3]) to develop in men in whom orchiopexy was delayed or was not performed, compared to those in whom it was performed early. CONCLUSIONS: Prepubertal orchiopexy may decrease the risk of testicular cancer. Thus, early surgical intervention is indicated in children with cryptorchidism. These findings suggest that the testicular environment, as well as underlying genetics, may have a role in testicular carcinogenesis. PMID- 17706710 TI - Levels of evidence in the urological literature. AB - PURPOSE: The concept of levels of evidence is one of the guiding principles of evidence based clinical practice. It is based on the understanding that certain study designs are more likely to be affected by bias than others. We provide an assessment of the type and levels of evidence found in the urological literature. MATERIALS AND METHODS: Three reviewers rated a random sample of 600 articles published in 4 major urology journals, including 300 each in 2000 and 2005. The level of evidence rating system was adapted from the Center of Evidence Based Medicine. Sample size was estimated to detect a relative increase in the proportion of studies that provided a high level of evidence (I and II combined) from 0.2 to 0.3 with 80% power. RESULTS: Of the 600 studies reviewed 60.3% addressed questions of therapy or prevention, 11.5% addressed etiology/harm, 11.3% addressed prognosis and 9.2% addressed diagnosis. The levels of evidence provided by these studies from I to IV were 5.3%, 10.3%, 9.8% and 74.5%, respectively. A high level of evidence was provided by 16.0% of studies in 2000 and by 15.3% in 2005 (p = 0.911). CONCLUSIONS: This study suggests that a majority of studies in the urological literature provide low levels of evidence that may not be well suited to guide clinical decision making. We propose that editors of leading urology journals should promote awareness for this guiding principle of evidence based clinical practice by providing a level of evidence designation with each published study. PMID- 17706712 TI - Association of procedure volume with radical cystectomy outcomes in a nationwide database. AB - PURPOSE: Studies of national databases yield important information about expected outcomes after radical cystectomy and factors that influence patient morbidity and mortality. We examined the hospital characteristics associated with outcomes after radical cystectomy in a cohort study using results from a single, high volume academic institution as well as a nationwide data set of academic institutions. MATERIALS AND METHODS: We obtained data from the University HealthSystem Consortium Clinical Database on 6,728 patients nationwide who underwent radical cystectomy for bladder cancer between 2002 and 2005 as well as on 421 who underwent cystectomy at our institution during this period. Outcomes were compared by hospital characteristics (geographic location, total hospital discharges and procedure volume). The outcome measures analyzed were length of hospital stay, the complication rate and in hospital mortality. RESULTS: The overall complication rate at our institution was 32.07% with an in hospital mortality rate of 0.95% and an average length of stay of 7.05 days. The overall complication rate in the University HealthSystem Consortium data set was 37.16% with an in hospital mortality rate of 1.47% and an average length of stay of 10.98 days. Institutions with higher cystectomy volumes had significantly better outcomes than institutions with lower procedure volumes. The mortality rate at institutions with greater than 50 cystectomies per year was 0.54% compared to 2.70% at institutions with 10 or fewer per year (p <0.0005). Outcomes varied only minimally with total hospital discharges or geographic region. CONCLUSIONS: Even among academic medical centers hospitals with a higher volume of cystectomies in 2002 to 2005 were associated with improved outcomes, including decreased mortality, shorter length of stay and lower rehospitalization rates. These data may provide a framework for self-assessment and help establish criteria for performance evaluation. PMID- 17706711 TI - Health care cost associated with prostate cancer, androgen deprivation therapy and bone complications. AB - PURPOSE: We ascertained the health care costs of androgen deprivation therapy and related skeletal events. MATERIALS AND METHODS: Using data from the MarketScan Medicare Supplemental and Coordination of Benefits Database, we identified cases with International Classification of Disease, 9th Revision codes indicating a diagnosis of prostate cancer who initiated androgen deprivation therapy between 1999 and 2002. The control group consisted of patients with prostate cancer with no androgen deprivation therapy use, matched by age, geographic region, insurance plan and index year. All had followup data for at least 36 months. The occurrence and cost of osteoporosis and any bone fracture were assessed using a propensity score matched sample. RESULTS: Of the 8,577 eligible men with prostate cancer, 3,055 initiated androgen deprivation therapy and 5,522 did not. At the time of androgen deprivation therapy initiation those on androgen deprivation therapy had more severe comorbidity (3.1 vs 2.6, p <0.001) and proportionally more bone metastases (2.8% vs less than 0.6%, p <0.001) but no difference in fracture rate. After 3 years of followup the androgen deprivation therapy group experienced significantly more fractures (18.7% vs 14.6%, p <0.001). The mean unadjusted total cost of health care during the 36-month period was $48,350 per person for cases and $26,097 for controls. CONCLUSIONS: Among men with prostate cancer, those on androgen deprivation therapy cost the health care system almost twice as much as those not on androgen deprivation therapy. After controlling for differences in health status, the majority of the excess cost is attributable to androgen deprivation therapy and then to a lesser extent, the fractures. These results suggest that the bone complications of osteoporosis and fractures in men on androgen deprivation therapy have important economic consequences. PMID- 17706713 TI - Variations in stress incontinence and prolapse management by surgeon specialty. AB - PURPOSE: Numerous studies have documented a relationship between provider specialty and outcomes for surgical procedures. In this study we sought to determine the effect of surgeon specialty on outcomes of sling surgery for women with stress urinary incontinence. MATERIALS AND METHODS: We analyzed the 1999 to 2001 Medicare claims data from a 5% national random sample of Medicare beneficiaries. Women 65 years or older who underwent a sling procedure between July 1, 1999 and December 31, 2000 were identified on the basis of CPT-4 codes and tracked for 12 months. Key complications were identified using CPT-4 and ICD 9 revision codes for relevant procedures and diagnoses. Outcomes were compared between urologists and gynecologists. RESULTS: A total of 1,356 sling procedures were performed. Of them 1,063 (78.4%) were performed by urologists, while 246 (18.1%) were performed by gynecologists. Urologists performed concomitant prolapse repairs in 29.1% of cases, and gynecologists performed prolapse repairs in 55.7% (p <0.0001). In the 12 months following sling surgery, urologists were more likely than gynecologists to perform a repeat incontinence procedure (9.3% vs 4.9%, p = 0.024) and prolapse repair (26.0% vs 12.2%, p <0.0001). The 2 surgical specialties did not differ in postoperative outlet obstruction, urological complications, or nonurological complications. CONCLUSIONS: Early prolapse management by gynecologists corresponded to fewer prolapse repairs in the year following the sling. Our findings suggest that gynecologists are more likely to identify and manage prolapse at the time of the evaluation of urinary incontinence, a strategy that appears to avoid the morbidity and cost of repeat surgery. PMID- 17706715 TI - Transperineal ultrasound for measurement of prostate volume: validation against transrectal ultrasound. AB - PURPOSE: We evaluated the transperineal ultrasound method to measure total and central prostate volume compared with the standard transrectal ultrasound. MATERIALS AND METHODS: Healthy men without prostate disease underwent transperineal and transrectal ultrasound at a single session to calculate total and central prostate volume by the ellipsoidal formula from maximal measured dimensions. Reproducibility within and between methods was evaluated by ICC, CV and Bland-Altman plots. RESULTS: In 13 men measured on 3 occasions within 2 weeks transperineal and transrectal ultrasound had high within method (ICC 0.92 and 0.97, and CV 7.2% and 5.1%, respectively) and between method (ICC 0.98 and CV 5.4%) agreement. Agreement for central prostate volume was good but it was lower within method (ICC 0.74 and 0.73, and CV 20.5% and 20.3%, respectively) and between method (ICC 0.85 and CV 19.7%). Transperineal ultrasound bias was -2.7% for total and -8.9% for central prostate volume. Of 287 healthy men the methods highly correlated for total prostate volume in 245 (ICC 0.92, 95% CI 0.90 to 0.94) and for central prostate volume in 217 (ICC 0.87, 95% CI 0.83 to 0.90). Transperineal ultrasound had minimal bias for total prostate volume (-3.7%, mean 1.0 ml, 95% CI -1.7 to -0.2 ml) and no bias for central prostate volume (-3.0%, mean bias 0.10 ml, 95% CI -0.3 to 0.5 ml). Transperineal ultrasound was more acceptable but it had a higher technical failure rate for total and central prostate volume (13.6% vs 1.4% and 23.7% vs 3.5%, respectively). CONCLUSIONS: Transperineal ultrasound provides an accurate, less invasive and more acceptable alternative but with a higher technical failure rate than transrectal ultrasound, especially for central prostate volume. By trading off acceptability for the failure rate transperineal ultrasound may enhance the feasibility of valid studies requiring repeat prostate volume measurement in asymptomatic men. PMID- 17706714 TI - Comparison of vitamin E and propionyl-L-carnitine, separately or in combination, in patients with early chronic Peyronie's disease: a double-blind, placebo controlled, randomized study. AB - PURPOSE: We compared the efficacy and safety of oral vitamin E and propionyl-L carnitine, separately or in combination, for the treatment of Peyronie's disease. MATERIALS AND METHODS: A total of 236 men (mean age 43.4 years) with Peyronie's disease were randomly assigned to 4 groups. Group 1 (58 men) received 300 mg vitamin E orally twice daily. Group 2 (59) received 1 gm propionyl-L-carnitine orally twice daily, and group 3 (60) received 300 mg vitamin E and 1 gm propionyl L-carnitine orally twice daily. Group 4 (control group, 59 men) received a similar regimen of placebo during the 6-month treatment period. The efficacy of the 4 treatments was assessed using responses to the International Index of Erectile Function, visual analog scale for pain evaluation, mean intercourse satisfaction domain, mean weekly coitus episodes, penile curvature, plaque size and adverse drug effects. RESULTS: Pain decreased in 60.4%, 63%, 62.3% and 59.2% of the patients treated with vitamin E, propionyl-L-carnitine, vitamin E plus propionyl-L-carnitine and placebo, respectively (p = 0.1). After therapy a reduction in penile curvature was observed by 18.9%, 20.4%, 22.6% and 18.4% of the patients in groups 1, 2, 3 and 4, respectively (p = 0.09), and a decrease in plaque size was noted in 11.3%, 12.9%, 13.2% and 11.1%, respectively (p = 0.1). CONCLUSIONS: This study did not show significant improvement in pain, curvature or plaque size in patients with PD treated with vitamin E, propionyl-L-carnitine, or vitamin E plus propionyl-L-carnitine compared with those treated with placebo. PMID- 17706716 TI - Outcomes following repeat mid urethral synthetic sling after failure of the initial sling procedure: rediscovery of the tension-free vaginal tape procedure. AB - PURPOSE: We evaluated outcomes of the repeat mid urethral sling to treat recurrent or persistent stress urinary incontinence after failure of an initial mid urethral sling. MATERIALS AND METHODS: We retrospectively analyzed data on patients who underwent the repeat mid urethral sling procedure due to persistent or recurrent stress urinary incontinence. Repeat slings were placed without removal of the previous sling. All patients were followed at least 1 year after the second mid urethral sling. RESULTS: Of the 31 female patients with a repeat mid urethral sling 29 were followed, including 13 with a retropubic and 16 with a transobturator sling. For the first mid urethral sling 17 patients received a retropubic sling (tension-free vaginal tape) and 12 received a transobturator sling (6 inside out and 6 outside in procedures). Cure and improvement rates irrespective of the approach were 75.9% (22 of 29 patients) and 6.9% (2 of 29), respectively. Cure rates for the retropubic and transobturator slings were 92.3% (12 of 13 patients) and 62.5% (10 of 16), respectively, a difference that did not quite attain statistical significance (p = 0.089). CONCLUSIONS: The repeat mid urethral sling for persistent or recurrent stress urinary incontinence has a lower cure rate than the initial sling. However, the retropubic approach tends to have a higher cure rate than the transobturator approach in repeat sling cases. PMID- 17706717 TI - The role of preoperative testing on outcomes after sling surgery for stress urinary incontinence. AB - PURPOSE: In this study we analyzed Medicare claims data to measure the effect of preoperative urodynamics and cystoscopy on outcomes after sling surgery. MATERIALS AND METHODS: We analyzed 1999 to 2001 Medicare claims data on a 5% national random sample of beneficiaries. Women who underwent sling procedures between July 1, 1999 and December 31, 2000 were identified on the basis of the presence of CPT-4 code 57288 (sling operation for stress incontinence). Subjects were tracked for 6 months before surgery to identify type of preoperative studies performed (urodynamics and cystoscopy) and for 12 months after surgery to assess short-term complications. RESULTS: Of 1,356 subjects 24.8% underwent preoperative cystoscopy and 27.4% underwent preoperative urodynamic testing. In postoperative year 1, 32.4% of subjects underwent cystoscopy and 30.5% underwent urodynamics. Patients who underwent preoperative urodynamics were more likely to be newly diagnosed with urge incontinence after surgery (21.9% vs 12.7%, p <0.0001). Those who underwent preoperative cystoscopy were significantly more likely to be diagnosed with (9.4% vs 6.1%, p <0.043) or treated for (10.6% vs 7.2%, p <0.047) outlet obstruction postoperatively than those who did not. Multivariate analysis revealed that subjects who underwent preoperative urodynamics were significantly less likely to undergo postoperative urodynamics than those who did not (OR 0.34, 95% CI 0.24-0.48). CONCLUSIONS: Our findings of worse outcomes among women who underwent preoperative testing may be due in part to case selection. Our finding that women who underwent preoperative urodynamics were only a third as likely to undergo postoperative urodynamics as those who did not supports the use of urodynamics in the preoperative setting. However, the true effect of urodynamics on sling outcomes remains controversial. PMID- 17706718 TI - Comparison of effectiveness of detrusor, suburothelial and bladder base injections of botulinum toxin a for idiopathic detrusor overactivity. AB - PURPOSE: We compared the effectiveness of detrusor, suburothelial and bladder base injections of botulinum toxin type A in patients with idiopathic detrusor overactivity. MATERIALS AND METHODS: A total of 45 patients with idiopathic detrusor overactivity refractory to antimuscarinic therapy were randomly allocated to receive 100 U botulinum toxin type A injected into detrusor, suburothelial and bladder base. Videourodynamic studies were performed at baseline and 3 months after treatment. Data collected included symptom score, urgency and incontinence episodes, and urgency severity score. A general satisfaction rating was also assessed as excellent, moderately improved, mildly improved or stationary. A moderately improved or excellent result was defined as successful treatment. RESULTS: A total of 15 patients were allocated to each treatment group. A successful result at 3 months was achieved in 14 (93%) patients with detrusor, 12 (80%) with suburothelial and 10 (67%) with bladder base injection. The success rate in the detrusor, suburothelial and bladder base injection groups decreased with time to 67%, 47% and 13% by 6 months, and 20%, 20% and 6.7% at 9 months, respectively (p = 0.0253). Vesicoureteral reflux was not found in any patient after botulinum toxin type A injection. Urgency severity scores improved significantly in all groups after treatment. At 3 months after treatment significant increases in cystometric capacity and post-void residual compared to baseline were found in the detrusor and suburothelial but not in the bladder base group. CONCLUSIONS: Intravesical injection of 100 U botulinum toxin type A by all 3 methods had a therapeutic effect on idiopathic detrusor overactivity. Bladder base botulinum toxin type A injection relieved urgency sensation but did not increase bladder capacity. PMID- 17706720 TI - Gunshot wound injuries of the prostate and posterior urethra: reconstructive armamentarium. AB - PURPOSE: Descriptions of posterior urethral penetrating injuries are rare in the literature and their management is poorly described. We reviewed the medical records of 19 men who sustained posterior urethral gunshot wounds and report our experience with various treatment options. MATERIALS AND METHODS: We retrospectively reviewed the records of 19 men (mean age 27 years) who sustained posterior urethral gunshot wound injuries confirmed by retrograde urethrography and/or exploratory laparotomy. Treatment options included immediate primary repair in 2 patients, delayed reconstruction in 15 and complete prostatectomy in 2. Outcomes were described by flow rates and lower urinary tract symptoms. RESULTS: Of 15 patients who underwent delayed repair 13 (86.6%) demonstrated normal flow rates and lack of lower urinary tract symptoms. The 2 remaining patients experienced obliterative stricture recurrences and were treated with open surgery. Both patients who underwent immediate primary repair had normal flow rates. Of the 2 men who underwent immediate prostatectomy 1 had moderate incontinence requiring absorbent pad use and the other was lost to followup after he was discharged home with a suprapubic catheter in place. CONCLUSIONS: An initial management strategy based on the principles of maximizing urinary catheter drainage, with direct retropubic repair/urethral realignment when possible and definitive perineal reconstruction when necessary, appears to provide acceptable outcomes while minimizing the number of subsequent interventions required. PMID- 17706719 TI - Overlap of voiding symptoms, storage symptoms and pain in men and women. AB - PURPOSE: We quantified the degree of symptomatic overlap in individuals who reported urological symptoms and compared these patterns between men and women. MATERIALS AND METHODS: A questionnaire was mailed to a random sample of the Kaiser Permanente Northwest membership with no medical record evidence of pelvic malignancy or neurological disease. The questionnaire included the International Prostate Symptom Scale, Interstitial Cystitis Symptom Index and Problem Index, and National Institutes of Health Chronic Prostatitis Symptom Index. The 701 men and 745 women who reported urological symptoms were selected for analysis. The degree of overlap of storage symptoms, voiding symptoms and pain symptoms was assessed. Multiple logistic regression was used to determine symptom predictors. RESULTS: There was a high degree of overlap among the 3 symptom categories with few observed differences between men and women. Of individuals with storage or voiding symptoms 34% of men and 43% of women also had pain symptoms. Of those with pain 90% of men and 94% of women also had voiding or storage symptoms. Logistic regression results indicated that frequency, urgency and any storage symptoms were statistically more common in women than in men, while a slow stream was more common in men than in women. CONCLUSIONS: As previously reported, there are limited differences in the degree and distribution of lower urinary tract symptoms in men and women. To our knowledge the novel finding of this study is that pain symptoms commonly coincide with voiding and storage symptoms in the 2 genders. This suggests that categorizing patients into disease categories, such as lower urinary tract symptoms or bladder conditions, may ignore the pain components of symptoms. A symptom based classification symptom may more accurately identify and address all patient complaints. PMID- 17706721 TI - The silence of the stones: asymptomatic ureteral calculi. AB - PURPOSE: We investigated the characteristics and diagnosis of primary asymptomatic ureteral calculi. MATERIALS AND METHODS: During a period of 12 years asymptomatic ureteral stones were prospectively investigated at the Urological Stone Center. We studied mode of diagnosis, stone size, localization, composition, hydronephrosis grade and patient characteristics. RESULTS: Between 1995 and 2006 a total of 40 patients with asymptomatic ureteral stones were identified among 3,711 patients with ureteral stones (1.1%). Mean age of the 33 male and 7 female asymptomatic patients was 58.3 years (range 28.1 to 87.1). Localization of stones was 19 proximal, 3 mid and 18 in the distal ureter. Mean stone size was 10.0 mm (+/-6). Mode of diagnosis of asymptomatic calculi was randomly diagnosed hydronephrosis in 10 patients (25%), microscopic hematuria in 8 (20%), randomly diagnosed stone on other than urological x-ray examination in 13 (32.5%) and stone diagnosed during followup after previous nephrolithiasis in 9 patients (22.5%). Primary therapy was extracorporeal shock wave lithotripsy in 35 patients (87.5%), ureterorenoscopic lithotripsy in 4 (10%), spontaneous stone passage before scheduled treatment in 1 and open ureteroneocystostomy in 1 patient. CONCLUSIONS: De novo asymptomatic ureteral calculi do exist. Characteristics of this small group of patients with ureterolithiasis have not been described thus far. Diagnosis is usually made during routine health care examinations, during the evaluation of nonurological diseases and during followup of patients who previously had nephrolithiasis. A large proportion of patients exhibit some degree of hydronephrosis as a sign of silent obstruction. PMID- 17706722 TI - Prevalence of and risk factors for prostatitis: population based assessment using physician assigned diagnoses. AB - PURPOSE: Previous studies to assess risk factors for prostatitis used patient self-reported data and, therefore, they were subject to recall bias. We 1) used coded physician diagnoses to calculate the prevalence of prostatitis and 2) compared these patients with matched controls to identify medical conditions that are associated with prostatitis. Subjects were male enrollees in the Kaiser Permanente Northwest, Portland, Oregon health maintenance organization. MATERIALS AND METHODS: A computer search of the Kaiser Permanente Northwest administrative database was performed for May 1, 1998 to April 30, 2004 to identify men with a coded diagnosis of prostatitis. Prostatitis cases were each age matched with 3 controls and the medical diagnoses (using 3-digit International Classification of Diseases, 9th Revision codes) assigned to these 2 groups were compared. RESULTS: A prostatitis diagnosis was present in 4.5% of the male population. There were 37 diagnoses that were significantly more common in cases than in controls (p <0.0001). Most of them were other urological codes to describe prostatitis symptoms, unexplained physical symptoms in other organ systems and psychiatric diagnoses. The strongest observed associations were with benign prostatic hyperplasia (OR 2.7), functional digestive disorders (OR 2.6), dyspepsia (OR 2.1), anxiety disorders (OR 2.0), other soft tissue disorders (OR 2.0), esophageal reflux (OR 1.8) and mood disorders (OR 1.8). CONCLUSIONS: Prostatitis is a commonly diagnosed condition in the community setting, affecting approximately 1/22 men. The diagnosis is associated with multiple other unexplained physical symptoms and certain psychiatric conditions. Studies to explore possible biological explanations for these associations are needed. PMID- 17706723 TI - Vascular endothelial growth factor and nitric oxide in rat liver regeneration. AB - In this work we investigated the role of nitric oxide (NO) in the angiogenesis mediated by vascular endothelial growth factor (VEGF) during rat liver regeneration after two-thirds partial hepatectomy. Sham operated (Sh) and partially hepatectomized (PH) male Wistar rats were randomized in three experimental groups: control (treated with vehicle); pre-treated with sodium nitroprusside (SNP: 0.25 mg/kg body weight, i.v. at a rate of 1 ml/h) and pre treated with the preferential iNOS inhibitor, aminoguanidine (AG, 100 mg/kg body weight, i.p.). Animals were killed at 5, 24 and 72 h after surgery. At 5 h post surgery, NO production was estimated by EPR (Sh-Control: 37.65+/-10.70; PH Control: 88.13+/-1.60(); Sh-SNP: 90.35+/-3.11(); PH-SNP: 119.5+/-12.10()(#); Sh AG: 33.27+/-5.23, PH-AG: 36.80+/-3.40(#)) (p<0.05 vs Sh-Control; (#)p<0.05 vs PH Control). At 24 h after PH, VEGF levels showed no difference between PH-Control and PH-SNP animals. However, after 72 h, VEGF protein levels in PH-SNP animals were found to be increased (above 300%) with respect to PH-Control. On the other hand, aminoguanidine (AG) pre-treatment blocked the rise of inhibition of NO generation and decreased VEGF expression. Our results demonstrated that NO plays a role in modulating VEGF protein expression after hepatectomy in rats. PMID- 17706724 TI - Mechanism of ethanol enhancement of apoptosis and caspase activation in serum deprived PC12 cells. AB - Neuronal death is one of the most prominent consequences of alcohol exposure during development. Ethanol-induced neuronal death appears to involve apoptosis. The objective of the present study was to characterize the effect of ethanol on neuronal cell viability and to determine the mechanism by which ethanol enhances apoptosis in neural cells. For these studies the rat pheochromocytoma (PC12) cells were used. PC12 cells were incubated for 24 h in the presence or absence of 100 mM ethanol. Apoptosis was induced by serum withdrawal. Ethanol in the presence of serum-containing media did not alter cell viability, while incubation of PC12 cells in serum-free media resulted in a significant increase in cell death that was further significantly increased by 35% in cells exposed to ethanol. The temporal response of the PC12 cells to serum withdrawal was studied over a period of 22 h. At least 18 h of ethanol exposure was necessary to observe a significant increase in death for cells incubated in serum-free media. An increase in the caspase-3 activity in PC12 cells deprived of serum was observed that was further increased by ethanol exposure. This increase of caspase-3 activity was correlated with an enhancement of caspase-9 activity. Ethanol exposure increased the amount of cytosolic cytochrome c in PC12 cells incubated in serum-free media but did not alter the level of cytochrome c in cells incubated in serum. Finally, a 26% increase was observed in the number of cells with depolarized mitochondria due to ethanol treatment. The present study implicates an increase in the mitochondrial outer membrane permeability as a potential mechanism of enhancement of apoptosis in serum-deprived PC12 cells by ethanol. PMID- 17706725 TI - Indirect mechanism of histamine-induced nociception in temporomandibular joint of rats. AB - A considerable amount of evidence suggests that temporomandibular joint (TMJ) pain associated with temporomandibular disorder results, at least in part, from an inflammatory episode. Although histamine can cause pain, it is not clear whether this mediator induces nociception in the TMJ. In this study, we investigated the contribution of endogenous histamine to formalin-induced nociception in the TMJ of rats. We also investigated whether the administration of histamine induces nociception in the TMJ and, if so, whether this effect is mediated by an indirect action on primary afferent nociceptors. Local administration of the H1-receptor antagonist pyrilamine prevented formalin induced nociception in the TMJ in a dose-dependent manner. Local administration of histamine (250 microg) in the TMJ induced nociceptive behavior that was inhibited by co-administration of the lidocaine N-ethyl bromide quaternary salt QX-314 (2%) or the selective H1-receptor antagonist pyrilamine (400 microg). Nociception induced by histamine was also inhibited by pre-treatment with sodium cromoglycate (800 microg) and by co-administration of the 5-HT(3) receptor antagonist tropisetron (400 mug), while pyrilamine (400 mug) did not inhibit nociception induced by 5-hydroxytryptamine (5-HT, 250 microg) in the TMJ. Furthermore, histamine, in a dose that did not induce nociception by itself, strongly enhanced 5-HT-induced nociception. Finally, the administration of a sub threshold dose of 5-HT (100 microg), but not of histamine (100 microg), elicited nociception in the TMJ previously challenged with the inflammatory agent carrageenan (100 microg). In conclusion, these data suggest that histamine induces TMJ nociception by an indirect mechanism involving endogenous release of 5-HT and activation of 5-HT(3) receptors on sensory afferents. It is proposed that histamine activates the H1 receptor to induce the release of 5-HT which depolarizes the nociceptor by activating 5-HT(3) receptor. PMID- 17706726 TI - Dose response of angiogenesis to basic fibroblast growth factor in rat corneal pocket assay: I. Experimental characterizations. AB - Understanding mechanisms of formation of vascular networks under different experimental conditions is essential for improving treatment of angiogenesis dependent diseases. To this end, we investigated the dose response of angiogenesis to basic fibroblast growth factor (bFGF) using the rat corneal pocket assay. The response was quantified, in terms of (i) the migration distance of vascular networks, (ii) the total vessel length, (iii) the distribution of the projected width of vessels, (iv) the distribution of the number of vessels, and (v) the distribution of vessel diameters. The quantification was based on new image analysis methods developed in the study. It was observed that the migration distance and the total vessel length increased by 82% and 199%, respectively, when the dose of bFGF was increased from 5 ng to 50 ng. The number and the diameter of vessels increased with the dose of bFGF as well. However, the last two parameters at a given dose of bFGF were approximately independent of the location in the middle region between the pellet and the limbus. These results provided useful information for understanding mechanisms of angiogenesis induced by bFGF and important data for validating a mathematical model of angiogenesis described in the second part of the study. PMID- 17706727 TI - Protection of halogenated DNA from strand breakage and sister-chromatid exchange induced by the topoisomerase I inhibitor camptothecin. AB - The fundamental nuclear enzyme DNA topoisomerase I (topo I), cleaves the double stranded DNA molecule at preferred sequences within its recognition/binding sites. We have recently reported that when cells incorporate halogenated nucleosides analogues of thymidine into DNA, it interferes with normal chromosome segregation, as shown by an extraordinarily high yield of endoreduplication, and results in a protection against DNA breakage induced by the topo II poison m-AMSA [F. Cortes, N. Pastor, S. Mateos, I. Dominguez, The nature of DNA plays a role in chromosome segregation: endoreduplication in halogen-substituted chromosomes, DNA Repair 2 (2003) 719-726; G. Cantero, S. Mateos, N. Pastor; F. Cortes, Halogen substitution of DNA protects from poisoning of topoisomerase II that results in DNA double-strand breaks (DSBs), DNA Repair 5 (2006) 667-674]. In the present investigation, we have assessed whether the presence of halogenated nucleosides in DNA diminishes the frequency of interaction of topo I with DNA and thus the frequency with which the stabilisation of cleavage complexes by the topo I poison camptothecin (CPT) takes place, in such a way that it protects from chromosome breakage and sister-chromatid exchange. This protective effect is shown to parallel a loss in halogen-substituted cells of the otherwise CPT-increased catalytic activity bound to DNA. PMID- 17706728 TI - [Intracranial hypertension in Proteus syndrome]. AB - Proteus syndrome, described for the first time in 1979, is a sporadic congenital poly-malformation syndrome named for its highly variable manifestations. We report the case of a 36-year-old male patient with several malformations including skull hyperostosis and huge frontal sinus hypertrophy compressing the brain. He complained of increasing headache for 5 years. Cerebrospinal fluid pressure monitoring revealed severe hypertension. The patient underwent frontoparietal craniectomy, which allowed partial decompression. Postoperatively headaches decreased and the intracranial pressure normalized. Proteus syndrome is a genetic disease with a mosaic pattern. Only a hundred cases have been reported, mostly in childhood. Common manifestations include disproportionate overgrowth of the limbs and the skull, various subcutaneous tumors, vascular, renal and pulmonary malformations. Brain abnormalities are not common in this syndrome. When present, retardation or seizure disorders are typically seen. Intracranial hypertension is described for the first time in this syndrome. PMID- 17706729 TI - [Intraventricular schwannoma: a case report]. AB - Ventricular schwannomas are very uncommon. We report such a tumor in the right lateral ventricle of a 16-year-old young man. The various etiopathogenic hypotheses are discussed. PMID- 17706730 TI - Calorie-restricted mice that gorge show less ability to compensate for reduced energy intake. AB - Caloric restriction in mice can trigger gorging behaviour, which is characterized by periods of excessive food ingestion in a short time. Animals that gorge are thought to have a reduced metabolism compared to those that nibble their food over a longer period and might therefore be more able to compensate for reduced energy intake. We examined whether mice that gorged showed less weigh loss during restriction. We placed female mice (n=60) on a restriction of 75% of their ad libitum food intake (FI) for 22 days. FI and body mass (BM) were measured at 1, 2 and 24 h after food provision. Ten controls remained feeding ad lib and we selected the 10 strongest gorgers and 10 strongest non-gorgers for comparison. Mice had BM, FI, resting metabolic rate (RMR), body composition, body temperature, daily energy expenditure (DEE) and circulating levels of the regulatory hormones leptin and ghrelin measured. Gorgers had a significantly lower BM at the end of restriction than non-gorgers or controls, indicating that they were less able to compensate for the reduced energy. Both groups of restricted mice had reduced RMR, however reduced activity was only used as an energy saving mechanism in non-gorgers. Gorging mice had a significantly lower level of circulating leptin than controls and non-gorgers but no differences in ghrelin levels. Gorging mice were, in fact, less able to compensate for reduced energy intake, as they reduced RMR by a similar extent as non-gorgers, but did not reduce activity compared to non-gorgers on the same restriction level. The reduced leptin levels may drive the gorging behaviour. PMID- 17706731 TI - Metabolon formation in dhurrin biosynthesis. AB - Synthesis of the tyrosine derived cyanogenic glucoside dhurrin in Sorghum bicolor is catalyzed by two multifunctional, membrane bound cytochromes P450, CYP79A1 and CYP71E1, and a soluble UDPG-glucosyltransferase, UGT85B1 (Tattersall, D.B., Bak, S., Jones, P.R., Olsen, C.E., Nielsen, J.K., Hansen, M.L., Hoj, P.B., Moller, B.L., 2001. Resistance to an herbivore through engineered cyanogenic glucoside synthesis. Science 293, 1826-1828). All three enzymes retained enzymatic activity when expressed as fluorescent fusion proteins in planta. Transgenic Arabidopsis thaliana plants that produced dhurrin were obtained by co-expression of CYP79A1/CYP71E1-CFP/UGT85B1-YFP and of CYP79A1/CYP71E1/UGT85B1-YFP but not by co expression of CYP79A1-YFP/CYP71E-CFP/UGT85B1. The lack of dhurrin formation upon co-expression of the two cytochromes P450 as fusion proteins indicated that tight interaction was necessary for efficient substrate channelling. Transient expression in S. bicolor epidermal cells as monitored by confocal laser scanning microscopy showed that UGT85B1-YFP accumulated in the cytoplasm in the absence of CYP79A1 or CYP71E1. In the presence of CYP79A1 and CYP71E1, the localization of UGT85B1 shifted towards the surface of the ER membrane in the periphery of biosynthetic active cells, demonstrating in planta dhurrin metabolon formation. PMID- 17706732 TI - Metabolite profiling of mycorrhizal roots of Medicago truncatula. AB - Metabolite profiling of soluble primary and secondary metabolites, as well as cell wall-bound phenolic compounds from roots of barrel medic (Medicago truncatula) was carried out by GC-MS, HPLC and LC-MS. These analyses revealed a number of metabolic characteristics over 56 days of symbiotic interaction with the arbuscular mycorrhizal (AM) fungus Glomus intraradices, when compared to the controls, i.e. nonmycorrhizal roots supplied with low and high amounts of phosphate. During the most active stages of overall root mycorrhization, elevated levels of certain amino acids (Glu, Asp, Asn) were observed accompanied by increases in amounts of some fatty acids (palmitic and oleic acids), indicating a mycorrhiza-specific activation of plastidial metabolism. In addition, some accumulating fungus-specific fatty acids (palmitvaccenic and vaccenic acids) were assigned that may be used as markers of fungal root colonization. Stimulation of the biosynthesis of some constitutive isoflavonoids (daidzein, ononin and malonylononin) occurred, however, only at late stages of root mycorrhization. Increase of the levels of saponins correlated AM-independently with plant growth. Only in AM roots was the accumulation of apocarotenoids (cyclohexenone and mycorradicin derivatives) observed. The structures of the unknown cyclohexenone derivatives were identified by spectroscopic methods as glucosides of blumenol C and 13-hydroxyblumenol C and their corresponding malonyl conjugates. During mycorrhization, the levels of typical cell wall-bound phenolics (e.g. 4 hydroxybenzaldehyde, vanillin, ferulic acid) did not change; however, high amounts of cell wall-bound tyrosol were exclusively detected in AM roots. Principal component analyses of nonpolar primary and secondary metabolites clearly separated AM roots from those of the controls, which was confirmed by an hierarchical cluster analysis. Circular networks of primary nonpolar metabolites showed stronger and more frequent correlations between metabolites in the mycorrhizal roots. The same trend, but to a lesser extent, was observed in nonmycorrhizal roots supplied with high amounts of phosphate. These results indicate a tighter control of primary metabolism in AM roots compared to control plants. Network correlation analyses revealed distinct clusters of amino acids and sugars/aliphatic acids with strong metabolic correlations among one another in all plants analyzed; however, mycorrhizal symbiosis reduced the cluster separation and enlarged the sugar cluster size. The amino acid clusters represent groups of metabolites with strong correlations among one another (cliques) that are differently composed in mycorrhizal and nonmycorrhizal roots. In conclusion, the present work shows for the first time that there are clear differences in development- and symbiosis-dependent primary and secondary metabolism of M. truncatula roots. PMID- 17706733 TI - Insights into the role and structure of plant ureases. AB - The broad distribution of ureases in leguminous seeds, as well as the accumulation pattern of the protein during seed maturation, are suggestive of an important physiological role for this enzyme. Since the isolation and characterization of jack bean urease by Sumner in 1926, many investigations have been dedicated to the structural and biological features of this enzyme; nevertheless, many questions still remain. It has been reported that ureases from plants (jack bean and soybean seeds) display biological properties unrelated to their ureolytic activity, notably a high insecticidal activity against Coleoptera (beetles) and Hemiptera (bugs), suggesting that ureases might be involved in plant defense. Besides the insecticidal activity, canatoxin, a jack bean urease isoform, causes convulsions and death in mice and rats, induces indirect hemagglutination (hemilectin activity) and promotes exocytosis in several cell types. Not only plant ureases but also some microbial ureases (found in Bacillus pasteurii and Helicobacter pylori) are able to induce activation of platelets in a process mediated by lipoxygenase-derived metabolites. This review summarizes the biological and structural properties of plant ureases, compares them with those displayed by bacterial ureases, and discusses the significance of these findings. PMID- 17706734 TI - Nucleomorphometric analysis of feline basal cell carcinomas. AB - Twenty-four feline spontaneous basal cell carcinomas (BCCs) were analyzed by computerized nuclear morphometry. The study included 15 non-recurrent and 9 recurrent tumours. In each case, the nuclei of at least 100 neoplastic cells were measured, and the mean nuclear area (MNA), mean nuclear perimeter (MNP) and mean nuclear diameter (MND) were calculated. The analysis of data of the non-recurrent BCCs and the recurrent tumours revealed statistically significant differences between those groups (p<0.001) as well as between infiltrative and clear types of BCCs (p<0.05). The results indicate that nuclear morphometry is able to predict recurrent tumour growth and helps to differentiate histological subtypes of BCCs in cats. PMID- 17706735 TI - Brief embryonic cadmium exposure induces a stress response and cell death in the developing olfactory system followed by long-term olfactory deficits in juvenile zebrafish. AB - The toxic effects of cadmium and other metals have been well established. A primary target of these metals is known to be the olfactory system, and fish exposed to a number of different waterborne metals display deficiencies in olfaction. Importantly, exposure over embryonic/larval development periods can cause deficits in chemosensory function in juvenile fish, but the specific cell types affected are unknown. We have previously characterized a transgenic zebrafish strain expressing the green fluorescent protein (eGFP) gene linked to the hsp70 gene promoter, and shown it to be a useful tool for examining cell specific toxicity in living embryos and larvae. Here we show that the hsp70/eGFP transgene is strongly and specifically upregulated within the olfactory sensory neurons (OSNs) of transgenic zebrafish larvae following a brief 3-h exposure to water-borne cadmium. This molecular response was closely correlated to an endpoint for tissue damage within the olfactory placode, namely cell death. Furthermore, cadmium-induced olfactory cytotoxicity in zebrafish larvae gives rise to more permanent effects. Juvenile zebrafish briefly exposed to cadmium during early larval development display deficits in olfactory-dependent predator avoidance behaviors 4-6 weeks after a return to clean water. Lateral line neuromasts of exposed zebrafish larvae also activate both the endogenous hsp70 gene and the hsp70/eGFP transgene. The data reveal that even a very brief exposure period that gives rise to cell death within the developing olfactory placode results in long-term deficits in olfaction, and that hsp70/eGFP may serve as an effective indicator of sublethal cadmium exposure in sensory cells. PMID- 17706736 TI - Effect of short-term stainless steel welding fume inhalation exposure on lung inflammation, injury, and defense responses in rats. AB - Many welders have experienced bronchitis, metal fume fever, lung function changes, and an increase in the incidence of lung infection. Questions remain regarding the possible mechanisms associated with the potential pulmonary effects of welding fume exposure. The objective was to assess the early effects of stainless steel (SS) welding fume inhalation on lung injury, inflammation, and defense responses. Male Sprague-Dawley rats were exposed to gas metal arc-SS welding fume at a concentration of 15 or 40 mg/m(3) x 3 h/day for 1, 3, or 10 days. The control group was exposed to filtered air. To assess lung defense responses, some animals were intratracheally inoculated with 5x10(4) Listeria monocytogenes 1 day after the last exposure. Welding particles were collected during exposure, and elemental composition and particle size were determined. At 1, 4, 6, 11, 14, and 30 days after the final exposure, parameters of lung injury (lactate dehydrogenase and albumin) and inflammation (PMN influx) were measured in the bronchoalveolar lavage fluid. In addition, particle-induced effects on pulmonary clearance of bacteria and macrophage function were assessed. SS particles were composed of Fe, Cr, Mn, and Ni. Particle size distribution analysis indicated the mass median aerodynamic diameter of the generated fume to be 0.255 microm. Parameters of lung injury were significantly elevated at all time points post-exposure compared to controls except for 30 days. Interestingly, no significant difference in lung PMNs was observed between the SS and control groups at 1, 4, and 6 days post-exposure. After 6 days post-exposure, a dramatic increase in lung PMNs was observed in the SS group compared to air controls. Lung bacteria clearance and macrophage function were reduced and immune and inflammatory cytokines were altered in the SS group. In summary, short-term exposure of rats to SS welding fume caused significant lung damage and suppressed lung defense responses to bacterial infection, but had a delayed effect on pulmonary inflammation. Additional chronic inhalation studies are needed to further examine the lung effects associated with SS welding fume exposure. PMID- 17706737 TI - Spatial and temporal patterns of alkaloid variation in the poison frog Oophaga pumilio in Costa Rica and Panama over 30 years. AB - A total of 232 alkaloids, representing 21 structural classes were detected in skin extracts from the dendrobatid poison frog Oophaga pumilio, collected from 53 different populations from over 30 years of research. The highly toxic pumiliotoxins and allopumiliotoxins, along with 5,8-disubstitiuted and 5,6,8 trisubstituted indolizidines, all of which are proposed to be of dietary mite origin, were common constituents in most extracts. One decahydroquinoline (DHQ), previously shown be of ant origin, occurred in many extracts often as a major alkaloid, while other DHQs occurred rather infrequently. Histrionicotoxins, thought to be of ant origin, did not appear to possess a specific pattern of occurrence among the populations, but when present, were usually found as major components. Certain 3,5-disubstituted pyrrolizidines and indolizidines, known to be of ant origin, did occur in extracts, but infrequently. Alkaloid composition differed with regard to geographic location of frog populations, and for populations that were sampled two or more times during the 30-year period significant changes in alkaloid profiles sometimes occurred. The results of this study indicate that chemical defense in a dendrobatid poison frog is dependent on geographic location and habitat type, which presumably controls the abundance and nature of alkaloid-containing arthropods. PMID- 17706739 TI - Stir bar sorptive extraction and trace analysis of selected endocrine disruptors in water, biosolids and sludge samples by thermal desorption with gas chromatography-mass spectrometry. AB - Stir bar sorptive extraction (SBSE) in combination with thermal desorption coupled to gas chromatography-mass spectrometry (GC-MS) was successfully applied to analyze a range of endocrine disrupting compounds (EDCs) in wastewater, solids and sludge. The targeted EDCs include sex steroid hormones, phthalates, alkylphenols and tamoxifen. Recovery for the EDCs using this analytical technique ranged from 44% to 128%. Limit of detection (LOD) of the compounds was 2.0 ng/L for water samples and 0.02 ng/g for solid samples, whereas the limit of quantitation (LOQ) was 5.0 ng/L for water samples and 0.06 ng/g for solid samples. When this analytical technique was applied to measure EDC concentration in a biological nutrient removal (BNR) wastewater treatment plant located in South East Queensland, Australia, the results showed that there were high amounts of phthalates, alkylphenols and female hormones present in the raw influent wastewater and solids. These concentrations were dramatically reduced after passing through the various treatment zones of the bioreactor (anaerobic, aerobic and anoxic). PMID- 17706738 TI - The vergence eye movements induced by radial optic flow: some fundamental properties of the underlying local-motion detectors. AB - Radial optic flow applied to large random dot patterns is known to elicit horizontal vergence eye movements at short latency, expansion causing convergence and contraction causing divergence: the Radial Flow Vergence Response (RFVR). We elicited RFVRs in human subjects by applying radial motion to concentric circular patterns whose radial luminance modulation was that of a square wave lacking the fundamental: the missing fundamental (mf) stimulus. The radial motion consisted of successive 1/4-wavelength steps, so that the overall pattern and the 4n+1 harmonics (where n=integer) underwent radial expansion (or contraction), whereas the 4n-1 harmonics--including the strongest Fourier component (the 3rd harmonic)- underwent the opposite radial motion. Radial motion commenced only after the subject had fixated the center of the pattern. The initial RFVRs were always in the direction of the 3rd harmonic, e.g., expansion of the mf pattern causing divergence. Thus, the earliest RFVRs were strongly dependent on the motion of the major Fourier component, consistent with early spatio-temporal filtering prior to motion detection, as in the well-known energy model of motion analysis. If the radial mf stimulus was reduced to just two competing harmonics--the 3rd and 5th- the initial RFVRs showed a nonlinear dependence on their relative contrasts: when the two harmonics differed in contrast by more than about an octave then the one with the higher contrast completely dominated the RFVRs and the one with lower contrast lost its influence: winner-take-all. We suggest that these nonlinear interactions result from mutual inhibition between the mechanisms sensing the motion of the different competing harmonics. If single radial-flow steps were used, a brief inter-stimulus interval resulted in reversed RFVRs, consistent with the idea that the motion detectors mediating these responses receive a visual input whose temporal impulse response function is strongly biphasic. Lastly, all of these characteristics of the RFVR, which we attribute to the early cortical processing of visual motion, are known to be shared by the Ocular Following Response (OFR)--a conjugate tracking (version) response elicited at short-latency by linear motion-and even the quantitative details are generally very similar. Thus, although the RFVR and OFR respond to very different patterns of global motion-radial vs. linear-they have very similar local spatiotemporal properties as though mediated by the same low-level, local-motion detectors, which we suggest are in the striate cortex. PMID- 17706740 TI - Quantifying variability within water samples: the need for adequate subsampling. AB - Accurate and precise determination of the concentration of nutrients and other substances in waterbodies is an essential requirement for supporting effective management and legislation. Owing primarily to logistic and financial constraints, however, national and regional agencies responsible for monitoring surface waters tend to quantify chemical indicators of water quality using a single sample from each waterbody, thus largely ignoring spatial variability. We show here that total sample variability, which comprises both analytical variability and within-sample heterogeneity, of a number of important chemical indicators of water quality (chlorophyll a, total phosphorus, total nitrogen, soluble molybdate-reactive phosphorus and dissolved inorganic nitrogen) varies significantly both over time and among determinands, and can be extremely high. Within-sample heterogeneity, whose mean contribution to total sample variability ranged between 62% and 100%, was significantly higher in samples taken from rivers compared with those from lakes, and was shown to be reduced by filtration. Our results show clearly that neither a single sample, nor even two sub-samples from that sample is adequate for the reliable, and statistically robust, detection of changes in the quality of surface waters. We recommend strongly that, in situations where it is practicable to take only a single sample from a waterbody, a minimum of three sub-samples are analysed from that sample for robust quantification of both the concentrations of determinands and total sample variability. PMID- 17706741 TI - Special issue: membranes. PMID- 17706742 TI - Eudismic analysis of tricyclic sesquiterpenoid alcohols: lead structures for the design of potent inhibitors of the human UDP-glucuronosyltransferase 2B7. AB - The epimeric tricyclic sesquiterpenoid alcohols globulol, epiglobulol, cedrol, epicedrol, longifolol, and isolongifolol were investigated in their ability to inhibit the recombinant human UDP-glucuronosyltransferase (UGT) 2B7. The stereoisomers displayed rapidly reversible competitive inhibition, which was substrate-independent. Longifolol and its stereoisomer isolongifolol displayed the lowest competitive inhibition constants (K(ic)) of 23 and 26 nM, respectively. The K(ic) values of cedrol and its epimer epicedrol were 0.15 and 0.21 microM, those of globulol and epiglobulol were 5.4 and 4.0 microM, respectively. The diastereomeric alcohols exhibited nearly identical affinities toward UGT2B7 indicating that the spatial arrangement of the hydroxy group had no influence on the dissociation of the enzyme-terpenoid complex. The high affinities stemmed presumably from mere hydrophobic interactions between the hydrocarbon scaffold of the terpenoid alcohol and the binding site of the enzyme. Glucuronidation assays revealed that there were large differences in the rates at which the epimeric alcohols were conjugated. Therefore, the spatial arrangement of the hydroxy group controlled the rate of the UGT2B7-catalyzed reaction. The introduction of a methyl group into the side chain of isolongifolol and longifolol increased the steric hindrance. As a result, the rate of the UGT2B7 catalyzed reaction was decreased by more than 88%. The findings indicated that the rate of the UGT2B7-catalyzed glucuronidation is significantly controlled by stereochemical and steric factors. Considering the high inhibition levels exerted by the tricyclic sesquiterpenoid alcohols, these compounds might serve as valuable lead structures for the design of potent inhibitors for UGT2B7. PMID- 17706743 TI - Emissions from simulated deep-seated fires in domestic waste. AB - The emissions from deep-seated fires in domestic waste have been investigated. The gas phase yields of PAH, PCDD/F, PCB, HCB, particles, and metals associated to the particulate matter were analysed during a series of simulated deep-seated fires. The method of extinguishment was varied and in cases where water was used for extinguishment, the runoff water was analysed for PAH, PCDD/F, PCB, hexachlorobenzene, and metals. In total six tests were performed. In four of the tests, samples of the fire residue were analysed for PCDD/F, PCBs, and chlorobenzenes. PMID- 17706744 TI - PCDD/PCDF reduction by the co-combustion process. AB - A novel process, termed the co-combustion process, has been developed and designed to utilise the thermal treatment of municipal solid waste (MSW) in cement clinker production and reduce PCDD/PCDF emissions. To test the conceptual design; detailed engineering design of the process and equipment was performed and a pilot plant was constructed to treat up to 40 tonnes MSW per day. The novel process features included several units external to the main traditional cement rotary kiln: an external calcinations unit in which the hot gas calcined the limestone thus making significant energy savings for this chemical reaction; the lime generated was used in a second chamber to act as a giant acid gas scrubber to remove SOx and particularly HCl (a source of chloride); an external rotary kiln and secondary combustion unit capable of producing a hot gas at 1200 degrees C; a gas cooler to simulate a boiler turbogenerator set for electricity generation; the incorporation of some of the bottom ash, calcined lime and dust collector solids into the cement clinker. A PCDD/PCDF inventory has been completed for the entire process and measured PCDD/PCDF emissions were 0.001 ng I TEQ/Nm(3) on average which is 1% of the best practical means [Hong Kong Environmental Protection Department, 2001. A guidance note on the best practicable means for incinerators (municipal waste incineration), BPM12/1] MSW incineration emission limit values. PMID- 17706745 TI - Digestive cell turnover in digestive gland epithelium of slugs experimentally exposed to a mixture of cadmium and kerosene. AB - Slugs, Arion ater (L), have been proposed as sentinel organisms to assess soil health. In slugs under the influence of pollutants, digestive cell loss and the concomitant increase of excretory cells of the digestive gland have been described. The aim of the present work was to determine up to what extent digestive cell loss affects biomarkers and whether the affectation is reversible after exposure to a mixture of metal and organic pollutants. Slugs were dosed with a mixture of cadmium and kerosene in the food for 27 days. Apart from chemical analyses, the volume density of black silver deposits (Vv(BSD)) after autometallography, and acyl-CoA oxidase (AOX) activity were used as biomarkers of exposure to metals and organic compounds, respectively. As effect biomarkers, changes in the volume density of the cell types that constitute the digestive gland epithelium were calculated. Proliferating cells were identified by means of bromodeoxyuridine (BrdU) immunohistochemistry. Results revealed that the mixture of pollutants provoked an increase in Vv(BSD) and AOX activity and a decrease in the number of digestive cells. These changes had no effect in the digestive gland accumulation capacity or in the effect and exposure biomarkers employed. BrdU labelling showed that exposure to pollutants provoked an enhanced digestive cell proliferation. PMID- 17706746 TI - Metabolism of chlorinated biphenyls: use of 3,3'- and 3,5-dichlorobiphenyl as sole sources of carbon by natural species of Ralstonia and Pseudomonas. AB - Ralstonia sp. SA-3, Ralstonia sp. SA-4 and Pseudomonas sp. SA-6 are natural strains with a novel capacity to utilize meta-substituted dichlorobiphenyls (diCBs) hitherto not known to serve as a sole source of carbon and energy for polychlorobiphenyl-degraders. In growth experiments, axenic cultures of isolates grew logarithmically on 3,3'-diCB with generation times that ranged insignificantly (t-test, P>0.05) from 30.4 to 33.8 h. Both 3-chlorobenzoate (3 CBA) and chloride produced as metabolites were recovered in non-stoichiometric quantities. The release of chloride by the cultures lagged substantially, indicating that the initial dioxygenase attack preceded cleavage of carbon chloride bonds and that chloride must have been released from the chlorinated hydroxypentadienoate. In the case of 3,5-diCB, SA-3 and SA-6 metabolised this substrate primarily to 3,5-CBA. The lack of chloride in the culture media coupled with stoichiometric recovery of 3,5-CBA suggests that growth by these strains occurred predominantly at the expense of the unsubstituted phenyl ring. The unique metabolic properties of these three aerobic isolates point to their potential usefulness as seeds for bioremediation of PCBs polluted environments without the need for repeated inoculation or supplementation by a primary growth substrate such as biphenyl. PMID- 17706747 TI - Surfactant enhanced electrokinetic remediation of DDT from soils. AB - Electrokinetic remediation has been investigated extensively as one of the noble technologies in remediation of metal contaminated soils. However, its applications in remediation of organic contaminants have been limited due to low solubilities of organics in water. In addition, most organic contaminants are non ionic and therefore, they are not mobile under electrical field. The use of surfactants may increase the remediation efficiency by increasing the solubility of organics. Significant fraction of organics associated with soil, can be transferred to micellar phase, which then can be transported toward either cathode or anode, depending on the ionic group of surfactants. In this study, the removal of hydrophobic organic contaminants from a soil using electrokinetic method was investigated in the presence of surfactants. A nonionic surfactant, Tween 80, and an anionic surfactant, SDBS, were used in the experiments. DDT was chosen as the model organic contaminant. Phase distribution studies and column experiments were conducted. It was found that both Tween 80 and SDBS had similar solubilization potentials for DDT. It was also shown that the aqueous DDT mass could reach from 0.01 to 13% of the total mass in the presence of 7500 mg/L of SDBS. No significant movement of DDT was observed when Tween 80 was used in the column experiments. This was attributed to low rates of electroosmotic flows and strong interaction of Tween 80 with the soil. The amount of surfactant was not enough to mobilize DDT significantly in the column studies. On the other hand, electrokinetic transport with SDBS yielded much better results. DDT transport toward the anode within the negatively charged micelles overcame the opposite electrosmotic flow. This was attributed to the lower degree of interaction between the soil and SDBS, and the electrokinetic transport of negatively charged micelles. PMID- 17706748 TI - Urokinase-type plasminogen activator and metalloproteinase-2 are independently related to the carotid atherosclerosis in haemodialysis patients. AB - INTRODUCTION: Matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs) system, and fibrinolytic system, have been implicated as important factors in atherosclerosis and vascular remodeling. However, no data are yet available on the associations between these two systems in relation to carotid atherosclerosis in hemodialysis (HD) patients. MATERIAL AND METHODS: We compared plasma levels of MMP-2, MMP-9, TIMP-1, TIMP-2; the parameters of fibrinolytic system: tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPAR) and its soluble receptor (suPAR), plasminogen activator inhibitor-1 (PAI-1), plasmin alpha2-antiplasmin (PAP) complexes; high sensitivity C-reactive protein (hs CRP) as a marker of inflammation and a surrogate of atherosclerotic disease-intima media thickness (IMT) in HD patients and in healthy controls. RESULTS: The values of the uPA, suPAR, PAP, MMP-2, TIMPs, hs CRP and IMT in the patients significantly exceeded those in controls. The concentrations of MMP-9, tPA and PAI-1 were similar in both investigated groups. uPA, uPAR and PAP were positively associated with MMP-2/TIMPs system; all mentioned above parameters (except TIMP 2) and hsCRP were associated with IMT. Multivariate analysis showed that uPA, MMP 2 and age were the strong independent variables linked to IMT values in HD patients. CONCLUSIONS: The patients on haemodialysis treatment have evidence of disordered fibrinolysis/proteolysis balance in the plasma, independently associated with IMT on multivariate analysis. These data suggest the importance of uPA and MMP-2 levels in the developing of atherosclerosis in these patients. PMID- 17706749 TI - Computer-assisted analysis of cell proliferation markers in oral lesions. AB - Abnormalities in any component of the cell cycle regulatory machine may result in oral cancer, and markers of cell proliferation have been used to determine the prognosis of tumor progression. The aim of this study was to determine whether silver-stained nucleolar organizer region (AgNOR) and Ki-67 measurements could improve the assessment of growth rates in oral lesions. Eighty-three oral biopsies were studied, 20 of which were classified as fibrous inflammatory hyperplasia (FIH), 40 as leukoplakia (LKP) and 23 as oral squamous cell carcinoma (OSCC). Within the LKP group, 22 out of 29 biopsies were diagnosed as non dysplastic leukoplakia (LK) and 18 as dysplastic leukoplakia (DLK), presenting discrete, moderate and severe dysplasia. Ki-67 immunolabeling of the lesions increased steadily in the following order: FIH, DLK, LK and OSCC, indicating that Ki-67 is a good marker for predicting the proliferative fraction among benign, premalignant and malignant oral lesions. The median values of AgNOR parameters indicate that the morphometric index gives better results regarding the proliferative rate than the numerical one. A series of linear regressions between AgNOR parameters and Ki-67 showed positive associations. We conclude that a combination of Ki-67 and morphometric AgNOR analyses could be used as an aid in the determination of the proliferative status of oral epithelial cells in oral cancer. PMID- 17706750 TI - Immunolocalization of protein C inhibitor in differentiation of human epidermal keratinocytes. AB - Keratinocytes propagated in low calcium (0.05 mM) serum-free medium grow as monolayers and exhibit morphological and biosynthetic phenotypes similar to the keratinocytes of the basal layer in normal epidermis. When the calcium in the medium is increased to 1.5 mM, the keratinocytes start to stratify and differentiate. Such differentiation is important in the formation of an epidermal barrier. Proteolysis plays a crucial role in the process. The functions of most of the plasminogen activator cascade components in human skin have been studied, but little was known about the expression and role of protein C inhibitor in the differentiation of human epidermal keratinocytes. In the present study, we used immunohistochemistry and immunocytochemistry to examine the immunolocalization of protein C inhibitor in normal human skin and in cultured keratinocytes in serum free medium with low and high calcium, respectively. The results indicated that protein C inhibitor is mainly localized in superficial and more differentiated keratinocytes in normal human epidermis. Keratinocytes positive for protein C inhibitor were detected in cultures containing both low and high calcium media, and the level of protein C inhibitor was increased in high calcium medium. This increase was accompanied by an altered intracellular distribution, from the perinuclear cytoplasm in undifferentiated keratinocytes to the whole cytoplasm in differentiated keratinocytes. Further study revealed that protein C inhibitor was incorporated into the cornified envelope in normal skin keratinocytes and cultured differentiated keratinocytes. Our results suggest that protein C inhibitor may be involved in the differentiation of keratinocytes. PMID- 17706751 TI - Immunohistochemical localization of parvalbumin calcium-binding protein in the heart tissues of various species. AB - Parvalbumin (PV), a cytoplasmic high-affinity Ca(2+)-binding protein, was recently identified in rat heart tissue and has been implicated in mediating relaxation in cardiac myocytes. The presence of PV in the heart of mouse, chicken, rabbit and pig was studied using immunohistochemistry. PV immunoreactivity (PV-ir) was identified in the heart of all four species. All cardiac myocytes of each species had an identical pattern of PV-ir in their cytoplasm. The highest intensity of PV-ir was observed in mouse and chicken cardiac myocytes. The intensity of PV-ir was lower in rabbit cardiac myocytes and lowest in pig cardiac myocytes compared to those of chicken and mouse. PV-ir was observed in the walls of all four cardiac chambers (left and right atria and left and right ventricles), with the left ventricle, in general, having the highest labeling intensity. The intensity of PV-ir may be correlated with the physical activity of the heart of each species. Some potential applications of these data for treatment of human diastolic heart dysfunctions are discussed. PMID- 17706752 TI - Lectin binding and effects in culture on human cancer and non-cancer cell lines: examination of issues of interest in drug design strategies. AB - By using a non-cancer and a cancer cell line originally from the same tissue (colon), coupled with testing lectins for cell binding and for their effects on these cell lines in culture, this study describes a simple multi-parameter approach that has revealed some interesting results that could be useful in drug development strategies. Two human cell lines, CCL-220/Colo320DM (human colon cancer cells, tumorigenic in nude mice) and CRL-1459/CCD-18Co (non-malignant human colon cells) were tested for their ability to bind to agarose microbeads derivatized with two lectins, peanut agglutinin (Arachis hypogaea agglutinin, PNA) and Dolichos biflorus agglutinin (DBA), and the effects of these lectins were assessed in culture using the MTT assay. Both cell lines bound to DBA derivatized microbeads, and binding was inhibited by N-acetyl-D-galactosamine, but not by L-fucose. Neither cell line bound to PNA-derivatized microbeads. Despite the lack of lectin binding using the rapid microbead method, PNA was mitogenic in culture at some time points and its mitogenic effect displayed a reverse-dose response. This was also seen with effects of DBA on cells in culture. While this is a simple study, the results were statistically highly significant and suggest that: (1) agents may not need to bind strongly to cells to exert biological effects, (2) cell line pairs derived from diseased and non diseased tissue can provide useful comparative data on potential drug effects and (3) very low concentrations of potential drugs might be initially tested experimentally because reverse-dose responses should be considered. PMID- 17706753 TI - Comparative morphological studies of the neurocranium and the gills of two species of blennies living in different habitats. AB - Two species of Blennies--Salaria fluviatilis, which lives in freshwaters, and Salaria pavo, which lives in the sea--are considered to be phylogenetically related. Due to the interesting feature of one species having a freshwater and one having a marine habitat, and because of the paucity of studies on the intraspecific and interspecific variability of skeletal characters, in the study reported here, several populations of S. fluviatilis and S. pavo were compared. The intraspecific and interspecific morphology of the cranial characteristics, as well as the branchial epithelium, was studied in relationship to the adaptation of the two species to different environments. Osteological results confirmed the intraspecific variability already found in S. fluviatilis and showed a notable interspecific differentiation between S. pavo and S. fluviatilis. Histological studies indicate that the two species have morphological differences, which are the result of the diversity of the environments in which they live. The results from the two approaches, taken together, are in agreement with the hypothesis of the origin of these two species being from a common marine ancestor. PMID- 17706754 TI - Bevacizumab plus cyclophosphamide in heavily pretreated patients with recurrent ovarian cancer. AB - OBJECTIVE: To investigate the efficacy and safety of bevacizumab in heavily pretreated patients with recurrent ovarian cancer. METHODS: Patients with recurrent ovarian cancer were treated with intravenous bevacizumab 10 mg/kg every other week plus oral cyclophosphamide 50 mg daily until disease progression or undue toxicity. Adverse events were graded according to the NCI Common Toxicity Criteria. Response rates were determined by CA-125 levels or changes in target lesions according to RECIST. RESULTS: Fifteen patients were treated. Median age was 57 years (range 42-69). The median number of previous chemotherapy regimens was 8 (range 5-15). The median time from the first diagnosis to treatment with bevacizumab was 68.9 months (range, 26.5-177.2). The median number of bevacizumab infusions was 8 (range, 2-12), and the total number was 113. Two patients (13.3%) had a complete response after 4 months of therapy. Six patients (40.0%) had a partial response. The median duration of this response was 3.9 months (range, 2.3 10.4). Three patients (20%) had stable disease of 4.0, 5.2 and 5.5 months' duration, and 4 patients (26.7%) had progressive disease. Despite being heavily pre-treated and having confirmed intra-abdominal cancer, no gastrointestinal perforations developed. Other toxicities included: grade 3 pancreatitis in 1 patient; grade 2 proteinuria and hypertension in another, which resolved with the cessation of bevacizumab. CONCLUSION: In our population of very heavily pre treated patients, with at least five prior regimens, bevacizumab in combination with oral cyclophosphamide has significant activity with a response rate of 53%, without significant toxicity. PMID- 17706755 TI - Comprehensive quality assessment of healthy school interventions. AB - OBJECTIVES: The number of healthy school interventions of unknown quality overwhelms schools. Quality is a construct that is differently interpreted by teachers and health promoters. The schoolBeat checklist for quality assessment of healthy school interventions incorporates the quality perceptions of both professional groups. To support quality improvements - and thus effectiveness - in school health promotion, this study evaluates the schoolBeat checklist. METHODS: Twenty-nine healthy school interventions were assessed in the Netherlands, each by two health promoters and two teachers-individually and at a consensus meeting. Generalizability coefficients were calculated for the nine specific quality criteria. RESULTS: The mean consensus score differs from the mean average individual score for two out of nine criteria. To obtain a threshold Generalizability coefficient of 0.70, the number of assessors required per criterion ranges from 1.6 to 10.8, with an average of 4.7. CONCLUSION: Quality assessment procedures of healthy school interventions using the schoolBeat checklist require about four experienced assessors from each professional domain to facilitate reliable quality scores based on individual assessment only. Publicly available quality scores enable the inclusion of high quality interventions in school policies in order to increase the impact of school health. PMID- 17706756 TI - No intention to comply with influenza and pneumococcal vaccination: behavioural determinants among smokers and non-smokers. AB - OBJECTIVE: Smoking increases the risk for influenza and pneumococcal disease, but vaccination uptake is lower among smokers than non-smokers. We therefore aimed to determine reasons for not complying with vaccination among smokers and non smokers. METHOD: In 2005 a self-administered questionnaire was sent to a random sample of Dutch patients (n=4,000) assessing medical, social and behavioural determinants. Independent factors associated with not complying with influenza and pneumococcal vaccination among smokers and non-smokers were assessed by multivariate logistic regression analysis. RESULTS: In all, 1,725 of 4,000 patients returned the questionnaire (response rate: 43%), 426 (25%) were smokers. Among smokers self-reported flu vaccine uptake was 42% and among non-smokers 52% among both only 0,2% received both vaccines. Most important predictors of not complying in smokers and non-smokers were patient's beliefs not to be susceptible to disease (odds ratio (OR) 4.0, 95% confidence interval (CI): 2.0, 8.0 and OR 2.8, CI: 2.0, 3.9), finding it difficult to go to the GP for vaccination (OR 2.5, CI: 1.3, 4.8 and OR 1.8, CI: 1.3, 2.6) and being against vaccination (OR 2.4 CI: 1.3, 4.4 and OR 1.8, CI: 1.3, 2.6), respectively. CONCLUSION: There are no substantial differences in determinants associated with not complying with influenza and pneumococcal vaccination between smokers and non-smokers but there is a trend towards stronger associations in smokers. PMID- 17706758 TI - In vitro developmental competence of buffalo oocytes collected at various stages of the estrous cycle. AB - The objective was to determine the in vitro developmental competence of buffalo oocytes collected from abattoir-derived ovaries at various stages of the estrous cycle and follicular status. In Experiment 1, ovaries (n=476 pairs) were collected and divided into the following five groups: (a) ovaries with a corpus hemorragicum and no dominant follicle (CH-NO-DF); (b) ovaries with a mature functional corpus luteum (CL) and a dominant follicle (CL-DF); (c) ovaries with a mature functional CL and no dominant follicle (CL-NO-DF); (d) ovaries with a regressing CL and a dominant follicle (RCL-DF); and (e) ovaries without any luteal structures and only small follicles (ANEST). In Experiment 2, 144 pairs of ovaries with a CL (or regressing CL) and a dominant follicle were collected and follicles were classified as dominant, largest subordinate, and subordinate. In both experiments, the dominant follicle was defined as any follicle >10mm in diameter that exceeded the diameter of all other (subordinate) follicles. Although oocytes were collected from each group of ovaries, only Grades A or B oocytes were used for in vitro embryo production. Cleavage rates were higher (P<0.05) from oocytes collected from ovaries in the CH-NO-DF (59.6%) and CL-NO-DF (59.2%) groups than those collected from CL-DF (52.2%) and ANEST (43.6%) groups. The yield of transferable embryos was higher (P<0.05) from oocytes collected from CH-NO-DF (27.4%) and CL-NO-DF (24.0%) ovaries than from CL-DF (16.2%), RCL-DF (15.4%), and lowest (P<0.05) from ANEST (8.8%). In Experiment 2, oocytes from the dominant follicle had a higher (P<0.05) cleavage rate (65.2 %) and transferable embryo yield (30.2%) than those collected from the largest subordinate and subordinate follicles. In conclusion, oocyte competence depended on the morphofunctional state of ovaries. Oocyte development was maximal in pairs of ovaries with a corpus hemorragicum or CL and no dominant follicle; in paired ovaries with a CL and a dominant follicle, development was maximal in oocytes derived from the dominant follicle. PMID- 17706757 TI - Comparison of ticarcillin and piperacillin in Kenney's semen extender. AB - Ticarcillin and piperacillin were compared to determine their effect on sperm motility and bacterial growth of equine semen samples diluted in Kenney's glucose skim milk semen extender. Each ejaculate (n=11) was divided into three portions and glucose skim milk semen extender solution was added. The control semen extender solution contained extended semen and no antibiotic, whereas ticarcillin and piperacillin solutions contained extended semen plus 1.0mg/mL of ticarcillin or piperacillin, respectively. An aliquot was removed (1h after collection) to evaluate sperm motility and microbial concentration. All three solutions were stored at 4 degrees C and aliquots were obtained at 24 and 48 h to determine sperm motility and microbial concentration. Mean percentages of motile and progressively motile sperm did not differ significantly among control and antibiotic-containing solutions after storage. Control-extended semen samples from ejaculates of stallions (n=11) were contaminated with aerobic gram-positive and gram-negative bacteria. In solutions that contained either antibiotic, growth of these microbes was inhibited after 1, 24, and 48 h at 4 degrees C. Semen samples from stallions (n=5) were extended with Kenney's glucose skim milk extender containing no antibiotic, ticarcillin or piperacillin and then inoculated with approximately 5 x 10(2)CFU/mL Klebsiella pneumoniae or Pseudomonas aeruginosa; there was no significant difference between antibiotics in the inhibition of microbial growth. In conclusion, piperacillin was an appropriate alternative to ticarcillin in extenders for equine semen. PMID- 17706759 TI - Metallurgical, surface, and corrosion analysis of Ni-Cr dental casting alloys before and after porcelain firing. AB - OBJECTIVES: A porcelain veneer is often fired on nickel-chromium casting alloys used in dental restorations for aesthetic purposes. The porcelain-fused-to-metal (PFM) process brings the temperature to over 950 degrees C and may change the alloy's corrosion properties. In this study, the metallurgical, surface, and corrosion properties of two Ni-Cr alloys were examined, before and after PFM firing. METHODS: Two types of alloy were tested-a high Cr, Mo alloy without Be and a low Cr, Mo alloy with Be. Before the PFM firing, specimens from both alloys were examined for their microstructures, hardness, electrochemical corrosion properties, surface composition, and metal ion release. After the PFM firing, the same specimens were again examined for the same properties. RESULTS: Neither of the alloys showed any differences in their electrochemical corrosion properties after the PFM firing. However, both alloys exhibited new phases in their microstructure and significant changes in hardness after firing. In addition, there was a slight increase in CrO(x) on the surface of the Be-free alloy and increased Mo-Ni was observed on the surface of both alloys via X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD). This might be one of the reasons why both alloys had increased Ni and Mo ion release after firing. SIGNIFICANCE: The PFM firing process changed the alloys' hardness, microstructure, and surface composition. No significant changes in the alloys' corrosion behavior were observed, however, the significant increase in metal ion release over a month may need to be further investigated for its clinical effects. PMID- 17706760 TI - Management of acute organophosphorus pesticide poisoning. AB - Organophosphorus pesticide self-poisoning is an important clinical problem in rural regions of the developing world, and kills an estimated 200,000 people every year. Unintentional poisoning kills far fewer people but is a problem in places where highly toxic organophosphorus pesticides are available. Medical management is difficult, with case fatality generally more than 15%. We describe the limited evidence that can guide therapy and the factors that should be considered when designing further clinical studies. 50 years after first use, we still do not know how the core treatments--atropine, oximes, and diazepam--should best be given. Important constraints in the collection of useful data have included the late recognition of great variability in activity and action of the individual pesticides, and the care needed cholinesterase assays for results to be comparable between studies. However, consensus suggests that early resuscitation with atropine, oxygen, respiratory support, and fluids is needed to improve oxygen delivery to tissues. The role of oximes is not completely clear; they might benefit only patients poisoned by specific pesticides or patients with moderate poisoning. Small studies suggest benefit from new treatments such as magnesium sulphate, but much larger trials are needed. Gastric lavage could have a role but should only be undertaken once the patient is stable. Randomised controlled trials are underway in rural Asia to assess the effectiveness of these therapies. However, some organophosphorus pesticides might prove very difficult to treat with current therapies, such that bans on particular pesticides could be the only method to substantially reduce the case fatality after poisoning. Improved medical management of organophosphorus poisoning should result in a reduction in worldwide deaths from suicide. PMID- 17706762 TI - Permanent, non-leaching antibacterial surface--2: how high density cationic surfaces kill bacterial cells. AB - Rational controlled synthesis of poly(quaternary ammonium) compounds has been used to prepare antimicrobial polymer brushes on inorganic surfaces. The systematic variation of several structural parameters of the polymeric brushes allowed us to elicit the minimum surface requirements and a probable mechanism of action for Escherichia coli cell kill. Polymeric brushes were prepared by surface initiated atom transfer radical polymerization of 2-(dimethylamino)ethyl methacrylate (DMAEMA), a method that allows the molecular weight of the polymer chains to be precisely controlled as they grow from the target surface. The tertiary amino groups of the polyDMAEMA were then quaternized with alkyl bromides to provide a surface with antimicrobial activity. Dry layer thickness of the polymer brushes was controlled by polymerization time and/or initiator density on the surface. This tunability of surface structure allows the antimicrobial polymer brushes to be tailored rationally. A combinatorial screening tool was developed to elucidate the role of chain length and chain density on cell kill in a single experiment. The results indicate that surface charge density, is a critical element in designing a surface for maximum kill efficiency. The most biocidal surfaces had charge densities of greater than 1-5 x 10(15) accessible quaternary amine units/cm(2). The relevance of this finding to the mechanism of action is discussed. PMID- 17706763 TI - Smart biomaterials design for tissue engineering and regenerative medicine. AB - As a prominent tool in regenerative medicine, tissue engineering (TE) has been an active field of scientific research for nearly three decades. Clinical application of TE technologies has been relatively restricted, however, owing in part to the limited number of biomaterials that are approved for human use. While many excellent biomaterials have been developed in recent years, their translation into clinical practice has been slow. As a consequence, many investigators still employ biodegradable polymers that were first approved for use in humans over 30 years ago. During normal development tissue morphogenesis is heavily influenced by the interaction of cells with the extracellular matrix (ECM). Yet simple polymers, while providing architectural support for neo-tissue development, do not adequately mimic the complex interactions between adult stem and progenitor cells and the ECM that promote functional tissue regeneration. Future advances in TE and regenerative medicine will depend on the development of "smart" biomaterials that actively participate in the formation of functional tissue. Clinical translation of these new classes of biomaterials will be supported by many of the same evaluation tools as those developed and described by Professor David F. Williams and colleagues over the past 30 years. PMID- 17706761 TI - The effect of hyaluronic acid size and concentration on branching morphogenesis and tubule differentiation in developing kidney culture systems: potential applications to engineering of renal tissues. AB - Hyaluronic acid (HA) is a glycosaminoglycan of tissue engineering importance that plays a vital role in mammalian development. In vitro kidney culture methods were utilized to investigate the importance of HA during renal organogenesis. We found that HA has the ability to simultaneously modulate ureteric bud (UB) branching, promote mesenchymal-to-epithelial transformation, and promote differentiation of both metanephric mesenchyme (MM) and the UB depending on the concentration and molecular weight (MW) of HA. Hyaluronidase inhibited branching morphogenesis in both isolated UB and whole kidney cultures, suggesting endogenous HA is required for branching morphogenesis. HA exhibited morphogen-like properties, stimulating branching morphogenesis at low concentrations (0.1%) and low MW (6.55 kDa), but inhibiting at high concentrations (3.75%) and high MW (234.4 kDa). Furthermore, HA of every MW tested promoted collecting duct differentiation as measured by AQP 2 expression. E-cadherin immunostaining and qPCR of nephron differentiation markers (OAT-1, NaP(i)-2, AQP-1, and THP) demonstrated that HA of a variety of MWs strongly promotes mesenchymal epithelialization and nephron differentiation in a concentration-dependent manner. Since the HA synthesis and degradation genes, has-2 and hyal-2, are highly expressed during kidney development, this data suggests that specific sizes and concentrations of HA may act to independently regulate UB branching and promote tubular maturation, representing a potential switch for ending branching morphogenesis, as well as initiating nephron differentiation. In addition, the ability of HA to promote in vitro embryonic kidney growth and maturation, together with the biocompatibility and crosslinking capability of HA, suggests a potential use of HA for both creating an instructive, 3D scaffold for in vitro kidney engineering from developmental tissues, as well as promoting tubule regeneration in injured or cryopreserved kidneys. PMID- 17706764 TI - Ultrasound effect on osteoblast precursor cells in trabecular calcium phosphate scaffolds. AB - This study investigated the in vitro effect of low-intensity pulsed ultrasound (LIPUS) on human embryonic palatal mesenchyme cells (HEPM, CRL-1486, ATCC, Manassas, VA), an osteoblast precursor cell line, during early adhesion to calcium phosphate scaffolds. Hydroxyapatite (HA) and beta-tricalcium phosphate (TCP) ceramic scaffolds were produced by a template coating method. Phospho specific antibody cell-based ELISA (PACE) technique was utilized on stress activation proteins, including the extracellular signal-regulated kinase (ERK1/2), P38, c-Jun N-terminal kinase (JNK) and the anti-apoptosis mediator protein kinase B (PKB/AKT). Cell-based ELISAs were also performed on the membrane anchoring protein vinculin and alpha6beta4 integrin. LIPUS stimulated activation of PERK 1/2, PJNK, PP38 and vinculin in traditional two-dimensional (2-D) culture. Calcium release from the scaffolds was partially involved in the activation of PERK 1/2 when cell response was compared between culture on 2-D surfaces and three-dimensional (3-D) HA and TCP scaffolds. Effects of calcium extracted media from scaffolds alone could not account for the full activation of PJNK, PP38, PAKT, vinculin and alpha6beta4 integrin. LIPUS stimulation further increased PERK activity on TCP scaffolds corresponding with an increase in both vinculin and alpha6beta4 integrin levels. It was concluded from this study that LIPUS treatment can significantly affect stress signaling mediators and adhesion proteins in osteoblast precursor cells during the early cell-attachment phase to trabecular patterned scaffolds. PMID- 17706765 TI - Growing a living blood vessel: insights for the second hundred years. AB - Cardiovascular disease continues to be the leading cause of death worldwide, and the prevalence of cardiovascular disease has reached epidemic proportions worldwide. Not surprisingly this has led to an increasing number of vascular procedures annually. Unfortunately, the success of these procedures over time continues to limit their long-term effects. Biomedical engineering approaches to improve upon current prosthetic grafts, developing new prosthetic grafts, and creating tissue engineered blood vessels for clinical application offer hope of improving the durability of vascular interventions and improving patients' treatment for cardiovascular disease. PMID- 17706766 TI - The lexicon of polyethylene wear in artificial joints. AB - The analysis of wear on polyethylene components that have been retrieved after use in patients has provided invaluable understanding of how wear occurs in vivo, and how it may be minimized through improved materials and implant design. The great number of such studies that have been published over the past three decades has lead to an extensive vocabulary to describe the tribology of prosthetic joints. However, these also have led to some confusion, due to the occasional misuse of terms from classical tribology, along with the use of multiple terms to describe the same wear phenomenon, and vice versa. The author has proposed that our understanding of wear in artificial joints may be enhanced by recognizing that there are four general subject areas: Modes, Mechanisms, Damage and Debris. Wear Mode 1 occurs when the two bearing surfaces are articulating against each other in the manner intended by the implant designer. Mode 2 occurs when a bearing surface articulates against a non-bearing surface. Mode 3 occurs when third-body abrasive particles have become entrapped between the two bearing surfaces, and Mode 4 occurs when two non-bearing surfaces are wearing against each other. The least wear occurs in Mode 1, whereas severe wear typically occurs in Modes 2, 3 and 4. The classical wear mechanisms that apply to prosthetic joints include adhesion, abrasion and fatigue. These can occur in varying amounts in either of the four wear modes. As used in the literature for the past three decades, wear "damage" can best be defined as the change surface texture or morphology that is caused by the action of the wear mechanisms. Although a wide variety of terms have been used, an overview of the literature indicates that about eight terms have been sufficient to describe the types of damage that occur on retrieved polyethylene components, i.e., burnishing, abrasion, scratches, plastic deformation, cracks, pits, delamination, and embedded third bodies. The author suggests that, as far as possible, investigators endeavor to limit their descriptions of surface damage to these terms and, importantly, to clearly and consistently distinguish the classical wear mechanisms from the types of damage produced by those mechanisms. Wear debris refers to the billions of particles, some measuring in nanometers, that are generated by the wear mechanisms, and that initiate biological reactions, such as osteolysis, that may lead to the failure of the implant. As the methods for recovering wear debris from joint fluids and tissues are improved, investigators are using a growing number of terms to describe them. As with the types of damage, it will be important in the coming years to maximize clarity and minimize redundancy of the vocabulary in this important area of research. PMID- 17706767 TI - In vivo biological evaluation of high molecular weight hyperbranched polyglycerols. AB - Hyperbranched polyglycerols (HPGs) are water-soluble polyether polyols that can be synthesized in a controlled manner with low polydispersity. Recently we reported the synthesis and characterization of very high molecular weight and narrowly polydispersed HPGs that could be used as potential alternatives to high generation dendrimers, their advantage being the relative simplicity of synthesis. Reported in this article are the pharmacokinetic properties of these polymers. Two polymers of number average molecular weights 106,000 and 540,000 were tested in mice for their pharmacokinetic behavior. The plasma half-life for the lower molecular weight polymer was around 32 h whereas that of the higher molecular weight HPG was approximately 57 h. Our results show that these high molecular weight HPGs, which can be prepared in a single step reaction, are potential candidates for drug delivery and imaging applications where a long circulating polymer is highly desirable. A detailed tissue distribution profile of these polymers as a function of molecular weight is described. These polymers were also found to be hydrolytically stable and the concentration dependence of solution viscosity measurements suggested the absence of any aggregation. PMID- 17706769 TI - Undersized, oversized? It is not one-size-fits-all in lymphoid clonality detection. AB - In clonality assessment in lymphoid malignancies expected size ranges of rearranged Ig/TCR PCR products are relevant and should be taken into account. Yet they should not be employed too strictly, as "undersized" and "oversized" products might still represent true rearrangement products. Now that Ig/TCR clonality testing has technically become relatively easy to perform in routine laboratories, correct interpretation becomes essential and preferably should be organized in close interaction between involved scientists. PMID- 17706768 TI - The TRPV3 mutation associated with the hairless phenotype in rodents is constitutively active. AB - TRPV3 is a non-selective cation channel activated by warm to hot temperatures. In rodents, TRPV3 is highly expressed in basal keratinocytes of skin and oral/nasal epithelia. TRPV3 knockout mice showed impaired responses to innocuous and noxious heat but otherwise normal appearance and reactions to many sensory modalities. However, point mutations of TRPV3 at Gly573 to Ser and Cys have recently been linked to autosomal dominant hairless phenotypes and spontaneous dermatitis in mice and rats, implicating an important role for TRPV3 in alopecia and skin diseases. Exactly, how the mutations affect TRPV3 function was unexplained. Here, we show that both G573S and G573C mutations of murine TRPV3 are constitutively active in heterologous systems. In HEK 293 cells, expression of the TRPV3 mutants causes cell death. In Xenopus oocytes, the constitutively active mutant channel is irresponsive to thermal and chemical stimuli but it reduces the temperature threshold and enhances the responses to heat and TRPV3 agonists of the wild type channel when they are co-expressed. We conclude that the G573S and G573C substitutions render the TRPV3 channel spontaneously active under normal physiological conditions, which in turn alters ion homeostasis and membrane potentials of skin keratinocytes, leading to hair loss and dermatitis-like skin diseases. PMID- 17706770 TI - Role of Myc in differentiation and apoptosis in HL60 cells after exposure to arsenic trioxide or all-trans retinoic acid. AB - Acute promyelocytic leukemia (APL) is highly malignant and frequently expresses the PML-RARalpha (promyelocytic leukemia-retinoic acid receptor-alpha) fusion protein. This fusion protein is targeted by all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3), presently used in APL therapy. We have evaluated effects of ATRA and As2O3 treatment in PML-RARalpha-negative HL60 promyelocytic leukemia cells, harboring amplified c-myc. Characterization of expression and activity of c-Myc and its target genes hTERT (human telomerase reverse transcriptase) and CAD (carbamoyltransferase-dihydroorotase) revealed marked down regulation in response to ATRA, but not As2O3. We suggest that blockage of terminal differentiation upon As2O3 treatment may be mediated through c-Myc. PMID- 17706771 TI - Anti-CD19 and anti-CD22 monoclonal antibodies increase the effectiveness of chemotherapy in Pre-B acute lymphoblastic leukemia cell lines. AB - The monoclonal antibodies (MAbs) HD37 and RFB4 bind to receptors on precursor B acute lymphoblastic leukemia (ALL) cells. These MAbs were tested alone and in combination with chemotherapy for their anti-leukemic activity. HD37 and not RFB4 increased the in vitro cytotoxicity of daunorubicin (DNR) and vincristine (VCR) in three Pre-B ALL cell lines. HD37 alone induced apoptosis in 30% of the cells versus 2% for RFB4. The treatment of SCID/ALL mice with either chemotherapy agent minimally prolonged their mean survival time (MST) versus controls but HD37 or RFB4 plus VCR significantly extended the MST. Forty percent of the mice treated with HD37 plus VCR survived. In conclusion, chemotherapy was made more effective when combined with HD37, and less so with RFB4. PMID- 17706773 TI - Molecular cloning and phylogenetic analysis on alpha2-macroglobulin (alpha2-M) of white shrimp Litopenaeus vannamei. AB - The full-length sequence of alpha2-macroglobulin (alpha2-M) was cloned from the hemocytes of white shrimp Litopenaeus vannamei by reverse transcription polymerase chain reaction (RT-PCR), cloning and sequencing of overlapping PCR, and the rapid amplification of cDNA ends method. The alpha2-M cDNA consists of 4682bp with an open reading frame of 4479bp, a 52-bp 5'-untranslated region, and a 132-bp 3'-untranslated region. The predicted molecular mass of the mature protein (1475 amino acids) is 167.1kDa, with an estimated pI of 5.70. The L. vannamei alpha2-M sequence contains putative functional domains including a bait region, a GCGEQNM (985-991) thiol ester domain, and a receptor-binding domain. Sequence comparison and phylogenetic analyses show that alpha2-M deduced amino acid sequence of L. vannamei has a high level of similarity to that of tiger shrimp Penaeus monodon and kuruma shrimp Marsupenaeus japonicus. The alpha2-M transcript was mainly expressed in hemocytes, and was significantly higher in premoult stage than in intermoult and postmoult stages. PMID- 17706772 TI - Non-specific antiviral response detected in RNA-treated cultured cells of the sandfly, Lutzomyia longipalpis. AB - Lutzomyia longipalpis is the principal vector of visceral leishmaniasis in the Americas, and can also transmit some viruses. To help develop a gene-silencing system for this sandfly, we transfected cultured embryonic cells with various double-stranded RNAs using West Nile virus (WNV) virus-like particles (VLPs) expressing luciferase as the target RNA to demonstrate effective gene knock-down. When luciferase dsRNA was introduced into these cells, they produced the expected reduction in VLP-encoded luciferase, suggesting specific silencing of the luciferase gene. Surprisingly, we found that unrelated dsRNAs, which included those specific for several L. longipalpis gene sequences and Escherichia coli beta-galactosidase, diminished replication of the VLP-encoded genome. These results are the first indication for a nucleic acid-induced, non-specific antiviral response in this important insect vector. PMID- 17706775 TI - Contagious bovine pleuropneumonia: a rationale for the development of a mucosal sub-unit vaccine. AB - Contagious bovine pleuropneumonia (CBPP) remains a major cattle disease in Africa with serious socio-economic consequences. Its eradication requires the development of improved vaccines. Knowledge on this disease and its causing agent, Mycoplasma mycoides subsp. mycoides biotype Small Colony (MmmSC), has been progressing significantly in the last years, opening new areas for vaccine design. Advances were achieved in the understanding of the protective immune responses to MmmSC infection and immunopathological mechanisms allowing the pathogen to escape the host immune response. Based on sequencing and genomic studies, some virulence factors and metabolic pathways were unraveled leading to the identification of potential MmmSC vaccine candidates. Based on these findings, this review presents a scientific strategy to design multi-component sub-unit vaccines for mucosal delivery as the most promising approach for efficient long-term protective vaccines to prevent CBPP. PMID- 17706774 TI - A Helix pomatia lectin binding protein on the extraembryonic membrane of the polyembryonic wasp Macrocentrus cingulum protects embryos from being encapsulated by hemocytes of host Ostrinia furnaclis. AB - The mechanism of how endoparasitoids avoid the host's cellular immune reaction is not well known. Evidence is presented here for the existence of a Helix pomatia lectin binding protein (HpLBP) on Macrocentrus cingulum extraembryonic membrane and its involvement in the protection of embryos against encapsulation by its host Ostrinia furnaclis. HpLBP is present in eggs, embryos and larvae and is located on the outmost layer of the extraembryonic membrane. While Sephadex A-25 beads and immature Macrocentrus eggs coated with follicular cells were encapsulated, Macrocentrus embryos were not after they were transplanted separately into naive O. furnaclis larvae. Moreover, embryos became encapsulated after being coated with anti-HpLBP serum. Furthermore, encapsulation of agarose H. pomatia lectin beads decreased significantly after the beads were coated with HpLBP. However, encapsulation of the HpLBP-coated agarose beads increased and the extent of encapsulation was enhanced significantly when the HpLBP-coated beads were pre-incubated with anti-HpLBP antibody. PMID- 17706776 TI - Biological characters of bats in relation to natural reservoir of emerging viruses. AB - Many investigators focused on bats (Chiroptera) for their specific character, i.e. echolocation system, phylogenic tree, food practice and unique reproduction. However, most of basic information about the vital functions related to anti viral activity has been unclear. For evaluating some animals as a natural reservoir or host of infectious pathogens, it is necessary that not only their immune system but also their biology, the environment of their living, food habits and physiological features should be clarified and they should be analyzed from these multi-view points. The majority of current studies on infectious diseases have been conducted for the elucidation of viral virulence using experimental animals or viral gene function in vitro, but in a few case, researchers focused on wild animal itself. In this paper, we described basic information about bats as follows; genetic background, character of the immunological factors, histological character of immune organs, the physiological function and sensitivity of bat cells to viral infection. PMID- 17706777 TI - Bovine viral diarrhea viruses modulate toll-like receptors, cytokines and co stimulatory molecules genes expression in bovine peripheral blood monocytes. AB - We have used noncytopathic (ncp) and cytopathic (cp) Bovine Viral Diarrhea Viruses (BVDV) to determine the expression levels of TLR genes, type I IFN, pro inflammatory and Th1/Th2 cytokine gene expression in bovine monocytes. In general, both BVDV strains had similar effects. However, we found some significant differences that could be due to biological differences between cp and ncp BVDV strains. TLR3 was significantly up-regulated in 1h ncp, but not in cp BVDV- infected monocytes, whereas TLR7 expression dominated in 24h infection with both BVDV strains. Type I IFN and IL-12 gene expression was also significantly up-regulated in 1h ncp, but not cp BVDV infection that correlated with the enhanced TLR3 gene expression. Both BVDV biotypes suppressed pro inflammatory cytokines TNF-alpha, IL-1beta, and IL-6, co-stimulatory molecules CD80 and CD86, but did not change Th1 type cytokine IL-12 and INF-gamma, gene expression after 24h infection. We hypothesize that BVDV may escape immune responses by altering the expression of TLR 3 and 7 and their signaling pathways. PMID- 17706778 TI - Vaccination against the feline immunodeficiency virus: the road not taken. AB - Natural infection of domestic cats by the feline immunodeficiency virus (FIV) causes acquired immunodeficiency syndrome (AIDS). FIV is genetically related to human immunodeficiency virus (HIV), and the clinical and biological features of infections caused by feline and human viruses in their respective hosts are highly analogous. Although the obstacles to vaccinating against FIV and HIV would seem to be of comparable difficulty, a licensed vaccine against feline AIDS is already in widespread use in several countries. While this seemingly major advance in prevention of AIDS would appear to be highly instructive for HIV vaccine development, its message has not been heeded by investigators in the HIV field. This review endeavours to relate what has been learned about vaccination against feline AIDS, and to suggest what this may mean for HIV vaccine development. PMID- 17706779 TI - Comparative aspects on the role of polypyrimidine tract-binding protein in internal initiation of hepatitis C virus and picornavirus RNAs. AB - We compared the effects of polypyrimidine tract-binding protein (PTB) on hepatitis C virus (HCV genotype IIa), encephalomyocarditis virus (EMCV) and poliovirus internal ribosome entry site (IRES) activities in vitro. It bound strongly to EMCV IRES, but weakly to PV and HCV RNAs. PV IRES showed the strongest dependency to PTB and it showed less than one-tenth of IRES activity after the immuno-depletion of PTB from HeLa S10 lysate with pre-coated anti-PTB IgG beads, comparing to the normal IgG beads-treated S10 lysate. EMCV IRES activity was approximately 40% of that of normal control after PTB depletion. Especially, HCV IRES activity was approximately 95%, and most weekly affected by the depletion of PTB. Repletion of PTB to depleted S10 lysate restored activities of PV and EMCV IRESs. The data suggest that PTB plays an important role in picornaviral IRESs, but not in HCV IRES. PMID- 17706780 TI - Mechanisms of action of deep brain stimulation(DBS) . AB - Deep brain stimulation (DBS) is remarkably effective for a range of neurological and psychiatric disorders that have failed pharmacological and cell transplant therapies. Clinical investigations are underway for a variety of other conditions. Yet, the therapeutic mechanisms of action are unknown. In addition, DBS research demonstrates the need to re-consider many hypotheses regarding basal ganglia physiology and pathophysiology such as the notion that increased activity in the globus pallidus internal segment is causal to Parkinson's disease symptoms. Studies reveal a variety of apparently discrepant results. At the least, it is unclear which DBS effects are therapeutically effective. This systematic review attempts to organize current DBS research into a series of unifying themes or issues such as whether the therapeutic effects are local or systems-wide or whether the effects are related to inhibition or excitation. A number of alternative hypotheses are offered for consideration including suppression of abnormal activity, striping basal ganglia output of misinformation, reduction of abnormal stochastic resonance effects due to increased noise in the disease state, and reinforcement of dynamic modulation of neuronal activity by resonance effects. PMID- 17706781 TI - The superior temporal sulcus performs a common function for social and speech perception: implications for the emergence of autism. AB - Within the cognitive neuroscience literature, discussion of the functional role of the superior temporal sulcus (STS) has traditionally been divided into two domains; one focuses on its activity during language processing while the other emphasizes its role in biological motion and social attention, such as eye gaze processing. I will argue that a common process underlying both of these functional domains is performed by the STS, namely analyzing changing sequences of input, either in the auditory or visual domain, and interpreting the communicative significance of those inputs. From a developmental perspective, the fact that these two domains share an anatomical substrate suggests the acquisition of social and speech perception may be linked. In addition, I will argue that because of the STS' role in interpreting social and speech input, impairments in STS function may underlie many of the social and language abnormalities seen in autism. PMID- 17706783 TI - In search of neutrophil granule proteins of the tammar wallaby (Macropus eugenii). AB - Two approaches have been used to isolate and identify proteins of the granules of neutrophils of the tammar wallaby, Macropus eugenii. Stimulation with PMA, Ionomycin and calcium resulted in exocytosis of neutrophil granules as demonstrated with electron microscopy. However proteomic analysis using two dimensional gel electrophoresis, in-gel trypsin digestion followed by nano liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) failed to identify any anticipated granule proteins in the reaction supernatants. Subsequent use of differential centrifugation and lysis followed by the application of the same proteomic analysis approach resulted in the isolation and confident identification of 39 proteins, many of which are known to be present in the granules of neutrophils of eutherian mammals or play a role in degranulation. These proteins notably consisted of the known antimicrobials, myeloperoxidase (MPO), serine proteinase, dermcidin, lysozyme and alkaline phosphatase. A number of important known antimicrobials, however, were not detected and these include defensins and cathelicidins. This is the first report of the neutrophil granule proteins of any marsupial and complements previous reports on the cytosolic proteins. PMID- 17706784 TI - DNA-fiber EPR investigation of the influence of amino-terminal residue stereochemistry on the DNA binding orientation of Cu(II).Gly-Gly-His-derived metallopeptides. AB - DNA fiber EPR was used to investigate the DNA binding stabilities and orientations of Cu(II).Gly-Gly-His-derived metallopeptides containing D- vs. L amino acid substitutions in the first peptide position. This examination included studies of Cu(II).D-Arg-Gly-His and Cu(II).D-Lys-Gly-His for comparison to metallopeptides containing L-Arg/Lys substitutions, and also the diastereoisomeric pairs Cu(II).D/L-Pro-Gly-His and Cu(II).D/L-Pro-Lys-His. Results indicated that L-Arg/Lys to D-Arg/Lys substitutions considerably randomized the orientation of the metallopeptides on DNA, whereas the replacement of L-Pro by D-Pro in Cu(II).L-Pro-Gly-His caused a decrease in randomness. The difference in the extent of randomness observed between the D- vs. L-Pro-Gly-His complexes was diminished through the substitution of Gly for Lys in the middle peptide position, supporting the notion that the epsilon-amino group of Lys triggered further randomization, likely through hydrogen bonding or electrostatic interactions that disrupt binding of the metallopeptide equatorial plane and the DNA. The relationship between the stereochemistry of amino acid residues and the binding and reaction of M(II).Xaa-Xaa'-His metallopeptides with DNA are also discussed. PMID- 17706782 TI - A reverse-translational approach to bipolar disorder: rodent and human studies in the Behavioral Pattern Monitor. AB - Mania is the defining feature of bipolar disorder (BD). There has been limited progress in understanding the neurobiological underpinnings of BD mania and developing novel therapeutics, in part due to a paucity of relevant animal models with translational potential. Hyperactivity is a cardinal symptom of mania, traditionally measured in humans using observer-rated scales. Multivariate assessment of unconditioned locomotor behavior using the rat Behavioral Pattern Monitor (BPM) developed in our laboratory has shown that hyperactivity includes complex multifaceted behaviors. The BPM has been used to demonstrate differential effects of drugs on locomotor activity and exploratory behavior in rats. Studies of genetically engineered mice in a mouse BPM have confirmed its utility as a cross-species tool. In a "reverse-translational" approach to this work, we developed the human BPM to characterize motor activity in BD patients. Increased activity, object interactions, and altered locomotor patterns provide multi dimensional phenotypes to model in the rodent BPM. This unique approach to modeling BD provides an opportunity to identify the neurobiology underlying BD mania and test novel antimanic agents. PMID- 17706786 TI - Sexsomnia: abnormal sexual behavior during sleep. AB - This review attempts to assemble the characteristics of a distinct variant of sleepwalking called sexsomnia/sleepsex from the seemingly scarce literature into a coherent theoretical framework. Common features of sexsomnia include sexual arousal with autonomic activation (e.g. nocturnal erection, vaginal lubrication, nocturnal emission, dream orgasms). Somnambulistic sexual behavior and its clinical implications, the role of precipitating factors, diagnostic, treatment, and medico-legal issues are also reviewed. The characteristics of several individuals described in literature including their family/personal history of parasomnia as well as the abnormal behaviors occurring during sleep are reported. PMID- 17706785 TI - Factors associated with candiduria and related mortality. AB - BACKGROUND: Although candiduria and bacteriuria have many attributes in common, little data is available regarding factors associated specifically with candiduria. Despite the high mortality in subjects with candiduria, factors associated with such mortality have not been studied. METHODS: We undertook a single-center case-control study to evaluate factors associated with candiduria over a 10.5 month period. Cases and controls were prospectively recruited from hospitalized subjects with candiduria and bacteriuria, respectively. A subgroup analysis was performed to identify factors associated with mortality following candiduria. RESULTS: Among 145 subjects with candiduria, Candida tropicalis (30.5%) and other non-albicans species accounted for 71% of isolates. Among them, clinical characteristics and associations were studied among 80 hospitalized subjects. Prior antimicrobial use was documented in 92% with candiduria, with cephalosporins used most commonly. Independent associations with candiduria were demonstrated for use of antimicrobial agents in the preceding 30 days (odds ratio (OR) 8.1; 95% confidence interval (CI) 2.1-31.9) and plasma glucose > 180 mg/dL (OR 3.1; 95% CI 1.1-9.1). Death occurred among 21 (26.2%) subjects with candiduria. Factors associated with death included use of urinary diversion devices (OR 8.8; 95% CI 1.1-70.5), > or = 2 classes of antimicrobials (OR 4.1; 95% CI 1.2-13.9), intensive care (OR 3.3; 95% CI 1.1-9.3), and renal failure (OR 2.9; 95% CI 1.1-8.2). CONCLUSIONS: Many risk factors traditionally linked to candiduria may be associated with urinary tract infections in general. Factors which predicted occurrence of candiduria, as opposed to bacteriuria, included prior use of antimicrobial agents and elevated plasma glucose. Since factors found to have associations with death in candiduria were those expected in seriously ill patients, the high mortality may be a function of the severity of underlying diseases. PMID- 17706787 TI - The role of the interhemispheric pathway in hearing. AB - The corpus callosum consists of heavily myelinated fibres connecting the two hemispheres. Its caudal portion and splenium contain fibres that originate from the primary and second auditory cortices, and from other auditory responsive areas. The anterior commissure in humans is much smaller than the corpus callosum, and it also contains interhemispheric fibres from auditory responsive cortical areas. The corpus callosum is exclusively present in placental mammals, while in acallosal mammals, most of the corpus callosum-related functions are carried out by the anterior commissure. The exact contribution of these two structures and of interhemispheric transfer in hearing in humans is still a matter of debate. In more recent years, human behavioural studies which employ psychoacoustic tasks designed to tap into interhemispheric transfer, combined with sophisticated neuroimaging paradigms, have helped to interpret information from animal experiments and post-mortem studies. This review will summarize and discuss the available information of the contributions of the human interhemispheric pathway in hearing in humans from behavioural, neuroimaging and histopathological studies in humans. PMID- 17706788 TI - A comparison of monopolar and bipolar recording techniques for examining the patterns of responses for electromyographic amplitude and mean power frequency versus isometric torque for the vastus lateralis muscle. AB - The purpose of the present study was to compare monopolar and bipolar recording techniques for the patterns of responses and mean values for absolute and normalized electromyographic (EMG) amplitude and mean power frequency (MPF) versus isometric torque for the vastus lateralis muscle. Ten healthy men (mean+/ S.D. age=23.6+/-3.0 years; body weight=80.9+/-15.6 kg) volunteered to perform submaximal to maximal isometric muscle actions of the dominant leg extensors. Monopolar and bipolar surface EMG signals were detected simultaneously from the vastus lateralis with an eight-channel linear electrode array. The results indicated that in 70-80% of the cases, monopolar and bipolar recording techniques resulted in the same patterns of responses for absolute and normalized EMG amplitude and MPF versus isometric torque. There were, however, differences between the two techniques for mean absolute EMG amplitude and MPF values, but not for the normalized values. Thus, these results supported the practice of normalization, and suggested that comparisons can be made between monopolar and bipolar recording methods for the patterns of responses and mean values for normalized (but not absolute) EMG amplitude and MPF versus isometric torque. PMID- 17706790 TI - A report on mood and cognitive outcomes with right unilateral ultrabrief pulsewidth (0.3 ms) ECT and retrospective comparison with standard pulsewidth right unilateral ECT. AB - BACKGROUND: Electroconvulsive therapy (ECT) is a highly effective treatment for depression but its use is limited by the risk of cognitive side effects. This study explored the potential of a novel approach, ultrabrief pulsewidth (0.3 ms) right unilateral (RUL-UB) ECT, to minimise cognitive effects while preserving efficacy. METHODS: Mood and neuropsychological functioning were objectively rated in 30 patients over a course of RUL-UB ECT at 6 times seizure threshold. Results (mood outcomes, ECT treatment parameters) were compared with a retrospectively assessed group of 30 age and gender matched patients who received RUL ECT (1.0 ms pulsewidth, 3.5 times seizure threshold) at the same hospital. RESULTS: Six treatments of RUL-UB ECT resulted in relatively few cognitive side effects, compared to reports of previous studies. The number of responders did not differ between groups but significantly more treatments were required in the RUL-UB group, suggesting a slower speed of response. LIMITATIONS: Patients were not randomised to the two forms of ECT and data was obtained retrospectively in the RUL ECT comparison group. CONCLUSIONS: This study suggests that RUL-UB ECT can be effective in treating depression while incurring lesser cognitive side effects than a commonly used form of RUL ECT, but a greater number of treatments may be required for response. PMID- 17706791 TI - A study of affective temperaments in Hungary: internal consistency and concurrent validity of the TEMPS-A against the TCI and NEO-PI-R. AB - BACKGROUND: TEMPS-A (Temperament Evaluation of the Memphis, Pisa, Paris and San Diego - Autoquestionnaire) is a new self-assessed temperament 110-item scale with depressive (D), cyclothymic (C), hyperthymic (H), irritable (I) and anxious (A) subscales. To date, it has been translated into 25 languages, and validated in 10. The present Hungarian version provides the most complete external validation across the Beck Depression Scale (BDI), Profile of Mood States (POMS), the BarOn Emotional Quotient Inventory (BarOn EQ-i), Temperament and Character Inventory (TCI), and the NEO Personality Inventory - Revised (NEO-PI-R). We were particularly interested in concurrent validation against the TCI and the NEO-PI R, the most important of the new personality instruments. METHODS: 1132 clinically-well subjects (27% male) from the general population and university students (16-81 years) were administered the above scales and instruments. The data were tested with standard psychometric batteries. RESULTS: Factor analysis revealed 5 factors approximating the original D, C, I, H, and A subscales, which in their superfactor confirmed an Emotional (D, C, I, A) vs. Hyperthymic structure. Except for the D (a=0.65), the Cronbach alpha for the remainder temperaments ranged from 0.75-0.81. Dominant temperaments ranged from the I (2.7%) to the C (4.2%); the highest prevalence was observed among men with C=6% and H=5.4%. The BDI and POMS correlated significantly with the relevant subscales, as did the BarOn. Of the many significant possible correlations with the TCI, the most noteworthy were novelty seeking and harm avoidance with D, A, C, as well as C, and persistence with H. As for the NEO-PI-R, we were struck by the positive correlation of openness with C, and conscientiousness negatively with C; most other positive correlations such as neuroticism with all temperaments but the hyperthymic were expected and strongly supportive of concurrent validity. LIMITATIONS: Higher educational background of the subjects studied relative to that of the general population of Hungary. The distribution of the data may have in some instances deviated somewhat from the underlying assumptions for the standard psychometric tests for normality. We did not conduct test-retest reliability. CONCLUSIONS: The factorial structure of the TEMPS-A shows good reliability and internal consistency. Although the superstructure is reminiscent of neuroticism-extraversion, within it are embedded discernible classical affective temperaments. A provocative finding is the high prevalence of cyclothymia in Hungarian males (6%), which is rather unique when compared with the other 10 countries studied to date. This finding, coupled with high male hyperthymia (5.4%), may explain the high lifetime prevalence of bipolar disorders reported from Hungary. Inter alia, our psychometric data along with the foregoing epidemiologic considerations, are very much in line with the cyclothymic-bipolar spectrum model proposed by the senior author [Akiskal, H.S., Djenderedjian, A.H., Rosenthal, R.H., Khani, M.K., 1977. Cyclothymic disorder: validating criteria for inclusion in the bipolar affective group. Am. J. Psychiatry 134, 1227-1233]. PMID- 17706789 TI - Increased cell suspension concentration augments the survival rate of grafted tyrosine hydroxylase immunoreactive neurons. AB - The poor survival rate (5-20%) of grafted embryonic dopamine (DA) neurons is one of the primary factors preventing cell replacement from becoming a viable treatment for Parkinson's disease. Previous studies have demonstrated that graft volume impacts grafted DA neuron survival, indicating that transplant parameters influence survival rates. However, the effects of mesencephalic cell concentration on grafted DA neuron survival have not been investigated. The current study compares the survival rates of DA neurons in grafts of varying concentrations. Mesencephalic cell suspensions derived from E14 Fisher 344 rat pups were concentrated to 25,000, 50,000, 100,000 and 200,000 cells/microl and transplanted into two 0.5 microl sites in the 6-OHDA-denervated rat striatum. Animals were sacrificed 10 days and 6 weeks post-transplantation for histochemical analysis of striatal grafts. The absolute number of DA neurons per graft increased proportionally to the total number of cells transplanted. However, our results show that the 200,000 cells/microl group exhibited significantly higher survival rates (5.48+/-0.83%) compared to the 25,000 cells/microl (2.81+/-0.39%) and 50,000 cells/microl (3.36+/-0.51%) groups (p=0.02 and 0.03, respectively). Soma size of grafted DA neurons in the 200,000 cells/microl group was significantly larger than that of the 25,000 cells/microl (p<0.0001) and 50,000 cells/microl groups (p=0.004). In conclusion, increasing the concentration of mesencephalic cells prior to transplantation, augments the survival and functionality of grafted DA neurons. These data have the potential to identify optimal transplantation parameters that can be applied to procedures utilizing stem cells, neural progenitors, and primary mesencephalic cells. PMID- 17706792 TI - Role of nuclear receptors and their ligands in human trophoblast invasion. AB - Human implantation involves a major invasion of the uterine wall and complete remodelling of uterine arteries by extravillous cytotrophoblasts (EVCT). Abnormality in these early steps of placental development leads to poor placentation, fetal growth defects and is often associated with preeclampsia, a major and frequent complication of human pregnancy. To study the mechanisms that control trophoblast invasion during early placental development and provide new insight in the understanding of preeclampsia, we have developed in vitro models of human invasive trophoblasts. We have shown that activation of the ligand activated nuclear receptor PPARgamma with synthetic (rosiglitazone) or natural (15deoxyPGJ(2)) agonists inhibits the trophoblastic invasion process. Analysis of PPARgamma-target genes revealed that placental growth hormone and the protease PAPP-A might be involved in the PPARgamma-mediated effect in an autocrine manner. We next investigated PPARgamma ligands at the materno-fetal interface and have shown that oxidized LDLs are present in EVCT in situ and decrease trophoblast invasion in vitro. Analysis of oxidized LDLs revealed that they contain potent PPARgamma agonists such as eicosanoids and also high levels of oxysterols, which are specific ligands for the liver X receptor (LXR). The isoform beta of LXR was found in EVCT in situ, and activation of LXRbeta with synthetic or natural ligands inhibits trophoblast invasion in vitro. Together, our data underscore a major role for PPARgamma and LXRbeta in the control of human trophoblast invasion and suggest that excess ligands such as oxidized LDLs at the implantation site might contribute to the development of preeclampsia. PMID- 17706793 TI - Effects of maternal exposure to LPS on the inflammatory response in the offspring. AB - To investigate the effects of maternal infection on the offspring's inflammatory response, pups born to LPS- or saline-treated dams were stimulated with LPS or saline, and the expression of cytokines and chemokines was examined. We found that at P21, pups born to LPS-treated dams exhibited diminished serum levels of TNF-alpha, IL-1beta, and IL-6, and inhibited mRNA levels of cytokines, including TNF-alpha, IL-1beta, and IL-6, and chemokines, including MIP-1beta, MIP-2, and KC, in the brain, as compared to pups born to saline-treated dams at 2 h following LPS stimulation. Our results suggest that maternal infection suppresses the offspring's inflammatory response to LPS. PMID- 17706796 TI - Etiologies of hearing impairment among infants and toddlers: 1986-1987 versus 2001. AB - OBJECTIVE: This study compares etiological factors for hearing loss, relevant neuro-sensory impairments and demographics between two groups of children referred for early hearing habilitation in Israel. Group I was referred in the years 1986-1987 (n=73) and group II was referred during 2001 (n=73). METHODS: Family history, pregnancy, risk factors, developmental milestones, medical history, auditory brainstem response, tympanometry, otoacoustic emissions and behavioral audiometric results were retrospectively retrieved in 2003 from medical records at the MICHA Society for Deaf Children in Israel. RESULTS: New referrals per year have doubled themselves over the 15 years that elapsed between 1986-1987 and 2001. No changes in gender and age at time of admission were found. The prevalence of mild-to-moderate hearing loss was higher in Group II while severe and profound hearing loss was more prevalent in Group I. Assisted reproductive technologies were involved only in Group II. There were more twin births and post-natal hypoxia in Group II. Rh incompatibility was reported only in Group I. Severe hearing loss was associated with younger age at admission. No significant associations were found between age at admission and etiology with the exception of the fact that children with genetic background were admitted at an earlier age. Since no significant association between genetic background and severity of hearing loss was found, it is conclude that the association between severity of hearing loss and age at admission did not account for changes in etiology in our sample. CONCLUSIONS: Classic risk factors for hearing loss among infants and toddlers have not changed much over time, and the few changes that have been noticed are probably due to expanded medical knowledge and improved technologies. PMID- 17706797 TI - Recovery from cisplatin-induced ototoxicity: a case report and review. AB - We present a pediatric case report of cisplatin-induced ototoxicity with subsequent recovery. The patient experienced tinnitus and fluctuating mild high frequency sensorineural hearing loss (SNHL) with a concomitant decrease in distortion product otoacoustic emissions (DPOAE). There was recovery of hearing loss and return of DPOAE at 1 year after completion of cisplatin therapy. Reports of recovery from cisplatin-induced ototoxicity in humans are limited in the literature, especially in the pediatric population. A review of cisplatin ototoxicity and mechanisms of recovery are discussed, with an emphasis on the particular chemotherapy regimen and dosing schedule in this case, given at 4-11 week intervals. PMID- 17706794 TI - Heterogeneity of immunopathological features of AChR/MuSK autoantibody-negative myasthenia gravis. AB - We compared B cells and germinal centers in thymus from myasthenia gravis (MG) patients either with anti-acetylcholine receptor (AChR) autoantibodies or with neither anti-muscle-specific tyrosine kinase (MuSK) nor anti-AChR (seronegative MG: SN-MG). The numbers and frequencies of total and germinal center B cells varied in the SN-MG thymi, some of which were normal/atrophic. Others were clearly hyperplastic, their B cell parameters overlapping with those in AChR positive MG, which implicates the thymus in pathogenesis. Indeed, some SN-MG patients apparently benefited from thymectomy, which should be considered a management option. PMID- 17706795 TI - A role for the neurotrophin receptor TrkB on maturing dendritic cells. AB - BACKGROUND: Neurotrophins are involved in neuroimmune interactions. However, the expression and role of neurotrophin receptors on dendritic cells have not been systematically studied. METHODS: The neurotrophin receptors p75NTR, TrkA, TrkB and TrkC were analyzed on immature and mature Human Monocyte-derived Dendritic Cells (HMDCs) using flow cytometry. In addition, we compared the impact of five different maturing protocols on the expression of neurotrophin receptors on HMDCs. Finally, the effect of neurotrophins on surface molecule expression and the survival of HMDCs was investigated. RESULTS: There was a low expression of p75NTR, TrkA and TrkB on immature HMDCs. HMDCs at different maturation stages did not show a significantly different expression of TrkA, as compared to immature HMDCs. By contrast, there was an upregulation of TrkB on suboptimally, but not optimally matured HMDC. In addition, there was a non-significant trend to a parallel increase of p75NTR expression on these cells. Functional experiments with maturing HMDCs revealed that both ligands of the TrkB receptor, Brain derived neurotrophic factor (BDNF) and Neurotrophin 4 (NT-4), significantly increased the expression of markers of antigen presentation (HLA-DR and CD80) and the survival of maturing HMDCs. CONCLUSION: These data suggest that the TrkB ligands BDNF and NT-4 can directly influence human dendritic cells during their maturation. PMID- 17706798 TI - Susceptibility of Autographa californica multiple nucleopolyhedrovirus to inhibitors of DNA replication. AB - The objectives of this study were to develop methods to evaluate the susceptibility of the type baculovirus AcMNPV to various antiviral compounds and to select potential inhibitors for investigating baculovirus DNA replication. In concert with the classical cytopathic effects (CPE) and cytotoxicity inhibition assays, two approaches, which could be amenable for high throughput application for evaluating several classes of known antiviral compounds were developed. (i) An indirect approach based on spectrofluorimetric analysis of EGFP expression in Sf21 cells infected with a recombinant AcMNPV (AcEGFP) and (ii) a direct DNA quantitative assay based on quantitative real time PCR (qPCR). Initial CPE results suggested that of 21 compounds tested, aphidicolin, abacavir, camptothecin, (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), l-mimosine, hydroxyurea and phosphonoacetic acid (PAA) were selective inhibitors of AcMNPV replication. Consistent with the CPE results, the EGFP fluorescence and the qPCR of viral DNA accumulation exhibited a dose dependent depression of EGFP expression and DNA accumulation, respectively, in infected cells exposed to them. The inhibitory effects of aphidicolin, abacavir, l-mimosine and hydroxyurea on AcMNPV DNA replication were reversible. Taken together, both spectrofluorimetric and qPCR assays are suitable and rapid quantitative approaches to investigate inhibitors of baculovirus DNA replication in infected cells. PMID- 17706799 TI - Transcription factor expression, RNA synthesis and NADPH-diaphorase across the rat brain and exposure to spatial novelty. AB - The molecular hypothesis of learning and memory processes is based on changes in synaptic weights in neural networks. Aim of this study was to map neural traces of exposure to a spatial novelty were mapped by (i) the transcription factors (TFs) c-fos, c-jun and jun-B using Northern blot and immunocytochemistry (ICC), (ii) RNA synthesis by (3)H-uridine autoradiography and RNA level, (iii) NADPH diaphorase (NADPH-d) expression by histochemistry. Thus, adult male albino rats were exposed to a Lat-maze and sacrificed at different times. Non-exposed rats served as controls. The latter showed a low constitutive expression of TF, RNA synthesis and NADPH-d across the brain. Northern blots showed a three-fold increase in TFs in exposed versus non-exposed rats in the cerebral cortex. ICC showed in exposed rats several TFs positive cells in the granular and pyramidal layers of the hippocampus and later in all layers of the somatosensory cortex, in the granular layer of the cerebellar cortex. The TF-positivity was stronger in rats exposed for the first time, and was time and NMDA-dependent. Autoradiography for RNA synthesis showed positive cells in the ependyma, hippocampus and cerebellum 6h after testing, and in the somatosensory cortex 24h later. In addition, exposure to novelty induced NADPH-d in the dorsal hippocampus, the caudate-putamen, all the layers of the somatosensory cortex. and the cerebellum. The positivity was absent immediately after exposure, appeared within 2h and disappeared 24h later. A strong neuronal discharge by the convulsant pentylenetetrazol, strongly induced TFs but not din not affect NADPH-d 2h later. Thus, data suggest that the processing of spatial and emotional components of experience activates neural networks across different organization levels of the CNS. PMID- 17706800 TI - Recent independent evolution of msp1 polymorphism in Plasmodium vivax and related simian malaria parasites. AB - The Plasmodium MSP-1 is a promising malaria vaccine candidate. However, the highly polymorphic nature of the MSP-1 gene (msp1) presents a potential obstacle for effective vaccine development. To investigate the evolutionary history of msp1 polymorphism in P. vivax, we construct phylogenetic trees of msp1 from P. vivax and related monkey malaria parasite species. All P. vivax msp1 alleles cluster in the P. vivax lineage and are not distributed among other species. Similarly, all P. cynomolgi msp1 alleles cluster in the P. cynomolgi lineage. This suggests that, in contrast to presumed ancient origin of P. falciparum msp1 polymorphism, the origin of P. vivax msp1 polymorphism is relatively recent. We observed positive selection in the P. vivax lineage but not in P. cynomolgi. Also, positive selection acts on different regions of msp1 in P. vivax and P. falciparum. This study shows that the evolutionary history of msp1 differs greatly among parasite lineages. PMID- 17706801 TI - CART peptide 55-102 microinjected into the nucleus accumbens inhibits the expression of behavioral sensitization by amphetamine. AB - CART peptide has been shown to regulate the actions of psychomotor stimulants. Here we have further investigated the role of the biologically active CART 55-102 peptide in the nucleus accumbens (NAcc) in the expression of behavioral sensitization by amphetamine (AMPH). Rats were pre-exposed 5 times to either saline or AMPH (1 mg/kg, i.p.). After 2 weeks of withdrawal, rats were microinjected into the NAcc with saline or CART 55-102 (1.0, or 2.5 microg/0.5 microl/side) followed by AMPH challenge (1 mg/kg, i.p.). The enhanced increase of locomotion and rearing produced by repeated AMPH pre-exposures was dose dependently inhibited by microinjection into the NAcc of CART 55-102 peptide. These results indicate that CART 55-102 peptide in the NAcc can play a compensatory inhibitory role in the expression of behavioral sensitization by AMPH and further suggest that CART peptide may be a useful target to control the drug addiction by psychomotor stimulants. PMID- 17706802 TI - Cardiac papillary fibroelastoma as a reason of transient ischemic attack for a young patient. AB - Cardiac papillary fibroelastoma is a rare primary cardiac tumor. It occurs mainly in the endothelium of cardiac valves. Although cardiac papillary fibroelastomas are benign tumors, they have potential life threatening complications such as sudden death, stroke, and myocardial infarction. A young man who presented two syncope attacks referred to our hospital for cardiac examination. A mass was found attached to the anterior mitral leaflet, detected by transthoracic echocardiography. We planned an urgent surgery for the patient. During operation, we found out the cauliflower shaped mass on the atrial side of the anterior mitral leaflet. We excised the tumor completely without damage to the mitral valve. We confirmed the diagnosis histopathologically. Intracardiac tumors must be excised urgently due to severe complications. It's so important to protect native valve leaflets during the excision of papillary fibroelastoma with low rates of recurrence. PMID- 17706803 TI - An unusual combination of possible causes of sudden death imaged by 64-slice computed tomography. AB - Hypertrophic cardiomyopathy and anomalous origin of the coronary arteries are important causes of sudden cardiac death in the young, for which several diagnostic imaging modalities are currently available. We report the case of a young sudden cardiac death survivor in whom the unusual coexistence of hypertrophic cardiomyopathy and anomalous origin of the left circumflex artery was demonstrated using 64-slice computed tomography. PMID- 17706804 TI - Percutaneous treatment of severe retrograde dissection of the circumflex artery involving left main stem and extending into the sinus of Valsalva. PMID- 17706805 TI - Perfusion CMR and SPECT in hypertrophic cardiomyopathy. PMID- 17706806 TI - Large bilateral coronary artery fistulae. AB - We describe a case of impressive/large bilateral coronary artery fistulae in a patient who developed transient symptoms of palpitations during pregnancy. As this woman remained asymptomatic and her haemodynamic reserves during multiple pregnancies had been good, it was decided to apply a conservative approach. Consideration, in certain circumstances, should be given as to closure of these fistulae, in view of the potential to develop pulmonary hypertension as a result of a significant cardiovascular shunt. PMID- 17706807 TI - Differences in management and outcome of ischemic and non-ischemic cardiomyopathy. AB - BACKGROUND: Ischemic and non-ischemic cardiomyopathy (ICM and NICM) both cause heart failure, but the different etiologies may result in differences in management and outcome, which were explored in this study. METHODS: Cohort study of 168 consecutive patients (90 ICM, 78 NICM) recruited from a tertiary referral heart failure clinic followed for 40+/-19 months. RESULTS: Patients with ICM were older than NICM with worse NYHA functional state but similar left ventricular ejection fraction (LVEF) and dimensions at baseline. Similar proportions (>80%) in both groups were on a beta-blocker and angiotensin-converting-enzyme inhibitor and/or angiotensin-II-receptor blocker (ACE inhibitor+/-ARB) by end of study. Mean LVEF improved in both groups over time (27.3+/-11.9% vs. 33.1+/-12.6%, p<0.05). Overall 40-month mortality was 17%. In univariate analysis of patients <80 years old, ICM, NYHA class, serum creatinine, ACE inhibitor+/-ARB, and amiodarone use were predictors of mortality, but only serum creatinine was significant in multivariate analysis, with a 2.9-fold relative risk of death (95%CI, 1.34-6.42, p<0.01) for creatinine >/=120 micromol/L compared to <120 micromol/L. CONCLUSIONS: Mortality of patients with cardiomyopathy remains high and is strongly related to serum creatinine. NICM patients were younger and showed greater improvement in symptoms and left ventricular function in long-term follow-up. PMID- 17706808 TI - Uncommon presentation of postcardiac injury syndrome: acute pericarditis after percutaneous coronary intervention. AB - Postcardiac injury syndrome (PCIS) is a common complication after cardiac surgery and myocardial infarction which is defined as a late developing pleuropericarditis accompanied by a friction rub, elevated inflammation markers and pericardial or pleural effusion. Although almost all of the cases follow a major cardiac operation or myocardial infarction, and are called as postpericardiotomy syndrome (PPS) and postmyocardial infarction syndrome (PMIS), unusual presentations after minor cardiac insults, have also been reported in the literature. We have described an unusual case of PCIS with typical clinical, laboratory, echocardiographic findings that occurred after a prolonged and complicated stent implantation procedure. PMID- 17706810 TI - Fluoroscopy to assess late heart and lung perforation by a permanent ventricular pacemaker lead. A case complicated by isolated hemothorax. AB - We report a female patient with a ventricular lead perforation late after implantation. The lead perforated heart and lung parenchyma and caused hemothorax but no cardiac effusion or tamponade. No definitive evidence for lead perforation was found by standard diagnostic assessment. Definitive diagnosis was established by cath-lab fluoroscopy. The surgical treatment including thoracotomy, lead removal, repair suture of the right ventricle and finally placement of an epicardial electrode was successful. PMID- 17706811 TI - Austin Flint murmur re-visited. AB - Austin Flint murmur is a mid-diastolic rumbling audible in subjects with severe aortic regurgitation. Several theories have been raised to explain mechanistically the nature of this particular phenomenon. We briefly review severe aortic regurgitation under the light of contemporary echocardiography in an illustrative case. PMID- 17706809 TI - A propensity-matched study of the effects of chronic diuretic therapy on mortality and hospitalization in older adults with heart failure. AB - BACKGROUND: Non-potassium-sparing diuretics may increase mortality and hospitalizations in heart failure patients. Most heart failure patients are older adults, yet the effect of diuretics on cause-specific mortality and hospitalizations in older adults with heart failure is unknown. The objective of this propensity-matched study was to determine the effect of diuretics on mortality and hospitalizations in heart failure patients >or=65 years. METHODS: Of the 7788 Digitalis Investigation Group participants, 4036 were >or=65 years and 3271 (81%) were receiving diuretics. Propensity scores for diuretic use for each of the 4036 patients were calculated using a non-parsimonious multivariable logistic regression model incorporating all measured baseline covariates, and were used to match 651 (85%) patients not receiving diuretics with 651 patients receiving diuretics. Effects of diuretics on mortality and hospitalization at 37 months of median follow-up were assessed using matched Cox regression models. RESULTS: All-cause mortality occurred in 173 patients not receiving diuretics and 208 patients receiving diuretics respectively during 2056 and 1943 person-years of follow-up (hazard ratio {HR}=1.36; 95% confidence interval {CI}=1.08-1.71; p=0.009). All-cause hospitalizations occurred in 413 patients not receiving and 438 patients receiving diuretics respectively during 1255 and 1144 person-years of follow-up (HR=1.18; 95% CI=0.99-1.39; p=0.063). Diuretic use was associated with significant increased risk of cardiovascular mortality (HR=1.50; 95% CI=1.15 1.96; p=0.003).and heart failure hospitalization (HR=1.48; 95% CI=1.13-1.94; p=0.005). CONCLUSIONS: Chronic diuretic use was associated with significant increased mortality and hospitalization in ambulatory older adults with heart failure receiving angiotensin converting enzyme inhibitor and diuretics. PMID- 17706812 TI - Metalloproteinases-2, -9 and TIMP-1 expression in stable and unstable coronary plaques undergoing PCI. AB - INTRODUCTION: Experimental models and ex-vivo studies suggest a crucial role of some matrix metalloproteinases (MMPs) in the development of acute coronary syndromes, but expression levels of MMP-2, MMP-9 and TIMP-1 in human coronary plaques causing stable angina or an acute coronary syndrome have not been reported, yet. METHODS: MMP-2, -9 and TIMP-1 expressions were assessed by real time PCR from the debris collected into distal protective vascular guards from patients with stable angina (SA-Group, n=16), acute coronary syndrome (ACS-Group, n=16) undergoing percutaneous coronary interventions (PCI). MMP-2 and -9 activities were also evaluated by gelatin-substrate zymography on plasma samples collected immediately before PCI, and compared to those of healthy subjects (Control-Group). RESULTS: The expression of MMP-2 was similar in ACS and SA Groups. MMP-9 (P=0.011), but not TIMP-1, expression was higher in debris samples from patients in the ACS-Group than in SA-Group. In both groups, the expression of MMP-2 and MMP-9 were inversely correlated (rho=-0.7; P<0.004). Zymography data indicated that pro and active MMP-9 were higher in ACS than in SA-Group, while no difference in MMP-2 was found. CONCLUSIONS: MMP-9, but not TIMP-1 or MMP-2 expression is increased in plaques causing acute coronary syndrome. PMID- 17706813 TI - Angioscopic findings of delayed healing at sites of sirolimus-eluting stent overlap after 21-month implantation. AB - Treatment of de novo coronary stenosis with sirolimus-eluting stents is associated with very low rates of target lesion revascularization and other major adverse cardiac events in the short-term after implantation, but a definite frequency of late-stent thrombosis (LST) over a long-term follow-up has become evident. One of the predictors of LST is stent overlap. We reported the angioscopic findings of very delayed healing at sites of sirolimus-eluting stent overlap 21 months post-implantation. PMID- 17706814 TI - Transient hyperglycemia in patients with acute myocardial infarction: time to define optimal glucose levels. AB - Although hyperglycemia during acute myocardial infarction (AMI) is associated with worse short and long-term cardiovascular outcomes, whether control of glycemia is sufficient to reduce morbidity and mortality is not proven at the present time. On the other hand, the target glucose levels in patients with AMI have yet to be defined. We believe that future major outcome studies will clearly define optimal glucose concentrations in patients with AMI. PMID- 17706815 TI - Ventricular arrhythmias during Tako-tsubo syndrome. AB - Tako-tsubo syndrome is a recently described form of cardiomyopathy. Its pathophysiology remains unknown. However, the main demographic, clinical, electrocardiographic and biologic characteristics of the disease have been described by previous reports. Retrospective studies are essential to help describe this rare disease, although they might have several skews. Previous reports have observed a mortality rate between 0 and 8%. In our serie, demographic, clinical, electrocardiographic and biologic results are similar with those previously reported. However, the mortality rate observed was higher than expected. Refractory ventricular arrhythmias leading to death have been encountered in 15% of patients. Tako-tsubo syndrome may present as sudden death and its mortality rate may have been underestimated in previous reports. PMID- 17706816 TI - Epidemiology of acute myocardial infarction with the emphasis on patients who did not reach the coronary care unit and non-AMI admissions. AB - OBJECTIVES: To describe the characteristics and outcome of patients with acute myocardial infarction (AMI) in a community, with particular emphasis on those who never reached a Coronary Care Unit (CCU) and those in whom the primary diagnosis was something other than a heart attack. METHODS: Patients hospitalised in the city of Goteborg, Sweden, and discharged (dead or alive) with a diagnosis of AMI. RESULTS: Among 1423 patient admissions the mean overall age was 75 years (81 years and 79 years in the two subsets). Among all patients, 33% had a history of heart failure and 20% had a history of cerebrovascular disease. The figures were even higher in the two subsets which were evaluated. In overall terms, an invasive strategy (coronary angiography) was used in 32% (in 5% and 9% in the two subsets respectively). The overall one-year and three-year mortality rate was 30% and 44% respectively. The three-year mortality rate among patients not admitted to a CCU was 65% and, among patients with no suspicion of a heart attack on admission, it was 68%. CONCLUSION: Even in the 21st century, patients with AMI who reach hospital alive run a high risk of death and nearly half are dead within the first three years. In overall terms, patients are characterised by high age and high co-morbidity. Among patients who do not reach a CCU and among patients with no suspicion of AMI on admission, approximately two thirds are dead within the subsequent three years. PMID- 17706818 TI - Prescription of antimicrobial drugs in Norwegian aquaculture with an emphasis on "new" fish species. AB - The usage of antimicrobial (AM) drugs in farmed fish in Norwegian aquaculture for the period 2000-2005 was investigated by using prescription data. These data were validated against national sales data of AM drugs sold for use in farmed fish and were found to be highly valid. The defined course dose (DCD) was applied as the unit of measurement to correct for the variations in the dosages between different AM drugs. The DCD(kg) was the amount of an AM drug recommended for the treatment of a 1-kg fish. The calculated number of prescribed DCD(kg)s is an estimate of the biomass of farmed fish that can be treated with a certain amount AM drug. In the present study, the number of prescriptions issued (i.e., numbers of initiated treatments), weight of active substance prescribed and biomass treated were applied to describe the usage. An increase, although modest, in the AM drug usage in Norwegian aquaculture was observed from 2002 to 2005. This increase was accounted for by new-farmed fish species (other than Atlantic salmon and rainbow trout), especially Atlantic cod. The increased usage of AM drugs in cod in the study period was significantly positively correlated to the biomass produced; even so from 2001 to 2005 the number of prescriptions for cod relative to the produced biomass declined. The AM drug usage in Atlantic halibut as well as the production varied during the study period. For other species such as turbot, coalfish and wolffish the usage of AM drugs was found to be negligible. "Mono-therapy" with quinolones may present a selective pressure in regard to development of quinolone resistance. PMID- 17706817 TI - Echocardiographic predictors of left ventricular functional recovery following valve replacement surgery for severe aortic stenosis. AB - OBJECTIVE: We aimed to identify the most sensitive echocardiographic measurements that predict recovery of left ventricular function following valve replacement surgery in patients with severe aortic stenosis (AS) and LV dysfunction. METHODS: We studied 66 patients (mean age 70+/-2 years, 53 male) who underwent AVR for severe AS with concurrent LV dysfunction between 1998 and 2003 at the Royal Brompton Hospital. Clinical symptoms, co-morbidities and echocardiographic measurements of LV function were recorded before and at a median follow-up of 46 months after AVR. Pre-operative LV systolic dysfunction was defined as LV ejection fraction (EF) <50% and the post-op LV recovery as an increase of EF >10%. RESULTS: Following AVR peak aortic pressure gradient decreased and aortic valve area index increased (64+/-3 to 19+/-1 mm Hg and 0.30+/-0.01 to 0.89+/-0.03 cm(2)/m(2), p<0.001 for both). LV EF increased (from 45+/-1 to 54+/-2%; p<0.001) and the LV dimensions fell (LVEDD index: from 33+/-1 to 30+/-1 mm/m(2); and LVESD index: from 27+/-1 to 20+/-1 mm/m(2); p<0.01 for both). LV diastolic dysfunction improved as evidenced by the fall in E/A ratio (from 2.6+/-0.2 to 1.9+/-0.4) and prolongation of total filling time; (from 29.2+/-0.6 to 31.4+/-0.5 s/min, p=0.01 for both). Among all echocardiographic variables, LV dimensions (LVEDD index, OR 0.70, CI 0.52-0.97, p<0.05; LVESD index, OR 0.57, CI 0.40-0.85, p=0.005) were the two independent predictors of post-operative LV functional recovery on multivariate analysis. A cut off value of pre-operative LVESD index=or<27.5 mm/m(2) was 85% sensitive and 72% specific in predicting intermediate-term recovery of LV function after AVR (AUC, 0.72, p=0.002). CONCLUSION: LV functional recovery was evident in majority of aortic stenotic patients with LV dysfunction after aortic valve replacement. A lower prevalence of LV functional recovery in patients with large pre-operative LV end systolic dimension index might signify the loss of contractile reserve and thus predict post-operative functional recovery. PMID- 17706819 TI - Udder health at a Swedish research farm with both organic and conventional dairy cow management. AB - Our aim was to compare udder health in groups of organically and conventionally managed cows, using data from a longitudinal study in a Swedish dairy-research farm. Management of the groups was identical except for feed composition and the feeding regimen. Our dataset included all lactating cows calving from 1 September 1990 to 31 August 2001 (145 organically and 151 conventionally managed cows). Udder health was assessed by the geometric average somatic-cell count (SCC) within 150 days after calving, by the number of monthly SCC tests >200,000 cells/ml within 150 days after calving and by presence of lactations with veterinary-treated cases of clinical mastitis. The effect of animal group was analysed by multivariable linear, Poisson and logistic-regression models, controlling for factors such as lactation number, breed, year, season and milk yield. The groups did not differ in any measure of udder health. We had power to rule out differences of at least 33,000 cells/ml in the geometric average somatic cell count, an incidence rate ratio of 0.65 in the incidence of high-SCC milk testing occasions, and an odds ratio of 0.43 in veterinary treated cases of mastitis. PMID- 17706820 TI - Further data on the production of beauvericin, enniatins and fusaproliferin and toxicity to Artemia salina by Fusarium species of Gibberella fujikuroi species complex. AB - The knowledge of toxigenic profiles of fungal plant pathogens is of extreme importance for evaluating the potential toxicity of infected plant products. Ninety-six fungal isolates belonging to 28 species in the Gibberella fujikuroi complex were studied for the production of beauvericin, enniatins and fusaproliferin in rice cultures. Toxin production ranged from 5 to 3000 microg/g for beauvericin, 2 to 131 microg/g for enniatins, and 4 to 440 microg/g for fusaproliferin. Beauvericin was the most common metabolite produced by 16 species followed by fusaproliferin with 11 species and enniatins with 4 species. The production of beauvericin by F. bulbicola, F. denticulatum, F. lactis, F. phyllophilum, F. pseudocircinatum, and F. succisae and fusaproliferin by F. antophilum, F. begoniae, F. bulbicola, F. circinatum, F. concentricum, F. succisae, and F. udum is reported here for the first time. Brine shrimp larvae were most sensitive to culture extracts of F. acutatum (up to 94+/-3%), F. concentricum (up to 99+/-1%), F. denticuatum (up to 100%) and F. sacchari (up to 100%). Toxicity towards brine shrimp was significantly correlated with the beauvericin content of the fungal extracts with few exceptions. These data indicate that beauvericin and fusaproliferin are common metabolites of species of the G. fujikuroi complex and pose a risk for a possible toxin accumulation in their respective host plant products. However, data from the brine shrimp bioassay showed that further toxic metabolites within this complex need to be characterized. PMID- 17706821 TI - Multiplex PCR for species discrimination of Sclerotiniaceae by novel laccase introns. AB - Common PCR-based targets for the identification of filamentous fungi and yeasts are the sequences of the internal transcribed spacer region (ITS1, 5.8S rDNA, ITS2). Within the Sclerotiniaceae the ITS-region is homogenous and the identification is almost impossible. Furthermore, the lack of IGS-data (intergenic spacer region) requires new specific marker genes for a rapid identification of phytopathogenic Sclerotiniaceae. We sequenced and analyzed new laccase2 (lcc2) genes from the phylogenetically related Sclerotinia sclerotiorum (Lib.) de Bary, Sclerotinia minor Jagger, and Monilinia fructigena Honey. Comparative analysis revealed remarkable differences in length and sequence compared to the well-known lcc2 gene of Botrytis cinerea caused by a different number of intron sequences. These results gave us the possibility to develop a primer set for a rapid multiplex PCR-identification of different species in environmental samples, e.g. wine, fruit, or soil. Therefore, the application of this technique allows the simultaneous detection of different phytopathogenic Sclerotiniaceae in complex microbiota like decomposed herbal material. In the present study prevailed problems in the field of a general identification of fungal specimen are highlighted. PMID- 17706822 TI - Effects of fungal interactions among Fusarium head blight pathogens on disease development and mycotoxin accumulation. AB - Published research on the effects of fungal interaction on disease development and subsequent mycotoxin accumulation was reviewed, focusing on pathogens related to Fusarium Head Blight (FHB). Almost all published studies showed that competitive interactions are the rule when fungal/disease development is considered. The fungi with the competitive advantage did not usually colonise significantly more than when inoculated alone, i.e. there was no advantage gained by the dominant pathogen from the presence of other weaker competing fungi. However, the effects of fungal interactions on mycotoxin accumulation were generally more complicated. Total mycotoxin production in mixed inoculation may decrease, increase or remain at a similar level compared with single-isolate inoculation, depending on the fungal species concerned and environmental conditions. However, the lack of accurate quantification of each competing fungal component in mixed inoculations in many studies prevented an accurate estimation of mycotoxin productivity per unit fungal biomass. A few recent studies, where each individual fungal component was quantified using molecular methods, suggested that mycotoxin productivity in mixed inoculations generally increased. PMID- 17706823 TI - Microbiological sampling of swine carcasses: a comparison of data obtained by swabbing with medical gauze and data collected routinely by excision at Swedish abattoirs. AB - Swab sample data from a 13-month microbiological baseline study of swine carcasses at Swedish abattoirs were combined with excision sample data collected routinely at five abattoirs. The aim was to compare the numbers of total aerobic counts, Enterobacteriaceae, and Escherichia coli, recovered by swabbing four carcass sites with gauze (total area 400 cm2) with those obtained by excision at equivalent sites (total area 20 cm2). The results are considered in relation to the process hygiene criteria that are stated in Commission Regulation (EC) No 2073/2005. These criteria apply only to destructive sampling of total aerobic counts and Enterobacteriaceae, but alternative sampling schemes, as well as alternative indicator organisms such as E. coli, are allowed if equivalent guarantees of food safety can be provided. Swab sampling resulted in higher mean log numbers of total aerobic counts at four of the five abattoirs, compared with excision, and lower or equal standard deviations at all abattoirs. The percentage of swab and excision samples positive for Enterobacteriaceae at the different abattoirs ranged from 68 to 100% and 15 to 24%, respectively. Similarly, the percentages of swab samples that were positive for E. coli were higher than the percentages of positive excision samples (range 52 to 84% and 3 to 14%, respectively). Due to the low percentage of positive excision results, the mean log numbers of Enterobacteriaceae and E. coli were only compared at two and one abattoirs, respectively, using log probability regression to substitute censored observations. Higher mean log numbers of Enterobacteriaceae were recovered by swabbing compared with excision at one abattoir, whereas the numbers of Enterobacteriaceae and E. coli did not differ significantly between sampling methods at one abattoir. This study suggests that the same process hygiene criteria as those stipulated for excision can be used for swabbing with gauze without compromising food safety. For monitoring of low numbers of Enterobacteriaceae and E. coli, like those found on swine carcasses at Swedish abattoirs, the results also show that swabbing of a relatively large area is superior to excision of a smaller area. PMID- 17706824 TI - Survival of Escherichia coli O157:H7 in needle-tenderized dry cured Westphalian ham. AB - Westphalian ham is a dry cured, ready-to-eat product that is manufactured without a lethal heat treatment. Hams are preserved by a process that involves curing, fermenting, smoking and drying, which may take 3 months or more to complete. The process can be accelerated by tenderizing the meat with solid needles, to increase the rate of cure-salt diffusion throughout muscle tissues. In this study, intact hams were immersed in a solution containing a five strain cocktail of Escherichia coli O157:H7 at 8 log cfu/mL, to determine whether needle treatment before cure application would internalize organisms from the surface. In two trials, the survival of E. coli O157:H7 on external surfaces and within deep tissues after needle treatment was followed during the ripening of hams. The injured E. coli O157:H7 cells were recovered by plating samples on pre-poured Tryptic Soy Agar plates which were incubated for 3 to 4 h at 35 degrees C, overlaid with Sorbitol MacConkey Agar containing cefixime and tellurite and re incubated at 35 degrees C for 48 to 72 h. Inoculated-injected hams initially carried E. coli O157:H7 at numbers of 7.3 and 4.6 log cfu/g E. coli O157:H7 on the surface and inside, respectively. After 112 d of ripening, which included 79 d of drying, no E. coli O157:H7 were detected at the surface of hams following enrichment, whereas in deep tissue the organism was recovered at numbers of 3.1 log cfu/g. The Westphalian ham ripening procedure evidently was not adequate to eliminate E. coli O157:H7 internalized by needle tenderization. PMID- 17706825 TI - Activity and stability of alkaline phosphatase (ALP) immobilized onto magnetic nanoparticles (Fe3O4). AB - Direct binding of alkaline phosphatase (ALP) on magnetic nanoparticles (Fe(3)O(4)) in the presence of carbodiimide (CDI) using two different methods is described. The activity and stability of immobilized ALP with both shaking and sonication method were compared. The results indicated the ALP binding efficiency to be in the range of 80-100% with both the immobilization techniques. The activities retained were in the range of 20-38% with shaking method and 30-43% with sonication method, respectively. The activities of the immobilized ALP preparations were found to be stable compared to the free (unbound) ALP for at least 16-week storage period. Moreover, ALP immobilized on magnetic nanoparticles was successfully used for dephosphorylation of plasmid DNA before it was used for ligation reaction. The use of immobilized ALP for plasmid dephosphorylation allows easy manipulation, reduces the procedural time, and also avoids exposure of reaction mixture to high temperature. PMID- 17706826 TI - Synergistic inhibition in cell-cell fusion mediated by the matrix and nucleocapsid protein of canine distemper virus. AB - Canine distemper virus (CDV) causes a chronic, demyelinating, progressive or relapsing neurological disease in dogs, because CDV persists in the CNS. Persistence of virulent CDV, such as the A75/17 strain has been reproduced in cell cultures where it is associated with a non-cytolytic infection with very limited cell-cell fusion. This is in sharp contrast to attenuated CDV infection in cell cultures, such as the Onderstepoort (OP) CDV strain, which produces extensive fusion activity and cytolysis. Fusion efficiency may be determined by the structure of the viral fusion protein per se but also by its interaction with other structural proteins of CDV. This was studied by combining genes derived from persistent and non-persistent CDV strains in transient transfection experiments. It was found that fusion efficiency was markedly attenuated by the structure of the fusion protein of the neurovirulent A75/17-CDV. Moreover, we showed that the interaction of the surface glycoproteins with the M protein of the persistent strain greatly influenced fusion activity. Site directed mutagenesis showed that the c-terminus of the M protein is of particular importance in this respect. Interestingly, although the nucleocapsid protein alone did not affect F/H-induced cell-cell fusion, maximal inhibition occurred when the latter was added to combined glycoproteins with matrix protein. Thus, the present study suggests that very limited fusogenicity in virulent CDV infection, which favours persistence by limiting cell destruction involves complex interactions between all viral structural proteins. PMID- 17706827 TI - Characterization of a late gene encoding for MCP in soft-shelled turtle iridovirus (STIV). AB - Major caspid protein (MCP) is the major structural component of virus particles and revealed to be very responsible for classification of new tentative iridovirus isolates. In this paper, the complete sequences of MCP gene was firstly identified and characterized from soft-shelled turtle iridovirus (STIV). The MCP, classified as a late transcript by drug inhibition, encodes a protein of 463 aa with a predicted molecular weight of 50kDa. Indirect immunofluorescence (IIF) and virus neutralization assay were developed to determine the sensitivity and virus neutralizing activity of MCP-specific antiserum. Furthermore, the MCP temporal expression pattern during STIV infection in vitro was characterized by Western blot and RT-PCR assays. The results suggest that STIV could be classified as a member of genus Ranavirus in family Iridoviridae and has cell-type-specific programs of viral gene expression. PMID- 17706828 TI - Characterization of minority subpopulations in the mutant spectrum of HIV-1 quasispecies by successive specific amplifications. AB - RNA viruses do not replicate as defined genomic nucleotide sequences but rather as complex distributions of mutant genomes termed viral quasispecies. Quasispecies dynamics has a number of relevant biological consequences in ribo- and retroviruses, among these the possible presence of memory genomes as minority components of their mutant spectra. Minority memory genomes reflect those viral subpopulations that were dominant at an earlier phase of viral evolution, and can quickly re-emerge to react to certain selective pressures, as it was documented with HIV-1 in vivo. Therefore, an adequate clinical management of HIV-1 requires the development of experimental methods for the detection and quantification of minority viral subpopulations, even at levels of less than 1% of the total quasispecies. We describe a new approach based on successive, highly specific PCR amplifications, which allows the genetic characterization of minority genomes present in increasingly smaller proportion in viral populations. We have coined the term 'quasispecies diving' to reflect the progressive draw on minority or 'deeper' genomes in the mutant spectrum of the quasispecies. In the case of the multidrug-resistant HIV-1 strain analyzed here, quasispecies diving allowed the detection of mutant minority genomes at an unprecedented level of 0.0054% of the amplified viral population. This approach represents a general strategy for the genetic characterization of smaller minority genomes in complex molecular populations. PMID- 17706829 TI - Polymer mobilization and drug release during tablet swelling. A 1H NMR and NMR microimaging study. AB - The objective of this study was to investigate the swelling characteristics of a hydroxypropyl methylcellulose (HPMC) matrix incorporating the hydrophilic drug antipyrine. We have used this matrix to introduce a novel analytical method, which allows us to obtain within one experimental setup information about the molecular processes of the polymer carrier and its impact on drug release. Nuclear magnetic resonance (NMR) imaging revealed in situ the swelling behavior of tablets when exposed to water. By using deuterated water, the spatial distribution and molecular dynamics of HPMC and their kinetics during swelling could be observed selectively. In parallel, NMR spectroscopy provided the concentration of the drug released into the aqueous phase. We find that both swelling and release are diffusion controlled. The ability of monitoring those two processes using the same experimental setup enables mapping their interconnection, which points on the importance and potential of this analytical technique for further application in other drug delivery forms. PMID- 17706830 TI - Analysis and modeling of swelling and erosion behavior for pure HPMC tablet. AB - This work is focused on the transport phenomena which take place during immersion in water of pure hydroxypropylmethylcellulose tablets. The water uptake, the swelling and the erosion during immersion were investigated in drug-free systems, as a preliminary task before to undertake the study of drug-loaded ones. The tablets, obtained by powder compression, were confined between glass slabs to allow water uptake only by lateral surface and then immersed in distilled water at 37 degrees C, with simultaneous video-recording. By image analysis the normalized light intensity profiles were obtained and taken as a measure of the water mass fraction. The time evolutions of the total tablet mass, of the water mass and of the erosion radius were measured, too. Thus a novel method to measure polymer and water masses during hydration was pointed out. Then, a model consisting in the transient mass balance, accounting for water diffusion, diffusivity change due to hydration, swelling and erosion, was found able to reproduce all experimental data. Even if the model was already used in literature, the novelty of our approach is to compare model predictions with a complete set of experimental data, confirming that the main phenomena were correctly identified and described. PMID- 17706831 TI - Rescue of SCID murine ischemic hindlimbs with pH-modified rhbFGF/poly(DL-lactic co-glycolic acid) implants. AB - Site-specific controlled release of biologically active angiogenic growth factors such as recombinant human basic fibroblast growth factor (rhbFGF) is a promising approach to improve collateral circulation in patients suffering from ischemic heart disease or peripheral vascular disease. Previously, we demonstrated stabilization of rhbFGF encapsulated in injectable poly(DL-lactic-co-glycolic acid) (PLGA) millicylindrical implants upon co-incorporation of Mg(OH)2 to raise the microclimate pH in the polymer. The purpose of this study was to compare stabilized (S; +Mg(OH)2+other stabilizers), partially stabilized (PS; Mg(OH)2+other stabilizers), unstabilized (US; no stabilizers), and blank (B) PLGA encapsulated rhFGF formulations to promote angiogenesis in SCID mice. Following 4 weeks subcutaneous implantation at a 0.1 microg dose in healthy animals, the S group exhibited significantly higher blood vessel density (62+/-17 vessels/mm2) compared with PS, US, and B groups (11+/-2*, 17+/-7*, and 3+/-1** respectively) (* p<0.05; ** p<0.01). Furthermore, the S group developed a thicker granulation layer at the tissue/implant interface relative to the other groups (39+/-7 vs 25+/-2**, 21+/-1***, and 12+/-1 microm*** respectively) (*** p<0.001). After 6 weeks implantation in mice with ischemic hindlimbs, the S group implants also markedly augmented both limb reperfusion (87+/-14%) and limb survival (5/5), whereas ischemic limbs did not recover in PS, US and B groups. Stabilized rhbFGF incorporated in pH modified PLGA millicylinders effectively promotes site directed in vivo angiogenesis and also enables preservation of ischemic hindlimb function. PMID- 17706832 TI - The significance of heterogeneity on mass flux from DNAPL source zones: an experimental investigation. AB - Understanding the process of mass transfer from source zones of aquifers contaminated with organic chemicals in the form of dense non-aqueous phase liquids (DNAPL) is of importance in site management and remediation. A series of intermediate-scale tank experiments was conducted to examine the influence of aquifer heterogeneity on DNAPL mass transfer contributing to dissolved mass emission from source zone into groundwater under natural flow before and after remediation. A Tetrachloroethylene (PCE) spill was performed into six source zone models of increasing heterogeneity, and both the spatial distribution of the dissolution behavior and the net effluent mass flux were examined. Experimentally created initial PCE entrapment architecture resulting from the PCE migration was largely influenced by the coarser sand lenses and the PCE occupied between 30 and 60% of the model aquifer depth. The presence of DNAPL had no apparent effect on the bulk hydraulic conductivity of the porous media. Up to 71% of PCE mass in each of the tested source zone was removed during a series of surfactant flushes, with associated induced PCE mobilization responsible for increasing vertical DNAPL distributions. Effluent mass flux due to water dissolution was also found to increase progressively due to the increase in NAPL-water contact area even though the PCE mass was reduced. Doubling of local groundwater flow velocities showed negligible rate-limited effects at the scale of these experiments. Thus, mass transfer behavior was directly controlled by the morphology of DNAPL within each source zone. Effluent mass flux values were normalized by the up-gradient DNAPL distributions. For the suite of aquifer heterogeneities and all remedial stages, normalized flux values fell within a narrow band with mean of 0.39 and showed insensitivity to average source zone saturations. PMID- 17706833 TI - Development of a scalable model for predicting arsenic transport coupled with oxidation and adsorption reactions. AB - Understanding the fundamentals of arsenic adsorption and oxidation reactions is critical for predicting its transport dynamics in groundwater systems. We completed batch experiments to study the interactions of arsenic with a common MnO2(s) mineral, pyrolusite. The reaction kinetics and adsorption isotherm developed from the batch experiments were integrated into a scalable reactive transport model to facilitate column-scale transport predictions. We then completed a set of column experiments to test the predictive capability of the reactive transport model. Our batch results indicated that the commonly used pseudo-first order kinetics for As(III) oxidation reaction neglects the scaling effects with respect to the MnO2(s) concentration. A second order kinetic equation that explicitly includes MnO2(s) concentration dependence is a more appropriate kinetic model to describe arsenic oxidation by MnO2(s) minerals. The arsenic adsorption reaction follows the Langmuir isotherm with the adsorption capacity of 0.053micromol of As(V)/g of MnO2(s) at the tested conditions. The knowledge gained from the batch experiments was used to develop a conceptual model for describing arsenic reactive transport at a column scale. The proposed conceptual model was integrated within a reactive transport code that accurately predicted the breakthrough profiles observed in multiple column experiments. The kinetic and adsorption process details obtained from the batch experiments were valuable data for scaling to predict the column-scale reactive transport of arsenic in MnO2(s)-containing sand columns. PMID- 17706834 TI - The involvement of indole-3-acetic acid in the control of stem elongation in dark and light-grown pea (Pisum sativum) seedlings. AB - We investigated the role of auxin on stem elongation in pea (Pisum sativum L.) grown for 10d in continuous darkness or under low-irradiance blue, red, far red and white light. The third internode of treated seedlings was peeled and the tissues (epidermis and cortex+central cylinder) were separately analyzed for the concentration of free and conjugated indole-3-acetic acid (IAA). Under red, far red and white light internode elongation was linearly related with the free IAA content of all internode tissues, suggesting that phytochrome-dependent inhibition of stem growth may be mediated by a decrease of free IAA levels in pea seedlings. The correlation between IAA and internode elongation, however, did not hold for blue light-grown seedlings. The hypothesis that the growth response under low-irradiance blue light might be correlated with the lack of phytochrome B signalling and changes in gibberellin metabolism is discussed in view of current knowledge on hormonal control of stem growth. PMID- 17706835 TI - Interleukin-12, interleukin-23, and psoriasis: current prospects. AB - The clinical phenotype of psoriasis results from infiltration of T cells in the skin and elaboration of inflammatory cytokines. Interleukin (IL)-12 and, more recently, IL-23 have been implicated in the pathogenesis of psoriatic lesions. New therapies, including a monoclonal antibody against a subunit shared by IL-12 and IL-23, have been developed to treat psoriasis. Our purpose was to review the literature on IL-12 and IL-23 as a basis for understanding the use of anti-IL 12/IL-23 therapy for psoriasis. A review of English-language articles was performed using PubMed to identify articles pertaining to IL-12, IL-23, and psoriasis. IL-12 and IL-23 share a common subunit (p40) and have a distinct subunit (p35 and p19, respectively). Transgenic mice that overexpress IL-12 p40 develop inflammatory skin lesions. Both IL-12 knockout mice, which are deficient in IL-12, and human beings with a genetic IL-12 deficiency show increased susceptibility to intracellular pathogens and defective delayed-type hypersensitivity responses. These genetic deficiency states suggest the potential for adverse side effects from clinical administration of anti IL-12 p40 therapy. IL-12 p40 antibody was well tolerated in a phase I clinical trial with few adverse events and substantial improvements in psoriasis in most individuals. There was dose-dependent efficacy and substantial improvement in a larger cohort of patients in a phase II clinical trial. Larger and longer trials of anti IL 12/IL-23 therapies are needed to assess their clinical use and potential for infection and other adverse events. PMID- 17706836 TI - Regulation of TLR expression, a new perspective for the role of VIP in immunity. AB - The contribution of VIP immune functions to the regulation of homeostasis and health is well known. Modulation of immune responses through new therapeutics is one of the main goals of physicians and scientists seeking to control inflammatory/autoimmune diseases in humans. Initial therapeutic strategies targeted adaptive immune responses; discovery of Toll-like receptors (TLR) has widened the horizon to include targeting the innate immune system. In this review we have summarized recent information about VIP modulation of TLR function, and we suggest that VIP represents a new therapeutic option in the management of several pathologies. PMID- 17706838 TI - Synthesis, properties and photodynamic inactivation of Escherichia coli by novel cationic fullerene C60 derivatives. AB - A novel N,N-dimethyl-2-(4'-N,N,N-trimethylaminophenyl)fulleropyrrolidinium iodide (DTC(60)(2+)) has been synthesized by 1,3-dipolar cycloaddition using 4-(N,N dimethylamino) benzaldehyde, N-methylglycine and fullerene C(60). This approach produced an N-methyl-2-(4'-N,N-dimethylaminophenyl)fulleropyrrolidine with 38% yield. Exhaustive methylation of this fullerene derivative with methyl iodide yielded 95% of dicationic DTC(60)(2+). The spectroscopic and photodynamic properties of the DTC(60)(2+) were compared with a non-charged N-methyl-2-(4' acetamidophenyl)fulleropyrrolidine (MAC(60)) and a monocationic N,N-dimethyl-2 (4'-acetamidophenyl)fulleropyrrolidinium iodide (DAC(60)(+)). The dicationic DTC(60)(2+) is essentially aggregated in solution of different solvents and it is partially dissolved as monomer in benzene/benzyl-n-hexadecyldimethyl ammonium chloride (BHDC) 0.1M/water (W(0)=10) reverse micelles. The singlet molecular oxygen, O(2) ((1)Delta(g)), production was evaluated using 1,3 diphenylisobenzofuran. The photodynamic effect was strongly dependent on the medium, diminishes when the sensitizer is aggregated and increases in an appropriately surrounded microenvironment. The photodynamic inactivation produced by these fullerene derivatives was investigated in vitro on a typical Gram negative bacterium, Escherichia coli. Photosensitized inactivation of E. coli cellular suspensions by DTC(60)(2+) exhibits a approximately 3.5 log decrease of cell survival (99.97% of cellular inactivation), when the cultures are treated with 1 microM of sensitizer and irradiated for 30 min. This photosensitized inactivation remains high even after one washing step. Also, the photodynamic activity was confirmed by growth delay of E. coli cultures. The growth was arrested when E. coli was exposed to 2 microM of cationic fullerene and irradiated, whereas a negligible effect was found for the non-charged MAC(60). These studies indicate that dicationic DTC(60)(2+) is an interesting agent with potential applications in photodynamic inactivation of bacteria. PMID- 17706837 TI - Neuroprotective effect of cobalt chloride on hypobaric hypoxia-induced oxidative stress. AB - Hypobaric hypoxia, characteristic of high altitude is known to increase the formation of reactive oxygen and nitrogen species (RONS), and decrease effectiveness of antioxidant enzymes. RONS are involved and may even play a causative role in high altitude related ailments. Brain is highly susceptible to hypoxic stress and is involved in physiological responses that follow. Exposure of rats to hypobaric hypoxia (7619 m) resulted in increased oxidation of lipids and proteins due to increased RONS and decreased reduced to oxidized glutathione (GSH/GSSG) ratio. Further, there was a significant increase in superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) levels. Increase in heme oxygenase 1 (HO-1) and heat shock protein 70 (HSP70) was also noticed along with metallothionein (MT) II and III. Administration of cobalt appreciably attenuated the RONS generation, oxidation of lipids and proteins and maintained GSH/GSSH ratio similar to that of control cells via induction of HO-1 and MT offering efficient neuroprotection. It can be concluded that cobalt reduces hypoxia oxidative stress by maintaining higher cellular HO-1 and MT levels via hypoxia inducible factor 1alpha (HIF-1alpha) signaling mechanisms. These findings provide a basis for possible use of cobalt for prevention of hypoxia-induced oxidative stress. PMID- 17706839 TI - Molecular modeling studies of phenoxypyrimidinyl imidazoles as p38 kinase inhibitors using QSAR and docking. AB - p38 Kinase plays a vital role in inflammation mediated by tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta) pathways and inhibitors of p38 kinase provide effective approach for the treatment of inflammatory diseases. Pyridinyl and pyrimidinyl imidazoles, selectively inhibit p38alpha MAP kinase, are useful in the treatment of inflammatory diseases like rheumatoid arthritis. Three dimensional quantitative structure-activity relationship studies (3D-QSAR) involving comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) and molecular docking were performed on 44 phenoxypyrimidinyl imidazole p38 kinase inhibitors to find out the structural relationship with the activity. The best predictive CoMFA model with atom fit alignment resulted in cross-validated r(2) value of 0.553, noncross-validated r(2) value of 0.908 and standard error of estimate 0.187. Similarly the best predictive CoMSIA model was derived with q(2) of 0.508, noncross-validated r(2) of 0.894 and standard error of estimate of 0.197, comprising steric, electrostatic, hydrophobic and hydrogen bond donor fields. These models were able to predict the activity of test set molecules efficiently within an acceptable error range. GOLD and FlexX were employed to dock the inhibitors into the active site of the p38 kinase and these docking studies revealed the vital interactions and binding conformation of the inhibitors. The information rendered by 3D-QSAR models and the docking interactions may afford valuable clues to optimize the lead and design new potential inhibitors. PMID- 17706840 TI - [A painful splenomegaly]. PMID- 17706841 TI - [A deformity of the hands]. PMID- 17706842 TI - A new hybrid model for exploring the adoption of online nursing courses. AB - With the advancement in educational technology and internet access in recent years, nursing academia is searching for ways to widen nurses' educational opportunities. The online nursing courses are drawing more attention as well. The online nursing courses are very important e-learning tools for nursing students. The research combines the innovation diffusion theory and technology acceptance model, and adds two research variables, perceived financial cost and computer self-efficacy to propose a new hybrid technology acceptance model to study nursing students' behavioral intentions to use the online nursing courses. Based on 267 questionnaires collected from six universities in Taiwan, the research finds that studies strongly support this new hybrid technology acceptance model in predicting nursing students' behavioral intentions to use the online nursing courses. This research finds that compatibility, perceived usefulness, perceived ease of use, perceived financial cost and computer self-efficacy are critical factors for nursing students' behavioral intentions to use the online nursing courses. By explaining nursing students' behavioral intentions from a user's perspective, the findings of this research help to develop more user friendly online nursing courses and also provide insight into the best way to promote new e-learning tools for nursing students. This research finds that compatibility is the most important research variable that affects the behavioral intention to use the online nursing courses. PMID- 17706844 TI - Cost-utility analysis of vaccination against HPV in Israel. AB - Using WHO-CHOICE methodology, we calculated cost-utility ratios for various interventions (PAP smear, HPV-DNA testing, VIA and vaccination against HPV) at various frequencies to reduce the burden of cervical cancer and condyloma (in the case of the HPV vaccination) in Israel, which has a low prevalence of cervical cancer. Assuming non-waning efficacy, HPV vaccinations will become cost effective, very cost-effective and cost saving when the cost per dose falls below $96.85, $50.42 and $27.20, respectively. Attempts should be made to raise compliancy with PAP smears from the current opportunistic 12.2-20.0% per annum either before and/or after the vaccination is introduced. PMID- 17706845 TI - Metaanalysis of vaccine effectiveness in varicella outbreaks. AB - There is a number of reports on varicella outbreaks in populations where a one dose varicella immunization program has been implemented. We performed a metaanalysis to provide a summary vaccine effectiveness (VE) estimate and to assess the possible impact of waning immunity by means of a subgroup analysis by time since immunization. We found a VE of 72.5% (95% CI 68.5-76.0) derived from 3157 children in 14 publications. Immunization coverage of the respective population was unrelated to VE. All studies (n=4) that allowed the computation of VE over time since immunization showed a substantial decrease. In total, waning immunity was assessed by nine studies. Two reported no relation between VE and time since immunization without specifying how this had been assessed. Seven studies calculated relative risks for contracting varicella after prolonged as compared to a shorter period since immunization and reported an increased relative risk for prolonged periods. In conclusion, this metaanalysis confirms a limited effectiveness of one dose of varicella vaccine and points to waning immunity as an important causal factor. Waning might also be an issue with the newly recommended two dose vaccination schedule. Sustained surveillance for varicella outbreaks in populations with varicella immunization programs therefore is mandatory. PMID- 17706843 TI - HIV-1(89.6) Gag expressed from a replication competent HSV-1 vector elicits persistent cellular immune responses in mice. AB - We have constructed a replication competent, gamma(1)34.5-deleted herpes simplex virus type-1 (HSV-1) vector (J200) that expresses the gag gene from human immunodeficiency virus type-1, primary isolate 89.6 (HIV-1(89.6)), as a candidate vaccine for HIV-1. J200 replicates in vitro, resulting in abundant Gag protein production and accumulation in the extracellular media. Immunization of Balb/c mice with a single intraperitoneal injection of J200 elicited strong Gag-specific CD8 responses, as measured by intracellular IFN-gamma staining and flow cytometry analysis. Responses were highest between 6 weeks and 4 months, but persisted at 9 months post-immunization, the last time-point evaluated. These data highlight the potential utility of neuroattenuated, replication competent HSV-1 vectors for delivery of HIV-1 immunogens. PMID- 17706846 TI - Reuse of the same facial flap. PMID- 17706847 TI - Characterization and isolation of some genes of the shikimate pathway in sensitive and resistant Centaurea jacea plants after ozone exposure. AB - Centaurea jacea has been suggested as a potential bioindicator for ozone, but little is known about its intraspecific variation in sensitivity, especially at molecular level. The effects of ozone (200 ppb, 5 h) on sensitive and resistant lines of Centaurea have been investigated at the end of fumigation. Sensitive plants showed characteristic symptoms of injury in the form of diffuse discoloration stipples on leaves. A PCR-based approach was used to identify and isolate a partial-length cDNA coding for PAL and CHS genes. The northern analysis of PAL showed accumulation of transcript in both lines correlated with a typical increase of PAL activity (+41 and +91% in resistant and sensitive material, respectively, compared to controls). On the contrary, the transcripts of CHS, in resistant and sensitive plants, did not change after treatment. Total phenols were not affected by ozone, while anthocyanins were quickly utilised by resistant clone as antioxidant compounds. PMID- 17706848 TI - Contaminant exposure in terrestrial vertebrates. AB - Here we review mechanisms and factors influencing contaminant exposure among terrestrial vertebrate wildlife. There exists a complex mixture of biotic and abiotic factors that dictate potential for contaminant exposure among terrestrial and semi-terrestrial vertebrates. Chemical fate and transport in the environment determine contaminant bioaccessibility. Species-specific natural history characteristics and behavioral traits then play significant roles in the likelihood that exposure pathways, from source to receptor, are complete. Detailed knowledge of natural history traits of receptors considered in conjunction with the knowledge of contaminant behavior and distribution on a site are critical when assessing and quantifying exposure. We review limitations in our understanding of elements of exposure and the unique aspects of exposure associated with terrestrial and semi-terrestrial taxa. We provide insight on taxa specific traits that contribute, or limit exposure to, transport phenomenon that influence exposure throughout terrestrial systems, novel contaminants, bioavailability, exposure data analysis, and uncertainty associated with exposure in wildlife risk assessments. Lastly, we identify areas related to exposure among terrestrial and semi-terrestrial organisms that warrant additional research. PMID- 17706849 TI - Agricultural opportunities to mitigate greenhouse gas emissions. AB - Agriculture is a source for three primary greenhouse gases (GHGs): CO(2), CH(4), and N(2)O. It can also be a sink for CO(2) through C sequestration into biomass products and soil organic matter. We summarized the literature on GHG emissions and C sequestration, providing a perspective on how agriculture can reduce its GHG burden and how it can help to mitigate GHG emissions through conservation measures. Impacts of agricultural practices and systems on GHG emission are reviewed and potential trade-offs among potential mitigation options are discussed. Conservation practices that help prevent soil erosion, may also sequester soil C and enhance CH(4) consumption. Managing N to match crop needs can reduce N(2)O emission and avoid adverse impacts on water quality. Manipulating animal diet and manure management can reduce CH(4) and N(2)O emission from animal agriculture. All segments of agriculture have management options that can reduce agriculture's environmental footprint. PMID- 17706850 TI - An exploratory spatial data analysis approach to understanding the relationship between deprivation and mortality in Scotland. AB - This paper considers the spatial characteristics of the relationship between deprivation and mortality rates in Scotland. Scotland not only has higher average mortality rates than England and Wales but the greatest spatial concentrations of the poorest health areas in Britain. Recent analysis has suggested that degree of deprivation alone cannot explain the majority of Scotland's 'excess' poor health relative to England and Wales, a finding referred to as the 'Scottish effect'. This analysis considers if the spatial patterning of deprivation could be significant to understanding of high mortality in Scotland. Exploratory spatial data analysis methods are implemented to study the spatial relationships between deprivation and standardised mortality ratios (SMRs) in post-code sectors in Scotland. Deprivation was measured using the 2001 Carstairs score, and the total number of deaths during a 3-year period around the 2001 census was used to calculate SMRs. A strong spatial relationship is observed between deprivation and mortality. Deprivation impacts mortality levels not only within the same areas but also in spatially proximate areas. It is concluded that, further research on the 'Scottish effect' can benefit from new methodological approaches which assess the variation in both the extent and spatial arrangement of deprivation and mortality in small areas. PMID- 17706851 TI - Loop analysis of causal feedback in epidemiology: an illustration relating to urban neighborhoods and resident depressive experiences. AB - The causal feedback implied by urban neighborhood conditions that shape human health experiences, that in turn shape neighborhood conditions through a complex causal web, raises a challenge for traditional epidemiological causal analyses. This article introduces the loop analysis method, and builds off of a core loop model linking neighborhood property vacancy rate, resident depressive symptoms, rate of neighborhood death, and rate of neighborhood exit in a feedback network. External interventions and models including resident social isolation and neighborhood greenspace programs are hypothesized to predict different effects upon depressive symptoms and neighborhood conditions. I justify and apply loop analysis to the specific example of depressive symptoms and abandoned urban residential property to show how inquiries into the behavior of causal systems can answer different kinds of hypotheses, and thereby compliment those of causal modeling using statistical models. Neighborhood physical conditions that are only indirectly influenced by depressive symptoms may nevertheless manifest the mental health experiences of their residents; conversely, neighborhood physical conditions may be a significant mental health risk for the population of neighborhood residents. I find that participatory greenspace programs are likely to produce adaptive responses in depressive symptoms and different neighborhood conditions, which are different in character to non-participatory greenspace interventions. PMID- 17706852 TI - Spirulina fusiformis provides protection against mercuric chloride induced oxidative stress in Swiss albino mice. AB - Oxidative stress induced by mercuric chloride (5 mg/kg body weight i.p.) in mice substantially increases the lipid peroxidation level along with corresponding decrease in the reduced glutathione and various antioxidant enzymes in liver and increase in serum transaminases activity. Supplementation of Spirulina (800 mg/kg body weight orally, in olive oil, along with mercuric chloride) for 40 days resulted in decreased LPO level, serum glutamate oxaloacetate and serum glutamate pyruvate transaminase activity along with increase in liver GSH level. The activities of antioxidants enzymes superoxide dismutase, catalase and glutathione S-transferase were also concomitantly restored to near normal level by Spirulina supplementation to mercuric chloride intoxicated mice. The results clearly demonstrate that Spirulina treatment augments the antioxidants defense mechanism in mercuric chloride induced toxicity and provides evidence that it may have a therapeutic role in free radical mediated diseases. PMID- 17706853 TI - Subchronic intoxication with chlorfenvinphos, an organophosphate insecticide, affects rat brain antioxidative enzymes and glutathione level. AB - Organophosphate pesticides (OP) belong to the class of xenobiotics that are intentionally released to the environment. Toxicity of these compounds is mainly due to inhibition of acetylcholinesterase (AChE), but many authors postulate that OP in acute as well as in chronic intoxication disturb the redox processes, changing the activities of antioxidative enzymes and causing enhancement of lipid peroxidation in many organs. Epidemiological studies have demonstrated a relationship of certain human diseases with pesticide exposure and with changes in antioxidative enzymes. There is also evidence that oxidative stress is an important pathomechanism of neurological disorders such as Alzheimer disease and Parkinson disease, cardiovascular disorders and many others. The study objective was to investigate the activities of brain antioxidative enzymes and reduced glutathione level in rats subchronically intoxicated with chlorfenvinphos. In the rat brain the activities of such enzymes as superoxide dismutase, catalase, glutathione peroxidase and reductase were found to increase, while reduced glutathione level decreased in chlorfenvinphos intoxication. Based on experimental findings of this study, it can be suggested that subchronic administration of chlorfenvinphos leads to a change in the brain oxidative status and that the change occurs at a dose of 0.3 mg/kg/day, i.e., twice smaller than LOAEL level for rats. PMID- 17706854 TI - The effect of phenobarbital on the methylation level of the p16 promoter region in rat liver. AB - It has been suggested that non-genotoxic carcinogens (NGCs) may cause modification of the DNA methylation status. We studied the effects of phenobarbital (PB) -- a non-genotoxic rodent liver carcinogen -- on the methylation level of the promoter region of the p16 suppressor gene, as well as on hepatomegaly, DNA synthesis, and DNA-methyltransferase (DNMTs) activity in the rat liver. Male Wistar rats received PB in 1, 3 or 14 daily oral doses (at 24-h intervals), each equivalent to 1/10 of the LD(50) value. The study showed that PB has caused persistent elevation in relative liver weight (RLW) as well as a transient increase in DNA synthesis. This suggests that the PB-induced increase in RLW was due to a combination of both hyperplasia and hypertrophy of liver cells. The effect of PB on DNA synthesis corresponded to an increase in the methylation pattern of the p16 promoter sequence. Methylation of cytosine in the analyzed CpG sites of the p16 gene was found after short exposure of the animals to PB. Treatment of rats with PB for 1 and 3 days also produced an increase in nuclear DNMTs activity. After prolonged administration (14 days), DNA synthesis declined, returning to the control level. No changes in methylation of the p16 gene nor in DNMTs activity were observed. The reversibility of early induced changes in target tissues is a mark characteristic of tumor promoters. Thus, transient changes in methylation of the p16 gene, although their direct role in the mechanisms of PB toxicity, including its carcinogenic action, remains doubtful, may therefore be a significant element of such processes. PMID- 17706855 TI - Emergency medicine in Poland. AB - The article describes the feature of Poland's emergency medicine services system. Pre-hospital emergency medical service (EMS) access, regional differences and the main features of the system are described. EMS personal education and skill level are discussed. The authors offer a critical analysis of the current situation and proposal for the future development of emergency medicine in Poland based on changes in law, organization and education. PMID- 17706856 TI - Do not "MET-usitate": an interesting addition to do-not-attempt resuscitate orders. PMID- 17706857 TI - The association of coagulopathy and traumatic brain injury in patients with isolated head injury. AB - The emergence of prothrombotic agents (e.g. activated factor VII) to treat traumatic brain injury (TBI) requires a better understanding of the association of coagulopathy with isolated head injury (IHI). OBJECTIVE: To investigate the association of IHI and coagulopathy. METHODS: Prospective, observational study in an urban level I trauma center. INCLUSION CRITERIA: Adult (> or = 13 years of age) patients with IHI. EXCLUSION CRITERIA: patients with known coagulopathies or on anticoagulant therapy. PREDICTOR VARIABLES: TBI (head abbreviated injury severity score > 2, or brain hematoma on CT scan), age, gender, mechanism of injury, Glasgow Coma Score (GCS), and loss of consciousness (LOC). OUTCOME VARIABLES: coagulopathy defined as elevated International Normalized Ratio (INR > 1.3) or activated partial thromboplastin time (PTT) greater than 34 s. We divided IHI subjects into two groups of patients with and without TBI. STATISTICAL ANALYSIS: Fisher's exact test and Mann-Whitney U were used to compare data where appropriate (alpha: 0.05, two-tailed). RESULTS: From July 2005 to December 2006, 276 patients with IHI were studied. The median age was 35 years (interquartile range: 25-52) with a 79% male predominance and 88% blunt trauma. Eight percent (95% CI, 5-12%) of patients had coagulopathy. The rate of coagulopathy in TBI patients (17%) was significantly higher than non-TBI patients (6%) (11% difference, 95% CI, 3-20%]. The relative risk of coagulopathy in TBI patients was 2.9 (95% CI, 1.3-6.6). CONCLUSION: Coagulopathy as defined by elevated INR and/or PTT is associated with TBI after isolated head injury. PMID- 17706858 TI - Pre-hospital thoracotomy: a radical resuscitation intervention come of age? PMID- 17706859 TI - Chromatin dysfunction in Huntington's disease. PMID- 17706860 TI - Management of treated pulp and paper mill effluent to achieve zero discharge. AB - Pulp and paper mills are one of the major effluent generating industries in the world. In most cases, mill effluent (treated or raw) is discharged back into a river, creek, stream or other water body; resulting in negative environmental impacts, as well as social concerns, among the downstream users. Pulp and paper mill effluent management, which could result in zero discharge into downstream water bodies, would present the best management option to address socio environmental concerns. This paper presents such an effort aimed at closing the water cycle by using treated effluent from the mill to irrigate forage and fodder crops for producing animals feed. The treated effluent is delivered from the mill through gravity into a winter storage dam of 490 ML capacity. For irrigation applications on 110 ha of farmland, which is 42% of the total farmland, the water is pumped from the winter storage dam to five individual paddocks with Centre Pivot (CP) irrigators and one rectangular paddock with a Soft Hose Travelling (SHT) irrigator. From October 2001 to June 2006, a total of 2,651 mm of wastewater was applied at the farm. The impact assessment results, obtained from field monitoring, investigations and analysis, indicated that the closed water cycle effluent management strategy described had resulted in a lessening of the impact on water resources usually associated with paper mills. However, social attitudes to the use of crops that have been irrigated with recycled waters and the resulting impact on market value of the produce may still be a major consideration. PMID- 17706861 TI - Prostate-sparing cystectomy: two sides of the moon. PMID- 17706862 TI - The coordination of the sequential appearance of MHR4 and dopa decarboxylase during the decline of the ecdysteroid titer at the end of the molt. AB - During the last larval molt in Manduca sexta, in response to an increasing, then decreasing ecdysteroid titer, a number of transcription factors such as E75B, MHR3, MHR4, and betaFTZ-F1 appear and disappear in the abdominal epidermis leading to dopa decarboxylase (DDC) expression. Messenger RNAs for both the 20E induced transcription factors, MHR3 and E75B, are maximal near the peak of the ecdysteroid titer with MHR4 mRNA appearing as the titer declines followed by betaFTZ-F1 and DDC mRNAs. E75B and MHR4 mRNA were not expressed in Manduca GV1 cells, either during exposure to 20E or after its removal. When either MHR3 dsRNA was transfected or E75B was constitutively expressed in these cells, MHR4 mRNA appeared in response to 20E by 6h. E75B was found to form a heterodimer with MHR3 using the BacterioMatch II two-hybrid assay. We conclude that MHR3 apparently suppresses MHR4 expression in the presence of 20E; the appearance of E75B then removes MHR3 by dimerization, allowing MHR4 to be expressed. Because of significant basal activity of the ddc promoter in the GV1 cells, we could perform rescue experiments by adding various factors. Constitutive expression of either E75B or MHR4 in the cells suppressed the significant basal activity of the 3.2kb ddc promoter in the GV1 cells, but 20E had no effect on this activity. Thus, E75B and MHR4 are 20E-induced inhibitory factors that suppress ddc expression and therefore act as ecdysteroid-regulated timers to coordinate the onset of ddc expression at the end of the molt. PMID- 17706863 TI - Quantification of CpG island methylation in progressive breast lesions from normal to invasive carcinoma. AB - Epigenetic silencing of specific genes is associated with cancer progression. CpG islands are present at higher frequency in promoter regions, their methylation leading to gene underexpression. Pyrosequencing provides sequencing analysis of genetic markers, e.g., single nucleotide polymorphisms and DNA methylation. We investigated methylation levels of a spectrum of neoplastic breast lesions, ranging from hyperplasia to invasive carcinoma obtained from the same patient. Assays were designed to analyze promoter regions of RASSF1A, GSTP1, RARbeta, and E-cadherin. Methylation increased from normal to hyperplasia, the increase being significantly higher in invasive and in situ tumors for RASSF1A (p=0.00006 and p=0.009, respectively). PMID- 17706864 TI - Impact of spatiotemporal fluctuations in airborne chemical concentration on toxic hazard assessment. AB - Models widely used to assess atmospheric chemical-dispersion hazards for emergency response rely on acute exposure guideline level (AEGL) or similar concentration guidelines to map geographic areas potentially affected by corresponding levels of toxic severity. By ignoring substantial, random variability in concentration over time and space, such standard methods routinely underestimate the size of potentially affected areas. Underestimation due to temporal fluctuation - applicable to chemicals like hydrogen cyanide (HCN) for which peak concentrations best predict acute toxicity - becomes magnified by spatial fluctuation, defined as heterogeneity in average concentration at each location relative to standard-method predictions. The combined impact of spatiotemporal fluctuation on size of assessed threat areas was studied using a statistical-simulation assessment method calibrated to Joint Urban 2003 Oklahoma City field-tracer data. For a hypothetical 60-min urban release scenario involving HCN gas, the stochastic method predicted that lethal/severe effects could occur in an area 18 or 25 times larger than was predicted by standard methods targeted to a 60-min AEGL, assuming wind speeds > or =2.0 or < or =1.5m/s, respectively. The underestimation doubled when the standard method was targeted to a 10-min AEGL. Further research and field data are needed for improved stochastic methods to assess spatiotemporal fluctuation effects. PMID- 17706865 TI - Photocatalytic removal of hazardous dye cyanosine from industrial waste using titanium dioxide. AB - In this paper, photocatalytic degradation studies of a hazardous water soluble xanthene dye cyanosine in aqueous suspensions of titanium dioxide under a variety of conditions, viz., catalyst concentration, substrate concentration, pH, temperature and electron acceptor hydrogen peroxide (H2O2) have been reported. It was observed that photocatalytic degradation by TiO2 is an effective, economic and faster mode of removing cyanosine from aqueous solution. The optimum conditions for the degradation of the dye was dye concentration 1x10(-4)M, pH 8, catalyst concentration 0.04g/L and temperature +/-30 degrees C. Chemical oxygen demand and dye absorbance of the photodegraded dye solution substantially decreased. PMID- 17706866 TI - Removal of Cr(VI) from aqueous solutions using agricultural waste 'maize bran'. AB - Novel biosorbent 'maize bran' has been successfully utilized for the removal of Cr(VI) from aqueous solution. The effect of different parameters such as contact time, sorbate concentration, pH of the medium and temperature were investigated and maximum uptake of Cr(VI) was 312.52 (mgg(-1)) at pH 2.0, initial Cr(VI) concentration of 200mgL(-1) and temperature of 40 degrees C. Effect of pH showed that maize bran was not only removing Cr(VI) from aqueous solution but also reducing toxic Cr(VI) into less toxic Cr(III). The sorption kinetics was tested with first order reversible, pseudo-first order and pseudo-second order reaction and it was found that Cr(VI) uptake process followed the pseudo-second order rate expression. Mass transfer of Cr(VI) from bulk to the solid phase (maize bran) was studied at different temperatures. Different thermodynamic parameters, viz., DeltaG degrees , DeltaH degrees and DeltaS degrees have also been evaluated and it has been found that the sorption was feasible, spontaneous and endothermic in nature. The Langmuir and Freundlich equations for describing sorption equilibrium were applied and it was found that the process was well described by Langmuir isotherm. Desorption studies was also carried out and found that complete desorption of Cr(VI) took place at pH of 9.5. PMID- 17706867 TI - Prediction of the copper (II) ions dynamic removal from a medium by using mathematical models with analytical solution. AB - A copper (II) ions biosorption by Sargassum sp. biomass was studied in a fixed bed column at 30 degrees C and pH 3.5. The experimental curves were obtained for the following feed concentrations -2.08, 4.16, 6.42 and 12.72mmol/L of the copper ions. The mathematical models developed by Thomas and Bohart-Adams were used for description of ions sorption process in the column. The models principle hypothesis is that the mass transfer controlling stage of the process is the adsorption kinetics between sorbate and adsorbent. The phenomena such as intraparticle diffusion, a mass transfer external resistance and axial dispersion effects were out of considerations. Some of the models parameters were experimentally determined (rho(B), epsilon, u(0), C(0)) and the others were evaluated on the bases of the experimental data (k(a1), k(a2)). The unique fitting parameter in all models was the adsorption kinetic constant. The identification procedure was based on the least square statistical method. Simulation results show that the models describe well a copper ions sorption process in a fixed bed column. The used models can be considered as useful tools for adsorption process design and optimization in fixed bed column by using algae biomass of Sargassum sp. as an adsorbent. PMID- 17706868 TI - Current evidence for a modulation of nociception by human genetic polymorphisms. PMID- 17706869 TI - The role of neurotrophic factors in genesis and maintenance of mechanical hypernociception after brachial plexus avulsion in mice. AB - Neurotrophic factors (NTFs), namely nerve growth factor (NGF), glial cell line derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), have recently emerged as a new exciting class of potential targets for the development of drugs to treat chronic pain. We have recently reported that brachial plexus avulsion (BPA) results in a marked and long-lasting mechanical hypernociception in rodents. Here we demonstrate that antibodies against NGF, NT-3, GDNF and BDNF were able to postpone the mechanical hypernociception in mice when dosed locally, systemically or intrathecally (i.t.) at the time of surgery. However, none of them were able to interfere with the mechanical hypernociception when administered intraventricularly (i.c.v.) at the moment of surgery or even i.p. on the 4th day after the injury. Interestingly, the anti-BDNF antibody was the only one that substantially reversed the mechanical hypernociceptive state when administered i.t. or i.c.v. on the 4th day after the BPA. We might suggest that NTFs, notably BDNF, are involved in the mechanisms underlying neuropathic pain-like behavior following BPA. These pieces of evidence corroborate the notion that NTF blockers might represent a new and interesting option for the management of neuropathic pain. PMID- 17706871 TI - Effect of lateral morphology formation of polymer blend towards patterning silane based SAMs using selective dissolution method. AB - A number of strategies have been developed including soft lithography and photolithography for patterning various surfaces. Here we have discussed a customized strategy for surface patterning of nanosized, silane-based SAMs and monolayer thickness measurement investigated using atomic force microscope (AFM). We have utilized the versatile morphology of a binary polymer blend to generate patterned SAMs over silicon substrate by employing a selective dissolution procedure. This method was confirmed with different organosilanes with varying number of C-atoms and to other polymer blend. The samples were imaged both in tapping mode and pulsed force mode AFM. PMID- 17706872 TI - Molecular typing of Sarcocystis neurona: current status and future trends. AB - Sarcocystis neurona is an important protozoal pathogen because it causes the serious neurological disease equine protozoal myeloencephalitis (EPM). The capacity of this organism to cause a wide spectrum of neurological signs in horses and the broad geographic distribution of observed cases in the Americas drive the need for sensitive, reliable and rapid typing methods to characterize strains. Various molecular methods have been developed and used to diagnose EPM due to S. neurona, to identify S. neurona isolates and to determine the heterogeneity and evolutionary relatedness within this species and related Sarcocystis spp. These methods included sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), immuno-fluorescent assay (IFA), slide agglutination test (SAT), SnSAG-specific ELISA, random amplified polymorphic DNA (RAPD), PCR based restriction fragment length polymorphism (RFLP), amplified fragment length polymorphism (AFLP) fingerprinting, and sequence analysis of surface protein genes, ribosomal genes, microsatellite alleles and other molecular markers. Here, the utility of these molecular methods is reviewed and evaluated with respect to the need for molecular approaches that utilize well-characterized polymorphic, simple, independent, and stable genetic markers. These tools have the potential to add to knowledge of the genetic population structure of S. neurona and to provide new insights into the pathogenesis of EPM and S. neurona epidemiology. In particular, these methods provide new tools to address the hypothesis that particular genetic variants are associated with adverse clinical outcomes (severe pathotypes). The ultimate goal is to utilize them in future studies to improve treatment and prevention strategies. PMID- 17706873 TI - A novel 57-kDa merozoite protein of Babesia gibsoni is a prospective antigen for diagnosis and serosurvey of canine babesiosis by enzyme-linked immunosorbent assay. AB - We isolated a novel single copy gene encoding a 57-kDa merozoite protein of Babesia gibsoni (BgP57). The nucleotide sequence of the cDNA was 2387 bp with an open reading frame (ORF) of 1644 bp encoding a 57-kDa predicted polypeptide having 547 amino acid residues. The recombinant BgP57 (rBgP57) without a predicted signal peptide was expressed in Escherichia coli as a soluble glutathione S-transferase (GST) fusion protein. Western blotting showed that the corresponding native protein was 57-kDa, consistent with molecular weight of predicted mature polypeptide. An indirect enzyme-linked immunosorbent assay (ELISA) using the rBgP57 detected specific antibodies in the sequential sera from a dog experimentally infected with B. gibsoni. Moreover, the antigen did not cross-react with antibodies to B. canis sub-species and closely related apicomplexan parasites indicating that the rBgP57 was a specific antigen for B. gibsoni antibodies. The diagnostic performance of ELISA based on rBgP57 using 107 sera from B. gibsoni-naturally infected dogs was the same as the previously identified rBgP32 but performed better than the previously studied rBgP50. Although, seminested PCR detected higher proportions (82%) of positive samples than the ELISAs, the Mcnemar's chi-square test showed that there was no significant difference in relative effectiveness of rBgP57-ELISA and seminested PCR (chi(2)=2.70; P=0.1003) in identifying positive samples. The rBgP57-ELISA when used in combination with rBgP32-ELISA and rBgP50-ELISA appeared to improve sensitivity of the rBgP57-ELISA for detection of B. gibsoni antibodies. Overall, the rBgP57-ELISA and seminested PCR when used in combination, could improve epidemiological surveys and clinical diagnosis of B. gibsoni infection. PMID- 17706870 TI - Morphine treatment accelerates sarcoma-induced bone pain, bone loss, and spontaneous fracture in a murine model of bone cancer. AB - Metastatic bone cancer causes severe pain that is primarily treated with opioids. A model of bone cancer pain in which the progression of cancer pain and bone destruction is tightly controlled was used to evaluate the effects of sustained morphine treatment. In cancer-treated mice, morphine enhanced, rather than diminished, spontaneous, and evoked pain; these effects were dose-dependent and naloxone-sensitive. SP and CGRP positive DRG cells did not differ between sarcoma or control mice, but were increased following morphine in both groups. Morphine increased ATF-3 expression only in DRG cells of sarcoma mice. Morphine did not alter tumor growth in vitro or tumor burden in vivo but accelerated sarcoma induced bone destruction and doubled the incidence of spontaneous fracture in a dose- and naloxone-sensitive manner. Morphine increased osteoclast activity and upregulated IL-1 beta within the femurs of sarcoma-treated mice suggesting enhancement of sarcoma-induced osteolysis. These results indicate that sustained morphine increases pain, osteolysis, bone loss, and spontaneous fracture, as well as markers of neuronal damage in DRG cells and expression of pro-inflammatory cytokines. Morphine treatment may result in "add-on" mechanisms of pain beyond those engaged by sarcoma alone. While it is not known whether the present findings in this model of osteolytic sarcoma will generalize to other cancers or opioids, the data suggest a need for increased understanding of neurobiological consequences of prolonged opioid exposure which may allow improvements in the use of opiates in the effective management of cancer pain. PMID- 17706874 TI - First identification of Neospora caninum infection in aborted bovine foetuses in China. AB - The first identification of Neospora caninum infection in the tissues of aborted bovine foetuses in China is reported. Aborted foetuses were collected from 16 dams, and 12 of the dams had high serum antibody titres to N. caninum determined using an ELISA test kit. The Nc-5 gene of N. caninum was amplified from DNA samples extracted from brains of four aborted foetuses using a Neospora-specific PCR assay, confirming N. caninum infection in the aborted foetuses. Histology and immunohistochemistry showed thick-walled (3 microm) tissue cyst in 25 microm diameter in the brain of one foetus. Non-suppurative encephalomyelitis, focal haemorrhage, hepatic lesions consisted of lymphocyte infiltration and haemorrhage were also found in the heart and lung of the foetus. Thus, we have confirmed for the first time the infection of N. caninum in aborted foetuses of cattle in the People's Republic of China. PMID- 17706875 TI - Food-borne parasitic zoonosis. Proceedings of the Fourth Annual Meeting of the European Veterinary Parasitology College. May 12, 2006. Parma, Italy. PMID- 17706876 TI - Cardiotonic steroids on the road to anti-cancer therapy. AB - The sodium pump, Na(+)/K(+)-ATPase, could be an important target for the development of anti-cancer drugs as it serves as a versatile signal transducer, it is a key player in cell adhesion and its aberrant expression and activity are implicated in the development and progression of different cancers. Cardiotonic steroids, known ligands of the sodium pump have been widely used for the treatment of heart failure. However, early epidemiological evaluations and subsequent demonstration of anti-cancer activity in vitro and in vivo have indicated the possibility of developing this class of compound as chemotherapeutic agents in oncology. Their development to date as anti-cancer agents has however been impaired by a narrow therapeutic margin resulting from their potential to induce cardiovascular side-effects. The review will thus discuss (i) sodium pump structure, function, expression in diverse cancers and its chemical targeting and that of its sub-units, (ii) reported in vitro and in vivo anti-cancer activity of cardiotonic steroids, (iii) managing the toxicity of these compounds and the limitations of existing preclinical models to adequately predict the cardiotoxic potential of new molecules in man and (iv) the potential of chemical modification to reduce the cardiovascular side-effects and improve the anti-cancer activity of new molecules. PMID- 17706877 TI - Amphetamine effects in microtine rodents: a comparative study using monogamous and promiscuous vole species. AB - We compared amphetamine-induced dopamine release in the nucleus accumbens of vole species that exhibit differing mating systems to examine potential interactions between social organization and substance abuse. We found no species or regional differences in basal extracellular dopamine, however, monogamous voles had greater and longer-lasting increases in extracellular dopamine after amphetamine treatment than did promiscuous voles. We then examined whether amphetamine induced increase in extracellular dopamine could induce pair bonds in monogamous voles. We found that, despite increasing dopamine in the nucleus accumbens, amphetamine administration did not induce pair-bonds in male prairie voles unless the animals were pretreated to preclude D1 receptor activation, which is known to inhibit pair-bond formation. These results support suggestions that social attachment and substance abuse share a common neural substrate. PMID- 17706879 TI - A high soy diet reduces programmed cell death and enhances bcl-xL expression in experimental stroke. AB - Soy phytoestrogens have been proposed as an alternative to estrogen replacement therapy and have demonstrated potential neuroprotective effects in the brain. We have shown that a high soy diet significantly reduces infarct size following permanent middle cerebral artery occlusion (MCAO). Here, we tested the hypothesis that a high soy diet would attenuate programmed cell death after stroke. Adult female Sprague-Dawley rats were ovariectomized and fed either an isoflavone reduced diet (IFP) or a high soy diet (SP) for 2 weeks before undergoing 90 min of transient middle cerebral artery occlusion (tMCAO) followed by 22.5 h reperfusion. Infarct size, as assessed by triphenyltetrazolium chloride staining, was significantly reduced by a high soy diet (P<0.05). Apoptosis in the ischemic cortex, measured by TUNEL staining, was significantly reduced by the high soy diet. The number of active caspase-3 positive cells and caspase-mediated alpha spectrin cleavage were also significantly decreased in the ischemic cortex of SP rats. Furthermore, nuclear translocation of apoptosis-inducing factor (AIF) was significantly reduced in the ischemic cortex of SP rats. Soy significantly increased bcl-x(L) mRNA and protein expression in the ischemic cortex compared with IFP rats. Immunohistochemistry revealed increased neuronal expression of bcl 2 and bcl-x(L) in the ischemic cortex of both IFP and SP rats following tMCAO. These results suggest that a high soy diet decreases both caspase-dependent and caspase-independent programmed cell death following tMCAO. Further, a high soy diet enhances expression of the cell survival factor bcl-x(L) following tMCAO, contributing to the neuroprotective effects of soy in the ischemic cortex. PMID- 17706878 TI - I.v. cocaine induces rapid, transient excitation of striatal neurons via its action on peripheral neural elements: single-cell, iontophoretic study in awake and anesthetized rats. AB - Cocaine's (COC) direct interaction with the dopamine (DA) transporter is usually considered the most important action underlying the psychomotor stimulant and reinforcing effects of this drug. However, some physiological, behavioral and psycho-emotional effects of COC are very rapid and brief and they remain intact during DA receptor blockade, suggesting possible involvement of peripheral non-DA neural mechanisms. To assess this issue, single-unit recording with microiontophoresis was used to examine changes in impulse activity of dorsal and ventral striatal neurons to i.v. COC (0.25-0.5 mg/kg) in the same rats under two conditions: awake with DA receptor blockade and anesthetized with urethane. In the awake preparation approximately 70% striatal neurons showed rapid and transient (latency approximately 6 s, duration approximately 15 s) COC-induced excitations. These effects were stronger in ventral than dorsal striatum. During anesthesia, these phasic effects were fully blocked and COC slowly decreased neuronal discharge rate. Cocaine-methiodide (COC-M), a derivative that cannot cross the blood-brain barrier, also caused phasic excitations in the awake, but not anesthetized condition. In contrast to regular COC, COC-M had no tonic effect on discharge rate in either preparation. Most striatal neurons that were phasically excited by both COC forms also showed short-latency excitations during tail-touch and tail-pinch in the awake preparation, an effect strongly attenuated during anesthesia. Finally, most striatal neurons that in awake conditions were phasically excited by somato-sensory stimuli and COC salts were also excited by iontophoretic glutamate (GLU). Although striatal neurons were sensitive to GLU in both preparations, the response magnitude at the same GLU current was higher in awake than anesthetized conditions. These data suggest that in awake animals i.v. COC, like somato-sensory stimuli, transiently excites striatal neurons via its action on peripheral neural elements and rapid neural transmission. While the nature of these neuronal elements needs to be clarified using other analytical techniques, they might involve voltage-gated K(+) and Na(+) channels, which have a high affinity for COC and are located on terminals of visceral sensory nerves that densely innervate peripheral vessels. Therefore, along with direct action on specific brain substrates, central excitatory effects of COC may occur via indirect action, involving afferents of visceral sensory nerves and rapid neural transmission. By providing a rapid sensory signal and triggering transient neural activation, such a peripherally triggered action might play a crucial role in the sensory effects of COC, thus contributing to learning and development of drug taking behavior. PMID- 17706880 TI - Somatostatin inhibits the excitability of rat small-diameter trigeminal ganglion neurons that innervate nasal mucosa and project to the upper cervical dorsal horn via activation of somatostatin 2a receptor. AB - This study investigated whether somatostatin (SST) modulates the excitability of nociceptive trigeminal ganglion (TRG) neurons that innervate the nasal mucosa and project to the upper cervical (C(1)) dorsal horn by using perforated-patch clamping, retrograde-labeling, and immunohistochemistry. Fluorogold (FG) retrograde labeling was used to identify the rat TRG neurons innervating the nasal mucosa, while microbeads (MB) were used to label neurons projected onto the superficial layer of the C(1) dorsal horn. FG-labeled small-diameter TRG neurons exhibited SST(2A) receptor immunoreactivity (19%) and half of these neurons were also labeled with MB. In whole-cell current-clamp mode, most (72%) of the dissociated FG-/MB-labeled TRG neurons were hyperpolarized by application of SST. The hyperpolarization was evoked by SST in a concentration-dependent manner (0.1 10 microM) and the responses were associated with a decrease in the cell input resistance. The minimum concentration to elicit a significant hyperpolarization was 1 microM. The repetitive firings during a depolarizing pulse were significantly reduced by SST (1 microM) application. The hyperpolarization and decreased firing evoked by SST were both blocked by the SST(2) receptor antagonist, CYN154806 (1 microM). Under voltage-clamp conditions, SST (1 microM) significantly increased the voltage-gated K(+) transient (I(A)) and sustained (I(K)) currents and these increases were abolished by coapplication of CYN154806 (1 microM). In the presence of both 4-aminopyridine (6 mM) and tetraethylammonium (10 mM), no significant changes in the membrane potential in response to SST application were found. These results suggest that modulation of trigeminal nociceptive transmission in the C(1) dorsal horn by activation of SST(2A) receptors occurs at the level of small-diameter TRG cell bodies and/or their afferent terminals, and that this may be related to regulation of protective upper-airway reflexes. PMID- 17706882 TI - Central tegmental field and sexual behavior in the male rat: effects of neurotoxic lesions. AB - The medial preoptic area/anterior hypothalamus (MPOA/AH) is a key structure in the control of male sexual behavior. This area has reciprocal connections with mesencephalic and brainstem structures including the central tegmental field (CTF). It has been suggested that the CTF receives somatosensory information generated in the genitals promoting activation of the MPOA/AH. In the present study we evaluated the effects of bilateral neurotoxic lesions of the CTF upon male rat sexual behavior. We also explored the effects of these lesions on sociosexual behaviors, partner preference, sexual incentive motivation and motor execution. Tests were performed before and after bilateral quinolinic acid infusions. The lesion was evaluated by quantifying neuronal nuclei (Neu-N) and by the presence of glial fibrillary acidic protein (GFAP) immunohistochemistries. A significant reduction in the percentage of animals displaying mounts, intromissions, and ejaculations was observed in the bilateral and misplaced lesion groups 1 week after the lesion. In the second week post-lesion, only animals with bilateral damage of the CTF showed a significant reduction in sexual behavior. In the third post-lesion test, the percentage of animals displaying sexual behavior returned to control levels. The frequency of pursuit and self grooming was reduced, and genital exploration was increased after the lesion. Partner preference and sexual incentive motivation were not affected by the lesion suggesting that the CTF is not involved in the appetitive aspects of sexual behavior. Mount, intromission, and ejaculation latency were increased in animals with damage of the CTF and in animals with lesions outside this region. Motor execution was also affected in both groups, suggesting that alterations in latencies could be associated with damage not specific to the CTF. PMID- 17706881 TI - Multiple conductances are modulated by 5-HT receptor subtypes in rat subthalamic nucleus neurons. AB - Firing patterns of subthalamic nucleus (STN) neurons influence normal and abnormal movements. The STN expresses multiple 5-HT receptor subtypes that may regulate neuronal excitability. We used whole-cell patch-clamp recordings to characterize 5-HT receptor-mediated effects on membrane currents in STN neurons in rat brain slices. In 80 STN neurons under voltage-clamp (-70 mV), 5-HT (30 microM) evoked inward currents in 64%, outward currents in 17%, and biphasic currents in 19%. 5-HT-induced outward current was caused by an increased K(+) conductance (1.4+/-0.2 nS) and was blocked by the 5-HT(1A) antagonist WAY 100135. The 5-HT-evoked inward current, which was blocked by antagonists at 5-HT(2C) and/or 5-HT(4) receptors, had two types of current-voltage (I-V) relations. Currents associated with the type 1 I-V relation showed negative slope conductance at potentials <-110 mV and were occluded by Ba(2+). In contrast, the type 2 I-V relation appeared linear and had positive slope conductance (0.64+/ 0.11 nS). Type 2 inward currents were Ba(2+)-insensitive, and the reversal potential of -19 mV suggests a mixed cation conductance. In STN neurons in which 5-HT evoked inward currents, 5-HT potentiated burst firing induced by N-methyl-d aspartate (NMDA). But in neurons in which 5-HT evoked outward current, 5-HT slowed NMDA-dependent burst firing. We conclude that 5-HT receptor subtypes can differentially regulate firing pattern by modulating multiple conductances in STN neurons. PMID- 17706883 TI - Abnormalities in neuromuscular junction structure and skeletal muscle function in mice lacking the P2X2 nucleotide receptor. AB - ATP is co-released in significant quantities with acetylcholine from motor neurons at skeletal neuromuscular junctions (NMJ). However, the role of this neurotransmitter in muscle function remains unclear. The P2X2 ion channel receptor subunit is expressed during development of the skeletal NMJ, but not in adult muscle fibers, although it is re-expressed during muscle fiber regeneration. Using mice deficient for the P2X2 receptor subunit for ATP (P2X2(-/ )), we demonstrate a role for purinergic signaling in NMJ development. Whereas control NMJs were characterized by precise apposition of pre-synaptic motor nerve terminals and post-synaptic junctional folds rich in acetylcholine receptors (AChRs), NMJs in P2X2(-/-) mice were disorganized: misapposition of nerve terminals and post-synaptic AChR expression localization was common; the density of post-synaptic junctional folds was reduced; and there was increased end-plate fragmentation. These changes in NMJ structure were associated with muscle fiber atrophy. In addition there was an increase in the proportion of fast type muscle fibers. These findings demonstrate a role for P2X2 receptor-mediated signaling in NMJ formation and suggest that purinergic signaling may play an as yet largely unrecognized part in synapse formation. PMID- 17706884 TI - Electrophysiological properties and chemosensitivity of acutely dissociated trigeminal somata innervating the cornea. AB - Adult rat sensory trigeminal ganglion neurons innervating the cornea (cTGNs) were isolated and identified following retrograde dye labeling with FM1-43. Using standard whole-cell patch clamp recording techniques, cTGNs could be subdivided by their action potential (AP) duration. Fast cTGNs had AP durations <1 ms (40%) while slow cTGNs had AP durations >1 ms and an inflection on the repolarization phase of the AP. With the exception of membrane input resistance, the passive membrane properties of fast cTGNs were different from those of slow cTGNs (capacitance: 61+/-4.5 pF vs. 42+/-2.6 pF, resting membrane potential: -59+/-0.7 mV vs. -53+/-0.9 mV, for fast and slow cTGNs respectively). Active membrane properties also differed between fast and slow cTGNs. Slow cTGNs had a higher AP threshold (-25+/-1.6 mV vs. -38+/-0.8 mV), a larger rheobase (14+/-1.9 pA/pF vs. 6.8+/-1.0 pA/pF), and a smaller AP undershoot (-56+/-1.7 mV vs. -67+/-2.5 mV). The AP overshoot, however was similar between the two types of neurons (46+/-3.1 mV vs. 48+/-4 mV). Slow cTGNs were depolarized by capsaicin (1 microM, 80%) and 60% of their APs were blocked by tetrodotoxin (TTX) (100 nM). Fast cTGNs were unaffected by capsaicin and 100% of their APs were blocked by TTX. Similarly, cTGNs were also heterogeneous with respect to their responses to exogenous ATP and 5-HT. The current work shows that cTGNs have distinctive electrophysiological properties and chemosensitivity profiles. These characteristics may mirror the distinct properties of corneal sensory nerve terminals. The availability of isolated identified cTGNs constitutes a tractable model system to investigate the biophysical and pharmacological properties of corneal sensory nerve terminals. PMID- 17706885 TI - High frequency stimulation of the subthalamic nucleus improves speed of locomotion but impairs forelimb movement in Parkinsonian rats. AB - The subthalamic nucleus (STN) plays an important role in motor and non-motor behavior in Parkinson's disease, but its involvement in gait functions is largely unknown. In this study, we investigated the role of the STN on gait in a rat model of PD using the CatWalk method. Parkinsonian rats received bilateral high frequency stimulation (HFS) with different stimulation amplitudes of the STN. Rats were rendered parkinsonian by bilateral injections of 6-hydroxydopamine (6 OHDA) into the striatum. One group of 6-OHDA animals was implanted bilaterally with stimulation electrodes at the level of the STN. Stimulations were performed at 130 Hz (frequency), 60 micros (pulse width) and varying amplitudes of 0, 3, 30 and 150 microA. Rats were evaluated in an automated quantitative gait analysis method (CatWalk method). After behavioral evaluations, rats were killed and the brains processed for histological stainings to determine the impact of the dopaminergic lesion (tyrosine hydroxylase immunohistochemistry) and the localization of the electrode tip (hematoxylin-eosin histochemistry). Results show that bilateral 6-OHDA infusion significantly decreased (70%) the number of dopaminergic cells in the substantia nigra pars compacta (SNc). Due to 6-OHDA treatment, the gait parameters changed considerably. There was a general slowness. The most pronounced effects were seen at the level of the hind paws. Due to implantation of STN electrodes the step pattern changed. STN electrical stimulation improved the general slowness but induced slowing of the forelimb movement. Furthermore, we found that HFS with a medium amplitude significantly changed speed, the so-called dynamic aspect of gait. The static features of gait were only significantly influenced with low amplitude. Remarkably, STN stimulation affected predominantly the forepaws/limbs. PMID- 17706886 TI - Nicotinic receptor-mediated biphasic effect on neuronal excitability in chick lateral spiriform neurons. AB - Local neuronal circuits integrate synaptic information with different excitatory or inhibitory time windows. Here we report that activation of nicotinic acetylcholine receptors (nAChRs) leads to biphasic effects on excitability in chick lateral spiriform (SPL) neurons during whole cell recordings in brain slices. Carbachol (100 microM in the presence of 1 microM atropine) produced an initial short-term increase in the firing rates of SPL neurons (125+/-14% of control) that was mediated by postsynaptic nAChRs. However, after 3 min exposure to nicotinic agonists, the firing rate measured during an 800 ms depolarizing pulse declined to 19+/-7% (100 microM carbachol) or 26+/-8% (10 microM nicotine) of the control rate and remained decreased for 10-20 min after washout of the agonists. Similarly, after 60 s of electrically-stimulated release of endogenous acetylcholine (ACh) from cholinergic afferent fibers, there was a marked reduction (45+/-5% of control) in firing rates in SPL neurons. All of these effects were blocked by the nAChR antagonist dihydro-beta-erythroidine (30 microM). The inhibitory effect was not observed in Ca(2+)-free buffer. The nAChR mediated inhibition depended on active G-proteins in SPL neurons and was prevented by the GABA(B) receptor antagonist phaclofen (200 microM), while the GABA(B) receptor agonist baclofen (10 microM) decreased firing rate in SPL neurons to 13+/-1% of control. The inhibitory response thus appears to be due to a nAChR-mediated enhancement of presynaptic GABA release, which then activates postsynaptic GABA(B) receptors. In conclusion, activation of nAChRs in the SPL initiates a limited time window for an excitatory period, after which a prolonged inhibitory effect turns off this window. The prolonged inhibitory effect may serve to protect SPL neurons from excessive excitation. PMID- 17706887 TI - Daily stressor sensitivity, abuse effects, and cocaine use in cocaine dependence. AB - This study highlights respondent sensitivity to daily hassles as it relates to situational cocaine use and perceived long-term effects of adverse events in childhood. Data were drawn from a larger study on stress reactivity in cocaine dependent individuals. Participants (n=104) were cocaine dependent men and women without comorbid posttraumatic stress disorder (PTSD). They completed the Early Trauma Inventory (ETI), the Daily Hassles Scale (DHS), the Inventory of Drug Taking Situations (IDTS), and the Time-Line Follow-Back (TLFB; for 90 days prior to interview). There were no gender differences in the amount or frequency of cocaine use, although the patterns of use differed between male and female users. Overall, there were some associations in the patterns of cocaine use and sensitivity to daily hassles, particularly the use in response to conflict with others. Early negative life events were positively related to response to daily hassles, but current triggers were more relevant. Reactivity to cocaine cues was related to daily hassle sensitivity among women only. Limitations and implications of the findings are discussed. PMID- 17706888 TI - Predicting functional outcomes among college drinkers: reliability and predictive validity of the Young Adult Alcohol Consequences Questionnaire. AB - Heavy drinking and associated consequences are widespread among U.S. college students. Recently, Read et al. (Read, J. P., Kahler, C. W., Strong, D., & Colder, C. R. (2006). Development and preliminary validation of the Young Adult Alcohol Consequences Questionnaire. Journal of Studies on Alcohol, 67, 169-178) developed the Young Adult Alcohol Consequences Questionnaire (YAACQ) to assess the broad range of consequences that may result from heavy drinking in the college milieu. In the present study, we sought to add to the psychometric validation of this measure by employing a prospective design to examine the test retest reliability, concurrent validity, and predictive validity of the YAACQ. We also sought to examine the utility of the YAACQ administered early in the semester in the prediction of functional outcomes later in the semester, including the persistence of heavy drinking, and academic functioning. Ninety-two college students (48 females) completed a self-report assessment battery during the first weeks of the Fall semester, and approximately one week later. Additionally, 64 subjects (37 females) participated at an optional third time point at the end of the semester. Overall, the YAACQ demonstrated strong internal consistency, test-retest reliability, and concurrent and predictive validity. YAACQ scores also were predictive of both drinking frequency, and "binge" drinking frequency. YAACQ total scores at baseline were an early indicator of academic performance later in the semester, with greater number of total consequences experienced being negatively associated with end-of-semester grade point average. Specific YAACQ subscale scores (Impaired Control, Dependence Symptoms, Blackout Drinking) showed unique prediction of persistent drinking and academic outcomes. PMID- 17706890 TI - Angiotensine converting enzyme inhibitors/estrogen/cortisol: maybe an additional option in the treatment of psychiatrically disordered patients? PMID- 17706892 TI - Medical Hypotheses 2006 impact factor rises to 1.3--a vindication of the 'editorial review' system for revolutionary science. AB - The Thomson Scientific Impact Factor (IF) for Medical Hypotheses has risen to 1.299 for 2006. This means that the IF has more than doubled since 2004, when it stood at 0.607. Using Elsevier's Scopus database; in 2004 there were 437 citations to Medical Hypotheses papers published in the previous two years--by 2006 this had trebled to 1216 citations. Monthly internet usage of Medical Hypotheses run at an average of about 26000 papers downloaded per month. An IF of 1.3 means that Medical Hypotheses has now entered the mainstream level of 'respectable' medical journals, in terms of its usage by other scientists. This is particularly pleasing given the aim of the journal is to publish radical and speculative ideas. A healthy IF is important to Medical Hypotheses because the journal deploys a system of editorial review, rather than peer review, for evaluation and selection of papers. Editorial review involves selection of a journal's content primarily by an editor who has broad experience and competence in the field, assisted by a relatively small editorial advisory board. The great advantage of editorial review is that it is able, by policy, to favour the publication of revolutionary science. But since editorial review relies on hard to-quantify and non-transparent individual judgments, it is important for its outcomes to be open to objective evaluations. Scientometric measures of usage such as citations, impact factors and downloads constitute objective evidence concerning a journal's usefulness. Since Medical Hypotheses is performing adequately by such criteria, this provides a powerful answer to those who fetishize peer review and regard any other system of evaluation as suspect. Journal review procedures are merely a means to the end, and the end is a journal that serves a useful function in the dynamic process of science. Medical Hypotheses can now claim to perform such a role. PMID- 17706893 TI - How can the English-language scientific literature be made more accessible to non native speakers? Journals should allow greater use of referenced direct quotations in 'component-oriented' scientific writing. AB - In scientific writing, although clarity and precision of language are vital to effective communication, it seems undeniable that content is more important than form. Potentially valuable knowledge should not be excluded from the scientific literature merely because the researchers lack advanced language skills. Given that global scientific literature is overwhelmingly in the English-language, this presents a problem for non-native speakers. My proposal is that scientists should be permitted to construct papers using a substantial number of direct quotations from the already-published scientific literature. Quotations would need to be explicitly referenced so that the original author and publication should be given full credit for creating such a useful and valid description. At the extreme, this might result in a paper consisting mainly of a 'mosaic' of quotations from the already existing scientific literature, which are linked and extended by relatively few sentences comprising new data or ideas. This model bears some conceptual relationship to the recent trend in computing science for component based or component-oriented software engineering - in which new programs are constructed by reusing programme components, which may be available in libraries. A new functionality is constructed by linking-together many pre-existing chunks of software. I suggest that journal editors should, in their instructions to authors, explicitly allow this 'component-oriented' method of constructing scientific articles; and carefully describe how it can be accomplished in such a way that proper referencing is enforced, and full credit is allocated to the authors of the reused linguistic components. PMID- 17706889 TI - Prevalence of alternative forms of tobacco use in a population of young adult military recruits. AB - Recent evidence suggests that the popularity of certain alternative forms of tobacco may be increasing in adolescents. Little is known, however, about the use of these products among young adults. This study examined the use of alternative tobacco products including bidis, cigars, kreteks (clove cigarettes), pipes, and smokeless tobacco in a large sample of young adult military recruits (N=31107). Overall, 18.5% of participants were using some form of alternative tobacco product prior to entry into Basic Military Training. Results revealed a relatively high prevalence of cigar (12.3%) and smokeless tobacco use (6.7%). Use of other products was less common, including 1.1% for pipes, 2.0% for bidis, and 3.0% for kreteks. With the exception of kreteks, which did not differ by gender, the prevalence of use of alternative tobacco products was greater for males than for females (p<.001). Patterns of use also differed according to other demographic characteristics including race, ethnicity, age, and income. Implications for surveillance and tobacco control efforts are discussed. PMID- 17706894 TI - Two new compounds from Cleidion brevipetiolatum. AB - Two new compounds, 4-ethoxycarbonyloxy-3,3',4'-trimethoxy-ellagic acid (1) and 4 E-propenyl-phenol-1-O-beta-D-rutinoside (2), together with four known compounds, 3,3',4'-trimethoxy-ellagic acid (3), 3,3'-dimethoxy-ellagic acid (4), 3,3',4' trimethoxy-ellagic acid-4-O-beta-D-glucopyranoside (5) and 3'-methoxy-ellagic acid-4-O-alpha-L-rhamnopyranoside (6), were isolated from the whole plant of Cleidion brevipetiolatum. Their structures were elucidated from spectral evidences. PMID- 17706897 TI - Response-reinforcer relations and resistance to change. AB - Behavioral momentum theory suggests that the relation between a response and a reinforcer (i.e., response-reinforcer relation) governs response rates and the relation between a stimulus and a reinforcer (i.e., stimulus-reinforcer relation) governs resistance to change. The present experiments compared the effects degrading response-reinforcer relations with response-independent or delayed reinforcers on resistance to change in conditions with equal stimulus-reinforcer relations. In Experiment 1, pigeons responded on equal variable-interval schedules of immediate reinforcement in three components of a multiple schedule. Additional response-independent reinforcers were available in one component and additional delayed reinforcers were available in another component. The results showed that resistance to disruption was greater in the components with added reinforcers than without them (i.e., better stimulus-reinforcer relations), but did not differ for the components with added response-independent and delayed reinforcement. In Experiment 2, a component presenting immediate reinforcement alternated with either a component that arranged equal rates of reinforcement with a proportion of those reinforcers being response independent or a component with a proportion of the reinforcers being delayed. Results showed that resistance to disruption tended to be either similar across components or slightly lower when response-reinforcer relations were degraded with either response-independent or delayed reinforcers. These findings suggest that degrading response-reinforcer relations can impact resistance to change, but that impact does not depend on the specific method and is small relative to the effects of the stimulus-reinforcer relation. PMID- 17706896 TI - Cooperating in the face of uncertainty: a consistent framework for understanding the evolution of cooperation. AB - The evolution of cooperative behaviour, whereby individuals enhance the fitness of others at an apparent cost to themselves, represents one of the greatest paradoxes of evolution. Individuals that engage in such cooperative behaviour can, however, be favoured by natural selection if cooperative actions confer higher fitness than alternative actions. To understand the evolution of cooperative behaviour, the direct and indirect genetic benefits that individuals accrue in the present and future must be summed - this can be accomplished without any reference to the colorful vocabulary typically associated with studies of cooperation. When benefits are accrued indirectly through relatives or directly in the future individuals must be able to assess and enhance their probability of accruing those benefits and behave accordingly. We suggest that, in the same way that studies of kin recognition systems improved our understanding of how individuals assess and enhance their probability of accruing indirect benefits, studies of various forms of inheritance and reciprocation recognition systems will improve our understanding of how individuals assess and enhance their probability of accruing future benefits. Recognizing the parallel between studies of indirect fitness and future fitness, at multiple levels of analysis, will move us toward a simpler and more consistent framework for understanding the evolution of cooperative behaviour. PMID- 17706898 TI - Detection of hepatitis E virus (HEV) in a demographic managed wild boar (Sus scrofa scrofa) population in Italy. AB - Hepatitis E virus (HEV) is the causative agent of Hepatitis E. Swine and human HEV strains are genetically related, suggesting the occurrence of zoonotic transmission. Recently, in Japan, cases of food-borne HEV transmission have been described in people after consuming raw or undercooked meat from wild boars or pigs. Although, swine HEV strains have been detected in pig herds in many European countries, only minimal information is presently available about the circulation and the prevalence of HEV in wild boars in Europe. In this study, we investigated the presence of HEV in a demographic managed wild boar population in Italy. Detection of HEV RNA was accomplished using a nested reverse-transcription polymerase chain reaction on bile samples from 88 shot animals. HEV RNA was detected in 22 out of 88 animals tested (25%). Phylogenetic analysis on the nucleotide sequences obtained from 10 positive PCR products indicated that only one HEV strain was circulating in the wild boar population considered, and that this strain was closer to human and swine HEV strains circulating in Europe than to wild boar Japanese strains. PMID- 17706899 TI - Antiproliferative effects and apoptosis induction by probiotic cytoplasmic extracts in fish cell lines. AB - Probiotic bacteria are known to exert a wide range of beneficial effects on their animal hosts. Control of intestinal homeostasis, inflammation suppression and a reduction in the incidence of cancer all rely on the antiproliferative potential of probiotics. In this paper, we assess the antiproliferative activity of probiotics in two teleost fish cell lines SAF-1, a fibroblast cell line and EPC, an epithelioma from carp. Cells were grown in the presence of cytoplasmic extracts obtained from two bacterial strains, Lactobacillus delbrueckii subsp. lactis (LDL) and 51M6. Proliferation and apoptosis were measured after 4, 24, 48 or 72h in culture by the crystal violet or by double staining flow cytometry assays, respectively. Generally, LDL had stronger effects on cell growth than 51M6. Moreover, SAF-1 cells were more susceptible to growth inhibition than EPC cells. Apoptosis took place following growth inhibition, especially when LDL extracts were used. The results are discussed in terms of the biological significance of probiotic bacteria that naturally occur on the fish mucosal surfaces with an emphasis on how dose and species specificity may be determinant factors. PMID- 17706900 TI - Susceptibility of sheep to European bat lyssavirus type-1 and -2 infection: a clinical pathogenesis study. AB - European bat lyssaviruses (EBLVs) have been known to cross the species barrier from their native bat host to other terrestrial mammals. In this study, we have confirmed EBLV-1 and EBLV-2 susceptibility in sheep (Ovis ammon) following intracranial and peripheral (intramuscular) inoculation. Notably, mild clinical disease was observed in those exposed to virus via the intramuscular route. Following the intramuscular challenge, 75% of the animals infected with EBLV-1 and 100% of those that were challenged with EBLV-2 developed clinical signs of rabies and then recovered during the 94-day observation period. Disease pathogenesis also varied substantially between the two viruses. Infection with EBLV-1 resulted in peracute clinical signs, which are suggestive of motor neuron involvement. Antibody induction was observed and substantial inflammatrory infiltrate in the brain. In contrast, more antigen was detected in the EBLV-2 infected sheep brains but less inflammatory infiltrate and no virus neutralising antibody was evident. The latter involved a more protracted disease that was behaviour orientated. A high infectious dose was required to establish EBLV infection under experimental conditions (> or =5.0 logs/ml) but the infectious dose in field cases remains unknown. These data confirm that sheep are susceptible to infection with EBLV but that there is variability in pathogenesis including neuroinvasiveness that varies with the route of infection. This study suggests that inter-species animal-to-animal transmission of a bat variant of rabies virus to a terrestrial mammal host may be limited, and may not always result in fatal encephalitis. PMID- 17706901 TI - Melatonin and estradiol effects on food intake, body weight, and leptin in ovariectomized rats. AB - OBJECTIVE: The study in ovariectomized (Ovx) rats, as a model of menopausal status, of the effects of melatonin (M) and/or estradiol (E), associated or not with food restriction, on body weight (BW) and serum leptin levels. METHODS: Female SD rats (200-250 g) were Ovx and treated with E, M, E+M or its diluents. Control sham-Ovx rats were treated with E-M diluents. After 7 weeks being fed ad libitum, the animals were exposed for 7 more weeks to a 30% food restriction. We measured: food intake, BW, nocturnal and diurnal urinary excretion of sulphatoxymelatonin (aMT6s), leptin in midday and midnight blood samples, glucose, total cholesterol, LDL, HDL and triglycerides. RESULTS: Day/night rhythm of aMT6s excretion was preserved in all cases. The increase of aMT6s excretion in M-treated animals basically affected the nocturnal period. In animals fed ad libitum, E fully prevented Ovx-induced increase of BW, leptin and cholesterol. Melatonin reduced food intake and partially prevented the increase of BW and cholesterol, without changing leptin levels. Under food restriction, M was the most effective treatment in reducing BW and cholesterol. Leptin levels were similar in M, E or E+M treated rats, and lower than in untreated Ovx rats. CONCLUSIONS: Our result gives a preliminary experimental basis for a post menopausal co-treatment with estradiol and melatonin. It could combine the effectiveness of estradiol (not modified by melatonin) with the positive effects of melatonin (improvement of sleep quality, prevention of breast cancer, etc.). The possible beneficial effects of melatonin which could justify its use, need to be demonstrated in clinical trials. PMID- 17706902 TI - Increased bioavailability of a transdermal application of a nano-sized emulsion preparation. AB - The aim of this study was to compare the transdermal application of a nano-sized emulsion versus a micron-sized emulsion preparation of delta tocopherol as it relates to particle size and bioavailability. Two separate experiments were performed using seven F1B Syrian Golden hamsters, 1 week apart. Each emulsion preparation consisted of canola oil, polysorbate 80, deionized water and delta tocopherol; the only difference between the two preparations was processing the nano-sized emulsion with the Microfluidizer Processor. Both were formulated into a cream and applied to the shaven dorsal area. The particle size of the micron sized emulsion preparation was 2788 nm compared to 65 nm for the nano-sized emulsion formulation. Two hours post-application, hamsters that were applied the nano-sized emulsion had a 36-fold significant increase of plasma delta tocopherol, where as hamsters that were applied the micron-sized emulsion only had a 9-fold significant increase, compared to baseline, respectively. At 3h post application, plasma delta tocopherol had significantly increased 68-fold for hamsters applied the nano-sized emulsion, whereas only an 11-fold significant increase was observed in hamsters applied the micron-sized emulsion, compared to baseline, respectively. Significant differences were also observed between the nano-sized and micron-sized emulsion at 2 and 3h post-application. This study suggests that nano-sized emulsions significantly increase the bioavailability of transdermally applied delta tocopherol. PMID- 17706903 TI - Design and in vivo evaluation of a patch delivery system for insulin based on thiolated polymers. AB - PURPOSE: The aim of this study was to develop and evaluate a novel three-layered oral delivery system for insulin in vivo. METHODS: The patch system consisted of a mucoadhesive layer, a water insoluble backing layer made of ethylcellulose and an enteric coating made of Eudragit. Drug release studies were performed in media mimicking stomach and intestinal fluids. For in vivo studies patch systems were administered orally to conscious non-diabetic rats. Orally administered insulin in aqueous solution was used as control. After the oral administration of the patch systems a decrease of glucose and increase of insulin blood levels were measured. RESULTS: The mucoadhesive layer, exhibiting a diameter of 2.5mm and a weight of 5mg, comprised polycarbophil-cysteine conjugate (49%), bovine insulin (26%), gluthatione (5%) and mannitol (20%). 74.8+/-4.8% of insulin was released from the delivery system over 6h. Six hours after administration of the patch system mean maximum decrease of blood glucose level of 31.6% of the initial value could be observed. Maximum insulin concentration in blood was 11.3+/-6.2ng/ml and was reached 6h after administration. The relative bioavailability of orally administered patch system versus subcutaneous injection was 2.2%. CONCLUSION: The results indicate that the patch system provides enhancement of intestinal absorption and thereby offers a promising strategy for peroral peptide delivery. PMID- 17706904 TI - Diuretic activity of Withania aristata: an endemic Canary Island species. AB - This study reports on the pharmacological evaluation of the diuretic activity of an infusion and a methanol extract of Withania aristata Ait. in laboratory rats. Water excretion rate, pH, density, conductivity, and content of Na(+), K(+) and Cl(-) were measured in the urine of rats subjected to hypersaline conditions. Both the infusion and the methanol extract showed a significant diuretic effect compared with non-treated controls, with notable increases in the rates of water and sodium excretion. There was also a potassium retention effect. The diuretic effect did not appear to be related to the potassium content in the material tested, but did have some relation to its content of active polar compounds. The results justify the use of Withania aristata as a diuretic agent in folk medicine of the Canary Islands. PMID- 17706905 TI - Neural cell death is induced by neutralizing antibody to nerve growth factor: an in vivo study. AB - The central nervous system (CNS) of vertebrates originates from neuroepithelial cells located within the embryonic neural tube. Coincidental with the processes of proliferation, migration and differentiation in the developing CNS, cell death is also a major phenomenon during normal development. The investigation of neural cell death in development has focused on the role of target-derived survival factors such as nerve growth factor (NGF). In this study, the effects of anti-NGF antibody on neural cell death in the cerebral cortex have been investigated. Injection of anti-NGF antibody into the cisterna magnum of mouse pups increased the number of neural cell deaths and resulted in thinning of the cerebral cortex compared with a control group. It is concluded that endogenous NGF is essential for cortical cell survival in the cerebral cortex of the newborn mouse. Moreover, this method may be applied to the other factors and different CNS regions, allowing identification of molecules and signals involved in neural cell survival. PMID- 17706906 TI - Clinical and MRI findings of brucellar spondylodiscitis. AB - OBJECTIVE: The aim of this retrospective study was to report the clinical features and MR imaging findings of patients with brucellar spondylodiscitis. MATERIALS AND METHODS: Twenty-two patients with spondylodiscitis, recruited among 152 patients with brucellosis referred from the Department of Infectious Diseases. Patients were diagnosed based on positive clinical findings, > or =1/160 titers of brucella agglutination tests and/or positive blood cultures. Magnetic resonance imaging (MRI) was performed to all of the patients with spondylodiscitis. Signal changes and enhancement of vertebral bodies, involvement of paravertebral soft tissues and epidural spaces, nerve root and cord compression and abscess formation were assessed. RESULTS: All of the patients (n=22; 7 F, 15 M) had > or =1/160 titers of brucella agglutination test and blood culture was positive in 9. A great majority of the patients had involvement at only one vertebrae level (n=21, 95.5%), whereas one patient (4.5%) had multilevel involvement. In MRI, eight patients had soft tissue involvement and three had abscess formation. All cases had vertebral and discal enhancement. Additionally epidural extension was detected in four cases, posterior longitudinal ligament (PLL) elevation in five cases and root compression in two cases. CONCLUSION: Brucella is still a public health problem in endemic areas. MRI is a highly sensitive and non-invasive imaging technique which should be first choice of imaging in the early diagnosis of spondylodiscitis. PMID- 17706908 TI - New Afipia and Bosea strains isolated from various water sources by amoebal co culture. AB - It has been suspected that some species belonging to the alphaproteobacteria might cause pneumonia in humans. It is thus of special interest to isolate new members of this phylum, and to further characterize their pathogenicity. The amoebal co-culture method allowed the isolation of various new bacterial species during the last few years, including fastidious alphaproteobacterial species that were isolated from complex environments. In this work, we isolated new bacterial strains from a drinking water network or from river water using amoebal co culture with Acanthamoeba castellanii. One Afipia sp. strain and two Bosea sp. strains presented 16SrDNA and partial rpoB gene sequences suggesting that they could be representative of new species, and were thus further characterized using phenotypic tests. PMID- 17706907 TI - Host-specific association between Flavobacterium columnare genomovars and fish species. AB - A total of 90 Flavobacterium columnare isolates were recovered from predominant wild fish species in the Mobile River, Alabama, USA. Isolates were identified and confirmed by fatty acid methyl ester analysis and specific PCR amplification. Genomovar ascription was performed using 16S-restriction fragment length polymorphism (RFLP) analysis. The majority of genomovar I isolates were recovered from threadfin shad while genomovar II isolates came from catfish (including channel and blue catfish). Additional genotyping methods, including multilocus sequence analysis (MLSA), internal spacer region-single strand conformation polymorphism analysis (ISR-SSCP) and amplified fragment length polymorphism (AFLP), confirmed a clear division of the isolates into two groups that matched genomovar ascription. Fingerprinting methods revealed a higher genetic diversity within genomovar II isolates. Our data confirmed the coexistence of F. columnare genomovars I and II in a natural environment. A statistically significant association between genomovar I and threadfin shad was demonstrated while genomovar II strains were mainly recovered from catfish species. PMID- 17706909 TI - Stability of [6]-gingerol and [6]-shogaol in simulated gastric and intestinal fluids. AB - The degradation kinetics of [6]-gingerol and [6]-shogaol were investigated in simulated gastric (pH 1) and intestinal (pH 7.4) fluids at 37 degrees C. Degradation products were quantitatively determined by HPLC (Lichrospher 60 RP select B column, 5 microm, 125 mm x 4 mm; mobile phase: methanol-water-acetic acid (60:39:1 v/v); flow rate: 0.6 ml/min; detection UV: 280 nm). In simulated gastric fluid (SGF) [6]-gingerol and [6]-shogaol underwent first-order reversible dehydration and hydration reactions to form [6]-shogaol and [6]-gingerol, respectively. The degradation was catalyzed by hydrogen ions and reached equilibrium at approximately 200 h. In simulated intestinal fluid (SIF) both [6] gingerol and [6]-shogaol showed insignificant interconversion between one another. Addition of amino acids glycine, 3-amino propionic acid (beta-alanine) and gamma-amino butyric acid (GABA), and ammonium acetate at a range of concentrations of 0.05-0.5mM had no effect on the rate of degradation of [6] shogaol in SGF and 0.1M HCl solution. However, at exceedingly high concentration (0.5M) of ammonium acetate and glycine, significant amounts of [6]-shogaol ammonia and glycine adducts were detected. The degradation profile of [6] gingerol and [6]-shogaol under simulated physiological conditions reported in this study will provide insight into the stability of these compounds when administered orally. PMID- 17706910 TI - Usefulness of the Threatening Medical Situations Inventory in individuals considering genetic testing for cancer risk. AB - OBJECTIVE: To assess the psychometric properties of the Threatening Medical Situations Inventory (TMSI) in a community sample (Study 1), and to examine its usefulness in individuals with a strong family history of cancer (Study 2). METHODS: Study 1 participants (N=276) completed 2 online surveys, 14 days apart. Study 2 participants (N=311) completed 2 questionnaires, 6 months apart. RESULTS: Both studies revealed the inventory was psychometrically sound, although some concerns were raised about the factor structure. High monitors in Study 1 reported desiring more health-related information and an active role in medical decision-making. High monitors in Study 2 had the greatest knowledge increase when they received a detailed decision aid, compared to a brief pamphlet. CONCLUSION: The TMSI is appropriate for use in both community and clinical samples. High monitors in the general community are more likely to prefer receiving as much health-related information as possible and desire an active role in decision-making about their health. PRACTICE IMPLICATIONS: Familial cancer clinic patients may benefit from tailoring the amount of information they receive to their coping style, such that patients who are vigilant information seekers may benefit most from receiving more detailed information about genetic testing. PMID- 17706911 TI - Genotoxicity and antigenotoxicity of cashew (Anacardium occidentale L.) in V79 cells. AB - The use of plants for the treatment of diseases continues to rise although there are few studies providing proof of these effects. One of these plants is the Anacardium occidentale, popularly known as the cashew. The present study evaluated the possible genotoxic and protective activities of cashew stem bark methanolic extract, in vitro, using methyl methanesulfonate (MMS) as a positive control, to compare possible mechanisms of DNA damage induction in the Comet assay. The antigenotoxicity protocols used were pre, simultaneous and post treatment in relation to MMS. In genotoxicity and antigenotoxicity assessments, besides MMS, PBS was used as the negative control and three concentrations of the A. occidentale extract (500 microg/mL, 1000 microg/mL and 2000 microg/mL) were used on Chinese hamster lung fibroblasts (V79 cells). The Comet assay revealed that the two lowest concentrations tested presented no genotoxic activity, whereas the highest presented genotoxicity. All of the concentrations showed protective activity in simultaneous and post-treatment in relation to MMS. Further studies are required to identify the substances that comprise the extract and more clearly comprehend the antigenotoxic mechanism detected in this study. PMID- 17706912 TI - Acute and subacute toxic effects produced by microcystin-YR on the fish cell lines RTG-2 and PLHC-1. AB - Approximately 80 microcystins (MCs) variants have been isolated in surface water worldwide. The toxicity of the most frequently MCs are encountered, MC-LR and MC RR, has been extensively studied in humans and animals. However, studies dealing with MC-YR toxicity are still scarce. In this work, the toxic effects of MC-YR were investigated in the fish cell line PLHC-1, derived from a hepatocellular carcinoma of the topminnow Poeciliopsis lucida, and RTG-2 fibroblast-like cells derived from the gonads of rainbow trout Oncorhynchus mykiss. After 48 h, morphological and biochemical changes (total protein content, neutral red uptake and methylthiazol tetrazolium salt metabolization) were determined. The most sensitive endpoint for both cell lines was the reduction of total protein content, with EC(50) values of 35 microM for PLHC-1 cells and 67 microM for the RTG-2 cell line. Lysosomal function and methylthiazol tetrazolium salt metabolization were stimulated at low concentrations, while they decreased at high doses. Increase of piknotic cells, rounding effects, reduction in cell number and cell size, hydropic degeneration, and death mainly by necrosis but also by apoptosis were observed in the morphological study. Furthermore, PLHC-1 cells are more sensitive than RTG-2 cells to MC-YR exposure. These results were similar to those obtained when both cell lines were exposed for 24h to a Microcystis aeruginosa isolated strain extract containing MC-LR. PMID- 17706913 TI - Promoter, alternative splice forms, and genomic structure of protocadherin 15. AB - We originally showed that the protocadherin 15 gene (Pcdh15) is necessary for hearing and balance functions; mutations in Pcdh15 affect hair cell development in Ames waltzer (av) mice. Here we extend that study to understand better how Pcdh15 operates in a cell. The original report identified 33 exons in Pcdh15, with exon 1 being noncoding; additional exons of Pcdh15 have since been reported. The 33 exons of Pcdh15 described originally are embedded in 409 kb of mouse genomic sequence, while the corresponding exons of human PCDH15 are spread over 980 kb of genomic DNA; the exons in Pcdh15/PCDH15 range in size from 9 to approximately 2000 bp. The genomic organization of Pcdh15/PCDH15 bears similarity to that of cadherin 23, but differs significantly from other protocadherin genes, such as Pcdhalpha, beta, or gamma. A CpG island is located approximately 2900 bp upstream of the PCDH15 transcriptional start site. The Pcdh15/PCDH15 promoter lacks TATAA or CAAT sequences within 100 bases upstream of the transcription start site; deletion mapping showed that Pcdh15 harbors suppressor and enhancer elements. Preliminary searches for alternatively spliced transcripts of Pcdh15 identified novel splice variants not reported previously. Results from our study show that both mouse and human protocadherin 15 genes have complex genomic structures and transcription control mechanisms. PMID- 17706916 TI - Neuropeptides: active participants in regulation of immune responses in the CNS and periphery. PMID- 17706914 TI - Comprehensive analysis of transport proteins encoded within the genome of Bdellovibrio bacteriovorus. AB - Bdellovibrio bacteriovorus is a bacterial parasite with an unusual lifestyle. It grows and reproduces in the periplasm of a host prey bacterium. The complete genome sequence of B. bacteriovorus has recently been reported. We have reanalyzed the transport proteins encoded within the B. bacteriovorus genome according to the current content of the Transporter Classification Database. A comprehensive analysis is given on the types and numbers of transport systems that B. bacteriovorus has. In this regard, the potential protein secretory capabilities of at least four types of inner-membrane secretion systems and five types of outer-membrane secretion systems are described. Surprisingly, B. bacteriovorus has a disproportionate percentage of cytoplasmic membrane channels and outer-membrane porins. It has far more TonB/ExbBD-type systems and MotAB-type systems for energizing outer-membrane transport and motility than does Escherichia coli. Analysis of probable substrate specificities of its transporters provides clues to its metabolic preferences. Interesting examples of gene fusions and of potentially overlapping genes are also noted. Our analyses provide a comprehensive, detailed appreciation of the transport capabilities of B. bacteriovorus. They should serve as a guide for functional experimental analyses. PMID- 17706915 TI - Chronic stress and regulation of cellular markers of inflammation in rheumatoid arthritis: implications for fatigue. AB - OBJECTIVES: This study examined whether chronic interpersonal stress is associated with cellular markers of inflammation and regulation of these responses by in vitro doses of glucocorticoids in rheumatoid arthritis (RA) patients. The association between these markers of inflammation and fatigue was also tested. METHODS: Fifty-eight RA patients completed up to 30 daily ratings of the stressfulness of their interpersonal relations. Interleukin-6 (IL-6) production was analyzed in lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cell cultures with and without varying concentrations of the glucocorticoid hydrocortisone. In addition, plasma levels of IL-6 and C-reactive protein (CRP) were analyzed, and subjective ratings of fatigue and pain were obtained on the day of blood sampling. RESULTS: Multilevel modeling showed that higher chronic interpersonal stress was associated with greater stimulated IL-6 production (p<0.05) as well as greater resistance to hydrocortisone inhibition of IL-6 production (p<0.05). These relations were not accounted for by demographic factors, body mass index, or steroid medication use. Stimulated production of IL 6, in turn, was associated with greater levels of self-reported fatigue, controlling for pain (p<0.05). Neither chronic stress ratings nor fatigue symptoms were related to plasma levels of IL-6 or CRP (ps>.05). CONCLUSIONS: Among RA patients, chronic interpersonal stress is associated with greater stimulated cellular production of IL-6 along with impairments in the capacity of glucocorticoids to inhibit this cellular inflammatory response. Moreover, these findings add to a growing body of data that implicate heightened proinflammatory cytokine activity in those at risk for fatigue symptoms. PMID- 17706918 TI - Predictors of inflammation in response to anthracycline-based chemotherapy for breast cancer. AB - Although chemotherapy for breast cancer can increase inflammation, few studies have examined predictors of this phenomenon. This study examined potential contributions of demographics, disease characteristics, and treatment regimens to markers of inflammation in response to chemotherapy for breast cancer. Thirty five women with stage I-III-A breast cancer (mean age 50 years) were studied prior to cycle 1 and prior to cycle 4 of anthracycline-based chemotherapy. Circulating levels of inflammatory markers with high relevance to breast cancer were examined, including C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), Interleukin-1 receptor antagonist (IL1-RA), vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule-1 (sICAM-1), Interleukin- (IL-6), soluble P-selectin (sP-selectin), and von Willebrand factor (vWf). Chemotherapy was associated with elevations in VEGF (p < or = 0.01), sICAM 1 (p < or = 0.01), sP-selectin (p < or = 0.02) and vWf (p < or = 0.05). Multiple regression analysis controlling for age and body mass index (BMI) showed that higher post-chemotherapy levels of inflammation were consistently related to higher pre-chemotherapy levels of inflammation (ps < or =0.05) as well as to certain disease characteristics. Post-chemotherapy IL-6 levels were higher in patients who had larger tumors (p < or = 0.05) while post-chemotherapy VEGF levels were higher in patients who had smaller tumors (p < or = 0.05). Post chemotherapy sP-selectin levels were highest in women who had received epirubicin, cytoxan, 5-fluorouracil chemotherapy (p < or = 0.01). These findings indicate that chemotherapy treatment can be associated with elevations in certain markers of inflammation, particularly markers of endothelial and platelet activation. Inflammation in response to chemotherapy is most significantly related to inflammation that existed prior to chemotherapy but also potentially to treatment regimen and to certain disease characteristics. PMID- 17706917 TI - Psychosocial influences on immunity, including effects on immune maturation and senescence. AB - Studies investigating the influence of psychosocial factors on immunity played a critical and formative role in the field of psychoneuroimmunology (PNI), and have been a major component of articles published in Brain, Behavior and Immunity (BBI). An analysis of papers during the first two decades of BBI from 1987-2006 revealed three behavior-related topics were most prominent: (1) stress-induced changes in immune responses, (2) immune correlates of psychopathology and personality, and (3) behavioral conditioning of immunity. Important subthemes included the effect of early rearing conditions on immune maturation in the developing infant and, subsequently, psychosocial influences affecting the decline of immunity in the senescent host. The responsiveness of cell functioning in the young and elderly helped to validate the view that our immune competence is malleable. Many technical advances in immune methods were also evident. Initially, there was a greater reliance on in vitro proliferative and cytolytic assays, while later studies were more likely to use cell subset enumerations, cytokine quantification, and indices of latent virus reactivation. The reach of PNI extended from the traditional clinical entities of infection, autoimmunity, and cancer to attain a broader relevance to inflammatory physiology, and thus to asthma, cardiovascular and gastrointestinal disease. There continue to be many theoretical and applied ramifications of these seminal findings. Fortunately, the initial controversies about whether psychological processes could really impinge upon and modify immune responses have now receded into the pages of history under the weight of the empirical evidence. PMID- 17706919 TI - Down syndrome time-clustering in January 1987 in Belarus: link with the Chernobyl accident? AB - The Chernobyl accident (April 26, 1986) exposed a large part of the Belarus population to ionizing radiation. We analyzed the time trends of Down syndrome (DS) in Belarus to evaluate whether either brief exposure at high dose rates during the plume passage or continuous exposure at low doses and dose rates of the residents of contaminated areas had any detectable impact on DS prevalence at birth. DS data came from the Belarus National Registry of Congenital Malformations (1981-2001). We observed a significant peak of DS in January 1987 (26 cases observed and 9.84 expected; observed/expected ratio=2.64; 95% CI=1.72 3.76), but found no positive long-term time trends in contaminated or control areas. The time occurrence of the January peak, high dose rates during the plume passage and experimental data showing a radiosensitive phase of oogenesis around conception time in mammals suggest that the January peak may be linked to the Chernobyl plume. PMID- 17706920 TI - Effect of bisphenol A on human chorionic gonadotrophin-stimulated gene expression of cultured mouse Leydig tumour cells. AB - Endocrine disrupting chemicals (EDCs) have been reported to affect the reproductive system of various animal species. However, their specific effects and modes of action on gonadal function remain largely unclear. We studied the effects of a model EDC, bisphenol A (BPA), on human chorionic gonadotrophin (hCG) stimulated global gene expression of cultured mouse Leydig tumour cells (mLTC-1). The time and dose of BPA exposure were set after semiquantitative (sq) RT-PCR analysis of response of candidate genes (StAR, Cyp 17 a1 and AR) to 3h at 10 microg/l hCG +/- 10(-5)M BPA. Affymetrix microarray analysis demonstrated > or =1.5-fold up-regulation of 8- and < or =1.5-fold down-regulated of 16 genes by BPA. Several of these genes were related to steroid/cholesterol metabolism/transport and cell cycle regulation. sqRT-PCR demonstrated induction of StAR expression by hCG stimulation and no effect of BPA. In conclusion, our results indicate that BPA has only subtle modulating effects on gene expression of gonadotrophin-stimulated mLTC-1 cells. PMID- 17706922 TI - L-Dopa treatment abolishes the numerical increase in striatal dopaminergic neurons in parkinsonian monkeys. AB - The striatum harbors a population of dopaminergic interneurons that increases in number in animal models of Parkinson's disease (PD), presumably to compensate for dopamine (DA) depletion. The purpose of the present study was to determine the fate of striatal dopaminergic neurons in parkinsonian monkeys in which striatal DA depletion had been alleviated by systemic administration of l-dopa. The number of striatal dopaminergic neurons, visualized with tyrosine hydroxylase (TH) immunohistochemistry, was measured in three groups of cynomolgus (Macaca fascicularis) monkeys: (1) normal untreated monkeys; (2) monkeys rendered parkinsonian following systemic injection of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), but otherwise untreated; and (3) MPTP-intoxicated monkeys that received oral l-dopa on a chronic basis. In agreement with previous studies, the number of striatal TH-positive (TH+) neurons in l-dopa-free parkinsonian monkeys was significantly higher (p<0.05) than in normal (non parkinsonian) monkeys. However, this increase was abolished in parkinsonian monkeys that received l-dopa treatment. In fact, the number of striatal TH+ neurons in l-dopa-treated parkinsonian monkeys was not significantly different (p>0.05) from values obtained in normal monkeys. These findings suggest that the DA concentration regulates the numerical density of this ectopic neuronal population, a phenomenon that is more likely the result of a shift in the phenotype of preexistent striatal interneurons rather than the recruitment of newborn neurons that would eventually develop a DA phenotype. Our data also reinforce the hypothesis that striatal TH+ neurons act as local DA source and, as such, are part of a compensatory mechanism that could be artificially enhanced to alleviate or delay PD symptoms. PMID- 17706924 TI - Heterooligomerization of human dopamine receptor 2 and somatostatin receptor 2 Co immunoprecipitation and fluorescence resonance energy transfer analysis. AB - Somatostatin and dopamine receptors are well expressed and co-localized in several brain regions, suggesting the possibility of functional interactions. In the present study we used a combination of pharmacological, biochemical and photobleaching fluorescence resonance energy transfer (pbFRET) to determine the functional interactions between human somatostatin receptor 2 (hSSTR2) and human dopamine receptor 2 (hD2R) in both co-transfected CHO-K1 or HEK-293 cells as well as in cultured neuronal cells which express both the receptors endogenously. In monotransfected CHO-K1 or HEK-293 cells, D2R exists as a preformed dimer which is insensitive to agonist or antagonist treatment. In control CHO-K1 cells stably co transfected with hD2R and hSSTR2, relatively low FRET efficiency and weak expression in co-immunoprecipitate from HEK-293 cells suggest the absence of preformed heterooligomers. However, upon treatment with selective ligands, hD2R and hSSTR2 exhibit heterodimerization. Agonist-induced heterodimerization was accompanied by increased affinity for dopamine and augmented hD2R signalling as well as prolonged hSSTR2 internalization. In contrast, cultured striatal neurons display constitutive heterodimerization between D2R and SSTR2, which were agonist independent. However, heterodimerization in neurons was completely abolished in the presence of the D2R antagonist eticlopride. These findings suggest that hD2R and hSSTR2 operate as functional heterodimers modulated by ligands in situ, which may prove to be a useful model in designing new therapeutic drugs. PMID- 17706921 TI - An evaluation of evidence for the carcinogenic activity of bisphenol A. AB - The National Institutes of Health (NIEHS, NIDCR) and the United States Environmental Protection Agency convened an expert panel of scientists with experience in the field of environmental endocrine disruptors, particularly with knowledge and research on bisphenol A (BPA). Five subpanels were charged to review the published literature and previous reports in five specific areas and to compile a consensus report with recommendations. These were presented and discussed at an open forum entitled "Bisphenol A: An Expert Panel Examination of the Relevance of Ecological, In Vitro and Laboratory Animal Studies for Assessing Risks to Human Health" in Chapel Hill, NC on 28-30 November 2006. The present review consists of the consensus report on the evidence for a role of BPA in carcinogenesis, examining the available evidence in humans and animal models with recommendations for future areas of research. PMID- 17706923 TI - The relation of low-level prenatal lead exposure to behavioral indicators of attention in Inuit infants in Arctic Quebec. AB - The aim of this study was to investigate the association between prenatal exposure to lead (Pb) and several aspects of behavioral function during infancy through examiner ratings and behavioral coding of video recordings. The sample consisted of 169 11-month-old Inuit infants from Arctic Quebec. Umbilical cord and maternal blood samples were used to document prenatal exposure to Pb. Average blood Pb levels were 4.6 mug/dL and 5.9 mug/dL in cord and maternal samples respectively. The Behavior Rating Scales (BRS) from the Bayley Scales of Infant Development (BSID-II) were used to assess behavior. Attention was assessed through the BRS and behavioral coding of video recordings taken during the administration of the BSID-II. Whereas the examiner ratings of behaviors detected very few associations with prenatal Pb exposure, cord blood Pb concentrations were significantly related to the direct observational measures of infant attention, after adjustment for confounding variables. These data provide evidence that increasing the specificity and the precision of the behavioral assessment has considerable potential for improving our ability to detect low-to moderate associations between neurotoxicants, such Pb and infant behavior. PMID- 17706926 TI - Antibacterial prophylaxis in neutropenic patients. AB - Antibiotic prophylaxis has been used for several decades to prevent infection in chemotherapy-induced neutropenia and its benefits have been debated just as long. Recent analysis suggests that quinolones may actually be life saving in high-risk groups such as acute leukaemia and autologous bone marrow transplant but these benefits are likely to be negated in the long term by the development of quinolone resistance. PMID- 17706927 TI - An advanced NMR protocol for the structural characterization of aluminophosphate glasses. AB - In this work a combination of complementary advanced solid-state nuclear magnetic resonance (NMR) strategies is employed to analyse the network organization in aluminophosphate glasses to an unprecedented level of detailed insight. The combined results from MAS, MQMAS and (31)P-{(27)Al}-CP-heteronuclear correlation spectroscopy (HETCOR) NMR experiments allow for a detailed speciation of the different phosphate and aluminate species present in the glass. The interconnection of these local building units to an extended three-dimensional network is explored employing heteronuclear dipolar and scalar NMR approaches to quantify P-O-Al connectivity by (31)P{(27)Al}-heteronuclear multiple quantum coherence (HMQC), -rotational echo adiabatic passage double resonance (REAPDOR) and -HETCOR NMR as well as (27)Al{(31)P}-rotational echo double resonance (REDOR) NMR experiments, complemented by (31)P-2D-J-RESolved MAS NMR experiments to probe P-O-P connectivity utilizing the through bond scalar J-coupling. The combination of the results from the various NMR approaches enables us to not only quantify the phosphate units present in the glass but also to identify their respective structural environments within the three-dimensional network on a medium length scale employing a modified Q notation, Q(n)(m),(AlO)(x), where n denotes the number of connected tetrahedral phosphate, m gives the number of aluminate species connected to a central phosphate unit and x specifies the nature of the bonded aluminate species (i.e. 4, 5 or 6 coordinate aluminium). PMID- 17706936 TI - Valproic acid metabolites inhibit dihydrolipoyl dehydrogenase activity leading to impaired 2-oxoglutarate-driven oxidative phosphorylation. AB - The effect of the antiepileptic drug valproic acid (VPA) on mitochondrial oxidative phosphorylation (OXPHOS) was investigated in vitro. Two experimental approaches were used, in the presence of selected respiratory-chain substrates: (1) formation of ATP in digitonin permeabilized rat hepatocytes and (2) measurement of the rate of oxygen consumption by polarography in rat liver mitochondria. VPA (0.1-1.0 mM) was found to inhibit oxygen consumption and ATP synthesis under state 3 conditions with glutamate and 2-oxoglutarate as respiratory substrates. No inhibitory effect on OXPHOS was observed when succinate (plus rotenone) was used as substrate. We tested the hypothesis that dihydrolipoyl dehydrogenase (DLDH) might be a direct target of VPA, especially its acyl-CoA intermediates. Valproyl-CoA (0.5-1.0 mM) and valproyl-dephosphoCoA (0.5-1.0 mM) both inhibited the DLDH activity, acting apparently by different mechanisms. The decreased activity of DLDH induced by VPA metabolites may, at least in part, account for the impaired rate of oxygen consumption and ATP synthesis in mitochondria if 2-oxoglutarate or glutamate were used as respiratory substrates, thus limiting the flux of these substrates through the citric acid cycle. PMID- 17706925 TI - Signaling crossroads: the function of Raf kinase inhibitory protein in cancer, the central nervous system and reproduction. AB - The Raf kinase inhibitory protein 1 (RKIP-1) and its orthologs are conserved throughout evolution and widely expressed in eukaryotic organisms. In its non phosphorylated form RKIP-1 negatively regulates the Raf/MEK/ERK pathway by interfering with the activity of Raf-1. In its phosphorylated state, RKIP-1 dissociates from Raf-1 and inhibits GRK-2, a negative regulator of G-protein coupled receptors (GPCRs). Available data indicate that the phosphorylation of RKIP-1 by PKC can stimulate both the Raf/MEK/ERK and GPCR pathways. RKIP-1 has also been implicated as a negative regulator of the NF-kappaB pathway. Recent studies have shown that phosphorylated RKIP-1 binds to the centrosomal and kinetochore regions of metaphase chromosomes, where it may be involved in regulating the partitioning of chromosomes and the progression through mitosis. The collective evidence indicates that RKIP-1 regulates the activity and mediates the crosstalk between several important cellular signaling pathways. A variety of ablative interventions suggest that reduced RKIP-1 function may influence metastasis, angiogenesis, resistance to apoptosis, and genome integrity. Attenuation of RKIP-1 may also affect cardiac and neurological functions, spermatogenesis, sperm decapacitation, and reproductive behavior. In this review, the role of RKIP-1 in cellular signaling, and especially its functions revealed using a mouse knockout model, are discussed. PMID- 17706937 TI - Expression of Ndi1p, an alternative NADH:ubiquinone oxidoreductase, increases mitochondrial membrane potential in a C. elegans model of mitochondrial disease. AB - The NADH:ubiquinone oxidoreductase or complex I of the mitochondrial respiratory chain is an intricate enzyme with a vital role in energy metabolism. Mutations affecting complex I can affect at least three processes; they can impair the oxidation of NADH, reduce the enzyme's ability to pump protons for the generation of a mitochondrial membrane potential and increase the production of damaging reactive oxygen species. We have previously developed a nematode model of complex I-associated mitochondrial dysfunction that features hallmark characteristics of mitochondrial disease, such as lactic acidosis and decreased respiration. We have expressed the Saccharomyces cerevisiae NDI1 gene, which encodes a single subunit NADH dehydrogenase, in a strain of Caenorhabditis elegans with an impaired complex I. Expression of Ndi1p produces marked improvements in animal fitness and reproduction, increases respiration rates and restores mitochondrial membrane potential to wild type levels. Ndi1p functionally integrates into the nematode respiratory chain and mitigates the deleterious effects of a complex I deficit. However, we have also shown that Ndi1p cannot substitute for the absence of complex I. Nevertheless, the yeast Ndi1p should be considered as a candidate for gene therapy in human diseases involving complex I. PMID- 17706938 TI - Dynamics of the glutamic acid 242 side chain in cytochrome c oxidase. AB - In many cytochrome c oxidases glutamic acid 242 is required for proton transfer to the binuclear heme a(3)/Cu(B) site, and for proton pumping. When present, the side chain of Glu-242 is orientated "down" towards the proton-transferring D pathway in all available crystal structures. A nonpolar cavity "above" Glu-242 is empty in these structures. Yet, proton transfer from Glu-242 to the binuclear site, and for proton-pumping, is well established, and the cavity has been proposed to at least transiently contain water molecules that would mediate proton transfer. Such proton transfer has been proposed to require isomerisation of the Glu-242 side chain into an "up" position pointing towards the cavity. Here, we have explored the molecular dynamics of the protonated Glu-242 side chain. We find that the "up" position is preferred energetically when the cavity contains four water molecules, but the "down" position is favoured with less water. We conclude that the cavity might be deficient in water in the crystal structures, possibly reflecting the "resting" state of the enzyme, and that the "up/down" equilibrium of Glu-242 may be coupled to the presence of active-site water molecules produced by O(2) reduction. PMID- 17706939 TI - Dopamine enhances mtNOS activity: implications in mitochondrial function. AB - Dopamine and nitric oxide systems can interact in different processes in the central nervous system. Dopamine and oxidation products have been related to mitochondrial dysfunction. In the present study, intact mitochondria and submitochondrial membranes were incubated with different DA concentrations for 5 min. Dopamine (1 mM) increased nitric oxide production in submitochondrial membranes and this effect was partially prevented in the presence of both DA and NOS inhibitor N(omega)-nitro-L-arginine (L-NNA). A 46% decrease in state 3 oxygen uptake (active respiration state) was found after 15 mM dopamine incubation. When mitochondria were incubated with 15 mM dopamine in the presence of L-NNA, state 3 respiratory rate was decreased by only 17% showing the involvement of NO. As shown for O(2) consumption, the inhibition of cytochrome oxidase by 1 mM DA was mediated by NO. Hydrogen peroxide production significantly increased after 15 mM DA incubation, being mainly due to its metabolism by MAO. Also, DA-induced depolarization was prevented by the addition of L-NNA showing the involvement of nitric oxide in this process too. This work provides evidence that in the studied conditions, dopamine modifies mitochondrial function by a nitric oxide-dependent pathway. PMID- 17706940 TI - A novel method to quantify H+-ATPase-dependent Na+ transport across plasma membrane vesicles. AB - To prevent sodium toxicity in plants, Na(+) is excluded from the cytosol to the apoplast or the vacuole by Na(+)/H(+) antiporters. The secondary active transport of Na(+) to apoplast against its electrochemical gradient is driven by plasma membrane H(+)-ATPases that hydrolyze ATP and pump H(+) across the plasma membrane. Current methods to determine Na(+) flux rely either on the use of Na isotopes ((22)Na) which require special working permission or sophisticated equipment or on indirect methods estimating changes in the H(+) gradient due to H(+)-ATPase in the presence or absence of Na(+) by pH-sensitive probes. To date, there are no methods that can directly quantify H(+)-ATPase-dependent Na(+) transport in plasma membrane vesicles. We developed a method to measure bidirectional H(+)-ATPase-dependent Na(+) transport in isolated membrane vesicle systems using atomic absorption spectrometry (AAS). The experiments were performed using plasma membrane-enriched vesicles isolated by aqueous two-phase partitioning from leaves of Populus tomentosa. Since most of the plasma membrane vesicles have a sealed right-side-out orientation after repeated aqueous two phase partitioning, the ATP-binding sites of H(+)-ATPases are exposed towards inner side. Leaky vesicles were preloaded with Na(+) sealed for the study of H(+) ATPase-dependent Na(+) transport. Our data implicate that Na(+) movement across vesicle membranes is highly dependent on H(+)-ATPase activity requiring ATP and Mg(2+) and displays optimum rates of 2.50 microM Na(+) mg(-1) membrane protein min(-1) at pH 6.5 and 25 degrees C. In this study, for the first time, we establish new protocols for the preparation of sealed preloaded right-side-out vesicles for the study of H(+)-ATPase-dependent Na(+) transport. The results demonstrate that the Na(+) content of various types of plasma membrane vesicle can be directly quantified by AAS, and the results measured using AAS method were consistent with those determined by the previous established fluorescence probe method. The method is a convenient system for the study of bidirectional H(+) ATPase-dependent Na(+) transport with membrane vesicles. PMID- 17706941 TI - Systemic administration of diazoxide induces delayed preconditioning against transient focal cerebral ischemia in rats. AB - Diazoxide is the prototypical opener of mitochondrial ATP-sensitive potassium channels (mitoK(ATP)) and protects neurons in vivo and in vitro against chemical and anoxic stresses. While we have previously shown that diazoxide administration induces acute preconditioning against transient cerebral ischemia in rats, the potential for delayed preconditioning of diazoxide has not been examined. The purpose of this study was to determine whether diazoxide promotes delayed preconditioning following 90 min of middle cerebral artery occlusion (MCAO) in male Wistar rats. Diazoxide (10 mg/kg) or vehicle was injected intraperitoneally 24 h before MCAO. Infarct volumes were measured 72 h after reperfusion. In animals anesthetized with halothane, treatment with diazoxide exhibited a 35% reduction (48.3+/-3.0% to 31.3+/-4.8%) and 18% reduction (35.1+/-2.2% to 28.9+/ 2.1%) in cortical and subcortical infarct volumes, respectively. Administration of the mitoK(ATP) blocker 5-hydroxydecanoate attenuated this beneficial effect. In contrast, diazoxide did not induce delayed preconditioning in isoflurane anesthetized rats. These findings support the concept that diazoxide produces delayed preconditioning via mitoK(ATP) activation but that physiological status can affect induction of preconditioning. PMID- 17706942 TI - Altered development of neuronal progenitor cells after stimulation with autistic blood sera. AB - Changes of brain structure and functions in people with autism may result from altered neuronal development, however, no adequate cellular or animal models are available to study neurogenesis in autism. Neuronal development can be modeled in culture of neuronal progenitor cells (NPCs) stimulated with serum to differentiate into neurons. Because sera from people with autism and age-matched controls contain different levels of numerous biologically active factors, we hypothesized that development of human NPCs induced to differentiate into neurons with sera from children with autism reflects the altered early neuronal development that leads to autism. The control and autistic sera were collected from siblings aged below 6 years that lived in the same environment. The effect of sera on differentiation of NPC neurospheres into neuronal colonies was tested in 72-h-long cultures by morphometry, immunocytochemistry and immunoblotting. We found that sera from children with autism significantly reduced NPCs' proliferation, but stimulated cell migration, development of small neurons with processes, length of processes and synaptogenesis. These results suggest that development of network of processes and synaptogenesis--the specific events in the brain during postnatal ontogenesis--are altered in autism. Further studies in this cell culture model may explain some of the cellular alterations described in autistic patients. PMID- 17706944 TI - Antioxidant strategies based on tomato-enriched food or pyruvate do not affect disease onset and survival in an animal model of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder which is mostly sporadic, although about 5-10% of the cases are inherited. About 15-20% of patients with familial ALS (FALS) carry mutations in the gene encoding the free radical scavenging enzyme Cu/Zn superoxide dismutase (SOD1). In this study, we explored the potential neuroprotective effects of antioxidant strategies based on either a tomato-enriched diet, or pyruvate administration, in an animal model of ALS. To that aim, transgenic mice expressing a mutant form of SOD1 [the gly(93) --> ala (G93A) substitution; G93A SOD1] were fed on either tomato enriched food pellets or the Altromin diet in which milk serum and proteins substitute for soy and fish flours. In both cases, treatments were started at the 29th day of age. In a second set of experiments, G93A SOD1 mice were treated with pyruvate intraperitoneally (500 mg/kg, i.p; starting at the 70th day of age) and compared with control mice receiving i.p. saline injections. Our results indicate that neither the tomato-enriched diet nor pyruvate administration caused any significant effect on the overall survival time and disease onset in G93A SOD1 mice. Thus, despite the wealth of data indicating the relevant role of oxidative stress and defective energy homeostasis both in patients and animal models of ALS, antioxidant strategies based on tomato-enriched food or pyruvate seem to be not sufficient to promote a disease modifying effect in an animal model of ALS. PMID- 17706943 TI - A pharmacological activator of AMP-activated protein kinase (AMPK) induces astrocyte stellation. AB - AMP-activated protein kinase (AMPK) represents a key energy-sensing molecule in many cell types. Because astrocytes are key mediators of metabolic signaling in the brain, we have initiated studies on the expression and activation of AMPK in these cells. Treatment of cultured rat cortical astrocytes with a pharmacological AMPK activator, AICA-riboside (AICAR) resulted in a time- and concentration dependent increase in phosphorylation of AMPK and acetyl-CoA carboxylase (ACC), a direct substrate. AICAR treatment also induced a transition from epithelioid to stellate morphology in a time- and concentration-dependent manner. As stellation is indicative of actin cytoskeletal reorganization, the formation of stress fibers and focal adhesions in response to AICAR was assessed. AICAR-induced stellation correlated with F-actin disassembly and focal adhesion dispersal. Furthermore, transient transfection of an activated RhoA construct prevented AICAR-induced stellation, indicating a mechanism upstream of RhoA. Use of pharmacological inhibitor compound C prevented AICAR-induced stellation demonstrating necessity of AMPK activity for the response. Our findings suggest that AMPK mediates morphological alterations of astrocytes in response to energy depletion. PMID- 17706945 TI - Involvement of the Snk-SPAR pathway in glutamate-induced excitotoxicity in cultured hippocampal neurons. AB - The serum-induced kinase (Snk)-spine-associated Rap GTPase-activating protein (SPAR) signaling pathway is reported as a new molecular mechanism in activity dependent remodeling of synapses. However, the relationship between Snk-SPAR pathway and glutamate-induced excitotoxicity is not well understood. We report here that in cultured hippocampal neurons, glutamate stimulation induces the activation of Snk-SPAR pathway, and leads to a loss of mature dendritic spines. The time-dependent changes in Snk and SPAR expression after glutamate exposure are also elucidated. Furthermore, the activation of Snk-SPAR pathway induced by glutamate treatment can be blocked by an NMDA receptor antagonist, MK801. These results demonstrate that Snk-SPAR pathway may play a pivotal role in glutamate induced excitotoxic damage in CNS through regulating the stability of synapse. PMID- 17706947 TI - Dynamic interaction between medial prefrontal cortex and nucleus accumbens as a function of both motivational state and reinforcer magnitude: a c-Fos immunocytochemistry study. AB - This study examined the effects of simultaneous variations in motivational state (food deprivation) and reinforcer magnitude (food presentation) on c-Fos immunoreactivity in the pre- and infralimbic medial prefrontal cortex (mPFC), nucleus accumbens (NAcc) core and shell, and dorsal striatum. In the first experiment, c-Fos was reliably increased in pre- and infralimbic mPFC of animals 12 and 36 h compared to 0 h deprived. In the second experiment, a small meal (2.5 g) selectively increased c-Fos immunoreactivity in both mPFC subdivisions of 36 h deprived animals, as well as in both NAcc subdivisions of 12 h deprived animals. Correlational analyses revealed a changing relationship between mPFC subregions and the NAcc compartments to which they project. In subjects 12 h deprived and allowed a small meal, c-Fos counts in prelimbic mPFC and NAcc core were positively correlated, as were those in infralimbic mPFC and NAcc shell (r=0.83 and 0.76, respectively). The opposite was true of animals 36 h deprived, with prelimbic mPFC/NAcc core and infralimbic mPFC/NAcc shell negatively correlated (r=-0.85 and -0.82, respectively). The third experiment examined the effects of unrestricted feeding (presentation of 20 g food) after 0, 12, or 36 h of deprivation. No differences between mean c-Fos counts were found, though prelimbic mPFC/NAcc core and mPFC/NAcc shell were positively correlated in animals 36 h deprived (r=0.76 and 0.89, respectively). These data suggest that the activity within the mPFC and NAcc, as well as the interaction between the two, changes as a complex combinatorial function of motivational state and reinforcer magnitude. PMID- 17706946 TI - Sensitivity of the hypothalamic paraventricular nucleus to the locomotor activating effects of neuromedin U in obesity. AB - Obesity is associated with a decrease in energy expenditure relative to energy intake. The decrease in physical activity associated with obesity in several species, including humans, contributes to decreased energy expenditure. Several hormones and neuropeptides that affect appetite also modulate physical activity, including neuromedin U (NMU), a peptide found in the gut and brain. We have demonstrated that NMU microinjected into the hypothalamic paraventricular nucleus (PVN) in rats increases the energy expenditure associated with physical activity, called non-exercise activity thermogenesis (NEAT). Here we examined whether obesity in rats is related to decreased sensitivity of the PVN to the locomotor activating effect of NMU. Diet-induced obese (DIO) rats and lean, diet-resistant (DR) rats were given PVN microinjections of increasing doses of NMU both before and after 1 month on a high-fat diet. We found that NMU increases physical activity, energy expenditure, and NEAT in a dose-dependent manner in both DR and DIO rats, both before and after 1 month on the high-fat diet. Before high-fat feeding, the obesity-prone and lean rats showed similar levels of physical activity after intra-PVN microinjections of NMU. After 1 month of the high-fat diet, however, the obesity-resistant rats showed significantly more NMU-induced physical activity compared to the obese DIO rats. Taken together with previous studies, these results suggest that obesity may represent a state associated with decreased central sensitivity to neuropeptides such as NMU that increase physical activity and therefore energy expenditure. PMID- 17706950 TI - Prefrontal white matter abnormalities in young adult with major depressive disorder: a diffusion tensor imaging study. AB - Prefrontal impairments have been hypothesized to be most strongly associated with the cognitive and emotional dysfunction in depression. Recently, white matter microstructural abnormalities in prefrontal lobe have been reported in elderly patients with major depressive disorder (MDD) using diffusion tensor imaging (DTI). However, it is still unclear whether the same changes exist in younger patients. In the present study, we first utilized DTI to detect prefrontal white matter in young adults with MDD. Nineteen first-episode, untreated young adults with MDD and twenty age- and gender-matched healthy controls were recruited. DTI and localizing anatomic data were acquired. Then, the regions of interest (ROIs) were located in prefrontal white matter at 4 mm inferior, and 0, 4, 8, 12, 16 and 20 mm superior to the anterior commissure-posterior commissure (AC-PC) plane, respectively. Compared with healthy controls, patients with MDD showed significantly lower fractional anisotropy (FA) values in prefrontal white matter at bilateral 20 mm, right 16 mm and right 12 mm above the AC-PC. Furthermore, there was no significant correlation between the FA value of any ROI and illness course as well as severity of depression. Together with previous findings, the present results suggest that microstructural abnormalities in prefrontal white matter may occur early in the course of MDD and may be related to the neuropathology of depression throughout adulthood from young to elderly. PMID- 17706949 TI - Effects of long-term administration of HMG-CoA reductase inhibitor, atorvastatin, on stroke events and local cerebral blood flow in stroke-prone spontaneously hypertensive rats. AB - The objective of this study was to determine whether the long-term administration of an HMG-CoA reductase inhibitor, atorvastatin, confers protective effects against stroke events in stroke-prone spontaneously hypertensive rats (SHRSPs). Atorvastatin (2 mg/kg, 20 mg/kg) or vehicle was orally administered to 8-week-old SHRSPs for 11 weeks. The survival ratio and stroke incidence were calculated, and plasma lipids and plasma levels of asymmetric dimethylarginine (ADMA), a circulating endogenous competitive inhibitor of NO synthase, were measured after sacrifice. The effect of atorvastatin on local cerebral blood flow (l-CBF) was also determined in 13-week-old SHRSPs after treatment with 20 mg/kg atorvastatin daily for 5 weeks. The survival ratios at 19 weeks of age were 15, 30, and 50% in the vehicle, low-dose (2 mg/kg), and high-dose groups (20 mg/kg), respectively. The survival ratio was significantly higher in the high-dose group than in the vehicle group. The incidence of stroke was significantly lower in the high-dose group than in the vehicle group. The levels of ADMA were 0.81+/-0.18 (mean+/ S.D.), 0.62+/-0.09, and 0.61+/-0.06 micromol/l in the vehicle, low-dose, and high dose groups, respectively. Atorvastatin administration significantly reduced the ADMA levels without affecting the levels of plasma lipids. The level of l-CBF tended to be higher in the treated group, but not to a significant extent. Thus, atorvastatin was determined to confer a protective effect against hypertension based stroke. The data suggest that the efficacy of the statin for stroke protection may be partially involved in the improvement of endothelial function via NO production and reduction of ADMA. Statins may confer useful protection against not only atherosclerosis-based stroke, but also hypertension-based stroke. PMID- 17706951 TI - Something is rotten in the state of angiogenesis -- H2S as gaseous stimulator of angiogenesis. PMID- 17706948 TI - Abnormal cerebellar cytoarchitecture and impaired inhibitory signaling in adult mice lacking TR4 orphan nuclear receptor. AB - Since testicular orphan nuclear receptor 4 (TR4) was cloned, its physiological functions remain largely unknown. In this study, the TR4 knockout (TR4(-/-)) mouse model was used to investigate the role of TR4 in the adult cerebellum. Behaviorally, these null mice exhibit unsteady gait, as well as involuntary postural and kinetic movements, indicating a disturbance of cerebellar function. In the TR4(-/-) brain, cerebellar restricted hypoplasia is severe and cerebellar vermal lobules VI and VII are underdeveloped, while no structural alterations in the cerebral cortex are observed. Histological analysis of the TR4(-/-) cerebellar cortex reveals reductions in granule cell density, as well as a decreased number of parallel fiber boutons that are enlarged in size. Further analyses reveal that the levels of GABA and GAD are decreased in both Purkinje cells and interneurons of the TR4(-/-) cerebellum, suggesting that the inhibitory circuits signaling within and from the cerebellum may be perturbed. In addition, in the TR4(-/-) cerebellum, immunoreactivity of GluR2/3 was reduced in Purkinje cells, but increased in the deep cerebellar nuclei. Together, these results suggest that the behavioral phenotype of TR4(-/-) mice may result from disrupted inhibitory pathways in the cerebellum. No progressive atrophy was observed at various adult stages in the TR4(-/-) brain, therefore the disturbances most likely originate from a failure to establish proper connections between principal neurons in the cerebellum during development. PMID- 17706952 TI - Infarct size limitation by adrenomedullin: protein kinase A but not PI3-kinase is linked to mitochondrial KCa channels. AB - AIM: Adrenomedullin (ADM) has been shown to protect the heart against ischaemic injury, but little is known of the underlying mechanism. Mitochondrial Ca(2+) activated K(+) (mitoK(Ca)) channels play a key role in cardioprotection. This study examined whether mitoK(Ca) channel is involved in the protection afforded by ADM. METHODS: Flavoprotein fluorescence in rabbit ventricular myocytes was measured to assay mitoK(Ca) channel activity. Infarct size in the isolated perfused rabbit hearts subjected to 30-min global ischaemia and 120-min reperfusion was determined by triphenyltetrazolium chloride staining. RESULTS: The mitoK(Ca) channel opener NS1619 (30 microM) partially oxidized flavoprotein. ADM (10 nM) augmented the NS1619-induced flavoprotein oxidation when applied after the effect of NS1619 had reached steady state. This potentiating effect of ADM was prevented by the protein kinase A (PKA) inhibitor KT5720 (200 nM), but not by the phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002 (5 microM). The mitoK(Ca) channel blocker paxilline (PX, 2 microM) completely blocked the oxidative effects of NS1619 in the presence of ADM. Treatment with ADM for 10 min before ischaemia significantly reduced infarct size after ischaemia/reperfusion from 63 +/- 3% in controls to 32 +/- 4% (P < 0.01). This infarct size-limiting effect of ADM was abolished by PX (61 +/- 2%), as well as by KT5720 (62 +/- 3%). ADM treatment for the first 10 min of reperfusion significantly reduced infarct size compared with controls (42 +/- 3%, P < 0.01). This cardioprotective effect of ADM was unaffected by PX (38 +/- 4%), but was abolished by LY294002 (60 +/- 4%). CONCLUSIONS: ADM augments the opening of mitoK(Ca) channels by PKA activation, but not by PI3-K activation. ADM treatment prior to ischaemia reduces infarct size via PKA-mediated activation of mitoK(Ca) channels. On the other hand, ADM treatment upon reperfusion reduces infarct size via a PI3-K-mediated pathway without activating mitoK(Ca) channels. PMID- 17706953 TI - Osteoprotegerin upregulates endothelial cell adhesion molecule response to tumor necrosis factor-alpha associated with induction of angiopoietin-2. AB - OBJECTIVE: Osteoprotegerin (OPG) and osteopontin (OPN) have been identified within unstable atherosclerosis and circulating concentrates have been linked to cardiovascular events. We studied the influence of OPG and OPN on endothelial adhesion molecule expression and monocyte binding. METHODS: Resting or tumor necrosis factor (TNF-alpha) activated human endothelial cells were incubated with OPG (0, 0.5, 5, and 10 ng/mL) or OPN (0, 2.5, 10 and 50 nmol/L). The expression of endothelial genes and proteins was investigated with the Oligo GEArray microarray series, multiplexed gene expression analysis, flow cytometry, ELISA and immunohistochemistry. Monocyte-binding studies were carried out using fluorescently labeled THP-1 cells and analysed by flow cytometry. RESULTS: OPG but not OPN stimulated a dose-dependent increase in the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E selectin by endothelial cells in the presence of TNF-alpha (p12 micromol/L) was significantly associated with sVCAM levels (p=0.036). The NOx levels were lower in the hyperhomocysteinemia group than in the normal homocysteine group, but the difference was not significant. The genotypes were not significantly associated with either sE-selectin or sICAM. CONCLUSIONS: The detrimental T allele exerted an additive effect to increase sVCAM and decrease NOx concentrations, which may contribute to atherosclerosis. PMID- 17707075 TI - Radiation therapy for cervical cancer in the elderly. AB - OBJECTIVE: To evaluate the long-term results of radical radiation therapy (RT) for cervical cancer in elderly patients. METHODS: We reviewed the clinical records of 727 patients with cervical cancer who underwent radical RT at the Tokushima University Hospital and compared the treatment results of three age groups: /=75 years (older group [OG], 132 patients). RESULTS: At the last follow-up, 155 YG (46%), 77 YOG (30%), and 48 OG patients (36%) had died of cervical cancer; the median follow-up periods were 82, 87, and 68 months, respectively. The 5-/10-year disease-specific survival rates were 60%/52% in YG, 76%/68% in YOG, and 66%/57% in OG. Differences between OG and the other groups were not significant. The 5-/10-year disease-specific survival rate of YOG was significantly superior to that of YG (p<0.001). Clinical stage was the only significant prognostic variable (p<0.001). Late radiation morbidity of grades 2-4 in the bladder and/or rectum occurred in 22% of YG, 31% of YOG, and 8% of OG patients. CONCLUSIONS: RT was well tolerated in elderly patients, and age was not a significant prognostic factor. In the management of cervical cancer, advanced age is not a contraindication to radical RT. PMID- 17707076 TI - Comparison of cyclists' and motorists' utilitarian physical activity at an urban university. AB - OBJECTIVE: Preliminary comparison of cyclists and motorists on: (1) distance lived from campus and, (2) the impact of transportation mode on physical activity. METHODS: A purposive sample of students (n=50; cyclists=26, motorists=24) living <5 miles from Arizona State University campus wore an accelerometer and completed a travel log for two on-campus days during fall 2005 spring 2006. Residence distance to campus was calculated by geocoded addresses (n=45; cyclists=23 vs. motorists=22). Final outcome variables were: distance lived from campus, accelerometer time moderate-to-vigorous physical activity, steps/day, total time moderate-to-vigorous physical activity (logged minutes cycling+accelerometer-derived moderate-to-vigorous physical activity), and minutes total active commuting (logged walking+cycling). RESULTS: Groups were significantly different for: distance lived from campus (cyclists=0.6+/-0.6 vs. motorists=2.0+/-1.1 miles; p<0.000); steps/day (cyclists=11,051+/-4295 vs. motorists=9174+/-3319; p=0.046); total time moderate-to-vigorous physical activity (cyclists=85.7+/-37.0 vs. motorists=50.3+/-23.8 minutes; p<0.001); minutes in motorized transport (cyclists=24.9+/-27.5 vs. motorists=61.6+/-32.9; p<0.001); and total active transport (cyclists=59.4+/-32.4 vs. motorists=29.5+/ 20.0; p<0.001). CONCLUSION: Among students living within 5 miles of campus, cyclists lived relatively closer to campus, accumulated more minutes of physical activity, and spent more time in active transportation than students who used motorized means. PMID- 17707077 TI - Beliefs about cervical cancer and human papillomavirus (HPV) and acceptability of HPV vaccination among Chinese women in Hong Kong. AB - OBJECTIVE: To assess the knowledge and beliefs on cervical cancer and HPV infection and to evaluate the acceptability of HPV vaccination among Chinese women. METHODS: Seven focus groups were conducted with ethnic Chinese women aged 18-25 (n=20), 26-35 (n=13), and 36 and above (n=16) in a community women's health clinic in Hong Kong in 2006. The discussions were audio taped, transcribed and analyzed. Recurrent themes related to cervical cancer, HPV infection and vaccination were highlighted. RESULTS: Diverse conceptions on likely causes of cervical cancer were noted, covering biological, psychological, environmental, lifestyle and sexual factors. Most women had not heard of HPV and its mode of transmission. The participants had difficulties understanding and accepting the linkage between cervical cancer and the sexually transmitted HPV infection. HPV infection was seen as personally stigmatizing with significant adverse impact on self-esteem and significant relationships. Participants favored HPV vaccination both for themselves and their teenage daughters if authoritative endorsement was provided. CONCLUSION: Inadequate knowledge and misconceptions on cervical cancer and HPV were common. Most participants welcomed and favored having HPV vaccination. Apart from promoting HPV vaccination, cervical cancer prevention should also include strategies to promote knowledge and minimize the stigmatizing effect of a sexually transmitted HPV infection. PMID- 17707078 TI - Smoking prevalence in Italy after the smoking ban: towards a comprehensive evaluation of tobacco control programs in Europe. PMID- 17707079 TI - A randomized trial of sequential and simultaneous multiple behavior change interventions for physical activity and fat intake. AB - BACKGROUND: Major questions remain unanswered about how best to accomplish multiple behavior change. The purpose of this study was to evaluate whether there are differences in successfully changing multiple behaviors in computer-tailored sequential and simultaneous interventions for physical activity (PA) promotion and fat intake (FI) reduction. METHODS: Participants (N=567) were randomly assigned to receive an intervention for PA and FI simultaneously; PA at baseline and FI at 3 months; or FI at baseline and PA at 3 months. Successful behavior change at 6 months was defined as: >60 min PA increase and/or 5% FI reduction. Using multinomial logistic regression the odds ratios of successful behaviors change (none, PA only, FI only, or both) were determined for intervention mode, gender, age, BMI and education. RESULTS: Overall drop-out was 26%. There was no behavior change for 20.2% of participants; 30.5% successfully decreased FI; 15.8% successfully increased PA; 33.5% successfully changed both behaviors. Intervention mode, gender and age were not associated with successful behavior change. Compared to those that did not change any behaviors: participants that successfully changed FI were more likely to be overweight/obese (OR=1.85); and participants that successfully changed both behaviors were more likely to be overweight/obese (OR=2.13) and have lower education (OR=2.46). CONCLUSIONS: Success in changing multiple behaviors was not associated with intervention mode; both simultaneous and sequential interventions can be applied. Being overweight might be an extra motivator to change health behaviors. PMID- 17707080 TI - Paediatric palliative care: challenges and emerging ideas. AB - Paediatric palliative care is an emerging subspecialty that focuses on achieving the best possible quality of life for children with life-threatening conditions and their families. To achieve this goal, the individuals working in this field need to: clearly define the population served; better understand the needs of children with life-threatening conditions and their families; develop an approach that will be appropriate across different communities; provide care that responds adequately to suffering; advance strategies that support caregivers and health care providers; and promote needed change by cultivating educational programmes. Despite these challenges, advances in paediatric palliative care have been achieved in a short period of time; we expect far greater progress as the field becomes more formalised and research networks are established. PMID- 17707081 TI - A century of neuroscience discovery: reflecting on the Nobel Prize awarded to Golgi and Cajal in 1906. PMID- 17707082 TI - Improving parameter estimation for cell surface FRAP data. AB - Fluorescence Recovery After Photobleaching (FRAP) using the confocal laser scanning microscope has become a standard method used to determine the diffusion coefficient and mobile fraction of cell surface proteins. A common experimental approach is to bleach a stripe on the cell surface and fit the ensuing FRAP curve to a 1D diffusion model. This model is derived from the time course of recovery to an infinitely long stripe bleached on an infinite flat plane. This choice of model dictates the use of a long bleach stripe. We demonstrate that, in the case of a long bleach stripe, the finite extent of the cell leads to significant errors in parameter estimation. We further show that these errors are reduced when a relatively small stripe is bleached. Unfortunately, diffusion to such a region is fundamentally two dimensional and therefore applying the 1D model of diffusion leads to significant errors. We derive an equation suitable for fitting to FRAP data acquired from small bleach regions and analyze its accuracy using simulated data. We propose that the use of a small bleach region along with a two dimensional diffusion model is the ideal protocol for cell surface FRAP. PMID- 17707083 TI - Assessment of pelt quality in leather making using a novel non-invasive sensing approach. AB - Excessive removal of structural material from skin during leather processing results in unattractive crease formation in leather. It is difficult to detect this in pelts at an early processing stage as it only becomes really apparent once the skin is made into leather. There would be great advantages in detecting the problem at the pickled pelt stage (skins treated with sodium sulphide and lime, bated with enzymes, and then preserved in NaCl and sulphuric acid) so that adjustments to the processing could be made to mitigate the effect. A novel bio sensor for inspection of pickled lamb pelts has been fabricated and developed. The sensor has the planar Interdigital structure. The experimental results show that the sensor has a great potential to predict the quality of leather in a non invasive and non-destructive way. PMID- 17707084 TI - An empirical test of a mediation model of the impact of the traditional male gender role on suicidal behavior in men. AB - BACKGROUND: Men die by suicide three to four times more often than women in Western countries. The adverse impact of the traditional male gender role as well as men's reluctance to seek help are possible explanations of this gender gap, but these hypotheses have not been well documented empirically. METHODS: This study compares two groups of men who experienced comparable severely stressful life events during the preceding 12 months: 40 men admitted to hospital emergency following suicide attempts, and 40 men with no history of suicide attempts. Structured interviews were conducted to measure adherence to the traditional male gender role, help seeking behaviour, social support, suicide acceptability and mental health. RESULTS: ANOVAS indicated that attempters are more likely to adhere to the traditional masculine gender role and regression analysis revealed that this relationship persists even when the presence of mental disorders is statistically controlled. Sequential regression analysis support the mediation model and show that the effects of the traditional male gender role on suicidal behavior are mediated through protective and risk factors for suicide, namely mental state, help seeking and social support. CONCLUSIONS: The traditional male gender role appears to increase the risk of suicidal behavior in men by undermining their mental state and by inhibiting the protective factors of help seeking and social support. This study underscores the importance of encouraging men to seek help. PMID- 17707085 TI - Treatment response of bipolar and unipolar alcoholics to an inpatient dual diagnosis program. AB - BACKGROUND: Depressed and bipolar alcoholics represent a significant affective subgroup that has a poorer prognosis than either diagnosis alone. To date few systematic treatment programs have been developed to treat dual diagnosis. METHODS: An inpatient treatment program was developed at St Patrick's Hospital Dublin to treat dual diagnosis clients with alcohol dependence and either unipolar or bipolar affective disorder. Clients (N=232) were assessed for depression, anxiety, elation, cravings, drink and drug intake on admission, discharge, 3 and 6 months post-discharge from the program. RESULTS: In the overall group there was a reduction in number of drinking days and units per drinking day over the study (p<.01). There was a 71.8% complete abstinent rate at 3 months and 55.8% at 6 months in the depression group, non-significantly greater than for the bipolar group at 64.7% and 54.1% respectively. Gamma GT, MCV and craving scores were significantly reduced over time (p<.01). Mania, depression and anxiety inventory scores fell over time in both groups (p<.01). 15-21-year olds were more severely anxious, had higher illicit drug use, and were more likely to relapse to drug use than older clients. Bipolar 1 clients were significantly more likely than bipolar 2 clients to be on mood stabilisers at all follow-up stages (p<.001). LIMITATIONS: No control group was used. CONCLUSIONS: There is evidence for efficacy of a specifically designed dual diagnosis inpatient treatment program as both depressed and bipolar alcoholics had significant reductions in all measurements of mood, craving, and alcohol/drug consumption by self report and biological markers, suggesting both diagnoses can be effectively treated together. PMID- 17707086 TI - Maternal state of mind regarding attachment predicts persistence of postnatal depression in the preschool years. AB - BACKGROUND: This prospective study aimed to determine predictors of persistent postnatal depression between child age one and four years, in a sample of mothers already identified as having a high incidence of postnatal depression at four months after birth and a relatively high prevalence of symptoms of depression at child age one year. METHODS: Data (self-report questionnaires and interview) were initially collected from 127 mothers of first-born infants recruited from a parent-craft hospital at four months postpartum. Women again completed questionnaires and interviews one year after the birth. Persistence of depression between one and four years was assessed by symptom checklists and diagnostic interview. RESULTS: Ninety-two mothers (72%) of the original sample participated at four years. Eleven women who had first onset of depression after one year were excluded from analyses. Thirty-eight percent of the remaining sample (56% of those diagnosed with depression at 4 months) reported ongoing depression between one and four years. Severity of depressive symptoms at four months and maternal state of mind regarding attachment (assessed at 1 year) were significant predictors of persistent depression. Women with an insecure state of mind regarding attachment at one year were seven times more likely to report ongoing depression. CONCLUSIONS: Findings confirm that postnatal depression is ongoing for many women and that vulnerability to persistent depression needs to be viewed in the context of inter-generational family problems. Severity of symptoms at four months postpartum can be used to identify those mothers most at risk of persistent depression. PMID- 17707088 TI - Age and gender differences in social anxiety symptoms during adolescence: the Social Phobia Inventory (SPIN) as a measure. AB - The aim of the present study was to examine age and gender differences in social anxiety symptoms during adolescence, and to investigate the psychometrics of the Social Phobia Inventory (SPIN) among adolescents. The SPIN was administered to a large general population sample (n=5252) of Finnish adolescents aged 12-16 years. Age and gender trends in scores and internal consistency and factorial composition of the SPIN were examined in this sample. The test-retest reliability of the SPIN was examined in a smaller sample of adolescents (n=802). Results showed that girls scored higher than boys on the SPIN full scale and three subscales across the whole age range. Eighth graders (14- to 15-year-olds) scored higher than seventh and ninth graders on the full scale, for boys the differences were significant. Good test-retest reliability (r=0.81), and internal consistency (alpha=0.89) were found for the SPIN. An exploratory factor analysis (EFA) performed on a random half (n=2625) of the population sample yielded a one-factor model accounting for 38% of the variance between items. This one-factor model, plus an alternative three-factor model, were examined in the holdout half of the population sample (n=2627) by means of a confirmatory factor analysis (CFA). Some support was gained for both factor structures. Our results indicate that symptoms of social phobia may increase in mid-adolescence. The SPIN appears to be a reliable self-report instrument among adolescents. PMID- 17707087 TI - Divalproex, lithium and suicide among Medicaid patients with bipolar disorder. AB - BACKGROUND: Suicide completion and attempted suicide are major concerns for people with bipolar disorder. Studies in the private sector have suggested that lithium treatment may be superior to divalproex therapy with regard to minimizing suicidal behavior among individuals with bipolar disorder. However, few data are available regarding Medicaid patients diagnosed with bipolar disorder. METHODS: Subjects were 12,662 Oregon Medicaid patients diagnosed with bipolar disorder and treated with medication between 1998 and 2003. Outcomes measures were completed suicide and emergency department visits for suicide attempts (including non-fatal poisoning). Cox proportional hazards models were used to adjust for demographics, co-morbidity, and concurrent psychotropic medication use. RESULTS: Divalproex was the most common mood stabilizer (used by 33% of subjects) followed by gabapentin (32%), lithium (25%), and carbamazepine (3%). There were 11 suicide deaths and 79 attempts. Adjusted hazard ratios (versus lithium users) for suicide attempts were 2.7 for divalproex users (p<0.001), 1.6 for gabapentin users (not significant) and 2.8 for carbamazepine users (not significant). For suicide deaths, the adjusted hazard ratios were 1.5 for divalproex users (not significant), 2.6 for gabapentin users (p<0.001), and not available for carbamazepine users. LIMITATIONS: It should be noted that subjects were not assigned at random to medication use, data on prior suicide attempts were not available, medication use was measured by automated pharmacy records, and duration of mood stabilizer utilization may have been brief. CONCLUSIONS: Lithium may have a protective effect with regard to suicide attempts among Medicaid patients with bipolar disorder. It remains unclear whether or not lithium protects these patients against completed suicide. PMID- 17707089 TI - Cystein cathepsin and Hsp90 activities determine the balance between apoptotic and necrotic cell death pathways in caspase-compromised U937 cells. AB - Caspase-inhibited cells induced to die may exhibit the traits of either apoptosis or necrosis or both, simultaneously. However, mechanisms regulating the commitment to these distinct forms of cell death are barely identified. We found that staurosporine induced both apoptotic and necrotic traits in U937 cells exposed to the caspase inhibitor benzyloxycarbonyl-Val-Ala-DL-Asp(OMe) fluoromethylketone. Morphology and flow cytometry revealed that individual cells exhibited either apoptotic or necrotic traits, but not the mixed phenotype. Inhibition of cathepsin activity by benzyloxycarbonyl-Phe-Ala-fluoromethylketone rendered caspase-compromised cells resistant to staurosporine-induced apoptosis, but switched the cell death form to necrosis. Inhibition of heat shock protein 90 kDa (Hsp90) chaperon activity by geldanamycin conferred resistance to necrosis in caspase-compromised cells but switched the cell death form to apoptosis. Combination of benzyloxycarbonyl-Phe-Ala-fluoromethylketone and geldanamycin halted the onset of both forms of cell death by saving mitochondrial trans membrane potential and preventing acidic volume (lysosomes) loss. These effects of benzyloxycarbonyl-Phe-Ala-fluoromethylketone and/or geldanamycin on cell death were restricted to caspase-inhibited cells exposed to staurosporine but influenced neither only the staurosporine-provoked apoptosis nor hydrogen peroxide (H2O2)-generated necrosis. Our results demonstrate that the staurosporine-induced death pathway bifurcates in caspase-compromised cells and commitment to apoptotic or necrotic phenotypes depends on cathepsin protease or Hsp90 chaperon activities. PMID- 17707090 TI - Isolated congenital left ventricular diverticulum in an elderly patient that was identified because of an incidental finding during a complete medical checkup. AB - Congenital left ventricular diverticulum is a rare cardiac malformation in an elderly patient. It frequently is associated with other cardiac or non-cardiac congenital malformations. We present an asymptomatic elderly patient, evaluated because of an incidental finding of a left ventricular anatomic change on chest computed tomography during a complete medical checkup. The diagnosis of isolated congenital left ventricular diverticulum was confirmed by echocardiography and cardiac catheterization. With the general use of a complete medical checkup, the incidental findings of patients with isolated congenital left ventricular diverticulum might increase, which might allow for a valid estimation of the morbidity and mortality of these patients. PMID- 17707091 TI - Greater symptom duration predicts response to immunomodulatory therapy in dilated cardiomyopathy. AB - BACKGROUND: Persistent inflammation contributes to cardiac dysfunction in chronic dilated cardiomyopathy (DCM). Trials of immunomodulatory therapy for DCM have been limited by small sample size and yielded conflicting results. We hypothesized that clinical response to immunomodulation would be dependent on symptom duration. Pooled immunomodulatory trial data was used to test this hypothesis. METHODS: Data from 130 subjects in 3 randomized, placebo-controlled trials of immunomodulatory therapy in DCM were combined and prospectively analyzed to evaluate change in left ventricular ejection fraction (LV-EF) at 6 and 12 months after randomization by Wilcoxon Rank-Sum test. Logistic regression analysis evaluated correlations between age, gender, symptom duration and change in LV-EF. RESULTS: Patients >or=6 months of symptoms before immunomodulatory therapy had a greater increase in LV-EF at 6 and 12 months than those receiving placebo (14.4% vs. 4.4%, p<0.001 and 19.5% vs. 5.6%, p<0.001, respectively). Patients with <6 months of symptoms had a similar increase in LV-EF compared to subjects treated with placebo (14.3% vs. 13.3%, p=0.84 and 14.8% vs. 15.2%, p=0.74, respectively). Older age and male gender were not associated with LV-EF change. CONCLUSION: Immunomodulatory therapy is associated with improved LV-EF in DCM patients with >or=6 or more months of symptom duration. PMID- 17707092 TI - A cold shock response triggering acute myocardial infarction. AB - Acute risk factors are activities and events that suddenly and transiently increase the risk of acute cardiac events, as reported recently in International Journal of Cardiology. It has already been reported that sudden submersion in cold water may provoke myocardial infarction in both subjects with atherosclerotic coronary disease and young people with angiographically normal coronary arteries. We report a case of an acute myocardial infarction triggered by sudden exposure to cold air temperature extreme in a young person with acutely occluded proximal part of the left anterior descending coronary artery and normal other coronary arteries who had extreme obesity and cigarette smoking as cardiovascular risk factors. Our report indicates that the sudden cold exposure and the resulting cold shock response may provoke acute myocardial infarction in young susceptible patients. PMID- 17707093 TI - Arterial stiffness in offspring of hypertensive parents: a pilot study. PMID- 17707094 TI - Coronary stent assessment on multidetector computed tomography: source and predictors of image distortion. AB - BACKGROUND: Metallic stent struts cause imaging artifacts on multidetector computed tomography (MDCT) which interfere with the assessment of in-stent coronary restenosis. We examined the degree of image distortion of implanted coronary stents on MDCT, comparing different stent types, sizes and orientation. METHODS: We quantified stent dimensions and image distortion of 151 non-opacified coronary stents in 89 patients (81% men, age 65+/-10 years) who underwent MDCT with a 40 slice MDCT scanner. Stent dimension by MDCT was compared with measurements obtained from quantitative coronary angiographic (QCA) in the immediate post-implantation angiogram and with manufacturers' data. RESULTS: Stent image quality was good for 107 stents (71%), moderate for 38 (25%) and poor in 6 (4%), 2 (<1%) of which were not assessable. Blooming artifact resulted in a mean MDCT luminal (inner) diameter 30+/-14% smaller than QCA diameter (2.0+/-0.5 vs 2.9+/-0.3 mm, p<0.001) and a mean outer diameter exceeding QCA by 31+/-14% (3.8+/-0.5 vs 2.9+/-0.3 mm, p<0.001). MDCT luminal stent diameter was unrelated to strut thickness or the vessel stented but appeared to be smaller for vertically orientated stents (p=0.017), cobalt alloy (vs stainless steel) (p=0.011) and also for different stent types (p=0.006). CONCLUSION: The luminal dimension of implanted coronary stents, as visualized with 40 slice MDCT, was one third smaller than on invasive angiography. This decrease in visualized stent luminal diameter forms the basis for the difficulty in accurate assessment of in stent restenosis by MDCT. PMID- 17707095 TI - Switching beta-blocker therapy in chronic heart failure. AB - BACKGROUND: A beneficial effect on survival has been proven for the four long acting beta-blockers. Such favorable results could not be obtained with short acting beta-blockers. AIMS: to study the safety of switching from short-acting metoprolol to long-acting bisoprolol in patients with cardiac failure and postinfarction impaired left ventricular systolic function. METHODS AND RESULTS: 282 patients with NYHA classes I-III heart failure and/or postinfarction reduced left ventricular ejection fraction were enrolled in the study. Metoprolol tartarate was discontinued 12 h before the initiation of bisoprolol therapy. Dosages were as follows: 28.5% of the patients reached the 10 mg target dose, 21.5% received 7.5 mg, and 42.5% received 5 mg, while 7.5% stayed on the lowest 2.5 mg initial dose. Mean heart rate was 84 bpm before the switch; this dropped to 67 bpm with the above doses. CONCLUSION: The switch from non-recommended short acting beta-blockers to long-acting beta-blockers may be carried out safely in stable heart failure patients. The significant reduction of the heart rate indicated that a more effective adrenergic blockage might be obtained with the switch, although physicians could titrate up to the target dose only in about one third of the cases. PMID- 17707096 TI - Spatial heterogeneity of muscarinic type 2 receptors in the atrium. AB - Atrial fibrillation (AF) is the most common arrhythmia in clinical practices. Mediated by muscarinic type 2 receptors (M(2)Rs), acetylcholine affects electrophysiological activities of atrial myocytes and may contribute to the onset of AF. In order to characterize the distribution of M(2)Rs in the atrial myocardium, different atrial regions in both the SD rat and human were dissected. Atrial myocytes were isolated with type II collagenase. The M(2)Rs expression in these atrial tissues and myocytes was detected by immunofluorescent staining and confocal laser scanning biological microscope. The results showed the highest density of M(2)Rs in atrial myocytes of the left atrial posterior wall. It is concluded that there is a marked spatial heterogeneity in the expression of the M(2)Rs in the atrium, which might create a substrate that would favor the initiation and maintenance of acetylcholine-induced AF. PMID- 17707097 TI - Impact of different Asian ethnic groups on correlation between heparin dose, activated clotting time and complications in percutaneous coronary intervention. AB - The current recommended weight-adjusted dosing regimen of unfractionated heparin and target activated clotting time (ACT) in percutaneous coronary intervention (PCI) is based on limited data from the western population, and the applicability in the various Asian ethnic groups remains unknown. This is a retrospective study in an Asian university teaching hospital. Among the 1287 patients who have undergone PCI, Chinese constituted 70.4% (n=906), Malay 15.5% (n=199) and Indian 14.1% (n=182). Overall, the mean total heparin dose was 6224+/-1548 U, mean weight-adjusted heparin dose was 95+/-30 U/kg, and mean ACT was 325+/-95 s. There was no significant difference in the 3 ethnic groups. Both the incidences of in hospital ischemic complications (Chinese 2.4%, Malay 3.5%, Indian 2.2%, p=0.641) as well as in-hospital bleeding complications (Chinese 4.5%, Malay 3.5%, Indian 6.0%, p=0.490) were similar in the 3 ethnic groups. When the patients were divided based on ACT into 3 groups:<250, 250-350 and>350 seconds, the incidence of ischemic complication (2.5%, 2.5%, 2.7%) was similar (p=819), while that of bleeding complications (4.1%, 3.5%, 6.8%) showed a strong trend (p=0.057) of increased risk in patients with ACT>350 s. In conclusion, the recommended weight adjusted heparin-dosing regimen in PCI derived from the western population is equally applicable to the Asian patients. ACT does not correlate with in-hospital ischemic complications, but increased bleeding complications were observed with ACT>350 s. PMID- 17707098 TI - Combined NT-pro-BNP and CW-Doppler ultrasound cardiac output monitoring (USCOM) in epirubicin and liposomal doxorubicin therapy. AB - BACKGROUND: Chemotherapy with epirubicin is approved in women with breast cancer and is associated with a certain degree of cardiotoxicity. HYPOTHESIS: Epirubicin changes stroke volume, cardiac output and systemic vascular resistance, while liposomal doxorubicin does not. METHODS: 75 patients with HER-2-positive metastatic breast cancer were continuously measured with CW-Doppler ultrasound for stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR) before, during and after drug infusion in combination with NT-pro-BNP before and 10 min after drug infusion. RESULTS: Epirubicin infusion increased stroke volume significantly in low-level NT-pro-BNP (62+/-23 ml vs. 74+/-29 ml, p=0.004) and high-level NT-pro-BNP (48+/-5 ml vs. 64+/-20 ml, p=0.131), while liposomal doxorubicin infusion increased stroke volume significantly in low-level NT-pro-BNP (54+/-16 ml vs. 67+/-22 ml, p=0.001) and high-level NT-pro-BNP (65+/ 22 ml vs. 82+/-27 ml, p=0.001). Cardiac output was significantly increased in epirubicin (p=0.004) by 20% (NT-pro-BNP<125 pg/ml) and not significantly 38% (NT pro-BNP>125 pg/ml; p=0.144), while in liposomal doxorubicin cardiac output was significantly increased by 23% (NT-pro-BNP<125 pg/ml; p=0.023) and 33% (NT-pro BNP>125 pg/ml; p=0.001). In liposomal doxorubicin cardiac index was significantly increased by 26% (NT-pro-BNP<125 pg/ml; p=0.021) and 33% (NT-pro-BNP>125 pg/ml; p=0.0001). SVR was significantly reduced during and after epirubicin therapy. CONCLUSION: Using the CW-Doppler USCOM a different hemodynamic response to epirubicin vs. liposomal doxorubicin is evident. Epirubicin leads to a significant upregulation of stroke volume and cardiac output, which is even more pronounced in the high-level NT-pro-BNP group, while liposomal doxorubicin does not change immediate hemodynamics. No deterioration of cardiac function using the real-time CW-Doppler ultrasound USCOM or an increase in NT-pro-BNP levels was evident during epirubicin or liposomal doxorubicin therapy. PMID- 17707099 TI - Coronary spasm and hypersensitivity to amoxicillin: Kounis or not Kounis syndrome? AB - Several reports have suggested that the onset of allergic phenomena in predisposed subjects may trigger an angina episode, and this association has been described as Kounis syndrome. However, no previous reports have convincingly demonstrated a causal relationship between allergic reactions and acute coronary syndrome, and other possible mechanisms have not been excluded as causes of angina onset. We present a patient with chronic metabolic acidosis because of ureteroileourethrostomy and history of hypersensivity to beta-lactamic agents. He suffered three episodes of documented vasospastic angina, two of them related to amoxicillin administration; however, worsening of metabolic acidosis was found in all three episodes. This report shows that although allergic phenomena could play a role triggering this kind of acute coronary syndrome, other uncommon underlying mechanisms should be considered before the diagnosis of Kounis syndrome is established. PMID- 17707100 TI - Impact of blood circulation on reendothelialization, restenosis and atrovastatin's restenosis prevention effects. AB - BACKGROUND: The independent effects of numerous circulating inflammatory cytokines and inflammatory associated blood cells on reendothelialization and restenosis after PCI has been elucidated, whereas the blood circulation's general effect on restenosis is still pending. Thereby, author investigated the impact of blood circulation on reendothelialization, restenosis and atrovastatin's restenosis prevention effects. METHODS AND RESULTS: 70 SD rats were divided equally in 7 groups: sham operation group, deendothelialization group, atrovastatin treatment group, occlusion group, occlusion and deendothelialization group, atrovastatin treatment after occlusion and deendothelialization group, and immediate sacrifice (after deendothelialization) group. The carotid model of deendothelialization by balloon and (or) thromboembolism occlusion was established, and 4 weeks after balloon injury, the reendothelialization ratio and restenosis ratio of each subjects were observed. The outcomes revealed that there is a natural self-repair phenomenon, featured as low level reendothelialization and restenosis inhibition, which can be significantly augmented under atrovastatin treatment. Yet when the blood circulation discontinued, not only the self-repair process, but also atrovastatin's beneficial effects on reendothelialization and restenosis disappeared. SPSS analysis revealed that there was inverse correlation between reendothelialization and restenosis. CONCLUSIONS: Blood circulation not only per se generally promote reendothelialization and inhibits restenosis, but also serves as a necessary pathway for atrovastatin exerting therapeutic effects on reendothelialization and restenosis; Accelerating reendothelialization is a promising approach of restenosis prevention. PMID- 17707101 TI - Surgical correction of tetralogy of Fallot in a seventy-five year old patient. AB - Tetralogy of Fallot is a congenital heart disease which is mostly diagnosed and treated in infancy. In the literature there are some cases where the diagnosis was made in adults. This report describes the case of a seventy-five year old man who presents with a dilated and severely hypertrophic right ventricle, a ventricular septum defect, an overriding aorta and a severe infundibular stenosis in the right ventricular outflow tract. The diagnosis of an unrepaired Tetralogy of Fallot was made. A full surgical correction of the Tetralogy was performed and the patient received an implantable defibrillator, making him the oldest patient repaired for Tetralogy of Fallot. PMID- 17707102 TI - Quantitative effect of atorvastatin on size and content of non-calcified plaques of coronary arteries 1 year after atorvastatin treatment by multislice computed tomography. AB - PURPOSE: Intensive lipid-lowering treatment with Atorvastatin reduced progression of coronary atherosclerosis, confirmed by IVUS. To quantitate the effect of Atorvastatin on the size and content of non-calcified coronary plaques (NCP) using multislice CT (MSCT) and by comparison of LDL cholesterol levels. MATERIALS AND METHODS: Twenty-one subjects (16 males, 35-79 years, median 69) with NCP by MSCT (Light Speed Ultra 16, GE) were enrolled. All were asymptomatic thereby distinguishing NCP from thrombi in coronary arteries. Following LDL cholesterol measurements, all were given 10 mg of Atorvastatin (2 were given 5 mg as LDL cholesterol levels were already <70 mg/dl) for 1 year, at which point MSCT and LDL cholesterol measurements were repeated. One remarkable NCP was selected in each subject and evaluated as representative of the effect of Atorvastatin. The area and CT values for NCP, excluding calcified portions, were manually measured from axial source or multiplanar reconstruction images under the same conditions using an workstation (Virtual Place Advance Plus, AZE). RESULTS: Twenty-one NCPs (18 left anterior descending branch, 2 left circumflex branch, and 1 right coronary artery) were evaluated. Mean LDL cholesterol levels were 122 mg/dl at the first scan and significantly decreased to 96 mg/ml at the second scan (P<0.05). The NCP areas were 2-31 mm(2) (mean 11.8) at the first scan, and 2-32 mm(2) (mean 12.6) at the second scan. These differences were not significantly different. The averages of CT values were 15-91 HU (mean 55 HU) at the first scan and 38-114 HU (mean 62 HU) at the second scan. SDs of CT values of the two scans were 14-64 HU (mean 40 HU) and 20-68 HU (mean 45 HU), respectively. The averages and SDs of CT values were significantly higher in the second scan (P<0.05). There was a weak but significant positive correlation between ratios (%) of change in area to baseline area at first scan of NCPs (y) and LDL cholesterol levels (x) after 1 year of Atorvastatin treatment (y=0.0106x-0.7265, R(2)=0.1514, R=0.39, P<0.05). CONCLUSION: Using MSCT, we could quantitate the effect of Atorvastatin to the size and content of NCP and compare those with LDL cholesterol levels. Atorvastatin may decrease area of NCP if LDL cholesterol levels are sufficiently reduced. Also, it may increase CT values, which could suggest a change in NCP composition. LDL cholesterol levels may be an important factor in decreasing NCP area. Further studies are needed using 64-slice MSCT in a larger population exhibiting greater decreases in LDL cholesterol levels. PMID- 17707103 TI - Costs of an early intervention versus a conservative strategy in acute coronary syndrome. AB - BACKGROUND: The Randomised Intervention Treatment of unstable Angina (RITA-3) found that non-ST-elevation myocardial infarction and unstable angina patients randomised to routine early arteriography experienced a lower rate of death or myocardial infarction than patients randomised to conservative therapy over a five year period of follow up. This paper uses data from the RITA-3 trial to compare the health service costs of the two strategies. METHODS: The resource use data included initial arteriography and revascularisation procedures in the early intervention group and subsequently in both groups; in-patient days in hospital for any reason in the first year of follow-up; incidence of myocardial infarction; and cardiac medication. RESULTS: After five years, the early intervention arm accrued a total mean cost of pound sterling 11,340 (euro 15,592) and the conservative arm a mean of pound sterling 9749(euro 13,405), an additional mean cost in the intervention arm of pound sterling 1591 (95% CI pound sterling 851 to pound sterling 2276) (euro 2188; 95%CI euro 1160 to euro 3228). On average, costs increased with age and were higher in male patients and in patients with severe angina. However, the incremental cost of the intervention strategy was consistent across different patient sub-groups. CONCLUSION: Over a period of 5 years, the initial additional cost of a strategy of early intervention is only partially offset by subsequent interventions in patients managed conservatively. PMID- 17707104 TI - Scanning strategies for simultaneous EEG-fMRI evoked potential studies at 3 T. AB - There are two basic strategies for applying simultaneous EEG-fMRI: either the fMRI data are acquired continuously, or the stimulus is presented during a brief gap in scanning when the EEG data is clear of gradient artefact. The former has the advantage that the protocol for the fMRI data acquisition is not affected by the presence of EEG. This study investigated the effect of these different strategies and the subsequent ballistocardiogram artefact removal methods (Average Artefact Subtraction (AAS) and Optimal Basis Set (OBS)) on EEG data quality recorded in response to a visual stimulus. Continuous scanning generally resulted in VEPs that were no worse, and in some cases were better, than those measured during a gap in scanning. The AAS and OBS methods lead to comparable results at the level of the grand average visual evoked potential (VEP), although when examined at the level of the single trial the OBS method was more effective. The spectral quality of the data was similar across scanning protocols, as demonstrated by the proportion of spectral power in each frequency band, although there was an effect of the artefact removal method on the overall spectral power. Some differences in the VEPs were also noted when a TR of 1.5 s was used relative to a TR of 3 s. The results indicate improved EEG quality when fMRI scanning is continuous and BCG artefacts are removed using the OBS method, confirming that EEG can be added to an fMRI experiment with minimal change to the experimental protocol. PMID- 17707105 TI - Molecular biology of Fusarium mycotoxins. AB - As the 20th century ended, Fusarium mycotoxicology entered the age of genomics. With complete genomes of Fusarium graminearum and F. verticillioides and several Fusarium gene expression sequence databases on hand, researchers worldwide are working at a rapid pace to identify mycotoxin biosynthetic and regulatory genes. Seven classes of mycotoxin biosynthetic genes or gene clusters have been identified in Fusarium to date; four are polyketide synthase gene clusters for equisetin, fumonisins, fusarins, and zearalenones. Other Fusarium mycotoxin biosynthetic genes include a terpene cyclase gene cluster for trichothecenes, a cyclic peptide synthetase for enniatins, and a cytochrome P450 for butenolide. From the perspective of the United States Department of Agriculture, the ultimate goal of research on Fusarium molecular biology is to reduce mycotoxins in cereal grains. With this goal in mind, efforts have focused on identifying aspects of mycotoxin biosynthesis and regulation that can be exploited for mycotoxin control. New information on fungal and plant genomes and gene expression will continue to provide information on genes important for fungal-plant interactions and to facilitate the development of targeted approaches for breeding and engineering crops for resistance to Fusarium infection and mycotoxin contamination. PMID- 17707106 TI - Quantitative structure-permeation relationship for iontophoretic transport across the skin. AB - The objective was to relate the efficiency of a charged drug to carry current across the skin during iontophoresis to its structural and/or physicochemical properties. The corollary was the establishment of a predictive relationship useful to predict the feasibility of iontophoretic drug delivery, and for the selection and optimization of drug candidates for this route of administration. A dataset of 16 cations, for which iontophoretic fluxes have been measured under identical conditions, with no competition from exogenous co-ions, was compiled. Maximum transport numbers correlated with ion mobilities and decreased with ionic size, the dependence indicating that the electromigration mechanism of iontophoresis would become negligible for drugs of hydrodynamic radius greater than about 8 A. Validation of the model was demonstrated by successfully predicting the transport numbers of three structurally distinct dipeptides, the iontophoretic data for which had been determined under distinctly different experimental conditions. Finally, for the "training" set of cations, a strong linear dependence between their transport numbers in skin and those in aqueous solution was demonstrated; the former were larger by approximately a factor of 1.4 consistent with skin's cation permselectivity. In conclusion, this research offers a practical contribution to the development of a predictive structure transport model of iontophoresis. PMID- 17707107 TI - Corneal gene therapy. AB - Gene therapy to the cornea can potentially correct inherited and acquired diseases of the cornea. Factors that facilitate corneal gene delivery are the accessibility and transparency of the cornea, its stability ex vivo and the immune privilege of the eye. Initial corneal gene delivery studies characterized the relationship between intraocular modes of administration and location of reporter gene expression. The challenge of achieving effective topical gene transfer, presumably due to tear flow, blinking and low penetration of the vector through epithlelial tight junctions left no alternative but invasive administration to the anterior chamber and corneal stroma. DNA vaccination, RNA interference and gene transfer of cytokines, growth factors and enzymes modulated the corneal microenvironment. Positive results were obtained in preclinical studies for prevention and treatment of corneal graft rejection, neovascularization, haze and herpetic stromal keratitis. These studies, corneal gene delivery systems and modes of administration, and considerations regarding the choice of animal species used are the focus of this review. Opportunities in the field of corneal gene therapy lie in expanding the array of corneal diseases investigated and in the implementation of recent designs of safer vectors with reduced immunogenicity and longer duration of gene expression. PMID- 17707108 TI - A Cu tolerant population of the earthworm Dendrodrilus rubidus (Savigny, 1862) at Coniston Copper Mines, Cumbria, UK. AB - Dendrodrilus rubidus were sampled from a mine spoil soil at Coniston Copper Mine, an abandoned Cu mine in Cumbria, UK and a Cu-free control site. Earthworms were maintained for 14d in both Kettering loam and a Moorland soil amended with Cu nitrate. Mortality, condition index, weight change and tissue concentration were determined. In both soils D. rubidus native to the mine site were able to tolerate significantly higher soil Cu concentrations (MWRT, p or =17 years. CONCLUSIONS: These data clearly demonstrate a nexus between early intercourse and reported violence and add to the evidence of risks associated with early sexual initiation. These findings substantiate the need to prevent or reduce rates of early sexual abuse, to protect very young women from sexual exposure and to assist and support young women in their sexual decision making. We need to identify young women who have already experienced abuse or violence and undertake therapeutic interventions to prevent further victimization. PMID- 17707124 TI - Factors associated with major depression among mothers in Los Angeles. AB - PURPOSE: The aim of this study was to identify factors associated with major depression among a sample of diverse mothers in Los Angeles while paying special attention to racial and ethnic as well as immigration status differences. METHODS: Using logistic regression models, we examined the association between major depression and race and ethnicity, immigration status, and other key covariates. Major depression was measured using the Comprehensive International Diagnostic Interview Short Form. This study was based on 1,856 racially and ethnically diverse mothers who participated in Wave 1 of the Los Angeles Family and Neighborhood Survey, which was fielded in 65 census tracts. MAIN FINDINGS: After controlling for key covariates, we found that non-Hispanic white mothers had 1.67 times the odds of having major depression than Hispanic mothers (95% confidence interval [CI], 0.99-2.80). In addition, single mothers had elevated rates of major depression compared with married mothers (odds ratio [OR], 1.54; 95% CI, 1.00-2.37). Mothers with a college degree or higher had significantly lower odds of being depressed compared with mothers without a college degree (OR, 0.50; 95% CI, 0.29-0.86); mothers with only adolescents in the home had significantly higher odds of major depression than mothers with at least one preadolescent child in the home (OR, 1.73; 95% CI, 1.11-2.70). CONCLUSION: Given the links between depressed mothers and child outcomes, our results have important implication for mothers with adolescent children, particularly those who are white, single, or less educated. PMID- 17707125 TI - Heritability of anterior cingulate response to conflict: an fMRI study in female twins. AB - Interference processing requires increased focus on relevant dimensions of environmental stimuli and selective allocation of attentional resources, in order to filter extraneous information and inhibit non-adaptive responses. This process is important in everyday life and is necessary for responding to novel and challenging situations. Dorsal anterior cingulate cortex (dACC) is involved in this process, and behavioral twin studies indicate that performance on interference processing tasks is highly heritable. However, the extent to which dACC activation related to such tasks is influenced by genetic factors has not been reported. In the current study, 10 pairs of monozygotic and 10 pairs of dizygotic female twins performed a validated interference processing task during fMRI. There were three main results: (1) increased dACC activation for incongruent (INC) minus congruent (CON) trials was observed; (2) dACC activation for INC minus CON trials was both moderately heritable and significantly correlated with the difference in reaction time (RT) between INC and CON trials; (3) RT for INC trials was moderately heritable. RT for CON trials and the latency difference between INC and CON trials were not influenced significantly by genetic factors. The current study provides the first functional imaging evidence that dACC activation during interference processing is significantly influenced by genes. These results suggest an endophenotype that may be applied to various psychiatric disorders that are both highly heritable and associated with altered dACC function. PMID- 17707126 TI - A novel approach for imaging brain-behavior relationships in mice reveals unexpected metabolic patterns during seizures in the absence of tissue plasminogen activator. AB - Medically refractory seizures cause inflammation and neurodegeneration. Seizure initiation thresholds have been linked in mice to the serine protease tissue plasminogen activator (tPA); mice lacking tPA exhibit resistance to seizure induction, and the ensuing inflammation and neurodegeneration are similarly suppressed. Seizure foci in humans can be examined using PET employing 2-deoxy 2[(18)F]fluoro-d-glucose ((18)FDG) as a tracer to visualize metabolic dysfunction. However, there currently exist no such methods in mice to correlate measures of brain activation with behavior. Using a novel method for small animal PET data analysis, we examine patterns of (18)FDG uptake in wild-type and tPA(-/ ) mice and find that they correlate with the severity of drug-induced seizure initiation. Furthermore, we report unexpected activations that may underlie the tPA modulation of seizure susceptibility. The methods described here should be applicable to other mouse models of human neurological disease. PMID- 17707127 TI - Points to consider emerging from a mini-workshop on cardiac safety: assessing torsades de pointes liability. AB - A mini-workshop on cardiac safety focusing on assessing drug-induced Torsades de Pointes (TdP) liability was convened as part of the 6th Annual Meeting of the Safety Pharmacology Society. The purpose of this brief publication is to disseminate the salient points emanating from this workshop as a means of engaging the scientific community in the appropriate discussions needed to advance this important field of human safety. The recommendations in this publication extend those of the workshop on "Moving Towards Better Predictors of Drug-Induced Torsades de Pointes" held in November 2005 under the auspice of the International Life Sciences Institute, Health and Environmental Sciences Institute; they fall into four key areas: molecular and cellular biology underlying TdP, dynamics of periodicity, models of TdP proarrhythmia and key considerations for demonstrating utility of non-clinical models. The reader is encouraged to consider the recommendations emanating from the two workshops and align these with ongoing studies in their laboratories. The authors intend to convene a workshop in 2009/2010 to judge advancements in the field of study of drug-induced TdP and make recommendations for a focused validation of those methods holding the greatest promise of improving the predictivity of this unwanted human cardiac risk. PMID- 17707128 TI - Toll-like receptor 2 senses beta-cell death and contributes to the initiation of autoimmune diabetes. AB - Although it is established that defective clearance and, hence, increased accumulation of apoptotic cells can lead to autoimmunity, the mechanism by which this occurs remains elusive. Here, we observed that apoptotic cells undergoing secondary necrosis but not intact apoptotic cells provoked substantial immune responses, which were mediated through the toll-like receptor 2 (TLR2) pathway. The development of autoimmune diabetes was markedly inhibited in Tlr2(-/-) mice but not in Tlr4(-/-) mice, showing that TLR2 plays an important role in the initiation of the disease. Apoptotic beta-cell injury could stimulate the priming of diabetogenic T cells through a TLR2-dependent, but TLR4-independent, activation of antigen-presenting cells. These findings suggest that beta-cell death and its sensing via TLR2 may be an initial event for the stimulation of antigen-presenting cells and development of autoimmune diabetes. PMID- 17707130 TI - Lovastatin enhances phenylbutyrate-induced MR-visible glycerophosphocholine but not apoptosis in DU145 prostate cells. AB - In this study the effects of lovastatin on DU145 prostate cancer cells treated with phenylbutyrate (PB) was investigated in order to determine the NMR detectable metabolic changes resulting from the cooperative activity of these two agents. DU145 cells were perfused with PB in the presence or absence of 10 microM of the HMG-CoA reductase inhibitor lovastatin, and the results monitored by 31P and diffusion-weighted 1H NMR spectroscopy. Lovastatin had additive effects on the PB-induced NMR-visible total choline in 1H spectra, and glycerophosphocholine in 31P spectra but no significant effect on NMR-visible lipid. Moreover, lovastatin had no effect on the ability of PB to either promote the formation of oil red O-detectable lipid droplets or arrest the cell cycle. The most remarkable observations from these studies were that lovastatin enhanced the increase in glycerophosphocholine while reversing late markers of apoptosis and the loss of NTP caused by PB. These results identify a branch point separating the neutral lipid production and the apoptotic cell death caused by the actions of differentiating agents. PMID- 17707131 TI - Topology of acyltransferase motifs and substrate specificity and accessibility in 1-acyl-sn-glycero-3-phosphate acyltransferase 1. AB - 1-acyl-sn-glycero-3-phosphate (AGP) acyltransferases (AGPAT) are involved in de novo biosynthesis of glycerolipids, such as phospholipids and triacylglycerol. Alignment of amino acid sequences from AGPAT, sn-glycerol-3-phosphate acyltransferase, and dihydroxyacetonephosphate acyltransferase reveals four regions with strong homology (acyltransferase motifs I-IV). The invariant amino acids within these regions may be part of a catalytically important site in this group of acyl-CoA acyltransferases. However, in human AGPAT1 a transmembrane domain is predicted to separate motif I on the cytosolic side from motifs II-III on the lumenal side, with motif IV near surface of the membrane. The topology of motifs I and III was confirmed by experiments with recombinant AGPAT1 containing potential glycosylation site near the motifs. This topology conflicts with the expectation that catalytically important sites are near one another, raising questions of whether the acyltransferase motifs really are important for AGPAT catalysis, and how substrates access motifs II-III on the lumenal side of the endoplasmic reticulum membrane. Using human AGPAT1 as a model, we have examined the catalytic roles of highly conserved residues in the four acyltransferase motifs by site-directed mutagenesis. Modifications of the sidechain structures of His104, Asp109, Phe146, Arg149, Glu178, Gly179, Thr180, Arg181 and Ile208 all affected AGPAT1 activity, indicating that the acyltransferase motifs indeed are important for AGPAT catalysis. In addition, we examined substrate accessibility to the catalytic domain of human AGPAT1 using a competition assay. Lysophosphatidic acid (LPA) with fatty acid chains shorter than 10 carbons did not access the catalytic domain, suggesting that LPA hydrophobicity is important. In contrast, short chain acyl-CoAs did access the catalytic domain but did not serve as the second substrate. These results suggest that motifs II and III are involved in LPA binding and motifs I and IV are involved in acyl-CoA binding. PMID- 17707132 TI - Dobutamine stress echocardiography and the effect of revascularization on outcome in diabetic and non-diabetic patients with chronic ischaemic left ventricular dysfunction. AB - AIM: To evaluate the interaction between prognostic effect of revascularization and viability in diabetic and non-diabetic patients with ischaemic left ventricular dysfunction. METHODS: 612 patients with angiographically proven coronary artery disease and left ventricular ejection fraction <35% underwent dobutamine stress echocardiography to assess viability (peak-rest wall motion score index >0.4). 262 patients (75 diabetics, 187 non-diabetics) underwent revascularization and 350 (88 diabetics, 262 non-diabetics) were on medical therapy. RESULTS: During follow-up 215 patients died. Independent predictors of mortality in revascularized patients were resting left ventricular ejection fraction (HR=0.93, 95% CI 0.89-0.97, p<0.0001), Delta WMSI>40 (HR=0.44, 95% CI 0.23-0.85, p=0.01), and age (HR=1.03, 95% CI 1.00-1.06, p=0.04). In medically treated patients, independent predictors of mortality were diabetes mellitus (HR=1.64, 95% CI 1.13-2.38, p=0.009), number of diseased vessels (HR=1.27, 95% CI 1.03-1.56, p=0.02), and age (HR=1.02, 95% CI 1.00-1.04, p=0.03). In revascularized patients, 4-year mortality was 15% in those with viability and 26% in those without viability (p=0.04), there was no difference between diabetics and non-diabetics (24% vs 22%; p=0.24). CONCLUSIONS: Viability at dobutamine stress echocardiography independently predicts improved outcome following revascularization in non-diabetics as well as diabetic patients with ischaemic left ventricular dysfunction. PMID- 17707129 TI - Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. AB - Cell-mediated immunity stems from the proliferation of naive T lymphocytes expressing T cell antigen receptors (TCRs) specific for foreign peptides bound to host major histocompatibility complex (MHC) molecules. Because of the tremendous diversity of the T cell repertoire, naive T cells specific for any one peptide:MHC complex (pMHC) are extremely rare. Thus, it is not known how many naive T cells of any given pMHC specificity exist in the body or how that number influences the immune response. By using soluble pMHC class II (pMHCII) tetramers and magnetic bead enrichment, we found that three different pMHCII-specific naive CD4(+) T cell populations vary in frequency from 20 to 200 cells per mouse. Moreover, naive population size predicted the size and TCR diversity of the primary CD4(+) T cell response after immunization with relevant peptide. Thus, variation in naive T cell frequencies can explain why some peptides are stronger immunogens than others. PMID- 17707133 TI - Effect of sildenafil on ventilatory efficiency and exercise tolerance in pulmonary hypertension. AB - BACKGROUND: The pulmonary vasculopathy in pulmonary arterial hypertension (PAH) results in increased resistance to pulmonary blood flow, limiting the cardiac output required for the increased O(2) demands of exercise. AIMS: We sought to determine the physiologic basis for clinical improvement in PAH patients receiving sildenafil, hypothesizing that the key mechanisms of improvement are improved blood flow and ventilatory efficiency, leading to improved exercise capacity and O(2) pulse over time. METHODS: We studied 28 PAH patients with (n=14) and without (n=14) sildenafil treatment. All received warfarin and diuretic therapy, and 13/14 sildenafil-treated patients were already receiving specific PAH drugs. Cardiopulmonary exercise testing was performed before and after sildenafil. RESULTS: Peak VO2 , peak O(2) pulse, V E/CO2 and PETCO2, were 0.84+/-0.1 L/min, 6.1+/-0.7 mL beat(- 1), 49+/-2 and 26+/-1.5 mm Hg, and improved after adding sildenafil to 0.91+/-0.1 L/min, 6.8+/-0.8 mL beat(- 1), 43+/-2, and 30+/-1.9, respectively, whereas control patients worsened (p=0.012, 0.008, 0.008 and 0.0002, treated vs. controls, respectively). CONCLUSIONS: Sildenafil improves PETCO2, V E/V CO(2), peak O2 pulse and peak VO2 during exercise compared to controls. A prospective, placebo-controlled study is needed to validate these findings. PMID- 17707134 TI - Prednisolone mediated suppression of HIV-1 viral load strongly correlates with C C chemokine CCL2: In vivo and in vitro findings. AB - CCL2 (MCP-1) is a proinflammatory chemokine induced in HIV-1 infection. We have previously demonstrated a significant correlation of CCL2 gene expression with HIV-1 viremia. In this study we investigated the effect of prednisolone on CCL2 gene expression and viral load in an HIV-1-infected patient receiving high-dose prednisolone for severe uveitis. We observed a >1 log reduction of HIV-1 viral load, associated with more than hundred fold reduction of CCL2 expression at day 3 of prednisolone treatment. In vitro HIV-1 infection of PBMC demonstrated reduced HIV-1 replication in the presence of prednisolone. Flow cytometric analysis revealed 50% reduction of LTR driven GFP activity by prednisolone in GHOST cells. These findings indicate that prednisolone suppresses both HIV-1 viral load and CCL2 mRNA expression, an association which might be exploited for future anti-inflammatory therapeutic strategies in HIV-1 infection. PMID- 17707135 TI - Vitellogenin-inducing activities of natural, synthetic, and environmental estrogens in primary cultured Xenopus laevis hepatocytes. AB - Vitellogenin (VTG)-inducing activities of natural estrogens (E1: estrone, E2:17beta-estradiol, E3: estriol, alpha-E2: 17alpha-estradiol), synthetic estrogens (EE2: 17alpha-ethynyl estradiol, DES: diethylstilbestrol,), phytoestrogen (GEN: genistein), and xeno-estrogens (BPA: bisphenol A, NP: nonylphenol, OP: octylphenol) were investigated by an assay system using primary cultured hepatocytes of Xenopus laevis. An enzyme-linked immunoabsorbent assay (ELISA) was able to detect VTG at a minimum detection limit of 0.06 ng/mL. Relative estrogenic activities of the compounds were determined from their dose response curves. The activities relative to E2 activity were 138% for DES, 121% for EE2, 6.1% for E3, 0.33% for E1, 0.29% for alpha-E2, 0.037% for GEN, 0.008% for BPA, 0.005% for NP, and 0.002% for OP. Comparison with data reported for other bioassay systems revealed that there were significant interspecies-and cell type-differences in the activities of DES, E3, E1 and alpha-E2. BPA was found to have a substantial antagonistic activity (approximately 0.8% of tamoxifen activity) under the influence of physiological concentrations of E2. Complex effects of endocrine disrupters on aquatic animals will be discussed. PMID- 17707136 TI - Effects of 17alpha-methyltestosterone exposure on steroidogenesis and cyclin-B mRNA expression in previtellogenic oocytes of Atlantic cod (Gadus morhua). AB - Steroid hormone (estrogens and androgens) synthesis and regulation involve a large number of enzymes and potential biochemical pathways. In the context of these biochemical pathways, it is believed that the true rate-limiting step in acute steroid production is the movement of cholesterol across the mitochondrial membrane by the steroidogenic acute regulatory (StAR) protein and the subsequent conversion to pregnenolone by cytochrome P450-mediated side-chain cleavage (P450scc) enzyme. Oocyte development is a complex process that is triggered by the maturation-promoting factor (MPF) involving cyclin-B as a regulatory factor. In the present study, we evaluated the endocrine effects of 17alpha methyltestosterone (MT) on steroidogenic pathways of Atlantic cod (Gadus morhua), using an in vitro previtellogenic oocyte culture technique that is based on an agarose floating method. Tissue was cultured in a humidified incubator at 10 degrees C for 1, 5, 10 and 20 days with different concentrations of the synthetic androgen MT (0 (control), 1, 10, 100 and 1000 microM) dissolved in ethanol (0.3%). Gene expressions for StAR, P450scc, aromatase-alpha (P450aromA) and cyclin-B were detected using validated real-time PCR with specific primer pairs. Cellular localization of the StAR protein and P450scc were performed using the immunohistochemical technique with antisera prepared against synthetic peptide for both proteins. Steroid hormones (estradiol-17beta: E2 and testosterone: T) levels were estimated using enzyme immunoassay. Our data showed significant concentration-specific increase (at day 1 and 5) and decrease (at day 10 and 20) of the StAR mRNA expression after exposure to MT. P450scc expression showed a MT concentration-specific decrease during the exposure periods and cyclin-B mRNA expression was decreased in MT concentration-dependent manner at days 10 and 20 (reaching almost total inhibition after exposure to 1000 microM MT). MT exposure produced variable effects on the P450aromA mRNA expression that can be described as concentration-specific increase (day 1) and decrease (days 5 and 10). Cellular localization of the StAR protein and P450scc demonstrated their expression mainly in ovarian follicular cells. MT produced an apparent concentration-and time dependent increase of E2 and T levels. Thus, the present study reveals some novel effects of pharmaceutical endocrine disruptor on the development of previtellogenic oocytes in cod. The impaired steroidogenesis and hormonal imbalance reported in the present study may have potential consequences for the vitellogenic process and overt fecundity in teleosts. PMID- 17707138 TI - Assessing performance of a randomized versus a non-randomized study design. AB - INTRODUCTION: Randomization is the most optimal design for evaluating program effectiveness. In practice, however, conducting a randomized controlled trial is not always feasible. For a non-randomized study into the effect of a parent management training, predefined intervention and control groups of families were matched on six key characteristics. The quality of this match was then compared with the quality which is to be expected from a randomized study. METHODS: The performance of matching intervention and control families for predefined and randomized groups was evaluated by simulating new hypothetical intervention and control groups. The Mahalanobis metric was used to assess the distance between families in the intervention and the control groups and pairwise matching was performed. The global distance between these groups was used as measure of the balance of covariates in all matched pairs, with a smaller distance indicating a higher match quality. RESULTS: In the ideal situation, when predefined groups are actually equal to randomized groups, the expected probability of a more equal balance of characteristics in the former groups than in the latter groups is 0.50. Using the data obtained in our study, and our predefined groups, this expected probability was 0.34. CONCLUSION: Even when randomized groups are more balanced than predefined groups, using the latter groups for analyses might still be acceptable when the differences in group means are small. Findings suggest that matching can be a viable alternative to randomization for situations in which randomization is not feasible due to pragmatic constraints. However, a more accurate judgment on the value of the results obtained in this study requires results from similar analyses performed in other studies for comparison. PMID- 17707139 TI - Heterologous prime-boost immunotherapy of melanoma patients with Influenza virosomes, and recombinant Vaccinia virus encoding 5 melanoma epitopes and 3 co stimulatory molecules. A multi-centre phase I/II open labeled clinical trial. AB - To the exception of early stages of disease, the morbidity and mortality of melanoma is considerable, with no acknowledged therapeutic options beyond surgery. Immunotherapy of melanoma has achieved some success, but further refinements are urgently needed in order to realize its potential. This paper describes a multi-centre phase I/II open labeled, controlled clinical trial investigating 2 innovative immunotherapeutic reagents. Two successive groups of 20 resected AJCC stages IIb-IV melanoma patients will be treated, first with melanoma epitopes included into Influenza virosomes (group 1), and second with a heterologous prime-boost protocol priming with a recombinant Vaccinia virus, and boosting with Influenza virosomes (group 2). Five melanoma epitopes from three different melanoma differentiation antigens were included into Influenza virosomes, that cross-stimulate CD4+ T cells and are endowed with high adjuvant capacity in the generation of CTL. The same five melanoma epitopes, two co stimulatory molecules CD80 and CD86, and the CD40 ligand, a marker known to play a crucial role in CTL generation and memory maintenance were encoded in a recombinant Vaccinia virus. GM-CSF will be administered as a supporting cytokine. Both Influenza virosomes and octo-recombinant Vaccinia virus are innovative and original constructs assessed for the first time in human. Immunotherapy foresees 12 weekly immunizations for each group. Toxicity and adverse events will be monitored clinically. Immunological efficacy will be assessed dynamically by ex vivo multimer analysis, Elispot, and quantitative real-time PCR for up to 3 months following completion of immunotherapy schedule. Disease free survival will be assessed by 4-monthly serial clinic visits, including physical and FDG-PET examinations, for a follow-up time of 2 years. Quality of life will be assessed with a dedicated FACT-BRM 4 questionnaire. PMID- 17707140 TI - Time-dependent effect of non-Hodgkin's lymphoma grade on disease-free survival of relapsed/refractory patients treated with high-dose chemotherapy plus autotransplantation. AB - Evaluation of time to event outcomes usually is examined by the Kaplan-Meier method and Cox proportional hazards models. We developed a modified statistical model based on histologic grade and other variables to describe the time dependent outcome for autologous stem cell transplant (autotransplant) performed for non-Hodgkin's lymphoma (NHL) based on histologic grade and other variables. One hundred and fourteen relapsed or refractory NHL patients were treated using BCNU 600 mg/m2, etoposide 2400 mg/m2, and cisplatin 200 mg/m2 IV followed by autotransplant. Median age was 53.5 (range: 25-70) years, 78 patients had aggressive NHL and 36 indolent NHL. Seventy-five patients received involved-field radiotherapy just prior to transplant. At a median follow-up of 33 (range: 3 to 118) months, the estimated 5-year Kaplan-Meier probabilities of overall survival and disease-free survival were 61% and 51%, respectively. Cox proportional hazards model analysis showed that proportionality did not hold for lymphoma grade, indicating that the relationship between the grade and disease-free survival differed over time. By piece-wise Cox model, the relative risk for experiencing relapse or death after 1 year in patients with indolent compared with patients with aggressive NHL was 2.81 (p=0.019) with 95% confidence interval (1.19, 6.65). The time-dependent effect of lymphoma grade on disease-free survival suggests the need for early (within first year) incorporation of novel therapeutic approaches in management of patients with indolent NHL undergoing autotransplant. PMID- 17707141 TI - CFTR protein analysis of splice site mutation 2789+5 G-A. AB - Ex vivo biochemical analysis of rectal biopsies of a carrier of the mild 2789+5 G A CFTR frameshift splice site mutation revealed mutant truncated CFTR of expected size and an imbalance of more core-glycosylated and less mature full-length CFTR. This first immunoblot analysis of a non-F508del CFTR mutant protein derived from human tissue demonstrates that splice site mutations should not only be investigated at the mRNA, but also at the protein level to properly interpret the associations between genotype, molecular pathology and disease. PMID- 17707142 TI - Oxidation reduces the fibrillation but not the neurotoxicity of the prion peptide PrP106-126. AB - There is increasing evidence that soluble oligomers of misfolded protein may play a role in the pathogenesis of protein misfolding diseases including the transmissible spongiform encephalopathies (TSE) where the protein involved is the prion protein, PrP. The effect of oxidation on fibrillation tendency and neurotoxicity of different molecular variants of the prion peptide PrP106-126 was investigated. It was found that methionine oxidation significantly reduced amyloid fibril formation and proteinase K resistance, but it did not reduce (but rather increase slightly) the neurotoxicity of the peptides in vivo (electroretinography after intraocular injections in mice) and in vitro (in primary neuronal cultures). We furthermore found that the bovine variant of PrP106-126, containing only one methionine residue, showed both reduced fibril forming capacity and in vivo and in vitro neurotoxicity. The findings imply (I) that there is not a simple relation between the formation of amyloid fibrils and neurotoxicity of PrP106-126 derived peptides, (II) that putative, soluble, non amyloid protofibrils, presumed to be present in increased proportions in oxidized PrP106-126, could play a role in the pathogenesis of TSE and III) that the number of methionine residues in the PrP106-126 peptide seems to have a pivotal role in determining the physical and biological properties of PrP106-126. PMID- 17707143 TI - The bacterial response to the chalcogen metalloids Se and Te. AB - Microbial metabolism of inorganics has been the subject of interest since the 1970s when it was recognized that bacteria are involved in the transformation of metal compounds in the environment. This area of research is generally referred to as bioinorganic chemistry or microbial biogeochemistry. Here, we overview the way the chalcogen metalloids Se and Te interact with bacteria. As a topic of considerable interest for basic and applied research, bacterial processing of tellurium and selenium oxyanions has been reviewed a few times over the past 15 years. Oddly, this is the first time these compounds have been considered together and their similarities and differences highlighted. Another aspect touched on for the first time by this review is the bacterial response in cell cell or cell-surface aggregates (biofilms) against the metalloid oxyanions. Finally, in this review we have attempted to rationalize the considerable amount of literature available on bacterial resistance to the toxic metalloids tellurite and selenite. PMID- 17707144 TI - Gaining insight into microbial physiology in the large intestine: a special role for stable isotopes. AB - The importance of the human large intestine for nutrition, health, and disease, is becoming increasingly realized. There are numerous indications of a distinct role for the gut in such important issues as immune disorders and obesity-linked diseases. Research on this long-neglected organ, which is colonized by a myriad of bacteria, is a rapidly growing field that is currently providing fascinating new insights into the processes going on in the colon, and their relevance for the human host. This review aims to give an overview of studies dealing with the physiology of the intestinal microbiota as it functions within and in interaction with the host, with a special focus on approaches involving stable isotopes. We have included general aspects of gut microbial life as well as aspects specifically relating to genomic, proteomic, and metabolomic studies. A special emphasis is further laid on reviewing relevant methods and applications of stable isotope-aided metabolic flux analysis (MFA). We argue that linking MFA with the ' omics' technologies using innovative modeling approaches is the way to go to establish a truly integrative and interdisciplinary approach. Systems biology thus actualized will provide key insights into the metabolic regulations involved in microbe-host mutualism and their relevance for health and disease. PMID- 17707145 TI - Bacterial physiology, regulation and mutational adaptation in a chemostat environment. AB - The chemostat was devised over 50 years ago and rapidly adopted for studies of bacterial physiology and mutation. Despite the long history and earlier analyses, the complexity of events in continuous cultures is only now beginning to be resolved. The application of techniques for following regulatory and mutational changes and the identification of mutated genes in chemostat populations has provided new insights into bacterial behaviour. Inoculation of bacteria into a chemostat culture results in a population competing for a limiting amount of a particular resource. Any utilizable carbon source or ion can be a limiting nutrient and bacteria respond to limitation through a regulated nutrient-specific hunger response. In addition to transcriptional responses to nutrient limitation, a second regulatory influence in a chemostat culture is the reduced growth rate fixed by the dilution rate in individual experiments. Sub-maximal growth rates and hunger result in regulation involving sigma factors and alarmones like cAMP and ppGpp. Reduced growth rate also results in increased mutation frequencies. The combination of a strongly selective environment (where mutants able to compete for limiting nutrient have a major fitness advantage) and elevated mutation rates (both endogenous and through the secondary enrichment of mutators) results in a population that changes rapidly and persistently over many generations. Contrary to common belief, the chemostat environment is never in "steady state" with fixed bacterial characteristics usable for clean comparisons of physiological or regulatory states. Adding to the complexity, chemostat populations do not simply exhibit a succession of mutational sweeps leading to a dominant winner clone. Instead, within 100 generations large populations become heterogeneous and evolving bacteria adopt alternative, parallel fitness strategies. Transport physiology, metabolism and respiration, as well as growth yields, are highly diverse in chemostat-evolved bacteria. The rich assortment of changes in an evolving chemostat provides an excellent experimental system for understanding bacterial evolution. The adaptive radiation or divergence of populations into a collection of individuals with alternative solutions to the challenge of chemostat existence provides an ideal model system for testing evolutionary and ecological theories on adaptive radiations and the generation of bacterial diversity. PMID- 17707146 TI - Metallosensors, the ups and downs of gene regulation. AB - In fungal cells, transcriptional regulatory mechanisms play a central role in both the homeostatic regulation of the essential metals iron, copper and zinc and in the detoxification of heavy metal ions such as cadmium. Fungi detect changes in metal ion levels using unique metallo-regulatory factors whose activity is responsive to the cellular metal ion status. New studies have revealed that these factors not only regulate the expression of genes required for metal ion acquisition, storage or detoxification but also globally remodel metabolism to conserve metal ions or protect against metal toxicity. This review focuses on the mechanisms metallo-regulators use to up- and down-regulate gene expression. PMID- 17707147 TI - Tests of utility independence when health varies over time. AB - In the conventional quality adjusted life year (QALY) model, people's preferences are assumed to satisfy utility independence. When health varies over time, utility independence implies that the value attached to a health state is independent of the health state that arise before or after it. Two separate studies were conducted involving a total of 155 respondents. In study one, we conducted five tests of utility independence using a standard gamble question. Three of the tests of utility independence were repeated in study two after randomisation was introduced in order to take account of possible ordering effects. Utility independence holds in the majority of cases examined here and so our work generally supports the use of utility independence to derive more tractable models. PMID- 17707148 TI - Cutaneous signs of child abuse. AB - Maltreatment of children is a major public health crisis, and it is estimated that each year more than 3 million children are victims of abuse. Safeguarding the welfare of children is a priority, and it is the moral and ethical responsibility of healthcare professionals to detect cases of abuse and intervene appropriately to prevent further harm. Clinicians are often challenged to differentiate signs of child abuse from skin conditions that mimic maltreatment. Because cutaneous injury represents the most recognizable and common form of abuse, dermatologists are often called upon to help distinguish signs of intentional injury from skin conditions that mimic maltreatment. However, few resources specific to dermatologic signs of abuse exist to aid in diagnosis. A review of the literature will provide an educational resource to assist dermatologists and other clinicians in differentiating cutaneous signs of child abuse, including physical and sexual abuse, from mimickers of inflicted injury. LEARNING OBJECTIVE: After completing this learning activity, participants should be able to distinguish signs of intentional injury from skin conditions that mimic maltreatment and understand the clinician's role in the diagnosis and reporting of cases of suspected child abuse. PMID- 17707149 TI - Prospective study of long-term patient perceptions of their skin cancer surgery. AB - BACKGROUND: We identified factors that influence patient perceptions of their skin cancer surgery through a prospective study of patients referred to a single surgeon during 18 months. METHOD: Patients having surgery resulting in a wound sutured and dressed were surveyed 6 to 9 months later. Monitoring for complaints continued for 3 years. RESULTS: In all, 74% of patients returned the survey (576 of 778). A total of 250 (43%) rated their scar excellent, 177 (31%) very good, 72 (12.5%) good, 40 fair (6.9%), and 14 (2.4%) poor or very poor. Age, sex, diagnosis, or closure method did not result in a variation in scar perception. In all, 27.3% of scars (21/77) on the trunk were rated neutral or negative compared with 6.9% (33/476) of scars elsewhere (P < .001) and only 5% (15/305) of head and neck scars (P < .001). Complications did not change scar or overall evaluation ratings. In all, 393 patients (68%) rated the overall service excellent, 145 (25%) very good, 22 (4%) good, and 3 (0.5%) fair. No patient rated the service poor or very poor. Patients rating the service lower were most dissatisfied with scar appearance, time waiting before surgery, pain from the local anesthetic, nursing care, follow-up care, cost, and written material. In all, 99% of patients who rated their scar very good or excellent rated the overall service optimally, compared with only 85% of patients who rated their scar as good or worse. LIMITATIONS: A single experienced surgeon in a southern Australia locale might not reflect the perceptions in other clinicians and locations. CONCLUSION: Complications and patient complaints do not identify patient dissatisfaction from cutaneous surgery. The patients' perception of their scars markedly influences their overall service perception. Patients experienced more dissatisfaction with repairs on the trunk. PMID- 17707150 TI - Usefulness of flow cytometry in the diagnosis of mycosis fungoides. AB - BACKGROUND: The pathologic evaluation of mycosis fungoides (MF) is a challenging area in dermatopathology. OBJECTIVE: We sought to determine the usefulness of flow cytometry for the diagnosis of MF from skin biopsy specimens. METHODS: Skin biopsy specimens from 22 patients with a clinical suggestion for MF were evaluated by 4-color flow cytometry. The results were correlated with the International Society for Cutaneous Lymphoma (ISCL) MF diagnostic score and molecular studies for T-cell receptor gene rearrangement. RESULTS: A T-cell abnormality by flow cytometry was identified in all 11 patients with diagnostic ISCL scores whereas the 7 patients with either subdiagnostic ISCL scores or reactive histology showed no phenotypic abnormality by flow cytometry. In all, 10 of 11 patients with diagnostic skin biopsy specimens for MF had T-cell receptor gene rearrangements by polymerase chain reaction. Gene rearrangements were not detected in the subdiagnostic group. LIMITATIONS: Small study size was a limitation. CONCLUSION: Flow cytometry of skin biopsy specimens is a sensitive method for detecting abnormalities in MF and should be considered part of the routine workup of patients with a clinical suggestion of MF. PMID- 17707151 TI - Dyskeratosis as a histologic feature in epidermolysis bullosa simplex-Dowling Meara. AB - BACKGROUND: Intracellular keratin aggregation and clumping is a characteristic ultrastructural feature in epidermolysis bullosa simplex (EBS)-Dowling Meara (DM) yet without histologic correlates in routinely stained specimens. OBJECTIVE: We sought to detect histologic clues to keratin aggregation and clumping in the involved epidermis of EBS-DM. METHODS: Four cases of EBS-DM caused by dominant keratin (KRT)5 and KRT14 mutations were studied histologically and ultrastructurally. The histologic slides of 11 additional EBS cases (9 Weber Cockayne subtypes and two Koebner subtypes) were also reviewed histologically. RESULTS: Intracytoplasmic aggregation and clumping of tonofilaments were observed ultrastructurally in all 4 EBS-DM cases. Intracytoplasmic eosinophilic homogenizations and inclusions (ie, dyskeratosis) in individual keratinocytes were detected histologically in 3 of the 4 EBS-DM cases, but in none of the 9 EBS Weber-Cockayne cases or the two EBS-Koebner cases. LIMITATIONS: This was a relatively small studied group. CONCLUSION: The histopathological detection of dyskeratosis in individual keratinocytes may provide a valuable clue to keratin aggregation and clumping, and to the diagnosis in EBS-DM. PMID- 17707152 TI - Apocrine mixed tumor of the skin ("mixed tumor of the folliculosebaceous-apocrine complex"). Spectrum of differentiations and metaplastic changes in the epithelial, myoepithelial, and stromal components based on a histopathologic study of 244 cases. AB - BACKGROUND: A systematic analysis of the entire spectrum of various forms of differentiation and metaplastic epiphenomena in cutaneous apocrine mixed tumor (AMT) has never been performed. OBJECTIVE: The purpose of our study was to study a large number of cutaneous mixed tumors so as to fully characterize the entire spectrum of differentiations and metaplastic changes that may occur in the epithelial, myoepithelial, and stromal components of AMT. METHODS: This article reports a light-microscopic study of 244 cases of cutaneous AMT, complemented by a literature review. RESULTS: All types of differentiation along the lines of the folliculosebaceous-apocrine unit can be seen in AMT. The spectrum of metaplastic changes in the epithelial components includes squamous metaplasia, mucinous metaplasia, oxyphilic metaplasia, clear cell change, columnar metaplasia, hobnail metaplasia, and cytoplasmic vacuolization. The following changes in the myoepithelial component were documented: clear cell change, hyaline cells, plasmacytoid cells, spindling, and collagenous spherulosis. Stromal alterations included chondroid metaplasia, osseous metaplasia, and adipose metaplasia. LIMITATIONS: This study utilizes tissue specimens that mainly came as consultations; therefore some inherent selection bias exists. CONCLUSIONS: AMT displays a wide range of differentiation and metaplastic changes in its epithelial, myoepithelial, and stromal components. These phenomena are not mutually exclusive. When unduly prominent, they may present diagnostic pitfalls. Our findings corroborate those of previous publications, stressing the remarkable diversity of differentiation and metaplasias that may be found in cutaneous AMT. We propose that the most appropriate name for these lesions is "mixed tumor of the folliculosebaceous-apocrine complex." PMID- 17707153 TI - Diffuse pain, hypophosphatemia, and a subcutaneous nodule. PMID- 17707154 TI - Peutz-Jeghers syndrome. AB - Dialogues in Dermatology, a monthly audio program from the American Academy of Dermatology, contains discussions between dermatologists on timely topics. Commentaries from Dialogues Editor-in-Chief Warren R. Heymann, MD, are provided after each discussion as a topic summary and are provided here as a special service to readers of the Journal of the American Academy of Dermatology. PMID- 17707155 TI - Frequently asked questions regarding self-plagiarism: How to avoid recycling fraud. PMID- 17707156 TI - Decreased activity of neutrophil glutathione peroxidase in chronic plaque-type psoriasis. PMID- 17707157 TI - Efficacy of simvastatin in plaque psoriasis: A pilot study. PMID- 17707158 TI - Lip edema. PMID- 17707159 TI - Comment on estrogen and the skin. PMID- 17707160 TI - Skin involvement in T-cell prolymphocytic leukemia. PMID- 17707162 TI - Does imiquimod work in infantile hemangiomas? PMID- 17707161 TI - Case of multiple verrucous carcinomas responding to treatment with acetretin more likely to have been a case of verrucous psoriasis. PMID- 17707165 TI - A practical guide to robust detection of GABA in human brain by J-difference spectroscopy at 3 T using a standard volume coil. AB - gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in human brain and has been implicated in several neuropsychiatric disorders. In vivo human brain GABA concentrations are near the detection limit for magnetic resonance spectroscopy ( approximately 1 mM), and because of overlap with more abundant compounds, spectral editing is generally necessary to detect GABA. In previous reports, GABA spectra edited by J-difference spectroscopy vary considerably in appearance. We have evaluated the factors that affect GABA spectra and the conditions necessary for robust acquisition of J-difference spectra from arbitrary brain regions. In particular, we demonstrate that variations in spectral quality can be explained in part by the incoherent addition of transients that results from shot to shot frequency and phase variations. An automated time-domain spectral alignment strategy that enables reproducible acquisition of high-quality GABA spectra at 3 T with a standard 30 cm T/R volume coil is presented. Representative GABA spectra from human frontal lobe, an area where susceptibility-induced frequency and phase variations are especially troublesome, that demonstrate the robustness of the acquisition and data handling strategy used in this study are presented. PMID- 17707164 TI - Monitoring chemotherapeutic response in RIF-1 tumors by single-quantum and triple quantum-filtered (23)Na MRI, (1)H diffusion-weighted MRI and PET imaging. AB - The effects of 5-fluorouracil (5FU, 150 mg/kg, ip) on subcutaneously implanted radiation-induced fibrosarcoma (RIF-1) tumors were monitored by in vivo (1)H MRI to evaluate the water apparent diffusion coefficient (ADC), by single-quantum (SQ) and triple-quantum-filtered (TQF) (23)Na MRI to evaluate compartmental Na(+) content and by positron emission tomography (PET) to evaluate 2-[(18)F]fluoro-2 deoxy-d-glucose (FDG) uptake in the tumor. The MRI experiments were performed on untreated control and treated mice once before and then daily for 3 days after treatment. The PET experiments were performed on separate groups of age- and tumor-volume-matched animals once before and then 3 days after treatment. Tumor volumes significantly decreased in treated animals 2 and 3 days posttreatment. At the same time points, in vivo MRI measurements showed an increase in both total tissue SQ (23)Na signal intensity (SI) and water ADC in treated tumors while control tumors showed no change in these parameters. TQF (23)Na SI and FDG uptake were significantly lower in treated tumors compared with control tumors 3 days after 5FU treatment. The correlated increases in total tissue (23)Na SI and water ADC following chemotherapy reflect an increase in extracellular space, while the lower TQF (23)Na SI and FDG uptake in treated tumors compared with control tumors suggest a shift in tumor metabolism from glycolysis to oxidation and/or a decrease in cell density. PMID- 17707166 TI - ANTHEM: anatomically tailored hexagonal MRI. AB - PURPOSE: This study aimed to investigate the use of anatomically tailored hexagonal sampling for scan-time and error reduction in MRI. MATERIALS AND METHODS: Anatomically tailored hexagonal MRI (ANTHEM), a method that combines hexagonal sampling with specific symmetry in anatomical geometry, is proposed. By using hexagonal sampling, aliasing artifacts are moved to regions where, due to the nature of the anatomy, aliasing is inconsequential. This can be used to either reduce scan time while maintaining spatial resolution or reduce residual errors in speedup techniques like UNFOLD and k-t BLAST/SENSE, which undersample k space and unwrap fold-over artifacts during reconstruction. Computer simulations as well as phantom and volunteer studies were used to validate the theory. A simplified reconstruction algorithm for hexagonally sampled and subsampled k space data was also used. RESULTS: A reduction in sampling density of 13.4% and 25% in each hexagonally sampled dimension was achieved for spherical and conical geometries without aliasing or reduction in spatial resolution. Optimal subsampling schemes that can be utilized by UNFOLD and k-t BLAST/SENSE were derived using hexagonal subsampling, which resulted in maximal, isotropic dispersal of the aliases. In combination with UNFOLD, ANTHEM was shown to move residual aliasing artifacts to the corners of the field of view, yielding reduced artifacts in CINE reconstructions. CONCLUSIONS: ANTHEM was successful in reducing acquisition time in conventional MRI and in reducing errors in UNFOLD imaging. PMID- 17707167 TI - Study of myocardial fiber pathway using magnetic resonance diffusion tensor imaging. AB - The purpose of this study was to investigate myocardial fiber pathway distribution in order to provide supplemental information on myocardial fiber architecture and cardiac mechanics. Diffusion tensor imaging (DTI) with medium diffusion resolution (15 directions) was performed on normal canine heart samples (N=6) fixed in formalin. With the use of diffusion tensor fiber tracking, left ventricle (LV) myocardial fiber pathways and helix angles were computed pixel by pixel at short-axis slices from base to apex. Distribution of DTI-tracked fiber pathway length and number was analyzed quantitatively as a function of fiber helix angle in step of 9 degrees . The long fiber pathways were found to have small helix angles. They are mostly distributed in the middle myocardium and run circumferentially. Fiber pathways tracked at the middle and upper LV are generally longer than those near the apex. Majority of fiber pathways have small helix angles between -20 degrees and 20 degrees , dominating the fiber architecture in myocardium. Likely, such myocardial fiber pathway measurement by DTI may reflect the spatial connectiveness or connectivity of elastic myofiber bundles along their preferential pathway of electromechanical activation. The dominance of the long and circumferentially running fiber pathways found in the study may explain the circumferential predominance in left ventricular contraction. PMID- 17707168 TI - Measuring information gain for frequency-encoded super-resolution MRI. AB - Super-resolution (SR)-based methods that implement multiple data sets related by spatial translations in the frequency-encoding (FE) direction have recently been proposed for resolution enhancement in MRI. This approach, however, was initially received with controversy. It was suggested that when the shifts are applied in the FE direction, no new information was acquired after the first image. Recent developments suggest, however, that shifting the object between image acquisitions can introduce new information to each data set. For this reason, SRMRI may be possible in the FE direction. In this article, we point out that the presence of new information in each acquisition is not sufficient for an SR algorithm to be practical. Indeed, there are situations where the amount of new information is relatively small and possibly not even measurable in the presence of noise. We explore the question of how much new information can be present in each acquisition for FE SRMRI. In particular, we investigate the extent to which the effect of the spatial shift - applied before the object is imaged - can be undone using simple image-processing techniques. Visual comparisons and numerical measures are used to characterize the amount of new information that is acquired in each data set. It is shown that since the amount of new information can be relatively small, each image can be approximated by applying simple signal processing techniques to a single data set. Ultimately, our research suggests that little progress may be possible by using this approach to perform resolution enhancement in the FE direction. PMID- 17707169 TI - Improving the resolution of functional brain imaging: analyzing functional data in anatomical space. AB - The accurate mapping of functional magnetic resonance imaging (fMRI) activations to anatomical structures is critical for fMRI studies of brain organization. In the commonly used functional space analysis method, functional images are realigned to a functional reference image and processed in low-resolution functional space. The average functional activations are then projected into high resolution anatomical space for visualization. Here, we describe a new technique, anatomical space analysis (ASA), whereby low-resolution functional images are first coregistered and resampled directly into high-resolution anatomical space with all subsequent data processing performed in high-resolution space. A major advantage of ASA is that minor scanner sampling instabilities and small head movements can increase spatial resolution by providing multiple samples of the relationship between functional and anatomical space. Both simulations and analyses of real fMRI data show that ASA improves the precision, objectivity and reproducibility of functional brain mapping. PMID- 17707170 TI - COmplex-Model-Based Estimation of thermal noise for fMRI data in the presence of artifacts. AB - Due to the presence of artifacts induced by fast-imaging acquisition in functional magnetic resonance imaging (fMRI) studies, it is very difficult to estimate the variance of thermal noise by traditional methods in magnitude images. Moreover, the existence of incidental phase fluctuations impairs the validity of currently available solutions based on complex datasets. In this article, a time-domain model is proposed to generalize the analysis of complex datasets for nonbrain regions by incorporating artifacts and phase fluctuations. Based on this model, a novel estimation schema has been developed to find an appropriate set of voxels in nonbrain regions according to their levels of artifact and phase fluctuation. In addition, noise intensity from these voxels is estimated. The whole schema is named COmplex-Model-Based Estimation (COMBE). Theoretical and experimental results demonstrate that the proposed COMBE method provides a better estimation of thermal noise in fMRI studies compared with previously proposed methods and suggest that the new method can adapt to a broader range of applications, such as functional connectivity studies, evaluation of sequence designs and reconstruction schemas. PMID- 17707171 TI - Noise distribution in SENSE- and GRAPPA-reconstructed images: a computer simulation study. AB - This work presents a descriptive study of noise distributions in images reconstructed according to the parallel imaging methods SENSE and GRAPPA. In the computer simulations, two different settings were used for describing an object. The first setting included a synthetic object and eight complex-valued coil sensitivities. In the second setting, a complex-valued in vitro object, composed of four individual coil images, was used. After adding noise and subsampling k space for each coil image, reconstruction was performed according to SENSE, with and without regularization, and GRAPPA for different reduction factors. A set of images was created for three different reduction factors. Noise distributions were determined for each data set and compared with each other. The results of this study show that the noise distributions in SENSE- and GRAPPA-reconstructed images differ. The noise in images reconstructed according to GRAPPA has a more uniform spatial distribution compared with SENSE-reconstructed images, in which the noise varies regionally according to the geometry factor. The noise distribution in SENSE-reconstructed images using regularization showed a similar but lowered pattern of noise compared with images reconstructed according to SENSE without regularization. PMID- 17707172 TI - Manganese-enhanced magnetic resonance microscopy of mineralization. AB - Paramagnetic manganese (II) can be employed as a calcium surrogate to sensitize magnetic resonance microscopy (MRM) to the processing of calcium during bone formation. At high doses, osteoblasts can take up sufficient quantities of manganese, resulting in marked changes in water proton T(1), T(2) and magnetization transfer ratio values compared to those for untreated cells. Accordingly, inductively coupled plasma mass spectrometry (ICP-MS) results confirm that the manganese content of treated cell pellets was 10-fold higher than that for untreated cell pellets. To establish that manganese is processed like calcium and deposited as bone, calvaria from the skull of embryonic chicks were grown in culture medium supplemented with 1 mM MnCl(2) and 3 mM CaCl(2). A banding pattern of high and low T(2) values, consistent with mineral deposits with high and low levels of manganese, was observed radiating from the calvarial ridge. The results of ICP-MS studies confirm that manganese-treated calvaria take up increasing amounts of manganese with time in culture. Finally, elemental mapping studies with electron probe microanalysis confirmed local variations in the manganese content of bone newly deposited on the calvarial surface. This is the first reported use of manganese-enhanced MRM to study the process whereby calcium is taken up by osteoblasts cells and deposited as bone. PMID- 17707174 TI - Quantitative MRS study of Balo's concentric sclerosis lesions. AB - Balo's concentric sclerosis (BCS) lesions display specific metabolite changes detected by magnetic resonance spectroscopy (MRS). We report on two cases of BCS lesions examined by MRS; the first case was evaluated 36 days after the onset of symptoms, whereas the second case was evaluated 9 days after the onset of symptoms. MRS data were obtained from single voxels located in the lesion and in the contralateral region. Relative to the creatine/phosphocreatine peak, BCS lesions displayed decreases of N-acetyl aspartate and increases of choline, myo inositol (mI), glutamine/glutamate (Glx), lactate and lipid+macromolecule signals, in agreement with previous reports. In addition, previously unreported decreases of mI (-19% to -29%) and increases of Glx (+55% to +198%) were measured; these could be useful in characterizing BCS lesions. PMID- 17707173 TI - Intramyocellular lipid quantification: comparison between 3.0- and 1.5-T (1)H MRS. AB - OBJECTIVE: This study aimed to prospectively compare measurement precision of calf intramyocellular lipid (IMCL) quantification at 3.0 and 1.5 T using (1)H magnetic resonance spectroscopy ((1)H-MRS). MATERIALS AND METHODS: We examined the soleus and tibialis anterior (TA) muscles of 15 male adults [21-48 years of age, body mass index (BMI)=21.9-38.0 kg/m(2)]. Each subject underwent 3.0- and 1.5-T single-voxel, short-echo-time, point-resolved (1)H-MRS both at baseline and at 31-day follow-up. The IMCL methylene peak (1.3 ppm) was scaled to unsuppressed water peak (4.7 ppm) using the LCModel routine. Full width at half maximum (FWHM) and signal-to-noise ratios (SNRs) of unsuppressed water peak were measured using jMRUI software. Measurement precision was tested by comparing interexamination coefficients of variation (CV) between different field strengths using Wilcoxon matched pairs signed rank test in all subjects. Overweight subjects (BMI>25 kg/m(2)) were analyzed separately to examine the benefits of 3.0-T acquisitions in subjects with increased adiposity. RESULTS: No significant difference between 3.0 and 1.5 T was noted in CVs for IMCL of soleus (P=.5). CVs of TA were significantly higher at 3.0 T (P=.02). SNR was significantly increased at 3.0 T for soleus (64%, P<.001) and TA (62%, P<.001) but was lower than the expected improvement of 100%. FWHM at 3.0 T was significantly increased for soleus (19%, P<.001) and TA (7%, P<.01). Separate analysis of overweight subjects showed no significant difference between 3.0- and 1.5-T CVs for IMCL of soleus (P=.8) and TA (P=.4). CONCLUSION: Using current technology, (1)H-MRS for IMCL at 3.0 T did not improve measurement precision, as compared with 1.5 T. PMID- 17707175 TI - Magnetically programmable shunt valve: MRI at 3-Tesla. AB - A magnetically programmable cerebrospinal fluid (CSF) shunt valve (Codman Hakim Programmable Valve, Codman, a Johnson & Johnson Company, Raynham, MA) was assessed for magnetic field interactions, heating, artifacts and functional changes at 3-Tesla. The programmable valve showed minor magnetic field interactions and heating (+0.4 degrees C). Artifacts were relatively large in relation to the size and shape of this implant and, as such, may create a problem if the area of interest is in proximity to this implant. While multiple exposures and various magnetic resonance imaging (MRI) conditions at 3-Tesla changed the settings of some valves (i.e., reprogramming was needed), the function of the programmable valve was not permanently affected. Therefore, this magnetically programmable CSF shunt valve is acceptable for a patient undergoing MRI at 3 Tesla or less when specific safety guidelines are followed, including resetting the valve, as needed. PMID- 17707176 TI - Genetic testing in cardiovascular disease. AB - Genetic testing is increasingly becoming possible for diagnosis, susceptibility testing, and prognostication in cardiovascular medicine. The practicing cardiologist, therefore, needs to be familiar with the clinical utilities and limitations of genetic testing. This review explores the major approaches to genetic testing and issues in test interpretation. Specific applications to cardiovascular diseases, including coronary artery disease, cardiomyopathies, cardiac arrhythmias, and pulmonary arterial hypertension are discussed. PMID- 17707177 TI - All is not well in the world of translational research. AB - It is not unusual for novel treatment strategies to fail in clinical trials, despite highly encouraging results in preclinical proof-of-concept studies. Typically, such "failures of translation" are blamed on the poor predictiveness of animal models. Often, however, the poor predictiveness of today's preclinical proof-of-concept studies is related not to limitations of the models but to investigator bias and a lack of scientific rigor. The resulting false-positive results only serve to mislead the field and impede medical progress. With the resurgence of translational research, it is useful to examine some of the problems that plague these studies and consider their solutions. With thoughtful planning, execution, and analysis, it is possible to generate reliable and predictive data from preclinical proof-of-concept studies, results that should more rapidly advance medical progress. PMID- 17707178 TI - Chronic mechanical circulatory support for inotrope-dependent heart failure patients who are not transplant candidates: results of the INTrEPID Trial. AB - OBJECTIVES: This study evaluated the impact of left ventricular assist device (LVAD) support on survival and quality of life in inotrope-dependent heart failure patients ineligible for cardiac transplantation. BACKGROUND: The role for LVADs as a bridge to cardiac transplantation has been established, but data supporting their role as permanent therapy in nontransplant candidates are limited. METHODS: The INTrEPID (Investigation of Nontransplant-Eligible Patients Who Are Inotrope Dependent) trial was a prospective, nonrandomized clinical trial comparing LVAD with optimal medical therapy (OMT). Fifty-five patients with New York Heart Association functional class IV symptoms who failed weaning from inotropic support were offered a Novacor LVAD. Eighteen of these patients did not receive an LVAD owing to patient preference (n = 14) or unavailability of the device (n = 4) but consented to follow-up and constitute a contemporaneous control group. RESULTS: The LVAD and OMT patients were well matched for demographic and disease severity measures, except OMT patients had a lower mean serum sodium (128 mg/dl vs. 134 mg/dl; p = 0.001) and a higher mean blood urea nitrogen concentration (59 vs. 40; p = 0.02). The LVAD-treated patients had superior survival rates at 6 months (46% vs. 22%; p = 0.03) and 12 months (27% vs. 11%; p = 0.02). Adverse event rates were higher in the OMT group. Eighty-five percent of the LVAD-treated patients had minimal or no heart failure symptoms. Five LVAD patients and 1 OMT patient improved sufficiently while on therapy to qualify for cardiac transplantation. CONCLUSIONS: Inotrope-dependent heart failure patients who are ineligible for transplantation have a high short-term mortality rate and derive a significant survival advantage from "destination" mechanical circulatory support. PMID- 17707179 TI - On the fledgling field of mechanical circulatory support. PMID- 17707180 TI - The association of differing measures of overweight and obesity with prevalent atherosclerosis: the Dallas Heart Study. AB - OBJECTIVES: This study sought to evaluate the associations between different measures of obesity and prevalent atherosclerosis in a large population-based cohort. BACKGROUND: Although obesity is associated with cardiovascular mortality, it is unclear whether this relationship is mediated by increased atherosclerotic burden. METHODS: Using data from the Dallas Heart Study, we assessed the association between gender-specific obesity measures (i.e., body mass index [BMI]; waist circumference [WC]; waist-to-hip ratio [WHR]) and prevalent atherosclerosis defined as coronary artery calcium (CAC) score >10 Agatston units measured by electron-beam computed tomography and detectable aortic plaque measured by magnetic resonance imaging. RESULTS: In univariable analyses (n = 2,744), CAC prevalence was significantly greater only in the fifth versus first quintile of BMI, whereas it increased stepwise across quintiles of WC and WHR (p trend <0.001 for each). After multivariable adjustment for standard risk factors, prevalent CAC was more frequent in the fifth versus first quintile of WHR (odds ratio 1.91, 95% confidence interval 1.30 to 2.80), whereas no independent positive association was observed for BMI or WC. Similar results were observed for aortic plaque in both univariable and multivariable-adjusted analyses. The c statistic for discrimination of prevalent CAC was greater for WHR compared with BMI and WC in women and men (p < 0.001 vs. BMI; p < 0.01 vs. WC). CONCLUSIONS: We discovered that WHR was independently associated with prevalent atherosclerosis and provided better discrimination than either BMI or WC. The associations between obesity measurements and atherosclerosis mirror those observed between obesity and cardiovascular mortality, suggesting that obesity contributes to cardiovascular mortality via increased atherosclerotic burden. PMID- 17707181 TI - Polymorphisms of KDR gene are associated with coronary heart disease. AB - OBJECTIVES: Our purpose was to determine whether the common polymorphisms (SNP 604, SNP1192, and SNP1719) in KDR are associated with risk of coronary heart disease. BACKGROUND: Vascular endothelial growth factor (VEGF) and its receptor KDR (kinase insert domain-containing receptor/fetal liver kinase-1, also called VEGFR2) play critical roles in angiogenesis and vascular repair, which are involved in the progress of coronary heart disease. METHODS: The association of the 3 polymorphisms with risk of coronary heart disease was determined in 2 independent case-control studies: one comprised of 665 patients with coronary heart disease and 1,015 control subjects, and the other comprised of 369 patients and 625 control subjects. The SNP functions of KDR gene were studied by using luciferase reporter assays, determination of serum levels of KDR, and ligand binding assays. RESULTS: The 2 independent population studies showed that the 3 polymorphisms were associated with risk of coronary heart disease with odds ratios of 1.37 for SNP-604 (p = 0.006), 1.41 for SNP1192 (p = 0.011), and 1.37 for SNP1719 (p = 0.007) in the first population, and 1.40 for SNP-604 (p = 0.015), 1.75 for SNP1192 (p = 0.003), and 1.50 for SNP1719 (p = 0.010) in the second population. The SNP-604C-bearing KDR promoter exhibited 68% of lower transcription activity than the SNP-604T-bearing promoter. The SNP1192 and SNP1719 could obviously influence the efficiency of VEGF binding to KDR. CONCLUSIONS: The KDR polymorphisms may serve as novel genetic markers for the risk of coronary heart disease. PMID- 17707182 TI - Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. AB - OBJECTIVES: We sought to evaluate the characteristics, treatments, and outcomes of patients with preserved and reduced systolic function heart failure (HF). BACKGROUND: Heart failure with preserved systolic function (PSF) is common but not well understood. METHODS: This analysis of the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure) registry compared 20,118 patients with left ventricular systolic dysfunction (LVSD) and 21,149 patients with PSF (left ventricular ejection fraction [EF] > or =40%). Sixty- to 90-day follow-up was obtained in a pre-specified 10% sample of patients. Analyses of patients with PSF defined as EF >50% were also performed for comparison. RESULTS: Patients with PSF (EF > or =40%) were more likely to be older, female, and Caucasian and to have a nonischemic etiology. Although length of hospital stay was the same in both groups, risk of in-hospital mortality was lower in patients with PSF (EF > or =40%) (2.9% vs. 3.9%; p < 0.0001). During 60- to 90-day post-discharge follow-up, patients with PSF (EF > or =40%) had a similar mortality risk (9.5% vs. 9.8%; p = 0.459) and rehospitalization rates (29.2% vs. 29.9%; p = 0.591) compared with patients with LVSD. Findings were comparable with those with PSF defined as EF >50%. In a risk- and propensity adjusted model, there were no significant relationships between discharge use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker or beta blocker and 60- to 90-day mortality and rehospitalization rates in patients with PSF. CONCLUSIONS: Data from the OPTIMIZE-HF registry reveal a high prevalence of HF with PSF, and these patients have a similar post-discharge mortality risk and equally high rates of rehospitalization as patients with HF and LVSD. Despite the burden to patients and health care systems, data are lacking on effective management strategies for patients with HF and PSF. (Organized Program To Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure [OPTIMIZE-HF]); http://www.clinicaltrials.gov/ct/show/NCT00344513?order=1; NCT00344513). PMID- 17707183 TI - Improvement of atrial function and atrial reverse remodeling after cardiac resynchronization therapy for heart failure. AB - OBJECTIVES: We sought to examine whether cardiac resynchronization therapy (CRT) improves atrial function and induces atrial reverse remodeling. BACKGROUND: Cardiac resynchronization therapy is an established therapy for advanced heart failure with prolonged QRS duration, which improves left ventricle (LV) function and is associated with LV reverse remodeling. METHODS: A total of 107 heart failure patients (66 +/- 11 years) who received CRT and were followed up for 3 months were studied. Atrial function was assessed by M-mode, 2-dimensional echocardiography, transmitral Doppler, tissue Doppler velocity, and strain (epsilon) imaging. Left atrial (LA) emptying fraction based on the change in areas (LAA-EF) and volumes (LAV-EF) were calculated. The LV reverse remodeling was defined by a reduction of LV end-systolic volume >10%. RESULTS: In the responders of LV reverse remodeling (n = 62), LAA-EF and LAV-EF were significantly increased (p < 0.001). Responders also had significant decrease in LA size area and volumetric measurements, both before (p < 0.05) and after atrial systole (p < 0.001). However, these parameters were unchanged in the nonresponders (n = 45, p = NS). In the responders, tissue Doppler velocity analysis showed improvement of contraction velocity in both left (p = 0.005) and right atria (p = 0.018), whereas epsilon in both atria were increased in all the phases of cardiac cycle, namely ventricular end-systole (p < 0.001), early diastole (p < 0.001), and late diastole (p = 0.007). CONCLUSIONS: Cardiac resynchronization therapy improves both left and right atrial pump function. The increase in atrial epsilon throughout the cardiac cycle is likely reflecting the improvement of atrial compliance. These changes lead to LA reverse remodeling with reduction of LA size before and after atrial systole. PMID- 17707184 TI - Reliable high-speed coronary computed tomography in symptomatic patients. AB - OBJECTIVES: Our objective was to prospectively evaluate the diagnostic performance of the high-speed dual-source computed tomography scanner (DSCT), with an increased temporal resolution (83 ms), for the detection of significant coronary lesions (> or =50% lumen diameter reduction) in a clinically wide range of patients. BACKGROUND: Cardiac motion artifacts may decrease coronary image quality with use of earlier computed tomography scanners that have a limited temporal resolution. METHODS: We prospectively studied 100 symptomatic patients (79 men, 21 women, mean age 61 +/- 11 years) with atypical (18%) or typical (55%) angina pectoris, or unstable coronary artery disease (27%) scheduled for conventional coronary angiography. Mean scan time was 8.58 +/- 1.52 s. Mean heart rate was 68 +/- 11 beats/min. Quantitative coronary angiography was used as the standard of reference. Irrespective of image quality or vessel size, all segments were included for analysis. RESULTS: Invasive coronary angiography demonstrated no significant disease in 23%, single-vessel disease in 31%, and multivessel disease in 46% of patients; 1,489 coronary segments, containing 220 significant (14.8%) stenoses, were available for analysis. Sensitivity, specificity, and positive and negative predictive values of DSCT coronary angiography for the detection of significant lesions on a segment-by-segment analysis were 95% (95% confidence interval [CI] 90 to 97), 95% (95% CI 93 to 96), 75% (95% CI 69 to 80), 99% (95% CI 98 to 99), respectively, and on a patient-based analysis 99% (95% CI 92 to 100), 87% (95% CI 65 to 97), 96% (95% CI 89 to 99), and 95% (95% CI 74 to 100), respectively. CONCLUSIONS: Noninvasive DSCT coronary angiography is highly sensitive to detect and to reliably rule out the presence of a significant coronary stenosis in patients presenting with atypical or typical angina pectoris, or unstable coronary artery disease. PMID- 17707185 TI - Outcome of surgical myectomy after unsuccessful alcohol septal ablation for the treatment of patients with hypertrophic obstructive cardiomyopathy. AB - OBJECTIVES: We sought to determine the outcome of myectomy after unsuccessful alcohol ablation. BACKGROUND: Alcohol septal ablation results in symptomatic improvement and a reduction in dynamic obstruction in most hypertrophic obstructive cardiomyopathy patients. However, a few patients remain with severe symptoms and obstruction and need surgery. The outcome of these cases is not well known. METHODS: The medical records of 375 patients who underwent alcohol ablation at our institution were reviewed. Twenty patients (5.3%, mean age 53 +/- 18 years, 17 women) subsequently needed surgical myectomy. The New York Heart Association (NYHA) functional class, angina class, exercise duration, left ventricular outflow tract (LVOT) gradient, ejection fraction, and septal thickness were tabulated. The anatomy and distribution of the septal perforator arteries were examined. RESULTS: After ablation, NYHA functional class (3 to 2.5; p < 0.05) and LVOT gradient (93 +/- 23 mm Hg to 71 +/- 26 mm Hg; p < 0.05) were slightly improved, without a change in exercise duration (171 +/- 124 s to 168 +/ 148 s; p > 0.5). Myectomy was performed at 19 +/- 15 months after ablation. There was no operative mortality, but permanent pacing was needed in 2 patients after surgery, and 3 other cases needed pacing before, or as a complication of, alcohol ablation. A significant improvement was noted, with the NYHA functional class decreasing to 1, exercise duration increasing to 423 +/- 171 s, and LVOT gradient decreasing to 6 +/- 11 mm Hg (all p < 0.05 versus post-alcohol ablation). CONCLUSIONS: Myectomy can be successfully performed after failed alcohol ablation, but with a higher incidence of heart block than in cases where only surgery is performed. Otherwise, alcohol ablation does not appear to adversely affect surgical outcome. PMID- 17707186 TI - Long-term predictors of descending aorta aneurysmal change in patients with aortic dissection. AB - OBJECTIVES: We sought to demonstrate the long-term natural course of descending aorta dilation after acute aortic dissection (AD) and identify early predictors for late aneurysmal change. BACKGROUND: Aneurysmal dilation of the aorta is a critical late complication in AD patients. METHODS: Contrast-enhanced computed tomography (CT) was performed during the acute phase in 100 AD patients, comprising 51 type 1 who underwent ascending aorta surgery and 49 type 3 AD patients. Clinical observation was conducted for 53 +/- 26 months, and CT was repeated for 31 +/- 27 months. RESULTS: Aneurysm (diameter > or =60 mm) occurred in 14.4%, 8.2%, 4.1%, and 3.1% of patients at the upper descending thoracic aorta (UT), mid descending thoracic aorta (MT), lower descending thoracic aorta (LT) and abdominal aorta (AA), respectively. Of 53 patients in whom CT was repeated for > or =2 years, the rates of aorta diameter enlargement at the UT, MT, LT, and AA levels were 3.43 +/- 3.66 mm/year, 3.21 +/- 2.70 mm/year, 2.62 +/- 2.19 mm/year, and 1.93 +/- 3.13 mm/year, respectively (p < 0.01), and aneurysm developed in 15 (28%). The initial false lumen diameter at the UT, the aorta diameter at the MT, and Marfan syndrome were independent predictors of late aneurysm. A > or =22-mm initial false lumen diameter at the UT predicted late aneurysm with a sensitivity of 100% and a specificity of 76%. The patients with initial UT false lumen diameter > or =22-mm (n = 42) showed higher event rate (aneurysm or death) than others (n = 58) (p < 0.001). CONCLUSIONS: The UT is the major site of late aneurysmal dilation. A large UT false lumen diameter on the initial CT portends late aneurysm and adverse outcome warranting early intervention. PMID- 17707187 TI - Dissection of the descending thoracic aorta: looking into the future. PMID- 17707189 TI - Summertime. PMID- 17707188 TI - Nitric oxide inhalation improves microvascular flow and decreases infarction size after myocardial ischemia and reperfusion. AB - OBJECTIVES: The purpose of this study was to test if nitric oxide (NO) could improve microvascular perfusion and decrease tissue injury in a porcine model of myocardial ischemia and reperfusion (I/R). BACKGROUND: Inhaled NO is a selective pulmonary vasodilator with biologic effects in remote vascular beds. METHODS: In 37 pigs, the midportion of the left anterior descending coronary artery was occluded for 50 min followed by 4 h of reperfusion. Pigs were treated with a saline infusion (control; n = 14), intravenous nitroglycerin (IV-NTG) at 2 microg/kg/min (n = 11), or inhaled nitric oxide (iNO) at 80 parts per million (n = 12) beginning 10 min before balloon deflation and continuing throughout reperfusion. RESULTS: Total myocardial oxidized NO species in the infarct core was greater in the iNO pigs than in the control or IV-NTG pigs (0.60 +/- 0.05 nmol/mg tissue vs. 0.40 +/- 0.03 nmol/mg tissue and 0.40 +/- 0.02 nmol/mg tissue, respectively; p < 0.01 for both). Infarct size, expressed as percentage of left ventricle area at risk (AAR), was smaller in the iNO pigs than in the control or IV-NTG pigs (31 +/- 6% AAR vs. 58 +/- 7% AAR and 46 +/- 7% AAR, respectively; p < 0.05 for both) and was associated with less creatine phosphokinase-MB release. Inhaled NO improved endocardial and epicardial blood flow in the infarct zone, as measured using colored microspheres (p < 0.001 vs. control and IV-NTG). Moreover, NO inhalation reduced leukocyte infiltration, as reflected by decreased cardiac myeloperoxidase activity (0.8 +/- 0.2 U/mg tissue vs. 2.3 +/- 0.8 U/mg tissue in control and 1.4 +/- 0.4 U/mg tissue in IV-NTG; p < 0.05 for both) and decreased cardiomyocyte apoptosis in the infarct border zone. CONCLUSIONS: Inhalation of NO just before and during coronary reperfusion significantly improves microvascular perfusion, reduces infarct size, and may offer an attractive and novel treatment of myocardial infarction. PMID- 17707190 TI - The UNLOAD trial: a "nephrologic" standpoint. PMID- 17707192 TI - Highlights of the 56th Annual Scientific Session of the American College of Cardiology, March 24-27, 2007. ACC.07 and i2 Summit Highlights: A Conversation With the Experts. PMID- 17707193 TI - Monte Carlo calculation of rectal dose when using an intrarectal balloon during prostate radiation therapy. AB - Air-filled intrarectal balloons can be used to localize and immobilize the prostate for radiation therapy, allowing dose escalation to the prostate and reducing the probability of radiation proctitis, but also introducing potentially significant heterogeneity. We compare the Eclipse treatment planning system (TPS) with Monte Carlo (MC) simulations for 5 patients to assess how well a conventional TPS includes the effect of the balloon on doses near the rectum. The MC results show that, for a 27-Gy prescription to the 95% isodose line, Eclipse overestimates the volume of the rectum receiving more than 26 Gy (96%) by 2 approximately 10 cc and the volume of the rectum receiving between 12 approximately 15 Gy by 10 approximately 20 cc. Differential dose volume histograms are also computed and compared for individual fields in the anterior expansion of the rectum, and the TPS is again shown to predict higher mean dose in the region by 0.3 approximately 1.0 Gy. PMID- 17707194 TI - 3D dose reconstruction to insure correct external beam treatment of patients. AB - Radiation therapy treatments have become increasingly more complicated. There are multiple opportunities for humans, machines, software, and combinations thereof to result in a treatment error that could be of significance. Current methods for quality assurance are often abstract in nature and may have unclear underlying assumptions as to what is assumed to be working correctly, or may depend upon the diligence of persons to discover errors from a review of the treatment plan. Here, an example will be shown of a direct method to reconstruct and demonstrate the dose and the dose distribution delivered to a particular patient. By measuring the radiation fields that come out of the accelerator, and using the measurement as input to a 3-dimensional (3D) dose algorithm, the delivered patient dose is determined and presented in a manner similar to the treatment plan. The intended treatment plan dose may be directly compared. Using this feedback mechanism, there is less abstraction and dependence upon the diligence of individuals checking multiple steps in a treatment process, and assumptions can be clearly stated. With this system, the dose is determined and presented minimizing assumptions and dependence upon other systems. PMID- 17707195 TI - Helical tomotherapy for radiotherapy in esophageal cancer: a preferred plan with better conformal target coverage and more homogeneous dose distribution. AB - We compare different radiotherapy techniques-helical tomotherapy (tomotherapy), step-and-shoot IMRT (IMRT), and 3-dimensional conformal radiotherapy (3DCRT)-for patients with mid-distal esophageal carcinoma on the basis of dosimetric analysis. Six patients with locally advanced mid-distal esophageal carcinoma were treated with neoadjuvant chemoradiation followed by surgery. Radiotherapy included 50 Gy to gross planning target volume (PTV) and 45 Gy to elective PTV in 25 fractions. Tomotherapy, IMRT, and 3DCRT plans were generated. Dose-volume histograms (DVHs), homogeneity index (HI), volumes of lung receiving more than 10, 15, or 20 Gy (V(10), V(15), V(20)), and volumes of heart receiving more than 30 or 45 Gy (V(30), V(45)) were determined. Statistical analysis was performed by paired t-tests. By isodose distributions and DVHs, tomotherapy plans showed sharper dose gradients, more conformal coverage, and better HI for both gross and elective PTVs compared with IMRT or 3DCRT plans. Mean V(20) of lung was significantly reduced in tomotherapy plans. However, tomotherapy and IMRT plans resulted in larger V(10) of lung compared to 3DCRT plans. The heart was significantly spared in tomotherapy and IMRT plans compared to 3DCRT plans in terms of V(30) and V(45). We conclude that tomotherapy plans are superior in terms of target conformity, dose homogeneity, and V(20) of lung. PMID- 17707196 TI - Does intensity modulation improve healthy tissue sparing in stereotactic radiosurgery of complex arteriovenous malformations? AB - This planning study evaluates the potential of intensity modulated treatment fields and inverse planning techniques in stereotactic radiosurgery to reduce healthy tissue dose. Twenty patients previously treated with stereotactic radiosurgery for arteriovenous malformation (AVM) were replanned with each of 4 techniques: circular non-coplanar arcs, dynamic arcs, static conformal fields, and intensity modulated radiosurgery (IMRS). Patients were selected having a maximum AVM dimension at least 20 mm, or volume greater than 10 cm(3). Target volumes ranged from 2.12 cm(3) to 13.87 cm(3) with a median of 6.03 cm(3). Resulting dose distributions show a statistically significant improvement in target conformality between circular arcs and all other techniques (p or =22). There was a positive correlation between the number of manic-hypomanic items endorsed and the number of depressive items endorsed. After controlling for lifetime history of mood disorder, severity of depressive and manic-hypomanic spectrum symptomatology also was associated with a history of self-induced vomiting and suicidality in patients with AN. CONCLUSION: These data provide initial evidence for the clinical significance of depressive and manic-hypomanic spectrum symptoms in patients with AN. Future work is needed to determine how mood spectrum psychopathology might impact the course and treatment of AN. PMID- 17707249 TI - Three-year medication prophylaxis in panic disorder: to continue or discontinue? A naturalistic study. AB - OBJECTIVE: Little is known about maintenance treatment for panic disorder. The purpose of this naturalistic study is to compare outcomes of remitted panic disorder patients continued on versus those successfully discontinued from maintenance medication. METHODS: After 3 years of sustained remission with medication in a naturalistic setting, 168 patients were continued on, whereas 37 successfully discontinued from medication. Continued and discontinued groups were followed for an additional 4 to 8 years and compared for differences in treatment outcome using chi(2) and Wilcoxon rank sum tests. Times to relapse were analyzed using the Kaplan-Meier product-limit method, and risk factors for relapse were assessed using Cox proportional hazards regression. RESULTS: The discontinued group was healthier at baseline but had a significantly worse outcome compared with the continued group. Panic-free survival probabilities for the continued group at 1, 2, 3, and 4 years were 0.87, 0.81, 0.71, and 0.64, respectively, and were significantly higher than respective probabilities of 0.53, 0.35, 0.29, and 0.15 for the discontinued group. Median survival time in the continued group was significantly longer, at 5.67 years, than in the discontinued group, at 1.17 years. Cognitive behavioral therapy significantly reduced hazard in the discontinued but not in the continued group. Residual symptoms in either group at time of assignment predicted poorer outcome. CONCLUSION: Our small study suggests that relapse of panic disorder in routine clinical practice occurs even after long-standing remission on maintenance medication, and that relapse risk appears to be markedly higher after medication discontinuation. Discontinuation may be more successful in candidates who received cognitive behavioral therapy and have minimal residual symptoms. PMID- 17707250 TI - Character and temperament in major depressive disorder and a highly anxious retarded subtype derived from melancholia. AB - BACKGROUND: An anxious-retarded subtype of major depressive disorder, defined by high scores for both anxiety and retardation, has been derived from melancholia and appeared to have higher external validity in terms of poor outcome and vasopressinergic stress hormone regulation. A specific personality could enhance the validity of this subtype, and the association with melancholia suggested the absence of a personality disorder. As 2 character dimensions of the Temperament and Character Inventory (TCI), self-directedness (SD) and cooperativeness, parsimoniously predict the presence of a personality disorder, the primary aim was to test whether patients with the highly anxious-retarded subtype of depression have both normal SD and normal cooperativeness. A secondary aim was to optimally account for the general personality characteristics of patients with a major depressive disorder. METHODS: Eighty-six patients with major depressive disorder and matched healthy controls were selected. Seventy patients were eventually recruited for a 2-year follow-up encompassing 5 assessments of personality (TCI) and psychopathology (Comprehensive Psychopathological Rating Scale). Full remission of depression was defined by the presence of less than 3 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition items of depression during 2 weeks. RESULTS: State-dependent changes of SD and harm avoidance (HA) scores were found in all depressed patients. Fully remitted patients had only high HA compared with healthy controls. Unexpectedly, fully remitted patients with the highly anxious-retarded subtype, in addition, had low SD. CONCLUSION: The temperament of high HA may be the predisposing TCI trait for major depressive disorder in general. Low SD may be a specific presumably premorbid character trait for the highly anxious-retarded subtype derived from melancholia. PMID- 17707251 TI - Worsening of psychosis in schizophrenia is longitudinally associated with tardive dyskinesia in the European Schizophrenia Outpatient Health Outcomes study. AB - OBJECTIVE: The objective of the study was to examine if worsening of psychosis predicts the emergence of tardive dyskinesia (TD). METHOD: Global measures of TD and Clinical Global Impression (CGI) overall symptom severity score were rated in 4 assessments in 12 months. In a risk set free of TD at baseline, associations between TD onset and change in CGI scores were assessed using Cox proportional hazard regression. RESULTS: A total of 8,620 patients yielded 23,565 follow-up observations, 8.8% of which represented a worsening in CGI overall symptom severity relative to the previous observation, yielding an incidence of TD of 5.2%, compared with 2.7% in observations without worsening of psychopathology (rate ratio, 1.9; 95% confidence interval, 1.3-2.7). Incidence of TD was longitudinally associated with a worsening of the CGI overall symptom severity in the months preceding TD onset (adjusted hazard ratio over 6 levels of CGI score, 1.3; 95% confidence interval, 1.1-1.4). CONCLUSION: Worsening in overall psychopathology in schizophrenia is longitudinally associated with the emergence of TD as measured by CGI overall symptom severity. PMID- 17707252 TI - Obsessive-compulsive disorder in pregnant women during the third trimester of pregnancy. AB - OBJECTIVE: The principal aims of this study were to examine the current prevalence rate, clinical characteristics, and related factors of obsessive compulsive disorder (OCD) in pregnant women during the third trimester of pregnancy. METHOD: The study data were gathered from 434 consecutive women in the third trimester of pregnancy who presented to the obstetric outpatient clinics of 2 university research centers and from 58 consecutive nonpregnant women with diagnosed with OCD who presented to the psychiatric outpatient clinics of the same centers. Obsessive-compulsive disorder was diagnosed by means of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The Yale-Brown Obsessive-Compulsive Scale was used to determine the severity and types of obsessions and compulsions. RESULTS: The prevalence rate of OCD was found to be 3.5% among the women in the third trimester of pregnancy. Two (0.5%) women reported that OCD developed during the second trimester (16th and 24th gestational weeks) of pregnancy. The most common obsessions were contamination (80.0%) and symmetry/exactness (60.0%), whereas the most common compulsions were cleaning/washing (86.7%) and checking (60.0%). Women with pregnancy-onset OCD and some women with previous diagnoses of OCD had obsessions and compulsions with themes focused on the fetus or newborn. Pregnant women with OCD had higher frequencies of family history of OCD compared with women without this disorder. Age, educational level, employment status, number of gestations and live births, history of abortion, frequency of primigravida, and the existence of gestational complications were unrelated to OCD in the pregnant women. Pregnant and nonpregnant women with OCD had similar characteristics of obsessive-compulsive symptoms. CONCLUSION: Our study suggests that OCD is present relatively frequently among pregnant women during the third trimester of pregnancy, and it has similar clinical features during gestation and nongestation. PMID- 17707253 TI - Relation of temperament and character properties with clinical presentation of bipolar disorder. AB - OBJECTIVES: The purpose of this study was to examine the underlying temperament and character properties of patients with bipolar disorder and explore the possible connections between these properties and clinical presentation of the illness. METHODS: The sociodemographic and clinical properties of 90 patients with bipolar disorder, who were euthymic according to Young Mania Rating Scale and Hamilton Depression Scale scores, were recorded. Their temperament and character features were evaluated by using Temperament and Character Inventory and results were compared with 90 age- and sex-matched healthy controls and between patients with different clinical properties. RESULTS: Patients' scores on subscales of self-directedness and cooperativeness were significantly lower compared with controls. Significant associations were found between Temperament and Character Inventory subtitles and comorbid personality disorder, number of episodes, subtype of the first episode, rapid cycling, and previous suicide attempt. CONCLUSIONS: Temperament and character features of patients with euthymic bipolar disorder show some significant differences compared to the healthy population and may vary according to different clinical presentations. PMID- 17707255 TI - The role of emotional intelligence and negative affect in bulimic symptomatology. AB - Emotions, particularly emotion dysregulation, play an important role in the development and maintenance of eating disorders as evidenced by the emphasis given to addressing emotions in a number of psychotherapeutic approaches that have been adapted for the treatment of women with disordered eating. The purpose of this study was to assess the role of emotional intelligence and other emotion regulation variables in the relationship between negative affect and bulimic symptomatology. One hundred fifty undergraduate females were assessed via a packet of self-report questionnaires that included measures of emotion regulation, including emotional intelligence (BarOn Emotional Quotient Inventory - Short Form), alexithymia (Twenty-Item Toronto Alexithymia Scale), and coping (Brief COPE Inventory), negative affect (Positive and Negative Affect Schedule -- Expanded Form and Affect Intensity Measure), and bulimic symptomatology (Bulimia Test -- Revised). Results of multiple regression analyses indicated that each conceptual area of interest contributed to the prediction of bulimic symptomatology. In addition, the measures of emotion regulation accounted for significant variance in bulimic symptomatology even after controlling for negative affect. Emotional intelligence and other emotion regulation variables did not moderate the relationship between negative affect and bulimic symptomatology. However, results highlight the role of emotion in disordered eating behaviors and support the negative affect and emotion dysregulation theories of eating disorders. PMID- 17707254 TI - Comparison of personality risk factors in bulimia nervosa and pathological gambling. AB - OBJECTIVE: The objective of the study was to assess the predictive value of personality profiles to classify individuals with bulimia nervosa (BN), pathological gambling (PG), and a nonpsychiatric comparison group while controlling for sex. METHODS: The sample comprised 270 BN (241 women, 29 men), 429 PG (42 women, 387 men), and 96 comparison (nonpsychiatric) subjects (35 women, 61 men). All patients were consecutively admitted to our Psychiatry Department and were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. We administered the Temperament and Character Inventory-Revised as well as other clinical indices. Multinomial and binary logistic regression models adjusted for age and stratified by sex were used to assess the predictive value of personality in relation to group status. RESULTS: In comparison to controls, high Novelty Seeking (P < .001) was specifically associated with a diagnosis of PG. Independently of sex, low Self-Directedness was associated with both BN (P < .001) and PG (P < .001). Some sex-specific differences were also observed; namely, women with BN and PG displayed higher Harm Avoidance and Cooperativeness than control women, whereas men with PG reported higher Reward Dependence and Persistence than control men. CONCLUSIONS: Our results suggested that, whereas there are some shared personality traits between BN and PG when compared with healthy controls, there are also some sex- and diagnostic-specific personality traits that weigh against the consideration of BN as an impulse control disorder. PMID- 17707256 TI - Influences of parental rearing on the personality traits of healthy Japanese. AB - Influences of parental rearing on the personality traits of healthy subjects were studied in 323 Japanese volunteers. Perceived parental rearing was assessed with the use of the Parental Bonding Instrument, which consists of the factors of care and protection, whereas personality traits were assessed with the use of the Temperament and Character Inventory, which has 7 dimensions. In male subjects, all personality dimensions except for novelty seeking were influenced by parental rearing; in female subjects, only the harm avoidance (HA) and self-directedness (SD) dimensions were affected by parenting. Paternal rearing influenced 3 dimensions in male subjects and 1 dimension in female subjects, whereas maternal rearing influenced 5 dimensions in male subjects and 2 dimensions in female subjects. In male subjects, higher HA was related to higher paternal protection (P < .05), whereas in female subjects, it was related to higher maternal protection (P < .01). In male subjects, lower SD was related to higher paternal protection (P < .05) and lower maternal care (P < .01), whereas in female subjects, it was related to lower paternal care (P < .05) and higher maternal protection (P < .01). These results suggest that parental rearing influences the personality traits of healthy subjects, especially HA and SD, with sex specificity in parents and recipients. PMID- 17707258 TI - The initial prodrome of schizophrenia: different duration, different underlying deficits? AB - In light of various suggestions concerning underlying deficits and transition patterns, approaching the initial schizophrenic prodrome is a multifaceted enterprise. Recently, the prodromal phase has largely been viewed as a singular concept. However, observations of greatly varying prodromal time courses prompted us to investigate whether these differences suggest the existence of diverse prodrome subtypes. Our sample consisted of 160 patients from the Cologne Early Recognition study. The 79 patients transiting from prodrome to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition schizophrenia were divided into 3 time groups according to the length of the prodromal state and compared for their initial symptomatology. We found differences in the prominent clinical picture not only regarding single symptoms but also in logistic equations calculated for each group including cognitive deficits only. Our results indicate different underlying deficits: disturbances in bottom-up and top-down loop processes associated with a long prodrome and in top-down processes with medium prodrome, and a deficient central integrating system with short prodrome. PMID- 17707257 TI - Low birth weight and risk of affective disorders and selected medical illness in offspring at high and low risk for depression. AB - Numerous studies have demonstrated that low birth weight (LBW) is associated with the development of medical conditions, such as hypertension and diabetes, and psychiatric disorders, such as depression. One possible mechanism through which LBW might increase risk for both medical and psychiatric disorders is by altering the biologic systems (such as the hypothalamic-pituitary-adrenal [HPA] axis function) that govern emotion regulation and physical reactivity. In this study, we conducted secondary data analyses in a longitudinal study originally designed to understand the intergenerational transmission of major depressive disorder (MDD). We examined the risk for both medical and psychiatric illnesses known to be influenced by HPA axis dysregulation in the context of parental depression. The study had 2 primary objectives: (1) to examine whether LBW increases the risk of selected adult illness that may be influenced by the HPA axis and (2) to examine whether the increased risk of illness varies by parental depression status. We conducted longitudinal assessments of 244 offspring of depressed and nondepressed parents for more than 20 years. Psychopathology and medical illness were assessed by direct interview conducted by clinicians blind to risk status and previous diagnosis. We examined the effect of BW in 3 categories: less than 2.5 kg (LBW), 2.5-3.5 kg, and more than 3.5 kg (reference group). Offspring with LBW had a significantly increased risk of MDD, anxiety disorders, phobia, suicidal ideation, impaired functioning, allergies, and hypertension compared to those with BW exceeding 3.5 kg. The association between LBW and depression was stronger among children of depressed parents than among children of nondepressed parents, with an interaction term (BW and parental depression status) significant for MDD (P = .05), suggesting that parental depression may augment the impact of LBW on offspring depression: PMID- 17707259 TI - Cross-cultural validation of a Chinese translation of the 20-item Toronto Alexithymia Scale. AB - BACKGROUND: The purpose of the present study was to develop a Chinese translation of the 20-item Toronto Alexithymia Scale (TAS-20-C) and examine its reliability and factorial validity. METHODS: The original English version of the TAS-20 was first translated into Chinese and then backtranslated and modified until cross language equivalence was established. This version was then completed by 870 undergraduate students and 179 clinical patients in China. Internal reliability, retest reliability, and factorial validity were evaluated. RESULTS: The TAS-20-C showed adequate internal and retest reliability in both samples. Average TAS-20-C scores in Chinese samples were slightly higher than, but comparable to, TAS-20 scores in English-speaking Canadian samples; as well, scores were higher in the clinical sample than in the student sample. Finally, confirmatory factor analysis supported the 3-factor structure of the TAS-20 in both samples. CONCLUSIONS: The TAS-20-C is a promising instrument for reliable and valid measurement of alexithymia in China. PMID- 17707260 TI - Epstein-Barr virus-associated lymphoproliferative disorders. AB - Epstein-Barr virus (EBV) is a member of the human herpesvirus family that was initially isolated from a cultured Burkitt lymphoma cell line by Epstein et al in 1964. Subsequent studies have proven that it is the causative agent in most cases of infectious mononucleosis. Primary infection is usually asymptomatic in childhood; but in adulthood, it is associated with a self-limiting infectious mononucleosis syndrome in approximately one third of the cases. EBV has been linked to many human neoplasms including hematopoietic, epithelial, and mesenchymal tumors. In this review, we will only discuss the EBV-associated lymphoproliferative disorders, dividing them into B-cell, T/NK-cell, and HIV related lymphoproliferative disorders. PMID- 17707261 TI - Recommendations for the reporting of prostate carcinoma. AB - It has been evident for decades that pathology reports are very variable even within a single institution. Standardization of reporting is the optimal way to insure that information necessary for patient management, prognostic and predictive factor assessment, grading, staging, analysis of outcomes, and tumor registries are included in pathology reports. The ADASP has chosen a pathologist expert in each field to assemble a group from within the pathology community (with clinician input if desired) to write specific cancer protocols. These were then approved by the ADASP council and subsequently by the membership. The American College of Surgery Commission on Cancer (COC) accredits cancer centers in the United States. Recently, the COC decided to require elements, deemed as essential by the CAP, to be described in all pathology reports in their accredited cancer centers as of January 2004. Importantly, they do not require that the specific College of Pathologists (CAP) protocols or synoptic reports be used. ADASP has updated all of its protocols to comply with the COC requirements in the form of uniform checklists. The checklists use the staging criteria cited in the American Joint Committee on Cancer 2002 staging manual (sixth edition) but include a variety of other references listed in each of the checklists. Moreover, the checklists are formatted for ease of use. They may be used as templates for uniform reporting and are designed to be compatible with voice-activated transcription. The different elements in these revised ADASP diagnostic checklists have been divided into Required and Optional. The term Required in this context only signifies compliance with the COC guidelines. ADASP realizes that specimens and practices vary, and it will not be possible to report these elements in every case. However, ADASP hopes that pathologists will find these checklists useful in daily clinical practice while facilitating compliance with the new COC requirements. PMID- 17707262 TI - Malignant mixed epithelial and stromal tumor of the kidney with rhabdoid features: report of a case including immunohistochemical, molecular genetic studies and comparison to morphologically similar renal tumors. AB - Mixed epithelial stromal tumor of the kidney (MEST)/adult cystic nephroma (CN) is a lesion characterized by epithelial lined tubular or cystic structures interspersed within a variably prominent, distinctive spindle-cell stroma. Although typically benign, cases with malignant features have been reported. Herein, we report a MEST/CN with malignant stromal features and rhabdoid differentiation arising in the left kidney of an 84-year-old woman. Histologically, the tumor displayed multiple tubules and variably sized cystic structures lined by benign epithelium with an intervening malignant-appearing spindle-cell stroma. The malignant stroma displayed condensation in the regions surrounding the epithelial component consistent with the ovarian-like stroma typically observed in MEST/CN. In addition, the stromal cells displayed extensive rhabdoid differentiation. Immunohistochemical analysis revealed strong expression of cytokeratin 7, CAM 5.2, AE1/AE3, wide-spectrum keratin, and epithelial membrane antigen by the epithelial component. The stromal component displayed strong immunohistochemical expression of WT-1, CD-99, CD-56, INI1, and estrogen receptor; focal actin positivity; and was negative for desmin, myogenin, and progesterone receptor. Analysis by reverse transcriptase polymerase chain reaction failed to identify the SYT-SSX1 or SYT-SSX2 fusion transcripts characteristic of synovial sarcoma. To our knowledge, this represents the first report in the literature of malignant MEST with rhabdoid features and suggests that this entity should be considered in the diagnosis of renal stromal malignancies with prominent rhabdoid features. PMID- 17707263 TI - Challenges in the clinical application of advanced technologies to reduce radiation-associated normal tissue injury. PMID- 17707264 TI - Patterns of failure after MammoSite brachytherapy partial breast irradiation: a detailed analysis. AB - PURPOSE: To report the results of a detailed analysis of treatment failures after MammoSite breast brachytherapy for partial breast irradiation from our single institution experience. METHODS AND MATERIALS: Between October 14, 2002 and October 23, 2006, 78 patients with early-stage breast cancer were treated with breast-conserving surgery and accelerated partial breast irradiation using the MammoSite brachytherapy applicator. We identified five treatment failures in the 70 patients with >6 months' follow-up. Pathologic data, breast imaging, and radiation treatment plans were reviewed. For in-breast failures more than 2 cm away from the original surgical bed, the doses delivered to the areas of recurrence by partial breast irradiation were calculated. RESULTS: At a median follow-up time of 26.1 months, five treatment failures were identified. There were three in-breast failures more than 2 cm away from the original surgical bed, one failure directly adjacent to the original surgical bed, and one failure in the axilla with synchronous distant metastases. The crude failure rate was 7.1% (5 of 70), and the crude local failure rate was 5.7% (4 of 70). Estimated progression-free survival at 48 months was 89.8% (standard error = 4.5%). CONCLUSIONS: Our case series of 70 patients with >6 months' follow-up and a median follow-up of 26 months is the largest single-institution report to date with detailed failure analysis associated with MammoSite brachytherapy. Our failure data emphasize the importance of patient selection when offering partial breast irradiation. PMID- 17707265 TI - Target volume delineation for partial breast radiotherapy planning: clinical characteristics associated with low interobserver concordance. AB - PURPOSE: To examine variability in target volume delineation for partial breast radiotherapy planning and evaluate characteristics associated with low interobserver concordance. METHODS AND MATERIALS: Thirty patients who underwent planning CT for adjuvant breast radiotherapy formed the study cohort. Using a standardized scale to score seroma clarity and consensus contouring guidelines, three radiation oncologists independently graded seroma clarity and delineated seroma volumes for each case. Seroma geometric center coordinates, maximum diameters in three axes, and volumes were recorded. Conformity index (CI), the ratio of overlapping volume and encompassing delineated volume, was calculated for each case. Cases with CI 0.2 cm(3) and/or resulting in extraprostatic disease on pathology were considered clinically significant. RESULTS: All nine significant tumor foci (one in each patient; volume range, 0.22-8.63 cm(3)) were detected both on pre-RT and post-RT MRI and displayed strikingly similar appearances on pre-RT and post-RT MRI and step-section pathology. Two clinically insignificant tumor foci (10 and the posttreatment PET standardized uptake value was <6, 100% achieved pathologic downstaging (p = 0.047). CONCLUSIONS: Variation in volume was significant, with 17% and 26% of patients requiring a change in treatment fields and patient management, respectively. Positron emission tomography can change the management for anorectal tumors by early detection of metastatic disease or disease outside standard radiation fields. PMID- 17707269 TI - Is the blood-brain barrier relevant in metastatic germ cell tumor? AB - PURPOSE: Germ cell tumors are uniquely chemosensitive and curable, even with advanced metastatic disease. Central nervous system recurrence can terminate a complete remission in other chemosensitive tumors, such as small cell lung cancer, because of the blood-brain barrier (BBB). We propose to document that the BBB is also relevant in germ cell tumors despite their dramatic chemosensitivity. METHODS AND MATERIALS: We present five cases illustrating the concept of the BBB in patients with metastatic testicular cancer treated with chemotherapy. RESULTS: In our large series of patients with metastatic testicular cancer treated with chemotherapy, we identified 5 unique patients. These patients were rendered free of disease only to experience relapse in the brain alone. This included 1 patient who initially had good-risk metastatic disease by means of the International Germ Cell Collaborative Group staging system at the onset of chemotherapy. CONCLUSIONS: The BBB is relevant in patients with metastatic testicular cancer. PMID- 17707270 TI - Expression and prognostic significance of a panel of tissue hypoxia markers in head-and-neck squamous cell carcinomas. AB - PURPOSE: To investigate the expression pattern of hypoxia-induced proteins identified as being involved in malignant progression of head-and-neck squamous cell carcinoma (HNSCC) and to determine their relationship to tumor pO(2) and prognosis. METHODS AND MATERIALS: We performed immunohistochemical staining of hypoxia-induced proteins (carbonic anhydrase IX [CA IX], BNIP3L, connective tissue growth factor, osteopontin, ephrin A1, hypoxia inducible gene-2, dihydrofolate reductase, galectin-1, IkappaB kinase beta, and lysyl oxidase) on tumor tissue arrays of 101 HNSCC patients with pretreatment pO(2) measurements. Analysis of variance and Fisher's exact tests were used to evaluate the relationship between marker expression, tumor pO(2), and CA IX staining. Cox proportional hazard model and log-rank tests were used to determine the relationship between markers and prognosis. RESULTS: Osteopontin expression correlated with tumor pO(2) (Eppendorf measurements) (p = 0.04). However, there was a strong correlation between lysyl oxidase, ephrin A1, and galectin-1 and CA IX staining. These markers also predicted for cancer-specific survival and overall survival on univariate analysis. A hypoxia score of 0-5 was assigned to each patient, on the basis of the presence of strong staining for these markers, whereby a higher score signifies increased marker expression. On multivariate analysis, increasing hypoxia score was an independent prognostic factor for cancer-specific survival (p = 0.015) and was borderline significant for overall survival (p = 0.057) when adjusted for other independent predictors of outcomes (hemoglobin and age). CONCLUSIONS: We identified a panel of hypoxia-related tissue markers that correlates with treatment outcomes in HNSCC. Validation of these markers will be needed to determine their utility in identifying patients for hypoxia-targeted therapy. PMID- 17707272 TI - DNA-PKcs-dependent modulation of cellular radiosensitivity by a selective cyclooxygenase-2 inhibitor. AB - PURPOSE: Inhibition of cyclooxygenase-2 has been shown to increase radiosensitivity. Recently, the suppression of radiation-induced DNA-dependant protein kinase (DNA-PK) activity by the selective cyclooxygenase-2 inhibitor celecoxib was reported. Given the importance of DNA-PK for repair of radiation induced DNA double-strand breaks by nonhomologous end-joining and the clinical use of the substance, we investigated the relevance of the DNA-PK catalytic subunit (DNA-PKcs) for the modulation of cellular radiosensitivity by celecoxib. METHODS AND MATERIALS: We used a syngeneic model of Chinese hamster ovarian cell lines: AA8, possessing a wild-type DNK-PKcs; V3, lacking a functional DNA-PKcs; and V3/WT11, V3 stably transfected with the DNA-PKcs. The cells were treated with celecoxib (50 muM) for 24 h before irradiation. The modulation of radiosensitivity was determined using the colony formation assay. RESULTS: Treatment with celecoxib increased the cellular radiosensitivity in the DNA-PKcs deficient cell line V3 with a dose-enhancement ratio of 1.3 for a surviving fraction of 0.5. In contrast, clonogenic survival was increased in DNA-PKcs wild type-expressing AA8 cells and in V3 cells transfected with DNA-PKcs (V3/WT11). The decrease in radiosensitivity was comparable to the radiosensitization in V3 cells, with a dose-enhancement ratio of 0.76 (AA8) and 0.80 (V3/WT11) for a survival of 0.5. CONCLUSIONS: We have demonstrated a DNA-PKcs-dependent differential modulation of cellular radiosensitivity by celecoxib. These effects might be attributed to alterations in signaling cascades downstream of DNA-PK toward cell survival. These findings offer an explanation for the poor outcomes in some recently published clinical trials. PMID- 17707271 TI - Cardiolipin-specific peroxidase reactions of cytochrome C in mitochondria during irradiation-induced apoptosis. AB - PURPOSE: To determine whether cytochrome c (cyt c) content and associated cardiolipin oxidation can be determinants of cell sensitivity to irradiation induced apoptosis. METHODS AND MATERIALS: The small interfering RNA (siRNA) approach was used to engineer HeLa cells with lowered contents of cyt c (14%, HeLa 1.2 cells). Cells were treated by gamma-irradiation (in doses of 5-40 Gy). Lipid oxidation was characterized by electrospray ionization mass spectrometry analysis and fluorescence high-performance liquid chromatography-based Amplex Red assay. Release of a proapoptotic factor (cyt c, Smac/DIABLO) was detected by Western blotting. Apoptosis was revealed by caspase-3/7 activation and phosphatidylserine externalization. RESULTS: Irradiation caused selective accumulation of hydroperoxides in cardiolipin (CL) but not in other phospholipids. HeLa 1.2 cells responded by a lower irradiation-induced accumulation of CL oxidation products than parental HeLa cells. Proportionally decreased release of a proapoptotic factor, Smac/DIABLO, was detected in cyt c deficient cells after irradiation. Caspase-3/7 activation and phosphatidylserine externalization were proportional to the cyt c content in cells. CONCLUSIONS: Cytochrome c is an important catalyst of CL peroxidation, critical to the execution of the apoptotic program. This new role of cyt c in irradiation-induced apoptosis is essential for the development of new radioprotectors and radiosensitizers. PMID- 17707274 TI - Dose-volume effects in rat thoracolumbar spinal cord: the effects of nonuniform dose distribution. AB - PURPOSE: To investigate dose-volume effects in rat spinal cord irradiated with nonuniform dose distributions and to assess regional differences in radiosensitivity. METHODS AND MATERIALS: A total of 106 rats divided into three groups were irradiated with (192)Ir gamma-rays at a high dose rate. The groups were irradiated with one, two, or six catheters distributed around the thoracolumbar spinal cord to create different dose distributions. After irradiation, the animals were tested for motor function for 9 months. The response was defined as motor dysfunction and WM or nerve root necrosis. Dose response data were analyzed with a probit analysis as function of the dose level at a percentage of the volume (D(%)) and with different normal tissue complication probability models. Additionally, the histologic responses of the individual dose voxels were analyzed after registration with the histologic sections. RESULTS: The probit analysis at D(24) (24% of the volume) gave the best fit results. In addition, the Lyman Kutcher Burman model and the relative seriality model showed acceptable fits, with volume parameters of 0.17 and 0.53, respectively. The histology-based analysis revealed a lower radiosensitivity for the dorsal (50% isoeffective dose [ED(50)] = 32.3) and lateral WM (ED(50) = 33.7 Gy) compared with the dorsal (ED(50) = 25.9 Gy) and ventral nerve roots (ED(50) = 24.1 Gy). CONCLUSIONS: For this nonuniform irradiation, the spinal cord did not show typical serial behavior. No migration terms were needed for an acceptable fit of the dose-response curves. A higher radiosensitivity for the lumbar nerve roots than for the thoracic WM was found. PMID- 17707273 TI - High relative biologic effectiveness of carbon ion radiation on induction of rat mammary carcinoma and its lack of H-ras and Tp53 mutations. AB - PURPOSE: The high relative biologic effectiveness (RBE) of high-linear energy transfer (LET) heavy-ion radiation has enabled powerful radiotherapy. The potential risk of later onset of secondary cancers, however, has not been adequately studied. We undertook the present study to clarify the RBE of therapeutic carbon ion radiation and molecular changes that occur in the rat mammary cancer model. METHODS AND MATERIALS: We observed 7-8-week-old rats (ACI, F344, Wistar, and Sprague-Dawley) until 1 year of age after irradiation (0.05-2 Gy) with either 290 MeV/u carbon ions with a spread out Bragg peak (LET 40-90 keV/mum) generated from the Heavy-Ion Medical Accelerator in Chiba or (137)Cs gamma-rays. RESULTS: Carbon ions significantly induced mammary carcinomas in Sprague-Dawley rats but less so in other strains. The dose-effect relationship for carcinoma incidence in the Sprague-Dawley rats was concave downward, providing an RBE of 2 at a typical therapeutic dose per fraction. In contrast, approximately 10 should be considered for radiation protection at low doses. Immunohistochemically, 14 of 18 carcinomas were positive for estrogen receptor alpha. All carcinomas examined were free of common H-ras and Tp53 mutations. Importantly, lung metastasis (7%) was characteristic of carbon ion-irradiated rats. CONCLUSIONS: We found clear genetic variability in the susceptibility to carbon ion-induced mammary carcinomas. The high RBE for carbon ion radiation further supports the importance of precise dose localization in radiotherapy. Common point mutations in H-ras and Tp53 were not involved in carbon ion induction of rat mammary carcinomas. PMID- 17707276 TI - Further radiobiologic modeling of palliative radiotherapy: use of virtual trials. AB - PURPOSE: To study duration of response in palliative radiotherapy in a population of tumors. METHODS AND MATERIALS: Models of dynamic changes in cell number with time were used to develop a function for the remission time (T(rem)) after palliative radiotherapy: [See Equation], where BED is the biologically effective dose, t(1) the duration of symptoms (i.e., the time between the onset of symptoms and the initiation of radiotherapy), K the daily BED repopulation equivalent, alpha the linear radiosensitivity parameter in the linear-quadratic model, and z the tumor regression rate. RESULTS: Simulations of clinical trials show marked variations in remission statistics depending on the tumor characteristics and are highly compatible with the results of clinical trials. Dose escalation produces both a higher proportion and extended duration of remissions, especially in tumors with high alpha/beta ratios and K values, but the predicted dose responses of acute and late side effects show that caution is necessary. The prospect of using particle beam therapy to reduce normal tissue radiation exposures or using hypoxic sensitizers to improve the tumor cell kill might significantly improve the results of palliative radiotherapy in carefully selected patients and could also be used for safer palliative re-treatments in patients with the potential for prolonged survival. The effect of tumor heterogeneity in determining palliative responses probably exceeds that in radical radiotherapy; as few as 100 patients in each treatment arm produce statistically unreliable results. CONCLUSIONS: Virtual trials of palliative radiotherapy can be useful to test the effects of competing schedules and better determine future strategies, including improved design of clinical trials as well as combinations of radiotherapy with other anticancer modalities. PMID- 17707277 TI - Principal component analysis-based pattern analysis of dose-volume histograms and influence on rectal toxicity. AB - PURPOSE: The variability of dose-volume histogram (DVH) shapes in a patient population can be quantified using principal component analysis (PCA). We applied this to rectal DVHs of prostate cancer patients and investigated the correlation of the PCA parameters with late bleeding. METHODS AND MATERIALS: PCA was applied to the rectal wall DVHs of 262 patients, who had been treated with a four-field box, conformal adaptive radiotherapy technique. The correlated changes in the DVH pattern were revealed as "eigenmodes," which were ordered by their importance to represent data set variability. Each DVH is uniquely characterized by its principal components (PCs). The correlation of the first three PCs and chronic rectal bleeding of Grade 2 or greater was investigated with uni- and multivariate logistic regression analyses. RESULTS: Rectal wall DVHs in four-field conformal RT can primarily be represented by the first two or three PCs, which describe approximately 94% or 96% of the DVH shape variability, respectively. The first eigenmode models the total irradiated rectal volume; thus, PC1 correlates to the mean dose. Mode 2 describes the interpatient differences of the relative rectal volume in the two- or four-field overlap region. Mode 3 reveals correlations of volumes with intermediate doses ( approximately 40-45 Gy) and volumes with doses >70 Gy; thus, PC3 is associated with the maximal dose. According to univariate logistic regression analysis, only PC2 correlated significantly with toxicity. However, multivariate logistic regression analysis with the first two or three PCs revealed an increased probability of bleeding for DVHs with more than one large PC. CONCLUSIONS: PCA can reveal the correlation structure of DVHs for a patient population as imposed by the treatment technique and provide information about its relationship to toxicity. It proves useful for augmenting normal tissue complication probability modeling approaches. PMID- 17707275 TI - Phenylbutyrate sensitizes human glioblastoma cells lacking wild-type p53 function to ionizing radiation. AB - PURPOSE: Histone deacetylase (HDAC) inhibitors induce growth arrest, differentiation, and apoptosis in cancer cells. Phenylbutyrate (PB) is a HDAC inhibitor used clinically for treatment of urea cycle disorders. Because of its low cytotoxicity, cerebrospinal fluid penetration, and high oral bioavailability, we investigated PB as a potential radiation sensitizer in human glioblastoma cell lines. METHODS AND MATERIALS: Four glioblastoma cell lines were selected for this study. Phenylbutyrate was used at a concentration of 2 mM, which is achievable in humans. Western blots were used to assess levels of acetylated histone H3 in tumor cells after treatment with PB. Flow cytometry was used for cell cycle analysis. Clonogenic assays were performed to assess the effect of PB on radiation sensitivity. We used shRNA against p53 to study the role of p53 in radiosensitization. RESULTS: Treatment with PB alone resulted in hyperacetylation of histones, confirmed by Western blot analysis. The PB alone resulted in cytostatic effects in three cell lines. There was no evidence of G(1) arrest, increase in sub-G(1) fraction or p21 protein induction. Clonogenic assays showed radiosensitization in two lines harboring p53 mutations, with enhancement ratios (+/- SE) of 1.5 (+/- 0.2) and 1.3 (+/- 0.1), respectively. There was no radiopotentiating effect in two cell lines with wild-type p53, but knockdown of wild-type p53 resulted in radiosensitization by PB. CONCLUSIONS: Phenylbutyrate can produce p21-independent cytostasis, and enhances radiation sensitivity in p53 mutant human glioblastoma cells in vitro. This suggests the potential application of combined PB and radiotherapy in glioblastoma harboring mutant p53. PMID- 17707278 TI - Comparison of plan quality provided by intensity-modulated arc therapy and helical tomotherapy. AB - PURPOSE: Intensity-modulated arc therapy (IMAT) is an arc-based approach to intensity-modulated radiotherapy (IMRT) that can be delivered on a conventional linear accelerator using a conventional multileaf collimator. In a previous work, we demonstrated that our arc-sequencing algorithm can produce highly conformal IMAT plans. Through plan comparisons, we explored the ability of IMAT to serve as an alternative to helical tomotherapy. METHODS AND MATERIALS: The IMAT plans were created for 10 patients previously treated with helical tomotherapy. Treatment plan comparisons, according to the target dose coverage and critical structure sparing, were performed to determine whether similar plan quality could be achieved using IMAT. RESULTS: In 8 of 10 patient cases, IMAT was able to provide plan quality comparable to that of helical tomotherapy. In 2 of these 8 cases, the use of non-axial coplanar or non-coplanar arcs in IMAT planning led to significant improvements in normal tissue sparing. The remaining 2 cases posed particular dosimetric challenges. In 1 case, the target was immediately adjacent to a spinal cord that had received previous irradiation. The second case involved multiple target volumes and multiple prescription levels. Both IMAT and tomotherapy were able to produce clinically acceptable plans. Tomotherapy, however, provided a more uniform target dose and improved critical structure sparing. CONCLUSIONS: For most cases, IMAT can provide plan qualities comparable to that of helical tomotherapy. For some intracranial tumors, IMAT's ability to deliver non-coplanar arcs led to significant dosimetric improvements. Helical tomotherapy, however, can provide improved dosimetric results in the most complex cases. PMID- 17707279 TI - Intensity-modulated radiotherapy for craniospinal irradiation: target volume considerations, dose constraints, and competing risks. AB - PURPOSE: To report the results of an analysis of dose received to tissues and organs outside the target volume, in the setting of spinal axis irradiation for the treatment of medulloblastoma, using three treatment techniques. METHODS AND MATERIALS: Treatment plans (total dose, 23.4 Gy) for a standard two-dimensional (2D) technique, a three-dimensional (3D) technique using a 3D imaging-based target volume, and an intensity-modulated radiotherapy (IMRT) technique, were compared for 3 patients in terms of dose-volume statistics for target coverage, as well as organ at risk (OAR) and overall tissue sparing. RESULTS: Planning target volume coverage and dose homogeneity was superior for the IMRT plans for V(95%) (IMRT, 100%; 3D, 96%; 2D, 98%) and V(107%) (IMRT, 3%; 3D, 38%; 2D, 37%). In terms of OAR sparing, the IMRT plan was better for all organs and whole-body contour when comparing V(10Gy), V(15Gy), and V(20Gy). The 3D plan was superior for V(5Gy) and below. For the heart and liver in particular, the IMRT plans provided considerable sparing in terms of V(10Gy) and above. In terms of the integral dose, the IMRT plans were superior for liver (IMRT, 21.9 J; 3D, 28.6 J; 2D, 38.6 J) and heart (IMRT, 9 J; 3D, 14.1J; 2D, 19.4 J), the 3D plan for the body contour (IMRT, 349 J; 3D, 337 J; 2D, 555 J). CONCLUSIONS: Intensity modulated radiotherapy is a valid treatment option for spinal axis irradiation. We have shown that IMRT results in sparing of organs at risk without a significant increase in integral dose. PMID- 17707280 TI - Clinical feasibility of using an EPID in CINE mode for image-guided verification of stereotactic body radiotherapy. AB - PURPOSE: To introduce a novel method for monitoring tumor location during stereotactic body radiotherapy (SBRT) while the treatment beam is on by using a conventional electronic portal imaging device (EPID). METHODS AND MATERIALS: In our clinic, selected patients were treated under a phase I institutional review board-approved SBRT protocol for limited hepatic metastases from solid tumors. Before treatment planning multiple gold fiducial markers were implanted on the periphery of the tumor. During treatment the EPID was used in cine mode to collect the exit radiation and produce a sequence of images for each field. An in house program was developed for calculating the location of the fiducials and their relative distance to the planned locations. RESULTS: Three case studies illustrate the utility of the technique. Patient A exhibited a systematic shift of 4 mm during one of the treatment beams. Patient B showed an inferior drift of the target of approximately 1 cm from the time of setup to the end of the fraction. Patient C had a poor setup on the first day of treatment that was quantified and accounted for on subsequent treatment days. CONCLUSIONS: Target localization throughout each treatment beam can be quickly assessed with the presented technique. Treatment monitoring with an EPID in cine mode is shown to be a clinically feasible and useful tool. PMID- 17707281 TI - Feasibility of pathology-correlated lung imaging for accurate target definition of lung tumors. AB - PURPOSE: To accurately define the gross tumor volume (GTV) and clinical target volume (GTV plus microscopic disease spread) for radiotherapy, the pretreatment imaging findings should be correlated with the histopathologic findings. In this pilot study, we investigated the feasibility of pathology-correlated imaging for lung tumors, taking into account lung deformations after surgery. METHODS AND MATERIALS: High-resolution multislice computed tomography (CT) and positron emission tomography (PET) scans were obtained for 5 patients who had non-small cell lung cancer (NSCLC) before lobectomy. At the pathologic examination, the involved lung lobes were inflated with formalin, sectioned in parallel slices, and photographed, and microscopic sections were obtained. The GTVs were delineated for CT and autocontoured at the 42% PET level, and both were compared with the histopathologic volumes. The CT data were subsequently reformatted in the direction of the macroscopic sections, and the corresponding fiducial points in both images were compared. Hence, the lung deformations were determined to correct the distances of microscopic spread. RESULTS: In 4 of 5 patients, the GTV(CT) was, on average, 4 cm(3) ( approximately 53%) too large. In contrast, for 1 patient (with lymphangitis carcinomatosa), the GTV(CT) was 16 cm(3) ( approximately 40%) too small. The GTV(PET) was too small for the same patient. Regarding deformations, the volume of the well-inflated lung lobes on pathologic examination was still, on average, only 50% of the lobe volume on CT. Consequently, the observed average maximal distance of microscopic spread (5 mm) might, in vivo, be as large as 9 mm. CONCLUSIONS: Our results have shown that pathology-correlated lung imaging is feasible and can be used to improve target definition. Ignoring deformations of the lung might result in underestimation of the microscopic spread. PMID- 17707282 TI - Four-dimensional treatment planning for stereotactic body radiotherapy. AB - PURPOSE: To investigate the influence of tumor motion on the calculation of four dimensional (4D) dose distributions of the gross tumor volume (GTV) in pulmonary stereotactic body radiotherapy. METHODS AND MATERIALS: For 7 patients with eight pulmonary tumors, a respiratory-correlated 4D-computed tomography study was acquired. The internal target volume was the sum of all tumor positions in the planning 4D-computed tomography study, and a 5-mm margin was used for generation of the planning target volume. Three-dimensional (3D) treatment plans were generated with a dose prescription of 3 x 12.5 Gy to the planning target volume enclosing the 65% and 80% isodose. After model-based nonrigid image registration, the 4D dose distributions were calculated. RESULTS: No significant difference was found in the dose to the GTV with the tumor in the end-exhalation, end inhalation, or mid-ventilation phase of the breathing cycle. The high-dose region was confined to the solid tumor, and lower doses were delivered to the surrounding pulmonary tissue of lower density. This nonstatic, variant dose distribution increased the 4D dose to the GTV by 6.2%, on average, compared with calculations using on a static dose distribution during the breathing cycle. The 4D accumulation resulted in a biologic effective dose (BED) of 143 +/- 8 Gy and 106 +/- 4 Gy to the GTV in the plan-65% and plan-80%, respectively. The dose to the ipsilateral lung was not different between the 3D and 4D dose calculations or between plan-65% and plan-80%. CONCLUSIONS: In this study, the dose to the GTV was not decreased or blurred in the 4D plan compared with the 3D plan. The 3D doses to the GTV, internal target volume, and dose at the isocenter were good approximations of the 4D dose calculations. The 3D dose at the planning target volume margin underestimated the 4D dose significantly. PMID- 17707283 TI - [18FDG] PET-CT-based intensity-modulated radiotherapy treatment planning of head and neck cancer. AB - PURPOSE: To define the best threshold for tumor volume delineation of the (18) fluoro-2-deoxy-glucose positron emission tomography ((18)FDG-PET) signal for radiotherapy treatment planning of intensity-modulated radiotherapy (IMRT) in head and neck cancer. METHODS AND MATERIALS: In 25 patients with head-and-neck cancer, CT-based gross tumor volume (GTV(CT)) was delineated. After PET-CT image fusion, window level (L) was adapted to best fit the GTV(CT), and GTV(PET) was delineated. Tumor maximum (S) and background uptake (B) were measured, and the threshold of the background-subtracted tumor maximum uptake (THR) was used for PET signal segmentation. Gross tumor volumes were expanded to planning target volumes (PTVs) and analyzed. RESULTS: The mean value of S was 40 kBq/mL, S/B ratio was 16, and THR was 26%. The THR correlated with S (r = -0.752), but no correlation between THR and the S/B ratio was seen (r = -0.382). In 77% of cases, S was >30 kBq/mL, and in 23% it was 30% +/- 1.6% kBq/mL and 40% in tumors with S /= 0.88). The three dimensional distance between the isocenter according to bone match and soft tissue registration was 1.7 +/- 0.7 mm, maximum 2.8 mm. Treatment of intracranial pressure with steroids did not influence the position of the lesion relative to the bony anatomy. CONCLUSION: With a time interval of approximately 1 week between planning and treatment, the bony anatomy of the skull proved to be an excellent surrogate for the target position in image-guided SRT. PMID- 17707285 TI - Intraoperative ultrasound-fluoroscopy fusion can enhance prostate brachytherapy quality. AB - PURPOSE: To evaluate a transrectal ultrasound (TRUS)-fluoroscopy fusion-based intraoperative dosimetry system. METHOD AND MATERIALS: Twenty-five patients were treated for prostate cancer with Pd-103 implantation. After the execution of the treatment plan, two sets of TRUS images were collected using the longitudinal and axial transducers of a biplanar probe. Then, three fluoroscopic images were acquired at 0, -15 and +15 degrees . The three-dimensional locations of all implanted seeds were reconstructed from fluoroscopic images. A subset of the implanted seeds was manually identified in TRUS images and used as fiducial markers to perform TRUS-fluoroscopy fusion. To improve the implant quality, additional seeds were placed if adverse isodose patterns were identified during visual inspection. If additional seeds were placed, intraoperative dosimetry was repeated. Day 0 computed tomography-based dosimetry was compared with final intraoperative dosimetry to validate dosimetry achieved in the implant suite. RESULTS: An average of additional 4.0 seeds was implanted in 16 patients after initial intraoperative dose evaluation. Based on TRUS-fluoroscopy fusion-based dosimetry, the V100 improved from 86% to 93% (p = 0.005), whereas D90 increased from 94% to 109% (p = 0.011) with the guided additional seed implantation. No statistical difference was observed in V200 and V300 values. V100 and D90 values were 95 +/- 4% and 120 +/- 24%, respectively, based on the final intraoperative dosimetry evaluation, compared with 95 +/- 4% and 122 +/- 24%, respectively, based on Day 0 computed tomography-based dosimetry. CONCLUSIONS: Implantation of extra seeds based on TRUS-fluoroscopy fusion-based intraoperative dosimetry can improve the final V100 and D90 values with minimal increase in V200 and V300 values. PMID- 17707286 TI - Effects of intrafractional motion on water equivalent pathlength in respiratory gated heavy charged particle beam radiotherapy. AB - PURPOSE: To analyze the water equivalent pathlength (WEL) fluctuations resulting from cardiac motion and display these variations on a beam's-eye-view image; the analysis provides insight into the accuracy of lung tumor irradiation with heavy charged particle beams. MATERIALS AND METHODS: Volumetric cine computed tomography (CT) images were obtained on 7 lung cancer patients under free breathing conditions with a 256-multislice CT scanner. Cardiac phase was determined by selecting systole and diastole. A WEL difference image (DeltaWEL) was calculated by subtracting the WEL image at end-systole from that at end diastole at respiratory exhalation phase. Two calculation regions were defined: Region 1 was limited to the volume defined by planes bounding the heart; Region 2 included the entire body thickness for a given beam's-eye-view angle. RESULTS: The DeltaWEL values observed in Region 1 showed fluctuations at the periphery of the heart that varied from 20.4 (SD, 5.2) mm WEL to -15.6 (3.2) mm WEL. The areas over which these range perturbation values were observed were 36.8 (32.4) mm(2) and 6.0 (2.8) mm(2) for positive and negative WEL, respectively. The WEL fluctuations in Region 2 increased by approximately 3-4 mm WEL, whereas negative WEL fluctuations changed by approximately -4 to -5 mm WEL, compared with WEL for Region 1; areas over 20 mm WEL changes in Region 2 increased by 9 mm(2) for positive DeltaWEL and 2 mm(2) for negative DeltaWEL. CONCLUSIONS: Cine CT with a 256-multislice CT scanner captures both volumetric cardiac and respiratory motion with a temporal resolution sufficient to estimate range fluctuations by these motions. This information can be used to assess the range perturbations that charged particle beams may experience in irradiation of lung or esophageal tumors adjacent to the heart. PMID- 17707287 TI - In regards to Munter et Al. (Int J Radiat Oncol Biol Phys 2007;67:651-659). PMID- 17707289 TI - The role of afterschool settings in positive youth development. PMID- 17707290 TI - Advocating the inclusion of adolescent work experience as part of routine preventive care. PMID- 17707291 TI - Obesity and secondary conditions in adolescents with disabilities: addressing the needs of an underserved population. AB - Children and adolescents with physical and cognitive disabilities have a higher prevalence of overweight compared to their non-disabled peers. This health risk can lead to a greater number of obesity-related secondary conditions (e.g., fatigue, pain, deconditioning, social isolation, difficulty performing activities of daily living) and can impose significant personal and economic hardship on the child and family. Effective strategies for reducing the risk of overweight/obesity in adolescents with disabilities must begin with greater awareness of the behavioral and environmental antecedents that lead to higher rates of obesity in this underserved segment of the youth population. Research on interventions to reduce obesity among adolescents with disabilities is an important area of future research for public health scientists. A range of interventions will be necessary to overcome the many barriers that youth with disabilities experience in achieving and maintaining a healthy weight. PMID- 17707292 TI - Youth in sub-Saharan Africa. AB - Sub-Saharan Africa is going through rapid social, political, and economic transformations that have a profound impact on youth. The present review explores trends and outcomes as they relate to education, family formation and sexual and reproductive health and the interrelationships among these areas. It is based on both published and unpublished reports. Over the past 20 years, school enrollment has increased for much of the subcontinent; although the gender gap has narrowed, females remain educationally disadvantaged. Likewise, marriage is occurring later today than a generation ago, posing new challenges of out-of-wedlock births, clandestine abortions, and an increased likelihood of engaging in premarital sex. So, too, although there has been a slowing of the population growth in much of the region, in many countries of sub-Saharan Africa, the population is doubling every 30 years. Although acquired immunodeficiency syndrome is the predominant cause of death among youth, maternal mortality remains a major risk of death for youth--in some countries 600 times greater than that of peers in the industrialized world. PMID- 17707293 TI - Impact of a positive youth development program in urban after-school settings on the prevention of adolescent substance use. AB - PURPOSE: Positive youth development (PYD) emphasizes a strengths-based approach to the promotion of positive outcomes for adolescents. After-school programs provide a unique opportunity to implement PYD approaches and to address adolescent risk factors for negative outcomes, such as unsupervised out-of-school time. This study examines the effectiveness of an after-school program delivered in urban settings on the prevention of adolescent substance use. METHODS: A total of 304 adolescents participated in the study: 149 in the intervention group and 155 in a control group. A comprehensive PYD intervention that included delivery of an 18-session curriculum previously found to be effective in preventing substance use in school settings was adapted for use in urban after-school settings. The intervention emphasizes adolescents' use of effective decision making skills to prevent drug use. Assessments of substance use attitudes and behaviors were conducted at program entry, program completion, and at the 1-year follow-up to program entry. Propensity scores were computed and entered in the analyses to control for any pretest differences between intervention and control groups. Hierarchical linear modeling (HLM) analyses were conducted to assess program effectiveness. RESULTS: The results demonstrate that adolescents receiving the intervention were significantly more likely to view drugs as harmful at program exit, and exhibited significantly lower increases in alcohol, marijuana, other drug use, and any drug use 1 year after beginning the program. CONCLUSIONS: A PYD intervention developed for use in an urban after-school setting is effective in preventing adolescent substance use. PMID- 17707294 TI - Adolescent occupational injuries and workplace risks: an analysis of Oregon workers' compensation data 1990-1997. AB - PURPOSE: Injuries to adolescents from occupational activities has been recognized as a significant public health concern. The objective of this study was to quantify adolescent injury rates, analyze risk factors, and measure the severity of injuries sustained using Oregon workers' compensation data. METHODS: From 1990 1997, a total of 8060 workers' compensation claims, submitted by claimants 16-19 years old, were accepted by Oregon and used in these analyses. Data from the Bureau of Labor Statistics were used to derive injury rates. RESULTS: An overall estimated claim rate of 134.2 (95% confidence interval [CI] 124.9-143.6) per 10,000 adolescent workers was found, with males having over twice the rate of females. The total average annual claim cost was $3,168,457, representing $3145 per claim. The average total temporary disability period per claim was 22.3 days. Precision production workers had the highest claim rate of 296.2 (95% CI 178.9 413.4) and highest associated costs ($8266) for all occupations, whereas those in the farming/fishing/forestry occupation had the longest average periods of indemnification with 31.6 days. Day shift workers had the highest claim rates and most severe injuries relative to other shifts. CONCLUSION: The injury rates found among adolescent workers demonstrates that continued safety interventions and increased training are needed. Because of high claim rate and injury severity, particular attention should be focused on adolescents in food service, manufacturing, and agricultural occupations. Understanding the differences of adolescent circadian rhythm patterns in establishing work schedules and supervisory practices could also prove valuable for decreasing injury risk. PMID- 17707296 TI - Improvement in cancer-related knowledge following use of a psychoeducational video game for adolescents and young adults with cancer. AB - PURPOSE: Adolescents with chronic illnesses have been shown to have management and treatment issues resulting in poor outcomes. These issues may arise from non interest in self care and illness knowledge. A video game, "Re-Mission," was developed to actively involve young people with cancer in their own treatment. Re Mission provides opportunities to learn about cancer and its treatment. METHOD: The efficacy of Re-Mission was investigated in a multi-site, randomized, controlled study with 375 adolescent and young adult cancer patients. Participants received either a regular commercial game (control) or both the regular game plus Re-Mission (Re-Mission group). Participants were given a mini PC with the games installed and requested to play for an hour each week for 3 months. A test on cancer-related knowledge was given prior to game play (baseline) and again after 1 and 3 months. At 3 months the Re-Mission group also rated the acceptability and credibility of Re-Mission. RESULTS: Analyses of the knowledge test scores showed that whereas scores of both groups improved significantly over the follow-up periods, the scores of the Re-Mission group improved significantly more. The size of this effect was related to usage of Re Mission. Credibility scores were negatively correlated with level of knowledge but not with change in knowledge level at 1 month or 3 months. CONCLUSIONS: The results indicate a specific effect of Re-Mission play on cancer knowledge that is not attributable to patients' expectations. It is concluded that video games can be an effective vehicle for health education in adolescents and young adults with chronic illnesses. PMID- 17707295 TI - Health outcomes related to early adolescent depression. AB - PURPOSE: The aim of the present study was to examine whether early adolescent major depressive disorder was associated with negative health outcomes in young adulthood after controlling for depression at the time of follow-up. In addition, indicators of medical and social costs associated with these health consequences were measured. METHODS: A total of 705 adolescents participating in a longitudinal study of children varying in risk for depression due to maternal depression were assessed for a history of depression at age 15 years, depressive disorders at age 20, and a variety of health outcomes at age 20. RESULTS: Results showed that even after controlling for the effects of concurrent depression at age 20, early adolescent depression continued to be associated with poorer interviewer-rated health, poorer self-perceived general health, higher health care utilization and increased work impairment due to physical health, although not with limitations to physical functioning or the presence of chronic medical conditions. CONCLUSIONS: Depression during early adolescence has consequences for health and associated costs during young adulthood. The implications of these findings for screening and treatment of adolescent depression are discussed. PMID- 17707297 TI - Pregnancy intentions and contraceptive behaviors among adolescent women: a coital event level analysis. AB - PURPOSE: Measuring pregnancy intentions has been difficult. This study examines questions regarding pregnancy intentions and their association with adolescents' sexual and contraceptive behaviors longitudinally. METHODS: Adolescent women completed an interview about pregnancy intentions followed by a 3-month daily diary period reporting coital activity and contraception use. Interviews assessed pregnancy intentions with: "Are you trying to get pregnant now?," "Are you trying to keep from getting pregnant now?," and "I'm very committed to not getting pregnant at this time in my life." The measured outcome was the occurrence of contraceptive protected versus non-protected coitus collected from diary data. Logistic regression was used to assess this relationship. RESULTS: A total of 289 women completed 677 face-to-face interviews and subsequent 3 months of diary collection. In all, 194 reported having sex during diary collection. Women trying to keep from getting pregnant (n = 265) had 51.8% of 2533 coital events covered by contraception, whereas 13.1% of 818 coital events were protected in those women who were not trying to keep from getting pregnant (OR = 9.2, 95% CI = 6.0, 13.9). Women who agreed that they were committed to not getting pregnant were more likely to have coital events protected (50.5% of 2574 events) than those who disagreed (21.2% of 576 events) (OR = 9.8, 95% CI = 5.5, 17.3). CONCLUSIONS: Adolescents' contraceptive behaviors were associated with reported intentions. However, approximately one half of coital events were not protected in women who agreed that they were committed to not getting pregnant. These women may represent a group at risk for unintended pregnancy. PMID- 17707298 TI - Road rage victimization among adolescents. AB - PURPOSE: Although much has been learned about road rage among adults, data on road rage experiences among adolescents has not been available previously. We examine the prevalence and demographic correlates of road rage victimization based on a population survey of Ontario students. METHODS: Based on the 2005 Ontario Student Drug Use Survey, a self-administered survey of Ontario students in grades 7-12 (n = 7726), the contribution of demographic factors (gender, region, driver's license status, grade, overall marks) to three road rage victimization measures was examined with logistic regression analysis. RESULTS: Just over half of students (53.2%) had been victims of shouts, curses and rude gestures in the past year, 8.9% were threatened with damage to their vehicle or personal injury and 6.2% experienced an attempt or actual damage to their vehicle or personal injury. Logistic regression analyses revealed that being a victim of shouting was significantly related to region, driver's license status, and grade. Victimization by threats was significantly related to gender, driver's license, grade, and marks. Being a victim of attempts or actual vehicle damage or injury was significantly related to region, driver's license, and marks. CONCLUSION: This study provides the first indication of prevalence of road rage victimization among adolescents. Road rage victimization in its milder form is common, involving just over half of Ontario students in grades 7-12. About 1 in 10 students were threatened with vehicle damage or personal injury, and about 1 in 20 were victims of attempts or actual damage or injury. PMID- 17707300 TI - Alcohol use, sexual activity, and perceived risk in high school athletes and non athletes. AB - PURPOSE: The current study examined one's sense of personal invincibility as a contributing factor to high school athletes' more frequent behavioral risks compared to those of non-athletes. Perceived risk was assessed as a mediator of sports participation and alcohol use, and sports participation and sexual activity among high school athletes. METHODS: Prior to leaving home, college bound high school graduates (n = 2,247) completed web-based surveys assessing alcohol use, sexual activity, sports participation, and perceived risk. The mediational models were analyzed using generalized linear modeling and the procedures of Baron and Kenny (1986). RESULTS: Relative to non-athletes, athletes reported greater alcohol use, more sexual partners, and lower perceived risk. Perceived risk mediated the association between sports participation and alcohol use for both young men and women. Perceived risk also mediated the association between sports participation and number of sexual partners for women and partially mediated this association for men. Perceived risk partially mediated the association between sports participation and episodes of unsafe sexual activity in both men and women. CONCLUSIONS: These findings suggest a potential cognitive mechanism which may account for differences in alcohol use and sexual activity between athletes and non-athletes during late adolescence. PMID- 17707299 TI - Adolescent bullying involvement and perceived family, peer and school relations: commonalities and differences across race/ethnicity. AB - PURPOSE: Although bullying is recognized as a serious problem in the United States, little is known about racial/ethnic differences in bullying risk. This study examined associations between bullying and family, peer, and school relations for white, black and Hispanic adolescents. METHODS: A nationally representative sample (n = 11,033) of adolescents in grades six to ten participated in the 2001 Health Behaviors in School-Aged Children survey, self reporting bullying involvement and information on family, peer and school relations. Descriptive statistics and multinomial logistic regression analyses controlling for gender, age and affluence were stratified by race/ethnicity. RESULTS: Nine percent of respondents were victims of bullying, 9% were bullies, and 3% were bully-victims. Black adolescents reported a significantly lower prevalence of victimization than white and Hispanic students. Multivariate results indicated modest racial/ethnic variation in associations between bullying and family, peer, and school factors. Parental communication, social isolation, and classmate relationships were similarly related to bullying across racial/ethnic groups. Living with two biological parents was protective against bullying involvement for white students only. Furthermore, although school satisfaction and performance were negatively associated with bullying involvement for white and Hispanic students, school factors were largely unrelated to bullying among black students. CONCLUSIONS: Although school attachment and performance were inconsistently related to bullying behavior across race/ethnicity, bullying behaviors are consistently related to peer relationships across black, white, and Hispanic adolescents. Negative associations between family communication and bullying behaviors for white, black, and Hispanic adolescents suggest the importance of addressing family interactions in future bullying prevention efforts. PMID- 17707301 TI - Mystery shopping and alcohol sales: do supermarkets and liquor stores sell alcohol to underage customers? AB - PURPOSE: The Dutch national policy regarding alcohol and youth relies on retailers' willingness to refuse to sell alcohol to underage customers. This study examined unobtrusively whether supermarkets and liquor stores do indeed comply with the legal age restrictions for alcohol sales. METHODS: A research protocol was developed based on the methodology of mystery shopping. Using the protocol, 150 supermarkets and 75 liquor stores were visited by 15-year-old adolescents who tried to buy soft alcoholic beverages (legal age, 16 years), and 75 liquor stores were visited by 17-year-old adolescents who tried to buy strong alcoholic beverages (legal age, 18). RESULTS: Of all 300 buying attempts, 86% were successful. In supermarkets, 88% of all attempts succeeded. In liquor stores, a difference was found between the purchase of strong alcohol by 17-year olds (89%) and the purchase of soft alcoholic beverages by 15-year-olds (77%). In only 71 of all visits, mystery shoppers were asked for an ID. In 39% of these cases, they were still able to buy alcohol. Female adolescents were more successful in buying alcohol than male adolescents. CONCLUSIONS: The results show that supermarkets and liquor stores generally fail to see the need for extra care when young customers try to buy alcohol. Legal age restrictions without enforcement and facilitation clearly do not suffice to protect adolescents from early exposure to alcohol. PMID- 17707302 TI - Household smoking as a risk indicator for caries in adolescents' permanent teeth. AB - This study investigated the association between household member's (HHM) smoking or secondhand smoke exposure and caries, using a cross-sectional sample of adolescents who had both dental examination and data on HHM smoking (n = 1,873). The results suggest that HHM smoking may be a risk indicator for caries in adolescents' permanent teeth. PMID- 17707304 TI - Elusive denominators and the illusions they create. PMID- 17707303 TI - Measuring adolescent functional health literacy: a pilot validation of the Test of Functional Health Literacy in Adults. AB - Most health literacy tools have been validated only for adults, but health literacy is also important for adolescents who must increasingly make personal health decisions. This pilot adolescent validation of the Test of Functional Health Literacy in Adults suggests that the reading comprehension component is valid for adolescents. PMID- 17707306 TI - Need for rapid communication. PMID- 17707307 TI - Detection of hemorrhagic hypointense foci in the brain on susceptibility-weighted imaging clinical and phantom studies. AB - RATIONALE AND OBJECTIVES: To determine the sensitivity of susceptibility-weighted imaging (SWI) for depicting hemorrhagic hypointense foci of the brain in comparison with gradient-recalled echo (GRE)- and GRE-type single-shot echo planar imaging (GREI, GRE-EPI), and to assess the basic characteristics of the susceptibility effect by using a phantom. MATERIALS AND METHODS: We prospectively examined 16 patients (9 males, 7 females, aged 10-74 years, mean 43 years) with hypointense foci using SWI, GREI, and GRE-EPI at a 1.5-T magnetic resonance (MR) unit. The contrast-to-noise ratio (CNR), sensitivity to small hypointese foci, and artifacts were evaluated. To assess the basic characteristics of SWI, we performed a phantom study using different concentrations of superparamagnetic iron oxide (SPIO). RESULTS: The CNR of lesions was significantly greater for SWI than the other images (P < .0001). SWI detected the greatest number of small hypointense foci, even in the near-skull-base and infratentorial regions. Quantitative and qualitative analyses in our clinical and phantom studies demonstrated that the degree of artifacts was similar with SWI and GREI. CONCLUSION: SWI was best for detecting small hemorrhagic hypointense foci. Artifacts of SWI were similar to GREI. PMID- 17707308 TI - Apparent diffusion coefficient of subcutaneous epidermal cysts in the head and neck comparison with intracranial epidermoid cysts. AB - RATIONALE AND OBJECTIVES: Subcutaneous epidermal cysts and intracranial epidermoid cysts are pathologically identical. Although diffusion-weighted imaging (DWI) studies of intracranial epidermoid cysts have been numerously reported, those of subcutaneous epidermal cysts have not been sufficiently investigated. Our hypothesis for this study is that the apparent diffusion coefficient (ADC) values of subcutaneous epidermal cysts and intracranial epidermoid cysts are not different. This study was intended to evaluate the ADC of subcutaneous epidermal cysts of the head and neck in comparison with that of intracranial epidermoid cysts. MATERIALS AND METHODS: The MR studies were performed in 14 patients with head and neck subcutaneous epidermal cysts and 10 patients with intracranial epidermoid cysts using line scan DWI (LSDWI). The ADC was measured and compared between the two types of cyst. RESULTS: The ADC values (mean +/- SD) were 0.81 +/- 0.14 x 10(-3) mm(2)/s in subcutaneous epidermal cysts and 1.06 +/- 0.12 x 10(-3) mm(2)/s in intracranial epidermoid cysts. A significant difference was found in ADC values between the two types (P = .0019). CONCLUSION: Our preliminary study has shown that the ADC provides useful information regarding tissue characterization of subcutaneous epidermal cysts. However, the ADC of subcutaneous epidermal cysts was significantly lower than that of intracranial epidermoid cysts. PMID- 17707309 TI - Evidence of brain dysfunction in attention deficit-hyperactivity disorder: a controlled study with proton magnetic resonance spectroscopy. AB - RATIONALE AND OBJECTIVES: Attention deficit-hyperactivity disorder (ADHD) is a socially disabling condition whose pathophysiology is mostly unknown. Previous magnetic resonance imaging (MRI)-based reports have shown structural abnormalities in the prefrontal region and the striatum, but with inconsistencies across the studies with regard to right/left specificity of changes. Our study is aimed at finding evidence of dysfunction with more refined MRI techniques such as diffusion-weighted MRI and spectroscopy. MATERIALS AND METHODS: We enrolled 22 ADHD children (mean age 9; SD 2.91) and 8 healthy children (mean age 7.5; SD 3). All of them underwent diffusion-weighted MRI in several areas of the brain bilaterally: prefrontal, lentiform nucleus, posterior cingulate, and centrum semiovale; and single-voxel proton magnetic resonance spectroscopy in the left centrum semiovale and right prefrontal region. RESULTS: We did not see either apparent structural abnormalities of the brain in conventional MRI or differences in the apparent-diffusion coefficients in any of the areas studied. However, we observed significant differences in the N-acetyl-aspartate/creatine ratios in relation to controls in the right prefrontal corticosubcortical region: 1.58 (SD 0.09) versus 1.47 (0.08), P = .01); and in the left centrum semiovale: 2.02 (0.13) versus 1.79 (0.13), P = .0003. This finding is consistent with a published report on eight ADHD children in whom N-acetyl-aspartate/creatine ratios were also elevated. CONCLUSIONS: Given these results, we hypothesize that a biochemical dysfunction might underlie in the brain of ADHD children. The N acetyl-aspartate/creatine ratio may be regarded as a potential marker of the disease. PMID- 17707310 TI - Computer-assisted mammography feedback program (CAMFP) an electronic tool for continuing medical education. AB - RATIONALE AND OBJECTIVES: Our goal was to develop and evaluate software to support a computer assisted mammography feedback program (CAMFP) to be used for continuing medical education (CME). MATERIALS AND METHODS: Thirty-five radiologists from our region signed consent to participate in an institutional review board-approved film-reading study. The radiologists primarily assessed digitized mammograms and received feedback in five film interpretation sessions. A bivariate analysis was used to evaluate the joint effects of the training on sensitivity and specificity, and the effects of image quality on reading performance were explored. RESULTS: Interpretation was influenced by the CAMFP intervention: Sensitivity increased (Delta sensitivity = 0.086, P < .001) and specificity decreased (Delta specificity = -0.057, P = .04). Variability in interpretation among radiologists also decreased after the training sessions (P = .035). CONCLUSION: The CAMFP intervention improved sensitivity and decreased variability among radiologist's interpretations. Although this improvement was partially offset by decreased specificity, the program is potentially useful as a component of continuing medical education of radiologists. Dissemination via the web may be possible using digital mammography. PMID- 17707312 TI - Functional imaging of estrogen receptors with radiolabeled-GAP-EDL in rabbit endometriosis model. AB - RATIONALE AND OBJECTIVES: Endometriosis is a common women's health problem. Animal models provide an invaluable tool to study the natural history of endometriosis. We previously have reported that (99m)Tc-labeled glutamate peptide estradiol ((99m)Tc-GAP-EDL) is a useful agent for imaging functional estrogen receptor (ER) via an ER-mediated process. This study was to evaluate the feasibility of using radiolabeled GAP-EDL to image ER-positive (ER +) endometriosis in nonprimate animal models. MATERIALS AND METHODS: 3-Aminoethyl estradiol (EDL) was conjugated to glutamate peptide (GAP) to yield GAP-EDL. In vitro cellular uptake studies of (99m)Tc and (68)Ga-GAP-EDL inhibition with cold estrone were conducted in 13,762 rat mammary tumor cells. To create a rabbit model with endometriosis, part of uterine tissue was dissected and grafted in the peritoneal wall. Eight weeks after surgery, scintigraphic images were obtained after intravenous injection of (99m)Tc-GAP-EDL (1 mCi/rabbit, intravenous) at 0.5 2.0 hours, and (68)Ga-GAP-EDL at 45 minutes. We also performed (68)Ga-GAP-EDL blocking study in rabbit model by using tamoxifen. The rabbits were sacrificed and the grafts were excised for histologic examination. RESULTS: In vitro uptake study of (99m)Tc- and (68)Ga-GAP-EDL in 13,762 rat breast cancer cells showed gradually increasing uptake of both tracers. Accumulation of (68)Ga-GAP-EDL in 13,762 cells was inhibited with cold estrone in a dose-dependent manner. In the endometriosis model, the grafted uterine tissue could be visualized by (99m)Tc GAP-EDL. Necropsy was performed at 2.5 hours after injection time. Four follicular endometrial lesions in eight implanted endometrial tissues were detected, and all lesions could be detected by (99m)Tc-GAP-EDL. Planar scintigraphy of uterus, ovary and implants of necropsy specimen revealed an increased uptake of (99m)Tc-GAP-EDL in comparison with surrounding abdominal wall tissue. Microscopic examinations support that (99m)Tc-GAP-EDL was accumulated in the microinvasive endometrial tissue. After blocking with tamoxifen, (68)Ga-GAP EDL accumulation in the endometrial grafts could not be visualized, and endometrial tissue-to-normal tissue count ratios were statistically higher in a nonblocked image than that in the blocked image. CONCLUSIONS: Endometriosis uptake of radiolabeled GAP-EDL was via an estrogen receptor-mediated process. Radiolabeled-GAP-EDLs are useful agents for imaging endometriosis. PMID- 17707311 TI - Effect of scanner type on the reproducibility of extracoronary measures of calcification: the multi-ethnic study of atherosclerosis. AB - RATIONALE AND OBJECTIVES: Cardiac computed tomography (CT) has been used extensively to measure coronary artery calcification. However, extracoronary calcifications, such as aortic valve calcification (AVC), may have independent clinical significance as well. The ability to track calcification is dependent on the reproducibility of the original measurement, and the variability of extracoronary calcification measurements still is unknown. Accurate quantification of calcification of the aortic valve, mitral annulus (MAC), and thoracic aortic (TAC) may be possible by using cardiac CT. METHODS: A total of 1,729 randomly chosen participants (ages 45-84, 53% female, 28% African-American, 36% Caucasian, 11% Chinese, 25% Hispanic) of the Multi-Ethnic Study of Atherosclerosis underwent dual scanning by electron beam CT (EBT) or multidetector CT (MDCT) to assess coronary and extra-coronary calcifications. Two calcium measurement methods--Agatston score (AS) and volume score (VS)--were measured for each scan. Concordance for calcium positivity was assessed among all scans. Mean absolute and relative differences between calcium measures on scans 1 and 2, excluding cases for which both scans had a measure of zero, was modeled by using linear regression to compare variability between scanner types. A repeated measures analysis of variance test was used to compare variability across calcium measures, with mean percentage absolute difference as the outcome measure. RESULTS: Concordances for the presence of calcium between duplicate scans were high and similar for both EBT and MDCT. Concordance was high for all three extracoronary measures, with a kappa statistic of kappa = 0.94-0.96. For all three extracoronary sites, Bland-Altman plots demonstrated excellent agreement, with almost all measures falling within the boundaries of the 95% confidence limits of reproducibility. AVC interscan variability was approximately 8% for both AS and VS, with improved variability for EBT as compared with MDCT. Mitral annular calcification demonstrated slightly lower variability than AVC for both scanner types (approximately 6%), with no significant differences between MDCT and EBT. Of the three extracoronary sites, TAC had the highest variability (10%), with MDCT variability slightly lower than EBT variability (9.3 vs. 10.2%, respectively, P = NS). Agatson and volume scores for each of the three extracoronary sites were similar. CONCLUSIONS: Overall rescan measurement variabilities for extracoronary calcification are low and should not be an impediment to the use of this test for studying progression of extracoronary calcification over time. PMID- 17707313 TI - In search of biologic correlates for liver texture on portal-phase CT. AB - RATIONALE AND OBJECTIVES: The acceptance of computer-assisted diagnosis (CAD) in clinical practice has been constrained by the scarcity of identifiable biologic correlates for CAD-based image parameters. This study aims to identify biologic correlates for computed tomography (CT) liver texture in a series of patients with colorectal cancer. MATERIALS AND METHODS: In 28 patients with colorectal cancer, total hepatic perfusion (THP), hepatic arterial perfusion, and hepatic portal perfusion (HPP) were measured using perfusion CT. Hepatic glucose use was also determined from positron emission tomography (PET) and expressed as standardized uptake value (SUV). A hepatic phosphorylation fraction index (HPFI) was determined from both SUV and THP. These physiologic parameters were correlated with CAD parameters namely hepatic densitometry, selective-scale, and relative-scale texture features in apparently normal areas of portal-phase hepatic CT. RESULTS: For patients without liver metastases, a relative-scale texture parameter correlated inversely with SUV (r = -0.587, P = .007) and, positively with THP (r = 0.512, P = .021) and HPP (r = 0.451, P = .046). However, this relative texture parameter correlated most significantly with HPFI (r = 0.590, P = .006). For patients with liver metastases, although not significant an opposite trend was observed between these physiologic parameters and relative texture features (THP: r < -0.4, HPFI: r > 0.35). CONCLUSION: Total hepatic blood flow and glucose metabolism are two distinct but related biologic correlates for liver texture on portal phase CT, providing a rationale for the use of hepatic texture analysis as a indicator for patients with colorectal cancer. PMID- 17707314 TI - Does computer-aided diagnosis for lung tumors change satisfaction of search in chest radiography? AB - RATIONALE AND OBJECTIVES: Computer-aided diagnosis (CAD) has been developed to ensure that the radiologist considers suspect focal opacities that may represent cancer in chest radiography. Although CAD was not developed to counteract the satisfaction of search (SOS) effect, it may be an effective intervention to do so. The objective of this study is to determine whether an idealized CAD can reduce SOS effects in chest radiography. MATERIALS AND METHODS: Fifty-seven chest radiographs, half of which demonstrated diverse, native abnormalities were read twice by 16 observers, once with and once without the addition of a simulated pulmonary nodule. Simulated CAD prompts were provided during the interpretation, which unerringly pointed to the added simulated nodule. Area under the ROC curve for detecting the native abnormalities was estimated for each observer in each treatment condition. In addition to testing for the SOS effect in the presence of CAD prompts, results were compared to those of a previous SOS study. RESULTS: Significantly more nodules were reported in the SOS with CAD experiment than in the original SOS experiment (49 versus 43, P < .01). An SOS effect was found even when CAD prompts were provided; ROC areas for detecting native abnormalities were reduced with added nodules [0.68 versus 0.65, P (one-tailed) < .05]. Comparison of the current experiment with CAD and the previous SOS experiments failed to show a significant difference of the magnitude of the SOS effect (P = .52). The threshold for reporting was more conservative with CAD prompts than in SOS studies (P = .052). CONCLUSION: Our results indicate that the CAD prompts, even those that always point to their target lesion without false-positive error, fail to counteract SOS in chest radiography. The stricter decision thresholds with CAD prompts may indicate less visual search for native abnormalities. PMID- 17707315 TI - Diffusion weighted imaging in breast MRI: comparison of two different pulse sequences. AB - RATIONALE AND OBJECTIVES: Comparison of two different diffusion weighted (DW) sequences in breast MRI regarding the differentiation between benign and malignant lesions. MATERIALS AND METHODS: Breast MRI including two different DW sequences was performed in 165 consecutive women. Inclusion criteria for DW imaging and ADC evaluation were histologically proven focal mass lesions with a diameter of more than 5 mm in dynamic contrast-enhanced MRI. The DW sequences were pre-contrast echo-planar imaging with spectral fat saturation (EPI fs) and DW EPI with inversion recovery (EPI STIR) (b-values: 50, 400, and 800). Lesions were analyzed regarding visibility in DW sequences and ADC values. RESULTS: Inclusion criteria were fulfilled in 56 women with 69 lesions. Five lesions could not be evaluated for different reasons. Finally, DW sequences were evaluated in 51 women with 64 focal mass lesions (15 benign, 49 malignant). The visibility of the lesions was significantly better in the EPI fs sequence (P<0.05). The ADC values (10(-3) mm(2)/s) in the EPI fs were 1.76, 2.58, and 1.21 (mean, maximum, minimum, respectively) for benign lesions and 0.90, 1.19, and 0.34 for malignant lesions. Respective values in the EPI STIR sequence were 1.92, 3.20, 1.10, and 0.91, 1.43, 0.35. Only in the EPI fs sequence there was no overlap in ADC values between benign and malignant lesions. CONCLUSION: The DW MRI of the breast with EPI fs and EPI STIR sequences has a high potential to differentiate between benign and malignant breast lesions. Due to better lesion visibility and selectivity, the EPI fs sequence should be preferred. PMID- 17707316 TI - Multiphase contrast-enhanced CT imaging in hepatocellular carcinoma correlation with immunohistochemical angiogenic activities. AB - RATIONALE AND OBJECTIVES: To evaluate the correlation between enhancement parameters of multiphase contrast-enhanced computed tomography (CT) and immunohistochemical activities of vascular endothelial growth factor (VEGF), VEGF receptors, and CD34 in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Twenty-seven patients underwent curative resection for HCC with no preoperative treatment. We defined several CT enhancement parameters by measuring attenuation values of tumor, liver parenchyma, and aorta. The stored tissue blocks were assayed for immunohistochemical activities of VEGF, two VEGF receptors (Flt-1, Flk-1), and CD34, which were correlated with the enhancement parameters of multiphase contrast-enhanced CT. RESULTS: The VEGF activities in HCC showed moderate positive correlation with phase difference in portal phase, delayed enhancement (DE), tumor-blood ratio, blood pool index, and tumor-parenchyma ratio in arterial phase. The Flk-1 activities in HCC showed moderate positive correlation only with DE. CD34 activity in HCC showed positive correlation with most of the CT parameters except for DE. CONCLUSION: Our study showed that several CT enhancement parameters representing mainly delayed enhancement features were well correlated with VEGF activity in HCC, and might be valuable indicators for assessing angiogenic activity in HCC. PMID- 17707317 TI - Evolving physician perception of world wide web education 2007 update and review of the literature. PMID- 17707318 TI - Estimating head circumference from pediatric imaging studies an improved method. AB - RATIONALE AND OBJECTIVES: Head circumference (HC) is an important developmental measure used both clinically and in research. This paper advances a method to estimate HC from imaging studies when a direct HC-tape measurement cannot be secured. Unlike former approaches, the model takes into account the fact that growth is nonlinear, and that HC growth rates are sexually dimorphic. MATERIALS AND METHODS: A model was first established based on published data to represent the normative HC growth curves for males and females. Then, using magnetic resonance (MR) studies of 90 subjects (birth to 18 years), a linear method to estimate HC was adapted to take into account the nonlinear and sex-specific HC normative growth curves. The accuracy of this model was tested prospectively by comparing the estimated HC with HC measurements from twelve computed tomography (CT) studies using the perimeter tracing of oblique slices that correspond to the plane at which a clinical HC-tape measurement is secured. RESULTS: Prospective comparison of estimated HC to HC tracings using a paired t-test validates that the model provides an accurate estimation of the measured HC (t=-.845, p=0.416 overall; t=.54, p=.615 for females and t=-2.34, p=.066 for males). DISCUSSION: HC can be calculated indirectly from imaging studies. The model is highly predictive of HC-tape measurements and provides the physician or scientist with a very reliable method to secure HC when it is not feasible to secure the HC-tape measurement. PMID- 17707320 TI - Learning radiology a survey investigating radiology resident use of textbooks, journals, and the internet. AB - RATIONALE AND OBJECTIVES: We surveyed radiology residents to understand which information sources residents use to learn radiology. MATERIALS AND METHODS: A 15 question survey on learning resources was given to radiology residents at one institution. The survey queried residents about their preferences for sources when encountering a question in the reading room and when attempting to learn radiology and about the frequency with which they read radiology/medical journals. Residents ranked Internet sites for these learning purposes. The IRB gave administrative approval for the survey. RESULTS: All residents (60 of 60) completed the survey. When a question is encountered in the reading room, 50 of 60 (83%) respondents prefer to use the Internet as a first-line resource, and 15% prefer a textbook. When using the Internet, 46 of 60 (77%) residents use Google as their first source, 12% use eMedicine, 3% use StatDx, 3% use UpToDate, and 2% use RSNA online journals. eMedicine was the most popular second resource at 65%. Of 60, 59 (98%) residents prefer to use physician/scientist professional Web sites (e.g., eMedicine) rather than consumer/patient-oriented Web sites. When using the Internet to learn radiology, 32% of residents prefer AuntMinnie, 30% use Edactic.com, 22% use ACR Case-In-Point, 3% use www.learningradiology.com, 2% use radquiz.com, and 2% use RadioGraphics online. On average, residents listed 6.2 Internet sites. For textbook learning, 58% of residents prefer case review or requisite books, while 32% prefer traditional textbooks. The mean number of textbooks owned is 5.3, while the mean number of case review or requisite books is 5.4. Of 60 residents, 8 own most or all the case review and requisite books. Twenty-eight percent of residents read radiology textbooks daily; 45%, weekly; 8%, monthly; and 15%, occasionally. Twenty-three percent of residents read radiology journals monthly; 15%, quarterly; 37%, occasionally; and 23%, never. Five percent of residents read medical journals (e.g., The New England Journal of Medicine) monthly; 2%, quarterly; 48%, occasionally; and 45%, never. CONCLUSION: Currently, residents prefer the Internet when researching a question, with Google as the Web site most commonly used. Case review or requisite books are more commonly used than are traditional textbooks. Radiology resident learning has rapidly shifted from traditional textbooks and journals to the Internet and short case review books. PMID- 17707319 TI - Reformatted Four-Chamber and Short-Axis Views of the Heart Using Thin Section (40 years, mean 51.36+/-8.32) pronounced significance only in older males (OR 2.4, CI=1.2-5.0, p=0.02). After adjustment for confounding factors the OR for hypertension remained unchanged and significant (adjusted OR 2.3, CI=1.0-5.4, p=0.04). CONCLUSION: Hemizygosity for the G allele was found to be susceptibility factor for hypertension in males. Still, clarifying the role of AT2R in development of human hypertension requires further replication studies in larger and different populations. PMID- 17707360 TI - Characterization of glycation adducts on human serum albumin by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - BACKGROUND: Non-enzymatic glycation of human serum albumin (HSA) is associated with the long-term complications of diabetes. We examined the structure and location of modifications on minimally-glycated HSA and considered their possible impact on the binding of drugs to this protein. METHODS: Minimally-glycated and normal HSA (used as a control) were digested with trypsin, Glu-C or Lys-C, followed by fractionation of the resulting peptides and their analysis by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to determine the structures and locations of glycation adducts. RESULTS: Several specific lysine and arginine residues were identified as modification sites in minimally-glycated HSA. Residues K12, K51, K199, K205, K439 and K538 were found to be modified through the formation of fructosyl-lysine, while the modification of K159 and K286 involved the formation of pyrraline or N(epsilon) carboxymethyl-lysine, respectively. Lysine K378 was found to give N(epsilon) carboxyethyl-lysine in some forms of glycated HSA but fructosyl-lysine in other forms. Residues R160 and R472 produced a modification based on N(epsilon)-(5 hydro-4-imidazolon-2-yl)ornithine. Lysine R222 was modified to produce argpyrimidine, N(epsilon)-[5-(2,3,4-trihydroxybutyl)-5-hydro-4-imidazolon-2 yl]ornithine or tetrahydropyrimidine. CONCLUSIONS: With the exception of K12, K199, K378, K439 and K525, all of the observed sites of modification for minimally-glycated HSA were new to this current study. The fact that many of these glycation-related modifications are located at or near known drug binding sites on HSA explains why some differences have been previously noted in the binding of certain drugs to normal vs glycated HSA. PMID- 17707361 TI - Proteomic approaches for identifying new allergens and diagnosing allergic diseases. AB - BACKGROUND: Allergic diseases are (IgE)-mediated hypersensitivity reactions affecting more than 25% of the world's population. Proteomic technologies have been increasingly used in the field of allergy and include the use of protein microarrays and two-dimensional gel electrophoresis coupled with immunoblotting. METHODS: The literature relevant to proteomic approaches to allergic diseases was searched using MEDLINE database. We reviewed proteomics approaches and applications, focusing specifically on two-dimensional immunoblotting techniques and allergen microarrays. RESULTS: The results obtained show that proteomic approaches using two-dimensional immunoblotting appear to be a powerful strategy for the identification of allergenic proteins. Likewise, the use of allergen microarrays allows a large number of IgE antibodies to be simultaneously identified. CONCLUSIONS: Proteomic approaches are only beginning to be applied to the study of allergy. In the field of in vitro diagnosis, allergen microarrays provide a promising tool not routinely used in the allergy laboratory. In the near future this powerful technique will be used as a standard technique for in vitro diagnosis of allergy. PMID- 17707362 TI - Real-time assessment of hepatic function is related to clinical outcome in critically ill patients after polytrauma. AB - OBJECTIVES: The aim was to investigate the outcome MODS/MOF in critically ill patients with regard to early hepatic dysfunction. METHODS: Thirty adult polytrauma patients admitted to the ICU, with ISS >or=16 were prospectively investigated. Real-time liver function was assessed using the MEGX test and arterial ketone body ratio (AKBR) 12-24 h after admittance to ICU, and on days 3, 5, 8, 12. RESULTS: Six patients (19%) died between days 4 and 29. Non-survivors were older (64.2 vs. 31.5 years), had a significantly higher ISS (40.5 vs. 30; p=0.002) and MODS score (9.5 vs. 5; p=0.001) on admittance to the ICU than survivors. On day 3 MEGX values (31 vs. 71.3 microg/L; p=0.001) and the AKBRs (0.6 vs. 1.3; p=0.001) were significantly lower in non-survivors than in survivors whereas IL-6 levels were significantly higher in the former group (519 vs. 61 microg/L; p=0.05). CONCLUSIONS: The MEGX test and AKBR are sensitive early indicators of hepatic dysfunction in severely injured polytrauma patients at risk for developing MODS/MOF. PMID- 17707363 TI - Individual differences in category learning: sometimes less working memory capacity is better than more. AB - We examined whether individual differences in working memory influence the facility with which individuals learn new categories. Participants learned two different types of category structures: rule-based and information-integration. Successful learning of the former category structure is thought to be based on explicit hypothesis testing that relies heavily on working memory. Successful learning of the latter category structure is believed to be driven by procedural learning processes that operate largely outside of conscious control. Consistent with a widespread literature touting the positive benefits of working memory and attentional control, the higher one's working memory, the fewer trials one took to learn rule-based categories. The opposite occurred for information-integration categories - the lower one's working memory, the fewer trials one took to learn this category structure. Thus, the positive relation commonly seen between individual differences in working memory and performance can not only be absent, but reversed. As such, a comprehensive understanding of skill learning - and category learning in particular - requires considering the demands of the tasks being performed and the cognitive abilities of the performer. PMID- 17707364 TI - Category contingent aftereffects for faces of different races, ages and species. AB - Exposure to faces biases perceptions of subsequently viewed faces such that normality judgments of similar faces are increased. Simultaneously inducing such an aftereffect in opposite directions for two groups of faces might indicate discrete responding of the neural populations coding for those groups. Here we show such "category contingent" aftereffects following exposure to faces differing in eye-spacing (wide versus narrow) for European versus African faces, adult versus infant faces, and human versus monkey faces. As aftereffects reflect changes in responses of neural populations that code faces, our results may then suggest that functionally distinct neural populations code faces of different ages, races and species and that the human brain potentially contains discrete representations of these categories. PMID- 17707365 TI - Cross regulation of intercellular gap junction communication and paracrine signaling pathways during organogenesis in Drosophila. AB - The spatial and temporal coordination of patterning and morphogenesis is often achieved by paracrine morphogen signals or by the direct coupling of cells via gap junctions. How paracrine signals and gap junction communication cooperate to control the coordinated behavior of cells and tissues is mostly unknown. We found that hedgehog signaling is required for the expression of wingless and of Delta/Notch target genes in a single row of boundary cells in the foregut associated proventriculus organ of the Drosophila embryo. These cells coordinate the movement and folding of proventricular cells to generate a multilayered organ. hedgehog and wingless regulate gap junction communication by transcriptionally activating the innexin2 gene, which encodes a member of the innexin family of gap junction proteins. In innexin2 mutants, gap junction mediated cell-to-cell communication is strongly reduced and the proventricular cell layers fail to fold and invaginate, similarly as in hedgehog or wingless mutants. We further found that innexin2 is required in a feedback loop for the transcriptional activation of the hedgehog and wingless morphogens and of Delta in the proventriculus primordium. We propose that the transcriptional cross regulation of paracrine and gap junction-mediated signaling is essential for organogenesis in Drosophila. PMID- 17707366 TI - Vg1 has specific processing requirements that restrict its action to body axis patterning centers. AB - Unlike most transforming growth factor-beta (TGF-beta) superfamily members, Vg1 has been shown not to produce gross phenotypic alterations in Xenopus embryos when overexpressed by mRNA injection. Experiments with artificial chimeric constructs and a recently identified second allele of Vg1 suggest that this may be due to unusually stringent requirements for proteolytic processing. We provide biological and biochemical evidence that cleavage by two distinct proteolytic enzymes is required for effective activation of Vg1. We demonstrate a tightly restricted overlap in expression patterns of Vg1 with the proteases required to release the mature peptide. The data presented may account for the long-standing observation that the vast majority of Vg1 protein, in vivo, is present in its unprocessed form. Taken together, these observations provide a plausible mechanism for local action of Vg1 consistent with requirements imposed by current models of pattern formation in the developing body axis. PMID- 17707367 TI - 9-Benzylidene-naphtho[2,3-b]thiophen-4-ones and benzylidene-9(10H)-anthracenones as novel tubulin interacting agents with high apoptosis-inducing activity. AB - Tubulin-binding 9-benzylidene-naphtho[2,3-b]thiophen-4-ones 1a and 1b and benzylidene-9(10H)-anthracenone 2 were evaluated for their ability to induce cell death. We examined the effect of the molecules on cell cycle progression, organization of microtubule networks, and apoptosis induction. As determined by flow cytometry, cancer cells were predominantly arrested in metaphase with 4N DNA before cell death occurred. By using indirect immunofluorescence techniques we visualized microtubule depolymerization recognizable by short microtubule fragments scattered around the nucleus. The incubation with 1a and 2 resulted in chromatin condensation, nuclear fragmentation, and cell shrinkage, which are, among others, typical features of apoptotic cell death. Furthermore, time- and dose-dependent induction of apoptosis in SH-SY5Y cells was detected via cleavage of Ac-DEVD-AMC, a fluorigenic substrate for caspase-3. We observed a lower apoptotic activity in neuroblastoma cells overexpressing Bcl-xL, suggesting activation of the mitochondrial apoptosis pathway. Western blot analysis demonstrated that caspase-3, an apoptosis mediator, was activated in a time dependent manner after exposure of SH-SY5Y cells to drugs 1a and 2. Taken together, the agents investigated in the present study display strong apoptosis inducing activity and therefore show promise for the development of novel chemotherapeutics. PMID- 17707368 TI - 15-Deoxy-delta(12,14)-prostaglandin J(2) down-regulates CXCR4 on carcinoma cells through PPARgamma- and NFkappaB-mediated pathways. AB - The chemokine receptor CXCR4 plays a key role in the metastasis of colorectal cancer and its growth at metastatic sites. Here, we have investigated the mechanisms by which CXCR4 on cancer cells might be regulated by eicosanoids present within the colorectal tumor microenvironment. We show that prostaglandins PGE(2), PGA(2), PGD(2), PGJ(2) and 15dPGJ(2) each down-regulates CXCR4 receptor expression on human colorectal carcinoma cells to differing degrees. The most potent of these were PGD(2) and its metabolites PGJ(2) and 15dPGJ(2). Down regulation was most rapid with the end-product 15dPGJ(2) and was accompanied by a marked reduction in CXCR4 mRNA. 15dPGJ(2) is known to be a ligand for the nuclear receptor PPARgamma. Down-regulation of CXCR4 was also observed with the PPARgamma agonist rosiglitazone, while 15dPGJ(2)-induced CXCR4 down-regulation was substantially diminished by the PPARgamma antagonists GW9662 and T0070907. These data support the involvement of PPARgamma. However, the 15dPGJ(2) analogue CAY10410, which can act on PPARgamma but which lacks the intrinsic cyclopentenone structure found in 15dPGJ(2), down-regulated CXCR4 substantially less potently than 15dPGJ(2). The cyclopentenone grouping is known to inhibit the activity of NFkappaB. Consistent with an additional role for NFkappaB, we found that the cyclopentenone prostaglandin PGA(2) and cyclopentenone itself could also down regulate CXCR4. Immunolocalization studies showed that the cellular context was sufficient to trigger a focal nuclear pattern of NFkappaB p50 and that 15dPGJ(2) interfered with this p50 nuclear localization. These data suggest that 15dPGJ(2) can down-regulate CXCR4 on cancer cells through both PPARgamma and NFkappaB. 15dPGJ(2), present within the tumor microenvironment, may act to down-regulate CXCR4 and impact upon the overall process of tumor expansion. PMID- 17707369 TI - A role for the Rab6B Bicaudal-D1 interaction in retrograde transport in neuronal cells. AB - The Rab6 subfamily of small GTPases consists of three different isoforms: Rab6A, Rab6A' and Rab6B. Both Rab6A and Rab6A' are ubiquitously expressed whereas Rab6B is predominantly expressed in brain. Recent studies have shown that Rab6A' is the isoform regulating the retrograde transport from late endosomes via the Golgi to the ER and in the transition from anaphase to metaphase during mitosis. Since the role of Rab6B is still ill defined, we set out to characterize its intracellular environment and dynamic behavior. In a Y-2H search for novel Rab6 interacting proteins, we identified Bicaudal-D1, a large coiled-coil protein known to bind to the dynein/dynactin complex and previously shown to be a binding partner for Rab6A/Rab6A'. Co-immunoprecipitation studies and pull down assays confirmed that Bicaudal-D1 also interacts with Rab6B in its active form. Using confocal laser scanning microscopy it was established that Rab6B and Bicaudal-D1 co-localize at the Golgi and vesicles that align along microtubules. Furthermore, both proteins co-localized with dynein in neurites of SK-N-SH cells. Live cell imaging revealed bi-directional movement of EGFP-Rab6B structures in SK-N-SH neurites. We conclude from our data that the brain-specific Rab6B via Bicaudal-D1 is linked to the dynein/dynactin complex, suggesting a regulatory role for Rab6B in the retrograde transport of cargo in neuronal cells. PMID- 17707370 TI - Hyaluronan production regulation from porcine hyalocyte cell line by cytokines. AB - The objective of this study were to establish a cell line derived from porcine hyalocytes and to investigate the regulation of hyaluronan (HA) synthesis in response to cytokines. After 50 passages of the cells derived from porcine vitreous tissue, a cell line was generated. The immortalized cells showed fibroblastic morphology. The cell doubling time was 56.9h. In the mRNA level, the cells expressed plate-derived growth factor (PDGF) alpha receptor, PDGF beta receptor, transforming growth factor-beta (TGF-beta) type I receptor, TGF-beta type II receptor, CD44, collagen type I, collagen type II, glial fibrillary acidic protein (GFAP), hyaluronan synthase (HAS) 2, HAS 3 and beta-actin. In the protein level, GFAP was expressed in this cell line. S-100 protein and cytokeratin were not detected. Stimulation with TGF-beta1 and/or PDGF-BB induced a marked increase in the expression level of HAS2 mRNA, and induced HA production. TGF-beta1 stimulated HAS2 expression through the signal transduction pathway including Smad 2,3,4. In summary, this report constitutes the first successful immortalization of porcine hyalocyte cells. The production of HA was induced from the generated porcine hyalocyte cell line under the stimulation of TGF-beta1 and/or PDGF-BB, which may be related to the pathogenesis of proliferative membrane formation in proliferative vitreo-retinal diseases. PMID- 17707371 TI - Comment on "AGEs mediated expression and secretion of TNF alpha in rat retinal microglia" by Dr Wang et al. PMID- 17707372 TI - Stathmin expression during newt retina regeneration. AB - Japanese common newts (Cynops pyrrhogaster) have high ability to regenerate their injured organs including neural tissues, for example, the neural retina belonging to central nervous system. We attempted to clarify the molecular mechanism underlying the formation of a neural network during newt retina regeneration, and focused on the microtubule dynamics controlled by stathmin family proteins. Stathmin is a small cytoplasmic phosphoprotein known to be a microtubule regulator. We isolated a clone encoding stathmin from the newt. The expression level of stathmin is higher in lung and spleen than in the adult intact retina where stathmin was localized on plexiform layers, the ganglion layer and in photoreceptor inner segments. However, in a regenerating process of the retina, stathmin was upregulated from an early regenerating stage until the retinal layered structure was formed. Immunohistochemical analyses revealed that stathmin existed all around the regenerating retina consisting of retinal progenitor cells. These results suggest that stathmin plays important roles in the construction and maintenance of retinal structure and its neural network, by controlling the proliferation of retinal progenitor cells and the microtubule dynamics of retinal neurons. Moreover, stathmin may function in the dedifferentiating process of retinal pigment epithelium cells. PMID- 17707374 TI - Squamous cell carcinoma antigen 1 is an inhibitor of parasite-derived cysteine proteases. AB - The physiological significance of the squamous cell carcinoma antigens 1 (SCCA1) and SCCA2, members of the ovalbumin serpin family, remains unresolved. In this study, we examined whether SCCA1 or SCCA2 inhibits protozoa- or helminth-derived cysteine proteases. SCCA1, but not SCCA2, potently inhibited the cysteine protease activities of CPB2.8 from Leishmania mexicana, cruzain from Trypanosoma cruzi, rhodesain from Trypanosoma brucei rhodesience, and cathepsin L2 from Fasciola hepatica. The inhibitory activities of SCCA1 were due to its resistance to cleavage by the cysteine proteases. The findings indicate that induction of cysteine protease inhibitors might be a novel defense mechanism against parasite development. PMID- 17707373 TI - Effects of ralfinamide, a Na+ channel blocker, on firing properties of nociceptive dorsal root ganglion neurons of adult rats. AB - Recent studies revealed that ralfinamide, a Na(+) channel blocker, suppressed tetrodotoxin-resistant Na(+) currents in dorsal root ganglion (DRG) neurons and reduced pain reactions in animal models of inflammatory and neuropathic pain. Here, we investigated the effects of ralfinamide on Na(+) currents; firing properties and action potential (AP) parameters in capsaicin-responsive and unresponsive DRG neurons from adult rats in the presence of TTX (0.5 microM). Ralfinamide inhibited TTX-resistant Na(+) currents in a frequency- and voltage dependent manner. Small to medium sized neurons exhibited different firing properties during prolonged depolarizing current pulses (600 ms). One group of neurons fired multiple spikes (tonic), while another group fired four or less APs (phasic). In capsaicin-responsive tonic firing neurons, ralfinamide (25 microM) reduced the number of APs from 10.6+/-1.8 to 2.6+/-0.7 APs/600 ms, whereas in capsaicin-unresponsive tonic neurons, the drug did not significantly change firing (8.4+/-0.9 in control to 6.6+/-2.0 APs/600 ms). In capsaicin-responsive phasic neurons, substance P and 4-aminopyridine induced multiple spikes, an effect that was reversed by ralfinamide (25 microM). In addition to effects on firing, ralfinamide increased the threshold, decreased the overshoot, and increased the rate of rise of the AP. To conclude, ralfinamide suppressed afferent hyperexcitability selectively in capsaicin-responsive, presumably nociceptive neurons, but had no measurable effects on firing in CAPS-unresponsive neurons. The action of ralfinamide to selectively inhibit tonic firing in nociceptive neurons very likely contributes to the effectiveness of the drug in reducing inflammatory and neuropathic pain as well as bladder overactivity. PMID- 17707375 TI - PKD is recruited to sites of actin remodelling at the leading edge and negatively regulates cell migration. AB - Protein kinase D (PKD) has been implicated in the regulation of cell shape, adhesion, and migration. At the leading edge of migrating cells active PKD co localizes with F-actin, Arp3 and cortactin. Platelet derived growth factor (PDGF) activates PKD and recruits the kinase to the leading edge, suggesting a role for PKD in actin remodelling. In support of this, PKD directly interacts with F-actin and phosphorylates cortactin in vitro. Interference with PKD function by overexpression of a dominant negative PKD or by PKD-specific siRNA enhanced cell migration, whereas cells overexpressing PKD wild type displayed reduced migratory potential. Taken together, these data reveal a negative regulatory function of PKD in cell migration. PMID- 17707376 TI - Expression and selective up-regulation of toxin-related mono ADP ribosyltransferases by pathogen-associated molecular patterns in alveolar epithelial cells. AB - Mono ADP-ribosyltransferases (ARTs) are a family of enzymes related to bacterial toxins that possess adenosine diphosphate ribosyltransferase activity. We have assessed that A549 constitutively expressed ART1 on the cell surface and shown that lipotheicoic acid (LTA) and flagellin, but not lipopolysaccharide (LPS), peptidoglycan (PG) and poly (I:C), up-regulate ART1 in a time and dose dependent manner. These agonists did not alter the expression of ART3 and ART5 genes. Indeed, LTA and flagellin stimulation increased the level of ART1 protein and transcript while ART4 gene was activated after stimulation of cells with LPS, LTA, PAM and PG via TLR2 and TLR4 receptors. These results show that human ARTs possess a differential capacity to respond to bacteria cell wall components and might play a crucial role in innate immune response in airways. PMID- 17707377 TI - peg10, an imprinted gene, plays a crucial role in adipocyte differentiation. AB - An imprinted gene, paternally expressed gene (peg) 10, was isolated as one of the genes expressed early in adipogenesis. The expression of peg10 was elevated after the addition of inducers, and was detected in adipocyte differentiable 3T3-L1 cells, but not observed in the non-adipogenic cell line NIH-3T3. Moreover, the knockdown of peg10 by RNA interference (RNAi) inhibited the differentiation of 3T3-L1 cells into lipid-laden adipocytes. Interestingly, peg10 RNAi-treatment reduced the expressions of C/EBPbeta and C/EBPdelta, and inhibited mitotic clonal expansion. These findings strongly indicate that peg10 plays a crucial role at the immediate early stage of adipocyte differentiation. PMID- 17707378 TI - Follicular growth and estradiol follow-up after subcutaneous xenografting of fresh and cryopreserved human ovarian tissue. AB - OBJECTIVE: To assess ovarian cortex surrounding benign ovarian cysts after cryopreservation and grafting to severe combined immunodeficient (SCID) mice. DESIGN: Animal study. SETTING: Academic research laboratories. PATIENT(S): Ovarian tissue obtained from 15 patients. INTERVENTION(S): Grafting of fresh and frozen/thawed ovarian tissue into the subcutaneous space of 22 SCID mice for 80 days. MAIN OUTCOME MEASURE(S): Histologic analysis before and after grafting. Serum E(2) measured before (after 37 days of grafting) and after FSH/LH supplementation (end of the study). RESULT(S): After grafting, follicular density had decreased for frozen/thawed tissue in all cases. The follicular distribution was modified in fresh tissue: Primordial follicles proportion was reduced (79% vs. 17%), whereas the primary and secondary ones were increased (21% vs. 57% and 0% vs. 23%, respectively). The same tendency was observed in frozen/thawed tissue. Significant E(2) secretion was obtained before and after FSH/LH supplementation in castrated mice, grafted with either fresh or frozen/thawed tissue. CONCLUSION(S): Fresh and cryopreserved ovarian cortex surrounding benign ovarian cysts grafted into the subcutaneous space of SCID mice is able to sustain ovarian tissue function, although follicular growth appears lower with frozen/thawed tissue. PMID- 17707379 TI - Regulation of protogynous sex change by competition between corticosteroids and androgens: an experimental test using sandperch, Parapercis cylindrica. AB - Cortisol, the dominant corticosteroid in fish, and 11-ketotestosterone (11KT), the most potent androgen in fish, are both synthesized and (or) deactivated by the same two enzymes, 11beta-hydroxylase and 11beta-hydroxysteroid dehydrogenase. Cortisol is synthesized in response to stress (such as that caused by interaction with a dominant conspecific), whereas 11KT is synthesized during protogynous sex change. It has been hypothesized that corticosteroids (such as cortisol) inhibit 11KT synthesis via substrate competition, thereby providing a mechanism for the regulation of socially mediated, protogynous sex change. We tested this hypothesis by administering cortisol (50 microg g(-1) body weight) to female sandperch (Parapercis cylindrica) under social conditions that were permissive to sex change (i.e. in the absence of suppressive male dominance). Twenty-one days later, mean physiological cortisol concentration in cortisol-treated fish was 4.2 fold greater than that in 'socially stressed' female fish maintained in a semi natural system. Although the dosage of cortisol was therefore considered to be favorable for engendering competitive inhibition of 11KT synthesis, all cortisol treated fish changed sex, as did all sham-treated and control fish (n=7 fish per treatment). In addition, there was no effect of cortisol treatment on the rate of sex change or on the pattern of steroidogenesis. Thus, our results refute the hypothesis that protogynous sex change is regulated by substrate competition between corticosteroids and androgens. PMID- 17707380 TI - Corticosterone and time-activity budget: an experiment with Black-legged kittiwakes. AB - In vertebrates, the well established increase in plasma corticosterone in response to food shortage is thought to mediate adjustments of foraging behavior and energy allocation to environmental conditions. However, investigating the functional role of corticosterone is often constrained by the difficulty to track time-activity budget of free-ranging animals. To examine how an experimental increase in corticosterone affects the activity budget of male Black-legged kittiwakes (Rissa tridactyla), we used miniaturized activity loggers to record flying/foraging, presence on the sea surface and nest attendance. To investigate how corticosterone affects allocation processes between self-foraging and foraging devoted to the brood, we monitored body mass change of males from capture (day 0) to recapture (day 3). Among control birds, males in poor condition at day 0 spent significantly more time flying/foraging and less time attending the nest site than did males in good condition. Corticosterone treatment affected time spent flying/foraging in interaction with body condition at day 0: corticosterone-implanted males in good condition spent more time flying/foraging than control ones; this was not observed in poor condition males. In control birds, change in body mass was negatively correlated with body condition at day 0. This was reinforced by corticosterone treatment and, on average, corticosterone-implanted males gained much more mass than controls. These results suggest that in Black-legged kittiwakes, body condition and corticosterone levels can interact to mediate foraging decisions and possibly energy allocation: when facing stressful environmental conditions, birds in good body condition may afford to increase the time spent foraging probably to maintain brood provisioning, whereas poor body condition birds seemed rather to redirect available energy from reproduction to self-maintenance. PMID- 17707383 TI - Increased circulating monocyte count is related to good collateral development in coronary artery disease. AB - Monocytes have been shown to take an important role in collateral growth in animal studies. The aim of the study was to investigate the relation of circulating monocyte count with collateral development in patients with severely stenotic CAD. Patients who had > or =95% stenosis in at least one major coronary artery were included in the study. Coronary angiograms of 210 eligible patients from our database were analyzed again and 103 of them had good and 107 had poor collateral development according to Cohen-Rentrop method. Only the monocyte count was found to be significantly different between two groups (671+/-218 mm(-3) versus 522+/-195 mm(-3), p<0.001) when multivariate analysis was performed and an increased monocyte count was observed in the good collateral group (Odds ration [OR], 2.918; 95% confidence interval [CI], 1.281-6.648, p=0.011). This study in which the relationship between monocyte count in blood and collateral development was disclosed has a potential importance in clinical and basic cardiovascular medicine. PMID- 17707382 TI - Purinergic receptor P2Y, G-protein coupled, 12 gene variants and risk of incident ischemic stroke, myocardial infarction, and venous thromboembolism. AB - Recent data have implicated a haplotype of the purinergic receptor P2Y, G-protein coupled, 12 gene (P2RY12), as potential risk determinant for atherothrombosis. However, to date, no prospective, genetic-epidemiological data are available. Using DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we examined the possible association of P2RY12 genetic variants, in particular a haplotype H2 (constituted by dbSNP rs10935838, rs2046934, rs5853517, and rs6809699) amongst 708 white males who subsequently developed a thromboembolic event (incident myocardial infarction (MI), ischemic stroke, or deep venous thromboembolism/pulmonary embolism (DVT/PE)) and amongst an equal number of age- and smoking-matched white males who remained free of reported vascular disease during follow-up (controls). The P2RY12 gene variants tested were in linkage disequilibrium. The haplotype H2 distribution was significantly different between the DVT/PE cases (12%) and their matched controls (21%), p-permuted=0.02. In an adjusted conditional logistic regression analysis, the haplotype H2 was significantly associated with a lower risk of incident DVT/PE as compared to the reference haplotype H1 (odds ratio=0.50, 95% CI=0.27 0.93, p=0.028). However, we found no evidence for an association of the P2RY12 variants or the haplotype H2 with incident MI or ischemic stroke. The present investigation provides evidence for an association of the P2RY12 haplotype H2 with lower risk of DVT/PE; however these findings require replication in other well-designed studies. PMID- 17707381 TI - An association of early puberty with disordered eating and anxiety in a population of undergraduate women and men. AB - Eating and anxiety disorders are more prevalent in females, increase during adolescence, and are associated with early pubertal development. This study examined whether timing of puberty onset is associated with disordered eating and anxiety in a large sample of postpubertal male and female undergraduate students. Self-report questionnaires assessed timing of puberty, disordered eating, anxiety, alcohol use, personality, and sensation seeking. Females scored significantly higher on measures of disordered eating (binge eating, dietary restraint, eating concerns, and weight and shape concerns) and anxiety (state and trait anxiety) than did males. In addition, early maturing women and men scored significantly higher on measures of disordered eating and anxiety than on time or late maturing women and men. Measures of alcohol use, sensation seeking, and personality characteristics differed in males and females but did not vary with pubertal timing. Findings suggest that early puberty is associated with disordered eating and anxiety, and this association may be due to an organizational effect of pubertal hormones. Despite important differences in body fat composition, both males and females experiencing early puberty had an increased incidence of disordered eating. The fact that early puberty was associated with increased eating and anxiety symptoms in both sexes suggests that puberty may influence these symptoms through both biological and psychosocial mechanisms. PMID- 17707384 TI - In vivo measurement of dynamic rectus femoris function at postures representative of early swing phase. AB - Forward dynamic models suggest that muscle-induced joint motions depend on dynamic coupling between body segments. As a result, biarticular muscles may exhibit non-intuitive behavior in which the induced joint motion is opposite to that assumed based on anatomy. Empirical validation of such predictions is important for models to be relied upon to characterize muscle function. In this study, we measured, in vivo, the hip and knee accelerations induced by electrical stimulation of the rectus femoris (RF) and the vastus medialis (VM) at postures representatives of the toe-off and early swing phases of the gait cycle. Seven healthy young subjects were positioned side-lying with their lower limb supported on air bearings while a 90 ms pulse train stimulated each muscle separately or simultaneously. Lower limb kinematics were measured and compared to predictions from a similarly configured dynamic model of the lower limb. We found that both RF and VM, when stimulated independently, accelerated the hip and knee into extension at these postures, consistent with model predictions. Predicted ratios of hip acceleration to knee acceleration were generally within 1 s.d. of average values. In addition, measured responses to simultaneous RF and VM stimulation were within 13% of predictions based on the assumption that joint accelerations induced by activating two muscles simultaneously can be found by adding the joint accelerations induced by activating the same muscles independently. These results provide empirical evidence of the importance of considering dynamic effects when interpreting the role of muscles in generating movement. PMID- 17707385 TI - Anterior hip joint force increases with hip extension, decreased gluteal force, or decreased iliopsoas force. AB - Abnormal or excessive force on the anterior hip joint may cause anterior hip pain, subtle hip instability and a tear of the acetabular labrum. We propose that both the pattern of muscle force and hip joint position can affect the magnitude of anterior joint force and thus possibly lead to excessive force and injury. The purpose of this study was to determine the effect of hip joint position and of weakness of the gluteal and iliopsoas muscles on anterior hip joint force. We used a musculoskeletal model to estimate hip joint forces during simulated prone hip extension and supine hip flexion under four different muscle force conditions and across a range of hip extension and flexion positions. Weakness of specified muscles was simulated by decreasing the modeled maximum force value for the gluteal muscles during hip extension and the iliopsoas muscle during hip flexion. We found that decreased force contribution from the gluteal muscles during hip extension and the iliopsoas muscle during hip flexion resulted in an increase in the anterior hip joint force. The anterior hip joint force was greater when the hip was in extension than when the hip was in flexion. Further studies are warranted to determine if increased utilization of the gluteal muscles during hip extension and of the iliopsoas muscle during hip flexion, and avoidance of hip extension beyond neutral would be beneficial for people with anterior hip pain, subtle hip instability, or an anterior acetabular labral tear. PMID- 17707386 TI - Oxidized multiwalled carbon nanotubes as a novel solid-phase microextraction fiber for determination of phenols in aqueous samples. AB - A simple and environmentally friendly method for determination of seven phenols using solid-phase microextraction (SPME) coupled to high-performance liquid chromatography (HPLC) has been developed. Several materials were used as stationary phase of SPME fibers and an oxidized multiwalled carbon nanotubes material was found to be effective in carrying out simultaneous extraction of phenols in aqueous samples. Compared with the widely used commercially available SPME fibers, this proposed fiber had much lower cost, longer lifetime (over 150 times), shorter analysis time (30 min of extraction and 3 min of desorption time) and comparable or superior extraction efficiency for the investigated analytes. The extraction and desorption conditions were evaluated and the calibration curves of seven phenols were linear (R(2)> or =0.9908) in the range from 10.2 to 1585 ng mL(-1). The limits of detection at a signal-to-noise (S/N) ratio of 3 were 0.25-3.67 ng mL(-1), and the limits of quantification calculated at S/N=10 were 0.83-12.25 ng mL(-1) for these compounds. The possibility of applying the proposed method to environmental water samples analysis was validated. PMID- 17707387 TI - Development of a multi-residue screening method for the determination of pesticides in cereals and dry animal feed using gas chromatography-triple quadrupole tandem mass spectrometry. AB - A multi-residue screening method for simultaneous analysis of 122 gas chromatography amenable pesticides in dry matrices such as cereal grain and certain feedingstuffs was developed. The method entails a simple extraction of re hydrated sample with acetonitrile followed by a dispersive solid phase extraction (dispersive-SPE) clean-up step prior to the final determination by gas chromatography/triple quadrupole tandem mass spectrometry (GC-MS/MS). Due to complexity of analyzed matrices, two MS/MS transitions were set for each pesticide to eliminate the need for re-analysis of potentially positive samples, and provide unequivocal identification of detected pesticides in accordance with recent guidelines, in a single analytical run. Thus, in the developed GC-MS/MS acquisition method, a total of 216 different multiple reactions monitoring (MRM) transitions were monitored in one set of experimental conditions. To evaluate performance of the method, validation experiments were carried out on wheat grain at three spiking levels (0.01, 0.02 and 0.05 mg kg(-1)). Additional recovery tests at 0.05 mg kg(-1) were carried out on several other matrices. The recoveries ranged between 73 and 129% with associated relative standard deviations between 1 and 29% for the majority of pesticides. Limits of detection were less or equal to 0.01 mg kg(-1) for approximately 68% of pesticides. The applicability of the proposed method to detect and quantify pesticide residues has been demonstrated in the analysis of 136 real samples. Additionally, the method was favorably compared with an acetone extraction method (accepted as a reference method by some of European and U.S. authorities) in the analysis of real samples known to contain pesticide residues. PMID- 17707388 TI - A versatile strategy to fabricate hydrogel-silver nanocomposites and investigation of their antimicrobial activity. AB - In this study, hydrogel-silver nanocomposites have been synthesized by a unique methodology, which involves formation of silver nanoparticles within swollen poly (acrylamide-co-acrylic acid) hydrogels. The formation of silver nanoparticles was confirmed by transmission electron microscopy (TEM) and surface plasmon resonance (SPR) which was obtained at 406 nm. The TEM of hydrogel-silver nanocomposites showed almost uniform distribution of nanoparticles throughout the gel networks. Most of the particles, as revealed from the particle-size distribution curve, were 24-30 nm in size. The X-ray diffraction pattern also confirmed the face centered cubic (fcc) structure of silver nanoparticles. The nanocomposites demonstrated excellent antibacterial effects on Escherichia coli (E. coli). The antibacterial activity depended on size of the nanocomposites, amount of silver nanoparticles, and amount of monomer acid present within the hydrogel-silver nanocomposites. It was also found that immersion of plain hydrogel in 20 mg/30 ml AgNO(3) solution yielded nanocomparticle-hydrogel composites with optimum bactericidal activity. PMID- 17707389 TI - Synthesis, size control and fluorescence studies of gold nanoparticles in carboxymethylated chitosan aqueous solutions. AB - A facile ultraviolet (UV) light irradiation method to synthesize gold nanoparticles (AuNPs) in the alkalic carboxymethylated chitosan (CM-chitosan) solution was first proposed in this paper. CM-chitosan, a water soluble polysaccharide derivative, served as both reducing agent for gold cations and stabilizing agent for AuNPs. The pH, the concentration of HAuCl(4) and irradiation time had obvious influence on the size, amount and morphology of AuNPs, which traced by UV-visible spectrometer and high resolution transmission electron microscopy. AuNPs synthesized in this method can be dispersed stably in alkalic CM-chitosan solution for more than 6 months. The possible stability mechanism of AuNPs was discussed based on the change of carboxyl group of CM chitosan chain with pH and FTIR analyses. XRD pattern confirmed the cubic crystal structure of AuNPs. The fluorescence emission band of AuNPs with an excitation wavelength of 316 nm can be observed at 400 nm, which was affected remarkably by irradiation time and concentration of HAuCl(4). PMID- 17707391 TI - Room temperature sphere-to-rod growth and gelation of PEO-PPO-PEO triblock copolymers in aqueous salt solutions. AB - The effects of NaCl and KF on the sphere-to-rod micellar growth behavior of triblock copolymers having two different compositions, (EO)20(PO)70(EO)20 (P123) and (EO)26(PO)40(EO)26 (P85), have been studied by dynamic light scattering (DLS), small angle neutron scattering (SANS) and dilute solution viscometry. NaCl can effectively tune the sphere-to-rod growth temperature of the micelles of both these copolymers and induce micellar growth down to the room temperature and below. The growth behavior is found to be dependent on the composition of the copolymer as P123 being more hydrophobic shows the room temperature growth in the presence of ethanol at significantly lesser NaCl concentration than the less hydrophobic copolymer P85. DLS studies depict for the first time the growth driven transition of the copolymer solutions from dilute to semi-dilute regime as a function of copolymer and salt concentrations. KF can also induce room temperature growth of the P123 micelles at lesser salt concentration than NaCl but it fails to induce any such growth of the P85 micelles. A pseudo-binary temperature-concentration phase diagram on 15% copolymer solutions shows the variation of the sphere-to-rod transition temperature and the cloud point of the copolymer solutions as a function of salt concentration. PMID- 17707390 TI - Mesoporous silica originating from a gaseous ammonia epoxide ring opening and the thermodynamic data on some divalent cation adsorptions. AB - An organofunctionalized mesoporous HMS-like compound has been synthesized by reacting the silylating agent 3-glycidoxypropyltrimethoxysilane with gaseous ammonia. The reaction path leads to the opening of the three membered epoxide ring to incorporate ammonia to give the modified silylating agent. This new silylating agent was used to synthesize a mesostructure inorganic-organic hybrid through the neutral template directing agent, dodecylamine, using a co condensation process, and exploring the ability of the silicon source tetraethoxysilane. The final solid named HMS-NH has been characterized through elemental analysis, X-ray powder diffraction, nitrogen gas adsorption, infrared spectroscopy and solid state NMR for the 29Si nucleus. An amount of 1.06+/-0.10 mmol of pendant groups is covalently bonded to the inorganic backbone. The attached basic centers adsorbed divalent cations to give the maxima adsorption capacity of 0.74+/-0.03, 0.55+/-0.06, 0.53+/-0.05 and 0.51+/-0.06 mmolg(-1) for copper, nickel, zinc and cobalt, respectively. From calorimetric determinations the quantitative thermal effects for all these cation/basic center interactions gave exothermic enthalpy, negative Gibbs free energy and positive entropy. These thermodynamic data confirmed the energetically favorable condition of such interactions at the solid/liquid interface for all systems. PMID- 17707392 TI - Raman spectroscopy and DFT calculations of As(III) complexation with a cysteine rich biomaterial. AB - Arsenite adsorption onto a protein-rich biomass and, more specifically, the chemical groups involved in the uptake were investigated using Raman spectroscopy and DFT calculations. The study was based on spectroscopic analyses of raw and arsenic-loaded biomass as well as standard samples of amino acids and arsenic salts. The predominant secondary structure of the protein was identified as the beta-sheet type, with some contribution from alpha-helix structures. The participation of sulphydryl groups from cystine/cysteine molecules during the adsorption of arsenite was demonstrated. Only the gauche-gauche-gauche (g-g-g) conformation type of the disulfide bonds was involved in arsenic complexation. The formation of a pyramidal trigonal As(HCys)(3) complex was modeled according to the density functional theory (DFT). The agreement of the DFT harmonic frequencies with the RAMAN spectra of the As(HCys)(3) complex demonstrated the relevant features of the cysteine-rich biomaterial regarding arsenic uptake as well as of the mechanism involved in the As(III)/biomass interaction at a molecular level. The results also illustrate that Raman spectroscopy can be successfully applied to investigate the mechanism of metal adsorption onto amorphous biomaterials. PMID- 17707393 TI - Copper phthalocyanine films deposited by liquid-liquid interface recrystallization technique (LLIRCT). AB - The simple recrystallization process is innovatively used to obtain the nanoparticles of copper phthalocyanine by a simple method. Liquid-liquid interface recrystallization technique (LLIRCT) has been employed successfully to produce small sized copper phthalocyanine nanoparticles with diameter between 3-5 nm. The TEM-SAED studies revealed the formation of 3-5 nm sized with beta-phase dominated mixture of alpha and beta copper phthalocyanine nanoparticles. The XRD, SEM, and the UV-vis studies were further carried out to confirm the formation of copper phthalocyanine thin films. The cyclic voltametry (CV) studies conclude that redox reaction is totally reversible one electron transfer process. The process is attributed to Cu(II)/Cu(I) redox reaction. PMID- 17707396 TI - Role of PKCs and NF-kappaB activation in myocardial inflammation: enemy or ally? PMID- 17707395 TI - Respiration of resting honeybees. AB - The relation between the respiratory activity of resting honeybees and ambient temperature (T(a)) was investigated in the range of 5-40 degrees C. Bees were kept in a temperature controlled flow through respirometer chamber where their locomotor and endothermic activity, as well as abdominal ventilatory movements was recorded by infrared thermography. Surprisingly, true resting bees were often weakly endothermic (thorax surface up to 2.8 degrees C warmer than abdomen) at a T(a) of 14-30 degrees C. Above 33 degrees C many bees cooled their body via evaporation from their mouthparts. A novel mathematical model allows description of the relationship of resting (standard) metabolic rate and temperature across the entire functional temperature range of bees. In chill coma (<11 degrees C) bees were ectothermic and CO(2) release was mostly continuous. CO(2) release rate (nls(-1)) decreased from 9.3 at 9.7 degrees C to 5.4 at 5 degrees C. At a T(a) of >11 degrees C CO(2) was released discontinuously. In the bees' active temperature range mean CO(2) production rate (nls(-1)) increased sigmoidally (10.6 at 14.1 degrees C, 24.1 at 26.5 degrees C, and 55.2 at 38.1 degrees C), coming to a halt towards the upper lethal temperature. This was primarily accomplished by an exponential increase in gas exchange frequency (0.54 and 3.1 breaths min(-1) at 14.1 and 38.1 degrees C) but not in released CO(2) volume per respiratory cycle (1487 and 1083 nl cycle(-1) at 14.1 and 38.1 degrees C). Emission of CO(2) bursts was mostly (98%) accompanied by abdominal ventilation movements even in small CO(2) bursts. Larger bursts coincided with a longer duration of active ventilation. An increased amount of CO(2) expelled per unit time of ventilation indicates a higher efficiency of ventilation at high ambient temperatures. PMID- 17707397 TI - Neutral sphingomyelinase inhibition participates to the benefits of N acetylcysteine treatment in post-myocardial infarction failing heart rats. AB - Deficiency in cellular thiol tripeptide glutathione (L-gamma glutamyl-cysteinyl glycine) determines the severity of several chronic and inflammatory human diseases that may be relieved by oral treatment with the glutathione precursor N acetylcysteine (NAC). Here, we showed that the left ventricle (LV) of human failing heart was depleted in total glutathione by 54%. Similarly, 2-month post myocardial infarction (MI) rats, with established chronic heart failure (CHF), displayed deficiency in LV glutathione. One-month oral NAC treatment normalized LV glutathione, improved LV contractile function and lessened adverse LV remodelling in 3-month post-MI rats. Biochemical studies at two time-points of NAC treatment, 3 days and 1 month, showed that inhibition of the neutral sphingomyelinase (N-SMase), Bcl-2 depletion and caspase-3 activation, were key, early and lasting events associated with glutathione repletion. Attenuation of oxidative stress, downregulation of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and its TNF-R1 receptor were significant after 1-month NAC treatment. These data indicate that, besides glutathione deficiency, N-SMase activation is associated with post-MI CHF progression, and that blockade of N SMase activation participates to post-infarction failing heart recovery achieved by NAC treatment. NAC treatment in post-MI rats is a way to disrupt the vicious sTNF-alpha/TNF-R1/N-SMase cycle. PMID- 17707394 TI - Loss of T cell responses following long-term cryopreservation. AB - Although cryopreservation of peripheral blood mononuclear cells (PBMC) is a commonly used technique, the degree to which it affects subsequent functional studies has not been well defined. Here we demonstrate that long-term cryopreservation has detrimental effects on T cell IFN-gamma responses in human immunodeficiency virus (HIV) infected individuals. Long-term cryopreservation caused marked decreases in CD4(+) T cell responses to whole proteins (HIV p55 and cytomegalovirus (CMV) lysate) and HIV peptides, and more limited decreases in CD8(+) T cell responses to whole proteins. These losses were more apparent in cells stored for greater than one year compared to less than six months. CD8(+) T cell responses to peptides and peptide pools were well preserved. Loss of both CD4(+) and CD8(+) T cell responses to CMV peptide pools were minimal in HIV negative individuals. Addition of exogenous antigen presenting cells (APC) did not restore CD4(+) T cell responses to peptide stimulation and partially restored T cell IFN-gamma responses to p55 protein. Overnight resting of thawed cells did not restore T cell IFN-gamma responses to peptide or whole protein stimulation. A selective loss of phenotypically defined effector cells did not explain the decrement of responses, although cryopreservation did increase CD4(+) T cell apoptosis, possibly contributing to the loss of responses. These data suggest that the impact of cryopreservation should be carefully considered in future vaccine and pathogenesis studies. In HIV-infected individuals short-term cryopreservation may be acceptable for measuring CD4(+) and CD8(+) T cell responses. Long-term cryopreservation, however, may lead to the loss of CD4(+) T cell responses and mild skewing of T cell phenotypic marker expression. PMID- 17707398 TI - Interaction of calcium/calmodulin-dependent protein kinase IIdeltaC with sorcin indirectly modulates ryanodine receptor function in cardiac myocytes. AB - Calcium/calmodulin dependent protein kinase II delta C (CaMKIIdelta(C)) and the EF-hand Ca(2+)-binding protein, sorcin have both been shown to regulate the excitation-contraction coupling process. This study explores the possibility that these two proteins interact directly and, as a result of this interaction, modulate cardiac calcium handling. Two independent methods (surface plasmon resonance (SPR) and overlay assays) were used to determine whether CaMKIIdelta(C) and sorcin interacted in a direct manner. The nature of this interaction was explored by (i) examining the effects of sorcin on CaMKIIdelta(C) activity using a selective kinase assay and (ii) studying whether sorcin was a substrate for CaMKIIdelta(C) using autoradiography. Ryanodine binding assays on mouse ventricular cardiomyocytes were used to determine specific functional effects of this interaction. SPR studies suggested that sorcin interacts with CaMKIIdelta(C) in a concentration-dependent manner. This interaction occurs in the presence of Ca(2+) and in the presence or absence of calmodulin (CaM). Overlay assays confirmed the existence of this interaction. Further experiments suggested that this interaction is reciprocal. Firstly, sorcin significantly inhibited both recombinant and native CaMKIIdelta(C) activity to similar extents. Secondly, sorcin was phosphorylated by CaMKIIdelta(C). Thirdly, sorcin inhibition of CaMKII activity occurred under conditions where sorcin remained dephosphorylated. Functionally, CaMKIIdelta(C)-mediated phosphorylation of sorcin served to abolish the inhibitory effect of sorcin on ryanodine receptor (RyR(2)) open probability (Po). Since both proteins are capable of directly modulating RyR(2) activity, this interaction may serve as an additional or alternative indirect route by which both proteins can regulate RyR(2) opening status in cardiac myocytes. PMID- 17707399 TI - Survival and maturation of human embryonic stem cell-derived cardiomyocytes in rat hearts. AB - Human embryonic stem cell (hESC)-derived cardiomyocytes are a promising cell source for cardiac repair. Whether these cells can be transported long distance, survive, and mature in hearts subjected to ischemia/reperfusion with minimal infarction is unknown. Taking advantage of a constitutively GFP-expressing hESC line we investigated whether hESC-derived cardiomyocytes could be shipped and subsequently form grafts when transplanted into the left ventricular wall of athymic nude rats subjected to ischemia/reperfusion with minimal infarction. Co localization of GFP-epifluorescence and cardiomyocyte-specific marker staining was utilized to analyze hESC-derived cardiomyocyte fate in a rat ischemia/reperfused myocardium. Differentiated, constitutively green fluorescent protein (GFP)-expressing hESCs (hES3-GFP; Envy) containing about 13% cardiomyocytes were differentiated in Singapore, and shipped in culture medium at 4 degrees C to Los Angeles (shipping time approximately 3 days). The cells were dissociated and a cell suspension (2 x 10(6) cells for each rat, n=10) or medium (n=10) was injected directly into the myocardium within the ischemic risk area 5 min after left coronary artery occlusion in athymic nude rats. After 15 min of ischemia, the coronary artery was reperfused. The hearts were harvested at various time points later and processed for histology, immunohistochemical staining, and fluorescence microscopy. In order to assess whether the hESC derived cardiomyocytes might evade immune surveillance, 2 x 10(6) cells were injected into immune competent Sprague-Dawley rat hearts (n=2), and the hearts were harvested at 4 weeks after cell injection and examined as in the previous procedures. Even following 3 days of shipping, the hESC-derived cardiomyocytes within embryoid bodies (EBs) showed active and rhythmic contraction after incubation in the presence of 5% CO(2) at 37 degrees C. In the nude rats, following cell implantation, H&E, immunohistochemical staining and GFP epifluorescence demonstrated grafts in 9 out of 10 hearts. Cells that demonstrated GFP epifluorescence also stained positive (co-localized) for the muscle marker alpha-actinin and exhibited cross striations (sarcomeres). Furthermore, cells that stained positive for the antibody to GFP (immunohistochemistry) also stained positive for the muscle marker sarcomeric actin and demonstrated cross striations. At 4 weeks engrafted hESCs expressed connexin 43, suggesting the presence of nascent gap junctions between donor and host cells. No evidence of rejection was observed in nude rats as determined by inspection for lymphocytic infiltrate and/or giant cells. In contrast, hESC derived cardiomyocytes injected into immune competent Sprague-Dawley rats resulted in an overt lymphocytic infiltrate. hESCs-derived cardiomyocytes can survive several days of shipping. Grafted cells survived up to 4 weeks after transplantation in hearts of nude rats subjected to ischemia/reperfusion with minimal infarction. They continued to express cardiac muscle markers and exhibit sarcomeric structure and they were well interspersed with the endogenous myocardium. However, hESC-derived cells did not escape immune surveillance in the xenograft setting in that they elicited a rejection phenomenon in immune competent rats. PMID- 17707400 TI - Evaluating and learning from RNA pseudotorsional space: quantitative validation of a reduced representation for RNA structure. AB - Quantitatively describing RNA structure and conformational elements remains a formidable problem. Seven standard torsion angles and the sugar pucker are necessary to characterize the conformation of an RNA nucleotide completely. Progress has been made toward understanding the discrete nature of RNA structure, but classifying simple and ubiquitous structural elements such as helices and motifs remains a difficult task. One approach for describing RNA structure in a simple, mathematically consistent, and computationally accessible manner involves the invocation of two pseudotorsions, eta (C4'(n-1), P(n), C4'(n), P(n+1)) and theta (P(n), C4'(n), P(n+1), C4'(n+1)), which can be used to describe RNA conformation in much the same way that varphi and psi are used to describe backbone configuration of proteins. Here, we conduct an exploration and statistical evaluation of pseudotorsional space and of the Ramachandran-like eta theta plot. We show that, through the rigorous quantitative analysis of the eta theta plot, the pseudotorsional descriptors eta and theta, together with sugar pucker, are sufficient to describe RNA backbone conformation fully in most cases. These descriptors are also shown to contain considerable information about nucleotide base conformation, revealing a previously uncharacterized interplay between backbone and base orientation. A window function analysis is used to discern statistically relevant regions of density in the eta-theta scatter plot and then nucleotides in colocalized clusters in the eta-theta plane are shown to have similar 3-D structures through RMSD analysis of the RNA structural constituents. We find that major clusters in the eta-theta plot are few, underscoring the discrete nature of RNA backbone conformation. Like the Ramachandran plot, the eta-theta plot is a valuable system for conceptualizing biomolecular conformation, it is a useful tool for analyzing RNA tertiary structures, and it is a vital component of new approaches for solving the 3-D structures of large RNA molecules and RNA assemblies. PMID- 17707401 TI - Molecular characterization of HTLV-1 Tax interaction with the KIX domain of CBP/p300. AB - The viral oncoprotein Tax mediates transcriptional activation of human T-cell leukemia virus type 1 (HTLV-1). Both Tax and the cellular transcription factor CREB bind to viral cyclic AMP response elements (vCREs) located in the viral promoter. Tax and serine 133 phosphorylated CREB (pCREB) bound to the HTLV-1 promoter facilitate viral transcription via the recruitment of the large cellular coactivators CBP/p300. While the interaction between the phosphorylated kinase inducible domain (pKID) of pCREB and the KIX domain of CBP/p300 has been well characterized, the molecular interactions between KIX, full-length Tax, and pCREB have not been examined. Here we biochemically characterized the interaction between Tax and KIX in a physiologically relevant complex containing pCREB and vCRE DNA. Our data show that Tax and pCREB simultaneously and independently bind two distinct surfaces on the KIX domain: Tax binds KIX at the previously characterized mixed-lineage leukemia (MLL) protein interaction surface while pCREB binds KIX at the pKID-KIX interface. These results provide evidence for a model in which Tax and pCREB bind distinct surfaces of KIX for effective CBP/p300 recruitment to the HTLV-1 promoter. We also show that MLL competes with Tax for KIX binding, suggesting a novel mechanism of Tax oncogenesis in which normal MLL function is disrupted by Tax. PMID- 17707402 TI - Mutation of a conserved active site residue converts tyrosyl-DNA phosphodiesterase I into a DNA topoisomerase I-dependent poison. AB - Tyrosyl-DNA phosphodiesterase 1 (Tdp1) catalyzes the resolution of 3' and 5' phospho-DNA adducts. A defective mutant, associated with the recessive neurodegenerative disease SCAN1, accumulates Tdp1-DNA complexes in vitro. To assess the conservation of enzyme architecture, a 2.0 A crystal structure of yeast Tdp1 was determined that is very similar to human Tdp1. Poorly conserved regions of primary structure are peripheral to an essentially identical catalytic core. Enzyme mechanism was also conserved, because the yeast SCAN1 mutant (H(432)R) enhanced cell sensitivity to the DNA topoisomerase I (Top1) poison camptothecin. A more severe Top1-dependent lethality of Tdp1H(432)N was drug independent, coinciding with increased covalent Top1-DNA and Tdp1-DNA complex formation in vivo. However, both H(432) mutants were recessive to wild-type Tdp1. Thus, yeast H(432) acts in the general acid/base catalytic mechanism of Tdp1 to resolve 3' phosphotyrosyl and 3' phosphoamide linkages. However, the distinct pattern of mutant Tdp1 activity evident in yeast cells, suggests a more severe defect in Tdp1H(432)N-catalyzed resolution of 3' phospho-adducts. PMID- 17707403 TI - Interplay among replicative and specialized DNA polymerases determines failure or success of translesion synthesis pathways. AB - Living cells possess a panel of specialized DNA polymerases that deal with the large diversity of DNA lesions that occur in their genomes. How specialized DNA polymerases gain access to the replication intermediate in the vicinity of the lesion is unknown. Using a model system in which a single replication blocking lesion can be bypassed concurrently by two pathways that leave distinct molecular signatures, we analyzed the complex interplay among replicative and specialized DNA polymerases. The system involves a single N-2-acetylaminofluorene guanine adduct within the NarI frameshift hot spot that can be bypassed concurrently by Pol II or Pol V, yielding a -2 frameshift or an error-free bypass product, respectively. Reconstitution of the two pathways using purified DNA polymerases Pol III, Pol II and Pol V and a set of essential accessory factors was achieved under conditions that recapitulate the known in vivo requirements. With this approach, we have identified the key replication intermediates that are used preferentially by Pol II and Pol V, respectively. Using single-hit conditions, we show that the beta-clamp is critical by increasing the processivity of Pol II during elongation of the slipped -2 frameshift intermediate by one nucleotide which, surprisingly, is enough to support subsequent elongation by Pol III rather than degradation. Finally, the proofreading activity of the replicative polymerase prevents the formation of a Pol II-mediated -1 frameshift product. In conclusion, failure or success of TLS pathways appears to be the net result of a complex interplay among DNA polymerases and accessory factors. PMID- 17707404 TI - Reconstitution of the mitochondrial PrxIII antioxidant defence pathway: general properties and factors affecting PrxIII activity and oligomeric state. AB - The mitochondrial 2-Cys peroxiredoxin PrxIII serves as a thioredoxin-dependent peroxidase operating in tandem with its cognate partners, an organelle-specific thioredoxin (Trx2) and NADP-linked thioredoxin reductase (TRR2). This PrxIII pathway is emerging as a primary regulator of intracellular H(2)O(2) levels with dual roles in antioxidant defence and H(2)O(2)-mediated signalling. Here we describe the reconstitution of the mammalian PrxIII pathway in vitro from its purified recombinant components and investigate some of its overall properties. Employing the site-directed PrxIII mutants C47S, C66S and C168S, the putative N and C-terminal catalytic cysteine residues are shown to be essential for function whereas the C66S mutant retains full activity. The pathway attains maximal capacity at low H(2)O(2) concentrations (<10 microM) and is progressively inhibited in the range 0.1 mM to 1.0 mM peroxide. Damage to PrxIII caused by over oxidation is confirmed by the appearance of abnormal oxidised species of PrxIII on SDS-PAGE at elevated H(2)O(2) levels. The presence of an N-terminal His-tag on PrxIII markedly enhances dodecamer stability, particularly apparent in its oxidised state. Its removal promotes oxidised PrxIII dissociation into dimers and leads to a 3.0-3.5-fold stimulation in peroxidase activity. The unusual concatenated crystal structure of PrxIII consisting of two-interlocked dodecameric rings is also evident in dilute solution employing transmission electron microscopy; however, it represents only 3-5% of the population with most molecules present as single toroids. Moreover, concatenated PrxIII C168S reverts to single toroids on crystal dissolution indicating that these higher-order structures are produced dynamically during the crystallisation process. PMID- 17707405 TI - Interleukin-8 production from human umbilical vein endothelial cells during brief hyperglycemia: the effect of tumor necrotic factor-alpha. AB - BACKGROUND: This study evaluated the changes in chemokine interleukin (IL)-8 production from endothelial cells under various hyperglycemic conditions and investigated whether the hyperglycemia associated with the acute inflammatory response could enhance the IL-8 production from the endothelial cells. MATERIALS AND METHODS: Human umbilical endothelial cells (HUVECs) were seeded at a concentration of 1 x 10(5) cells/well and cultured. The culture medium was replaced with Medium 199 containing various concentrations of glucose (final glucose concentration of culture medium was 100, 200, 300, 400, 500 mg/dL; n = 7 each) with or without 100 ng of tumor necrosis factor-alpha (TNF-alpha). After 12 or 24 h at 37 degrees C, the supernatants were collected from the cultures and stored at -80 degrees C until cytokine assay. IL-8 levels of the samples from the supernatants were quantified using a commercially available enzyme-linked immunosorbent assay kit. RESULTS: The IL-8 production by the HUVECs was significantly higher in the high glucose culture than in the control culture (glucose concentration of 100 mg/dL) (P < 0.05). Moreover, the hyperglycemia associated with elevated TNF-alpha was found to enhance the level of IL-8 production by the HUVECs cultured at all glucose concentrations and over both time courses, compared to the control (P < 0.05). CONCLUSIONS: In this study we observed a significant augmentation of IL-8 production by endothelial cells during short-term hyperglycemia, and a similar but significantly stronger augmentation was obtained through TNF treatment. These findings suggest that the hyperglycemia associated with acute inflammatory response after trauma may put the patients at high risk for secondary tissue damage. PMID- 17707406 TI - EMLA and water immersion cause similar vasodilatation in replanted fingers. AB - BACKGROUND: Skin wrinkling on water immersion is a reliable and simple test of sympathetic innervation. The eutectic mixture of local anesthetic (EMLA) cream has been shown to induce near identical clinical wrinkling scores and reduction in digit blood flow as that following water immersion in people with normal sympathetic innervation. This study was designed to investigate the vasomotor response to EMLA in replanted fingers that had poor sympathetic innervation. METHODS: Laser Doppler imaging (PeriScan PIM II; Perimed AB, Stockholm, Sweden) was used to detect perfusion changes in the pulps of fourteen replanted fingers before and after 0.5 g of 5% EMLA cream application and water immersion in a 40 degrees C normal saline for 30 min, respectively. Comparisons were made with the contralateral corresponding normal fingers. RESULTS: After water immersion and EMLA application, all of the normal fingers showed a considerable and similar decrease in blood perfusion that demonstrated in the absolute perfusion units (pU) (baseline: 1.57 +/- 0.33 pU, after water-immersion, 1.19 +/- 0.22 pU, P < 0.001; decrease: 23.6 +/- 7.7%, after EMLA application: 1.20 +/- 0.18 pU, P < 0.001; decrease: 22.4 +/- 8.9%). In contrast, all of the replanted fingers showed a statistically significant vasodilatatory response (baseline: 1.20 +/- 0.29 pU, after water-immersion: 1.36 +/- 0.28 pU, P < 0.001; increase: 15.2 +/- 9.1%, after EMLA application: 1.38 +/- 0.27 pU, P < 0.001; increase: 16.8 +/- 9.1%). CONCLUSIONS: EMLA and water immersion both cause vasodilatation and no skin wrinkling in replanted fingers. These results imply that intact sympathetic nerve function is required to induce the vasoconstrictive effect of EMLA. PMID- 17707408 TI - Bacterial toxins and Multiple Sclerosis. AB - The primary pathogenetic mechanism responsible for the distinctive demyelinating lesions in the Central Nervous System (CNS) in Multiple Sclerosis (MS), first described in remarkable detail by Charcot more than 170 years ago, remains one of the most baffling conundrums in medicine. A possible role for bacterial cell molecules and transportable proteins in the pathogenesis of MS is reviewed. The ability of bacterial toxins to distort immunity and to cause distinctive toxic damage in the nervous system is discussed in the light of largely forgotten data linking bacterial nasopharyngeal infections with optic neuritis, optochiasmatic arachnoiditis and MS. While the blood-brain barrier substantially protects the CNS from hematogenous toxins, there is a route by which the barrier may be by passed. Data is reviewed which shows that the CSF and extra-cellular fluid circulation is bi-directionally linked to the lymphatic drainage channels of the nasopharyngeal mucosa. While this provides a facility by which the CNS may mount immunological responses to antigenic challenges from within, it is also a route by which products of nasopharyngeal infection may drain into the CNS and be processed by the immune cells of the meninges and Virchow-Robin perivascular spaces. If potentially toxic bacterial products are identified in early MS tissues at these sites, this would provide an entirely new insight into the pathogenetic mechanisms of this frustratingly enigmatic disease. PMID- 17707410 TI - Nutritional optic neuropathies. AB - Nutritional deficiency may be the cause of a genuine optic neuropathy, sometimes associated with involvement of the peripheral nervous system. Nutritional optic neuropathies are usually bilateral, painless, chronic, insidious and slowly progressive. Most often, they present as a non-specific retrobulbar optic neuropathy. The differential diagnosis with other causes of optic nerve involvement, in particular of toxic origin, may be particularly difficult. Nutritional deficits are often associated with toxic effects from alcohol and tobacco; therefore, the separation of the nutritional and toxic components is often illusory and artificial. The pathophysiological mechanisms involved in nutritional -- and toxic -- optic neuropathies affect biochemical pathways involved in cell energetic production, correction of oxidative stress and quenching of free radicals. The recognition of these mechanisms could provide future therapeutic alternatives. Currently, the treatment is limited to the intensive use of vitamins with variable results in individual cases, and to the implementation of preventive measures, when feasible. PMID- 17707407 TI - Chylomicron-bound LPS selectively inhibits the hepatocellular response to proinflammatory cytokines. AB - BACKGROUND/AIMS: Pretreatment of rodent hepatocytes with chylomicron-bound lipopolysaccharide (CM-LPS) renders these cells unresponsive to subsequent stimulation by proinflammatory cytokines. We sought to test the selectivity of this response. METHODS: Cellular responses to hypoxia, oxidative stress, apoptosis, and heat-shock response, and thermotolerance induced in CM-LPS pretreated hepatocytes were compared with responses in non-pretreated cells. RESULTS: CM-LPS inhibited the hepatocellular response to proinflammatory cytokines without affecting the response to the other cellular stressors. It did not affect the response to oxidative stress, as measured by mitochondrial activity after hydrogen peroxide was added, or protein induction before or after stimulation with cobalt chloride. Also, induction of heat shock proteins did not differ between the CM-LPS pretreated cells and non-pretreated cells. CM-LPS did not interfere with the adoption of the thermotolerant phenotype, as shown by similar mitochondrial activity between pretreated and non-pretreated cells. Although stimulation with tumor necrosis factor-alpha and actinomycin D increased activity of the apoptotic enzymes, there were no differences between cells pretreated with CM-LPS and non-pretreated hepatocytes. CONCLUSION: When the response to proinflammatory cytokines is inhibited, hepatocellular responses to hypoxia, oxidative stress, heat shock, and apoptosis remain intact after pretreatment with CM-LPS. CM-LPS may have a specific anti-inflammatory effect on hepatocytes. PMID- 17707409 TI - A novel point mutation in PMP22 gene in an Italian family with hereditary neuropathy with liability to pressure palsies. AB - Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant inherited disorder characterized by recurrent sensory or motor dysfunction. In 85% of HNPP cases the genetic defect is a 1.4 Mb deletion on chromosome 17p11.2, encompassing the PMP22 gene. Point mutations in the PMP22 gene responsible for HNPP phenotypes are rare. We investigated a 17-years-old girl who led to our detecting a novel mutation in PMP22 gene. The mutation was also detected in her father and corresponded to a deletion of one tymidine at position 11 in exon2 (c.11delT). This novel mutation creates a shift on the reading frame starting at codon 4 and leads to the introduction of a premature stop at codon 6. PMID- 17707424 TI - Computational model for predicting the chance of early resolution in children with vesicoureteral reflux. AB - PURPOSE: Minimally invasive treatment options and concern regarding long-term antibiotics have increased emphasis on predicting the chance of early vesicoureteral reflux resolution. Computational models, such as artificial neural networks, have been used to assist decision making in the clinical setting using complex numeric constructs to solve multivariable problems. We investigated various computational models to enhance the prediction of vesicoureteral reflux resolution. MATERIALS AND METHODS: We reviewed the records of 205 children with vesicoureteral reflux, including 163 females and 42 males. In addition to reflux grade, several clinical variables were recorded from the diagnostic visit. Outcome was noted as resolved or unresolved at 1 and 2 years after diagnosis. Two separate data sets were prepared for the 1 and 2-year outcomes, sharing the same input features. The data sets were randomized into a modeling set of 155 and a cross-validation set of 50. The model was constructed with several constructs using neUROn++, a set of C++ programs that we developed, to best fit the data. RESULTS: A linear support vector machine was found to have the highest accuracy with a test set ROC curve area of 0.819 and 0.86 for the 1 and 2-year models, respectively. The model was deployed in JavaScript for ready availability on the Internet, allowing all input variables to be entered and calculating the odds of 1 and 2-year resolution. CONCLUSIONS: This computational model allowed the use of multiple variables to improve the individualized prediction of early reflux resolution. This is a potentially useful clinical tool regarding treatment decisions for vesicoureteral reflux. PMID- 17707411 TI - Prion proteins: physiological functions and role in neurological disorders. AB - Stanley Prusiner was the first to promote the concept of misfolded proteins as a cause for neurological disease. It has since been shown by him and other investigators that the scrapie isoform of prion protein (PrP(Sc)) functions as an infectious agent in numerous human and non-human disorders of the central nervous system (CNS). Interestingly, other organ systems appear to be less affected, and do not appear to lead to major co-morbidities. The physiological function of the endogenous cellular form of the prion protein (PrP(C)) is much less clear. It is intriguing that PrP(c) is expressed on most tissues in mammals, suggesting not only biological functions outside the CNS, but also a role other than the propagation of its misfolded isotype. In this review, we summarize accumulating in vitro and in vivo evidence regarding the physiological functions of PrP(C) in the nervous system, as well as in lymphoid organs. PMID- 17707425 TI - The common ileal ureter: a new technique for compliant ureterocystoplasty. AB - PURPOSE: Ureterocystoplasty is an effective technique for bladder reconstruction in patients with megaureter. Initial reports were encouraging but later repeat augmentation with bowel was necessary in many patients. We evaluated whether repeat augmentation after ureterocystoplasty could be avoided using two-thirds of each megaureter. MATERIALS AND METHODS: Ureterocystoplasty was performed in 6 patients using the distal two-thirds of the 2 ureters. Continuity was reestablished by anastomosis of the remaining proximal ureters to a tubularized and tapered piece of ileum, which was reimplanted in an antireflux manner into the reconstructed bladder. All patients underwent preoperative and postoperative evaluation with ultrasound, creatinine, voiding cystourethrogram, nuclear renal scan and videourodynamic testing. RESULTS: Patient age at ureterocystoplasty was between 7 and 15 years with a median followup of 45.3 months. Preoperative videourodynamics demonstrated low capacity bladders with grade 5 vesicoureteral reflux and a poor mean bladder compliance of 7.4 ml/cm H2O. Bladder capacity increased up to 12-fold postoperatively with a mean compliance rate of 58 ml/cm H2O and vesicoureteral reflux resolved in all patients. One patient required endoscopic incision of the reimplanted common ileal ureter but no other complications occurred. CONCLUSIONS: The common ileal ureter provided a long-term compliant reservoir without the need for future repeat augmentation in all patients. Using standard urological techniques the complication rates remained low and recovery time was similar to that of standard ureterocystoplasty. PMID- 17707426 TI - Corporeal sparing dismembered clitoroplasty: an alternative technique for feminizing genitoplasty. AB - PURPOSE: Management for clitoral enlargement remains controversial. New understanding of clitoral function stimulated a search for more conservative surgical approaches, such as recession or partial resection. However, these techniques risk decreasing clitoral sensation or causing painful erections. Moreover, irreversibility continues to be the principal problem that fuels patient, surgeon and societal anxiety in the management of this challenging developmental issue. We describe a new technique, corporeal sparing dismembered clitoroplasty, that dismembers the corporeal bodies and preserves all clitoral structures. MATERIALS AND METHODS: After obtaining full informed consent and institutional review board approval 8 consecutive patients with clitoral enlargement underwent corporeal sparing dismembered clitoroplasty. Five girls had congenital adrenal hyperplasia (Prader IV and V in 4 and 1, respectively), 1 had ovotesticular disorder of sexual differentiation and 2 had partial androgen insensitivity syndrome. One pubertal girl was tested with warm, cold and pain clitoral stimulation before and after surgery. For the clitoroplasty technique the glans and its neurovascular bundles are dissected from the corpora. The isolated corpus is then completely divided starting at the bifurcation. Each separated hemicorpus is rotated inferior and lateral, to be placed inside the labial scrotal folds. The glans is reduced by superficial excision of its epithelium and fixed to the pubic attachments. Labia minora are constructed with preputial Byars flaps. Labioplasty and vaginoplasty are then routinely performed. RESULTS: Eight patients 6 months to 13 years old underwent this procedure. Followup was 6 to 12 months. All patients recovered well from surgery without early complications. The initial cosmetic result was good in all girls. The hemicorpora were easily palpated inside their labia majora pouches, which retained the desired cosmetic appearance following feminizing genitoplasty. All glans clitoris were preserved. The teenaged patient does not report painful erections. She has maintained clitoral sensation and is satisfied with the cosmetic result. CONCLUSIONS: Conservative reconfiguration of the female genitalia without removing genital structures is feasible in girls with clitoral enlargement. The cosmetic appearance of the genitalia is acceptable, at least to the surgeon and parents, in that the enlarged clitoris is hidden. The physiological consequences of the current operation and any surgery in the future to reverse it are unknown. With these aspects in mind we believe that corporeal sparing dismembered clitoroplasty should be incorporated into the armamentarium of surgeons involved in the treatment of clitoral enlargement and presented as an option for feminizing genitoplasty. PMID- 17707427 TI - Which is better--retroperitoneoscopic or laparoscopic dismembered pyeloplasty in children? AB - PURPOSE: Groups at multiple institutions have documented the efficacy of minimally invasive repair of ureteropelvic junction obstruction with a retroperitoneoscopic or laparoscopic approach. To our knowledge no group has compared the 2 operative procedures directly at a single institution. MATERIALS AND METHODS: The records of 49 consecutive patients with a history of retroperitoneoscopic pyeloplasty or transperitoneal laparoscopic pyeloplasty for ureteropelvic junction obstruction were reviewed retrospectively, of whom 29 underwent attempted retroperitoneoscopic pyeloplasty and 20 underwent laparoscopic pyeloplasty. Retroperitoneoscopic pyeloplasty cases were performed first in the series before changing to the laparoscopic pyeloplasty approach. Retroperitoneoscopic pyeloplasty was performed using an anterolateral approach with retroperitoneal balloon distention. Laparoscopic pyeloplasty repair was performed using a transmesenteric approach for left ureteropelvic junction obstruction or after right colon mobilization for right repairs. Dismembered pyeloplasty was performed over a stent using 5-zero polydioxanone suture. Stents were placed antegrade or retrograde based on anatomy and presenting symptoms. Parameters studied were patient age, operative time, postoperative analgesic requirement during hospitalization, hospital stay and success rate. RESULTS: No difference was observed between the 2 groups in patient age, success rate, hospital stay or analgesic narcotic requirement. Average operative time for retroperitoneoscopic pyeloplasty was significantly longer than for laparoscopic pyeloplasty (239.1 vs 184.8 minutes). Overall success rates were also statistically equivalent (25 of 27 retroperitoneoscopic and 19 of 19 laparoscopic pyeloplasties) with incomplete followup in 1 patient in the retroperitoneoscopic pyeloplasty group and 1 in the laparoscopic pyeloplasty group. Three children, including 2 with retroperitoneoscopic and 1 with laparoscopic pyeloplasty, had transient urinary extravasation postoperatively, which was related to poorly positioned stents. Five patients in the retroperitoneoscopic group and 1 in the laparoscopic group underwent balloon dilation for indistinct but persistent postoperative flank pain with equivocal radiological findings. There were no major complications following either technique. CONCLUSIONS: In our experience no major difference exists between the retroperitoneoscopic and laparoscopic approaches for correcting ureteropelvic junction obstruction. The difference in operative time likely reflects the learning curve for laparoscopic suturing and dissection. Currently we prefer the laparoscopic approach because of the larger working space for suturing, the perceived ease of antegrade stent placement and the subjective improvement in cosmetic outcome. The 2 techniques should be considered equal with regard to the successful correction of ureteropelvic junction obstruction. PMID- 17707428 TI - Renal function outcomes in patients treated with nephron sparing surgery for bilateral Wilms tumor. AB - PURPOSE: Management of bilateral Wilms tumor represents a particular challenge in the consideration of long-term renal function for affected patients. Aggressive surgical resection to prevent recurrence must be balanced with the desire to preserve renal function. We evaluated our institutional experience with nephrological outcomes in patients treated with nephron sparing surgery for bilateral Wilms tumor. MATERIALS AND METHODS: We identified all patients with synchronous bilateral Wilms tumors presenting to St. Jude Children's Research Hospital between October 1987 and February 2004. We also included patients with Wilms tumor involving a solitary kidney presenting during the same period. A total of 17 patients were identified who underwent nephron sparing surgery, including 16 with bilateral tumors and 1 with tumor in a solitary kidney. Institutional review board approval was obtained to retrospectively review records and analyze outcomes based on long-term renal function, hypertension, proteinuria, need for dialysis and indications for renal transplantation. RESULTS: Eight of the 17 patients initially underwent bilateral nephron sparing surgery and 9 initially underwent a combination of nephrectomy and contralateral nephron sparing surgery. Two patients were eventually rendered anephric following further resections secondary to local recurrence. Before the initiation of therapy all patients had normal baseline creatinine clearance, which was calculated using the Schwartz formula. At a median followup from diagnosis of 72 months (range 15 to 207) 1 patient had renal insufficiency and another 3 had renal failure requiring dialysis. One of the 3 patients on dialysis died of metastatic Wilms and 2 await renal transplantation. None of the remaining patients had evidence of proteinuria. Ten of the 17 patients (58.8%) had hypertension at diagnosis and 9 (52.9%) required antihypertensive medications at the most recent followup. The overall survival rate in this group of patients was 88.2% with no evidence of disease in survivors at the most recent followup. CONCLUSIONS: When combined with adjuvant radiation and/or chemotherapy, nephron sparing surgery provides an opportunity to preserve renal function, while maintaining excellent long-term oncological outcomes for patients with bilateral Wilms tumor. PMID- 17707429 TI - Incidence based fetal urological counseling using the virtual pediatric urology registry: importance of insignificant fetal pyelectasis (sonographically evident renal pelvis). AB - PURPOSE: Since 1985, counseling for fetal renal pelvic dilatation has been done to determine whether there is need for newborn urological evaluation. This is likely if the anteroposterior width of the renal pelvis exceeds categorical cutoffs, ie 4 mm or greater before gestational age 33 weeks, or 7 mm or greater after 33 weeks. Cases below these categorical cutoffs are deemed not to merit newborn testing. We examined our fetal registry to determine the incidence of urological pathology in cases deemed not to merit newborn testing. MATERIALS AND METHODS: Since 1980, we have prospectively input fetal ultrasound and postnatal followup data into customized Virtual Pediatric Urology Registry software. The Virtual Pediatric Urology Registry compares index case findings against those archived in the registry and then outputs the incidence of newborn diagnoses. Diagnoses are grouped as having limited or extensive urological care. RESULTS: The Virtual Pediatric Urology Registry has 1,128 cases registered and data on 2,292 fetal ultrasound studies that were done between gestational ages 12 and 43 weeks (average +/- SD 29.3 +/- 7). There are measurements of anteroposterior pelvic width for 1,712 cases. Pediatric data include ultrasound for 2,596 cases, diuretic renal scan for 449 and voiding cystourethrogram for 574. Surgery was done for renal/bladder obstruction or vesicoureteral reflux in 358 cases (32%). Mean followup was 9.8 months old (range 1 day to 14 years). Of the total of 1,128 fetal cases 148 (13%) showed anteroposterior pelvic width below categorical cutoffs, so that they were deemed not to merit newborn testing. However, the Virtual Pediatric Urology Registry incidence based method identified that extensive urological care extended to 30 of these 148 cases (20%). There were 31 cases identified at less than gestational age 33 weeks, which showed newborn urological pathology in 11 (35%), including hydronephrosis in 4, surgery in 3, vesicoureteral reflux in 2, solitary kidney in 1 and death in 1. There were 117 cases identified at gestational age 33 weeks or greater, which showed newborn urological pathology in 19 (16%), including vesicoureteral reflux in 8, hydronephrosis in 7 and surgery in 4. CONCLUSIONS: We found that about 13% of cases of fetal renal pelvic dilatation were insignificant because the measurement was below currently accepted cutoffs that merit postnatal followup. However, 20% of these cases in fact showed extensive urological care needs. The Virtual Pediatric Urology Registry provides an array of likely newborn diagnoses in neonates. Counseling by the incidence based method is more effective than by the current cutoff method. PMID- 17707430 TI - The use of botulinum toxin A injection for the management of external sphincter dyssynergia in neurologically normal children. AB - PURPOSE: Botulinum toxin A has previously been used for neurogenic and nonneurogenic urgency and urge incontinence. We evaluated the effects of sphincteric botulinum toxin A injection in a series of neurologically normal children with evidence of external sphincter dyssynergia with various voiding problems documented by abnormal voiding electromyography as well as voiding cystourethrography to assess its effectiveness for eliminating post-void residual urine. MATERIALS AND METHODS: We retrospectively reviewed the charts of 16 dysfunctional voiders who underwent botulinum toxin A injection to the external sphincter between 2002 and 2006, including 1 to 3 injections in 14, 1 and 1, respectively. Of 19 injections 17 were performed with 300 U to the sphincter, while 2 of 19 were done with 200 U. Two patients also received 100 U injected into the detrusor. Mean patient age at surgery was 9.0 years (range 6 to 16). Preoperative clinical data were recorded, including medications, electromyography, uroflowmetry with post-void residual urine, ultrasound and voiding cystourethrography. Before botulinum toxin A injection medical therapies had failed in all patients, including alpha-blockers in 100%, biofeedback in 100%, oxybutynin in 33% and tricyclics in 3 (20%). One patient was on intermittent catheterization. All patients were refractory to bowel regimens and timed voiding. Postoperative parameters consisted of medications, symptoms and post-void residual urine. In the 3 males the resolution of epididymitis symptoms and prevention of recurrence were evidence of success. RESULTS: Before treatment patients experienced symptoms of urge incontinence (14 of 16), recurrent urinary tract infections (66%), voiding postponement (45%) and epididymitis (3 of 16). All patients had external sphincter dyssynergia, as documented by preoperative electromyography or voiding cystourethrography. Average preoperative post-void residual urine was 107 cc (range 49 to 218). Two patients who underwent preoperative voiding cystourethrography had unilateral grade 1 reflux. Of the 16 children 12 (75%) were dry at the first postoperative visit. The remaining 2 patients had decreased enuresis and 13 of 16 were dry at the second postoperative visit. The last patient became dry after treatment for attention deficit disorder was initiated. Average initial postoperative post-void residual urine volume was 43 cc (range 0 to 141) and the average best postoperative visit post-void residual urine was 8 cc (range 0 to 26). Uroflow data revealed no difference in uroflow before or after injections. Neuropsychiatric problems were present in 9 of the 16 patients, including depression in 4, anxiety in 3 and attention deficit disorder in 2. CONCLUSIONS: Before our study in the pediatric literature doses between 50 and 100 U were used. We used a significantly higher dose with increased efficacy and no increased morbidity. Endoscopic botulinum toxin A injection of the external sphincter appears to be a safe and efficacious way to treat refractory nonneurogenic voiding dysfunction in children with external sphincter dyssynergia. Long-term followup is necessary and repeat endoscopic injections may be required in select patients. PMID- 17707431 TI - The durability of intravesical oxybutynin solutions over time. AB - PURPOSE: Intravesical oxybutynin is prescribed for patients who do not tolerate the side effects of oral intake. Standard oral tablets are broken up, dissolved and instilled. For convenience some families create a large volume of solutions to use for weeks. We investigated the stability of oxybutynin concentration in these solutions and the effect of varying solvents and solutes. MATERIALS AND METHODS: Solutions of oxybutynin were created with a starting concentration of 125 mug/ml. We varied the method of pill preparation (crushed vs passive dissolution), type of solvent (tap water vs normal saline) and the presence of the commonly instilled antibiotic, gentamicin sulfate (0.48 mg/ml). Solutions were aged for 1 to 4 weeks. Concentrations of oxybutynin were measured by gas chromatography. RESULTS: Tap water as a solvent had the greatest decrease in concentration, declining below 50% by week 2 and reaching 25% by week 4. The mean concentration of the other solutions decreased less, maintaining 80% of the starting concentration at week 4. The use of normal saline as a solvent and the addition of gentamicin sulfate helped slow the decrease. Crushing vs passive dissolution showed no effect. CONCLUSIONS: Homemade oxybutynin solutions degrade with time. Tap water solvent alone should be avoided. Solutions and additives that lower pH and are more acidic help oxybutynin solubility and stability. Storing oxybutynin solutions for later intravesical use appears feasible up to 4 weeks. The clinical effect of the 20% degradation remains to be demonstrated. PMID- 17707432 TI - Incontinence Symptom Index-Pediatric: development and initial validation of a urinary incontinence instrument for the older pediatric population. AB - PURPOSE: Although urinary incontinence is common in children, no validated pediatric instruments exist for measuring urinary incontinence symptoms and bother. We developed and validated a patient reported pediatric survey for urinary incontinence measurement. MATERIALS AND METHODS: The Incontinence Symptom Index-Pediatric is an 11-item instrument comprising 2 domains, that is 1) impairment and 2) symptom severity, including subdomains for stress urinary incontinence, urge urinary incontinence, insensate urinary incontinence, nocturnal urinary incontinence and pad use. The survey was self-administered twice, 2 weeks apart, to boys and girls ages 11 to 17 years. Children completed the survey independently. Cases consisted of patients presenting to pediatric urology clinic with the chief complaint of urinary incontinence. Controls consisted of healthy children presenting for evaluation up at a general pediatric practice. Formal validation analysis was performed. RESULTS: A total of 19 subjects per arm completed at least 1 survey. Internal consistency was good with a Cronbach's alpha of 0.84 for the complete instrument. Item-scale correlations were greater than 0.60 for all except 1 item. Test-retest reliability was also good (r = 0.97, p <0.0001). Discriminative validity was good with a total severity scale score of 9.3 in wet children and 0.7 in controls (p <0.0001). Impairment scale scores differed by 2.2 points (p <0.0001). Mean scores differed significantly between subscales for all domains except pad use. The most dramatic difference was in the urge urinary incontinence domain, which differed by a mean of 3.6 points (p = 0.0002). CONCLUSIONS: This pilot study provides initial validation of a survey instrument for urinary incontinence in children and adolescents. This instrument can be used in children ages 11 to 17 years to objectively and reproducibly measure patient reported urinary incontinence. PMID- 17707433 TI - Office management of pediatric primary nocturnal enuresis: a comparison of physician advised and parent chosen alternative treatment outcomes. AB - PURPOSE: We compared the remission of pediatric primary nocturnal enuresis in groups of children who used a physician advised practice plan vs a parent chosen alternative. MATERIALS AND METHODS: Between January 2004 and January 2006 there were 119 patients with primary nocturnal enuresis enrolled in this prospective, nonrandomized study. For this study primary nocturnal enuresis was defined as wetting at night during sleep during any 6-month interval without any known causative problem. A total of 76 children received the physician advised treatment plan and used an alarm, oxybutynin, desmopressin, an elimination diet and a bowel program, as indicated. A total of 43 children received a parent chosen alternative treatment plan, which consisted of any single or combination of treatments involving an alarm, oxybutynin, desmopressin and an elimination diet or bowel program. Parents from each group completed an intake survey that measured functional bladder capacity using a 3-day home diary and they identified demographic variables. Followup occurred at 2 weeks and then monthly for 12 weeks to study end. RESULTS: We found that the probability of remission by the end of the study for the physician advised treatment group was significantly higher than that of the parent choice group (88% vs 29%, Kaplan-Meier curve p <0.0001). CONCLUSIONS: The group of children who followed physician advised treatment for primary nocturnal enuresis showed significantly earlier remission of primary nocturnal enuresis than children who followed the parent choice treatment (25th percentile 2 vs 10 weeks). PMID- 17707435 TI - Spinal cord magnetic resonance imaging for investigation of nonneurogenic lower urinary tract dysfunction--can the yield be improved? AB - PURPOSE: Magnetic resonance imaging has been used to detect occult neuropathy in patients with nonneurogenic lower urinary tract dysfunction. There is substantial controversy surrounding the role of this test for lower urinary tract dysfunction. We identified factors associated with positive magnetic resonance imaging to improve patient selection. MATERIALS AND METHODS: A case-control study was done in all pediatric patients referred to our radiology department for spinal magnetic resonance imaging primarily because of lower urinary tract symptoms between 1995 and 2004. Patients with known neurological disorders or anomalies associated with neurogenic bladder (overt spinal dysraphism, imperforate anus, etc) were excluded. A total of 80 patients with a median age of 6.5 years (range 4 to 17) were identified, of whom 47 (59%) were female. Bivariate analysis was used to evaluate the association of certain variables with positive magnetic resonance imaging findings, including patient age, gender, type of urinary symptoms, fecal soiling, abnormal neuro-orthopedic examination, lumbar cutaneous findings, resistance to medical management and urodynamic findings. RESULTS: Magnetic resonance imaging revealed spinal abnormalities in 6 cases (7.5%), including intradural arachnoid cyst in 1, sacral dysgenesis in 3, syrinx/hydromyelia in 1 and tethered cord in 1. An abnormal lumbar cutaneous finding was the only variable associated with positive magnetic resonance imaging (Fisher's exact test p = 0.002). CONCLUSIONS: Spinal magnetic resonance imaging has a low impact in the management of lower urinary tract dysfunction. With proper patient selection the pretest probability of positive magnetic resonance imaging may be increased and, therefore, many unnecessary studies may be avoided. Abnormal cutaneous findings are associated with abnormal magnetic resonance imaging. PMID- 17707434 TI - Development of an objective score to quantify the pediatric cystometrogram. AB - PURPOSE: We developed a reliable tool for quantitative assessment of the pediatric cystometrogram. MATERIALS AND METHODS: Scores for expected capacity (EV), compliance (EV20), activity and sensation were developed according to established formulas for norms. Ordinal scores were derived by calculating observed over expected findings. Based on the derived percents scores of 1 to 5 were assigned. For EV--0 to 5 the formula used was EV = (age + 2) x 30 and for EV20--0 to 5 the formula used was EV20 = 17 x age + 55. Activity was determined as the volume of the first, total number and magnitude of involuntary contractions, each scored 0 to 5 and divided by 3. Sensation was scored as 0 to 3 according to volume at first sensation. A total of 87 blinded cystometrograms in 49 patients were independently scored twice by 3 pediatric urologists. The resultant 522 total and 2,088 component scores were assessed for reliability. RESULTS: Intrarater reliability was strong with 80% of total scores (208 of 261) within +/- 1 point from initial to subsequent retest. Reliability component scores were stronger with 94% (983 of 1,044) within +/- 1 point from test to retest. Spearman's rank correlations for total score was 0.82 to 0.98, indicating a strong relationship between test and retest. Interrater reliability of components was strong with 89% of scores (1,851 of 2,088) between urologists within +/- 1 point. Correlation coefficients for total scores were 0.80 to 0.96, indicating a high degree of consistency between urologist assessments (p <0.05). CONCLUSIONS: This score appears to reliably quantify the pediatric cystometrogram. Its application may be useful for the objective assessment of detrusor behavior before and after intervention. Further applications should allow refinement of this tool. PMID- 17707436 TI - Protease-activated receptor 4-mediated Ca2+ signaling in mouse lung alveolar epithelial cells. AB - Protease-activated receptor (PAR)-4 is a recently identified low-affinity thrombin receptor that plays a pathophysiological role in many types of tissues including the lung. Here, we showed for the first time that PAR4 mRNA and protein are expressed on primary cultured mouse lung alveolar epithelial cells by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunocytochemical analyses. In a fura 2-AM-loaded single epithelial cell, stimulation with thrombin (1 U/ml) and a PAR4 agonist peptide (AYPGKF-NH(2), 1-100 microM) increased intracellular Ca(2+) concentration ([Ca(2+)](i)), which consisted of an initial peak phase followed by a slowly decaying delayed phase, while a PAR1 agonist peptide, TFLLR NH(2) (1-100 microM), induced a transient increase in [Ca(2+)](i). AYPGKF-NH(2) (10 microM)-induced [Ca(2+)](i) response was attenuated by a PAR4 antagonist peptide (tcY-NH(2)), a phospholipase C inhibitor, U-73122 (1-10 microM) or a Ca(2+)-ATPase inhibitor, thapsigargin (1 microM). Removal of extracellular Ca(2+) or an inhibitor of store-operated Ca(2+) entry, trans-resveratrol (1 microM) shortened the time to shut off the Ca(2+) response without any significant effects on the magnitude of the peak [Ca(2+)](i). Thus, stimulation of PAR4 appeared to mobilize Ca(2+) from intracellular stores in the initial peak response and to enhance Ca(2+) entry through the store depletion-operated pathway in the delayed phase. The latter mechanism probably contributed to the longer responsiveness of PAR4 stimulation. PMID- 17707437 TI - Erythropoietin protects post-ischemic hearts by preventing extracellular matrix degradation: role of Jak2-ERK pathway. AB - Factors predisposing to extracellular matrix degradation associated with myocardial ischemia/reperfusion (IR) usually cause cell death. Recombinant human erythropoietin (EPO) protects the myocardium from IR, but whether it affects extracellular matrix (ECM) degradation is not known. This study examined the effect of the Jak2-ERK pathway, which is triggered by EPO, on the expression of matrix metalloproteinases (MMPs), tissue inhibitor of MMP 4 (TIMP-4), and collagen in post-ischemic hearts. Rat hearts were isolated and perfused in a Langendorff apparatus. IR was induced by 40 min of stopped flow and 120 min of aerobic reperfusion; EPO was added immediately before reperfusion. Compared to untreated controls, poor recovery of the left ventricular developed pressure (LVDP) was seen in IR hearts. IR resulted in myocyte injury measured by creatine kinase MB release and infarction. Western blot analysis showed increased levels of MMP-2 and MMP-9 and reduced levels of TIMP-4 and collagen III. IR rats given 5 IU/ml of EPO showed improved LVDP with reduced injury. EPO increased Jak2 and ERK activity, decreased MMP expression, increased TIMP-4 expression, and prevented collagen degradation in IR hearts. All these effects were blocked by the upstream ERK inhibitor, U0126 (5 microM). These observations show that EPO attenuates extracellular matrix degradation following IR and this may be the basis of the protection from cell death. Jak2-ERK phosphorylation may be an important signal in this process. PMID- 17707438 TI - Effect of an enriched cholesterol diet during gestation on fatty acid synthase, HMG-CoA reductase and SREBP-1/2 expressions in rabbits. AB - Pregnancy is associated with hyperlipidemia and hypercholesterolemia in humans. These changes take place to support fetal growth and development, and modifications of these maternal concentrations may influence lipids and cholesterol synthesis in the dam, fetus and placenta. Administration of a 0.2% enriched cholesterol diet (ECD) during rabbit gestation significantly increased cholesterol and triglyceride (TG) levels in maternal livers and decreased fetal weight by 15%. Here we used Western blot analysis to examine the impact of gestation and 0.2% ECD on the expression levels of fatty acid synthase (FAS), HMGR and SREBP-1/2, which are involved in either lipid or cholesterol synthesis. We confirmed that gestation modifies the hepatic and circulating lipid profile in the mother. Our data also suggest that the maternal liver mainly supports lipogenesis, while the placenta plays a key role in cholesterol synthesis. Thus, our data demonstrate a decrease in HMGR protein levels in dam livers by feeding an ECD. In the placenta, SREBPs are highly expressed, and the ECD supplementation increased nuclear SREBP-1/2 protein levels. In addition, our results show a decrease in FAS protein levels in non-pregnant liver and in the liver of offspring from ECD-treated animals. Finally, our data suggest that the placenta does not modify its own cholesterol synthesis in response to an increase in circulating cholesterol. However, the dam liver compensates for this increase by essentially decreasing the level of HMGR expression. Because HMGR and FAS expressions do not correlate with the circulating lipid profile, it would be interesting to find which genes are then targeted by SREBP-1/2 during gestation. PMID- 17707439 TI - Nitric oxide and cardiac function. AB - Nitric oxide (NO) participates in the control of contractility and heart rate, limits cardiac remodeling after an infarction and contributes to the protective effect of ischemic pre- and postconditioning. Low concentrations of NO, with production of small amounts of cGMP, inhibit phosphodiesterase III, thus preventing the hydrolysis of cAMP. The subsequent activation of a protein-kinase A causes the opening of sarcolemmal voltage-operated and sarcoplasmic ryanodin receptor Ca(2+) channels, thus increasing myocardial contractility. High concentrations of NO induce the production of larger amounts of cGMP which are responsible for a cardiodepression in response to an activation of protein kinase G (PKG) with blockade of sarcolemmal Ca(2+) channels. NO is also involved in reduced contractile response to adrenergic stimulation in heart failure. A reduction of heart rate is an evident effect of NO-synthase (NOS) inhibition. It is noteworthy that the direct effect of NOS inhibition can be altered if baroreceptors are stimulated by increases in blood pressure. Finally, NO can limit the deleterious effects of cardiac remodeling after myocardial infarction possibly via the cGMP pathway. The protective effect of NO is mainly mediated by the guanylyl cyclase-cGMP pathway resulting in activation of PKG with opening of mitochondrial ATP-sensitive potassium channels and inhibition of the mitochondrial permeability transition pores. NO acting on heart is produced by vascular and endocardial endothelial NOS, as well as neuronal and inducible synthases. In particular, while in the basal control of contractility, endothelial synthase has a predominant role, the inducible isoform is mainly responsible for the cardiodepression in septic shock. PMID- 17707440 TI - Sodium nitroprusside activates p38 mitogen activated protein kinase through a cGMP/PKG independent mechanism. AB - The objective of this study was to understand the mechanism of action of nitric oxide (NO) in the heart by determining whether nitric oxide (NO) released from sodium nitroprusside (SNP) induces p38 mitogen activated protein kinase (p38 MAPK) phosphorylation and whether this is mediated through a cyclic GMP (cGMP)/protein kinase G (PKG) pathway. p38 MAPK activation was examined by Western blotting of whole cell lysates of embryonic chick cardiomyocytes with antibodies specific to the native or phosphorylated forms of p38 MAPK. SNP, 1 mM, which released significant amounts of NO as determined by Griess reaction, induced p38 MAPK phosphorylation that was apparent within 10 min, was significantly (p<0.05) greater than control at 60 min and remained higher than initial levels up to the 4 h end point of the experiment. This could not be attributed to hydrogen peroxide release from SNP as catalase did not affect SNP induced p38 MAPK phosphorylation. SB202190, a relatively selective inhibitor of p38 MAPK, mainly p38alpha MAPK, inhibited SNP-induced p38 MAPK phosphorylation. SNP-induced p38 MAPK phosphorylation was not altered by pre-treatment with the PKG inhibitor KT 5823 or by ODQ a potent and selective inhibitor of NO-sensitive guanylyl cyclase. p38 MAPK phosphorylation was not induced by the cell permeable cGMP analogue, 8-Br-cGMP. In summary, considering that new therapeutic strategies aimed at NO and p38 MAPK are being considered for myocardial injury and heart failure, these data demonstrate that SNP induces p38 MAPK phosphorylation through a pathway that is independent of NO-induced activation of cGMP/PKG pathways and suggest that non cGMP/PKG regulatory proteins leading to p38 MAPK phosphorylation merit further investigation to address this therapeutic target. PMID- 17707441 TI - Role of incidence function in vaccine-induced backward bifurcation in some HIV models. AB - The phenomenon of backward bifurcation in disease models, where a stable endemic equilibrium co-exists with a stable disease-free equilibrium when the associated reproduction number is less than unity, has important implications for disease control. In such a scenario, the classical requirement of the reproduction number being less than unity becomes only a necessary, but not sufficient, condition for disease elimination. This paper addresses the role of the choice of incidence function in a vaccine-induced backward bifurcation in HIV models. Several examples are given where backward bifurcations occur using standard incidence, but not with their equivalents that employ mass action incidence. Furthermore, this result is independent of the type of vaccination program adopted. These results emphasize the need for further work on the incidence functions used in HIV models. PMID- 17707442 TI - A poroelastic model of transcapillary flow in normal tissue. AB - Starling's seminal work on the absorption of fluids from connective tissue spaces (and Starling's hypothesis that the energy for transcapillary flow lies in the difference between hydrostatic and osmotic pressures across the capillary wall) has long formed the basis of much of experimental physiology. Related recent experimental evidence points to a more active role of the interstitium in controlling interstitial fluid pressure (IFP) which has significant implications for clinical oncology. In light of these considerations, it is clearly of importance to reconsider the relationship between IFP and transcapillary transport, in addition to the regulation of IFP in normal tissue. In this paper, we adopt the Michel-Weinbaum viewpoint on the locality of Starling forces and model the capillary wall as a poroelastic solid using Biot's consolidation theory. However, the incorporation of the Michel-Weinbaum hypothesis requires an extension of Darcy's law to include the effects of oncotic pressure in the mechanism of filtration through the capillary wall. A unique feature of the model of transcapillary flow developed here is its ability to predict the stress and strain distribution across the capillary wall, which to our knowledge has not been attempted previously. We are optimistic that, with rapidly advancing technological capabilities, experimentalists will soon be able to test many of the model predictions. PMID- 17707443 TI - Insights from child development on the relationship between episodic and semantic memory. AB - The present study was motivated by a recent controversy in the neuropsychological literature on semantic dementia as to whether episodic encoding requires semantic processing or whether it can proceed solely based on perceptual processing. We addressed this issue by examining the effect of age-related limitations in semantic competency on episodic memory in 4-6-year-old children (n=67). We administered three different forced-choice recognition memory tests for pictures previously encountered in a single study episode. The tests varied in the degree to which access to semantically encoded information was required at retrieval. Semantic competency predicted recognition performance regardless of whether access to semantic information was required. A direct relation between picture naming at encoding and subsequent recognition was also found for all tests. Our findings emphasize the importance of semantic encoding processes even in retrieval situations that purportedly do not require access to semantic information. They also highlight the importance of testing neuropsychological models of memory in different populations, healthy and brain damaged, at both ends of the developmental continuum. PMID- 17707444 TI - Facial expression and gaze-direction in human superior temporal sulcus. AB - The perception of facial expression and gaze-direction are important aspects of non-verbal communication. Expressions communicate the internal emotional state of others while gaze-direction offers clues to their attentional focus and future intentions. Cortical regions in the superior temporal sulcus (STS) play a central role in the perception of expression and gaze, but the extent to which the neural representations of these facial gestures are overlapping is unknown. In the current study 12 subjects observed neutral faces with direct-gaze, neutral faces with averted-gaze, or emotionally expressive faces with direct-gaze while we scanned their brains with functional magnetic resonance imaging (fMRI), allowing a comparison of the hemodynamic responses evoked by perception of expression and averted-gaze. The inferior occipital gyri, fusiform gyri, STS and inferior frontal gyrus were more strongly activated when subjects saw facial expressions than when they saw neutral faces. The right STS was more strongly activated by the perception of averted-gaze than direct-gaze faces. A comparison of the responses within right STS revealed that expression and averted-gaze activated distinct, though overlapping, regions of cortex. We propose that gaze-direction and expression are represented by dissociable overlapping neural systems. PMID- 17707445 TI - Inactivation of pea genes by RNAi supports the involvement of two similar O methyltransferases in the biosynthesis of (+)-pisatin and of chiral intermediates with a configuration opposite that found in (+)-pisatin. AB - (+)-Pisatin, the major phytoalexin of pea (Pisum sativum L.), is believed to be synthesized via two chiral intermediates, (-)-7,2'-dihydroxy-4',5' methylenedioxyisoflavanone [(-)-sophorol] and (-)-7,2'-dihydroxy-4',5' methylenedioxyisoflavanol [(-)-DMDI]; both have an opposite C-3 absolute configuration to that found at C-6a in (+)-pisatin. The expression of isoflavone reductase (IFR), which converts 7,2'-dihydroxy-4',5'-methylenedioxyisoflavone (DMD) to (-)-sophorol, sophorol reductase (SOR), which converts (-)-sophorol to ( )-DMDI, and hydroxymaackiain-3-O-methyltransferase (HMM), believed to be the last step of (+)-pisatin biosynthesis, were inactivated by RNA-mediated genetic interference (RNAi) in pea hairy roots. Some hairy root lines containing RNAi constructs of IFR and SOR accumulated DMD or (-)-sophorol, respectively, and were deficient in (+)-pisatin biosynthesis supporting the involvement of chiral intermediates with a configuration opposite to that found in (+)-pisatin in the biosynthesis of (+)-pisatin. Pea proteins also converted (-)-DMDI to an achiral isoflavene suggesting that an isoflavene might be the intermediate through which the configuration is changed to that found in (+)-pisatin. Hairy roots containing RNAi constructs of HMM also were deficient in (+)-pisatin biosynthesis, but did not accumulate (+)-6a-hydroxymaackiain, the proposed precursor to (+)-pisatin. Instead, 2,7,4'-trihydroxyisoflavanone (TIF), daidzein, isoformononetin, and liquiritigenin accumulated. HMM has a high amino acid similarity to hydroxyisoflavanone-4'-O-methyltransferase (HI4'OMT), an enzyme that methylates TIF, an early intermediate in the isoflavonoid pathway. The accumulation of these four compounds is consistent with the blockage of the synthesis of (+)-pisatin at the HI4'OMT catalyzed step resulting in the accumulation of liquiritigenin and TIF and the diversion of the pathway to produce daidzein and isoformononetin, compounds not normally made by pea. Previous results have identified two highly similar "HMMs" in pea. The current results suggest that both of these O methyltransferases are involved in (+)-pisatin biosynthesis and that one functions early in the pathway as HI4'OMT and the second acts at the terminal step of the pathway. PMID- 17707446 TI - Reduced PKCalpha expression in pulmonary arterioles of broiler chickens is associated with early feed restriction. AB - OBJECTIVE: The present study was conducted to investigate the effect of early feed restriction on protein kinase Calpha (PKCalpha) expression in pulmonary arterioles, which has been revealed to promote pulmonary vascular remodeling in pulmonary hypertensive broilers. METHODS: A total of 270day-old mixed sex commercial broilers were randomly distributed to a normal temperature control group (NT), a low temperature control group (LT) and a low temperature plus feed restriction group (LR). The PHS incidence, the right/total ventricular weight ratio (RV/TV), the vessel wall area/vessel total area ratio (WA/TA), the mean media thickness in pulmonary arterioles (mMTPA) and the expression of PKCalpha in the pulmonary arterioles were measured weekly. RESULTS: Low temperature treatment significantly increased the PHS mortality. The RV/TV, WA/TA and mMTPA values of group LT were significantly elevated compared with those of group NT on d 35 and 42. The LT chickens had increased PKCalpha expression compared with their NT counterparts on d 28 and afterwards. Feed restriction reduced the PHS mortality, RV/TV, WA/TA and mMTPA in cold-exposed broilers. The LR chickens had much lower PKCalpha expression in pulmonary arterioles than the LT chickens. CONCLUSION: Early time feed restriction inhibited pulmonary vascular remodeling in broilers, which might be partly attributed to reduced PKCalpha expression in pulmonary arterioles. PMID- 17707447 TI - Sulfadoxine-pyrimethamine plus artesunate compared with chloroquine for the treatment of vivax malaria in areas co-endemic for Plasmodium falciparum and P. vivax: a randomised non-inferiority trial in eastern Afghanistan. AB - Chloroquine (CQ) is an effective treatment of choice for vivax malaria in most settings, but with the spread of CQ-resistant Plasmodium falciparum, many countries now use artemisinin-based combination therapy for treatment of falciparum malaria. In areas co-endemic for falciparum and vivax malaria incorrect differential diagnosis is always a risk. In Afghanistan the adoption of sulfadoxine-pyrimethamine plus artesunate (SP+AS) as first-line falciparum treatment raises the prospect of a significant proportion of vivax malaria being misdiagnosed and treated with the combination. SP is considered to have limited efficacy against vivax malaria, and the efficacy of SP+AS against Plasmodium vivax has not been established in areas that are using SP+AS. A randomised, non inferiority trial comparing SP+AS with CQ monotherapy was undertaken on 190 vivax malaria patients in eastern Afghanistan. Standard WHO procedures for in vivo evaluation of antimalarial drugs were followed. A total of 180 individuals completed the trial to day 42. Using a per protocol analysis, both regimens resulted in > or =96% treatment success at 28 d, but significantly more cases failed in the CQ arm (46%) than in the SP+AS arm (24%) by day 42. In areas where vivax infections might be misdiagnosed as falciparum infections and treated with SP+AS, patient management would be as good, or better than, with the standard CQ treatment. PMID- 17707448 TI - The morphology and ultrastructure of the peripheral olfactory organ in newly metamorphosed coral-dwelling gobies, Paragobiodon xanthosomus Bleeker (Gobiidae, Teleostei). AB - We examined the peripheral olfactory organ in newly metamorphosed coral-dwelling gobies, Paragobiodon xanthosomus (SL=5.8mm+/-0.8mm, N=15), by the aid of electron microscopy (scanning and transmission) and light microscopy. Two bilateral olfactory placodes were present in each fish. They were oval-shaped and located medio-ventrally, one in each of the olfactory chambers. Each placode had a continuous cover of cilia. The placode epithelium contained three different types of olfactory receptor neurons: ciliated, microvillous and crypt cells. The latter type was rare. Following a pelagic larval phase, P. xanthosomus settle to the reef and form an obligate association with one species of coral, Seriatopora hystrix. Their well-developed olfactory organs likely enable larvae of P. xanthosomus to detect chemical cues that assist in navigating towards and selecting appropriate coral habitat at settlement. Our findings support past studies showing that the peripheral olfactory organ develops early in coral reef fishes. PMID- 17707449 TI - Characterization of keratins and associated proteins involved in the corneification of crocodilian epidermis. AB - Crocodilian keratinocytes accumulate keratin and form a corneous cell envelope of which the composition is poorly known. The present immunological study characterizes the molecular weight, isoelectric point (pI) and the protein pattern of alpha- and beta-keratins in the epidermis of crocodilians. Some acidic alpha-keratins of 47-68 kDa are present. Cross-reactive bands for loricrin (70, 66, 55 kDa), sciellin (66, 55-57 kDa), and filaggrin-AE2-positive keratins (67, 55 kDa) are detected while caveolin is absent. These proteins may participate in the formation of the cornified cell membranes, especially in hinge regions among scales. Beta-keratins of 17-20 kDa and of prevalent basic pI (7.0-8.4) are also present. Acidic beta-keratins of 10-16 kDa are scarce and may represent altered forms of the original basic proteins. Crocodilian beta-keratins are not recognized by a lizard beta-keratin antibody (A68B), and by a turtle beta-keratin antibody (A685). This result indicates that these antibodies recognize specific epitopes in different reptiles. Conversely, crocodilian beta-keratins cross-react with the Beta-universal antibody indicating they share a specific 20 amino acid epitope with avian beta-keratins. Although crocodilian beta-keratins are larger proteins than those present in birds our results indicate presence of shared epitopes between avian and crocodilian beta-keratins which give good indication for the future determination of the sequence of these proteins. PMID- 17707450 TI - Immunohistochemical localization of 2-Cys peroxiredoxins in human ciliary body. AB - 2-Cys peroxiredoxins (PRDX) are novel antioxidant enzymes that eliminate the hydrogen peroxide in cells to protect the cellular components from reactive oxygen species. To evaluate whether 2-Cys PRDX family plays a role in human ciliary body, the expression of PRDX I, II and III on normal human ciliary body was investigated. Three normal human ciliary body tissues obtained from three donor eyeballs were examined by an immunohistochemistry using light microscopy and fluorescent microscopy with antibodies directed against the PRDX I, II and III. In the normal human ciliary body, PRDX I, II and III were immunolocalized to the non-pigmented epithelial cells and ciliary muscle fibers. It suggests that 2 Cys PRDXs may have physiological functions to protect cells in human ciliary body. PMID- 17707451 TI - Neurotoxicological effects of cinnabar (a Chinese mineral medicine, HgS) in mice. AB - Cinnabar, a naturally occurring mercuric sulfide (HgS), has long been used in combination with traditional Chinese medicine as a sedative for more than 2000 years. Up to date, its pharmacological and toxicological effects are still unclear, especially in clinical low-dose and long-term use. In this study, we attempted to elucidate the effects of cinnabar on the time course of changes in locomotor activities, pentobarbital-induced sleeping time, motor equilibrium performance and neurobiochemical activities in mice during 3- to 11-week administration at a clinical dose of 10 mg/kg/day. The results showed that cinnabar was significantly absorbed by gastrointestinal (G-I) tract and transported to brain tissues. The spontaneous locomotor activities of male mice but not female mice were preferentially suppressed. Moreover, frequencies of jump and stereotype-1 episodes were progressively decreased after 3-week oral administration in male and female mice. Pentobarbital-induced sleeping time was prolonged and the retention time on a rotating rod (60 rpm) was reduced after treatment with cinnabar for 6 weeks and then progressively to a greater extent until the 11-week experiment. In addition, the biochemical changes in blood and brain tissues were studied; the inhibition of Na(+)/K(+)-ATPase activities, increased production of lipid peroxidation (LPO) and nitric oxide (NO) were found with a greater extent in male mice than those in female mice, which were apparently correlated with their differences in the neurological responses observed. In conclusion, these findings, for the first time, provide evidence of the pharmacological and toxicological basis for understanding the sedative and neurotoxic effects of cinnabar used as a Chinese mineral medicine for more than 2000 years. PMID- 17707452 TI - Visual search training in subjects with severe to profound low vision. AB - Effects of practicing on feature search tasks (a 2 degrees square target amid 1 degrees square distracters) for 5 days were compared between 45 visually impaired (VI) subjects with severe to profound low vision and 23 age-matched normal controls (NV). Search accuracy and speed improved in both groups. VI subjects had larger training gains than NV subjects, but their proportional gains were similar to that of NV subjects. There were no significant differences in training effect at different set sizes in both groups. Search performance on a 40 degrees field improved more than that on a 10 degrees or 20 degrees field in VI subjects, but not in NV subjects. No significant change was found between day 5 and 1-month follow-up. The fact that feature search training is equally efficient in VI and NV subjects encourages development of general purpose perceptual training protocols for low vision rehabilitation. PMID- 17707453 TI - A bias for looming stimuli to predominate in binocular rivalry. AB - Concentric gratings that expand outwards are seen for a greater period of time relative to contracting gratings when engaged in binocular rivalry. During binocular rivalry (BR), which is a fluctuation in visual awareness between different images presented separately to each eye, equivalent images tend to be seen in equal proportion over the observation period. When one eye's image is particularly salient, brighter, or moving, this equality is curtailed, and the stronger image predominates. Here a specific direction of motion is found to predominate over another of equal speed. This tendency is consistent with the ability of looming objects to orient attention, coupled with previous accounts of the role of stimulus-driven attention in BR. PMID- 17707454 TI - Antimony leaching from polyethylene terephthalate (PET) plastic used for bottled drinking water. AB - Antimony is a regulated contaminant that poses both acute and chronic health effects in drinking water. Previous reports suggest that polyethylene terephthalate (PET) plastics used for water bottles in Europe and Canada leach antimony, but no studies on bottled water in the United States have previously been conducted. Nine commercially available bottled waters in the southwestern US (Arizona) were purchased and tested for antimony concentrations as well as for potential antimony release by the plastics that compose the bottles. The southwestern US was chosen for the study because of its high consumption of bottled water and elevated temperatures, which could increase antimony leaching from PET plastics. Antimony concentrations in the bottled waters ranged from 0.095 to 0.521 ppb, well below the US Environmental Protection Agency (USEPA) maximum contaminant level (MCL) of 6 ppb. The average concentration was 0.195+/ 0.116 ppb at the beginning of the study and 0.226+/-0.160 ppb 3 months later, with no statistical differences; samples were stored at 22 degrees C. However, storage at higher temperatures had a significant effect on the time-dependent release of antimony. The rate of antimony (Sb) release could be fit by a power function model (Sb(t)=Sb 0 x[Time, h]k; k=8.7 x 10(-6)x[Temperature ( degrees C)](2.55); Sb 0 is the initial antimony concentration). For exposure temperatures of 60, 65, 70, 75, 80, and 85 degrees C, the exposure durations necessary to exceed the 6 ppb MCL are 176, 38, 12, 4.7, 2.3, and 1.3 days, respectively. Summertime temperatures inside of cars, garages, and enclosed storage areas can exceed 65 degrees C in Arizona, and thus could promote antimony leaching from PET bottled waters. Microwave digestion revealed that the PET plastic used by one brand contained 213+/-35 mgSb/kg plastic; leaching of all the antimony from this plastic into 0.5L of water in a bottle could result in an antimony concentration of 376 ppb. Clearly, only a small fraction of the antimony in PET plastic bottles is released into the water. Still, the use of alternative types of plastics that do not leach antimony should be considered, especially for climates where exposure to extreme conditions can promote antimony release from PET plastics. PMID- 17707455 TI - Denitrification in cypress swamp within the Atchafalaya River Basin, Louisiana. AB - Nitrogen has been implicated as a major cause of hypoxia in shallow water along the Louisiana/Texas, USA coasts. Excess nitrogen (mainly nitrate) from Mississippi and Atchafalaya River drainage basins may drive the onset and duration of hypoxia in the northern Gulf of Mexico. Restoring and enhancing denitrification have been proposed to reduce and control coastal hypoxia and improve water quality in the Mississippi River Basin. Sediments were collected from six baldcypress restoration sites within the Atchafalaya River Basin, Louisiana, USA. The acetylene blockage technique was used to measure background and potential sediment denitrification rates. Denitrification fluxes were measured before nitrate addition (background rates) and after nitrate addition of 100mgNl(-1) (potential denitrification) at three seasonal temperatures. Background denitrification was low across all cypress swamp sites ranging from 0.9 to 8.8, 0.6 to 28.5 and 8.8 to 47.5g N evolved ha(-1)d(-1) at water/sediment column temperatures of 8, 22 and 30 degrees C, respectively. After nitrate addition, temperature had a significant effect on sediment denitrification potential. Maximum rates measured at 8, 22 and 30 degrees C were approximately 250-260, 550 and 970gNha(-1)d(-1), respectively. Most of the added nitrate in water columns, incubated at 8 degrees C, was removed after 65d compared to 32d and 17d at 22 and 30 degrees C, respectively. These results indicate cypress swamps have the potential to assimilate and process elevated levels of floodwater nitrate with denitrification being a major removal mechanism. PMID- 17707456 TI - Total and subcellular distribution of trace elements (Cd, Cu and Zn) in the liver and kidney of green turtles (Chelonia mydas) from the Mediterranean Sea. AB - This study investigated the subcellular distribution of Cd, Cu and Zn in liver and kidney of green turtles (Chelonia mydas) stranded along the Italian coast of the South Adriatic Sea (Eastern Mediterranean). Cd and Zn mean concentrations did not differ significantly between liver (4.26microgg(-1) and 34.53microgg(-1), respectively) and kidney (5.06microgg(-1) and 26.39microgg(-1), respectively), whereas the levels of Cu were significantly higher in liver (32.75microgg(-1)) than in kidney (8.20microgg(-1)) (p<0.009). Most of Cd, Cu and Zn was present in hepatic and renal cytosol, and their concentrations increased with total levels in both organs, indicating that cytosol has a crucial role in metal accumulation. Cd and Cu in hepatic and renal cytosol were present mostly in metallothionein fractions (MTs), whereas Zn was fractionated into MTs and high-molecular-weight substances (HMWS). The comparison with the results of other investigations on individuals of the same species collected in different marine areas shows good agreement relatively to essential metals. For Cd our data are comparable with those encountered in specimens from the Mediterranean Sea (Cyprus) confirming the homogeneity of the area comprising the south-eastern basin of the Mediterranean Sea from an ecological point of view. PMID- 17707457 TI - Effect of Tween 80 and beta-cyclodextrin on degradation of decabromodiphenyl ether (BDE-209) by White rot fungi. AB - The environmental safety of decabromodiphenyl ether (BDE-209), a widely used flame retardant, has been the topic of controversial discussions during the past several years. Degradation of BDE-209 into lower brominated diphenyl ether congeners, exhibiting a higher bioaccumulation potential, has been a critical issue. White rot fungi are known to degrade a wide variety of recalcitrant pollutants. In this work, white rot fungi were used to degrade BDE-209 in liquid culture medium, and the effects of Tween 80 and beta-cyclodextrin on BDE-209 degradation by white rot fungi were evaluated. On the basis of these results, it appears that BDE-209 could be degraded by white rot fungi, and Tween 80 and beta cyclodextrin can both increase the biodegradation. The best result in Tween 80 experiments was obtained at a Tween 80 concentration of 500mgl(-1) within 10d, which showed 96.5% (w/w) BDE-209 transformed. Tween 80 at a high concentration will restrain the fungal growth and the degradation of BDE-209. However, beta cyclodextrin had positive effects both on the BDE-209 degradation and the fungal growth. PMID- 17707458 TI - Theoretical study on the chemical properties of polybrominated diphenyl ethers. AB - Density functional theory calculations at the B3LYP/6-31+G(d) and B3LYP/aug-cc pVDZ levels were performed to obtain the equilibrium structures, thermodynamic properties, and electron affinities (EA) of 14 polybrominated diphenyl ether (PBDE) congeners in the gas phase. All congeners except for those of symmetric BDE are found to have two or more conformational isomers. The optimized geometries of the most stable conformational isomers are in agreement with recently published X-ray crystallographic data. The thermodynamic properties of the congeners with a given number of bromine substitutions are strongly dependent on the substitution pattern, whereas the EA values also depend on the number of bromine substitutions. The vertical electron affinities (EA(Ver)) calculated for the selected BDE congeners at the B3LYP/aug-cc-pVDZ level are all positive except for di-BDEs, and are correlated with the initial reductive debromination rate constants obtained recently [Keum, Y.-S., Li, Q.X., 2005. Reductive debromination of polybrominated diphenyl ethers by zerovalent iron. Environ. Sci. Technol. 39, 2280]. All adiabatic electron affinities (EA(Ada)) are positive, and suggest that the BDE congeners act as electron acceptors when reacting with receptors in living cells. The calculated EA(Ada) values differ considerably from those of EA(Ver) because of the large geometrical relaxation from the neutral to the anionic BDE congeners, highlighted by the lengthening of a C-Br bond. The elongated C-Br bond, which occurs at the alpha position, is directly involved in the debromination of n-bromodiphenyl to (n-1)-bromodiphenyl ethers in the reductive debromination experiments. PMID- 17707459 TI - Correlative evidence that prostate cancer cell-derived caveolin-1 mediates angiogenesis. AB - Up-regulation of caveolin-1 (cav-1) has been implicated in human prostate cancer progression/metastasis and shown to promote cancer cell survival. It has also been shown that cav-1 is secreted by tumor cells and may regulate the growth, functional activities, and migration of vascular endothelial cells. However, the relationship of cav-1 expression in prostate cancer cells and tumor associated endothelial cells (TAEC) to tumor-associated angiogenesis remains to be investigated. Dual immunofluorescent labeling with antibodies to CD34 and cav-1 was performed on 56 prostate cancer specimens obtained by radical prostatectomy and stratified according to cav-1 positivity in cancer cells. The tumor microvessel densities (MVD) and cav-1 expression in TAEC within these specimens were measured and correlated with cav-1 expression in prostate cancer cells. The MVD values were significantly higher in cav-1-positive (n = 25) than in the cav-1 negative (n = 31) tumors (median of 44 versus 25 vessels/field, P = .0140). Additional studies showed that the cav-1 positivity in microvessels within tumor specimens was significantly less frequent than in the blood vessels of benign prostatic tissues (94.4% versus 98.6%, P = .0012). In contrast, the percentage of cav-1-positive TAEC in cav-1-positive tumors was significantly higher than in cav 1-negative tumors (95.8% versus 92.7%, P = .0024). This increased cav-1 positivity in TAEC was predominantly confined to regions with cav-1-positive tumor cells corresponding to the higher percentage of cav-1-positive microvessels within these regions in cav-1-positive, as opposed to cav-1-negative tumors (P = .0086). These positive correlations provide new evidence for the involvement of prostate cancer cell derived cav-1 in mediating angiogenesis during prostate cancer progression. They also establish a conceptual framework for further investigation of cav-1 proangiogenic activities. PMID- 17707460 TI - Spatial resolution requirements for acquisition of the virtual screening slide for digital whole-specimen breast histopathology. AB - We examined the effect of lateral spatial resolution and reader specialty on the accuracy of detection of breast cancer. The motivation for this pilot study was the need to acquire and display very large data sets in whole-specimen 3D digital breast histopathology imaging. The ultimate goal is to determine the minimum resolution adequate for detection of malignancy. Twenty-three histologic slides were selected from breast pathology cases and digitized at 2 sampling distances (3.2 and 1.9 microm pixels). Images were viewed by 14 pathologists, of whom 5 had breast pathology as their primary specialty. The readers assessed the likelihood of malignancy on a 5-point Likert scale, and provided a provisional diagnosis. For the detection task, sensitivity, specificity, overall accuracy of detection, and area under the receiver-operator curve were calculated. An overall diagnostic score, and scores grouped by malignancy type, were also computed. Outcome measures were examined for significant resolution and specialty effects. Increasing the lateral resolution significantly improved accuracy in diagnosis (P=.004) but no effect was found for detection. Breast specialists achieved significantly higher scores for all outcome measures except specificity. Differences in performance between the 2 groups of readers tended to be greater for the diagnostic task compared to detection, especially at the higher resolution. However, specimen coverage may also be a significant factor. Factors related to the readers may have also affected performance in this study. Based on these results, a more comprehensive study should examine pixel sizes between 0.7 and 1.9 microm. PMID- 17707462 TI - High-degree tumor budding and podia-formation in sporadic colorectal carcinomas with K-ras gene mutations. AB - In vitro ras activation enhances the epithelial-mesenchymal transition of colorectal carcinoma cells. But ras effects are known to be highly dependent on cell types and the tissue context. Therefore, this study was made to test the hypothesis that in clinical colorectal carcinoma specimens, aggressive invasion phenotypes, specifically tumor budding and podia formation, would correlate with K-ras gene mutations. In a series of 95 clinically sporadic primary colorectal carcinomas collected ad hoc, tumor budding and podia formation were counted using pan-cytokeratin immunohistochemistry, and K-ras gene mutations in codons 12 and 13 were determined. Consistent with the hypothesis, tumor budding and podia formation were observed to be significantly higher in the 32 (34.7%) of the tumors with K-ras gene mutations (29 mutations in codon 12, 3 in codon 13), and this correlation was observed independent of the patterns of invasion (expansive versus infiltrative). Microsatellite status, numbers of losses of heterozygosity, adenomatous polyposis coli and p53 gene mutations, and degree of promoter methylations (CIMP status) were not associated with K-ras gene mutations. Besides their effects on the tumor cell cycles, oncogenic K-ras gene mutations in colorectal carcinomas could be important for aggressive tumor invasion. This may be important in metastasizing disease and could provide a rationale for developing drugs that interrupt ras-signaling cascades. PMID- 17707461 TI - Persistent uroplakin expression in advanced urothelial carcinomas: implications in urothelial tumor progression and clinical outcome. AB - As the terminal differentiation products of human urothelium, uroplakins (UPs) would be expected to diminish during urothelial tumorigenesis. Surprisingly, recent studies found UPs to be retained even by well-advanced urothelial carcinomas, suggesting that the loss of UPs does not strictly parallel urothelial transformation. Little is known, however, about whether the status of UPs is associated with a particular pathologic parameter, the tumor's biological behavior, or patient outcome. Here we assessed UP expression by immunohistochemistry on tissue arrays from 285 patients with bladder urothelial carcinomas or nontumor conditions. UPs were expressed in all 9 normal urothelial specimens, 63 of 74 (85%) patients with non-muscle-invasive urothelial carcinomas on transurethral resection, 104 of 202 (51.5%) patients who underwent radical cystectomy for advanced urothelial carcinomas, and 33 of 50 (66%) lymph node metastases. Normally associated with urothelial apical surface, UPs were localized aberrantly in tumors, including microluminal, basal-laminal, cytoplasmic, or uniform patterns. In non-muscle-invasive diseases, there was no association between UP expression and disease recurrence, progression, or mortality. In contrast, in invasive diseases, absent UP expression was significantly associated with advanced pathologic stage, lymph node metastases, disease recurrence, and bladder cancer-specific mortality (P = .042, P = .035, P = .023, and P = .022, respectively) in univariate analyses. Furthermore, UP status was independent of key cell-cycle regulators, including p53, pRb, p27, and cyclin D1, thus excluding a functional link between these 2 groups of proteins. Our data demonstrate for the first time that persistent UP expression is associated with a favorable clinical outcome and that UPs may be used as adjunct markers for predicting the prognoses of patients with invasive and metastatic bladder carcinomas. Our results also suggest that UP-positive and -negative carcinomas have different clonal origins or may be derived from different cancer stem cells. PMID- 17707463 TI - Up-regulation of CXC chemokines and their receptors: implications for proinflammatory microenvironments of ovarian carcinomas and endometriosis. AB - Molecular abnormalities in the epithelial cells of endometriosis and their relevance to carcinogenesis of the ovary have been well studied. On the other hand, the differences of proinflammatory microenvironments between endometriosis and ovarian carcinomas have not been well documented yet. In this study, the expression patterns of CXC chemokines (IL-8, ENA-78, GRO-alpha, I-TAC, Mig, and SDF-1) and their receptors (CXCR2, CXCR3, and CXCR4) were compared among 12 ovarian carcinomas, 8 endometriosis, and 6 normal ovaries using quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. The CXCR3-mediated signaling in ovarian carcinoma cells in vitro was also investigated. In quantitative reverse transcriptase polymerase chain reaction, ENA-78 was up-regulated both in endometriosis and carcinomas, whereas I-TAC was detected exclusively in carcinomas. CXCR3 was up-regulated both in carcinomas and endometriosis. However, immunohistochemical studies revealed that the localization of CXCR3 in carcinomas was distinctively different from that in endometriosis. In carcinoma-endometriosis coexisting cases, CXCR3-positive lymphocytes in benign lesions decreased in proportion as CXCR3-positive tumor cells replaced the tissues. CXCR3 was also detected in ovarian carcinoma cell lines in vitro. Administration of interferon gamma (IFN-gamma)-inducible chemokines induced extracellular signal-regulated kinase phosphorylation in these carcinoma cells. The results indicated that CXC chemokines might contribute to the progression of ovarian carcinomas and endometriosis in different manners. Aberrant expression of IFN-gamma-inducible chemokines and CXCR3 in carcinoma cells in association with reduced CXCR3-positive immune cells raised the possibility that IFN-gamma-inducible chemokines might not exert effective antitumor immune responses but that they might work in favor of tumor progression. PMID- 17707464 TI - Age-related differences in the performance, diffusion, and maintenance of stone handling, a behavioral tradition in Japanese macaques. AB - Identifying the sources of behavioral diversity in non-human primates is vital to understanding the evolution of human behavior. Stone handling (SH, hereafter) is a form of object play consisting of the manipulation of stones by performing various behavioral patterns. This behavior is socially transmitted from generation to generation in Japanese macaques (Macaca fuscata), as a behavioral tradition. SH behavior in particular may reflect on the origin and evolution of stone-tool material culture. The objective of this study was to assess how group size, age structure, and age- and sex-related differences may account for the substantial intra- and inter-troop variations in SH reported in ten troops of Japanese macaques. Our results supported the hypothesis that patterns of variation in SH across troops reflected variability in group size and composition in age classes. We found that troop size was correlated with the proportion of troop members exhibiting SH simultaneously. The effect of troop size on the synchronized performance of SH may reveal the contagious nature of play. Our results suggest that the age structure of the group may affect the diffusion of SH. As predicted by the surplus energy hypothesis, a major functional hypothesis about play, intra-group variation in SH reflected more age- than sex-related differences. SH mainly occurred and was more frequent in younger than in older individuals, whereas no significant sex differences were found. SH episodes were shorter, more vigorous, and SH patterns were more diverse and less complex in immature than in mature individuals. The present findings reveal that age-related factors and group size may constrain the performance, diffusion, and maintenance of SH within a troop. Contrary to most other socially transmitted stone-tool using behaviors in non-human primates and early hominids, there is no optimal SH pattern. Provided some form of social learning, the non-adaptive nature of SH may allow particular SH pattern preferences to emerge at the group level. Our findings urge the use of an inter-populational comparative approach based on multivariate analyses when addressing the question of the evolution of behavioral traditions in primate and human populations. PMID- 17707465 TI - Basic principle of the lifespan in the nematode C. elegans. AB - We present a biophysical model based on the principles of fluctuation and regulation to explain the effect of stochastics on survival. The model is a good fit for the survivorship and mortality rates observed in the nematode Caenorhabditis elegans. A parameter included in the theory, which is called the fluctuation constant, correlates well with a change (or declining rate) of respiration with age, which we term the physiological decline rate. The square of the physiological decline rate is proportional to the reciprocal of the fluctuation constant as revealed in a diffusion equation. In addition, the maximum and mean life spans are proportional to the reciprocal of the decline rate. The framework involved in the fluctuation theory is compatible with the existence of a regulatory system such as that acting in the insulin/insulin-like growth factor-1 (IGF-1) signaling pathway during adulthood, and that sensing, switching, and memorizing the rate of mitochondrial respiration early in life. PMID- 17707466 TI - Hair analysis in sled dogs (Canis lupus familiaris) illustrates a linkage of mercury exposure along the Yukon River with human subsistence food systems. AB - The dog has been an important biomedical research model and hair samples from sled dogs could be used as a biomarker of exposure to metals. Hair samples were used as a non-invasive indicator of mercury exposure in sled dogs fed commercial food and traditional village diets. Sled dog populations living in rural New York and Alaska were sampled in 2005 and 2006. Total mercury (THg) content was determined on the entire hair sample in sled dogs from reference sites in North Creek, New York and Salcha Alaska. Both sites fed a commercial feed for high performance dogs and had mean THg levels of 36.6 ng/g for New York sled dogs while Alaskan sled dogs, occasionally supplemented with fish oil showed THg mean of 58.2 ng/g. These THg levels are below levels that are suggested to cause adverse effects and should be considered baseline levels. Yukon River sled dogs had higher THg, ranging from 139 to 15,800 ng/g and showed decreasing mean levels from the delta area to upriver. There were significant differences between THg in the dogs from Russian Mission (10,908.3+/-3028 ng/g), the farthest west village, and Ft. Yukon (1822.4+/-1747 ng/g), the farthest east village. All village dogs along the Yukon had higher THg levels than the THg mean level (657+/-273 ng/g) of hair from ancient dogs of the Seward Peninsula. PMID- 17707467 TI - Reading between the (Guidelines). Management of submassive pulmonary embolism in the first trimester of pregnancy. PMID- 17707468 TI - Distribution of androgen receptor and steroid hormone concentrations in ovaries of immature bank voles: effect of photoperiod. AB - Immunolocalisation of androgen receptor (AR) and steroid contents were analyzed in the ovaries of 7- and 14-day-old bank voles, reared in a long (LD) and short (SD) photoperiod. The strongest AR immunoreaction was found in the stromal cells, especially in the ovaries of 7-day-old animals, and in the granulosa cells of all types of ovarian follicles. Oocytes and the cells of surface epithelium were AR positive. The amount of ovarian androgens was relatively high, whereas the level of estradiol was negligible. This finding, and the presence of numerous ARs in various ovarian compartments, suggest that aromatization was very low during development and the primary function of androgens was hormonal action via a receptor-mediated pathway. Age- and photoperiod-related differences in ovarian progesterone (P4) levels were higher in animals kept in LD than in SD, rising significantly on day 14. Androgen content tended to be lower in LD voles and slightly decreased on day 14. Photoperiod-related differences concerning AR immunolabeling were apparent only in 14-day-old animals. In LD, ovaries already possessed early antral follicles, showing strong AR immunolabeling in the cumulus cells. Immunoreaction of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) showed that the primary interstitial and theca cells were the first to be active in ovarian steroidogenesis. In conclusion, AR is present in juvenile vole ovaries as early as day 7. The influence of the photoperiod on their number is observed beginning on day 14. Differences in steroid contents due to LD conditions occur in 7-day-old, and progresses in 14-day-old animals. PMID- 17707469 TI - Meningiomas of the falcotentorial junction: selection of the surgical approach according to the tumor type. AB - BACKGROUND: We retrospectively analyzed a series of patients harboring a FT meningioma with regard to clinical presentation, surgical technique, and follow up results. METHODS: Clinical data in a consecutive series of 13 patients treated for a meningioma of the FT junction were retrospectively reviewed. Tumors were classified into 4 types according to their dural origin and tumor extent as depicted from preoperative MRI. RESULTS: Main presenting symptom in 9 women and 4 men (mean age, 56 years) was headache (69%) and gait disturbance (54%). Clinical examination revealed gait ataxia in 62% of the patients. The tumor displaced the vein of Galen inferiorly in 6 patients, superiorly in 2, and medially in 5 cases. The main surgical approach to the meningioma was via an occipital interhemispheric route (10 patients). Additional resection of the falx and/or incision of the tentorium was performed in 6 cases each. A complete resection (Simpson grade 1 and 2) was achieved in 85% of patients. Permanent surgical morbidity was 23%. One tumor recurrence in an atypical meningioma was observed after the mean follow-up period of 6.2 years (range, 1-14 years) with clinical and MRI examination and had to be reoperated. Eighty-five percent of the patients regained full daily activity on follow-up. CONCLUSIONS: The surgical approach should be tailored to the dural origin and extent of the tumor as depicted from preoperative MRI. Preservation of the straight sinus and Galenic venous system is recommended. PMID- 17707470 TI - Imaging in the position that causes pain. AB - BACKGROUND: Magnetic resonance imaging has the diagnostic advantages of being noninvasive and able to visualize soft tissue. However, conventional recumbent MRI may underestimate a disease because the position of imaging takes stress off the spine. CASE DESCRIPTION: A 37-year-old woman presented with complaints of pain in the neck that radiated down her right arm when she turned her head to the right and increased with extension. She complained of paresthesias, numbness/tingling in the index and middle fingers and thumb, in the C6 and C7 nerve root dermatomes. Conventional conservative measures, including anti inflammatories, muscle relaxants, opiates, and physical therapy, had been tried without positive results. Magnetic resonance imaging was performed in a weight bearing upright neutral position, in the extended upright position, and in the extended upright position with the head turned to the right. The latter images showed a clear protrusion at C5-C6 and C6-C7. These protrusions were not clearly evident in the upright neutral position. A targeted epidural block at C5-C6 and C6-C7 relieved the patient's pain, and she has been able to continue work. CONCLUSIONS: Magnetic resonance imaging of the cervical spine in the position that causes the patient's symptoms may increase the sensitivity and accuracy of the diagnostic study and thus provide the spine-care professional with a potentially more accurate diagnosis and a targeted treatment plan. Such MRIs may also decrease the need for myelography. PMID- 17707476 TI - Continuation of poor surgical outcome after elderly brain injury. AB - BACKGROUND: In spite of the decline in mortality among trauma patients, with advanced trauma care, the outcome for elderly patients remains poor. Both operative and nonoperative outcome for elderly patients after head trauma has resisted improvement. METHODS: Forty-five consecutive patients 70 years or older were included in the study. All these patients were admitted from January 2000 to June 2005. Road-traffic accidents caused most of the head injuries. RESULTS: Most of the patients (n = 33) belonged to severe head injury category. Contusions were the commonest CT scan finding (n = 27), for which surgery was indicated. Unexplained clinical deterioration, in spite of timely surgery and satisfactory postoperative CT scans, in a significant number of patients (n = 29) was noteworthy. Over the same period, the comparative group of younger patients (20 40 years, n = 1026) was also analyzed. CONCLUSION: Elderly patients experienced higher mortality and poorer functional outcome. The natural history of traumatized brain among elderly patients remains unchanged till the present times. The nihilistic scenario asks for reevaluation of interventions, relook into the neurobiology of aging brain, and aggressive research for remedial measures for such patients, especially among severe head injury group. PMID- 17707477 TI - Dural arteriovenous fistula of the anterior cranial fossa associated with a ruptured ophthalmic aneurysm: case report and review of the literature. AB - BACKGROUND: Dural arteriovenous fistula (DAVF) accompanied by intracranial aneurysms is an extremely rare situation. CASE DESCRIPTION: A 65-year-old man presented with sudden loss of consciousness for about half an hour. Computed tomographic scan of the brain showed subarachnoid hemorrhage. Angiogram revealed an ophthalmic aneurysm. In addition, a DAVF located in the anterior cranial fossa was also found. The ruptured aneurysm was completely occluded by coil embolization and the DAVF of the anterior cranial fossa was treated with gamma knife radiosurgery after an uneventful postoperative course. The patient was managed nonoperatively and discharged with close follow-up. CONCLUSION: An unusual case of anterior cranial fossa DAVF associated with a ruptured ophthalmic aneurysm is reported. We feel special consideration may be required in deciding the priority of treatment in such cases. PMID- 17707480 TI - Sex steroid and epidermal growth factor profile of giant meningiomas associated with pregnancy. AB - BACKGROUND: An association between meningioma, breast cancer, and increased growth of meningiomas during pregnancy, and the luteal phase of the menstrual cycle have been shown in previous reports, but the mechanisms still remain unclear. These data suggest that sex steroids and growth factors may have a role in the growth of meningiomas. This is an important factor to consider during the development of more effective nonsurgical treatment options. METHODS: We described 3 patients with meningioma who presented during the early postpartum period. The lesions were completely resected, and immunohistochemical evaluation of PR, ER, EGF receptor, and Ki67 antigen was performed. RESULTS: Pathologic studies of tumor specimens revealed atypical meningioma (grade 2), syncytial meningioma (grade 1), and transitional-psammomatous meningioma (grade 1), for cases 1, 2, and 3, respectively. Immunohistochemical studies demonstrated positive PR staining in all of the cases, and there was no immunostaining for ER in any of the cases. Immunohistochemistry for EGF receptor showed membranous staining in less than 10% of the tumor cells, membranous staining in more than 50% of the tumor cells, and no staining in cases 1, 2, and 3, respectively. Immunohistochemistry for Ki67 resulted in positive staining in 20% of the tumor cells for case 1, 10% for case 2, and less than 5% for case 3. CONCLUSIONS: Although many reports indicating an association between meningioma and pregnancy have been published, the number of immunohistochemical studies is limited. This study suggested the importance of targeting the PR, Ki67 antigen, and EGF receptor in the development of nonsurgical therapeutic regimens. PMID- 17707481 TI - Unusual complications and presentations of intracranial abscess: experience of a single institution. AB - BACKGROUND: Complicating events and unusual presentations associated with intracranial abscess are rare but potentially fatal conditions. This study was undertaken to shed light on the unusual complications and presentations of intracranial abscess treated at a single institution. METHODS: We retrospectively reviewed 116 cases of intracranial abscesses that were treated at our institution over the last 10 years and identified 11 (9.4%) cases with unusual complications. RESULTS: These complications consisted of (1) rupture within the abscess, (2) hemorrhage into the abscess, (3) hemispheric infarction due to ICA thrombosis, (4) acute visual loss due to pituitary abscess, (5) acute neurologic deterioration due to rapid gas formation within the abscess, (6) acute hydrocephalus, (7) trigeminal neuralgia, (8) fungal abscess developing secondary to intracranial extension of a temporal bone tumor, (9) Cryptococcus abscess with different morphology, (10) pontine infarction, and (11) sigmoid sinus thrombosis. Sinusitis accompanied 8 (72.7%) of the cases, and there were 5 (45.4%) mortalities. Culture results were unyielding in 4 patients, whereas Streptococcus species were identified in 4 and fungi in the rest. CONCLUSION: Intracranial abscesses and their complications still continue to be challenging entities in the neurosurgical practice. Our experience may provide an informational source for those who are taking care of patients with intracranial abscess. PMID- 17707482 TI - Multiple brain hemorrhages and hematomas associated with ectopic fascioliasis in brain and eye. AB - BACKGROUND: Fascioliasis is a parasitic infection caused by Fasciola hepatica. Human beings can be infected accidentally by an ingestion of the metacercariae; and the parasite exists almost persistently in the bile ducts, but rarely in other organs. We report an interesting case of ectopic fascioliasis in both the brain and the right eye of a school-aged boy, which was associated with 2 unruptured intracranial aneurysms. To our knowledge, no case report such as this has been found in the medical literature. CASE DESCRIPTION: After an ingestion of Potamon denticulata (a fresh crab) for 4 months, a 10-year-old boy presented with neurologic manifestations caused by 5 episodes of intracranial hemorrhages and hematomas. The boy simultaneously suffered repeated affliction in the right eye accompanied by headache, vomiting, ophthalmalgia, exophthalmos, and abducens nerve palsy. Digital subtraction angiography revealed 2 unruptured intracranial aneurysms. The definitive diagnosis of this case had been confirmed by an observation of the parasite moving out of the patient's swelling conjunctiva and by the results of the laboratory tests. The patient was treated with praziquantel and completely recovered. The 2 aneurysms were not surgically treated but underwent a long-term follow-up. The follow-up DSA revealed that one aneurysm disappeared but the other remained unchanged. CONCLUSIONS: Multiple brain hemorrhages and hematomas can be associated with ectopic fascioliasis in brain and eyes. An intracranial infection occasionally caused by F hepatica or other parasites can be indicated by a fever of unknown origin, eosinophilia, and iterative intracranial hemorrhages. Ingestion of P denticulata may be an uncommon transmission route of fascioliasis. Fascioliasis can be successfully treated. PMID- 17707485 TI - Role of diffusion tensor imaging in a patient with spontaneous intracerebral hematoma treated by stereotactic evacuation. AB - BACKGROUND: Diffusion tensor imaging is a newly developed technique used to visualize the white matter fibers in the human brain. In previous reports, DTI has been applied in patients with neoplasms, lacunar infarction, ischemic stroke, degenerative motor disease, and diffuse axonal injury, and has become a powerful tool in predicting clinical outcome. However, the implementation of DTI in patients with spontaneous ICH treated by stereotactic evaluation of hematoma has never been reported. CASE DESCRIPTION: The authors describe a case of a well predicted outcome of DTI in a 37-year-old right-handed man who presented with sudden onset of vomiting and weakness of right extremities 2 hours before admission. Computed tomographic head scan revealed 1 hyperdense hematoma measuring about 3.9 x 2.2 x 2.6 cm (about 15 mL in volume) located in the left putamen, compressing the posterior limb of left internal capsule. Preoperative DTI revealed that white matter tracts were compressed by the hematomas. After the patient underwent stereotactic evacuation of hematoma, good recovery of muscle power was noted in the right extremities. Postoperative DTI revealed the restoration of white matter tracts. CONCLUSION: Diffuse tensor imaging is a useful tool for the visualization of white matter tracts, especially the corticospinal tract, which regulates motor function in human beings. In patients with ICH treated by stereotactic aspiration of hematomas, clinical outcome could be more precisely predicted by preoperative DTI. PMID- 17707489 TI - Double dural patch in decompressive craniectomy to preserve the temporal muscle: technical note. AB - BACKGROUND: In frontotemporal decompressive craniectomy and subsequent cranioplasty, temporal muscle damage is frequently observed as a result of surgical manipulation, lack of bone attachment, and prolonged muscle inactivity. We investigated the use of a double dural patch in decompressive craniectomy to favor the safe surgical dissection of the temporal muscle in the subsequent cranioplasty and reduce temporal muscle damage. METHODS: In 11 patients submitted to a decompressive craniectomy and duraplasty, a second (external) dural sheet was positioned to separate the inner dural patch from the temporal muscle. RESULTS: When bone repositioning was performed, the detachment of the deep temporal muscle surface, covered by the external dural sheet, was easy and fast, with reduced blood loss. All the muscle fibers were preserved. CONCLUSION: The technique described in this article reduces the damage to the temporal muscle and can improve the functional and cosmetic results after decompressive craniectomy and cranioplasty. PMID- 17707490 TI - Multiple intracranial cavernous malformations: clinical features and treatment. AB - BACKGROUND: Although patients with MCMs have increasingly been found in clinics, little has been focused on them. Thus, we intended to investigate these patients' clinical presentations, family history, radiological characters, and treatment strategy. METHODS: A retrospective review of the files and family investigations were conducted for 30 patients with MCMs. All patients underwent MRI examination. Symptomatic patients underwent the surgical treatment with image-guided technique. RESULTS: There were 19 male and 11 female patients with a total 79 lesions. The common presentations were seizures, hemorrhages, or focal neurological deficits. Nine patients had positive or doubtful family history. The FLAIR sequence of MRI showed the highest sensitivity in the detection of CM lesions. In 27 symptomatic patients with 69 lesions, total removal was achieved in 19 patients with 48 lesions. In the other 8 patients with 21 lesions, 13 lesions were removed. Preoperative symptoms were improved in 21 patients and unchanged in 5. Preoperative neurological deficits temporarily worsened in one, and a new onset of seizure occurred in other one; but both gradually improved during the follow-up period. Among 3 patients with asymptomatic MCMs, one patient had hemorrhage during the follow-up period and underwent surgical operation. CONCLUSIONS: Because a high frequency of family CM occurs in MCMs, a detailed family investigation is mandatory for each patient with MCM. Selection of higher sensitive MRI sequence would contribute to detection of more CM lesions. Microsurgery assisted with the neuroimaging techniques is the treatment of choice for symptomatic MCMs. PMID- 17707491 TI - Successful treatment of a giant isolated cerebral mucormycotic (zygomycotic) abscess using endoscopic debridement: case report and therapeutic considerations. AB - BACKGROUND: Cerebral mucormycosis without rhino-orbital or systemic involvement is an extremely rare condition mostly associated with parenteral drug abuse. CASE DESCRIPTION: We report the case of a 42-year-old woman who presented with hemiparesis of the left side and altered mental status. Neuroradiologic workup demonstrated an inflammatory lesion involving the right basal ganglia. Proton magnetic resonance spectroscopy demonstrated features consistent with a pyogenic abscess. Computed tomography-guided stereotactic biopsy led to the diagnosis of cerebral mucormycosis. Parenteral AMB-L treatment was conducted, but the patient worsened clinically, presenting with a complete hemiplegia, and cerebral magnetic resonance imaging (MRI) scans demonstrated a voluminous abscess formation. Then, under stereotactic guidance, a surgical endoscopic debridement of the abscess cavity associated with the placement of an Ommaya reservoir was performed. Systemic and intralesional treatment with AmB associated with an adjunctive immune therapy was conducted. At 3-year follow-up, the patient had recovered partially from her left hemiplegia, allowing her to walk without help, and cerebral MRI scans showed complete resorption of the abscess. CONCLUSION: Our good results suggest that surgical endoscopic debridement associated with intravenous and intracavitary antifungal therapy might be valuable in treating voluminous deep-seated mucormycotic lesions. PMID- 17707492 TI - Electrophysiologic and clinical data support the use of dorsal root entry zone myelotomy in syringosubarachnoid shunting for syringomyelia. AB - BACKGROUND: The objectives of this study were to correlate preoperative changes in SEPs with clinical sensory dysfunction and to establish their importance in planning the microsurgical approach, either by DM myelotomy or by DREZ myelotomy, for patients with syringomyelia. METHODS: In addition to conducting clinical sensory examination, we evaluated the N13 potential after median nerve stimulation and CPs after tibial nerve stimulation intraoperatively before performing myelotomy on patients with syringomyelia (N = 14). RESULTS: Eleven patients with intact DS presented with unilateral PTD, and 9 had distressing unilateral dermatomal pain. Deep sensibility was affected in 3 patients (bilaterally in 1 patient) without PTD. Patients with PTD were likely to have spontaneous pain (P = .005). A significant correlation between preoperative PTD and the absence of the N13 potential was demonstrated on the right (P = .015) and left (P = .004) sides. In patients with PTD, DREZ myelotomy on the symptomatic side is suggested as the treatment of choice, whereas DM myelotomy might be superior in patients without PTD. CONCLUSIONS: Absence of pain or temperature sensation in patients with syringomyelia is usually accompanied by same-sided loss of the N13 potential, suggesting damage to the DH gray matter. Deep sensibility is typically normal, and DREZ myelotomy with preservation of DCs is proposed as the treatment of choice. Conducted potentials are usually distorted in patients with normal pain or temperature sensation and affected vibration and posture sensation, suggesting damage to DCs and making DM myelotomy the treatment of choice. Electrophysiologic and clinical data support the use of DREZ myelotomy in syringosubarachnoid shunting for syringomyelia in patients whose DCs have an intact function. PMID- 17707493 TI - Risk factors related to hydrocephalus after traumatic subarachnoid hemorrhage. AB - BACKGROUND: Posttraumatic hydrocephalus is a common complication of head injury. However, hydrocephalus after tSAH has seldom been addressed. We present this clinical study to determine the incidence of hydrocephalus and analyze the risk factors for developing hydrocephalus in patients with tSAH. METHODS: A consecutive series of 301 patients with tSAH were retrospectively reviewed to determine the effects of the admission GCS score, age, sex, decompressive craniectomy, intraventricular hemorrhage, and features of tSAH (according to the initial computerized tomography scans) on the development of hydrocephalus. Risk factors for hydrocephalus were evaluated by using logistic regression analysis. RESULTS: Of the 301 patients, hydrocephalus was observed in 36 (11.96%). Increasing age (P< .05), intraventricular hemorrhage (P< .05), and thickness (P< .01) or distribution (P< .05) of tSAH were significantly associated with the development of hydrocephalus. No relationship was found between hydrocephalus and sex, admission GCS score, location of tSAH, or decompressive craniectomy. CONCLUSION: Hydrocephalus frequently occurs in patients with tSAH. Increasing age, low GCS score on admission, intraventricular hemorrhage, and severe SAH could be risk factors for facilitating the development of hydrocephalus. PMID- 17707495 TI - Impact of a new bicycle path on physical activity. PMID- 17707496 TI - Knowledge and perceptions regarding colorectal cancer screening among Chinese--a community-based survey in Singapore. AB - OBJECTIVE: Despite the increase in colorectal cancer (CRC) incidence among Chinese in Asia, there are no data on predictors of CRC screening uptake in this population. This study investigated how knowledge and perceptions about CRC correlated with screening behavior in Singaporean-Chinese. METHODS: A community based cross-sectional study was carried out on Singaporean-Chinese at least 50 years old in Queenstown Estate, Singapore between 1/1/2006 and 1/2/2006. A questionnaire administered via face-to-face interviews elicited knowledge, perceptions and screening behavior of subjects. RESULTS: The response rate was 72.4%, with 514 completed responses. Expense was the commonest perceived barrier to screening (56.6% agreed), unlike for other populations. Social influence is important, with 67.5% agreeing to the statement "I would go for CRC screening if my family wanted me to". After excluding confounders, Chinese who had been for fecal occult blood test (FOBT) screening had higher knowledge score (p<0.001), lower perceived severity (p<0.01), were more likely to have been influenced by their family/friends to go for screening (p=0.04) and to have attended screening tests for other diseases (p<0.001). CONCLUSION: FOBT screening uptake is associated with specific areas of knowledge and perception among Singaporean Chinese. To increase screening uptake within Chinese populations, clinicians should consider these factors in their approach to patients. PMID- 17707494 TI - Higher locomotor response to cocaine in female (vs. male) rats selectively bred for high (HiS) and low (LoS) saccharin intake. AB - Rats selectively bred for high saccharin consumption (HiS) self-administer more oral ethanol and i.v. cocaine than those selectively bred for low saccharin consumption (LoS). Male and female drug-seeking-prone (HiS) and -resistant (LoS) rats were used in the present experiment to test the prediction that cocaine induced locomotor activity and sensitization varied with sex and their selective breeding status (HiS and LoS). All rats were intermittently exposed over 2 weeks to pairs of sequential saline and cocaine injections, separated by 45 min. The first 5 pairs of injections, each separated by 2-3 days (10-12 days total), were given to examine the development of cocaine-induced locomotor activity and the development of locomotor sensitization, which was determined by comparing the effects of cocaine injection 1 with injection 6 (given 2 weeks after the 5 pairs of intermittent injections). Results indicated that after the first injection pair (saline, cocaine) the HiS and LoS groups did not differ (saline vs. cocaine) in locomotor activity; however, after cocaine injection pairs 1, 5, and 6, HiS females were more active than HiS males and LoS females. There were also significant phenotype differences (HiS>LoS) in locomotor activity after cocaine injections 5 and 6. There was a weak sensitization effect in cocaine-induced locomotor activity in HiS females after cocaine injection 5 (compared to 1); however it was not present after injection 6 or in other groups. The lack of a strong sensitization effect under these temporal and dose conditions was inconsistent with previous reports. However, the results showing HiS>LoS and females>males on cocaine-induced activity measures are consistent with several measures of cocaine-seeking behavior (acquisition, maintenance, escalation, extinction, and reinstatement), and they suggest that cocaine-induced locomotor activity and sensitization are behavioral markers of drug-seeking phenotypes. PMID- 17707497 TI - Ten-year comparison of estimates of overweight and obesity, diagnosed diabetes and use of office-based physician services for treatment of diabetes in the United States. AB - OBJECTIVE: To compare trends in the prevalence of overweight and obesity, diagnosed diabetes and numbers of visits to office-based physicians for diabetes care. RESEARCH DESIGN AND METHODS: Data from the Behavioral Risk Factor Surveillance System and the National Ambulatory Medical Care Survey (1995-2004) were used to compare trends among adults aged 18 years and older for overweight, obesity and visits made to office-based physicians where diabetes was the primary diagnosis. Estimates for overweight and obesity and office visits were made for each year. RESULTS: The prevalence of overweight and obesity increased by nearly 24%. The prevalence of diabetes increased by approximately 76%. The numbers of visits to office-based physicians where diabetes was the primary diagnosis have more than doubled. The average age among adults, who were overweight or obese, was 46.9 years compared to 60.1 years for those seeking care for a diabetes related issue from an office-based physician. CONCLUSIONS: As the prevalence of overweight and obesity increases, the incidence of diabetes will increase along with the demand for treatment of diabetes later in life. It is imperative to promote population-based programs for reducing overweight and obesity at younger ages in order to reduce the morbidity, mortality and economic cost of the disease as the population ages. PMID- 17707498 TI - Physical activity level and health-related quality of life in the general adult population: a systematic review. AB - OBJECTIVE: Little is known regarding health-related quality of life and its relation with physical activity level in the general population. Our primary objective was to systematically review data examining this relationship. METHODS: We systematically searched MEDLINE, EMBASE, CINAHL, and PsycINFO for health related quality of life and physical activity related keywords in titles, abstracts, or indexing fields. RESULTS: From 1426 retrieved references, 55 citations were judged to require further evaluation. Fourteen studies were retained for data extraction and analysis; seven were cross-sectional studies, two were cohort studies, four were randomized controlled trials and one used a combined cross sectional and longitudinal design. Thirteen different methods of physical activity assessment were used. Most health-related quality of life instruments related to the Medical Outcome Study SF-36 questionnaire. Cross sectional studies showed a consistently positive association between self reported physical activity and health-related quality of life. The largest cross sectional study reported an adjusted odds ratio of "having 14 or more unhealthy days" during the previous month to be 0.40 (95% Confidence Interval 0.36-0.45) for those meeting recommended levels of physical activity compared to inactive subjects. Cohort studies and randomized controlled trials tended to show a positive effect of physical activity on health-related quality of life, but similar to the cross-sectional studies, had methodological limitations. CONCLUSION: Cross-sectional data showed a consistently positive association between physical activity level and health-related quality of life. Limited evidence from randomized controlled trials and cohort studies precludes a definitive statement about the nature of this association. PMID- 17707499 TI - The impact of socioeconomic level on influenza vaccination among Italian adults and elderly: a cross-sectional study. AB - OBJECTIVE: To assess the predictive factors of influenza vaccination among Italian adults, focusing on socioeconomic differences. METHODS: A cross-sectional study was carried out using interview and self-reported data on 102,095 subjects aged 25-89 years from the national survey "health conditions and health care services use" conducted in Italy in 1999-2000. Analyses were stratified by age and multiple logistic regression models were used to estimate odds ratios (OR) of influenza vaccination. RESULTS: Approximately one in six individuals (17.3%) received an influenza vaccine in the previous 12 months. Older age, poor health status and former smoking were all positively associated with influenza vaccination (P-value<0.05). Lower educated individuals and subjects with manual occupations were less likely to be vaccinated than those better off, with an OR ranging from 0.65 (95% CI 0.55, 0.77) to 0.82 (95% CI 0.71, 0.93). Among individuals aged 65-89 there was no apparent influence of both variables on the likelihood of receiving the influenza vaccine. CONCLUSIONS: Socioeconomic inequalities in influenza vaccine uptake were present among the adults but not among the elderly. Because in Italy the National Health Service provides influenza vaccination to the elderly free of charge, it is possible that this policy attenuated the socioeconomic differential. PMID- 17707500 TI - 'Does Broca's area exist?' Christofredo Jakob's 1906 response to Pierre Marie's holistic stance. AB - In 1906, Pierre Marie triggered a heated controversy and an exchange of articles with Jules Dejerine over the localization of language functions in the human brain. The debate spread internationally. One of the timeliest responses, that appeared in print 1 month after Marie's paper, came from Christofredo Jakob, a Bavarian-born neuropathologist working in Buenos Aires. The present study comprises an English translation of Jakob's 1906 paper and a discussion of Jakob's ideas on the localizationist-holistic approach regarding the role of Broca's area. This issue is still at the core of scientific debate in the light of current neuropsychological and neuroimaging findings. PMID- 17707501 TI - Does Donglan lacquer tree belong to Rhus vernicifera species? AB - The lacquer trees in Donglan of Guangxi Province, China, were identified totally as the species Rhus succedanea found in Vietnam and Taiwan region, based on the results of pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS), an easy and effective method to identify species of trees among those with similar properties. Analyses by IR and NMR, the drying properties, and conventional morphology also confirmed that the Donglan lacquer trees do not belong to Rhus vernicifera, like most trees of the China mainland. Some differences, however, such as the enzymatic activity and the components of the lacquer, were found between the Donglan lacquer and the Vietnam lacquer. The Donglan lacquer has a shorter drying time than the latter. PMID- 17707502 TI - Microengineered hydrogels for tissue engineering. AB - Hydrogels have been extensively used in various biomedical applications such as drug delivery and biosensing. More recently the ability to engineer the size and shape of biologically relevant hydrogels has generated new opportunities in addressing challenges in tissue engineering such as vascularization, tissue architecture and cell seeding. Here, we discuss the use of microengineered hydrogels for tissue engineering applications. We will initially provide an overview of the various approaches that can be used to synthesize hydrogels with controlled features and will subsequently discuss the emerging applications of these hydrogels. PMID- 17707504 TI - NAADP+ is an agonist of the human P2Y11 purinergic receptor. AB - Nicotinic acid adenine dinucleotide phosphate (NAADP+) is an intracellular second messenger releasing Ca2+ from intracellular stores in different cell types. In addition, it is also active in triggering [Ca2+](i) increase when applied extracellularly and various underlying mechanisms have been proposed. Here, we used hP2Y(11)-transfected 1321N1 astrocytoma cells to unequivocally establish whether extracellular NAADP+ is an agonist of the P2Y(11) receptor, as previously reported for beta-NAD+ [I. Moreschi, S. Bruzzone, R.A. Nicholas, et al., Extracellular NAD+ is an agonist of the human P2Y11 purinergic receptor in human granulocytes, J. Biol. Chem. 281 (2006) 31419-31429]. Extracellular NAADP+ triggered a concentration-dependent two-step elevation of [Ca2+](i) in 1321N1 hP2Y(11) cells, but not in wild-type 1321N1 cells, secondary to the intracellular production of IP(3), cAMP and cyclic ADP-ribose (cADPR). Specifically, the transient [Ca2+](i) rise proved to be related to IP(3) overproduction and to consequent Ca2+ mobilization, while the sustained [Ca2+](i) elevation was caused by the cAMP/ADP-ribosyl cyclase (ADPRC)/cADPR signalling cascade and by influx of extracellular Ca2+. In human granulocytes, endogenous P2Y(11) proved to be responsible for the NAADP+-induced cell activation (as demonstrated by the use of NF157, a selective and potent inhibitor of P2Y(11)), unveiling a role of NAADP+ as a pro-inflammatory cytokine. In conclusion, we provide unequivocal evidence for the activation of a member of the P2Y receptor subfamily by NAADP+. PMID- 17707503 TI - Targeted binding of PLA microparticles with lipid-PEG-tethered ligands. AB - Solid core polymeric particles are an attractive delivery vehicle as they can efficiently encapsulate drugs of different physical and chemical characteristics. However, the effective targeting of such particles for therapeutic purposes has been somewhat elusive. Here, we report novel polymeric particles comprised of poly(lactic acid) (PLA) with incorporated poly(ethylene glycol)-lipids (PEG lipids). Particles are characterized for morphology, surface charge, and composition with field-emission scanning electron microscopy (FESEM), zeta potential measurements, and proton nuclear magnetic resonance ((1)H NMR) spectroscopy, respectively. The surface densities of PEG lipids determined by (1)H NMR and particle size distributions are consistent with scaling theory for adsorption of chains onto a surface. We observe significant binding of liganded PEG-lipid tethers when the molecular weight is greater than the unliganded PEG lipids for significant binding events. Importantly, the binding is not completely lost when the unliganded PEG molecular weight is greater than the liganded PEG lipid tether. We observe a similar trend for the lower affinity ligand (thioctic acid), but the degree of binding is significantly lower than the high affinity ligand (biotin). This novel technique used to fabricate these liganded particles combined with the lipid bilayer binding studies provides a platform for systematic optimization of particle binding. PMID- 17707505 TI - Dynamic regulation of ryanodine receptor type 1 (RyR1) channel activity by Homer 1. AB - Homer, a family of scaffolding proteins originally identified in neurons, is also expressed in skeletal muscle. Previous studies showed that splice variants of Homer 1 (H1) amplify the gain of the ryanodine receptor type 1 (RyR1) channel complex. Using [3H]ryanodine ([3H]Ry) to probe the conformational state of RyR1, the actions of long- and short-forms of H1 are examined singly and in combination. At < or =200 nM, H1 long-forms (H1b or H1c possessing coiled-coil (CC) domains) and short-forms (H1a or H1EVH1 lacking CC domains) enhance specific [3H]Ry binding to RyR1. However, at a concentration > 200 nM, either H1 form completely inhibited [3H]Ry binding. Importantly, the combinations of H1c+H1EVH1, or H1b+H1a acted in an additive manner to enhance or inhibit [3H]Ry-binding activity. H1a and H1c individually or in combination produced the same dynamic pattern in regulating purified RyR1 channels reconstituted in planar lipid bilayers. In combination, their net action on RyR1 channels depends on total concentrations of H1. These data provide a mechanism by which constitutively and transiently expressed H1 forms can tightly regulate RyR1 channel activity in response to changing levels of expression and degradation of H1 proteins. PMID- 17707507 TI - Aspects of vaccine development. Introduction. PMID- 17707506 TI - Hailey-Hailey disease from a clinical perspective. PMID- 17707508 TI - Mechanisms underlying embodiment, disembodiment and loss of embodiment. AB - Bodily experience is a complex, mostly unconscious, process that requires the integration of multiple sensory inputs. This paper reviews the sensory systems involved in internal representations of the body--primarily the proprioceptive, motor, vestibular, and visual systems. Various neurological disorders are defined by aberrations in bodily experience--including the perceptual ablation or disembodiment of body parts, "filling in" of amputated body parts, or reduplication of body parts. These perceptual aberrations are discussed and their implications for the central and peripheral systems involved in updating and retrieving internal representations of the body are highlighted. Bodily perception and egocentric frames of reference can be experimentally manipulated through visual capture (e.g., using rubber limbs), functional adaptation and embodiment of tools and prostheses, and changes in afferent sensory feedback (e.g., through stimulation of muscle spindles). These perceptual illusions are described, and discussed for their implications for the mechanisms underlying bodily perception. PMID- 17707510 TI - Thermodynamic analysis of additivity between the heavy and light chains in affinity maturation of an antibody. AB - In a recent article published in Molecular Immunology [Furukawa, K., Shimizu, T., Murakami, A., Kono, R., Nakagawa, M., Sagawa, T., Yamato, I., Azuma, T., 2007. Strategy for affinity maturation of an antibody with high evolvability to (4 hydroxy-3-nitrophenyl) acetyl hapten. Mol. Immunol. 44, 2436-2445], the authors measure thermodynamic parameters of the antigen-antibody interaction for a set of antibodies using an isothermal titration calorimetry to quantitatively assess the contribution of amino acid replacements to an increase in affinity during antibody maturation. One of the findings in their study is that the binding free energy change elicited by mutations in the heavy and light chains is additive. In this letter, we report our analysis of their results in terms of equilibrium thermodynamics to show that enthalpy-entropy compensation is responsible for the additivity. PMID- 17707511 TI - Postnatal lead poisoning impairs behavioral recovery following brain damage. AB - Lead is a potent environmental toxicant with well-known effects on intelligence, school achievement and behavior. Lead exposure is also associated with an increased risk of a variety of health problems including cancer, hypertension, cardiovascular disease, and renal disease. Considering the risk of hypertension, cardiovascular problems, and stroke following lead exposure, the current research assessed the extent to which postnatal exposure to environmentally relevant levels of lead could impair the recovery from a later occurring brain injury. Using a photochemical thrombotic stroke model we found that postnatal lead exposure significantly impaired post-stroke recovery of beam walking ability and proprioceptive limb placing. Considering the increased risk for hypertension and cardiovascular disease in lead-exposed humans, diminished capacity for repair or adaptation following lead exposure needs to now be examined in greater detail. PMID- 17707509 TI - Paratope diversity in the human antibody response to Bacillus anthracis protective antigen. AB - The active component of the licensed human anthrax vaccine (BioThrax, or AVA) is a Bacillus anthracis toxin known as protective antigen (PA). Second generation anthrax vaccines currently under development are also based on a recombinant form of PA. Since the current and future anthrax vaccines are based on this toxin, it is important that the immunobiology of this protein in vaccinated humans be understood in detail. We have isolated and analyzed the PA-specific antibody repertoire from an AVA-vaccinated individual. When examined at the clonal level, we find an antibody response that is complex in terms of the combinatorial elements and immunoglobulin variable genes employed. All PA-specific antibodies had undergone somatic hypermutation and class switch recombination, both signs of affinity maturation. Although the antigenic epitopes recognized by the response were distributed throughout the PA monomer, the majority of antibodies arising in this individual following vaccination recognize determinants located on the amino terminal (PA20) sub-domain of the molecule. This latter finding may have implications for the rational design of future PA-based anthrax vaccines. PMID- 17707512 TI - The influence of lying positions and postural control on hand-mouth and hand-hand behaviors in 0-4-month-old infants. AB - The purpose of this study was to verify how and when body position and postural control affect hand-mouth and hand-hand behaviors in infants during their first 4 months of life. Forty healthy infants were positioned in supine, prone and side lying positions so that frequency and duration of the behaviors were quantified. Postural control when in supine and prone was also analyzed. The prone position elicited hand-mouth behavior in 0-2-month-old infants. The side-lying position elicited hand-mouth behavior in 3-4-month-old infants and hand-hand behavior in 2 4-month-olds. The increased postural control promoted the emergence of hand-hand behavior when in supine, and decreased hand-mouth behavior when in prone. The results show that self-exploratory behaviors may be affected not only by extrinsic constraints, represented by different body positions, but also by intrinsic constraints, represented by characteristic action possibilities and postural control of each age group. PMID- 17707513 TI - Self medication with St. John's wort in depressive disorders: an observational study in community pharmacies. AB - BACKGROUND: Depressive disorders are frequent. They are frequently unrecognised or sufferers use self help or self medication, e.g. with St. John's wort (SJW), instead of seeking professional help. The purpose of this study is to examine patients who buy SJW for the treatment of depression. METHODS: In pharmacies from all over Germany customers who bought SJW and the pharmacists were asked to fill in a questionnaire on the cause for buying SJW, their health status and the type of counselling they received. RESULTS: 588 individuals were included, 293 purchased SJW as an OTC preparation, 230 had a prescription (65 missing answers). The majority in both groups were women (78.8% in OTC group, 74.3% in prescription group. Self medication patients were significantly younger. Subjects with a prescription took SJW longer (26.99+/-26.84 vs. 15.25+/-20.84 months). Both groups did not differ in self rated symptoms of depression (severity of depression, anxiety, endurance). LIMITATIONS: No standardized interviews were used to establish the diagnosis of depression. CONCLUSIONS: Patients who buy SJW for self medication report pronounced and persistent depressive symptoms. As this is a large group of patients they should get more attention in research. Pharmacists are the only professionals who come in contact with these patients and should therefore be considered as an important group of carers. PMID- 17707514 TI - Monthly variation in prevalence rates of comorbid depression and anxiety in the general population at 63-65 degrees North: the HUNT study. AB - BACKGROUND: To investigate monthly variation in depression, anxiety and their comorbidity (COM) in an epidemiologic study and their association to monthly variation in suicide rates. METHODS: 60,995 participants of the Health Study of Nord-Trondelag County in 1995-97 rated themselves on the Hospital Anxiety and Depression Scale (HADS) in all months except July. All 10,670 male and 3833 female suicides in Norway from 1969 through 1996 were included. RESULTS: The prevalence of comorbid anxiety and depression was highest in spring (April, May) and in October (p<0.01). There was a correlation between the monthly variation in the national suicide rate and monthly variation in comorbid anxiety and depression (r=0.72, df=11, p=0.01) and for male alone (r=0.67, df=11, p=0.03). There was also a significant monthly variation in the prevalence of depression (p<0.001) and no monthly variation in the prevalence of anxiety. LIMITATIONS: Limited information about the third of the population who did not take part in the HUNT-2 Study. HADS based depression and anxiety cover psychological symptoms, not somatic and social ones. In relation to DSM-IV and ICD-10 defined anxiety disorders and depressions, the sensitivity and specificity of HADS caseness, give a considerable number of false-positive cases. CONCLUSIONS: Increased prevalence of comorbid depression and anxiety in males during spring, and its association with suicidality should have clinical importance, as identification and treatment could influence suicide rates. PMID- 17707515 TI - Risk factors for anxiety and depression in the elderly: a review. AB - BACKGROUND: Although a number of studies have examined risk factors for anxiety and depression at a later age, there have been no systematic comparisons of risk profiles across studies. Knowledge on such risk profiles may further our understanding of both the etiology and early recognition of these highly prevalent disorders. This paper gives a comprehensive overview and compares risk factors associated with anxiety and depression in the elderly. METHODS: The databases MEDLINE, PsycINFO and Sociological Abstracts were systematically searched, and relevant English-language articles from January 1995 to December 2005 were reviewed. Cross-sectional and longitudinal studies on risk factors in elderly from a community or primary care setting were included. The associations between risk factors and pure anxiety or depressive symptoms or disorders were summarized and compared. RESULTS: The abstracted risk factors from studies on anxiety (N=17) and depression (N=71) were clustered into the categories biological, psychological and social. Although risk factors for anxiety and depression showed many similarities, some differences were found. Biological factors may be more important in predicting depression, and a differential effect of social factors on depression and anxiety was found. LIMITATION: Due to a high heterogeneity between studies, no meta-analysis could be conducted. CONCLUSIONS: There is considerable overlap between the risk profiles for anxiety and depression in the elderly, which suggests a dimensional approach on the interrelationship between anxiety and depression is more appropriate. To improve the recognition and preventive mental health programs, a clearer understanding of differentiating etiological factors will be needed. PMID- 17707516 TI - Decision-making and neuroendocrine responses in pathological gamblers. AB - Recent neuropsychological research indicates that patients with pathological gambling (PG) exhibit deficits in laboratory tasks of decision-making which are suggested to be associated with neurochemical alterations within the prefrontal cortex. Some studies also revealed that hypothalamic-pituitary-adrenal axis activity in gamblers is altered. To date, very little is known about the relationship between decision-making and neuroendocrine parameters. Therefore, we examined patients with PG (n = 22) and healthy comparison subjects (n = 19) with a laboratory task of decision-making (Game of Dice Task) and sampled salivary cortisol and alpha-amylase (sAA) concentrations before and in the course of task performance. Results showed that the PG patients' neuroendocrine responses were comparable to those of the healthy subjects, even though the patients had severe decision-making deficits. Within both groups, there were no changes in cortisol and sAA responses. However, correlations and a subgroup analysis for sAA revealed that only those patients who showed less disadvantageous decision-making patterns had an increase of sAA during the task. Accordingly, the increase of sAA--as an indirect marker of sympathetic nervous system activity--in those patients with less severe decision-making deficits could reflect the use of somatic markers biasing the decision-making process. PMID- 17707517 TI - Cross-reactivity of human leukocyte differentiation antigen monoclonal antibodies on carp and rainbow trout cells. AB - Three hundred and seventy-seven monoclonal antibodies (mabs) directed against human CD antigens and non-classified human leukocyte surface antigens were assayed for their reactivity with common carp (Cyprinus carpio L.) and rainbow trout (Oncorhynchus mykiss) peripheral blood leukocytes (PBL) and thymocytes within the animal homologue section of the 8th International Workshop on Human Leukocyte Differentiation Antigens (HLDA8). Four of the mabs clearly reacted with rainbow trout PBL and two with carp PBL. Positive mabs were investigated further by two-colour flow cytometry with established mabs directed against carp and rainbow trout leukocyte subpopulations. None of these mabs were suitable for Western blotting and immunoprecipitation. Three mabs were found to stain cells in fixed cryostate sections of the lymphatic organs thymus, pronephros and spleen. In this study, for the first time an anti-CD14 mab was found to cross-react with fish cells. This mab could be a valuable tool complementing the limited toolbox of population-specific mabs in fish. The low number of cross-reactive mabs analyzed in this workshop is another indication for the great phylogenetic difference between mammals and osteichthyes. PMID- 17707518 TI - Screening of anti-human leukocyte monoclonal antibodies for reactivity with equine leukocytes. AB - Three hundred and seventy-nine monoclonal antibodies (mAbs) against various human CD molecules supplied to the HLDA8 animal homologues section (including four isotype controls) were analysed for cross-reactivity with equine leukocytes. First, flow cytometric identification of positively reacting mAbs was performed in one laboratory. Thereafter, a second round of flow cytometric evaluation was performed, involving three laboratories participating in the study. The first test-round indicated 17 mAbs as potentially positive. After the second round of flow cytometric analysis, 14 mAbs remained (directed against CD2, CD11a, CD18, CD44, CD45, CD49d, CD91, CD163 and CD172) where cross-reactivity was anticipated based on similarities between the human and equine staining pattern. Additionally, there was 1 mAb with weak likely positive reactivity, 12 mAbs with positive staining, which likely do not reflect valuable data, 5 mAbs with clear alternate expression pattern from that expected from humans, 5 mAbs with a questionable staining pattern itself, i.e. that was variable between the three labs, 32 mAbs with weak-positive expression and alternate staining pattern, and 279 negative mAbs (including the four isotype controls) were detected. In 31 cases, more appropriate target cells, such as thymocytes or stem cells, were not available for the screening. The results underline the value of this "cross reactivity" approach for equine immunology. However, as only a few mAbs against leukocyte surface antigens reacted positively (approximately 4% of the mAbs submitted), the analysis of further anti-human mAbs and directed efforts to develop species-specific anti-CD mAb are still required. PMID- 17707519 TI - A RealTime HIV-1 viral load assay for automated quantitation of HIV-1 RNA in genetically diverse group M subtypes A-H, group O and group N samples. AB - The Abbott RealTime HIV-1 assay is an automated test for monitoring HIV-1 viral load in plasma samples. The assay uses reverse transcription polymerase chain reaction (RT-PCR) technology with homogeneous real-time fluorescent detection. Automated sample preparation is performed on the m2000sp instrument where RNA is isolated using magnetic microparticle technology and dispensed to a PCR tray together with the amplification reagents. The PCR tray is then transferred to the Abbott m2000rt instrument for amplification and real-time detection. The assay utilizes two distinct sets of primers and probes for HIV-1 and for internal control (IC). The IC is processed along with each sample to control for sample recovery and inhibition. The HIV-1 primer and probe sequences are targeted to the integrase (IN) region of the polymerase (pol) gene. Due to the selection of a highly conserved target region and a novel, mismatch tolerant probe design, the assay can quantitate HIV-1 group M subtypes A-H, group O, and group N isolates. The assay provides high reproducibility and a wide dynamic range, allowing quantitation from 40 copies to 10 million copies of HIV-1 RNA per milliliter of plasma. HIV-1 RNA concentrations detected with 95% probability were 25copies/mL with 1.0mL of plasma, 39copies/mL with 0.6mL of plasma, 65copies/mL with 0.5mL of plasma, and 119copies/mL with 0.2mL of plasma. PMID- 17707521 TI - Age-dependent effects of environmental enrichment on spatial reference memory in male mice. AB - Although environmental enrichment has been shown to improve various types of memory in young and aging mice, no study has directly compared the degree to which enrichment improves memory at different ages throughout the lifespan in male mice. Therefore, the present study investigated the effects of long-term continuous enrichment in young (3 months), middle-aged (15 months), and aged (21 months) male C57BL/6 mice. Spatial reference memory was tested in the Morris water maze. Results demonstrate that 24h/day environmental enrichment for approximately 6 weeks significantly improved spatial memory in the Morris water maze in aged males, but not in young or middle-aged males. These data also indicate that 24h exposure to complex enriched housing conditions increases the magnitude of enrichment-induced improvements in memory among aged mice relative to those previously reported by this lab and others. PMID- 17707522 TI - Quantification of shoaling behaviour in zebrafish (Danio rerio). AB - Zebrafish has been a favourite of developmental biologists and numerous genetic tools have been developed for this species. In recent years, zebrafish has become an increasingly popular subject of neuroscientists and behavioural scientists. One of the typical characteristics of zebrafish is shoaling, individuals forming a tight group in which fish swim together. The biological mechanisms of social behaviours are complex and not well understood in vertebrates, and zebrafish, due to its highly social nature and the genetic tools developed for it, may represent an excellent animal model with which these mechanisms may be studied. Improvement of behavioural quantification methods would facilitate research in this area. We describe a custom software application that allows the precise quantification of several parameters of group cohesion in zebrafish. We also present three experimental examples to illuminate the use of our methodology, and show how group cohesion changes in response to manipulations of the environment. PMID- 17707523 TI - Regulation of prostaglandin E synthases: effects of siRNA-mediated inhibition of microsomal prostaglandin E synthase-1. AB - Prostaglandin E2 (PGE2) is a key mediator involved in several inflammatory conditions. In this study, we investigated the expression and regulation of the terminal PGE2 synthesizing enzyme prostaglandin E synthases (mPGES-1, mPGES-2 and cPGES) in gingival fibroblasts stimulated with pro-inflammatory cytokines. We used siRNA knockdown of mPGES-1 to elucidate the impact of mPGES-1 inhibition on mPGES-2 and cPGES expression, as well as on PGE2 production. The cytokines TNFalpha and IL-1beta increased protein expression and activity of mPGES-1, accompanied by increased COX-2 expression and PGE2 production. The isoenzymes mPGES-2 and cPGES, constitutively expressed at mRNA and protein levels, were unaffected by the pro-inflammatory cytokines. We show for the first time that treatment with mPGES-1 siRNA down-regulated the cytokine-induced mPGES-1 protein expression and activity. Interestingly, mPGES-1 siRNA did not affect the cytokine stimulated PGE2 production, whereas PGF(2alpha) levels were enhanced. Neither mPGES-2 nor cPGES expression was affected by siRNA silencing of mPGES-1. Dexamethasone and MK-886 both inhibited the cytokine-induced mPGES-1 expression while mPGES-2 and cPGES expression remained unaffected. In conclusion, mPGES-1 siRNA down-regulates mPGES-1 expression, and neither mPGES-2 nor cPGES substituted for mPGES-1 in a knockdown setting in gingival fibroblasts. Moreover, mPGES-1 siRNA did not affect PGE2 levels, whereas PGF(2alpha) increased, suggesting a compensatory pathway of PGE2 synthesis when mPGES-1 is knocked down. PMID- 17707520 TI - Interactions among ovarian hormones and time of testing on behavioral sensitization and cocaine self-administration. AB - Ovarian hormones play a role in the use of drugs of abuse in women. In female rats estradiol has been shown to enhance acquisition of cocaine self administration and behavioral sensitization induced by repeated cocaine treatment. Experiments were conducted to determine the effects of estradiol and/or progesterone on cocaine self-administration and behavioral sensitization to cocaine (10mg/kg; in animals with unilateral 6-hydroxydopamine lesions). Five groups of ovariectomized females were tested: (1) oil vehicle; (2) estradiol (E); (3) progesterone (P); (4) estradiol and progesterone given concurrently (EPC); (5) estradiol and progesterone given sequentially (EPS: 3 days of estradiol, 1 day progesterone, 1 day oil). All animals were tested during the dark phase of the light:dark cycle at ZT1600 and ZT2000-2100. Behavioral sensitization results: there was substantial conditioned turning throughout the habituation periods, and all animals exhibited behavioral sensitization with repeated cocaine treatment. Multivariate analysis indicated a significant effect of hormone treatment, time of day and day of testing. When individual groups were compared, however, only at ZT1600 did the E-treated and the EPS-treated animals show a trend (p<0.06) for greater behavioral sensitization to cocaine relative to the oil-treated animals. Self-administration results: all groups showed rapid acquisition of cocaine self administration at 0.3 mg/kg/infusion, so we did not see an effect of ovarian hormones on acquisition, or a difference between groups tested at ZT1600 versus ZT2100 (p<0.05). There was, however, enhanced total intake of cocaine at 0.75 mg/kg/infusion in the E and the EPS groups. Concurrent administration of progesterone with estradiol counteracted the effect of estradiol on cocaine intake at 0.75 mg/kg/infusion, while progesterone alone did not enhance cocaine self-administration. PMID- 17707524 TI - Incremental prevalence of fractionated and inhomogeneous propagation of sinus impulses with increasing atrial depolarization abnormality among outpatients. AB - INTRODUCTION: Prolonged P-wave duration (P-dur) and excessive P-wave dispersion (P-disp) are purported arrhythmogenic substrates for atrial fibrillation. However, the extent of involvement of inhomogeneous, sinus impulse propagation demonstrated by excessive P-disp (> 40 ms) has not been evaluated in relation to increasing P-dur. METHODS: We appraised our previously studied sample of 500 consecutively numbered, otherwise unselected, electrocardiograms (ECGs) of outpatients from the University of Massachusetts, Worcester, Massachusetts for P disp, P-dur and P-wave axis (P-axis). P-disp, defined as the difference of the duration between the widest and narrowest P wave, and the greatest P-dur after a 12-lead ECG search, was measured manually to the nearest 10 ms. Normal P-axis was considered 0 to + 75 degrees by manually constructing the mean frontal plane electrical P-axis from the limb leads. RESULTS: After excluding those with atrial arrhythmias, paced rhythms, errors in lead placement, P waves with low amplitude or overall technically poor tracing, 428 ECGs depicting sinus rhythm formed our final sample. P-dur was strongly associated with P-disp (p<0.0001) but the correlation remained weak (r=0.42). However, when P-dur was divided into 10 ms increments, the prevalence of abnormal P-disp rose incrementally with P-dur, with or without consideration of the P-axis. The prevalence of abnormal P-disp doubled from 30% in those with P-dur of 100 ms to > 60% in those with P-dur of 120 ms. Further, the prevalence exceeded 80% with P-dur of 130 ms and reached 100% with P dur > 160 ms. CONCLUSION: With increasingly prolonged atrial depolarization, the associated inhomogeneity of sinus impulse propagation across the atria increases. P-dur and P-disp are associated with each other and are consistent with abnormal atrial conduction properties. PMID- 17707525 TI - Sympathoadrenergic overstimulation in Tako-Tsubo cardiomyopathy triggered by physical and emotional stress. AB - Tako-Tsubo cardiomyopathy (TTC) which is usually precipitated by profound emotional stress has been widely reported in the past. Recently, several co morbidities have been found to be associated with this new cardiac entity. In this case we report from a female patient suffering from both, physical and emotional stress. After a persistent episode of severe abdominal pain due to acute cholecystitis and recurrent events of emotional stress, characteristic features of TTC could be documented. Histopathological analysis documented characteristic structural alterations including contraction band necrosis. Thus, this case confirms the hypothesis of an overstimulated sympthatoadrenergic system in TTC resulting from both, severe physical and emotional stress. PMID- 17707526 TI - Quantitative 4-dimensional volumetric analysis of left ventricle in ischemic heart disease by 64-slice computed tomography: a comparative study with invasive left ventriculogram. AB - OBJECTIVE: To elucidate the usefulness of CT in evaluating left ventricular (LV) volumes and ejection fraction (EF) in ischemic heart disease (IHD), we compared 64-slice CT with conventional left ventriculography (CLVG). MATERIALS AND METHODS: 71 subjects with suspected or confirmed IHD underwent ECG-gated enhanced CT before or after cardiac catheterization. End-diastolic volume (EDV) and end systolic volume (ESV) of LV were selected in 20 phases of R-R interval of ECG, and data sets were reconstructed to determine EDV, ESV, SV, and EF of LV using a multislice area summation method; in CLVG these parameters were calculated from the right anterior oblique 30-degree projection. RESULTS: Correlation coefficients between CT and CLVG for EDV, ESV, SV, and EF were 0.759, 0.895, 0.550, and 0.836, respectively (P<0.01). In 35 subjects without apical asynergy of LV wall motion, correlation coefficients between CT and CLVG were 0.77, 0.91, 0.63, and 0.87 respectively (P<0.01); in 36 subjects, with apical asynergy, the correlation coefficients were 0.751, 0.875, 0.503, and 0.738, respectively (P<0.01). The limits of agreement of all parameters were wider in the subjects with apical asynergy of LV wall motion than the subjects without. CONCLUSION: There was good correlation between EDV, ESV, SV, and EF estimated by CT and those by CLVG, but CT tended to overestimate EDV and ESV and underestimate EF. In subjects with apical asynergy of LV wall motion, estimates of EF were less correlated between CT and CLVG and the limits of agreement of all parameters were wider than in those without. These discrepancies may come from the capability of CT to estimate LV wall asynergy 3-dimensionally and more accurately. PMID- 17707527 TI - Cardiac involvement of Echinococcus granulosus evaluated by multi-contrast CMR imaging. AB - Cardiac manifestations of hydatid cysts are rare and occur in about 0.2 to 3% of all cases of human hydatidosis. We report the case of a young man with a known 4 year old infection with Echinoccus granulosus. Cardiovascular magnetic resonance imaging (CMR) was performed and showed two cysts in the left ventricular wall. The smaller cyst had a thin, noncontinuous membrane to the left ventricle. The T1 and T2-weighted images showed an isointense signal of the cysts compared to blood; fat-suppressed images showed no fatty components. To highlight the potential small signal differences we assigned the contents of the gray images to red, green and blue channels of a conventional color image. Blood and the content of the cysts had the same color, making a connection between the cysts and the LV blood pool highly probable. This was confirmed by first pass perfusion imaging, which showed simultaneous contrast agent arrival in the left ventricular cavity and the cysts. Delayed enhancement (DE) revealed fibrotic tissue surrounding the cysts. MR seems to be the most complete method of diagnosing the disease, as anatomical structures, type of content of the cyst (liquid or solid) and its relation to the myocardium can be assessed within one study. PMID- 17707528 TI - Superior vena cava syndrome: a rare complication of saphenous vein graft stenting: a case report. AB - Rupture of coronary artery bypass graft during percutaneous coronary intervention is a rare but serious complication. These perforations are often associated with myocardial infarction, pericardial tamponade, immediate or delayed, emergency bypass surgery and even death. We report an interesting case where perforation of a saphenous vein graft occurred after direct stenting, resulting in a very rare complication of superior vena cava (SVC) syndrome. PMID- 17707529 TI - Massive intracardiac metastases secondary to squamous cell carcinoma located at the level of the penis. AB - Penile cancer is an uncommon malignancy in the Developed World. They are dispersed mainly via the lymphatic pathway. We present a single case of massive intracardiac metastases secondary to epidermoid carcinoma of the penis. This is an extremely rare entity which has scarcely been documented. PMID- 17707530 TI - Pretreatment of male guinea pigs by 17-beta-estradiol induces hypersensitivity of beta-adrenoceptors in electrically driven left atria. AB - BACKGROUND: It is well known that estrogen can modulate distribution and function of adrenergic receptors in the heart of different species. We reported here gender differences in adrenergic responsiveness of electrically driven guinea pig left atria. METHODS: Experiments were performed on the guinea pigs divided in four groups: males control (MC), males treated by 17-beta-estradiol (MTE), females control (FC) and females treated by tamoxifen (FTT). After two weeks of treatment, the animals were sacrificed, the left atria were isolated and force of contraction (Fc), velocity of contraction (+dF/dt), velocity of relaxation ( dF/dt) and time to peak contraction (ttp) and relaxation time at 10% of amplitude (tt(10) ) were measured. RESULTS: Apart from significantly lower Fc and longer tt10 in FC (0.97+/-0.12 mN, 233+/-7 ms, respectively) vs. MC (1.66+/-0.3, 176.3+/ 18 ms, respectively, n=6, P<0.05), isoprenaline (ISO) and noradrenaline (NOR) (in the presence of prazosine) concentration-response curves were strongly shifted leftward in comparison with male group. Additionally, the maximal effects of. NOR was significantly lower in FC (about 40%) than in MC. Application of 17-beta estradiol to males and tamoxifen to females guinea pigs confirmed crucial role of estrogen in observed phenomenon. CONCLUSION: Our results indicate that estrogen not only downregulates beta1-adrenoceptors, but induces its hypersensitivity to catecholamines, at least in guinea pig left atria. PMID- 17707531 TI - Automaticity with anterograde conduction of a concealed accessory pathway due to radiofrequency energy application. AB - We report a case of a patient with recurrent episodes of supraventricular tachycardia in which a concealed left-posterior accessory pathway-mediated orthodromic tachycardia was reproducibly induced during the EP study. Two interesting and very unusual electrophysiological phenomenon were observed at the same time during the ablation procedure of the accessory pathway: 1- Automaticity of the regular accessory atrioventricular pathway; 2- Emergence of manifest preexcitation following radiofrequency application exclusively during the automatic accessory pathway-mediated rhythm. PMID- 17707532 TI - Heart-hand syndrome. AB - Heart-hand syndromes show substantial clinical and genetic heterogeneity. The unusual case of a patient with a heart-hand syndrome consisting of preaxial polydactylia, postaxial syndactylia, parachute mitral valve, mild subaortic stenosis, and double outlet right ventricle is presented and discussed. The importance of distinguishing Holt-Oram syndrome from its phenocopies and other heart-hand syndromes is underlined. PMID- 17707533 TI - Giant-cell myocarditis in a patient presenting with dilated cardiomyopathy and ventricular tachycardias treated by immunosuppression: a case report. PMID- 17707534 TI - Cannabis smoking and acute coronary syndrome: two illustrative cases. AB - Cannabis is a common substance of drug abuse among the young adults because of its euphoric and addictive effects. The pathophysiological effects of cannabis smoking and its relation to adverse cardiovascular events are well known. However, the relative contribution of cannabis smoking when combined with tobacco smoking to coronary artery disease is unclear and has not been well emphasized. We describe two cases of acute coronary syndrome occurring in cannabis smokers who were tobacco smoker too. One, a 23 year old young boy who suffered from hypertension and acute coronary syndrome at a very young age and other, a 50 year old male admitted with acute coronary syndrome, developed asymptomatic dynamic electrocardiographic changes and had beta-blocker induced severe bronchospasm. The modifiable nature of cannabis smoking and cigarette smoking, which often go hand in hand, needs no over emphasis. The cessation of twin smoking habits along with correction of other coronary artery disease risk factors is an important part of primary and secondary prevention. PMID- 17707535 TI - Accessory mitral valve as a potential source of cardioembolism. AB - An accessory mitral valve (AMV) is considered to arise from abnormal development of endocardial cushion tissue. It is a very rare entity, commonly diagnosed in childhood and associated with symptomatic left ventricular outflow tract (LVOT) obstruction. Here we describe the presence of AMV in a 58-year old patient who presented with a transient ischemic attack. Transesophageal echocardiography visualized a spherical structure attached to the ventricular aspect of the anterior mitral valve leaflet. PMID- 17707536 TI - Giant Chiari network mimics intracardiac tumor in a case of neurofibromatosis. AB - Neurocutaneos syndromes are associated with cardiac or heart related extracardiac tumors, as well as atrial or ventricular septal defect, pulmonary stenosis, coarctation of aorta. Here we describe a case of neurofibromatosis with valvular pulmonary stenosis and giant Chiari network, which mimics a right atrial tumor originating from interatrial septum. PMID- 17707537 TI - The BRCA1/BRCA2/Rad51 complex is a prognostic and predictive factor in early breast cancer. AB - BACKGROUND AND PURPOSE: The breast cancer susceptibility genes BRCA1 and BRCA2 interact with Rad51, one of the central components in the homologous recombination repair pathway. This study evaluates the prognostic and predictive role of BRCA1, BRCA2 and Rad51, individually and as a complex, in breast cancer. MATERIALS AND METHODS: Expression of BRCA1, BRCA2 and Rad51 was investigated using immunohistochemistry in tumours from 224 women with early breast cancer, who were randomised to receive postoperative radiotherapy or adjuvant chemotherapy (CMF). RESULTS: Fifty-three percent (112/212) of the tumours had reduced expression of the BRCA1/BRCA2/Rad51 complex. Low expression correlated to high histologic grade (p=0.05). Patients with low expression of the complex developed significantly more local recurrences as compared to patients with high expression (RR=3.20, 95% CI 1.48-6.88, p=0.003). Expression of the BRCA1/BRCA2/Rad51 complex was an independent prognostic factor in multivariate analysis (p=0.03). Patients with low expression of the complex responded well to radiotherapy (RR=0.31, 95% CI 0.14-0.70, p=0.005), whereas patients with high expression had few local recurrences and no additional benefit from radiotherapy (RR=1.08, 95% CI 0.40-2.90, p=0.88). CONCLUSIONS: Low expression of the BRCA1/BRCA2/Rad51 complex is a marker of poor prognosis, but predicts good response to radiotherapy in patients with early breast cancer. PMID- 17707538 TI - Frontal theta EEG activity correlates negatively with the default mode network in resting state. AB - We used simultaneously recorded EEG and fMRI to investigate in which areas the BOLD signal correlates with frontal theta power changes, while subjects were quietly lying resting in the scanner with their eyes open. To obtain a reliable estimate of frontal theta power we applied ICA on band-pass filtered (2-9 Hz) EEG data. For each subject we selected the component that best matched the mid frontal scalp topography associated with the frontal theta rhythm. We applied a time-frequency analysis on this component and used the time course of the frequency bin with the highest overall power to form a regressor that modeled spontaneous fluctuations in frontal theta power. No significant positive BOLD correlations with this regressor were observed. Extensive negative correlations were observed in the areas that together form the default mode network. We conclude that frontal theta activity can be seen as an EEG index of default mode network activity. PMID- 17707539 TI - Actinomycin D enhances TRAIL-induced caspase-dependent and -independent apoptosis in SH-SY5Y neuroblastoma cells. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted great attention as a promising anti-cancer reagent. Recombinant soluble TRAIL (rsTRAIL) derivatives induce apoptosis in various cancer cells, but not in most normal cells. However, a number of cancerous cell types are resistant to TRAIL cytotoxicity, limiting its application in cancer therapy. In the present study, we report that actinomycin D (Act D) pretreatment increases apoptosis in human neuroblastoma SH-SY5Y cells treated with rsTRAIL. Both caspase-9 and caspase-7, but not caspase-3, were activated during the apoptosis process. z-VAD-fmk, a pan caspase inhibitor, only partially suppressed apoptosis of the cells, suggesting that the Act D-enhanced apoptosis of SH-SY5Y occurred via caspase-dependent and independent manners. In cells pretreated with Act D, we found decreased mitochondrial transmembrane potential, high levels of reactive oxygen species (ROS), and up-regulated apoptotic-inducing factor (AIF). Cell death was blocked in cells stably transfected with AIF-siRNA plasmid. Taken together, these data indicate that Act D sensitizes SH-SY5Y cells to rsTRAIL-induced apoptosis via caspase activation, impairment of the mitochondrial membrane, release of ROS, and up-regulation of AIF expression. This study provides a novel strategy for the therapy of malignant neuroblastoma resistant to rsTRAIL cytotoxicity. PMID- 17707540 TI - Effective oral delivery of insulin in animal models using vitamin B12-coated dextran nanoparticles. AB - The potential utility of vitamin B12 carrier system for the oral delivery of conjugated peptides/proteins and enhancement of nanoparticles (NPs) transport has been demonstrated. The present study aims to optimize the effectiveness of VB12 NPs conjugates using different levels of cross-linking, linked with different VB(12)-coatings and evaluates in animal models to investigate an efficient insulin carrier. Amino alkyl VB12 derivatives suitable for oral delivery were synthesized at 5'hydoxy ribose and e-propionamide sites via carbamate and ester/amide linkages, and were coupled to succinic acid modified dextran NPs of varied cross-linking. VB12 binding was confirmed by XPS analysis, and was quantified by HPLC (4.0 to 5.7% w/w of NPs). These polydisperse NPs conjugates showed higher size, high insulin entrapment and faster insulin release with low levels of cross-linking. These VB12-NPs conjugates (150-300 nm) showed profound (70-75% blood glucose reductions) and prolonged (54 h) anti-diabetic effects with biphasic behaviour in STZ diabetic rats. NPs with the low levels of cross-linking were found to be superior carriers, and were more effective with VB12 derivatives of carbamate linkage. The pharmacological availability relative to SC insulin was found to be 29.4%, which was superior compared to NPs conjugate of ester linked VB12 (1.5 fold) and relatively higher cross-linked particles (1.1 fold). Further, the NPs carrier demonstrated a similar oral insulin efficacy in congenital diabetic mice (60% reduction at 20 h). Significant quantities of plasma insulin were found in both animal models (231 and 197 muIU/ml). At two investigated doses, the carrier system shows dose response. Pre-dosing with a large excess of free VB12 minimized the observed activity, indicating predominance of VB12 mediated uptake. It is concluded that VB12-dextran NPs conjugate is a viable carrier for peroral insulin delivery to treat diabetics. PMID- 17707541 TI - Stroke presentation in Type 2 diabetes and the metabolic syndrome. AB - INTRODUCTION: The metabolic syndrome (MetS) is associated with macrovascular disease and an altered pattern of cerebrovascular disease. We investigated stroke subtype presentation in Type 2 diabetic (T2D) patients, and analysed patients with and without the MetS. METHODS: We performed a retrospective analysis of 243 T2D patients with first presentation of stroke from our Diabetes Centre database. The MetS was diagnosed in patients with T2D and two or more additional risk factors (obesity, low HDL cholesterol, elevated triglycerides or hypertension). We analysed the clinical stroke subtype presentation, using the Oxford classification of stroke, into cortical and lacunar (small vessel disease) stroke. RESULTS: The MetS was diagnosed in 151 T2D patients (62%), with 86 male and 65 female patients (age: 71.8+/-9.7). Comparing the MetS and non-MetS groups, the distribution of stroke subtypes adjusted for age and sex were: cortical stroke (13.2% versus 15.2%; P=0.56), lacunar stroke (43.7% versus 43.5%; P=0.87) and TIA (38.4% versus 39.1%; P=0.98). Lacunar stroke incidence was significantly higher compared to cortical stroke in both groups (P<0.001). CONCLUSION: In this study of T2D patients, lacunar stroke (small vessel disease) was the most common stroke subtype in both patients with and without the MetS. PMID- 17707543 TI - Integrated modeling methodology for microtubule dynamics and Taxol kinetics with experimentally identifiable parameters. AB - Microtubule dynamics play a critical role in cell function and stress response, modulating mitosis, morphology, signaling, and transport. Drugs such as paclitaxel (Taxol) can impact tubulin polymerization and affect microtubule dynamics. While theoretical methods have been previously proposed to simulate microtubule dynamics, we develop a methodology here that can be used to compare model predictions with experimental data. Our model is a hybrid of (1) a simple two-state stochastic formulation of tubulin polymerization kinetics and (2) an equilibrium approximation for the chemical kinetics of Taxol drug binding to microtubule ends. Model parameters are biologically realistic, with values taken directly from experimental measurements. Model validation is conducted against published experimental data comparing optical measurements of microtubule dynamics in cultured cells under normal and Taxol-treated conditions. To compare model predictions with experimental data requires applying a "windowing" strategy on the spatiotemporal resolution of the simulation. From a biological perspective, this is consistent with interpreting the microtubule "pause" phenomenon as at least partially an artifact of spatiotemporal resolution limits on experimental measurement. PMID- 17707542 TI - Uses of first line emergency services in Cuba. AB - OBJECTIVES: To rationalise the use of hospital emergency units, the Cuban health system developed from 1996 onwards an extra muros first line emergency system (FLES). We analyse the use of the FLES and its determinants, in order to develop proposals to channel inappropriate users to their family doctor. METHODS: In the FLES of an urban (Cerro) and a rural (Baracoa) municipality we collected, from July 1999 to June 2001, data on the moment of consultation, age and sex of the patient, referral status, motive of consultation, emergency classification, diagnosis and medical conduct. A variable "inappropriate use" was constructed. We used multivariate logistic regression to quantify the strength of the associations between patient characteristics, the night-time use, medical procedures, referral, and inappropriate use of the FLES. RESULTS: Over the 2 years observation period, 24879 and 59795 patient contacts were registered with the principal emergency policlinic in Baracoa and Cerro, respectively. In both municipalities the overall "inappropriate" use was almost 60%. There was no correlation with age and gender but inappropriate use was 50% more frequent during the day. Referred patients in both localities were up to 12 times more frequently hospitalized. CONCLUSION: Cuba's FLES attract patients that would be better attended by their family doctor. To strengthen his central position in the health system, one should strengthen the family doctor's technical platform, increase his permanence at the cabinet, and improve communication with the community on the rationale of the family doctor--FLES set up. PMID- 17707544 TI - Modeling oxaliplatin drug delivery to circadian rhythms in drug metabolism and host tolerance. AB - To make possible the design of optimal (circadian and other period) time scheduled regimens for cytotoxic drug delivery by intravenous infusion, a pharmacokinetic-pharmacodynamic (PK-PD, with circadian periodic drug dynamics) model of chemotherapy on a population of tumor cells and its tolerance by a population of fast renewing healthy cells is presented. The application chosen for identification of the model parameters is the treatment by oxaliplatin of Glasgow osteosarcoma, a murine tumor, and the healthy cell population is the jejunal mucosa, which is the main target of oxaliplatin toxicity in mice. The model shows the advantage of a periodic time-scheduled regimen, compared to the conventional continuous constant infusion of the same daily dose, when the biological time of peak infusion is correctly chosen. Furthermore, it is well adapted to using mathematical optimization methods of drug infusion flow, choosing tumor population minimization as the objective function and healthy tissue preservation as a constraint. Such a constraint is in clinical settings tunable by physicians by taking into account the patient's state of health. PMID- 17707546 TI - Intracellular trafficking of adenovirus: many means to many ends. AB - The intracellular trafficking of adenovirus capsids has been described mainly through observations of trafficking by capsids from subgroup C adenoviruses in transformed cell lines. The basic elements of the trafficking pathway include high affinity binding of the adenovirus capsid to receptors at the cell surface, internalization by endocytosis, lysis of the endosomal membrane resulting in escape to the cytosol, trafficking along microtubules, binding to the nuclear envelope, and insertion of the viral genome through the nuclear pore. The net effect of this basic pathway is to deliver the adenovirus genome to the nucleus in a highly efficient manner with greater than 80% of the genome reaching the nucleus in approximately 1 h. However, exceptions to this trafficking pattern have been noted, including: (1) variations based on adenovirus serotype; (2) variations based on target cell type; and (3) variations based on cell physiology. This review summarizes the classical adenovirus infection pathway along with the exceptions to that trafficking pathway, providing an overview of intracellular trafficking of adenovirus. PMID- 17707547 TI - Response of a thymic mucoepidermoid carcinoma to combination chemotherapy with cisplatin and irinotecan: a case report. AB - A chemotherapeutic regimen for advanced thymic carcinoma has not yet been established. We describe a patient with advanced thymic mucoepidermoid carcinoma who achieved a complete response to combination chemotherapy with cisplatin (Randa) and irinotecan hydrochloride (Campto). A 74-year-old man was admitted to our hospital because of chest pain, general fatigue, appetite loss and weight loss. Chest computed tomography examinations revealed an anterior mediastinal tumour (5.5cmx3.5cmx9.5cm) that had invaded the subcutis through the sternum. The patient was treated with three courses of cisplatin and irinotecan hydrochloride followed by radiotherapy; he has since exhibited a complete response for 3 months. PMID- 17707548 TI - Polymorphisms of CAK genes and risk for lung cancer: a case-control study in Chinese population. AB - The incidence of lung cancer has been increasing over recent decades. Previous studies show that polymorphisms of the genes involved in carcinogen-detoxication, DNA repair and cell cycle control compose of the risk factors for lung cancer. Recent observations reveal that the components of CAK: Cdk7, MAT1 and cyclin H, may play important roles in cell cycle control, transcriptional control, and DNA repairing process, all of which are important in carcinogenesis. To test whether the genetic variants of CAK genes modify the risk of lung cancer, we compared the manifestation of 25 single nucleotide polymorphisms (SNPs) and the haplotypes of Cdk7, MAT1 and cyclin H between 500 patients with lung cancer and 517 healthy controls. Our results indicated that the genotype frequency of MAT1 79023A/G (p = 0.042) and MAT1 85693C/T (p = 0.005) of cases significantly differed from those of the controls. Further analyses revealed that cyclin H 11817C/T, MAT1 12199A/G, MAT1 70650A/G, MAT1 79023A/G and MAT1 85693C/T significantly influenced the susceptibility of lung cancer in a dominant genetic model while cyclin H 12128A/T and MAT1 42172A/G did in a recessive model. Strongest association between cyclin H alleles and lung cancer patients was found in the non-smoke subpopulation. The haplotype 'TAC' (p = 0.007) increased and the haplotype 'TTC' (p = 0.043) decreased the risk of lung cancer. The potential gene-gene and gene-environmental interactions on lung cancer risk was evaluated using MDR software. A significant interaction between the three CAK component genes was identified and the combination of smoking status and genetic factors barely increased the accuracy. Our results suggested that genetic variants in CAK genes, Cdk7, cyclin H, MAT1, might modulate the risk of lung cancer in a gene-gene interaction mode, which consist to the biochemical interaction of corresponding proteins. PMID- 17707549 TI - Molecular cloning of glutathione reductase cDNAs and analysis of GR gene expression in cowpea and common bean leaves during recovery from moderate drought stress. AB - Two cDNAs of the enzyme glutathione reductase (GR; EC 1.6.4.2) encoding a dual targeted isoform (dtGR) and a cytosolic isoform (cGR), were cloned from leaves of common bean (Phaseolus vulgaris L.). Moderate drought stress (Psi w=-1.5MPa) followed by re-watering was applied to common bean cultivars, one tolerant to drought (IPA), the other susceptible (Carioca) and to cowpea (Vigna unguiculata L. Walp) cultivars, one tolerant to drought (EPACE-1), and the other susceptible (1183). mRNA levels were much higher for PvcGR than for PvdtGR in all cases. Moderate drought stress induced an up-regulation of the expression of PvcGR in the susceptible cultivars. On the contrary, PvdtGR expression decreased. In the tolerant cowpea EPACE-1, GR gene expression remained stable under drought. During recovery from drought, an up-regulation of the two GR isoforms occurred, with a peak at 6-10h after re-hydration. This suggests that moderate drought stress may lead to a hardening process and acclimation tolerance. The role of GR isoforms in plant tolerance and capacity to recover from drought stress is discussed. PMID- 17707550 TI - 2,3-benzodiazepine-type AMPA receptor antagonists and their neuroprotective effects. AB - AMPA receptors are fast ligand-gated members of glutamate receptors in neuronal and many types of non-neuronal cells. The heterotetramer complexes are assembled from four subunits (GluR1-4) in region-, development- and function-selective patterns. Each subunit contains three extracellular domains (a large amino terminal domain, an agonist-binding domain and a transducer domain), and three transmembrane segments with a loop (pore forming domain), as well as the intracellular carboxy terminal tail (traffic and conductance regulatory domain). The binding of the agonist (excitatory amino acids and their derivatives) initiates conformational realignments, which transmit to the transducer domain and membrane spanning segments to gate the channel permeable to Na+, K+ and more or less to Ca2+. Several 2,3-benzodiazepines act as non-competitive antagonists of the AMPA receptor (termed also negative allosteric modulators), which are thought to bind to the transducer domains and inhibit channel gating. Analysing their effects in vitro, it has been possible to recognize a structure-activity relationship, and to describe the critical parts of the molecules involved in their action at AMPA receptors. Blockade of AMPA receptors can protect the brain from apoptotic and necrotic cell death by preventing neuronal excitotoxicity during pathophysiological activation of glutamatergic neurons. Animal experiments provided evidence for the potential usefulness of non-competitive AMPA antagonists in the treatment of human ischemic and neurodegenerative disorders including stroke, multiple sclerosis, Parkinson's disease, periventricular leukomalacia and motoneuron disease. 2,3-benzodiazepine AMPA antagonists can protect against seizures, decrease levodopa-induced dyskinesia in animal models of Parkinson's disease demonstrating their utility for the treatment of a variety of CNS disorders. PMID- 17707551 TI - Cytoprotective role of mitochondrial amyloid beta peptide-binding alcohol dehydrogenase against a cytotoxic aldehyde. AB - Recent reports on amyloid beta peptide (A beta) binding-alcohol dehydrogenase (ABAD) have revealed the link of A beta with oxidative stress derived from mitochondria in the pathogenesis of Alzheimer's disease (AD). As a novel function of ABAD, we speculate that ABAD may detoxify aldehydes, such as 4-hydroxy-2 nonenal (4-HNE). To verify this speculation, we transfected cDNA encoding ABAD into cultured cells (HeLa and SH-SY5Y), where ABAD was localized to mitochondria. ABAD-transfectants decreased the levels of externally added 4-HNE in cultured medium as detected by TLC and became resistant against external 4-HNE. Moreover, ABAD suppressed the cytotoxic effects caused by cellular 4-HNE, which were produced through excess reactive oxygen species (ROS) by treatment with an inhibitor of mitochondrial respiration, antimycin A or by adding H(2)O(2). Catabolism of 4-HNE by ABAD was inhibited by A beta, resulting in the abolishment of the cytoprotective function by ABAD against ROS. These results propose an additional role of ABAD in neural cell death in AD: ABAD detoxifies aldehydes, such as 4-HNE derived from lipid peroxides in healthy brains, and inhibited by A beta in the development of AD. PMID- 17707552 TI - Age-dependent association of KIBRA genetic variation and Alzheimer's disease risk. AB - An association between memory performance in healthy young, middle aged an elderly subjects and variability in the KIBRA gene (rs17070145) has been recently described. We analyzed this polymorphism in 391 sporadic Alzheimer's disease (AD) patients and 428 cognitively normal control subjects. The current study reveals that KIBRA (rs17070145) T allele (CT and TT genotypes) is associated with an increased risk (OR 2.89; p=0.03) for very-late-onset (after the age of 86 years) AD. PMID- 17707553 TI - Insight into the reactive form of the anticancer agent iproplatin. AB - The reaction of iproplatin with reduced glutathione at different mole ratios yielded cis-di(isopropylamine)chloro-glutathionatoplatinum(II), not the expected cis-dichloro- species, indicating a mode of action of this anticancer agent that is different from that of cis-diamminedichloroplatinum(II). PMID- 17707554 TI - [Efficiency of rituximab in acquired hemophilia: report of two cases and review of literature]. AB - INTRODUCTION: Acquired hemophilia due to an inhibitor of factor VIII is a rare clinical situation. EXEGESIS: Rituximab is now used in the treatment of acquired hemophilia. We report two cases of acquired hemophilia treated by rituximab with efficiency. CONCLUSION: Rituximab appears to be a first line immunosuppressive therapy in acquired hemophilia, especially in post-partum hemophilia. PMID- 17707545 TI - "Alternative" endocytic mechanisms exploited by pathogens: new avenues for therapeutic delivery? AB - Some pathogens utilize unique routes to enter cells that may evade the intracellular barriers encountered by the typical clathrin-mediated endocytic pathway. Retrograde transport and caveolar uptake are among the better characterized pathways, as alternatives to clathrin-mediated endocytosis, that are known to facilitate entry of pathogens and potential delivery agents. Recent characterization of the trafficking mechanisms of prion proteins and certain bacteria may present new paradigms for strategizing improvements in therapeutic spread and retention of therapy. This review will provide an overview of such endocytic pathways, and discuss current and future possibilities in using these routes as a means to improve therapeutic delivery. PMID- 17707555 TI - Examination of host immune resistance against Listeria monocytogenes infection in cyclophosphamide-treated mice after dietary lipid administration. AB - BACKGROUND & AIMS: Despite the beneficial effects in the resolution of inflammatory disorders due to their immunosuppressive properties, n-3 polyunsaturated fatty acids are associated with a reduction of immune resistance to some microorganisms. Here, we examine the influence of different dietary lipids on host immune resistance against Listeria monocytogenes in mice treated with cyclophosphamide (CPA). METHODS: Balb/c mice were fed one of four diets, which contained either olive oil (OO), fish oil (FO), hydrogenated coconut oil (HCO) or low fat (LF) for 4 weeks. Subsequently, mice were treated with CPA or PBS, prior to L. monocytogenes infection. Splenocyte proliferation, survival analysis, counts of viable bacteria from spleens and livers, and measurement of pro-inflammatory cytokine levels were determined. RESULTS: The FO-rich diet reduced survival, particularly in CPA-treated mice. CPA was responsible for a significant increase of viable bacteria recovery from spleens and livers within each group fed high fat diets, which was aggravated in mice fed an FO diet. In addition, a significant increase of both TNF-alpha and IL-12p70 levels was detected in this group. These results may acquire a crucial relevance in clinical nutrition, particularly when FO diets are administered to immunocompromised patients. CONCLUSIONS: The mechanism(s) that impair(s) the elimination of L. monocytogenes could be associated with a low mitogen-stimulated splenocyte proliferation, and with an alteration of pro-inflammatory cytokine production. The application of the neutropenic agent CPA moderately aggravates the immunosuppressive state mainly in FO-fed animals. PMID- 17707556 TI - An economic evaluation of thermostable vaccines in Cambodia, Ghana and Bangladesh. AB - This paper evaluates the incremental health and programmatic cost impacts of new vaccine products, as compared to the standard vaccine products in multi-dose vials in Cambodia, Ghana, and Bangladesh. The authors use a cost-effectiveness model to estimate the impacts of introducing four thermostable vaccines with single-dose presentations: measles, yellow fever, bacille Calmette-Guerin, and diphtheria-tetanus-pertussis-hepatitis B. The effectiveness of all of the vaccines increases with the thermostable formats. The incremental costs associated with the introduction of thermostable vaccines increases for three out of four vaccines. Single-dose presentations of thermostable vaccines are potentially cost-effective interventions to reduce childhood deaths and disability in low-resource settings in Asia and Africa. PMID- 17707557 TI - Short-term response to a booster dose of hepatitis B vaccine in anti-HBs negative adolescents who had received primary vaccination 16 years ago. AB - We conducted a revaccination study to investigate the short-term response to booster hepatitis B (HB) vaccination in seronegative adolescents who had received primary infantile HB vaccination. A booster dose of recombinant HB vaccine was administered to 395 adolescents 15-18 years of age whose serum titers of antibody against hepatitis B surface antigen (HBsAg) (anti-HBs) were <10 mIU/mL. Seventy seven percent of the booster recipients converted to anti-HBs seropositivity (postbooster titers> or =10 mIU/mL). As compared with adolescents who had undetectable prebooster anti-HBs titers (<0.1 mIU/mL), the seropositive rates and geometric mean titers (GMTs) of 2-month and 1-year postbooster were significantly higher for those of prebooster titers of 0.1-0.9 and 1.0-9.9 mIU/mL (all p<0.0001). Postbooster titers declined significantly more rapidly for those with undetectable prebooster anti-HBs titers than for those with prebooster titers of 0.1-0.9 and 1.0-9.9 mIU/mL. Our observations indicate that a booster dose of HB vaccine maybe unable to induce sufficient immunological response in adolescents who had undetectable residual anti-HBs titers. PMID- 17707558 TI - Quality control of routine, experimental and real-time aged diphtheria toxoids by in vitro analytical techniques. AB - Physicochemical and immunochemical techniques can be used to assess the quality of diphtheria toxoid vaccines. In a previous paper [Metz B, Jiskoot W, Hennink WE, Crommelin DJA, Kersten GFA. Physicochemical and immunochemical techniques predict the quality of diphtheria toxoid vaccines. Vaccine 2003;22(2):156-67], techniques were introduced which indicated toxoid quality with respect to safety and potency: SDS-PAGE, primary amino group determination, fluorescence/denaturation, circular dichroism and biosensor analyses. These analyses were performed with experimental toxoids from one toxin batch. In the present study, the quality of regular vaccine batches of different manufacturers, the properties of real-time aged products and a number of experimental toxoids were investigated, using the above-mentioned analytical techniques. We had the unique opportunity to analyse toxoids that were up to 40 years old. The real-time aged diphtheria toxoids showed hardly any structural differences as compared to the recently prepared products in both the analytical chemical techniques and the conventional potency and safety tests. The analytical assays discriminated between regular diphtheria toxoids and experimental toxoids prepared by methylation, acetylation or glutaraldehyde treatment. The analytical data showed a clear correlation with potency and safety of these toxoids. Based on the results, we refined the described physicochemical and immunochemical criteria that a standard diphtheria toxoid has to meet. We recommend further validation of these techniques for quality control of diphtheria toxoid vaccine because of their high precision and easy performance as compared to conventional in vivo procedures. PMID- 17707559 TI - Investigations on indoor radon in Austria, Part 1: Seasonality of indoor radon concentration. AB - In general, indoor radon concentration is subject to seasonal variability. The reasons are to be found (1) in meteorological influence on the transport properties of soil, e.g. through temperature, frozen soil layers and soil water saturation; and (2) in living habits, e.g. the tendency to open windows in summer and keep them closed in winter, which in general leads to higher accumulation of geogenic Rn in closed rooms in winter. If one wants to standardize indoor Rn measurements originally performed at different times of the year, e.g. in order to make them comparable, some correction transform as a function of measurement time which accounts for these effects must be estimated. In this paper, the seasonality of indoor Rn concentration measured in Austria is investigated as a function of other factors that influence indoor Rn. Indoor radon concentration is clearly shown to have seasonal variability, with higher Rn levels in winter. However, it is complicated to quantify the effect because, as a consequence of the history of an Rn survey, the measurement season maybe correlated to geological regions, which may introduce a bias in the estimate of the seasonality amplitude. PMID- 17707560 TI - Stable and radioiodine concentrations in cow milk: dependence on iodine intake. AB - For testing the potential use of stable iodine as a countermeasure to reduce radioiodine transfer to milk, concentrations of stable iodine and radioiodine in the milk of dairy cows fed different amounts of stable iodine were measured. The results indicated that, compared to a normal average stable iodine intake of about 20 mg d(-1) for cows, low iodine dietary intake (<1.5 mg d(-1)) resulted in a reduced transfer of radioiodine to milk by 25%, varying stable iodine intakes in the range of 10-500 mg d(-1) did have no significant effect; at stable iodine intake rates above 1000 mg I d(-1), a reduction by a factor of approximately two was achieved. The high dietary iodine intakes--being about 100 times the normal iodine supply--required to reduce the radioiodine transfer significantly, will result in stable iodine concentrations in milk in excess of advised or legal limits for human consumption. Nevertheless, the provision of stable iodine via the milk pathway might be considered for emergency situations when stable iodine is used as a preventative measure for dose reduction to humans. PMID- 17707561 TI - Biomonitoring atmospheric pollution: the challenge of times in environmental policy on air quality. PMID- 17707562 TI - Anxiety in the eating disorders: understanding the overlap. AB - This paper reviews research investigating the comorbidity between eating disorders and anxiety disorders. Whilst there is some inconsistency in the literature, it appears that women with eating disorders have higher rates of anxiety disorders than normal controls. Potential causal relationships between eating disorders and anxiety disorders are outlined, though their relative chronology appears to be somewhat inconsistent. Safety behaviours and cognitive avoidance strategies (i.e., cognitive narrowing and blocking) are suggested as potential mechanisms linking the disorders. A model outlining this hypothesised relationship is developed throughout the review. It is suggested that eating disorders and anxiety disorders might share common aetiological factors, and that these factors can increase an individual's susceptibility to either disorder. Potential implications for the treatment of eating disorders are outlined, and suggestions are made for further research. PMID- 17707564 TI - Introduction to the special issue on medically unexplained symptoms: background and future directions. AB - This special issue is devoted to the topic of medically unexplained symptoms (MUS), a heterogeneous group of conditions characterized by persistent physical symptoms that cannot be explained by medical illness or injury. Although psychological factors have long been regarded as central to these problems, patients with MUS have typically been managed within medical settings and referrals to mental health services have been relatively rare. In recent years, however, interest in the psychological nature and treatment of MUS has expanded, culminating in the development of tailored psychological interventions for these conditions. This, coupled with the increasing willingness of practitioners to diagnose conditions such as chronic fatigue syndrome, fibromyalgia and irritable bowel syndrome, has led to an increase in the number of patients who are referred for psychological treatment. At present, however, many psychological therapists are unfamiliar with the literature on MUS. With this in mind, this special issue presents a series of papers that provide an overview of what is known about the nature, aetiology and treatment of medically unexplained illness. This introductory paper provides general information about the clinical presentation, diagnosis, classification, terminology and epidemiology of MUS in adults, and concludes with an examination of important areas for future development in the field. Subsequent papers address the psychological mechanisms [Deary, V., Chalder, T., & Sharpe, M. (2007-this issue). The cognitive behavioural model of medically unexplained symptoms: A theoretical and empirical review. Clinical Psychology Review; Iverson, A., Chalder, T., & Wessely, S. (2007-this issue). Gulf war illness: Lessons from medically unexplained illness. Clinical Psychology Review; Rief, W., & Broadbent, E. (2007-this issue). Explaining medically unexplained symptoms: Models and mechanisms. Clinical Psychology Review; Roelofs, K., & Spinhoven, P. (2007-this issue). Trauma and medically unexplained symptoms: Towards an integration of cognitive and neuro-biological accounts. Clinical Psychology Review] and management [Deary, V., Chalder, T., & Sharpe, M. (2007 this issue). The cognitive behavioural model of medically unexplained symptoms: A theoretical and empirical review. Clinical Psychology Review] of these conditions. A separate overview of the literature on MUS in children and adolescents is provided by Eminson [Eminson, J. (2007-this issue). Medically unexplained symptoms in children and adolescents. Clinical Psychology Review]. PMID- 17707563 TI - Mental health following traumatic injury: toward a health system model of early psychological intervention. AB - In 2005, over 2 million people in the United States of America were hospitalised following non-fatal injuries. The frequency with which severe injury occurs renders it a leading cause of posttraumatic stress disorder and other trauma related psychopathology. In order to develop a health system model of early psychological intervention for this population, we review the literature that pertains to mental health early intervention. The relevant domains include prevalence of psychopathology following traumatic injury, the course of symptoms, screening, and early intervention strategies. On the basis of available evidence, we propose a health system model of early psychological intervention following traumatic injury. The model involves screening for vulnerability within the hospital setting, follow-up screening for persistent symptoms at one month posttrauma, and early psychological intervention for those who are experiencing clinical impairment. Recommendations are made to facilitate tailoring early intervention psychological therapies to the special needs of the injury population. PMID- 17707565 TI - Racially mixed neighborhoods, perceived neighborhood social cohesion, and adolescent health in Canada. AB - Using data from the Canadian Census and the National Longitudinal Survey of Children and Youth, we examine the effects of neighborhood concentration of racial minorities on general health status and depressive symptoms of Canadian adolescents. We also examine the role of perceived neighborhood cohesion and the extent to which it contributes to adolescent health. Our findings show that the racial concentration of ethnic minorities represents a health disadvantage for visible minority youth while perceived neighborhood cohesion is found to be a protective factor for both health outcomes. Perceived neighborhood cohesion is beneficial for the general health status (but not depression) of adolescents residing in neighborhoods with a high concentration of racial minorities. PMID- 17707567 TI - Specific personality traits and dopamine, serotonin genes in anxiety-depressive alcoholism among Han Chinese in Taiwan. AB - BACKGROUND: Cloninger [Cloninger CR. 1987. Neurogenetic adaptive mechanisms in alcoholism. Science 236: 410-416.] had proposed a psychobiological model suggesting that three main personality dimensions distinguish the alcoholism into two subtypes (type I and type II). However, the classification was equivocal for clinical diagnosis. Recently, anxiety-depressive alcohol dependence (ANX/DEP ALC) has been posited as a genetically specific subtype of alcoholism. Its clinical characteristics were similar to individuals with type I alcoholism [Cloninger, C.R. 1987. Neurogenetic adaptive mechanisms in alcoholism. Science 236: 410-6.] such as having a high comorbidity with mood disorder, late-onset and more anxious/depressed traits. We attempted to investigate whether the dopamine D2 receptor (DRD2) and the serotonin transporter promoter region (5-HTTLPR) genes were involved in Novelty Seeking (NS) and Harm Avoidance (HA) of ANX/DEP ALC. METHODS: We recruited 46 pure alcohol dependents (Pure ALC) and 87 anxiety depression alcohol dependents (ANX/DEP ALC). All participants were diagnosed by DSM-IV criteria, genotyped by the PCR method and assessed with Tridimensional Personality Questionnaire (TPQ). RESULTS: Both NS and HA were high in ANX/DEP ALC (p = 0.021; p = 0.001, respectively). The association between NS and ANX/DEP ALC only existed in subjects with DRD2 TaqI A1(+) allele (A1/A1 or A1/A2 genotypes) (p = 0.004) and in those with S/S genotype of 5-HTTLPR (p = 0.005). With the stratification of DRD2 TaqI A1(+) allele, high NS of ANX/DEP ALC existed only in carriers of 5-HTTLPR S/S genotype (p=0.001). Moreover, ANX/DEP ALC was related to high HA only in samples carrying 5-HTTLPR S/L or L/L genotype (p = 0.02). CONCLUSIONS: These findings provided the empirical genetic characterization of the specific personality traits in ANX/DEP ALC among Han Chinese population in Taiwan. PMID- 17707568 TI - Lack of carcinogenicity of lyophilized Agaricus blazei Murill in a F344 rat two year bioassay. AB - The Brazilian mushroom Agaricus blazei Murill has antimutagenic, antioxidant, immunostimulatory and antitumorigenic activities, and is increasingly consumed as a health food worldwide. We undertook the present study to evaluate the chronic toxicity and oncogenicity of A. blazei Murill in F344 rats. To establish a no observed-adverse-effect level (NOAEL), four treatment groups of 100 rats each (50 males and 50 females) were fed a powder diet containing lyophilized A. blazei aqueous extract at 0, 6250, 12,500, and 25,000 ppm for up to 2 years. During this period, there was no remarkable change in mean body weight, body weight gain, hematologic or serum chemistry parameters, or absolute or relative organ weights in control or treatment groups. Mortality in male treatment groups (26%, 16%, and 30%), however, was significantly lower than in controls (48%). Histopathological studies showed no increased incidence of tumors in any treatment group, and total tumor incidence across all groups was comparable to historical data. In conclusion, an A. blazei Murill lyophilized powder diet even at 25,000 ppm (1176 mg/kgb x w x /day for male rats and 1518 mg/kgb.w./day for female rats) resulted in no remarkable carcinogenic effects in F344 rats over a 2-year period. Therefore, the dietary NOAEL is 25,000 ppm. PMID- 17707569 TI - Flavonoid effects on DNA oxidation at low concentrations relevant to physiological levels. AB - Flavonoids, which are abundant in fruits and vegetables, are known to have many beneficial health effects. Antioxidant activity is likely to be a main function but has been mostly studied at high flavonoid concentrations which are not feasible at the intracellular level. In this experiment, several flavonoids (e.g., catechin, quercetin, myricetin, luteolin, morin and cyanidin) were examined at low physiologically relevant concentrations. Calf thymus DNA was treated with different flavonoids at concentrations of 0.1, 1, 10 and 100 microM using Fenton conditions to induce oxidation and several oxidative adducts including 8-hydroxy guanine (7,8-dihydro-8-oxo-2'-deoxyguanosine; 8-OH guanine) were analyzed using gas chromatography-mass spectrometry-selective ion monitoring (GC-MS-SIM). Catechin, quercetin and cyanidin inhibited 8-OH guanine formation by 92%, 33% and 45%, respectively, at low concentrations (0.1 microM). In addition catechin and quercetin showed antioxidant activities on 8-OH guanine formation over all concentrations. When the oxidative DNA adduct 4,6-diamino-5 formamidopyrimidine (fapy-adenine) was measured, however, the highest concentrations of catechin and quercetin actually increased adduct formation. These results indicate that flavonoids can act as antioxidants at low concentrations relevant to physiological levels. However measuring only one oxidative DNA adduct as a biomarker may result in misleading conclusions regarding antioxidant activities of natural products. PMID- 17707570 TI - Determination of patulin in commercial apple juice by micellar electrokinetic chromatography. AB - A novel and validated micellar electrokinetic capillary chromatography (MEKC) method using ultraviolet detection (UV) has been applied to the quantitative analysis of patulin (PAT) in commercial apple juice. Patulin was extracted from samples with an ethylacetate solution. The micellar electrokinetic capillary chromatography (MECK) parameters studied for method optimization were buffer composition, voltage, temperature, and a separation between PAT and 5 hydroxymethylfurfural (HMF) (main interference in apple juice PAT analysis) peaks until reaching baseline. The method passes a series of validation tests including selectivity, linearity, limit of detection and quantification (0.7 and 2.5 microgL(-1), respectively), precision (within and between-day variability) and recovery (80.2% RSD=4%), accuracy, and robustness. This method was successfully applied to the measurement of 20 apple juice samples obtained from different supermarkets. One hundred percent of the samples were contaminated with a level greater than the limit of detection, with mean and median values of 41.3 and 35.7 microgL(-1), respectively. PMID- 17707566 TI - The neurobiology of retinoic acid in affective disorders. AB - Current models of affective disorders implicate alterations in norepinephrine, serotonin, dopamine, and CRF/cortisol; however treatments targeted at these neurotransmitters or hormones have led to imperfect resolution of symptoms, suggesting that the neurobiology of affective disorders is incompletely understood. Until now retinoids have not been considered as possible contributors to affective disorders. Retinoids represent a family of compounds derived from vitamin A that perform a large number of functions, many via the vitamin A product, retinoic acid. This signaling molecule binds to specific retinoic acid receptors in the brain which, like the glucocorticoid and thyroid hormone receptors, are part of the nuclear receptor superfamily and regulate gene transcription. Research in the field of retinoic acid in the CNS has focused on the developing brain, in part stimulated by the observation that isotretinoin (13 cis retinoic acid), an isomer of retinoic acid used in the treatment of acne, is highly teratogenic for the CNS. More recent work has suggested that retinoic acid may influence the adult brain; animal studies indicated that the administration of isotretinoin is associated with alterations in behavior as well as inhibition of neurogenesis in the hippocampus. Clinical evidence for an association between retinoids and depression includes case reports in the literature, studies of health care databases, and other sources. A preliminary PET study in human subjects showed that isotretinoin was associated with a decrease in orbitofrontal metabolism. Several studies have shown that the molecular components required for retinoic acid signaling are expressed in the adult brain; the overlap of brain areas implicated in retinoic acid function and stress and depression suggest that retinoids could play a role in affective disorders. This report reviews the evidence in this area and describes several systems that may be targets of retinoic acid and which contribute to the pathophysiology of depression. PMID- 17707572 TI - Use of RAPD to detect sodium arsenite-induced DNA damage in human lymphoblastoid cells. AB - Inorganic arsenic is a known human carcinogen, yet its mechanism of action remains unclear. Our previous study showed that arsenite significantly induces oxidative DNA adducts and DNA-protein cross-links in several mammalian cell lines. In the present study, we used the random amplified polymorphic DNA (RAPD) assay to evaluate the possible target in the genomic DNA of human lymphoblastoid cells that were exposed to sodium arsenite. Treatment with both 10 and 80 microM arsenite for 4h induced significant changes in RAPD profiles compared with the control pattern. Two 10-mer RAPD primers (D11 and F1) produced the most distinguishable banding profiles between arsenite-treated and control genomic DNA. The sequencing of four arsenite-sensitive RAPD bands showed that the RB1CC1 and PACE4 genes might be the DNA targets of sodium arsenite treatment. We propose that arsenite may induce sequence- or gene-specific damage and then change the RAPD profile in human lymphoblastoid cells. The results of our study also show that RAPD combined with other techniques is a good tool for detecting alterations in genomic DNA and for the direct screening of new molecular markers related to arsenite-induced carcinogenesis. PMID- 17707573 TI - Short interfering RNA (siRNA), a novel therapeutic tool acting on angiogenesis. AB - The formation of new blood vessels, uncontrolled cell expansions and invasions are the common feature of cancer, neovascular inflammatory and ocular diseases, such as age-related macular degeneration (AMD). Short interfering RNA (siRNA) and short-hairpin RNA (shRNA) have recently helped extend our understanding of the mechanisms regulating angiogenesis and tumor developments. Moreover, the early success of these tools has reinforced the therapeutic hopes of preventing endogenous or exogenous gene translation. In vivo experiments using several animal tumor models and human pre-clinical trials augured many benefits to control protein expression and cell signaling. The high specificity of siRNA and shRNA to target a protein is crucial to design a new generation of therapeutic agents. At the present, several investigations are focused on the understanding of both gene function and the proof-of-concept for siRNA-mediated anti angiogenesis. Taken together, in vitro and in vivo studies shed light on the efficiency of siRNA as a new alternative therapeutic agent. PMID- 17707571 TI - Comparative in vivo effects of parathion on striatal acetylcholine accumulation in adult and aged rats. AB - Aged rats are more sensitive to the acute toxicity of the prototype organophosphate insecticide, parathion. We compared the acute effects of parathion on diaphragm and brain regional cholinesterase activity, muscarinic receptor binding and striatal acetylcholine levels in 3- and 18-month-old male Sprague-Dawley rats. Adult and aged rats were surgically implanted with a microdialysis cannula into the right striatum 5-7 days prior to parathion treatment. Rats were given either vehicle (peanut oil, 2 ml/kg) or one of a range of dosages of parathion (adult: 1.8, 3.4, 6.0, 9.0, 18 and 27 mg/kg, s.c.; aged: 1.8, 3.4, 6 and 9 mg/kg, s.c.) and body weight, functional signs of toxicity, and nocturnal motor activity were recorded for seven days. Three and seven days after parathion treatment, microdialysis samples were collected and rats were subsequently sacrificed for biochemical measurements. Higher dosages of parathion led to significant time-dependent reductions in body weight in both age groups. Rats in both age groups treated with lower dosages showed few overt signs of cholinergic toxicity while equitoxic high dosages (adult, 27 mg/kg; aged, 9 mg/kg) elicited marked signs of cholinergic toxicity (involuntary movements and SLUD [i.e., acronym for Salivation, Lacrimation, Urination and Defecation] signs) with peak effects being noted 3-4 days after treatment. Nocturnal activity (ambulation and rearing) was reduced in both age groups following parathion dosing, with more prominent effects in adults and rearing being more consistently affected. Dose- and time-dependent inhibition of cholinesterase activity was noted in both diaphragm and striatum. Total muscarinic receptor ([(3)H]quinuclidinyl benzilate, QNB) binding was significantly lower in aged rats, and both total binding and muscarinic agonist ([(3)H]oxotremorine methiodide] binding was significantly reduced in both age-groups treated with the highest dosages of parathion (adult, 27 mg/kg; aged, 9 mg/kg). In contrast to relatively similar levels of cholinesterase inhibition, striatal extracellular acetylcholine levels were significantly lower (2.2- to 2.9-fold) in aged rats at both 3 and 7 day time-points compared to adult rats treated with equitoxic dosages (i.e., 9 and 27 mg/kg, respectively). No age-related differences in in vitro striatal acetylcholine synthesis or in vivo acetylcholine accumulation following direct infusion of the cholinesterase inhibitor neostigmine (1 microM) were noted. While aged rats are more sensitive than adults to the acute toxicity of parathion, lesser acetylcholine accumulation was noted in the striatum of aged rats exhibiting similar levels of cholinesterase inhibition. These findings suggest that lesser acetylcholine accumulation may be required to elicit cholinergic signs in the aged rat, possibly based on aging-associated changes in muscarinic receptor density. PMID- 17707574 TI - Indicators for managing biosolids in Ireland. AB - Sustainable development indicators (SDIs) have emerged as a tool to measure progress towards sustainable development for a number of fields. However, no indicator initiative to date has been aimed at biosolids management at local authority, regional or national levels. This paper presents a study where stakeholders involved in the management of biosolids in Ireland participated in the development of SDIs for managing biosolids at the local/regional level. A significant 81% of participating stakeholders find SDIs either 'useful' or 'very useful' as a tool for managing biosolids. A suite of 22 indicators has been developed and arranged according to the driving force-pressure-state-impact response (DPSIR) indicator framework. The indicators address all the domains of biosolids management namely, production, quality, cost, legislation/regulation, training/research and recycling/disposal. The stakeholder approach is recognition that no effective indicator set can be developed without the input of stakeholders. PMID- 17707575 TI - Re: Francesco Montorsi. A plea for integrating laparoscopy and robotic surgery in everyday urology: the rules of the game. Eur urol 2007;52:307-9. PMID- 17707576 TI - Inflammation, metabolic syndrome, erectile dysfunction, and coronary artery disease: common links. AB - OBJECTIVE: Erectile dysfunction (ED) may be the early clinical manifestation of a generalized vascular disease and carries an independent risk for cardiovascular events. Low-grade subclinical inflammation affects endothelial function and is involved in all stages of the atherosclerotic process. This review identifies potential pathophysiologic links among low-grade inflammation, ED, metabolic syndrome, and coronary artery disease (CAD) and presents the clinical implications in terms of ED diagnosis, assessment of patient risk, and therapy. METHODS: A comprehensive evaluation was performed for available published data in full-length papers that were identified in MedLine up to July 2007. RESULTS: Studies support an association between metabolic syndrome, ED, and increased inflammatory state. Increased circulating levels of inflammatory and endothelial prothrombotic compounds are related to the presence and severity of ED. Specific inflammatory biomarkers and their combination appear to have the potential to aid ED diagnosis or exclusion. ED and CAD may confer a similar unfavorable impact on the inflammatory and prothrombotic state, whereas ED adds an incremental activation on top of CAD; these findings have important implications for cardiovascular risk. Lifestyle and risk factor modification, as well as pharmacologic therapy, are associated with anti-inflammatory effects. CONCLUSIONS: Low-grade systemic inflammation could be an important element of the association between metabolic syndrome, ED, and CAD. Its individualized assessment may be a valuable tool for ED diagnosis, risk assessment, and rationalized therapeutic approach especially in patients with ED who have metabolic syndrome and carry an intermediate risk for future cardiovascular events. PMID- 17707577 TI - Real-time MRI of orthotopic ileal neobladder voiding: preliminary findings. AB - OBJECTIVES: The purpose of this preliminary study was to analyze the dynamic changes in the configuration of the neobladder and naive bladder during voiding using real-time MRI. METHODS: This study included 10 male patients who had a radical cystectomy and an ileal orthotopic neobladder due to organ-confined bladder cancer and had good urinary function, and 5 male control volunteers. With the subjects in the lateral decubitus position, real-time MRI was performed during micturition. A sagittal slice orientation was used to depict the bladder and the entire length of the urethra; individual movements along the X-axis and Y axis of the bottom and top of the neobladder and the naive bladder were recorded and analyzed. Urodynamic studies (UDS) and video voiding cystourethrography were performed in patients. RESULTS: Five of the 10 neobladder patients could void in the lateral decubitus position. In normal controls and patients who could void, the bladder outlet bladder moved ventrocranially during micturition. The ileal bladder outlet moved a significantly longer distance than the naive bladder during micturition (X-axis, -13.4+/-1.5 vs. -3.6+/-4.3 cm, p=0.0014; Y-axis, 10.6+/-0.5 vs. -2.0+/-6.5 cm, p=0.0187). The distance that the bladder top moved between the naive bladders and the neobladder did not differ. UDS did not show a difference between patients who could and could not void at lateral position. CONCLUSIONS: During micturition, the neobladder was found to rotate and move more dynamically than the naive bladder. Real-time MRI is useful for assessing dynamic voiding function of orthotopic neobladders. PMID- 17707578 TI - Stem cell therapy in the treatment of stress urinary incontinence: a significant step in the right direction? PMID- 17707579 TI - Cyclooxygenase-2 inhibitors demonstrate anti-proliferative effects in oesophageal cancer cells by prostaglandin E(2)-independent mechanisms. AB - The incidence of oesophageal cancer (OC) has risen in recent decades, with survival rates remaining poor despite surgical treatment and adjuvant chemotherapy. Studies have reported cyclooxygenase-2 (COX-2) overexpression in OC and current evidence suggests NSAIDs have major potential for chemoprevention through COX-2 inhibition. However, several reports have questioned the specificity of these inhibitors, suggesting they may act through mechanisms other than COX-2. We evaluated the effects of specific COX-2 inhibitors, NS-398 and nimesulide, on cell lines of both histological types of OC. COX-2 protein expression varied in the cell lines and corresponded with levels of prostaglandin E(2) (PGE(2)) production. Following treatment with low concentrations of NS-398 (0.1 microM), PGE(2) production was reduced dramatically, indicating inhibition of COX-2 activity. Examination of cellular morphology, caspase-3 activity and mitochondrial membrane integrity found no major induction of apoptotic cell death at concentrations below 100 microM. Tumour cell proliferation was significantly reduced at high concentrations (50-100 microM) of both inhibitors over 6 days. Cellular responses were more evident in NS-398-treated adenocarcinoma cells. However, concentrations required to inhibit proliferation were up to 1000-fold higher than those needed to inhibit enzyme activity. Addition of exogenous PGE(2) to NS-398-treated adenocarcinoma cells failed to reverse the inhibitory effects, indicating PG and COX-2 independence. It remains possible that in vivo COX-2 is the primary target, as enzyme inhibition can be achieved at low concentrations, however, inhibition of proliferation is not the primary mechanism of their anti tumour activity. PMID- 17707580 TI - Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in water and suspended particulate matter from the Xijiang River, China. AB - Concentrations of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in water and suspended particulate matter (SPM) collected from the Xijiang River, China, were measured by the quarter from September 2005 to June 2006. Total PCDD/F concentration ranged from 2.659 to 4.596pg/L for water and from 562.4 to 3259.5pg/g for SPM. Concentrations were high in summer and low in winter. I-TEQ values in water and SPM were low, ranging from 0.012 to 0.075pg/L, with a mean value of 0.039pg/L. Calculated annual loadings of total PCDD/Fs and I-TEQ were 8.55kg and 0.026kg, respectively. Composition and homologue distribution of PCDD/Fs were varied because of large seasonal differences in discharge from the Xijiang River into the South China Sea. Comparison of the PCDD/Fs homologue and congener profiles of atmospheric deposition, soil, and water revealed that soil was the dominant source of PCDD/Fs in the Xijiang River. Industrial effluents were also possible sources of PCDD/Fs. A good correlation between logK(oc) and logK(ow) was observed for 2,3,7,8-substituted PCDDs and PCDFs and correlation coefficients were 0.71 and 0.84, indicating organic matter in SPM played a dominant role in PCDD/Fs partition between SPM and water. PMID- 17707581 TI - Removal of color from real dyeing wastewater by Electro-Fenton technology using a three-dimensional graphite cathode. AB - This work investigates the removal of color from wastewater that contains low dyestuff concentrations by the Electro-Fenton process. The color was removed by in situ electrogenerated hydrogen peroxides at a three-dimensional graphite cathode with added ferrous sulfates. Experimental runs were conducted to evaluate the effect of the operating parameters, such as the oxygen contact mode, the oxygen sparging rate, the applied current density, the concentration of ferrous ions, the solution temperature and the pH among others, on the removal of color. The removal efficiency of the color in the cathodic chamber reached 70.6% under specified operation conditions in 150 min. The removal efficiency was controlled by the mass transfer when the oxygen-sparging rate was less than 0.3 dm(3)/min for the reactor configuration herein. The optimal applied current density was 68 A/m(2) when the energy consumption was considered. The highest removal efficiency was obtained by adding 20 mM Fe(II) to the solution. The optimal solution pH was 3 in this work. The temperature negatively affected color removal. PMID- 17707582 TI - Removal of malodorous organic sulfides with molecular oxygen and visible light over metal phthalocyanine. AB - Organic sulfides are malodorous compounds in environment. In this work, deodorization of model substrates, methyl phenyl sulfide, 2-mercaptobenzoic acid and benzyl 2-propenyl sulfide, have been studied in an aerated methanolic aqueous solution under visible light irradiation (lambda>450nm), using metal phthalocyanine sulfonate (MPcS, M=Al, Pd) as a photocatalyst. The result shows that all the representative sulfides could be efficiently oxidized, with concomitant formation of sulfoxide and sulfone as the main products. Kinetic study using sodium azide and benzoquinone as reactive species scavenger reveals that the sulfide oxidation is mainly initiated by singlet oxygen. It is also observed that the rate of sulfide oxidation increases with increasing the water content in the mixed solvent. Recycle experiments with immobilized PdPcS on organoclay or immobilized AlPcS on anionic resin demonstrates that the sensitizer could be repeatedly used, without significant loss in the photosensitization activity. PMID- 17707583 TI - Selective adsorption and partitioning of nonionic surfactants onto solids via liquid chromatograph mass spectra analysis. AB - The sorption characteristics of three Triton series surfactants (Triton-100, Triton-305, and Triton-405) from aqueous solution onto four different solids with a wide range of organic matter (OM) content were studied through the liquid chromatograph mass spectrometry (LC-MS) analysis. The examined surfactant concentrations ranged from below to above the critical micelle concentration (CMC) of the selected surfactants. A parameter, Phi, defined as the ratio of the average ethylene oxide (EO) number of surfactant on the adsorbed phase to that in the aqueous solution, was used to distinguish the controlling mechanism (adsorption or partitioning) of surfactants from aqueous solution onto the solids. For solids with very low OM content, adsorption was the primary mechanism and the Phi values were found to be larger than 1.0 and might reduce to 1.0 with the increasing surfactant concentration. On the other hand, the Phi values for solids with very high content of OM were equal to or less than 1.0 and remained constant as the surfactant concentrations varied, in which partitioning was the most likely dominant mechanism. For solids with an intermediate content of OM, adsorption and partitioning mechanisms coexisted and the Phi values could be larger or less than 1.0 and decreased with the increasing surfactant concentration. PMID- 17707584 TI - Analysis of dechlorination kinetics of chlorinated aliphatic hydrocarbons by Fe(II) in cement slurries. AB - Degradative solidification/stabilization with ferrous iron (DS/S-Fe(II)) has been found to be effective in degrading a number of chlorinated aliphatic hydrocarbons including 1,1,1-trichloroethane (1,1,1-TCA), 1,1,2,2-tetrachloroethane (1,1,2,2 TeCA), tetrachloroethylene (PCE), trichloroethylene (TCE), 1,1-dichloroethylene (1,1-DCE), vinyl chloride (VC), carbon tetrachloride (CT) and chloroform (CF). Previous studies have characterized degradation kinetics in DS/S-Fe(II) systems as affected by Fe(II) dose, pH and initial target organic concentration. The goal of this study is to investigate the importance of various chemical properties on degradation kinetics of DS/S-Fe(II). This was accomplished by first measuring rate constants for degradation of 1,1,1-TCA, 1,1,2,2-TeCA and 1,2-dichloroethane (1,2-DCA) in individual batch experiments. Rate constants developed in these experiments and those obtained from the literature were related to thermodynamic parameters including one-electron reduction potential, two-electron reduction potential, bond dissociation energy and lowest unoccupied molecular orbital energies. Degradation kinetics by Fe(II) in cement slurries were generally represented by a pseudo-first-order rate law. The results showed that the rate constants for chlorinated methanes (e.g. CT, CF) and chlorinated ethanes (e.g. 1,1,1-TCA) were higher than those for chlorinated ethylenes (e.g. PCE, TCE, 1,1 DCE and VC) under similar experimental conditions. The log of the pseudo-first order rate constant (k) was found to correlate better with lowest unoccupied molecular orbital energies (E(LUMO)) (R2=0.874) than with other thermodynamic parameter descriptors. PMID- 17707585 TI - Differential effect of arecoline on the endogenous dioxin-responsive cytochrome P450 1A1 and on a stably transfected dioxin-responsive element-driven reporter in human hepatoma cells. AB - Dioxin-responsive element-mediated chemical activated luciferase expression (DRE CALUX) is one of alternative bioassays for the determination of dioxin levels. We have previously established a DRE-CALUX cell line, Huh7-DRE-Luc, by using stable transfection of Huh-7 cells with a reporter plasmid (4xDRE-TATA-Luc) carrying a DRE-driven firefly luciferase gene. It was also shown that arecoline, a major areca nut alkaloid, inhibited the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced cytochrome P450 1A1 (CYP1A1) activation in Huh-7 cells. The TCDD activated aryl hydrocarbon receptor (AhR) induces the DRE-CALUX activation and CYP1A1 gene expression via binding to DRE in promoter regions of these dioxin responsive genes. In the present study, the effect of arecoline on the TCDD induced activation of DRE-CALUX and CYP1A1 enzyme in Huh7-DRE-Luc and Huh-7 cells, respectively, was examined. It was found that arecoline inhibited TCDD induced CYP1A1 activation and however enhanced TCDD-induced DRE-CALUX activation. This finding indicates the differential effect of arecoline on the endogenous dioxin-responsive CYP1A1 and on a stably transfected DRE-driven reporter in human hepatoma cells. The present study suggests that induction of DRE-CALUX alone does not necessarily parallel with endogenous CYP1A1 gene expression, and that the reporter assay may detect interactions that are not functional in endogenous gene. PMID- 17707586 TI - MAPT gene duplications are not a cause of frontotemporal lobar degeneration. AB - Recurrent deletions of the 17q21.31 region encompassing the microtubule associated protein tau (MAPT) gene have recently been described in patients with mental retardation. This region is flanked by segmental duplications that make it prone to inversions, deletions and duplications. Since gain-of-function mutations of the MAPT gene cause frontotemporal lobar degeneration (FTLD) characterized by deposition of tau protein, we hypothesize that MAPT duplication affecting gene dosage could also lead to disease. Gene dosage alterations have already been found to be involved in the etiology of neurodegenerative disorders caused by protein or peptide accumulation, such as Alzheimer's and Parkinson's diseases. To determine whether MAPT gene copy number variation is involved in FTLD, 70 patients with clinical diagnosis of FTLD and no MAPT mutation (including 12 patients with pathologically proven tau-positive FTLD) were screened by using multiplex ligation probe amplification (MLPA) with specific oligonucleotide probes. No copy number variation in the MAPT gene was observed in cases. Although our study was limited by the relatively small number of patients, it does not support the theory that chromosomal rearrangements in this region are a cause of FTLD. PMID- 17707588 TI - A pain assessment scale for population-based studies: development and validation of the pain module of the Standard Evaluation Questionnaire. AB - The objectives of this study were to develop and validate a tool for assessing pain in population-based observational studies and to develop three subscales for back/neck, upper extremity and lower extremity pain. Based on a literature review, items were extracted from validated questionnaires and reviewed by an expert panel. The initial questionnaire consisted of a pain manikin and 34 items relating to (i) intensity of pain in different body regions (7 items), (ii) pain during activities of daily living (18 items) and (iii) various pain modalities (9 items). Psychometric validation of the initial questionnaire was performed in a random sample of the German-speaking Swiss population. Analyses included tests for reliability, correlation analysis, principal components factor analysis, tests for internal consistency and validity. Overall, 16,634 of 23,763 eligible individuals participated (70%). Test-retest reliability coefficients ranged from 0.32 to 0.97, but only three coefficients were below 0.60. Subscales were constructed combining four items for each of the subscales. Item-total coefficients ranged from 0.76 to 0.86 and Cronbach's alpha were 0.75 or higher for all subscales. Correlation coefficients between subscales and three validated instruments (WOMAC, SPADI and Oswestry) ranged from 0.62 to 0.79. The final Pain Standard Evaluation Questionnaire (SEQ Pain) included 28 items and the pain manikin and accounted for the multidimensionality of pain by assessing pain location and intensity, pain during activity, triggers and time of onset of pain and frequency of pain medication. It was found to be reliable and valid for the assessment of pain in population-based observational studies. PMID- 17707587 TI - Expression levels of adenosine receptors in hippocampus and frontal cortex in argyrophilic grain disease. AB - Expression of adenosine receptors of the A1, A2A and A2B type has been examined in the post-mortem frontal cortex and hippocampus in argyrophilic grain disease (AGD), a tauopathy affecting the hippocampus but usually not the frontal cortex, in an attempt to learn about the modulation of the adenosine pathway in this disorder. Significant increased levels of A1, but not of A2A and A2B, have been observed in AGD in the hippocampus but not in the frontal cortex, when compared with age-matched controls. This is accompanied by increased levels of adenylyl cyclase (AC), an effector of A1, and by increased (although not significant) percentage of inhibition of forskolin-stimulated AC by the A1 agonist cyclohexyladenosine in the hippocampus in AGD. These findings indicate sensitization of A1/AC in the hippocampus in AGD, and support a putative activation of the A1/AC pathway that may facilitate protection of this preferentially involved region in AGD. PMID- 17707589 TI - A systematic review of the effect of waiting for treatment for chronic pain. AB - In many countries timely access to care is a growing problem. As medical costs escalate health care resources must be prioritized. In this context there is an increasing need for benchmarks and best practices in wait-time management. The Canadian Pain Society struck a Task Force in December 2005 to identify benchmarks for acceptable wait-times for treatment of chronic pain. As part of the mandate a systematic review of the literature regarding the relationship between waiting times, health status and health outcomes for patients awaiting treatment for chronic pain was undertaken. Twenty-four studies met the inclusion criteria for the review. The current review supports that patients experience a significant deterioration in health related quality of life and psychological well being while waiting for treatment for chronic pain during the 6 months from the time of referral to treatment. It is unknown at what point this deterioration begins as results from the 14 trials involving wait-times of 10 weeks or less yielded mixed results with wait-times amounting to as little as 5 weeks, associated with deterioration. It was concluded that wait-times for chronic pain treatment of 6 months or longer are medically unacceptable. Further study is necessary to determine at what stage the deterioration begins from the onset of pain to treatment and the impact of waiting on treatment outcomes. Most important is the need to improve access to appropriate care for patients with chronic pain, an escalating public health care problem with significant human and economic costs. PMID- 17707590 TI - Inhibition of L-selectin binding by polyacrylamide-based conjugates under defined flow conditions. AB - Selectins mediate tethering and rolling of leukocytes along the endothelium in a shear force-dependent manner. This key step in the cellular immune response is a target for experimental anti-inflammatory therapies. In the present paper we have examined the inhibitory activity of the minimal selectin ligand sialyl Lewis x (SiaLe(x)), its isomer sialyl Lewis a (SiaLe(a)) and sulfated tyrosine (sTyr) residues under dynamic flow reflecting the rheological conditions in the blood stream. The monomeric ligands were compared to multivalent polyacrylamide (PAA) based conjugates under defined flow conditions on the molecular level, using surface plasmon resonance (SPR) technology, and on the cellular level, using a parallel-plate flow chamber. SPR measurements showed that a spatial arrangement of binding epitopes mimicking the selectin binding motif of the natural ligand PSGL-1 inhibits L-selectin binding successfully with IC(50) values in the nanomolar range. Using a flow chamber adhesion assay it could be shown that the multivalent inhibitors efficiently blocked rolling and tethering of NALM-6 pre-B cells transfected with human L-selectin to activated endothelium and that the inhibitory activity increased with rising shear stress. While PAA-conjugates were almost not inhibitory at low shear stress, NALM-6 cell rolling was nearly completely inhibited at high shear stress. The results indicate that multimeric conjugates of SiaLe(x), SiaLe(a) and sTyr are highly effective inhibitors of L selectin-mediated cell adhesion particularly under flow conditions. Consequently, SiaLe(x), SiaLe(a) and/or sTyr on macromolecular carriers may be promising candidates for anti-inflammatory therapy. PMID- 17707591 TI - Purification of the receptor for the N-acetyl-D-glucosamine specific adhesin of Mannheimia haemolytica from bovine neutrophils. AB - The GlcNAc-specific adhesin from Mannheimia haemolytica (MhA) has been shown to participate in pathogenicity of mannheimiosis due to its capacity to adhere to tracheal epithelial cells and activate the oxidative burst of bovine neutrophils. In this work, we purified the MhA receptor from bovine neutrophils (MhAr) by affinity chromatography on MhA-Sepharose. The MhAr, which corresponded to approximately 2% of the protein from cell lysate, is a glycoprotein mainly composed of Glu, Ala, Ser, Gly, and Asp, without cysteine. The glycan portion, which corresponds to 20% by weight, is composed of GalNAc, GlcNAc, Man, Gal, and NeuAc. The receptor is a 165-kDa glycoprotein, as determined by molecular sieve chromatography under native conditions; SDS-PAGE analysis shows a heterodimer of 83 and 80 kDa subunits. This work suggests that the GlcNAc-containing receptor plays a relevant role by activating bovine neutrophils through non-opsonic mechanisms. PMID- 17707592 TI - Enhanced inflammatory hyperalgesia after recovery from burn injury. AB - Severe burn induces severe pain. While chronic as well as acute pain syndromes are reported, the peripheral mechanisms of burn-induced chronic pain syndromes have not been studied. We tested the hypothesis that burn induces plastic changes in primary afferent nociceptors that predispose to chronic pain states. Mechanical nociceptive thresholds were measured using the Randall-Selitto paw withdrawal test in male Sprague-Dawley rats, before and following a small (<1% total body surface area) partial-thickness thermal injury to the dorsal surface of one hind paw. This burn induced mechanical hyperalgesia, which lasted over 2 weeks. After recovery, local injection of prostaglandin E2 (PGE2), to mimic re injury, induced an enhanced and markedly prolonged mechanical hyperalgesia compared to the hyperalgesic effect of PGE2 in the control contralateral paw. This prolonged PGE2-induced hyperalgesia was reversed by a selective inhibitor of protein kinase C-epsilon (PKCepsilon). Our findings suggest PKCepsilon as a peripheral mechanism for burn-induced chronic pain syndromes. PMID- 17707593 TI - Current status of excision repair cross complementing-group 1 (ERCC1) in cancer. AB - Cisplatin, carboplatin and oxaliplatin are some of the most widely used anti cancer agents in solid tumours. The cytotoxicity of platinating agents is directly related to their ability to cause DNA intra-strand crosslinks that trigger a series of intracellular events that ultimately result in cell death. DNA intra-strand crosslinks are processed and repaired by the nucleotide excision repair pathway. It is now clear that nucleotide excision repair (NER) capacity may have a major impact on the emergence of resistance, normal tissue tolerance and patient outcomes. ERCC1 is a key player in NER. In this review, we provide an overview of mammalian NER and then focus on biochemical, structural and pre clinical aspects of ERCC1. We then present current clinical evidence implicating ERCC1 as a predictive and prognostic marker in cancer. Early evidence also suggests that ERCC1 or the pathways involved in the regulation of ERCC1 expression may be attractive anti-cancer targets. Such agents are expected to potentiate the cytotoxicity of platinating agents and could have a major impact on cancer therapy. PMID- 17707595 TI - Concept formation based on value relations evaluated with a matching-to-sample procedure. AB - To study concept formation based on relations, adults were taught and tested on complex discriminations involving figures that varied in colors, forms, and orientations. In Experiment 1, participants learned to select figures with values A1 and B1 or values B1 and C1; thereafter, they consistently selected figures with values A1 and C1. Selections were based on the relations among the values, rather than on perceptual properties. Experiments 2 and 3 studied generalization with a matching-to-sample procedure: participants learned to select "yes" in the presence of the positive figures, such as A1B1, and "no" in the presence of the negative figures. Thereafter, all figures that resulted from combining three values of the three relevant dimensions were probed. Participants typically selected "yes" in the presence of the novel figures that had two or three values related to one another and selected "no" in the presence of the other figures. Finally, two participants learned a simple discrimination. They did not generalize responding to other figures with the same values; instead, their performance in the generalization test remained almost unaltered. Thus, the concept based on relations was not affected by the simple discrimination. These results showed some unique properties of the concept based on relations and challenge previous theories on concept formation. PMID- 17707594 TI - Efficacy of counselor vs. computer-delivered intervention with mandated college students. AB - The purpose of this study was to evaluate the efficacy of two brief interventions and the inclusion of a 1-month booster session with college students who were referred to attend alcohol education following an alcohol-related incident. Participants (N=225; 48.9% male) were randomly assigned to receive one session of a Brief Motivational Interview (BMI) or computer-delivered intervention (CDI) with the Alcohol 101 CD-ROM. Participants were also randomly assigned to booster/no booster. At 3-month follow up, participants in BMI reported greater help seeking and use of behavioral strategies to moderate drinking. At 12-month follow up, BMI participants were drinking more frequently and CDI participants were consuming a greater number of drinks per occasion than at baseline. Mediation analyses showed that the use of specific behavioral strategies mediated the effect of the BMI condition on drinking volume. There was no intervention effect on alcohol problems, and the booster condition did not significantly affect outcomes. Promoting specific behaviors in the context of in-person brief interventions may be a promising approach to reducing drinking volume among identified at-risk students. PMID- 17707596 TI - Cooperative reading: some suggestions for integration of the cooperation literature. PMID- 17707597 TI - Application of an integrated cooperation approach to human cooperative breeders. PMID- 17707598 TI - Evolution of melanocortin receptors in teleost fish: the melanocortin type 1 receptor. AB - The melanocortin type 1 receptor (Mc1r) belongs to a family of G-protein-coupled receptors involved in various physiological processes in vertebrates. Melanocortins, the Mcr natural agonists, are pituitary peptide hormones including adrenocorticotropin and melanocyte-stimulating hormones. In mammals and birds, Mc1r is involved in pigmentation and expressed in melanocytes and melanoma. Activation of Mc1r leads to eumelanin production as well as to proliferation and survival of melanocytes in the epidermis. Here we report the molecular and evolutionary analysis of mc1r from three major fish models, the zebrafish Danio rerio, the medaka Oryzias latipes and the platyfish Xiphophorus maculatus. In contrast to some other melanocortin receptor genes, mc1r has been conserved as a single copy gene in divergent fish species. Its expression was detected in all organs tested in platyfish and medaka but was restricted to eyes, skin, brain and testis in zebrafish, this possibly reflecting differences in the distribution of extracutaneous melanophores. The mc1r gene was found to be expressed during embryogenesis, as well as in Xiphophorus hybrid melanoma, similar to human tumours. Protein sequence comparison between fish and mammalian Mc1r revealed a remarkable concordance between evolutionary and functional analyses for the identification of residues and regions critical for receptor function. PMID- 17707599 TI - Evidence for a slightly deleterious effect of intron polymorphisms at the EF1alpha gene in the deep-sea hydrothermal vent bivalve Bathymodiolus. AB - A multilocus analysis was initiated in order to infer the general effect of demography and the indirect effect of positive selection on some chromosome segments in Bathymodiolus. Mussels of the genus Bathymodiolus inhabit the very hostile, fragmented and variable environment of deep-sea hydrothermal vents which is thought to cause recurrent population bottlenecks via extinction/colonisation processes and adaptation to new environmental conditions. In the course of this work we discovered that the assumption of neutrality of non-coding polymorphisms usually made in genome scan experiments was likely to be violated at one of the loci we analysed. The direct effect of slight purifying selection on non-coding polymorphisms shares many resemblances with the indirect effect of positive selection through genetic hitchhiking. Combining polymorphism with divergence data for several closely related species allowed us to obtain different expectations for the direct effect of negative selection and the indirect effect of positive selection. We observed a strong excess of rare non-coding polymorphisms at the second intron of the EF1alpha gene in the two species Bathymodiolus azoricus and Bathymodiolus thermophilus, while two other loci, the mitochondrial COI gene and an intron of the Lysozyme gene, did not exhibit such a deviation. In addition, the divergence rate of the EF1alpha intron was estimated to be unexpectedly low when calibrated using the closure of the Panama Isthmus that interrupted gene flow between the two species. The polymorphism to divergence ratio was similar to the one observed for the other two loci, in accordance to the hypothesis of purifying selection. We conclude that slight purifying selection is likely to act on polymorphic intronic mutations of the EF1alpha second intron and discuss the possible relationship with the specific biology of Bathymodiolus mussels. PMID- 17707600 TI - Transcription factor hStaf/ZNF143 is required for expression of the human TFAM gene. AB - The mitochondrial transcription factor A (Tfam) is essential for transcription initiation and replication of mitochondrial DNA. It was previously reported that transcription factors Sp1, NRF-1, NRF-2 were critical for maintaining the normal transcription levels of the mammalian TFAM gene. In this work, investigation of the transcriptional regulation of the human TFAM gene revealed the presence of two cross-species conserved binding sites for the transcription factor hStaf/ZNF143. By using promoter binding assays, transient expression of mutant TFAM reporter gene constructs and chromatin immunoprecipitation experiments, we provided insight into the involvement of hStaf/ZNF143 in promoter activity. Furthermore, we reported the identification of two other functionally important elements. Altogether, our data led to the conclusion that the promoter of the human TFAM gene harbors a complex organization with at least six transcriptional regulatory elements. PMID- 17707601 TI - Oral delivery of insulin loaded poly(fumaric-co-sebacic) anhydride microspheres. AB - The bioadhesive polymer, poly(fumaric-co-sebacic) anhydride, p(FASA), was used to fabricate small diameter insulin microspheres and evaluate their in vivo performance in a type 1 diabetic rat as well as a type 1 diabetic dog model. The process of phase inversion nanoencapsulation was used to fabricate p(FASA) microspheres containing insulin. Using laser diffraction spectrometry, 90% of the microspheres used in the fed double dose rat experiments were found to have a volumetric diameter of 5.9 microm or smaller. In comparison, 90% of the microspheres used in fed single dose rat experiments were found to have a volumetric diameter of 2.6 microm or smaller while the microspheres used in the diabetic dog experiments were found to have a volumetric diameter of 1.2 microm or smaller. Insulin microspheres administered to diabetic rats in the fed double dose experiment produced a relative bioavailability (RB) of 23.3% while insulin microspheres administered to diabetic rats in the fed single dose experiment produced a RB of 5.5+/-1.7%. Insulin microspheres administered to fasted diabetic dogs produced a RB of 5.5+/-3.4%. PMID- 17707602 TI - Surface pressure measurements in particle interaction and stability studies of poly(lactic acid) nanoparticles. AB - Stability of nanoparticle dispersion in different environments is one key issue in determining the performance and safety of the drug delivery system in question. In this study, aggregation tendency and particle-particle interactions of poly(lactic acid) nanoparticles were evaluated by their interfacial behavior upon compression. Surface pressure versus trough area (pi vs. A) isotherms of the nanoparticles were registered on different subphases (pH, electrolyte concentration). The compressed particle populations were transferred to silica plates by Langmuir-Schaefer deposition and analyzed with scanning electron microscope. Aggregation of the electrostatically stabilized surfactant-free nanoparticles due to subphase alterations was clearly detected from the isotherms even though zeta potential value of the nanoparticles (-35mV) suggested a stable system. When steric stabilization, provided by a surfactant (Poloxamer 188) in this study, was involved besides the electrostatic stabilization, the nanoparticles remained non-aggregated over a wider range of conditions. Steric stabilization together with electrostatic stabilization extended the repulsion to a longer distance. PMID- 17707604 TI - Parental view of epilepsy in Rett Syndrome. AB - Few instruments exist to measure the impact of epilepsy on the quality of life in Rett Syndrome (RS). METHODS: We attended to describe seizures characteristics, parental opinion and quality of life related in RS by using a newly developed self administered questionnaire, postal sent to parents of French Association for Rett Syndrome (AFSR). RESULTS: Two-hundred completed questionnaires were returned. Mean age of patients was 14.8+/-8.1 years [3-42]. Parents reported that 70% of children had epileptic and non-epileptic seizures and mean age at first seizures was 7.3+/-5.1 years [1-24]. No statistical difference was found between the ages of first seizures, diagnosis of epilepsy and introduction of treatment. Seizures had a negative impact on child and family's life (68% of cases), strongly correlated to the existence of generalized, prolonged, cyanotic and drug resistant seizures, on the child's level of alertness and progress in communication skills and psycho-social consequences such as fear of seizures, and difficulties to find home care aids. CONCLUSIONS: We identified major concerns of parents with RS that determine the impact of seizures on children and their family's quality of life. Our results suggest that in order to improve seizures management in RS, better information should reduce fear about seizures and should improve the quality of life of RS. PMID- 17707603 TI - Toxicity and mutagenic activity of some selected Nigerian plants. AB - The toxicity and mutagenic potential of most African plants implicated in the management of cancer have not been investigated. The ethanolic extracts of selected Nigerian plants were subsequently studied using the brine shrimp lethality tests, inhibition of telomerase activity and induction of chromosomal aberrations in vivo in rat lymphocytes. Morinda lucida root bark, Nymphaea lotus whole plant and Garcinia kola root were active in the three test systems. Bryophyllum calycinum whole plant, Annona senegalensis root, Hymenocardia acida stem bark, Erythrophleum suaveolens leaves and Spondiathus preussii stem bark were toxic to brine shrimps and caused chromosomal damage in rat lymphocytes. Ficus exasperata leaves, Chrysophyllum albidum root bark and Hibiscus sabdariffa leaves were non-toxic to all the three test systems. Chenopodium ambrosioides whole plant was non-toxic to brine shrimps and rat lymphocyte chromosomes but showed inhibition in the conventional telomerase assay indicating a possible selectivity for human chromosomes. The result justified the use of the first eight plants and Chenopodium ambrosioides in the management of cancer in south west Nigeria although they appear to be non-selective and their mode of action may be different from plant to plant. All these plants except Chenopodium ambrosioides are also mutagenic and cytotoxic. PMID- 17707605 TI - [Treatment and follow up of disseminated and late Lyme disease]. AB - The aim of this review was to analyze the current strategies of treatment and follow-up of disseminated and late Lyme borreliosis. A comprehensive search was performed using the Medline database. Only relevant reviews, expert guidelines and randomized controlled clinical trials were selected and, if necessary, open trials. Major drugs used in these studies were amoxicillin, doxycycline, penicillin G, and ceftriaxone. Oral administration of antibiotics was preferred in Lyme arthritis whereas parenteral drugs were mostly used in neuroborreliosis. The treatment duration usually ranged from 14 to 30 days. Prolonged antibiotic courses recommended by some authors in post-Lyme syndromes were not validated by several randomized placebo controlled studies. Follow up patterns were analyzed in order to determine possible prognosis parameters allowing to distinguih active Borrelia burgdorferi infection from a sequel of infection. PMID- 17707606 TI - Application of a new combined guiding technique in RF ablation of subphrenic liver tumors. AB - We present an unreported technique used to treat with RF ablation hepatic subphrenic hepatocellular carcinoma. It consists in the combination of fluoroscopic and computed tomography guidance for lesions already embolized with lipiodol located at the hepatic dome, approached in parallel fashion with a 22 gauge chiba "finder" needle followed by the RF electrode. PMID- 17707607 TI - Identification of new metabolites of morroniside produced by rat intestinal bacteria and HPLC-PDA analysis of metabolites in vivo. AB - Morroniside, the most abundant iridoid glycoside of traditional Chinese medicines Fructus Corni, was shown to prevent diabetic angiopathies. During the course of our studies on its metabolism by intestinal bacteria, two metabolites (mor-1 and mor-2) were isolated and purified by thin layer chromatography (TLC) and preparative high performance liquid chromatography (HPLC), and then identified as nitrogen-containing compounds along with the known aglycones on the basis of mass spectrometry (MS), and by one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy. Mor-1 and mor-2 were proved to be new compounds. The structures of the metabolites of morroniside detected in rat urine, bile, feces and contents of intestine after oral administration of morroniside proved to be identical with those of the microbial metabolites mor-1 and mor-2. PMID- 17707608 TI - 1H NMR study of the effects of sample contamination in the metabolomic analysis of mouse urine. AB - Nuclear magnetic resonance (NMR) spectroscopy was used to evaluate and optimize the strategy for collecting mouse urine samples. A series of normal urine samples and those mixed with folate-deficient food, turkey or mouse fecal particles were analyzed using principal component analysis (PCA). The metabolic profile of urine mixed with folate-deficient food was found to be extremely different than that of clean urine. Changes in the urine composition caused by mixing with turkey or feces are relatively small as judged by the output of PCA. As a result, turkey may be considered as an applicable food source for obtaining uncontaminated urine samples for metabolomics-based research. PMID- 17707609 TI - Disrupted social connectedness among Dominican women with chronic filarial lymphedema. AB - OBJECTIVE: The objectives of this paper were to identify specific factors associated with intact or disrupted social connectedness among Dominican women with chronic filarial lymphedema and better understand the impact of disrupted connectedness on their lives. METHODS: Data were collected through 28 individual interviews and 3 focus group discussions of 28 women from filariasis-endemic areas of the Dominican Republic presenting with lymphedema of one or both legs. RESULTS: The confluence of chronic and acute stressors with severity of lymphedema lead women to rely on others for social support. Women described complications of aging, disability, reduced social networks, and inability to adhere to cultural scripts as contributing to disrupted social connectedness. CONCLUSION: Social disconnectedness appears to exacerbate the negative consequences of living with lymphedema among women. Social connectedness and cultural scripts often define a social role for women that transcend physical deformity and disability, while disrupted social connectedness contributes to social isolation, depressive symptoms, and poor health outcomes. PRACTICE IMPLICATIONS: Further behavioral research into the contribution of intact social connectedness to resiliency and coping is warranted in order to develop effective interventions for women. Identifying women with disrupted social connectedness and engaging them in behavioral interventions to enhance natural social networks and create new or enhanced social support opportunities may mitigate the negative effects of social disconnectedness and improve quality of life. PMID- 17707610 TI - Transcriptional regulation in eukaryotic ribosomal protein genes. AB - Understanding ribosomal protein gene regulation provides a good avenue for understanding gene regulatory networks. Even after 5 decades of research on ribosomal protein gene regulation, little is known about how higher eukaryotic ribosomal protein genes are coordinately regulated at the transcriptional level. However, a few recent papers shed some light on this complicated problem. PMID- 17707611 TI - Vector edge operators for cDNA microarray spot localization. AB - This paper introduces a vector-based framework for edge detection and spot localization in cDNA microarray data. Since cDNA microarray images can be viewed as vector fields, both their spectral and spatial characteristics should be used to determine edges, discontinuities and structural elements. Building upon the powerful nature of nonlinear operators, the proposed vector edge operators can effectively localize microarray spots outperforming the commonly used scalar edge detectors. Moreover, due to the utilization of the principle of robust statistics, vector edge detectors are relatively immune to the noise present in microarray images. Simulation studies reported in this paper indicate that the proposed framework yields excellent performance and it can be readily incorporated in the cDNA microarray processing pipeline. PMID- 17707612 TI - Streptococcus pneumoniae bacteraemia in children. AB - Occult bacteraemia is the most frequent invasive disease caused by Streptococcus pneumoniae in children less than 3 years of age. Despite the relative frequency of this infection, its management is still a challenging task for paediatricians because fever is often the only symptom and a considerable overlap exists in the clinical presentation of children with fever without a focus due to viral illness and children with occult bacteraemia. Management protocols take into account the age of the patient, the clinical score for severity and the results of laboratory tests such as the white blood cell count, the C-reactive protein and the blood procalcitonin level in order to define accurately who will benefit from an antibiotic treatment. Despite appropriate healthcare facilities and access to care the case fatality rate in developed countries is around 9% in children aged less than 1 year. Prevention with the 7-valent conjugate vaccine against S. pneumoniae will decrease morbidity and mortality associated with invasive disease due to these bacteria. However, replacement by non-vaccine serotypes has been noted in countries where the vaccine is widely used and this concern needs to be monitored carefully over the next few years. PMID- 17707613 TI - Molecular diagnosis of bloodstream infections caused by non-cultivable bacteria. AB - Bloodstream infections are an important cause of morbidity and mortality in patients. Blood culture is clearly the most important diagnostic procedure for identifying micro-organisms involved in bloodstream infections except when the patient has previously received antibiotics or in the presence of slow-growing or intracellular micro-organisms. Detection of micro-organisms, mainly in blood, using pathogen-specific or broad-range PCR assays is promising. However, it is very important to emphasise that the interpretation of this molecular tool is critical because of the risk of interfering contamination, underlining the necessity to interpret the results obtained with caution. Presently, due to more widely available data and to rapid advances in biotechnology, two significant improvements allow new perspectives for molecular diagnosis. Indeed, the complete sequences of genomes have provided an important source of gene sequences for PCR based assays. In addition, the development of real-time PCR offers several advantages in comparison to conventional PCR, including speed, simplicity, quantitative capability and low risk of contamination. Herein, we review the usefulness of molecular diagnosis of highly fastidious micro-organisms in the context of three different bloodstream infections: systemic diseases (rickettsiosis, Q fever, bartonellosis, Whipple's disease), blood-culture negative endocarditis and bioterrorism attack. PMID- 17707614 TI - N,N'-Hexadecanoyl l-2-diaminomethyl-18-crown-6 surfactant: synthesis and aggregation features in aqueous solution. AB - Bolas surfactants can be inserted into bi-layers and may operate as permanent holes in such membranes. Significant synthetic work and an exhaustive characterisation of their properties in the bulk was performed. On this purpose, the phase diagram of the system composed by water and 1,16-hexadecanoyl-bis-(2 aminomethyl)-18-crown-6 (termed Bola A16) was investigated in a wide temperature and concentration range. No liquid crystalline phases were observed and a large micellar solution was present, up to about 50 surfactant wt%. Surface tension experiments defined adsorption and micelle formation. The low observed cmc value is important for pharmacological applications, in fact, considering intravenous administration, only micelles with low cmc value can exist in blood. Nuclear magnetic resonance experiments determined both water and surfactant self diffusion. According to the aforementioned experiments, slight, if any, modifications in the structure of micelles were inferred on increasing Bola A16 content. Dynamic rheological experiments probed the solution micro-structure. The observed rheological behaviour is newtonian. The solution viscosity and the shear relaxation processes were rationalized assuming the presence of spherical aggregates, occurring up to high surfactant content. The viscometric behaviour was rationalised in terms of a former theory of flow as a cooperative phenomenon. The number of micelles coordinated each other during the viscous flow and the interaction strength between them was obtained as a function of Bola A16 concentration. Such value is close to unity and practically independent of surfactant content in the whole concentration range we investigated. This behaviour points out that little, or none, interactions among micellar aggregates occur. The absence of shear induced changes in the aggregate shape implies no change in drug delivery properties under flow, this is useful in the pharmaco dynamics field, since drug delivery usually operates in mechanically stressed conditions. Thanks to the above properties, the material results particularly suitable for application in pharmaceutical field, may solubilize lipid membranes and selectively transport ions across them. Ancillary effects, such as the uptake of counter-ions in the crown ether, are to be considered. PMID- 17707616 TI - The Effect of Exposure of Guinea Pig to Cigarette Smoke and their Sensitization in Tracheal Responsiveness to Histamine and Histamine Receptor (H(1)) Blockade by Chlorpheniramine. AB - Airway responsiveness to histamine and histamine H(1) receptor blockade by chlorpheniramine (CR-1) on guinea pig trachea were examined. Chronic obstructive pulmonary disease (COPD) and asthma were induced in guinea pigs by exposing them to cigarette smoke for 3 months and by sensitization with injection and inhalation of ovalbumin (OA). The responses of tracheal chains of COPD (n=8), COPD+asthma (n=6) and control animals (n=8) to histamine (EC(50) H) and (CR-1) were measured. The in vitro histamine responses of COPD and COPD+asthmatic guinea pigs in tracheal chains were significantly higher than those of control animals (p<0.001 and p<0.01, respectively). The CR-1 blockade was also significantly greater in trachea of COPD and COPD+asthma compared to that of controls (p<0.01 and p<0.05, respectively). There were significant correlations between EC(50) H and (CR-1) (r=-0.542, p<0.01). The hematocrit in COPD and COPD+asthma groups was also significantly higher than in controls (p<0.001 for both groups). The contractility of tracheal chains to histamine in COPD+asthma animals was significantly greater than those of control and COPD groups (p<0.05 for both cases). The differences in contractility between COPD and COPD+asthmatic groups, however, suggests different basic mechanisms for AHR in COPD and asthma. PMID- 17707615 TI - Enhanced cytotoxicity of monoclonal anticancer antibody 2C5-modified doxorubicin loaded PEGylated liposomes against various tumor cell lines. AB - Doxorubicin-loaded long-circulating liposomes (Doxil, ALZA Corp.) were additionally modified with the nucleosome-specific monoclonal antibody 2C5 (mAb 2C5) recognizing a broad variety of tumor cells via the tumor cell surface-bound nucleosomes. These mAb 2C5-modified PEGylated liposomes demonstrated 3-8-fold increase in the in vitro binding and internalization by multiple cancer cell lines of diverse origins (murine LLC, 4T1, C26 and human BT-20, MCF-7, and PC3), as shown by flow cytometry (FACS) and epi and confocal microscopy. As a result, mAb 2C5-modified Doxil demonstrated significantly higher cytotoxicity towards various cancer cells, including those resistant to doxorubicin, than all control preparations. The specific internalization of the mAb 2C5-Doxil into cytosol, along with the nuclear localization of their drug load, inside the target cancer cells were mainly responsible the superior anticancer activity. The IC50 values of mAb 2C5-Doxil with various murine and human cancer cells were 5-8-fold lower than those of control doxorubicin-loaded liposomes, Doxil or Doxil modified with a nonspecific IgG. PMID- 17707617 TI - Feature selection and classification model construction on type 2 diabetic patients' data. AB - OBJECTIVE: Diabetes affects between 2% and 4% of the global population (up to 10% in the over 65 age group), and its avoidance and effective treatment are undoubtedly crucial public health and health economics issues in the 21st century. The aim of this research was to identify significant factors influencing diabetes control, by applying feature selection to a working patient management system to assist with ranking, classification and knowledge discovery. The classification models can be used to determine individuals in the population with poor diabetes control status based on physiological and examination factors. METHODS: The diabetic patients' information was collected by Ulster Community and Hospitals Trust (UCHT) from year 2000 to 2004 as part of clinical management. In order to discover key predictors and latent knowledge, data mining techniques were applied. To improve computational efficiency, a feature selection technique, feature selection via supervised model construction (FSSMC), an optimisation of ReliefF, was used to rank the important attributes affecting diabetic control. After selecting suitable features, three complementary classification techniques (Naive Bayes, IB1 and C4.5) were applied to the data to predict how well the patients' condition was controlled. RESULTS: FSSMC identified patients' 'age', 'diagnosis duration', the need for 'insulin treatment', 'random blood glucose' measurement and 'diet treatment' as the most important factors influencing blood glucose control. Using the reduced features, a best predictive accuracy of 95% and sensitivity of 98% was achieved. The influence of factors, such as 'type of care' delivered, the use of 'home monitoring', and the importance of 'smoking' on outcome can contribute to domain knowledge in diabetes control. CONCLUSION: In the care of patients with diabetes, the more important factors identified: patients' 'age', 'diagnosis duration' and 'family history', are beyond the control of physicians. Treatment methods such as 'insulin', 'diet' and 'tablets' (a variety of oral medicines) may be controlled. However lifestyle indicators such as 'body mass index' and 'smoking status' are also important and may be controlled by the patient. This further underlines the need for public health education to aid awareness and prevention. More subtle data interactions need to be better understood and data mining can contribute to the clinical evidence base. The research confirms and to a lesser extent challenges current thinking. Whilst fully appreciating the requirement for clinical verification and interpretation, this work supports the use of data mining as an exploratory tool, particularly as the domain is suffering from a data explosion due to enhanced monitoring and the (potential) storage of this data in the electronic health record. FSSMC has proved a useful feature estimator for large data sets, where processing efficiency is an important factor. PMID- 17707618 TI - Lipid nanoparticles for alkyl lysophospholipid edelfosine encapsulation: development and in vitro characterization. AB - The ether lipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine, edelfosine (ET-18-OCH(3)) is the prototype molecule of a promising class of antitumor drugs named alkyl-lysophospholipid analogues (ALPs) or antitumor ether lipids. This drug presents a very important drawback as can be the dose dependent haemolysis when administered intravenously. Lipid nanoparticles have been lately proposed for different drug encapsulation as an alternative to other controlled release delivery systems, such as liposomes or polymeric nanoparticles. The aim of this study was to develop a lipid nanoparticulate system that would decrease systemic toxicity as well as improve the therapeutic potential of the drug. Lipids employed were Compritol 888 ATO and stearic acid. The nanoparticles were characterized by photon correlation spectroscopy for size and size distribution, and atomic force microscopy (AFM) was used for the determination of morphological properties. By both differential scanning calorimetry (DSC) and X-ray diffractometry, crystalline behaviour of lipids and drug was assessed. The drug encapsulation efficiency and the drug release kinetics under in vitro conditions were measured by HPLC-MS. It was concluded that Compritol presents advantages as a matrix material for the manufacture of the nanoparticles and for the controlled release of edelfosine. PMID- 17707619 TI - Nutritional state influences shoaling preference for familiars. AB - Preferences for grouping with familiar individuals are shown in many animal species, including the three-spined stickleback (Gasterosteus aculeatus). Shoaling with familiars is advantageous because of more precise anti-predator behaviours or more stable dominance hierarchies. Additionally, associations with familiar individuals facilitate the evolution of altruistic behaviour. Thus, in situations of increased competition one might expect an increased preference for familiar fish. We gave single juvenile sticklebacks of different nutritional state the choice between shoals composed either of familiar or unfamiliar individuals. Satiated fish preferred to shoal with familiar individuals. A comparative analysis of 8 stickleback studies with 15 different tests using familiars showed that all tests gave similar results, i.e. sticklebacks of all age classes preferred to shoal with familiars in a non-sexual context. In contrast, hungry test fish did not prefer to shoal with familiar fish, but even showed a preference for the unfamiliar group. Because sticklebacks use early-life familiarity to recognize kin, the results suggest the avoidance of competition with relatives. To our knowledge, this is the first study showing an impact of nutritional state on social interactions with familiar individuals. PMID- 17707620 TI - Fungal transcriptomics. AB - We have now entered in the post-genomic era, where we have knowledge of plethora of fungal genomes and cutting edge technology is available to study global mRNA, protein and metabolite profiles. These so-called 'omic' technologies (transcriptomics, proteomics and metabolomics) provide the possibility to characterize plant-pathogen interactions and pathogenesis at molecular level. This article provides an overview of transcriptomics and its applications in fungal plant pathology. PMID- 17707621 TI - Changes in Azospirillum brasilense motility and the effect of wheat seedling exudates. AB - The rhizobacterium Azospirillum brasilense Sp245 swims, swarms (Swa(+) phenotype) or, very rarely, migrates with the formation of granular macrocolonies (Gri(+) phenotype). Our aims were (i) to identify Sp245 mutants that swarm faster than the parent strain or differ from it in the mode of spreading and (ii) to compare the mutants' responses to wheat seedling exudates. In isotropic liquid media, the swimming speeds of all motile A. brasilense strains were not influenced by the exudates. However, the exudates significantly stimulated the swarming of Sp245. In several Sp245 mutants, the superswarming phenotype was insensitive to local colonial density and to the presence of wheat seedling exudates. An A. brasilense polar-flagellum-defective Gri(+) mutant BK759.G gave rise to stable Swa(++) derivatives with restored flagellum production. This transition was concurrent with plasmid rearrangements and was stimulated in the presence of wheat seedling exudates. The swarming rate of the Swa(++) derivatives of BK759.G was affected by the local density of their colonies but not by the presence of the exudates. PMID- 17707623 TI - The 2R hypothesis: an update. AB - Nearly forty years ago, Susumu Ohno proposed that one or two rounds of whole genome duplication took place close to the origin of vertebrates. The refined version of this proposal, known as the two round (2R) hypothesis, assumes that the genome of jawed vertebrates has been shaped by two rounds of whole genome duplication that took place after the emergence of urochordates and before the radiation of jawed vertebrates. Although this hypothesis has been a focus of heated debate in recent years, it is increasingly supported by genome-wide analysis of key chordate species. The 2R hypothesis has important implications for understanding the evolution of the immune system, including the origin of the major histocompatibility complex and natural killer receptors. PMID- 17707622 TI - Ucma--A novel secreted factor represents a highly specific marker for distal chondrocytes. AB - Growth and development of most parts of the vertebrate skeleton takes place by endochondral ossification, a process during which chondrocytes undergo distinct stages of differentiation resulting in a successive replacement of the cartilage anlagen by bone. In the context of an EST project we isolated a novel transcript from a human fetal growth plate cartilage cDNA library. The transcript which we called Ucma (unique cartilage matrix-associated protein) encodes a short protein of 138 amino acids. The protein sequence is evolutionary conserved throughout vertebrates and comprises a signal peptide, a coiled-coil domain, and a putative dibasic cleavage site for proprotein convertases. Using RNA in situ hybridization and immunohistochemistry with a polyclonal anti-Ucma antibody we found high expression of Ucma uniquely in distal (resting) chondrocytes in developing long bones of wildtype mice. This restricted expression could also be observed in Ihh( /-), Ihh(-/-); Gli3(-/-), Gli3(-/-) mice, and in mice that overexpress Ihh under the control of the Col2a1 promoter indicating that expression of Ucma is regulated independent of hedgehog signaling. During insulin-induced differentiation of ATDC5 cells we found gradual increase of Ucma expression at day 21 with a maximum at day 24 and a decrease correlating with a simultaneous increase in the expression of cartilage link protein (Crtl1), a protein with maximum expression in column-forming proliferating chondrocytes. The present data strongly suggest an important function of Ucma in the early phase of chondrocyte differentiation. PMID- 17707624 TI - Retroviral proteins that interact with the host cell cytoskeleton. AB - In the past decade, several lines of evidence have highlighted the importance of the host cell cytoskeleton in various stages of retroviral infection. To complete their lifecycle, retroviruses must penetrate the outer barrier of the cell membrane, and viral cores containing the viral genome must traverse the cytoplasm to the nucleus and then viral gene products must make the journey back to the cell surface in order to release new progeny. The presence of a dense cytoskeletal network and organelles in the cytoplasm creates an environment that greatly impedes diffusion of macromolecules such as viruses. As such, retroviruses have evolved means to hijack actin as well as microtubule cytoskeletal networks that regulate macromolecular movement within the host cell. Developing studies are discovering several host and viral factors that play important roles in retroviral trafficking. PMID- 17707626 TI - Genetic variation and pathogenicity of anastomosis group 2 isolates of Rhizoctonia solani in Australia. AB - A collection of isolates of Rhizoctonia solani anastomosis group (AG) 2 was examined for genetic diversity and pathogenicity. Anastomosis reactions classified the majority of isolates into the known subgroups of AG 2-1 and AG 2-2 but the classification of several isolates was ambiguous. Morphological characters were consistent with the species, with no discriminating characters existing between subgroups. Vertical PAGE of pectic enzymes enabled the separation of zymogram group (ZG) 5 and 6 within AG 2-1, but not the separation of ZG 4 and 10 within AG 2-2. PCR analysis using inter-simple sequence repeats (ISSR) and the intron-splice junction (ISJ) region supported the separation of ZG 5 and 6, while the AG 2-2 isolates were separated by geographic region. A comparison of distance matrices produced by the zymogram analysis and PCR indicated a strong correlation between the marker types. Pathogenicity studies suggested canola (Brassica napus) cultivars were most severely affected by AG 2 1, while cultivars of two species of medic (Medicago truncatula cv. Caliph and M. littoralis cv. Herald) were susceptible to both AG 2-1 and 2-2. The results indicate that AG 2 is a polyphyletic group in which the classification of subtypes is sometimes difficult. Further investigation of the population structure within Australia is required to determine the extent and origin of the observed diversity. PMID- 17707625 TI - Chitosan-mediated changes in cell wall composition, morphology and ultrastructure in two wood-inhabiting fungi. AB - The effect of chitosan on cell wall deposition was investigated in the two wood inhabiting fungal species Trichoderma harzianum (CBS 597.91) and Sphaeropsis sapinea (NZFS 2725). The study used three independent analytical techniques to quantify chitin in the fungal mycelium. A colorimetric method for the detection of D-glucosamine was compared with two gas chromatography-mass spectroscopy (GC MS) methods employing alditol acetates analysis and pyrolysis. The latter used a stable-isotope-labelled internal standard, d(3)-N-acetyl glucosamine. At least in the case of S. sapinea, the study provided evidence of an increase in the chitin content in the mycelium due to chitosan treatment, indicating that chitosan treatment affected cell wall deposition. Electron microscopy techniques showed alteration in surface morphology and cell wall texture due to chitosan treatment. The implications of these results are discussed with a view to analysing possible mechanisms for growth inhibitory effects of chitosan on fungal hyphae. PMID- 17707627 TI - Identification of PaPKS1, a polyketide synthase involved in melanin formation and its use as a genetic tool in Podospora anserina. AB - In the filamentous fungus Podospora anserina, many pigmentation mutations map to the median region of the complex locus '14', called segment '29'. The data presented in this paper show that segment 29 corresponds to a gene encoding a polyketide synthase, designated PaPKS1, and identifies two mutations that completely or partially abolish the activity of the PaPKS1 polypeptide. We present evidence that the P. anserina green pigment is a (DHN)-melanin. Using the powerful genetic system of PaPKS1 cloning, we demonstrate that in P. anserina trans-duplicated sequences are subject to the RIP process as previously demonstrated for the cis-duplicated regions. PMID- 17707628 TI - Mechanisms through which sulfur amino acids control protein metabolism and oxidative status. AB - Amino acids regulate protein synthesis and breakdown (i.e., protein turnover) and consequently protein deposition, which corresponds to the balance between the two processes. Elucidating the mechanisms involved in such regulation is important from fundamental and applied points of view since it can provide a basis to optimize amino acid requirements and to control protein mass, body composition and so forth. Amino acids, which have long been considered simply as precursors of protein synthesis, are now recognized to exert other significant influences; that is, they are precursors of essential molecules, act as mediators or signal molecules and affect numerous functions. For example, amino acids act as mediators of metabolic pathways in the same manner as certain hormones. Thus, they modulate the activity of intracellular protein kinases involved in the regulation of metabolic pathways such as mRNA translation. We provide here an overview of the roles of amino acids as regulators of protein metabolism, by focusing particularly on sulfur amino acids. The potential importance of methionine as a "nutrient signal" is discussed in the light of recent findings. Emphasis is also placed on mechanisms controlling oxidative status since sulfur amino acids are involved in the synthesis of intracellular antioxidants (glutathione, taurine etc.) and in the methionine sulfoxide reductase antioxidant system. PMID- 17707629 TI - Green tea catechins and broccoli reduce fat-induced mortality in Drosophila melanogaster. AB - Dietary fat accelerates the ageing process and causes a greater mortality by accumulating lipid hydroperoxide (LPO) in Drosophila melanogaster. The present study found that the life span of D. melanogaster was shortened from 54 to 6 days in a dose-dependent manner when fat in diet increased from 0% to 25%. The results showed that supplementation of both green tea catechins (GTC) and broccoli extract (BE) reversed partially the fat-induced mortality. The maximum life span was 44 days for the control group fed with a 5% fat, whereas it increased to 50 and 59 days in the GTC- and BE-supplemented groups, respectively. The 50% survival time for the control flies fed with a 5% fat diet was 30 days. In contrast, it increased to 32 and 48 days when GTC and BE were supplemented in the diet. This was consistent with a significant reduction in total body LPO level in D. melanogaster maintained on the GTC- and BE-supplemented diet. Accordingly, catalase and superoxide dismutase (SOD) activities increased significantly in the flies fed with a GTC or a BE diet compared with those fed with a control 5% fat diet. Reverse transcriptase-polymerase chain reaction analysis indicated that the increase in enzymatic activities of catalase and SOD was accompanied by up regulation of genes for catalase, copper-zinc containing SOD and manganese containing SOD. It was concluded that GTC and BE reversed the fat-induced mortality in D. melanogaster, most likely but necessarily solely, by up regulation of endogenous antioxidant enzymes. PMID- 17707630 TI - Localization of polypyrimidine-tract-binding protein is involved in the regulation of albumin synthesis by branched-chain amino acids in HepG2 cells. AB - Long-term supplementation of branched-chain amino acids (BCAA) improves hypoalbuminemia in patients with cirrhosis. Our previous findings have suggested that the binding of polypyrimidine-tract-binding protein (PTB) to rat albumin mRNA attenuates its translation. The aim of the present study was to investigate the role of PTB in the regulation of albumin synthesis by BCAA in human hepatoma cells. HepG2 cells were cultured in a medium containing no amino acids (AA-free medium), a medium containing only 1 amino acid (a BCAA: valine, leucine or isoleucine) or a medium containing all 20 amino acids (AA-complete medium). HepG2 cells cultured in AA-complete medium secreted much more albumin than cells cultured in AA-free medium, with no difference in albumin mRNA levels. In cells cultured in AA-free medium, nuclear export of PTB was observed, and the level of the albumin mRNA-PTB complex was greater than in cells cultured in AA-complete medium. Addition of amino acids stimulated nuclear import of PTB. However, addition of amino acids with rapamycin inhibited the nuclear import of PTB. The addition of leucine, but not of valine or isoleucine, to AA-free medium increased albumin secretion and stimulated the nuclear import of PTB. These data indicate that the mammalian target of rapamycin is involved in the regulation of PTB localization and that leucine promotes albumin synthesis by inhibiting the formation of the albumin mRNA-PTB complex. PMID- 17707632 TI - Dietary methionine effects on plasma homocysteine and HDL metabolism in mice. AB - The effects of dietary manipulation of folate and methionine on plasma homocysteine (Hcy) and high-density lipoprotein cholesterol (HDL-C) levels in wild-type and apolipoprotein-E-deficient mice were determined. A low-folate diet with or without folate and/or methionine supplementation in drinking water was administered for 7 weeks. Fasted Hcy rose to 23 microM on a low-folate/high methionine diet, but high folate ameliorated the effect of high methionine on fasted plasma Hcy to approximately 10 microM. Determination of nonfasted plasma Hcy levels at 6-h intervals revealed a large diurnal variation in Hcy consistent with a nocturnal lifestyle. The daily average of nonfasted Hcy levels was higher than fasted values for high-methionine diets but lower than fasted values for low methionine diets. An acute methionine load by gavage of fasted mice increased plasma Hcy 2.5 h later, but mice that had been on high-methionine diets had a lower fold induction. Mice fed high-methionine diets weighed less than mice fed low-methionine diets. Based on these results, two solid-food diets were developed: one containing 2% added methionine and the other containing 2% added glycine. The methionine diet led to fasted plasma Hcy levels of >60 microM, higher than those with methionine supplementation in drinking water. Mice on methionine diets had >20% decreased body weights and decreased HDL-C levels. An HDL turnover study demonstrated that the HDL-C production rate was significantly reduced in mice fed the methionine diet. PMID- 17707631 TI - 3,3'-Diindolylmethane stimulates murine immune function in vitro and in vivo. AB - 3,3'-Diindolylmethane (DIM), a major condensation product of indole-3-carbinol, exhibits chemopreventive properties in animal models of cancer. Recent studies have shown that DIM stimulates interferon-gamma (IFN-gamma) production and potentiates the IFN-gamma signaling pathway in human breast cancer cells via a mechanism that includes increased expression of the IFN-gamma receptor. The goal of this study was to test the hypothesis that DIM modulates the murine immune function. Specifically, the effects of DIM were evaluated in a panel of murine immune function tests that included splenocyte proliferation, reactive oxygen species (ROS) generation, cytokine production and resistance to viral infection. DIM was found to induce proliferation of splenocytes as well as augment mitogen- and interleukin (IL)-2-induced splenocyte proliferation. DIM also stimulated the production of ROS by murine peritoneal macrophage cultures. Oral administration of DIM, but not intraperitoneal injection, induced elevation of serum cytokines in mice, including IL-6, granulocyte colony-stimulating factor (G-CSF), IL-12 and IFN-gamma. Finally, in a model of enteric virus infection, oral DIM administration to mice enhanced both clearance of reovirus from the GI tract and the subsequent mucosal IgA response. Thus, DIM is a potent stimulator of immune function. This property might contribute to the cancer inhibitory effects of this indole. PMID- 17707633 TI - Changes in copper and zinc status and response to dietary copper deficiency in metallothionein-overexpressing transgenic mouse heart. AB - Previous studies have shown that cardiac-specific overexpression of metallothionein (MT) inhibits progression of dietary copper restriction-induced cardiac hypertrophy. Because copper and zinc are critically involved in myocardial response to dietary copper restriction, the present study was undertaken to understand the effect of MT on the status of copper and zinc in the heart and the subsequent response to dietary copper restriction. Dams of cardiac specific MT-transgenic (MT-TG) mouse pups and wild-type (WT) littermates were fed copper-adequate (CuA) or copper-deficient (CuD) diet starting on the fourth day post delivery, and the weanling mice were continued on the same diet until they were sacrificed. Zinc and copper concentrations were significantly elevated in MT TG mouse heart, but the extent of zinc elevation was much more than that of copper. Dietary copper restriction significantly decreased copper concentrations to the same extent in both MT-TG and WT mouse hearts, and decreased zinc concentrations along with a decrease in MT concentrations in the MT-TG mouse heart. Copper deficiency-induced heart hypertrophy was significantly inhibited, but copper deficiency-induced suppression of serum ceruloplasmin or hepatic Cu,Zn SOD activities was not inhibited in the MT-TG mice. These results suggest that elevation in zinc but not in copper in the heart may be involved in the MT inhibition of copper deficiency-induced cardiac hypertrophy. PMID- 17707634 TI - Determination of the best appropriate management methods for the health-care wastes in Istanbul. AB - Health-care waste management has been a significant problem in most economically developing countries as it is in Turkey. Most of the time, the main reason for the mismanagement of these wastes is the lack of appropriate legislation and effective control; other reasons are: financial strains and a lack of awareness. Being aware of the significance of the subject, in this paper the management of the health-care wastes in Istanbul, as a Metropolitan City of Turkey, was analyzed to create an integrated health-care waste management system in the city. Within the scope of the study, the existing situation and management practices such as the amount of the health-care wastes generated, segregation procedures, collection, temporary storage and transportation of the wastes within and outside of the institution were examined. Deficiencies, inconsistencies and improper applications were revealed. The existing Turkish Medical Wastes Control Regulation and institutional structure of the health-care waste management body were reviewed. After the evaluation and comparison with the requirements of other national and international organizations, items to be changed/added in the Regulation were identified. At the end of the study, the best management methods for the Istanbul City were determined and started to be applied at the institutions. After this study, the existing Regulation has been changed. The modified Regulation was published in 2005 and implementation has started. It is expected that by the application and implementation of the research outcomes, the management of health-care wastes in Istanbul and then in all over Turkey will be improved. The results obtained can also be used in most economically developing countries where there are similar environmental problems and strict budgets. PMID- 17707635 TI - The thalamus is more than just a relay. AB - The lateral geniculate nucleus and pulvinar are examples of two different types of relay: the former is a first order relay, transmitting information from a subcortical source (retina), while the latter is mostly a higher order relay, transmitting information from layer 5 of one cortical area to another cortical area. First and higher order thalamic relays can also be recognized for much of the rest of thalamus, and most of thalamus seems to be comprised of higher order relays. Higher order relays seem especially important to general corticocortical communication, and this challenges and extends the conventional view that such communication is based on direct corticocortical connections. PMID- 17707637 TI - Genetic polymorphisms of glutathione-S-transferase genes (GSTM1, GSTT1 and GSTP1) and upper aerodigestive tract cancer risk among smokers, tobacco chewers and alcoholics in an Indian population. AB - The glutathione-S-transferase (GST) genes are involved in the detoxification of various carcinogens that increase the risk to upper aerodigestive tract (UADT) cancers. In the present study, 408 unrelated histopathologically confirmed cases and 220 population based controls, matched by age and gender, which belonged to the Tamilian population of south India were genotyped for polymorphisms in GSTM1, GSTT1 and GSTP1 using polymerase chain reaction (PCR) based methods. The multivariate logistic regression analyses demonstrated that GSTT1 null genotype was significantly associated with increased risk for UADT cancers (odds ratio (OR) 2.5; 95% confidence intervals (CIs) 1.3-4.7). The combined effects of GST genes have shown that concurrent lack of GSTM1 and GSTT1 had a significantly increased risk (OR 4.6; 95% CI 1.3-15.6), while GSTT1 null genotype along with GSTP1 polymorphic variants further increased the cancer risk (OR 5.3; 95% CI 2.0 13.6). The most remarkable risk was seen among individuals carrying GSTM1 null, GSTT1 null genotypes and GSTP1 polymorphic variants (OR 7.8; 95% CI 1.0-61.0). Tobacco chewers carrying GSTM1 null genotype had an enhanced risk for UADT cancers. An enhanced risk among tobacco chewers and alcoholics (regular) was noted in individuals with GSTT1 null genotype. Similarly, a significant interaction was observed among smokers (>40 pack-year (PY)) and tobacco chewers carrying GSTP1 mutant genotypes. Although the null genotype of GSTT1 is a strong predisposing risk factor for UADT cancers, we conclude that the significant gene gene and gene-environment interactions of GST genes may confer a substantial risk to UADT cancers in the Tamilian population of south India. PMID- 17707638 TI - Maintenance therapy in cutaneous T-cell lymphoma: who, when, what? AB - The aim of current therapy for cutaneous T-cell lymphoma (CTCL) is to induce clinically meaningful remission, provide symptom relief, improve patient quality of life (QoL) and prolong disease-free and overall survival. A key research question is whether such remissions or minimal disease status can be maintained in the long term. There have been few formal studies of maintenance therapy in CTCL. Some skin-directed therapies such as total-skin electron-beam therapy and high-dose psoralen plus ultraviolet A may not be considered suitable, because of the risk of long-term cumulative toxicities. Other therapies such as nitrogen mustard, interferon (IFN)-alpha and bexarotene have demonstrated positive effects in prolonging remissions in small numbers of patients. Large longitudinal studies are required to investigate the efficacy of maintenance treatments in CTCL and their impact on patients' QoL and overall survival. Of the systemic therapies currently approved for the treatment of CTCL, bexarotene and IFN-alpha are obvious candidates for testing, because they can be self-administered by the patient and provide good long-term tolerability. PMID- 17707636 TI - A mechanism for active hearing. AB - The remarkable sensitivity, frequency selectivity, and nonlinearity of the cochlea have been attributed to the putative 'cochlear amplifier', which consumes metabolic energy to amplify the cochlear mechanical response to sounds. Recent studies have demonstrated that outer hair cells actively generate force using somatic electromotility and active hair-bundle motion. However, the expected power gain of the cochlear amplifier has not been demonstrated experimentally, and the measured location of cochlear nonlinearity is inconsistent with the predicted location of the cochlear amplifier. We instead propose a 'cochlear transformer' mechanism to interpret cochlear performance. PMID- 17707639 TI - Nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). AB - Nonrhabdmyosarcoma soft tissue sarcoma (NRSTS) is a heterogenous group of tumors analyzed as a unique group because of the rarity of each histopathological subtype. Initial information available has been obtained from adult series or pediatric case studies. Recent reports by several multi-center groups have been published that evaluated prognostic factors and treatment protocols. Established prognostic factors include tumor grade, invasiveness, size, and intergroup rhabdomyosarcoma study (IRS) group. Identification of sarcoma-specific chromosomal translocations has allowed for more accurate definitive diagnosis. Some may have prognostic significance and may offer as potential therapeutic targets. Surgery remained important, as many of the tumors are scarcely chemosensitive. With the development of multimodalities, surgical management has evolved over the years. Patients with localized unresectable disease are managed with surgery +/- radiotherapy with very good results. Localized unresectable disease is intermediate in behavior and prognosis. Patients are treated with neoadjuvant chemotherapy, +/- radiotherapy, followed by delayed surgical resection. Prognosis in patients with metastatic disease has been poor despite combination chemotherapy with surgical resection. The addition of ifosfamide and doxorubicin in the chemotherapy regimes has provided some improvement. With the lack of new active agents, we will depend on advances in molecular techniques to develop novel targeted therapies, better molecular markers and histology-specific trials to evaluate this group of tumors. PMID- 17707640 TI - Pyrimidine benzamide-based thrombopoietin receptor agonists. AB - A series of pyrimidine benzamide-based thrombopoietin receptor agonists is described. The lead molecule contains a 2-amino-5-unsubstituted thiazole, a group that has been associated with idiosyncratic toxicity. The potential for metabolic oxidation at C-5 of the thiazole, the likely source of toxic metabolites, was removed by substitution at C-5 or by replacing the thiazole with a thiadiazole. Potency in the series was improved by modifying the substituents on the pyrimidine and/or on the thiazole or thiadiazole pendant aryl ring. In vivo examination revealed that compounds from the series are not highly bioavailable. This is attributed to low solubility and poor permeability. PMID- 17707641 TI - Angiogenesis as targeted breast cancer therapy. AB - Neo-angiogenesis appears to be a critical feature of tumor growth, migration, and metastasis. Therefore, inhibition of angiogenesis is an appealing strategy for treatment of cancer. Since angiogenesis is the result of several mechanistic processes, controlled by numerable pro- and anti-angiogenic factors and their receptors, multiple possibilities to prevent or reverse tumor-induced neo vascularization have been proposed. Of these, currently, the most promising approach has been the use of bevacizumab, a humanized monoclonal antibody directed against the most potent pro-angiogenic factor, vascular endothelial growth factor (VEGF). Bevacizumab has been shown to be active in several malignancies, in particular colo-rectal cancer. Although early studies of bevacizumab in far-advanced metastatic breast cancer were disappointing, the results of a recently reported clinical trial by the Eastern Oncology Group comparing first line paclitaxel with or without bevacizumab has demonstrated statistically significant improvements in response rates and time progression. Ongoing studies are now investigating the benefits of bevacizumab with other chemotherapeutic and biologic agents in early metastatic disease as well as in the adjuvant setting. Other anti-angiogenic agents remain in early clinical trials. Small molecular inhibitors of VEGF receptor tyrosine kinase activity, such as sunitinib, appear promising. Nearly 40 years after it was first proposed, inhibition of angiogenesis appears to be gaining a role in medical oncology. PMID- 17707642 TI - North American perception of the prestige of biomechanics serials. AB - Biomechanics is a discipline with many applications and sub-areas so scholars often publish their work in journals in different subject categories used in the ISI Journal Citation Reports (JCR). It is not known whether the quality/prestige of journals in the discipline of biomechanics matches the ISI Impact Factor (IF) ratings reported in JCR. A survey of the membership of the American Society of Biomechanics (ASB) was conducted to rate the quality/prestige of typical papers in serials publishing biomechanics research on a five point scale. Seventy-eight of 610 ASB members responded to the survey. Mean journal prestige ratings were only weakly correlated (r=0.35) with the IF for 2005, with serial ratings differing across the interest areas of the ASB respondents. It was concluded that IF's should be used with caution in evaluating the prestige of journals publishing biomechanics research. Furthermore, investigators should consider interest area specific ratings within biomechanics when selecting journals for publishing their research. PMID- 17707643 TI - Elderly unilateral transtibial amputee gait on an inclined walkway: a biomechanical analysis. AB - The greatest population of amputees in developed nations are elderly dysvascular transtibial amputees. Conventional prostheses, e.g. the solid ankle cushioned heel (SACH) foot, create difficulties in walking on inclines. The aim of this study was to analyse the gait characteristics of elderly amputees walking on an incline, through quantitative three-dimensional biomechanical analysis, by comparing them to age-matched controls. Participants walked up and down an inclined (5 degrees) instrumented walkway at a self-selected pace. A Vicon System 370 was used to acquire gait data, including temporo-spatial characteristics, ground reaction forces (GRF), electromyography (EMG), kinematics, and kinetics of the lower limb. Compared to the age-matched controls, the amputees demonstrated reduced speed, knee and hip range of motion, hip moments, vertical GRF, along with increased amplitude and periods of muscle activation. The residual limb also had shorter single support stance phase, small stance phase knee moments, and the smallest moments and powers. These differences demonstrate instability in stance of the residual limb. The sources of this instability include the prosthesis' limited range of ankle motion and ankle power generation, coupled with the residual limb's limited proprioception and tolerance of force. For these amputees to regain a gait pattern equivalent to their able-bodied counterparts on inclined walkways, they must be equipped with a prosthesis that has a full range of ankle motion and active power generation at the ankle. Prosthesis design and rehabilitation training should also improve the proprioception of their residual limb and increase their tolerance of force through the residual limb. PMID- 17707644 TI - Highly efficient antitumor agents of heterocycles containing sulfur atom: linear and angular thiazonaphthalimides against human lung cancer cell in vitro. AB - A novel series of aminothiazonaphthalimides, A(1-2) and B(1-2), has been regioselectively synthesized. The linear compounds B(1-2) were evaluated to be far more active than their angular isomers A(1-2) in antitumor evaluation. The linear compounds C-F, derived from compound B(1), all showed highly efficient antitumor activities against A549 and P388 cell lines. Also, cytotoxicities of these four analogues against two tumor cells were highly dependent on the length of the side chains. The compound A(1) or B(1), with two methylene units in the side chain, was more cytotoxic than its corresponding homologue A(2) or B(2), with one more methylene unit. PMID- 17707645 TI - Nondestructive inspection of low atomic number media using inelastic photon scattering. AB - The purpose of this study was to examine the potential of using scatter information to evaluate tissue density at selected sites. A method for non invasively generating profiles of density distribution within an object using Compton scattered X-rays is presented. The Compton scatter method is modified to scan longitudinal sections of composite phantoms and samples of tissue substitute materials. Line scan data are used to describe how the detected count rate changes in response to localized density variations within an extended object. The physical limitations of quantification are discussed, including the effect of attenuation, multiple scatter, and limited spatial resolution. Further, the theory of the method, its performance and results of experimental phantom studies are described. The results presented indicate that the suggested method has the potential for measuring physical density distribution within an object with a spatial resolution of 2mm and an accuracy of approximately 4% under the circumstances in which attenuation correction is avoided. PMID- 17707646 TI - Interpretation of radiotracer experiments in an industrial battery of desanders with simultaneous stochastic and non-stochastic flows. AB - Radiotracer experiments have been conducted in an industrial battery of twelve desanders located at the water treatment plant of Lima. The flow behavior is complex because it includes the superposition of a stochastic flow, which is intrinsic to the process itself, and of a non-stochastic flow induced by local strong currents at the surface. These currents are non-stochastic because they are different from one desander to another one even if all the desanders are identical. A general model has been proposed to simulate the whole behavior of the process. The model is composed of two parts: the first one, describes the stochastic flow behavior, and is the same for each desander; the second one is adapted to represent the turbulent shortcuts at the surface of each desander. The parameters of stochastic part have been determined to be consistent with the physical description of the process. The value of the Peclet number of the shortcut is a monotonic function of the flow rate. Despite remaining uncertainties due both to the complexity of the flow and to specific problems of tracer measurements in large industrial water treatment plant, this paper proposes an extension of the applications of radiotracer experiments and interpretation. PMID- 17707647 TI - Is preoperative demonstration of Adamkiewicz's artery a clinical reality in acute aortic dissection? PMID- 17707648 TI - A three-dimensional echocardiographic comparison of a deep pericardial stitch versus an apical suction device for heart positioning during beating heart surgery. AB - BACKGROUND: Heart positioning during beating heart surgery produces significant haemodynamic compromise either when a deep pericardial stitch (DPS) or apical suction devices (ApSDs) are used. In this study the two techniques' haemodynamic performance and effect on intracardiac structures were compared through transoesophageal echocardiography (TEE) obtained volume measurements and three dimensional ventricular and mitral valve computer reconstructions. METHODS: Sequential 0 degrees to 180 degrees TEE images of the left heart were obtained in 10 patients undergoing beating heart surgery. Measurements with both techniques in three different positions were obtained: at baseline, the heart elevated to access its inferior surface and the heart elevated and rotated to access its lateral surface. Three-dimensional computer reconstructions of the mitral valve and the left heart were generated. Ventricular volume measurements were used to calculate stroke volume, ejection fraction and differences from baseline. An analysis of variance between each technique in all three positions was performed. RESULTS: Central venous, left atrial and pulmonary artery pressures were significantly increased with either technique during positioning. Both techniques significantly affected left ventricular function decreasing stroke volume and ejection fraction. In the vertical and rotated position, the ApSD produced a significant decrease from baseline both in stroke volume (DPS: 32.8+/-18.7 vs ApSD: 55.46+/-21.7; p=0.02) and in ejection fraction (DPS: 19.3+/-10.5 vs ApSD: 40.9+/-24.6; p=0.02). The three-dimensional reconstructions demonstrated significant distortion of the atrioventricular geometry and the mitral valve, which was more pronounced with the DPS. CONCLUSION: Both techniques produce variable degrees of deformation with associated cardiac dysfunction and haemodynamic instability. Cardiac function is impeded more with an ApSD with the heart elevated and rotated. PMID- 17707649 TI - Preoperative CYFRA 21-1 levels as a prognostic factor in c-stage I non-small cell lung cancer. AB - OBJECTIVE: The clinical importance of preoperative CYFRA 21-1 measurement in early-stage non-small cell lung cancer (NSCLC) is still unclear. The aim of this study is to clarify the prognostic value of preoperative CYFRA 21-1 levels in clinical stage (c-stage) I NSCLC. METHODS: The records of 101 c-stage I NSCLC patients who had undergone complete resection were analyzed to correlate preoperative CYFRA 21-1 levels to both the pathologic factors of resected specimens and postoperative outcomes. The cut-off value was set at 3.5 ng/ml. RESULTS: Six cases (5.9%) showed high CYFRA 21-1 (> or =3.5 ng/ml). The 5-year survival of normal and high CYFRA 21-1 groups was 83.3% and 50.0%, respectively. Patients with high CYFRA 21-1 had significantly poor outcomes (P=0.006). In univariate analysis, preoperative serum CYFRA 21-1 level, pT, pN, and p-stage were significantly associated with prognosis. Multivariate analysis showed that only CYFRA 21-1 level was retained as an independent prognostic factor (relative risk=9.79, P=0.002). CONCLUSIONS: CYFRA 21-1 is an independent predictor of poor outcome for c-stage I NSCLC. Elevated preoperative CYFRA 21-1 levels in early stage NSCLC may indicate a subgroup at high risk of early death, which has the potential for better survival with additional systemic chemotherapy. PMID- 17707650 TI - Primary lung cancer and extrapulmonary malignancy. AB - OBJECTIVE: The incidence of second primary malignancies seems to be increasing. The aim of this study was to investigate the incidence, treatment and outcome for patients with second primary lung cancer (SPLC). METHODS: Between January 1996 and December 2005, 163 patients with SPLC, occurring after an extrapulmonary malignancy, were recruited by the Tumor Center of Halle (Saale), which represents a region of nearly 1.0 million inhabitants in Germany. The SPLCs were treated under curative aim (n=59), with palliative intend (n=76) or best supportive care (n=28). RESULTS: The incidence of SPLC was 1.6 per 100,000 inhabitants. The localization of the first tumor differed depending on the sex of the patients. The actuarial 5-year survival rate of all patients was 12.7% (median survival time 11.4 months). Univariate analysis revealed treatment strategy as a prognostic factor (p=0.0001). Patients with SPLC having undergone curative treatment turned out to have the best prognosis (median survival: 31.0 months). The Cox proportional hazards model demonstrated that only TNM-staging system was a multivariate and significant independent prognostic predictor for overall survival. The method of surgery, standard lung resection (e.g. lobectomy) versus limited resection had no considerable influence on overall survival (p=0.22), respectively recurrence-free survival (p=0.55). CONCLUSIONS: In cases of operability, standard resection must be the method of choice, because of its best survival rates. The results support the demand of an exact and short-term oncological care system to detect early stages of SPLC for patients operated upon for tumors at different sites. PMID- 17707651 TI - Secondary subaortic stenosis in heart defects without any initial subaortic obstruction: a multifactorial postoperative event. AB - BACKGROUND/OBJECTIVE: Secondary subaortic stenosis (SSS) can occur after surgery for various congenital heart defects with or without initial left ventricular outflow tract obstruction (LVOTO). The objective of this study was to highlight the anatomical lesions and surgical procedures associated with the development of SSS after surgery on defects without initial LVOTO. METHODS: A retrospective study of 4710 patients was performed (1984-2005). The criterion for inclusion was a fixed subaortic obstruction requiring surgery, after an open- or closed-heart operation. The criterion for exclusion was an LVOTO at the time of the first operation. RESULTS: Twenty-eight patients were studied. The mean age at initial surgery was 32 months (4 days-47 years; median: 2 months). SSS occurred after three main types of surgery: repair of coarctation of the aorta, repair of AVSD and LV-aorta rerouting for double outlet right ventricle or transposition of great arteries. The mean delay of occurrence was 4.4 years (2 months-19 years). Frequently associated initial anatomical conditions were coarctation of the aorta (40%), lesions of the mitral valve (32%), bicuspid aortic valve (21%) and left superior vena cava (LSVC) (14%). Preoperative anatomical lesions of the LVOT were present in 93% of the cases. After the initial operation, only one patient had a mean echo-Doppler pressure gradient across the LVOT>20 mmHg. SSS was most frequently a subaortic membrane (n=23). The mean pressure gradient across SSS at the time of reoperation was 47+/-29 mmHg. Five patients developed a second SSS after 7.4 years (mean). One patient developed a third SSS. No patient died. When compared with patients without SSS, significant risk factors for SSS were low age at surgery (32 vs 74.9 months, p<10(-4)), pre-existing coarctation of the aorta (40 vs 10%, p<10(-4)), bicuspid aortic valve (21 vs 6%, p=0.002) and LSVC (14 vs 4%, p=0.02). CONCLUSIONS: SSS development is multifactorial, depending on initial anatomical lesions and initial surgery. Low age at initial surgery, coarctation of the aorta, bicuspid aortic valve and LSVC significantly increase the risk of SSS. These elements warrant long-term follow-up for early detection of SSS. PMID- 17707652 TI - Structure, expression and function of HLA-G in renal cell carcinoma. AB - Tumors have developed different strategies to escape from immune cell recognition which include the downregulation or loss of the classical HLA class I antigens as well as aberrant expression of non-classical HLA antigens like HLA-G. Abnormalities in MHC class surface expression have also been described in renal cell carcinoma (RCC) and represent mechanisms to avoid elimination by immune effector cells. We here review the structure/polymorphism, mRNA and protein expression profile of HLA-G in RCC and corresponding normal kidney epithelium, its mode of regulation and its functional consequences on immune responses. A heterogeneous constitutive HLA-G mRNA and/or protein expression was found in both RCC lesions and RCC cell lines, whereas normal kidney epithelium totally lack HLA G mRNA and protein expression. In comparison to other tumor entities, the frequency of HLA-G expression is relatively high in RCC. Since HLA-G expression is lost during cultivation of RCC cells, the tumor microenvironment and/or endothelium appear to be involved in the regulation of HLA-G expression in this disease. HLA-G expression could be transcriptionally upregulated in RCC by interferons, IL-10 and gangliosides. Silencing of HLA-G expression in RCC is often associated with methylation of the HLA-G promoter which could be reverted by the treatment with demethylating agents. Functional studies using natural killer cells, lymphokine activated killer cells as well as antigen-specific CD8+ cytotoxic T lymphocytes demonstrated that HLA-G expression prevents lysis of RCC cells by these different immune effector cells. In contrast, HLA-G-negative normal kidney cells as well as HLA-G-negative RCC cells were not recognized by NK and T cells. Thus, HLA-G represents one important immune escape mechanism of human RCC which has an impact on the design of T and NK cell-based immunotherapies in this disease. PMID- 17707653 TI - ERK-FosB signaling in dorsal MPOA neurons plays a major role in the initiation of parental behavior in mice. AB - During mouse parental behavior, neurons in the dorsal medial preoptic area (MPOAd) are activated and express transcription factors such as c-Fos and FosB. FosB-knockout mice are reported to be defective in parental care. To clarify molecular signaling responsible for parental behavior, we investigated gene expression profiles in the MPOAd of parental versus nonparental mice. We identified upregulation of NGFI-B, SPRY1, and Rad in parental mice, together with c-Fos and FosB. A common inducer of these genes, the extracellular signal regulated kinase (ERK) was phosphorylated in MPOAd neurons upon pup exposure. Pharmacological blockade of ERK phosphorylation inhibited the FosB upregulation in MPOAd, and the initiation of pup retrieving in virgin female mice, but did not affect the established parenting in parous females. Furthermore, induction of SPRY1 and Rad was impaired in MPOAd of nonparental FosB-knockout mice. These results suggest the pivotal role of ERK-FosB signaling in the initiation of parental care. PMID- 17707654 TI - Specific expression of low-voltage-activated calcium channel isoforms and splice variants in thalamic local circuit interneurons. AB - It has been suggested that the specific burst firing patterns of thalamic neurons reflect differential expression of low-voltage-activated (LVA) Ca(2+) channel subtypes and their splice variants. By combining electrophysiological, molecular biological, immunological, and computational modeling techniques we here show that diverging LVA Ca(2+) currents of thalamocortical relay (TC) and GABAergic interneurons of the dLGN correlate with a differential expression of LVA Ca(2+) channel splice variations and isoforms (alpha1G-a in TC; alpha1G-bc and alpha1I in interneurons). Implementation of the observed LVA Ca(2+) current differences into a TC neuron model changed the burst firing from TC-like to interneuron-like. We conclude that alternative splicing of the alpha1G isoform in dLGN TC and interneurons, and the exclusive expression of the alpha1I isoform in interneurons play a prominent role in setting the different LVA Ca(2+) current properties of TC and interneurons, which critically contribute to the diverging burst firing behavior of these neurons. PMID- 17707656 TI - Expression and purification of ancrod, an anticoagulant drug, in Pichia pastoris. AB - Ancrod is known as a thrombin-like enzyme from the venom of Calloselasma rhodostoma. The cDNA encoding ancrod was synthesized with a yeast bias codon and inserted into the eukaryotic expression vector pPIC9 and was subsequently expressed in the yeast Pichia pastoris. Recombinant ancrod was produced in 5-L bioreactor using a sorbitol-methanol feeding strategy and recovered from the fermentation broth by hydrophobic, affinity, and ion exchange chromatography. SDS PAGE analysis revealed that ancrod was heterogeneously glycosylated and running at the expected molecular weight of 43-48 kDa which decreased to about 29 kDa after deglycosylation with N-glycosidase F. The fibrinogenolytic and zymographic activity of the recombinant ancrod were determined and were found to be similar to that of the native protein. PMID- 17707657 TI - JUST (Java User Segmentation Tool) for semi-automatic segmentation of tomographic maps. AB - We are presenting a program for interactive segmentation of tomographic maps, based on objective criteria so as to yield reproducible results. The strategy starts with the automatic segmentation of the entire volume with the watershed algorithm in 3D. The watershed regions are clustered successively by supervised classification, allowing the segmentation of known organelles, such as membranes, vesicles and microtubules. These organelles are processed with topological models and input parameters manually derived from the tomograms. After known organelles are extracted from the volume, all other watershed regions can be organized into homogeneous assemblies on the basis of their densities. To complete the process, all voxels in the volume are assigned either to the background or individual structures, which can then be extracted for visualization with any rendering technique. The user interface of the program is written in Java, and computational routines are written in C. For some operations, involving the visualization of the tomogram, we refer to existing software, either open or commercial. While the program runs, a history file is created, that allows all parameters and other data to be saved for the purposes of comparison or exchange. Initially, the program was developed for the segmentation of synapses, and organelles belonging to these structures have thus far been the principal targets modeled with JUST. Since each organelle is clustered independently from the rest of the volume, however, the program can accommodate new models of different organelles as well as tomograms of other types of preparations of tissue, such as cytoskeletal components in vitreous ice. PMID- 17707655 TI - The Drosophila ARC homolog regulates behavioral responses to starvation. AB - The gene encoding dARC1, one of three Drosophila homologs of mammalian activity regulated cytoskeleton-associated protein (ARC), is upregulated in both seizure and muscular hypercontraction mutants. In this study we generate a null mutant for dArc1 and show that this gene is not involved in synaptic plasticity at the larval neuromuscular junction or in formation or decay of short-term memory of courtship conditioning, but rather is a modifier of stress-induced behavior. dARC1 is expressed in a number of neurosecretory cells and mutants are starvation resistant, exhibiting an increased time of survival in the absence of food. Starvation resistance is likely due to the fact that dArc1 mutants lack the normal hyperlocomotor response to starvation, which is almost universal in the animal kingdom. dARC1 acts in insulin-producing neurons of the pars intercerebralis to control this behavior, but does not appear to be a general regulator of insulin signaling. This suggests that there are multiple modes of communication between the pars and the ring gland that control starvation-induced behavioral responses. PMID- 17707659 TI - Impact of study design on proarrhythmia prediction in the SCREENIT rabbit isolated heart model. AB - INTRODUCTION: Prediction of the propensity of a compound to induce Torsades de Pointes continues to be a formidable challenge to the pharmaceutical industry. Development of an in vitro model for assessment of proarrhythmic potential offers the advantage of higher throughput and reduced compound quantity requirements when compared to in vivo studies. A rabbit isolated heart model (SCREENIT) has been reported to identify compounds with proarrhythmic potential based on the observance of compound-induced triangulation and instability of the monophasic action potential (MAP), ectopic beats, and reverse-use dependence of prolongation of the MAP duration. Previous reports have indicated that this model qualitatively identifies proarrhythmic compounds and suggest the use of this model to assign safety margins for human clinical use. The intent of this series of studies was to evaluate the impact of study design on the proarrhythmic concentration predicted by this model. METHODS: Nine compounds of varying proarrhythmic potential and a negative control were tested in a blinded fashion using a series of different experimental protocols: Compounds were tested at multiple concentration ranges and extended perfusion times were also evaluated. RESULTS: In general when the dataset is viewed as a whole, the model did identify proarrhythmic compounds, however the concentration at which action potential prolongation, triangulation, instability, reverse-use dependence and ectopic beats occurred often varied based on the concentration range selected. Further analysis using extended compound perfusion times demonstrated that variability may be due in part to lack of adequate equilibration of compound with the cardiac tissue. DISCUSSION: We report that the model correctly identified proarrhythmic agents in a qualitative manner, but that study design impacts the proarrhythmic concentration derived from the model. PMID- 17707658 TI - Atypical neural substrates of Embedded Figures Task performance in children with Autism Spectrum Disorder. AB - Superior performance on the Embedded Figures Task (EFT) has been attributed to weak central coherence in perceptual processing in Autism Spectrum Disorder (ASD). The present study used functional magnetic resonance imaging to examine the neural basis of EFT performance in 7- to 12-year-old ASD children and age- and IQ-matched controls. ASD children activated only a subset of the distributed network of regions activated in controls. In frontal cortex, control children activated left dorsolateral, medial and dorsal premotor regions whereas ASD children only activated the dorsal premotor region. In parietal and occipital cortices, activation was bilateral in control children but unilateral (left superior parietal and right occipital) in ASD children. Further, extensive bilateral ventral temporal activation was observed in control, but not ASD children. ASD children performed the EFT at the same level as controls but with reduced cortical involvement, suggesting that disembedded visual processing is accomplished parsimoniously by ASD relative to typically developing brains. PMID- 17707660 TI - An MRI derived articular cartilage visualization framework. AB - OBJECTIVE: We present a multi-dimensional framework for the visualization of femoral articular cartilage. The framework comprises methods for visualizing and quantifying changes in cartilage thickness and surface morphology derived from MRI based cartilage segmentation. Adequate visualization of cartilage allows accurate and clinically meaningful assessment of cartilage surface morphology and thickness. In current practice the routine use of conventional 2D MR images provides limited qualitative information and is inconvenient because the imaged volume has to be reviewed slice by slice. METHOD: A Graphical User Interface (GUI) that encapsulates the framework described above was developed. In the first stage of the analysis MR images of the knee are segmented to delineate cartilage boundaries. Cartilage thicknesses are subsequently measured. The detected points and corresponding thickness data are utilized to produce a visualization framework. RESULTS: The system was tested using data from six example patients. The spatial distribution of cartilage on the articular surface was visualized using a 3D WearMap. The 2D WearMap allowed the entire cartilage surface to be studied at once. Quantitative interaction with the 2D WearMap was assisted by the ability to ascertain cartilage surface dimensions and TrackBack from a point of interest to the original MR image. As a result, the detection of wear patterns and lesions was efficiently carried out. CONCLUSION: A means of quantitatively visualizing cartilage defects non-invasively is presented. This stands to reduce clinician reporting times, as well as allowing quantitative follow-up that facilitates osteoarthritis (OA) screening and planning/evaluating interventions. PMID- 17707662 TI - N-Methyl-D-aspartate receptors in the ventral tegmental area are involved in retrieval of inhibitory avoidance memory by nicotine. AB - The interaction of opiate, cholinergic, glutamatergic and (possibly) dopaminergic inputs in the ventral tegmental area (VTA) influencing a learned behavior is certainly a topic of great interest. In the present study, the effect of intra VTA administration of N-methyl-d-aspartate (NMDA) receptor agents on nicotine's effect in morphine state-dependent learning was investigated. An inhibitory avoidance (IA) task was used for memory assessment in male Wistar rats. Subcutaneous (s.c.) administration of morphine (5 and 7.5mg/kg) immediately after training decreased IA response on the test day, which was reinstated by pre-test administration of the same doses of the opioid; this is known as state dependency. Moreover, pre-test administration of nicotine (0.2, 0.4 and 0.6 mg/kg, s.c.) also reversed the decrease in IA response because of post-training morphine (5mg/kg). Here, we also show that when infused into the VTA before testing, NMDA (0.01 and 0.1 microg/rat) reverse the post-training morphine effect on memory. In addition, the sub-effective doses of NMDA (0.0001 and 0.001 microg/rat) in combination with a low dose of nicotine (0.1mg/kg) which had no effects by themselves, synergistically improved retrieval of IA memory on the test day. In contrast, pre-test administration of a competitive NMDA receptor antagonist D-AP5 (0.5, 1 and 2 microg/rat) which had no effect alone prevented the nicotine reversal of morphine effect on memory. Our data indicate that NMDA receptors in the VTA are involved in the reversing effect of nicotine on morphine induced state-dependency. PMID- 17707661 TI - Stress-induced signaling pathways in hyalin chondrocytes: inhibition by Avocado Soybean Unsaponifiables (ASU). AB - OBJECTIVE: Avocado-Soybean Unsaponifiables (ASU) represent one of the most commonly used drugs for symptomatic osteoarthritis (OA). The mechanisms of its activities are still poorly understood. We investigate here the effects of ASU on signaling pathways in mouse or human chondrocytes. METHODS: Mouse or human chondrocytes stimulated with interleukin-1beta (IL1beta, 10 ng/ml) and cartilage submitted to a compressive mechanical stress (MS) were studied in the presence or absence of ASU (10 microg/ml). Nuclear factor kappaB (NF-kappaB) activation was assessed by immunoblot, using an I-kappa B alpha antibody, nuclear translocation of NF-kappaB using p65 antibody, and extra-cellular signal-regulated kinase (ERK)1/2 activation using phospho and ERK1/2 antibodies. The binding of the p50/p65 complex on DNA was studied by electrophoretic mobility shift assay. RESULTS: ASU decrease matrix metalloproteinases-3 and -13 expressions and Prostaglandin E(2) (PGE(2)) release in our model. The degradation of I-kappa B alpha is prevented in the presence of ASU as shown by the persistent expression of I-kappa B alpha protein in the cytosol when chondrocytes are stimulated by IL1beta or MS. Nuclear translocation of the NF-kappaB complex is shown by the decrease of the p65 protein from the cytosol, whereas p65 appears in the nucleus under IL1beta stimulation. This translocation is abolished in the presence of ASU. Moreover, bandshift experiments show an inhibition of the IL1beta-induced binding of p50/p65 complexes to NF-kappaB responsive elements in response to ASU. Finally, among the different mitogen-activated protein kinases known to be induced by IL1beta, ERK1/2 was the sole kinase inhibited by ASU. CONCLUSION: These results demonstrate that ASU express a unique range of activities, which could counteract deleterious processes involved in OA, such as inflammation. PMID- 17707663 TI - Learning strategy determines auditory cortical plasticity. AB - Learning modifies the primary auditory cortex (A1) to emphasize the processing and representation of behaviorally relevant sounds. However, the factors that determine cortical plasticity are poorly understood. While the type and amount of learning are assumed to be important, the actual strategies used to solve learning problems might be critical. To investigate this possibility, we trained two groups of adult male Sprague-Dawley rats to bar-press (BP) for water contingent on the presence of a 5.0 kHz tone using two different strategies: BP during tone presence or BP from tone-onset until receiving an error signal after tone cessation. Both groups achieved the same high levels of correct performance and both groups revealed equivalent learning of absolute frequency during training. Post-training terminal "mapping" of A1 showed no change in representational area of the tone signal frequency but revealed other substantial cue-specific plasticity that developed only in the tone-onset-to-error strategy group. Threshold was decreased approximately 10 dB and tuning bandwidth was narrowed by approximately 0.7 octaves. As sound onsets have greater perceptual weighting and cortical discharge efficacy than continual sound presence, the induction of specific learning-induced cortical plasticity may depend on the use of learning strategies that best exploit cortical proclivities. The present results also suggest a general principle for the induction and storage of plasticity in learning, viz., that the representation of specific acquired information may be selected by neurons according to a match between behaviorally selected stimulus features and circuit/network response properties. PMID- 17707666 TI - Pharmacophore modeling and virtual screening studies to design some potential histone deacetylase inhibitors as new leads. AB - Histone deacetylase is one of the important targets in the treatment of solid tumors and hematological cancers. A total of 20 well-defined inhibitors were used to generate Pharmacophore models using and HypoGen module of Catalyst. These 20 molecules broadly represent 3 different chemotypes. The best HypoGen model consists of four-pharmacophore features--one hydrogen bond acceptor, one hydrophobic aliphatic and two ring aromatic centers. This model was validated against 378 known HDAC inhibitors with a correlation of 0.897 as well as enrichment factor of 2.68 against a maximum value of 3. This model was further used to retrieve molecules from NCI database with 238,819 molecules. A total of 4638 molecules from a pool of 238,819 molecules were identified as hits while 297 molecules were indicated as highly active. Also, a Similarity analysis has been carried out for set of 4638 hits with respect to most active molecule of each chemotypes which validated not only the Virtual Screening potential of the model but also identified the possible new Chemotypes. This type of Similarity analysis would prove to be efficient not only for lead generation but also for lead optimization. PMID- 17707665 TI - Determination of NMR interaction parameters from double rotation NMR. AB - It is shown that the anisotropic NMR parameters for half-integer quadrupolar nuclei can be determined using double rotation (DOR) NMR at a single magnetic field with comparable accuracy to multi-field static and MAS experiments. The (17)O nuclei in isotopically enriched l-alanine and OPPh(3) are used as illustrations. The anisotropic NMR parameters are obtained from spectral simulation of the DOR spinning sideband intensities using a computer program written with the GAMMA spin-simulation libraries. Contributions due to the quadrupolar interaction, chemical shift anisotropy, dipolar coupling and J coupling are included in the simulations. In l-alanine the oxygen chemical shift span is 455 +/- 20 ppm and 350 +/- 20 ppm for the O1 and O2 sites, respectively, and the Euler angles are determined to an accuracy of +/- 5-10 degrees . For cases where effects due to heteronuclear J and dipolar coupling are observed, it is possible to determine the angle between the internuclear vector and the principal axis of the electric field gradient (EFG). Thus, the orientation of the major components of both the EFG and chemical shift tensors (i.e., V(33) and delta(33)) in the molecular frame may be obtained from the relative intensity of the split DOR peaks. For OPPh(3) the principal axis of the (17)O EFG is found to be close to the O-P bond, and the (17)O-(31)P one-bond J coupling ((1)J(OP)=161 +/- 2 Hz) is determined to a much higher accuracy than previously. PMID- 17707664 TI - Matrix metalloproteinases as modulators of inflammation. AB - An increased expression of members of the matrix metalloproteinase (MMP) family of enzymes is seen in almost every human tissue in which inflammation is present. Through the use of models of human disease in mice with targeted deletions of individual MMPs, it has become clear that MMPs act broadly in inflammation to regulate barrier function, inflammatory cytokine and chemokine activity, and the generation of chemokine gradients. Individual MMPs regulate both normal and pathological inflammatory processes, and therefore, developing rational therapies requires further identification of specific MMP substrates and characterization of the downstream consequences of MMP proteolytic activity. PMID- 17707667 TI - Neural regulation of mucosal function. AB - Nociceptive, parasympathetic and sympathetic nerves play critical roles in regulating glandular, vascular and other processes in airway mucosa. These functions are vital for cleaning and humidifying ambient air before it is inhaled into the lungs. Recent identification of subsets of nociceptive nerves has tipped the donkey cart of dogma and led to the discovery of new receptor and ion channel families that respond to culinary odorants ("aromatherapy"), inhaled irritants, temperature and other "humors"; a new interpretation of airway nociceptive nerve axon responses; and an understanding of the neural plasticity induced by inflammation and different neurotrophic factors. PMID- 17707668 TI - Ubiquitous expression of myostatin in chicken embryonic tissues: its high expression in testis and ovary. AB - The skeletal muscle of mammals is known to express myostatin (GDF-8) that acts as a potent negative regulator of skeletal muscle growth. However, the function of GDF-8 is not limited to skeletal muscle, because of its ubiquitous expression in fish. Here we investigated whether GDF-8 is expressed in various tissues including gonads during chicken embryogenesis. As revealed by RT-PCR and Western blotting, the transcript and protein for GDF-8 were detected in brain, eye, gizzard, muscle, heart, small gut, large gut, mesonephroi, testis and ovary of chicken embryos at E12, but not in liver. GDF-8 was constitutively expressed in testis and ovary as well as muscle at E6-E21, as demonstrated by in situ hybridization on section and whole-mount. Some cell population in testis, but not identified, highly expressed GDF-8. On the other hand, the medulla and germinal epithelium of ovary highly expressed it. Collectively, these results indicate that GDF-8 is ubiquitously expressed in various tissues of chicken embryos including testis and ovary through the stage of embryogenesis. PMID- 17707669 TI - The importance of dissolved salts to the in vivo efficacy of antifreeze proteins. AB - Antifreeze proteins (AFP) and antifreeze glycoproteins (AFGP) lower the freezing point of marine fish plasma non-colligatively by specifically adsorbing to certain surfaces of ice crystals, modifying their structure and inhibiting further growth. While the freezing point is lowered, the melting point is unaltered and the difference between the two is termed thermal hysteresis (TH). In pure water, the level of TH is directly related to the intrinsic activity of the specific AF(G)P in solution and to their concentration. Results of this study indicate that when AF(G)P are dissolved in salt solutions, such as NaCl, encompassing the range they could encounter in nature, there is a synergistic enhancement of basal TH that is positively related to the salt concentration. This enhancement is likely a result of the hydration shell surrounding the dissolved ions and, as a consequence, reducing freezable water. A secondary reason for the enhancement is that the salt could be influencing the hydration shell surrounding the AF(G)P, increasing their solubility and thus the protein surface area available to adsorb to the ice/water interface. The former hypothesis for the salt enhanced TH has implications for the in vivo function of AF(G)P, particularly at the seawater/external epithelia (gills, skin, stomach) interface. The latter hypothesis is likely only relevant to in vitro situations where freeze dried protein is dissolved in low salt solutions. PMID- 17707670 TI - Trypsin from the pyloric caeca of bluefish (Pomatomus saltatrix). AB - Trypsin was purified from the pyloric caeca of bluefish (Pomatomus saltatrix) by ammonium sulfate precipitation, acetone precipitation and soybean trypsin inhibitor-Sepharose 4B affinity chromatography. Bluefish trypsin migrated as a single band using both sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and native-PAGE and had a molecular mass of 28 kDa. The optima pH and temperature for the hydrolysis of benzoyl-dl-arginine-p-nitroanilide (BAPNA) were 9.5 and 55 degrees C, respectively. The enzyme was stable over a broad pH range (7 to 12), but was unstable at acidic pH, and at temperatures greater than 40 degrees C. The enzyme was inhibited by specific trypsin inhibitors: soybean trypsin inhibitor (SBTI), N-p-tosyl-l-lysine chloromethyl ketone (TLCK) and the serine protease inhibitor phenylmethyl sulfonylfluoride (PMSF). CaCl2 partially protected trypsin against activity loss at 40 degrees C, but NaCl (0 to 30%) decreased the activity in a concentration dependent manner. The N-terminal amino acid sequence of trypsin was determined as IVGGYECKPKSAPVQVSLNL and was highly homologous to other known vertebrate trypsins. PMID- 17707672 TI - [Breech presentation and vaginal delivery: evolution of acceptability by obstetricians and patients]. AB - OBJECTIVE: To investigate the influence of obstetrician and patient respectively on mode of delivery in case of breech presentation at term. PATIENTS AND METHODS: This retrospective study included all women with a singleton pregnancy in a breech presentation delivered at term in a tertiary care maternity unit from January 1998 to December 2004. Mode of delivery was suggested by a score based on maternal age, parity, obstetrical past history, radiopelvimetry and cephalopelvic confrontation. The obstetrician was free to follow or not the score indication and patient's informed consent was required concerning the mode of delivery. Our main outcome measurements were mode of delivery and neonatal parameters. RESULTS: Two hundred cases were identified. Elective cesarean section increased progressively (from 52% in 1998 to 80% in 2004 [P=0,002]). Neonatal status and proportion of score in favour of vaginal birth remained stable during the study period. The rise in cesarean section rate was mainly due to patient's request (P=0,001) whereas the trend of obstetrician in favour of cesarean did not reach significance (P=0,3). DISCUSSION AND CONCLUSION: The rise of elective cesarean section for term breech delivery in a maternity unit using a predefinite score is mainly induced by patient's request. This evolution has no effect on neonatal status. PMID- 17707671 TI - Differential perturbation of the Fgf/Erk1/2 and Shh pathways in the C57BL/6N and SWV embryonic limb buds after mid-gestational cadmium chloride administration. AB - The differential susceptibility of inbred mouse strains to teratogen-induced malformations can serve as a model to assess the molecular pathogenesis of dysmorphology. Using such a model, the teratogenic effect of cadmium chloride (CdCl(2)), which results in limb reduction deformities in the C57BL/6N mouse strain, but not in the SWV strain, was found to correlate with reduction of the expression domains of Fgf8/4 (fibroblast growth factor-8 and -4) in the apical ectodermal ridge (AER) and Shh (sonic hedgehog) in the posterior mesenchyme, as well as reduction of MAPK/Erk1/2 (the mitogen-activated protein kinase/extracellular regulated kinase 1/2) phosphorylation (pErk1/2) in the mesenchyme throughout the limb bud. The pattern of pErk1/2 reduction did not consistently reflect the pattern of Fgf8/4 reduction suggesting that CdCl(2) might affect pErk1/2 through an Fgf-independent pathway. Other potential downstream mediators of the Fgf pathway including Mkp3 and Fgf10 as well as pMek (phosphorylated MAPK/Erk1/2 kinase) were not different in limb buds between the two strains at the studied time points. The effect of CdCl(2) on skeletogenesis was traced in time to the early stages of pre-chondrogenic condensation as determined by the Sox9 expression domain. The data of the present study indicate that a differential strain response to CdCl(2)-induced forelimb digital loss may be due to a polymorphic interference with the Fgf/Shh positive feedback loop and Erk1/2 phosphorylation. PMID- 17707673 TI - [Chronic inflammatory disorders and reproduction]. AB - The desire of reproduction is a true challenge for the physicians in charge of patients with chronic inflammatory disorders such as rheumatoid arthritis or other connective tissue diseases. It requires: 1) the strict evaluation of the potential risks of flare of the rheumatic disease because of the pregnancy; 2) the assessment of risks on pregnancy outcome and fetus development; 3) the management of the different anti-rheumatic agents in order to maintain optimal control of disease activity and avoid any teratogenic problem. Besides this, it clearly appears that inflammatory rheumatic diseases may have an impact on patients' fertility, which may be explained by different mechanisms, physical, psychological, hormonal or immunological. Moreover, some treatments may directly affect fertility, which may justify specific managements in order to preserve gonadic functions. PMID- 17707674 TI - [Female fertility preservation in autoimmune diseases: possibilities and practises in France]. AB - Cancer is not the only disease where the question of the female fertility preservation is asked. In autoimmune diseases, alkylating agents are also used and it is now established that 20 g as a cumulative dose of cyclophosphamide is associated with premature ovarian failure in 50% of 20-year-old patients. Several strategies are discussed and offered to these patients to prevent the ovarian failure: GnRH agonist treatment, in vitro fertilization and embryos cryopreservation, oocytes cryopreservation and ovarian cortex cryopreservation. These techniques might also be associated one with the other. A survey was conducted in France in order to assess the practices realised in these diseases. Four centres were asked for these diseases, concerning 17 patients (mean age: 26.2 +/- 1.8 SEM [15-43]) and systemic lupus erythematosus was the most frequent disease (7/17). Ovarian cortex cryopreservation was realised for 6 patients. Embryos or oocytes cryopreservation was realised for 2 patients including one where ovarian cortex cryopreservation was associated. In 10 cases, considering the treatment and the patient's wish no fertility preservation was realised. Female fertility preservation in autoimmune diseases is a difficult question and a national registry, such as the one conducted by the GRECOT, can help to answer this question. PMID- 17707675 TI - [Abnormal placental caryotype in severe intrauterine growth retardations (IUGR). Case report]. AB - Except for cases due to maternal hypertension, severe and early intrauterine growth retardations are most usually due to fetal abnormalities. We report a case of confined placental homogenous tetraploidy associated with major fetal growth retardation leading to the premature delivery of a life born baby with a normal caryotype. We discuss the interest of chorionic villus sampling in cases of unexplained severe fetal growth retardation. PMID- 17707676 TI - [Intra-uterine insemination: ovarian stimulation or not?]. AB - Conflicting results have been published about intra-uterine insemination efficacy. In many studies, success rates is due to ovarian stimulation and number of follicles. In the present fight against multiple pregnancies, ovarian stimulation is discussed and present pregnancy rates are weak. Our aim is to demonstrate that there is a place for the association controlled ovarian hyperstimulation and intra-uterine insemination in the field of infertility treatments. It is possible to try and recognise women at high risk of multiple pregnancies, keeping the benefit of ovarian stimulation. PMID- 17707677 TI - A control system for automatic electrical stimulation of abdominal muscles to assist respiratory function in tetraplegia. AB - This letter refers to a paper published by Gollee et al. [Gollee H, Hunt KJ, Allan DB, Fraser MH, McLean AN. A control system for automatic electrical stimulation of abdominal muscles to assist respiratory function in tetraplegia. Med Eng Phys 2007;29:799-807]. We address here the consequences of continuous use and suggest a refinement that may improve the cough peak flow under more chronic conditions. PMID- 17707678 TI - Screening for cognitive deficits in Parkinson's disease with the Parkinson neuropsychometric dementia assessment (PANDA) instrument. AB - Cognitive and affective dysfunctions are frequent but often neglected symptoms in Parkinson's disease (PD). We developed the screening tool Parkinson neuropsychometric dementia assessment (PANDA) with five cognitive tasks and a short depression questionnaire. Healthy subjects and patients without cognitive impairment (PD), mild cognitive disorder (PD-MCD), or dementia (PDD) were examined. The cognition part had a specificity of 91% and a sensitivity of 90% for PDD and 77% for PDD plus PD-MCD patients. The mood questionnaire also had high sensitivity and specificity. We conclude that the PANDA is an economical, easy-to-use and sensitive tool to detect neuropsychological dysfunctions in PD patients in clinical practice. PMID- 17707679 TI - The rationale for continuous dopaminergic stimulation in advanced Parkinson's disease. AB - Control of movement depends on the continuous release of dopamine by neurons in the basal ganglia of the brain. The degeneration of these neurons in Parkinson's disease (PD) interferes with the flow of dopamine, leading to classic motor symptoms. In early PD, enough dopaminergic neurons remain to store dopamine provided by periodic dosing with oral levodopa and relatively normal, tonic levels of dopamine release are maintained. PD progression leads to degeneration of remaining dopaminergic terminals and loss of buffering capacity for exogenous levodopa. As a result, there are supraphysiological levels of dopamine after dosing and troughs when the available dopamine has been depleted. These divergent levels are associated with dyskinesia and 'off' states, respectively. Treatment strategies that provide a continuous flow of dopamine and can thus mimic normal physiological dopamine stimulation have potential to improve motor control for patients with advanced PD. PMID- 17707680 TI - Lens cells: more than meets the eye. AB - Lens cells originate from the head ectoderm and differentiate into an avascular organ constituted from two contiguous cell subpopulations of very different morphology. Lens cells, together with corneal cells, are responsible for the transmission and focusing of light onto the retina. Loss of transparency within the lens, via disruption of membrane transport or protein aggregation, results in cataract. PMID- 17707682 TI - The amygdala and ventromedial prefrontal cortex in morality and psychopathy. AB - Recent work has implicated the amygdala and ventromedial prefrontal cortex in morality and, when dysfunctional, psychopathy. This model proposes that the amygdala, through stimulus-reinforcement learning, enables the association of actions that harm others with the aversive reinforcement of the victims' distress. Consequent information on reinforcement expectancy, fed forward to the ventromedial prefrontal cortex, can guide the healthy individual away from moral transgressions. In psychopathy, dysfunction in these structures means that care based moral reasoning is compromised and the risk that antisocial behavior is used instrumentally to achieve goals is increased. PMID- 17707681 TI - Peptides derived from type I thrombospondin repeat-containing proteins of the CCN family inhibit proliferation and migration of endothelial cells. AB - Angiogenesis, or neovascularization, is tightly orchestrated by endogenous regulators that promote or inhibit the process. The fine-tuning of these pro- and anti-angiogenic elements (the angiogenic balance) helps establish the homeostasis in tissues, and any aberration leads to pathologic conditions. The type I thrombospondin repeats are a family of protein structural elements involved in the control of angiogenesis, and some proteins containing these repeats have been identified as negative regulators of angiogenesis. Here we identify a set of 11 novel, anti-angiogenic 18-20-amino acid peptides that are derived from proteins that belong to the CCN protein family and contain type I thrombospondin motifs. We have named these peptides spondinstatin-1, cyrostatin, connectostatin, nephroblastostatin, wispostatin-2, wispostatin-3, netrinstatin-5C, netrinstatin 5D, adamtsostatin-like-4, fibulostatin-6.1, and complestatin-C6 to reflect their origin. We have shown that these peptides inhibit proliferation and migration of human umbilical vein endothelial cells in vitro. By conducting a clustering analysis of the amino acid sequences using sequence similarity criteria and of the experimental results using a hierarchical clustering algorithm, we have demonstrated that there is an underlying correlation between the sequence and activity of the identified peptides. This combination of experimental and computational approaches introduces a novel systematic framework for studying peptide activity, identifying novel peptides with anti-angiogenic activity, and designing mimetic peptides with tailored properties. PMID- 17707683 TI - Imaging recollection and familiarity in the medial temporal lobe: a three component model. AB - The medial temporal lobe (MTL) plays a crucial role in supporting memory for events, but the functional organization of regions in the MTL remains controversial, especially regarding the extent to which different subregions support recognition based on familiarity or recollection. Here we review results from functional neuroimaging studies showing that, whereas activity in the hippocampus and posterior parahippocampal gyrus is disproportionately associated with recollection, activity in the anterior parahippocampal gyrus is disproportionately associated with familiarity. The results are consistent with the idea that the parahippocampal cortex (located in the posterior parahippocampal gyrus) supports recollection by encoding and retrieving contextual information, whereas the hippocampus supports recollection by associating item and context information. By contrast, perirhinal cortex (located in the anterior parahippocampal gyrus) supports familiarity by encoding and retrieving specific item information. We discuss the implications of a 'binding of item and context' (BIC) model for studies of recognition memory. This model argues that there is no simple mapping between MTL regions and recollection and familiarity, but rather that the involvement of MTL regions in these processes depends on the specific demands of the task and the type of information involved. We highlight several predictions for future imaging studies that follow from the BIC model. PMID- 17707684 TI - Cellular differentiation and host invasion by the rice blast fungus Magnaporthe grisea. AB - This review describes current advances in understanding the biology of plant infection by the rice blast fungus Magnaporthe grisea. Development of the specialized infection structure, the appressorium, in M. grisea has recently been shown to be controlled by cell cycle progression and initiation of autophagic, programmed cell death in the fungal spore. Re-cycling of the contents of the fungal spore and peroxisomal fatty acid beta-oxidation are therefore important processes for appressorium function. Following entry to the host plant, new evidence suggests that M. grisea grows biotrophically within rice cells, bounded by the plant plasmalemma, and the fungus moves from cell-to-cell by means of plasmodesmata. Biotrophic proliferation of the fungus is likely to require secretion of effector proteins and suppression of host defences. Consistent with this, a component of the polarized exocytosis machinery of M. grisea is necessary for pathogenicity and also for induction of host defences in an incompatible interaction. Large-scale insertional mutagenesis is now allowing the rapid analysis of gene function in M. grisea, heralding a new approach to the study of this important fungal pathogen. PMID- 17707686 TI - Antibacterial targets in fatty acid biosynthesis. AB - The fatty acid biosynthesis pathway is an attractive but still largely unexploited target for the development of new antibacterial agents. The extended use of the antituberculosis drug isoniazid and the antiseptic triclosan, which are inhibitors of fatty acid biosynthesis, validates this pathway as a target for antibacterial development. Differences in subcellular organization of the bacterial and eukaryotic multienzyme fatty acid synthase systems offer the prospect of inhibitors with host versus target specificity. Platensimycin, platencin, and phomallenic acids, newly discovered natural product inhibitors of the condensation steps in fatty acid biosynthesis, represent new classes of compounds with antibiotic potential. An almost complete catalog of crystal structures for the enzymes of the type II fatty acid biosynthesis pathway can now be exploited in the rational design of new inhibitors, as well as the recently published crystal structures of type I FAS complexes. PMID- 17707687 TI - Infection-related gene expression in Candida albicans. AB - Research into the major fungal pathogen, Candida albicans has firmly entered the post-genomics era. The current challenge is to apply these technologies to the analysis of C. albicans infections. Initial studies, which focused on the expression of specific virulence genes, have supported the view that secreted hydrolases and adhesins are expressed in a niche-specific fashion during infection. However, genome-wide expression profiling has revealed that most infection-related changes in C. albicans gene expression reflect environmental adaptation. Initial contacts with the host and disease progression are clearly associated with metabolic and stress adaptation. These studies, together with analyses of C. albicans mutants, indicate that physiological fitness plays a central role in the pathogenicity of this fungus, alongside virulence factors. PMID- 17707685 TI - Cryptococcus neoformans, a fungus under stress. AB - Cryptococcus neoformans is a human fungal pathogen that survives exposure to stresses during growth in the human host, including oxidative and nitrosative stress, high temperature, hypoxia, and nutrient deprivation. There have been many genes implicated in resistance to individual stresses. Notably, the catalases do not have the expected role in resistance to external oxidative stress, but specific peroxidases appear to be critical for resistance to both oxidative and nitrosative stresses. Signal transduction through the HOG1 and calcineurin/calmodulin pathways has been implicated in the stress response. Microarray and proteomic analyses have indicated that the common responses to stress are induction of metabolic and oxidative stress genes, and repression of genes encoding translational machinery. PMID- 17707688 TI - RXLR effectors of plant pathogenic oomycetes. AB - Oomycetes are a phylogenetically distinct group of organisms that include some of the most devastating plant pathogens. Recent characterization of four oomycete Avr genes revealed that they encode effector proteins with a common modular structure, including a N-terminal conserved RXLR motif. Several lines of evidence initially indicated, with support from more recent works, that these Avr proteins are secreted by the pathogen and then translocated into the host cell during infection. In addition to elucidating the machinery required for host-cell transport, future works remain to determine the myriad virulence functions of oomycete RXLR effector proteins. PMID- 17707689 TI - Re: cyto- and genotoxicity of ultrafine TiO(2) particles in cultured human lymphoblastoid cells. PMID- 17707690 TI - Development of a microtiter plate version of the yeast DEL assay amenable to high throughput toxicity screening of chemical libraries. AB - The yeast plate-based deletion (DEL) assay has been previously shown to detect a wide range of carcinogens. Of 60 compounds of known carcinogenic activity, 92% were correctly detectable with the DEL assay whereas 62% were correctly detectable with the Ames assay [W.W. Ku, J. Aubrecht, R.J. Mauthe, R.H. Schiestl, A.J. Fornace Jr., Why not start with a single test: a transformational alternative to genotoxicity hazard and risk assessment, Toxicol. Sci. (2007)]. In this manuscript we describe a modification of the yeast DEL assay into a colorimetric assay using the MTS tetrazolium compound (3-(4,5-dimethylthiazol-2 yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) to allow for efficient detection of chemical genotoxicity. It has been micro-scaled and can be performed in 96- or 384-well format. Chemicals previously characterized with the DEL plate-based assay were utilized to test the new well based format, and a group of cross-linking agents, previously uncharacterized by the DEL assay, were scored for genotoxicity using this new assay format. These compounds induced a range of genotoxicity detectable with the well-based DEL assay, and a lack of sensitivity was found only at extremely low genotoxic levels determined by the plate-based DEL assay. We suggest this new well-based version of the DEL assay can be used as an economical alternative to the plate-based assay to screen large numbers of compounds, such as chemical libraries in a high throughput screening setting. PMID- 17707692 TI - Associations between physical inactivity and a measure of social capital in a sample of Queensland adults. AB - How social capital is related to an increasingly important disease risk-physical inactivity has not yet been investigated. In the present study the associations between social capital and physical inactivity were investigated in a sample of Queensland (Australia) adults. Data was collected from 1278 persons by means of a computer-assisted-telephone-interview survey. The association between the social capital variables and physical inactivity was studied using logistical regression. Multivariate analysis adjusted for the effects of selected socio demographic factors in the investigation of the association between physical inactivity and quartile groupings of social capital scores. Physical inactivity was negatively associated with the measure of social capital. Individuals in the top two quartiles of social capital were significantly less likely to be physically inactive than those in the two lowest quartiles. In summary, low social capital was associated with physical inactivity. The results offer implications for health promotion programs aimed at increasing levels of physical activity at the community or population level. PMID- 17707691 TI - Combined therapy with human cord blood cell transplantation and basic fibroblast growth factor delivery for treatment of myocardial infarction. AB - BACKGROUND: Transplanting cord blood-derived cells has been shown to augment neovascularization in ischaemic tissue. AIM: To test whether sustained delivery of basic fibroblast growth factor (bFGF) enhances the efficacy of angiogenic cord blood mononuclear cell (CBMNC) transplantation therapy in treating myocardial infarction. METHODS: Three weeks after myocardial infarction, Sprague-Dawley rats were randomised to either injection of medium only (control), CBMNC transplantation, sustained bFGF delivery, or combined CBMNC transplantation and sustained bFGF delivery. Six weeks after treatment, tissue formation, neovascularization, and apoptotic activity in the infarct regions were evaluated by histology and immunohistochemistry. Left ventricular (LV) dimensions and function were evaluated by magnetic resonance imaging. RESULTS: Combined bFGF delivery and CBMNC transplantation significantly enhanced neovascularization in the ischaemic myocardium, as compared with either therapy alone. The enhanced neovascularization was likely due to increased VEGF and bFGF expression. The combined therapy also exhibited a reduced infarct area and apoptosis in the ischaemic myocardium, as compared with either individual therapy. The combined therapy did not attenuate LV dilation or increase ejection fraction significantly over either individual therapy. CONCLUSION: This study demonstrates that sustained bFGF delivery enhances the angiogenic efficacy of CBMNC transplantation in rat myocardial infarction models. PMID- 17707693 TI - A light load eccentric exercise confers protection against a subsequent bout of more demanding eccentric exercise. AB - This study investigated the hypothesis that a light eccentric exercise (ECC) that does not induce a loss of muscle function and delayed onset muscle soreness would confer a protective effect against a more strenuous ECC. Eighteen young men were randomly placed into two groups: 10-40% (n=9) and 40% (n=9). Subjects in the 10 40% group performed ECC of the elbow flexors (six sets of five reps) using a dumbbell set at 10% of maximal isometric strength (MVC) at an elbow joint angle of 90 degrees , followed 2 days later by ECC using a dumbbell weight of 40% MVC. Subjects in the 40% group performed the 40% ECC only. Changes in MVC, range of motion (ROM), upper arm circumference (CIR), plasma creatine kinase (CK) activity and muscle soreness before, immediately after, 1-5 and 7 days following the 40% ECC were compared between groups by a two-way repeated measures ANOVA. No significant changes in any of the criterion measures were found immediately and 1 2 days after the 10% ECC. Following the 40% ECC, the 10-40% group showed significantly (P<0.05) smaller decreases in MVC and ROM, and smaller increases in muscle soreness compared with the 40% group, but no significant differences between groups were evident for CIR and plasma CK activity. These results suggest that the 10% ECC induced some protection against a subsequent bout of 40% ECC performed 2 days later. It appears that the light eccentric exercise preconditioned the muscles for exposure to the subsequent damaging eccentric exercise bout. PMID- 17707694 TI - Plasma exchange in critically ill patients with sickle cell disease. AB - Red cell exchange transfusion is the recommended therapy for patients with sickle cell disease who have complicated vaso-occlusive episodes. However, the role of the therapeutic plasma exchange in the management of the potentially life threatening complications in patients with sickle cell disease is not well known. To determine whether plasma exchange had a cumulative effect on the red cell exchange in patients with sickle cell disease who developed multi-organ failure during the post red cell exchange period, we performed plasma exchange in the nine episodes of multi-organ failure of 7 patients with sickle cell anemia. The median age of those patients was 21 years (range, 9-50 years). The criterion of the multi-organ failure was defined as organ failure of two or more organs i.e. lung, liver, or renal, established according to Acute Physiological and Chronic Health Evaluation-II (APACHE-II) criteria. The average total plasma exchange volume was 1.0 times the patient's plasma volume. The patients had a good outcome, with a survival rate at 86% after one year of follow-up. Plasma exchange may have cumulative benefits in the treatment of severe illness in patients with sickle cell disease who underwent automatic red cell exchange therapy. PMID- 17707695 TI - An audit on the current practice of red blood cell transfusion following elective primary hip arthroplasty. AB - This audit encompassing a six-month period on the current practice of red blood cell transfusion following elective primary total hip arthroplasty showed that the rate of allogeneic blood avoidance was 84.8% for preoperative autologous blood donors and 47.8% for non-donors (p<0.001). Lower preoperative hemoglobin level was associated with an increased allogeneic unit transfusion (p<0.001). The intraoperative use of autologous blood collection and transfusion systems did not reduce the transfusion risk, and the use of the colloid volume expander was associated with a 1.8-fold increased risk of transfusion (p=0.022). PMID- 17707696 TI - Availability of blood components and plasma derived medicines in Iran. AB - Iran is a country with advanced health care system. In 1974 government of Iran established a centralized transfusion system. Since then donations of blood may not be remunerated and therapy with blood and its components is free of charge for all Iranian patients in need of the treatment. Most of donors in Iran are educated middle age men. In 2005 Iranian donated more than 1.6 millions units of blood. Although Iran population has doubled in past three decades blood donation has increased several folds. Donations are meticulously screened through interviewing of donors and lab testing of the donations using serological methods. In contrary to blood and blood components, Iran is heavily depends on importation of plasma derived medicines. Irrational use of blood components and low surveillance on use of plasma derived medicines, which are highly subsidized by the government, is a major challenge in transfusion medicines in Iran. PMID- 17707697 TI - Relationship between mitochondrial DNA mutations and clinical characteristics in human lung cancer. AB - Mitochondrial DNA (mtDNA) is known for its high frequencies of polymorphisms and mutations, some of which are related to various diseases, including cancers. However, roles of mutations and polymorphisms in some diseases are among heated debate, especially for cancer. To investigate the possible role of mtDNA mutations in lung cancer, we sequenced complete mtDNA of lung cancer tissues, corresponding normal (i.e., non-cancerous) lung tissues, and peripheral blood samples from 55 lung cancer patients and examined the relationship between mtDNA mutations or polymorphisms and clinical parameters. We identified 56 mutations in 33 (60%) of the 55 patients, including 48 point mutations, four single-nucleotide insertions, and four single-nucleotide deletions. Nineteen of these mutations resulted in amino acid substitution. These missense mtDNA mutations were distributed in 9 of 13 mitochondrial DNA coding genes. Three hundred eighty eight polymorphisms were identified among the 55 patients. Seventy-three polymorphisms resulted in amino acid substitution. There was no association of incidence of specific mtDNA mutation or polymorphism with patients' gender, age at diagnosis, smoking history, tumor type or tumor stage (P>0.05). This study revealed a variety of mtDNA mutations and mtDNA polymorphisms in human lung cancer, some of which might be involved in human lung carcinogenesis. PMID- 17707698 TI - Improved surface EMG electrode for measuring genioglossus muscle activity. AB - Activation of the genioglossus (GG) muscles is necessary to maintain the patency of the upper airway. In the condition of obstructive sleep apnea (OSA) this mechanism fails and the possible role of fatigue in its pathogenesis is still not fully understood. In this paper, a new electrode design for recording the genioglossus surface electromyogram (sEMG) is presented. The new design differs from a widely used GG surface electrode in both electrode configuration (unilateral rather than bilateral) and electrode material (Ag-AgCl rather than stainless steel (SS)). The separate effects of these factors were evaluated during force-varying and fatiguing contractions on normal human subjects and using GG sEMG model simulations. Unilateral sEMG was found to have lower amplitude, lower frequency content and a different rate of change of median frequency during fatiguing contractions. It was shown to overcome several disadvantages posed by the bilateral configuration and be more selective. Ag-AgCl has more favorable impedance characteristics and resulted in greater signal amplitudes. It was concluded that the new design is more suitable for detecting GG sEMG and allows more reliable interpretation of changes in sEMG due to physiological mechanisms, thus providing a new methodology for studying GG function and the role of fatigue in OSA. PMID- 17707700 TI - Improved RP-HPLC method to determine neferine in dog plasma and its application to pharmacokinetics. AB - Existing methods to determine neferine, a bisbenzylisoquinline alkaloid, either have no internal standard or lack selectivity, or take longer time. Here an improved reverse-phase high-performance liquid chromatographic (RP-HPLC) method was established in biological samples. The extraction recovery was 90.9% for neferine at concentration level of 0.2 microg/ml and 77.7% for dauricine (the internal standard) at 5 microg/ml in dog plasma, respectively. The linear quantification range of the method was 25-2000 ng/ml in dog plasma, with linear correlation coefficients greater than 0.999. The intra-day and inter-day relative standard deviations (R.S.D.s) for neferine at 50, 200 and 1000 ng/ml levels in dog plasma fell in the range of 3.0-5.4% and 4.3-9.5%, respectively. The RP-HPLC method was successfully applied to a pharmacokinetics study, in which experimental dogs received a single dose of neferine (5 mg/kg i.v. or 10 mg/kg p.o.). The pharmacokinetic result was presented. PMID- 17707699 TI - Fluid secretion by submucosal glands of the tracheobronchial airways. AB - Submucosal glands of the tracheobronchial airways provide the important functions of secreting mucins, antimicrobial substances, and fluid. This review focuses on the ionic mechanism and regulation of gland fluid secretion and examines the possible role of gland dysfunction in the lethal disease cystic fibrosis (CF). The fluid component of gland secretion is driven by the active transepithelial secretion of both Cl(-) and HCO(3)(-) by serous cells. Gland fluid secretion is neurally regulated with acetylcholine, substance P, and vasoactive intestinal peptide (VIP) playing prominent roles. The cystic fibrosis transmembrane conductance regulator (CFTR) is present in the apical membrane of gland serous cells and mediates the VIP-induced component of liquid secretion whereas the muscarinic component of liquid secretion appears to be at least partially CFTR independent. Loss of CFTR function, which occurs in CF disease, reduces the capacity of glands to secrete fluid but not mucins. The possible links between the loss of fluid secretion capability and the complex airway pathology of CF are discussed. PMID- 17707701 TI - Cofactor-specific modulation of 11beta-hydroxysteroid dehydrogenase 1 inhibitor potency. AB - 11beta-hydroxysteroid dehydrogenase 1 regulates the tissue availability of cortisol by interconverting cortisone and cortisol. It is capable of functioning as both a reductase and a dehydrogenase depending upon the surrounding milieu. In this work, we have studied the reaction mechanism of a soluble form of human 11beta-hydroxysteroid dehydrogenase 1 and its mode of inhibition by potent and selective inhibitors belonging to three different structural classes. We found that catalysis follows an ordered addition with NADP(H) binding preceding the binding of the steroid. While all three inhibitors tested bound to the steroid binding pocket, they differed in their interactions with the cofactor NADP(H). Compound A, a pyridyl amide bound more efficiently to the NADPH-bound form of 11beta-hydroxysteroid dehydrogenase 1. Compound B, an adamantyl triazole, was unaffected by NADP(H) binding and the sulfonamide, Compound C, showed preferential binding to the NADP+ -bound form of 11beta-hydroxysteroid dehydrogenase 1. These differences were found to augment significant selectivity towards inhibition of the reductase reaction versus the dehydrogenase reaction. This selectivity may translate to differences in the in vivo effects of 11beta hydroxysteroid dehydrogenase 1 inhibitors. PMID- 17707702 TI - What matters in the long term: reflections on the context of adult outcomes versus detailed measures in childhood. AB - The primary goals of modern perinatal intensive care are to improve survival and neurodevelopmental outcomes of high-risk infants. The detailed assessments at follow-up in the early years provide us with valuable information on the performance of the children at a given point in time. With increasing age of the subjects, the investigation into their outcome has evolved from a narrow focus of neurodevelopmental status to broader considerations of their overall morbidity, accomplishments and self-perception of their health and quality of life. In this chapter, we will reflect on the importance of the detailed measures in the early years, the impact of moderating background variables on predictability of outcomes, implications for the future and what really matters at young adulthood for infants born prematurely. We will explore the perspectives of different respondents and the need to look beyond the traditional measures to obtain complementary information. PMID- 17707703 TI - Bilateral breast reconstruction with DIEP flaps: 4 years' experience. AB - Bilateral prophylactic mastectomy without reconstruction is not accepted by the majority of patients. Successful reconstruction is therefore a mandatory condition for prophylactic mastectomy. Of the many options for autologous breast reconstruction, the deep inferior epigastric perforator (DIEP) flap best meets requirements for bilateral reconstruction in selected patients. The goal of this study is to verify the feasibility of the procedure in our conditions and to find out how it is accepted by patients. We present 55 consecutive patients who were scheduled for bilateral DIEP flap reconstruction during a 4-year period. We reviewed medical charts, performed clinical assessments and processed anonymous questionnaires. There were 77 immediate and 33 delayed breast reconstructions. There was 100% flap survival and no microanastomoses revisions. In 11 patients (10%) the surgeon preferred to convert the DIEP into a mini transverse rectus abdominis muscle (miniTRAM) flap in order to provide adequate blood supply. COMPLICATIONS: revision for haematoma under the flap in four patients (7.2%), excessive blood loss in four patients (7.2%) and partial mastectomy skin flap necrosis in 10 immediate breast reconstructions (12.9%). Patients' evaluation of the aesthetic result was good or excellent in 96.2% of cases. In 33.9% of patients the postoperative quality of life was considered unchanged and 50.9% of them it even improved. The DIEP flap is recommended for bilateral breast reconstruction. Occasional conversion into a miniTRAM flap can increase the total flap survival rate. Bilateral prophylactic mastectomy and DIEP flap reconstruction are very well accepted by patients. PMID- 17707704 TI - 22q11 Deletion in children with cleft lip and palate--is routine screening justified? AB - OBJECTIVE: To ascertain the prevalence of 22q11 deletion in children with a diagnosis of cleft lip and/or palate that had been referred to the Cleft Lip & Palate Service, Newcastle-upon-Tyne. DESIGN: Retrospective analysis of results of 22q11 FISH testing performed in all such referrals. PARTICIPANTS: 191 children, of whom 13 had a bilateral cleft lip and palate, two had a median cleft, 77 had a cleft palate only, 44 had a unilateral cleft lip, 47 had a unilateral cleft lip and palate and eight had a submucous cleft palate. RESULTS: nine patients had a positive 22q11 FISH test. CONCLUSION: This represents a higher percentage than has been previously reported. All children with cleft lip and/or palate should routinely have a 22q11 FISH test in view of the implications of a diagnosis of velocardiofacial syndrome. PMID- 17707705 TI - A new dog ear correction technique. AB - When moving a local flap, a dog ear sometimes appears at the base of the flap. If we try to correct the dog ear primarily, the blood supply to the flap may be disturbed. In such a case, the dog ear is prone to be corrected secondarily. In the present report we show a new technique for correcting a dog ear that enables correction to be done primarily and sufficiently. The principle of the technique is to de-epithelialise the dog ear portion and dig it in to the dermis to preserve the subdermal plexus at the base of the flap intact. This method is useful especially at the base of a transposition flap because the pedicle tends to be narrowed by the conventional correction. PMID- 17707706 TI - Should naevus sebaceus be excised prophylactically? A clinical audit. PMID- 17707707 TI - Useful material for skin flap training for inexperienced residents. PMID- 17707708 TI - Effect of combined humanPTH(1-34) and calcitonin treatment in ovariectomized rats. AB - We examined the combined effects of human parathyroid hormone 1-34 (hPTH) and elcatonin (ECT: a synthetic derivative of eel calcitonin) to prevent loss of bone mass, architecture and strength in ovariectomized (OVX) rats. Fifty-four female rats (aged 13 weeks) were assigned to one of nine groups: Sham (fake surgery performed), OVX, ECT (15 U/kg administered), PTH5, PTH10 and PTH20 (5, 10 or 20 microg/kg administered), and E+PTH5, E+PTH10 and E+PTH20 (15 U/kg of ECT and 5, 10 or 20 microg/kg of hPTH administered). The drug or vehicle was subcutaneously administered three times a week for 12 weeks. The femurs were removed at the completion of the experiment. The right distal femoral metaphysis was used for measuring bone mineral density (BMD), analyzing trabecular bone structure by micro-computed tomography (microCT), and conducting the bone strength test, and the left femur was used for histomorphometric analysis. Trabecular bone volume (BV/TV) and other bone mass parameters were greater in the ECT and PTH groups than in the OVX group. The number of nodes (N.Nd/TV) and trabecular number (Tb.N) were significantly greater in the ECT group, and trabecular thickness (Tb.Th) and trabecular bone pattern factor (TBPf) were significantly greater in the PTH group. These results indicate that these drugs preserve the bone architecture by different means. Analysis by means of microCT revealed that BV/TV, Tb.N, fractal D and N.Nd/TV were significantly greater in the E+PTH groups than in the PTH groups at each concentration. Trabecular separation (Tb.Sp) was significantly lower in the E+PTH5 and E+PTH10 groups than in the respective PTH5 and PTH10 groups. When the maximum load was applied in a compression test on the distal femur, the E+PTH groups had higher values than the PTH groups, however, the three point bending strength of the diaphysis of femur in the E+PTH10 and E+PTH20 groups tended to be low compared to those in the PTH10 and PTH20 groups. These results indicate that combination therapy using PTH and ECT preserves the trabecular microarchitecture better than single-drug therapy using ECT or PTH in OVX rats, however, it is necessary to optimize the calcitonin (CT) dosage and administration in order to achieve the optimal combined effect of PTH and CT. PMID- 17707709 TI - Structural parameters and mechanical strength of cancellous bone in the femoral head in osteoarthritis do not depend on age. AB - For normal bone, aging has been associated with a decrease of both density and failure strength, and with the development of pathologies such as osteoporosis. Conversely, it has been reported that another common disease, osteoarthritis, may alter these age-related changes in cancellous bone, suggesting that it may have a protective role against osteoporosis and the correspondent fracture risk. It was reported that in the principal compressive region of the femoral head in osteoarthritis the bone density does not depend on age. However, it is not clear if this independence on age of the cancellous bone density corresponds also to a reduced dependence on age of the strength to failure. The present work examined cancellous bone from the principal compressive region of the femoral head of 37 patients having severe osteoarthritis. The aim was (1) to investigate the dependence on age of both the structural parameters and the ultimate stress and (2) to investigate the relationships between the ultimate stress and the structural parameters. Using X-ray microcomputed tomography, three-dimensional structural parameters, such as bone volume fraction, direct trabecular thickness and structure model index were calculated. Then the specimens were compressed to failure to determine the ultimate stress. It was found that none of the investigated structural parameters did depend on age, and also the ultimate stress did not depend on age (p>0.05 for all regressions on age). In addition, the ultimate stress was significantly correlated with the structural parameters, primary with the minimum bone volume fraction and the average bone volume fraction (R(2)=0.95 and R(2)=0.84, respectively). These findings show that severe osteoarthritis or a related factor may change the age dependences of both the structural parameters and the mechanical properties usually reported for normal cancellous bone. These results suggest for this pathology to have a protective role against the age-related decrease in density, the age-related deterioration of the microarchitecture and the age-related decrease of the failure strength for the cancellous bone in the principal compressive region of the human femoral head. PMID- 17707710 TI - Consequences of poor compliance with bisphosphonates. AB - BACKGROUND: Prior research on the ability of bisphosphonates to prevent fractures and related health care utilization has been based on high levels of compliance achievable in clinical trial settings. This study was undertaken to assess rates of osteoporotic fractures and health care utilization as a function of bisphosphonate compliance in usual clinical practice. METHODS: This retrospective cohort study used 2000-2004 pharmacy and medical claims data from 45 large U.S. employers. Our sample included persons diagnosed with osteoporosis, aged 40 years or older, and who initiated use of either alendronate or risedronate. Main outcome measures were medication compliance, rates of osteoporotic fracture, and costs for inpatient care, outpatient services, and prescription drugs. RESULTS: We identified 17,988 new users of bisphosphonate therapy. After 1 to 3 years of follow-up, only 30.6% to 42.9% of patients could achieve high compliance (80% 100%), 17.4%-23.0% moderate compliance (79%-40%), and 33.8%-52.0% had low compliance (0%-39%). Multivariate models of fracture risk showed benefits (p<10) with compliance levels of at least 60%, after which no risk benefit could be detected. Multivariate models of health care costs showed statistically significant (p<.05) total costs savings of $859 to $366 per year with high to moderate compliance levels. However, individuals achieving less than 40% compliance had no detectable decrease in inpatient or outpatient costs to offset the increase in drug costs. CONCLUSIONS: Reductions in fracture risk and overall health costs can be detected in individuals achieving as little as 60% to 40% compliance with bisphosphonates. However, as many as 34% of patients in the first year of therapy and 52% by the third year will not reach even the minimal compliance levels required to receive benefits. PMID- 17707711 TI - Enhancement of graft bone healing by intermittent administration of human parathyroid hormone (1-34) in a rat spinal arthrodesis model. AB - Bone grafting is commonly used to treat skeletal disorders associated with large bone defect or unstable joint. It can take several months, however, to achieve a solid union and bony fusion sometimes delays or fails especially in osteoporosis patients. Therefore, we used a rat spinal arthrodesis model to examine whether intermittent administration of human PTH(1-34) accelerates bone graft healing. Eighty-two male Sprague-Dawley rats underwent posterolateral spinal arthrodesis surgery using autologous bone grafts. Animals were given daily subcutaneous injections of hPTH(1-34) (40 microg/kg/day PTH group) or 0.9% saline vehicle (control group) from immediately after surgery till death. Five rats each were killed 2, 4, 7, and 14 days after the surgery, and mRNA expression analysis was performed on harvested grafted bone. Seven rats each were killed 14, 28, and 42 days after the surgery, and the lumbar spine, which contained the grafted spinal segment, was subjected to fusion assessment, microstructural analysis using three dimensional micro-computed tomography, and histologic examination. Serum bone metabolism markers were analyzed. The results indicated that PTH administration decreased the time required for graft bone healing and provided a structurally superior fusion mass in the rat spinal arthrodesis model. PTH administration increased the fusion rate on day 14 (14% in the control group and 57% in the PTH group), accelerated grafted bone resorption, and produced a larger and denser fusion mass compared to control. mRNA expression of both osteoblast- and osteoclast-related genes was upregulated by PTH treatment, and serum bone formation and resorption marker levels were higher in the PTH group than in the control group. Histologically calculated mineral apposition rate, mineralized surface and osteoclast surface were also higher in the PTH group than in the control group. These findings suggest that intermittent administration of PTH(1 34) enhanced bone turn over dominantly on bone formation at the graft site, leading to the acceleration of the spinal fusion. Based on the results of this study, intermittent injection of hPTH(1-34) might be an efficient adjuvant intervention in spinal arthrodesis surgery and all other skeletal reconstruction surgeries requiring bone grafts. PMID- 17707712 TI - Voxel-based modeling and quantification of the proximal femur using inter-subject registration of quantitative CT images. AB - We have developed a general framework which employs quantitative computed tomography (QCT) imaging and inter-subject image registration to model the three dimensional structure of the hip, with the goal of quantifying changes in the spatial distribution of bone as it is affected by aging, drug treatment or mechanical unloading. We have adapted rigid and non-rigid inter-subject registration techniques to transform groups of hip QCT scans into a common reference space and to construct composite proximal femoral models. We have applied this technique to a longitudinal study of 16 astronauts who on average, incurred high losses of hip bone density during spaceflights of 4-6 months on the International Space Station (ISS). We compared the pre-flight and post-flight composite hip models, and observed the gradients of the bone loss distribution. We performed paired t-tests, on a voxel by voxel basis, corrected for multiple comparisons using false discovery rate (FDR), and observed regions inside the proximal femur that showed the most significant bone loss. To validate our registration algorithm, we selected the 16 pre-flight scans and manually marked 4 landmarks for each scan. After registration, the average distance between the mapped landmarks and the corresponding landmarks in the target scan was 2.56 mm. The average error due to manual landmark identification was 1.70 mm. PMID- 17707713 TI - Maintaining access to safe abortion in the United States: a post-Gonzales primer and guide to action. PMID- 17707714 TI - Bleeding patterns associated with oral contraceptive use: a review of the literature. AB - The regulation of vaginal bleeding is an important effect impacting the choice of contraceptive methods. However, comparing vaginal bleeding control and disturbance between various contraceptive studies is often limited by the lack of uniformity in the analysis and reporting of the bleeding patterns. In 1986, the World Health Organization (WHO) issued recommendations for the standardized collection, analysis and reporting of bleeding associated with contraceptives based on 90-day reference periods. We systematically reviewed MEDLINE and EMBASE for all articles reporting bleeding data by reference periods in healthy women using oral contraception. Overall, 17 publications between 1986 and September 2006 were included for review. There was marked variability in the reporting of bleeding data with most studies reporting a few selected bleeding parameters. However, these studies showed, in general, that oral contraceptive users have the greatest bleeding (i.e., results in the highest number of bleeding/spotting days) during the first reference period which decreases by Reference Period 4. Reporting of the bleeding/spotting data using the WHO recommendations may be useful in objectively comparing vaginal bleeding patterns among different oral contraceptive products. PMID- 17707715 TI - Effect of an oral contraceptive containing 30 microg ethinylestradiol plus 3 mg drospirenone on body composition of young women affected by premenstrual syndrome with symptoms of water retention. AB - PURPOSE: This study was conducted to evaluate body weight and composition during oral contraception with 30 microg ethinylestradiol plus 3 mg drospirenone (30EE+DRSP) in women affected by premenstrual syndrome (PMS) with somatic symptoms related to water retention. DESIGN: This prospective study was performed using multifrequency bioelectrical impedance analysis in 18 normally cycling PMS patients (mean age, 28.8 years) evaluated at baseline, during the luteal phase of the menstrual cycle and after 3 and 6 cycles of 30EE+DRSP. Total body water (TBW), intracellular water (ICW), extracellular water (ECW), fat mass and fat free mass were evaluated. Body weight, waist-to-hip ratio and blood pressure were also determined at each visit. Basal values were compared with those measured in 31 healthy females without PMS (controls). RESULTS: PMS patients have higher levels of TBW and ICW than controls. After 6 months of 30EE+DRSP, TBW and ECW were significantly lower than before treatment. No significant variations in ICW or in the other parameters were observed. CONCLUSION: In women with PMS, 30EE+DRSP reduces the concentrations in TBW and ECW. This effect is likely due to the antimineralocorticoid activity of DRSP. Whether these changes may account for the improvement of premenstrual fluid-related symptoms reported with this formulation is discussed. PMID- 17707716 TI - Effectiveness of the levonorgestrel-releasing intrauterine system in the treatment of adenomyosis diagnosed and monitored by magnetic resonance imaging. AB - BACKGROUND: This study was conducted to evaluate the effect of the levonorgestrel releasing intrauterine system (LNG-IUS) on adenomyotic lesions diagnosed and monitored by magnetic resonance imaging (MRI). STUDY DESIGN: LNG-IUS was inserted during menstrual bleeding in 29 women, 24 to 46 years of age, with MRI-diagnosed adenomyosis associated with menorrhagia and dysmenorrhea. Clinical evaluations were carried out at baseline and at 3 and 6 months postinsertion. MRI was performed at baseline and at 6 months postinsertion and was used to calculate junctional zone thickness (in mm), to define the junctional zone borders, to identify the presence of high-signal foci on T(2)-weighted images and to calculate uterine volume (in mL). RESULTS: A significant reduction of 24.2% in junctional zone thickness was observed (p<.0001); however, no significant decrease in uterine volume was observed (142.6 mL vs. 136.4 mL; p=.2077) between baseline and the 6-month evaluation. A significant decrease in pain score was observed at 3 and 6 months after insertion (p<.0001); however, six women continued to report pain scores >3 at 6 months of observation. At 3 months of use, the most common bleeding pattern was spotting, and at 6 months of observation, oligomenorrhea was the most common pattern observed, although spotting was present in one third of the women. CONCLUSIONS: The insertion of an LNG-IUS led to a reduction in pain and abnormal bleeding associated with adenomyosis. MRI was useful for monitoring response of adenomyotic lesions to the LNG-IUS. PMID- 17707717 TI - Evaluation of iron deficiency in young women in relation to oral contraceptive use. AB - BACKGROUND: The purpose of this study was to identify the optimal measures for diagnosing iron deficiency (ID) in oral contraceptive (OC) users and nonusers, and to estimate ID frequency in relation to OC use. STUDY DESIGN: Conventional biomarkers of iron status - serum ferritin, iron, transferrin (Tf) and transferrin saturation (TfS) - were compared with serum soluble Tf receptor (sTfR) and the sTfR/log ferritin ratio (sTfR-F index). Two hundred two healthy menstruating white Italian women (aged 24+/-4.8 years) were analyzed. Serum ferritin concentrations <12 microg/L were considered as ID. RESULTS: ID was detected in 29.7% (60/202) of the study women. Fifty-nine women were OC users (59/202, 29.2%). OC use did not significantly affect ID prevalence (p=.24). However, OC use markedly increased Tf in OC users, who had an odds ratio (OR) of 9.3 (CI 3.8-22.7, p<.001) for elevated Tf >330 mg/dL. No other iron status measure was affected by OC. Of the markers for ID adjunctive to ferritin, an elevated sTfR-F index >or =1.5 showed the best performance. Specifically in OC users, the elevated sTfR-F index had better sensitivity (81.0% vs. 33.3%), specificity (94.7% vs. 92.1%), efficiency (89.8% vs. 71.2%), positive predictive value (89.5% vs. 70.0%) and negative predictive value (90.0% vs. 71.1%) than a TfS <15%. Additionally, the sTfR-F index allowed the identification of low iron stores in 4.5% (9/202) of women with ferritin > or =12 microg/L. CONCLUSION: Among healthy OC users and non-OC users, the sTfR-F index had the highest performance for diagnosing ID compared with other serum markers adjunctive to ferritin measurements, whereas sTfR by itself had a low sensitivity. We showed that neither the sTfR nor sTfR-F index was affected by third-generation OC use. The sTfR measurement is useful in the diagnosis of ID, especially in women using OC, where Tf and TfS tests may be misleading. PMID- 17707718 TI - Attitudes towards long-acting reversible methods of contraception in general practice in the UK. AB - INTRODUCTION: Recently published national guidance in England recommended that increased use of long-acting reversible methods of contraception could reduce unintended pregnancy rates. Usage rates of long-acting reversible methods of contraception in the UK are currently low. Since these methods require medical intervention, attitudes of professionals are important determinants of prevalence of use. STUDY DESIGN: A questionnaire survey was conducted of 321 health professionals working in general practice which sought practitioner views on safety, efficacy and acceptability of contraceptive methods, and on the feasibility and desirability of prescribing long-acting methods. RESULTS: A high proportion of practitioners (80.2%) endorsed the role of LARC in preventing teenage pregnancy, but fewer than half (47.1%) saw them as returning to favor. The combined oral contraceptive pill is still the mainstay of prescriptions. Lack of skill in providing was seen by 60.6% as a barrier to provision of long-acting methods of contraception. Half of respondents (50.3%) thought that irregular bleeding deterred women from using LARC and 20.6% were concerned about high discontinuation rates. Misconceptions about side effects of contraceptive methods were common. CONCLUSION: Investment in professional education and training is needed for health professionals in general practice if the goal of increased provision of long-acting contraceptive methods is to be realized. PMID- 17707720 TI - Mechanism of emergency contraception with gestrinone: a preliminary investigation. AB - BACKGROUND: A previous investigation showed that among 120 healthy women treated with a single oral dose of gestrinone for emergency contraception (EC), there was only one pregnancy. The effect of a single oral dose of gestrinone given for EC on ovarian function and endometrial development was studied. STUDY DESIGN: Healthy fertile women were randomly assigned to Group A (n=8) or Group B (n=7). Gestrinone 5 mg was orally administered to each woman before (Group A) or after (Group B) ovulation. The day of ovulation was determined by transvaginal ultrasound and by urinary luteinizing hormone (LH) measured by enzyme immunoassay (One Step LH Ovulation Test). An endometrial biopsy was performed during implantation. Endometrial maturation and expression of markers of endometrial receptivity were analyzed. The tested markers were integrins alpha(1)beta(1), alpha(4)beta(1) and beta(3). Serum estradiol (E(2)) and progesterone (P) levels in serum were determined by radioimmunoassay, and estradiol receptors and progesterone receptors (PRs) in the endometrium were assessed by immunohistochemistry. RESULTS: Gestrinone administered during the periovulatory period did not affect follicular development, ovulation, menstrual cycle length and E(2) and P levels but decreased the expression of PR in the endometrium. Integrin alpha(4)beta(1) tended to increase after treatment with gestrinone without reaching statistical significance. CONCLUSION: The mode of action of gestrinone used for EC is probably inhibition of implantation by acting on the endometrium rather than inhibition of ovulation. PMID- 17707719 TI - Oral mifepristone and buccal misoprostol administered simultaneously for abortion: a pilot study. AB - BACKGROUND: Simultaneous oral mifepristone and vaginal misoprostol has a 24-h expulsion rate of approximately 90% when used for abortion through 63 days' gestation. This pilot study sought to determine if a simultaneous regimen using buccal misoprostol would be similarly effective and merit further investigation. STUDY DESIGN: One hundred twenty women were enrolled into three equal groups by gestational age: < or =49 days (Group 1), 50-56 days (Group 2) and 57-63 days (Group 3). After swallowing 200 mg of mifepristone, subjects received 800 mcg buccal misoprostol. Participants returned in 24+/-1 h for evaluation of expulsion by ultrasonography. Women with a persistent gestational sac received 800 mcg vaginal misoprostol. Further follow-up occurred at 1, 2 and 5 weeks by telephone or in person, as appropriate. Sample sizes for each group were estimated with the aim of establishing a 24-h expulsion rate of 90% (95% CI=76-95). RESULTS: The 24 h expulsion rates for Groups 1, 2 and 3 were 73% (95% CI=56-85), 69% (95% CI=52 83) and 73% (95% CI=56-85), respectively. Common side effects were nausea (62%), vomiting (33%) and diarrhea (48%), which did not differ by gestational age. Forty three percent of subjects found the taste of buccal misoprostol objectionable; 30% found buccal retention uncomfortable or inconvenient, and 10% reported oral irritation, sensitivity, numbness or oral ulcers. CONCLUSIONS: Simultaneous oral mifepristone and buccal misoprostol had a lower-than-hypothesized expulsion rate at 24 h. Although overall success rates at 7 or 15 days could have been higher than those observed at 24 h, we believe that this regimen does not warrant further study. PMID- 17707721 TI - Development of a high-performance liquid chromatographic method for the determination of mifepristone in human plasma using norethisterone as an internal standard: application to pharmacokinetic study. AB - OBJECTIVE: The objective of this study was to develop a simple, sensitive, stable and validated HPLC method for the determination of mifepristone levels in human plasma. METHODS: Solid-phase extraction cartridges were used to extract plasma samples. Separation was carried out on a C(18) column maintained at 20 degrees C with acetonitrile-water (80:20, v/v) as mobile phase at a flow rate of 0.6 mL/min. Norethisterone was employed as the internal standard. Dual wavelength mode was used, with mifepristone monitored at UV 302 nm and norethisterone at 240 nm. RESULTS: The calibration curve was linear in the concentration range of 5 10000 ng/mL, with linear correlation coefficient r being 0.9999. The limit of detection for the assay was 3 ng/mL. The inter-day accuracy ranged from 92.4% to 98.4% and precision 3.6% to 11.4%. The intra-day accuracy ranged from 92.1% to 100.6% and precision 4.7% to 12.2%. The absolute recovery was 91.7-100.1%. Plasma samples were stable for at least 1 month if stored at -20 degrees C. This validated HPLC method was successfully applied to pharmacokinetic study of mifepristone in human plasma samples collected from volunteers after oral administration of 10 mg mifepristone. CONCLUSION: The simple, accurate and stable method allows the sensitive determination of mifepristone in human plasma at the nanogram level. It could be applied to assess the plasma level of mifepristone in women up to 5 days after oral administration of 10 mg mifepristone. PMID- 17707722 TI - Release behavior of copper ion in a novel contraceptive composite. AB - PURPOSE: The universally used contraceptive method, the Cu-IUD, an effective contraceptive, is being increasingly used worldwide for family planning. To avoid abnormal bleeding, pain, partial and complete expulsion associated with the burst release of copper during the first few days, a novel cross-linked composite based on poly vinyl alcohol (PVA) that contains copper ions, but not metallic copper, was synthesized. MATERIAL AND METHODS: PVA, well known for its good processability, high strength, long-term temperature and pH stability and biocompatibility, was used as the matrix material. The corrosion products and the release rate of copper ions after soaking in simulated body fluid (SBF) for different time spans were studied by environmental scanning electron microscopy, X-ray energy dispersive spectroscopy, X-ray diffraction and atomic absorption spectrophotometer. RESULTS: No significant change on time dependence for the release rate of copper ions in the composite compared with that of metallic copper was found. Moreover, no other new elements, such as P, Cl and Ca, appeared on the surface of the composite and no Cu(2)O formed after immersing in SBF for 90 days. CONCLUSION: Burst release of copper ions can be avoided by loading copper ions in this polymer material. Release channels would not be obstructed by the deposition of corrosion products and nearly all of the copper loaded in the composites could be an effective contraceptive. PMID- 17707723 TI - Magnetic resonance imaging of SILCS diaphragm: anatomical considerations and corroboration with clinical fit. AB - BACKGROUND: We performed a pilot study to evaluate in vivo the fit of the new SILCS diaphragm, a single-size cervical barrier, using magnetic resonance imaging (MRI) in a group of women varying in body mass and parity. STUDY DESIGN: Two healthy premenopausal women were recruited for each of the following groups: body mass index (BMI)<25, BMI=25-30 and BMI>30. One woman in each group was nulliparous and one was multiparous. Subjects were instructed on the placement of the SILCS diaphragm. Each subject underwent three MRI scans: baseline, with the SILCS diaphragm in place and after placement of intravaginal contrast and simulated intercourse. RESULTS: The SILCS diaphragm was easily identified on MRI. In all subjects, the diaphragm covered the cervix. The position of the diaphragm did not change after simulated intercourse. The appropriate position of the diaphragm, as assessed by the subjects and the practitioner, was corroborated by the MR images. The intravaginal contrast was not readily visible on the images, precluding assessment of the diaphragm's barrier properties. CONCLUSION: MRI confirms the anatomic position of the SILCS diaphragm in vivo, among a sample of women varying in body mass and parity. PMID- 17707725 TI - A single intrauterine injection of the serine protease inhibitor 4-(2 aminoethyl)benzenesulfonyl fluoride hydrochloride reversibly inhibits embryo implantation in mice. AB - BACKGROUND: The study was conducted to investigate the inhibitory effect of 4-(2 aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) on embryo implantation in mice with a view to identifying whether it might be a suitable agent for postcoital contraception. STUDY DESIGN: The anti-implantation efficacy of AEBSF was determined by counting the number of visible implanted embryos on Day 8 of pregnancy following a single intrauterine injection of AEBSF at doses of 30, 300 and 3000 microg per mouse uterine horn on Day 3 of pregnancy. The reversibility of the inhibitory effect of AEBSF on implantation was further evaluated by observing the outcome of a subsequent pregnancy without AEBSF treatment. RESULTS: A dose-dependent inhibitory effect of AEBSF on embryo implantation in vivo was observed. Morphological analysis revealed no significant cytotoxicity of AEBSF on the mouse uterine epithelia. Furthermore, the anti-implantation effect of AEBSF was reversible. CONCLUSION: Intrauterine administration of AEBSF at an appropriate dose might provide a basis for the development of novel contraception. PMID- 17707724 TI - Safety and acceptability of 6% cellulose sulfate vaginal gel applied four times per day for 14 days. AB - BACKGROUND: Six percent cellulose sulfate (CS) is a vaginal gel that has been in development as a microbicide. STUDY DESIGN: This was a single-center, multi-dose, Phase I, placebo-controlled, randomized, fully masked study conducted in Yaounde, Cameroon, and involving sexually active women at low risk for sexually transmitted infections (STIs). METHODS: The study assessed the effect of CS and K Y Jelly applied vaginally four times per day, for 14 consecutive days, on genital epithelial disruption, candidiasis and bacterial vaginosis (BV). Acceptability of the products was also assessed. Twenty-seven women were enrolled in each treatment group. RESULTS: Two (7.4%) of the women in each group developed genital epithelial disruption. One (3.7%) of the women in each group developed candidiasis, and one (3.7%) of the K-Y users developed BV. One (3.7%) of the CS users said she would not buy her product for pregnancy prevention but would for STI prevention. All the remaining women indicated they would buy their product for both indications. CONCLUSION: The results suggest that the safety and acceptability of 6% CS gel are comparable to that of K-Y Jelly. PMID- 17707726 TI - The empirical and ethical questions of induced versus natural losses of preimplantation embryos. PMID- 17707727 TI - Surgical management of intra-abdominal mislocated intrauterine devices(IUDs). PMID- 17707728 TI - Hypertension: uncontrolled and conquering the world. PMID- 17707729 TI - The unjustifiable firing of Nozizwe Madlala-Routledge. PMID- 17707730 TI - Access to investigational drugs in the USA. PMID- 17707731 TI - Coronary restenosis: a new strategy for the future? PMID- 17707732 TI - An arm and a leg to protect the heart? PMID- 17707733 TI - Breaking the immunogenicity barrier of bird flu vaccines. PMID- 17707734 TI - Apical-ballooning syndrome. PMID- 17707735 TI - NICE vindicated in UK's High Court. PMID- 17707736 TI - Disability and human rights. PMID- 17707737 TI - Clinical update: codeine maintenance in opioid dependence. PMID- 17707738 TI - Nizal Sarrafzadegan: leading cardiovascular research in Iran. PMID- 17707739 TI - Alcohol consumption and public health in Russia. PMID- 17707740 TI - Alcohol consumption and public health in Russia. PMID- 17707741 TI - Conduct of clinical trials in developing countries. PMID- 17707742 TI - Conduct of clinical trials in developing countries. PMID- 17707743 TI - Risk of cancer from blood donated by people with cancer. PMID- 17707745 TI - Risk of cancer from blood donated by people with cancer. PMID- 17707746 TI - Disseminated tuberculosis after anti-TNFalpha treatment. PMID- 17707748 TI - International certificate of vaccination or prophylaxis. PMID- 17707747 TI - Disseminated tuberculosis after anti-TNFalpha treatment. PMID- 17707750 TI - Zero G in a patient with advanced amyotrophic lateral sclerosis. PMID- 17707751 TI - Effect of celecoxib on restenosis after coronary angioplasty with a Taxus stent (COREA-TAXUS trial): an open-label randomised controlled study. AB - BACKGROUND: In-vitro and animal experiments have shown that the cyclo-oxygenase 2 inhibitor celecoxib can reduce formation of neointima within stents. We aimed to test whether celecoxib has similar effects in a clinical setting. METHODS: In a randomised two-centre trial, we enrolled 274 patients who had angina pectoris or a positive stress test and who had native coronary artery lesions for which implantation of paclitaxel-eluting stents was feasible. All patients were given aspirin (100 mg daily) and clopidogrel (75 mg daily). 136 patients were randomly assigned to receive celecoxib (400 mg before the intervention, and 200 mg twice daily for 6 months after the procedure). The primary endpoint was late luminal loss on quantitative coronary angiography at 6 months after the intervention. Secondary endpoints were cardiac death, non-fatal myocardial infarction, and revascularisation of the target lesion. Analysis was done on a modified intention to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00292721. FINDINGS: At 6 months, mean in-stent late luminal loss was lower in the celecoxib group (0.49 mm, SD 0.47) than in the control group (0.75 mm, 0.60) (absolute difference 0.26 mm; 95% CI 0.12-0.40). Frequency of secondary outcomes at 6 months was also lower in the celecoxib group, mainly because of a reduced need for revascularisation of the target lesion. INTERPRETATION: These data suggest that the adjunctive use of celecoxib for 6 months after stent implantation in patients with coronary artery disease is safe and can reduce the need for revascularisation of the target lesion. PMID- 17707753 TI - Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. AB - BACKGROUND: Antigen sparing is regarded as crucial for pandemic vaccine development because worldwide influenza vaccine production capacity is limited. Adjuvantation is an important antigen-sparing strategy. We assessed the safety and immunogenicity of a recombinant H5N1 split-virion vaccine formulated with a proprietary adjuvant system and investigated whether it can induce cross-reactive immunity. METHODS: Two doses of an inactivated split A/Vietnam/1194/2004 NIBRG-14 (recombinant H5N1 engineered by reverse genetics) vaccine were administered 21 days apart to eight groups of 50 volunteers aged 18-60 years. We studied four antigen doses (3.8 microg, 7.5 microg, 15 microg, and 30 microg haemagglutinin) given with or without adjuvant. Blood samples were collected to analyse humoral immune response. Adverse events were recorded up through study day 51. Safety analyses were of the whole vaccinated cohort and immunogenicity analyses per protocol. This trial is registered with the ClinicalTrials.gov, number NCT00309634. FINDINGS: All eight vaccine formulations had a good safety profile. No serious adverse events were reported. The adjuvanted vaccines induced more injection-site symptoms and general symptoms than did the non-adjuvanted vaccines, but most were mild to moderate in intensity and transient in nature. The adjuvanted formulations were significantly more immunogenic than the non adjuvanted formulations at all antigen doses. At the lowest antigenic dose (3.8 microg), immune responses for the adjuvanted vaccine against the recombinant homologous vaccine strain (A/Vietnam/1194/2004 NIBRG-14, clade 1) met or exceeded all US Food and Drug Administration and European Union licensure criteria. Furthermore, 37 of 48 (77%) participants receiving 3.8 microg of the adjuvanted vaccine seroconverted for neutralising antibodies against a strain derived by reverse genetics from a drifted H5N1 isolate (A/Indonesia/5/2005, clade 2). INTERPRETATION: Adjuvantation conferred significant antigen sparing that could increase the production capacity of pandemic influenza vaccine. Moreover, the cross-clade neutralising antibody responses recorded imply that such a vaccine could be deployed for immunisation before a pandemic. PMID- 17707752 TI - Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. AB - BACKGROUND: Whether remote ischaemic preconditioning, an intervention in which brief ischaemia of one tissue or organ protects remote organs from a sustained episode of ischaemia, is beneficial for patients undergoing coronary artery bypass graft surgery is unknown. We did a single-blinded randomised controlled study to establish whether remote ischaemic preconditioning reduces myocardial injury in these patients. METHODS: 57 adult patients undergoing elective coronary artery bypass graft surgery were randomly assigned to either a remote ischaemic preconditioning group (n=27) or to a control group (n=30) after induction of anaesthesia. Remote ischaemic preconditioning consisted of three 5-min cycles of right upper limb ischaemia, induced by an automated cuff-inflator placed on the upper arm and inflated to 200 mm Hg, with an intervening 5 min of reperfusion during which the cuff was deflated. Serum troponin-T concentration was measured before surgery and at 6, 12, 24, 48, and 72 h after surgery. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00397163. FINDINGS: Remote ischaemic preconditioning significantly reduced overall serum troponin-T release at 6, 12, 24, and 48 h after surgery. The total area under the curve was reduced by 43%, from 36.12 microg/L (SD 26.08) in the control group to 20.58 microg/L (9.58) in the remote ischaemic preconditioning group (mean difference 15.55 [SD 5.32]; 95% CI 4.88-26.21; p=0.005). INTERPRETATION: We have shown that adult patients undergoing elective coronary artery bypass graft surgery at a single tertiary centre could benefit from remote ischaemic preconditioning, using transient upper limb ischaemia. PMID- 17707754 TI - Sudden visual loss. PMID- 17707755 TI - Essential hypertension. AB - Essential hypertension can be defined as a rise in blood pressure of unknown cause that increases risk for cerebral, cardiac, and renal events. In industrialised countries, the risk of becoming hypertensive (blood pressure >140/90 mm Hg) during a lifetime exceeds 90%. Essential hypertension usually clusters with other cardiovascular risk factors such as ageing, being overweight, insulin resistance, diabetes, and hyperlipidaemia. Subtle target-organ damage such as left-ventricular hypertrophy, microalbuminuria, and cognitive dysfunction takes place early in the course of hypertensive cardiovascular disease, although catastrophic events such as stroke, heart attack, renal failure, and dementia usually happen after long periods of uncontrolled hypertension only. All antihypertensive drugs lower blood pressure (by definition) and this decline is the best determinant of cardiovascular risk reduction. However, differences between drugs exist with respect to reduction of target-organ disease and prevention of major cardiovascular events. Most hypertensive patients need two or more drugs for blood-pressure control and concomitant statin treatment for risk factor reduction. Despite the availability of effective and safe antihypertensive drugs, hypertension and its concomitant risk factors remain uncontrolled in most patients. PMID- 17707756 TI - Management of atrial fibrillation. AB - Atrial fibrillation is the most common sustained cardiac rhythm disorder, and confers a substantial mortality and morbidity from stroke, thromboembolism, heart failure, and impaired quality of life. With the increasingly elderly population in the developed world, as well as improvements in the management of myocardial infarction and heart failure, the prevalence of atrial fibrillation is increasing, resulting in a major public-health problem. This Review aims to provide an overview on the modern management of atrial fibrillation, with particular emphasis on pharmacological and non-pharmacological approaches. Irrespective of a rate-control or rhythm-control strategy, stroke prevention with appropriate thromboprophylaxis still remains central to the management of this common arrhythmia. Electrophysiological approaches could hold some promise for a curative approach in atrial fibrillation. PMID- 17707757 TI - Neglected diseases, civil conflicts, and the right to health. AB - Neglected diseases remain one of the largest causes of disease and mortality. In addition to the difficulties in provision of appropriate drugs for specific diseases, many other factors contribute to the prevalence of such diseases and the difficulties in reducing their burden. We address the role that poor governance and politically motivated oppression have on the epidemiology of neglected diseases. We give case examples including filariasis in eastern Burma and vector-borne diseases (Chagas' disease, leishmaniasis, and yellow fever) in Colombia, we show the links between systematic human rights violations and the effects of infectious disease on health. We also discuss the role of researchers in advocating for and researching within oppressed populations. PMID- 17707758 TI - Not a broken heart. PMID- 17707759 TI - Interstitial MR lymphangiography - a diagnostic imaging method for the evaluation of patients with clinically advanced stages of lymphedema. AB - BACKGROUND: To assess the feasibility of interstitial magnetic resonance lymphangiography with intracutaneous injection of a commercially available, non ionic, extracellular paramagnetic contrast agent, to visualize lymphatic vessels in patients with clinically advanced stages of primary lymphedema. METHODS: Sixteen lower extremities in 8 patients with clinically advanced stages of primary lymphedema were examined with magnetic resonance lymphangiography. A 18 mL of gadodiamide and 2 mL of mepivacainhydrochloride 1% were subdivided into 10 portions and injected intracutaneously into the dorsal aspect of both feet. For MRL, a 3D spoiled gradient-echo sequence (Volumetric Interpolated Breathold Examination, VIBE) was performed. RESULTS: The beaded appearance of lymphatic vessels extending from the injection site was detected in all 16 lower extremities (100%). In 10 lower extremities (63%), lymphatic vessels of the upper leg could be visualized. A contrast enhancement was observed in 10/16 inguinal lymph node groups (63%). In 12 lower extremities (75%) collateral vessels with dermal back-flow areas between lymphatic vessels were seen. CONCLUSION: Magnetic resonance lymphangiography is safe, technically feasible, and assists the clinician in the therapeutic planning of patients with clinically advanced stages of primary lymphedema by imaging the pathologically modified lymphatic vessels and accompanying complications non-invasively. PMID- 17707760 TI - Review on the dynamics and micro-structure of pH-responsive nano-colloidal systems. AB - This review presents an overview on the research on pH-responsive microgel particles in the last 10 years. Microgels are cross-linked latex particles that are swollen in a good solvent. Significant quantitative studies have been conducted to investigate the swelling behavior (microscopic) and rheological (macroscopic) properties of the pH-responsive microgel particles as a function of neutralization degree, ionic strength, and cross-linked density. Mono-dispersed, alkali-swellable microgels containing carboxylic acid lattices, whose properties display extreme pH sensitivity in water is considered in detail in terms of swelling behavior and rheological properties. Their stability in solution and ability to undergo reversible volume phase transitions in response to pH makes them ideal model systems for the development of a semi-empirical as well as theoretical approach for predicting the viscosity of dilute and concentrated hard and soft sphere systems. The review concludes with a discussion of some recent applications of pH-responsive microgel particles. PMID- 17707761 TI - [Sunitinib and hypothyroidism]. AB - Sunitinib inhibits numerous tyrosine kinase receptors involved in tumor growth, angiogenesis, and metastatic invasion. It is indicated in case of metastatic renal carcinomas and gastrointestinal stromal tumors (GIST) resistant to imatinib. Prospective and retrospective studies have shown association between use of sunitinib and hypothyroidism affecting more than 50% of patients in some series. More amazing, was the non-visualisation of thyroid tissue evaluated with thyroid ultrasonography in two cases. Mechanisms of this side effect are not elucidated. Some studies have suggested destructive thyroiditis but no evidence of autoimmunity has been demonstrated. Anti angiogenic effect could be another hypothesis. Recently antithyroperoxidase activity of sunitinib has been demonstrated. Because hypothyroidism is easily accessible to treatment, screening of thyroid abnormalities is mandatory every three months to improve quality of life of these patients. This unique thyroid side effect of sunitinib with the non visualisation of thyroid suggests a possible and promising antitumor activity in thyroid cancer. PMID- 17707762 TI - [Labyrinthitis, or inflammatory pseudotumor after stapedectomy]. AB - OBJECTIVES: To describe an extensive pseudotumor as a complication of stapes surgery. METHODS: Radiological workup and surgical exploration in a 38-year-old man suffering from postoperative hearing loss. The patient presented with tinnitus, inferior facial palsy, vertigo, and rapidly progressive hearing loss after his operation. RESULTS: The initial postoperative CT scan was normal. However, seven months after surgery, the CT scan showed an enlargement of the inner ear canal and complete vestibular destruction. The CISS sequence of the magnetic resonance imaging (MRI) enhanced after gadolinium injection revealed the presence of a mass filling the entire inner ear canal, the cochlear, the posterior labyrinth, and the middle ear. The aspect suggested an inflammatory pseudotumor. Surgical exploration confirmed the invasive aspect of the mass and pathological analysis revealed inflammatory tissue associated with microcalcifications. DISCUSSION: Hearing loss, vertigo, and tinnitus after stapes surgery require a radiologic workup. The CT scan is done first. It could be normal or eliminate other diagnoses. MRI may lead to a more precise diagnosis. It can reveal an inflammatory process of the inner ear after gadolinium injection. Surgical exploration is indicated in case of aggressive and extensive lesions. CONCLUSION: In the context of hearing loss complicating otosclerosis surgery, an imaging workup should include a CT scan. In case of a suspected expansive and inflammatory mass, it should be completed by an MRI (CISS sequence and gadolinium injection). An inflammatory lesion of the inner ear could indicate extensive pseudotumor. PMID- 17707763 TI - Isolation and sequencing of two FMRFamide-related peptides from the gut of Locusta migratoria L. AB - Two FMRFamide-related peptides (FaRPs) have been isolated and sequenced from the whole gut of Locusta migratoria L. Peptides were extracted from 500 locust whole guts and separated using reversed-phase high performance liquid chromatography (RP-HPLC). Fractions containing FMRFamide-like immunoreactive (FLI) material were identified using radioimmunoassay (RIA). Sequencing of fractions, using tandem mass spectrometry (MALDI-TOF MS/MS), revealed the myosuppressin previously isolated from the locust CNS, SchistoFLRFamide (PDVDHVFLRFamide), and a novel extended RFamide (LWENLRFamide). The isolation of SchistoFLRFamide from midgut tissue supports the hypothesis that this myosuppressin is released locally from FLI processes over the gut and/or from endocrine-like midgut cells to play a role in the regulation of digestion. PMID- 17707764 TI - In yeast, Ca2+ and octylguanidine interact with porin (VDAC) preventing the mitochondrial permeability transition. AB - In yeast, Ca(2+) and long chain alkylguanidines interact with mitochondria modulating the opening of the yeast mitochondrial unspecific channel. Mammalians possess a similar structure, the mitochondrial permeability transition pore. The composition of these pores is under debate. Among other components, the voltage dependent anion channel has been proposed as a component of either pore. In yeast from an industrial strain, octylguanidine and calcium closed the yeast mitochondrial unspecific channel. Here, the effects of the cations Ca(2+) or octylguanidine and the voltage-dependent anion channel effector decavanadate were evaluated in yeast mitochondria from either a wild type or a voltage-dependent anion channel deletion laboratory strain. It was observed that in the absence of voltage-dependent anion channel, the yeast mitochondrial unspecific channel was desensitized to Ca(2+), octylguanidine or decavanadate but remained sensitive to phosphate. It is thus suggested that in yeast mitochondria, the voltage-dependent anion channel has a cation binding site where Ca(2+) and octylguanidine interact, conferring cation sensitivity to the yeast mitochondrial unspecific channel. PMID- 17707765 TI - A bold new beginning for midwifery in Afghanistan. PMID- 17707766 TI - Carbon monoxide dehydrogenase in mycobacteria possesses a nitric oxide dehydrogenase activity. AB - CO dehydrogenase (CO-DH) catalyzes the oxidation of CO to CO(2) in carboxydobacteria. Cell-free extracts prepared from several mycobacteria, including Mycobacterium tuberculosis H37Ra, showed NO dehydrogenase (NO-DH) activity in a reaction mixture containing sodium nitroprusside (SNP) as the source of NO. The association of the NO-DH activity with CO-DH was revealed by activity staining and confirmed by enzyme assay with purified CO-DH from Mycobacterium sp. strain JC1, a carboxydotrophic mycobacterium. SNP stimulated the production of CO-DH with a coincidental increase in NO-DH activity in the bacterium, further supporting this association and implying the existence of a possible SNP-induced CO-DH gene expression. The addition of purified CO-DH to cultures of Escherichia coli revealed that the enzyme protected E. coli from SNP induced killing in a dose-dependant way. The present results indicate that mycobacterial CO-DH also acts as a NO-DH, which may function in the protection of mycobacterial pathogens from nitrosative stress during infection. PMID- 17707767 TI - Potential biochemical therapy of glioma cancer. AB - Glioma is a highly invasive, rapidly spreading form of brain cancer that is resistant to surgical and medical treatment. The recent progresses made in intracellular and ion channels of glioma cells provide a potential new approach for biochemical therapy of brain tumor. In this paper, we reviewed clinical data on chemotherapy by temozolomide and results from new studies on voltage-gated potassium channels, large-conductance Ca(2+)-activated K(+) channels, volume activated chloride channels, glioma-specific chloride channel and their modulators. These new findings may represent future directions for brain tumor studies and treatment. PMID- 17707768 TI - Acetylcholine induces neurite outgrowth and modulates matrix metalloproteinase 2 and 9. AB - The matrix metalloproteinases (MMPs), responsible for the degradation of extracellular matrix (ECM) proteins, may regulate brain cellular functions. Choline acetyltransferase (ChAT) transfected murine neuroblastoma cell line N18TG2, that synthesize acetylcholine and show enhancement of several neurospecific markers (i.e., sinapsin I, voltage gated Na(+) channels, high affinity choline uptake) and fiber outgrowth, were studied for the MMP regulation during neuronal differentiation. Zymography of N18TG2 culture medium revealed no gelatinolytic activity, whereas after carbachol treatment of cells both MMP-9 and activated MMP-2 forms were detected. ChAT-transfected clone culture medium contains three MMP forms at 230, 92, and 66kDa. Carbachol treatment increased MMP 2 and MMP-9 gene expression in N18TG2 cells and higher levels for both genes were also observed in ChAT transfected cells. The data are consistent with the hypothesis that acetylcholine brings about the activation of an autocrine loop modulating MMP expression. PMID- 17707769 TI - Identification of functional type 1 ryanodine receptors in human dendritic cells. AB - Ryanodine receptor (RyR) is a Ca(2+) channel that mediates Ca(2+) release from intracellular stores. Altered Ca(2+) homeostasis in skeletal muscle which usually occurs as a result of point mutations in type 1 RyR1 (RyR1) is a key molecular event triggering malignant hyperthermia (MH). There are three RyR isoforms, and we herein show, for the first time, that human dendritic cells (DCs) preferentially express RyR1 mRNA among them. The RyR activator, 4-chloro-m-cresol (4CmC), induced Ca(2+) release in DCs, and this response was eliminated by dantrolene, an inhibitor of the RyR1, and was unaffected by xestospongin C, a selective inhibitor of IP(3) receptor. Activation of RyR1 reduced LPS-induced IL 10 production, promoted the expression of HLA-DR and CD86, and thereby exhibited an improved capacity to stimulate allogeneic T cells. These findings demonstrate that RyR1-mediated calcium signaling modifies diverse DC responses and suggest the feasibility of using DC preparations for the diagnosis of MH. PMID- 17707770 TI - Effects of daunorubicin on ganglioside expression and neuronal differentiation of mouse embryonic stem cells. AB - Gangliosides are implicated in neuronal development processes. The regulation of ganglioside levels is closely related to the induction of neuronal cell differentiation. In this study, the relationship between ganglioside expression and neuronal cell development was investigated using an in vitro model of neural differentiation from mouse embryonic stem (mES) cells. Daunorubicin (DNR) was applied to induce the expression of gangliosides in embryoid body (EB) (4+). We observed an increase in expression of gangliosides in all stages of EBs by treatment of DNR (2microM). High-performance thin-layer chromatography (HPTLC) showed that gangliosides GD3, GD1a, GT1b, and GQ1b increased in DNR-treated 7-day old EB (4+) [EB (4+):7]. DNR treatment significantly increased the expression of gangliosides, especially GT1b and GQ1b in comparison to control cells. Interestingly, GQ1b co-localized with microtubule-associated protein 2 (MAP-2) expressing cells in DNR-treated EB (4+):7. The co-localization of GQ1b and MAP-2 was found in neurite-bearing cells in DNR-treated 15-day-old EB (4+) [EB (4+):15], whereas no significant expression of GQ1b and less neurite formation were observed in untreated control. Also, the expression of synaptophysin and NF200, both neuronal markers associated with neruites, was increased by DNR treatment. These results demonstrate that DNR increases expression of gangliosides, especially GQ1b, in differentiating neuronal cells. Further, neurite-bearing neuronal cell differentiation can be facilitated by DNR, possibly through the induction of gangliosides. Thus, the present data suggest that DNR is beneficial for facilitating neuronal differentiation from ES cells and among the gangliosides analyzed in the present study, GQ1b is mainly involved in neurite formation. PMID- 17707771 TI - Glutathione peroxidase 3 of Saccharomyces cerevisiae suppresses non-enzymatic proteolysis of glutamine synthetase in an activity-independent manner. AB - Glutathione peroxidase 3 (Gpx3) is ubiquitously expressed and is important antioxidant enzyme in yeast. It modulates the activities of redox-sensitive thiol proteins, particularly those involved in signal transduction pathway and protein translocation. Through immunoprecipitation/two-dimensional gel electrophoresis (IP-2DE), MALDI-TOF mass spectrometry, and a pull down assay, we found glutamine synthetase (GS; EC 6.3.1.2) as a candidate interacting protein with Gpx3. GS is a key enzyme in nitrogen metabolism and ammonium assimilation. It has been known that GS is non-enzymatically cleaved by ROS generated by MFO (thiol/ Fe(3+)/O(2) mixed-function oxidase) system. In this study, it is demonstrated that GS interacts with Gpx3 through its catalytic domain both in vivo and in vitro regardless of redox state. In addition, Gpx3 helps to protect GS from inactivation and degradation via oxidative stress in an activity-independent manner. Based on the results, it is suggested that Gpx3 protects GS from non enzymatic proteolysis, thereby contributing to cell homeostasis when cell is exposed to oxidative stress. PMID- 17707772 TI - Inductive effects of dexamethasone on the mineralization and the osteoblastic gene expressions in mature osteoblast-like ROS17/2.8 cells. AB - We examined the effects of dexamethasone (Dex), a synthetic glucocorticoid, on the formation of mineralized bone nodules and the gene expressions of the late osteoblastic markers, bone sialoprotein (BSP), osteocalcin (OC), and osteopontin (OPN) in mature osteoblast ROS17/2.8 cells. Treatment of ROS17/2.8 cells with Dex resulted in the induction of mineralization accompanied with increasing BSP and OC expressions. Previous reports have demonstrated that BSP and OC expressions are regulated by Runx2. Then, we hypothesized that Dex might promote osteoblastic differentiation and mineralization on ROS17/2.8 by Runx2. In this study, no effect was observed in mRNA and protein expression of Runx2. However, the transcriptional activity of Runx2 was enhanced by Dex treatment. Furthermore, the Dex-induced BSP and OC expressions decreased after the transfection of Runx2 small-interfering RNAs (siRNAs). These results suggested that the enhancement of Runx2 transcriptional activity by Dex treatment may be followed by the activation of osteoblast marker genes, such as BSP and OC to thereby produce a bone-specific matrix that subsequently becomes mineralized. PMID- 17707773 TI - The N-terminal region of eukaryotic translation initiation factor 5A signals to nuclear localization of the protein. AB - The eukaryotic translation initiation factor 5A (eIF5A) is a ubiquitous protein of eukaryotic and archaeal organisms which undergoes hypusination, a unique post translational modification. We have generated a polyclonal antibody against murine eIF5A, which in immunocytochemical assays in B16-F10 cells revealed that the endogenous protein is preferentially localized to the nuclear region. We therefore analyzed possible structural features present in eIF5A proteins that could be responsible for that characteristic. Multiple sequence alignment analysis of eIF5A proteins from different eukaryotic and archaeal organisms showed that the former sequences have an extended N-terminal segment. We have then performed in silico prediction analyses and constructed different truncated forms of murine eIF5A to verify any possible role that the N-terminal extension might have in determining the subcellular localization of the eIF5A in eukaryotic organisms. Our results indicate that the N-terminal extension of the eukaryotic eIF5A contributes in signaling this protein to nuclear localization, despite of bearing no structural similarity with classical nuclear localization signals. PMID- 17707775 TI - Analogue inhibitors by modifying oseltamivir based on the crystal neuraminidase structure for treating drug-resistant H5N1 virus. AB - The worldwide spread of H5N1 avian influenza and the increasing reports about its resistance to the existing drugs have made a priority for the development of the new anti-influenza molecules. The crystal structure of H5N1 avian influenza neuraminidase reported recently by Russell et al. [R.J. Russell, L.F. Haire, D.J. Stevens, P.J. Collins, Y. P. Lin, G.M. Blackburn, A.J. Hay, S.J. Gamblin, J.J. Skehel, The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design, Nature 443 (2006) 45-49] have provided new opportunities for drug design in this regard. It is revealed through the structure that the active sites of the group-1 neuraminidases, which contain the N1 subtype, have a very different three-dimensional structure from those of group 2 neuraminidases. The key difference is in the 150-loop cavity adjacent to the conserved active site in neuraminidase. Based on these findings and by modifying oseltamivir, six analog inhibitors were proposed as candidates for developing inhibitors against H5N1 virus, particularly against the oseltamivir-resistant H5N1 virus strain. PMID- 17707774 TI - Inhibition of NADPH oxidase subunits translocation by tea catechin EGCG in mast cell. AB - The inhibitory mechanism of tea catechins for allergy remains undefined. We studied the effect of catechins, mainly EGCG, on the activation of mast cell line canine cutaneous mastocytoma cells (CM-MC). Compound 48/80 induced the degranulation in CM-MC dose dependently, whereas its release of beta hexosaminidase was inhibited by EGCG and O-methylated EGCG (EGCG-Me). Both catechins were found to inhibit intracellular ROS generation dose dependently together with DPI. Intracellular ROS generation in human polymorphonuclear leukocytes was also inhibited by EGCG. Neither L-NAME, ebeselen nor NAC inhibited ROS generation. From the Western blot analysis of the subunits components of NADPH oxidase, we detected cytosolic subunits; p47(phox), p67(phox), p40(phox), rac2 and membrane subunits; gp91(phox), p22(phox) in CM-MC. Cytosolic subunits were translocated from cytosol to membrane time dependently after stimulation with compound 48/80. EGCG and DPI inhibited cytosolic subunits from translocating into membrane. These data suggest that EGCG inhibits the activation of NADPH oxidase in CM-MC. PMID- 17707776 TI - Transgenic mice with neuron-specific overexpression of HtrA2/Omi suggest a neuroprotective role for HtrA2/Omi. AB - Mammalian serine protease HtrA2/Omi has been known as an apoptosis inducer involved inactivation of caspase-dependent as well as caspase-independent cell death. Recent studies with the HtrA2/Omi mutant and knockout mouse models, however, suggested that HtrA2/Omi might play a protective role in neurons. It is important to establish a transgenic mouse model with neuron-specific overexpression of HtrA2/Omi to clarify the physiological function of mammalian HtrA2/Omi in neurons. In the present study, a transgene containing HtrA2/Omi cDNA downstream of a rat neuron-specific enolase promoter was constructed and microinjected into the pronuclei of fertilized zygotes to establish transgenic mice. Transgenic mice successfully overexpressed HtrA2/Omi in brain tissue. As expected, HtrA2/Omi-overexpressing transgenic mice showed normal development without any sign of apoptotic cell death. Our results suggest that the primary function of neuronal HtrA2/Omi might be to protect neurons against stress in contrast to its role in the somatic system. PMID- 17707777 TI - Different roles of Loop 7 in inhibition of calcineurin. AB - Calcineurin (CN) is the receptor for two immunophilin-immunosuppressant complexes, Cyp-CsA and FKBP-FK506. It is a heterodimer composed of a catalytic subunit (CNA) and a regulatory subunit (CNB). It is also inhibited by its own auto-inhibitory domain (AID). Loop 7 is a beta-hairpin within CNA that makes close contact with bound immunophilin-immunosuppressant complexes and with the AID. To investigate the role of Loop 7 in inhibition, we generated a series of deletion and substitution mutants and examined their inhibition by Cyp-CsA, FKBP FK506 and an AID peptide. Our results demonstrate that the contacts made by Loop 7 are critical for its role in CN inhibition. Intriguingly, single residue deletions of Val314 and neighboring residues increased inhibition by FKBP-FK506 >6-fold, whereas they reduced Cyp-CsA inhibition >3-fold and abolished inhibition by the AID peptide. Most of the single substitution mutations also decreased Cyp CsA inhibition. Loop 7 thus plays different roles in the inhibition of CN by the different inhibitors. PMID- 17707778 TI - Interface peptide of Alzheimer's amyloid beta: application in purification. AB - Protein precipitation is a process commonly observed during bacterial expression of heterologous proteins. The high concentration of currently used solubilizing agents limits the scope of purification procedures. Protein solubilizers acting at very low concentrations will allow function-based purification protocols. Such applications are possible where sequence dependent protein-protein interactions occur. Oligomerization and higher order structure formation by proteins are examples where the interface peptide sequences are inhibitors of such interactions. In this study, we show that a partial sequence of Alzheimer's amyloid beta (Abeta) peptide can inhibit the aggregation. This enables the purification of protein containing Abeta sequence. PMID- 17707779 TI - Allosteric modulation of nicotinic acetylcholine receptors. AB - Allosteric modulation refers to the concept that proteins could exist in multiple conformational states and that binding of allosteric ligands alters the energy barriers or "isomerization coefficients" between various states. In the context of ligand gated ion channels such as nicotinic acetylcholine receptors (nAChRs), it implies that endogenous ligand acetylcholine binds at the orthosteric site, and that molecules that bind elsewhere on the nAChR subunit(s) acts via allosteric interactions. For example, studies with the homomeric alpha7 nAChRs indicate that such ligand interactions can be well described by an allosteric model, and that positive allosteric effectors can affect energy transitions by (i) predominantly affecting the peak current response (Type I profile) or, (ii) both peak current responses and time course of agonist-evoked response (Type II profile). The recent discovery of chemically heterogeneous group of molecules capable of differentially modifying nAChR properties without interacting at the ligand binding site illustrates the adequacy of the allosteric model to predict functional consequences. In this review, we outline general principles of the allosteric concept and summarize the profiles of novel compounds that are emerging as allosteric modulators at the alpha7 and alpha4beta2 nAChR subtypes. PMID- 17707780 TI - Theoretical investigation of hydrogen bonding effects on oxygen, nitrogen, and hydrogen chemical shielding and electric field gradient tensors of chitosan/HI salt. AB - A density functional theory study has been carried out to calculate the (17)O, (15)N, (13)C, and (1)H chemical shielding as well as (17)O, (14)N, and (2)H electric field gradient tensors of chitosan/HI type I salt. These calculations were performed using the B3LYP functional and 6-311++G (d,p) and 6-31++G (d,p) basis sets. Calculated EFG and chemical shielding tensors were used to evaluate the (17)O, (14)N, and (2)H nuclear quadruple resonance, NQR, and (17)O, (15)N, (13)C, and (1)H nuclear magnetic resonance, NMR, parameters in the cluster model, which are in good agreement with the available experimental data. The difference in the isotropic shielding (sigma(iso)) and quadrupole coupling constant (C(Q)) between monomer and target molecule in the cluster was analyzed in detail. It was shown that both EFG and CS tensors are sensitive to hydrogen-bonding interactions, and calculating both tensors is an advantage. A different influence of various hydrogen bond types, N-Hcdots, three dots, centeredI, O-Hcdots, three dots, centeredI, and N-Hcdots, three dots, centeredO was observed on the calculated CS and EFG tensors. On the basis of this study, nitrogen and O-6 are the most important nuclei to confirm crystalline structure of chitosan/HI. These nuclei have large change in their CS and EFG tensors because of forming intermolecular hydrogen bonds. Moreover, the quantum chemical calculations indicated that the intermolecular hydrogen-bonding interactions play an essential role in determining the relative orientation of CS and EFG tensors of O-6 and nitrogen atoms in the molecular frame axes. PMID- 17707781 TI - Study on the production of chitin and chitosan from shrimp shell by using Bacillus subtilis fermentation. AB - Fermentation of shrimp shell in jaggery broth using Bacillus subtilis for the production of chitin and chitosan was investigated. It was found that B. subtilis produced sufficient quantities of acid to remove the minerals from the shell and to prevent spoilage organisms. The protease enzyme in Bacillus species was responsible for the deprotenisation of the shell. The pH, proteolytic activity, extent of demineralization and deprotenisation were studied during fermentation. About 84% of the protein and 72% of the minerals were removed from the shrimp shell after fermentation. Mild acid and alkali treatments were given to produce characteristic chitin and their concentrations were standardized. Chitin was converted to chitosan by N-deacetylation and the properties of chitin and chitosan were studied. FTIR spectral analysis of chitin and chitosan prepared by the process was carried out and compared with spectra of commercially available samples. PMID- 17707782 TI - Generation of chimeric HBc proteins with epitopes in E.coli: formation of virus like particles and a potent inducer of antigen-specific cytotoxic immune response and anti-tumor effect in vivo. AB - The major aim of the project was to develop the virus-like particles (VLPs) displaying single or multi-epitope of hepatocellular carcinomas (HCC) in Escherichia coli and to evaluate the effect on inducing Ag-specific CD8(+) T cell response and antitumor efficacy as candidate vaccines. To this end, hepatitis B virus core (HBc) particles were used as a carrier of HCC epitopes. Four HCC epitopes MAGE-1(278-286aa), MAGE-3(271-279aa), AFP1 (158-166aa) or AFP2 (542 550aa) were fused to the 3' terminus of the truncated HBV core gene, respectively, or conjunctively. Not all recombinant plasmids led to expression of chimeric proteins in expression strain E. coli BL21 (DE3), but chimeric proteins which are expressed in inclusion bodies resulted in the formation of complete "mature" VLPs. E. coli-derived truncated HBc(1-144) chimeric protein self assembled into VLPs that both morphologically and physically are similar to the wild-type ones and they still remained activity after purification and refolding from 6M urea solution. We also showed that they could be internalized and presented by DCs in vitro. Additionally, DCs pulsed with the chimeric HBc-VLPs could induce stronger CTL activity and greater IFN-gamma secretion by responding T cells compared with peptid-pulsed DCs. In the B16-pIR-HH tumor therapy model, the growth of established tumors was significantly inhibited by immunization using VLP-pulsed DCs, resulting in significantly higher survival rate of immunized animals. Thus, the results of the current study have demonstrated the principal possibility of using VLP on the basis of HBcAg for creation of a new type of HCC-specific immunogen. PMID- 17707783 TI - Effect of trehalose on the contributions to the dipole potential of lipid monolayers. AB - The dipole potential and the area changes induced by trehalose on dimyristoyl phosphatidylcholine (DMPC), 1,2-di-O-tetradecyl-sn-glycero-3-phosphocholine (dietherPC), dimyristoyl phosphatidylethanolamine (DMPE), 1,2-di-O-tetradecyl-sn glycero-3-phosphoethanolamine (dietherPE) monolayers have been studied at different temperatures. The insertion of trehalose into DMPC monolayers in the fluid and gel states requires of the presence of carbonyl groups. The area increase observed at 0.15M trehalose is congruent with the decrease in the dipole potential. However, in dietherPC, in which trehalose does not affect the area, a decrease in the dipole potential is also observed. This is interpreted as a result of the displacement of water from the phosphate groups exposed to the aqueous phase. In DMPE, trehalose also decreases the dipole potential without affecting the area of saturated monolayers and in dietherPE no effect on dipole potential and area was observed. It is concluded that the spacer effect of trehalose depends on the specific interaction with CO, which is modulated by the strength of the interaction of the PO groups with lateral NH groups. However, it is not the only contribution to the dipole potential decrease. PMID- 17707784 TI - Preparation of laser micropore porcine acellular dermal matrix for skin graft: an experimental study. AB - In our previous study, we used composite grafts consisting of meshed porcine acellular dermal matrix (PADM) and thin split-thickness autologous epidermis to cover full thickness burn wounds in clinical practice. However, a certain degree of contraction might occur because the distribution of dermal matrix was not uniform in burn wound. In this study, we prepare a composite skin graft consisting of PADM with the aid of laser to improve the quality of healing of burn wound. METHODS: PADM was prepared by the trypsin/Triton X-100 method. Micropores were produced on the PADM with a laser punch. The distance between micropores varied from 0.8, 1.0, 1.2 to 1.5mm. Full thickness defect wounds were created on the back of 144 SD rats. The rats were randomly divided into six groups: micropore groups I-IV in which the wound were grafted with PADM with micropores, in four different distances, respectively and split-thickness autograft; mesh group rats received meshed PADM graft and split-thickness autograft; control group received simple split-thickness autografting. The status of wound healing was histologically observed at regular time points after surgery. The wound healing rate and contraction rate were calculated. RESULTS: The wound healing rate in micropore groups I and II was not statistically different from that in control group, but was significantly higher than that in mesh group 6 weeks after grafting. The wound healing rate in micropore groups III and IV was lower than that in mesh and control groups 4 and 6 weeks after grafting. The wound contraction rate in micropore groups I and II was remarkably lower than that in control group 4 and 6 weeks after surgery and it was significantly much lower than that in mesh group 6 weeks after surgery. Histological examination revealed good epithelization, regularly arranged collagenous fibers and integral structure of basement membrane. CONCLUSION: Laser micropore PADM (0.8 or 1.0mm in distance) grafting in combination with split thickness autografting can improve wound healing. The PADM with laser micropores in 1.0mm distance is the better choice. PMID- 17707785 TI - Body image, mood and quality of life in young burn survivors. AB - This study looks at the body image, mood and quality of life of a group of 36 young people aged between 11 and 19 years who had burns as children, compared with an age-matched control group of 41 young people who had not had these injuries. Participants completed the Body Esteem Scale (BES), the Satisfaction With Appearance Scale (SWAP), the Beck Depression Inventory-II (BDI-II) and the Youth Quality of Life Questionnaire (YQOL). It was hypothesised that young burn survivors would report more dissatisfaction with their appearance, a lower mood and a lower quality of life compared with non-injured controls. However, young burn survivors reported significantly more positive evaluations of how others view their appearance (p=0.018), more positive weight satisfaction (p=0.001) and a higher quality of life (p=0.005) than the control group. They also reported more positive general feelings about their appearance, although this was just below the level for statistical significance (p=0.067) and a similar mood to the school sample (p=0.824). The data suggest that young burn survivors appear to be coping well in comparison to their peers, and in some areas may be coping better, in spite of living with the physical, psychological and social consequences of burns. PMID- 17707786 TI - A novel method to prevent tissue desiccation during burn surgery: saline spray. PMID- 17707787 TI - A direct screening procedure for diuretics in human urine by liquid chromatography-tandem mass spectrometry with information dependent acquisition. AB - BACKGROUND: Diuretics are a class of compounds largely used for either therapeutic (edemas, hypertension, etc.) or illegal (doping) purposes. Probably owing to the substantial variety of their chemical structures, which makes them hardly extractable from a biological matrix in a single procedure, a quite short list of screening methods can be retrieved in the literature. METHODS: This work presents a screening procedure for 24 diuretics based on the direct injection of urine (after 50 folds dilution) in a LC-ESI-MS/MS system (Applied Biosytems 4000 QTrap). Two information dependent acquisitions (IDA), one in positive, one in negative ionization, allowed the acquisition of one selected reaction monitoring transition for each compound, which, when a significant peak was found, triggered the acquisition of the enhanced product ion (EPI) spectrum. RESULTS AND CONCLUSIONS: EPI spectra were stored in a library and the procedure was able to recognize by library matching various diuretics in real positive samples. The limits of detection were comprised between 0.002 and 0.25 mg/l and ion suppression was not found to significantly influence the analysis. PMID- 17707788 TI - Holistic or compositional representation of two-digit numbers? Evidence from the distance, magnitude, and SNARC effects in a number-matching task. AB - Whether two-digit numbers are represented holistically (each digit pair processed as one number) or compositionally (each digit pair processed separately as a decade digit and a unit digit) remains unresolved. Two experiments were conducted to examine the distance, magnitude, and SNARC effects in a number-matching task involving two-digit numbers. Forty undergraduates were asked to judge whether two two-digit numbers (presented serially in Experiment 1 and simultaneously in Experiment 2) were the same or not. Results showed that, when numbers were presented serially, unit digits did not make unique contributions to the magnitude and distance effects, supporting the holistic model. When numbers were presented simultaneously, unit digits made unique contributions, supporting the compositional model. The SNARC (Spatial-Numerical Association of Response Codes) effect was evident for the whole numbers and the decade digits, but not for the unit digits in both experiments, which indicates that two-digit numbers are represented on one mental number line. Taken together, these results suggested that the representation of two-digit numbers is on a single mental number line, but it depends on the stage of processing whether they are processed holistically or compositionally. PMID- 17707789 TI - The developmental course of lexical tone perception in the first year of life. AB - Perceptual reorganisation of infants' speech perception has been found from 6 months for consonants and earlier for vowels. Recently, similar reorganisation has been found for lexical tone between 6 and 9 months of age. Given that there is a close relationship between vowels and tones, this study investigates whether the perceptual reorganisation for tone begins earlier than 6 months. Non-tone language English and French infants were tested with the Thai low vs. rising lexical tone contrast, using the stimulus alternating preference procedure. Four- and 6-month-old infants discriminated the lexical tones, and there was no decline in discrimination performance across these ages. However, 9-month-olds failed to discriminate the lexical tones. This particular pattern of decline in nonnative tone discrimination over age indicates that perceptual reorganisation for tone does not parallel the developmentally prior decline observed in vowel perception. The findings converge with previous developmental cross-language findings on tone perception in English-language infants [Mattock, K., & Burnham, D. (2006). Chinese and English infants' tone perception: Evidence for perceptual reorganization. Infancy, 10(3)], and extend them by showing similar perceptual reorganisation for non-tone language infants learning rhythmically different non tone languages (English and French). PMID- 17707790 TI - Cryopreservation of Radopholus similis, a tropical plant-parasitic nematode. AB - For obligate plant-parasitic nematodes, cryopreservation has advantages over the usual preservation methods on whole plants or axenic culture systems, because the latter two are labourious and time and space consuming. In addition, cross contamination among different isolates can occur easily. Moreover, specific genetic studies require maintenance of the original population. The nematode under investigation, Radopholus similis, is a plant-parasitic nematode from the humid tropics. Therefore, any treatment at low temperatures is likely to add extra stress to the nematode, making the development of a cryopreservation protocol extremely difficult. In this paper, we describe experiments to achieve a successful cryopreservation protocol for the tropical nematode R. similis using vitrification solution-based methods based on a well defined mixture of cryoprotectants in combination with ultra-rapid cooling and thawing rates. A two step treatment was used consisting of an incubation in glycerol followed by the application of a vitrifying mixture of methanol, glycerol and glucose. After cryopreservation, the pathogenicity of the nematodes was not altered, since they could infect and reproduce on carrot discs after recovery in the Ringer solution. The cryopreservation method described can be used for routine cryopreservation of R. similis lines from different origins. PMID- 17707791 TI - The toposome, essential for sea urchin cell adhesion and development, is a modified iron-less calcium-binding transferrin. AB - We describe the structure and function of the toposome, a modified calcium binding, iron-less transferrin, the first member of a new class of cell adhesion proteins. In addition to the amino acid sequence of the precursor, we determined by Edman degradation the N-terminal amino acid sequences of the mature hexameric glycoprotein present in the egg as well as that of its derived proteolytically modified fragments necessary for development beyond the blastula stage. The approximate C-termini of the fragments were determined by a combination of mass spectrometry and migration in reducing gels before and after deglycosylation. This new member of the transferrin family shows special features which explain its evolutionary adaptation to development and adhesive function in sea urchin embryos: (i) a protease-inhibiting WAP domain, (ii) a 280 amino acid cysteine less insertion in the C-terminal lobe, and (iii) a 240 residue C-terminal extension with a modified cystine knot motif found in multisubunit external cell surface glycoproteins. Proteolytic removal of the N-terminal WAP domain generates the mature toposome present in the oocyte. The modified cystine knot motif stabilizes cell-bound trimers upon Ca-dependent dissociation of hexamer-linked cells. We determined the positions of the developmentally regulated cuts in the cysteine-less insertion, which produce the fragments observed previously. These fragments remain bound to the hexameric 22S particle in vivo and are released only after treatment of the purified toposome with reducing agents. In addition, some soluble smaller fragments with possible signal function are produced. Sequence comparison of five sea urchin species reveals the location of the cell cell contact site targeted by the species-specific embryo dissociating antibodies. The evolutionary tree of 2-, 1-, and 0-ferric transferrins implies their evolution from a basic cation-activated allosteric design modified to serve multiple functions. PMID- 17707793 TI - Isokotomolide A, a new butanolide extracted from the leaves of Cinnamomum kotoense, arrests cell cycle progression and induces apoptosis through the induction of p53/p21 and the initiation of mitochondrial system in human non small cell lung cancer A549 cells. AB - This study is the first to investigate isokotomolide A (IKA), a butanolide compound isolated from the leaves of Cinnamomum kotoense Kanehira & Sasaki (Lauraceaee), which exhibits an anti-proliferative activity in human non-small cell lung cancer A549 cells. The results show that IKA inhibits the proliferation of A549 by blocking cell cycle progression in the G0/G1 phase and inducing apoptosis. Blockade of cell cycle was associated with increased p21/WAF1 levels and reduced amounts of cyclin D1, cyclin E, Cdk2, Cdk4, and Cdk6 in a p53 mediated manner. IKA treatment also increased p53 phosphorylation (Ser15) and decreased the interaction of p53-MDM2. IKA treatment triggered the mitochondrial apoptotic pathway, indicated by changing Bax/Bcl-2 ratios, cytochrome c release and caspase-9 activation. In addition, pre-treatment of cells with caspase-9 inhibitor inhibited IKA-induced apoptosis, indicating that caspase-9 activation was involved in A549 cells' apoptosis induced by IKA. Our study reports here for the first time that the induction of p53/p21 and the initiation of the mitochondrial apoptotic system may participate in the anti-proliferative activity of IKA in human non-small cell lung cancer cells. PMID- 17707792 TI - Effects of kappa opioid agonists alone and in combination with cocaine on heart rate and blood pressure in conscious squirrel monkeys. AB - As kappa agonists have been proposed as treatments for cocaine abuse, the cardiovascular effects of the kappa opioid receptor agonists ethylketocyclazocine (EKC) and enadoline were investigated in conscious squirrel monkeys. Both EKC and enadoline increased heart rate with little effect on blood pressure. This effect appeared to be specific for kappa receptors as the mu opioid agonist morphine did not mimic the effects of the kappa agonists. The opioid antagonist naltrexone, at a dose of 1.0 mg/kg, blocked the effect of EKC. An action at both central and peripheral receptors may be responsible for the heart rate increase following kappa agonist treatment. The ganglionic blocker chlorisondamine partially antagonized the effect of EKC on heart rate, suggesting central involvement, while the peripherally-acting agonist ICI 204,448 ((+/-)-1-[2,3- (Dihydro-7 methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride) also increased heart rate, supporting a peripheral site of action. When given in combination with cocaine, EKC produced effects that were sub-additive, suggesting that the kappa agonists may be used safely as cocaine abuse treatments. PMID- 17707794 TI - RhoE participates in the stimulation of the inflammatory response induced by ethanol in astrocytes. AB - Astroglial cells are involved in the neuropathogenesis of several inflammatory diseases of the brain, where the activation of inflammatory mediators and cytokines plays an important role. We have previously demonstrated that ethanol up-regulates inflammatory mediators in both brain and astroglial cells. Since Rho GTPases are involved in inflammatory responses of astrocytes where loss of stress fibers takes place and RhoE/Rnd3 disorganizes the actin cytoskeleton, the aim of the present study was to investigate the implication of this protein in the stimulation of inflammatory signaling induced by ethanol. Our findings show that RhoE expression induces a decrease in both RhoA and Rac. In addition, RhoE not only induces actin cytoskeleton disorganization but it also stimulates both the IRAK/ERK/NF-kappaB pathway and the COX-2 expression associated with the inflammatory response in these cells. Our results also show that ethanol exposure induces RhoE signaling in astrocytes. Preincubation of astrocytes with GF109203X, an inhibitor of PKCs, reduces the RhoE levels and abolishes the ethanol-induced activation of IRAK, NF-kappaB and the COX-2 expression. Furthermore, RhoE overexpression restores ethanol responses in astrocytes treated with the PKCs inhibitor. Altogether, our findings suggest that this small GTPase is involved in the stimulation of the inflammatory signaling induced by ethanol in astrocytes. These findings provide new insights into the molecular mechanism involved in the inflammatory responses in astrocytes. PMID- 17707795 TI - TRB3 protects cells against the growth inhibitory and cytotoxic effect of ATF4. AB - Tribbles homolog 3 (TRB3) is a pseudokinase the level of which is increased in response to various stresses. We and other researchers have previously shown that TRB3 interacts with activating transcription factor 4 (ATF4) and may function as a negative feedback regulator of ATF4. In the present study, we investigate the effect of ATF4 and TRB3 on cell growth and viability, using both the enforced expression and silencing of the genes. HEK293 cells overexpressing ATF4 show retarded growth in the complete medium and decreased viability in the glucose free medium. The enforced expression of ATF4 increases the level of reactive oxygen species (ROS) and the supplementation of the medium with ROS scavenging and reducing compounds supports the growth and survival of cells overexpressing ATF4. The deleterious effects of elevated ATF4 are suppressed by the coexpression of TRB3, which downregulates ATF4 transcriptional activity and results in the decrease of intracellular ROS. Also, the coexpression of TRB3 rescues postmitotic neuronally differentiated PC12 cells from the apoptosis evoked by ATF4 overexpression. The silencing of ATF4 and TRB3 genes by RNA interference reveals that endogenous ATF4 promotes and TRB3 suppresses the death of glucose-deprived SaOS2 cells. Together, the results indicate that TRB3 protects cells against the growth inhibitory and cytotoxic effect of ATF4. PMID- 17707796 TI - PERK-dependent compartmentalization of ERAD and unfolded protein response machineries during ER stress. AB - Accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the ER membrane kinases PERK and IRE1 leading to the unfolded protein response (UPR). We show here that UPR activation triggers PERK and IRE1 segregation from BiP and their sorting with misfolded proteins to the ER-derived quality control compartment (ERQC), a pericentriolar compartment that we had identified previously. PERK phosphorylates translation factor eIF2alpha, which then accumulates on the cytosolic side of the ERQC. Dominant negative PERK or eIF2alpha(S51A) mutants prevent the compartmentalization, whereas eIF2alpha(S51D) mutant, which mimics constitutive phosphorylation, promotes it. This suggests a feedback loop where eIF2alpha phosphorylation causes pericentriolar concentration at the ERQC, which in turn amplifies the UPR. ER-associated degradation (ERAD) is an UPR-dependent process; we also find that ERAD components (Sec61beta, HRD1, p97/VCP, ubiquitin) are recruited to the ERQC, making it a likely site for retrotranslocation. In addition, we show that autophagy, suggested to play a role in elimination of aggregated proteins, is unrelated to protein accumulation in the ERQC. PMID- 17707797 TI - Tissue transglutaminase clusters soluble A-type ephrins into functionally active high molecular weight oligomers. AB - The Eph receptors and their ligands, the ephrins, are thought to act at points of close cell-cell contact to elicit bi-directional signaling in receptor and ligand expressing cells. However, when cultured in vitro, some A-type ephrins are released from the cell surface and it is unclear if these soluble ephrins participate in Eph receptor activation. We show that soluble ephrin A5 is subject to oligomerization. Ephrins A1 and A5 are substrates for a cross-linking enzyme, tissue transglutaminase, which mediates the formation of oligomeric ephrin. Transglutaminase-cross-linked ephrin binds to A-type Eph receptors, stimulates Eph kinase activity, and promotes invasion and migration of HeLa cells. Transglutaminase-mediated oligomerization of soluble ephrin potentially represents a novel mechanism of forward signaling through Eph receptors and may extend the influence of A-type ephrins beyond cell contact mediated signaling. PMID- 17707798 TI - Isostructural folate conjugates radiolabeled with the matched pair 99mTc/188Re: a potential strategy for diagnosis and therapy of folate receptor-positive tumors. AB - (99m)Tc-technetium ((99m)Tc) and (188)Re-rhenium ((188)Re) represent an interesting pair of radionuclides for diagnosis and therapy. The aim of this study was to synthesize and characterize in vitro/in vivo the first (188)Re folate derivative [(188)Re(CO)(3)-picolylamine monoacetic acid 188/Re-OANA-folate (2)] for potential targeted radionuclide therapy of FR-positive tumors. The data were compared with those of the isostructural (99m)Tc-analog [(99m)Tc-PAMA folate (1)] reported previously. METHODS: In vitro stability of compound 2 was tested in phosphate-buffered saline and human plasma. Cell binding experiments were performed with FR-positive human KB cells. Biodistribution was assessed in female nude mice, bearing KB tumor xenografts. RESULTS: Cell binding experiments showed high and FR-specific uptake. In vivo, compound 2 accumulated specifically in the FR-positive tumors with maximal values 4 h post injection (p.i.) ['2: 1.87+/-0.04 percent injected dose per gram of weight tissue (% ID/g) vs. '1: 2.33+/-0.36% ID/g]. Unfavorably high retention of radioactivity was found in FR-positive kidneys (12.04+/-0.62% ID/g; 4 h p.i.). Tumor-to-blood ratio of radioactivity ('2: 14.5+/-1.32, 4 h p.i.) was lower than for compound '1 (58.0+/-12.2, 4 h p.i.), whereas tumor-to-kidney ratios were in the same range ('2: 0.15+/-0.01 vs. '1: 0.13+/-0.02, 4 h p.i.). Preadministration of the antifolate pemetrexed significantly improved the tumor-to-kidney ratio (2: 1.59+/-0.30, 4 h p.i.). CONCLUSIONS: The isostructural radiofolates 1 and '2 displayed almost identical pharmacokinetic profiles and accumulated both specifically in FR-positive tumors. However, only the coapplication of the antifolate pemetrexed improved the biodistribution of the radiotracers in such ways that a potential therapeutic application of compound '2 can be envisaged in the future. PMID- 17707799 TI - Dose-dependent effects of (anti)folate preinjection on 99mTc-radiofolate uptake in tumors and kidneys. AB - INTRODUCTION: The folate receptor (FR) is frequently overexpressed in tumors and can be targeted with folate-based (radio)pharmaceuticals. However, significant accumulation of radiofolates in FR-positive kidneys represents a drawback. We have shown that preadministration of the antifolate pemetrexed (PMX) significantly improved the tumor-to-kidney ratio of radiofolates in mice. The aim of this study was to investigate the dose dependence of these effects and whether the same results could be achieved with folic acid (FA) or 5-methyl tetrahydrofolate (5-Me-THF). METHODS: Biodistribution was assessed 4 h postinjection of the organometallic (99m)Tc-picolylamine monoacetic acid folate in nude mice bearing FR-positive KB tumor xenografts. PMX (50-400 microg/mouse) was injected 1 h previous to radioactivity. The effects of FA and 5-Me-THF (0.5 50 microg/mouse) were investigated likewise. Tissues and organs were collected and counted for radioactivity and the values tabulated as percentage of injected dose per gram tissue (% ID/g). RESULTS: PMX administration reduced renal retention (<1.6% ID/g vs. control: >10% ID/g), while the tumor uptake (average 1.35%+/-0.40% ID/g vs. control: 1.79%+/-0.49% ID/g) was only slightly affected independent of the PMX dose. Replacement of PMX by FA or 5-Me-THF (50 microg/mouse) resulted in a significant renal blockade (<0.1% ID/g) but at the same time in an undesired reduction of tumor uptake (<0.2% ID/g). CONCLUSIONS: Selective reduction of radiofolate uptake in kidneys under retention of high tumor accumulation could be achieved in combination with PMX over a broad dose range but not with FA or 5-Me-THF. PMID- 17707800 TI - Cellular studies of binding, internalization and retention of a radiolabeled EGFR binding affibody molecule. AB - INTRODUCTION: The cellular binding and processing of an epidermal growth factor receptor (EGFR) targeting affibody molecule, (Z(EGFR:955))(2), was studied. This new and small molecule is aimed for applications in nuclear medicine. The natural ligand epidermal growth factor (EGF) and the antibody cetuximab were studied for comparison. METHODS: All experiments were made with cultured A431 squamous carcinoma cells. Receptor specificity, binding time patterns, retention and preliminary receptor binding site localization studies were all made after (125)I labeling. Internalization was studied using Oregon Green 488, Alexa Fluor 488 and CypHer5E markers. RESULTS: [(125)I](Z(EGFR:955))(2) and [(125)I]cetuximab gave a maximum cellular uptake of (125)I within 4 to 8 h of incubation, while [(125)I]EGF gave a maximum uptake already after 2 h. The retention studies showed that the cell-associated fraction of (125)I after 48 h of incubation was approximately 20% when delivered as [(125)I](Z(EGFR:955))(2) and approximately 25% when delivered as [(125)I]cetuximab. [(125)I]EGF-mediated delivery gave a faster (125)I release, where almost all cell-associated radioactivity had disappeared within 24 h. All three substances were internalized as demonstrated with confocal microscopy. Competitive binding studies showed that both EGF and cetuximab inhibited binding of (Z(EGFR:955))(2) and indicated that the three substances competed for an overlapping binding site. CONCLUSION: The results gave information on cellular processing of radionuclides when delivered with (Z(EGFR:955))(2) in comparison to delivery with EGF and cetuximab. Competition assays suggested that [(125)I](Z(EGFR:955))(2) bind to Domain III of EGFR. The affibody molecule (Z(EGFR:955))(2) can be a candidate for EGFR imaging applications in nuclear medicine. PMID- 17707801 TI - A simple quantitative assay for the activity of thymidine kinase 1 in solid tumors. AB - INTRODUCTION: The activity of the pyrimidine salvage pathway enzyme thymidine kinase 1 (TK1) is tightly cell cycle regulated and has been investigated as a prognostic indicator of cancer in a variety of tissues. However, using the in vitro assay of TK1 to rank order a series of unique tumor samples by their TK1 activity can be problematic due to the complex nature of TK1 enzyme substrate kinetics. We present a refined TK1 in vitro assay and method of analysis which address these problems. METHODS: Extracts were prepared of the resected lung lesions from eight patients and assayed for TK1 activity using an in vitro assay modified to account for nonlinearities in extract protein concentration. A separate extract of exponentially growing A549 human lung carcinoma cells was used as a cross-assay control. RESULTS: In extracts prepared from eight frozen samples of resected human lung lesions, TK1 activity (mean=0.0070+/-0.0077 pmol [(3)H]-TMP/microg protein/minute) was 2 orders of magnitude below that of exponentially growing A549 human lung carcinoma cells (mean=0.1572+/-0.0218 pmol [(3)H]-TMP/microg protein/minute; n=9). TK1 activity was nonlinear with respect to extract protein concentration in both groups, with A549 cell extracts exhibiting evidence of positive cooperativity which could not be explained by the presence of detergents in the cell lysis buffer. Lung tumor extracts demonstrated evidence of negative cooperativity. CONCLUSIONS: The modified TK1 assay takes into account these nonlinearities by averaging the results of several complete time-course curves measured over a range of extract protein concentrations. An extract prepared from exponentially growing A549 cells is included in each assay for use as a cross-assay control. We demonstrate that these modifications allow for the accurate rank ordering of TK1 activity in solid tumors. PMID- 17707802 TI - 2-[methyl-(11)C]methoxyestradiol: synthesis, evaluation and pharmacokinetics for in vivo studies on angiogenesis. AB - 2-Methoxyestradiol (1) is an endogenous metabolite of estradiol that has been shown to inhibit cell proliferation and angiogenesis. In this study, 2-[methyl (11)C]methoxyestradiol ([(11)C]1) was synthesized and evaluated for in vivo studies on angiogenesis. Radiotracer [(11)C]1 was synthesized at a decay corrected radiochemical yield of 25-34% from [(11)C]CH(3)I with a specific activity of 34-38 GBq/micromol. In vitro human umbilical vein endothelial cell uptake studies demonstrated that [(11)C]1 uptake increased time-dependently and that this uptake was inhibited by 70% in the presence of Compound 1, indicating its specific binding to cells. Tissue distribution in mice implanted with Lewis lung carcinoma cells showed high radioactivity accumulation in the liver, lungs and kidneys, and a tumor-to-muscle uptake ratio of 2.36. Pharmacokinetic analysis in mice intravenously injected with [(11)C]1 demonstrated a t(1/2)alpha of 0.36 min, a t(1/2)beta of 19 min, a clearance of 0.36 ml/min and a volume of distribution of 52.9 ml. In addition, Compound 1 showed linear pharmacokinetics at dose levels between 0.14 and 8.5 microg in mice. Taken together, [(11)C]1 may be useful for in vivo studies on angiogenesis. PMID- 17707803 TI - Renal uptake and retention of radiolabeled somatostatin, bombesin, neurotensin, minigastrin and CCK analogues: species and gender differences. AB - INTRODUCTION: During therapy with radiolabeled peptides, the kidney is most often the critical organ. Newly developed peptides are evaluated preclinically in different animal models before their application in humans. In this study, the renal retention of several radiolabeled peptides was compared in male and female rats and mice. METHODS: After intravenous injection of radiolabeled peptides [somatostatin, cholecystokinin (CCK), minigastrin, bombesin and neurotensin analogues], renal uptake was determined in both male and female Lewis rats and C57Bl mice. In addition, ex vivo autoradiography of renal sections was performed to localize accumulated radioactivity. RESULTS: An equal distribution pattern of renal radioactivity was found for all peptides: high accumulation in the cortex, lower accumulation in the outer medulla and no radioactivity in the inner medulla of the kidneys. In both male rats and mice, an increasing renal uptake was found: [(111)In-DTPA]CCK8<[(111)In-DTPA-Pro(1),Tyr(4)]bombesin approximately [(111)In DTPA]neurotensin<[(111)In-DTPA]octreotide<<[(111)In-DTPA]MG0. Renal uptake of [(111)In-DTPA]octreotide in rats showed no gender difference, and renal radioactivity was about constant over time. In mice, however, renal uptake in females was significantly higher than that in males and decreased rapidly over time in both genders. Moreover, renal radioactivity in female mice injected with [(111)In-DTPA]octreotide showed a different localization pattern. CONCLUSIONS: Regarding the renal uptake of different radiolabeled peptides, both species showed the same ranking order. Similar to findings in patients, rats showed comparable and constant renal retention of radioactivity in both genders, in contrast to mice. Therefore, rats appear to be the more favorable species for the study of the renal retention of radioactivity. PMID- 17707804 TI - Synthesis and preliminary biological studies of the novel conjugate 188Re-labeled meso-tetrakis(4-sulfophenyl)porphyrin in mice. AB - OBJECTIVE: The objective of this study was to evaluate the biological behaviors of a novel (188)Re-labeled meso-tetrakis(4-sulfophenyl)porphyrin (TPPS(4)) in normal mice and tumor-bearing mice. METHODS: TPPS(4) was synthesized and labeled by (188)ReO(4)(-). Normal KM mice and BALB/c nude mice bearing melanoma or hepatoma were prepared for distribution studies. RESULTS: The [(188)Re]TPPS(4) yield was >98% with a specific activity of 11.2 GBq/mol, and vitamin C could increase its stability in vitro. In normal KM mice, [(188)Re]TPPS(4) had a fast blood clearance ( approximately 90%, 24 h postinjection), low retention in vital organs and hepatotropic characteristics. In nude mice, uptakes of >4.1% and 6.5% ID/g tumor at 8 h postinjection were observed in melanoma and hepatoma, respectively; this remained at high levels of 4.7% and 5.7%, respectively, after 24 h. At 8 h, the tumor/blood and tumor/muscle ratios in melanoma-bearing and hepatoma-bearing mice were 6.2-15.2 and 6.1-24.2, respectively. Twenty-four hours later, these high ratios still continued at 8.6-22.1 and 12-26.1, respectively. CONCLUSION: The results obtained in this study indicate that [(188)Re]TPPS(4) has a high tumor affinity and retainable accumulation characteristics in carcinoma, which can potentially be used for tumor-targeted therapy. PMID- 17707805 TI - Preclinical evaluation of [99mTc/EDDA/tricine/HYNIC0, 1-Nal3, Thr8]-octreotide as a new analogue in the detection of somatostatin-receptor-positive tumors. AB - PURPOSE: Radiolabeled somatostatin analogues are important tools for the in vivo localization and targeted radionuclide therapy of somatostatin-receptor-positive tumors. The aim of this study was to evaluate a new somatostatin analogue designed for the labeling with (99m)Tc: [6-hydrazinopyridine-3-carboxylic acid (HYNIC(0)), 1-Nal(3), Thr(8)]-octreotide ([HYNIC]-NATE), using ethylenediamine N,N'-diacetic acid (EDDA) and tricine as coligands. METHODS: Synthesis was preformed on a solid phase using a standard Fmoc strategy. Labeling with (99m)Tc was performed at 100 degrees C for 10 min using SnCl(2) as a reductant. Radiochemical analysis involved ITLC and high-performance liquid chromatography methods. Peptide conjugate affinity was determined in AR4-2J cell membranes. The internalization and externalization rates were studied in sstr(2)-expressing AR4 2J cells. Biodistribution of radiopeptide was studied in rats bearing the AR4-2J tumor. RESULTS: Radiolabeling was performed at high specific activities, and radiochemical purity was >95%. Peptide conjugate showed high affinity binding for sstr(2). The radioligand showed a moderate and specific internalization into AR4 2J cells (14.13+/-0.61% at 4 h). In animal biodistribution studies, a receptor specific uptake of radioactivity was observed in somatostatin-receptor-positive organs. After 4 h, uptake in the AR4-2J tumor was 1.33+/-0.23%ID/g (percentage of injected dose per gram of tissue). CONCLUSION: These data show that [(99m)Tc/EDDA/tricine/HYNIC]-NATE is a specific radioligand for the somatostatin receptor-positive tumors and is a suitable candidate for clinical studies. PMID- 17707806 TI - Transport of D-[1-14C]-amino acids into Chinese hamster ovary (CHO-K1) cells: implications for use of labeled d-amino acids as molecular imaging agents. AB - INTRODUCTION: The fact that d-amino acids have been found in various tissues and are involved in various functions is a clue to how to develop new imaging agents. We examined d-amino acid transport mechanisms in Chinese hamster ovary (CHO-K1) cells because CHO-K1 cells are widely used in biomedical studies and are thought to be useful for expression of genes involved in metabolism of D-amino acids. METHODS: Uptake experiments were performed. CHO-K1 cells cultured in 60-mm plastic culture dishes under ordinary culture conditions were incubated with 18.5 kBq of radiolabeled amino acid in 2 ml of phosphate-buffered-saline-based uptake solution at 37 degrees C. The following radiolabeled amino acid tracers were used: D-[1-(14)C]-alanine, L-[1-(14)C]-alanine, D-[1-(14)C]-serine, L-[1-(14)C] serine, D-[1-(14)C]-methionine, L-[1-(14)C]-methionine, D-[1-(14)C] phenylalanine, L-[1-(14)C]-phenylalanine, D-[1-(14)C]-leucine, L-[1-(14)C] leucine, D-[1-(14)C]-valine, L-[1-(14)C]-valine, D-[1-(14)C]-tyrosine, L-[1 (14)C]-tyrosine, D-[1-(14)C]-glutamic acid, L-[1-(14)C]-glutamic acid, D-[1 (14)C]-lysine, L-[1-(14)C]-lysine, D-[1-(14)C]-arginine and L-[L-(14)C]-arginine. We tested the inhibitory effects of the following compounds (1.0 mM) on transport: 2-(methylamino)isobutyric acid (a specific inhibitor of system A, in Na(+)-containing uptake solution) and 2-amino-bicyclo[2,2,1]heptane-2-carboxylic acid (a specific inhibitor of system L, in Na(+)-free uptake solution). RESULTS: D-[1-(14)C]-methionine, D-[1-(14)C]-phenylalanine and D-[1-(14)C]-tyrosine accumulated mainly via system L. D-[1-(14)C]-alanine and D-[1-(14)C]-serine accumulated primarily via system ASC. High uptake of D-[1-(14)C]-alanine, D-[1 (14)C]-methionine, D-[1-(14)C]-phenylalanine and D-[1-(14)C]-leucine was observed. The uptake of radiolabeled serine, valine, tyrosine, glutamic acid and arginine into CHO-K1 was highly stereoselective for l-isomers. CONCLUSIONS: We observed high uptake of D-[1-(14)C]-alanine via system ASC (most likely alanine serine-cysteine-selective amino acid transporter-1) and high uptake of D-[1 (14)C]-methionine and D-[1-(14)C]-phenylalanine via system L (most likely L-type amino acid transporter-1). PMID- 17707807 TI - Imaging the norepinephrine transporter in humans with (S,S)-[11C]O-methyl reboxetine and PET: problems and progress. AB - Results from human studies with the PET radiotracer (S,S)-[(11)C]O-methyl reboxetine ([(11)C](S,S)-MRB), a ligand targeting the norepinephrine transporter (NET), are reported. Quantification methods were determined from test/retest studies, and sensitivity to pharmacological blockade was tested with different doses of atomoxetine (ATX), a drug that binds to the NET with high affinity (K(i)=2-5 nM). METHODS: Twenty-four male subjects were divided into different groups for serial 90-min PET studies with [(11)C](S,S)-MRB to assess reproducibility and the effect of blocking with different doses of ATX (25, 50 and 100 mg, po). Region-of-interest uptake data and arterial plasma input were analyzed for the distribution volume (DV). Images were normalized to a template, and average parametric images for each group were formed. RESULTS: [(11)C](S,S) MRB uptake was highest in the thalamus (THL) and the midbrain (MBR) [containing the locus coeruleus (LC)] and lowest for the caudate nucleus (CDT). The CDT, a region with low NET, showed the smallest change on ATX treatment and was used as a reference region for the DV ratio (DVR). The baseline average DVR was 1.48 for both the THL and MBR with lower values for other regions [cerebellum (CB), 1.09; cingulate gyrus (CNG) 1.07]. However, more accurate information about relative densities came from the blocking studies. MBR exhibited greater blocking than THL, indicating a transporter density approximately 40% greater than THL. No relationship was found between DVR change and plasma ATX level. Although the higher dose tended to induce a greater decrease than the lower dose for MBR (average decrease for 25 mg=24+/-7%; 100 mg=31+/-11%), these differences were not significant. The different blocking between MBR (average decrease=28+/-10%) and THL (average decrease=17+/-10%) given the same baseline DVR indicates that the CDT is not a good measure for non-NET binding in both regions. Threshold analysis of the difference between the average baseline DV image and the average blocked image showed the expected NET distribution with the MBR (LC) and hypothalamus>THL>CNG and CB, as well as a significant change in the supplementary motor area. DVR reproducibility for the different brain regions was approximately 10%, but intersubject variability was large. CONCLUSIONS: The highest density of NETs was found in the MBR where the LC is located, followed by THL, whereas the lowest density was found in basal ganglia (lowest in CDT), consistent with the regional localization of NETs in the nonhuman primate brain. While all three doses of ATX were found to block most regions, no significant differences between doses were found for any region, although the average percent change across subjects of the MBR did correlate with ATX dose. The lack of a dose effect could reflect a low signal-to-noise ratio coupled with the possibility that a sufficient number of transporters were blocked at the lowest dose and further differences could not be detected. However, since the lowest (25 mg) dose is less than the therapeutic doses used in children for the treatment of attention deficit/hyperactivity disorder ( approximately 1.0 mg/kg/day), this would suggest that there may be additional targets for ATX's therapeutic actions. PMID- 17707808 TI - Brain and whole-body imaging in nonhuman primates with [11C]MeS-IMPY, a candidate radioligand for beta-amyloid plaques. AB - [(11)C]MeS-IMPY ([S-methyl-(11)C]N,N-dimethyl-4-(6-(methylthio)imidazo[1,2 a]pyridine-2-yl)aniline) is a potential radioligand for imaging beta-amyloid plaques with positron emission tomography (PET). The aims of this study were to evaluate [(11)C]MeS-IMPY uptake in nonhuman primate brain and to estimate radiation exposure from serial whole-body images. Eight PET studies were performed in rhesus monkeys to measure the brain uptake and washout of [(11)C]MeS IMPY. Time-activity data were analyzed with one-tissue and two-tissue compartmental models using radiometabolite-corrected plasma input function. In addition, two whole-body PET scans were acquired for 120 min to determine the biodistribution of [(11)C]MeS-IMPY. Tomographic PET images were compressed into a single planar image to identify organs with the highest radiation exposures. Estimates of the absorbed dose of radiation were calculated using OLINDA 1.0. Injection of [(11)C]MeS-IMPY caused little change in pulse rate, blood pressure, respiratory rate and temperature. [(11)C]MeS-IMPY showed high standardized brain uptake values of approximately 500% and 600% between 2 and 3 min in cortical regions and the cerebellum, respectively. The brain uptake of [(11)C]MeS-IMPY was widespread and quite uniform across all cortical regions. Activity rapidly washed out of the brain, with 20% of peak activity remaining at 40 min. Thus, all brain regions showed minimal retention of radioactivity, consistent with these healthy young animals having negligible amyloid plaques. Regional brain activity fitted well into a one-tissue compartment model. The average volume of distribution in all brain regions was 7.66+/-2.14 ml/cm(3) (n=4). The organs with the highest radiation exposure (muSv/MBq) were the gallbladder wall (33.4), urinary bladder (17) and lungs (12.9), with a resulting effective dose of 4.9 microSv/MBq (18 mrem/mCi). The high brain uptake, rapid washout and quantifiable volume of distribution in nonhuman primate brain further support the evaluation of [(11)C]MeS-IMPY. Calculated dosimetry results are comparable with those for other (11)C-labeled brain imaging radioligands. PMID- 17707809 TI - PET imaging of infection with a HYNIC-conjugated LTB4 antagonist labeled with F 18 via hydrazone formation. AB - It was previously shown that the (99m)Tc-labeled hydrazinonicotinamide (HYNIC) conjugated LTB4 antagonist MB81 visualized infectious foci in rabbits adequately and within a few hours after injection. Here, the bivalent HYNIC-conjugated LTB4 antagonist MB67 (analog of MB81) was fluorinated with (18)F via hydrazone formation and tested in vivo. METHODS: MB67 was [(18)F]-fluorinated via reaction of the [(18)F]-fluorinated intermediate p-[(18)F]-fluorobenzaldehyde ([(18)F]FB) and the HYNIC moiety of MB67 via hydrazone formation. For comparison, MB67 was also labeled with (99m)Tc. The biodistribution of (18)F- and (99m)Tc-labeled MB67 was investigated in rabbits with intramuscular infection. RESULTS: [(18)F]-MB67 was obtained at a maximum specific activity of 1200 GBq/mmol and proved to be stable in phosphate buffered saline (PBS) at 37 degrees C for at least 4 h. PET images obtained with [(18)F]-MB67 clearly delineated the abscess at 2 and 4 h pi. Counting of dissected tissues at 4 h pi revealed an abscess uptake of 0.073+/ 0.005 %ID/g, as compared to 0.160+/-0.010 %ID/g for the (99m)Tc-labeled analog. Abscess-to-muscle ratios were 23+/-4 for [(18)F]-MB67 and 35+/-9 for [(99m)Tc] MB67. CONCLUSION: The present study showed the feasibility of a new [(18)F] labeling methodology and its application in the production of a new PET tracer for imaging of infection, [(18)F]-MB67. PMID- 17707810 TI - In vivo characterization of radioiodinated (+)-2-[4-(4-iodophenyl) piperidino] cyclohexanol as a potential sigma-1 receptor imaging agent. AB - In this study, the (+)-enantiomer of radioiodinated 2-[4-(4 iodophenyl)piperidino]cyclohexanol [(+)-[(125)I]-p-iodovesamicol] [(+) [(125)I]pIV], which is reported to bind with high affinity to sigma-1 receptors in vitro, was tested for its usefulness in imaging sigma-1 receptors in the central nervous system (CNS) in vivo. In biodistribution studies, significant amounts (approximately 3% of the injected dose) of (+)-[(125)I]pIV accumulated in rat brain, and its retention was prolonged. In blocking studies, the accumulation of (+)-[(125)I]pIV in the rat brain was significantly reduced by the coadministration of sigma-ligands such as pentazocine (5.0 micromol), haloperidol (0.5 micromol) or SA4503 (0.5 micromol). The blocking effect of pentazocine (selective sigma-1 ligand) was similar to the blocking effects of SA4503 and haloperidol [nonselective sigma (sigma-1 and sigma-2) ligands]. Ex vivo autoradiography of the rat brain at 45 min following intravenous injection of (+) [(125)I]pIV showed high localization in brain areas rich in sigma-1 receptors. Thus, the distribution of (+)-[(125)I]pIV was thought to bind to sigma-1 receptors in the CNS in vivo. These results indicate that radioiodinated (+)-pIV may have the potential to image sigma-1 receptors in vivo. PMID- 17707811 TI - PET measurement of FK506 concentration in a monkey model of stroke. AB - INTRODUCTION: The immunosuppressive agent FK506 (tacrolimus) has neuroprotective properties in an experimental model of cerebral ischemia. To improve the accuracy of clinical studies in acute stroke, a clinical dose setting should be based on the brain concentration, but not on the blood concentration of agents in humans. We have already established a measurement method using PET for FK506 concentration in the normal monkey brain, which could be applicable for human study; however, under ischemic conditions, in this study, we aimed to examine the brain concentration of FK506 in a monkey model of stroke. METHODS: Studies were performed on six male cynomolgus monkeys (Macaca fascicularis) and a middle cerebral artery (MCA) occlusion model was used. Regional cerebral blood flow (rCBF) was measured by an intravenous injection of [(15)O]H(2)O 165 min after MCA occlusion. FK506 (0.1 mg/kg) containing [(11)C]FK506 was intravenously injected into the monkeys 180 min after MCA occlusion, and dynamic PET images were acquired for 30 min after administration. FK506 concentrations in the brain were calculated in moles per liter (M) units using the specific activity of injected FK506. RESULTS: MCA occlusion produced ischemia, confirmed by rCBF measurement before the administration of [(11)C]FK506. Fifteen minutes after FK506 (0.1 mg/kg) administration, the concentrations in the contralateral and ipsilateral cortex were 22.4+/-6.4 and 19.7+/-4.0 ng/g, respectively. CONCLUSION: We successfully measured the brain concentration of FK506 in a monkey model of stroke. The difference between the contralateral and ipsilateral concentrations of FK506 was not significant. This characteristic that FK506 readily penetrates ischemic tissue as well as normal tissue might explain the neuroprotective effect of FK506 in the ischemic brain and is suitable for the treatment of stroke patients. PMID- 17707812 TI - Initial evaluation of new 99mTc(CO)3 renal imaging agents having carboxyl-rich thioether ligands and chemical characterization of ReCO3 analogues. AB - INTRODUCTION: The first human studies of a characterized radiopharmaceutical containing a {(99m)Tc(CO)(3)}(+) core, Na[(99m)Tc(CO)(3)(LAN)], demonstrated that Na[(99m)Tc(CO)(3)(LAN)] was an excellent renal imaging agent; however, its clearance was less than that of (131)I-orthoiodohippurate ((131)I-OIH), and it did not provide a direct measure of effective renal plasma flow. In order to develop a (99m)Tc renal agent with pharmacokinetic properties equivalent to those of (131)I-OIH, we investigated the (99m)Tc(CO)(3)/Re(CO)(3) complexes formed from carboxymethylmercaptosuccinic acid (CMSAH(3)) and thiodisuccinic acid (TDSAH(4)). Once the ligand is bound to (99m)Tc(CO)(3) through a thioether and two carboxyl groups, the complexes have at least one unbound carboxyl group, essential for the interaction with the renal tubular transporter. METHODS: X-ray crystal structural analysis of [NMe(4)][Re(CO)(3)(CMSAH)] was performed to interpret the nature of (99m)Tc tracers. CMSAH(3) and TDSAH(4) were radiolabeled by incubating each ligand and the precursor [(99m)Tc(CO)(3)(H(2)O)(3)](+) at 70 degrees C (pH 7) for 30 min. The products were purified by reversed-phase high-performance liquid chromatography, and biodistribution studies were performed in Sprague-Dawley rats, with (131)I-OIH as an internal control at 10 and 60 min. RESULTS: Radiolabeling CMSAH(3) and TDSAH(4) with the [(99m)Tc(CO)(3)(H(2)O)(3)](+) precursor gave products quantitatively. Analysis of the Re(CO)(3) complexes with the CMSAH(3) and TDSAH(4) ligands demonstrates that ligands are bound in (99m)Tc/Re(CO)(3) complexes through a thioether and two deprotonated carboxyl groups (forming tridentate dianionic moieties, generally with two 5-membered chelate rings). Renal excretion at 60 min (activity in the urine as a percentage of (131)I-OIH) was 68+/-1% for Na(3)[(99m)Tc(CO)(3)(TDSA)] but was 98+/-1% for Na(2)[(99m)Tc(CO)(3)(CMSA)]. CONCLUSION: In rats, Na(2)[(99m)Tc(CO)(3)(CMSA)] is extracted by the kidneys and eliminated in the urine almost as rapidly as (131)I OIH; consequently, Na(2)[(99m)Tc(CO)(3)(CMSA)] may provide a direct measure of effective renal plasma flow, and further evaluation in humans is warranted. PMID- 17707813 TI - Preparation and biological evaluation of 2-amino-6-[18F]fluoro-9-(4-hydroxy-3 hydroxy-methylbutyl) purine (6-[18F]FPCV) as a novel PET probe for imaging HSV1 tk reporter gene expression. AB - INTRODUCTION: 2-Amino-6-[(18)F]fluoro-9-(4-hydroxy-3-hydroxy-methylbutyl) purine (6-[(18)F]FPCV) was prepared via a one-step nucleophilic substitution and evaluated as a novel probe for imaging the expression of herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene. METHODS: Log P of 6-[(18)F]FPCV was calculated in octanol/phosphate-buffered saline (PBS). Stability studies were performed in PBS and bovine serum albumin (BSA). Cell uptake was performed at various time points in wild-type cells and transduced cells. For in vivo studies, tumors were grown in nude mice by inoculation with C6 cells, wild type and tk positive. The radiotracer was intravenously injected to animals, and micro-PET imaging was performed. Biodistribution of 6-[(18)F]FPCV was performed on another group of animals at different time points. RESULTS: Log P of 6-[(18)F]FPCV was 0.517. 6-[(18)F]FPCV was fairly stable in PBS and BSA at 6 h. The tracer uptake in C6-tk cells was 5.5-18.8 times higher than that in wild-type cells. The plasma half-life of 6-[(18)F]FPCV was as follows: alpha t(1/2)=1.2 min and beta t(1/2)=73.7 min. The average ratio of tumor uptake between the transduced tumor and the wild-type tumor was 1.69 at 15 min. CONCLUSION: Biological evaluation showed that 6-[(18)F]FPCV is a potential probe for imaging HSV1-tk gene expression. However, its in vivo defluorination may limit its application in PET imaging of gene expression. PMID- 17707814 TI - Schistosoma mansoni: the dicer gene and its expression. AB - RNA interference (RNAi) is a gene silencing mechanism that plays an important role in regulating gene expression in many eukaryotes and has become a valuable molecular tool for analyzing gene function. Multi-domain nucleases called Dicer proteins play pivotal roles in RNAi. In this paper, we characterize the structure and expression of the Dicer gene from the platyhelminth parasite Schistosoma mansoni. The gene (SmDicer) is over 54kb long and comprises 30 exons that potentially encode a 2641 amino acid protein. This is the largest Dicer protein yet described. SmDicer contains all domains that are characteristic of metazoan dicers including an amino terminal helicase domain, DUF283, a PAZ domain, two RNAse III domains and an RNA binding domain. An examination of the available S. mansoni genome sequence suggests that the Dicer gene described here is the only Dicer gene in the parasite genome. SmDicer is expressed throughout schistosome development suggesting that RNAi technologies might be employed in deciphering gene function in all life stages of this parasite. PMID- 17707815 TI - Trichinella spiralis: characterization of phage-displayed specific epitopes and their protective immunity in BALB/c mice. AB - Trichinellosis is a global zoonosis mainly caused by Trichinella spiralis. We have previously reported that a novel Ts87 gene from the cDNA library of adult T. spiralis was cloned and expressed in a prokaryotic expression system. Vaccination with recombinant Ts87 protein (rTs87) induced a muscle larvae burden reduction in BALB/c mice by 29% in response to T. spiralis infection. In the present study, we screened a random phage-displayed peptide library using monoclonal antibody 5A3 which recognized Ts87 protein. Four positive phage clones were selected to subcutaneously immunize BALB/c mice without adjuvant. Two phage clones could effectively stimulate specific antibodies against rTs87. Mice vaccinated with these two combined phage clones showed a 28.7% worm burden reduction as compared to the control group. Therefore, the identified phage clones displayed peptides representing specific epitopes of Ts87 protein and could be considered as potential vaccine candidates for T. spiralis. PMID- 17707816 TI - Altered neuropeptide profile of Caenorhabditis elegans lacking the chaperone protein 7B2 as analyzed by mass spectrometry. AB - Cellular synthesis of naturally occurring, bioactive peptides requires the proprotein convertase PC2/EGL-3 for cleavage from the larger peptide precursors. A neuroendocrine chaperone 7B2 is needed for the proteolytical activation of proPC2, as extensively studied in mouse models. To determine the role of its orthologue in Caenorhabditis elegans, we analyzed wild-type and 7B2-null strains by HPLC and matrix-assisted laser desorption ionization time-of-flight mass spectrometry, which allowed the identification of a novel neuropeptide gene, flp 33. The presence and/or absence of some neuropeptides in 7B2-null animals strongly differs form the peptide profile in wild-type, suggesting a specific and determined action of 7B2 in C. elegans. PMID- 17707817 TI - tRNA import into yeast mitochondria is regulated by the ubiquitin-proteasome system. AB - In Saccharomyces cerevisiae, one of two cytosolic lysine-tRNAs is partially imported into mitochondria. We demonstrate that three components of the ubiquitin/26S proteasome system (UPS), Rpn13p, Rpn8p and Doa1p interact with the imported tRNA and with the essential factor of its mitochondrial targeting, pre Msk1p. Genetic and biochemical assays demonstrate that UPS plays a dual regulatory role, since the overall inhibition of cellular proteasome activity reduces tRNA import, while specific depletion of Rpn13p or Doa1p increases it. This result suggests a functional link between UPS and tRNA mitochondrial import in yeast and indicates on the existence of negative and positive import regulators. PMID- 17707818 TI - A hypothesis on the identification of the editing enzyme in plant organelles. AB - RNA editing in plant organelles is an enigmatic process leading to conversion of cytidines into uridines. Editing specificity is determined by proteins; both those known so far are pentatricopeptide repeat (PPR) proteins. The enzyme catalysing RNA editing in plants is still totally unknown. We propose that the DYW domain found in many higher plant PPR proteins is the missing catalytic domain. This hypothesis is based on two compelling observations: (i) the DYW domain contains invariant residues that match the active site of cytidine deaminases; (ii) the phylogenetic distribution of the DYW domain is strictly correlated with RNA editing. PMID- 17707819 TI - Sleep and circadian rhythms: key components in the regulation of energy metabolism. AB - In this review, we present evidence from human and animal studies to evaluate the hypothesis that sleep and circadian rhythms have direct impacts on energy metabolism, and represent important mechanisms underlying the major health epidemics of obesity and diabetes. The first part of this review will focus on studies that support the idea that sleep loss and obesity are "interacting epidemics." The second part will discuss recent evidence that the circadian clock system plays a fundamental role in energy metabolism at both the behavioral and molecular levels. These lines of research must be seen as in their infancy, but nevertheless, have provided a conceptual and experimental framework that potentially has great importance for understanding metabolic health and disease. PMID- 17707820 TI - Structural element responsible for the Fe(III)-phytosiderophore specific transport by HvYS1 transporter in barley. AB - Hordeum vulgare L. yellow stripe 1 (HvYS1) is a selective transporter for Fe(III) phytosiderophores, involved in primary iron acquisition from soils in barley roots. In contrast, Zea mays yellow stripe 1 (ZmYS1) in maize possesses broad substrate specificity, despite a high homology with HvYS1. Here we revealed, by assessing the transport activity of a series of HvYS1-ZmYS1 chimeras, that the outer membrane loop between the sixth and seventh transmembrane regions is essential for substrate specificity. Circular dichroism spectra indicated that a synthetic peptide corresponding to the loop of HvYS1 forms an alpha-helix in solution, whereas that of ZmYS1 is flexible. We propose that the structural difference at this particular loop determines the substrate specificity of the HvYS1 transporter. PMID- 17707821 TI - Modulation of the protein environment in the hydrophilic pore of the ammonia transporter protein AmtB upon GlnK protein binding. AB - The conduction of ammonia/ammonium (NH3/NH4(+)) through the channel protein AmtB is inhibited by the binding of the signal transduction protein GlnK. In the AmtB GlnK binding interface, there exists an NH3/NH4(+) binding site--Am6. The calculated pK(a) values at the Am6 sites in both the AmtB-GlnK complex and isolated AmtB implies the dominance of an uncharged NH3 state. The GlnK protein binding causes a significant downshift in the Am6 pK(a) value of the AmtB. However, this downshift is perfectly compensated by the reorientation of the protein backbone (carbonyl group of Cys312 from the AmtB part) upon AmtB-GlnK complex formation. PMID- 17707822 TI - Comparing vaginal tape and transobturator tape for the treatment of mild and moderate stress incontinence. AB - OBJECTIVE: To compare the efficacy and safety of the tension-free vaginal tape (TVT) and transobturator suburethral tape (TVT-O) procedures for the treatment of mild and moderate stress urinary incontinence (SUI). METHODS: A total of 56 women were randomly selected to undergo the TVT-O or the TVT procedure. In some patients, vaginal repair or vaginal hysterectomy was done simultaneously for associated indications. RESULTS: Mean blood loss and hospital stay duration were the same for the 2 groups, but mean +/- SD operative time was significantly shorter in the TVT-O than in the TVT group (16+/-4 min vs 27+/-6 min; P<0.001). On the second day following surgery a residual urine volume less than 100 mL was noted in 86% and 89% of the patients in the TVT-O and TVT groups, respectively; cure was achieved in 92.9% and 92.6% of the patients. No serious complications occurred in either group. Outcome was subjectively assessed, with the patients followed-up for a mean of 27.6 months. CONCLUSION: No significant differences in rates of cure, postoperative urine retention, or operative complications were found following the TVT-O or the TVT procedure. PMID- 17707826 TI - Introduction: Chronic lymphocytic leukemia in perspective. AB - Although during the past two decades there has been considerable progress in our understanding of the pathophysiology of chronic lymphocytic leukemia (CLL) and in our ability to treat this disease, actual integration of the newly identified pathophysiological mechanisms has not occurred. This perspective essay identifies some of the questions which deserve to be addressed by clinicians and scientists involved in the study of CLL. The most important unresolved remaining issue, however, is the need for standardization of tests performed by commercial labs to assure the reliability and reproducibility of results of ZAP-70, CD38, IgV(H) gene mutation status and fluorescence in-situ hybridization (FISH) cytogenetics. PMID- 17707824 TI - The smiley as a simple screening tool for depression after stroke: a preliminary study. AB - In Hong Kong, there is a paucity of evidence to support which tool is superior in measuring depression after stroke (DAS). A simple, non-language-based, culturally neutral, non-verbal and easy to apply tool that is not highly dependent on training will be desirable. OBJECTIVES: The present study aimed to examine the clinical utility of three smiley pictures in detecting DAS for older Chinese patients at 1 month after first-ever ischemic stroke. METHODS: This was a cross sectional study. A total of 253 stroke patients were interviewed by a research nurse at 1-month follow-up. RESULTS: Taking Diagnostic and Statistic Manual (DSM IV) as the gold standard, the measurement properties of emoticon (sad) in terms of sensitivity, specificity, positive and negative predictive values, as well as Kappa's value were found comparable to Geriatric Depression Scale (GDS). The emoticon (happy) demonstrated a highly significant inverse relationship with all depression assessment tools (p<0.001). It was also found that the emoticon (flat) could capture 98% of all depressed subjects identified by DSM IV, although its predictive values were less satisfactory. CONCLUSIONS: The smiley pictures seemed to fulfil the requirements for early and prompt screening among older patients. Cultural implication regarding emotions dissipation among Chinese patients should be further studied. PMID- 17707827 TI - Differential diagnosis in chronic lymphocytic leukaemia. AB - The diagnosis of chronic lymphocytic leukaemia (CLL) is based on clinical and laboratory features. Morphology and immunophenotype are the key initial diagnostic tests. In cases with atypical features, these investigations should be complemented with cytogenetics and/or histology to confirm the diagnosis and to exclude other B-cell disorders. Morphologically, CLL can be classified into typical and atypical forms. Cell-marker studies provide a robust foundation to establish the diagnosis as the lymphocytes have a distinct immunophenotypic signature. Although no single antigen is exclusively expressed in CLL cells, when several markers are compounded into a scoring system the results allow firming up of the diagnosis. Other immunological markers, such as CD38 or ZAP-70, have an important prognostic impact. Fluorescence in-situ hybridization (FISH) analysis also provides prognostic information, chiefly by detecting 17 (p53 locus) and 11q deletion, and may determine the type of therapy. PMID- 17707829 TI - Cell proliferation and death: forgotten features of chronic lymphocytic leukemia B cells. AB - Chronic lymphocytic leukemia (CLL) results from an accumulation of abnormal B cells due to an imbalance between birth and death rates such that the former exceeds the latter. This imbalance can occur as a result of increased birth, decreased death, or a combination of the two. CLL has long been considered a disease in which cell accumulation results from decreased death, due to a genetic defect, with minimal birth of the leukemic clone. This view was promulgated when experimental options were limited and observations in vivo and in vitro were less precise--e.g. CLL cells appeared as resting lymphocytes by light microscopy and responded poorly to mitogens (primarily T-cell mitogens)--at a time when T- and B cell discrimination was not well appreciated. However, recent studies using more sophisticated measures suggest that the initial characterization of CLL biology needs re-evaluation. Using a safe, non-radioactive in-vivo labeling method that permits the determination of CLL-cell birth rates, we have directly documented that a small fraction of the clone (approximately 0.1-1.75%), i.e., between approximately 1x10(9) and 1x10(12) cells are born each day in all patients studied. With this value, we calculated death rates of between 0 and 1x10(12) per day of leukemic cells from individual patients. Thus the dynamic interplay between birth and death that characterizes other leukemias and lymphomas applies to CLL. Therefore, CLL is a disease of both proliferation and accumulation in which a homeostatic balance exists in patients with stable lymphocyte counts or an imbalance exists in patients with rising lymphocyte counts. PMID- 17707828 TI - The normal counterpart to the chronic lymphocytic leukemia B cell. AB - Chronic lymphocytic leukemia (CLL) is characterized by the monoclonal expansion of small mature-looking B cells that accumulate in the blood, marrow, and lymphoid organs, and have a remarkable phenotypic homogeneity. By definition, CLL cells co-express CD5 and CD23 with faint to undetectable amounts of monoclonal surface immunoglobulins (sIg). The concept of phenotypic homogeneity has been reinforced by gene expression profiling data, which suggest that the pathogenesis of CLL has to be associated with a fairly common mechanism of transformation. In recent years the biology of CLL has been enriched by an unprecedented flurry of new observations that are leading to a better understanding of the natural history of the disease. Still CLL cells have so far defied any attempt to satisfactorily answer the simple time-honored question of what their cell of origin is. It is the purpose of this review to discuss the features a cell must possess to be considered with reasonable approximation the normal counterpart of a CLL B cell. PMID- 17707830 TI - The B-cell receptor and ZAP-70 in chronic lymphocytic leukemia. AB - In addition to the important observations relating immunoglobulin (Ig) mutation status to clinical behavior, studies on the Ig expressed in chronic lymphocytic leukemia (CLL) have revealed compelling evidence that antigen selection contributes to the pathogenesis of this disease. CLL cells that use unmutated Ig can generally be distinguished from CLL cells that use Ig with somatic mutations by expression of the 70-kD zeta-associated protein (ZAP-70). ZAP-70 apparently enhances the capacity of CLL cells to respond to antigen, and therefore might play a causal role in the relatively aggressive clinical behavior noted for patients who have CLL cells that use unmutated Ig. Clinical surveys have found that expression of ZAP-70 by CLL cells is apparently a stronger predictor of early disease progression than is the use by CLL cells of unmutated Ig. As such, strategies that respectively monitor or target Ig-receptor signaling in CLL might be very useful in the risk assessment or treatment of this disease. PMID- 17707831 TI - The role of microRNA and other non-coding RNA in the pathogenesis of chronic lymphocytic leukemia. AB - New findings support the view that chronic lymphocytic leukemia (CLL) is a genetic disease in which the main alterations occur in a new class of genes named microRNAs (miRNAs). Cases with good prognostic features typically are characterized by miRNA down-regulation of genes miR-15a and miR-16-1, located at 13q14.3. Both microRNAs negatively regulate BCL2 at a post-transcriptional level. On the other hand, in CLL cases that use unmutated immunoglobulin heavy-chain variable-region genes (IgV(H)) or have high-level expression of the 70-kD zeta associated protein (ZAP-70) have high levels of TCL1 due to low-level expression of miR-29 and miR-181, which directly target this oncogene. Conceivably, these miRNAs might be used to target BCL2 or TCL1 for therapy of this disease. PMID- 17707832 TI - Genetics and risk-stratified approach to therapy in chronic lymphocytic leukemia. AB - The clinical staging systems developed by Rai and Binet have remained the mainstay for clinical decision-making in patients with chronic lymphocytic leukemia (CLL). However, there is substantial heterogeneity in the course of the disease. In recent years molecular and cellular markers have helped to predict the prognosis of patients with CLL. Ig V(H) status and genomic aberrations subdivide CLL into distinct clinical subgroups. Fluorescence in-situ hybridization (FISH) can identify genomic aberrations in approximately 80% of CLL cases. The most frequent aberrations are deletions in 13q, 11q, or 17p, and trisomy 12. Apart from providing insights into the pathogenesis, genomic aberrations identify subgroups of patients with distinct clinical pictures: lymphadenopathy (11q-) or resistance to therapy (17p-). Deletions at 11q and particularly 17p are associated with rapid disease progression or inferior survival. Patients with these genetic abnormalities may be candidates for clinical trials investigating alternative treatments and stem-cell transplantation. PMID- 17707833 TI - Prognostic markers in chronic lymphocytic leukaemia. AB - Rai and Binet staging of chronic lymphocytic leukaemia (CLL) is being superseded by new prognostic markers. The mutational status of the immunoglobulin variable region heavy-chain genes segregates the disease into more benign and more malignant versions, and has been confirmed as an important prognostic marker in prospective clinical trials. A search for surrogate markers for this difficult-to perform assay has led to flow cytometric assays for CD38 and ZAP-70 expression, although in both cases there are problems with standardization and interpretation of the assays. A separate pathway of research has revealed two chromosomal aberrations--deletions of 11q and 17p--as important prognostic markers. Fluorescent in-situ hybridization has made their detection readily available. These five markers are in different stages of evaluation, but some of them are ready to be used for risk-adapted therapy in clinical trials. Other assays are in earlier stages of assessment. PMID- 17707834 TI - Revision of the guidelines for diagnosis and therapy of chronic lymphocytic leukemia (CLL). AB - During the past 10 years, significant progress has been achieved in defining new prognostic markers, diagnostic parameters, and treatment options in chronic lymphocytic leukemia (CLL). These developments have led to revision of the National Cancer Institute-sponsored Working Group (NCI-WG) guidelines on CLL established in 1988 and 1996. The update of these guidelines will clarify the role of new prognostic markers in CLL, improve the definitions of response and refractory disease, and add information on the prevention and management of infectious and autoimmune complications. PMID- 17707835 TI - Chemoimmunotherapy of chronic lymphocytic leukemia. AB - The past two decades have seen a major paradigm shift in the therapy of chronic lymphocytic leukemia (CLL), with the treatment goal shifting from symptom palliation to the attainment of maximal disease control using the most effective frontline regimens available, thus prolonging survival and possibly leading to cure. The most potent therapeutic regimens developed to date include the chemoimmunotherapy combinations incorporating purine analogs and monoclonal antibodies. We review the evolution of modern chemoimmunotherapy for CLL, and discuss current research directions for further refining the potency of these regimens. PMID- 17707836 TI - Minimal residual disease assessment in chronic lymphocytic leukaemia. AB - The concept of minimal residual disease (MRD) eradication in chronic lymphocytic leukaemia (CLL) is a relatively new one, as conventional therapy with alkylating agents is relatively ineffective and responding patients almost always have a significant tumour burden remaining at the end of treatment. However, a variety of novel therapies is now yielding higher response rates, and responses of better quality are now routinely achieved. This progress in therapy has been paralleled by an improvement in laboratory assays, allowing detection of CLL cells to levels as low as ten CLL cells in a million leukocytes. In this chapter we briefly review the existing methods for MRD assessment, the clinical relevance of MRD eradication in CLL, and the therapies available to attain this endpoint. PMID- 17707837 TI - Stem-cell transplantation in chronic lymphocytic leukaemia. AB - Excellent response rates are now achieved with modern chemoimmunotherapeutic approaches in chronic lymphocytic leukaemia (CLL), but the disease remains incurable. Younger patients and those with adverse prognostic factors will die from their disease, and are therefore candidates for clinical trials investigating the potential role of haematopoietic stem-cell transplantation (SCT) in the management of their disease. Autologous SCT is feasible and safe, but there is a high incidence of subsequent relapse. Myeloablative allogeneic SCT is associated with high treatment-related morbidity and mortality but few late relapses. Attempts to exploit the graft-versus-leukaemia effect of allogeneic donor cells but to reduce the toxicity are being explored in studies of reduced intensity conditioning allogeneic SCT in CLL. With many potential treatments available, appropriate patient selection and the timing of SCT in the management of CLL remain controversial and the focus of ongoing clinical trials. PMID- 17707838 TI - The role of stem-cell transplantation in chronic lymphocytic leukemia risk adapted therapy. AB - Because of the lack of a curative treatment for chronic lymphocytic leukemia (CLL) and the poor prognosis of patients refractory to the newer and more effective therapies for this disease, stem-cell transplantation (SCT) is being increasingly performed in patients with CLL. The available evidence indicates that autologous SCT may prolong survival in highly selected patients, but does not result in cure. Conversely, allogeneic SCT may cure a proportion of patients, including those who are refractory to purine-analog-based therapy or with other unfavorable risk parameters, but at the cost of high morbidity and mortality. Reduced-intensity conditioning (non-myeloablative) regimens may contribute to reducing toxic deaths while preserving the antileukemic effect of the allograft, and results are encouraging in patients with chemosensitive disease. Ongoing randomized studies will hopefully contribute to clarification of the role of SCT in the management of CLL. Meanwhile, SCT in patients with CLL should be performed only within clinical studies. PMID- 17707839 TI - Novel agents and strategies for treatment of p53-defective chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is a common leukemia with a highly variable natural history. A subset of patients with high-risk CLL rapidly progress to develop symptomatic disease requiring treatment. Over-represented in this group are those who have a deletion of 17p13.1, the chromosomal location of the tumor suppressor gene P53. Of all prognostic factors examined in CLL, del(17p13.1) has a superior predictive value for poor response to conventional therapy. In this article we review the current published data on prognostic factors relevant to treatment in CLL. We next provide therapeutic recommendations for patients with del(17p13.1) that are available to oncologists in general practice. Chemoimmunotherapy, alemtuzumab, or high-dose corticosteroids are all effective as initial therapy for these patients, but progression is generally rapid. If allogeneic immune therapy is to be considered, it should be approached as part of initial or first salvage therapy. The investigational agent flavopiridol has also demonstrated clinical activity in this subset of patients. Identification of small molecules and new treatment approaches for patients with del(17p13.1) is a major focus of several investigators. Selection of therapy based on high-risk genomic features represents an appropriate treatment approach supported by currently available published data. PMID- 17707840 TI - Gene therapy and active immune therapy of hematologic malignancies. AB - Gene therapy for patients with hematologic malignancies, particularly chronic lymphocytic leukemia (CLL), have focused on transducing primary leukemia cells with a virus vector to express immune-stimulating genes which can induce and propagate a productive and clinically significant immune response against the malignant cells. A variety of replication-defective vectors has been studied to transduce genes for cytokines and function-associated surface molecules. Active vaccines have been developed in vitro, and their activity has been confirmed in clinical trials. Ongoing work aims to optimize this strategy and to identify the appropriate and optimal patient groups in which to apply vaccine therapy. Clinical trials also have provided insight into unexpected alternative mechanisms through which these strategies might provide a clinical benefit. PMID- 17707842 TI - The tip of the spear. PMID- 17707841 TI - Gender-enriched transcripts in Haemonchus contortus--predicted functions and genetic interactions based on comparative analyses with Caenorhabditis elegans. AB - In the present study, a bioinformatic-microarray approach was employed for the analysis of selected expressed sequence tags (ESTs) from Haemonchus contortus, a key parasitic nematode of small ruminants. Following a bioinformatic analysis of EST data using a semiautomated pipeline, 1885 representative ESTs (rESTs) were selected, to which oligonucleotides (three per EST) were designed and spotted on to a microarray. This microarray was hybridized with cyanine-dye labelled cRNA probes synthesized from RNA from female or male adults of H. contortus. Differential hybridisation was displayed for 301 of the 1885 rESTs ( approximately 16%). Of these, 165 (55%) had significantly greater signal intensities for female cRNA and 136 (45%) for male cRNA. Of these, 113 with increased signals in female or male H. contortus had homologues in Caenorhabditis elegans, predicted to function in metabolism, information storage and processing, cellular processes and signalling, and embryonic and/or larval development. Of the rESTs with no known homologues in C. elegans, 24 ( approximately 40%) had homologues in other nematodes, four had homologues in various other organisms and 30 (52%) had no homology to any sequence in current gene databases. A genetic interaction network was predicted for the C. elegans orthologues of the gender enriched H. contortus genes, and a focused analysis of a subset revealed a tight network of molecules involved in amino acid, carbohydrate or lipid transport and metabolism, energy production and conversion, translation, ribosomal structure and biogenesis and, importantly, those associated with meiosis and/or mitosis in the germline during oogenesis or spermatogenesis. This study provides a foundation for the molecular, biochemical and functional exploration of selected molecules with differential transcription profiles in H. contortus, for further microarray analyses of transcription in different developmental stages of H. contortus, and for an extended functional analysis once the full genome sequence of this nematode is known. PMID- 17707843 TI - Male versus female genital alteration: differences in legal, medical, and socioethical responses. AB - The different legal, social, and medical approaches to ritually based male and female genital circumcision in the United States are highlighted in this article. The religious and historical origins of these practices are briefly examined, as well as the effect of changing policy statements by American medical associations on the number of circumcisions performed. Currently, no state or federal laws single out male circumcision for regulation. The tolerant attitudes toward male circumcision in law, medicine, and societal opinion stand in striking contrast to the attitudes of those disciplines toward even the least invasive form of female genital alteration. US law tacitly condones male circumcision by providing exemptions that are not available for other medical procedures, while criminalizing any similar or even less extensive procedure on females. The increase in immigration, over the past few decades, of people from countries in which female genital alteration is a cultural tradition has brought the issue to the United States. The medical profession's changing approach over time toward male circumcision is primarily responsible for such different legal and societal reactions toward female genital alteration. PMID- 17707844 TI - Why females are mosaics, X-chromosome inactivation, and sex differences in disease. AB - At every age, males have a higher risk of mortality than do females. This sex difference is most often attributed to the usual suspects: differences in hormones and life experiences. However, the fact that XY males have only one X chromosome undoubtedly contributes to this vulnerability, as any mutation that affects a gene on their X chromosome will affect their only copy of that gene. On the other hand, cellular mosaicism created by X inactivation provides a biologic advantage to females. There are 1100 genes on the X chromosome, and most of them are not expressed from the Y chromosome. Therefore, sex differences in the expression of these genes are likely to underlie many sex differences in the expression of diseases affected by these genes. In fact, this genetic biology should be considered for any disease or phenotype that occurs in one sex more than the other, because the disease mechanism may be influenced directly by an X linked gene or indirectly through the consequences of X inactivation. PMID- 17707845 TI - Antiretroviral pharmacokinetic profile: a review of sex differences. AB - BACKGROUND: Emerging evidence suggests that female sex may be associated with increased risk of developing antiretroviral toxicities. Although the mechanisms of sex-related antiretroviral pharmacodynamic differences remain poorly understood and may be multifactorial, they appear to be mediated through a common pathway of pharmacokinetic variability between the sexes. OBJECTIVE: This article reviews sex differences in the pharmacokinetics of the major classes of antiretroviral drugs currently approved for HIV treatment by the US Food and Drug Administration, identifies knowledge gaps, and provides recommendations for future research directions. METHODS: To identify pertinent articles for this review, the MEDLINE database was searched from 1990 to June 2006 using the terms sex, gender, antiretroviral therapy, ART, HAART, pharmacokinetics, pharmacodynamics, NRTI, NNRTI, and protease inhibitors. Search results were restricted to English language and human studies. The reference lists of identified articles were also used, as well as abstracts from relevant conferences. In addition, individual antiretroviral drugs were searched by sex/gender or by pharmacokinetics. RESULTS: Current evidence, though limited, does suggest the existence of a sex disparity in antiretroviral pharmacokinetics, and such disparity has been shown to have pharmacodynamic implications for some drugs. Sex-mediated intracellular pharmaco-enhancement was associated with superior antiviral activities for the zidovudine and lamivudine members of the nucleoside reverse transcriptase inhibitor class. There appears to be divergent opinions about whether sex is a significant determinant of either nevirapine or efavirenz plasma concentrations. For certain protease inhibitors (PIs) (eg, saquinavir [SQV] and indinavir [IDV]), clinically significant relationships between sex differences in plasma drug concentrations and clinical outcomes have been observed. There appears to be a trend toward higher drug exposure in women than in men when PIs are boosted with ritonavir (RTV). Nelfinavir, the only PI that is currently administered unboosted with RTV, does not exhibit a sex difference in its plasma concentrations. Unboosted amprenavir exposure was lower in women compared with men. Sex differences in the pharmacokinetics of SQV and IDV were observed only in the setting of RTV boosting. CONCLUSIONS: A common weakness in many studies addressing sex-based differences in the pharmacokinetics of antiretroviral drugs is the relatively small number of women participating. Many of these studies were retrospective in design, and some had limited pharmacokinetic parameters for comparison. Antiretroviral treatment trials should be designed with sufficient power (adequate female participation) to detect sex based differences both in pharmacokinetics and in clinical response. Future studies should explore the molecular basis for sex-based differences in plasma drug concentrations and antiretroviral drug response. The roles of drug transporter proteins and cellular kinases, and the activities of metabolizing enzymes in mediating differential plasma and intracellular antiretroviral concentrations, should be further assessed. PMID- 17707846 TI - Gender differences in dementia risk factors. AB - BACKGROUND: With the aging of the population, dementia has become an important health concern in most countries. There is a growing body of literature on the importance of cardiovascular risk factors in the development of Alzheimer's disease (AD), vascular dementia, and mixed dementia (AD with cerebrovascular disease). OBJECTIVE: This article reviews the role of major risk factors in dementia between both sexes. METHODS: The MEDLINE, PubMed, and HealthSTAR databases were searched between 1966 and January 2007 for English-language articles on the risk factors for dementia. RESULTS: The distribution and prevalence of major risk factors between the sexes and age groups are varied. Female sex has been associated with increased risk of the development of AD. In women aged >75 years, rates of hypertension, hyperlipidemia, and diabetes are higher than in similarly aged men. Apolipoprotein E epsilon 4 genotype status appears to have a greater deleterious effect on gross hippocampal pathology and memory performance in women compared with men. Midlife hypertension and hypercholesterolemia in both sexes predict a higher risk of developing AD in later life. Diabetes is increasing in frequency to a greater extent in women than in men, and is associated with a substantial risk for cognitive impairment. Dementia in women (probably) and in men (possibly) is influenced by obesity in the middle of life. CONCLUSIONS: It remains critical that large prospective clinical trials be designed to assess the effect of optimum management of vascular risk factors on cognitive functioning and dementia as the primary outcome, and include women and men in numbers adequate for assessment of gender effects. PMID- 17707847 TI - Peripheral circulatory responses in vivo from regional brachial biceps and lumbar muscles in healthy men and women during pushing and pulling exercise. AB - BACKGROUND: Although women have been performing increasingly more manual labor in the workplace in the past 2 decades, their physiological responses and gender based differences in muscle microvascularity during occupational activities have not yet been extensively documented. OBJECTIVE: This study assessed gender differences and tissue heterogeneity in peripheral circulatory responses from 2 muscle groups during pushing and pulling exercise until volitional exhaustion. METHODS: In healthy men and women, near-infrared spectroscopy was used to determine peripheral responses, oxygenation, and blood volume simultaneously from the right biceps brachii and lumbar erector spinae. Pulmonary oxygen uptake was assessed using a metabolic measurement cart. RESULTS: Although the 11 men who participated in the study demonstrated greater pulmonary oxygen uptake and power output at volitional exhaustion, their peak peripheral responses for both muscles were similar to those of the 11 women participating. In both sexes, oxygenations trends decreased in both muscles with an increase in workload. However, whereas blood volume increased in the biceps, it decreased in the lumbar muscle in both sexes. At 20% to 60% levels of peak pulmonary oxygen uptake, the percent change in peripheral bicep responses was greater for men than for women (P < 0.05). In contrast, women demonstrated greater change in lumbar muscle oxygenation compared with men at 40% to 60% of peak pulmonary oxygen uptake (P < 0.05). CONCLUSIONS: Similar peripheral responses for biceps and lumbar muscles at the point of volitional exhaustion suggest that gender differences in pulmonary oxygen uptake are independent of oxygen extraction or delivery across the muscle groups monitored. However, at submaximal levels of exercise, the peripheral changes in each muscle were gender dependent. Although biceps and lumbar muscles are 2 discrete muscle groups, based on the heterogeneity found in the blood volume trends it is likely that oxygen supply and demand are regulated by muscle location and muscle fiber characteristics. Overall, gender-based assessment of occupational activities should incorporate both pulmonary and peripheral circulatory responses to understand each sex's performance effectiveness. PMID- 17707848 TI - High frequency of anxiety and angina pectoris in depressed women with coronary heart disease. AB - BACKGROUND: Depression is an unfavorable state that is difficult to recognize in patients with coronary heart disease (CHD). Little is known about the characteristics of depressed female CHD patients. OBJECTIVE: The purpose of this study was to investigate the occurrence of depressive symptoms in women entering a cardiac rehabilitation program, and furthermore, to examine whether women who have CHD and depressive symptoms display any unfavorable physical or psychological characteristics that could be helpful in identifying female CHD patients at increased risk of depression. METHODS: In a Swedish cross-sectional survey of Swedish women entering a randomized, female cardiac rehabilitation trial, patients with a Beck Depression Inventory (BDI) score indicating depression were compared with patients without depressive symptoms. RESULTS: Of the 121 women with CHD who participated in the study, 23.1% had BDI scores consistent with moderate to severe depression (BDI > or =19). Scores of > or =19 were strongly correlated to established angina pectoris (P = 0.007) and higher rates of anxiety on the Beck Anxiety Inventory (P < 0.001). Depressed women also were more likely to have a family history of heart disease (P = 0.036) and were less likely to care for their health in the future (P = 0.005). CONCLUSIONS: This study suggests a strong relationship between depression and angina pectoris in women with CHD. The study also confirms previous findings that depressive symptoms are common in women with CHD. Findings of more pronounced cardiac symptoms in depressed women with CHD suggest that depressive symptoms may present differently or alter cardiac symptoms in female CHD patients. Consequently, the occurrence of increased cardiac symptoms indicates the need to screen for depression, whether depressive symptoms are apparent or not. The higher scores for anxiety in depressed women with CHD and their poorer health care practices, in combination with their more pessimistic beliefs about lifestyle changes, highlight the need to identify depression to enhance adherence to treatment regimens in the cardiac rehabilitation process. PMID- 17707849 TI - Sex hormones and aortic wall remodeling in an arteriovenous fistula. AB - BACKGROUND: An arteriovenous fistula (AVF) creates high blood flow through the artery and fistula. With this high flow, there is flow-induced remodeling and an increase in diameter, but no intimal hyperplasia. Estrogen has been shown to modify vascular remodeling, decreasing intimal hyperplasia after endothelial injury. OBJECTIVE: These experiments tested the hypothesis that estrogen administration would decrease wall thickness in an AVF model. Because estrogen may decrease wall thickness, we also tested the hypothesis that testosterone would increase wall thickness. METHODS: A fistula was created between the abdominal aorta and the inferior vena cava in Sprague-Dawley rats to generate high blood flow conditions in the aorta. Four groups of female animals were examined: sham, control with AVF ovariectomized (OVX) with AVF and OVX plus testosterone with AVF Four groups of male animals were also examined: sham, control with AVF castrated with AVF and castrated plus estrogen with AVF Five weeks after creation of the AVF, the aortas were collected and fixed; wall thickness was measured both proximal and distal to the AVF. RESULTS: Ovariectomy resulted in a significant decrease in estrogen levels (P < 0.01). Testosterone administration tended to increase testosterone levels in the OVX females, but values did not approach levels observed in the control males. No difference was noted in the proximal wall thickness between the control and the OVX animals. The OVX females receiving testosterone exhibited a significant increase in both proximal and distal wall thickness compared with control females (P < 0.001). In the male animals, there was no significant change in aortic wall thickness in the castrated rats compared with the controls. Estrogen administration in the castrated males resulted in a significant decrease in wall thickness in the proximal and distal aorta (P < 0.05). CONCLUSION: These studies suggest that, in a model of vascular remodeling, estrogen administration decreases wall thickness, and testosterone administration increases wall thickness. PMID- 17707850 TI - Early inequalities in excellent health and performance among young adult women and men in Sweden. AB - BACKGROUND: Although health inequality between young adult women and men has been strikingly evident in symptoms of ill health, we found no studies examining these inequalities with a focus on positive health and performance. OBJECTIVE: The aim of the present study was to examine possible inequalities between young adult women and men in a combined assessment of positive health and health-related performance. METHODS: Women and men aged 18 to 25 years studying medicine or computer science at 6 colleges/universities in 5 cities in Sweden were recruited for this study. All respondents answered a Web-based questionnaire regarding health, health-related performance, information and communication technology exposure, mood, and individual factors. A combined assessment of excellent health and health-related performance (EHHP) was defined and tested. Prevalence ratios (PRs) with 95% CIs of EHHP were calculated separately for female and male respondents. To assess potential determinants of EHHP, differences in the relationships between EHHP and the explanatory factors were compared for both sexes. RESULTS: In a study group of young adult students consisting of 1046 women and 1312 men, women were less likely than men to have EHHP (PR 0.90 [95% CI, 0.83 0.98]). This inequality was even stronger within each course of study (medicine or computer science). Health-related factors showed similar patterns of relationship to EHHP for women and men; however, the strength of these relationships differed between the sexes. Logical relationships were observed between EHHP and almost all of the symptoms as well as between EHHP, the mood index, and health-related behavior. CONCLUSIONS: The well-known inequality in symptoms of ill health between young adult women and men was prevalent even in a combined assessment of positive health and health-related performance. That this inequality was prevalent in a relatively homogeneous sample of young adults indicates the importance of gender-based psychological and psychosocial factors beyond the more well-known structural gender-differentiating factors of vertical and horizontal segregation and disproportional responsibilities for domestic work. It may therefore be essential to emphasize these gender-based psychological and psychosocial factors when designing future studies and health promotion programs. PMID- 17707851 TI - Effects of Levosimendan on circulating markers of oxidative and nitrosative stress in patients with advanced heart failure. AB - BACKGROUND: Oxidative stress is associated with maladaptive cardiac remodeling and vascular dysfunction and may be an important contributor to chronic heart failure (CHF) deterioration. We sought to investigate if the calcium sensitizer levosimendan beneficially modulates circulating markers of oxidative and nitrosative stress thus lessening their deleterious effects in patients with advanced CHF. METHODS: Thirty-nine patients with advanced CHF (mean NYHA 3.5+/ 0.4; ischemic/dilated: 23/16; mean left ventricular ejection fraction: 26+/-7%) who were hospitalized due to syndrome worsening, were randomized (2:1) to receive either a 24-h levosimendan infusion of 0.1 microg/(kg min) (n=26) or placebo (n=13). Plasma b-type natriuretic peptide (BNP), circulating markers of oxidative [protein carbonyls, malondialdehyde (MDA)] and nitrosative (nitrotyrosine) stress, and cyclic GMP (cGMP) were measured at baseline and 48 h after each treatment. RESULTS: Baseline characteristics and medications were well balanced in the two treatment groups. A significant improvement in left ventricular ejection fraction (P<0.01), NYHA class (P<0.01), and plasma BNP (P<0.01) was observed post-treatment only in the levosimendan group. Markers such as MDA, protein carbonyls and nitrotyrosine remained stable in the levosimendan-treated group, but significantly increased (P<0.05) in the placebo-treated patients. Neither therapeutic intervention changed the levels of circulating cGMP. CONCLUSION: Levosimendan does not increase markers of oxidative and nitrosative stress in contrast to the placebo treatment, thus, exerting cardioprotective effects in advanced CHF patients. Moreover, levosimendan may exert its biologic action through non-cGMP-dependent biochemical pathways. PMID- 17707852 TI - Experimental implementation of automatic 'cycle to cycle' control of a chiral simulated moving bed separation. AB - In the absence of a suitable controller, currently simulated moving beds (SMBs) are operated suboptimally to cope with system uncertainties and to guarantee robustness of operation. Recently, we have developed a 'cycle to cycle' optimizing controller that not only makes use of minimal system information, i.e. only the Henry constants and average bed voidage, but also optimizes the process performance and taps the full economic potential of the SMB technology. The experimental implementation of the 'cycle to cycle' optimizing controller had been carried out for achiral separation. For chiral separation however, application of any online controller has not been possible because an appropriate online monitoring system has not been available. This work reports and discusses the first experimental implementation of the 'cycle to cycle' optimizing control for chiral separations. A mixture of guaifenesin enantiomers is separated on Chiralcel OD columns with ethanol as mobile phase in a eight-column four sections laboratory SMB unit. The results show that the controller, although using minimal information about the retention of the two enantiomers, is able to meet product and process specifications, can optimize the process performance, and is capable of rejecting disturbances that may occur during the operation of the SMB plant. PMID- 17707853 TI - Composite films of lecithin and heme proteins with electrochemical and electrocatalytic activities. AB - Functional composite films made from lecithin micelles and the two heme proteins of met-myoglobin (Mb) and met-hemoglobin (Hb) are reported in this paper. Proteins in functional composite films have much higher rates of electron transfer than proteins in solutions on carbon paste (CP) electrodes. Cyclic voltammograms (CVs) all give a pair of well-defined and quasi-reversible peaks, corresponding to the heme FeIII/FeII redox couple of proteins. Differential pulse voltammograms (DPVs) also show the same formal potential (E0') values of proteins under identical conditions. Electronic and vibrational spectra indicate that proteins in these films are not denatured, but their conformational differences from native states may exist. The E0' value for Mb in the lecithin film is found to be pH dependent. The Mb lecithin film can catalytically reduce O2 and H2O2, and its analytical application to H2O2 determination is established. PMID- 17707854 TI - Counterion and composition effects on discotic nematic lyotropic liquid crystals I. Size and order. AB - Counterion and composition effects on the size and interface dynamics of discotic nematic lyotropic liquid crystals made of tetradecyltrimethylammonium halide (TTAX)-decanol (DeOH)-water-NaX, with X = Cl(-) and Br(-), were investigated using NMR and fluorescence spectroscopies. The dynamics of the interface was examined by measuring deuterium quadrupole splittings from HDO (0.1% D(2)O in H(2)O) and 1,1-dideuterodecanol (20% 1,1-dideuterodecanol in DeOH) in 27 samples of each liquid crystal. Aggregation numbers, N(D), from 15 samples of each mesophase were obtained using the fluorescence of pyrene quenched by hexadecylpyridinium chloride. N(D) of TTAB and TTAC are about 230+/-30 and 300+/ 20, respectively. N(D) of TTAC increases with increasing concentration of all mesophase components, whereas TTAB shows no correlation between size and composition. The dimension of these aggregates prevents the occurrence of undulations, previously observed in lamellar phases. The quadrupole splitting of decanol-d(2) in TTAC is about 5 kHz smaller than in TTAB, and the splitting of HDO is observed only in TTAB. All results are consistent with a more dynamic TTAC interface. The TTAC aggregate should be more dissociated from counterions and the excess ammonium-ammonium electrostatic repulsions contribute to increase the mobility of the interface components. PMID- 17707855 TI - Thermodynamic quantities of surface formation of aqueous electrolyte solutions VII. Aqueous solution of alkali metal nitrates LiNO3, NaNO3, and KNO3. AB - To compare the effect of nitrate anions on the surface tension increments of aqueous solutions with that of halide anions, the surface tension of aqueous solutions of lithium nitrate, sodium nitrate, and potassium nitrate was measured as a function of temperature and concentration. It is shown that the surface tension of aqueous alkali metal nitrate solutions is determined primarily by the kinds of anions, since the surface tension increments of these nitrates were of the same magnitude. The importance of the electrical double layer at the surface is discussed in relation to these surface tension increments. PMID- 17707856 TI - Interfacial properties of heat-treated ovalbumin. AB - The interfacial properties (kinetics of adsorption at the air/water interface, rheology of the interfacial layer) of ovalbumin molecules, unheated or previously heat-denatured in solution (10 g L(-1), pH 7, NaCl 50 mM) under controlled conditions (up to 40 min at 80 degrees C), were investigated. Heat treatments induced the formation of covalent aggregates which surface exhibits a higher hydrophobicity and an increased exposition of sulfhydryl groups when compared to native ovalbumin (unheated). Although they have a larger hydrodynamic size, aggregates adsorb as fast as native ovalbumin at the air/water interface. However, aggregates are able to established rapid contacts in the interfacial layer as shown by the fast increase of both surface pressure and shear elastic constant. In contrast, native ovalbumin needs longer time to developed intermolecular contacts and exhibits lower foam stability even if the shear elastic constant on aging reached higher value than for ovalbumin aggregates. PMID- 17707857 TI - Dewetting and surface properties of ultrathin films of cellulose esters. AB - Surface properties of ultrathin films of cellulose esters deposited onto silicon wafers have been investigated by means of contact angle measurements and atomic force microscopy (AFM). Cellulose acetate (CA), cellulose acetate propionate (CAP), and cellulose acetate butyrate (CAB) films adsorbed or spin-coated onto Si wafers were annealed up to one week. Film stability was monitored by AFM. Dewetting has been observed for CA and CAP. Only CAB films with lower degree of esterification presented dewetting, CAB films with high degree of butyrate were stable even after one week annealing. Surface energy of CA, CAP, and CAB was indirectly determined by contact angle measurements using drops of water, formamide and diiodomethane. The surface energy decreased as the size of alkyl ester group or the degree of esterification increased because van der Waals interactions became weaker. Effective Hamaker constant A(eff) was calculated for CA, CAP, and CAB onto Si wafers in air. Negative values of A(eff) were found for CA, CAP, and lower butyrate content CAB, which are related to instability and agree with dewetting phenomena observed by AFM. In contrast, a positive A(eff) was determined for higher butyrate content CAB, corroborating with experimental observations. PMID- 17707858 TI - Nonideal mixed micelles of Gemini surfactant homologues and their application as templates for mesoporous material MCM-48. AB - The micellization properties of aqueous solutions of the mixed Gemini surfactant homologues GEM16-6-16 and GEM16-12-16 with various compositions were investigated. The measured critical micelle concentration (CMC) deviated significantly from the ideal mixing model. Good agreement was found with a nonideal mixing model, the Margules model, which has two optimal parameters, A12= 3.611 and A21=-6.318. It was shown that the properties of mixed micelles were not sensitive to the compositions, and most of the GEM16-12-16 molecules were aggregated into the micelles. Dynamic laser light-scattering measurements revealed that the mixed micelles had almost the same size and similar zeta potential. When the mixed micelles were used as templates, a series of highly ordered cubic MCM-48 mesoporous materials, characterized by XRD and TEM, were produced through self-assembly. The N2 adsorption-desorption measurements suggested that the pores of these materials had similar average diameters of 2.2 2.5 nm. This further demonstrated the nonideal behavior of the homologue mixture. PMID- 17707859 TI - The synthesis of mesoporous aluminosilicate using microcline for adsorption of mercury(II). AB - An economical mesoporous aluminosilicate was synthesized with microcline as starting material and the precursor 13X zeolite as seed for crystal structure on mesoporous walls. In this method, a mixture of microcline and Na2CO3 with a molar ratio of 1:1.05 was first calcined at 1093 K for 2.5 h. The calcined materials were mixed with 35 ml C16TMABr aqueous solution (containing 8.2 g C16TMABr) and the precursors of 13X zeolite, resulting in mesoporous aluminosilicate after crystallization of the solution at 378 K for 48 h and calcination of the powder at 823 K for 5 h. The as-synthesized sample has a uniform pore diameter distribution centered at 3.7 nm. The as-synthesized sample had BET surface area of 725 m2/g and BJH mean pore diameter of 3.7 nm. The FT-IR results revealed that the building units of 13X zeolite were inserted into the pore walls of the as synthesized sample. The adsorption ratio of mercury(II) onto the as-synthesized adsorbent was about 95%. The adsorption process was found to be spontaneous and can be explained by particle diffusion and chemical ion-exchange mechanisms. The equilibrium concentration of mercury(II) using the as-synthesized sample as the adsorbent was under 1 microg/L, making the concentration of mercury meet the limit for drinking water in China as recommended by the World Health Organization. PMID- 17707860 TI - High-resolution structure of the major periplasmic domain from the cell shape determining filament MreC. AB - Bacterial cell shape is dictated by the cell wall, a plastic structure that must adapt to growth and division whilst retaining its function as a selectively permeable barrier. The modulation of cell wall structure is achieved by a variety of enzymatic functions, all of which must be spatially regulated in a precise manner. The membrane-spanning essential protein MreC has been identified as the central hub in this process, linking the bacterial cytoskeleton to a variety of cell wall-modifying enzymes. Additionally, MreC can form filaments, believed to run perpendicularly to the membrane. We present here the 1.2 A resolution crystal structure of the major periplasmic domain of Streptococcus pneumoniae MreC. The protein shows a novel arrangement of two barrel-shaped domains, one of which shows homology to a known protein oligomerization motif, with the other resembling a catalytic domain from a bacterial protease. We discuss the implications of these results for MreC function, and detail the structural features of the molecule that may be responsible for the binding of partner proteins. PMID- 17707861 TI - Structures of smooth muscle myosin and heavy meromyosin in the folded, shutdown state. AB - Remodelling the contractile apparatus within smooth muscle cells allows effective contractile activity over a wide range of cell lengths. Thick filaments may be redistributed via depolymerisation into inactive myosin monomers that have been detected in vitro, in which the long tail has a folded conformation. Using negative stain electron microscopy of individual folded myosin molecules from turkey gizzard smooth muscle, we show that they are more compact than previously described, with heads and the three segments of the folded tail closely packed. Heavy meromyosin (HMM), which lacks two-thirds of the tail, closely resembles the equivalent parts of whole myosin. Image processing reveals a characteristic head region morphology for both HMM and myosin, with features identifiable by comparison with less compact molecules. The two heads associate asymmetrically: the tip of one motor domain touches the base of the other, resembling the blocked and free heads of this HMM when it forms 2D crystals on lipid monolayers. The tail of HMM lies between the heads, contacting the blocked motor domain, unlike in the 2D crystal. The tail of whole myosin is bent sharply and consistently close to residues 1175 and 1535. The first bend position correlates with a skip in the coiled coil sequence, the second does not. Tail segments 2 and 3 associate only with the blocked head, such that the second bend is near the C-lobe of the blocked head regulatory light chain. Quantitative analysis of tail flexibility shows that the single coiled coil of HMM has an apparent Young's modulus of about 0.5 GPa. The folded tail of the whole myosin is less flexible, indicating interactions between the segments. The folded tail does not modify the compact head arrangement but stabilises it, indicating a structural mechanism for the very low ATPase activity of the folded molecule. PMID- 17707863 TI - Mathematical analysis of an integral equation arising from population dynamics. AB - In this paper, we establish the existence of travelling wave solution to an intrinsically non-linear differential-integral equation formed as a result of mathematical modelling of the evolution of an asexual population in a changing environment. This equation is first converted to a non-linear integral equation. The discretization and manipulation of the corresponding eigenvalue problem allows us to use the theory of positive matrices to get some very useful estimates and then to confirm the existence of solution. We also exhibit numerical simulation results and explain the biological meaning of the results. PMID- 17707865 TI - [Cystic meningioma. Case report and literature review]. AB - BACKGROUND: Cystic meningioma is a rare variety of meningioma. It represents 1,6 to 10% of intracranial meningiomas, the authors report a case of intracranial cystic meningioma with a review of literature. CASE REPORT: A 46-year-old female presented with left parietooccipital headache followed by right side hemiparesis. CT scan brain showed a left parietal tumor with double solid and cystic components thought to be glioma or metastasis preoperatively. At surgery the extraaxial solid and cystic lesion had a well defined capsule that could be easily separated from the perilesional cortical surface. The tumor was totally removed. The histological study showed a cystic meningioma. CONCLUSION: Cystic meningioma is an uncommon tumor that should be considered in the differential diagnosis of brain tumors with a cystic component. PMID- 17707866 TI - [Fractionated stereotactic radiotherapy for optic nerve sheath meningioma: eight cases]. AB - Optic nerve sheath meningioma (ONSM) accounts for one-third of primary optic nerve tumors, and 2% of all meningiomas. ONSM must be distinguished from other meningiomas, in particular from cavernous meningiomas because of the different prognosis and treatment. The most frequent clinical sign is a progressive or sudden unilateral visual loss. Treatment of ONSM is still subject to discussion. This report covers a series of eight ONSM patients treated with fractionated stereotactic radiotherapy. MATERIAL AND METHODS: Between 2000 and 2006, we managed eight patients with ONSM. The average patient age was 47 years. There were five women and three men. The most frequent clinical signs were visual loss (100%), proptosis (35%), diplopia (25%). One patient was initially treated with surgery. All patient have been treated by fractionated stereotactic radiotherapy. 45 Gy in 25 fractions were delivered on the meningioma area at a rate of 5 fractions of 1.8 Gy per week. We used a Brainlab framework associated with a thermo-formed mask. A computed tomography then magnetic resonance imaging was obtained for each patient. The data was merged and planning took place on a Brainlab dosimetric console. The treatment was performed with a head-only Varion linear accelerator, with a Brainlab multi-blade collimator. RESULTS: The average follow-up was 27 months. Each patient had a complete radiological and ophthalmologic exam every 3 months during the first year, then every 6 months thereafter. Tumor control rate was 100%. Vision was re-established in five patients and three patients had improvement, including one patient during treatment. 100% of proptosis and diplopias regressed. No side effect was reported. CONCLUSION: This is still a preliminary study, but the results suggest that fractionated stereotactic radiotherapy may emerge as a primary treatment for ONSM, delaying surgery, which has proven functionally disappointing. PMID- 17707867 TI - [Paraganglioma of the cavernous sinus. Case report]. AB - A case of paraganglioma arising from the cavernous area is presented. A 51-year old woman presented with a parasellar mass causing decreased visual acuity, oculomotor nerve paresis and retro-orbital headaches without endocrinological dysfunction. Diagnosis was confirmed by histological appearance and electron microscopy. The patient was treated with surgery followed by radiation therapy consisting of 45 Gy. The clinicopathological features and the possible pathogenesis are discussed. PMID- 17707862 TI - Factors in the pathophysiology of the liver ischemia-reperfusion injury. AB - Hepatic ischemia-reperfusion injury is commonplace in liver surgery, particularly in hepatic transplantation, hepatic resection, and trauma. The signaling events contributing to local hepatocellular damage are diverse and complex and involve the interaction between hepatocytes, sinusoidal endothelial cells, Kupffer cells, as well as infiltrating neutrophils, macrophages, and platelets. Signaling mediators include cytokines, reactive oxygen and nitrogen species, calcium, complement, and several transcription factors. The purpose of this review article was to summarize the factors that contribute to the pathophysiology of hepatic ischemia-reperfusion injury. PMID- 17707868 TI - Cannabinoid receptor-mediated translocation of NO-sensitive guanylyl cyclase and production of cyclic GMP in neuronal cells. AB - Cannabinoid agonists regulate NO and cyclic AMP production in N18TG2 neuroblastoma cells, leading to the hypothesis that neuronal cyclic GMP production could be regulated by CB(1) cannabinoid receptors. NO (nitric oxide) sensitive guanylyl cyclase (GC) is a heterodimeric cytosolic protein that mediates the down-stream effects of NO. Genes of proteins in the cyclic GMP pathway (alpha(1), alpha(2), and beta(1) subunits of NO-sensitive GC and PKG1, but not PKG2) were expressed in N18TG2 cells, as was the CB(1) but not the CB(2) cannabinoid receptor. Stimulation of N18TG2 cells by cannabinoid agonists CP55940 and WIN55212-2 increased cyclic GMP levels in an ODQ-sensitive manner. GC-beta(1) in membrane fractions was increased after 5 or 20 min stimulation, and was significantly depleted in the cytosol by 1h. The cytosolic pool of GC-beta(1) was replenished after 48 h of continued cannabinoid drug treatment. Translocation of GC-beta(1) from the cytosol was blocked by the CB(1) antagonist rimonabant (SR141716) and by the Gi/o inactivator pertussis toxin, indicating that the CB(1) receptor and Gi/o proteins are required for translocation. Long-term treatment with rimonabant or pertussis toxin reduced the amount of GC-beta(1) in the cytosolic pool. We conclude that CB(1) receptors stimulate cyclic GMP production and that intracellular translocation of GC from cytosol to the membranes is intrinsic to the mechanism and may be a tonically active or endocannabinoid regulated process. PMID- 17707869 TI - Inefficient executive cognitive control in schizophrenia is preceded by altered functional activation during information encoding: an fMRI study. AB - Working memory deficits are a core feature of schizophrenia. Previous working memory studies suggest a load dependent storage deficit. However, explicit studies of higher executive working memory processes are limited. Moreover, few studies have examined whether subcomponents of working memory such as encoding and maintenance of information are differentially affected by these deficits. Therefore, the aim of the present study was to examine the neural substrates of working memory subprocesses requiring stimulus encoding, maintenance and higher executive processing. Using functional magnetic resonance imaging a modified Sternberg working memory task involving verbal stimulus material was applied. The event-related design enabled the segregation of encoding, active maintenance and executive manipulation of information. Forty-one patients with schizophrenia and 41 healthy subjects were included. Relative to normal controls, schizophrenic patients demonstrated a significantly stronger activation pattern in a fronto parietal network during executive information manipulation. Additionally, significant relative hypoactivity was detectable in the thalamus. Conversely, during stimulus encoding the patients demonstrated lower activation relative to controls in the prefrontal cortex and the anterior cingulate gyrus. The present findings indicate a pronounced prefrontal functional hyperactivation within the neural network subserving higher executive working memory control processes in schizophrenia. Moreover, they suggest that these altered activations during executive control are related to a preceding abnormality of information encoding. During encoding, a reduced activation in mainly dorsolateral prefrontal and anterior cingulate regions was observed. These results could be explained by increased top-down control processing from prefrontal cortex as a compensation for functional deficits occurring during encoding. PMID- 17707871 TI - Flavaglines and triterpenoids from the leaves of Aglaia forbesii. AB - Three structurally complex flavaglines of the cyclopenta[bc]benzopyran type, named desacetylpyramidaglains A, C, D (1-3), and the triterpene 23, 24, 25 trihydroxycycloartan-3-one (4) were isolated from the leaves of Aglaia forbesii together with the two rare pregnane steroids 2beta,3beta-dihydroxy-5alpha-pregn 17(Z)-en-16-one and 2beta,3beta-dihydroxy-5alpha-pregn-17(E)-en-16-one, as well as the bisamide pyramidatine, the sesquiterpene spathulenol, and the widespread triterpenoids lupeol, lupenone, and a mixture of beta-sitosterol and stigmasterol. Their structures were elucidated by 1D and 2D NMR spectroscopy and mass spectrometry. Compounds 3, 4, 5, and 6 were tested for antituberculosis and antiviral activity. PMID- 17707870 TI - Social defeat-induced contextual conditioning differentially imprints behavioral and adrenal reactivity: a time-course study in the rat. AB - The present experiments were based on the rat resident-intruder paradigm and aimed at better understanding the long-term conditioning properties of this social stress model. Intruders were exposed to aggressive conspecifics residents. During 3 daily encounters, intruders were either defeated or threatened by residents, providing the defeated-threatened (DT) and threatened-threatened (TT) groups respectively, or exposed to a novel empty cage (EC). The effect of such exposures was assessed in 3 separate experiments 8, 14, or 21 days following the last session on both behavior and hypothalamus-pituitary-adrenal (HPA) axis parameters. A specific and persistent behavioral conditioning due to social defeat but also to the sole social threat experience was observed as defensive behaviors and anxiety-like behaviors were observed respectively in DT and TT rats, highlighting a lack of habituation for the conditioning properties of this social stressor. On the other hand, at the earlier time points examined a less specific activation of the HPA axis parameters was found, starting to show habituation at day 21 in EC but not in DT or TT rats. These data give further support to the lasting effects of this social stress model, bestowing a special emphasis upon the impact of its psychological component and upon the relevance of its development and maintenance over time. PMID- 17707872 TI - New pregnane glycosides from the roots of Cynanchum otophyllum. AB - Six new pregnane glycosides with an acyl at C-12 and a straight sugar chain at C 3, namely otophyllosides H-M (1-6), were isolated from the roots of Cynanchum otophyllum (Asclepiadaceae) collected from Eryuan County in Yunnan province of China. Their structures were characterized to be qingyangshengenin 3-O-beta-d glucopyranosyl-(1-->4)-beta-d-glucopyranosyl-(1-->4)-beta-d-cymaropyranosyl-(1- >4)-beta-d-oleandropyranosyl-(1-->4)-beta-d-digitoxopyranoside (1), qingyangshengenin 3-O-beta-d-glucopyranosyl-(1-->4)-beta-d-oleandropyranosyl-(1- >4)-beta-d-cymaropyranosyl-(1-->4)-beta-d-digitoxopyranoside (2), qingyangshengenin 3-O-beta-d-glucopyranosyl-(1-->4)-beta-d-cymaropyranosyl-(1- >4)-beta-d-oleandropyranosyl-(1-->4)-beta-d-cymaropyranosyl-(1-->4)-beta-d digitoxopyranoside (3), qingyangshengenin 3-O-beta-d-glucopyranosyl-(1-->4)-beta d-thevetopyranosyl-(1-->4)-beta-d-cymaropyranosyl-(1-->4)-beta-d digitoxopyranoside (4), caudatin 3-O-beta-d-glucopyranosyl-(1-->4)-beta-d glucopyranosyl-(1-->4)-beta-d-cymaropyranosyl-(1-->4)-beta-d-oleandropyranosyl-(1 ->4)-beta-d-cymaropyranoside (5), caudatin 3-O-beta-d-glucopyranosyl-(1-->4)-beta d-cymaropyranosyl-(1-->4)-beta-d-oleandropyranosyl-(1-->4)-beta-d-cymaropyranosyl (1-->4)-beta-d-cymaropyranoside (6), respectively, on the basis of detailed spectroscopic analysis and chemical method. PMID- 17707873 TI - Modelling sexually transmitted infections: the effect of partnership activity and number of partners on R0. AB - We model a sexually transmitted infection in a network population where individuals have different numbers of partners, separated into steady and casual partnerships, where the risk of transmission is higher in steady partnerships. An individual's number of partners of the two types defines its degree, and the degrees in the community specify the degree distribution. For this structured network population a simple model for disease transmission is defined and the basic reproduction number R0 is derived, R0 being a size-biased (i.e. biasing individuals with many partners) average number of new infections caused by individuals during the early stages of the epidemic. First a homosexual population is considered and then a heterosexual population. The heterosexual model is fitted to data from a census survey on sexual activity from the Swedish island of Gotland. The main empirical finding is that, for relevant transmission rates, the effect that so-called superspreaders have on R0 is over-estimated when not admitting for different types of partnerships. PMID- 17707874 TI - Urinary arsenic and porphyrin profile in C57BL/6J mice chronically exposed to monomethylarsonous acid (MMAIII) for two years. AB - Arsenicals are proven carcinogens in humans and it imposes significant health impacts on both humans and animals. Recently monomethylarsonous acid (MMA(III)), the toxic metabolite of arsenic has been identified in human urine and believed to be more acutely toxic than arsenite and arsenate. Arsenic also affects the activity of a number of haem biosynthesis enzymes. As a part of 2-year arsenic carcinogenicity study, young female C57BL/6J mice were given drinking water containing 0, 100, 250 and 500 microg/L arsenic as MMA(III)ad libitum. 24 h urine samples were collected at 0, 1, 2, 4, 8 weeks and every 8 weeks for up to 104 weeks. Urinary arsenic speciation and porphyrins were measured using HPLC-ICP-MS and HPLC with fluorescence detection respectively. DMA(V) was a major urinary metabolite detected. Significant dose-response relationship was observed between control and treatment groups after 1, 4, 24, 32, 48, 56, 88, 96 and 104 weeks. The level of uroporphyrin in 250 and 500 microg As/L group is significantly different from the control group after 4, 8, 16, 32, 56, 72, 80, 96 and 104 weeks. Coproporphyrin I level in 500 microAs/L group is significantly different from control group after 8, 24, 32, 40, 56, 72, 80, 88 and 104 weeks. After 4 weeks the level of coproporphyrin III concentration significantly increased in all the treatment groups compared to the control except week 16 and 48. Our results show urinary DMA(V) and porphyrin profile can be used as an early warning biomarker for chronic MMA(III) exposure before the onset of cancer. PMID- 17707876 TI - Enumeration of aromatic oxygenase genes to evaluate monitored natural attenuation at gasoline-contaminated sites. AB - Monitoring groundwater benzene, toluene, ethylbenzene, and xylene (BTEX) concentrations is the typical method to assess monitored natural attenuation (MNA) and bioremediation as corrective actions at gasoline-contaminated sites. Conclusive demonstration of bioremediation, however, relies on converging lines of chemical and biological evidence to support a decision. In this study, real time PCR quantification of aromatic oxygenase genes was used to evaluate the feasibility of MNA at two gasoline-impacted sites. Phenol hydroxylase (PHE), ring hydroxylating toluene monooxygenase (RMO), naphthalene dioxygenase (NAH), toluene monooxygenase (TOL), toluene dioxygenase (TOD), and biphenyl dioxygenase (BPH4) genes were routinely detected in BTEX-impacted wells. Aromatic oxygenase genes were not detected in sentinel wells outside the plume indicating that elevated levels of oxygenase genes corresponded to petroleum hydrocarbon contamination. Total aromatic oxygenase gene copy numbers detected in impacted wells were on the order of 10(6)-10(9)copies L(-1). PHE, RMO, NAH, TOD, and BPH4 gene copies positively correlated to total BTEX concentration. Mann-Kendall analysis of benzene concentrations was used to evaluate the status of the dissolved BTEX plume. The combination of trend analysis of contaminant concentrations with quantification of aromatic oxygenase genes was used to assess the feasibility of MNA as corrective measures at both sites. PMID- 17707877 TI - Biological nutrient removal in a small-scale MBR treating household wastewater. AB - The biological nutrient-removal potential of an on-site Membrane bioreactor (MBR) located in the basement of a four-person house treating domestic wastewater was investigated. The reactor consists of two tanks in series. This treatment plant differs from other conventional MBRs by a highly fluctuating influent water flow and a lack of pretreatment. During the first period, the first reactor was operated as a primary clarifier, resulting in nitrogen and phosphorus removals of 50% and 25%, respectively. Primary sludge production and bad odors in the basement were further disadvantages. When using the first reactor as an anaerobic/anoxic reactor by recycling activated sludge and mixing the first reactor, nitrogen and phosphorus removals of over 90% and 70% were achieved, respectively. By applying a dynamic model of the plant, the return sludge ratio was identified as the most important parameter. With a return sludge ratio of about 1.2, optimal PAO growth and phosphorous removal up to 90% was reached. Since only activated sludge is produced with this operational mode, on-site sludge dewatering is possible. During vacation periods without loading, the Bio-P activity is kept constant if the aeration is reduced to 5-20 min d(-1). PMID- 17707875 TI - Venezuelan equine encephalitis virus infection of mosquito cells requires acidification as well as mosquito homologs of the endocytic proteins Rab5 and Rab7. AB - Venezuelan equine encephalitis virus (VEEV) is a New World alphavirus that can cause fatal encephalitis in humans. It remains a naturally emerging disease as well as a highly developed biological weapon. VEEV is transmitted to humans in nature by mosquito vectors. Little is known about VEEV entry, especially in mosquito cells. Here, a novel luciferase-based virus entry assay is used to show that the entry of VEEV into mosquito cells requires acidification. Furthermore, mosquito homologs of key human proteins (Rab5 and Rab7) involved in endocytosis were isolated and characterized. Rab5 is found on early endosomes and Rab7 on late endosomes and both are important for VEEV entry in mammalian cells. Each was shown to have analogous function in mosquito cells to that seen in mammalian cells. The wild-type, dominant negative and constitutively active mutants were then used to demonstrate that VEEV requires passage through early and late endosomes before infection can take place. This work indicates that the infection mechanism in mosquitoes and mammals is through a common and ancient evolutionarily conserved pathway. PMID- 17707878 TI - Column biosorption of lanthanum and europium by Sargassum. AB - Batch and column biosorption of La(3+) (lanthanum) and Eu(3+) (europium) was studied using protonated Sargassum polycystum biomass. The ion exchange sorption mechanism was confirmed by the proportional release of protons and by the total normality of the solution, which remained constant during the process. Equilibrium isotherms were determined for the binary systems, La/H and Eu/H for a total normality of 3 meq g(-1), which produced separation factors of 2.7 and 4.7, respectively, demonstrating a higher affinity of the biomass towards europium. Column runs with a single metal feed were used to estimate the intra-particle mass transfer coefficients for La and Eu (6.0 x 10(-4) and 3.7 x 10(-4) min(-1), respectively). Modeling batch and column binary systems with proton as the common ion was able to predict reasonably well the behavior of a ternary system containing protons. The software FEMLAB was used for solving the set of coupled partial differential equations. Moreover, a series of consecutive sorption/desorption runs demonstrated that the metal could be recovered and the biomass reused in multiple cycles by using 0.1N HCl with no apparent loss in the biosorbent metal uptake capacity. PMID- 17707879 TI - Adducts of uridine and glycals as potential substrates for glycosyltransferases. AB - We report on the synthesis of 2-deoxyglycosyl derivatives of uridine as potential donor substrates for glycosyltransferases. The totally stereoselective synthesis is accomplished by two sequential addition reactions of uridine derivatives to glycals promoted by triphenylphosphine-hydrogen bromide. PMID- 17707880 TI - Trace element levels in adults from the west coast of Canada and associations with age, gender, diet, activities, and levels of other trace elements. AB - The purpose of this study was to assess trace element levels in whole blood, serum and urine of 61 non-smoking adults living on the west coast of Canada and to determine their association with the following variables: age, gender, diet, participation in certain hobby and/or occupational activities, and levels of other trace elements. Participants or their spouses were employed as oyster growers and were originally recruited to study the absorption of cadmium from oyster consumption. Trace elements were measured using inductively-coupled plasma mass spectrometry. A telephone interview was used to assess participant's intake of selected foods and the amount of time they have spent on certain activities over the lifetime. Comparison of results to previous studies revealed that blood lead, blood mercury, serum nickel, serum selenium and urine molybdenum levels were generally higher in this study than have previously been measured, possibly due to higher consumption of seafood in this sample. Men had statistically higher levels of serum iron, blood lead, and serum selenium, while women had statistically higher levels of serum copper and blood manganese. Blood lead levels increased with age. Diet had a statistically significant association with several elements. Consumption of spinach, seaweed, organ meats, and shellfish tended to be positively correlated with trace element concentrations and consumption of various forms of potatoes tended to be negatively correlated. Several statistically significant correlations were also observed between trace elements. PMID- 17707881 TI - Levels of PCDDs, PCDFs and dioxin-like PCBs in raw cow's milk collected in France in 2006. AB - Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) as well as polychlorinated biphenyls (PCBs) are widespread environmental contaminants. A French national survey was carried out in April 2006 to assess the concentrations of PCDD/Fs and dioxin-like PCBs (DL-PCBs) in raw cow's milk. A random sampling scheme stratified by region was applied to collect 239 raw milk samples from 93 plants belonging to 17 dairy companies. Compared to a previous survey led in 1998 analyzing half-skimmed drinking milk in France, the PCDD/Fs level was cut by half, with an average concentration of 0.33 pg toxic equivalent (TEQ)/g fat in 2006. The mean DL-PCBs concentration was 0.57 pg TEQ/g fat and subsequently the sum of PCDD/Fs and DL-PCBs was 0.90 pg/g fat, values below the thresholds defined by the European Union regulations. PMID- 17707882 TI - Extension of coupled multispecies metal transport and speciation (TRANSPEC) model to soil. AB - Atmospheric deposition of metals emitted from mining operations has raised metal concentrations in the surrounding soils. This repository may be remobilized and act as a source of metals to nearby surface aquatic systems. It is important to understand metal dynamics and the impact of various chemistry and fate parameters on metal movement in the soil environment in order to evaluate risk associated with metals in terrestrial ecosystems and accurately establish critical discharge limits that are protective of aquatic biota. Here we extend our previously developed coupled multispecies metal fate-TRANsport and SPECiation/complexation (TRANSPEC) model, which was applicable to surface aquatic systems. The extended TRANSPEC, termed TRANSPEC-II, estimates the partition coefficient, K(d), between the soil-solid and -soluble phases using site-specific data and a semi-empirical regression model obtained from literature. A geochemical model calculates metal and species fractions in the dissolved and colloidal phases of the soil solution. The multispecies fugacity/aquivalence based fate-transport model then estimates inter-media transport rates such as leaching from soil, soil runoff, and water sediment exchanges of each metal species. The model is illustratively applied to Ni in the Kelly Lake watershed (Sudbury, Ontario, Canada), where several mining operations are located. The model results suggest that the current atmospheric fallout supplies only 4% of Ni removed from soil through soil runoff and leaching. Soil runoff contributes about 20% of Ni entering into Kelly Lake with the rest coming from other sources. Leaching to groundwater, apart from runoff, is also a major loss process for Ni in the soil. A sensitivity analysis indicates that raising soil pH to above 6 may substantially reduce metal runoff and improve water quality of nearby water bodies that are impacted by runoff. PMID- 17707883 TI - Efficiency of recycled wool-based nonwoven material for the removal of oils from water. AB - The aim of this study was to highlight the potential use of recycled wool-based nonwoven material for the removal of diesel fuel, crude, base, vegetable and motor oil from water. Sorption capacity of the material in water and in oil without water, oil retention, sorbent reusability and buoyancy in static and dynamic conditions were investigated. The results show high sorption capacity of recycled wool for different kinds of oil. This sorbent also exhibited excellent buoyancy after 24h of sorption as well as a good reusability since the decrease in sorption capacity did not exceed 50% of the initial value after five sorption cycles in oil without water. PMID- 17707884 TI - Janus kinase 2 V617F mutation is detectable in spleen of patients with chronic myeloproliferative diseases suggesting a malignant nature of splenic extramedullary hematopoiesis. AB - Extramedullary hematopoiesis occurs in patients with a variety of hematologic diseases, and the spleen is a common site. Extramedullary hematopoiesis is very common in chronic myeloproliferative diseases and myeloproliferative/myelodysplastic diseases. The pathogenesis of extramedullary hematopoiesis is unknown. Using JAK2 V617F mutation as a molecular marker, we assessed paired spleen and bone marrow samples of 15 patients with various types of chronic myeloproliferative diseases and myeloproliferative/myelodysplastic diseases. The diagnosis was chronic idiopathic myelofibrosis (n=8), polycythemia vera (n=3), and chronic myelomonocytic leukemia (n=4). DNA was extracted from fixed, paraffin-embedded tissue and assessed for JAK2 V617F by real-time polymerase chain reaction assay followed by melting curve analysis. Concordant JAK2 mutation was detected in the paired samples in 7 patients. A discordant result with JAK2 V617F found in the spleen but not bone marrow was noted in 1 patient. These results indicate that extramedullary hematopoiesis in patients with chronic myeloproliferative diseases and myeloproliferative/myelodysplastic diseases is a clonal process and lend support to the theory that the cells of extramedullary hematopoiesis are carried from the bone marrow. PMID- 17707885 TI - A note on elevated total gaseous mercury concentrations downwind from an agriculture field during tilling. AB - Elevated mercury concentrations were measured at the University of Connecticut's mercury forest flux tower during spring agricultural field operations on an adjacent corn field. Concentrations at the tower were elevated, a peak of 7.03 ng m(-3) over the background concentration of 1.74+/-0.26 ng m(-3), during times when the prevailing wind was from the direction of the corn field and during periods when the soil was disturbed by tilling. Strong deposition to the forest was recorded at the point of measurement when atmospheric mercury concentrations were elevated. The strongest deposition rate was a 1 hour maximum of -4011 ng m( 2) h(-1) following the initial peak in atmospheric concentrations, Analyses of the meteorological conditions and mercury content in agricultural soil, manure and the diesel consumed in the tilling operation indicate that the source of the mercury was from the agricultural tilling operations and it was advected over the tower enriching the atmospheric concentrations above the forest canopy leading to deposition. These results indicate that agriculture operations resulting in a disturbed soil surface may be a source of atmospheric mercury originating from the pool of mercury bound in the soil. This represents a previously undocumented source of mercury emissions resulting from anthropogenic activities. PMID- 17707886 TI - Immunohistochemical evaluation of the effect of lead exposure on subcommissural organ innervation and secretion in Shaw's Jird (Meriones shawi). AB - The secretory activity of subcommissural organ cells is controlled by various extrinsic and intrinsic factors. Lead has been recognised as a neurotoxic heavy metal, since it induces morphological and functional abnormalities in the brain. In this work, we examined the effect of lead exposure on the subcommissural organ (SCO), a brain gland known by its secretion of Reissner's fiber (RF) in cerebro spinal fluid. Glycoprotein secretion and serotonin (5HT) innervation of the SCO was examined after acute and chronic lead exposures in the sub-desert rodent Meriones shawi. Lead exposures were achieved by, respectively, intra-peritoneal injection of 25 mg/kg body weight of lead acetate for 3 days and 0.5% of lead acetate in the drinking water over 4 months until adult age. 5HT and RF immunolabeling in the SCO revealed several serotoninergic fibers reaching the SCO and abundant secretory material. An increase in both 5HT innervation and secretory material of the SCO was recorded after both acute and chronic lead exposure. These results show that lead exposure affects the serotonergic innervation of the SCO. Moreover, the enhancement of SCO secretion suggests a role of this gland in neuroprotection and lead detoxification of the brain in Meriones shawi. PMID- 17707887 TI - Validity of Pelvic Pain, Urgency, and Frequency questionnaire in patients with interstitial cystitis/painful bladder syndrome. AB - OBJECTIVES: To determine the validity of the Pelvic Pain, Urgency, and Frequency (PUF) questionnaire according to its correlation with cystoscopy with hydrodistension (C-HD) findings. METHODS: A prospective study of new patients with a clinical history consistent with interstitial cystitis/painful bladder syndrome (IC/PBS) was undertaken. All patients underwent history and physical examination, urinalysis, and urine culture and completed a PUF questionnaire before undergoing C-HD. The pertinent data collected included the preoperative PUF scores, bladder capacity, and cystoscopic findings consistent with IC/PBS (petechial hemorrhage and/or terminal hematuria). Statistical analysis was performed. RESULTS: From June 1, 2005 to December 31, 2005, 97 patients with a new clinical diagnosis of IC/PBS were prospectively evaluated. All patients completed a PUF questionnaire before C-HD. The average PUF score was 21 (range 8 to 35). The mean bladder capacity was 756 mL (range 250 to 1400). The C-HD was positive in 54 (56%) of 97 patients. Of these 54 patients, 27 had a PUF score of less than 20, 22 had a PUF score of 20 to 29, and 5 patients had a PUF score of greater than 30. When evaluated statistically, no correlation was apparent between the PUF questionnaire scores and the cystoscopic findings of IC/PBS (P <0.05). CONCLUSIONS: As determined by the correlation with the C-HD, the PUF questionnaire appears to be neither a reliable predictor of IC/PBS nor a valuable predictor of disease severity. However, the inherent limitations of C-HD and the lack of a definitive diagnostic instrument for IC/PBS limit any authoritative conclusions. Therefore, the diagnosis of IC/PBS should remain one of exclusion and should depend on a constellation of widely recognized symptoms. PMID- 17707888 TI - Role of laparoscopic nephrectomy for management of symptomatic nephrogenic hypertension. AB - OBJECTIVES: To investigate the efficacy of laparoscopic nephrectomy for the management of hypertension associated with a unilateral poorly functioning kidney in adults and the role of some variables in the prediction of its outcome in the management of nephrogenic hypertension. METHODS: We conducted this study on 22 hypertensive patients with a unilateral, minimally functioning kidney. We included patients with a well-functioned contralateral kidney, no renal tumors, no renovascular hypertension, and no diagnosis of end-stage renal disease. All patients had poorly controlled hypertension or preferred to discontinue medical therapy. Their age at the onset of hypertension, gender, age at laparoscopic nephrectomy, and the interval from diagnosis to intervention were evaluated. A complete response was defined as blood pressure normalization without medical treatment. A partial response was defined as a decrease in the medication requirements and/or a 10-mm Hg decrease in diastolic blood pressure after surgery. Measurement of plasma renin activity was not available in our country at the time of the study. RESULTS: After nephrectomy, 12 (54.5%), 2 (9.1%), and 8 (36.4%) patients had a complete, partial, or no response to the surgery, respectively. No significant association was found between the response to laparoscopic nephrectomy and age, gender, and mean blood pressure. Only the hypertension-related signs and symptoms before surgery were significantly associated with the response to laparoscopic nephrectomy (P = 0.01) on both univariate and multivariate analysis. CONCLUSIONS: Nephrectomy seems effective for the management of nephrogenic hypertension in patients who wish to discontinue medical therapy. We suggest paying attention to the preoperative hypertension-related symptoms for the prediction of the response to nephrectomy. PMID- 17707889 TI - Outcomes and quality of life of adults undergoing continent catheterizable vesicostomy for neurogenic bladder. AB - OBJECTIVES: To evaluate the functional outcomes and quality of life of adult patients with neurogenic bladders who had undergone Casale Spiral Monti vesicostomy. METHODS: Twelve patients who underwent Casale Spiral Monti vesicostomy from May 1999 to December 2004 were evaluated with the Medical Outcomes Study 36-item short-form health survey to assess for postoperative quality of life. Complications and patient reported continence were also documented. RESULTS: The 12 patients (mean age 27.4 years) were followed up for a mean of 2.8 years. All 12 reported excellent urinary continence after the procedure, with only 7 patients who had the capacity to self-catheterize. Two patients reported wearing one light pad per day over the stoma. Two patients required one endoscopic dilation each for stomal stenosis, and one patient was readmitted 3 weeks postoperatively for the management of paralytic ileus. Eight patients reported no urinary tract infection since the operation. All 12 patients reported being very satisfied with the procedure. CONCLUSIONS: The results of this study have demonstrated that Casale Spiral Monti vesicostomy can have dramatic positive effects on the quality of life in adults with a neurogenic bladder by granting them social independence, convenient bladder management, and excellent continence rates. PMID- 17707890 TI - Laparoscopic ureterocalicostomy for salvage of giant hydronephrotic kidney: initial experience. AB - Reconstructive surgery for salvage of giant hydronephrosis is associated with unique challenges. We introduce the surgical technique of laparoscopic ureterocalicostomy for giant hydronephrosis. A transperitoneal five-port access was created and, after reflecting the colon, the lower pole of the hydronephrotic sac was excised. A wide, spatulated end-to-end ureterocaliceal anastomosis was performed. The sac was decompressed slowly in a controlled manner, which helped during dissection. At 3 months of follow-up, the patient was symptom free, and retrograde ureterography showed a wide, patent anastomosis. Laparoscopic ureterocalicostomy is technically feasible for the salvage of a giant hydronephrotic kidney and duplicates the results of open surgery. PMID- 17707891 TI - Nephrolithiasis in patients with duchenne muscular dystrophy. AB - OBJECTIVES: To present the first series of patients with Duchenne muscular dystrophy (DMD) and nephrolithiasis. METHODS: A retrospective chart review was done to identify patients with DMD who were referred for urologic consultation because of nephrolithiasis from June 2004 to April 2006. RESULTS: Four patients were identified with DMD and nephrolithiasis. Of the 4 patients, 2 underwent treatment, and their stones were obtained for analysis. The other 2 patients had stones diagnosed by computed tomography. Their stones were passed but not retrieved. Stone analysis for the available patients revealed a mixed calcareous composition. All 4 patients had had a relatively small stone burden. The patients ranged in age from 18 to 31 years. CONCLUSIONS: Stone disease appears to have many of the same characteristics in patients with DMD as it does in the general population. Risk factors, including immobilization and corticosteroid use, are present. Additional studies are needed before conclusions can be made regarding the associations between DMD and nephrolithiasis. PMID- 17707893 TI - Preventing the forgotten ureteral stent: implementation of a web-based stent registry with automatic recall application. AB - OBJECTIVES: To describe and analyze a unique computerized system that tracks ureteral stents and automatically sends a notice by e-mail to clinical staff if a stent becomes overdue for removal. METHODS: We have developed an electronic stent register (ESR) and stent extraction reminder facility (SERF) located within our hospital computer network. After stent insertion, a stent "episode" is created in the ESR with a mandatory maximal stent life (MSL). The SERF interrogates the ESR on a daily basis and identifies stents that have breached its MSL, generating daily e-mail notices to personnel until the stent is removed and the ESR updated. The episode data capture initially employing manual entry was changed to barcode technology acquisition. We analyzed the success of patient recall and conducted a prospective, blinded review to determine the success of the data acquisition. RESULTS: A total of 293 episodes were created within 2.4 years. Of the 241 (86%) episodes that were closed, 123 (51%) went beyond the MSL. The mean delay from designated MSL to stent removal was 20.89 days (SD 19.71). In the 7 months before barcode data acquisition, 43 of 71 stents were entered into the ESR (data capture rate 61%). In the 7 months after barcode data acquisition, 52 of 60 stents were entered (data capture rate 87%; P = 0.0009). CONCLUSIONS: The results of our study have shown the ESR and SERF to be robust and valuable tools for the treatment of patients with ureteral stents. Barcode acquisition significantly improved the stent insertion capture rate. This system ensures improved patient safety with an element of protection from potential litigation. PMID- 17707892 TI - Changes in prognostic significance and predictive accuracy of Gleason grading system throughout PSA era: impact of grade migration in prostate cancer. AB - OBJECTIVES: To describe the changes in the Gleason grading system over time and evaluate how a shift in Gleason grading has affected the overall predictive accuracy of the system in predicting biochemical disease-free survival after radical prostatectomy. METHODS: The Columbia University Urologic Oncology Database was reviewed, and 1515 patients who met the inclusion criteria were identified who had undergone radical prostatectomy from 1988 to 2004. The patients were divided into two time cohorts (1988 to 1997 and 1998 to 2004). To determine whether a shift in the Gleason sum distribution has occurred, a chi square test was performed. Survival curves and log-rank tests were used to compare the biochemical disease-free survival between cohorts stratified by the Gleason sum. To estimate the predictive ability of the Gleason system over time, concordance indexes were calculated. RESULTS: A shift toward greater Gleason sums over time was confirmed using the chi-square test (P <0.001). A significant difference was observed in biochemical disease-free survival between the two time cohorts for those with Gleason sum 6 cancer (P <0.01). The concordance indexes corresponding to Gleason sum alone for each time cohort were 0.71 and 0.87, demonstrating that the Gleason sum's predictive ability improved significantly over time. After adjusting for other variables, the Gleason sum continued to demonstrate a significantly improved predictive ability in the more recent time cohort. CONCLUSIONS: We found a trend toward the assignment of increasing Gleason sums over time in our data set. This shift in Gleason sum distribution between the two time cohorts has resulted in a significant improvement in the predictive ability of the Gleason system. PMID- 17707894 TI - Causes of failed urethral botulinum toxin A treatment for emptying failure. AB - OBJECTIVES: Urethral injection of botulinum toxin A (BTX-A) can reduce urethral resistance in patients with voiding dysfunction. However, some patients do not benefit from this treatment. It is essential to identify the causes for these failed procedures. METHODS: A total of 200 patients receiving urethral BTX-A injections for voiding dysfunction refractory to conventional medication during a 5-year period were included in this study. The patients received 50 or 100 U of BTX-A injected into the urethral sphincter. Treatment was considered successful when patients were subjectively satisfied with the outcome and (a) patients with chronic urinary retention resumed spontaneous voiding, (b) patients with a large postvoid residual volume had a reduction in postvoid residual of more than 50%, (c) patients voided with a lower detrusor pressure or lower abdominal pressure to urinate adequately. The therapeutic results and causes of failed treatment were retrospectively analyzed. RESULTS: The overall success rate was 88.5% (177 patients), including 47.5% (95 patients) with an excellent result and 41% (82 patients) with an improved result. The causes of failed treatment in 23 patients were detrusor underactivity with very low abdominal straining pressure in 7, a tight urethral sphincter in 7, bladder neck obstruction in 7, and psychological inhibition of voiding in 2. Transurethral incision of the bladder neck was performed in 7 patients, and all had an improved result. CONCLUSIONS: BTX-A urethral treatment failed in 11.5% of patients with voiding dysfunction refractory to medical treatment after one session. Careful investigation of the underlying causes of failed treatment is mandatory to achieve a satisfactory outcome. PMID- 17707895 TI - Treatment of microinvasive adenocarcinoma of the uterine cervix: a retrospective study and review of the literature. AB - OBJECTIVE: To investigate the efficacy of different treatment modalities used in microinvasive adenocarcinoma (AC) of the uterine cervix (FIGO stage IA1 and IA2), and review the literature. METHODS: Medical and histopathological records of 38 patients treated for microinvasive AC of the cervix were studied retrospectively, and compared with the literature. RESULTS: Twenty-nine patients had stage IA1 and nine stage IA2 cancers. Treatment modalities ranged from radical hysterectomy with pelvic lymph node dissection (PLND) to conization only. Eighteen patients underwent a conization, including two patients with stage IA2 disease, of whom 11 had 18 pregnancies in total, resulting in 13 live births, two terminations and three spontaneous abortions. In two patients a hysterectomy was performed after pregnancy. No recurrences were noted during an average follow-up of 72 months. In the literature 1565 patients were reported. Of the 814 patients undergoing PLND, 12 had positive nodes. Lymphovascular space invasion (LVSI) was present in 25 patients, all without node involvement. None of the 356 described parametria were involved. Twenty-nine recurrences occurred. In total, 21 pregnancies with 16 live births occurred in those patients treated to preserve fertility. CONCLUSIONS: There is no uniformity in the treatment of microinvasive AC of the uterine cervix. For stage IA1 disease, conization seems to be safe and PLND is only recommended where LVSI is present. Although the number of reported cases is small, for stage IA2 disease, conization with PLND in case of LVSI seems advisable. More studies are desirable to define the optimal treatment for patients with microinvasive AC of the cervix, especially with regard to those patients with stage IA2 disease. PMID- 17707896 TI - Letter commenting on the article "CA 125 expression pattern, prognosis and correlation with serum CA 125 in ovarian tumor patients" (104:508-515) by Hogdall, et al and on the Editorial "CA 125: megadaltons of novel opportunities" (104:505-507). PMID- 17707897 TI - R-rated film viewing and adolescent smoking. AB - OBJECTIVES: As smoking is very common in R-rated films, we sought to determine if viewing R-rated films is associated with adolescent smoking. METHODS: Three annual cross-sectional surveys conducted of 88,505 Year 10 students of largely European, Maori, Asian or Pacific Islander ethnicity in secondary schools in New Zealand between 2002 and 2004. Outcomes of interest were: intention to smoke among never smokers; past experimentation with smoking among current non-smokers; current smoking status; and current frequency of smoking. RESULTS: Dose-response relationships were observed between the frequency of viewing R-rated films and all outcome measures controlling for age, gender, ethnicity, peer smoking, parental smoking, socioeconomic status, pocket money and household smoking rules. Compared to never viewing R-rated films, viewing at least weekly nearly tripled the relative risk (2.81; 95% confidence interval 2.57, 3.09) of never smokers being susceptible to smoking, and more than doubled the risk of both past experimentation (2.28; 95% CI 2.12, 2.45) and smoking>/=monthly (2.31; 95% CI 2.10, 2.54). Each of these risks was seen across all ethnic groups. CONCLUSIONS: Our results extend the association that has been demonstrated between viewing R rated films and current smoking in American youth by demonstrating the same association in youth of different ethnic and cultural backgrounds in New Zealand. PMID- 17707898 TI - The pediatric residency training on tobacco project: four-year resident outcome findings. AB - OBJECTIVE: To evaluate the efficacy of a special program for training pediatric residents to address tobacco. METHODS: In a study conducted at the New Jersey Medical School, sixteen pediatric residency training programs in the New York/New Jersey metropolitan area were assigned randomly to either special or standard training conditions. All of the residents were invited to take part in the training. Only second- and third-year residents participated in data collection activities (baseline and follow-up tobacco surveys and objective structured clinical examinations [OSCEs]). Baseline data were collected in the spring of 2001, and follow-up data were collected annually through the spring of 2005. Special training consisted of a hybrid website/CD-ROM training program on tobacco, a seminar series, companion intervention material, and clinic mobilization. Standard training residents participated in the seminar series and utilized standard educational and self-help material. RESULTS: The percent of residents in special training, but not of those in standard training, who provided assistance for modifying environmental tobacco smoke, preventing use, and helping patients and parents stop smoking increased significantly from baseline to year 4 of training, as did the percent who felt prepared to address tobacco. Performance on the OSCEs was consistent with survey outcomes as special training residents revealed mastery of key interviewing and intervention skills. CONCLUSION: The special training program, with Solutions for Smoking as its centerpiece, was found to be effective for training pediatric residents to address tobacco, and it may serve as a model for pediatric residency training programs. Ways of improving the program are discussed. PMID- 17707899 TI - Effects of hydrostatic pressure on microtubule organization and cell cycle in gynogenetically activated eggs of olive flounder (Paralichthys olivaceus). AB - Indirect immunofluorescence staining was used to detect cytological changes of isolated blastodisks during mitosis of flounder haploid eggs treated with hydrostatic pressure. Changes in microtubule structure and expected cleavage suppression were observed from blastodisk formation to the third cell cycle, with obvious differences between treated and control eggs. In most eggs, microtubules were disassembled and the nucleation capacity of the centrosome was temporarily inhibited after pressure treatment. Within 15-20 min after treatment, the nucleation capacity of the centrosome began to gradually recover, with slow regeneration of microtubules; approximately 25 min after treatment, the nucleation capacity of the centrosome recovered completely, regenerated distinct bipolar spindles, and the first mitosis ensued. During the second cell cycle, approximately 61% of the embryos were at the two-cell stage, with a monopolar spindle in each blastomere; that treatment was effective was based on second cleavage blockage. Approximately 15% of the eggs still remained at the one-cell stage and had a monopolar spindle (treatment was effective, according to the general model of first cleavage blockage). However, treatment was ineffective in approximately 15% of the embryos (bipolar spindle in each blastomeres) and in another 8% (bipolar spindle in one of the two blastomeres and a monopolar spindle in the other; both mechanisms operating in different parts of the embryo). This is the first report elucidating mitotic gynogenetic diploid induction by hydrostatic pressure in marine fishes and provides a cytological basis for developing an efficient method of inducing mitotic gynogenesis in olive flounder. PMID- 17707900 TI - Post-thaw viability of bull AI-doses with low-sperm numbers. AB - Use of AI-doses containing low-sperm numbers are increasingly been used to optimise use of elite bulls as well as to accommodate an eventual wider application of sex-sorted semen. Since spermatozoa might, however, suffer from high extension rates, thus compromising fertility, this study evaluated the post thaw sperm quality of semen from commercial progeny-tested, high-ranked AI-sires whose semen was within acceptable limits of normality, frozen in a split-design to 15 (control, 15M) or 2 x 10(6) total spermatozoa (treatment, 2M) per straw. Assessment post-thaw included computer-evaluated sperm motility (CASA), membrane integrity (SYBR-14/PI), membrane stability (Annexin-V/PI), acrosome integrity (Carboxy-SNARF-1/PI/FITC-PSA), and chromatin integrity (AO of in situ acid induced DNA denaturation). High extension did not affect the proportions of linearly motile spermatozoa, of membrane integrity or stability nor chromatin integrity, immediately post-thaw. However, high extension clearly affected linear sperm motility following incubation at 38 degrees C for 30 min, sperm viability when assessed by SNARF and, particularly, acrosome integrity of the otherwise viable spermatozoa. Individual sire variation was evident. Fertility was preliminarily evaluated for one of the less affected bulls in a blind field trial. A total of 109 dairy cows were randomly inseminated with 15M or 2M-straws without differences in pregnancy rate between them (47% versus 43%). This similarity in fertility rates, confirmed the in vitro methods used were appropriate for identifying cryosurvival and further suggested the site of sperm deposition was not crucial for the fertility of low-sperm AI-numbers for this particular sire. However, the inter-bull variation seen calls for caution when cryopreserving low concentrations of bull spermatozoa with conventional freezing protocols. PMID- 17707901 TI - Provisional crown and fixed partial denture materials: mechanical properties and degree of conversion. AB - OBJECTIVES: This study aimed to investigate the flexural strength (FS) and flexural modulus (FM) of temporary crown and bridge materials (t-c&b) at different storage times and to identify possible correlations between the mechanical properties and the degree of conversion (DC). METHODS: FS and FM of four proprietary di-methacrylate-based t-c&bs were tested in a 3-point bending test according to EN ISO 4049:2000 at various storage times after mixing (37 degrees C dry/water) including thermocycling (5000x, 5-55 degrees C). DC was determined by calculating the percentage of reacted CC double bonds using FTIR analysis (baseline method). Mean values of all measurements were calculated and subjected to the Games-Howell test for statistical analysis (p=0.05) as well as a logarithmic regression analysis. RESULTS: FS and FM were very low 10min after mixing for all materials tested (FS: 14.5-24.5MPa; FM: 96.1-211.2MPa). A very high correlation was observed between FS and FM on the one hand and storage time on the other. The DC was on a high level already 10min after mixing (57.7-69.8%) for all materials except for Structur Premium (42.2%). Structur Premium showed a significantly higher FS and FM (p<0.05) compared to all other materials tested though a significantly lower DC (p<0.05). SIGNIFICANCE: FS and FM of t-c&bs significantly depend on the time after mixing. Dentists should be aware of the fact that the mechanical stability of temporary crowns is comparably low in the first hours after fabrication. The DC does not allow drawing conclusions about the mechanical stability of a t-c&b. PMID- 17707903 TI - Confocal spectrofluorimetric evidence for the hetero-aggregation of sequence scrambled forms of two model all-beta sheet proteins. AB - Can two unrelated proteins with deliberately compromised folding abilities, marked propensities to aggregate upon increase of protein concentration, and proclivities towards beta sheet formation, be caused to hetero-aggregate? We address this question here using the 'designer' backbone-reversed forms of two model all-beta sheet proteins, E. coli CspA and C. elegans HSP12.6, both earlier created and characterized by our group. These were covalently labeled with fluorescent dyes of well-resolved spectral characteristics [retro-CspA with FITC, and retro-HSP12.6 with TRITC] and then allowed to aggregate within the same reaction vessel. The resultant aggregates are shown by spectrofluorimetry-coupled confocal laser scanning microscopy to constitute uniform mixtures of both proteins, existing within every cylindrical volume element of approximately 200nm diameter, and comparable height, in all sections of the co-aggregated material suggesting that the two proteins do not selectively associate with copies of themselves during aggregation. Thus, it would appear that aggregation can occur without reference to protein molecular identity. PMID- 17707904 TI - A 12 month in vivo study on the response of bone to a hydroxyapatite polymethylmethacrylate cranioplasty composite. AB - We investigated the osteoconductivity and biocompatibility in vivo of a new hydroxyapatite-polymethylmethacrylate (HA-PMMA) composite developed for use as an implant material for cranioplasty, which is expected to have the good osteoconductivity of HA together with the strength and ease of handling of PMMA. The HA-PMMA composites were implanted in eight full-grown beagles and then 6, 12, 24 weeks and 1 year after implantation, the animals were sacrificed and the implanted materials removed along with the surrounding tissues. Extirpated specimens were studied using an optical microscope and micro-computed tomography (micro-CT). Fibrous connective tissue was prominent in the interface of the composite at 6 weeks. New bone formation was seen around the implant, 12 and 24 weeks after operation. At 1 year, new bone filled in the interface of the HA-PMMA composite and adhered to the surrounding autogenous bone. Mixing HA and PMMA did not interfere with the osteoconductivity of the HA component. In micro-CT findings, the new bone growing on the HA-PMMA composite could be seen attaching preferentially to HA particles exposed at the composite surface, rather than the PMMA. This study demonstrated that this HA-PMMA composite is a good candidate for cranial bone implants due to its good osteoconductivity and biocompatibility. PMID- 17707902 TI - Maternal substance use and HIV status: adolescent risk and resilience. AB - We examined the risk and protective factors and mental health problems of 105 low SES, urban adolescents whose mothers were coping with alcohol abuse and other drug problems. Approximately half of the mothers were also HIV-infected. As hypothesized, there were few differences between adolescents of HIV-infected and HIV-uninfected mothers in background characteristics, mental health issues and current substance use risk behaviors. In addition to maternal substance abuse, youth in both groups experienced similar risk factors including early foster care placement and high levels of maltreatment. Current patterns of emerging risk behaviors were evident among youth in both groups as well as signs of resiliency including high levels of school attendance. These results underscore the importance of interventions for youth of substance abusing mothers, particularly those living in urban poverty. PMID- 17707906 TI - On the mutagenic action of adenine. AB - The deamination of cytosine and adenine is mutagenic; the deamination of guanine is not. The deamination of cytosine leads to G=C-->A=T point mutation and to G- >A and C-->T transition in the DNA molecule; the deamination of adenine leads to the opposite A-->G and T-->C transition. It is shown that adenine lack could be as mutagenic as adenine deamination and it is also shown schematically that adenine lack through defective adenine synthesis could give rise to a population of genetically abnormal cells incapable of any degree of differentiation, a state perhaps reminiscent of the most acute of leukaemias and the most anaplastic of cancers. PMID- 17707907 TI - Chromosome 5q deletion: specific diagnoses and cytogenetic details among 358 consecutive cases from a single institution. AB - The purpose of this study was to define the spectrum of hematologic neoplasms and chromosomal breakpoints associated with del(5q); separate analyses were performed to account for prior cytotoxic treatment. A total of 358 consecutive del(5q) cases were identified; specific diagnoses included myelodysplastic syndrome (MDS; 53%), acute myeloid leukemia (AML; 22%), plasma cell proliferative disorder (PCPD; 9%), myeloproliferative disorder (MPD; 7%), acute lymphoblastic leukemia (ALL; 2%), PCPD with MDS (2%), MDS/MPD (2%), and malignant lymphoma (ML; 2%). The corresponding figures in the absence/presence of prior cytotoxic treatment (n=250/108) were 61%/34% for MDS, 24%/19% for AML, 4%/20% for PCPD, 6%/8% for MPD, 1%/4% for ALL, and 2%/4% for ML. del(5q) occurred as the sole cytogenetic abnormality in 88 cases (25%) including 76 without prior cytotoxic therapy. Among the latter, 82% had MDS, 8% AML, 5% MPD, 4% PCPD, and 1% ML. Chromosome 5 breakpoints included q13q33 in 49% of the cases, q15q33 in 22%, q22q33 in 8%, and q13 in 3% and their distribution was not affected by specific diagnosis or treatment history. del(5q)-associated lymphoid disorders featured a higher prevalence of previous cytotoxic therapy and smaller number del(5q)-positive metaphases, when compared to their counterparts with myeloid neoplasms. We conclude that del(5q), although most prevalent in MDS, is seen across the spectrum of myeloid disorders including MPD and its occurrence in lymphoid disorders might signify, for the most part, an occult myeloid clone. PMID- 17707905 TI - The IGF axis in baboon pregnancy: placental and systemic responses to feeding 70% global ad libitum diet. AB - Information on the influence of poor maternal nutrition on the regulation of responses to pregnancy, placental and fetal growth and development is critical to a better understanding of pregnancy physiology and pathophysiology. We determined normal changes and effects of controlled and monitored moderate nutrient restriction (NR) (global nutrient intake reduced to 70% of food consumed by mothers feeding ad libitum from 0.16 to 0.5 of gestation) in the baboon, on important hematological, biochemical, and hormonal indices of fetal growth and placental function. Serum IGF-I:IGFBP-3 ratio was lower in pregnant than control non-pregnant baboons feeding ad libitum. Serum concentrations of total and free IGF-I were decreased in NR mothers compared with controls (p<0.05). The decrease in fetal IGF-I did not reach significance (p=0.057). Serum IGF-I: IGFBP-3 ratio was decreased by NR in both mothers and fetuses. Maternal serum IGF-II was unchanged by NR. Placental IGF-I mRNA and protein abundance were similarly reduced whereas IGF-II mRNA increased in placental tissue of NR compared to control mothers. Systemic (maternal) and local (placental) IGFBP-1 and IGFBP-3 mRNA and protein abundance were unchanged by NR. Type 1 IGF receptor protein in the syncytiotrophoblast increased in NR. Type 2 IGF receptor protein was present in the stem villi core, and decreased after NR. We conclude that moderate NR in this important non-human primate model significantly disrupts the maternal and placental IGF-IGFBP axis and influences placental expression of this key system at the gene and protein level. Changes observed appear to be directed toward preserving placental growth. PMID- 17707908 TI - Development of the first Gateway firefly luciferase vector and use of reverse transcriptase in FLOE (Fluorescently Labeled Oligonucleotide Extension) reactions. AB - To study promoters we usually use primer extension to map the transcription start site and a panel of PCR generated deletion mutants. This strategy is complex and time-consuming. Therefore, we decided to improve it by using Gateway and FLOE (Fluorescently Labeled Oligonucleotide Extension). In this report we developed the first luciferase reporter "destination vector" (GW luc basic) for the Gateway technology and tested its efficacy, accuracy and background level by transfecting two distant cell lines (THP1 monocytic and SH-SY5Y neural cells). This vector is a real advantage for the cloning of many PCR fragments and sustains reporter activity also in THP1 cells, which are known to be problematic for transfection/expression. FLOE is a straightforward method to map transcription start sites but a bias in the capillary electrophoretic migration pattern of ROX weight markers has been reported: ROX markers migrated as if they were some bp longer. We hypothesized that this could depend on the use of different enzymes for the two principal reactions (DNA polymerase for the dideoxy chain terminated reaction on DNA and reverse transcriptase for the primer extension on RNA). Therefore, we used the same reverse transcriptase enzyme on both reactions, demonstrating that the reported bias is not due to the use of different enzymes but is an intrinsic feature of the ROX markers. The proposed procedure is important not only because of the timeliness but also for the global impact on the study of the first layer of the gene regulation. PMID- 17707909 TI - The first antimicrobial peptide from sea amphibian. AB - The crab-eating frog, Rana cancrivora, is one of only a handful of amphibians worldwide that tolerates saline waters. It typically inhabits brackish water of mangrove forests of Southeast Asia. A large amount of antimicrobial peptides belonging to different families have been identified from skins of amphibians inhabiting freshwater. No antimicrobial peptide from sea amphibians has been reported. In this paper, we firstly reported the antimicrobial peptide and its cDNA cloning from skin secretions of the crab-eating frog R. cancrivora. The antimicrobial peptide was named cancrin with an amino acid sequence of GSAQPYKQLHKVVNWDPYG. By BLAST search, cancrin had no significant similarity to any known peptides. The cDNA encoding cancrin was cloned from the cDNA library of the skin of R. cancrivora. The cancrin precursor is composed of 68 amino acid residues including a signal peptide, acidic spacer peptide, which are similar to other antimicrobial peptide precursors from Ranid amphibians and mature cancrin. The overall structure is similar to other amphibian antimicrobial peptide precursors although mature cancrin is different from known peptides. The current results reported a new family of amphibian antimicrobial peptide and the first antimicrobial peptide from sea amphibian. PMID- 17707910 TI - Identification of novel non-pathogenic mutation in SH3 domain of Btk in an XLA patient. AB - A first report of an XLA patient with a polymorphism in Btk SH3 domain has been identified after sequencing of the entire gene. SH3 domain variants might not be detected due to well characterized mutations outside the domain. PMID- 17707911 TI - In vivo bicarbonate requirement for water oxidation by Photosystem II in the hypercarbonate-requiring cyanobacterium Arthrospira maxima. AB - While the presence of inorganic carbon in the form of (bi)carbonate has been known to be important for activity of Photosystem II (PSII), the vast majority of studies on this "bicarbonate effect" have been limited to in vitro studies of isolated thylakoid membranes and PSII complexes. Here we report an in vivo requirement for bicarbonate that is both reversible and selective for this anion for efficient water oxidation activity in the hypercarbonate-requiring cyanobacterium Arthrospira (Spirulina) maxima, originally isolated from highly alkaline soda lakes. Using a non-invasive internal probe of PSII charge separation (variable fluorescence), primary electron acceptor (Q(A)(-)/Q(A)) reoxidation rate, and flash-induced oxygen yield, we report the largest reversible bicarbonate effect on PSII activity ever observed, which is due to the requirement for bicarbonate at the water-oxidizing complex. Temporal separation of this donor side bicarbonate requirement from a smaller effect of bicarbonate on the Q(A)(-) reoxidation rate was observed. We expect the atypical way in which Arthrospira manages intracellular pH, sodium, and inorganic carbon concentrations relative to other cyanobacteria is responsible for this strong in vivo bicarbonate requirement. PMID- 17707912 TI - In vivo inhibition of E. coli growth by a Ru(II)/Pt(II) supramolecule [(tpy)RuCl(dpp)PtCl2](PF6). AB - Supramolecular complexes consisting of ruthenium chromophores and a cisplatin unit represent an emerging class of bioactive molecules of interest as anti cancer agents. Although the ability of Ru(II)/Pt(II) heteronuclear complexes to bind to DNA has been demonstrated, the in vivo activity of these complexes has not yet been reported. In the present work, we report the anti-bacterial activity of the complex [(tpy)RuCl(dpp)PtCl(2)](PF(6)) (where dpp=2,3-bis(2 pyridyl)pyrazine, tpy=2,2':6',2''-terpyridine). The impact on bacterial cell growth of exposure to different concentrations of [(tpy)RuCl(dpp)PtCl(2)](PF(6)) and cisplatin was studied. The bioactivity of this complex was found to be due to the presence of the cis-PtCl(2) moiety, as the monometallic synthon [(tpy)RuCl(dpp)](PF(6)) did not inhibit bacterial cell growth. PMID- 17707913 TI - The link between maternal interaction style and infant action understanding. AB - The present study investigates whether the maternal interaction style is related to 6-month-old infants' action interpretation. We tested 6-month-olds ability to interpret an unfamiliar human action as goal-directed using a modified version of the paradigm used by Woodward, A. L. (1999). Infant's ability to distinguish between purposeful and non-purposeful behaviours. Infant Behavior & Development, 22, 145-160 and Kiraly, I., Jovanovic, B., Prinz, W., Aschersleben, G., & Gergely, G. (2003). The early origins of goal attribution in infancy. Consciousness & Cognition, 12, 732-751. Additionally, all infants and their mothers participated in a free play situation to assess maternal interaction styles as measured by the CARE-Index. According to mothers' distinct interaction styles, infants were divided into three groups. Results suggest that at 6 months of age infants of mothers with a modestly controlling interaction style are better at interpreting a human action as goal-directed than infants of sensitive and relative unresponsive mothers. The ability to understand human action as goal directed might be a corollary of an adaptive strategy in infancy. PMID- 17707915 TI - A review on cognitive impairments in depressive and anxiety disorders with a focus on young adults. AB - BACKGROUND: There is growing evidence for cognitive dysfunction in depressive and anxiety disorders. Nevertheless, the neuropsychological profile of young adult patients has not received much systematic investigation. The following paper reviews the existing literature on cognitive impairments in depressive and anxiety disorders particularly among young adults. Additionally, the focus of young adult age group and the effect of confounding variables on study results are discussed. METHODS: Electronic database searches were conducted to identify research articles focusing on cognitive impairments in depressive or anxiety disorders among young adults published in English during years 1990-2006. RESULTS: Cognitive impairments are common in young adults with major depression and anxiety disorders, although their nature remains partly unclear. Accordingly, executive dysfunction is evident in major depression, but other more specific deficits appear to depend essentially on disorder characteristics. The profile of cognitive dysfunction seems to depend on anxiety disorder subtype, but at least obsessive-compulsive disorder is associated with deficits in executive functioning and visual memory. The conflicting results may be explained by heterogeneity within study participants, such as illness status, comorbid mental disorders, and medication, and other methodological issues, including inadequate matching of study groups and varying testing procedures. LIMITATIONS: The study is a comprehensive review, but not a formal meta-analysis, due to methodological heterogeneity. CONCLUSIONS: Cognitive impairments are common in major depression and anxiety disorders. However, more research is needed to confirm and widen these findings, and to expand the knowledge into clinical practice. Controlling of confounding variables in future studies is highly recommended. PMID- 17707916 TI - Modulation of human lung fibroblast functions by ciclesonide: evidence for its conversion into the active metabolite desisobutyryl-ciclesonide. AB - BACKGROUND: Ciclesonide, an inhaled corticosteroid administered as inactive compound with almost no binding affinity for the glucocorticoid receptor, is clinically effective in asthma being converted by airway epithelial cells into its active metabolite desisobutyryl-(des)-ciclesonide. AIM: To evaluate whether ciclesonide could directly modulate in vitro bronchial fibroblast functions being converted into des-ciclesonide by these pluripotent cells involved in the regulation of airway inflammation and remodelling. METHODS: Ciclesonide (0.09-9.0 microM) was added to a human adult lung fibroblast cell line (CCL-202), seeded in medium in the presence of the following cytokines and growth factors: (a) basic fibroblast growth factor (bFGF) for cell proliferation, measured by tritiated thymidine ([3H]TdR) incorporation; (b) tumour necrosis factor (TNF)-alpha, to stimulate intercellular adhesion molecule (ICAM)-1 expression and monocyte chemoattractant protein-1 (MCP-1) and eotaxin release, evaluated by flow cytometry and ELISA, respectively; (c) transforming growth factor (TGF)-beta1, for induction of alpha smooth muscle actin (alpha-SMA) protein expression and modification of the organization of alpha-SMA stress fibres, evaluated by Western blot analysis and fluorescence microscopy. RESULTS: The presence of ciclesonide in cell cultures induced a significant downregulation of: (a) bFGF-induced fibroblast proliferation and TNF-alpha-induced ICAM-1 expression, at the 0.3-9.0 microM concentrations (p<0.05); (b) TNF-alpha-induced MCP-1 release, at all the concentrations tested (p<0.05); (c) TNF-alpha-induced eotaxin release, at the three highest concentrations (0.9-9.0 microM) (p<0.05); (d) TGF-beta1-induced of alpha-SMA protein expression at the 0.3-3.0 microM concentrations, associated with a reduction in the organization of alpha-SMA stress fibres. CONCLUSIONS: These data show at cellular level an effective anti-inflammatory activity of ciclesonide on human lung fibroblasts and support the hypothesis that also these cells, in addition to airway epithelial cells, may be involved in converting the parental compound into its active metabolite in the airways. PMID- 17707914 TI - Mechanistic similarities in docking of the FYVE and PX domains to phosphatidylinositol 3-phosphate containing membranes. AB - Phosphatidylinositol 3-phosphate [PtdIns(3)P], a phospholipid produced by PI 3 kinases in early endosomes and multivesicular bodies, often serves as a marker of endosomal membranes. PtdIns(3)P recruits and activates effector proteins containing the FYVE or PX domain and therefore regulates a variety of biological processes including endo- and exocytosis, membrane trafficking, protein sorting, signal transduction and cytoskeletal rearrangement. Structures and PtdIns(3)P binding modes of several FYVE and PX domains have recently been characterized, unveiling the molecular basis underlying multiple cellular functions of these proteins. Here, structural and functional aspects and current mechanisms of the multivalent membrane anchoring by the FYVE and PX domains are reviewed and compared. PMID- 17707917 TI - Acute mastoiditis in Norway: no evidence for an increase. AB - OBJECTIVE: In a large Norwegian newspaper in November 2005, an otolaryngologist at Rikshospitalet claimed that the increasing number of children hospitalized for acute mastoiditis was worrying and questioned the restrictive use of antibiotics in Norway. Based on latter he recommended that all children below age 2 with symptoms of uncomplicated acute otitis media should receive antibiotics. Our purpose was to incidence variation and characteristics of acute mastoiditis in children. METHODS: Registry based study with complete data on hospitalization for acute mastoiditis and cortical mastoidectomy in Norway during 1999-2005. RESULTS: Three hundred and ninety-nine Norwegian children aged 0-16 years were included. The incidence of acute mastoiditis in children below 2 ranged from 13.5 to 16.8 per 100,000 during the study period. Corresponding numbers for children 2-16 years were 4.3-7.1 per 100,000 children. No incidence increase was found during the study period. Age-specific incidence revealed a peak during the second and third year of life, and acute mastoiditis was most common in boys. Cortical mastoidectomy was equally common in the young and older age group, 22% received surgery. For children aged 2 and above, significantly fewer children were hospitalized for acute mastoiditis media during the period July, August and September. CONCLUSION: Despite the introduction of restrictive Norwegian guidelines for antibiotic treatment of acute otitis media in children aged 1 year and above, our data did not give evidence for an increase in acute mastoiditis. Except for the high incidence of acute mastoiditis in young children, hospitalization characteristics were remarkably similar in children below and above 2 years. PMID- 17707918 TI - Comparison of Versant HBV DNA 3.0 and COBAS AmpliPrep-COBAS TaqMan assays for hepatitis B DNA quantitation: Possible clinical implications. AB - We compared two commercial assays for HBV DNA quantitation, Versant HBV 3.0, System 340 (bDNA; Bayer Diagnostics) and COBAS AmpliPrep-COBAS TaqMan HBV Test (TaqMan; Roche Diagnostics). Analytical sensitivity, calculated on WHO International Standard, predicted 95% detection rate at 11.4 and 520.2IU/ml for TaqMan and bDNA, respectively. Specificity, established on 50 blood donor samples, was 100% and 84% for TaqMan and bDNA, respectively. When using clinical samples, HBV DNA was detected by TaqMan in 21/55 samples negative to bDNA. Mean values of HBV DNA obtained with bDNA were higher than those obtained with TaqMan (4.09log(10)+/-1.90 versus 3.39log(10)+/-2.41, p<0.001), and 24.4% of samples showed differences in viral load values >0.5log(10), without association with HBV genotype. There was a good correlation for HBV DNA concentrations measured by the two assays (r=0.94; p<0.001) within the overlapping range, and the distribution of results with respect to relevant clinical threshold recently confirmed (20,000 and 2000IU/ml) was similar. Approximately 50% of samples with low HBV DNA, appreciated by TaqMan but not by bDNA, were successfully sequenced in pol region, where drug resistance mutations are located. PMID- 17707919 TI - The effect of caffeine to increase reaction time in the rat during a test of attention is mediated through antagonism of adenosine A2A receptors. AB - Caffeine produces effects on cognitive function particularly relating to aspects of attention such as reaction time. Considering the plasma exposure levels following regular caffeine intake, and the affinity of caffeine for known protein targets, these effects are likely mediated by either the adenosine A(1) or A(2A) receptor. In the present studies, two rat strains [Long-Evans (LE) and CD] were trained to asymptote performance in a test of selective attention, the 5-choice serial reaction time task (5-CSRTT). Next, the effects of caffeine were compared to the selective A(2A) antagonists, SCH 412348 and KW-6002 (Istradefylline), and the A(1) antagonist, DPCPX. Further studies compared the psychostimulant effects of each drug. Finally, we tested the A(2A) agonist, CGS-21680, on 5-CSRTT performance and given the antipsychotic potential of this drug class, studied the interaction between CGS-21680 and amphetamine in this task. Caffeine (3-10mg/kg IP) increased reaction time in both LE and CD rats, with no effect on accuracy, an effect replicated by SCH 412348 (0.1-1mg/kg PO) and KW-6002 (1-3mg/kg PO), but not DPCPX (3-30 mg/kg PO). At least with SCH 412348, these effects were at doses that were not overtly psychostimulant. In contrast, CGS-21680 (0.03-0. 3mg/kg IP) slowed reaction speed and increased omissions. Interestingly, at a comparatively low dose of 0.03 mg/kg, CGS-21680 attenuated the increased premature responding produced by amphetamine (1mg/kg IP). The present results suggest that the attention-enhancing effects of caffeine are mediated through A(2A) receptor blockade, and selective A(2A) receptor antagonists may have potential as therapies for attention-related disorders. Furthermore, the improvement in response control in amphetamine-treated rats following CGS-21680 pretreatment supports the view that A(2A) agonists have potential as novel antipsychotics. PMID- 17707920 TI - Dorsal, ventral, and complete excitotoxic lesions of the hippocampus in rats failed to impair appetitive trace conditioning. AB - Three experiments examined appetitive trace and delay conditioning of the licking response (LR). In Experiment 1, normal rats were trained in trace conditioning using different trace intervals (2, 4, or 8s) and in delay conditioning (i.e., with a 0-s trace) in order to determine an appropriate trace interval for the following lesion experiments. Only the rats trained with a 2-s trace interval ultimately reached the same level of learning as rats trained in delay conditioning. In Experiments 2A and 2B, the performance of rats with dorsal, ventral, and complete excitotoxic hippocampal lesions was compared to that of sham-operated rats in LR conditioning with a 2-s trace. In Experiment 2B, the performance of rats in trace LR conditioning was also compared to that of rats tested in the delay paradigm. In both experiments, acquisition did not differ in lesioned and sham-operated rats and, in Experiment 2B, it was faster in the delay than in the trace paradigm. These results contrast with those showing that aversive trace conditioning is impaired after hippocampal damage. Experiment 3 examined whether the differential effects of hippocampal lesions on aversive and appetitive trace conditioning could be related to a parametric difference, that is, the relative durations of the conditional stimulus and of the trace interval. Again, hippocampal damage failed to produce a learning impairment. It is suggested that the procedure of aversive, but not of appetitive, trace conditioning is context-specific and that an intact hippocampus is required only in these situations. PMID- 17707921 TI - Exploratory and habituation phenotype of heterozygous and homozygous COMT knockout mice. AB - Catechol-O-methyltransferase (COMT) inactivates dopamine in prefrontal cortex and is associated clinically with a schizophrenia endophenotype. Using an ethologically based approach, the phenotype of mice with heterozygous COMT deletion was characterised by decreased rearing with increased sifting and chewing. Heterozygous COMT deletion is associated with a distinctive phenotype. This differs from that which we have reported previously for heterozygous deletion of the schizophrenia risk gene neuregulin-1. PMID- 17707922 TI - Effects of Montreal municipal sewage effluents on immune responses of juvenile female rainbow trout (Oncorhynchus mykiss). AB - The objective of this study was to examine the immunotoxicity of treated Montreal sewage effluents on juvenile female rainbow trout (Oncorhynchus mykiss). A comprehensive panel of immunological assays was used to evaluate the effects of exposure for 1 and 4 weeks to 1, 3, 10 and 20% sewage effluent. Phagocytic ingestion of fluorescent latex beads by head kidney macrophages and granulocytes was suppressed following 1-week of exposure, with the highest exposure concentration being the most suppressive. Phagocytic activity returned to control levels after 4 weeks of exposure. The cytotoxic activity of head kidney derived non-specific cytotoxic cells was enhanced after a 1-week exposure, especially at the lowest exposure concentration, and returned to control levels after 4 weeks of exposure. In vitro lymphocyte proliferation in response to LPS and ConA activation was not affected following sewage effluent exposure, but nonactivated, spontaneous proliferation of lymphocytes was suppressed in a dose-dependent manner after 4 weeks of exposure. Plasma lysozyme activity was elevated at lowest exposure concentration after 4 weeks. No changes were noted in either the blood leukocyte/erythrocyte ratio or in the proportion of circulating lymphocytes and thrombocytes. The proportion of circulating granulocytes increased following exposure for 4 weeks to the low effluent concentration. Plasma cortisol levels were not affected by effluent exposure suggesting that mechanisms other than stress influenced the observed immunomodulation. In summary, this study demonstrates that sewage effluent can alter the immune functions of rainbow trout. PMID- 17707924 TI - Reactive oxygen species (ROS) mediate the effects of leucine on translation regulation and type I collagen production in hepatic stellate cells. AB - The amino acid leucine causes an increase of collagen alpha1(I) synthesis in hepatic stellate cells through the activation of translational regulatory mechanisms and PI3K/Akt/mTOR and ERK signaling pathways. The aim of the present study was to evaluate the role played by reactive oxygen species on these effects. Intracellular reactive oxygen species levels were increased in hepatic stellate cells incubated with leucine 5 mM at early time points, and this effect was abolished by pretreatment with the antioxidant glutathione. Preincubation with glutathione also prevented 4E-BP1, eIF4E and Mnk-1 phosphorylation induced by leucine, as well as enhancement of procollagen alpha1(I) protein levels. Inhibitors for MEK-1 (PD98059), PI3K (wortmannin) or mTOR (rapamycin) did not affect leucine-induced reactive oxygen species production. However, preincubation with glutathione prevented ERK, Akt and mTOR phosphorylation caused by treatment with leucine. The mitochondrial electron chain inhibitor rotenone and the NADPH oxidase inhibitor apocynin prevented reactive oxygen species production caused by leucine. Leucine also induced an increased phosphorylation of IR/IGF-R that was abolished by pretreatment with either rotenone or apocynin. Therefore, leucine exerts on hepatic stellate cells a prooxidant action through NADPH oxidase and mitochondrial Reactive oxygen species production and these effects mediate the activation of IR/IGF-IR and signaling pathways, finally leading to changes in translational regulation of collagen synthesis. PMID- 17707923 TI - HDAC1 bound to the Cyp1a1 promoter blocks histone acetylation associated with Ah receptor-mediated trans-activation. AB - Metabolic bioactivation of polycyclic aromatic hydrocarbons, such as the environmental procarcinogen benzo[a]pyrene, is catalyzed by a cytochrome P450 monooxygenase encoded by the substrate-inducible Cyp1a1 gene. Cyp1a1 induction requires trans-activation by the heterodimeric transcriptional complex formed by the liganded Ah receptor (AHR) and its partner, ARNT. Previously, we showed that constitutively bound HDAC1 dissociates from Cyp1a1 promoter chromatin after ligand-mediated induction, concomitantly with the recruitment of AHR/ARNT complexes and p300. Here, we investigated the hypothesis that HDAC1 binding maintains the Cyp1a1 gene in a silenced state in uninduced cells. We find that Cyp1a1 induction by the AHR/ARNT is associated with modification of specific chromatin marks, including hyperacetylation of histone H3K14 and H4K16, trimethylation of histone H3K4, and phosphorylation of H3S10. HDAC1 and DNMT1 form complexes on the Cyp1a1 promoter of uninduced cells but HDAC1 inhibition alone is not sufficient to induce Cyp1a1 expression, although it allows for the hyperacetylation of H3K14 and H4K16 to levels similar to those found in B[a]P induced cells. These results show that by blocking the modification of histone marks, HDAC1 plays a central role in Cyp1a1 expression and that its removal is a necessary but not sufficient condition for Cyp1a1 induction, underscoring the requirement for a concerted series of chromatin-remodeling events to complete the initial steps of gene trans-activation by the Ah receptor. PMID- 17707925 TI - Proper modeling strategies selection for the assessment of post-infarction costs. AB - BACKGROUND: The evaluation of the economic impact of ischemic disease has gained increasing interest. Such field of investigation is suffering however of the heterogeneity of methods used in evaluating costs, limiting the comparison of study results. OBJECTIVE: The aim of the study is to show how estimates of 1-year costs of treatment of patients with uncomplicated acute myocardial infarction can vary significantly in relation to the statistical method adopted in the analysis. RESEARCH DESIGN AND METHODS: The study analyses post-IMA costs as a function of demographic and clinical covariates, by applying the following statistical survival models: the parametric survival model assuming Weibull distribution, the Cox proportional hazard (PH) model and the Aalen additive regression for modelling costs. The Aalen approach is robust both for the non-proportionality in hazard and for departures from normality. In addition it is able to easily model the effect of covariates on the extreme costs. This cost analysis is based on data collected in the two COSTAMI trials (N=487). RESULTS: There is agreement in all models with the effects of the considered covariates (age, sex, duration of disease and presence of other pathologies). There is a clear tendency of both the Aalen and the Cox model to provide a lower mean cost estimate than the other model, but with the additional feature for the Aalen model to be able to cope with all the other models in furnishing unbiased estimates with the advantage of a greater flexibility in representing the covariates' effect on the cost process. CONCLUSIONS: An appropriate choice of the model is crucial in avoiding mis interpretation of cost determinants of IMA patients. For our data set the Aalen model proved itself to be a realistic and informative way to characterize the effect of covariates on costs. PMID- 17707927 TI - Anomalous origin of the septal perforating artery from the right sinus of Valsalva. AB - The first septal perforating artery can anomalously originate from the aortic root. This finding is rare, benign and usually associated with other congenital coronary anomalies. We describe a patient with an isolated anomaly, a septal perforating artery which originated separately from the right sinus of Valsalva. PMID- 17707926 TI - The added prognostic value of ventilatory efficiency to the Weber classification system in patients with heart failure. AB - BACKGROUND: The Weber classification system is a well established method for categorizing patients according to peak oxygen consumption (VO(2)), but it is unknown whether ventilatory efficiency adds prognostic value. The purpose of the current study was to assess the added prognostic value of the minute ventilation/carbon dioxide production (VE/VCO(2)) slope to the Weber classification system in patients diagnosed with heart failure (HF). METHODS: Five hundred and forty-eight subjects with HF participated in this analysis. Mean left ventricular ejection fraction was 32.9+/-13.3%. Subjects were tracked for cardiac-related mortality following the exercise test. RESULTS: The numbers of subjects in Weber Classes A-D were 144, 119, 212 and 71, respectively. One hundred and eight major cardiac events (91 deaths, 10 emergent heart transplants and 7 LVAD implantations) occurred during a mean tracking period of 33.8+/-28.6 months. Receiver operating characteristic (ROC) curve analysis revealed the VE/VCO(2) slope prognostic classification schemes were significant in each of the four Weber classes (A: area=0.84, optimal threshold=31.3, 79% sensitivity/90% specificity, p<0.01; B: area=0.66, optimal threshold=33.9, 73% sensitivity/67% specificity, p<0.05; C: area=0.71, optimal threshold=36.0, 65% sensitivity/68% specificity, p<0.01; D: area=0.66, optimal threshold=41.8, 68% sensitivity/58% specificity, p<0.05). CONCLUSIONS: These results indicate that the VE/VCO(2) slope improves the identification of individuals at higher risk for mortality within each Weber class. These findings further support the routine clinical application of ventilatory efficiency in the HF population. PMID- 17707928 TI - Unusual sinus arrhythmia. AB - A juxtaposition of long and short RR intervals was observed in 2 hypertensive patients recovering from major surgery under spontaneous ventilation. Sinus rhythm was ascertained throughout the recording. These oscillations could not be linked one-to-one to ventilatory cycles. PMID- 17707929 TI - Right coronary artery aneurysm: percutaneous treatment with graft-coated stent during the acute phase of myocardial infarction. AB - We report a case of acute myocardial infarction due to acute thrombosis of the right coronary artery just before a large atherosclerotic aneurysm. The patient was treated with primary percutaneous coronary angioplasty (PCA) and deployment of graft-coated stent with optimal final result. Patients with atherosclerotic coronary aneurysms usually show the same cardiovascular risk factors and the same clinical presentation of patients with atherosclerotic obstructive coronary artery disease, but with an increased risk of endovascular thrombosis and consequently more frequent episodes of distal coronary embolism. Furthermore, they may develop other specific complications, such as rapid aneurysm enlargement and rupture leading to cardiac tamponade. In conclusion, our report shows that percutaneous approach to coronary aneurysms with exclusion of aneurismal lumen by placement of graft-coated stent is a feasible and safety procedure even during the acute phase of myocardial infarction, and it may probably reduce the risk of subsequent distal embolization, improving myocardial perfusion. PMID- 17707930 TI - MDCT detection of anomalous origins of the left main coronary artery: report of 2 cases. AB - The left main coronary artery (LMCA) arising either from the right sinus of Valsalva, separately from the right coronary artery (RCA), or from the RCA as a single coronary artery is an extremely rare coronary artery anomaly. We report 2 cases of anomalous origins of the LMCA detected by multidetector-row computed tomography. PMID- 17707931 TI - Detection of myocardial inflammation by contrast-enhanced MRI in a patient with Churg-Strauss syndrome. AB - This case report emphasizes the application of a combined CMR protocol for the diagnosis of acute myocardial inflammation and fibrosis in CSS. PMID- 17707932 TI - Utility of multislice computed tomography with a 64-data acquisition system for four-dimensional volumetric analysis using a pulsating phantom and considering pulsation rate and reconstruction methods. AB - PURPOSE: To evaluate 64-data acquisition system (DAS) MSCT (Light Speed VCT, GE) at 0.625 mm slice thickness, 0.35 s/rotation, tube 120 kV at 400 mA, ECG-gated for 4-D volumetric analysis, we used pulsating phantoms to measure end-diastolic (EDV) and end-systolic (ESV) volume and ejection fraction (EF) to assess reconstruction methods especially for higher pulsation rates. MATERIALS AND METHODS: A pulsating device (AZ-631N, Anzai Medical) with contrast material (300 mgI/dl) diluted 10x with saline was moved at 40-110 to-and-fro movements/min. ECG gated MSCT was performed x5 per pulsation rate. The EDV and ESV were measured using workstation (Virtual Place Advance Plus, Aze). RESULTS: The mean EDV and ESV were 98, 97, 97 96, 95, 94, and 101% and 145, 143, 142, 144, 145, 149, 156 and 160%, respectively, compared to the static state. EF was 80, 81, 81, 80, 79, 77, 73, and 76% at 40-110 pulsations/min, when reconstructed by the segmented method, but was improved to 82, 83, 85, and 84% at 80-110 beat/min when reconstructed by the burst method. The latter is therefore more appropriate for higher rates. CONCLUSION: This 64-DAS MSCT can measure EDV even at high beat rates (up to 110 beats per minute) compared to the static state. Because ESV tended to be overestimated by approximately 140-160% compared with the static state, EF tended to be underestimated by approximately 73-81% compared with the static state. However, at higher beat rates of >70 beat/min, an appropriate reconstruction method (the burst method) may further improve the accuracy of EF measurement. PMID- 17707933 TI - Accuracy of an indirect fluorescent-antibody test and of a complement-fixation test for the diagnosis of Babesia caballi in field samples from horses. AB - We evaluated the indirect fluorescent-antibody (IFA) test and complement-fixation (CF) test for diagnosis of equine piroplasmosis in the absence of a gold standard. Using Evan's blue, we estimated the specificity of the IFA test on a parasite-free, field horse population to be 98% (95% confidence interval=97, 99). We observed an excellent test agreement (kappa=0.83) between two collaborating laboratories when the IFA test was performed on identical samples from an endemic area. Using Bayesian analysis with informative prior probability distributions, we estimated the sensitivity of the IFA test to be 92% (95% probability interval, PI=81, 98), and specificity to be 95% (95% PI=88, 99). The CF test sensitivity and specificity estimates were 28% (95% PI=15, 47) and 99% (95% PI=96, 100), respectively. We found the IFA to be superior to the CF test, and the inclusion of Evan's blue in test protocol improved the performance of the IFA test. We conclude that the IFA test for Babesia caballi is a sensitive and specific test for the diagnosis of equine piroplasmosis. PMID- 17707934 TI - Use of group-randomized trials in pet population research. AB - Communities invest considerable resources to address the animal welfare and public health concerns resulting from unwanted pet animals. Traditionally, research in this area has enumerated the pet-owning population, described pet population dynamics in individual communities, and estimated national euthanasia figures. Recent research has investigated the human-animal bond and explored the community implications of managed feral cat colonies. These reports have utilized traditional epidemiologic study designs to generate observational data to describe populations and measure associations. However, rigorous scientific evaluations of potential interventions at the group level have been lacking. Group-randomized trials have been used extensively in public health research to evaluate interventions that change a population's behavior, not just the behavior of selected individuals. We briefly describe the strengths and limitations of group-randomized trials as they are used to evaluate interventions that promote social and behavioral changes in the human public health field. We extend these examples to suggest the appropriate application of group-randomized trials for pet population dynamics research. PMID- 17707935 TI - Systematic identification of substrates for profiling of secreted proteases from Aspergillus species. AB - Reliable and early diagnosis of life-threatening invasive mycoses in neutropenic patients caused by fungi of the Aspergillus species remains challenging because current clinical diagnostic tools lack in sensitivity and/or specificity. During invasive growth a variety of fungal proteases are secreted into the bloodstream and protease profiling with reporter peptides might improve diagnosis of invasive aspergillosis in serum specimens. To characterise the specific protease activity of Aspergillus fumigatus and Aspergillus niger we analyzed Aspergillus culture supernatants, human serum and the mixture of both. A systematic screening for optimised protease substrates was performed using a random peptide library consisting of 360 synthetic peptides featuring fluorescence resonance energy transfer (FRET). We could identify numerous peptides that are selectively cleaved by fungus-specific proteases. These reporter peptides might be feasible for future protease profiling of serum specimens to improve diagnosis and monitoring of invasive aspergillosis. PMID- 17707936 TI - Erectile dysfunction after radiotherapy for prostate cancer and radiation dose to the penile structures: a critical review. AB - Erectile dysfunction (ED) is a common sequela after external beam radiotherapy and brachytherapy for prostate cancer. There are several structures in the vicinity of the prostate that are critical to erectile function and that receive a substantial radiation dose: neurovascular bundles (NVBs), internal pudendal arteries (IPAs), accessory pudendal arteries, corpora cavernosa and the penile bulb. Most reports analyzing the correlation between radiation dose to these structures and radiation-induced ED are limited by the small number of patients analyzed in each study. So far, there is no evidence for a role of the NVBs in radiation-induced ED. There are no reports on the IPAs, based on reduced arterial flow in the penis. Several studies show contradicting results on the corpora cavernosa, which house the erectile tissue required for erection. There are contradicting reports on the penile bulb, although studies with more patients tend not to find any correlation. Sparing of the penile bulb to improve potency preservation is not sufficiently supported by the current literature. If sparing of the penile bulb is achieved by reducing the margin for the apex, an oncological risk is taken, while it is uncertain whether this will improve potency-preservation. PMID- 17707937 TI - A comparison between 2-Step IMRT and conventional IMRT planning. AB - BACKGROUND AND PURPOSE: 2-Step intensity modulated radiation therapy (2-Step IMRT) is an IMRT segmentation procedure based on analytical approximations [Bratengeier K. 2-Step IMAT and 2-Step IMRT: a geometrical approach. Med Phys 2005;32:777-785; Bratengeier K. 2-Step IMAT and 2-Step IMRT in three dimensions. Med Phys 2005;32:3849-3861]. The aim was to benchmark it with other IMRT algorithms and to establish it as planning tool for fast IMRT application with a reduced number of segments. MATERIALS AND METHODS: 2-Step IMRT plans were compared with IMRT-solutions obtained with methods from a commercial planning system (Pinnacletrade mark TPS). The four clinical cases chosen were: paraspinal tumour, carcinoma of the prostate, head and neck carcinoma and breast carcinoma. In addition the "Quasimodo" phantom study was used to compare the quality of the 2-Step IMRT method with respect to other planning procedures in the ESTRO study. RESULTS: The number of segments (and - to a minor degree - the monitor units per dose) of the majority of 2-Step IMRT plans was lower than for the commercial algorithms. The quality of the 2-Step IMRT-plan was comparable. In the Quasimodo comparison 2-Step IMRT plans with nine beams would place in the mid-range of all participants, whereas the 15-beam arrangements could compete with the best results. CONCLUSIONS: 2-Step IMRT is a valuable IMRT segmentation method, especially if the number of segments is to be limited (e.g. for reasons of precision, speed and leakage radiation). PMID- 17707938 TI - A study on adaptive IMRT treatment planning using kV cone-beam CT. AB - BACKGROUND AND PURPOSE: Changes in tumor size during the course of radiotherapy warrant performing adaptive radiotherapy (ART). This work investigates the feasibility and usefulness of acquiring on-board cone-beam CT (CBCT) for ART for patients with bulky head and neck tumors treated with IMRT and for prostate patients with potentially significant target position variations during the treatment course. MATERIALS AND METHODS: A phantom designed for CT quality assurance was used to compare the dosimetric and geometric accuracy between conventional CT and CBCT from a linear accelerator's on-board imager. Patient planning CT and CBCT images were acquired before treatment and at mid-course. The IMRT plans made on the CT were applied to the CBCT and dose-volume histograms were calculated. RESULTS: In both phantom and patient studies, the dose-volume histograms (DVHs) based on CBCT images were in excellent agreement with DVHs based on planning CT images. Minimum, maximum and mean doses agreed very well. In a patient study, doses for targets and normal tissues from the same IMRT plans calculated on CBCT images agreed within 1-3% with those calculated on planning CT images. CONCLUSIONS: CBCT images can be used to accurately predict dosimetric results. It is feasible to use CBCT to determine dosimetric consequences resulting from tumor shrinkage and patient geometry changes. An additional planning CT may be necessary to perform IMRT re-planning at present in order to accurately delineate tumor and organs. The CBCT has potential to become a very useful tool for on-line ART. PMID- 17707939 TI - Sound level dependence of auditory evoked potentials: simultaneous EEG recording and low-noise fMRI. AB - The simultaneous recording of EEG and fMRI offers the advantage of combining precise spatial information about neuronal processing obtained by fMRI data with the high temporal resolution of EEG data. One problem for the analysis of auditory processing, however, is the noisy environment during fMRI measurements, especially when EPI sequences are employed. While EEG studies outside an MRI scanner repeatedly demonstrated a clear sound level-dependent increase of N1 amplitude, this finding was less obvious in simultaneous recordings inside a scanner. Based on the assumption that this inconsistency might be due to the confounding effect of the rather loud EPI noise, we employed a low-noise fMRI protocol. This method was previously used to reveal level-dependent fMRI activation in auditory cortex areas. We combined this method with simultaneous EEG recordings to investigate the effect of different sound intensities on the auditory evoked potentials. Eight participants without hearing deficits took part in our experiment. Frequency modulated tones (FM) were presented monaurally with two sound intensities (60 and 80 dB HL). The task of the participants was to categorize the FM-direction (rising vs. falling). Our results inside the scanner replicate the sound level dependence of AEPs from previous EEG studies outside the scanner. The data analysis revealed a significant shortening of N1 latency and an increase in the N1-P2 peak-to-peak amplitude for the higher sound intensity. On a descriptive level, the 80 dB HL stimulation yielded more activated voxels in fMRI and stronger activations. This effect was pronounced over the right hemisphere. Our results suggest that low-noise sequences might be advantageous for the examination of auditory processing in simultaneous EEG and fMRI recordings. PMID- 17707940 TI - Involvement of Gq/11 in both integrin signal-dependent and -independent pathways regulating endothelin-induced neural progenitor proliferation. AB - We have previously shown that endothelin-B receptor stimulation increases neural progenitor proliferation, partly in G(i) and extracellular matrix molecule dependent manner. In the present study, we investigated whether G(q/11) is also involved in this response and how G(i) and G(q/11) might regulate the extracellular signal-regulated kinase (ERK) pathway and integrin signaling. Endothelin-induced ERK phosphorylation was independent of integrin ligands, and an inhibitor of G(q/11), YM-254890, as well as pertussis toxin, partially inhibited endothelin-stimulated phosphorylation of Raf-1 and ERK. Endothelin stimulated protein kinase C (PKC) was partially inhibited by both YM-254890 and pertussis toxin, while only pertussis toxin attenuated endothelin-induced Ras activation. In contrast, endothelin increased tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin in an integrin ligand-dependent manner. Both YM-254890 and pertussis toxin partially inhibited endothelin-stimulated phosphorylation of these proteins. A PKC inhibitor and down-regulation of PKC prevented endothelin-induced phosphorylation of paxillin and ERK. In addition, endothelin-induced proliferation and DNA synthesis were partially inhibited by YM 254890 and pertussis toxin. Taken together, the results indicate that endothelin activates PKC via G(q/11) and G(i), and consequently stimulates the ERK cascade in cooperation with Ras signaling stimulated by G(i). PKC appears to increase tyrosine phosphorylation of paxillin to enhance integrin signaling, which further increases DNA synthesis and proliferation. PMID- 17707942 TI - Skin autofluorescence in type 2 diabetes: beyond blood glucose. AB - BACKGROUND AND AIM: Skin autofluorescence (AF), which has been proposed as a measure of tissue content of advanced glycation end-products, is a predictor of health outcomes in diabetic patients. Aim of this study is the assessment of parameters associated with increased AF in a sample of type 2 diabetic patients. METHODS: AF was determined in a consecutive series of type 2 diabetic 92 patients aged 69.1+/-12.4 years. Univariate and multivariate correlations with several clinical and chemical parameters were assessed. RESULTS: A significant (p<0.01) correlation of AF was found with age (r=0.33) and HbA1c (r=0.34). After adjusting for age and HbA1c, micro- or macrovascular complications of diabetes were associated with higher AF. Furthermore, a higher AF was found in patients with metabolic syndrome (2.7+/-1.0 AU versus 2.2+/-0.7 AU; p<0.05). Waist circumference, triglyceride, and HDL cholesterol showed a significant correlation with AF after adjustment for age and HbA1c (adj. r=0.30, 0.29, and -0.27; all p<0.05). CONCLUSIONS: Skin autofluorescence in type 2 diabetic patients is associated not only with degree of hyperglycaemia and age, but also with adiposity and metabolic syndrome. PMID- 17707941 TI - Intracytoplasmic cytokine levels and neutrophil functions in early clinical stage of type 1 diabetes. AB - Studies indicate that both CD4(+) and CD8(+) T lymphocytes and their cytokines play a critical role in different clinical stages of type 1 diabetes (T1D). Disturbances of oxidative burst and phagocytic activities in neutrophils of diabetic patients compared to uncontrolled disease support the importance of neutrophil functions in the treatment and follow up of diabetic patients. This study is designed in order to investigate Th1 and Th2 cytokine profiles and neutrophil functions in early clinical stage of T1D. Patients diagnosed as T1D but not yet under insulin therapy (Group 1; n=15) and T1D patients with disease duration of <3 months (Group 2; n=20) were compared to healthy subjects (Group 3; n=15). All subjects with T1D were positive for islet cell antibody (ICA) and glutamic acid decarboxylase antibody (GADA), their fasting glucose levels were >126 mg/dl and A1(c) levels were >8. Intracytoplasmic interleukin (IL)-2, IL-10, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha levels of isolated CD4(+) and CD8(+) T cells, and neutrophil functions were determined by flow cytometry. Intracellular TNF-alpha level of CD4(+) T lymphocytes was significantly decreased in Group 1 compared to Group 2 and healthy subjects. In contrast, TNF-alpha in CD8(+) T lymphocytes was higher in Group 1 compared to Group 2. Increased TNF-alpha content of CD8(+) T lymphocytes was also obtained in Groups 1 and 2 compared to healthy subjects. Increased TNF-alpha secretion of CD8(+) T cells might reflect the role of CD8(+) T cells in beta cell destruction. Similar to cytokine content, phagocytic and oxidative burst activities in Group 1 were significantly lower compared to Group 2 and healthy subjects. Impaired neutrophil functions could be recovered by the treatment of the disease. PMID- 17707943 TI - Assessment of health-related quality of life (HRQoL) of patients with type 2 diabetes in Turkey. AB - We measured the health-related quality of life (HRQoL) in a sample of 376 type 2 diabetes patients in Turkey using the Diabetes Quality of Life (DQOL) instrument and examined which patient socio-demographic and diabetes-related clinical characteristics are associated with better quality of life (QoL). The influence of patient socio-demographic and clinical characteristics on QoL was examined using independent sample t-tests and one-way analysis of variance. Diabetes significantly affected the HRQoL of patients included in this study. The mean score of the total DQOL measure was higher among patients who were less than 40 years of age, male, married, had less than 8 years of education, lived with their family and had no family history of diabetes (p<0.05). Similarly, patients with less than 5 years of disease duration, no complications or prior hospitalization, receive insulin, and with HbA(1)c<7 reported significantly better overall HRQoL (p<0.05). Patients with BMI<24 had higher levels of satisfaction with diabetes than those with BMI>or=24 (p<0.05). Diabetes-related HRQoL information is clearly of supreme importance to family physicians and policy makers to identify and implement appropriate interventions for achieving better management of diabetes and ultimately improving the QoL of diabetes patients. PMID- 17707944 TI - DAISY: a new software tool to test global identifiability of biological and physiological systems. AB - A priori global identifiability is a structural property of biological and physiological models. It is considered a prerequisite for well-posed estimation, since it concerns the possibility of recovering uniquely the unknown model parameters from measured input-output data, under ideal conditions (noise-free observations and error-free model structure). Of course, determining if the parameters can be uniquely recovered from observed data is essential before investing resources, time and effort in performing actual biomedical experiments. Many interesting biological models are nonlinear but identifiability analysis for nonlinear system turns out to be a difficult mathematical problem. Different methods have been proposed in the literature to test identifiability of nonlinear models but, to the best of our knowledge, so far no software tools have been proposed for automatically checking identifiability of nonlinear models. In this paper, we describe a software tool implementing a differential algebra algorithm to perform parameter identifiability analysis for (linear and) nonlinear dynamic models described by polynomial or rational equations. Our goal is to provide the biological investigator a completely automatized software, requiring minimum prior knowledge of mathematical modelling and no in-depth understanding of the mathematical tools. The DAISY (Differential Algebra for Identifiability of SYstems) software will potentially be useful in biological modelling studies, especially in physiology and clinical medicine, where research experiments are particularly expensive and/or difficult to perform. Practical examples of use of the software tool DAISY are presented. DAISY is available at the web site http://www.dei.unipd.it/~pia/. PMID- 17707945 TI - Three different synchronous primary lung tumours: a case report with extensive genetic analysis and review of the literature. AB - Synchronous triple lung tumours are rare and little is known as for their genetic basis. Here we report a case of a 59 years old male with three synchronous independent and histological different primary tumours of the left lung. Two nodules were located in the upper lobe and consisted of an adenocarcinoma (ADC) and an endobronchial poorly differentiated squamous cell carcinoma (SCC). A third nodule of the lower lobe corresponded to a small cell neuroendocrine carcinoma (SCLC). To assess if they represented independent primary tumours and have common genetic profiles, tumours were investigated for loss of heterozygosity (LOH) at 40 chromosomal markers. A comparable fractional allelic loss of 0.52 was observed in the ADC and SCLC, while it was 0.28 in the SCC. Microallelotyping analysis did not reveal a common genetic profile, supporting the hypothesis that the three synchronous tumours are truly independent primaries with different histogenesis. PMID- 17707946 TI - Cloning and characterization of a salt stress-inducible small GTPase gene from the model grass species Lolium temulentum. AB - A gene encoding a small guanosine triphosphate (GTP)-binding protein (smGTP) related to the Rab2 gene family of GTPases was identified during the analysis of a salt stress suppression subtractive hybridization (SSH) expression library from the model grass species Lolium temulentum L. (Darnel ryegrass). The smGTP gene was found to have a low-level constitutive expression and was strongly induced by salt stress in root, crown and leaf tissues. The expression pattern of the smGTP gene was compared against two additional stress genes identified in the SSH expression library, the well-characterized dehydration stress tolerance gene, delta 1-pyrroline-5-carboxylate synthetase (P5CS) encoding for a key enzyme in proline biosynthesis, and the cold response gene COR413. The genes were analyzed for their response to salinity as well as their responses to 7 different forms of abiotic stress in L. temulentum plants. The smGTP gene displayed an expression pattern similar to the P5CS gene, suggesting a role in dehydration stress. In contrast, the COR413 gene was found to be up-regulated in response to all stresses tested and has utility as a general stress marker in grass plants. PMID- 17707947 TI - How emotions affect eating: a five-way model. AB - Despite the importance of affective processes in eating behaviour, it remains difficult to predict how emotions affect eating. Emphasizing individual differences, previous research did not pay full attention to the twofold variability of emotion-induced changes of eating (variability across both individuals and emotions). By contrast, the present paper takes into account both individual characteristics and emotion features, and specifies five classes of emotion-induced changes of eating: (1) emotional control of food choice, (2) emotional suppression of food intake, (3) impairment of cognitive eating controls, (4) eating to regulate emotions, and (5) emotion-congruent modulation of eating. These classes are distinguished by antecedent conditions, eating responses and mediating mechanisms. They point to basic functional principles underlying the relations between emotions and biologically based motives: interference, concomitance and regulation. Thus, emotion-induced changes of eating can be a result of interference of eating by emotions, a by-product of emotions, and a consequence of regulatory processes (i.e., emotions may regulate eating, and eating may regulate emotions). PMID- 17707948 TI - Feeding strategies used by mothers of 3-5-year-old children. AB - Appropriate use of parental feeding strategies could help establish healthy childhood eating practices. Research suggests that repeated taste exposure and modelling may be effective, pressuring and restricting may be counterproductive, and rewards may be effective or counterproductive depending on their use. However, little is known about the extent to which parents employ these strategies and within what contexts. The present study explored this using qualitative interviews with twelve mothers of children aged 3-5 years. Common strategies involved modelling, attempts to influence the child's attitudes and norms, and use of moderate pressure. The results are discussed in relation to the literature. PMID- 17707950 TI - Analysis of the role of central and peripheral alpha2-adrenoceptor subtypes in gastric mucosal defense in the rat. AB - The present study confirmed our previous assumption on the crucial role of central alpha2B-like adrenoceptor subtype in gastric mucosal defense. It was found that beside clonidine, rilmenidine, an alpha2/imidazoline receptor agonist and ST-91, an alpha2B-adrenoceptor preferring agonist inhibited the mucosal lesions induced by ethanol given intracerebroventricularly (i.c.v.). The ED50 values for clonidine, rilmenidine and ST-91 are 0.2, 0.01 and 16 nmol/rat i.c.v., respectively. The effect was reversed by the intracerebroventricularly injected alpha2B/2C-adrenoceptor antagonists prazosin and ARC-239, indicating the potential involvement of central alpha2B/2C-adrenoceptor subtype in the protective action. The gastroprotective effect of adrenoceptor stimulants was reversed by bilateral cervical vagotomy, suggesting that vagal nerve is likely to convey the central action to the periphery. In gastric mucosa both nitric oxide and prostaglandins may mediate the centrally-induced effect, since both indomethacin and N(G)-nitro-L-arginine reversed the protective effect of alpha2 adrenergic stimulants. Though expression of mRNA of alpha2B-, as well as alpha2A- and alpha2C-adrenoceptor subtypes was demonstrated in gastric mucosa of the rat, the hydrophilic ST-91, given peripherally (orally, subcutaneously), failed to exert mucosal protection, in contrast with clonidine and rilmenidine which were also effective. Consequently, while peripheral alpha2B-adrenoceptors are not likely to be involved in gastric mucosal protection, activation of central alpha2B-like adrenoceptor subtype may initiate a chain of events, which result in a vagal dependent gastroprotective action. PMID- 17707949 TI - Deconstructing the vanilla milkshake: the dominant effect of sucrose on self administration of nutrient-flavor mixtures. AB - Rats and humans avidly consume flavored foods that contain sucrose and fat, presumably due to their rewarding qualities. In this study, we hypothesized that the complex mixture of corn oil, sucrose, and flavor is more reinforcing than any of these components alone. We observed a concentration-dependent increase in reinforcers of sucrose solutions received (0%, 3%, 6.25%, and 12.5%) in both fixed ratio and progressive ratio procedures, but with equicaloric corn oil solutions (0%, 1.4%, 2.8%, and 5.6%) this finding was replicated only in the fixed ratio procedure. Likewise, addition of 1.4% oil to 3% or 12.5% sucrose increased fixed ratio, but not progressive ratio, reinforcers received relative to those of sucrose alone. Finally, addition of 3% vanilla flavoring did not change self-administration of 3% sucrose or 3% sucrose+1.4% oil solutions. These data suggest that, calorie-for-calorie, sucrose is the dominant reinforcing component of novel foods that contain a mixture of fat, sucrose, and flavor. PMID- 17707952 TI - Synthesis, characterization and biological activity of Pt(II) and Pt(IV) complexes with 5-methyl-5(4-pyridyl)-2,4-imidazolidenedione. AB - New platinum(II) and platinum(IV) complexes with 5-methyl-5(4-pyridyl)-2,4 imidazolidenedione and various halogen ions with general formula [PtL(2)X(2)] and [PtL(2)Cl(4)], where L is the organic ligand and X is Cl(-), Br(-), J(-), were synthesized. The molecular formulae of all the complexes were confirmed by elemental analysis, IR, (1)H, (13)C NMR spectral analyses and molar conductivity. The cytotoxic effects of these complexes were examined on some human tumor cell lines. The newly synthesized cis-[PtL(2)Cl(2)] exerted cytotoxic activity against SKW-3, MCF-7, EJ, U-266 tumor cell lines, while cis-[PtL(2)Br(2)], trans [PtL(2)I(2)] were less active. The higher oxidation state complex cis [PtL(2)Cl(4)] was inactive in all cell lines but in SKW-3 some augmentation of the cytotoxicity was seen after co-administration of ascorbic acid but not when treated in combination with reduced glutathione or N-acetylcysteine. A DNA fragmentation analysis revealed that the cytotoxicity of the dichloro analogue, characterized with superior activity compared to the other complexes, is mediated by induction of apoptotic cell death. PMID- 17707951 TI - QSAR studies on benzoylaminobenzoic acid derivatives as inhibitors of beta ketoacyl-acyl carrier protein synthase III. AB - Fatty acid biosynthesis is essential for most of the bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, beta-ketoacyl-ACP synthase III, is a attractive target since it is central to the initiation of fatty acid biosynthesis. Quantitative structure-activity relationship (QSAR) studies have been carried out on a series of benzoylaminobenzoic acid derivatives as potent inhibitors of FabH and antibacterial activity against Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Neisseria meningitidis and Escherichia coli, which demonstrate FabH inhibitory activity in cell free and whole cell system. The QSAR studies revealed that inhibitory activity increases with increase in hydrophobicity, molar refractivity, aromaticity, and presence of OH group (on x position of the nucleus). On the other side presence of hetero-atoms like N, O, or S at R(1) position of the nucleus decreases the inhibitory activity. The comparison of QSAR between the FabH inhibitory activity and antibacterial activity against S. aureus, S. pneumoniae, S. pyogenes, E. faecalis, N. meningitidis also demonstrates that the hydrophobicity, aromaticity and presence of OH group (on x position of the nucleus) are conducive for the inhibitory activity. PMID- 17707953 TI - Selectivity criterion for pyrazolo[3,4-b]pyrid[az]ine derivatives as GSK-3 inhibitors: CoMFA and molecular docking studies. AB - In the development of drugs targeted for GSK-3, its selective inhibition is an important requirement owing to the possibility of side effects arising from other kinases for the treatment of diabetes mellitus. A three-dimensional quantitative structure-activity relationship study (3D-QSAR) has been carried out on a set of pyrazolo[3,4-b]pyrid[az]ine derivatives, which includes non-selective and selective GSK-3 inhibitors. The CoMFA models were derived from a training set of 59 molecules. A test set containing 14 molecules (not used in model generation) was used to validate the CoMFA models. The best CoMFA model generated by applying leave-one-out (LOO) cross-validation study gave cross-validation r(cv)(2) and conventional r(conv)(2) values of 0.60 and 0.97, respectively, and r(pred)(2) value of 0.55, which provide the predictive ability of model. The developed models well explain (i) the observed variance in the activity and (ii) structural difference between the selective and non-selective GSK-3 inhibitors. Validation based on the molecular docking has also been carried out to explain the structural differences between the selective and non-selective molecules in the given series of molecules. PMID- 17707954 TI - A sensitive cell-based assay for the detection of residual infectious West Nile virus. AB - Ensuring complete viral inactivation is critical for the safety of vaccines based on an inactivated virus. Detection of residual infectious virus is dependent on sensitivity of the assay, sample volume analyzed and the absence of interference with viral infection. Here we describe the development and qualification of a sensitive cell-based assay for the detection of residual infectious West Nile Virus (WNV). The results of the assay are in good agreement with the assumption that at low concentrations the number of infectious units in relatively small samples follows a Poisson distribution. The assay can detect 1 infectious unit with a confidence of 99%, provides statistical controls for interference and can easily be scaled up to test large amounts of vaccine material. Furthermore, we show equivalence in sensitivity between the cell-based assay and an in vivo assay for detection of infectious WNV. Finally, the assay has been used for successful release testing of clinical lots of inactivated WNV vaccine. Given the principle and generic setup of the method we envision broad applicability to the detection of very low concentrations of infectious virus. PMID- 17707955 TI - The Schistosoma bovis Sb14-3-3zeta recombinant protein cross-protects against Schistosoma mansoni in BALB/c mice. AB - Current control programs against schistosomiasis could be reinforced through the use of an effective vaccine. Schistosome 14-3-3 proteins have been proposed as candidates for vaccine against the respective infections, and were seen to elicit high protection levels against Schistosoma bovis in a previous work done by our group. We have therefore investigated the protective capacity of the 14-3-3 protein from S. bovis - Sb14zeta - against Schistosoma mansoni in mice. In addition, we have addressed the influence of the co-administration of three different immunomodulators with the 14-3-3 polypeptide. Protection was high when the Sb14zeta protein was combined in two independent experiments with the AA2829 and PAL immunomodulatory molecules as regards both the reduction of worm numbers (mean: 64.8%) and egg loads in liver (mean: 73.9%) or intestine (mean: 71.5%). In contrast, the degree of protection achieved with the Sb14zeta-CpG vaccine was very low (14.9% reduction in worm numbers, and 46.6% and 32% reduction in liver and intestinal egg loads). The immune responses observed in the vaccinated animals showed that the production of IFNgamma and the absence of IL-4, accompanied by a strong humoral response, are insufficient to elicit protection against S. mansoni. PMID- 17707956 TI - Candidate HIV-1 gp140DeltaV2, Gag and Tat vaccines protect against experimental HIV-1/MuLV challenge. AB - Pre-clinical HIV-1 vaccine protocols, using multiple vaccine modalities and a potent adjuvant were assessed for vaccine efficacy in an experimental HIV-1 challenge model. C57Bl/6 mice were immunized with DNA plasmids encoding HIV-1 gp140, Gag and Tat alone or in combination with the corresponding recombinant proteins formulated in the adjuvant MF59. HIV-1 DNA alone or a DNA prime protein boost schedule resulted in complete protection against challenge with HIV-1/MuLV infected murine cells. Although HIV-1 protein immunization in combination with MF59 resulted in partial protection, the DNA priming seemed to be crucial for obtaining full protection against the challenge. It is likely that the partial protection seen after immunization with protein alone is, to a certain extent, due to effects of the adjuvant since some animals that received the adjuvant MF59 alone were protected from the challenge. For the most part, antigen-specific cell mediated immune responses as detected in the spleen (in contrast to responses detected in peripheral blood) of immunized animals appeared to be associated with protection in this study. PMID- 17707957 TI - Age-specific seroprevalence of serogroup C meningococcal serum bactericidal antibody activity and serogroup A, C, W135 and Y-specific IgG concentrations in the Turkish population during 2005. AB - Like many other developing countries; there is no accurate information about the antibody levels against Neisseria meningitidis in Turkey. We collected serum samples from four health centers located in different geographic regions and stratified according to age in order to obtain a baseline seroprevalence of protective antibodies to meningococcal serogroup C and provide data on seroprevalence of IgG antibodies to serogroups A, C, W135 and Y. Sera were tested for serum bactericidal antibodies (SBA) to serogroup C meningococci using rabbit serum as the complement source and by a bead based assay for serogroup A, C, W135 and Y-specific IgG. It was observed that 30% and 12% of individuals within the study population had SBA titers of > or =8 and > or =128, respectively. Overall; at least 70% of the population are susceptible (SBA titer <8) to meningococcal serogroup C disease. The rate of susceptibility was highest in infants aged 7-12 months and young children (1-4 years). Regardless of age, for serogroup A, C, W135 and Y, 60.5%, 27.2%, 12.3% and 19.2% of subjects, respectively, had serogroup-specific IgG concentrations > or =2 microg/mL. These data highlight that a large proportion of the Turkish population are susceptible to serogroups C, W135 and Y and should be considered, along with serogroup-specific disease incidence data, in future decisions on possible meningococcal vaccination programmes. PMID- 17707958 TI - Characterization of the MUC1.Tg/MIN transgenic mouse as a model for studying antigen-specific immunotherapy of adenomas. AB - A bigenic MUC1.Tg/MIN mouse model was developed by crossing Apc/(MIN/+) (MIN) mice with human MUC1 transgenic mice to evaluate MUC1 antigen-specific immunotherapy of intestinal adenomas. The MUC1.Tg/MIN mice developed adenomas at a rate comparable to that of MIN mice and had similar levels of serum MUC1 antigen. A MUC1-based vaccine consisting of MHC class I-restricted MUC1 peptides, a MHC class II-restricted pan-helper peptide, unmethylated CpG oligodeoxynucleotide and GM-CSF caused flattening of adenomas and significantly reduced the number of large adenomas. Immunization was successful in generating a MUC1-directed immune response evidenced by increased MUC1 peptide-specific anti tumor cytotoxicity and IFN-gamma secretion by lymphocytes. PMID- 17707960 TI - The feasibility of HIV vaccine efficacy trials among Russian injection drug users. AB - IDU exposure remains a primary driver of the Russian HIV epidemic, and recent incidence data provide little evidence that this epidemic is slowing. While there are multiple important challenges that need to be further explored before starting vaccine trials, most importantly access to evidence-based drug treatment services for trial participants, the current context of high HIV incidence and low genetic diversity of HIV strains, suggests the need for intensified prevention strategies and supports the feasibility of mounting efficacy trials of HIV vaccines among IDUs in the Russian Federation. PMID- 17707959 TI - The use of health economics to guide drug development decisions: Determining optimal values for an RSV-vaccine in a model-based scenario-analytic approach. AB - Health-economic modelling is useful for assessing the clinical requirements and impact of new vaccines. In this study, we estimate the impact of potential vaccination for respiratory syncytial virus (RSV) of infants in the Netherlands. A decision analysis model was employed using seasonal data from a cohort of children (1996-1997 through 1999-2000) to assess hospitalisation, costs and impact of vaccination. Yearly, an estimated 3670 infants are hospitalised with RSV-infection in the Netherlands, vaccination protecting infants from 3 months of life onwards could prevent approximately 1000-3000 hospitalisations, depending on the effectiveness of the potential vaccine. Additionally, vaccination could prevent a major share of RSV-related costs. Comparison of the calculated break even prices with the average price of recently introduced vaccines indicates that pricing for a potential RSV-vaccine most likely allows for only a single dose vaccination or several doses at a relatively low price per dose in order to achieve cost savings. However, if evidence on relevant RSV-related mortality would become available, higher pricing would be justified, while still remaining below accepted thresholds for cost-effectiveness. PMID- 17707961 TI - Conjugate vaccine-induced immunological priming is not protective against acute meningococcal C infection. PMID- 17707962 TI - Study of the risk factors for severe childhood pertussis based on hospital surveillance data. AB - We used data collected through the French national hospital-based pertussis surveillance network to investigate the risk factors for severe childhood pertussis and more specifically the impact of the vaccination status. For infants, factors associated with a decreased risk of severe disease (defined as hospitalization in intensive care unit, assisted ventilation or death) were having received the first dose of vaccine, being seen late in the course of the disease and in a local hospital. Data also suggested that protection may increase with the number of doses administered. For older children, factors associated with a decreased risk of severity, measured by the hospitalization, were having received a recent booster injection and identification of the contaminator in the close environment. This study reinforces the need for an early start of the primary course in infants and the administration of booster injections in older children. PMID- 17707964 TI - [What are the effects of altitude and aircraft environment on the respiratory tract?]. PMID- 17707963 TI - Modelling radiocaesium transfer and long-term changes in reindeer. AB - A dynamic model on (137)Cs in reindeer is presented, taking into consideration short- and long-term mechanisms, including the effect of ground deposition, transfer to vegetation, reindeer diet, feed intake, absorption and depletion of radiocaesium in the reindeer body. The model was optimised to fit measured activity concentrations in Swedish reindeer after the Chernobyl fallout. For comparison, regression analyses were made and aggregated transfer factors and effective ecological half-lives were estimated. The fit of the simulated model to observed activity concentrations was slightly better than the fit obtained by linear regressions. Improved knowledge about radiocaesium in vegetation would make the model more accurate for predictive purposes. Presently, the use of Tag and T(eff) is probably better for predictions, provided that their temporal and geographical limitations are taken into consideration. The dynamic model describes mechanisms better and may explain how changes in the system influence on activity concentrations of radiocaesium in the animal. PMID- 17707965 TI - [What are the general principles and management of patients presenting with respiratory diseases and preparing for air travel? General problems and principal logistic aspects of air travel in cases of respiratory anomalies]. PMID- 17707966 TI - [What are the general principles and management of patients presenting with respiratory diseases and preparing for air travel? How to evaluate the respiratory risk before air travel?]. PMID- 17707967 TI - [What are the peculiarities of management in respiratory insufficiency patients coupled with air travel? Air travel in patients undergoing long-term oxygen therapy]. PMID- 17707968 TI - [What are the peculiarities of management of respiratory insufficiency patients coupled with air travel? Air travel in patients undergoing mechanical ventilation]. PMID- 17707969 TI - [Respiratory equipment and air travel: what problems, what solutions?]. PMID- 17707970 TI - [Who are the patients in which air travel comprises a risk of respiratory insufficiency?]. PMID- 17707972 TI - [Smoking cessation and air travel: what problems, what solutions?]. PMID- 17707973 TI - Music therapy in the management of chronic osteoarthritis pain. AB - The results of the study by McCaffrey and Freeman (2003) are pertinent to the group project as they reflect the therapeutic benefit of music therapy. Suggestions for future research include studying music intervention on other types of pain as well as selecting a larger, more random sample to increase rigor and control. The availability of educational funds and the shortage of staffing and other resources are feasibility issues that must be looked at when teaching nursing students about the benefits of music as a nursing intervention. PMID- 17707971 TI - [What is the risk of venous thromboembolism induced by air travel and how is it managed?]. PMID- 17707974 TI - AR: tubal ligation fails--pregnancy results: nurse practictioner missed 'tubal' pregnancy. Summerville v. Thrower, No. 06-501 (Ark. 03/15/2007) S.W.3d. -AR. PMID- 17707976 TI - Effects of orlistat therapy on plasma concentrations of oxygenated and hydrocarbon carotenoids. AB - Orlistat is a lipase inhibitor that is applied for treating obesity. Lipases are required for digestion and absorption of dietary lipids and fat-soluble vitamins and carotenoids. The aim of this study was to compare the effects of orlistat therapy on plasma concentrations of oxygenated (beta-cryptoxanthin, lutein/zeaxanthin) and hydrocarbon (alpha-, beta-carotene, lycopene) carotenoids. Six patients with a body mass index (BMI) > or = 30 kg/m2 received 360 mg/d orlistat over 4.5 mon. Plasma carotenoid concentrations were determined at baseline (T0) and after 3 (T3) and 4.5 mon (T4.5) along with anthropometric, dietary, and biochemical indices, including plasma lipids, retinol, (alpha- and gamma-tocopherols, and FA. Baseline BMI was 32.7 +/- 1.97 kg/m2. Five of six patients lost weight; the average weight loss was 3.6 +/- 2.4% (P = 0.47). There were no significant changes in dietary carotenoid intakes. In contrast, plasma alpha- and beta-carotene concentrations decreased significantly from T0 to T4.5 by 45% (P = 0.006) and 32% (P = 0.013), respectively. Plasma lycopene decreased from T0 to T3 but increased again from T3 to T4.5, while beta-cryptoxanthin and lutein/zeaxanthin concentrations did not change. There were no significant alterations in tocopherol, retinol, and FA concentrations. In conclusion, even though weight loss was not significant, orlistat therapy was associated with significant decreases in plasma concentrations of the highly lipophilic hydrocarbon carotenoids, alpha- and beta-carotene. PMID- 17707975 TI - Regulation of the alpha-tocopherol transfer protein in mice: lack of response to dietary vitamin E or oxidative stress. AB - The alpha-tocopherol transfer protein (TTP) plays an important role in the regulation of plasma alpha-tocopherol concentrations. We hypothesized that hepatic TTP levels would be modulated by dietary vitamin E supplementation and/or by oxidative stress. Mice were fed either a High E (1150 mg RRR-alpha-tocopheryl acetate/kg diet) or a Low E (11.5 mg/kg diet) diet for 2 wk. High E increased plasma and liver alpha-tocopherol concentrations approximately 8- and 40-fold, respectively, compared with Low E-fed mice, whereas hepatic TTP increased approximately 20%. Hepatic TTP concentrations were unaffected by fasting (24 h) in mice fed either diet. To induce oxidative stress, chow-fed mice were exposed for 3 d to environmental tobacco smoke (ETS) for 6 h/d (total suspended particulate, 57.4 +/- 1.8 mg/m3). ETS exposure, while resulting in pulmonary and systemic oxidative stress, had no effect on hepatic alpha-tocopherol concentrations or hepatic TTP. Overall, changes in hepatic TTP concentrations were minimal in response to dietary vitamin E levels or ETS-related oxidative stress. Thus, hepatic TTP concentrations may be at sufficient levels such that they are unaffected by either modulations of dietary vitamin E or by the conditions of environmentally related oxidative stress used in the present studies. PMID- 17707977 TI - Positive association between plasma antioxidant capacity and n-3 PUFA in red blood cells from women. AB - PUFA are susceptible to oxidation. However, the chain-reaction of lipid peroxidation can be interrupted by antioxidants. Whether an increased concentration of PUFA in the body leads to decreased antioxidant capacity and/or increased consumption of antioxidants is not known. To elucidate the relationship between plasma total antioxidant capacity (TAC), the concentration of antioxidant vitamins, and the proportion of PUFA in red blood cells (RBC), plasma TAC was measured by a Trolox equivalent antioxidant capacity assay in blood samples from 99 Icelandic women. Concentrations of tocopherols and carotenoids in the plasma were determined by HPLC, and the FA composition of RBC total lipids was analyzed by GC. Plasma TAC and the plasma concentration of alpha-tocopherol correlated positively with the proportion of total n-3 PUFA, 20:5n-3, and 22:6n-3 in RBC, whereas the plasma lycopene concentration correlated negatively with the proportion of total n-3 PUFA and 20:5n-3. On the other hand, plasma TAC correlated negatively with the proportion of n-6 PUFA in RBC. Plasma TAC also correlated positively with the plasma concentration of alpha-tocopherol, alcohol consumption, and age. Both the plasma concentration of alpha-tocopherol and age correlated positively with the proportion of n-3 PUFA in RBC; however, n-3 PUFA contributed independently to the correlation with plasma TAC. Because the proportion of n-3 PUFA in RBC reflects the consumption of n-3 PUFA, these results suggest that dietary n-3 PUFA do not have adverse effects on plasma TAC or the plasma concentration of most antioxidant vitamins. PMID- 17707978 TI - Cholesterol-lowering ability of a phytostanol softgel supplement in adults with mild to moderate hypercholesterolemia. AB - Plant sterols, incorporated into spreads and other food sources, have been shown to lower serum cholesterol concentrations. The effect of phytostanol supplementation in softgel form has not been assessed. Our objective was to examine the effects of sitostanol as sitostanol ester in softgel form on serum lipid concentrations in hypercholesterolemic individuals. Thirty hypercholesterolemic adults were supplemented with 1.6 g of free phytostanol equivalents as phytostanol ester (2.7 g stanol esters) or placebo per day for 28 d in a randomized, double-blind, parallel study design. Phytostanol supplementation resulted in a significant decrease in total cholesterol (TC) ( 8%) and LDL-cholesterol (-9%). There were no alterations in concentrations of HDL cholesterol or TG. Nor were the ratios of LDL/HDL or TC/HDL altered significantly. Thus, use of phytostanol ester softgel supplements improved serum total and LDL-cholesterol concentrations in hypercholesterolemic individuals. PMID- 17707979 TI - Dose-dependent hypocholesterolemic actions of dietary apple polyphenol in rats fed cholesterol. AB - The dose-dependent hypocholesterolemic and antiatherogenic effects of dietary apple polyphenol (AP) from unripe apple, which contains approximately 85% catechin oligomers (procyanidins), were examined in male Sprague-Dawley rats (4 wk of age) given a purified diet containing 0.5% cholesterol. Dietary AP at 0.5 and 1.0% levels significantly decreased the liver cholesterol level compared with that in the control (AP-free diet-fed) group. Dietary AP also significantly lowered the serum cholesterol level compared with that in the control group. However, the HDL cholesterol level was significantly higher in the 1.0% AP-fed group than in the control group. Accordingly, the ratio of HDL-cholesterol/total cholesterol was significantly higher in the 0.5% AP-fed group and 1.0% AP-fed group than in the control group. Moreover, the atherogenic indices in the 0.5 and 1.0% AP-fed groups were significantly lower than those in the control group. The activity of hepatic cholesterol 7alpha-hydroxylase tended to be increased by dietary AP in a dose-dependent manner. In accord with this observation, dietary AP increased the excretion of acidic steroids in feces. Dietary AP also significantly promoted the fecal excretion of neutral steroids in a dose dependent manner. These observations suggest that dietary AP at a 0.5 or 1.0% level exerts hypocholesterolemic and antiatherogenic effects through the promotion of cholesterol catabolism and inhibition of intestinal absorption of cholesterol. PMID- 17707980 TI - Effects of margarine and butter consumption on distribution of trans-18:1 fatty acid isomers and conjugated linoleic acid in major serum lipid classes in lactating women. AB - Trans FA (TFA) have at least one trans double bond and comprise several isomers and types, including many of the CLA (e.g., c9,t11-18:2 CLA). Some TFA may have adverse effects (e.g., cardiovascular disease), whereas some are thought to have beneficial effects (e.g., anticarcinogenicity). The presence of TFA in human tissues and fluids is related to dietary intake, although this relationship is not completely understood--especially in regard to serum lipid fractions. This study was conducted as part of an investigation designed to test the influence of butter (B), "low TFA" margarine (LT), and regular margarine (RM) on milk fat content. Here we tested the secondary hypothesis that consumption of B, LT, and RM by lactating women would result in differential distribution of TFA and CLA in major serum lipid classes. Breast-feeding women (n = 11) participated in this randomized Latin-square study consisting of five periods: intervention I (5 d), washout I (7 d), intervention II (5 d), washout II (7 d), and intervention III (5 d). Extracted serum lipid was separated into cholesterol ester (CE), TAG, and phospholipid (PL) fractions and analyzed for total and isomeric TFA and CLA concentrations. Data indicate that TAG consistently contained the highest concentration of total t-18:1. No interaction between treatment and fraction was found for any of the t-18:1 isomers identified. Absolute concentration of each t 18:1 isomer was greatest during the RM period, regardless of fraction. On a relative basis, concentrations of t10-18:1 and t12-18:1 were most responsive to treatment in the CE fraction. The concentration of c9,t11-18:2 CLA was highest in the TAG fraction and lowest in the PL fraction, regardless of treatment. In summary, these results indicate (i) that there is a differential distribution of some isomeric TFA and CLA among human serum lipid fractions and (ii) that dietary TFA intake influences absolute and relative concentrations of some of the isomers in selected fractions. PMID- 17707981 TI - Effect of substitution of low linolenic acid soybean oil for hydrogenated soybean oil on fatty acid intake. AB - Low linolenic acid soybean oil (LLSO) has been developed as a substitute for hydrogenated soybean oil to reduce intake of trans FA while improving stability and functionality in processed foods. We assessed the dietary impact of substitution of LLSO for hydrogenated soybean oil (HSBO) used in several food categories. All substitutions were done using an assumption of 100% market penetration. The impact of this substitution on the intake of five FA and trans FA was assessed. Substitution of LLSO for current versions of HSBO resulted in a 45% decrease in intake of trans FA. Impacts on other FA intakes were within the realm of typical dietary intakes. No decrease in intake of alpha-linolenic acid was associated with the use of LLSO in place of HSBO because LLSO substitutes for HSBO that are already low in alpha-linolenic acid. PMID- 17707982 TI - A high-saturated fat diet enriched with phytosterol and pectin affects the fatty acid profile in guinea pigs. AB - This paper presents the results of a study whose aim was to test the effects of several doses of pectin and phytosterols on the body weight gain and the FA content in female guinea pigs. The treatments resulted from supplementing with pectin and plant sterol a guinea pig diet (rich in saturated FA), following a 3 x 3 factorial design, with three levels of pectin (0, 3.67 and 6.93%) and three levels of phytosterols (0, 1.37, and 2.45%). Seventy-two female Dunkin Hartley guinea pigs were randomly assigned to the treatment groups (8 animals/group), the duration of the treatment being 4 wk. Pectin dietary intake led to a significant increase in body weight (P < 0.001), food consumption (P = 0.025), and feed efficiency (P < 0.001), but no influence of phytosterols on weight gain or food consumption was detected. We found a significant negative effect of the addition of phytosterols on lauric, myristic, and palmitic acid contents in feces, and a positive effect on their concentration in plasma and liver, but no significant effect on stearic acid content. Apparent FA absorption was assessed by calculating the ratio of FA in feces and diets that the absorption of the different FA could be compared, and the negative effect of phytosterol supplementation on these ratios, especially for lauric and myristic acids, was established. PMID- 17707983 TI - Thia fatty acids with the sulfur atom in even or odd positions have opposite effects on fatty acid catabolism. AB - As tools for mechanistic studies on lipid metabolism, with the long-term goal of developing a drug for the treatment of lipid disorders, thia FA with the sulfur atom inserted at positions 3-9 from the carboxyl group were fed to male Wistar rats for 1 wk to determine their impact on key parameters in lipid metabolism and hepatic levels of thia FA metabolites. Thia FA with the sulfur atom in even positions decreased hepatic and cardiac mitochondrial beta-oxidation and profoundly increased hepatic and cardiac TAG levels. The plasma TAG level was unchanged and the hepatic acyl-CoA oxidase activity increased. In contrast, thia FA with the sulfur atom in odd positions, especially 3-thia FA, tended to increase hepatic and cardiac FA oxidation and acyl-CoA oxidase and carnitine palmitoyltransferase-II activities, and decreased the plasma TAG levels. The effects seem to be related to differences in the catabolic rate of the thia FA. Differences between the two groups of acids were also observed with respect to the regulation of genes involved in FA transport and catabolism. Feeding experiments with 3- and 4-thia FA in combination indicated that the 4-thia FA partly attenuated the effects of the 3-thia FA on mitochondrial FA oxidation and the hepatic TAG level. In summary, the position of the sulfur atom in the alkyl chain, especially whether it is placed in the even or odd position, is crucial for the biological effect of the thia FA. PMID- 17707984 TI - Conjugated linoleic acid reduces hepatic steatosis, improves liver function, and favorably modifies lipid metabolism in obese insulin-resistant rats. AB - CLA has been shown to induce or suppress excess liver lipid accumulation in various animal models. Interestingly, the state of insulin resistance may be an important modulator of this effect. The objective of the current study was to determine how feeding a dietary CLA mixture would affect liver lipid accumulation in insulin-resistant/obese and lean rats in relation to liver function, lipidemia, liver TAG and phospholipid FA composition, and expression of hepatic markers of FA transport, oxidation, and synthesis. Six-week-old fa/fa and lean Zucker rats (n = 20/genotype) were fed either a 1.5% CLA mixture or a control diet for 8 wk. CLA supplementation reduced liver lipid concentration of fa/fa rats by 62% in concurrence with improved liver function (lower serum alanine aminotransferase and alkaline phosphatase) and favorable modification of the serum lipoprotein profile (reduced VLDL and LDL and elevated HDL) compared with controlfed fa/fa rats. The fa/fa genotype had two-thirds the amount of CLA (as % total FA) incorporated into liver TAG and phospholipids compared with the lean genotype. In both genotypes, CLA altered the hepatic FA profile (TAG greater than phospholipids) and these changes were explained by a desaturase enzyme index. Liver-FA-binding protein and acyl CoA oxidase, markers of FA transport and oxidation, respectively, were expressed at higher levels in CLA-fed fa/fa rats. In summary, these results illustrate a strong relationship between the state of insulin resistance and liver lipid metabolism and suggest that CLA acts to favorably modify lipid metabolism in fa/fa Zucker rats. PMID- 17707986 TI - Characterization of hair lipid images by argon sputter etching-scanning electron microscopy. AB - Hair lipid images, as visualized by argon sputter etching-scanning electron microscopy (ASE-SEM), reveal convex structures with a stitch pattern (SP) at the cell membrane complex (CMC) in the transverse hair plane. Based on interindividual variation, different features of the convex SP were classified into Types 0 to 4 with the corresponding scores 0 to 4. Observations using hair fibers collected from 27 Japanese females revealed significant positive correlations between the scores and the levels of exogenous lipids, which suggests that exogenous lipids internalized at the CMC predominantly constitute the convex SP. Intraindividual variation with different levels of exogenous lipids among hair fibers derived from individual females may be relevant to the uneven physicochemical properties of hair fibers on the scalp. Observations of 380 hair fibers collected from Japanese (Mongoloid), German and American (Caucasoid) females aged 3 to 77 yr demonstrated similar age-related changes in the lipid images, which represent an increase and then a decrease in levels of exogenous lipids with increasing age. This suggests that age-related changes in exogenous lipids are attributable to alterations in sebum excreted during aging and that this elicits age-related changes in physical parameters, which affect human hair texture. PMID- 17707988 TI - Flashy style vs. healthy smile: getting a grip on grills. PMID- 17707985 TI - Selective incorporation of docosahexaenoic acid into lysobisphosphatidic acid in cultured THP-1 macrophages. AB - Lysobisphosphatidic acid (LBPA) is highly accumulated in specific domains of the late endosome and is involved in the biogenesis and function of this organelle. Little is known about the biosynthesis and metabolism of this lipid. We examined its FA composition and the incorporation of exogenous FA into LBPA in the human monocytic leukemia cell line THP-1. The LBPA FA composition in THP-1 cells exhibits an elevated amount of oleic acid (18:1n-9) and enrichment of PUFA, especially DHA (22:6n-3). DHA supplemented to the medium was efficiently incorporated into LBPA. In contrast, arachidonic acid (20:4n-6) was hardly esterified to LBPA under the same experimental conditions. The turnover of DHA in LBPA was similar to that in other phospholipids. Specific incorporation of DHA into LBPA was also observed in baby hamster kidney fibroblasts, although LBPA in these cells contains very low endogenous levels of DHA in normal growth conditions. Our resuIts, together with published observations, suggest that the specific incorporation of DHA into LBPA is a common phenomenon in mammalian cells. The physiological significance of DHA-enriched LBPA is discussed. PMID- 17707989 TI - Testing your diagnostic skills. Case no. 1: odontogenic neoplasm. PMID- 17707987 TI - Lower weight gain and higher expression and blood levels of adiponectin in rats fed medium-chain TAG compared with long-chain TAG. AB - Previous studies demonstrated that, compared with long-chain TAG (LCT), dietary medium-chain TAG (MCT) could improve glucose tolerance in rats and humans. It has been well established that adiponectin acts to increase insulin sensitivity. The effects of dietary MCT on adiponectin serum concentration and mRNA levels in adipose tissue were studied in rats. Male Sprague-Dawley rats were fed a diet containing 20% MCT or LCT for 8 wk. After 6 wk of dietary treatment, an oral glucose tolerance test was performed. Rats fed the MCT diet had less body fat accumulation than those fed the LCT diet (P < 0.01). The cell diameter of the perirenal adipose tissue, one of the abdominal adipose tissues, was smaller (P < 0.01) in the MCT diet group. The serum adiponectin concentration was higher (P < 0.01) in the MCT diet group than in the LCT diet group. The adiponectin content in the perirenal adipose tissue was higher (P < 0.01) in the MCT diet group. The MCT-fed group had a higher adiponectin mRNA level in their perirenal adipose tissue (P < 0.05). The increase of the plasma glucose concentration after glucose administration (area under the curve) was smaller (P < 0.01) in the MCT diet group than in the LCT diet group. These findings suggest that dietary MCT, compared with LCT, results in a higher serum adiponectin level with transcriptional activation of the adiponectin gene in rats. We speculate that improved glucose tolerance in rats fed an MCT diet may be, at least in part, ascribed to this higher serum adiponectin level. PMID- 17707990 TI - FDA member turns empathy into action. PMID- 17707991 TI - Avandia and your heart. PMID- 17707992 TI - Emotional eating. A sneak attack on weight loss. PMID- 17707993 TI - Summer meals. Keys to keeping cool. PMID- 17707994 TI - Finding a therapist. Tips to get started. PMID- 17707995 TI - More diabetes genes. PMID- 17707996 TI - Migraines may mean heart risk in men. PMID- 17707997 TI - Type 1 teens: save cinnamon for your toast. PMID- 17707998 TI - Insulin shots. Choosing the right spot. PMID- 17707999 TI - Our top doc. Acting Surgeon General Kenneth P. Moritsugu, MD, MPH, keeps tabs on his own health--and the health of all Americans. PMID- 17708000 TI - Small plates, great taste. Whether you call them tapas, meze, or small plates, reduced-portion eating is a trend that is here to stay. PMID- 17708002 TI - Special effects: tobacco policies and low socioeconomic status girls and women. PMID- 17708001 TI - Research profile. The picture. Addressing the needs of seniors. Medha Munshi, MD. PMID- 17708003 TI - The Tobacco Research Network on Disparities (TReND). PMID- 17708004 TI - Examining the effects of tobacco control policy on low socioeconomic status women and girls: an initiative of the Tobacco Research Network on Disparities (TReND). PMID- 17708005 TI - Pathways of disadvantage and smoking careers: evidence and policy implications. AB - OBJECTIVES: To investigate in older industrialised societies (a) how social disadvantage contributes to smoking risk among women (b) the role of social and economic policies in reducing disadvantage and moderating wider inequalities in life chances and living standards. METHODS: Review and analysis of (a) the effects of disadvantage in childhood and into adulthood on women's smoking status in early adulthood (b) policy impacts on the social exposures associated with high smoking risk. MAIN RESULTS: (a) Smoking status--ever smoking, current smoking, heavy smoking, and cessation--is influenced not only by current circumstances but by longer term biographies of disadvantage (b) social and economic policies shape key social predictors of women's smoking status, including childhood circumstances, educational levels and adult circumstances, and moderate inequalities in the distribution of these dimensions of life chances and living standards. Together, the two sets of findings argue for a policy toolkit that acts on the distal determinants of smoking, with interventions targeting the conditions in which future and current smokers live. CONCLUSIONS: An approach to tobacco control is advocated that combines changing smoking habits with reducing inequalities in the social trajectories in which they are embedded. Policies to level up opportunities and living standards across the lifecourse should be championed as part of an equity oriented approach to reducing the disease burden of cigarette smoking. PMID- 17708006 TI - Cigarette smoking transition in females of low socioeconomic status: impact of state, school, and individual factors. AB - STUDY OBJECTIVE: To examine whether young, especially low socioeconomic status (SES), females are influenced by tobacco control policies in terms of smoking initiation and transition to more adverse stages of smoking behaviour from adolescence to young adulthood. DESIGN AND SETTING: Data from 2697 young female respondents to the national longitudinal study of adolescent health wave 1 (1994 1995) and wave 3 (2001-2002). MEASUREMENTS: The following factors were used to predict the likelihood of smoking initiation and transition to heavier tobacco use between adolescence and young adulthood among females of low, middle, and high SES groups: state level tobacco control policy scores, developed by the US National Cancer Institute, state cigarette excise tax, smoking rate at school, cigarette availability at home, and number of best friends smoking. MAIN RESULTS: Stronger state level tobacco policies were associated with lower likelihood of smoking initiation and adverse transition among low SES women, although the effect sizes were small. Adolescents who attended schools with higher student smoking rates; adolescents who had easier access to cigarettes at home; and adolescents who had more friends smoking were all more likely to be adverse transitioners by young adulthood. CONCLUSIONS: State level tobacco control policies and individual level factors during adolescence are independently associated with smoking initiation and adverse transition by the onset of young adulthood, especially for low SES females. While states may have very little direct influence on individual level behaviours, through their policies they do have the potential to exert considerable influence on smoking behaviour that persists through adolescence into young adulthood. PMID- 17708007 TI - Tobacco control policies and smoking in a population of low education women, 1992 2002. AB - STUDY OBJECTIVE: To examine recent trends and the role of tobacco control policies associated with smoking among women of low socioeconomic status. DESIGN: Using four waves of the nationally representative tobacco use supplement to the current population survey (TUS-CPS)--(1992-2002), the study examined trends and used multivariate logistic models of smoking prevalence among low education women to examine the role of cigarette prices, clean air regulations, and tobacco control media campaigns, while controlling for other personal characteristics. SETTING: USA. PARTICIPANTS: Women ages 18 and older who report not having completed high school, compared with other women with greater educational attainment and men ages 18 and older with less than a high school degree. MAIN RESULTS: Smoking among low education women declined at a greater rate over the study period than among more highly educated women, in contrast with trends of earlier periods. Low education women were found to be particularly responsive to media messages as well as price, especially in comparison with high education women. CONCLUSIONS: The relation between health and socioeconomic status is not immutable; selected tobacco control policies, such as tax increases and media campaigns targeting low education women, may make inroads in reducing the smoking prevalence of this population. PMID- 17708008 TI - Political coalitions and working women: how the tobacco industry built a relationship with the Coalition of Labor Union Women. AB - OBJECTIVES: To assess how the tobacco industry established a political relationship with the Coalition of Labor Union Women (CLUW) and to learn from this example how tobacco control advocates can work more effectively with organisations with which working class women are affiliated. METHODS: The study reviewed tobacco industry documents to determine Tobacco Institute strategy, using the CLUW News and other published material to corroborate our findings. RESULTS: The Tobacco Institute was effective at framing excise tax and smokefree worksite issues in a way that facilitated CLUW's support of industry positions on these issues. The Tobacco Institute was also willing to reciprocate by providing financial and other kinds of support to CLUW. CONCLUSIONS: While tobacco control missed an opportunity to partner with CLUW on smokefree worksites and excise taxes in the 1980s and 1990s, tobacco control can also use issue framing and reciprocity to form coalitions with organisations representing the interests of working women. PMID- 17708010 TI - Association between home smoking restrictions and changes in smoking behaviour among employed women. AB - STUDY OBJECTIVE: Examine trends in home smoking restrictions among employed women not living alone and assess the associations of such restrictions with smoking behaviour. DESIGN: Multivariate logistic regression analysis of major demographic variables and household composition characteristics. STUDY PARTICIPANTS: 128 024 employed female respondents to the Census Bureau's current population survey over the 10 year period 1992 to 2002. MAIN RESULTS: The prevalence of smoke free homes has increased significantly over the past decade. This increase was evident across all demographic and household characteristics examined with the greatest rate of increase seen among smoking households. Nearly 90% of households consisting of all never smoking adult members reported having a smoke free home in 2001-02 compared with 22% of households consisting of all smokers. The extent of smoking restrictions in the home was the most powerful determinant of cessation of all the factors examined in the regression model. Odds of becoming a former smoker (any length) and quit for three months or more were seven to eight times greater among those women reporting their homes were smoke free compared with those whose homes permitted smoking anywhere in the home. CONCLUSIONS: Smoke free homes were associated with a highly significant increase in quitting (p<0.0001). However, at this time it is not clear what proportion of the observed effect can be attributed to living in a smoke free home. None the less, the significantly increased probability of quitting correlated with having a smoke free home found in this analysis, are substantially higher than the odds reported in most workplace studies published to date; additional studies are needed to elucidate this relation. PMID- 17708009 TI - Workplace and home smoking restrictions and racial/ethnic variation in the prevalence and intensity of current cigarette smoking among women by poverty status, TUS-CPS 1998-1999 and 2001-2002. AB - STUDY OBJECTIVE: Recognition of the health consequences of exposure to environmental tobacco smoke has led government agencies and many employers to establish policies that restrict cigarette smoking in public and workplaces. This cross sectional study examines the association of workplace smoking policies and home smoking restrictions with current smoking among women. DESIGN: Participants were employed US women ages 18-64 who were self respondents to the 1998-1999 or 2000-2001 tobacco use supplement to the current population survey supplements. Cross tabulations and multivariate logistic regression analyses examine the association of selected demographic characteristics, occupation, income, workplace and home smoking policies/restrictions with current smoking, consumption patterns, and quit attempts among women by poverty level for five race/ethnic groups. MAIN RESULTS: The prevalence of either having an official workplace or home smoking policy that completely banned smoking increased with increased distance from the poverty level threshold. A complete ban on home smoking was more frequently reported by African American and Hispanic women although Hispanic women less frequently reported an official workplace smoking policy. In general, policies that permitted smoking in the work area or at home were associated with a higher prevalence of current smoking but this varied by poverty level and race/ethnicity. Home smoking policies that permitted smoking were associated with lower adjusted odds of having a least one quit attempt for nearly all poverty level categories but there was no association between having one quit attempt and workplace policies. CONCLUSION: Home smoking policies were more consistently associated with a lower prevalence of current smoking irrespective of poverty status or race/ethnicity than workplace policies. These findings underscore the importance of examining tobacco control policies in multiple domains (work and home) as well as by race/ethnicity and socioeconomic position. PMID- 17708011 TI - Tobacco free workplace policies and low socioeconomic status female bartenders in San Francisco. AB - STUDY OBJECTIVE: Multiple studies have found that, compared with employees in other settings, workers in bars and restaurants have been exposed to high levels of secondhand smoke, putting them at increased risk for health complications. Among these bar employees are many women of low socioeconomic status (SES). Smoke free workplace ordinances have been extended to bars and restaurants in cities and states throughout the USA; some bars, however, continue to be out of compliance with these laws. The objective of this study is to assess the relation between bartender gender and smoke free workplace compliance in bars. DESIGN: This paper reports on analyses of observational data on compliance with smoke free workplace policy in 121 randomly selected bars together with qualitative data from semi-structured interviews with bartenders and patrons in bars. SETTING: San Francisco County bars. MAIN RESULTS: Findings from this research showed that smoke free policy non-compliance was associated with bars in which women were bartenders, increasing their tobacco exposure compared with male bartenders. In interviews, although some female bartenders expressed ambivalence toward the smoke free ordinance, many others described experiencing positive health and social consequences when the bars in which they worked could eliminate interior smoking. CONCLUSIONS: The analyses presented here shed light on the benefits of improving the workplace environment for low SES female bartenders through the extension of strong smoke free workplace policies to all workplaces, including bars. PMID- 17708013 TI - The editors' note regarding the notice of retraction. PMID- 17708012 TI - Tobacco policies and vulnerable girls and women: toward a framework for gender sensitive policy development. AB - This article assesses the effects of comprehensive tobacco control policies on diverse subpopulations of girls and women who are at increased vulnerability to tobacco use because of disadvantage. The authors report on a recent assessment of experimental literature examining tobacco taxation; smoking location restrictions in public and private spaces; and sales restrictions. A comprehensive search was undertaken to identify relevant studies and evaluation reports. Gender based and diversity analyses were performed to identify pertinent sex differences and gender influences that would affect the application and impact of the policy. Finally, the results were contextualised within the wider literature on women's tobacco use and women's health. The authors consider not only the intended policy effects, but also explicitly examine the gendered and/or unintended consequences of these policies on other aspects of girls and women's health and wellbeing. A framework for developing gender sensitive tobacco programmes and policies for low income girls and women is provided. PMID- 17708014 TI - Effect of aerobic fitness on the physiological stress responses at work. AB - OBJECTIVES: The aim of the present study was to examine the effects of aerobic fitness on physiological stress responses experienced by teachers during working hours. MATERIALS AND METHODS: Twenty-six healthy female and male teachers aged 33 62 years participated in the study. The ratings of perceived stress visual analogue scale (VAS), and the measurement of physiological responses (norepinephrine, epinephrine, cortisol, diastolic and systolic blood pressure, heart rate (HR), and trapezius muscle activity by electromyography (EMG), were determined. Predicted maximal oxygen uptake (VO(2)max) was measured using the submaximal bicycle ergometer test. The predicted VO(2)max was standardized for age using residuals of linear regression analyses. RESULTS: Static EMG activity, HR and VAS were associated with aerobic fitness in teachers. CONCLUSIONS: The results suggest that a higher level of aerobic fitness may reduce muscle tension, HR and perceived work stress in teachers. PMID- 17708015 TI - Evaluation of voice acoustic parameters related to the vocal-loading test in professionally active teachers with dysphonia. AB - INTRODUCTION: Teachers are at risk of developing voice disorders. A clinical battery of vocal function tests should include non-invasive and accurate measurements. The quantitative methods (e.g., voice acoustic analysis) make it possible to objectively evaluate voice efficiency and outcomes of dysphonia treatment. MATERIALS AND METHODS: To identify possible signs of vocal fatigue, acoustic waveform perturbations during sustained phonation were measured before and after the vocal-loading test in 51 professionally active female teachers with functional voice disorders, using IRIS software. All the participants were also subjected to laryngological/phoniatric examination involving videostroboscopy combined with self-estimation by voice handicap index (VHI)-based scale. RESULTS: The phoniatric examination revealed glottal insufficiency with bowed vocal folds in 35.2%, soft vocal nodules in 31.4%, and hyperfunctional dysphonia with a tendency towards vestibular phonation in 19.6% of the patients. In the VHI scale, 66% of the female teachers estimated their own voice problems as moderate disability. An acoustic analysis performed after the vocal-loading test showed an increased rate of abnormal frequency perturbation parameters (pitch perturbation quotient (Jitter), relative average perturbation (RAP), and pitch period perturbation quotient (PPQ)) compared to the pre-test outcomes. The same was true of pitch-intensity contour of vowel /a:/, an indication of voice instability during sustained phonation. DISCUSSION AND CONCLUSIONS: The recorded impairments of voice acoustic parameters related to vocal loading provide further evidence of dysphonia. The voice acoustic analysis performed before and after the vocal loading test can significantly contribute to objective voice examinations useful in diagnosis of dysphonia among teachers. PMID- 17708016 TI - Fish intake during pregnancy and mercury level in cord and maternal blood at delivery: an environmental study in Poland. AB - OBJECTIVES: The purpose of this study was to estimate the amount of absorbed mercury (Hg) by mothers and their infants as a result of fish consumption during pregnancy. MATERIALS AND METHODS: The cohort consisted of 313 mother-infant pairs recruited initially from ambulatory prenatal clinics in the first and second trimesters of pregnancy. The customary pattern of fish consumption during pregnancy reported by mothers was correlated with Hg levels in cord and maternal blood at delivery. Blood Hg level was measured using atomic absorption spectrometry. RESULTS: The mean Hg concentration in cord blood was markedly higher than in maternal blood at delivery (1.09 microg/L; 95%CI: 1.00-1.13 microg/L vs. 0.83 microg/L, 95%CI: 0.76-0.91 microg/L). There was significant correlation (r(s)=0.62, 95%CI: 0.55-0.69) between Hg levels in cord and maternal blood. The overall ratio of Hg in cord blood vs. maternal blood was 1.7 (95%C: 1.50-1.89). Fish consumed during the last pregnancy trimester correlated stronger with umbilical cord concentrations (r(s)=0.32; 95%CI: 0.22-0.40) than with Hg in maternal blood (r(s)=0.23; 95%CI: 0.14-0.33). CONCLUSIONS: The study shows that in Poland, babies are exposed to moderate levels of mercury prior to birth and that fish eating in pregnancy significantly contributes to prenatal Hg exposure. The findings also suggest that the level of cord blood Hg should not be used for describing inter-individual differences in maternal exposure to Hg unless a proper correction factor is introduced. PMID- 17708017 TI - Abstracts of the 17th European Meeting on Hypertension, Milan, Italy, June 15-19, 2007. PMID- 17708018 TI - Abstracts from the National Meeting of the Association for Clinical Biochemistry, Manchester, United Kingdom, 23-26 April 2007. PMID- 17708019 TI - Progress in Motor Control VI, August 9-12, 2007, Santos, Brazil. Abstracts. PMID- 17708020 TI - Abstracts from the 38th Annual Wound, Ostomy and Continence Conference, June 24 28, 2006, Minneapolis, Minnesota, USA. PMID- 17708021 TI - Abstracts from the Neurosonology Conference 2007, Budapest, Hungary. PMID- 17708022 TI - Abstracts of the 8th International Congress on Systemic Lupus Erythematosus, May 23-27, 2007, Shanghai, China. PMID- 17708023 TI - [Heart failure. Insufficient diagnostic]. PMID- 17708025 TI - Help your patients manage diabetes. PMID- 17708024 TI - Top 5 risk management tips for dental practices. How does your practice stack up? PMID- 17708026 TI - [Lung abscess and pectoral pyomiositis by Staphylococcus aureus]. PMID- 17708027 TI - Testing your diagnostic skills. Case No. 1: a relatively rare jaw neoplasm called a myofibroma. PMID- 17708028 TI - [Nail abnormalities and cutaneous lesions]. PMID- 17708029 TI - Florida's dental education leaders face unique challenges. PMID- 17708030 TI - Credentialing, reciprocity: clarifying the licensure process. PMID- 17708031 TI - Hurricane season draws near--prepare now, not later. PMID- 17708033 TI - [Digestive haemorrhage of rare origin]. PMID- 17708032 TI - [Limited edema to an upper extremity like a form or presentation of polymyositis]. PMID- 17708034 TI - [Cellulitis of the elbow]. PMID- 17708035 TI - [Abstracts of the XXXIV National Meeting on Socio-Drug-Alcohol, 22-24 March 2007, Valencia, Spain]. PMID- 17708036 TI - Adaptive management and the philosophy of environmental policy. PMID- 17708037 TI - Nervous management of modern science. PMID- 17708038 TI - [Hors-d'oeuvre]. PMID- 17708039 TI - [Reaction to 'Coping and the need for professional care in cases of subclinical psychosis']. PMID- 17708040 TI - Dental licensure: what is its purpose? PMID- 17708041 TI - Diagnostic quiz. Case No. 1: seborrheic keratosis. PMID- 17708042 TI - Detecting heart disease in the dental office. Interview by David Meinz. PMID- 17708044 TI - What your physician doesn't tell you about cholesterol. PMID- 17708043 TI - Biceps tendon and superior labrum injuries: decision-marking. PMID- 17708045 TI - Providing dental care to heart kids. Treatment doesn't always require a specialist. PMID- 17708046 TI - Specialty licensure by credentialing: what does it mean? PMID- 17708047 TI - Diagnostic quiz. Case No. 1: pyogenic granuloma. PMID- 17708048 TI - Diagnostic quiz. Case No. 2: mandibular buccal cyst (buccal bifurcation cyst. PMID- 17708049 TI - The truth about fluoride: separating fact from fiction. PMID- 17708050 TI - Material success alone is hollow success. PMID- 17708051 TI - AORN Guidance Statement: The value of clinical learning activities in the perioperative setting in undergraduate nursing curricula. PMID- 17708052 TI - Diagnostic quiz. Case No. 1: epithelial dysplasia. PMID- 17708053 TI - Building a better dental practice. PMID- 17708054 TI - Florida children receive much-needed care during Give Kids a Smile. PMID- 17708055 TI - Licensure by credentials is not the answer. PMID- 17708056 TI - Quality update. Are we ready for real quality? PMID- 17708057 TI - Following the rules 2. Community benefit and tax-exempt status. PMID- 17708058 TI - Recommendation of occupational exposure limits (2007-2008). PMID- 17708059 TI - Subunit localization studies of antibiotic inhibitors of protein synthesis. PMID- 17708060 TI - [A three-year-old boy with bullous skin eruptions and paresis]. PMID- 17708061 TI - [Can it be celiac disease?]. PMID- 17708062 TI - Chirality and pharmacokinetics: an area of neglected dimensionality? AB - Drug stereochemistry has, until relatively recently, been an area of neglected dimensionality with the development of the majority of synthetic chiral drugs as racemates. This situation has changed in recent years as a result of advances in the chemical technologies associated with the synthesis, analysis and preparative scale resolution of the enantiomers of chiral molecules. As a result of the application of these technologies the potential significance of the differential pharmacodynamic and pharmacokinetic properties of the enantiomers present in a racemate have become appreciated. Many of the processes involved in drug disposition, i.e. absorption, distribution, metabolism and excretion, involve a direct interaction with chiral biological macromolecules, e.g. transporters, membrane lipids and enzymes, and following administration of a racemate the individual enantiomers frequently exhibit different pharmacokinetic profiles and rarely exist in a 1:1 ratio in biological fluids. The magnitude of the differences between a pair of enantiomers observed in their pharmacokinetic parameters tends to be relatively modest in comparison to their pharmacodynamic properties. However, the observed stereoselectivity may be either amplified or attenuated depending on the organisational level, e.g. whole body, organ or macromolecular, the particular parameter represents. Differences in parameters involving a direct interaction between a drug enantiomer and a biological macromolecule, e.g. intrinsic metabolite formation clearance and fraction unbound, tend to be largest, and comparison of parameters reflecting the whole body level of organisation, e.g. half-life, clearance, volume of distribution, may well mask significant stereoselectivity at the macromolecular level. In spite of the recent interest in drug chirality relatively limited pharmacokinetic data are available for the enantiomers of a number of commonly used racemic drugs. Factors influencing the stereo-selectivity of drug disposition include: formulation and route of administration; in vivo stereochemical stability, both chemical and enzymatic; drug interactions, both enantiomeric and with a second drug; disease state; age; gender; race; and pharmacogenetics. As a result of such factors estimation of pharmacokinetic parameters, development of complex pharmacokinetic models and plasma-concentration-effect relationships based on 'total' drug concentrations following administration of a racemate are of limited value and potentially useless. PMID- 17708063 TI - A review on the relation between the brain-serum concentration ratio of drugs and the influence of P-glycoprotein. AB - This overview on the brain-serum relationship for drugs illustrates the importance of the drug transporter P-glycoprotein at the blood-brain barrier. Generally, an inverse relationship exists between the magnitude of the brain serum ratio and the influence of P-glycoprotein. Concerning the pharmacogenomics of P-glycoprotein, no clear effect of single nucleotide polymorphisms (SNPs) has been demonstrated in humans. PMID- 17708064 TI - Evaluation of the chemoprotective effect of Biophytum sensitivum (L.) DC extract against cyclophosphamide induced toxicity in Swiss albino mice. AB - An alcoholic extract of Biophytum sensitivum was studied against cyclophosphamide (CTX) induced toxicity in mice. Intraperitoneal administration of the extract with CTX significantly increased the total WBC count (3,356 +/- 236 cells/cm2), bone marrow cellularity (15.6 +/- 0.42 cells/femur) and alpha-esterase positive cells (846 +/- 30 cells) when compared to control mice treated with CTX alone. The relative organ weight of the spleen and thymus was also found to be increased after B. sensitivum administration when compared to the control mice. Reduction of GSH in liver (4.9 +/- 0.22 nmol/mg protein) and in intestinal mucosa (10.6 +/- 1.02 nmol/mg protein) of CTX treated controls was significantly reversed by B. sensitivum administration (liver: 6.5 +/- 0.18 nmol/mg protein; intestinal mucosa: 16.5 +/- 0.88 nmol/mg protein), with amelioration of changes in serum and liver ALP, GPT and lipid peroxidation. Histopathological analysis of the small intestine also suggests that B. sensitivum could reduce CTX induced intestinal damage. The level of the pro-inflammatory cytokine, TNF-alpha, which was elevated during CTX administration, was significantly reduced by the administration of B. sensitivum extract. The lowered levels of cytokines IFN-gamma, IL-2 and GM-CSF after CTX treatment were also found to be increased by B. sensitivum extract administration. PMID- 17708065 TI - Effect of rifampicin pretreatment on the transport across rat intestine and oral pharmacokinetics of ornidazole in healthy human volunteers. AB - Increased exsorption of ornidazole was observed from different parts of the small intestine of the rat after pretreated with rifampicin and sodium butyrate by the everted sac method. Based on the in vitro studies the effect of rifampicin pretreatment on the pharmacokinetics of ornidazole was investigated in eight healthy male volunteers. After an overnight fast, 500 mg ornidazole was administered to the volunteers, either alone or after 6 days pretreatment with a once daily dose of 600 mg rifampicin. Serum concentrations of ornidazole were estimated by reverse phase HPLC. Pharmacokinetic parameters were determined based on non-compartmental model analysis using the computer program Win Nonlin 1.1. Rifampicin preteatment resulted in a significant decrease in AUC, C(max) and t1/2, by 21.16%, 20.43% and 18.11%, respectively. Clearance was increased significantly by 32.14%. This may be due to increased induction of cytochrome P450 enzymes and/or increased expression of P-glycoprotein. This interaction may have clinical significance when ornidazole is co-administered with rifampicin in chronic treatment conditions, such as tuberculosis, leprosy and other infections of joints, bones, etc. PMID- 17708066 TI - Bioavailability of diclofenac sodium after pretreatment with diosmin in healthy volunteers. AB - Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAID). It undergoes extensive Phase I and Phase II metabolism and in vitro it is a specific CYP2C9 substrate. The first part of the study consisted of oral administration of 100 mg of diclofenac sodium (Voveran100) to 12 healthy male volunteers. Blood samples were collected from the antecubital vein at intervals of 0, 0.5, 1, 2, 3, 4, 5, 6, 7, and 8 hours. The second part of the study was conducted after a washout period of 7 days. Treatment with 500 mg p.o. of diosmin (Venex 500) was given daily for 9 days. On day 10, 100 mg of diclofenac sodium (Voveran 100) was administered. Blood samples were obtained as mentioned earlier and pharmacokinetic parameters of diclofenac before and after pretreatment with diosmin analyzed by HPLC. Diosmin pretreatment significantly enhanced AUC, C(max) and t1/2 with a concomitant reduction in CL/f. Diosmin might have inhibited the microsomal CYP2C9 mediated oxidation of diclofenac sodium. PMID- 17708067 TI - Effect of silymarin on the oral bioavailability of ranitidine in healthy human volunteers. AB - The effect of silymarin pretreatment on the pharmacokinetics of ranitidine was investigated in 12 healthy male human volunteers aged 19-26 years. After an overnight fast, ranitidine 150 mg was administered to the volunteers either alone or after 7 days pretreatment with thrice daily dose of 140 mg silymarin. The wash out period between each treatment was 7 days. Serum levels of ranitidine were determined by HPLC. Pharmacokinetic parameters were determined based on non compartmental model analysis using the computer program KINETICA. There was no influence of silymarin on the pharmacokinetics of ranitidine. Concomitant administration of silymarin at this dosage did not alter ranitidine C(max) and AUC(0-infinity). There was a significant difference in area under the first moment curve (AUMC) and mean residence time. This result is useful in predicting the interaction of silymarin with other cytochrome 3A4 and P-glycoprotein substrates at normal dosage. PMID- 17708069 TI - Rhabdomyolysis after addition of digitoxin to chronic simvastatin and amiodarone therapy. AB - Rhabdomyolysis is a well known side effect of statin therapy. Several drugs may increase its risk by drug-drug interactions. In particular, patients with heart disease receive more and more different compounds to cope with all the pathomechanisms involved and may therefore be of high risk for side effects. We report a case of rhabdomyolysis in a patient with heart failure on a multi-drug regimen caused by a drug interaction between chronic statin therapy (simvastatin), amiodarone and newly administrated digitoxin. The patient recovered fully after cessation of simvastatin therapy, the other drugs were given continuously. Potential mechanisms of this event are discussed. Most interesting in this case is that rhabdomyolysis occurred only after starting digitoxin after long-term therapy with the statin. PMID- 17708068 TI - Isoflurane reduces the synthesis of surfactant-related protein a of alveolar type II cells injured by H2O2. AB - The influence of isoflurane (Iso) on the synthesis of surfactant-related protein A (SP-A) of alveolar type II (AT II) cells in primary culture and after injury by H2O2 was investigated. AT II cells were isolated and purified from adult Sprague Dawley rats and used for experiments after 32 h in primary culture. The cell cultures were randomized to six groups (n = 8 in each group): control group (no treatment), 0.28 mM Iso group, 2.8 mM Iso group, 75 microM H2O2 group, 75 microM H2O2 + 0.28 mM Iso group, and 75 microM H2O2 + 2.8 mM Iso group. Each group was continuously incubated for 3 h after administration of Iso and/or H2O2. The intracellular SP-A and the SP-A of the culture medium were measured with an enzyme-linked immunosorbent assay (ELISA). Iso significantly decreased the intracellular SP-A content and that of the culture medium, and aggravated the decrease of SP-A content induced by H2O2. These findings suggest that Iso itself may decrease SP-A synthesis of AT II cells in vitro, and aggravate the damage to AT II cells under peroxidation conditions. PMID- 17708070 TI - Polycyclic aromatic hydrocarbons in the South American environment. AB - Pollution of the environment with polycyclic aromatic hydrocarbons (PAHs) should be a global concern, especially in urbanized areas. In South American countries, where notable increase in urban populations has been observed in the past few years, reliable information about the pollution status of these urban environments is not always easily accessible, and therefore an effort to collect updated information is required. This review attempts to contribute by analyzing the existing information regarding environmental levels of PAHs in some South American countries. A regional trend for environmental PAH information is an uneven contribution, because some countries, such as Bolivia, Peru, Paraguay, and Ecuador, have reported no information at all in the scientific literature, reflecting to a certain extent the different patterns of economic, technical, and scientific development. PAH air monitoring is one of the areas that has received the most attention during the last few years, mainly in Brazil, Chile, and Argentina, where data represent a few geographical areas within the region. PAH levels in air from some urban areas in Argentina, Brazil, and Chile, considered moderate to high (100-1000ng/m3), are probably among the highest values reported in the open literature. Urbanization, vehicle pollution, and wood fires are the principal contributors to the high reported levels. In more temperate areas, a clear distinction is observed between summer and winter levels. PAH monitoring in soils is very limited within the region, with few data available, and most information indicates widespread pollution. In Brazil, values for many representative ecosystems were found. In Chile, data from forestry and agricultural areas indicate in general low concentrations, in spite of a relatively high detection frequency. Pollution levels in soils are highly dependent on their closeness to PAH sources and certain cultural practices (agricultural burnings, forest fires, etc.). Water PAH levels are rarely reported in the scientific literature for South American countries. Few data were available, even though many regulatory agencies perform routine analysis of hydrocarbons in waters. No information was found specifically related to PAH compounds, which could indicate generally low PAH levels in waters. Regional PAH information for sediments also indicates higher levels. Overall, as observed for water, sediment data indicate a complex situation in densely populated areas affected by urban-industrial inputs where high PAH levels are found. In contrast, in remote areas a typical profile of diagenetic PAHs dominates. Concentrations are greatly variable and are principally related to several highly contaminated sites in Argentina and Brazil (hot spots) with levels four to five orders of magnitude higher. Even though PAHs have carcinogenic properties, little attention has been paid to the analysis of aquatic organisms except in the case of bivalves. As observed for other environmental receptors, the regional data distribution is uneven and is heavily centered in coastal environments and in a few countries (Argentina, Brazil, Chile, and Peru). The most comprehensive PAH monitoring program in the South American coastal environment is the Mussel Watch. Baseline PAH concentrations range from 200 to 700 microg kg(-1) lipids in unpolluted sites; from 1,000 to 3,000 microg kg(-1) in moderately contaminated sites; and from 4,000 to 13,000 microg/kg lipids in the most affected bivalves that come from areas of Rio de la Plata (Argentine side), Recife (Brazil), and Punta Arenas (Chile). Critical data gaps exist with respect to PAH analysis in biota, including humans, in foodstuffs, and subsequent effects. Considering the high levels reported in the air compartment, risk assessment procedures in highly populated areas need to be performed. Additionally, few countries within the region have information on PAH levels. In these countries, this type of analysis needs to be performed, and the laboratory capacity needs to be built to assure the accomplishment of these objectives. PMID- 17708071 TI - Silver as a disinfectant. AB - Silver has been used as an antimicrobial for thousands of years. Over the past several decades, it has been introduced into numerous new venues such as in the treatment of water, in dietary supplements, in medical applications, and to produce antimicrobial coatings and products. Silver is often used as an alternative disinfectant in applications in which the use of traditional disinfectants such as chlorine may result in the formation of toxic by-products or cause corrosion of surfaces. Silver has also been demonstrated to produce a synergistic effect in combination with several other disinfectants. Many mechanisms of the antibacterial effect of silver have been described, but its antiviral and antiprotozoal mechanisms are not well understood. Both microbial tolerance and resistance to silver have been reported; however, the effect of silver has been observed against a wide variety of microorganisms over a period of years. Further research is needed to determine the antimicrobial efficacy of silver in these new applications and the effects of its long-term usage. PMID- 17708073 TI - Critical soil concentrations of cadmium, lead, and mercury in view of health effects on humans and animals. AB - Assessment of the risk of elevated soil metal concentrations requires appropriate critical limits for metal concentrations in soil in view of ecological and human toxicological risks. This chapter presents an overview of methodologies to derive critical total metal concentrations in soils for Cd, Pb, and Hg as relevant to health effects on animals and humans, taking into account the effect of soil properties. The approach is based on the use of nonlinear relationships for metals in soil, soil solution, plants, and soil invertebrates, including soil properties that affect metal availability in soil. Results indicate that the impact of soil properties on critical soil metal concentrations is mainly relevant for Cd because of significant soil-plant, soil-solution, and soil-worm relationships. Critical Cd levels in soil thus derived are sometimes lower than those related to ecotoxicological impacts on soil organisms/processes and plants, which is especially true for critical soil Cd concentrations in view of food quality criteria for wheat, drinking water quality, and acceptable daily intakes of worm-eating birds and mammals. There are, however, large uncertainties involved in the derivation from assumptions made in the calculation and uncertainties in acceptable daily intakes and in relationships for Cd in soil, soil solution, plants, and soil invertebrates. Despite these uncertainties, the analyses indicate that present Cd concentrations in parts of the rural areas are in excess of the critical levels at which effects in both agricultural and nonagricultural systems can occur. PMID- 17708072 TI - Impact of soil properties on critical concentrations of cadmium, lead, copper, zinc, and mercury in soil and soil solution in view of ecotoxicological effects. AB - Risk assessment for metals in terrestrial ecosystems, including assessments of critical loads, requires appropriate critical limits for metal concentrations in soil and soil solution. This chapter presents an overview of methodologies used to derive critical (i) reactive and total metal concentrations in soils and (ii) free metal ion and total metal concentrations in soil solution for Cd, Pb, Cu, Zn, and Hg, taking into account the effect of soil properties related to ecotoxicological effects. Most emphasis is given to the derivation of critical free and total metal concentrations in soil solution, using available NOEC soil data and transfer functions relating solid-phase and dissolved metal concentrations. This approach is based on the assumption that impacts on test organisms (plants, microorganisms, and soil invertebrates) are mainly related to the soil solution concentration (activity) and not to the soil solid-phase content. Critical Cd, Pb, Cu, Zn, and Hg concentrations in soil solution vary with pH and DOC level. The results obtained are generally comparable to those derived for surface waters based on impacts to aquatic organisms. Critical soil metal concentrations, related to the derived soil solution limits, can be described as a function of pH and organic matter and clay content, and varying about one order of magnitude between different soil types. PMID- 17708074 TI - Fluoroquinolone antibiotics in the environment. AB - Fluoroquinolones (FQs) are used in large amounts for human and animal medical care. They are excreted as parent compound, as conjugates, or as oxidation, hydroxylation, dealkylation, or decarboxylation products of the parent compound. A considerable amount of FQs and their metabolites may reach the soil as constituents of urine, feces, or manure. The residues of FQs in foods of animal origin may pose hazards to consumers through emergence of drug-resistant bacteria. FQs bind strongly to topsoil, reducing the threat of surface water and groundwater contamination. The strong binding of FQs to soil and sediments delays their biodegradation and explains the recalcitrance of FQs. Wastewater treatment is an efficient elimination step (79%-87% removal) for FQs before they enter rivers. FQs are susceptible to photodegradation in aqueous medium, involving oxidation, dealkylation, and cleavage of the piperazine ring. PMID- 17708076 TI - The P&T Committee's role in managing drugs for rare diseases. PMID- 17708075 TI - Explosives: fate, dynamics, and ecological impact in terrestrial and marine environments. AB - An explosive or energetic compound is a chemical material that, under the influence of thermal or chemical shock, decomposes rapidly with the evolution of large amounts of heat and gas. Numerous compounds and compositions may be classified as energetic compounds; however, secondary explosives, such as TNT, RDX, and HMX pose the largest potential concern to the environment because they are produced and used in defense in the greatest quantities. The environmental fate and potential hazard of energetic compounds in the environment is affected by a number of physical, chemical, and biological processes. Energetic compounds may undergo transformation through biotic or abiotic degradation. Numerous organisms have been isolated with the ability to degrade/transform energetic compounds as a sole carbon source, sole nitrogen source, or through cometabolic processes under aerobic or anaerobic conditions. Abiotic processes that lead to the transformation of energetic compounds include photolysis, hydrolysis, and reduction. The products of these reactions may be further transformed by microorganisms or may bind to soil/sediment surfaces through covalent binding or polymerization and oligomerization reactions. Although considerable research has been performed on the fate and dynamics of energetic compounds in the environment, data are still gathering on the impact of TNT, RDX, and HMX on ecological receptors. There is an urgent need to address this issue and to direct future research on expanding our knowledge on the ecological impact of energetic transformation products. In addition, it is important that energetic research considers the concept of bioavailability, including factors influencing soil/sediment aging, desorption of energetic compounds from varying soil and sediment types, methods for modeling/predicting energetic bioavailability, development of biomarkers of energetic exposure or effect, and the impact of bioavailability on ecological risk assessment. PMID- 17708077 TI - A context for decisions regarding employer coverage of vaccines. PMID- 17708078 TI - Clinical outcomes of patients with upper respiratory tract infections and acute sinusitis managed with a Web-based protocol in primary care practice. AB - A Web-based system for management of patients with symptoms of upper respiratory tract infection (URI) or sinusitis was developed and implemented for a primary care practice. Researchers conducted a retrospective analysis of the clinical records of 241 patients who accessed the Web-based protocol for these symptoms. A total of 137 patients (57%) fulfilled the criteria for management of their symptoms by registered nurses who followed established treatment guidelines; 51 patients were diagnosed as having URI symptoms and 86 with symptoms of acute sinusitis. For 84% of the patients with URI symptoms, no antibiotics were prescribed. First-line antibiotics were prescribed for 80% of the patients with sinusitis. The outcomes were no different from those of patients who had been treated with the same guidelines using a telephone protocol. Web-based protocolized care proved efficient, and exhibits outcomes similar to those derived from telephone-based treatment. PMID- 17708079 TI - Management of anemia using erythropoiesis-stimulating agents. PMID- 17708080 TI - Outpatient erythropoietin administered through a protocol-driven, pharmacist managed program may produce significant patient and economic benefits. AB - To assess the effect of a disease management program in anemia of chronic kidney disease (CKD), the authors reviewedthe records of all adults treated with epoetin alfa (EPO) at their institution between September 2003 and April 2006 and compared them with a group treated through a pharmacist-managed program with patients managed by PCPs in terms of time to target hemoglobin (Hb) (11-12.9 mg/dL), percent of Hb values maintained in target range, average weekly dose of EPO, and percent of iron-saturation (T-sat) values within target range (20%-50%) over a period of six months to one year. Although pharmacist-managed patients received lower weekly EPO doses than those managed by PCPs (6,698 vs. 12,000 units, respectively; P = .0001), they achieved goal Hb faster (47.5 vs. 62.5 days, P = .11) and maintained a higher percentage of Hb and T-sat values in target range (69.8% vs. 43.9%, P = .0001, and 64.8% (vs. 40.4%, respectively; P = .043). A pharmacist-managed program may present significant clinicaland economic benefits in anemia of CKD. PMID- 17708081 TI - Trust us! PMID- 17708082 TI - Patient counseling women using oral contraceptives. AB - Oral contraceptives (OCs) are the most widely used form of reversible birth control in the United States. However, incorrect and/or inconsistent use may result in increased failure rates and unintended pregnancies, which present a significant cost burden to the health care system and HMOs. One of the best mechanisms to improve outcomes is through high-quality clinician-patient communication. Managed care organizations may benefit from encouraging their providers to counsel and educate patients on the proper use of OCs, as this may reduce unnecessary follow-up visits, lower the number of unintended pregnancies, and increase patient satisfaction with their health care. PMID- 17708083 TI - [Forty years of health research in agricultural work]. PMID- 17708084 TI - [1966-2006: from occupational medicine to occupational health in agriculture]. AB - Occupational medicine in agriculture was established in 1966 in a different and specific way as compared to occupational medicine in the commerce and industry social security scheme. The long preliminary debates resulted in the establishment of an occupational medicine for all farm employees and voluntary operators. This mission was entrusted to the Mutualite sociale agricole (MSA), a French welfare agency, which directly hires specifically trained occupational physicians. In parallel, preventive medicine examinations have been implemented for those insured by the MSA. The order adopted on May 11th, 1982, a reference regulation regarding occupational medicine in agriculture, was amended by the reform adopted in 2004. Occupational health in agriculture is now codified in the rural law. PMID- 17708085 TI - [Agricultural occupational health and social security]. AB - The Mutualite Sociale Agricole (MSA) is the French social security agency for all agricultural wage earners and non-wage earners. It is the second French social security scheme after the general scheme, providing coverage for wage earners in commerce and industry. The MSA covers the whole spectrum of benefits (recovery, illness, family, retirement, occupational injury and disease) within a unique business window. The management of the MSA is overseen by elected representatives, thus creating a unique social democracy in the world of social security. Among the services managed by the MSA, occupational health and safety hold an original position: the MSA is indeed the only social security agency dealing with occupational health. 350 occupational physicians and 250 prevention consultants work in a multidisciplinary environment for the benefit of agricultural wage earners, as well as farmers, since the MSA implemented in 2002 an occupational risk prevention scheme for farmers. PMID- 17708086 TI - [The French National Institute for Agricultural Medicine (INMA)]. AB - Since 1958, the French National institute for agricultural medicine (INMA) has been studying the determinant health factors (non-exclusively medical) in the agricultural and rural environment. To reach this objective, the INMA organizes various types of training (degree in agricultural medicine, training for the physicians from the Mutualite Sociale Agricole--a French social security agency- , continuing education, seminars and symposiums etc.) designed for various health and safety professionals (occupational physicians, consultant physicians, general practitioners, especially from rural areas, members of safety committees etc.). This agricultural and rural specificity of the INMA is also one of the characteristics of its oldest training (2,500 physicians trained to date): the degree in agricultural medicine, which, following one or two years of courses, allows trainees to carry on occupational medicine in the agricultural sector. Through its holdings, the INMA website (www.inma.fr) provides physicians with a lot of answers to their questions regarding the health issue in agriculture. PMID- 17708088 TI - [Network for surveillance of zoonoses in agriculture]. AB - Currently, health risk monitoring and observation are major issues in terms of prevention. These principles specifically apply to biological risks with the onset of emerging or re-emerging zoonoses and the implementation of a specific regulation on workers' protection against these risks. It is in this context that the Mutualite Sociale Agricole (French social security agency) decided in 1999 to create a monitoring network for non-food zoonoses in agriculture, supported by field professionals. More than a case recording system, it is an exchange network between various actors specialized in human health, prevention and animal health. Many different actions were initiated: studies, surveys, training, development of information tools etc., to give the various actors means to know and create awareness on these often ill-known diseases, to strengthen risk assessment, adapt prevention measures to each situation and react in the event of a sanitary crisis. PMID- 17708087 TI - [Phyt'attitude: network for toxicovigilance in agriculture]. AB - Phyt'attitude, a specific observatory on risks associated with the use of pest control products, was created in 1997 by the Mutualite Sociale Agricole (MSA- French social security agency). Its objectives are: to better identify the acute and subacute impact of pest control products so as to develop individual prevention strategies taking into account the actual work; and to improve prevention through providing feedback to public authorities and manufacturers. Professional users can report the disorders they believe to be associated with pest control treatment (headache, difficult breathing, vomiting, skin irritation) by dialing the following French toll-free number: 0 800 887 887 or by contacting the occupational health-safety teams at the MSA. A reporting file completed by the occupational physician and the prevention consultant is forwarded to an expert toxicologist. Accountability is found in 2 out of 3 cases. Several concrete measures were adopted: new product labeling, time limits for re-entering the treated areas, removal of sodium arsenite and change in the formulation. Reports are published periodically. The last one covers the year 2004 and the first semester 2005. PMID- 17708090 TI - [Prevention of avian flu]. AB - Since 1997, highly pathogenic avian influenza has evolved from an exclusively animal disease to a zoonosis. In 2003, the H5N1 HP virus developed in poultry in South-Eastern Asia, before spreading to European countries and Africa. Human cases are systematically associated with a close and intensive contact with infected poultry; their number is currently limited as compared to the total number of exposed people in the world. Many precautionary measures have been taken to prevent the extension of foci, as much in terms of animal health as in terms of protection of those potentially exposed to infected birds. Besides the zoonotic aspect, the genetic evolutionary potential of influenza viruses and the unusual world H5N1 HP virus circulation in birds have raised concerns about a potential new influenza pandemic. This is the reason why public authorities have initiated a large-scale preparedness plan to face this contingency. PMID- 17708089 TI - [Monitoring occupational hazards and farm machinery injuries]. AB - The Mutualite Sociale Agricole (MSA--French social security agency) closely examines the circumstances and consequences of the accidents and diseases occurring in agriculture as part of the professional activity of farmers and their employees. During work as such, identified as being the first source of accidents, approximately 35,000 and 70,000 accidents occur each year, respectively to farmers and employees. In both populations, the accident frequency is around 60 out of every 1,000 insured persons. The evolution is positive for employees, but serious, non-fatal accidents remain a major area of concern. Accidents to and from work mainly involve employees. Their number has markedly decreased and the anualy frequency is close to 3 out of every 1,000 employers. The number of occupational diseases is constantly increasing, mainly as the consequence of the recognition of periarticular diseases. This article also summarizes the main conclusions of a French survey conducted in 2003 among 50,000 wage earners in the agricultural sector, as part of the medical monitoring of professional risks (SUMER). PMID- 17708091 TI - [Parkinson's disease and rural environment]. AB - Parkinson's disease, the primary cause of parkinsonian syndrome, is, after Alzheimer's disease, the most frequent neurodegenerative disorder. Parkinson's disease is currently considered as a multifactorial disease resulting from the effect of genetic and environmental susceptibility. Several epidemiological studies have shown a moderate association between Parkinson's disease and farmer occupation or exposure to pesticides. Nevertheless, no product has been incriminated in a repeatable manner in these studies. The main methodological difficulty of these studies is associated with the complexity in assessing the occupational exposure to pesticides. The results of the toxicological studies point equally in this direction and provide arguments in favor of this relationship. However, some questions remain to be answered, particularly the role of low-dose exposure, the gene-environment interactions and the implied biological mechanisms. PMID- 17708092 TI - [Cancers and pesticides]. AB - Cancers, cancer incidence and cancer-associated deaths remain an area of concern. The proportion of cancers of occupational origin is estimated between 2 and 8 percent of the mortality per cancer. Pesticides (insecticides, fungicides and herbicides) are widely used in France. Epidemiological studies on cancers in agriculture have been conducted for approximately forty years. While meta analyses have revealed a lower rate of certain types of cancer in farmers (lung, esophagus, bladder), others seem to be slightly over-represented. Some cancers, such as hematological malignancies, are studied more frequently when it comes to an association with pesticides, but other suspected risk factors, often associated, are studied as well. Simultaneously, the IARC has conducted several research studies on pesticides, which are progressively classified according to their carcinogenicity. Currently, a better statistical validity is reached with cohort studies. In 2005, France initiated a large-scale cohort, "AGRIGAN", including 175,000 subjects. PMID- 17708093 TI - [Musculoskeletal disorders in agriculture]. AB - Musculoskeletal disorders (MSD) are a major area of concern in the occupational world. The agricultural industry is particularly affected: 93 percent of occupational diseases in agriculture are MSD. Carpal tunnel syndrome occurs in one third of the cases. Shoulder is the second most common location. The most affected occupational areas are meat production, viticulture, market gardening, horticulture and small animal farming. This MSD phenomenon, of multifactorial origin, which has been amplifying for two decades, has led to some consensus in terms of definition and prevention strategy. The aim is to identify, limit or even suppress risk factors through worker training as well as through actions related to work organization. Regarding occupational health and safety in agriculture, two fronts of progress have been mentioned: the creation of a statistic observatory of MSD (disease, occupational area and cost) and the assessment of prevention activities. Finally, a new issue is being discussed: sustainable prevention of MSD. PMID- 17708094 TI - [Psychosocial risk]. AB - Psychosocial risk is an emerging hazard in occupational health, also present in the agricultural sector with specific particularities. It is not limited to occupational stress, of which the prevalence is 28 percent in Europe, but also involves the risk of mental distress associated with the professional activity. The French and European regulations now require that work conditions, work organization, as well as mental health be taken into consideration in occupational risk assessment. In companies, the external violence with the public and internal violence among employees are considered. A global approach makes it possible to repair or to limit the effects on individuals but also to act on the source. In the agricultural environment, psychosocial risk is regularly studied and various appropriate prevention methods are implemented as far ahead of the risk as possible. An evaluation survey on stress level as well as a management protocol for workplace assault victims are presented. PMID- 17708095 TI - [Lung diseases in farmers]. AB - Respiratory diseases in farmers are complex and intricate diseases. Their diagnosis, management and treatment are difficult and their social and financial consequences can be painful. Respiratory diseases include: hypersensitivity pneumopathies, the most frequent and recognized one being farmer's lung disease; agricultural chronic bronchitis; allergic or non-allergic asthmas and rhinitis; and toxic bronchopneumopathies, of which organic dust toxic syndrome (or dust fever) is the most common, especially in animal breeding environments. The purpose of this article is to shortly describe these diseases, indicate their frequency and the main elements of their management: treatments and prevention methods. PMID- 17708096 TI - [Agricultural occupational diseases regulatory system]. AB - In the agricultural social security scheme, as well as in the general scheme, occupational diseases are recognized in tables referring to a presumption of origin or, on a case-by-case basis, through a supplementary plan seeking the advice of a multidisciplinary specialized committee. In agriculture, occupational diseases have their specific tables; their hazards are close to those of the general scheme but of course, tasks are adapted to the reality of agricultural exposures. The regulatory system is identical, in terms of declaration, recognition procedures and especially resort to the supplementary plan. Like farm employees, which have been covered since 1955 (publication date of the first tables in the agricultural social security scheme), farmers also receive benefit payment since 2002. PMID- 17708097 TI - SPACE and EVA-3S: two failed studies? PMID- 17708098 TI - ANCA-associated vasculitis: diagnosis, clinical characteristics and treatment. AB - The primary systemic vasculitides are a group of diseases characterized by an inflammatory process of the vessel walls and classified according to the smallest vessels involved. Small vessel vasculitides comprise the largest subgroup divided into diseases with a pauci-immune vasculitis and ANCA and diseases with deposition of immunoglobulin without ANCA. ANCA-associated systemic vasculitides include Wegener's granulomatosis, microscopic polyangiitis comprising renal limited vasculitis and Churg-Strauss syndrome. Diagnosis is based on clinical manifestation, ANCA-testing and histology. Beside the role of ANCA as a diagnostic marker many studies and animal models have focused on the pathogenic role. The treatment of ANCA-associated vasculitis has changed from a standardized "Fauci-protocol" to an individualized less toxic strategy taking into consideration disease severity) organ manifestation, age of the patient and individual risk factors (e.g. increased bone marrow toxicity in patients with renal insufficiency). For remission induction patients are sub-grouped according to limited or generalized disease with moderate or severe renal involvement. Thus cyclophosphamide is only used in patients with generalized disease or - regarding Churg-Strauss-syndrome - patients with risk factors. For maintenance of remission azathioprine should be used in most of the patients. PMID- 17708099 TI - Current treatment options of femoral pseudoaneurysms. AB - Femoral pseudoaneurysm (PA) is a common complication that occurs in up to 6% of diagnostic or therapeutic catheterisation. Spontaneous closure is the rule for small PA. Large and complex PA need treatment to prevent complications such as diffuse hemodynamically effective bleeding or embolisation. A manual compression repair with or without ultrasound (US) guidance remains the first line treatment. A surgical approach is indicated in selected cases and requires anaesthesia, wound healing, longer hospital stay and extensive costs. New therapies have emerged recently that are non invasive and appropriate to most patients, even in critically ill patients. We here review the non-surgical treatment options that include compression therapy, endoprosthesis placement, coil embolisation, percutaneous collagen and thrombin injection. PMID- 17708100 TI - Occlusion of iatrogenic pseudoaneurysms with percutaneous ultrasound guided thrombin injection. AB - BACKGROUND: Pseudoaneurysm is a common complication of cardiac catheterization and coronary intervention with an incidence of 2% even in experienced centers. PATIENTS AND METHODS: In a feasibility study conducted between December 2004 and February 2006 we enrolled 76 patients consecutively to receive local thrombin injection (mean 329 IU; range 100-800 IU) into the aneurysma sac. RESULTS: Ultrasound guided thrombotic occlusion of pseudoaneurysms was successful after one injection in 83% of the patients, 17% of the patients required more than one injection. The overall success rate of the procedure was 98,9%. No peripheral embolisation of thrombin was noted during any injection and we registered no other complication that needed any further intervention. CONCLUSIONS: We conclude that ultrasound guided occlusion of pseudoaneurysms using thrombin injection with a success rate of the procedure of 98,9% is feasible and safe. PMID- 17708101 TI - "One-stop-shop" ultrasound diagnosis of functional, structural and physicomechanical properties of the brachial artery. AB - BACKGROUND: The pathogenesis of atherosclerosis comprises endothelial dysfunction, thickening as well as impaired compliance of the arterial vessel wall. Early assessment of these alterations of the vessel wall at the same site of the vascular tree has yet been hampered by the lack of highly sensitive diagnostic approaches suitable for clinical routine. We therefore aimed to develop and validate a single non-invasive examination of the brachial artery for simultaneous and highly accurate measurement of functional, structural and physicomechanical parameters of the brachial artery. PATIENTS AND METHODS: 20 healthy individuals were investigated using high resolution ultrasound. Flow mediated dilation (FMD), fractional diameter changes (FDC) and intima-media thickness (IMT) were measured in the same segment of the brachial artery. Coefficients of variation, day-to-day-variability, between- and within-observer variability were investigated in 5 individuals. All measurements were performed manually and by an automated PC-based analyzing system. RESULTS: Mean values for all measured parameters were 7.65 +/- 0.8% for FMD, 0.02 +/- 0.002 for FDC, 0.351 +/- 0.007 mm for IMT and followed an even distribution throughout the study population. Automated analysis of coefficient of variation, day-to-day-, between- and within-observer variabilities were: 0. 78%, 1.3%, 0.8%, 0.8% (FMD); 4.7%, 2.8%, 4.2%, 2.7% (FDC); 1.8%, 1.1%, 1.9%, 1.1% (IMT). Coefficient of variation, day-to-day-, between- and within-observer variabilities for the manual readings were significantly higher. CONCLUSIONS: Functional, structural and physicomechanical parameters of the brachial artery can be quantified consecutively, time-saving and highly reproducibly as an "one-stop-shop" in a single session using high resolution ultrasound with digitized post-processing. This highlights the future possibility of early, sensitive and non-invasive diagnostic testing of vascular function in patients prone to vascular disease. PMID- 17708102 TI - Blunt renal trauma: comparison of contrast-enhanced CT and angiographic findings and the usefulness of transcatheter arterial embolization. AB - BACKGROUND: The purpose of this study was to evaluate the role of contrast enhanced CT and the usefulness of superselective embolization therapy in the management of arterial damage in patients with severe blunt renal trauma. PATIENTS AND METHODS: Nine cases of severe renal trauma were evaluated. In all cases, we compared contrast-enhanced CT findings with angiographic findings, and performed transcatheter arterial embolization (TAE) in six of them with microcoils and gelatin sponge particles. Morphological changes in the kidney and site of infarction after TAE were evaluated on follow-up CT Chronological changes in blood biochemistry findings after injury, degree of anemia and renal function were investigated. Adverse effects or complications such as duration of hematuria, fever, abdominal pain, renovascular hypertension and abscess formation were also evaluated. RESULTS: The CT finding of extravasation was a reliable sign of active bleeding and useful for determining the indication of TAE. In all cases, bleeding was effectively controlled with superselective embolization. There was minimal procedure-related loss of renal tissue. None of the patients developed abscess, hypertension or other complications. CONCLUSIONS: In blunt renal injury, contrast-enhanced CT was useful for diagnosing arterial hemorrhage. Arterial bleeding may produce massive hematoma and TAE was a useful treatment for such cases. By using selective TAE for a bleeding artery, it was possible to minimize renal parenchymal damage, with complications of TAE rarely seen. PMID- 17708103 TI - Is initial success of thrombolytic therapy with rt-PA in patients with lower limb ischemia durable? A long-term follow-up series. AB - BACKGROUND: Catheter-directed intraarterial thrombolytic therapy with rt-PA has been established as an alternative to surgery in selected patients with lower limb ischemia. The purpose of this study is to evaluate its long-term results and to try to identify patient variables influencing outcome. PATIENTS AND METHODS: The results of thrombolytic treatment for acute or subacute lower limb ischemia in 82 patients (51 male, 31 female) were retrospectively analysed. Clinical data (time of symptoms onset, clinical stage, type of affected vessel, anatomical localisation) as well as comorbidities were recorded. The success rate of thrombolysis as well as the incidence of adverse events was evaluated. Patients with initial success were followed up after a median of 52,5 months. RESULTS: Thrombolytic therapy was successful in 67 cases (82%). An additional endovascular or surgical procedure was necessary in 39 of these patients (48%). The overall bleeding rate was 18% and the mortality and major amputation rate was 1%. 42 patients with early clinical success were available for follow-up. 34 of them (81%) were free of ischemic symptoms and the overall limb salvage rate was 96%. We could not identify factors significantly influencing early or long-term results, although there was a trend towards better results in patients with acute ischemia and in patients with occluded native arteries. CONCLUSIONS: Intraarterial local thrombolytic therapy has a relatively high initial success rate in selected patients with lower limb ischemia, but is associated with a significant number of bleeding complications. Furthermore, additional procedures are required in almost half the patients. Initial success is durable at the long term in the majority of cases. Better selection of patients and refinements of the thrombolytic therapy might help to further improve results and lower the bleeding complications. PMID- 17708104 TI - An unusual cause of peripheral artery embolism: floating thrombus of the thoracic aorta surgically removed. AB - Intraluminal mobile thrombus of the descending aorta are rare disorders. They are at high risk for peripheral embolism and therefore indication for treatment is mandatory. We report on a 54-year-old patient with peripheral arterial embolization who was treated by surgical thrombus removement by thoracotomy and staged peripheral bypass grafting. New diagnostic tools are presented, therapy and prognosis are discussed. PMID- 17708105 TI - [The Klippel-Trenaunay syndrom associated with multiple visceral arteries aneurysms]. AB - The Klippel-Trenaunay-syndrom (KTS) is a congenital angiodysplasia of venous vessels characterized by three main symptoms: cutanous vascular naevi, hyperthropy of a limb and varicosis or venous malformations. The coincidence of KTS and arterial malformations such as renal artery aneurysm has been described twice in the literature. We report the case study of a 40-years-old male patient with KTS and aneurysms of a renal artery, the splenic artery, the superior mesenteric artery and of a popliteal artery and popliteal vein. After documenting the diagnostic and therapeutic course we describe this case as it relates to the clinical literature. In the differential diagnosis of KTS two different syndroms have to be pointed out: the Servelle-Martorell-syndrom and the Frederick Parkes Weber-syndrom. PMID- 17708106 TI - [Anomaly of the vena cava inferior with paracaval venous aneurysm and renal collateralisation]. AB - Aneurysms of the great venous vessels represent anatomical rarities. Most malformations of the venous system published so far concern mainly the inferior vena cava and arise in different formations. Reports of malformations of the renal veins are limited to a few case reports and may lead to diagnostic and therapeutic difficulties. We report on an case of a asymptomatic, aneurysmatic venous malformation of the vena cava inferior With consideration of the entire findings we preferred a conservative treatment of the patient. PMID- 17708107 TI - [Ulcers associated with arteriovenous fistula within a Stewart-Bluefarb syndrome: arterial and/or venous therapy?]. AB - We report on a 46-year old female patient with a 2-year history of ulceration over the dorsum of her right foot associated with a congenital arteriovenous fistula. About 12 years ago she had an ulcer at the same site. Despite an insufficient occlusion of the arteriovenous fistula after coil-embolization complete healing of the ulcer was achieved for a period of 10 years. At present hyperpigmentation could be seen surrounding the ulcer as a clinical sign for a venous insufficiency. The ulcer healed completely under a conservative therapy of the venous component of the arteriovenous fistula. The pathogenesis and therapy of ulcers associated with arteriovenous fistula within a Stewart-Bluefarb syndrome are discussed in this case report. PMID- 17708109 TI - Diagnosis of colo-rectal cancer revealed by haemorrhagic complication of intraarterial thrombolysis. AB - Haemorrhage is a recognized complication of catheter-directed thrombolysis. We report one case of an afore unknown colo-rectal carcinoma, which was detected due to rectal bleeding following intraarterial thrombolysis. As reported with warfarin induced gastrointestinal bleeding complications, patients with unknown tumor developing rectal bleeding after thrombolysis procedure, should receive full diagnostic work-up of the gastrointestinal tract in order to exclude serious but potentially curable disease. PMID- 17708108 TI - Coil embolisation of an internal iliac artery aneurysm after surgical repair of an infrarenal aortic aneurysm. AB - We report a case of an 86-year-old asymptomatic patient, who underwent a repair of the infrarenal abdominal aortic aneurysm 13 years ago. He presented with a left internal iliac artery (IIA) aneurysm with a short neck of 3 mm, and a partially thrombosed lumen with a cross sectional diameter of 5.6 cm and a length of 8.9 cm. With respect to the high morbidity and mortality and awareness of the recommendation to treat aneurysms larger than 3 cm in diameter, we discussed the optimal treatment options. As endoprosthesis implantation was not feasible we performed a selective coil embolisation of the distal branches of the left internal artery, which successively lead to a complete thrombosis of the aneurysm. Although coiling additive to other procedures is applied frequently, only few cases of internal iliac aneurysm were treated with coil embolisation alone. During a first outpatient visit 2 months following the procedure the aneurysm was still completely thrombosed. PMID- 17708110 TI - Popliteal artery pseudoaneurysm after total knee replacement. AB - We report the case of a popliteal pseudoaneurysm following total knee replacement. A 70-year-old woman underwent total left knee replacement because of severe osteoarthritis. Eight days later she presented with oedema and pain in her left calf She had palpable foot pulses on the left leg and the ankle-brachial index was 0.98. The patient was treated for deep vein thrombosis. Two days later her calf pain and oedema deteriorated and her distal pulses were no longer palpable, while she developed limb coldness and paraesthesia, and the ankle brachial index dropped to 0.4. Sonography was urgently performed indicating a large popliteal artery aneurysm (5.8 x 6.9 x 7.2 cm), confirmed by angiography. The patient was managed with removal of a 3.5 cm long segment of the popliteal artery and reconstruction with synthetic graft (PTFE 6 mm). Her condition soon improved and the patient is capable of walking approximately 1 km per day at 18 month follow-up. PMID- 17708111 TI - A presenter's view of partnering with providers. AB - This column offers a snapshot of the presenter's perspective of providing continuing education activities. PMID- 17708112 TI - Emphysema and lung volume reduction surgery. AB - Patients with emphysema suffer from a poor quality of life. Treatment options vary, but surgical treatment may have the greatest positive effect on this patient population. PMID- 17708113 TI - Using webcasts for continuing education in nursing. AB - This column evaluates the advantages and disadvantages of the use of Webcasts for continuing education, and offers strategies to improve learner outcomes. PMID- 17708114 TI - Tips for facilitating learning: the lecture deserves some respect. AB - The lecture has become less popular as a teaching method in recent years. Yet even in our enlightened age, when active learning methods abound, some educational purposes are well served by the lecture method. This article identifies appropriate purposes for the lecture and approaches that can be used to overcome its limitations, rendering it maximally effective. Selected research findings and recommendations of recognized authorities are presented. PMID- 17708115 TI - Baccalaureate entry to practice: a systems view. AB - As the focus of health care shifts from inpatient hospital treatment to primary, community-based prevention, nurses will be required to learn new skills to take on new responsibilities. The authors use systems theory and a brief review of the history of nursing educational reform to explore the proposed requirement of a baccalaureate nursing degree for entry to practice and its potential effect on the nursing profession. PMID- 17708116 TI - Development at the bedside: evolutionary development of the experienced registered nurse. AB - The purpose of this study was to describe the evolution of skills acquisition required for nurses to develop expertise within their clinical specialty. The goal of the research was to identify a professional career path that could be better supported through institutional infrastructures and educational programs. The results of the study demonstrate that reinforcing developmental and support loops serve as the living foundation for experienced practice and identify blockers and competing forces for skill acquisition. This article presents the nurses' perspectives of their development and focuses on the implications their responses have for staff development educators. PMID- 17708117 TI - A medication safety education program to reduce the risk of harm caused by medication errors. AB - A medication safety education program was developed and implemented to reduce the harm caused to patients by medication errors, specifically errors related to the intravenous infusion of high-alert medications. Participants were required to complete two 30-minute computer modules focusing on medication safety. Changes in the climate of safety, nurses' knowledge and behavior, and the number of infusion pump alerts and reported medication errors were evaluated both before and after completion of the education program. A statistically significant change in knowledge regarding medication errors occurred, but there was no change in the climate of safety scores, the use of behaviors advocated in the medication safety education program to improve medication infusion safety, the number of infusion pump alerts, or the number of reported errors. It was concluded that there was a need for strong administrative support and follow-up to foster changes in behavior, which can lead to a reduction in harm caused by medication errors. PMID- 17708118 TI - Outcome evaluation: does continuing education make a difference? AB - This article describes how an outcome evaluation model was used for a 1-day continuing education conference focusing on genomics implications for nursing practice. Findings from this evaluation process are described, including results from subjects who participated in surveys prior to the conference (n = 119), immediately after the conference (n = 119), and 3 months after the conference (n = 59). Significant differences in overall genomics knowledge were measured before and immediately after the conference and these gains were maintained 3 months following the conference. There also was evidence that the conference participants used the information gained through continuing education to transform their nursing practice. This model can be used to evaluate continuing education, especially with newer knowledge such as genomics. PMID- 17708119 TI - Nebulized lidocaine for intractable cough near the end of life. PMID- 17708120 TI - Endoscopic therapy for malignant bowel obstruction. AB - Mechanical obstruction is common in advanced gastrointestinal malignancies and may be associated with significant morbidity. Patients with malignant bowel obstruction are often poor surgical candidates due to advanced disease, malnutrition, hypoalbuminemia, and dehydration. Recent advances in endoscopy have led to a variety of highly efficacious, nonsurgical treatment options that relieve mechanical bowel obstruction. This articles reviews endoscopic techniques to treat malignant small bowel and colonic obstruction including decompression tubes, enteral stents, and ablative methods such as laser therapy and argon plasma coagulation. PMID- 17708121 TI - Stents and bowel obstruction: practical considerations. PMID- 17708122 TI - Malignant bowel obstruction: comparing the treatments. PMID- 17708123 TI - Fentanyl buccal tablet for relief of breakthrough pain in opioid-tolerant patients with cancer-related chronic pain. AB - Fentanyl buccal tablet (FBT) is a new opioid formulation providing rapid-onset analgesia for the treatment of breakthrough pain (BTP). This study evaluated FBT for BTP in opioid-tolerant patients with chronic cancer pain. The study had a randomized, double-blind, placebo-controlled design and was conducted at 30 outpatient treatment centers in the United States. Following open-label titration, patients were randomly assigned to 1 of 18 double-blind dose sequences (7 FBT tablets, 3 placebo) to treat 10 BTP episodes. Pain intensity was measured on an 11-point scale (0 = no pain; 10 = worst pain). The primary efficacy measure was the sum of pain intensity differences (PIDs) for the first 60 minutes (SPID60); secondary efficacy measures included PIDs and pain relief (PR) measured from 5 minutes through 2 hours. Adverse events (AEs) were recorded. Of 129 patients enrolled, 87 entered the double-blind phase. SPID60 significantly favored FBT versus placebo (mean +/- SE, 9.7 +/- 0.63 vs 4.9 +/- 0.50; P < 0.0001). Secondary measures also favored FBT: PIDs and PR showed significant differences versus placebo at 10 minutes (0.9 vs 0.5; 0.815 vs 0.606, respectively, P < 0.0001) and all subsequent time points (P < 0.0001). AEs were typical of opioids (eg, nausea, dizziness, fatigue). In conclusion, in this study of opioid-tolerant patients with chronic cancer pain and BTP, FBT was efficacious, well tolerated, demonstrated rapid onset of analgesia (within 10 minutes), and had a sustained effect. PMID- 17708124 TI - Identifying and treating fluoropyrimidine-associated hand-and-foot syndrome in white and non-white patients. PMID- 17708125 TI - Colorectal cancer screening lacks evidence of benefit. AB - Although some studies indicate that screening with fecal occult blood testing or colonoscopy prevents deaths from colorectal cancer, the benefits may be offset by more deaths from other causes. Whether this phenomenon is due to anxiety, test bias, or merely chance, more evidence is needed; widespread screening in the general population is premature. PMID- 17708126 TI - Chronic hepatitis B virus infection: issues in treatment. AB - As research continues to define the optimal management of chronic hepatitis B virus (HBV) infection, clinicians must deal with a number of yet unresolved issues: Should we treat all patients with HBV infection to prevent liver cancer, even if they have no evidence of active disease? Which is the best treatment strategy? What do we do with patients who develop resistance to our current drugs? Should we treat patients with HBV infection who have already developed cirrhosis? PMID- 17708127 TI - Modafinil in the treatment of excessive daytime sleepiness. AB - Modafinil (Provigil) is approved for treating excessive daytime sleepiness associated with narcolepsy, for shift-work sleep disorder, and as an adjunctive treatment in patients with obstructive sleep apnea syndrome who have residual daytime sleepiness despite optimal treatment with continuous positive airway pressure. Although modafinil improves measures of sleepiness, it does not generally normalize them, and it may be less effective than other stimulants for some narcoleptic patients. We need head-to-head comparisons of modafinil with traditional stimulants in humans to better define its role. We review the current approved and off-label uses of this drug and the evidence behind them. PMID- 17708128 TI - Implications of the Spine Patient Outcomes Research Trial in the clinical management of lumbar disk herniation. PMID- 17708129 TI - Interpreting the Spine Patient Outcomes Research Trial. Medical vs surgical treatment of lumbar disk herniation: implications for future trials. AB - The Spine Patient Outcomes Research Trial (SPORT) consisted of two parallel studies: an observational study and a randomized comparison of medical and surgical treatment of disk herniation. In the long-term, patients did well with either treatment, and an intention-to-treat analysis found no difference in outcomes. However, at 2 years 40% of patients in the surgical group of the randomized study still hadn't had surgery, and 40% of the medical patients did have surgery, muddying the results. Surgery was superior according to an analysis by the treatment patients actually received, but the study has been criticized for methodologic shortcomings, and the topic remains controversial. PMID- 17708130 TI - New insights into ischemic heart disease in women. AB - Coronary artery disease is different in women than in men in its pathogenesis, symptoms, and prognosis. Needed is a strategy for detecting and assessing coronary disease specifically in women. This review highlights recent evidence on sex differences in coronary artery disease. PMID- 17708131 TI - Atypical antipsychotics: new drugs, new challenges. AB - Compared with the first-generation, or "typical" antipsychotic drugs, second generation or atypical antipsychotics cause fewer extrapyramidal (motor) problems, but they pose new challenges, as they often contribute to metabolic disturbances such as weight gain, hyperlipidemia, insulin resistance, and type 2 diabetes mellitus. Patients taking atypical antipsychotics should be monitored for glycemic and cardiovascular risk factors and should receive treatment for such problems as they arise. PMID- 17708132 TI - Importance of influenza vaccination for children. PMID- 17708133 TI - Is genetic testing for cytochrome P450 polymorphisms ready for implementation? PMID- 17708134 TI - Are some screening tests doing more harm than good? PMID- 17708135 TI - Interventions to improve blood pressure control in patients with hypertension. PMID- 17708136 TI - Alpha-glucosidase inhibitors may reduce the risk of type 2 diabetes. PMID- 17708137 TI - Antiretroviral prophylaxis for occupational exposure to HIV. PMID- 17708138 TI - Prevention of recurrent ischemic stroke. AB - Recurrent ischemic stroke and transient ischemic attack are common problems in primary care, with stroke survivors averaging 10 outpatient visits per year. Risk factors such as hypertension, diabetes, and hypercholesterolemia should be evaluated during each office visit. Attention should be given to lifestyle modification including management of obesity, smoking cessation, reduction in alcohol consumption, and promotion of physical activity. The choice of an antiplatelet agent (e.g., aspirin, ticlopidine, clopidogrel, dipyridamole) or the anticoagulant warfarin is based on the safety, tolerability, effectiveness, and price of each agent. Aspirin is a common first choice for prevention of recurrent stroke, but the combination of dipyridamole and aspirin should be considered for many patients because of its superior effectiveness in two clinical trials. Clopidogrel is recommended for patients with aspirin intolerance or allergy, or for those who cannot tolerate dipyridamole. Warfarin and the combination of aspirin and clopidogrel should not be used in the prevention of ischemic stroke. Carotid endarterectomy is appropriate for select patients; carotid stenting was recently shown to be less effective and less safe than endarterectomy. PMID- 17708139 TI - Information from your family doctor. Preventing another stroke: what you should know. PMID- 17708140 TI - The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. AB - Cytochrome P450 enzymes are essential for the metabolism of many medications. Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6. Genetic variability (polymorphism) in these enzymes may influence a patient's response to commonly prescribed drug classes, including beta blockers and antidepressants. Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures. Interactions with warfarin, antidepressants, antiepileptic drugs, and statins often involve the cytochrome P450 enzymes. Knowledge of the most important drugs metabolized by cytochrome P450 enzymes, as well as the most potent inhibiting and inducing drugs, can help minimize the possibility of adverse drug reactions and interactions. Although genotype tests can determine if a patient has a specific enzyme polymorphism, it has not been determined if routine use of these tests will improve outcomes. PMID- 17708141 TI - Recommendations for preconception care. AB - Every woman of reproductive age who is capable of becoming pregnant is a candidate for preconception care, regardless of whether she is planning to conceive. Preconception care is aimed at identifying and modifying biomedical, behavioral, and social risks through preventive and management interventions. Key components include risk assessment, health promotion, and medical and psychosocial interventions. Patients should formulate a reproductive life plan that outlines personal goals about becoming pregnant based on the patient's values and resources. Preconception care can be provided in the primary care setting and through activities linked to schools, workplaces, and the community. PMID- 17708142 TI - Turner syndrome: diagnosis and management. AB - Turner syndrome occurs in one out of every 2,500 to 3,000 live female births. The syndrome is characterized by the partial or complete absence of one X chromosome (45,X karyotype). Patients with Turner syndrome are at risk of congenital heart defects (e.g., coarctation of aorta, bicuspid aortic valve) and may have progressive aortic root dilatation or dissection. These patients also are at risk of congenital lymphedema, renal malformation, sensorineural hearing loss, osteoporosis, obesity, diabetes, and atherogenic lipid profile. Patients usually have normal intelligence but may have problems with nonverbal, social, and psychomotor skills. Physical manifestations may be subtle but can include misshapen ears, a webbed neck, a broad chest with widely spaced nipples, and cubitus valgus. A Turner syndrome diagnosis should be considered in girls with short stature or primary amenorrhea. Patients are treated for short stature in early childhood with growth hormone therapy, and supplemental estrogen is initiated by adolescence for pubertal development and prevention of osteoporosis. Almost all women with Turner syndrome are infertile, although some conceive with assisted reproduction. PMID- 17708143 TI - Acute renal failure. PMID- 17708144 TI - FPIN's clinical inquiries. Angiotensin blockade in patients with diabetic nephropathy. PMID- 17708145 TI - Pruritic rash after an ocean swim. PMID- 17708146 TI - Should physicians accept gifts from patients? PMID- 17708147 TI - Goats as alternative hosts of cattle ticks. AB - The objective of this study was to compare the presence on goats and cattle of adult ticks that usually infest cattle. To this end ticks collected from sets of five goats were compared with those collected from sets of five cattle at 72 communal dip-tanks in the eastern region of the Eastern Cape Province. Amblyomma hebraeum was present on goats at 25 and on cattle at 39 dip-tanks, and a total of 61 goats and 138 cattle were infested. Adult Rhipicephalus (Boophilus) microplus was present on goats at 48 and on cattle at 69 dip-tanks, and a total of 113 goats and 242 cattle were infested. The lengths of 84 of 148 female R. (Boophilus) microplus collected from the goats exceeded 5 mm or more, indicating that they could successfully engorge on these animals. The differences between the proportions of dip-tanks at which A. hebraeum or R. (Boophilus) microplus was present on goats and cattle and also between the proportions of goats and cattle that were infested were significant (Chi-square test, P < 0.01). Adult Rhipicephalus appendiculatus was present on goats at 70 and on cattle at 67 dip tanks, and a total of 296 goats and 271 cattle were infested. The proportion of dip-tanks at which cattle were infested did not differ significantly from the proportion of tanks at which goats were infested (Fischer's exact probability test, P = 0.44), but the proportion of infested cattle was significantly lower than the proportion of infested goats (Chi-square test, P < 0.05). Adult Rhipicephalus evertsi evertsi was present on goats and cattle at all 72 sampling localities, and a total of 334 goats and 316 cattle were infested. The proportion of infested cattle was significantly lower than the proportion of infested goats (Chi-square test, P < 0.05). These results underscore the necessity of including goats in any tick control programme designed for cattle at the same locality. PMID- 17708148 TI - Comparison of the survival on ice of thawed Theileria parva sporozoites of different stocks cryoprotected by glycerol or sucrose. AB - Stabilates of Theileria parva sporozoites are mostly delivered in liquid nitrogen tanks to the East Coast fever immunization points. Using an in vitro titration model, we assessed the loss of infectivity of several stabilates when they are stored in ice baths for up to 24 h. Comparisons, with respect to rates of loss of infectivity, were made between T. parva stocks (Chitongo and Katete), cryoprotectants (sucrose and glycerol) and method of assessment (in vivo and in vitro techniques). Chitongo and Katete stabilates showed similar loss dynamics. The losses were 1-4% (depending on parasite stock) and 3% per hour of storage for glycerol and sucrose stabilates respectively, and the loss rates were not significantly different. The results suggest that Chitongo stabilates and sucrose cryoprotected suspensions can be delivered on ice as is done for Katete. A graphical relationship of in vitro effective dose at 50% infectivity (ED50) and in vivo protection rate was made. The relationship showed a 35% loss of protection for a relatively low corresponding increase of ED50 from 0.006 to 0.007 tick equivalent. PMID- 17708149 TI - Occurrence of multiple drug resistance in Trypanosoma brucei rhodesiense isolated from sleeping sickness patients. AB - The occurrence of cross-resistance among melarsoprol-resistant Trypanosoma brucei rhodesiense isolates was investigated in this study. The isolates, T. b. rhodesiense KETRI 237, 2538, 1992, 2709, 2694 and 3530, had been obtained from sleeping sickness patients in Kenya and Uganda between 1960 and 1985. Five groups consisting of six mice each were inoculated intraperitoneally with 10(5) parasites of each isolate, and 24 h later treated with either melarsoprol, homidium chloride, diminazene aceturate or isometamidium chloride. The control group comprised infected but untreated mice. The mice were monitored for cure for a period of 60 days post-treatment. The mean prepatent period in the control mice was 5 days while the mean survival period was 22 days. Five of the stabilates, KETRI 237, 2538, 2709, 2694, and 3530, were confirmed to be melarsoprol resistant. Cross-resistance was observed, with the majority of the isolates being resistant to homidium chloride (5/6) and diminazene aceturate (5/6), but all were sensitive to isometamidium chloride (6/6). However T. b. rhodesiense KETRI 1992, which was previously considered as melarsoprol resistant, was sensitive to all the drugs tested. In conclusion, our study has revealed the existence of cross resistance among the melarsoprol resistant isolates which could only be cured by isometamidium. PMID- 17708150 TI - Prevalence and determinants of Cryptosporidium spp. infection in smallholder dairy cattle in Iringa and Tanga Regions of Tanzania. AB - The prevalence of Cryptosporidium spp. infection in a cross-sectional study of dairy cattle, from two contrasting dairying regions in Tanzania, were determined by staining smears of faecal samples with the modified Ziehl-Neelsen technique. Of the 1 126 faecal samples screened, 19.7% were positive for Cryptosporidium spp. The prevalence was lower in Tanga Region than in Iringa Region. The prevalence of affected farms was 20% in Tanga and 21% in Iringa. In both regions, the probability of detecting Cryptosporidium oocysts in faeces varied with animal class, but these were not consistent in both regions. In Tanga Region, Cryptosporidium oocysts were significantly more likely to be found in the faeces of milking cows. In Iringa Region, the likelihood that cattle had Cryptosporidium positive faeces declined with age, and milking cattle were significantly less likely to have Cryptosporidium-positive faeces. In this region, 7% of cattle were housed within the family house at night, and this was marginally associated with a higher likelihood that animals had Cryptosporidium-positive faeces. Our study suggests that even though herd sizes are small, Cryptosporidium spp. are endemic on many Tanzanian smallholder dairy farms. These protozoa may impact on animal health and production, but also on human health, given the close associations between the cattle and their keepers. Further studies are required to assess these risks in more detail, and understand the epidemiology of Cryptosporidium spp. in this management system. PMID- 17708151 TI - Studies on the toxicity of an aqueous extract of the leaves of Abrus precatorius in rats. AB - The toxic effects of an aqueous extract of Abrus precatorius were studied in 20 male white rats over a period of 18 days. The rats were divided into four groups of five rats per group. Those in Group A served as controls while the rats in Groups B, C and D were dosed per os with 400 mg/kg, 800 mg/kg and 1 600 mg/kg of the extract, respectively. Blood samples were collected for haematological and biochemical analysis and specimens of the liver, kidney and testes were taken for histopathological studies. The study showed that the extract of A. precatorius caused decreased levels of packed cell volume, haemoglobin concentration, red blood cell count, white blood cell count, mean corpuscular volume and mean corpuscular haemoglobin. The extract also resulted in increased levels of total serum protein, albumin, alanine amino transaminase, aspartate amino transferase, alkaline phosphatase and total bilirubin. Histologically, testicular degeneration characterized by decreased numbers of lining cells of the epithelium as well as reduction in sperm cells with presence of scattered Sertoli cells were noted. The study thus showed that aqueous extract of Abrus precatorius is toxic and caution should be exercised in its use for medicinal purpose. PMID- 17708152 TI - Red blood cell volume as a predictor of fatal reactions in cattle infected with Theileria parva Katete. AB - A comparison of mean corpuscular volume (MCV) and packed cell volume (PCV) was made between cattle undergoing lethal and non-lethal reactions following experimental infections with the apicomplexan protozoa, Theileria parva Katete. This work confirmed that anaemia occurs in infected animals. However, the fall in PCV was steeper in lethal reactions compared to non-lethal reactions. Our results show that animals with initially lower MCV values are more prone to fatal reaction, despite having normal PCV profiles. The study also found that small red blood cells are more likely to be infected with T. parva. These findings suggest that animals with a higher proportion of small red blood cells in circulation will be more likely to succumb to T. parva infections. The potential for using MCV as a predictor of the outcome of infection challenge is discussed. PMID- 17708153 TI - Climate change and the genus Rhipicephalus (Acari: Ixodidae) in Africa. AB - The suitability of present and future climates for 30 Rhipicephalus species in Africa are predicted using a simple climate envelope model as well as a Division of Atmospheric Research Limited-Area Model (DARLAM). DARLAM's predictions are compared with the mean outcome from two global circulation models. East Africa and South Africa are considered the most vulnerable regions on the continent to climate-induced changes in tick distributions and tick-borne diseases. More than 50% of the species examined show potential range expansion and more than 70% of this range expansion is found in economically important tick species. More than 20% of the species experienced range shifts of between 50 and 100%. There is also an increase in tick species richness in the south-western regions of the sub continent. Actual range alterations due to climate change may be even greater since factors like land degradation and human population increase have not been included in this modelling process. However, these predictions are also subject to the effect that climate change may have on the hosts of the ticks, particularly those that favour a restricted range of hosts. Where possible, the anticipated biological implications of the predicted changes are explored. PMID- 17708155 TI - Ticks (Acari: Ixodidae) collected from animals in three western, semi-arid nature reserves in South Africa. AB - The objective of this study was to make an inventory of the ixodid tick species infesting wild animals in three western, semi-arid nature reserves in South Africa. To this end 22 animals in the Kgalagadi Transfrontier Park, 10 in the West Coast National Park and 16 in the Karoo National Park were examined. Fourteen tick species were recovered, of which Hyalomma truncatum, Rhipicephalus exophthalmos and Rhipicephalus glabroscutatum were each present in two reserves and the remainder only in one. The distributions of two of the 14 tick species recovered, namely Rhipicephalus capensis and Rhipicephalus neumanni, are virtually confined to the western semi-arid regions of southern Africa. Hyalomma truncatum, R. capensis and R. glabroscutatum were the most numerous of the ticks recovered, and eland, Taurotragus oryx, were the most heavily infested with the former two species and gemsbok, Oryx gazella, and mountain reedbuck, Redunca fulvorufula, with R. glabroscutatum. PMID- 17708154 TI - The prevalence, organ distribution and fertility of cystic echinoccosis in feral pigs in tropical North Queensland, Australia. AB - An investigation was carried out to study the prevalence of Echinococcus granulosus hydatidosis in feral pigs (Sus domesticus) in the Charters Towers region of tropical North Queensland. Data were collected from a total of 238 carcasses, which were hunted and shot in the Burdekin River catchment area. Organs of the abdominal, thoracic, and pelvic cavities were examined for the presence of hydatid cysts. In the laboratory, cysts and hydatid cyst fluids were examined under a stereoscopic binocular microscope and a compound microscope. An overall prevalence of E. granulosus hydatid cysts in feral pigs was found to be 31.1%. There was no significant difference in either sex or age between infected and non-infected feral pigs. The predilection sites of cysts were livers (23%) and lungs (62%), with more cysts in lungs (252) than livers (48). The ratio of livers to lungs infected with fertile cysts was 1:4 compared to 1:8 sterile cysts. The overall fertility of cysts was 70.1%. The percentage of fertile cysts in liver and lung was 79.2% and 68.7%, respectively. The diameter of fertile cysts ranged from 15 to over 60 mm. There was no significant difference in size between fertile and non-fertile cysts in lungs. The high prevalence rate and fertility of cysts in feral pigs confirm that feral pigs can take part in the sylvatic cycle of the parasite in the region. The public health significance of this observation is potentially very important. PMID- 17708156 TI - Optional active compliance chamber performance in a pulmonary artery-pulmonary artery configured paracorporeal artificial lung. AB - INTRODUCTION: Our group has developed a paracorporeal artificial lung (PAL) attached in a pulmonary artery (PA) to PA in series configuration to address profound respiratory failure and serve as a bridge to transplant and/or recovery. We recently designed, developed and converted our passive pre-PAL compliance chamber to an active, synchronized, counterpulsating assist device to relieve right heart strain and offset increased work placed on the right ventricle when the PAL is attached. In this study, we evaluated the safety and performance of both a valved and non-valved optional active compliance chamber (OACC) in a PA-PA PAL for right heart assistance in normal adult sheep. METHODS: Eleven sheep (30 50 kg) were divided into non-valved OACC (n = 6) and valved (n = 5) OACC groups. To mimic pulmonary hypertension, a C-clamp was placed distal to the OACC-PAL and occluded until a 20% decrease in cardiac output (CO) was achieved. The OACC was activated, and right ventricular pressure (RVP), pulmonary artery pressure (PAP), mean arterial pressure (MAP) and CO were recorded. RESULTS: All eleven animals tolerated the implantation of the OACC PAL. Activation of the OACC resulted in a significant increase in CO. Systolic and diastolic right ventricular pressure decreased in both groups. Lastly, counterpulsation increased the mean PAP in all animals and peak PAP reached 89 mmHg. Despite providing right heart assistance, synchronizing the counterpulsation was technically difficult, and the high peak PA pressures resulted in anastomotic bleeding in all animals and anastomotic breakdown in 4/11 animals. CONCLUSIONS: An OACC PAL perfused by the right ventricle applied in series with the pulmonary circulation reduces ventricular load and improves cardiac efficiency. These preliminary data suggest the potential of an artificial lung in unloading the strained right ventricle and acting as a bridge to transplantation. The augmented peak PA pressures, resulting in bleeding and anastomotic breakdown, and complexity in synchronizing the cardiac cycle with the pulsations of the augmented OACC, compromise this configuration. PMID- 17708157 TI - Changes in potassium concentration and haematocrit associated with cardiopulmonary bypass in paediatric cardiac surgery. AB - INTRODUCTION: A blood prime is frequently required for paediatric bypass surgery to maintain adequate haematocrit (Hct). However, stored blood can have high extracellular potassium levels and this study aims to investigate the effect of stored blood on the potassium concentration, both in the prime and subsequently in the patient after cardiopulmonary bypass (CPB) has been established. In neonatal surgery, the stored blood may be irradiated if there is a question of impaired immunity. Irradiation may cause a further increase in potassium levels. METHODS: Blood-primed circuits prepared for 320 consecutive paediatric bypass cases were analysed for electrolyte levels, Hct and acid-base status before and immediately after establishment of CPB. Patients were divided into three groups according to body weight (<5kg, 5-10kg and > 10 kg) and both stored blood and irradiated blood primes were compared. RESULTS: The potassium concentration was above the physiological range in all bypass primes pre-CPB and was significantly higher when using irradiated blood (8.12 +/- 2.54 mmol/L versus 4.94 +/- 3.35 mmol/L, p < 0.0001). Despite this, on commencing CPB, the potassium level remained within the physiological range in the majority of patients (4.16 +/- 2.72mmol/L for stored blood prime and 4.55 +/- 1.01mmol/L for irradiated blood, p = 0.02). However, in smaller patients (<5 kg) who had irradiated blood prime potassium level > 7.0 mmol/L, there was resultant hyperkalaemia (5.60 +/-0.90 mmol/L) on commencing CPB, that returned to normal later. No adverse clinical events were associated with the hyperkalaemia. Hct was well maintained on CPB (22 25%) in all groups and was not related to patient weight. CONCLUSION: Blood primes result in high potassium concentrations in the prime fluid that is more severe if irradiated blood is used. The concentration is not sufficient to cause hyperkalaemia in the patients on commencing CPB except when irradiated blood prime is used in infants < 5 kg. Hct is well maintained in all patient groups with the use of blood prime. PMID- 17708159 TI - Does cold blood cardioplegia solution cause deterioration in clinical pulmonary function following coronary artery bypass graft surgery? AB - OBJECTIVE: Deterioration in pulmonary function is a common complication following coronary artery bypass graft surgery and there is still speculation to the precise causative factors thereof. Cardioplegia solution not drained by the atriocaval cannula enters the lung parenchyma unless removed by a pulmonary artery (PA) vent. The hypothesis of the present study was that cold blood cardioplegia solution damages the lung parenchyma, resulting in an observed deterioration of clinical lung function. METHODS: A prospective, double-blind, randomised trial was conducted on 142 patients. The study group of 71 patients had a PA vent inserted at the time of cannulation, preventing cardioplegia from going through the lungs. In addition, positive end expiratory pressure (PEEP) was applied and low-volume lung ventilation carried out during cardiopulmonary bypass (CPB). The control group (n =71) had cardioplegia enter the lung parenchyma during cardiopulmonary bypass. Clinical parameters of arterial blood gases, including estimated shunt fraction, spirometry tests and radiographic analysis was made preoperatively and at set times through the postoperative period. RESULTS: Baseline demographics and intraoperative and postoperative management was the same in both groups, thus, yielding a homogenous sample for analysis. Significant changes were noted in arterial blood gases, spirometry, and radiographic analysis of effusion and atelectasis over the time periods studied (p<0.001). There was, however, no significant difference between the study and control groups at any point (p > 0.05). CONCLUSIONS: The data, therefore, suggest that allowing cold blood cardioplegia solution to circulate the lungs during cardiopulmonary bypass does not have any (beneficial or detrimental) effect on clinical lung function postoperatively. PMID- 17708158 TI - Pulmonary sequestration of cardioplegia administered via the aortic root during aortocoronary bypass surgery. AB - A semi-quantitative method was devised of tracing blood flow through the heart and lungs at the time of cardioplegia delivery and circulatory arrest of the heart during coronary artery bypass graft surgery (CABG). There were no previous studies confirming or disputing an accepted 'observation' by cardiac surgeons that cardioplegia solution does enter the lung parenchyma during cardiopulmonary bypass (CPB). This study was conducted as part of a larger (n = 142) double blind, randomised, controlled, clinical research study. OBJECTIVE: The objective was initially to establish the efficacy of measures to prevent cardioplegia entering the lungs and, subsequently, to determine whether cardioplegia indeed circulates through the lung parenchyma or merely accumulates and 'pools'. METHOD: A prospective study on 20 consecutive patients (5 per group) admitted for CABG was made. Technetium (Tc-99m), a radioactive isotope, was added to the cold blood cardioplegia solution prior to cardioplegia delivery in order to track flow of cardioplegia solution. An independent nuclear medicine radiographer measured the samples with the use of a 'Curimentor' dose calibrator for presence and quantity of radiation in the samples. Decay was factored into the results. The Tc-99m tracer samples were also analysed using Gamma Acquisition and Analysis on the Genie 2000vdm Well Counter to confirm the presence and quantity of Tc-99m. RESULTS: In the four groups, it was confirmed that the pulmonary artery (PA) vent is 90-100% effective in retrieving any cardioplegia solution not drained by the atriocaval cannulae. CONCLUSIONS: The PA vent is effective in preventing cold blood cardioplegia solution from entering the lungs. Any cardioplegia that does enter the lung parenchyma during CPB circulates through the lungs and can be retrieved by a vent in the left atrium. This method may be useful in other studies that require investigation. PMID- 17708160 TI - Comparison of perfusion modes on microcirculation during acute and chronic cardiac support: is there a difference? AB - Although heart-lung machines and cardiac assist devices have been used successfully for acute and chronic cardiac support for decades, controversies still remain concerning the benefits of pulsatile and non-pulsatile perfusion. The core of the debate is whether enough energy is generated by the artificial pulse to keep capillary beds open and cell metabolism stabilized during acute or chronic cardiac support. In other words, does artificial pulsatility exist in the microcirculation: small vessels of less than 100 microm in diameter? Many investigators have tried to use different tools and biomarkers to reflect directly or indirectly the state of the microcirculation when comparing the two different perfusion modes during acute and chronic cardiac support. However, the results are controversial. First, direct observation of the state of the microcirculation during acute and chronic cardiac support is limited; and reports concerning direct observation of the microcirculation with different perfusion modes in contemporary literature are rare. Secondly, different investigators have used their own criteria to define pulsatile flow. Therefore, it is necessary to develop more efficient methodologies, enabling direct observation of the microcirculation during acute and chronic cardiac support and also establish common criteria that will precisely quantify the pulsatile flow in terms of energy equivalent pressure (EEP) and surplus hemodynamic energy (SHE) levels. Using these critical parameters may explain how excess energy is created by pulsatile flow and maintains perfusion through the microcirculation by ensuring capillary patency. PMID- 17708161 TI - Hypertonic hydroxyethyl starch solution for hypovolaemia correction following heart surgery. AB - BACKGROUND: The aim of the study was to evaluate the effect of hypertonic NaCl hydroxyethyl starch solution on haemodynamics and cardiovascular parameters in the early postoperative period in patients for correction of hypovolaemia after heart surgery. METHODS: Eighty patients undergoing myocardial revascularisation at the Clinic of Cardiac Surgery of the Heart Centre (Kaunas University of Medicine) were randomly divided into two groups. The HyperHaes group (n = 40) received 250ml 7.2% NaCl/6% HES solution and the control Ringer's acetate group (n = 40) received placebo (500 ml Ringer's acetate solution) for volume correction after the surgery. RESULTS: After infusion of HyperHaes solution, cardiac index increased from 2.69 (0.7) to 3.52 (0.8) l/min/m2, systemic vascular resistance index, pulmonary vascular resistance index and the gradient between central and peripheral temperature decreased, and oxygen transport parameters improved. Ringer's group patients needed more intensive infusion therapy (4050.0 (1102.2) ml in the Ringer's group, 3513.7(762.5) ml in the HyperHaes group). During the first 24 hours postoperatively, diuresis was significantly higher in the HyperHaes group (3640.0 (1122.9) ml and 2736.0 (900.7) ml), total fluid balance was lower in HyperHaes group (1405.6 (1519.0) ml and 2718.3 (1508.0)ml, respectively). After the infusion of HyperHaes solution, no adverse events were noted. CONCLUSIONS: HyperHaes solution had a positive effect on haemodynamic parameters and microcirculation. Oxygen transport was more effective after HyperHaes solution infusion. Higher diuresis, lower need for the infusion therapy for the first 24 hours and lower total fluid balance were determined in the HyperHaes group. No adverse effects were observed after HyperHaes solution infusion. PMID- 17708162 TI - Tissue and plasma concentrations of cephuroxime during cardiac surgery in cardiopulmonary bypass--a microdialysis study. AB - AIM: Wound and mediastinal infections are still very serious complications of open-heart surgery, in spite of the use of prophylactic antibiotics. The use of cardiopulmonary bypass (CPB) is associated with profound physiological changes affecting the pharmacokinetic behaviour of antibiotics. The aim of this pilot study was to monitor the tissue concentrations of cephuroxime (prophylactic antibiotic) in skeletal muscle during cardiac surgery using CPB by interstitial microdialysis. These concentrations were compared with plasma concentrations of cephuroxime. MATERIAL AND METHODS: Nine adult patients operated on using CPB were enrolled in this study. Cephuroxime was used as a prophylactic antibiotic (1st dose - 3 g of cefuroxime i.v. with anesthesia induction, 2nd dose - 1.5 g i.v. after CPB with protamine sulphate, 3rd dose - 1.5 g i.v. 8 hours after the surgery). Interstitial microdialysis was performed by probe CMA 60 (CMA Microdialysis AB, Sweden) inserted into the patient's deltoid muscle. Concentrations of cephuroxime in dialysates and in plasma were determined by the modified fluid chromatography method. The unbound cephuroxime fraction in plasma was obtained by using an ultrafiltration method. Samples of dialysates were collected at the following intervals: before CPB, each 30 minutes of CPB, at the end of CPB. Samples of blood were collected at these intervals: incision, start of CPB, each 30 minutes of CPB, at the end of CPB, at the end of surgery. Concentrations of cephuroxime in tissue were corrected by in vivo recoveries of the microdialysis probes. RESULTS: Plasma concentrations of cephuroxime were 163.5 +/- 40.1, 79.3 +/- 17.4, 73.7 +/- 16.8, 66.1 +/- 18.3, 57.0 +/- 10.9, 120.7 +/- 29.9 (mg L(-1)) and concentrations of free plasma fraction of cephuroxime were 119.5 +/- 35.2, 67.8 +/- 15.5, 66.0 +/- 12.5, 54.8 +/- 12.2, 49.6 +/- 9.8, 102.6 +/-26.0 (mg L(-1)). The concentrations of cephuroxime in dialysates were 44.3 +/- 15.7, 36.1 +/- 11.6, 31.9 +/- 9.3, 34.6 +/- 12.3, 27.6 +/-12.9, 56.7 +/- 17.6 (mg L(-1)). The mean in vivo recovery of cephuroxime in this study was 30%. Corrected concentrations (calculated by in vivo recovery) of cephuroxime in skeletal muscle were 148, 120, 106, 115, 92, 189 (mg L(-l)). CONCLUSION: Our preliminary results show that CPB can modify the time course of cephuroxime plasma and tissue concentrations. A decrease in plasma drug concentrations occurred at the start of CPB and lasted until CPB ended. An increase in plasma concentrations corresponds to the second drug dose after CPB. The concentrations of cephuroxime in skeletal muscle (corrected by recovery) during CPB are higher than plasma concentrations. It is influenced by important changes during CPB; closely associated with hemodilution, a shift of intravascular volume, solutes and albumin to the extravascular space and inconstant protein binding of cephuroxime during operation. PMID- 17708163 TI - Perfusionists in the world of tissue engineering--a quick and easy method for safe isolation of huge quantities of porcine cardiomyocytes. AB - Isolation of huge quantities of primary cells from whole organs like the heart becomes increasingly important, especially for the emerging research field of tissue engineering and regenerative medicine. This study deals with the isolation of pig cardiomyocytes, in contrast to the standard mouse or rat models, because we aimed to draw attention to the species, which are genetically more closely related to the human organism. The bigger operative and veterinary expenditure of the pig-heart model can only be justified by a technique that supplies a big amount of qualitative high-grade cardiomyocytes. In our model, the quality is guaranteed by protection of the heart, already in situ, by a cardioplegia and a careful application of collagenase to soften the tissue. The construction of a new apparatus which includes enormous costs was not necessary, since the perfusion equipment was realized from two commercially available HLMsets, which were modified and connected to each other. Our model makes it possible to rinse the whole myocardium, which leads to a better output than models that only prepare a part of the myocardium around a coronary artery. The careful harvesting of high-grade cardiomyocytes is an important source of successful cell cultures to be used for numerous experimental applications, may reduce animal experiments and, additionally, represents a chance for perfusionists to become an important partner in interdisciplinary research projects. PMID- 17708164 TI - Heparin during neonatal bypass. PMID- 17708165 TI - The growing interest in a comparative clinical effectiveness center. PMID- 17708166 TI - Consumer-directed health plans: what happened? AB - CDHPs can stabilize growth in health costs, but the health plan-subscriber relationship should be more transparent. CFOs should ensure that increased cost exposure in CDHPs is paired with broad, deep disease management and employee assistance support. Hospitals should plan for the likelihood that, one way or another, consumers will be paying more of their healthcare bill. PMID- 17708168 TI - Jim Collins: taking health care from good to great. PMID- 17708167 TI - A journey toward revenue cycle excellence. AB - The Nebraska Medical Center's multidisciplinary approach to revenue cycle improvement reduced gross days revenue outstanding (GDRO) by 30 days and led to improved customer and employee satisfaction. PMID- 17708169 TI - Time for a second look at SOX compliance. AB - Incentives for tax-exempt healthcare organizations to comply with the Sarbanes Oxley Act (SOX) abound from many quarters, including government, various associations, and the capital markets. New proposals from the Securities and Exchange Commission and the Public Company Accountability Oversight Board will streamline the processes of SOX compliance, even as the cost of compliance is dropping. Voluntary SOX compliance can best be achieved by adopting a four-phased control rationalization approach to implementation and maintenance. PMID- 17708170 TI - Sarbanes-Oxley impetus for enterprise risk management. AB - By improving the integrity of financial reporting, voluntary compliance with the Sarbanes-Oxley Act can help a not-for-profit healthcare organization preserve its reputation within its community. Because SOX compliance is not mandatory for not for-profits, they have great flexibility in how they structure their compliance activities. Making SOX compliance a part of a larger enterprise risk management program can help not-for-profits to streamline and coordinate their approach to all risk-be it financial, operational, or strategic. PMID- 17708171 TI - IRS increases emphasis on not-for-profit health care. AB - In light of the increased attention the IRS is paying to not-for-profit organizations, healthcare financial managers should stay alert to developments regarding: community benefit standard, executive compensation, corporate governance, transparency and form 990, political activity. PMID- 17708172 TI - Economic value added: can it apply to an S corporation medical practice? AB - Typically, owners of medical practices use financial formulas such as ROI and net present value to evaluate the financial benefit of new projects. However, economic value added, a concept used by many large corporations to define and maximize return, may add greater benefit in helping medical practice owners realize a reasonable return on their core business. PMID- 17708173 TI - Coping with connectivity. AB - When evaluating scripting products, hospitals should consider these factors: match business requirements to functionality; choose a standalone product that offers a full range of features; make sure the product is interoperable with different types of applications, systems, file types, data formats, and messaging types; verify that the company will provide the training necessary for hospital staff to get the most out of the product. PMID- 17708174 TI - Quality: the new healthcare imperative. AB - Increasing evidence shows that besides saving lives, quality initiatives can increase volume and market share, shorten hospital stays, and result in fewer complications and readmissions. A look at the American Heart Association's Get With The Guidelines program shows how evidence-based therapies have improved quality and patient outcomes. PMID- 17708175 TI - Root cause analysis to improve payer profiling. PMID- 17708176 TI - Financial leadership and health reform: be careful what you ask for. PMID- 17708177 TI - Does HIE before EHR put the cart before the horse? PMID- 17708178 TI - What would you do? Are freestanding emergency centers an idea whose time has come? PMID- 17708179 TI - Bad debt, deductions, and utilization by payer. PMID- 17708180 TI - Parent bed spaces in the PICU: effect on parental stress. AB - The purpose of this comparative descriptive study was to identify the impact of providing a parent bed space in the PICU, allowing for continual parental presence, on stress of the parents of critically ill children. Data were collected from parents (n = 86) at two children's hospitals 3 months prior to the opening of new PICUs with parent bed spaces. Following a transition period, data were collected from a sample of parents (n = 92) who had used the parent bed to stay overnight with their child. Parental stress was measured with the Parental Stressor Scale: Pediatric Intensive Care (PSS: PICU). Stress scores were significantly lower (p = .02) for parents who utilized the parent beds in the new PICUs. New PICU environments that facilitate continual parental presence may reduce parental stress related to a child's hospitalization. PMID- 17708182 TI - Anesthesia services outside of the operating room. AB - In January 2000, Primary Children's Medical Center (PCMC) nurses and physicians of specific disciplines including hematology/oncology, surgery, Emergency Department (ED), and anesthesia, identified a need to provide general anesthesia for children undergoing procedures outside of the operating room. This need was based upon two factors: (a) limited availability of the operating room, and (b) lack of proper monitoring of children receiving conscious sedation for painful procedures in PCMC clinics. In September 2000, the Rapid Treatment Unit (RTU) service was developed to provide cost-effective, efficient, patient/family centered care for a variety of procedures. With limited literature on the subject of anesthesia services outside of the operating room, many hours of planning, education, and organizing occurred to develop this unique service. Parents have reported satisfaction with the service verbally and through an anonymous survey. Increasing numbers of patients seeking services from Utah, Idaho, Nevada, Wyoming, and Montana indicate a need for service expansion within the five-state region surrounding Salt Lake City. The RTU Anesthesia service is an important asset to PCMC and continues to expand to provide safe, efficient health care for children. PMID- 17708181 TI - Pilot study of low-income parents' perspectives of managing asthma in high-risk infants and toddlers. AB - This pilot study describes the challenges low-income parents face in managing asthma in their infants and toddlers who are at high risk of morbidity due to asthma. Five families of children younger than 3 years and recently hospitalized for asthma were interviewed from 1 to 5 times and asked to give narratives about the everyday management of asthma in their high risk infants and toddlers. Interpretive phenomenology was used as the method to describe parents' perspectives on managing the illness. The parents, all single mothers, struggled to manage asthma in crowded conditions, with limited transportation for frequently needed emergency care, and in face of the complicating needs of other children and family members. Not knowing then knowing the diagnosis, and provider availability and lack of availability were two dichotomous challenges mothers faced when managing asthma in their very young children. PMID- 17708184 TI - Fever and sore throat in a 16-year-old female. PMID- 17708183 TI - Camp nursing: rewards and challenges. AB - Every summer, millions of children attend summer camp, bringing with them flashlights, sleeping bags, bug spray, and a wide array of acute and chronic medical conditions. Registered nurses provide care to these children in an environment that is fun-filled, rewarding, and challenging. Familiarity with camp settings, as well as with expectations of the nurse at camp, are important because the demands are quite different from traditional nursing practice. Due to the challenges that are inherent in the camp nursing role, nurses considering this area of practice must be knowledgeable about the various camp settings, camp nurse responsibilities, practice issues for camp nursing, implications for education and research, and resources for the nurse contemplating a camp nursing position. PMID- 17708185 TI - A primary care approach to functional abdominal pain. AB - This article reviews the literature related to functional abdominal pain (FAP) in childhood, including the definition, etiology, contributing factors, clinical diagnosis, therapy and management, and associated long-term health effects. FAP is determined when no specific structural, infectious, inflammatory, or biochemical cause can be found in a child with chronic pain. The presence of abdominal pain as an isolated symptom is more suggestive of FAP, whereas multiple symptoms are more likely to be due to an organic or biochemical condition. While the exact cause of FAP is not completely understood, most researchers and clinicians agree that it is of multi-factorial etiology coupled with an altered brain-gut interaction. Children are highly susceptible to influences around them and can experience pain in response to normal childhood feelings and experiences. Psychological disorders such as anxiety and depression are common in both children with FAP and their parents. Children with FAP tend to have low levels of self-directedness, internalize their feelings and worries, and ruminate over issues they cannot control. The biopsychosocial model has proved to be a worthwhile framework for children with FAP, as it recognizes the interaction between social and environmental influences, psychological processes, and the state of the body. Interventions that focus on the child's cognitive processes associated with abdominal pain and the family's response to the pain have increased efficacy over standard education and reassurance. Providing children and families with techniques to use when experiencing pain decreases alterations in normal daily activities and improves long-term health outcomes. PMID- 17708186 TI - The many roles of families in "family-centered care"--part IV. AB - A parent whose premature twins were cared for at Children's Hospitals and Clinics of Minnesota describes giving back to the hospital as a member of the Hospital's Family Advisory Council. Members of the Council play a range of roles in the hospital. Family Advisory Council members assist the administration in developing, implementing and evaluating the services and the facilities of the hospital system and have input into hospital policies and initiatives. Members also educate hospital leadership, staff, managers, students, and new employees through orientations and in-service training addressing the needs of families and how care can be improved. Family Advisory Council members interact with other patients and families by fielding concerns and suggestions. Children's Hospitals and Clinics of Minnesota have a strong commitment to involving family members as advisors in every aspect of health care and on every level of the hospital system that impacts children and their families. PMID- 17708188 TI - HIV disease in children 25 years later. PMID- 17708187 TI - Politically-motivated torture and child survivors. AB - It is critical that healthcare providers recognize behaviors common to children who have endured politically-motivated torture in order to create a safe and reliable treatment plan for such children and their families. Three vignettes taken from actual cases illustrate the way child survivors of torture are likely to present in educational, medical, or healthcare settings. Children or youth are resilient and can be helped to process their traumatic experiences and thrive emotionally and physically if providers are observant, competent and responsive. Federally funded resource centers exist to assist in caring for children who have survived torture. PMID- 17708190 TI - Nurses, physicians get behind effort to introduce preoperative briefings. PMID- 17708191 TI - 'Just culture' strikes a balance for safety. PMID- 17708192 TI - Debriefings are an early-warning system. PMID- 17708193 TI - Timeout: it's as easy as apple pie! PMID- 17708194 TI - Protecting postop patients from VAP. PMID- 17708195 TI - Interspinous process decompression: what's the state of the evidence? PMID- 17708196 TI - Support for staff when things go wrong. PMID- 17708197 TI - 'Diamond standard' for managing supply chain. PMID- 17708198 TI - How will Medicare rates impact your ASC? PMID- 17708199 TI - Open house highlights ASC's impact. PMID- 17708200 TI - Disaster-proofing your practice. Preparation is key. PMID- 17708201 TI - Are Americans taking tooth whitening too far? PMID- 17708202 TI - All systems go. PMID- 17708203 TI - Is 'branding' a dirty word? PMID- 17708204 TI - Jane Austen goes to the dentist. PMID- 17708205 TI - How to punish cheaters. PMID- 17708207 TI - Measuring social-ecological dynamics behind the generation of ecosystem services. AB - The generation of ecosystem services depends on both social and ecological features. Here we focus on management, its ecological consequences, and social drivers. Our approach combined (1) quantitative surveys of local species diversity and abundance of three functional groups of ecosystem service providers (pollinators, seed dispersers, and insectivores) with (2) qualitative studies of local management practices connected to these services and their underlying social mechanisms, i.e., institutions, local ecological knowledge, and a sense of place. It focused on the ecology of three types of green areas (allotment gardens, cemeteries, and city parks) in the city of Stockholm, Sweden. These are superficially similar but differ considerably in their management. Effects of the different practices could be seen in the three functional groups, primarily as a higher abundance of pollinators in the informally managed allotment gardens and as differences in the composition of seed dispersers and insectivores. Thus, informal management, which is normally disregarded by planning authorities, is important for ecosystem services in the urban landscape. Furthermore, we suggest that informal management has an important secondary function: It may be crucial during periods of instability and change as it is argued to promote qualities with potential for adaptation. Allotment gardeners seem to be the most motivated managers, something that is reflected in their deeper knowledge and can be explained by a sense of place and management institutions. We propose that co management would be one possible way to infuse the same positive qualities into all management and that improved information exchange between managers would be one further step toward ecologically functional urban landscapes. PMID- 17708206 TI - Poverty and corruption compromise tropical forest reserves. AB - We used the global fire detection record provided by the satellite-based Moderate Resolution Imaging Spectroradiometer (MODIS) to determine the number of fires detected inside 823 tropical and subtropical moist forest reserves and for contiguous buffer areas 5, 10, and 15 km wide. The ratio of fire detection densities (detections per square kilometer) inside reserves to their contiguous buffer areas provided an index of reserve effectiveness. Fire detection density was significantly lower inside reserves than in paired, contiguous buffer areas but varied by five orders of magnitude among reserves. The buffer: reserve detection ratio varied by up to four orders of magnitude among reserves within a single country, and median values varied by three orders of magnitude among countries. Reserves tended to be least effective at reducing fire frequency in many poorer countries and in countries beset by corruption. Countries with the most successful reserves include Costa Rica, Jamaica, Malaysia, and Taiwan and the Indonesian island of Java. Countries with the most problematic reserves include Cambodia, Guatemala, Paraguay, and Sierra Leone and the Indonesian portion of Borneo. We provide fire detection density for 3964 tropical and subtropical reserves and their buffer areas in the hope that these data will expedite further analyses that might lead to improved management of tropical reserves. PMID- 17708208 TI - Post-socialist forest disturbance in the Carpathian border region of Poland, Slovakia, and Ukraine. AB - Forests provide important ecosystem services, and protected areas around the world are intended to reduce human disturbance on forests. The question is how forest cover is changing in different parts of the world, why some areas are more frequently disturbed, and if protected areas are effective in limiting anthropogenic forest disturbance. The Carpathians are Eastern Europe's largest contiguous forest ecosystem and are a hotspot of biodiversity. Eastern Europe has undergone dramatic changes in political and socioeconomic structures since 1990, when socialistic state economies transitioned toward market economies. However, the effects of the political and economic transition on Carpathian forests remain largely unknown. Our goals were to compare post-socialist forest disturbance and to assess the effectiveness of protected areas in the border triangle of Poland, Slovakia, and Ukraine, to better understand the role of broadscale political and socioeconomic factors. Forest disturbances were assessed using the forest disturbance index derived from Landsat MSS/TM/ETM+ images from 1978 to 2000. Our results showed increased harvesting in all three countries (up to 1.8 times) in 1988-1994, right after the system change. Forest disturbance rates differed markedly among countries (disturbance rates in Ukraine were 4.5 times higher than in Poland, and those in Slovakia were 4.3 times higher than in Poland), and in Ukraine, harvests tended to occur at higher elevations. Forest fragmentation increased in all three countries but experienced a stronger increase in Slovakia and Ukraine (approximately 5% decrease in core forest) than in Poland. Protected areas were most effective in Poland and in Slovakia, where harvesting rates dropped markedly (by nearly an order of magnitude in Slovakia) after protected areas were designated. In Ukraine, harvesting rates inside and outside protected areas did not differ appreciably, and harvests were widespread immediately before the designation of protected areas. In summary, the socioeconomic changes in Eastern Europe that occurred since 1990 had strong effects on forest disturbance. Differences in disturbance rates among countries appear to be most closely related to broadscale socioeconomic conditions, forest management practices, forest policies, and the strength of institutions. We suggest that such factors may be equally important in other regions of the world. PMID- 17708209 TI - Reconciling divergent interpretations of quaking aspen decline on the northern Colorado Front Range. AB - Ecologists have debated over the past 65 years whether quaking aspen (Populus tremuloides Michx.) has or has not declined in abundance, vigor, or regeneration in western North America. Many studies have provided divergent interpretations of the condition of aspen forests, leading to difficulty in translating this ecological information into management recommendations. To reconcile these contrasting conclusions and to test the hypothesis that multiple types of aspen decline and persistence occur simultaneously on heterogeneous landscapes, we assessed 91 aspen stands across the northern Colorado Front Range to determine the range of ecological conditions that underlie aspen decline or persistence. Approximately 15% of aspen forest area in our sample exhibited dieback of mature stems coupled with a lack of young trees indicative of declining stands, most often at lower elevations where elk browsing is heavy and chronic, and where effects of fire exclusion have been most significant. However, 52% of the area sampled had multiple cohorts indicative of self-replacing or persistent stands. Conifer dominance was increasing in over 33% of all aspen forest area sampled, most often at high elevations among lodgepole pine (Pinus contorta var. latifolia Englem. ex Wats.) forests. Reconstructions of relative basal area and density of aspen and lodgepole pine in these stands suggest cyclical dominance of these species, where conifers gradually replace aspen over long fire intervals, and aspen vigorously re-establish following stand-replacing fires. The diversity of ecological contexts across the northern Colorado Front Range creates a variety of aspen dynamics leading to decline or persistence, and no single trend describes the general condition of aspen forests in appropriate detail for managers. Active management may be useful in preserving individual stands at fine scales, but management prescriptions should reflect specific drivers of decline in these stands. PMID- 17708210 TI - The role of stochasticity and priority effects in floodplain restoration. AB - This paper is a test of two widely held assumptions in the practice of riparian restoration: (1) if physical processes are restored, plant communities will naturally reassemble themselves, and (2) restored communities will resemble reference sites. Seasonal flooding was restored to two interconnected floodplains in the Central Valley of California (USA), and plant community establishment was studied for six years at 300 permanent vegetation plots. If these two assumptions are valid, then the two floodplains should end up with similar plant assemblages, and they should both have followed a similar trajectory. Then, once the relevant physical processes are restored, (1) plots with similar environmental conditions should have increasingly similar species compositions, (2) plant communities should become more stable and cohesive, (3) both species distributions and plant communities should respond to changes in environmental conditions, (4) plot diversity should decrease, and (5) perennial species should replace annuals. The plots were classified into communities using TWINSPAN, and these communities differed significantly with respect to the main environmental gradient (inundation). Bray-Curtis similarities were calculated for each pair of plots. Patterns in similarity were used to test the strength of communities and the relative importance of proximity and inundation. On the northern floodplain, there was a trend of increasing similarity for plots with similar environmental conditions over the course of the study; plant communities became more stable and clearly responded to changes in environmental conditions. Plot diversity decreased, and the proportion of perennial species increased. On the southern floodplain, however, plots with similar environmental conditions became less similar, while plots that were close together became more similar; plant communities did not become more stable though they did shift in response to changes in environmental conditions. Taken together, this evidence suggests that assembly of communities is more stochastic than deterministic. PMID- 17708211 TI - Forest structure and light regimes following moderate wind storms: implications for multi-cohort management. AB - Moderate-severity disturbances appear to be common throughout much of North America, but they have received relatively little detailed study compared to catastrophic disturbances and small gap dynamics. In this study, we examined the immediate impact of moderate-intensity wind storms on stand structure, opening sizes, and light regimes in three hemlock-hardwood forests of northeastern Wisconsin. These were compared to three stands managed by single-tree and group selection, the predominant forest management system for northern hardwoods in the region. Wind storms removed an average of 41% of the stand basal area, compared to 27% removed by uneven-aged harvests, but both disturbances removed trees from a wide range of size classes. The removal of nearly half of the large trees by wind in two old-growth stands caused partial retrogression to mature forest structure, which has been hypothesized to be a major disturbance pathway in the region. Wind storms resulted in residual stand conditions that were much more heterogeneous than in managed stands. Gap sizes ranged from less than 10 m2 up to 5000 m2 in wind-disturbed stands, whereas the largest opening observed in managed stands was only 200 m2. Wind-disturbed stands had, on average, double the available solar radiation at the forest floor compared to managed stands. Solar radiation levels were also more heterogeneous in wind-disturbed stands, with six times more variability at small scales (0.1225 ha) and 15 times more variability at the whole-stand level. Modification of uneven-aged management regimes to include occasional harvests of variable intensity and spatial pattern may help avoid the decline in species diversity that tends to occur after many decades of conventional uneven-aged management. At the same time, a multi-cohort system with these properties would retain a high degree of average crown cover, promote structural heterogeneity typical of old-growth forests, and maintain dominance by late-successional species. PMID- 17708212 TI - Mercury cycling in litter and soil in different forest types in the Adirondack region, New York, USA. AB - The fate of mercury in decomposing leaf litter and soil is key to understanding the biogeochemistry of mercury in forested ecosystems. We quantified mercury dynamics in decomposing leaf litter and measured fluxes and pools of mercury in litterfall, throughfall, and soil in two forest types of the Adirondack region, New York, USA. The mean content of total mercury in leaf litter increased to 134% of its original mass during two years of decomposition. The accumulation pattern was seasonal, with significant increases in mercury mass during the growing season (+4.9% per month). Litterfall dominated mercury fluxes into the soil in the deciduous forest, whereas throughfall dominated fluxes into the coniferous forest. The increase in mercury mass in decomposing deciduous litter during the growing season was greater than could be accounted for by throughfall inputs during the growing season (P < 0.05), suggesting translocation of mercury from the soil to the decomposing deciduous litter. This internal recycling mechanism concentrates mercury in the organic horizons and retards transport through the soil, thereby increasing the residence time of mercury in the forest floor. A mass balance assessment suggests that the ultimate fate of mercury in the landscape depends upon forest type and associated differences in the delivery and incorporation of mercury into the soil. Our results show that incorporation of mercury into decaying leaf litter increases its residence time in the landscape and may further delay the recovery of surface waters, fish, and associated biota following control of mercury emissions to the atmosphere. PMID- 17708213 TI - Soil responses to management, increased precipitation, and added nitrogen in ponderosa pine forests. AB - Forest management, climatic change, and atmospheric N deposition can affect soil biogeochemistry, but their combined effects are not well understood. We examined the effects of water and N amendments and forest thinning and burning on soil N pools and fluxes in ponderosa pine forests near Flagstaff, Arizona (USA). Using a 15N-depleted fertilizer, we also documented the distribution of added N into soil N pools. Because thinning and burning can increase soil water content and N availability, we hypothesized that these changes would alleviate water and N limitation of soil processes, causing smaller responses to added N and water in the restored stand. We found little support for this hypothesis. Responses of fine root biomass, potential net N mineralization, and the soil microbial N to water and N amendments were mostly unaffected by stand management. Most of the soil processes we examined were limited by N and water, and the increased N and soil water availability caused by forest restoration was insufficient to alleviate these limitations. For example, N addition caused a larger increase in potential net nitrification in the restored stand, and at a given level of soil N availability, N addition had a larger effect on soil microbial N in the restored stand. Possibly, forest restoration increased the availability of some other limiting resource, amplifying responses to added N and water. Tracer N recoveries in roots and in the forest floor were lower in the restored stand. Natural abundance delta15N of labile soil N pools were higher in the restored stand, consistent with a more open N cycle. We conclude that thinning and burning open up the N cycle, at least in the short-term, and that these changes are amplified by enhanced precipitation and N additions. Our results suggest that thinning and burning in ponderosa pine forests will not increase their resistance to changes in soil N dynamics resulting from increased atmospheric N deposition or increased precipitation due to climatic change. Restoration plans should consider the potential impact on long-term forest productivity of greater N losses from a more open N cycle, especially during the period immediately after thinning and burning. PMID- 17708214 TI - Effects of intensive mariculture on sediment biochemistry. AB - The exponential growth of off-shore mariculture that has occurred worldwide over the last 10 years has raised concern about the impact of the waste produced by this industry on the ecological integrity of the sea bottom. Investigations into this potential source of impact on the biochemistry of the sea floor have provided contrasting results, and no compelling explanations for these discrepancies have been provided to date. To quantify the impact of fish-farm activities on the biochemistry of sediments, we have investigated the quantity and biochemical composition of sediment organic matter in four different regions in the temperate-warm Mediterranean Sea: Akrotiri Bay (Cyprus), Sounion Bay (Greece), Pachino Bay (Italy), and the Gulf of Alicante (Spain). In these four study regions, the concentrations of phytopigments, proteins, carbohydrates, and lipids in the sediments were measured, comparing locations receiving wastes from fish farms to control locations in two different habitats: seagrass beds and soft nonvegetated substrates. Downward fluxes were also measured in all of the regions, up to 200 m from the fish farms, to assess the potential spatial extent of the impact. In all four regions, with the exception of seagrass sediments in Spain, the biochemistry of the sediments showed significant differences between the control and fish-farm locations. However, the variables explaining the differences observed varied among the regions and between habitats, suggesting idiosyncratic effects of fish-farm waste on the biochemistry of sediments. These are possibly related to differences in the local physicochemical variables that could explain a significant proportion of the differences seen between the control and fish-farm locations. Biodeposition derived from the fish farms decreased with increasing distance from the fish-farm cages, but with different patterns in the four regions. Our results indicate that quantitative and qualitative changes in the organic loads of the sediments that arise from intensive aquaculture are dependent upon the ecological context and are not predictable only on the basis of fish-farm attributes and hydrodynamic regimes. Therefore, the siting of fish farms should only be allowed after a case-by-case assessment of the ecological context of the region, especially in terms of the organic matter load and its biochemical composition. PMID- 17708215 TI - Soil erosion and significance for carbon fluxes in a mountainous Mediterranean climate watershed. AB - In topographically complex terrains, downslope movement of soil organic carbon (OC) can influence local carbon balance. The primary purpose of the present analysis is to compare the magnitude of OC displacement by erosion with ecosystem metabolism in such a complex terrain. Does erosion matter in this ecosystem carbon balance? We have used the Revised Universal Soil Loss Equation (RUSLE) erosion model to estimate lateral fluxes of OC in a watershed in northwestern Mexico. The watershed (4900 km2) has an average slope of 10 degrees +/- 9 degrees (mean +/- SD); 45% is >10 degrees, and 3% is >30 degrees. Land cover is primarily shrublands (69%) and agricultural lands (22%). Estimated bulk soil erosion averages 1350 Mg x km(-2) x yr(-1). We estimate that there is insignificant erosion on slopes < 2 degrees and that 20% of the area can be considered depositional. Estimated OC erosion rates are 10 Mg x km(-2) x yr(-1) for areas steeper than 2 degrees. Over the entire area, erosion is approximately 50% higher on shrublands than on agricultural lands, but within slope classes, erosion rates are more rapid on agricultural areas. For the whole system, estimated OC erosion is approximately 2% of net primary production (NPP), increasing in high-slope areas to approximately 3% of NPP. Deposition of eroded OC in low-slope areas is approximately 10% of low-slope NPP. Soil OC movement from erosional slopes to alluvial fans alters the mosaic of OC metabolism and storage across the landscape. PMID- 17708216 TI - Human influence on California fire regimes. AB - Periodic wildfire maintains the integrity and species composition of many ecosystems, including the mediterranean-climate shrublands of California. However, human activities alter natural fire regimes, which can lead to cascading ecological effects. Increased human ignitions at the wildland-urban interface (WUI) have recently gained attention, but fire activity and risk are typically estimated using only biophysical variables. Our goal was to determine how humans influence fire in California and to examine whether this influence was linear, by relating contemporary (2000) and historic (1960-2000) fire data to both human and biophysical variables. Data for the human variables included fine-resolution maps of the WUI produced using housing density and land cover data. Interface WUI, where development abuts wildland vegetation, was differentiated from intermix WUI, where development intermingles with wildland vegetation. Additional explanatory variables included distance to WUI, population density, road density, vegetation type, and ecoregion. All data were summarized at the county level and analyzed using bivariate and multiple regression methods. We found highly significant relationships between humans and fire on the contemporary landscape, and our models explained fire frequency (R2 = 0.72) better than area burned (R2 = 0.50). Population density, intermix WUI, and distance to WUI explained the most variability in fire frequency, suggesting that the spatial pattern of development may be an important variable to consider when estimating fire risk. We found nonlinear effects such that fire frequency and area burned were highest at intermediate levels of human activity, but declined beyond certain thresholds. Human activities also explained change in fire frequency and area burned (1960 2000), but our models had greater explanatory power during the years 1960-1980, when there was more dramatic change in fire frequency. Understanding wildfire as a function of the spatial arrangement of ignitions and fuels on the landscape, in addition to nonlinear relationships, will be important to fire managers and conservation planners because fire risk may be related to specific levels of housing density that can be accounted for in land use planning. With more fires occurring in close proximity to human infrastructure, there may also be devastating ecological impacts if development continues to grow farther into wildland vegetation. PMID- 17708217 TI - Responses of pond-breeding amphibians to wildfire: short-term patterns in occupancy and colonization. AB - Wildland fires are expected to become more frequent and severe in many ecosystems, potentially posing a threat to many sensitive species. We evaluated the effects of a large, stand-replacement wildfire on three species of pond breeding amphibians by estimating changes in occupancy of breeding sites during the three years before and after the fire burned 42 of 83 previously surveyed wetlands. Annual occupancy and colonization for each species was estimated using recently developed models that incorporate detection probabilities to provide unbiased parameter estimates. We did not find negative effects of the fire on the occupancy or colonization rates of the long-toed salamander (Ambystoma macrodactylum). Instead, its occupancy was higher across the study area after the fire, possibly in response to a large snowpack that may have facilitated colonization of unoccupied wetlands. Naive data (uncorrected for detection probability) for the Columbia spotted frog (Rana luteiventris) initially led to the conclusion of increased occupancy and colonization in wetlands that burned. After accounting for temporal and spatial variation in detection probabilities, however, it was evident that these parameters were relatively stable in both areas before and after the fire. We found a similar discrepancy between naive and estimated occupancy of A. macrodactylum that resulted from different detection probabilities in burned and control wetlands. The boreal toad (Bufo boreas) was not found breeding in the area prior to the fire but colonized several wetlands the year after they burned. Occupancy by B. boreas then declined during years 2 and 3 following the fire. Our study suggests that the amphibian populations we studied are resistant to wildfire and that B. boreas may experience short-term benefits from wildfire. Our data also illustrate how naive presence-non-detection data can provide misleading results. PMID- 17708218 TI - Covariates affecting spatial variability in bison travel behavior in Yellowstone National Park. AB - Understanding mechanisms influencing the movement paths of animals is essential for comprehending behavior and accurately predicting use of travel corridors. In Yellowstone National Park (USA), the effects of roads and winter road grooming on bison (Bison bison) travel routes and spatial dynamics have been debated for more than a decade. However, no rigorous studies have been conducted on bison spatial movement patterns. We collected 121 380 locations from 14 female bison with GPS collars in central Yellowstone to examine how topography, habitat type, roads, and elevation affected the probability of bison travel year-round. We also conducted daily winter bison road use surveys (2003-2005) to quantify how topography and habitat type influenced spatial variability in the amount of bison road travel. Using model comparison techniques, we found the probability of bison travel and spatial distribution of travel locations were affected by multiple topographic and habitat type attributes including slope, landscape roughness, habitat type, elevation, and distances to streams, foraging areas, forested habitats, and roads. Streams were the most influential natural landscape feature affecting bison travel, and results suggest the bison travel network throughout central Yellowstone is spatially defined largely by the presence of streams that connect foraging areas. Also, the probability of bison travel was higher in regions of variable topography that constrain movements, such as in canyons. Pronounced travel corridors existed both in close association with roads and distant from any roads, and results indicate that roads may facilitate bison travel in certain areas. However, our findings suggest that many road segments used as travel corridors are overlaid upon natural travel pathways because road segments receiving high amounts of bison travel had similar landscape features as natural travel corridors. We suggest that most spatial patterns in bison road travel are a manifestation of general spatial travel trends. Our research offers novel insights into bison spatial dynamics and provides conceptual and analytical frameworks for examining movement patterns of other species. PMID- 17708219 TI - Grizzly bear habitat selection is scale dependent. AB - The purpose of our study is to show how ecologists' interpretation of habitat selection by grizzly bears (Ursus arctos) is altered by the scale of observation and also how management questions would be best addressed using predetermined scales of analysis. Using resource selection functions (RSF) we examined how variation in the spatial extent of availability affected our interpretation of habitat selection by grizzly bears inhabiting mountain and plateau landscapes. We estimated separate models for females and males using three spatial extents: within the study area, within the home range, and within predetermined movement buffers. We employed two methods for evaluating the effects of scale on our RSF designs. First, we chose a priori six candidate models, estimated at each scale, and ranked them using Akaike Information Criteria. Using this method, results changed among scales for males but not for females. For female bears, models that included the full suite of covariates predicted habitat use best at each scale. For male bears that resided in the mountains, models based on forest successional stages ranked highest at the study-wide and home range extents, whereas models containing covariates based on terrain features ranked highest at the buffer extent. For male bears on the plateau, each scale estimated a different highest ranked model. Second, we examined differences among model coefficients across the three scales for one candidate model. We found that both the magnitude and direction of coefficients were dependent upon the scale examined; results varied between landscapes, scales, and sexes. Greenness, reflecting lush green vegetation, was a strong predictor of the presence of female bears in both landscapes and males that resided in the mountains. Male bears on the plateau were the only animals to select areas that exposed them to a high risk of mortality by humans. Our results show that grizzly bear habitat selection is scale dependent. Further, the selection of resources can be dependent upon the availability of a particular vegetation type on the landscape. From a management perspective, decisions should be based on a hierarchical process of habitat selection, recognizing that selection patterns vary across scales. PMID- 17708220 TI - Model of Japanese serow (Capricornis crispus) energetics predicts distribution on Honshu, Japan. AB - Understanding what determines a species' range is a central objective in ecology and evolutionary biology. It has important applications for predicting species distributions and how they might respond to environmental perturbations. This paper describes a mechanistic approach to predict past and present distribution of the Japanese serow (Capricornis crispus) on Honshu, Japan. We applied state-of the-art microclimate and animal biophysical/behavioral models coupled with climate and vegetation data to estimate the distribution of potential range expansion under protection. We tested the model results against detailed empirical distribution data from the Ministry of the Environment for a five prefecture area in central Honshu. We also applied the models to time-series land use/cover maps to investigate the historical transitions in habitat suitability during 1947-1999 in the Arai-Keinan region. This is the first time to our knowledge that mechanistic models have successfully predicted the landscape scale distribution of a mammal species in the absence of other animal species interactions, such as predators. In this case, animal energetics/behavior-plant interactions seem to be critical. Forest cover appears to be important in summer and winter for suitable serow habitats. The energetics model results indicate that the serow can overheat in some open environments in midday hours in summer. In winter, simulation results suggested that forest cover provides effective refuge to avoid increased metabolic demands of cold temperatures and strong winds. The model simulations suggested that land use/cover changes documented during 1947-1999 resulted in increased suitable serow habitat due to expanding forest cover from agricultural marginalization and ecological succession. The models provide a unique tool for estimating species' range expansion under protection or for selecting suitable reintroduction sites. PMID- 17708222 TI - Does scale matter in predicting species distributions? case study with the Marbled Murrelet. AB - Hierarchical selection orders (selection of microsite, patch, home range, population block, and geographic range) are ideal for dictating spatial grain and extent of animal habitat models, but the resultant conditional models are poor for creating predictive maps. I proposed a two-step approach for accurately mapping probability of animal use that incorporates a single-grain analysis of each selection order in the first step and creates a multi-grain model that combines key variables from each selection order in the second step. Such two step multi-grain models are strongly recommended because they allow interpretation of the scale of selection for a variable. Using a large data set for the Marbled Murrelet (Brachyramphus marmoratus) as a case study and five selection orders, information theory criteria provided strong support that such models are superior to simpler one-step single-grain models for the murrelet. However, a single-grain model can produce high classification accuracy if it represents the most limiting scale. Notably, accuracy of the two-step multi-grain model was no better than a traditional one-step multi-grain model that ignores selection orders, indicating the advantage of two-step modeling is in elucidating scaling effects, not necessarily in improving accuracy of species distribution maps. PMID- 17708221 TI - Minimum viable metapopulation size, extinction debt, and the conservation of a declining species. AB - A key question facing conservation biologists is whether declines in species' distributions are keeping pace with landscape change, or whether current distributions overestimate probabilities of future persistence. We use metapopulations of the marsh fritillary butterfly Euphydryas aurinia in the United Kingdom as a model system to test for extinction debt in a declining species. We derive parameters for a metapopulation model (incidence function model, IFM) using information from a 625-km2 landscape where habitat patch occupancy, colonization, and extinction rates for E. aurinia depend on patch connectivity, area, and quality. We then show that habitat networks in six extant metapopulations in 16-km2 squares were larger, had longer modeled persistence times (using IFM), and higher metapopulation capacity (lambdaM) than six extinct metapopulations. However, there was a > 99% chance that one or more of the six extant metapopulations would go extinct in 100 years in the absence of further habitat loss. For 11 out of 12 networks, minimum areas of habitat needed for 95% persistence of metapopulation simulations after 100 years ranged from 80 to 142 ha (approximately 5-9% of land area), depending on the spatial location of habitat. The area of habitat exceeded the estimated minimum viable metapopulation size (MVM) in only two of the six extant metapopulations, and even then by only 20%. The remaining four extant networks were expected to suffer extinction in 15 126 years. MVM was consistently estimated as approximately 5% of land area based on a sensitivity analysis of IFM parameters and was reduced only marginally (to approximately 4%) by modeling the potential impact of long-distance colonization over wider landscapes. The results suggest a widespread extinction debt among extant metapopulations of a declining species, necessitating conservation management or reserve designation even in apparent strongholds. For threatened species, metapopulation modeling is a potential means to identify landscapes near to extinction thresholds, to which conservation measures can be targeted for the best chance of success. PMID- 17708223 TI - Geographic assignment of seabirds to their origin: combining morphologic, genetic, and biogeochemical analyses. AB - Longline fisheries, oil spills, and offshore wind farms are some of the major threats increasing seabird mortality at sea, but the impact of these threats on specific populations has been difficult to determine so far. We tested the use of molecular markers, morphometric measures, and stable isotope (delta15N and delta13C) and trace element concentrations in the first primary feather (grown at the end of the breeding period) to assign the geographic origin of Calonectris shearwaters. Overall, we sampled birds from three taxa: 13 Mediterranean Cory's Shearwater (Calonectris diomedea diomedea) breeding sites, 10 Atlantic Cory's Shearwater (Calonectris diomedea borealis) breeding sites, and one Cape Verde Shearwater (C. edwardsii) breeding site. Assignment rates were investigated at three spatial scales: breeding colony, breeding archipelago, and taxa levels. Genetic analyses based on the mitochondrial control region (198 birds from 21 breeding colonies) correctly assigned 100% of birds to the three main taxa but failed in detecting geographic structuring at lower scales. Discriminant analyses based on trace elements composition achieved the best rate of correct assignment to colony (77.5%). Body measurements or stable isotopes mainly succeeded in assigning individuals among taxa (87.9% and 89.9%, respectively) but failed at the colony level (27.1% and 38.0%, respectively). Combining all three approaches (morphometrics, isotopes, and trace elements on 186 birds from 15 breeding colonies) substantially improved correct classifications (86.0%, 90.7%, and 100% among colonies, archipelagos, and taxa, respectively). Validations using two independent data sets and jackknife cross-validation confirmed the robustness of the combined approach in the colony assignment (62.5%, 58.8%, and 69.8% for each validation test, respectively). A preliminary application of the discriminant model based on stable isotope delta15N and delta13C values and trace elements (219 birds from 17 breeding sites) showed that 41 Cory's Shearwaters caught by western Mediterranean long-liners came mainly from breeding colonies in Menorca (48.8%), Ibiza (14.6%), and Crete (31.7%). Our findings show that combining analyses of trace elements and stable isotopes on feathers can achieve high rates of correct geographic assignment of birds in the marine environment, opening new prospects for the study of seabird mortality at sea. PMID- 17708224 TI - Satellite detection of bird communities in tropical countryside. AB - The future of biodiversity hinges partly on realizing the potentially high conservation value of human-dominated countryside. The characteristics of the countryside that promote biodiversity preservation remain poorly understood, however, particularly at the fine scales at which individual farmers tend to make land use decisions. To address this problem, we explored the use of a rapid remote sensing method for estimating bird community composition in tropical countryside, using a two-step process. First, we asked how fine-grained variation in land cover affected community composition. Second, we determined whether the observed changes in community composition correlated with three easily accessible remote sensing metrics (wetness, greenness, and brightness), derived from performing a tasseled-cap transformation on a Landsat Enhanced Thematic Mapper Plus image. As a comparison, we also examined whether the most commonly used remote sensing indicator in ecology, the Normalized Difference Vegetation Index (NDVI), correlated with community composition. We worked within an agricultural landscape in southern Costa Rica, where the land comprised a complex and highly heterogeneous mosaic of remnant native vegetation, pasture, coffee cultivation, and other crops. In this region, we selected 12 study sites (each < 60 ha) that encompassed the range of available land cover possibilities in the countryside. Within each site, we surveyed bird communities within all major land cover types, and we conducted detailed field mapping of land cover. We found that the number of forest-affiliated species increased with forest cover and decreased with residential area across sites. Conversely, the number of agriculture-affiliated species using forest increased with land area devoted to agricultural and residential uses. Interestingly, we found that the wetness and brightness metrics predicted the number of forest- and agriculture-affiliated species within a site as well as did detailed field-generated maps of land cover. In contrast, NDVI and the closely correlated greenness metric did not correlate with land cover or with bird communities. Our study shows the strong potential of the tasseled-cap transformation as a tool for assessing the conservation value of countryside for biodiversity. PMID- 17708225 TI - Recovery of Durvillaea antarctica (Durvilleales) inside and outside Las Cruces Marine Reserve, Chile. AB - We present the results for over two decades of monitoring on intertidal food gatherers and the population of the low rocky shore dweller kelp Durvillaea antarctica, a short-distance disperser, inside and outside the no-take marine reserve, Estacion Costera de Investigaciones Marinas (ECIM), at Las Cruces, central Chile. It was hypothesized that protection of an initially extremely depleted population would recover by recolonizing first the no-take area and then adjacent non-protected (exploited) areas. We found that recovery of D. antarctica occurred slowly inside ECIM, with increase in density and biomass, of up to three orders of magnitude as compared to an adjacent non-protected area, which showed approximately 2-yr delay. These results suggest that the kelp population inside ECIM was likely regulated via intraspecific competition, which did not occur outside. Results showed no evidence for juvenile vs. adult density dependence other than a weak relationship for the central area of ECIM. These findings also suggest that the population recovery and cross-boundary seeding subsides affected the population dynamics. Understanding these dynamics may enhance management and conservation policies. Our work highlights the critical value of baseline and long-term comparative studies in marine no-take protected and non-protected areas for understanding how population processes respond to human and conservation practices. PMID- 17708227 TI - Predicting [corrected] extinction risk in spite of predator-prey oscillations. AB - Most population viability analyses (PVA) assume that the effects of species interactions are subsumed by population-level parameters. We examine how robust five commonly used PVA models are to violations of this assumption. We develop a stochastic, stage-structured predator-prey model and simulate prey population vital rates and abundance. We then use simulated data to parameterize and estimate risk for three demographic models (static projection matrix, stochastic projection matrix, stochastic vital rate matrix) and two time series models (diffusion approximation [DA], corrupted diffusion approximation [CDA]). Model bias is measured as the absolute deviation between estimated and observed quasi extinction risk. Our results highlight three generalities about the application of single-species models to multi-species conservation problems. First, our collective model results suggest that most single-species PVA models overestimate extinction risk when species interactions cause periodic variation in abundance. Second, the DA model produces the most (conservatively) biased risk forecasts. Finally, the CDA model is the most robust PVA to population cycles caused by species interactions. CDA models produce virtually unbiased and relatively precise risk estimates even when populations cycle strongly. High performance of simple time series models like the CDA owes to their ability to effectively partition stochastic and deterministic sources of variation in population abundance. PMID- 17708226 TI - Reconstruction of Pacific salmon abundance from riparian tree-ring growth. AB - We use relationships between modern Pacific salmon (Oncorhynchus spp.) escapement (migrating adults counted at weirs or dams) and riparian tree-ring growth to reconstruct the abundance of stream-spawning salmon over 150-350 years. After examining nine sites, we produced reconstructions for five mid-order rivers and four salmon species over a large geographic range in the Pacific Northwest: chinook (O. tschwatcha) in the Umpqua River, Oregon, USA; sockeye (O. nerka) in Drinkwater Creek, British Columbia, Canada; pink (O. gorbuscha) in Sashin Creek, southeastern Alaska, USA; chum (O. keta) in Disappearance Creek, southeastern Alaska, USA; and pink and chum in the Kadashan River, southeastern Alaska, USA. We first derived stand-level, non-climatic growth chronologies from riparian trees using standard dendroecology methods and differencing. When the chronologies were compared to 18-55 years of adult salmon escapement we detected positive, significant correlations at five of the nine sites. Regression models relating escapement to tree-ring growth at the five sites were applied to the differenced chronologies to reconstruct salmon abundance. Each reconstruction contains unique patterns characteristic of the site and salmon species. Reconstructions were validated by comparison to local histories (e.g., construction of dams and salmon canneries) and regional fisheries data such as salmon landings and aerial surveys and the Pacific Decadal Oscillation climate index. The reconstructions capture lower-frequency cycles better than extremes and are most useful for determination and comparison of relative abundance, cycles, and the effects of interventions. Reconstructions show lower population cycle maxima in both Umpqua River chinook and Sashin Creek pink salmon in recent decades. The Drinkwater Creek reconstruction suggests that sockeye abundance since the mid-1990s has been 15-25% higher than at any time since 1850, while no long-term deviations from natural cycles are detected for salmon in the Kadashan River or in Disappearance Creek. Decadal-scale cycles in salmon abundance with periods of 25-68 years were detected in all of the reconstructions. This novel approach provides river-specific, long-term perspectives on salmon abundance and cycles. Additionally, it provides a new frame of reference for maintaining and rebuilding individual stocks and for striking a balance between societal demands and the limited, always-changing salmon resource. PMID- 17708228 TI - [The evolution of surgery]. PMID- 17708229 TI - [The da Vinci surgical system in digestive surgery]. AB - Since 1990, laparoscopy and minimally invasive techniques in general, have been widely adopted in the field of digestive surgery. However, due to its technical limitations, the use of conventional laparoscopy remains limited to procedures of low (cholecystectomy, appendectomy) or intermediate (Nissen fundoplication, sigmoidectomy) complexity. This paper reviews the technical aspects of the da Vinci robot, as well as its potential applications to digestive surgery. While robotic-assisted cholecystectomy and fundoplication are feasible, this approach is not superior to conventional laparoscopy; by contrast, preliminary data suggest that robotic-assisted surgery might be superior to laparoscopy in more complex procedures, such as gastric bypass and total mesorectum excision for rectal cancer. PMID- 17708231 TI - [Xenotransplantation, soon a clinical reality?]. AB - Organ transplantation has encountered great development during the 80's. However, the number of organ donations and transplantations performed stabilized during the 90ies, with a concomitant increase of patients on the waiting list. Xenotransplantation, i.e. the use of animal organs for transplantation to humans, is one among various alternatives to human organ donation. Xenotransplantation offers several advantages, e.g. it would be possible to transplant all patients at an early stage of their disease. The main barriers to xenotransplantation are the strong immunological responses that human develop against animal antigens and zoonoses. To overcome these hurdles, genetically modified pigs have been engineered by cloning and could allow the initiation of new clinical trials in a near future. PMID- 17708230 TI - [Islet autotransplantation to prevent diabetes after pancreatectomy for benign disease of the pancreas]. AB - Patients with benign pancreatic disease (chronic pancreatitis, benign tumors) requiring extensive pancreatic surgery are subject to major metabolic changes. Many of them are at risk of developing diabetes. Surgical diabetes is very difficult to manage because of the lack of counter regulation mechanisms. Islet autotransplantation after isolation from the resected pancreas allows to avoid the development of surgical diabetes. Insulin independance can be maintained in 40 to 50% of the patients. Success rate depends on the number of isolated and transplanted islets and on the type of pancreatic disease. Procedures-related complications are rare, the most frequent being thrombosis of the portal vein, through which the islets are transplanted. Islet autotransplantation has been used successfully in chronic pancreatitis and benign tumors. PMID- 17708232 TI - [Surgical managment of colorectal liver metastasis]. AB - Surgery offer the only curative treatment for colorectal hepatic metastasis. Nowadays, five-year survival increases up to 58% in selected cases, due to the improvement and combination of chemotherapy, surgery and ablative treatment like embolisation, radio-frequency or cryoablation. Surgery should be integrated in a multi disciplinary approach and initial work-up must take in account patient general conditions, tumor location, and possible extra hepatic extension. Thus, a surgical resection may be performed immediately or after preparation with chemotherapy or selective portal embolization. Management of liver metastasis should be carried out in oncological hepato-biliary centre. PMID- 17708233 TI - [Sacral nerve stimulation, an effective treatment for fecal incontinence]. AB - Sacral nerve stimulation (SNS) became recently an essential therapeutic modality in the treatment of anal incontinence. Indications range from anorectal functional disorders to limited sphincteric lesions. An electrode is inserted through a sacral foramen, generally S3, to stimulate the corresponding nerve root. Patient's selection needs a meticulous multidisciplinary approach. Improved continence of more than 50% is frequently encountered and quality of life is significantly improved after implantation. SNS is a minimal-invasive technique, with very few risks of complications. PMID- 17708234 TI - [Acute abdominal pain: what about analgesia]. AB - Acute abdominal pain tends not to be treated by surgeons and emergency physicians. However, literature has become clear that analgesics are effective and do not disturb clinical examination, diagnostic process and do not delay surgery. Thus, early treatment of acute abdominal pain is recommended. In the absence of scientific evidence, protocols must be established by each institution and validated by quality process. PMID- 17708235 TI - [The quality of Internet medical sites]. PMID- 17708236 TI - [Some question in the genes]. PMID- 17708237 TI - [Doping in French youth, alcoholics in the Ural region]. PMID- 17708238 TI - [The innocence and culpability of cholesterol (I)]. PMID- 17708239 TI - [Detailed observation around a Sarkosian intoxication]. PMID- 17708240 TI - [Medicinal laughter]. PMID- 17708241 TI - Lack of activity of imatinib in two cases of KIT+ retroperitoneal liposarcoma. PMID- 17708242 TI - Microwave ablation in locally advanced pancreatic carcinoma--a new look. AB - BACKGROUND/AIMS: Pancreatic carcinoma is by far the most common malignancy and is the 5th most lethal cancer in the world and 40% of these carcinomas are locally advanced and unresectable at the time of presentation. Palliative surgery and chemoradiotherapy have not produced significant improvement in survival. The overall prognosis of these pancreatic cancers is poor, if left untreated without any form of palliation. Out of many palliative methods adopted for such locally advanced pancreatic carcinoma, none has shown much survival benefit. Microwave ablation is a well established and safe local ablative method for liver tumors and microwave ablation for locally advanced pancreatic tumors has been extensively used around the world. This is our largest series of microwave ablation in 15 patients with locally advanced pancreatic head carcinoma. The aim of this study was to evaluate the safety, efficacy, feasibility and complications of microwave ablation in unresectable locally advanced pancreatic carcinoma. METHODOLOGY: In total, 15 patients, from January 2004 to December 2006, were included in this study all having locally advanced pancreatic tumors which were found to be unresectable on radiological evaluation. The 15 patients (10 male and 5 female) with a mean age of 67 years were subjected to open microwave ablation after laparotomy and additional palliative procedure like biliary bypass (end-to side hepaticojejunostomy) and gastric obstruction bypass by antecolic gastrojejunostomy was performed in 6 patients. The location of tumor was predominantly in the head and/or uncinate portion of the pancreas (n=12) and head and body (n=3). The average size of tumor was 6cm (range 4-8cm) and almost all had major regional vascular invasion on CT or MR angiogram. All tumors were histologically proven before the procedure by core needle and frozen section biopsy. Patients with distant metastasis were not included in this study. RESULTS: In all 15 patients, partial necrosis was achieved. There was no major procedure-related morbidity or mortality. Minor complications were seen in 6 out of 15 patients, mild pancreatitis (2), asymptomatic hyperamylasia (2), pancreatic ascites (1), and minor bleeding (1). All patients had close follow-up and the longest surviving patient had a follow-up of 22 months. CONCLUSIONS: Microwave ablation is a beneficial therapy as a local effective procedure which is feasible and safe with acceptable minor complications in a locally advanced pancreatic tumor which can be used as part of a palliative or multimodality treatment, however, further long-term and properly designed studies are required to prove its usefulness in achieving survival benefit. PMID- 17708243 TI - Bisegmentectomy VII-VIII for hepatocellular carcinoma in cirrhotic livers. AB - BACKGROUND/AIMS: Preservation of nontumorous liver parenchyma should be a priority in hepatic surgery in order to avoid the risk of life-threatening liver failure and maximize the possibility of repeat resection. METHODOLOGY: A tumor localized in segments VII, VIII and infiltrating the main trunk of the superior right hepatic vein usually indicates a need to perform a right hepatectomy. With the presence of a stout inferior right hepatic vein, bisegmentectomy VII, VIII can be carried out without the risk of hepatic congestion in the remaining segment VI. We retrospectively review our experience with this rare and challenging hepatic resection. RESULTS: In 23 of 715 patients with primary hepatocellular carcinoma, the tumor was localized in segments VII, VIII and involved with the superior right hepatic vein. Eleven underwent bisegmentectomy VII, VIII. Mean operative blood loss was estimated to be 300mL (200-1200mL), and only three patients required blood transfusions less than 2U each person. No patient had postoperative life-threatening liver failure and there was no postoperative mortality. All resection margins were negative. Median overall and disease-free survivals were 31 and 11 months, respectively, with five patients alive and disease-free. CONCLUSIONS: Bisegmentectomy VII and VIII is an oncologically radical but parenchyma-preserving liver resection. Though a rare hepatic resection, it can be performed safely with low morbidity and mortality in selected patients. PMID- 17708244 TI - Usefulness of linear stapling device in distal pancreatic resection. AB - BACKGROUND/AIMS: Although the mortality rate related to pancreatic surgery has been reduced, postoperative pancreatic fistula (POPF) remains high. The rate of POPF is reportedly between 5 and 34%. The pancreatic stump is typically closed by hand using suture materials. Recently, linear stapling devices have been employed in pancreatic resection, but the efficacy and safety of this procedure remain uncertain. METHODOLOGY: Efficacy and safety were retrospectively analyzed for distal pancreatic resection using a linear stapling device in open and laparoscopic procedures starting from January 1999 (Group A: n=20), and perioperative data were compared with those for hand-sewn stump closure starting from January 1990 (Group B: n=28). RESULTS: Mean operative times in Group A and Group B were 165 min and 200 min, respectively (p < 0.05). POPF was observed in two cases in Group A (10%) and 10 cases in Group B (35%) (p < 0.05). POPF was not observed in the three patients who underwent laparoscopic pancreatic resection with the linear stapling device. Mean hospital stay for Groups A and B was 14 days and 20 days, respectively (p < 0.05). In POPF patients, no clinical symptoms were observed, but drains were removed 10 postoperative days later than in patients without POPF, from whom drains were withdrawn at 7 days (p < 0.05). Patients exhibiting POPF were treated conservatively and all patients were discharged in good health. CONCLUSIONS: It may be concluded that: (1) drains should be withdrawn carefully according to the volume and characteristics of exudates; (2) mechanical staplers are promising devices for distal pancreatic resection; and (3) laparoscopic procedures are also promising for distal pancreatic resection. PMID- 17708245 TI - Age is not a discriminating factor for outcomes of therapeutic upper gastrointestinal endoscopy. AB - BACKGROUND/AIMS: To compare the efficacy and complications of therapeutic endoscopy for acute nonvariceal upper gastrointestinal bleeding between the geriatric (aged 65 and older) and non-geriatric patients. METHODOLOGY: A total of 134 out of 259 hospitalized patients in the year 2005 had high-risk endoscopic lesions in UGI endoscopy and received therapeutic endoscopy. Seventy-six out of 134 patients were aged 65 and older (44 men), while 58 patients were aged 64 and younger (51 men). We compared clinical presentations, co-morbidities, endoscopic therapeutic procedures, endoscopic treatment failure, hospitalization days, blood transfusion, post-endoscopy complications (fever, acute coronary syndrome, aspiration pneumonia), and in-hospital mortality after therapeutic endoscopy. RESULTS: Geriatric patients had lower hemoglobin on arrival (9.19 +/- 2.7 vs. 10.64 +/- 2.46 g/dL, p = 0.002) and larger gastric ulcers (7.3 +/- 6.9 vs. 4.0 +/ 3.6 mm, p = 0.008). Failure of therapeutic endoscopy, defined as salvage endoscopy or surgery within 48 hours after first endoscopy, showed no difference (14% vs. 14%, p = 0.98). Hospitalization stay (mean 7.47 vs. 5.97 days, p = 0.2), blood transfusion more than 4 units (47% vs. 34%, p = 0.13), post-endoscopic complications, in-hospital mortality were all comparable between geriatrics and non-geriatrics. CONCLUSIONS: Our results serve a scientific basis that age is not a discriminating factor for outcomes in current therapeutic endoscopy. PMID- 17708246 TI - Common bile duct investigation in patients with mild biliary pancreatitis. when and how? A prospective analysis of 48 patients. AB - BACKGROUND/AIMS: To define how and when patients with mild acute biliary pancreatitis must have their biliary tree investigated. METHODOLOGY: We analyzed 48 patients' files with mild biliary pancreatitis between 1995 and 2004. After clinical treatment, magnetic resonance or endoscopic retrograde cholangiopancreatography and then surgery was performed. Statistical data were analyzed through SPSS version 11.0. RESULTS: Of the 48 patients, 13 (27%) patients had choledocholithiasis. Five of these (38%) were diagnosed and treated by endoscopic retrograde cholangiopancreatography and 8 (62%) patients had choledocholithiasis at magnetic resonance cholangiopancreatography. These 8 patients underwent endoscopic retrograde cholangiopancreatography which found common bile duct stones in only 4 (50%) of them that were treated successfully with papillotomy. All patients underwent laparoscopic cholecystectomy at the same hospital stay with a low morbidity and no mortality. CONCLUSIONS: We believe that patients with mild biliary pancreatitis should have their biliary tree investigated just after clinical recovery and as close as possible to the operation because many gallstones pass spontaneously through the papillae. We believe that magnetic resonance cholangiopancreatography can avoid an unnecessary endoscopic retrograde cholangiopancreatography. PMID- 17708247 TI - Laparoscopic cholecystectomy; a retrospective 10-year study. AB - BACKGROUND/AIMS: To evaluate results of laparoscopic cholecystectomies realized in our department and to compare results concerning local and general complications with those reported in the literature. METHODOLOGY: We analyzed retrospectively all the 1255 laparoscopic cholecystectomies realized in our department between January 95 and December 2004. Local and general complications were analyzed. Mean age was 55.6 (21-94) years, sex ratio (F/M) was 3.9. Common bile duct stones were extracted by endoscopic retrograde endoscopy (ERCP) before surgery or by choledochotomy (less than 1% of cases). The operation was performed with 4 trocars, as described by Dubois. RESULTS: Conversion rate was 1.95%. Mean postoperative hospitalization duration was2.7 days. Morbidity was 5.8% with equal repartition between local and general complications. Therevere 2 common bile duct injuries (0.16%). Six patients suffered from residual bile duct stone after cholecystectomy; 5 were treated by ERCP and 1 by choledochotomy. Three patients died (0.24%) after general complications. CONCLUSIONS: Laparoscopic cholecvstectomv is a common operation with potential possible dramatic complications. We think that a radiological study of the biliary tract must be performed before surgery to avoid mistakes during the operation. PMID- 17708248 TI - Predictors of mortality and morbidity in acute obstructive jaundice: implication of preventive measures. AB - BACKGROUND/AIMS: The afferent events in acute obstructive jaundice (AOJ) are characterized by endotoxemia-induced decrease in systemic vascular resistance and bile salt mediated natriuresis and diuresis leading to diminished effective plasma volume. METHODOLOGY: A prospective protocol aimed at preventing those alterations was carried out in 104 consecutive patients with AOJ. The preoperative risk factors that predict postoperative mortality and morbidity were reevaluated and correctable factors were identified. RESULTS: The average duration between the initiation of jaundice and surgery was 9.3 days. The perioperative mortality was 0%. The essentials of the treatment protocol were lactulose and cefazolin administration respectively for the prevention of portal endotoxemia and biliary sepsis and maintenance of body weight with adequately replaced fluid and electrolytes. Clinically relevant nutritional deficit was not observed in any of the patients during the perioperative period. The unique factor that predicted late mortality was the preoperative alanine transaminase value. Renal hemodynamics and hematologic parameters were completely correctable before the operation and patients with malignant or benign biliary strictures benefited and responded to the treatment similarly. CONCLUSIONS: Measures taken to prevent the activation and progression of the afferent events in AOJ, have resulted in excellent clinical outcomes. PMID- 17708249 TI - Modifications of coagulation and fibrinolysis mechanism in laparoscopic vs. open cholecystectomy. AB - BACKGROUND/AIMS: The incidence of thromboembolic complications following laparoscopic cholecystectomy as well as the indication for prophylactic thrombophylaxis is still controversially discussed. The aim of this study is to evaluate the alterations of the coagulation and fibrinolytic mechanism after laparoscopic vs. open cholecystectomy. METHODOLOGY: Forty-five patients, who were submitted to laparoscopic (LC-group, n=30) or open cholecystectomy (OC-group, n=15) were included in the study. The following parameters were measured preoperatively and 24h and 48h postoperatively: platelet count (PLT), prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen (FG), d-dimers (DD) and antithrombin III (AT-III). RESULTS: The preoperative values were within the normal range and did not differ between the two groups. No significant alterations were noted concerning PT and PTT. FG and PLT were significantly increased in both groups at 24h and 48h compared to the baseline values, with no statistical significant difference between them at all time points. D-dimers were significantly elevated at 24h and 48h postoperatively in both groups. The LC group showed significantly higher AT-III levels at 24h, and significantly lower DD levels at 24h and 48h compared to the OC-group (p < 0.05). CONCLUSIONS: Laparoscopic cholecystectomy seems to induce a lower activation of the hemostatic mechanism compared to open cholecystectomy. PMID- 17708250 TI - Intestinal trefoil factor (TFF-3) and extracellular signal-regulated kinase (ERK) in cholangiocarcinoma. AB - BACKGROUND/AIMS: The mucin-associated trefoil factor (TFF) peptides are integral to cytoprotection. TFF-3 is aberrantly expressed in colorectal and hepatocellular cancer and associated with an invasive phenotype. TFF-3 is also expressed in normal biliary epithelium. However, its role in biliary cancers is unknown. The biological effects of TFFs may result from EGFR, PI3 kinase, COX-2 and STAT mediated signaling. We investigated the expression of TFF-3, Erk, Akt, EGFR and COX-2 in biliary cancer. METHODOLOGY: Twenty-four consecutive cases of cholangiocarcinoma treated from 1996-2002 were studied. Immunohistochemistry was performed using monoclonal antibodies to TFF-3, EGFR, pEGFR, Erk, pErk, Akt, pAkt and COX-2 using validated techniques. Kendall's tau (exact method) and Pearson correlation test were employed to investigate the associations between biomarkers. RESULTS: Median age was 67 years. Surveillance, Epidemiology and End Results (SEER) stage was local in 1, regional in 15 and distant in 8. TFF-3 expression was detected in 19 cases. There were no significant associations between TFF-3 expression and sex, stage, grade, survival or SEER score. Erk expression in the tumor showed a borderline, negative correlation with TFF-3 (Pearson's p= -0.3988, p = 0.0588). CONCLUSIONS: TFF-3 is commonly expressed in biliary cancers and may have a negative reciprocal relationship with Erk expression. PMID- 17708251 TI - Locally advanced intrahepatic cholangiocarcinoma successfully resected after transcatheter arterial chemoembolization with degradable starch microspheres: report of a case. AB - We describe a case of initially unresectable locally advanced intrahepatic cholangiocarcinoma that showed remarkable regression after transcatheter arterial chemoembolization with degradable starch microspheres, allowing for subsequent successful curative resection. A 75-year-old female was referred to our hospital with a large hepatic mass. Computerized tomography examination showed a huge mass in the right liver extended partially to the left liver. Intrahepatic cholangiocarcinoma was strongly suspected, but surgical resection was abandoned due to the local spread in the liver. Three courses of transcatheter arterial chemoembolization with degradable starch microspheres were performed. The anticancer agents, mitomycin C and epirubicin, combined with degradable starch microspheres were injected from the catheter for chemoembolization. After three courses of transcatheter arterial chemoembolization, the tumor size decreased from 10cm to 5.5cm in diameter. Then right trisegmentectomy together with extra hepatic bile duct excision was performed. At 25 months after the first therapy and 21 months after operation, the patient remains healthy without recurrence. Transcatheter arterial chemotherapy with degradable starch microspheres may be a treatment of choice with locally advanced intrahepatic cholangiocarcinoma. PMID- 17708252 TI - Benign biliary inflammatory pseudotumor mimicking a Klatskin tumor. AB - Most biliary tumors at the liver hilum are malignant and, when possible, require radical surgical resection. However, few rare benign lesions exist, for which the differential diagnosis with malignancy is important in order to avoid aggressive surgical treatment. This is a retrospective case report. We report on two patients suffering from presumed inflammatory pseudotumor of the main biliary convergence, mimicking a Klatskin's tumor. Complete multidisciplinary work-up in a specialized hepatobiliary centre, including tumor markers, imaging studies and FDG-PET were strongly in favor of malignancy. The benign nature of the lesions was only suspected on the natural radiological evolution during the time waiting for surgical resection, with progressive spontaneous disappearance of tumor masses. Therefore, we were able to avoid extensive hepatobiliary surgery in both patients, including performance of an extended right hepatectomy. However, the patients had portal vein embolization as a first step in treating the disease, hopefully with no long-term consequences on patient status and liver function tests. Clinicians should be aware that tumors arising at the hepatic bifurcation are not always malignant, even if it is the most frequent cause. Despite extensive multidisciplinary work-up, there are still persisting difficulties in this differential diagnosis. PMID- 17708253 TI - Multiorgan resection for advanced abdominal malignancies--is it feasible? AB - BACKGROUND/AIMS: In everyday clinical practice many unfortunate patients present with advanced abdominal malignancies and are referred to a medical oncologist for palliative chemoradiotherapy and very few of them are offered surgical treatment. Many such patients, detected either preoperatively or on exploration, are considered to be inoperable and left to live a short and morbid life. The aim of this study was to assess the feasibility and effect of aggressive surgical management with adjuvant chemotherapy in advanced abdominal malignancies requiring resection of one or more organs along with the primary organ of the disease. We retrospectively analyzed our experience of treating such patients. METHODOLOGY: A total of 62 patients were included in this study attending the clinic between January 2001 and January 2006. These patients were diagnosed to have advanced abdominal malignancies because of spread of the disease from the organ of origin to either contiguous or noncontiguous abdominal organ(s). The patients with ovarian and uterine (n=18) malignancy underwent resection of colon (5), omentum (18), distal pancreatectomy and splenectomy (2), cystectomy (4), parietal peritoneal excision (9), small bowel excision in various combinations along with radical hysterectomy. Twelve patients with advanced colorectal carcinoma (n=12) along with abdominoperineal excision, anterior resection or colonic resection underwent cystectomy (3), hysterectomy (4), small bowel resection (4), hepatic resection (7) or parietal peritoneal excision (4) in various combinations. A total of 14 patients with gastric and gastroesophageal junction malignancy (n=14) underwent gastrectomy or gastroesophagectomy with omentectomy (14), distal pancreatico-splenectomy (5), hepatic resection (9), transverse colectomy (2) and parietal peritoneal excision (2) due to advanced disease. Patients with pancreatic carcinoma (n=12) underwent Whipple's pancreaticoduodenectomy or distal pancreatectomy with hepatic resection (6), transverse colectomy (1), splenectomy (3), left nephrectomy and adrenalectomy (3), small bowel excision (1) and parietal peritoneal excision (3). Along with excision of nonsolid organ retroperitoneal tumors (n=6) the organs resected were left kidney with adrenal (2), spleen (2) right kidney and adrenal (2), segmental inferior vena cava (1) and colon (2). All patients (except those who died in the early postoperative period) received adjuvant chemotherapy (43) or chemobiologic therapy (12) or radiotherapy. RESULTS: Out of the total 62 patients who underwent multiorgan resection 7 patients died in the immediate postoperative period due to massive pulmonary embolism (2), cardiorespiratory insufficiency (2) or sepsis (3). Important morbidities seen in the early postoperative period were anastomotic leak (3), hemorrhage (2), pulmonary infection (5), pancreatitis (1), wound infection (4) and urinary tract infection (2). There was 100% postoperative follow-up of the patients. The survival rate was 77% in the first, 56.45% in the second, 47% in the third, 32% in the fourth and 22% at the end of the five-year follow-up. CONCLUSIONS: Aggressive surgical intervention by multiorgan resection and adjuvant chemo or chemobiological therapy is a feasible option in patients with advanced abdominal malignancies with statistically improved survival rate. Furthermore, it helps in getting better response to therapeutic manipulations and improved quality of life of the patients. PMID- 17708255 TI - Back-flow bleeding control during resection of right-sided liver tumors by means of ultrasound-guided finger compression of the right hepatic vein at its caval confluence. AB - BACKGROUND/AIMS: Limiting the backflow bleeding from the hepatic veins is a priority in liver resections. We describe an ultrasound-guided technique for backflow bleeding control from the right hepatic vein (RHV) during right-sided liver resection. METHODOLOGY: Right surface of the extrahepatic RHV is exposed to allow its compression by surgeon's finger-tips: the effectiveness of finger compression is checked by color-Doppler intraoperative ultrasonography. RESULTS: This technique was adopted in 47 consecutive patients with tumors located in the right segments and not infiltrating the RHV close to its caval confluence. There was no hospital mortality or major morbidity. Mean blood loss was 310 mL, and 4 patients required blood transfusion. The maneuver here described was used 2.3 times per patients, and taping of the RHV was never needed. CONCLUSIONS: The technique here described allows easy and safe control of the RHV patency without its skeletonization and encirclement. PMID- 17708254 TI - Study on the inhibitory effect of tyroserleutide on tumor growth and metastasis in nude mice model of human hepatocellular carcinoma metastasis. AB - BACKGROUND/AIMS: Previous study has shown that small tripeptide tyroserleutide has inhibitory effect on liver cancer both in vitro and in vivo. This study was designed to test the effect of tyroserleutide on tumor growth and metastasis in a nude mice model of human hepatocellular carcinoma (HCC) metastasis. METHODOLOGY: Highly metastatic human HCC cell HCCLM6 was used to construct orthotopic implantation model of HCC metastasis in 20 BALB/c-nu/nu nude mice, which were randomized into treatment group and control group each with 10 mice. The former received daily CMS024 intraperitoneal injection at the dose of 300 microg/kg beginning from the second postoperative day, and the latter received intraperitoneal injection of equal amount of 0.85% sodium chloride solution. The mice were observed for signs of disease development. Thirty-five days later, the mice were sacrificed and abdominal and pulmonary metastasis was recorded and peripheral blood hematological and biochemical parameters were determined. RESULTS: After 35 days of intervention, all the 10 mice in the treatment group were alive and well, but there were only 9 living mice in the control group. The mean tumor weights were 1.9 +/- 0.5 g in the treatment group and 2.3 +/- 0.8 g in the control group (P > 0.05). The abdominal wall metastasis and intraperitoneal metastasis were 100% for the control group and only 60% and 50%, respectively, for the treatment group (P < 0.05). Bloody ascites and gross intrahepatic metastatic nodules were found in 70% and 90% of nude mice, respectively for the control group, and 20% and 40%, respectively, for the treatment group (P > 0.05). The median number of grades I, II, III and IV pulmonary metastasis were 92, 24, 15 and 16, respectively, for the control group, and 24, 20, 10 and 8, respectively, for the treatment group. There were statistically significant differences in the number of grade I pulmonary metastasis between the treatment group and the control group (24 vs. 92, P < 0.05). No statistically significant differences in the body weight, peripheral blood hematological and biochemical parameters were observed between the two groups. No toxic effects were observed during the observation period. CONCLUSIONS: Small molecule tyroserleutide demonstrated positive effects to retard tumor growth and inhibit loco-regional and long distance metastasis in a nude mice model of human HCC metastasis, and no obvious toxic or side effects on the tumor bearing nude mice. PMID- 17708256 TI - Effect of a single layer continuous suture between pancreatic parenchyma and jejunum after duct-to-mucosa anastomosis in pancreaticoduodenectomy: a single surgeon's experiences. AB - BACKGROUND/AIMS: The aim of the present study is to ascertain the effect of a single layer continuous suture between pancreatic parenchyma and jejunum after duct-to-mucosa anastomosis in pancreaticoduodenectomy through a single surgeon's experiences. METHODOLOGY: From March 1, 2002 to March 31, 2005, among 512 patients who had pancreaticoduodenectomy at Asan Medical Center, 56 patients who had a single layer continuous suture between pancreatic parenchyma and jejunum after duct-to-mucosa anastomosis were selected consecutively for prospective study. RESULTS: There were 44 pylorus-preserving pancreaticoduodenectomy, 10 pancreaticoduodenectomy, 2 hepatopancreaticoduodenectomy. No pancreatic leakage was reported. All three wound infections recovered after conservative treatment, and a gastric ulcer bleeding was resolved by suture-ligation through laparotomy. There was no mortality after surgery. CONCLUSIONS: Although it is a report with low surgical volume, a single layer continuous suture between pancreatic parenchyma and jejunum after duct-to-mucosa anastomosis in pancreaticoduodenectomy is thought to be a good method to prevent the complications of pancreatic leakage using a tight close attachment of pancreas and jejunum. PMID- 17708257 TI - Basic fibroblast growth factor enema improves experimental colitis in rats. AB - BACKGROUND/AIMS: Growth factors have a potential role in gastrointestinal mucosal repair. Although basic fibroblast growth factor (bFGF) is known to contribute to wound healing, however, the role of bFGF in the treatment of inflammatory bowel disease has not been established. The aim of this study is to investigate the therapeutic effects of intracolonic bFGF administration on both the clinical symptoms and histological mucosal repair in an experimental model of colitis in rats. METHODOLOGY: Acute colitis was induced with 5% dextran sulfate sodium (DSS) given for one week in drinking water. The rats were treated daily with recombinant human bFGF enema (400 microg/kg/day) or vehicle once daily from day 1 to day 7. Clinical score (stool consistency, weight loss and hemoccult/gross rectal bleeding), colon length and histological score of mucosal injury in colonic tissue samples were analyzed. RESULTS: Administration of bFGF enema significantly reduced clinical score (p < 0.01) and histological score (p < 0.01). No specific side effect of bFGF was noted. CONCLUSIONS: These results suggest that bFGF enema is clinically safe and useful in the treatment of inflammatory bowel disease. BFGF enema may contribute as a novel therapy of IBD. PMID- 17708258 TI - The usefulness of diffusion-weighted imaging (DWI) for the detection of gastric cancer. AB - BACKGROUND/AIMS: Diffusion-weighted imaging (DWI) is already utilized in the important clinical diagnosis of brain ischemia and also for differentiating brain abscesses from metastatic brain tumors. Recent technical developments make DWI of the body feasible. Several studies have revealed the usefulness of DWI for the diagnosis of liver, ovary, parotid gland, kidney, and breast tumors. We herein present cases of gastric cancer detected by DWI and discuss the efficacy of DWI for the diagnosis of gastric cancer. METHODOLOGY: We performed DWI, enhanced computed tomography (CT) and endoscopic examinations on 15 patients with gastric cancer. MR examinations were performed using the 1.5-T imager (Toshiba). We measured the signal intensity in a series of DWI images and calculated the apparent diffusion coefficient (ADC) values in order to differentiate the tumors from normal tissues and inflammations. Two experienced radiologists evaluated the depth of tumor invasion into the gastric wall (tumor staging), the involvement of regional lymph nodes (nodal staging), and the presence or absence of metastasis (metastatic staging) on DWI and CT images according to the TMN classification system. TMN staging of each tumor was compared with the pathologic and surgical findings. RESULTS: There were no differences between the DWI and the CT images regarding their abilities to detect advanced gastric cancer. However, DWI could detect peritoneal dissemination, liver metastasis, lymph nodes metastasis without any enhancement material more clearly than CT. CONCLUSIONS: DWI is therefore considered to have the potential to be clinically effective for the evaluation of preoperative TMN staging of gastric cancer. PMID- 17708259 TI - Hepatic adenoma. Timing for surgery. AB - BACKGROUND/AIMS: Hepatic adenoma (HA) is a rare benign tumor of the liver. Tumor resection has been recommended for symptomatic or enlarging HA because of the risk of intraperitoneal, intrahepatic hemorrhage or even the development of hepatocellular carcinoma. From 1989 to 2003 we reviewed the medical records and radiology files of 28 patients with a proved diagnosis of hepatic adenoma. This article summarizes a single-center experience with surgical treatment of hepatic adenoma. METHODOLOGY: 24 patients were female and 4 were male. Twenty-two patients had a history of oral contraceptive use. Abdominal pain was presented in 19 patients and 3 of them had had an acute episode. The mean age was 36.3 years. Preoperative assessment included liver test, ultrasonography and computed tomography in all patients plus technetium (99mTc)-sulfur colloid and 99mTc labeled DISIDA (dimethyliminoacetic acid) liver scintigraphy (n=19) and magnetic resonance imaging (n=22). RESULTS: Operative procedures included enucleation in 3 patients, two of them associated with hepatic segmentectomy; resection of one or two segments in 14 patients; left and right hemihepatectomy respectively in 7 and 3 patients; right extended hepatectomy in one patient and nonanatomic resection in one patient. There was no postoperative death and the complications were: bile leakage (re-operation) one patient, intraperitoneal abscess (re-operation) one patient, pleural effusion two patients, venous thrombosis one patient and wound infection one patient. CONCLUSIONS: We recommend that since the diagnosis has been well-established both enucleation or anatomically based resections of hepatic adenoma should be performed in all cases mainly in female patients taking oral contraceptives with tumors greater than 3cm for the risk of hepatic hemorrhage or even when malignancy cannot be excluded. PMID- 17708260 TI - Endoscopic clips prevent self-expandable metallic stent migration. AB - BACKGROUND/AIMS: Self-expandable metallic stents (SEMS) have been used for many years in the palliation of esophageal cancer symptoms. Stent migration is one of the most recognized complications of SEMS. To prevent SEMS migration, this study reported the use of endoscopic clips, and carefully analyzed the patients who underwent implantation. METHODOLOGY: From January 2000 to December 2002, nine patients consecutively underwent SEMS implantation. After successful placement of the SEMS and to maintain its position, endoscopic clips were used to fix the branch of the upper end of the stent to the esophageal mucosa. RESULTS: Stent implantation was technically successful in all patients, three of whom had strictures and six of whom had digestive-respiratory fistulas. No stent migration was observed in any of the patients, and dysphagia improved significantly after stent placement. Five patients did, however, experience delayed complications, two in the form of obstructions, two with recurrent fistulas, and one with a perforation. CONCLUSIONS: In conclusion, this new technique is recommended as endoscopic clipping can diminish the risks of stent migration, in particular those associated with esophago-respiratory fistulas without luminal obstruction. PMID- 17708261 TI - Irinotecan and S-1 neoadjuvant chemoradiation therapy in patients with advanced rectal cancer. AB - We performed preoperative chemoradiotherapy in locally advanced cases of rectal cancer without distant metastasis. The methods for drug administration and irradiation were as follows: oral administration of S-1 at 80 mg/m2/day on days 1 5, 8-12, 22-26, and 29-33, with periods of 5 days on drug and 2 days off drug and intravascular administration of CPT-11 for 120 minutes on days 1, 8, 22, and 29, at doses of 60 mg/m2/day in Case 1 and 70 mg/m2/day in Case 2. The radiation dosage was a fractionated exposure of 1.8 Gy/day x 5 days/week for 5 weeks, for a total of 45 Gy. No major adverse events were observed in either case, and the treatment was performed as per the protocol. No postoperative complications were observed in either case. Both patients showed complete pathological remission with no evidence of tumor cells in the primary focus and no lymph node metastases. Preoperative chemoradiotherapy with a combination of S-1 and CPT-11 may be a new treatment for rectal cancer. PMID- 17708263 TI - The relationship between GDNF and integrins in human colorectal cancer cell activity. AB - BACKGROUND/AIMS: This study was performed to determine whether GDNF influences the expression of integrins in colorectal cancer cell lines and to elucidate the mechanisms of adhesion to and invasion of extracellular matrix (ECM) proteins. METHODOLOGY: The expression of integrin subunits and alteration of this expression by GDNF were examined by flow-cytometric analysis and cellular enzyme linked immunosorbent assay in four human colorectal cancer cell lines. Assays to evaluate adhesion and invasion of cancer cells toward ECM proteins were conducted to investigate whether increased integrin expression affects the interaction between cancer cells and putative integrin ECM ligands. RESULTS: The RET/GFRalpha 1 receptor complex for GDNF was expressed in all four colorectal cancer cell lines. The expression of the Beta1 integrin subunit in these cells was significantly enhanced by GDNF. The enhancement and associated increase in adhesion and invasion abilities in response to by GDNF were inhibited by blocking the GDNF receptor or the integrin P1 subunit. CONCLUSIONS: In colorectal cancer, the enhancement of integrin expression by signaling through the GDNF receptor strongly influences adhesion to and invasion of ECM proteins. PMID- 17708262 TI - Clinical trial of low-dose leucovorin plus 5-fluorouracil for patients with metastatic colorectal cancer. AB - BACKGROUND/AIMS: To establish an effective and practical treatment of Japanese patients with metastatic colorectal cancer in an outpatient setting, we conducted a clinical trial using a modified Mayo regimen. METHODOLOGY: A bolus injection of low-dose (20 mg/m2) d,l-leucovorin (LV) was administered, followed one hour later by an intravenous injection of 333 mg/m2 5-fluorouracil (5-FU) for another hour. The two drugs were given on days 1, 2, and 3, and the treatment was repeated every 2 weeks. RESULTS: In the 17 patients enrolled in the study, the tumor response rate was 25%, and time-to-treatment failure and median survival time were 7 and 24 months, respectively. The treatment was well tolerated, with no adverse effects greater than grade 3, and could be completed in all patients in the outpatient setting. One patient with lung, liver, and parailiac lymph node metastasis showed a complete response and survived for more than 6 years with tumor-free status. CONCLUSIONS: These results suggest that although the sample size studied was too small to allow us to draw definitive conclusions, this regimen may be an effective and practical alternative to the Mayo regimen in an outpatient setting for Japanese patients with metastatic colorectal cancer. PMID- 17708264 TI - Factors affecting the technical difficulty of colonoscopy. AB - BACKGROUND/AIMS: Colonoscopy is a standard diagnostic tool for screening and surveillance of diseases affecting the colon. Colonoscopy may be painful for patients and difficult for the endoscopist. The aim of this study was to identify the factors affecting the technical difficulty of a colonoscopic examination and to predict potential difficult patients who will undergo colonoscopy. METHODOLOGY: A total of 646 outpatients were consecutively included in this study. Patient's age and gender, body mass index (BMI), prior surgical history, and the duration and symptoms of irritable bowel syndrome (IBS) were recorded before the procedure. The quality of bowel preparation, the difficulty of examination reported by the colonoscopist, the degree of patient pain, the degree of pain as reported by an observer, cecal intubation time andcolonoscopic findings were assessed after the procedure. RESULTS: We evaluated the difficulty of colonoscopy by cecal intubation time. Advanced age (>50 years), female gender, low BMI (< or = 23 Kg/m2), poor bowel preparation, prior surgical history, patient pain and the presence of IBS were associated with prolonged cecal intubation time. A multivariate logistic regression analysis demonstrated that advanced age, female gender, low BMI, poor bowel preparation and patient pain were independent factors related to prolonged cecal intubation time. CONCLUSIONS: In patients with advanced age, female gender and low BMI, information that colonoscopy may be difficult and painful should be provided. If a colonoscopy is not absolutely indicated, barium enema or CT colonography may be performed as alternative diagnostic modalities. PMID- 17708265 TI - Does surgery affect certain mediators of thrombocytopoiesis in patients with colorectal cancer? AB - BACKGROUND/AIMS: The most common method to treat colorectal cancer is a surgical procedure involving tumor resection. Surgery induces systemic metabolic changes like hypoxia, acidosis, production of hormones and proinflammatory cytokines, which participate in hematopoiesis. METHODOLOGY: We examined 38 patients with colorectal cancer and 35 healthy subjects as a control group. In these patients, thrombopoietin concentration, interleukin-6, percentage of reticulated platelets and platelet count were estimated three times: before surgery, 3 days and 12 days after surgery. RESULTS: In colorectal cancer, before surgery, thrombopoietin, interleukin-6, percentage of reticulated platelets and platelet count were significantly higher than in controls. 3 days after surgery we observed a 2-fold increase in thrombopoietin concentration and a 5-fold increase in interleukin-6 concentration, compared to the baseline. The platelet count was significantly decreased. 12 days after surgery thrombopoietin and interleukin concentration were markedly reduced and platelet count was significantly increased. CONCLUSIONS: Depending on the time that has passed since surgery, we observed significant changes in platelet count and thrombocytopoietic indices. Three days after surgery, platelet count was reduced while concentrations of the cytokines increased, which resulted in a significant rise in platelet count 12 days after surgery. Tumor resection in colorectal cancer patients regulates thrombocytopoiesis and restores physiological relationship between PLT and Tpo. The elevated IL-6 level in our study may indicate its involvement not only in the neoplastic and inflammatory processes, but also in thrombocytopoiesis. PMID- 17708266 TI - Elective surgery for recurrent diverticulitis. AB - BACKGROUND/AIMS: After two documented episodes of uncomplicated diverticulitis, elective colon resection is recommended to prevent complications of the disease but the nature of symptoms in non-operated patients requires specification. METHODOLOGY: A detailed questionnaire concerning clinical variables was mailed to two hundred and sixty patients admitted into our hospital for symptoms of acute sigmoid diverticulitis between 1981 and 2002. One hundred and seventy-one patients (70 percent) answered the questions adequately. Based on the clinical symptoms reported by the patients on the questionnaires, three patient groups set up, i.e. patients treated non-operatively or operatively for recurrent diverticulitis and patients operated on for diverticular perforation. The results of the patients treated non-operatively were analyzed with special reference to readmissions and age. RESULTS: The need for treatment by a physician, the need for hospital treatment, the presence of abdominal cramps, the presence of febrile left lower abdominal pain, the need for antibiotics and the need for NSAIDs were more common in the patients treated non-operatively for recurrent diverticulitis. When the patients treated non-operatively for recurrent diverticulitis were compared in a logistic regression model in relation to the number of admissions, the need for treatment by a physician and the presence of left lower abdominal pain were significantly more common in the patients admitted twice or more often. The same variables remained significantly different when the patients admitted once or twice were compared. Age did not correlate with any of the variables tested. CONCLUSIONS: On the basis of our results, we recommend that patients with recurrent uncomplicated diverticulitis should be operated on after two documented episodes to reduce the symptoms of the patients. PMID- 17708267 TI - Thrombophilic abnormalities of natural anticoagulants in patients with ulcerative colitis. AB - BACKGROUND/AIMS: Ulcerative colitis patients have increased risk for thromboembolic events. Factors predisposing to thrombosis in ulcerative colitis are poorly defined. The aim of this study was to evaluate possible thrombophilic abnormalities in patients with ulcerative colitis. METHODOLOGY: Fifty-one patients with ulcerative colitis and 51 healthy controls were studied. Disease activity, clinical and endoscopic, was assessed by standard criteria. Plasma levels of antithrombin, protein C, free protein S and activated protein C resistance were determined in both study groups. Genetic test for factor V Leiden was performed in cases with abnormal activated protein C resistance. Parameters of inflammation and fibrinogen were additionally measured in ulcerative colitis patients. RESULTS: Mean values of free protein S were significantly lower in ulcerative colitis patients (84.01 +/- 21.57) compared to healthy controls (100.17 +/- 24.7) (p < 0.001). Mean values of protein C were higher in ulcerative colitis patients (124.6 +/- 39.03) than healthy controls (100.19 +/- 19.86) (p < 0.001). No other significant differences were observed, but there was a trend towards higher prevalence of low values for antithrombin (9.8% vs. 0%, p = 0.056) and free protein S (19.6% vs. 5.9%, p = 0.072) in ulcerative colitis patients. Three ulcerative colitis patients and three healthy controls had low activated protein C resistance ratio. All these subjects were heterozygous for factor V Leiden. No correlation was observed between abnormalities in thrombophilic parameters and clinical, endoscopic or inflammatory parameters in ulcerative colitis group. CONCLUSIONS: Abnormalities in natural anticoagulants are more common in ulcerative colitis patients compared to healthy controls, irrespective of disease activity. Low activated protein C resistance ratio due to factor V Leiden is not more common in ulcerative colitis patients than in healthy controls. PMID- 17708268 TI - Clinicopathologic significance in serum presence of anti-p53 antibody in patients with colorectal carcinoma. AB - BACKGROUND/AIMS: Alteration of p53 gene links to the appearance and detection of anti-p53 antibodies in the serum. The aim of this study is to find the clinicopathologic significance for serum presence of anti-p53 antibodies in patients with colorectal carcinoma. METHODOLOGY: Serum presence of anti-p53 antibodies was examined for sera of 36 patients with colorectal carcinoma using enzyme-linked immunosorbent assay. RESULTS: Frequency of serum presence of anti p53 antibodies was 47.2% (17 of 36). Incidence of lymph node metastasis and lymphatic invasion in tumors coexisting with serum presence of anti-p53 antibodies (70.6%, 12 of 17 and 94.1%, 16 of 17) were significantly higher than those in tumors without serum presence of anti-p53 antibodies (17.6%, 3 of 17 and 68.4%, 13 of 19; p = 0.007 and p = 0.041, respectively). Stages of the tumors were significantly more advanced in carcinomas coexisting with serum presence of anti-p53 antibodies (p = 0.023). Frequency in serum presence of anti-p53 antibodies among patients with tumors expressing p53 (73.7%, 14 of 19) was significantly higher than that among patients with tumors without p53 expression (17.6%, 3 of 17; p = 0.0005). CONCLUSIONS: Preoperative serum appearance of anti 53 antibodies can be an indicator for more malignant potential of colorectal carcinoma. PMID- 17708269 TI - Pudendal nerve terminal motor latency in evaluation of evacuatory disorder following low anterior resection for rectal carcinoma. AB - BACKGROUND/AIMS: Pudendal neuropathy is one of the causative factors for soiling following restorative proctocolectomy. However, there has been no report clarifying the impact of sphincter-preserving operation for colorectal carcinoma on the pudendal nerve and its relation to postoperative evacuatory disorder. METHODOLOGY: Twenty-three consecutive patients undergoing resection for rectal or sigmoid colon carcinoma were assessed with patient questionnaire, anorectal manometry, and pudendal nerve terminal motor latency study (PNTML) before and 6 months after surgery. RESULTS: Eleven patients (48%) had postoperative evacuatory disorder. The prevalence of lower anastomosis was significantly higher in the evacuatory disorder group. In manometry, maximum tolerable volume and neorectal capacity were significantly smaller in the evacuatory disorder group than in the nonevacuatory disorder group. Manometric study showed no difference between the two groups in terms of postoperative anal squeezing pressure, which is generated by the external anal sphincter, which is innervated by the pudendal nerve. Five patients showed bilateral and 2 patients showed unilateral absence of PNTML in the evacuatory disorder group postoperatively. Multivarite analysis revealed that low anastomosis (p < 0.001) was a significant risk factor for postoperative evacuatory disorder. The absence of bilateral or unilateral PNTML tended to be an affecting factor for evacuatory disorder (p = 0.06). CONCLUSIONS: Low level anastomosis was an independent risk factor for postoperative evacuatory disorder. The implication of absence of PNTML in evacuatory disorder awaits further study. PMID- 17708270 TI - p53 and MIB-1 expression of esophageal carcinoma concominant with achalasia. AB - Achalasia, insufficient relaxation of the lower esophageal sphincter (LES) causes the retention and stasis of food and secretions, chronic hyperplastic esophagitis and eventual malignant transformation. p53 alternation has been suggested to play an important role in the malignant transformation. A 53-year-old man was endoscopically followed up for esophageal achalasia for seven years, and endoscopy revealed an ulcerative region in the upper thoracic esophagus, and histopathologically the biopsy specimens showed moderately differentiated squamous cell carcinoma. In resected specimens, p53 staining was strong and diffuse in the tumor and MIB-1 immunoreactivity was strong and patchy in the tumor and the basal layer of squamous mucosa of the esophagus. No staining for either immunostains was noted in normal esophageal mucosa. It is necessary for patients with esophageal achalasia to be followed-up with endoscopy, and that p53 and MIB-1 immunostaining of biopsy specimens should be performed to detect pre cancerous lesions. PMID- 17708271 TI - Triple-combined herniorrhaphy for inguinal hernia repair: experience of 1411 cases. AB - BACKGROUND/AIMS: The optimum method for inguinal hernia repair has not yet been determined. Triple-Combined Herniorrhaphy, using the combined methods of McVay, Shouldice and Halsted repairs, was developed in our hospital over the past years in order to improve the overall results of treatment of inguinal hernia. The aim of this study was to verify the value of this surgical technique for primary inguinal hernia in a specialized hospital setting. METHODOLOGY: We describe our experience of 1411 consecutive patients for whom Triple-Combined Herniorrhaphy was performed for inguinal hernia repair at our hospital between September 2000 and August 2003, under local anesthesia with a "one-day surgery" regimen. RESULTS: The type of hernias included 342 direct inguinal hernias, 913 indirect inguinal hernias, and 156 pantaloon (mixed) type inguinal hernias. No mortality or major intraoperative complications were observed. The median duration of operation time was 25 min. Wound infection and hematoma formation requiring drainage was observed in 9 and 16 patients, respectively. Patients had fast convalescence with rapid resumption of working activity. The postoperative recurrence rate was 1.2%. CONCLUSIONS: Triple-Combined Herniorrhaphy is a simple, safe, comfortable, and effective method with low early and later morbidity and recurrence rate. The good results of this procedure constitute a good alternative to mesh or other open inguinal repairs. PMID- 17708272 TI - Factor V Leiden G1691A, prothrombin G20210A, and MTHFR C677T mutations in Turkish inflammatory bowel disease patients. AB - BACKGROUND/AIMS: Patients with inflammatory bowel disease (IBD) have an increased risk for thromboembolic complications. We investigated the incidence of factor V Leiden G1691A, methylene tetrahydrofolate reductase (MTHFR) C677T, and prothrombin G20210A mutation in 27 Turkish IBD patients with no history of thromboembolic disease. METHODOLOGY: Twenty-seven patients, 22 with ulcerative colitis (UC) and 5 with Crohn's disease (CD), and 47 healthy were included to the study. The DNAs were obtained from peripheral blood by using pure polymerase chain kit. Then, factor V Leiden G1691A, which active protein C resistance positive, prothrombin G20210A and MTHFR C677T mutations were investigated in DNA by using LightCycler-Factor V Leiden G1691A mutation, Prothrombin G20210A and MTHFR C677T estimate kits. RESULTS: The heterozygote factor V Leiden G1691A mutation was detected in 3 (11.1%) patients with IBD and 2 (4.3%) controls (p > 0.05). The homozygote factor V Leiden G1691A mutation was not estimated among patients and controls. Heterozygote prothrombin G20210A mutation was detected in 2 (7.4%) patients with IBD and in 0 (0%) controls (p > 0.05). There was no homozygote prothrombin G20210A mutation in IBD and controls. Heterozygote MTHFR C677T mutation was 10 of 27 (37%) patients with IBD while 15 of 47 (32%) controls (p > 0.05). Homozygote MTHFR C677T mutation was detected in 4 patients (14.9%) with IBD and 3 (6.3%) controls (p > 0.05). CONCLUSIONS: Our study did not reveal any association between IBD and the most common hereditary thrombophilic factors and these mutations interfere with neither disease manifestations nor the thrombotic complications. PMID- 17708273 TI - pANCA and ASCA in the diagnosis of different subtypes of inflammatory bowel disease. AB - BACKGROUND/AIMS: The measurement of perinuclear antineutrophil cytoplasmic (pANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) has recently been suggested as a valuable and noninvasive diagnostic approach in the differentiation of ulcerative colitis (UC), Crohn's disease (CD) and indeterminate colitis (IC). The aim of the study was to determine the prevalence of pANCA and ASCA in patients with inflammatory bowel disease (IBD) subgroups of different clinical course and to assess their accuracy in differential diagnosis. METHODOLOGY: The study was performed in 109 patients: 50 patients with UC, 17 with CD, 18 with IC and 24 non-IBD controls. Antibodies status has been measured with ELISA, using commercial antibody panel by MedTek kits, confirmed by IIF technique using Euroimmun panels. RESULTS: Sensitivity and specificity of pANCA+/ ASCA- pattern for UC diagnosis was 36% and 98%; pANCA-/ASCA+ for CD: 35% and 88%, pANCA/ASCA- for IC: 72% and 63%, respectively. In addition the significant positive correlation between antibodies profiles: pANCA+/ASCA- and active disease; pANCA-/ASCA+ and number of operations, as well as the negative correlation between pANCA-/ASCA- and patient's age has been found. CONCLUSIONS: Our study lends further support to the opinions that serologic assessment identifies a large subset of different subtypes of IBD patients. PMID- 17708274 TI - Laparoscopic nissen's fundoplication: retrospective study of 168 cases, long-term follow-up. AB - BACKGROUND/AIMS: Laparoscopic anti-reflux surgery has shown its efficiency since its description by B. Dallemagne in Belgium and T. Geagea in Canada in 1991. As encountered in the laparotomic approach, this technique can be associated with mid- and long-term postoperative side effects. METHODOLOGY: A retrospective study about 168 patients operated for a gastro-esophageal reflux using the Nissen's technique with division of the short gastric vessels through a laparoscopic approach. There were 73 men (43%) and 95 women (57%) with a median age of 44 years (mean: 54 years, range: 17-82). The patients were seen 10 days, one month and three months postoperatively. After one year, they were seen or contacted by phone. The mean follow-up duration was 19.8 months (median: 12 months, range: 0.33-132). RESULTS: The mean operation time was 109 minutes (range: 57-210). There was no death. The postoperative morbidity rate was 5%. 142 patients (84%) had a third month control gastroscopy. 123 patients (86.6%) didn't report any complaint related to their reflux after 3 months. After one year, 166 patients (98.8%) were contacted. A reflux recurrence was reported by 4 patients (2.4%), 157 (94.2%) had no complaints. Our results are similar to those found in the literature published about laparoscopic anti-reflux surgery. In our series, we noted less mechanical complications than in the literature. The choice of the technique and the characteristics of our patients could explain this difference. CONCLUSIONS: The laparoscopic total fundoplication with division of the short gastric vessels is, for most of the authors, the first choice technique in the surgical treatment of the gastro-esophageal reflux. PMID- 17708275 TI - Surgical outcomes and immunohistochemical features for gastrointestinal stromal tumors (GISTS) of the stomach: with special reference to prognostic factors. AB - BACKGROUND/AIMS: Stomach is the most common site of gastrointestinal stromal tumors (GISTs). But the preoperative pathologic diagnosis is often difficult to make and it is hard to decide an appropriate surgical extent and also adjuvant therapy due to obscure malignant potential. Our purpose was to observe the outcomes for the patients with GIST of the stomach and reveal the significant prognostic factors. METHODOLOGY: Forty patients operated for primary GIST of the stomach expressing CD 117 were studied. We evaluated immunohistochemical and clinicopathologic features, and analyzed them to reveal the significant prognostic factors. The surgical outcomes of the patients were also investigated. RESULTS: Multivariate analysis for disease-free survival disclosed mitotic activity was the only independent factor, but the immunohistochemical features did not have any prognostic value. Among the patients with recurrence, all of the patients treated with imatinib mesylate (formerly STI-571) have survived until now, but half of the untreated patients died. CONCLUSIONS: In gastric GISTs, most important prognostic factor is mitotic count, not tumor size. We suggest that the wider application of imatinib mesylate to clinically malignant gastric GIST as adjuvant therapy may contribute to the improvement of outcomes. PMID- 17708276 TI - Surgical anatomy of the gastroduodenal artery in Chinese adults and its clinical applications. AB - BACKGROUND/AIMS: Hemorrhage occurs in 15-25% of duodenal ulcers, mostly on the posterior wall of the proximal duodenum. Erosion of the gastroduodenal artery is responsible for serious hemorrhages. Therefore, the relationship between bile duct and gastroduodenal artery should be discerned to prevent bile duct injury. METHODOLOGY: Cadavers from 52 Chinese adults (44 males, 8 females) were dissected for the anatomic relationships of the GDA and bile duct. RESULTS: The gastroduodenal artery has many possible origins, with the common hepatic artery (92.3%) the most common. The mean distance between gastroduodenal artery and pylorus was 2.7 cm; arterial length (from its origin) was 1.2 cm. The relationships between gastroduodenal artery and bile duct could be divided into 4 anatomic types according to Prudhomme's classification. We found 22 samples (42%) of Type 1; 10 samples (19%) of Type 2; 14 samples (27%) of Type 3 (in 8 samples of Type 3, there was about 8mm thickness of pancreatic tissue between the artery and the bile duct); 6 samples (12%) of Type 4. In 12 cases (24%) there was no interposed pancreatic tissue. CONCLUSIONS: These anatomic variations could lead to injury during surgical intervention. Our study provides detailed information about anatomic variability in Chinese adults that may help avoid such injury to the common bile duct during duodenal bleeding hemostasis. PMID- 17708278 TI - Allele-sharing of cytokine genes in familial inflammatory bowel disease. AB - BACKGROUND/AIMS: The pathogenesis of inflammatory bowel disease is complex, multifactorial, and involves genetic predisposition. This predisposition is likely to include various chromosomal loci, but simple Mendelian inheritance cannot be excluded in a subset of families with inflammatory bowel disease. METHODOLOGY: We evaluated allele-sharing in 17 sib-pairs with inflammatory bowel disease as an approach to select candidate genes for further studies in individual families. It was determined whether each sib-pair had inherited the same alleles for interleukin-2, interleukin-2 receptor beta, interleukin-4, interleukin-4 receptor, interleukin-10, interleukin-10 receptor, tumor necrosis factor alpha, tumor necrosis factor alpha receptor 1 and 2. RESULTS: The results were very different per individual family. The estimated probability of sharing both alleles identical-by-descent at interleukin-4 receptor, interleukin-10, interleukin-10 receptor, and tumor necrosis factor alpha were 50%, 39%, 40%, and 33% respectively. The LOD score was significant for interleukin-4 receptor (p = 0.04). CONCLUSIONS: In this small group of sib-pairs with inflammatory bowel disease a modestly increased allele-sharing was found for some inflammatory related genes. Different results per family may suggest genetic heterogeneity. This method can be useful as a first step to further evaluation of specific candidate genes which may play a pathogenetic role in individual families. PMID- 17708277 TI - Changes in glucagon processing occurring in the intestines of surgically stressed patients. AB - BACKGROUND/AIMS: The kinetics of the pancreatic hormone glucagon in surgically stressed patients has not been investigated as thoroughly as that of insulin, despite its significant influence on energy metabolism in surgically stressed conditions. In the present study, we examined the kinetics of glucagon and glucagon-related peptides assessed by radioimmunoassay, and the molecular forms of these peptides using gel filtration chromatography, and in addition discuss glucagon processes in the pancreas and intestine in surgically stressed patients. METHODOLOGY: Ten patients who had undergone abdominal surgery for acute abdominal disorders were enrolled in this study (group S). Ten healthy volunteers were also enrolled as normal controls (group C). The serum level of glucagon and glucagon related peptides were assessed in the early morning fasting state in both groups, on the second postoperative day in group S, using glucagon nonspecific N-terminal (glucagon-like immunoreactivity: GLI) and specific C-terminal (immunoreactive glucagon: IRG) radioimmunoassays. The molecular forms of these peptides were also estimated using the gel filtration chromatography method. RESULTS: Serum IRG in group S was significantly higher than that of group C (P < 0.05). Serum GLI was not significantly different between the two groups. In all patients except one in group S, a peculiar glicentin-like peptide (GLLP: MW about 8000) other than pancreatic glucagon was seen in gel filtration chromatography, which was not seen in group C. CONCLUSIONS: The kinetics and processing of glucagon in surgically stressed patients were quite different from those of healthy subjects. In surgically stressed patients, peculiar processing of glucagon occurred in the intestine, which was quite different from ordinary glucagon processing either in the pancreas or the intestine, generating GLLP. PMID- 17708279 TI - The significance of serum transforming growth factor beta 1 in detecting of gastric and colon cancers. AB - BACKGROUND/AIMS: TGF-beta1 is a growth factor with wide ranging effects on proliferation, differentiation, immune suppression, apoptosis and matrix remodeling. We aimed to clarify the clinical significance of circulating levels of TGF-beta1 as a tumor marker in gastrointestinal tract cancers by comparing it to CEA across a range of parameters such as cancer type and severity. METHODOLOGY: Sera collected from patients with gastrointestinal tract cancers (32 gastric, 36 colon) and from 25 healthy volunteers were analyzed for TGF-beta1 and CEA. Relations between serum TGF-beta1 levels and tumor stage and tumor grade were also evaluated. RESULTS: Mean serum TGF-beta1 levels were higher in patients with gastric or colon cancer compared to the control group (p = 0.001). In both types of cancer there were no differences in TGF-beta1 levels associated with serosal involvement, lymph node involvement, vascular invasion, distant metastasis or tumor size. Mean serum TGF-beta1 levels were also not statistically different across histopathological tumor grades in either type of cancer. The sensitivity of TGF-beta1 was higher in patients with gastric cancer than in patients with colon cancer. TGF-beta1 had greater sensitivity than CEA in gastric cancer patients. CONCLUSIONS: TGF-beta1 has higher sensitivity in gastric and colon cancers. Since it may be increased even in cancer without closed and distant metastasis, TGF-beta1 may be used as a tumor marker and combined with CEA particularly in gastric cancers. PMID- 17708280 TI - Ileoanal-pouch reconstruction does not impair sphincter function or quality of life. AB - BACKGROUND/AIMS: A retrospective trial with regard to continence function and quality of life was conducted in patients who had undergone proctocolectomy and ileo-anal-pouch (IAP) reconstruction for ulcerative colitis (UC) or familial polyposis (FAP), and continence function was compared to patients under conservative treatment for UC. The aim of the study was to evaluate, if proctocolectomy and IAP differed in quality of life and sphincter function from those patients with chronic UC who were not operated on. METHODOLOGY: 50 patients were included in this study: 25 patients had undergone proctocolectomy and ileo pouch-anal-anastomosis (IPAA) for UC (n=13) or FAP (n=12). The control group included 25 patients under medical treatment for UC (n=25). Anal manometry was performed and quality of life questionnaires were evaluated. RESULTS: No significant differences in maximum basal and squeeze pressure were found. There was a significantly later pouch perception in the patient group (55mL in patients vs. 39mL in controls; p = 0.0054) as well as a significantly greater stool frequency (6 vs. 4 per day; p = 0.0018) and a shorter high pressure zone in the patients' group (25 mm vs. 35 mm; p < 0.0001). Patients demonstrated superior but not significantly better values for Gastrointestinal Quality of Life Score (GLQI) and Activity Index (AI). Furthermore, there was a significant negative correlation between perception values and GLQI (p = 0.014) and AI (p = 0.04) in this group, indicating that the later the perception the worse the Quality of Life and Activity Index. CONCLUSIONS: Proctocolectomy combined with IPAA neither deteriorates anorectal function nor quality of life compared to conservatively treated controls. These data support that prophylactic proctocolectomy in patients who are at high risk for the development of colorectal cancer can be performed at an early stage of the disease. PMID- 17708281 TI - Serum D-lactate: a useful diagnostic marker for acute appendicitis. AB - BACKGROUND/AIMS: Acute appendicitis is the most common acute surgical infection seen in emergency department. The present study aims to evaluate the sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) of the serum D-lactate levels as a marker for the diagnosis of acute appendicitis. D-lactate is the stereoisomer of the mammalian L(+)-lactate, and is produced by indigenous bacteria (Escherichia coli, Klebsiella, Bacteroides, Lactobacillus) in the gastrointestinal tract. Once obstruction occurs, appendix is a good medium for bacterial proliferation, and ischemic injury leads to an increase in D-lactate levels. METHODOLOGY: A total of thirty-two consecutive patients with the suspicion of acute appendicitis were prospectively included in the study. Patient characteristics, ultrasonography (US) and laboratory assessment including white blood cell (WBC), C-reactive protein (CRP), D-lactate and intraoperative findings, histology results, clinical outcome were evaluated. RESULTS: WBC level above 10(9)/L had an accuracy of 66%, whereas a CRP level above 5 mg/L had an accuracy of 75%. We observed that when the D-lactate level was greater than 0.25 mmol/L in acute appendicitis, the specificity was 60%, the false negative rate was 25% and the accuracy was 90%. The false negative rate of CRP (67%) was higher than that of D-lactate levels (25%). Ultrasound had a sensitivity of 96%, specificity 40% and accuracy 87% in our study. CONCLUSIONS: We found positive correlations between serum D-lactate levels and acute appendicitis and serum D-lactate had the lowest false negative rate among the other parameters. Therefore, we conclude that D-lactate might be a simple and reliable diagnostic marker for appendicitis. PMID- 17708282 TI - Prevention of postoperative infections by administration of antimicrobial agents immediately before surgery for patients with gastrointestinal cancers. AB - BACKGROUND/AIMS: This study was conducted to judge the effect of intravenous administration of antimicrobial agents immediately before surgery for patients with gastrointestinal cancers to prevent postoperative surgical site infections (SSIs) and remote site infections. METHODOLOGY: A total of 3437 patients with gastrointestinal cancers underwent standby operations in Wakayama Medical University Hospital between 1987 and 2002. Of these, 1483 were treated between 1987 and 1995, and intravenous antimicrobial agents were used only postoperatively for 2 to 5 days (no AMP group). In addition to the postoperative administration, antimicrobial agents were injected immediately before surgery in 1954 patients (AMP group). If the operation continues more than 3 hours, antimicrobial agents were injected every 3 hours during operation. A comparison was made between the no AMP group and AMP group concerning the bacteria detected and the incidence of SSIs and remote site infections. RESULTS: The incidence of superficial or deep incisional SSI after surgery was higher in esophageal cancer (17.2%) throughout the whole period than in gastric cancer (4.2%), colon cancer (5.2%) and hepatic/biliary/pancreatic cancers (4.9%) (p < 0.00001). On the other hand, the incidence of space/organ SSI after surgery was higher in hepatic/biliary/pancreatic cancers (14.7%) than esophageal cancer (8.4%; p = 0.02), gastric cancer (7.9%), and colon cancer (8.1%; p < 0.00001). The overall incidence of superficial or deep incisional SSI after surgery for gastrointestinal cancers was 7.2% in the no AMP group, and 4.1% in the AMP group (p = 0.00006). However, in the overall incidence of space/organ SSI, no significant difference was observed between the no AMP group (10.3%) and the AMP group (8.8%). In addition, the incidence of remote site infections also showed no significant difference between the two groups. Regarding bacterial isolates detected after surgery, the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) decreased from 10.8% to 6.2% among the bacterial strains detected (p = 0.00009), and Pseudomonas sp. also decreased from 13.5% to 10.2% (p = 0.002), but Enterococcus sp. increased from 12.1% to 20.4% (p < 0.00001). CONCLUSIONS: Preoperative AMP was useful to suppress postoperative superficial or deep incisional SSI, but was unlikely to suppress organ/space SSI or remote site infections. In addition, due to preoperative AMP, MRSA and Pseudomonas sp., which showed SSIs, were decreased in detection rates, whereas the detection rate of Enterococcus sp., which is resistant to cephems, was increased. PMID- 17708283 TI - Hemostatic parameters after hepatectomy for cancer. AB - BACKGROUND/AIMS: Epidural analgesia improves postoperative outcome, and should benefit patients undergoing hepatectomy for cancer. However, the combination of underlying disease, surgery, and blood loss after hepatectomy may lead to hemostatic changes that, theoretically, increase the risk of epidural hematoma. To quantify these changes, we retrospectively reviewed the records of 229 patients at the Prince of Wales Hospital, Hong Kong. METHODOLOGY: We analyzed the hemostatic parameters of those in whom there were complete data (n=143) up to postoperative day 3. RESULTS: We found considerable derangements in the international normalized ratio (INR), prothrombin time, activated partial thromboplastin time (aPTT), and platelet counts, with peak derangements occurring around postoperative day 2. The amount of liver resected and the preoperative Model for End-Stage Liver Disease score were predictors of peak INR > or = 1.5 in the postoperative period. CONCLUSIONS: We conclude that commonly measured hemostatic parameters are deranged after hepatectomy for cancer. Because of the complex cancer- and surgery-related hemostatic changes, whether these changes indeed indicate increased risk of neuraxial hematoma associated with neuraxial blocks is unclear. We also found that most Chinese patients were managed adequately with patient-controlled intravenous morphine. Clinicians contemplating neuraxial block on patients undergoing hepatectomy for cancer must weigh the potential risks and benefits. PMID- 17708284 TI - A comparative study of damage to liver function after TACE with use of low-dose versus conventional-dose of anticancer drugs in hepatocellular carcinoma. AB - BACKGROUND/AIMS: To study liver function damage after transcatheter arterial chemoembolization (TACE) with use of low-dose versus conventional-dose anticancer drugs in patients with hepatocellular carcinoma (HCC). METHODOLOGY: One hundred and twelve patients with unresectable HCC were randomly divided into two groups to receive superselective TACE. Patients in group A (n=52) received low-dose anticancer drugs: mitomycin C (MMC) 2-8 mg, epirubicin (EPI) 5-10 mg and carboplatin (CBP) 100mg were used. Patients in group B (n=60) were given conventional-dose of anticancer drugs (MMC 10 mg, EPI 40 mg, CBP 300 mg). Lipiodol-anticancer drugs emulsion was injected into the feeding arteries of tumors followed by gelatin sponge (GS) or polyvinyl alcohol (PVA) particles embolization. Liver function was evaluated with Child-Pugh scores, total bilirubin (TBIL), albumin (ALB) and alanine aminotransferase (ALT) before TACE, three days, one week (wk) and four wk after procedures. RESULTS: In both groups, TBIL, ALT, and Child-Pugh scores increased (P < 0.001 or P < 0.05) and ALB decreased (P < 0.001 or P < 0.01) three days and one wk after TACE. The different between the parameters obtained four wk after the procedure and baseline parameters was not significant in group A (P > 0.05). In group B, however, significant difference (P < 0.05) was found in all parameters except ALT. CONCLUSIONS: Superselective TACE with use of low-dose anticancer drugs induces transient impairment in liver function, but use of conventional-dose anticancer drugs can cause lasting, more serious worsening of liver function. PMID- 17708285 TI - Prediction of liver fibrosis in patients with chronic hepatitis B by serum markers. AB - BACKGROUND/AIMS: Liver biopsy has been considered as the gold standard for assessing fibrosis in patients with chronic hepatitis. The objective of this study was to explore the feasibility of using serum tests to predict the presence of fibrosis in patients with chronic hepatitis B. METHODOLOGY: Fibrosis scores for 153 patients were established by examining liver biopsy specimens. Serum was obtained from each patient around the time of the biopsy and analyzed by standard laboratory techniques. Student's t test, univariate analysis, and multivariate logistic regression were employed to test the presence of statistical significance. RESULTS: Only platelet count was an independent factor that could predict the presence of significant fibrosis. Platelet count was lower (p = 0.04) in the group with moderate/severe fibrosis. When platelet count was above 150 x 10(9)/L, the negative prediction value and specificity for the presence of significant fibrosis was 0.78 and 0.87 (AUC under ROC curve was 0.68). In this study, AST/ALT ratio was not associated with either activity or fibrosis. CONCLUSIONS: This study suggests that platelet count is an independent noninvasive marker for prediction of the presence of significant liver fibrosis in patients with chronic hepatitis B. PMID- 17708286 TI - Surgical treatment of hepatic injury: morbidity and mortality analysis of 109 cases. AB - BACKGROUND/AIMS: We aimed to determine the factors that affect morbidity and mortality in patients that underwent surgery for hepatic injury. METHODOLOGY: Records of 109 blunt or penetrating hepatic trauma patients that underwent surgery in the Third Surgical Clinic of Izmir Atatturk Training and Research Hospital between 1994 and 2004 were reviewed retrospectively. Evaluated parameters were: age, gender, cause of injury, diagnostic procedures, preoperative blood pressure (BP), hemoglobin (Hb) level, amount of intraabdominal blood, associated injuries, the number of involved hepatic segments and anatomic distribution, severity of injury, abdominal trauma index (ATI), amount of blood transfusions, type of surgery, hospital stay, and rates of morbidity and mortality. RESULTS: Median age of the patients was 29 years. The injury was penetrating in 53.2% of the patients and blunt in 46.8%. Abdominal blood was 500cc or less in 70 (64.2%) patients. Isolated hepatic injury was encountered in 29 (26.6%) cases. 22.9% of the patients had major injuries. Hemostasis was achieved by electrocautery, sponge-gel, primary suturing, hepatic resection or perihepatic packing. Morbidity and mortality rates were 40.4% and 14.6% respectively. CONCLUSIONS: Age, type of the injury, BP and Hb levels, amount of intraabdominal blood, degree of injury, ATI, and accompanying organ injuries significantly affect morbidity and/or mortality. PMID- 17708287 TI - Factors affecting the serum levels of adipokines in Korean male patients with nonalcoholic fatty liver disease. AB - BACKGROUND/AIMS: Adipokines are associated with various metabolic disorders including insulin resistance, obesity, and dyslipidemia. Metabolic disorders have also been reported to be associated with nonalcoholic fatty liver disease (NAFLD). The aim of this study was to determine the relationship between the serum adipokine levels and the degrees of hepatic fat infiltration in NAFLD. This study also attempted to determine the independent factors influencing the serum adipokine levels in NAFLD. METHODOLOGY: Sixty-five Korean male patients were enrolled in this study. The degree of hepatic fat infiltration was classified into the following three groups according to the ultrasonographic findings: Group I, normal liver; Group II, mild fatty liver; and Group III, moderate to severe fatty liver. The anthropometric parameters, fasting serum adipokine levels including leptin, adiponectin and resistin were measured in all subjects. The level of insulin resistance was estimated using the HOMA-IR. RESULTS: The serum leptin levels increased with increasing degree of hepatic fat infiltration (mean +/- SD: Group I, 2.052 +/- 1.071; Group II, 2.879 +/- 1.016; and Group III, 4.457 +/- 1.965 ng/mL, P < 0.001). However, the serum adiponectin and resistin levels were similar. The fasting serum insulin level was only a related factor for the changes in the serum leptin levels (P = 0.004). There were no related factors for the change in the serum adiponectin and resistin levels. CONCLUSIONS: This study suggests an indirect role for leptin in the pathogenesis of NAFLD by inducing insulin resistance, resulting in increased fasting serum insulin level. PMID- 17708288 TI - Partial hepatic resection for liver metastases of non-colorectal origin, is it justified? AB - BACKGROUND/AIMS: The liver is a common site of metastases for many solid tumors. Resection of noncolorectal liver metastases is controversial. The aim of this retrospective study is to evaluate partial liver resection as a treatment option for non-colorectal liver metastases. METHODOLOGY: During a 20-year period, 480 patients underwent partial liver resection. Thirty-two patients (17 male, 15 female, median age 55 years) who received partial liver resection for noncolorectal liver metastases were identified. A detailed analysis of these patients was conducted. RESULTS: Primary tumors were: medullary thyroid cancer (n=3), Grawitz tumor (n=2), breast carcinoma (n=2), stomach carcinoma (n=2), neuroendocrine carcinoma (n=10), unknown primary origin (n=9) and various other carcinomas (n=4). Operative morbidity and mortality for partial liver resection were 28 and 6%, respectively. The median overall survival time was 37 months, with an actuarial 5-year survival of 42%. Actuarial 5-year survival rates for patients with neuroendocrine and the non-neuroendocrine carcinomas were 22 and 52% respectively (NS). Median survival for patients with carcinoma of unknown primary origin was 43 months with an actual 5-year survival of 44%. CONCLUSIONS: Partial liver resection for liver metastases of non-colorectal primaries can be performed safely and has survival rates comparable to that of colorectal metastases in carefully selected cases and should therefore be considered. PMID- 17708289 TI - Multimodality therapy using brachytherapy for caval tumor of hepatocellular carcinoma. AB - BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) invading the inferior vena cava will expose patients to a risk of sudden death. Effective therapeutic approaches have not been established for caval tumor. This pilot study was conducted to evaluate the feasibility, safety, and clinical efficacy of multimodality therapy using endovascular brachytherapy with iridium-192 for caval tumor. METHODOLOGY: Six consecutive patients underwent endovascular high-dose-rate brachytherapy. An iridium-192 source was placed adjacent to the caval tumor through a vascular sheath introduced via the femoral vein. The total dose of brachytherapy ranged from 10 to 14Gy (5-7Gy per fraction). Hepatic arterial infusion chemotherapy was used in combination in all patients and external-beam radiotherapy was performed in 5 patients. RESULTS: Endovascular brachytherapy was technically successful in all patients. There were no complications related to brachytherapy. The median period of follow-up was 14.5 months (range, 3-29 months). Complete response and partial response were achieved in 2 (33%) and 4 (67%) patients, respectively. The 1- and 2-year survival rates were 50% and 17%, respectively, with a median survival of 14 months. CONCLUSIONS: Multimodality therapy using endovascular brachytherapy was a feasible, safe, and effective treatment for patients with advanced HCC invading the inferior vena cava. PMID- 17708290 TI - Vascular endothelial growth factor receptor-1 levels in hepatocellular carcinoma and correlations with clinicopathological features. AB - BACKGROUND/AIMS: To determine the serum vascular endothelial growth factor receptor-1 (VEGFR-1) levels in hepatocellular carcinoma patients and its correlations with the clinical and laboratory parameters. METHODOLOGY: Serum VEGFR-1 levels were measured in 18 biopsy-proven treatment-naive hepatocellular carcinoma patients (female/male: 5/13; mean age: 59.22 +/- 13.15 years) and in age- and sex-matched healthy controls. Possible associations were also evaluated between serum VEGFR-1 levels and etiology and severity of chronic liver disease, serum alpha-fetoprotein levels, presence of ascites and portal vein thrombosis, and tumor number, size and stage. RESULTS: Serum VEGFR-1 levels were undetectable in all healthy subjects, while all of the patients with hepatocellular carcinoma had increased VEGFR-1 (p < 0.001). Serum VEGFR-1 levels did not correlate with the clinical and laboratory parameters and tumor characteristics in hepatocellular carcinoma. CONCLUSIONS: VEGFR-1 is involved in the regulation of carcinogenesis in hepatocellular carcinoma. PMID- 17708291 TI - Phenotypic analysis of tumor-infiltrating lymphocytes in hepatocellular carcinoma. AB - BACKGROUND/AIMS: Tumor may induce local immunosuppression and make the tumor infiltrating lymphocytes (TILs) functionally inhibited and lose the antitumor effects. Therefore, we did the phenotypic analysis of TILs in hepatocellular carcinoma (HCC) tissues. METHODOLOGY: Lymphocytes were isolated from paired HCC tissues (TILs) and the corresponding non-tumor liver tissues (non-tumor-liver infiltrating lymphocytes, NILs) of 28 patients and were subjected to flow cytometric analysis. RESULTS: Compared with the non-tumor portion, HCC tissues had less intensity of lymphocyte infiltration. TILs had higher CD3+/CD56+ ratio than NILs. Around 70%-90% NILs or TILs expressed the antigen-experienced or memory phenotypes. Around 60%-70% CD4+ or CD8+ NILs and TILs expressed the activation markers CD69 and HLA-DR. However, we found that CD25 is under expressed in both the CD8+ NILs and TILs. In addition, more percentage of CD4+ CD25+ T cells was detected in the TILs than in the NILs. CONCLUSIONS: HCC tissues had less lymphocytes infiltration. Most of infiltrating lymphocytes from the HCC tissues and the corresponding non-tumor liver tissues were activated and expressed antigen-experienced phenotypes. However, the CD25 was underexpressed in the CD8+ TILs and the CD4+ CD25+ T cells were increased in the TILs. These factors might impair the antitumor immunity in HCCs. PMID- 17708292 TI - Comparison of seven prognostic staging systems in patients who undergo hepatectomy for hepatocellular carcinoma. AB - BACKGROUND/AIMS: Various staging systems containing both the tumor and liver function factors for hepatocellular carcinoma (HCC) have been proposed. The aim of this study was to evaluate the appropriate staging system in patients received hepatic resection for HCC. METHODOLOGY: The prognosis of the 235 patients who had undergone hepatectomy in these 15 years were analyzed according to the 7 staging systems, the Cancer of the Liver Italian Program (CLIP) score, the Barcelona Clinic Liver Cancer (BCLC) staging, the Groupe d'Etude et de Traitment du Carcinome Hepatocellulaire (GETCH) classification, the Chinese University Prognostic Index (CUPI) grade, the Japan Integrated Staging (JIS) score, modified JIS (mJIS) score, and Tokyo score. The capabilities to differentiate the postoperative survival between the neighboring score in each staging system were examined. Statistical analyses of the log-rank test, linear trend test, likelihood ratio (LR) test, Akaike Information Criteria (AIC), and Harrels' c index were used. RESULTS: The patients were widely distributed in the most of the staging system with the exceptions of GETCH classification and CUPI grade where almost all patients were classified to only the two groups. CLIP, JIS, mJIS, and Tokyo scores significantly differentiated the postoperative survival rate between 2 or 3 neighboring scores, whereas other staging systems only did between one. Statistical evaluations of prognostic stratification by the LR test, AIC, and Harrels' c-index showed that the JIS score system was the best among the 7 staging systems. CONCLUSIONS: JIS score is the best staging system for HCC in patients who undergo hepatectomy. PMID- 17708294 TI - Practical experience of a no abdominal drainage policy in patients undergoing liver resection. AB - BACKGROUND/AIMS: Routine use of abdominal drainage after liver resection is controversial. The aim of this study was to investigate the practical application of a "no abdominal drainage" policy for consecutive patients undergoing hepatic resection. METHODOLOGY: The present trial included 60 consecutive patients who underwent elective hepatic resection. Fifty-two patients underwent no abdominal drainage, and in the remaining eight drainage was necessary because of gross contamination of the surgical field associated with bilioenteric anastomosis, uncontrollable bile leakage from the cut surface of the liver, or the surgeon's preference. Patient demographics, intraoperative data, and postoperative complications and mortality were evaluated. RESULTS: There was no hospital death. Eight complications occurred in 8 patients in the no-drainage group (morbidity rate 15.4%, 8/52): bleeding, abscess, ascites requiring peritoneal tap, pleural effusion requiring thoracentesis, and pneumonia in one case each, and three cases of wound infection. Three complications were encountered in 2 patients in the drainage group (morbidity rate 25%, 2/8): bleeding, infected biloma and pleural effusion in one case each. Postoperative hospital stay tended to be shorter in the no-drainage group (10.7 +/- 3.9 days) than in the drainage group (15.6 +/- 6.4 days) (p = 0.07). Considering early uneventful removal of the drain on the morning of postoperative day 1, half of the drained patients might have not required drainage. Furthermore, in the setting of concomitant bilioenteric anastomosis (n=4), one patient underwent hepatectomy uneventfully without drainage, and two of three patients with drainage had their drains removed successfully on day 1. The third patient retained the drain for an unnecessarily long period, but did not develop subsequent complications. CONCLUSIONS: Our data support the view that prophylactic abdominal drainage is unnecessary in most patients who undergo elective hepatic resection. Bilioenteric anastomosis may not be a contraindication for a no abdominal drainage policy. PMID- 17708293 TI - Pitfalls of radiofrequency assisted liver resection. AB - BACKGROUND/AIMS: Radiofrequency has been used recently for bloodless liver resection. We studied the safety and feasibility of using RF energy for liver parenchymal transection in 8 patients. METHODOLOGY: We performed eight (n=8) open RF assisted liver resection for various malignancies. There were 5 men and 3 women, with mean age of 56.5 years (range 20-80 years). RESULTS: All patients had successful liver resection. The mean operating time for liver resection was 45 minutes (range 25-60 min). The average blood loss for wedge resections and segmentectomies was 30 mL (range 10-100 mL). None of the patients required postoperative transfusion. Three out of eight patients developed minor complications in the form of intra-abdominal abscesses which were managed by USG guided drainage of abscess in two patients and one patient had open surgical drainage of the subhepatic abscess. CONCLUSIONS: RF assisted liver resection is safe and effective with minimal blood loss for minor liver resections. Though the procedure is slightly more time consuming presently, with further improvement in technology and needles, the operative time may be reduced for this technique. RF assisted liver resection should be avoided in the presence of overt local sepsis. PMID- 17708295 TI - Liver regeneration following portal blood arterialization and splenectomy in acute hepatic failure. AB - BACKGROUND/AIMS: The purpose of the experiment was to estimate an influence of portal blood arterialization in animals with tetrachloromethane-induced acute hepatic failure. METHODOLOGY: Thirty-five pigs were divided into four groups: three groups of 10 and a control group of 5 animals. On day 1 of the experiment an intraperitoneal dose of 477 mg CCl4//kg body wt. in a suspension of corn oil was given to the trial groups to induce an acute hepatic failure. On day 3 after the intoxication all animals were operated on. Aortovenous splenic anastomosis without splenectomy, aorto-venous splenic anastomosis with splenectomy, and splenectomy procedure alone, were performed in groups I, II, and III, respectively. In the control group only laparotomy was performed. Histopathologic estimation of hematoxylin- and eosin-stained specimens and immunohistochemical analysis of regenerating hepatocytes by applying monoclonal serum for CK19, CD56, CD117 were carried out. RESULTS: Liver biopsies demonstrated no quantitative differences concerning the surface of damaged lobules between groups I, II, and III. The phenomenon of parenchyma regeneration was observed in both groups (with and without splenectomy procedure performed). Small stem cells could be observed mainly in the central part of lobules. The immunohistochemical analysis showed that part of the regenerating cells had CD56 and CD117 antigens' receptors, demonstrating no expression of antigen CK19. In the third group of animals (splenectomy without blood arterialization) neither the phenomenon of parenchyma regeneration nor the presence of cells of hepatoblast phenotype were observed. CONCLUSIONS: The arterialization of portal blood in pigs with acute hepatic failure triggered off the regeneration of damaged parenchyma through the colonization of impaired areas of lobules by small stem cells. The lack of the receptor for antigen CK19 could mean that the cells do not originate in bile duct epithelium. PMID- 17708296 TI - Hemodiafiltration treatment for high bilirubinemia state after hepatectomy. AB - Hyperbilirubinemia which developed after right hepatectomy is reported in a 66 year-old male. The application of hemodiafiltration treatment in the postoperative course of the patient and the effect of treatment in his healing process are summarized and discussed. PMID- 17708297 TI - Repeat hepatectomy for colonic liver metastasis presenting intrabiliary growth- application of percutaneous transhepatic portal vein embolization for impaired liver. AB - A 77-year-old man, whose past history included hepatitis C viral infection, transverse colectomy for transverse colon carcinoma, and right hepatectomy for colonic liver metastasis with intrabiliary growth, demonstrated left lateral sectional bile duct dilatation by computed tomography (CT). Percutaneous transhepatic cholangioscopy following percutaneous transhepatic biliary drainage demonstrated a papillary tumor compatible with recurrent liver metastasis presenting with intrabiliary growth. The recurrent tumor extended both into the left lateral inferior (B2) and superior (B3) bile duct branches. Percutaneous transhepatic portal vein embolization (PTPE) of the left lateral sectional branches was performed selectively to enhance the safety of hepatectomy in patients with impaired liver. Expected liver resection volume decreased from 48% to 36% by CT volumetry before and 5 weeks after PTPE. Left lateral sectionectomy was performed without serious postoperative complications. Resected specimen showed a solid tumor measuring 30x25mm and intraluminal tumor extension in B3 and B2. All surgical margins including the bile duct stump were free from carcinoma invasion. The patient survived for 4 years and 5 months postoperatively and died of other causes. An aggressive surgical strategy and PTPE provided significant palliation in this selected patient. PMID- 17708298 TI - Right hepatectomy with anterior approach for ruptured liver cell adenoma. AB - We report a case of a 37-year-old woman who was referred to a peripheral hospital with severe abdominal pain, vomiting and hemorrhagic shock. Ultrasonography and CT scan showed a large ruptured adenoma of the right liver. Because of hemodynamic instability, she underwent laparotomy with gauze packing and then she was referred to our department with a bleeding persisting at a rate of about 100 mL per hour from the abdominal drain. She underwent relaparotomy and a ruptured liver cell adenoma with a huge hepatic hematoma completely involving the right liver and part of segment 4 was confirmed. Considering the size of the lesion and the presence of a large hematoma, a right hepatectomy with anterior approach was performed. In case of emergency liver resections, the anterior approach is preferable not only to avoid tumor manipulation and the risk of its rupture, but mainly to reduce liver bleeding and to prevent sudden fall of the blood pressure due to inferior vena cava twisting in a hemodynamically instable patient. Intraoperative blood loss was 1500 mL. The postoperative course was uneventful. The patient is doing well ten months after operation. PMID- 17708299 TI - Spontaneous regression of multiple lung metastases following regression of hepatocellular carcinoma after transcatheter arterial embolization. A case report. AB - Spontaneous regression of hepatocellular carcinoma (HCC) is a rare phenomenon. Some reports have described cases of spontaneous regression of HCC, but there have been few cases with spontaneous regression of only metastatic lesions from HCC. We report a case of a 70-year-old woman with multiple lung metastases from HCC that regressed spontaneously following regression of HCC after transcatheter arterial embolization (TAE). To our knowledge, this is the first reported case that multiple lung metastases regressed spontaneously following TAE for HCC. Numerous mechanisms for spontaneous regression of HCC have been suggested such as subintimal damage, blood transfusion, alcohol withdrawal, infection, hemorrhagic shock, hepatic artery occlusion and herbal medicine. Our case, however, had no connection with any such symptom and medication. Our case suggests that the mechanisms leading to spontaneous regression in remote organs may be associated with activation of host immune response involving cytokines. PMID- 17708300 TI - Preservation of segment 4 inferior by distal middle hepatic vein reconstruction combined with extended right hepatectomy after portal vein embolization in a patient with a huge initially unresectable HCC. AB - An extended hepatectomy combined with preoperative portal venous embolization can offer curative resection in patients with initially unresectable hepatocellular carcinoma. However, hypertrophy of the future remnant liver is occasionally unsatisfactory after portal venous embolization in some patients to remove the initially unresectable tumor. In these patients, hepatic venous reconstruction to preserve hepatic parenchyma may contribute to the possibility of resection. The present case report shows a patient with an initially unresectable huge hepatocellular carcinoma in whom transarterial chemoembolization, portal vein embolization, and an extended right hepatectomy combined with distal middle hepatic venous reconstruction were performed to preserve Segment 4 inferior. The patient was a 66-year-old male. He presented with a huge hepatocellular carcinoma located at Segment 8, 7 and 4 superior, but the volume of the left lateral segment was only 267 mL. Transarterial chemoembolization was performed twice and right portal vein embolization was performed once, but the volume of the left lateral segment was only 318 mL compared to 487 mL which was a limit of future remnant liver volume. We therefore performed an extended right hepatectomy combined with distal middle hepatic venous reconstruction to preserve Segment 4 inferior. The left saphenous venous graft was used for this hepatic venous reconstruction. His postoperative course was almost uneventful. Postoperative abdominal computed tomography showed the satisfactorily preserved Segment 4 inferior. Distal hepatic venous reconstruction combined with an extended hepatectomy may further offer a chance of a curative resection for patients in whom enough hypertrophy of the future remnant liver is not obtained after portal venous embolization. PMID- 17708301 TI - Split liver transplantation for acute Wilson's disease: new option for urgent recipient? AB - Wilson's disease is a rare metabolic disorder that may lead to fulminant hepatitis and subsequent liver failure. Herein, we present a case of split liver transplantation performed on a patient with acute Wilson's disease. A 27-year-old female with acute presentation of Wilson's disease and advanced neurological impairment, received a Right Split liver Graft (Segments: IV, V, VI, VII and VIII) transplant. The graft was obtained by an in situ splitting technique. The graft implantation was performed in a standard fashion. No acute rejection episodes of the organ occurred. The postoperative course was uneventful. The graft function, ceruloplasmine level and copper levels progressively normalized. The patient totally recovered from neurological symptoms and the Kayser-Fleischer rings disappeared within one month. At 13 months of follow-up, the patient presented with no symptoms and in good condition. The current literature reports high preoperative mortality rate in patients that underwent partial liver graft for acute hepatic failure. However, our experience indicates that in situ split technique of liver may be a feasible and effective alternative to whole graft transplantation in urgent cases. Moreover, to our knowledge, this is the first successfully case of in situ split liver transplantation for acute Wilson's disease described in literature. PMID- 17708302 TI - Comparison of the postoperative outcome after a pancreatoduodenectomy using the Billroth I and II type of reconstruction. AB - BACKGROUND/AIMS: Several types of gastrointestinal reconstruction have been employed after a pancreatoduodenectomy (PD), however, it remains controversial as to which type is the most beneficial. The aim of this study was to investigate the effects of a gastrointestinal reconstruction on the postoperative outcome after PD. METHODOLOGY: The medical records of 68 patients who underwent a PD between 1994 and 2004 were retrospectively reviewed. A total of 28 patients underwent a Billroth I reconstruction while 40 had the Billroth II reconstruction. Both the occurrence of postoperative complications and the nutritional status were compared between the two groups. RESULTS: The patient age, gender, preoperative symptoms, and operation profiles were the same between the two groups. The morbidity and mortality did not differ between the two groups; however, the prevalence of leakage after a hepaticojejunostomy was higher in the Billroth II group than that in the Billroth I group (23% vs. 0%, P = 0.007). All cases of bile leakage were successfully treated by conservative therapy. The day that oral intake was resumed and the length of the hospital stay also did not differ between the two groups. Both groups showed a similar postoperative nutritional status after a PD, as assessed by body weight, the serum albumin and cholesterol concentrations, and the number of lymphocytes. CONCLUSIONS: Bile leakage tends to occur after a PD using a Billroth II reconstruction, however, this can be easily managed by conservative therapy, and it does not influence morbidity, the resumption of oral intake, or the length of hospital stay. Therefore, we could not clearly identify any advantages of one group or another in terms of postoperative complications and the nutrition status after PD. Further investigations from other points of view are therefore necessary to clarify the effect of a gastrointestinal reconstruction after PD. PMID- 17708303 TI - A phase I study of hypofractionated radiotherapy followed by systemic chemotherapy with full-dose gemcitabine in patients with unresectable locally advanced pancreatic cancer. AB - BACKGROUND/AIMS: Hypofractionated radiotherapy can shorten the irradiation period and allow systemic chemotherapy with full-dose gemcitabine to be started earlier. The purpose of this study was to determine the feasible dose of hypofractionated radiotherapy that could be followed by full-dose gemcitabine in patients with locally advanced pancreatic cancer. METHODOLOGY: Nine patients with unresectable locally advanced pancreatic cancer were enrolled in this study. Three patients received radiotherapy at 45Gy in 15 fractions (level 1) and six at 40 Gy in 8 fractions (level 2). Systemic chemotherapy with gemcitabine was started 3 months after the start of irradiation and was administered as a 30-minute intravenous infusion of a dose of 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle. RESULTS: No patients experienced dose-limiting toxicity at either level of radiotherapy. Gemcitabine was started in two of the three patients treated at the level 1 on schedule. At level 2, grade 3 nausea, vomiting and anorexia was observed in all 6 patients, and gemcitabine could not be started on schedule in 4 of the 6 patients. Two (22%) of the 9 patients achieved a partial response. The median time to progression was 5.8 months and the median overall survival time was 9.5 months. CONCLUSIONS: Hypofractionated radiotherapy with 40 Gy in 8 fractions was not feasible in patients with locally advanced pancreatic cancer. PMID- 17708304 TI - The incidence of pancreatic and extrapancreatic cancers in Japanese patients with chronic pancreatitis. AB - BACKGROUND/AIMS: Although an association between chronic pancreatitis and malignancies has been reported in the Western literature, in Japan there have been few reports that have dealt with this issue. We investigated the incidence of pancreatic and extrapancreatic cancers in Japanese patients with chronic pancreatitis. METHODOLOGY: We studied 170 Japanese patients with definite chronic pancreatitis with respect to the occurrence of pancreatic and extrapancreatic cancers during follow-up and compared the incidence with that reported in the Western literature. RESULTS: The patients developed 29 cancers including 5 pancreatic cancers. Four patients had two different types of cancer. The extrapancreatic cancer incidence (24/170: 14.1%) was significantly higher than in the West (8.3%, p < 0.01). The major organs in which cancer developed were stomach (n=9), pancreas (n=5), esophagus (n=4), colon (n=3), lung (n=2) and hemopoietic tissue (n=2). The overall incidence (8.2%) of associated cancers of the digestive system including, stomach, intestine, liver, biliary duct, and gallbladder, was significantly higher than in the West (1.3%, p < 0.01). CONCLUSIONS: The risk of extrapancreatic cancers during the course of chronic pancreatitis is significantly increased in Japan than in Western countries. In particular, cancers of the digestive system are frequently associated with chronic pancreatitis in Japan. PMID- 17708306 TI - Intraductal papillary-mucinous carcinoma of the pancreas with tumor thrombus in the portal vein: a report of two cases. AB - Intraductal papillary-mucinous carcinoma (IPMC) is a recently recognized pancreatic tumor and this is the first report to present two patients with IPMC complicating tumor thrombi in the portal vein. Two women, a 74- and a 55-year old, each revealed a round, cystic and well-demarcated tumor of the pancreas in an abdominal computed tomography (CT). However, the inner lumen of the splenic and portal veins was insufficiently stained during iv-infusion of the contrast medium, suggesting the presence of tumor thrombi. Owing to this information, the presence of tumor thrombus was investigated and correctly identified during laparotomy, and it was completely removable together with the primary pancreatic tumor. The resected tumors showed expansive growth because mucin and tumor tissues rose up when they were cut. Microscopically, the tumor was diagnosed as adenocarcinoma without ovarian-like stroma, and the final diagnosis of branch type of IPMC was made for the two patients. However, within one postoperative year, both patients developed liver metastasis. Although IPMC is known as having a lower potential for metastasis or invasion, the tumor thrombi can form when it reveals an expansive growth suggesting a high inner pressure. In addition, a higher possibility for subsequent liver metastasis should be anticipated after the tumor forms a thrombus in the portal vein. PMID- 17708305 TI - Small pancreatic lipoma: case report and literature review. AB - Pancreatic lipomas are very rare and only 19 cases have so far been reported. We present a case of small asymptomatic pancreatic lipoma found incidentally in a 45 year-old man with findings of ultrasonography, computed tomography, and magnetic resonance imaging, including fat-suppressed proton-density-weight imaging. We also provide a brief review of the literature. PMID- 17708307 TI - Pancreaticoduodenectomy without reconstruction of remnant pancreas for pancreas tumors with acquired fatty replacement of distal pancreas. AB - We report herein two patients with acquired fatty replacement of the distal pancreas, who underwent pancreaticoduodenectomy (PD) without reconstruction of remnant pancreas. Slow-growing tumors resulted in obstructive pancreatitis of the distal pancreas and insufficient focal blood flow, resulting in marked atrophy of the pancreas and fatty replacement. Suspected disappearance and fatty replacement of the body and tail of the pancreas were noted. In this situation, the PD procedure can be achieved without the reconstruction of remnant pancreas. Interestingly, the patients did not require insulin support postoperatively. PMID- 17708308 TI - Clinical significance of changes in tumor markers, extracellular matrix, MMP-9 and VEGF in patients with gastric carcinoma. AB - BACKGROUND/AIMS: The aim of this study was to evaluate the prognostic significance of some serum tumor marker level, extracellular matrix (ECM), matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF) in patients with gastric cancer. METHODOLOGY: The serum tumor markers included CEA, CA50 and CA19-9, ECM included laminin (LN), hyaluronic acid (HA), and collagen type III and IV were measured in 40 patients with gastric carcinoma and 20 matched healthy controls by radioimmunoassay. MMP-9, VEGF and MVD were measured with immunohistochemical methods and the computer image analyzer. Microvascular density (MVD) in tissues of patients with gastric carcinoma was detected. RESULTS: The levels of CEA, CA50, CA19-9, HA, LN and collagen type IV in the patients with metastasis were significantly higher than those in the patients without metastasis (p < 0.05). The expression of MMP-9 and collage type IV in the patients with metastasis and poorly differentiated carcinomas were significantly higher than those in the patients without metastasis whose tumors were well/moderately differentiated (p < 0.05). CONCLUSIONS: CEA, CA50, CA19-9, HA, LN and collagen type IV levels can be used as a signal of metastasis and disease progression in patients with gastric carcinoma. When a gastric carcinoma expresses a high level of MMP-9 and VEGF with high MVD, the power of infiltration and metastasis of the gastric carcinoma is enhanced. PMID- 17708309 TI - Bone disorder and vitamin D after gastric cancer surgery. AB - BACKGROUND/AIMS: The present study was conducted to investigate the relationship between bone metabolic disorder after gastrectomy for gastric cancer and vitamin D metabolites or the hormones involved in calcium metabolism. METHODOLOGY: Twenty one patients who had undergone gastrectomy for gastric cancer and had been followed for less than 10 years were assessed for bone disorder by microdensitometry. The levels of 1,25-dihydroxy vitamin D (1,25(OH)2VD), 25 hydroxy vitamin D (25(OH)VD), 24,25-dihydroxy vitamin D (24,25(OH)2VD), N-PTH, calcitonin, estradiol, osteocalcin, and ALP were measured and assessed for correlations with clinicopathological factors, including the operative procedure and the number of years since surgery. RESULTS: Bone disorder was found in 9 out of 21 patients (42.9%). The prevalence was significantly higher in patients who had undergone surgery more than 2 years before assessment, so there was a relationship between the period after surgery and bone disorder. Among the vitamin D metabolites, the level of 1,25(OH)2VD was normal in all patients, whereas 25(OH)VD was reduced in 6 out of 21 patients (28.6%) and 24,25(OH)2VD was reduced in 17 patients (81.0%). The 1,25(OH)2VD was significantly higher in the patients with Grade I to III bone disorder compared to the patients with normal bones or early bone disease. The 1,25(OH)2VD/25(OH)VD ratio was significantly higher in the patients without passage of food through the duodenum due to the reconstructive method, while the 25(OH)VD/24,25(OH)2VD ratio was significantly higher in the patients with remaining of duodenal food passage. PTH was decreased in about 50% of the patients, while calcitonin was normal in all patients. Estradiol was decreased in one female patient, while it was elevated in 10 of the 17 men (58.8%). The osteocalcin level was high in all patients irrespective of the period after surgery. CONCLUSIONS: After gastrectomy, the incidence of bone metabolic disorder increases with time. Changes of vitamin D metabolites, particularly 25(OH)VD and 24,25(OH)2VD, seem to be closely associated with post gastrectomy bone disease. PMID- 17708310 TI - 13C-urea breath test in patients having undergone total gastrectomy. AB - BACKGROUND/AIMS: In this study, we performed 13C-urea breath test in patients who had undergone total gastrectomy and investigated the content of (13)CO2 in the CO2 gas expired after direct influx of 13C-urea into the small intestine. METHODOLOGY: 13C-Urea breath test was performed in 31 patients who had undergone total gastrectomy at this department for the treatment of stomach cancer and consented to participate in this study. The test was performed in two ways, i.e. with and without mouth washing (gargling) on taking 13C-urea. RESULTS: Among 41 measurements, the delta13C was less than 2.5% per hundred in 9 measurements (22.2%) and less than 2.0% per hundred in 6 measurements (14.6%). The delta13C exceeded 50% per hundred, in 4 subjects (9.8%). There were no differences between the methods with and without gargling. CONCLUSIONS: The results of this study suggested the possibility that 13C-urea is decomposed even in the jejunum or the lower part of intestine resulting in absorption of H(13)CO3 and another possibility that 13C-urea is directly absorbed from the intestine and decomposed in the blood. PMID- 17708311 TI - Higher incidence of gastric remnant cancer after proximal than distal gastrectomy. AB - BACKGROUND/AIMS: Proximal gastrectomy has been widely accepted as a standard operation for early stage gastric cancer located in the upper third of the stomach. Therefore, cancer of the distal gastric remnant is now increasing. The aims of this study were to clarify and compare the incidences of gastric remnant cancer after proximal and distal gastrectomy. METHODOLOGY: Data on a consecutive series of 809 cases of gastrectomy performed for early gastric cancer from 1991 to 2003 in Shikoku Cancer Center were analyzed retrospectively with respect to the incidence of gastric remnant cancer. RESULTS: We performed distal gastrectomy in 624 patients and proximal gastrectomy in 47 patients during the study period. After those operations, the gastric remnants of 457 cases and 33 cases, respectively, were surveyed periodically by endoscopic examination at our hospital. Among those surveyed cases, 10 patients (2.2%) and 3 patients (9.1%) were diagnosed as having gastric remnant cancer, respectively. The gastric remnant cancer-free survival after proximal gastrectomy was significantly lower than that after distal gastrectomy. CONCLUSIONS: Because of the higher incidence of gastric remnant cancer after proximal gastrectomy, it is more important to survey the gastric remnant after proximal gastrectomy periodically by postoperative endoscopic examination. PMID- 17708312 TI - Why cosmetic/aesthetic dentistry should be a specialty. PMID- 17708313 TI - New age periodontics: what's coming down the pike. PMID- 17708314 TI - Laboratory perspectives on continuing education: it takes a team! PMID- 17708315 TI - Oral cancer detection: be the hero to your patients. PMID- 17708316 TI - Biomimetic endodontics: the final evolution? AB - We are seeing a gradual evolution by a small but growing number of endodontists and general dentists toward delicate biomimetic, microscope-based shaping. This old-fashioned respect for periradicular dentin is paired with microscopes, ultrasonics, and an appreciation for root morphology. Although no 2 roots are the same, general anatomic patterns allow the microscope-equipped clinician to search for major pulpal regions that will yield a high probability of cleaning and shaping the clinically available pulpal zones. There are complex, anatomically improbable, and clinically impossible areas of pulp that are beyond the reach of even the most gifted hands. Regardless, the clinician has the responsibility to begin each procedure seeking perfection and joyfully finishing with excellence. The shapes that were introduced during the Schilder (crown-down) era have served as a transitional technique to allow the first real 3-dimensional compaction of gutta-percha. Nonetheless, endodontics is in the end a restoratively driven procedure. Large, arbitrary, round shapes create beautiful endodontics but can dramatically weaken the tooth. The shaping philosophy advanced in this treatise allows perfectly adequate shapes to achieve the hydraulics needed for modern obturation. It will require different skills and materials to shape, pack, and restore the exotic architecture of nature. (See Tables 1 to 3.). PMID- 17708317 TI - Use of a resin-based root canal sealer followed by apicoectomy on two teeth. PMID- 17708318 TI - Disposable micro air abrasion: a minimally invasive restorative technique. PMID- 17708320 TI - Dental compression syndrome and TMD: examining the relationship. AB - Fifty years ago, McCollum and Stuart described a subtle pathology of function in the human masticatory system that was difficult to understand. That subtle pathology is the damage that results from compression of teeth. It is subtle because often the patient is unaware. It is pathologic because it applies untoward stress to the dentition, alveolar bone, and the TMJ. It is difficult to understand for many reasons: multiple etiology, few patient complaints, poor understanding of the deformations caused by DCS, the role of equilibration during treatment is unclear, and the dissimilar ways it takes its toll. For proper management of DCS, the general dentist should monitor for signs of compression and wear, educate the patient about the problem, and provide treatment. While every patient with a flattened dentition should not have their teeth dramatically altered or reconstructed, the dental profession should form a consensus that the natural, sharp morphology of teeth is superior to a flattened dentition, and should be preserved throughout one's lifetime. PMID- 17708319 TI - Replacing a traditional stainless steel crown: with CEREC CAD/CAM technology. PMID- 17708321 TI - One-stage surgical crown lengthening and provisional prosthetic placement: an interdisciplinary approach. PMID- 17708322 TI - Placing dental implants and/or natural tooth restorations in the aesthetic zone: achieving proper gingival contours. PMID- 17708323 TI - Restoring the partially edentulous patient in the aesthetic zone: computer-guided implant surgery. PMID- 17708325 TI - Physician referrals and the new dental medicine. PMID- 17708324 TI - Maximizing efficiency by delegating duties. PMID- 17708326 TI - Computer-generated smile analysis: Part 1. PMID- 17708327 TI - Quality improvement, research, and the institutional review board. AB - Is an activity quality improvement (QI), or is it research? And why does the distinction make a difference? While national leaders deliberate on how to answer these questions, healthcare organizations must act to ensure patient safety in both QI and research activities. The current system used by researchers for more than 30 years has not always protected human subjects. The result has been patient injuries and even death. Could QI activities result in patient injuries and death? This article offers healthcare quality professionals information that will better equip them to ensure safe practice and protect human subjects. PMID- 17708328 TI - Assessing quality of care for African Americans with hypertension. AB - African Americans bear a disproportionate burden of hypertension. A causal modeling design, using Donabedian's Quality Framework, tested hypothesized relationships among structure, process, and outcome variables to assess quality of care provided to this population. Structural assessment revealed that administrative and staff organization affected patients' trust in their provider and satisfaction with their care. Interpersonal process factors of racism, cultural mistrust, and trust in providers had a significant effect on satisfaction, and perceived racism had a negative effect on blood pressure (BP). Poorer quality in technical processes of care was associated with higher BP. Findings support the utility of Donabedian's framework for assessing quality of care in a disease-specific population. PMID- 17708329 TI - Bernard Rosof on the state of medical quality. PMID- 17708330 TI - Data distribution and analysis: a step to improving nursing quality. AB - Measurement is a cornerstone for improvement activities, and although the MetroHealth Medical Center in Cleveland, OH, gathered a significant amount of improvement data, it did not have a consistent mechanism for sharing the data with the nursing unit and the frontline nursing staff. A process was implemented to improve data distribution, thus making the data more accessible. Following the implementation of this process, the frontline nurses were more engaged in improvement activities, and significant improvement was noted on several measures. The findings suggest that consistent and meaningful data distribution is an important component in improving the quality of care. PMID- 17708331 TI - Understanding patterns of change over time to improve mammography rates. AB - This retrospective cohort study determined trends and patterns of mammography rates during 5 years (1997-2001) among female Medicare beneficiaries ages 50 years and older in Connecticut to better understand changes in rates over time and to plan future interventions. Time series analysis and hierarchical Longitudinal logistic regression were used to assess changes over time. Mammography rates increased significantly during the 5-year period (p < .001). A cyclical pattern was observed for all age groups and counties, with dips and peaks in the spring and fall each year (average increase 8% per year), consistent with concentrated intervention activity at those times. PMID- 17708333 TI - Patient satisfaction: evaluating the success of hospital ward redesign. AB - Patients who were moved from a traditional medical ward to a new state-of-the-art medical ward were surveyed regarding their perceptions of quality during their hospitalization. Respondents rated the environment of the state-of-the-art facility, as well as the overall quality of their hospital stay, more positively. However, fewer differences in perceptions of the quality of the broader hospital environment and little difference in the perceived quality of staff-patient interactions were found. Findings indicated that enhancing the facilities of the patient care environment improved patients' overall perceptions of the quality of their hospital stay. PMID- 17708332 TI - Promoting consistent clinical preventive services guidelines among competing health plans. AB - Clinicians are confronted with various and often conflicting sets of practice guidelines that direct provision of preventive care. This conflict among guidelines is detrimental to the delivery of preventive care and creates a major barrier to improving these services. This study used a systematic approach to reach consensus among health plan medical directors on clinical preventive services (CPS) guidelines. A consistent set of 17 CPS guidelines was identified that all health plans could endorse as being a priority for implementation. This approach provides a template for competing health plans nationwide to reach consensus on guidelines that support clinicians in the delivery of CPS. PMID- 17708334 TI - Institute for Healthcare Improvement's 18th Annual National Forum on Quality Improvement in Health Care. PMID- 17708335 TI - Nitric oxide-containing neurons in long-term grafts in a rat model of Parkinson's disease. AB - The role that nitric oxide may play in modulating graft function in long-term fetal ventral mesencephalic grafts in an animal model of Parkinson's disease was investigated. Mature grafts harvested from the entire fetal ventral mesencephalon possessed a large number of neuronal nitric oxide synthase (nNOS)/NADPH diaphorase-containing neurons throughout the graft intermingled with dopaminergic neurons. The morphological and neurochemical characteristics of these NADPH diaphorase neurons resembled those in centers adjacent to the substantia nigra of adult brain but not that of the striatum. Pretreatment with the nNOS blocker, 7 nitroindazole, resulted in contralateral rotations following methamphetamine challenge in long-term grafted animals that previously showed normalized rotational behavior. In contrast, mature grafts derived from fetal ventral mesencephalon without the midline areas possessed only a few nNOS-containing neurons within the grafts, and a similar methamphetamine challenge following 7 nitroindazole pretreatment in long-term grafted rats that previously showed normalized rotational behavior resulted in random movements. Our results indicate that nitric oxide-containing neurons inadvertently included during grafting may affect graft function, and excluding the midline areas of the ventral mesencephalon during tissue harvesting may minimize this effect. PMID- 17708337 TI - Combined treatment of neurotrophin-3 gene and neural stem cells is propitious to functional recovery after spinal cord injury. AB - We present an insight of the effects of combination therapy with neurotrophin-3 and neural stem cell on functional recovery after spinal cord injury (SCI). Total RNA was extracted from neural stem cell line C17.2 and reversed transcribed into cDNA. Neurotrophin-3 (NT-3) gene was amplified by PCR and subcloned into plasmid to construct an expression vector pNT-3. A positive clone containing pNT-3, named SHN2, was obtained and used for transplantation. Thirty adult mice received mechanical injury at the T8 vertebra level. Cell survival, NT-3 gene expression, and functional recovery were observed through X-Gal staining, RT-PCR, and open field locomotion, respectively. The results show that NT-3 gene comprising 777 bp nucleotides was cloned and a more than twofold expression was detected when transfected into neural stem cell line C17.2. Quantitative analysis of cellular density revealed a significant increase in SHN2 compared to the control cells (p < 0.01). Thirty days after transplantation, SHN2 showed significant increase near the lesion site. Furthermore, the functional recovery indicated an active effect by detecting Basso-Beattie-Bresnahan (BBB) locomotor rating scale (p < 0.01). In conclusion, combined treatment of neural stem cells and NT-3 gene can facilitate functional recovery. It offers an effective approach to treat SCI. PMID- 17708336 TI - The effect of truncated human alpha-synuclein (1-120) on dopaminergic cells in a transgenic mouse model of Parkinson's disease. AB - Alpha-Synuclein is thought to play an important role in the pathology of Parkinson's disease (PD). Truncated forms of this protein can be found in PD brain extracts, and these species aggregate faster and are more susceptible to oxidative stress than the full-length protein. We investigated the effect of truncated alpha-synuclein on dopaminergic cells using a transgenic mouse expressing alpha-synuclein (1-120) driven by the rat tyrosine hydroxylase promoter on a mouse alpha-synuclein null background. We found a selective reduction in the yield of dopaminergic cells from transgenic embryonic ventral mesencephalic cell cultures. However, in vivo the substantia nigra/ventral tegmentum dopaminergic cell counts were not reduced in transgenics, although these mice are known to have reduced striatal dopamine. When transplanted to the striatum in the unilateral 6-hydroxydopamine-lesioned mouse model of PD, dopaminergic cells derived from transgenic embryonic ventral mesencephala were significantly smaller at 6 weeks, and showed a trend towards being less effective at ameliorating rotational asymmetry than those from control alpha-synuclein null mice. These results suggest that alpha-synuclein (1-120) renders dopaminergic cells more susceptible to stress, which may have important implications as to how this truncated protein might contribute to dopaminergic cell death in sporadic PD. PMID- 17708340 TI - Time course and quantification of pancreatic islet revascularization following intraportal transplantation. AB - A large proportion of islets are lost after transplantation partly due to a lack of functional vasculature. Islets revascularize from host tissue but the process takes up to 2 weeks and has been suggested to result in reduced vascular density in engrafted islets. We describe a method for observing and quantifying the revascularization of intraportally transplanted islets that includes number, density, and branching of islet capillaries. Syngeneic islets were transplanted selectively into the two right posterior lobes of the liver of adult Lewis rats. Sections of the livers were dual stained for insulin and Bandeiraea simplicifolia and analyzed for islet morphology, area, and vascular density from day 0 to day 14 posttransplant and compared to native islets. Vascular density was 1431 +/- 75.7 vessels/mm2 in native islets and fell to 325.3 +/- 30.8 vessels/mm2 (p < 0.001) by day 1 posttransplant and subsequently increased until day 14 when it was significantly higher than in native islets (2612.5 +/- 107.8 vessels/mm2, p < 0.001). The percentage of islet area occupied by vascular space was 9.1 +/- 0.9% in native islets. After falling to 2.3 +/- 0.3% (p < 0.001) 1 day posttransplant this rose to supranormal levels (21.5 +/- 0.8%, p < 0.001) by day 14. The index of capillary branching was 0.771 +/- 0.017 in native islets and fell to 0.465 +/- 0.02 (p = 0.001) by day 3 but returned to native values by day 7 posttransplantation (0.726 +/- 0.03). This technique provides a robust method for tracking and quantifying the revascularization of intraportally transplanted islets, which should enable the comparison of different strategies aimed at accelerating islet revascularization. PMID- 17708338 TI - An immortalized rat ventral mesencephalic cell line, RTC4, is protective in a rodent model of stroke. AB - One therapeutic approach to stroke is the transplantation of cells capable of trophic support, reinnervation, and/or regeneration. Previously, we have described the use of novel truncated isoforms of SV40 large T antigen to generate unique cell lines from several primary rodent tissue types. Here we describe the generation of two cell lines, RTC3 and RTC4, derived from primary mesencephalic tissue using a fragment of mutant T antigen, T155c (cDNA) expressed from the RSV promoter. Both lines expressed the glial markers vimentin and S100beta, but not the neuronal markers NeuN, MAP2, or beta-III-tubulin. A screen for secreted trophic factors revealed substantially elevated levels of platelet-derived growth factor (PDGF) in RTC4, but not RTC3 cells. When transplanted into rat cortex, RTC4 cells survived for at least 22 days and expressed PDGF. Because PDGF has been reported to reduce ischemic injury, we examined the protective functions of RTC4 cells in an animal model of stroke. RTC4 or RTC3 cells, or vehicle, were injected into rat cortex 15-20 min prior to a 60-min middle cerebral artery ligation. Forty-eight hours later, animals were sacrificed and the stroke volume was assessed by triphenyl-tetrazolium chloride (TTC) staining. Compared to vehicle or RTC3 cells, transplanted RTC4 cells significantly reduced stroke volume. Overall, we generated a cell line with glial properties that produces PDGF and reduces ischemic injury in a rat model of stroke. PMID- 17708339 TI - Chondroitinase ABC treatment enhances synaptogenesis between transplant and host neurons in model of retinal degeneration. AB - Although recent studies revealed chondroitinase ABC (ChABC), an enzyme that degrades chondroitin sulfate proteoglycans, promotes CNS regeneration in vivo, the usefulness of its application for transplantation is not clear. We investigated if treatment with ChABC can promote synapse formation between graft and host neurons following retinal transplantation. Dissociated retinal cells were prepared from neonatal Nrl-GFP transgenic mice in which rod photoreceptors and their progenitor cells are labeled with GFP. Each cell suspension with or without ChABC (Nrl/ChABC group and Nrl group, respectively) was injected subretinally into the eyes of mice following chemically induced photoreceptor degeneration. The survival and functional integration of the transplanted photoreceptors were examined by histologically and electrophysiologically. Up to 4 weeks after transplantation, almost all the grafted GFP+ photoreceptor cells were widely distributed at the outer margin of the host retina where the photoreceptor layer was located originally. In the Nrl/ChABC group, 33.6% of the GFP+ photoreceptors elaborated neurites horizontally or vertically, and 4.6% elaborated neurites toward the retina. These neurites extended over the glial seal at the graft-host interface, and established synaptic contacts with neurons in the host retina as determined by confocal microscopy and three-dimensional analysis. Although 30.7% cells (p = 0.68) elaborated neurites in the Nrl group, only 1.2% cells (p < 0.05) projected neurites towards the host tissue and synaptic contacts were rare. Our results illustrate the potential utility of ChABC for enhancing synaptogenesis between transplanted neurons and host retina. PMID- 17708341 TI - Role of blood glucose in cytokine gene expression in early syngeneic islet transplantation. AB - In islet transplantation, local production of cytokines at the grafted site may contribute to the initial nonspecific inflammation response. We have determined whether the metabolic condition of the recipient modulates the cytokine expression in islet grafts in the initial days after transplantation. Normoglycemic and hyperglycemic streptozotocin-diabetic Lewis rats were transplanted with 500 syngeneic islets, an insufficient beta cell mass to restore normoglycemia in hyperglycemic recipients. The expression of IL-1beta, TNF-alpha, IFN-gamma, IL-6, IL-10, and IL-4 genes was determined by real-time PCR in freshly isolated islets, in 24-h cultured islets and in islet grafts on days 1, 3, and 7 after transplantation. IL-1beta mRNA was strongly and similarly increased in normoglycemic and hyperglycemic groups on days 1, 3, and 7 after transplantation compared with freshly isolated and cultured islets. TNF-alpha mRNA was also strongly increased on day 1, and it remained increased on days 3 and 7. IL-6 and IL-10 were not detected in freshly isolated islets, but their expression was clearly enhanced in 24-h cultured islets and islet grafts. IL-6 was further increased in hyperglycemic grafts. IL-10 expression was increased in both normoglycemic and hyperglycemic grafts on day 1 after transplantation, and remained increased in hyperglycemic grafts compared to 24-h cultured islets. IFN gamma mRNA was barely detected in a few grafts, and IL-4 mRNA was never detected. Thus, the inflammatory response in islet grafts was maximal on day 1 after transplantation, it was sustained, although at lower levels, on days 3 and 7, and it was partly enhanced by hyperglycemia. PMID- 17708342 TI - Cell loss during pseudoislet formation hampers profound improvements in islet lentiviral transduction efficacy for transplantation purposes. AB - Islet transplantation is a promising treatment in type 1 diabetes, but the need for chronic immunosuppression is a major hurdle to broad applicability. Ex vivo introduction of agents by lentiviral vectors-improving beta-cell resistance against immune attack-is an attractive path to pursue. The aim of this study was to investigate whether dissociation of islets to single cells prior to viral infection and reaggregation before transplantation would improve viral transduction efficacy without cytotoxicity. This procedure improved transduction efficacy with a LV-pWPT-CMV-EGFP construct from 11.2 +/- 4.1% at MOI 50 in whole islets to 80.0 +/- 2.8% at MOI 5. Viability (as measured by Hoechst/PI) and functionality (as measured by glucose challenge) remained high. After transplantation, the transfected pseudoislet aggregates remained EGFP positive for more than 90 days and the expression of EGFP colocalized primarily with the insulin-positive beta-cells. No increased vulnerability to immune attack was observed in vitro or in vivo. These data demonstrate that dispersion of islets prior to lentiviral transfection and reaggregation prior to transplantation is a highly efficient way to introduce genes of interest into islets for transplantation purposes in vitro and in vivo, but the amount of beta-cells needed for normalization of glycemia was more than eightfold higher when using dispersed cell aggregates versus unmanipulated islets. The high price to pay to reach stable and strong transgene expression in islet cells is certainly an important cell loss. PMID- 17708344 TI - Intrasplenic hepatocyte transplantation prolonged the survival in Nagase analbuminemic rats with liver failure induced by common bile duct ligation. AB - It has already been established that hepatocyte transplantation (HTx) in animal models, such as both chemically and surgically induced acute liver failure, liver based metabolic disease, and cirrhosis, resulted in significant improvement of liver function and survival. However, the efficacy of hepatocyte transplantation in secondary cholestatic liver disease is not well known. In this study, we transplanted hepatocytes into the spleen of Nagase analbuminemic rats (NARs) with common bile duct ligation (CBDL) to evaluate the function of transplanted hepatocytes by both of serum albumin levels and total bilirubin levels. CBDL was carried out on NARs to induce liver failure. Lewis rat hepatocytes were transplanted in NARs 7 days after CBDL. Animals, in groups of four, underwent the following interventions: group 1--intrasplenic transplantation of 30 x 106 primary Lewis rat hepatocytes in NARs with CBDL (n=4), group 2--intrasplenic injection of 0.5 ml DMEM in NARs with CBDL (n=4); group 3--CBDL only (n=4); group 4--intrasplenic transplantation of 30 x 106 primary Lewis rat hepatocytes in NARs (n=4). Both bilirubin levels and albumin levels in NARs with CBDL were significantly improved post-HTx. Animals receiving hepatocyte transplantation survived longer than animals in nontransplant control groups. This study indicates that hepatocytes can be transplanted to temporarily provide life supporting liver-specific metabolic function and prolong the survival in recipient rats with liver failure induced by CBDL. PMID- 17708343 TI - Improved quantity and in vivo function of islets isolated by reduced pressure controlled injection of collagenase in a rat model. AB - In islet transplantation, insufficient yield is a major obstacle to one-donor/one recipient transplant. Collagenase, which is injected via a pancreatic duct to separate islets from acini, can so easily distribute into the islet core that it may result in disruption of islets. The purpose of this study was to evaluate the superiority of reduced pressure-controlled collagenase injection (RPCI) at 80 mmHg on islet isolation to injection at 180 mmHg by examining in vivo transplant experiments besides the yield and the glucose stimulation test in a rat model. Lewis rat pancreases were distended with collagenase solution at 80 mmHg pressure as the RPCI group (group 1) and at 180 mmHg (group 2), followed by isolation. The yield in group 1 (1100 +/- 160 islets with 2750 +/- 530 IEQ) was significantly higher than that in group 2 (900 +/- 130 islets with 1570 +/- 350 IEQ, p < 0.01) due to the significant difference of the number of islets sized >150 microm in diameter, although the purity was not significantly different between the two groups. Stimulation indices in the glucose stimulation tests were 2.88 +/- 1.12 in group 1 and 1.93 +/- 0.62 in group 2 (p < 0.05). The cure rate by transplantation of 100 islets to diabetic nude mice in group 1 (8/10) was significantly higher than that in group 2 (3/10, p < 0.05). In a syngenic transplant model of 90% of islets isolated from one donor, the cure rates were 100% and 67% in groups I and 2, respectively (NS). The area under the curve on the graph of IPGTT on postoperative day 28 in group I was significantly smaller than that in group 2 (p < 0.05). In conclusion, our data show that RPCI at 80 mmHg could contribute to consistently high islet yield and in vivo function in a rat model. It was suggested that the current human protocol should be reviewed from this viewpoint. PMID- 17708345 TI - Comparison of mesenchymal stem cells from different tissues to suppress T-cell activation. AB - Graft-versus-host disease (GvHD) and graft rejection have remained significant complications of allogeneic stem cell transplantation. Mesenchymal stem cells (MSCs) from the bone marrow have been shown to suppress T-cell activation in vitro and in vivo, and may be used to reduce GvHD in the recipient or to facilitate engraftment across MHC barriers. MSCs can be derived from a variety of tissues. Thus, we asked whether MSCs from different tissues might have differential effects on T-cell responses. We were particularly interested in MSCs derived from adipose tissue because of its abundance and accessibility. We investigated and compared the immunosuppressive potential of murine MSCs derived from muscle tissue, adipose tissue, omentum, and bone. Cells from the different tissues were enriched for MSCs and cultured for 2-3 weeks to deplete hematopoietic cells. Mixed lymphocyte reactions (MLRs) including MSCs were performed using concanavalin A or allogeneic T cells as inducers of T-cell activation. MSCs from all tissues differentiated into multiple lineages. Mitogen induced T-cell activation, as well as allogeneic T-cell responses, was reduced in MLRs mediated by the addition of MSCs. Reduction of T-cell activation was most pronounced for muscle tissue in the mitogen-induced MLR and fat tissue during the allogeneic MLR. These data demonstrate that MSCs from multiple tissues efficiently reduce T-cell activation. The results suggest that MSCs from adipose tissue can serve as an alternative source for MSCs to bone or bone marrow for the modulation of GvHD after allogeneic stem cell transplantation or to enhance engraftment across MHC barriers. PMID- 17708346 TI - Effects of acute exposure to a 1439 MHz electromagnetic field on the microcirculatory parameters in rat brain. AB - THE AIM of this study was to determine the potential of radio-frequency electromagnetic fields (RF-EMF) to affect cerebral microcirculation, including blood-brain barrier function, in rat brain. MATERIALS AND METHODS: The head of the rat was exposed for 10 min to 1439 MHz RF-EMF having three intensity doses: 0.6, 2.4, 4.8 W/kg of brain averaged specific absorption rate (BASAR). Four microcirculatory parameters: blood-brain barrier permeability, leukocyte behavior, plasma velocity, and vessel diameter were measured before and after RF EMF exposure using a closed cranial window method. RESULTS: No extravasation of intravenously injected dyes from pial venules was found at any BASAR level. No significant changes in the number of endothelial-adhering leukocytes after exposure were found. The hemodynamics indicated that the plasma velocities and vessel diameters remained constant within the physiological range throughout each exposure. CONCLUSION: These findings suggest that there were no effects on the cerebral microcirculation under the given RF-EMF exposure conditions. PMID- 17708347 TI - Effects of subchronic exposure to a 1439 MHz electromagnetic field on the microcirculatory parameters in rat brain. AB - THE AIM of this study was to investigate whether repeated exposure to radio frequency electromagnetic field (RF-EMF) of 1439 MHz affects the cerebral microcirculation, including blood-brain barrier function, in a rat brain. MATERIALS AND METHODS: The head of the rat was exposed for four weeks (60 min/day, 5 days/week) to RF-EMF at 2.4 W/kg of brain averaged specific absorption rate (BASAR). Three microcirculatory parameters: blood-brain barrier permeability, leukocyte behavior and plasma velocity were measured before and after RF-EMF exposure using a closed cranial window method. RESULTS: No extravasation of intravenously injected dyes from pial venules was found at any BASAR level. No significant changes in the number of endothelial-adhering leukocytes after exposure were found. The plasma velocity remained constant within the physiological range through each exposure. CONCLUSION: These findings suggest that there were no effects on the cerebral microcirculation under the given RF-EMF exposure conditions. PMID- 17708348 TI - Histone H1 and cdk1 kinase activities in early embryos of four mouse strains after X-irradiation. AB - The cdk1/cyclin B1 complex is a universal regulator known to be responsible for driving the cell-cycle from the G2- to the M-phase. To investigate the effects of irradiation on the activity of this complex in preimplantation embryos, we irradiated one- and two-cell mouse embryos with X-rays, and measured the fluctuations of histone H1 and cdk1 kinase activity. Four mouse strains with different radiation sensitivities were chosen: the BALB/c and the Heiligenberger (radiation-sensitive) and the C57BL and the CF1 (radiation-resistant) strains. Embryos irradiated in the first cell-cycle arrested in the G2-phase. However, the dynamics of this radiation-induced G2-block were different between the mouse strains tested. Indeed, in the C57BL and the CF1 strains, X-irradiation with 2.5 Gy induced a very short G2 block before the one-cell embryos could then proceed to mitosis. On the contrary, X-irradiation in BALB/c induced a G2-arrest that lasted about 20 h, with the percentage of embryos blocked in G2 depending on the dose, whilst in the Heiligenberger strain, all irradiated embryos developed a G2 block, which was dependent in duration on the radiation dose. In all mouse strains, the histone H1 kinase activity remained low during the G2 arrest, while it showed values comparable to that of control embryos during mitosis. X irradiation is known to induce a change in the phosphorylation state of the cdk1 protein kinase in adult somatic cells. In embryos from the BALB/c and C57BL strains, the histone H1 kinase activities were confirmed by the cdk1 phosphorylation pattern: the inactive and phosphorylated form of cdk1 was observed in G2 arrested 1-cell embryos, while the active and dephosphorylated form of cdk1 was present in dividing control and irradiated 1-cell embryos. X irradiation at the 2-cell stage only induced a short G2-arrest in all tested mouse strains. In conclusion, cell-cycle effects in early embryos under normal conditions and after irradiation are strictly paralleled by changes in the activity of the central cell-cycle driving enzyme complex. PMID- 17708349 TI - Increased bone mineral density in aged rats with spontaneous mammary dysplasia. AB - Spontaneous mammary tumors were seen in seven of the 12 breeding female rats aged 2 years. All mammary tumors were diagnosed as mammary dysplasia (MD). Bone mineral contents (BMC) and bone mineral density (BMD) of their lumbar vertebrae and femur were determined using dual energy X-ray absorptiometry (DXA). In rats with MD, body weight (BW), BMD of the lumbar vertebrae and BMC of the femur were significantly higher than in the rats without MD. Although corpus luteum (CL) and follicles were seen in the ovaries of all animals, the number of CL in rats with MD was significantly lower than the rats without MD. It was suggested that high BMD, BW and decreased CL promoted mammary tumors. PMID- 17708351 TI - Overexpression of CHP2 enhances tumor cell growth, invasion and metastasis in ovarian cancer. AB - BACKGROUND: Calcineurin B homologous protein isoform 2 (CHP2) was identified to be expressed in various malignant cell lines including ovarian cancer, but not in the normal tissue counterpart. The biological function of CHP2 related to cancer progression is still unknown. MATERIALS AND METHODS: A CHP2-negative human epithelial ovarian cancer cell line OVCAR3 was used for this study. CHP2 was analyzed before and after gene transfection. Cell proliferation, adhesion, motility, and invasion capacities were assessed in parental and transfected OVCAR3/CHP2 cell lines to explore the possible functions of CHP2 in ovarian cancer progression. RESULTS: With RT-PCR analysis, CHP2-transfected OVCAR3/CHP2 cancer cells showed high CHP2 gene expression, whereas non-transfected clones did not produce detectable CHP2 mRNA. CHP2-transfected OVCAR3/CHP2 cells showed increased proliferation rates and exhibited increased activities of cell adhesion, migration and invasion. The current study provides the first evidence that overexpression of the CHP2 gene affects the biological behavior of ovarian cancer cell line OVCAR3 and is one of key mechanisms for ovarian carcinoma progression, suggesting that CHP2 may be an attractive target for biological anticancer therapy. PMID- 17708350 TI - Intracellular signal transduction in mouse oocytes and irradiated early embryos. AB - In order to determine the effect of X-irradiation on intracellular signal transduction in mouse oocytes and embryos, JNK, ERK and p38 kinase activities were measured by the state of phosphorylation of their respective substrates (c Jun, Elk-1 and ATF-2, respectively) in two mouse strains differing in radiation sensitivity, namely C57BL and BALB/c. In a first step, control oocytes and embryos were compared for their respective kinase activities at various stages of oocyte maturation (germinal vesicle and metaphases of 1st and 2nd meiosis stages) and early embryonic development (1-, 2-, 4-, 8- and 16-cell, morula and blastula stages). Levels of p38, ERK or JNK kinase activities were shown to vary with the stage of oocyte maturation and embryo development. In a second step, 1- and 2 cell embryos were X-irradiated with 2.5 Gy during the S-phase of the 1st or the 2nd cell-cycle, respectively. There were no significant differences in p38, ERK and JNK kinase activities between control and irradiated embryos, whatever the stage or mouse strain was considered. In conclusion, p38, ERK and JNK kinase activities were shown to vary during oocyte maturation and early embryonic development. Apparently, X-irradiation did not affect these kinase activities at the 1- and 2-cell stages in either mouse strains regardless of their difference in radiation sensitivity. PMID- 17708353 TI - Effect of saliva, epigallocatechin gallate and hypoxia on Cu-induced oxidation and cytotoxicity. AB - We have previously reported that contact with copper (Cu) induced immediate cell death via an oxidation-involved mechanism in human promyelocytic leukemic HL-60 cells, whereas contact with other metals (Au, Ag, Pd) produced no discernible effect. In the present study, we investigated the conditions under which Cu induced oxidative stress can be reduced. Contact with a Cu plate in the absence of cells enhanced the rate of consumption of cystine to the greatest extent, followed by that of methionine and histidine. Under hypoxic conditions, the consumption of all these amino acids was significantly reduced. On the other hand, the addition of saliva slightly, but not significantly, reduced the amino acid oxidation. The addition of epigallocatechin gallate (EGCG) slightly, but significantly reduced the consumption of cystine and histidine. The inhibitory effect of EGCG on the methionine consumption was more prominent, especially at higher concentrations. The Cu-induced cell death was significantly inhibited when freshly-prepared human gingival fibroblasts were incubated under hypoxic conditions. The present study demonstrates for the first time that the Cu-induced oxidation and cell death were effectively alleviated under hypoxic conditions. PMID- 17708352 TI - Schistosome-induced pathology is exacerbated and Th2 polarization is enhanced during pregnancy. AB - THE AIM of this study was to investigate the immunopathological impact of pregnancy on an ongoing experimental schistosomiasis infection. MATERIALS AND METHODS: Female BALB/c mice were randomly divided into three groups (A, B and C) of 15 animals each. The mice in Groups A and B were infected with 40 S. mansoni cercariae, percutaneously. Six weeks post-infection, the mice in Groups B and C (schistosome-naive controls) were mated. Schistosome-induced morbidity and cytokine recall responses were subsequently evaluated at weeks 7 and 8 post infection. RESULTS: Hepatic and pulmonary lesions resulting from trapped schistosome eggs were more frequent and more severe in Group B mice than in Group A mice. Group C mice had suppressed mitogen-stimulated interleukin 4 (IL-4) but maintained high intereferon gamma (IFN-gamma) responses. In contrast, Group A mice had elevated mitogen- and parasite-specific IL-4 but muted IFN-gamma responses. Group B mice had an early (week 7) high IL-4 response, even higher than in group A mice. CONCLUSION: Taken together the data suggest that pregnancy exacerbates schistosome-induced morbidity, probably through up-regulation of parasite-specific IL-4. PMID- 17708354 TI - Fluoroscopic-guided intradiscal oxygen-ozone injection therapy for thoracolumbar intervertebral disc herniations in dogs. AB - BACKGROUND: To investigate the effect of oxygen-ozone (O2-O3) injection on thoracolumbar intervertebral disc herniation (IVDH) in dogs. MATERIALS AND METHODS: Ten herniated discs of five dogs were treated with percutaneous injection of an O2-O3 gas mixture with O3 concentration of 32 microg/microl intradiscally (1.5-2 microl) under fluoroscopy guidance. RESULTS: Five weeks after treatment, the mean size of herniated discs was measured by computed tomography and showed significant reduction of disc volumes in all animals (8.8%+/-3.82%). The degree of shrinkage was negatively linearly correlated with disc mineralization (correlation coefficient=-0.636) and statistically significant at p<0.05. All five dogs regained their gait function and none recurred. CONCLUSION: We conclude that intradiscal O2-O3 injection can decompress affected discs by disc shrinkage. PMID- 17708355 TI - Diabetes increases both N-ras and ets-1 expression during rat oral oncogenesis resulting in enhanced cell proliferation and metastatic potential. AB - BACKGROUND: The expression of N-ras and ets-1 proteins was investigated in an experimental model of chemically-induced carcinogenesis in normal and diabetic (type I) Sprague-Dawley rats. MATERIALS AND METHODS: Tissue sections ranging from normal mucosa to moderately-differentiated oral squamous cell carcinoma were studied using monoclonal antibodies against N-ras and ets-1 proteins. RESULTS: In diabetic rats, N-ras expression increased with tumor advancement, while in normal rats N-ras was not detected in initial stages of oral oncogenesis and increased only in well-differentiated OSCC. The same pattern of elevated ets-1 expression was observed both in diabetic and normal rats, but in cancerous stages this expression was higher in diabetic than in normal rats. CONCLUSION: It seems that diabetes may contribute to increased cell proliferation due to N-ras constitutive activation, as well as to enhanced invasion and metastatic potential by increasing ets-1 levels. PMID- 17708356 TI - Diabetes does not influence oral oncogenesis through fibroblast growth factor receptors. AB - BACKGROUND: Increased expression of fibroblast growth factors and their receptors (FGFRs) has recently been described in oral squamous cell carcinoma. In addition, we have previously described a molecular basis for an association between oral cancer and diabetes. The expression of FGFR-2 and FGFR-3 investigated in an experimental model of chemically induced carcinogenesis in normal and diabetic (type I) rats. MATERIALS AND METHODS: Tissue sections ranging from normal mucosa to moderately-differentiated oral squamous cell carcinoma were studied using monoclonal antibodies against FGFR-2 and FGFR-3 proteins. RESULTS: A similar pattern of elevated FGFR-2 and FGFR-3 expression was observed in the initial stages of oncogenesis for both diabetic and non-diabetic animals. In the last stages of oral oncogenesis, the expression of both proteins remained relatively stable. CONCLUSION: It seems that diabetes does not affect the FGFR-2 and FGFR-3 pattern of expression throughout the various stages of oral oncogenesis. PMID- 17708358 TI - Elimination of plasmids by SILA compounds that inhibit efflux pumps of bacteria and cancer cells. AB - Patented SILA compounds 409 and 421, previously shown to inhibit the efflux pumps of bacteria and cancer cells, have been studied for their ability to reduce or eliminate the presence of plasmids from Escherichia coli strains that have been induced to high level resistance to tetracycline by gradual exposure to increasing concentrations of the antibiotic. The results demonstrate that SILA compound 421, which has greater efflux pump inhibitory activity than its parent SILA compound 409, can reduce plasmid loads by 5 logs, over that present in the absence of the drug. The ability of the SILA compound to eliminate much larger plasmids is substantially lower. Because in vivo studies have shown that these compounds are not toxic to the mouse, the results obtained in our study suggest a potential role for SILA compound 421 as an adjunct for the therapy of antibiotic resistant E. coli infections whose resistance is plasmid-mediated. In addition, because plasmid-mediated resistance is often found in tetracycline-treated cattle, SILA compound 421 may have potential as an adjunct during the time that the cattle are maintained on tetracycline prior to slaughter. PMID- 17708357 TI - Tenascin-C is required for proliferation of astrocytes in primary culture. AB - Astrocytes in primary culture can be classified morphologically into two types: fibrous astrocytes and protoplasmic astrocytes. To examine the role of tenascin-C (TN) in an in vitro astrocyte culture, primary cultures of astrocytes prepared from the brains of wild-type and of TN-deficient embryonic mice were analyzed. In primary culture of astrocytes from TN-deficient mice fibrous astrocytes did not appear and astrocytes did not become tile-shaped when they came in contact with each other. The rate of 5-bromo-2'-deoxyuridine incorporation in a cell proliferation assay was much lower for astrocytes from TN-deficient mice than for astrocytes from wild-type mice. These results suggest that TN is an essential molecule for maintaining the proliferation and proper morphology of astrocytes in primary culture. PMID- 17708359 TI - Fractal dimension as an index of brain cortical changes throughout life. AB - The fractal dimension (FD) of the cerebral cortex was measured in 93 individuals, aged from 3 months to 78 years, with normal brain MRI's in order to compare the convolutions of the cerebral cortex between genders and age groups. Image J, an image processing program, was used to skeletonize cerebral cortex and the box counting method applied. FDs on slices taken from left and right hemispheres were calculated. Our results showed a significant degree of lateralization in the left hemisphere. It appears that basal ganglia development, mainly in the left hemisphere, is heavily dependent upon age until puberty. In addition, both left and right cortex development equally depends on age until puberty, while the corresponding right hemisphere convolutions continue to develop until a later stage. An increased developmental activity appears between the ages of 1 and 15 years, indicating a significant brain remodelling during childhood and adolescence. In infancy, only changes in basal ganglia are observed, while the right hemisphere continues to remodel in adulthood. PMID- 17708360 TI - Immune and endocrine mechanisms of advanced cancer-related hypercortisolemia. AB - BACKGROUND: Cancer progression depend on the immune and endocrine status of the patients. In particular, it has been observed that abnormally high levels of cortisol and/or an altered circadian secretion are associated with a poor prognosis in advanced cancer patients. The present study was performed to establish whether cancer-induced hypercortisolemia depends on an activation of the hypothalamic-pituitary axis or on a direct adrenal stimulation by inflammatory cytokines, such as IL-6, which have been proven to induce cortisol secretion. PATIENTS AND METHODS: The study included 50 metastatic solid tumor patients, who were evaluated before the onset of chemotherapy. Venous blood samples were collected in the morning to measure IL-10, IL-6, ACTH and cortisol serum levels. Moreover, to analyze its circadian secretion, cortisol levels were also evaluated on venous blood samples collected at 4.00 p.m. RESULTS: Abnormally high morning levels of cortisol were observed in 19/50 (38%) patients. Moreover, a lack of a normal circadian rhythm of cortisol was seen in 8/50 (16%) patients. None of the patients showed high levels of ACTH. Abnormally high concentrations of IL-6 and IL-10 were present in 21/50 (42%) and in 14/50 (28%) patients, respectively. Mean serum levels of both IL-6 and IL-10 were significantly higher in patients with hypercortisolemia than in those with normal cortisol values (p<0.005 and p<0.001, respectively). According to previous clinical studies, these results confirm that the advanced neoplastic disease may be associated with enhanced cortisol levels and alterations of its circadian secretion. The lack of enhanced ACTH secretion excludes the possibility that the abnormal cortisol production is due to the activation of the hypothalamic-pituitary axis. On the contrary, the evidence of significantly higher concentrations of IL-6 in hypercortisolemic patients would suggest that cancer-related enhanced cortisol production may depend on a direct adrenal stimulation by IL-6 itself The well demonstrated stimulatory role of cortisol on IL-10 production would explain the enhanced IL-10 secretion in hypercortisolemic patients. CONCLUSION: Cancer related hypercortisolemia would seem to depend on alterations of the feedback mechanisms between endocrine and cytokine secretions, occurring in the neoplastic disease. PMID- 17708361 TI - Evaluation of bioactive glass for mastoid obliteration: a guinea pig model. AB - BACKGROUND: Mastoid obliteration seeks to replace an open mastoid cavity with material that will become viable and free of infection and cholesteatoma. The purpose of this study was to evaluate the efficacy of bioactive glass ceramic particles for mastoid obliteration using a guinea pig animal model. MATERIALS AND METHODS: Ten male guinea pigs (weighing 250-300 g) with normal eardrums and Preyer reflexes were used. Bulla obliteration using bioactive glass was performed on the left side in all guinea pigs. The implanted bioactive glass ceramic particles were examined clinically and radiologically by computed tomography (CT) and histologically. RESULTS: Clinically, there were no signs of inflammation, infection or implant exposure in all guinea pigs. The CT scans showed hyperintense areas that represented new bone formation. Histological evidence of new bone formation was observed in the implant specimens that included: active osteoblasts, osteocytes, chondrocytes and osteoid tissue. There was a definite bond between the implant and the bone interface at the areas of new bone formation. No inflammatory or foreign body reactions, caused by the bioactive glass ceramic particle implantation, were observed in the surrounding tissue. CONCLUSION: Our results suggest that bioactive glass ceramic particles are an ideal implant material. Further studies on bioactive glass ceramic particles should include a larger animal trial to lay the groundwork for human studies. PMID- 17708362 TI - Assessment of DNA damage in multiple organs from mice exposed to X-rays or acrylamide or a combination of both using the comet assay. AB - BACKGROUND: X-rays and acrylamide (AA) are present in the general environment and workplace and are potential hazards for human health. Combined exposure to both agents is possible, especially at low doses. MATERIALS AND METHODS: The induction of DNA damage after single or combined exposure to X-rays and/or AA was measured in multiple mice organs using a comet assay. RESULTS: X-rays and AA alone induced generally dose-dependent increases in DNA damage of somatic and germ cells. Combined exposure to 0.10 Gy + 50 mg/kg bw AA induced higher DNA damage than each agent alone in the spleen, kidneys, lungs and testes. In bone marrow lymphocytes there was clear increase in DNA damage compared to that produced by X-rays only. Significant DNA damage was observed in liver cells only after combined exposure to 0.25 Gy + 50 mg/kg bw AA. CONCLUSION: Combined exposure to X-rays and AA enhanced DNA damage after single exposure to each agent. PMID- 17708363 TI - Fas-1377 A/G polymorphism in lung cancer. AB - BACKGROUND: Reduced expression of Fas and/or increased expression of FasL is known to exist in some cancer types including lung cancer, so the Fas/FasL system may play a role in the course of cancer. Lack of cell surface Fas expression is one of the main routes of apoptotic resistance in tumor formation and progression. Functional mutations in the Fas gene that impair apoptotic signal transduction are associated with susceptibility to various types of cancer. In this study, we focused on lung cancer. PATIENTS AND METHODS: The genotypic tendencies that may occur due to a specific point mutation (Fas-1377 G -->A) on promoter region for Fas were evaluated. RESULTS: We did not find any relationship between Fas-1377 G-->A polymorphism and lung cancer. But there was a significantly higher number of AG patients who smoked than GG ones. CONCLUSION: There was no relationship between Fas-1377 G-->A polymorphism and lung cancer, but it was statistically significant that smoking might increase the possibility of creating lung cancer in AG genotypes more than in other genotypes. PMID- 17708364 TI - Commercial soy milk enhances the development of 7,12-dimethylbenz(a)anthracene induced mammary tumors in rats. AB - BACKGROUND: Soy milk is a major soy food in China and Japan. Isoflavones in soy food are considered to protect women again breast cancer. MATERIALS AND METHODS: The effects of soy milk consumption on 7,12-dimethylbenz(a) anthracene (DMBA) induced mammary tumors in adult female rats was investigated. Sprague-Dawley rats were given 5 mg DMBA via intragastric intubation and then assigned to receive soy milk or water in addition to a normal rodent diet. Body weights, liquid and food intake, tumor number, location and development were recorded. After 20 weeks, liver, uterus and mammary tumors were removed from the sacrificed animals and examined. Plasma 17beta-estradiol concentration was also determined. RESULTS: After 20 weeks of DMBA administration, all of the rats that drank soy milk developed mammary tumors, while the incidence in the control group was 70% (p <0.01). Tumor multiplicity increased in the soy milk group with borderline significance (p=0.06). Total tumor weight and size in the soy milk group were 1.5 fold greater than in the control group, without a significant difference (p>0.05). Uterine weight and plasma 17beta-estradiol concentrations were similar in the two groups. CONCLUSION: Our results suggest that commercial soy milk enhanced the development of DMBA-induced mammary tumors in rats. Thus, careful consideration should be given when explaining the beneficial effects of soy food. PMID- 17708365 TI - Correlation of HER-2/neu protein overexpression with other prognostic and predictive factors in invasive ductal breast cancer. AB - BACKGROUND: The objective of our study was to investigate the association between Her-2/neu status and other clinicopathological characteristics of ductal breast carcinoma. PATIENTS AND METHODS: A total of 120 cases of breast carcinoma were included in this study. The immunohistochemical staining for HER-2/neu, hormone receptors, p53 and Ki-67 were evaluated. RESULTS: HER-2/neu protein overexpression was present in 4 out of 63 T1 lesions, in 13 out of 44 T2 lesions, in 3 out of 7 T3 lesions, and in 3 out of 6 T4 lesions. Protein overexpression was found in 10 out of 21 grade III tumors and 13 out of 72 grade II tumors. Overexpression was not detected in grade I tumors. Of the 23 Her-2/Neu-positive cases, ER- and PR-negative status was detected in 61% and 69%, respectively. Her 2 protein overexpression was seen in 23 out of 93 high Ki-67 tumors, whereas overexpression was not detected in low Ki-67 cases. CONCLUSION: Statistically significant correlation was found between HER-2/neu protein overexpression and large tumour size, high histological grade, ER and PR negativity, and high Ki-67 proliferative index. PMID- 17708367 TI - Fibrinogen, lipoprotein (a), albumin and bilirubin (F-L-A-B) levels and cardiovascular risk calculated using the Framingham equation. AB - OBJECTIVES: To determine the correlation between cardiovascular risk calculated using the Framingham equation and the circulating levels of 4 'emerging'predictors of vascular events: fibrinogen (Fib), lipoprotein (a) (Lp(a)), albumin (Alb) and bilirubin (Bil) (F-L-A-B). PATIENTS AND METHODS: A retrospective survey was carried out using patients referred to a specialist university-based clinic. A total of 376 patients with primary dyslipidaemia (209 men), without overt vascular disease, had their cardiovascular risk estimated using the Framingham equation. RESULTS: Among the men, smokers (n=45) were significantly younger (p =0.014) than non-smokers (n=164). Smokers when compared with non-smokers had significantly higher median Fib levels (3.84 (1.15-5.87) vs. 3.08 (1.44-5.47) g/l; p<0.0001) and lower median Bil levels (8 (3-17) vs. 10 (1 28) micromol/l; p=0.016). When non-smoker men without clinically evident vascular disease were considered, there was a significant positive Fib and negative Alb correlation with calculated risk, whether the family history was considered or not. Moreover in smokers, the only significant correlation was a negative one between Bil and cardiovascular disease risk. Lp(a) correlated with risk for stroke in women non-smokers whether the family history was considered or not, while Alb correlated with risk for stroke in women non-smokers without family history. CONCLUSION: Fib, Lp(a), Alb and Bil (F-L-A-B) may be predictors of vascular events in high-risk populations. Prospective studies should evaluate whether the F-L-A-B markers are useful in the assessment of cardiovascular risk load. Such an advantage would make treatment more cost effective by improving patient targeting. The F-L-A-B markers could eventually become targets for new drugs. PMID- 17708366 TI - Description of patients with midgut carcinoid tumours: clinical database from a Danish centre. AB - BACKGROUND: We have initiated a clinical database of patients with neuroendocrine tumours (n = 132). Data on patients with well-differentiated endocrine carcinoma (WHO classification) previous classified as midgut carcinoid patients, are presented. PATIENTS AND METHODS: Retrospectively, 56 patients with midgut carcinoid tumours were evaluated with respect to symptoms, primary tumour size, metastases, tumour markers, treatment and survival. RESULTS: Flushing was described in 29%, diarrhoea in 52%, abdominal pain in 34%, bronchial constriction in 2% and carcinoid heart disease in 4% of the patients. Fifty-two percent had liver metastases at referral. Twenty-seven percent were considered to have had radical surgery. Patients not considered for radical surgery and patients with liver metastases had significantly higher tumour marker levels (serum chromogranin A (CgA), serum serotonin and urinary 5-hydroxyindolic acid (5-HIAA)) compared to radically-operated patients and to patients without liver metastases (p<0.05, respectively). For all the midgut carcinoid tumour patients the overall 5-year survival rate was 72%. The radically-operated patients had a 5-year survival rate of 100% (other death causes excluded). The patients with normal CgA or <5 liver metastases at referral had a 100% 5-year survival rate. The patients with <5 liver metastases had a significantly better 5-year survival rate compared to patients with multiple liver metastases (100% vs. 50%, p<0.05). CONCLUSION: This group of patients exhibited the same characteristic clinical features with similar survival as reported from other specialised centres. Radical surgery, normal CgA level and <5 liver metastases indicated a good prognosis and patients with <5 liver metastases had a significantly better survival compared to patients with multiple liver metastases. PMID- 17708368 TI - Subglottic MALT lymphoma of the larynx--more attention to the glottis. AB - BACKGROUND: Mucosa-associated lymphoid tissue (MALT) lymphoma of the larynx is a rare but well-documented entity which may arise from chronic inflammatory process. Supraglottic left regions are predominant due to unknown reason. CASE REPORT: We present the case of a 62-year-old man with a dry cough, stridor and developing exertional dyspnea. This subglottic almost circumferential MALT lymphoma showed a temporary distinct disappearance after cortisone administration during the diagnostic process. Bronchoscopy confirmed the diagnosis of a primary MALT lymphoma of the larynx. The patient received chemotherapy according to CHOP scheme plus rituximab. A reliable post-treatment care period of 15 months showed no sign of recurrence. CONCLUSION: MALT lymphoma of the larynx are believed to arise from preexisting or acquired lymphoid tissue of the upper airway. Acquired lymphoid tissue is documented in the supraglottic region and may be associated with a chronic inflammatory process. However, in subglottic cases it is unclear whether the chronic inflammation arises from a local or systemic process. PMID- 17708369 TI - Evaluation of apolipoprotein E (apoE) and lipoprotein profile in severe alcohol dependent individuals. AB - BACKGROUND: Chronic alcohol consumption down-regulates the expression of sialytransferase genes resulting in impaired sialylation of apolipoprotein E (apoE) and decreased association with HDL. There are a limited number of studies with contradictory data on the effect of alcohol dependence on human plasma apoE. The aim of the present work is to determine and compare the levels of apoE in relation to the other lipoproteins in alcohol-dependent individuals in order to evaluate the possible role of apoE in lipoprotein metabolism in conditions of severe alcohol dependence. PATIENTS AND METHODS: The sample of our study comprised 43 DSM-IV diagnosed alcohol-dependent/abusing subjects (33 males and 10 females), treated on an inpatient basis according to a standard detoxification protocol, and 27 healthy people (9 males and 18 females, as a control group). Serum concentration of hepatic enzymes (AST, ALT, gammaGT), as well as measures of cholesterol and lipoproteins were obtained at baseline and at discharge after a detoxification period of 4-5 weeks. RESULTS: Upon admission, all alcohol dependent individuals had significantly higher hepatic enzyme levels, apoE and HDL values compared to controls. After completion of alcohol detoxification, all the above parameters returned to normal levels. Additionally, a significant correlation was observed between alcohol consumption during the previous year of alcohol abuse and the apoE values both upon admission to and on discharge from the detoxification program. CONCLUSION: The statistical correlation between apoE on admission and discharge with alcohol consumption during the previous year suggests that apoE is dependent on alcohol consumption and can serve as a sensitive marker of severe alcohol abuse. PMID- 17708370 TI - Evaluation of oxidative stress markers after vaginal delivery or Caesarean section. AB - BACKGROUND: The effects of vaginal delivery (VD) and of cesarean section (CS) on the markers of oxidative stress were investigated. MATERIALS AND METHODS: Umbilical blood samples were analyzed from 74 full-term neonates, 46 born via VD, 28 via elective CS. The level of lipid peroxidation (LP), protein and DNA damage and the antioxidant status were compared. RESULTS: Differences between CS and VD groups were generally non-significant for oxidative markers, except for the GSH concentrations (VD: 4.18 vs. CS: 2.77 microM/mg protein x 10(-3); p<0.05). LP was significantly higher in the CS group (0.078 vs. 0.042 nM MDA/mg protein; p <0.05). The level of carbonyl proteins was high in the VD group and significantly lower in the elective CS group (9.5 vs. 8.1 mM/mg protein x 10(-4); p<0.05). We found 0.78% more strand breaks in elective CS group than in VD group. CONCLUSION: CS does not have an advantage over VD with respect to oxidative stress. PMID- 17708372 TI - The social six redux: is that really all there is? PMID- 17708373 TI - Costs of individuals with disabilities who were born in Texas in 2000. PMID- 17708374 TI - Disability insurance for dentists? PMID- 17708375 TI - Oral and maxillofacial pathology case of the month. Ameloblastic fibro-odontoma. PMID- 17708376 TI - A new research focus for skin breakdown. PMID- 17708377 TI - Clinical effectiveness of a low-tech versus high-tech pressure-redistributing mattress. AB - OBJECTIVE: To compare the effectiveness of a high-specification foam mattress (control) with a high-tech (Duo2, Hill Rom) alternating/continuous low-pressure mattress (treatment) in the prevention of pressure ulceration. The study also evaluated if there is a difference in performance between the two working modalities (alternating and continuous low pressure) of the high-tech mattress in a comparable sample of patients. METHOD: Thirty-three patients were observed for two weeks in the control group. In the treatment group, 86 patients were randomised to receive alternating low pressure and 84 continuous low pressure. Incidence of pressure ulcers in both arms was recorded. Student's t-test was used to compare all Braden scores, and the chi-square test and Fisher's exact test to evaluate differences between groups. RESULTS: There was a high difference in the number of new pressure ulcers in the control group when compared with the treatment group. There was no difference in performance between the alternating and continuous low-pressure modes. However, the sample size is too small to prove or disprove a statistically significant difference between the two modalities. CONCLUSION: The high-tech mattress was markedly more effective than the high specification foam mattress in preventing the onset of pressure ulcers. Initial data suggest that the use of alternating or continuous low pressure made little or no difference to the results. PMID- 17708378 TI - Evaluation of pH measurement as a method of wound assessment. AB - OBJECTIVE: To assess variations in wound pH levels and explore the relationship between wound pH and the state of wound healing. METHOD: Fifty patients with acute or chronic wounds attending the wound clinic at University Hospital,Varanasi, India were included. Wound pH was measured using litmus paper strips and recorded weekly. Other parameters recorded were the wound condition, exudate level and culture. RESULTS: The baseline pH of most of the wounds was greater than 8.5. As the wound condition improved and exudate levels decreased, the pH reduced to less than 8.0. Fifty-eight per cent of the wounds were culture positive, and an association was observed between the type of organism present and the wound pH. CONCLUSION: Wound pH measurements can be performed efficiently and are non-invasive, causing no discomfort to the patient. As the wounds healed, the pH reduced. This change in pH can help predict the likelihood of wound healing. PMID- 17708379 TI - Parathyroidectomy, excision and skin grafting with topical negative pressure for calciphylactic ulcers. AB - The combined use of four treatment modalities for calciphylactic ulcers--all of which have proved effective on an individual basis--may provide the optimal treatment approach. This is the first time such a combined use has been reported. PMID- 17708380 TI - Wound healing activity of Matricaria recutita L. extract. AB - OBJECTIVE: To evaluate the wound healing activity of M. recutita (chamomile) extract in rats. METHOD: Wound healing activity was determined using excision, incision and dead space wound models. The animals were divided into two groups of six for each model: animals in the test group were treated with the aqueous extract of M. recutita (120mg/kg/day), which was mixed in their drinking water. Animals in the control group were maintained with plain drinking water. Healing was assessed by the rate of wound contraction, period of epithelialisation, wound breaking strength, granulation tissue weight and hydoxyproline content. Antimicrobial activity of the extract against various microorganisms was assessed. RESULTS: On day 15 animals in the test group exhibited a greater reduction in the wound area when compared with the controls (61 % versus 48%), faster epithelialisation and a significantly higher wound-breaking strength (p<0.002). In addition, wet and dry granulation tissue weight and hydroxyproline content were significantly higher. CONCLUSION: The increased rate of wound contraction, together with the increased wound-breaking strength, hydroxyproline content and histological observations, support the use of M. recutita in wound management. However, this needs to be studied further before it can be considered for clinical use. PMID- 17708381 TI - Development of a pathway of care for venous leg ulcer management. AB - During the implementation of a leg ulcer care pathway, it became apparent that training on this subject was often inaccessible and cursory. Additional education was provided, which included a competency assessment of all participants. PMID- 17708382 TI - Practice based commissioning: implications for community wound-care practitioners. AB - Practitioners can do much to ensure that wound care benefits from practice based commissioning, although the actions needed to achieve this are complex and time consuming. This paper describes the key issues to consider. PMID- 17708383 TI - Nitric oxide restores impaired healing in normoglycaemic diabetic rats. AB - OBJECTIVE: Hyperglycaemia impairs wound healing. However, little is known about the underlying cellular mechanisms that lead to diminished wound repair in insulin-controlled and non-insulin-controlled diabetes. This study investigated the role of endogenous and exogenous nitric oxide on incisional wound healing in diabetic rats. METHOD: Groups of 10 wild-typeWistar control rats - 10 genetically diabetic BioBreeding rats and 10 genetically diabetic BioBreeding rats treated with subcutaneous insulin implants to render them normoglycaemic - underwent dorsal skin incision followed by subcutaneous insertion of polyvinyl alcohol sponges. The rats were sacrificed 10 days later to determine the wound-breaking strength and reparative collagen deposition. Nitric oxide, an important mediator in diabetic wound healing and collagen synthesis, was measured in wound fluid. Wound-derived fibroblasts were tested for ex vivo synthesis of nitric oxide and collagen. Exogenous nitric oxide was used for the therapeutic interventions. RESULTS: Wound-breaking strength and wound collagen deposition were significantly impaired in the hyperglycaemic diabetic animals (p<0.01). Wound nitric-oxide synthesis and ex vivo wound fibroblast nitric-oxide production were reduced in the hyperglycaemic rats (p<0.01). Insulin treatment partially reversed some of the effects of hyperglycaemia on wound repair (p<0.05). Exogenous nitric oxide further restored wound mechanical strength, collagen deposition and fibroblast collagen synthesis (p<0.01) in insulin-treated (normoglycaemic) diabetic animals. CONCLUSION: Wound healing is impaired in hyperglycaemic and normoglycaemic diabetic rats. This is reflected in impaired wound fibroblast nitric-oxide synthesis. Used in combination with insulin, exogenous nitric oxide further improves healing outcomes, making it a potential target for therapeutic intervention in insulin-treated normoglycaemic diabetes. PMID- 17708384 TI - Effects of honey and sugar dressings on wound healing. AB - OBJECTIVE: To investigate whether there is a difference between the efficacy of honey and sugar as wound dressings. METHOD: Patients with open or infected wounds were randomised to receive either honey or sugar dressings. Bacterial colonisation, wound size, wound ASEPSIS score and pain were assessed at the start of treatment and at weekly intervals until full healing occurred. RESULTS: Forty patients were enrolled; 18 received sugar dressings and 22 honey dressings. In the honey group, 55% of patients had positive wound cultures at the start of treatment and 23% at one week, compared with 52% and 39% respectively in the sugar group.The median rate of healing in the first two weeks of treatment was 3.8cm2/week for the honey group and 2.2cm2/week for the sugar group. After three weeks of treatment 86% of patients treated with honey had no pain during dressing changes, compared with 72% treated with sugar. CONCLUSION: Honey appears to be more effective than sugar in reducing bacterial contamination and promoting wound healing, and slightly less painful than sugar during dressing changes and motion. PMID- 17708385 TI - Evidence for best veterinary practice: clinical veterinary research. PMID- 17708387 TI - Use of conventional and real-time polymerase chain reaction to determine the epidemiology of hemoplasma infections in anemic and nonanemic cats. AB - BACKGROUND: The goals of this study were to develop and apply conventional (c) and real-time TaqMan polymerase chain reaction (PCR) assays for Mycoplasma haemofelis (Mhf), 'Candidatus Mycoplasma haematoparvum' (Mhp), and 'Candidatus Mycoplasma haemominutum' (Mhm) to blood samples of cats to determine the epidemiology of these infections in cats. HYPOTHESIS: Cats are infected with >2 hemoplasma species, and organism load correlates with disease induced by these organisms. ANIMALS: Blood samples from 263 anemic and nonanemic cats were used. METHODS: A retrospective study was conducted. RESULTS: Forty-seven (18%) samples were positive. Three samples (1%) yielded 170 base pair cPCR products, 1 of which was positive for Mhf using real-time PCR. Forty-four samples (17%) yielded 193 base pair cPCR products, 40 of which were positive for Mhm using real-time PCR. Organism loads ranged from 375 X 10(6)/mL to 6.9 x 10(6)/mL of blood. Sequencing of cPCR products from samples testing negative using real-time PCR identified 2 Mhp-like sequences, 1 Mhm-like sequence, and 1 sequence resembling 'Candidatus Mycoplasma turicensis'. Cats infected with Mhm were less likely to be anemic than uninfected cats. Older age, outdoor exposure, feline immunodeficiency virus (FIV) seropositivity, cutaneous squamous cell carcinoma (SCC), and stomatitis were associated with Mhm infection. Cats from the Sacramento Valley were more often infected with Mhm than cats from the San Francisco bay area. CONCLUSIONS AND CLINICAL IMPORTANCE: Cats may be infected with 4 hemoplasma species. The association between Mhm infection, FIV, and SCC may reflect outdoor roaming status of infected cats. The clustered distribution of infection suggests an arthropod vector in transmission. PMID- 17708386 TI - Thyroid imaging in the dog: current status and future directions. AB - This review describes the advantages and disadvantages of radiography, ultrasonography, and nuclear medicine in the 2 most frequent thyroid pathologies of the dog: acquired primary hypothyroidism and thyroid neoplasia. Ultrasonography and scintigraphy remain the 2 most indicated imaging modalities for these thyroid abnormalities. However, as in human medicine, computed tomography and magnetic resonance imaging also have potential indications. This is especially the case in the evaluation of the extent, local invasiveness, and local or distant metastases of thyroid neoplasia. Based on experience with different imaging modalities in people, we suggest future directions in the imaging of the canine thyroid gland. PMID- 17708388 TI - Treatment of severe immune-mediated thrombocytopenia with human IV immunoglobulin in 5 dogs. AB - BACKGROUND: Glucocorticoids with or without other immunotherapy are the initial treatment of choice for dogs with severe immune-mediated thrombocytopenia (IMT). The majority of treated dogs will have improvements in platelet counts within 5 to 7 days of starting therapy, but complications from hemorrhage often occur before a response is seen. Human IV immunoglobulin (hIVIG) blocks Fc receptors on mononuclear phagocytic cells in dogs; it is used in people with idiopathic thrombocytopenic purpura. HYPOTHESIS: The purpose of this study was to describe adverse effects and benefit of hIVIG in addition to conventional immunosuppressive therapy in dogs with severe IMT. ANIMALS: Five client-owned dogs with severe primary IMT. METHODS: Case series. The hospital database was searched for dogs with primary IMT treated with hIVIG. RESULTS: No adverse effects were noted during or after hIVIG infusion in any treated dog. Over a 6 month follow-up, all dogs were clinically normal when using conventional immunosuppressive therapy. Human IVIG was administered 3 days after initiation of immunosuppressive therapy in 4 dogs, and, after 2 days, in 1 dog. In all dogs, the mean platelet counts pre- and 24 hours post-hIVIG infusion (0.28-0.76 g/kg) were 2,500/pL and 50,600/microL (62,750/microL for the 4 responders), respectively. One dog failed to respond as promptly to hIVIG (0.34 g/kg), and the platelet count increased to 66,000/microL after 9 days of immunosuppressive therapy. The mean duration of hospitalization post-hIVIG in all 5 dogs was 1.8 days (12 hours for responders), and the mean total length of hospitalization was 4.6 days (3.5 days for responders). Active hemorrhage resolved and no packed red blood cell transfusions were required after hIVIG infusion for responders. CONCLUSIONS AND CLINICAL IMPORTANCE: Human IVIG was well tolerated and appeared to be associated with rapid platelet count recovery and amelioration of clinical signs in most dogs with IMT. PMID- 17708389 TI - Chronic enteropathies in dogs: evaluation of risk factors for negative outcome. AB - HYPOTHESIS: Certain variables that are routinely measured during the diagnostic evaluation of dogs with chronic enteropathies will be predictive for outcome and a new clinical disease activity index incorporating these variables can be applied to predict outcome of disease. ANIMALS: Seventy dogs were entered into a sequential treatment trial with elimination diet (FR, food-responsive group) followed by immunosuppressive treatment with steroids if no response was seen with the dietary trial alone (ST, steroid-treatment group). A 3rd group consisted of dogs with panhypoproteinemia and ascites (PLE, protein-losing enteropathy) that were treated with immunosuppressive doses of steroids. METHODS: Three years of follow-up information was available for all dogs. Clinicopathologic variables were tested for their ability to predict negative outcome, defined as euthanasia due to refractoriness to treatment. Different scoring systems including different combinations of these variables were evaluated using receiver operating characteristic (ROC) curves. RESULTS: Thirteen of 70 (18%) dogs were euthanized because of intractable disease. Univariate analysis identified a high clinical activity index, high endoscopic score in the duodenum, hypocobalaminemia (<200 ng/L) and hypoalbuminemia (<20 g/L) as risk factors for negative outcome. CONCLUSIONS AND CLINICAL IMPORTANCE: Based on the factors identified by logistic regression and ROC curve analysis, a new clinical scoring index (CCECAI) was defined that predicts negative outcome in dogs suffering from chronic enteropathies. PMID- 17708390 TI - Diagnostic accuracy of electrocardiography and thoracic radiography in the assessment of left atrial size in cats: comparison with transthoracic 2 dimensional echocardiography. AB - BACKGROUND: Left atrial (LA) enlargement (LAE) is a morphologic expression of the severity and chronicity of left ventricular (LV) diastolic dysfunction, volume overload, and increased atrial pressure and has diagnostic, therapeutic, and prognostic importance in cats. The noninvasive gold standard for assessing LA size is 2-dimensional echocardiography (2DE). HYPOTHESIS: ECG and thoracic radiography may be used to predict LAE in cats. ANIMALS: Twenty-one healthy control cats and 31 cats with cardiomyopathy were prospectively studied. METHODS: 2DE studies, including determination of the maximum LA dimension (LAD) and area (LAA), were performed prospectively in all cats and compared to the assessment of LA size based on thoracic radiography and indices obtained from a 6-lead ECG. Results obtained from healthy cats were used to generate discrimination limits suggestive of LAE as defined by LAD > 1.57 cm and LAA > 2.75 cm2. RESULTS: In cats with LAE, P wave duration and PR interval were prolonged and radiographic LA vertebral heart size (LA-VHS) was increased (P < .05). P wave-related indices had low sensitivity (Se; range, 0.12 to 0.60) but high specificity (Sp; range, 0.81 to 1.00) for the prediction of LAE. Radiographic indices had low Se (range, 0.28 to 0.72) and high Sp (range, 0.74 to 0.95) for the prediction of LAE. Correlation analyses identified correlations between LAA and P wave duration (r = 0.47, P = .003) and LAD and LA-VHS (r = 0.70, P < .001). CONCLUSION AND CLINICAL IMPORTANCE: ECG and thoracic radiography are reasonably specific but less sensitive predictors of LAE in cats. PMID- 17708391 TI - Assessment of regional systolic and diastolic myocardial function using tissue Doppler and strain imaging in dogs with dilated cardiomyopathy. AB - BACKGROUND: Tissue Doppler Imaging (TDI) or strain (St) imaging could provide sensitive indices for early detection and treatment follow-up of canine dilated cardiomyopathy (DCM). Analysis of TDI and St features in dogs with overt DCM is a prerequisite before using these new criteria in prospective screenings of predisposed families or in clinical trials. HYPOTHESIS: Radial and longitudinal right and left myocardial motion, assessed by TDI and St variables, is altered in dogs with DCM. ANIMALS: Case records for 26 dogs; 14 with DCM and 12 healthy controls of comparable age and weight were reviewed. METHODS: A retrospective analysis was conducted of conventional echocardiography, 2-dimensional color TDI, and St imaging data. RESULTS: The DCM group was characterized by decreases in radial and longitudinal systolic velocity gradients of the left ventricular free wall (LVFW), radial and longitudinal absolute values of peak systolic St of the LVFW, and longitudinal systolic right ventricular (RV) velocities (all P < .001 versus control) associated with longitudinal postsystolic contraction waves in 7/14 dogs. Early diastolic LVFW velocities also were decreased for longitudinal (P < .01) and radial (P < .05) motions. All radial LVFW, longitudinal basal LVFW, and RV systolic velocities were negatively correlated with heart rate (P < .01). CONCLUSIONS AND CLINICAL IMPORTANCE: LV contractility along both the short and long axes is impaired in dogs with spontaneous DCM, as is systolic RV and diastolic LVFW function. These myocardial alterations are associated with an inverse force-frequency relationship. Studies now are needed to determine the comparative sensitivity of TDI and St variables for the early detection of canine DCM. PMID- 17708392 TI - The effects of age and heart rate on tricuspid annular motion velocities in healthy nonsedated cats. AB - BACKGROUND: Age and heart rate have effects on myocardial velocities as assessed by color tissue Doppler imaging (TDI) in people. A similar phenomenon has been identified when left ventricular velocities are assessed in cats. To date, the effects of age and heart rate on tricuspid annular velocities of cats have not been assessed. OBJECTIVES: This study was designed to determine the relationships between age and heart rate and tricuspid annular velocities in cats as assessed by 2-dimensional (2D) color TDI. ANIMALS: Fifty healthy nonsedated cats with age range from 3 months to 19 years old were studied. METHODS: Tricuspid annular velocities were obtained with 2D color TDI. Effects of age and heart rate on tricuspid annular velocities were evaluated by simple linear regression. The strength of the linear relationship was determined by using coefficient of determination (R2). RESULTS: A significant weak negative relationship was found between age and peak early diastolic annular velocity (E'; R2 = 0.135, P = .018). No significant relationships between age and right ventricular (RV) systolic TDI values were found. Diastolic and systolic TDI parameters were not affected by heart rate with the exception of deceleration rate of early diastolic motion (DR; R2 = 0.100, P = .025). CONCLUSIONS AND CLINICAL IMPORTANCE: Age and heart rate have minimal effects on tricuspid annular velocities. The present study provides reference ranges for tricuspid annular velocities in healthy cats and information for assessing the clinical utility of color TDI for evaluation of RV function in cats. PMID- 17708393 TI - Papillary muscle measurements in cats with normal echocardiograms and cats with concentric left ventricular hypertrophy. AB - BACKGROUND: Papillary muscle hypertrophy can occur in conjunction with, or as the only indication of, hypertrophic cardiomyopathy or other diseases that result in left ventricular concentric hypertrophy (LVCH). Assessment of papillary muscle size is usually subjective because objective measures have not been reported. HYPOTHESIS: The study hypothesis was that papillary muscle dimensions are different between normal cats and cats with LVCH. ANIMALS: Echocardiograms from 44 normal cats and 40 cats with LVCH were included in the study. METHODS: All measurements were taken from the right parasternal short-axis view at the level of the papillary muscles at end-diastole. Three methods were used to assess papillary muscle size: the area subtraction method, the direct area trace method, and the diameter method. Measurements were compared between cat groups and method comparisons were made among methods for area determination. RESULTS: Cats with LVCH were older and had significantly greater left ventricular septal and free wall thicknesses and larger left atrial measurements than normal cats (P < .0006). Papillary muscle measurements were significantly greater by all measurement methods in cats with LVCH than in cats with normal echocardiograms (P < .0001). The area subtraction method and direct area trace method showed moderate agreement. CONCLUSIONS AND CLINICAL IMPORTANCE: Papillary muscle measurements were larger for LVCH cats than normal cats; however, some overlap was present. The establishment of these objective measures adds to the echocardiographic examination of cats. PMID- 17708394 TI - Comparative adverse cardiac effects of pimobendan and benazepril monotherapy in dogs with mild degenerative mitral valve disease: a prospective, controlled, blinded, and randomized study. AB - BACKGROUND: Pimobendan (PIMO) is an inodilator that may have some beneficial effects in canine degenerative mitral valve disease (MVD). However, little information is available about its cardiac effects in dogs without systolic myocardial dysfunction. HYPOTHESIS: Compared to benazepril (BNZ), an angiotensin converting enzyme inhibitor, PIMO may worsen valve regurgitation in early canine MVD. ANIMALS: Twelve Beagles with asymptomatic MVD were randomized into 2 groups (n = 6) receiving BNZ or PIMO at dosages of 0.25 mg/kg PO q24h and q12h respectively, for 512 days. METHODS: The study followed a blinded, randomized, prospective, and parallel group design. After day 512, the dogs were necropsied, and cardiac histopathology was performed in a blinded manner. RESULTS: A significant treatment effect was observed as soon as day 15 with increased systolic function in the PIMO group by comparison to baseline value as assessed by fractional shortening (P < .0001) and tissue Doppler variables (P = .001). Concurrently, the maximum area and peak velocity of the regurgitant jet signal increased (P < .001), whereas these variables remained stable in the BNZ group. Histologic grades of mitral valve lesions were more severe in the PIMO group than in the BNZ group. Moreover, acute focal hemorrhages, endothelial papillary hyperplasia, and infiltration of chordae tendinae with glycosaminoglycans were observed in the mitral valves of dogs from the PIMO group but not in those of the BNZ group. CONCLUSIONS AND CLINICAL IMPORTANCE: PIMO has adverse cardiac functional and morphologic effects in dogs with asymptomatic MVD. Additional investigation in dogs with symptomatic MVD is now warranted. PMID- 17708395 TI - Premature death, risk factors, and life patterns in dogs with epilepsy. AB - BACKGROUND: Epilepsy in dogs is often difficult to medically control, resulting in premature death of dogs with epilepsy. However, the risks of premature death are not known. HYPOTHESIS: Dogs with epilepsy have an increased risk of premature death as compared to a general population of dogs. ANIMALS: Sixty-three dogs diagnosed with epilepsy between 1993 and 1996 were included in this study. METHODS: A prospective longitudinal study of the population was performed from the diagnosis of epilepsy until the time of euthanasia, death, or a maximum of 12 years to investigate mortality and risk factors. Information about sex, onset, type, frequency, and control of seizures, remission of epilepsy, death, cause of death, and owner's perspective was collected and analyzed. RESULTS: The median age at death of dogs was 7.0 years. The life span of dogs in which euthanasia or death was directly caused by their epileptic condition was significantly shorter as compared with epileptic dogs that were euthanized because of other causes (P = .001). The median number of years that a dog lived with epilepsy was 2.3 years. Females lived longer with epilepsy than males (P = .036). Seizure type (primary generalized versus focal seizures) was not significantly associated with survival time. The remission rate of epilepsy (spontaneous remission and remission with treatment) was 15%. CONCLUSION AND CLINICAL IMPORTANCE: The diagnosis of epilepsy implies an increased risk of premature death. The prognosis for dogs with epilepsy is dependent on a combination of veterinary expertise, therapeutic success, and the owner's motivation. PMID- 17708396 TI - Effects of L-asparaginase on plasma amino acid profiles and tumor burden in cats with lymphoma. AB - BACKGROUND: L-Asparaginase (Elspar(a)), is an Escherichia coli-derived enzyme that depletes lymphoma cells of asparagine, inhibiting protein synthesis and resulting in cell death. The single agent response rate in cats with lymphoma and impact of L-asparaginase on plasma amino acid concentrations is unknown. HYPOTHESES: L-Asparaginase significantly reduces plasma asparagine concentrations and has demonstrable efficacy against untreated lymphoma in cats. ANIMALS: Thirteen cats with confirmed lymphoma (LSA) of any anatomic site were given 1 dose 400 IU/kg IM) of L-asparaginase for initial LSA treatment. METHODS: Plasma collected at 0, 2, and 7 days after L-asparaginase therapy was assayed for ammonia, asparagine, aspartic acid, glutamine, and glutamic acid concentrations. Cats were restaged 7 days later to assess tumor response. RESULTS: Eight cats had T-cell LSA, 4 cats had B-cell LSA, and 1 cat's immunophenotype was unknown. Two complete and 2 partial responses to L-asparaginase were seen. Four cats had stable disease, and 5 cats had progressive disease. Ammonia and aspartic acid concentrations were increased from baseline at 2 and 7 days posttreatment. Asparagine concentrations were decreased from baseline at 2 days but not 7 days posttreatment. Glutamic acid concentrations were increased at day 2 compared to day 7 posttreatment but not compared to baseline. Glutamine concentrations were unchanged. CONCLUSIONS AND CLINICAL IMPORTANCE: L-asparaginase significantly reduced asparagine concentrations within 2 days of treatment, but this effect was lost within 7 days. The apparent overall response rate of feline LSA to L asparaginase in this study was 30%. PMID- 17708398 TI - Photodynamic therapy of feline cutaneous squamous cell carcinoma using a newly developed liposomal photosensitizer: preliminary results concerning drug safety and efficacy. AB - BACKGROUND: Squamous cell carcinomas are common skin tumors in cats. We investigated photodynamic therapy (PDT) using a new liposomal photosensitizer as a minimally invasive, effective treatment that can be easily performed while achieving good cosmetic results. AIM: The goal of this study was to assess and describe possible toxicities using a liposomal formulation of the photosensitizer meta-(Tetrahydroxyphenyl)Chlorin (m-THPC) and investigate if favorable pharmacokinetics translate into favorable tumor response and control. ANIMALS: Eighteen client-owned cats with 20 spontaneous cutaneous squamous cell carcinomas were included in the study. METHODS: PDT was performed using a new, liposomal formulation of the photosensitizer. Toxicity, tumor response, and tumor control were evaluated retrospectively. RESULTS: No general adverse effects were observed in cats treated with the new liposomal formulation. Mild local toxicity such as erythema and edema were seen in 15% of the patients. All cats responded to therapy, with a complete response rate of 100%. The overall 1-year control rate was 75%. The tumor recurrence rate was 20% with a median time to recurrence of 172.25 +/-87.1) days. CONCLUSIONS AND CLINICAL IMPORTANCE: A new liposomal photosensitizer was successfully used for squamous cell carcinoma in cats and was well tolerated. There were no systemic adverse effects observed with the liposomal formulation. The favorable pharmacokinetics of the liposomal drug resulted in a favorable tumor response. PMID- 17708397 TI - Continuous low-dose oral chemotherapy for adjuvant therapy of splenic hemangiosarcoma in dogs. AB - BACKGROUND: Hemangiosarcoma (HSA) is a highly metastatic and often rapidly fatal tumor in dogs. At present, conventional adjuvant chemotherapy provides only a modest survival benefit for treated dogs. Continuous oral administration of low dose chemotherapy (LDC) has been suggested as an alternative to conventional chemotherapy protocols. Therefore, we evaluated the safety and effectiveness of LDC using a combination of cyclophosphamide, etoposide, and piroxicam as adjuvant therapy for dogs with stage II HSA. HYPOTHESIS: We hypothesized that oral adjuvant therapy with LDC could be safely administered to dogs with HSA and that survival times would be comparable to those attained with conventional doxorubicin (DOX) chemotherapy. ANIMALS: Nine dogs with stage II splenic HSA were enrolled in the LDC study. Treatment outcomes were also evaluated retrospectively for 24 dogs with stage II splenic HSA treated with DOX chemotherapy. METHODS: Nine dogs with stage II splenic HSA were treated with LDC over a 6-month period. Adverse effects and treatment outcomes were determined. The pharmacokinetics of orally administered etoposide were determined in 3 dogs. Overall survival times and disease-free intervals were compared between the 9 LDC-treated dogs and 24 DOX-treated dogs. RESULTS: Dogs treated with LDC did not develop severe adverse effects, and long-term treatment over 6 months was well-tolerated. Oral administration of etoposide resulted in detectable plasma concentrations that peaked between 30 and 60 minutes after dosing. Both the median overall survival time and the median disease-free interval in dogs treated with LDC were 178 days. By comparison, the overall survival time and disease-free interval in dogs treated with DOX were 133 and 126 days, respectively. CONCLUSIONS: Continuous orally administered LDC may be an effective alternative to conventional high-dose chemotherapy for adjuvant therapy of dogs with HSA. PMID- 17708399 TI - Regulation of COX-2 expression in canine prostate carcinoma: increased COX-2 expression is not related to inflammation. AB - BACKGROUND: Cyclooxygenase-2 (COX-2) expression has been documented in human and canine prostate carcinoma (PCA). Canine PCA is a histologically heterogeneous tumor, sometimes including inflammatory infiltrates. However, it is unknown whether COX-2 expression in canine PCA is related to the histologic type of tumor, to the presence of inflammation, or to both. Moreover, little is known about the mechanisms regulating COX-2 expression in neoplastic tissue. HYPOTHESIS: COX-2 expression is related to the presence of inflammation in canine PCA and correlates with the degree of tumor differentiation. METHODS: The expression of COX-2 was examined in 28 cases of canine PCA by immunohistochemistry. In addition, a neoplastic and a nonneoplastic canine prostatic cell line were used to investigate the effects of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), phorbol 12-myristate 13-acetate (PMA), epithelial growth factor (EGF), and specific signal transduction pathway inhibitors on COX-2 expression. RESULTS: Twenty-four of the 28 prostate tumors showed COX-2 expression. The presence of inflammatory infiltrates in tumor tissue was associated with lower COX-2 expression scores. In vitro, TNF-alpha, IL-6, and EGF increased COX-2 expression in nonneoplastic cells but not in PCA cells, where baseline expression was high. COX-2 expression in PCA cells could be suppressed by means of specific phosphatidyl inositol-3 kinase (PI3K), protein kinase C (PKC), or inhibitor of extracellular signal-related kinase (ERK/MAPK) inhibitors. CONCLUSIONS AND CLINICAL IMPORTANCE: COX-2 is expressed in canine PCA; however, expression is not related to the presence of inflammatory infiltrates. This conclusion is further supported by the finding that the cytokines TNF-alpha and IL-6 and their involved signaling pathways do not stimulate COX-2 expression in malignant canine prostate cells. PMID- 17708400 TI - Doxorubicin and BAY 12-9566 for the treatment of osteosarcoma in dogs: a randomized, double-blind, placebo-controlled study. AB - BACKGROUND: This study was designed to assess the efficacy of a matrix metalloproteinase inhibitor in prolonging posttreatment survival for dogs with appendicular osteosarcoma after treatment with amputation and doxorubicin chemotherapy. HYPOTHESIS: Survival will be prolonged in dogs receiving BAY 12 9566. ANIMALS: The study included 303 dogs with appendicular osteosarcoma. METHODS: Dogs were treated with doxorubicin (30 mg/m2) every 2 weeks for 5 treatments starting 2 weeks after amputation. Dogs were randomly allocated to receive a novel nonpeptidic biphenyl inhibitor of matrix metalloproteinases (MMPs, BAY 12-9566; 4-[4-4-(chlorophenyl)phenyl]-4-oxo-2S-(phenylthiomethyl) butanoic acid) or placebo after doxorubicin chemotherapy. RESULTS: Median survival for all 303 dogs was 8 months; and 1-year, 2-year, and 3-year survival rates were 35%, 17%, and 9%, respectively. Treatment with BAY 12-9566 did not influence survival. Multivariate analysis revealed that increasing age (P = .004), increasing weight (P = .006), high serum alkaline phosphatase (ALP) (P = .012) and high bone ALP (P < .001) were independently associated with shorter median survival times. Additional analyses on available data indicated that as the number of mitotic figures in the biopsy increased (P = .013), and as plasma active MMP-2 concentrations increased (P = .027), the risk of dying increased. CONCLUSIONS AND CLINICAL IMPORTANCE: Doxorubicin is an effective adjuvant to amputation in prolonging survival for dogs with appendicular osteosarcoma. PMID- 17708401 TI - Plasma adrenocorticotropin, cortisol, and adrenocorticotropin/cortisol ratios in septic and normal-term foals. AB - BACKGROUND: Little information exists on the hypothalamic-pituitary-adrenal axis in septic foals. HYPOTHESIS: The plasma concentrations of adrenocorticotropin (ACTH) and cortisol are expected to be higher in septic foals as compared to normal foals. The concentrations of hormones in septic foals also are expected to differ further depending upon survival. ANIMALS: Twenty-eight control foals and 46 septic foals <14 days of age were included in this study. METHODS: Blood was collected in EDTA once from 28 normal foals born in the University of Georgia or Cornell University equine research herds and from 46 septic foals within 12 hours after admission to 1 of the 3 tertiary care referral centers involved in the study. Septic foal selection was based on a sepsis score of >11 or a positive blood culture. The control foals were age matched to the septic foals in the study. ACTH and cortisol concentrations were measured by a chemiluminescent immunoassay system. RESULTS: Cortisol concentrations in control foals did not vary with age. Septic foals had significantly higher mean ACTH, cortisol, and ACTH/cortisol ratios than did normal foals. Within the septic foal group, 28 foals survived to discharge, and 18 were euthanized or died. The mean age was not significantly different between the septic surviving and nonsurviving foals. The mean ACTH/cortisol ratio was significantly higher in the septic nonsurviving foals as compared to the septic surviving foals. CONCLUSIONS AND CLINICAL IMPORTANCE: Septic foals had higher hormone concentrations as compared to normal foals, which is an expected endocrine response to critical illness. The increased ACTH/cortisol ratio in nonsurviving septic foals in comparison to surviving septic foals could indicate hypothalamic-pituitary-adrenal axis dysfunction at the level of the adrenal gland in critically ill septic foals. PMID- 17708403 TI - Humoral immune responses in the horse after intrathecal challenge with ovalbumin. AB - BACKGROUND: Diagnosis of neuro-inflammatory conditions in the horse can be challenging. Current methods include evaluation of cerebrospinal fluid (CSF) for inflammation and determination of specific antibody status. The antibody index (AI) and Goldman-Witmer coefficient (C-value) can be used to aid in the interpretation. HYPOTHESIS: The null hypothesis to be tested was that the Al and C-values do not change in horses with neuroinflammation. ANIMALS: Twelve horses of various ages (3-17 years) and breeds (Thoroughbred, Thoroughbred cross, draft, and Arabian) were included in the study. METHODS: The study was designed as a prospective randomized study. All horses were immunized with ovalbumin in adjuvant, twice. Horses of Group 1 then were challenged by intrathecal (IT) injection of ovalbumin, whereas horses of Group 2 were challenged IM. The Al and C-values for ovalbumin and equine herpesvirus were calculated. RESULTS: The Al for ovalbumin increased up to 5.92 in horses after intrathecal challenge, and remained normal (<1) in horses challenged IM. The C-value for ovalbumin reached a peak of 7.48, whereas for equine herpesvirus it achieved a value of 2.69. The changes in ovalbumin C-value and AI were significantly different between days 20 and 30 in horses after intrathecal challenge at day 20 (P = .002 and .0005, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: The results confirm the value of the Al and C-value in the evaluation of neuroinflammation in the horse. PMID- 17708402 TI - Serum opsonization capacity, phagocytosis, and oxidative burst activity in neonatal foals in the intensive care unit. AB - BACKGROUND: Phagocytic activity of neonatal foals has been reported to be similar to that of adult horses, but serum opsonization capacity develops with age and may be further altered when opsonins are consumed during infection. HYPOTHESIS: Phagocytosis, oxidative burst activity, and serum opsonization capacity in neonatal foals admitted to an intensive care unit are reduced in comparison with control foals. ANIMALS: Blood samples were collected from hospitalized neonatal foals and from control foals. Hospitalized foals were characterized as sick or septic on the basis of a sepsis score and received intravenous plasma transfusion. METHODS: Phagocytosis, oxidative burst activity, and serum opsonization capacity were tested with flow cytometric analysis. Serum immunoglobulin and complement component 3 concentrations were determined with radial immunodiffusion. Serum amyloid A concentration was assayed with a commercially available solid-phase Sandwich ELISA Kit. Data were analyzed with nonparametric and regression methods. Alpha was set at P = .05. RESULTS: Phagocytic functions of septic and sick foals were lower than control foals in the initial phase of the study (P = .01). Opsonization capacity was significantly higher when bacteria were opsonized with serum from septic (P = .029) and sick (P = .006) foals than from control foals on day 1. Opsonization capacity in septic foals was comparable with control foals on days 2 and 5. This effect was not accompanied by an increase in serum complement C3 or immunoglobulin G concentrations independently. CONCLUSIONS AND CLINICAL IMPORTANCE: Our results suggest that phagocytic function could be decreased in hospitalized foals. The synergistic effect of opsonic elements provided by plasma transfusion may sustain opsonization capacity during sepsis. PMID- 17708404 TI - Confirmed and presumptive cervical vertebral compressive myelopathy in older horses: a retrospective study (1992-2004). AB - BACKGROUND: Cervical vertebral compressive myelopathy (CVCM) is a common cause of myelopathy in horses aged 6 months to 4 years. Little information is available regarding the types of lesions, treatment, and outcomes in horses with CVCM that are > or =4 years old. ANIMALS: Twenty-two affected horses (10 with a confirmed diagnosis of CVCM and 12 presumptive cases) and 210 contemporaneous control horses. METHODS: Horses > or =4 years old that were diagnosed with CVCM between January 1992 and January 2004 were identified from medical records at Texas A&M University and the University of Florida. Data analyzed included history, signalment, neurologic examination findings, lesion location, treatment, and outcome. Signalment was also recorded in a population of contemporaneous controls. RESULTS: Horses identified had a median age of 8.4 years, and there was a greater percentage of male horses among the cases than among the controls. The most common breeds represented were warmblood (n=6) and quarter horse (n=5) types; warmbloods were significantly (P < .05) overrepresented relative to control horses. The caudal cervical vertebral column was the most common site of CVCM lesions, and the C5-C6 (4/9) and C6-C7 (3/9) articulations were most often identified as abnormal via myelography. The most common lesions seen with radiography and myelography were articular process osteophytes. Of the 22 affected horses, 8 were euthanized and a diagnosis of CVCM was confirmed by necropsy for all; 5 of 8 of these horses had spinal cord compression caused, entirely or in part, by articular process osteophytes. Medical management was the therapy chosen in all horses, and administration of corticosteroids and nonsteroidal anti-inflammatory drugs resulted in improvement in the greatest number of horses. CONCLUSIONS AND CLINICAL IMPORTANCE: CVCM should be a differential diagnosis in older horses with cervical myelopathy. Articular process osteophytes are the most frequently identified cause of spinal cord compression in this group. Male horses and horses of warmblood or Tennessee Walking Horse breeds may be predisposed to this condition. PMID- 17708405 TI - Echocardiographic evidence of left atrial mechanical dysfunction after conversion of atrial fibrillation to sinus rhythm in 5 horses. AB - BACKGROUND: Atrial contractile dysfunction occurs in some species after conversion of atrial fibrillation (AF) to normal sinus rhythm (NSR) but has not been reported in horses with naturally occurring AF. HYPOTHESIS: Transthoracic echocardiography allows detection of left atrial (LA) mechanical dysfunction in horses after conversion of AF to NSR. ANIMALS: Five Standardbreds with AF and 6 healthy Standardbreds of similar age, weight, and athletic condition were included in this study. METHODS: Four horses were treated pharmacologically (quinidine), and 1 horse was treated by means of transvenous electrical cardioversion. Echocardiographic examinations were performed in normal horses (once) and in AF horses (24 hours and 72 hours after conversion to NSR) by means of 2-dimensional echocardiography (2DE), transmitral flow Doppler, and tissue Doppler imaging (TDI) techniques. Echocardiographic indices of LA mechanical function were compared between normal horses and AF horses. RESULTS: Two dimensional echocardiography and TDI indices of LA mechanical function revealed significant decreases in LA contractile function and LA reservoir function 24 hours after cardioversion. This decrease was no longer statistically significant 72 hours after cardioversion, but changes in echocardiographic variables between 24 and 72 hours varied among horses. CONCLUSIONS AND CLINICAL IMPORTANCE: LA contractile dysfunction can be evaluated in horses by use of 2DE, transmitral Doppler flow velocity profiles, and analyses of LA wall motion by TDI. The results of this study are consistent with AF-induced atrial remodeling, although residual treatment effects or influence of underlying primary myopathy cannot be excluded. PMID- 17708406 TI - Use of Fourier-transform infrared spectroscopy for the diagnosis of failure of transfer of passive immunity and measurement of immunoglobulin concentrations in horses. AB - BACKGROUND: The economic, accurate, and rapid screening of foals for failure of transfer of passive immunity (FPT) is essential to ensure timely intervention. HYPOTHESIS: Infrared (IR) spectroscopy of foal sera and pattern recognition may be used to diagnose FPT and quantify serum IgG. SAMPLES: Sera from 194 foals (24 72 hours) with serum immunoglobulin G (IgG) concentrations determined previously by radial immunodiffusion assay (RID) were used. METHODS: IR spectra were recorded for the serum samples, and the data were randomly divided into training and independent test sets, each containing both FPT-positive (IgG <400 mg/dL) and non-FPT samples. A genetic optimal region selection algorithm and linear discriminant analysis were used to partition the training spectra, and the resulting classifier was then validated by comparing the IR-predicted FPT status for each of the test samples to that provided by the RID IgG assay. A quantitative IR-based assay for IgG was developed using partial least squares (PLS) and validated by testing its ability to predict IgG concentrations. RESULTS: Specificity, sensitivity, and accuracy for the combined data were 92.5, 96.8, and 95.9%, respectively. Corresponding positive (88.1%) and negative predictive (98.0%) values determined a success rate of 95-97% as compared to RID based IgG concentrations. The IR-based quantitative assay yielded correlation coefficients for IR spectroscopy versus RID-based IgG concentrations of 0.90 and 0.86 for the training and test sets, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: The overall performance of the IR-based test was similar to that of the colorimetric assay and was superior and more economic than other available tests. PMID- 17708407 TI - Clinicopathologic evaluation of hepatic lipidosis in periparturient dairy cattle. AB - BACKGROUND: Fatty change of the liver (FCL) is very common in dairy cattle periparturiently. Many laboratory methods have been implicated in order to assist the diagnosis. HYPOTHESIS: To investigate whether FCL in dairy cattle could be evaluated by assessment of ornithine carbamoyl transferase (OCT) by means of an assay modified for bovine serum, other enzyme activity, serum bile acids (SBA) concentration, or other biochemical constituents. ANIMALS: A total of 187 dairy cattle were included: 106 were suspected to have liver dysfunction and were examined after referral by veterinarians; 70 were clinically healthy with mild FCL; and 11 were clinically healthy without FCL. METHODS: Blood and liver biopsy samples were obtained after clinical examination. Histologic examination by light microscopy and classification of samples according to the severity of FCL was done, and total lipid and triglyceride concentration was measured. In serum, OCT, aspartate aminotransferase (AST), alanine aminotransferase (ALT), sorbitol dehydrogenase (SDH), glutamate dehydrogenase (GDH), alkaline phosphatase (ALP), and gamma-glutamyltransferase (gamma-GT) activity as well as SBA, glucose, ketones, total bilirubin (tBIL), and nonesterified fatty acids (NEFA) concentration were measured. RESULTS: OCT and AST activity and tBIL concentration correlate well with the degree of FCL. SBA concentration does not contribute well to FCL diagnosis. The majority of FCL cases appeared within the first 21 days-in milk (DIM). The majority of moderate-to-severe and severe FCL cases arose in the first 7 DIM. CONCLUSIONS AND CLINICAL IMPORTANCE: Except for OCT, AST, and tBIL, none of the biochemical tests used, including SBA, had sufficient discriminatory power to differentiate reliably between mild and severe FCL because of poor sensitivity. A weak correlation between clinical signs and the extent of FCL was evident. PMID- 17708408 TI - Eastern equine encephalitis in 9 South American camelids. AB - BACKGROUND: Eastern equine encephalitis (EEE) virus is a mosquito-borne togavirus (alphavirus) that causes severe (often fatal) encephalitis in many mammalian species, but it has not been reported previously in South American camelids. HYPOTHESIS: South American camelids can become naturally infected with EEE virus and show encephalitic signs similar to those observed in other affected species. ANIMALS: Nine cases (8 alpacas and 1 llama, aged 3.5 weeks to 12 years) were identified; 4 of 9 were 510 weeks old. All cases were from the East Coast of the United States and presented in late summer and fall. METHODS: A retrospective study was performed to include confirmed cases of EEE in camelids in North America before 2006. RESULTS: Eight of nine (89%) camelids died or were euthanized in extremis, with the mean time to death of 2 days. Clinical signs were consistent with encephalitis and included fever, lethargy, ataxia, seizures, recumbency, torticollis, opisthotonus, and vestibular signs. No consistent hematologic abnormalities were identified, and cerebrospinal fluid contained an increased protein concentration in the single camelid analyzed. No successful therapy was identified. EEE was confirmed by alphavirus detection by using immunohistochemistry (IHC) and polymerase chain reaction (PCR) in the central nervous system (CNS) and by serology. Findings included polioencephalitis with lymphocytic perivascular cuffing; neutrophil infiltration; gliosis; neuron satellitosis; necrosis; and edema, with intracytoplasmic alphavirus within neurons and glial cells. No virus was detected in extraneural tissues. CONCLUSIONS AND CLINICAL IMPORTANCE: In endemic areas, EEE should be considered a differential diagnosis for young and adult camelids with CNS disease. Brain histopathology with indirect IHC or PCR is diagnostic. PMID- 17708409 TI - Liver abscesses in Holstein dairy cattle: 18 cases (1992-2003). AB - BACKGROUND: The characteristic clinical manifestations, clinicopathologic findings, treatment, and outcome of dairy cattle with liver abscess are poorly defined. ANIMALS: The study included 18 Holstein cows with liver abscesses. METHODS: A retrospective study of medical records was performed. Cattle with liver abscess were identified by ultrasound examination or exploratory laparotomy. RESULTS: The most common reason for examination was anorexia (14/18). Five cows had fever, 5 were bradycardic, and 5 were tachycardic. Peritonitis (n=6) and vagal indigestion (n=4) were the most frequently associated diseases. Neutrophilia (n=14), hyperfibrinogenemia (n=11), and high serum globulin concentration (n=10) were characteristic of chronic inflammation. Evidence of liver disease on serum biochemistry profile was uncommon. The most common bacterium isolated from the abscess was Arcanobacterium pyogenes (n=4). Anaerobic bacteria were isolated frequently (n=7). There were 6 polymicrobial isolates, with both aerobic and anaerobic bacteria, out of 8 positive samples. Medical treatment was successful in 5 of 7 cattle. Five cows were euthanized and postmortem examination revealed 2 cattle with thrombosis of caudal vena cava. CONCLUSIONS AND CLINICAL IMPORTANCE: Holstein dairy cattle affected by liver abscess exhibit no pathognomonic clinical signs. Clinicopathologic findings were often consistent with a chronic active inflammation. Liver abscesses should be included in the differential diagnosis in cattle with a chronic inflammatory process, cranial peritonitis, or vagal indigestion. Prolonged treatment with antimicrobials might be successful. PMID- 17708410 TI - Resolution of acute kidney injury in a cat after lily (Lilium lancifolium) intoxication. PMID- 17708411 TI - Spinal intramedullary aberrant Spirocerca lupi migration in 3 dogs. PMID- 17708412 TI - Magnetic resonance imaging findings in metabolic and toxic disorders of 3 small ruminants. PMID- 17708414 TI - Diagnosis and treatment of a selective immunoglobulin M glomerulonephropathy in a quarter horse gelding. PMID- 17708413 TI - Treatment of doxorubicin extravasation with intravenous dexrazoxane in a cat. PMID- 17708415 TI - Treatment with amiodarone of refractory ventricular tachycardia in a horse. PMID- 17708416 TI - When half is not enough: gene expression and dosage in the 22q11 deletion syndrome. AB - The 22q11 Deletion Syndrome (22q11DS, also known as DiGeorge or Velo-Cardio Facial Syndrome) has a variable constellation of phenotypes including life threatening cardiac malformations, craniofacial, limb, and digit anomalies, a high incidence of learning, language, and behavioral disorders, and increased vulnerability for psychiatric diseases, including schizophrenia. There is still little clear understanding of how heterozygous microdeletion of approximately 30 50 genes on chromosome 22 leads to this diverse spectrum of phenotypes, especially in the brain. Three possibilities exist: 1) 22q11DS may reflect haploinsufficiency, homozygous loss of function, or heterozygous gain of function of a single gene within the deleted region; 2) 22q11DS may result from haploinsufficiency, homozygous loss of function, or heterozygous gain of function of a few genes in the deleted region acting at distinct phenotypically compromised sites; 3) 22q11DS may reflect combinatorial effects of reduced dosage of multiple genes acting in concert at all phenotypically compromised sites. Here, we consider evidence for each of these possibilities. Our review of the literature, as well as interpretation of work from our laboratory, favors the third possibility: 22q11DS reflects diminished expression of multiple 22q11 genes acting on common cellular processes during brain as well as heart, face, and limb development, and subsequently in the adolescent and adult brain. PMID- 17708418 TI - Expression pattern for unc5b, an axon guidance gene in embryonic zebrafish development. AB - Branching processes such as nerves and vessels share molecular mechanisms of path determination. Our study focuses on unc5b, a member of the unc5 axon guidance gene family. Here, we have cloned the full-length zebrafish ortholog of unc5b, mapped its chromosome location in the zebrafish genome, and compared its expression patterns to robo4, another axon guidance family member. In situ show that unc5b is expressed predominantly in sensory structures such as the eye, ear, and brain. Both unc5b and robo4 show robust expression in all three compartments of the embryonic brain, namely forebrain, midbrain, and hindbrain. In particular, the hindbrain rhombomere expression displays interesting patterns in that robo4 is expressed in medial rhombomere cell clusters when compared to unc5b expressed in lateral rhombomere clusters. A similar medial-lateral theme is observed in other neural structures such as the neural tube. Our expression analysis provides a starting point for studying the role of axon guidance genes in embryonic hindbrain patterning. PMID- 17708417 TI - Guarding the blood-brain barrier: a role for estrogen in the etiology of neurodegenerative disease. AB - Although the effect of estrogen replacement therapy on the incidence of the neurodegenerative disease such as Alzheimer's disease is controversial, experimental studies indicate that estrogen replacement to young adult animals is neuroprotective and that perimenopausal estrogen replacement is associated with a decreased incidence of Alzheimer's disease. Estrogen affects a wide variety of cellular processes that can protect neuronal health. This article considers the disruption of the blood-brain barrier in Alzheimer's disease and forwards the hypothesis that estrogen may preserve neural health by maintaining the integrity of the blood-brain barrier. PMID- 17708421 TI - Old think. PMID- 17708422 TI - Some challenges for physician leadership. PMID- 17708419 TI - Dominant-negative suppression of big brain ion channel activity by mutation of a conserved glutamate in the first transmembrane domain. AB - The neurogenic protein Drosophila big brain (BIB), which is involved in the process of neuroblast determination, and the water channel aquaporin-1 (AQP1) are among a subset of the major intrinsic protein (MIP) channels that have been found to show gated monovalent cation channel activity. A glutamate residue in the first transmembrane (M1) domain is conserved throughout the MIP family. Mutation of this residue to asparagine in BIB (E71N) knocks out ion channel activity, and when coexpressed with BIB wild-type as shown here generates a dominant-negative effect on ion channel function, measured in the Xenopus oocyte expression system using two-electrode voltage clamp. cRNAs for wild-type and mutant BIB or AQP1 channels were injected individually or as mixtures. The magnitude of the BIB ionic conductance response was greatly reduced by coexpression of the mutant E71N subunit, suggesting a dominant-negative mechanism of action. The analogous mutation in AQP1 (E17N) did not impair ion channel activation by cGMP, but did knock out water channel function, although not via a dominant-negative effect. This contrast in sensitivity between BIB and AQP1 to mutation of the M1 glutamate suggests the possibility of interesting structural differences in the molecular basis of the ion permeation between these two classes of channels. The dominant negative construct of BIB could be a tool for testing a role for BIB ion channels during nervous system development in Drosophila. The neurogenic protein Drosophila big brain (BIB), which is involved in the process of neuroblast determination, and the water channel aquaporin-1 (AQP1) are among a subset of the major intrinsic protein (MIP) channels that have been found to show gated monovalent cation channel activity. A glutamate residue in the first transmembrane (M1) domain is conserved throughout the MIP family. Mutation of this residue to asparagine in BIB (E71N) knocks out ion channel activity, and when coexpressed with BIB wild-type as shown here generates a dominant-negative effect on ion channel function, measured in the Xenopus oocyte expression system using two-electrode voltage clamp. cRNAs for wild-type and mutant BIB or AQP1 channels were injected individually or as mixtures. The magnitude of the BIB ionic conductance response was greatly reduced by coexpression of the mutant E71N subunit, suggesting a dominant-negative mechanism of action. The analogous mutation in AQP1 (E17N) did not impair ion channel activation by cGMP, but did knock out water channel function, although not via a dominant-negative effect. This contrast in sensitivity between BIB and AQP1 to mutation of the M1 glutamate suggests the possibility of interesting structural differences in the molecular basis of the ion permeation between these two classes of channels. The dominant negative construct of BIB could be a tool for testing a role for BIB ion channels during nervous system development in Drosophila. PMID- 17708420 TI - Gene expression analysis in myotonic dystrophy: indications for a common molecular pathogenic pathway in DM1 and DM2. AB - An RNA gain-of-function of expanded transcripts is the most accredited molecular mechanism for myotonic dystrophy type 1 (DM1) and 2 (DM2). To disclose molecular parallels and divergences in pathogenesis of both disorders, we compared the expression profile of muscle biopsies from DM1 and DM2 patients to controls. DM muscle tissues showed a reduction in the major skeletal muscle chloride channel (CLCN1) and transcription factor Sp1 transcript levels and an abnormal processing of the CLCN1 and insulin receptor (IR) pre-mRNAs. No essential differences were observed in the muscle blind-like gene (MBNL1) and CUG binding protein 1 (CUGBP1) transcript levels as well as in the splicing pattern of the myotubularin-related 1 (MTMR1) gene. Macroarray analysis of 96 neuroscience-related genes revealed a considerable similar expression profile between the DM samples, reflective of a common muscle pathology origin. Using a twofold threshold, we found six misregulated genes important in calcium and potassium metabolism and in mitochondrial functions. Our results indicate that the DM1 and DM2 overlapping clinical phenotypes may derive from a common trans acting mechanism that traps and influences shared genes and proteins. An RNA gain-of-function of expanded transcripts is the most accredited molecular mechanism for myotonic dystrophy type 1 (DM1) and 2 (DM2). To disclose molecular parallels and divergences in pathogenesis of both disorders, we compared the expression profile of muscle biopsies from DM1 and DM2 patients to controls. DM muscle tissues showed a reduction in the major skeletal muscle chloride channel (CLCN1) and transcription factor Sp1 transcript levels and an abnormal processing of the CLCN1 and insulin receptor (IR) pre-mRNAs. No essential differences were observed in the muscle blind-like gene (MBNL1) and CUG binding protein 1 (CUGBP1) transcript levels as well as in the splicing pattern of the myotubularin-related 1 (MTMR1) gene. Macroarray analysis of 96 neuroscience-related genes revealed a considerable similar expression profile between the DM samples, reflective of a common muscle pathology origin. Using a twofold threshold, we found six misregulated genes important in calcium and potassium metabolism and in mitochondrial functions. Our results indicate that the DM1 and DM2 overlapping clinical phenotypes may derive from a common trans acting mechanism that traps and influences shared genes and proteins. PMID- 17708423 TI - Part X. Tetracycline and glycylcycline antimicrobials. PMID- 17708424 TI - [Histological comparison of different biopolymers in osseous defects]. AB - The goal of this animal study in Goettingen minipigs was to compare Ethisorb with its modification Ethisorb Rapid where the hydrolytic degradation process has started, with respect to degradation and bony substitution qualitites. For comparison, both biopolymers were implanted with and without addition of autogenic spongiosa chips in comparison with blank defects in metaphysis of the tibia. The animals were killed after six, 12, 26 and 52 weeks. Undecalcified bone cuts were obtained and subjected to a histomorphometric and histomorphological analysis. All in all, with increasing time after implantation a continuous decrease of the density of trabecula could be observed. In comparison to Ethisorb Rapid and blank defects, the implantation of the slowly degrading but quickly resorbing Ethisorb led to statistically significantly higher densities of trabecula (Tuckey Test, p < or = 0.05) and to best bone regeneration. In contrast to this, Ethisorb Rapid could be degraded more quickly but resorbed more slowly. In the polarizing microscope, Ethisorb could still be detected after 12 weeks of implantation. Ethisorb Rapid could still be detected after 26 weeks of implantation. To conclude, Ethisorb proved to be a suitable scaffold for autogenic spongiosa-chips in critical-size defects of the tibia so that a multiloculated bone regeneration could be obtained. PMID- 17708425 TI - [High risk lesions of the oral mucosa--Diagnosis, therapy and follow-up in two cases]. AB - Stomatologic lesions at risk to develop an oral squamous cell carcinoma (OSCC) such as oral leukoplakia, erythroplakia/erythroleukoplakia, or oral lichen planus, need an early detection, diagnosis and a long-term/lifelong follow-up to prevent malignant transformation. In the following report, two patients are presented with oral mucosal lesions, who were referred, diagnosed, treated, and underwent follow-up examinations at the Stomatology Service of the Department of Oral Surgery and Stomatology at the University of Bern. These two cases emphasize the importance of early detection and managment of precancerous lesions or initial stages of OSCC. Additionally, risk factors, such as tobacco and alcohol consumption and their influence on stomatologic lesions and their prognosis, will be discussed. PMID- 17708426 TI - [Malnutrition in the elderly--a interdisciplinary problem for the dentist]. AB - Success in dental treatment and long-term care of elderly persons requires an interdisciplinary consideration of aging. Medical knowledge, which is far beyond specific dental expertise, is assumed. A typical example is that of malnutrition, which in spite of its high frequency in the elderly, has not yet been considered to be important in dentistry. Missing diagnosis and therapy of malnutrition lead to increasing morbidity and mortality. Clarifying the nutritional conditions of aging persons therefore should also become a part of dental diagnosis to guarantee early medical diagnosis and therapy as well as to avoid oral complications. PMID- 17708427 TI - Defining systems biology: an engineering perspective. PMID- 17708428 TI - Modelling the CheY(D10K,Yl00W) Halobacterium salinarum mutant: sensitivity analysis allows choice of parameter to be modified in the phototaxis model. AB - A recent phototaxis model of Halobacterium salinarum composed of the signalling pathway and the switch complex of the motor explained all considered experimental data on spontaneous switching and response time to repellent or attractant light stimuli. However, the model which considers symmetric processes in the clockwise and counter-clockwise rotations of the motor cannot explain the behaviour of a CheY(D10K,Yl00W) mutant which always moves forward and does not respond to light. We show that the introduction of asymmetry in the motor switch model can explain this behaviour. Sensitivity analysis allowed us to choose parameters for which the model is sensitive and whose values we then change in either direction to obtain an asymmetric model. We also demonstrate numerically that at low concentrations of CheYP, the symmetric and asymmetric models behave similarly, but at high concentrations, differences in the clockwise and counter-clockwise modes become apparent. Thus, those experimental data that could previously be explained only by ad hoc assumptions are now obtained 'naturally' from the revised model. PMID- 17708430 TI - Conservation laws and unidentifiability of rate expressions in biochemical models. AB - New experimental techniques in bioscience provide us with high-quality data allowing quantitative mathematical modelling. Parameter estimation is often necessary and, in connection with this, it is important to know whether all parameters can be uniquely estimated from available data, (i.e. whether the model is identifiable). Dealing essentially with models for metabolism, we show how the assumption of an algebraic relation between concentrations may cause parameters to be unidentifiable. If a sufficient data set is available, the problem with unidentifiability arises locally in individual rate expressions. A general method for reparameterisation to identifiable rate expressions is provided, together with a Mathematica code to help with the calculations. The general results are exemplified by four well-cited models for glycolysis. PMID- 17708429 TI - Simultaneous high gain and wide dynamic range in a model of bacterial chemotaxis. AB - Mathematical modelling and sensitivity analysis of the signal transduction pathway underlying chemotaxis in Escherichia coli suggests a mechanism for high sensitivity over a dynamic range of five orders of magnitude. The analysis reveals that the enhancement in sensing ability occurs in the signal receiving module that is comprised of ligand binding, change of occupancy and change of receptor activities. The clustering of receptors contributes to the signal capability by exploiting interactions between receptors for the activity change. The role of the autophosphorylation of the histidine kinase CheA and the phosphotransfer to the response regulator protein CheY is to relay the signal to the cell's motor apparatus at little expense to the sensitivity at low stimuli. The results also provide insight on the values of kinetic parameters that maximise the efficiency of the signalling pathway. PMID- 17708431 TI - Dynamical robustness of biological networks with hierarchical distribution of time scales. AB - Concepts of distributed robustness and r-robustness proposed by biologists to explain a variety of stability phenomena in molecular biology are analysed. Then, the robustness of the relaxation time using a chemical reaction description of genetic and signalling networks is discussed. First, the following result for linear networks is obtained: for large multiscale systems with hierarchical distribution of time scales, the variance of the inverse relaxation time (as well as the variance of the stationary rate) is much lower than the variance of the separate constants. Moreover, it can tend to 0 faster than 1/n, where n is the number of reactions. Similar phenomena are valid in the nonlinear case as well. As a numerical illustration, a model of signalling network is used for the important transcription factor NFkappaB. PMID- 17708432 TI - Family tree of Markov models in systems biology. AB - Motivated by applications in systems biology, a probabilistic framework based on Markov processes is proposed to represent intracellular processes. The formal relationships between different stochastic models referred to in the systems biology literature are reviewed. As part of this review, a novel derivation of the differential Chapman-Kolmogorov equation for a general multidimensional Markov process made up of both continuous and jump processes, is presented. First, the definition of a time-derivative for a probability density is focused, but placing no restrictions on the probability distribution, in particular, it is not assumed to be to be confined to a region that has a surface (on which the probability is zero). In this derivation, the master equation gives the jump part of the Markov process and the Fokker-Planck equation gives the continuous part. As a result, a 'family tree' for stochastic models in systems biology is sketched, providing explicit derivations of their formal relationship and clarifying assumptions involved. PMID- 17708433 TI - Studies on betaxanthin profiles of vegetables and fruits from the Chenopodiaceae and Cactaceae. AB - The present study provides an update on the betaxanthin (bx) compositions of red and yellow beetroots, yellow-coloured Swiss chard petioles, and yellow-orange cactus pear. Applying RP-HPLC coupled with positive ion electrospray mass spectrometry and by comparison with UV-vis and mass spectrometric characteristics as well as retention times of semi-synthesized reference compounds, 24 betaxanthins were identified in red and yellow beetroot hypocotyls. Twenty-five and thirteen betaxanthins were present in yellow Swiss chard petioles and the cactus pear cultivar 'Gialla', respectively. Ethanolamine-bx and threonine-bx were found to be novel betaxanthins in Chenopodiaceae representatives, which to the best of our knowledge have not been reported as genuine pigments so far. Furthermore, aspartic acid-bx (miraxanthin II), lysine-bx, and methionine-bx, hitherto found in other families, were identified in the Chenopodiaceae for the first time. Additionally, tyrosine-bx (portulacaxanthin II) and tryptophan-bx have not been earlier reported to occur in the Cactaceae. These findings provide valuable phytochemical information and may be useful for a better understanding of the functional properties of betaxanthins in plants. PMID- 17708434 TI - Cytotoxic cholestane and pregnane glycosides from Tribulus macropterus. AB - The methanol extract of the whole parts of Tribulus macropterus Boiss. (family Zygophyllaceae) showed cytotoxic activity against a human tumour cell line (hepatocyte generation 2, HepG2) (IC50 = 2.9 microg/ml). The n-butanolic fraction obtained from successive fractionation of the methanolic extract exhibited activity against HepG2 (IC50 = 2.6 microg/ml). Therefore, this fraction was subjected to separation using different chromatographic techniques. Five compounds, 1-5, were isolated and identified as: (22S,25S)-16beta,22,26 trihydroxy-cholest-4-en-3-one-16-O-beta-D-glucopyranosyl-(1-->3)-beta-D xylopyranoside (1), (22S,25S)-16beta,22,26-trihydroxy-cholest-4-en-3-one-16-O beta-D-glucopyranosyl-(1-->3)-beta-D-glucopyranoside (2), sucrose (3), D-pinitol (4) and 3beta-hydroxy-5a-pregn-16(17)en-20-one-3-O-beta-D-xylopyranosyl-(1-->2) [beta-D-xylopyranosyl-(1-->3)]-beta-D-glucopyranosyl-(1-->4)-[alpha-L rhamnopyranosyl-(1-->2)]-beta-D-ga-lactopyranoside (5) on the basis of spectroscopic and chemical data. The three steroidal compounds 1, 2 and 5 were also tested against the same cell line HepG2 and their IC50 values were 2.4, 2.2 and 1.1 microg/ml, respectively. PMID- 17708435 TI - Phenolic compounds with antioxidant activity from Anthemis tinctoria L. (Asteraceae). AB - From the aerial parts of Anthemis tinctoria L. subsp. tinctoria var. pallida DC. (Asteraceae), one new cyclitol glucoside, conduritol F-1-O-(6'-O-E-p-caffeoyl) beta-D-glucopyranoside (1), has been isolated together with four flavonoids, nicotiflorin (2), isoquercitrin (3), rutin (4) and patulitrin (5). The structures of the isolated compounds were established by means of NMR, MS, and UV spectral analyses. Methanolic extract and pure isolated compounds were examined for their free radical, scavenging activity, using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free stable radical, and for their inhibitory activity toward soybean lipoxygenase, using linoleic acid as substrate. Compounds 1 and 5 showed a strong scavenging effect in the DPPH radical assay. In addition 5 also exhibited high inhibitory activity on soybean lipoxygenase. PMID- 17708436 TI - Anti-cancer and immunostimulatory activity of chromones and other constituents from Cassia petersiana. AB - Phytochemical investigation of Cassia petersiana Bolle leaves afforded four new compounds, including two chromone derivatives, 7-acetonyl-5-hydroxy-2 methylchromone (petersinone 1, 1) and 7-(propan-2'-ol-l'-yl)-5-hydroxy-2 methylchromone (petersinone 2, 2), two benzoic acid derivatives, 5-methyl-3 (propan-2'-on-1'-yl) benzoic acid (petersinone 3, 3) and 5-(methoxymethyl)-3 (propan-2'-ol-1'-yl) benzoic acid (petersinone 4, 4), and glyceryl-1 tetracosanoate (6), in addition to the known compound sistosterol-3-beta-D glycoside (5). The structures of these compounds were determined by comprehensive NMR studies, including DEPT, COSY, HMQC, HMBC, MS and IR. Compounds 1, 2, 5 and 6 were tested for antioxidant, anti-cancer and immunostimulatory properties. The biological investigations indicated that compound 6, among others, possessed the highest anti-cancer activity against hepatocellular carcinoma, immunoproliferative activity via induction of T-lymphocytes and macrophage proliferation, anti-inflammatory activity as indicated by NO inhibition, and antioxidant activity against DPPH radicals. Moreover, compound 5 was the most effective cytotoxic compound against breast carcinoma and stimulated a consistent immunoproliferative effect on lymphocytes and macrophages combined with strong NO inhibitory activity, while compound 1 was promising as immunoproliferative agent and may act as anti-inflammatory agent as a consequence of its NO inhibitory activity. PMID- 17708437 TI - Ethanolic crude extract and flavonoids isolated from Alternanthera maritima: neutrophil chemiluminescence inhibition and free radical scavenging activity. AB - Extracts from Alternanthera maritima are used in Brazilian folk medicine for the treatment of infectious and inflammatory diseases. Bioassay-guided fractionation of A. maritima aerial parts yielded an ethanolic crude extract, its butanolic fraction and seven isolated flavonoids (two aglycones, two O-glycosides and three C-glycosides) with antioxidative activity. The ability of these samples to scavenge enzymatically generated free radicals (luminol-horseradish peroxidase H2O2 reaction) and inhibit reactive oxygen species (ROS) production by opsonized zymosan-stimulated human neutrophils (PMNLs) was evaluated by chemiluminescence methods. In both assays, the butanolic fraction was significantly more active than the ethanolic crude extract, the flavonoid aglycones had high inhibitory activities and the C-glycosylated flavonoids had no significant effect even at the highest concentration tested (50 micromol/L). However, the O-glycosylated flavonoids inhibitory effects on chemiluminescence were strongly dependent on the chemical structure and assay type (cellular or cell-free system). Under the conditions tested, active samples were not toxic to human PMNLs. PMID- 17708438 TI - Crude ethanolic extract, lignoid fraction and yangambin from Ocotea duckei (Lauraceae) show antileishmanial activity. AB - Crude ethanolic extract, lignoid fraction and the purified compound yangambin were obtained from Ocotea duckei (Lauraceae) and their antileishmanial activity was tested against promastigote forms of Leishmania chagasi and Leishmania amazonensis cultivated in Schneider medium, supplemented with 20% of fetal bovine serum. All substances presented antileishmanial activity with IC50 values of 135.7 microg/mL for the crude ethanolic extract, 26.5 microg/mL for the lignoid fraction and 49.0 microg/mL for yangambin on L. chagasi. For L. amazonensis the IC50 values were 143.7 microg/mL, 48.2 microg/mL and 64.9 microg/mL for the crude ethanolic extract, the lignoid fraction, and the purified compound yangambin, respectively. The crude ethanolic extract, lignoid fraction, and yangambin caused an inhibition higher than Glucantime, a reference drug used for the treatment of leishmaniasis. PMID- 17708439 TI - Chromanones with leishmanicidal activity from Calea uniflora. AB - The dichloromethane extract of Calea uniflora afforded a mixture of two novel chromanones, uniflorol-A (1) and uniflorol-B (2), and one known chromanone, 2,2 dimethyl-6-(1-hydroxyethyl)-chroman-4-one (3). The structures of these compounds were determined by spectroscopic methods. Biological activity of the compounds against Leishmania major promastigotes was evaluated. Mixture of the novel chromanones 1 and 2 showed significant growth inhibition of the parasite in the micrograms per milliliter range. PMID- 17708440 TI - Elastase release by stimulated neutrophils inhibited by flavonoids: importance of the catechol group. AB - Pathogenesis of chronic inflammatory diseases is associated with excessive elastase release through neutrophil degranulation. In the present study, inhibition of human neutrophil degranulation by four flavonoids (myricetin, quercetin, kaempferol, galangin) was evaluated by using released elastase as a biomarker. Inhibitory potency was observed in the following order: quercetin > myricetin > kaempferol = galangin. Quercetin, the most potent inhibitor of elastase release also had a weak inhibitory effect on the enzyme catalytic activity. Furthermore, the observed effects were highly dependent on the presence of a catechol group at the flavonoid B-ring. The results of the present study suggest that quercetin may be a promising therapeutic agent in the treatment of neutrophil-dependent inflammatory diseases. PMID- 17708441 TI - Antifeedant and phytotoxic activity of cacalolides and eremophilanolides. AB - The antifeedant effect of six cacalolides and six eremophilanolides was tested against the herbivorous insects Spodoptera littoralis, Leptinotarsa decemlineata, and Myzus persicae. The test compounds included several natural products isolated from Senecio madagascariensis (14-isovaleryloxy-1,2-dehydrocacalol methyl ether, 4), S. barba-johannis (13-hydroxy-14-oxocacalohastine, 5; 13-acetyloxy-14 oxocacalohastine, 6) and S. toluccanus [6-hydroxyeuryopsin, 7; 1(10)-epoxy-6 hydroxyeuryopsin, 9; toluccanolide A, 11] and the derivatives cacalol methyl ether (1); cacalol acetate (2); 1-acetyloxy-2-methyloxy-1,2,3,4 tetradehydrocacalol acetate (3); 6-acetyloxyeuryopsin (8); 6-acetyloxy-1(10) epoxyeuryopsin (10), and toluccanolide A acetate (12). Compound 11 and its derivative 12 exhibited moderate antifeedant activity against S. littoralis; 2, 7 10, and 12 showed strong activity against L. decemlineata, while the aphid M. persicae was moderately deterred in the presence of compounds 1, 4, 8, 10, and 12. The phytotoxic activity of 1-12 on Lactuca sativa was also evaluated. Compounds 2 and 4-12 moderately inhibited seed germination at 24 h, while compounds 1-4, 6, 9, and 10 had a significant inhibition effect on L. sativa radicle length (over 50%). PMID- 17708442 TI - Assessment of phytotoxicity of parthenin. AB - Phytotoxicity of parthenin, a sesquiterpene lactone, was evaluated against four weedy species (Amaranthus viridis, Cassia occidentalis, Echinochloa crus-galli, and Phalaris minor) through a series of experiments conducted under laboratory or greenhouse conditions to assess its herbicidal potential. Under laboratory conditions, parthenin (0.5-2 mM) severely reduced seedling growth (root and shoot) and dry weight of test weeds. However, the effect was greater on root growth. Parthenin (1 mM) suppressed the mitotic activity in the onion root tip cells that could possibly be responsible for the reduction in seedling growth. Both pre- and post-emergent application of parthenin caused a significant loss of chlorophyll pigments and affected photosynthesis. Parthenin ( > or =1 mM) caused an excessive electrolyte leakage in the plant tissues which was light-dependent. The root inhibition was associated with swelling and blackening of the root tip, shriveling and damage to the epidermal tissue and non-formation of root hairs. The study concludes that parthenin possesses weed-suppressing potential (both pre and post-). PMID- 17708443 TI - Identification of serine proteases from Leishmania braziliensis. AB - Leishmania (V) braziliensis is one of the most important ethiologic agents of the two distinct forms of American tegumentary leishmaniasis (cutaneous and mucosal). The drugs of choice used in leishmaniasis therapy are significantly toxic, expensive and are associated with frequent refractory infections. Among the promising new targets for anti-protozoan chemotherapy are the proteases. In this study, serine proteases were partially purified from aqueous, detergent and extracellular extracts of Leishmania braziliensis promastigotes by aprotinin agarose affinity chromatography. By zymography, the enzymes purified from the aqueous extract showed apparent activity bands of 60 kDa and 45 kDa; of 130 kDa, 83 kDa, 74 kDa and 30 kDa from the detergent extract; and of 62 kDa, 59 kDa, 57 kDa, 49 kDa and 35 kDa from the extracellular extract. All purified proteases exhibited esterase activity against Nalpha-benzoyl-L-arginine ethyl ester hydrochloride and Nalpha-p-tosyl-L-arginine methyl ester hydrochloride (serine protease substrates) and optimal activity at pH 8. 0. Proteases purified from the aqueous and extracellular extracts were effectively inhibited by benzamidine (trypsin inhibitor) and those from the detergent extract were inhibited by N tosyl-L-phenyl-alanine chloromethyl ketone (chymotrypsin inhibitor) indicating that all these enzymes are serine proteases. These findings indicate that L. braziliensis serine proteases display some biochemical similarities with L. amazonensis serine proteases, demonstrating a conservation of this enzymatic class in the Leishmania genus. This is the first study to report the purification of a serine protease from Leishmania braziliensis. PMID- 17708444 TI - Pectate hydrolases of parsley (Petroselinum crispum) roots. AB - The presence of various enzyme forms with terminal action pattern on pectate was evaluated in a protein mixture obtained from parsley roots. Enzymes found in the soluble fraction of roots (juice) were purified to homogeneity according to SDS PAGE, partially separated by preparative isoelectric focusing and characterized. Three forms with pH optima 3.6, 4.2 and 4.6 clearly preferred substrates with a lower degree of polymerization (oligogalacturonates) while the form with pH optimum 5.2 was a typical exopolygalacturonase [EC 3. 2.1.67] with relatively fast cleavage of polymeric substrate. The forms with pH optima 3.6, 4.2 and 5.2 were released from the pulp, too. The form from the pulp with pH optimum 4.6 preferred higher oligogalacturonates and was not described in plants previously. The production of individual forms in roots was compared with that produced by root cells cultivated on solid medium and in liquid one. PMID- 17708445 TI - Establishment of Croton stellatopilosus suspension culture for geranylgeraniol production and diterpenoid biosynthesis. AB - Diterpenoids in higher plants are biosynthesized from isoprene units obtained from two distinct pathways: the mevalonate pathway and the deoxyxylulose phosphate pathway. The metabolic partitioning of both pathways in plant species is dependent upon the type of culture. In order to study the diterpenoid biosynthesis in Croton stellatopilosus cell culture, callus culture was firstly induced from C. stellatopilosus young leaves in Murashige and Skoog (MS) medium in the presence of 1.0 mg/l 2,4-dichlorophenoxyacetic acid (2,4-D), 1.0 mg/l benzyladenine (BA), 3% (w/v) sucrose and 0.8% (w/v) agar. The suspension culture was further induced from its callus in the same medium without gelling agent. Detection of diterpenoid accumulation by gas chromatography-mass spectrometry revealed that a cell culture could accumulate a low amount of geranylgeraniol (GGOH) and a high content of fatty acids and phytosterols. To improve the GGOH production, the culture conditions were optimized by medium manipulation in terms of hormonal factors. The growth rates of cell cultures were similar in all kinds of media. The GGOH production curve indicated that GGOH plays an important role as a primary metabolite in the cell culture. The optimum medium for GGOH production was MS medium supplemented with 2.0 mg/l 2,4-D and 2 mg/l BA that could produce GGOH with a yield of 1.14 mg/g FW. PMID- 17708446 TI - Enantioselective hydrolysis of bromo- and methoxy-substituted 1-phenylethanol acetates using carrot and celeriac enzymatic systems. AB - Enantioselective hydrolysis of bromo- and methoxy-substituted 1-phenylethanol acetates was conducted using comminuted carrot (Daucus carota L.) and celeriac (Apium graveolens L. var. rapaceum) roots. Hydrolysis of the acetates led to alcohols, preferentially to R-(+)-enantiomers. Efficiencies of both reactions - hydrolysis of the acetates with an electron-donating methoxy group and oxidation of the resulting alcohols - increased in the following order: ortho < meta < para. The presence of an electron-withdrawing bromine atom in the aromatic ring had the opposite effect. Oxidation of alcohols with both types of substituents in the aromatic ring showed that location of a substituent had stronger impact on the oxidation rate than its electronic properties. PMID- 17708447 TI - A chlorophyll-less barley mutant "NYB" is insensitive to water stress. AB - "NYB" is a chlorophyll-less barley mutant, which grows relatively slow and unhealthily. The effects of water stress on photosystem II (PSII) of NYB and its wild type (WT) were investigated. Unexpected results indicated that the mutant was more resistant to water stress, because: PSII core proteins D1, D2 and LHCII declined more in WT than in NYB under water stress, and the corresponding psbA, psbD and cab mRNAs also decreased more dramatically in WT; CO2 assimilation, stomatal conductance, maximum efficiency of PSII photochemistry (Fv/Fm), efficiency of excitation energy capture by open PSII reaction centres (Fv'/Fm'), quantum yield of PSII electron transport (Phi(PSII)) and DCIP photoreduction in NYB were less sensitive to water stress than in WT, although the non photochemical quenching coefficient (q(N)) and the photochemical quenching coefficient (q(P)) were almost the same in NYB and WT. Effective chlorophyll utilization and improved PSII protein formation in the mutant may be the reason for the enhanced stress resistance. Other possible mechanisms are also discussed. PMID- 17708449 TI - Copper and cadmium tolerance, uptake and effect on chloroplast ultrastructure. Studies on Salix purpurea and Phragmites australis. AB - We have compared the effect of toxic Cu and Cd concentrations on growth, metal accumulation, and chloroplast ultrastructure of willow (Salix purpurea L.) and reed [Phragmites australis (Cav.) Trin. ex Steud.]. After a 10-day treatment, both species have tolerated to some extent the lowest concentration of both metals; however, plant growth was strongly reduced at the highest Cu and Cd concentrations. These plants could be described as Cu-tolerant at the lowest concentration tested, showing a higher tolerance index in reed than in willow; in contrast, willow exhibited higher tolerance against Cd. Both plants appeared to be moderate root accumulators of Cu and Cd. Ultrastructural studies revealed special features that can provide some protection against heavy metals stress, such as ferritin aggregates in the stroma. In addition, Cu and Cd induced distortion of thylakoids, reduction of grana stacks, as well as an increased number and size of plastoglobuli and peripheral vesicles. PMID- 17708448 TI - Influence of drought on oxidative stress and flavonoid production in cell suspension culture of Glycyrrhiza inflata Batal. AB - The effect of water deficit on flavonoid production and physiological parameters characteristic for oxidative stress were studied in a cell suspension culture of Glycyrrhiza inflata Batal to investigate its drought tolerance. The result indicated that appropriate water deficit enhanced biomass accumulation of 27.1 g L(-1) and flavonoid production of 151.5 mg L(-1), which was about 2-fold and 1.5 fold of the control, respectively. But it decreased the water content. Drought stress led to hydrogen peroxide accumulation more than in the control. Moreover, under drought conditions, malondialdehyde content, the activities of catalase and peroxidase increased to a greater extent than the control, and each reached a maximum value of 91.3 micromol g(-1) dry weight, 85.6 U and 1951 U g(-1) dry weight per min, which was 1.5-, 1.7- and 3.7-fold of the control, respectively. All above showed that appropriate water deficit could activate the antioxidative defense enzymes system to maintain stability in plants subjected to drought stress. On the contrary, the activity of phenylalanine ammonia lyase of the control increased in company with the biosynthesis of flavonoids, which indicated that phenylalanine ammonia lyase might play an important role in the path of the biosynthesis of flavonoids. PMID- 17708450 TI - Tin compounds interaction with membranes of egg lecithin liposomes. AB - This work is a continuation of earlier research concerning the influence of tin compounds on the dynamic properties of liposome membranes produced with lecithin hen egg yolks (EYL). The experiments were carried out at room temperature (about 25 degrees C). Four tin compounds were chosen, including three organic ones, (CH3)4Sn, (C2H5)4Sn and (C3H7)3SnCl, and one inorganic, SnCl2. The investigated compounds were admixed to water dispersions of liposomes. The content of the admixture changed within the range 0 mol-% to 11mol-% in proportion to EYL. Two spin probes were used in the experiment: 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and 2-ethyl-2-(15-methoxy-15-oxopentadecyl)-4,4-dimethyl-3 oxazolidinyloxyl (16-DOXYL-stearic acid), which penetrated through different areas of the membrane. It was found that tin compounds containing chlorine were the most active in interaction with liposome membranes. In the case of (C3H7)3SnCl, after exceeding 4% admixture content, an additional line appeared in the spectrum of the TEMPO probe which can be a result of formation of domain structures in the membranes of the studied liposomes. Compounds containing chlorine are of ionized form in water solution. The obtained results can thus mean that the activity of admixtures can be seriously influenced by their ionic character. In case of an admixture of non-ionic compounds the compound with a longer hydrocarbon chain displayed a slightly stronger effect on the spectroscopic parameters of the probes. PMID- 17708451 TI - A surface-active agent from Saccharomyces cerevisiae influences staphylococcal adhesion and biofilm development. AB - Bacterial biofilms which are responsible for a number of diseases are very difficult to control effectively because of their high resistance to antibiotics and the host defence system. The use of natural products decreasing or preventing initial adhesion of bacteria and biofilm formation is one of the alternative therapeutic strategies taken into consideration. We ask the question, whether a crude extract from the cell wall of Saccharomyces cerevisiae (mannoprotein), which possesses surfactant activity, may be used as inhibitor of Staphylococcus aureus and S. epidermidis biofilm development. By using the "bactericidal spot assay" it was demonstrated that mannoprotein had no direct antibiotic activity against the tested strains. The influence of this extract on initial adhesion, biofilm formation and dispersal of preformed biofilms was studied using the 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. In this assay, live bacteria with an active electron transport system reduce the tetrazolium salt to a water-soluble purple formazan product, and optical density reading (A550) values are directly dependent on their cell numbers. Yeast-derived surfactant, when adsorbed in the microplate wells or present in the medium, was effective both in decreasing the initial deposition of staphylococci and in reducing the amount of growing biofilm, quantitated after 24 h of co-incubation with the bacteria. It also changed the parameters of biofilm morphology analyzed by PHLIP - the confocal laser scanning microscopy image quantification package. Mannoprotein also accelerated the detachment of mature staphylococcal biofilms, preformed in optimal conditions. It was concluded that mannoprotein anti-biofilm action reflects its influence on cell surface hydrophobicity. PMID- 17708452 TI - Batch and fed-batch production of betalains by red beet (Beta vulgaris) hairy roots in a bubble column reactor. AB - Hairy root cultures from red beet (Beta vulgaris L.), which could be used for the commercial production of biologically active betalain pigments, were cultivated in a 3 L bubble column bioreactor in batch mode with various rates of air supply. Both the growth of the roots and betalain volumetric yields were highest (12.7 g accumulated dry biomass/L and 330.5 mg/ L, respectively) with a 10 L/h (0.083 vvm) air supply. The air flow rate also influenced the betacyanins/betaxanthins ratios in the cultures. Growth and betalains production were then examined in two fed-batch regimes (with a 10 L/h air supply), in which nutrient medium was fed just once or on five occasions, designated FBI and FBII, respectively. The root mass accumulation was increased in the FBI feeding regime (to 13.3 g accumulated dry biomass/ L), while in FBII the betalains content was ca. 11% higher (15.1 mg betacyanins/g dry weight and 14.0 mg betaxanthins/g dry weight) than in the most productive batch regime. Data on the time course of the utilization of major components in the medium during both operational modes were also collected. The implications of the information acquired are discussed, and the performance of the hairy roots (in terms of both growth and betalains production) in the bubble column reactor and previously investigated cultivation systems is compared. PMID- 17708453 TI - Free radical scavengers from Cymbopogon citratus (DC.) stapf plants cultivated in bioreactors by the temporary immersion (TIS) principle. AB - The biomass production of Cymbopogon citratus shoots cultivated in bioreactors according to the temporary immersion (TIS) principle was assessed under different growth conditions. The effect of gassing with CO2-enriched air, reduced immersion frequency, vessel size and culture time on total phenolic and flavonoid content and free radical scavenging effect of the methanolic extracts was measured. From the TIS-culture of C. citratus, seven compounds were isolated and identified as caffeic acid (1), chlorogenic acid (2), neochlorogenic acid (3), p-hydroxybenzoic acid (4), p-hydroxybenzoic acid 3-O-beta-D-glucoside (5), glutamic acid (6) and luteolin 6-C-fucopyranoside (7). The occurrence of compounds 1-7 and their variability in C. citratus grown under different TIS conditions was determined by HPLC. The free radical scavenging effect of the methanolic extract and compounds was measured by the discoloration of the free radical 1,1-diphenyl-2 picrylhydrazyl (DPPH). The main metabolites in 6- and 8-week-old cultures, both in 5 and 10 1 vessels, were chlorogenic acid (2) (100-113 mg%) and neochlorogenic acid (3) (80-119 mg%), while in the cultures with CO2-enriched air and reduced immersion frequency the main compound detected in the extracts was glutamic acid (6) (400 and 670 mg% for the green and white biomass and 619 and 630 mg% for the green and white biomass, respectively). The most active compounds, as free radical scavengers, in the DPPH discoloration assay were caffeic acid (1), chlorogenic acid (2), neochlorogenic acid (3) and the flavonoid luteolin 6-C fucopyranoside (7). PMID- 17708454 TI - Induction of apoptosis by alkaloids, non-protein amino acids, and cardiac glycosides in human promyelotic HL-60 cells. AB - The induction of apoptosis by 66 alkaloids of the quinoline, quinolizidine, pyrrolizidine, isoquinoline, indole, terpene, tropane, steroid, purine, and piperidine type, of 9 cardiac glycosides, 11 non-protein amino acids and 10 further secondary metabolites was assayed in HL-60 cell cultures and measured by quantification of the subdiploid DNA content by flow cytometry, detection of DNA fragmentation by gel electrophoresis, and cell morphology. Several alkaloids of the isoquinoline, quinoline, and indole type were active, whereas quinol-izidine, tropane, pyrrolizidine, terpene and piperdine alkaloids were mostly inactive. The proapoptotic alkaloids can be characterized by their property to inhibit protein biosynthesis and their intercalation into DNA at the same time, or by their inhibition of microtubule formation. All cardiac glycosides, which are both membrane detergents and Na+,K+-ATPase inhibitors, are potent apoptosis inducers. Also proapoptotic were a few non-protein amino acids, podophyllotoxin and the flavonoid quercetin. PMID- 17708455 TI - EP3OS 2007: European position paper on rhinosinusitis and nasal polyps 2007. A summary for otorhinolaryngologists. PMID- 17708456 TI - Observations on the ability of the nose to warm and humidify inspired air. AB - The major function of the nose is to warm and humidify air before it reaches to the lungs for gas exchange. Conditioning of inspired air is achieved through evaporation of water from the epithelial surface. The continuous need to condition air leads to a hyperosmolar environment on the surface of the epithelium. As ventilation increases, the hyperosmolar surface moves more distally, covering a larger surface area of the airway, and stimulates epithelial cells to release mediators that lead to inflammation. This inflammation is not identical to allergic inflammation, but causes both short-term and long-term changes in the epithelium. In the short-term, it increases paracellular water transport in an attempt to enhance conditioning, and it stimulates sensory nerves to initiate neural reflexes. It also disrupts channels in the cellular membrane, which might permit greater penetration of foreign proteins, such as allergens, leading to further inflammatory cascades. The long-term inflammation induced over time by the hyperosmolar milieu could worsen the ability of the nose to condition air, requiring more of the conditioning to occur in the lower airway and leading to adverse consequences for the respiratory system. PMID- 17708457 TI - Does rhinitis lead to asthma? AB - Rhinitis and asthma are commonly linked even if the precise pathological mechanisms explaining the relationship are not fully understood. Although there is increasing evidence that rhinitis may influence the development of asthma, there remain many gaps in our understanding of the processes involved. The complexity of this relationship is mainly due to the multiple interactions between genetic background, environmental factors and the specific host reaction. Epidemiological surveys have highlighted significant clinical associations and identified some factors that favour the progression from rhinitis to asthma. Basic research has demonstrated numerous similarities in inflammatory and immunological mechanisms. PMID- 17708458 TI - Prevalence of rhinitis among Brazilian schoolchildren: ISAAC phase 3 results. AB - OBJECTIVE: The International Study of Asthma and Allergies in Childhood (ISAAC) is a standardized method that allows international and regional comparisons of asthma and allergic diseases prevalence. The objective of this study was to evaluate the prevalence of rhinitis and related symptoms among 6-7 year-old children (SC) and 13-14 year-old adolescents (AD) from 20 Brazilian cities applying the ISAAC's standardized written questionnaire (WQ). METHODS: ISAAC's WQ was applied to 23,422 SC and 58,144 AD living in different regions of Brazil: North (N), Northeast (NE), Middle West (MW), Southeast (SE), and South (S). RESULTS: The prevalence of rhinoconjunctivitis in the last year ranged from 10.3% to 17.4% and from 8.9% to 28.5% among SC and AD, respectively. Considering SC the highest values were observed in SE region. In NE, the prevalence in countryside centres was higher than those along the coast. Among AD, the highest values were observed in N and S regions, mainly in Para (Belem). The evaluation of populations probably with the same genetic background has shown higher prevalence among those living in urban centres (capital) in comparison to those in the countryside. CONCLUSIONS: The prevalence of rhinitis and related symptoms were variable and predominate in Brazilian N and NE centres. PMID- 17708459 TI - BDNF and DPP-IV in polyps and middle turbinates epithelial cells. AB - HYPOTHESIS: Neuropeptides released from sensory nerves may contribute to airway inflammation, particularly if their metabolism is impaired through defective inactivation and/or increased production. In the airways, neuropeptides are subjected to degradation by enzymes such as dipeptidyl peptidase (DPP-IV), and are upregulated by neurotrophins such as brain derived neurotrophic factor (BDNF). We therefore assessed in primary human nasal epithelial cells the expression of DPP-IV and BDNF under basal and inflammatory conditions. METHODS: Human epithelial cells were isolated from nasal polyps and middle turbinates, and grown on collagen-coated polycarbonate filters with an air liquid-interface. After three weeks of culture, constitutive cellular expression of DPP-IV and BDNF was assessed by measuring its activity and by ELISA, respectively. To mimick in vivo inflammatory conditions, cells were exposed apically and basolaterally to 50 ng/ml of TNFalpha, IL-1beta, and IFN-gamma for two days. DPP-IV activity and BDNF protein expression were measured in cell lysates and in the apical and basolateral media. RESULTS: Constitutive DPP-IV activity was similar in polyps and turbinates cells. In contrast, polyps epithelial cells expressed higher amounts of BDNF compared to turbinates derived cells. On the other hand, TNFalpha, IL-1beta, and IFN-gamma did not affect DPP-IV activity but significantly increased the cellular expression and the basolateral secretion of BDNF. CONCLUSIONS: Our data show for the first time that primary human airway epithelial cells produced DPP-IV and BDNF under basal conditions. Furthermore, the production and secretion of BDNF were markedly increased in response to pro inflammatory cytokines, confirming the involvement of BDNF in airway inflammation. PMID- 17708460 TI - Side-effects of injective allergen immunotherapy administered to intermittent or persistent allergic rhinitis patients. AB - AIM: Evaluation of the side-effects of conventional subcutaneous allergen immunotherapy in inhalant allergy. MATERIAL AND METHODS: Retrospective analysis of early and late, local and systemic, short-term and long-term side-effects of 4723 injections given to 224 patients suffering from intermittent or persistent allergic rhinitis. RESULTS: There were 65 systemic reactions in 48 patients (21%) after 61 injections (1.29%). Most of them were late, and included dyspnoea, rhinorrhoea, fever, fatigue and urticaria. Incidence of systemic reactions did not correlate to age or sex, but was higher in grass pollen than in house dust mite allergy and during the up-dosing phase of treatment. Late intense local reactions were observed after 1.6% of injections. CONCLUSIONS: Allergen immunotherapy in inhalant allergy is a safe method of treatment. PMID- 17708461 TI - Quantitative analysis of nasal vascularization in allergic patients treated with mometasone furoate. AB - The purpose of this study was to compare vascularization of the nasal mucous membrane among non-allergic, non-treated allergic and allergic patients treated with mometasone furoate, by means of the stereology method in quantitative analysis. Three groups of patients (GP), each containing 10 patients were examined. The first group (GP 1) had a negative inhalatory allergen test while the second (GP 2) and third (GP 3) group both had positive results with the same test. GP 3 included allergic patients treated with mometasone furoate for 15 days before analysis, when a small piece of the nasal mucous membrane was taken from the frontal pole of the lower nasal shell. The specimens were examined immunohistochemically for expression of CD31 and VEGF-C. Vascular phase was determined by using length density (L(v)). Differences in CD31 and VEGF-C expression were compared using one-way ANOVA and Tukey HSD post-hoc tests. CD31 expression in GP 1 had significantly lower values than in the GP 2 and GP 3 groups (p < 0.001). VEGF-C expression in GP 1 was significantly lower than in GP 2 (p = 0.007), but not in GP 3 (p = 0.292). We have shown that 15-day treatment with mometasone furoate results in a significant reduction of the density of vascular elements in allergic patients. PMID- 17708462 TI - The relationship between subjective assessment instruments in chronic rhinosinusitis. AB - PROBLEM: To provide an evidence-based definition for the relationship between three subjective instruments for assessing severity of chronic rhinosinusitis- visual analogue scale, 'mild' 'moderate' and 'severe' (MMS) classification and perception of whether quality of life (QoL) is affected. METHOD OF STUDY: One hundred sixteen subjects with chronic rhinosinusitis filled in a questionnaire rating simultaneously their perception of disease severity based (1) upon visual analogue scale, (2) MMS classification and (3) stating whether they felt their QoL was affected. MAIN RESULTS: The mean age of subjects was 50. The inter quartile range of VAS scores for the respective MMS groups were: Mild 0.80-3.50, Moderate 4.40-6.33, Severe 7.70-9.50. In the group who perceived effects on QoL, the inter-quartile range for VAS scores was 5.10-8.68. This range was 1.53-4.57 in the other group with no effects on QoL. 30.3% of patients in the 'mild' category, 79.6% in the 'moderate' category and 97.4% in the 'severe' category felt that their QoL was affected. PRINCIPLE CONCLUSIONS: We propose a statistically validated definition of the relationship between MMS classification and VAS scoring. Based on our study we would define 'mild' as being 0- 3 inclusive, 'moderate, as > 3- 7 inclusive and 'severe' as > 7- 10 inclusive on the VAS scoring system. We further propose that in general QoL is more likely to be affected with VAS scores of 5 or more. PMID- 17708463 TI - Histological structure of the nasal cartilages and their perichondrial envelope. I. The septal and lobular cartilage. AB - The cellular elements and extracellular matrix of the nasal septal cartilage and the lateral crus of the lobular cartilage were studied in serial coronal sections of five human cadaver noses. To discern the various tissue components, the sections were stained according to the methods of Mallory-Cason, Azan, Herovici, Verhoeff-van Gieson, and Lawson as well as by immunohistochemistry to demonstrate the presence of collagen type I and II. A characteristic gradual transition of the chondrocytes was observed in both septal and lobular cartilage: from numerous small flat cells oriented parallel to the surface of the cartilage to less numerous larger ovaloid cells oriented perpendicular to the surface. This difference between the peripheral and central zones of the cartilage was particularly marked in lobular cartilage. Both septal and lobular cartilage have a high density of type II collagen but almost none of type I. The peripheral zones of the matrix showed a higher density of collagen than the central zone. This difference was more pronounced in septal than lobular cartilage. The high density of type II collagen in septal cartilage, particularly in the peripheral zones, suggests that one of the primary tasks of the septum is providing stiffness to the external nose. That idea is consistent with findings from our study of the perichondrial envelope. PMID- 17708464 TI - Histological structure of the nasal cartilages and their perichondrial envelope. II. The perichondrial envelope of the septal and lobular cartilage. AB - The perichondrial envelopes of the septal cartilage and the lateral crus of the lobular cartilage were studied in serial coronal sections of five human noses. To differentiate between the various tissue components, the sections were stained according to Mallory-Cason, Azan, Herovici, Verhoeff-van Gieson, and Lawson. Collagen types I and II were immunohistochemically stained. The results demonstrated that the perichondrium of the septal cartilage and the lateral crus of the lobular cartilage consists of a homogeneous layer of type I collagen fibers and elastic fibers. The elastic fibers have a network-like arrangement and are most numerous in the perichondrium of the lateral crus of the lobular cartilage. Clearly distinguishable zones in the perichondrial envelopes could not be observed. The perichondrium on the outside of the lateral crus of the lobular cartilage and the triangular cartilage is significantly thicker than the inner perichondrium. It is speculated that these morphological characteristics of the perichondrial envelopes are related to functional differences between the cartilages. The mobility of the lateral crus of the lobular cartilage requires a higher content of elastic fibers in its perichondrium than the more rigid septal cartilage. A thicker outer perichondrium of the lateral crus of the lobular cartilage and the triangular cartilage may be related to muscular forces that are exerted on the outer side of the cartilages only. PMID- 17708465 TI - Forty-one cases of congenital choanal atresia over 26 years--retrospective analysis of outcome and technique. AB - This retrospective analysis reflects the outcome of various techniques used in a series of 41 cases of choanal atresia treated at the Department of Otoloaryngology, Head- and Neck Surgery at the University of Mainz between 1980 and 2006. Thirteen bilateral and 28 unilateral cases are included. After endonasal management in 38 and a transpalatine approach in 3 cases a total of 15 patients needed revision surgery between 1 and 5 times to establish a stable result. Postoperative stenting was used in 23 patients with a failure rate of 35%, whereas only 11% of the 18 patients without stenting had to be revised. None of those 5 cases where Mitomycin C had been applied intraoperatively in combination with postoperative transnasal dilations needed surgical revision. We conclude that the endonasal micro-endoscopic surgical approach is successful if combined with postoperative dilations for up to one year. Stenting should be abandoned as it stimulates granulation formation that frequently leads to restenosis. The intraoperative application of Mitomycin C offers a promising adjunct in achieving a stable PMID- 17708466 TI - Screening of olfactory function using odourized markers. AB - BACKGROUND: The goal of our study was to create a psychophysical test for the screening of olfactory function on the basis of commercially available odourized markers (OM). There are six coloured markers in one package filled with different odourants at suprathreshold levels. In order to identify the best approach, we investigated five different variations of the technique. MATERIALS AND METHODS: Olfaction was investigated in 189 subjects. Healthy participants as well as patients suffering from olfactory disorders were tested. Initially subjects were tested by one of five methods using OM. Finally, the "Sniffin' Sticks" test (butanol odour threshold, odour identification) was performed. RESULTS: Correlation of the OM screening test and the "Sniffin' Sticks" ranged from 0.49 to 0.93 indicating that variations of the technique strongly influence the results of testing. The best technique for evaluating olfactory function included spontaneous naming of odours and odour identification from a list of four distractors. The sensitivity of this method was sufficient to determine anosmia. CONCLUSIONS: The odourized markers screening test can be used to screen for anosmia in the general population. However, the precise quantification of olfactory function is not possible, because of the relatively small amount of odours. PMID- 17708467 TI - Histamine induces nasal obstruction via calcitonin gene-related peptide in sensitized guinea pigs. AB - The purpose of this study was to characterize the late phase nasal obstruction that is induced by a nasal histamine challenge in sensitized guinea pigs. The volume of the nasal cavity was measured using an acoustic rhinometer. A nasal histamine challenge to unsensitized animals induced nasal obstruction at 30 minutes after the challenge while a challenge to sensitized animals induced nasal obstruction not only at 30 minutes but also at 4-6 hours. Histamine (measured by high-performance liquid chromatography), cysteinyl leukotriene (enzyme-linked immunosorbent assay (ELISA)), prostaglandin D2 (ELISA), eosinophils and basophilic cells of sensitized guinea pigs were not changed in the late phase after histamine challenge. Administration of pyrilamine, a histamine H1 receptor antagonist, and calcitonin gene-related peptide (CGRP) (8-37), a CGRP-1 receptor antagonist, significantly improved histamine-induced nasal obstruction at 30 minutes and in the late phase, respectively. These results suggest that a nasal histamine challenge induces nasal obstruction not only immediately through the histamine H1 receptors but also in a late phase via CGRP. PMID- 17708468 TI - [Infectious markers among blood donors in Democratic Republic of Congo (DRC)]. AB - In sub-saharian Africa, two factors account for the difficulties encountered to reach optimal blood safety: high frequency in the general population of various infections of which some are transmissible by blood transfusion and a still insufficient proportion of voluntary donors which constitute the safest group. The Kisangani transfusion center in DRC does not escape from this rule since in addition to voluntary blood donors (29.2%), its blood supply is mainly assured by family (or replacement) donors (69.2%). Persistence of a few remunerated donors (1.6%) was also noted at the period of the study. In this study, we determined seroprevalence of HIV, HBV and of syphilis infections in these three categories of donors and defined their characteristics by a retrospective analysis carried out on 3.390 subjects between January 2003 to December 2004. It revealed that 4.7% of the donors were positive for HIV, 5.4% for HBV and 3.7% for syphilis. There were significant differences according to studied groups : voluntary blood donors (n=989; HIV+ = 2.2%; VHB+ =3%; syphilis+ = 1.1%), family donors (n = 2.345; HIV+ = 4.6%; HBV+ = 4.9%; syphilis+ = 3.6%) and remunerated donors (n=56; HIV=50%; HBV+ = 64.3%; syphilis+ = 53.6%). These results indicate that it is necessary to intensify promotion of voluntary donation by a policy of information and education and to abolish practice of remunerated donation. Within the limits of possible, family donation should be gradually discouraged. PMID- 17708469 TI - [The phantasm of the perfect child and phantoms of eugenism]. AB - The perfect child phantasm is a frequent problem in prenatal diagnosis. However, the definition of a perfect child is complex and is different from a couple to another. The chromosomal analysis of the fetus and amniocentesis are therefore frequently demanded by the parents. However, this could lead to foetal loss. The diminution of the number of unjustified amniocentesis is time consuming and requires a psychological approach. Dialogue, appropriate screening, ultrasound examination, and eventually late amniocentesis can avoid some pregnancy loss. PMID- 17708470 TI - [Wrist perilunate dislocation]. AB - Carpal perilunate dislocations are rare and underdiagnosed because of an ignorance of the pathology and an inappropriate incidence of radiography. The carpus is composed of two rows of bones and 33 ligaments. These ligaments are fundamental for wrist stability. Typically, the injury occurs in young male adults exposed to high-energy trauma with a wrist in hyperextension. The diagnosis is easy with a physical examen and standard postero-anterior and lateral radiographs. The Witvoet and Allieu classification of the perilunate dislocations is the most used. This classification is composed of three grades. The treatment is usually surgical and has to be realised in a short delay to minimize the important complications. PMID- 17708471 TI - [Balloon kyphoplasty for treatment of vertebral osteoporotic compression fractures]. AB - Kyphoplasty, the newest of the tools treating vertebral osteoporotic compression fractures (VOCF) is the evolution of vertebroplasty, allowing not only pain control and strengthening of the fractured vertebra, but also offering the possibility to restore vertebral height with a lower risk of complications. We present our series of 41 consecutive VOCF treated by kyphoplasty in 30 patients between October 2003 and March 2006. Systematic spinal X rays and CT scan have be performed, occasionally followed by bone scintigraphy or spinal MRI. The mean preoperative duration of symptoms before surgery was 52 days. Pain control after the operation was considered excellent in all cases and all patients were mobilized the day after surgery. Kyphoplasty allowed a 50% restoration of vertebral height in 66% of the treated vertebras. The results were better when surgery was performed within the first three months after the fracture. The mean vertebral deformity correction by comparison of the pre- and postoperative Cobb angles was 9.7 degrees. One patient showed cement leakage in the spinal canal without neurological deterioration. The mean postoperative stay was 2.5 days. We found kyphoplasty to be a safe technique allowing immediate pain control after VOCF, with minimal risks of cement leakage or pulmonary embolism. Vertebral height and deformity correction are best achieved with early surgery, but pain control is always excellent even with a delayed procedure. PMID- 17708472 TI - [Anti-mullerian hormone and its role in the regulation of ovarian function. Review of the literature]. AB - Anti-mullerian hormone, also called AMH, belongs to the large family of transforming growth factor P. Its role in the sexual differentiation of male fetus is now well known. Recently, AMH has been demonstrated to play an important role in the ovarian function. In fact, AMH seems to regulate the kinetics of follicular development, inhibiting the follicular recruitment and the follicular growth. Thus, this intra-gonadic cybernin could be a decisive determinant of the rapidity of follicular pool exhaustion. Today, some experimental data from the literature suggest that AMH could be a reliable marker of ovarian reserve. This review summarizes the present knowledge about AMH and its role in physiology but also in ovarian pathology. PMID- 17708473 TI - [If the chicks would have teeth?]. AB - 130 millions years ago, birds have diverged from other archosaurs. Except the most primitive birds of the cretaceous, they lost the property to produce teeth. Tooth development requires complex epithelialmesenchymal interactions, which imply the expression of numerous genes, which begin to be well known. Four different experiments have permitted to obtain tooth rudiments in chick embryos. The association of oral chick ectoderm with mouse molar mesenchyme, the exposition of oral chick ectoderm to BMP's and FGF's, the transposition of mouse neural crest in young chick embryos, and the use of a Talpid mutation lead to tooth anlage development in the chick embryo. PMID- 17708474 TI - [Falls of older individuals: medical assessment]. AB - Falls are one of the most common problems that threaten the independence of older individuals. They usually occur when impairments in multiple domains compromise the compensatory ability of the individual, as is the case for many geriatric syndromes. A number of the physical conditions and environmental situations predispose to falls. The medical risk factors of falls are reviewed. Falls in older individuals are rarely due to a single cause. Mechanisms that maintain postural stability are altered with aging (balance, gait speed, cardiovascular function). Female gender, past history of a fall, cognitive impairment, lower extremity weakness, balance problems, psychotropic drug use, arthritis, history of stroke, orthostatic hypotension, dizziness, and anemia represent the most frequent causes of risk of falls. Physical examination should focus upon the above mentioned risk factors and also on the presence of orthostatic hypotension, visual acuity, hearing assessment, examination of the extremities for deformities or neuropathies, and carotid sinus hypersensitivity which contributes to falls in people with unexplained falls. In conclusion, assessment of older individual at risk of falls or who fall present medical specificities. However, these latter specificities should be included in a comprehensive assessment which focus on intrinsic and extrinsic factors. Interventional strategies including comprehensive and interdisciplinary assessment lead to effective prevention. PMID- 17708475 TI - [Is it necessary to found an exemption from the medical secrecy concerning the health of politicians?]. AB - In its book " The great secrecy", Dr. Gubler revealed that President of French Republic, Franpois Mitterrand, had lied on his cancer as of his accession with the capacity. 1981 to 1994, Dr. Gubler was the personal doctor of the President of French Republic, deceased on January 8, 1996. The great secrecy was diffused on January 17, 1996. French Justice ordered the interruption of its diffusion on January 18, 1996. The recourse led to a compensation for family of President. However, the European Court of the Humans Right (CEDH), May 18, 2004, condemned France retaining that the general and absolute character medical secrecy could not attack the freedom of expression and to the right to knowledge by the Nation of the truth on health of its former President of Republic. The CEDH however approves initial prohibition but not the maintenance of this prohibition, 9 months later. The great secrecy remained interdict in France until 2004 and was republished at the beginning of 2005. Dr Gubler was condemned for violation of medical secrecy and was erased Order of the doctors, decision confirmed by the Council of State. This story started again the medical, legal and political debate around the medical secrecy concerning politicians. In September 2005, President of French Republic, Jacques Chirac, was hospitalized after a cerebral vascular accident. Communicate were regularly published on its health, but questions were asked concerning medical activity under these conditions. PMID- 17708476 TI - [Three pregnancies on nasal CPAP: a case report]. AB - We report on a sleepy woman, suffering from morbid obesity, with a diagnosis of severe sleep apnea syndrome made at the age of 30 year, treated with nocturnal ventilatory support (nasal CPAP). The patient had an history of preeclampsia during a first pregnancy. In the following years, this patient remained very compliant with nasal CPAP, was no longer sleepy and was three times pregnant, without any complication. PMID- 17708477 TI - [An unusual foot drop: the fibular intraneural cyst]. AB - Fibular intraneural cysts are a rare cause of fibular neuropathy. Echography and MRI are helpful in the detection of cysts of the knee. Surgical ablation of the cyst arising from the superior tibio-fibular joint is necessary for a good recovery. PMID- 17708478 TI - [A report on the 4th International Forum of Medical Education]. PMID- 17708479 TI - [Considerations apropos of a survey on the ending of life]. PMID- 17708480 TI - [Fifty years ago, the International Academy Of Cytology was founded in Brussels. An opportunity to remind the contribution of our university in the field of clinical cytology]. AB - Fifty years ago, the International Academy of Cytology, a scientific society devoted to the promotion of clinical cytology and the publication of a bimonthly journal, was founded in Brussels. The choice of Brussels did not happen by chance: the quality and the importance of the scientific work of the Belgian school of clinical cytology, particularly the one of the Universite Libre de Bruxelles, justified this choice. PMID- 17708482 TI - [On the Quebec side]. PMID- 17708481 TI - [Early prenatal care: hinging on thoughtful perinatal prevention]. PMID- 17708483 TI - [Prenatal diagnosis in the Nord-Pas-de-Calais in 2004: organisational issues and challenges]. AB - The development of the Regional Plan for Health Organisation (SROS III) in the Nord-Pas-de-Calais has provided an opportunity for further reflection on the operation and organisation of professionals and structures in the field of prenatal diagnoses. The alleged claims resulting from this reflection process are not only integrated in the perinatal stream of the SROS but also in the objectives of the regional public health plan. The study which was carried out takes into account the regional data available, complemented by interviews with professionals working on the ground, which are then compared with national data. All of these elements contributed to the construction of proposals for an improved organisation of this regional management system, on the one hand curative and on the other preventive. PMID- 17708484 TI - [Specialist hospitals' management of care for cardiovascular in-patients]. AB - In order to identify and describe the organisation of specialist hospitals' technical services and activities for patients with cardiovascular disease, we applied the classification method of Barrubes et al. to their in-patients' hospitalisation period for a duration of 24 hours or more. Technical activities are defined as the state-of-the-art medicine for extremely complex diseases requiring specifically skilled attention. This simple method enabled the identification of specialist technical activities for treating patients with cardiovascular disease and to learn more about the role of the public and private providers of hospital care, roles which vary according to French geographic areas and regions. PMID- 17708486 TI - [Social responsibility in health and the global health situation: towards new health and social indicators]. AB - New approaches to social responsibility and health must be developed to ensure that scientific and technological progress contribute to justice, equity and the interest of humanity. The current state of health in several regions of the world is a matter of great concern. Using various indicators, composite indices have been developed that provide us with socio-medical, demographic and economic data and make it possible to analyse socio-health conditions worldwide. The Universal Declaration on Bioethics and Human Rights considers health as a social and human good and recommends better access to and improved quantities of quality health care and medicine, as well as access to drinking water. In order to implement these recommendations, we believe that current developments should be monitored utilising composite indices. PMID- 17708485 TI - [Evaluating activity in the psychiatric sector: attempting to develop a typology of options for care]. AB - Assessing activity in the psychiatric sector is a contemporary issue, and it is rendered even more complex by the variety of pathologies and the diversity of the existing organisational structures of care. Data collection has been taking place for more than 15 years, but is insufficiently utilised. The Department of Medical Information attempted to analyse a typology of patients' options of courses to care. This analysis demonstrates that the elements for forecasting the amount and level of care provided are not linked as much to the pathology being treated, as they are to the organisation of the range of services which take care of the management and delivery of the care. PMID- 17708488 TI - [Perspectives of general practitioners on the role of patients' caregivers in the process of consultation and treatment]. AB - The aim of this study is to describe, from the perspective of general practitioners, the role of relatives and caregivers who accompany a patient in their consultation and treatment processes. 435 general practitioners filled out two questionnaires: the first was self administered and the second described specific clinical situations and the possible role of the family caregiver in the case of a patient with Alzheimer's diseases, Parkinson's disease, depression, epilepsy, asthma, cardiovascular disease, or type II diabetes. General practitioners think that overall they offer satisfactory responses to relatives' requests and concerns regarding the disease itself and its treatment. However, they do not feel skilled or qualified enough to answer them with regard to administrative or social questions. The relative's role is for the most part, perceived as positive, and seems to contribute to the efficacy of the care provided. This description corresponds to a new trend in modern medical practice, dominated by the burden of chronic and disabling diseases which implies, and in some cases requires, the need to involve a relative's presence and on-going support. PMID- 17708487 TI - [Qualitative evaluation of the enforcement of the perinatal decree--strengthening mechanisms for over-medicalisation]. AB - In France, the policy on decentralisation and the organisation of prenatal care is governed and mandated by a decree issued in 1998 whose objective is to improve prevention of pre-maturity and prenatal risks. Within this context, 49 maternal and child health professionals were interviewed by using a qualitative questionnaire to evaluate the implementation and enforcement of the decree specifically in the region of Lyon. This report presents an analysis of the mechanisms and psychosocial issues of the over-medicalisation of birth. This over medicalisation stems from the inseparable interactions between the ranking of skills within a firm hierarchy - linked in and of itself to the hierarchical status of health facilities - and the progression of attributing the birthing process as one with is more disease-based, surgically-based and judicially-based. PMID- 17708489 TI - [About " L'alibi ethique", by Didier Sicard. Ethics and society: the need for a strong commitment to respect human dignity and solidarity]. PMID- 17708493 TI - [Gerontology and informatics, what role for new information and communication technologies?]. PMID- 17708494 TI - [The goals of the Francilienne Association for the Quality Care of the Elderly]. PMID- 17708495 TI - [Preventing heat stroke]. PMID- 17708496 TI - [Multiple missions for the Nurses College of the French Society of Geriatrics and Gerontology]. PMID- 17708497 TI - [Why talk about geriatric oncology?]. PMID- 17708499 TI - [Clinical research in geriatrics]. PMID- 17708498 TI - [Geriatric oncology, a national report]. PMID- 17708500 TI - [The initial consultation in geriatric oncology and the key role of the nurse clinician]. PMID- 17708501 TI - [Psychological aspects in the management of the elderly person with cancer]. PMID- 17708502 TI - [Geriatric and oncologic evaluations at the Center for Gerontologic Evaluation and Personal Autonomy of Senlis]. PMID- 17708503 TI - [Cognition, chemotherapy, anemia and erythropoietin]. PMID- 17708504 TI - [The Charter of the Rights and Liberties of the Dependent Elderly Person. 2/7 Living arrangements, choice of life and maintenance of social life]. PMID- 17708505 TI - [Aerosol therapy]. PMID- 17708506 TI - [6/5--Irritant dermatitis and mycoses]. PMID- 17708507 TI - Development of novel guanidino-labelling derivatisation (GLaD) reagents for liquid chromatography/matrix-assisted laser desorption/ionisation analysis. AB - A new generation of guanidino-labelling (GLaD) reagents were developed for quantitative proteomics using offline microcapillary liquid chromatography (LC) matrix-assisted laser desorption/ionisation mass spectrometry (MALDI-MS). In order to reduce the unwanted overlapping between the isotopic envelopes of the two differentially labelled peptide ions, a novel synthetic route was described for production of both (13)C- and (15)N-containing isotopomers of N,O dimethylisourea. The use of these types of isotopes has no deleterious effect on the retention times of both differentially labelled peptides during offline microbore reversed-phase LC. In addition, the possibility to incorporate a mass difference of 4 Da can be exploited during post-source decay analysis to generate product ion spectra in which fragment ions containing the modifications appear as doublets in the corresponding product ion spectra, thus facilitating identification of the C-terminal fragment ions. PMID- 17708509 TI - Development of a qualitative liquid chromatography/tandem mass spectrometric method for the detection of narcotics in urine relevant to doping analysis. AB - A new screening procedure for 18 narcotics in urine for anti-doping purposes has been developed using liquid chromatography/triple quadrupole mass spectrometry (LC/MS). Electrospray ionization (ESI) was used as interface. Infusion experiments were performed for all substances to investigate their mass spectrometric behaviour in terms of selecting product specific ions. These product ions were then used to develop a tandem mass spectrometric method using selected reaction monitoring (SRM). For the LC/MS analysis, chromatography was performed on an octadecylsilane column. The total run time of the chromatographic method was 5.5 min. For the sample preparation prior to LC/MS analysis, the urine samples were liquid-liquid extracted at pH 9.5 after overnight enzymatic hydrolysis. Two extraction solvents were evaluated: dichloromethane/methanol 9/1 (v/v), which is currently used for the extraction of narcotics, and diethyl ether, used for the extraction of steroids. With diethyl ether the detection limits for all compounds ranged between 0.5 and 20 ng/mL and with the mixture containing dichloromethane the detection limits ranged between 0.5 and 10 ng/mL. Taking into account the minimum required performance limits of the World Anti Doping Agency of 200 ng/mL for narcotics, diethyl ether can also be considered as extraction solvent for narcotics. Finally, the described method was applied to the analysis of urine samples previously found to contain narcotics by our routine gas chromatography/mass spectrometry (GC/MS) method. PMID- 17708508 TI - Postoperative infections in cytoreductive surgery with hyperthermic intraperitoneal intraoperative chemotherapy for peritoneal carcinomatosis. AB - BACKGROUND: Peritoneal carcinomatosis is a common evolution of many abdominal and pelvic malignancies. Over the last decade novel therapeutic approaches have emerged combining cytoreductive surgery with perioperative intraperitoneal chemotherapy. Aim of our study was to assess frequency, sites, and organisms of postoperative infections in this surgery and to evaluate associated risk factors and clinical outcome. METHODS: Retrospective study of postoperative infection in 30 patients undergoing combined cytoreductive surgery and hypertermic intraoperative chemotherapy in an oncologic surgery in Rome, between June 2001 and December 2004. RESULTS: Twenty-nine postoperative infections were recorded in 11 patients (36.7%; 2.6 infections per patient), including 13 surgical site infections, 8 clinical sepsis, 6 bloodstream infections, and 2 pneumonias. At multivariate analysis, total peritonectomy was found as independent variable associated to postoperative infection. Mortality rates were 36.4% and 5% among patients with and without postoperative infections, respectively (P = 0.04). Four of the 5 patients with invasive candidosis died. CONCLUSIONS: Peritonectomy procedures have an high risk of postoperative infections, prolonged hospital stay, and high morbidity and mortality. The increasing role of this surgery for the treatment of peritoneal carcinomatosis should strengthen the need for a careful evaluation of possible risk factors for postoperative infections, including the role of colonizing organisms. PMID- 17708510 TI - Dissipation behaviour of spinosad insecticide in soil, cabbage and cauliflower under subtropical conditions. AB - BACKGROUND: Pesticides used on cauliflower and cabbage, which are important vegetable crops for India, must be investigated for the persistence and magnitude of their residues in the crops and soil to ensure human and environmental safety. The behaviour of spinosad, an effective insecticide with a favourable environmental profile, was investigated in field trials under subhumid and subtropical conditions. RESULTS: The persistence of spinosad in soil, cabbage and cauliflower was evaluated at two application rates (17.5 and 35.0 g ha(-1)) by high-performance liquid chromatography (HPLC). At 17.5 g ha(-1), spinosad persisted up to 7 days in soil, cabbage and cauliflower. However, at 35.0 g ha( 1), spinosad residues persisted up to 7 days in soil and 10 days in cabbage and cauliflower. CONCLUSION: The dissipation of the insecticide from soil, cabbage and cauliflower appeared to occur in a single phase and conformed to first-order kinetics. The half-lives of spinosad residues in cabbage, cauliflower and soil were calculated as 1.5, 2.8 and 2.8 days respectively for the 17.5 g ha(-1) treatment, and as 2.6, 2.0 and 2.0 days for the 35 g ha(-1) treatment. PMID- 17708511 TI - A Bayesian hierarchical modeling approach for studying the factors affecting the stage at diagnosis of prostate cancer. AB - We extend the baseline-category logits model for categorical response data to accommodate two distinct kinds of clustering. Our extension introduces random effects that have one component exhibiting spatial dependence and a second component that is distributed independently. We use this enhanced categorical logits model for investigating the factors that affect the geographical distribution of the diagnostic stage of prostate cancer (PrCA) in South Carolina (SC). Using incidence data from the SC registry, we fit three types of models: the baseline-category logits model, the proportional odds model, and the adjacent categories logits model, each incorporating our two-component random effects. The deviance information criterion (DIC) is used for selecting the best-fitting model. The results from the best model are presented and interpreted. The county specific random effects are mapped to characterize the spatial distribution pattern of diagnostic stage of PrCA in the study region. In terms of spatial distribution of the diagnostic stage of PrCA, an area of excess (unexplained) risk was found in the north-west area, and an area of low excess risk in the north-east area for regional-stage cancer in SC was identified through the analysis of the cancer registry data. PMID- 17708512 TI - Pyrethroid resistance discovered in a major agricultural pest in southern Australia: the redlegged earth mite Halotydeus destructor (Acari: Penthaleidae). AB - BACKGROUND: The redlegged earth mite (Halotydeus destructor Tucker) is an important pest of field crops and pastures. Control of this pest relies heavily on chemicals, with few genuine alternatives presently available. Pesticide responses of H. destructor from the field with reported chemical control failures were compared with mites from susceptible 'control' populations. Toxicology bioassays were conducted on adult mites across multiple generations. RESULTS: Very high levels of resistance to two synthetic pyrethroids, bifenthrin and alpha cypermethrin, were detected in this species for the first time. For bifenthrin, LC(50) estimates showed a difference in resistance of greater than 240 000-fold. Resistance to alpha-cypermethrin was almost 60 000-fold. This resistance was shown to be heritable, persisting after several generations of culturing. There was no evidence that resistance to organophosphorus chemicals had evolved, which is likely to be a direct consequence of the history of chemical applications these mites have experienced. CONCLUSION: These results highlight the need for more judicious management decisions in order to control pest species in a sustainable manner. The implications of these findings in regard to the management and future research of the redlegged earth mite are discussed. PMID- 17708513 TI - Improved accuracy when screening for human growth disorders by likelihood ratios. AB - The standard deviation score (SDS) is a powerful tool for screening for growth related problems. However, referral rules of the type 'if SDS(Y)/=45 years at presentation, follicular thyroid cancer, tumor extension beyond the thyroid capsule, vascular invasion, distant metastasis, increasing tumor size, stage, and high MACIS-AMES scores were found to be statistically significant adverse prognostic factors in univariate analysis for DFS and OAS. Multivariate analysis for DFS and OAS confirmed that distant metastasis, follicular thyroid cancer, tumor extension beyond the thyroid capsule, vascular invasion, primary tumor size, TNM stage, and high MACIS score were independent prognostic factors. CONCLUSION: In DTC patients, in addition to traditional risk factors, prognostic factors, such as vascular invasion and capsular invasion, need to be evaluated; not only for achieving an adequate therapeutic approach, but also for avoiding overtreatment of low-risk patients. PMID- 17708544 TI - Modulating effects in learned helplessness of dyadic dominance-submission relations. AB - In this experiment, learned helplessness was studied from an ethological perspective by examining individual differences in social dominance and its influence on the effects of helplessness. Ninety animals were used, 30 randomly selected and 60 selected because of their clear dominance or submission. Each condition (dominant, submissive, and random) was distributed in three subgroups corresponding to the triadic design. The test consisted of an escape/avoidance task. The results showed that the animals in the uncontrollable condition performed worse than those in the controllable and no treatment conditions. Social submission and dominance reduced vulnerability of the subjects against learned helplessness. Submission had a facilitating effect on subsequent learning, independently of whether pretreatment was controllability or uncontrollability. Learned mastery was observed in the submissive condition, because submission benefited the subjects in the controllable condition in comparison with the untreated subjects, and dominance impaired the subjects in the controllable condition. PMID- 17708541 TI - Cell surface restriction of EGFR by a tenascin cytotactin-encoded EGF-like repeat is preferential for motility-related signaling. AB - The 14th EGFL-repeat (Ten14) of human tenascin cytotactin activates the epidermal growth factor receptor (EGFR) with micromolar affinity; however, unlike EGF, Ten14-mediated activation of EGFR does not lead to receptor internalization. As the divergent signaling pathways downstream of EGFR have been shown to be triggered from plasma membrane and cytosolic locales, we investigated whether Ten14-mediated surface restriction of EGFR resulted in altered biochemical and cellular responses as compared to EGF. Molecules associated with migratory cascades were activated to a relatively greater extent in response to Ten14, with very weak activation of proliferation-associated cascades. Activation of phospholipase C gamma (PLCgamma) and m-calpain, associated with lamellipod protrusion and tail retraction, respectively, were noted at even at sub saturating doses of Ten14. However, activation of ERK/MAPK, p90RSK, and Elk1, factors affecting proliferation, remained low even at high Ten14 concentrations. Similar activation profiles were observed for EGF-treated cells at 4 degrees C, a maneuver that limits receptor internalization. We demonstrate a concurrent effect of such altered signaling on biophysical responses-sustained migration was observed at levels of Ten14 that activated PLCgamma, but did not stimulate proliferation significantly. Here, we present a novel class of EGFR ligands that can potentially signal as a part of the extracellular matrix, triggering specific intracellular signaling cascades leading to a directed cellular response from an otherwise pleiotropic receptor. This work extends the signaling paradigm of EGFL repeat being presented in a restricted fashion as part of the extracellular matrix. PMID- 17708545 TI - Vascular endothelial growth factor staining and elevated INR in advanced epithelial ovarian carcinoma. AB - BACKGROUND: The purpose of this study was to determine whether vascular endothelial growth factor (VEGF) expression in tumors correlates with the incidence of an elevated prothrombin time (PT), specifically an international normalized ratio (INR) > or = 1.4, in patients undergoing primary surgical cytoreduction for ovarian cancer. METHODS: INRs were obtained on all patients perioperatively. VEGF expression was determined by immunostaining of tumor specimens using published protocols. RESULTS: One hundred patients underwent surgical cytoreduction. Sixty-seven percent of patients had postoperative INR of 1.4 or greater. INRs of greater than or equal to 1.8 were found in 5% of patients. INR elevation was independent of mean estimated blood loss (EBL) with the EBL in the patients with INRs > or = 1.4 not significantly different than the EBL in the patients with INRs < 1.4 (660 ml vs. 530 ml, P = 0.09). There was a significant correlation between elevated INR and tumor VEGF immunostaining (P < 0.005). All but one patient with an elevated INR had positive VEGF staining. CONCLUSIONS: In conclusion, development of an elevated INR (INR > or = 1.4) is common in patients undergoing primary surgical cytoreduction. Positive tumor VEGF staining is very common in patients having a postoperative coagulopathy. PMID- 17708546 TI - Low performance of the MSKCC nomogram in preoperatively ultrasonically negative axillary lymph node in breast cancer patients. AB - BACKGROUND AND OBJECTIVES: In order to predict the nonsentinel lymph node (NSLN) metastases in sentinel lymph node (SLN) positive patients a nomogram was created at the Memorial Sloan Kettering Cancer Centre (MSKCC). The aim of our study was to validate the MSKCC nomogram in patients grouped by the preoperative ultrasound (US) examination of the axillary lymph nodes. METHODS: The MSKCC nomogram was validated separately in three groups of patients: (US-0) only clinically preoperatively negative axillary lymph nodes (126 patients), (US-1) US negative axillary lymph nodes (109 patients), and (US-2) US suspicious but fine needle aspiration biopsy (FNAB) negative axillary lymph nodes (41 patients). RESULTS: The predicted probability underestimates the actual probability with the mean absolute error equal to 0.116 in the US-0 group (P = 0.003), and overestimates the actual probability (mean absolute error equal to 0.084) in US-1 group (P = 0.033) and US-2 group (mean absolute error is 0.110) (P = 0.275). CONCLUSION: We found that the MSKCC nomogram overestimates the probability of the NSLN metastases in breast cancer patients with (i) preoperatively US negative or (ii) US suspicious, but FNAB negative axillary lymph nodes. We also found that MSKCC nomogram has only limited value in patients with only clinically negative axillary lymph nodes. PMID- 17708547 TI - Glomus tumor of the omentum: a case report. AB - Computed tomography revealed a well-enhanced omental mass. Magnetic resonance imaging demonstrated a mass with low signal intensity on T1-weighted images (WI) and high signal intensity on T2-WI. Resected specimens immunohistochemically showed positive results for alpha-smooth muscle actin, muscle-specific actin (HHF35) and vimentin, and negative results for S-100 protein, CD34, desmin, EMA, keratin, calretinin, HBME1, and c-kit. This is the first case of an omental glomus tumor reported in the English literature. PMID- 17708548 TI - The role of pelvic exenteration and reconstruction for treatment of advanced or recurrent gynecologic malignancies: Analysis of risk factors predicting recurrence and survival. AB - BACKGROUND AND OBJECTIVES: Pelvic exenteration offers the last chance of cure for some advanced or recurrent gynecologic malignancy patients. The aim of this prospective study was to analyze factors associated with recurrence and survival after pelvic exenteration. METHODS: Forty-six women with advanced or recurrent gynecologic malignancies were enrolled between July 2001 and February 2006. All pelvic exenteration surgery was performed by the same gynecological oncologist. RESULTS: Two patients were excluded due to the discovery of peritoneal disease during surgery. Multivariate analysis showed that a tumor size >4 cm was the only factor associated with risk of recurrence after surgery (P = 0.014), that margin status was the only factor associated with disease-free survival (P = 0.0.047), and that margin status and lymph node metastasis were associated with overall survival (P = 0.017 and 0.012, respectively). CONCLUSIONS: Pelvic exenteration and reconstruction was found to have a potential to provide long-term survival without postoperative mortality although the morbidity rate is somewhat high. Multivariate analysis showed that tumor size >4 cm was a predictive factor for recurrence, and that margin status and lymph node metastasis were predictive factors for survival. PMID- 17708549 TI - Safety of modified double-stapling end-to-end gastroduodenostomy in distal subtotal gastrectomy. AB - BACKGROUND AND OBJECTIVES: Double-stapling end-to-end gastroduodenostomy (DS-BI) has several potential advantages over other anastomotic techniques in that it is a simple procedure, with no additional gastrotomy on the remnant stomach, and less tension on the anastomosis site. We evaluated the safety of DS-BI by comparing it with the hand-sewn Billroth II gastrojejunostomy (B-II). METHODS: Medical records of 933 consecutive patients (DS-BI 428, B-II 505) who underwent distal subtotal gastrectomy were retrospectively reviewed. Several clinicopathological features and treatment results were compared between the two groups. RESULTS: The overall complication rates were 9.3% in the DS-BI group and 15.2% in the B-II group (P = 0.007). Anastomosis-related complications, such as anastomosis-site leakage, stenosis, and intraluminal bleeding, did not differ between the two groups (1.2% in the DS-BI group and 1.8% in the B-II group, P = 0.59). All the anastomosis-related complications were managed conservatively. Postoperative mortality rates were 0% in the DS-BI group and 0.4% (2/505) in the B-II group. CONCLUSIONS: Modified DS-BI is a safe procedure, with short-term results similar to those of hand-sewn Billroth II anastomosis. PMID- 17708550 TI - SSO approved training programs in breast cancer care. PMID- 17708551 TI - Opposite effects of glucocorticoid receptor activation on hippocampal CA1 dendritic complexity in chronically stressed and handled animals. AB - Remodeling of synaptic networks is believed to contribute to synaptic plasticity and long-term memory performance, both of which are modulated by chronic stress. We here examined whether chronic stress modulates dendritic complexity of hippocampal CA1 pyramidal cells, under conditions of basal as well as elevated corticosteroid hormone levels. Slices were prepared from naive, handled or chronically stressed animals and briefly treated with vehicle or corticosterone (100 nM); neurons were visualized with a fluorescent dye injected into individual CA1 pyramidal cells. We observed that 21 days of unpredictable stress did not affect hippocampal CA1 apical or basal dendritic morphology compared with naive animals when corticosteroid levels were low. Only when slices from stressed animals were also exposed to elevated corticosteroid levels, a significant reduction in apical (but not basal) dendritic length became apparent. Unexpectedly, animals that were handled or 3 weeks showed a reduction in both apical dendritic length and number of apical branch points when compared with naive animals. Apical dendritic length and number of branch points were restored to levels found in naive animals several hours after in vitro treatment with 100 nM corticosterone. All effects of acute corticosterone administration could be prevented by the glucocorticoid receptor antagonist RU38486 given during the last 4 days of the stress or handling protocol. We conclude that brief exposure to high concentrations of corticosterone can differently affect apical dendritic structure, depending on the earlier history of the animal, a process that critically depends on involvement of the glucocorticoid receptor. PMID- 17708552 TI - Alcohol consumption and risk for stroke among Chinese men. AB - OBJECTIVE: Stroke is a leading cause of death and long-term disability in China. The objective of this study was to examine the relation between alcohol consumption and risk for stroke among Chinese men. METHODS: We conducted a prospective cohort study among 64,338 Chinese men aged > or = 40 years who were free of stroke at baseline. Data on frequency and type of alcohol consumed were collected at the baseline examination in 1991 using a standard protocol. Follow up evaluation was conducted in 1999 to 2000, which included determining vital status, interviewing participants or proxies, and obtaining hospital and medical records for incident and fatal strokes. RESULTS: Over the course of 493,351 person-years of follow-up, we documented 3,434 incident strokes (1,848 stroke deaths). After adjustment for age, body mass index, physical activity, urbanization (urban vs rural), geographic variation (north vs south), cigarette smoking, history of diabetes, and education, compared with nondrinkers, relative risk (95% confidence interval) of incident stroke was 0.92 (0.80-1.06) for participants consuming 1 to 6 drinks/week, 1.02 (0.93-1.13) for those consuming 7 to 20 drinks/week, 1.22 (1.07-1.38) for those consuming 21 to 34 drinks/week, and 1.22 (1.08-1.37) for those consuming 35 or more drinks per week (p for linear trend < 0.0001). The corresponding relative risks for stroke mortality were 0.93 (0.76-1.14), 0.98 (0.85-1.13), 1.15 (0.95-1.38), and 1.30 (1.11-1.52), respectively (p for linear trend = 0.0004; p for quadratic trend = 0.03). INTERPRETATION: These results suggest that heavy alcohol drinking may increase the risk for stroke in Chinese men and should be the target of strategies for prevention. PMID- 17708553 TI - Viral load of episomal and integrated forms of human papillomavirus type 33 in high-grade squamous intraepithelial lesions of the uterine cervix. AB - The association between total and integrated HPV-33 DNA loads and high-grade squamous intraepithelial lesions (HSIL) of the uterine cervix was investigated. Of 5,347 women recruited in 4 studies, 89 (64 without SIL, 7 low-grade SIL (LSIL), 15 HSIL, 3 unknown grade) were infected by HPV-33. HPV-33 E6, HPV-33 E2 and beta-globin DNA were measured with real-time PCR that allowed to assess total (E6), episomal (E2) and integrated (E6-E2) HPV-33 viral loads. HPV-33 E6/E2 ratios >/=>/=2.0 suggesting the presence of integrated HPV-33 were obtained for 28.6% (n = 18) of women without SIL and 21.4% (n = 3) of women with HSIL (p = 0.74). Although median viral loads were similar, there was a trend toward having a greater proportion of women with HSIL in the fourth quartile (>/=>/=10(6.69) copies/mug DNA) of total HPV-33 viral loads compared to normal women. Controlling for age, site, ethnicity and LCR polymorphism by logistic regression, HPV-33 total loads in the fourth quartile {odds ratio (OR) 4.5 [95% confidence interval (CI) 1.2-17.3]; p = 0.03} and episomal loads in the fourth quartile (>/=>/=10(6.64) copies/mug DNA) [OR 3.9 (95% CI 1.1-13.2); p = 0.05] but not integrated HPV-33 load in the fourth quartile [OR 1.0 (95% CI 0.3-3.3); p = 0.50] were associated with HSIL. Controlling for age, study site and SIL grade, HPV-33 episomal load [OR 0.2 (95% CI 0.1-0.5), p = 0.0004] was associated with the presence of HPV-33 integration. High episomal loads in HSIL and the presence of integration in women without SIL are likely to weaken the usefulness of HPV load of integrated forms in clinical practice. PMID- 17708554 TI - Diagnostic value of mucins (MUC1, MUC2 and MUC5AC) expression profile in endoscopic ultrasound-guided fine-needle aspiration specimens of the pancreas. AB - Mucins are aberrantly expressed in various malignancies. We immunohistochemically tested mucins expression (MUC1, MUC2 and MUC5AC) in EUS-FNA samples from pancreatic occupying lesions for the diagnostic utility. The prevalence of MUC1, MUC2 and MUC5AC expression in pancreatic cancers were 77.5% (31/40), 10.0% (4/40) and 80.0% (32/40), respectively, and in the benign pancreatic diseases 25% (4/16), 31.3% (5/16) and 43.8% (7/16). MUC1 and MUC5AC significantly overexpressed in pancreatic cancer, and MUC1 negatively related with tumor differentiation degree (p < 0.05). The prevalence of MUC1, MUC2 and MUC5AC expression in pancreatic mucinous neoplasms were 66.7% (12/18), 38.9% (7/18) and 88.9% (16/18), respectively, and in the pancreatic non-mucinous neoplasms 60.5% (23/38), 5.3% (2/38) and 57.9% (22/38). MUC2 and MUC5AC significantly overexpressed in pancreatic mucinous neoplasms, especially MUC2 in benign mucinous neoplasms (p < 0.05). Compared with cytology alone, the combination test of MUC1+cytology, and MUC5AC+cytology could achieve higher sensitivity (85 vs. 65%, 100 vs. 65%) and accuracy (89.3% vs. 73.2%, 91.1% vs. 73.2%) for pancreatic cancer diagnosis; the combination test of MUC2 + cytology, and MUC5AC + cytology could achieve higher sensitivity (77.8% vs. 38.9%, 100% vs. 38.9%), and specificity (97.4% vs. 60.5%, 71.1% vs. 60.5%) accuracy (100% vs. 51.8%, 80.4% vs. 51.8%) for mucinous neoplasm diagnosis. The panel MUC1+/MUC2-/MUC5AC+/ was higher specific in pancreatic cancer diagnosis, as well as MUC1-/MUC2+/MUC5AC+/ in pancreatic mucinous neoplasms. Our observations suggest the mucins expression profile in EUS-FNA specimens has higher value for the diagnosis of pancreatic cancer and mucinous neoplasms. PMID- 17708555 TI - (99m)Tc-MIBI imaging for prediction of therapeutic effects of second-generation MDR1 inhibitors in malignant brain tumors. AB - The aim of this study was to explore whether (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) is suitable to elucidate multidrug resistance and prediction of potentiation of antitumor agents by second-generation MDR1 inhibitors (PSC833, MS 209) in malignant brain tumors in rat. Malignant tumor cells (RG2 and C6 gliomas, Walker 256 carcinoma) were incubated with low dose vincristine (VCR) to induce multidrug resistance. MTT assay demonstrated a significant increase of surviving fractions in VCR-resistant sublines compared to those of drug-naive cells. Reverse transcriptase polymerase chain reaction revealed higher expression of MDR1 mRNA in VCR-resistant cells than drug-naive cells in each line. Volume distribution (V(d)) of (99m)Tc-MIBI was negatively correlated with MDR1 mRNA expression among drug-naive and VCR-resistant cells. MDR1 inhibitors decreased surviving fractions and increased V(d) of (99m)Tc-MIBI significantly in VCR resistant sublines, whereas MDR1 mRNA expression was unchanged. These findings indicate that (99m)Tc-MIBI efflux was functionally suppressed by MDR1 inhibitors. Autoradiographic images of (99m)Tc-MIBI revealed higher uptake in drug-naive cells at basal ganglia compared with VCR-resistant cells at the opposite basal ganglia of rats. Oral administration of the second-generation MDR1 inhibitors significantly increased (99m)Tc-MIBI accumulation of both tumors. Therapeutic effects of VCR with or without the MDR1 inhibitors were also evaluated autoradiographically using (14)C-methyl-L-methionine ((14)C-Met) and MIB-5 index. (14)C-Met uptake and MIB-5 index of both tumors treated with VCR following the MDR1 inhibitor treatment significantly decreased compared with tumors treated with VCR alone. Analysis of (99m)Tc-MIBI accumulation is considered informative for detecting MDR1-mediated drug resistance and for monitoring the therapeutic effects of MDR1 inhibitors in malignant brain tumors. PMID- 17708556 TI - Personal sun exposure and risk of non Hodgkin lymphoma: a pooled analysis from the Interlymph Consortium. AB - In 2004-2007 4 independent case-control studies reported evidence that sun exposure might protect against NHL; a fifth, in women only, found increased risks of NHL associated with a range of sun exposure measurements. These 5 studies are the first to examine the association between personal sun exposure and NHL. We report here on the relationship between sun exposure and NHL in a pooled analysis of 10 studies participating in the International Lymphoma Epidemiology Consortium (InterLymph), including the 5 published studies. Ten case-control studies covering 8,243 cases and 9,697 controls in the USA, Europe and Australia contributed original data for participants of European origin to the pooled analysis. Four kinds of measures of self-reported personal sun exposure were assessed at interview. A two-stage estimation method was used in which study specific odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for potential confounders including smoking and alcohol use, were obtained from unconditional logistic regression models and combined in random-effects models to obtain the pooled estimates. Risk of NHL fell significantly with the composite measure of increasing recreational sun exposure, pooled OR = 0.76 (95% CI 0.63 0.91) for the highest exposure category (p for trend 0.01). A downtrend in risk with increasing total sun exposure was not statistically significant. The protective effect of recreational sun exposure was statistically significant at 18-40 years of age and in the 10 years before diagnosis, and for B cell, but not T cell, lymphomas. Increased recreational sun exposure may protect against NHL. PMID- 17708557 TI - Abnormal brain tryptophan metabolism and clinical correlates in Tourette syndrome. AB - Symptoms in Tourette syndrome (TS) are likely related to abnormalities involving multiple neurotransmitter systems in striatal-thalamo-cortical circuitry. Although prior studies have found abnormal levels of tryptophan, serotonin, and their metabolites in blood, cerebrospinal fluid and brain tissue of TS patients, understanding of focal brain disturbances and their relationship to clinical phenotype remains poor. We used alpha-[(11)C]methyl-L-tryptophan (AMT) positron emission tomography (PET) to assess global and focal brain abnormalities of tryptophan metabolism and their relationship to behavioral phenotype in 26 children with TS and nine controls. Group comparisons on regional cortical and subcortical AMT uptake revealed decreased AMT uptake in bilateral dorsolateral prefrontal cortical and bilaterally increased uptake in the thalamus (P = 0.001) in TS children. The ratio of AMT uptake in subcortical structures to dorsolateral prefrontal cortex was significantly increased bilaterally (P < 0.01) in TS patients also. Behaviorally defined subgroups within the TS sample revealed differences in the pattern of AMT uptake in the fronto-striatal-thalamic circuit. This study demonstrates cortical and subcortical abnormalities of tryptophan metabolism in TS and provides neuroimaging evidence for a role of serotonergic mechanisms in the pathophysiology of TS. PMID- 17708558 TI - Benign SCA14 phenotype in a German patient associated with a missense mutation in exon 3 of the PRKCG gene. PMID- 17708559 TI - The medial and lateral bellies of gastrocnemius: a cadaveric and ultrasound investigation. AB - It is commonly reported that the medial belly (MG) of the gastrocnemius muscle extends further distally than the lateral belly (LG). This observation is made in several standard anatomy texts with no explanation or quantitative data. In this study, the medial and lateral bellies of gastrocnemius in 45 embalmed cadavers were measured. The observed difference in length of the two bellies was found to be highly significant (mean difference in length = 1.74 cm, P < 0.001). In 8 out of 84 legs examined (9.5%), however, the MG was found to be shorter than the LG (three right legs, five left legs, bilateral in two individuals). Surprisingly, there was no correlation between the difference in muscle belly length in any individual and ipsilateral leg length or total body length, suggesting that the difference in belly length may be unrelated to biomechanical function. An ultrasound investigation into the activity pattern of the two bellies was carried out on five volunteers. Muscle activity was monitored during passive and active movements of the ankle and knee joints at different leg positions. During knee flexion and ankle plantarflexion, the LG contracted first in four of the five subjects, followed by the MG, then a period of either LG predomination or equal contraction. The fifth subject, who showed a reversed pattern of activity, had previously suffered an inversion injury of the ankle. We suggest that the initial activation of the LG may help to stabilize the ankle during plantarflexion. We found no evidence that gastrocnemius acts as a shunt muscle during distraction of the knee. PMID- 17708560 TI - An investigation into medical students' approaches to anatomy learning in a systems-based prosection course. AB - Students' approaches to learning anatomy are driven by many factors and perceptions, e.g., the curriculum, assessment, previous educational experience, and the influence of staff and fellow students. However, there has been remarkably little research into characterizing how students approach their anatomy learning. What is known, based on a sample of 243 students, is that students studying medicine at the University of Southampton adopt primarily a "deep" approach to learning. Medical students at Southampton learn anatomy in a systems-based curriculum through prosections. Analysis of data from an Approaches to Study Inventory (ASSIST) revealed that students preferred using a deep approach over a strategic or surface approach (P < 0.001 and P < 0.001, respectively). They also adopted an increasingly strategic approach as they moved through the medical curriculum. There was a relationship between anatomy examination results and approach to learning. Students who adopted a strategic approach performed better (R = 0.266, P < 0.001). It is argued that curriculum design, including the form of assessment, is the key to promote effective anatomy education and the goal of deep and meaningful learning in preparation for professional practice. PMID- 17708561 TI - Variant triple origin of the flexor digiti minimi brevis (manus) muscle in relation to ulnar nerve and artery compression at the wrist. PMID- 17708562 TI - Unexpected motor axons in the distal superficial radial and posterior interosseous nerves: a cadaver study. AB - The prevalence of motor variations in the nerves supplying muscles of the first web space was evaluated by a visual dissection and immunohistochemical analysis from 56 cadaver hands. By microscopic visualization, 30% of the superficial radial nerves (SRNs) sent branches into muscles of the first web space. Since these unexpected penetrating branches were expected to be sensory or proprioceptive, markers of sensory and motor axons were used for confirmation. Positive identifications of motor axons (as identified by positive immunostaining for choline acetyltransferase) were made in 30% of SRNs and in 28.5% of posterior interosseous nerves. Classical teachings that the SRNs and PINs are exclusively sensory have been brought into question. Our data are in agreement with the rare clinical finding that motor function occasionally persists following devastating injury to both the ulnar and median nerves. Anatomic prevalence for this variation appears much higher than previous descriptions have indicated. PMID- 17708563 TI - Comment on "Superficial palmar communications between the ulnar and median nerves in Turkish cadavers". PMID- 17708564 TI - Coracoid process anatomy: implications in radiographic imaging and surgery. AB - The coracoid process forms an important part of scapular-glenoid construct and is involved in many surgical procedures on the glenohumeral joint. The unique three dimensional orientation of each coracoid pillar makes radiographic imaging difficult. Congenital variations and minimal traumatic/iatrogenic changes in this orientation can predispose to subcoracoid impingement. We performed a quantitative and statistical analysis of the osseous anatomy of the coracoid process in 101 scapulae; the purpose was to determine the anatomical variations and gender-specific differences in the length, breadth, thickness, vertical and horizontal projections, and triplane angulations of each individual coracoid pillar. All parameters were measured in reference to the glenoid plane to ensure surgical and radiological applicability. The mean dimensions of the inferior coracoid pillar were 31.1 x 16.6 x 9.9 mm and that of the superior coracoid pillar were 41.7 x 14.2 x 8.4 mm (medial)/6.6 mm (lateral). The mean maximal harvestable coracoid length measured 19.0 mm. The mean angular orientation of the inferior coracoid pillar, with reference to the glenoid, measured 51.2 degrees (axial), 126.1 degrees (sagittal), and 134.6 degrees (coronal), and that of the superior coracoid pillar measured 146.1 degrees (axial) with an interpillar angulation of 84.9 degrees (axial). A statistically significant gender difference (P < 0.05) was found in the lengths, breadths, and projections of each coracoid pillar. We used data from this study to devise two new radiographic views (for imaging individual coracoid pillars), to calculate dimensions and orientation of internal fixation/prosthetic hardware during surgery, and conceptualize a geometric model to explain the role of measured parameters in coracoid impingement syndrome. PMID- 17708565 TI - Protective intercoronary continuity. PMID- 17708566 TI - Preliminary observations on the microarchitecture of the human abdominal muscles. AB - Precise knowledge of muscle architecture and innervation patterns is essential for the development of accurate clinical and biomechanical models. Although the gross anatomy of the human abdominal muscles has been investigated, the finer details of their microanatomy are not well described. Fascicles were systematically sampled from each of the human abdominal muscles, and small fiber bundles from selected fascicles stained with acetylcholinesterase to determine the location of motor endplate bands, myomyonal junctions, and myotendinous junctions. Statistical analysis was used to ascertain the association between fascicular length and number of endplate bands. The number of endplate bands along a fascicle was variable between different portions of each muscle, but was strongly correlated with fascicular length (r = 0.814). In fascicles less than 50 millimeters (mm) in length, only a single endplate band was generally present, while multiple endplate bands (usually two or three) were found in fascicles longer than 50 mm. The presence of myomyonal junctions throughout the longer (>50 mm) fascicles verified that they were composed of short, intrafascicularly terminating fibers, while shorter fascicles comprised fibers spanning the entire fascicular length. This preliminary study provides evidence that multiple endplate bands are contained in some regions of the abdominal muscles, an arrangement that differs from most human appendicular muscles. It is not clear whether the variations in the described fine architectural features reflect regional differences in muscle function. PMID- 17708567 TI - Unique variant of levator glandulae thyroideae muscle. PMID- 17708568 TI - Comparison of four methods for the estimation of intracranial volume: a gold standard study. AB - Investigators can infer how much reduction in volume has occurred since brain volume was at its peak, by combining measures of brain volume with measures of intracranial volume (ICV). Several methodologies have been proposed to asses the ICV. However, we have not seen a gold-standard study evaluating the results of the methodologies for the assessment of ICV. In the present study, the actual intracranial volume of 20 dry skulls was measured using the water-filling method, using this as a gold standard. Anthropometry, cephalometry, point-counting, and planimetry techniques were applied to the same skulls to estimate the ICV. Anthropometric and cephalometric measurements were carried out directly on skulls and roentgenograms, respectively. Consecutive computed tomography sections at a thickness of 10 mm were used to estimate the ICV of the skulls by means of the point-counting and planimetry methods. The mean (+/-SD) of the actual ICV measured by the water-filling method was 1,262.0 +/- 160.4 cm(3) (1,389.5 +/- 96.5 cm(3) for males and 1,134.5 +/- 94.3 cm(3) for females, respectively). Our results showed that the estimated values obtained by all four methods differed from the actual volumes of the skulls (P < 0.05). The data obtained by anthropometry resulted in overestimation. However, cephalometry, point-counting, and planimetry methods produced underestimation. After calibration, there were no significant differences between the actual volumes and the results of the four methods (P > 0.05). While the anthropometric method is easy and quick to apply, its result may deviate from the actual values. The optimized stereological techniques of point-counting and planimetry methods may provide unbiased ICV results since they take the third dimension of the structures into account. PMID- 17708569 TI - A South African mixed ancestry family with Huntington disease-like 2: clinical and genetic features. AB - Huntington disease-like 2 (HDL2) is a neurodegenerative disorder caused by an expansion of a CTG repeat in the junctophilin-3 gene (JPH3). A limited number of HDL2 families have been reported, all of apparently Black African ancestry. We report on a South African family that presented with progressive dementia and a movement disorder affecting numerous family members. Genotyping of the JPH3 CTG repeat revealed pathogenic expansions in three affected individuals. Whereas HDL2 is thought to be clinically indistinguishable from Huntington disease (HD), 2 of the patients in this study presented with clinical symptoms that differed substantially from HD; one had myoclonus and the other had Parkinsonism. Moreover, brain magnetic resonance imaging scans of these patients showed imaging features atypical for HD. Mitochondrial DNA and Y-chromosome DNA analysis on a family member showed that his maternal and paternal ancestries are typical of that found among the South African mixed ancestry or colored population. A difference in the distribution of CTG repeats between Caucasian and Black individuals was detected. We conclude that the phenotype of HDL2 is broad and can differ from that of typical HD. The diagnosis therefore should be considered in a wide spectrum of neuropsychiatric and abnormal movement presentations. PMID- 17708572 TI - Influence of education level on breast cancer risk and survival in Sweden between 1990 and 2004. AB - On account of limited recent data regarding the role of education in breast cancer risk and prognosis, we conducted this study to assess the association between education level and in situ and invasive breast cancer risk and invasive breast cancer survival, using the 2006 update of the Swedish Family-Cancer Database. Cox's proportional hazards models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) adjusted for age, time-period, parity, age at first birth, county of residence, and family history of breast cancer. Compared to women completing less than 9 years of education, university graduates were more likely to be diagnosed with in situ (HR = 1.44, 95% CI: 1.28 1.63) and invasive (HR = 1.28, 95% CI: 1.20-1.36) breast cancer, and the lack of homogeneity between these two HRs was statistically significant, p = 0.007. Further stratification revealed that the lack of homogeneity was greatest for breast cancers diagnosed before age 50. Compared to women completing less than 9 years of education, university graduates were associated with the highest survival following a breast cancer diagnosis (lowest fatality hazard ratio), HR = 0.68, 95% CI: 0.61-0.75. Further research is warranted to elucidate possible behaviors or characteristics associated with education that could explain the differences in incidence and survival, such as compliance with cancer screening. PMID- 17708571 TI - ANXA7 expression represents hormone-relevant tumor suppression in different cancers. AB - Tumor suppressor function of ubiquitously expressed Annexin-A7, ANXA7 (10q21) that is involved in exocytosis and membrane fusion was based on cancer prone phenotype in Anxa7(+/-) mice as well as ANXA7 role in human prostate and breast cancers. To clarify ANXA7 biomarker and tumor suppressor function, we analyzed its expression pattern in comparison to the prostate-specific biomarker NKX3.1. Immunohistochemistry-based ANXA7 and NKX3.1 protein expression was analyzed on human tissue microarrays of 4,061 specimens from a wide spectrum of the histopathologically well-characterized tumors in different stages compared to corresponding normal tissues. Decreased ANXA7 expression was mostly associated with high invasive potential in multiple tumors. Although some metastases retained relatively high ANXA7 rates compared to primary cancer tissues, the lymph node metastases from different sites (including prostate and breast) had decreased ANXA7 expression in comparison to the intact lymphatic tissues. Major ANXA7 downregulation pattern was deviated in tumors of glandular (especially neuroendocrine) origin. ANXA7 and NKX3.1 proteins were synexpressed in the male urogenital system and adrenal gland. Gene expression profiling in prostate and breast cancers (SMD) revealed distinct hormone-related profiles for NKX3.1 and ANXA7, where ANXA7 expression correlated with steroid sulfatase which has a pivotal role in steroidogenesis. Abundant protein presence in adrenal gland and its loss in hormone-refractory prostate cancer indicated that ANXA7 can be relevant to steroidogenesis and androgen sensitivity in particular. With tumor suppressor pattern validated in different tumors, ANXA7 can be an attractive diagnostic and therapeutic target associated with the hormone and/or neurotransmitter-mediated modulation of tumorigenesis. PMID- 17708573 TI - Elemental mercury poisoning probably causes cortical myoclonus. AB - Mercury toxicity causes postural tremors, commonly referred to as "mercurial tremors," and cerebellar dysfunction. A 23-year woman, 2 years after injecting herself with elemental mercury developed disabling generalized myoclonus and ataxia. Electrophysiological studies confirmed the myoclonus was probably of cortical origin. Her deficits progressed over 2 years and improved after subcutaneous mercury deposits at the injection site were surgically cleared. Myoclonus of cortical origin has never been described in mercury poisoning. It is important to ask patients presenting with jerks about exposure to elemental mercury even if they have a progressive illness, as it is a potentially reversible condition as in our patient. PMID- 17708574 TI - The timing of rhDNase in relation to airway clearance therapy-unplugged. PMID- 17708575 TI - Longitudinal quantification of growth and changes in primary tracheobronchomalacia sites in children. AB - RATIONALE: Longitudinal follow-up of children with tracheobronchomalacia is essential to improving our understanding of these disorders, yet currently, there is no such data. OBJECTIVES: To longitudinally define malacia sites and quantify the cross-sectional area (CSA) of the lumen using a bronchoscopic technique and to relate these measurements to illness profiles. METHODS: The validated color histogram mode technique was utilized to quantify primary malacia lesions and airway sites' CSA. Illness frequency, validated scales of illness and cough diary scores were prospectively used to assess clinical profiles. RESULTS: Thirty-five malacia sites were defined from the 2 studies of 21 children. CSA of 21 (60%) of the malacia lesions increased, 5 (14%) new lesions appeared, 5 (14%) decreased in size, 3 (8%) remained unchanged, and 1(3%) was indeterminate. Overall there was no statistically significant change in paired-data assessments of malacia sites' area while there was a significant increase in area of non-malacia sites. The median yearly growth rate for the malacia sites and non-malacia was 3.65 mm2/year sites and 5.38 mm2/year, respectively (P = 0.31). The type and severity of lesion was not associated with any difference in growth rates, illness frequency or clinical scores. CONCLUSIONS: Malacia lesions increase in size at the same rate as non-malacia sites. However malacia may worsen and new primary lesions may develop. Neither malacia type nor severity influences their growth pattern or illness profile. PMID- 17708576 TI - Long-chain fatty acyl-coenzyme A-induced inhibition of glucokinase in pancreatic islets from rats depleted in long-chain polyunsaturated omega3 fatty acids. AB - The metabolism of D-glucose was recently reported to be impaired in pancreatic islets from second generation rats depleted in long-chain polyunsaturated omega3 fatty acids. Considering the increased clearance of circulating non-esterified fatty acids prevailing in these rats, a possible inhibition of glucokinase in insulin-producing cells by endogenous long-chain fatty acyl-CoA was considered. The present study was mainly aimed at assessing the validity of the latter proposal. The activity of glucokinase in islet homogenates, as judged from the increase in D-glucose phosphorylation rate in response to a rise in the concentration of the hexose represented, in the omega3-depleted rats, was only 81.8 +/- 4.8% (n = 11; p < 0.005) of the paired value recorded in control animals. This coincided with the fact that the inclusion of D-glucose 6-phosphate (3.0 mM) and D-fructose 1-phosphate (1.0 mM) in the assay medium resulted in a lesser fractional decrease of D-glucose phosphorylation in omega3-depleted rats than in control animals. Moreover, whereas palmitoyl-CoA (50 microM) decreased the activity of glucokinase by 38.0 +/- 6.0% (n = 4; p < 0.01) in islet homogenates from normal rats, the CoA ester failed to affect significantly the activity of glucokinase in islet homogenates from omega3-depleted rats. These findings afford direct support for the view that glucokinase is indeed inhibited by endogenous long-chain fatty acyl-CoA in islets from omega3-depleted rats, such an inhibition probably participating to the alteration of D-glucose catabolism prevailing in these islets. PMID- 17708577 TI - Evidence that PAR2-triggered prostaglandin E2 (PGE2) formation involves the ERK cytosolic phospholipase A2-COX-1-microsomal PGE synthase-1 cascade in human lung epithelial cells. AB - We investigated possible involvement of three isozymes of prostaglandin E synthase (PGES), microsomal PGES-1 (mPGES-1), mPGES-2 and cytosolic PGES (cPGES) in COX-2-dependent prostaglandin E(2) (PGE(2)) formation following proteinase activated receptor-2 (PAR2) stimulation in human lung epithelial cells. PAR2 stimulation up-regulated mPGES-1 as well as COX-2, but not mPGES-2 or cPGES, leading to PGE(2) formation. The PAR2-triggered up-regulation of mPGES-1 was suppressed by inhibitors of COX-1, cytosolic phospholipase A(2) (cPLA(2)) and MEK, but not COX-2. Finally, a selective inhibitor of mPGES-1 strongly suppressed the PAR2-evoked PGE(2) formation. PAR2 thus appears to trigger specific up regulation of mPGES-1 that is dependent on prostanoids formed via the MEK/ERK/cPLA(2)/COX-1 pathway, being critical for PGE(2) formation. PMID- 17708578 TI - An observational study of the effectiveness and safety of intramuscular olanzapine in the treatment of acute agitation in patients with bipolar mania or schizophrenia/schizoaffective disorder. AB - OBJECTIVE: To determine the effect of intramuscular (IM) olanzapine in severely agitated patients. METHODS: This was an open-label multicenter 1-week observational study of IM olanzapine treatment in severely agitated inpatients and psychiatric emergency services with bipolar mania (n = 22) or schizophrenia (n = 52). Mean change from baseline to 2 h post-first injection (LOCF) in agitation was assessed by PANSS-Excited Component (PANSS-EC) (score range: 5-35 points) mean change from baseline to 15, 30, 45, 60, 90, and 120 min post-first injection, and visit-wise mean changes from mixed-model repeated measures analysis of variance. Kaplan-Meier survival curve analyses estimated time to categorical response (rating of 0.05). CONCLUSION: E-cad expression is relatively low in the internal obstruction of stagnant toxin type and the in-coordination between liver and stomach type, where tumor development and metastasis may be associated with low E-cad expression, or with low homogeneous adhesiveness between tumor cells. PMID- 17708600 TI - Female hepatology: favorable role of estrogen in chronic liver disease with hepatitis B virus infection. AB - Chronic hepatitis B virus (HBV) infection is the most common cause of hepatic fibrosis and hepatocellular carcinoma (HCC), mainly as a result of chronic necroinflammatory liver disease. A characteristic feature of chronic hepatitis B infection, alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD) is hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which, in turn, activates hepatic stellate cells (HSCs). HSCs are the primary target cells for inflammatory and oxidative stimuli, and these cells produce extracellular matrix components. Chronic hepatitis B appears to progress more rapidly in males than in females, and NAFLD, cirrhosis and HCC are predominately diseases that tend to occur in men and postmenopausal women. Premenopausal women have lower hepatic iron stores and a decreased production of proinflammatory cytokines. Hepatic steatosis has been observed in aromatase-deficient mice, and has been shown to decrease in animals after estradiol treatment. Estradiol is a potent endogenous antioxidant which suppresses hepatic fibrosis in animal models, and attenuates induction of redox sensitive transcription factors, hepatocyte apoptosis and HSC activation by inhibiting a generation of reactive oxygen species in primary cultures. Variant estrogen receptors are expressed to a greater extent in male patients with chronic liver disease than in females. These lines of evidence suggest that the greater progression of hepatic fibrosis and HCC in men and postmenopausal women may be due, at least in part, to lower production of estradiol and a reduced response to the action of estradiol. A better understanding of the basic mechanisms underlying the sex-associated differences in hepatic fibrogenesis and carciogenesis may open up new avenues for the prevention and treatment of chronic liver disease. PMID- 17708605 TI - Cystamine ameliorates liver fibrosis induced by carbon tetrachloride via inhibition of tissue transglutaminase. AB - AIM: To investigate the anti-fibrosis effect of the tissue transglutaminase (tTG) specific inhibitor cystamine on liver fibrosis. METHODS: Sixty-eight male Sprague Dawley rats were divided into three groups: normal control, liver fibrosis control and cystamine-treated group. Liver fibrosis was induced by intraperitoneal injection of carbon tetrachloride (CCl(4)), and Cystamine was administrated by intraperitoneal injection starting 2 d before the first administration of CCl(4). Animals in each group were further divided into 2 subgroups according to two time points of 4 wk and 8 wk after treatment. Hepatic function, pathological evaluation (semi-quantitative scoring system, SSS) and liver hydroxyproline (Hyp) content were examined. Real-time PCR was used to detect the expression of tTG, smooth muscle alpha actin (alpha-SMA), tissue inhibitor of metalloproteinase 1 (TIMP-1) and collagen-1 mRNA. The expressions of tTG and alpha-SMA protein were detected by Western Blotting. RESULTS: Eight weeks after treatment, the SSS score of liver was significantly less in the cystamine group than that in the fibrosis control group (P < 0.01). The levels of alanine aminotransferase (ALT) and total bile acid (TBA) at the 4 wk and 8 wk time points were decreased in the cystamine group compared with those in fibrosis controls (P < 0.01). Liver hydroxyproline content at the 4 wk and 8 wk time points showed a substantial reduction in the cystamine group compared to fibrosis controls (P < 0.01). The expression of tTG, alpha-SMA, collagen-1, TIMP-1 mRNA and tTG, as well as alpha-SMA protein was downregulated in the cystamine group compared to fibrosis controls. CONCLUSION: Cystamine can ameliorate CCl(4) induced liver fibrosis and protect hepatic function. The possible mechanism is related to the reduced synthesis of the extracellular matrix (ECM) caused by the inhibition of hepatic stellate cell activation and decreased expression of TIMP-1. PMID- 17708606 TI - Clinical presentation and endoscopic management of Dieulafoy's lesions in an urban community hospital. AB - AIM: To identify rates of occurrence, common clinical and endoscopic features, and to review the outcome of endoscopic management of Dieulafoy's lesions in the upper gastrointestinal (GI) tract in an urban community hospital setting. METHODS: Endoscopic data from esophagogastroduodenoscopies (EGDs), done at Wyckoff Heights Medical Center, Brooklyn, NY between 2000 and 2006 were reviewed to identify patients with Dieulafoy's lesions. Demographic data, medical history, examination findings, lab data, endoscopic findings and details of therapy for patients treated for Dieulafoy's lesions were reviewed retrospectively. RESULTS: Dieulafoy's lesions were documented to be the cause of bleeding in approximately 1% of patients presenting with upper gastrointestinal bleeding, while they were detected in only 2 patients when the indications for EGDs were different from active GI bleeding. When we analyzed EGDs performed in patients above age 65 years presenting with gastrointestinal bleeding, prevalence of Dieulafoy's lesions approached 10 percent. The most common location of the lesion was the body of stomach (7), followed by the cardia (4) and the esophagus (2). One patient had this lesion in the fundus and one patient in the duodenal apex. All patients were initially treated endoscopically with epinephrine injection, in eight cases heater probe was applied following epinephrine and endoscopic clips were applied in two cases. All but one of the patients did well in near and intermediate term follow-up (average follow-up period of 18 mo). One patient died of multi-organ failure during the same hospital stay. Average length hospital stay was 7 d. CONCLUSION: Community hospital gastroenterologists and endoscopists should be aware that Dieulafoy's lesions are an uncommon cause of upper GI bleeding among elderly patients. Early accurate diagnosis through emergent endoscopy and endoscopic therapy, especially in patients with multiple co-morbid conditions, can be very effective and life saving. PMID- 17708607 TI - Effects of long term hydrophilic bile acid therapy on in vitro contraction of gallbladder muscle strips in patients with cholesterol gallstones. AB - AIM: To evaluate ursodeoxycholic acid (UDCA) therapy on the in vitro contraction of gallbladder smooth muscle strips from cholesterol gallstone patients. METHODS: The contraction forces of gallbladder smooth muscle strips from 28 patients with cholesterol gallstones treated with UDCA were compared with contraction forces from 14 untreated patients. The strips were stimulated with increasing concentrations of cholecystokinin-8 (CCK-8). RESULTS: Although the contraction forces that developed in response to CCK-8 were higher in strips from specimens of UDCA treated patients compared to untreated patients, longer treatment periods (6-wk) caused more contraction responses than the short treatment period of 3-wk (F = 19.297, 1.85 +/- 0.22 g vs 1.70 +/- 0.10 g, P < 0.01). Contraction forces developed with maximal stimulation with KCl in the 6-wk treatment group were also higher than contraction forces in the untreated group (F = 4.274, 3.77 +/- 0.45 g vs 3.30 +/- 0.30 g, P < 0.05). CONCLUSION: Six-week UDCA treatment caused an increase in contractions of muscle strips from patients with cholesterol gallstones when compared to shorter treatment administration or controls. We suggest that extending UDCA treatment periods may cause more effective contractions in the gallbladder, and thereby increase the rate of response to treatment. PMID- 17708608 TI - Effect of vitamin E on oxidative stress status in small intestine of diabetic rat. AB - AIM: To investigate the effect of vitamin E on oxidative stress status in the small intestine of diabetic rats. METHODS: Twenty-four male Wistar rats were randomly divided into three groups: Control (C), non-treated diabetic (NTD) and vitamin E-treated diabetic (V(E)TD) groups. The increases in lipid peroxidation, protein oxidation and superoxide dismutase (SOD) in these three groups was compared after 6 wk. RESULTS: There was no significant difference in catalase activity between NTD and control rats. Compared to NTD rats, the treatment with vitamin E significantly decreased lipid peroxidation and protein oxidation, and also increased catalase activity and SOD. CONCLUSION: The results revealed the occurrence of oxidative stress in the small intestine of diabetic rats. Vitamin E, as an antioxidant, attenuates lipid peroxidation and protein oxidation, and increases antioxidant defense mechanism. PMID- 17708609 TI - Role of serum interleukin-18 as a prognostic factor in patients with hepatocellular carcinoma. AB - AIM: To determine whether serum interleukin-18 (IL-18) levels correlated with clinicopathologic features and prognosis in patients with hepatocellular carcinoma (HCC). METHODS: Serum IL-18, IL-6 and IL-12 levels were measured by enzyme-linked immunosorbent assay (ELISA) from 70 patients with HCC and 10 healthy controls. RESULTS: Serum IL-18, IL-6 and IL-12 levels of patients with HCC were significantly higher that those of the controls. The levels of IL-18 correlated significantly with the presence of venous invasion and advanced tumor stages classified by Okuda's criteria. Patients with high serum IL-18 levels (>= 10(5) pg/mL) had a poorer survival than those with low serum IL-18 levels (< 10(5) pg/mL) (4 and 11 mo, respectively, P = 0.015). Multivariate analyses showed that serum IL-18 level, but not IL-6 and IL-12 levels, was a significant and independent prognostic factor of survival. CONCLUSION: These findings demonstrate that serum IL-8 may a useful biological marker of tumor invasiveness and an independent prognostic factor of survival for patients with HCC. Thus, the detailed mechanisms of IL-18 involving in tumor progression should be further investigated. PMID- 17708610 TI - Genetic polymorphism of UL144 open reading frame of human cytomegalovirus DNA detected in colon samples from infants with Hirschsprung's disease. AB - AIM: To explore the genetic diversities of UL144 open reading frame (ORF) of cytomegalovirus DNA detected in colon tissue from infants with Hirschsprung's disease (HD) by sequencing UL144 DNA in 23 aganglionic colon tissue and 4 urine samples from 25 HD infants. METHODS: Nest PCR was performed for amplification of the UL144 gene. The UL144 gene was analyzed with softwares, such as DNAclub, BioEdit, PROSITE database, and DNAstar. RESULTS: The strains from HD patients were distributed among three genotypes of UL144: group 1A (64%), group 2 (24%), and group 3 (12%). The UL144 genotypes between strains from HD and control group were compared by chi square test (c2 = 1.870, P = 0.393). Strains from the colon were sporadically distributed in UL144 genotypes. CONCLUSION: There are genetic diversities of UL144 ORF in colon tissue of infants with HD. However, cytomegalovirus UL144 genotypes are not associated with clinical manifestations of HD. PMID- 17708611 TI - Association of high expression in rat gastric mucosal heat shock protein 70 induced by moxibustion pretreatment with protection against stress injury. AB - AIM: To study the effect of moxibustion on Zusanli or Liangmeng point on gastric mucosa injury in stress-induced ulcer rats and its correlation with the expression of heat shock protein 70 (HSP70). METHODS: Sixty healthy SD rats (30 males, 30 females) were divided into control group, injury model group, Zushanli point group, Liangmeng point group. Stress gastric ulcer model was induced by binding cold stress method. Gastric mucosa ulcer injury (UI) index was calculated by Guth method. Gastric mucosa blood flow (GMBF) was recorded with a biological signal analyzer. Protein content and gene expression in gastric mucosal HSP70 were detected by immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR). Thiobarbital method was used to determine malondialdehyde (MDA) content. Gastric mucosal endothelin (ET) and prostaglandin E(2) (PGE(2)) were analyzed by radioimmunoassay. RESULTS: High gastric mucosal UI index, high HSP70 expression, low GMBF and PGF(2), elevated MDA and ET were observed in gastric mucosa of rats subjected to cold stress. Moxibustion on Zusanli or Liangmeng point decreased rat gastric mucosal UI index, MDA and ET. Conversely, the expression of HSP70, GMBF, and PGE(2) was elevated in gastric mucosa after pretreatment with moxibustion on Zusanli or Liangmeng point. The observed parameters were significantly different between Zusanli and Liangmeng points. CONCLUSION: Pretreatment with moxibustion on Zusanli or Liangmeng point protects gastric mucosa against stress injury. This protection is associated with the higher expression of HSP70 mRNA and protein, leading to release of PGE(2) and inhibition of MDA and ET, impairment of gastric mucosal index. PMID- 17708612 TI - Effects of body-resistance strengthening and tumor-suppressing granules on immune adhesion function of red blood cells and expression of metastasis protein CD44 in tumor cells of patients with esophageal carcinoma. AB - AIM: To investigate the effects of Fuzheng Yiliu granules (body-resistance strengthening and tumor-suppressing granules) in patients with esophageal carcinoma. METHODS: We compared the immune adherent properties of red blood cells (RBCs), the expression of metastasis protein CD44, and the metastasis inhibition factor nm23, in esophageal carcinoma tumor cells of patients before and after radiotherapy in the presence and absence of orally administered Fuzheng Yiliu granules. Sixty-three hospitalized patients with esophageal carcinoma were treated with standard radiotherapy and randomly divided into treatment group (n = 30) treated with both radiotherapy and Fuzheng Yiliu granules and control group (n = 33) given radiotherapy only. Blood samples and tumor tissue were obtained before and after 21 d of treatment. The rosette rates for complement receptor type 3b (C3bRR) and immune complex receptor (ICRR) on RBCs were measured by erythrocyte immunological methods. Expression of CD44 and nm23 in tumor tissue sections was determined by immunohistochemical staining with monoclonal antibodies CD44v6 ad nm23H-1, respectively. RESULTS: The positivity of RBC-C3bRR before and after 21 d of treatment increased from 7.78% +/- 1.59% to 10.03% +/- 2.01% in the double treatment group, while it changed only slightly from 7.18% +/ 1.29% to 7.46% +/- 1.12% in the radiotherapy group. The positive rate for RBC ICRR decreased from 37.68% +/- 2.51% to 22.55% +/- 1.65% after the double treatment, and from 37.28% +/- 2.41% to 24.69% +/- 1.91% in radiotherapy group at the same time points. The difference in erythrocyte immune adherent function between the two groups was significant (P < 0.01, t-test). The CD44(+)-cases were reduced from 21 (70.00%) to 12 (40.00%) after treatment with Fuzheng Yiliu granules, whereas the CD44(+)-cases (69.70%) in the radiotherapy group remained unchanged. The difference between the treatment (40.00%) and control (69.70%) groups was significant (P < 0.05). Although the nm23(+)-cases were increased from 4 (13.33%) to 6 (20.00%) in the double treatment group and from 6 (18.18%) to 7 (21.21%) in the radiotherapy group, the difference was not significant (P > 0.05). CONCLUSION: Fuzheng Yiliu granules enhance the immune adhesion function of RBCs and reduce the number of CD44(+)-cells in esophageal carcinoma patients, suggesting a potential role of these Chinese herbals in suppression of invasion and metastasis of malignant cells. However, this anti-metastatic effect has yet to be validated in vivo. PMID- 17708614 TI - A meta-analysis of the yield of capsule endoscopy compared to double-balloon enteroscopy in patients with small bowel diseases. AB - AIM: To compare the diagnostic yield of capsule endoscopy (CE) with that of double-balloon enteroscopy (DBE). METHODS: Pubmed, Embase, Elsevier ScienceDirect, the China Academic Journals Full-text Database, and Cochrane Controlled Trials Register were searched for the trials comparing the yield of CE with that of DBE. Outcome measure was odds ratio (OR) of the yield. Fixed or random model method was used for data analysis. RESULTS: Eight studies (n = 277) which prospectively compared the yield of CE and DBE were collected. The results of meta-analysis indicated that there was no difference between the yield of CE and DBE [170/277 vs 156/277, OR 1.21 (95% CI: 0.64-2.29)]. Based on sub analysis, the yield of CE was significantly higher than that of double-balloon enteroscopy without combination of oral and anal insertion approaches [137/219 vs 110/219, OR 1.67 (95% CI: 1.14-2.44), P < 0.01), but not superior to the yield of DBE with combination of the two insertion approaches [26/48 vs 37/48, OR 0.33 (95% CI: 0.05-2.21), P > 0.05)]. A focused meta-analysis of the fully published articles concerning obscure GI bleeding was also performed and showed similar results wherein the yield of CE was significantly higher than that of DBE without combination of oral and anal insertion approaches [118/191 vs 96/191, fixed model: OR 1.61 (95% CI: 1.07-2.43), P < 0.05)] and the yield of CE was significantly lower than that of DBE by oral and anal combinatory approaches [11/24 vs 21/24, fixed model: OR 0.12 (95% CI: 0.03-0.52), P < 0.01)]. CONCLUSION: With combination of oral and anal approaches, the yield of DBE might be at least as high as that of CE. Decisions made regarding the initial approach should depend on patient's physical status, technology availability, patient's preferences, and potential for therapeutic endoscopy. PMID- 17708613 TI - Change in expression of apoptosis genes after hyperthermia, chemotherapy and radiotherapy in human colon cancer transplanted into nude mice. AB - AIM: To investigate the change in expression of p53, Bcl-2, and Bax genes in human colon cancer cells transplanted into nude mice after hyperthermia, chemotherapy, radiotherapy, thermochemotherapy, thermoradiotherapy and thermochemoradiotherapy. METHODS: Human colon cancer cell line (HT29) was transplanted into the hind limbs of nude mice. Under laboratory simulated conditions of hyperthermia (43 centigrade, 60 min), the actual radiation doses and doses of mitomycin C (MMC) were calculated in reference to the clinical radiotherapy for human rectal cancer and chemotherapy prescription for colon cancer. The mice were divided into 6 groups according to the treatment approaches: hyperthermia, chemotherapy, radiotherapy, thermochemotherapy, thermoradiotherapy, and thermochemoradiotherapy. The mice were sacrificed at different time points and the tumor tissue was taken for further procedures. The morphologic changes in membrane, cytoplasm and nuclei of tumor cells of p53, Bcl 2, and Bax after treatment, were observed by immunohistochemistry staining. RESULTS: All of the six treatment modalities down-regulated the expression of p53, Bcl-2 and up-regulated the expression of Bax at different levels. The combined therapy of hyperthermia, with chemotherapy, and/or irradiation showed a greater effect on down-regulating the expression of p53 (0.208 +/- 0.009 vs 0.155 +/- 0.0115, P < 0.01) and Bcl-2 (0.086 +/- 0.010 vs 0.026 +/- 0.0170, P < 0.01) and up-regulating Bax expression (0.091 +/- 0.0013 vs 0.207 +/- 0.027, P < 0.01) compared with any single therapy. CONCLUSION: Hyperthermia enhances the effect of radio- and chemotherapy on tumors by changing the expression of apoptosis genes, such as p53, Bcl-2 and Bax. PMID- 17708615 TI - Safety evaluation of donors for living-donor liver transplantation in Chinese mainland: a single-center report. AB - AIM: To discuss the safety of donors during living donor liver transplantation (LDLT) and the authors' experience with 50 cases. METHODS: Between January 1995 and March 2006, 50 patients with end-stage liver disease received LDLT in our department. Donors (at the age of 27-58 years) were healthy and antibody (ABO) compatible. The protocol of evaluation and selection of donors, choice of surgical methods and strategy applied in the safety evaluation of donors were analyzed. RESULTS: A total of 115 candidate donors were evaluated for LDLT at our center. Of these, 50 underwent successful hepatectomy for living donation. The elimination rate for donors was 43.5%. Positive hepatitis serology and ABO incompatibility were the main factors for excluding candidates. All donors recovered uneventfully. The follow-up time ranged from 3 to 135 mo. The incidence of major and minor medical complications was 12.0% and 28.0%, respectively. CONCLUSION: LDLT provides an excellent approach to the problem of donor shortage in China. With a thorough and complete preoperative workup and meticulous intra- and postoperative management, LDLT can be performed with minimal donor morbidity. PMID- 17708616 TI - New precut sphincterotomy for endoscopic retrograde cholangiopancreatography in difficult biliary duct cannulation. AB - AIM: To retrospectively investigate the effect and safety of various new type precut sphincterotomy techniques (VNTPST) in endoscopic retrograde cholangiopancreato-graphy (ERCP) due to difficult biliary duct cannulation (DBC). METHODS: A plough-like pull-type sphincterotome (PLPTS) or improved short nose sphincterotome or improved needle knife was applied. VNTPST was carried out in 30 of 280 patients, whose biliary tract could not be exposed well or deep cannulation was difficult to perform during ERCP with traditional methods. Patients were followed up for short-term complications and the therapeutic effect of VNTPS was observed and compared with that of traditional endoscopic sphincterotomy (EST). RESULTS: A total 280 patients underwent ERCP, of which 3 failed in operation because of pathological features in stomch or duodenum, 247 successfully underwent traditional ERCP (89.1%, 247/277), 30 failed (10.8%, 30/277). VNTPS technique succeeded in 24 (80%, 24/30) of 30 cases. The successful rate of deep biliary duct cannulation increased 8.6% (24/277), the total cannulation successful rate following precut was 97.7%. There was a significant difference between the two groups (97.7% vs 89.1%, c2 = 17.1, P < 0.01). The incidence of complications was 9.3% (26/277) for traditional ERCP group and 13.3% (4/30) for VNTPS technique group. Guideline tip was broken in pancreatic duct (KPDGP) of one patient, and there was no pancreatitis, slight or moderate bleeding postoperatively occurred in 2 patients, 1 patient had bleeding during operation (PDWN). There were no differences between VNTPS technique group and traditional ERCP (TRERCP) group (13.3% vs 9.3%, c2 = 0.478, P > 0.05). CONCLUSION: VNTPS procedure and Deng's precut are highly effective methods to get biliary access during ERCP with DBC. With skillful techniques, it can increase the successful rate for deep cannulation of biliary duct and decrease complications. VNTPS technique, especially Deng's precut is as effective and safe as EST. This technique can be well performed in hospitals without particular equipments. PMID- 17708617 TI - Listeria monocytogenes following orthotopic liver transplantation: central nervous system involvement and review of the literature. AB - Listeria monocytogene is a well-recognized cause of bacteremia in immunocompromised individuals, including solid organ transplant recipients, but has been rarely reported following orthotopic liver transplantation. We describe a case of listeria meningitis that occurred within a week after liver transplantation. The patient developed a severe headache that mimicked tacrolimus encephalopathy, and was subsequently diagnosed with listeria meningitis by cerebrospinal fluid culture. The infection was successfully treated with three week course of intravenous ampicillin. Recurrent hepatitis C followed and was successfully treated with interferon alfa and ribavirin. Fourteen cases of listeriosis after orthotopic liver transplantation have been reported in the English literature. Most reported cases were successfully treated with intravenous ampicillin. There were four cases of listeria meningitis, and the mortality of them was 50%. Early detection and treatment of listeria meningitis are the key to obtaining a better prognosis. PMID- 17708619 TI - Successful treatment of hypovascular advanced hepatocellular carcinoma with lipiodol-targetting intervention radiology. AB - We report a case of hypovascular advanced hepa-tocellular carcinoma (HCC) successfully treated with a novel combination therapy of percutaneous ethanol lipiodol injection (PELI) and intervention radiology (IVR), lipiodol-targetting IVR (Lipi-IVR). The present case had a hypovascular HCC (3 cm in diameter) located in the S6 region of the liver. Although the tumor was not detectable at all by both of early and late phase of helical dynamic computed tomography (CT), it could be detected by ultrasonography (US) as a low echoic space occupying lesion (SOL) beside the gallbladder and right kidney. Serum levels of alpha fetoprotein (AFP) and AFP-L3 were extremely high. Combination therapy of PELI, firstly reported in our department, and IVR (PELI and IVR, lipiodol-targetting IVR) was performed twice for the treatment. PELI could effectively visualize the location of the tumor for IVR treatment and show the presence of a thin blood vessel branching from the right hepatic artery flowing into the lipiodol deposit. After treatment, the serum levels of AFP and AFP-L3 were rapidly decreased to normal and maintained for more than eight months. Thus, this case expressing the tremendous effect might give us insight into the effectiveness of the novel combination therapy of PELI and IVR for the treatment of hypovascular HCC. PMID- 17708620 TI - Hepatocellular carcinoma with chronic B-type hepatitis complicated by autoimmune hemolytic anemia: a case report. AB - A 57-year-old man consulted a local hospital because of a persistent slight fever. At the age of 37 years he was diagnosed having B-type hepatitis, but left the liver dysfunction untreated. Twenty years later, he was diagnosed having chronic hepatitis B, hepatocellular carcinoma (HCC) and macrocytic anemia, and referred to our hospital for further investigation. A HCC with a maximum diameter of 5.2 cm was detected in segment 8. Results of blood tests included 1.8 mg/dL serum total bilirubin, 0.9 mg/dL bilirubin, less than 10 mg/dL haptoglobin, 7.9 g/dL hemoglobin, 130 fL MCV, and 14.5% reticulocytes. A bone marrow sample showed erythroid hyperplasia. The direct Coombs test gave a positive result. We diagnosed the anemia as autoimmmune hemolytic anemia (AIHA), for which prednisolone could not be administered due to positivity for HBsAg and HBeAg. After preparation of washed blood cells for later transfusion, the patient underwent systematic resection of segment 8. The cut surface of the resected specimen demonstrated an encapsulated yellow-brownish tumor measuring 52 mm multiply 40 mm which was diagnosed pathologicaly as moderately differentiated HCC. On the 9th postoperative day, the patient's temperature rose to 38 centigrade, and exacerbated hemolysis was observed. The maximum total bilirubin value was 5.8 mg/dL and minimum hemoglobin level was 4.6 g/dL. He tolerated this period without blood transfusion. Currently he is being followed up as an outpatient, and shows no signs of HCC recurrence or symptoms of anemia. AIHA associated with HBV infection has been described in only three previous cases, and the present case is the first in which surgery was performed for accompanying HCC. PMID- 17708618 TI - Fulminant hepatic failure in a case of autoimmune hepatitis in hepatitis C during peg-interferon-alpha 2b plus ribavirin treatment. AB - A 27-year-old Caucasian female with hepatitis C virus (HCV) infection treated with interferon (IFN) who developed severe autoimmune hepatitis (AIH) is described. The infecting viral strain was of genotype Ib and the pre-treatment HCV viral load was at a high level. The patient was treated with pegylated IFN alpha 2b and ribavirin, and her HCV-RNA became negative at wk 12, but after that she developed fulminant hepatic failure. The patient recovered after steroid pulse therapy consisting of methylprednisolone 1000 mg/d for three days which was administered twice. A needle liver biopsy revealed the typical pathological findings of AIH. PMID- 17708621 TI - Spontaneous rupture of the liver in a patient with chronic hepatitis B and D. AB - Spontaneous rupture of the liver is a rare condition with serious consequences, if not recognized and treated in time. It has been reported as a complication of several disorders, including benign or malignant liver tumors, connective tissue disease, infiltrating liver disease, preeclampsia, and post anticoagulant therapy. We report a case of spontaneous rupture of liver in a non-cirrhotic, chronic hepatitis B and D patient presenting with acute hemoperitoneum and shock. The subcapsular hematoma and rupture of liver were documented by image studies. The patients' condition gradually stabilized after fluid resuscitation. The reported case and literature review suggest that spontaneous rupture of liver must be considered in a differential diagnosis of acute hemoperitoneum. A high index of suspicion and early diagnosis with imaging are critically important. PMID- 17708623 TI - Ganodermataceae: natural products and their related pharmacological functions. AB - The objective of this paper is to review the natural products and the pharmacological functions of Ganodermataceae family. Presently, studies on the bioactive components of Lingzhi are focused on polysaccharides and triterpenes/triterpenoids compounds. New Ganoderma polysaccharides, including their molecular weights, glycosyl residue compositions, glycosyl linkage and branches, are summarized in this paper. Also presented are new types of triterpenes and their characteristics from Lingzhi. Taking Ganoderma lucidum as an example, we reviewed its pharmacological functions in anti-tumor and immune modulating activities for treating hypoglycemosis, hepatoprotection, and the effect on blood vessel system. Based on the advances in Lingzhi research in the past few decades, both G. lucidum and G. sinense are considered as the representative species of medicinal mushroom Lingzhi in China. Until 2001, G. tsugae was only advised to be used as the materials of the health products. The biologically-active components related to pharmacological functions of these three species were studied more than other Ganodermataceae family species; however, which have been used in less modern folk medicine. PMID- 17708624 TI - The efficacy of Chinese medicine for SARS: a review of Chinese publications after the crisis. AB - During the SARS crisis in China, 40-60% infected patients, at some stages of their treatment, received Chinese medicine treatment on top of the standard modern medicine treatment. This practice was endorsed and encouraged by the Chinese Center for Disease Control and Prevention, and some details of the herbal treatment were recommended. A review of the publications during and after the SARS crisis enabled us to get an objective view of the true value of the adjuvant therapy using Chinese medicinal herbs. Of the 130 articles searched, 90 were of reasonable quality and contained sufficient information for the enlightenment of the situation. These were reviewed. The results revealed positive but inconclusive indications about the efficacy of the combined treatments using Chinese medicine as an adjuvant. Positive effects using adjuvant herbal therapy included better control of fever, quicker clearance of chest infection, lesser consumption of steroids and other symptoms relief. In a few reports, some evidences of immunological boosterings were also found. More caution is required on the allegation about the efficacy of herbal medicine for the treatment or prevention of viral infection affecting the respiratory tract, while more clinical studies are indicated. PMID- 17708622 TI - Commonly used antioxidant botanicals: active constituents and their potential role in cardiovascular illness. AB - Cardiovascular disease continues to be the leading cause of death in the US. Recent studies found that reactive oxygen species (ROS) have been incriminated in the pathogenesis of both acute and chronic heart disease. Many botanicals possess antioxidant properties, and these herbal antioxidants may protect against cardiovascular diseases by contributing to the total antioxidant defense system of the human body. In this article, we reviewed the antioxidant components and properties of four putative antioxidant botanicals (i.e., grape seeds, green tea, Scutellaria baicalensis, and American ginseng), and their potential role in treating cardiovascular illness. The antioxidant activities of the herbal active constituents, and the relationship between their chemical structures and biological functions were also discussed. Further investigations are needed on the mechanisms of action of these botanicals as they affect salient cellular and molecular pathways involved in major diseases. Data obtained from future studies will have the potential for translation into practical benefits for human health. PMID- 17708625 TI - Treatment with rhubarb improves brachial artery endothelial function in patients with atherosclerosis: a randomized, double-blind, placebo-controlled clinical trial. AB - Rhubarb has been used to decrease plasma cholesterol levels and reduce vascular endothelial cellular damage in recent years. However, it is not known whether reported lipid-lowering effects are associated with the improvement of endothelial function. This work aimed to elucidate the therapeutic effects of rhubarb on serum lipids and brachial artery endothelial function, as well as to investigate the relationship between them. One hundred and three patients with atherosclerosis were randomly divided into two groups: patients in the control and the trial group received a placebo and rhubarb, respectively, in addition to the 6 month baseline therapy. Serum lipids and brachial artery endothelial functions were measured in all patients before and after treatment. A total of 83 patients completed the 6-month follow-up protocol. Serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in the trial group decreased significantly and LDL-C was significantly lower than that in the control group. Flow-mediated dilation (FMD) in the trial group was significantly higher after treatment in comparison to the baseline and to the control group. Improvement in FMD correlated with the decreased magnitude of TC and LDL-C levels. The results obtained appeared to confirm that rhubarb significantly improves endothelial function mainly due to lipid-lowering effects in patients with atherosclerosis. PMID- 17708626 TI - Effects of a Taiji and Qigong intervention on the antibody response to influenza vaccine in older adults. AB - Previous studies have suggested that Taiji practice may improve immune function. This study was intended to examine whether 5 months of moderate Taiji and Qigong (TQ) practice could improve the immune response to influenza vaccine in older adults. Fifty older adults (mean age 77.2 +/- 1.3 years) participated in this study (TQ N = 27; wait-list control [CON] N = 23). Baseline pre-vaccine blood samples were collected. All subjects then received the 2003-2004 influenza vaccine during the first week of the intervention. Post-vaccine blood samples were collected 3, 6 and 20 weeks post-intervention for analysis of anti-influenza hemagglutination inhibition (HI) titers. We found a significant (p < 0.05) increase in the magnitude and duration of the antibody response to influenza vaccine in TQ participants when compared to CON. The vaccination resulted in a 173, 130, and 109% increase in HI titer at 3, 6, and 20 weeks post-vaccine, respectively, in the TQ group compared to 58, 54, and 10% in CON. There was a significant between group difference at 3 and 20 weeks post-vaccine and at 20 weeks the TQ group had significantly higher titers compared to the pre-vaccine time point, whereas the CON group did not. A higher percentage of TQ subjects also responded to the influenza A strains with a protective (> 40HI) antibody response (37% TQ vs. 20% CON for the H1N1 strain and 56% TQ vs. 45% CON for the H3N2 strain), but the differences between groups were not statistically significant. Traditional TQ practice improves the antibody response to influenza vaccine in older adults, but further study is needed to determine whether the enhanced response is sufficient to provide definitive protection from influenza infection. PMID- 17708627 TI - Transcriptome analysis of cold syndrome using microarray. AB - Microarrays are widely used to study changes in gene expression in diseases. In this paper, we use this technology to discover gene expression patterns in the cold syndrome in Chinese medicine. We identify differentially expressed genes and extracted gene modules that are enriched with differentially expressed genes in the cold syndrome by analyzing cDNA samples, which are purified from blood taken from a pedigree. Our results suggest that the cold syndrome might be caused by the physiological imbalance and/or the disorder of metabolite processes. The study confirms the hypotheses about molecular pathways responsible to human metabolic-related diseases. PMID- 17708628 TI - Relationship between iris constitution analysis and TNF-alpha gene polymorphism in hypertensives. AB - Iridology is a complementary and alternative medicine that involves the diagnosis of medical conditions by noting irregularities of the pigmentation in the iris. Iris constitution has a strong hereditary component. Tumor necrosis factor-alpha (TNFalpha), a pleiotropic cytokine, has been implicated in many pathological processes including hypertension. In this paper, the relationship between iris constitution and TNFalpha gene polymorphism in those with hypertension is investigated. Eighty seven hypertensive individuals and 79 controls were classified according to iris constitution and the TNFalpha genotype of each individual determined. Compared to the controls, the frequency of the TNFalpha GA heterozygote was lower in the hypertensive group, although the statistical significance was marginal (p = 0.08). This result implies an association with resistance to the disease. In addition, the frequency of the cardio-renal connective tissue weakness type was significantly higher in the hypertensive group with the TNFalpha GG genotype, as compared to the controls (p = 0.001). An association is demonstrated among TNFalpha gene polymorphism, Koreans with hypertension, and iris constitution. PMID- 17708629 TI - Improvement of sperm production in subfertile boars by Cordyceps militaris supplement. AB - Cordyceps species have been traditionally used for the enhancement of sexual function, however, there is few direct evidence to prove this. We investigated the spermatogenic effect of Cordyceps militaris (CM) by supplementation with CM mycelium to subfertile boars. Seventeen Duroc and 12 Landrace boars (29 to 40 months old) were selected to feed with regular diet (control groups, n = 8 and 6, respectively) or diet supplemented with CM mycelium (treatment groups, n = 9 and 6, respectively) for 2 months. Semen was collected once a week. The quality of fertile sperm (normally greater than 62% of motility and 70% of normal morphology) and the quantity (semen volume, and total sperm number) were compared in these boars. The result showed that sperm production was enhanced significantly at the end of first month (p < 0.05), peaked at the second month (p < 0.01) of supplementation with CM and was maintained for 2 weeks after stopping the treatment (p < 0.01). Plasma cordycepin concentration was detected in boars supplemented with CM but not in the controls. More importantly, the percentages of motile sperm cells and sperm morphology were also improved significantly in most of treated boars during the second month of supplementation (p < 0.01) and 2 weeks after the treatment (p < 0.05) as compared to their initial values. These results indicate that supplementation with CM mycelium improves sperm quality and quantity in subfertile boars and may partly support the role of Cordyceps in sexual enhancement. PMID- 17708630 TI - Ginkgo biloba extract prevents ethanol induced dyslipidemia. AB - Ginkgo biloba extract (EGB) functions as a natural substantial antioxidant and hypolipidemic. Chronic alcohol abuse leads to sustained dyslipidemia characterized by hyperlipidemia and lipid peroxidation. Thus, the present study investigates the effect of EGB on lipid disorders induced by ethanol in rats. Male Sprague-Dawley rats were fed with ethanol (2.4 g/kg), and pretreated with a daily dose of low or high EGB (48 or 96 mg/kg, respectively). During the experiment, serum was collected on day 30, 60, and 90. Serum lipid profile, including lipid peroxidation, was determined by colorimetric methods. Our data showed that ethanol intake resulted in a time-dependent increase in serum levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and malondialdehyde (MDA), and a decrease of the ratio of high-density lipoprotein cholesterol (HDL-C) against TC. EGB prophylactic medication (48 and 96 mg/kg), especially at the high dose, significantly increased HDL-C content, and normalized the abnormal lipid profile and peroxidation in comparison to ethanol-fed only rats. These results suggest that ethanol results in time dependent hypercholesterolemia, hypertriglyceridemia and promotes serum lipid peroxidation. EGB pretreatment prevents hyperlipidemia and ameliorates lipid peroxidation induced by ethanol. PMID- 17708631 TI - Protective effect of pharmacological preconditioning of total flavones of abelmoschl manihot on cerebral ischemic reperfusion injury in rats. AB - The present study was to investigate the effect of pharmacological preconditioning of total flavones of abelmoschl manihot (TFA) on cerebral ischemic reperfusion injury in rats. Rat cerebral ischemia/reperfusion injury was induced by occluding the right middle cerebral artery (MCA). The infarct size was determined by staining with 2,3,5-triphenyl tetrazalium chloride (TTC). The serum malonaldehyde (MDA), nitric oxide (NO) and lactate dehydrogenase (LDH) levels were measured by using spectrophotometry; Inducible NO synthase (iNOS) mRNA expression was detected by RT-PCR method. The percentage of cerebral infarction volume was 28.1 +/- 0.8 in the model group, while TFA or nimodipine (Nim) pretreatment 36 hours prior to the ischemic insult significantly decreased the infarction volume. Increases of serum LDH activity and MDA level were observed after ischemia/reperfusion, but these changes were inhibited in rats pretreated with either TFA (20, 40, 80, 160 mg/kg) or Nim, indicating a delayed protective effect of TFA preconditioning on cerebral ischemic reperfusion injury. In addition, the serum NO level and the cerebral iNOS mRNA were up-regulated, suggesting a possible mechanism for the protective effect of TFA pretreatment on cerebral ischemic reperfusion injury. PMID- 17708632 TI - Anti-osteoporosis activity of naringin in the retinoic acid-induced osteoporosis model. AB - Isoflavonoids isolated from plants have been confirmed to fight osteoporosis and promote bone health. However, few studies have been conducted to describe the anti-osteoporosis activity of botanical flavonone. Based on the experimental outcomes, we demonstrated the ability of naringin to fight osteoporosis in vitro. We developed a retinoic acid-induced osteoporosis model of rats to assess whether naringin has similar bioactivity against osteoporosis in vitro. After a 14-day supplement of retinoic acid to induce osteoporosis, SD rats were administered naringin. A blood test showed that naringin-treated rats experienced significantly lower activity of serum alkaline phosphatase and had higher femur bone mineral density, compared to untreated rats. All three dosages of naringin improved the decrease in bone weight coefficient, the length and the diameter of the bone, the content of bone ash, calcium, and phosphorus content induced by retinoic acid. The data of histomorphological metrology of naringin groups showed no difference as compared to normal control rats. These outcomes suggest that naringin offer a potential in the management of osteoporosis in vitro. PMID- 17708633 TI - Psoralea corylifolia extract ameliorates experimental osteoporosis in ovariectomized rats. AB - We evaluated the protective effect of Psoralea corylifolia L. (PCL) extract on the ovariectomized (OVX) rat model. The biochemical markers of bone turnover, calcium metabolism, and calcium balance were examined. PCL extract (25 mg or 50 mg/kg body weight/day) was orally administrated to OVX rats for 3 months. PCL extract did not alter weight gain or uterus weight in OVX rats. PCL extract significantly increased serum Ca (calcium) levels (p < 0.05, vs. OVX group) as well as decreased urinary Ca excretion (p < 0.05 vs. OVX group) in OVX rats. The upregulation of serum osteocalcin level by ovariectomy was suppressed by treatment with PCL extract in rats (p < 0.05, vs. OVX group). PCL extract increased bone mineral density at 50 mg/kg body weight/day in OVX rats (p < 0.05, vs. OVX group). Our results indicate that orally administrated PCL extract can decrease urinary calcium excretion and decrease serum osteocalcin in OVX rats, resulting in positive effects on bone mineral density as well as bone formation. In conclusion, our studies showed that PCL might be a potential candidate for treatment of postmenopausal osteoporosis. PMID- 17708634 TI - The neuroprotective effect of picroside II from hu-huang-lian against oxidative stress. AB - Picroside II is an active constituent extracted from the traditional Chinese medicine (TCM) hu-huang-lian. To evaluate the neuroprotective effect of picroside II, PC12 cells were treated with glutamate in vitro and male ICR mice were treated with AlCl(3) in vivo. Pre-treatment of PC12 cells with picroside II could enhance the cell viability and decrease the level of intracellular reactive oxygen species (ROS) induced by glutamate. By DNA fragmentation and flow cytometry assay, picroside II (1.2 mg/ml) significantly prevented glutamate induced cell apoptosis. In the animal study, amnesia was induced in mice by AlCl(3) (100 mg/kg/d, i.v.). Pricroside II, at the dose of 20 and 40 mg/kg/d (i.g.), markedly ameliorated AlCl(3)-induced learning and memory dysfunctions and attenuated AlCl(3)-induced histological changes. This was associated with the significant increased superoxide dismutase (SOD) activity in the brain of experimental mice. All these results indicated that picroside II possessed the therapeutic potential in protecting against neurological injuries damaged by oxidative stress. PMID- 17708635 TI - Treatment of chronic liver injuries in mice by oral administration of ethanolic extract of the fruit of Hovenia dulcis. AB - The present study examined the effects of an ethanolic extract of the fruit of Hovenia dulcis (EHD) on chronic hepatitis induced by carbon tetrachloride (CCl(4)) in mice. CCl(4) (5%; 0.1 ml/10 g body weight) was given twice a week for 9 weeks, and mice received EHD throughout the entire experimental period. Plasma activities of GPT and GOT, and hepatic levels of malondialdehyde were significantly lowered in mice treated with EHD as compared to mice treated with CCl(4) only. Histological evaluation showed that EHD could attenuate the liver fibrosis and necrosis caused by CCl(4). RT-qPCR analysis also showed that EHD treatment decreased hepatic collagen (alpha1)(I) and collagen (alpha1)(III) mRNA expressions. Chronic CCl(4) treatment caused liver injuries in mice, characterized by an increase in hepatic methionine adenosyltransferase (MAT) 2A gene expression, and decreased MAT1A gene expression. EHD significantly reduced the changes in MAT gene expression due to the chronic CCl(4) treatment. These results clearly demonstrate that the EHD can reduce hepatic injuries in mice induced by CCl(4). PMID- 17708636 TI - Pharmacological studies on anti-hyperglycemic effect of folium eriobotryae. AB - Folium eriobotryae, dried leaves of Eriobotrya japonica (Thunb.) Lindl. is a traditional Chinese medicine with rich resources in China. This research investigated the anti-hyperglycemic effect of folium eriobotryae on normal and alloxan-diabetic mice. The 70% ethanol extract of folium eriobotryae (EJA-0) in doses of 15, 30 and 60 g (crude drug)/kg exerted a significant hypoglycemic effect on alloxan-diabetic mice, among which 30 g/kg of EJA-0 was more effective than 100 mg/kg of phenformin. The total sesquiterpenes (EJA-1) 30 g (crude drug)/kg had significant effect on lowering blood glucose level in normal or/and alloxan-diabetic mice. The tests of maximum dosage and acute toxicity showed that EJA-1 was safe (MD = 360 g/kg, LD(50) = 400.1 g/kg). The pharmacological tests on anti-hyperglycemic effects of EJA-0 and EJA-1 prove that folium eriobotryae is an outstanding material to develop medicine for treatment of diabetes mellitus. PMID- 17708637 TI - Effects of hypocrellin A on expression of vascular endothelial growth factor and endothelin-1 in human umbilical endothelial cells. AB - Increased endothelin-1 (ET-1), vascular endothelial growth factor (VEGF) and activation of protein kinase C (PKC) are co-contributors to endothelial hyperpermeability in diabetes. Several lines of evidence have suggested a hypothesis that activation of specific PKC isoforms are the causative factor in ET-1 and VEGF mediated endothelial dysfunction. In the present study, we tested this hypothesis with hypocrellin A, a naturally occurring PKC inhibitor from a Chinese plant. Human umbilical vein endothelial cells (HUVECs) were incubated with 20 mM glucose in both the presence and absence of hypocrellin A, after which, the protein expression and release of VEGF and mRNA expression and release of ET-1 were measured. VEGF and ET-1 were released into the medium and expressions of VEGF protein and ET-1 mRNA were significantly increased in HUVECs incubated with 20 mM glucose. Hypocrellin A (150 nM) significantly decreased VEGF release (117 +/- 3 vs. 180 +/- 11 pg/mg, p < 0.05) and VEGF protein expression (from 130 +/- 14% to 88 +/- 18.5%, p < 0.05). ET-1 release was also reduced in hypocrellin A treated HUVECs (63.3 +/- 9.9 vs. 75.2 +/- 12.6 ng/mg). Hypocrellin A significantly reversed the effect of high glucose on ET-1 mRNA expression (p < 0.05). The results revealed that PKC activation plays a pivotal role in VEGF and ET-1 mediated endothelial permeability. The naturally occurring compound hypocrellin A may be a potentially novel treatment for endothelial dysfunction in diabetes. PMID- 17708638 TI - Furan formation in sugar solution and apple cider upon ultraviolet treatment. AB - Furan is a possible human carcinogen induced by thermal processing of food. While ultraviolet C (UVC) is used to decontaminate apple cider and to sterilize sugar solutions, it is unknown whether UVC induces furan formation in cider or solutions of its major components. This study was conducted to investigate the possible formation of furan by UVC in apple cider and in solutions of common constituents of apple cider. Our results showed that UVC treatment induced furan formation in apple cider, and the major source of furan was apparently fructose. UVC treatment (at incident doses up to 9 J/cm (2)) of fructose solutions produced a higher amount of furan, while very low concentrations of furan were induced by UVC in glucose or sucrose solutions, and virtually no furan was induced by UVC from solutions of ascorbic acid or malic acid. When an isotope (d(4)-furan) of furan was treated with UVC, d(4)-furan was destroyed rapidly even at low doses in fructose solution, suggesting that the accumulation of furan is the balance between destruction and formation. The UV sensitivity of E. coli K12 (a surrogate of E. coli O157:H7) in two sources of apple cider was also determined. At UVC doses that could inactivate 5-log of E. coli, very low concentrations (<1 ppb) of furan were induced. Our results suggest that UVC could induce furan formation, but when used for the purpose of juice pasteurization, little furan was induced in apple cider. PMID- 17708639 TI - Metabolic characterization of Brassica rapa leaves by NMR spectroscopy. AB - The Brassica has been intensively studied due to the nutritional and beneficial effects. However, many species, varieties, and cultivars of this genus and the resulting large metabolic variation have been obstacles for systematic research of the plant. In order to overcome the problems posed by the biological variation, the metabolomic analysis of various cultivars of Brassica rapa was performed by NMR spectroscopy combined with multivariate data analysis. Discriminating metabolites in different cultivars and development stages were elucidated by diverse 2D-NMR techniques after sorting out different significant signals using (1)H NMR measurements and principal component analysis. Among the elucidated metabolites, several organic and amino acids, carbohydrates, adenine, indole acetic acid (IAA), phenylpropanoids, flavonoids, and glucosinolates were found to be the metabolites contributing to the differentiation between cultivars and age of Brassica rapa. On the basis of these results, the distribution of plant metabolites among different cultivars and development stages of B. rapa is discussed. PMID- 17708640 TI - Cultivar differences on nonesterified polyunsaturated fatty acid as a limiting factor for the biogenesis of virgin olive oil aroma. AB - The relationship between the content of nonesterified polyunsaturated fatty acids and the contents of oil aroma compounds that arise during the process to obtain virgin olive oil (VOO) was studied in two olive cultivars, Picual and Arbequina, producing oils with distinct aroma profiles and fatty acid compositions. Results suggest that the biosynthesis of VOO aroma compounds depends mainly on the availability of nonesterified polyunsaturated fatty acids, especially linolenic acid, during the process and then on the enzymatic activity load of the lipoxygenase/hydroperoxide lyase system. Both availability of substrates and enzymatic activity load seem to be cultivar-dependent. PMID- 17708641 TI - HPLC analysis of rosmarinic acid in feed enriched with aerial parts of Prunella vulgaris and its metabolites in pig plasma using dual-channel coulometric detection. AB - This paper describes a sensitive isocratic HPLC/ECD method developed for the determination of rosmarinic acid (RA) in plant material, animal feed, and pig plasma. The plasma sample preparation only includes protein precipitation and adjustment of the pH. The applicability of the method was tested on plasma samples of pigs that were exposed to a 91-day oral intake of RA via feed enriched by aerial parts of Prunella vulgaris. The plasma was directly analyzed using the method described as well as after enzymatic hydrolysis. When no hydrolysis step was included, RA and caffeic acid (CA) were quantified in the plasma. In hydrolyzed plasma samples, several other metabolites were determined, including dihydrocaffeic, ferulic, and dihydroferulic acid. The dual-channel coulometric detection employed, as an alternative to mass spectrometry, offers good selectivity and sensitivity owing to the electrochemical properties of the phenolic constituents. PMID- 17708642 TI - Development and agronomical validation of new fertilizer compositions of high bioavailability and reduced potential nutrient losses. AB - To optimize the economical cost of each unit of fertilizer applied and to reduce the environmental contamination caused by nutrient losses, the development of highly efficient granulated fertilizers is of great importance. This study proposes a strategy that consists of developing specific fertilizers having nutrient release patterns that are dependent on plant activity in the rhizosphere. This type of fertilizer is named "rhizosphere-controlled fertilizer" (RCF fertilizer). This fertilizer is based on the introduction of an organomineral matrix composed of metal [Mg (Ca is also possible), Zn (Fe and other metals are also possible)]-humic phosphates. The presence of this matrix modifies the nutrient release pattern of the fertilizer. In this way there are two main nutrient fractions: (i) a water-soluble fraction or "starter" fraction and (ii) a "rhizosphere-controlled" fraction insoluble in water but soluble by the action of the rhizospheric acids released by plants and microorganisms. This study shows the chemical and structural characterization of the organomineral matrix, as well as its efficiency in slowing the nutrient release rate of the RCF fertilizer, principally with respect to P and N. It is demonstrated how these properties of the matrix were also reflected in the significant reduction in both ammonia volatilization and N leaching in a pot system consisting of wheat plants cultivated in a calcareous soil and fertilized with a RCF fertilizer. PMID- 17708643 TI - Characterization and in vitro digestibility of bovine beta-lactoglobulin glycated with galactooligosaccharides. AB - Galactooligosaccharides (GOS) are well-known prebiotic ingredients which can form the basis of new functional dairy products. In this work, the production and characterization of glycated beta-lactoglobulin (beta-LG) with prebiotic GOS through the Maillard reaction under controlled conditions ( a(w) = 0.44, 40 degrees C for 23 days) have been studied. The extent of glycation of beta-LG was evaluated by formation of furosine which progressively increased with storage for up to 16 days, suggesting that the formation of Amadori compounds prevailed over their degradation. RP-HPLC-UV, SDS-PAGE, and IEF profiles of beta-LG were modified as a consequence of its glycation. MALDI-ToF mass spectra of glycated beta-LG showed an increase of up to approximately 21% in its average molecular mass after storage for 23 days. Moreover, a decrease in unconjugated GOS (one tri , two tetra-, and one pentasaccharide) was observed by HPAEC-PAD upon glycation. These results were confirmed by ESI MS. The stability of the glycated beta-LG to in vitro simulated gastrointestinal digestion was also described and compared with that of the unglycated protein. The yield of digestion products of glycated beta-LG was lower than that observed for the unglycated protein. The conjugation of prebiotic carbohydrates to stable proteins and peptides could open new routes of research in the study of functional ingredients. PMID- 17708644 TI - Carotenoids in white- and red-fleshed loquat fruits. AB - Fruits of 23 loquat ( Eriobotrya japonica Lindl.) cultivars, of which 11 were white-fleshed and 12 red-fleshed, were analyzed for color, carotenoid content, and vitamin A values. Color differences between two loquat groups were observed in the peel as well as in the flesh. beta-Carotene and lutein were the major carotenoids in the peel, which accounted for about 60% of the total colored carotenoids in both red- and white-fleshed cultivars. beta-Cryptoxanthin and, in some red-fleshed cultivars, beta-carotene were the most abundant carotenoids in the flesh, and in total, they accounted for over half of the colored carotenoids. Neoxanthin, violaxanthin, luteoxanthin, 9- cis-violaxanthin, phytoene, phytofluene, and zeta-carotene were also identified, while zeaxanthin, alpha carotene, and lycopene were undetectable. Xanthophylls were highly esterified. On average, 1.3- and 10.8-fold higher levels of colored carotenoids were observed in the peel and flesh tissue of red-fleshed cultivars, respectively. The percentage of beta-carotene among colored carotenoids was higher in both the peel and the flesh of red-fleshed cultivars. Correlations between the levels of total colored carotenoids and the color indices were analyzed. The a* and the ratio of a*/ b* were positively correlated with the total content of colored carotenoids, while L*, b*, and H degrees correlated negatively. Vitamin A values, as retinol equivalents (RE), of loquat flesh were 0.49 and 8.77 microg/g DW (8.46 and 136.41 microg/100 g FW) on average for white- and red-fleshed cultivars, respectively. The RE values for the red-fleshed fruits were higher than fruits such as mango, red watermelon, papaya, and orange as reported in the literature, suggesting that loquat is an excellent source of provitamin A. PMID- 17708646 TI - Modeling the relationship between the main emulsion components and stability, viscosity, fluid behavior, zeta-potential, and electrophoretic mobility of orange beverage emulsion using response surface methodology. AB - The possible relationships between the main emulsion components (namely, Arabic gum, xanthan gum, and orange oil) and the physicochemical properties of orange beverage emulsion were evaluated by using response surface methodology. The physicochemical emulsion property variables considered as response variables were emulsion stability, viscosity, fluid behavior, zeta-potential, and electrophoretic mobility. The independent variables had the most and least significant ( p < 0.05) effect on viscosity and zeta-potential, respectively. The quadratic effect of orange oil and Arabic gum, the interaction effect of Arabic gum and xanthan gum, and the main effect of Arabic gum were the most significant ( p < 0.05) effects on turbidity loss rate, viscosity, viscosity ratio, and mobility, respectively. The main effect of Arabic gum was found to be significant ( p < 0.05) in all response variables except for turbidity loss rate. The nonlinear regression equations were significantly ( p < 0.05) fitted for all response variables with high R (2) values (>0.86), which had no indication of lack of fit. The results indicated that a combined level of 10.78% (w/w) Arabic gum, 0.56% (w/w) xanthan gum, and 15.27% (w/w) orange oil was predicted to provide the overall optimum region in terms of physicochemical properties studied. No significant ( p > 0.05) difference between the experimental and the predicted values confirmed the adequacy of response surface equations. PMID- 17708645 TI - HlMyb3, a putative regulatory factor in hop (Humulus lupulus L.), shows diverse biological effects in heterologous transgenotes. AB - A hop-specific cDNA library from glandular tissue-enriched hop cones was screened for Myb transcription factors. cDNA encoding for R2R3 Myb, designated HlMyb3, was cloned and characterized. According to the amino acid (aa) sequence, HlMyb3 shows the highest homology to GhMyb5 from cotton and is unrelated to the previously characterized HlMyb1 from the hop. Southern blot analyses indicated that HlMyb3 is a unique gene, which was detected in various Humulus lupulus cultivars, but not in Humulus japonicus. Reverse transcription and real-time PCR revealed the highest levels of HlMyb3 mRNA in hop cones at a late stage of maturation and in colored petiole epidermis, while the lowest levels were observed in hop flowers. Two alternative open reading frames starting in the N-terminal domain of HlMyb3, encoding for proteins having 269 and 265 amino acids with apparent molecular masses of 30.3 and 29.9 kDa, respectively, were analyzed as transgenes that were overexpressed in Arabidopsis thaliana, Nicotiana benthamiana, and Petunia hybrida plants. Transformation with the longer 269 aa variant designated l-HlMyb3 led to a flowering delay and to a strong inhibition of seed germination in A. thaliana. Nearly complete flower sterility, dwarfing, and leaf curling of P. hybrida and N. benthamiana l-HlMyb3 transgenotes were noted. On the contrary, the shorter 265-aa encoding s-HlMyb3 transgene led in A. thaliana to the stimulation of initial seed germination, to fast initiation of the lateral roots, and to quite specific branching phenotypes with many long lateral stems formed at angles near 90 degrees . Limited plant sterility but growth stimulation and rather branched phenotypes were evident for s-HlMyb3 transgenotes of P. hybrida and N. benthamiana. It was found that both HlMyb3 transgenes interfere in the accumulation and composition of flavonol glycosides and phenolic acids in transformed plants. These effects on heterologous transgenotes suggest that the HlMyb3 gene may influence hop morphogenesis, as well as metabolome composition during lupulin gland maturation. PMID- 17708647 TI - Solvent effects on extraction and HPLC analysis of soybean isoflavones and variations of isoflavone compositions as affected by crop season. AB - Spring (February to June) and fall (August to December) crops of soybean grown yearly in Taiwan with reverse temperature patterns provide a novel model to assess the effect of the crop season. In this study, three soybean cultivars, namely CH 1, VS-KS 2, and HBS, were grown for 2001 fall, 2002 spring, 2003 fall, 2004 spring, 2004 fall, and 2005 spring crops. The harvested and sun-dried soybeans were lyophilized, pulverized, and stored at -25 degrees C until HPLC analyses of isoflavone compositions were performed. As affected by extraction solvent and HPLC mobile phase, the amount of isoflavones extracted by methanol H(2)O was higher than those extracted by acetic acid-acetonitrile. In addition, when both extracts were subjected to HPLC analysis with reversed C18 column run respectively with methanol-H(2)O and acetic acid-acetonitrile mobile phases, malonyldaidzin, malonylglycitin, and malonylgenistin were not detected in the former phase. Accordingly, all harvested soybeans were subjected to methanol H(2)O extraction and HPLC analysis with the acetic acid-acetonitrile mobile phase. Among the detected soybeans, daidzin, genistin, malonyldaidzin, and malonylgenistin were the majors and glycitin, malonylglycitin, daidzein, and genistein were the minors of isoflavones. As affected by crop season for each cultivar grown for 3 years, daidzin, genistin, malonyldaidzin, and malonylgenistin contents of soybeans of the fall crops were significantly higher than those of their spring crops ( p < 0.05). PMID- 17708648 TI - Antimicrobial and antioxidant properties of rosemary and sage (Rosmarinus officinalis L. and Salvia officinalis L., Lamiaceae) essential oils. AB - The essential oils of rosemary ( Rosmarinus officinalis L.) and sage ( Salvia officinalis L.) were analyzed by means of gas chromatography-mass spectrometry and assayed for their antimicrobial and antioxidant activities. Antimicrobial activity was tested against 13 bacterial strains and 6 fungi, including Candida albicans and 5 dermatomycetes. The most important antibacterial activity of both essential oils was expressed on Escherichia coli, Salmonella typhi, S. enteritidis, and Shigella sonei. A significant rate of antifungal activity, especially of essential oil of rosemary, was also exhibited. Antioxidant activity was evaluated as a free radical scavenging capacity (RSC), together with the effect on lipid peroxidation (LP). RSC was assessed by measuring the scavenging activity of essential oils on 2,2-diphenyl-1-picrylhydrazil (DPPH) and hydroxyl radicals. Effects on LP were evaluated following the activities of essential oils in Fe(2+)/ascorbate and Fe(2+)/H2O2 systems of induction. Investigated essential oils reduced the DPPH radical formation (IC50 = 3.82 microg/mL for rosemary and 1.78 microg/mL for sage) in a dose-dependent manner. Strong inhibition of LP in both systems of induction was especially observed for the essential oil of rosemary. PMID- 17708649 TI - A new procedure to measure the antioxidant activity of insoluble food components. AB - The measurement of antioxidant activity was limited to soluble components to date. Functional groups, which are bound to insoluble matters, may exert antioxidant activity by a surface reaction phenomenon. This hypothesis was tested on the insoluble matters of foods, food ingredients, and Maillard reaction products (MRPs). Insoluble matters were prepared by consecutive washes with water and methanol followed by a lyophilization of the insoluble residue. The measurement was performed by a new procedure using 2,2'-azinobis(3 ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazil (DPPH) colored radicals. These insoluble matters always showed antioxidant activity. Alkali hydrolysis reduced up to 90% the antioxidant activity of cereal based insoluble matters, thus confirming that fiber-bound compounds have a major role in their antioxidant activity. The antioxidant activity of the insoluble MRPs was not significantly affected by processing conditions, but severe treatments increased the ratio between insoluble and soluble matters. The contribution of insoluble matter to total antioxidant activity was limited for fruits and vegetables, but it was relevant for cereal-based foods and increased over 50% for dietary-fiber-rich ingredients. PMID- 17708650 TI - A comparative study of the antioxidant power of flavonoid catechin and its planar analogue. AB - The antioxidant ability of the flavanol catechin and its planar derivative, catechin 1 (PC1), was explored using the DF/B3LYP theoretical approach. Their potentiality in the hydrogen abstraction and electron transfer reactions, the main working mechanisms of antioxidants, was evaluated by computing the values of two key parameters, which are the OH bond dissociation energy and the ionization potential. Results indicated that the effect of a planar arrangement in the catechin molecule is small in the case of the hydrogen abstraction but greater for the electron transfer, since the in vacuo ionization potential value decreases by about 3 kcal/mol. The reaction of these molecules with the hydroperoxyl radical (*)OOH indicated that the H(*) abstraction is faster with the planar catechin. PMID- 17708651 TI - Volatile compounds characterizing Tunisian Chemlali and Chetoui virgin olive oils. AB - A total of 33 virgin olive oil samples of the two main Tunisian cultivars, Chemlali and Chetoui, were characterized by their volatile compounds. The olive oil samples were obtained from olives harvested at four stages of ripeness in costal and inland farms of different geographical places. Major volatiles, mostly C6 and C5 compounds produced from linolenic and linoleic acids through the lipoxygenase cascade, were quantified by solid-phase microextraction-gas chromatography. Mathematical procedures allowed for the determination of the volatiles that not only are able to discriminate the olive oils by their olive cultivar (hexanal, E-2-hexenal, and total ketones) and ripeness (pentanal and 1 penten-3-one) but also contribute to their distinctive aroma. Finally, an electronic nose based on metal oxide sensors was checked for a rapid and at-line implementation of Tunisian olive oil varietal traceability. The classification of the samples by the sensors was explained by their sensitivity to volatiles E-2 hexanal, hexanal, 1-penten-3-one, ethanol, and Z-3-hexenol. Multivariate procedures of discriminant analysis and principal component analysis were used in the study. PMID- 17708652 TI - Profiling proteasome activity in tissue with fluorescent probes. AB - With proteasome inhibitors in use in the clinic for the treatment of multiple myeloma and with clinical trials in progress investigating the treatment of a variety of hematologic and solid malignancies, accurate methods that allow profiling of proteasome inhibitor specificity and efficacy in patients are in demand. Here, we describe the development, full biochemical validation, and comparison of fluorescent proteasome activity reporters that can be used to profile proteasome activities in living cells with high sensitivity. Seven of the synthesized probes tested label proteasomes in lysates, although the fluorescent dye used affects their specificity. Two differentially labeled probes tested are suitable for studying proteasome activity in living cells by gel-based assays, by confocal laser scanning microscopy, and by flow cytometry. We established methods using these fluorescent reporters to profile proteasome activity in different mouse tissues, carefully avoiding postlysis artifacts, and we show that proteasome subunit activity is regulated in an organ-specific manner. The techniques described here could be used to study in vivo pharmacological properties of proteasome inhibitors. PMID- 17708653 TI - Methotrexate conjugated to gold nanoparticles inhibits tumor growth in a syngeneic lung tumor model. AB - Methotrexate (MTX), a stoichiometric inhibitor of dihydrofolate reductase, is a chemotherapeutic agent for treating a variety of neoplasms. Impairment of drug import into cells and increase in drug export from cells may render cells resistant to MTX. MTX, when locally administered in a soluble form, is rapidly absorbed through capillaries into the circulatory system, which may also account for therapeutic failure in patients. To retain MTX within tumor cells for longer duration and alter its pharmacokinetic behavior, we proposed a new formulation of MTX bound to the gold nanoparticle (AuNP) that serves as drug carriers. In this study, we developed the MTX-AuNP conjugate and examined its cytotoxic effect in vitro and antitumor effect in vivo. Spectroscopic examinations revealed that MTX can be directly bound onto AuNP via the carboxyl group (-COOH) to form the MTX AuNP complex and kinetically released from the nanoparticles. The accumulation of MTX is faster and higher in tumor cells treated with MTX-AuNP than that treated with free MTX. Notably, MTX-AuNP shows higher cytotoxic effects on several tumor cell lines compared with an equal dose of free MTX. This can be attributed to the "concentrated effect" of MTX-AuNP. Administration of MTX-AuNP suppresses tumor growth in a mouse ascites model of Lewis lung carcinoma (LL2), whereas an equal dose of free MTX had no antitumor effect. In conclusion, these results suggest that by combining nanomaterials with anticancer drugs MTX-AuNP may be more effective than free MTX for cancer treatment. PMID- 17708654 TI - Role of formulation composition in folate receptor-targeted liposomal doxorubicin delivery to acute myelogenous leukemia cells. AB - Targeted drug delivery has the potential to improve the efficacy of a therapeutic agent while reducing its side effects. The folate receptor type beta (FR-beta) is a cell surface marker selectively expressed in the leukemic cells of approximately 70% of acute myeloid leukemia (AML) patients. Upregulation of FR beta may also be selectively induced in AML cells by treatment with all-trans retinoic acid (ATRA). In this study, the role of formulation composition in FR targeted liposomal doxorubicin (DOX) delivery to AML cells was investigated. Liposomal formulations with a variable percentage of folate-polyethylene glycol distearoyl phosphatidylethanolamine (f-PEG-DSPE) were synthesized and evaluated for FR-beta-targeted DOX delivery in MV4-11 AML cells in vitro and for their pharmacokinetic properties in vivo. The formulation containing 0.5 mol % f-PEG DSPE exhibited the highest efficiency of cellular uptake and in vitro cytotoxicity, as well as a long systemic circulation time in mice. In MV4-11 cells, the binding and cytotoxicity of FR-targeted liposomal DOX based on this formulation was also enhanced by ATRA-induced FR-beta upregulation. PMID- 17708656 TI - Pordamacrines A and B, alkaloids from Daphniphyllum macropodum. AB - The new Daphniphyllum alkaloids, pordamacrines A (1) and B (2), have been isolated from the leaves of Daphniphyllum macropodum, and their structures were elucidated on the basis of interpretation of spectroscopic data and by the single crystal X-ray diffraction analysis of 2. Pordamacrines A (1) and B (2) exhibited moderate vasorelaxant effects on the rat aorta. PMID- 17708655 TI - Glycogen synthase kinase-3 (GSK-3) inhibitory activity and structure-activity relationship (SAR) studies of the manzamine alkaloids. Potential for Alzheimer's disease. AB - Manzamine A and related derivatives isolated from a common Indonesian sponge, Acanthostrongylophora, have been identified as a new class of GSK-3beta inhibitors. The semisynthesis of new analogues and the first structure-activity relationship studies with GSK-3beta are also reported. Moreover, manzamine A proved to be effective in decreasing tau hyperphosphorylation in human neuroblastoma cell lines, a demonstration of its ability to enter cells and interfere with tau pathology. Inhibition studies of manzamine A against a selected panel of five different kinases related to GSK-3beta, specifically CDK 1, PKA, CDK-5, MAPK, and GSK-3alpha, show the specific inhibition of manzamine A on GSK-3beta and CDK-5, the two kinases involved in tau pathological hyperphosphorylation. These results suggest that manzamine A constitutes a promising scaffold from which more potent and selective GSK-3 inhibitors could be designed as potential therapeutic agents for Alzheimer's disease. PMID- 17708657 TI - Aryl hydrocarbon receptor-mediated effects of chlorinated polycyclic aromatic hydrocarbons. AB - Chlorinated polycyclic aromatic hydrocarbons (ClPAHs) with 3-5 rings are ubiquitous environmental contaminants. However, toxicities of ClPAHs remain unclear. In this study, aryl hydrocarbon receptor (AhR)-mediated activities of ClPAHs were investigated by using a yeast assay system. All environmentally relevant 18 ClPAHs showed the AhR activities in the test; the activities were elevated with the number of chlorine atoms on the lower molecular weight PAH ( approximately three-ring and fluoranthene derivatives) but not for higher molecular weight ClPAHs (>four-ring). The similar trends were also observed in certain ClPAHs-induced cytochrome P450 1A1 expression in MCF-7 cells. The structure-activity relationship between the AhR activity and the corresponding solvent accessible surface area of ClPAHs revealed a parabolic relationship, with approximately 350 A (2)/molecule as the optimal dimensions as the ligand for binding to AhR. These findings indicate that the spatial dimensions of ClPAHs apparently influence their ability to activate the AhR. Finally, we discussed the toxicity of exposure to ClPAHs based on the AhR activities, estimated that it would be approximately 30-50 times higher than that of dioxins. PMID- 17708658 TI - Ionic liquid phase synthesis of tetrahydropyrano- and tetrahydrofuranoquinolines under microwave irradiation. PMID- 17708659 TI - Selective fluoroalkylations with fluorinated sulfones, sulfoxides, and sulfides. AB - Efficient fluoroalkylations have been proven to be a highly useful strategy for the synthesis of bioactive fluorine-containing compounds and other materials. The design and use of a single category of reagents for multiple synthetic goals are much more attractive to preparative organic chemists. In this Account, we show how we have succeeded in the nucleophilic trifluoromethylation, difluoromethylation, difluoromethylenation, (phenylsulfonyl)difluoromethylation, (phenylthio)difluoromethylation, and monofluoromethylation as well as radical (phenylsulfonyl)difluoromethylation and electrophilic difluoromethylation by using fluorinated sulfones, sulfoxides, sulfides, or fluorinated sulfonium salts. The chemistry not only provides practically powerful synthetic methods, but the molecular design concept that we have developed may also be adopted to tackle other related chemical problems. PMID- 17708660 TI - Communicating science to the first degree. PMID- 17708664 TI - Science at the interface of chemistry and biology at the University of Texas Southwestern Medical Center. PMID- 17708665 TI - Bringing the excitement of biological research into the chemistry classroom at MIT. PMID- 17708666 TI - Closing the gap between interdisciplinary research and disciplinary teaching. PMID- 17708667 TI - Balancing teaching and research in obtaining a faculty position at a predominantly undergraduate institution. PMID- 17708668 TI - When conjugated polymers meet amyloid fibrils. AB - In the early 1900s, Alois Alzheimer diagnosed one of his patients with a devastating neurological impairment, and this form of dementia became known as Alzheimer's disease (AD). Much research over the past century has clearly established that numerous human diseases, ranging from AD and Parkinson's disease to dialysis-related amyloidosis, are best characterized by the abnormal aggregation of specific proteins. However, in the case of AD, the true toxic molecular species is still debated. Thus, the recent development of new diagnostic agents capable of distinguishing between different morphologies of aggregated proteins is of much interest. PMID- 17708669 TI - Linking SIRT2 to Parkinson's disease. AB - A recent study has identified selective inhibitors of the human silent information regulator 2 NAD (+)-dependent protein deacetylase, SIRT2, and has shown that these compounds protect against alpha-synuclein-mediated toxicity in cellular models of Parkinson's disease. The inhibitors were found to ameliorate dopaminergic cell death in vitro and in a Drosophila model of Parkinson's disease. Although the molecular mechanism of action is unclear, the compounds may function by promoting the formation of enlarged inclusion bodies, which are suggested to provide a cell-survival advantage. PMID- 17708670 TI - Unleashing biocatalysis/chemical catalysis synergies for efficient biomass conversion. AB - The goal of incorporating renewable carbon into the fuel and chemical enterprise will most likely be successful when combined systems of biocatalysts and chemical catalysts are exploited. Significant efforts in the biocatalytic release of sugars from biomass are being pursued for subsequent use in fermentation. Two recent papers demonstrate an alternative approach to converting these sugars to a liquid fuel by using chemical catalysts. PMID- 17708673 TI - Influence of albumin on sorption kinetics in solid-phase microextraction: consequences for chemical analyses and uptake processes. AB - Because of its simplicity, solid-phase microextraction (SPME) is an increasingly popular technique to use in experiments measuring freely dissolved concentrations of compounds in biological and environmental samples. However, a number of studies have shown that sorption kinetics of compounds in such SPME systems is dependent on the presence of a binding matrix. This affects the interpretability of nonequilibrium SPME data. In this study, this phenomenon was investigated by measuring the rate of depletion of pyrene from a "loaded" poly(dimethylsiloxane) fiber into surrounding cell culture medium containing different concentrations of bovine serum albumin (BSA). The rate of depletion was found to steadily increase with increasing concentrations of BSA. It was postulated that BSA facilitated the transport of pyrene through the medium. This phenomenon was modeled by considering diffusion of BSA-bound pyrene in addition to diffusion of unbound pyrene in the aqueous boundary layer (BL) around the fiber. The model closely fit the experimental data and illustrated that diffusion in the BL was rate limiting because the analyte's affinity for the fiber was high and the BL thickness significant. The concentration of binding matrix and the analyte's affinity for the matrix further determined the extent to which BSA-facilitated transport contributed to the kinetics of the system. PMID- 17708672 TI - Stable isotope assisted assignment of elemental compositions for metabolomics. AB - Assignment of individual compound identities within mixtures of thousands of metabolites in biological extracts is a major challenge for metabolomic technology. Mass spectrometry offers high sensitivity over a large dynamic range of abundances and molecular weights but is limited in its capacity to discriminate isobaric compounds. In this article, we have extended earlier studies using isotopic labeling for elemental composition elucidation (Rodgers, R. P.; Blumer, E. N.; Hendrickson, C. L.; Marshall, A. G. J. Am. Soc. Mass Spectrom. 2000, 11, 835-40) to limit the formulas consistent with any exact mass measurement by comparing observations of metabolites extracted from Arabidopsis thaliana plants grown with (I) (12)C and (14)N (natural abundance), (II) (12)C and (15)N, (III) (13)C and (14)N, or (IV) (13)C and (15)N. Unique elemental compositions were determined over a dramatically enhanced mass range by analyzing exact mass measurement data from the four extracts using two methods. In the first, metabolite masses were matched with a library of 11,000 compounds known to be present in living cells by using values calculated for each of the four isotopic conditions. In the second method, metabolite masses were searched against masses calculated for a constrained subset of possible atomic combinations in all four isotopic regimes. In both methods, the lists of elemental compositions from each labeling regime were compared to find common formulas with similar retention properties by HPLC in at least three of the four regimes. These results demonstrate that metabolic labeling can be used to provide additional constraints for higher confidence formula assignments over an extended mass range. PMID- 17708674 TI - Dual-channel method for interference-free in-channel amperometric detection in microchip capillary electrophoresis. AB - A novel in-channel amperometric detection method for microchip capillary electrophoresis (CE) has been developed to avoid the interference from applied potential used in the CE separation. Instead of a single separation channel as in conventional CE microchips, we use a dual-channel configuration consisting of two different parallel separation and reference channels. A working electrode (WE) and a reference electrode (RE) are placed equally at a distance 200 microm from its outlet on each channel. Running buffer flows through the reference channel. Our dual-channel CE microchips consist of a poly(dimethylsiloxane) (PDMS) upper plate and a glass lower plate to form a PDMS/glass hybrid chip. Amperometric signals are measured without any potential shift and interference from the applied CE potential, and CE separation maintains its high resolution because this in-channel configuration does not allow additional band broadening that is notorious in end-channel and off-channel configurations. The high performance of this new in-channel electrochemical detection methodology for CE has been demonstrated by analyzing a mixture of electrochemically active biomolecules: dopamine (DA), norepinephrine, and catechol. We have achieved a 0.1 pA detectability from the analysis of DA, which corresponds to a 1.8 nM concentration. PMID- 17708671 TI - Modulating hypoxia-inducible transcription by disrupting the HIF-1-DNA interface. AB - Transcription mediated by hypoxia-inducible factor (HIF-1) contributes to tumor angiogenesis and metastasis but is also involved in activation of cell-death pathways and normal physiological processes. Given the complexity of HIF-1 signaling, it could be advantageous to target a subset of HIF-1 effectors rather than the entire pathway. We compare the genome-wide effects of three molecules that each interfere with the HIF-1-DNA interaction: a polyamide targeted to the hypoxia response element, small interfering RNA targeted to HIF-1alpha, and echinomycin, a DNA-binding natural product with a similar but less specific sequence preference than the polyamide. The polyamide affects a subset of hypoxia induced genes consistent with its binding site preferences. For comparison, HIF 1alpha siRNA and echinomycin each affect the expression of nearly every gene induced by hypoxia. Remarkably, the total number of genes affected by either polyamide or HIF-1alpha siRNA over a range of thresholds is comparable. The data show that polyamides can be used to affect a subset of a pathway regulated by a transcription factor. In addition, this study offers a unique comparison of three complementary approaches towards exogenous control of endogenous gene expression. PMID- 17708675 TI - New class of Ag/AgCl electrodes based on hydrophobic ionic liquid saturated with AgCl. AB - A new type of Ag/AgCl electrodes based on a hydrophobic ionic liquid has been proposed. The electrode consists of a Ag/AgCl electrode immersed in or coated with a AgCl-saturated ionic liquid, 1-methyl-3-octylimidazolium bis(trifluoromethylsulfonyl)imide ([C(8)mim+][C(1)C(1)N-]), instead of the internal aqueous solution. The [C(8)mim+][C(1)C(1)N-] phase plays dual roles, that is, as a medium dissolving AgCl and an ionic-liquid-type salt bridge upon contact with an aqueous solution. The gelation of the [C(8)mim+][C(1)C(1)N-] phase allows us to prepare coated-wire-type solid-state reference electrodes with a well-defined thermodynamic basis for the electrode potential. Both gelled and nongelled types show stable electrode potentials against the change in the concentration of KCl between 0.05 mmol dm(-3) and 2 mol dm(-3). This new class of reference electrodes opens the way for a variety of miniaturized and solid-state reference electrodes. PMID- 17708676 TI - Enzyme-based colorimetric detection of nucleic acids using peptide nucleic acid immobilized microwell plates. AB - The development of label-free or nonlabeling assays for nucleic acids is important in basic biological research and biomedical diagnosis. In this study, we have developed an enzyme-based colorimetric assay for nucleic acids, which combines the robustness of nonlabeling of DNA and RNA samples and the adequate sensitivity of enzymatic reactions. The core of this assay is the use of neutral peptide nucleic acid (PNA) as capture probe and the electrostatic adsorption of horseradish peroxidase (HRP) on hybridized, negatively charged nucleic acids to report the hybridization events, through HRP-catalyzed color reactions of 3,3',5,5'-tetramethylbenzidine and H(2)O(2). The proposed assay has been validated with fully complementary and single base-mismatched DNAs of different chain lengths. The proposed assay has also been validated with total RNA samples extracted from two human cancer cell lines (A 549 lung cancer cell and HeLa cell) for microRNA detection in real samples. Through extensive optimizations of HRP adsorption and nucleic acid hybridization conditions, detection limits of 0.1-0.2 nM for DNA (depending on chain length) and approximately 2 microg of total RNA have been achieved. Surface plasmon resonance spectroscopy has been used to elucidate the HRP adsorption and PNA-nucleic acid hybridizations through real time measurements and to provide guidance for the development of the colorimetric assay. PMID- 17708677 TI - On state-space reduction in multi-strain pathogen models, with an application to antigenic drift in influenza A. AB - Many pathogens exist in phenotypically distinct strains that interact with each other through competition for hosts. General models that describe such multi strain systems are extremely difficult to analyze because their state spaces are enormously large. Reduced models have been proposed, but so far all of them necessarily allow for coinfections and require that immunity be mediated solely by reduced infectivity, a potentially problematic assumption. Here, we suggest a new state-space reduction approach that allows immunity to be mediated by either reduced infectivity or reduced susceptibility and that can naturally be used for models with or without coinfections. Our approach utilizes the general framework of status-based models. The cornerstone of our method is the introduction of immunity variables, which describe multi-strain systems more naturally than the traditional tracking of susceptible and infected hosts. Models expressed in this way can be approximated in a natural way by a truncation method that is akin to moment closure, allowing us to sharply reduce the size of the state space, and thus to consider models with many strains in a tractable manner. Applying our method to the phenomenon of antigenic drift in influenza A, we propose a potentially general mechanism that could constrain viral evolution to a one dimensional manifold in a two-dimensional trait space. Our framework broadens the class of multi-strain systems that can be adequately described by reduced models. It permits computational, and even analytical, investigation and thus serves as a useful tool for understanding the evolution and ecology of multi-strain pathogens. PMID- 17708678 TI - Automated protein subfamily identification and classification. AB - Function prediction by homology is widely used to provide preliminary functional annotations for genes for which experimental evidence of function is unavailable or limited. This approach has been shown to be prone to systematic error, including percolation of annotation errors through sequence databases. Phylogenomic analysis avoids these errors in function prediction but has been difficult to automate for high-throughput application. To address this limitation, we present a computationally efficient pipeline for phylogenomic classification of proteins. This pipeline uses the SCI-PHY (Subfamily Classification in Phylogenomics) algorithm for automatic subfamily identification, followed by subfamily hidden Markov model (HMM) construction. A simple and computationally efficient scoring scheme using family and subfamily HMMs enables classification of novel sequences to protein families and subfamilies. Sequences representing entirely novel subfamilies are differentiated from those that can be classified to subfamilies in the input training set using logistic regression. Subfamily HMM parameters are estimated using an information sharing protocol, enabling subfamilies containing even a single sequence to benefit from conservation patterns defining the family as a whole or in related subfamilies. SCI-PHY subfamilies correspond closely to functional subtypes defined by experts and to conserved clades found by phylogenetic analysis. Extensive comparisons of subfamily and family HMM performances show that subfamily HMMs dramatically improve the separation between homologous and non homologous proteins in sequence database searches. Subfamily HMMs also provide extremely high specificity of classification and can be used to predict entirely novel subtypes. The SCI-PHY Web server at http://phylogenomics.berkeley.edu/SCI PHY/ allows users to upload a multiple sequence alignment for subfamily identification and subfamily HMM construction. Biologists wishing to provide their own subfamily definitions can do so. Source code is available on the Web page. The Berkeley Phylogenomics Group PhyloFacts resource contains pre calculated subfamily predictions and subfamily HMMs for more than 40,000 protein families and domains at http://phylogenomics.berkeley.edu/phylofacts/. PMID- 17708679 TI - Elucidating the altered transcriptional programs in breast cancer using independent component analysis. AB - The quantity of mRNA transcripts in a cell is determined by a complex interplay of cooperative and counteracting biological processes. Independent Component Analysis (ICA) is one of a few number of unsupervised algorithms that have been applied to microarray gene expression data in an attempt to understand phenotype differences in terms of changes in the activation/inhibition patterns of biological pathways. While the ICA model has been shown to outperform other linear representations of the data such as Principal Components Analysis (PCA), a validation using explicit pathway and regulatory element information has not yet been performed. We apply a range of popular ICA algorithms to six of the largest microarray cancer datasets and use pathway-knowledge and regulatory-element databases for validation. We show that ICA outperforms PCA and clustering-based methods in that ICA components map closer to known cancer-related pathways, regulatory modules, and cancer phenotypes. Furthermore, we identify cancer signalling and oncogenic pathways and regulatory modules that play a prominent role in breast cancer and relate the differential activation patterns of these to breast cancer phenotypes. Importantly, we find novel associations linking immune response and epithelial-mesenchymal transition pathways with estrogen receptor status and histological grade, respectively. In addition, we find associations linking the activity levels of biological pathways and transcription factors (NF1 and NFAT) with clinical outcome in breast cancer. ICA provides a framework for a more biologically relevant interpretation of genomewide transcriptomic data. Adopting ICA as the analysis tool of choice will help understand the phenotype pathway relationship and thus help elucidate the molecular taxonomy of heterogeneous cancers and of other complex genetic diseases. PMID- 17708680 TI - Many globally isolated AD hybrid strains of Cryptococcus neoformans originated in Africa. AB - Interspecific and intervarietal hybridization may contribute to the biological diversity of fungal populations. Cryptococcus neoformans is a pathogenic yeast and the most common fungal cause of meningitis in patients with AIDS. Most patients are infected with either of the two varieties of C. neoformans, designated as serotype A (C. neoformans var. grubii) or serotype D (C. neoformans var. neoformans). In addition, serotype AD strains, which are hybrids of these two varieties, are commonly isolated from clinical and environmental samples. While most isolates of serotype A and serotype D are haploid, AD strains are diploid or aneuploid, and contain two sets of chromosomes and two mating type alleles, MATa and MATalpha, one from each of the serotypes. The global population of serotype A is dominated by isolates with the MATalpha mating type (Aalpha); however, about half of the globally analyzed AD strains possess the extremely rare serotype A MATa allele (Aa). We previously described an unusual population of serotype A in Botswana, in which 25% of the strains contain the rare MATa allele. Here we utilized two methods, phylogenetic analysis of three genes and genotyping by scoring amplified fragment length polymorphisms, and discovered that AD hybrid strains possessing the rare serotype A MATa allele (genotype AaDalpha) cluster with isolates of serotype A from Botswana, whereas AD hybrids that possess the MATalpha serotype A allele (AalphaDa and AalphaDalpha) cluster with cosmopolitan isolates of serotype A. We also determined that AD hybrid strains are more resistant to UV irradiation than haploid serotype A strains from Botswana. These findings support two hypotheses: (i) AaDalpha strains originated in sub-Saharan Africa from a cross between strains of serotypes A and D; and (ii) this fusion produced hybrid strains with increased fitness, enabling the Botswanan serotype A MATa genome, which is otherwise geographically restricted, to survive, emigrate, and propagate throughout the world. PMID- 17708681 TI - Unbiased gene expression analysis implicates the huntingtin polyglutamine tract in extra-mitochondrial energy metabolism. AB - The Huntington's disease (HD) CAG repeat, encoding a polymorphic glutamine tract in huntingtin, is inversely correlated with cellular energy level, with alleles over approximately 37 repeats leading to the loss of striatal neurons. This early HD neuronal specificity can be modeled by respiratory chain inhibitor 3 nitropropionic acid (3-NP) and, like 3-NP, mutant huntingtin has been proposed to directly influence the mitochondrion, via interaction or decreased PGC-1alpha expression. We have tested this hypothesis by comparing the gene expression changes due to mutant huntingtin accurately expressed in STHdh(Q111/Q111) cells with the changes produced by 3-NP treatment of wild-type striatal cells. In general, the HD mutation did not mimic 3-NP, although both produced a state of energy collapse that was mildly alleviated by the PGC-1alpha-coregulated nuclear respiratory factor 1 (Nrf-1). Moreover, unlike 3-NP, the HD CAG repeat did not significantly alter mitochondrial pathways in STHdh(Q111/Q111) cells, despite decreased Ppargc1a expression. Instead, the HD mutation enriched for processes linked to huntingtin normal function and Nf-kappaB signaling. Thus, rather than a direct impact on the mitochondrion, the polyglutamine tract may modulate some aspect of huntingtin's activity in extra-mitochondrial energy metabolism. Elucidation of this HD CAG-dependent pathway would spur efforts to achieve energy based therapeutics in HD. PMID- 17708682 TI - Identification and characterization of cell type-specific and ubiquitous chromatin regulatory structures in the human genome. AB - The identification of regulatory elements from different cell types is necessary for understanding the mechanisms controlling cell type-specific and housekeeping gene expression. Mapping DNaseI hypersensitive (HS) sites is an accurate method for identifying the location of functional regulatory elements. We used a high throughput method called DNase-chip to identify 3,904 DNaseI HS sites from six cell types across 1% of the human genome. A significant number (22%) of DNaseI HS sites from each cell type are ubiquitously present among all cell types studied. Surprisingly, nearly all of these ubiquitous DNaseI HS sites correspond to either promoters or insulator elements: 86% of them are located near annotated transcription start sites and 10% are bound by CTCF, a protein with known enhancer-blocking insulator activity. We also identified a large number of DNaseI HS sites that are cell type specific (only present in one cell type); these regions are enriched for enhancer elements and correlate with cell type-specific gene expression as well as cell type-specific histone modifications. Finally, we found that approximately 8% of the genome overlaps a DNaseI HS site in at least one the six cell lines studied, indicating that a significant percentage of the genome is potentially functional. PMID- 17708684 TI - Population density and suicide in Scotland. AB - INTRODUCTION: Suicide rates among men have increased in Scotland while falling in neighbouring countries. A national suicide prevention strategy has been produced. Previous work found that some rural areas of Scotland had higher than average rates of male suicide and undetermined deaths. This article describes the association between population density and suicide and undetermined death rates in Scotland. METHODS: Anonymised information on deaths from suicide and undetermined cause in Scotland were obtained from the General Registrar Office for 1981-1999, including information on postcode sector. Each postcode sector was assigned a deprivation and population density score. Loglinear models were used to examine the effects of time period (grouped into four periods), deprivation quintiles, population density (grouped into four categories) and their interactions in each sex in three age groups. A significance level of 5% was used throughout. Adjusted rate ratios and 95% confidence intervals were based on models that included only significant factors and interactions. RESULTS: In men, there were higher rate ratios in the most densely populated and least densely populated quartiles, with intermediate rate ratios in other areas. There was no association with population density in women aged less than 25 years, a similar pattern to men in 25-44 year old women, and lower rates in rural areas in older women. Higher levels of deprivation were associated with higher rate ratios of suicide in both sexes and all age groups. Rate ratios over time increased in younger men and women, remained stable in older men, and declined in older women. CONCLUSIONS: Deprivation is associated with higher rates of suicide and undetermined deaths at all levels of population density and in all age groups. The highest rates of suicide among men are in the most and least densely populated areas, after adjusting for deprivation. The effect is different among women, with no effect among younger women, and lower rates among older women in areas with lower population density. PMID- 17708685 TI - The cancer-aging interface and the significance of telomere dynamics in cancer therapy. AB - The efficacy of most cancer treatments depends markedly on the high replication rate of cancer cells, a characteristic frequently observed in neoplasms with higher grades of malignancy. Yet, the same characteristic is present in many normal regenerative tissues of the body, which makes them susceptible to the cytotoxic effects of chemotherapeutics and accounts for many of the toxic side effects of these drugs. In response to cell killing by chemotherapeutics, normal regenerative tissues replicate at a faster rate to regenerate, resulting in accelerated telomere attrition and leaving different cell populations with telomeres shorter than they would normally have in the absence of treatment. This accelerated erosion has implications regarding the recurrence of cancers at secondary sites because reduced replicative ability may compromise effective subsequent immune responses. In this review we discuss recent reports describing the effect of chemotherapeutics on telomere loss, how this may impact healthy tissues in an age-dependent manner, and describe in brief emerging cancer treatments that may avoid this telomere erosion effect. PMID- 17708686 TI - Therapeutic ultrasound applications in craniofacial growth, healing and tissue engineering. AB - Previous reports have shown that therapeutic ultrasound enhances healing of fractured bone as well as cut tendons. Moreover, it has been shown that therapeutic ultrasound enhances bone formation during distraction osteogenesis that is also known as Ilizarove technique. It has been recently reported that therapeutic ultrasound enhances tooth formation and eruption during mandible distraction osteogenesis in rabbits. This enhanced tooth formation and eruption was caused by new dental tissue formation, known as dentin and cementum. This led to a clinical trial in human that showed that therapeutic ultrasound can enhance repairing tooth root resorption caused by orthodontic treatment. This discovery can lead to many applications of ultrasound in the dental as well as in the craniofacial reconstructions. This paper provides an overview of the molecular basis of the achieved clinical results. Moreover, potential future application will be elaborated. PMID- 17708683 TI - Maintenance of paternal methylation and repression of the imprinted H19 gene requires MBD3. AB - Paternal repression of the imprinted H19 gene is mediated by a differentially methylated domain (DMD) that is essential to imprinting of both H19 and the linked and oppositely imprinted Igf2 gene. The mechanisms by which paternal specific methylation of the DMD survive the period of genome-wide demethylation in the early embryo and are subsequently used to govern imprinted expression are not known. Methyl-CpG binding (MBD) proteins are likely candidates to explain how these DMDs are recognized to silence the locus, because they preferentially bind methylated DNA and recruit repression complexes with histone deacetylase activity. MBD RNA and protein are found in preimplantation embryos, and chromatin immunoprecipitation shows that MBD3 is bound to the H19 DMD. To test a role for MBDs in imprinting, two independent RNAi-based strategies were used to deplete MBD3 in early mouse embryos, with the same results. In RNAi-treated blastocysts, paternal H19 expression was activated, supporting the hypothesis that MBD3, which is also a member of the Mi-2/NuRD complex, is required to repress the paternal H19 allele. RNAi-treated blastocysts also have reduced levels of the Mi-2/NuRD complex protein MTA-2, which suggests a role for the Mi-2/NuRD repressive complex in paternal-specific silencing at the H19 locus. Furthermore, DNA methylation was reduced at the H19 DMD when MBD3 protein was depleted. In contrast, expression and DNA methylation were not disrupted in preimplantation embryos for other imprinted genes. These results demonstrate new roles for MBD3 in maintaining imprinting control region DNA methylation and silencing the paternal H19 allele. Finally, MBD3-depleted preimplantation embryos have reduced cell numbers, suggesting a role for MBD3 in cell division. PMID- 17708688 TI - Engineering away lysosomal junk: medical bioremediation. AB - Atherosclerosis, macular degeneration, and neurodegenerative diseases such as Alzheimer's disease, are associated with the intracellular accumulation of substances that impair cellular function and viability. Reversing this accumulation may be a valuable therapy, but the accumulating substances resist normal cellular catabolism. On the other hand, these substances are naturally degraded in the soil and water by microorganisms. Thus, we propose the concept of "medical bioremediation," which derives from the successful field of in situ environmental bioremediation of petroleum hydrocarbons. In environmental bioremediation, communities of microorganisms mineralize hydrophobic organics using a series of enzymes. In medical bioremediation, we hope to utilize one or several microbial enzymes to degrade the intracellular accumulators enough that they can be cleared from the affected cells. Here, we present preliminary, but promising results for the bacterial biodegradation of 7-ketocholesterol, the main accumulator of foam cells associated with atherosclerosis. In particular, we report on the isolation of several Nocardia strains able to biodegrade 7 ketocholesterol and as an ester of 7-ketocholoesterol. We also outline key intermediates in the biodegradation pathway, a key step towards identifying the key enzymes that may lead to a therapy. PMID- 17708692 TI - Earliest validated supercentenarian by nation of birth. PMID- 17708689 TI - Nutrition as a determinant of successful aging: description of the Quebec longitudinal study Nuage and results from cross-sectional pilot studies. AB - Optimal nutrition is essential for general well being, maintenance of physical and functional capacities and prevention of chronic disease in the elderly. The 5 year longitudinal study, NuAge, was designed to assess the pivotal role of nutrition on physical and cognitive status, functional autonomy and social functioning. A cohort of 1793 men and women, selected from three age groups (68 72, 73-77, 78-82) at recruitment, has been followed annually since 2003-2004. A plurimethodological approach, including basic, clinical, epidemiologic, and social research has been used. Data on various facets of nutritional status (diet, food habits, appetite, anthropometry and body composition), and functional (muscle strength, physical activity, physical and functional capacities and performance), medical (physical, mental and cognitive health, medication) and social data (network, support, participation) are collected by questionnaires or direct measurements. Blood, urine, and saliva samples are also collected and processed for genomic, transcriptomic, proteomic, and biochemical analyses and to study markers of endocrine, immune, and cognitive functions. Selected bio-psycho social characteristics of the cohort, consumption of macronutrients, and biologic variables are presented, including the impact of intake of certain foods on total antioxidant status. Understanding the aging process as regulated by a modifiable factor such as nutrition should facilitate the development of targeted strategies for promoting successful aging. PMID- 17708691 TI - Mitochondria in aging and Alzheimer's disease. AB - Two significant risk factors are inextricably linked with Alzheimer's disease: advancing age, and accumulation of the amyloid-beta peptide. Over the age of 65 the risk of developing Alzheimer's disease increases almost exponentially with age, and the amyloid-beta rich neuritic plaques of the Alzheimer's disease brain are a histopathological hallmark of the disease. Since its identification as a major constituent of neuritic plaques amyloid-beta has attracted intense research focus as the primary causative agent in the development of Alzheimer's disease. As a result, numerous reports now exist to propose potential neurotoxic mechanisms mediated by amyloid-beta. Despite these research efforts, there is still a scarcity of information on the biologic link between aging and amyloid beta in Alzheimer's disease, and although increasing evidence indicates that intracellular amyloid-beta is acutely toxic, there is also a paucity of information on the mechanisms of neurotoxicity mediated by intracellular amyloid beta. Functional decline of mitochondria with aging is well established, and growing evidence attributes this decline to loss of mitochondrial DNA integrity in postmitotic cells including neurons. Oxidative stress due to mitochondrial failure may drive increased amyloidogenic processing of the amyloid-beta precursor protein, contributing to a loss of amyloid-beta precursor protein functionality and increased amyloid-beta production. Importantly, recent data show that amyloid-beta accumulates within mitochondria of the Alzheimer's disease brain. We speculate that age-related somatic mutation of mitochondrial DNA may be an important factor underlying sporadic Alzheimer's disease. PMID- 17708693 TI - Time, damage, and aging: what really matters? AB - This presentation was one of three short talks in the introductory session at the 2007 Edmonton Aging Symposium titled "The Damage of Aging: Present and Future Therapies." This title implies that if we can document what biological damage occurs with increasing age, then by either preventing, reducing or repairing this damage, we could intervene to delay the onset and severity of the adverse age related phenotypes that accompany aging, and perhaps increase life span as well. While this assumption seems quite reasonable, some recent results suggest that this approach is not as straightforward as it might seem. PMID- 17708694 TI - Genetics of body mass stability and risk for chronic disease: a 28-year longitudinal study. AB - We examined the contributions of genetic and environmental factors to body mass index (BMI) over approximately 28 years. Participants were 693 male, predominantly middle-class, twins (355 monozygotic, 338 dizygotic) from the Vietnam Era Twin Registry. The phenotypic correlation between age 20 and age 48 BMI was 0.52; the genetic correlation was 0.60. Most of the remaining variance at both times was accounted for by nonshared environmental factors. Since genetic factors are not perfectly correlated, this indicates that other genes affect BMI at one or both time points, leaving room for further exploration of the genetics of body mass stability. Mean BMI increased significantly from 22.7 (normal) to 27.8 (overweight). Overweight BMI at age 20 predicted midlife adult onset diabetes (adjusted odds ratio = 4.62, 95% CI 1.91 to 11.18), but not hypertension. Depending on one's vantage point, the results indicate elements of both stability and change in BMI. Very similar phenotypic and genetic correlations were observed over a similar time period in a WW II twin sample, but without the substantial mean increase in BMI. It seems unlikely that different genes influence BMI in the two cohorts. Therefore, we argue that nonshared environmental factors are probably primarily responsible for the secular increase in midlife BMI. Our results also provide prospective evidence that early excess BMI may have serious long-term health consequences, and that this risk is not limited to minorities or adults of lower socioeconomic status. PMID- 17708695 TI - Examining the heritability of a laboratory-based smoking endophenotype: initial results from an experimental twin study. AB - The objective of this study was to examine the heritability of an endophenotype relevant to nicotine dependence, namely tension reduction after smoking. This study also examined whether common genetic, shared environmental, and nonshared environmental factors influence this endophenotype measured repeatedly during an experimental paradigm. Twin and sibling pairs, all of whom were regular smokers, completed a laboratory paradigm in which they reported on levels of tension at baseline and after smoking each of 3 cigarettes. Univariate twin analyses suggested a sizeable role of additive genetic effects on tension reduction, with heritability estimates ranging between 47 and 68%. Result of multivariate Cholesky analyses indicated that there were additive genetic influences common to tension reduction assessed after cigarettes 1, 2, and 3. Multivariate models including genetic and nonshared environmental effects provided the best fit to the data. To the best of our knowledge, this is the first study to examine the genetic basis of a laboratory smoking endophenotype, in this case tension reduction after smoking. Implications for genetic association studies are discussed. PMID- 17708697 TI - Trauma exposure and stress response: exploration of mechanisms of cause and effect. AB - People differ markedly in their risk for developing posttraumatic stress symptoms (PTSS) after exposure to traumatic events. Twin studies suggest that the trauma PTSS relationship is moderated by genetic and environmental influences. The present study tested for specific types of genetic and environmental interaction effects on PTSS. A sample of 222 monozygotic and 184 dizygotic twin pairs reported on lifetime frequency of assaultive and nonassaultive trauma and associated PTSS. Biometric analyses indicated that in the case of nonassaultive trauma, PTSS were directly affected by environmental factors that also influence exposure to nonassaultive trauma. For assaultive trauma both genetic and non shared environmental influences jointly affected PTSS, and the number of traumatic events moderated the severity of PTSS. Genetic factors were found to become less important beyond some threshold (e.g., 3 or 4 types of serious trauma) suggesting that genetic factors - which may confer either risk or resilience to PTSS - modify these symptoms within a range of human experience, beyond which environmental effects supervene. PMID- 17708696 TI - Internet cognitive testing of large samples needed in genetic research. AB - Quantitative and molecular genetic research requires large samples to provide adequate statistical power, but it is expensive to test large samples in person, especially when the participants are widely distributed geographically. Increasing access to inexpensive and fast Internet connections makes it possible to test large samples efficiently and economically online. Reliability and validity of Internet testing for cognitive ability have not been previously reported; these issues are especially pertinent for testing children. We developed Internet versions of reading, language, mathematics and general cognitive ability tests and investigated their reliability and validity for 10- and 12-year-old children. We tested online more than 2500 pairs of 10-year-old twins and compared their scores to similar internet-based measures administered online to a subsample of the children when they were 12 years old (> 759 pairs). Within 3 months of the online testing at 12 years, we administered standard paper and pencil versions of the reading and mathematics tests in person to 30 children (15 pairs of twins). Scores on Internet-based measures at 10 and 12 years correlated .63 on average across the two years, suggesting substantial stability and high reliability. Correlations of about .80 between Internet measures and in person testing suggest excellent validity. In addition, the comparison of the internet-based measures to ratings from teachers based on criteria from the UK National Curriculum suggests good concurrent validity for these tests. We conclude that Internet testing can be reliable and valid for collecting cognitive test data on large samples even for children as young as 10 years. PMID- 17708698 TI - Does sharing the same class in school improve cognitive abilities of twins? AB - This article analyzes the effect of classroom separation of twins on their cognitive abilities, measured at different ages in Dutch primary education. We use a large longitudinal school-based sample of twins and their classmates. The analysis tries to reduce the bias by unobserved factors due to the nonrandom assignment of twins by taking into account differences in school environment, previous test scores and variation in class assignment between years. We find that classroom separation matters for language in Grade 2. Nonseparated twins score higher on language, and the difference is larger for same-sex pairs. This finding is robust for various methods that take unobserved effects into account. In addition, there is some evidence for higher scores in arithmetic in Grade 2. For the higher grades we find no effect of classroom separation on cognitive ability. In the analysis of the effect of a separation of at least 3 years we find that separation increases language performance between Grade 6 and 8 for opposite-sex pairs. PMID- 17708699 TI - Birthweight predicts IQ: fact or artefact? AB - It has been shown that lower birthweight is associated with lower IQ, but it remains unclear whether this association is causal or spurious. We examined the relationship between birthweight and IQ in two prospective longitudinal birth cohorts: a UK cohort of 1116 twin pairs (563 monozygotic [MZ] pairs), born in 1994-95, and a New Zealand cohort of 1037 singletons born in 1972-73. IQ was tested with the Wechsler Intelligence Scales for Children. Birthweight differences within MZ twin pairs predicted IQ differences within pairs, ruling out genetic and shared environmental explanations for the association. Birthweight predicted IQ similarly in the twin and nontwin cohorts after controlling for social disadvantage, attesting that the association generalized beyond twins. An increase of 1000 g in birthweight was associated with a 3 IQ point increase. Results from two cohorts add to evidence that low birthweight is a risk factor for compromised neurological health. Our finding that birthweight differences predict IQ differences within MZ twin pairs provides new evidence that the mechanism can be narrowed to an environmental effect during pregnancy, rather than any familial environmental influence shared by siblings, or genes. With the increasing numbers of low-birthweight infants, our results support the contention that birthweight could be a target for early preventive intervention to reduce the number of children with compromised IQ. PMID- 17708700 TI - Depressive symptomatology in child and adolescent twins with attention-deficit hyperactivity disorder and/or developmental coordination disorder. AB - Previous research has demonstrated a link between attention-deficit/hyperactivity disorder (ADHD), developmental coordination disorder (DCD), and depression. The present study utilized a monozygotic (MZ) differences design to investigate differences in depressive symptomatology between MZ twins discordant for ADHD or DCD. This extends previous research as it controls for genetic effects and shared environmental influences and enables the investigation of nonshared environmental influences. In addition, children and adolescents with comorbid ADHD and DCD were compared on their level of depressive symptomatology to those with ADHD only, DCD only, and no ADHD or DCD. The parent-rated Strengths and Weaknesses of ADHD Symptoms and Normal Behavior, Developmental Coordination Disorder Questionnaire, and Sad Affect Scale were used to assess ADHD, DCD, and depressive symptomatology respectively. The results revealed higher levels of depressive symptomatology in MZ twins with ADHD or DCD compared to their nonaffected co-twins. In addition, children and adolescents with comorbid ADHD and DCD demonstrated higher levels of depressive symptomatology compared to those with ADHD only, DCD only, and no ADHD or DCD. The implications of these findings are discussed with emphasis on understanding and recognizing the relationship between ADHD, DCD, and depression in the assessment and intervention for children and adolescents with these disorders. PMID- 17708701 TI - Coffee and smoking as risk factors of twin pregnancies: the Danish National Birth Cohort. AB - Twinning rates have changed substantially over time for reasons that are only partly known. In this study we studied smoking, coffee and alcohol intake, and their possible interaction with obesity as potential determinants of twinning rates using data from the Danish National Birth Cohort between 1996 and 2002. We identified 82,985 pregnancies: 81,954 singleton and 1031 twins. For the twins we had data to classify 121 as monozygotic, 189 dizygotic (same sex), 313 dizygotic (opposite sex) but, 408 were of the same sex but with unknown zygosity. All mothers were interviewed about their prepregnancy weight and height, coffee and alcohol intake, smoking habits, and potential confounding factors at early stages of pregnancy. We identified smoking (> 10 cigarettes/day) as a possible determinant of twinning, particularly for dizygotic twinning rates (same sex) and furthermore corroborated that obesity and the mother's age are strong correlates of twinning. Others have found coffee intake to increase twinning rates but that is not seen in these data. PMID- 17708702 TI - Large-scale zygosity testing using single nucleotide polymorphisms. AB - A requirement for performing robust genetic and statistical analyses on twins is correctly assigned zygosities. In order to increase the power to detect small risk factors of disease, zygosity testing should also be amenable for high throughput screening. In this study we validate and implement the use of a panel of 50 single nucleotide polymorphisms (SNPs) for reliable high throughput zygosity testing and compare it to a panel of 16 short tandem repeats (STRs). We genotyped both genomic (gDNA) and whole genome amplified DNA (WGA DNA), ending up with 47 SNP and 11 STR markers fulfilling our quality criteria. Out of 99 studied twin pairs, 2 were assigned a different zygosity using SNP and STR data as compared to self reported zygosity in a questionnaire. We also performed a sensitivity analysis based on simulated data where we evaluated the effects of genotyping error, shifts in allele frequencies and missing data on the qualitative zygosity assignments. The frequency of false positives was less than 0.01 when assuming a 1% genotyping error, a decrease of 10% of the observed minor allele frequency compared to the actual values and up to 10 missing markers. The SNP markers were also successfully genotyped on both gDNA and WGA DNA from whole blood, saliva and filter paper. In conclusion, we validate a robust panel of 47 highly multiplexed SNPs that provide reliable and high quality data on a range of different DNA templates. PMID- 17708703 TI - Temporal trends in the rates of multiple maternities in England and Wales. AB - After a long continuous decrease, the twinning and higher multifetal rates in many developed countries have increased during the last 2 to 3 decades. This change has been attributed to delayed childbearing and to increased use of subfertility treatments, particularly in women over 35 years of age. In this study we analyze how these new trends depend on changes in the effect of maternal age on the rates of multiple maternities. Our study is based on data for England and Wales for the period 1938 to 2003. The temporal variations show a decreasing trend to a trough around 1980 and after that a steady increase. This increase was more marked for higher multifetal rates and was particularly high for quadruplets. Furthermore, we identified changes in the age-specific rates resulting in increased levels for older mothers. These findings are in good agreement with our results from Nordic populations. PMID- 17708704 TI - The comparison of twinning rates between urban and rural areas in China. AB - Based on the birth record data from the National Vital Statistics in the 1990 Census of China, the present study analyzed the differences between urban and rural areas on monozygotic (MZ) and dizygotic (DZ) twin rates by maternal age in 1989. The twins by zygosity were calculated with Weinberg's differential method. Results show that the MZ and DZ twinning rates in China were associated with maternal age and that there were substantial differences between urban and rural areas. The MZ twinning rates in urban and rural areas were 2.36 pairs and 2.11 pairs per 1000 deliveries respectively, significantly lower than that in most studied populations. Furthermore, our analysis indicated that MZ twinning rates remained relatively constant for mothers under the age group of 36 to 38 years, but rose over this age group in both areas, albeit with a different slope. The DZ twinning rates were strikingly affected by maternal age, but the age for peak DZ rates was found within the age group of 33 to 35 years. In all maternal age groups except for 24 to 26 years, the DZ twinning rates in urban areas were higher than in rural areas. It remains unclear as to why the DZ twinning rates reversed to reach higher values within the older maternal age groups in China, but it is almost certain that the high twinning rates had nothing to do with in vitro fertilization. PMID- 17708705 TI - The frequency of recurrent multiple maternities using two sets of census data in Japan: 1990 and 1995. AB - Frequencies of recurrent multiple maternities were estimated using two sets of census data in Japan in 1990 and 1995. The repeat frequency (RF) of the twinning rate is the frequency of 2 sets of twins among families or couples who have already had 1 set of twins and 2 more siblings. The overall RFs were 9.6 per 1000 couples in 1990 and 9.3 in 1995. The RFs of the monozygotic (MZ) twinning rates were 5.9 per 1000 couples in 1990 and 5.5 in 1995. The RFs of the dizygotic (DZ) twinning rates were 3.7 in 1990 and 3.8 in 1995. For unlike-sexed propositus twins, the RF of MZ twins were 5.0 per 1000 couples in 1990 and 5.5 in 1995. The RF of DZ twins were 5.3 in 1990 and 4.6 in 1995. As for like-sexed propositus twins, the corresponding RFs were 6.2 and 5.5 for MZ twins, and 3.4 and 3.6 for DZ twins, respectively. In mothers who have experienced a twin maternity, the overall RF of twinning was 1.5 to 2 times as high as the average mother's chance of having twins. There was no RF for triplets for both census years. As for geographic variations of the overall RF, the rates in Okinawa (16.2) and Hokkaido (15.3) were significantly higher than those in the Tohoku (8.7), Kanto (8.0) and Kyushu (7.4) districts. PMID- 17708706 TI - Sudden infant death syndrome in twins and singletons. AB - Twins compared with singletons and monozygous (MZ) compared with dizygous (DZ) twins are at increased risk of fetal and infant death, cerebral palsy and many congenital anomalies. The aim of this study is to investigate whether zygosity is a risk factor for the sudden infant death syndrome (SIDS). Birth registration data and draft infant death certificates for all multiple births in England and Wales 1993 to 2003 were provided by the Office for National Statistics. As a partial proxy for zygosity, same-sex was compared with opposite-sex twins for birthweight-specific mortality and mortality attributed to SIDS. Data on singleton infants were obtained by subtraction of multiple births from routinely published population births and infant deaths. SIDS mortality among low birthweight infants was significantly less in twins than singletons. The twin singleton relative risk was reversed in infants of normal birthweight. Among infants of normal birthweight, neonatal SIDS was significantly more common in same- compared with opposite-sex pairs. Among infants of low birthweight, postneonatal SIDS was significantly more common in same- compared with opposite sex pairs. The difference in birthweight distribution of same- compared with opposite-sex twins for neonatal SIDS suggests that zygosity is a risk factor for SIDS. As congenital cerebral anomalies are a feature of many monozygous twin conceptions, a detailed macro- and microscopical examination of the brain in twin SIDS may indicate an otherwise unrecognised pathology. PMID- 17708707 TI - Does a probability of breech presentation of more than 50% exist among diseases and medical conditions? AB - The aim was to study the effect of twin gestations in a uterus with 2 bodies on the probability of breech presentation at delivery. The hypothesis was that the probability of breech presentation was not higher than 50%. A review was undertaken of MEDLINE (1966-2004) and of the article reference list for statistical analysis of presentation at delivery among twins in a normal uterus, singleton gestations in a uterus with 2 bodies, and case studies of twins in a uterus with 2 bodies. There are 10 studies of twin gestations in a normal uterus (Twin A 3036 cases, breech presentation 22.36%; Twin B 2758 cases, breech presentation 36.87%), 2 studies of singleton gestations in a uterus with 2 bodies (297 cases, breech presentation 42.09%), and 57 case report studies of twin gestations in a uterus with 2 bodies (Twin A 56 cases, breech presentation 14.29%; Twin B 54 cases, breech presentation 18.52%). The odds ratio and chi square test for differences in probabilities show a significantly lower incidence of breech presentation for twins in a uterus with 2 bodies compared with twins in a normal uterus (Twin A, odds ratio = 0.58; chi(2) = 2.08, p > .05, Twin B, odds ratio = 0.39, chi(2) = 7.67, p < .05), and singleton gestations in a uterus with 2 bodies (Twin A, odds ratio = 0.23, chi(2) = 15.51, p < .05; Twin B, odds ratio = 0.31, chi(2) = 10.72, p < .05). Twin gestations in a uterus with 2 bodies decrease the probability of breech presentation. PMID- 17708708 TI - SCE frequency measurement could be useful in the prenatal diagnosis of Roberts syndrome. AB - In a previously published article (Resta et al., 2006) on Robert's syndrome in prenatal diagnosis, a case of a 36-year-old woman and her 36-year-old, nonconsanguineous husband were presented. Our findings suggest the existence of nonsense mediated decay (NMD) variability which could account for the varying severity reported in carriers of identical mutations. Furthermore, fetal cells were used to evaluate the influence of premature centromere separation (PCS) on the sister chromatid exchange (SCE) and micronucleus (MN) frequency. Given the similar variation observed in the SCE frequencies, dependent on tissue/cell type (amniotic fluid sample, chorionic villus sampling) and duration of in vitro cultures (48 hours or 72 hours), the idea was that this new piece of information could be interesting. It seems that the SCE frequency increased proportionally to the cell cycle increasing (1 degrees < 2 degrees < 3 degrees ... n). Obviously, our observations are too scarce to draw conclusions, but further investigation could be useful to corroborate or dispute these results, considering that the two techniques, (MN and SCE), are simple to perform and do not require expensive laboratory equipment. PMID- 17708709 TI - Identical twin parents; research reviews: twin pregnancy risk factors, a new twin type and a school legislation update; twin parents and twin researchers in the news. AB - Some legal and social complications that arise when identical twins have children are examined. The specific case presented concerns assignment of paternity. This section is followed by a review of recent studies of multiple birth pregnancy risk factors, namely mother to infant HIV transmission and congenital hypothyroidism. Honors given to recently recognized twin researchers are noted, as is the birth of twins to an older mother in the United States. PMID- 17708710 TI - Abstracts for the 6th Australasian Gene Mapping Meeting, August 29-31, 2007, Brisbane. PMID- 17708712 TI - Thyroid hormone interacts with the Wnt/beta-catenin signaling pathway in the terminal differentiation of growth plate chondrocytes. AB - Thyroid hormone activates Wnt-4 expression and Wnt/beta-catenin signaling in rat growth plate chondrocytes. Wnt antagonists Frzb/sFRP3 and Dkk1 inhibit T3-induced Wnt/beta-catenin activation and inhibit the maturation-promoting effects of T3 in growth plate cells. This study indicates that thyroid hormone regulates terminal differentiation of growth plate chondrocytes in part through modulating Wnt/beta catenin signaling. INTRODUCTION: Thyroid hormone is a potent regulator of skeletal maturation in the growth plate, yet the molecular mechanisms underlying this profound effect remain unknown. Wnt signaling has recently been recognized as an important signal transduction pathway in regulating chondrogenesis and terminal differentiation of growth plate chondrocytes. The objective of this study was to explore the interaction between the thyroid hormone and Wnt signaling pathways in the growth plate. MATERIALS AND METHODS: Rat epiphyseal chondrocytes were maintained in 3D pellet culture and treated with triiodothyronine (T3). Activation of Wnt/beta-catenin signaling pathway in response to T3 was detected by measurement of the expression of Wnt-4 mRNA, the cellular accumulation of beta-catenin, the transcriptional activity of TCF/LEF, and the expression of the Wnt/beta-catenin responsive gene Runx2/cbfa1. Terminal differentiation of the chondrocytes was assessed by measurement of alkaline phosphatase enzymatic activity and Col10a1 gene expression. RESULTS: Thyroid hormone treatment of growth plate chondrocytes upregulated both Wnt-4 mRNA and protein expression, increased cellular accumulation of stabilized beta-catenin, increased TCF/LEF transcriptional activity, and stimulated the expression of the Runx2/cbfa1 gene. Overexpression of either Wnt-4 or a stabilized form of beta catenin promoted growth plate chondrocyte terminal differentiation. Blocking Wnt ligand/receptor interactions with the secreted Wnt antagonists Frzb/sFRP3 or Dkk1 inhibited these T3-induced increases in beta-catenin accumulation and Runx2 gene expression and inhibited the maturation-promoting effects of T3 in growth plate cells. CONCLUSIONS: These data suggest that thyroid hormone regulates terminal differentiation of growth plate chondrocytes in part through modulating canonical Wnt/beta-catenin signaling. PMID- 17708711 TI - Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. AB - Denosumab is a monoclonal antibody to RANKL. In this randomized, placebo controlled study of 412 postmenopausal women with low BMD, subcutaneous denosumab given every 3 or 6 mo was well tolerated, increased BMD, and decreased bone resorption markers for up to 24 mo. Continued study of denosumab is warranted in the treatment of low BMD in postmenopausal women. INTRODUCTION: Denosumab is a fully human monoclonal antibody that inhibits RANKL, a key mediator of osteoclastogenesis and bone remodeling. This prespecified exploratory analysis evaluated the efficacy and safety of denosumab through 24 mo in the treatment of postmenopausal women with low BMD. MATERIALS AND METHODS: Four hundred twelve postmenopausal women with lumbar spine BMD T-scores of -1.8 to -4.0 or femoral neck/total hip T-scores of -1.8 to -3.5 were randomly assigned to receive double blind, subcutaneous injections of placebo; denosumab 6, 14, or 30 mg every 3 mo; denosumab 14, 60, 100, or 210 mg every 6 mo; or open-label oral alendronate 70 mg once weekly. Outcome measures included BMD at the lumbar spine, total hip, distal one-third radius, and total body; bone turnover markers; and safety. RESULTS: Denosumab increased BMD at all measured skeletal sites and decreased concentrations of bone turnover markers compared with placebo at 24 mo. At the lumbar spine, BMD increases with denosumab ranged from 4.13% to 8.89%. BMD changes with denosumab 30 mg every 3 mo and > or =60 mg every 6 mo were similar to, or in some cases greater than, with alendronate. The incidence of adverse events was similar in the placebo, denosumab, and alendronate treatment groups. Exposure-adjusted adverse events over 2 yr of treatment were similar to those reported during the first year of treatment. CONCLUSIONS: In these postmenopausal women with low BMD, treatment with denosumab for 2 yr was associated with sustained increases in BMD and reductions in bone resorption markers compared with placebo. PMID- 17708713 TI - Prediction of clinical non-spine fractures in older black and white men and women with volumetric BMD of the spine and areal BMD of the hip: the Health, Aging, and Body Composition Study*. AB - In a prospective study of 1446 black and white adults 70-79 yr of age (average follow-up, 6.4 yr), vertebral TrvBMD from QCT predicted non-spine fracture in black and white women and black men, but it was not a stronger predictor than total hip aBMD from DXA. Hip aBMD predicted non-spine fracture in black men. INTRODUCTION: Areal BMD (aBMD) at multiple skeletal sites predicts clinical non spine fractures in white and black women and white men. The predictive ability of vertebral trabecular volumetric BMD (TrvBMD) for all types of clinical non-spine fractures has never been tested or compared with hip aBMD. Also, the predictive accuracy of hip aBMD has never been tested prospectively for black men. MATERIALS AND METHODS: We measured vertebral TrvBMD with QCT and hip aBMD with DXA in 1446 elderly black and white adults (70-79 yr) in the Health, Aging, and Body Composition Study. One hundred fifty-two clinical non-spine fractures were confirmed during an average of 6.4 yr of >95% complete follow-up. We used Cox proportional hazards regression to determine the hazard ratio (HR) and 95% CIs of non-spine fracture per SD reduction in hip aBMD and vertebral TrvBMD. RESULTS: Vertebral TrvBMD and hip aBMD were both associated with risk of non-spine fracture in black and white women and black men. The age-adjusted HR of fracture per SD decrease in BMD was highest in black men (hip aBMD: HR = 2.04, 95% CI = 1.03, 4.04; vertebral TrvBMD: HR = 3.00, 95% CI = 1.29, 7.00) and lowest in white men (hip aBMD: HR = 1.23, 95% CI = 0.85, 1.78; vertebral TrvBMD: HR = 1.06, 95% CI = 0.73, 1.54). Adjusted for age, sex, and race, each SD decrease in hip aBMD was associated with a 1.67-fold (95% CI = 1.36, 2.07) greater risk of fracture, and each SD decrease in vertebral TrvBMD was associated with a 1.47-fold (95% CI = 1.18, 1.82) greater risk. Combining measurements of hip aBMD and vertebral TrvBMD did not improve fracture prediction. CONCLUSIONS: Low BMD measured by either spine QCT or hip DXA predicts non-spine fracture in older black and white women and black men. Vertebral TrvBMD is not a stronger predictor than hip aBMD of non-spine fracture. PMID- 17708714 TI - Aromatase deficiency causes altered expression of molecules critical for calcium reabsorption in the kidneys of female mice *. AB - Kidney stones increase after menopause, suggesting a role for estrogen deficiency. ArKO mice have hypercalciuria and lower levels of calcium transport proteins, whereas levels of the klotho protein are elevated. Thus, estrogen deficiency is sufficient to cause altered renal calcium handling. INTRODUCTION: The incidence of renal stones increases in women after menopause, implicating a possible role for estrogen deficiency. We used the aromatase deficient (ArKO) mouse, a model of estrogen deficiency, to test the hypothesis that estrogen deficiency would increase urinary calcium excretion and alter the expression of molecular regulators of renal calcium reabsorption. MATERIALS AND METHODS: Adult female wildtype (WT), ArKO, and estradiol-treated ArKO mice (n = 5-12/group) were used to measure urinary calcium in the fed and fasting states, relative expression level of some genes involved in calcium reabsorption in the distal convoluted tubule by real-time PCR, and protein expression by Western blotting or immunohistochemistry. Plasma membrane calcium ATPase (PMCA) activity was measured in kidney membrane preparations. ANOVA was used to test for differences between groups followed by posthoc analysis with Dunnett's test. RESULTS: Compared with WT, urinary Ca:Cr ratios were elevated in ArKO mice, renal mRNA levels of transient receptor potential cation channel vallinoid subfamily member 5 (TRPV5), TRPV6, calbindin-D28k, the Na+/Ca+ exchanger (NCX1), and the PMCA1b were significantly decreased, and klotho mRNA and protein levels were elevated. Estradiol treatment of ArKO mice normalized urinary calcium excretion, renal mRNA levels of TRPV5, calbindin-D(28k), PMCA1b, and klotho, as well as protein levels of calbindin-D28k and Klotho. ArKO mice treated with estradiol had significantly greater PMCA activity than either untreated ArKO mice or WT mice. CONCLUSIONS: Estrogen deficiency caused by aromatase inactivation is sufficient for renal calcium loss. Changes in estradiol levels are associated with coordinated changes in expression of many proteins involved in distal tubule calcium reabsorption. Estradiol seems to act at the genomic level by increasing or decreasing (klotho) protein expression and nongenomically by increasing PMCA activity. PMCA, not NCX1, is likely responsible for extruding calcium in response to in vivo estradiol hormonal challenge. These data provide potential mechanisms for regulation of renal calcium handling in response to changes in serum estrogen levels. PMID- 17708716 TI - Postoperative uptake in the thyroid bed, not tumor stage, determines the usefulness of diagnostic whole body scan in the first year after ablation with radioiodine. PMID- 17708715 TI - Wnt10b increases postnatal bone formation by enhancing osteoblast differentiation. AB - Overexpression of Wnt10b from the osteocalcin promoter in transgenic mice increases postnatal bone mass. Increases in osteoblast perimeter, mineralizing surface, and bone formation rate without detectable changes in pre-osteoblast proliferation, osteoblast apoptosis, or osteoclast number and activity suggest that, in this animal model, Wnt10b primarily increases bone mass by stimulating osteoblastogenesis. INTRODUCTION: Wnt signaling regulates many aspects of development including postnatal accrual of bone. Potential mechanisms for how Wnt signaling increases bone mass include regulation of osteoblast and/or osteoclast number and activity. To help differentiate between these possibilities, we studied mice in which Wnt10b is expressed specifically in osteoblast lineage cells or in mice devoid of Wnt10b. MATERIALS AND METHODS: Transgenic mice, in which mouse Wnt10b is expressed from the human osteocalcin promoter (Oc-Wnt10b), were generated in C57BL/6 mice. Transgene expression was evaluated by RNase protection assay. Quantitative assessment of bone variables was done by radiography, muCT, and static and dynamic histomorphometry. Mechanisms of bone homeostasis were evaluated with assays for BrdU, TUNEL, and TRACP5b activity, as well as serum levels of C-terminal telopeptide of type I collagen (CTX). The endogenous role of Wnt10b in bone was assessed by dynamic histomorphometry in Wnt10b(-/-) mice. RESULTS: Oc-Wnt10b mice have increased mandibular bone and impaired eruption of incisors during postnatal development. Analyses of femoral distal metaphyses show significantly higher BMD, bone volume fraction, and trabecular number. Increased bone formation is caused by increases in number of osteoblasts per bone surface, rate of mineral apposition, and percent mineralizing surface. Although number of osteoclasts per bone surface is not altered, Oc-Wnt10b mice have increased total osteoclast activity because of higher bone mass. In Wnt10b(-/-) mice, changes in mineralizing variables and osteoblast perimeter in femoral distal metaphyses were not observed; however, bone formation rate is reduced because of decreased total bone volume and trabecular number. CONCLUSIONS: High bone mass in Oc-Wnt10b mice is primarily caused by increased osteoblastogenesis, with a minor contribution from elevated mineralizing activity of osteoblasts. PMID- 17708717 TI - Novel intra-tissue perfusion system for culturing thick liver tissue. AB - Innovative scaffold fabrication, angiogenesis promotion, and dynamic tissue culture techniques have been utilized to improve delivery of media into the core of large tissue constructs in tissue engineering. We have developed here an intra tissue perfusion (ITP) system, which incorporates an array of seven micron-sized needles as a delivery conduit, to improve mass transfer into the core of thick liver tissues slices (>>300 microm mass transport limit). The ITP system improves the uniformity and distribution of media throughout the tissue, resulting in improved cell viability over the static-cultured controls. The ITP-cultured thick liver slices also exhibit improved phase I and phase II metabolic functions and albumin and urea synthetic functions after 3-day culture, which is the minimal period required by the U.S. Food and Drug Administration (FDA) for studying drug drug interaction. This ITP system can also be used for culturing other thick tissue constructs of larger dimensions for various in vitro and in vivo applications, including bridging integration of the in vitro cultured constructs into living host tissues. PMID- 17708718 TI - Effects of regulatory factors on engineered cardiac tissue in vitro. AB - We tested the hypothesis that supplemental regulatory factors can improve the contractile properties and viability of cardiac tissue constructs cultured in vitro. Neonatal rat heart cells were cultured on porous collagen sponges for up to 8 days in basal medium or medium supplemented with insulin-like growth factor I (IGF), insulin-transferrin-selenium (ITS), platelet-derived growth factor-BB (PDGF), or angiopoietin-1 (ANG). IGF and ITS enhanced contractile properties of the 8-day constructs significantly more than with unsupplemented controls according to contractile amplitude and excitation threshold, and IGF also significantly increased the amount of cardiac troponin-I and enhanced cell viability according to different assays (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH), and terminal deoxynucleotidyl transferase biotin-2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL)). PDGF significantly increased the contractile amplitude of 4 day constructs and enhanced cell viability according to MTT, LDH, and TUNEL; ANG enhanced cell viability according to the LDH assay. Our results demonstrate that supplemental regulatory molecules can differentially enhance properties of cardiac tissue constructs and imply that these constructs can provide a platform for systematic in vitro studies of the effects of complex stimuli that occur in vivo to improve our basic understanding of cardiogenesis and identify underlying mechanisms that can potentially be exploited to enhance myocardial regeneration. PMID- 17708720 TI - Interventions to halt child abuse in Aboriginal communities. PMID- 17708719 TI - Transcriptome of primary adipocytes from obese women in response to a novel hydroxycitric acid-based dietary supplement. AB - BACKGROUND: Obesity is a global public health problem. Traditional herbal medicines may have some potential in managing obesity. The dried fruit rind of Garcinia cambogia, also known as Malabar tamarind, is a unique source of (-) hydroxycitric acid (HCA), which exhibits a distinct sour taste and has been safely used for centuries in Southeastern Asia to make meals more filling. Recently it has been demonstrated that when taken orally, a novel, highly soluble calcium/potassium salt of HCA (HCA-SX) is safe and bioavailable in the human plasma. Although HCA-SX seems to be conditionally effective in weight management in experimental animals and in humans, its mechanism of action remains unclear. METHODS: In this study, subcutaneous preadipocytes collected from obese women with body mass index>25 kg/m2 were differentiated to adipocytes for 2 weeks in culture. The effects of low-dose HCA-SX on lipid metabolism and on the adipocyte transcriptome were tested. HCA-SX augmented isoproterenol- and 3-isobutyryl-1 methylxanthine-induced lipolysis. Using oil red O, the production of lipid storage droplets by the cultured mature human adipocytes was visualized and enumerated. RESULTS: HCA-SX caused droplet dispersion facilitating lipase action on the lipids. HCA-SX markedly induced leptin expression in the adipocytes. In the microarray analyses, a total of 54,676 probe sets were screened. HCA-SX resulted in significant down-regulation of 348, and induction of 366 fat- and obesity-related genes. HCA-SX induced transactivation of hypoxia inducible factor (HIF), a novel approach in the management of obesity. CONCLUSION: Taken together, the net effects support the antilipolytic and antiadipogenic effects of HCA-SX. Further human studies are warranted. PMID- 17708721 TI - Skin cancer: changing paradigms of practice and medical education. PMID- 17708722 TI - Skin cancer surgery in Australia 2001-2005: the changing role of the general practitioner. AB - OBJECTIVE: To describe changing patterns of skin cancer surgery by Australian general practitioners and make comparisons with specialists. DESIGN AND SETTING: Analysis of Medicare Australia item number reports for skin cancer excisions and for flap and graft repairs between 2001 and 2005. MAIN OUTCOME MEASURES: GPs' and specialists' rates of non-melanoma skin cancer (NMSC) excisions, melanoma excisions, flap repairs and graft repairs; excision to flap ratios. RESULTS: NMSC excisions in Australia increased from 338 712 (2001) to 451 628 (2005), a mean annual increase of 1.11/1000 population (P = 0.04); GPs did 51.1% of excisions in 2001, increasing to 54.4% in 2005, representing a higher mean annual rate increase than in specialists (P = 0.003). Nationally, melanoma excisions increased from 20 414 (2001) to 25 580 (2005); GPs did 34.3% of excisions in 2001, increasing to 35.8% in 2005--a similar mean annual rate increase to that in specialists (P = 0.25). Total flap repairs increased from 58 550 (2001) to 80 742 (2005); GPs did 21.3% of flap repairs in 2001, increasing to 26.9% in 2005--a similar mean annual rate increase to that in specialists (P = 0.83). Nationally, the excision to flap ratio for GPs fell from 14 : 1 (2001) to 12 : 1 (2005); in Queensland the ratio fell from 14 : 1 to 9 : 1 over the same period. CONCLUSION: GPs excise the majority of skin cancers, and the proportion excised by GPs is increasing. GPs are increasingly using skin flaps for repair, suggesting substantial changes to patterns of treatment, especially in Queensland. PMID- 17708723 TI - Diagnosing skin cancer in primary care: how do mainstream general practitioners compare with primary care skin cancer clinic doctors? AB - OBJECTIVE: To measure and compare the casemix and diagnostic accuracy of excised or biopsied skin lesions managed by mainstream general practitioners and doctors within primary care skin cancer clinics. DESIGN, SETTING AND PARTICIPANTS: Prospective comparative study of 104 GPs and 50 skin cancer clinic doctors in south-eastern Queensland, involving 28 755 patient encounters. The study was conducted in 2005. MAIN OUTCOME MEASURES: Prevalence of each type of skin lesion; sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the clinical diagnosis against histology; number needed to excise or biopsy (NNE) for a diagnosis of skin cancer. RESULTS: GPs excised or biopsied 3175 skin lesions (mean 2.5/week) including 743 basal cell carcinomas (BCCs) (23.4%), 704 squamous cell carcinomas (SCCs) (22.2%) and 49 melanomas (1.5%). Skin cancer clinic doctors excised or biopsied 7941 skin lesions (mean 34/week), including 2701 BCCs (34.0%), 1274 SCCs (16.0%) and 103 melanomas (1.3%). Overall, sensitivity for diagnosing any skin cancer was similar for skin cancer clinic doctors (0.94) and GPs (0.91), although higher for skin cancer clinic doctors for BCC (0.89 v 0.79; P < 0.01) and melanoma (0.60 v 0.29; P < 0.01). The overall NNE was similar for skin cancer clinic doctors (1.9; 95% CI, 1.8%-2.1%) and GPs (2.1; 95% CI, 1.9%-2.3%). This did not change after adjusting for years of clinical experience. CONCLUSIONS: GPs and skin cancer clinic doctors in Queensland treat large numbers of skin cancers and diagnose these with overall high sensitivity. The two groups diagnosed skin cancer with similar accuracy. PMID- 17708724 TI - Asthma among school children in the Barwon region of Victoria. AB - OBJECTIVES: To determine (i) the relationship between asthma management and socioeconomic status; (ii) whether recent estimates from the International Study of Asthma and Allergies in Childhood (ISAAC) conducted in Melbourne apply to a broader cross-section of Victorian children; and (iii) age-related trends in asthma prevalence. DESIGN: A questionnaire survey, based on the ISAAC protocol. PARTICIPANTS AND SETTING: Subjects were children aged 4-13 years from a random sample of primary schools in the Barwon region of Victoria. The survey was conducted between March and September 2005. MAIN OUTCOME MEASURES: Parent reported wheeze and wheeze-related use of health resources during the preceding 12 months. RESULTS: Questionnaires were returned by 7813/9258 students (84%). Lower socioeconomic status was associated with increased frequency of regular asthma reviews (P < 0.01 for trend), but not of emergency department visits (P = 0.19). The prevalence of wheeze among 6- and 7-year-old children in the Barwon region was similar to that in Melbourne children (20.2% v 20.0%, respectively). There was an age-related increase in the proportion of children with > or = 12 episodes of wheeze (P = 0.01); but an age-related decrease in emergency department visits (P = 0.02). CONCLUSIONS: Disadvantaged children have good access to regular asthma reviews and are no more likely to attend an emergency department with an episode of acute wheeze. Asthma prevalence in 6- and 7-year old children in the Barwon region is similar to that in Melbourne. The prevalence of children with very frequent wheeze increases with age, but their use of health resources decreases. PMID- 17708726 TI - Preventing suicide after traumatic brain injury: implications for general practice. AB - People with traumatic brain injury (TBI) have an increased risk of suicide, suicide attempts and suicide ideation compared with the general population. Most suicide deaths and attempts involve self-poisoning. General practitioners are strategically placed to make a significant contribution to preventing suicide in this group. Assessment approaches need to take into account the chronic nature of suicide risk in people with TBI. The assessment of post-TBI depression is complicated by the confounding effect of post-TBI motor-sensory and cognitive impairments, but psychological symptoms (feelings of hopelessness, worthlessness, and anhedonia, in particular) suggest the diagnosis of depression after TBI. Management includes close attention to how medications are prescribed, dispensed and administered. Family and community brain injury agencies can be enlisted to provide emotional support and monitoring of people with TBI. GPs can facilitate access to needed mental health services for people with TBI during times of suicidal crisis. Clinical practice guidelines for the care of people living with traumatic brain injury in the community, recently published for general practice, may be of use in managing people with TBI. PMID- 17708725 TI - Issues for clinicians training international medical graduates: a systematic review. AB - OBJECTIVE: To ascertain the specialised communication issues clinicians need to understand when preparing international medical graduates (IMGs) for clinical practice in Australia. STUDY DESIGN: Systematic review. DATA SOURCES: A series of searches using MEDLINE (1990-2006) was conducted with relevant keywords. Literature from countries with experience in the integration of IMGs into their medical workforces was included. All except four articles were published between 1997 and 2006. STUDY SELECTION: The initial search identified 748 articles, which reduced to 234 evidence-based English language articles for review. Of these, only articles relating to postgraduate medical training and overseas trained doctors were selected for inclusion. DATA EXTRACTION: Titles and abstracts were independently reviewed by two reviewers, with a concordance rate of 0.9. Articles were included if they addressed communication needs of IMGs in training. Any disparities between reviewers about which articles to include were discussed and resolved by consensus. DATA SYNTHESIS: Key issues that emerged were the need for IMGs to adjust to a change in status; the need for clinicians to understand the high level of English language proficiency required by IMGs; the need for clinicians to develop IMGs' skills in communicating with patients; the need for clinicians to understand IMGs' expectations about teaching and learning; and the need for IMGs to be able to interact effectively with a range of people. CONCLUSION: Training organisations need to ensure that clinicians are aware of the communication issues facing IMGs and equip them with the skills and tools to deal with the problems that may arise. PMID- 17708727 TI - Loss of chance: a new development in medical negligence law. AB - The concept of "loss of chance" as an alternative cause of action in cases of medical negligence has succeeded in recent cases where actions based on causation have failed. The plaintiff must prove negligence and loss of a chance of a better outcome. The quantity of loss of chance must be more than "speculative" (1%). Damages are awarded as a proportion of the total injury commensurate with the loss of chance. More claims may be expected, although damages will generally be less than those awarded under causation. Doctors' insurance premiums may rise. PMID- 17708728 TI - Three cases of endometrial cancer associated with "bioidentical" hormone replacement therapy. AB - We describe three women who developed endometrial cancer after taking "bioidentical" hormone replacement therapy (HRT) to relieve menopausal symptoms. Although pharmaceutical HRT is a well established and tested therapy, little is known about the quality control, safety and efficacy of bioidentical HRT. Women should be advised to avoid bioidentical HRT, and those who continue to use it should receive regular endometrial surveillance. PMID- 17708729 TI - A giant splenic artery aneurysm. PMID- 17708730 TI - Colonoscopy capacity in selected New South Wales hospitals. PMID- 17708731 TI - Airline security and diabetes. PMID- 17708732 TI - Comparing survival outcomes for patients with colorectal cancer treated in public and private hospitals. PMID- 17708733 TI - Use of dermoscopy in Australia. PMID- 17708734 TI - The effects of oxygen therapy in patients presenting to an emergency department with exacerbation of chronic obstructive pulmonary disease. PMID- 17708735 TI - Potential link between HMG-CoA reductase inhibitor (statin) use and interstitial lung disease. PMID- 17708736 TI - Attitudes towards cosmetic surgery among university students. PMID- 17708737 TI - Words, words, words. PMID- 17708738 TI - Entry tests for graduate medical programs: is it time to re-think? PMID- 17708739 TI - Interleukin-6--a key mediator of systemic and local symptoms in rheumatoid arthritis. AB - Interleukin-6 (IL-6) is a pleiotropic cytokine, present at elevated levels in patients with rheumatoid arthritis (RA). Il-6 signaling involves both a specific IL-6 receptor (IL-6R) and a ubiquitous signal-transducing protein, gp130 that is also utilized by other members of the IL-6 family. Il-6 signaling occurs by two mechanisms. Conventional signaling involves the binding of IL-6 to transmembrane IL-6R on cells expressing this receptor. In contrast, trans-signaling involves binding between the complex of soluble IL-6R/IL-6 and membrane-bound gp130. Trans signaling allows IL-6 to affect cells that do not express IL-6R, including many synovial cells. The biological activities of IL-6 contribute to both systemic and local RA symptoms. Il-6 is a strong inducer of the acute-phase response, which can result in fever, secondary amyloidosis, anemia, and elevations in acute-phase proteins, such as C-reactive protein (CRP). The ability of IL-6 to induce B-cell differentiation may lead to the formation of rheumatoid factor and other autoantibodies. In joints, IL-6 promotes osteoclast activation and induces the release of matrix metalloproteinases, thus contributing to joint damage. In patients with RA, IL-6 levels correlate with markers of disease activity and clinical symptoms, and animal studies support the concept that this cytokine plays a role in the development of inflammatory arthritis. Clinical trials with tocilizumab, a humanized monoclonal antibody to soluble IL-6R, have shown that blocking IL-6 signaling reduces RA symptoms and markers of disease activity. Current evidence thus strongly supports the association between IL-6 and RA symptoms and suggests that IL-6 blockade will be a useful therapeutic strategy for patients with this disease. PMID- 17708740 TI - Interleukin-6 inhibition and clinical efficacy in rheumatoid arthritis treatment- data from randomized clinical trials. AB - Interleukin 6 (IL-6), a pleiotropic cytokine with numerous and varied effects on the inflammatory cascade and immune response, appears to be an attractive target for novel immunomodulatory therapy for systemic inflammatory autoimmune diseases. Proof of principal for this approach has come from studies of the anti-IL-6 receptor monoclonal antibody, tocilizumab. Tocilizumab has been assessed in a number of studies in recent years, mainly in patients with rheumatoid arthritis (RA). Data from randomized controlled clinical trials demonstrate the efficacy of tocilizumab in improving the signs and symptoms of RA. In addition, it appears that such inhibition of IL-6 can have positive effects on functional status, an important outcome for RA patients. Finally, data suggest that treatment with this agent may also inhibit the progression of disease as assessed radiographically. Data from studies currently underway will help refine the ultimate use of this novel approach to treatment, and help clinicians optimize therapy using this approach. PMID- 17708741 TI - Interleukin-6 inhibition--tolerability profile and clinical implications. AB - Tocilizumab, humanized monoclonal antibody to sIL-6R, is a promising new agent for the treatment of rheumatoid arthritis. Safety data from randomized controlled trials (RCT) to date have been overall reassuring with no evidence of increased opportunistic infections or malignancies, and some signals for elevated liver function tests and changed lipid profiles. The true implications of these signals in RCTs must be addressed in larger numbers of RA patients with longer term exposure before firm conclusions are reached. PMID- 17708742 TI - Monitoring response to treatment in rheumatoid arthritis--which tool is best suited for routine "real world" care? AB - Rheumatoid arthritis treatment is a fast changing and advancing area. Current drugs are now better utilized and new medications continue to be developed. The main challenge is to identify which patients are responding to treatment and to objectively quantify their response or nonresponse. There is a need for more rheumatologists to pursue use of an objective assessment tool in routine clinical care. Therefore, knowledge of the various tools available to rheumatologists in clinical trials and routine care and their practical differences is important to progress in patient evaluation and management. The tool that is easiest for both the patient and the physician to use and that still provides important treatment response and prognostic information has the best chance to be consistently and successfully applied by busy clinicians. PMID- 17708743 TI - Patient questionnaires and formal education as more significant prognostic markers than radiographs or laboratory tests for rheumatoid arthritis mortality- limitations of a biomedical model to predict long-term outcomes. PMID- 17708744 TI - Interleukin-6 in the pathogenesis of rheumatoid arthritis. AB - Cytokines such as TNF-alpha and IL-1beta play key roles in driving the inflammation and synovial cell proliferation that characterize rheumatoid arthritis (RA) joint destruction. It is, therefore, not surprising that therapies for RA have targeted these cytokines. While blockade of TNF-alpha or IL-1beta has been efficacious for many patients with RA, adequacy and maintenance of response are not universal, and increased risk of adverse events such as infection and malignancy remains a concern. Therefore, new targets in the treatment of RA continue to be examined. As interleukin-6 (IL-6) has been implicated in the pathogenesis of RA, blockade of its activity is of both scientific and clinical interest. The basic biology of IL-6, the in vitro animal data supporting its role in RA, and the human trials to date that test the possible efficacy of IL-6 directed therapy for RA are reviewed. PMID- 17708746 TI - Elevated plasma arginase-1 does not affect plasma arginine in patients undergoing liver resection. AB - Arginine is an important substrate in health and disease. It is a commonly held view that arginase-1 release from injured erythrocytes and hepatocytes leads to arginine breakdown; however, the true relationship between plasma arginase-1 concentration and activity has remained unaddressed. In the present study, blood was sampled from patients undergoing liver resection, a known cause of hepatocyte injury and arginase-1 release, to determine arginase-1, arginine and ornithine plasma levels. Arginase activity was assessed in vitro by measuring changes in arginine and ornithine plasma levels during incubation of plasma and whole-blood samples at 37 degrees C. Arginase-1 plasma levels increased 8-10-fold during liver resection, whereas arginine and ornithine levels remained unchanged. In accordance with these in vivo findings, arginine and ornithine levels remained unchanged in plasma incubated at 37 degrees C irrespective of the arginase-1 concentration. In contrast, arginine plasma levels in whole blood decreased significantly during incubation, with ornithine increasing stoichiometrically. These changes were irrespective of arginase-1 plasma levels and were explained by arginase activity present in intact erythrocytes. Next, plasma samples with 1000 fold normal arginase-1 concentrations were obtained from patients undergoing cadaveric liver transplantation. A significant decrease in arginine plasma levels occurred in vivo and in vitro. In contrast with commonly held views, moderately increased arginase-1 plasma levels do not affect plasma arginine. Very high plasma arginase-1 levels are required to induce potential clinically relevant effects. PMID- 17708745 TI - Determination of protein regions responsible for interactions of amelogenin with CD63 and LAMP1. AB - The enamel matrix protein amelogenin is secreted by ameloblasts into the extracellular space to guide the formation of highly ordered hydroxyapatite mineral crystallites, and, subsequently, is almost completely removed during mineral maturation. Amelogenin interacts with the transmembrane proteins CD63 and LAMP (lysosome-associated membrane protein) 1, which are involved in endocytosis. Exogenously added amelogenin has been observed to move rapidly into CD63/LAMP1 positive vesicles in cultured cells. In the present study, we demonstrate the protein region defined by amino acid residues 103-205 for CD63 interacts not only with amelogenin, but also with other enamel matrix proteins (ameloblastin and enamelin). A detailed characterization of binding regions in amelogenin, CD63 and LAMP1 reveals that the amelogenin region defined by residues PLSPILPELPLEAW is responsible for the interaction with CD63 through residues 165-205, with LAMP1 through residues 226-251, and with the related LAMP2 protein through residues 227 259. We predict that the amelogenin binding region is: (i) hydrophobic; (ii) largely disordered; and (iii) accessible to the external environment. In contrast, the binding region of CD63 is likely to be organized in a '7' shape within the mushroom-like structure of CD63 EC2 (extracellular domain 2). In vivo, the protein interactions between the secreted enamel matrix proteins with the membrane-bound proteins are likely to occur at the specialized secretory surfaces of ameloblast cells called Tomes' processes. Such protein-protein interactions may be required to establish short-term order of the forming matrix and/or to mediate feedback signals to the transcriptional machinery of ameloblasts and/or to remove matrix protein debris during enamel biomineralization. PMID- 17708747 TI - New properties of inclusion bodies with implications for biotechnology. AB - Human G-CSF (granulocyte colony-stimulating factor) is a well-known biopharmaceutical drug being mostly produced by overexpression in Escherichia coli, where it appears in the form of IBs (inclusion bodies). Following our initial findings that properties of inclusion bodies strongly depend on the growth conditions used, especially growth temperature, we compared the characteristics of the G-CSF inclusion bodies prepared at two different temperatures, namely 42 and 25 degrees C. IBs formed at higher growth temperatures have properties similar to the usually described IBs, containing mainly denatured recombinant protein and being almost completely insoluble in aqueous solutions containing mild detergents or low concentrations of denaturants. In contrast, when produced at lower growth temperature of 25 degrees C, IBs show significantly different properties. Such IBs contain a significant proportion of G-CSF that is easily and directly extractable in the biologically active form, using non-denaturing solutions, which can be exploited for environmentally friendly biotechnological production. Irrespective of the production temperature, a significant decrease in IB volume was observed when transferring IBs from neutral to acidic (around 4) pH. Irreversible contraction of IBs at low pH was documented at the macro- and micro-scopic level using electron microscopy as a characterization tool. Together with volume decrease, a higher density, and thus decreased solubility, of IBs was observed at low pH, resulting in slower and less efficient extractability of the target protein. PMID- 17708748 TI - Sialidase NEU3 is a peripheral membrane protein localized on the cell surface and in endosomal structures. AB - Sialidase NEU3 is also known as the plasma-membrane-associated form of mammalian sialidases, exhibiting a high substrate specificity towards gangliosides. In this respect, sialidase NEU3 modulates cell-surface biological events and plays a pivotal role in different cellular processes, including cell adhesion, recognition and differentiation. At the moment, no detailed studies concerning the subcellular localization of NEU3 are available, and the mechanism of its association with cellular membranes is still unknown. In the present study, we have demonstrated that sialidase NEU3, besides its localization at the plasma membrane, is present in intracellular structures at least partially represented by a subset of the endosomal compartment. Moreover, we have shown that NEU3 present at the plasma membrane is internalized and locates then to the recycling endosomal compartment. The enzyme is associated with the outer leaflet of the plasma membrane, as shown by selective cell-surface protein biotinylation. This evidence is in agreement with the ability of NEU3 to degrade gangliosides inserted into the plasma membrane of adjacent cells. Moreover, the mechanism of the protein association with the lipid bilayer was elucidated by carbonate extraction. Under these experimental conditions, we have succeeded in solubilizing NEU3, thus demonstrating that the enzyme is a peripheral membrane protein. In addition, Triton X-114 phase separation demonstrates further the hydrophilic nature of the protein. Overall, these results provide important information about the biology of NEU3, the most studied member of the mammalian sialidase family. PMID- 17708749 TI - Molecular cloning and biochemical characterization of sialidases from zebrafish (Danio rerio). AB - Sialidases remove sialic acid residues from various sialo-derivatives. To gain further insights into the biological roles of sialidases in vertebrates, we exploited zebrafish (Danio rerio) as an animal model. A zebrafish transcriptome- and genome-wide search using the sequences of the human NEU polypeptides as templates revealed the presence of seven different genes related to human sialidases. neu1 and neu4 are the putative orthologues of the mammalian sialidases NEU1 and NEU4 respectively. Interestingly, the remaining genes are organized in clusters located on chromosome 21 and are all more closely related to mammalian sialidase NEU3. They were thus named neu3.1, neu3.2, neu3.3, neu3.4 and neu3.5. Using RT-PCR (reverse transcription-PCR) we detected transcripts for all genes, apart from neu3.4, and whole-mount in situ hybridization experiments show a localized expression pattern in gut and lens for neu3.1 and neu4 respectively. Transfection experiments in COS7 (monkey kidney) cells demonstrate that Neu3.1, Neu3.2, Neu3.3 and Neu4 zebrafish proteins are sialidase enzymes. Neu3.1, Neu3.3 and Neu4 are membrane-associated and show a very acidic pH optimum below 3.0, whereas Neu3.2 is a soluble sialidase with a pH optimum of 5.6. These results were further confirmed by subcellular localization studies carried out using immunofluorescence. Moreover, expression in COS7 cells of these novel zebrafish sialidases (with the exception of Neu3.2) induces a significant modification of the ganglioside pattern, consistent with the results obtained with membrane-associated mammalian sialidases. Overall, the redundancy of sialidases together with their expression profile and their activity exerted on gangliosides of living cells indicate the biological relevance of this class of enzymes in zebrafish. PMID- 17708750 TI - Comparison of four methods for the purification and refolding of human interleukin-2-mouse granulocyte/macrophage colony-stimulating factor fusion protein. AB - The combination of IL-2 (interleukin-2) and GM-CSF (granulocyte/macrophage colony stimulating factor) has been broadly studied in antitumour immune therapy, but its efficacy is uncertain. To better exert the activities of the two cytokines and study them in a mouse model, we have constructed a bifunctional protein, hIL 2-mGM-CSF (human IL-2-mouse GM-CSF), fused to a C-terminal tag of six histidine residues (His(6)). The fusion protein was expressed in Escherichia coli as IBs (inclusion bodies). After extracting and clarifying the IBs, four methods of protein purification and refolding were compared in order to optimize the preparation technique. Of these methods, the best result was obtained with a four step process consisting of (1) purification with denaturing affinity chromatography, (2) followed by fully denaturing the protein with system conversion, (3) then refolding by isovolumetric ultrafiltration and (4) finally, purification by anion-exchange chromatography. The purity of the hIL-2-mGM-CSF was approx. 95%, yielding approx. 20 mg of protein/l of culture. The fusion protein retained the natural activities of IL-2 and GM-CSF, with specific activities of 8.7 x 10(6) and 1.1 x 10(7) i.u./mg respectively. Flow-cytometric analysis indicated that hIL-2-mGM-CSF could specifically bind to the corresponding receptor-positive cells. The present study provides important preliminary information for studying the antitumour activity of hIL-2-mGM-CSF in vivo, which will facilitate future clinical research into the use of hIL-2/hGM CSF in immune therapy. PMID- 17708751 TI - Trends in testicular germ cell tumours by ethnic group in the United States. AB - The incidence of testicular germ cell tumours (TGCT) has increased in white and black men in the United States. Little is known, however, about trends among men of other racial/ethnic groups. The current study sought to examine TGCT patterns among men of Asian/Pacific Islander/American Indian/ Alaska Native (API/AIAN) and Hispanic ancestries and to determine whether tumours in these groups are diagnosed at comparable stages and sizes to tumours in white and black men. TGCT incidence data and tumour characteristics were drawn from the Surveillance, Epidemiology and End Results registries for two time periods: 1973-2003 and 1992 2003. In 1973-2003, TGCT rates were significantly lower among black (rate ratio = 0.18, p < 0.001) and API/AIAN (rate ratio = 0.37, p < 0.001) men than among white men. Among white and API/AIAN men, rates increased over 60%, mainly prior to 1989 1993. Among black men, rates increased almost 40%, mainly after 1989-1993. Among white and API/AIAN men, increasing proportions of localized disease were diagnosed over time, while the opposite trend was seen among black men. In 1992 2003, TGCT incidence among Hispanic white men (3.46/100 000) was significantly lower than it was among non-Hispanic white men, but rates of both seminoma and non-seminoma increased. While the incidence of TGCT increased among all men, different patterns in the increase were evident. These data suggest that rates are increasing among Hispanic white men and black men, but are stabilizing among white men and API/AIAN men. The peak of the TGCT epidemic may have been reached in these latter groups. PMID- 17708752 TI - Environmental, occupational and familial risks for testicular cancer: a hospital based case-control study. AB - Testicular cancer (TC) risk factors remain largely unknown, except for personal history of cryptorchidism and familial history of TC. We conducted a hospital based case-control study on familial, environmental and occupational conditions in which we compared 229 cases and 800 controls. TC was correlated with cryptorchidism (OR = 3.02; CI: 1.90-4.79), a history of cryptorchidism in relatives (OR = 2.85; CI: 1.70-4.79), and TC (OR = 9.58; CI: 4.01-22.88], prostate cancer (OR = 1.80; CI: 1.08-3.02) and breast cancer (OR = 1.77; CI: 1.20 2.60) in relatives. Living in a rural area or having regular gardening activity (growing fruit or vegetables) was associated with an increased risk of TC (OR = 1.63; CI: 1.16-2.29; OR = 1.84; CI: 1.23-2.75). Regarding occupation, we found a relationship with employment in metal trimming (OR = 1.96; CI: 1.00-3.86), chemical manufacture (OR = 1.88; CI: 1.14-3.10), industrial production of glue (OR = 2.21; CI: 1.15-4.25), and welding (OR = 2.84; CI: 1.51-5.35). In a multivariate model, only a history of cryptorchidism in the men, cryptorchidism in relatives, TC, and breast cancer remained significant. Our findings contribute further evidence to a pattern of TC risk factors, which include the significant weight of personal reproductive history and also of testicular and breast cancer in relatives. By including in a multivariate model variables linked to environmental and occupational exposure and related to familial cancer history, neither living in a rural area nor any occupational exposure appeared to be a potential environmental TC risk factor. PMID- 17708754 TI - Determinants and status of quality of life after long-term botulinum toxin therapy for cervical dystonia. AB - The aim of this study was to assess health-related quality of life (HRQoL), using the Short Form Health Survey-36 (SF-36), in 70 cervical dystonia (CD) patients after long-term botulinum toxin (BTX) treatment (median 5.5 years), and to identify factors determining reduced HRQoL. We used combined patient-and physician-based measures to assess both CD severity [Toronto Western Spasmodic Torticollis Rating Scale, (TWSTRS)] and effect of long-term BTX treatment, and the Hospital Anxiety and Depression Scale (HAD) and General Health Questionnaire 30 to assess psychological distress. Mean SF-36 domain scores of the CD patients were reduced by <1 SD compared with age- and gender-matched population samples. High TWSTRS total scores and high HAD-depression (HAD-D) scores were the main factors associated with reduced scores in the physical and mental SF-36 domains, respectively. Patients evaluated to have a 'good effect' of long-term BTX treatment (n = 47), had significantly lower median TWSTRS total score, and a 3x lower frequency of high HAD-D scores, than those evaluated to an 'unsatisfactory effect' (n = 23). In conclusion, most CD patients enjoy a good HRQoL after long term BTX therapy. Reduced HRQoL was associated with more severe disease and/or depressive symptoms. PMID- 17708753 TI - Self-reported depression and anti-depressant medication use in essential tremor: cross-sectional and prospective analyses in a population-based study. AB - There are few data on the co-morbidity of essential tremor (ET) with depression. To assess the associations of ET with self-reported depression and antidepressant medication use. In a population-based study in central Spain, participants were evaluated at baseline (1994-1995) and 3 years later. Self-reported depression and use of antidepressant medications were evaluated at each assessment. In cross sectional analyses, prevalent ET cases were twice more probably than controls to report depression [103 (43.8%) of 235 cases versus 1137 (26.0%) of 4379 controls; adjusted odds ratio (OR) 2.20, 95% confidence interval (CI) 1.66-2.93, P < 0.001] and three times more probably to be taking antidepressant medications [16 (6.8%) cases versus 113 (2.6%) controls; adjusted OR 3.33, 95% CI 1.91-5.82, P = 0.001]. In prospective analyses, baseline self-reported depression (adjusted RR 1.78, 95% CI 1.11-2.89, P = 0.018) and, perhaps, baseline use of antidepressant medication (adjusted RR 1.90, 95% CI 0.59-6.05, P = 0.28) were associated with incident ET. Rather than being totally benign, ET seems to be associated with a mood disorder. Furthermore, as well as being a secondary response to disease manifestations, this mood disorder may be a primary feature of the underlying disease. PMID- 17708755 TI - Stereotactic cortical resection in non-lesional extra-temporal partial epilepsy. AB - The presentation and treatment of a patient with extra-temporal non-lesional partial epilepsy is discussed herein. His clinical semiology was consistent with supplementary motor area seizures; however, MR imaging did not demonstrate a lesion. A region of stable cortical glucose hypermetabolism in the left frontal region was noted with 2-fluoro-2-deoxy-D-glucose (FDG)-PET. This was consistent with the frequent interictal discharges evident over the left fronto-temporal region and the stereotypic high amplitude ictal discharges arising with highest amplitude from the left frontal region. Epileptiform activity evident on an intracranial 64-point subdural recording grid placed over the left dorsolateral frontal cortex confirmed a distribution concordant with FDG-PET findings. The subsequent resection was guided by the PET and EEG findings rather than structural MR imaging, and a limited cortical resection led to an immediate and substantial reduction in seizure frequency. PMID- 17708756 TI - Membrane cell fusion activity of the vaccinia virus A17-A27 protein complex. AB - Vaccinia virus enters cells by endocytosis and via a membrane fusion mechanism mediated by viral envelope protein complexes. While several proteins have been implicated in the entry/fusion event, there is no direct proof for fusogenic activity of any viral protein in heterologous systems. Transient coexpression of A17 and A27 in mammalian cells led to syncytia formation in a pH-dependent manner, as ascertained by confocal fluorescent immunomicroscopy. The pH-dependent fusion activity was identified to reside in A17 amino-terminal ectodomain after overexpression in insect cells using recombinant baculoviruses. Through the use of A17 ectodomain deletion mutants, it was found that the domain important for fusion spanned between residues 18 and 34. To further characterize A17-A27 fusion activity in mammalian cells, 293T cell lines stably expressing A17, A27 or coexpressing both proteins were generated using lentivectors. A27 was exposed on the cell surface only when A17 was coexpressed. In addition, pH-dependent fusion activity was functionally demonstrated in mammalian cells by cytoplasmic transfer of fluorescent proteins, only when A17 and A27 were coexpressed. Bioinformatic tools were used to compare the putative A17-A27 protein complex with well characterized fusion proteins. Finally, all experimental evidence was integrated into a working model for A17-A27-induced pH-dependent cell-to-cell fusion. PMID- 17708757 TI - Genome bioinformatic analysis of nonsynonymous SNPs. AB - BACKGROUND: Genome-wide association studies of common diseases for common, low penetrance causal variants are underway. A proportion of these will alter protein sequences, the most common of which is the non-synonymous single nucleotide polymorphism (nsSNP). It would be an advantage if the functional effects of an nsSNP on protein structure and function could be predicted, both for the final identification process of a causal variant in a disease-associated chromosome region, and in further functional analyses of the nsSNP and its disease associated protein. RESULTS: In the present report we have compared and contrasted structure- and sequence-based methods of prediction to over 5500 genes carrying nearly 24,000 nsSNPs, by employing an automatic comparative modelling procedure to build models for the genes. The nsSNP information came from two sources, the OMIM database which are rare (minor allele frequency, MAF, < 0.01) and are known to cause penetrant, monogenic diseases. Secondly, nsSNP information came from dbSNP125, for which the vast majority of nsSNPs, mostly MAF > 0.05, have no known link to a disease. For over 40% of the nsSNPs, structure-based methods predicted which of these sequence changes are likely to either disrupt the structure of the protein or interfere with the function or interactions of the protein. For the remaining 60%, we generated sequence-based predictions. CONCLUSION: We show that, in general, the prediction tools are able distinguish disease causing mutations from those mutations which are thought to have a neutral affect. We give examples of mutations in genes that are predicted to be deleterious and may have a role in disease. Contrary to previous reports, we also show that rare mutations are consistently predicted to be deleterious as often as commonly occurring nsSNPs. PMID- 17708759 TI - Rice pseudomolecule-anchored cross-species DNA sequence alignments indicate regional genomic variation in expressed sequence conservation. AB - BACKGROUND: Various methods have been developed to explore inter-genomic relationships among plant species. Here, we present a sequence similarity analysis based upon comparison of transcript-assembly and methylation-filtered databases from five plant species and physically anchored rice coding sequences. RESULTS: A comparison of the frequency of sequence alignments, determined by MegaBLAST, between rice coding sequences in TIGR pseudomolecules and annotations vs 4.0 and comprehensive transcript-assembly and methylation-filtered databases from Lolium perenne (ryegrass), Zea mays (maize), Hordeum vulgare (barley), Glycine max (soybean) and Arabidopsis thaliana (thale cress) was undertaken. Each rice pseudomolecule was divided into 10 segments, each containing 10% of the functionally annotated, expressed genes. This indicated a correlation between relative segment position in the rice genome and numbers of alignments with all the queried monocot and dicot plant databases. Colour-coded moving windows of 100 functionally annotated, expressed genes along each pseudomolecule were used to generate 'heat-maps'. These revealed consistent intra- and inter-pseudomolecule variation in the relative concentrations of significant alignments with the tested plant databases. Analysis of the annotations and derived putative expression patterns of rice genes from 'hot-spots' and 'cold-spots' within the heat maps indicated possible functional differences. A similar comparison relating to ancestral duplications of the rice genome indicated that duplications were often associated with 'hot-spots'. CONCLUSION: Physical positions of expressed genes in the rice genome are correlated with the degree of conservation of similar sequences in the transcriptomes of other plant species. This relative conservation is associated with the distribution of different sized gene families and segmentally duplicated loci and may have functional and evolutionary implications. PMID- 17708758 TI - Prediction of the burial status of transmembrane residues of helical membrane proteins. AB - BACKGROUND: Helical membrane proteins (HMPs) play a crucial role in diverse cellular processes, yet it still remains extremely difficult to determine their structures by experimental techniques. Given this situation, it is highly desirable to develop sequence-based computational methods for predicting structural characteristics of HMPs. RESULTS: We have developed TMX (TransMembrane eXposure), a novel method for predicting the burial status (i.e. buried in the protein structure vs. exposed to the membrane) of transmembrane (TM) residues of HMPs. TMX derives positional scores of TM residues based on their profiles and conservation indices. Then, a support vector classifier is used for predicting their burial status. Its prediction accuracy is 78.71% on a benchmark data set, representing considerable improvements over 68.67% and 71.06% of previously proposed methods. Importantly, unlike the previous methods, TMX automatically yields confidence scores for the predictions made. In addition, a feature selection incorporated in TMX reveals interesting insights into the structural organization of HMPs. CONCLUSION: A novel computational method, TMX, has been developed for predicting the burial status of TM residues of HMPs. Its prediction accuracy is much higher than that of previously proposed methods. It will be useful in elucidating structural characteristics of HMPs as an inexpensive, auxiliary tool. A web server for TMX is established at http://service.bioinformatik.uni-saarland.de/tmx and freely available to academic users, along with the data set used. PMID- 17708760 TI - Comparison of quenching and extraction methodologies for metabolome analysis of Lactobacillus plantarum. AB - BACKGROUND: A reliable quenching and metabolite extraction method has been developed for Lactobacillus plantarum. The energy charge value was used as a critical indicator for fixation of metabolism. RESULTS: Four different aqueous quenching solutions, all containing 60% of methanol, were compared for their efficiency. Only the solutions containing either 70 mM HEPES or 0.85% (w/v) ammonium carbonate (pH 5.5) caused less than 10% cell leakage and the energy charge of the quenched cells was high, indicating rapid inactivation of the metabolism.The efficiency of extraction of intracellular metabolites from cell cultures depends on the extraction methods, and is expected to vary between micro organisms. For L. plantarum, we have compared five different extraction methodologies based on (i) cold methanol, (ii) perchloric acid, (iii) boiling ethanol, (iv) chloroform/methanol (1:1) and (v) chloroform/water (1:1). Quantification of representative intracellular metabolites showed that the best extraction efficiencies were achieved with cold methanol, boiling ethanol and perchloric acid. CONCLUSION: The ammonium carbonate solution was selected as the most suitable quenching buffer for metabolomics studies in L. plantarum because (i) leakage is minimal, (ii) the energy charge indicates good fixation of metabolism, and (iii) all components are easily removed during freeze-drying. A modified procedure based on cold methanol extraction combined good extractability with mild extraction conditions and high enzymatic inactivation. These features make the combination of these quenching and extraction protocols very suitable for metabolomics studies with L. plantarum. PMID- 17708761 TI - Extensive horizontal transfer of core genome genes between two Lactobacillus species found in the gastrointestinal tract. AB - BACKGROUND: While genes that are conserved between related bacterial species are usually thought to have evolved along with the species, phylogenetic trees reconstructed for individual genes may contradict this picture and indicate horizontal gene transfer. Individual trees are often not resolved with high confidence, however, and in that case alternative trees are generally not considered as contradicting the species tree, although not confirming it either. Here we conduct an in-depth analysis of 401 protein phylogenetic trees inferred with varying levels of confidence for three lactobacilli from the acidophilus complex. At present the relationship between these bacteria, isolated from environments as diverse as the gastrointestinal tract (Lactobacillus acidophilus and Lactobacillus johnsonii) and yogurt (Lactobacillus delbrueckii ssp. bulgaricus), is ambiguous due to contradictory phenotypical and 16S rRNA based classifications. RESULTS: Among the 401 phylogenetic trees, those that could be reconstructed with high confidence support the 16S-rRNA tree or one alternative topology in an astonishing 3:2 ratio, while the third possible topology is practically absent. Lowering the confidence threshold for trees to be taken into consideration does not significantly affect this ratio, and therefore suggests that gene transfer may have affected as much as 40% of the core genome genes. Gene function bias suggests that the 16S rRNA phylogeny of the acidophilus complex, which indicates that L. acidophilus and L. delbrueckii ssp. bulgaricus are the closest related of these three species, is correct. A novel approach of comparison of interspecies protein divergence data employed in this study allowed to determine that gene transfer most likely took place between the lineages of the two species found in the gastrointestinal tract. CONCLUSION: This case-study reports an unprecedented level of phylogenetic incongruence, presumably resulting from extensive horizontal gene transfer. The data give a first indication of the large extent of gene transfer that may take place in the gastrointestinal tract and its accumulated effect. For future studies, our results should encourage a careful weighing of data on phylogenetic tree topology, confidence and distribution to conclude on the absence or presence and extent of horizontal gene transfer. PMID- 17708763 TI - Helicobacter species are associated with possible increase in risk of biliary lithiasis and benign biliary diseases. AB - BACKGROUND: Hepato-biliary tract lithiasis is common and present either as pain or as asymptomatic on abdominal ultrasonography for other causes. Although the DNA of Helicobacter species are identified in the gallbladder bile, tissue or stones analyzed from these cases, still a causal relationship could not be established due to different results from different geographical parts. METHODS: A detailed search of pubmed and pubmedcentral was carried out with key words Helicobacter and gallbladder, gallstones, hepaticolithiasis, cholelithiasis and choledocholithiasis, benign biliary diseases, liver diseases. The data was entered in a data base and meta analysis was carried out. The analysis was carried out using odds ratio and a fixed effect model, 95% confidence intervals for odds ratio was calculated. Chi square test for heterogeneity was employed. The overall effect was calculated using Z test. RESULTS: A total of 12 articles were identified. One study used IgG for diagnosis while others used the PCR for Ure A gene, 16 S RNA or Cag A genes. A couple of studies used culture or histopathology besides the PCR. The cumulative results show a higher association of Helicobacter with chronic liver diseases (30.48%), and stone diseases (42.96%)(OR 1.77 95% CI 1.2-2.58; Z = 2.94, p = 0.003), the effect of each could not be identified as it was difficult to isolate the effect of helicobacter due to mixing of cases in each study. CONCLUSION: The results of present meta analysis shows that there is a slight higher risk of cholelithiasis and benign liver disease (OR 1.77), however due to inherent inability to isolate the effect of stone disease from that of other benign lesions it is not possible to say for sure that Helicobacter has a casual relationship with benign biliary disease or stone disease or both. PMID- 17708762 TI - Inefficient cognitive control in adult ADHD: evidence from trial-by-trial Stroop test and cued task switching performance. AB - BACKGROUND: Contemporary neuropsychological models of ADHD implicate impaired cognitive control as contributing to disorder characteristic behavioral deficiencies and excesses; albeit to varying degrees. While the traditional view of ADHD postulates a core deficiency in cognitive control processes, alternative dual-process models emphasize the dynamic interplay of bottom-up driven factors such as activation, arousal, alerting, motivation, reward and temporal processing with top-down cognitive control. However, neuropsychological models of ADHD are child-based and have yet to undergo extensive empirical scrutiny with respect to their application to individuals with persistent symptoms in adulthood. Furthermore, few studies of adult ADHD samples have investigated two central cognitive control processes: interference control and task-set coordination. The current study employed experimental chronometric Stroop and task switching paradigms to investigate the efficiency of processes involved in interference control and task-set coordination in ADHD adults. METHODS: 22 adults diagnosed with persistent ADHD (17 males) and 22 matched healthy control subjects performed a manual trial-by-trial Stroop color-word test and a blocked explicitly cued task switching paradigm. Performance differences between neutral and incongruent trials of the Stroop task measured interference control. Task switching paradigm manipulations allowed for measurement of transient task-set updating, sustained task-set maintenance, preparatory mechanisms and interference control. Control analyses tested for the specificity of group x condition interactions. RESULTS: Abnormal processing of task-irrelevant stimulus features was evident in ADHD group performance on both tasks. ADHD group interference effects on the task switching paradigm were found to be dependent on the time allotted to prepare for an upcoming task. Group differences in sustained task-set maintenance and transient task-set updating were also found to be dependent on experimental manipulation of task preparation processes. With the exception of Stroop task error rates, all analyses revealed generally slower and less accurate ADHD group response patterns. CONCLUSION: The current data obtained with experimental paradigms deliver novel evidence of inefficient interference control and task-set coordination in adults with persistent ADHD. However, all group differences observed in these central cognitive control processes were found to be partially dependent on atypical ADHD group task preparation mechanisms and/or response inconsistency. These deficiences may have contributed not only to inefficient cognitive control, but also generally slower and less accurate ADHD group performance. Given the inability to dissociate these impairments with the current data, it remains inconclusive as to whether ineffecient cognitive control in the clinical sample was due to top-down failure or bottom-up engagement thereof. To clarify this issue, future neuropsychological investigations are encouraged to employ tasks with significantly more trials and direct manipulations of bottom-up mechanisms with larger samples. PMID- 17708766 TI - Brace related stress in scoliosis patients - Comparison of different concepts of bracing. AB - BACKGROUND: The BSSQbrace questionnaire has been shown to be reliable with good internal consistency and reproducibility estimating the stress scoliosis patients have whilst wearing their brace. Eight questions are provided focussing on this topic. A max. score of 24 can be achieved (from 0 for most stress to 24 for no stress). The subdivision of the score values is: 0-8 (strong stress), 9-16 (medium stress) and 17-24 (little stress). STUDY DESIGN: Two BSSQbrace questionnaires have been posted to 65 patients under brace treatment from our Cheneau light data base. All patients had another kind of brace prior to the Cheneau light. The patients have been asked to rate their stress level using one questionnaire for the current brace and the other for the previous one. RESULTS: 63 Patients (59 girls and 4 boys) returned their fully completed questionnaires (average age 13,6 years, average Cobb angle 43,7 degrees). Stress level in the previous brace was 11,04 and in the Cheneau light(r) 13,87. The differences were highly significant in the t-test; t = -4,67; p < 0,001. CONCLUSION: The use of the Cheneau light(R) brace leads to reduced stress and/or impairment for the patients under treatment compared to heavier brace models used so far. PMID- 17708765 TI - A highly conserved regulatory element controls hematopoietic expression of GATA-2 in zebrafish. AB - BACKGROUND: GATA-2 is a transcription factor required for hematopoietic stem cell survival as well as for neuronal development in vertebrates. It has been shown that specific expression of GATA-2 in blood progenitor cells requires distal cis acting regulatory elements. Identification and characterization of these elements should help elucidating transcription regulatory mechanisms of GATA-2 expression in hematopoietic lineage. RESULTS: By pair-wise alignments of the zebrafish genomic sequences flanking GATA-2 to orthologous regions of fugu, mouse, rat and human genomes, we identified three highly conserved non-coding sequences in the genomic region flanking GATA-2, two upstream of GATA-2 and another downstream. Using both transposon and bacterial artificial chromosome mediated germline transgenic zebrafish analyses, one of the sequences was established as necessary and sufficient to direct hematopoietic GFP expression in a manner that recapitulates that of GATA-2. In addition, we demonstrated that this element has enhancer activity in mammalian myeloid leukemia cell lines, thus validating its functional conservation among vertebrate species. Further analysis of potential transcription factor binding sites suggested that integrity of the putative HOXA3 and LMO2 sites is required for regulating GATA-2/GFP hematopoietic expression. CONCLUSION: Regulation of GATA-2 expression in hematopoietic cells is likely conserved among vertebrate animals. The integrated approach described here, drawing on embryological, transgenesis and computational methods, should be generally applicable to analyze tissue-specific gene regulation involving distal DNA cis-acting elements. PMID- 17708767 TI - Dissociating object familiarity from linguistic properties in mirror word reading. AB - BACKGROUND: It is known that the orthographic properties of linguistic stimuli are processed within the left occipitotemporal cortex at about 150-200 ms. We recorded event-related potentials (ERPs) to words in standard or mirror orientation to investigate the role of visual word form in reading. Word inversion was performed to determine whether rotated words lose their linguistic properties. METHODS: About 1300 Italian words and legal pseudo-words were presented to 18 right-handed Italian students engaged in a letter detection task. EEG was recorded from 128 scalp sites. RESULTS: ERPs showed an early effect of word orientation at ~150 ms, with larger N1 amplitudes to rotated than to standard words. Low-resolution brain electromagnetic tomography (LORETA) revealed an increase in N1 to rotated words primarily in the right occipital lobe (BA 18), which may indicate an effect of stimulus familiarity. N1 was greater to target than to non-target letters at left lateral occipital sites, thus reflecting the first stage of orthographic processing. LORETA revealed a strong focus of activation for this effect in the left fusiform gyrus (BA 37), which is consistent with the so-called visual word form area (VWFA). Standard words (compared to pseudowords) elicited an enhancement of left occipito/temporal negativity at about 250-350 ms, followed by a larger anterior P3, a reduced frontal N400 and a huge late positivity. Lexical effects for rotated strings were delayed by about 100 ms at occipito/temporal sites, and were totally absent at later processing stages. This suggests the presence of implicit reading processes, which were pre-attentive and of perceptual nature for mirror strings. CONCLUSION: The contrast between inverted and standard words did not lead to the identification of a purely linguistic brain region. This finding suggests some caveats in the interpretation of the inversion effect in subtractive paradigms. PMID- 17708768 TI - The Biological Big Bang model for the major transitions in evolution. AB - BACKGROUND: Major transitions in biological evolution show the same pattern of sudden emergence of diverse forms at a new level of complexity. The relationships between major groups within an emergent new class of biological entities are hard to decipher and do not seem to fit the tree pattern that, following Darwin's original proposal, remains the dominant description of biological evolution. The cases in point include the origin of complex RNA molecules and protein folds; major groups of viruses; archaea and bacteria, and the principal lineages within each of these prokaryotic domains; eukaryotic supergroups; and animal phyla. In each of these pivotal nexuses in life's history, the principal "types" seem to appear rapidly and fully equipped with the signature features of the respective new level of biological organization. No intermediate "grades" or intermediate forms between different types are detectable. Usually, this pattern is attributed to cladogenesis compressed in time, combined with the inevitable erosion of the phylogenetic signal. HYPOTHESIS: I propose that most or all major evolutionary transitions that show the "explosive" pattern of emergence of new types of biological entities correspond to a boundary between two qualitatively distinct evolutionary phases. The first, inflationary phase is characterized by extremely rapid evolution driven by various processes of genetic information exchange, such as horizontal gene transfer, recombination, fusion, fission, and spread of mobile elements. These processes give rise to a vast diversity of forms from which the main classes of entities at the new level of complexity emerge independently, through a sampling process. In the second phase, evolution dramatically slows down, the respective process of genetic information exchange tapers off, and multiple lineages of the new type of entities emerge, each of them evolving in a tree-like fashion from that point on. This biphasic model of evolution incorporates the previously developed concepts of the emergence of protein folds by recombination of small structural units and origin of viruses and cells from a pre-cellular compartmentalized pool of recombining genetic elements. The model is extended to encompass other major transitions. It is proposed that bacterial and archaeal phyla emerged independently from two distinct populations of primordial cells that, originally, possessed leaky membranes, which made the cells prone to rampant gene exchange; and that the eukaryotic supergroups emerged through distinct, secondary endosymbiotic events (as opposed to the primary, mitochondrial endosymbiosis). This biphasic model of evolution is substantially analogous to the scenario of the origin of universes in the eternal inflation version of modern cosmology. Under this model, universes like ours emerge in the infinite multiverse when the eternal process of exponential expansion, known as inflation, ceases in a particular region as a result of false vacuum decay, a first order phase transition process. The result is the nucleation of a new universe, which is traditionally denoted Big Bang, although this scenario is radically different from the Big Bang of the traditional model of an expanding universe. Hence I denote the phase transitions at the end of each inflationary epoch in the history of life Biological Big Bangs (BBB). CONCLUSION: A Biological Big Bang (BBB) model is proposed for the major transitions in life's evolution. According to this model, each transition is a BBB such that new classes of biological entities emerge at the end of a rapid phase of evolution (inflation) that is characterized by extensive exchange of genetic information which takes distinct forms for different BBBs. The major types of new forms emerge independently, via a sampling process, from the pool of recombining entities of the preceding generation. This process is envisaged as being qualitatively different from tree-pattern cladogenesis. PMID- 17708769 TI - Ancient intron insertion sites and palindromic genomic duplication evolutionally shapes an elementally functioning membrane protein family. AB - BACKGROUND: In spite of the recent accumulation of genomic data, the evolutionary pathway in the individual genes of present-day living taxa is still elusive for most genes. Among ion channels, inward K+ rectifier (IRK) channels are the fundamental and well-defined protein group. We analyzed the genomic structures of this group and compared them among a phylogenetically wide range with our sequenced Halocynthia roretzi, a tunicate, IRK genomic genes. RESULTS: A total of 131 IRK genomic genes were analyzed. The phylogenic trees of amino acid sequences revealed a clear diversification of deuterostomic IRKs from protostomic IRKs and suggested that the tunicate IRKs are possibly representatives of the descendants of ancestor forms of three major groups of IRKs in the vertebrate. However, the exon-intron structures of the tunicate IRK genomes showed considerable similarities to those of Caenorhabditis. In the vertebrate clade, the members in each major group increased at least four times those in the tunicate by various types of global gene duplication. The generation of some major groups was inferred to be due to anti-tandem (palindromic) duplication in early history. The intron insertion points greatly decreased during the evolution of the vertebrates, remaining as a unique conservation of an intron insertion site in the portion of protein-protein interaction within the coding regions of all vertebrate G-protein-activated IRK genes. CONCLUSION: From the genomic survey of a family of IRK genes, it was suggested that the ancient intron insertion sites and the unique palindromic genomic duplication evolutionally shaped this membrane protein family. PMID- 17708771 TI - A detailed transcript-level probe annotation reveals alternative splicing based microarray platform differences. AB - BACKGROUND: Microarrays are a popular tool used in experiments to measure gene expression levels. Improving the reproducibility of microarray results produced by different chips from various manufacturers is important to create comparable and combinable experimental results. Alternative splicing has been cited as a possible cause of differences in expression measurements across platforms, though no study to this point has been conducted to show its influence in cross-platform differences. RESULTS: Using probe sequence data, a new microarray probe/transcript annotation was created based on the AceView Aug05 release that allowed for the categorization of genes based on their expression measurements' susceptibility to alternative splicing differences across microarray platforms. Examining gene expression data from multiple platforms in light of the new categorization, genes unsusceptible to alternative splicing differences showed higher signal agreement than those genes most susceptible to alternative splicing differences. The analysis gave rise to a different probe-level visualization method that can highlight probe differences according to transcript specificity. CONCLUSION: The results highlight the need for detailed probe annotation at the transcriptome level. The presence of alternative splicing within a given sample can affect gene expression measurements and is a contributing factor to overall technical differences across platforms. PMID- 17708770 TI - Species-specific shifts in centromere sequence composition are coincident with breakpoint reuse in karyotypically divergent lineages. AB - BACKGROUND: It has been hypothesized that rapid divergence in centromere sequences accompanies rapid karyotypic change during speciation. However, the reuse of breakpoints coincident with centromeres in the evolution of divergent karyotypes poses a potential paradox. In distantly related species where the same centromere breakpoints are used in the independent derivation of karyotypes, centromere-specific sequences may undergo convergent evolution rather than rapid sequence divergence. To determine whether centromere sequence composition follows the phylogenetic history of species evolution or patterns of convergent breakpoint reuse through chromosome evolution, we examined the phylogenetic trajectory of centromere sequences within a group of karyotypically diverse mammals, macropodine marsupials (wallabies, wallaroos and kangaroos). RESULTS: The evolution of three classes of centromere sequences across nine species within the genus Macropus (including Wallabia) were compared with the phylogenetic history of a mitochondrial gene, Cytochrome b (Cyt b), a nuclear gene, selenocysteine tRNA (TRSP), and the chromosomal histories of the syntenic blocks that define the different karyotype arrangements. Convergent contraction or expansion of predominant satellites is found to accompany specific karyotype rearrangements. The phylogenetic history of these centromere sequences includes the convergence of centromere composition in divergent species through convergent breakpoint reuse between syntenic blocks. CONCLUSION: These data support the 'library hypothesis' of centromere evolution within this genus as each species possesses all three satellites yet each species has experienced differential expansion and contraction of individual classes. Thus, we have identified a correlation between the evolution of centromere satellite sequences, the reuse of syntenic breakpoints, and karyotype convergence in the context of a gene-based phylogeny. PMID- 17708772 TI - Combined sterno-clavicular approach as an alternative technique in hybrid exclusion of aortic arch aneurysm. AB - BACKGROUND: We describe a modified access technique for the proximal (open) part of single stage hybrid exclusion of aneurysm of the aortic arch. CASE PRESENTATION: 3 patients had a bifurcated Dacron graft for the innominate and left subclavian arteries and an additional end-to-side anastomosis of the left common carotid artery on the limb to the left subclavian artery. With our modification, access to the left subclavian artery is by left subclavicular incision and creation of an anterior tunnel via the left thoracic outlet from the origin of the left subclavian artery along its anatomical course to the subclavicular plane. DISCUSSION: Advantages and disadvantages of this technique in relation to anatomy and pathology. PMID- 17708773 TI - The impact of operative approach on outcome of surgery for gastro-oesophageal tumours. AB - BACKGROUND: The choice of operation for tumours at or around the gastro oesophageal junction remains controversial with little evidence to support one technique over another. This study examines the prevalence of margin involvement and nodal disease and their impact on outcome following three surgical approaches (Ivor Lewis, transhiatal and left thoraco-laparotomy) for these tumours. METHODS: A retrospective analysis was conducted of patients undergoing surgery for distal oesophageal and gastro-oesophageal junction tumours by a single surgeon over ten years. Comparisons were undertaken in terms of tumour clearance, nodal yield, postoperative morbidity, mortality, and median survival. All patients were followed up until death or the end of the data collection (mean follow up 33.2 months). RESULTS: A total of 104 patients were operated on of which 102 underwent resection (98%). Median age was 64.1 yrs (range 32.1-79.4) with 77 males and 25 females. Procedures included 29 Ivor Lewis, 31 transhiatal and 42 left-thoraco laparotomies. Postoperative mortality was 2.9% and median survival 23 months. Margin involvement was 24.1% (two distal, one proximal and 17 circumferential margins). Operative approach had no significant effect on nodal clearance, margin involvement, postoperative mortality or morbidity and survival. Lymph node positive disease had a significantly worse median survival of 15.8 months compared to 39.7 months for node negative (p = 0.007), irrespective of approach. CONCLUSION: Surgical approach had no effect on postoperative mortality, circumferential tumour, nodal clearance or survival. This suggests that the choice of operative approach for tumours at the gastro-oesophageal junction may be based on the individual patient and tumour location rather than surgical dogma. PMID- 17708774 TI - PyCogent: a toolkit for making sense from sequence. AB - We have implemented in Python the COmparative GENomic Toolkit, a fully integrated and thoroughly tested framework for novel probabilistic analyses of biological sequences, devising workflows, and generating publication quality graphics. PyCogent includes connectors to remote databases, built-in generalized probabilistic techniques for working with biological sequences, and controllers for third-party applications. The toolkit takes advantage of parallel architectures and runs on a range of hardware and operating systems, and is available under the general public license from http://sourceforge.net/projects/pycogent. PMID- 17708775 TI - Quantitative genomics of locomotor behavior in Drosophila melanogaster. AB - BACKGROUND: Locomotion is an integral component of most animal behaviors, and many human health problems are associated with locomotor deficits. Locomotor behavior is a complex trait, with population variation attributable to many interacting loci with small effects that are sensitive to environmental conditions. However, the genetic basis of this complex behavior is largely uncharacterized. RESULTS: We quantified locomotor behavior of Drosophila melanogaster in a large population of inbred lines derived from a single natural population, and derived replicated selection lines with different levels of locomotion. Estimates of broad-sense and narrow-sense heritabilities were 0.52 and 0.16, respectively, indicating substantial non-additive genetic variance for locomotor behavior. We used whole genome expression analysis to identify 1,790 probe sets with different expression levels between the selection lines when pooled across replicates, at a false discovery rate of 0.001. The transcriptional responses to selection for locomotor, aggressive and mating behavior from the same base population were highly overlapping, but the magnitude of the expression differences between selection lines for increased and decreased levels of behavior was uncorrelated. We assessed the locomotor behavior of ten mutations in candidate genes with altered transcript abundance between selection lines, and identified seven novel genes affecting this trait. CONCLUSION: Expression profiling of genetically divergent lines is an effective strategy for identifying genes affecting complex behaviors, and reveals that a large number of pleiotropic genes exhibit correlated transcriptional responses to multiple behaviors. PMID- 17708776 TI - Coexistence of gastrointestinal stromal tumor (GIST) and colorectal adenocarcinoma: A case report. AB - BACKGROUND: Gastrointestinal stromal tumors (GIST) represent the most common mesenchymal tumors of the digestive tract. Over the last ten years the management of GISTs has dramatically altered but their coexistence with other gasrointesinal tumors of different histogenesis presents a special interest. The coexistence of GISTs with other primaries is usually discovered incidentally during GI surgery for carcinomas. CASE PRESENTATION: We present here, a case of a 66-year-old patient with intestinal GIST and a synchronous colorectal adenocarcinoma discovered incidentally during surgical treatment of the recurrent GIST. Immunohistochemical examination revealed the concurrence of histologically proved GIST (strongly positive staining for c-kit, vimentin, SMA, and focal positive in S-100, while CD-34 was negative) and Dukes Stage C, (T3, N3, M0 according the TNM staging classification of colorectal cancer). CONCLUSION: The coexistence of GIST with either synchronous or metachronous colorectal cancer represents a phenomenon with increasing number of relative reports in the literature the last 5 years. In any case of GIST the surgeon should be alert to recognize a possible coexistent tumor with different histological origin and to perform a thorough preoperative and intraoperative control. The correct diagnosis before and at the time of the surgical procedure is the cornerstone that secures the patients' best prognosis. PMID- 17708777 TI - Dental otalgia. AB - BACKGROUND: Secondary or referred otalgia can represent a diagnostic challenge to the otolaryngologist. Collectively, dental disorders are the most common causes of secondary otalgia presenting to the ENT clinic, and may account for up to 50 per cent of referred otalgia. Temporomandibular joint dysfunction syndrome represents the most common dental cause of referred otalgia. Decay and pulpal inflammation of posterior teeth can also frequently present as otalgia. The common embryological developmental origin of both oral and dental structures and the ear is responsible for their overlapping sensory nerve supplies, and this explains referred otalgia secondary to dental and temporomandibular joint disorders. These disorders can be easily overlooked, resulting in unnecessary and costly investigations. AIMS: This review aims to give a succinct overview of common dental causes of otalgia, and to provide ENT clinicians with guidelines for performing a rapid and simple dental and temporomandibular joint examination, which will reliably diagnose or exclude dental otalgia. PMID- 17708778 TI - Compromised myelin integrity during psychosis with repair during remission in drug-responding schizophrenia. AB - Functional connection among the information-processing (grey-matter) centres within the CNS are necessary for the coordinated processing of perception, affect, thought and behaviour. Myelinated neuronal bundles provide the links among such processing centres. Magnetic resonance diffusion tensor imaging (DTI) can assess the physical integrity of myelin. Using DTI, the authors assessed diffusivity (Dm) within whole brain in 14 controls and within 13 acutely psychotic, drug-free schizophrenics both before and after 28 d of antipsychotic drug treatment. Drug-responder schizophrenicss (D-RS) (n=8) were differentiated from poor responders (PR) (n=5) according to previously defined criteria. Differences of Dm at both baseline and following treatment were assessed using Dm distributional analyses and Statistical Parametric Software (SPM2). Impaired physical integrity of myelin, demonstrated by an increase (overall p<0.05) of Dm, was found in the D-RS patients, with multiple regions demonstrating p<0.0005 patient-control differences. The pathological increase in Dm was reduced (p<0.03) following treatment-associated reduction of psychotic symptoms by 84%. Dm of PR patients did not differ from controls at baseline or following subacute treatment. While the pathophysiology(ies) underlying psychosis in poorly responsive (PR) schizophrenics does not appear to be related to a disordered myelin, the findings are consistent with a partially reversible disorder of myelin integrity, and may underlie a dys-synchrony of information processing in a major subgroup of drug-responsive patients with schizophrenia. An antipsychotic drug-induced cascade may partially restore myelin integrity and functional connectivity concomitant with antipsychotic effects in such D-RS patients. PMID- 17708779 TI - PET analysis of the 5-HT2A receptor inverse agonist ACP-103 in human brain. AB - The mechanisms underlying the clinical properties of atypical antipsychotics have been postulated to be mediated, in part, by interactions with the 5-HT2A receptor. Recently, it has been recognized that clinically effective antipsychotic drugs are 5-HT2A receptor inverse agonists rather than neutral antagonists. In the present study, which is part of the clinical development of the novel, selective 5-HT2A receptor inverse agonist ACP-103, we applied positron emission tomography (PET) with the radioligand [11C]N-methylspiperone ([11C]NMSP) to study the relationship between oral dose, plasma level, and uptake of ACP-103 in living human brain. The safety of drug administration was also assessed. Four healthy volunteers were examined by PET at baseline, and after the oral administration of various single doses of ACP-103. Two subjects each received 1, 5, and 20 mg doses, and two subjects each received 2, 10, and 100 mg doses, respectively. ACP-103 was well tolerated. Detectable receptor binding was observed at very low ACP-103 serum levels. Cortical [11C]NMSP binding was found to be dose-dependent and fitted well to the law of mass action. A reduction in binding was detectable after an oral dose of ACP-103 as low as 1 mg, and reached near maximal displacement following the 10-20 mg dose. In conclusion, administration of ACP-103 to healthy volunteers was found to be safe and well tolerated, and single oral doses as low as 10 mg were found to fully saturate 5 HT2A receptors in human brain as determined by PET. PMID- 17708780 TI - rTMS treatment for depression in Parkinson's disease increases BOLD responses in the left prefrontal cortex. AB - The mechanisms underlying the effects of antidepressant treatment in patients with Parkinson's disease (PD) are unclear. The neural changes after successful therapy investigated by neuroimaging methods can give insights into the mechanisms of action related to a specific treatment choice. To study the mechanisms of neural modulation of repetitive transcranial magnetic stimulation (rTMS) and fluoxetine, 21 PD depressed patients were randomized into only two active treatment groups for 4 wk: active rTMS over left dorsolateral prefrontal cortex (DLPFC) (5 Hz rTMS; 120% motor threshold) with placebo pill and sham rTMS with fluoxetine 20 mg/d. Event-related functional magnetic resonance imaging (fMRI) with emotional stimuli was performed before and after treatment - in two sessions (test and re-test) at each time-point. The two groups of treatment had a significant, similar mood improvement. After rTMS treatment, there were brain activity decreases in left fusiform gyrus, cerebellum and right DLPFC and brain activity increases in left DLPFC and anterior cingulate gyrus compared to baseline. In contrast, after fluoxetine treatment, there were brain activity increases in right premotor and right medial prefrontal cortex. There was a significant interaction effect between groups vs. time in the left medial prefrontal cortex, suggesting that the activity in this area changed differently in the two treatment groups. Our findings show that antidepressant effects of rTMS and fluoxetine in PD are associated with changes in different areas of the depression-related neural network. PMID- 17708781 TI - [Connexin 43 expression and interacellular communicating function in acute leukemia bone marrow stroma cells]. AB - This study was purposed to investigate the connexin 43 (Cx43) expression level in acute leukemia bone marrow stromal cells (ABMSCs) and normal bone marrow stromal cells (NBMSCs), and to explore the difference in communicating functions between these cells. The Cx43 expression levels of ABMSCs and NBMSCs were detected by using immunohistochemistry and computer gray scale assay, and the difference of gap junction intercellular communication (GJIC) was examined through dry transfer technique. The results showed that expression level of Cx43 in ABMSCs was lower than that in NBMSCs and its function of GJIC in ABMSCs was also weaker than that in NBMSCs. It is concluded that cell-cell communication function is lowered in ABMSCs. PMID- 17708782 TI - [High tumorigenicity of human acute monocytic leukemic cell Line SHI-1 in nude mice and its mechanism]. AB - This study was purposed to explore the tumorigenicity of a novel human monocytic leukemic cell line SHI-1 in nude mice and its mechinism. The tumorigenicity in mice was evaluated in sixteen nude mice subcutaneously injected with the SHI-1 cell line. The tumor specimen was studied by the conventional pathologic examination. The mononuclear cells (MNC) of the tumor was assayed by RHG banding, the transcription of MLL-AF6 fusion gene and the VEGF gene was detected by RT PCR. Gelatin zymography method was used to study the expression of MMP-9 and MMP 2 in the supernatant of the SHI-1 cell line. Matrigel invasion assay was employed for the study of migration of the SHI-1 cell in vitro. The results showed that the tumor masses were found in all sixteen mude mice after subcutaneous injection of SHI-1 cells, the tumor mass was mainly composed of leukemia cells, the transcription of MLL-AF6 fusion gene and VEGF gene was proved by RT-PCR analysis, the expressions of MMP-2 and MMP-9 in the serum-free culture supernatant of the SHI-1 cell line were significantly higher than those in U937, K562, and NB4 cell lines. The SHI-1 cell line exhibited significantly higher in vitro invasiveness than other leukemia cell lines, the blocking antibody of MMP-2 could inhibit the migration of the SHI-1 cell line significantly. It is concluded that the SHI-1 cell line presents higher tumorigenicity in nude mice than other leukemia cell line and the mechanism is associated with p53 gene alteration, high transcription level of VEGF gene, high expression level of MMP, and significantly higher invasiveness. PMID- 17708783 TI - [Immunologic characteristics and prognosis of acute myeloid leukemia M1]. AB - The study was aimed to investigate the immunological characteristics and prognosis of acute myeloid leukemia (AML) M(1) and to find the main points in immunology to differentiate AML M(1) from M(2), and M(1) from ALL (proB, preB, T). Immunophenotyping was performed in 41 AML M(1) patients by three-color flow cytometry analysis using CD45/SSC gating, meanwhile the cytogenetic analysis was performed in 17 patients. 51 newly diagnosed AML M(2) patients and 58 newly diagnosed ALL patients were used as control at the same time. The results showed that the positive rate of CD33 in M(1) was 100%, which was high in sensitivity, but low in specificity; the positive rate of CD11b, CD15, MPO, CD117 in M(1) were significantly lower than that in M(2) (p < 0.05); the positive rate of T-lineage antigen in Ly + AML M(1) was higher than that in M(2) (p < 0.05); compared with ALL ProB, M(1) had high expression of HLA-DR, simultaneously myeloid antigen CD13, CD15, CD33, CD117, MPO and T-lineage antigen CD4, CD7 were all highly expressed (p < 0.05); compared with ALL PreB, M(1) had high expression of HLA-DR, CD34, meanwhile myeloid antigen CD13, CD15, CD33, CD117, MPO and T-lineage antigen CD4, CD5 were all highly expressed (p < 0.05); as compared with T-ALL, the early-phase antigen HLA-DR, CD34, myeloid antigen CD13, CD15, CD33, CD117, MPO of M(1) were all significantly highly expressed (p < 0.05). In M(1), the complete remission (CR) rate in patients with CD7 positive had no statistical difference from that in patients with CD7 negative (p > 0.05); the CR rate of patients with CD34 positive had no statistical difference from that of patients with CD34 negative (p > 0.05); CR rate in M(1) was lower than that in M(2) (p < 0.05), time to reach CR was longer, the incidence of hyperleukocytic acute leukemia was higher (p < 0.05), CR rate in hyperleukocytic acute leukemia was lower (p < 0.05). It is concluded that the myeloid antigen CD33, CD13 in M(1) are highly expressed, early-phase antigen HLA-DR in M(1) is also highly expressed, but the myeloid antigen CD11b, CD15, MPO, CD117 in M(1) are lowly expressed, T lineage antigen CD4, CD7 in M(1) are highly expressed in the meantime. There is no definite characteristic marker in immunology to differentiate M(1) from M(2), but as the positive rate of CD11b, CD15, MPO, CD117 in M(1) are significantly lower than that of M(2), CD11b, CD15, MPO, CD117 can be used as reference indicators to differentiate M(1) from M(2). AML M(1), ALL ProB, ALL PreB and T ALL, which are difficult to differentiate in morphology can be well seperated through the analysis of immunological phenotype. CD117 is mainly expressed in AML, which is useful for the differentiation diagnosis between AML and ALL. The prognosis of M(1) is worse than that of M(2). PMID- 17708784 TI - [Immunophenotyping characteristics of T-cell acute lymphoblastic leukemia]. AB - The objective of this study was to investigate the immunophenotypic characteristics of T-cell acute lymphoblastic leukemia (T-ALL). Immunophenotyping was performed in 140 T-ALL patients by flow cytometry using a panel of monoclonal antibodies and CD45/SSC gating. The results showed that the T-lineage-associated antigen expressions were CD7 > CD2 > CD3 > CD5 successively. The positive rate of CD10 was 19.42% in patients. Among 140 cases of T-ALL, 12 (8.57%) was accompanied by B-lineage associated antigen expression. Myeloid antigen expression was identified in 31 out of 136 cases (22.79%). None of them expressed CD14 antigen. The positive rate of CD34 was 31.06%. The positive rate of myeloid antigen expression in CD34(+) T-ALL (36.58%) was significantly higher than that in CD34( ) T-ALL (15.38%) (p < 0.01). The expression of CD3 in child T-ALL was higher than that in adult T-ALL, whereas the expression of CD33 in children was lower than that in adults. It is concluded that immunophenotyping is an important tool for diagnosis of T-ALL. Immunophenotypic characteristics of T-ALL is heterogeneous. PMID- 17708785 TI - [Immunophenotypic and cytogenetic features in 51 cases of chronic lymphocytic leukemia]. AB - The study was aimed to investigate the immunophenotypic and cytogenetic features of chronic lymphocytic leukemia (CLL) in order to provide an evidence for diagnosis and therapy. Immunophenotypic analysis was performed by using a panel of monoclonal antibodies and three-color immunofluorescence staining methods of flow cytometry in 51 patients with CLL, and the cytogenetic features were analyzed by R-banding technique. The results indicated that among 51 CLL cases, the positive rate of CD19 and CD23 was 96.1%, followed by CD15 (94.1%), CD20 (82.4%) and CD22 (78.4%). The positive rate of CD38 was 23.5%. Forty-six patients expressed both CD5 and CD19. Seven main clonal chromosomal abnormalities were detected by conventional cytogenetics (CC) in eighteen cases (35.3%), with three cases of +12, two cases of 13q(-), other chromosomal abnormalities included +14, 6q(-), t (11; 14), t (14; 18) and t (2; 7). Expression of the antigens had no relationship with chromosomal abnormalities. It is concluded that typical CLL express CD5, CD19 and CD23, and the positive rate detected by CC in CLL is low. Immunophenotyping in combination with cytogenetic technique plays an important role in the diagnosis and prognosis of CLL. PMID- 17708786 TI - [Clinical significance of FLT3 internal tandem duplication in acute myeloid leukemia with chromosome abnormality]. AB - This study was to explore the clinical significance of FLT3 internal tandem duplication (FLT3/ITD) in acute myeloid leukemia (AML) with chromosome abnormality. Karyotypes in 125 AML patients were analyzed by R banding technique. Using genomic PCR and sequencing, FLT3/ITD mutation in AML patients with or without chromosome abnormity were examined. The results indicated that chromosome abnormality with various types was found in 46 out of 125 samples, the positive rate was 36.8%. The positive rate in different chromosome subtypes included M(0) 57.14%, M(1) 55.56%, M(2) 38.71%, M(3) 50.0%, M(4) 50.0%, M(5) 30.77%, M(6)/M(7) 10.0% and M(7) 18.75% respectively. In various chromosome abnormality types, t (16, 21) occurred in 9 samples with highest rate 19.78%, and the others were t (8, 21) in 7 samples, t (4, 11) in 6 samples with the occurrence rate 15.22%, 13.04% respectively. Besides, t (6, 9) was detected in 3 samples which was seldom found domestically, the positive rate was 6.52%. In 79 samples without chromosome abnormality, FLT3 gene expression was detected in 56 samples, the positive rate was 70.89%. In 46 samples with chromosome translocation, FLT3 gene expression could be detected in 31 samples, the positive rate was 67.39%. The difference between them was no significant (p > 0.05). And the FLT3/ITD mutation rates in these two groups were 11.39% and 24.09% respectively, whose difference was statistically significant (p < 0.05). Clinical data showed that the difference was no statistically significant (p > 0.05) in leukocyte counting and Hb assay in peripheral blood as well as leukocyte ratio in bone marrow of these two groups with or without chromosome abnormality. Most FLT3/ITD mutation patients with or without chromosome abnormality died in short time, the difference of death rate was not statistically significant between these two groups (p > 0.05) while the life span of FLT3/ITD mutation patients with chromosome abnormality was even shorter than the other. The difference between them was statistically significant (p < 0.05). It is concluded that prognosis is relatively poor in FLT3/ITD mutation patients with chromosome abnormality. FLT3/ITD mutation may be an important marker for poor prognosis of AML. PMID- 17708787 TI - [Dynamic detection of FLT3 gene in patients with AML and its significance]. AB - Minimal residual disease (MRD) is an important cause of relapse and disease-free survival time decrease in patients with acute myeloid leukemia (AML). This study was aimed to explore the role of FLT3 gene in AML pathogenesis and its significanse for detection of MRD. Using genomic PCR, 125 AML patients were detected for FLT3 gene expression before and after chemical therapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT), meantime the AML patients with FLT3 positive expression were observed by follow-up. The results showed that the sensitivity of PCR was 10(-4) in FLT3 gene detection; the rates of FLT3 positive expression were 69.6% and 44.90% in the newly diagnosed AML patients and complete remission (CR) patients respectively. The rate of FLT3 expression coverted to negative was 48.98% in treated AML patients, while no change of FLT 3 expression was found in 6.12% treated patients. The FLT3 expression converted to positive in relapsed patients, and FLT3 expression remains positive in non-remitted patients. The CR rate in FLT3 positive expression patients before treatment was significantly lower than that in FLT3 negative expression patients, the difference of which was statistically significant (p < 0.05). The AML relapse rate in FLT3 positive patients was significantly higher than that in FLT3 negative expression patients (p < 0.05). It is concluded that FLT3 gene expression is related to leukemia pathogenesis; the dynamic levels of FLT3 expression before and after treatment can be used for estimating prognosis of AML patients and detecting MRD. PMID- 17708788 TI - [Detection of FLT3 gene mutation in hematologic malignancies and its clinical significance]. AB - To study the FLT3 gene expression and its internal tandem duplication in hematologic malignancies and its clinical significance, polymerase chain reaction (PCR) and DNA sequencing were used to detect the FLT3/ITD mutation in blast cells of bone marrow from 86 patients with hematologic malignancies, including 32 cases of acute myeoloid leukemia (AML), 18 cases of acute lymphoblastic leukemia (ALL), 2 cases of acute hybrid leukemia (AHL), 12 cases of myelodysplastic syndromes (MDS), 10 cases of chronic myelogenous leukemia (CML), 3 cases of non-Hodgkin's lymphoma (NHL) and 9 cases of multiple myeloma (MM). The resultes showed that the expression of FLT3/ITD gene could be detected in 5 of 32 (15.6%) AML patients, including 1/7 of M(3), 1/10 of M(4) and 3/10 of M(5). More FLT3 aberrations were found in AML-M(5). No FLT3/ITD was found in 18 cases of ALL, in 2 cases of AHL, in 12 cases of MDS and in 10 cases of CML. No FLT3 was found in 3 cases of NHL and in 9 cases of MM. Sequence analysis in 2 case with abnormal PCR electrophoretic patterns revealed that the ITDs were located within exon 14 from 27 to 63 bp, which was a simple tandem duplication, and did not altered the reading frame. FLT3/ITD was associated with a higher peripheral blood white cell count (p < 0.01), higher percentage of bone marrow blast cells (p < 0.01) and lower complete mission rate. It is concluded that more FLT3/ITD mutation occurs in AML-M(5) patients. Sequence of the mutants is in frame mutation. FLT3/ITD mutation is associated with higher peripheral blood white cell count, higher percentage of bone marrow blast cells and lower complete remission rate, FIT3/IID gene mutation may be used to predict prognosis of patients with AML. PMID- 17708789 TI - [Detection of PML/RARa transcripts in acute promyelocytic leukemia by real-time quantitative reverse transcription polymerase chain reaction]. AB - This study was purposed to establish a real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) for detection of PML/RARa fusion gene in patients with acute promyelocytic leukemia (APL) and to explore the relationship between the expression level of PML/RARa fusion gene transcript and the clinical status or efficacy of the therapy in APL. The conventional RT-PCR was used to amplify PML/RARa gene from cultured NB4 cells. Standard curves were constructed by modified real-time PCR on standard template after 10-fold serial dilutions of cDNA of 1 microg NB4 cells. The sensitivity, stability and repeatability of this method was determined. The PML/RARa gene transcripts of bone marrows in 4 APL patients before and after treatment and in 1 APL patient relapsed after complete remission were dynamically detected by modified real-time quantitative RT-PCR. The results indicated that the sensitivity of real-time quantitative RT-PCR for detecting PML/RARa fusion gene was about 10(-5) microg cDNA from NB4 cells, the repeatability and reproducibility of this method were satisfactory, intra-and inter-assay coefficients of variation were 2.1% and 3.8%. The copy numbers of PML/RARa transcripte reflecting PML/RARa fusion gene expression level in 4 newly diagnosed patients with APL were 1884, 5533, 1803, 4677 and the median was 3 475. After ATRA + chemotherapy copy numbers of PML/RARa transcript decreased to 40, 135, 79, 29, and mean was 121. Another patient's PML/RARa gene copy number was 8600 at diagnosis, the gene copy number was 730 after therapy for 4 months, although he was in complete remission, but copy number increased to 11 000 when APL relapsed 3 months later. The copy number efficiently reduced to 1200 after ATRA + chemotherapy. It is concluded that the established real-time quantitative RT-PCR method is sensitive, reliable, accurate and repeatable. The efficiency of method was finally tested for patient samples, showing a PML/RARa transcript copy number in APL patients significantly decrease after therapy, and increase at the time of relapse which indicate that changes of fusion gene expression levels coincide with clinical progress of disease. This method can be used to detect the minimal residual disease, assess response to treatment and evaluate prognosis of disease. PMID- 17708790 TI - [Ultrastructural characteristics of megakaryocytes in 11 patients with acute megakaryocytic leukemia]. AB - The purpose of study was to investigate the ultrastructural features of leukemic megakarocyte (LMK) in patients with acute megakaryocytic leukemia (M(7)). Analyzing the ultrastructure characteristics of LMK and positive ratio of platelet peroxides (PPO) in 11 patients with M(7) were analyzed on basis of transmission electron microscopic observation retrospectively. The results showed that the diameter of LMK in 7 out of 11 cases was less than 20 microm, in 2 cases of them, the LMK diameter was from 10 to 15 microm and their PPO positive ratio was more than 50%, most LMK displayed regular shape, less protrusions, irregular nucleus, high nuclear/cytoplasm ratio, tiny granules, undeveloped demarcation membrane system (DMS) and irregular tubules in cytoplasm; in 5 out of those 7 cases the diameter of LMK was about 20 microm, PPO positive cell count was from 8% to 22%, most showing round or horseshoe nuclei, more or less heterochromatin, no DMS and granules were found in LMK in 3 cases and 2 cases occasionally. In other 5 out of 11 cases, the diameter of LMK was from 20 to 40 microm and PPO positive ratio was from 16% to 80%, in which smaller LMKs were similar to those in former cases in shape, and the larger LMK had irregular protrusions, varied nuclear/cytoplasm ratio, more heterochromatin, prominent nucleolus, some of them contained developed DMS, tubules and alpha-granules. It is concluded that most patients with M(7) are predominant of LMK in stage-I and minority contained LMK in II or III stage simultaneously. The differentiation degrees of LMK are different in individual and various cases. PMID- 17708791 TI - [Effect of hyperthermia in combination with chemotherapy on K562/AO2 cells in vitro]. AB - This study was purposed to investigate the inhibitory effect, apoptosis, Bcl-2 and P-gp expression of K562/AO2 cells by hyperthermia combined with adriamycin. The working concentration of adriamycin against K562/AO2 was determined by MTT assay. The hyperthermia and chemotherapy were used alone or in combination, then the cell survival rate was detected at 48 hours. The inhibitory effect was evaluated by MTT assay. The apoptosis rate, Bcl-2 and P-gp expression of K562/AO2 were determined by flow cytometry. The concentration of adriamycin in the experiment was defined as its IC(50) at 48 hours action. The results indicated that the hyperthermia at 40, 41 and 42 degrees C for 60 minutes showed obvious inhibitory effect on K562/AO2 cells (p < 0.01). Adriamycin chemotherapy combined with hyperthermia showed more obvious inhibitory effect on K562/AO2. According to flow cytometric analysis, the hyperthermia and adriamycin used alone or in combination could obviously increase the apoptosis rate and down-regulate Bcl-2 and P-gp expression of K562/AO2 cells (p < 0.01). It is concluded that the adriamycin chemotherapy combined with hyperthermia for 60 minutes shows obvious inhibitory effect on K562/AO2 cells, which increases the apoptosis rate and down regulates expression of Bcl-2 and P-gp. PMID- 17708792 TI - [Mechanism of trichosanthin against human leukemia/lymphoma cells in vitro]. AB - The study was aimed to investigate the mechanism of cytotoxic effect of trichosanthin (TCS) on leukemia or lymphoma cell lines. Trypan blue exclusion was used to measure the effect of TCS on cell growth and flow cytometry was used to detect the effects of TCS on cell apoptosis and cell cycle. The results indicated that the TCS could inhibit proliferation of various leukemia/lymphoma cell lines at 12.5 microg/ml concentration, but the effect of TCS on T-lymphocyte and macrophage cell lines showed inducing cell apoptosis and the effect of TCS on B lymphocyte cell line showed inhibiting cell growth. Detection of the cell cycle revealed that TCS could arrest B lymphocytes at S phase, but not had this effect on T lymphocytes at the same condition. It is concluded that TCS can kill leukemia/lymphoma cells through different mechanisms such as inducing cell apoptosis or arresting cell cycle according to cell types. PMID- 17708793 TI - [Effect of WISp39 on proliferation, cell cycle and apoptosis of U937 cells]. AB - To investigate the effect of a novel p21-modulating protein WISp39 on proliferation, apoptosis and cell cycle of leukemia cells, the plasmid pLenti6/V5 WISp39 was constructed and transfected into the human myelocytic leukemia cell line-U937 cells. The expression of WISp39 was detected by real-time PCR at 48 hours after transfection, proliferation of U937 cells assayed by CCK-8, apoptosis and cell cycle were determined by flow cytometry. The results showed that plasmid pLenti6/V5-WISp39 could readily enhance the expression of WISp39 in U937 cells. A significant growth inhibition (37.6%) was observed in cells tranfected with pLenti6/V5-WISp39, while the control plasmid pLenti6/V5-lacZ showed little effect on U937 growth. Further analysis revealed that pLenti6/V5-WISp39 did not show obvious apoptosis induction effect, but it could really regulate U937 proliferation via cell cycle modulation. Compared with pLenti6/V5-lacZ, pLenti6/V5-WISp39 resulted in increase of cells in G(0)/G(1) phase by 10% at 48 hours after transfection. It is concluded that the WISp39 gene has no significant apoptosis induction effect on leukemic cells, but it can increase cells at G(0)/G(1) phase via effect on cell cycle, thus inhibiting the U937 proliferation. This result means WISp39 gene can act as a negative modulator on tumour cells. PMID- 17708794 TI - [Correlation between expression of apoptosis-related gene pnas-2 and leukemia]. AB - The study was purposed to explore the correlation between apoptosis-related gene pnas-2 and leukemia. The RT-PCR was performed to detect the expression levels of pnas-2 gene in NB4, K562, U937 cells before and after treatment with AS(4)S(4), and to analysis the expression change of pnas-2 gene in bone marrow cells from patients with acute leukemia before and after chemotherapy. The results showed that the expression of pnas-2 gene in arsenic sulfide treated NB4 cells was down regulated in time-dependent manner, but the same outcome in K562 and U937 cells after being treated with AS(4)S(4) was not found. The positive expression rate of pnas-2 in cells from untreated patients with acute leukemia was 100%, and was significantly higher than that in normal control group. After chemotherapy, the expression was negative in complete remission patients, whereas in no-remission patients there were no significant differences of expression of pnas-2 before and after treatment. It is concluded that the pnas-2 gene may be closely related with apotosis of arsenic sulfide treated APL cells, and may consider as a molecular biological remission marker in acute leukemia. PMID- 17708796 TI - [Preparation of Fe3O4-magnetic nanoparticles loaded with adriamycin and its reversal of multidrug resistance in vitro]. AB - To prepare Fe(3)O(4)-magnetic nanoparticles loaded with adriamycin and investigate the reversal role of drug-loaded nanoparticles in K562 and resistant cell line K562/A02, the drug-loaded nanoparticles were prepared by using mechanical absorption polymerization at different conditions of 4 degrees C or 37 degrees C for 24 or 48 hours. The survival of cells cultured with drug-loaded nanoparticles for 48 hours was detected by MTT assay, then the growth inhibition efficacy of cells was calculated. The results showed that the growth inhibition efficacy of both two cell lines was enhanced with increasing concentration of Fe(3)O(4)-magnetic nanoparticles. The inhibitory ratio of two cell lines obtained at 4 degrees C and for 48 hours was significantly better than that at 37 degrees C and 24 hours. In conclusion, Fe(3)O(4)-magnetic nanoparticles can load adriamycin by using mechanical absorption polymerization, but depended on proper temperature and time. Furthermore, drug-loaded nanoparticles showed an ability reversing multidrug resistance. PMID- 17708795 TI - [Apoptosis of human myelodysplastic syndrome cell Line MUTZ-1 induced by sodium valproate]. AB - To study the effects of sodium valproate (VPA) on human myelodysplastic syndrome cell line MUTZ-1. The cell proliferation was determined by MTT assay, apoptotic morphological features were observed by light microscopy and transmission electronmicroscopy, cell apoptosis and cell cycle shift were analyzed by flow cytometry (FCM). The results showed that VPA could inhibit the growth of MUTZ-1 cells in dose-and time-dependent manners. The typical apoptotic morphological features appeared in MUTZ-1 cells treated with 4 mmol/L VPA for 72 hours. Pyknosis of cells and nuclei, disintegration of nuclear chromatin and apoptotic body could be observed by light microscopy. Aggregation and margination of nuclear chromatin, concentration of plasm, increment of density and chromatin mass of irregular size could be observed by transmission electronmicroscope. The flow cytometric analysis indicated that the VPA could induce cell apoptosis, apoptosis rate increased in dose-dependent manner, ratio of cells at G(0)/G(1) phase increased and ratio of cells at S phase decreased in dose-dependent manner, the cells were arrested at G(0)/G(1) phase. It is concluded that the VPA can induce apotosis and inhibite proliferation of MUTZ-1 cells via arresting cells at G(0)/G(1) phase. PMID- 17708797 TI - [Synergistic reversal effect of Chinese medicine compound FFJZ combined with cyclosporine A on multidrug resistance of leukemia K562/VCR cell line]. AB - The study was purposed to investigate the synergistic reversal effect of Chinese medicine compound FFJZ in combination with cyclosporine A (CsA) on the multidrug resistance (MDR) of human leukemia K562/VCR cell line, as to search effective combination of MDR modulators. MTT (methyl-thazol-tetrazolinum) assay were used to determine the cytotoic and reversal effects on K562/VCR cell line, FCM (flow cytometry) was used to assess the intracellular adriamycin (ADM) concentration and the expression of P-gp in cells. The results showed that the FFJZ in combination with CsA could reverse the drug-resistance of K562/VCR cells and increase the sensitivity K562/VCR cells to adriamycin. They had not the toxic effect on the K562/VCR cells in effective dose and no significant influence on P gp positive rate of the K562/VCR cells. It is concluded that the FFJZ in combination with CsA may become a safe and effective multidrug resistance reversing agent with low toxicity in leukemia chemotherapy. PMID- 17708798 TI - [Reversal effect of sodium selenite on multidrug resistance in K562/ADR cell line and its mechanisms]. AB - This study was purposed to investigate the reversal effect of sodium selenite on multidrug resistance in adriamycin-resistant leukemic cell line K562/ADR and its mechanisms. The cytotoxicity and the reversal effect of sodium selenite on K562/ADR cells were assayed by MTT method; the apoptosis rate of K562 and K562/ADR cells were detected by flow cytometery, the mRNA expressions of mdr1 and bcl-2 were measured by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). The results showed that 10 micromol/L sodium selenite significantly increased the cytotoxicity of adriamycin to K562/ADR cell and the reverse index (RI) was 2.31; the early apoptosis rate of K562 cells was elevated after treatment with 5 micromol/L Na(2)SeO(3) for 48 hours; and the medium-term and late apoptosis rate was elevated after treatment with both 5 and 10 micromol/L Na(2)SeO(3) for 48 and 72 hours. Both doses of 5 and 10 micromol/L Na(2)SeO(3) increased the early apoptosis rate of K562/ADR at 48 hours, and also increased the medium-term and late apoptosis rate after treating for 48 and 72 hours. The apoptosis rate was higher at dose of 10 micromol/L than that at 5 micromol/L, the apoptosis rate at 72 hours also was higher than that at 48 hours. The expressions of mdr1 mRNA and bcl-2 mRNA were decreased significantly by 10 micromol/L sodium selenite. It is concluded that sodium selenite can reverse the multidrug resistance in K562/ADR partially by down-regulating the expressions of mdr1 mRNA and bcl-2 mRNA, and increasing apoptosis rate of K562/ADR cells. PMID- 17708799 TI - [Effect of curcumin on expression of survivin, Bcl-2 and Bax in human multiple myeloma cell line]. AB - To explore the mechanisms of suppression growth and induction apoptosis of curcumin on human multiple myeloma cell line RPMI8226, the suppressive effect of curcumin on RPMI8226 was examined by MTT assay; the induction apoptosis and cell cycle arrest of curcumin on RPMI8226 were determined by flow cytometry (FCM); the changes of survivin, Bcl-2, Bax mRNA levels were detected by RT-PCR. The results showed that curcumin obviously suppressed the proliferation of RPMI8226 in both time- and dose-dependent manners, and the IC(50) were 12.15 micromol/L, 4.9 micromol/L for 24 and 48 hours respectively. FCM indicated that the apoptosis ratio rose from 10.6% of untreated cells up to 36.9% of treated cells (p < 0.05), and curcumin arrested cell cycle of RPMI8226 at G(2)/M phase. RT-PCR showed that RPMI8226 cells expressed survivin, Bcl-2 strongly and Bax slightly; while RPMI8226 cells were treated with curcumin 10 micromol/L for 24 hours, the expressions of survivin, Bcl-2 mRNA were apparently down-regulated, and the expression of Bax mRNA was markedly up-regulated. It is concluded that curcumin can suppress the proliferation of human multiple myeloma cell line RPMI8226, and induce their apoptosis. The mechanism of antitumous effect of curcumin may be related to down-regulation of survivin, Bcl-2 mRNA and up-regulation of Bax mRNA. PMID- 17708800 TI - [Expression of nuclear transcription factor kappaB in childhood acute lymphoblastic leukemia and its significance]. AB - To investigate the expression of nuclear transcription factor kappaB (NF-kappaB) in childhood acute lymphoblastic leukemia (ALL) and its significance, the biotin streptavidin method and microscopy were used to detect NF-kappaB P65 protein in cells from 32 childhood ALL patients and 40 children without hematologic malignancies as control. The results showed that the positive expression rate of NF-kappaB P65 protein in cells from 32 childhood ALL patients was 87.50%, obviously higher than that in control group (12.50%) (chi(2) = 40.56, p < 0.01). In 28 childhood ALL patients with positive expression, the ratio of weakly positive (+) cases to all positive cases was 10.71% (3/28); the ratio of generally positive (++) case was 42.86% (12/28), and the ratio of strongly positive (+++) cases was 46.43% (13/28). While in the control group the of NF kappaB P65 protein showed low expression with 100% (5/5). There was significant difference in the level of NF-kappaB P65 protein between ALL patients and control group. While the level of NF-kappaB P65 protein had no significent difference in morphology, immunophenotype (T-lineage ALL and B-lineage ALL) and the courses in the de novo and the relaspsed cases. It is concluded that NF-kappaB P65 protein expresses in cells of childhood ALL, the inhibition of NF-kappaB transduction pathway may have significant value in childhood ALL treatment. This study provides experimental basis concerning clinical treatment for ALL, when NF-kappaB is taken as a target. PMID- 17708801 TI - [Expression of BMP-4 in stromal cells in vitro derived from human aorta-gonad mesonephros region]. AB - The objective of this study was to investigate the expression of BMP-4 in stromal cells in vitro derived from human aorta-gonad-mesonephros (AGM) region. Stromal cells derived from human AGM region (hAGM S1-S5) and fibroblasts derived from human fetal trunk (hFT) were cultured in vitro. RT-PCR was used to analyze the expression of BMP-4 in hAGM S1-S5 stromal cells at mRNA level. And BMP-4 level was detected in the supernatant of hAGM S1-S5 stromal cells by ELISA assay. hFT cells were used as control group. The results showed that the heterogenous hAGM S1-S5 stromal cells displyed shapes of fibroblast-like and endothelial-like cells. hAGM S1-S5 stromal cells expressed BMP-4 mRNA, but fetal trunk fibroblasts (hFT) did not express BMP-4 mRNA. In the supernatant of hAGM S1-S5 cells, BMP-4 could be detected by ELISA assay ana its levels were statistically higher than that in hFT group (p < 0.05), while there was no significant difference between groups of hAGM S1-S5 (p > 0.05). It is concluded that human AGM-derived stromal cells in vitro express BMP-4, and the establishment of a new culture system based on the feeder cells of AGM stroma would promote the differention of embryonic stem cells into hematopoietic stem cells at a high proportion. PMID- 17708802 TI - [Effects of Ginseng panaxadiol saponin on proliferation and differentiation of human bone marrow CD34+ cells]. AB - The study was purposed to investigate the effects of the panaxadiol saponin (PDS) from Ginseng on proliferation and differentiation of human CD34(+) cells from human bone marrow. Highly purified CD34(+) cells were isolated from human bone marrow by using the Dynal CD34 Cell Selection System (Dynal, Norway). The cells were exposed to PDS at various concentrations in both agar semi-solid culture of CFU-Mix and suspension culture of myeloid and erythroid cells in order to observe the effects of PDS on proliferation of CD34(+) cells. The cells were marked with 4 kinds of monoclonal antibody in related with their differentiation toward to myeloid and erythroid lineages, then examined by flow cytometry (FACS) after being incubated with PDS for 14 days. The results showed that the number of CD34(+) cells was 1.0 +/- 0.15% out of marrow nuclear cells after being purified by Dynal beads system. The enrichment of CD34(+) cells reached to 86.8 +/- 2.8%. The best efficiency in promoting proliferation of CD34(+) cells in vitro was obtained when the concentration of PDS was 25 mg/L, the formation of CFU-Mix colonies significantly increased by 56.3 +/- 3.5% over those of no-PDS control (p < 0.01). The results from suspension culture revealed that myeloid cells elevated in a dose-dependent manner with a peak increasing rate of 35.6 +/- 3.2%, and erythroid cells significantly increased by 22.3 +/- 2.1% over those of no-PDS control (all p < 0.01). After incubation with PDS for 14 days, number of CD33(+) cells increased in a dose-dependent manner with a peak increasing rate at 50 mg/L. CD71(+) cells reaching the peak were at 25 mg/L, while G-A(+) cells were increased by 7.2 +/- 1.3% (p < 0.01) at 10 mg/L, but the number of CD15(+) cells was not found to be changed before and after treating with PDS. It is concluded that PDS not only enhance the proliferation of CD34(+) cells, but also induce differentiation of CD34(+) cells toward to myeloid and erythroid lineages. PDS may play the roles as like hematopoietic growth factor, or provide synergistic effects on growth factor in the regulation of hematopoiesis. PMID- 17708803 TI - [CFU-HPP colony formation of bone marrow hematopoietic proginitor cells in psoriatic patients and methylation of p16 gene promotor in CFU-HPP colony cells]. AB - This study was purposed to investigate the colony formation of high-proliferative potential colony-forming units (CFU-HPP) from bone marrow-derived hematopoietic cells of psoriatic patients and p16 gene promotor methylation in CFU-HPP cells, and to explore the relationship between the colony formation and the methylation status of p16 gene promoter. Bone marrow-derived mononuclear cells from psoriatic patients and normal controls were separated by density gradient centrifugation, and were cultured in methycellulose semi-solid culture medium with SCF, GM-CSF, IL-3 and IL-6 for 14 days to measure the colonies of CFU-HPP. The CFU-HPP colony cells were collected and methylation status of p16 gene promoter of CFU-HPP cell DNA modified with sodium bisulfite was detected by the methylation-specific polymerase chain reaction (MSP). The results showed that in methycellulose semi solid culture system, the number and the size of CFU-HPP colonies of bone marrow of psoriatic patients were all significantly less than that of normal controls, the positive frequency of p16 gene promoter methylation in CFU-HPP cells was lower than that in CFU-HPP colony cells of normal controls. It is concluded that the colony formation capability of CFU-HPP from bone marrow hematopoietic progenitor cells in psoriatic patients is lower than that in normal controls, and the lower positive frequency of P16 gene promoter methylation in CFU-HPP cells perhaps closely correlated with lower CFU-HPP colony-forming capability. PMID- 17708804 TI - [Effect of human bone marrow mesenchymal stem cells on allogeneic regulatory T cells and its possible mechanism]. AB - The study was purposed to investigate the immune regulatory effects of human bone marrow mesenchymal stem cells (hMSCs) on Foxp3 expressing CD4(+)CD25(+) regulatory T cells and to explore the mechanism of immune modulation by hMSCs. Human MSCs were isolated and expanded from bone marrow cells, and identified with cell morphology, and the phenotypes were assessed by immunohistochemistry. Human peripheral blood mononuclear cells (hPBMNCs) were prepared by centrifugation on a Ficoll Hypaque density gradient. The hMSCs (1 x 10(3), 1 x 10(4), 1 x 10(5)) were added into wells containing hPBMNCs (1 x 10(6)) from an unrelated donor in the presence of rhIL-2. After 5 days of co-culture, the percentage of CD4(+)CD25(+) T cells was detected by flow cytometry. T cell proliferation was assessed by [(3)H] thymidine incorporation using a liquid scintillation counter. The expression of Foxp3 in CD4(+)CD25(+) T cells was detected by reverse transcription polymerase chain reaction (RT-PCR). Cytokines (TGF-beta, IL-12, IFN-gamma, IL-10) concertrations of cultured supernatants were measured with ELISA. The results indicated that in all the experiments, the presence of hMSCs with hPBMNCs resulted in a statistically significant decrease in T cell proliferation, in dose dependent manner. The increase of percentage of CD4(+)CD25(+) T cells in the peripheral CD4(+) T cell was observed after coculturing lymphocytes with hMSCs (p < 0.01). The expression of Foxp3-mRNA (Foxp3/beta-actin) in hMSCs groups was significantly higher than that in the control and was negatively associated with the value of CPM representing T proliferation. The levels of TGF-beta and IL-10 were higher in hMSCs groups than that in the control, and the levels of TGF-beta and IL-10 correlated positively with Foxp3-mRNA expression and the percentage of CD4(+)CD25(+) T cells. However, the secretion of IL-12 and IFN-gamma was significantly attenuated by hMSCs coculture, and there was no correlation with Foxp3-mRNA expression and the percentage of CD4(+)CD25(+) T cells. It is concluded that the Foxp3 expressing regulatory T cells may play an important role in the immune regulatory by hMSCs. Its mechanism is related to that the hMSCs mediated TGF-beta and IL-10 convert CD4(+)CD25(-) T cells into CD4(+)CD25(+) T regulatory T cells, which specifically inhibits the proliferation of T cells. PMID- 17708805 TI - [Effects of rhG-CSF on mobilization of mouse mesenchymal stem cells]. AB - To evaluate the effects of rhG-CSF on mobilization of mesenchymal stem cells (MSCs) of mouse bone marrow at different time point, thirty mice were randomly divided into rhG-CSF treatment group and control group. The mice were subcutaneously injected with rhG-CSF in a dose of 80 microg/kg or saline for 5 days. The bone marrow and peripheral blood were obtained at time points of 6, 12, 168 hours after final injection of rhG-CSF or saline. Bone marrow mononuclear cells (BMMNCs) were seeded at density of 1 x 10(6) MNCs onto 12-well plate for culture expansion in DMEM supplemented with 10% FBS, and the number of colony forming unit - fibroblast (CFU-F) was counted after 14 days. The cells were collected by trypsinization and the surface antigens CD34, CD133, CD90 and CD105 were analyzed by flow cytometry. The multi-differentiation of MSCs were done in the culture condition of induced-adipocyte and osteocyte. Peripheral blood MNCs examination was same as the bone marrow. The results indicated that the number of CFU-F of bone marrow in rhG-CSF group was more than that in control group (p < 0.01), the number of CFU-F in rhG-CSF group at 6 hours was more than that at 12 hours and 168 hours, respectively (p < 0.01). There was no obvious difference between CFU-F at 12 hours and at 168 hours (p > 0.05). MSCs were positive for CD90, CD105 and negative for CD34 and CD133. MSCs were found to differentiate into adipocyte and osteocyte in vitro. The CFU-F of PBMNCs obtained and cultured in vitro in the same culture conditions could be observed after the rhG-CSF injection at 6 hours, but cloning efficiency was (0.50 +/- 0.11) x 10(-6) MNCs and showed statistical difference as compared with control. It is concluded that rhG-CSF to mobilize hemopoietic stem cells can be used to induce mouse MSCs in vivo expansion, which showed the peak value within 6 hours after final injection of rhG-CSF. rhG-CSF have the mini-mobilization effect on murine MSCs derived from bone marrow. PMID- 17708806 TI - [Clonal kinetic proliferative change of TCR Vbeta subfamilies in peripheral blood of patients transplanted with allogeneic hematopoietic stem cells and its relation to GVHD]. AB - This study was purposed to investigate the dynamic change of clonal proliferation of T cell receptor V subfamilies in peripheral blood of patients received allo hematopoietic stem cell transplantation (allo-HSCT) and to analyze the relationship between T cell clonal proliferative changes and GVHD. The peripheral blood mononuclear cell samples from 70 cases (17 GVHD patients) undergoing allo PBCST patients were detected for CDR3 (complementarity determining region 3 repertoire analysis of T cell receptor Vbetagene) using reverse-transcriptase polymerase chain reaction (RT-PCR). The products were further analyzed by genescan to identify T cell clonality. The results showed that the patients of HSCT generally passed through a transformation from monoclone to polyclone. At day 60 - 90 after HSCT, half of the cases were monoclonal and the remainders were polyclonal. After 120 days, most of patients without GVHD transferred into polyclones, however, patients with GVHD remained monoclonal after one year because of immunosuppressive agents and GVHD itself. The peripheral blood of GVHD patients mainly expressed monoclone/biclone at the time of target organ damage conspicuously, after medication intervention, partial monoclone or bioclone expressed TCR Vbeta subfamilies were diverted to polyclonal expression. It is concluded that the T cells present clonal proliferation and T cell receptors are prone to be used when patients are in earlier period of transplantation or with GVHD especially. The expression of TCR Vbeta subfamilies can return to normal polycloning along with the recovery of hematopoiesis and immunity in patients. PMID- 17708807 TI - [Combined transplantation of umbilical cord blood and bone marrow from same sibling donor in children with beta-thalassemia major]. AB - The objective of this study was to investigate the curative effect of combined sibling umbilical cord blood and bone marrow transplantation in treatment of beta thalassemia major. Combined umbilical cord blood and bone marrow transplantation from an HLA-identical sibling were performed for 3 patients with beta-thalassemia major. The nucleated cells infused into 3 recipients were 19.5 x 10(7)/kg, 20.8 x 10(7)/kg and 23.3 x 10(7)/kg respectively. They accepted the conditioning regimen consisting of busulfan, cyclophosphamide, antithymocyteglobulin. The results showed that three patients gained protracted and stable engraftment. The time to achieve more than 0.5 x 10(9)/L neutrophils in three patients was 16, 18, and 17 days respectively; the time to achieve more than 50 x 10(9)/L platelet in three patients was 48, 50, and 49 days respectively. The speed of hematopoietic recovery was faster than that of umbilical cord blood transplantation (UCBT) only. Three patients all suffered from acute graft-versus-host disease (aGVHD) of I grade. They had lived with free-thalassemia for 1.5, 2.0 and 2.1 years respectively. Their Hb had been maintained at normal level without transfusion. It is concluded that combined UCBT and BMT may be an effective and safe way to treat pediatric beta-thalassemia major. PMID- 17708808 TI - [Quantitative change of Th cell subsets in patients with acute graft-versus-host disease and its clinical significance]. AB - This study was purposed to investigate the change of Th cell subsets in the patients with acute graft-versus host disease (aGVHD) and to explore its role in the pathogenesis of aGVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT). 23 patients underwent allo-HSCT were selected for analysis. The aGVHD in patients was diagnosed according to clinical features, and was confirmed by skin biopsy in some patients. The peripheral blood from 23 patients was collected before and after allo-HSCT. The quantitative chenges of Th1 and Th2 cells in peripheral blood samples were detected by using flow cytometry. The results showed that out of 23 patieats the aGVHD occured in 8 patients including 1 case of grade I, 2 case of grade II, 3 cases of grade III; no aGVHD occured in 15 patients. The flow cytometry analysis revealed that the amount of Th1 cells in patients with aGVHD was much higher than that in patients without aGVHD (p < 0.01), the IFN-gamma expression of Th1 cells in patients with aGVHD of grad II - III significantly was higher than that in patients without aGVHD (p < 0.01), meanwhie the IL-4 expression of Th2 cells in patients with aGVHD of grade II - III was significantly lower than that in patients without aGVHD (p < 0.05). Dynamical detection indicated that the Th1 obviously increased before occurrence of aGVHD and before treatment of aGVHD, while the Th1 cells obviously decreased after treatment of aGVHD. The Th1 cells not changed significantly in patients without aGVHD before and after allo-HSCT. It is concluded that Th1 cells obviously increase in patients with aGVHD, this increase is related to aGVHD pathogenesis. Detecting the changes of Th cell subsets in the early stage after allo-HSCT may be contributed to early diagnosis and therapy of aGVHD. PMID- 17708809 TI - Impact of incompatible killer cell immunoglobulin-like receptor and its ligand on the outcome of haploidentical bone marrow transplantation. AB - The purpose of study was to investigate the impact of killer immunoglobulin-like receptor (KIR) and its ligand on haploidentical bone marrow transplantation. 74 cases were analyzed for the distribution frequencies and characteristics of KIR and its ligand as well as the impact of KIR ligand for the haploidentical bone marrow transplantation in terms of the overall survival, disease-free survival (DFS), GVHD and relapse. The results showed that among the 19 KIR genotypes currently nominated KIR2DL1, KIR2DL4 and KIR3DL2-3 could be detected in all the cases. Other high frequency genotypes included KIR3DP1 (98.6%), KIR2DP1 (98.6%), KIR3DL1 (97.3%) and KIR2DL3 (97.3%). Inhibitory receptor genotypes were 1.37-fold of activating receptor genotypes. KIR2DL1, KIR3DL2, KIR3DL3 and KIR2DL4 were found in all haplotypes and at least one genotype of KIR2DL2 and/or KIR2DL3 existed in all haplotypes. Among the 14 genotypes found in the test, the HLA-Cw7 was the most popular (37.8%) and the group 2 (HLA-Cw1, 3, 7, 8, 13, 14) recognized by KIR2DL2/2DL3 counted for 43.2%. The incompatibility of KIR for 32 cases of haploidentical BMT was 43.8%, of which 9/14 were KIR2DL incompatible, 5/14 were KIR2DL2 or KIR3DL1 incompatible. Among the 46 cases of haploidentical BMT, 29 cases were HLA-Cw matched and 14 cases were mismatched. The completed mismatch ratio of HLA-Cw was 30.4% and the match ratio was 63.4%. The survival rate was higher for the 14 cases of KIR genotype compatible group than the 13 cases of KIR genotype incompatible group (p = 0.032). The disease-free survival was significantly higher for the 17 cases of mismatched KIR ligands (HLA-Cw) group than the matched group (p = 0.024). The survival rate was higher in GVHD group than that in non-GVHD group when the KIR ligand was missing. The acute and severe GVHD was related to the existence of activating receptor of KIR2DS1/2DS2. The incompatibility group was accompanied with frequent acute and severe GVHD and less relapse and vice versa for the compatibility group. One patient died after BMT among the 14 mismatched KIR ligand group suffering from myelogenous leukemia while 4 patients out of 12 patients died in the matched group. It is concluded that the haploidentical BMT is characterized by mismatch between donor and recipient and its immunological reactions also features by the incompatibility of KIR genotype and missing ligand. The missing ligand for the donor KIR has strong effect on the outcome of BMT and it means a lot to analyze the KIR genotype and its ligand for the selection of best donor and prognostic evaluation in haploidentical BMT. PMID- 17708810 TI - [Antithymocyte globulin used for treatment of severe acute graft versus host disease after haploidentical bone marrow transplantation]. AB - The objective of study was to investigate the effect of low-dose antithymocyte globulin (ATG) on steroid-resistant severe acute graft versus host disease (aGVHD). Six patients with steroid-resistant severe aGVHD after haploidentical bone marrow transplantation (BMT) received the treatment with ATG at a low dose of 1.25 mg/kg for 3 - 5 doses every other day. The results showed that 3 out of 6 patients got completely remission (CR), among them 2 patients have still been in disease-free survival, 1 patient died from leukemia relapse. 1 out of the other 3 patients got partial remissin (PR), 2 patients were aggravated. The other 3 patients all died from GVHD. The major complications observed in these patients were infections. In conclusion, low-dose ATG is effective for some patients with steroid-resistant severe aGVHD, and has not severe side effect. To strengthen environmental protection should be considered as important for prevention of infection. PMID- 17708812 TI - [Preparation and identification of monoclonal antibody against Homo sapiens hemoglobin alpha 2 (HBA2)]. AB - This study was purposed to prepare and identify monoclonal antibodies (McAbs) against Homo sapiens hemoglobin alpha 2 (HBA2). Normal human fetal liver tissues were homogenized, and human liver nuclear proteins were isolated by centrifugation. The total human fetal liver nuclear proteins were used to immunize BALB/c mice for preparing McAbs by hybridoma technique. The McAbs specificity was identified by ELISA, Western blot, and immunohistochemistry. The antigen was identified by Uni-ZAP expression library screening. The results showed that one hybridoma cell line, AEE091, secreting specific McAb against HBA2 was established. The Ig subclass of this McAb was IgG1 (kappa). Data from immunohistochemistry assay showed that AEE091 could recognize human liver nuclear protein. Using AEE091 McAb, isolation of the protein antigen by IP revealed that AEE091 McAb could recognize 15 kD protein. Screening the Uni-ZAP XR pre-made liver cDNA library with AEE091 hybridoma cell supernatants demonstrated that AEE091 McAb specially reacted with HBA2. It is concluded that a hybridoma cell line stably secreting specific McAb against HBA2 is established. The specific McAb against HBA2 would be very useful for studying HBA2 function and screening thalassemia. PMID- 17708811 TI - [Donor peripheral blood mononuclear cell infusion (DMNCI) for treatment of patients with relapsed leukemia after haploidentical bone marrow transplantation]. AB - This study was aimed to investigate the therapeutic effect of growth factor primed donor peripheral mononuclear stem cell infusion (DMNCI) for patients with relapsed leukemia after haploidentical bone marrow transplantation (BMT). The donor was the same individual for both BMT and DMNCI. All the three patients described here were Philadelphia chromosome positive leukemia before haploidentical BMT; one case was newly diagnosed as acute lymhoblastic leukemia (ALL) and the others were chronic myeloid leukemia (CML). Two cases (one with ALL and one with CML) manifested with clinical relapse and the third case was in the stage of molecular relapse. The former 2 patients received a single bulk dose of DMNCI, the inoculums of which contained mononuclear cells of 8.25 x 10(8)/kg or 5.24 x 10(8)/kg and CD3-positive cells of 1.87 x 10(8)/kg or 1.14 x 10(8)/kg respectively. The third case received initial dose of DMNCI which was 2.0 x 10(7)/kg, and received CD3 positive cells of 1.1 x 10(7)/kg. The results indicated that the different therapeutic responses were found in all three patients. Two patients with clinical relapse received temporal remission, and died of severe graft versus host disease (GVHD), relapse and failure at day 41 and 49 after DMNCI. The third patient with molecular relapse received molecular remission after 2 infusions of DMNCI. All three patients developed acute GVHD, but two patients among them developed GVHD of grad IV, other one developed GVHD of grad I and has survived in disease-free state during half a year follow-up. It is concluded that the DMNCI may be effective for the treatment of relapsed leukemia after haploidentical BMT and this treatment can be safe if the initial dose of DMNCI is 10(7)/kg and subsequent single dose of DMNCI gradually increases. PMID- 17708813 TI - [Cloning, expression and identification of functional fragment rC3B of human complement C3 in E. Coli]. AB - This study was purposed to verify the binding part of human complement C3 to complement receptor III (CRIII) in monocytes, the peptide rC3B, including the binding-site, was expressed, purified and identified. rC3B, the binding part of human complement C3 to CRIII, was selected by computer-aided modeling and summarizing researches published. Then, rC3B gene fragment was amplified by PCR, and cloned into prokaryotic vector pQE30a. The fusion protein rC3B was expressed in E.coli M15 and purified by Ni(2+)-chelating affinity chromatography. The activity of rC3B was identified by Western blot and adherence assay with monocytes. The results showed that rC3B fragment was obtained, and a prokaryotic expression vector pQE30-rC3B was constructed. rC3B was efficiently expressed and purified. In Western blot, the target protein showed the activity of binding with C3 antibody, while the purified protein showed the activity of adherence with monocytes. It is concluded that the recombinant C3B was obtained and identified, and this study lay the basis for the further functional analysis of C3. PMID- 17708815 TI - [In vitro transcription synthesis and effects of FLT3 targeted short hairpin RNA]. AB - FMS-like tyrosine kinase 3 (FLT3) is a receptor of tyrosine kinase that is constitutively activated in most of acute myeloid leukemia patients and seems to give an adverse prognosis. In order to explore the silencing effect of FLT3 targeted short hairpin RNA (FLT3-shRNA) on acute leukaemia cell line THP-1, three FLT3-shRNAs (shRNA1, shRNA2, shRNA3) were designed and synthesized by transcription system in vitro and then transfected into THP-1 cells. FLT3 mRNA was analyzed by semi-quantitative RT-PCR, FLT3 protein was detected by Flow cytometry and immunofluorescence. The results indicated that FLT3 expression was downregulated by shRNA1 and shRNA3, and shRNA1 showed stronger inhibitory effect. At 48 hours following transfection, the inhibitory rate of 25 nmol/L shRNA1 was 72.95 +/- 2.07%, lasting 72 hours. The 5 nmol/L and more concentration of FLT3 shRNA1 could downregulate FLT3 mRNA level, which displayed a quantity-effect relation; the inhibitory rate of 15 nmol/L shRNA1 was 67.53 +/- 0.66%. FLT3 protein was located on THP-1 cell membrance, its expression was downregulated obviously by shRNA1, at 72 hours following transfection the inhibitory rate of shRNA1 was 79.67 +/- 0.66%. shRNA1 showed the best inhibitory effect on FLT3 protein, the optimal time of which was 72 hours with an inhibitory rate of 79.67%. It is concluded that FLT3-shRNA1 shows a desireable FLT3-targeted inhibitory effect, which can be used for further investigation of FLT3 mechanism or FLT3 targeting treatment. PMID- 17708814 TI - [Immune response of dendritic cells capturing antigens from apoptotic U937 cells induced by artesunate]. AB - The objective of study was to investigate whether U937 cells-loaded dendritic cells (DCs) could induce anti-leukemic immune activity. The apoptosis of U937 cells was induced by artesunate (ART). DCs derived from peripheral blood mononuclear cells of health donors were loaded with apoptotic U937 cells, and induced to maturation in the presence of TNF-alpha. Matured DCs were cocultured with autologous T-lymphocytes, and combined with IL-2 in order to induce the leukemia-specific CTL. The phenotypes of DCs and T lymphocytes were tested by flow cytometry. The ability of DC capturing antigens was measured by Dextran-FITC endocytosis. The IL-12p70 level was assayed by ELISA kit. The proliferation of CTL and CTL activity were measured by MTT assay. The results showed that the apoptotic rate of the U937 cells was 51.2% when U937 cells were induced by 1 microg/ml ART for 48 hours in vitro. DCs had the most powerful ability of endocytosis in its immature phase. Apoptotic U937 cells could not induce the features of DC maturation, and apoptotic U937 cell-pulsed immature DCs could be matured with TNF-alpha. The IL-12p70 level secreded by apoptotic U937 cell-loaded mature DCs (mDC-(Apo)U937) was higher than that of non-loaded mDC. The proliferation of autologous T lymphocytes co-cultured with mDC-(Apo)U937 was significantly remarkable and the content of CD8(+) CTL was significantly higher in comparison with any other groups. CTL induced by mDC-(Apo)U937 had stronger killing effect on U937 cells than NB4 (p < 0.01). It is concluded that the mDC (Apo)U937 can effectively generate T cell-mediated dendritic antileukemic responses in vitro. PMID- 17708816 TI - [Expression of recombinated canine factor VIII in vitro mediated by lentiviral vector]. AB - The study was purposed to prepare the recombinant lentiviral vector pTK161 and pTK162 carrying B-domain-deleted canine factor (BDDcFVIII) gene, and to investigate whether the canine FVIII (cVIII) can be expressed in vitro. The BDDcFVIII gene was ligated behind PUB and 2OH1 promotors to create lentiviral vectors pTK161 and pTK162. Meantime lentiviral vectors pTK161' and pTK161' were produced by cloning a green fluorescent protein (GFP) into pTK151 and pTK152, which was driven by PUB and 2OH1 promotors respectively. Vector supernatant were prepared by using transfer calcium phosphate mediated-cotransfection of 293T cells. The virus vector, DeltaNRF packaging-plasmid, and VSV-G envelope-plasmid was assayed by titers and cFVIII activity in cell culture supernatant after infection into 293T cells. pTK161, pTK162, pTK161' and pTK161' were identified by restriction enzyme analyzing. The results showed that the lentiviral vectors pTK161, pTK162, pTK161' and pTK161' were successfully constructed, and the titers of pTK161' and pTK161' reached to 1.54 x 10(6) U/ml and 2.83 x 10(6) U/ml; the activity of cFVIII could be detected at 24 hours after infection of 293T cells by pTK161 and pTK162, and achieved the highest level at 72 hours later. The higher level of cFVIII activity was achieved by transfected with pTK162 than that of pTK161 (p < 0.05), which closed to the cFVIII activity in normal dog plasma. 1/4 of the highest level could be detected 6 weeks later. It is concluded that the prepared HIV1-based lentiviral vectors can infect 293T cells to express cFVIII effectively. The results provide the basis for further studying HIV-1-based lentiviral vector gene therapy for hemophilia A. PMID- 17708817 TI - [Effect of vascular endothelial growth factor antisense oligonucleotide on human leukemic cell line HL-60]. AB - This study was aimed to investigate expression of vascular endothelial growth factor mRNA (VEGF mRNA) and its relationship with leukemic cell apoptosis after VEGF antisense oligonucleotide (VEGF ASODN) transferred into HL-60 cells. The phosphorothiate VEGF ODN was transferred into HL-60 cells in vitro by using cation poly mediated method, the inhibitory rate of cell proliferation was assayed by MTT, expression of VEGF mRNA was measured by RT-PCR, cell apoptosis was detected by cell morphology observation, DNA agarose gel electrophoresis and flow cytometer (FCM). The results showed that difference of the inhibitory rate of cell proliferation and the relative expression of VEGF mRNA between ASODN group and MSODN or control groups under the same condition (p < 0.05) was statistic significant, but no significant difference (p > 0.05) was found between MSODN and control. The number of clusters of cells in ASODN group decreased; the morphology features of apoptotic cells involved cell shrinking, more granulation in cytoplasm, nuclear contracting and many fragments of cells. In MSODN and control groups, however, cells were plump and clear, and grow healthly. The result of electrophoresis revealed DNA ladder in ASODN group, while only one band of DNA in control groups. The rate of cell apoptosis was 19.46% in ASODN group with a significant difference as compared with MSODN groups and control (p < 0.05). The rate of HL-60 cell apoptosis in combination of VEGF ASODN with VP16 was significantly higher than that in VP16 alone (p < 0.05) and showed time- and dose- dependence. It is concluded that VEGF ASODN can down-regulate expression of VEGF mRNA of HL-60 cells, induces the apoptosis, inhibits the proliferation of HL 60 cells and enhances VP16-induced apoptosis in HL-60 cells, the VEGF ASODN in combination with VP16 shows additive effect. PMID- 17708818 TI - Effect of antisense oligodeoxynucleotides on the expression of vascular endothelial growth factor in Namalwa cell in vitro. AB - In order to study the effects of phosphorothioated antisense oligodeoxynucleotides (ASODN) on the expression of VEGF in human lymphoma cell line Namalwa cells, human lymphoma cell line Namalwa cells were incubated with VEGF ASODN (the final concentrations of VEGF ASODN were 5, 10, 20 micromol/L respectively), or scrambled sequence for 24 or 48 hours. The expressions of VEGF mRNA and VEGF protein were detected by reverse transcriptase-polymerase chain reaction and streptavidin peroxidase (SP) immunohistochemistry respectively. The results showed that the expression levels of VEGF mRNA in Namalwa cells treated with three concentration levels (5, 10, 20 micromol/L of ASODN) were 1.38, 0.96 and 0.57 respectively. Those in PBS-treated cells and scrambled sequence treated cells were 1.79 and 1.84. When treated with 20 micromol/L VEGF ASODN for 48 hours, VEGF protein of Namalwa cells decreased greatly. Meanwhile, there was no obvious change in the scrambled sequence treated group. It is concluded that VEGF ASODN can suppress the VEGF expression in Namalwa cells in vitro. PMID- 17708819 TI - [Effects of platelet-derived membrane microparticles on the proliferation and apoptosis of human umbilical vein endothelial cells]. AB - This study was purposed to investigate the effects of platelet-derived membrane microparticles (PMP) on the proliferation and apoptosis of human umbilical vein endothelial cells (HUVEC). Different concentrations of thrombin were adopted to activate the platelets so as to release PMPs. Flow cytometry (FCM) was adopted to evaluate the efficiencies of different concentrations of thrombin to release PMPs. By using the HUVEC cultivated in vitro as vector, the effects of PMPs on the proliferation and apoptosis of HUVEC were investigated by MTT and FCM. The results showed that the efficiencies releasing PMPs from platelets activated by 2.0, 1.5, 1.0, 0.5 U/ml thrombin were 28.7, 47.7, 50.1 and 43.9% respectively; PMPs induced proliferation of HUVEC in a dose dependent manner. At the concentration of 40 microg/ml PMPs, the proliferation rate of HUVEC was 1.8 +/- 0.3 times as much as blank control, the proliferation rate in group of vascular endothelial growth factor was 1.9 +/- 0.5 times of as much as blank control, there was no statistic difference (p > 0.05). The PMPs inhibited HUVEC apoptosis. Compared with the apoptosis rate of control (9.4 +/- 0.5)%, apoptosis rate in PMP group (40 microg/ml) was (3.9 +/- 0.4)% (p < 0.05). The addition of VEGF (10 microl/ml) did not successfully prevented apoptosis of HUVEC with apoptosis rate of (8.0 +/- 0.8)%. It is concluded that platelets activated by 1 U/ml thrombin gets the best efficiency of PMP release, which stimulates proliferation of HUVEC and inhibits its apoptosis. PMID- 17708820 TI - [Angioimmunoblastic T-cell lymphoma with autoimmune hemolytic anemia and pure red cell aplasia]. AB - Angioimmunoblastic T-cell lymphoma (AILT) is a peripheral T-cell lymphoma often complicated autoimmune phenomena such as autoimmune cytopenia, and is a truly rare type of NHL. In order to investigate the clinical features, pathological manifestation of this lymphoma, and to explore its therapy protocol, a 37-years old patient with AILT was investigated. The routine blood examination, bone marrow smear, lymphonodus biopsy, Coombs test, flow cytometry for bone marrow mononuclear cells, serological test, immunochemistry method etc were performed for this patient. The results showed that the systemic lymphadenectasis and hepatosplenomegaly were seen in patient, the cervical lymphonode biopsy revealed AITL. The hematoglobin level and number of reticulocytes were very low. Coombs test was positive. Simultaneously, the bone marrow aspirate revealed erythroid aplasia. The warm type autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) were co-existed. After one course of chemotherapy with CHOP-E, infiltration sign of AITL patient with AIHA and PRCA disappeared. In conclusion, the AITL patient complicated with AIHA and PRCA was successfully diagnosed, the lymphonode biopsy and bone marrow smear showed more significant, the chemotherapy protocol of CHOP-E can give some effect to cure such angioimmunoblastic T cell lymphoma. PMID- 17708821 TI - [Double times of autologous peripheral blood stem cell transplantation to treat multiple myeloma]. AB - In order to explore the security and feasibility of double autologous peripheral blood stem cell transplantation (APBSCT) for treatment of multiple myeloma, a 49 years old female patient with multiple myeloma was therapied with double APBSCT. The first peripheral blood stem cell (PBSC) mobilization regimen included CTX 2 g/m(2) x 1d and G-CSF [10 microg/(kgxd)] x 5 d. The conditioning regimen was given melphalan 200 mg/m(2). The transplanted number of mononuclear cells was 6.1 x 10(8)/kg and that of CD34(+) cells was 4.7 x 10(6)/kg. The second APBSCT was performed six months later. PBSC mobilization regimen was G-CSF [10 microg/(kgxd)] x 5 d. The conditioning regimen was melphalan 200 mg/m(2). The transplanted number of mononuclear cells was 10.2 x 10(8)/kg and that of CD34(+) cells was 5.9 x 10(6)/kg. The results showed that the absolute neutrophil count (ANC) rose to above 0.5 x 10(9)/L on day 17 and platelet count exceeded 20 x 10(9)/L on day 15 after first transplantation. After second transplantation ANC rose to above 0.5 x 10(9)/L on day 22 and platelet count exceeded 20 x 10(9)/L on day 13. There were neither obvious adverse reaction nor severe complication during the double transplantations. The patient's ostealgia and anemia were healed through above therapy. In the follow-up of 7 months, the patient's general status was good and she remained in complete remission phase. It is concluded that double APBSCT is safe, effective and feasible for the treatment of multiple myeloma. PMID- 17708822 TI - [Identification and sequence analysis of a null HLA-B allele HLA-B*5408N newly detected]. AB - The study was purposed to investigate the molecular genetic basis for HLA novel allele HLA-B*5408N in Chinese population. DNA was extracted from whole blood by commercial DNA extraction kit, the HLA-B exons 2 - 4 of the proband was amplified by allele specific primers PCR and the amplified product was sequenced for exons 2, 3 and 4 bidirectionally. The sequencing results showed HLA-B alleles of the proband as B*1527 and the novel allele. The sequences of the novel allele have been submitted to Genbank (DQ295998, DQ295999, DQ296000). After blast analysis, the novel allele showed a single nucleotide mismatch with HLA-B*5401 in exon 3 at position 553 G-->T, which resulted in an amino acid changing from Glu to premature stop codon at position 161. No the HLA-B54 antigen specificity expression in the proband cells was found using HLA-AB serological Typing Trays. It is concluded that this allele is a novel null allele and has been officially named B*5408N by the WHO Nomenclature Committee. PMID- 17708823 TI - [Influence of cryopreservation on leukemic dendritic cells derived from leukemia patients]. AB - This study was aimed to investigate the influence of cryopreservation on biological properties and function of leukemic dendritic cells (L-DCs) derived from patients with acute or chronic leukemia. Some fresh leukemic cells were detected immediately; some were cultured immediately; some were cryopreserved in 80 degrees C with 5% DMSO-6% HES as cryopreservor. After being thawed, they were cultured. The combination of rhGM-CSF, rhIL-4, rhTNF-alpha and other cytokines were added into the culture system. 12 days later, L-DCs were assayed for morphology, immunophenotype, mixed lymphocytic reaction (MLR) and CTL cytotoxicity on autologous leukemic cells. The results showed that both fresh and cryopreserved leukemic cells obtained from patients with acute or chronic leukemia revealed typical DC morphologically by means of using combinations of cytokines in culture, but there was no significant difference between pre-or post cryopreservations. L-DCs also upregulated the expression of CD80, CD54, HLA-DR, CD1a, CD83 and CD86, and downregulated the expression of CD14, but there was also no difference as compared with L-DCs befor cryopreservation. L-DCs derived from leukemic cells were also capable of stimulating MLR and inducing CTL which could kill autologous leukemic cells obviously. It is concluded that leukemic cells, regardless of fresh or frozen, can induce L-DCs after culture with cytokine combination. The L-DCs can induce CTL targeting autologous leukemic cells, and may be used to treat MRD as immunotherapy. The induction and biological properties of L-DCs are not influenced by cryopreservation. PMID- 17708824 TI - [Qualitative comparison between buffy-coat-collected platelet concentrates and those by single-donor plateletpheresis]. AB - This study was aimed to compare the difference of quality between buffy-coat collected platelet concentrates (BC-PC) and single-donor plateletpheresis (SDP). 15 packs of BC-PC and 15 units SDP were stored at 20 degrees C - 24 degrees C with agitation. Platelet concentration, platelet volume, residual leukocyte and residual erythrocyte in two groups were examined after preparation for 1 hour. Mean platelet volume, pH value, hypotonic shock response (HSR), CD62p expression and CD62p re-expression of platelet were detected on 0, 1, 2, 3, 4, 5 days of platelet preservation. The results showed that the platelet yields, residual leukocyte and residual erythrocyte in two groups accorded with the national quality standard respectively, but residual leukocyte and residual erythrocyte in BC-PC group were higher than those in SDP group when platelet yields in two groups were equal (p < 0.01). Lactate concentration, CD62p expression of platelet increased with prolongation of preseved time, while pH value decreased gradually. Compared with SDP group, there were significant differences in CD62p expression, CD62p re-expression of platelet preserved for 0 - 5 days (p < 0.01), and in pH value of platelet preserved 2 - 5 days (p < 0.01). There was no changes in HSR of SDP group for 0 - 5 days, while HSR in BC-PC group decreased gradually. There were significant differences in HSR of platelet preserved for 1 - 5 days (p < 0.01). It is concluded that the platelet concentrates prepared by BC-PC are not equal to SDP in quality, the preparation technology of BC-PC should be optimized further in order to reduce residual leukocyte, residual erythrocyte and activated platelet yields, as well as improve the quality of BC-PC. PMID- 17708825 TI - [Effect of benzyl alcohol on trehalose-loading red blood cells before lyophilization]. AB - This study was aimed to evaluate the effect of benzyl alcohol on trehalose loading red blood cells (RBCs). The RBCs were incubated in 10, 30, 50 and 100 mmol/L concentrations of benzyl alcohol-trehaloe solution at 4 degrees C for 24 hours. The hemolysis rate of loaded RBCs was detected by using cyanohemoglobin kit, the intracellular trehalose level were assayed by sulfate anthrone method. The results showed that the intracellular trehalose concentration in group with 100 mmol/L benzyl alcohol was 72 +/- 12.98 mmol/L, compared with that in groups of 10, 30 and 50 mmol/L, the statistical difference were significant (p = 0.000); the hemolysis rate of loaded RBCs in group with 100 mmol/L of benzyl alcohol was 17.99 +/- 3.75%, as compared with groups of 10, 30 and 50 mmol/L, the statistical difference was significant (p = 0.000). It is concluded that benzyl alcohol can enhance the intracellular trehalose concentration. As concentration of benzyl alcohol ascends, the intracellular trehalose concentration increases. 100 mmol/L benzyl alcohol may be proper for loading RBCs. PMID- 17708826 TI - [Investigation of the characteristics of Rh blood group of Uygur nationality in Xinjiang]. AB - The study was to investigate the characteristics of Rh blood group of Uygur nationality in Xinjiang. 1 230 blood samples of Uygur nationality were studied by Rh serological typing, modified antiglobulin test, chloroform/trichloroethylene absorption elution test, upstream, downstream and hybrid Rhesus boxes, 10 exons of D gene, RHD(psi) pseudogene. The results showed that the frequency of RHD negative was 5.8%, and no Del type was found. The further investigation of 72 samples of RhD (-) found that ccee (57.02%) and Ccee (29.08%) phenotype as well as RHD(-)/RHD(-) genotype (94.44%) and complete deletion type of D gene exon (91.12%) were all in high frequency, no RHD(psi) pseudugene was detected. In conclusion, the Rh blood group of Uygurs nationality in Xinjiang possesses both oriental and caucasian Rh characteristics, which enriches the diversity of blood types in chinesenation. PMID- 17708827 TI - [Application of microcolumn gel immunoassay in screening the platelet antibody]. AB - The purpose of this study was to explore the clinical value of the platelet antibody screening and typing in platelets transfusion by using microcolumn gel immunoassay (MGIA). The platelets antigen-antibody reactions including the antibody screen and blood crossmatch were detected by MGIA. The results indicated that the detection of platelet antibody showed positive in 30 cases of aplastic anemia (AA), 11 cases of myelodysplastic syndrome (MDS), 24 out of 25 cases of leukemia and 1 out of cases of other diseases, while detection of platelet antibody showed negative in 20 normal volunteer donors. The number of platelet antibody crossmatch coincidence in 112 specimens of AA, 42 specimens of MDS and 95 specimens of leukemia were 45, 20 and 40, the coincidence rates were 40.18%, 47.62% and 42.11%. The mean corrected count increment (CCI) in 20 patients received platelet transfusion many times was 18.2 after crossmatch and 4.7 before crossmatch. It is concluded that the positive rate of platelet antibody screening is very high in patients with hematologic malignancies, the coincidence rate of platelet antibody crossmatch in 249 blood samples is between 40% and 48%, and the efficiency of using crossmatched platelets in clinic is enhanced significantly. PMID- 17708828 TI - [Advance of study on Mer function]. AB - Mer is one member of Axl receptor tyrosine kinase family, and its ligand Gas6 can stimulate activity of Mer receptor tyrosine kinase after binding it, and then activate the downstream signal transduction pathway, Mer participates in cell inflammation, apoptosis, tumorigenesis, thrombosis and hemostasis. Rencet advances of study on Mer function were reviewed, and its potential prospects of antithrombosis and antitumor were discussed in this article. PMID- 17708829 TI - [Effects of proteasome inhibitors on leukemias]. AB - The proteasome is primarily responsible for intracellular protein degradation. The abnormality of its activity is sign of tumorigenesis. It was confirmed that proteasome inhibitors have activities against a variety of malignancies. Bortezomib, the first proteasome inhibitor, obtained permission of clinical trial and on sale. Multiple myeloma patients treated with bortezomib have gained a high overall response rate and complete remission rate. A lot of studies on effects of proteasome inhibitors on leukemias, including plasma cell leukemia; chronic lymphocytic leukemia, adult T cell lymphoma/leukemia, chronic myeloid leukemia and acute myeloid leukemia, were reviewed in this article. PMID- 17708830 TI - [Problematic issues in clinical trials of mesenchymal stem cells and unraveling strategies]. AB - With the capacities of multiple differentiation, immunoregulatory activities and easy handling for isolation and culture expansion, human bone marrow mesenchymal stem cells (MSCs) have been utilized in clinical trials for the prevention and treatment of graft-versus-host disease in allogeneic bone marrow transplantation, repair of bone and cartilage defects and treatment of cardiac infarction and liver injury. However, increasingly experimental data indicate that a great deal of issues, such as intra-neutralization of calf serum proteins into cultured MSCs, survival of engrafted cells and subsequent cell differentiation tendency, should be in stringent consideration before clinical trials are designed. In this paper, these issues that should be raised and solved in clinical trials with MSCs were reviewed. PMID- 17708831 TI - [Mesenchymal stem cells applied in therapy for acute radiation injury]. AB - Mesenchymal stem cells are a kind of non-hematopoietic adult stem cells with selfrenewal and multilineage differentiation potential, which have special biological characteristics, such as secreting hematopoietic growth factors, reconstructing hematopoietic microenvironment, low immunogenicity, and can be transfected and expressed by exogenous gene. This article summarizes the biological characteristics of MSCs and their models of application to acute radiation disease in animals. PMID- 17708832 TI - Psychosocial interventions for carers of survivors of stroke: a systematic review of interventions based on psychological principles and theoretical frameworks. AB - PURPOSE: Most stroke survivors are cared for at home by informal carers, usually their partners or children. The chronic burden of meeting these care needs can have a significant impact on the psychological well-being of the carer. The aim of this review is to analyse interventions that target psychosocial functioning in carers of stroke survivors to understand how such interventions can reduce the burden of caring. METHOD: Seven studies that reported on randomized controlled trials of psychosocial interventions for informal adult carers of a survivor of stroke, which reported validated measures of psychological health outcome and met a satisfactory rating of quality were included in this systematic review. RESULTS: A forest plot of two studies that used education and counselling as the intervention for patients and spouses indicate a more favourable outcome for the intervention on the global family functioning scale. The Clarke, Rubenach, and Winsor (2003) study showed that patients were more likely to benefit from an intervention consisting of counselling and education than spouses. CONCLUSIONS: It is noted that there are relatively few studies investigating the impact of psychologically based interventions for carers of stroke survivors and the quality of evidence is varied. However, there is evidence of good quality to show that stroke patients benefit from a counselling combined with education intervention. The clinical implications of this review suggests, according to current available evidence, that those working with survivors of stroke and their families should consider providing counselling and education interventions to patients in the first instance. More research is needed to determine the effectiveness of interventions aimed at improving the psychosocial functioning of carers of survivors of stroke. PMID- 17708833 TI - Cultural differences in personal identity in post-traumatic stress disorder. AB - OBJECTIVES: This study investigated cultural differences in goals, self-defining memories, and self-cognitions in those with and without post-traumatic stress disorder (PTSD). METHOD: Trauma survivors with and without PTSD, from independent and interdependent cultures (N=106) provided major personal goals, self-defining memories, and self-cognitions. RESULTS: Trauma survivors with PTSD from independent cultures reported more goals, self-defining memories, and self cognitions that were trauma-related than non-PTSD trauma survivors from independent cultures. In contrast, for those from interdependent cultures, there was no difference between trauma survivors with and without PTSD in terms of trauma-centred goals, self-defining memories, and self-cognitions. CONCLUSIONS: The results suggest cultural variability in the impact of trauma on memory and identity, and highlight the need for contemporary models of PTSD to more explicitly consider culture in their accounts of PTSD. Clinical implications of these findings, such as cultural considerations in assessment and treating trauma relevant self-schema in cognitive therapy for PTSD, are discussed. PMID- 17708834 TI - [Practical guidelines for management of severe acute pancreatitis with integrated Chinese traditional and Western medicine (Draft)]. AB - OBJECTIVE: To draft the practical guidelines for management of severe acute pancreatitis (SAP) with integrated Chinese traditional and Western medicine. METHODS: With evidence based data as the foundation, a systematic review of literature was undertaken, with reference of published guidelines and solicitation of opinions from specialists, a preliminary guideline was drafted. The recommendations were categorized into five grades from A to E, with A being the highest, according to a modified Delphi criteria, which were adopted by the International Sepsis Forum held in 2001. RESULTS: SAP is a critical acute abdomen which usually has three clinical phases. It is essential to manage the patients in an intensive care unit with full monitoring and systems support in the early phase. Adequate prompt fluid resuscitation is crucial in the Prevention of systemic complications. Despite initial encouraging results, antiproteases such as gabexate, antisecretory agents such as octreotide, and anti-inflammatory agents such as lexipafant have all proved disappointing in large randomized studies, and they are not recommended for routine use. Antibiotic Prophylaxis may be potentially beneficial in preventing infection, but there remains no consensus of opinion regarding the value of antibiotic prophylaxis. If antibiotic prophylaxis is used, it should be given for a maximum of 14 days. Nutritional support is required in patients with SAP. The enteral route should be used if tolerated, and the nasogastric route for feeding is feasible. Urgent therapeutic endoscopic retrograde cholangiopancreatography (ERCP) should be performed in patients with gallstone-associated SAP, with co-existing cholangitis, jaundice, or a dilated common bile duct. Fine-needle peritoneal aspiration for bacteriology should be performed to differentiate sterile from infected pancreatic necrosis in patients with sepsis syndrome. Infected pancreatic necrosis in patients with clinical signs and symptoms of sepsis is an indication for intervention, including surgery and drainage under radiological guide. The option of surgical intervention for removal of necrotic tissue, and subsequent postoperative management depends on patient's general condition and expertise of the attending surgeon. The Chinese traditional medicine therapy has been proved to be a valuable treatment strategy in reducing mortality rate and clinical course. CONCLUSION: The present guideline is drafted with evidence-based recommendations and should be updated when new evidence based opinions are gathered. PMID- 17708835 TI - [Expression of substance P in intestinal tissue and the relation between substance P and mucosa permeability in acute necrotizing pancreatitis in rat]. AB - OBJECTIVE: To investigate the expression of substance P in the intestinal tissue and the relation between expression of substance P and pathological change of intestinal mucosa or mucosal Permeability in acute necrotizing pancreatitis (ANP) in rat. METHODS: One hundred and fifty adult Sprague-Dawley rats were randomly divided into sham operation group (n=50) and ANP group (n=100). In sham operation group, the pancreatic was only flipped over. In ANP group, ANP was produced by administration of 5% sodium taurocholate into the pancreatic duct. Rats were sacrificed at 0, 6, 12, 24 and 48 hours after reproduction of pancreatitis in both groups. The intestinal mucosal permeability was assessed with (99m)Technetium Diethylene Triamine Pentaacetic Acid method, and the expression of substance P was evaluated with reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting analysis. RESULTS: In ANP group, level of serum amylase raised at different time points after reproduction, intestinal mucosal permeability and the expression of substance P were also significantly higher than those in the sham operation group (P<0.01, respectively). The expression of substance P was positively correlated with mucosal pathological score (r=0.67, P<0.01) and intestinal mucosal permeability index (r=0.78, P<0.01) in ANP. CONCLUSION: The expression of the substance P and the permeability in intestine of rats are enhanced significantly in ANP. The expression of substance P is positively correlated with intestinal mucosal permeability. PMID- 17708836 TI - [Selective action of broad-spectrum antibiotics on intestinal flora in sepsis in rats]. AB - OBJECTIVE: To investigate the selective effect of broad-spectrum antibiotics on the intestinal flora in sepsis in rats. METHODS: Fifty-six SD rats were randomly divided into normal control group, scald group [before ceftriaxone sodium (rocephin) treatment group], scald group with 3 days of rocephin treatment, scald group with 9 days of rocephin treatment, and sepsis group (before rocephin treatment group), sepsis group with 3 days of rocephin treatment, and sepsis group with 9 days of rocephin treatment. All the animals were incurred with 30% III degree burns on their back followed by endotoxin challenge with a dose of 20 mg/kg 24 hours after the burn injury. The animals were treated with intraperitoneal injection of ceftriaxone 24 hours (60 mg/kg, quaque 12 hours) after the second hit with endotoxin. At the end of the treatment, the bacteria in stomach, intestine and colon were cultured. The number and kind of the bacteria were also determined. RESULTS: Antibiotics significantly increased the number of cocci (P<0.05 or P<0.01). The ratio between cocci and bacilli was markedly inverted. In selective culture of gut bacilli, E.Coli was almost the only bacteria in the contents of stomach, intestine and colon in normal control group, but after burns and endotoxin challenge, Klebsiella pneumoniae, Proteus mirabilis appeared. After the rats received antibiotics treatment, E. coli decreased in number or disappeared, and was replaced mainly by Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, Enterobacter cloacae and Proteus and other bacilli. CONCLUSION: Broad-spectrum antibiotics can induce imbalance of bacteria flora in the gut, resulting in a reversion of the ratio between cocci and bacilli, and also reduction in intestinal colonization resistance. Then, opportunistic pathogens become dominant flora in gut, which may cause antibiotic related gut-origin diseases. PMID- 17708837 TI - [Assessment of severity of acute pancreatitis in early stage]. AB - OBJECTIVE: To assess the accuracy of indexes for predicting severe acute pancreatitis (SAP). METHODS: Thirty-nine patients suffering from acute pancreatitis (AP) were randomly selected, including 20 SAP cases and 19 mild acute pancreatitis (MAP) cases. The levels of polymorphonuclear leucocyte elastase (PMN-E), serum phospholipase A2 (PLA2), pancreatic PLA2 (Pan-PLA2), PLA2 catalytic activity (CA-PLA2), amylase, as well as C-reactive protein (CRP) were determined Acute Physiology and chronic health evaluation II (APACHE II) was scored in every patient. Sensitivity and specificity of all the parameters were assessed, and receiver operator characteristic curve (ROC) was plotted. Positive predictive value, negative predictive value, and overall accuracy were then analyzed. RESULTS: PMN-E, CRP and CA-PLA2 were obviously higher in SAP than in MAP, and were indicative of the severity of the disease (all P < 0.01). Pan-PLA2 and amylase of AP patients raised at the onset of the disease, and they showed no difference between the SAP groups and MAP groups. When SAP was predicted by PMN E, sensitivity was 94.5%, specificity was 99.4%, positive predictive value was 97.8%, negative predictive value was 99.4%, overall accuracy was 98.7%, higher than other indexes. When SAP was Predicted by CRP, the overall accuracy was also high and reached 84.0%. CONCLUSION: PMN-E, CA-PLA2, CRP, and APACHE II are all indexes for the diagnosis of SAP. PMN-E is found to be the best index in predicting SAP. PMID- 17708838 TI - [Effects of carbachol on apoptosis of intestinal epithelial cells after gut ischemia/reperfusion in rat]. AB - OBJECTIVE: To investigate the effects of carbachol on apoptosis of intestinal epithelial cells in rats after gut ischemia/reperfusion (I/R). METHODS: A jejunal sac was formed in Wistar rats. The superior mesenteric artery (SMA) was occluded for 45 minutes followed by 240 minutes of reperfusion. Immediately after occlusion of SAM blood flow, either 0.1 mg/kg of carbachol or same amount of 0.9% saline normal was injected into the jejunal sac. Animals were randomized into three groups (each n=40): sham operation, I/R+normal saline injection (I/R model) and I/R+carbachol injection (0.1 mg/kg, Ca). The Pathological changes in gut epithelial cells were assessed by Chiu's scores. The apoptosis index of intestinal epithelial cell was determined with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. Expressions of caspase-3 and Bcl-2 in intestinal epithelial cells were assayed by immunohistochemistry method. All measurements were done at 0, 30, 60, 120 and 240 minutes after reperfusion. RESULTS: The Pathological injuries were less severe in Ca group than those in I/R model group. Apoptosis index of intestinal epithelial cell and expressions of caspase-3 were significantly decreased, while the expressions of Bcl-2 increased dramatically (all P<0.01) after I/R in Ca group compared with those in I/R model group, especially at 120 minutes after reperfusion. CONCLUSION: Enteral administration of carbachol can inhibit apoptosis of intestinal epithelial cells in rats after gut I/R injury. PMID- 17708840 TI - [Effect of the recombinant staphylokinase on pancreatic ischemia in severe acute pancreatitis of rats]. AB - OBJECTIVE: To investigate the changes in plasma endothelin-1 (ET-1) , von Willebrand factor (vWF), serum 6-keto-prostaglandin(1alpha) (PGF(1alpha)) , thromboxane B2 (TXB2), platelet aggregation rate maximum (PAGm) and pancreatic blood flow after reproduction of severe acute pancreatitis (SAP) in rat, and the effect of recombinant staphylokinase (r-Sak) on SAP. METHODS: Eighty-one SD rats were divided randomly into the sham-operated group (n=27), the SAP model group (n=27), and the r-Sak treatment group (n=27). SAP was produced by administration of 5% sodium taurocholate into the pancreatic duct. The abdomen of rats was opened at 6, 12 and 18 hours after reproduction of SAP for determining the pancreatic blood flow. Blood was obtained at 6, 12 and 18 hours after reproduction of SAP for determining the concentration of plasma vWF with enzyme labeled immunosorbent assay (ELISA). The concentration of plasma ET-1 and serum 6 keto-PGF(1alpha), and TXB2 were detected by radioimmunoassay. The PAGm induced by collagen and eicosanoids was assessed. RESULTS: Pancreatic blood flow in the SAP group appeared to have a decreasing trend at 6,12 and 18 hours after operation and were significantly decreased at all time points after reproduction of the model, compared with those of the sham-operated group (all P<0.05). The PAGm, content of plasma ET-1, vWF, and TXB2 were significantly increased at all time points after reproduction of the model, while 6-keto-PGF(1alpha) was significantly decreased, compared with those of the sham-operated group (all P < 0.05). Compared with SAP model group, PAGm, the content of plasma ET-1, vWF, and serum TXB2 in the r-Sak group were decreased at all time points, however, the content of serum 6-keto-PGF(1alpha) was increased (all P<0.05). CONCLUSION: The r Sak can improve pancreatic microcirculation and enhance pancreatic blood flow in rats with SAP, and may be beneficial in the treatment of SAP. PMID- 17708841 TI - [A study of expression of Tcf-4 in the small intestine mucosa crypt during severe abdominal infection]. AB - OBJECTIVE: To explore the expression of T cell factor 4(Tcf-4) in the process of severe abdominal infection in rats. METHODS: Forty healthy adult Wistar rats were randomly divided into control group (celiotomy only) and groups of 12, 24, 48 hours after establishment of abdominal infection. The latter groups included rats receiving cecal ligation and puncture (CLP) to establish the severe abdominal infection. Each group consisted of 10 rats. Immunohistochemistry (IHC) and reverse transcription-polymerase chain reaction (RT-PCR) were used to detect the number of Tcf-4-positive cells and expression of Tcf-4 mRNA in the crypts of the mucosa of the small intestine. RESULTS: It showed that the expression of Tcf-4 in the mucosal crypts of the small intestine in control group was weak but the number of cells with positive Tcf-4 expression was increased in crypts of small intestinal mucosa 12 hours after CLP, reaching its peak level at 24 hours, and remained higher than control group at 48 hours (all P<0.01). The transcription level of Tcf-4 was associated with the stages of the severe abdominal infection. RT-PCR showed that Tcf-4 mRNA was upregulated rapidly 12 hours after CLP (0.21+/ 0.01, P<0.01), and it reached peak level after 24 hours (0.28+/-0.02, P<0.01), decreased slowly but still obviously higher (0.20+/-0.01, P<0.05) than that of control group (0.19+/-0.01). CONCLUSION: The expression of Tcf-4 is induced by severe abdominal infection. The results suggest that Tcf-4 might be related with the proliferation and differentiation of intestinal stem cell during severe abdominal infection, and plays an important role in damage and repair of enteric mucosa. PMID- 17708842 TI - [Effect of L-Arginine on intestinal mucosal injury of rats with severe abdominal infection]. AB - OBJECTIVE: To investigate the effect of L-Arginine on intestinal mucosal injury of rats with severe abdominal infection. METHODS: Rats received cecal ligation and puncture (CLP) to reproduce sepsis model. A total of 18 Wistar rats were divided into two groups randomly (each n=9): L-Arginine group and model group. Three hundred mg/kg of L-Arginine was injected into the abdomen in rats of L- Arginine group after CLP. Model group received equal volume of normal saline. Blood sample was harvested and the serum levels of nitric oxide (NO) and inducible nitric oxide synthase (iNOS) were determined at 24 hours after operation in both groups. The histopathological change of intestinal mucosa was observed under light microscope and mucosa damage index was determined. RESULTS: The intestinal mucosal damage was observed both in model group and L- Arginine group after CLP, but the injury was milder in L- Arginine group. There was significant difference in mucosa injury index between L-Arginine group and model group (3.4+/-0.6 vs. 4.1+/-0.5, P<0.05). The serum level of NO [(76.1+/-26.2) micromol/L vs. (87.3+/-16.7) micromol/L, P>0.05] and iNOS [(30.6+/-7.4) U/L vs(44.4+/-6.6) U/L, P<0.01] in L-Arginine group were lower than those in model group. CONCLUSION: L-Arginine could protect against intestinal mucosal injury and depress the serum level of iNOS in severe abdominal infection of rats. PMID- 17708844 TI - [Effect of platelet activating factor receptor antagonist on the tight junction associated protein between the epithelial cells of intestinal mucosa during endotoxemia in young rats]. AB - OBJECTIVE: To investigate the effect of platelet activating factor (PAF) on the beta-catenin between the epithelial cells of intestinal mucosa during endotoxemia in rats, and to explore the mechanism of prospective effect of PAF receptor antagonist on intestinal epithelial barrier integrity. METHODS: Rat model of endotoxemia was reproduced by intraperitoneal injection of lipopolysaccharide (LPS). Rats receiving PAF receptor antagonist BN52021 5 mg/kg before and 30 minutes after LPS injection were taken as pretreatment group and treatment group, respectively. In control group, rats received normal saline instead of LPS. The ileum tissue was harvested at 1.5, 3, 6, 24, 48 and 72 hours after LPS injection. Immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) were used to determine beta-catenin protein and beta-catenin mRNA expression in intestinal mucosa. RESULTS: beta-catenin immunohistochemical labeling was evidently observed in the control rats, where beta-catenin labeling appeared mainly in the shape of lines defining the pericellular spaces between cells. This was in contrast to what was observed in rats after LPS challenge, where beta catenin labeling was substantially reduced or irregularly distributed around many cells. The beta-catenin contents of optical density average and beta-catenin mRNA were obviously decreased in the LPS challenge group compared with that in the control group (P<0.01). The content of beta-catenin mRNA significantly decreased at 3 to 24 hours(all P<0.01). The levels of beta-catenin protein and beta-catenin mRNA in pretreatment group and treatment group were higher than those in the LPS group at each time point but without statistically significant difference. CONCLUSION: PAF plays a role in the injury to intestinal mechanical barrier function during endotoxemia. Preventive and remedial use of PAF receptor antagonist BN52021 may alleviate intestinal injury. PMID- 17708846 TI - [Effect of early enriched parenteral alanyl-glutamine on heat shock protein 70 (HSP70) expression in critical patients]. AB - OBJECTIVE: To evaluate the effect of early parenteral glutamine (Gln) administration on heat shock protein (HSP70) expression and clinical outcome in critical patients. METHODS: Forty-four Patients requiring parenteral nutrition (PN) for more than 7 days, admitted to emergency intensive care unit (EICU) and neurosurgical intensive care units (NICU) were randomly divided into two groups, one was the control group, the other was the Gln treatment group (each n=22). Patients in both group received PN and enteral nutrition (EN). In addition, glutamine 0.4 g/kg per day was given to patients of Gln treatment group for 7 days. Serum HSP70, Gln concentrations were measured at admission and 7 days after the nutritional supplementation. Observations of clinical outcome included the length of mechanical ventilation, the length of stay in intensive care unit (ICU), the incidence of liver and kidney dysfunction before and after treatment. RESULTS: Serum HSP70 and Gln level showed no significant changes in control group and Gln treatment group before the treatment (both P>0.05), though they were mildly increased after conventional treatment compared with the control group, but without statistically significant difference. In Gln treatment group, between serum HSP70, Gln concentrations were significantly higher than those before treatment (both P<0.01), and they showed significant difference between control group and Gln group after treatment (both P<0.01). HSP70 level was significantly positively correlated with Gln level in critical patients (r=0.650 5, P=0.001). The ratios of liver dysfunction and the length of mechanical ventilation showed significant difference between Gln group and control group (both P<0.05). The ratios of kidney dysfunction and the length of stay in ICU showed no obvious changes between two groups (both P>0.05). CONCLUSION: Early parenteral glutamine administration can improve clinical outcome, decrease the ratio of organ dysfunction possibly by the mechanism of increasing serum HSP70 in critical patients. PMID- 17708847 TI - [Cholinesterase activity is not parallel to symptoms in patients suffering from organophosphorous pesticide poisoning through skin or by gastrointestinal tract]. AB - OBJECTIVE: To sum up the experience of treating patients suffering from organophosphorous pesticide poisoning either through skin or through gastrointestinal tract. METHODS: The cholinesterase activity was less than 0.50 in all patients. They were divided into two groups: poisoning through skin (skin group) and by gastrointestinal route (gastrointestinal group). The number of poisoning through skin or gastrointestinal tract was 34 (19 cases of middle degree and 15 cases of severe degree) and 50 (22 cases of middle degree and 28 cases of severe degree), respectively. The blood cholinesterase activities were determined during the disease course, the clinical symptoms and signs were recorded, and the quantity of atropine used for treatment in respective group was also recorded. RESULTS: There were no difference in the cholinesterase activities at the same degree between two groups before treatment (P>0.05). But the symptoms of the patients in gastrointestinal group were more serious than in skin group. The cholinesterase activities of the patients in the skin group were higher significantly than that in the gastrointestinal group at 24, 48 and 72 hours after treatment (P<0.05 or P<0.01). The total amount of atropine to achieve atropinization was less in the skin group than that of the gastrointestinal group. The time for restoration of cholinesterase activity was shorter in skin group than the gastrointestinal group (both P<0.01). CONCLUSION: With the same level of enzymatic activity of cholinesterase, the symptoms of the patients poisoned via gastrointestinal tract are more serious than poisoning through skin, and the quantity of atropine is used very much more. Reactivation of the cholinesterase is earlier in patients poisoned by skin route. PMID- 17708848 TI - [Effects of Xuebijing injection on protein C and tumor necrosis factor-alpha mRNA in rats with sepsis]. AB - OBJECTIVE: To investigate the effects of the integrated traditional Chinese medicine Xuebijing injection on protein C (PC) and tumor necrosis factor-alpha (TNF-alpha) mRNA in rats with sepsis. METHODS: Sepsis was induced in Wistar rats by cecal ligation and puncture (CLP). Ninety-six healthy animals were randomly divided into four groups: normal group, sham-operation group, CLP model group, and Xuebijing-treated group. The two latter groups were divided into 2, 8, 24, 48, and 72-hour subgroups with 8 rats in each subgroup. Platelet count of blood obtained from abdominal aorta was determined and tissue samples from liver and lungs were collected to measure tissue PC and TNF-alpha mRNA expression. RESULTS: PC gene expression levels in lung tissues were significantly lowered (all P<0.01), but they were dramatically raised by Xuebijing injection during 8-72 hours post-CLP (all P<0.01). Compared with normal group, TNF-alpha mRNA levels in liver and lungs were significantly elevated at 2 hours post-CLP (P<0.05 or P<0.01). However, treatment with Xuebijing injection markedly reduced TNF-alpha mRNA both in liver and lungs at 2-24 hours (P<0.05 or P<0.01). In CLP group, blood platelet count was significantly decreased to certain extent at different intervals within 8-72 hours, and it was markedly elevated in the Xuebijing treated group (P<0.05 or P<0.01). CONCLUSION: The current study suggests that Xuebijing injection could exert preventing effect on the development of severe sepsis by suppressing PC and TNF-alpha mRNA. PMID- 17708849 TI - [Reduction in cost of stay in intensive care unit with price education program of drugs]. AB - OBJECTIVE: To study if the cost of stay in intensive care unit (ICU) could be reduced by educating intensivists with price of drugs used in ICU. METHODS: A ten bed ICU of a teaching hospital, with admittance of about 40 patients every month, was involved, and cost of stay was charged by computer system, and it could be calculated and checked by computer on line. Firstly, the knowledge of the prices of 100 drugs usually used in ICU among the 7 intensivists was investigated, then an education program of drug price was launched to train the 7 intensivists,and they were urged those the drugs with lower price instead of higher price treatment results .Finally, the cost of stay in ICU for 2 months before and after the education program was analyzed and their difference was compared. RESULTS: The intensivists understood only the prices of 18% of drugs used in ICU. The cost of drugs was reduced by 8.6% during 2 months after education program (31.8%) compared with that before education program (40.4%), but there was no significant statistical difference (P>0.05). However, the cost of clinical examinations and check-up was lower after education than that before education (P<0.01). The total cost of stay in ICU was 5,688 yuan each day before education program and 5,267 yuan after education program. The total cost daily was reduced by 421 yuan, but with no significant statistical difference (P>0.05). CONCLUSION: The price education program of drugs can reduce the expense of drug and total cost of stay in ICU. PMID- 17708861 TI - [The nutrition and health status of children should be improved by increasing milk and its product consumption in their diets]. PMID- 17708863 TI - [The relationship of milk consumption and development of 3 - 6 years old preschool children]. AB - OBJECTIVE: To study the relationship between milk intake of 3 - 6 years old preschool children and their growth. METHODS: The data bank of 2002 China National and Health Survey were used to analyze the relationship of milk consumption and the growth of children aged 3 - 6 in urban and rural areas. RESULTS: The percentages of the diet with milk in urban and rural areas were 46.9% and 8.2% respectively, there was significant difference between the urban and rural areas. The averaged milk intake of preschool children were 23.8 g/d, the milk intake of urban children was significantly higher than that in the rural areas (P < 0.01). The height and weight of children with milk or its products in their diets in the group aged 4, 5 and 6 years were significantly higher than those of children without milk or its products in their diets (P < 0.05). CONCLUSION: There was close relationship between milk intake of children 3 - 6 years old and their growth, the volume of milk intake of preschool children should be improved in urban and rural areas. PMID- 17708864 TI - [Evaluation of milk intake and calcium supplement on bone mineral density and growth in children through Meta-analysis]. AB - OBJECTIVE: Based on peer-reviewed random-control studies, effects of calcium supplement and intake of milk on bone mineral density (BMD) and growth in children were evaluated. METHODS: Meta-analysis was applied to review published data in random-control studies related to the effects of calcium supplement and milk consumption on BMD, body height and body weight in children. RESULTS: Eleven peer-reviewed papers published during 1993 to 2006 were selected in this study. Homogeneity test showed that random effect model should be selected for weighting and pooling data. The combined means of improvement in BMD, height and body weight in children with milk intervention were 2.01 (0.92 - 3.09), 0.25 (0.09 - 0.41) and 0.63 (0.33 - 0.93), respectively, and the data from children with calcium intervention were 1.05 (0.66 - 1.43), -0.10 (-0.25 - 0.05) and -0.75 ( 1.98 - 0.49), respectively. CONCLUSION: Both milk and calcium intakes could improve BMD of children significantly, and the difference in BMD gain through milk intake was the same as that with calcium intervention, however, compared with the control group, increasing milk intake did significantly promote growth and development of children compared to the calcium supplement group. PMID- 17708865 TI - [The methods to reduce the prevalence of lactose intolerance in children]. AB - OBJECTIVE: To identify methods in reducing the prevalence of lactose intolerance in children. METHODS: A hydrogen respiration test (HRT) method was used in screening lactose intolerance (LI) subjects after taking 25 g of lactose among 106 children aged from 10 to 11 years old in a primary school located in the suburban area of Beijing. A cross-design was used to detect the effects of low lactose milk, yogurt and cereal-effect among 68 selected LI children. RESULTS: The incidence of LI was 80.2% after the children took 25 g of lactose, and after taking a 250 ml of full milk, lactase-fermented milk, coinfected milk, yogurt, or milk with meal, the LI incidences were 21.1% (12/57), 0% (0/25), 6.1% (2/33), 8.6% (3/35) and 13.6% (3/22) respectively. CONCLUSION: Low lactose milks and yogurt could reduce the LI incidence among LI children significantly. PMID- 17708866 TI - [Status and influencing factors of the duration of breast feeding in Shihezi]. AB - OBJECTIVE: To report the duration of breastfeeding among a population of Shihezi women and to identify factors that are associated with the duration of any breastfeeding. METHODS: A cohort study was performed among 399 infants and mothers randomly recruited both in the People's Hospital and the Maternal and Child Health Institute in 2003 in Shihezi City to investigate the feeding practices and feeding duration by month. Cox's proportional hazards model was used to identify factors that were associated with the risk for termination of breastfeeding before 24 months. RESULTS: The median of breastfeeding duration was 6 months (25% quartile was 5 months and 75% quartile was 11 months). A majority of infants were weaned in the sixth month. By 12 months, only 21.8% of infants were still receiving breastfeeding and 0.5% by 24 months. Breastfeeding duration was associated with mother's return to work. CONCLUSIONS: The duration of breastfeeding in Shihezi City was short. PMID- 17708868 TI - [Cross-sectional study on the current situation of breast feeding in western China rural areas]. AB - OBJECTIVE: To know the situation of breastfeeding of infants in western China rural areas. METHOD: Probability proportional to size sampling was used in 45 projects counties 10 provinces in western China, and then totally 13 433 children who were under 3 years old were selected to investigate their feeding situation and health situation by questionnaire. SPSS software was used to carry on the statistical analysis. RESULTS: The proportion of adding starch, egg, milk, bean, meat, vegetable and water was 75.3%, 58.4%, 39.0%, 26.4%, 42.7%, 52.0% and 93.4% respectively. The rate of exclusive breastfeeding of infant less than four months and six months was 16.0% and 2.5% respectively. The proportion of not adding starch, egg, milk, bean, meat, vegetable and water of infants who were one year old was 5.2%, 15.0%, 30.3%, 11.2%, 9.1%, 4.8% and 0.6% respectively. CONCLUSIONS: The rate of exclusive breastfeeding in western rural areas was still low and complementary feeding was still unreasonable. PMID- 17708870 TI - [Diagnosis, treatment and long-term following up of 223 patients with hyperphenylalaninemia detected by neonatal screening programs]. AB - OBJECTIVE: To investigate the incidence of hyperphenylalaninemia (HPA) caused by different etiologic factors in China and the relationship between the phenylalanine and mental development of patients with HPAs who were diagnosed by neonatal screening and early treated. METHODS: Two hundred and twenty-three patients with HPA detected by neonatal screening programs were refered to us at the age of (41 +/- 27) days after birth. The differential diagnosis was performed by BH(4) (20 mg/kg) loading test, urinary pterin analysis and dihydropteridine reductase (DHPR) activity determination respectively. The control of phenylalanine (Phe) metabolism, growth and mental development were evaluated in all treated patients. Related gene mutation analysis was performed in some patients RESULTS: One hundred and twenty-nine of 223 patients (57.8%) were diagnosed as phenylalanine hydroxylase deficiency (PAHD), 64 patients (28.7%) as BH(4) responsive PAHD, 30 patients (13.5%) as 6-pyruvoyl tetrahydropterin synthase deficiency (PTSD). One hundred and forty-nine patients were followed at age of 4 m - 2 y in our clinic. The 136 of 149 patients were treated according to different etiology at the age of 1.6 m (0.5 - 3.5 m) after birth. Thirteen patients were followed up without the need for treatment. All patients had normal growth development. One hundred and eight (79.4%) of 136 treated patients had normal mental development. The negative correlation (r = -0.439, P < 0.01) between IQ and average Phe levels were observed in 58 patients. Twenty-eight patients were able to go to primary school or even university. Nine kinds of PTS gene mutations were found in 9 cases with PTSD, among which 286G-->A and 259C-->T were most commonly seen, accounting for 45%. Seven kinds of PAH gene mutations were found in 13 cases with BH(4) responsive PAHD with the R241C (43.8%) mutation being the most frequent one. CONCLUSION: The differential diagnosis should be quickly made in all HPA patients detected by neonatal screening. Near 80% patients early treated had normal mental development. The good control of blood Phe level is a key factor for mental development. PMID- 17708869 TI - [Contribution of diabetes to the burden of diseases]. AB - OBJECTIVE: To overview the contribution of diabetes in the burden of diseases. METHODS: Based on the data published by MOH, prevalence rate, mortality rate, cause eliminated life year were used to calculate the health burden of disease. Meanwhile, direct economic burden of diseases was presented. RESULTS: According the calculation, about 23 million of people suffered from diabetes and 90,000 died from diabetes. The cause eliminated life year attributed to diabetes is different between urban and rural, 0.21 years for urban and 0.08 years for rural. Moreover, the direct economic burden reached 1.071 billion RMB, about 1.88% of national health expenditure at the same period. CONCLUSION: The burden of diabetes, based on calculation of both health and economic burden, and will give a heavy pressure to the government and society. PMID- 17708871 TI - [Study on the association between urinary organic arsenic and 8 hydroxydeoxyguanine in workers exposed to arsenic]. AB - OBJECTIVE: To evaluate the association between metabolism of arsenic and DNA oxidative damage in workers in a arsenic mill. METHODS: Urinary organic arsenic and 8-hydroxydeoxyguanine were detected in 37 workers highly exposed to arsenic and 16 administrative and logistic staff with mild exposure in a arsenic mill in Yunnan province, and also 28 local people who did not have the exposure in the near past time. The correlation between metabolism of arsenic and DNA oxidative damage was evaluated. RESULTS: The urinary organic arsenic concentration was respectively (0.48 +/- 0.37) mg/L and (0.08 +/- 0.05) mg/L for men with high and low exposure, and was respectively 0.11 mg/L and (0.30 +/- 0.24) mg/ L for women with high and low exposure, while it was lower than 0.02 mg/L in the controls. Urinary 8-hydroxydeoxyguanine concentration was (18.07 +/- 11.68) micromol/mol creatinine, (11.79 +/- 8.25) micromol/mol creatinine, (10.07 +/- 3.04) micromol/mol creatinine for the males with high and low exposure and of controls, respectively, (P < 0.05), and it was 84.35 micromol/mol creatinine, (21.27 +/- 5.89) micromol/mol creatinine, (14.43 +/- 2.58) micromol/mol creatinine for females with high and low exposure and of controls, respectively. The female workers exposed to arsenic had higher urinary 8-hydroxydeoxyguanine levels than males did (P < 0.05). The increased tendencies of urinary 8-hydroxydeoxyguanine levels with the organic arsenic concentration were found in workers (r(s) = 0.279, P = 0.019). CONCLUSION: Occupational individuals exposed to arsenic have obvious DNA oxidative damage, which is more severe in females. The difference of metabolism of arsenic may play a key role. PMID- 17708872 TI - [Quality of life and hostile mentality trend among 299 patients living with HIV/AIDS]. AB - OBJECTIVE: To assess the quality of life (QOL) and hostile mentality trend (HMT) of 299 patients living with HIV/AIDS (Human immunodeficiency virus/Acquired immune deficiency syndrome) in three provinces in China, and to understand the major concerns of the these patients. METHODS: The SF-36 (short form -36) was used for assessing the QOL among 299 HIV-infected patients in Sichuan, Hubei and Guizhou provinces. Reliability and validity of SF-36 were evaluated. Consulting with experts and professionals, seven additional items were developed to evaluate the HMT. Mean scores of the 8 scales were compared between the patients and general rural residents in Sichuan province. RESULTS: For SF-36, internal consistent coefficients (Cronbach's alpha) of the 8 scales were between 0.75 to 0.90, test-retest reliability coefficient ranged from 0.54 to 0.80. The item subscale correlation coefficients ranged from 0.46 to 0.97. Mean scores of the 8 scales of the patients ranged from 28.50 to 77.87, and 70.27 to 91.87 for the general rural residents. The variations of the scales were tested by means of Mann-Whitney test with u value ranged from -17.43 to -23.87. The QOL of the patients living with HIV/AIDS were significantly inferior to those of general population (all P < 0.01). The mean scores of the seven items to evaluate HMT ranged from 46.21 to 82.89. The major concerns of the patients living with HIV/AIDS included financial insecurity and family responsibilities, followed by death threat and no cure of HIV/AIDS. CONCLUSION: The SF-36 is a reliable instrument for assessing QOL of patients living with HIV/AIDS. The QOL of the patients living with HIV/AIDS in China is poor. PMID- 17708873 TI - [A case-control study on the relations between insulin resistance and essential hypertension in YI NATIONALITY living in Liangshan, Sichuang Province]. AB - OBJECTIVE: To determine whether insulin resistance (IR) was associated with essential hypertension (EH) in YI nationality living in Liangshan, Sichuang Province. METHODS: A case-control study consisting of 113 YI hypertensives as cases and 156 YI normotensives as controls were conducted to investigate the level of fasting glucose (FG) and fasting insulin (FINS), and insulin resistance index was used as the indicator of IR. RESULTS: It was found that impaired fasting glucose (IFG) and IR were associated with EH significantly among YI migrants, and OR (95% CI) were 3.98 (2.14 approximately 7.42, P < 0.001) and 2.55 (1.35 approximately 4.83, P = 0.004) respectively. Being stratified by sex, both IFG and IR were associated with EH significantly among YI male migrant, and OR were 4.31 (2.01 approximately 9.24, P < 0.001) and 3.14 (1.45 approximately 6.82, P = 0.003) respectively; but only IFG was associated with EH significantly among YI female migrant and OR was 3.46 (1.17 approximately 10.22, P = 0.022). Among YI farmers, both IFG and IR were not associated with EH significantly. The non conditional logistic regression analysis showed that IR was associated significantly with EH among YI migrants. This was not as same as observed in YI farmers. CONCLUSION: It is likely that IR is the risk factor of EH among YI migrants in our study. However, the association between IR and EH among YI farmers needs some further studies. PMID- 17708874 TI - [Study on prevalence and risk factors of sleep disorder among Chinese children aged 0 to 23 months in city]. AB - OBJECTIVE: To investigate the prevalence and main influences on sleep disorder among Chinese children aged 0 to 23 months, as to providing scientific interventions for infant sleep disorder. METHODS: All 7601 children under two years old were selected by stratifying samples from twelve cities in China. The objects' parents were surveyed with questionnaire. All data were analyzed with SPSS statistical software. RESULTS: The total incidence of sleep disorders at 0 to 23 months was 21.94%. The main problems were difficulty falling asleep, nighttime waking and snoring. Feeding manner, sleep environment, sleep-associated habits and medical conditions were all influences on infant's sleep disorder. CONCLUSIONS: Enhancing sleep health education to change parents' nurturing modes should be an important role in preventing infant sleep disorders. PMID- 17708875 TI - [Investigation on status of pollution of vibrio cholera in seafood and aquatic products in 12 provinces of China in 2005]. AB - OBJECTIVE: To understand the pollution rates of vibrio cholera (V. cholera) in different seafood, aquatic products and their circulatory processes, so as to help making measures for cholera control and prevention. METHODS: Different seafood, aquatic products and breed water specimen collected from 12 provinces of China were tested from July to September in 2005. RESULT: A total of 12 104 samples of seafood and aquatic products were tested and the average pollution rate of vibrio cholera was 0.52%. The positive isolate rate of turtle sample (1.72%) was the highest among all samples. The second higher isolated rate was 1.14% in water specimen of turtle breed pool. The positive rate of bullfrog was 0.50%. The percentage of toxin strains was 47.54% and 79.31% of them were isolated from turtle and water samples of turtle breed pool. The important sector of the pollution of vibrio cholera was in turtle breed pool (2.38%). CONCLUSION: The average pollution rate of vibrio cholera in seafood and aquatic products in 12 provinces of China was low. It should be very necessary to supervise the sanitation in turtle breed for controlling and preventing the vibrio cholera. PMID- 17708876 TI - [Effects of folic acid, vitamin B(6) and vitamin B(12) on learning and memory function in cerebral ischemia rats]. AB - OBJECTIVE: To investigate the effects of folic acid, vitamin B(6) and B(12) on plasma homocysteine and on learning and memory functions in focal cerebral ischemia rats. METHODS: Sprague-Dawley rats were randomly divided into four groups. They were sham operation group (Sham OP), middle cerebral artery occlusion model group (MCAO), MCAO + folic acid group (MCAO + FA) and MCAO + compound vitamin (folate, vitamin B(6) and B(12)) group (MCAO + CV). Plasma homocysteine was measured before and after supplementation and after ischemia. RESULTS: The level of plasma homocysteine in MCAO + FA and MCAO + CV groups were significantly lower than those in Sham OP and MCAO groups after supplementation and ischemia (6.92 +/- 1.04) micromol/L and (5.49 +/- 1.00) micromol/L vs (9.33 +/- 1.11) micromol/L, (10.90 +/- 2.03 micromol/L), P < 0.05. While in MCAO + CV group was lower than that in MCAO + FA group (5.49 +/- 1.00) micromol/L vs (6.92 +/- 1.04) micromol/L, P < 0.05. The neurological deficit scores and shock times in Y-type maze of MCAO + FA and MCAO + CV groups were lower than those in MCAO group (1.75 +/- 0.46 and 1.38 +/- 0.52 vs 2.62 +/- 0.52; 123.50 +/- 39.77 and 86.25 +/- 21.39 vs 173.25 +/- 46.32, P < 0.05). The correct times of MCAO + CV group in Y-type maze was higher than that in MCAO group (3.75 +/- 0.42 vs 2.12 +/ 0.45, P < 0.05). CONCLUSION: Folic acid intake could not only reduce plasma homocysteine concentration but also promote the recovery of the learning and memory functions of rats with cerebral ischemia. The effects of folic acid combined with vitamin B(6) and vitamin B(12) on cerebral ischemia rats was better than that of single folate. PMID- 17708890 TI - Roles for endocytosis in lentiviral replication. AB - Endocytosis is essential for the entry of many viruses into cells. The primate lentiviruses [human immunodeficiency virus (HIV) 1 and 2, and the simian immunodeficiency viruses (SIVs)], however, use endocytosis in other aspects of their life cycles. Here, the authors describe the ways in which the endocytic pathway is used by HIV and SIV and discuss the mechanisms through which endocytosis may contribute to the pathogenic properties of these viruses. PMID- 17708891 TI - Cell-to-cell transport of macromolecules through plasmodesmata: a novel signalling pathway in plants. AB - Cell-to-cell communication is vital to the growth and development of multicellularly structured organisms. Recent studies have demonstrated that plants have an endogenous machinery to transport macromolecules such as proteins and nucleic acids between cells through plasmodesmata. Such transport may be a novel means of cell-to-cell signalling. Here, Biao Ding discusses the mechanisms underlying this newly discovered biological function. PMID- 17708892 TI - Mechanisms restricting DNA replication to once per cell cycle: the role of Cdc6p and ORC. PMID- 17708893 TI - Understanding covalent modifications of proteins by lipids: where cell biology and biophysics mingle. AB - Much effort has been expended on the in vitro characterization of enzymes that covalently attach lipids to proteins. Less information is available about properties conferred on modified proteins by their attached lipid groups, but biophysical studies of simple model systems have begun to shed light on this issue. Recent evidence suggests that the specificity of lipid modifications may be dependent upon the intracellular compartmentalization of the lipid and protein substrates of lipidating enzymes. The function and targeting of their lipidated products appear to be regulated dynamically through addition or subtraction of lipid moieties, other covalent or noncovalent modifications, as well as several devices that at this point can only be inferred. This field of research illustrates the necessity of integrating cell-biological and biophysical perspectives. PMID- 17708894 TI - Light signal transduction in plants. AB - Light signal-transduction pathways are a central component of the mechanisms that regulate plant development. These pathways provide the means by which information from specific wavelengths of light may be amplified and coordinated, resulting in complex physiological and developmental responses. This review focuses upon recent approaches towards establishing the intermediates that transmit signals from photoreceptors, phytochromes in particular, to target elements in the promoters of light-regulated genes. PMID- 17708896 TI - A passionate few days in the forest. PMID- 17708895 TI - Endocytosis and secretion in trypanosomatid parasites - Tumultuous traffic in a pocket. AB - Trypanosomatids are flagellated protozoan parasites of invertebrates, vertebrates and plants. Some species, found in the subtropics and tropics, cause chronic diseases in humans and domestic animals. The surface of the trypanosomatid provides a shield against environmental challenges, ligands for interaction with host cells, as well as receptors and transporters for the uptake of nutrients. Communication between the parasite and its environment is confined to the flagellar pocket, an invagination of the plasma membrane around the base of the flagellum. In this review, the authors discuss endocytosis, secretion and membrane trafficking in Trypanosoma and Leishmania. PMID- 17708897 TI - New faces for the new year. PMID- 17708898 TI - Extracellular matrix: the central regulator of cell and tissue homeostasis. PMID- 17708899 TI - Clathrin-associated adaptor proteins - putting it all together. AB - Adaptors are multifunctional linker proteins that, as a coated vesicle assembles, tether the clathrin lattice to the underlying membrane bud site. Each adaptor is composed of four distinct protein submits, but how these assemble into the functional complex is not clear. Here, some features of the protein sequences are discussed in an attempt to develop a speculative, low-resolution structural model of possible subunit interactions. PMID- 17708900 TI - Clathrin assembly: phosphorylation and peptides provide new tools. PMID- 17708901 TI - Netrins find their partners. PMID- 17708902 TI - P53 and IRF-1: two players in the same game? PMID- 17708903 TI - Cutting and pasting chromosomes in vivo. PMID- 17708904 TI - The ins and outs of HIV endocytosis. PMID- 17708905 TI - BIME joins the destruction team. PMID- 17708906 TI - Endoplasmicreticulum-induced signal transduction and gene expression. AB - Cells can respond to perturbations in endoplasmic reticulum (ER) function by activating two distinct signal-transduction pathways: one responds to unfolded proteins, the other to an overload of the organelle with membrane proteins. A third pathway is activated upon sterol depletion of cells and involves the cleavage and subsequent nuclear translocation of an ER membrane-bound transcription factor. Thus, three distinct pathways each activated by a different signal are currently known to project from the ER into the nucleus. This review summarizes the current understanding of these three pathways. PMID- 17708907 TI - Prion protein and the transmissible spongiform encephalopathies. AB - Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases that occur in a wide variety of mammals. In humans, TSE diseases include kuru, sporadic and iatrogenic Creutzfeldt-Jakob disease (CJD), Gerstmann Straussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI). So far, TSE diseases occur only rarely in humans; however, scrapie is a widespread problem in sheep, and the recent epidemic of bovine spongiform encephalopathy (BSE or mad cow disease) has seriously affected the British cattle industry. Of special concern is the recent appearance of a new variant of CJD in humans that is suspected of being caused by infections from BSE-infected cattle products. In all these diseases, an abnormal form of a host protein, prion protein (PrP), is essential for the pathogenic process. The relationship of this protein to the transmissible agent is currently the subject of great interest and controversy and is the subject of this review. PMID- 17708908 TI - Cell-cycle control: POLO-like kinases join the outer circle. AB - Named after the polo gene of Drosophila, POLO-like kinases (PLKs) constitute a novel, evolutionarily conserved family of essential cell-cycle regulators. As emphasized in this review, recent studies identify important roles for vertebrate PLKs at the onset of mitosis: Plx1, a Xenopus PLK, has been implicated in the activation of Cdc25 phosphatase (and hence the activation of Cdc2), while human Plk1 is required for the proper maturation of the poles of mitotic spindles. These studies suggest a major role for Plk1/Plx1 in coordinating spindle assembly with the activation of Cdc2-cyclin complexes, and they establish a direct link between PLKs and the core cell-cycle-regulatory machinery. Genetic and biochemical studies in yeasts and Drosophila point to additional roles for PLKs at later stages of mitosis. Finally, mammals express multiple PLKs, suggesting that different family members might function at distinct cell-cycle transitions, reminiscent of cyclin-dependent kinases. PMID- 17708909 TI - Nuclear envelope assembly after mitosis. AB - In higher eukaryotes, the entire nucleus disassembles during prometaphase of the cell cycle and later reassembles around daughter chromosomes. Remarkably, the complex events that occur to create a functional nucleus in vivo can be duplicated in vitro by using cell-free extracts. Current experiments are aimed at understanding the molecular mechanisms of assembly and disassembly of the nuclear pore complexes and nuclear membranes, and the functional roles of four identified inner membrane proteins, two of which bind to both chromatin and the nuclear lamina. PMID- 17708910 TI - Pictures in cell biology Forever blebbing - a story of extended apoptosis. PMID- 17708911 TI - Measurement of intracellular pH and pCa with a confocal microscope. AB - In the late 1980s, the field of biological confocal microscopy exploded. So did traffic on the Internet. Considering the ongoing interest in the role of intracellular pH and pCa in all aspects of cell physiology, it is not surprising that the most frequently asked question on the Internet's confocal forum has been: 'How do I measure pH/pCa with a confocal microscope?' This article was inspired by these Internet discussions and attempts to answer this question by presenting the rationale for using (or not using) a confocal approach to measure intracellular ion concentration, assessing the feasibility of performing this task with currently prevailing hardware, assembling the currently available 'know how' and telling 'how'. PMID- 17708912 TI - An immersion in nucleocytoplasmic transport at the Garda lake. PMID- 17708913 TI - Annexins. AB - Ten years after the discovery of annexins, we are just understanding the functions of these enigmatic proteins, been a frustrating decade for those in this field because appear capable of performing a multitude of function: to the sceptic apparently do nothing in vivo. Their in including inhibition of phospholipase A(2), promotion fusion, anticoagulation and formation of ion channel documented and have proved fertile ground for function In this review, Stephen Moss discusses new findings the view that, despite their many similarities, annexins divers activities in fundamentally important areas of a. PMID- 17708914 TI - Protein translocation at the ER membrane: A complex process becomes more so. AB - Protein transport across or insertion into a membrane is facilitated by multicomponent protein complexes that reside in the bilayer. Current models propose that these complexes mediate translocation and integration by an obligate sequence of interactions between the substrate polypeptide and other components. Recent discoveries extend and complicate these models, but, more importantly, they remind us that our current level of understanding of the actual molecular mechanisms involved is crude and represents only the tip of the iceberg. PMID- 17708916 TI - Coats and vesicle budding. AB - Transport vesicles need coat proteins in order to form. The coat proteins are recruited from the cytosol onto a particular membrane, where they drive vesicle budding and select the vesicle cargo. So far, three types of coated transport vesicles have been purified and characterized, and candidates for components of other types of coats have been identified. This review gives a brief overview of what is known about the various coats and their role in transport vesicle formation. PMID- 17708915 TI - Recent advances on cyclins, CDKs and CDK inhibitors. AB - In eukaryotes, cell division is controlled by cyclin-dependent kinases (CDKs). Here we summarize a few new developments on the regulation of the cell cycle by CDK-cyclin complexes. We have focused on three aspects in which there has been recent progress: the structural analysis of these complexes, the phenotypes of mice carrying knockouts of CDK inhibitors and the role of proteolysis in the regulation of the cell cycle. PMID- 17708917 TI - Import of proteins into mitochondria and chloroplasts. AB - Although mitochondria and chloroplasts synthesize some of their own proteins, they must import most of them from the cytosol. Import is mediated by molecular chaperones in the cytosol, receptors and channels in the organelle membranes and ATP-driven 'import motors' inside the organelles. Many of these components are now known, allowing informed guesses on how they might work. PMID- 17708918 TI - Cell adhesion - spreading frontiers, intricate insights. AB - Cell-cell and cell-matrix adhesions play important roles in determining the structural organization and behaviour of cells in tissues. These adhesions are mediated by specific cell-surface receptors that are linked to the actin cytoskeleton through submembranous multiprotein complexes that also serve to generate intracellular signals. The molecular mechanisms by which regulation of cell adhesiveness is coordinated with other aspects of cell behaviour are now under study and some aspects of this are highlighted in this short review. New scope for analysis of the roles of individual adhesion molecules in vivo is being provided by mouse gene knockouts. PMID- 17708919 TI - Apoptosis: alive and kicking in 1997. AB - The various cellular signalling pathways and biochemical activities involved in apoptotic death are now under intense study in many different laboratories. Recent studies using both molecular cloning approaches and in vitro systems have identified a class of highly specific cellular proteases, termed caspases, that appear to have important roles in apoptotic execution. One of these enzymes may lie near the head of the death pathway in certain cells, whereas others may be involved in the final stages of cellular disassembly. Other recent studies using both live cell and in vitro systems have suggested that mitochondria have an essential role in apoptosis. Mitochondria apparently release at least two factors - a protease and cytochrome C - that are capable of triggering apoptotic changes in isolated cell nuclei. The release of the apoptogenic protease appears to be under the control of the Bcl-2 gene product. PMID- 17708920 TI - MHC class II molecules: transport pathways for antigen presentation. AB - During biosynthesis, MHC class II molecules travel through the endocytic pathway and interact with antigenic peptides before their stable insertion in the plasma membrane. The process of class II association with these peptides and their final deposition at the cell surface are essential steps in boosting specific antibody responses. Therefore, the study of class II molecules is important in understanding how cell-biological events can direct an immune response. PMID- 17708921 TI - Unconventional myosins: new frontiers in actin-based motors. AB - The unconventional myosins are a superfamily of actin-based motors responsible for a rich array of intracellular motility events. Recent evidence suggests that these motors play important roles in cell migration, endocytosis and intracellular transport. Several genetic mutants have been identified whose abnormalities are the result of the loss of a specific myosin. This article describes how analysis of these mutants, coupled with basic studies of the intracellular localization and biochemical properties of individual myosins, is leading to a clearer understanding of the in vivo function of a number of these interesting motor proteins. PMID- 17708922 TI - Protein sorting by tyrosine-based signals: adapting to the Ys and wherefores. AB - The endocytic and secretory pathways of eukaryotic cells consist of an array of membrane-bound compartments, each of which contains a characteristic cohort of transmembrane proteins. Understanding how these proteins are targeted to and maintained within their appropriate compartments will be crucial for unravelling the mysteries of organelle biogenesis and function. A common event in the sorting of many transmembrane proteins is the interaction between a sorting signal in the cytosolic domain of the targeted protein and a component of an organellar protein coat. Here, we summarize recent findings on the mechanism of sorting by one type of signal, characterized by the presence of a critical tyrosine (Y) residue, and attempt to integrate these findings into a hypothetical model for protein sorting in the endocytic and late (post-Golgi) secretory pathways. PMID- 17708923 TI - Molecular chaperones: towards a characterization of the heat-shock protein 70 family. AB - The characterization of molecular chaperones is of central importance for an understanding of cellular protein-folding reactions. Numerous biochemical and genetic studies have now been complemented by the high-resolution structures of Hsp70 and GroEL, representatives of the two major classes of chaperone proteins, and the availability of a complete eukaryotic genome, revealing the presence of 14 distinct genes for Hsp70s in the yeast Saccharomyces cerevisiae. Here, the authors focus on recent progress in understanding the interactions of Hsp70s with their substrates and the enzymology of their regulation. PMID- 17708924 TI - Protein phosphorylation and the nuclear organization of pre-mRNA splicing. AB - Controlled execution of transcription and pre-mRNA splicing is crucial for proper gene expression. The organization of these essential events within the cell nucleus is only beginning to be understood. Here, we describe a model for the cellular arrangement of transcription and pre-mRNA splicing based on recent biochemical and morphological data: transcription and pre-mRNA splicing are spatially and temporally coordinated, and protein phosphorylation regulates both the activity and the subnuclear localization of pre-mRNA splicing factors in nuclear subcompartments. PMID- 17708926 TI - TSG101: a new culprit in breast cancer. PMID- 17708925 TI - Cell biology and the genome projects a concerted strategy for characterizing multiprotein complexes by using mass spectrometry. AB - New developments in biological mass spectrometry and the growth of sequence databases are revolutionizing protein analysis. As recent results demonstrate, the high sensitivity and high throughput of this approach allow the rapid characterization of gel-separated proteins and the identification of cognate cDNA and expressed-sequence tag (EST) clones. We advocate here exploiting this new technology for the systematic characterization of multiprotein complexes. The analysis of proteins as components of specific complexes provides an immediate link to biological function and is a powerful method for deciphering the functions of open reading frames uncovered in the genome-sequencing projects. PMID- 17708928 TI - Ironing out the wrinkles of cytokinesis. PMID- 17708927 TI - Stop signal for neurons put on hold. PMID- 17708930 TI - Nuclear transport: probing the GAP. PMID- 17708929 TI - What's going on? PMID- 17708931 TI - Gagging the secretory pathway. PMID- 17708932 TI - Integrins, adhesion and apoptosis. AB - Integrin-mediated adhesion to extracellular matrix proteins is required for survival of many cell types. This phenomenon appears to be a mechanism of tumour suppression and to participate in embryogenesis. Here, our current understanding of how integrin-dependent signals prevent apoptosis and implications of anchorage dependent survival for development, physiology and pathology are discussed. PMID- 17708933 TI - ER-associated and proteasomemediated protein degradation: how two topologically restricted events came together. AB - A protein-degradation pathway associated with the endoplasmic reticulum (ER) can selectively remove polypeptides from the secretory pathway. The mechanisms of this ER-associated protein degradation were obscure, but recent studies using both yeast and mammalian cells have indicated that substrates for degradation are targeted to the cytosol where proteolysis is catalysed by the proteasome. The degradation process is now known to comprise at least three distinct events: first, recognition of a polypeptide for degradation; second, efflux of this substrate from the ER to the cytosol; and, finally, degradation by the proteasome. This review summarizes recent advances in understanding how each of these steps is achieved. PMID- 17708934 TI - Cdc37: a protein kinase chaperone? AB - The activity of most protein kinases is highly regulated, typically via phosphorylation and/or subunit association. However, the folding of protein kinases into an active state or a form capable of activation is now emerging as another important step through which they can be regulated. The 50-kDa protein Cdc37 and the associated heat-shock protein Hsp90 have been found to bind to, and be required for the activity of, diverse protein kinases, including Cdk4, v-Src, Raf and SEVENLESS. Together, Cdc37 and Hsp90 may act as a general chaperone for protein kinases, in particular those involved in signal-transduction pathways and cell-cycle control. PMID- 17708935 TI - Emerging from the Pak: the p21-activated protein kinase family. AB - The p21-activated protein kinases (PAKs) are members of a growing family of regulatory enzymes that may play roles in diverse phenomena such as cellular morphogenesis, the stress response and the pathogenesis of AIDS. PAKs were initially discovered as binding partners for small (21 kDa) GTPases that regulate actin polymerization, and recent evidence has shown that some members of the PAK family may be effectors for related GTPases that are involved in intracellular vesicle trafficking. Because the downstream signalling pathways for all such GTPases are poorly understood, intense studies are under way to discern the role of PAK and its cousins. In this review, the authors highlight some of the established properties of the extended PAK family and discuss current controversies regarding their possible roles as GTPase effectors. PMID- 17708936 TI - Proteome analysis: from protein characterization to biological function. PMID- 17708937 TI - New fashions in vesicle coats. AB - Clathrin-coated vesicles are responsible for the sorting transport of membrane proteins within cells. Their co of the self-assembling protein clathrin, and adaptor r. interact with the vesicle cargo and localize clathrin tc Recently, novel clathrin-like and adaptor-like proteins identified. Here, Frances Brodsky discusses various in these findings, including the possibility that the novel expanded functions beyond the conventional roles of the in coated-vesicle formation. In this context, the mech which coats influence vesicle formation is reconsidere. PMID- 17708938 TI - Rab, GAP and GEP make three. PMID- 17708939 TI - Angiostatic therapy gets moving. PMID- 17708940 TI - The convoluted nucleus. PMID- 17708941 TI - Phosphorylation makes cyclin (B)eeline for the nucleus. PMID- 17708942 TI - Pieces of eight: bioactive fragments of extracellular proteins as regulators of angiogenesis. AB - Specific stages of angiogenesis are regulated by extracellular proteins. This review discusses the endogenous proteolysis of eight of these proteins and the release of polypeptide fragments that have biological activities different from those of the native, parent protein. The generation of natural cleavage products could provide a precise mechanism for the regulation of angiogenesis. Although further experimental confirmation of this mechanism is needed, this leitmotif offers an attractive explanation, in part, for the complex role of proteolysis in vascular morphogenesis. PMID- 17708943 TI - TGF-beta signalling through the Smad pathway. AB - Trans forming growth factor beta(TGF-beta) and related cytokines regulate cell fate by signalling through two receptor serine kinases that act in sequence. Signalling by these receptors is mediated by the recently identified Smad protein family. Upon phosphorylation by activated receptors, Smads form complexes, move into the nucleus, associate with DNA-bindingproteins and activate gene transcription. Responses mediated by Smads include crucial morphogenic events during fly and frog development as well as cell-cycle arrest in mammalian cells. Furthermore, Smads that mediate growth-inhibitory responses are tumour suppressors mutated in cancer. This review describes how the discovery of the Smad family lets us, for the first time, trace a signalling pathway from TGF-beta receptors to target genes. PMID- 17708944 TI - Calnexin, calreticulin and the folding of glycoproteins. AB - Calnexin and calreticulin are molecular chaperones in the endoplasmic reticulum (ERJ. They are lectins that interact with newly synthesized glycoproteins that have undergone partial trimming of their core N-linked oligosaccharides. Together with the enzymes responsible for glucose removal and a glucosyltransferase that re-glucosylates already-trimmed glycoproteins, they provide a novel mechanism for promoting folding, oligomeric assembly and quality control in the ER. PMID- 17708945 TI - Heterochromatin: a meiotic matchmaker? AB - During meiosis, the pairing of chromosomes is crucial for a successful partitioning of the genetic material and its transmission into the developing gamete. The classical view of meiotic pairing involves recombination between homologues as an integral part of the pairing mechanism. But, in cases where no recombination occurs, how do chromosome partners find one another? And how do they pair up and then segregate appropriately? Recently, a combination of molecular genetics and fluorescence in situ hybridization appears to have provided an answer to these questions by demonstrating a crucial role for heterochromatin in chromosome pairing. PMID- 17708946 TI - Membrane protein biosynthesis - all sewn up? AB - The biosynthesis of integral membrane proteins requires regions of nascent polypeptide to be inserted into, and assembled within, a lipid bilayer. Membrane protein integration at the endoplasmic reticulum (ER) has been shown to involve a defined set of protein components. In addition, thephospholipid bilayer may also make a specific contribution to a functional ER integration site. This review focuses on recent studies of membrane protein insertion and subsequent maturation events, both of which are prerequisites for the synthesis of functional integral membrane proteins. PMID- 17708947 TI - Techniques update The Sos-recruitment assay - a new type of two-hybrid system. PMID- 17708948 TI - Src: more than the sum of its parts. AB - The Src family of protooncoproteins is required for prc through at least two phases of the cell cycle and for sc cell-type-specific functions. Recent crystal structures of fragments of two representatives reveal a compact am their Src homology 3 (SH3), SH2 and catalytic domai embodies an unexpected mechanism of regulation. Th. the enzymatic activity of Src is controlled by intramol associations between the SH2 domain and C-tail and SH3 domain and a surprising internal target. The stn highlight a mechanism by which substrates can comp internal sequences for binding to the SH3 and SH2 do thereby stimulating kinase activity. This implies that distinction between upstream activators and downstre will sometimes be ambiguous. PMID- 17708949 TI - A model for sperm-egg binding and fusion based on ADAMs and integrins. AB - Once a sperm meets an egg, several events must occur in order for fertilization to proceed. Sperm must bind to the zona pellucida, undergo the acrosome reaction, penetrate the zona pellucida and then bind to and fuse with the egg plasma membrane. Shortly thereafter, the egg must be activated for zygotic development. This review focuses on mammalian sperm-egg plasma membrane binding and fusion, and in particular on the roles of two families of cell-adhesion molecules, ADAMs and integrins, in this important union. PMID- 17708950 TI - Nonclassical protein sorting. AB - Recent characterization of the major protein-targeting systems in both yeast and mammalian cells has provided detailed descriptions of how cellular transport processes operate. Increasingly, however, novel protein-sorting mechanisms are being uncovered. These newly discovered 'alternative' mechanisms of protein sorting ensure accurate delivery of numerous cellular constituents either to their resident compartment or, in many cases, to the cellular protein-degradation machinery. Like the better characterized 'classical' protein-sorting systems, 'nonclassical' targeting mechanisms involve both membrane translocation through protein channels and vesicle-mediated transport. This review discusses our current understanding of these nonclassical protein-sorting pathways and their role in eukaryotic cells. PMID- 17708951 TI - The p300/CBP family: integrating signals with transcription factors and chromatin. AB - Studies on the mechanisms through which the oncogene products of DNA tumour viruses subvert the physiological processes that control cell proliferation have yielded many important insights into the mammalian cell cycle. In the case of the adenovirus E1a oncoprotein, a number of distinct protein domains are required for it to exert its growth-promoting effects. These domains allow E1a to associate physically with and inactivate cellular proteins that normally restrain proliferation. Recently, a group of E1a-interacting proteins discovered in part through studies on viral oncoproteins has become a major focus of research activity. Members of this family, known as p300/CBP, function to regulate transcription and chromatin, and thereby enable diverse signals, particularly those that facilitate differentiation, to be integrated and coordinated with gene expression. Furthermore, accumulating evidence connects genes encoding p300/CBP with diseases such as cancer. PMID- 17708952 TI - Regulatory recruitment of signalling molecules to the cell membrane by pleckstrinhomology domains. AB - Pleckstrin-homology (PH) domains are small protein modules found in more than 100 proteins, most of which require association with the cell membrane to mediate their biological functions. Recent studies have demonstrated that some PH domains bind specifically to phosphoinositides, and that PH-domain-mediated recruitment of certain proteins to the cell membrane is important in regulation of their activities or functions. This provides the cell with a simple and efficient mechanism for linking growth-factor-induced changes in the levels of specific membrane phosphoinositides with other signalling pathways that control diverse processes such as protein synthesis, DNA synthesis and cell adhesion. PMID- 17708953 TI - Neurofilaments and motor neuron disease. AB - Amyotrophic lateral sclerosis (ALS) is an adult-onset and heterogeneous neurological disorder that affects primarily motor neurons in the brain and spinal cord. Although multiple genetic and environmental factors might be implicated in ALS, the striking similarities in the clinical and pathological features of sporadic ALS and familial ALS suggest that similar mechanisms of disease may occur. A common and perhaps universal pathological finding in ALS is the presence of abnormal accumulations of neurofilaments (often called spheroids or Lewy body-like deposits) in the cell body and proximal axon of surviving motor neurons. Such neurofilament deposits have been widely viewed as a consequence of neuronal dysfunction, perhaps reflecting axonal transport defects. This review discusses the emerging evidence, based primarily on transgenic mouse studies and on the discovery of deletion mutations in a neurofilament gene associated with ALS, that neurofilament proteins can play a causative role in motor neuron disease. PMID- 17708954 TI - CFTR:a multifaceted epithelial molecule. PMID- 17708955 TI - Nuclear moguls meet. PMID- 17708956 TI - Is dynamin really a 'pinchase'? AB - The motivation for this article was a recent conversation with an author of a major cell-biology textbook who was gratified that the problem of ?pinching off? membrane vesicles from donor membranes had been solved.It was now known, the author claimed, that the large GTPase dynamin was a ?pinchase? severing the necks of budding vesicles.We are concerned that this appealing speculation has been prematurely elevated to cell-biological dogma.Furthermore, by seeing dynamin exclusively as a pinchase we might fail to recognize alternative functions.In this article, we review briefly the evidence that dynamin is a pinchase, discuss some problems with that speculation and show that other possible functions for dynamin may be at least as appealing. PMID- 17708957 TI - Motoring down the highways of the cell. AB - All eukaryotic cells contain large numbers of motor proteins (kinesins, dyneins and myosins), each of which appears to carry out a specialized force-generating function within the cell. They are known to have roles in muscle contraction, ciliary movement, organelle and vesicle transport, mitosis and cytokinesis. These motor proteins operate on different cytoskeletal filaments; myosins move along actin filaments, and kinesins and dyneins along microtubules. Recently published crystal structures of the motor domains of two members of the kinesin superfamily reveal that they share the same overall fold that is also found at the core of the larger myosin motor. This suggests that they may share a common mechanism as well as a common ancestry. PMID- 17708958 TI - HIV and chemokines: ligands sharing cell-surface receptors. AB - At the cell surface, chemokine receptors and CD4 act in concert to bind to human immunodeficiency virus (HIV) and trigger its entry into and infection of cells. Several different chemokine receptors can act as co-receptors for HIV entry, although either CCR5 or CXCR4 is used by all HIV-1 strains studied so far. The capacity of different HIV strains to exploit different chemokine receptors influences their cell tropism, cytopathicity and pathogenicity. Chemokines, the natural ligands for these receptors, can block HIV entry and are thus potential starting points for the design of novel therapeutic agents against HIV infection. PMID- 17708959 TI - Stages of regulated exocytosis. AB - Despite its unique features of spatial organization, Ca;2;+ regulation and speed, neurotransmitter secretion is a paradigm for studies of membrane fusion because it shares homologous proteins and common mechanisms with constitutive exocytosis in all eukaryotic cells.Recent advances have expanded knowledge of the number of gene products required for neurosecretion, and a current major challenge is to determine their mechanisms of action and the stages at which they function in the multistep exocytic pathway.This review discusses progress in this direction from in vivo and in vitro studies that have characterized roles for specific proteins in post-docking steps proximal to membrane fusion. PMID- 17708960 TI - A novel subfamily of Hsp70s in the endoplasmic reticulum. AB - The endoplasmic reticulum contains a number of proteins involved in the processing of secretory polypeptides. These include BiP, which is an Hsp70-family member highly conserved throughout evolution. BiP is known to be intimately involved in several aspects of protein biogenesis, but our understanding of these events has been complicated by the recent description of a novel Hsp70-related protein in yeast, Lhauthorp, whose functions overlap with those of BiP. Current indications are that this protein is distributed widely among eukaryotes and that it represents a distinct subfamily of the Hsp70 class of molecular chaperones. PMID- 17708961 TI - Targets of checkpoints controlling mitosis: lessons from lower eukaryotes. AB - Prevention of mitosis if DNA is damaged, or not fully replicated, is a widespread mechanism used by eukaryotic cells to maintain their ploidy and prevent accumulation of mutations. Such 'checkpoints' must inhibit mitotic regulators to prevent mitotic progression when DNA is not ready for segregation. The mitotic regulators targeted for negative regulation by these checkpoints differ among cell types, but two conserved targets have emerged, the anaphase-promoting complex (APC) and tyrosine phosphorylation of p34(cdc2). One potential downstream target of both these regulators has also been identified, the mitosis-promoting NIMA kinase. PMID- 17708962 TI - Adhesive interactions in the immune system. AB - The immune system is composed of bone-marrow-derived, nucleated cells, many of which circulate through the mammalian host in search of sites of pathogen invasion and other environmental dangers. The key to successful host defence is the ability of these leukocytes to mobilize rapidly to such sites of perturbation of homeostasis. Regulated adhesive interactions of these cells with the endothelium, extracellular matrix, cells of the solid organs and each other are a central feature of the immune response. This review considers the molecules involved in adhesion by cells of the immune system - with particular emphasis on the aspects of adhesion that are unique to leukocytes, namely transendothelial migration, regulation of adhesiveness, and leukocyte activation. PMID- 17708963 TI - The identification of telomerase subunits: catalysing telomere research. AB - Telomerase is the ribonucleoprotein complex responsible for the addition of simple sequences onto the physical ends, or telomeres, of most eukaryotic chromosomes. The activity of this complex is essential for the maintenance of genome integrity. Recent studies have begun to dissect the mechanism of telomerase action through the identification of a reverse-transcriptase-like activity as a catalytic subunit. At the same time, the regulation of telomere length appears to be a complex and possibly species-specific process, involving factors that are likely to interact with both the telomere and telomerase. PMID- 17708964 TI - A consensus nomenclature for the protein-import components of the chloroplast envelope. PMID- 17708965 TI - Drosophila immunity. AB - Septic injury induces in Drosophila the rapid and transient transcription of several genes encoding potent antimicrobial peptides. Significant structural and functional similarities exist between the injury-induced signalling cascades leading to antimicrobial peptide gene expression in Drosophila and cytokine induced expression of mammalian acute-phase proteins. Here, the authors discuss their understanding of these pathways and their relationships to those found in mammalian cells. They also analyse non-self recognition and the role of blood cells in Drosophila host defence. PMID- 17708966 TI - Similarities between insect and plant host defences. PMID- 17708967 TI - Proteins that bind to double-stranded regions of telomeric DNA. AB - In budding yeast, the DNA-binding protein Rap1p orchestrates a negative feedback on regulation of telomere length and the organization of a heterochromatin-like telomeric compartment. Recent studies have led to the identification of functionally related telomeric proteins from fission yeast and mammals. These advances underline the key role played by the proteins that bind to the duplex part of telomeric DNA and reveal an important structural diversity among telomeric proteins. PMID- 17708968 TI - Mammalian cell mutants of membrane phospholipid biogenesis. AB - Cultured mammalian cell mutants defective in the biosynthesis of membrane phospholipids, although limited in number, are increasing our understanding of the molecular mechanisms underlying the biogenesis and the biological significance of membrane phospholipids in higher eukaryotes. This review summarizes the progress in the isolation and characterization of such mutants, focusing on those isolated from cultured Chinese hamster ovary (CHO) cells. PMID- 17708969 TI - Keith r. porter and the first electron micrograph of a cell. PMID- 17708970 TI - A degrading business: the biology of proteolysis. PMID- 17708971 TI - Box 1 - viral anti-apoptotic proteins. PMID- 17708973 TI - Mitochondrial excitement. PMID- 17708972 TI - The iap genes: unique arbitrators of cell death. AB - The iap family of anti-apoptotic genes, originally discovered in viruses, has grown considerably in the past two years with the addition of a number of evolutionary conserved cellular homologues. Although the mechanism(s) by which these novel proteins block cell death is still unknown, intriguing clues to their function have been revealed by the discovery of interactions between some of the IAP homologues and cellular proteins involved in carrying out apoptotic signalling. Here, Rollie Clem and Colin Duckett discuss how the various IAP proteins may function in regulating apoptosis. PMID- 17708975 TI - Proliferating pathways. PMID- 17708974 TI - Cross-talk silenced with scaffolding. PMID- 17708976 TI - Pop go rum1 and cdc18. PMID- 17708977 TI - mdm-2: p53's escort to the proteasome. PMID- 17708978 TI - Focal adhesion assembly. AB - The GTP-binding protein Rho regulates the assembly of focal adhesions and their associated bundles of actin filaments. Two different lines of research have converged to reveal how Rho might regulate assembly of these structures. One approach has been the identification of downstream effectors of Rho, whereas the other has been the exploration of the role of contractility in promoting assembly. It is now apparent that Rho is a key regulator of actomyosin-based contractility in nonmuscle cells and that contractility, combined with adhesion to a rigid substrate, leads to the formation of both stress fibres and focal adhesions. PMID- 17708979 TI - The extracellular matrix and mitogenic growth factors control G1 phase cyclins and cyclin-dependent kinase inhibitors. AB - Most cell types require both mitogenic growth factors and cell adhesion to the extracellular matrix (ECM) for proliferation. Over the past few years, these growth requirements have received renewed attention and can now be explained by studies showing that signals provided by growth factors and the ECM are jointly required to stimulate the cyclin-dependent kinases (CDKs) that mediate cell-cycle progression through G1 phase. This article summarizes our current understanding of the control of G1 cyclins and CDK inhibitors by growth factors and the ECM. In addition, we have highlighted one or two signal-transduction pathways that presently seem closely linked to regulation of the G1 phase cyclin-CDK system. PMID- 17708980 TI - The search for physiological substrates of MAP and SAP kinases in mammalian cells. AB - Mitogen-activated protein kinases (MAPKs) and stress-activated protein kinases (SAPKs) respond to many extracellular signals, but the large number of these enzymes and their overlapping specificities in vitro has made it extremely difficult to identify the physiological roles and substrates of individual family members. This review discusses recent progress in understanding some of the functions of these enzymes that has been made possible by the introduction of some novel approaches, particularly the use of two specific inhibitors. PMID- 17708981 TI - FtsZ, a tubulin homologue in prokaryote cell division. AB - Sequence alignments convincingly demonstrate that FtsZ is a prokaryotic homologue of eukaryotic tubulins. FtsZ appears to be universal in eubacteria and archaebacteria and has also been identified in chloroplasts. Like tubulin, it appears to have a cytoskeletal role as both proteins assemble into two types of characteristic polymers in vitro - protofilament sheets and mini-rings. Recent advances in immunofluorescence and the use of green fluorescent protein have provided clear images of FtsZ localized in a ring at the septation site in bacteria, and new insights into assembly of this Z-ring. PMID- 17708982 TI - Nematode sperm: amoeboid movement without actin. AB - Nematodes produce amoeboid sperm that crawl over surfaces in a manner reminiscent of many actin-rich cells. However, these sperm contain no F-actin, and their motility is powered by a dynamic filament system composed of polymers of the 14 kDa major sperm protein (MSP). These simple cells use this unique motility apparatus exclusively for locomotion. Recent studies have capitalized on this feature to explore the key structural properties of MSP related to its role in motility and to reconstitute the motility apparatus both in vivo and in vitro. This review discusses how these investigations have laid the foundation for understanding the physical basis of amoeboid movement by identifying the mechanistic properties shared by the MSP-based machinery and the more familiar actin-based systems. PMID- 17708983 TI - Techniques update Small-pool screening. PMID- 17708985 TI - Slow axonal transport: the polymer transport model. PMID- 17708984 TI - The riddle of slow transport - an introduction. AB - The three articles in this debate section are intended to be read as a unit. Dennis Bray's introduction sets the scene, then Baas and Brown (pages 380-384) and Hirokawa et al. (pages 384-388) argue in favour of two different models for the mechanism by which the microtubules, microfilaments and neurofilaments that make up the neuronal cytoskeleton are transported along axons. These discussions frequently involve very different interpretations of the same experiments, and finding the real answer is a complicated task. As Dennis Bray says, it's a fascinating riddle, and we hope that you will enjoy thinking about possible solutions. PMID- 17708986 TI - Slow axonal transport: the subunit transport model. AB - A central problem concerning slow transport of cytoskeletal proteins along nerve axons is where they are assembled and the form in which they are transported. The polymer and subunit transport models are the two major hypotheses. Recent developments using molecular and cellular biophysics, molecular cell biology and gene technology have enabled visualization of moving forms of cytoskeletal proteins during their transport. Here, we argue that these studies support the subunit transport theory. PMID- 17708987 TI - Chromatin research gathers pace. PMID- 17708988 TI - Apical targeting in polarized epithelial cells: There's more afloat than rafts. AB - Most metazoan cells are 'polarized'. A crucial aspect of this polarization is that the plasma membrane is divided into two or more domains with different protein and lipid compositions or example, the apical and basolateral domains of epithelial cells or the axonal and somatodendritic domains of neurons. This polarity is established and maintained by highly specific vesicular membrane transport in the biosynthetic, endocytic and transcytotic pathways. Two important concepts, the 'SNARE' and the 'raft' hypotheses, have been developed that together promise at least a partial understanding of the underlying general mechanisms that ensure the necessary specificity of these pathways. PMID- 17708989 TI - Peroxisomes: Organelles at the crossroads. AB - Recent years have seen remarkable progress in our understanding of the function of peroxisomes in higher and lower eukaryotes. Combined genetic and biochemical approaches have led to the identification of many genes required for the biogenesis of this organelle. This review summarizes recent, rather surprising, results and discusses how they can be incorporated into the current view of peroxisome biogenesis. PMID- 17708990 TI - Pictures in cell biology Microtubule dynamics in migrating cells. PMID- 17708991 TI - SUMO-1: Ubiquitin gains weight. AB - The highly conserved ubiquitin polypeptide functions by covalently modifying other proteins. This modification has a well-established role in facilitating substrate degradation by the proteasome and can regulate some proteins by ways other than targeting them to the proteasome. It has now emerged that proteins bearing only distant similarity to ubiquitin can also be attached to specific proteins. The consequences of most of these modifications are not yet understood. However, two recent papers on one ubiquitin-like protein, SUMO-1, demonstrate a role in targeting a protein crucial for nucleocytoplasmic trafficking to the nuclear pore complex. These and other recent findings suggest a much wider influence of the 'ubiquitin system' on cell biology and raise intriguing regulatory and mechanistic questions. PMID- 17708992 TI - The library in the digital age. AB - Electronic publication is an increasingly popular forum within the scientific community, and many are talking about the possibility of dispensing with paper publications entirely in years to come. How likely is this to happen, and if so how quickly? What will be its impact on the way we use and contribute to the scientific knowledge base? This article discusses the elements of today's digital library and how they might evolve as we confront the online world. PMID- 17708993 TI - Connecting up the pathways in Drosophila development. PMID- 17708994 TI - A new mechanism of scatter factor action. PMID- 17708995 TI - Not so senile. PMID- 17708996 TI - Breaking symmetry in the CNS. PMID- 17708997 TI - Nuclear inclusions in Huntington's disease. PMID- 17708998 TI - Pictures in cell biology Asymmetric localization of Drosophila NUMB and INSCUTEABLE during mitosis. PMID- 17708999 TI - Growth factors: a role in guiding axons? AB - A remarkable finding to emerge in recent years is that the early brain neuroepithelium is highly patterned before axonogenesis begins. Growth factors are among a variety of classes of molecules whose regionalized expression divides the early brain into molecularly distinct domains. Thus, when axons first grow to their synaptic targets, growth factor signalling may help them to navigate. This review discusses recent studies that reveal that growth factors can act as chemoattractants and repellents and that growth factor signalling is important for target entry. These new findings raise the compelling idea that growth factors play an active role in axon navigation. PMID- 17709000 TI - Control of EGF receptor activation in Drosophila. AB - Diverse biological and developmental functions are mediated by signalling through the epidermal growth factor (EGF) receptor. In flies, many different mechanisms are used to control and restrict EGF-R signalling, including ligand processing, ligand variety (an inhibitor as well as activators), transcription and perhaps subcellular localization of the receptor. Since the components of EGF-R signalling have been well conserved, understanding these different modes of receptor regulation in flies should lead to general insights into the strategies of receptor activation. PMID- 17709001 TI - The NOTCH receptor and its ligands. AB - An intricate interplay of signalling pathways dictates the acquisition of specific cell fates during development. The NOTCH receptor is the central element in a cell-interaction mechanism that controls the fate of a very broad spectrum of precursor cells. Conservation across species implies that signalling through this receptor is a tool frequently used by metazoans to modulate the fate of precursor cells. This article describes recent advances in the genetic and molecular dissection of this developmentally fundamental pathway that have provided new insights into the mechanism by which extracellular signals act through the NOTCH receptor to determine or alter cellular fate. PMID- 17709002 TI - Pictures in cell biology Rho-family proteins control polarized cytoskeletal rearrangements during wing hair formation in Drosophila. PMID- 17709003 TI - Recent advances in hedgehog signalling. AB - Hedgehog (HH) proteins are an important class of secreted intercellular signals. The HH signal-transduction pathway is not fully understood, but a number of novel features have been elucidated recently. It is now clear that, during processing to generate an active signal, Drosophila HH proteins become covalently linked to cholesterol and are thereby largely tethered to the cell surface. HH signalling could therefore be affected by cholesterol metabolism. In addition, the pathway downstream of receptor binding involves a unique signalling complex containing the transcription factor CUBITUS INTERRUPTUS (CI), which becomes dissociated from microtubules in response to HH. This review discusses these new findings and their implications for HH signalling. PMID- 17709005 TI - Pictures in cell biology You won't believe your eyes - the 'master control gene' for eye development. PMID- 17709004 TI - Knowing in your heart what's right. AB - During heart formation in all vertebrate species, the linear heart tube undergoes rightward looping followed by the formation of the atrial and ventricular chambers. The direction of cardiac looping is determined in part by the asymmetric expression of members of the transforming growth factor beta family across the left-right axis of the embryo. The basic helix-loop-helix (bHLH) transcription factors dHAND and eHAND are expressed in the heart tube within specific cardiogenic precursors destined to form the right and left ventricular regions, respectively, and loss-of-function experiments have demonstrated the importance of these factors for looping morphogenesis and ventricular development. We propose a model in which the HAND gene products interpret asymmetric positional information in the developing heart and participate in transcriptional programmes that control development of the right and left ventricular compartments of the heart. PMID- 17709006 TI - Expanding insights into the role of cell proliferation in plant development. AB - Development in plants relies largely on the activity of meristems, which are regions at the apices of shoots and roots that are capable of prolonged organogenesis. Developmental patterning and morphogenesis in plants is principally determined by post-embryonic regulation of the shoot, root and flower meristems, which enable plants to modify their form rapidly in response to different environmental conditions. Because meristems are continually generating new organs and tissues, they provide excellent model systems in which to study the processes of cell division, differentiation and organ formation. Here, we describe recent studies and several classic experiments that are helping to uncover the mechanisms controlling meristem development and the role of cell division in morphogenesis and patterning in plants. PMID- 17709007 TI - What my mother told me: Examining the roles of maternal gene products in a vertebrate. AB - In Xenopus, mRNAs synthesized during oocyte differentiation are inherited by the egg and direct all protein synthesis until the late-blastula stage. This provides an opportunity to study the roles of maternally expressed genes in embryonic development of a vertebrate. Oocytes can be depleted of specific mRNAs by the injection of antisense deoxyoligonucleotides and then fertilized to assay for developmental abnormalities. The ease of experimental manipulation of early Xenopus embryos in culture gives considerable opportunity for the analysis of the abnormalities seen. PMID- 17709008 TI - Slippery slopes: Understanding gradients and asymmetries in development. PMID- 17709009 TI - Programmed cell death: a missing link is found. AB - Two families of proteins have advanced our understanding of the molecular basis of programmed cell death (PCD) in animal cells - the caspases and Bcl-2-related proteins. While caspases lie at the heart of the death programme, Bcl-2-related proteins act as key intracellular regulators. Although there has been considerable progress in elucidating the biochemical functions of caspases, how Bcl-2-related proteins regulate caspase activation and thereby PCD, has remained a mystery. One key to resolving this mystery seems to lie with a new third family of proteins related to the Caenorhabditis elegans cell-death protein CED-4, which connects Bcl-2-related proteins to caspases. An important step in defining this new family has been made by the identification of a human CED-4 homologue. PMID- 17709010 TI - Regulation through inhibitory receptors: Lessons from natural killer cells. AB - Natural killer (NK) cells employ an unconventional mode of recognition: they kill target cells that lack ligands for inhibitory NK cell receptors. Activation of NK cytotoxicity is tightly controlled by inhibitory receptors that recruit and activate the tyrosine phosphatase SHP-1 through the tyrosine-phosphorylated [I/V]xYxxL amino acid sequence in their cytoplasmic tail. This sequence motif, often referred to as an immunoreceptor tyrosine-based inhibitory motif (ITIM), is found in several other receptors that deliver similar negative signals in diverse types of cells. We suggest that this kind of regulation through inhibition is a widespread mechanism for the control of various cellular responses. PMID- 17709011 TI - The alpha- and beta-tubulin folding pathways. AB - The alpha-beta tubulin heterodimer is the subunit from which microtubules are assembled. The pathway leading to correctly folded alpha- and beta-tubulins is unusually complex: it involves cycles of ATP-dependent interaction of newly synthesized tubulin subunits with cytosolic chaperonin, resulting in the production of quasi-native folding intermediates, which must then be acted upon by additional protein cofactors. These cofactors form a supercomplex containing both alpha- and beta-tubulin polypeptides, from which native heterodimer is released in a GTP-dependent reaction. Here, we discuss the current state of our understanding of the function of cytosolic chaperonin and cofactors in tubulin folding. PMID- 17709012 TI - Expeditions to the pole: RNA localization in Xenopus and Drosophila. AB - In Xenopus and Drosophila oocytes, a number of maternally synthesized RNAs encoding molecules that act in formation and patterning of embryonic tissues are localized to the vegetal and posterior poles, respectively. In Drosophila, and probably in Xenopus, localization of their RNAs within the oocyte generates the regionalized distributions of these molecules in the early embryo that are required for proper development. Studies described here have begun to reveal components of the cellular machinery that effects RNA localization. While specific aspects of localization differ among RNAs, similarities between pathways used by Xenopus and Drosophila suggest that common themes have been conserved among localization mechanisms. PMID- 17709013 TI - Who binds wins: Competition for PCNA rings out cell-cycle changes. AB - PCNA, proliferating cell nuclear antigen, is a pivotal protein in DNA replication, DNA repair and possibly cell-cycle control. The protein has a trimeric ring structure that might slide along duplex DNA and form a platform for association with a variety of proteins, in particular holding the DNA polymerases in close association with their template. This article reviews evidence suggesting that the activity of PCNA in replication and repair is coordinated within the cell cycle by cooperative and competitive interactions with an extensive network of enzymes and regulatory proteins. PMID- 17709014 TI - Cell biologists sort things out: Analysis and purification of intracellular organelles by flow cytometry. AB - Flow cytometry was established originally for measuring DNA content and for the analysis of cell-surface markers in combination with cell sorting. During the past two decades, it has added new dimensions to various areas of immunology and medicine. Increased sensitivity and precision of flow cytometers, accompanied by the development of new fluorescent dyes and probes, has led to new applications in molecular cell biology and genetics. This article focuses on applications of flow cytometry in analysis and sorting of intracellular organelles. PMID- 17709015 TI - Production and presentation of digital movies. PMID- 17709016 TI - The centrosome on centre stage. PMID- 17709018 TI - Introduction: global perspectives on double balloon enteroscopy. PMID- 17709019 TI - Diagnosis and treatment of small-bowel stricture by double balloon endoscopy. AB - BACKGROUND: The source of small-bowel stricture is often difficult to diagnose due to the difficulty of placing an endoscope into the small bowel. It has recently become possible to examine the entire small bowel and perform balloon dilatation for stricture by means of double balloon endoscopy (DBE). OBJECTIVE: To identify clinical features of small-bowel stricture and determine the validity of balloon dilatation as a treatment option. DESIGN: Retrospective multicenter study. SETTING: Researchers at 7 institutions affiliated with the DBE Working Group. PATIENTS: One hundred seventy-nine patients with stricture among a total of 1035 patients who underwent DBE at the 7 institutions. INTERVENTIONS: Surgical treatment or balloon dilatation was performed as clinically indicated. MAIN OUTCOME MEASUREMENTS: Ability to detect stricture lesions by DBE, types of lesions, locations of small-bowel strictures, details of strictures, treatments for strictures, and outcomes of balloon dilatation for strictures associated with inflammatory disease. RESULTS: The total number of patients with strictures was 179. Lesions were detected within the small bowel in 156 patients. Inflammatory disease was the most common (n = 87) in patients with small-bowel stricture, and the ileum was the most common site of the inflammatory disease. Crohn's disease was the most common of the inflammatory diseases (n = 57). Balloon dilatations were performed in 31 patients with inflammatory disease, and long-term success was achieved in 22 patients. LIMITATIONS: The number of patients treated by balloon dilatation was small. CONCLUSION: DBE appears to be useful for the detection as well as treatment of small-bowel lesions. PMID- 17709020 TI - Current status of double balloon enteroscopy with focus on the Wiesbaden results. PMID- 17709021 TI - Technical matters in double balloon enteroscopy. PMID- 17709023 TI - Foreword: double balloon endoscopy. PMID- 17709022 TI - Diagnostic value of double balloon enteroscopy for small-intestinal disease: experience from China. AB - BACKGROUND: Diseases of the small intestine include, among others, ulceration, chronic inflammation, Meckel's diverticula, vascular deformities, and cancer. OBJECTIVE: To study the diagnostic value of double balloon enteroscopy (DBE) for small-intestinal disease in a Chinese patient cohort. DESIGN: DBE was performed via the mouth, anus, or both approaches to diagnose small-intestinal disease. PATIENTS: We studied 155 patients with clinically suspected small-intestinal disease: 110 men and 45 women. Their age ranged from 6 to 75 (mean 41). There were 92 cases with small-intestinal hemorrhage, 39 with abdominal pain, 7 with diarrhea, 13 with abdominal distention, 3 cases with malnutrition, and 1 with diarrhea and refractory hypoalbuminemia. RESULTS: Among the 155 patients, lesions were found in 126 (81.3%). These lesions found were small-intestinal ulcers (including Crohn's disease), chronic inflammation, Meckel's diverticulae, vascular deformities, and carcinoma. Eighty-five of the 92 patients with suspected intestinal hemorrhage were confirmed, with a positive rate of 92.4%. Also confirmed were 24 of the 39 patients with abdominal pain (positive rate of 61.5%); 16 of the 23 patients with diarrhea, abdominal distention, or malnutrition (positive rate of 69.6%); and 1 patient with refractory hypoalbuminemia. Among the 126 patients with positive findings, the lesions were located in the small intestine in 116 patients, in the stomach and duodenum in 9 patients, and in the colon in 1 patient. In the 45 patients with small-intestinal ulcer, 29 patients had recurrent hemorrhage, 9 had abdominal pain, 4 had abdominal distention, 2 had malnutrition, and 1 had diarrhea. Ulcers were located in the jejunum in 20 patients, in the ileum in 20 patients, and in both the jejunum and ileum in 5 patients. For 7 patients with small-intestinal ulceration diagnosed as Crohn's disease, the concordance rate of diagnosis between preoperative and postoperative diagnosis was 57.1%, lower than other diseases (P < .01). One patient had a perforation. CONCLUSION: DBE is effective and safe for the diagnosis of small-intestine disease in a Chinese patient cohort. PMID- 17709024 TI - Korean experience with double balloon endoscopy: Korean Association for the Study of Intestinal Diseases multi-center study. AB - BACKGROUND: Double balloon endoscopy (DBE) is a new diagnostic and therapeutic tool for the management of patients with small-bowel disease. OBJECTIVE: To evaluate the feasibility, clinical usefulness, and safety of DBE in Korean patients with suspected or known small-bowel disease. DESIGN: Retrospective, multicenter study from April 2004 to March 2006. SETTING: University hospitals. PATIENTS: Two hundred twenty-five consecutive patients. INTERVENTIONS: Subjects underwent 311 procedures with DBE via the oral and/or anal routes. MAIN OUTCOME MEASUREMENTS: The indications, diagnostic yield, therapeutic use, and complications. RESULTS: Overall diagnostic yield was 75% (169/225). Diagnostic yields for obscure GI bleeding (OGIB) (n = 137), chronic abdominal pain (n = 32), radiologic/capule endoscopic abnormality (n = 25), polyposis (n = 9), and chronic diarrhea (n = 9) were 73.7% (101/137), 75.0% (24/32), 64% (16/25), 100% (9/9), and 0% (0/9), respectively. In patients with OGIB, ulcerating lesions (n = 54) were more common than vascular lesions (n = 20) or tumors (n = 27). Some lesions detected in DBE were treated effectively with electrocoagulation or argon plasma coagulation, polypectomy, and dilation. Entrapped capsules were removed easily with polypectomy snare in 3 patients with small-bowel stricture. Some patients with strictures had transient abdominal discomfort during and/or after the procedure. With the exception of 1 mucosal tear, there were no technical problems or serious complications. LIMITATIONS: Descriptive, retrospective study. CONCLUSIONS: DBE is safe and useful for diagnosis and treatment of a variety of small-bowel diseases. The most common indication of DBE was OGIB. Ulcerating small-bowel lesions are more common than vascular lesions in Korea. PMID- 17709025 TI - Efficacy of carbon dioxide insufflation in endoscopic balloon dilation therapy by using double balloon endoscopy. PMID- 17709026 TI - New frontiers of endoscopy from the large intestine to the small intestine. PMID- 17709027 TI - Current status of double balloon endoscopy--indications, insertion route, sedation, complications, technical matters. AB - BACKGROUND: The recent development of double balloon endoscopy (DBE) has revolutionized enteroscopy. This system allows for endoscopic scrutiny and treatment of the entire small bowel, but general consensus has not yet been reached regarding procedural guidelines. METHODS: We have been using the DBE system since June 2003, at Nippon Medical School Hospital, Tokyo, Japan, where 163 patients have undergone 265 DBE examinations. This study presents a detailed analysis of the current status of DBE examination at our institution, with particular focus on indications, contraindications, sedation, choice of insertion route, complications, and relevant technical points. OBSERVATIONS: The most common indication for DBE was obscure GI bleeding. Patients were placed under conscious or deep sedation and their vital signs were monitored throughout the examination. The choice of either an oral or anal insertion route was determined on the basis of clinical symptoms or any previous examination data. When analyzing the entire small bowel, we began via the anal route and marked the intestine with India ink at the furthest insertion point lying closest to the oral route. We then switched our approach to the oral route, and confirmed total enteroscopy when the enteroscope reached the India-ink mark. With regard to complications, we encountered 1 case of acute pancreatitis and 2 cases of aspiration pneumonia after examination. CONCLUSIONS: The DBE system allows for full investigation of the pathology of the small intestine and timely endoscopic treatment. However, for the DBE system to achieve more widespread acceptance, it is critical that we establish a universal method for its safe and efficient use. PMID- 17709028 TI - Clinical importance of the location of lesions with regard to mesenteric or antimesenteric side of the small intestine. PMID- 17709029 TI - Training and new indications for double balloon endoscopy (with videos). PMID- 17709030 TI - Double balloon endoscopy for pancreatic and biliary access in altered anatomy (with videos). AB - BACKGROUND: Access to the papilla of Vater or enteral anastomoses to the biliary tract or pancreatic duct is difficult in patients with altered anatomy. The usual approach to the papilla of Vater with a side-viewing duodenoscope, designed for passage through the stomach, pyloric channel, and proximal duodenum, is not suitable in postoperative patients with challenging anatomic rearrangements. There is therefore a need for better instrumentation to achieve access in patients with difficult anatomy. OBJECTIVE: To assess the potential of the new double balloon endoscope system for use in difficult postsurgical anatomic configurations. This system has now been utilized in several of these types of anatomic rearrangements with successful access to the papilla of Vater and hepatico-jejunal, choledocho-jejunal, or pancreatico-jejunal anastomoses. The technique of advancing the system and achieving cannulation is described. The accessories necessary and therapeutic potential are addressed. INTERVENTIONS: Diagnostic and therapeutic management of pancreatic and biliary disorders in altered anatomy. CONCLUSION: Double balloon enteroscopy has provided a means to access the stomach, duodenum, biliary tract, and pancreatic duct after surgical procedures that have made access by the usual routes with the usual instruments not possible. PMID- 17709032 TI - Double balloon endoscopy in pediatric patients. PMID- 17709031 TI - Future perspective of double balloon endoscopy: newer indications. AB - BACKGROUND: Double balloon endoscopy (DBE) is an emerging modality for complete endoscopic visualization of the small intestine. Although the most common indication of DBE is currently for evaluation of obscure GI bleeding or suspected small-bowel pathology, the unique technical features of the double balloon endoscope have led to its newer uses. OBJECTIVE: To evaluate the utility of DBE by the retrograde approach to perform a complete evaluation of the colon. PATIENTS: Sixteen patients in whom examination of the entire colon could not be achieved with conventional colonoscopy. RESULTS: Using DBE by the retrograde approach, we achieved a high success rate of complete endoscopic examination of the entire colon, and we were also able to perform appropriate therapeutic interventions. The procedures were well tolerated by the patients and could be performed with the patient under conscious sedation and without the use of fluoroscopy. LIMITATIONS: This study comprised a small number of patients and there was no control group. CONCLUSIONS: Anecdotal data suggest that other areas in which DBE technology may be potentially helpful are ERCP in patients with surgically altered anatomy, and endoscopic evaluation of the bypassed segment of the upper GI tract in patients who have undergone bariatric surgery, but such applications will require the development of appropriate accessories and substantial technical modification to currently available instruments. PMID- 17709033 TI - New indications of double balloon endoscopy. PMID- 17709034 TI - Double balloon endoscopy in GI hemorrhage. PMID- 17709035 TI - Double balloon endoscopy in obscure GI bleeding: the Danish experience. PMID- 17709036 TI - Obscure GI bleeding in the world of capsule endoscopy, push, and double balloon enteroscopies. PMID- 17709037 TI - Double balloon endoscopy in obscure GI bleeding. PMID- 17709038 TI - The First International Workshop on Double Balloon Endoscopy: a consensus meeting report. PMID- 17709040 TI - Diagnosis and treatment of obscure GI bleeding with double balloon endoscopy. PMID- 17709039 TI - Diagnosis and treatment of obscure GI bleeding at double balloon endoscopy. AB - BACKGROUND: Double balloon endoscopy (DBE) and videocapsule endoscopy (VCE) have been useful in managing obscure GI bleeding (OGIB). OBJECTIVE: This study evaluated the usefulness of DBE for diagnosis, treatment, and prognosis of OGIB and compared diagnostic yield between DBE and VCE in Japan. METHODS: Detection rates of abnormalities and diagnostic yields between VCE and DBE were compared in 74 patients at 5 centers. Of 244 patients who underwent DBE at Nagoya University Hospital, 130 (53%) with OGIB were enrolled for investigation of therapeutic procedures. SETTING: Seven Japanese medical centers. PATIENTS: Of 1034 patients who underwent DBE between September 2000 and December 2005 at 7 medical centers, 479 (46%) with OGIB were enrolled. RESULTS: Overall diagnostic yield of DBE for OGIB was 277 of 479 (58%). In patients with overt-ongoing bleeding, overt previous bleeding of sporadic type, overt-previous bleeding of first attack only, occult bleeding with continuous positive fecal occult blood test (FOBT), or occult bleeding with 1 positive FOBT with iron deficiency anemia, diagnostic yield was 24 of 31 (77%), 179 of 310 (58%), 34 of 72 (47%), 24 of 35 (71%), and 56 of 93 (60%), respectively. Regarding positive findings in 277 patients, ulcers or erosions (53%) were the most frequent, followed by angiodysplasia (23%), tumors or polyps (22%), and diverticula (4%). Diagnoses in these patients were as follows: chronic inflammatory diseases (24%), vascular diseases (24%), tumor or polyps (21%), drug or radiation injury (7%), other small-bowel diseases (7%), upper GI diseases (9%), colorectal diseases (9%), and biliary disease (0.4%). Small-bowel diseases were confirmed in 226 patients (47%). Comparison of overall detection rate of abnormalities in the small bowel between VCE (65%) and DBE (53%) was not significantly different, nor was that of overall diagnostic yield between VCE (50%) and DBE (53%). Eight acute pancreatitis and 4 perforation episodes occurred with no mortalities at DBE. Of 130 patients at Nagoya University Hospital, 78 (60%) were diagnosed with small-bowel diseases and underwent treatments as follows: medication or observation only (n = 30), enteroscopic therapies (electrocoagulation in 21, clipping in 4, and polypectomy in 3), and surgery (n = 22). Small-bowel vascular diseases were more prone to rebleeding than small-bowel nonvascular diseases in patients without surgical treatment at a median follow-up of 423 days. CONCLUSIONS: DBE was relatively safe and useful for diagnosis and treatment of OGIB. A spectrum of small-bowel diseases presenting with OGIB in Japan may be distinct from that in the Western world. PMID- 17709041 TI - Double balloon enteroscopy in Crohn's disease and related disorders: our experience. PMID- 17709042 TI - Crohn's disease: diagnostic and therapeutic potential of modern small-bowel endoscopy. PMID- 17709043 TI - Role of double balloon enteroscopy in Crohn's disease. PMID- 17709044 TI - Double balloon endoscopy in small intestinal Crohn's disease and other inflammatory diseases such as cryptogenic multifocal ulcerous stenosing enteritis (CMUSE). PMID- 17709045 TI - Chronic nonspecific multiple ulcers of the small intestine: a proposal of the entity from Japanese gastroenterologists to Western enteroscopists. PMID- 17709047 TI - Images in emergency medicine. Intrauterine twin gestation with single live intrauterine pregnancy, single septic abortion, and an IUD. PMID- 17709046 TI - Insomnia: a ticking clock for depression? PMID- 17709049 TI - Images in emergency medicine. Xanthogranulomatous pyelonephritis. PMID- 17709050 TI - Clinical policy: critical issues in the management of patients presenting to the emergency department with acetaminophen overdose. AB - This clinical policy focuses on critical issues concerning the management of patients presenting to the emergency department (ED) with acetaminophen overdose. The subcommittee reviewed the medical literature relevant to the questions posed. The critical questions are: 1. What are the indications for N-acetylcysteine (NAC) in the acetaminophen overdose patient with a known time of acute ingestion who can be risk stratified by the Rumack-Matthew nomogram? 2. What are the indications for NAC in the acetaminophen overdose patient who cannot be risk stratified by the Rumack-Matthew nomogram? Recommendations are provided on the basis of the strength of evidence of the literature. Level A recommendations represent patient management principles that reflect a high degree of clinical certainty; Level B recommendations represent patient management principles that reflect moderate clinical certainty; and Level C recommendations represent other patient management strategies that are based on preliminary, inconclusive, or conflicting evidence, or based on committee consensus. This guideline is intended for physicians working in EDs. PMID- 17709051 TI - Bad reputation: separating past and present. PMID- 17709052 TI - Images in emergency medicine. Serum sickness-like reaction to amoxicillin. PMID- 17709053 TI - Bridging orders and a dedicated admission nurse decreases emergency department turnaround times while increasing patient satisfaction. PMID- 17709054 TI - Heroin: what's in the mix? PMID- 17709055 TI - Additional thoughts on the controversy of lidocaine administration before rapid sequence intubation in patients with traumatic brain injuries. PMID- 17709056 TI - Response to "Delayed fluid resuscitation in hemorrhagic shock induces proinflammatory cytokine response". PMID- 17709059 TI - Confessions of a researcher: are we guilty of reviewing homeopathy to the point of irrelevance? PMID- 17709060 TI - A randomised study of the effects of massage therapy compared to guided relaxation on well-being and stress perception among older adults. AB - OBJECTIVE: The objective was to assess the effects of massage compared to guided relaxation on stress perception and well-being among older adults. DESIGN: A randomised pilot study enrolled adults ages 60 and older to receive 50 min, twice weekly massage therapy or guided relaxation sessions. Questionnaires were administered at pre-test (1 week before the first session) and post-test (after the last session). SETTING: Participants came to the University of South Carolina campus for sessions. Adults aged 60 and older were recruited from community venues and were briefly screened by telephone for contraindications. INTERVENTION: Participants (n=54) received 50 min massage or guided relaxation sessions twice weekly for 4 weeks. The massage included Swedish, neuromuscular, and myofascial techniques. For the relaxation group, an appropriately trained assistant read a script to guide the participant in using visualization and muscle relaxation. MAIN OUTCOME MEASURES: The General Well-being Schedule is an 18-item scale with subscales measuring anxiety, depression, positive well-being, self-control, vitality, and general health. The Perceived Stress Scale is a 14 item scale assessing the degree to which situations in one's life are appraised as stressful during the past month. RESULTS: Significant improvements were found for the anxiety, depression, vitality, general health, and positive well-being subscales of the General Well-being Schedule and for Perceived Stress among the massage participants compared to guided relaxation. CONCLUSIONS: Findings indicate that massage therapy enhances positive well-being and reduces stress perception among community-dwelling older adults. PMID- 17709061 TI - A modified yoga-based exercise program in hemodialysis patients: a randomized controlled study. AB - AIM: To evaluate the effects of a yoga-based exercise program on pain, fatigue, sleep disturbance, and biochemical markers in hemodialysis patients. MATERIALS AND METHODS: In 2004 a randomized controlled trial was carried out in the outpatient hemodialysis unit of the Nephrology Department, Uludag University Faculty of Medicine. Clinically stable hemodialysis patients (n=37) were included and followed in two groups: the modified yoga-based exercise group (n=19) and the control group (n=18). Yoga-based exercises were done in groups for 30 min/day twice a week for 3 months. All of the patients in the yoga and control groups were given an active range of motion exercises to do for 10 min at home. The main outcome measures were pain intensity (measured by the visual analogue scale, VAS), fatigue (VAS), sleep disturbance (VAS), and grip strength (mmHg); biochemical variables-- urea, creatinine, calcium, alkaline phosphatase, phosphorus, cholesterol, HDL-cholesterol, triglyceride, erythrocyte, hematocrit- were evaluated. RESULTS: After a 12-week intervention, significant improvements were seen in the variables: pain -37%, fatigue -55%, sleep disturbance -25%, grip strength +15%, urea -29%, creatinine -14%, alkaline phosphatase -15%, cholesterol -15%, erythrocyte +11%, and hematocrit count +13%; no side-effects were seen. Improvement of the variables in the yoga-based exercise program was found to be superior to that in the control group for all the variables except calcium, phosphorus, HDL-cholesterol and triglyceride levels. CONCLUSION: A simplified yoga-based rehabilitation program is a complementary, safe and effective clinical treatment modality in patients with end-stage renal disease. PMID- 17709062 TI - Randomised trial of trigger point acupuncture compared with other acupuncture for treatment of chronic neck pain. AB - INTRODUCTION: There is some evidence for the efficacy of acupuncture in chronic neck pain (CNP) treatment, but it remains unclear which acupuncture modes are most effective. Objective was to evaluate the effects of trigger point acupuncture on pain and quality of life (QOL) in CNP patients compared to three other acupuncture treatments (acupoints, non-trigger point and sham treatment). METHODS: Forty out-patients (29 women, 11 men; age range: 47-80 years) from the Department of Orthopaedic Surgery, Meiji University of Oriental Medicine, with non-radiating CNP for at least 6 months and normal neurological examination were randomised to one of four groups over 13 weeks. Each group received two phases of acupuncture treatment with an interval between them. The acupoint group (standard acupuncture; SA, n=10) received treatment at traditional acupoints for neck pain, the trigger point (TrP, n=10) and non-trigger point (non-TrP, n=10) groups received treatment at tenderness points for the same muscle, while the other acupuncture group received sham treatments on the trigger point (SH, n=10). Outcome measures were pain intensity (visual analogue scale; VAS 0-100mm) and disease specific questionnaire (neck disability index; NDI, 60-point scale). RESULTS: After treatment, the TrP group reported less pain intensity and improved QOL compared to the SA or non-TrP group. There was significant reduction in pain intensity between the treatment and the interval for the TrP group (p<0.01, Dunnett's multiple test), but not for the SA or non-TrP group. CONCLUSION: These results suggest that trigger point acupuncture therapy may be more effective on chronic neck pain in aged patients than the standard acupuncture therapy. PMID- 17709064 TI - Developing classification indices for Chinese pulse diagnosis. AB - AIM: To develop classification criteria for Chinese pulse diagnosis and to objectify the ancient diagnostic technique. METHODS: Chinese pulse curves are treated as wave signals. Multidimensional variable analysis is performed to provide the best curve fit between the recorded Chinese pulse waveforms and the collective Gamma density functions. RESULTS: Chinese pulses can be recognized quantitatively by the newly-developed four classification indices, that is, the wave length, the relative phase difference, the rate parameter, and the peak ratio. The new quantitative classification not only reduces the dependency of pulse diagnosis on Chinese physician's experience, but also is able to interpret pathological wrist-pulse waveforms more precisely. CONCLUSIONS: Traditionally, Chinese physicians use fingertips to feel the wrist-pulses of patients in order to determine their health conditions. The qualitative theory of the Chinese pulse diagnosis is based on the experience of Chinese physicians for thousands of years. However, there are no quantitative theories to relate these different wrist-pulse waveforms to the health conditions of patients. In this paper, new quantified classification indices have been introduced to interpret the Chinese pulse waveform patterns objectively. PMID- 17709063 TI - Physician and treatment characteristics in a randomised multicentre trial of acupuncture in patients with osteoarthritis of the knee. AB - OBJECTIVE: The aim of this paper is to describe the treatment and physician characteristics in a randomised trial of acupuncture for osteoarthritis of the knee. DESIGN: Three-armed, randomised, controlled multicentre trial with 1-year follow-up. SETTING: Twenty-eight outpatient centres in Germany. INTERVENTIONS: A total of 294 patients with osteoarthritis of the knee were randomised to 12 sessions of semi-standardised acupuncture (at least 6 local and 2 distant points needled per affected knee from a selection of predefined points, but individual choice of additional body or ear acupuncture points possible), 12 sessions of minimal acupuncture (superficial needling of at least 8 of 10 predefined, bilateral, distant non-acupuncture points) or a waiting list control (2 months no acupuncture). OUTCOME: Participating trial physicians and interventions. RESULTS: Forty-seven physicians specialised in acupuncture (mean age 43+/-8 years, 26 females) provided study interventions in 28 outpatient centres in Germany. The median duration of acupuncture training completed by participating physicians was 350 h (range 140-2508). The total number of needles used was 17.4+/-4.8 in the acupuncture group compared to 12.9+/-3.3 in the minimal acupuncture group. In total, 39 physicians (83%) stated that they would have treated patients in either a similar or in exactly the same way outside of the trial, whereas 7 (15%) stated that they would have treated patients differently (1 missing). CONCLUSIONS: Our documentation of the trial interventions shows that semi-standardised acupuncture strategy represents an acceptable compromise for efficacy studies. However, a substantial minority of participating trial physicians stated that they would have treated patients differently outside of the trial. PMID- 17709065 TI - Management of depression by homeopathic practitioners in Sydney, Australia. AB - OBJECTIVES: The study investigates the demographic profile, caseload and treatment for depression provided by homeopathic practitioners in Australia. DESIGN: A postal survey comprising a self-administered questionnaire which included a combination of close-ended and open-ended response categories. SETTING: The questionnaire was mailed to 128 homeopathic practitioners working in the metropolitan areas of Sydney, Australia. RESULTS: The demographic profile of the respondents showed that most were in the 45-50 year age group, and female practitioners comprised 68% of the sample. Symptoms of depression reported in the homeopathic practice had parallel description of symptoms listed in the ICD-10. Overall, treatment of mental health disorders, such as depression, grief, anxiety and phobia were a significant feature of the practice caseload of the respondents. Eighty-four percent of the respondents had patients presenting for homeopathic treatment that were also receiving some form of external therapy, most commonly antidepressant medications. Sixty percent of the respondents incorporated 'concurrent' therapies in the treatment approach, most commonly counselling, nutrition and lifestyle management. CONCLUSION: The paper shows that most homeopathic practitioners provide a pluralistic approach to management of depression which is in accordance with principles of holistic care. The implications of the research findings are discussed. PMID- 17709066 TI - Use of herbal preparations in the treatment of oxidant-mediated inflammatory disorders. AB - Complementary and alternative medicine (CAM) use has increased in popularity in recent years and herbal therapy alone is now a billion dollar market. For centuries herbs have been used as food and for medicinal purposes. Various herbs have been identified as possessing anti-inflammatory and antioxidative properties, and they are currently being used to treat inflammatory disorders as well as those caused by reactive oxygen species (ROS). Asthma, Alzheimer's disease, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and atherogenesis are all disorders where inflammation and ROS are involved in their pathogenesis. This review examines the pathogenesis of the above mentioned ROS mediated inflammatory disorders, as well as discusses the antioxidant and anti inflammatory mechanisms of various herbs and the clinical trials where herbs have been used to treat these disorders. PMID- 17709067 TI - Current issues and future directions in complementary and alternative medicine (CAM) research. AB - This paper examines the topics discussed over the course of the Complementary Therapies in Medicine (CAM) research methods series and looks ahead at research methods that either have not been discussed so far in the series or are currently emerging as potentially useful research tools. It is emphasised that an in-depth knowledge of methodological advances (and existing tools) is vital if researchers are to design and implement appropriate programs with the ability to adequately address the vast range of research questions pertinent to CAM. PMID- 17709068 TI - Management of cervical root fracture using orthodontic extrusion and crown reattachment: a case report. AB - Root fractures involve damage to pulp, cementum, dentin, and periodontal ligaments. These injuries affect 0.5% to 7% of permanent teeth. Cervical root fractures are less frequently seen and have a worse prognosis compared with the fractures in the apical or middle third of the root. This case report describes the treatment of a cervical root fracture in a maxillary central incisor. After removal of the coronal fragment, the root was filled temporarily with calcium hydroxide and orthodontic extrusion was initiated. The remaining root portion was elevated above the epithelial attachment and a successful coronal restoration was made using the natural crown of the traumatized tooth. PMID- 17709069 TI - The accuracy of root canal measurements using the Mini Apex Locator and Root ZX II: an evaluation in vitro. AB - OBJECTIVE: The aim of this in vitro study was to compare the capacity of the Root ZX-II and Mini Apex Locator, electronic apex locators (EALS), to prevent overestimated working length. STUDY DESIGN: Forty extracted human teeth were used for the study. The cervical portion of each canal was flared using Gates Glidden drills and the teeth were embedded in an alginate model. Canals were irrigated with 2.5% sodium hypochlorite. The actual length (AL) and electronic length (EL) measurements were made on each specimen separately with both devices with the aid of a k-type file. RESULTS: The results obtained with each EAL were compared with the corresponding actual length. The statistical analysis of the results showed EAL reliability to prevent overestimated working length to be 100% for the Mini Apex Locator and 97.44% for the Root ZX-II, within a tolerance of +/-0.5 mm into account. A paired sample t test showed that there was no statistically significant difference between the accuracy of the devices (P = .5841). CONCLUSION: The results of this study indicate that the Root ZX-II and Mini Apex Locator are accurate devices to prevent overestimated working length. PMID- 17709070 TI - Radiographic evaluation of periapical healing of permanent teeth with periapical lesions after extrusion of AH Plus sealer. AB - The aim of this study was to clinically and radiographically examine the effects of extrusion of AH Plus sealer on the healing of permanent teeth with apical periodontitis. A total of 87 root canals radiographically detected with apical periodontitis were included in the study. Posttreatment radiographs indicated sealer extrusion into 49 canals (Group 1) and no sealer extrusion into 38 canals (Group 2). Periapical treatment was judged as complete healing (CH), incomplete healing (IH) and no healing (NH) at the end of a 4-year follow-up period. Amounts of extraradicular sealer were recorded as "unchanged," "reduced," "almost absent," or "absent." The t test was used for the statistical analyses. In Group 1, CH was detected in 41 canals, IH in 4 canals, and NH in 4 canals. Differences between CH and both IH and NH were statistically significant (P < .001). In Group 2, CH was detected in 34 canals and NH in 4 canals. The difference between CH and NH was statistically significant (P < .001). A statistically significant difference (P < .05) between treatment groups was observed for CH at the 6-month follow-up appointment only; other than that instance, there were no statistical differences for CH or NH between the groups. In conclusion, extruded AH Plus does not prevent periapical healing, but can be a delaying factor for healing in children. PMID- 17709071 TI - Improving translational research for oral cancer screening aids: putting my "money" where my mouth is. PMID- 17709072 TI - Accuracy of measurements and reliability of landmark identification with computed tomography (CT) techniques in the maxillofacial area: a systematic review. AB - OBJECTIVE: The objective of this study was to evaluate the available published information on the reliability and accuracy of skeletal CT landmark identification and associated measurement accuracy through CT in the maxillofacial region. STUDY DESIGN: Electronic databases were searched with the help of a senior health sciences librarian. Abstracts that appeared to fulfill the initial selection criteria were selected by consensus. The original articles were then retrieved and their references hand-searched for possible missing articles. RESULTS: A total of 8 articles met the selection criteria. Differences between the magnitudes of errors of landmarks and their associated measurements were discussed. CONCLUSIONS: It was concluded that each landmark exhibited a characteristic pattern of error that contributed to measurement inaccuracy, and with repeated practice of landmark identifications, the error can be reduced to within 0.5 mm for 2-D CT. Considerations have to be given to some of the 3-D CT reliability values because they can have diagnosis implications. PMID- 17709073 TI - The effect of EDTA, EGTA, EDTAC, and tetracycline-HCl with and without subsequent NaOCl treatment on the microhardness of root canal dentin. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of single and combined use of ethylenediamine tetra acetic acid (EDTA), ethylene glycol bis [b aminoethylether] N,N,N',N'-tetraacetic acid (EGTA), EDTA plus Cetavlon (EDTAC), tetracycline-HCl, and NaOCl on the microhardness of root canal dentin. STUDY DESIGN: The crowns of 30 single-rooted human teeth were discarded at the cementoenamel junction and the roots were bisected longitudinally to obtain root halves (N = 60). The specimens were embedded in autopolymerizing acrylic resin, leaving the root canal dentin exposed. Dentin surfaces were prepared for microhardness test by grinding and polishing. The reference microhardness values of untreated specimens were recorded using a Vicker's microhardness tester at the apical, midroot, and cervical levels of the root canal. Thereafter, the specimens treated with single (test solution only) or combined (test solution, followed by 2.5% NaOCl) versions of the irrigants for 5 minutes. Posttreatment microhardness values were obtained as with initial ones. Statistical comparisons between the test groups and among single and combined treatments were carried out using 2-way ANOVA with repeated measures (P =.05). Comparisons within each group with respect to application regions were made with Friedman's nonparametric 2-way analysis of variance at the same level of significance. RESULTS: All treatment regimens except distilled water significantly decreased the microhardness of the root canal dentin (P < . 05). The single and combined use of EDTA decreased the microhardness of the root canal dentin significantly more than all other treatment regimens (P < .05). Compared with their single-treatment versions, all combined treatment regimens decreased the mean microhardness values significantly (P < .05). A comparison of single and combined treatment regimens revealed significant decreases only for EDTA and EDTA + NaOCl in the coronal region and for EDTAC and EDTAC + NaOCl in the apical and middle regions of the root canal (P < .05). CONCLUSIONS: The use of EDTA alone or prior to NaOCl resulted in the maximum decrease in dentin microhardness. The softening effect of subsequent NaOCl treatment was both material and region dependent. However, for combined treatment regimens, subsequent use of NaOCl levels the statistical differences between the regional microhardness values obtained after treatment with EGTA, EDTAC, and tetracycline-HCl. PMID- 17709074 TI - Immediate root canal disinfection with ultraviolet light: an ex vivo feasibility study. AB - OBJECTIVE: The study was designed to test application of ultraviolet light to root canal walls, as a mean of complementary immediate disinfection after the use of sodium hypochlorite. STUDY DESIGN: Root canals were infected ex vivo with Enterococcus faecalis for 48 hours. Non-attached bacteria were washed away, and the remaining attached bacteria were subjected to disinfection, with 5% sodium hypochlorite alone or followed by exposure to ultraviolet light (254 nm, 300 mJ/cm(2)). Root canals were then tested for remaining viable bacteria. Canals were obturated and tested again after 14 days. RESULTS: Sodium hypochlorite alone achieved negative cultures in only 47% of the cases, but 96% was achieved with sodium hypochlorite followed by ultraviolet light (P < .001). This status was also maintained after 14 days. CONCLUSIONS: Illumination of root canals with ultraviolet light may be an effective supplementary means to achieve immediate disinfection of infected root canals. PMID- 17709075 TI - Pulpal cellular reactions to experimental tooth movement in rats. AB - OBJECTIVE: The objective was to study the early cellular reactions of the dental pulp during experimental tooth movement. STUDY DESIGN: A total number of 98 male rats were used. Tooth movement was induced for 1 to 168 hours by inserting elastic bands between maxillary first and second molars of animals, which were labeled with tritiated thymidine. Pathologic signs, macrophage content, and proliferation of fibroblasts and endothelial cells were assessed histologically on autoradiographs of second molar pulps. Data were analyzed using ANOVA with Tukey's test as post hoc pairwise comparison. RESULTS: Pathologic signs and macrophage content generally increased with time after the induction of tooth movement. The proliferation of pulpal connective tissue progenitor cells and endothelial cells increased as a reaction to the force application. CONCLUSIONS: Force-induced tooth movement may lead to extensive, however temporary, trauma of the pulpal tissues, which react with early wound-healing events, such as macrophage invasion, cell proliferation, and angiogenesis. PMID- 17709077 TI - Tools of the trade for CTA: MDCT scanners and contrast medium injection protocols. AB - The introduction of multi-detector row computed tomography (MDCT) scanners in 1998 ushered in new advances in CT angiography (CTA). The subsequent expansion of MDCT scanner capabilities, coupled with advances in understanding of contrast medium (CM) dynamics, has further improved the clinical availability and consistency of CTA. We will review recent advances in CT scanner technology and discuss early CM dynamics. Specifically, we describe an approach tailored to the available scanner technology and to patient size aimed at providing consistently robust CTA studies across all vascular territories. A rational method to design combined CTA scan/injection protocols to facilitate this goal will be described. Our current experience with a simplified protocol for CTA with 64-MDCT will also be explained. PMID- 17709078 TI - CT angiography of peripheral arterial occlusive disease. AB - Lower extremity computed tomography angiography (CTA) is an effective, noninvasive, and robust imaging modality that is being used increasingly to evaluate patients with peripheral arterial occlusive disease (PAOD). It is important for vascular and interventional radiologists, and vascular surgeons to be familiar with the strengths and limitations, diagnostic accuracy, and practical application of lower extremity CTA. In this article, we review the technical principles of image acquisition, visualization techniques to effectively interpret the large volumetric datasets generated, and the current practical application of lower extremity CTA with respect to PAOD. PMID- 17709079 TI - Mesenteric CT angiography: a discussion of techniques and selected applications. AB - Sixty-four slice MDCT with advanced three-dimensional (3D) visualization software provides a unique opportunity for noninvasive evaluation of the mesenteric vasculature. Although standard axial computed tomography (CT) scanning has always allowed identification of the mesenteric arteries and veins, it is limited in its ability to adequately image small branches and complex anatomy. However, the submillimeter collimation possible with 64-slice CT scanners now allows the acquisition of true isotropic data and therefore high spatial resolution is now maintained in any imaging plane. This ability to visualize the mesenteric vasculature in real-time using 3D rendering and multiplanar reconstruction is crucial for comprehensive review of the complex mesenteric vessels. In this article, we discuss CT scanning protocols and 3D imaging techniques that can be utilized for CT angiography of the mesenteric vessels. Additionally, we will discuss several key conditions that illustrate the value of 3D imaging over standard axial images in mesenteric CT angiography. PMID- 17709080 TI - CT angiography of extremity trauma. AB - With the advent of multi-detector computed tomography, CT angiography (CTA) has rapidly become the first line imaging modality for detecting extremity arterial injuries in blunt and penetrating trauma patients. A variety of significant injuries are detected with high sensitivity and specificity. The information provided by CTAs in this patient population is often sufficient for making therapeutic decisions, such as the need for and type of surgical or endovascular interventions. Technological advances have allowed for isotropic imaging and improved quality of multi-planar and three-dimensional reformations, which aid in diagnosis and surgical planning. The rapid acquisition speed of 64 multi-detector CT scanners has facilitated integration of CTA into routine trauma CT imaging using a single contrast bolus injection. PMID- 17709081 TI - Techniques in interventional radiology: renal CT angiography. AB - Multidetector row CT angiography has become an important tool in the evaluation of patients with suspected renovascular hypertension. The following article presents a review of the published data on accuracy of this method of evaluation as well as a comparison to other diagnostic strategies, in particular, renal MR angiography. PMID- 17709082 TI - CT angiography of lower extremity vascular bypass grafts. AB - Over the past several years computed tomography (CT) technology has advanced to such a degree that CT angiography (CTA) has become the study of choice at our institution for imaging lower extremity vascular bypass grafts. CTA quickly provides anatomic information about the state of the graft and identifies virtually all forms of bypass graft failure and related complications. Furthermore, detailed vascular anatomy is seen beyond the graft and affords sufficient anatomic detail for surgical revision without the need for other angiographic studies. Although catheter angiography, duplex-ultrasound, magnetic resonance angiography, and nuclear medicine studies all continue to play some role in the evaluation of vascular grafts, they are more often used as problem solving modalities when CTA findings are equivocal. Whereas it was once essential to catheterize directly through a failing bypass graft or pass catheters into the graft from a distant arterial puncture to obtain an angiogram of a failing bypass graft, CTA produces arteriograms with only intravenous contrast administration, a brief visit to the CT scanner, and return to daily activities without catheterization, discomfort, or risk to the bypass conduit. PMID- 17709083 TI - Pulmonary artery CTA. AB - The latest with the introduction of multidetector row computed tomography (MDCT), CT has been firmly established as the modality of choice for imaging the pulmonary arteries, particularly as the de facto first line test for imaging patients with suspected acute pulmonary embolism (PE). Before the introduction of MDCT, remaining concerns regarding CTs accuracy for diagnosis of isolated peripheral emboli had prevented the unanimous acceptance of this test as the reference standard for imaging PE. After a decade of uncertainty, there is now conclusive evidence that CT, if positive, provides reliable confirmation of the presence of PE and, more importantly, if negative effectively rules out clinically significant PE. Current endeavors to streamline and facilitate workflow for CT diagnosis of PE will further improve the acceptance, utility, and importance of this test. Examples include improvements in workflow, CT derivation of right ventricular function parameters for triage and prognostication of patients with acute PE and the comprehensive assessment of patients with acute chest pain for PE, coronary disease, aortic disease, and pulmonary disease by means of a single, contrast enhanced, ECG-synchronized CT scan. Although the diagnosis or exclusion of acute PE is the most common and important application of CT pulmonary angiography, the ease of scan acquisition and the high spatial resolution of modern CT techniques make this test ideally suited for the greatest majority of congenital and acquired, acute and chronic disorders of the pulmonary arteries. PMID- 17709084 TI - A practical approach to CT angiography of the neck and brain. AB - Computed tomography angiography (CTA) is a rapidly developing technology with great potential. This is particularly true for evaluating neurovascular disease. Clinical stroke because of atherosclerotic disease of the carotid and vertebral arteries is a common examination indication; areas of stenosis, and soft and calcified plaque along the entire vessel, not only at the carotid bifurcation, permit a full assessment of the patient's disease process. Other diseases including dissection, trauma, intracranial stenosis, thrombosis, and aneurysms can be readily diagnosed. Although duplex ultrasound may be a first line examination in many patients, both magnetic resonance angiography (MRA) and CTA offer distinct advantages over it. CTA and MRA are both highly accurate but CTA has several key advantages. CTA has been advanced by the development of improved multidetector CT (MDCT) and workstations that postprocess the data. Methods to obtain quality CTA images and to rapidly analyze the data for abnormalities are the subject of this chapter. In addition, evolving techniques in future CT scanners and workstations, and developing methods of vulnerable plaque and CT perfusion imaging are discussed. PMID- 17709085 TI - Coronary CT angiography: insights into patient preparation and scanning. AB - Cardiac computed tomography (CT) and coronary CT angiography represent a breakthrough in cardiac diagnostic power and are already making an impact on clinical practice. Yet, technical limitations remain and patients must be appropriately selected for this new and exciting examination. An understanding of those limitations will help guide patient selection and maximize the clinical yield of the test. The most significant issues to deal with are those of inherently increased image noise, vulnerability to cardiac and respiratory motion and arrhythmia, and image artifacts that result from the presence of coronary calcification and stents. Fortunately, there are methods to overcome all of these limitations. These predominantly involve diligent and attentive patient preparation before the scan, focusing on clinical, hemodynamic, and basic eletrocardiographic parameters. With proper premedication to optimize heart rate, simple patient coaching, attention to detail during the acquisition, and the use of software tools to optimize the axial image reconstruction, cardiac CT should consistently yield very satisfying results. PMID- 17709086 TI - Coronary artery anomalies. AB - Coronary artery anomalies are uncommon findings but can be of significant clinical importance in a small number of individuals. Clinical presentation depends on the specific anomaly. Most coronary artery anomalies are benign and clinically insignificant, however, some anomalies are potentially significant and can lead to heart failure and even death. Noninvasive imaging has emerged as the preferred way to image coronary anomalies. Both electron beam computed tomography (EBCT) and magnetic resonance angiography (MRA) are useful for the diagnosis of anomalous coronary arteries. Recently, MDCT has also proven to be very useful in the detection and characterization of anomalous coronary arteries. This chapter will review the appearance of the most commonly encountered coronary anomalies on MDCT. PMID- 17709087 TI - Coronary artery CTA: imaging of atherosclerosis in the coronary arteries and reporting of coronary artery CTA findings. AB - Invasive coronary angiography remains the standard for assessment of coronary anatomy and pathology, and for determining the extent and severity of coronary lumen obstruction in coronary artery disease. Recent advances in multidetector row computed tomography (MDCT) technology allowing noninvasive imaging of the coronary arteries has led to widespread enthusiasm for the use of noninvasive coronary angiography. A comprehensive and clinically useful MDCT study should incorporate an understanding of the patient history and reason for performance of the test, an overall assessment of study quality, and a complete description of pertinent findings. Because the majority of cardiac computed tomography (CT) studies are now being performed for the evaluation of the coronary arteries and obstructive coronary disease, a clear understanding of what the clinician wants to know from a CTA is critical to its comprehensive interpretation. In this manuscript, we provide an overview of the necessary components of CT coronary angiogram interpretation, from the point of view of the practicing invasive cardiologist. PMID- 17709089 TI - rDNA-ITS2-PCR assay for grouping the cryptic species of Anopheles culicifacies complex (Diptera: Culicidae). AB - Anopheles culicifacies, a predominant vector of malaria in India exists as a complex of five sibling species A, B, C, D and E, of which, except species B, all the rest are vectors with varying vectorial capacities. With a combination of PCR assays, it is possible to identify all the five members of this species complex. These assays include amplification of the rDNA-ITS2 region followed by digestion of the ITS2 amplicon using restriction enzyme, Rsa I which groups the five members of the An. culicifacies complex into two categories: species A and D forming one category and species B, C and E forming another. The samples grouped thus are then subjected to two allele-specific PCR assays (AD-PCR and BCE-PCR), which has been designed using sequence differences in the mitochondrial cytochrome oxidase II (CO II) subunit. The AD-PCR assay distinguishes species A and D, whereas the BCE-PCR assay distinguishes species B, C and E. In the present study, the differences in the ITS2 region of the five species was used to design a PCR assay which groups the five members into the same two categories as obtained after digestion of the ITS2-PCR product. This assay uses a common forward primer based on the 5.8S region and two reverse primers, which is specific for the two categories. Amplification of a PCR product of size 253bp indicates the presence of species A/D, while a product of size 409bp indicates the presence of species B/C/E. By using this ITS2 PCR assay, the three-step procedure is reduced to two cutting down the time and cost involved. The ITS2 PCR assay has been validated on specimens collected from different regions of India and the results confirm to the earlier reports on the distribution of the members of the An. culicifacies complex. PMID- 17709088 TI - Prevalence of Toxocara spp., Toxascaris leonina and ancylostomidae in public parks and beaches in different climate zones of Costa Rica. AB - This epidemiological study was conducted in different regions of Costa Rica to determine the prevalence of the developmental stages of potential zoonotic intestinal helminths of dogs and cats in public places. Samples were collected within three main climate zones including rural and urban areas during both the rainy and the dry season. Faecal and environmental samples were taken from 69 parks and beaches. Of the faecal samples 3% contained Toxascaris spp. eggs, 7% Toxocara spp. eggs and 55% contained ancylostomidae eggs. Of the soil samples, 2% contained ancylostomidae eggs and 0.8% contained ascarid eggs. Significant differences in the presence of parasites were found in faecal samples of dry, moist and wet climate zones and between the dry and rainy seasons. Significant differences in the presence of eggs and larvae were also found in the grass samples in the dry, the moist and the wet climate zones and between the different seasons. No significant differences were found between rural and urban areas. PMID- 17709090 TI - A one-tube site-directed mutagenesis method using PCR and primer extension. PMID- 17709092 TI - Colorimetric quantification of alpha-D-galactose 1-phosphate. PMID- 17709091 TI - Online monitoring of BALB/3T3 metabolism and adhesion with multiparametric chip based system. AB - A multiparametric chip-based system was employed to measure cell adhesion, metabolism, and response to metal compounds previously classified as cytotoxic in immortalized mouse fibroblasts (BALB/3T3 cell line). The system measures in parallel, online, and in label-free conditions the extracellular acidification rates (with pH-sensitive field effect transistors [ISFETs]), the cellular oxygen consumption (with amperometric electrode structures [Clark-type sensors]), and cell adhesion (with impedimetric interdigitated electrode structures [IDESs]). The experimental protocol was optimized to monitor metabolism and adhesion of the BALB/3T3 cell line. A total of 70,000 cells and a bicarbonate buffer-free running low-glucose Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal clone serum III and 1mM Hepes were selected to maintain cells in good conditions on the chip during the measurements performed under perfusion conditions. Cells were exposed to sodium arsenite, cadmium chloride, and cis-platinum at concentrations ranging from 1 to 100 microM. The kinetics of cell response to these compounds was analyzed and suggests that the Clark-type sensors can be more sensitive than IDESs and ISFETs in detecting the presence of high chemical concentration when short exposure times (i.e., 2h) are considered. The cytotoxicity data obtained from the online measurements of acidification, respiration, and adhesion at 24h compare well, in terms of half-inhibition concentration values (IC(50)), with the ones obtained using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test and colony-forming efficiency (CFE) assay. The results show a good sensitivity of the system combined with the advantages of the online and label free detection methods that allow following cell status before, during, and after the treatment in the same experiment. PMID- 17709093 TI - Content difference between normal and abnormal obsessions. AB - Although it has long been thought that experiencing an obsession is a psychiatric symptom, more recent literature, has seen the normalisation of obsessions and other presumably clinical phenomena. That is, not only people suffering from psychiatric disorders experience obsessions but non-clinical individuals also do so. Furthermore, it has been argued that such normal obsessions are very similar to abnormal ones, in terms of content. However, in the present study, evidence was obtained indicating that normal and abnormal obsessions do differ in content. A sample of 133 healthy undergraduates was given a list of 70 obsessions, with some originating from obsessive-compulsive disorder (OCD) patients, and others stemming from healthy volunteers. Participants were asked to indicate whether they had ever experienced these obsessions. Participants endorsed significantly more normal than abnormal obsessions, suggesting that the two kinds of obsessions do differ from each other. In addition, the experience of clinical obsessions was more strongly associated with scores on a measure of OCD symptoms, than was the experience of normal obsessions. PMID- 17709094 TI - Methyl dynamics of the amyloid-beta peptides Abeta40 and Abeta42. AB - To probe the role of side chain dynamics in Abeta aggregation, we studied the methyl dynamics of native Abeta40 and Abeta42 by measuring cross relaxation rates with interleaved data collection. The methyl groups in the C-terminus are in general more rigid in Abeta42 than in Abeta40, consistent with previous results from backbone (15)N dynamics. This lends support to the hypothesis that a rigid C terminus in Abeta42 may serve as an internal aggregation seed. Interestingly, two methyl groups of V18 located in the central hydrophobic cluster are more mobile in Abeta42 than in Abeta40, most likely due to the paucity of V18 intra-molecular interactions in Abeta42. V18 may then be more available for inter-molecular interactions to form Abeta42 aggregates. Thus, the side chain mobility of the central hydrophobic cluster may play an important role in Abeta aggregation and may contribute to the difference in aggregation propensity between Abeta40 and Abeta42. PMID- 17709095 TI - AMPK links energy status to cell structure and mitosis. AB - AMP-activated protein kinase (AMPK) is known as an important cellular energy sensor, but its in vivo role has not been fully understood. Recent studies provided surprising results that AMPK regulates cell polarity and mitosis under the control of tumour suppressor LKB1. Moreover, these newly found in vivo functions of AMPK are regulated by energy status in a cell autonomous manner. These findings provide novel insights into the physiological function of AMPK and the treatment of AMPK-related diseases such as cancer and diabetes. PMID- 17709096 TI - Impact of diabetic serum on endothelial cells: an in-vitro-analysis of endothelial dysfunction in diabetes mellitus type 2. AB - Diabetic endothelial dysfunction was characterized by altered levels of adhesion molecules and cytokines. Aim of our study was to evaluate the effects of diabetic serum on cell-growth and proinflammatory markers in human saphenous vein endothelial cells (HSVEC) from diabetic and non-diabetic patients. Diabetic serum showed (1) complementary proliferative activity for non-diabetic and diabetic HSVEC, (2) unchanged surface expression of adhesion molecules, and (3) elevated levels of sICAM-1 in HSVEC of all donors. The concentration of sVCAM-1 was increased only in diabetic cells. The proinflammatory state of diabetic HSVEC characterized by increased levels of cytokines was compensated. We concluded that even under normoglycemic conditions the serum itself contains critical factors leading to abnormal regulation of inflammation in diabetics. We introduced an in vitro model of diabetes representing the endothelial situation at the beginning of diabetes (non-diabetic cells/diabetic serum) as well as the diabetic chronic state (diabetic cells/diabetic serum). PMID- 17709098 TI - Identification of one capa and two pyrokinin receptors from the malaria mosquito Anopheles gambiae. AB - We cloned the cDNA of three evolutionarily related G protein-coupled receptors from the malaria mosquito Anopheles gambiae and functionally expressed them in Chinese hamster ovary cells. One receptor, Ang-Capa-R, was only activated by the two Anopheles capa neuropeptides Ang-capa-1 (GPTVGLFAFPRVamide) and Ang-capa-2 (pQGLVPFPRVamide) with EC(50) values of 8.6x10(-9)M and 3.3x10(-9)M, respectively, but not by any other known mosquito neuropeptide. The second receptor, Ang-PK-1-R, was selectively activated by the Anopheles pyrokinin-1 peptides Ang-PK-1-1 (AGGTGANSAMWFGPRLamide) and Ang-PK-1-2 (AAAMWFGPRLamide) with EC(50) values of 3.3x10(-8)M and 2.5x10(-8)M, respectively, but not by mosquito capa or pyrokinin-2 peptides. For the third receptor, Ang-PK-2-R, the most potent ligands were the pyrokinin-2 peptides Ang-PK-2-1 (DSVGENHQRPPFAPRLamide) and Ang PK-2-2 (NLPFSPRLamide) with EC(50) values of 5.2x10(-9)M and 6.4x10(-9)M, respectively. However, this receptor could also be activated by the two pyrokinins-1, albeit with lower potency (EC(50): 2-5x10(-8)M). Because Ang-capa-1 and -2 and Ang-PK-1-1 are located on one preprohormone and the other peptides on another prohormone, these results imply a considerable crosstalk between the capa, pyrokinin-1 and pyrokinin-2 systems. Gene structure and phylogenetic tree analyses showed that Ang-Capa-R was the orthologue of the Drosophila capa receptor CG14575, Ang-PK-1-R the orthologue of the Drosophila pyrokinin-1 receptor CG9918, and Ang-PK-2-R the orthologue of the Drosophila pyrokinin-2 receptors CG8784 and CG8795. This is the first report on the functional characterization and crosstalk properties of capa and pyrokinin receptors in mosquitoes. PMID- 17709097 TI - Dissociation of AMP-activated protein kinase and p38 mitogen-activated protein kinase signaling in skeletal muscle. AB - AMP-activated protein kinase (AMPK) is widely recognized as an important regulator of glucose transport in skeletal muscle. The p38 mitogen-activated protein kinase (MAPK) has been proposed to be a component of AMPK-mediated signaling. Here we used several different models of altered AMPK activity to determine whether p38 MAPK is a downstream intermediate of AMPK-mediated signaling in skeletal muscle. First, L6 myoblasts and myotubes were treated with AICAR, an AMPK stimulator. AMPK phosphorylation was significantly increased, but there was no change in p38 MAPK phosphorylation. Similarly, AICAR incubation of isolated rat extensor digitorum longus (EDL) muscles did not increase p38 phosphorylation. Next, we used transgenic mice expressing an inactive form of the AMPKalpha2 catalytic subunit in skeletal muscle (AMPKalpha2i TG mice). AMPKalpha2i TG mice did not exhibit any defect in basal or contraction-induced p38 MAPK phosphorylation. We also used transgenic mice expressing an activating mutation in the AMPKgamma1 subunit (gamma1R70Q TG mice). Despite activated AMPK, basal p38 MAPK phosphorylation was not different between wild type and gamma1R70Q TG mice. In addition, muscle contraction-induced p38 MAPK phosphorylation was significantly blunted in the gamma1R70Q TG mice. In conclusion, increasing AMPK activity by AICAR and AMPKgamma1 mutation does not increase p38 MAPK phosphorylation in skeletal muscle. Furthermore, AMPKalpha2i TG mice lacking contraction-stimulated AMPK activity have normal p38 MAPK phosphorylation. These results suggest that p38 MAPK is not a downstream component of AMPK-mediated signaling in skeletal muscle. PMID- 17709100 TI - The structure of the carbohydrate backbone of the LPS from Myxococcus xanthus strain DK1622. AB - Gram-negative rod shaped bacterium Myxococcus xanthus DK1622 produces a smooth type LPS. The structure of the polysaccharide O-chain and the core-lipid A region of the LPS has been determined by chemical and spectroscopic methods. The O-chain was built up of disaccharide repeating units having the following structure: - >6)-alpha-D-Glcp-(1-->4)-alpha-D-GalpNAc6oMe*-(1--> with partially methylated GalNAc residue. The core region consisted of a phosphorylated hexasaccharide, containing one Kdo residue, unsubstituted at O-4, and no heptose residues. The lipid A component consisted of beta-GlcN-(1-->6)-alpha-GlcN1P disaccharide, N acylated with 13-methyl-C14-3OH (iso-C15-3OH), C16-3OH, and 15-methyl-C16-3OH (iso-C17-3OH) acids. The lipid portion contained O-linked iso-C16 acid. PMID- 17709099 TI - Selective serotonin reuptake inhibitors--a new modality for the treatment of lymphoma/leukaemia? AB - Selective serotonin reuptake inhibitors (SSRIs) have recently been reported to specifically kill malignant cells of B-lymphoid origin, i.e., cells derived from Burkitt lymphoma. Accordingly, SSRIs have been proposed as lead compounds in the development of new approaches to the treatment of lymphoma/leukaemia. Here we attempted to dissect the underlying signaling pathways by comparing susceptible and resistant cell lines. However, we found that all cell lines investigated underwent apoptotic cell death when exposed to SSRI concentrations exceeding 10 microM regardless of whether the cell lines were derived from B- (e.g., Namalwa, Ramos, Daudi, RL7), T-lymphoid tumors (e.g., Molt-4, Jurkat, CCRF-CEM) or other sources. The structure-activity relationship readily distinguished the pro apoptotic and growth inhibitory effect of SSRIs from their eponymous action (blockage of the serotonin transporter): acetylation of the SSRIs fluvoxamine and paroxetine abrogated the ability of these compounds to inhibit 5HT-uptake, but did not impair their cytotoxic action. Based on these data we conclude that (i) SSRIs inhibit growth of transformed cells, but that (ii) this effect is neither specific for malignant cells nor specific for any particular cellular subset. (iii) The pro-apoptotic effect of SSRIs (at microM concentrations) is unrelated to their principal pharmacological action, i.e., inhibition of serotonin uptake (at nM concentrations). SSRIs or improved versions thereof are therefore unlikely to represent useful lead compounds for inducing apoptosis in B-cell derived tumors: the underlying mechanism is not confined to any specific cell lineage. PMID- 17709101 TI - Structural investigation of a heteropolysaccharide isolated from the pods (fruits) of Moringa oleifera (Sajina). AB - A water-soluble polysaccharide was isolated from the aqueous extract of pods of Moringa oleifera. The polysaccharide contains d-galactose, 6-O-Me-D-galactose, D galacturonic acid, l-arabinose, and l-rhamnose in a molar ratio of 1:1:1:1:1. On the basis of total hydrolysis, methylation analysis, periodate oxidation, and NMR ((1)H, (13)C, TOCSY, DQF-COSY, NOESY, ROESY, HSQC, and HMBC) studies, the repeating unit of the polysaccharide is established as [structure: see text]. PMID- 17709102 TI - The effect of generalized discriminate analysis (GDA) to the classification of optic nerve disease from VEP signals. AB - In this paper, we have investigated the effect of generalized discriminate analysis (GDA) on classification performance of optic nerve disease from visual evoke potentials (VEP) signals. The GDA method has been used as a pre-processing step prior to the classification process of optic nerve disease. The proposed method consists of two parts. First, GDA has been used as pre-processing to increase the distinguishing of optic nerve disease from VEP signals. Second, we have used the C4.5 decision tree classifier, Levenberg Marquart (LM) back propagation algorithm, artificial immune recognition system (AIRS), linear discriminant analysis (LDA), and support vector machine (SVM) classifiers. Without GDA, we have obtained 84.37%, 93.75%, 75%, 76.56%, and 53.125% classification accuracies using C4.5 decision tree classifier, LM back propagation algorithm, AIRS, LDA, and SVM algorithms, respectively. With GDA, 93.75%, 93.86%, 81.25%, 93.75%, and 93.75% classification accuracies have been obtained using the above algorithms, respectively. These results show that the GDA pre-processing method has produced very promising results in diagnosis of optic nerve disease from VEP signals. PMID- 17709103 TI - Probabilistic neural networks employing Lyapunov exponents for analysis of Doppler ultrasound signals. AB - The implementation of probabilistic neural networks (PNNs) with the Lyapunov exponents for Doppler ultrasound signals classification is presented. This study is directly based on the consideration that Doppler ultrasound signals are chaotic signals. This consideration was tested successfully using the nonlinear dynamics tools, like the computation of Lyapunov exponents. Decision making was performed in two stages: computation of Lyapunov exponents as representative features of the Doppler ultrasound signals and classification using the PNNs trained on the extracted features. The present research demonstrated that the Lyapunov exponents are the features which well represent the Doppler ultrasound signals and the PNNs trained on these features achieved high classification accuracies. PMID- 17709104 TI - Insulin-like Growth Factor Binding Protein-3 expression in the human corneal epithelium. AB - Insulin-like Growth Factor Binding Protein-3 (IGFBP3) is a high-affinity binding protein shown to regulate cell growth, differentiation, and apoptosis in a variety of cellular systems. The primary aim of this study was to characterize IGFBP3 expression in the human corneal epithelium and in a corneal epithelial cell line and to establish a potential role for IGFBP3-mediated apoptotic signaling in corneal epithelial cells. Using a telomerase-immortalized human corneal epithelial (hTCEpi) cell line cultured in serum-free media and fresh human eye bank donor tissue, expression and localization of IGFBP3 were established in situ and in vitro by indirect immunofluorescence and western blotting. Real-time PCR was used to measure IGFBP3 mRNA levels following Trichostatin A (TSA) treatment and as a function of confluence. IGFBP3 protein levels were assessed in resting human tears and in conditioned media by western blotting as was the ability of recombinant human IGFBP3 protein to associate with the cell surface. Apoptotic signaling was assessed in vitro using TSA and recombinant human (rh)IGFBP3. Apoptosis was measured by Viability/Cytotoxicity, Annexin V, and TUNEL assays. IGFBP3 was localized to the plasma membrane of human corneal epithelial cells in situ and was upregulated in surface cells in the central cornea. IGFBP3 was secreted in conditioned media of growing cells, with a robust upregulation following confluence (P=0.014) and differentiation. IGFBP3 was undetectable in human tears. Addition of TSA to the culture media resulted in an upregulation of IGFBP3 mRNA (P<0.001) and protein. In addition, TSA treatment led to a significant increase in Annexin V positive cells at 18 and 24h (P<0.001) and TUNEL positive cells at 24 and 48 h (P<0.001). The addition of rhIGFBP3 to the cell culture media appeared to induce occasional membrane blebbing, but cells failed to become positive with Annexin V or TUNEL. Taken together, these results demonstrate that cell membrane-associated IGFBP3 is produced by corneal epithelial cells and associates with the plasma membrane of superficial cells in situ and in cultured cells, but not present in human tears. The differential localization and effect(s) on apoptosis suggest that the effects of IGFBP3 are likely tissue compartment and receptor specific and may be regulated by glycosylation. PMID- 17709105 TI - Trichomonas vaginalis: reactive oxygen species mediates caspase-3 dependent apoptosis of human neutrophils. AB - There are many neutrophils in the vaginal discharge from women infected with Trichomonas vaginalis. The aim of our study was to determine whether human neutrophil apoptosis may be regulated by reactive oxygen species (ROS) in response to trichomonads infection. Incubation of human neutrophils with live trichomonads caused marked receptor shedding of CD16, decrease of mitochondrial membrane potential (MMP) and caspase-3 activation in human neutrophils. These proapoptotic effects of T. vaginalis on neutrophils were inhibited by pretreatment of neutrophils with an inhibitor of NADPH oxidase, diphenyleneiodonium chloride (DPI), suggesting an important role of intracellular ROS accumulation in T. vaginalis-triggered apoptosis. Indeed, large amounts of ROS levels were detected in neutrophils incubated with live trichomonads, and were also effectively inhibited by DPI. However, pan-caspase inhibitor z-VAD-fmk or caspase-3 inhibitor z-DEVD-fmk did not affect T. vaginalis-induced ROS generation in neutrophils. These results suggest that ROS-dependent caspase-3 activation plays an important role in apoptosis of human neutrophils induced by T. vaginalis. PMID- 17709106 TI - Real time mass flow rate measurement using multiple fan beam optical tomography. AB - This paper presents the implementing multiple fan beam projection technique using optical fibre sensors for a tomography system. From the dynamic experiment of solid/gas flow using plastic beads in a gravity flow rig, the designed optical fibre sensors are reliable in measuring the mass flow rate below 40% of flow. Another important matter that has been discussed is the image processing rate or IPR. Generally, the applied image reconstruction algorithms, the construction of the sensor and also the designed software are considered to be reliable and suitable to perform real-time image reconstruction and mass flow rate measurements. PMID- 17709107 TI - Problem and its solution for actuator saturation of integrating process with dead time. AB - The modified Smith predictor (MSP) for integrating process with dead time (IPDT) has at least one pole at the origin of s-plane. The integral effect leads to large overshoot and slow settling time when the control signal exceeds the saturation limits of the system actuator. The windup problem in MSP is presented and studied. Based on the two degrees of freedom (2DOF) control schemes presented by Normey-Rico and Camacho, an anti-windup controller (AWC) is proposed. By simulation, significant performance improvement demonstrates the effectiveness of the proposed scheme. PMID- 17709108 TI - High gametocyte complexity and mosquito infectivity of Plasmodium falciparum in the Gambia. AB - The purpose of this work was to determine the infectivity to mosquitoes of genetically diverse Plasmodium falciparum clones seen in natural infections in the Gambia. Two principal questions were addressed: (i) how infectious are gametocytes of sub-patent infections, particularly at the end of the dry season; and (ii) are all clones in multiclonal infections equally capable of infecting mosquitoes? The work was carried out with two cohorts of infected individuals. Firstly, a group of 31 P. falciparum-infected people were recruited in the middle of the dry season (May, 2003), then examined for P. falciparum at the beginning (August 2003) and middle (October, 2003) of the transmission season. On each occasion, we examined the genotypes of asexual forms and gametocytes by PCR and RT-PCR, as well as their infectivity to Anopheles gambiae using membrane feeds. One individual gave rise to infected mosquitoes in May, and two in August. Different gametocyte genotypes co-existed in the same infection and fluctuated over time. The mean multiplicity of infection was 1.4, 1.7 and 1.5 clones in May, August and October, respectively. Second, a group of patients undergoing drug treatment during August 2003 was tested for asexual and gametocyte genotypes and their infectivity to mosquitoes. Forty-three out of 100 feeds produced infections. The genetic complexity of the parasites in mosquitoes was sometimes greater than that detectable in the blood on which the mosquitoes had fed. This suggested that gametocytes of clones existing in the blood below PCR detection limits at the time of the feed were at least as infectious to the mosquitoes as the more abundant clones. These findings emphasise the crucial role of gametocyte complexity and infectivity in generating the remarkable diversity of P. falciparum genotypes seen in infected people, even in an area of seasonal transmission. PMID- 17709109 TI - Indices of reverse cholesterol transport in subjects with metabolic syndrome after treatment with rosuvastatin. AB - OBJECTIVE: The effects of the statin, rosuvastatin on indices of reverse cholesterol transport were studied in a randomized, placebo-controlled, cross over trial in 25 overweight subjects with defined metabolic syndrome. RESULT: Four weeks' treatment with 40 mg/day rosuvastatin significantly reduced levels of plasma cholesterol (44%), LDL cholesterol (60%) and triglyceride (38%). HDL cholesterol (mean [S.D.]) rose (0.97[0.17] to 1.05[0.17]mmol/L; P<0.05) and the LpA-I component of HDL from 39[7] to 45[9]mg/dL (P<0.05). LCAT activity fell (0.55[0.13] to 0.35[0.07]nmol/mL/h; P<0.05); CETP activity and mass fell from 89[13] to 80[11]nmol//L/h and from 1.66[0.57] to 1.28[0.41]mug/mL respectively, (P<0.05). Cholesterol efflux in vitro (to plasmas from THP-1 activated cells) fell from 7.1[1.8]% (placebo) to 6.2[1.7]% (rosuvastatin); P<0.05, but when plasmas depleted of apoB lipoproteins were studied, the difference in efflux was no longer statistically significant. During placebo efflux was paradoxically inversely correlated with HDL-C (P=0.016) and LpA-I (P=0.035) concentrations but these correlations were absent after rosuvastatin. CONCLUSIONS: The data suggest possible HDL dysfunctionality in subjects with metabolic syndrome. The reduced capacity of plasmas following statin treatment to stimulate cholesterol efflux in vitro occurred in association with reduction in apoB lipoproteins and reduced activities of CETP and LCAT, and despite increased levels of HDL cholesterol. PMID- 17709110 TI - Translational constraint influences dynamic spinal canal occlusion of the thoracic spine: an in vitro experimental study. AB - Mechanical constraints to spine motion can arise in a variety of real-world situations such as when shoulder belts prevent anterior translation of the thorax during automotive collisions. The effect of such constraint on spinal column spinal cord interaction during injury remains unknown. The purpose of the present study was to compare maximal dynamic spinal canal occlusion, measured via a specialized transducer, in cadaveric upper thoracic spine specimens under a variety of anterior-posterior constraint conditions. Four injury models were produced using 24 cadaveric spine specimens (T1-T4). Incremental compressive trauma was applied under constrained (i.e. blocked anterior-posterior translation) flexion-compression, pure-compression and extension-compression, and under unconstrained (i.e. free anterior-posterior translation) flexion compression. All displacements were applied at 500 mm/s. For all three constrained trauma groups, complete transducer occlusion occurred between 20 and 30 mm of compressive displacement. The extension-compression caused transducer occlusion significantly less than the other constrained models (p < 0.022) at 20 mm compression. For unconstrained flexion-compression, a compression of up to 50 mm resulted in a mean of 26% transducer occlusion. The constrained pure compression tests led to burst fracture with significant body height loss at T2. The constrained flexion-compression and extension-compression tests caused fracture-dislocation injury at the T2-T3 level. Constrained trauma clearly led to more spinal canal occlusion than the unconstrained in these models, and more severe injury to the spinal column. The results add to our understanding of the effect of column injury pattern on spinal cord injury. This information has clear implications for the design of injury prevention devices. PMID- 17709111 TI - Comparison of standard and new generation hydrophobic interaction chromatography resins in the monoclonal antibody purification process. AB - Recent efforts to improve hydrophobic interaction chromatography (HIC) for use in monoclonal antibody (mAb) purification have focused on two approaches: optimization of resin pore size to facilitate mAb mass transport, and use of novel hydrophobic charge induction (HCIC) mixed mode ligands that allow capture of mAbs under low salt conditions. We evaluated standard HIC and new generation HIC and HIC-related chromatography resins for mAb purification process efficiency and product quality both as isolated chromatography steps and in purification process trains. We find that HIC resins with optimized pore size have significantly improved binding capacity which can increase HIC purification unit operation efficiency. The HCIC Mercapto-Ethyl-Pyridine (MEP) resin, which shows a different salt impact trend and impurity resolution pattern from standard HIC resin, can not only capture mAb from crude CHO fermentation supernatant but also substantially enhance mAb purification process flow efficiency when serving as a polishing role. PMID- 17709113 TI - Evaluation of on-line solid-phase extraction parameters for hyphenated, high performance liquid chromatography-solid-phase extraction-nuclear magnetic resonance applications. AB - The hyphenated technique HPLC-SPE-NMR is proving to be a useful analytical tool for structure elucidation of mixture components, particularly for mass-limited samples where traditional isolation procedures are either time consuming or challenging. In this work, we investigated SPE trapping performance of 25 model natural products within a format corresponding to that of HPLC-SPE-NMR hyphenation. Six different silica-based bonded phases and two polymeric phases were evaluated. The trapping efficiency of polystyrene/divinylbenzene polymers was generally superior compared to silica bonded phases, which showed variable results and performed well only with hydrophobic analytes. Acetonitrile concentration in the loading solvent was critical for trapping on polymeric phase (Resin GP), as small changes of the organic solvent concentration (+/-3%) could alter the trapping efficiency significantly. Flow rate changes of the loading solvent within 0.8-5.0 mL/min did not affect trapping kinetics. Simulation of multiple trapping showed excellent performance of this approach for hydrophobic analytes, and moderate gain for more polar analytes that do not trap quantitatively in a single trapping step. Determination of 50% breakthrough levels by frontal chromatography analysis showed feasibility of accumulation of analyte amounts corresponding to about 0.5 micromol (10 mm x 2 mm i.d. Resin GP cartridge). PMID- 17709112 TI - Characterization of (E,E)-farnesol and its fatty acid esters from anal scent glands of nutria (Myocastor coypus) by gas chromatography-mass spectrometry and gas chromatography-infrared spectrometry. AB - Several volatile compounds, including terpenoids, fatty alcohols, fatty acids and some of their esters, were identified from solvent extracts prepared from anal scent glands of nutria (a.k.a. coypu), a serious rodent pest ravaging wetlands in the USA. The major terpenoid constituents were identified as (E,E)-farnesol and its esters by a comparison of their gas chromatographic retention times, and electron-ionization (EI) and chemical-ionization (CI) mass spectra with those of authentic compounds. EI mass spectra of the four farnesol isomers are very similar, however, the ChemStation (Agilent) and GC-MS Solution (Shimadzu) software algorithms were able to identify the natural compound as the (E,E) isomer, when a high-quality mass spectral library was compiled from reference samples and used for searching. Similarly, the esters were identified as those of (E,E)-farnesol. In contrast to EI spectra, the CI spectra of the (E,E)- and (E,Z) isomers are distinctly different from those of the (Z,E)- and (Z,Z)-isomers. The intensities (I) of the peaks for the m/z 137 and 121 ions in the CI spectra offer a way of determining the configuration of the C-2 double bond of farnesols (for 2E isomers I(137)>I(121), whereas for 2Z isomers I(137)3) are found, they must have a geometrical diameter larger than 3 microm. We have demonstrated that using an interplay of different experimental techniques, it is possible to safely verify the complete transformation of asbestos minerals in this temperature-induced process. The product of transformation of cement-asbestos (CATP) has a phase composition similar to that of a natural or a low temperature clinker with the exception of having a larger content of aluminium, iron and magnesium. This product can be safely recycled for the production of stoneware tile mixtures. The addition of 3-5 mass% of CATP does not bear significant variations to the standard parameters of white porcelain tile mixtures. PMID- 17709184 TI - Nitric oxide synthase inhibition in rostral ventrolateral medulla attenuates pressor response to psychological stress in rabbits. AB - Nitric oxide (NO) has been critically implicated in the central regulation of autonomic function. We recently found, however, that acute (up to 30min) blockade of NO synthase (NOS) in the rostral ventrolateral medulla (RVLM) inhibited sympathetic baroreflex transmission, without altering the cardiovascular response to psychological (air-jet) stress in rabbits. In the present study, we examined the effect of the later phase (1-3h) of NOS inhibition in the RVLM on the pressor and sympathetic responses to air-jet stress in conscious rabbits. Air-jet evoked a sustained increase in blood pressure (+14+/-2mmHg), heart rate (+37+/ 9beats/min) and renal sympathetic nerve activity (+52+/-8%). Bilateral microinjection of a NOS inhibitor l-NAME (10nmol) into RVLM did not affect resting parameters or stress responses during the first 30min after injection. Conversely, in the later phase of NOS inhibition, the pressor, tachycardic and renal sympathetic responses to air-jet stress were reversibly attenuated by 48 72%. Microinjection of l-NAME outside the RVLM did not change stress responses. Microinjection of glutamate (3nmol) into the RVLM induced similar pressor effects before and after l-NAME (+30+/-6mmHg and +26+/-6mmHg, respectively). Microinjection of d-NAME altered neither stress responses nor pressor response to glutamate. These results suggest that NOS inhibition in the RVLM has a dual effect on the autonomic response to psychological stress. In the early phase, NOS inhibition has little impact on this response. However, in the later phase, NOS inhibition attenuates the stress response, perhaps via indirect mechanisms such as altering the local redox state. PMID- 17709185 TI - Corticosterone disrupts glucose-, but not lactate-supported hippocampal PS-LTP. AB - We previously reported that acute exposure of rat hippocampal brain slices to stress levels of corticosterone aggravated ischemic neuronal damage. The present study examined whether or not an acute stress level corticosterone exposure interferes with expression of rat hippocampal CA1 population spike long-term potentiation (PS-LTP) in slices supplemented either with glucose or lactate. Exposure of glucose-supplemented (5mM) slices to corticosterone (1microM) for 90min significantly diminished their ability to generate and maintain PS-LTP compared to equicaloric lactate-supplemented (10mM) slices (p<0.05). Moreover, this diminished expression of LTP in glucose-supplemented slices was ameliorated by either treatment with RU38486 (5microM), a potent corticosterone receptor antagonist or with10mM glucose. These results suggest that lactate may serve as an effective alternate energy substrate during exposure to elevated levels of corticosterone, allowing maintenance of glucocorticoid-sensitive neuronal functions such as synaptic potentiation during metabolically critical periods when glucose utilization is compromised. PMID- 17709186 TI - Expression of Nav1.1 in rat retinal AII amacrine cells. AB - In retinal ganglion cells (RGCs), the expression of various types of voltage gated sodium channel (Nav) alpha-subunits (Nav1.1, Nav1.2, Nav1.3, and Nav1.6) has been reported. Like RGCs, certain subsets of retinal amacrine cells, including AII amacrine cells, generate tetrodotoxin (TTX)-sensitive action potentials in response to light; however, the Nav subtypes expressed in these cells have not been identified. We examined the Nav subtypes expressed in rat retinal amacrine cells by in situ hybridization (ISH) using RNA probes specific for TTX-sensitive Na(v)s (Nav1.1, Nav1.2, Nav1.3, Nav1.6, and Nav1.7). Our results confirmed that Nav1.1, Nav1.2, Nav1.3, and Nav1.6 are localized in the ganglion cell layer (GCL). Interestingly, Nav1.1 was expressed not only in the GCL, but also in the inner nuclear layer (INL). The cell bodies of the Nav1.1 positive cells in the INL were located at the INL/inner plexiform layer (IPL) border. The cell bodies of AII amacrine cells are located close to the INL/IPL border, and these cells can be labeled with antibodies against parvalbumin (PV). Therefore, we combined ISH with immunohistochemistry and discovered that most of the PV-immunoreactive cells located at the INL/IPL border express Nav1.1. Our results show that AII amacrine cells express Nav1.1. PMID- 17709187 TI - Changes in pigment epithelium-derived factor expression following kainic acid induced cerebellar lesion in rat. AB - Pigment epithelium-derived factor (PEDF) is a potent and broad-acting neurotrophic factor that protects various types of cultured neurons against glutamate excitotoxicity and induced apoptosis. The expression pattern and functions of PEDF in the central nervous system (CNS) remain largely undetermined. In this study, we analyzed the spatial and temporal expression of PEDF in normal and kainic acid (KA)-induced lesioned rat cerebellum using immunoblotting, immunohistochemistry and fluorescent in situ hybridization techniques. In normal rat cerebellum, PEDF protein and mRNA were mostly confined and co-localized with calbindin-positive cells in the Purkinje cell layer of the cerebellum, but not with glial fibrillary acidic protein (GFAP)-, 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase)-, and isolectin B4-positive cells. Injection of KA into the right cellebellum caused severe loss of calbindin positive Purkinje neurons, and an increased number of GFAP-positive astrocytes and isolectin B4-positive microglia was observed on the ipsilateral side of the lesioned cerebellum. Although the PEDF level on the ipsilateral side of the cerebellum was dramatically decreased 2 days after KA treatment, significantly elevation of PEDF levels was observed at 7 days. In agreement with these results, PEDF protein and PEDF mRNA expression were co-localized with GFAP-positive reactive astrocytes in the ipsilateral side 7 days after KA treatment. Although the mechanism by which PEDF is induced in reactive astrocytes remains unclear, the increase in PEDF expression in injured brain may form part of a compensation mechanism against neuronal degeneration. PMID- 17709188 TI - 14-3-3 proteins interact with the beta-thymosin repeat protein Csp24. AB - Conditioned stimulus pathway protein 24 (Csp24) is a beta-thymosin-like protein that is homologous to other members of the family of beta-thymosin repeat proteins that contain multiple actin binding domains. Actin co-precipitates with Csp24 and co-localizes with it in the cytosol of type-B photoreceptor cell bodies. Several signal transduction pathways have been shown to regulate the phosphorylation of Csp24 and contribute to cellular plasticity. Here, we report the identification of the adapter protein 14-3-3 in lysates of the Hermissenda circumesophageal nervous system and its interaction with Csp24. Immunoprecipitation experiments using an antibody that is broadly reactive with several isoforms of the 14-3-3 family of proteins showed that Csp24 co precipitates with 14-3-3 protein, and nervous systems stimulated with 5-HT exhibited a significant increase in co-precipitated Csp24 probed with a phosphospecific antibody as compared with controls. These results indicate that post-translational modifications of Csp24 regulate its interaction with 14-3-3 protein, and suggest that this mechanism may contribute to the control of intrinsic enhanced excitability. PMID- 17709189 TI - Brain wave synchronization and entrainment to periodic acoustic stimuli. AB - As known, different brainwave frequencies show synchronies related to different perceptual, motor or cognitive states. Brainwaves have also been shown to synchronize with external stimuli with repetition rates of ca. 10-40 Hz. However, not much is known about responses to periodic auditory stimuli with periodicities found in human rhythmic behavior (i.e. 0.5-5 Hz). In an EEG study we compared responses to periodic stimulations (drum sounds and clicks with repetition rates of 1-8 Hz), silence, and random noise. Here we report inter-trial coherence measures taken at the Cz-electrode that show a significant increase in brainwave synchronization following periodic stimulation. Specifically, we found (1) a tonic synchronization response in the delta range with a maximum response at 2 Hz, (2) a phasic response covering the theta range, and (3) an augmented phase synchronization throughout the beta/gamma range (13-44 Hz) produced through increased activity in the lower gamma range and modulated by the stimulus periodicity. Periodic auditory stimulation produces a mixture of evoked and induced, rate-specific and rate-independent increases in stimulus related brainwave synchronization that are likely to affect various cognitive functions. The synchronization responses in the delta range may form part of the neurophysiological processes underlying time coupling between rhythmic sensory input and motor output; the tonic 2 Hz maximum corresponds to the optimal tempo identified in listening, tapping synchronization, and event-interval discrimination experiments. In addition, synchronization effects in the beta and gamma range may contribute to the reported influences of rhythmic entrainment on cognitive functions involved in learning and memory tasks. PMID- 17709190 TI - Glutamate binding is altered in hippocampus and cortex of Wistar rats after pilocarpine-induced Status Epilepticus. AB - Several evidences have pointed to biochemical alterations in some brain structures after experimental Status Epilepticus (SE). Thus, the effects of pilocarpine-induced SE on the glutamate binding in the hippocampus and cortex of Wistar rats were evaluated. Groups of animals were submitted to a 3h SE induced by intrahippocampal microinjection of pilocarpine, which was interrupted by the administration of sodium thiopental. Two weeks later the animals were sacrificed and had their cerebral cortices and hippocampi removed in order to perform the binding experiments. The results show that the pilocarpine-induced SE provoked an increase in 2.5-fold in the B(max) values for glutamate binding in the cortex, but not in the hippocampus. Moreover, we observed a 4-fold increase for the Kd values in the hippocampus and a 2-fold increase in the cortex. These findings might indicate that the epileptogenesis involves alterations in the glutamate receptors that are not restricted to the limbic system. Moreover, changes in these receptors are not exclusively of number, but rather involve the affinity for their ligands. PMID- 17709191 TI - Measure of the electroencephalographic effects of sevoflurane using recurrence dynamics. AB - This paper proposes a novel method to interpret the effect of anesthetic agents (sevoflurane) on the neural activity, by using recurrence quantification analysis of EEG data. First, we reduce the artefacts in the scalp EEG using a novel filter that combines wavelet transforms and empirical mode decomposition. Then, the determinism in the recurrence plot is calculated. It is found that the determinism increases gradually with increasing the concentration of sevoflurane. Finally, a pharmacokinetic and pharmacodynamic (PKPD) model is built to describe the relationship between the concentration of sevoflurane and the processed EEG measure ('determinism' of the recurrence plot). A test sample of nine patients shows the recurrence in EEG data may track the effect of the sevoflurane on the brain. PMID- 17709192 TI - Effect of electrostimulation training-detraining on neuromuscular fatigue mechanisms. AB - The aim of this study was to evaluate the effects of neuromuscular electrical stimulation (NMES) training and subsequent detraining on neuromuscular fatigue mechanisms. Ten young healthy men completed one NMES fatigue protocol before and after a NMES training program of 4 weeks and again after 4 weeks of detraining. Muscle fatigue (maximal voluntary torque loss), central fatigue (activation failure), and peripheral fatigue (transmission failure and contractile failure) of the plantar flexor muscles were assessed by using a series of electrically evoked and voluntary contractions with concomitant electromyographic and torque recordings. At baseline, maximal voluntary torque decreased significantly with fatigue (P<0.001), due to both activation and transmission failure. After detraining, maximal voluntary torque loss was significantly reduced (P<0.05). In the same way, the relative decrease in muscle activation after training and detraining was significantly lower compared to baseline values (P<0.05). Short term NMES training-detraining of the plantar flexor muscles significantly reduced the muscle fatigue associated to one single NMES exercise session. This was mainly attributable to a reduction in activation failure, i.e., lower central fatigue, probably as a result of subject's accommodation to pain and discomfort during NMES. PMID- 17709193 TI - Neuroprotective effects of anthocyanins and their in vivo metabolites in SH-SY5Y cells. AB - Recent in vivo studies have highlighted an important role for the neuroprotective actions of dietary anthocyanins. However, one consistent result of these studies is that the systemic bioavailability of anthocyanins, including cyanidin 3-O glucopyranoside (Cy-3G), is very poor. Cy-3G has been demonstrated to be highly instable at physiological pH, so its in vivo metabolites, such as the aglycon cyanidin (Cy) and protocatechuic acid (PA), may be responsible for both the antioxidant activitiy and the neuroprotective effects observed in vivo. Therefore, we investigated the protective effects of Cy-3G, Cy and PA against H(2)O(2)-induced oxidative stress in a human neuronal cell line (SH-SY5Y). We determined their ability to counteract reactive oxygen species (ROS) formation and to inhibit apoptosis in terms of mitochondrial functioning loss and DNA fragmentation induced by H(2)O(2). We demonstrated that pretreatment of SH-SY5Y cells with Cy-3G, Cy and PA inhibits H(2)O(2)-induced ROS formation at different cellular levels: Cy-3G at membrane level, PA at cytosolic level and Cy at both membrane and cytosolic levels. In addition, Cy showed a higher antioxidant activity at membrane and cytosolic level than Cy-3G and PA, respectively. Interestingly, both Cy and PA, but not Cy-3G, could inhibit H(2)O(2)-induced apoptotic events, such as mitochondrial functioning loss and DNA fragmentation. These results suggest that Cy and PA may be considered as neuroprotective molecules and may play an important role in brain health promotion. These in vitro findings should encourage further research in animal models of neurological diseases to explore the potential neuroprotective effects of compounds generated during in vivo metabolism of anthocyanins. PMID- 17709194 TI - Coincidence-enhanced stochastic resonance: experimental evidence challenges the psychophysical theory behind stochastic resonance. AB - Stochastic resonance (SR) is the counterintuitive phenomenon in which noise enhances detection of sub-threshold stimuli. The SR psychophysical threshold theory establishes that the required amplitude to exceed the sensory threshold barrier can be reached by adding noise to a sub-threshold stimulus. The aim of this study was to test the SR theory by comparing detection results from two different randomly-presented stimulus conditions. In the first condition, optimal noise was present during the whole attention interval; in the second, the optimal noise was restricted to the same time interval as the stimulus. SR threshold theory predicts no difference between the two conditions because noise helps the sub-threshold stimulus to reach threshold in both cases. The psychophysical experimental method used a 300 ms rectangular force pulse as a stimulus within an attention interval of 1.5 s, applied to the index finger of six human subjects in the two distinct conditions. For all subjects we show that in the condition in which the noise was present only when synchronized with the stimulus, detection was better (p<0.05) than in the condition in which the noise was delivered throughout the attention interval. These results provide the first direct evidence that SR threshold theory is incomplete and that a new phenomenon has been identified, which we call Coincidence-Enhanced Stochastic Resonance (CESR). We propose that CESR might occur because subject uncertainty is reduced when noise points at the same temporal window as the stimulus. PMID- 17709195 TI - Effects of a two-diopter vertical prism on posture. AB - Postural control in upright stance requires the central integration of visual, vestibular, somatosensory (as cutaneous receptors) and proprioceptive (as joint receptors) inputs. Clinical studies seem to indicate an association between vertical heterophoria (VH) and balance control. The purpose of the study was to simulate a VH and examine its influence on body stabilisation in quiet stance. We studied 15 healthy subjects (25.6+/-3.0 years). The postural stability was measured with a platform under the following conditions: normal viewing, with a two-diopter prism base down placed on the dominant eye (PDE) or the non-dominant eye (PNDE). Both eyes were open in all conditions. All conditions were run at two distances: 200 and 40 cm. The results showed: (i) PNDE increased the antero posterior body sway for both distances; this result could be related to sensory processing of disparity and/or to inappropriate eye movement response to the disparity induced by the prism; (ii) PDE improved the postural stability only at far distance (reduction of the center-of-pressure excursion area and of the lateral body sway). Such positive result could be due to appropriate sensory processing of disparity and/or eye movement response; the latter would reduce vertical disparity and modify the dynamic and tonic eye muscle activity relative to normal viewing at far distance. We conclude that: (i) experimentally induced vertical phoria does indeed influence postural control; (ii) vertical prisms, even of small power, can have complex effects, positive or negative, depending on the eye wearing it and at the distance fixated. PMID- 17709196 TI - Optical recordings from the human nasal mucosa in response to olfactory stimulation. AB - Using the intrinsic optical signal the present study aimed to investigate changes in blood flow at the nasal epithelium in response to specific olfactory stimulation. Recording equipment included an endoscope, a CCD camera, and a light source of 617 nm. Two concentrations of the specific olfactory stimulant H(2)S (2.8 and 5.6 ppm), generated by a computer-controlled olfactometer, were used for olfactory stimulation. Eight healthy normosmic volunteers participated. Using 5.6 ppm H(2)S stimuli, responses were typically recorded from the olfactory cleft, middle turbinate, and middle meatus while responses were less pronounced for 2.8 ppm H(2)S stimuli. Response areas were significantly larger for the 5.6 ppm H(2)S stimuli. While further experiments are needed, recordings of the intrinsic optical signal may be used to obtain responses from the nasal cavity to specific olfactory stimuli. PMID- 17709197 TI - The free-radical scavenger edaravone restores the differentiation of human neural precursor cells after radiation-induced oxidative stress. AB - Recently, it has been elucidated that cognitive dysfunction following cranial radiotherapy might be linked to the oxidative stress-induced impairment of hippocampal neurogenesis that is mediated by proliferating neural stem or progenitor cells. The novel free-radical scavenger edaravone (3-methyl-1-phenyl-2 pyrazolin-5-one) has been clinically used to reduce neuronal damage following ischemic stroke. Here, we demonstrate via in vitro studies that edaravone protects human neural stem cells (NSCs) from cell death and restores their differentiation ability after irradiation; however, the protective effect of edaravone is not observed in human brain tumor cells. Our study may shed some light on the beneficial effects of free-radical scavengers in impaired neurogenesis following cranial radiation therapy. PMID- 17709198 TI - Neuron-specific phosphorylation of c-Jun N-terminal kinase increased in the brain of hypoxic preconditioned mice. AB - Accumulated studies have suggested that mitogen-activated protein kinase (MAPK) play a pivotal role in the development of cerebral hypoxic preconditioning (HPC). By using our "auto-hypoxia"-induced HPC mouse model, we have reported increased phosphorylation level of p38 MAPK, and decreased phosphorylation and protein expression levels of extracellular signal regulated kinases 1/2 (ERK1/2) in the brain of HPC mice. In the current study, we investigated the involvement of c-Jun N-terminal kinase (JNK) in the brain of HPC mice. By using Western blot analysis, we found that the phosphorylation levels of JNK at Thr183 and Tyr185 sites (phospho-Thr183/Tyr185 JNK), but not its protein expression, increased significantly (p<0.05, n=6 for each group) both in the hippocampus and frontal cortex of early (H1-H4) and delayed (H5 and H6) HPC mice than that of the normoxic group (H0, n=6). Similarly, enhanced phospho-Thr183/Tyr185 JNK was also observed by immunostaining in the hippocampus and frontal cortex of mice following series of hypoxic exposures (H3 and H6). In addition, we found that phospho-Thr183/Tyr185 JNK predominantly co-localized with a neuron-specific protein, neurogranin, in both the hippocampus and frontal cortex of HPC mice (H3) by using double-labeled immunofluorescence. These results suggest that the increased neuron-specific phosphorylation of JNK at Thr183/Tyr185, not protein expression, might be involved in the development of cerebral HPC of mice. PMID- 17709199 TI - Multimodal reference frame for the planning of vertical arms movements. AB - In this study we investigated the reference frames used to plan arm movements. Specifically, we asked whether the body axis, visual cues and graviception can each play a role in defining "up" and "down" in the planning and execution of movements along the vertical axis. Horizontal and vertical pointing movements were tested in two postures (upright and reclined) and two visual conditions (with and without vision) to identify possible effects of each of these cues on kinematics of movement. Movements were recorded using an optical 3D tracking system and analysis was conducted on velocity profiles of the hand. Despite a major effect of gravity, our analysis shows an effect of the movement direction with respect to the body axis when subjects were reclined with eyes closed. These results suggest that our CNS takes into account multimodal information about vertical in order to compute an optimal motor command that anticipates the effects of gravity. PMID- 17709200 TI - Localization of septin 8 in murine retina, and spatiotemporal expression of septin 8 in a murine model of photoreceptor cell degeneration. AB - The septins, which form a conserved family of cytoskeletal GTP-binding proteins in mammals, comprise stable heteromeric complexes and have diverse roles in protein scaffolding, cytokinesis, vesicle trafficking and plasma membrane integrity following cell division. The goal of this study was to determine the localization of septin 8 in murine adult retina, and analyze the spatiotemporal expression of septin 8 in a murine model of photoreceptor cell degeneration. Expression of septin 8 in the normal retina of mouse and rat was observed by using immunohistochemistry and Western blotting. Furthermore, time course of the expression of septin 8 in mouse photoreceptor cell degeneration were examined by immunohistochemistry combined with hematoxylin and eosin staining, and in situ DNA fragment labeling method. In normal mouse and rat retina, localization of septin 8 is restricted in nuclei of photoreceptor cells. 96 h after intravitreal injection of cobalt chloride most photoreceptor cells lost septin 8 immunostaining at the same time as nuclear DNA fragmentation. The results of this study show that septin 8 protein is present in the specific location within the retina. Furthermore, the disappearance of septin 8 in the nuclei of photoreceptor cells is concomitant with nuclear DNA fragmentation. This suggests that loss of septin 8 could be a useful prognostic indicator for photoreceptor cell degeneration. PMID- 17709202 TI - Normal aging decreases regional homogeneity of the motor areas in the resting state. AB - Our knowledge about aging modulation of the central motor system remains sparse and contradictory. In the current study, we used functional MRI (fMRI) to study the aging influence on regional homogeneity of the motor-related brain areas in the resting state. We found that regional homogeneity in extensive motor regions, like the cingulate motor area, cerebellum, primary motor cortex, premotor area, supplementary motor area, thalamus, globus pallidus and putamen was significantly decreased in aged subjects. Our study indicates that normal aging process may disrupt the function of motor areas in the resting state, which may contribute to the declined motor ability in aged population. PMID- 17709201 TI - Fatty acid synthase gene regulation in primary hypothalamic neurons. AB - Understanding the mechanisms that regulate feeding is critical to the development of therapeutic interventions for obesity. Many studies indicate that enzymes within fatty acid metabolic pathways may serve as targets for pharmacological tools to treat this epidemic. We, and others have previously demonstrated that C75, a fatty acid synthase (FAS) inhibitor, induced significant anorexia and weight loss by both central and peripheral mechanisms. Because the hypothalamus is important in the regulation of homeostatic processes for feeding control, we have identified pathways that alter the gene expression of FAS in primary hypothalamic neuronal cultures. Insulin, glucose and AICAR (an activator of AMP activated protein kinase) affected changes in hypothalamic FAS mRNA, which may be regulated via the SREBP1c dependent or independent pathway. PMID- 17709204 TI - Dendritic spines in the posterodorsal medial amygdala after restraint stress and ageing in rats. AB - Several evidences suggest that the posterodorsal medial amygdala (MePD) can be a relevant part of the rat neural circuitry for the regulation of hypothalamic neuroendocrine secretion and for ontogenetically different behavioral displays. The dendritic spine density of Golgi-impregnated neurons from the MePD was evaluated in young rats following acute or chronic restraint stress and in aged animals (24 months old). Compared to the control group, a single 1 h restraint stress session promoted a decreased spine density (p<0.01) whereas a single 6 h restraint stress session or daily 6-h restraint sessions for 28 consecutive days did not lead to the same effect (p>0.05). Aged rats showed no difference in this dendritic spine parameter when compared to young adults (p>0.05). These results indicate that short-term stress (1 h) can affect MePD dendritic spines and that neural plasticity is involved with adaptive responses onwards in restrained rats. On the other hand, brain structural modifications related with ageing appear not to influence the number of certain postsynaptic sites in the MePD of rats. PMID- 17709203 TI - Beta-amyloid toxicity and reversal in embryonic rat septal neurons. AB - Alzheimer's disease is characterized mainly by loss of neurons from the septal nucleus. In this study, neurons from the septal nucleus of the embryonic day 16 (E16) rat were grown in culture with a plane of astrocytes from the embryonic rat and in a defined medium in the absence of serum. Neurons were treated with beta amyloid (Abeta: 0.1, 1 and 10 microM) on day in vitro (DIV) 1 and DIV 4 and fluorescent microscopy was used to measure survival and apoptosis following exposure of the treated cells on DIV 7. Reversal of neurotoxicity was studied using the potentially neuroprotective agents nerve growth factor (NGF, 100 ng/ml), basic fibroblast growth factor (bFGF, 5 ng/ml), insulin-like growth factors (IGF1 and IGF2, 10 ng/ml) and estrogen (10 nM), administered on DIV 4 and DIV 5, that is, subsequent to the Abeta (10 microM)-induced neurotoxicity. Abeta caused a significant decrease in survival at 10 microM, and a significant increase in apoptosis at 0.1 and 10 microM. IGF1, IGF2 and bFGF all caused a reversal of the Abeta-induced neurotoxic effect on survival while NGF and estrogen did not under these experimental conditions. PMID- 17709205 TI - Relationship of the Ubiquilin 1 gene with Alzheimer's and Parkinson's disease and cognitive function. AB - Ubiquilin 1 (UBQLN1) is involved in the ubiquitination machinery, which has been implicated in Alzheimer's disease (AD) as well as Parkinson's disease (PD). A polymorphism in the gene encoding for UBQLN1 has been previously associated with a higher risk of AD. We studied the role of the SNP rs12344615 on the UBQLN 1 gene in AD, PD and cognitive function in a population-based study, the Rotterdam Study, and a family-based study embedded in the genetic research in isolated population (GRIP) program. The Rotterdam Study includes 549 patients with AD and 157 patients with PD. The GRIP program includes a series of 123 patients with AD and a study of 1049 persons who are characterized for cognitive function. Data were analysed using logistic and multiple regression analysis. We found no significant difference in risk of AD or PD by the UBQLN1 SNP rs12344615 in our overall and stratified analyses in the Rotterdam Study. In our family-based study, we did not find evidence for linkage of AD to the region including the UBQLN1 gene. In the family-based study we also failed to detect an effect of this polymorphism on cognitive function. Our results suggest that it is unlikely that the SNP rs12344615 of the UBQLN1 gene is related to the onset of AD, PD or cognitive function. PMID- 17709206 TI - Inhibition of cortical responses to Adelta inputs by a preceding C-related response: testing the "first come, first served" hypothesis of cortical laser evoked potentials. AB - Although laser pulses activate concomitantly Adelta and C fibres, the corresponding brain evoked responses remain strictly limited to the Adelta component, without any potential consistent with C-fibre activation. To investigate whether this phenomenon depends on the order of arrival to the cortex ("first come first served" hypothesis) or is simply explained by A-to-C inhibition and/or lower energy associated with the desynchronised C-fibre input, we devised an experiment where the physiological order of arrival to the cortex was artificially inverted. Following a conditioning C-pulse, the cortical response to a second laser stimulus was significantly attenuated, whether it was Adelta or C. Thus, a C-volley was able to depress the response to a subsequent Adelta stimulus, in support of the "first come first served" hypothesis. However, the conditioning C-fibre stimulus attenuated significantly more a subsequent C volley than a subsequent Adelta-volley, indicating that the suppression effect does not depend solely on the order of arrival to the cortex, but also on the ratio of energy per unit time conveyed by the successive inputs. This supports the notion that cortical evoked potentials to laser pulses (and probably to other sensory stimuli) reflect networks detecting rapid energy changes relative to a preceding baseline. The output of such networks should depend both on the time elapsed between successive inputs and on the relative energy per unit time conveyed by successive volleys. Such dedicated networks aimed at detecting energy changes may be related to orienting reactions, and can be dissociated from subjective perception. PMID- 17709207 TI - Supra-additive effects of tramadol and acetaminophen in a human pain model. AB - The combination of analgesic drugs with different pharmacological properties may show better efficacy with less side effects. Aim of this study was to examine the analgesic and antihyperalgesic properties of the weak opioid tramadol and the non opioid acetaminophen, alone as well as in combination, in an experimental pain model in humans. After approval of the local Ethics Committee, 17 healthy volunteers were enrolled in this double-blind and placebo-controlled study in a cross-over design. Transcutaneous electrical stimulation at high current densities (29.6+/-16.2 mA) induced spontaneous acute pain (NRS=6 of 10) and distinct areas of hyperalgesia for painful mechanical stimuli (pinprick hyperalgesia). Pain intensities as well as the extent of the areas of hyperalgesia were assessed before, during and 150 min after a 15 min lasting intravenous infusion of acetaminophen (650 mg), tramadol (75 mg), a combination of both (325 mg acetaminophen and 37.5mg tramadol), or saline 0.9%. Tramadol led to a maximum pain reduction of 11.7+/-4.2% with negligible antihyperalgesic properties. In contrast, acetaminophen led to a similar pain reduction (9.8+/ 4.4%), but a sustained antihyperalgesic effect (34.5+/-14.0% reduction of hyperalgesic area). The combination of both analgesics at half doses led to a supra-additive pain reduction of 15.2+/-5.7% and an enhanced antihyperalgesic effect (41.1+/-14.3% reduction of hyperalgesic areas) as compared to single administration of acetaminophen. Our study provides first results on interactions of tramadol and acetaminophen on experimental pain and hyperalgesia in humans. Pharmacodynamic modeling combined with the isobolographic technique showed supra additive effects of the combination of acetaminophen and tramadol concerning both, analgesia and antihyperalgesia. The results might act as a rationale for combining both analgesics. PMID- 17709208 TI - Self-rated pain and perceived health in relation to stress and physical activity among school-students: a 3-year follow-up. AB - The aim of this longitudinal study was to assess changes with age regarding prevalence of pain and perceived health in a student population, as well as change over time at grade level. Pain included frequency of headache, abdominal, and musculoskeletal pain and perceived health included problems sleeping and/or if they often felt tired, lonely, and sad. If gender, age (grade level), stress, physically activity were related to pain and health complaints were tested with multivariate logistic regression analysis. The students (n=1908) came from randomly selected schools throughout Sweden and attended grades 3, 6 and 9 (ages 9, 12 and 15 at the onset of the year) in 2001. Three years later, 67% (n=1276) of the same students answered a questionnaire that was constructed for the purpose of the studies. The responses given by the same students showed that girls' complaints of pain and perceived health increased with age and boys decreased. Over half (56%) of the girls and two-thirds (67%) of the boys reported no frequent complaints either year. At grade level most variables were rated the same as three years earlier by the same age group. Stress was significantly related to pain and health complaints for girls and the risk of complaints, as calculated with odds ratio, was most evident for students who were characterized as being physically inactive in 2001 and remained inactive three years later. Jointly, significant predictors, such as stress, being physically inactive, gender and grade level, explained 8-20% of the frequent complaints. PMID- 17709209 TI - Therapeutic and prophylactic efficacy of imidocarb dipropionate on experimental Babesia ovis infection of lambs. AB - The objective of this study was to evaluate the therapeutic and prophylactic efficacy of imidocarb dipropionate (IMDP) against babesiosis and to determine specific antibodies against Babesia ovis in experimentally infected lambs. Thirty six 6-month-old splenectomized lambs were used. The lambs were randomly divided into six groups with six animals each, and were intravenously inoculated with 50 mL B. ovis-infected erythrocytes as follows: group I (therapy group) was treated with IMDP (1.2 mg/kg body weight) starting on the day of onset of clinical signs of babesiosis after the inoculation; group II (untreated control animals) was not treated with any therapeutic treatment after the inoculation; groups III, IV, V and VI (prophylaxis groups) were administered IMDP (2.4 mg/kg body weight) 1, 2, 3 and 4 weeks before the inoculation, respectively. The animals were housed in a tick-proof room with water and food ad libitum up to the 30th day post inoculation (PI). The lambs were monitored from the first day PI by recording the manifestation of clinical disease, rectal temperature, and the degree of parasitaemia. All the lambs became infected with B. ovis, except five animals from group III, which were treated 1 week prior to experimental infection. Other animals showed signs of acute clinical babesiosis. The animals treated with IMDP (group I) were able to clear the parasite from the blood circulation after 48 h post-treatment. The recrudescence of B. ovis was observed in two lambs 7 days after treatment, and they were treated with the second similar dose of the drug. Six lambs (1, 1, 2 and 2 lambs in group III, IV, V and VI, respectively) from the prophylaxis groups died within 7-17 days after showing high parasitaemia and clinical symptoms of the disease. Regardless of the clinical symptoms, 83.30% and 66.66% of the lambs which were administered IMDP 1-2 and 3-4 weeks before, were determined to be protected against the virulent field strain of B. ovis. PMID- 17709210 TI - Does yawning increase arousal through mechanical stimulation of the carotid body? AB - Yawning is a stereotyped event that occurs in humans and animals from fish to mammals, but neither its mechanisms nor its functions are entirely known. Its widespread nature suggests that it has important physiological functions. It is associated with stretching of muscles in a large area, but the function of this stretching is understood far from completely. It has been proposed that yawning increases arousal and that it is an arousal defense reflex, whose aim is to reverse brain hypoxia. Whilst yawning has been speculated to have an important role in reversing hypoxia, there is a structure in the neck that is known to be intimately involved in the regulation of oxygen homeostasis, namely the carotid body. It senses acute changes in oxygen levels. In spite of this, a connection has never been proposed either between the carotid body and arousal, or between yawning and the carotid body. We propose that yawning stimulates mechanically the carotid body (and possibly other structures in the neck). We further propose that this stimulation gives rise to increased arousal, alertness and wakefulness and that one important physiological function of yawning is increase of arousal through this stimulation. We also propose that mechanical effects on the shunt system of the carotid body may be involved in this stimulation. Our hypothesis is supported by several facts. For example, yawning causes movements and compressions that may affect the carotid body that is situated strategically at the bifurcation of the common carotid artery. Thus, yawning may stimulate the carotid body. The carotid body is highly vascular and compressions may affect its shunt system and blood flow and for example give rise to release of hormones or other substances. Also several facts related to situations where people yawn or do not yawn support our hypothesis and are discussed. Further support comes from facts related to somnogenic substances, hormones and transmitters, and from facts related to the interconnection of homeostatic mechanisms, sleep, arousal and ventilation. PMID- 17709211 TI - Could echocardiography yield a cardiovascular profile of the tinnitus prone subject? AB - The possible genesis of some damage of the inner ear from a hemodynamic imbalance of functional origin, possibly linked to hypotension followed by an abnormal vasomotor regulatory activity, has been pointed out by our group over the years. As tinnitus, which is often referable to an inner ear origin, can represent a signal of incoming sufferance of the organ of Corti and may not necessarily be linked to hearing impairment, it seemed of some utility to investigate on the prevalence of tinnitus under various well monitored hemodynamic conditions. This led to observe that the prevalence of this symptom, regardless of audiological features, was increased under "aggressive" antihypertensive therapy as well as in particularly severe degree of heart decompensation. These data represent a first step and encourage in searching for a profile of subject who could be more prone to the development of tinnitus with respect to the normal population, even in absence of pathological conditions. With this aim, echocardiography is thought to be able to yield useful informations in addition to standard and ambulatory blood pressure monitoring, in order to obtain a better definition of the correlations between cardiovascular function (and related changes) and inner ear insufficient perfusion. PMID- 17709212 TI - Development of a real time reverse transcriptase polymerase chain reaction for the detection of bovine respiratory syncytial virus in clinical samples and its comparison with immunohistochemistry and immunofluorescence antibody testing. AB - Bovine respiratory syncytial virus is an agent involved in calf pneumonia complex, a disease of significant economic importance. Accurate diagnosis of the agents involved on farm premises is important when formulating disease control measures, including vaccination. We have developed a real time reverse transcriptase polymerase chain reaction (rtRT-PCR) and compared it with the diagnostic tests currently available in the United Kingdom: immunohistochemistry (IHC) and immunofluorescence antibody test (IFAT). The rtRT-PCR had a detection limit of 10 gene copies and was 96% efficient. Recent UK isolates and clinical samples were tested; the rtRT-PCR was more sensitive than both conventional tests. PMID- 17709213 TI - Mixing gilts in early pregnancy does not affect embryo survival. AB - There is general acceptance that mixing sows during the first 3 weeks of gestation is detrimental to embryo development and survival. However, there is a paucity of data describing the influence of group housing and remixing during the first 14 days of gestation on pregnancy outcomes. Using 96 purebred maternal (Large White)/terminal (Duroc) line gilts, the current study determined the effects of regrouping, and the timing of regrouping, during the pre-implantation period on embryo mortality. The study was conducted in 2 blocks, with 12 gilts allocated to each of 4 treatments in each block. At 175 days of age, the combination of PG600 and 20 min of daily physical boar contact was used to stimulate puberty, with boar contact resuming 12 days after first detection of oestrus and gilts receiving two artificial inseminations (AIs), 24 h apart, at their second oestrus. After their first AI gilts were allocated to one of four treatment groups (n=12 gilts/treatment). Gilts in one treatment group were housed individually in stalls (STALL). The remaining gilts continued to be housed in their pre-AI groups and were either not remixed (NOMIX), or remixed to form new groups on day 3/4 (RMIXD3/4) or day 8/9 (RMIXD8/9) of gestation (day 0=day of first detection of second oestrus and first insemination). Group-housed gilts were housed in groups of 6, with a space allowance of 2.4 m2/gilt. All gilts were fed once a day (2.2 kg/gilt). Reproductive tracts were collected on day 26.6+/ 0.13 of gestation, and the number of corpora lutea (CL) and viable embryos counted. Pregnancy rate was similar across all treatments, averaging 94.5% across the four treatment groups. The number of embryos present on day 26 of gestation was unaffected by housing treatments (P>0.05); gilts in the STALL, NOMIX, RMIXD3/4 and RMIXD8/9 groups possessed 13.2+/-0.67, 12.9+/-0.66, 14.1+/-0.46 and 13.8+/-0.57 embryos, respectively. Similarly, embryo survival rates were 0.91+/ 0.04, 0.85+/-0.04, 0.91+/-0.02 and 0.87+/-0.05 for the STALL, NOMIX, RMIXD3.4 and RMIXD8/9 groups, respectively (P>0.05). In conclusion, the current data indicate that individually housing gilts immediately after their first AI does not improve embryo survival. There also appear to be no adverse effects on embryo development or survival when group-housed, mated gilts are remixed during the first 10 days of gestation. PMID- 17709215 TI - Drug development and imperfect design. AB - Several factors affect or control design of any new object and these could be- cost, time, quality, aesthetics, technology, and strategy. The object designed is never perfect. The article extends this concept to the drug industry and discusses various imperfections. In spite of these imperfections, the drug industry is serving mankind satisfactorily and improving quality of our lives. The discussion leads to steps, which can be taken to make better drug products. Individualized medicines, combination drug products, and targeted drug delivery systems could be some of the options. Natural medicines may guide us to develop "perfect" drug products. PMID- 17709214 TI - Duck egg yolk in extender improves the freezability of buffalo bull spermatozoa. AB - We investigated the use of duck egg yolk (DEY), Guinea fowl egg yolk (GFEY) and Indian indigenous hen (Desi) egg yolk (IDEY) in extender for improving the post thaw quality of buffalo (Bubalus bubalis) bull spermatozoa, and compared it with commercial hen egg yolk (CHEY; control). For this purpose, two consecutive ejaculates of semen from each of two Nili-Ravi buffalo bulls were collected on 1 day each week for 5 weeks (replicates; n=5) with artificial vagina (42 degrees C). Split pooled ejaculates, were diluted in tris-citric acid glycerol extender containing either DEY or GFEY or IDEY or CHEY at 37 degrees C. Extended semen was cooled to 4 degrees C in 2 h and equilibrated for 4 h at 4 degrees C. Cooled semen was then filled in 0.5 ml straws at 4 degrees C and frozen in programmable cell freezer. Thawing of semen was performed at 37 degrees C for 30 s. Sperm motility, plasma membrane integrity and sperm morphology (acrosome integrity, head, mid-piece and tail abnormalities) of each semen sample were assessed at 0, 3 and 6 h after thawing and incubation at 37 degrees C. Visual motility (%) and percentage of intact plasma membranes assessed at 6h post-thaw of buffalo bull spermatozoa were highest (P<0.05) due to DEY as compared to GFEY, IDEY and control. The percentage of spermatozoa with normal acrosomes at 0, 3 and 6 h post thaw was highest (P<0.05) in DEY extender than GFEY, IDEY and CHEY. Sperm tail abnormalities (%) observed at 0, 3 and 6 h post-thaw in samples cryopreserved with freezing extender having DEY were lower (P<0.05) as compared to extender containing GFEY, IDEY and CHEY. In conclusion, DEY compared to other avian yolks in extender improves the frozen-thawed quality of buffalo bull spermatozoa. PMID- 17709216 TI - Formulation, antimalarial activity and biodistribution of oral lipid nanoemulsion of primaquine. AB - Primaquine (PQ) is one of the most widely used antimalarial and is the only available drug till date to combat relapsing form of malaria especially in case of Plasmodium vivax and Plasmodium ovale. Primaquine acts specifically on the pre erythrocytic schizonts which are concentrated predominantly in the liver and causes relapse after multiplication. However application of PQ in higher doses is limited by severe tissue toxicity including hematological and GI related side effects which are needed to be minimized. Lipid nanoemulsion has been widely explored for parenteral delivery of drugs. Primaquine when incorporated into oral lipid nanoemulsion having particle size in the range of 10-200 nm showed effective antimalarial activity against Plasmodium bergheii infection in swiss albino mice at a 25% lower dose level as compared to conventional oral dose. Lipid nanoemulsion of primaquine exhibited improved oral bioavailability and was taken up preferentially by the liver with drug concentration higher at least by 45% as compared with the plain drug. PMID- 17709217 TI - Incorporation of novel 1-alkylcarbonyloxymethyl prodrugs of 5-fluorouracil into poly(lactide-co-glycolide) nanoparticles. AB - Incorporation of 1-alkylcarbonyloxymethyl prodrugs of 5FU into poly(lactide-co glycolide) nanoparticles using nanoprecipitation methods gave increased loading efficiencies over that obtained using the parent drug substance. SEM studies revealed spherical nanoparticles of around 200nm in diameter, corresponding well with measurements made using photon correlation spectroscopy. The C(7) prodrug gave the best mean loading of 47.23%, which compared favourably to 3.68% loading achieved with 5FU. Loading efficiency was seen to follow the hydrophilic lipophilic balance in the homologue series, where increases in lipophilicities alone were not good predictors of loading. Drug release, in terms of resultant 5FU concentration, was monitored using a flow-through dissolution apparatus. Cumulative drug release from nanoparticles loaded with the C(5) prodrug was linear over 6h, with approximately 14% of the total available 5FU dose released and with no evidence of a burst effect. The flux profile of the C(5)-loaded nanoparticles showed an initial peak in flux in the first sampling interval, but became linear for the remainder of the release phase. C(7)-loaded nanoparticles released considerably less (4% in 6h) with a similar flux pattern to that seen with the C(5) prodrug. The C(9)-loaded nanoparticles released less than 1% of the available 5FU over 6h, with a similar zero-order profile. The C(7) prodrug was deemed to be the prodrug of choice, achieving the highest loadings and releasing 5FU, following hydrolysis, in a zero-order fashion over a period of at least 6h. Given the lack of burst effect and steady-state flux conditions, this nanoparticulate formulation offers a better dosing strategy for sustained intravenous use when compared to that arising from nanoparticles made by direct incorporation of 5FU. PMID- 17709218 TI - Cisplatin-induced hair cell loss in zebrafish (Danio rerio) lateral line. AB - We have used time-lapse imaging to study cisplatin-induced hair cell death in lateral line neuromasts of zebrafish larvae in vivo. We found that cisplatin induced hair cell death occurred much more slowly than had been shown to occur in aminoglycoside-induced hair cell death. By prelabeling hair cells with FM1-43FX, and assessing hair cell damage, it was established that cisplatin causes hair cell loss in the lateral line in a dose-dependent fashion. The kinetics of hair cell loss during exposure to different concentrations of cisplatin was also assessed and it was found that the onset of hair cell loss correlated with the accumulated dose of cisplatin. These data demonstrate the feasibility and repeatability of cisplatin damage protocols in the zebrafish lateral line and set the stage for future evaluations of modulation of cisplatin-induced hair cell death. PMID- 17709219 TI - Pharmacognostical studies of the plant drug Mimosae tenuiflorae cortex. AB - The bark of the Mimosa tenuiflora (Willd.) Poiret (Leguminoseae) tree, known as tepescohuite in Mexico, is commonly used in this country and in Central America to elaborate different products for the treatment of skin burns and lesions. The cicatrizing properties of extracts obtained from this bark have been scientifically studied, attributing the main biological activity to its tannin and saponin content. Studies include clinical trials of phytodrugs based on Mimosae tenuiflora bark extracts for treatment of venous leg ulcerations. Recent commercialization of the plant drug Mimosae tenuiflorae cortex requires pharmacognostical information to develop quality-control methods for raw materials and extracts produced with this plant drug. The present paper reports a group of ethnobotanical, morphological, chemical, and molecular studies performed with Mimosae tenuiflora materials obtained by collection in the southeastern Mexican state of Chiapas. Macro- and micro-morphological parameters were established to authenticate the genuine drug that allowed detection of adulterants usually found in commercial samples of this plant material. These morphological characteristics can be used for rapid identification of the drug and are particularly useful in the case of powdered materials. The chemical studies performed demonstrated that tannins represent the major component group in the bark. Its content in genuine tepescohuite is 16% and is mainly composed of proanthocyanidins, a condition permitting a tannin-based chemical-control method for fingerprinting the plant drug. Contrariwise, the saponin concentration in Mimosae tenuiflora bark is extremely low, and its isolation and content evaluation represent a complex procedure that is unsuitable for routine control purposes. Finally, random amplified DNA (RAPD) analysis results a useful tool for obtaining DNA specific markers of Mimosae tenuiflora species which should be useful in future studies involving raw material authentication by molecular methods. PMID- 17709220 TI - Telomere dynamics in arteries and mononuclear cells of diabetic patients: effect of diabetes and of glycemic control. AB - Telomeres serve as a mitotic clock and biological marker of senescence. Diabetes mellitus (DM) is associated with damage to target organs and premature aging. We assessed the effect of glycemic control on telomere dynamics in arterial cells of 58 patients undergoing coronary artery bypass and in mononuclear blood cells of other diabetic (32 type I and 47 type II) patients comparing well controlled to uncontrolled patients. All were compared to age-dependent curve of healthy controls. Telomeres were significantly shorter in the arteries of diabetic versus non-diabetic patients (p=0.049) and in mononuclear cells of both type I and type II diabetes. In all study groups good glycemic control attenuated shortening of the telomeres. In arterial cells good glycemic control attenuated, but not abolished, the telomere shortening. In type II DM the mononuclear telomere attrition was completely prevented by adequate glycemic control. Telomere shortening in mononuclear cells of type I diabetic patients was attenuated but not prevented by good glycemic control. Results of this study suggest that diabetes is associated with premature cellular senescence which can be prevented by good glycemic control in type II DM and reduced in type I DM. PMID- 17709221 TI - Down-regulation of AMP-activated protein kinase by calorie restriction in rat liver. AB - AMP-activated protein kinase (AMPK) may act as a key enzyme for metabolic adaptation to calorie restriction (CR) or reduced growth hormone (GH)-insulin like growth factor (IGF)-1 signaling, an experimental intervention for lifespan extension in animals. We investigated the protein levels of AMPKalpha and a downstream enzyme, acetyl-CoA carboxylase (ACC), by immunoblotting of liver and quadriceps femoris muscle (QFM) extracts from 6-month-old wild-type (W) and GH suppressed transgenic (Tg) Wistar rats fed ad libitum (AL) or 30% CR diets from 6weeks of age. A modified alternate-day feeding regimen for CR yielded a fed fasted cycle in CR rats, and therefore the effects of overnight fasting in W-AL rats were also evaluated. CR decreased threonine-172-phosphorylated AMPKalpha (p AMPKalpha; an activated form) levels in the liver, whereas the CR-fed-fasted cycle or overnight fasting did not significantly affect the p-AMPKalpha level. In the QFM, the p-AMPKalpha level was slightly elevated in the CR-fasted phase, but greatly increased in the AL-fasted phase. Suppression of GH did not affect the p AMPKalpha level. The phosphorylated-ACC levels did not alter in parallel with the p-AMPKalpha level, particularly in the liver. The present results suggest that CR down-regulates the AMPK activity in the liver on a long-term basis. PMID- 17709222 TI - CT of blunt pancreatic trauma: a pictorial essay. AB - Blunt trauma to pancreas is uncommon and clinical features are often non-specific and unreliable leading to possible delays in diagnosis and therefore increased morbidity. CT has been established as the imaging modality of choice for the diagnosis of abdominal solid-organ injury in the blunt trauma patient. The introduction of multidetector-row CT allows for high resolution scans and multiplanar reformations that improve diagnosis. Detection of pancreatic injuries on CT requires knowledge of the subtle changes produced by pancreatic injury. The CT appearance of pancreatic injury ranges from a normal initial appearance of the pancreas to active pancreatic bleeding. Knowledge of CT signs of pancreatic trauma and a high index of suspicion is required in diagnosing pancreatic injury. PMID- 17709223 TI - Proton MR spectroscopy of the prostate. AB - PURPOSE: To summarize current technical and biochemical aspects and clinical applications of proton magnetic resonance spectroscopy (MRS) of the human prostate in vivo. MATERIAL AND METHODS: Pertinent radiological and biochemical literature was searched and retrieved via electronic media (medline, pubmed. Basic concepts of MRS of the prostate and its clinical applications were extracted. RESULTS: Clinical MRS is usually based on point resolved spectroscopy (PRESS) or spin echo (SE) sequences, along with outer volume suppression of signals from outside of the prostate. MRS of the prostate detects indicator lines of citrate, choline, and creatine. While healthy prostate tissue demonstrates high levels of citrate and low levels of choline that marks cell wall turnover, prostate cancer utilizes citrate for energy metabolism and shows high levels of choline. The ratio of (choline+creatine)/citrate distinguishes between healthy tissue and prostate cancer. Particularly when combined with magnetic resonance (MR) imaging, three-dimensional MRS imaging (3D-CSI, or 3D-MRSI) detects and localizes prostate cancer in the entire prostate with high sensitivity and specificity. Combined MR imaging and 3D-MRSI exceed the sensitivity and specificity of sextant biopsy of the prostate. When MRS and MR imaging agree on prostate cancer presence, the positive predictive value is about 80-90%. Distinction between healthy tissue and prostate cancer principally is maintained after various therapeutic treatments, including hormone ablation therapy, radiation therapy, and cryotherapy of the prostate. CONCLUSIONS: Since it is non invasive, reliable, radiation-free, and essentially repeatable, combined MR imaging and 3D-MRSI of the prostate lends itself to the planning of biopsy and therapy, and to post-therapeutic follow-up. For broad clinical acceptance, it will be necessary to facilitate MRS examinations and their evaluation and make MRS available to a wider range of institutions. PMID- 17709224 TI - Simultaneous analysis of glycyrrhizin, paeoniflorin, quercetin, ferulic acid, liquiritin, formononetin, benzoic acid and isoliquiritigenin in the Chinese proprietary medicine Xiao Yao Wan by HPLC. AB - A high performance liquid chromatography coupled with photodiode-array detection method was developed for simultaneous determination of glycyrrhizin, paeoniflorin, benzoic acid, quercetin, ferulic acid, formononetin, liquiritin and isoliquiritigenin in the Chinese proprietary medicine "Xiao Yao Wan" (XYW). The analysis was performed by reverse phase gradient elution, using an aqueous mobile phase (containing 0.1% phosphoric acid) modified by acetonitrile and detection made simultaneously at four wavelengths. The method was validated for accuracy, precision and limits of detection and quantification. Ten batches of XYW obtained from different pharmaceutical companies were analyzed and found to contain different amounts of the eight bioactive markers. This method could be used for quality assessment of this herbal medicine. PMID- 17709225 TI - Hydrate modifications of the non-steroidal anti-inflammatory drug diclofenac sodium: Solid-state characterisation of a trihydrate form. AB - Diclofenac sodium is a non-steroidal anti-inflammatory drug widely used in painful and inflammatory diseases. It can exist in different hydrate phases. By exposure to different conditions of temperature and relative humidity can be isolated a trihydrate form never described in literature. The methods of preparation of the trihydrate form (named DSH3) were described and its physico chemical properties were investigated. Data from FTIR spectroscopy, X-ray powder diffraction and thermal analysis were used for identification and characterisation of DSH3 in comparison with the anhydrous form (DS, the commercial form) and the hydrate form DSH (obtained by exposure of DS to relative humidity even below 60% and already described and characterised in a previous article of the same authors). Intrinsic dissolution studies were performed to compare the pharmaceutical properties of DS and DSH with DSH3, since this form was accidentally found on the Italian market as active pharmaceutical ingredient (API). This work stresses the importance of assessing the correct crystalline form also in API of well-established use to guarantee quality, safety and efficacy of the final dosage form. Furthermore, this study suggests that isomorphic hydrate forms with a different dislocation of water within the crystal structures can exist. PMID- 17709226 TI - Identification and quantification of metabolites common to 17alpha methyltestosterone and mestanolone in horse urine. AB - Anabolic steroids with the 17alpha-methyl,17beta-hydroxyl group, which were developed as oral formulations for therapeutic purposes, have been abused in the field of human sports. These anabolic steroids are also used to enhance racing performance in racehorses. In humans, structurally related 17alpha methyltestosterone (MTS) and mestanolone (MSL), which are anabolic steroids with the 17alpha-methyl,17beta-hydroxyl group, have metabolites in common. The purpose of this study was to determine metabolites common to these two steroids in horses, which may serve as readily available screening targets for the doping test of these steroids in racehorses. Urine sample collected after administering MTS and MSL to horses was treated to obtain unconjugated steroid, glucuronide, and sulfate fractions. The fractions were subjected to gas chromatography/mass spectrometry (GC/MS), and 17alpha-methyl-5alpha-androstan-3beta,17beta-diol, 17alpha-hydroxymethyl-5alpha-androstan-3beta,17beta-diol, 17alpha-methyl-5alpha androstan-3beta,16beta,17beta-triol, and 17alpha-methyl-5alpha-androstan 3beta,16alpha,17beta-triol were detected as the common metabolites by comparison with synthesized reference standards. The urinary concentrations of these metabolites after dosing were determined by GC/MS. 17Alpha-methyl-5alpha androstan-3beta,16beta,17beta-triol was mainly detected in the sulfate fractions of urine samples after administration. This compound was consistently detected for the longest time in the urine samples after dosing with both steroids. The results suggest that 17alpha-methyl-5alpha-androstan-3beta,16beta,17beta-triol is a very useful screening target for the doping test of MTS and MSL in racehorses. PMID- 17709227 TI - Extra-abdominal primary fibromatosis: Aggressive management could be avoided in a subgroup of patients. AB - OBJECTIVE: To evaluate the impact of surgery as first-line treatment on event free survival (EFS) of primary aggressive fibromatosis. PATIENTS AND METHODS: Treatments were categorized into: surgery with or without radiotherapy and nonsurgical strategies with systemic treatment alone or wait and see policy. Eighty-nine patients had initial resection of their primary tumour followed by postoperative radiotherapy in 13 cases. Twenty-three did not undergo surgery but received systemic treatment or watch and wait policy. RESULTS: Median follow-up was 76 months. Overall 3 years EFS was 49%. In the univariate analysis, patients with microscopically complete surgery had a similar outcome to patients in the no surgery group (3 years EFS of 65% and 68%, respectively). Gender, age, tumour size, treatment period and strategy (surgery versus no-surgery) were not statistically significant. Quality of resection according to margins and the tumour site were the only prognostic factors. There was a significant correlation between tumour site and quality of surgery (p=0.0002). CONCLUSIONS: A subset of patients with extra-abdominal fibromatosis could be managed with a nonaggressive policy, as growth arrest concerned 2/3 of nonoperated patients. When surgery is finally necessary, it should be performed with the aim of achieving negative margins. PMID- 17709228 TI - Survival in breast cancer after nipple-sparing subcutaneous mastectomy and immediate reconstruction with implants: a prospective trial with 13 years median follow-up in 216 patients. AB - AIM: Validation of the oncological safety of nipple-sparing subcutaneous mastectomy and immediate reconstruction with implants (NSM) and of the outcome in patients with locoregional recurrences (LRRs) after this procedure. METHODS: Two hundred and sixteen patients, mean age of 52.8 (29-81) years with primary unilateral breast cancer, not suitable for partial mastectomy because of large (>3cm) or multifocal carcinoma, underwent NSM, a single procedure lasting about 1h 30min, between December 1988 and September 1994. Lymph node metastases were found in 40.3% of the patients, and 47 patients received radiotherapy (RT) postoperatively. All patients were monitored for at least 11.6 years or as long as they lived. Median follow-up was 13 years. The end-points were locoregional recurrence (LRR) or distant metastases (DM) as first events, disease-free survival (DFS) and overall survival (OS). RESULTS: Specificity at frozen section from sub-areolar tissues was 98.5%. LRR occurred in 52 patients and DM in 44 patients. DFS was 51.3% and OS was 76.4%. The frequency of LRR was 8.5% among irradiated and 28.4% among non-irradiated patients (p=0.025). These results compare well with results after conventional mastectomy in other trials. All patients were monitored for at least 6 years after the occurrence of LRR, finding 5 years freedom from further LRR or DM of 60% and OS of 82%. CONCLUSIONS: NSM is an oncologically safe procedure and could be offered to most patients with breast cancer unsuitable for sector resection only. RT effectively lowers the frequency of LRR. The occurrence of LRR after this operation does not significantly affect OS. PMID- 17709229 TI - Selective hepatic vascular exclusion and Pringle maneuver: a comparative study in liver resection. AB - OBJECTIVE: Most liver resections require champing of the hepatic pedicle (Pringle maneuver) to avoid excessive blood loss. But Pringle maneuver cannot control backflow bleeding of the hepatic vein. Resection of liver tumors involving hepatic veins may cause massive hemorrhage or air embolism from injuries of the hepatic vein. Although total hepatic vascular exclusion (THVE) can prevent bleeding of the hepatic vein effectively, it also may result in systemic hemodynamic disturbance because of the clamped inferior vena cava (IVC). SHVE, a new technique, can control the inflow and outflow of the liver without clamping the vena cava. We compared the effects of selective hepatic vascular exclusion (SHVE) and Pringle maneuver in resection of liver tumors involving the junction of the hepatic vein. METHODS: From January 2000 to October 2005, 2100 patients with liver tumors had undergone liver resections in our department. Among them, tumors of 235 cases adhered to or were close to the junction of one or more hepatic veins. Both SHVE and Pringle maneuver were used to control blood loss during hepatectomy. These 235 cases were divided into two groups: Pringle maneuver group (110) from January 2000 to December 2002 and SHVE group (125) from January 2003 to October 2005. Data were analyzed regarding the intraoperative and postoperative courses of the patients. In the SHVE group, total SHVE (clamping the porta hepatis and all major hepatic veins) was used in 69 cases and partial SHVE (clamping the porta hepatic and one or two hepatic veins) in 56 cases. There were three methods in hepatic veins occlusion: ligating with suture, encircling and occluding with tourniquets and clamping with Satinsky clamps. RESULTS: There was no difference between the two groups regarding the age, gender, tumor size, cirrhosis and HBsAg rate, ischemia time and operating time. Intraoperative blood loss and transfusion requirements were significantly decreased in the SHVE group. Hepatic veins rupture with massive blood loss occurred in 14 and air embolism in three during the tumor resection, but there was no massive blood loss and air embolism in the SHVE group due to hepatic vein occlusion. Postoperative bleeding, reoperation, liver failure and mortality rate were higher, and ICU stay and hospital stay were longer in the Pringle group than those in the SHVE group. CONCLUSION: SHVE is much more effective than Pringle maneuver in controlling intraoperative bleeding. It can prevent massive blood loss and air embolism from hepatic veins rupture and can reduce the postoperative complication rate and mortality rate. Clamping the hepatic veins with Satinsky clamps is much safer and easier than ligating with suture and occluding with tourniquets. PMID- 17709230 TI - First report of the carbapenem-resistant Pseudomonas aeruginosa producing IMP-7 metallo-beta-lactamase in Slovakia. PMID- 17709231 TI - Functional distinctness of closely related transcription factors: a comparison of the Atonal and Amos proneural factors. AB - Using the well-characterised paradigm of Drosophila sensory nervous system development, we examine the functional distinctness of the Amos and Atonal (Ato) proneural transcription factors, which have different mutant phenotypes but share very high similarity in their signature bHLH domains. Using misexpression and mutant rescue assays, we show that Ato and Amos proteins have abundantly distinct intrinsic proneural capabilities in much of the ectoderm. The eye, however, is an exception: here both proteins share the capability to direct the R8 photoreceptor fate choice. Therefore, functional distinctness between these closely related transcription factors vary with developmental context, indicating different molecular mechanisms of specificity in different contexts. Consistent with this, the structural basis for their distinctness also varies depending upon the function in question. In previous studies of neural bHLH factors, specificity invariably mapped to the bHLH domain sequence. Similarly, and despite their high similarity, much of the Amos' specificity relative to Ato maps to Amos-specific residues in its bHLH domain. For Ato-specific functions, however, the Amos bHLH domain can substitute for that of Ato. Consequently, Ato's specificity relative to Amos requires the non-bHLH portion of the Ato protein. Ato provides a powerful precedence for a role of non-bHLH sequences in modulating bHLH functional specificity. This has implications for structural and functional comparisons of other closely related transcription factors, and for understanding the molecular basis of specificity. PMID- 17709232 TI - A global role for zebrafish klf4 in embryonic erythropoiesis. AB - There are two waves of erythropoiesis, known as primitive and definitive waves in mammals and lower vertebrates including zebrafish. The founding member of the Kruppel-like factor (KLF) family of CACCC-box binding proteins, EKLF/Klf1, is essential for definitive erythropoiesis in mammals but only plays a minor role in primitive erythropoiesis. Morpholino knockdown experiments have shown a role for zebrafish klf4 in primitive erythropoiesis and hatching gland formation. In order to generate a global understanding of how klf4 might influence gene expression and differentiation, we have performed expression profiling of klf4 morphants, and then performed validation of many putative target genes by qRT-PCR and whole mount in situ hybridization. We found a critical role for klf4 in embryonic globin, heme synthesis and hatching gland gene expression. In contrast, there was an increase in expression of definitive hematopoietic specific genes such as larval globin genes, runx1 and c-myb from 24 hpf, suggesting a selective role for klf4 in primitive rather than definitive erythropoiesis. In addition, we show klf4 preferentially binds CACCC box elements in the primitive zebrafish beta-like globin gene promoters. These results have global implications for primitive erythroid gene regulation by KLF-CACCC box interactions. PMID- 17709234 TI - Evidence based guidelines. Still fit for purpose or past their sell by date? PMID- 17709233 TI - The radiobiology of Papillon-type treatments. AB - The dominant influence in all types of contact therapy is physical rather than radiobiological in nature and is associated with the rapid fall-off of dose with increasing depth in tissue. Even at a depth of only 20 mm the dose has typically fallen to around 15% of the surface dose, meaning that the deeper (and, potentially, dose-limiting) structures are physically spared. Papillon treatments therefore owe their clinical success largely to this simple characteristic and the radiobiological issues, although of interest, might be dismissed as being of secondary importance. However, consideration of the associated radiobiology is useful as it provides a deeper insight into why Papillon-type treatments are effective and also helps to identify the circumstances in which more careful planning of treatment might be required. Some of the most relevant issues are discussed in this paper. The essential points are introduced in a qualitative manner and then followed by some quantitative assessments. PMID- 17709235 TI - Embryonic stem cells: protecting pluripotency from alloreactivity. AB - There can be little doubt that 2006 turned out to be the annus horribilis for therapeutic cloning by somatic nuclear transfer (SNT). As the full extent of the fraud surrounding the generation of patient-specific embryonic stem (ES) cell lines became apparent, hopes began to fade for the advent of cell replacement therapies (CRT), free from the confounding issues of immune rejection. While the dust begins to settle, it is perhaps pertinent to ask whether the promise of SNT is still worth pursuing or whether alternative strategies for immune evasion might help fill the void. PMID- 17709236 TI - Spatial complexity and control of a bacterial cell cycle. AB - A major breakthrough in understanding the bacterial cell cycle is the discovery that bacteria exhibit a high degree of intracellular organization. Chromosomal loci and many protein complexes are positioned at particular subcellular sites. In this review, we examine recently discovered control mechanisms that make use of dynamically localized protein complexes to orchestrate the Caulobacter crescentus cell cycle. Protein localization, notably of signal transduction proteins, chromosome partition proteins, and proteases, serves to coordinate cell division with chromosome replication and cell differentiation. The developmental fate of daughter cells is decided before completion of cytokinesis, via the early establishment of cell polarity by the distribution of activated signaling proteins, bacterial cytoskeleton, and landmark proteins. PMID- 17709237 TI - Odorant and pheromone receptor gene regulation in vertebrates. AB - The largest mammalian gene family codes for odorant receptors and is exclusively devoted to the perception of the outside world. Its expression is very peculiar, since olfactory sensory neurons are only allowed to express a single of its numerous members, from a single parental allele. How this is achieved is unknown, but recent work points to multiple regulatory mechanisms, possibly shared by pheromone receptor genes, acting at (a) a general level, via the expression of the chemoreceptor itself and (b) a more restricted level, defined by activator elements. PMID- 17709238 TI - Mammalian pheromone sensing. AB - The traditional distinction that the mammalian main olfactory system recognizes general odor molecules and the accessory (vomeronasal) system detects pheromones is no longer valid. The emerging picture is that both systems have considerable overlap in terms of the chemosignals they detect and the effects that they mediate. Recent investigations have discovered large families of pheromonal signals together with a rich variety of specific receptor systems and nasal detection pathways. Selective genetic targeting of these subsystems should help to unravel their biological role in pheromone-mediated behavioral responses. PMID- 17709239 TI - The hazards of time. AB - Temporal expectations are continuously formed and updated, and interact with expectations about other relevant attributes of events, in order to optimise our interaction with unfolding sensory stimulation. In this paper, we will highlight some evidence revealing the pervasive effects of temporal expectations in modulating perception and action, and reflect on the current state of understanding about their underlying neural systems and mechanisms. PMID- 17709240 TI - Analyzing the activity of large populations of neurons: how tractable is the problem? AB - Understanding how the brain performs computations requires understanding neuronal firing patterns at successive levels of processing-a daunting and seemingly intractable task. Two recent studies have made dramatic progress on this problem by showing how its dimensionality can be reduced. Using the retina as a model system, they demonstrated that multineuronal firing patterns can be predicted by pairwise interactions. PMID- 17709241 TI - Subunit assembly of plant lectins. AB - Lectins are a structurally diverse group of carbohydrate recognizing proteins that are involved in various biological processes and exhibit substantial structural diversity. Interestingly, in spite of having varied carbohydrate binding specificities, they show modest variation in their secondary and tertiary structure. However, very similar tertiary folds give rise to a range of quaternary structures by simply varying the mutual orientations of the subunits involved. The variety in the quaternary structure generates multivalency in sugar specificities among lectins along with the requisite surface topology to allow for unobstructed recognition events. PMID- 17709242 TI - Survival of elderly rectal cancer patients not improved: analysis of population based data on the impact of TME surgery. AB - INTRODUCTION: The incidence of rectal cancer is highest in elderly patients. However, these patients are often underrepresented in randomised studies. Therefore, it is not clear whether results of rectal cancer studies are equally applicable to both elderly and younger patients. In this paper, the Dutch Total Mesorectal Excision (TME) study is revisited, focused on patients aged 75 years and above. The rectal cancer databases of the Comprehensive Cancer Centres (CCC) South and West were combined to analyse the effect of the TME-study in three different periods: before (1990-1995), during (1996-1999) and after (2000-2002) the trial. RESULTS: Implementation of preoperative radiotherapy, as investigated in the TME trial, and the introduction of TME surgery resulted in improved 5 year survival during the subsequent periods, in patients younger than 75 years, of 60% (1990-1995) to 67% (1996-1999) and 70% (2000-2002) (log rank p<0.0001). The older patients did not improve and remained at 41%, 40% and 43% at 5 years in the respective periods. Furthermore, mortality during the first 6-month period after treatment is significantly raised compared to younger patients: 14% in the elderly, compared to 3.9% in the younger TME-study patient (p<0.0001 X2). In the CCC database these figures were confirmed at 16% and 3.9% (p<0.0001 X2). CONCLUSION: Overall survival was not improved in the elderly rectal cancer patient after introduction of preoperative radiotherapy and TME-surgery. Non cancer related mortality is a significant problem in the first 6 months after surgery. PMID- 17709243 TI - Comparative study on chemical pretreatment methods for improving enzymatic digestibility of crofton weed stem. AB - In order to utilize and control the invasive weed, crofton weed (Eupatorium adenophorum Spreng), a potential pathway was proposed by using it as a feedstock for production of fermentable sugars. Three chemical pretreatment methods were used for improving enzymatic saccharification of the weed stem. Mild H2SO4 pretreatment could obtain a relatively high yield of sugars in the pretreatment (32.89%, based on initial holocellulose), however, it led to only a slight enhancement of enzymatic digestibility. NaOH pretreatment could obtain a higher enzymatic conversion ratio of cellulose compared with H2SO4 pretreatment. Peracetic acid (PAA) pretreatment seemed to be the most effective for improving enzymatic saccharification of the weed stem in the three chemical pretreatment methods under the same conditions. The conversion ratio of cellulose in the sample pretreated by PAA under the "optimal" condition was increased to 50% by cellulase loading of 80 FPU/g cellulose for 72 h incubation. A number of empirical quadratic models were successfully developed according to the experimental data to predict the yield of sugar and degree of delignification. PMID- 17709244 TI - Performance study of vegetated sequencing batch coal slag bed treating domestic wastewater in suburban area. AB - A practical and affordable wastewater treatment system serving small community in suburban areas was studied. The system was a vegetated sequencing batch coal slag bed integrated with the rhythmical movement of wastewater and air like that of a sequencing batch reactor. The removal mechanisms capitalized on the pollutant removal process in conventional constructed wetland. Cyperus alternifolius was planted into the coal slag bed to form a novel plant-soil-microbial interactive system. Nutrients in the domestic wastewater, which cause environmental nuisance like eutrophication, were targeted to be eliminated by the process design. Operated with the contact time of 18 h, the treatment systems achieved around 60% removal efficiency for carbonaceous matters. The removals of ammonia nitrogen and phosphorus were about 50% and 40%, respectively, while the removal of total suspended solids was approaching 80%. From the current study, the construction cost of the vegetated sequencing batch coal slag bed was 256 RMB/m3 and the operation cost was 0.13 RMB/m3. With the advantages of ease of operation, low costs, desirable treatment efficiency and aesthetic value, the vegetated sequencing batch coal slag bed is proposed to be an alternative for onsite domestic wastewater treatment in suburban areas. PMID- 17709245 TI - Presence of nitrogen fixing Klebsiella pneumoniae in the gut of the Formosan subterranean termite (Coptotermes formosanus). AB - A gram-negative facultative anaerobic enteric bacterium, Klebsiella pneumoniae was isolated from the hindgut of the Formosan subterranean termite (FST). It was characterized using, fatty acid methyl ester (FAME) analysis, BIOLOG assay, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and biochemical studies. The role of this isolate seems to be nitrogen fixation because the termite's diet is nitrogen deficient and the isolate produced significant amounts of ammonia when it was grown on nitrogen deficient medium under anaerobic condition with nitrogen gas in the headspace. PMID- 17709246 TI - The integration of methanogenesis with shortcut nitrification and denitrification in a combined UASB with MBR. AB - A combined system consisting of an up-flow anaerobic sludge blanket (UASB) and an aerobic membrane bioreactor (MBR) was operated at 28-30 degrees C and pH 7.8-8.1 for the treatment of low-strength synthetic wastewater enriched with organic carbon and NH4Cl. The MBR slurry was recirculated into the UASB with a ratio of 50-800%. It was found that nitrite was able to accumulate steadily during the nitrification step in the MBR at a low TOC/NH4+-N ratio. The mixed liquid containing NOX(-)-N in the MBR was recirculated to the UASB, and denitrification rather than methanogenesis became the preferred pathway. Whereas, the less carbon requirement for denitrification via nitrite rather than nitrate allowed methanogenesis to proceed simultaneously in the same reactor. The combination of membrane filtration and partial nitrification in the MBR with simultaneous denitrification and methanogenesis in the UASB could stably reach 98% TOC removal and 48.1-82.8% TN removal with recirculation ratio increasing from 50% to 800%. PMID- 17709247 TI - Design and synthesis of quinolin-2(1H)-one derivatives as potent CDK5 inhibitors. AB - Cyclin-dependent kinase 5 (CDK5) is a serine/threonine protein kinase and its deregulation is implicated in a number of neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and ischemic stroke. Using active site homology modeling between CDK5 and CDK2, we explored several different chemical series of potent CDK5 inhibitors. In this report, we describe the design, synthesis, and CDK5 inhibitory activities of quinolin-2(1H)-one derivatives. PMID- 17709248 TI - Correlation of carboxylic acid pKa to protein binding and antibacterial activity of a novel class of bacterial translation inhibitors. AB - Previously we reported the discovery and initial optimization of a novel anthranilic acid derived class of antibacterial agents which suffered from extensive protein binding. This report describes efforts directed toward understanding the relationship of the acidity of the carboxylic acid with the extent of protein binding. The pK(a) of the acid was modified via the synthesis of a number of anthranilic acid analogs which vary the aromatic ring substituent at the 4-position. The pK(a) and HSA binding constants have been determined for each of the analogs. Our results indicate a correlation between pK(a) and HSA K(d). The physical properties and antibacterial activities will be discussed as well as how these results help address the protein binding issue with this series of compounds. PMID- 17709249 TI - Outcome of initially only magnetic resonance mammography-detected findings with and without correlate at second-look sonography: distribution according to patient history of breast cancer and lesion size. AB - The purpose of the study was to evaluate the outcome of initially only magnetic resonance mammography (MRM)-detected breast lesions as a function of radiologic features, history of breast cancer and lesion size. We evaluated core needle biopsy (CNB) (148) and follow-up (25) results of 173 initially only MRM-detected lesions-142 with and 31 without "second-look" correlate, as a function of (1) radiologic features (sonographic correlate, MRI BI-RADS category); (2) history of breast cancer; (3) MRM indication in case of history of breast neoplasm; (4) side and size of synchronous cancer; (5) lesion diameter. (1) Overall malignancy rate was 28.3% (49/173); significantly higher among lesions with a sonographic correlate (46/142), than among those without (3/31) (p=0.014). Frequencies of malignancy for MRI BI-RADS categories 2, 3, 4 and 5, were 0% (0/1), 5.4% (4/73), 26.1% (17/65) and 82.3% (28/34), respectively. (2) Malignancy rate was significantly higher in case of history of breast carcinoma (40/118 versus 9/55; p=0.027); in particular, of 42 MRI BI-RADS category 3 lesions in women with history of breast cancer and of 31 in patients without history, 3 (7%) and 1 (3%) proved to be malignant, respectively (non-significant). (3) Malignancy was more frequent when MRM was performed for pre-operative assessment than for follow-up (30/78 versus 10/40; non-significant). (4) Malignancy rate increased in presence of ipsilateral (19/35 versus 11/43; p=0.018), large (cut-off 6 mm: 30/75 versus 0/3, non-significant; 11 mm: 28/61 versus 2/17, p=0.011; 16 mm: 24/48 versus 6/30, p=0.015; 21 mm: 14/21 versus 16/57, p=0.004) primary tumors. (5) The frequency of malignancy was significantly higher in lesions equal to or larger than 6, 11 and 16 mm, compared with smaller lesions (6 mm: 45/136 versus 4/37, p=0.007; 11 mm: 21/51 versus 28/122, p=0.025; 16 mm: 12/24 versus 37/149, p=0.021). Radiologic features, history of breast cancer and large diameter are associated with high likelihood of malignancy in case of initially only MRM detected lesions. Nevertheless, biopsy might be spared just for MRI BI-RADS 3 lesions in patients without history of breast carcinoma. PMID- 17709250 TI - Atomic force microscopy probing of cell elasticity. AB - Atomic force microscopy (AFM) has recently provided the great progress in the study of micro- and nanostructures including living cells and cell organelles. Modern AFM techniques allow solving a number of problems of cell biomechanics due to simultaneous evaluation of the local mechanical properties and the topography of the living cells at a high spatial resolution and force sensitivity. Particularly, force spectroscopy is used for mapping mechanical properties of a single cell that provides information on cellular structures including cytoskeleton structure. This entry is aimed to review the recent AFM applications for the study of dynamics and mechanical properties of intact cells associated with different cell events such as locomotion, differentiation and aging, physiological activation and electromotility, as well as cell pathology. Local mechanical characteristics of different cell types including muscle cells, endothelial and epithelial cells, neurons and glial cells, fibroblasts and osteoblasts, blood cells and sensory cells are analyzed in this paper. PMID- 17709251 TI - Correlation between joint [F-18] FDG PET uptake and synovial TNF-alpha concentration: a study with two rabbit models of acute inflammatory arthritis. AB - The objective of this study was to verify that the [F-18]FDG PET synovial uptake is correlated with the synovial fluid (SF) TNF-alpha concentration. Two rabbit models of acute inflammatory arthritis induced by human interleukin-8 and lipopolysaccharide were used. Modified standard uptake values (MSUVs) obtained from PET images of the animals were compared with results of SF TNF-alpha measurements. Statistically significant correlations were found between the MSUVs and the SF TNF-alpha ratios. An equation to estimate the TNF-alpha ratio from a MSUV was also derived. PMID- 17709252 TI - Effects of normothermic organ bath and verapamil-nitroglycerin solution alone or in combination on the blood flow of radial artery. AB - OBJECTIVE: Radial artery pedicle tissue cooling during harvesting is one of the major causes of vasospasm. We aimed to compare the effects of the pedicle rewarming method, normothermic organ bath, and one of the most preferred topical antispasmodic agents, verapamil-nitroglycerin solution alone or in combination on the blood flow of radial artery. METHODS: Consecutively randomized patients (n=80) undergoing coronary bypass were organized as four equal-sized groups. Effects of normothermic organ bath and topically performed verapamil nitroglycerin solution alone or in combination on the blood flow of radial artery were investigated. In the control group no antispasmodic treatment was performed. Free flows were measured at three stages: as initial flow after minimal distal harvesting, post-harvesting flow after total harvesting, and post-treatment flow following a waiting period after the application of the antispasmodic protocol. At each stage, pedicle and esophageal temperatures were also recorded. RESULTS: Radial artery pedicle temperatures decreased significantly during harvesting in all groups (p<0.001). Normothermic organ bath, topical verapamil-nitroglycerin solution treatment, and their combination increased flow significantly (p<0.001, from 40.3+/-10.48 ml/min to 64.3+/-18.8 ml/min, from 38.9+/-13.91 ml/min to 62.75+/-15.23 ml/min, from 41.4+/-11.19 ml/min to 75.4+/-15.32 ml/min, respectively). The differences between the initial and post-treatment flows were not significant in the combined procedure group (p>0.05), whereas the initial levels were not reached in the post-treatment flows (p<0.05) in the normothermic organ bath and verapamil-nitroglycerin groups. CONCLUSIONS: Hypothermia plays an important role in radial artery vasospasm. Normothermic organ bath and verapamil nitroglycerin solution alone or in combination relieve spasm of radial artery. PMID- 17709253 TI - Re: Topical use of antifibrinolytic agents reduces postoperative bleeding: a double-blind, prospective, randomized study. PMID- 17709255 TI - Interactions between colloidal silver and photosynthetic pigments located in cyanobacteria fragments and in solution. AB - Changes in the yield of the fluorescence emitted by pigments of photosynthetic organisms could be used for the establishment of the presence of some toxic substances. The presence of colloidal metals can be indicated by enhancement of pigments' emission as a result of plasmons generation. The spectra of the pigments of cyanobacterium Synechocystis located in the bacterium fragments and in solutions with and without colloidal silver additions have been measured. The quantum yield of the pigments' fluorescence in solution has been observed to increase at some wavelength of excitation, while the fluorescence of the pigments in the bacteria fragments has been only quenched as a consequence of interactions with colloidal silver particles. Close contact between pigment molecules located in bacteria fragments and silver particles is probably not possible. We plan in future to investigate the influence of other, more typical metal pollutants of water, using similar spectral methods and several other photosynthetic bacteria pigments, in solution, in cell fragments and in the whole bacteria organisms. PMID- 17709256 TI - Porphyromonas gingivalis antagonises Campylobacter rectus induced cytokine production by human monocytes. AB - Porphyromonas gingivalis and Campylobacter rectus are two major bacterial species implicated in the pathogenesis of periodontitis. P. gingivalis can antagonise the inflammatory response to other periodontal pathogens, a property commonly attributed to its lipopolysaccharide (LPS). The aim of this study was to investigate the capacity of P. gingivalis to antagonise C. rectus induced cytokine stimulation from human monocytes, and to investigate the involvement of its LPS. Primary human monocytes and Monomac-6 cells were challenged with culture supernatants from P. gingivalis and C. rectus, and levels of IL-1beta, IL-6 and IL-8 produced were measured by ELISA after 6h incubation. Purified P. gingivalis LPS was also added alone or in combination with C. rectus culture supernatant. Both species significantly stimulated the production of all three cytokines from the two cell lines, but P. gingivalis was considerably weaker inducer. Co stimulation of the cells with P. gingivalis and C. rectus suppressed the cytokine stimulatory capacity of the latter. P. gingivalis LPS alone was sufficient to antagonise IL-6 and IL-8, but not IL-1beta stimulation by C. rectus. In conclusion, mixed infections may impair host immune responses by reducing pro inflammatory cytokine levels, which may be of relevance to the pathogenesis of periodontitis. PMID- 17709258 TI - Expression, purification and characterization of recombinant phospholipase B from Moraxella bovis with anomalous electrophoretic behavior. AB - Moraxella bovis is the causative agent of infectious bovine keratoconjunctivitis (IBK) also known as pinkeye, a highly contagious and painful eye disease that is common in cattle throughout the world. Vaccination appears to be a reasonable and cost-effective means of control of pinkeye. Identification of genes encoding novel secreted antigens have been reported, and these antigens are being assessed for use in a vaccine. One of the genes encodes phospholipase B, which can be expressed with high purity and yield in recombinant Escherichia coli as a secreted, soluble, non-tagged, mature construct (less signal peptide with predicted mass 63 kDa). The recombinant phospholipase B exhibited anomalous electrophoretic mobility that was dependent on the temperature of the denaturing process, with bands observed at either 52 or 63 kDa. Analysis by in-gel digestion and liquid chromatography-mass spectrometry revealed these two distinct forms most likely had identical sequences. Phospholipase B is a compact, globular protein with a predicted structure typical of a conventional autotransporter. It is suggested that high temperature is required to unfold the protein (to denature the beta-barrel-rich transporter domain) and to ensure accessibility of the reducing agent. Interestingly, the two forms of the enzyme, differing in size and isoelectric points, were also detected in cell-free supernatants of M. bovis cultures, indicating that native phospholipase B may exist in two differentially folded states possibly also differing in oxidation status of cysteine residues. PMID- 17709257 TI - Protective effect of Foeniculum vulgare essential oil and anethole in an experimental model of thrombosis. AB - In a previous screening work, Foeniculum vulgare essential oil emerged from a pool of 24 essential oils for its antiplatelet properties and its ability to destabilize the retraction of the coagulum. In the present work the main component of the oil, anethole, tested in guinea pig plasma was as potent as fennel oil in inhibiting arachidonic acid-, collagen-, ADP- and U46619-induced aggregation (IC(50) from 4 to 147 microg ml(-1)). It also prevented thrombin induced clot retraction at concentrations similar to fennel oil. The essential oil and anethole, tested in rat aorta with or without endothelium, displayed comparable NO-independent vasorelaxant activity at antiplatelet concentrations which have been proved to be free from cytotoxic effects in vitro. In vivo, both F. vulgare essential oil and anethole orally administered in a subacute treatment to mice (30 mg kg(-1)day(-1) for 5 days) showed significant antithrombotic activity preventing the paralysis induced by collagen-epinephrine intravenous injection (70% and 83% protection, respectively). At the antithrombotic dosage they were free from prohemorrhagic side effect at variance with acetylsalicylic acid used as reference drug. Furthermore, both F. vulgare essential oil and anethole (100 mg kg(-1) oral administration) provided significant protection toward ethanol induced gastric lesions in rats. In conclusion, these results demonstrate for F. vulgare essential oil, and its main component anethole, a safe antithrombotic activity that seems due to their broad spectrum antiplatelet activity, clot destabilizing effect and vasorelaxant action. PMID- 17709259 TI - Cell surface display of functionally active lipases from Yarrowia lipolytica in Pichia pastoris. AB - The lipase genes of Yarrowia lipolytica, LIPY7 and LIPY8, fused with FLO flocculation domain sequence from Saccharomyces cerevisiae at their N-termini, were expressed in Pichia pastoris KM71. Following the induction with methanol, the recombinant proteins were displayed on the cell surface of P. pastoris, as confirmed by the confocal laser scanning microscopy. The LipY7p and LipY8p were anchored on P. pastoris via the flocculation functional domain of Flo1p. The surface-displayed lipases were characterized for their application as the whole cell biocatalyst. These lipases can also be cleaved off from their anchor by enterokinase treatment to yield functionally active proteins in the supernatant offering an alternative purification method for LipY7p and LipY8p. PMID- 17709261 TI - Motor unit discharge pattern and conduction velocity in patients with upper motor neuron syndrome. AB - Motor unit properties were analyzed in patients with upper motor neuron syndrome (UMNS). Multi-channel surface electromyographic (EMG) signals were recorded for 300s from the biceps brachii muscle of seven male subacute patients (time from lesion, mean+/-SE, 4.9+/-1.0 months). In three patients, both arms were investigated, leading to 10 recorded muscles. Patients were analyzed in rest-like condition with motor units activated due to pathological muscle overactivity. For a total of 12 motor units, the complete discharge pattern was extracted from EMG decomposition. Interpulse interval variability was 7.8+/-0.9%. At minimum discharge rate (6.4+/-0.4 pulses per second, pps), conduction velocity was smaller than at maximum discharge rate (12.0+/-0.9pps) in all motor units (3.60+/ 0.21m/s vs. 3.84+/-0.20m/s). Conduction velocity changed by 1.35+/-0.48% (different from zero, P<0.01) for each increase of 1pps in discharge rate. It was concluded that conduction velocity of low-threshold motor units in subacute patients with UMNS had similar values as reported in healthy subjects and was positively correlated to instantaneous discharge rate (velocity recovery function of muscle fibers). PMID- 17709260 TI - Characterization of ubiquitin C-terminal hydrolase 1 (YUH1) from Saccharomyces cerevisiae expressed in recombinant Escherichia coli. AB - The YUH1 gene coding for ubiquitin C-terminal hydrolase 1, a deubiquitinating enzyme, was cloned from the Saccharomyces cerevisiae genomic DNA and expressed in Escherichia coli. YUH1 was fused with the 6 histidine tag at the N-terminus (H6YUH1) or C-terminus (YUH1H6) and purified by an immobilized metal affinity chromatography with high purity. By using a fluorogenic substrate, Z-Arg-Leu-Arg Gly-Gly-AMC, the deubiquitinating activities for H6YUH1 (1.72U/mg) and YUH1H6 (1.61U/mg) were about 18 times higher than 0.092U/mg for H6UBP1, ubiquitin specific protease 1 of S. cerevisiae containing the 6 histidine residue at the N terminus which is normally used in protein engineering. YUH1 had the optimal temperature of 27 degrees C and acidity of pH 8.5. Analysis of thermal deactivation kinetics of H6YUH1 estimated 3.2 and 1.4h of half lives at 4 and 52 degrees C, respectively. Immobilization onto the Ni-NTA affinity resin and environmental modulation were carried out to improve the stability of YUH1. Incubation of the immobilized YUH1 in 50% glycerol solution at -20 degrees C resulted in 52% of decrease in specific activity for 7days, corresponding to a 2.7-fold increase compared with that of the free YUH1 incubated in the same solution at 4 degrees C. PMID- 17709262 TI - Interrelationships of the 11 gasterosteiform families (sticklebacks, pipefishes, and their relatives): a new perspective based on whole mitogenome sequences from 75 higher teleosts. AB - The fishes currently recognized as members of the order Gasterosteiformes (sticklebacks, pipefishes, and their relatives) number 278 species, classified into two suborders (Gasterosteoidei and Syngnathoidei), 11 families and 71 genera. Members of this group exhibit unique appearances, many of which are derived from armored bodies with bony plates in various forms. Although recent molecular phylogenetic studies have repeatedly questioned the monophyly of this order, none of the studies examined all of the representative families and the phylogenetic reality of the group has remained unclear. In this study, we examined whole mitochondrial genome (mitogenome) sequences from 13 gasterosteiform species representing all 11 families in the order, and subjected them to partitioned maximum likelihood and Bayesian analyses, with additional data from other percomorphs and outgroups (75 mitogenome sequences considered overall, including 10 newly determined). The resultant phylogenies indicated explicitly that previously recognized members of Gasterosteiformes had diverged basally within the Percomorpha into three different clades with the following subgroups: Syngnathoidei, Gasterosteoidei (minus Indostomidae), and Indostomidae. Monophyly of the order Gasterosteiformes and any combinations of the three subgroups were confidently rejected by statistical tests. Syngnathoidei (together with Dactylopteroidei) formed a monophyletic group, a sister-group relationship between Gasterosteoidei (minus Indostomidae) and Zoarcoidei was reconfirmed and Indostomidae was nested within the Synbranchiformes, rendering the latter group paraphyletic. Our study demonstrates a new perspective of gasterosteiform phylogeny, which will provide fundamental information for future studies of phylogeny, systematics, and evolution. PMID- 17709263 TI - Phylogenetic analysis of nuclear and mitochondrial genes supports species groups for Columbicola (Insecta: Phthiraptera). AB - The dove louse genus Columbicola has become a model system for studying the interface between microevolutionary processes and macroevolutionary patterns. This genus of parasitic louse (Phthiraptera) contains 80 described species placed into 24 species groups. Samples of Columbicola representing 49 species from 78 species of hosts were obtained and sequenced for mitochondrial (COI and 12S) and nuclear (EF-1alpha) genes. We included multiple representatives from most host species for a total of 154 individual Columbicola, the largest molecular phylogenetic study of a genus of parasitic louse to date. These sequences revealed considerable divergence within several widespread species of lice, and in some cases these species were paraphyletic. These divergences correlated with host association, indicating the potential for cryptic species in several of these widespread louse species. Both parsimony and Bayesian maximum likelihood phylogenetic analyses of these sequences support monophyly for nearly all the non monotypic species groups included in this study. These trees also revealed considerable structure with respect to biogeographic region and host clade association. These patterns indicated that switching of parasites between host clades is limited by biogeographic proximity. PMID- 17709265 TI - Efficient cross polarization with simultaneous adiabatic frequency sweep on the source and target channels. AB - In this work, we propose a new and efficient heteronuclear cross polarization scheme, in which adiabatic frequency sweeps from far off-resonance toward on resonance are applied simultaneously on both the source and target spins. This technique, which we call as Simultaneous ADIabatic Spin-locking Cross Polarization (SADIS CP), is capable of efficiently locking both the source and target spins with moderate power even in the presence of large spectral distribution and fast relaxation. It is shown that by keeping the time-dependent Hartmann-Hahn mismatch minimal throughout the mixing period, polarization transfer can be accelerated. Experiments are demonstrated in a powder sample of L alanine. PMID- 17709264 TI - Differential involvement of M1-type and M4-type muscarinic cholinergic receptors in the dorsomedial striatum in task switching. AB - Previous experiments have demonstrated that the rat dorsomedial striatum is one brain area that plays a crucial role in learning when conditions require a shift in strategies. Further evidence indicates that muscarinic cholinergic receptors in this brain area support adaptations in behavioral responses. Unknown is whether specific muscarinic receptor subtypes in the dorsomedial striatum contribute to a flexible shift in response patterns. The present experiments investigated whether blockade of M1-type and/or M4-type cholinergic receptors in the dorsomedial striatum underlie place reversal learning. Experiment 1 investigated the effects of the M1-type muscarinic cholinergic antagonist, muscarinic-toxin 7 (MT-7) infused into the dorsomedial striatum in place acquisition and reversal learning. Experiment 2 investigated the effects of the M4-type muscarinic cholinergic antagonist, muscarinic-toxin 3 (MT-3) injected into the dorsomedial striatum in place acquisition and reversal learning. All testing occurred in a modified cross-maze across two consecutive sessions. Bilateral injections of MT-7 into the dorsomedial striatum at 1 or 2 microg, but not 0.05 microg impaired place reversal learning. Analysis of the errors revealed that MT-7 at 1 and 2 microg significantly increased regressive errors, but not perseverative errors. An injection of MT-7 2 microg into the dorsomedial striatum prior to place acquisition did not affect learning. Experiment 2 revealed that dorsomedial striatal injections of MT-3 (0.05, 1 or 2 microg) did not affect place acquisition or reversal learning. The findings suggest that activation of M1-type muscarinic cholinergic receptors in the dorsomedial striatum, but not M4 type muscarinic cholinergic receptors facilitate the flexible shifting of response patterns by maintaining or learning a new choice pattern once selected. PMID- 17709266 TI - Frequent intravenous pulses of growth hormone together with alanylglutamine supplementation in prolonged critical illness after multiple trauma: effects on glucose control, plasma IGF-I and glutamine. AB - OBJECTIVE: We aim to demonstrate that low dose growth hormone (GH) administered in i.v. pulses every 3h is able to normalize IGF-I levels in subjects with prolonged critical illness, after multiple trauma. We also ask whether it is possible to control glycaemia during such a treatment and how alanylglutamine (AG) supplementation influences plasma glutamine concentration. METHODS: We used a prospective double-blind (group 1 vs. 2), randomized trial with an open-label control arm (group 3). Thirty multiple trauma patients (median age: 36, 42, 46 years) were randomized on day 4 after trauma to receive (group 1, n=10) i.v. AG supplementation (0.3 g/kg day from day 4 till 17) and i.v. GH (0.05 mg/kg day divided into 8 boluses, maximum dose at 3 AM, administered on days 7-17) or AG and placebo (group 2, n=10). Group 3 (n=10) received isocaloric isonitrogenous (proteins 1.5 g/kg day) nutrition without AG. Glycaemia was controlled by i.v. insulin infusion according to a routine protocol. RESULTS: GH treatment caused an increase of IGF-I (from median 169 on day 4 to 493 ng/ml on day 17), IGFBP-3 (from 2.4 to 3.2 microg/ml) and a fall in IGFBP-1 (from 11.5 to 3.1 microg/ml), whilst in both groups 2 and 3 these indices remained unchanged. At the end of the study (day 17) IGF-I and IGFBP-1 differed significantly among groups (p=0.008 resp. p=0.010, Kruskal-Wallis). Plasma glutamine remained below the normal range through the study in all groups (median: 0.18-0.30 mM), but had a tendency to rise in group 2 in contrast with a fall in groups 1 and 3 (NS). Group 1 required more insulin (p<0.01) than did the control group but median glycaemia was only 0.4-0.5 mM higher in group 1 (6.5 mM) than in groups 2 and 3 (6.1 resp. 6.0 mM). CONCLUSIONS: GH (0.05 g/kg day) administered in i.v. pulses is able to normalize IGF-I levels in subjects with prolonged critical illness after trauma. During this treatment, the standard dose of AG prevents worsening of plasma glutamine deficiency and glucose control is possible using routine algorithms, but it requires higher insulin doses. PMID- 17709267 TI - Insulin-like growth factor system gene expression in cervical scrapes from women with squamous intraepithelial lesions and cervical cancer. AB - BACKGROUND: There is ample evidence that the insulin-like growth factors (IGF) system is involved in the development of several types of cancer. The aim of this study was to evaluate the expression levels of IGF-I, IGF-II, IGF binding protein 3 (IGFBP-3) and IGF-I receptor (IGF-IR) in exfoliated cervical cells in cervical carcinogenesis. METHODS: mRNA levels of IGF-I, IGF-II, IGFBP-3 and IGF-IR were assessed by real-time PCR in 105 cervical scrapes obtained from 16 patients diagnosed with low-grade squamous intraepithelial lesions (LSIL), 24 with high grade SIL (HSIL), 23 with cervical cancer, and 42 from controls with normal Papanicolau (Pap) test. RESULTS: IGF-I mRNA levels were very low and no significant differences were seen between control and other groups. IGF-II mRNA levels were significantly lower in LSIL than in control group (median [arbitrary units]: 0.38 vs. 2.42, P=0.006) but its expression in HSIL and cervical cancer was similar to the one observed in controls. IGFBP-3 mRNA levels were significantly lower in cancer than in controls (median [arbitrary units]: 0.43 vs. 0.73, P=0.03). We observed a decrease in IGF-IR gene expression as the SIL degree increased (median for controls, LSIL, HSIL, and cervical carcinoma [arbitrary units]: 31.24, 9.08, 8.95, and 3.56, respectively). IGF-IR mRNA levels were significantly lower in HSIL and cervical cancer in comparison with controls (P=0.043 and P<0.001, respectively). CONCLUSIONS: The present observations suggest that a reduced expression of IGFBP-3 and IGF-IR can be associated with progression to cervical cancer; the specific role played by the IGF-IR in this process remains unclear. PMID- 17709268 TI - Lysophospholipase from the human blood fluke, Schistosoma japonicum. AB - BACKGROUND: Given the unusual nature of the schistosome surface (a highly unusual lipid bi-layer) and the central role of the schistosome tegument in host-parasite relations, an enhanced understanding of the lipid biochemistry of the schistosome surface can be expected to provide new insights into schistosome pathogenesis and lead to new interventions. METHODS: Bioinformatics approaches including three dimensional homology modeling, along with recombinant expression, dimensional gel electrophoresis, immunoblotting, and Southern hybridizations were employed to characterize a novel lysophospholipase gene transcript from Schistosoma japonicum. RESULTS: A transcript encoding a small form lysophospholipase from the egg stage of S. japonicum was isolated as an expressed sequence tag (EST). The deduced polypeptide included 227 amino acid residues, shared identity with lysophospholipases of Schistosoma mansoni and Rattus norvegicus, and esterase A of Pseudomonas fluorescens, appeared to belong to the abhydrolase_2 family of phospholipases and carboxylesterases, and was structurally related to the alpha/beta-hydrolases (pfam00561). The S. japonicum enzyme exhibited the GXSXG consensus active site characteristic of serine proteases, esterases, and lipases, and included the catalytic triad motif of Ser-Asp-His residues characteristic of serine hydrolases. Three-dimensional structural predictions accomplished using the coordinates of human acyl protein thioesterase and P. fluorescens esterase indicated that the putative catalytic triad formed by these three residues was located at the alpha/beta-hydrolase fold characteristic of the lipases and esterases. Soluble S. japonicum lysophospholipase was expressed in Escherichia coli as a recombinant enzyme of approximately 26kDa and employed to raise a mono specific antiserum. Immunoblot analysis revealed a single 23-kDa band in both membrane-associated and soluble tissue fractions of adult schistosomes. Southern hybridization and bioinformatics analyses indicated the likely presence of allelic-specific polymorphisms and/or two copies of the lysophospholipase gene in the S. japonicum genome. CONCLUSIONS: A small form lysophospholipase has been characterized from the human schistosome, S. japonicum. The availability of the recombinant S. japonicum lysophospholipase should facilitate further characterization of the enzyme, including its substrate and inhibition profiles and its potential as an interventional target. Schistosome lysophospholipase may represent a new target for anti-schistosomal chemotherapy given that metrifonate, which targets the related enzyme acetylcholinesterase, is an effective and safe medicine for treatment of urinary schistosomiasis. PMID- 17709269 TI - Degenerative joint disease in patients with spinal cord injury. PMID- 17709270 TI - Thoracic myelopathy caused by calcified ligamentum flavum. AB - Calcification of the ligamentum flavum is a rare manifestation of the calcium pyrophosphate dihydrate deposition disease (CPPD). In CPPD deposition disease, spinal involvement is rare. Until now, thoracic spine CPPD causing thoracic cord compression has been reported in only sporadic cases. We report a new case of thoracic calcification of the ligamentum flavum. In our case, similar to the other reported cases, an affected middle-aged woman despite the clinical and MRI signs of myelopathy had an unexpected important and rapid improvement of the neurological picture. This condition should be considered in differential diagnosis of thoracic cord compression to offer the patient an early and useful surgical treatment. PMID- 17709271 TI - Measurement of local strains induced into the femur by trochanteric Gamma nail implants with one or two distal screws by V. Filardi and R. Montanini [Med. Eng. Phys. 1 (2007) 38-47]. PMID- 17709272 TI - Power output and metabolic cost of synchronous and asynchronous submaximal and peak level hand cycling on a motor driven treadmill in able-bodied male subjects. AB - PURPOSE: To evaluate external power output and physiological responses of synchronous (SYNC) and asynchronous hand cycling (ASYNC) at submaximal and peak levels of exercise. METHODS: n=9 able-bodied male subjects (age: 20.1+/-2.1 years) performed two (sub)maximal continuous hand cycle exercise tests, using the SYNC and ASYNC mode in a standardized commercial add-on hand cycle unit (counter balanced order). Treadmill speed (1.89 and 2.17 m s(-1)) and slope (steps of +1%) were changed in a fixed sequence of 3-min exercise steps. Gears were adjusted to 65 rpm. External power output (PO) was continuously monitored with a strain-gauge instrumented chain ring ((SRM) Schoberer Rad Messtechnik). A conventional wheelchair drag test was performed to validate mean external power for each speed slope combination. Heart rate (HR; bpm) and oxygen uptake (VO2; ml kg(-1) min( 1), SMTP) were continuously monitored. Paired T-tests and ANOVA for repeated measures evaluated effects of mode and exercise level (p<0.05). RESULTS: Subjects reached peak levels of performance (RER: 1.05+/-0.07 versus 1.10+/-0.1 for SYNC and ASYNC). Peak PO and V(o2) were significantly higher for SYNC (81.6+/-11.8 W versus 68.5+/-10.6 W; 26.4+/-4.5 ml kg(-1) min(-1) versus 21.2+/-3.0 ml kg(-1) min(-1)). At submaximal exercise levels, gross mechanical efficiency (ME) was significantly higher for SYNC (12.1+/-0.9% versus 9.7+/-1.4% at 41 W). No significant differences were found for PO (at equal velocity and slope), as derived from the SRM (SYNC and ASYNC), and from the drag test. DISCUSSION: The absence of any differences in PO between SYNC and ASYNC, and with respect to the drag test, rules out 'additional external work due to maintain the desired heading' in the ASYNC as an explanation for the lower performance in this mode. Lower peak performance and ME in ASYNC may be explained by the increased stabilizing muscle effort in the upper extremities and trunk in order to combine power production with stable steering. ASYNC is less efficient compared to SYNC. Similarly, peak performance capacity was higher for SYNC. CONCLUSION: External work does not differ between SYNC and ASYNC hand cycling. SRM readings appear valid for PO monitoring in hand cycling within the studied range of PO. SYNC is more efficient than ASYNC and leads to higher peak performance. PMID- 17709273 TI - Thrombomodulin: from haemostasis to inflammation and tumourigenesis. AB - Thrombomodulin (TM), a transmembrane endothelial receptor, participates in coagulation, in inflammation, in cancer and plays a role during embryogenesis. The nucleotide sequence of the TM cDNA allows the structure of this protein to be visualized. The protein starts with a signal peptide, followed by the N-terminal globular domain, six repeats of epidermal growth factor-like sequence, a serine/threonine-rich region, a transmembrane domain and a cytoplasmic domain. High-resolution nuclear magnetic resonance (NMR) spectroscopy was employed to define the exact thrombin-binding region. Residues Y(413)ILDD(417) and D(423)IDE(426) are crucial for binding to thrombin; the two critical amino acids for thrombin binding, Ile(414) and Ile(424), are brought into spatial proximity by beta-sheet structure. There also exist some residues for co-factor activity, namely Asp(349), Glu(357), Tyr(358), Phe(376) and Met(388). The complex transcriptional and post-transcriptional control of TM underline its importance in a wide variety of biological systems and pathophysiological processes. PMID- 17709274 TI - The cytosolic N-terminus of presenilin-1 potentiates mouse ryanodine receptor single channel activity. AB - Ryanodine receptors (RyRs) amplify intracellular Ca(2+) signals by massively releasing Ca(2+) from intracellular stores. Exaggerated chronic Ca(2+) release can trigger cellular apoptosis underlying a variety of neurodegenerative diseases. Aberrant functioning of presenilin-1 (PS1) protein instigates Ca(2+) dependent apoptosis, providing a basis for the "calcium hypothesis" of Alzheimer's disease (AD). To get insight into this problem, we hypothesized that the previously reported physical interaction between RyR and PS1 modulates functional properties of the RyR. We generated a soluble cytoplasmic N-terminal fragment of PS1 comprising the first 82 amino acid (PS1 NTF(1-82)), the candidate for interaction with putative cytoplasmic modulatory sites of the RyR, and studied its effect on single channel currents of mouse brain RyRs incorporated in lipid bilayers. PS1 NTF(1-82) strongly increased both mean currents (EC(50)=12nM, Hill coefficient (n(H)) approximately 1) and open probability for higher sublevels for single RyR channels (EC(50)=7nM, n(H) approximately 2). Bell-shaped Ca(2+)-activation curve remained unchanged, suggesting that PS1 NTF(1-82) allosterically potentiates RyRs, but that the channel still requires Ca(2+) for activation. Corroborating such an independent mechanism, the RyR potentiation by PS1 NTF(1-82) was overridden by receptor desensitization at high [Ca(2+)] (pCa>5). This potentiation of RyR by PS1 NTF(1-82) reveals a new mechanism of physiologically relevant PS1-regulated Ca(2+) release from intracellular stores, which could be alternative or additional to recently reported intracellular Ca(2+) leak channels formed by PS1 holoproteins. PMID- 17709275 TI - Isoform-specific activation of protein kinase c in irradiated human fibroblasts and their bystander cells. AB - Studies over the last several years have revealed the existence of a biological phenomenon known as "bystander effect", wherein cells that are not exposed to radiation elicit a similar response to that of irradiated cells. Understanding the mechanism(s) underlying the bystander effect is important not only for radiation risk assessment but also for evaluation of protocols for cancer radiotherapy. Evaluation of signaling pathways in bystander cells may provide an insight to understand the molecular mechanisms(s) responsible for this complex phenomenon. With this objective, the time course kinetics of intracellular distribution of protein kinase C (PKC isoforms PKC-betaII, PKC-alpha/beta, PKC theta) was investigated in total and subcellular (cytosolic and nuclear) fractions of human lung fibroblast (MRC-5) cells. MRC-5 cells were either irradiated or treated with the irradiated conditioned medium collected 1h after 1 or 10 Gy of gamma-irradiation. The radiation dose selected was in the range of therapeutic usage of radiation for the human cancer treatment. Unexpectedly, bystander cells showed higher activation of protein kinase C isoforms as compared to irradiated and sham-treated control cells. Protein kinase C isoforms were more enriched in the nuclear fraction than the cytosolic fraction proteins. Induction of PKC isoforms in bystander cells are due to post-translational modifications as shown by the non-phosphorylated protein kinase C level in both irradiated and bystander cells did not differ from the sham-treated control cells. The specific activation of protein kinase C isoforms in bystander cells as demonstrated for the first time in this study may help to identify the effect of therapeutically used radiation exposure for the tumor destructions along with its implications for adjacent non-irradiated cells and organs. PMID- 17709276 TI - ROP/RAC GTPase signaling. AB - ROP/RAC GTPases are versatile signaling molecules in plants. Recent studies of ROP/RAC regulators and effectors have generated new insights into the molecular basis of their functional versatility. Significant progress has also been made in our understanding of the mechanism for the localization of ROP/RAC signaling to specific domains of the plasma membrane. PMID- 17709277 TI - Involvement of phospholipid signaling in plant growth and hormone effects. AB - Biochemical and genetics studies demonstrated the critical roles of phospholipid signaling and relevant molecules in regulating multiple processes of plant growth and development, signal transduction, mediating hormone effects and cell responses to environmental stimuli, through modulating protein subcellular localization, cross-talking with other signaling or metabolic pathways, or interacting with signaling molecules. The updated achievements of physiological effects and functional mechanism of phospholipid signaling in higher plants were reviewed. PMID- 17709278 TI - Epigenetic regulation of flowering. AB - The acceleration of flowering by prolonged low temperature treatment (vernalization) has unique properties including the floral transition occurring at a time separate from the vernalization treatment. This implies the vernalization condition is inherited through mitotic divisions, but this vernalized state is not inherited from one generation to the next. FLC, the key gene mediating this response in the Arabidopsis is repressed by histone modifications involving the VRN2 protein complex. Other protein complexes participate in activating the gene. While many plant species depend on vernalization for optimising flowering time, the genes involved differ between dicot and monocot plants in both Arabidopsis and cereals, vernalization regulates photoperiod control of flowering by preventing the induction of the floral promoter FT by long days in autumn but allowing induction of FT in spring and hence flowering occurs at an optimal time in the annual life cycle. PMID- 17709279 TI - Conservation and evolution of miRNA regulatory programs in plant development. AB - Over the past two years, microarray technologies, large-scale small RNA and whole genome sequencing projects, and data mining have provided a wealth of information about the spectrum of miRNAs and miRNA targets present in different plant species and the alga Chlamydomonas. Such studies have shown that a number of key miRNA regulatory modules for plant development are conserved throughout the plant kingdom, suggesting that these programs were crucial to the colonization of land. New genetic and biochemical studies of miRNA pathways in Arabidopsis, the spatiotemporal expression patterns of several conserved miRNAs and their targets, and the characterization of mutations in Arabidopsis and maize have begun to reveal the functions of these ancient miRNA-regulated developmental programs. In addition to these conserved miRNAs, there are many clade and species-specific miRNAs, which have evolved more recently and whose functions are currently unknown. PMID- 17709280 TI - Advances in understanding the genetic basis of antimalarial drug resistance. AB - The acquisition of drug resistance by Plasmodium falciparum has severely curtailed global efforts to control malaria. Our ability to define resistance has been greatly enhanced by recent advances in Plasmodium genetics and genomics. Sequencing and microarray studies have identified thousands of polymorphisms in the P. falciparum genome, and linkage disequilibrium analyses have exploited these to rapidly identify known and novel loci that influence parasite susceptibility to antimalarials such as chloroquine, quinine, and sulfadoxine pyrimethamine. Genetic approaches have also been designed to predict determinants of in vivo resistance to more recent first-line antimalarials such as the artemisinins. Transfection methodologies have defined the role of determinants including pfcrt, pfmdr1, and dhfr. This knowledge can be leveraged to develop more efficient methods of surveillance and treatment. PMID- 17709281 TI - Pre-erythrocytic stage malaria vaccines: time for a change in path. AB - Vaccines against the pre-erythrocytic stages of malaria hold the greatest promise as an effective intervention tool against malaria, as shown by immunization with radiation-attenuated sporozoites over four decades ago. To date, however, the development of subunit vaccines, while generating high expectations and investment, has not lived up at all to the promise. This path has been characterized by insufficient research into both identification of key defense mechanisms in humans and the discovery of better antigens, focusing rather on a technological race of how to present mainly a single antigen. The lack of success has also led, perhaps from desperation, to a revival of the live attenuated sporozoite approach, handicapped, however, by major bottlenecks in production, safety, and regulatory issues. It should now be clear that the field can no longer continue to succeed in mice and fail in the clinic. We advocate here in favor of a third option, relying on an understanding of the basis of attenuated sporozoite immunity in humans, to provide leads to the discovery of critical immunogens and the use of models with validated relevance to the human situation in order to rationalize and renew the promise of pre-erythrocytic subunit vaccines. PMID- 17709283 TI - Synthesis, spectral, optical and thermal studies of 1-methyl-2,6-dimethyl-4 hydroxypyridinium chloride monohydrate and bromide monohydrate. AB - Semiorganic 1-methyl-2,6-dimethyl-4-hydroxypyridinium chloride monohydrate (MDMPCl.H(2)O) and bromide monohydrate (MDMPBr.H(2)O) salts have been synthesized. Single crystals of MDMPCl.H(2)O and MDMPBr.H(2)O were grown by the slow evaporation method from aqueous solution at constant temperatures 30 and 32 degrees C respectively. The grown crystals were characterized by elemental analysis, FT-IR and FT-NMR techniques and their molecular structures were elucidated. Thermogravimetric, differential thermal analyses and differential scanning calorimetry reveal the presence of water molecules in the crystal lattices and thermal stabilities. Optical transmittance windows in aqueous solution were found as 300-1100 nm using UV-vis-NIR spectrophotometer. PMID- 17709284 TI - Energy transfer in zinc porphyrin-phthalocyanine heterotrimer and heterononamer studied by fluorescence resonance energy transfer (FRET). AB - Two or eight zinc triphenyl porphyrins were conjugated with Zn-phthalocyanine or H2-phthalocyanine to form ZnPc-(ZnTPP)2, ZnPc-(ZnTPP)8, H2Pc-(ZnTPP)2 and H2Pc (ZnTPP)8. Energy transfers from the porphyrin moiety to phthalocyanine part were quantitatively studied with the modality of fluorescence resonance energy transfer (FRET). By measuring the fluorescence increment from the phthalocyanine moiety and the decrease from porphyrin part under selective excitation at the B band of the porphyrin part in those conjugated compounds and their equimolar mixture of compositions, energy transfer efficiencies were estimated to be 90% for H2Pc-(ZnTPP)8 and ZnPc-(ZnTPP)8, and 60%, 30% for ZnPc-(ZnTPP)2 and H2Pc (ZnTPP)2, respectively. PMID- 17709286 TI - The influence of caloric nystagmus on flash evoked transient and steady-state potentials. AB - OBJECTIVE: Caloric stimulation leads to a reduction of the cerebral blood flow in the visual cortex. This reduction has been attributed to the suppression of visual input caused by nystagmus induced by caloric stimulation. We investigated the influence of caloric stimulation on transient flash and steady-state flash visual evoked potentials. METHODS: Visual evoked potentials to 1 and 10 Hz flash stimulation were recorded in 12 normal subjects at baseline, during nystagmus induced by caloric stimulation with cold water, and after the cessation of nystagmus. RESULTS: Neither the amplitude of the transient flash visual evoked potentials (1 Hz stimulation) nor the amplitude of the steady-state flash visual evoked potentials (10 Hz stimulation) was influenced by caloric stimulation compared to baseline. CONCLUSIONS: The deactivation of the visual cortex by caloric stimulation does not seem to affect transient flash or steady-state flash visual evoked potentials. Reduction of cerebral blood flow in the visual cortex does not affect the processing of visual qualities (e.g., luminance and pattern). SIGNIFICANCE: Caloric stimulation does not reduce the amplitudes of transient flash or steady-state flash visual evoked potentials. PMID- 17709285 TI - Clinical and genetic characterization of measles viruses isolated from adult patients in Shanghai in 2006. AB - BACKGROUND: In recent years there has been an increase in adult measles cases in Shanghai, and an outbreak occurred in 2005. Although there have been many studies analyzing the genotype of measles virus from pediatric patients in various parts of China, there is little information on the clinical findings and genetic makeup of adult measles. OBJECTIVES: Clinical information and phylogenetic analysis of adult measles infection in Shanghai. STUDY DESIGN: Blood, urine, throat swabs, and clinical information were collected from adult measles patients reporting to three major hospitals in Shanghai. Measles virus was isolated in Vero-SLAM cells. The C-terminus of the N gene of the isolates was sequenced and analyzed with reference to sequences obtained from GenBank. RESULTS: More than half of the patients developed severe clinical symptoms. None of the patients knew their measles vaccination history. All measles virus isolates had the same amino acid substitutions as the two standard H1a measles strains at position 484 and were classified as H1a genotype and could be further divided into three small clusters. CONCLUSIONS: The genotype of the predominant measles virus causing disease in adults in Shanghai is H1a. PMID- 17709287 TI - Disturbed surround inhibition in preclinical parkinsonism. AB - OBJECTIVE: Surround inhibition in the motor system is an essential mechanism for selective execution of desired movements. To evaluate the functional operation of surround inhibition in Parkinson disease, we performed a transcranial magnetic stimulation (TMS) study in the asymptomatic hands of hemiparkinsonism patients. METHODS: TMS was set to be triggered by self-initiated flexion of the index finger at different intervals from 3 to 2000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of control TMS at rest. Normalized MEP amplitudes of the patients' self-triggered TMS sessions at different intervals were compared to those of the controls. RESULTS: During index finger flexion, MEP amplitudes from the little finger muscle were unchanged in normal subjects. However, they were enhanced in Parkinson patients, despite the absence of any motor disturbance. CONCLUSIONS: These results suggest that the functional operation of surround inhibition is impaired in Parkinson disease. This disturbance may precede motor disturbance in Parkinson disease. SIGNIFICANCE: Impaired surround inhibition can be useful to detect preclinical parkinsonism. PMID- 17709288 TI - Emergent EEG in clinical practice. AB - OBJECTIVE: Emergency situations require a rapid and precise diagnostic approach. However, the exact role and value of the electroencephalogram (EEG) in emergent conditions have yet to be clearly defined. Our objective was to determine why clinicians order an emergency EEG, to assess to what extent it helps establish a correct diagnosis and to evaluate the result it has on subsequent patient management. METHODS: We studied all successive emergency EEGs ordered during a 3 month period in our institution. We analyzed the reasons why each EEG was ordered and interviewed the prescribing clinicians in order to determine the impact the result of the EEG had on the diagnosis and subsequent therapeutic management. RESULTS: We prospectively studied a total of 111 consecutive recordings. The main reasons for ordering an emergent EEG were: suspected cerebral death (21%), non convulsive status epilepticus (19.7%), subtle status epilepticus (14%) and follow up of convulsive status epilepticus (11.2%). In 77.5% of the cases the clinicians considered that the EEG contributed to making the diagnosis and that it helped confirm a clinically-suspected diagnosis in 36% of the cases. When subtle status epilepticus (SSE) or non-convulsive status epilepticus (NCSE) was suspected, the diagnosis was confirmed in 45% and 43.3% of the cases, respectively. In 22.2% of the requests involving follow-up of convulsive status epilepticus after initial treatment, the EEG demonstrated persistent status epilepticus. It resulted in a change in patient treatment in 37.8% of all the cases. When the EEG helped establish the diagnosis, patient treatment was subsequently modified in 46.6% of the cases. CONCLUSIONS: This prospective study confirms the value of an emergent EEG in certain specific clinical contexts: the management of convulsive status epilepticus following initial treatment or to rule out subtle status epilepticus. An emergent EEG can also be ordered if one suspects the existence of non convulsive status epilepticus when a patient presents with mental confusion or altered wakefulness after first looking for the specific signs suggesting this diagnostic hypothesis. SIGNIFICANCE: After 50 years of development and use in daily practice, the EEG remains a dependable, inexpensive and useful diagnostic tool in a number of clearly-defined emergency situations. PMID- 17709289 TI - Latency effect of the pitch response due to variations of frequency and spectral envelope. AB - OBJECTIVE: A clear definition of pitch and timbre is still an open debate and often both terms are mixed up in investigations of tone height. However, fundamental frequency (f(0)) and spectral envelope of a sound play a major role in the perception of tone height. Recent electrophysiological experiments showed that one sub-component of the complex N 100-signal was found to be highly correlated to the perceived tone height. METHODS: Tone height was independently varied by both, a change of f(0) and spectral envelope in order to disentangle the influence of both parameters. Relative tone height was determined psychoacoustically. Neuromagnetic responses were evaluated using source-analysis. RESULTS: Perceived tone height increases with increasing f(0) or spectral envelope. Latency of the pitch change response (PCR) reacts oppositely for the two modi of tone height change. For increasing f(0) and fixed bandpass condition, tone height increases and the latency of the PCR decreases. In contrast, for increasing the center frequency of the bandpass with fixed f(0), tone height increases, but the latency of the PCR increases. CONCLUSIONS: The neuromagnetic pitch response is influenced by both, f(0) and spectral envelope. SIGNIFICANCE: Further investigations of the influence of pitch and timbre on neurophysiological pitch responses have to take into account that both, f(0) and spectral envelope, affect tone height and latency of the PCR. PMID- 17709290 TI - Evaluation of atrophy of foot muscles in diabetic neuropathy -- a comparative study of nerve conduction studies and ultrasonography. AB - OBJECTIVE: To evaluate the relation between the findings at nerve conduction studies and the size of small foot muscles determined by ultrasonography. METHODS: In 26 diabetic patients the size of the extensor digitorum brevis muscle (EDB) and of the muscles between the first and second metatarsal bone (MIL) was determined. Motor nerve conduction studies of the peroneal and tibial nerves were performed with determination of the amplitudes of the CMAPs and of the nerve conduction velocities (NCV). Further, a standardised clinical examination was performed providing a neurological impairment score. RESULTS: Seventeen patients fulfilled the criteria for diabetic neuropathy. The cross-sectional area of the EDB muscle and the thickness of the MIL muscle were 116 +/- 65 mm2 and 29.6 +/- 8.2 mm, respectively. Close relations were established between muscle size and the amplitude of the CMAP of the peroneal (r=0.77, p<0.001) and of the tibial nerve (r=0.70, p<0.01). Further there were close relations between the muscle size and the NCV of the peroneal (r=0.62, p<0.01) and of the tibial nerve (r=0.71, p<0.001). CONCLUSIONS: The amplitude of the CMAP of the peroneal and of the tibial nerves is closely related to the size of the small foot muscles as determined by ultrasonography. SIGNIFICANCE: In diabetic patients motor nerve conduction studies can reliably determine the size of small foot muscles. PMID- 17709291 TI - Repetitive Transcranial Magnetic Stimulation of the Supplementary Motor Area in the treatment of Tourette Syndrome: report of two cases. PMID- 17709292 TI - Cyclic alternating pattern sequences and non-cyclic alternating pattern periods in human sleep. AB - OBJECTIVE: The CAP cycle is a module of activation (phase A) and inhibition (phase B) which repeats itself in sequences. The study aims at testing the hypothesis that the duration of CAP sequences is determined primarily by the number and not by the length of CAP cycles. METHODS: The polysomnographic recordings of 24 normal subjects, 12 males and 12 females, ranging in age from 20 to 35 years (mean 27.8+/-7.2), were examined. RESULTS: A total of 1053 CAP sequences were counted with an average of 43.9 sequences per night. The mean duration of CAP sequences was 2 min and 33 s. Each CAP sequence was composed of an average of 5.6 CAP cycles. All subjects presented CAP sequences lasting at least 5 min and 30s. The mean duration of CAP cycles was 26.9+/-4.1s. CAP cycles including subtypes A1 presented the highest correlation with the CAP sequence length (r=0.92; p<0.0001). CONCLUSIONS: The progressive increase of CAP sequences length is linked to the progressive accumulation of CAP cycles. SIGNIFICANCE: CAP sequences can be considered as strings of time-constant modules, i.e., CAP cycles, which are involved in the dynamic tailoring of sleep structure. PMID- 17709293 TI - Segregating two inhibitory circuits in human motor cortex at the level of GABAA receptor subtypes: a TMS study. AB - OBJECTIVE: To investigate if different interneuronal circuits in human motor cortex mediate inhibition through different subtypes of the gamma-aminobutyric acid A receptor (GABAAR). METHODS: Two distinct forms of motor cortical inhibition were measured in 10 healthy subjects by established transcranial magnetic stimulation (TMS) protocols: short interval intracortical inhibition (SICI) and short latency afferent inhibition (SAI). Their modification by a single oral dose of three different positive GABAAR modulators (20 mg of diazepam, 2.5 mg of lorazepam and 10 mg of zolpidem) with different affinity profiles at the various alpha-subunit bearing subtypes of the GABAAR (diazepam: non-selective, lorazepam: unknown, zolpidem: 10-fold higher affinity to alpha1- than alpha2- or alpha3-subunit bearing GABAARs, no affinity to alpha5-subunits) was tested in a randomized crossover design. In addition, the sedative drug effects were recorded by a visual analogue scale. RESULTS: Diazepam and lorazepam increased SICI, whereas zolpidem did not change SICI. In contrast, diazepam had no effect on SAI, whereas lorazepam and zolpidem decreased SAI. The sedative effects were not different between drugs. CONCLUSIONS: The dissociating patterns of drug modification of SICI versus SAI strongly suggest that different GABAAR subtypes are involved in SICI and SAI. SIGNIFICANCE: We provide evidence, for the first time, for a dissociation of effects of diazepam and zolpidem on SAI and confirm the previously reported differential effect of zolpidem and of diazepam and lorazepam on SICI. The differential effects of the three benzodiazepines on SAI and SICI suggest that neuronal circuits in human motor cortex that mediate inhibition through different GABAAR subtypes can be segregated by TMS. PMID- 17709294 TI - Sensory integration in writer's cramp: comparison with controls and evaluation of botulinum toxin effect. AB - OBJECTIVE: Abnormal temporal and spatial sensory integration have been described in mixed groups of dystonic patients. We tested somatosensory integration and the effect of botulinum toxin (BoNT) in patients with writer's cramp (WC). METHODS: Median and ulnar SEPs were recorded in 29 WC patients and in 10 controls. We performed: individual and simultaneous stimulation of median and ulnar nerves (MU) and paired stimulation of median nerve at interstimulus-interval (ISI) of 40 and 100 ms. All the trials were repeated after blinded randomized treatment with placebo or BoNT-A. RESULTS: We found no differences between patients and controls in standard SEPs. Spatial (except for N9) and temporal suppression after ISI 40 were present in both groups for all the waves; after ISI 100, suppression was present only for N70. There were no differences between patients and controls. After BoNT-A treatment, no changes were observed. CONCLUSIONS: In contrast with previous findings in heterogeneous dystonic groups, and although some studies suggest impairment of spatial and temporal sensory discrimination in patients with focal dystonia, in our large cohort of patients with WC we found no evidence of abnormal somatosensory integration investigated by means of SEPs and no changes in somatosensory variables after BoNT-A treatment. SIGNIFICANCE: Our findings may suggest pathophysiological differences between focal and generalized dystonia, and may also point to an inferior sensitivity of SEPs in detecting abnormalities in sensory discrimination as compared to methods based on subjective discrimination. PMID- 17709295 TI - Effects of levetiracetam vs topiramate and placebo on visually evoked phase synchronization changes of alpha rhythm in migraine. AB - OBJECTIVE: Recent theories about migraine pathogenesis have outlined an abnormal central processing of sensory signals, also suggested by an abnormal pattern of EEG hyper-synchronization under visual stimulation. The aim of the present study was to test the efficacy of topiramate and levetiracetam vs placebo in a double blind project observing the effects of the three treatments on the EEG synchronization in the alpha band under sustained flash stimulation. METHODS: Forty-five migraine without aura outpatients (MO) were selected and randomly assigned to 100mg topiramate, 1000 mg levetiracetam or placebo treatment. In addition, 24 non-migraine healthy controls were submitted to EEG analysis. The EEG was recorded by 19 channels: flash stimuli with a luminosity of 0.2J were delivered, in a frequency range from 3 to 30 Hz. We evaluated the phase synchronization index, that we previously applied in migraine, after EEG signals filtering in the alpha band. Our approach was based on the Hilbert transform. RESULTS: Both levetiracetam and topiramate significantly decreased migraine frequency, compared with placebo. MO patients displayed increased alpha-band phase synchronization as an effect of stimulus frequency; on the other hand the stimuli had an overall desynchronizing effect on control subjects. The phase synchronization index separates the two stages, before and after the treatment, only for levetiracetam, at stimulus frequencies of 9, 18, 24 and 27 Hz. CONCLUSIONS: An abnormal alpha band synchronization under visual stimuli was confirmed in migraine; this phenomenon was reversed by levetiracetam preventive treatment. SIGNIFICANCE: These results confirmed in humans the inhibiting action of levetiracetam on neuronal hyper-synchronization. PMID- 17709297 TI - Brain dynamics in the active vs. passive auditory oddball task: exploration of narrow-band EEG phase effects. AB - OBJECTIVE: We aimed to examine relationships between the phase of narrow-band electroencephalographic (EEG) activity at stimulus onset and the resultant event related potentials (ERPs) in active vs. passive auditory oddball tasks, using a novel conceptualisation of orthogonal phase effects. METHODS: This study focused on the operation of three recently-reported phase-influenced mechanisms, and ERP responses to the standard stimuli were analysed. Prestimulus narrow-band EEG activity (in 1 Hz bands from 1 to 13 Hz) at Cz was assessed for each trial using digital filtering. For each frequency, the cycle at stimulus onset was used to sort trials into four phases, for which ERPs were derived from both the filtered and unfiltered EEG activity at Fz, Cz and Pz. RESULTS: Preferred brain states at various frequencies were indicated by approximately 20% differential occurrence within the orthogonal phase dimensions explored. CONCLUSIONS: The preferred states were associated with more efficient processing of the stimulus, as reflected in differences in latency and/or amplitude of various ERP components, and provided evidence for the operation of the three separate phase-influenced mechanisms. SIGNIFICANCE: Both the occurrence of preferred brain states, and the mechanisms linking them to ERP outcomes focused on here, appeared relatively invariant across tasks, suggesting that they largely reflect reflexive brain processes. PMID- 17709296 TI - Heartbeat perception and P300 amplitude in a visual oddball paradigm. AB - OBJECTIVE: The perception of bodily signals ("interoceptive awareness") was found to modulate evoked potential components, especially the P300, in response to emotional pictures and to internal signals. It remains an open question whether this variable is related to more elaborated information processing in general. METHODS: The present study investigated the relationship between heartbeat perception and the amplitude of the P300 to target stimuli in a visual oddball paradigm. RESULTS: Interoceptive awareness was positively correlated with the P300 amplitude at Cz which remained significant after controlling for anxiety differences. CONCLUSIONS: Our results demonstrate a positive relationship between interoceptive awareness and the attentive processing of visual stimuli. SIGNIFICANCE: Interoception is related to more elaborated information processing in general. This effect could be mediated by arousal differences and might rely on common neuroanatomical structures. PMID- 17709298 TI - Exploding head syndrome--more than "snapping of the brain"? PMID- 17709299 TI - Breast cancer follow-up: literature review and discussion. AB - This paper presents a review of the evidence for long-term breast cancer follow up to determine if routine clinical review post treatment for breast cancer has benefits for patients. There is little evidence that clinical review of patients beyond 3 years post-diagnosis leads to improved patient survival. Separate to survival there is a dearth of inquiry relating to the value of long-term clinical review of patient in terms of psychological outcomes, quality of life, patient satisfaction, access to specialist advice regarding management of symptoms, and reassurance. Regardless of supporting evidence, most breast units in the UK continue to undertake routine six monthly clinical reviews of patients up to a minimum of 5 years. A literature search for the period 1989 to January 2006 was undertaken using the CINAHL, MEDLINE, and PsychINFO databases. Keywords such as 'cancer follow-up', 'cancer survivorship', and 'psychological outcomes of cancer' were utilised. Hand searching was also undertaken. Overall a paucity of evidence was found in relation to the long-term needs of breast cancer survivors. Alternatives to hospital-based follow-up are reported such as GP or nurse-led follow-up, but the fundamental question of the importance of follow-up in relation to psychological morbidity and quality of life still remains unanswered. Further research is needed to investigate the importance of follow-up to patient survivorship. Research to explore the concept of point of need access, as well as the qualitative experiences of patients post-discharge, informational needs at discharge and on-going psychosocial support is suggested. Ultimately this paper argues for a greater choice and involvement of patients in determining their future follow up needs, providing the patient with a personalised package of care based on risk assessment and subsequent education programmes to empower patients towards self-management following discharge. PMID- 17709300 TI - Functional recovery following resection of an epileptogenic focus in the motor hand area. AB - Despite recent technical advances, the surgical management of epileptic foci in the primary motor area, especially the motor hand area, continues to represent a significant challenge because of the risk of permanent neurological deficit. We describe the case of a 19-year-old woman with intractable epilepsy secondary to cortical dysplasia of the motor hand area who was treated with surgical resection. The patient showed immediate complete motor deficit, started improving at around 1 month of follow-up, and had a substantial recovery at 6 months, with only mild limitations of fine hand movements. At the latest follow-up (3 years), she remained seizure-free. This case demonstrates that, in selected cases, resections in the primary motor cortex can be performed and that the immediately observed motor deficit is transient. We discuss the proposed mechanisms for recovery based on available data from experimental animal and clinical human studies. PMID- 17709301 TI - Clinical application of functional MRI for memory using emotional enhancement: deficit and recovery with limbic encephalitis. AB - Although some functional MRI memory studies show reliable neural activity in the hippocampus and mesial temporal lobe (MTL), most typically report results from group studies. However, fMRI memory probes need to be robust enough to show MTL activity in individual patients to be helpful in diagnosis and treatment planning. We present the case of a patient with non-paraneoplastic limbic encephalitis who had severe anterograde amnesia with subsequent recovery to illustrate a fMRI probe of MTL activity that is easily administered to neurological patients. The task uses emotionally positive and affiliative stimuli to elicit responsivity in the amygdala-hippocampus region. In this patient, weak bilateral hippocampal activation was observed in the acute stage that increased after recovery, paralleling findings on structural MRI and neuropsychological memory assessment. This case study demonstrates that using emotional stimuli to enhance memory responsivity may be an effective way to visualize clinical changes in individual patients. PMID- 17709302 TI - Prognostic Bayesian networks II: an application in the domain of cardiac surgery. AB - A prognostic Bayesian network (PBN) is new type of prognostic model that implements a dynamic, process-oriented view on prognosis. In a companion article, the rationale of the PBN is described, and a dedicated learning procedure is presented. This article presents an application here of in the domain of cardiac surgery. A PBN is induced from clinical data of cardiac surgical patients using the proposed learning procedure; hospital mortality is used as outcome variable. The predictive performance of the PBN is evaluated on an independent test set, and results were compared to the performance of a network that was induced using a standard algorithm where candidate networks are selected using the minimal description length principle. The PBN is embedded in the prognostic system ProCarSur; a prototype of this system is presented. This application shows PBNs as a useful prognostic tool in medical processes. In addition, the article shows the added value of the PBN learning procedure. PMID- 17709303 TI - UvrA and UvrB enhance mutations induced by oxidized deoxyribonucleotides. AB - Oxidatively damaged DNA precursors (deoxyribonucleotides) are formed by reactive oxygen species. After the damaged DNA precursors are incorporated into DNA, they might be removed by DNA repair enzymes. In this study, to examine whether a nucleotide excision repair enzyme, Escherichia coli UvrABC, could suppress the mutations induced by oxidized deoxyribonucleotides in vivo, oxidized DNA precursors, 8-hydroxy-2'-deoxyguanosine 5'-triphosphate and 2-hydroxy-2' deoxyadenosine 5'-triphosphate, were introduced into uvrA, uvrB, and uvrC E. coli strains, and mutations in the chromosomal rpoB gene were analyzed. Unexpectedly, these oxidized DNA precursors induced mutations only slightly in the uvrA and uvrB strains. In contrast, effect of the uvrC-deficiency was not observed. Next, mutT, mutT/uvrA, and mutT/uvrB E. coli strains were treated with H2O2, and the rpoB mutant frequencies were calculated. The frequency of the H2O2-induced mutations was increased in all of the strains tested; however, the increase was three- to four-fold lower in the mutT/uvrA and mutT/uvrB strains than in the mutT strain. Thus, UvrA and UvrB are involved in the enhancement, but not in the suppression, of the mutations induced by these oxidized deoxyribonucleotides. These results suggest a novel role for UvrA and UvrB in the processing of oxidative damage. PMID- 17709304 TI - Development and validation of an enantioselective HPLC-UV method using Chiralpak AD-H to quantify (+)- and (-)-torcetrapib enantiomers in hamster plasma- application to a pharmacokinetic study. AB - A chiral selective, accurate and reproducible high-performance liquid chromatographic (HPLC) method was developed and validated for direct separation of individual enantiomers of torcetrapib (TTB) [(+)-TTB and (-)-TTB]. TTB enantiomers and IS were extracted from a small aliquot of plasma (100 microL) by simple liquid-liquid extraction using acetonitrile as extraction solvent. The enantiomers were resolved on Chiralpak AD-H (250 mm x 4.6 mm, 5 microm) with the mobile phase consisting of n-hexane:isopropyl alcohol (IPA) in the ratio of 95:5 (v/v). The eluate was monitored using an UV detector set at 254 nm. Baseline separation of the TTB enantiomers and the internal standard (IS, DRL-17859), free from endogenous interferences was achieved. The resolution factor between the enantiomers was optimized and found to be not less than five. During method development, the IPA content in the mobile phase was optimized for separation of peaks of interest. Additionally, both flow rate and column temperature were optimized for an improved baseline separation of the enantiomers. Ratio of peak area of each enantiomer to IS was used for quantification of plasma samples. Nominal retention times of (+)-TTB, (-)-TTB and IS were 9.4, 13.8 and 17.5 min, respectively. The standard curves for TTB enantiomers were linear (r(2)>0.999) in the concentration range 0.1-10 microg/mL for each enantiomer. Absolute recovery, when compared to neat standards, was 88.7-90.0% for TTB enantiomers and 100% for IS from the hamster plasma. The lower limit of quantification (LLOQ) for each enantiomer of TTB was 0.1 microg/mL. The inter-day precisions were in the range of 4.57-6.32 and 5.66-11.0% for (+)-TTB and (-)-TTB, respectively. The intra-day precisions were in the range of 1.60-7.36 and 2.76-13.6% for (+)-TTB and (-)-TTB, respectively. Accuracy in the measurement of quality control (QC) samples was in the range of 95.6-109% and 92.7-108% for (+)-TTB and (-)-TTB, respectively. Both enantiomers were stable in a series of stability studies, viz. bench-top (up to 12h), auto-sampler (up to 24h) and freeze/thaw cycles (n=3). Stability of TTB enantiomers was established in hamster plasma for 15 days at -80 degrees C. The application of the assay to a pharmacokinetic study of (-)-TTB in hamsters is described. PMID- 17709305 TI - In vitro metabolism of BYZX in human liver microsomes and the structural elucidation of metabolite by liquid chromatography-mass spectrometry method. AB - In vitro phase I metabolism of BYZX, a novel central-acting cholinesterase inhibitor for the treatment of the symptoms of Alzheimer's disease, was studied in human liver microsomes (HLM) and the metabolite formation pathways were investigated by chemical inhibition experiments and correlation analysis. The residual concentration of substrate and the metabolite formed in incubate were determined by HPLC method. The calibration curves of BYZX were linear over the concentration range from 5.07 microM to 200.74 microM. The relative standard deviations of within day and between day were less than 5% (n=5). The limit of detection (LOD) was 0.18 microg/mL (S/N=3) and the limit of quantification (LOQ) was 0.55 microg/mL (R.S.D.=5.2%, n=5). The determination recoveries of BYZX were in the range of 98.2-104.8%. The apparent K(m) of BYZX in HLM was 53.25+/-17.2 microM, the V(max) was 0.94+/-0.77 microM/min/mg protein, and the intrinsic clearance value (Cl(int)) was 0.018+/-0.02 mL/min/mg protein. Ketoconazole and cyclosporin A were the most potent inhibitors on BYZX metabolism in HLM with IC(50) being 0.89 microM and 18.17 microM, respectively. And the inhibition constant (K(i)) of ketoconazole was 0.42 microM. The metabolite of BYZX was N-des ethyl-BYZX elucidated by LC-MS-MS. The results demonstrated that the developed HPLC method was reliability, simple technique, and was applicable to be used for the researches of in vitro metabolism of BYZX. CYP3A4 was the major isozyme responsible for BYZX metabolism; N-dealkylation was the major metabolic pathway of BYZX. The predominant metabolite of BYZX was N-des-ethyl-BYZX detected in vitro phase I metabolism in HLM. PMID- 17709306 TI - Qualitative screening for basic drugs in autopsy liver samples by dual-plate overpressured layer chromatography. AB - An overpressured layer chromatography (OPLC) method was evaluated for broad-scale screening of basic drugs in 5g autopsy liver samples using two parallel OPLC systems. Sample preparation included enzymatic digestion with trypsin and liquid liquid extraction with butyl chloride. Chromatographic separation was performed as dual-plate analysis, with mobile phases composed of trichloroethylene methylethylketone-n-butanol-acetic acid-water (17:8:25:6:4, v/v) (OPLC1), and butyl acetate-ethanol (96.1%)-tripropylamine-water (85:9.25:5:0.75, v/v). Identification was based on automated comparison of corrected R(f) values (hR(f)c) and in situ UV spectra with library values by dedicated software. The identification limit was determined for 25 basic drugs in liver ranging from 0.5 to 10mg/kg. The OPLC method proved to be well suited for routine screening analysis of basic drugs in post-mortem samples of varying quality, combining the benefit from moderately high separation power with the ease of disposable plates. PMID- 17709307 TI - Atypical cellular neurothekeoma--a diagnosis to be aware of. AB - We present a rare case of atypical cellular neurothekeoma arising in the area of a previous nose piercing on the ala of a 34-year-old female. Neurothekeoma is a benign tumour of probable nerve sheath origin. The cell of origin for neurothekeoma is still unknown but most ultrastructural and immunohistochemical studies have favoured the Schwann cell perineurium or fibroblasts. A similar but distinct, more cellular variant with a less prominent myxoid component, was termed cellular neurothekeoma and, unlike myxoid neurothekeoma, the cellular variety generally lacks immunoreactivity to most neuronal markers. Atypical cellular neurothekeoma is characterised by the following features: large size of up to 6 cm, penetration into subcutaneous fat and or muscle, diffusely infiltrating borders, vascular invasion, a high mitotic rate and marked cytological pleomorphism. In this report we provide a review of the relevant literature and describe the clinical, histological and immunohistochemical features of an atypical cellular neurothekeoma excised from the ala nasi of a 34 year-old female, a hitherto unreported lesion in the plastic surgery literature. PMID- 17709308 TI - Equanimity: synchronous fine-needle aspiration cytology and core biopsy of thyroid nodules. PMID- 17709309 TI - Comparison of thyroid fine-needle aspiration and core needle biopsy. AB - We compared the adequacy and accuracy of fineneedle aspiration (FNA) with core needle aspiration in a total of 377 patients who underwent both tests. The adequacy rate for core needle biopsy (82.2%) was significantly higher than that of FNA (70.3%; P < .001), but the combined adequacy was significantly higher than that for either test alone (88.9%; P < .001). Overall concordance between the tests was 67.9%. In 70 cases, the core was adequate and negative (55 cases) or atypical (15 cases) and the aspirate was nondiagnostic; in 25 cases, the aspirate was adequate and negative (15 cases) or atypical (10 cases) and the core was nondiagnostic. In 21 cases, the FNA diagnosis was atypical and the core was negative; histologic follow-up supported the FNA diagnosis in all 14 cases with resection, of which 9 were malignant, and 8 of the 9 were papillary carcinoma. On review, it seemed that the core biopsy missed the lesion. Core needle biopsy has a higher adequacy rate than FNA but seems less sensitive, especially for papillary carcinoma. The combination of FNA with core needle biopsy seems to have the highest adequacy rate and sensitivity. PMID- 17709310 TI - Steroid hormone receptor and COX-2 expression in chordoma. AB - Reports of sex steroid receptor expression in chordoma suggest that these tumors may be responsive to hormone manipulation therapy. Immunohistochemical stains for estrogen receptor (ER)-alpha, ER-beta, progesterone receptor (PR), androgen receptor (AR), and cyclooxygenase 2 (COX-2), were performed on a tissue microarray containing 21 samples of chordoma. Most chordomas expressed COX-2, ER beta, and AR, whereas ER-alpha and PR stains were negative in all cases. ER-beta expression did not correlate with AR expression (P = .4142; McNemar test). There were no statistically significant correlations between the expression of any of these markers and anatomic location of tumor, patient sex, patient age, or disease-free survival. Chordomas commonly express COX-2, AR, and ER-beta. These findings may have therapeutic implications concerning the use of agents that inhibit or modulate these signaling molecules. PMID- 17709311 TI - Cytoplasmic immunoreactivity of thyroid transcription factor-1 (clone 8G7G3/1) in hepatocytes: true positivity or cross-reaction? AB - The nuclear immunoreactivity for thyroid transcription factor-1 (TTF-1) is a useful marker for identification of carcinomas of thyroid and lung origin. Our aim was to determine whether cytoplasmic staining in the liver is a result of cross-reaction of anti-TTF-1 antibody (clone 8G7G3/1, DAKO, Carpinteria, CA) or true positivity resulting from aberrant expression of TTF-1 or products of the alternatively sliced TTF-1 gene. Fresh tissue samples from liver, thyroid, and lung were obtained for H&E-stained sections, TTF-1 immunostaining, and RNA and protein analyses. Western blot revealed an abundant band corresponding to an approximately 160-kd protein from liver but not either thyroid or lung tissue samples. By reverse transcriptase-polymerase chain reaction, messenger RNA of TTF 1 was not detectable in liver tissue. Our study demonstrates that TTF-1 immunoreactivity (clone 8G7G3/1) in the hepatocyte cytoplasm is due to an approximately 160-kd protein; this unique protein is not an alternative splicing product of TTF-1 and neither is it expressed in thyroid and lung tissues. PMID- 17709312 TI - Survivin, a member of the inhibitors of apoptosis family, is down-regulated in breast carcinoma effusions. AB - We analyzed the expression and prognostic role of inhibitors of apoptosis in breast carcinoma effusions. We used immunoblotting to analyze 22 effusions for XIAP, survivin, and livin expression. Based on immunoblotting results, 49 effusions and 46 corresponding solid tumors were immunostained for XIAP and survivin. Results were analyzed for association with anatomic site, clinicopathologic parameters, and survival. Immunoblotting showed frequent expression of XIAP and survivin and no expression of livin. Carcinoma cells in effusions showed lower survivin immunostaining compared with lymph node metastases (P = .008) and primary carcinomas (P = .041). Higher cytoplasmic survivin expression correlated with poor disease-free survival for patients with postchemotherapy effusions (P = .035). XIAP and survivin, but not livin, are frequently expressed in advanced breast carcinoma. Survivin is down-regulated in effusions compared with solid tumors, possibly in relation to the different cellular economy at this anatomic site. Survivin expression may predict disease free survival for patients with postchemotherapy effusions. PMID- 17709313 TI - "Low-grade squamous intraepithelial lesion, cannot exclude high-grade squamous intraepithelial lesion" is a distinct cytologic category: histologic outcomes and HPV prevalence. AB - We examined the histologic outcomes and prevalence of high-risk human papillomavirus (HR-HPV) in women with liquid-based Papanicolaou (Pap) tests interpreted as "low-grade squamous intraepithelial lesion, cannot exclude high grade squamous intraepithelial lesion" (LSIL-H) compared with the 2001 Bethesda System (TBS 2001) cytologic categories of LSIL, high-grade SIL (HSIL), and atypical squamous cells, cannot exclude HSIL (ASC-H). A computer search identified 426 LSIL, 86 ASC-H, 81 LSIL-H, and 110 HSIL cytologic interpretations during a 1-year period, each with up to 2 years of histologic follow-up. The risk of histologic cervical intraepithelial neoplasia (CIN) 2 or worse (CIN 2+) associated with LSIL-H (32/81 [40%]) was intermediate between LSIL (46/426 [10.8%]) and HSIL (72/110 [65.5%]), but not significantly different from ASC-H (23/86 [27%]). However, LSIL-H was more frequently associated with a definitive histologic diagnosis of any CIN (CIN 1+) than ASC-H (53/81 [65%] vs 35/86 [41%]). Moreover, the prevalence of HR-HPV was significantly greater in patients with LSIL-H than in patients with ASC-H (15/15 [100%] vs 43/73 [59%]). The histologic outcomes and HR-HPV prevalence associated with LSIL-H differ significantly from the established categories of TBS 2001 and provide evidence to support the recognition of LSIL-H as a distinct cytologic category. PMID- 17709314 TI - Urokinase-type plasminogen activator and plasminogen activator inhibitor type-1 mRNA assessment in breast cancer by means of NASBA: correlation with protein expression. AB - Urokinase plasminogen activator (uPA) and its main inhibitor, plasminogen activator inhibitor type-1 (PAI-1) determined in tumor tissue by means of enzyme linked immunosorbent assay (ELISA) can discriminate patients with primary breast cancer at high risk vs low risk for recurrence. The aim of this study was to analyze uPA and PAI-1 messenger RNA (mRNA) expression by means of quantitative nucleic acid sequence-based amplification (NASBA) on 77 primary breast tumor samples and to correlate this expression with the uPA and PAI-1 protein content. We observed that the 2 markers were significantly overexpressed (uPA, P < .0001; PAI-1, P = .0042) in mRNA in the ELISA+ group. The receiver operating characteristic (ROC) curves demonstrated high concordance between NASBA and ELISA (area under the ROC curve of 0.84 and 0.70 for uPA and PAI-1, respectively) and showed that uPA and PAI-1 status could be predicted by using the molecular assay with sensitivity and specificity values of 80.8% and 82.4% and sensitivity and specificity values of 66.7% and 74.0%, respectively. PMID- 17709315 TI - Cytomorphologic features of primary peritoneal mesothelioma in effusion, washing, and fine-needle aspiration biopsy specimens: examination of 49 cases at one institution, including post-intraperitoneal hyperthermic chemotherapy findings. AB - Primary peritoneal mesotheliomas (PPMs) are rare tumors of adults. At our institution, PPMs are treated with a combination of cytoreductive surgery and intraperitoneal hyperthermic chemotherapy (IPHC) in appropriate patients. We present a summary of cytologic features of PPM in 49 positive (malignant) specimens during a 15-year period at 1 institution. Of the corresponding 49 PPM histologic specimens, 46 were epithelial, 2 sarcomatoid, and 1 multicystic mesothelioma. This includes our experience with washing specimens obtained from patients with PPM following treatment with cytoreductive surgery combined with IPHC. The rarity of PPM makes this neoplasm unfamiliar to most pathologists. However, cytologic features can be diagnostic in a majority of cases. We present a summary of cytologic features that, in our experience, we find to be most useful in making or excluding a diagnosis of PPM. To our knowledge, this is the first large series reporting the cytomorphologic features of PPM in peritoneal effusions, pelvic washing specimens, and infradiaphragmatic fine-needle aspiration biopsy specimens. PMID- 17709316 TI - The Henry Ford Production System: measures of process defects and waste in surgical pathology as a basis for quality improvement initiatives. AB - We implemented a continuous quality improvement initiative in pursuit of a "zero defects" performance goal in surgical pathology that required design of novel data collection tools to assess our current condition and sources of defects and waste. We defined defect as a flaw, an imperfection, or a deficiency in specimen processing requiring delaying or stopping work or returning work to the sender. These defects were noninterpretive, nondiagnostic defects critical to quality. Through a blameless work environment and contributions from all workers, we defined a baseline surgical pathology case defect rate of 27.9%, mostly arising in the laboratory (89.3%); only 8.3% were preanalytic; 2.4% resulted in amended reports. Additional focus on fidelity of patient and specimen identification allowed us to define defective identification in 1.67% of cases, with blocks and slides accounting for 78% of the defects. The misidentification defect rates per million opportunities for all sources were 4.3 to 4.8 sigma. These misidentification defects for 3 weeks required 159 hours of manual rework, or an annualized 1.3 full-time-equivalent employees. We found that through deep and honest exposure and the concerted effort of all workers, we could identify numerous sources of waste in our processes. This knowledge formed the structure for effective changes to strive toward a zero-defect performance goal. PMID- 17709317 TI - High-level SLP-2 expression and HER-2/neu protein expression are associated with decreased breast cancer patient survival. AB - There is sufficient evidence that human stomatin-like protein 2 (SLP-2) is a novel cancer-related gene. Its protein is overexpressed in many human cancers. SLP-2 can contribute to the promotion of cell growth, cell adhesion, and tumorigenesis in esophageal squamous cell carcinoma and lymph node metastasis in laryngeal squamous cell carcinoma. Immunohistochemical detection of SLP-2, estrogen and progesterone receptors, and HER-2/neu were performed on 263 cases of primary invasive breast cancer with a tissue microarray. Of 263 cases, 138 (52.5%) showed high expression of SLP-2 protein, and 125 (47.5%) showed low or absent expression. In addition, there were significant positive associations between tumor stage and size (P = .020), lymph node metastasis (P < .001), clinical stage (P < .001), distant metastasis (P = .002), and HER-2/neu protein expression (P = .037) and high-level SLP-2 expression. High-level SLP-2 expression was associated with decreased overall survival (P = .011) and was more often found in patients with tumors larger than 20 mm, lymph node metastasis, advanced clinical stage, distant metastasis, and HER-2/neu protein-positive expression. More important, lymph node metastasis, HER-2/neu-positive expression, and high-level SLP-2 expression were associated with significantly decreased survival. PMID- 17709318 TI - Interference with hemoglobin A(1C) determination by the hemoglobin variant Shelby. AB - Hemoglobin variant carrier status was found in a 46-year-old African American man following detection of a falsely elevated hemoglobin A1c (HbA1c) by ionexchange high-performance liquid chromatography (HPLC, VARIANT A1c, Bio-Rad Laboratories, Hercules, CA). Additional analysis of the hemoglobin variant using the Beta Thal Short program (Bio-Rad) revealed an unknown peak with a retention time of 4.84 minutes and a proportion of 26.3%. No mass shift in alpha-globin or beta-globin proteins was observed by mass spectrometry. DNA sequencing revealed a missense mutation in 1 beta-globin allele corresponding to the hemoglobin Shelby trait. The patient was asymptomatic with a normal hemoglobin value of 13.6 g/dL (136 g/L) but had increased target cells on a peripheral blood smear. An alternative method for HbA1c determination using boronate-affinity HPLC provided a value of 3.9% (0.04; reference range, 4.0%-6.9% [0.04-0.07]), more consistent with the patient's recent blood glucose values in the normal range. PMID- 17709319 TI - CD4+/CD56+ hematodermic neoplasm ("blastic natural killer cell lymphoma"): neoplastic cells express the immature dendritic cell marker BDCA-2 and produce interferon. AB - CD4+/CD56+ hematodermic neoplasm ("blastic natural killer [NK]-cell lymphoma") is a rare highly aggressive neoplasm associated with cutaneous manifestations followed by dissemination to blood, bone marrow, and other tissues. Neoplastic cells exhibit a lineage-negative CD4+/CD56+/CD43+/HLA-DR+ immunophenotype, initially suggesting an NK-cell derivation. The recent discovery of CD123 antigen expression by tumor cells has provided evidence for a relationship to immature dendritic cells (DCs), a group of myeloid and lymphoid early-committed progenitors capable of differentiating into antigen-presenting DCs. Based on flow cytometric analysis, myeloid DCs represent the majority of human peripheral blood DCs and are positive for blood dendritic cell antigen (BDCA)-1 (or CD1c), CD13, CD11c(high), CD33, and CD123(low). Plasmacytoid DCs are BDCA-2+/ CD123(high)+/CD13-/CD33- and produce interferon (IFN)-alpha when triggered by antigens. IFN-alpha production may be detected in tissue sections using antibodies for myxovirus A (MxA) protein, a surrogate marker. This report describes the clinical, histologic, immunophenotypic, cytogenetic, and molecular genetic findings for 3 cases of CD4+/CD56+ hematodermic neoplasms. In all cases, neoplastic cells were reactive for CD123, BDCA-2, and MxA protein, providing strong evidence for an immature plasmacytoid DC derivation for this rare neoplasm. PMID- 17709320 TI - Automated enumeration of immature granulocytes. AB - The performance characteristics of the XE-2100 (Sysmex, Kobe, Japan) automated immature granulocyte (IG) count were studied. The automated IG count was compared with the manual morphology count and with a proposed reference flow cytometric count. The comparison data were analyzed by both least-squares and Passing-Bablok regression analysis. Long-term imprecision using preserved blood quality control specimens at different levels showed a range from 2.59% to 3.57% coefficient of variation (CV) for within-run imprecision and 3.57% to 6.85% CV for total imprecision. The within-run reproducibility performed using fresh blood on 3 different specimens showed a range from 5.55% to 8.24% CV. The counts were stable at both room temperature and after refrigeration for 24 hours.Passing-Bablok regression analysis showed excellent agreement between the proposed reference flow cytometric IG count and the XE-2100 IG count, while there was less agreement with the manual morphology count. Our results indicate that the automated IG count can replace the manual morphology count for IG counting in the clinical laboratory. The results also confirm that the flow cytometric IG count is superior to and can replace the manual morphology count as a reference method for IG counting. PMID- 17709321 TI - MALT lymphoma involving the kidney: a report of 10 cases and review of the literature. AB - Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) can arise at any anatomic site, but involvement of the kidney is rare. We describe 10 cases of kidney MALT lymphoma, including 6 localized cases. No predisposing inflammatory conditions were identified, with the possible exception of coexistent renal Actinomyces infection in 1 case. We performed fluorescence in situ hybridization (FISH) using a malt1 break-apart probe in 7 cases. A malt1 gene rearrangement was identified in 1 case (14%). This case was further assessed by FISH using an IgH breakapart probe that showed IgH gene rearrangement. These results are suggestive of the t(14;18) involving malt1 and IgH. Immunostaining for NF-kappaB p65 showed nuclear positivity, consistent with NF-kappaB activation, in 3 of 5 cases assessed. Our results indicate that kidney MALT lymphomas share similarities with MALT lymphomas arising at other sites in that MALT lymphoma-associated translocations and NF-kappaB activation occur in a subset of cases. PMID- 17709322 TI - The reliability of lymphoma diagnosis in small tissue samples is heavily influenced by lymphoma subtype. AB - A specific pathologic diagnosis is important in malignant lymphoma because the diverse disease subtypes require tailored approaches to clinical management. Reliance on small samples obtained with cutting needles has been advocated as a less invasive alternative to using larger, excised samples. Although published studies have demonstrated the safety and apparent sufficiency of this approach in informing clinical care, none have systematically determined the accuracy of pathologic lymphoma subtyping based on very small samples. We used a tissue microarray representing 67 cases of malignant lymphoma and 17 samples of nonneoplastic lymphoid tissue to model lymphoma diagnosis in small samples. Overall, 73.8% of the cases were diagnosed with a level of confidence deemed sufficient for directing clinical management; 85.9% of these diagnoses were accurate. Small cell lymphomas with highly distinctive immunophenotypes, including small lymphocytic, mantle cell, and T-lymphoblastic lymphoma, were recognized most consistently and accurately in the small samples. In contrast, follicular lymphoma and marginal zone lymphoma were especially difficult. Our results indicate that the reliability of lymphoma diagnoses based on small samples is heavily influenced by lymphoma subtype. PMID- 17709323 TI - Evaluation of an integrative diagnostic algorithm for the identification of people at risk for alpha1-antitrypsin deficiency. AB - An integrative diagnostic algorithm for alpha1-antitrypsin (AAT) deficiency testing in the clinical laboratory was developed and evaluated. A novel rapid LightCycler (Roche, Indianapolis, IN) molecular assay was used to detect the common S and Z deficiency allelic variants. However, use of such molecular assays for these variants also can result in the misclassification of significant numbers of "at-risk" patient samples containing other rare AAT deficiency alleles. In the diagnostic algorithm presented herein, patient samples with selected genotypes that exhibit abnormally low AAT concentrations by immunoassay are phenotyped by isoelectric focusing. To test the efficacy of this algorithm, we retrospectively evaluated a data set of 50,020 serum samples for which protein phenotype and AAT concentration had been determined. This algorithm can successfully detect the majority of at-risk samples containing rare deficiency alleles. PMID- 17709324 TI - The effects of adulterants and selected ingested compounds on drugs-of-abuse testing in urine. AB - Household chemicals such as bleach, table salt, laundry detergent, toilet bowl cleaner, vinegar, lemon juice, and eyedrops are used for adulterating urine specimens. Most of these adulterants except eyedrops can be detected by routine specimen integrity tests (creatinine, pH, temperature, and specific gravity); however, certain adulterants such as Klear, Whizzies, Urine Luck, and Stealth cannot. These adulterants can successfully mask drug testing if the concentrations of certain abused drugs are moderate. Several spot tests have been described to detect the presence of such adulterants in urine. Urine dipsticks are commercially available for detecting the presence of such adulterants, along with performance of tests for creatinine, pH, and specific gravity. Certain hair shampoo and saliva-cleaning mouthwashes are available to escape detection in hair or saliva samples, but the effectiveness of such products in masking drugs-of abuse testing has not been demonstrated. Ingestion of poppy seed cake may result in positive screening test results for opiates, and hemp oil exposure can cause positive results for marijuana. These would be identified as true-positive results in drugs-of-abuse testing even though they do not represent the actual drug of abuse. PMID- 17709326 TI - Brassinosteroid transport. AB - Brassinosteroids (BRs) are steroidal plant hormones that are important regulators of plant growth. These compounds are widely distributed throughout reproductive and vegetative plant tissues. This raises the question of whether or not BRs are transported over long distances between these tissues. Several lines of evidence indicate that this is not the case. Exogenous BRs move only slowly, if at all, after application to leaves; grafting BR-deficient mutants to wild-type plants has no phenotypic effect; removal of the apical bud or mature leaves does not reduce BR levels in the remaining internodes; and, in tomato, wild-type sectors do not substantially alter the growth of BR-deficient sectors when the two types are together in a variegated leaf. Although BRs do not undergo long-distance transport they may influence long-distance signalling by altering auxin transport. At the cellular level, BRs do appear to be transported. The enzymes for BR biosynthesis appear to be located within the cell, and to be associated with the endoplasmic reticulum, in particular. BR reception, on the other hand, is thought to occur on the exterior cell surface. Therefore, BRs must move from the interior of the cell to the exterior, where they are perceived by the same cell or by neighbouring cells. The existence of a feedback system, whereby bioactive BRs negatively regulate their own biosynthesis, provides further evidence that individual cells are able to both perceive and synthesize BRs. PMID- 17709325 TI - Strength statistics of adhesive contact between a fibrillar structure and a rough substrate. AB - Equal distribution of load among fibrils in contact with a substrate is an important characteristic of fibrillar structures used by many small animals and insects for contact and adhesion. This is in contrast with continuum systems where stress concentration dominates interfacial failure. In this work, we study how adhesion strength of a fibrillar system depends on substrate roughness and variability of the fibril structure, which are modelled using probability distributions for fibril length and fibril attachment strength. Monte Carlo simulations are carried out to determine the adhesion strength statistics where fibril length follows normal or uniform distribution and attachment strength has a power-law form. Our results indicate that the strength distribution is Gaussian (normal) for both the uniform and the normal distributions for length. However, the fibrillar structure having normally distributed lengths has higher strength and lower toughness than one having uniformly distributed lengths. Our simulations also show that an increase in the compliance of the fibrils can compensate for both the substrate roughness and the attachment strength variation. We also show that, as the number of fibrils n increases, the load carrying efficiency of each fibril goes down. For large n, this effect is found to be small. Furthermore, this effect is compensated by the fact that the standard deviation of the adhesive strength decreases as 1/ square root n. PMID- 17709328 TI - Body mass index and risk of Parkinson's disease: a prospective cohort study. AB - High body mass index has been associated with increased risk of several chronic diseases, including cardiovascular disease, and, recently, Alzheimer's disease. There are few data on the association of body mass index with Parkinson's disease, and results have been inconsistent. The authors conducted a prospective study among 10,812 men in the Harvard Alumni Health Study, followed from 1988 to 1998 (mean age at baseline: 67.7 years), to test the hypothesis that body mass index is associated with Parkinson's disease risk. Among 106 incident cases of Parkinson's disease, body mass index at baseline was not associated with Parkinson's disease risk (for body mass index <22.5, 22.5-<24.9, and > or =25.0 kg/m2: multivariate relative risks = 1.51 (95% confidence interval: 0.95, 2.40), 1.00 (referent), and 0.86 (95% confidence interval: 0.53, 1.41)). The authors had information on body mass index during late adolescence, when men entered college; this was unrelated to Parkinson's disease risk as well. Subjects who lost at least 0.5 units of body mass index per decade between college entry and 1988 had a significantly increased Parkinson's disease risk, compared with men having stable body mass index (multivariate relative risk = 2.60, 95% confidence interval: 1.10, 6.10). The authors conclude that body mass index is unrelated to Parkinson's disease risk and speculate that the observation of increased risk with body mass index loss since late adolescence may reflect weight loss due to Parkinson's disease that preceded clinical diagnosis. PMID- 17709327 TI - Re: "Confidence intervals for biomarker-based human immunodeficiency virus incidence estimates and differences using prevalent data". PMID- 17709329 TI - Is radiographic vertebral fracture a risk factor for mortality? AB - Clinical fractures predict increased mortality risk, but few studies report mortality based on prevalent radiographically defined vertebral fracture. This study examined whether radiographically defined vertebral fracture is a risk factor for mortality in older adults. The 1,580 participants in California (631 men, 949 women) were aged > or =50 years in 1992-1996. Lateral spine radiographs, and information about medical history and behaviors, were obtained. Overall, 55 (8.7%) men and 123 (13%) women had at least one prevalent fracture at baseline; of these, 48 women and 14 men had two or more. Over 7.6 years, 460 participants died, 27.6% without and 41.0% with prevalent fractures (p < 0.001). Prevalent vertebral fracture was not associated with all-cause mortality in both sexes combined (adjusted hazard ratio = 1.09, 95% confidence interval: 0.84, 1.42) or sex-specific analyses (women: adjusted hazard ratio = 1.15, 95% confidence interval: 0.83, 1.59; men: adjusted hazard ratio = 0.89, 95% confidence interval: 0.55, 1.46). However, women with two or more prevalent fractures had increased risk of all-cause mortality (adjusted hazard ratio = 1.56, 95% confidence interval: 1.01, 2.40; p = 0.04). Women with any prevalent vertebral fractures also had increased mortality risk from "other" causes (adjusted hazard ratio = 1.59, 95% confidence interval: 1.03, 2.45; p = 0.04) but not cardiovascular disease or cancer. A single radiographic vertebral fracture is not a risk for mortality in older women; larger, longer studies of men and those with two or more radiographic vertebral fractures are needed. PMID- 17709330 TI - Lipopolysaccharide and trovafloxacin coexposure in mice causes idiosyncrasy-like liver injury dependent on tumor necrosis factor-alpha. AB - Idiosyncratic adverse drug reactions (IADRs) occur in a small subset of patients, are unrelated to the pharmacological action of the drug, and occur without an obvious relationship to dose or duration of drug exposure. The liver is often the target of these reactions. Why they occur is unknown. One possibility is that episodic inflammatory stress interacts with the drug to precipitate a toxic response. We set out to determine if lipopolysaccharide (LPS) renders mice sensitive to trovafloxacin (TVX), a fluoroquinolone antibiotic linked to idiosyncratic hepatotoxicity in humans and if the cytokine tumor necrosis factor alpha (TNFalpha) is involved in the development of liver injury. Male mice were treated with a nontoxic dose of TVX followed 3 h later by a nonhepatotoxic dose of LPS. Coexposure to TVX and LPS led to a significant increase in liver injury as determined by plasma alanine aminotransferase activity and histopathological examination. In contrast, coexposure of mice to LPS and levofloxacin (LVX), a fluoroquinolone without liability for causing IADRs in humans, was not hepatotoxic. Measurements of TNFalpha concentration in the plasma revealed a significant, selective increase in TVX/LPS-treated mice at times prior to and at the onset of liver injury. Treatment with either pentoxifylline to inhibit TNFalpha transcription or etanercept to inhibit TNFalpha activity significantly reduced TVX/LPS-induced liver injury. The results suggest that the model in mice is able to distinguish between drugs with and without the propensity to cause idiosyncratic liver injury and that the hepatotoxicity is dependent on TNFalpha. PMID- 17709331 TI - Adsorbed proteins influence the biological activity and molecular targeting of nanomaterials. AB - The possible combination of specific physicochemical properties operating at unique sites of action within cells and tissues has led to considerable uncertainty surrounding nanomaterial toxic potential. We have investigated the importance of proteins adsorbed onto the surface of two distinct classes of nanomaterials (single-walled carbon nanotubes [SWCNTs]; 10-nm amorphous silica) in guiding nanomaterial uptake or toxicity in the RAW 264.7 macrophage-like model. Albumin was identified as the major fetal bovine or human serum/plasma protein adsorbed onto SWCNTs, while a distinct protein adsorption profile was observed when plasma from the Nagase analbuminemic rat was used. Damaged or structurally altered albumin is rapidly cleared from systemic circulation by scavenger receptors. We observed that SWCNTs inhibited the induction of cyclooxygenase-2 (Cox-2) by lipopolysaccharide (LPS; 1 ng/ml, 6 h) and this anti inflammatory response was inhibited by fucoidan (scavenger receptor antagonist). Fucoidan also reduced the uptake of fluorescent SWCNTs (Alexa647). Precoating SWCNTs with a nonionic surfactant (Pluronic F127) inhibited albumin adsorption and anti-inflammatory properties. Albumin-coated SWCNTs reduced LPS-mediated Cox 2 induction under serum-free conditions. SWCNTs did not reduce binding of LPS(Alexa488) to RAW 264.7 cells. The profile of proteins adsorbed onto amorphous silica particles (50-1000 nm) was qualitatively different, relative to SWCNTs, and precoating amorphous silica with Pluronic F127 dramatically reduced the adsorption of serum proteins and toxicity. Collectively, these observations suggest an important role for adsorbed proteins in modulating the uptake and toxicity of SWCNTs and nano-sized amorphous silica. PMID- 17709332 TI - Mind the gaps: evidence of bias in estimates of multiple sequence alignments. AB - Multiple sequence alignment (MSA) is a crucial first step in the analysis of genomic and proteomic data. Commonly occurring sequence features, such as deletions and insertions, are known to affect the accuracy of MSA programs, but the extent to which alignment accuracy is affected by the positions of insertions and deletions has not been examined independently of other sources of sequence variation. We assessed the performance of 6 popular MSA programs (ClustalW, DIALIGN-T, MAFFT, MUSCLE, PROBCONS, and T-COFFEE) and one experimental program, PRANK, on amino acid sequences that differed only by short regions of deleted residues. The analysis showed that the absence of residues often led to an incorrect placement of gaps in the alignments, even though the sequences were otherwise identical. In data sets containing sequences with partially overlapping deletions, most MSA programs preferentially aligned the gaps vertically at the expense of incorrectly aligning residues in the flanking regions. Of the programs assessed, only DIALIGN-T was able to place overlapping gaps correctly relative to one another, but this was usually context dependent and was observed only in some of the data sets. In data sets containing sequences with non-overlapping deletions, both DIALIGN-T and MAFFT (G-INS-I) were able to align gaps with near perfect accuracy, but only MAFFT produced the correct alignment consistently. The same was true for data sets that comprised isoforms of alternatively spliced gene products: both DIALIGN-T and MAFFT produced highly accurate alignments, with MAFFT being the more consistent of the 2 programs. Other programs, notably T COFFEE and ClustalW, were less accurate. For all data sets, alignments produced by different MSA programs differed markedly, indicating that reliance on a single MSA program may give misleading results. It is therefore advisable to use more than one MSA program when dealing with sequences that may contain deletions or insertions, particularly for high-throughput and pipeline applications where manual refinement of each alignment is not practicable. PMID- 17709333 TI - Extraintestinal virulence is a coincidental by-product of commensalism in B2 phylogenetic group Escherichia coli strains. AB - The selective pressures leading to the evolution and maintenance of virulence in the case of facultative pathogens are quite unclear. For example, Escherichia coli, a commensal of the gut of warm-blooded animals and humans, can cause severe extraintestinal diseases, such as septicemia and meningitis, which represent evolutionary dead ends for the pathogen as they are associated to rapid host death and poor interhost transmission. Such infectious process has been linked to the presence of so-called "virulence genes." To understand the evolutionary forces that select and maintain these genes, we focused our study on E. coli B2 phylogenetic group strains that encompass both commensal and pathogenic (extra- and intraintestinal) strains. Multilocus sequence typing (MLST), comparative genomic hybridization of the B2 flexible gene pool, and quantification of extraintestinal virulence using a mouse model of septicemia were performed on a panel of 60 B2 strains chosen for their genetic and ecologic diversity. The phylogenetic history of the strains reconstructed from the MLST data indicates the emergence of at least 9 subgroups of strains. A high polymorphism is observed in the B2 flexible gene pool among the strains with a good correlation between the MLST-inferred phylogenetic history of the strains and the presence/absence of specific genomic regions, indicating coevolution between the chromosomal background and the flexible gene pool. Virulence in the mouse model is a highly prevalent and widespread character present in all subgroups except one. Association studies reveal that extraintestinal virulence is a multigenic process with a common set of "virulence determinants" encompassing genes involved in transcriptional regulation, iron metabolism, adhesion, lipopolysaccharide (LPS) biosynthesis, and the recently reported peptide polyketide hybrid synthesis system. Interestingly, these determinants can also be viewed as intestinal colonization and survival factors linked to commensalism as they can increase the fitness of the strains within the normal gut environment. Altogether, these data argue for an ancestral emergence of the extraintestinal virulence character that is a coincidental by-product of commensalism. Furthermore, the phenotypic and genotypic markers identified in this work will allow further epidemiological studies devoted to test the niche specialization hypothesis for the B2 phylogenetic subgroups. PMID- 17709334 TI - Evolution of prokaryotic two-component system signaling pathways: gene fusions and fissions. AB - Two-component systems (TCSs) are common signal transduction systems, typically comprising paired histidine protein kinase (HK) and response regulator (RR) proteins. In many examples, it appears RR and HK genes have fused, producing a "hybrid kinase " We have characterized a set of prokaryotic genes encoding RRs, HKs, and hybrid kinases, enabling characterization of gene fusion and fission. Primary factors correlating with fusion rates are the presence of transmembrane helices in HKs and the presence of DNA-binding domains in RRs, features that require correct (and separate) spatial location. In the absence of such features, there is a relative abundance of fused genes. The order of paired HK and RR genes and the nucleotide distance between encoded domains also correlate with apparent gene fusion rates. We propose that localization requirements and relative positioning of encoded domains within TCS genes affect the function (and therefore retention) of hybrid kinases resulting from gene fusion. PMID- 17709335 TI - A long-term evolutionary pressure on the amount of noncoding DNA. AB - A significant part of eukaryotic noncoding DNA is viewed as the passive result of mutational processes, such as the proliferation of mobile elements. However, sequences lacking an immediate utility can nonetheless play a major role in the long-term evolvability of a lineage, for instance by promoting genomic rearrangements. They could thus be subject to an indirect selection. Yet, such a long-term effect is difficult to isolate either in vivo or in vitro. Here, by performing in silico experimental evolution, we demonstrate that, under low mutation rates, the indirect selection of variability promotes the accumulation of noncoding sequences: Even in the absence of self-replicating elements and mutational bias, noncoding sequences constituted an important fraction of the evolved genome because the indirectly selected genomes were those that were variable enough to discover beneficial mutations. On the other hand, high mutation rates lead to compact genomes, much like the viral ones, although no selective cost of genome size was applied: The indirectly selected genomes were those that were small enough for the genetic information to be reliably transmitted. Thus, the spontaneous evolution of the amount of noncoding DNA strongly depends on the mutation rate. Our results suggest the existence of an additional pressure on the amount of noncoding DNA, namely the indirect selection of an appropriate trade-off between the fidelity of the transmission of the genetic information and the exploration of the mutational neighborhood. Interestingly, this trade-off resulted robustly in the accumulation of noncoding DNA so that the best individual leaves one offspring without mutation (or only neutral ones) per generation. PMID- 17709336 TI - Attachment, cognitive, and motor development in adopted children: short-term outcomes after international adoption. AB - OBJECTIVE: To examine infant attachment and developmental functioning shortly after international adoption. METHODS: At 14 months, infant-mother attachment and mental (MDI) and psychomotor (PDI) development were assessed in 70 internationally adopted children. Mean age at arrival was 5.5 months, mean stay in the adoptive family 8.7 months. RESULTS: Adopted children's MDI and PDI did not deviate from normative scores. Also, their secure-insecure attachment distribution was comparable with that of normative groups. However, more adoptees were disorganized attached (36 vs. 15% in normative groups). Temporary residence in a foster home in the country of origin before adoption was related to higher MDI and PDI, whereas disorganized attachment in the adoptive family was related to lower MDI and PDI scores. CONCLUSIONS: The majority of internationally adopted children form secure attachment relationships and function at normative developmental levels shortly after adoption. Residence in a foster family before adoption may partly prevent developmental delays. PMID- 17709338 TI - Natively unstructured regions in proteins identified from contact predictions. AB - MOTIVATION: Natively unstructured (also dubbed intrinsically disordered) regions in proteins lack a defined 3D structure under physiological conditions and often adopt regular structures under particular conditions. Proteins with such regions are overly abundant in eukaryotes, they may increase functional complexity of organisms and they usually evade structure determination in the unbound form. Low propensity for the formation of internal residue contacts has been previously used to predict natively unstructured regions. RESULTS: We combined PROFcon predictions for protein-specific contacts with a generic pairwise potential to predict unstructured regions. This novel method, Ucon, outperformed the best available methods in predicting proteins with long unstructured regions. Furthermore, Ucon correctly identified cases missed by other methods. By computing the difference between predictions based on specific contacts (approach introduced here) and those based on generic potentials (realized in other methods), we might identify unstructured regions that are involved in protein protein binding. We discussed one example to illustrate this ambitious aim. Overall, Ucon added quality and an orthogonal aspect that may help in the experimental study of unstructured regions in network hubs. AVAILABILITY: http://www.predictprotein.org/submit_ucon.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 17709337 TI - Zinc status and relation to thyroid hormone profile in Iranian schoolchildren. AB - Zinc is an essential element involved in many basic biochemical reactions in thyroid. However, little is known about concentration of this mineral in goitrous Iranian schoolchildren. This study was undertaken to determine the prevalence of zinc deficiency and the current zinc status in goitrous schoolchildren. A cross sectional study in which 1188 schoolchildren in the age group of 8-13 years were evaluated for goiter prevalence, urinary iodine and zinc status. Zinc measurement was performed by atomic absorption spectrometry apparatus and urinary iodine was measured by digestion method. Goiter was graded according to WHO classification and serum concentration of thyroid hormones and thyroid-stimulating hormone were determined by commercial kits. This study showed an adequate iodine supply. Eleven percent of all cases had low zinc levels and the mean serum zinc concentration was 84.1 +/- 20.7 microg/dl with a significant difference between the boys and girls (86.6 +/- 22.7 microg/dl vs. 82 +/- 18.7 microg/dl, p = 0.017). The mean concentration in goitrous children was 85.1 +/- 23 microg/dl and for those without goiters was 82.6 +/- 16.7 microg/dl which was not statistically significant. No significant difference was noticed between those with low and normal zinc levels in the prevalence of goiter. In view of normal iodine status, other goitrogenic factors should be evaluated to explain the residual goiter prevalence. PMID- 17709339 TI - A Laboratory Information Management System (LIMS) for a high throughput genetic platform aimed at candidate gene mutation screening. AB - High throughput mutation screening in an automated environment generates large data sets that have to be organized and stored reliably. Complex multistep workflows require strict process management and careful data tracking. We have developed a Laboratory Information Management Systems (LIMS) tailored to high throughput candidate gene mutation scanning and resequencing that respects these requirements. Designed with a client/server architecture, our system is platform independent and based on open-source tools from the database to the web application development strategy. Flexible, expandable and secure, the LIMS, by communicating with most of the laboratory instruments and robots, tracks samples and laboratory information, capturing data at every step of our automated mutation screening workflow. An important feature of our LIMS is that it enables tracking of information through a laboratory workflow where the process at one step is contingent on results from a previous step. AVAILABILITY: Script for MySQL database table creation and source code of the whole JSP application are freely available on our website: http://www-gcs.iarc.fr/lims/. SUPPLEMENTARY INFORMATION: System server configuration, database structure and additional details on the LIMS and the mutation screening workflow are available on our website: http://www-gcs.iarc.fr/lims/ PMID- 17709341 TI - Methods of remote homology detection can be combined to increase coverage by 10% in the midnight zone. AB - MOTIVATION: A recent development in sequence-based remote homologue detection is the introduction of profile-profile comparison methods. These are more powerful than previous technologies and can detect potentially homologous relationships missed by structural classifications such as CATH and SCOP. As structural classifications traditionally act as the gold standard of homology this poses a challenge in benchmarking them. RESULTS: We present a novel approach which allows an accurate benchmark of these methods against the CATH structural classification. We then apply this approach to assess the accuracy of a range of publicly available methods for remote homology detection including several profile-profile methods (COMPASS, HHSearch, PRC) from two perspectives. First, in distinguishing homologous domains from non-homologues and second, in annotating proteomes with structural domain families. PRC is shown to be the best method for distinguishing homologues. We show that SAM is the best practical method for annotating genomes, whilst using COMPASS for the most remote homologues would increase coverage. Finally, we introduce a simple approach to increase the sensitivity of remote homologue detection by up to 10%. This is achieved by combining multiple methods with a jury vote. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 17709340 TI - Con-Struct Map: a comparative contact map analysis tool. AB - Con-Struct Map is a graphical tool for the comparative study of protein structures. The tool detects potential conserved residue contacts shared by multiple protein structures by superimposing their contact maps according to a multiple structure alignment. In general, Con-Struct Map allows the study of structural changes resulting from, e.g. sequence substitutions, or alternatively, the study of conserved components of a structure framework across structurally aligned proteins. Specific applications include the study of sequence-structure relationship in distantly related proteins and the comparisons of wild type and mutant proteins. AVAILABILITY: http://pdbrs3.sdsc.edu/ConStructMap/viewer_argument_generator/singleArguments. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 17709342 TI - Real-time assembly and disassembly of human RAD51 filaments on individual DNA molecules. AB - The human DNA repair protein RAD51 is the crucial component of helical nucleoprotein filaments that drive homologous recombination. The molecular mechanistic details of how this structure facilitates the requisite DNA strand rearrangements are not known but must involve dynamic interactions between RAD51 and DNA. Here, we report the real-time kinetics of human RAD51 filament assembly and disassembly on individual molecules of both single- and double-stranded DNA, as measured using magnetic tweezers. The relative rates of nucleation and filament extension are such that the observed filament formation consists of multiple nucleation events that are in competition with each other. For varying concentration of RAD51, a Hill coefficient of 4.3 +/- 0.5 is obtained for both nucleation and filament extension, indicating binding to dsDNA with a binding unit consisting of multiple (> or =4) RAD51 monomers. We report Monte Carlo simulations that fit the (dis)assembly data very well. The results show that, surprisingly, human RAD51 does not form long continuous filaments on DNA. Instead each nucleoprotein filament consists of a string of many small filament patches that are only a few tens of monomers long. The high flexibility and dynamic nature of this arrangement is likely to facilitate strand exchange. PMID- 17709343 TI - Properties of an unusual DNA primase from an archaeal plasmid. AB - Primases are specialized DNA-dependent RNA polymerases that synthesize a short oligoribonucleotide complementary to single-stranded template DNA. In the context of cellular DNA replication, primases are indispensable since DNA polymerases are not able to start DNA polymerization de novo. The primase activity of the replication protein from the archaeal plasmid pRN1 synthesizes a rather unusual mixed primer consisting of a single ribonucleotide at the 5' end followed by seven deoxynucleotides. Ribonucleotides and deoxynucleotides are strictly required at the respective positions within the primer. Furthermore, in contrast to other archaeo-eukaryotic primases, the primase activity is highly sequence specific and requires the trinucleotide motif GTG in the template. Primer synthesis starts outside of the recognition motif, immediately 5' to the recognition motif. The fidelity of the primase synthesis is high, as non complementary bases are not incorporated into the primer. PMID- 17709344 TI - A systematic strategy for large-scale analysis of genotype phenotype correlations: identification of candidate genes involved in African trypanosomiasis. AB - It is increasingly common to combine Microarray and Quantitative Trait Loci data to aid the search for candidate genes responsible for phenotypic variation. Workflows provide a means of systematically processing these large datasets and also represent a framework for the re-use and the explicit declaration of experimental methods. In this article, we highlight the issues facing the manual analysis of microarray and QTL data for the discovery of candidate genes underlying complex phenotypes. We show how automated approaches provide a systematic means to investigate genotype-phenotype correlations. This methodology was applied to a use case of resistance to African trypanosomiasis in the mouse. Pathways represented in the results identified Daxx as one of the candidate genes within the Tir1 QTL region. Subsequent re-sequencing in Daxx identified a deletion of an amino acid, identified in susceptible mouse strains, in the Daxx p53 protein-binding region. This supports recent experimental evidence that apoptosis could be playing a role in the trypanosomiasis resistance phenotype. Workflows developed in this investigation, including a guide to loading and executing them with example data, are available at http://workflows.mygrid.org.uk/repository/myGrid/PaulFisher/. PMID- 17709345 TI - Ubc9 fusion-directed SUMOylation identifies constitutive and inducible SUMOylation. AB - Constitutive and induced protein SUMOylation is involved in the regulation of a variety of cellular processes, such as regulation of gene expression and protein transport, and proceeds mainly in the nucleus of the cell. So far, several hundred SUMOylation targets have been identified, but presumably they represent only a part of the total of proteins which are regulated by SUMOylation. Here, we used the Ubc9 fusion-dependent SUMOylation system (UFDS) to screen for constitutive and induced SUMOylation of 46 randomly chosen proteins with proven or potential nuclear localization. Fourteen new UFDS-substrate proteins were identified of which eight could be demonstrated to be SUMOylated in a UFDS independent manner in vivo. Of these, three were constitutively SUMOylated (FOS, CRSP9 and CDC37) while the remaining five substrates (CSNK2B, TAF10, HSF2BP, PSMC3 and DRG1) showed a stimulation-dependent SUMOylation induced by the MAP3 kinase MEKK1. Hence, UFDS is appropriate for the identification and characterization of constitutive and, more importantly, induced protein SUMOylation in vivo. PMID- 17709347 TI - EMMA--the European mouse mutant archive. AB - The European Mouse Mutant Archive (EMMA) offers the worldwide scientific community a free archiving service for its mutant mouse lines and access to a wide range of disease models and other research tools. EMMA is currently comprised of seven partners who operate as the primary mouse repository in Europe. EMMA' s primary objectives are to establish and manage a unified repository for maintaining mouse mutations and to make them available to the scientific community. In addition to these core services, the consortium can generate germ-free (axenic) mice for its customers and also hosts courses in cryopreservation. EMMA is a founder member of the Federation of International Mouse Resources (FIMRe). The EMMA network is funded by the participating institutes, national research programmes and the European Commission Research Infrastructures Programme. PMID- 17709346 TI - Transcriptome annotation using tandem SAGE tags. AB - Analysis of several million expressed gene signatures (tags) revealed an increasing number of different sequences, largely exceeding that of annotated genes in mammalian genomes. Serial analysis of gene expression (SAGE) can reveal new Poly(A) RNAs transcribed from previously unrecognized chromosomal regions. However, conventional SAGE tags are too short to identify unambiguously unique sites in large genomes. Here, we design a novel strategy with tags anchored on two different restrictions sites of cDNAs. New transcripts are then tentatively defined by the two SAGE tags in tandem and by the spanning sequence read on the genome between these tagged sites. Having developed a new algorithm to locate these tag-delimited genomic sequences (TDGS), we first validated its capacity to recognize known genes and its ability to reveal new transcripts with two SAGE libraries built in parallel from a single RNA sample. Our algorithm proves fast enough to experiment this strategy at a large scale. We then collected and processed the complete sets of human SAGE tags to predict yet unknown transcripts. A cross-validation with tiling arrays data shows that 47% of these TDGS overlap transcriptional active regions. Our method provides a new and complementary approach for complex transcriptome annotation. PMID- 17709348 TI - Role of medications in symptomatic hyperkalemia. PMID- 17709349 TI - Autonomic imbalance in patients with takotsubo cardiomyopathy: cause or association? PMID- 17709351 TI - Personal risk. PMID- 17709352 TI - Supporting those responsible for the health care for children in the developing world: CHILD2015. PMID- 17709353 TI - Improving underserved children's access to health care: practitioners' views. AB - This article describes the results of three focus groups conducted with a variety of children's health care providers in a county in the southeastern United States. The purpose of the research was to investigate practitioners' views on the barriers impeding access to health care for medically underserved children. The focus groups were the third phase of a larger study designed to collect data on communication patterns among children's health care providers as well as information on children's access to care. The results include suggestions for actions practitioners can take to improve medically underserved children's access to health care. PMID- 17709354 TI - Parental assessment and management of children's postoperative pain: a randomized clinical trial. AB - As day case surgery increases, one needs to improve the management of pain in children at home. This study wished to determine whether the use of a self-report pain scale would result in children receiving more analgesia. Eighty-eight children aged four to 12 years undergoing tonsillectomy, whose parents agreed they could participate, were randomly assigned into two groups. Group A received the routine postoperative advice and a three-day prescription of paracetamol, ibuprofen and codeine. In addition, group B used the Wong-Baker Faces Pain Scale. Seventy-two children completed the study. There was no difference in the total number of analgesics administered to children in the two groups (p = 0.26, Mann- Whitney U-test). It appears that a self-report pain scale does not improve the postoperative management of pain in children at home. PMID- 17709355 TI - Adolescents' experiences of emergency admission to children's wards. AB - The impact of the numerous changes associated with adolescence are likely to be intensified in hospitalization. This qualitative study examines adolescents' experiences of emergency admission to children's wards. Semi-structured interviews were conducted post-discharge with six individuals (aged 11-15) who were inpatient on a paediatric orthopaedic or general surgical ward. The results show that adolescents' experiences are more positive than research has indicated previously, which might question the findings of preceding studies and current recommendations for practice. Areas within current practice fostering a positive experience were highlighted, for example, relationships with health care professionals and participation in care. Also, areas in need of improvement were identified, including ward facilities and measures to assist individuals to attain sufficient sleep and rest and peer support. Further research is necessary on adolescent units in order to establish an evidence base from which to conclude best practice for inpatient adolescents. PMID- 17709356 TI - Home next day: early discharge of children following appendicectomy. AB - Fifty-six children in two groups were discharged within 24 hours of an uncomplicated appendicectomy. While the children in the first group (N = 21) were visited by a nurse at home within 24 hours of discharge, the second group (N = 35) just received telephone calls. The cohort was evaluated by telephone interviews two weeks after discharge. All children fulfilling the discharge standards were discharged safely within 24 hours of surgery. Any physical complaints post-discharge were considered minor. The nurses were able to provide reassurance to the families, give advice and deal with minor problems. As a result the families felt safe and reassured, and in only one case did the fragility of parental confidence become obvious. This study has demonstrated the safety of discharging these children within 24 hours of surgery and the value to nursing contacts in enabling the families to care for their children at home. PMID- 17709357 TI - Listening to service users: young homeless people's experiences of a new mental health service. AB - The aim of this study was to investigate young homeless people's experiences of ;Strong Minded', a new mental health service set up within selected homeless shelters and run by a voluntary sector organization. Semi-structured interviews were conducted with 19 residents from five homeless shelters across the UK. All of the young people who had accessed Strong Minded had benefited from their engagement. The young people also identified several key inherent and important aspects of Strong Minded relating to both the practical, supportive therapeutic approach and the flexibility of the interventions offered, which contributed to the service's success. This service model of engaging vulnerable young people in transition could have useful implications for the future interface between voluntary and statutory mental health services. PMID- 17709358 TI - The contribution of nurses to child health and child health services: findings of a scoping exercise. AB - Historically, nurses have made a significant contribution to the health of children. To date, few attempts have been made to conceptualize the nature of that contribution. This article describes a scoping exercise undertaken to provide a conceptual basis for examining the contribution of nurses to child health and child health services. Three approaches were utilized: strategic topic focused literature reviews (asthma, cancer, disadvantaged families, minor ailments, school health, sick neonates, teenage pregnancy, children with complex needs, children in need of protection or looked-after, troubled schoolchildren), stakeholder conferences and an expert panel. The contribution of nurses to child health and child health services was found to be broad-ranging and diffuse. The contribution is expressed in four integrated dimensions: assessment, health promotion, clinical care and health care organization. The conceptual models detailed in the scoping exercise provide a platform for future inquiry. PMID- 17709359 TI - Peer victimization in children with attention-deficit hyperactivity disorder. AB - This study examined the correlation of peer victimization to psychosocial adjustment in a sample of children diagnosed with attention-deficit hyperactivity disorder (ADHD). A total of 303 files of youth who received a psycho-educational assessment were reviewed; of these, 116 had an ADHD diagnosis. The data collected included the Child Behavior Checklist (which includes items assessing peer victimization), Conner's Parent Rating Scale, Revised Children's Manifest Anxiety Scale and Children's Depression Inventory. Peer victimization was positively correlated with parent reports of anxiety, depression, social problems, delinquent behavior and aggressive behavior. Children with a comorbid psychiatric diagnosis with ADHD reported higher rates of peer victimization than those without a comorbid diagnosis. Children diagnosed with ADHD along with a comorbid externalizing psychiatric diagnosis experienced higher rates of peer victimization than those with a comorbid internalizing psychiatric diagnosis. The implications of this study concerning peer victimization and psychosocial adjustment in children with ADHD are discussed. PMID- 17709360 TI - COREC and IRMER--is co-existence achievable? AB - The competitive pressures within clinical research are severe, and the need for a streamlined process to enable first-class research is self-evident. Conflict between ethical approval processes and legal requirements for the use of radiation within research has hindered such streamlining and has led to a call for action. This Commentary explores the background to this conflict and describes recent initiatives to generate a smoother process and unblock bottlenecks in relevant approval systems. It concludes by suggesting ways to improve the integration of these systems. PMID- 17709361 TI - Uptake characteristics of fluorodeoxyglucose (FDG) in deep fibromatosis and abdominal desmoids: potential clinical role of FDG-PET in the management. AB - In this preliminary report, we explore the uptake pattern of fluorodeoxyglucose (FDG) in fibromatosis and hypothesize the potential clinical role of FDG-positron emission tomography (PET) in the management of this benign but locally aggressive heterogeneous group of soft-tissue tumours. Five patients were studied (two men and three women, age range 23-35 years), among whom were three cases of deep musculoskeletal fibromatosis, one of abdominal fibromatosis (abdominal desmoid) associated with familial adenomatous polyposis (Gardner's syndrome) and one case of both deep musculoskeletal fibromatosis and abdominal desmoid. The FDG uptake in the lesions was heterogeneous in four cases and relatively homogeneous in one case. The uptake ranged from low to moderate grade with areas or foci of relatively avid FDG uptake. The maximum standardized uptake value (SUV(max)) observed was up to 4.7; the avidity probably related to the biological aggressiveness and tendency for recurrence, characteristic of fibromatosis. A dual-point FDG-PET carried out over four active foci in two cases registered an increase in SUV ranging from 6.93% to 25.85% (mean 19.28%). Treatment monitoring with chemotherapy was carried out in two cases: the reduction in FDG uptake was consistent with the histological evidence of fibrosis and reduction in mitosis. Hence, a baseline FDG-PET can serve a valuable role in monitoring the effect of systemic pharmacotherapy in patients with recurrent progressive disease after unsuccessful local-regional treatment. The findings in this report can be extrapolated and have implications for studying the utility of FDG-PET in defining aggressiveness, guiding biopsy and defining excision site in a large tumour and in monitoring therapy in fibromatosis. PMID- 17709362 TI - Sequential MRI changes in Wilson's disease with de-coppering therapy: a study of 50 patients. AB - Wilson's disease (WD) is clinically and radiologically a dynamic disorder. However, there is a paucity of studies involving sequential MRI changes in this disease with or without therapy This study looked at serial MRI changes and their clinical correlate in patients with WD The severity of MRI changes using 1.5 T MRI in 50 patients with WD was graded based on alteration in signal intensity of focal lesions and atrophy. Details of clinical manifestations, Schwab and England Activities of daily living (MSEADL) score, Neurological Symptom Score (NSS) and Chu staging were recorded. Clinical severity and disability scores were correlated with MRI scores using SPSS v10 The mean age at onset of illness and diagnosis was 12.8+/-5.6 years and 14.4+/-6.0 years, respectively. At the time of first MRI, patients had been treated for 49.0+/-77.3 months. At a follow-up of 24.2+/-12.2 months, clinically 36 patients had improved, 9 remained the same and 5 had worsened. Serial imaging revealed an improvement in MRI parameters in 35 patients, no significant changes in 10, worsening in 4 and an admixture of resolving and evolving changes in 1. The overall MRI score improved from 8.2+/ 5.7 to 5.9+/-6.6. There was an improvement in measures of disability and impairment in all: Chu stage, 11.5+/-0.7 to 1.3+/-0.6; MSEADL score (%), 79.7+/ 27.6 to 88.0+/-25.4; NSS, 10.6+/-11.2 to 8.0+/-11.6, with good clinico radiological correlation. Patients with extensive changes, white-matter involvement and severe diffuse atrophy had a poor prognosis In conclusion, the majority of patients with WD showed variable improvement in clinical and MRI features when treated. PMID- 17709363 TI - Influence of display quality on radiologists' performance in the detection of lung nodules on radiographs. AB - The purpose of this study was to evaluate the influence of display quality on radiologists' performance in the detection of lung nodules. Display systems with various technical properties were considered based on their general availability in a radiology department. Their quality was assessed by physical tests. Multireader-multicase receiver operating characteristic (ROC) analysis was used to evaluate observer performance. The area under the curve (Az) was used as a metric for detectability of simulated lung nodules with diameters of 5 mm and 10 mm, and peak contrast values ranging from 0.1 (subtle) to 0.4 (evident) that were digitally superimposed on normal chest radiographs. Three experienced radiologists interpreted a batch of 60 radiographs on five different display systems; four monitors (two liquid crystal display (LCD) and two cathode ray tube (CRT) monitors) and one printed hardcopy. The physical tests showed superior performance of the two LCD monitors. ROC analysis resulted in the following Az scores: LCD-5MP Az = 0.78, hardcopy Az = 0.77, LCDc-2MP Az = 0.75, CRT-5MP Az = 0.72 and CRTc-1MP Az = 0.71. Difference in Az scores between the LCD-5MP monitor and both the CRT-5MP (p = 0.04) and CRTc-1MP (p = 0.01) monitors was significant. The primary class CRT-5MP monitor that showed reduced observer performance failed to comply with physical acceptance requirements. Luminance response was particularly observed to be insufficient. The results indicate that a quality assurance program has the potential to detect non-optimised display systems that could otherwise result in reduced observer performance. PMID- 17709364 TI - A method to optimize the processing algorithm of a computed radiography system for chest radiography. AB - A test methodology using an anthropomorphic-equivalent chest phantom is described for the optimization of the Agfa computed radiography "MUSICA" processing algorithm for chest radiography. The contrast-to-noise ratio (CNR) in the lung, heart and diaphragm regions of the phantom, and the "system modulation transfer function" (sMTF) in the lung region, were measured using test tools embedded in the phantom. Using these parameters the MUSICA processing algorithm was optimized with respect to low-contrast detectability and spatial resolution. Two optimum "MUSICA parameter sets" were derived respectively for maximizing the CNR and sMTF in each region of the phantom. Further work is required to find the relative importance of low-contrast detectability and spatial resolution in chest images, from which the definitive optimum MUSICA parameter set can then be derived. Prior to this further work, a compromised optimum MUSICA parameter set was applied to a range of clinical images. A group of experienced image evaluators scored these images alongside images produced from the same radiographs using the MUSICA parameter set in clinical use at the time. The compromised optimum MUSICA parameter set was shown to produce measurably better images. PMID- 17709365 TI - Fibrinolysis in coronary artery surgery: detection by thromboelastography. AB - Sixty-five patients scheduled for coronary surgery were randomized into three groups: A - conventional coronary artery bypass grafting, B - off-pump surgery, C - coronary artery bypass grafting with modified, rheoparin coated cardiopulmonary bypass with the avoidance of re-infusion of cardiotomy blood into the circuit. On the completion of peripheral bypass anastomoses, highly significant inter-group differences were found in the thromboelastographic parameter lysis of set time at 60 min of assessment (P=0.003) and at 150 min of assessment (P<0.001), the mean values of these parameters were significantly lower in group A as compared with both groups B and C, which were statistically indistinguishable. Lysis on set time on the completion of peripheral bypass anastomoses <50% was detected in 12 patients (52.2%) originating from group A. At the other sampling times (preoperatively, 15 min after sternotomy, at the end of the procedures, and 24 h later) thromboelastographic parameters were similar in all groups. In group A no significant correlations between lysis on set time, postoperative blood loss and D-dimer levels were found. Based on our results, thromboelastographic signs of fibrinolysis were clearly detectable during cardiopulmonary bypass in group A, but not at any time in groups B and C. PMID- 17709366 TI - Nitric oxide is involved in nitrate-induced inhibition of root elongation in Zea mays. AB - BACKGROUND AND AIMS: Root growth and development are closely dependent upon nitrate supply in the growth medium. To unravel the mechanism underlying dependence of root growth on nitrate, an examination was made of whether endogenous nitric oxide (NO) is involved in nitrate-dependent growth of primary roots in maize. METHODS: Maize seedlings grown in varying concentrations of nitrate for 7 d were used to evaluate the effects on root elongation of a nitric oxide (NO) donor (sodium nitroprusside, SNP), a NO scavenger (methylene blue, MB), a nitric oxide synthase inhibitor (N(omega)-nitro-L-arginine, L-NNA), H(2)O(2), indole-3-acetic acid (IAA) and a nitric reducatse inhibitor (tungstate). The effects of these treatments on endogenous NO levels in maize root apical cells were investigated using a NO-specific fluorescent probe, 4, 5 diaminofluorescein diacetate (DAF-2DA) in association with a confocal microscopy. KEY RESULTS: Elongation of primary roots was negatively dependent on external concentrations of nitrate, and inhibition by high external nitrate was diminished when roots were treated with SNP and IAA. MB and L-NNA inhibited root elongation of plants grown in low-nitrate solution, but they had no effect on elongation of roots grown in high-nitrate solution. Tungstate inhibited root elongation grown in both low- and high-nitrate solutions. Endogenous NO levels in root apices grown in high-nitrate solution were lower than those grown in low-nitrate solution. IAA and SNP markedly enhanced endogenous NO levels in root apices grown in high nitrate, but they had no effect on endogenous NO levels in root apical cells grown in low-nitrate solution. Tungstate induced a greater increase in the endogenous NO levels in root apical cells grown in low-nitrate solution than those grown in high-nitrate solution. CONCLUSIONS: Inhibition of root elongation in maize by high external nitrate is likely to result from a reduction of nitric oxide synthase-dependent endogenous NO levels in maize root apical cells. PMID- 17709368 TI - The birth of new exons: mechanisms and evolutionary consequences. AB - A significant amount of literature was dedicated to hypotheses concerning the origin of ancient introns and exons, but accumulating evidence indicates that new exons are also constantly being added to evolving genomes. Several mechanisms contribute to the creation of novel exons in metazoan genomes, including whole gene and single exon duplications, but perhaps the most intriguing are events of exonization, where intronic sequences become exons de novo. Exonizations of intronic sequences, particularly those originating from repetitive elements, are now widely documented in many genomes including human, mouse, dog, and fish. Such de novo appearance of exons is very frequently associated with alternative splicing, with the new exon-containing variant typically being the rare one. This allows the new variant to be evolutionarily tested without compromising the original one, and provides an evolutionary strategy for generation of novel functions with minimum damage to the existing functional repertoire. This review discusses the molecular mechanisms leading to exonization, its extent in vertebrate genomes, and its evolutionary implications. PMID- 17709369 TI - P-glycoprotein-mediated active efflux of the anti-HIV1 nucleoside abacavir limits cellular accumulation and brain distribution. AB - P-glycoprotein (P-gp)-mediated efflux at the blood-brain barrier has been implicated in limiting the brain distribution of many anti-HIV1 drugs, primarily protease inhibitors, resulting in suboptimal concentrations in this important sanctuary site. The objective of this study was to characterize the interaction of abacavir with P-gp and determine whether P-gp is an important mechanism in limiting abacavir delivery to the central nervous system (CNS). In vitro and in vivo techniques were employed to characterize this interaction. Abacavir stimulated P-gp ATPase activity at high concentrations. The cellular accumulation of abacavir was significantly decreased by approximately 70% in Madin-Darby canine kidney II (MDCKII)-MDR1 monolayers compared with wild-type cells and was completely restored by the P-gp inhibitors ((R)-4-((1aR,6R,10bS)-1,2-difluoro 1,1a,6,10b-tetrahydrodibenzo(a,e)cyclopropa(c)cycloheptan-6-yl)-alpha-((5 quinoloyloxy)methyl)-1-piperazineethanol, trihydrochloride) (LY335979) and N-[4 [2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxo 10H-acridine-4-carboxamide (GF120918). Directional flux experiments indicated that abacavir had greater permeability in the basolateral-to-apical direction (1.58E-05 cm/s) than in the apical-to-basolateral direction (3.44E-06 cm/s) in MDR1-transfected monolayers. The directionality in net flux was abolished by both LY335979 and GF120918. In vivo brain distribution studies showed that the AUC(plasma) in mdr1a(-/-) CF-1 mutant mice was approximately 2-fold greater than the AUC(plasma) in the wild type, whereas the AUC(brain) in the mutant was 20 fold higher than that in the wild type. Therefore, the CNS drug targeting index, defined as the ratio of AUC brain-to-plasma for mutant over wild type, was greater than 10. These data are the first in vitro and in vivo evidence that a nucleoside reverse transcriptase inhibitor is a P-gp substrate. The remarkable increase in abacavir brain distribution in P-gp-deficient mutant mice over wild type mice suggests that P-gp may play a significant role in restricting the abacavir distribution to the CNS. PMID- 17709370 TI - Effect of commonly used organic solvents on the kinetics of cytochrome P450 2B6- and 2C8-dependent activity in human liver microsomes. AB - The effect of common organic solvents on the activities of various human cytochromes P450 has been reported. However, very little is known about their influence on CYP2B6 and CYP2C8 enzymes. The purpose of this study was to investigate the effect of solvents on the kinetics of representative CYP2B6 (bupropion hydroxylase) and CYP2C8 (paclitaxel hydroxylase) reactions in human liver microsomes. Methanol, ethanol, dimethyl sulfoxide (DMSO), and acetonitrile were studied at increasing volumes (v/v). Acetonitrile, DMSO, and ethanol were shown to increase the Km and decrease the intrinsic clearance (CLint) of CYP2B6 mediated bupropion hydroxylation in a concentration-dependent manner. These solvents did not noticeably alter the Vmax at concentrations of < or =1% (v/v). Unlike the other solvents studied, the effect of methanol (< or =0.5%, v/v) on CYP2B6 kinetics was negligible. Both DMSO and ethanol increased the Km and decreased the CL(int) of CYP2C8-mediated paclitaxel hydroxylation in a concentration-dependent manner. Acetonitrile had minimal influence on CYP2C8 enzyme kinetics at concentrations of < or =1% (v/v). Methanol decreased the Km of paclitaxel at low concentrations followed by an increase at concentrations of > or =2% (v/v). This differential influence on Km resulted in an increased CLint at low concentrations followed by a decrease at high concentrations. The studied solvents had minimal influence on Vmax of paclitaxel. Collectively, DMSO and ethanol were not suitable for characterizing CYP2B6- and CYP2C8-mediated reactions because they showed concentration-dependent inhibition. Methanol and acetonitrile at concentrations of < or =0.5% and < or =1% (v/v) appeared to be suitable for the measurement of CYP2B6- and CYP2C8-mediated activities, respectively. PMID- 17709371 TI - Bioavailable flavonoids: cytochrome P450-mediated metabolism of methoxyflavones. AB - Methoxylated flavones were recently shown to be promising cancer chemopreventive agents. Their high metabolic stability compared with the hydroxylated analogs was shown in our laboratory using the human hepatic S9 fraction with cofactors for glucuronidation, sulfation, and oxidation. In the present study, the resistance of methoxylated flavones toward oxidative metabolism was investigated with human liver microsomes and recombinant cytochrome P450 (P450) isoforms. Among 15 methoxylated flavones investigated, the two partially methylated compounds, tectochrysin and kaempferide, were among the most susceptible to microsomal oxidation (Cl(int) 283 and 82 ml/min/kg). Of the fully methylated compounds, 5,7 dimethoxyflavone and 5-methoxyflavone were the most stable (Cl(int) 13 and 18 ml/min/kg, respectively), whereas 4'-methoxyflavone, 3'-methoxyflavone, 5,4' dimethoxyflavone, and 7,3'-dimethoxyflavone were the least stable (Cl(int) 161, 140, 119, and 92 ml/min/kg, respectively), emphasizing the importance of the positions of the methoxy substituents in the flavone ring system. Among the five P450 isoforms tested, CYP1A1 showed the highest rate of metabolism of fully methylated compounds, followed by CYP1A2 and CYP3A4. CYP2C9 and CYP2D6 gave minimal disappearance of the parent compound. Finally, in incubations with hepatic S9 fraction with cofactors for oxidation and both conjugation reactions, partially methylated flavones, as expected, were much less metabolically stable than fully methylated flavones, confirming that oxidative demethylation is the rate-limiting metabolic reaction for fully methylated flavones only. In summary, the rate of oxidative metabolism of methoxylated flavones, mainly involving CYP1A1 and CYP1A2, varied widely, even between compounds with very similar structures. PMID- 17709373 TI - Regulation of human lung adenocarcinoma cell migration and invasion by macrophage migration inhibitory factor. AB - Macrophage migration inhibitory factor (MIF) is expressed and secreted in response to mitogens and integrin-dependent cell adhesion. Once released, autocrine MIF promotes the activation of RhoA GTPase leading to cell cycle progression in rodent fibroblasts. We now report that small interfering RNA mediated knockdown of MIF and MIF small molecule antagonism results in a greater than 90% loss of both the migratory and invasive potential of human lung adenocarcinoma cells. Correlating with these phenotypes is a substantial reduction in steady state as well as serum-induced effector binding activity of the Rho GTPase family member, Rac1, in MIF-deficient cells. Conversely, MIF overexpression by adenovirus in human lung adenocarcinoma cells induces a dramatic enhancement of cell migration, and co-expression of a dominant interfering mutant of Rac1 (Rac1(N17)) completely abrogates this effect. Finally, our results indicate that MIF depletion results in defective partitioning of Rac1 to caveolin-containing membrane microdomains, raising the possibility that MIF promotes Rac1 activity and subsequent tumor cell motility through lipid raft stabilization. PMID- 17709374 TI - Cross-sequence transmission of sporadic Creutzfeldt-Jakob disease creates a new prion strain. AB - The genotype (methionine or valine) at polymorphic codon 129 of the human prion protein (PrP) gene and the type (type 1 or type 2) of abnormal isoform of PrP (PrP(Sc)) are major determinants of the clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD). Here we found that the transmission of sCJD prions from a patient with valine homozygosity (129V/V) and type 2 PrP(Sc) (sCJD-VV2 prions) to mice expressing human PrP with methionine homozygosity (129M/M) generated unusual PrP(Sc) intermediate in size between type 1 and type 2. The intermediate type PrP(Sc) was seen in all examined dura mater graft associated CJD cases with 129M/M and plaque-type PrP deposits (p-dCJD). p-dCJD prions and sCJD-VV2 prions exhibited similar transmissibility and neuropathology, and the identical type of PrP(Sc) when inoculated into PrP-humanized mice with 129M/M or 129V/V. These findings suggest that p-dCJD could be caused by cross sequence transmission of sCJD-VV2 prions. PMID- 17709375 TI - Substrate modification with lysine 63-linked ubiquitin chains through the UBC13 UEV1A ubiquitin-conjugating enzyme. AB - Protein modification with lysine 63-linked ubiquitin chains has been implicated in the non-proteolytic regulation of signaling pathways. To understand the molecular mechanisms underlying this process, we have developed an in vitro system to examine the activity of the ubiquitin-conjugating enzyme UBC13-UEV1A with TRAF6 in which TRAF6 serves as both a ubiquitin ligase and substrate for modification. Although TRAF6 potently stimulates the activity of UBC13-UEV1A to synthesize ubiquitin chains, it is not appreciably ubiquitinated. We have determined that the presentation of Lys(63) of ubiquitin by UEV1A suppresses TRAF6 modification. Based on our observations, we propose that the modification of proteins with Lys(63)-linked ubiquitin chains occurs through a UEV1A independent substrate modification and UEV1A-dependent Lys(63)-linked ubiquitin chain synthesis mechanism. PMID- 17709372 TI - Human enteric microsomal CYP4F enzymes O-demethylate the antiparasitic prodrug pafuramidine. AB - CYP4F enzymes, including CYP4F2 and CYP4F3B, were recently shown to be the major enzymes catalyzing the initial oxidative O-demethylation of the antiparasitic prodrug pafuramidine (DB289) by human liver microsomes. As suggested by a low oral bioavailability, DB289 could undergo first-pass biotransformation in the intestine, as well as in the liver. Using human intestinal microsomes (HIM), we characterized the enteric enzymes that catalyze the initial O-demethylation of DB289 to the intermediate metabolite, M1. M1 formation in HIM was catalyzed by cytochrome P450 (P450) enzymes, as evidenced by potent inhibition by 1 aminobenzotriazole and the requirement for NADPH. Apparent K(m) and V(max) values ranged from 0.6 to 2.4 microM and from 0.02 to 0.89 nmol/min/mg protein, respectively (n = 9). Of the P450 chemical inhibitors evaluated, ketoconazole was the most potent, inhibiting M1 formation by 66%. Two inhibitors of P450-mediated arachidonic acid metabolism, HET0016 (N-hydroxy-N'-(4-n-butyl-2 methylphenyl)formamidine) and 17-octadecynoic acid, inhibited M1 formation in a concentration-dependent manner (up to 95%). Immunoinhibition with an antibody raised against CYP4F2 showed concentration-dependent inhibition of M1 formation (up to 92%), whereas antibodies against CYP3A4/5 and CYP2J2 had negligible to modest effects. M1 formation rates correlated strongly with arachidonic acid omega-hydroxylation rates (r(2) = 0.94, P < 0.0001, n = 12) in a panel of HIM that lacked detectable CYP4A11 protein expression. Quantitative Western blot analysis revealed appreciable CYP4F expression in these HIM, with a mean (range) of 7 (3-18) pmol/mg protein. We conclude that enteric CYP4F enzymes could play a role in the first-pass biotransformation of DB289 and other xenobiotics. PMID- 17709376 TI - Synergy between the RE-1 silencer of transcription and NFkappaB in the repression of the neurotransmitter gene TAC1 in human mesenchymal stem cells. AB - The RE-1 silencer of transcription (REST) is a transcriptional regulator that represses neuron-specific genes in non-neuronal tissues by remodeling chromatin structure. We have utilized human mesenchymal stem cells (MSCs) as a research tool to understand the molecular mechanisms that regulate a neurogenic program of differentiation in non-neuronal tissue. MSCs are mesoderm-derived cells that generate specialized cells such as stroma, fat, bone, and cartilage. We have reported previously the transdifferentiation of MSCs into functional neuronal cells (Cho, K. J., Trzaska, K. A., Greco, S. J., McArdle, J., Wang, F. S., Ye, J. H., and Rameshwar, P. (2005) Stem Cells 23, 383-391). Expression of the neurotransmitter gene TAC1 was detected only in neuronal cells and thus served as a model to study transcriptional regulation of neuron-specific genes in undifferentiated MSCs. Bone marrow stromal cells are known to transiently express TAC1 following stimulation with the microenvironmental factor interleukin-1alpha. We thus compared the effects of interleukin-1alpha stimulation and neuronal induction of MSCs on TAC1 regulation. Transcription factor mapping of the 5' flanking region of the TAC1 promoter predicted two REST-binding sites adjacent to one NFkappaB site within exon 1. Chromatin immunoprecipitation, mutagenesis, and loss-of-function studies showed that both transcription factors synergistically mediated repression of TAC1 in the neurogenic and microenvironmental models. Together, the results support the novel finding of synergism between REST and NFkappaB in the suppression of TAC1 in non-neuronal cells. PMID- 17709377 TI - T-cell ubiquitin ligand affects cell death through a functional interaction with apoptosis-inducing factor, a key factor of caspase-independent apoptosis. AB - The lymphoid protein T-cell ubiquitin ligand (TULA)/suppressor of T-cell receptor signaling (Sts)-2 is associated with c-Cbl and ubiquitylated proteins and has been implicated in the regulation of signaling mediated by protein-tyrosine kinases. The results presented in this report indicate that TULA facilitates T cell apoptosis independent of either T-cell receptor/CD3-mediated signaling or caspase activity. Mass spectrometry-based analysis of protein-protein interactions of TULA demonstrates that TULA binds to the apoptosis-inducing protein AIF, which has previously been shown to function as a key factor of caspase-independent apoptosis. Using RNA interference, we demonstrate that AIF is essential for the apoptotic effect of TULA. Analysis of the subcellular localization of TULA and AIF together with the functional analysis of TULA mutants is consistent with the idea that TULA enhances the apoptotic effect of AIF by facilitating the interactions of AIF with its apoptotic co-factors, which remain to be identified. Overall, our results shed new light on the biological functions of TULA, a recently discovered protein, describing its role as one of very few known functional interactors of AIF. PMID- 17709378 TI - Phosphorylation of TPL-2 on serine 400 is essential for lipopolysaccharide activation of extracellular signal-regulated kinase in macrophages. AB - Tumor progression locus 2 (TPL-2) kinase is essential for Toll-like receptor 4 activation of the mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) and for upregulation of the inflammatory cytokine tumor necrosis factor (TNF) in lipopolysaccharide (LPS)-stimulated macrophages. LPS activation of ERK requires TPL-2 release from associated NF-kappaB1 p105, which blocks TPL-2 access to its substrate, the ERK kinase MEK. Here we demonstrate that TPL-2 activity is also regulated independently of p105, since LPS stimulation was still needed for TPL-2-dependent activation of ERK in Nfkb1(-/-) macrophages. In wild type macrophages, LPS induced the rapid phosphorylation of serine (S) 400 in the TPL-2 C-terminal tail. Mutation of this conserved residue to alanine (A) blocked the ability of retrovirally expressed TPL-2 to induce the activation of ERK in LPS-stimulated Nfkb1(-/-) macrophages. TPL-2(S400A) expression also failed to reconstitute LPS activation of ERK and induction of TNF in Map3k8(-/-) macrophages, which lack endogenous TPL-2. Consistently, the S400A mutation was found to block LPS stimulation of TPL-2 MEK kinase activity. Thus, induction of TPL-2 MEK kinase activity by LPS stimulation of macrophages requires TPL-2 phosphorylation on S400, in addition to its release from NF-kappaB1 p105. Oncogenic C-terminal truncations of TPL-2 that remove S400 could promote its transforming potential by eliminating this critical control step. PMID- 17709379 TI - The forkhead factor FoxE1 binds to the thyroperoxidase promoter during thyroid cell differentiation and modifies compacted chromatin structure. AB - The Forkhead box (Fox) transcription factors play diverse roles in differentiation, development, hormone responsiveness, and aging. A pioneer activity of the Forkhead factors in developmental processes has been reported, but how this may apply to other contexts of Forkhead factor regulation remains unexplored. In this study, we address the pioneer activity of the thyroid specific factor FoxE1 during thyroid differentiation. In response to hormone induction, FoxE1 binds to the compacted chromatin of the inactive thyroperoxidase (TPO) promoter, which coincides with the appearance of strong DNase I hypersensitivity at the FoxE1 binding site. In vitro, FoxE1 can bind to its site even when this is protected by a nucleosome, and it creates a local exposed domain specifically on H1-compacted TPO promoter-containing nucleosome arrays. Furthermore, nuclear factor 1 binds to the TPO promoter simultaneously with FoxE1, and this binding has an additive effect on FoxE1-mediated chromatin structure alteration. On the basis of our findings, we propose that FoxE1 is a pioneer factor whose primary mechanistic role in mediating the hormonal regulation of the TPO gene is to enable other regulatory factors to access the chromatin. The presented model extends the reported pioneer activity of the Forkhead factors to processes involved in hormone-induced differentiation. PMID- 17709381 TI - Activation of the RalGEF/Ral pathway promotes prostate cancer metastasis to bone. AB - A hallmark of metastasis is organ specificity; however, little is known about the underlying signaling pathways responsible for the colonization and growth of tumor cells in target organs. Since tyrosine kinase receptor activation is frequently associated with prostate cancer progression, we have investigated the role of a common signaling intermediary, activated Ras, in prostate cancer metastasis. Three effector pathways downstream of Ras, Raf/extracellular signal regulated kinase (ERK), phosphatidylinositol 3-kinase, and Ral guanine nucleotide exchange factors (RalGEFs), were assayed for their ability to promote the metastasis of a tumorigenic, nonmetastatic human prostate cancer cell line, DU145. Oncogenic Ras promoted the metastasis of DU145 to multiple organs, including bone and brain. Activation of the Raf/ERK pathway stimulated metastatic colonization of the brain, while activation of the RalGEF pathway led to bone metastases, the most common organ site for prostate cancer metastasis. In addition, loss of RalA in the metastatic PC3 cell line inhibited bone metastasis but did not affect subcutaneous tumor growth. Loss of Ral appeared to suppress expansive growth of prostate cancer cells in bone, whereas homing and initial colonization were less affected. These data extend our understanding of the functional roles of the Ral pathway and begin to identify signaling pathways relevant for organ-specific metastasis. PMID- 17709380 TI - IkappaB kinase beta phosphorylates the K63 deubiquitinase A20 to cause feedback inhibition of the NF-kappaB pathway. AB - Misregulation of NF-kappaB signaling leads to infectious, inflammatory, or autoimmune disorders. IkappaB kinase beta (IKKbeta) is an essential activator of NF-kappaB and is known to phosphorylate the NF-kappaB inhibitor, IkappaBalpha, allowing it to undergo ubiquitin-mediated proteasomal degradation. However, beyond IkappaBalpha, few additional IKKbeta substrates have been identified. Here we utilize a peptide library and bioinformatic approach to predict likely substrates of IKKbeta. This approach predicted Ser381 of the K63 deubiquitinase A20 as a likely site of IKKbeta phosphorylation. While A20 is a known negative regulator of innate immune signaling pathways, the mechanisms regulating the activity of A20 are poorly understood. We show that IKKbeta phosphorylates A20 in vitro and in vivo at serine 381, and we further show that this phosphorylation event increases the ability of A20 to inhibit the NF-kappaB signaling pathway. Phosphorylation of A20 by IKKbeta thus represents part of a novel feedback loop that regulates the duration of NF-kappaB signaling following activation of innate immune signaling pathways. PMID- 17709382 TI - Histone deacetylase inhibitors reduce steroidogenesis through SCF-mediated ubiquitination and degradation of steroidogenic factor 1 (NR5A1). AB - Histone deacetylase (HDAC) inhibitors such as trichostatin A and valproic acid modulate transcription of many genes by inhibiting the activities of HDACs, resulting in the remodeling of chromatin. Yet this effect is not universal for all genes. Here we show that HDAC inhibitors suppressed the expression of steroidogenic gene CYP11A1 and decreased steroid secretion by increasing the ubiquitination and degradation of SF-1, a factor important for the transcription of all steroidogenic genes. This was accompanied by increased expression of Ube2D1 and SKP1A, an E2 ubiquitin conjugase and a subunit of the E3 ubiquitin ligase in the Skp1/Cul1/F-box protein (SCF) family, respectively. Reducing SKP1A expression with small interfering RNA resulted in recovery of SF-1 levels, demonstrating that the activity of SCF E3 ubiquitin ligase is required for the SF 1 degradation induced by HDAC inhibitors. Overexpression of exogenous SF-1 restored steroidogenic activities even in the presence of HDAC inhibitors. Thus, increased SF-1 degradation is the cause of the reduction in steroidogenesis caused by HDAC inhibitors. The increased SKP1A expression and SCF-mediated protein degradation could be the mechanism underlying the mode of action of HDAC inhibitors. PMID- 17709383 TI - A highly polymorphic meiotic recombination mouse hot spot exhibits incomplete repair. AB - The recent mapping of recombination hot spots in the human genome has demonstrated that crossover is a nonrandom process that occurs at well-defined positions along chromosomes. However, the mechanisms that direct hot-spot turnover in complex mammalian genomes are poorly understood. Analyses of the human genome are impaired by the inability to genetically dissect and molecularly manipulate recombinogenic regions to test their roles in regulating hot spots. Here, using the BXD recombinant inbred strains as a crossover library, three new recombination hot spots have been identified on mouse chromosome 19. Analyses of a highly polymorphic recombination hot spot (HS22) revealed that approximately 4% of recombinant molecules display complex and incomplete repair with discontinuous conversion tracts, as well as persistent heteroduplex DNA at crossover sites in mature spermatozoa. Also, sequence analysis of the wild house mouse revealed instability at the center of this hot spot. This suggests that complete repair is not required for completion of mammalian meiosis, a scenario that leaves duplex DNA containing mismatches at crossover sites. PMID- 17709384 TI - pRb-dependent cyclin D3 protein stabilization is required for myogenic differentiation. AB - The expression of retinoblastoma (pRb) and cyclin D3 proteins is highly induced during the process of skeletal myoblast differentiation. We have previously shown that cyclin D3 is nearly totally associated with hypophosphorylated pRb in differentiated myotubes, whereas Rb-/- myocytes fail to accumulate the cyclin D3 protein despite normal induction of cyclin D3 mRNA. Here we report that pRb promotes cyclin D3 protein accumulation in differentiating myoblasts by preventing cyclin D3 degradation. We show that cyclin D3 displays rapid turnover in proliferating myoblasts, which is positively regulated through glycogen synthase kinase 3beta (GSK-3beta)-mediated phosphorylation of cyclin D3 on Thr 283. We describe a novel interaction between pRb and cyclin D3 that maps to the C terminus of pRb and to a region of cyclin D3 proximal to the Thr-283 residue and provide evidence that the pRb-cyclin D3 complex formation in terminally differentiated myotubes hinders the access of GSK-3beta to cyclin D3, thus inhibiting Thr-283 phosphorylation. Interestingly, we observed that the ectopic expression of a stabilized cyclin D3 mutant in C2 myoblasts enhances muscle specific gene expression; conversely, cyclin D3-null embryonic fibroblasts display impaired MyoD-induced myogenic differentiation. These results indicate that the pRb-dependent accumulation of cyclin D3 is functionally relevant to the process of skeletal muscle cell differentiation. PMID- 17709386 TI - Mutations in the ubiquitin binding UBZ motif of DNA polymerase eta do not impair its function in translesion synthesis during replication. AB - Treatment of Saccharomyces cerevisiae cells with DNA-damaging agents elicits lysine 164-linked PCNA monoubiquitination by Rad6-Rad18. Recently, a number of ubiquitin (Ub) binding domains (UBDs) have been identified in translesion synthesis (TLS) DNA polymerases and it has been proposed that the UBD in a TLS polymerase affects its binding to Ub on PCNA and that this binding mode is indispensable for a TLS polymerase to access PCNA at the site of a stalled replication fork. To evaluate the contribution of the binding of UBDs to the Ub moiety on PCNA in TLS, we have examined the effects of mutations in the C2H2 zinc binding motif and in the conserved D570 residue that lies in the alpha-helix portion of the UBZ domain of yeast Poleta. We find that mutations in the C2H2 motif have no perceptible effect on UV sensitivity or UV mutagenesis, whereas a mutation of the D570 residue adversely affects Poleta function. The stimulation of DNA synthesis by Poleta with PCNA or Ub-PCNA was not affected by mutations in the C2H2 motif or the D570 residue. These observations lead us to suggest that the binding of Ub on PCNA via its UBZ domain is not a necessary requirement for the ability of polymerase eta to function in TLS during replication. PMID- 17709385 TI - Acetylation-induced transcription is required for active DNA demethylation in methylation-silenced genes. AB - A hallmark of vertebrate genes is that actively transcribed genes are hypomethylated in critical regulatory sequences. However, the mechanisms that link gene transcription and DNA hypomethylation are unclear. Using a trichostatin A (TSA)-induced replication-independent demethylation assay with HEK 293 cells, we show that RNA transcription is required for DNA demethylation. Histone acetylation precedes but is not sufficient to trigger DNA demethylation. Following histone acetylation, RNA polymerase II (RNAP II) interacts with the methylated promoter. Inhibition of RNAP II transcription with actinomycin D, alpha-amanitin, or CDK7-specific small interfering RNA inhibits DNA demethylation. H3 trimethyl lysine 4 methylation, a marker of actively transcribed genes, was associated with the cytomegalovirus promoter only after demethylation. TSA-induced demethylation of the endogenous cancer testis gene GAGE follows a similar sequence of events and is dependent on RNA transcription as well. These data suggest that DNA demethylation follows rather than precedes early transcription and point towards a novel function for DNA demethylation as a memory of actively transcribed genes. PMID- 17709387 TI - Association of tyrosine phosphatase epsilon with microtubules inhibits phosphatase activity and is regulated by the epidermal growth factor receptor. AB - Protein tyrosine phosphatases (PTPs) are key mediators that link physiological cues with reversible changes in protein structure and function; nevertheless, significant details concerning their regulation in vivo remain unknown. We demonstrate that PTPepsilon associates with microtubules in vivo and is inhibited by them in a noncompetitive manner. Microtubule-associated proteins, which interact strongly with microtubules in vivo, significantly increase binding of PTPepsilon to tubulin in vitro and further reduce phosphatase activity. Conversely, disruption of microtubule structures in cells reduces their association with PTPepsilon, alters the subcellular localization of the phosphatase, and increases its specific activity. Activation of the epidermal growth factor receptor (EGFR) increases the PTPepsilon-microtubule association in a manner dependent upon EGFR-induced phosphorylation of PTPepsilon at Y638 and upon microtubule integrity. These events are transient and occur with rapid kinetics similar to EGFR autophosphorylation, suggesting that activation of the EGFR transiently down-regulates PTPepsilon activity near the receptor by promoting the PTPepsilon-microtubule association. Tubulin also inhibits the tyrosine phosphatase PTP1B but not receptor-type PTPmu or the unrelated alkaline phosphatase. The data suggest that reversible association with microtubules is a novel, physiologically regulated mechanism for regulation of tyrosine phosphatase activity in cells. PMID- 17709388 TI - NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis. AB - The NF-E2 p45-related factor 2 (NRF2) and the aryl hydrocarbon receptor (AHR) are transcription factors controlling pathways modulating xenobiotic metabolism. AHR has recently been shown to affect Nrf2 expression. Conversely, this study demonstrates that NRF2 regulates expression of Ahr and subsequently modulates several downstream events of the AHR signaling cascade, including (i) transcriptional control of the xenobiotic metabolism genes Cyp1a1 and Cyp1b1 and (ii) inhibition of adipogenesis in mouse embryonic fibroblasts (MEFs). Constitutive expression of AHR was affected by Nrf2 genotype. Moreover, a pharmacological activator of NRF2 signaling, CDDO-IM {1-[2-cyano-3,12-dioxooleana 1,9(11)-dien-28-oyl]imidazole}, induced Ahr, Cyp1a1, and Cyp1b1 transcription in Nrf2+/+ MEFs but not in Nrf2-/- MEFs. Reporter analysis and chromatin immunoprecipitation assay revealed that NRF2 directly binds to one antioxidant response element (ARE) found in the -230-bp region of the promoter of Ahr. Since AHR negatively controls adipocyte differentiation, we postulated that NRF2 would inhibit adipogenesis through the interaction with the AHR pathway. Nrf2-/- MEFs showed markedly accelerated adipogenesis upon stimulation, while Keap1-/- MEFs (which exhibit higher NRF2 signaling) differentiated slowly compared to their congenic wild-type MEFs. Ectopic expression of Ahr and dominant-positive Nrf2 in Nrf2-/- MEFs also substantially delayed differentiation. Thus, NRF2 directly modulates AHR signaling, highlighting bidirectional interactions of these pathways. PMID- 17709389 TI - A conditional role of U2AF in splicing of introns with unconventional polypyrimidine tracts. AB - Recognition of polypyrimidine (Py) tracts typically present between the branch point and the 3' splice site by the large subunit of the essential splicing factor U2AF is a key early step in pre-mRNA splicing. Diverse intronic sequence arrangements exist, however, including 3' splice sites lacking recognizable Py tracts, which raises the question of how general the requirement for U2AF is for various intron architectures. Our analysis of fission yeast introns in vivo has unexpectedly revealed that whereas introns lacking Py tracts altogether remain dependent on both subunits of U2AF, introns with long Py tracts, unconventionally positioned upstream of branch points, are unaffected by U2AF inactivation. Nevertheless, mutation of these Py tracts causes strong dependence on the large subunit U2AF59. We also find that Py tract diversity influences the requirement for the conserved C-terminal domain of U2AF59 (RNA recognition motif 3), which has been implicated in protein-protein interactions with other splicing factors. Together, these results suggest that in addition to Py tract binding by U2AF, supplementary mechanisms of U2AF recruitment and 3' splice site identification exist to accommodate diverse intron architectures, which have gone unappreciated in biochemical studies of model pre-mRNAs. PMID- 17709390 TI - Involvement of nuclear import and export factors in U8 box C/D snoRNP biogenesis. AB - Box C/D snoRNPs, factors essential for ribosome biogenesis, are proposed to be assembled in the nucleoplasm before localizing to the nucleolus. However, recent work demonstrated the involvement of nuclear export factors in this process, suggesting that export may take place. Here we show that there are distinct distributions of U8 pre-snoRNAs and pre-snoRNP complexes in HeLa cell nuclear and cytoplasmic extracts. We observed differential association of nuclear export (PHAX, CRM1, and Ran) factors with complexes in the two extracts, consistent with nucleocytoplasmic transport. Furthermore, we show that the U8 pre-snoRNA in one of the cytoplasmic complexes contains an m3G cap and is associated with the nuclear import factor Snurportin1. Using RNA interference, we show that loss of either PHAX or Snurportin1 results in the incorrect localization of the U8 snoRNA. Our data therefore show that nuclear export and import factors are directly involved in U8 box C/D snoRNP biogenesis. The distinct distribution of U8 pre-snoRNP complexes between the two cellular compartments together with the association of both nuclear import and export factors with the precursor complex suggests that the mammalian U8 snoRNP is exported during biogenesis. PMID- 17709391 TI - A regulatory circuit mediating convergence between Nurr1 transcriptional regulation and Wnt signaling. AB - The orphan nuclear receptor Nurr1 is essential for the development and maintenance of midbrain dopaminergic neurons, the cells that degenerate during Parkinson's disease, by promoting the transcription of genes involved in dopaminergic neurotransmission. Since Nurr1 lacks a classical ligand-binding pocket, it is not clear which factors regulate its activity and how these factors are affected during disease pathogenesis. Since Wnt signaling via beta-catenin promotes the differentiation of Nurr1(+) dopaminergic precursors in vitro, we tested for functional interactions between these systems. We found that beta catenin and Nurr1 functionally interact at multiple levels. In the absence of beta-catenin, Nurr1 is associated with Lef-1 in corepressor complexes. Beta catenin binds Nurr1 and disrupts these corepressor complexes, leading to coactivator recruitment and induction of Wnt- and Nurr1-responsive genes. We then identified KCNIP4/calsenilin-like protein as being responsive to concurrent activation by Nurr1 and beta-catenin. Since KCNIP4 interacts with presenilins, the Alzheimer's disease-associated proteins that promote beta-catenin degradation, we tested the possibility that KCNIP4 induction regulates beta catenin signaling. KCNIP4 induction limited beta-catenin activity in a presenilin dependent manner, thereby serving as a negative feedback loop; furthermore, Nurr1 inhibition of beta-catenin activity was absent in PS1(-/-) cells or in the presence of small interfering RNAs specific to KCNIP4. These data describe regulatory convergence between Nurr1 and beta-catenin, providing a mechanism by which Nurr1 could be regulated by Wnt signaling. PMID- 17709392 TI - DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics. AB - Chromatin reorganization plays an important role in DNA repair, apoptosis, and cell cycle checkpoints. Among proteins involved in chromatin reorganization, TIP60 histone acetyltransferase has been shown to play a role in DNA repair and apoptosis. However, how TIP60 regulates chromatin reorganization in the response of human cells to DNA damage is largely unknown. Here, we show that ionizing irradiation induces TIP60 acetylation of histone H2AX, a variant form of H2A known to be phosphorylated following DNA damage. Furthermore, TIP60 regulates the ubiquitination of H2AX via the ubiquitin-conjugating enzyme UBC13, which is induced by DNA damage. This ubiquitination of H2AX requires its prior acetylation. We also demonstrate that acetylation-dependent ubiquitination by the TIP60-UBC13 complex leads to the release of H2AX from damaged chromatin. We conclude that the sequential acetylation and ubiquitination of H2AX by TIP60 UBC13 promote enhanced histone dynamics, which in turn stimulate a DNA damage response. PMID- 17709393 TI - Vaccinia-related kinase 2 modulates the stress response to hypoxia mediated by TAK1. AB - Hypoxia represents a major stress that requires an immediate cellular response in which different signaling pathways participate. Hypoxia induces an increase in the activity of TAK1, an atypical mitogen-activated protein kinase kinase kinase (MAPKKK), which responds to oxidative stress by triggering cascades leading to the activation of c-Jun N-terminal kinase (JNK). JNK activation by hypoxia requires assembly with the JIP1 scaffold protein, which might also interact with other intracellular proteins that are less well known but that might modulate MAPK signaling. We report that TAK1 is able to form a stable complex with JIP1 and thus regulate the activation of JNK, which in turn determines the cellular stress response to hypoxia. This activation of TAK1-JIP1-JNK is suppressed by vaccinia-related kinase 2 (VRK2). VRK2A is able to interact with TAK1 by its C terminal region, forming stable complexes. The kinase activity of VRK2 is not necessary for this interaction or the downregulation of AP1-dependent transcription. Furthermore, reduction of the endogenous VRK2 level with short hairpin RNA can increase the response induced by hypoxia, suggesting that the intracellular levels of VRK2 can determine the magnitude of this stress response. PMID- 17709394 TI - The SCL +40 enhancer targets the midbrain together with primitive and definitive hematopoiesis and is regulated by SCL and GATA proteins. AB - The SCL/Tal-1 gene encodes a basic helix-loop-helix transcription factor with key roles in hematopoietic and neural development. SCL is expressed in, and required for, both primitive and definitive erythropoiesis. Thus far, we have identified only one erythroid SCL enhancer. Located 40 kb downstream of exon 1a, the +40 enhancer displays activity in primitive erythroblasts. We demonstrate here that a 3.7-kb fragment containing this element also targets expression to the midbrain, a known site of endogenous SCL expression. Although the 3.7-kb construct was active in primitive, but not definitive, erythroblasts, a larger 5.0-kb fragment, encompassing the 3.7-kb region, was active in both fetal and adult definitive hematopoietic cells. This included Ter119+ erythroid cells along with fetal liver erythroid and myeloid progenitors. Unlike two other SCL hematopoietic enhancers (+18/19 and -4), +40 enhancer transgenes were inactive in the endothelium. A conserved 400-bp core region, essential for both hematopoietic and midbrain +40 enhancer activity in embryos, relied on two GATA/E-box motifs and was bound in vivo by GATA-1 and SCL in erythroid cells. These results suggest a model in which the SCL +18/19 and/or -4 enhancers initiate SCL expression in early mesodermal derivatives capable of generating blood and endothelium, with subsequent activation of the +40 enhancer via an autoregulatory loop. PMID- 17709395 TI - The transcription-dependent dissociation of P-TEFb-HEXIM1-7SK RNA relies upon formation of hnRNP-7SK RNA complexes. AB - The positive transcription elongation factor P-TEFb controls the elongation of transcription by RNA polymerase II. P-TEFb is inactivated upon binding to HEXIM1 or HEXIM2 proteins associated with a noncoding RNA, 7SK. In response to the inhibition of transcription, 7SK RNA, as well as HEXIM proteins, is released by an unknown mechanism and P-TEFb is activated. New partners of 7SK RNA were searched for as potential players in this feedback process. A subset of heterogeneous ribonuclear proteins, hnRNPs Q and R and hnRNPs A1 and A2, were thus identified as major 7SK RNA-associated proteins. The degree of association of 7SK RNA with these hnRNPs increased when P-TEFb-HEXIM1-7SK was dissociated following the inhibition of transcription or HEXIM1 knockdown. This finding suggested that 7SK RNA shuttles from HEXIM1-P-TEFb complexes to hnRNPs. The transcription-dependent dissociation of P-TEFb-HEXIM1-7SK complexes was attenuated when both hnRNPs A1 and A2 were knocked down by small interfering RNA. As hnRNPs are known to interact transiently with RNA while it is synthesized, hnRNPs released from nascent transcripts may trap 7SK RNA and thereby contribute to the activation of P-TEFb. PMID- 17709396 TI - Functional analysis of the transcription repressor PLU-1/JARID1B. AB - The PLU-1/JARID1B nuclear protein, which is upregulated in breast cancers, belongs to the ARID family of DNA binding proteins and has strong transcriptional repression activity. To identify the target genes regulated by PLU-1/JARID1B, we overexpressed or silenced the human PLU-1/JARID1B gene in human mammary epithelial cells by using adenovirus and RNA interference systems, respectively, and then applied microarray analysis to identify candidate genes. A total of 100 genes showed inversely correlated differential expression in the two systems. Most of the candidate genes were downregulated by the overexpression of PLU 1/JARID1B, including the MT genes, the tumor suppressor gene BRCA1, and genes involved in the regulation of the M phase of the mitotic cell cycle. Chromatin immunoprecipitation assays confirmed that the metallothionein 1H (MT1H), -1F, and -1X genes are direct transcriptional targets of PLU-1/JARID1B in vivo. Furthermore, the level of trimethyl H3K4 of the MT1H promoter was increased following silencing of PLU-1/JARID1B. Both the PLU-1/JARID1B protein and the ARID domain selectively bound CG-rich DNA. The GCACA/C motif, which is abundant in metallothionein promoters, was identified as a consensus binding sequence of the PLU-1/JARID1B ARID domain. As expected from the microarray data, cells overexpressing PLU-1/JARID1B have an impaired G(2)/M checkpoint. Our study provides insight into the molecular function of the breast cancer-associated transcriptional repressor PLU-1/JARID1B. PMID- 17709397 TI - Regulation of H-ras splice variant expression by cross talk between the p53 and nonsense-mediated mRNA decay pathways. AB - When cells are exposed to a genotoxic stress, a DNA surveillance pathway that involves p53 is activated, allowing DNA repair. Eukaryotic cells have also evolved a mechanism called mRNA surveillance that controls the quality of mRNAs. Indeed, mutant mRNAs carrying premature translation termination codons (PTCs) are selectively degraded by the nonsense-mediated mRNA decay (NMD) pathway. However, in the case of particular genes, such as proto-oncogenes, mutations that do not create PTCs and therefore that do not induce mRNA degradation, can be harmful to cells. In this study, we showed that the H-ras gene in the absence of mutations produces an NMD-target splice variant that is degraded in the cytosol. We observed that a treatment with the genotoxic stress inducer camptothecin for 6 h favored the production of the H-ras NMD-target transcript degraded in the cytosol by the NMD process. Our data indicated that the NMD process allowed the elimination of transcripts produced in response to a short-term treatment with camptothecin from the major proto-oncogene H-ras, independently of PTCs induced by mutations. The camptothecin effects on H-ras gene expression were p53 dependent and involved in part modulation of the SC35 splicing factor. Interestingly, a long-term treatment with camptothecin as well as p53 overexpression for 24 h resulted in the accumulation of the H-ras NMD target in the cytosol, although the NMD process was not completely inhibited as other NMD targets are not stabilized. Finally, Upf1, a major NMD effector, was necessary for optimal p53 activation by camptothecin, which is consistent with recent data showing that NMD effectors are required for genome stability. In conclusion, we identified cross talk between the p53 and NMD pathways that regulates the expression levels of H-ras splice variants. PMID- 17709399 TI - The Notch signaling pathway controls the size of the ocular lens by directly suppressing p57Kip2 expression. AB - The size of an organ must be tightly controlled so that it fits within an organism. The mammalian lens is a relatively simple organ composed of terminally differentiated, amitotic lens fiber cells capped on the anterior surface by a layer of immature, mitotic epithelial cells. The proliferation of lens epithelial cells fuels the growth of the lens, thus controling the size of the lens. We report that the Notch signaling pathway defines the boundary between proliferation and differentiation in the developing lens. The loss of Notch signaling results in the loss of epithelial cells to differentiation and a much smaller lens. We found that the Notch effector Herp2 is expressed in lens epithelium and directly suppresses p57Kip2 expression, providing a molecular link between Notch signaling and the cell cycle control machinery during lens development. PMID- 17709400 TI - Novel interferon-beta-induced gene expression in peripheral blood cells. AB - Type I IFNs are used for treating viral, neoplastic, and inflammatory disorders. The protein products encoded by IFN-stimulated genes (ISGs) likely mediate clinical effects of IFN in patients. Macroarray assays, used for studying ISG induction in IFN-treated patients, comprise genes identified predominantly through analysis of long-term cell lines. To discover genes induced selectively by IFN-beta in PBMC, we exposed whole blood to physiological concentrations of IFN-beta. PBMC were prepared, and RNA was extracted, reverse-transcribed, and hybridized to cDNA microarrays, and microarray analysis identified 39 ISGs and 20 IFN-repressed genes (IRGs). Thirty-three ISGs were known previously, and six ISGs were novel. New ISGs included GTP cyclohydrolase 1; hypothetical protein LOC129607; hypothetical protein FLJ38348; leucine aminopeptidase 3; squalene epoxidase; and GTP-binding protein overexpressed in skeletal muscle. Twenty IRGs included IL-1beta and CXCL8, which had been identified earlier. CXCL1 was a novel IRG identified in the current study. PCR analysis demonstrated the regulation of six novel ISGs and CXCL1 as an IRG in PBMC and astrocytoma cells. Results were validated using RNA obtained ex vivo from blood of patients after injection with IFN-beta. Identification of new ISGs and IRGs in primary PBMC will enhance macroarray assays for monitoring IFN responsiveness. PMID- 17709398 TI - The Swi/Snf complex is important for histone eviction during transcriptional activation and RNA polymerase II elongation in vivo. AB - The Swi/Snf nucleosome-remodeling complex is recruited by DNA-binding activator proteins, whereupon it alters chromatin structure to increase preinitiation complex formation and transcription. At the SUC2 promoter, the Swi/Snf complex is required for histone eviction in a manner that is independent of transcriptional activity. Swi/Snf travels through coding regions with elongating RNA polymerase (Pol) II, and swi2 mutants exhibit sensitivity to drugs affecting Pol elongation. In FACT-depleted cells, Swi/Snf is important for internal initiation within coding regions, suggesting that Swi/Snf is important for histone eviction that occurs during Pol II elongation. Taken together, these observations suggest that Swi/Snf is important for histone eviction at enhancers and that it also functions as a Pol II elongation factor. PMID- 17709401 TI - Apoptosis triggered by phagocytosis-related oxidative stress through FLIPS down regulation and JNK activation. AB - Tumor necrosis factor-alpha (TNF-alpha)-activated neutrophils phagocytose and eliminate bacteria by using such oxidants as hydrogen peroxide (H(2)O(2)) and hypochlorous acid (HOCl), which is produced from H(2)O(2) by myeloperoxidase (MPO). Thereafter, neutrophils eventually undergo apoptosis to prevent excessive inflammation. However, it is unclear how this process is regulated. Here, we show that cotreatment of TNF-alpha-resistant neutrophilic HL-60 cells with taurine chloramine (TauCl), a detoxified form of HOCl, and TNF-alpha renders them susceptible to apoptosis, mostly by preventing nuclear factor-kappaB (NF-kappaB) activation. Of several NF-kappaB target genes tested, FLICE inhibitory protein short form (FLIP(S)) was specifically down-regulated by TauCl. TNF-alpha/TauCl cotreatment-induced apoptosis was largely blocked by stable expression of FLIP(S). Cotreatment with TNF-alpha and H(2)O(2) promoted apoptotic signaling via MPO activation and subsequent attenuation of FLIP(S) expression. TNF-alpha priming with H(2)O(2) or bacteria caused MPO-dependent apoptosis in human neutrophils. However, FLIP(S) knock-down by siRNA did not affect the viability of cells treated with TNF-alpha, implying that TauCl may affect another pathway in TNF-alpha-driven apoptosis. Indeed, oxidization of thioredoxin-1 (Trx-1) by TauCl induced the activation of apoptosis signal-regulating kinase 1 (ASK1) and cJun N terminal kinase (JNK), thereby triggering TNF-alpha-mediated apoptosis. Taken together, these results indicate that the antiapoptotic signaling induced by TNF alpha via NF-kappaB activation can be altered to promote apoptosis via H(2)O(2) MPO-mediated FLIP(S) down-regulation and JNK activation. PMID- 17709402 TI - Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation. AB - The action of matrix metalloproteinases (MMPs) was originally believed to be restricted to degradation of the extracellular matrix; however, in recent years, it has become evident that these proteases can modify many nonmatrix substrates, such as cytokines and chemokines. The use of MMP-deficient animals has revealed that these proteases can indeed influence the progression of various inflammatory processes. This review aims to provide the reader with a concise overview of these novel MMP functions in relation to leukocyte migration. PMID- 17709403 TI - LPA3 receptor mediates chemotaxis of immature murine dendritic cells to unsaturated lysophosphatidic acid (LPA). AB - Increasing evidence supports roles for lipids in the biology of immune cells. In particular, bioactive lipids such as sphingosine-1-phosphate (S1P) bind to cognate G protein-coupled receptors (GPCRs) and modulate leukocyte trafficking and homeostasis. Lysophosphatidic acid (LPA) represents a family of bioactive lipids, which differ in the length and degree of saturation of the fatty acyl chain. LPA is structurally related to S1P and exerts cellular effects by binding to five known GPCRs (LPA(1-5)). Its function in the immune system is less clear, although it was shown to induce chemotaxis of human dendritic cells (DCs) and activated T cells. In this study, we show that LPA can induce chemotaxis of immature but not mature mouse DCs and that only unsaturated and not saturated LPA species are efficient chemoattractants. However, both LPA species do not alter DC maturation or chemotaxis to other chemokines. The loss of DC migration capability correlated with the down-regulation of expression of the receptors LPA(3) and LPA(5), and expression of LPA(1), LPA(2), and LPA(4) did not change. A LPA(3) antagonist reduced immature DC migration to LPA by 70%, suggesting that LPA(3) mediates immature DC chemotaxis to unsaturated species of LPA. Furthermore, isolated, immature DCs from mice lacking LPA(3) exhibited a 50% reduction in migration to LPA. In summary, our results indicate that immature mouse DCs migrate preferentially in response to unsaturated LPA and that LPA(3) is important in this response. PMID- 17709404 TI - Estimating the number needed to vaccinate to prevent diseases and death related to human papillomavirus infection. AB - BACKGROUND: A vaccine against human papillomavirus (HPV) types 6, 11, 16 and 18 is now licensed for use in Canada and many other countries. We sought to estimate the number needed to vaccinate to prevent HPV-related diseases and death. METHODS: A cohort model of the natural history of HPV infection was developed. Model simulations were based on 209 different parameter sets that reproduced Canadian HPV type-specific data for infection, cervical intraepithelial neoplasia, cervical cancer and genital warts. The number needed to vaccinate was calculated as the number of women who would need to be vaccinated to prevent an HPV-related event during their lifetime. RESULTS: Among 12-year-old girls, we estimated that the number needed to vaccinate to prevent an episode of genital warts would be 8 (80% credibility interval [CrI] 5-15) and a case of cervical cancer 324 (80% CrI 195-757). These estimates were based on the assumption that the vaccine procures lifelong protection and that its efficacy is 95%. If vaccine protection is assumed to wane at 3% per year, the predicted number needed to vaccinate would increase to 14 (80% CrI 6-18) and 9080 (80% CrI 1040-does not prevent), respectively. The latter number would be greatly reduced with the addition of a booster dose, to 480 (80% CrI 254-1572). INTERPRETATION: Our model predictions suggest that vaccination with the currently available HPV vaccine may significantly reduce the incidence of genital warts, cervical intraepithelial neoplasia and cervical cancer. However, the benefits (particularly in terms of cervical cancer reduction) are highly dependent on the duration of vaccine protection, on which evidence is currently limited. PMID- 17709405 TI - CMA considers election and structural reforms. PMID- 17709407 TI - Brucella abortus requires the heme transporter BhuA for maintenance of chronic infection in BALB/c mice. AB - The gene annotated BAB2_1150 in the Brucella abortus 2308 genome sequence is predicted to encode a homolog of the well-characterized heme transporter ShuA of Shigella dysenteriae and accordingly has been given the designation bhuA (Brucella heme utilization). Phenotypic analysis of an isogenic bhuA mutant derived from B. abortus 2308 verified that there is a link between BhuA and the ability of the parent strain to use heme as an iron source in in vitro assays. Maximum expression of bhuA in B. abortus 2308 is observed during stationary phase when this strain in cultivated in low-iron minimal medium, and a comparison of the growth characteristics of the B. abortus bhuA mutant and 2308 in this medium suggested that heme serves as an important iron source for the parent strain during stationary phase. The B. abortus bhuA mutant HR1703 exhibits significant attenuation in cultured murine macrophages compared to strain 2308, and unlike its parent strain, the B. abortus bhuA mutant is unable to maintain a chronic spleen infection in experimentally infected BALB/c mice. These experimental findings suggest that heme and/or heme-containing proteins represent important iron sources for B. abortus 2308 during its residence in the mammalian host and that BhuA is required for efficient utilization of these iron sources. PMID- 17709406 TI - Coxiella burnetii inhibits activation of host cell apoptosis through a mechanism that involves preventing cytochrome c release from mitochondria. AB - Coxiella burnetii is an obligate intracellular pathogen and the etiological agent of the human disease Q fever. C. burnetii infects mammalian cells and then remodels the membrane-bound compartment in which it resides into a unique lysosome-derived organelle that supports bacterial multiplication. To gain insight into the mechanisms by which C. burnetii is able to multiply intracellularly, we examined the ability of host cells to respond to signals that normally induce apoptosis. Our data show that mammalian cells infected with C. burnetii are resistant to apoptosis induced by staurosporine and UV light. C. burnetii infection prevented caspase 3/7 activation and limited fragmentation of the host cell nucleus in response to agonists that induce apoptosis. Inhibition of bacterial protein synthesis reduced the antiapoptotic effect that C. burnetii exerted on infected host cells. Inhibition of apoptosis in C. burnetii-infected cells did not correlate with the degradation of proapoptotic BH3-only proteins involved in activation of the intrinsic cell death pathway; however, cytochrome c release from mitochondria was diminished in cells infected with C. burnetii upon induction of apoptosis. These data indicate that C. burnetii can interfere with the intrinsic cell death pathway during infection by producing proteins that either directly or indirectly prevent release of cytochrome c from mitochondria. It is likely that inhibition of apoptosis by C. burnetii represents an important virulence property that allows this obligate intracellular pathogen to maintain host cell viability despite inducing stress that would normally activate the intrinsic death pathway. PMID- 17709408 TI - Bacillus anthracis exosporium protein BclA affects spore germination, interaction with extracellular matrix proteins, and hydrophobicity. AB - Bacillus collagen-like protein of anthracis (BclA) is the immunodominant glycoprotein on the exosporium of Bacillus anthracis spores. Here, we sought to assess the impact of BclA on spore germination in vitro and in vivo, surface charge, and interaction with host matrix proteins. For that purpose, we constructed a markerless bclA null mutant in B. anthracis Sterne strain 34F2. The growth and sporulation rates of the DeltabclA and parent strains were nearly indistinguishable, but germination of mutant spores occurred more rapidly than that of wild-type spores in vitro and was more complete by 60 min. Additionally, the mean time to death of A/J mice inoculated subcutaneously or intranasally with mutant spores was lower than that for the wild-type spores even though the 50% lethal doses of the two strains were similar. We speculated that these in vitro and in vivo differences between mutant and wild-type spores might reflect the ease of access of germinants to their receptors in the absence of BclA. We also compared the hydrophobic and adhesive properties of DeltabclA and wild-type spores. The DeltabclA spores were markedly less water repellent than wild-type spores, and, probably as a consequence, the extracellular matrix proteins laminin and fibronectin bound significantly better to mutant than to wild-type spores. These studies suggest that BclA acts as a shield to not only reduce the ease with which spores germinate but also change the surface properties of the spore, which, in turn, may impede the interaction of the spore with host matrix substances. PMID- 17709409 TI - Role of CD14 in responses to clinical isolates of Escherichia coli: effects of K1 capsule expression. AB - Severe bacterial infections leading to sepsis or septic shock can be induced by bacteria that utilize different factors to drive pathogenicity and/or virulence, leading to disease in the host. One major factor expressed by all clinical isolates of gram-negative bacteria is lipopolysaccharide (LPS); a second factor expressed by some Escherichia coli strains is a K1 polysaccharide capsule. To determine the role of the CD14 LPS receptor in the pathogenic effects of naturally occurring E. coli, the responses of CD14-/- and CD14+/+ mice to three different isolates of E. coli obtained from sepsis patients were compared; two isolates express both smooth LPS and the K1 antigen, while the third isolate expresses only LPS and is negative for K1. An additional K1-positive isolate obtained from a newborn with meningitis and a K1-negative isogenic mutant of this strain were also used for these studies. CD14-/- mice were resistant to the lethal effects of the K1-negative isolates. This resistance was accompanied by significantly lower levels of systemic tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) in these mice than in CD14+/+ mice, enhanced clearance of the bacteria, and significantly fewer additional gross symptoms. In contrast, CD14-/- mice were as sensitive as CD14+/+ mice to the lethal effects of the K1 positive isolates, even though they had significantly lower levels of TNF-alpha and IL-6 than CD14+/+ mice. These studies show that different bacterial isolates can use distinctly different mechanisms to cause disease and suggest that new, nonantibiotic therapeutics need to be directed against multiple targets. PMID- 17709410 TI - In vitro and in vivo characterization of anthrax anti-protective antigen and anti lethal factor monoclonal antibodies after passive transfer in a mouse lethal toxin challenge model to define correlates of immunity. AB - Passive transfer of antibody may be useful for preexposure prophylaxis against biological agents used as weapons of terror, such as Bacillus anthracis. Studies were performed to evaluate the ability of anthrax antiprotective antigen (anti PA) and antilethal factor (anti-LF) neutralizing monoclonal antibodies (mAbs) to protect against an anthrax lethal toxin (LeTx) challenge in a mouse model and to identify correlates of immunity to LeTx challenge. Despite having similar affinities for their respective antigens, anti-PA (3F11) and anti-LF (9A11), passive transfer of up to 1.5 mg of anti-PA 3F11 mAb did not provide significant protection when transferred to mice 24 h before LeTx challenge, while passive transfer of as low as 0.375 mg of anti-LF 9A11 did provide significant protection. Serum collected 24 h after passive transfer had LeTx-neutralizing activity when tested using a standard LeTx neutralization assay, but neutralization titers measured using this assay did not correlate with protection against LeTx challenge. However, measurement of LeTx-neutralizing serum responses with an LeTx neutralization assay in vitro employing the addition of LeTx to J774A.1 cells 15 min before the addition of the serum did result in neutralization titers that correlated with protection against LeTx challenge. Our results demonstrate that only the LeTx neutralization titers measured utilizing the addition of LeTx to J774A.1 cells 15 min before the addition of sample correlated with protection in vivo. Thus, this LeTx neutralization assay may be a more biologically relevant neutralization assay to predict the in vivo protective capacity of LeTx-neutralizing antibodies. PMID- 17709411 TI - Identification and isolation of Brucella suis virulence genes involved in resistance to the human innate immune system. AB - Brucella strains are facultative intracellular pathogens that induce chronic diseases in humans and animals. This observation implies that Brucella subverts innate and specific immune responses of the host to develop its full virulence. Deciphering the genes involved in the subversion of the immune system is of primary importance for understanding the virulence of the bacteria, for understanding the pathogenic consequences of infection, and for designing an efficient vaccine. We have developed an in vitro system involving human macrophages infected by Brucella suis and activated syngeneic gamma9delta2 T lymphocytes. Under these conditions, multiplication of B. suis inside macrophages is only slightly reduced. To identify the genes responsible for this reduced sensitivity, we screened a library of 2,000 clones of transposon-mutated B. suis. For rapid and quantitative analysis of the multiplication of the bacteria, we describe a simple method based on Alamar blue reduction, which is compatible with screening a large library. By comparing multiplication inside macrophages alone and multiplication inside macrophages with activated gamma9delta2 T cells, we identified four genes of B. suis that were necessary to resist to the action of the gamma9delta2 T cells. The putative functions of these genes are discussed in order to propose possible explanations for understanding their exact role in the subversion of innate immunity. PMID- 17709412 TI - The surface protein Srr-1 of Streptococcus agalactiae binds human keratin 4 and promotes adherence to epithelial HEp-2 cells. AB - Streptococcus agalactiae is frequently the cause of bacterial sepsis and meningitis in neonates. In addition, it is a commensal bacterium that colonizes the mammalian gastrointestinal tract. During its commensal and pathogenic lifestyles, S. agalactiae colonizes and invades a number of host compartments, thereby interacting with different host proteins. In the present study, the serine-rich repeat protein Srr-1 from S. agalactiae was functionally investigated. Immunofluorescence microscopy showed that Srr-1 was localized on the surface of streptococcal cells. The Srr-1 protein was shown to interact with a 62-kDa protein in human saliva, which was identified by matrix-assisted laser desorption ionization-time-of-flight analysis as human keratin 4 (K4). Immunoblot and enzyme-linked immunosorbent assay experiments allowed us to narrow down the K4 binding domain in Srr-1 to a region of 157 amino acids (aa). Furthermore, the Srr-1 binding domain of K4 was identified in the C-terminal 255 aa of human K4. Deletion of the srr-1 gene in the genome of S. agalactiae revealed that this gene plays a role in bacterial binding to human K4 and that it is involved in adherence to epithelial HEp-2 cells. Binding to immobilized K4 and adherence to HEp-2 cells were restored by introducing the srr-1 gene on a shuttle plasmid into the srr-1 mutant. Furthermore, incubation of HEp-2 cells with the K4 binding domain of Srr-1 blocked S. agalactiae adherence to epithelial cells in a dose dependent fashion. This is the first report describing the interaction of a bacterial protein with human K4. PMID- 17709413 TI - Differential contribution of bacterial N-formyl-methionyl-leucyl- phenylalanine and host-derived CXC chemokines to neutrophil infiltration into pulmonary alveoli during murine pneumococcal pneumonia. AB - Despite the development of new potent antibiotics, Streptococcus pneumoniae remains the leading cause of death from bacterial pneumonia. Polymorphonuclear neutrophil (PMN) recruitment into the lungs is a primordial step towards host survival. Bacterium-derived N-formyl peptides (N-formyl-methionyl-leucyl phenylalanine [fMLP]) and host-derived chemokines (KC and macrophage inflammatory protein 2 [MIP-2]) are likely candidates among chemoattractants to coordinate PMN infiltration into alveolar spaces. To investigate the contribution of each in the context of pneumococcal pneumonia, CD1, BALB/c, CBA/ca, C57BL/6, and formyl peptide receptor (FPR)-knockout C57BL/6 mice were infected with 10(6) or 10(7) CFU of penicillin/erythromycin-susceptible or -resistant serotype 3 or 14 S. pneumoniae strains. Antagonists to the FPR, such as cyclosporine H (CsH) and chenodeoxycholic acid, or neutralizing antibodies to KC and MIP-2 were injected either 1 h before or 30 min after infection, and then bronchoalveolar lavage fluids were obtained for quantification of bacteria, leukocytes, and chemokines. CsH was effective over a short period after infection with a high inoculum, while anti-CXC chemokine antibodies were effective after challenge with a low inoculum. CsH prevented PMN infiltration in CD1 mice infected with either serotype 3 or 14, whereas antichemokine antibodies showed better efficacy against the serotype 3 strain. When different mouse strains were challenged with serotype 3 bacteria, CsH prevented PMN migration in the CD1 mice only, whereas the antibodies were effective against CD1 and C57BL/6 mice. Our results suggest that fMLP and chemokines play important roles in pneumococcal pneumonia and that these roles vary according to bacterial and host genetic backgrounds, implying redundancy among chemoattractant molecules. PMID- 17709414 TI - Expression of Helicobacter pylori virulence factors and associated expression profiles of inflammatory genes in the human gastric mucosa. AB - Helicobacter pylori virulence factors have been suggested to be important in determining the outcome of infection. The H. pylori adhesion protein BabA2 is thought to play a crucial role in bacterial colonization and in induction of severe gastric inflammation, particularly in combination with expression of CagA and VacA. However, the influence of these virulence factors on the pathogenesis of H. pylori infection is still poorly understood. To address this question, the inflammatory gene expression profiles for two groups of patients infected with triple-negative strains (lacking expression of cagA, babA2, and vacAs1 but expressing vacAs2) and triple-positive strains (expressing cagA, vacAs1, and babA2 but lacking expression of vacAs2) were investigated. The gene expression patterns in the antrum gastric mucosa from patients infected with different H. pylori strains were very similar, and no differentially expressed genes could be identified by pairwise comparisons. Our data thus suggest that there is a lack of correlation between the host inflammatory responses in the gastric mucosa and expression of the babA2, cagA, and vacAs1 genes. PMID- 17709415 TI - Two domains of cytotoxic necrotizing factor type 1 bind the cellular receptor, laminin receptor precursor protein. AB - Cytotoxic necrotizing factor type 1 (CNF1) and CNF2 are highly homologous toxins that are produced by certain pathogenic strains of Escherichia coli. These 1,014 amino-acid toxins catalyze the deamidation of a specific glutamine residue in RhoA, Rac1, and Cdc42 and consist of a putative N-terminal binding domain, a transmembrane region, and a C-terminal catalytic domain. To define the regions of CNF1 that are responsible for binding of the toxin to its cellular receptor, the laminin receptor precursor protein (LRP), a series of CNF1 truncated toxins were characterized and assessed for toxin binding. In particular, three truncated toxins, DeltaN63, DeltaN545, and DeltaC469, retained conformational integrity and in vitro enzymatic activity and were immunologically reactive against a panel of anti-CNF1 monoclonal antibodies (MAbs). Based on a comparison of these truncated toxins with wild-type CNF1 and CNF2 in LRP and HEp-2 cell binding assays and in MAb and LRP competitive binding inhibition assays and based on the results of confocal microscopy, we concluded that CNF1 contains two major binding regions: one located within the N terminus, which contained amino acids 135 to 164, and one which resided in the C terminus and included amino acids 683 to 730. The data further indicate that CNF1 can bind to an additional receptor(s) on HEp-2 cells and that LRP can also serve as a cellular receptor for CNF2. PMID- 17709417 TI - Antibody-mediated protection through cross-reactivity introduces a fungal heresy into immunological dogma. PMID- 17709416 TI - Chicken cecum immune response to Salmonella enterica serovars of different levels of invasiveness. AB - Day-old chicks are very susceptible to infections with Salmonella enterica subspecies. The gut mucosa is the initial site of host invasion and provides the first line of defense against the bacteria. To study the potential of different S. enterica serovars to invade the gut mucosa and trigger an immune response, day old chicks were infected orally with Salmonella enterica serovar Enteritidis, S. enterica serovar Typhimurium, S. enterica serovar Hadar, or S. enterica serovar Infantis, respectively. The localization of Salmonella organisms in gut mucosa and the number of immune cells in cecum were determined by immunohistochemistry in the period between 4 h and 9 days after infection. Using quantitative real time reverse transcription (RT)-PCR, mRNA expression of various cytokines, chemokines, and inducible nitric oxide synthase (iNOS) was examined in cecum. As a result, all S. enterica serovars were able to infect epithelial cells and the lamina propria. Notably, serovar Enteritidis showed the highest invasiveness of lamina propria tissue, whereas serovars Typhimurium and Hadar displayed moderate invasiveness and serovar Infantis hardly any invasion capabilities. Only a limited number of bacteria of all serovars were found within intestinal macrophages. Elevated numbers of granulocytes, CD8+ cells, and TCR1+ cells and mRNA expression rates for interleukin 12 (IL-12), IL-18, tumor necrosis factor alpha factor, and iNOS in cecum correlated well with the invasiveness of serovars in the lamina propria. In contrast, changes in numbers of TCR2+ and CD4+ cells and IL-2 mRNA expression seemed to be more dependent on infection of epithelial cells. The data indicate that the capability of Salmonella serovars to enter the cecal mucosa and invade lower regions affects both the level and character of the immune response in tissue. PMID- 17709418 TI - Analysis of the in vitro transcriptional response of human pharyngeal epithelial cells to adherent Streptococcus pneumoniae: evidence for a distinct response to encapsulated strains. AB - Infection of the human host by Streptococcus pneumoniae begins with colonization of the nasopharynx, which is mediated by the adherence of bacteria to the respiratory epithelium. Several studies have indicated an important role for the pneumococcal capsule in this process. Here, we used microarrays to characterize the in vitro transcriptional response of human pharyngeal epithelial Detroit 562 cells to the adherence of serotype 2 encapsulated strain D39, serotype 19F encapsulated strain G54, serotype 4 encapsulated strain TIGR4, and their nonencapsulated derivatives (Deltacps). In total, 322 genes were found to be upregulated in response to adherent pneumococci. Twenty-two genes were commonly induced, including those encoding several cytokines (e.g., interleukin 1beta [IL 1beta] and IL-6), chemokines (e.g., IL-8 and CXCL1/2), and transcriptional regulators (e.g., FOS), consistent with an innate immune response mediated by Toll-like receptor signaling. Interestingly, 85% of genes were induced specifically by one or more encapsulated strains, suggestive of a capsule dependent response. Importantly, purified capsular polysaccharides alone had no effect. Over a third of these loci encoded products predicted to be involved in transcriptional regulation and signal transduction, in particular mitogen activated protein kinase signaling pathways. Real-time PCR of a subset of 10 genes confirmed the microarray data and showed a time-dependent upregulation of, especially, innate immunity genes. The downregulation of epithelial genes was most pronounced upon adherence of D39Deltacps, as 68% of the 161 genes identified were repressed only by this nonencapsulated strain. In conclusion, we identified a subset of host genes specifically induced by encapsulated strains during in vitro adherence and have demonstrated the complexity of interactions occurring during the initial stages of pneumococcal infection. PMID- 17709419 TI - L-fucose stimulates utilization of D-ribose by Escherichia coli MG1655 DeltafucAO and E. coli Nissle 1917 DeltafucAO mutants in the mouse intestine and in M9 minimal medium. AB - Escherichia coli MG1655 uses several sugars for growth in the mouse intestine. To determine the roles of L-fucose and D-ribose, an E. coli MG1655 DeltafucAO mutant and an E. coli MG1655 DeltarbsK mutant were fed separately to mice along with wild-type E. coli MG1655. The E. coli MG1655 DeltafucAO mutant colonized the intestine at a level 2 orders of magnitude lower than that of the wild type, but the E. coli MG1655 DeltarbsK mutant and the wild type colonized at nearly identical levels. Surprisingly, an E. coli MG1655 DeltafucAO DeltarbsK mutant was eliminated from the intestine by either wild-type E. coli MG1655 or E. coli MG1655 DeltafucAO, suggesting that the DeltafucAO mutant switches to ribose in vivo. Indeed, in vitro growth experiments showed that L-fucose stimulated utilization of D-ribose by the E. coli MG1655 DeltafucAO mutant but not by an E. coli MG1655 DeltafucK mutant. Since the DeltafucK mutant cannot convert L fuculose to L-fuculose-1-phosphate, whereas the DeltafucAO mutant accumulates L fuculose-1-phosphate, the data suggest that L-fuculose-1-phosphate stimulates growth on ribose both in the intestine and in vitro. An E. coli Nissle 1917 DeltafucAO mutant, derived from a human probiotic commensal strain, acted in a manner identical to that of E. coli MG1655 DeltafucAO in vivo and in vitro. Furthermore, L-fucose at a concentration too low to support growth stimulated the utilization of ribose by the wild-type E. coli strains in vitro. Collectively, the data suggest that L-fuculose-1-phosphate plays a role in the regulation of ribose usage as a carbon source by E. coli MG1655 and E. coli Nissle 1917 in the mouse intestine. PMID- 17709420 TI - Mycobacterium tuberculosis-induced gamma interferon production by natural killer cells requires cross talk with antigen-presenting cells involving Toll-like receptors 2 and 4 and the mannose receptor in tuberculous pleurisy. AB - Tuberculous pleurisy allows the study of human cells at the site of active Mycobacterium tuberculosis infection. In this study, we found that among pleural fluid (PF) lymphocytes, natural killer (NK) cells are a major source of early gamma interferon (IFN-gamma) upon M. tuberculosis stimulation, leading us to investigate the mechanisms and molecules involved in this process. We show that the whole bacterium is the best inducer of IFN-gamma, although a high-molecular weight fraction of culture filtrate proteins from M. tuberculosis H37Rv and the whole-cell lysate also induce its expression. The mannose receptor seems to mediate the inhibitory effect of mannosylated lipoarabinomannan, and Toll-like receptor 2 and 4 agonists activate NK cells but do not induce IFN-gamma like M. tuberculosis does. Antigen-presenting cells (APC) and NK cells bind M. tuberculosis, and although interleukin-12 is required, it is not sufficient to induce IFN-gamma expression, indicating that NK cell-APC contact takes place. Indeed, major histocompatibility complex class I, adhesion, and costimulatory molecules as well as NK receptors regulate IFN-gamma induction. The signaling pathway is partially inhibited by dexamethasone and sensitive to Ca2+ flux and cyclosporine. Inhibition of p38 and extracellular-regulated kinase mitogen activated protein kinase pathways reduces the number of IFN-gamma+ NK cells. Phosphorylated p38 (p-p38) is detected in ex vivo PF-NK cells, and M. tuberculosis triggers p-p38 in PF-NK cells at the same time that binding between NK and M. tuberculosis reaches its maximum value. Thus, interplay between M. tuberculosis and NK cells/APC triggering IFN-gamma would be expected to play a beneficial role in tuberculous pleurisy by helping to maintain a type 1 profile. PMID- 17709421 TI - Contribution of the stg fimbrial operon of Salmonella enterica serovar Typhi during interaction with human cells. AB - Salmonella serovars contain a wide variety of putative fimbrial systems that may contribute to colonization of specific niches. Salmonella enterica serovar Typhi is the etiologic agent of typhoid fever and is a pathogen specific to humans. In a previous study, we identified a gene, STY3920 (stgC), encoding the predicted usher of the stg fimbrial operon, that was expressed by serovar Typhi during infection of human macrophages. The stg genes are located in the glmS-pstS intergenic region in serovar Typhi and certain Escherichia coli strains, but they are absent in other S. enterica serovars. We cloned the stg fimbrial operon into a nonfimbriate E. coli K-12 strain and into S. enterica serovar Typhimurium. We demonstrated that the stg fimbrial operon contributed to increased adherence to human epithelial cells. Transcriptional fusion assays with serovar Typhi suggested that stg is preferentially expressed in minimal medium. Deletion of stg reduced adherence of serovar Typhi to epithelial cells. However, deletion of stg increased uptake of serovar Typhi by human macrophages, and overexpression of stg in serovar Typhi and serovar Typhimurium strains reduced phagocytosis by human macrophages. These strains survived inside macrophages as well as the wild-type parent. Although the stgC gene contains a premature stop codon that disrupts the expected open reading frame encoding the usher and is therefore considered a pseudogene, our results show that the stg operon may encode a functional fimbria. Thus, this serovar Typhi-specific fimbrial operon contributes to interactions with host cells, and further characterization is important for understanding the role of the stg fimbrial cluster in typhoid fever pathogenesis. PMID- 17709422 TI - Nucleotide-binding oligomerization domain protein 2-deficient mice control infection with Mycobacterium tuberculosis. AB - Nucleotide-binding oligomerization domain proteins (NODs) are modular cytoplasmic proteins implicated in the recognition of peptidoglycan-derived molecules. NOD2 has recently been shown to be important for host cell cytokine responses to Mycobacterium tuberculosis, to synergize with Toll-like receptor 2 (TLR2) in mediating these responses, and thus to serve as a nonredundant recognition receptor for M. tuberculosis. Here, we demonstrate that macrophages and dendritic cells from NOD2-deficient mice were impaired in the production of proinflammatory cytokines and nitric oxide following infection with live, virulent M. tuberculosis. Mycolylarabinogalactan peptidoglycan (PGN), the cell wall core of M. tuberculosis, stimulated macrophages to release tumor necrosis factor (TNF) and interleukin-12p40 in a partially NOD2-dependent manner, and M. tuberculosis PGN required NOD2 for the optimal induction of TNF. However, NOD2-deficient mice were no more susceptible to infection with virulent M. tuberculosis than wild type mice: they controlled the replication of M. tuberculosis in lung, spleen, and liver as well as wild-type mice, and both genotypes displayed similar lung pathologies. In addition, mice doubly deficient for NOD2 and TLR2 were similarly able to control an M. tuberculosis infection. Thus, NOD2 appears to participate in the recognition of M. tuberculosis by antigen-presenting cells in vitro yet is dispensable for the control of the pathogen during in vivo infection. PMID- 17709424 TI - Mutations of the Igbeta gene cause agammaglobulinemia in man. AB - Agammaglobulinemia is a rare primary immunodeficiency characterized by an early block of B cell development in the bone marrow, resulting in the absence of peripheral B cells and low/absent immunoglobulin serum levels. So far, mutations in Btk, mu heavy chain, surrogate light chain, Igalpha, and B cell linker have been found in 85-90% of patients with agammaglobulinemia. We report on the first patient with agammaglobulinemia caused by a homozygous nonsense mutation in Igbeta, which is a transmembrane protein that associates with Igalpha as part of the preBCR complex. Transfection experiments using Drosophila melanogaster S2 Schneider cells showed that the mutant Igbeta is no longer able to associate with Igalpha, and that assembly of the BCR complex on the cell surface is abrogated. The essential role of Igbeta for human B cell development was further demonstrated by immunofluorescence analysis of the patient's bone marrow, which showed a complete block of B cell development at the pro-B to preB transition. These results indicate that mutations in Igbeta can cause agammaglobulinemia in man. PMID- 17709423 TI - Expansion and function of Foxp3-expressing T regulatory cells during tuberculosis. AB - Mycobacterium tuberculosis (Mtb) frequently establishes persistent infections that may be facilitated by mechanisms that dampen immunity. T regulatory (T reg) cells, a subset of CD4(+) T cells that are essential for preventing autoimmunity, can also suppress antimicrobial immune responses. We use Foxp3-GFP mice to track the activity of T reg cells after aerosol infection with Mtb. We report that during tuberculosis, T reg cells proliferate in the pulmonary lymph nodes (pLNs), change their cell surface phenotype, and accumulate in the pLNs and lung at a rate parallel to the accumulation of effector T cells. In the Mtb-infected lung, T reg cells accumulate in high numbers in all sites where CD4(+) T cells are found, including perivascular/peribronchiolar regions and within lymphoid aggregates of granulomas. To determine the role of T reg cells in the immune response to tuberculosis, we generated mixed bone marrow chimeric mice in which all cells capable of expressing Foxp3 expressed Thy1.1. When T reg cells were depleted by administration of anti-Thy1.1 before aerosol infection with Mtb, we observed approximately 1 log less of colony-forming units of Mtb in the lungs. Thus, after aerosol infection, T reg cells proliferate and accumulate at sites of infection, and have the capacity to suppress immune responses that contribute to the control of Mtb. PMID- 17709425 TI - Cross-competition of CD8+ T cells shapes the immunodominance hierarchy during boost vaccination. AB - CD8+ T cell responses directed against multiple pathogen-derived epitopes are characterized by defined immunodominance hierarchy patterns. A possible explanation for this phenomenon is that CD8+ T cells of different specificities compete for access to epitopes on antigen-presenting cells, and that the outcome of this so-called cross-competition reflects the number of induced T cells. In our study using a vaccinia virus infection model, we found that T cell cross competition is highly relevant during boost vaccination, thereby shaping the immunodominance hierarchy in the recall. We demonstrate that competition was of no importance during priming and was unaffected by the applied route of immunization. It strongly depended on the timing of viral antigen expression in infected APCs, and it was characterized by poor proliferation of T cells recognizing epitopes derived from late viral proteins. To our knowledge, this is the first demonstration of the functional importance of T cell cross-competition during a viral infection. Our findings provide a basis for novel strategies for how boost vaccination to defined antigens can be selectively improved. They give important new insights into the design of more efficient poxviral vectors for immunotherapy. PMID- 17709426 TI - BubR1 and APC/EB1 cooperate to maintain metaphase chromosome alignment. AB - The accurate segregation of chromosomes in mitosis requires the stable attachment of microtubules to kinetochores. The details of this complex and dynamic process are poorly understood. In this study, we report the interaction of a kinetochore associated mitotic checkpoint kinase, BubR1, with two microtubule plus end associated proteins, adenomatous polyposis coli (APC) and EB1, providing a potential link in stable kinetochore microtubule attachment. Using immunodepletion from and antibody addition to Xenopus laevis egg extracts, we show that BubR1 and its kinase activity are essential for positioning chromosomes at the metaphase plate. BubR1 associates with APC and EB1 in egg extracts, and the complex formation is necessary for metaphase chromosome alignment. Using purified components, BubR1 directly phosphorylates APC and forms a ternary complex with APC and microtubules. These findings support a model in which BubR1 kinase may directly regulate APC function involved in stable kinetochore microtubule attachment. PMID- 17709427 TI - Two distinct arginine methyltransferases are required for biogenesis of Sm-class ribonucleoproteins. AB - Small nuclear ribonucleoproteins (snRNPs) are core components of the spliceosome. The U1, U2, U4, and U5 snRNPs each contain a common set of seven Sm proteins. Three of these Sm proteins are posttranslationally modified to contain symmetric dimethylarginine (sDMA) residues within their C-terminal tails. However, the precise function of this modification in the snRNP biogenesis pathway is unclear. Several lines of evidence suggest that the methyltransferase protein arginine methyltransferase 5 (PRMT5) is responsible for sDMA modification of Sm proteins. We found that in human cells, PRMT5 and a newly discovered type II methyltransferase, PRMT7, are each required for Sm protein sDMA modification. Furthermore, we show that the two enzymes function nonredundantly in Sm protein methylation. Lastly, we provide in vivo evidence demonstrating that Sm protein sDMA modification is required for snRNP biogenesis in human cells. PMID- 17709428 TI - Maintaining the proper connection between the centrioles and the pericentriolar matrix requires Drosophila centrosomin. AB - Centrosomes consist of two centrioles surrounded by an amorphous pericentriolar matrix (PCM), but it is unknown how centrioles and PCM are connected. We show that the centrioles in Drosophila embryos that lack the centrosomal protein Centrosomin (Cnn) can recruit PCM components but cannot maintain a proper attachment to the PCM. As a result, the centrioles "rocket" around in the embryo and often lose their connection to the nucleus in interphase and to the spindle poles in mitosis. This leads to severe mitotic defects in embryos and to errors in centriole segregation in somatic cells. The Cnn-related protein CDK5RAP2 is linked to microcephaly in humans, but cnn mutant brains are of normal size, and we observe only subtle defects in the asymmetric divisions of mutant neuroblasts. We conclude that Cnn maintains the proper connection between the centrioles and the PCM; this connection is required for accurate centriole segregation in somatic cells but is not essential for the asymmetric division of neuroblasts. PMID- 17709429 TI - OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. AB - OPA1, a dynamin-related guanosine triphosphatase mutated in dominant optic atrophy, is required for the fusion of mitochondria. Proteolytic cleavage by the mitochondrial processing peptidase generates long isoforms from eight messenger RNA (mRNA) splice forms, whereas further cleavages at protease sites S1 and S2 generate short forms. Using OPA1-null cells, we developed a cellular system to study how individual OPA1 splice forms function in mitochondrial fusion. Only mRNA splice forms that generate a long isoform in addition to one or more short isoforms support substantial mitochondrial fusion activity. On their own, long and short OPA1 isoforms have little activity, but, when coexpressed, they functionally complement each other. Loss of mitochondrial membrane potential destabilizes the long isoforms and enhances the cleavage of OPA1 at S1 but not S2. Cleavage at S2 is regulated by the i-AAA protease Yme1L. Our results suggest that mammalian cells have multiple pathways to control mitochondrial fusion through regulation of the spectrum of OPA1 isoforms. PMID- 17709430 TI - Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. AB - The dynamin-related protein Opa1 is localized to the mitochondrial intermembrane space, where it facilitates fusion between mitochondria. Apoptosis causes Opa1 release into the cytosol and causes mitochondria to fragment. Loss of mitochondrial membrane potential also causes mitochondrial fragmentation but not Opa1 release into the cytosol. Both conditions induce the proteolytic cleavage of Opa1, suggesting that mitochondrial fragmentation is triggered by Opa1 inactivation. The opposite effect was observed with knockdown of the mitochondrial intermembrane space protease Yme1. Knockdown of Yme1 prevents the constitutive cleavage of a subset of Opa1 splice variants but does not affect carbonyl cyanide m-chlorophenyl hydrazone or apoptosis-induced cleavage. Knockdown of Yme1 also increases mitochondrial connectivity, but this effect is independent of Opa1 because it also occurs in Opa1 knockdown cells. We conclude that Yme1 constitutively regulates a subset of Opa1 isoforms and an unknown mitochondrial morphology protein, whereas the loss of membrane potential induces the further proteolysis of Opa1. PMID- 17709432 TI - Nutrition, an under-recognized factor in bacterial vaginosis. PMID- 17709431 TI - Neurofascin assembles a specialized extracellular matrix at the axon initial segment. AB - Action potential initiation and propagation requires clustered Na(+) (voltage gated Na(+) [Nav]) channels at axon initial segments (AIS) and nodes of Ranvier. In addition to ion channels, these domains are characterized by cell adhesion molecules (CAMs; neurofascin-186 [NF-186] and neuron glia-related CAM [NrCAM]), cytoskeletal proteins (ankyrinG and betaIV spectrin), and the extracellular chondroitin-sulfate proteoglycan brevican. Schwann cells initiate peripheral nervous system node formation by clustering NF-186, which then recruits ankyrinG and Nav channels. However, AIS assembly of this protein complex does not require glial contact. To determine the AIS assembly mechanism, we silenced expression of AIS proteins by RNA interference. AnkyrinG knockdown prevented AIS localization of all other AIS proteins. Loss of NF-186, NrCAM, Nav channels, or betaIV spectrin did not affect other neuronal AIS proteins. However, loss of NF-186 blocked assembly of the brevican-based AIS extracellular matrix, and NF-186 overexpression caused somatodendritic brevican clustering. Thus, NF-186 assembles and links the specialized brevican-containing AIS extracellular matrix to the intracellular cytoskeleton. PMID- 17709433 TI - Dietary oleic and palmitic acids modulate the ratio of triacylglycerols to cholesterol in postprandial triacylglycerol-rich lipoproteins in men and cell viability and cycling in human monocytes. AB - The postprandial metabolism of dietary fats produces triacylglycerol (TG)-rich lipoproteins (TRL) that could interact with circulating cells. We investigated whether the ratios of oleic:palmitic acid and monounsaturated fatty acids (MUFA):SFA in the diet affect the ratio of TG:cholesterol (CHOL) in postprandial TRL of healthy men. The ability of postprandial TRL at 3 h (early postprandial period) and 5 h (late postprandial period) to affect cell viability and cycle in the THP-1 human monocytic cell line was also determined. In a randomized, crossover experiment, 14 healthy volunteers (Caucasian men) ate meals enriched (50 g/m(2) body surface area) in refined olive oil, high-palmitic sunflower oil, butter, and a mixture of vegetable and fish oils, which had ratios of oleic:palmitic acid (MUFA:SFA) of 6.83 (5.43), 2.36 (2.42), 0.82 (0.48), and 13.81 (7.08), respectively. The ratio of TG:CHOL in postprandial TRL was inversely correlated (r = -0.89 to -0.99) with the ratio of oleic:palmitic acid and with the MUFA:SFA ratio in the dietary fats (P < 0.05). Postprandial TRL at 3 h preferentially increased the proportion of necrotic cells, whereas postprandial TRL at 5 h increased the proportion of apoptotic cells (P < 0.05). Cell cycle analysis showed that postprandial TRL blocked the human monocytes in S-phase. Our findings suggest that the level of TG and CHOL into postprandial TRL is associated with the ratios of oleic:palmitic acid and MUFA:SFA in dietary fats, which determines the ability of postprandial TRL to induce cytotoxicity and disturb the cell cycle in THP-1 cells. PMID- 17709435 TI - Whole blood NAD and NADP concentrations are not depressed in subjects with clinical pellagra. AB - Population surveys for niacin deficiency are normally based on clinical signs or on biochemical measurements of urinary niacin metabolites. Status may also be determined by measurement of whole blood NAD and NADP concentrations. To compare these methods, whole blood samples and spot urine samples were collected from healthy subjects (n = 2) consuming a western diet, from patients (n = 34) diagnosed with pellagra and attending a pellagra clinic in Kuito (central Angola, where niacin deficiency is endemic), and from female community control subjects (n = 107) who had no clinical signs of pellagra. Whole blood NAD and NADP concentrations were measured by microtiter plate-based enzymatic assays and the niacin urinary metabolites 1-methyl-2-pyridone-5-carboxamide (2-PYR) and 1 methylnicotinamide (1-MN) by HPLC. In healthy volunteers, inter- and intra-day variations for NAD and NADP concentrations were much lower than for the urinary metabolites, suggesting a more stable measure of status. However, whole blood concentrations of NAD and NADP or the NAD:NADP ratio were not significantly depressed in clinical pellagra. In contrast, the concentrations of 2-PYR and 1 MN, expressed relative to either creatinine or osmolality, were lower in pellagra patients and markedly higher following treatment. The use of the combined cut offs (2-PYR <3.0 micromol/mmol creatinine and 1-MN <1.3 micromol/mmol creatinine) gave a sensitivity of 91% and specificity of 72%. In conclusion, whole blood NAD and NADP concentrations gave an erroneously low estimate of niacin deficiency. In contrast, spot urine sample 2-PYR and 1-MN concentrations, relative to creatinine, were a sensitive and specific measure of deficiency. PMID- 17709434 TI - Feeding Drosophila a biotin-deficient diet for multiple generations increases stress resistance and lifespan and alters gene expression and histone biotinylation patterns. AB - Energy restriction increases stress resistance and lifespan in Drosophila melanogaster and other species. The roles of individual nutrients in stress resistance and longevity are largely unknown. The vitamin biotin is a potential candidate for mediating these effects, given its known roles in stress signaling and gene regulation by epigenetic mechanisms, i.e. biotinylation of histones. Here, we tested the hypothesis that prolonged culture of Drosophila on biotin deficient (BD) medium increases stress resistance and lifespan. Flies were fed a BD diet for multiple generations; controls were fed a biotin-normal diet. In some experiments, a third group of flies was fed a BD diet for 12 generations and then switched to control diets for 2 generations to eliminate potential effects of short-term biotin deficiency. Flies fed a BD diet exhibited a 30% increase in lifespan. This increase was associated with enhanced resistance to the DNA damaging agent hydroxyurea and heat stress. Also, fertility increased significantly compared with biotin-normal controls. Biotinylation of histones was barely detectable in biotin-deprived flies, suggesting that epigenetic events might have contributed to effects of biotin deprivation. PMID- 17709436 TI - Thermally oxidized oil increases the expression of insulin-induced genes and inhibits activation of sterol regulatory element-binding protein-2 in rat liver. AB - Administration of oxidized oils to rats or pigs causes a reduction of their cholesterol concentrations in liver and plasma. The reason for this effect is unknown. We tested the hypothesis that oxidized oils lower cholesterol concentrations by inhibiting the proteolytic activation of sterol regulatory element-binding protein (SREBP)-2 in the liver and transcription of its target genes involved in cholesterol synthesis and uptake through an upregulation of gene expression of insulin-induced genes (Insig). For 6 d, 18 rats were orally administered either sunflower oil (control group) or an oxidized oil prepared by heating sunflower oil. Rats administered the oxidized oil had higher messenger RNA (mRNA) concentrations of acyl-CoA oxidase and cytochrome P450 4A1 in the liver than control rats (P < 0.05), indicative of activation of PPARalpha. Furthermore, rats administered the oxidized oil had higher mRNA concentrations of Insig-1 and Insig-2a, a lower concentration of the mature SREBP-2 in the nucleus, lower mRNA concentrations of the SREBP-2 target genes 3-hydroxy-3-methylglutaryl CoA reductase and LDL receptor in their livers, and a lower concentration of cholesterol in liver, plasma, VLDL, and HDL than control rats (P < 0.05). In conclusion, this study shows that reduced cholesterol concentrations in liver and plasma of rats administered an oxidized oil were due to an inhibition of the activation of SREBP-2 by an upregulation of Insig, which in turn inhibited transcription of proteins involved in hepatic cholesterol synthesis and uptake. PMID- 17709437 TI - An apolipoprotein A-II polymorphism (-265T/C, rs5082) regulates postprandial response to a saturated fat overload in healthy men. AB - Apolipoprotein (Apo) A-II is an apolipoprotein with an unknown role in lipid metabolism. It has been suggested that the presence of the less frequent allele of a single nucleotide polymorphism (Apo A-II -265T/C, rs5082) reduces the transcription rate of Apo A-II and enhances VLDL postprandial clearance in middle aged men. To further investigate the role of Apo A-II -265T/C on lipid metabolism, we studied 88 normolipidemic young men. The participants were given a fatty meal containing 1 g fat and 7 mg cholesterol/kg weight and capsules containing 60,000 IU vitamin A (retinyl palmitate, 15.15 mg RE) per square meter body surface area. Postprandial lipemia was assessed during the 11 h following the meal. Total cholesterol (Chol) and triacylglycerols (TG) in plasma and TG rich lipoproteins (TRL) (large TRL and small TRL) were measured, as well as HDL, Apo A-I, Apo B, Apo B-48, and Apo B-100. Postprandial responses were higher in the TT group than in carriers of the minor allele (CC/TC) for total TG in plasma (21.37% of change of area under curve, P = 0.014), large TRL-TG (24.75% change, P = 0.017) and small TRL-Chol (26.63% change, P = 0.003). Our work shows that carriers of the minor allele for Apo A-II -265T/C (CC/TC) have a lower postprandial response compared with TT homozygotes. This finding may partially explain the role of Apo A-II in lipid metabolism and can identify a population with a decreased risk of cardiovascular disease, as corresponds to the lower level of postprandial hypertriglyceridemia. PMID- 17709438 TI - Consumption of soy protein isolate modulates the phosphorylation status of hepatic ATPase/ATP synthase beta protein and increases ATPase activity in rats. AB - ATPase/ATP synthase plays important roles in the regulation of carbohydrate, protein, and lipid metabolism through modulating energy homeostasis. The purpose of this study was to examine the effects of feeding soy proteins and isoflavones (ISF) on the enzymatic activity and protein modification of hepatic mitochondrial ATPase/ATP synthase. In Expt. 1, Sprague-Dawley rats aged 50 d were fed diets containing either 20% casein or 20% alcohol-washed soy protein isolate (SPI) with or without supplemental ISF (770.7 micromol/kg diet) for 70 d. In Expt. 2, weanling Sprague-Dawley rats were fed diets containing 20% casein with or without added ISF (154.1 micromol/kg diet) or 20% SPI for 90 d. Hepatic mitochondrial ATPase activity was significantly higher in the rats fed SPI than in those fed casein. Addition of ISF to SPI eliminated the action of SPI. ATPase/ATP synthase beta protein contents in the liver were unchanged; however, its patterns measured by 2-dimensional Western blot were different among dietary groups. The rats fed SPI or SPI plus ISF had 3 more major protein spots with the same molecular weights (80 kDa and 55 kDa) as those presented in the rats fed casein but with different isoelectric points. Pretreatment of hepatic mitochondrial proteins from the rats fed casein with alkaline phosphatase produced the same ATPase/ATP synthase beta patterns as observed in the SPI-fed rats and significantly elevated the ATPase activity. These results suggest that consumption of soy proteins increases hepatic ATPase activity, which might be a consequence of increased dephosphorylation or decreased phosphorylation of the mitochondrial ATPase/ATP synthase beta protein. PMID- 17709439 TI - Changes in mitochondrial DNA deletion, content, and biogenesis in folate deficient tissues of young rats depend on mitochondrial folate and oxidative DNA injuries. AB - We aimed to characterize folate-related changes in mitochondrial (mt) DNA of various tissues of young rats. Weaning Wistar rats were fed folate-deficient (FD) or folate-replete (control) diet for 2 or 4 wk. The mtDNA 4834-bp large deletion (mtDNA(4834) deletion) and mtDNA content were analyzed by quantitative real-time PCR. Compared with pooled 2-wk and 4-wk control groups, 4-wk folate deprivation significantly increased the frequency of the mtDNA(4834) deletion in pancreas, heart, brain, liver, and kidney and reduced mtDNA contents in brain, heart, and liver (P < 0.05). Decreased mt folate levels were correlated with increased mtDNA(4834) deletion frequency in tissues from FD rats after 2 wk (r = -0.380, P = 0.001) and 4 wk FD (r = -0.275, P = 0.033) and with reduced mtDNA content after 4 wk (r = 0.513, P = 0.005). In liver of 4-wk FD rats, the accumulated mtDNA large deletions and decline in mtDNA accompanied increased expressions of messenger RNAs (mRNA) of factors that regulate mtDNA proliferation and transcription, including nuclear respiratory factor 1, mt transcriptional factor A, mt single-strand DNA-binding protein, and mt polymerase r. In parallel, expression of mRNA for nuclear-encoded cytochrome c oxidase subunits (CcOX) IV, V, cytochrome c, and mtDNA-encoded CcOX III increased significantly. This enhanced mt biogenesis in 4-wk FD liver coincided with an elevated ratio of 8 hydroxydeoxyguanosine (8-OHdG):deoxyguanosine (dG) (2.67 +/- 1.41) relative to the controls (0.99 +/- 0.36; P = 0.0002). The 8-OHdG:dG levels in FD liver were correlated with liver mt folate (r = -0.819, P < 0.001), mtDNA deletions (r = 0.580, P = 0.001), and mtDNA contents (r = -0.395, P = 0.045). Thus, folate deprivation induced aberrant changes of mtDNA(4834) deletion and mtDNA content in a manner that was dependent on mt folate and oxidative DNA injuries. The folate related mt biogenesis provides a molecular mechanism to compensate mtDNA impairment in FD tissues. PMID- 17709441 TI - Differential tissue dose responses of (n-3) and (n-6) PUFA in neonatal piglets fed docosahexaenoate and arachidonoate. AB - Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are commonly added to infant formula worldwide; however, dietary concentrations needed to obtain optimal tissue levels have not been established. Hence, we studied tissue responses in piglets fed various doses of DHA and ARA. Doses were 0, 1, 2, and 5 times those used in U.S. infant formulas and DHA/ARA in Diet 0, Diet 1, Diet 2, and Diet 5 were 0, 4.1/8.1, 8.1/16.2, and 20.3/40.6 mg/100 kJ formula, respectively. Supplementation of dietary DHA and ARA increased DHA in brain, retina, liver, adipose tissue, plasma, and erythrocyte by 1.1- to 25.8-fold of Diet 0 (P-trend < 0.01). Tissue ARA (1.1- to 6.0-fold of Diet 0) responded to dietary ARA in liver, adipose tissue, plasma, and erythrocytes (P-trend < 0.05); brain and retina ARA was, however, unresponsive to dietary DHA and ARA. Plasma and erythrocyte DHA were positively associated with DHA in neural (brain and retina) and visceral (liver and adipose) tissues (r(2) = 0.11-0.56; P < 0.001-P = 0.042). Plasma and erythrocyte ARA did not correlate with neural ARA. Only plasma ARA was associated with liver ARA (r(2) = 0.222; P = 0.02) and adipose ARA (r(2) = 0.867; P < 0.001) and erythrocyte ARA correlated with adipose ARA (r(2) = 0.470; P < 0.001). We conclude that dietary DHA supplementation affords an effective strategy for enhancing tissue DHA, ARA in visceral but not neural tissues is sensitive to dietary ARA, and erythrocyte and plasma DHA can be used as proxies for tissue DHA, although blood-borne ARA is not an indicator of neural ARA. PMID- 17709440 TI - Protocatechuic acid is the major human metabolite of cyanidin-glucosides. AB - The metabolic fate of dietary anthocyanins (ACN) has not been fully clarified in humans. In all previous studies, the proportion of total ACN absorbed and excreted in urine was <1% intake. This study aimed to elucidate the human metabolism of cyanidin-glucosides (CyG) contained in blood orange juice (BOJ). One liter of BOJ, containing 71 mg CyG, was consumed by 6 healthy, fasting volunteers. Blood, urine, and fecal samples were collected at baseline and at different times up to 24 h after juice consumption. The content of native CyG, glucuronidated/methylated derivatives, and various phenolic acids was determined by HPLC/MS/MS. The serum maximal concentration of cyanidin-3-glucoside (Cy-3-glc) was 1.9 +/- 0.6 nmol/L and that of protocatechuic acid (PCA) was 492 +/- 62 nmol/L at 0.5 h and 2 h after juice consumption, respectively. The calculated total amounts in plasma corresponded for Cy-3-glc to 0.02% and for PCA to 44% of CyG ingested. CyG and glucuronidated/methylated metabolites, but not PCA, were detected in urine. ACN recovered in 24-h urine collections represented approximately 1.2% of the ingested dose. Both CyG (1.90 +/- 0.04 nmol/g) and PCA (277 +/- 0.2 nmol/g) were recovered in 24-h fecal samples. Data explained the metabolic fate of 74% of BOJ ACN. PCA was for the first time, to our knowledge, identified in humans as a CyG metabolite, accounting for almost 73% of ingested CyG. A high concentration of PCA may explain the short-term increased plasma antioxidant activity observed after intake of cyanidin-rich food and it can also contribute to the numerous health benefits attributed to dietary ACN consumption. PMID- 17709442 TI - Oxidized fat reduces milk triacylglycerol concentrations by inhibiting gene expression of lipoprotein lipase and fatty acid transporters in the mammary gland of rats. AB - Feeding oxidized fats to lactating rats causes a strong reduction of triacylglycerol concentration in the milk. The reason for this, however, has not yet been elucidated. Pregnant Sprague-Dawley rats were assigned to 2 groups of 11 rats each and fed diets containing either fresh fat (FF group) or an oxidized fat (OF group) from d 1 to d 20 of lactation. Concentrations of triacylglycerols and long-chain fatty acids in the milk and weight gain of suckling pups were lower in the OF group than in the FF group (P < 0.05). Concentrations of medium-chain fatty acids in the milk and messenger RNA (mRNA) abundance of lipogenic enzymes in the mammary gland did not differ between the 2 groups of rats. However, the OF group had a lower concentration of triacylglycerols and nonesterified fatty acids (NEFA) in plasma and lower mRNA concentrations of lipoprotein lipase and fatty acid transporters in the mammary gland than the FF group (P < 0.05). Moreover, the OF group had higher mRNA concentrations of hepatic lipase, fatty acid transporters, and several genes involved in fatty acid oxidation in the liver than the FF group (P < 0.05). The present findings suggest that a dietary oxidized fat lowers the concentration of triacylglycerols in the milk by a reduced uptake of fatty acids from triacylglycerol rich-lipoproteins and NEFA into the mammary gland. The study, moreover, indicates that an oxidized fat impairs normal metabolic adaptations during lactation, which promote the utilization of metabolic substrates by the mammary gland for the synthesis of milk. PMID- 17709443 TI - LDL-receptor mRNA expression in men is downregulated within an hour of an acute fat load and is influenced by genetic polymorphism. AB - Little is known about the immediate effects of dietary fat on the expression of genes involved in cholesterol metabolism in humans. We investigated the effects of a high-fat meal on circulating mononuclear cell messenger RNA (mRNA) for the LDL receptor (LDLR), LDLR-related protein (LRP), and 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) over 10 h. Selection of 12 C and 7 T homozygotes for the LRP exon 22 C200T polymorphism for the study also enabled us to examine the influence of this polymorphism on postprandial mRNA expression and lipoproteins, of relevance because of LRP's role in postprandial lipoprotein metabolism and association of the polymorphism with coronary artery disease. We found a postprandial decrease in LDLR mRNA abundance relative to the reference beta-actin (BA) mRNA. The decreased LDLR/BA mRNA value was apparent at 1 h (P < 0.005) and decreased to 25% of baseline at 6 h (P < 0.005). The LRP/BA mRNA value was also lower at 6 h (16% decrease, P < 0.05). HMGCR mRNA expression was unchanged. C homozygotes for the C200T polymorphism had higher LDLR/BA values than T homozygotes (P = 0.01) and although plasma LDL cholesterol (LDL-C) concentrations decreased in the postprandial period (P < 0.002), the decrease was less in C than in T homozygotes (P < 0.05). This study constitutes the first observation, to our knowledge, of postprandial changes in LDLR and LRP mRNA expression. It documents immediate effects of a fatty meal on these mRNA as well as an LRP genotype effect on LDLR mRNA and LDL-C. PMID- 17709444 TI - Isoflavones at concentrations present in soy infant formula inhibit rotavirus infection in vitro. AB - Rotavirus (RV) infections are a major cause of acute gastroenteritis in children and domestic animals, infecting virtually all children within their first 5 y of life. Infants consuming soy-based infant formula (SBIF) are exposed to high levels of isoflavones that exhibit antiviral activity on numerous viruses in vitro and in vivo. Thus, the hypothesis that isoflavones would inhibit RV infection was tested. All isoflavones at SBIF concentrations were tested individually and as a mixture (MIX). Virus infectivity was assessed in MA-104 cells using a focus forming unit assay. Genistin and MIX significantly reduced RV infectivity by 33-62% and 66-74%, respectively, compared with the control and across a wide range of RV concentrations. When tested without genistin, the MIX lost its anti-RV activity, suggesting that genistin is the biologically active isoflavone in our model. In a dose response assay, genistin significantly reduced RV infectivity at a concentration as low as 30 mumol/L. We investigated several possible mechanisms of action. Isoflavones decreased RV infectivity by modulating virion attachment to the host cells and by modulating a postbinding step. Isoflavones did not alter RV triple-layered structure and genistin did not act through inhibition of protein tyrosine kinases and topoisomerase II or by mimicking the effect of estrogens. To our knowledge, this is the first study showing the inhibition of RV infectivity by isoflavones present in SBIF. The modulation of SBIF isoflavone composition and concentration represents novel nutritional approaches to potentially reduce the severity of RV infection in human and production animals. PMID- 17709445 TI - Acute oral leucine administration stimulates protein synthesis during chronic sepsis through enhanced association of eukaryotic initiation factor 4G with eukaryotic initiation factor 4E in rats. AB - Sepsis induces the loss of muscle proteins by impairing skeletal muscle protein synthesis through an inhibition of messenger RNA (mRNA) translation initiation. Amino acids and Leu (Leu) in particular stimulate mRNA translation initiation. The experiments were designed to test the effects of Leu on potential signal transduction pathways that may be important in accelerating mRNA translation initiation in skeletal muscle of rats with chronic (5-6 d) septic intra-abdominal abscess. Gastrocnemius from male Sprague Dawley rats gavaged with Leu or water were sampled 5-6 d following development of an intra-abdominal sterile or septic abscess. Gavage with Leu stimulated protein synthesis and enhanced the assembly of the active eukaryotic initiation factor (eIF)4G-eIF4E complex. Increased assembly of the active eIF4G-eIF4E complex was associated with a robust rise in phosphorylation of eIF4G(Ser(1108)) and a decreased assembly of inactive eIF4E binding protein-1 (4E-BP1)-eIF4E complex in both sterile inflammatory and septic rats. The reduced assembly of 4E-BP1-eIF4E complex was associated with an increase in phosphorylation of 4E-BP1 in the gamma-form following Leu gavage. Phosphorylation of 70-kDa ribosomal protein S6 kinase on Thr(389) was also increased following Leu gavage, as well as the phosphorylation of mammalian target of rapamycin on Ser(2448) or Ser(2481). In contrast, phosphorylation of protein kinase B (PKB) on Thr(308) or Ser(473) was not augmented following Leu gavage in septic rats. We conclude that Leu stimulates a PKB-independent signal pathway elevating the eIF4G-eIF4E complex assembly through increased phosphorylation of eIF4G and decreased association of 4E-BP1 with eIF4E in skeletal muscle during sepsis. PMID- 17709446 TI - Low dietary boron reduces parasite (nematoda) survival and alters cytokine profiles but the infection modifies liver minerals in mice. AB - Although boron (B) is an essential trace mineral, any interactions that it may have with gastrointestinal (GI) nematode infections are unknown. This study explored whether low dietary B would: 1) alter survival or reproduction of Heligmosomoides bakeri (Nematoda); 2) modify the resulting cytokine response to this parasitic infection; or 3) influence liver mineral concentrations in the infected host. Balb/c mice were fed either a low-B (0.2 microg B/g), marginal (2.0 microg B/g), or control (12.0 microg B/g) diet. Diets commenced 3 wk before a primary infection and were fed for 4 wk (primary infection protocol) and 8-9 wk (challenge infection protocol). Mice were killed 6 d post-primary infection (d6ppi), or dewormed then reinfected (challenge infection protocol) and killed 14 or 21 d post-challenge infection (d14pci or d21pci, respectively). Low and marginal dietary B intakes impaired survival of the parasite, reduced intestinal inflammation, and modulated a broad range of cytokines and chemokines despite similar liver B concentrations in diet groups. Compared with control mice, cytokine production was lower following low and marginal B intakes at d6ppi but was elevated at d21pci. Serum alkaline phosphatase was higher at d6ppi than at d14pci and d21pci. Compared with d14pci, liver zinc, iron, and B concentrations were reduced at d21pci when worm numbers were also lower, whereas concentrations of sodium, potassium, molybdenum, chromium, and sulfur were higher. This study shows that parasite survival and cytokine and inflammatory responses are modified by dietary B intake but indicates that a GI nematode infection alters liver mineral concentrations. PMID- 17709447 TI - Maternal food insecurity is associated with increased risk of certain birth defects. AB - Food insecurity represents a lack of access to enough food to meet basic needs. We hypothesized that food insecurity may increase birth defect risks, because it is an indicator of increased stress or compromised nutrition, which are both implicated in birth defect etiologies. This study used population-based case control data. Included in the analysis were 1,189 case mothers and 695 control mothers who were interviewed by telephone. We calculated a food insecurity score as the number of affirmative responses to 5 questions from a shortened instrument designed to measure food insecurity. OR for the food insecurity score specified as a linear term indicated that a higher score was associated with increased risk of cleft palate, d-transposition of the great arteries, tetralogy of Fallot, spina bifida, and anencephaly, but not with cleft lip with or without cleft palate, after adjustment for maternal race-ethnicity, education, BMI, intake of folic acid-containing supplements, dietary intake of folate and energy, neighborhood crime, and stressful life events. In addition, several models suggested effect modification by certain factors. For example, for anencephaly, among women with the worst score for neighborhood crime (i.e. 6), the OR associated with a 1-unit change in the food insecurity score was 1.57 (95% CI 1.06, 2.33), whereas among women with a low crime score (i.e. 2), the corresponding OR was 1.16 (95% CI 0.96, 1.38). This study suggests that increased risks of certain birth defects may be included among the negative consequences of food insecurity. PMID- 17709448 TI - Plasma homocysteine is associated with the risk of mild cognitive impairment in an elderly Korean population. AB - Elderly individuals with mild cognitive impairment (MCI) are at high risk for developing dementia, including Alzheimer's disease. Previous studies have proposed that elevated plasma homocysteine might be a risk factor for dementia. However, the impact of plasma homocysteine on MCI remains controversial. We investigated the relation between hyperhomocysteinemia and the risk of MCI in an elderly Korean population. A total of 1215 elderly subjects (aged 60-85 y) were selected from the Ansan Geriatric study to participate in this study. MCI was diagnosed on the basis of the Mayo Clinic criteria. Mean plasma homocysteine concentrations were higher in elderly subjects with MCI than in normal elderly subjects (17.6 +/- 7.4 vs. 15.7 +/- 4.8 micromol/L; P < 0.001). Subjects with hyperhomocysteinemia (>15 micromol/L) also had a higher prevalence of MCI. The unadjusted OR for MCI was greater in subjects with hyperhomocysteinemia than in normal subjects and it increased according to the degree of hyperhomocysteinemia (OR = 1.39; 95% CI = 1.09-1.79 vs. OR = 2.61; 95% CI = 1.22-5.61). These trends did not differ after adjustment for age, sex, and other putative risk factors for cognitive dysfunction (OR = 1.40; 95% CI = 1.07-1.83 vs. OR = 2.40; 95% CI = 1.08 5.31). In conclusion, hyperhomocysteinemia may be an independent risk factor for MCI in elderly Koreans. A causal relationship between plasma homocysteine levels and cognitive impairment should be evaluated in a follow-up study of elderly Korean subjects. PMID- 17709449 TI - Antioxidant supplementation increases the risk of skin cancers in women but not in men. AB - This research aimed to test whether supplementation with a combination of antioxidant vitamins and minerals could reduce the risk of skin cancers (SC). It was performed within the framework of the Supplementation in Vitamins and Mineral Antioxidants study, a randomized, double-blinded, placebo-controlled, primary prevention trial testing the efficacy of nutritional doses of antioxidants in reducing incidence of cancer and ischemic heart disease in the general population. French adults (7876 women and 5141 men) were randomized to take an oral daily capsule of antioxidants (120 mg vitamin C, 30 mg vitamin E, 6 mg beta carotene, 100 microg selenium, and 20 mg zinc) or a matching placebo. The median time of follow-up was 7.5 y. A total of 157 cases of all types of SC were reported, from which 25 were melanomas. Because the effect of antioxidants on SC incidence varied according to gender, men and women were analyzed separately. In women, the incidence of SC was higher in the antioxidant group [adjusted hazard ratio (adjusted HR) = 1.68; P = 0.03]. Conversely, in men, incidence did not differ between the 2 treatment groups (adjusted HR = 0.69; P = 0.11). Despite the small number of events, the incidence of melanoma was also higher in the antioxidant group for women (adjusted HR = 4.31; P = 0.02). The incidence of nonmelanoma SC did not differ between the antioxidant and placebo groups (adjusted HR = 1.37; P = 0.22 for women and adjusted HR = 0.72; P = 0.19 for men). Our findings suggest that antioxidant supplementation affects the incidence of SC differentially in men and women. PMID- 17709450 TI - Diet quality of North African migrants in France partly explains their lower prevalence of diet-related chronic conditions relative to their native French peers. AB - Mediterranean migrant men living in France have lower mortality and morbidity than local-born populations for nutrition-related noncommunicable diseases (NR NCD). We studied diet quality and its influence on NR-NCD in Tunisian migrants compared with 2 nonmigrant male groups: local-born French and nonmigrant Tunisians, using a retrospective cohort study. We performed quota sampling (n = 147) based on age and place of residence. Using logistic regression models, components of the Diet Quality Index-International (DQI-I) were tested as potential mediators for the effect of migration on overweight, hypertension, hypercholesterolemia, type-2 diabetes, and cardiovascular diseases (CVD). The total DQI-I score revealed good overall diet quality ( approximately 60/100) for all groups. Migrants scored higher than the French in variety, adequacy, and moderation and lower than Tunisians in overall balance. Migrants displayed a lower prevalence of overweight than French, lower prevalence of diabetes and CVD than Tunisians, and lower prevalence of hypertension and hypercholesterolemia than the 2 nonmigrant groups. No mediator was found for overweight. Diet adequacy, fruits, and vitamin C were mediators of the difference in hypercholesterolemia between migrants and French and the effect on hypertension was mediated by diet adequacy and fiber. Compared with Tunisians, the effect of migration on hypercholesterolemia was mediated by saturated fat. No mediator was found for hypertension, diabetes, or CVD. Despite increasing NR-NCD levels in both France and Tunisia, migrants appear to have conserved some healthy dietary characteristics that partly explain their difference in NR-NCD with local-born French, but other lifestyle factors may contribute to the favorable effect of migration. PMID- 17709451 TI - Folic acid and vitamin B-12 supplementation does not favorably influence uracil incorporation and promoter methylation in rectal mucosa DNA of subjects with previous colorectal adenomas. AB - Adequate folate availability is necessary to sustain normal DNA synthesis and normal patterns of DNA methylation and these features of DNA can be modified by methylenetetrahydrofolate reductase (MTHFR) C677T genotype. This study investigated the effect of MTHFR C677T genotype and daily supplementation with 5 mg folic acid and 1.25 mg vitamin B-12 on uracil misincorporation into DNA and promoter methylation. Subjects (n = 86) with a history of colorectal adenoma and MTHFR CC or TT genotype were randomly assigned to receive folic acid plus vitamin B-12 or placebo for 6 mo. Uracil misincorporation and promoter methylation of 6 tumor suppressor and DNA repair genes were assessed in DNA from rectal biopsies at baseline and after the intervention. The biomarkers did not differ between the treated group and the placebo group after 6 mo compared with baseline. The uracil concentration of DNA increased in the treated group (5.37 fmol/microg DNA, P = 0.02), whereas it did not change in the placebo group (P = 0.42). The change from baseline of 4.01 fmol uracil/microg DNA tended to differ between the groups (P = 0.16). An increase in promoter methylation tended to occur more often in the intervention group than in the placebo group (OR = 1.67; P = 0.08). This study suggests that supplementation with high doses of folic acid and vitamin B-12 may not favorably influence uracil incorporation and promoter methylation in subjects with previous colorectal adenomas. Because such alterations may potentially increase the risk of neoplastic transformation, more research is needed to fully define the consequences of these molecular alterations. PMID- 17709452 TI - Surrogate markers of insulin resistance are associated with consumption of sugar sweetened drinks and fruit juice in middle and older-aged adults. AB - In this study, we examined the association between sugar-sweetened drink, diet soda, and fruit juice consumption and surrogate measures of insulin resistance. Sugar-sweetened drink, diet soda, and fruit juice consumption was estimated using a semiquantitative FFQ in 2500 subjects at the fifth examination (1991-1995) of the Framingham Offspring Study. Surrogate markers of insulin resistance measured in this study included fasting insulin, fasting glucose, homeostatic model assessment of insulin resistance, and the insulin sensitivity index (ISI(0,120)). Sugar-sweetened drink consumption was positively associated with fasting insulin (none vs. > or = 2 servings/d, 188 vs. 206 pmol/L, P-trend <0.001) after adjusting for potential confounders. Sugar-sweetened drink consumption was not associated with fasting glucose or ISI(0,120). Fruit juice consumption was inversely associated with fasting glucose (none vs. > or = 2 servings/d, 5.28 vs. 5.18 mmol/L, P-trend = 0.006), but not with fasting insulin (none vs. > or = 2 servings/d, 200 vs. 188 pmol/L, P-trend = 0.37) or ISI(0,120) (none vs. > or = 2 servings/d, 26.0 vs. 27.0, P-trend = 0.19) in multivariate models. Diet soda consumption was not associated with any surrogate measures of insulin resistance after adjustment for potential confounders (insulin: none vs. > or = 2 servings/d, 195 vs. 193 pmol/L, P-trend = 0.59; glucose: 5.26 vs. 5.24 mmol/L, P trend = 0.84; and ISI(0,120): 26.2 vs. 26.7, P-trend = 0.37). In these healthy adults, sugar-sweetened drink consumption appears to be unfavorably associated with surrogate measures reflecting hepatic more than peripheral insulin sensitivity. Studies of long-term beverage consumption using more direct measures of insulin sensitivity are clearly warranted. PMID- 17709454 TI - Change in food security status and change in weight are not associated in urban women with preschool children. AB - Cross-sectional studies have suggested that food insecurity leads to obesity in women. The objective of this longitudinal study was to determine whether changes in women's food security status were associated with changes in their body weight. In 20 large U.S. cities, 1707 mothers of preschool children were followed for 2 y. At baseline (2001-2003) and follow-up (2003-2005), women's height and weight were measured and food security status was assessed with the US Household Food Security Survey Module. Those with no positive responses on the food security items were considered fully food secure and those with any positive responses were considered not fully food secure. Seventy-one percent were unmarried and 45% had incomes below the U.S. poverty threshold. At baseline, 41% were obese (BMI > or = 30 kg/m(2)) and 31% were not food secure. After adjusting for sociodemographic characteristics and baseline BMI, there were no significant differences in 2-y weight increases between 4 groups that differed in food security status: food secure at both time points (n = 1000), 1.7 kg (95% CI = 1.1 2.3); food secure at baseline, but not at follow-up (n = 183), 2.1 kg (95% CI = 0.7-3.5); not food secure at either time point (n = 257), 1.7 kg (95% CI = 0.5 2.9); and not food secure at baseline but food secure at follow-up (n = 267), 1.9 kg (95% CI = 0.7-3.0). In this population of urban women, changes in food security status over 2 y were not significantly associated with changes in weight. These findings do not support a causal association between food insecurity and obesity. PMID- 17709453 TI - Dietary intake of selected nutrients affects bacterial vaginosis in women. AB - Bacterial vaginosis (BV), a condition of altered vaginal flora, is associated with various adverse reproductive health outcomes. We evaluated the association between diet and the presence of BV in a subset of 1521 women (86% African American) from a larger study of vaginal flora. Participants completed the Block Food Questionnaire and clinical assessments and self-report measures of sexual and hygiene behavior. A total of 42% of the women were classified as having BV (Nugent score > or = 7). Severe BV (Nugent score > or = 9 and vaginal pH > or = 5) was present in 14.9% of the women. BV was associated [adjusted OR (AOR)] with increased dietary fat (1.5, 1.1-2.4) after adjusting for other energy nutrients and behavioral and demographic covariates. Severe BV was associated with total fat (2.3, 1.3-4.3), saturated fat (2.1, 1.2-3.9), and monounsaturated fat (2.2, 1.2-4.1). Energy intake was only marginally associated (P = 0.05) with BV (1.4, 1.0-1.8). There were significant inverse associations between severe BV and intakes of folate (0.4, 0.2-0.8), vitamin E (0.4, 0.2-0.8), and calcium (0.4, 0.3 0.7). We conclude that increased dietary fat intake is associated with increased risk of BV and severe BV, whereas increased intake of folate, vitamin A, and calcium may decrease the risk of severe BV. PMID- 17709455 TI - Intake of alcoholic beverages is a predictor of iron status and hemoglobin in adult Tanzanians. AB - Iron deficiency is widespread in sub-Saharan Africa, but its predictors are not fully understood. We conducted a cross-sectional study among adults around Lake Victoria to describe iron status and asses the role of dietary and infectious predictors. Linear regression analyses were used to assess the role of infections and intake of meat, fish, fruit/vegetables, alcoholic beverages, and soil on hemoglobin and serum ferritin, while controlling for elevated serum alpha(1) antichymotrypsin (ACT). Among 1498 participants, the mean age was 33.3 (14-87) y with 53.9% females. More than one-half ate fish daily, 6% ate fruit/vegetables daily, and only 11% ate meat weekly. One-third consumed alcoholic beverages and one-fifth of females consumed soil. Hookworm (80.3%), Schistosoma mansoni (64.7%), and HIV (7.3%) infection were common. Anemia was found in 48.2% of females (<120 g/L hemoglobin) and 40.1% of males (<130 g/L hemoglobin), and 22.3% of females and 7.0% of males had depleted iron stores (serum ferritin <12 microg/L). In multivariate analyses, alcoholic beverage consumption and HIV were positive, whereas soil eating and hookworm infection were negative predictors of serum ferritin. Alcoholic beverage consumption was a positive predictor of hemoglobin, and soil eating, HIV, and hookworm infection were negative predictors. Intakes of meat, fish, and fruit or vegetables were not predictors. Elevated serum ACT was a predictor of both hemoglobin and serum ferritin. Anemia and depleted iron stores were common, whereas iron overload was rare. In conclusion, the associations between alcoholic beverage intake and hemoglobin and iron status suggest that alcoholic beverages may contain micronutrients essential to erythropoiesis. The role of alcoholic beverage intake and other determinants of hemoglobin and iron status in low-income populations needs to be better elucidated. PMID- 17709456 TI - A multiple-micronutrient-fortified beverage affects hemoglobin, iron, and vitamin A status and growth in adolescent girls in rural Bangladesh. AB - Adolescent girls have high nutrient needs and are susceptible to micronutrient deficiencies. The objective of this study was to test the effect of a multiple micronutrient-fortified beverage on hemoglobin (Hb) concentrations, micronutrient status, and growth among adolescent girls in rural Bangladesh. A total of 1125 girls (Hb > or = 70 g/L) enrolled in a randomized, double-blind, placebo controlled trial and were allocated to either a fortified or nonfortified beverage of similar taste and appearance. The beverage was provided at schools 6 d/wk for 12 mo. Concentrations of Hb and serum ferritin (sFt), retinol, zinc, and C-reactive protein were measured in venous blood samples at baseline, 6 mo, and 12 mo. In addition, weight, height, and mid-upper arm circumference (MUAC) measurements were taken. The fortified beverage increased the Hb and sFt and retinol concentrations at 6 mo (P < 0.01). Adolescent girls in the nonfortified beverage group were more likely to suffer from anemia (Hb <120 g/L), iron deficiency (sFt <12 microg/L), and low serum retinol concentrations (serum retinol <0.70 micromol/L) (OR = 2.04, 5.38, and 5.47, respectively; P < 0.01). The fortified beverage group had greater increases in weight, MUAC, and BMI over 6 mo (P < 0.01). Consuming the beverage for an additional 6 mo did not further improve the Hb concentration, but the sFt level continued to increase (P = 0.01). The use of multiple-micronutrient-fortified beverage can contribute to the reduction of anemia and improvement of micronutrient status and growth in adolescent girls in rural Bangladesh. PMID- 17709457 TI - Out-of-home food intake is often omitted from mothers' recalls of school children's intake in rural Kenya. AB - Children often consume foods from outside the home (OH foods), which can decrease the accuracy of dietary recalls collected from the parents. The objectives of this study were to describe the types and composition of OH foods consumed by rural school-aged Kenyan children, to assess their contribution to the daily intake of the child, and to evaluate the ability of the mother to estimate intake of OH foods. To capture any seasonal differences, the study was conducted twice, once during a food shortage season and again during the subsequent harvest season. School children were asked to recall the types and amounts of OH foods consumed on the previous day. Mothers were asked to report on the types and amounts of all foods consumed by their children during the day of interest. OH foods contributed 13 and 19% of daily energy intake in the food shortage and harvest seasons, respectively, but mothers missed 77 and 41% of the OH energy intake. OH foods were most likely to be fruits (guavas, mangoes, and wild fruit) and starchy foods (bread and fried wheat dough). Nutrients most likely to be under-reported on the mothers' recalls were vitamin C (59 and 26% was missed in the food shortage and harvest seasons, respectively) and vitamin A (approximately 22% was missed in both seasons). To ensure that all food intake is recalled, it is important that school children be included in dietary assessment interviews about their own intakes. PMID- 17709458 TI - Food insecurity works through depression, parenting, and infant feeding to influence overweight and health in toddlers. AB - We used the Early Childhood Longitudinal Study-Birth Cohort 9- and 24-mo surveys (n = 8693) and Structural Equation Modeling to examine direct and indirect associations between food insecurity and toddlers' overweight (weight for length), physical health, and length for age. There were significant effects of food insecurity on parental depression and parental depression in turn influenced physical health. There were also significant effects of food insecurity on parenting practices, which in turn were significantly associated with infant feeding and subsequently toddlers' overweight. There were no significant direct or indirect associations between food insecurity and toddlers' length for age. Our results show that food insecurity influences parenting, including both depression and parenting practices. Findings suggest parental depression is a stressor on parenting behavior that social policy should address to alleviate problematic child health outcomes. Findings underscore the importance of continuing and strengthening policy initiatives to ensure that families with infants and toddlers have sufficient, predictable, and reliable food supply. PMID- 17709459 TI - Caveat regarding dendritic cell numbers and functions in murine protein-energy malnutrition. PMID- 17709460 TI - Comparison of beta-lactam and macrolide combination therapy versus fluoroquinolone monotherapy in hospitalized Veterans Affairs patients with community-acquired pneumonia. AB - Data comparing the treatment outcomes of the two most frequently recommended empirical antibiotic regimens for community-acquired pneumonia (CAP)--combination therapy with an extended-spectrum beta-lactam and a macrolide (BL+M) or fluoroquinolone (F) monotherapy--for patients with severe CAP are sparse. The purpose of this study was to compare empirical BL+M combination therapy with F monotherapy for Veterans Affairs (VA) patients with severe CAP. This retrospective study included patients with CAP who received empirical therapy with BL+M or F between October 1999 and May 2003 in the Upstate New York VA Network. Outcome measures were 14-day mortality, 30-day mortality, and length of hospital stay (LOS). Severe CAP was defined as a class V pneumonia severity index (PSI). During the study period, 261 patients received BL+M and 254 received F. Disease severity was similar for the two treatment groups at admission, and the presence of tachycardia was the only difference noted. For PSI class V patients, there were lower 14-day and 30-day mortality rates with BL+M than with F (14-day rates, 8.2% versus 26.8% [P = 0.02]; 30-day rates, 18.4% versus 36.6% [P = 0.05]). No differences in mortality between treatment groups were noted for the lower PSI classes. The overall median LOS was significantly longer for the BL+M combination group than for the F monotherapy group (6.0 days versus 5.0 days, respectively [P = 0.01]), but no difference in LOS was noted among PSI class V patients. Our study showed that improved outcomes may be realized with BL+M in cases of severe CAP. A randomized clinical study is warranted based on these results. PMID- 17709461 TI - Quinuclidine derivatives as potential antiparasitics. AB - There is an urgent need for the development of new drugs for the treatment of tropical parasitic diseases such as Chagas' disease and leishmaniasis. One potential drug target in the organisms that cause these diseases is sterol biosynthesis. This paper describes the design and synthesis of quinuclidine derivatives as potential inhibitors of a key enzyme in sterol biosynthesis, squalene synthase (SQS). A number of compounds that were inhibitors of the recombinant Leishmania major SQS at submicromolar concentrations were discovered. Some of these compounds were also selective for the parasite enzyme rather than the homologous human enzyme. The compounds inhibited the growth of and sterol biosynthesis in Leishmania parasites. In addition, we identified other quinuclidine derivatives that inhibit the growth of Trypanosoma brucei (the causative organism of human African trypanosomiasis) and Plasmodium falciparum (a causative agent of malaria), but through an unknown mode(s) of action. PMID- 17709462 TI - Composite structure of Streptococcus pneumoniae containing the erythromycin efflux resistance gene mefI and the chloramphenicol resistance gene catQ. AB - In recent years mef genes, encoding efflux pumps responsible for M-type macrolide resistance, have been investigated extensively for streptococci. mef(I) is a recently described mef variant detected in particular isolates of Streptococcus pneumoniae instead of the more common mef(E) and mef(A). This study shows that mef(I) is located in a new composite genetic element, whose sequence was completely analyzed and the left and right junctions determined, demonstrating a unique genetic organization. The new composite structure (30,505 bp), designated the 5216IQ complex, consists of two halves: a left one (15,316 bp) formed by parts of the known transposons Tn5252 and Tn916, and a right one (15,115 bp) formed by a new fragment, designated the IQ element. While the defective Tn916 contained a silent tet(M) gene, the IQ element, ending with identical transposase genes on both sides and containing the mef(I) gene with an adjacent new msr(D) gene variant and a catQ chloramphenicol acetyltransferase gene, was completely different from the genetic elements carrying other mef genes in pneumococci. This is the first report demonstrating catQ in S. pneumoniae and showing its linkage with a mef gene. Analysis of the chromosomal region beyond the left junction revealed an organization more similar to that of S. pneumoniae strain TIGR4 than to that of strain R6. The 5216IQ complex was apparently nonmobile, with no detectable transfer of erythromycin resistance being obtained in repeated transformation and conjugation assays. PMID- 17709463 TI - TEM-158 (CMT-9), a new member of the CMT-type extended-spectrum beta-lactamases. AB - TEM-158 was found to include the substitutions previously observed for TEM-12 and TEM-35. This enzyme presented hydrolytic activity against ceftazidime and a high level of resistance against clavulanate, which can alter its detection. Its discovery highlights the need for accurate detection methods. PMID- 17709465 TI - The macrolide resistance genes erm(B) and mef(E) are carried by Tn2010 in dual gene Streptococcus pneumoniae isolates belonging to clonal complex CC271. AB - The genetic elements carrying macrolide resistance genes in Streptococcus pneumoniae isolates belonging to CC271 were investigated. The international clone Taiwan(19F)-14 was found to carry Tn2009, a Tn916-like transposon containing tet(M) and mef(E). The dual erm(B) mef(E) isolates carried Tn2010, which is similar to Tn2009 with the addition of a putative new transposon, the erm(B) genetic element. PMID- 17709464 TI - Novel small-molecule inhibitors of transmissible gastroenteritis virus. AB - We used swine testicle (ST) cells infected with transmissible gastroenteritis virus (TGEV) and an indirect immunofluorescent assay with antibodies against TGEV spike and nucleocapsid proteins to screen small-molecule compounds that inhibit TGEV replication. Analogues of initial hits were collected and subjected to a 3CL protease (3CL(pro)) inhibition assay with recombinant 3CL(pro) and a fluorogenic peptide substrate. A series of benzothiazolium compounds were found to have inhibitory activity against TGEV 3CL(pro) and to exert anti-TGEV activities in terms of viral protein and RNA replication in TGEV-infected ST cells, with consequent protection of TGEV-infected ST cells from cytopathic effect by blocking the activation of caspase-3. PMID- 17709466 TI - In vitro antimycobacterial spectrum of a diarylquinoline ATP synthase inhibitor. AB - The diarylquinoline R207910 is in clinical development for tuberculosis treatment. The MIC(50) for 41 drug-susceptible and 44 multidrug-resistant Mycobacterium tuberculosis clinical isolates was 0.032 microg/ml. Out of 20 additional mycobacterial species, three were found to be naturally resistant to R207910 and were shown to exhibit a polymorphism in their atpE genes. PMID- 17709467 TI - Influence of inoculum size on the selection of resistant mutants of Escherichia coli in relation to mutant prevention concentrations of marbofloxacin. AB - We demonstrate using an in vitro pharmacodynamic model that the likelihood of selection of Escherichia coli mutants resistant to a fluoroquinolone was increased when the initial size of the bacterial population, exposed to fluoroquinolone concentrations within the mutant selection window, was increased. PMID- 17709468 TI - Growth and drug resistance phenotypes resulting from cytomegalovirus DNA polymerase region III mutations observed in clinical specimens. AB - Recombinant phenotyping of cytomegalovirus (CMV) pol region III mutations from clinical specimens showed that T813S and G841A each conferred foscarnet resistance and approximately threefold increased ganciclovir resistance; adding the UL97 mutation C592G increased ganciclovir resistance to approximately sixfold. Bacterial artificial chromosome CMV clones containing pol mutation L845P were nonviable unless repaired with the wild-type sequence. PMID- 17709469 TI - In vitro and in vivo activities of novel fluoroquinolones alone and in combination with clarithromycin against clinically isolated Mycobacterium avium complex strains in Japan. AB - The recommended treatments for Mycobacterium avium complex (MAC) infectious disease are combination regimens of clarithromycin (CLR) or azithromycin with ethambutol and rifamycin. However, these chemotherapy regimens are sometimes unsuccessful. Recently developed antimicrobial agents, such as newer fluoroquinolones (FQs) containing C-8 methoxy quinolone (moxifloxacin [MXF] and gatifloxacin [GAT]), are expected to be novel antimycobacterial agents. Here, we evaluated the in vitro and in vivo antimycobacterial activities of three FQs (MXF, GAT, and levofloxacin) and CLR against clinically isolated MAC strains. Subsequently, the in vitro and in vivo synergic activities of FQ-CLR combinations against MAC strains were investigated. CLR and the individual FQs alone showed promising activity against MAC strains in vitro, and the bacterial counts in organs (lungs, liver, and spleen) of MAC-infected mice treated with single agents were significantly reduced compared to control mice. CLR showed the best anti-MAC effect in vivo. When the three FQs were individually combined with CLR in vitro, mild antagonism was observed for 53 to 57% of the tested isolates. Moreover, mice were infected with MAC strains showing mild antagonism for FQ-CLR combinations in vitro, and the anti-MAC effects of the FQ-CLR combinations were evaluated by counting the viable bacteria in their organs and by histopathological examination after 28 days of treatment. Several FQ-CLR combinations exhibited bacterial counts in organs significantly higher than those in mice treated with CLR alone. Our results indicate that the activity of CLR is occasionally attenuated by combination with an FQ both in vitro and in vivo and that this effect seems to be MAC strain dependent. Careful combination chemotherapy using these agents against MAC infectious disease may be required. PMID- 17709470 TI - Cyclic tetrapyrrole sulfonation, metals, and oligomerization in antiprion activity. AB - Cyclic tetrapyrroles are among the most potent compounds with activity against transmissible spongiform encephalopathies (TSEs; or prion diseases). Here the effects of differential sulfonation and metal binding to cyclic tetrapyrroles were investigated. Their potencies in inhibiting disease-associated protease resistant prion protein were compared in several types of TSE-infected cell cultures. In addition, prophylactic antiscrapie activities were determined in scrapie-infected mice. The activity of phthalocyanine was relatively insensitive to the number of peripheral sulfonate groups but varied with the type of metal bound at the center of the molecule. The tendency of the various phthalocyanine sulfonates to oligomerize (i.e., stack) correlated with anti-TSE activity. Notably, aluminum(III) phthalocyanine tetrasulfonate was both the poorest anti TSE compound and the least prone to oligomerization in aqueous media. Similar comparisons of iron- and manganese-bound porphyrin sulfonates confirmed that stacking ability correlates with anti-TSE activity among cyclic tetrapyrroles. PMID- 17709471 TI - Polymyxin B induces lysis of marine pseudoalteromonads. AB - Polymyxin B (PMB) is a cationic antibiotic that interacts with the envelopes of gram-negative bacterial cells. The therapeutic use of PMB was abandoned for a long time due to its undesirable side effects; however, the spread of resistance to currently used antibiotics has forced the reevaluation of PMB for clinical use. Previous studies have used enteric bacteria to examine the mode of PMB action, resulting in a somewhat limited understanding of this process. This study examined the effects of PMB on marine pseudoalteromonads and demonstrates that the frequently accepted view that "what is true for Escherichia coli is true for all bacteria" does not hold true. We show here that in contrast to the growth inhibition observed for enteric bacteria, PMB induces lysis of pseudoalteromonads, which is not prevented by high concentrations of divalent cations. Furthermore, we demonstrate that a high membrane voltage is required for the interaction of PMB with the cytoplasmic membranes of pseudoalteromonads, further elucidating the mechanisms by which PMB interacts with the cell envelopes of those gram-negative bacteria. PMID- 17709472 TI - Antiprion activity of cholesterol esterification modulators: a comparative study using ex vivo sheep fibroblasts and lymphocytes and mouse neuroblastoma cell lines. AB - Our studies on the role of cholesterol homeostasis in the pathogenesis of scrapie revealed abnormal accumulation of cholesterol esters in ex vivo peripheral blood mononuclear cells (PBMCs) and skin fibroblasts from healthy and scrapie-affected sheep carrying a scrapie-susceptible genotype compared to sheep with a resistant genotype. Similar alterations were observed in mouse neuroblastoma N2a cell lines persistently infected with mouse-adapted 22L and RML strains of scrapie that showed up to threefold-higher cholesterol ester levels than parental N2a cells. We now report that proteinase K-resistant prion protein (PrPres)-producing cell populations of subclones from scrapie-infected cell lines were characterized by higher cholesterol ester levels than clone populations not producing PrPres. Treatments with a number of drugs known to interfere with different steps of cholesterol metabolism strongly reduced the accumulation of cholesterol esters in ex vivo PBMCs and skin fibroblasts from scrapie-affected sheep but had significantly less or no effect in their respective scrapie-resistant or uninfected counterparts. In scrapie-infected N2a cells, inhibition of cholesterol esters was associated with selective antiprion activity. Effective antiprion concentrations of cholesterol modulators (50% effective concentration [EC(50)] range, 1.4 to 40 microM) were comparable to those of antiprion reference compounds (EC(50) range, 0.6 to 10 microM). These data confirm our hypothesis that abnormal accumulation of cholesterol esters may represent a biological marker of susceptibility to prion infection/replication and a novel molecular target of potential clinical importance. PMID- 17709473 TI - Molecular and epidemiological evidence for spread of multiresistant methicillin susceptible Staphylococcus aureus strains in hospitals. AB - The excision of the staphylococcal chromosomal cassette mec (SCCmec) from methicillin-resistant Staphylococcus aureus (MRSA) strains results in methicillin susceptible S. aureus (MSSA) strains. In order to determine the proportion and diversity of multidrug-resistant MSSA (MR-MSSA) strains derived from MRSA strains, 247 mecA-negative isolates recovered in 60 French hospitals between 2002 and 2004 were characterized. The spa types of all strains were determined, and a subset of the strains (n = 30) was further genotyped by multilocus sequence typing. The IDI-MRSA assay was used to test the isolates for the presence of the SCCmec element, which was detected in 68% of all isolates analyzed. Molecular analysis of the samples suggested that 92% of the MR-MSSA isolates were derived from MRSA clones of diverse genetic backgrounds, of which the clone of sequence type 8 and SCCmec type IV(A) accounted for most of the samples. High variations in incidence data and differences in the molecular characteristics of the isolates from one hospital to another indicate that the emergence of MR-MSSA resulted from independent SCCmec excisions from epidemic MRSA isolates, as well as the diffusion of methicillin-susceptible strains after the loss of SCCmec. MR MSSA could constitute a useful model for the study of the respective genetic and environmental factors involved in the dissemination of S. aureus in hospitals. PMID- 17709474 TI - Functional characterization of TcaA: minimal requirement for teicoplanin susceptibility and role in Caenorhabditis elegans virulence. AB - The inactivation of TcaA contributes to intrinsic teicoplanin resistance in experimental and clinical isolates of glycopeptide-intermediate resistant Staphylococcus aureus. PhoA fusions confirmed that TcaA is a transmembrane protein with a short intracellular N-terminal domain containing a C-4 zinc finger binding motif, a single membrane-spanning domain, and a large extracellular C terminal domain. The region conferring teicoplanin susceptibility was narrowed down to the transmembrane part and the first third of the extracellular domain of TcaA, suggesting that neither the C-4 zinc finger binding motif nor the C terminus contributed to teicoplanin susceptibility. TcaA belongs to the cell wall stress stimulon, which comprises a set of genes universally upregulated by cell wall damage. Induction of tcaA was shown to be fully dependent on the two component regulatory system VraSR. A 66-bp region upstream of the transcriptional start site, which contained an inverted repeat partially covering the promoter box, was shown to be essential for VraSR-mediated induction by cell wall stress. Interestingly, the induction or overexpression of tcaA did not contribute further to teicoplanin susceptibility, suggesting that small amounts of TcaA, such as those present under normal uninduced conditions, were sufficient for TcaA mediated teicoplanin susceptibility. The strong attenuation of tcaA deletion mutants in a Caenorhabditis elegans survival assay suggested that TcaA may, in addition to affecting glycopeptide susceptibility, also play a role in virulence. PMID- 17709475 TI - Characterizing MHC-associated peptides by mass spectrometry. PMID- 17709476 TI - Pillars article: Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science 1992. 255: 1261-1263. PMID- 17709477 TI - The multitasking mast cell: positive and negative roles in the progression of autoimmunity. AB - Among the potential outcomes of an aberrantly functioning immune system are allergic disease and autoimmunity. Although it has been assumed that the underlying mechanisms mediating these conditions are completely different, recent evidence shows that mast cells provide a common link. Mast cells reside in most tissues, are particularly prevalent at sites of Ag entry, and act as sentinel cells of the immune system. They express many inflammatory mediators that affect both innate and adaptive cellular function. They contribute to pathologic allergic inflammation but also serve an important protective role in bacterial and parasite infections. Given the proinflammatory nature of autoimmune responses, it is not surprising that studies using murine models of autoimmunity clearly implicate mast cells in the initiation and/or progression of autoimmune disease. In this review, we discuss the defined and hypothesized mechanisms of mast cell influence on autoimmune diseases, including their surprising and newly discovered role as anti-inflammatory cells. PMID- 17709478 TI - Cutting edge: The IkappaB kinase (IKK) inhibitor, NEMO-binding domain peptide, blocks inflammatory injury in murine colitis. AB - Inflammatory mediators such as TNF-alpha, IL-6, and IL-1 are important in the pathogenesis of inflammatory bowel diseases and are regulated by the activation of NF-kappaB. The aim of the present study was to investigate whether the NF kappaB essential modulator (NEMO)-binding domain (NBD) peptide, which has been shown to block the association of NEMO with the IkappaB kinasebeta subunit (IKKbeta) and inhibit NF-kappaB activity, reduces inflammatory injury in mice with colitis. Two colitis models were established by the following: 1) inclusion of dextran sulfate sodium salt (DSS) in the drinking water of the mice; and 2) a trinitrobenzene sulfonic acid enema. Marked NF-kappaB activation and expression of proinflammatory cytokines were observed in colonic tissues. The NBD peptide ameliorated colonic inflammatory injury through the down-regulation of proinflammatory cytokines mediated by NF-kappaB inhibition in both models. These results indicate that an IKKbeta-targeted NF-kappaB blockade using the NBD peptide could be an attractive therapeutic approach for inflammatory bowel disease. PMID- 17709479 TI - Cutting edge: TNF-alpha-converting enzyme (TACE/ADAM17) inactivation in mouse myeloid cells prevents lethality from endotoxin shock. AB - TNF-alpha, a potent proinflammatory cytokine, is synthesized as a membrane anchored precursor and proteolytically released from cells. Soluble TNF is the primary mediator of pathologies such as rheumatoid arthritis, Crohn's disease, and endotoxin shock. The TNF-alpha converting enzyme (TACE), a disintegrin and metalloprotease 17 (ADAM17), has emerged as the best candidate TNF sheddase, but other proteinases can also release TNF. Because TACE-deficient mice die shortly after birth, we generated conditional TACE-deficient mice to address whether TACE is the relevant sheddase for TNF in adult mice. In this study, we report that TACE inactivation in myeloid cells or temporal inactivation at 6 wk offers strong protection from endotoxin shock lethality in mice by preventing increased TNF serum levels. These findings corroborate that TACE is the major endotoxin stimulated TNF sheddase in mouse myeloid cells in vivo, thereby further validating TACE as a principal target for the treatment of TNF-dependent pathologies. PMID- 17709480 TI - Cutting edge: Peyer's patch plasmacytoid dendritic cells (pDCs) produce low levels of type I interferons: possible role for IL-10, TGFbeta, and prostaglandin E2 in conditioning a unique mucosal pDC phenotype. AB - The organized lymphoid tissues of the intestine likely play an important role in the balance between tolerance harmless mucosal Ags and commensal bacteria and immunity to mucosal pathogens. We examined the phenotype and function of plasmacytoid dendritic cells (pDCs) from murine Peyer's patches (PPs). When stimulated with CpG-enriched oligodeoxynucleotides in vitro, PPs and spleen pDCs made equivalent levels of IL-12, yet PP pDCs were incapable of producing significant levels of type I IFNs. Three regulatory factors associated with mucosal tissues, PGE(2), IL-10, and TGFbeta, inhibited the ability of spleen pDCs to produce type I IFN in a dose-dependent fashion. These studies suggest that mucosal factors may regulate the production of type I IFN as well as IL-12 by pDCs. In the intestine, this may be beneficial in preventing harmful innate and adaptive immune responses to commensal microorganisms. PMID- 17709481 TI - Cutting edge: Complement (C3d)-linked antigens break B cell anergy. AB - C3dg adducts of Ag can coligate complement receptor type 2 (CR2; CD21) and the B cell Ag receptor. This interaction significantly amplifies BCR-mediated signals in Ag-naive wild-type mice, lowering the threshold for B cell activation and the generation of humoral immune responses as much as 1000-fold. In this study we demonstrate that CR2-mediated complementation of BCR signals can also overcome B cell anergy. Unlike Ag alone, BCR/CR2 costimulation (Ars-CCG/C3dg complexes) of anergic Ars/A1 B cells led to Ca(2+) mobilization in vitro and the production of autoantibodies in vivo. Interestingly, the in vivo immune response of anergic cells occurs without the formation of germinal centers. These results suggest that the Ag unresponsiveness of anergic B cells can be overcome by cross-reactive (self-mimicking) Ags that have been complement-opsonized. This mechanism may place individuals exposed to complement-fixing bacteria at risk for autoimmunity. PMID- 17709482 TI - Cutting edge: Evidence of direct TCR alpha-chain interaction with superantigen. AB - Superantigens are known to activate a large number of T cells. The SAg is presented by MHC class II on the APC and its classical feature is that it recognizes the variable region of the beta-chain of the TCR. In this article, we report, by direct binding studies, that staphylococcal enterotoxin (SE) H (SEH), a bacterial SAg secreted by Staphylococcus aureus, instead recognizes the variable alpha-chain (TRAV27) of TCR. Furthermore, we show that different SAgs (e.g., SEH and SEA) can simultaneously bind to one TCR by binding the alpha-chain and the beta-chain, respectively. Theoretical three-dimensional models of the penta complexes are presented. Hence, these findings open up a new dimension of the biology of the staphylococcal enterotoxins. PMID- 17709483 TI - CD154 tone sets the signaling pathways and transcriptome generated in model CD40 pluricompetent L3055 Burkitt's lymphoma cells. AB - Activated B cells reacting to small amounts of CD40L (CD154) maintain homeostasis by suppressing default apoptosis. Additional outcomes, particularly differentiation, demand higher CD40 occupancy. Here, focusing on survival, we compared changes in the transcriptome of pleiotropically competent, early passage L3055 Burkitt's lymphoma cells confronted with low (picomolar) and high (nanomolar) concentrations of CD154 to gain insight into how a single receptor sets these distinct phenotypes. Of 267 genes altering transcriptional activity in response to strong CD154 tone, only 25 changed coordinately on low receptor occupancy. Seven of the top nine common up-regulated genes were targets of NF kappaB. Direct measurement and functional inhibition of the NF-kappaB pathway revealed it to be central to a CD40-dependent survival signature. Although the canonical NF-kappaB axis was engaged by both signaling strengths equally, robust alternative pathway activation was a feature selective to a strong CD40 signal. Discriminatory exploitation of the two separate arms of NF-kappaB activation may indicate a principle whereby a cell senses and reacts differentially to shifting ligand availability. Identifying components selectively coupling CD40 to each axis could indicate targets for disruption in B cell pathologies underpinned by ectopic and/or hyper-CD154 activity such as neoplasia and some autoimmunities. PMID- 17709484 TI - Antigen transmission by replicating antigen-bearing dendritic cells. AB - During steady-state conditions, conventional spleen dendritic cells (DC) turn over every 2-3 days. Recent evidence indicates that in situ proliferation of DC arising from immediate conventional DC precursors is an important contributor to their homeostasis. In this study, we report that replication-competent conventional DC precursors and DC can internalize and transfer model particulate and soluble Ags directly to their DC progeny during cell division. Real-time confocal microscopy and flow cytometry indicated that Ag transmission to progeny was symmetrical, and suggested that other mechanisms of inter-DC Ag transfer were not involved. Soluble protein Ags inherited by DC progeny were presented effectively to Ag-specific T lymphocytes. Furthermore, we show that the number of DC, and the proportion that are actively proliferating, expands several-fold during an immune response against a viral infection. Our results point to an unanticipated mechanism in which DC are continuously replaced from Ag-bearing replication-competent precursor cells that pass Ag molecules onto their progeny through successive cell divisions. Our findings help explain how Ag may persist in a population of DC despite the brief lifespan of individual mature DC. PMID- 17709485 TI - PDGF synergistically enhances IFN-gamma-induced expression of CXCL10 in blood derived macrophages: implications for HIV dementia. AB - There is increasing cumulative evidence that activated mononuclear phagocytes (macrophages/microglia) releasing inflammatory mediators in the CNS are a better correlate of HIV-associated dementia (HAD) than the actual viral load in the brain. Earlier studies on simian HIV/rhesus macaque model of NeuroAIDS confirmed that pathological changes in brains of macaques with encephalitis were associated with up-regulation of platelet-derived growth factor (PDGF) and the chemokine, CXCL10. Because the complex interplay of inflammatory mediators released by macrophages often leads to the induction of neurotoxins in HAD, we hypothesized that PDGF could interact with IFN-gamma to modulate the expression of CXCL10 in these primary virus target cells. Although PDGF alone had no effect on the induction of CXCL10 in human macrophages, in conjunction with IFN-gamma, it significantly augmented the expression of CXCL10 RNA & protein through transcriptional and posttranscriptional mechanisms. Signaling molecules, such as JAK and STATs, PI3K, MAPK, and NF-kappaB were found to play a role in the synergistic induction of CXCL10. Furthermore, PDGF via its activation of p38 MAPK was able to increase the stability of IFN-gamma-induced CXCL10 mRNA. Understanding the mechanisms involved in the synergistic up-regulation of CXCL10 could aid in the development of therapeutic modalities for HAD. PMID- 17709486 TI - Novel exosome-targeted CD4+ T cell vaccine counteracting CD4+25+ regulatory T cell-mediated immune suppression and stimulating efficient central memory CD8+ CTL responses. AB - T cell-to-T cell Ag presentation is increasingly attracting attention. In this study, we demonstrated that active CD4+ T (aT) cells with uptake of OVA-pulsed dendritic cell-derived exosome (EXO(OVA)) express exosomal peptide/MHC class I and costimulatory molecules. These EXO(OVA)-uptaken (targeted) CD4+ aT cells can stimulate CD8+ T cell proliferation and differentiation into central memory CD8+ CTLs and induce more efficient in vivo antitumor immunity and long-term CD8+ T cell memory responses than OVA-pulsed dendritic cells. They can also counteract CD4+25+ regulatory T cell-mediated suppression of in vitro CD8+ T cell proliferation and in vivo CD8+ CTL responses and antitumor immunity. We further elucidate that the EXO(OVA)-uptaken (targeted)CD4+ aT cell's stimulatory effect is mediated via its IL-2 secretion and acquired exosomal CD80 costimulation and is specifically delivered to CD8+ T cells in vivo via acquired exosomal peptide/MHC class I complexes. Therefore, EXO-targeted active CD4+ T cell vaccine may represent a novel and highly effective vaccine strategy for inducing immune responses against not only tumors, but also other infectious diseases. PMID- 17709487 TI - Respiratory syncytial virus decreases p53 protein to prolong survival of airway epithelial cells. AB - Respiratory syncytial virus (RSV) is a clinically important pathogen. It preferentially infects airway epithelial cells causing bronchiolitis in infants, exacerbations in patients with obstructive lung disease, and life-threatening pneumonia in the immunosuppressed. The p53 protein is a tumor suppressor protein that promotes apoptosis and is tightly regulated for optimal cell growth and survival. A critical negative regulator of p53 is murine double minute 2 (Mdm2), an E3 ubiquitin ligase that targets p53 for proteasome degradation. Mdm2 is activated by phospho-Akt, and we previously showed that RSV activates Akt and delays apoptosis in primary human airway epithelial cells. In this study, we explore further the mechanism by which RSV regulates p53 to delay apoptosis but paradoxically enhance inflammation. We found that RSV activates Mdm2 1-6 h after infection resulting in a decrease in p53 6-24 h after infection. The p53 down regulation correlates with increased airway epithelial cell longevity. Importantly, inhibition of the PI3K/Akt pathway blocks the activation of Mdm2 by RSV and preserves the p53 response. The effects of RSV infection are antagonized by Nutlin-3, a specific chemical inhibitor that prevents the Mdm2/p53 association. Nutlin-3 treatment increases endogenous p53 expression in RSV infected cells, causing earlier cell death. This same increase in p53 enhances viral replication and limits the inflammatory response as measured by IL-6 protein. These findings reveal that RSV decreases p53 by enhancing Akt/Mdm2 mediated p53 degradation, thereby delaying apoptosis and prolonging survival of airway epithelial cells. PMID- 17709488 TI - African trypanosomiasis: naturally occurring regulatory T cells favor trypanotolerance by limiting pathology associated with sustained type 1 inflammation. AB - Tolerance to African trypanosomes requires the production of IFN-gamma in the early stage of infection that triggers the development of classically activated macrophages controlling parasite growth. However, once the first peak of parasitemia has been controlled, down-regulation of the type 1 immune response has been described. In this study, we have evaluated whether regulatory T cells (Tregs) contribute to the limitation of the immune response occurring during Trypanosoma congolense infection and hereby influence the outcome of the disease in trypanotolerant C57BL/6 host. Our data show that Foxp3+ Tregs originating from the naturally occurring Treg pool expanded in the spleen and the liver of infected mice. These cells produced IL-10 and limited the production of IFN-gamma by CD4+ and CD8+ effector T cells. Tregs also down-regulated classical activation of macrophages resulting in reduced TNF-alpha production. The Treg-mediated suppression of the type 1 inflammatory immune response did not hamper parasite clearance, but was beneficial for the host survival by limiting the tissue damages, including liver injury. Collectively, these data suggest a cardinal role for naturally occurring Tregs in the development of a trypanotolerant phenotype during African trypanosomiasis. PMID- 17709489 TI - CD4+ T cell-specific deletion of IL-4 receptor alpha prevents ovalbumin-induced anaphylaxis by an IFN-gamma-dependent mechanism. AB - IL-4Ralpha-mediated STAT6 activation serves an essential role in various animal models of allergy and asthma at both the sensitization and effector phases. IL-4 and IL-13 signaling via the IL-4Ralpha chain exacerbates murine anaphylaxis, but the cell-specific requirements for IL-4Ralpha expression are unclear. The purpose of this study was to elucidate the mechanisms of systemic anaphylaxis to OVA in gene-targeted mice with a deletion of the IL-4Ralpha chain in the macrophage/neutrophil or CD4+ T lymphocyte population. Results demonstrated that anaphylaxis in this model was entirely dependent upon the FcgammaRII/III and was associated with mast cell degranulation. Expression of the IL-4Ralpha on CD4+ T cells, but not macrophages or neutrophils, was critical for severe anaphylaxis, characterized by diarrhea, hypothermia, and death. Ab depletion experiments demonstrated that IFN-gamma protected against mortality and severe intestinal pathology despite the presence of Ag and specific Ab. This protection was associated with reduced levels of mast cell protease, a marker of mast cell degranulation, suggesting that IFN-gamma may inhibit mast cell degranulation in vivo. These data suggest that it may be possible to limit the severity of anaphylaxis using rational therapies designed to increase numbers of IFN-gamma producing cells by targeting IL-4Ralpha signaling in CD4+ T lymphocytes. PMID- 17709490 TI - Prostaglandin D2 suppresses human NK cell function via signaling through D prostanoid receptor. AB - NK cells play critical roles in immune responses against tumors or virus infections by generating type 1 cytokine and cytotoxicity responses. In contrast, during type 2 dominant immune responses, such as allergic diseases, activities of NK cells are often impaired. These type 2 immune-mediated diseases have been reported to be closely associated with local production of PGD(2). PGD(2) is an eicosanoid primarily synthesized by mast cells and alveolar macrophages, and it functions through two major receptors, D prostanoid receptor (DP) and chemoattractant receptor-like molecule on the Th2 cell. Within the immune system, PGD(2) binding to DP generally leads to suppression of cellular functions. In the current study, we show that: 1) DP is expressed in human NK cells as detected by mRNA analysis and Western blot; 2) PGD(2) inhibits cytotoxicity, chemotaxis, and type 1 cytokine production of human NK cells via signaling through DP; 3) PGD(2) signaling via DP elevates intracellular cAMP levels and the inhibitory effects on NK cells are cAMP dependent; 4) PGD(2) binding to DP suppresses Ca(2+) mobilization triggered by the cross-linking of the activating receptor, CD16. Together, these data uncover a novel mechanism by which PGD(2) functions through DP to suppress type 1 and cytolytic functions of human NK cells, thus contributing to the promotion of a type 2 immune response. PMID- 17709491 TI - CXCR3 signaling reduces the severity of experimental autoimmune encephalomyelitis by controlling the parenchymal distribution of effector and regulatory T cells in the central nervous system. AB - The chemokine receptor CXCR3 promotes the trafficking of activated T and NK cells in response to three ligands, CXCL9, CXCL10, and CXCL11. Although these chemokines are produced in the CNS in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), their role in the pathogenesis of CNS autoimmunity is unresolved. We examined the function of CXCR3 signaling in EAE using mice that were deficient for CXCR3 (CXCR3(-/-)). The time to onset and peak disease severity were similar for CXCR3(-/-) and wild-type (WT) animals; however, CXCR3(-/-) mice had more severe chronic disease with increased demyelination and axonal damage. The inflammatory lesions in WT mice consisted of well-demarcated perivascular mononuclear cell infiltrates, mainly in the spinal cord and cerebellum. In CXCR3(-/-) mice, these lesions were more widespread throughout the CNS and were diffused and poorly organized, with T cells and highly activated microglia/macrophages scattered throughout the white matter. Although the number of CD4(+) and CD8(+) T cells infiltrating the CNS were similar in CXCR3(-/-) and WT mice, Foxp3(+) regulatory T cells were significantly reduced in number and dispersed in CXCR3(-/-) mice. The expression of various chemokine and cytokine genes in the CNS was similar in CXCR3(-/-) and WT mice. The genes for the CXCR3 ligands were expressed predominantly in and/or immediately surrounding the mononuclear cell infiltrates. We conclude that in EAE, CXCR3 signaling constrains T cells to the perivascular space in the CNS and augments regulatory T cell recruitment and effector T cell interaction, thus limiting autoimmune-mediated tissue damage. PMID- 17709492 TI - CD8+ T cell-mediated airway hyperresponsiveness and inflammation is dependent on CD4+IL-4+ T cells. AB - CD4+ T cells, particularly Th2 cells, play a pivotal role in allergic airway inflammation. However, the requirements for interactions between CD4+ and CD8+ T cells in airway allergic inflammation have not been delineated. Sensitized and challenged OT-1 mice in which CD8+ T cells expressing the transgene for the OVA(257-264) peptide (SIINFEKL) failed to develop airway hyperresponsiveness (AHR), airway eosinophilia, Th2 cytokine elevation, or goblet cell metaplasia. OT 1 mice that received naive CD4+IL-4+ T cells but not CD4+IL-4- T cells before sensitization developed all of these responses to the same degree as wild-type mice. Moreover, recipients of CD4+IL-4+ T cells developed significant increases in the number of CD8+IL-13+ T cells in the lung, whereas sensitized OT-1 mice that received primed CD4+ T cells just before challenge failed to develop these responses. Sensitized CD8-deficient mice that received CD8+ T cells from OT-1 mice that received naive CD4+ T cells before sensitization increased AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged with allergen. In contrast, sensitized CD8-deficient mice receiving CD8+ T cells from OT-1 mice without CD4+ T cells developed reduced AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged. These data suggest that interactions between CD4+ and CD8+ T cells, in part through IL-4 during the sensitization phase, are essential to the development of CD8+IL-13+ T cell dependent AHR and airway allergic inflammation. PMID- 17709493 TI - Polylactide-coglycolide microspheres co-encapsulating recombinant tandem prion protein with CpG-oligonucleotide break self-tolerance to prion protein in wild type mice and induce CD4 and CD8 T cell responses. AB - Prion diseases are fatal neurodegenerative diseases that are characterized by the conformational conversion of the normal, mainly alpha-helical cellular prion protein (PrP) into the abnormal beta-sheet-rich infectious isoform (PrP(Sc)). The immune system neither shows reaction against cellular PrP nor PrP(Sc), most likely due to profound self-tolerance. In previous studies, we were able to partly overcome self-tolerance using recombinantly expressed dimeric PrP (tandem PrP (tPrP)), in association with different adjuvants. Proof of principle for antiprion efficacy was obtained in vitro and in vivo. In this study, we demonstrate the induction of a specific Th1 T cell response in wild-type mice immunized with tPrP and CpG-oligonucleotide (ODN). Biochemical influences such as refolding conditions, ionic strength, pH, and interaction with CpG-ODN affected antigenic structure and thus improved immunogenicity. Furthermore, s.c. immunization with tPrP and CpG-ODN co-encapsulated in biodegradable polylactide coglycolide microspheres (PLGA-MS) enhanced CD4 T cell responses and, more prominent, the induction of CD8 T cells. In this vaccination protocol, PLGA-MS function as endosomal delivery device of Ag plus CpG-ODN to macrophages and dendritic cells. In contrast, PLGA-MS-based DNA vaccination approaches with a tPrP construct generated poor humoral and T cell responses. Our data show that prophylactic and therapeutic immunization approaches against prion infections might be feasible using tPrP Ag and CpG-ODN adjuvant without detectable side effects. PMID- 17709494 TI - CD101 surface expression discriminates potency among murine FoxP3+ regulatory T cells. AB - CD4+CD25+FoxP3+ regulatory T cells (Treg) have been shown to be protective in animal models of autoimmunity and acute graft-vs-host disease. However, owing to the functional heterogeneity among CD4+CD25+ T cells, surface markers expressed selectively on functionally active Treg would be useful for purposes of identifying and isolating such cells. We generated a rabbit mAb against murine CD101, a transmembrane glycoprotein involved in T cell activation. Among freshly isolated T cells, CD101 was detected on 25-30% of CD4+CD25+ Treg and approximately 20% of conventional memory T cells. CD101(high) Treg displayed greater in vitro suppression of alloantigen-driven T cell proliferation as compared with CD101(low) Treg. In a model of graft-vs-host disease induced by allogeneic bone marrow transplantation in vivo bioluminescence imaging demonstrated reduced expansion of donor-derived luciferase-labeled conventional T cells in mice treated with CD101(high) Treg, compared with CD101(low) Treg. Moreover, treatment with CD101(high) Treg resulted in improved survival, reduced proinflammatory cytokine levels and reduced end organ damage. Among the CD101(high) Treg all of the in vivo suppressor activity was contained within the CD62L(high) subpopulation. We conclude that CD101 expression distinguishes murine Treg with potent suppressor activity. PMID- 17709495 TI - Regulation of antibody-dependent cellular cytotoxicity by IgG intrinsic and apparent affinity for target antigen. AB - Unconjugated mAbs have emerged as useful cancer therapeutics. Ab-dependent cellular cytotoxicity (ADCC) is believed to be a major antitumor mechanism of some anticancer Abs. However, the factors that regulate the magnitude of ADCC are incompletely understood. In this study, we described the relationship between Ab affinity and ADCC. A series of human IgG1 isotype Abs was created from the anti HER2/neu (also named c-erbB2) C6.5 single-chain Fv (scFv) and its affinity mutants. The scFv affinities range from 10(-7) to 10(-11) M, and the IgG Abs retain the affinities of the scFv from which they were derived. The apparent affinity of the Abs ranged from nearly 10(-10) M (the lowest affinity variant) to almost 10(-11) M (the other variants). The IgG molecules were tested for their ability to elicit ADCC in vitro against three tumor cell lines with differing levels of HER2/neu expression using unactivated human PBMC from healthy donors as the effector cells. The results demonstrated that both the apparent affinity and intrinsic affinity of the Abs studied regulate ADCC. High-affinity tumor Ag binding by the IgGs led to the most efficient and powerful ADCC. Tumor cells expressing high levels of HER2/neu are more susceptible to the ADCC triggered by Abs than the cells expressing lower amounts of HER2/neu. These findings justify the examination of high affinity Abs for ADCC promotion. Because high affinity may impair in vivo tumor targeting, a careful examination of Ab structure to function relationships is required to develop optimized therapeutic unconjugated Abs. PMID- 17709496 TI - The antiproliferative effect of mesenchymal stem cells is a fundamental property shared by all stromal cells. AB - Although it has been widely demonstrated that human mesenchymal stem cells exert potent immunosuppressive effects, there is little information as to whether more mature mesenchymal stromal cells (SC) share the same property. Accordingly, we set out to test the ability of SC from different human tissues to inhibit the proliferation of PBMC following polyclonal stimuli. Chondrocytes, as well as fibroblasts from synovial joints, lung, and skin, were used as a source of SC. Irrespective of their differentiation potential and/or content of progenitor cells, SC from all tissues exhibited antiproliferative functions. This was in marked contrast to parenchymal cells. Although SC did not interfere with early T lymphocyte activation, they arrested stimulated T cells in the G(0)/G(1) phase of the cell cycle and rescued them from apoptosis. In addition, IFN-gamma and TNF alpha production were reduced. We observed that the inhibitory effect is ultimately mediated by soluble factors, the production of which requires SC to be licensed in an inflammatory environment by cell contact. We conclude that the immunosuppressive effect of mesenchymal cells is not confined to multipotent stem cells, but is a fundamental characteristic of all stroma. Our data suggest that SC, appropriately licensed, regulate T cell homeostasis. PMID- 17709497 TI - IgE-antibody-dependent immunotherapy of solid tumors: cytotoxic and phagocytic mechanisms of eradication of ovarian cancer cells. AB - Abs have a paramount place in the treatment of certain, mainly lymphoid, malignancies, although tumors of nonhemopoietic origin have proved more refractory ones. We have previously shown that the efficacy of immunotherapy of solid tumors, in particular ovarian carcinoma, may be improved by the use of IgE Abs in place of the conventional IgG. An IgE Ab (MOv18 IgE) against an ovarian tumor-specific Ag (folate binding protein), in combination with human PBMC, introduced into ovarian cancer xenograft-bearing mice, greatly exceeded the analogous IgG1 in promoting survival. In this study, we analyzed the mechanisms by which MOv18 IgE may exert its antitumor activities. Monocytes were essential IgE receptor-expressing effector cells that mediated the enhanced survival of tumor-bearing mice by MOv18 IgE and human PBMC. Monocytes mediated MOv18 IgE dependent ovarian tumor cell killing in vitro by two distinct pathways, cytotoxicity and phagocytosis, acting respectively through the IgE receptors FcepsilonRI and CD23. We also show that human eosinophils were potent effector cells in MOv18 IgE Ab-dependent ovarian tumor cell cytotoxicity in vitro. These results demonstrate that IgE Abs can engage cell surface IgE receptors and activate effector cells against ovarian tumor cells. Our findings offer a framework for an improved immunotherapeutic strategy for combating solid tumors. PMID- 17709498 TI - Targeting T cell-specific costimulators and growth factors in a model of autoimmune hemolytic anemia. AB - Although it is established that failure of regulatory mechanisms underlies many autoimmune diseases, the stimuli that activate autoreactive lymphocytes remain poorly understood. Defining these stimuli will lead to therapeutic strategies for autoimmune diseases. IL-2-deficient mice develop spontaneous autoimmunity, because of a deficiency of regulatory T cells, and on the BALB/c background, they rapidly die from autoimmune hemolytic anemia. To define the importance of costimulatory pathways in various components of this autoimmune disorder, we first intercrossed IL-2-deficient mice with mice lacking CD28 or CD40L. Elimination of CD28 reduced the activation of autoreactive T cells and lymphoproliferation as well as production of autoantibodies, whereas elimination of CD40L reduced autoantibody production without affecting T cell expansion and accumulation. To examine the role of IL-7, we blocked IL-7R signaling with neutralizing Abs. This treatment inhibited the production of autoantibodies and the development of autoimmune hemolytic anemia. Together, these data indicate that specific costimulatory and cytokine signals are critical for the spontaneous autoantibody-mediated disease that develops in IL-2-deficient mice. PMID- 17709499 TI - Altered immune function during long-term host-tumor interactions can be modulated to retard autochthonous neoplastic growth. AB - Ag-specific and generalized forms of immunosuppression have been documented in animal tumor models. However, much of our knowledge on tumor-induced immunosuppression was acquired using tumor implant models, which do not reiterate the protracted nature of host-tumor interactions. Therefore, a transgenic mouse model of autochthonous mammary tumor development and progression was chosen to investigate the long-term consequences of neoplastic growth on the immune system. In vitro proliferation of unfractionated splenocytes from tumor-bearing mice, as assessed by [(3)H]thymidine uptake, was inhibited by the presence of suppressor cells within these splenocyte preparations, because purifying the T cells restored their biological activity. However, the level of inhibition did not correlate with either tumor load or the percentage of myeloid-derived CD11b+Gr1+ cells. To evaluate tumor-specific immune dysfunction, transgenic mice were challenged with autologous tumor cells. Mice with extensive, but not minimal autochthonous tumor burdens demonstrated a significantly enhanced rate of autologous tumor growth compared with age-matched controls. In contrast, an allogeneic tumor challenge was efficiently rejected from both groups of transgenic mice. It was also noted that allogeneic tumor challenge of mice with minimal disease significantly inhibited autochthonous primary tumor growth. We therefore demonstrated that 1) a generalized form of immunosuppression occurred, but not as a result of permanent alterations to T cell function, because purified T cell subsets retained normal biological activity following polyclonal or allostimulation; and 2) tumor-specific immunosuppression emerged as a consequence of tumor progression, but could be modulated to enhance antitumor responses against autochthonous primary neoplastic growth. PMID- 17709500 TI - Targeting molecular and cellular inhibitory mechanisms for improvement of antitumor memory responses reactivated by tumor cell vaccine. AB - Development of effective vaccination approaches to treat established tumors represents a focus of intensive research because such approaches offer the promise of enhancing immune system priming against tumor Ags via restimulation of pre-existing (memory) antitumoral helper and effector immune cells. However, inhibitory mechanisms, which function to limit the recall responses of tumor specific immunity, remain poorly understood and interfere with therapies anticipated to induce protective immunity. The mouse renal cell carcinoma (RENCA) tumor model was used to investigate variables affecting vaccination outcomes. We demonstrate that although a whole cell irradiated tumor cell vaccine can trigger a functional antitumor memory response in the bone marrows of mice with established tumors, these responses do not culminate in the regression of established tumors. In addition, a CD103+ regulatory T (Treg) cell subset accumulates within the draining lymph nodes of tumor-bearing mice. We also show that B7-H1 (CD274, PD-L1), a negative costimulatory ligand, and CD4+ Treg cells collaborate to impair the recall responses of tumor-specific memory T cells. Specifically, mice bearing large established RENCA tumors were treated with tumor cell vaccination in combination with B7-H1 blockade and CD4+ T cell depletion (triple therapy treatment) and monitored for tumor growth and survival. Triple treatment therapy induced complete regression of large established RENCA tumors and raised long-lasting protective immunity. These results have implications for developing clinical antitumoral vaccination regimens in the setting in which tumors express elevated levels of B7-H1 in the presence of abundant Treg cells. PMID- 17709501 TI - Dynamic control of self-specific CD8+ T cell responses via a combination of signals mediated by dendritic cells. AB - It is acknowledged that T cell interactions with mature dendritic cells (DC) lead to immunity, whereas interactions with immature DC lead to tolerance induction. Using a transgenic murine system, we have examined how DC expressing self peptides control naive, self-reactive CD8+ T cell responses in vitro and in vivo. We have shown, for the first time, that immature DC can also stimulate productive activation of naive self-specific CD8+ T cells, which results in extensive proliferation, the expression of a highly activated cell surface phenotype, and differentiation into autoimmune CTL. Conversely, mature DC can induce abortive activation of naive CD8+ T cells, which is characterized by low-level proliferation, the expression of a partially activated cell surface phenotype which does not result in autoimmune CTL. Critically, both CD8+ T cell responses are determined by a combination of signals mediated by the DC, and that altering any one of these signals dramatically shifts the balance between autoimmunity and self-tolerance induction. We hypothesize that DC maintain the steady state of self-tolerance among self-specific CD8+ T cells in an active and dynamic manner, licensing productive immune responses against self-tissues only when required. PMID- 17709502 TI - CCL19 and CXCL13 synergistically regulate interaction between B cell acute lymphocytic leukemia CD23+CD5+ B Cells and CD8+ T cells. AB - Interacting with T cells, cytokine-producing B cells play a critical protective role in autoimmune diseases. However, the interaction between malignant B and T cells remains to be fully elucidated. In a previous study, we have reported that ligation of CCL19-CCR7 and CXCL13-CXCR5 activates paternally expressed gene 10 (PEG10), resulting in an enhancement of apoptotic resistance in B-cell acute lymphocytic leukemia (B-ALL) CD23+CD5+ B cells. Here, we report that B-ALL CD23+CD5+ B cells produce IL-10 at high level, which can be further elevated by costimulation with CCL19 and CXCL13. CCL19/CXCL13-activated B-ALL CD23+CD5+ B cells, in turn, increase IL-10 expression in syngeneic CD8+ T cells in a B cell derived IL-10-dependent manner and requiring a cell-cell contact. IL-10 secreted from B-ALL CD23+CD5+ B cells in vitro impairs tumor-specific CTL responses of syngeneic CD8+ T cells. The impairment of cytotoxicity of syngeneic CD8+ T cells is escalated by means of CCL19/CXCL13-induced up-regulation of IL-10 from B-ALL CD23+CD5+ B cells. Moreover, using a short hairpin RNA to knockdown PEG10, we provide direct evidence that increased expression of PEG10 in B-ALL CD23+CD5+ B cells is involved in malignant B-T cell interaction, contributing to the up regulation of IL-10 expression, as well as to the impairment of cytotoxicity of syngeneic CD8+ T cells. Thus, malignant B-ALL CD23+CD5+ B cells play an immunoregulatory role in controlling different inflammatory cytokine expressions. IL-10 may be one of the critical cellular factors conferring B-ALL CD23+CD5+ B cells to escape from host immune surveillance. PMID- 17709504 TI - Tumors hamper the immunogenic competence of CD4+ T cell-directed dendritic cell vaccination. AB - Dendritic cells loaded with tumor-derived peptides induce protective CTL responses and are under evaluation in clinical trails. We report in this study that prophylactic administration of dendritic cells loaded with a MHC class II restricted peptide derived from a model tumor Ag (Leishmania receptor for activated C kinase (LACK)) confers protection against LACK-expressing TS/A tumors, whereas therapeutic vaccination fails to cure tumor-bearing mice. Although CD4+ T cell-directed dendritic cell vaccination primed effector-like (CD44(high)CD62L(low), IL-2(+), IFN-gamma(+)) and central memory-like lymphocytes (CD44(high)CD62L(high), only IL-2(+)) in tumor-free mice, this was not the case in tumor-bearing animals in which both priming and persistence of CD4+ T cell memory were suppressed. Suppression was specific for the tumor-associated Ag LACK, and did not depend on CD25+ T cells. Because T cell help is needed for protective immunity, we speculate that the ability of tumors to limit vaccine induced CD4+ T cell memory could provide a partial explanation for the limited efficacy of current strategies. PMID- 17709503 TI - T cells express alpha7-nicotinic acetylcholine receptor subunits that require a functional TCR and leukocyte-specific protein tyrosine kinase for nicotine induced Ca2+ response. AB - Acute and chronic effects of nicotine on the immune system are usually opposite; acute treatment stimulates while chronic nicotine suppresses immune and inflammatory responses. Nicotine acutely raises intracellular calcium ([Ca(2+)](i)) in T cells, but the mechanism of this response is unclear. Nicotinic acetylcholine receptors (nAChRs) are present on neuronal and non neuronal cells, but while in neurons, nAChRs are cation channels that participate in neurotransmission; their structure and function in nonexcitable cells are not well-defined. In this communication, we present evidence that T cells express alpha7-nAChRs that are critical in increasing [Ca(2+)](i) in response to nicotine. Cloning and sequencing of the receptor from human T cells showed a full length transcript essentially identical to the neuronal alpha7-nAChR subunit (>99.6% homology). These receptors are up-regulated and tyrosine phosphorylated by treatment with nicotine, anti-TCR Abs, or Con A. Furthermore, knockdown of the alpha7-nAChR subunit mRNA by RNA interference reduced the nicotine-induced Ca(2+) response, but unlike the neuronal receptor, alpha-bungarotoxin and methyllycaconitine not only failed to block, but also actually raised [Ca(2+)](i) in T cells. The nicotine-induced release of Ca(2+) from intracellular stores in T cells did not require extracellular Ca(2+), but, similar to the TCR-mediated Ca(2+) response, required activation of protein tyrosine kinases, a functional TCR/CD3 complex, and leukocyte-specific tyrosine kinase. Moreover, CD3zeta and alpha7-nAChR co-immunoprecipitated with anti-CD3zeta or anti-alpha7-nAChR Abs. These results suggest that in T cells, alpha7-nAChR, despite its close sequence homology with neuronal alpha7-nAChR, fails to form a ligand-gated Ca(2+) channel, and that the nicotine-induced rise in [Ca(2+)](i) in T cells requires functional TCR/CD3 and leukocyte-specific tyrosine kinase. PMID- 17709505 TI - Proteinase-activated receptor-2 promotes allergic sensitization to an inhaled antigen through a TNF-mediated pathway. AB - The reason why particular inhaled Ags induce allergic sensitization while others lead to immune tolerance is unclear. Along with a genetic predisposition to atopy, intrinsic characteristics of these Ags must be important. A common characteristic of many allergens is that they either possess proteinase activity or are inhaled in particles rich in proteinases. Many allergens, such as house dust mite and cockroach allergens, have the potential to activate the proteinase activated receptor (PAR)-2. In this study, we report that PAR-2 activation in the airways at the same time as exposure to inhaled Ags induces allergic sensitization, whereas exposure to Ag alone induces tolerance. BALB/c mice were administered OVA with a PAR-2 activating peptide intranasally. Upon allergen re exposure mice developed airway inflammation and airway hyperresponsiveness, as well as OVA-specific T cells with a Th2 cytokine profile when restimulated with OVA in vitro. Conversely, mice given OVA alone or OVA with a PAR-2 control peptide developed tolerance. These tolerant mice did not develop airway inflammation or airway hyperresponsiveness, and developed OVA-specific T cells that secreted high levels of IL-10 when restimulated with OVA in vitro. Furthermore, pulmonary dendritic cell trafficking was altered in mice following intranasal PAR-2 activation. Finally, we showed that PAR-2-mediated allergic sensitization was TNF-dependent. Thus, PAR-2 activation in the airways could be a critical factor in the development of allergic sensitization following mucosal exposure to allergens with serine proteinase activity. Interfering with this pathway may prove to be useful for the prevention or treatment of allergic diseases. PMID- 17709506 TI - FcR gamma-chain dependent signaling in immature neutrophils is mediated by FcalphaRI, but not by FcgammaRI. AB - Neutrophil-mediated tumor cell lysis is more efficiently triggered by FcalphaRI (CD89), than by FcgammaRI (CD64). This difference is most evident in immature neutrophils in which FcgammaRI-mediated tumor cell lysis is absent. In this study, we show that FcR gamma-chain-dependent functions (such as Ab-dependent cellular cytotoxicity and respiratory burst), as well as signaling (calcium mobilization and MAPK phosphorylation), were potently triggered via FcalphaRI, but not via FcgammaRI, in immature neutrophils. Internalization, an FcR gamma chain-independent function, was, however, effectively initiated via both receptors. These data suggest an impaired functional association between FcgammaRI and the FcR gamma-chain, which prompted us to perform coimmunoprecipitation experiments. As a weaker association was observed between FcgammaRI and FcR gamma-chain, compared with FcalphaRI and FcR gamma-chain, our data support that differences between FcalphaRI- and FcgammaRI-mediated functions are attributable to dissimilarities in association with the FcR gamma-chain. PMID- 17709507 TI - Identification of an IL-7-dependent pre-T committed population in the spleen. AB - Several extrathymic T cell progenitors have been described but their various contributions to the T cell lineage puzzle are unclear. In this study, we provide evidence for a splenic Lin(-)Thy1.2(+) T cell-committed population, rare in B6 mice, abundant in TCRalpha(-/-), CD3epsilon(-/-), and nude mice, and absent in IL 7- and Rag-2-deficient mice. Neither B nor myeloid cells are generated in vivo and in vitro. The incidence of these pre-T cells is under the control of thymus and/or mature T cells, as revealed by graft experiments. Indeed, IL-7 consumption by mature T cells inhibits the growth of these pre-T cells. Moreover, the nude spleen contains an additional Lin(-)Thy1.2(+)CD25(+) subset which is detected in B6 mice only after thymectomy. We establish that the full pre-T cell potential and proliferation capacity are only present in the c-kit(low) fraction of progenitors. We also show that most CCR9(+) progenitors are retained in the spleen of nude mice, but present in the blood of B6 mice. Thus, our data describe a new T cell lineage restricted subset that accumulates in the spleen before migration to the thymus. PMID- 17709508 TI - Effector mechanisms of recombinant IgA antibodies against epidermal growth factor receptor. AB - IgA is the most abundantly produced Ab isotype in humans, but its potential as immunotherapeutic reagent has hardly been explored. In this study, we describe anti-tumor mechanisms of mouse/human chimeric IgA Abs against the epidermal growth factor receptor (EGF-R). EGF-R Abs of IgG isotype are currently approved for the treatment of colon or head and neck cancers. As expected, the human IgG1, IgA(1), and IgA(2) variants of the 225 Ab demonstrated similar binding to EGF-R. Furthermore, IgA Abs were as effective as IgG in mediating direct effector mechanisms such as blockade of EGF binding, inhibition of EGF-R phosphorylation, and induction of growth inhibition. None of the three variants induced complement mediated lysis. Human IgG1 effectively recruited MNC for ADCC, but activated PMN only weakly, whereas both IgA isoforms proved to be effective in triggering neutrophils. Interestingly, the IgA(2) isoform was significantly superior to its IgA(1) counterpart in recruiting PMN as effector cells. Because neutrophils constitute the most abundant effector cell population in human blood, this enhanced neutrophil recruitment lead to increased killing of EGF-R expressing tumor cells in whole blood assays. This killing was further enhanced when blood from G-CSF-primed donors was compared with healthy donor blood. Together, these data suggest EGF-R Abs of human IgA isotype to bear promise for therapeutic use in cancer. PMID- 17709509 TI - Dynamics of CD8+ T cell responses during acute and chronic lymphocytic choriomeningitis virus infection. AB - Infection of mice with lymphocytic choriomeningitis virus (LCMV) is frequently used to study the underlying principles of viral infections and immune responses. We fit a mathematical model to recently published data characterizing Ag-specific CD8+ T cell responses during acute (Armstrong) and chronic (clone 13) LCMV infection. This allows us to analyze the differences in the dynamics of CD8+ T cell responses against different types of LCMV infections. For the four CD8+ T cell responses studied, we find that, compared with the responses against acute infection, responses against chronic infection are generally characterized by an earlier peak and a faster contraction phase thereafter. Furthermore, the model allows us to give a new interpretation of the effect of thymectomy on the dynamics of CD8+ T cell responses during chronic LCMV infection: a smaller number of naive precursor cells is sufficient to account for the observed differences in the responses in thymectomized mice. Finally, we compare data characterizing LCMV specific CD8+ T cell responses from different laboratories. Although the data were derived from the same experimental model, we find quantitative differences that can be solved by introducing a scaling factor. Also, we find kinetic differences that are at least partly due to the infrequent measurements of CD8+ T cells in the different laboratories. PMID- 17709510 TI - CD8+ T cell activation is governed by TCR-peptide/MHC affinity, not dissociation rate. AB - Binding of peptide/MHC (pMHC) complexes by TCR initiates T cell activation. Despite long interest, the exact relationship between the biochemistry of TCR/pMHC interaction (particularly TCR affinity or ligand off-rate) and T cell responses remains unresolved, because the number of complexes examined in each independent system has been too small to draw a definitive conclusion. To test the current models of T cell activation, we have analyzed the interactions between the mouse P14 TCR and a set of altered peptides based on the lymphocytic choriomeningitis virus epitope gp33-41 sequence bound to mouse class I MHC D(b). pMHC binding, TCR-binding characteristics, CD8+ T cell cytotoxicity, and IFN gamma production were measured for the peptides. We found affinity correlated well with both cytotoxicity and IFN-gamma production. In contrast, no correlation was observed between any kinetic parameter of TCR-pMHC interaction and cytotoxicity or IFN-gamma production. This study strongly argues for an affinity threshold model of T cell activation. PMID- 17709511 TI - Airway hyperresponsiveness through synergy of gammadelta} T cells and NKT cells. AB - Mice sensitized and challenged with OVA were used to investigate the role of innate T cells in the development of allergic airway hyperresponsiveness (AHR). AHR, but not eosinophilic airway inflammation, was induced in T cell-deficient mice by small numbers of cotransferred gammadelta T cells and invariant NKT cells, whereas either cell type alone was not effective. Only Vgamma1+Vdelta5+ gammadelta T cells enhanced AHR. Surprisingly, OVA-specific alphabeta T cells were not required, revealing a pathway of AHR development mediated entirely by innate T cells. The data suggest that lymphocytic synergism, which is key to the Ag-specific adaptive immune response, is also intrinsic to T cell-dependent innate responses. PMID- 17709512 TI - Identification of ERdj3 and OBF-1/BOB-1/OCA-B as direct targets of XBP-1 during plasma cell differentiation. AB - Plasma cell differentiation is accompanied by a modified unfolded protein response (UPR), which involves activation of the Ire1 and activating transcription factor 6 branches, but not the PKR-like endoplasmic reticulum kinase branch. Ire1-mediated splicing of XBP-1 (XBP-1(S)) is required for terminal differentiation, although the direct targets of XBP-1(S) in this process have not been identified. We demonstrate that XBP-1(S) binds to the promoter of ERdj3 in plasmacytoma cells and in LPS-stimulated primary splenic B cells, which corresponds to increased expression of ERdj3 transcripts in both cases. When small hairpin RNA was used to decrease XBP-1 expression in plasmacytoma lines, ERdj3 transcripts were concomitantly reduced. The accumulation of Ig gamma H chain protein was also diminished, but unexpectedly this occurred at the transcriptional level as opposed to effects on H chain stability. The decrease in H chain transcripts correlated with a reduction in mRNA encoding the H chain transcription factor, OBF-1/BOB-1/OCA-B. Chromatin immunoprecipitation experiments revealed that XBP-1(S) binds to the OBF-1/BOB-1/OCA-B promoter in the plasmacytoma line and in primary B cells not only during plasma cell differentiation, but also in response to classical UPR activation. Gel shift assays suggest that XBP-1(S) binding occurs through a UPR element conserved in both murine and human OBF-1/BOB-1/OCA-B promoters as opposed to endoplasmic reticulum stress response elements. Our studies are the first to identify direct downstream targets of XBP-1(S) during either plasma cell differentiation or the UPR. In addition, our data further define the XBP-1(S)-binding sequence and provide yet another role for this protein as a master regulator of plasma cell differentiation. PMID- 17709513 TI - Immune evasion of the human pathogen Pseudomonas aeruginosa: elongation factor Tuf is a factor H and plasminogen binding protein. AB - Pseudomonas aeruginosa is an opportunistic human pathogen that can cause a wide range of clinical symptoms and infections that are frequent in immunocompromised patients. In this study, we show that P. aeruginosa evades human complement attack by binding the human plasma regulators Factor H and Factor H-related protein-1 (FHR-1) to its surface. Factor H binds to intact bacteria via two sites that are located within short consensus repeat (SCR) domains 6-7 and 19-20, and FHR-1 binds within SCR domain 3-5. A P. aeruginosa Factor H binding protein was isolated using a Factor H affinity matrix, and was identified by mass spectrometry as the elongation factor Tuf. Factor H uses the same domains for binding to recombinant Tuf and to intact bacteria. Factor H bound to recombinant Tuf displayed cofactor activity for degradation of C3b. Similarly Factor H bound to intact P. aeruginosa showed complement regulatory activity and mediated C3b degradation. This acquired complement control was rather effective and acted in concert with endogenous proteases. Immunolocalization identified Tuf as a surface protein of P. aeruginosa. Tuf also bound plasminogen, and Tuf-bound plasminogen was converted by urokinase plasminogen activator to active plasmin. Thus, at the bacterial surface Tuf acts as a virulence factor and binds the human complement regulator Factor H and plasminogen. Acquisition of host effector proteins to the surface of the pathogen allows complement control and may facilitate tissue invasion. PMID- 17709514 TI - Staphylococcal complement inhibitor: structure and active sites. AB - The pathogenic bacterium Staphylococcus aureus counteracts the host immune defense by excretion of the 85 residue staphylococcal complement inhibitor (SCIN). SCIN inhibits the central complement convertases; thereby, it reduces phagocytosis following opsonization and efficiently blocks all downstream effector functions. In this study, we present the crystal structure of SCIN at 1.8 A resolution and the identification of its active site. Functional characterization of structure based chimeric proteins, consisting of SCIN and the structurally but nonfunctional homologue open reading frame-D, indicate an 18 residue segment (Leu-31-Gly-48) crucial for SCIN activity. In all complement activation pathways, chimeras lacking these SCIN residues completely fail to inhibit production of the potent mediator of inflammation C5a. Inhibition of alternative pathway-mediated opsonization (C3b deposition) and formation of the lytic membrane attack complex (C5b-9 deposition) are strongly reduced for these chimeras as well. For inhibition of the classical/lectin pathway-mediated C3b and C5b-9 deposition, the same residues are critical although additional sites are involved. These chimeras also display reduced capacity to stabilize the C3 convertases of both the alternative and the classical/lectin pathway indicating the stabilizing effect is pivotal for the complement inhibitory activity of SCIN. Because SCIN specifically and efficiently inhibits complement, it has a high potential in anti-inflammatory therapy. Our data are a first step toward the development of a second generation molecule suitable for such therapeutic complement intervention. PMID- 17709515 TI - NF-kappaB signaling regulates functional expression of the MHC class I-related neonatal Fc receptor for IgG via intronic binding sequences. AB - The neonatal Fc receptor for IgG (FcRn) functions to transport maternal IgG to a fetus or newborn and to protect IgG from degradation. Although FcRn is expressed in a variety of tissues and cell types, the extent to which FcRn expression is regulated by immunological and inflammatory events remains unknown. Stimulation of intestinal epithelial cell lines, macrophage-like THP-1, and freshly isolated human monocytes with the cytokine TNF-alpha rapidly up-regulated FcRn gene expression. In addition, the TLR ligands LPS and CpG oligodeoxynucleotide enhanced the level of FcRn expression in THP-1 and monocytes. Treatment of TNF stimulated THP-1 cells with the NF-kappaB-specific inhibitor or overexpression of a dominant negative mutant inhibitory NF-kappaB (IkappaBalpha; S32A/S36A) resulted in down-regulation of FcRn expression. By using chromatin immunoprecipitation we identified three NF-kappaB binding sequences within introns 2 and 4 of the human FcRn gene. An EMSA confirmed the p50/p50 and/or p65/p50 complex (s) bound to intron 2- or 4-derived oligonucleotides containing putative NF-kappaB binding sequences, respectively. The intronic NF-kappaB sequences in combination with the promoter or alone regulated the expression of a luciferase reporter gene in response to TNF-alpha stimulation or overexpression of NF-kappaB p65 and p50. DNA looping interactions potentially occurred after the stimulation between intronic NF-kappaB sequences and the FcRn promoter as shown by a chromosome conformation capture assay. Finally, TNF-alpha stimulations enhanced IgG transport across an intestinal Caco-2 epithelial monolayer. Together, these data provide the first evidence that NF-kappaB signaling via intronic sequences regulates FcRn expression and function. PMID- 17709516 TI - Sensitive and specific real-time polymerase chain reaction assays to accurately determine copy number variations (CNVs) of human complement C4A, C4B, C4-long, C4 short, and RCCX modules: elucidation of C4 CNVs in 50 consanguineous subjects with defined HLA genotypes. AB - Recent comparative genome hybridization studies revealed that hundreds to thousands of human genomic loci can have interindividual copy number variations (CNVs). One of such CNV loci in the HLA codes for the immune effector protein complement component C4. Sensitive, specific, and accurate assays to interrogate the C4 CNV and its associated polymorphisms by using submicrogram quantities of genomic DNA are needed for high throughput epidemiologic studies of C4 CNVs in autoimmune, infectious, and neurological diseases. Quantitative real-time PCR (qPCR) assays were developed using TaqMan chemistry and based on sequences specific for C4A and C4B genes, structural characteristics corresponding to the long and short forms of C4 genes, and the breakpoint region of RP-C4-CYP21-TNX (RCCX) modular duplication. Assignments for gene copy numbers were achieved by relative standard curve methods using cloned C4 genomic DNA covering 6 logs of DNA concentrations for calibrations. The accuracies of test results were cross confirmed internally in each sample, as the sum of C4A plus C4B equals to the sum of C4L plus C4S or the total copy number of RCCX modules. These qPCR assays were applied to determine C4 CNVs from samples of 50 consanguineous subjects who were mostly homozygous in HLA genotypes. The results revealed eight HLA haplotypes with single C4 genes in monomodular RCCX that are associated with multiple autoimmune and infectious diseases and 32 bimodular, 4 trimodular, and one quadrimodular RCCX. These C4 qPCR assays are proven to be robust, sensitive, and reliable, as they have contributed to the elucidation of C4 CNVs in >1000 human samples with autoimmune and neurological diseases. PMID- 17709517 TI - Severe depletion of mucosal CD4+ T cells in AIDS-free simian immunodeficiency virus-infected sooty mangabeys. AB - HIV-infected humans and SIV-infected rhesus macaques experience a rapid and dramatic loss of mucosal CD4+ T cells that is considered to be a key determinant of AIDS pathogenesis. In this study, we show that nonpathogenic SIV infection of sooty mangabeys (SMs), a natural host species for SIV, is also associated with an early, severe, and persistent depletion of memory CD4+ T cells from the intestinal and respiratory mucosa. Importantly, the kinetics of the loss of mucosal CD4+ T cells in SMs is similar to that of SIVmac239-infected rhesus macaques. Although the nonpathogenic SIV infection of SMs induces the same pattern of mucosal target cell depletion observed during pathogenic HIV/SIV infections, the depletion in SMs occurs in the context of limited local and systemic immune activation and can be reverted if virus replication is suppressed by antiretroviral treatment. These results indicate that a profound depletion of mucosal CD4+ T cells is not sufficient per se to induce loss of mucosal immunity and disease progression during a primate lentiviral infection. We propose that, in the disease-resistant SIV-infected SMs, evolutionary adaptation to both preserve immune function with fewer mucosal CD4+ T cells and attenuate the immune activation that follows acute viral infection protect these animals from progressing to AIDS. PMID- 17709519 TI - Virally induced CD4+ T cell depletion is not sufficient to induce AIDS in a natural host. AB - Peripheral blood CD4+ T cell counts are a key measure for assessing disease progression and need for antiretroviral therapy in HIV-infected patients. More recently, studies have demonstrated a dramatic depletion of mucosal CD4+ T cells during acute infection that is maintained during chronic pathogenic HIV as well as SIV infection. A different clinical disease course is observed during the infection of natural hosts of SIV infection, such as sooty mangabeys (Cercocebus atys), which typically do not progress to AIDS. Previous studies have determined that SIV+ mangabeys generally maintain healthy levels of CD4+ T cells despite having viral replication comparable to HIV-infected patients. In this study, we identify the emergence of a multitropic (R5/X4/R8-using) SIV infection after 43 or 71 wk postinfection in two mangabeys that is associated with an extreme, persistent (>5.5 years), and generalized loss of CD4+ T cells (5-80 cells/microl of blood) in the absence of clinical signs of AIDS. This study demonstrates that generalized CD4+ T cell depletion from the blood and mucosal tissues is not sufficient to induce AIDS in this natural host species. Rather, AIDS pathogenesis appears to be the cumulative result of multiple aberrant immunologic parameters that include CD4+ T cell depletion, generalized immune activation, and depletion/dysfunction of non-CD4+ T cells. Therefore, these data provide a rationale for investigating multifaceted therapeutic strategies to prevent progression to AIDS, even following dramatic CD4 depletion, such that HIV+ humans can survive normal life spans analogous to what occurs naturally in SIV+ mangabeys. PMID- 17709520 TI - Central memory Vgamma9Vdelta2 T lymphocytes primed and expanded by bacillus Calmette-Guerin-infected dendritic cells kill mycobacterial-infected monocytes. AB - In humans, innate immune recognition of mycobacteria, including Mycobacterium tuberculosis and bacillus Calmette-Guerin (BCG), is a feature of cells as dendritic cells (DC) and gammadelta T cells. In this study, we show that BCG infection of human monocyte-derived DC induces a rapid activation of Vgamma9Vdelta2 T cells (the major subset of gammadelta T cell pool in human peripheral blood). Indeed, in the presence of BCG-infected DC, Vgamma9Vdelta2 T cells increase both their expression of CD69 and CD25 and the production of TNF alpha and IFN-gamma, in contrast to DC treated with Vgamma9Vdelta2 T cell specific Ags. Without further exogenous stimuli, BCG-infected DC expand a functionally cytotoxic central memory Vgamma9Vdelta2 T cell population. This subset does not display lymph node homing receptors, but express a high amount of perforin. They are highly efficient in the killing of mycobacterial-infected primary monocytes or human monocytic THP-1 cells preserving the viability of cocultured, infected DC. This study provides further evidences about the complex relationship between important players of innate immunity and suggests an immunoregulatory role of Vgamma9Vdelta2 T cells in the control of mycobacterial infection. PMID- 17709518 TI - Acute loss of intestinal CD4+ T cells is not predictive of simian immunodeficiency virus virulence. AB - The predictive value of acute gut-associated lymphoid tissue (GALT) CD4+ T cell depletion in lentiviral infections was assessed by comparing three animal models illustrative of the outcomes of SIV infection: pathogenic infection (SIVsmm infection of rhesus macaques (Rh)), persistent nonprogressive infection (SIVagm infection of African green monkeys (AGM)), and transient, controlled infection (SIVagm infection of Rh). Massive acute depletion of GALT CD4+ T cells was a common feature of acute SIV infection in all three models. The outcome of this mucosal CD4+ T cell depletion, however, differed substantially between the three models: in SIVsmm-infected Rh, the acute GALT CD4+ T cell depletion was persistent and continued with disease progression; in SIVagm, intestinal CD4+ T cells were partially restored during chronic infection in the context of normal levels of apoptosis and immune activation and absence of damage to the mucosal immunologic barrier; in SIVagm-infected Rh, complete control of viral replication resulted in restoration of the mucosal barrier and immune restoration. Therefore, our data support a revised paradigm wherein severe GALT CD4+ T cell depletion during acute pathogenic HIV and SIV infections of humans and Rh is necessary but neither sufficient nor predictive of disease progression, with levels of immune activation, proliferation and apoptosis being key factors involved in determining progression to AIDS. PMID- 17709521 TI - Polymorphisms in genes involved in innate immunity predispose toward mycetoma susceptibility. AB - Madurella mycetomatis is the main causative agent of mycetoma, a tumorous fungal infection characterized by the infiltration of large numbers of neutrophils at the site of infection. In endemic areas the majority of inhabitants have Abs to M. mycetomatis, although only a small proportion of individuals actually develop mycetomal disease. It therefore appears that neutrophils are unable to clear the infection in some individuals. To test this hypothesis, 11 single nucleotide polymorphisms involved in neutrophil function were studied in a population of Sudanese mycetoma patients vs geographically and ethnically matched controls. Significant differences in allele distribution for IL-8 (CXCL8), its receptor CXCR2, thrombospondin-4 (TSP-4), NO synthase 2 (NOS2), and complement receptor 1 (CR1) were found. Further, the NOS2(Lambarene) polymorphism was clearly associated with lesion size. The genotypes obtained for CXCL8, its receptor CXCR2, and TSP-4 all predisposed to a higher CXCL8 expression in patients, which was supported by the detection of significantly elevated levels of CXCL8 in patient serum. The NOS2 genotype observed in healthy controls was correlated with an increase in NOS2 expression and higher concentrations of nitrate and nitrite in control serum. We present the first evidence of human genetic predisposition toward susceptibility to mycetoma, a neglected infection of the poor. PMID- 17709522 TI - Protein phosphatase 2A plays an important role in stromal cell-derived factor 1/CXC chemokine ligand 12-mediated migration and adhesion of CD34+ cells. AB - Migration of hemopoietic stem and progenitor cells (HSPC) is required for homing to bone marrow following transplantation. Therefore, it is critical to understand signals underlying directional movement of HSPC. Stromal cell-derived factor-1 (SDF-1)/CXCL12 is a potent chemoattractant for HSPC. In this study, we demonstrate that the serine-threonine protein phosphatase (PP)2A plays an important role in regulation of optimal level and duration of Akt/protein kinase B activation (a molecule important for efficient chemotaxis), in response to SDF 1. Inhibition of PP2A, using various pharmacological inhibitors of PP2A including okadaic acid (OA) as well as using genetic approaches including dominant-negative PP2A-catalytic subunit (PP2A-C) or PP2A-C small interfering RNA, in primary CD34(+) cord blood (CB) cells led to reduced chemotaxis. This was associated with impairment in polarization and slower speed of movement in response to SDF-1. Concomitantly, SDF-1-induced Akt phosphorylation was robust and prolonged. Following SDF-1 stimulation, Akt and PP2A-C translocate to plasma membrane with enhanced association of PP2A-C with Akt observed at the plasma membrane. Inhibition of PI3K by low-dose LY294002 partially recovered chemotactic activity of cells pretreated with OA. In addition to chemotaxis, adhesion of CD34(+) cells to fibronectin was impaired by OA pretreatment. Our study demonstrates PP2A plays an important role in chemotaxis and adhesion of CD34(+) CB cells in response to SDF-1. CD34(+) CB cells pretreated with OA showed impaired ability to repopulate NOD-SCID mice in vivo, suggesting physiological relevance of these observations. PMID- 17709523 TI - A galectin of unique domain organization from hemocytes of the Eastern oyster (Crassostrea virginica) is a receptor for the protistan parasite Perkinsus marinus. AB - Invertebrates display effective innate immune responses for defense against microbial infection. However, the protozoan parasite Perkinsus marinus causes Dermo disease in the eastern oyster Crassostrea virginica and is responsible for catastrophic damage to shellfisheries and the estuarine environment in North America. The infection mechanisms remain unclear, but it is likely that, while filter feeding, the healthy oysters ingest P. marinus trophozoites released to the water column by the infected neighboring individuals. Inside oyster hemocytes, trophozoites resist oxidative killing, proliferate, and spread throughout the host. However, the mechanism(s) for parasite entry into the hemocyte are unknown. In this study, we show that oyster hemocytes recognize P. marinus via a novel galectin (C. virginica galectin (CvGal)) of unique structure. The biological roles of galectins have only been partly elucidated, mostly encompassing embryogenesis and indirect roles in innate and adaptive immunity mediated by the binding to endogenous ligands. CvGal recognized a variety of potential microbial pathogens and unicellular algae, and preferentially, Perkinsus spp. trophozoites. Attachment and spreading of hemocytes to foreign surfaces induced localization of CvGal to the cell periphery, its secretion and binding to the plasma membrane. Exposure of hemocytes to Perkinsus spp. trophozoites enhanced this process further, and their phagocytosis could be partially inhibited by pretreatment of the hemocytes with anti-CvGal Abs. The evidence presented indicates that CvGal facilitates recognition of selected microbes and algae, thereby promoting phagocytosis of both potential infectious challenges and phytoplankton components, and that P. marinus subverts the host's immune/feeding recognition mechanism to passively gain entry into the hemocytes. PMID- 17709524 TI - FMS-like tyrosine kinase 3 ligand aggravates the lung inflammatory response to Streptococcus pneumoniae infection in mice: role of dendritic cells. AB - Pretreatment of mice with the hemopoietic growth factor, FMS-like tyrosine kinase 3 ligand (Flt3L), has been shown to increase monocyte-derived myeloid dendritic cells (DC) in lung parenchymal tissue, with possible implications for protective immunity to lung bacterial infections. However, whether Flt3L treatment improves lung innate immunity of mice to challenge with Streptococcus pneumoniae has not been investigated previously. Mice pretreated with Flt3L exhibited a peripheral monocytosis and a strongly expanded lung myeloid DC pool, but responded with a similar proinflammatory cytokine release (TNF-alpha, IL-6, keratinocyte derived cytokine, MIP-2, CCL2) and neutrophilic alveolitis upon infection with S. pneumoniae as did control mice with a normal lung DC pool. Unexpectedly, however, Flt3L-pretreated mice, but not control mice, infected with S. pneumoniae developed vasculitis and increased lung permeability by days 2-3 postinfection, and florid pneumonia accompanied by sustained increased bacterial loads by days 3 4 postinfection. This was associated with an overall increased mortality of approximately 35% by day 4 after pneumococcal challenge. Application of anti-CCR2 Ab MC21 to block inflammatory monocyte-dependent lung mononuclear phagocyte mobilization significantly reduced the lung leakage, but not vasculitis in Flt3L pretreated mice infected with S. pneumoniae, without affecting the intra-alveolar cytokine liberation or the concomitantly developing neutrophilic alveolitis. Together, the data demonstrate that previous Flt3L-induced lung DC accumulation is not protective in lung innate immunity to challenge with S. pneumoniae, and support the concept that CCR2-dependent mononuclear phagocyte as opposed to neutrophil recruitment contributes to increased lung leakage in Flt3L-pretreated mice challenged with S. pneumoniae. PMID- 17709525 TI - The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4. AB - Ileal Crohn's disease (CD), a chronic mucosal inflammation, is characterized by two pertinent features: a specific decrease of Paneth cell-produced antimicrobial alpha-defensins and the presence of mucosal-adherent bacteria. A mutation in NOD2, the muramyl dipeptide recognition receptor, is found in some patients, which leads to an even more pronounced alpha-defensin decrease. However, the underlying mechanism remains unclear for the majority of patients. In this study, we report a reduced expression in ileal CD of the Wnt-signaling pathway transcription factor Tcf-4, a known regulator of Paneth cell differentiation and alpha-defensin expression. Within specimens, the levels of Tcf-4 mRNA showed a high degree of correlation with both HD5 and HD6 mRNA. The levels of Tcf-4 mRNA were decreased in patients with ileal disease irrespective of degree of inflammation, but were not decreased in colonic CD or ulcerative colitis. As a functional indicator of Tcf-4 protein, quantitative binding analysis with nuclear extracts from small intestine biopsies to a Tcf-4 high-affinity binding site in the HD-5 and HD-6 promoters showed significantly reduced activity in ileal CD. Furthermore, a causal link was shown in a murine Tcf-4 knockout model, where the comparably reduced expression of Tcf-4 in heterozygous (+/-) mice was sufficient to cause a significant decrease of both Paneth cell alpha-defensin levels and bacterial killing activity. Finally, the association between Paneth cell alpha defensins and Tcf-4 was found to be independent of the NOD2 genotype. This new link established between a human inflammatory bowel disease and the Wnt pathway/Tcf-4 provides a novel mechanism for pathogenesis in patients with ileal CD. PMID- 17709526 TI - Damping excessive inflammation and tissue damage in Mycobacterium tuberculosis infection by Toll IL-1 receptor 8/single Ig IL-1-related receptor, a negative regulator of IL-1/TLR signaling. AB - Toll IL-1R 8/single Ig IL-1-related receptor (TIR8/SIGIRR) is a member of the IL 1R family, expressed by epithelial tissues and immature dendritic cells, and is regarded as a negative regulator of TLR/IL-1R signaling. Tir8-deficient mice were rapidly killed by intranasal administration of low doses of Mycobacterium tuberculosis, despite controlling efficiently the number of viable bacilli in different organs. Tir8(-/-)-infected mice showed an increased number of neutrophils and macrophages in the lungs; however, mycobacteria-specific CD4 and CD8 T cells were similar in Tir8(-/-) and Tir8(+/+) mice. Exaggerated mortality of Tir8(-/-) mice was due to massive liver necrosis and was accompanied by increased levels of IL-1beta and TNF-alpha in lung mononuclear cells and serum, as well as by increased production of IL-1beta and TNF-alpha by M. tuberculosis infected dendritic cells in vitro. Accordingly, blocking IL-1beta and TNF-alpha with a mix of anti-cytokine Abs, significantly prolonged survival of Tir8(-/-) mice. Thus, TIR8/SIGIRR plays a key role in damping inflammation and tissue damage in M. tuberculosis infection. PMID- 17709527 TI - gp340 expressed on human genital epithelia binds HIV-1 envelope protein and facilitates viral transmission. AB - During sexual transmission of HIV in women, the first cells likely to be infected are submucosal CD4(+) T cells and dendritic cells of the lower genital tract. HIV is segregated from these target cells by an epithelial cell layer that can be bypassed even when healthy and intact. To understand how HIV penetrates this barrier, we identified a host protein, gp340, that is expressed on genital epithelium and binds the HIV envelope via a specific protein-protein interaction. This binding allows otherwise subinfectious amounts of HIV to efficiently infect target cells and allows this infection to occur over a longer period of time after binding. Our findings suggest a mechanism of viral entry during heterosexual transmission where HIV is bound to intact genital epithelia, which then promotes the initial events of infection. Understanding this step in the initiation of infection will allow for the development of tools and methods for blocking HIV transmission. PMID- 17709528 TI - Viral replication capacity as a correlate of HLA B57/B5801-associated nonprogressive HIV-1 infection. AB - HLA B57 and the closely related HLA B5801 are over-represented among HIV-1 infected long-term nonprogressors (LTNPs). It has been suggested that this association between HLA B57/5801 and asymptomatic survival is a consequence of strong CTL responses against epitopes in the viral Gag protein. Moreover, CTL escape mutations in Gag would coincide with viral attenuation, resulting in low viral load despite evasion from immune control. In this study we compared HLA B57/5801 HIV-1 infected progressors and LTNPs for sequence variation in four dominant epitopes in Gag and their ability to generate CTL responses against these epitopes and the autologous escape variants. Prevalence and appearance of escape mutations in Gag epitopes and potential compensatory mutations were similar in HLA B57/5801 LTNPs and progressors. Both groups were also indistinguishable in the magnitude of CD8+ IFN-gamma responses directed against the wild-type or autologous escape mutant Gag epitopes in IFN-gamma ELISPOT analysis. Interestingly, HIV-1 variants from HLA B57/5801 LTNPs had much lower replication capacity than the viruses from HLA B57/5801 progressors, which did not correlate with specific mutations in Gag. In conclusion, the different clinical course of HLA B57/5801 LTNPs and progressors was not associated with differences in CTL escape mutations or CTL activity against epitopes in Gag but rather with differences in HIV-1 replication capacity. PMID- 17709529 TI - Inhibition of HIV-1 infectivity and epithelial cell transfer by human monoclonal IgG and IgA antibodies carrying the b12 V region. AB - Both IgG and secretory IgA Abs in mucosal secretions have been implicated in blocking the earliest events in HIV-1 transit across epithelial barriers, although the mechanisms by which this occurs remain largely unknown. In this study, we report the production and characterization of a human rIgA(2) mAb that carries the V regions of IgG1 b12, a potent and broadly neutralizing anti-gp120 Ab which has been shown to protect macaques against vaginal simian/HIV challenge. Monomeric, dimeric, polymeric, and secretory IgA(2) derivatives of b12 reacted with gp120 and neutralized CCR5- and CXCR4-tropic strains of HIV-1 in vitro. With respect to the protective effects of these Abs at mucosal surfaces, we demonstrated that IgG1 b12 and IgA(2) b12 inhibited the transfer of cell-free HIV 1 from ME-180 cells, a human cervical epithelial cell line, as well as Caco-2 cells, a human colonic epithelial cell line, to human PBMCs. Inhibition of viral transfer was due to the ability of b12 to block both viral attachment to and uptake by epithelial cells. These data demonstrate that IgG and IgA MAbs directed against a highly conserved epitope on gp120 can interfere with the earliest steps in HIV-1 transmission across mucosal surfaces, and reveal a possible mechanism by which b12 protects the vaginal mucosal against viral challenge in vivo. PMID- 17709531 TI - SIR2-deficient Leishmania infantum induces a defined IFN-gamma/IL-10 pattern that correlates with protection. AB - The ability to manipulate the Leishmania genome to create genetically modified parasites by introducing or eliminating genes is considered a powerful alternative for developing a new generation vaccine against leishmaniasis. Previously, we showed that the deletion of one allele of the Leishmania infantum silent information regulatory 2 (LiSIR2) locus was sufficient to dramatically affect amastigote axenic proliferation. Furthermore, LiSIR2 single knockout (LiSIR2(+/-)) amastigotes were unable to replicate in vitro inside macrophages. Because this L. infantum mutant persisted in BALB/c mice for up to 6 wk but failed to establish an infection, we tested its ability to provide protection toward a virulent L. infantum challenge. Strikingly, vaccination with a single i.p. injection of LiSIR2(+/-) single knockout elicits complete protection. Thus, vaccinated BALB/c mice showed a reversal of T cell anergy with specific anti Leishmania cytotoxic activity and high levels of NO production. Moreover, vaccinated mice simultaneously generated specific anti-Leishmania IgG Ab subclasses suggestive of both type 1 and type 2 responses. A strong correlation was found between the elimination of the parasites and an increased Leishmania specific IFN-gamma/IL-10 ratio. Therefore, we propose that the polarization to a high IFN-gamma/low IL-10 ratio after challenge is a clear indicator of vaccine success. Furthermore these mutants, which presented attenuated virulence, represent a good model to understand the correlatives of protection in visceral leishmaniasis. PMID- 17709533 TI - Complement-dependent enhancement of CD8+ T cell immunity to lymphocytic choriomeningitis virus infection in decay-accelerating factor-deficient mice. AB - Decay-accelerating factor (DAF, CD55) is a GPI-anchored membrane protein that regulates complement activation on autologous cells. In addition to protecting host tissues from complement attack, DAF has been shown to inhibit CD4+ T cell immunity in the setting of model Ag immunization. However, whether DAF regulates natural T cell immune response during pathogenic infection is not known. We describe in this study a striking regulatory effect of DAF on the CD8+ T cell response to lymphocytic choriomeningitis virus (LCMV) infection. Compared with wild-type mice, DAF knockout (Daf-1(-/-)) mice had markedly increased expansion in the spleen of total and viral Ag-specific CD8+ T cells after acute or chronic LCMV infection. Splenocytes from LCMV-infected Daf-1(-/-) mice also displayed significantly higher killing activity than cells from wild-type mice toward viral Ag-loaded target cells, and Daf-1(-/-) mice cleared LCMV more efficiently. Importantly, deletion of the complement protein C3 or the receptor for the anaphylatoxin C5a (C5aR) from Daf-1(-/-) mice reversed the enhanced CD8+ T cell immunity phenotype. These results demonstrate that DAF is an important regulator of CD8+ T cell immunity in viral infection and that it fulfills this role by acting as a complement inhibitor to prevent virus-triggered complement activation and C5aR signaling. This mode of action of DAF contrasts with that of CD59 in viral infection and suggests that GPI-anchored membrane complement inhibitors can regulate T cell immunity to viral infection via either a complement-dependent or independent mechanism. PMID- 17709532 TI - Association of TLR4 polymorphisms with symptomatic respiratory syncytial virus infection in high-risk infants and young children. AB - Respiratory syncytial virus (RSV) is a leading cause of infant mortality worldwide. Although anti-RSV Ab prophylaxis has greatly reduced infant mortality in the United States, there is currently no vaccine or effective antiviral therapy. RSV fusion (F) protein activates cells through TLR4. Two single nucleotide polymorphisms (SNPs) encoding Asp299Gly and Thr399Ile substitutions in the TLR4 ectodomain were previously associated with TLR4 hyporesponsiveness and increased susceptibility to bacterial infection. Prevalence of these SNPs was analyzed in a case series of 105 DNA samples extracted from archived nasal lavage samples from high-risk infants/young children with confirmed RSV disease who participated in two seminal clinical trials for anti-RSV prophylaxis. Frequencies of TLR4 SNPs in the case series were compared with those of literature controls, healthy adults, infants, and young children who presented with symptoms of respiratory infections (but not preselected for high risk for RSV). Both SNPs were highly associated with symptomatic RSV disease in this largely premature population (p < 0.0001), with 89.5% and 87.6% of cases being heterozygous for Asp299Gly and Thr399Ile polymorphisms versus published control frequencies of 10.5% and 6.5%, respectively. The other two control groups had similarly low frequencies. Our data suggest that heterozygosity of these two extracellular TLR4 polymorphisms is highly associated with symptomatic RSV disease in high-risk infants and support a dual role for TLR4 SNPs in prematurity and increased susceptibility to RSV not revealed by analysis of either alone. PMID- 17709530 TI - Influence of EBV on the peripheral blood memory B cell compartment. AB - Peripheral blood memory B cells latently infected with EBV bear somatic mutations and are typically isotype switched consistent with being classical Ag-selected memory B cells. In this work, we performed a comparative analysis of the expressed Ig genes between large sets of EBV-infected and uninfected peripheral blood B cells, isolated from the same infectious mononucleosis patients, to determine whether differences exist that could reveal the influence of EBV on the production and maintenance of these cells. We observed that EBV(+) cells on average accumulated more somatic hypermutations than EBV(-) cells. In addition, they had more replacement mutations and a higher replacement-silent ratio of mutations in their CDRs. We also found that EBV occupies a skewed niche within the memory compartment, due to its exclusion from the CD27(+)IgD(+)IgM(+) subset, but this skewing does not affect the overall structure of the compartment. These results indicate that EBV impacts the mutation and selection process of infected cells but that once they enter memory they cannot be distinguished from uninfected cells by host homeostasis mechanisms. PMID- 17709534 TI - Codominance of TLR2-dependent and TLR2-independent modulation of MHC class II in Mycobacterium tuberculosis infection in vivo. AB - Mycobacterium tuberculosis is an exceptionally successful human pathogen. A major component of this success is the ability of the bacteria to infect immunocompetent individuals and to evade eradication by an adaptive immune response that includes production of the macrophage-activating cytokine, IFN gamma. Although IFN-gamma is essential for arrest of progressive tuberculosis, it is insufficient for efficacious macrophage killing of the bacteria, which may be due to the ability of M. tuberculosis to inhibit selected macrophage responses to IFN-gamma. In vitro studies have determined that mycobacterial lipoproteins and other components of the M. tuberculosis cell envelope, acting as agonists for TLR2, inhibit IFN-gamma induction of MHC class II. In addition, M. tuberculosis peptidoglycan and IL-6 secreted by infected macrophages inhibit IFN-gamma induction of MHC class II in a TLR2-independent manner. To determine whether TLR2 dependent inhibition of macrophage responses to IFN-gamma is quantitatively dominant over the TLR2-independent mechanisms in vivo, we prepared mixed bone marrow chimeric mice in which the hemopoietic compartment was reconstituted with a mixture of TLR(+/+) and TLR2(-/-) cells. When the chimeric mice were infected with M. tuberculosis, the expression of MHC class II on TLR2(+/+) and TLR2(-/-) macrophages from the lungs of individual infected chimeric mice was indistinguishable. These results indicate that TLR2-dependent and -independent mechanisms of inhibition of responses to IFN-gamma are equivalent in vivo, and that M. tuberculosis uses multiple pathways to abrogate the action of an important effector of adaptive immunity. This work was supported by National Institutes of Health Grants AI 065357-AI 020010. PMID- 17709535 TI - A streptococcal penicillin-binding protein is critical for resisting innate airway defenses in the neonatal lung. AB - Group B streptococcus (GBS) is a major cause of neonatal pneumonia. The early interactions between innate airway defenses and this pathogen are likely to be a critical factor in determining the outcome for the host. The surface-localized penicillin-binding protein (PBP)1a, encoded by ponA, is known to be an important virulence trait in a sepsis model of GBS infection that promotes resistance to neutrophil killing and more specifically to neutrophil antimicrobial peptides (AMPs). In this study, we used an aerosolization model to explore the role of PBP1a in evasion of innate immune defenses in the neonatal lung. The ponA mutant strain was cleared more rapidly from the lungs of neonatal rat pups compared with the wild-type strain, which could be linked to a survival defect in the presence of alveolar macrophages (AM). Rat AM were found to secrete beta-defensin and cathelicidin AMP homologues, and the GBS ponA mutant was more susceptible than the wild-type strain to killing by these peptides in vitro. Collectively, our observations suggest that PBP1a-mediated resistance to AM AMPs promotes the survival of GBS in the neonatal lung. Additionally, AM are traditionally thought to clear bacteria through phagocytic uptake; our data indicate that secretion of AMPs may also participate in limiting bacterial replication in the airway. PMID- 17709536 TI - Rapid CD8+ T cell repertoire focusing and selection of high-affinity clones into memory following primary infection with a persistent human virus: human cytomegalovirus. AB - To investigate the mechanism of selection of individual human CD8+ T cell clones into long-term memory following primary infection with a persistent human virus (human CMV (HCMV)), we undertook a longitudinal analysis of the diversity of T cell clones directed toward an immunodominant viral epitope: we followed this longitudinally from early T cell expansion through the contraction phase and selection into the memory pool. We show that following initial HCMV infection, the early primary response against a defined epitope was composed of diverse clones possessing many different TCR Vbeta segments. Longitudinal analysis showed that this usage rapidly focused predominantly on a single TCR Vbeta segment within which dominant clones frequently had public TCR usage, in contrast to subdominant or contracted clones. Longitudinal clonotypic analysis showed evidence of disproportionate contraction of certain clones that were abundant in the primary response, and late expansion of clones that were subdominant in the primary response. All dominant clones selected into memory showed similar high functional avidity of their TCR, whereas two clones that greatly contracted showed substantially lower avidity. Expression of the IL-7R is required for survival of murine effector CD8+ T cells into memory, but in primary HCMV infection IL-7R was not detected on circulating Ag-specific cells until memory had been established. Thus, the oligoclonal T cell repertoire against an immunodominant persistent viral epitope is established early in primary infection by the rapid selection of public clonotypes, rather than being a stochastic process. PMID- 17709537 TI - IL-18, but not IL-12, regulates NK cell activity following intranasal herpes simplex virus type 1 infection. AB - Infection of the respiratory tract with HSV type 1 (HSV-1) can have severe clinical complications, yet little is known of the immune mechanisms that control the replication and spread of HSV-1 in this site. The present study investigated the protective role of IL-12 and IL-18 in host defense against intranasal HSV-1 infection. Both IL-12 and IL-18 were detected in lung fluids following intranasal infection of C57BL/6 (B6) mice. IL-18-deficient (B6.IL-18(-/-)) mice were more susceptible to HSV-1 infection than wild-type B6 mice as evidenced by exacerbated weight loss and enhanced virus growth in the lung. IL-12-deficient (B6.IL-12(-/ )) mice behaved similarly to B6 controls. Enhanced susceptibility of B6.IL-18(-/ ) mice to HSV-1 infection correlated with a profound impairment in the ability of NK cells recovered from the lungs to produce IFN-gamma or to mediate cytotoxic activity ex vivo. The weak cytotoxic capacity of NK cells from the lungs of B6.IL 18(-/-) mice correlated with reduced expression of the cytolytic effector molecule granzyme B. Moreover, depletion of NK cells from B6 or B6.IL-12(-/-) mice led to enhanced viral growth in lungs by day 3 postinfection; however, this treatment had no effect on viral titers in lungs of B6.IL-18(-/-) mice. Together these studies demonstrate that IL-18, but not IL-12, plays a key role in the rapid activation of NK cells and therefore in control of early HSV-1 replication in the lung. PMID- 17709538 TI - Neisseria meningitidis PorB, a TLR2 ligand, induces an antigen-specific eosinophil recall response: potential adjuvant for helminth vaccines? AB - Efficacious adjuvants are important components of new vaccines. The neisserial outer membrane protein, PorB, is a TLR2 ligand with unique adjuvant activity. We demonstrate that PorB promotes Th2-skewed cellular immune response to the model Ag, OVA, in mice, including Ag-specific recall eosinophil recruitment to the peritoneum. PorB induces chemokine secretion by myeloid cells using both TLR2 dependent and -independent mechanisms, suggesting that anatomical distribution of TLR2(+) cells may not be a limiting factor for potential vaccine strategies. The results from this study suggest that PorB, and other TLR2 ligands, may be ideal for use against pathogens where eosinophilia may be protective, such as parasitic helminths. PMID- 17709540 TI - Individual variation of scavenger receptor expression in human macrophages with oxidized low-density lipoprotein is associated with a differential inflammatory response. AB - Atherosclerosis is an inflammatory disease in which oxidized low-density lipoprotein (oxLDL) plays important roles. Scavenger receptors (SR) CD36, SR-A, and LOX-1 uptake over 90% of the oxLDL leading to foam cell formation and secretion of inflammatory cytokines. To investigate whether the interindividual differences in macrophage SR gene expression could determine the inflammatory variability in response to oxLDL, we quantified the gene and protein expression of SR and inflammatory molecules from macrophages isolated from 18 volunteer subjects and incubated with oxLDL for 1, 3, 6, and 18 h. The individual gene expression profile of the studied SR at 1 h of incubation was highly variable, showing a wide fold-change range: CD36: -3.57-4.22, SR-A: -5.0-4.43, and LOX-1: 1.56-75.32. We identified subjects as high and low responders depending on whether their SR gene expression was above or below the median, showing a different inflammation response pattern. CD36 and LOX-1 gene expression correlated positively with IL-1beta; SR-A correlated negatively with IL-8 and positively with PPARgamma and NF-kappaBIotaA. These results were confirmed in the same subjects 3 mo after the first sampling. Furthermore, a negative correlation existed between CD36 and SR-A at protein level after 18 h of oxLDL incubation (R = -0.926, p = 0.024). These data would suggest that the type of SR could determine the macrophage activation: more proinflammatory when associated to CD36 and LOX-1 than when associated with SR-A. PMID- 17709539 TI - A dual role of lipocalin 2 in the apoptosis and deramification of activated microglia. AB - Activated microglia are thought to undergo apoptosis as a self-regulatory mechanism. To better understand molecular mechanisms of the microglial apoptosis, apoptosis-resistant variants of microglial cells were selected and characterized. The expression of lipocalin 2 (lcn2) was significantly down-regulated in the microglial cells that were resistant to NO-induced apoptosis. lcn2 expression was increased by inflammatory stimuli in microglia. The stable expression of lcn2 as well as the addition of rLCN2 protein augmented the sensitivity of microglia to the NO-induced apoptosis, while knockdown of lcn2 expression using short hairpin RNA attenuated the cell death. Microglial cells with increased lcn2 expression were more sensitive to other cytotoxic agents as well. Thus, inflammatory activation of microglia may lead to up-regulation of lcn2 expression, which sensitizes microglia to the self-regulatory apoptosis. Additionally, the stable expression of lcn2 in BV-2 microglia cells induced a morphological change of the cells into the round shape with a loss of processes. Treatment of primary microglia cultures with the rLCN2 protein also induced the deramification of microglia. The deramification of microglia was closely related with the apoptosis prone phenotype, because other deramification-inducing agents such as cAMP elevating agent forskolin, ATP, and calcium ionophore also rendered microglia more sensitive to cell death. Taken together, our results suggest that activated microglia may secrete LCN2 protein, which act in an autocrine manner to sensitize microglia to the self-regulatory apoptosis and to endow microglia with an amoeboid form, a canonical morphology of activated microglia in vivo. PMID- 17709541 TI - Genetic control directed toward spontaneous IFN-alpha/IFN-beta responses and downstream IFN-gamma expression influences the pathogenesis of a murine psoriasis like skin disease. AB - Psoriasis is an inflammatory skin disease, onset and severity of which are controlled by multiple genetic factors; aberrant expression of and responses to several cytokines including IFN-alpha/IFN-beta and IFN-gamma are associated with this "type 1" disease. However, it remains unclear whether genetic regulation influences these cytokine-related abnormalities. Mice deficient for IFN regulatory factor-2 (IRF-2) on the C57BL/6 background (IRF-2(-/-)BN mice) exhibited accelerated IFN-alpha/IFN-beta responses leading to a psoriasis-like skin inflammation. In this study, we found that this skin phenotype disappeared in IRF-2(-/-) mice with the BALB/c or BALB/c x C57BL/6 F(1) backgrounds. Genome wide scan revealed two major quantitative trait loci controlled the skin disease severity. Interestingly, these loci were different from that for the defect in CD4(+) dendritic cells, another IFN-alpha/IFN-beta-dependent phenotype of the mice. Notably, IFN-gamma expression as well as spontaneous IFN-alpha/IFN-beta responses were up-regulated several fold spontaneously in the skin in IRF-2(-/ )BN mice but not in IRF-2(-/-) mice with "resistant" backgrounds. The absence of such IFN-gamma up-regulation in IRF-2(-/-)BN mice lacking the IFN-alpha/IFN-beta receptor or beta(2)-microglobulin indicated that accelerated IFN-alpha/IFN-beta signals augmented IFN-gamma expression by CD8(+) T cells in the skin. IFN-gamma indeed played pathogenic roles as skin inflammation was delayed and was much more infrequent when IRF-2(-/-)BN mice lacked the IFN-gamma receptor. Our current study thus revealed a novel genetic mechanism that kept the skin immune system under control and prevented skin inflammation through regulating the magnitude of IFN-alpha/IFN-beta responses and downstream IFN-gamma production, independently of CD4(+) dendritic cells. PMID- 17709542 TI - A role for dietary selenium and selenoproteins in allergic airway inflammation. AB - Asthma is driven by allergic airway inflammation and involves increased levels of oxidative stress. This has led to speculation that antioxidants like selenium (Se) may play important roles in preventing or treating asthma. We fed diets containing low (0.08 parts per million), medium (0.25 parts per million), or high (2.7 parts per million) Se to female C57BL/6 mice and used an established OVA challenge protocol to determine the relationship between Se intake and the development of allergic airway inflammation. Results demonstrated that mice fed medium levels of Se had robust responses to OVA challenge in the lung as measured by lung cytokine levels, airway cellular infiltrate, eosinophilia, serum anti-OVA IgE, airway hyperreactivity, goblet cell hyperplasia, and phosphorylated STAT-6 levels in the lung. In contrast, responses to OVA challenge were less robust in mice fed low or high levels of Se. In particular, mice fed low Se chow showed significantly lower responses compared with mice fed medium Se chow for nearly all readouts. We also found that within the medium Se group the expression of lung glutathione peroxidase-1 and liver selenoprotein P were increased in OVA challenged mice compared with PBS controls. These data suggest that Se intake and allergic airway inflammation are not related in a simple dose-response manner, which may explain the inconsistent results obtained from previous descriptive studies in humans. Also, our results suggest that certain selenoproteins may be induced in response to Ag challenges within the lung. PMID- 17709543 TI - Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis. AB - IL-27 has been shown to play a suppressive role in experimental autoimmune encephalomyelitis (EAE) as demonstrated by more severe disease in IL-27R deficient (WSX-1(-/-)) mice. However, whether IL-27 influences the induction or effector phase of EAE is unknown. This is an important question as therapies for autoimmune diseases are generally started after autoreactive T cells have been primed. In this study, we demonstrate maximal gene expression of IL-27 subunits and its receptor in the CNS at the effector phases of relapsing-remitting EAE including disease peak and onset of relapse. We also show that activated astrocyte cultures secrete IL-27p28 protein which is augmented by the endogenous factor, IFN-gamma. To investigate functional significance of a correlation between gene expression and disease activity, we examined the effect of IL-27 at the effector phase of disease using adoptive transfer EAE. Exogenous IL-27 potently suppressed the ability of encephalitogenic lymph node and spleen cells to transfer EAE. IL-27 significantly inhibited both nonpolarized and IL-23-driven IL-17 production by myelin-reactive T cells thereby suppressing their encephalitogenicity in adoptive transfer EAE. Furthermore, we demonstrate a strong suppressive effect of IL-27 on active EAE in vivo when delivered by s.c. osmotic pump. IL-27-treated mice had reduced CNS inflammatory infiltration and, notably, a lower proportion of Th17 cells. Together, these data demonstrate the suppressive effect of IL-27 on primed, autoreactive T cells, particularly, cells of the Th17 lineage. IL-27 can potently suppress the effector phase of EAE in vivo and, thus, may have therapeutic potential in autoimmune diseases such as multiple sclerosis. PMID- 17709544 TI - Effects of gamma radiation on FcepsilonRI and TLR-mediated mast cell activation. AB - Ionizing gamma radiation has several therapeutic indications including bone marrow transplantation and tumor ablation. Among immune cells, susceptibility of lymphocytes to gamma radiation is well known. However, there is little information on the effects of gamma radiation on mast cells, which are important in both innate and acquired immunity. Previous studies have suggested that mast cells may release histamine in response to high doses of gamma radiation, whereas other reports suggest that mast cells are relatively radioresistant. No strong link has been established between gamma radiation and its effect on mast cell survival and activation. We examined both human and murine mast cell survival and activation, including mechanisms related to innate and acquired immune responses following gamma radiation. Data revealed that human and murine mast cells were resistant to gamma radiation-induced cytotoxicity and, importantly, that irradiation did not directly induce beta-hexosaminidase release. Instead, a transient attenuation of IgE-mediated beta-hexosaminidase release and cytokine production was observed which appeared to be the result of reactive oxygen species formation after irradiation. Mast cells retained the ability to phagocytose Escherichia coli particles and respond to TLR ligands as measured by cytokine production after irradiation. In vivo, there was no decrease in mast cell numbers in skin of irradiated mice. Additionally, mast cells retained the ability to respond to Ag in vivo as measured by passive cutaneous anaphylaxis in mice after irradiation. Mast cells are thus resistant to the cytotoxic effects and alterations in function after irradiation and, despite a transient inhibition, ultimately respond to innate and acquired immune activation signals. PMID- 17709545 TI - Th2 differentiation in distinct lymph nodes influences the site of mucosal Th2 immune-inflammatory responses. AB - Allergic individuals rarely present with concurrent multiple-organ disease but, rather, with manifestations that privilege a specific site such as the lung, skin, or gastrointestinal tract. Whether the site of allergic sensitization influences the localization of Th2 immune-inflammatory responses and, ultimately, the organ-specific expression of disease, remains to be determined. In this study, we investigated whether both the site of initial Ag exposure and concomitant Th2 differentiation in specific lymph nodes (LNs) privileges Th2 memory responses to mucosal and nonmucosal sites, and whether this restriction is associated with a differential expression in tissue-specific homing molecules. In mice exposed to Ag (OVA) via the peritoneum, lung, or skin, we examined several local and distal LNs to determine the site of Ag-specific proliferation and Th2 differentiation. Whereas respiratory and cutaneous Ag exposure led to Ag-specific proliferation and Th2 differentiation exclusively in lung- and skin-draining LNs, respectively, Ag delivery to the peritoneum evoked responses in gut-associated, as well as distal thoracic, LNs. Importantly, only mice that underwent Th2 differentiation in thoracic- or gut-associated LNs mounted Th2 immune inflammatory responses upon respiratory or gastric Ag challenge, respectively, whereas cutaneous Th2 recall responses were evoked irrespective of the site of initial sensitization. In addition, we observed the differential expression of gut homing molecules (CCR9, alpha(4), beta(7)) in gut-associated LNs and, unexpectedly, a universal induction of skin-related homing molecules (CCR4, CCR10) in all LNs. These data suggest that the site of initial Th2 differentiation and differential homing molecule expression restricts Th2 immune inflammatory responses to mucosal, but not cutaneous, tissues. PMID- 17709546 TI - Urokinase-type plasminogen activator stimulation of monocyte matrix metalloproteinase-1 production is mediated by plasmin-dependent signaling through annexin A2 and inhibited by inactive plasmin. AB - Chronic inflammatory diseases are associated with connective tissue turnover that involves a series of proteases, which include the plasminogen activation system and the family of matrix metalloproteinases (MMPs). Urokinase-type plasminogen activator (uPA) and plasmin, in addition to their role in fibrinolysis and activation of pro-MMPs, have been shown to transduce intracellular signals through specific receptors. The potential for uPA and plasmin to also contribute to connective tissue turnover by directly regulating MMP production was examined in human monocytes. Both catalytically active high m.w. uPA, which binds to the uPAR, and low m.w. uPA, which does not, significantly enhanced MMP-1 synthesis by activated human monocytes. In contrast, the N-terminal fragment of uPA, which binds to uPAR, but lacks the catalytic site, failed to induce MMP-1 production, indicating that uPA-stimulated MMP-1 synthesis was plasmin dependent. Endogenous plasmin generated by the action of uPA or exogenous plasmin increased MMP-1 synthesis by signaling through annexin A2, as demonstrated by inhibition of MMP-1 production with Abs against annexin A2 and S100A10, a dimeric protein associated with annexin A2. Interaction of plasmin with annexin A2 resulted in the stimulation of ERK1/2 and p38 MAPK, cyclooxygenase-2, and PGE(2), leading to increased MMP-1 production. Furthermore, binding of inactive plasmin to annexin A2 inhibited plasmin induction of MMP-1, suggesting that inactive plasmin may be useful in suppressing inflammation. PMID- 17709547 TI - CD4+ T cells generated de novo from donor hemopoietic stem cells mediate the evolution from acute to chronic graft-versus-host disease. AB - Acute and chronic graft-versus-host disease (GVHD) remain the major complications limiting the efficacy of allogeneic hemopoietic stem cell transplantation. Chronic GVHD can evolve from acute GVHD, or in some cases may overlap with acute GVHD, but how acute GVHD evolves to chronic GVHD is unknown. In this study, in a classical CD8+ T cell-dependent mouse model, we found that pathogenic donor CD4+ T cells developed from engrafted hemopoietic stem cells (HSCs) in C57BL/6SJL(B6/SJL, H-2(b)) mice suffering from acute GVHD after receiving donor CD8+ T cells and HSCs from C3H.SW mice (H-2(b)). These CD4+ T cells were activated, infiltrated into GVHD target tissues, and produced high levels of IFN gamma. These in vivo-generated CD4+ T cells caused lesions characteristic of chronic GVHD when adoptively transferred into secondary allogeneic recipients and also caused GVHD when administered into autologous C3H.SW recipients. The in vivo generation of pathogenic CD4+ T cells from engrafted donor HSCs was thymopoiesis dependent. Keratinocyte growth factor treatment improved the reconstitution of recipient thymic dendritic cells in CD8+ T cell-repleted allogeneic hemopoietic stem cell transplantation and prevented the development of pathogenic donor CD4+ T cells. These results suggest that de novo-generated donor CD4+ T cells, arising during acute graft-versus-host reactions, are key contributors to the evolution from acute to chronic GVHD. Preventing or limiting thymic damage may directly ameliorate chronic GVHD. PMID- 17709548 TI - Peripheral tolerance and the qualitative characteristics of autoreactive T cell clones in primary biliary cirrhosis. AB - Primary biliary cirrhosis is characterized by autoreactive T cells specific for the mitochondrial Ag PDC-E2(163-176). We studied the ability of eight T cell clones (TCC) specific for PDC-E2(163-176) to proliferate or become anergic in the presence of costimulation signals. TCC were stimulated with either human PDC E2(163-176), an Escherichia coli 2-oxoglutarate dehydrogenase mimic (OGDC-E2(34 47)), or analogs with amino acid substitutions using HLA-matched allogeneic PBMC or mouse L-DR53 fibroblasts as APC. Based on their differential responses to these peptides (human PDC-E2(163-176), E. coli OGDC-E2(34-47)) in the different APC systems, TCC were classified as costimulation dependent or independent. Only costimulation-dependent TCC could become anergic. TCC with costimulation dependent responses to OGDC-E2 become anergic to PDC-E2 when preincubated with mimic, even if costimulation is independent for PDC-E2(163-176). Anergic TCC produced IL-10. One selected TCC could not become anergic after preincubation with PDC-E2(163-176)-pulsed L-DR53 but became anergic using L-DR53 pulsed with PDC-E2 peptide analogs with a substitution at a critical TCR binding site. TCC that only respond to peptide-pulsed PBMC, but not L-DR53, proliferate with peptide-pulsed CD80/CD86-transfected L-DR53; however, anergy was not induced with peptide-pulsed L-DR53 transfected with only CD80 or CD86. These data highlight that costimulation plays a dominant role in maintaining peripheral tolerance to PBC-specific Ags. They further suggest that, under specific circumstances, molecular mimicry of an autoantigen may restore rather than break peripheral tolerance. PMID- 17709549 TI - "Cytokine storm" in the phase I trial of monoclonal antibody TGN1412: better understanding the causes to improve preclinical testing of immunotherapeutics. AB - The CD28-specific mAb TGN1412 rapidly caused a life-threatening "cytokine storm" in all six healthy volunteers in the Phase I clinical trial of this superagonist, signaling a failure of preclinical safety testing. We report novel in vitro procedures in which TGN1412, immobilized in various ways, is presented to human white blood cells in a manner that stimulates the striking release of cytokines and profound lymphocyte proliferation that occurred in vivo in humans. The novel procedures would have predicted the toxicity of this superagonist and are now being applied to emerging immunotherapeutics and to other therapeutics that have the potential to act upon the immune system. Data from these novel procedures, along with data from in vitro and in vivo studies in nonhuman primates, suggest that the dose of TGN1412 given to human volunteers was close to the maximum immunostimulatory dose and that TGN1412 is not a superagonist in nonhuman primates. PMID- 17709550 TI - Tumor-derived chemokine MCP-1/CCL2 is sufficient for mediating tumor tropism of adoptively transferred T cells. AB - To exert a therapeutic effect, adoptively transferred tumor-specific CTLs must traffic to sites of tumor burden, exit the circulation, and infiltrate the tumor microenvironment. In this study, we examine the ability of adoptively transferred human CTL to traffic to tumors with disparate chemokine secretion profiles independent of tumor Ag recognition. Using a combination of in vivo tumor tropism studies and in vitro biophotonic chemotaxis assays, we observed that cell lines derived from glioma, medulloblastoma, and renal cell carcinoma efficiently chemoattracted ex vivo-expanded primary human T cells. We compared the chemokines secreted by tumor cell lines with high chemotactic activity with those that failed to elicit T cell chemotaxis (Daudi lymphoma, 10HTB neuroblastoma, and A2058 melanoma cells) and found a correlation between tumor-derived production of MCP-1/CCL2 (> or =10 ng/ml) and T cell chemotaxis. Chemokine immunodepletion studies confirmed that tumor-derived MCP-1 elicits effector T cell chemotaxis. Moreover, MCP-1 is sufficient for in vivo T cell tumor tropism as evidenced by the selective accumulation of i.v. administered firefly luciferase-expressing T cells in intracerebral xenografts of tumor transfectants secreting MCP-1. These studies suggest that the capacity of adoptively transferred T cells to home to tumors may be, in part, dictated by the species and amounts of tumor-derived chemokines, in particular MCP-1. PMID- 17709551 TI - Enhancing effect of IL-1alpha on neurogenesis from adult human mesenchymal stem cells: implication for inflammatory mediators in regenerative medicine. AB - Mesenchymal stem cells (MSCs) are mesoderm-derived cells, primarily resident in adult bone marrow. MSCs show lineage specificity in generating specialized cells such as stroma, fat, and cartilage. MSCs express MHC class II and function as phagocytes and APCs. Despite these immune-enhancing properties, MSCs also exert veto functions and show evidence for allogeneic transplantation. These properties, combined with ease in isolation and expansion, demonstrate MSCs as attractive candidates for tissue repair across allogeneic barriers. MSCs have also been shown to transdifferentiate in neuronal cells. We have reported expression of the neurotransmitter gene, Tac1, in MSC-derived neuronal cells, with no evidence of translation unless cells were stimulated with IL-1alpha. This result led us to question the potential role of immune mediators in the field of stem cell therapy. Using Tac1 as an experimental model, IL-1alpha was used as a prototypical inflammatory mediator to study functions on MSC-derived neuronal cells. Undifferentiated MSCs and those induced to form neurons were studied for their response to IL-1alpha and other proinflammatory cytokines using production of the major Tac1 peptide, substance P (SP), as readout. Although IL-1alpha induced high production of SP, a similar effect was not observed for all tested cytokines. The induced SP was capable of reuptake via its high-affinity NK1R and was found to stabilize IL-1R mRNA. IL-1alpha also enhanced the rate of neurogenesis, based on expression of neuronal markers and cRNA microarray analyses. The results provide evidence that inflammatory mediators need to be considered when deciding the course of MSC transplantation. PMID- 17709552 TI - Depletion of B cells in murine lupus: efficacy and resistance. AB - In mice, genetic deletion of B cells strongly suppresses systemic autoimmunity, providing a rationale for depleting B cells to treat autoimmunity. In fact, B cell depletion with rituximab is approved for rheumatoid arthritis patients, and clinical trials are underway for systemic lupus erythematosus. Yet, basic questions concerning mechanism, pathologic effect, and extent of B cell depletion cannot be easily studied in humans. To better understand how B cell depletion affects autoimmunity, we have generated a transgenic mouse expressing human CD20 on B cells in an autoimmune-prone MRL/MpJ-Fas(lpr) (MRL/lpr) background. Using high doses of a murine anti-human CD20 mAb, we were able to achieve significant depletion of B cells, which in turn markedly ameliorated clinical and histologic disease as well as antinuclear Ab and serum autoantibody levels. However, we also found that B cells were quite refractory to depletion in autoimmune-prone strains compared with non-autoimmune-prone strains. This was true with multiple anti-CD20 Abs, including a new anti-mouse CD20 Ab, and in several different autoimmune prone strains. Thus, whereas successful B cell depletion is a promising therapy for lupus, at least some patients might be resistant to the therapy as a byproduct of the autoimmune condition itself. PMID- 17709555 TI - Inheritance of flower color in pickerelweed (Pontederia cordata L.). AB - Pickerelweed (Pontederia cordata L.) is a diploid (2n = 2x = 16), erect, emergent, herbaceous aquatic perennial. The showy inflorescences of pickerelweed make this species a prime candidate for inclusion in water gardens and aquascapes. The objective of this experiment was to determine the number of loci, number of alleles, and gene action controlling flower color (blue vs. white) in pickerelweed. Two blue-flowered and one white-flowered parental lines were used in this experiment to create S(1) and F(1) populations. F(2) populations were produced through self-pollination of F(1) plants. Evaluation of S(1), F(1), and F(2) generations revealed that flower color in these populations was controlled by 2 alleles at one locus with blue flower color completely dominant to white. We propose that this locus be named white flower with alleles W and w. PMID- 17709554 TI - B subunit of Shiga toxin-based vaccines synergize with alpha-galactosylceramide to break tolerance against self antigen and elicit antiviral immunity. AB - The nontoxic B subunit of Shiga toxin (STxB) targets in vivo Ag to dendritic cells that preferentially express the glycolipid Gb(3) receptor. After administration of STxB chemically coupled to OVA (STxB-OVA) or E7, a polypeptide derived from HPV, in mice, we showed that the addition of alpha galactosylceramide (alpha-GalCer) resulted in a dramatic improvement of the STxB Ag delivery system, as reflected by the more powerful and longer lasting CD8(+) T cell response observed even at very low dose of immunogen (50 ng). This synergy was not found with other adjuvants (CpG, poly(I:C), IFN-alpha) also known to promote dendritic cell maturation. With respect to the possible mechanism explaining this synergy, mice immunized with alpha-GalCer presented in vivo the OVA(257-264)/K(b) complex more significantly and for longer period than mice vaccinated with STxB alone or mixed with other adjuvants. To test whether this vaccine could break tolerance against self Ag, OVA transgenic mice were immunized with STxB-OVA alone or mixed with alpha-GalCer. Although no CTL induction was observed after immunization of OVA transgenic mice with STxB-OVA, tetramer assay clearly detected specific anti-OVA CD8(+) T cells in 8 of 11 mice immunized with STxB-OVA combined with alpha-GalCer. In addition, vaccination with STxB-OVA and alpha-GalCer conferred strong protection against a challenge with vaccinia virus encoding OVA with virus titers in the ovaries reduced by 5 log compared with nonimmunized mice. STxB combined with alpha-GalCer therefore appears as a promising vaccine strategy to more successfully establish protective CD8(+) T cell memory against intracellular pathogens and tumors. PMID- 17709556 TI - Rhesus monkey and human share a similar topography of the corpus callosum as revealed by diffusion tensor MRI in vivo. AB - A recent study of the corpus callosum (CC) in humans revealed a new topographical arrangement of the cortical connectivity pattern. To explore the CC topography in nonhuman primates, we applied magnetic resonance diffusion tensor imaging and tract tracing techniques in individual rhesus monkeys in vivo. The results demonstrate that the CC topography of primates and humans is surprisingly similar. In particular, the relatively large representation and caudal extension of commissural frontal fibers in the CC is observed in both the monkey and human brain. If evolutionary changes in relative brain volumes are reflected in the arrangement of related fibers crossing the CC, the current study is in line with the fact that the relative volume of the frontal lobe did not significantly increase after the split of the hominid line from other primates. PMID- 17709553 TI - Natural killer cells in perinatally HIV-1-infected children exhibit less degranulation compared to HIV-1-exposed uninfected children and their expression of KIR2DL3, NKG2C, and NKp46 correlates with disease severity. AB - NK cells play an integral role in the innate immune response by targeting virally infected and transformed cells with direct killing and providing help to adaptive responses through cytokine secretion. Whereas recent studies have focused on NK cells in HIV-1-infected adults, the role of NK cells in perinatally HIV-1 infected children is less studied. Using multiparametric flow cytometric analysis, we assessed the number, phenotype, and function of NK cell subsets in the peripheral blood of perinatally HIV-1-infected children on highly active antiretroviral therapy and compared them to perinatally exposed but uninfected children. We observed an increased frequency of NK cells expressing inhibitory killer Ig-like receptors in infected children. This difference existed despite comparable levels of total NK cells and NK cell subpopulations between the two groups. Additionally, NK cell subsets from infected children expressed, with and without stimulation, significantly lower levels of the degranulation marker CD107, which correlates with NK cell cytotoxicity. Lastly, increased expression of KIR2DL3, NKG2C, and NKp46 on NK cells correlated with decreased CD4+ T lymphocyte percentage, an indicator of disease severity in HIV-1- infected children. Taken together, these results show that HIV-1-infected children retain a large population of cytotoxically dysfunctional NK cells relative to perinatally exposed uninfected children. This reduced function appears concurrently with distinct NK cell surface receptor expression and is associated with a loss of CD4+ T cells. This finding suggests that NK cells may have an important role in HIV-1 disease pathogenesis in HIV-1-infected children. PMID- 17709557 TI - Management of pregnant women with artificial heart valves: inconsistency in ESC publications. PMID- 17709558 TI - Immunoendocrine aspects of endometrial function and implantation. AB - Effective ovarian and uterine function relies on a complex interplay between the endocrine and immune systems. It is generally accepted that in reproductive tissues, oestradiol and progesterone have pro- and anti-inflammatory activities respectively and, in this regard, the paracrine effects of the sex steroids on the ovary are similar to the endocrine effects on the uterus. Ovarian leukocyte recruitment and cytokine release are central to follicle development, ovulation and corpus luteum function. At the uterine level, the cyclical changes in sex steroids regulate the number and distribution of endometrial and decidual immune cells as well as other immune signalling and surveillance factors. The uterine mucosa is unique, in that it must tolerate sperm and the allogeneic blastocyst in a way that does not compromise uterine immune surveillance against bacteria, yeast and viruses. Crosstalk between the sex steroids and immune mediators (systemic and local) are central to these functions, and this article will review these mechanisms and their importance for successful reproductive function and pregnancy success. PMID- 17709559 TI - Beneficial effects of brain-derived neurotropic factor on in vitro maturation of porcine oocytes. AB - In an effort to improve the quality of in vitro produced porcine embryos, we investigated the effect of brain-derived neurotropic factor (BDNF), a neurotropin family member, on in vitro maturation (IVM) of porcine oocytes. The expression of BDNF and truncated isoforms of its receptor, tyrosine kinase B (TrkB), and p75 common neurotropin receptor was detected in both follicular cells and metaphase-I stage oocytes by RT-PCR. However, mRNA of full-length TrkB was not found in oocytes although it was detected in follicular cells. The expression pattern of BDNF and TrkB was confirmed by immunohistochemistry. Supplementation with BDNF (30 ng/ml) during IVM significantly (P < 0.05) increased the first polar body extrusion and glutathione levels in oocytes, whereas the effect of BDNF on nuclear maturation was diminished when gonadotropin and epidermal growth factor (EGF) were added to the culture media. However, treatment with BDNF (30 ng/ml) along with EGF (10 ng/ml) in the presence of gonadotropin significantly (P < 0.05) increased the developmental competence of oocytes to the blastocyst stage after both in vitro fertilization (IVF; 29.1% when compared with control, 15.6%) and somatic cell nuclear transfer (SCNT; 13.6% when compared with control, 3%). This appeared to reflect a stimulatory interaction between BDNF and EGF to enhance the cytoplasmic maturation of oocytes to support successful preimplantation development. In conclusion, BDNFenhanced nuclearand cytoplasmic maturation of oocytes by autocrine and/or paracrine signals. Also, when used together with EGF, BDNF increased the developmental potency of embryos after IVF and SCNT, demonstrating an improved in vitro production protocol for porcine oocytes. PMID- 17709560 TI - Carbohydrate metabolism by murine ovarian follicles and oocytes grown in vitro. AB - Metabolic markers are potentially valuable for assessment of follicle development in vitro. Carbohydrate metabolism of murine preantral follicles grown to maturity over 13 days in vitro has been measured, and metabolism of resulting oocyte cumulus complexes (OCCs) and denuded oocytes has been compared with in vivo ovulated control counterparts. Spent follicle culture media were analysed for glucose, lactate and pyruvate concentrations. During follicle in vitro growth, glycolysis accounted for a rise from approximately 24 to 60% of all glucose consumed. Ovulation induction caused a significant increase in glucose uptake and lactate production by in vitro-grown follicles to 71.7+/-1.2 and 96.6+/-4.8 nmoles/day respectively. OCCs grown in vitro had significantly higher rates of glucose consumption and lactate and pyruvate production (110.1+/- 3.5, 191.8+/- 8.9 and 31.7+/- 1.7 pmoles/h respectively) than in vivo ovulated controls (67.4+/ 8.1, 113.9+/- 17.1 and 20.2+/- 4.0 pmoles/h respectively), but a reduced capacity for pyruvate consumption (1.13+/- 0.06 vs 1.49+/- 0.06 pmoles/h by in vivo ovulated oocytes). Metabolism of OCCs was affected by the quality of the original follicle. In vitro-grown oocytes had a reduced cytoplasmic volume when compared with controls (168.3+/- 2.0 vs 199.0+/- 3.2 proportionately respectively) but a similar rate of metabolism per unit volume. Meiotic status influenced metabolism of both OCCs and denuded oocytes. In conclusion, glucose consumption and lactate production by cultured follicles increased in tandem with developmental progression and were stimulated prior to ovulation. Additionally, the metabolic profiles of in vitro produced OCCs and the oocytes within them are affected by long-term exposure to the culture environment. PMID- 17709561 TI - In spermatozoa, Stat1 is activated during capacitation and the acrosomal reaction. AB - A role for sperm-specific proteins during the early embryonic development has been suggested by a number of recent studies. However, little is known about the participation of transcription factors in that stage. Here, we show that the signal transducer and activator of transcription 1 (Stat1), but not Stat4, was phosphorylated in response to capacitation and the acrosomal reaction (AR). Moreover, Stat1 phosphorylation correlated with changes in its localization: during capacitation, Stat1 moved from the cytoplasm to the theca/flagellum fraction. During AR, Stat1 phosphorylation increased again. In addition, blocking protein kinase A (PKA) and PKC during capacitation abolished both phosphorylation and migration of Stat1. Our results show tight spatio-temporal rearrangements of Stat1, suggesting that after fertilization Stat1 participates in the first rounds of transcription within the male pronucleus. PMID- 17709562 TI - Porcine sperm motility is regulated by serine phosphorylation of the glycogen synthase kinase-3alpha. AB - Sperm functions are critically controlled through the phosphorylation state of specific proteins. Glycogen synthase kinase-3 (GSK3) is a serine/threonine kinase with two different isoforms (alpha and beta), the enzyme activity of which is inhibited by serine phosphorylation. Recent studies suggest that GSK3 is involved in the control of bovine sperm motility. Our aim was to investigate whether GSK3 is present in porcine spermatozoa and its role in the function of these cells. This work shows that both isoforms of GSK3 are present in whole cell lysates of porcine sperm and are phosphorylated on serine in spermatozoa stimulated with the cAMP analog, 8Br-cAMP. A parallel increase in serine phosphorylation of the isoform GSK3alpha, but not in the isoform GSK3beta, is observed after treatments that also induce a significant increase in porcine sperm velocity parameters. Therefore, a significant positive correlation among straight-line velocity, circular velocity, average velocity, rapid-speed spermatozoa, and GSK3alpha serine phosphorylation levels exists. Inhibition of GSK3 activity by alsterpaullone leads to a significant increase in the percentage of rapid- and medium-speed spermatozoa as well as in all sperm velocity parameters and coefficients. Moreover, pretreatment of porcine spermatozoa with alsterpaullone significantly increased the percentage of capacitated porcine spermatozoa and presents no effect in the number of acrosome-reacted porcine spermatozoa. Our work suggests that the isoform GSK3alpha plays a negative role in the regulation of porcine sperm motility and points out the possibility that sperm motile quality might be modulated according the activity state of GSK3alpha. PMID- 17709564 TI - Regulation of the gonadal transcriptome during sex determination and testis morphogenesis: comparative candidate genes. AB - Gene expression profiles during sex determination and gonadal differentiation were investigated to identify new potential regulatory factors. Embryonic day 13 (E13), E14, and E16 rat testes and ovaries were used for microarray analysis, as well as E13 testis organ cultures that undergo testis morphogenesis and develop seminiferous cords in vitro. A list of 109 genes resulted from a selective analysis for genes present in male gonadal development and with a 1.5-fold change in expression between E13 and E16. Characterization of these 109 genes potentially important for testis development revealed that cytoskeletal associated proteins, extracellular matrix factors, and signaling factors were highly represented. Throughout the developmental period (E13-E16), sex-enriched transcripts were more prevalent in the male with 34 of the 109 genes having testis-enriched expression during sex determination. In ovaries, the total number of transcripts with a 1.5-fold change in expression between E13 and E16 was similar to the testis, but none of those genes were both ovary enriched and regulated during the developmental period. Genes conserved in sex determination were identified by comparing changing transcripts in the rat analysis herein, to transcripts altered in previously published mouse studies of gonadal sex determination. A comparison of changing mouse and rat transcripts identified 43 genes with species conservation in sex determination and testis development. Profiles of gene expression during E13-E16 rat testis and ovary development are presented and candidate genes for involvement in sex determination and testis differentiation are identified. Analysis of cellular pathways did not reveal any specific pathways involving multiple candidate genes. However, the genes and gene network identified influence numerous cellular processes with cellular differentiation, proliferation, focal contact, RNA localization, and development being predominant. PMID- 17709563 TI - Retrovirus-mediated in vitro gene transfer into chicken male germ line cells. AB - Chicken testicular cells, including spermatogonia, transplanted into the testes of recipient cockerels sterilized by repeated gamma-irradiation repopulate the seminiferous epithelium and resume the exogenous spermatogenesis. This procedure could be used to introduce genetic modifications into the male germ line and generate transgenic chickens. In this study, we present a successful retroviral infection of chicken testicular cells and consequent transduction of the retroviral vector into the sperm of recipient cockerels. A vesicular stomatitis virus glycoprotein G-pseudotyped recombinant retroviral vector, carrying the enhanced green fluorescent protein reporter gene was applied to the short-term culture of dispersed testicular cells. The efficiency of infection and the viability of infected cells were analyzed by flow cytometry. No significant CpG methylation was detected in the infected testicular cells, suggesting that epigenetic silencing events do not play a role at this stage of germ line development. After transplantation into sterilized recipient cockerels, these retrovirus-infected testicular cells restored exogenous spermatogenesis within 9 weeks with approximately the same efficiency as non-infected cells. Transduction of the reporter gene encoding the green fluorescent protein was detected in the sperms of recipient cockerels with restored spermatogenesis. Our data demonstrate that, similarly as in mouse and rat, the transplantation of retrovirus-infected spermatogonia provides an efficient system to introduce genes into the chicken male germ line. PMID- 17709565 TI - 11Beta-hydroxysteroid dehydrogenase enzymes in the testis and male reproductive tract of the boar (Sus scrofa domestica) indicate local roles for glucocorticoids in male reproductive physiology. AB - 11Beta-hydroxysteroid dehydrogenase (11betaHSD) enzymes modulate the target cell actions of corticosteroids by catalysing metabolism of the physiological glucocorticoid (GC), cortisol, to inert cortisone. Recent studies have implicated GCs in boar sperm apoptosis. Hence, the objective of this study was to characterise 11betaHSD enzyme expression and activities in the boar testis and reproductive tract. Although 11betaHSD1 and 11betaHSD2 mRNA transcripts and proteins were co-expressed in all tissues, cortisol-cortisone interconversion was undetectable in the corpus and cauda epididymides, vas deferens, vesicular and prostate glands, irrespective of nucleotide cofactors. In contrast, homogenates of boar testis, caput epididymidis and bulbourethral gland all displayed pronounced 11betaHSD activities in the presence of NADPH/NADP(+) and NAD(+), and the penile urethra exhibited NAD(+)-dependent 11beta-dehydrogenase activity. In kinetic studies, homogenates of boar testis, caput epididymidis and bulbourethral gland oxidised cortisol with K(m) values of 237-443 and 154-226 nmol/l in the presence of NADP(+) and NAD(+) respectively. Maximal rates of NADP(+)-dependent cortisol oxidation were 7.4- to 28.5-fold greater than the V(max) for NADPH- dependent reduction of cortisone, but were comparable with the rates of NAD(+) dependent cortisol metabolism. The relatively low K(m) estimates for NADP(+) dependent cortisol oxidation suggest that either the affinity of 11betaHSD1 has been increased or the cortisol inactivation is catalysed by a novel NADP(+) dependent 11betaHSD enzyme in these tissues. We conclude that in the boar testis, caput epididymidis and bulbourethral gland, NADP(+)- and NAD(+)-dependent 11betaHSD enzymes catalyse net inactivation of cortisol, consistent with a physiological role in limiting any local actions of GCs within these reproductive tissues. PMID- 17709566 TI - Impaired expression of genes coding for reactive oxygen species scavenging enzymes in testes of Mtfr1/Chppr-deficient mice. AB - Mtfr1/Chppr is a nuclear gene coding for a mitochondrial protein capable of inducing fission of this organelle in a sequence-specific manner. Here we show that in mice, Mtfr1/Chppr is ubiquitously expressed and displays the highest level of expression in pubertal and adult testes and in particular in spermatids and Leydig cells. To investigate Mtfr1 function in vivo, we analyzed homozygous mice null for this gene obtained through a gene trap approach. We show that these mice fail to express Mtfr1 and that in their testes several genes coding for enzymes involved in the defense against oxidative stress are downregulated. Among these, we studied in particular glutathione peroxidase 3 and show its expression in selected testis cell types. Furthermore, we demonstrate oxidative DNA damage specifically in testes of Mtfr1-deficient mice likely resulting from a reduced antioxidant activity. As a whole, these data suggest that Mtfr1 protects the male gonads against oxidative stress. PMID- 17709567 TI - Differential modulation of bovine epididymal activity by oxytocin and noradrenaline. AB - Passage of spermatozoa through the epididymis and emission of sperm during ejaculation are based on spontaneous and induced contractions of epididymal peritubular muscle layers. This study deals with the ejaculation-relevant factors noradrenaline (NA) and oxytocin (OT) and their contractile effects in the course of the bovine epididymal duct. Muscle tension recording revealed excitatory effects of NA in all duct regions. A peculiarity was found in a duct section between the mid-cauda and ductus deferens, where the responsiveness to NA was particularly faint in comparison with the adjacent regions. NA-induced contraction was primarily mediated by postjunctional alpha(2)-adrenoceptors (ADRA) in the caput and corpus regions, and by alpha(1)-ADRA in the cauda region. Contrary to NA, OT exerted regionally varying effects. The peptide induced contraction in intact and epithelium-denuded caput as well as in epithelium denuded corpus segments but had a relaxant net effect in intact corpus and proximal cauda segments. Within the mid-cauda, OT evoked strong contraction, which progressively decreased distally. Receptor specificity of the epididymal OT effects was verified using the selective OT receptor (OTR) agonist [Thr(4),Gly(7)]OT and vasopressin. OTR immunoreactivity was detected in the epididymal peritubular muscle wall and epithelial principal cells. RT-PCR analysis confirmed the presence of OTR in all duct regions. In summary, different contractile responses to OT and NA occur in the course of the epididymal duct, possibly preventing excessive sperm transport through the corpus and serving orthograde emission of sperm during ejaculation. PMID- 17709568 TI - The expression of transforming growth factor beta in pregnant rat myometrium is hormone and stretch dependent. AB - From a quiescent state in early pregnancy to a highly contractile state in labor, the myometrium displays tremendous growth and remodeling. We hypothesize that the transforming growth factor beta (TGFbeta) system is involved in the differentiation of pregnant myometrium throughout gestation and labor. Furthermore, we propose that during pregnancy the mechanical and hormonal stimuli play a role in regulating myometrial TGFbetas. The expression of TGFbeta1-3 mRNAs and proteins was examined by real-time PCR, Western immunoblot, and localized with immunohistochemistry in the rat uterus throughout pregnancy and labor. Tgfbeta1-3 genes were expressed differentially in pregnant myometrium. Tgfbeta2 gene was not affected by pregnancy, whereas the Tgfbeta1 gene showed a threefold increase during the second half of gestation. In contrast, we observed a dramatic bimodal change in Tgfbeta3 gene expression throughout pregnancy. Tgfbeta3 mRNA levels first transiently increased at mid-gestation (11-fold on day 14) and later at term (45-fold at labor, day 23). Protein expression levels paralleled the changes in mRNA. Treatment of pregnant rats with the progesterone (P4) receptor antagonist RU486 induced premature labor on day 19 and increased Tgfbeta3 mRNA, whereas artificial maintenance of elevated P4 levels at late gestation (days 20 23) caused a significant decrease in the expression of Tgfbeta3 gene. In addition, Tgfbeta3 was up-regulated specifically in the gravid horn of unilaterally pregnant rats subjected to a passive biological stretch imposed by the growing fetuses, but not in the empty horn. Collectively, these data indicate that the TGFbeta family contributes in the regulation of myometrial activation at term integrating mechanical and endocrine signals for successful labor contraction. PMID- 17709569 TI - Regulation of homeobox A10 expression in the primate endometrium by progesterone and embryonic stimuli. AB - Homeobox A10 (HOXA10), a member of abdominal B subclass of homeobox genes, is responsible for uterine homeosis during development. Intriguingly, in the adult murine uterus, HOXA10 has been demonstrated to play important roles in receptivity, embryo implantation, and decidualization. However, the roles of HOXA10 in the primate endometrium are not known. To gain insights into the roles of HOXA10 in the primate endometrium, its expression was studied in the endometria of bonnet monkey (Macaca radiata) in the receptive phase and also in the endometria of monkeys treated with antiprogestin onapristone (ZK98.299) or in conception cycle where the presence of preimplantation stage blastocyst was verified. In addition, the mRNA expression of HOXA11 and insulin-like growth factor-binding protein 1 (IGFBP1) was evaluated by real-time PCR in these animals.The results revealed that HOXA10 in the luteal phase primate endometrium is differentially expressed in the functionalis and the basalis zones, which is modulated in vivo by progesterone and also by the signals from the incoming embryo suggesting the involvement of HOXA10 in the process of establishment of pregnancy in primates. In addition, the results also demonstrated that the expression of IGFBP1 but not HOXA11 is coregulated with HOXA10 in the endometria of these animals. The pattern of changes in the expression of HOXA10 in response to the two stimuli suggests that endometrial receptivity and implantation not only requires a synchrony of maternal and embryonic signaling on endometrial cells in the primates but there also exists a controlled differential response among the cells of various uterine compartments. PMID- 17709570 TI - Stable inhibition of interleukin 1 receptor type II in Ishikawa cells augments secretion of matrix metalloproteinases: possible role in endometriosis pathophysiology. AB - Our previous studies showed a marked deficiency in interleukin 1 receptor type II (IL1R2) in the endometrial tissue of women with endometriosis, particularly in epithelial cells. We believe that such a deficiency in IL1R2, a potent and specific IL1 inhibitor, makes endometrial cells more sensitive to IL1 and less capable of buffering the cytokine's effects, which may lead to functional changes that favor endometriosis development. The main objective of our study was to stably inhibit IL1R2 expression in endometrial cells in order to evaluate the role of IL1R2 deficiency in endometriosis pathophysiology. Stable clones of Ishikawa adenocarcinoma endometrial cells transfected with IL1R2 antisense and showing downregulation of IL1R2 protein expression, or with the empty expression vector alone and showing no noticeable difference in IL1R2 expression, were selected. The downregulation of IL1R2 expression in IL1R2 antisense transfectants when compared with control cells was confirmed by ELISA, Western blot and immunofluorescence. In these cells, IL1R2 expression was markedly reduced, compared with non-transfected cells or cells transfected with the empty vector, and there was a significant increase in the basal and the IL1-beta (IL1B)-induced levels of matrix metalloproteinase (MMP)-2 and MMP-9 secretion. Furthermore, a significant decrease in IL1B-induced secretion of tissue inhibitor of MMPs-1, a known MMP-9 inhibitor, was observed. These in vitro data make plausible a role for IL1R2 deficiency in the capability of endometrial cells to invade the host tissue and develop in ectopic locations. PMID- 17709571 TI - Expression and localisation of extracellular matrix degrading proteases and their inhibitors during the oestrous cycle and after induced luteolysis in the bovine corpus luteum. AB - The corpus luteum (CL) offers the opportunity to study high proliferative processes during its development and degradation processes during its regression. We examined the mRNA expression of matrix metalloproteases (MMP)-1, MMP-2, MMP-9, MMP-14, MMP-19, tissue inhibitor of MMP (TIMP)-1, TIMP-2, tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), uPA-receptor (uPAR), PA inhibitors (PAI)-1, PAI-2 in follicles 20 h after GnRH application, CLs during days 1-2, 3-4, 5-7 and 8-12 of the oestrous cycle as well as after induced luteolysis. Cows in the mid-luteal phase were injected with Cloprostenol and the CLs were collected at 0.5, 2, 4, 12, 24, 48 and 64 h after PGF2alpha injection. Real-time RT-PCR determined mRNA expressions. Expression from 20 h after GnRH to day 12: MMP-1, MMP-2, MMP-14 and tPA showed a clear expression, but no regulation. TIMP-1 and uPAR mRNA increased when compared with the follicular phase. TIMP-2, MMP-9, MMP-19 and uPA increased from the follicular phase to days 8-12. PAI-1 and PAI-2 expression increased from days 1-7 and decreased to days 8 12. Induced luteolysis: MMP-1, MMP-2, MMP-9, MMP-14, MMP-19 and TIMP-1 all increased at different time points and intensities, whereas TIMP-2 was constantly decreased from 24 to 64 h. The plasminogen activator system and their inhibitors were up-regulated from 2 to 64 h, tPA was already increased after 0.5 h. Immunohistochemistry for MMP-1, MMP-2, MMP-14: an increased staining for MMP-1 and MMP-14 was seen in large luteal cells beginning 24 h after PGF2alpha application. MMP-2 showed a strong increase in staining in endothelial cells at 48 h. PMID- 17709572 TI - Advances in cochlear implant telemetry: evoked neural responses, electrical field imaging, and technical integrity. AB - During the last decade, cochlear implantation has evolved into a well-established treatment of deafness, predominantly because of many improvements in speech processing and the controlled excitation of the auditory nerve. Cochlear implants now also feature telemetry, which is highly useful to monitor the proper functioning of the implanted electronics and electrode contacts. Telemetry can also support the clinical management in young children and difficult cases where neural unresponsiveness is suspected. This article will review recent advances in the telemetry of the electrically evoked compound action potential that have made these measurements simple and routine procedures in most cases. The distribution of the electrical stimulus itself sampled by "electrical field imaging" reveals general patterns of current flow in the normal cochlea and gross abnormalities in individual patients; models have been developed to derive more subtle insights from an individual electrical field imaging. Finally, some thoughts are given to the extended application of telemetry, for example, in monitoring the neural responses or in combination with other treatments of the deaf ear. PMID- 17709574 TI - Perceptual learning and auditory training in cochlear implant recipients. AB - Learning electrically stimulated speech patterns can be a new and difficult experience for cochlear implant (CI) recipients. Recent studies have shown that most implant recipients at least partially adapt to these new patterns via passive, daily-listening experiences. Gradually introducing a speech processor parameter (eg, the degree of spectral mismatch) may provide for more complete and less stressful adaptation. Although the implant device restores hearing sensation and the continued use of the implant provides some degree of adaptation, active auditory rehabilitation may be necessary to maximize the benefit of implantation for CI recipients. Currently, there are scant resources for auditory rehabilitation for adult, postlingually deafened CI recipients. We recently developed a computer-assisted speech-training program to provide the means to conduct auditory rehabilitation at home. The training software targets important acoustic contrasts among speech stimuli, provides auditory and visual feedback, and incorporates progressive training techniques, thereby maintaining recipients' interest during the auditory training exercises. Our recent studies demonstrate the effectiveness of targeted auditory training in improving CI recipients' speech and music perception. Provided with an inexpensive and effective auditory training program, CI recipients may find the motivation and momentum to get the most from the implant device. PMID- 17709575 TI - Effects of triamcinolone acetonide injections with and without preservative. PMID- 17709573 TI - Binaural-bimodal fitting or bilateral implantation for managing severe to profound deafness: a review. AB - There are now many recipients of unilateral cochlear implants who have usable residual hearing in the non-implanted ear. To avoid auditory deprivation and to provide binaural hearing, a hearing aid or a second cochlear implant can be fitted to that ear. This article addresses the question of whether better binaural hearing can be achieved with binaural/bimodal fitting (combining a cochlear implant and a hearing aid in opposite ears) or bilateral implantation. In the first part of this article, the rationale for providing binaural hearing is examined. In the second part, the literature on the relative efficacy of binaural/bimodal fitting and bilateral implantation is reviewed. Most studies on comparing either mode of bilateral stimulation with unilateral implantation reported some binaural benefits in some test conditions on average but revealed that some individuals benefited, whereas others did not. There were no controlled comparisons between binaural/bimodal fitting and bilateral implantation and no evidence to support the efficacy of one mode over the other. In the third part of the article, a crossover trial of two adults who had binaural/bimodal fitting and who subsequently received a second implant is reported. The findings at 6 and 12 months after they received their second implant indicated that binaural function developed over time, and the extent of benefit depended on which abilities were assessed for the individual. In the fourth and final parts of the article, clinical issues relating to candidacy for binaural/ bimodal fitting and strategies for bimodal fitting are discussed with implications for future research. PMID- 17709577 TI - Which colour suits the vitreoretinal surgeon? PMID- 17709578 TI - Polypoidal choroidal vasculopathy with an appearance similar to classic choroidal neovascularisation on fluorescein angiography. PMID- 17709579 TI - Polypoidal choroidal vasculopathy. PMID- 17709580 TI - Back to basics - ephrins, axonal guidance, neuroprotection and glaucoma. PMID- 17709581 TI - An out-pouching of the eye? PMID- 17709582 TI - Causes and temporal trends of childhood blindness in Indonesia: study at schools for the blind in Java. AB - AIMS: To ascertain the causes of blindness and severe visual impairment (BL/SVI) in schools for the blind in Java, to identify preventable and treatable causes and to evaluate temporal trends in the major causes. METHODS: From a total of 504 students, 479 were examined. Data was collected using a modified World Heath Organization Prevention of Blindness (WHO/PBL) eye examination record for children. RESULTS: The majority of the students (95%) were blind and 4.6% were severely visually impaired. The major anatomical site of BL/SVI was whole globe in 35.9%, retina in 18.9%, lens in 16.4% and cornea in 16.1%. The major underlying aetiology of BL/SVI was undetermined/unknown in 32.7% (mainly microphthalmia, anterior segment dysgenesis and cataract), hereditary factors 31.9% (mainly retinal dystrophies), and childhood disorders 28.5%. Avoidable causes of BL/SVI accounted for 59.9% of the total students, whereas measles blindness was the underlying condition for 23.1% of the preventable causes; cataract and glaucoma accounted for 15.5% and 8.2% of the treatable causes, respectively. Exploration on trends of SVI/BL among two different age groups <16 years and > or = 16 years suggested that childhood disorders and corneal factors have declined, while hereditary disorders have increased. Optic nerve disorder, although not counted as a major cause of blindness, seems to be on the increase. CONCLUSIONS: More than half of the BL/SVI causes are potentially avoidable. Cataract and corneal disorders related to measles or vitamin A deficiency were the major treatable and preventable causes. Declining proportions of childhood factors and corneal disorders over a period of 10-20 years could reflect improved vitamin A supplementation and measles vaccination coverage in Indonesia. This finding, and the increased proportion of hereditary disease causes, could suggest improving levels of socioeconomic development and health care services. PMID- 17709583 TI - Poverty as a barrier to accessing cataract surgery: a study from Tanzania. AB - AIM: Many sub-Saharan African governments expect patients to contribute towards health care. We investigated what happens to patients who reported being too poor too pay for cataract surgery. METHODS: Over 1 year, patients who did not accept cataract surgery after being advised to do so at outreach clinics were enrolled in a prospective cohort study, then followed-up to determine who returned. A subsample was traced for further interviews to learn what they had undertaken to try to obtain funds. RESULTS: A total of 198 patients did not accept surgery and 157 (79%) of these stated the reason was lack of funds. At follow-up, 36 had returned for surgery, 32 with money and 4 with letters from village leaders verifying inability to pay. There was no association between age, sex, or blindness and returning. Interviews with a representative subsample revealed that 44% patients with stated poverty actually had other reasons for not accepting surgery; only 22% took advantage of a free waiver issued at the interview. CONCLUSIONS: Of patients who reported being too poor to pay for cataract surgery, 20% accessed funds after counselling. A significant proportion of those who did not return supplied other reasons for not accepting surgery when interviewed later at home, and did not use a free waiver granted at that time. Access to health care is a complex issue; however, this study does not support the notion that charging small fees for cataract surgery in this setting creates a major barrier to access. That said, it is important to find simple, valid methods to identify those too poor to pay for surgery if we hope to develop sustainable systems to achieve VISION 2020 targets. PMID- 17709584 TI - Prevalence and causes of blindness and low vision in Timor-Leste. AB - AIM: To estimate the prevalence and causes of blindness and low vision in people aged > or = 40 years in Timor-Leste. METHOD: A population-based cross-sectional survey using multistage cluster random sampling to identify 50 clusters of 30 people. A cause of vision loss was determined for each eye presenting with visual acuity worse than 6/18. RESULTS: Of 1470 people enumerated, 1414 (96.2%) were examined. The age, gender and domicile-adjusted prevalence of functional blindness (presenting vision worse than 6/60 in the better eye) was 7.4% (95% CI 6.1 to 8.8), and for blindness at 3/60 was 4.1% (95% CI 3.1 to 5.1). The adjusted prevalence for low vision (better eye presenting vision of 6/60 or better, but worse than 6/18) was 17.7% (95% CI 15.7 to 19.7). Gender was not a risk factor for blindness or low vision, but increasing age, illiteracy, subsistence farming, unemployment and rural domicile were risk factors for both. Cataract was the commonest cause of blindness (72.9%) and an important cause of low vision (17.8%). Uncorrected refractive error caused 81.3% of low vision. CONCLUSION: Strategies that make good-quality cataract and refractive error services available, affordable and accessible, especially in rural areas, will have the greatest impact on vision impairment. PMID- 17709586 TI - Slit-lamp technique of draining interface fluid following Descemet's stripping endothelial keratoplasty. AB - AIM: To describe a new slit-lamp technique for draining interface fluid to manage complete donor disc detachments following Descemet's stripping (automated) endothelial keratoplasty (DSEK/DSAEK). METHODS: Interventional case series. Five DSEK/DSAEK patients presented on the first postoperative day with complete detachment of the donor lenticule. Slit-lamp biomicroscopy showed interface fluid preventing attachment of the donor disc to the host stromal bed. A new slit-lamp technique is described to drain the interface fluid. This technique involved completely filling the anterior chamber with an air bubble using a 30-gauge needle on a 3 ml syringe. Following this, a 0.12 forceps was used to open the inferior mid-peripheral corneal drainage slit to drain the interface fluid. RESULTS: This technique was successful in draining the interface fluid in all five patients, leading to immediate complete reattachment of the donor disc. CONCLUSION: Donor disc detachments following DSEK/DSAEK can be successfully managed by this slit-lamp technique of draining the interface fluid. PMID- 17709587 TI - Management of intraoperative tilting of the scleral-fixated intraocular lens in classical aniridia. PMID- 17709588 TI - Skills acquired during training: a cause for concern? PMID- 17709589 TI - A case of bilateral endophthalmitis and carriage of beta-defensin 1 44CC genotype. PMID- 17709590 TI - Symptomatic interferon retinopathy successfully treated by hypertension management. PMID- 17709591 TI - Keloid of the conjunctiva simulating a conjunctival malignancy. PMID- 17709592 TI - Spontaneous resolution of an inflammation-associated epiretinal membrane with previously documented posterior vitreous detachment. PMID- 17709593 TI - Pressure dependent stromal oedema following deep anterior lamellar keratoplasty. PMID- 17709595 TI - Age and cataract surgery complications. PMID- 17709596 TI - Retinal venous occlusion associated with depot medroxyprogesterone acetate. PMID- 17709597 TI - Lung dendritic cells have a potent capability to induce production of immunoglobulin A. AB - The mucosal immune system provides the first line of defense against inhaled pathogens in the lung. This system is largely mediated by immunoglobulin A (IgA) locally produced by plasma cells, which originate from homing IgA-committed B cells. It has not been determined what types of antigen-presenting cells (APCs) primarily induce B cell differentiation for IgA production in the lung. In addition, although mucosal dendritic cells (DCs) are functionally distinct from DCs in other tissues, it is unclear whether IgA-inducing capability differs between mucosal lung DCs (LDCs) and nonmucosal DCs. The present study was conducted to identify APCs principally responsible for IgA induction in the lung, and to determine potential differences in IgA-inducing capacity between LDCs and nonmucosal DCs. We measured immunoglobulin and cytokine production in a coculture system containing naive IgD(+) B cells, naive T cells from ovalbumin-specific T cell-receptor transgenic mice, and APCs including LDCs, alveolar macrophages (AMs), or spleen DCs (SDCs). LDCs induced significantly greater levels of IgA, IgG1, IL-6, and TGF-beta than AMs and SDCs, whereas no differences were found in the production of IgM or IgG2a. In addition, the IgA percentage of total class switched immunoglobulin was highest in cocultures with LDCs (38.4%) when compared with those with AMs (15.1%) and SDCs (22.7%). Neutralizing TGF-beta, but not IL 6, significantly decreased IgA induction by LDCs and SDCs, but not by AMs. This study suggests that LDCs are the primary APCs introducing IgA to the lung, and have a more potent IgA-inducing capacity than nonmucosal DCs. PMID- 17709599 TI - CHOP transcription factor mediates IL-8 signaling in cystic fibrosis bronchial epithelial cells. AB - Interleukin (IL)-8 is a potent neutrophil chemoattractant that drives the inflammatory response in cystic fibrosis (CF). Traditional approaches to the pathophysiology of this inflammation have focused on targeting NF-kappaB dependent signaling and therapy with glucocorticoids. We test the hypothesis that an alternative pathway, independent of NF-kappaB, operates through prostaglandin E2 (PGE-2) receptor EP-2 and stimulates IL-8 chemokine secretion. Using CF bronchial epithelial cells (IB3-1) in vitro, exogenous PGE-2 induces IL-8 release in a dose-dependent manner. These events are associated with elevation in the EP 2 receptors. Inhibition of cyclooxygenase (Cox)-2 with NS-398 was associated with reductions in Cox-2 (2-fold) and IL-6 (1.3-fold) mRNA transcripts, and in IL-8 and PGE-2 chemokine secretion. The inhibition of Cox-2 signaling led to down regulation of the downstream C/EBP homologous protein (CHOP) transcription factor, resulting in a decrease in IL-8 activation. We confirmed the regulation of IL-8 promoter by CHOP in CF cells using the IL-8 reporter assay. We conclude that PGE-2 stimulates IL-8 production through the CHOP transcription factor in CF cells. PMID- 17709600 TI - Th1/Th2 cytokines reciprocally regulate in vitro pulmonary angiogenesis via CXC chemokine synthesis. AB - Hypervascularity is known as an important element of airway remodeling in bronchial asthma. However, it remains obscure how allergic inflammation relates to angiogenesis in the lung. In this study, we examined the in vitro effects of inflammatory cytokines on endothelial cell functions, particularly angiogenesis. Human microvascular endothelial cells from normal lung (HMVEC-Ls) were cultured with TNF-alpha, IFN-gamma, IL-4, a combination of TNF-alpha and IFN-gamma, or a combination of TNF-alpha and IL-4, and the cell proliferation and tube-forming activities were evaluated. IL-4 slightly enhanced the proliferation of HMVEC-Ls in the presence of vascular endothelial growth factor (VEGF), whereas TNF-alpha and IFN-gamma tended to inhibit it. Synergistic inhibition was observed when TNF alpha and IFN-gamma were simultaneously added to the culture medium. The combination of IL-4 and TNF-alpha markedly promoted tube formation by HMVEC-Ls, even in the absence of VEGF. The IL-4 and TNF-alpha combination induced autocrine production of CXCR2 chemokines, which are known to have angiogenic activity, whereas the production of angiostatic CXCR3 chemokines was dramatically up regulated when TNF-alpha and IFN-gamma were present. The marked IL-4- and TNF alpha-induced tube formation was inhibited by a selective CXCR2 antagonist. These results suggest that, in the presence of TNF-alpha, IL-4 and IFN-gamma reciprocally regulate tube formation by HMVEC-Ls through autocrine synthesis of CXCR2 and CXCR3 chemokines, respectively. Of note, the CXCR2 chemokine-induced tube formation was independent of VEGF. Therefore, CXCR2 chemokines may represent potential therapeutic targets for bronchial asthma. PMID- 17709598 TI - Alveolar epithelial beta2-adrenergic receptors. AB - beta(2)-adrenergic receptors are present throughout the lung, including the alveolar airspace, where they play an important role for regulation of the active Na(+) transport needed for clearance of excess fluid out of alveolar airspace. beta(2)-adrenergic receptor signaling is required for up-regulation of alveolar epithelial active ion transport in the setting of excess alveolar edema. The positive, protective effects of beta(2)-adrenergic receptor signaling on alveolar active Na(+) transport in normal and injured lungs provide substantial support for the use of beta-adrenergic agonists to accelerate alveolar fluid clearance in patients with cardiogenic and noncardiogenic pulmonary edema. In this review, we summarize the role of beta(2)-adrenergic receptors in the alveolar epithelium with emphasis on their role in the regulation of alveolar active Na(+) transport in normal and injured lungs. PMID- 17709601 TI - Lowering of blood pressure by increasing hematocrit with non nitric oxide scavenging red blood cells. AB - Isovolemic exchange transfusion of 40% of the blood volume in awake hamsters was used to replace native red blood cells (RBCs) with RBCs whose hemoglobin (Hb) was oxidized to methemoglobin (MetHb), MetRBCs. The exchange maintained constant blood volume and produced different final hematocrits (Hcts), varying from 48 to 62% Hct. Mean arterial pressure (MAP) did not change after exchange transfusion, in which 40% of the native RBCs were replaced with MetRBCs, without increasing Hct. Increasing Hct with MetRBCs lowered MAP by 12 mm Hg when Hct was increased 12% above baseline. Further increases of Hct with MetRBCs progressively returned MAP to baseline, which occurred at 62% Hct, a 30% increase in Hct from baseline. These observations show a parabolic "U" shaped distribution of MAP against the change in Hct. Cardiac index, cardiac output divided by body weight, increased between 2 and 17% above baseline for the range of Hcts tested. Peripheral vascular resistance (VR) was decreased 18% from baseline when Hct was increased 12% from baseline. VR and MAP were above baseline for increases in Hct higher than 30%. However, vascular hindrance, VR normalized by blood viscosity (which reflects the contribution of vascular geometry), was lower than baseline for all the increases in Hct tested with MetRBC, indicating prevalence of vasodilation. These suggest that acute increases in Hct with MetRBCs increase endothelium shear stress and stimulate the production of vasoactive factors (e.g., nitric oxide [NO]). When MetRBCs were compared with functional RBCs, vasodilation was augmented for MetRBCs probably due to the lower NO scavenging of MetHb. Consequently, MetRBCs increased the viscosity related hypotension range compared with functional RBCs as NO shear stress vasodilation mediated responses are greater. PMID- 17709603 TI - The role of FDG-PET scans in patients with lymphoma. AB - 18-Fluoro-deoxyglucose positron emission tomography (FDG-PET) is a noninvasive, 3 dimensional imaging modality that has become widely used in the management of patients with malignant lymphomas. This technology has been demonstrated to be more sensitive and specific than either (67)gallium scintigraphy or computerized tomography, providing a more accurate distinction between scar or fibrosis and active tumor. PET scans have been evaluated in pretreatment staging, restaging, monitoring during therapy, posttherapy surveillance, assessment of transformation, and, more recently, as a surrogate marker in new drug development. Data to support these various roles require prospective validation. Moreover, caution must be exercised in the interpretation of PET scans because of technical limitations, variability of FDG avidity among the different lymphoma histologic subtypes, and in the large number of etiologies of false-negative and false-positive results. Recent attempts to standardize PET in clinical trials and incorporation of this technology into uniformly adopted response criteria will hopefully lead to improved outcome for patients with lymphoma. PMID- 17709602 TI - Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA positive chronic eosinophilic leukemia: implications for optimal dosing. AB - Although imatinib is clearly the treatment of choice for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia (CEL), little is known about optimal dosing, duration of treatment, and the possibility of cure in this disorder. To address these questions, 5 patients with FIP1L1/PDGFRA-positive CEL with documented clinical, hematologic, and molecular remission on imatinib (400 mg daily) and without evidence of cardiac involvement were enrolled in a dose de-escalation trial. The imatinib dose was tapered slowly with close follow-up for evidence of clinical, hematologic, and molecular relapse. Two patients with endomyocardial fibrosis were maintained on imatinib 300 to 400 mg daily and served as controls. All 5 patients who underwent dose de-escalation, but neither of the control patients, experienced molecular relapse (P < .05). None developed recurrent symptoms, and eosinophil counts, serum B12, and tryptase levels remained suppressed. Reinitiation of therapy at the prior effective dose led to molecular remission in all 5 patients, although 2 patients subsequently required increased dosing to maintain remission. These data are consistent with suppression rather than elimination of the clonal population in FIP1L1/PDGFRA-positive CEL and suggest that molecular monitoring may be the most useful method in determining optimal dosing without the risk of disease exacerbation. This trial was registered at http://www.clinicaltrials.gov as no. NCT00044304. PMID- 17709604 TI - Evidence for MPL W515L/K mutations in hematopoietic stem cells in primitive myelofibrosis. AB - The MPL (W515L and W515K) mutations have been detected in granulocytes of patients suffering from certain types of primitive myelofibrosis (PMF). It is still unknown whether this molecular event is also present in lymphoid cells and therefore potentially at the hematopoietic stem cell (HSC) level. Toward this goal, we conducted MPL genotyping of mature myeloid and lymphoid cells and of lymphoid/myeloid progenitors isolated from PMF patients carrying the W515 mutations. We detected both MPL mutations in granulocytes, monocytes, and platelets as well as natural killer (NK) cells but not in T cells. B/NK/myeloid and/or NK/myeloid CD34(+)CD38(-)-derived clones were found to carry the mutations. Long-term reconstitution of MPL W515 CD34(+) cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice was successful for as long as 12 weeks after transplantation, indicating that MPL W515 mutations were present in HSCs. Moreover, the 2 MPL mutations induced a spontaneous megakaryocytic growth in culture with an overall normal response to thrombopoietin (TPO). In contrast, erythroid progenitors remained EPO dependent. These results demonstrate that in PMF, the MPL W515L or K mutation induces a spontaneous megakaryocyte (MK) differentiation and occurs in a multipotent HSCs. PMID- 17709605 TI - Leukocytoclastic vasculitis due to thalidomide in multiple myeloma. AB - Thalidomide is successfully used in the treatment of multiple myeloma, leprosy and various autoimmune diseases due to its anti-angiogenic, immunomodulatory and anti-inflammatory effects. Thalidomide's most common side effects are constipation, neuropathy, fatigue, sedation, rash, tremor and peripheral edema. We achieved complete response with a 400 mg/day dose thalidomide therapy in a 58 year-old male patient diagnosed with relapsing refractory multiple myeloma. While continuing thalidomide for sustainable response, the therapy was terminated at the ninth month due to development of leukocytoclastic vasculitis. We describe the case and discuss the place of thalidomide in the treatment of multiple myeloma and the rare occurrence of leukocytoclastic vasculitis during thalidomide therapy in multiple myeloma, since only one such case has been reported in the literature thus far. PMID- 17709606 TI - Evaluation of prognostic factors of esophageal squamous cell carcinoma (stage II III) after concurrent chemoradiotherapy using biopsy specimens. AB - BACKGROUND: Recently, attention has been directed to concurrent chemoradiotherapy (CRT) for the treatment of squamous cell carcinoma of the esophagus with regard to efficacy, quality of life and functional preservation, and survival periods comparable to those after standard surgical therapy have been reported in responders to CRT. However, there are some non-responders to CRT, and the prediction of the outcome after CRT is an important subject for future studies. In this study, using biopsy specimens obtained before CRT, we evaluated the relationships between biological markers and the outcome after CRT in order to determine the prognostic factors of CRT. METHODS: The subjects were 51 patients (42 males and nine females: median age 68 years). who were histologically confirmed to have squamous cell carcinoma of the esophagus at stage II or III (UICC). Concurrent CRT consisting of chemotherapy using 5FU and CDDP and radiation therapy (60 Gy) was performed as the initial treatment, and the relationships of overexpression of EGFR, p53, VEGF, PCNA and CyclinD1 were examined immunohistochemically in biopsy specimens collected before treatment. Overall survival was estimated by multivariate analysis. RESULTS: The percentages of patients overexpressing p53, VEGF, PCNA, CyclinD1, and EGFR were 33, 31, 37, 31 and 29%, respectively. On multivariate analysis, T stage (P = 0.0393) and PCNA (P = 0.0302) were found to be significant prognostic factors. CONCLUSIONS: PCNA overexpression appears to be a prognostic factor for squamous cell carcinoma of the esophagus after CRT. PMID- 17709607 TI - Scavenger receptor class-A is a novel cell surface receptor for double-stranded RNA. AB - Double-stranded RNA (dsRNA) is a potent signal to the host immune system for the presence of an ongoing viral infection. The presence of dsRNA, intracellularly or extracellularly, leads to the induction of innate inflammatory cytokines in many cell types including epithelial cells. However, the cell surface receptor for recognition of extracellular dsRNA is not yet determined. Here, we report that extracellular dsRNA is recognized and internalized by scavenger receptor class-A (SR-A). Treatment of human epithelial cells with specific antagonists of SR-A or with an anti-SR-A antibody significantly inhibited dsRNA induction of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, and regulated on activation normal T-cell expressed and secreted (RANTES). Furthermore, intranasal dsRNA treatment of SR-A-deficient (SR-A(-/-)) mice showed a significant decrease in the expression of inflammatory cytokines and a corresponding decrease in the accumulation of polymorphonuclear leukocytes (PMNs) in lungs. These data provide direct evidence that SR-A is a novel cell surface receptor for dsRNA, and therefore, SR-A may play a role in antiviral immune responses. PMID- 17709608 TI - Synaptotagmin VII splice variants alpha, beta, and delta are expressed in pancreatic beta-cells and regulate insulin exocytosis. AB - Synaptotagmins (SYT) are calcium-binding proteins that participate in regulated exocytosis. Although SYTI to IX isoforms are expressed in insulin-producing cell lines, hitherto only SYTIX has been associated with native beta-cell insulin granules and implicated in exocytosis. SYTVII was also proposed to regulate insulin exocytosis, but its subcellular location and number of alternative splice variants produced remain controversial. Only transcripts of SYTVII alpha, beta, and a novel splice variant delta are expressed in beta-cells and INS-1E cells. Western blotting revealed that INS-1E cells predominantly produced SYTVII alpha and low levels of SYTVII beta, whereas SYTVII delta was undetectable. The protein colocalized with insulin granules but not with synaptic-like microvesicles. Overexpression of SYTVII alpha resulted in decreased insulin granule content with a concomitant translocation of the variant to the plasma membrane, while SYTVII beta retained largely a granular pattern. Overexpressed SYTVII delta exhibited a distribution different to that of insulin granules and inhibited exocytosis when assessed by whole cell patch clamp capacitance recording. Silencing of SYTVII alpha by targeted RNA interference suppressed secretion, while repression of beta slightly increased release. Our results demonstrate that SYTVII is expressed on insulin granules and that only SYTVII alpha is implicated in exocytosis under physiological conditions. PMID- 17709609 TI - A pediatric otolaryngologist learns to diagnose acute otitis media. PMID- 17709610 TI - Epidemiologic study of smell disturbance in 2 medical insurance claims populations. AB - OBJECTIVE: To report the rates of medical claims for sense of smell disturbance (SD) and their association with diseases and medications in a managed care population. DESIGN: Descriptive determination of demographics, prevalence, and incidence of SD and case-control analysis of risk factors. Preselected drug and disease groups were entered into a stepwise regression model to determine risk factors for SD. SETTING: Managed care organizations in the United States. PATIENTS: Patients identified through medical claims within IMS Health's LifeLink: Integrated Claims Solution (IMS) and i3 Magnifi Private Managed Care Organizations (MCO) medical insurance databases for 3-year observation periods. MAIN OUTCOME MEASURES: Prevalence and incidence of smell disturbance; adjusted odds ratios and 95% confidence intervals (CIs) of associated conditions and medications. RESULTS: The mean annual prevalence rate of SD was 26.2 per 100 000 for IMS (95% CI, 23.1-29.6) and 17.2 per 100 000 for MCO (95% CI, 15.6-18.7). The mean annual incidence per 100 000 was 26.3 for IMS (95% CI, 23.1-29.8) and 15.9 for MCO (95% CI, 14.5-17.5). The 5 strongest risk factors for SD were chronic sinusitis, oropharyngeal inflammatory disorders, other upper respiratory tract disease excluding sinusitis, cerebrovascular disease, and systemic viral disease. The regression model also retained 3 drug groups (corticosteroids, calcium channel blockers, and nasal and/or sinus products) among the significant risk factors for the presence of SD. CONCLUSIONS: The annual prevalence and incidence rates of SD are lower than prior estimates partly owing to reliance on specific medical claims. A number of conditions preceding the diagnosis of SD were significantly associated with the condition. Uses of certain medications were also risk factors for SD compared with controls. PMID- 17709611 TI - Hearing results after stapedotomy with a nitinol piston prosthesis. AB - OBJECTIVE: To compare the hearing results in patients with otosclerosis who underwent a stapedotomy with either a platinum wire prosthesis or a commercially available, heat-activated nitinol stapes piston prosthesis. DESIGN: Retrospective medical chart review. SETTING: Academic tertiary care medical center. PATIENTS: Seventy-nine consecutive patients diagnosed as having otosclerosis who underwent primary stapedotomy (33 men and 46 women) were included in this study (41 ears per group). INTERVENTION: Stapedotomy. MAIN OUTCOME MEASURES: The operative records of the senior surgeon (B.J.G.) were retrospectively reviewed, and hearing results were obtained. The hearing results of the patients who received a platinum wire prosthesis were compared with those who received a nitinol prosthesis. RESULTS: Results for the platinum wire prosthesis group revealed a postoperative mean (SD) air-bone gap (ABG) of 7 (6) dB, a mean (SD) ABG closure of 21 (12) dB, and a postoperative mean (SD) speech reception threshold of 25 (16) dB. Results for the nitinol prosthesis group revealed a postoperative ABG of 8 (6) dB, an ABG closure of 25 (10) dB, and a postoperative speech reception threshold of 25 (12) dB. CONCLUSIONS: These data show that the nitinol prosthesis is equivalent to the platinum wire prosthesis in closing the ABG in patients with otosclerosis. Comparable efficacy combined with the ease and safety of heat activated crimping supports the continued use of this prosthesis for stapes surgery. PMID- 17709612 TI - Sonotubometry: a useful tool to measure intra-individual changes in eustachian tube ventilatory function. AB - OBJECTIVE: To determine whether intra-individual changes in eustachian tube (ET) function induced by local application of a histamine phosphate solution can be detected using an improved sonotubometer. DESIGN: The function of the ET was measured with a revised sonotubometer before and after histamine was applied to the nasopharyngeal ostium of the ET. SETTING: Tertiary referral hospital. PATIENTS: Twenty-five otologically healthy adults. INTERVENTIONS: A histamine phosphate solution with a concentration of 16 mg/mL was applied to the nasopharyngeal ostium of the ET using a pressure nebulizer. MAIN OUTCOME MEASURES: The number of openings during 10 acts of swallowing. This outcome value could range from 0 to 10. The number of ET openings before and after histamine application was compared. RESULTS: The mean number of ET openings dropped dramatically: from 8.4 before application of histamine to 2.7 after application. This difference was statistically significant; there was a mean difference of 5.6 (95% confidence interval, 4.4-6.9; P < .001). CONCLUSION: Sonotubometry is capable of detecting intra-individual changes in ET function and may therefore be a very useful tool in monitoring and/or clinical research of ET dysfunction or function. PMID- 17709613 TI - Vocal fold medialization in children: injection laryngoplasty, thyroplasty, or nerve reinnervation? AB - OBJECTIVE: To review surgical interventions for pediatric unilateral vocal fold immobility (UVFI). DESIGN: Retrospective medical chart review. SETTING: Two tertiary academic centers. PATIENTS: All children who underwent vocal fold medialization for dysphonia, with or without aspiration, from January 2004 to September 2006. INTERVENTIONS: Injection laryngoplasty, ansa cervicalis-recurrent laryngeal nerve anastomosis, or thyroplasty. MAIN OUTCOME MEASURES: Age, sex, intervention, etiology, time from onset of UVFI to surgery, subjective success in improving voice, subjective duration of improvement, and complications. RESULTS: Twenty-seven procedures were performed in 15 patients (mean age, 10.6 years). Nineteen injection laryngoplasties, 3 thyroplasties (1 bilateral), 2 ansa cervicalis-recurrent laryngeal nerve reinnervation procedures, 1 adduction arytenoidopexy, and 1 cricothyroid joint subluxation were performed. Causes of UVFI included thoracic surgery in 6 cases (40%), prolonged intubation in 4 (26%), central nervous system neoplasm in 3 (20%), unknown etiology in 1 (7%), and anoxic brain injury in 1 (7%). The mean duration from onset of symptoms to treatment was 47 months. There was 1 surgical complication (postoperative aspiration pneumonia following thyroplasty while the patient was under local anesthesia). Parents reported a satisfactory outcome in all cases. CONCLUSIONS: Injection laryngoplasty, thyroplasty, and nerve reinnervation can be performed in pediatric patients with good outcomes and an acceptable safety profile. This article describes the experiences of 2 institutions with phonosurgery for UVFI in children and provides insight into the advantages and disadvantages of each procedure. Prospective studies, with validated quality-of-life measurements, are needed to greater clarify the role of different types of phonosurgery in children with UVFI. PMID- 17709614 TI - Balloon laryngoplasty as a primary treatment for subglottic stenosis. AB - OBJECTIVE: To present our experience with balloon laryngoplasty (BL) as a means of establishing control of the compromised airway and as a definitive alternative to open surgery in infants with acquired subglottic stenosis (SGS). DESIGN: The medical charts of 10 consecutive infants diagnosed as having acquired SGS secondary to a history of intubation and treated initially with BL were reviewed. SETTING: Academic tertiary care children's hospital. PATIENTS: A total of 10 patients (3 girls and 7 boys), with a mean age of 4.8 months (range, 2-12 months), met the inclusion criteria for the study. MAIN OUTCOME MEASURES: The medical charts were assessed for the patients' demographics, clinical presentation, and outcomes, which were defined by postoperative symptomatology, endoscopic grading of residual SGS, complications, and the need for subsequent interventions to control SGS. RESULTS: All 10 patients presented with biphasic stridor, and 8 had significant retractions noted on examination. In all patients, control of the airway was established with BL followed by intubation. Four patients were completely asymptomatic after the initial BL. An additional 3 patients had recurrent stridor during the postoperative period and required a second BL before having complete, persistent resolution of symptoms. Balloon laryngoplasty failed in 3 patients, of whom 2 went on to undergo single-staged laryngotracheal reconstruction and 1 required a tracheotomy. CONCLUSIONS: Balloon laryngoplasty is a safe means of establishing the airway in infants with obstruction secondary to acquired SGS. It was an effective, stand-alone procedure for the management of SGS in 7 of our 10 patients, obviating the need for tracheotomy or cricoid split. PMID- 17709615 TI - Preventing lateral synechia formation after endoscopic sinus surgery with a silastic sheet. AB - OBJECTIVES: To investigate whether the insertion of a Silastic sheet between the middle turbinate and lateral nasal wall can prevent lateral synechia formation when an unstable, floppy middle turbinate results from endoscopic sinus surgery (ESS). DESIGN: Prospective study. SETTING: University hospital. PATIENTS: Thirty patients who developed an unstable, floppy middle turbinate during ESS were allocated in order of occurrence as follows: group 1, 15 patients, 17 sides including 2 bilateral cases; group 2, 15 patients, 18 sides including 3 bilateral cases. INTERVENTIONS: In group 1, a fan-shaped Silastic sheet was inserted between the middle turbinate and lateral nasal wall and secured to the caudal septum. In group 2, no specific procedure was performed except for meticulous postoperative care to prevent lateralization of the middle turbinate. MAIN OUTCOME MEASURE: We observed the patients for 5 months and compared the occurrence rate of synechia formation between the 2 groups. RESULTS: Synechiae developed in 1 of 17 sides (6%) in group 1 and 8 of 18 sides (44%) in group 2, for success rates of 94% and 56%, respectively. The success rates differed significantly. The middle turbinate was preserved in all patients in group 1. CONCLUSION: The results of this study suggest that the insertion of a Silastic sheet in the middle meatus is a useful method for preventing lateral synechia formation and for preserving the middle turbinate. PMID- 17709616 TI - Endoscopic optic nerve decompression for nontraumatic optic neuropathy. AB - OBJECTIVE: To determine the efficacy of endoscopic optic nerve decompression for the treatment of patients with nontraumatic optic neuropathy. DESIGN: Retrospective case series. SETTING: Academic medical center. PATIENTS: Ten optic nerve decompressions were performed on 7 patients with nontraumatic optic neuropathy caused by various pathologic entities, including meningioma, lymphangioma, fibro-osseous lesions (fibrous dysplasia and osteoma), mucopyocele, and Graves orbitopathy. INTERVENTIONS: Endoscopic instrumentation was used in a transnasal fashion to decompress the optic nerve. MAIN OUTCOME MEASURES: Visual acuity and complication rates. RESULTS: Mean visual acuity improved from 20/300 preoperatively to 20/30 after surgery. Visual acuity improved by at least 2 lines on the Snellen chart following 7 of the 10 decompressions. Median operative time was 133 minutes, and median length of stay was less than 24 hours. Complications were limited to postoperative hyponatremia and corneal abrasions, both of which resolved with conservative therapy. Mean follow-up time was 6.1 months. CONCLUSION: Endoscopic optic nerve decompression appears to be an effective treatment for restoring visual acuity in select patients who present with compressive optic neuropathy. PMID- 17709617 TI - Health insurance and stage at diagnosis of laryngeal cancer: does insurance type predict stage at diagnosis? AB - OBJECTIVE: To examine whether patients with no insurance or Medicaid are more likely to present with advanced-stage laryngeal cancer. DESIGN: Retrospective cohort study from the National Cancer Database, 1996-2003. SETTING: Hospital based practice. PARTICIPANTS: Patients with known insurance status diagnosed as having invasive laryngeal cancer at Commission on Cancer facilities (N = 61 131) were included. Adjusted and unadjusted logistic regression models analyzed the likelihood of presenting at a more advanced stage. MAIN OUTCOME MEASURES: Overall stage of laryngeal cancer (early vs advanced) and tumor size (T stage) at diagnosis. RESULTS: Patients with advanced-stage laryngeal cancer at diagnosis were more likely to be uninsured (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.79-2.15) or covered by Medicaid (OR, 2.40; 95% CI, 2.21-2.61) compared with those with private insurance. Similarly, patients were most likely to present with the largest tumors (T4 disease) if they were uninsured (OR, 2.92; 95% CI, 2.60-3.28) or covered by Medicaid (OR, 3.97; 95% CI, 3.56-4.34). Patients who were black, between ages 18 and 56 years, and who resided in zip codes with low proportions of high school graduates or low median household incomes were also more likely to be diagnosed as having advanced disease and/or larger tumors. CONCLUSIONS: Individuals lacking insurance or having Medicaid are at greatest risk for presenting with advanced laryngeal cancer. Results for the Medicaid group may be influenced by the postdiagnosis enrollment of uninsured patients. It is important to consider the impact of insurance coverage on stage at diagnosis and associated morbidity, mortality, quality of life, and costs. PMID- 17709618 TI - Latissimus-serratus-rib free flap for oromandibular and maxillary reconstruction. AB - OBJECTIVE: To review complications and outcomes associated with latissimus serratus-rib free flap oromandibular and midface reconstruction. DESIGN: Retrospective medical record review. SETTING: Two academic tertiary care medical centers. PATIENTS: Twenty-eight patients with segmental resection of the mandible and 1 patient with combined resection of the mandible and maxilla after excision of neoplasms of the oral cavity, who were believed to be poor candidates for fibula free flap reconstruction, were identified. INTERVENTIONS: Twenty-seven latissimus-serratus-rib osteomusculocutaneous free flap reconstructions and 2 serratus-rib osteomuscular free flap reconstructions were performed. MAIN OUTCOME MEASURES: The outcome of microvascular free tissue transfer as well as short- and long-term complications were recorded. RESULTS: There were no perioperative free flap failures. Delayed partial rib graft resorption occurred in 1 patient 33 months after free flap transfer for maxillary reconstruction. Among 28 cases of mandibular reconstruction, 1 case of bone graft nonunion was noted after a postoperative period of 57 months. All other cases achieved successful restoration of mandibular continuity. Donor site morbidity was well-tolerated in all patients. CONCLUSION: Latissimus-serratus-rib osteomusculocutaneous free flaps are effective for reconstruction of composite defects of the mandible in patients who are not candidates for more commonly used vascularized bone containing free flaps. PMID- 17709619 TI - Regional recurrence of squamous cell carcinoma of the nasal cavity: a systematic review and meta-analysis. AB - OBJECTIVE: To demonstrate whether the regional recurrence (RR) of squamous cell carcinoma (SCC) of the nasal cavity is higher than previously suspected. DATA SOURCES: Original articles, including a previously published series from our institution, were identified from systematic searches of the MEDLINE database. STUDY SELECTION: Studies that analyzed tumors other than SCC or tumors from sites other than the nasal cavity were excluded. Studies that did not report an RR were also excluded. DATA EXTRACTION: Studies identified by the literature search were reviewed by a single reviewer (W.C.S.), and studies not excluded were reviewed for data extraction by 2 reviewers (W.C.S. and M.Y.C.). DATA SYNTHESIS: From the 23 studies reviewed, the average weighted percentage RR for SCC of the nasal cavity was 18.1% (95% confidence interval, 13.4%-22.8%). CONCLUSIONS: Currently, few authors advocate elective treatment of the neck in patients with high-risk SCC of the nasal cavity. The results of this systematic review and meta-analysis demonstrate that the RR of this entity may be higher than previously suspected. Because many studies included other histopathologies or analyzed recurrence data from tumors of multiple subsites, a true RR for SCC of the nasal cavity has not been firmly established. Now that a uniform staging system exists for nasal cavity cancers, better prospective analysis of these tumors will be available. The authors suggest that the risk of RR of certain high-risk SCCs of the nasal cavity to the lymph nodes, including the perifacial and upper cervical lymphatics, may approach the frequently cited 20% risk suggestive of consideration for elective regional therapy. PMID- 17709620 TI - Detection of occult bone metastases from head and neck squamous cell carcinoma: impact of positron emission tomography computed tomography with fluorodeoxyglucose F 18. AB - OBJECTIVES: To assess the ability of positron emission tomography-computed tomography with fluorodeoxyglucose F 18 (FDG-PET/CT) to provide early, accurate detection of bone metastases from head and neck squamous cell carcinoma (HNSCC) and to determine the impact of detecting occult bone metastases on patient care. DESIGN: Retrospective medical chart review. SETTING: Single academic medical center. PATIENTS: The study population comprised 13 patients with FDG-PET/CT scans detecting bone lesions suggestive of HNSCC metastases. These patients were identified from a retrospective review of 683 consecutive FDG-PET/CT scans performed for initial staging (n = 198) or restaging (n = 485) of HNSCC between October 2002 and December 2005. MAIN OUTCOME MEASURES: Rate of biopsy confirmation of bone lesions detected by FDG-PET/CT as suggestive of metastases, presence of concurrent symptoms or laboratory serologic evidence for bone metastasis, timing of bone metastasis detection relative to initial diagnosis of HNSCC, and change in therapeutic decision making based on bone metastasis detection. RESULTS: Eleven FDG-PET/CT studies that detected bone metastasis were performed to restage a suspected or known recurrence, and 2 studies were performed for radiographic restaging of disease after completion of therapy. Bone biopsy confirmation was performed in 5 patients, and 4 of the biopsy results were positive for metastatic HNSCC. All patients lacked clinical symptoms of bone involvement, and 82% (n = 9) had serum alkaline phosphatase levels in the normal (n = 7) or minimally elevated (n = 2) range. At the time of bone metastasis detection, 6 of the 12 patients (50%) had no other identifiable distant metastatic disease. Furthermore, 2 patients (17%) lacked disease at any other local, regional, or distant site. The identification of bone metastases influenced therapeutic decisions in 5 of 13 cases (38%). CONCLUSION: Use of FDG PET/CT in restaging HNSCC allows for detection of occult bone metastases, and this early detection frequently influences therapeutic decision making. PMID- 17709621 TI - Sentinel node biopsy in N0 squamous cell carcinoma of the oral cavity and oropharynx in patients previously treated with surgery or radiation therapy: a pilot study. AB - OBJECTIVES: To assess the feasibility of sentinel lymph node (SLN) localization and to determine the predictive value of SLN biopsy for occult neck metastases in patients previously treated with surgery or radiation therapy and with N0 squamous cell carcinoma of the oral cavity or oropharynx. DESIGN: Prospective case series. SETTING: Tertiary academic hospital. PATIENTS: Eleven patients with T1 to T4 N0 squamous cell carcinoma of the oral cavity or oropharynx. INTERVENTIONS: Patients underwent preoperative peritumoral injection of technetium Tc 99m sulfur colloid followed by dynamic lymphoscintigraphy and operative localization of the SLN(s) with the use of a handheld gamma probe. MAIN OUTCOME MEASURES: The presence or absence of metastatic disease in N0 squamous cell carcinoma of the oral cavity and oropharynx in patients previously treated with surgery or radiation therapy as identified by SLN biopsy findings. RESULTS: In each of the 11 patients, 1 to 3 SLNs were identified by lymphoscintigraphy. All SLNs identified by lymphoscintigraphy were successfully identified and removed with the use of an intraoperative gamma probe. In 10 of the 11 patients, the biopsy findings from the SLN(s) accurately predicted the presence or absence of occult neck metastasis. There was 1 instance of a negative SLN with a positive neck dissection. The overall negative predictive value of the study was 91%. No aberrant lymphatic drainage patterns were observed in this study. CONCLUSION: In patients previously treated with surgery or radiation therapy, SLN biopsy was as effective as in previously untreated patients according to published reports and warrants inclusion of this patient group into larger studies. PMID- 17709622 TI - Differential responses of human papillary thyroid cancer cell lines carrying the RET/PTC1 rearrangement or a BRAF mutation to MEK1/2 inhibitors. AB - OBJECTIVES: To examine the effects of 2 mitogen-activated protein kinase kinase (MEK1/2) inhibitors on papillary thyroid carcinoma (PTC) cell lines carrying the RET/PTC1 rearrangement or a BRAF mutation. In PTC, RET/PTC1 rearrangement or BRAF mutations results in constitutional activation of RET kinase or BRAF, respectively. Along the RET or BRAF signaling cascades, the activated RET kinase or BRAF activates MEK1/2, and then mitogen-activated protein kinases (extracellular signal-related kinase 1/2 [ERK1/2]) is activated. Activated ERK1/2 enters the nucleus and phosphorylates a variety of transcription factors, resulting in cancer cell proliferation. The MEK1/2 inhibitors, PD98059 and U0126, have been shown to inhibit cell growth in other cancers. DESIGN: In vitro study. SUBJECTS: Papillary thyroid carcinoma cell lines carrying the RET/PTC1 rearrangement (BHP2-7) or a BRAF mutation (BHP5-16). INTERVENTION: We treated PTC cells carrying the RET/PTC1 rearrangement or a BRAF mutation with 2 MEK1/2 inhibitors (PD98059 and U0126). MAIN OUTCOME MEASURES: Using Western blot analysis, we detected the expression of phosphorylated ERK1/2 and expression of cleaved poly(ADP-ribose) polymerase (PARP) in cells after treatment with either inhibitors. Growth inhibition was monitored by the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: Using Western blot analysis, we detected the dephosphorylation of ERK1/2 in PTC cells carrying the RET/PTC1 rearrangement or a BRAF mutation after treating the cells with 2 MEK1/2 inhibitors (PD98059 and U0126). In addition, both PD98059 and U0126 completely inhibited the growth of the PTC cells carrying a BRAF mutation but partially inhibited the growth of the PTC cells carrying the RET/PTC1 rearrangement. Finally, we observed PARP cleavage only in cells with a BRAF mutation in the Western blot analysis. CONCLUSION: These data suggested that treatment with MEK1/2 inhibitors can be used as tools for inhibiting the growth of PTC cells. PMID- 17709623 TI - Atypical facial access: an unusually high prevalence of use among patients with skull base tumors treated at 2 centers. AB - OBJECTIVE: To analyze the influence of the unique percentage of skin carcinomas with skull base invasion on the choice of the facial surgical approach. DESIGN: Multi-institutional retrospective analysis of the medical charts of all patients who had undergone oncological craniofacial operations from 1981 to 2005. Data were collected on demographic distribution, location of the primary tumor, histologic type, type of operation, reconstruction, complications, and outcome. Special attention was directed toward the choice of facial approach. SETTING: Two major tertiary care centers. PATIENTS: A total of 484 patients who had undergone major skull base operations. INTERVENTION: Frequency of atypical facial approaches. MAIN OUTCOME MEASURES: Impact on the need for more sophisticated reconstructions and on surgical morbidity. RESULTS: During this 25-year period, 484 patients underwent major skull base operations in the 2 centers; data concerning 467 cases were available for analysis. The median age of the patients was 52.8 years (range, 4-88 years), and the male-female ratio was 1.9:1.0. The initial location of the tumor was the craniofacial skin in 63.5% of cases, ethmoid in 10.8%, maxilla in 2.3%, orbit in 1.9%, and other origins, including endocranial, in 19.4%. The histologic type of the lesions was basal cell carcinoma in 42.0% of cases, squamous cell carcinoma in 29.5%, esthesioneuroblastoma in 5.3%, adenocarcinoma in 3.9%, adenoid cystic carcinoma in 2.8%, and other types in 16.5%. Owing to this high prevalence of advanced skin carcinomas, the most commonly employed facial approach was atypical, tailored to encompass all compromised skin and underlying tissues, in 55.5% of cases, followed by the Weber-Ferguson approach, with all its variations (eg, nasal swing) in 17.8%, lateral rhinotomy in 12.2%, facial translocation in 3.8%, and other facial techniques in 7.7%. No facial approach was required in 1.5% of cases. CONCLUSION: In most situations, head and neck surgeons chose an atypical surgical approach to properly resect all facial structures invaded by very advanced skin cancers. PMID- 17709624 TI - Sentinel lymph node biopsy for sebaceous cell carcinoma and melanoma of the ocular adnexa. AB - OBJECTIVE: To provide clinical details and long-term outcome data for a series of patients with eyelid or conjunctival melanoma or eyelid sebaceous cell carcinoma who underwent sentinel lymph node (SLN) biopsy. DESIGN: Retrospective interventional case series with review of clinical records and pathologic specimens. SETTING: Tertiary comprehensive cancer center. PATIENTS: Twenty-five consecutive patients treated at 1 institution for eyelid or conjunctival melanoma or eyelid sebaceous cell carcinoma from December 2000 to October 2004. INTERVENTIONS: Surgical removal of the eyelid or conjunctival tumor and SLN biopsy. MAIN OUTCOME MEASURES: Local treatment modalities; lymphatic basins in which SLNs were identified; status of SLNs; false-negative rate; and long-term patterns of local recurrence, regional and distant metastasis, and survival. RESULTS: Seven patients had conjunctival melanoma, 8 had eyelid-margin melanoma with a considerable palpebral conjunctival component, and 10 had eyelid sebaceous cell carcinoma. The SLNs were identified in all but 1 patient by using technetium Tc 99m sulfur colloid as a tracer. Intraoperatively, in 16 patients in whom blue dye was used in addition to technetium Tc 99m sulfur colloid during mapping, no SLN was blue. One patient with conjunctival melanoma and 1 patient with eyelid melanoma had a histologically positive SLN. Two patients with eyelid melanoma and 2 patients with eyelid sebaceous cell carcinoma had negative findings from SLN biopsy but developed recurrence in their regional lymph nodes during the follow up period. Overall, during follow-up, 2 of 10 patients with sebaceous cell carcinoma (20%) and 5 of 15 patients with eyelid or conjunctival melanoma (33%) had regional lymph node metastasis. Four patients with melanoma who had regional metastasis also developed distant organ metastasis. Two patients with sebaceous cell carcinoma--1 with regional metastasis and 1 without--developed distant organ metastasis. CONCLUSIONS: The detection of histologically positive SLNs in this series of patients may justify further study of SLN biopsy for high-risk patients with ocular adnexal melanoma or eyelid sebaceous cell carcinoma. The false negative rate is higher than that reported for SLN biopsy at most other anatomic sites. Patients with negative findings from SLN biopsy still require careful long term follow-up because they may develop regional or distant metastasis. PMID- 17709625 TI - Cochlear implant electrode misplaced in the carotid canal. PMID- 17709626 TI - Supraclavicular lymphadenopathy due to silicone breast implants. PMID- 17709627 TI - Radiology quiz case 1. Diagnosis: ancient schwannoma of the right temporal region. PMID- 17709629 TI - Pathology quiz case 1. Diagnosis: nodular fasciitis of the medial canthus simulating dacryocystitis. PMID- 17709628 TI - Radiology quiz case 2. Diagnosis: lingual thyroid. PMID- 17709630 TI - Pathology quiz case 2. Diagnosis: pilomatrix carcinoma. PMID- 17709631 TI - Notice of duplicate publication: "Biofilm Surface Area in the Pediatric Nasopharynx: Chronic Rhinosinusitis vs Obstructive Sleep Apnea" (Arch Otolaryngol Head Neck Surg. 2007;133[2]:110-114). PMID- 17709632 TI - Common genetic variation in KCNH2 is associated with QT interval duration: the Framingham Heart Study. AB - BACKGROUND: QT prolongation is associated with increased risk of sudden cardiac death in the general population and in people exposed to QT-prolonging drugs. Mutations in the KCNH2 gene encoding the HERG potassium channel cause 30% of long QT syndrome, and binding to this channel leads to drug-induced QT prolongation. We tested common KCNH2 variants for association with continuous QT interval duration. METHODS AND RESULTS: We selected 17 single nucleotide polymorphisms and rs1805123, a previously associated missense single nucleotide polymorphism, for genotyping in 1730 unrelated men and women from the Framingham Heart Study. rs3807375 genotypes were associated with continuous QT interval duration in men and women (2-df P=0.002), with a dominant model suggested (P=0.0004). An independent sample of 871 Framingham Heart Study men and women replicated the association (1-sided dominant P=0.02). On combined analysis of 2123 subjects, individuals with AA or AG genotypes had a 0.14-SD (SE, 0.04) or 3.9-ms higher age , sex- and RR-adjusted QT interval compared with GG individuals (P=0.00006). The previously reported association of rs1805123 (K897T) replicated under a dominant (AA/AC, 0.12 [corrected] SD [SE, 0.07] or 3.1 ms higher versus CC; 1-sided P=0.04) or additive model (0.06 SD [SE, 0.03] or 1.6 ms higher per A allele; 1 sided P=0.01). CONCLUSIONS: Two common genetic variants at the KCNH2 locus are associated with continuous QT interval duration in an unselected community-based sample. Studies to determine the influence of these variants on risk of sudden cardiac death and drug-induced arrhythmias should be considered. PMID- 17709633 TI - Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart Study. AB - BACKGROUND: Excess adiposity is associated with greater systemic inflammation. Whether visceral adiposity is more proinflammatory than subcutaneous abdominal adiposity is unclear. METHODS AND RESULTS: We examined the relations of abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), assessed by multidetector computerized tomography, to circulating inflammatory and oxidative stress biomarkers in 1250 Framingham Heart Study participants (52% women; age 60+/-9 years). Biomarkers were examined in relation to increments of SAT and VAT after adjustment for age, sex, smoking, physical activity, menopause, hormone replacement therapy, alcohol, and aspirin use; additional models included body mass index and waist circumference. SAT and VAT were positively and similarly (with respect to strength of association) related to C-reactive protein, fibrinogen, intercellular adhesion molecule-1, interleukin-6, P-selectin, and tumor necrosis factor receptor-2 (multivariable model R2 0.06 to 0.28 [SAT] and 0.07 to 0.29 [VAT]). However, compared with SAT, VAT was more highly associated with urinary isoprostanes and monocyte chemoattractant protein-1 (SAT versus VAT comparison: isoprostanes, R2 0.07 versus 0.10, P=0.002; monocyte chemoattractant protein-1, R2 0.07 versus 0.08, P=0.04). When body mass index and waist circumference were added to the models, VAT remained significantly associated with only C-reactive protein (P=0.0003 for women; P=0.006 for men), interleukin-6 (P=0.01), isoprostanes (P=0.0002), and monocyte chemoattractant protein-1 (P=0.008); SAT only remained associated with fibrinogen (P=0.01). CONCLUSIONS: The present cross-sectional data support an association between both SAT and VAT with inflammation and oxidative stress. The data suggest that the contribution of visceral fat to inflammation may not be completely accounted for by clinical measures of obesity (body mass index and waist circumference). PMID- 17709635 TI - Identification of promoter variants in baboon endothelial lipase that regulate high-density lipoprotein cholesterol levels. AB - BACKGROUND: High-density lipoprotein cholesterol (HDL) levels are a major risk factor for cardiovascular disease. Previously we identified a quantitative trait locus on baboon chromosome 18 that regulates HDL. From positional cloning studies and expression studies, we identified the endothelial lipase gene (LIPG) as the primary candidate gene for the quantitative trait locus. The mechanism by which LIPG variation influences HDL levels has not been determined. METHODS AND RESULTS: We identified 164 LIPG polymorphisms in a panel of sibling baboons discordant for HDL1 and genotyped putative regulatory polymorphisms in a population of 951 pedigreed baboons. With the use of quantitative trait nucleotide analysis we identified 3 polymorphisms in the LIPG promoter associated with variation in serum HDL1 levels. In addition, we demonstrated that these 3 polymorphisms affect LIPG promoter activity in vitro. In silico analysis was used to identify putative transcription factors that differentially bind the functional promoter polymorphisms. CONCLUSIONS: These results reveal LIPG variants that specifically contribute to HDL1 levels and demonstrate mechanisms by which these polymorphisms may regulate LIPG promoter activity. Results from the present study provide a mechanism, namely variation in LIPG promoter activity possibly caused by altered transcription factor binding, by which LIPG variation affects HDL levels. PMID- 17709634 TI - In vivo characterization of murine myocardial perfusion with myocardial contrast echocardiography: validation and application in nitric oxide synthase 3 deficient mice. AB - BACKGROUND: The ability to noninvasively evaluate murine myocardial blood flow (MBF) in vivo would provide an important tool for cardiovascular research. Myocardial contrast echocardiography (MCE) has been used to measure MBF; however, it has not been validated in mice. This study assesses whether MCE can evaluate MBF at rest and after vasodilation and measure the maximal augmentation (coronary reserve) of MBF in mice. Wild-type (WT) and nitric oxide synthase 3 (NOS3) deficient (NOS3-/-) mice were studied. METHODS AND RESULTS: MCE was performed at baseline and after intravenous infusion of acetylcholine or adenosine. Definity contrast agent was infused, and parasternal views were acquired in real-time mode. Replenishment curves of myocardial contrast were obtained, and rates of signal rise (beta) and plateau intensity (A) were calculated. MBF estimated by the product of A and beta (Abeta) was compared with that measured with fluorescent microspheres. MCE analysis was feasible in 98% (52/53) of mice. MBF measured by microspheres increased with adenosine and correlated closely with Abeta. There was no difference in MCE-derived MBF between WT and NOS3-/- mice at rest. Adenosine infusion increased MBF by 3.0+/-0.6-fold in NOS3-/- mice and 2.5+/-0.3-fold in WT (P=0.58 between genotypes). Acetylcholine induced an increase of 2.4+/-0.2-fold in MBF in WT mice but did not increase MBF in NOS3-/- mice (P<0.0005 versus WT). CONCLUSIONS: MBF, coronary reserve, and vasodilator responses can be evaluated accurately in the intact mouse by MCE. This method demonstrated a preserved coronary response to adenosine but an impaired acetylcholine-induced vasodilation in NOS3-/- mice compared with WT mice. PMID- 17709636 TI - Expression of cholesteryl ester transfer protein in mice promotes macrophage reverse cholesterol transport. AB - BACKGROUND: Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from high-density lipoproteins to apolipoprotein (apo) B-containing lipoproteins and in humans plays an important role in lipoprotein metabolism. However, the role that CETP plays in mediation of reverse cholesterol transport (RCT) remains unclear. We used a validated in vivo assay of macrophage RCT to test the effect of CETP expression in mice (which naturally lack CETP) on macrophage RCT, including in mice that lack the low-density lipoprotein receptor or the scavenger receptor class B, type I. METHOD AND RESULTS: A vector based on adeno-associated virus serotype 8 (AAV8) with a liver-specific thyroglobulin promoter was used to stably express human CETP in livers of mice and was compared with an AAV8-lacZ control vector. The RCT assay was performed 4 weeks after vector injection and involved the intraperitoneal injection of acetylated low density lipoprotein cholesterol-loaded and 3H-cholesterol-labeled J774 macrophages in mice with plasma sampling at several time points, liver and bile sampling at 48 hours, and continuous fecal collection to measure 3H-sterol as an integrated readout of macrophage RCT. In apobec-1-null mice, CETP expression reduced plasma high-density lipoprotein cholesterol levels but significantly increased fecal 3H-sterol excretion. In low-density lipoprotein receptor/apobec-1 double-null mice, CETP expression reduced high-density lipoprotein cholesterol levels and had no effect on fecal 3H-sterol excretion. Finally, in scavenger receptor class B, type I-null mice, CETP expression reduced high-density lipoprotein cholesterol levels and significantly increased fecal 3H-sterol excretion. CONCLUSION: The present results demonstrate that CETP expression promotes macrophage RCT in mice, that this effect is dependent on the low-density lipoprotein receptor, and that CETP expression restores to normal the impaired RCT in mice deficient in scavenger receptor class B, type I. PMID- 17709637 TI - Aortic diameter >or = 5.5 cm is not a good predictor of type A aortic dissection: observations from the International Registry of Acute Aortic Dissection (IRAD). AB - BACKGROUND: Studies of aortic aneurysm patients have shown that the risk of rupture increases with aortic size. However, few studies of acute aortic dissection patients and aortic size exist. We used data from our registry of acute aortic dissection patients to better understand the relationship between aortic diameter and type A dissection. METHODS AND RESULTS: We examined 591 type A dissection patients enrolled in the International Registry of Acute Aortic Dissection between 1996 and 2005 (mean age, 60.8 years). Maximum aortic diameters averaged 5.3 cm; 349 (59%) patients had aortic diameters <5.5 cm and 229 (40%) patients had aortic diameters <5.0 cm. Independent predictors of dissection at smaller diameters (<5.5 cm) included a history of hypertension (odds ratio, 2.17; 95% confidence interval, 1.03 to 4.57; P=0.04), radiating pain (odds ratio, 2.08; 95% confidence interval, 1.08 to 4.0; P=0.03), and increasing age (odds ratio, 1.03; 95% confidence interval, 1.00 to 1.05; P=0.03). Marfan syndrome patients were more likely to dissect at larger diameters (odds ratio, 14.3; 95% confidence interval, 2.7 to 100; P=0.002). Mortality (27% of patients) was not related to aortic size. CONCLUSIONS: The majority of patients with acute type A acute aortic dissection present with aortic diameters <5.5 cm and thus do not fall within current guidelines for elective aneurysm surgery. Methods other than size measurement of the ascending aorta are needed to identify patients at risk for dissection. PMID- 17709639 TI - Ventricular preexcitation modulates strain and attenuates cardiac remodeling in a swine model of myocardial infarction. AB - BACKGROUND: Myocardial infarction modifies the distribution of stress within the heart, increasing wall stress in ischemic and surrounding tissue, which often leads to adverse left ventricular remodeling. Electrical preexcitation pacing with appropriate timing of high-stress regions can reduce local strain and may attenuate global remodeling. METHODS AND RESULTS: Myocardial infarction was induced in 24 swine to study the short-term (n=12) and long-term (n=12) effects of therapy. Sonomicrometry and hemodynamic measurements were used to show the mechanistic effects of preexcitation and to determine the optimal stimulation site and atrioventricular delay. Lagrangian strain was used to assess regional loading characteristics. Long-term study animals were randomized to 8 weeks of preexcitation (therapy) or no pacing (control). Echocardiograms were performed 2 days after myocardial infarction and repeated at 60 days, when tissue weights and apoptosis were assessed. Preexcitation reduced regional strain in the short term, with the best results achieved when the border region was paced at an atrioventricular delay of 50% of the intrinsic PR interval. In the long term, the changes in left ventricular internal diameter and left atrial size were decreased in therapy animals versus control animals (0.9+/-0.3 versus 1.5+/-0.5 cm, P=0.03, and 1.06+/-0.78 versus 2.32+/-0.88 cm, P<0.04, respectively). Heart weight was significantly lower in the therapy animals than in the control animals (319.8+/ 20.8 versus 359.6+/-29.3 g, P=0.02). Although not significant, cardiomyocyte apoptosis trended lower in the therapy group. CONCLUSIONS: Preexcitation of the left ventricle after myocardial infarction reduced strain and stroke work in the infarct and border regions in the short term and attenuated adverse ventricular remodeling in the long term. PMID- 17709638 TI - Influence of inpatient service specialty on care processes and outcomes for patients with non ST-segment elevation acute coronary syndromes. AB - BACKGROUND: Since the broad dissemination of practice guidelines, the association of specialty care with the treatment of patients with acute coronary syndromes has not been studied. METHODS AND RESULTS: We evaluated 55 994 patients with non ST-segment elevation acute coronary syndromes (ischemic ST-segment changes and/or positive cardiac markers) included in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) Quality Improvement Initiative from January 2001 through September 2003 at 301 tertiary US hospitals with full revascularization capabilities. We compared baseline characteristics, the use of American College of Cardiology/American Heart Association guidelines class I recommendations, and in-hospital outcomes by the specialty of the primary in-patient service (cardiology versus noncardiology). A total of 35 374 patients (63.2%) were primarily cared for by a cardiology service, and these patients had lower-risk clinical characteristics, but they more commonly received acute ( or = 75% luminal stenosis in coronary angiography (available in 611 of 873 patients), which was present in 118 of 611 patients (19%). For Kaplan-Meier analysis, we defined fatal cardiac events as lethal acute myocardial infarction, sudden cardiac death, and graft failure. Stenotic microvasculopathy was present in 379 of 873 patients (43%) and was due to medial (345/379; 91%) rather than endothelial disease (2/379; 1%) or a combination of both (31/379; 8%; P<0.001). Endothelial disease (median [95% CI], 12.07 [10.69 to 13.44] versus 12.73 years [10.16 to 15.30]; P=0.3329) and nonstenotic medial disease (12.44 [11.14 to 13.74] versus 12.43 years [10.51 to 14.35]; P=0.4047) did not decrease overall survival or time to fatal cardiac event. Stenotic microvasculopathy was associated with poor overall survival (10.90 [9.16 to 12.60] versus 13.40 years [11.79 to 15.07]; P=0.0374) and decreased freedom from fatal cardiac events (1, 5, 10 years, 95.6+/-1.4%, 86.9+/-2.3%, 75.5+/-3.1% versus 99.1+/-0.5%, 96.8+/ 1.0%, 89.8+/-1.9%; P<0.0001). This finding was independent of epicardial transplant vasculopathy (P=0.0031). CONCLUSIONS: Stenotic microvasculopathy is frequent in routinely processed biopsies and a new prognostic factor for long term survival after heart transplantation. PMID- 17709644 TI - Viewpoint: Heart valve engineering. Interview by James Butcher. PMID- 17709645 TI - Images in cardiovascular medicine. Pseudomitral intraventricular valve. PMID- 17709646 TI - Images in cardiovascular medicine. Papillary muscle infarction after cardiopulmonary resuscitation. PMID- 17709647 TI - Letter by Wetzels regarding article, "Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL): a randomized comparison of 3 preventive strategies". PMID- 17709648 TI - Podagra, uric acid, and cardiovascular disease. PMID- 17709649 TI - Glucose for the aging heart? PMID- 17709650 TI - Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure. AB - Since the discovery that neuregulin-1 (NRG-1)/ErbB signaling is indispensable in cardiac development, evidence has shown that this system also plays a crucial role in the adult heart. In patients, an inhibitory ErbB2 antibody, trastuzumab, used in the treatment of mammary carcinomas, increases the risk for the development of cardiotoxic cardiomyopathy. Postnatal disruption of NRG-1/ErbB signaling by gene targeting in mice leads to dilated cardiomyopathy. Initially, the search for the mechanisms behind these observations focused mainly on the effects of NRG-1 on cardiomyocyte growth and survival and revealed that NRG-1 has Akt-dependent antiapoptotic effects in cultured cardiomyocytes. In vivo studies, however, did not uniformly reinforce a role for apoptosis in the development of cardiomyopathy induced by impaired NRG-1/ErbB signaling. More recent studies have revealed that NRG-1 is involved in the regulation of cardiac sympathovagal balances by counterbalancing adrenergic stimulation of the adult myocardium and through an obligatory interaction with the muscarinic cholinergic system. NRG-1 is synthesized and released by the endocardial and cardiac microvascular endothelium, dynamically controlled by neurohormonal and biomechanical stimuli. The physiology of the cardiac NRG-1/ErbB system has implications for the treatment of both cancer and heart failure. Clinical studies in breast cancer with novel ErbB inhibitors are currently underway. Novel oncological indications for ErbB inhibition are emerging; cardiovascular side effects need to be carefully monitored. On the other hand, pharmacological activation of ErbB signaling is likely an unrecognized and beneficial effect of currently used drugs in heart failure and a promising therapeutic approach to prevent or reverse myocardial dysfunction. PMID- 17709651 TI - Drug-eluting stent update 2007: part II: Unsettled issues. PMID- 17709652 TI - Spontaneous resolution of idiopathic aldosteronism after long-term treatment with potassium canrenoate. PMID- 17709653 TI - Still building on candidate-gene strategy in hypertension? PMID- 17709654 TI - Role of xanthine oxidoreductase in the reversal of diastolic heart failure by candesartan in the salt-sensitive hypertensive rat. AB - The role of angiotensin II and reactive oxygen species in the exacerbation of diastolic heart failure is unknown. We examined the therapeutic effect of angiotensin blockade on hypertensive diastolic heart failure, focusing on the role of xanthine oxidoreductase and reduced nicotinamide-adenine dinucleotide phosphate oxidase, major enzymes producing reactive oxygen species. Dahl salt sensitive hypertensive rats (DS rats) with established diastolic heart failure were given vehicle, candesartan (an angiotensin II receptor subtype 1 receptor blocker), oxypurinol (a xanthine oxidoreductase inhibitor), apocynin (a reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor), or hydralazine (a vasodilator), and their therapeutic effects on diastolic heart failure were compared. Candesartan treatment of DS rats with established diastolic heart failure reversed cardiac remodeling, improved cardiac relaxation abnormality, and prolonged survival, being accompanied by the attenuation of the increase in cardiac superoxide, reduced nicotinamide-adenine dinucleotide phosphate oxidase, and xanthine oxidoreductase activities. Thus, the beneficial effect of candesartan in DS rats appears to be mediated by the inhibition of cardiac reactive oxygen species. Cardiac xanthine oxidoreductase inhibition with oxypurinol significantly reduced cardiac superoxide, prevented the progression of cardiac remodeling, and delayed the mortality in DS rats. Apocynin, which significantly inhibited cardiac reduced nicotinamide-adenine dinucleotide phosphate oxidase activity, prevented the exacerbation of diastolic heart failure more than hydralazine. However, compared with candesartan or oxypurinol, apocynin did not improve cardiac reactive oxygen species, remodeling, and function in DS rats. In conclusion, candesartan slowed the exacerbation of hypertensive diastolic heart failure in DS rats by causing reverse cardiac remodeling. Cardiac xanthine oxidoreductase contributed to these beneficial effects of candesartan. PMID- 17709655 TI - Successful treatment of notalgia paresthetica with botulinum toxin type A. PMID- 17709656 TI - Skin cancer awareness and sun protection behaviors in white Hispanic and white non-Hispanic high school students in Miami, Florida. AB - OBJECTIVE: To examine skin cancer awareness and behavior in white Hispanic (WH) and white non-Hispanic (WNH) high school students because increasing incidence and delayed diagnosis of skin cancer in the growing Hispanic population in the United States represent an emerging health issue. DESIGN: Pilot survey study. SETTING: A high school in Miami, Florida. PARTICIPANTS: A total of 369 high school students (221 WHs and 148 WNHs) were surveyed in the study. MAIN OUTCOME MEASURES: Survey data were collected regarding skin cancer knowledge, perceived risk, and sun protection behaviors. Differences between the 2 groups were compared with chi(2) tests. RESULTS: White Hispanic students were more likely to tan deeply (P = .04) but less likely to have heard of (P < .01) or been told how to perform (P < .01) skin self-examination. White Hispanics were less likely to wear sun-protective clothing or to use sunscreen with a sun protection factor of 15 or higher and reported a greater use of tanning beds. White Hispanic students also thought their chance of developing skin cancer was less than that of WNH students (P < .01), which remained significant after adjustment for age, sex, family history, and skin sensitivity to sun. After adjustment, WHs were 2.5 times more likely than WNHs to have used a tanning bed in the past year. White Hispanics were also 60% less likely to have heard of skin self-examination (P < .01) and 70% less likely than WNHs to have ever been told to perform the examination (P = .03). White Hispanics are about 1.8 and 2 times more likely to never or rarely wear protective clothing (P < .01) and to use sunscreen (P = .01), respectively. CONCLUSION: There are disparities in knowledge, perceived risk of skin cancer, and sun-protective behaviors among WH and WNH high school students. PMID- 17709658 TI - Immunohistochemical expression of platelet growth factor and vascular endothelial growth factor in patients with melanoma with and without redness (Brenner sign). AB - OBJECTIVE: To assess whether an erythematous eruption in the vicinity of or distant from a melanoma lesion might be related to the vascular endothelial growth factor, the platelet-derived endothelial cell growth factor, or both. METHODS: Biopsy specimens from 13 patients with primary melanoma, 6 of whom had erythematous eruptions and 7 who did not, were studied by immunohistochemistry for the expression of vascular endothelial growth factor and platelet-derived endothelial cell growth factor. RESULTS: Vascular endothelial growth factor was positive in 3 of 6 patients (50%) with melanoma and redness (Brenner sign) and in 4 of 7 patients (57%) with melanoma without redness. Platelet-derived endothelial cell growth factor was positive in all 6 patients (100%) with melanoma and redness and in 4 of 7 patients (57%) with melanoma without redness. CONCLUSION: Platelet-derived endothelial cell growth factor may have a part in the pathogenesis of the redness observed in patients with melanoma, called Brenner sign, by affecting vasculature function. PMID- 17709657 TI - Distance to diagnosing provider as a measure of access for patients with melanoma. AB - OBJECTIVE: To examine the effect of travel distance and other sociodemographic factors on access to a diagnosing provider for patients with melanoma. DESIGN: Analysis was performed of all incident cases of melanoma in 2000 from 42 North Carolina counties. SETTING: Academic research. PARTICIPANTS: Patients and providers from 42 North Carolina counties were geocoded to street address. MAIN OUTCOME MEASURES: Associations between Breslow thickness and clinical and sociodemographic factors (age, sex, poverty rate, rurality, provider supply, and distance to diagnosing provider) were examined. RESULTS: Of 643 eligible cases, 4.4% were excluded because of missing data. The median Breslow thickness was 0.6 mm (range, 0.1-20.0 mm). The median distance to diagnosing provider was 8 miles (range, 0-386 miles). For each 1-mile increase in distance, Breslow thickness increased by 0.6% (P =.003). For each 1% increase in poverty rate, Breslow thickness increased by 1% (P =.04). Breslow thickness was 19% greater for patients aged 51 to 80 years than for those aged 0 to 50 years (P =.02) and was 109% greater for patients older than 80 years than for those aged 0 to 50 years (P < .001). Sex, rurality, and supply of dermatologists were not associated with Breslow thickness. CONCLUSIONS: For patients with melanoma, distance to the diagnosing provider is a meaningful measure of access that captures different information than community-level measures of rurality, provider supply, and socioeconomic status. Future work should be targeted at identifying factors that may affect distance to diagnosing provider and serve as barriers to melanoma care. PMID- 17709659 TI - Age- and site-specific variation in the dermoscopic patterns of congenital melanocytic nevi: an aid to accurate classification and assessment of melanocytic nevi. AB - OBJECTIVES: To describe the dermoscopic features of congenital melanocytic nevi (CMN) and assess whether predominant dermoscopic patterns present in CMN are related to an individual's age (<12 years vs >or=12 years), sex, or lesional site (head, neck, and trunk vs extremities). DESIGN: Nonrandomized observational study. PATIENTS: A total of 77 consecutive patients, each with 1 CMN (n = 77 lesions), from an outpatient dermatology clinic. A diagnosis of CMN was established by (1) documentation of a melanocytic nevus during the first year of life or (2) by clinical examination and either clinical history or biopsy findings. MAIN OUTCOME MEASURES: Images of CMN were evaluated for specific dermoscopic structures and patterns. The distribution of patterns was assessed by age, sex, and lesional site. RESULTS: Most of the 77 lesions exhibited 1 of the following predominant dermoscopic patterns: reticular (18 lesions [23%]), globular (14 [18%]), or reticuloglobular (12 [16%]). Globular CMN were present in 5 of the 19 individuals who were younger than 12 years (26%) but in only 9 of the 58 individuals 12 years or older (16%). Reticular CMN were seen exclusively in the individuals who were 12 years or older. Congenital melanocytic nevi exhibiting no predominant pattern were more commonly present in the individuals younger than 12 years. Globular CMN were present in 11 head, neck, and trunk lesions (30%) compared with 3 extremity lesions (8%). Conversely, reticular CMN were present in 16 extremity lesions (40%) compared with 2 head, neck, and trunk lesions (5%). The predominant dermoscopic pattern did not vary based on sex. The most commonly observed dermoscopic structures were globules (in 64 lesions [83%]), hypertrichosis (in 61 [79%]), and reticular networks (in 55 [71%]). CONCLUSIONS: Our results suggest that the predominant dermoscopic patterns of CMN vary according to age and lesional site. These differences may inform future studies on the pathogenesis of CMN. PMID- 17709660 TI - Narrowband UV-B phototherapy, alefacept, and clearance of psoriasis. AB - OBJECTIVE: To determine whether the addition of 311-nm narrowband UV-B (NB UV-B) phototherapy accelerates and improves the therapeutic efficacy of alefacept, a biological antipsoriatic drug approved for the treatment of moderate to severe psoriasis. DESIGN: Randomized half-body comparison study. SETTING: Ambulatory section of a university hospital photodermatology unit. PATIENTS: Fourteen patients with moderate to severe psoriasis. INTERVENTIONS: All patients were treated with 7.5 mg of intravenous alefacept once weekly for 12 weeks. Three times each week, a randomly selected body half (left or right) was treated with NB UV-B light until complete remission, defined as a reduction in the Psoriasis Area Severity Index (PASI) to 3 or lower, was achieved on the irradiated body half. MAIN OUTCOME MEASURES: Modified PASI, self-assessed visual analogue scale rating of skin lesions, and self-assessed therapeutic efficacy. RESULTS: After 12 weeks of treatment, the mean PASIs on UV-irradiated and nonirradiated body halves were significantly reduced by 81% and 62%, respectively (P < .001). From week 3 to week 12, the mean PASI was significantly lower on UV-irradiated body halves than on nonirradiated body halves (P < .001). At week 12, PASI reductions of greater than 75% had been achieved significantly more often on UV-irradiated body halves (86%, 12 of 14) than on nonirradiated body halves (43%, 6 of 14), and complete remission had been achieved significantly more often on UV-irradiated body halves (43%, 6 of 14) than on nonirradiated body halves (0 of 14) (McNemar test P = .03). CONCLUSIONS: In this randomized half-side comparison of alefacept with and without phototherapy for psoriasis, alefacept with NB UV-B phototherapy accelerated and improved the clearance of psoriasis. This suggests a promising future for this combination as antipsoriatic therapy. PMID- 17709661 TI - Nephrogenic systemic fibrosis: relationship to gadolinium and response to photopheresis. AB - BACKGROUND: Nephrogenic systemic fibrosis (NSF), previously known as nephrogenic fibrosing dermopathy, is an idiopathic condition seen in patients with renal disease that is characterized by cutaneous sclerosis that can often result in contractures, pain, and functional disability as well as systemic complications. Recent reports have suggested a possible link with exposure to gadolinium, a commonly used radiocontrast agent. No current therapy has clearly demonstrated efficacy for NSF, although case reports suggest that extracorporeal photopheresis (ECP) may be of benefit. The purpose of this study was to explore the plausibility of a gadolinium linkage with NSF as well as to assess the efficacy of ECP in the treatment of a cohort of patients with NSF. OBSERVATIONS: We report our experience with 8 consecutive patients with NSF seen at the Stanford Medical Center, Palo Alta, California, from 2004 to 2006. Of the 8 patients, 6 had a history of arterial or venous thrombotic disease and 7 had a documented exposure to gadolinium within 1 week to several months prior to the onset of NSF. Specifically, all patients were exposed to gadodiamide. We treated 5 of the patients with ECP. After a mean number of 34 treatment sessions over a mean of 8.5 months, 3 patients experienced a mild improvement in skin tightening, range of motion, and/or functional capacity. CONCLUSIONS: Our data support the hypothesis that exposure to gadolinium, perhaps specifically gadodiamide, plays a role in the pathogenesis of NSF. Larger epidemiologic studies will be needed to confirm this association. In addition, our experience suggests that, if used for extended periods, ECP might have some mild benefit for patients with NSF. Larger, randomized, placebo-controlled trials of ECP should be performed to more specifically assess the benefit of ECP in the treatment of NSF. PMID- 17709662 TI - Treatment of severe pemphigus with rituximab: report of 12 cases and a review of the literature. AB - BACKGROUND: Treatment of pemphigus vulgaris can be challenging. Systemic steroids associated with other immunosuppressant agents are the mainstay of therapy and have dramatically reduced morbidity and mortality from pemphigus vulgaris. In some patients, however, these agents are not able to control the disease or have severe adverse effects. Rituximab (MabThera; Roche, Basel, Switzerland), a chimeric monoclonal anti-CD20 antibody, induces depletion of B cells in vivo and has shown efficacy in patients with refractory antibody-mediated autoimmune disorders. We report 10 cases of pemphigus vulgaris and 2 cases of pemphigus foliaceous treated with rituximab--to our knowledge the largest series of patients so far--and review the existing literature on the topic. OBSERVATION: The 12 patients were selected for treatment with the anti-CD20 antibody. Rituximab was administered intravenously at a dosage of 375 mg/m(2) once weekly for 4 weeks. The treatment was well tolerated, and all 12 patients showed a good clinical response during an 18-month follow-up period, along with a consensual decline of the serum antidesmoglein titers. No infectious complications were observed. CONCLUSIONS: Rituximab is able to induce a prolonged clinical remission in patients with both pemphigus vulgaris and pemphigus foliaceous after a single course of 4 treatments. The preliminary experiences worldwide make rituximab a promising therapeutic option for patients with autoimmune diseases. The high costs and the limited knowledge of long-term adverse effects, however, limit its use to selected patients with treatment-resistant or life-threatening disease. PMID- 17709663 TI - Active angiogenesis in an extensive arteriovenous vascular malformation: a possible therapeutic target? PMID- 17709664 TI - Chronic urticaria and monoclonal IgM gammopathy (Schnitzler syndrome): report of 11 cases treated with pefloxacin. AB - BACKGROUND: Schnitzler syndrome is characterized by chronic urticarial rash and monoclonal IgM gammopathy and is sometimes associated with periodic fever, arthralgias, and bone pain. Current treatment is unsatisfactory. OBSERVATIONS: Eleven patients with Schnitzler syndrome were treated with oral pefloxacin mesylate (800 mg/d). In 10 patients, we observed a dramatic and sustained improvement of urticarial and systemic manifestations. Corticosteroid therapy could be stopped or reduced in 6 patients. In 9 patients, pefloxacin was administered for more than 6 months (0.06 microg/L) presented in 29%, 25(OH)D deficiency (<50 nmol/L) in 81.6%, elevated PTH (>6.5 pmol/L) in 53%, and excessive bone resorption (increased DPD and/or NTx excretion) in 93.7%. Multivariate logistic regression showed that elevated serum PTH level is a major predictor of peri-operative myocardial injury (OR = 2.13; 95% CI 1.01-4.51; p = 0.049) and in-hospital all-cause mortality (OR = 18.5; 95% CI 2.0-72.3; p = 0.010), independent of age, sex, 25(OH)D status, and comorbidities. The degree of hyperparathyroidism was associated with the risk of cTnI elevation and the mortality rate. In cTnI positive patients, PTH levels correlated with cTnI concentrations (r = 0.28; p = 0.026) and urine DPD exretion (r = 0.37; p = 0.004). These results suggest for the first time that in older patients with HF, elevated PTH level is associated with peri-operative myocardial injury and in hospital all-cause mortality, and that elevated PTH level contributes to both disturbed bone metabolism and poor outcomes. PMID- 17709686 TI - Is serum Cystatin-C a suitable marker of renal function in children? AB - Cystatin C (Cys-C) is a low-molecular weight (13 kDa) protein that is a member of the cysteine protease family and is produced by all nucleated cells. In normal conditions, serum Cys-C is almost completely filtered by the renal glomerulus and largely catabolized by proximal tubular cells. Since serum Cys-C levels are closely correlated with the glomerular filtration rate (GFR), serum Cys-C assay has been introduced as a marker of renal function in patients with kidney diseases. In this review, we focus on studies reported during the past decade in which serum Cys-C levels have been compared to serum creatinine levels as a marker of GFR in pediatric populations. All but one of these studies showed diagnostic superiority or equivalence of serum Cys-C levels vs serum creatinine levels in children. The recent evidence from clinical trials generally supports the use of serum Cys-C assays as a renal function test in pediatric patients. However, clinicians should be cognizant of extrarenal conditions and pharmacological factors that can influence the results of serum Cys-C assays. PMID- 17709687 TI - Clostridium difficile infection in an urban medical center: five-year analysis of infection rates among adult admissions and association with the use of proton pump inhibitors. AB - C. difficile-associated diarrhea (CDAD) has become a major cause of morbidity in hospitalized patients. In this study of five-year (2001-2005, inclusive) trends of incidence of CDAD among adults in an inner-city medical center, the overall annual incidence increased from 5.08 to 8.42 cases/10(3) admissions (p = 0.0005). Age distribution remained fairly constant for 2001-2004 but decreased significantly in 2005 (p = 0.005); no significant change was observed for gender. During the five-year period, we observed a decline in the use of histamine type 2 receptor antagonists (H2A) with a concomitant increase in the use of proton pump inhibitors (PPI) as a prophylactic measure to prevent stress ulcers. The usage of PPI correlated exactly (r(s) = 1.0; p = 0.017) with the increase in CDAD incidence. A case (n = 122)-control (n = 244) study for the final year was conducted, examining the association of PPI and H2A with CDAD. After controlling for the effect of antibiotic use, PPI either pre- or during admission was associated with CDAD (odds ratio, OR (adjusted) = 2.75, 95% CI = 1.68 to 4.52; p = 0.0001); the association with H2A was not significant (OR (adjusted) = 0.95, 95% CI = 0.39 to 2.34; p = 0.9153). If only first-time use during hospital stay is considered, PPI were also strongly associated with CDAD (OR (adjusted) = 1.88, 95% CI: 1.07 to 3.31; p = 0.0283) and H2A were not associated with CDAD (OR (adjusted) = 0.73, 95%CI: 0.26 to 2.06; p = 0.5520). These data suggest that the widespread prescription of PPI for stress ulcer prophylaxis in acute care facilities may contribute to the increased incidence of CDAD. PMID- 17709688 TI - Comparison of protocols for surveillance of methicillin-resistant Staphylococcus aureus (MRSA): medical staff vs ICU patients. AB - To compare the sensitivity of various protocols for methicillin-resistant Staphylococcus aureus (MRSA) surveillance, active surveillance for detecting MRSA nasal colonization was performed on 97 members of the medical staff and 218 patients in the Intensive Care Unit (ICU) of a university hospital. Duplicate nasal swabs were collected from each participant. One was plated directly on a blood agar plate (D-BAP) and observed at 24 and 48 hr. Another was incubated overnight in tryptic soy broth (TSB) with 6.5% NaCl, and subcultured on both BAP (B-BAP) and mannitol salt agar with 4 mg/L of oxacillin (B-MSAOXA). The MRSA colonization rate was similar in the medical staff and patient samples (16.5% vs 11.9%, p = 0.285). Among the medical staff members, the sensitivity of MRSA detection was the same (93.8%) in D-BAP and B-BAP. In the ICU patients, which are a high-risk group, the sensitivity of MRSA detection was improved by adding a pre enrichment step (73.1% on D-BAP vs 96.2% on B-BAP). The simple direct plating protocol was sufficiently sensitive for the medical staff members, but pre enrichment was an essential step to increase detection of MRSA in the ICU patients. PMID- 17709689 TI - Screening for hemoglobinopathies during routine hemoglobin A1c testing using the Tosoh G7 Glycohemoglobin Analyzer. AB - Approximately 5.1% of the US population has diabetes mellitus, and hemoglobin (Hb) A1c levels are routinely measured to monitor long-term glycemic control in these patients. Many laboratories use ion exchange chromatography for such measurements, and the presence of hemoglobin variants and hemoglobinopathies often results in abnormal peaks on the chromatogram. The goal of this study was to evaluate the potential that detection of these abnormal peaks provides as a screening tool for Hb variants and hemoglobinopathies. We examined 366 specimens with abnormal peaks observed during routine Hb A1c measurements using the G7 Glycohemoglobin Analyzer (Tosoh Bioscience, Inc.). Hb variants and hemoglobinopathies were characterized by alkaline and acid electrophoresis, solubility testing for Hb S, and clinical parameters. In 252 cases, sickle cell trait was identified with a mean retention time (RT) of 1.44 (SD +/-0.02) min. In 82 cases, Hb C trait was identified with a mean RT of 1.66 +/-0.03 min. RTs for other Hb abnormalities, including sickle cell disease, homozygous Hb C disease, C Harlem trait, alpha-chain Hb variants, Hb D trait, Hb G trait, Hb J trait, Hb Raleigh, and Hb Lepore were also determined. Our results demonstrate that routine Hb A1c testing provides a potential screening tool for the detection of common hemoglobin variants and hemoglobinopathies. The previously unreported RTs for the G7 Glycohemoglobin Analyzer are provided, which can facilitate further testing in previously undiagnosed patients and confirm the cause of abnormal peaks in patients with known hemoglobin abnormalities. PMID- 17709690 TI - Comparison of the Abbott Architect i2000 assay, the Roche Modular Analytics E170 assay, and an immunoradiometric assay for serum hepatitis B virus markers. AB - Serum hepatitis B virus (HBV) markers are the most important data for epidemiological screening and clinical diagnosis of HBV infection, especially in endemic areas. We compared the results of the Roche Modular Analytics E170 assay, the Abbott Architect i2000 assay, and an immunoradiometric assay (IRMA) for HBV surface antigen (HBsAg), anti-HBV surface antigen (anti-HBs), HBV e antigen (HBeAg), and anti-HBV e antigen (anti-HBe). A number of serum samples (264, 263, 224, and 202 for HBsAg, anti-HBs, HBeAg, and anti-HBe, respectively) were studied. For samples giving discrepant results for HBeAg between methods, real time PCR assays were performed. The concordance rates among the three methods were high for HBsAg (100%) and HBeAg (94.6), but low for anti-HBs (91.6%) and anti-HBe (82.2%). For anti-HBs, which could be measured quantitatively by the Modular E170 and Architect i2000 procedures, discrepant results were observed at low levels of anti-HBs. For anti-HBe, the positive rate was highest with Modular E170 (60.9%) followed by the IRMA kit (54.1%) and Architect i2000 (51.0%). This study shows substantial differences between the assay results by the three methods, which should be taken into account in determinations of serum HBV markers. PMID- 17709691 TI - Comparison of the MicroScan system and the agar dilution assay for Quinupristin/Dalfopristin susceptibility of Enterococcus faecium. AB - We compared the results of Quinupristin/Dalfopristin (Q/D) susceptibility tests by the Positive Combo Panel (Type 11) of the MicroScan Walk Away 96 analyzer (Dade Behring, Inc.) with those obtained by the reference agar dilution method. From September 2003 to August 2004, a total of 410 E. faecium isolates were obtained from clinical samples. Of these, 65 (15.9%) strains were non susceptible, and 345 (84.1%) strains were susceptible to Q/D. We collected consecutively 65 Q/D non-susceptible E. faecium isolates (42 resistant, 23 intermediate), and randomly selected 32 Q/D susceptible E. faecium isolates using the MicroScan system. The minimal inhibitory concentrations (MICs) of Q/D, vancomycin, and teicoplanin were determined by the agar dilution method according to CLSI guidelines. The agreement rates between the two methods were 100% for Q/D susceptible strains, 85.7% for Q/D-resistant strains, and 26.1% for Q/D intermediate strains of E. faecium. The major error rate (S-->R) was 11.9%, and the minor error rate (S-->I) was 13.0%. No very major errors were found. We conclude that for MicroScan 'non-susceptible' test results for Q/D, it is necessary to confirm the result using a reference method. The Q/D-resistance rate was higher in glycopeptide-susceptible (78.0% for vancomycin, 82.0% for teicoplanin) than glycopeptide-resistant E. faecium (22.0% for vancomycin, 16.0% for teicoplanin). Further studies are needed to determine whether Q/D use in hospitals or virginiamycin use in animals, or other factors, are responsible for the high rates of glycopeptide-susceptible and Q/D-resistant E. faecium strains in Korea. PMID- 17709692 TI - CD20 positive T-cell lymphoma/leukemia: a rare entity with potential diagnostic pitfalls. AB - Mature T-cell neoplasms are relatively uncommon, accounting for approximately 10% of all non-Hodgkin lymphomas. This category of hematopoietic neoplasms is clinically aggressive and shows a poor response to therapy and shortened survival. The antigen CD20 has long been thought to be a specific marker for B cell lineage and has been used to help differentiate T-cell and B-cell neoplasms. We present two cases of a rare subset of T-cell leukemia/lymphoma having a unique immunophenotype, both being CD20+. The significance of CD20 antigen in T-cell lymphomas is yet to be determined, but may allow treatment with novel therapeutic agents (eg, rituximab, a recombinant anti-CD20 monoclonal antibody). PMID- 17709693 TI - Intraparenchymal leiomyoma of the breast: a case report and review of the literature. AB - We report a case of an intraparenchymal leiomyoma of the breast with description of the radiologic, histopathologic, and immunohistochemical findings. To the best of our knowledge, this is the first case of an intraparenchymal leiomyoma of the breast diagnosed by core needle biopsy and the 22nd case described in the literature. In addition, we review the literature on this uncommon breast neoplasm. PMID- 17709694 TI - Hemangiopericytoma of the oral cavity after a ten-year follow-up. AB - Hemangiopericytoma (HPC) is a mesenchymal tumour that may be benign, malignant, or occur in an intermediate form. We report an unusual case of hemangiopericytoma located in the buccal mucosal region. The histopathologic features showed increased cellularity, necrosis, hemorrhage, low proliferation index, and 4 or less mitotic figures per 10 high-power fields. Since this histological pattern suggests an intermediate form characterized by unpredictable clinical behavior, life-long follow-up is essential. In this patient no recurrences or distant metastases were evident at 10-yr follow-up. PMID- 17709695 TI - Rapid resolution of consumptive hypothyroidism in a child with hepatic hemangioendothelioma following liver transplantation. AB - We report a unique case of a 3-mo-old female with consumptive hypothyroidism and liver hemangioendothelioma who required pharmacological doses of thyroid hormones and was cured following liver transplantation. Liver hemangioendotheliomas are capable of producing an excess of the thyroid hormone inactivating enzyme, type-3 iodothyronine deiodinase. The increased tumoral enzyme activity leads to rapid degradation of thyroid hormones, resulting in consumptive hypothyroidism. Review of similar cases indicated variable outcomes. We focus on our patient's clinical course and describe in detail the thyroid hormone replacement therapy and a unique outcome of this rare type of hypothyroidism. This first example of a prompt and complete resolution of consumptive hypothyroidism in an infant after liver transplantation confirms the concept and the reversibility of consumptive hypothyroidism and provides novel insights into the rapidity of response of the infant's hypothalamic-pituitary-thyroid axis to thyroid hormone replacement. PMID- 17709696 TI - Interactive urology-pathology conferences: a preparatory tool for the urologic national board examination. AB - An educational program is described that was developed with the specific purpose of enhancing resident performance on the pathology portion of the Urologic National Board Examination. A pathologist and a urologist serve as moderators to ensure appropriate clinico-pathologic correlation. The program consists of a series of interactive lectures/discussions offered in a repeating annual cycle that addresses the neoplastic and non-neoplastic pathologic features of urologic diseases. Special attention is focused on topics that have been stressed in prior examinations. PMID- 17709697 TI - Serum transferrin receptor concentration and its ratio to bone marrow erythroblasts in iron deficiency anemia and anemia of chronic diseases. PMID- 17709698 TI - Serum free light chain analysis in B-cell dyscrasias. PMID- 17709699 TI - Persecution of noted physicians and medical scientists. PMID- 17709701 TI - Dementia with Lewy bodies and Parkinson disease with dementia: can MRI make the difference? PMID- 17709702 TI - What is next in ALS clinical trials? PMID- 17709703 TI - Frontal presentation in progressive supranuclear palsy. AB - BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive hypokinetic rigid disorder with supranuclear gaze palsy and frequent falls. Although clinical consensus criteria are available, an atypical presentation may lead to clinical misdiagnosis in the initial phase. In the present study we investigated the clinical presentation of PSP and its relationship to initial clinical diagnosis and survival. METHODS: We ascertained patients with PSP in a prospective cohort by nationwide referral from neurologists and nursing home physicians. All patients underwent a structural interview and clinical examination before entering the study. Medical records were reviewed for the presence of symptoms during the first 2 years. RESULTS: A total of 152 patients ascertained between 2002 and 2005 fulfilled the international consensus criteria for PSP. Categorical principal component analysis of clinical symptoms within the first 2 years showed apart from a cluster of typical PSP symptoms, the clustering of cognitive dysfunction and behavioral changes. Further analysis showed that 20% of patients had a predominant frontal presentation with less than two other PSP symptoms. Survival analysis showed that this subgroup had a similar prognosis to that of the total group of patients with PSP. CONCLUSIONS: There exists a subgroup of patients with progressive supranuclear palsy (PSP) with a predominant frontal presentation, who progressed into typical PSP over the course of the disease. PMID- 17709704 TI - Inherited prion disease with 5-OPRI: phenotype modification by repeat length and codon 129. AB - BACKGROUND: Human prion diseases have sporadic, acquired and inherited etiologies and show considerable phenotypic heterogeneity. An individual inherited prion disease offers an opportunity to study the determinants of this clinicopathologic heterogeneity among individuals with the same causal mutation. METHODS: We report clinical and pathologic data from three families with different 5-octapeptide repeat insertion (5-OPRI) mutations of the prion protein gene (PRNP), extending the reported phenotypic range of this mutation. RESULTS: The proband of a South African family presented with a rapidly progressive dementia and atypical pathology associated with kuru-like prion protein plaques. The original mutation in this family probably occurred on a PRNP allele encoding a 1-octapeptide repeat deletion polymorphism. This has not been previously reported as a precursor allele in over 30 other OPRI mutation kindreds. An English family with a genetically distinct mutation but identical protein product showed clinical onsets that varied 30 years between father and daughter, an effect that may be explained by their genotypes at PRNP codon 129. A patient from Northern Ireland with a phenotype of sporadic Creutzfeldt-Jakob disease presenting with visual disturbance was unexpectedly found to have a 5-OPRI. CONCLUSIONS: When these cases were combined with the existing world literature, the mean age at onset for patients with 5-octapeptide repeat insertion (5-OPRI) was significantly later than that for patients with 6-OPRI, but both mutations exhibit a similar powerful disease modifying effect of PRNP codon 129. PMID- 17709705 TI - Incident dementia in women is preceded by weight loss by at least a decade. AB - BACKGROUND: Although several studies reported weight loss preceding the onset of dementia, other studies suggested that obesity in midlife or even later in life may be a risk factor for dementia. METHODS: The authors used the records-linkage system of the Rochester Epidemiology Project to ascertain incident cases of dementia in Rochester, MN, for the 5-year period 1990 to 1994. The authors defined dementia using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). Each case was individually matched by age (+/-1 year) and sex to a person drawn randomly from the same population, and free from dementia in the index year (year of onset of dementia in the matched case). Weights were abstracted from the medical records in the system. RESULTS: There were no differences in weight between cases and controls 21 to 30 years prior to the onset of dementia. However, women with dementia had lower weight than controls starting at 11 to 20 years prior to the index year, and the difference increased over time through the index year. We found a trend of increasing risk of dementia with decreasing weight in women both at the index year (test for linear trend; p < 0.001) and 9 to 10 years before the index year (test for linear trend; p = 0.001). CONCLUSIONS: Even accounting for delays in diagnosis, weight loss precedes the diagnosis of dementia in women but not in men by several years. This loss may relate to predementia apathy, loss of initiative, and reduced olfactory function. PMID- 17709706 TI - Gray matter atrophy in Parkinson disease with dementia and dementia with Lewy bodies. AB - BACKGROUND: The nosologic relationship between dementia with Lewy bodies (DLB) and Parkinson disease with dementia (PDD) is continuously being debated. We conducted a study using voxel-based morphometry (VBM) to explore the pattern of cortical atrophy in DLB and PDD. METHODS: Seventy-four patients and healthy elderly were imaged (healthy elderly n = 20, PDD n = 15, DLB n = 18, and Alzheimer dementia [AD] n = 21).Three dimensional T1-weighted MRI were acquired, and images analyzed using VBM. The following diagnostic criteria were used: criteria proposed by the third report of the DLB Consortium for DLB, the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Diseases Association criteria for AD, and Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria for dementia in PDD. RESULTS: Overall dementia severity was similar in the dementia groups. We found more pronounced cortical atrophy in DLB than in PDD in the temporal, parietal, and occipital lobes. Patients with AD had reduced gray matter concentrations in the temporal lobes bilaterally, including the amygdala, compared to PDD. Compared to DLB, the AD group had temporal and frontal lobe atrophy. CONCLUSION: We found that despite a similar severity of dementia, patients with dementia with Lewy bodies (DLB) had more cortical atrophy than patients with Parkinson disease with dementia (PDD), indicating different brain substrates underlying dementia in the two syndromes. Together with previous studies reporting subtle clinical and neurobiologic differences between DLB and PDD, our findings support the hypothesis that PDD and DLB are not identical entities, but rather represent two subtypes of a spectrum of Lewy body disease. PMID- 17709707 TI - Multiple auras: clinical significance and pathophysiology. AB - BACKGROUND: Patients with partial epilepsy may report multiple types of aura during their seizures. The significance of the occurrence of multiple auras in the same patient is not known. METHODS: The clinical and electrophysiologic characteristics of patients with more than one aura type (abdominal, auditory, autonomic, gustatory, olfactory, psychic, somatosensory, and visual auras), evaluated in the Cleveland Clinic epilepsy monitoring unit between 1989 and 2005, were studied. RESULTS: Thirty-one patients experienced multiple aura types during a seizure. Ninety percent of patients with at least two aura types (n = 31) and 100% percent of patients with at least three aura types (n = 12) had seizures arising from the right/nondominant hemisphere. EEG seizures remained restricted in all patients during their auras. nineteen [corrected] patients had epilepsy surgery with seizure freedom in 53%. Subdural EEG recordings in six patients showed either a march of sequential auras, or in one case, several ictal onset zones resulting in separate isolated auras. Ictal SPECT in six patients with right-sided seizures showed a lack of activation in brainstem structures. CONCLUSIONS: Most patients who report multiple aura types have localized epilepsy in the nondominant hemisphere, and are good surgical candidates. A common mechanism for multiple auras may be a spreading but restricted EEG seizure activating sequential symptomatogenic zones, but without the ictal activation of deeper structures or contralateral spread to cause loss of awareness and amnesia for the auras. PMID- 17709708 TI - CT perfusion predicts secondary cerebral infarction after aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: To prospectively assess the diagnostic accuracy of CT perfusion (CTP) and transcranial Doppler sonography (TCD) for the prediction of secondary cerebral infarction (SCI) after aneurysmal subarachnoid hemorrhage (SAH). METHODS: During 2 weeks after SAH, 38 consecutive patients completed an average of 3.5 CT/CTP and 10.7 TCD examinations at regular intervals as required by the study protocol. SCI was defined as delayed infarction on native CT between 3 and 14 days after SAH and developed in n = 14 patients (n = 24 without SCI). Analysis was based on examination dates before SCI. Common measures of diagnostic accuracy were calculated for qualitative CTP (visual color-map ratings from two blinded observers) and TCD assessments (mean flow velocity >120 cm/s in anterior, middle, and posterior cerebral artery territories). Quantitative measures, which for CTP were obtained from cortical a priori regions of interest corresponding to the vascular territories, were analyzed by binary logistic regression. RESULTS: Time of prediction for SCI by CTP was at a median of 3 days (range 2 to 5 days) before manifestation of complete infarction on native CT. Visual assessment of time-to peak (TTP) color maps performed best for the prediction of SCI with 0.93 sensitivity (95% CI: 0.7 to 1.0) and 0.67 specificity (95% CI: 0.53 to 0.7). On quantitative analysis, the odds ratio (OR) for 1 second of side-to-side delay in TTP was 1.4 (p = 0.01, Wald chi(2) = 8.57, CI: 1.07 to 1.82). Daily TCD measures were not significantly related to SCI at any time before complete infarction on native CT. CONCLUSIONS: Time to peak as indicated by CT perfusion is a sensitive and early predictor of secondary cerebral infarction. PMID- 17709709 TI - Meta-analysis of APOE genotype and subarachnoid hemorrhage: clinical outcome and delayed ischemia. AB - BACKGROUND: Emerging evidence suggests that the APOE4 allele may increase the risk of a negative outcome in patients with aneurysmal subarachnoid hemorrhage (SAH), but the results are conflicting. A genetic variable predicting the individual clinical course is currently lacking. OBJECTIVE: To examine the association between the APOE4 allele and a negative outcome. A secondary objective was to investigate the association between the APOE4 allele and delayed ischemia, a major complication of SAH. METHODS: We searched MEDLINE, EMBASE, the Cochrane Library, CINHAL, LILACS, and www.google.it through March 2006. We hand searched journals, international conference proceedings, and reference lists of retrieved articles. Individual patient data were requested from the corresponding authors of the original articles. Information on study design, participant characteristics, clinical outcome, delayed ischemia, and confounder distribution were independently abstracted by two investigators. RESULTS: We included eight observational studies (696 patients for the clinical outcome and 600 for the delayed ischemia analyses). The corresponding authors of all the retrieved publications but one gave their original data. Summary odds ratios (ORs) were calculated by means of the random-effect model. The risk of a negative outcome (OR = 2.558; 95% CI 1.610 to 4.065) and delayed ischemia (OR = 2.044; 95% CI 1.269 to 3.291) were increased in the E4 carriers. CONCLUSIONS: In patients with subarachnoid hemorrhage, the expression of the E4 allele is associated with a higher risk of a negative outcome and delayed ischemia. PMID- 17709710 TI - Phase II/III randomized trial of TCH346 in patients with ALS. AB - BACKGROUND: TCH346 exerts antiapoptotic effects by binding to glyceraldehyde 3 phosphate dehydrogenase (GAPDH) and blocking the apoptotic pathway in which GAPDH is involved. Apoptosis is considered to be a key pathogenic mechanism in neurodegenerative diseases including ALS. METHODS: Patients were randomly assigned in a double-blind fashion to receive either placebo or one of four doses of TCH346 (1.0, 2.5, 7.5, or 15 mg/day) administered orally once daily for at least 24 weeks. The primary outcome measure was the rate of change in the revised ALS functional rating scale (ALSFRS-R). The trial design included a 16-week lead in phase to determine each patient's rate of disease progression. The between treatment comparison was adjusted for the individual pretreatment rates of progression. The study was powered to detect a 25% reduction in the rate of decline of the ALSFRS-R as compared with placebo. Secondary outcome measures included survival, pulmonary function, and manual muscle testing (MMT). RESULTS: Five hundred ninety-one patients were enrolled at 42 sites in Europe and North America. There were no differences in baseline variables. There were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures (survival, pulmonary function, and MMT). CONCLUSION: The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS. PMID- 17709711 TI - Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results. AB - OBJECTIVE: Daclizumab is an interleukin 2 receptor alpha chain specific humanized monoclonal antibody that has shown promising therapeutic effects in multiple sclerosis (MS). Daclizumab treatment in patients with relapsing and remitting MS was administered to determine effects on MRI and clinical outcomes. METHODS: Patients with MS on interferon (IFN) therapy but with continuing relapses and contrast enhancing lesions (CEL) were selected. Patients were evaluated with monthly MRI scans and clinical rating scales starting 3 months prior to treatment and then at 0.5 to 27.5 months during treatment. Daclizumab (1 mg/kg IV) was administered twice in the first month (initiated and administered again in 2 weeks), followed by treatments every 4 weeks. IFN was continued until 5.5 months after daclizumab was initiated. Patients were then placed on daclizumab monotherapy. Patients with recurrent CEL were restarted on IFN with daclizumab therapy at (1.5 mg/kg IV) every 28 days. RESULTS: Nine patients qualified for inclusion and completed the trial. Efficacy measured by both total CEL and new CEL (p < 0.001), relapses, timed ambulation, Expanded Disability Status Scale, and Neurologic Rating Scale (p < 0.05 to p < 0.01) was observed. CONCLUSION: Daclizumab was effective in reducing contrast enhancing lesions and improving clinical scores in patients with relapsing and remitting multiple sclerosis with active disease not controlled by interferon therapy. These results provide evidence for long-term efficacy and support further clinical development of daclizumab. PMID- 17709713 TI - Tissue plasminogen activator: beyond thrombolysis. PMID- 17709712 TI - The hemodynamic and neurohumoral phenotype of postural tachycardia syndrome. AB - BACKGROUND: Previous studies of patients with postural tachycardia syndrome (POTS) have been hampered by relatively small cohorts, failure to control medications and diet, and inconsistent testing procedures. METHODS: The Vanderbilt Autonomic Dysfunction Center Database provided results of posture studies performed in 165 patients and 66 normal controls after dietary and medication restrictions. All posture studies were performed after an overnight fast and > or =30 minutes of supine rest. RESULTS: In both the supine and standing positions, heart rate (HR) and plasma concentrations of norepinephrine (NE), epinephrine, and dopamine were higher in patients with POTS compared with the healthy controls. Supine diastolic blood pressure (BP) was also elevated in POTS, whereas supine plasma l-3,4-dihydroxyphenyalanine was reduced. In an analysis of patient subgroups with either an upright plasma NE > or = 3.54 nM (high NE) or an upright plasma NE < 3.54 nM (normal NE), HR and BP were greater in the patient subgroup with high NE. In addition to these significant differences in hemodynamic and catechol measurements, we demonstrated that supine and standing plasma aldosterone and the aldosterone/renin ratio were decreased in patients with POTS. Plasma renin activity (PRA) tended to be higher in patients, and standing HR for those in the highest PRA quartile was significantly greater than for those in the lowest PRA quartile. CONCLUSIONS: Our results from larger cohorts of patients and controls than previously studied confirm published findings and contribute additional evidence of sympathetic activation in postural tachycardia syndrome (POTS). Abnormalities in the renin-angiotensin-aldosterone system may also contribute to the POTS phenotype. PMID- 17709714 TI - Anti-musk antibody after thymectomy in a previously seropositive myasthenic child. PMID- 17709715 TI - A Japanese adult form of CPT II deficiency associated with a homozygous F383Y mutation. PMID- 17709716 TI - Toxocariasis of the CNS simulating acute disseminated encephalomyelitis. PMID- 17709717 TI - When the "dense triangle" in dural sinus thrombosis is round. PMID- 17709718 TI - Effect of galantamine on verbal repetition in AD: a secondary analysis of the VISTA trial. PMID- 17709719 TI - Limb-kinetic apraxia in Parkinson disease. PMID- 17709720 TI - How migraines impact cognitive function: findings from the Baltimore ECA. PMID- 17709721 TI - Neurosurgery at an earlier stage of Parkinson disease. PMID- 17709722 TI - The new generation of surgeons: a panel discussion at the pacific coast surgical association. PMID- 17709724 TI - Impact of the 80-hour workweek on patient care at a level I trauma center. AB - HYPOTHESIS: The 80-hour workweek limitation for surgical residents is associated with an increase in mortality and complication rates among adult trauma surgical patients. DESIGN: Retrospective cohort study. SETTING: Academic level I trauma center. PATIENTS: Trauma patients admitted before and after the 80-hour workweek limitation. METHODS: We compared death and complication rates for adult trauma patients admitted during a 24-month period before (2001-2003) and a 24-month period after (2004-2006) implementation of the 80-hour workweek at our institution. Relative risk and its 95% confidence intervals were examined. MAIN OUTCOME MEASURES: Patient care outcomes included preventable and nonpreventable complications and deaths. RESULTS: The patient populations from the 2 time periods were clinically similar. No significant differences were found in the total and the preventable death rates. The time period after the 80-hour workweek mandate had a significantly higher total complication rate (5.64% vs 7.28%; relative risk, 1.29; 95% confidence interval, 1.15-1.45; P < .001), preventable complication rate (0.89% vs 1.28%; relative risk, 1.43; 95% confidence interval, 1.06-1.91; P = .02), and nonpreventable complication rate (4.75% vs 5.81%; relative risk, 1.22; 95% confidence interval, 1.08-1.39; P = .002). CONCLUSION: Although there was no difference in deaths between the 2 time periods, there was a significant increase in total, preventable, and nonpreventable complications. This increase in complication rate may be due, in part, to the new 80-hour workweek policy. PMID- 17709725 TI - Identification of molecular markers altered during transformation of differentiated into anaplastic thyroid carcinoma. AB - HYPOTHESIS: A change in tumor expression profile will be observed during the transformation of differentiated into anaplastic thyroid carcinoma. DESIGN: Cohort study. SETTING: Population-based sample (British Columbia). PATIENTS: Sequential archival cases of anaplastic thyroid cancer with an adjacent associated differentiated thyroid cancer focus, and with available paraffin blocks, that had been diagnosed and treated in British Columbia during a 20-year period (12 cases; January 1, 1984, through December 31, 2004) were identified through the provincial tumor registry for tissue microarray construction. MAIN OUTCOME MEASURE: Significant associations between marker staining and tumor pathologic diagnosis (differentiated vs anaplastic) were determined with contingency table and marginal homogeneity tests. A classifier algorithm was also used to identify useful and important molecular classifiers. RESULTS: Overall, there were 3 up-regulated and 5 down-regulated markers when comparing the anaplastic carcinoma with associated differentiated thyroid cancers. Contingency table statistics identified 5 markers (thyroglobulin, Bcl-2, MIB-1, E-cadherin, and p53) to be significantly differentially expressed by the anaplastic and differentiated tumor foci. These 5 markers and 3 others (beta-catenin, topoisomerase II-alpha, and vascular endothelial growth factor) were significant when evaluated using the marginal homogeneity test. Clustering and classification analysis based on these same 8 markers readily separated differentiated and anaplastic thyroid tumors with a high degree of accuracy. CONCLUSION: The markers we observed to change during thyroid tumor progression may not only show promise as molecular diagnostic or prognostic tools but also warrant further study as potential targets for treatment of disease. PMID- 17709726 TI - Change in practice patterns of an academic division of vascular surgery. AB - HYPOTHESIS: Technological advances have required that faculty of academic divisions of vascular surgery acquire new technical skills and significantly alter their past clinical practice patterns. DESIGN: Retrospective medical record review. SETTING: An academic tertiary referral center and a community teaching hospital. PATIENTS: All patients undergoing 10 specific vascular procedures during a 5-year period. MAIN OUTCOME MEASURES: We analyzed volumes for 10 specific open and endovascular index procedures performed by 5 vascular surgeons during a 60-month period. Procedures reviewed included open abdominal aortic aneurysm repair, endovascular abdominal aortic aneurysm repair, carotid endarterectomy, carotid artery stent, suprainguinal arterial reconstruction, suprainguinal percutaneous transluminal angioplasty/stent (PTA/S), infrainguinal arterial reconstruction, infrainguinal PTA/S, renal and visceral arterial reconstruction, and renal and visceral PTA/S. In-hospital length of stay was compared between open procedures and their endovascular counterparts. RESULTS: In 2000, 453 open and 44 endovascular index procedures were performed. In contrast, by 2005, open index cases had decreased by 47.0% (239) and endovascular index cases had increased by 679.5% (299). Open abdominal aortic aneurysm repairs had decreased by 54.5% (68 vs 31), carotid endarterectomies by 28.8% (139 vs 99), suprainguinal arterial reconstructions by 47.5% (40 vs 21), infrainguinal arterial reconstructions by 56.5% (186 vs 81), and renal/visceral arterial reconstructions by 65.0% (20 vs 7). In 2005, 62 endovascular abdominal aortic aneurysm repairs and 45 carotid stents were performed, whereas none were performed in 2000. In addition, infrainguinal PTA/S had increased by 675.0% (12 vs 81) and suprainguinal PTA/S by 20.0% (20 vs 24). CONCLUSIONS: Although the total number of procedures performed has remained relatively constant, there has been a dramatic increase in the number of endovascular procedures as well as an associated decline in the number of open procedures. This change in practice pattern has allowed the members of our division to maintain a significant role in the care of patients undergoing vascular surgery, as evidenced by stable overall procedural volume. This will provide a platform for future outcome-related analyses of open vs endovascular procedures performed within a single specialty group. PMID- 17709727 TI - Association of angiogenesis markers with lymph node metastasis in early colorectal cancer. AB - HYPOTHESIS: We hypothesized that p53 mutations (mp53) are associated with decreased expression of thrombospondin 1 (TSP-1) and that decreased TSP-1 expression is associated with lymph node metastases. DESIGN: A retrospective study of lymphatic mapping and pathologic determination of angiogenesis markers in primary colorectal cancer. SETTING: Tertiary care cancer institute. PATIENTS: Sixty-one patients with colorectal cancer underwent lymphatic mapping. Lymph nodes that stained negative by hematoxylin-eosin were examined with immunohistochemistry for micrometastases. Primary tumors were analyzed by immunohistochemistry for mp53 and TSP-1 expression. The t test and the Mann Whitney U test were used to examine the mean difference in TSP-1 expression between tumors. MAIN OUTCOME MEASURES: Mutant p53 expression, TSP-1 expression, and metastatic progression. RESULTS: Thirty-six of the 61 patients (59%) had nodal metastases shown by hematoxylin-eosin or immunohistochemistry in the sentinel node (N2, N1, N1mi, or N0[i+]). Patients with a truly negative sentinel node (pN0[i-][sn]) had significantly higher TSP-1 expression compared with those with some degree of nodal metastases (57.7 vs 30.1; P < .001). Acquisition of mp53 was associated with a decreased mean TSP-1 expression. Tumors without mp53 expression had a mean TSP-1 optical density value of 51.3 while tumors with elevated mp53 had a mean TSP-1 optical density value of 31.8 (P < .03). CONCLUSIONS: Patients with primary colorectal cancer with low TSP-1 expression, with or without detection of mp53 gene product, are more likely to harbor lymph node metastasis than patients with higher expression. Patients with a truly negative sentinel node (pN0[i-][sn]) frequently have higher expression of TSP-1 that may have inhibited metastatic progression. Further studies will investigate the relationship between mp53, TSP expression, and disease progression. PMID- 17709728 TI - Autologous tissue reconstruction of ventral hernias in morbidly obese patients. AB - HYPOTHESIS: Separation of components is a safe and effective technique for abdominal wall reconstruction in morbidly obese patients. DESIGN: Review of a prospectively accumulated database. SETTING: University tertiary care medical center. PATIENTS: Thirty morbidly obese patients who underwent ventral hernia repair using the separation of components technique between August 1, 2001, and August 31, 2005. INTERVENTION: Ventral hernia repair using the separation of components technique. MAIN OUTCOME MEASURES: Postoperative complications and hernia recurrence. RESULTS: Thirty morbidly obese patients (mean body mass index [calculated as weight in kilograms divided by height in meters squared], 61; range, 35-93) underwent ventral hernia repair by the separation of components technique (mean width of defect, 12.8 cm; mean length, 17.6 cm). Twenty-five patients (83%) had comorbidities. Twelve (40%) had undergone previous repairs (9 had undergone multiple repairs; mean, 2.4 repairs per patient; range, 2-4 repairs) and 6 (20%) had infected mesh. Sixteen patients (53%) underwent simultaneous panniculectomies and 6 (20%) underwent simultaneous bariatric procedures (Roux-en-Y gastric bypass). Postoperatively, cellulitis developed in 2 patients (7%), which was treated with antibiotics; wound infections occurred in 2 patients (7%), which were managed with local wound care; and a seroma developed in 1 patient (3%), which resolved spontaneously. The lone recurrent hernia (3%) was repaired with mesh. The mean length of follow-up was 44 months. CONCLUSIONS: These results show that (1) separation of components is a safe and effective technique for repairing primary and recurrent ventral hernias in morbidly obese patients; (2) performance of a simultaneous panniculectomy or bariatric procedure does not affect the outcome; and (3) comorbidities do not compromise the results. PMID- 17709729 TI - Impact of multiple lymphatic channel drainage to a single nodal basin on outcomes in melanoma. AB - OBJECTIVE: To determine the impact of multiple lymphatic channels (MLCs) on outcome in melanoma. DESIGN: Retrospective cohort study. SETTING: Academic tertiary care center. PATIENTS: Of 1198 consecutive selective sentinel lymphadenectomies performed from 1995 to 2000 for primary invasive melanoma, 502 patients were identified with extremity or truncal melanoma that drained to a single nodal basin. Three cohorts were formed based on lymphatic channels (none, single, and multiple). Tumors with drainage to multiple nodal basins as well as all head and neck tumors were excluded. MAIN OUTCOME MEASURES: Multiple variables, including patterns of lymphatic drainage, were analyzed for impact on disease-free and overall survival. RESULTS: Demographics were similar among groups, with a median follow-up of 5.6 years. Univariate analysis revealed MLCs as an independent risk factor for both disease-free (P = .04) and overall survival (P = .003). Multivariate analysis confirmed that tumor depth, sentinel lymph node status, and MLCs were risk factors for both disease-free and overall survival. Kaplan-Meier analysis showed worse survival in the MLCs group. CONCLUSIONS: Our study reveals that MLCs are an independent risk factor for recurrence and mortality in melanoma. Multiple lymphatic channels may facilitate the process of metastasis. PMID- 17709730 TI - Effects of resident duty-hours restrictions on surgical and nonsurgical teaching faculty. AB - OBJECTIVE: To evaluate the effects of resident duty-hours restrictions on teaching faculty, patient care, and the institutional climate at a single center. METHODS: An anonymous questionnaire was provided to all teaching faculty (N = 606) at a single institution from March through October 2006. The questionnaire focused on perceptions of job satisfaction, workload changes, and effects on patient care and the institution. RESULTS: Overall response rate was 41% (n = 248). More than half of faculty (n = 140 [56%]) feel they have less time for teaching, 33% report less time for extracurricular activities, and 42% report increased work hours. Forty-three percent of respondents (n = 106) were less satisfied with their jobs after implementation of resident duty-hours restrictions, while only 2% (n = 5) were more satisfied. Of the respondent faculty, surgeons were more likely than nonsurgeons to report increased work hours (54% vs 34%; P = .002), decreased time for teaching (66% vs 51%; P = .03), lower job satisfaction (55% vs 35%; P = .003), and negative effects on their personal relationships outside of work (24% vs 12%; P = .01). Although most responses suggest that the restrictions on resident duty hours have not adversely affected patient care or the institutional climate, 33% of respondents (n = 82) felt that patient care was worse. CONCLUSIONS: Surgeons reported a particularly negative effect from resident duty-hours reform, especially within the areas of job satisfaction, time for teaching, and workload. Efforts to counteract these effects will be critical to maintain and recruit teaching faculty. PMID- 17709731 TI - Accuracy of staging node-negative pancreas cancer: a potential quality measure. AB - OBJECTIVE: To determine the optimal number of lymph nodes to examine for accurate staging of node-negative pancreatic adenocarcinoma after pancreaticoduodenectomy. DESIGN, SETTING, AND PATIENTS: Data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program (1988-2002) were used to identify 3505 patients who underwent pancreaticoduodenectomy for adenocarcinoma of the pancreas, including 1150 patients who were pathologically node negative (pN0) and 584 patients with a single positive node (pN1a). Perioperative deaths were excluded. Univariate and multivariate survival analyses were performed. MAIN OUTCOME MEASURE: Examination of 15 lymph nodes appears to be optimal for accurate staging of node-negative adenocarcinoma of the pancreas after pancreaticoduodenectomy. RESULTS: The number of nodes examined ranged from 1 to 54 (median, 7 examined nodes). Univariate survival analysis demonstrated that dichotomizing the pN0 cohort on 15 or more examined lymph nodes resulted in the most statistically significant survival difference (log-rank chi(2) = 14.49). Kaplan-Meier survival curves demonstrated a median survival difference of 8 months (P < .001) in favor of the patients who had 15 or more examined nodes compared with patients with fewer than 15 examined nodes. Multivariate analysis validated that having 15 or more examined nodes was a statistically significant predictor of survival (hazard ratio, 0.63; 95% confidence interval, 0.49-0.80; P < .0001). Furthermore, a multivariate model based on the survival benefit of each additional node evaluated in the pN0 cohort demonstrated only a marginal survival benefit for analysis of more than 15 nodes. Approximately 90% of the pN1a cohort was identified with examination of 15 nodes. CONCLUSIONS: Examination of 15 lymph nodes appears to be optimal to accurately stage node-negative adenocarcinoma of the pancreas after pancreaticoduodenectomy. Furthermore, evaluation of at least 15 lymph nodes of a pancreaticoduodenectomy specimen may serve as a quality measure in the treatment of pancreatic adenocarcinoma. PMID- 17709732 TI - Outcome of liver transplantation in septuagenarians: a single-center experience. AB - HYPOTHESIS: We hypothesized that selected septuagenarians may do as well after transplantation as those of a younger group of older recipients. This work compares post-liver transplant survival in septuagenarians with that of patients aged 50 to 59 years. DESIGN: Review of a prospectively maintained database. SETTING: University transplant center. PATIENTS: First-time liver transplant recipients treated from January 1, 1988, to December 31, 2005. Group 1 consisted of liver transplant recipients aged 70 years or older at the time of transplant. Group 2 was a younger cohort of patients aged 50 to 59 years. INTERVENTIONS: Liver transplantation. MAIN OUTCOME MEASURES: Patient survival. Survival data were stratified, Kaplan-Meier survival was calculated, and a multivariate analysis was performed. RESULTS: Group 1 included 62 patients aged 70 years or older (average, 71.9 +/- 2.1 years). Group 2 included 864 patients aged 50 to 59 years (average, 54.3 +/- 2.9 years). Unadjusted patient survival of group 1 at 1, 3, 5, and 10 years was 73.3%, 65.8%, 47.1%, and 39.7%, respectively. Unadjusted patient survival of group 2 at 1, 3, 5, and 10 years was 79.4%, 71.5%, 65.3%, and 45.2%, respectively. The difference was not statistically significant (P = .14). Multivariate analysis for factors affecting survival demonstrated preoperative hospitalization, cold ischemia time, and hepatitis C/ethanol as risk factors for death. Age 70 years or more was not a strong risk factor (mortality ratio, 1.28; P = .27). CONCLUSIONS: When other risk factors for mortality are controlled in older recipients, risk of death due to age is reduced in well-selected recipients. Age by itself should not be used to limit liver transplantation. PMID- 17709733 TI - Laparoscopic reintervention for failed antireflux surgery: subjective and objective outcomes in 176 consecutive patients. AB - HYPOTHESIS: Laparoscopy has become the standard approach for surgical treatment of uncomplicated gastroesophageal reflux disease. Laparoscopic reintervention following failure of primary antireflux surgery (ARS) remains controversial. The purposes of this study were to assess outcomes in patients operated on for failed ARS, to describe reasons for failure of the primary surgery, and to identify factors predictive of failure of the revision. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Tertiary-care teaching hospital. PATIENTS: A total of 176 patients (20 with multiple ARS) undergoing laparoscopic reintervention between September 12, 1993, and August 1, 2006, for failed ARS. INTERVENTIONS: Patients had preoperative subjective and/or objective documentation of failure after primary ARS: 131 patients had reoperative Nissen fundoplication, 28 patients had a partial wrap, and 17 patients had other procedures. MAIN OUTCOME MEASURES: Preoperative and postoperative symptom scores and results of objective studies were prospectively collected. Postoperative patients with symptom scores of 2 or greater and/or abnormal 24-hour pH study results (DeMeester score > 14.7) were considered to have treatment failures. Logistic regression was performed to identify variables significant for poor outcomes. RESULTS: Median follow-up was 9.2 months in 145 patients (82.4%). One hundred eight patients (74.5%) demonstrated excellent symptomatic outcomes (P = .001). Twenty of 37 patients with failures had reflux symptoms and 23 experienced dysphagia. Sixty-seven patients had 24-hour pH and manometry studies; 18 (11 asymptomatic) patients had a DeMeester score greater than 14.7. Odds of failure were higher among patients presenting with dysphagia (odds ratio, 3.38; 95% confidence interval, 1.35-8.40; P = .009) or requiring an esophageal-lengthening procedure (odds ratio, 5.77; 95% confidence interval, 1.38-24.11; P = .02). CONCLUSIONS: Laparoscopic reintervention following failed primary ARS provides excellent subjective and objective outcomes in most patients. Patients having laparoscopic reintervention for dysphagia relief or those requiring an esophageal lengthening procedure have a significantly greater chance of a poor outcome. PMID- 17709734 TI - Image of the month. Visceral aortic atherosclerosis. PMID- 17709735 TI - Image of the month. Combined spigelian and Richter hernias. PMID- 17709736 TI - Procalcitonin levels and sequential organ failure assessment scores in secondary peritonitis. PMID- 17709737 TI - Human cardiac stem cells. AB - The identification of cardiac progenitor cells in mammals raises the possibility that the human heart contains a population of stem cells capable of generating cardiomyocytes and coronary vessels. The characterization of human cardiac stem cells (hCSCs) would have important clinical implications for the management of the failing heart. We have established the conditions for the isolation and expansion of c-kit-positive hCSCs from small samples of myocardium. Additionally, we have tested whether these cells have the ability to form functionally competent human myocardium after infarction in immunocompromised animals. Here, we report the identification in vitro of a class of human c-kit-positive cardiac cells that possess the fundamental properties of stem cells: they are self renewing, clonogenic, and multipotent. hCSCs differentiate predominantly into cardiomyocytes and, to a lesser extent, into smooth muscle cells and endothelial cells. When locally injected in the infarcted myocardium of immunodeficient mice and immunosuppressed rats, hCSCs generate a chimeric heart, which contains human myocardium composed of myocytes, coronary resistance arterioles, and capillaries. The human myocardium is structurally and functionally integrated with the rodent myocardium and contributes to the performance of the infarcted heart. Differentiated human cardiac cells possess only one set of human sex chromosomes excluding cell fusion. The lack of cell fusion was confirmed by the Cre-lox strategy. Thus, hCSCs can be isolated and expanded in vitro for subsequent autologous regeneration of dead myocardium in patients affected by heart failure of ischemic and nonischemic origin. PMID- 17709738 TI - Characterization of the role of the Synaptotagmin family as calcium sensors in facilitation and asynchronous neurotransmitter release. AB - Ca(2+) influx into presynaptic nerve terminals activates synaptic vesicle exocytosis by triggering fast synchronous fusion and a slower asynchronous release pathway. In addition, a brief rise in Ca(2+) after consecutive action potentials has been correlated with a form of short-term synaptic plasticity with enhanced vesicle fusion termed facilitation. Although the synaptic vesicle protein Synaptotagmin 1 (Syt1) has been implicated as the Ca(2+) sensor for synchronous fusion, the molecular identity of the Ca(2+) sensors that mediate facilitation and asynchronous release is unknown. To test whether the synchronous Ca(2+) sensor, Syt1, or the asynchronous Ca(2+) sensor is involved in facilitation, we analyzed whether genetic elimination of Syt1 in Drosophila results in a concomitant impairment in facilitation. Our results indicate that Syt1 acts as a redundant Ca(2+) sensor for facilitation, with the asynchronous Ca(2+) sensor contributing significantly to this form of short-term plasticity. We next examined whether other members of the Drosophila Syt family functioned in Ca(2+)-dependent asynchronous release or facilitation in vivo. Genetic elimination of other panneuronally expressed Syt proteins did not alter these forms of exocytosis, indicating a non-Syt Ca(2+) sensor functions for both facilitation and asynchronous release. In light of these findings, the presence of two presynaptic Ca(2+) sensors can be placed in a biological context, a Syt1 based Ca(2+) sensor devoted primarily to baseline synaptic transmission and a second non-Syt Ca(2+) sensor for short-term synaptic plasticity and asynchronous release. PMID- 17709739 TI - Effects of light on development of mammalian zygotes. AB - It is generally assumed that light has no effect on the physiology of oocytes, zygotes, or early embryos. Therefore, little or no attention has been paid to lighting conditions during the handling of these cells in vitro. Here we show that cool white fluorescent light, rich in short-wavelength visible light and commonly used in research and clinical laboratories, produces more reactive oxygen species in mouse and hamster zygotes than does warm white fluorescent light. Mouse blastocysts that developed from zygotes shielded from light best developed to term fetuses followed by those exposed to warm white fluorescent light and then by those exposed to cool white fluorescent light. We hypothesized that light is one of the physical factors affecting embryonic environment and that its effects on cultured mammalian zygotes and embryos should not be overlooked. PMID- 17709740 TI - Jammed traffic impedes parasite growth. PMID- 17709741 TI - DNA transposition target immunity and the determinants of the MuB distribution patterns on DNA. AB - MuB, an ATP-dependent DNA-binding protein, is critical for the selection of target sites on the host chromosome during the phage Mu transposition. We developed a multichannel fluidic system to study the MuB-DNA interaction dynamics at the single DNA molecule level by total internal reflection fluorescence microscopy. We analyzed the distribution of MuB along DNA during the assembly and disassembly of MuB polymers on immobilized DNA molecules. The results reveal the absence of a significant correlation of MuB polymer distribution between the assembly and disassembly phases. These observations argue against a model in which MuB polymers on DNA represent a mixture of higher and lower affinity forms, with higher affinity forms being the first to appear and the last to disappear. Instead, assembly and disassembly of MuB polymers involve independent stochastic events. Additionally, we demonstrate that MuB disassembles from the polymer ends at a higher rate than from internal regions of the polymer and MuA stimulates MuB disassembly both at the polymer ends and internally. PMID- 17709742 TI - HIV protease inhibitors and nuclear lamin processing: getting the right bells and whistles. PMID- 17709743 TI - Increases in nitrogen uptake rather than nitrogen-use efficiency support higher rates of temperate forest productivity under elevated CO2. AB - Forest ecosystems are important sinks for rising concentrations of atmospheric CO(2). In previous research, we showed that net primary production (NPP) increased by 23 +/- 2% when four experimental forests were grown under atmospheric concentrations of CO(2) predicted for the latter half of this century. Because nitrogen (N) availability commonly limits forest productivity, some combination of increased N uptake from the soil and more efficient use of the N already assimilated by trees is necessary to sustain the high rates of forest NPP under free-air CO(2) enrichment (FACE). In this study, experimental evidence demonstrates that the uptake of N increased under elevated CO(2) at the Rhinelander, Duke, and Oak Ridge National Laboratory FACE sites, yet fertilization studies at the Duke and Oak Ridge National Laboratory FACE sites showed that tree growth and forest NPP were strongly limited by N availability. By contrast, nitrogen-use efficiency increased under elevated CO(2) at the POP EUROFACE site, where fertilization studies showed that N was not limiting to tree growth. Some combination of increasing fine root production, increased rates of soil organic matter decomposition, and increased allocation of carbon (C) to mycorrhizal fungi is likely to account for greater N uptake under elevated CO(2). Regardless of the specific mechanism, this analysis shows that the larger quantities of C entering the below-ground system under elevated CO(2) result in greater N uptake, even in N-limited ecosystems. Biogeochemical models must be reformulated to allow C transfers below ground that result in additional N uptake under elevated CO(2). PMID- 17709744 TI - Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity induced insulin resistance. AB - S6K1 has emerged as a critical signaling component in the development of insulin resistance through phosphorylation and inhibition of IRS-1 function. This effect can be triggered directly by nutrients such as amino acids or by insulin through a homeostatic negative-feedback loop. However, the role of S6K1 in mediating IRS 1 phosphorylation in a physiological setting of nutrient overload is unresolved. Here we show that S6K1 directly phosphorylates IRS-1 Ser-1101 in vitro in the C terminal domain of the protein and that mutation of this site largely blocks the ability of amino acids to suppress IRS-1 tyrosine and Akt phosphorylation. Consistent with this finding, phosphorylation of IRS-1 Ser-1101 is increased in the liver of obese db/db and wild-type, but not S6K1(-/-), mice maintained on a high-fat diet and is blocked by siRNA knockdown of S6K1 protein. Finally, infusion of amino acids in humans leads to the concomitant activation of S6K1, phosphorylation of IRS-1 Ser-1101, a reduction in IRS-1 function, and insulin resistance in skeletal muscle. These findings indicate that nutrient- and hormonal-dependent activation of S6K1 causes insulin resistance in mice and humans, in part, by mediating IRS-1 Ser-1101 phosphorylation. PMID- 17709745 TI - Aberrant infection and persistence of varicella-zoster virus in human dorsal root ganglia in vivo in the absence of glycoprotein I. AB - Varicella-zoster virus (VZV) causes varicella, establishes latency in sensory ganglia, and reactivates as herpes zoster. Human dorsal root ganglia (DRGs) xenografts in immunodeficient mice provide a model for evaluating VZV neuropathogenesis. Our investigation of the role of glycoprotein I (gI), which is dispensable in vitro, examines the functions of a VZV gene product during infection of human neural cells in vivo. Whereas intact recombinant Oka (rOka) initiated a short replicative phase followed by persistence in DRGs, the gI deletion mutant, rOkaDeltagI, showed prolonged replication with no transition to persistence up to 70 days after infection. Only a few varicella-zoster nucleocapsids and cytoplasmic virions were observed in neurons, and the major VZV glycoprotein, gE, was retained in the rough endoplasmic reticulum in the absence of gI. VZV neurotropism was not disrupted when DRG xenografts were infected with rOka mutants lacking gI promoter elements that bind cellular transactivators, specificity factor 1 (Sp1) and upstream stimulatory factor (USF). Because gI is essential and Sp1 and USF contribute to VZV pathogenesis in skin and T cells in vivo, these DRG experiments indicate that the genetic requirements for VZV infection are less stringent in neural cells in vivo. The observations demonstrate that gI is important for VZV neurotropism and suggest that a strategy to reduce neurovirulence by deleting gI could prolong active infection in human DRGs. PMID- 17709746 TI - High-throughput fluorescent-based optimization of eukaryotic membrane protein overexpression and purification in Saccharomyces cerevisiae. AB - Eukaryotic membrane proteins are often difficult to produce in large quantities, which is a significant obstacle for further structural and biochemical investigation. Based on the analysis of 43 eukaryotic membrane proteins, we present a cost-effective high-throughput approach for rapidly screening membrane proteins that can be overproduced to levels of >1 mg per liter in Saccharomyces cerevisiae. We find that 70% of the well expressed membrane proteins tested in this system are stable, targeted to the correct organelle, and monodisperse in either Fos-choline 12 (FC-12) or n-dodecyl-beta-D-maltoside. We illustrate the advantage of such an approach, with the purification of monodisperse human and yeast nucleotide-sugar transporters to unprecedented levels. We estimate that our approach should be able to provide milligram quantities for at least one-quarter of all membrane proteins from both yeast and higher eukaryotic organisms. PMID- 17709747 TI - The Atg5 Atg12 conjugate associates with innate antiviral immune responses. AB - Autophagy is an essential process for physiological homeostasis, but its role in viral infection is only beginning to be elucidated. We show here that the Atg5 Atg12 conjugate, a key regulator of the autophagic process, plays an important role in innate antiviral immune responses. Atg5-deficient mouse embryonic fibroblasts (MEFs) were resistant to vesicular stomatitis virus replication, which was largely due to hyperproduction of type I interferons in response to immunostimulatory RNA (isRNA), such as virus-derived, double-stranded, or 5' phosphorylated RNA. Similar hyperresponse to isRNA was also observed in Atg7 deficient MEFs, in which Atg5-Atg12 conjugation is impaired. Overexpression of Atg5 or Atg12 resulted in Atg5-Atg12 conjugate formation and suppression of isRNA mediated signaling. Molecular interaction studies indicated that the Atg5-Atg12 conjugate negatively regulates the type I IFN production pathway by direct association with the retinoic acid-inducible gene I (RIG-I) and IFN-beta promoter stimulator 1 (IPS-1) through the caspase recruitment domains (CARDs). Thus, in contrast to its role in promoting the bactericidal process, a component of the autophagic machinery appears to block innate antiviral immune responses, thereby contributing to RNA virus replication in host cells. PMID- 17709749 TI - NS3 helicase actively separates RNA strands and senses sequence barriers ahead of the opening fork. AB - RNA helicases regulate virtually all RNA-dependent cellular processes. Although much is known about helicase structures, very little is known about how they deal with barriers in RNA and the factors that affect their processivity. The hepatitis C virus encodes NS3, an RNA helicase that is essential for viral RNA replication. We have used optical tweezers to determine at the single-molecule level how the local stability of the RNA substrate affects the enzyme rate of strand separation, whether separation occurs by an active or a passive mechanism, and whether processivity is affected. We show that sequence barriers in RNA modulate NS3 activity. NS3 processivity depends on barriers ahead of the opening fork. Our results rule out a model where NS3 passively waits for the thermal fraying of double-stranded RNA. Instead, we find that NS3 destabilizes the duplex before separating the strands. Failure to do so before a strong barrier leads to helicase dissociation and limits the processivity of the enzyme. PMID- 17709748 TI - A modular and extensible RNA-based gene-regulatory platform for engineering cellular function. AB - Engineered biological systems hold promise in addressing pressing human needs in chemical processing, energy production, materials construction, and maintenance and enhancement of human health and the environment. However, significant advancements in our ability to engineer biological systems have been limited by the foundational tools available for reporting on, responding to, and controlling intracellular components in living systems. Portable and scalable platforms are needed for the reliable construction of such communication and control systems across diverse organisms. We report an extensible RNA-based framework for engineering ligand-controlled gene-regulatory systems, called ribozyme switches, that exhibits tunable regulation, design modularity, and target specificity. These switch platforms contain a sensor domain, comprised of an aptamer sequence, and an actuator domain, comprised of a hammerhead ribozyme sequence. We examined two modes of standardized information transmission between these domains and demonstrate a mechanism that allows for the reliable and modular assembly of functioning synthetic RNA switches and regulation of ribozyme activity in response to various effectors. In addition to demonstrating examples of small molecule-responsive, in vivo functional, allosteric hammerhead ribozymes, this work describes a general approach for the construction of portable and scalable gene-regulatory systems. We demonstrate the versatility of the platform in implementing application-specific control systems for small molecule-mediated regulation of cell growth and noninvasive in vivo sensing of metabolite production. PMID- 17709750 TI - How gene order is influenced by the biophysics of transcription regulation. AB - What are the forces that shape the structure of prokaryotic genomes: the order of genes, their proximity, and their orientation? Coregulation and coordinated horizontal gene transfer are believed to promote the proximity of functionally related genes and the formation of operons. However, forces that influence the structure of the genome beyond the level of a single operon remain unknown. Here, we show that the biophysical mechanism by which regulatory proteins search for their sites on DNA can impose constraints on genome structure. Using simulations, we demonstrate that rapid and reliable gene regulation requires that the transcription factor (TF) gene be close to the site on DNA the TF has to bind, thus promoting the colocalization of TF genes and their targets on the genome. We use parameters that have been measured in recent experiments to estimate the relevant length and times scales of this process and demonstrate that the search for a cognate site may be prohibitively slow if a TF has a low copy number and is not colocalized. We also analyze TFs and their sites in a number of bacterial genomes, confirm that they are colocalized significantly more often than expected, and show that this observation cannot be attributed to the pressure for coregulation or formation of selfish gene clusters, thus supporting the role of the biophysical constraint in shaping the structure of prokaryotic genomes. Our results demonstrate how spatial organization can influence timing and noise in gene expression. PMID- 17709751 TI - Inositol 1,3,4,5-tetrakisphosphate controls proapoptotic Bim gene expression and survival in B cells. AB - The contribution of the B isoform of inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] 3-kinase (or Itpkb) and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P(4)], its reaction product, to B cell function and development remains unknown. Here, we show that mice deficient in Itpkb have defects in B cell survival leading to specific and intrinsic developmental alterations in the B cell lineage and antigen unresponsiveness in vivo. The decreased B cell survival is associated with a decreased phosphorylation of Erk1/2 and increased Bim gene expression. B cell survival, development, and antigen responsiveness are normalized in parallel to reduced expression of Bim in Itpkb(-/-) Bim(+/-) mice. Analysis of the signaling pathway downstream of Itpkb revealed that Ins(1,3,4,5)P(4) regulates subcellular distribution of Rasa3, a Ras GTPase activating protein acting as an Ins(1,3,4,5)P(4) receptor. Together, our results indicate that Itpkb and Ins(1,3,4,5)P(4) mediate a survival signal in B cells via a Rasa3-Erk signaling pathway controlling proapoptotic Bim gene expression. PMID- 17709752 TI - Mendel's green cotyledon gene encodes a positive regulator of the chlorophyll degrading pathway. AB - Mutants that retain greenness of leaves during senescence are known as "stay green" mutants. The most famous stay-green mutant is Mendel's green cotyledon pea, one of the mutants used in determining the law of genetics. Pea plants homozygous for this recessive mutation (known as i at present) retain greenness of the cotyledon during seed maturation and of leaves during senescence. We found tight linkage between the I locus and stay-green gene originally found in rice, SGR. Molecular analysis of three i alleles including one with no SGR expression confirmed that the I gene encodes SGR in pea. Functional analysis of sgr mutants in pea and rice further revealed that leaf functionality is lowered despite a high chlorophyll a (Chl a) and chlorophyll b (Chl b) content in the late stage of senescence, suggesting that SGR is primarily involved in Chl degradation. Consistent with this observation, a wide range of Chl-protein complexes, but not the ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) large subunit, were shown to be more stable in sgr than wild-type plants. The expression of OsCHL and NYC1, which encode the first enzymes in the degrading pathways of Chl a and Chl b, respectively, was not affected by sgr in rice. The results suggest that SGR might be involved in activation of the Chl-degrading pathway during leaf senescence through translational or posttranslational regulation of Chl-degrading enzymes. PMID- 17709753 TI - Amyolid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter. AB - The key pathological features of Alzheimer's disease include synaptic dysfunction, profound changes in the cholinergic system, and deposition of beta amyloid peptides generated by proteolytic processing of the amyloid-beta precursor protein (APP). However, the pathways linking APP with synaptic activity and cholinergic neuronal function are poorly understood. We report here that APP is essential in regulating the presynaptic expression and activity of the high affinity choline transporter (CHT), a molecule that mediates the rate-limiting step of cholinergic synaptic transmission in both the neuromuscular junction and central cholinergic neurons. Loss of APP leads to aberrant localization of CHT at the neuromuscular synapses and reduced CHT activity at cholinergic projections. At the cellular level, we show that APP and CHT can be found in Rab5-positive endosomal compartments and that APP affects CHT endocytosis. Furthermore, we demonstrate that APP interacts with CHT through the C-terminal domain, providing support for a specific and direct regulation of CHT by APP through protein protein interactions. These results identify a physiological activity of APP in cholinergic neurons, and our data indicate that deregulation of APP function may contribute to cholinergic impairment and AD pathogenesis. PMID- 17709754 TI - Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo. AB - MAPK signaling pathways function as critical regulators of cellular differentiation, proliferation, stress responsiveness, and apoptosis. One branch of the MAPK signaling pathway that culminates in ERK1/2 activation is hypothesized to regulate the growth and adaptation of the heart to both physiologic and pathologic stimuli, given its known activation in response to virtually every stress- and agonist-induced hypertrophic stimulus examined to date. Here we investigated the requirement of ERK1/2 signaling in mediating the cardiac hypertrophic growth response in Erk1(-/-) and Erk2(+/-) mice, as well as in transgenic mice with inducible expression of an ERK1/2-inactivating phosphatase in the heart, dual-specificity phosphatase 6. Although inducible expression of dual-specificity phosphatase 6 in the heart eliminated ERK1/2 phosphorylation at baseline and after stimulation without affecting any other MAPK, it did not diminish the hypertrophic response to pressure overload stimulation, neuroendocrine agonist infusion, or exercise. Similarly, Erk1(-/-) and Erk2(+/-) mice showed no reduction in pathologic or physiologic stimulus induced cardiac growth in vivo. However, blockade or deletion of cardiac ERK1/2 did predispose the heart to decompensation and failure after long-term pressure overload in conjunction with an increase in myocyte TUNEL. Thus, ERK1/2 signaling is not required for mediating physiologic or pathologic cardiac hypertrophy in vivo, although it does play a protective role in response to pathologic stimuli. PMID- 17709756 TI - Summaries for patients. Invasive streptococcal infections in hospitals in Ontario, Canada, 1992 to 2000. PMID- 17709755 TI - Norepinephrine enables the induction of associative long-term potentiation at thalamo-amygdala synapses. AB - Emotional arousal, linked to a surge of norepinephrine (NE) in the amygdala, leads to creation of stronger and longer-lasting memories. However, little is known about the synaptic mechanisms of such modulatory NE influences. Long-term potentiation (LTP) in auditory inputs to the lateral nucleus of the amygdala was recently linked to the acquisition of fear memory. Therefore we explored whether LTP induction at thalamo-amygdala projections, conveying the acoustic conditioned stimulus information to the amygdala during fear conditioning, is under adrenergic control. Using whole-cell recordings from amygdala slices, we show that NE suppresses GABAergic inhibition of projection neurons in the lateral amygdala and enables the induction of LTP at thalamo-amygdala synapses under conditions of intact GABA(A) receptor-mediated inhibition. Our data indicate that the NE effects on the efficacy of inhibition could result from a decrease in excitability of local circuit interneurons, without direct effects of NE on release machinery of the GABA-containing vesicles or the size of single-quanta postsynaptic GABA(A) receptor-mediated responses. Thus, adrenergic modulation of local interneurons may contribute to the formation of fear memory by gating LTP in the conditioned stimulus pathways. PMID- 17709757 TI - Surveillance for hospital outbreaks of invasive group a streptococcal infections in Ontario, Canada, 1992 to 2000. AB - BACKGROUND: Streptococcus pyogenes can cause severe disease in the individual patient and dramatic hospital outbreaks. OBJECTIVE: To describe the epidemiology of hospital outbreaks of invasive group A streptococcal infection in order to understand the potential benefit of proposed outbreak investigation and management strategies. DESIGN: Prospective, population-based surveillance. SETTING: Short-term care hospitals in Ontario, Canada. PATIENTS: Persons with a positive culture for group A streptococcus from a normally sterile site between 1 January 1992 and 31 December 2000. MEASUREMENTS: Laboratory-based surveillance identified patients with nosocomial invasive group A streptococcal infection. Epidemiologic and microbiological investigations were used to detect transmission. RESULTS: Of 2351 cases of invasive group A streptococcal disease, 291 (12%) were hospital acquired. Twenty-nine (10%) nosocomial cases occurred as part of 20 outbreaks. Seventy percent (14 of 20) of outbreaks involved nonsurgical, nonobstetric patients. Community-acquired cases initiated 25% of outbreaks; most were cases of necrotizing fasciitis in patients admitted to the intensive care unit. Outbreaks were small (median, 2 cases [range, 2 to 10 cases]) and short (median duration, 6 days [range, 0 to 30 days]). The median time between the first 2 cases was 4.5 days. The most common mode of propagation was patient-to-patient transmission. A staff carrier was the primary mode of transmission in 2 (10%) outbreaks, but 1 or more health care workers were colonized with the outbreak strain in 6 of 18 (33%) other outbreaks. LIMITATIONS: Some outbreaks with 1 case of invasive disease may have been missed; advice provided to participating hospitals may have reduced the number and size of outbreaks. CONCLUSIONS: Practices to prevent hospital transmission of group A streptococci should include isolation of patients admitted to the intensive care unit with necrotizing fasciitis, investigation after a single nosocomial case, and emphasis on identifying and treating health care worker carriers on surgical and obstetric services and patient reservoirs on other wards. PMID- 17709758 TI - Nephropathic cystinosis in adults: natural history and effects of oral cysteamine therapy. AB - BACKGROUND: The full burden of nephropathic cystinosis in adulthood and the effects of long-term oral cysteamine therapy on its nonrenal complications have not been elucidated. OBJECTIVE: To assess the severity of cystinosis in adults receiving and not receiving oral cysteamine therapy. DESIGN: Case series. SETTING: National Institutes of Health Clinical Center. PATIENTS: 100 persons (58 men and 42 women) age 18 to 45 years with nephropathic cystinosis examined between January 1985 and May 2006. MEASUREMENTS: Historical data were collected on renal transplantation, administration of oral cysteamine, and time and cause of death. Patients were evaluated for height and weight; thyroid, pulmonary, and swallowing function; muscle atrophy; hypogonadism (in men); retinopathy; vascular and cerebral calcifications; diabetes mellitus; and homozygosity for the common 57-kb deletion in CTNS. Laboratory studies were also performed. RESULTS: Of 100 adults with nephropathic cystinosis, 92 had received a renal allograft and 33 had died. At least half of the patients had hypothyroidism, hypergonadotropic hypogonadism (in men), pulmonary insufficiency, swallowing abnormalities, or myopathy. One third of the patients had retinopathy or vascular calcifications, and 24% had diabetes. Homozygosity for the 57-kb CTNS deletion was associated with an increased risk for death and morbidity. The 39 patients who received long term (> or =8 years) oral cysteamine therapy were taller and heavier, had a renal allograft later in life, had lower cholesterol levels, and experienced fewer complications and deaths than patients who received cysteamine for fewer than 8 years. The frequency of diabetes mellitus, myopathy, pulmonary dysfunction, hypothyroidism, and death increased as time off cysteamine treatment increased, and it decreased as time on cysteamine therapy increased. LIMITATIONS: The study was retrospective and not randomized. The criteria used to measure adequacy of treatment were arbitrary. CONCLUSIONS: Untreated nephropathic cystinosis causes extensive morbidity and death in adulthood. Long-term oral cysteamine therapy mitigates these effects. PMID- 17709759 TI - Systematic review: implantable cardioverter defibrillators for adults with left ventricular systolic dysfunction. AB - BACKGROUND: Patients with left ventricular (LV) systolic dysfunction have an increased risk for ventricular arrhythmias. PURPOSE: To summarize the evidence about benefits and harms of implantable cardioverter defibrillators (ICDs) in adult patients with LV systolic dysfunction. DATA SOURCES: A search of electronic databases (including MEDLINE, EMBASE, Cochrane Central, and U.S. Food and Drug Administration reports) from 1980 through April 2007, not limited by language of publication, was supplemented by hand searches and contact with study authors and device manufacturers. STUDY SELECTION: Two reviewers independently selected studies on the basis of prespecified criteria. They selected 12 randomized, controlled trials (RCTs) (8516 patients) that reported on mortality and 76 observational studies (96 951 patients) that examined safety or effectiveness. DATA EXTRACTION: Data were extracted in duplicate and independently by 2 reviewers. DATA SYNTHESIS: In adult patients with LV systolic dysfunction, 86% of whom had New York Heart Association class II or III symptoms, ICDs reduced all cause mortality by 20% (95% CI, 10% to 29%) in the RCTs and by 46% (CI, 32% to 57%) in the observational studies. Death associated with implantation of ICDs occurred during 1.2% (CI, 0.9% to 1.5%) of procedures. The frequency of postimplantation complications per 100 patient-years included 1.4 (CI, 1.2 to 1.6) device malfunctions, 1.5 (CI, 1.3 to 1.8) lead problems, and 0.6 (CI, 0.5 to 0.8) site infection. Rates of inappropriate discharges per 100 patient-years ranged from 19.1 (CI, 16.5 to 22.0) in RCTs to 4.9 (CI, 4.5 to 5.3) in observational studies. LIMITATIONS: Studies were of short duration and infrequently reported nonfatal outcomes. Few studies evaluated dual-chamber ICDs. Lack of individual-patient data prevents identification of subgroup-specific effects. CONCLUSIONS: Implantable cardioverter defibrillators are efficacious in reducing mortality for adult patients with LV systolic dysfunction, and this benefit extends to nontrial populations. Improved risk stratification tools to identify patients who are most likely to benefit from ICD are needed. PMID- 17709760 TI - Update in perioperative medicine. PMID- 17709761 TI - Treating the enemy. PMID- 17709762 TI - Literacy and misunderstanding prescription drug labels. PMID- 17709763 TI - Literacy and misunderstanding prescription drug labels. PMID- 17709764 TI - Literacy and misunderstanding prescription drug labels. PMID- 17709765 TI - Rituximab for patients with idiopathic thrombocytopenic purpura. PMID- 17709766 TI - Literacy and misunderstanding prescription drug labels. PMID- 17709767 TI - Lingering racism calls for reflection and action. PMID- 17709768 TI - Branch retinal artery occlusion after injection of a long-acting risperidone preparation. PMID- 17709769 TI - Cellular and molecular regulation of muscle growth and development in meat animals. AB - Although in vivo and in vitro studies have established that anabolic steroids, transforming growth factor-beta (TGF-beta), and myostatin affect muscle growth in meat-producing animals, their mechanisms of action are not completely understood. Anabolic steroids have been widely used as growth promoters in feedlot cattle for over 50 yr. A growing body of evidence suggests that increased muscle levels of IGF-I and increased muscle satellite cell numbers play a role in anabolic steroid enhanced muscle growth. In contrast to anabolic steroids, the members of the TGF beta-myostatin family suppress muscle growth in vivo and suppress both proliferation and differentiation of cultured myogenic cells. Recent evidence suggests that IGFBP-3 and IGFBP-5 play a role in mediating the proliferation suppressing actions of both TGF-beta and myostatin on cultured myogenic cells. Consequently, this review will focus on the roles of IGF-I and IGFBP in the cellular and molecular mechanisms of action of anabolic steroids and TGF-beta and myostatin, respectively. PMID- 17709771 TI - Indicators of genetic erosion in an endangered population: the Alentejana cattle breed in Portugal. AB - A study was conducted to characterize genetic diversity in the Alentejana breed of cattle based on its demographic trends and to investigate the major factors affecting genetic erosion in this breed. Herdbook information collected between 1940 and 2004, including pedigree records on 100,562 animals in 155 herds, was used to estimate demographic parameters. The mean generation intervals were 6.0 +/- 2.4 yr and 6.8 +/- 3.2 yr for sires and dams of calves, respectively. Average inbreeding increased steadily over the period analyzed, with an annual rate of inbreeding of 0.33 +/- 0.004% (P < 0.01) and an effective population size of 23.3. In the reference population (28,531 calves born between 2000 and 2003) the average inbreeding was 8.35 +/- 9.02% and nearly 80% of the calves were inbred, whereas the average relationship among all animals was 0.026 +/- 0.040. Nevertheless, the mean relationship was 0.328 +/- 0.264 and 0.022 +/- 0.026 for animals born in the same and in different herds, respectively. The computed genetic contributions to the reference population resulted in estimates for the effective number of founders, ancestors, founding herds, and herds supplying sires of 121.6, 55.0, 17.1, and 26.9, respectively, the 2 most influential herds and ancestors contributing 24.2 and 15.1%, respectively, of the current genetic pool. Of the 671 founding sires, only 24 Y-chromosomes are currently represented, but 1 sire alone contributes nearly 60% of this representation, such that the effective number of Y-chromosomes is only 2.73. The observed inbreeding per herd was, on average, 0.053 +/- 0.071 lower than expected from the relationship among the generation of parents of calves in the reference population, indicating that producers have followed breeding strategies that have kept inbreeding at lower levels than anticipated with random selection and mating. When compared with other cattle breeds, Alentejana has some of the highest levels of mean inbreeding and annual rate of inbreeding, and an effective population size that is nearly half of the minimum recommended for maintenance of genetic variability. These critical indicators demonstrate the need to adopt strategies aimed at minimizing inbreeding to avoid further losses of genetic diversity. PMID- 17709770 TI - Effects of dietary methionine and lysine sources on nutrient digestion, nitrogen utilization, and duodenal amino acid flow in growing goats. AB - This study investigated the effects of supplementation of various sources of Met and Lys on nutrient digestion, N utilization, and duodenal AA flows in growing goats. Four 4-mo-old Liuyang Black wether goats were used in a 4 x 4 Latin square experiment and were assigned to 4 dietary treatments: (1) control, (2) control + lipid-coated Met-Zn chelate and Lys-Mn chelate (PML), (3) control + Met-Zn chelate and Lys-Mn chelate (CML), and (4) control + dl-Met, l-Lys-HCl, ZnSO(4).7H(2)O, and MnSO(4).H(2)O (FML). Compared with control, PML reduced (P < 0.05) ruminal NH(3) concentration, urinary N excretion, and plasma urea N concentration and increased (P < 0.05) the activity of ruminal endo-1,4-beta-d glucanase and beta-glucosidase, the duodenal flow of N, N retention (g/d as well as % of absorbed N), the duodenal flows of Met, Lys, His, Val, and total essential AA, and plasma concentrations of Lys, Val, Phe, and total essential AA. Supplementing Zn-Met and Mn-Lys chelates had similar (P > 0.05) but lesser effects on these measures compared with PML, and the effects on most of the measures were not statistically significant (P > 0.05) when compared with control. Supplementing free-form Met and Lys had no effects compared with control (P > 0.05). The results indicate that lipid coating and chelating of AA provide a protection, and to a lesser extent by only chelating, of the AA from microbial degradation in the rumen and possibly has effects on rumen fermentation, which increases MP supply. This technology could improve productive performance and be of potential benefit to ruminant production if cost-effective products are developed. PMID- 17709772 TI - Genetic and physiological determinants of maternal behavior and lamb survival: implications for low-input sheep management. AB - The relatively intensive supervision afforded many ewes at lambing time is a barrier to the development of low-input sheep management systems. However, in some flocks, reduction in this level of supervision may initially affect lamb mortality and animal welfare. In this review, possibilities for optimizing behavioral interaction between the ewe and lamb are considered, with the goal of improving lamb survival without the need for high levels of human supervision. At birth, ewes show specific behavioral patterns (e.g., licking or grooming, low pitched bleats, udder acceptance) that facilitate the transition of the lamb from pre- to postnatal life and that accompany the formation of an exclusive olfactory memory for the lamb. The lamb also performs a specific sequence of behaviors directed toward standing, finding the udder, and sucking. The successful accomplishment of these behavior patterns is vital for the formation of a strong attachment between both partners, and for lamb survival. The expression of maternal behavior in the ewe is affected by her previous maternal experience, by nutrition in pregnancy, by breed, by temperament, and, to some extent, by the behavior of her lamb. The maternal care expressed by a ewe at parturition is indicative of her behavior throughout that lactation and in successive pregnancies, suggesting an underlying basis to maternal care intrinsic to that ewe. Studies with Scottish Blackface and Suffolk ewes show that ewes expressing high levels of maternal care have elevated plasma estradiol in late gestation compared with ewes with poorer maternal care, and that circulating estradiol concentration is correlated with maternal behaviors. Although the genetic basis of maternal behaviors has still to be fully determined, there are possibilities of improving maternal behavior by selection, and a better understanding of the neuroendocrine processes underlying individual differences in maternal behavior may help in developing selection strategies. In addition, selection on lamb behaviors, which show some genetic basis, may also be a route to improve lamb survival. Because behavior of both the ewe and lamb is affected by environmental factors, appropriate management, through pregnancy and at parturition, will enhance the expression of maternal behavior and lamb vigor, and so contribute to improving lamb survival. PMID- 17709773 TI - Bidirectional communication: growth and immunity in domestic livestock. AB - Evidence continues to mount supporting the existence of a bidirectional communication network between the immune system and the somatotropic axis in a variety of species. For more than 4 decades, researchers have sought and identified linkages between the growth axis and the immune system. Although significant advances have been made with regard to elucidation of various bidirectional communication pathways between the immune system and growth axis in humans and rodents, the current paper focuses on the relationships between the immune system and somatotropic axis in sheep, cattle, and swine. Aspects from historical and current research associated with changes in somatotropic function following immune challenges with endotoxin, parasites, viruses, and bacteria have been provided. Collectively, these studies demonstrate that a bidirectional communication network, similar to that described in humans and rodents, also exists in a variety of domestic livestock. Identifying and understanding this bidirectional communication network could have significant economic benefits if it leads to intervention strategies to prevent production losses associated with sickness and disease. PMID- 17709774 TI - Effects of concentrations of cyanocobalamin in the gestation diet on some criteria of vitamin B12 metabolism in first-parity sows. AB - In swine nutrition, little is known about the role of vitamin B(12) in the reproductive processes. The current study was undertaken to obtain information on the dose-response pattern of different metabolic criteria related to the homeostasis of vitamin B(12) and homocysteine in gestating sows receiving various concentrations of dietary vitamin B(12) (cyanocobalamin). Homocysteine is a detrimental intermediate metabolite of the vitamin B(12)-dependent remethylation pathway of Met. Forty nulliparous (Large White x Landrace) sows were randomly assigned during gestation to dietary treatments containing 5 concentrations of cyanocobalamin (0, 20, 100, 200, or 400 microg/kg). During lactation, a diet containing 25 microg of cyanocobalamin/kg (as-fed) was given to all sows. During gestation, plasma vitamin B(12) increased as concentrations of dietary cyanocobalamin increased (linear and quadratic, P < 0.01) and the effect persisted during lactation (21 d postpartum) both in plasma (linear and quadratic, P < 0.05) and the liver (linear and quadratic, P < 0.04). Plasma homocysteine decreased with concentrations of cyanocobalamin provided to sows during gestation (linear, quadratic, and cubic, P < 0.01). At parturition, vitamin B(12) in colostrum increased as concentrations of cyanocobalamin increased (linear and quadratic, P < 0.01), but the treatment effect persisted (linear, P = 0.01) only up to 1 d postfarrowing. However, in piglets there was no treatment effect (P = 0.59) on plasma vitamin B(12) before colostrum intake, but a linear effect of concentrations of cyanocobalamin (P = 0.04) was observed 1 d later. Plasma homocysteine in piglets during lactation decreased with increasing concentrations of cyanocobalamin given to sows in gestation (linear and quadratic, P < 0.01). Based on a broken-line regression model, the concentrations of dietary cyanocobalamin that maximized plasma vitamin B(12) and minimized plasma homocysteine of sows during gestation were estimated to be 164 and 93 microg/kg, respectively. The maximal residual responses in sows and piglets during lactation were observed with treatments of 100 or 200 microg of cyanocobalamin/kg. The dietary cyanocobalamin concentration necessary to optimize the response of these metabolic criteria remains to be refined within lower and narrower ranges of cyanocobalamin concentrations (i.e., <200 mg/kg). Moreover, the biological significance of such concentrations of cyanocobalamin needs to be validated with performance criteria by using greater numbers of animals during several parities. PMID- 17709775 TI - Polymorphisms of the prion gene promoter region that influence classical bovine spongiform encephalopathy susceptibility are not applicable to other transmissible spongiform encephalopathies in cattle. AB - Two regulatory region polymorphisms in the prion gene of cattle have been reported to have an association with resistance to classical bovine spongiform encephalopathy (BSE). However, it is not known if this association also applies to other transmissible spongiform encephalopathies (TSE) in cattle. In this report, we compare the relationship between these 2 polymorphisms and resistance in cattle affected with naturally occurring atypical BSE as well as in cattle experimentally inoculated with either scrapie, chronic wasting disease, or transmissible mink encephalopathy. Our analysis revealed no association between genotype and resistance to atypical BSE or experimentally inoculated TSE. This indicates the promoter polymorphism correlation is specific to classical BSE and that atypical BSE and experimentally inoculated TSE are bypassing the site of influence of the polymorphisms. This genetic discrepancy demonstrates that atypical BSE progresses differently in the host relative to classical BSE. These results are consistent with the notion that atypical BSE originates spontaneously in cattle. PMID- 17709776 TI - Growth rate and changes of the somatotropic axis in beef cattle administered exogenous bovine somatotropin beginning at two hundred, two hundred fifty, and three hundred days of age. AB - To determine the effects of bovine somatotropin (bST) treatment beginning at 3 ages on the growth rate and components of the somatotropic axis, 40 beef cattle (200 +/- 21 d of age) were randomly assigned to 1 of 4 treatments (10 animals/treatment). Three of the treatment groups received bST (33 mug/kg of BW) daily beginning at 200, 250, or 300 d of age until all animals reached 400 d of age; the fourth group served as controls (0 bST). Animals were housed in pens (5 animals per pen; 2 pens per treatment) and fed a diet formulated for an ADG of 1.2 kg/d. Feed intake (per pen) was measured daily, and BW was determined weekly. Blood samples (10 mL) and ultrasound measurements were collected at 200, 250, 300, 350, and 400 d of age. Serum concentrations of ST and IGF-I were determined by RIA and IGFBP-2 and -3 by ligand blot procedures. Overall, cattle gained 284.0 +/- 14.7 kg of BW with a treatment x week interaction (P < 0.01), such that during the treatment period ADG was 11.6, 8.7, and 15.8% greater (P < 0.05) in cattle treated with bST beginning at 200, 250, and 300 d, respectively, relative to controls during the same time frame. Average DMI was 13.6% less (P < 0.05) in bST-treated cattle than in controls. Increases in ADG coupled with a reduction in DMI resulted in 11.7, 14.0, and 26.4% increases (P < 0.01) in the efficiency of gain (G:F) in bST-treated cattle beginning at 200, 250, and 300 d of age, respectively, compared with contemporary controls. Backfat thickness increased (P < 0.05) over time, but the magnitude of the increase was less in the bST-treated cattle (treatment x week interaction; P < 0.05). Area of the LM increased (P < 0.05) over time but was similar across treatment groups. Serum concentrations of ST, IGF-I, and IGFBP-3 increased (P < 0.05), whereas IGFBP-2 decreased (P < 0.05) over time. The changes in the components of somatotropic axis were more pronounced in bST-treated cattle compared with controls, with the greatest magnitude of response in animals that began bST treatment at 300 d of age. In conclusion, the exogenous bST-induced growth response was greater in animals that began to receive bST administration at 300 d of age and received it for a shorter period (100 d) compared with animals that received bST beginning at 200 or 250 d of age. PMID- 17709777 TI - Growth performance and muscle oxidation in rats fed increasing amounts of high tannin sorghum. AB - Oxidative processes deteriorate the quality of meat products. High tannin sorghums (HTS) contain flavonoid oligomers known as proanthocyanidins or condensed tannins. These compounds act as anti-oxidants in vitro, but their effectiveness in vivo remains unclear. We tested the hypothesis that moderate amounts of dietary HTS could reduce markers of oxidation on muscle of rats without having detrimental effects in growth. We used 2 groups of 38 male Sprague Dawley rats at 5 and 13 wk of age each. Each age group was fed 4 diets in a completely randomized design. The younger group was fed the experimental diets for 10 wk (10W); whereas the older group was fed for 2 wk (2W). The diets were modified from the NIH-07 diet and contained HTS and corn at ratios of 0:50 (S0, control), 20:30 (S20), 35:15 (S35), and 50:0 (S50) as a percentage of the diet. Growth and the efficiency of gain were assessed periodically measuring BW, ADFI, ADG, and G:F. Oxidation in muscle was measured in fresh tissue and after 6 d of aerobic-refrigerated storage. Muscles evaluated were LM and soleus (SM). Fresh liver was also evaluated. Thiobarbituric acid-reactive substances (TBARS) and carbonyl content were used as markers of lipid and protein oxidation, respectively. No differences in BW, ADFI, ADG, and G:F were observed in 2W rats. Greater (P < 0.05) ADFI and ADG were observed in 10W-S35 group between d 1 and 7 and greater BW (P = 0.049) was observed in group 10W-S35 at d 70 compared with 10W-S0. No differences were observed between S0 and any HTS diet in G:F in 10W and 2W rats. No differences in TBARS or carbonyls were observed in liver. No differences in TBARS were observed in fresh and aged LM and SM. When LM samples were aged for 6 d, decreased carbonyl contents (P < 0.01) were observed in 10W S35 and 10W-S50 diets compared with 10W-S0. Reductions in carbonyls were also observed in aged SM between 2W-S50 and 2W-S0 (P = 0.013). We concluded that inclusion of 35% HTS in the diet increased intake and growth rate of young, fast growing rats without changing the efficiency of gain. Feeding HTS reduced markers of protein oxidation in rat muscle after 6 d of refrigerated storage. If similar results are observed in animals such as swine or cattle, the use of HTS as animal feed should be reassessed. PMID- 17709778 TI - Board-invited review: Applications of genomic information in livestock. AB - The availability of whole genome sequences for individual species will change the landscape for livestock genomic research. Animal scientists will have access to whole-genome sequence-based technologies such as high-throughput SNP genotyping assays, gene expression profiling, methylation profiling, RNA interference, and genome resequencing that will revolutionize the scale upon which research will be conducted. These technologies will also alter the ways we think about addressing industry and scientific problems. In this review, we discuss the scientific bases for these emerging technologies and present recent highlights of their application in human, model species, and livestock as well as their potential for future applications in livestock. Additionally, we discuss strategies for their use in the genetic improvement and management of livestock. In particular, we present a strategy for the simultaneous identification of causal mutations underlying phenotypic traits in livestock and discuss issues that will arise in the application of whole genome selection for the prediction of genetic merit in livestock. We also point out that the statistical analysis that underlies the whole genome selection methodology is a sophisticated enhancement of single marker association mapping analysis to allow the entire genome to be simultaneously analyzed. PMID- 17709779 TI - Induction of milk ejection and milk removal in different production systems. AB - Milk ejection is important during milking or suckling to obtain the alveolar milk fraction, which can represent more than 80% of the milk stored in the udder of dairy cows. In response to tactile teat stimulation, either manually or by the milking machine, milk ejection is induced by the release of oxytocin and resultant myoepithelial contraction. The time from the start of tactile stimulation until the occurrence of milk ejection spans 40 s to > 2 min and increases with a decreasing degree of udder filling. Therefore, cows need a longer prestimulation in the late stages of lactation or if the milking is performed shortly after the previous milking, whereas in full udders prestimulation is less important. Milk ejection is disturbed under several conditions, such as during milking in unfamiliar surroundings (i.e., a novel milking environment) or for several weeks immediately after parturition in primiparous cows. Disturbed milk ejection is due to a reduction of or absence of oxytocin release from the pituitary. The severity of disturbed milk ejection and the coping capacity toward a novel milking environment is related to cortisol release in response to ACTH (i.e., adrenal cortex activity). Therefore, susceptibility of individual cows to the inhibition of oxytocin release and milk ejection can be predicted by an ACTH challenge test. Comfortable surroundings, such as feeding in and lighting of the milking parlor, can increase the secretion of oxytocin. Overcoming the lack of oxytocin release by injection of exogenous oxytocin for an extended time results in a reduction of the mammary response to endogenous oxytocin. In different production systems, it has to be verified that udder stimulation is sufficient to prevent disturbed milk ejection. Different brands of automatic milking systems induce a sufficient prestimulation of the udder, even if a few minutes are needed for a successful onset of the teat clusters. Specific breeds used for less intense milk production may need the presence of their calves for sufficient oxytocin release during milking. In conclusion, in all milk production systems, the maximal possible reduction of stress has to be targeted and proper udder prestimulation must be performed for an optimal milking of the cow by the farmer. PMID- 17709780 TI - Direct and indirect selection of visceral lipid weight, fillet weight, and fillet percentage in a rainbow trout breeding program. AB - We assessed whether visceral lipid weight, fillet weight, and percentage fillet from BW, 3 traits laborious to record, could be genetically improved by indirect selection on more easily measured traits in farmed rainbow trout. Visceral lipid is discarded as waste during slaughter, influencing production efficiency and production costs. Fillet weight and fillet percentage directly influence economic returns in trout production. The study comprised 3 steps. First, we assessed the degree to which selection on percentage of visceral weight from BW indirectly changes visceral lipid weight and the size of intestines and internal organs. The phenotypic analysis of weights of viscera, intestines, visceral lipid, liver, and gonads measured from 40 fish revealed that phenotypic selection against visceral weight was most strongly directed to visceral lipid, and to a lesser degree to intestines and gonads. Because genetic relationships among these traits were not established, it is not known whether indirect selection leads to genetic responses. Second, we examined whether direct selection for the fillet traits could be replaced by indirect selection on BW, eviscerated BW, visceral weight, visceral percentage, head volume, and relative head volume (head volume relative to BW). The selection index calculations based on the quantitative genetic parameters obtained from multigenerational pedigree data showed that genetic improvement of fillet percentage through direct selection (selection accuracy, r(TI) = 0.54) was equally efficient compared with indirect selection on visceral percentage ( r(TI) = 0.54). Genetic improvement of fillet weight through direct selection (r(TI) = 0.56) was always more efficient than indirect selection, yet indirect selection for eviscerated BW ( r(TI) = 0.50) was almost as efficient as direct selection. Third, the expected genetic responses to alternative selection indices showed that improved fillet percentage was mainly a result of a moderate decrease in visceral weight rather than of a major increase in absolute fillet weight. Moreover, fillet percentage is challenging to improve, even if it exhibits moderate heritability (h(2) = 0.29). This is because fillet percentage displays low phenotypic variation. In conclusion, fillet weight and fillet percentage can be increased by indirect selection against visceral percentage and for high eviscerated BW. PMID- 17709781 TI - Effect of low vitamin A diets with high-moisture or dry corn on marbling and adipose tissue fatty acid composition of beef steers. AB - Angus-cross steers (n = 165; 295 +/- 16 kg of BW) were used evaluate the effect of low vitamin A diets with high-moisture corn (HMC) or dry corn (DC) on marbling and fatty acid composition. Steers were allotted to 24 pens (7 steers/pen), such that each pen had the same average initial BW. Treatments were randomly allotted to the pens. The experiment had a completely randomized design, with a 2 x 2 factorial arrangement of treatments: low vitamin A (Lo, no supplemental vitamin A) and HMC (LoHMC); LoDC; high vitamin A (Hi, supplemented with 2,200 IU of vitamin A/kg of DM) and HMC (HiHMC); and HiDC. Diets contained 76% corn, 10% corn silage, 11% protein supplement, and 3% soybean oil (DM basis). Samples of feed ingredients were collected for carotenoid analysis. Blood samples were collected for serum retinol determination. Steers were slaughtered after 145 d on feed. Carcass characteristics and LM composition were determined. Samples from the s.c. fat depot were analyzed for fatty acid composition. High-moisture corn had a greater vitamin A content, based on its carotenoid content, than DC (614 vs. 366 IU/kg of DM, P < 0.01). No vitamin A x corn type interactions were detected for feedlot performance, carcass characteristics, or serum, s.c. fat, or liver retinol concentration. Average daily gain, DMI, and G:F were not affected by vitamin A (P > 0.05). Marbling score and USDA quality grade were greater (P < 0.05) in Lo vs. Hi steers. Hot carcass weight, backfat, and yield grade were not affected by the treatments (P > 0.05). Vitamin A and corn type did not affect LM composition (DM, ash, CP, or ether-extractable fat, P > 0.05). Vitamin A supplementation increased (P < 0.06) serum retinol on d 112 and 145 and increased (P < 0.01) liver retinol at slaughter (Lo = 38.7 vs. Hi = 102.9 mug/g). The s.c. fat retinol concentrations were less (P < 0.01) for Lo (0.8 mug/g) than for Hi (1.4 mug/g) at slaughter. Cell diameter of adipocytes in the i.m. depot was not affected by dietary vitamin A (P > 0.05). A vitamin A x corn type interaction was observed (P < 0.05) for the s.c. fat cellularity. Feeding HMC increased the number of cells per square millimeter when Lo diets were fed (LoHMC = 128 vs. LoDC = 100 cells/mm(2), P < 0.05), but not when Hi diets were fed (HiHMC = 109 vs. HiDC = 111 cells/mm(2), P > 0.05). The CLA content of adipose tissue was not affected by the treatments. Regardless of the corn type used, feeding low vitamin A diets for 145 d to Angus-cross steers increased marbling and quality grade without affecting yield grade, animal health, or performance. PMID- 17709782 TI - Effects of supplemental ruminally degradable protein versus increasing amounts of supplemental ruminally undegradable protein on nitrogen retention, apparent digestibility, and nutrient flux across visceral tissues in lambs fed low-quality forage. AB - Two experiments were conducted to determine effects of supplemental ruminally degradable protein (RDP) vs. increasing amounts of supplemental ruminally undegradable protein (RUP) on intake, apparent digestibility, N retention, and nutrient flux across visceral tissues in lambs fed low-quality forage. Lambs were fed a basal diet of crested wheatgrass hay (4.2% CP) for ad libitum consumption, plus 1 of 4 protein supplements: isolated soy protein (RDP source) fed to meet estimated RDP requirements (CON), or corn gluten meal (RUP source) fed at 50, 100, or 150% of the supplemental N provided by CON (C50, C100, and C150, respectively). In Exp. 1, 12 lambs (29.9 +/- 2.7 kg) were used. Forage OM intake was not affected (P = 0.46) by protein degradability or by increasing RUP (P >/= 0.31). Apparent total tract OM digestibility was not affected (P = 0.10) by protein degradability, but increased (P /= 0.40) by protein degradability or level of RUP. In Exp. 2, 16 catheterized lambs (32 +/- 5 kg) were used. Net release of ammonia-N from the portal-drained viscera (PDV) was greater (P = 0.02) for CON than for C100 and increased linearly (P = 0.002) as RUP increased. Net uptake of ammonia-N by liver was not affected (P = 0.23) by protein degradability, but increased linearly (P = 0.04) as RUP increased. Net urea-N release from liver was not affected (P >/= 0.49) by protein degradability or level of RUP. Net uptake of urea-N by PDV was greater (P = 0.02) for C100 compared with CON and increased (P = 0.04) with increasing RUP. Neither net release from PDV nor hepatic uptake of alpha-amino N were affected (P >/= 0.12) by protein degradability or level of RUP. Hepatic ammonia-N uptake accounted for 82, 38, 98, and 79% of net urea-N release from the liver for CON, C50, C100, and C150, respectively. Hepatic alpha-amino N uptake for all treatments greatly exceeded that required for the remaining urea-N release by the liver, suggesting that alpha-amino N may serve as a temporary means of storing excess N by liver between supplementation events. The pattern of net release or uptake of N metabolites between supplementation events requires further investigation. PMID- 17709783 TI - Neutral detergent-soluble fiber improves gut barrier function in twenty-five-day old weaned rabbits. AB - The effect of neutral detergent-soluble fiber level on gut barrier function and intestinal microbiota was examined in weaned rabbits. A control diet (AH) containing 103 g of neutral detergent-soluble fiber/ kg of DM included alfalfa hay as main source of fiber. Another diet (B-AP) was formulated by replacing half of the alfalfa hay with a mixture of beet and apple pulp resulting in 131 g of soluble fiber/kg of DM. A third diet (OH) was obtained by substituting half of the alfalfa hay with a mix of oat hulls and a soybean protein concentrate and contained 79 g of soluble fiber/kg of DM. Rabbits weaned at 25 d and slaughtered at 35 d were used to determine ileal digestibility, jejunal morphology, sucrase activity, lamina propria lymphocytes, and intestinal microbiota. Suckling 35-d old rabbits were used to assess mucosa morphology. Mortality (from weaning to 63 d of age) was also determined. Villous height of the jejunal mucosa increased with soluble fiber (P = 0.001). Rabbits fed with the greatest level of soluble fiber (BA-P diet) showed the highest villous height/ crypt depth ratio (8.14; P = 0.001), sucrase specific activity (8,671 mumol of glucose/g of protein; P = 0.019), and the greatest ileal starch digestibility (96.8%; P = 0.002). The opposite effects were observed in rabbits fed decreased levels of soluble fiber (AH and OH diets; 4.70, 5,848 mumol of glucose/g of protein, as average, respectively). The lowest ileal starch digestibility was detected for animals fed OH diet (93.2%). Suckling rabbits of the same age showed a lower villous height/crypt depth ratio (6.70) compared with the B-AP diet group, but this ratio was higher than the AH or OH diet groups. Lower levels of soluble fiber tended (P = 0.074) to increase the cellular immune response (CD8+ lymphocytes). Diet affected IL-2 production (CD25+, P = 0.029; CD5+CD25+, P = 0.057), with no clear relationship between soluble fiber and IL-2. The intestinal microbiota biodiversity was not affected by diets (P >/= 0.38). Rabbits fed the B-AP and AH diets had a reduced cecal frequency of detection compatible with Campylobacter spp. (20.3 vs. 37.8, P = 0.074), and Clostridium perfringens (4.3 vs. 17.6%, P = 0.047), compared with the OH diet group. Moreover, the mortality rates decreased from 14.4 (OH diet) to 5.1% (B-AP diet) with the increased presence of soluble fiber in the diet. In conclusion, increased levels of dietary soluble fiber improve mucosal integrity and functionality. PMID- 17709784 TI - Intermittent suckling during an extended lactation period: effects on piglet behavior. AB - The objectives of the current study were to determine how intermittent suckling (IS) affects nursing behavior, litter activity, and general behavioral patterns during lactation, and whether IS during an extended lactation period results in behavioral patterns associated with piglet distress. Intermittent suckling was applied either with 6-h separation intervals (IS6) or with 12-h separation intervals (IS12) and was compared with the conventional treatment (CT). In the CT (n = 17 litters), sows were continuously present until weaning (d 21, d 0 = farrowing). In both IS6 and IS12, sows were separated from their litter for 12 h/d, beginning at d 14 and lasting until weaning (d 43 +/- 1 d). In IS6, litters (n = 14) and sows were separated from 0800 to 1400 and from 2000 to 0200; in IS12 litters (n = 14) and sows were separated between 0800 and 2000. In IS litters, the activity pattern over the 24-h cycle was markedly changed by IS; litter activity was lower (P < 0.001) during sow absence and greater (P < 0.001) during sow presence compared with the unweaned CT litters. Moreover, both total nursing frequency (P < 0.001) and the percentage (P < 0.002) of successful nursings were reduced by IS. Although total nursing frequency was greater in IS6 compared with IS12 (on d 21 and 28), no differences in the frequency of successful nursings existed between IS6 and IS12 from d 14 onward. Eating behavior was increased shortly after the onset of IS (d 17) in both IS6 (P = 0.059) and IS12 (P < 0.001) compared with the unweaned CT litters. The IS12 litters showed more eating behavior compared with IS6 and their exploratory behavior increased in time (P < 0.001), whereas IS6 showed more nursing behavior. Aggressive or manipulative behavior of both IS treatments was similar compared with the unweaned CT, and remained relatively unaltered with time in IS12 and IS6. Weaning in the CT resulted in more manipulative (P < 0.001) and aggressive (P = 0.004) behavior compared with pre-weaning values. Intermittent suckling may contribute to adaptation to the postweaning state by stimulating eating behavior, without causing obvious behavioral distress. PMID- 17709785 TI - Factors affecting the selling price of feeder cattle sold at Arkansas livestock auctions in 2005. AB - Data were collected from 15 Arkansas livestock auctions to determine factors affecting selling price. Data included how calves were sold (single or groups), sex, breed or breed type, color, muscle thickness, horn status, frame score, fill, body condition, age, health, BW, and price. Data were randomly collected on 52,401 lots consisting of 105,542 calves. Selling prices for steers ($124.20 +/- 0.07), bulls ($117.93 +/- 0.12), and heifers ($112.81 +/- 0.07) were different from each other (P <0.001). Hereford x Charolais feeder calves sold for the highest price ($122.66 +/- 0.14) and Longhorns sold for the lowest price ($74.52 +/- 0.46). Yellow feeder cattle received the highest selling price ($96.47 +/- 0.12), and spotted or striped feeder cattle received the lowest price ($83.84 +/- 0.23). The selling price of singles was lower than the price for calves sold in groups of 6 or more ($117.26 +/- 0.06 vs. $122.61 +/- 0.21; P <0.001). For cattle classified as having muscle scores of 1, 2, 3, and 4, selling prices were $120.45 +/- 0.05, $111.31 +/- 0.09, $96.28 +/- 0.44, and $82.21 +/- 1.87, respectively. Polled feeder cattle sold for $118.57 +/- 0.05, and horned feeder cattle sold for $114.87 +/- 0.14 (P <0.001). Interactions (P <0.001) were detected between frame score and BW groups, and muscle score and BW groups on the selling price of cattle. A number of management and genetic factors affected the selling price of feeder cattle. PMID- 17709786 TI - Interleukin-15: a muscle-derived cytokine regulating fat-to-lean body composition. AB - An increasing body of literature links immune and inflammatory factors to modulation of growth and control of fat:lean body composition. Recent progress in understanding the control of body composition has been made through identification of inflammatory cytokines and other factors produced by adipose tissue that affect body composition, often by direct effects on skeletal muscle tissue. Adipose-derived factors such as leptin, tumor necrosis factor-alpha, resistin, and adiponectin have been shown to affect muscle metabolism, protein dynamics, or both, by direct actions. This review summarizes recent results that support the existence of a reciprocal muscle-to-fat signaling pathway involving release of the cytokine IL-15 from muscle tissue. Cell culture studies, short term in vivo studies, and human genotype association studies all support the model that muscle-derived IL-15 can decrease fat deposition and adipocyte metabolism via a muscle-to-fat endocrine pathway. Fat:lean body composition is an important factor determining the efficiency of meat production, as well as the fat content of meat products. Modulation of the IL-15 signaling axis may be a novel mechanism to affect body composition in meat animal production. PMID- 17709787 TI - Genetic relationships of body composition and feed utilization traits in European whitefish (Coregonus lavaretus L.) and implications for selective breeding in fishmeal- and soybean meal-based diet environments. AB - Body composition traits have potential use in fish breeding programs as indicator traits for selective improvement of feed efficiency. Moreover, feed companies are increasingly replacing traditional fish meal (FM) based ingredients in feeds for carnivorous farmed fish with plant protein ingredients. Therefore, genetic relationships of composition and feed utilization traits need to be quantified for both current FM-based and future plant-based aquaculture feeds. Individual whole-body lipid% and protein%, daily gain (DG), ADFI, and G:F (daily gain/daily feed intake) were measured on 1,505 European whitefish (Coregonus lavaretus) from 70 half/full-sib families reared in a split-family design with either a typical FM or a novel soybean meal (SBM) based diet. Diet-specific genetic parameters were estimated with multiple-trait animal models. Lipid% was significantly greater in the FM diet group than in the SBM group, even independent of final BW or total feed intake. In both diets, lipid% showed moderate heritability (0.12 to 0.22) and had positive phenotypic and genetic correlations with DG (0.37 to 0.82) and ADFI (0.36 to 0.88). Therefore, selection against lipid% can be used to indirectly select for lower feed intake. Protein% showed low heritability (0.05 to 0.07), and generally very weak or zero correlations with DG and ADFI. In contrast to many previous studies on terrestrial livestock, lipid% showed zero or very weak phenotypic and genetic correlations with G:F. However, selection index calculations demonstrated that simultaneous selection for high DG and reduced lipid% could be used to indirectly increase G:F; this strategy increased absolute genetic response in G:F by a factor of 1.5 to 1.6 compared with selection on DG alone. Lipid% and protein% were not greatly affected by genotype-diet environment interactions, and therefore, selection strategies for improving body composition within current FM diets should also improve populations for future SBM diets. PMID- 17709789 TI - Effects of energy, mineral supplementation, or both, in combination with monensin on performance of steers grazing winter wheat pasture. AB - A 2-yr study was conducted during the 2004 to 2005 (YR1) and 2005 to 2006 (YR2) winter wheat grazing seasons to determine the effects of supplementation strategies and delivery methods on supplement intake and growth performance of grazing steers (YR1, n = 253, initial BW 255 +/- 25 kg; YR2, n = 116, initial BW 287 +/- 14 kg). The 5 treatments were as follows: 1) negative control (NC), no supplemental nutrients; 2) free-choice, nonmedicated mineral (MIN); 3) free choice, medicated mineral with 1,785 mg of monensin/kg of mineral mixture (RMIN); 4) RMIN and soybean hulls (SH-RMIN); and 5) a soybean hull-based energy supplement containing 165 mg of monensin/kg (GRNGOLD). Energy supplements were hand-fed on alternate days (average daily intake = 0.91 kg/steer). Inclusion of monensin in the free-choice mineral mixture decreased intake of the mineral mixture by 63% in YR1 and 55% in YR2 when no other supplement was offered. Consumption of RMIN provided from 129 to 161 mg of monensin/steer on average, whereas GRNGOLD provided 150 mg of monensin/d. Compared with NC, MIN did not affect ADG in YR1 (P = 0.38) but increased (P = 0.01) ADG by 0.22 kg/steer in YR2. Conversely, ADG of RMIN steers was greater (P = 0.03) than that of MIN steers during YR1 (0.72 vs. 0.55 kg/steer) but not different (P = 0.35) in YR2. Providing supplemental energy increased ADG by 0.13 kg/steer (0.85 vs. 0.72 +/- 0.053) in YR1 compared with RMIN, but no increase in ADG was observed in YR2. No difference (P > 0.24) was observed in ADG between SH-RMIN and GRNGOLD in either year. Conversion of the energy supplements (kg of as-fed supplement divided by kg of additional ADG) was excellent in YR1, resulting in 1 kg of BW gain for each 3.1 kg of supplement consumed. However, due to smaller increases in ADG with the energy and monensin supplements in YR2, supplement conversion for YR2 averaged 17.6. The absence of a difference (P > 0.24) in ADG between steers that received SH-RMIN and GRNGOLD suggests that the method of delivery (separate packages vs. a single package) for energy, monensin, and mineral supplementation is not important. PMID- 17709788 TI - Effects of supplemental ruminally degradable protein versus increasing amounts of supplemental ruminally undegradable protein on site and extent of digestion and ruminal characteristics in lambs fed low-quality forage. AB - Four ruminally and duodenally cannulated Suffolk wether lambs (34.5 +/- 2 kg initial BW) were used in a 4 x 4 Latin square designed experiment to compare effects of supplemental ruminally degradable protein (RDP) vs. increasing amounts of supplemental ruminally undegradable protein (RUP) on ruminal characteristics and site and extent of digestion in lambs. Lambs were fed a basal diet of crested wheatgrass hay (4.2% CP) for ad libitum consumption, plus 1 of 4 protein supplements: isolated soy protein (RDP source) fed to meet estimated RDP requirements assuming a microbial efficiency of 11% of TDN (CON) or corn gluten meal (RUP source) fed at 50, 100, or 150% of the supplemental N provided by CON (C50, C100, and C150, respectively). Neither NDF nor ADF intake was affected (P >/= 0.18) by protein degradability, but they increased or tended to increase (P /= 0.26) for CON and C100, but increased (P /= 0.33) by protein degradability. However, true ruminal N digestibility was greater (P = 0.03) for CON compared with C100. Ruminal ammonia concentrations were greater (P = 0.002) for CON compared with C100 lambs, and increased (P = 0.001) with increasing RUP. Microbial N flows were not affected (P >/= 0.12) by protein degradability or increasing RUP. Likewise, neither ruminal urease activity (P >/= 0.11) nor microbial efficiency (P >/= 0.50) were affected by protein degradability or level of RUP. Total tract OM, NDF, and ADF digestibility was greater (P .05) in sensitivity or specificity between the two techniques for the detection of polyps 6 mm or larger, whereas the median review time with virtual dissection was significantly (P<.05) shorter. This may have implications for the application of computed tomographic (CT) colonography for screening the asymptomatic average-risk population. PMID- 17709821 TI - Is MR-guided attenuation correction a viable option for dual-modality PET/MR imaging? PMID- 17709822 TI - The practice of ethics in the era of evidence-based radiology. AB - Various methods to provide an ethical conscience in the modern practice of radiology are available, but they all require time and effort. Although this is part of a series dedicated to evidence-based radiology (EBR), this article cannot provide recommendations supported by evidence. However, the method we propose is inspired from the analytic process found in EBR. It emphasizes autonomous reflection; systematic identification of roles, motives, and consequences of current actions and organizations; clarification of aims and means; selection of principles and values; and equilibration, application, and validation. This personal process is followed by the search for common values shared by the group, in a rational, scientific context centered on preserving the patient-physician relationship. This method entails constant vigilance and repeated revisions, but the allowance of time to think about ethical matters can decrease confusion and moral perplexity. The result is a stronger moral personal identity and a brighter horizon for a satisfying professional life. PMID- 17709823 TI - Molecular imaging: integration of molecular imaging into the musculoskeletal imaging practice. AB - Chronic musculoskeletal diseases such as arthritis, malignancy, and chronic injury and/or inflammation, all of which may produce chronic musculoskeletal pain, often pose challenges for current clinical imaging methods. The ability to distinguish an acute flare from chronic changes in rheumatoid arthritis, to survey early articular cartilage breakdown, to distinguish sarcomatous recurrence from posttherapeutic inflammation, and to directly identify generators of chronic pain are a few examples of current diagnostic limitations. There is hope that a growing field known as molecular imaging will provide solutions to these diagnostic puzzles. These techniques aim to depict, noninvasively, specific abnormal cellular, molecular, and physiologic events associated with these and other diseases. For example, the presence and mobilization of specific cell populations can be monitored with molecular imaging. Cellular metabolism, stress, and apoptosis can also be followed. Furthermore, disease-specific molecules can be targeted, and particular gene-related events can be assayed in living subjects. Relatively recent molecular and cellular imaging protocols confirm important advances in imaging technology, engineering, chemistry, molecular biology, and genetics that have coalesced into a multidisciplinary and multimodality effort. Molecular probes are currently being developed not only for radionuclide-based techniques but also for magnetic resonance (MR) imaging, MR spectroscopy, ultrasonography, and the emerging field of optical imaging. Furthermore, molecular imaging is facilitating the development of molecular therapies and gene therapy, because molecular imaging makes it possible to noninvasively track and monitor targeted molecular therapies. Implementation of molecular imaging procedures will be essential to a clinical imaging practice. With this in mind, the goal of the following discussion is to promote a better understanding of how such procedures may help address specific musculoskeletal issues, both now and in the years ahead. PMID- 17709824 TI - Current status of breast MR imaging. Part 2. Clinical applications. AB - Magnetic resonance (MR) imaging is emerging as the most sensitive modality that is currently available for the detection of primary or recurrent breast cancer. Although this technique has been shown to be an extremely powerful diagnostic tool, it is still relatively rarely used in clinical practice, as compared with other applications of MR imaging such as for musculoskeletal or brain and spine imaging. This is the second of a two-part series on the current status of breast MR. Part two provides an overview of the use of breast MR imaging in clinical patient care, the body of evidence that supports its use. A discussion is provided on the many controversies that exist regarding breast MR imaging for preoperative staging and for screening. PMID- 17709825 TI - Body and cardiovascular MR imaging at 3.0 T. AB - Potential advantages of magnetic resonance (MR) imaging at 3 T include higher signal-to-noise ratios, better image contrast, particularly in gadolinium enhanced applications, and better spectral separation for spectroscopic applications. In terms of clinical imaging, these advantages can mean higher spatial-resolution images, faster imaging, and improved MR spectroscopy. However, achieving superior imaging and spectroscopic quality at 3 T can be challenging. This review discusses many of the problems encountered in body and cardiovascular MR imaging at 3 T, such as increased susceptibility, B1 field inhomogeneity, and increased specific absorption rate. The article also considers solutions that are being pursued, such as parallel imaging, variable-rate selective excitation, and variable flip angle sequences. A review of the most commonly used pulse sequences provides practical tips on how these can be optimized for 3-T imaging. In the coming few years, substantial improvements in 3-T technology for clinical imaging and spectroscopy will undoubtedly be seen. An understanding of the basic principles on which these developments are based will help radiologists translate the advances into better imaging studies and, ultimately, better patient care. PMID- 17709826 TI - Randomized trial of screen-film versus full-field digital mammography with soft copy reading in population-based screening program: follow-up and final results of Oslo II study. AB - PURPOSE: To prospectively compare performance indicators at screen-film mammography (SFM) and full-field digital mammography (FFDM) in a population-based screening program. MATERIALS AND METHODS: The regional ethics committee approved the study; informed consent was obtained from patients. Women aged 45-69 years were assigned to undergo SFM (n=16 985) or FFDM (n=6944). Two-view mammograms were interpreted by using independent double reading and a five-point rating scale for probability of cancer. Positive scores were discussed at consensus meetings before decision for recall. The group was followed up for 1.5 years (women aged 45-49 years) and 2.0 years (women aged 50-69 years) to include subsequent cancers with positive scores at baseline interpretation and to estimate interval cancer rate. Recall rates, cancer detection, positive predictive values (PPVs), sensitivity, specificity, tumor characteristics, and discordant interpretations of cancers were compared. RESULTS: Recall rate was 4.2% at FFDM and 2.5% at SFM (P<.001). Cancer detection rate was 0.59% at FFDM and 0.38% at SFM (P=.02). There was no significant difference in PPVs. Median size of screening-detected invasive cancers was 14 mm at FFDM and 13 mm at SFM. Including cancers dismissed at consensus meetings, overall true-positive rate at baseline reading was 0.63% at FFDM and 0.43% at SFM (P=.04). Sensitivity was 77.4% at FFDM and 61.5% at SFM (P=.07); specificity was 96.5% and 97.9%, respectively (P<.005). Interval cancer rate was 17.4 at FFDM and 23.6 at SFM. The proportion of cancers with discordant double readings was comparable at FFDM and SFM. CONCLUSION: FFDM resulted in a significantly higher cancer detection rate than did SFM. The PPVs were comparable for the two imaging modalities. PMID- 17709828 TI - Renal cyst pseudoenhancement: influence of multidetector CT reconstruction algorithm and scanner type in phantom model. AB - PURPOSE: To prospectively determine the dependence of renal cyst pseudoenhancement on multidetector computed tomographic (CT) scanner type and convolution kernel in a phantom model. MATERIALS AND METHODS: A customized anthropomorphic phantom was created to accept interchangeable 40-, 140-, and 240 HU renal inserts that contained stacked 0- and 50-HU cylindric cysts measuring 7, 10, and 15 mm in diameter. Each phantom and insert was scanned with five different multidetector CT scanners on five separate occasions by using 120 kVp, low and high tube current settings, 3.00-3.75-mm collimation, and standard and high-spatial-resolution kernels. A total of 2340 CT attenuation measurements were obtained by using standardized regions of interest. The effect of multidetector CT imaging regimen, tube current, cyst diameter, and renal attenuation on pseudoenhancement incidence was assessed by using generalized estimating equations based on a binary logistic regression model. Within this framework, a Bonferroni multiple comparison correction was used to assess pseudoenhancement frequency differences among imaging regimens. RESULTS: Pseudoenhancement occurred in both 0- and 50-HU cysts; was significantly correlated with multidetector CT imaging regimen (P<.0001), cyst diameter (P<.0001), and renal attenuation (P.3). When convolution kernels on specific scanners were compared, significant differences (P<.04) between kernels were identified with all five scanners in terms of observed pseudoenhancement incidence. Generational differences in equipment were noted, with pseudoenhancement incidence ranging from 1.7% to 8.3%, 1.7% to 16.7%, and 18.3% to 56.7% across relevant kernels for three scanners from one manufacturer. CONCLUSION: Pseudoenhancement is strongly dependent on multidetector CT convolution kernel. Varying this parameter may mitigate this phenomenon, which is independent of volume-averaging effects. PMID- 17709827 TI - Inflammatory breast cancer: dynamic contrast-enhanced MR in patients receiving bevacizumab--initial experience. AB - PURPOSE: To retrospectively compare three dynamic contrast material-enhanced magnetic resonance (MR) imaging (dynamic MR imaging) analytic methods to determine the parameter or combination of parameters most strongly associated with changes in tumor microvasculature during treatment with bevacizumab alone and bevacizumab plus chemotherapy in patients with inflammatory or locally advanced breast cancer. MATERIALS AND METHODS: This study was conducted in accordance with the institutional review board of the National Cancer Institute and was compliant with the Privacy Act of 1974. Informed consent was obtained from all patients. Patients with inflammatory or locally advanced breast cancer were treated with one cycle of bevacizumab alone (cycle 1) followed by six cycles of combination bevacizumab and chemotherapy (cycles 2-7). Serial dynamic MR images were obtained, and the kinetic parameters measured by using three dynamic analytic MR methods (heuristic, Brix, and general kinetic models) and two region of-interest strategies were compared by using two-sided statistical tests. A P value of .01 was required for significance. RESULTS: In 19 patients, with use of a whole-tumor region of interest, the authors observed a significant decrease in the median values of three parameters measured from baseline to cycle 1: forward transfer rate constant (Ktrans) (-34% relative change, P=.003), backflow compartmental rate constant extravascular and extracellular to plasma (Kep) (-15% relative change, P<.001), and integrated area under the gadolinium concentration curve (IAUGC) at 180 seconds (-23% relative change, P=.009). A trend toward differences in the heuristic slope of the washout curve between responders and nonresponders to therapy was observed after cycle 1 (bevacizumab alone, P=.02). The median relative change in slope of the wash-in curve from baseline to cycle 4 was significantly different between responders and nonresponders (P=.009). CONCLUSION: The dynamic contrast-enhanced MR parameters Ktrans, Kep, and IAUGC at 180 seconds appear to have the strongest association with early physiologic response to bevacizumab. Clinical trial registration no. NCT00016549 PMID- 17709829 TI - CT in the evaluation of nontraumatic abdominal pain in pregnant women. AB - PURPOSE: To retrospectively determine sensitivity and specificity of computed tomography (CT) for the diagnosis of appendicitis in pregnant women with nontraumatic abdominal pain and retrospectively compare findings at CT and ultrasonography (US) in patients who underwent both examinations, with surgery or clinical follow-up as a reference standard. MATERIALS AND METHODS: Institutional review board approval was obtained, and the study was HIPAA compliant. Informed consent was waived. Findings of 80 consecutive CT examinations performed in 78 pregnant women (mean age, 25.9 years; range, 17-43 years) for abdominal pain between September 2000 and October 2004 were compared with findings at prior US (n=52), surgery, and clinical follow-up. Sensitivity and specificity were calculated for the diagnosis of appendicitis. The average fetal radiation dose was 16 mGy (1.6 rad) (range, 4-45 mGy [4-4.5 rad]). RESULTS: CT findings were normal in 51 examinations (64%) and abnormal in 29 (36%). Abnormal findings were appendicitis (n=13), urinary tract calculi (n=6), small-bowel obstruction (n=2), cholelithiasis (n=2), pyelonephritis (n=2), diaphragmatic hernia (n=1), cecal bascule (n=1), ileus (n=1), and metastatic lymphadenopathy (n=1). One surgically confirmed case of appendicitis was not detected at CT. For diagnosis of appendicitis, sensitivity of CT was 92% (12 of 13 examinations), specificity was 99% (66 of 67), and negative predictive value was 99% (66 of 67). Fifty-two CT studies were performed after US. US findings were normal in 46 patients (88%) and abnormal in six (12%). Abnormal findings were cholelithiasis (n=3), obstructive hydronephrosis (n=1), small-bowel dilatation (n=1), and appendicitis (n=1). Among 46 patients with normal US findings, CT findings were abnormal in 14, nine of whom required surgery. CT added important diagnostic information in 14 of 46 patients (30%). CONCLUSION: CT findings established the diagnosis in 35% of examinations in pregnant women with abdominal pain (28 of 80), with a negative predictive value of 99% for appendicitis; when CT followed negative US findings, CT findings established the diagnosis in 30% of patients. PMID- 17709830 TI - PET/MR images acquired with a compact MR-compatible PET detector in a 7-T magnet. AB - PURPOSE: To prospectively use compact avalanche photodiodes instead of photomultiplier tubes to integrate a positron emission tomographic (PET) detector and a 7-T magnetic resonance (MR) imager. MATERIALS AND METHODS: All animal experiments were performed in accordance with the University of Tubingen guidelines and the German law for the protection of animals. A compact lutetium oxyorthosilicate-avalanche photodiode PET detector was built and optimized to operate within a 7-T MR imager. The detector performance was investigated both outside and inside the magnet, and MR image quality was evaluated with and without the PET detector. Two PET detectors were set up opposite each other and operated in coincidence to acquire PET images in the step-and-shoot mode in a mouse head specimen after injection of fluorine 18 fluorodeoxyglucose. RESULTS: The performance of the PET detector when operated inside the magnet during MR image acquisition showed little degradation in energy resolution (increase from 14.6% to 15.9%). The PET detector did not influence MR imaging. The fused PET and MR images showed an anatomic match and no degradation of image quality. CONCLUSION: Simultaneous PET and MR imaging with a 7-T system was deemed feasible. PMID- 17709831 TI - Quantitative magnetization transfer imaging in Alzheimer disease. AB - PURPOSE: To prospectively measure magnetization transfer (MT) parameters, along with established atrophy parameters, in patients with Alzheimer disease (AD) and in age- and sex-matched control subjects. MATERIALS AND METHODS: Participants provided informed consent, and additional assent was obtained from next of kin of all patients with AD. The study was approved by the local ethics committee. Fourteen patients with AD (seven men; mean age, 67.2 years+/-6.5 [standard deviation]) and 14 control subjects (nine men; mean age, 65.5 years+/-9.4) underwent volumetric T1-weighted magnetic resonance and MT imaging. Whole-brain and total hippocampal volumes were adjusted for total intracranial volume. MT images were processed to derive four fundamental parameters in the hippocampal region by using the two-pool model of the MT phenomenon. Pearson correlation coefficients were used to assess the association between volumetric and MT parameters and Mini-Mental State Examination (MMSE) results. Logistic regression models were used to investigate whether combinations of parameters associated with MMSE could help provide better group discrimination. RESULTS: Patients with AD had significantly reduced whole-brain (P=.001) and total hippocampal (P<.001) volumes compared with those of control subjects. Two MT parameters were significantly reduced in the hippocampal region of patients: 1/(RAT2A)--that is, ratio of relaxation times of free proton pool, where RA equals 1/T1A and is the inverse of the longitudinal relaxation time of the free proton pool (P=.01)--and f*b, which equals fb/[RA(1-fb)], where fb is the restricted proton fraction (P<.001). Among patients with AD, whole-brain volume and hippocampal were correlated with MMSE results. When both parameters were included in a logistic regression model, only hippocampal was significantly associated with case-control status (P=.03). CONCLUSION: Certain MT parameters may serve as useful biomarkers of AD. PMID- 17709832 TI - Biliary atresia: US diagnosis. AB - PURPOSE: To evaluate prospectively the sensitivity of ultrasonography (US) in the diagnosis of biliary atresia (BA), with surgery as the reference standard. MATERIALS AND METHODS: After institutional ethical approval and with informed parental consent, 90 consecutive fasting infants with conjugated hyperbilirubinemia underwent detailed US studies performed by a single operator with a 7.5-MHz curvilinear transducer and a 13.5-MHz linear-array transducer. The following features were prospectively recorded: gallbladder morphology, triangular cord sign, presence of a common bile duct, liver size and echotexture, splenic appearance, and vascular anatomy. The operator was blinded to results of other investigations. Sensitivity, specificity, and positive and negative predictive values were calculated for each US variable. BA and non-BA groups were compared by means of the Fisher exact test for categorical variables and an unpaired t test for continuous variables. RESULTS: Thirty infants (13 male, 17 female) had surgically confirmed BA, and 60 (35 male, 25 female) had other documented causes of neonatal jaundice; the mean ages at US assessment were 48.5 and 52.4 days, respectively (P>.5). Eight US features showed a significant difference between BA and non-BA groups (P<.001, Fisher exact test). The features with the greatest individual sensitivity and specificity, respectively, in the diagnosis of BA were triangular cord sign (73% and 100%), abnormal gallbladder wall (91% and 95%) and shape (70% and 100%), and an absent common bile duct (93% and 92%). The hepatic artery diameter was significantly larger in infants with BA than in those without BA (mean+/-standard deviation, 2.2 mm+/-0.59 vs 1.6 mm+/ 0.40, P<.001), but portal vein diameters were not significantly different. By means of all these US features, 88 of 90 infants were correctly classified as having or not having BA, for an overall accuracy of 98%. CONCLUSION: BA can be distinguished with US from other causes of conjugated hyperbilirubinemia in 98% of infants if multiple US features are carefully evaluated. PMID- 17709833 TI - Two- versus three-dimensional colon evaluation with recently developed virtual dissection software for CT colonography. AB - This retrospective study was institutional review board approved; the requirement for informed patient consent was waived. The purpose of this study was to retrospectively compare a two-dimensional (2D) data interpretation technique with a three-dimensional (3D) colon dissection technique in terms of interpretation time and sensitivity for colonic polyp detection, with colonoscopy as the reference standard. Ninety-six patients (56 men, 40 women; mean age, 54.8 years) underwent colonoscopy and multidetector computed tomographic (CT) colonography on the same day. Two radiologists independently analyzed the data on a per-polyp and per-patient basis. The sensitivity of both approaches was compared by using the McNemar test. The time required to interpret CT colonographic data with each technique was also assessed. Compared with the conventional 2D colonic polyp detection method, primary 3D interpretation with use of virtual dissection software for CT colonography revealed comparable per-polyp (77% and 69% for two readers) and per-patient (77% and 73% for two readers) sensitivities and comparable per-patient specificity (99% and 89% for two readers) for the detection of polyps 6 mm in diameter or larger and involved a shorter interpretation time. PMID- 17709834 TI - Is It possible to recognize pulmonary infarction on multisection CT images? AB - PURPOSE: To retrospectively determine sensitivity and specificity of four findings for distinguishing pulmonary infarction from other causes of peripheral pulmonary consolidations on multidetector computed tomographic (CT) images, with other CT and clinical findings as reference. MATERIALS AND METHODS: Institutional review board approved the study and waived informed consent. Three independent radiologists blindly analyzed selected multisection CT images of 50 pulmonary infarctions-not showing direct arterial signs of pulmonary embolism-and 100 peripheral consolidations of other origins. Readers analyzed four findings: triangular shape, vessel sign (defined as presence of an enlarged vessel at the apex of consolidation), central lucencies, and air bronchograms. Interobserver agreement; frequency on CT images with and without infarct; and sensitivity, specificity, and positive likelihood ratio (LR) for diagnosis of pulmonary infarction were assessed for each finding. RESULTS: One hundred fifty peripheral consolidations were analyzed in 134 (75 men, 59 women) patients (mean age, 55.9 years+/-17.4 [standard deviation] vs 54.7+/-19.9; P=.71). Interobserver agreement was good for central lucencies and air bronchograms and poor to moderate for the other two findings (kappa<0.61). Compared with CT images without infarct, CT images with infarct had a higher frequency of vessel sign (32% [16 of 50] vs 11% [11 of 100], P=.029) and central lucencies (46% [23 of 50] vs 2% [two of 100], P<.001) and a lower frequency of air bronchograms (8% [four of 50] vs 40% [40 of 100], P=.003). Frequency of triangular shape was similar in both groups (52% [26 of 50] vs 40% [40 of 100], P=.17). Positive LR was 23.0 for central lucencies, 2.9 for vessel sign, 1.3 for triangular shape, and 0.2 for air bronchograms. Presence of central lucencies had 98% specificity and 46% sensitivity for pulmonary infarction. When the vessel sign and negative air bronchogram were combined with central lucencies, specificity increased to 99% but sensitivity decreased to 14%. CONCLUSION: Central lucencies in peripheral consolidations are highly suggestive of pulmonary infarction. PMID- 17709835 TI - Monitoring of smoking-induced emphysema with CT in a lung cancer screening setting: detection of real increase in extent of emphysema. AB - PURPOSE: To retrospectively establish the minimum increase in emphysema score (ES) required for detection of real increased extent of emphysema with 95% confidence by using multi-detector row computed tomography (CT) in a lung cancer screening setting. MATERIALS AND METHODS: The study was a substudy of the NELSON project that was approved by the Dutch Ministry of Health and the ethics committee of each participating hospital, with patient informed consent. For this substudy, original approval and informed consent allowed use of data for future research. Among 1684 men screened with low-dose multi-detector row CT (30 mAs, 16 detector rows, 0.75-mm section thickness) between April 2004 and March 2005, only participants who underwent repeat multi-detector row CT with the same scanner after 3 months because of an indeterminate pulmonary nodule were included. Extent of emphysema was considered to remain stable in this short period. Extent of low attenuation areas representing emphysema was computed for repeat and baseline scans as percentage of lung volume below three attenuation threshold values (-910 HU, -930 HU, -950 HU). Limits of agreement were determined with Bland-Altman approach; upper limits were used to deduce the minimum increase in ES required for detecting increased extent of emphysema with 95% probability. Factors influencing the limits of agreement were determined. RESULTS: In total, 157 men (mean age, 60 years) were included in the study. Limits of agreement for differences in total lung volume between repeat and baseline scans were -13.4% to +12.6% at -910 HU, -4.7% to +4.2% at -930 HU, and -1.3% to +1.1% at -950 HU. Differences in ES showed weak to moderate correlation with variation in level of inspiration (r=0.20-0.49, P<.05). Scanner calibration could be excluded as a factor contributing to variation in ES. CONCLUSION: Increase in ES required to detect increased extent of smoking-related emphysema with 95% probability varies between 1.1% of total lung volume at -950 HU and 12.6% at -910 HU for low-dose multi-detector row CT. Clinical trial registration no. ISRCTN63545820. PMID- 17709836 TI - Enhancement patterns of hepatocellular carcinoma at contrast-enhanced US: comparison with histologic differentiation. AB - PURPOSE: To retrospectively compare the arterial and portal venous phase enhancement patterns of hepatocellular carcinoma (HCC) at contrast material enhanced ultrasonography (US) with the degree of HCC histologic differentiation. MATERIALS AND METHODS: This study was approved by the research ethics board, and informed consent was obtained. The study population included 112 consecutive patients (91 men, 21 women; aged 25-86 years) with 112 histologically proved HCCs: 23 well differentiated, 77 moderately differentiated, and 12 poorly differentiated. All underwent continuous real-time low-mechanical-index contrast enhanced US from wash-in of contrast material to 300 seconds by using a blood pool microbubble agent. Initial image interpretation included arterial enhancement, dysmorphic intratumor arteries, and presence and time of negative enhancement (washout). Enhancement patterns were compared with histologic differentiation by using the Fisher exact test. RESULTS: In the arterial phase, 97 of 112 (87%) HCCs showed hypervascularity, with a significantly higher proportion in moderately differentiated HCCs (74 of 77, 96%) when compared with well- (14 of 23, 61%; P<.001) and poorly differentiated HCC (nine of 12, 75%; P<.004). Eight of 112 (7%) were isovascular and seven (6%) were hypovascular. Dysmorphic arteries were seen in 81 (72%) HCCs. Of 97 hypervascular tumors, only 42 (43%) showed typical washout by 90 seconds. Late washout appeared in 25 (26%) HCCs in the 91-180 seconds phase and in 21 (22%) in the 181-300 seconds phase. The remaining nine showed no washout up to 300 seconds and seven (78%) were well differentiated HCCs. CONCLUSION: Moderately differentiated HCC generally shows classic enhancement features, while well- and poorly differentiated tumors account for most atypical variations. Extended observation in the portal phase is important as late washout occurs with slightly more frequency than washout in the conventionally defined portal venous phase. PMID- 17709837 TI - Intraindividual comparison of high-spatial-resolution abdominal MR angiography at 1.5 T and 3.0 T: initial experience. AB - PURPOSE: To prospectively compare three-dimensional (3D) contrast material enhanced abdominal magnetic resonance (MR) angiography at 1.5 and 3.0 T intraindividually in healthy volunteers. MATERIALS AND METHODS: After institutional review board approval and informed consent were obtained, 15 healthy male volunteers (age range, 24-41 years) underwent one abdominal 3D contrast-enhanced MR angiographic examination each at 1.5 and 3.0 T in random order. Fast 3D gradient-echo sequence with parallel imaging acceleration factor of three was used for MR angiography; acquired spatial resolutions were 1x0.8x1 mm3 (imaging time, 19 seconds) at 1.5 T and 0.9x0.8x0.9 mm3 (imaging time, 18 seconds) at 3.0 T. With the latter, volume of the 3D slab was 8% larger. At 1.5 T, 20-mL bolus of gadobenate dimeglumine was delivered at 2 mL/sec; at 3.0 T, 15 mL bolus was delivered at 2.5 mL/sec. Two blinded radiologists rated image quality of aorta and proximal renal arteries in consensus with five-point scale (4=very good, 0=nondiagnostic) according to sequence and in direct intraindividual comparison. Visibility of proximal and segmental renal arteries was rated with three-point scale (3=completely visible, 1=nonvisible). Signal-to noise ratio (SNR) was determined with phantoms. For statistical analysis of the SNRs, t tests were used. RESULTS: All MR angiographic measurements were diagnostic. Median score for image quality at both field strengths was 4. Depiction of proximal renal arteries was rated 3 at both field strengths. The visibility of the distal renal arteries was better at 3.0 T (median score, 3) than at 1.5 T (median score, 2). With direct comparison, 3.0-T MR angiography was better in 14 of 15 cases; no field strength was preferred in the other case. Mean SNR was significantly (P<.001) higher at 3.0 T (17.8+/-0.09 [standard deviation]) than at 1.5 T (11.9+/-0.10). CONCLUSION: MR angiography at 3.0 T provided better vessel visibility and SNR than did that at 1.5 T, although voxel size and imaging time were reduced. PMID- 17709840 TI - Case 120: ischemic colitis limited to the cecum. PMID- 17709841 TI - Case 121: familial adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing syndrome. PMID- 17709842 TI - The pronator quadratus sign. PMID- 17709843 TI - Effect of B1 inhomogeneity on breast MR imaging at 3.0 T. PMID- 17709845 TI - Pulmonary arteriovenous malformations treated with embolotherapy. PMID- 17709844 TI - Are patients with moderate renal failure at risk for developing nephrogenic systemic fibrosis? PMID- 17709846 TI - Differential diagnosis of spinal epidural meningioma and hemangioma at MR imaging. PMID- 17709847 TI - Immediate interlocking nailing versus external fixation followed by delayed interlocking nailing for Gustilo type IIIB open tibial fractures. AB - PURPOSE: To compare immediate interlocking nailing with external fixation followed by delayed interlocking nailing, for Gustilo type IIIB open tibial fractures. METHODS: 23 patients with Gustilo IIIB open tibial fractures were treated with either immediate unreamed interlocking nailing (n=9) or external fixation followed by delayed unreamed interlocking nailing (n=14). Patient age, sex ratio, fracture site, fracture type, and severity were similar in both groups. The time to union, deep infection rate, and nonunion rate in the 2 groups were compared. RESULTS: In the immediate and delayed nailing groups, respective mean times to union were 21 (standard deviation [SD], 14) months and 14 (SD, 8) months; nonunion rates were 44% (4/9) and 36% (5/14), and deep infection rates were 22% (2/9) and 7% (1/14). All corresponding differences were not statistically significant. CONCLUSION: Prospective, randomised, multicentre studies are needed to assess whether there are significant differences between the 2 treatment methods. PMID- 17709848 TI - Small wire external fixation for high-energy tibial plateau fractures. AB - PURPOSE: To assess results of small wire external fixation using a ligamentotaxis technique for high-energy tibial plateau fractures. METHODS: Between April 2002 and May 2004, 38 consecutive patients aged 21 to 60 (mean, 32) years underwent small wire external fixation for high-energy tibial plateau fractures. 15 involved the right and 23 the left knee. 34 were closed and 4 were open injuries. Fractures were classified according to Schatzker's staging system. After a minimal of 2 years' follow-up (range, 24-42 months), each affected knee was evaluated using Rasmussen's (1) 30-point clinical grading system and (2) radiological evaluation. RESULTS: There were 22 type-VI and 16 type-V Schatzker tibial plateau fractures. Complications consisted of: 2 superficial infections, 3 pin site infections, and 4 peroneal nerve palsies. No soft tissue necrosis or devitalisation occurred. The mean range of knee movement was 132 degrees. The mean Rasmussen radiological score was 14 (range, 10-18): excellent in 6, good in 26, and fair in 6. The mean Rasmusssen functional score was 26 (range, 17-30): excellent in 19 patients, good in 17, and fair in 2. Clinical results did not parallel the radiological results. CONCLUSION: Small wire external fixation allows anatomical reconstruction of the articular surface, stable fixation of fracture fragments, early movement of the joint, and care of associated soft tissue injuries, without a high rate of complications. PMID- 17709849 TI - Osteosynthesis for intra-articular calcaneal fractures. AB - PURPOSE: To correlate treatment results of intra-articular calcaneal fractures with their computed tomographic (CT) classification. METHODS: 36 men and 4 women with 48 intra-articular calcaneal fractures (8 bilateral) underwent open reduction and internal fixation with bone grafting via an extensile lateral approach. Based on 2-dimensional CT scans, the fractures were categorised using the Sanders classification. There were 16 type-II, 20 type-III, and 12 type-IV fractures. Radiographs and Maryland foot scores were used for evaluation of the results at a mean of 38 (range, 26-66) months. RESULTS: Anatomic reduction of the posterior calcaneal facet was achieved in 38 of 48 fractures. The Bohler and Gissane angles were restored to between 92 and 99% of normal, respectively. Despite this, the mean functional scores were 84 in type-II, 83 in type-III and 67 in type-IV fractures. CONCLUSION: Surgical results were superior in type-II and -III fractures. Type-IV fractures fared poorly, despite excellent restoration of calcaneal anatomy; subtalar arthrodesis should have been considered. PMID- 17709850 TI - Knee flexion after total knee arthroplasty. AB - PURPOSE: To identify factors related to knee flexion after total knee arthroplasty in a Chinese population. METHODS: Records of 242 total knee arthroplasties were retrospectively reviewed. The parameters evaluated were age, gender, diagnosis, preoperative knee flexion and extension, preoperative flexion arc, tibiofemoral angle, Knee Society knee score and functional score, and implant design. RESULTS: Advanced age, female gender, and good preoperative flexion and flexion arc were related to better postoperative flexion. Postoperative flexion tended to migrate to the middle range despite different ranges of preoperative flexion. Preoperative tibiofemoral malalignment had no significant effect on postoperative flexion. CONCLUSION: Contemporary designs of posterior stabilised prostheses with right and left femoral components were superior to older designs. PMID- 17709851 TI - Delayed onset of deep infection after total knee arthroplasty: comparison based on the infecting organism. AB - PURPOSE: To identify the organisms causing delayed deep infection following primary total knee arthroplasty (TKA) and to compare the differences in outcome based on the infecting organism. METHODS: Between the period April 1998 and March 2004 inclusive, patients presenting with delayed deep infection following primary TKA and/or those who underwent a salvage procedure (amputation or arthodesis) were retrospectively studied. RESULTS: Organisms were isolated in 27 patients; 44% were methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis. When the organism was resistant, the mean number of surgical procedures per patient was significantly higher and the proportion of patients with satisfactory outcomes was significantly lower. CONCLUSION: Deep infection with methicillin-resistant S. aureus or S. epidermidis is increasing. Strict infection control measures must be in place to combat such problems. PMID- 17709852 TI - Staged bilateral hip or knee arthroplasties. AB - PURPOSE: To compare the operating time, amount of blood transfused, length of hospital stay, and early complications (within 6 months) between 2-week staged bilateral arthroplasties and matched randomised controls undergoing unilateral arthroplasties. METHODS: From October 1992 to October 2000, 90 patients who underwent bilateral hip or knee arthroplasties with a 2-week interval were compared with matched randomised controls undergoing unilateral arthroplasties. A single surgeon performed all procedures. RESULTS: After the match-up process, 30 pairs of patients were included in the analysis. There were no significant differences in the operating times, amount of blood transfused, and early complication rates. The mean difference in length of hospital stay was significant (t=-3.552, df=29, p<0.001). CONCLUSION: Compared to staged procedures with an interval months apart, staged sequential arthroplasty with a 7- to 10-day interval during one hospital admission is more efficient, as it facilitates earlier rehabilitation without higher complication rates, and entails shorter hospital stays. PMID- 17709853 TI - Periprosthetic femoral fractures treated with a modular distally cemented stem. AB - PURPOSE: To assess the treatment outcome of revision hip arthroplasty for Vancouver type B3 periprosthetic femoral fractures using a modular distally cemented stem. METHODS: 22 men and 14 women (37 hips) aged 66 to 79 (mean, 70) years underwent revision hip arthroplasty for Vancouver type B3 periprosthetic femoral fractures. The indication for surgery was periprosthetic fracture with stem loosening and loss of proximal bone stock. The patients were referred from other hospitals after previous surgeries had failed: 8 with 3 previous surgeries, 19 with 2, and 9 with one. Using a transtrochanteric approach, the existing prosthesis was removed and a modular proximal femoral replacement stem was inserted, bypassing the area of proximal femoral fracture and bone loss. The stem was distally cemented. Patients were immobilised within 48 hours of surgery. RESULTS: Patients were followed up for a mean of 14 (range, 8-18) years. The mean Harris hip score improved from 29 (range, 5-40) to 78 (range, 56-88); 24 patients attained excellent or good scores (>80), 10 attained fair, and 2 attained poor scores. The mean healing time was 7 (range, 6-14) months; there was no non-union. Improvement in proximal bone stock was noted on serial radiographs. None of the stems had cement fracture or migration, requiring revision. Two (5%) of the patients had dislocations. CONCLUSION: Vancouver type B3 periprosthetic femoral fractures can be successfully treated with a distally cemented modular proximal femoral replacement prosthesis. PMID- 17709855 TI - Medial humeral epicondylar fracture in children and adolescents. AB - PURPOSE: To assess treatment outcomes of young patients with medial epicondylar fracture of the elbow using standard operative protocols. METHODS: 24 consecutive patients with medial humeral epicondylar fracture underwent surgery by one of the 3 methods: (1) 2 parallel Kirschner wires, (2) 2 parallel Kirschner wires plus a tension-band wire, and (3) a screw plus an anti-rotation Kirschner wire. Fractures displaced less than 5 mm were treated conservatively (casting for 3 weeks). Outcome was assessed clinically and radiologically. The Mayo Clinic Elbow Performance Index was measured. RESULTS: The 3 patients with undisplaced fractures had good radiological results and scores. One patient with a displaced fracture refused surgery and subsequently developed pseudarthrosis and cubitus valgus. All operatively treated patients had good scores, but 2 treated with 2 parallel Kirschner wires alone developed pseudarthrosis. Patients in this group needed longer rehabilitation to attain a functional range of movement than those in other groups (treated together with a tension-band wire or screw). CONCLUSION: Surgery is recommended for children with displaced medial epicondylar fractures of more than 5 mm. The use of a tension-band wire, instead of a screw, together with Kirschner wires is the preferred treatment for younger children. PMID- 17709854 TI - Omnifit acetabular component: a solution to preventing and treating dislocation. AB - PURPOSE: To assess short- to medium-term outcome of the Omnifit constrained acetabular component in preventing dislocation in at-risk patients after total hip arthroplasty (THA). METHODS: 81 patients (mean age, 77 years) underwent either primary or revision THA with an Omnifit constrained acetabular component and were followed up clinically and radiologically for a mean period of 24 months. RESULTS: There was one dislocation and one revision for avulsion of the acetabulum. The remaining prostheses remained well fixed. CONCLUSIONS: In the short- to medium-term, the Omnifit constrained acetabular component is effective in preventing primary and recurrent dislocation in at-risk patients. Long-term follow-up is needed to assess whether good fixation is maintained. The Omnifit acetabular cup is recommended for elderly patients with limited life expectancy and functional demands. PMID- 17709856 TI - Treatment of flexion-type supracondylar humeral fracture in children. AB - PURPOSE: To assess the results of treatment for flexion-type supracondylar humeral fracture in children. METHODS: The treatment of 14 children with flexion type supracondylar humeral fracture was reviewed. Severity was classified according to the Gartland system for extension-type fractures. Type-I fractures were treated with immobilisation in an extension cast. For type-II and -III fractures, closed reduction was first attempted followed by percutaneous pinning. If closed reduction failed, open reduction and internal fixation was performed. RESULTS: Patients were followed up for at least one year (range, 14-36 months). Treatment results were excellent in 7 patients, good in 4, fair in 3, and poor in none. Patients were pain-free and satisfied and none suffered any activity restriction. CONCLUSION: Closed reduction and percutaneous pinning is a good treatment option for type-II and -III flexion-type supracondylar humeral fractures. PMID- 17709857 TI - Surgical management for late presentation of supracondylar humeral fracture in children. AB - PURPOSE: To report the results of surgical management for late-presenting displaced supracondylar fractures of the humerus in children. METHODS: Between February 2002 and June 2003, 40 children (mean age, 7 years) with late presentation (range, 2-12 days) of displaced supracondylar humeral fractures were prospectively recruited. Gentle closed manipulation under image intensification was attempted in all patients, except one with a compound open fracture. Manipulation was successful in 25 patients and percutaneous skeletal stabilisation with Kirschner wires was performed. The remaining 15 patients were treated with open reduction and Kirschner wire fixation, using a mediolateral approach. RESULTS: The mean delay in presentation was approximately 4 days. No patients presenting more than 7 days after injury had the fracture reduced by closed manipulation. The mean hospital stay was 41 hours. At the final follow-up (mean, 18 months), 88% of the patients had a satisfactory result, according to Flynn's criteria. CONCLUSION: Operative treatment for late presentation of supracondylar humeral fractures in children is effective. It minimises the risk of complications and the need for continuous traction or corrective osteotomy. PMID- 17709858 TI - Neurological outcome following early versus delayed lower cervical spine surgery. AB - PURPOSE: To determine whether the timing of surgery affects neurological outcome in patients with lower cervical spine trauma. METHODS: 29 patients with a fracture and 38 with a fracture-dislocation of C3 to C7 cervical vertebrae were treated operatively during the inclusive period January 1987 to December 2000. Surgery was performed as soon as the patient's medical condition allowed, within 72 hours in 31 and more than 72 hours after the injury in 36. RESULTS: Only patients with incomplete spinal cord injury had neurological improvement after surgery. There was no statistically significant difference in final neurological outcomes in patients having early as opposed to delayed surgery. CONCLUSION: Surgical intervention for cervical injuries is safe, as no postoperative neurological deterioration was recorded. Timing of surgery does not affect neurological outcome. PMID- 17709859 TI - Computed tomographic measurement of cervical pedicles for transpedicular fixation in a Malay population. AB - PURPOSE: To measure the cervical pedicles and assess the feasibility of transpedicular fixation in a Malay population. METHODS: 960 computed tomography (CT) scans of bilateral C2 to C7 pedicles of 80 Malays were compared. 22 men and 24 women aged <60 (mean, 37.3; range, 18-56) years were defined as young patients, whereas 18 men and 16 women aged 60 or over (mean, 63.9; range, 60-76) years as elderly patients. An inner diameter of <3.0 mm (85% of a 3.5-mm screw) was defined as 'unfeasible' and a medial or lateral wall thickness of <1.0 mm as 'unsafe' for cervical pedicle screw fixation. RESULTS: In the respective young versus elderly groups, the inner diameters ranged from 1.94 to 2.80 mm versus 2.51 to 3.37 mm in men, and from 1.52 to 2.31 mm versus 1.64 to 2.46 mm in women. Medial wall thickness ranged from 1.25 to 1.46 mm versus 1.13 to 1.48 mm in men, and from 1.28 to 1.72 mm versus 1.10 to 1.24 mm in women. Lateral wall thickness ranged from 0.80 to 0.90 mm versus 0.66 to 0.88 mm in men, and from 0.85 to 0.99 mm versus 0.59 to 0.86 mm in women. CONCLUSION: The cervical spine of Malays may not be adequate to accommodate a 3.5-mm pedicle screw for transpedicular fixation, as this procedure may risk adjacent vital structures. PMID- 17709860 TI - Posterior 360-degree stabilisation of the upper thoracic spine: a technical note. AB - PURPOSE: To describe a technique involving posterior 360-degree stabilisation of the upper thoracic spine: spinal cord decompression, posterior vertebral body replacement, and then posterior instrumentation and intercostal posterolateral vertebral stabilisation. METHODS: Three men and 4 women aged 41 to 77 (mean, 58) years underwent posterior 360-degree stabilisation of the upper thoracic spine. Their indications for surgery were bone metastasis (n=5), burst fracture (n=1), and osteoporotic collapse with cord compression (n=1). Their clinical and radiological findings and treatment outcomes were retrospectively reviewed. RESULTS: Pain status of all patients improved after surgery: 4 had severe and 3 had mild pain preoperatively; in 3 pain became minimal and 4 had none postoperatively. All patients except one had Frankel/American Spinal Injury Association scores of E after surgery indicating complete recovery of sensory and motor function. There were no complications related to surgery or instrumentation construct. At the time of review, one patient had died of old age 8.6 years after surgery and another from local recurrence and lung metastasis 5.7 years after surgery. All other patients were living. CONCLUSION: One-stage posterior 360 degree stabilisation and vertebral body replacement is a useful technique for upper thoracic spine surgery. PMID- 17709861 TI - Arthroscopic subacromial decompression for stage-II impingement. AB - PURPOSE: To evaluate outcomes of arthroscopic subacromial decompression for stage II impingement. METHODS: Records of 42 consecutive patients with stage-II impingement treated by arthroscopic subacromial decompression from January 2000 to February 2002 were reviewed. Clinical outcomes were measured using the UCLA shoulder rating scale, and radiological outcomes using anteroposterior and supraspinatus outlet shoulder radiographs. RESULTS: The mean follow-up period was 14.6 (range, 12-30) months. Using the UCLA scale, 14 (33%) patients had an excellent result, 21 (50%) had a good result, 4 (10%) had a fair result, and 3 (7%) had a poor result. Mean component scores for the UCLA scale were: 8.0 for pain, 8.8 for function, 4.5 for forward flexion, and 4.5 for strength. The mean extent of resection was 2.9 mm in the anteroposterior and 2.0 mm in the supraspinatus outlet radiographs. There was no correlation between the extent of acromial resection and the UCLA shoulder rating scores. CONCLUSION: Short-term results of arthroscopic subacromial decompression for stage-II impingement are favourable. PMID- 17709862 TI - Reconstructions of the shoulder following tumour resection. AB - PURPOSE: To review and compare the postoperative outcomes of 3 types of shoulder reconstructions: prosthetic arthroplasty, clavicula pro humero reconstruction, and allograft arthrodesis. METHODS: Records of 25 shoulder reconstructions following tumour resection were retrospectively reviewed. Perioperative data, oncological prognoses, postoperative complications, and functions were assessed. RESULTS: We performed 10 prosthetic arthroplasties, 7 clavicula pro humero procedures, 4 allograft arthrodeses, and 4 soft tissue reconstructions. Eight patients died of their diseases. Three developed complications and underwent revision surgery. 19 patients achieved stable shoulders. Ten patients attended for functional assessments. Respective mean scores using the Musculoskeletal Tumor Society-International Symposium on Limb Salvage and the Toronto Extremity Salvage Score were: 77% and 82% for prosthetic arthroplasties, 67% and 62% for clavicula pro humero procedures, 83% and 70% for allograft arthrodeses, and 93% and 98% for soft tissue reconstructions. CONCLUSION: A stable construct is the treatment goal for shoulder reconstructions, as it enables effective function of the arm and hand. PMID- 17709863 TI - A combined use of a free vascularised flap and an external fixator for reconstruction of lower extremity defects in children. AB - PURPOSE: To describe a combined use of a free vascularised flap and an external fixator for reconstruction of lower extremity defects in children, and correction of equinus contracture developed after removal of the external fixator using a circular dynamic frame. METHODS: Seven children (4 males) aged 4 to 12 (mean, 8) years were treated with 9 free vascularised flaps for 8 limbs (bilaterally in one patient and for a failed flap in another). Patient pathologies included: 3 soft tissue degloving injuries, one soft tissue and bone avulsion, one severe burn contracture, one resurfacing of soft tissue and bone necrosis, and one osteosarcoma resection defect. Free flap reconstruction was delayed in 6 patients (range, 3 weeks to 4 years). Static external fixators were used to stabilise the free vascularised flaps at the time of reconstruction, with the ankle in a neutral position. RESULTS: The mean follow-up was 5 (1-10) years. All flaps but one survived; the failed one was immediately reconstructed with a contralateral, latissimus dorsi flap. One anastomosis following a Kirschner-wire injury was successfully revised. Six patients had pin tract infections and were treated with oral antibiotics. Two patients developed equinus contracture 6 and 3 years later, after removal of the external fixator, and were corrected by distraction, using a dynamic Ilizarov frame. CONCLUSION: The combined use of a free flap and an external fixator for salvage of lower extremities is useful in children. Late development of equinus contracture can be safely corrected by distraction, without compromising flap viability. PMID- 17709864 TI - Dynamic treatment for proximal phalangeal fracture of the hand. AB - PURPOSE: To assess a protected mobilisation programme (dynamic treatment) for proximal phalangeal fracture of the hand, irrespective of the geometry. METHODS: Clinical and radiological results of 32 consecutive patients with proximal phalangeal fracture of the hand treated from January 2001 to February 2007 were evaluated. Our supervised rehabilitation programme was strictly followed to gain full range of movement of the proximal interphalangeal joint and to prevent the development of an extension lag contracture. Patients were followed up for a mean period of 15 (range, 13-16) months. Results were evaluated using the Belsky classification. RESULTS: The results were excellent in 72% of the patients, good in 22%, and poor in 6%. Some patients defaulted follow-up, which made long-term assessment difficult. The poor results may have been related to patient non compliance or default from rehabilitation. Many good results upgraded to excellent following further rehabilitation. CONCLUSION: Skeletal stability, not rigidity, is necessary for functional movements of the hand. Proximal phalangeal fractures can be effectively treated by closed methods, using the stabilising effect of soft tissues (zancolli complex-metacarpophalangeal retention apparatus) and external devices (metacarpophalangeal block splint), thus enabling bone healing and movement recovery at the same time. PMID- 17709865 TI - Review article: anatomic double bundle anterior cruciate ligament reconstruction. AB - The anterior cruciate ligament (ACL) consists of 2 bundles: a slightly larger anteromedial bundle and a posterolateral bundle, named according to their relative tibial insertion sites. Both bundles are crucial to knee stability. Although it is more technically demanding, a double bundle ACL reconstruction restores the knee biomechanics better and provides more rotational stability than a single bundle ACL reconstruction. Intermediate and long-term clinical investigation including the measurement of rotational laxity and the evaluation of osteoarthritic change is needed to confirm biomechanical and short-term clinical outcomes. PMID- 17709866 TI - Cement leakage into the posterior spinal canal during balloon kyphoplasty: a case report. AB - We report a case of cement leakage into the posterior spinal canal due to inadvertent pedicle perforation during balloon kyphoplasty. The leakage was corrected immediately without any sequelae. Features seen on radiography and the minimally invasive procedure used for removal are described. The postoperative radiographs of 100 consecutive patients treated with balloon kyphoplasty were subsequently reviewed. Only one patient had a similar leakage but had no neurological complications. PMID- 17709867 TI - Pyogenic sacroiliitis and adult respiratory distress syndrome: a case report. AB - Staphylococcus aureus sacroiliitis is uncommon and may lead to bacteraemia, sepsis, and death if diagnosis and treatment are delayed. Its association with pulmonary symptoms has not been reported. We report a 36-year-old Thai woman who presented with a 4-day history of right buttock pain, aggravated by walking, which came on after having a traditional foot massage. She later developed adult respiratory distress syndrome. She was treated with open drainage, respiratory support, and antibiotics. PMID- 17709868 TI - Bone trephining for osteoid osteoma excision: a case report. AB - Osteoid osteomas may be treated medically or surgically; both have similar long term outcomes. Nonetheless, only surgery allows complete excision of the lesion for histological analysis. Excessive removal of surrounding bone may destabilise and weaken the bony structure and predispose it to fractures. We describe a surgical technique using a bone graft trephine to enable precise lesion removal with minimal bone excision. PMID- 17709869 TI - Primary aneurysmal bone cyst of the patella: a case report. AB - Aneurysmal bone cysts account for less than 1% of primary bone tumours and have a predilection for the metaphyses of the long bones of the leg. Only 1% of all aneurysmal bone cysts occur in the patella. We report on a 30-year-old man with a primary aneurysmal bone cyst in the right patella treated with curettage. The defect was filled with demineralised bone matrix and allogeneic cancellous bone graft. At the 1.5-year follow-up, the bone graft was well incorporated, the patient experienced no pain or tenderness and had a full range of knee movement. PMID- 17709870 TI - Subcapital femoral neck fracture following successful trochanteric fracture treatment with a dynamic hip screw: a report of five cases. AB - A subcapital femoral neck fracture complicating a healed trochanteric fracture is rare. Such cases are managed in a rather heterogeneous manner, i.e. there exists a mixture of cases treated by either fixed angle devices or dynamic compression screws. We describe 5 patients who developed subcapital femoral neck fractures after healed trochanteric fractures treated with dynamic compression screws. The subjects' clinical data, operative records, and radiographs have been studied retrospectively and the literature reviewed. The risk factors for such a complication include being of advanced age, female, osteoporotic, and having a small femoral head and neck, and a basicervical type of fracture. PMID- 17709871 TI - Occult acetabular fractures in elderly patients: a report of three cases. AB - Three elderly patients with acetabular fractures not evident on the initial plain radiographs are presented. All had a fall and were unable to bear weight. Cross sectional imaging and repeated plain radiography confirmed fractures of the acetabulum. Occult acetabular fractures may occur in elderly patients after a fall and present with persistent discomfort and difficulty walking. When there is reason to suspect such a fracture, further diagnostic studies, including a Judet view radiograph, bone scan, computed tomographic scan or magnetic resonance image should be performed. PMID- 17709872 TI - Extensor digitorum longus tenosynovitis caused by talar head impingement in an ultramarathon runner: a case report. AB - Stenosing tenosynovitis of the extensor digitorum longus tendon is an injury related to ultramarathon running. A 32-year-old male ultramarathon runner developed chronic tenosynovitis of the ankle dorsiflexors. He was diagnosed with extensor digitorum longus tenosynovitis caused by talar head impingement associated with exostosis. He failed to respond to non-operative management and decided to undergo tenosynovectomy of the extensor digitorum longus tendon. The pain was relieved without functional disturbance of the foot and ankle, and the patient returned to running 3 weeks postoperatively. At the 2-year follow-up, he was participating fully in ultramarathons. PMID- 17709873 TI - Ureteropelvic junction disruption and distal ureter injury associated with a Chance fracture following a traffic accident: a case report. AB - A 10-year-old girl sustained a ureteropelvic junction disruption and distal ureter injury associated with the Chance fracture following a traffic accident. She was sitting on the rear seat of a car wearing a lap belt. Extensive small bowel mesenteric trauma was noted. Radiography revealed a left haemothorax with mediastinal shift and an unstable flexion-distraction vertebral fracture at L2 (Chance fracture). Subsequent intravenous pyelography demonstrated proximal extravasation from the right kidney without continuity to the upper and mid ureter, indicating a ureteropelvic junction avulsion or necrosis. Definitive surgery was delayed until day 33 because of urosepsis. Due to extensive small bowel resection, ischaemia of the ureter, and the history of urosepsis, a right subcapsular nephrectomy (rather than ureteral reconstruction) was considered the safest option for minimising further complications. It is important that trauma specialists recognise additional injuries after major trauma. Early use of a multidisciplinary approach is recommended to reduce morbidity and mortality. PMID- 17709874 TI - Surgery for clavicular and humeral fractures in an osteopetrotic patient: a case report. AB - Osteopetrosis is a rare disease characterised by generalised sclerosis of the bone. Surgical treatment for fractures in osteopetrotic bones is difficult due to their hardness. We report successful surgical treatment of humeral and clavicular fractures in a 30-year-old osteopetrotic patient with severe multiple trauma. Two years after surgery, the patient had a full range of movement at the shoulder and elbow, with good bone union and alignment. PMID- 17709875 TI - Uncemented primary press-fit total hip arthroplasty: a 3 to 6 years of experience. PMID- 17709876 TI - Childhood obesity and insulin resistance. AB - Insulin resistance (IR) in childhood has importance to the understanding and prevention of the growing epidemic of insulin resistance syndrome (IRS) in adults with attendant obesity, type 2 diabetes (T2DM), atherosclerotic diseases, hypertension, gout, non-alcoholic, steato-hepatitis (NASH), gall bladder disease, nephropathy, polycystic ovarian disease (PCOS), infertility and premature senility. The severity of IR and its' complications in children unfortunately and usually progresses in their pubertal transition to adulthood; affected young children are more likely than adults to have underlying causal monogenic disorders; the sequence of natural history and events give insights into disease pathogeneses, and optimal life style choices that last are best made during the early formative years. Some features of IR in children discussed herein are: a strong tendency to low birth weight for gestational age, adverse effects of adrenarche and therapeutic steroid therapy, predisposition to premature pubarche, acanthosis nigricans, tall stature despite pituitary GH suppression, allergic diathesis, hyperandrogenism and PCOS, dyslipidemia and fatty liver disease, and diagnosis by clinical and biochemical markers of IR including insulin regulated hepatic hormonal binding proteins such as IGFBP-1. The national preoccupation with the "metabolic syndrome" T2DM and obesity, should be appropriately directed to an improved understanding of IR in children and their management, if the looming health crisis in affected adults is to be seriously addressed. The nation is facing its' first generation of children who will be less healthy and die younger than the previous generation (Marks (2005) Presentation to the American Association of Diabetes Educators 32nd Annual Meeting and Exhibition, August 10 13, Washington, DC). PMID- 17709877 TI - Role of lipids and fatty acids in macrosomic offspring of diabetic pregnancy. AB - Diabetic pregnancy frequently results in macrosomia or fetal obesity. It seems that the anomalies in carbohydrate and lipid metabolism in macrosomic infants of diabetic mothers are due to maternal hyperglycemia, which leads to fetal hyperinsulinemia. We have developed a rat model of macrosomic offspring and assessed the onset of obesity in these animals. The macrosomic offspring born to diabetic mothers are prone to the development of glucose intolerance and obesity as a function of age. It seems that in utero programming during diabetic pregnancy creates a "metabolic memory" which is responsible for the development of obesity in macrosomic offspring. We have demonstrated that the metabolism of lipids, and altered anti-oxidant status and immune system are implicated in the etiopathology of obesity in these animals. We have reported beneficial effects of n-3 polyunsaturated fatty acids (PUFAs) in obese animals, born to diabetic dams. PMID- 17709878 TI - PCK1 and PCK2 as candidate diabetes and obesity genes. AB - The PCK1 gene (Pck1 in rodents) encodes the cytosolic isozyme of phosphoenolpyruvate carboxykinase (PEPCK-C), which is well-known for its function as a gluconeogenic enzyme in the liver and kidney. Mouse studies involving whole body and tissue-specific Pck1 knockouts as well as tissue-specific over expression of PEPCK-C have resulted in type 2 diabetes as well as several surprising phenotypes including obesity, lipodystrophy, fatty liver, and death. These phenotypes arise from perturbations not only in gluconeogenesis but in two additional metabolic functions of PEPCK-C: (1) cataplerosis which maintains metabolic flux through the Krebs cycle by removing excess oxaloacetate, and (2) glyceroneogenesis which produces glycerol-3-phosphate as a precursor for fatty acid esterification into triglycerides. PEPCK-C catalyzes the conversion of oxaloacetate + GTP to phosphoenolpyruvate + GDP + CO2. It is in part the tissue specificity of this simple reaction that results in the variety of phenotypes listed above. Briefly: (1) A 7-fold over-expression of PEPCK-C in the livers of mice causes excessive glucose production. (2) Mice with a whole-body knockout of Pck1 die within 2-3 days of birth, not from hypoglycemia, but probably because the Krebs cycle slows to approximately 10% of normal in the absence of cataplerosis. (3) Mice with a liver-specific knockout have an inability to remove oxaloacetate from the Krebs cycle, which leads to a fatty liver following a fast. (4) An adipose-specific knockout of Pck1 results in a fraction of the mice developing lipodystrophy due to lost glyceroneogenesis and a consequent decrease in fatty acid re-esterification. (5) Finally, disregulated over-expression of PEPCK-C in adipose tissue increases fatty acid re-esterification leading to obesity. These varied experimental phenotypes in mice have led us to postulate that abnormal production of PEPCK isozymes encoded by two PEPCK genes, PCK1 and PCK2, in humans could have similar consequences (Beale, E. G. et al. (2004). Trends in Endocrinology and Metabolism, 15, 129-135). The purpose of this review is to further explore these possibilities. PMID- 17709879 TI - Impact of bariatric surgery on type 2 diabetes. AB - The management and prevention of diabetes through lifestyle modifications and weight loss should be the mainstay of therapy in appropriate candidates. Although the results from the Diabetes Prevention Trial and the Finnish Prevention Study support this approach, over 95% of patients not participating in a prevention research study are unable to achieve and maintain any significant weight loss over time. Bariatric surgery for weight loss is an emerging option for more sustainable weight loss in the severely obese subject, especially when obesity is complicated by diabetes or other co-morbidities. The two most common types of procedures currently used in the United States are adjustable gastric bands and Roux-en-Y gastric bypass. These procedures can be performed laparoscopically, further reducing the perioperative morbidity and mortality associated with the surgery. While the gastric bypass procedure usually results is greater sustained weight loss (40-50%) than adjustable gastric banding (20-30%), it also carries greater morbidity and nutritional/metabolic issues, such as deficiencies in iron, B12, calcium, and vitamin D. Following bariatric surgery most subjects experience improvements in diabetes control, hypertension, dyslipidemia, and other obesity related conditions. In patients with impaired glucose tolerance most studies report 99-100% prevention of progression to diabetes, while in subjects with diabetes prior to surgery, resolution of the disease is reported in 64-93% of the cases. While improvements in insulin resistance and beta-cell function are related to surgically induced weight loss, the rapid post-operative improvement in glycemia is possibly due to a combination of decreased nutrient intake and changes in gut hormones as a result of the bypassed intestine. Post-prandial hyperinsulinemic hypoglycemia associated with nesidioblastosis has been described in a series of patients following gastric bypass surgery, and may be related to the described changes in GLP-1 and other gut hormones. PMID- 17709880 TI - Insulin signaling and glucose transport in insulin resistant human skeletal muscle. AB - Insulin increases glucose uptake and metabolism in skeletal muscle by signal transduction via protein phosphorylation cascades. Insulin action on signal transduction is impaired in skeletal muscle from Type 2 diabetic subjects, underscoring the contribution of molecular defects to the insulin resistant phenotype. This review summarizes recent work to identify downstream intermediates in the insulin signaling pathways governing glucose homeostasis, in an attempt to characterize the molecular mechanism accounting for skeletal muscle insulin resistance in Type 2 diabetes. Furthermore, the effects of pharmaceutical treatment of Type 2 diabetic patients on insulin signaling and glucose uptake are discussed. The identification and characterization of pathways governing insulin action on glucose metabolism will facilitate the development of strategies to improve insulin sensitivity in an effort to prevent and treat Type 2 diabetes mellitus. PMID- 17709881 TI - Does IGF-I stimulate pancreatic islet cell growth? AB - Both IGF-I and its receptor (IGF-IR) are specifically expressed in various cell types of the endocrine pancreas. IGF-I has long been considered a growth factor for islet cells as it induces DNA synthesis in a glucose-dependent manner, prevents Fas-mediated autoimmune beta-cell destruction and delays onset of diabetes in non-obese diabetic (NOD) mice. Islet-specific IGF-I overexpression promotes islet cell regeneration in diabetic mice. However, in the last few years, results from most gene-targeted mice have challenged this view. For instance, combined inactivation of insulin receptor and IGF-IR or IGF-I and IGF II genes in early embryos results in no defect on islet cell development; islet beta-cell-specific inactivation of IGF-IR gene causes no change in beta-cell mass; liver- and pancreatic-specific IGF-I gene deficiency (LID and PID mice) suggests that IGF-I exerts an inhibitory effect on islet cell growth albeit indirectly through controlling growth hormone release or expression of Reg family genes. These results need to be evaluated with potential gene redundancy, model limitations, indirect effects and ligand-receptor cross-activations within the insulin/IGF family. Although IGF-I causes islet beta-cell proliferation and neogenesis directly, what occur in normal physiology, pathophysiology or during development of an organism might be different. Locally produced and systemic IGF I does not seem to play a positive role in islet cell growth. Rather, it is probably a negative regulator through controlling growth hormone and insulin release, hyperglycemia, or Reg gene expression. These results complicate the perspective of an IGF-I therapy for beta-cell loss. PMID- 17709882 TI - The role of islet neogenesis-associated protein (INGAP) in islet neogenesis. AB - Islet Neogenesis-Associated Protein (INGAP) is a member of the Reg family of proteins implicated in various settings of endogenous pancreatic regeneration. The expression of INGAP and other RegIII proteins has also been linked temporally and spatially with the induction of islet neogenesis in animal models of disease and regeneration. Furthermore, administration of a peptide fragment of INGAP (INGAP peptide) has been demonstrated to reverse chemically induced diabetes as well as improve glycemic control and survival in an animal model of type 1 diabetes. Cultured human pancreatic tissue has also been shown to be responsive to INGAP peptide, producing islet-like structures with function, architecture and gene expression matching that of freshly isolated islets. Likewise, studies in normoglycemic animals show evidence of islet neogenesis. Finally, recent clinical studies suggest an effect of INGAP peptide to improve insulin production in type 1 diabetes and glycemic control in type 2 diabetes. PMID- 17709883 TI - Chronic oxidative stress as a mechanism for glucose toxicity of the beta cell in type 2 diabetes. AB - Type 2 diabetes is characterized by a relentless decline in pancreatic islet beta cell function and worsening hyperglycemia despite optimal medical treatment. Our central hypothesis is that residual hyperglycemia, especially after meals, generates reactive oxygen species (ROS), which in turn causes chronic oxidative stress on the beta cell. This hypothesis is supported by several observations. Exposure of isolated islets to high glucose concentrations induces increases in intracellular peroxide levels. The beta cell has very low intrinsic levels of antioxidant proteins and activities and thus is very vulnerable to ROS. Treatment with antioxidants protects animal models of type 2 diabetes against complete development of phenotypic hyperglycemia. The molecular mechanisms responsible for the glucose toxic effect on beta cell function involves disappearance of two important regulators of insulin promoter activity, PDX-1 and MafA. Antioxidant treatment in vitro prevents disappearance of these two transcription factors and normalizes insulin gene expression. These observations suggest that the ancillary treatment with antioxidants may improve outcomes of standard therapy of type 2 diabetes in humans. PMID- 17709884 TI - Novel inhibitors of glycation and AGE formation. AB - Accelerated formation of advanced glycation/lipoxidation and endproducts (AGEs/ALEs) has been implicated in the pathogenesis of various diabetic complications. Several natural and synthetic compounds have been proposed and tested as inhibitors of AGE/ALE formation. We have previously reported the therapeutic effects of several new AGE/ALE inhibitors on the prevention of nephropathy and dyslipidemia in streptozotocin (STZ)-induced diabetic rats. In this study, we investigated the effects of various concentrations of a compound, LR-90, on the progression of renal disease and its effects on AGE and receptor for AGE (RAGE) protein expression on the kidneys of diabetic STZ-rats. Diabetic male Sprague-Dawley rats were treated with or without LR-90 (0, 5, 20, 25, and 50 mg/l of drinking water). After 32 weeks, body weight, glycemic status, renal function, and plasma lipids were measured. Kidney histopathology and AGE/ALE accumulation and RAGE protein expression in tissues were also determined. In vitro studies were also performed to determine the possible mechanism of action of LR-90 in inhibiting AGE formation and AGE-protein cross-linking. LR-90 protected the diabetic kidneys by inhibiting the increase in urinary albumin-to creatinine ratio and ameliorated hyperlipidemia in diabetic rats in a concentration-dependent fashion without any effects on hyperglycemia. LR-90 treatment also reduced kidney AGE/ALE accumulation and RAGE protein expression in a concentration-dependent manner. In vitro, LR-90 exhibited general antioxidant properties by inhibiting metal-catalyzed reactions and reactive oxygen species (OH radical) and reactive carbonyl species (methlyglyoxal, glyoxal) generations without any effect on pyridoxal 5' phosphate. The compound also prevents AGE protein cross-linking reactions. These findings demonstrate the bioefficacy of LR 90 in treating nephropathy and hyperlipidemia in diabetic animals by inhibiting AGE accumulation, RAGE protein expression, and protein oxidation in the diabetic kidney. Additionally, our study suggests that LR-90 may be useful also to delay the onset and progression of diabetic atherosclerosis as the compound can inhibit the expression of RAGE and inflammation-related pathology, as well as prevent lipid peroxidation reactions. PMID- 17709886 TI - Treg in type 1 diabetes. AB - At the time of this writing, a major void exists; the lack of a method to prevent and/or reverse type 1 diabetes in humans. We believe this void to a large extent is the result of our lack in understanding the mechanisms of autoimmunity that underlie beta cell destruction, a failure to understand the immunologic factors that contribute to type 1 diabetes, and the absence of immunologic tools which would allow for a better understanding of the mechanisms underlying disease development and monitoring of therapeutic interventions. Due to this, an intense degree of research interest has recently been generated to understand the mechanisms that regulate the immune response and form a state of immunological tolerance. While some progress has been made towards these goals, additional investigations are needed to address the aforementioned knowledge voids including the role for regulatory T cells (Treg), defined by their co-expression of CD4 and CD25 as well as the transcription factor FOXP3, in the pathogenesis and natural history of type 1 diabetes. We and others have recently reported findings related to the frequency and function of Treg cells in type 1 diabetes, yet the resulting literature represents a somewhat conflicting body of findings. Our studies did not support the notion that altered Treg frequencies are associated with type 1 diabetes, but rather did identify alterations in the functional (i.e., suppressive) activities of these cells in subjects with the disease. The need to bring resolution to the aforementioned published discrepancies in frequency and function of Treg in type 1 diabetes represents the impetus for this critical review. In addition, we hope to highlight the need for expanded studies that address specific knowledge gaps regarding the cellular and molecular mechanism(s) related to the frequency and function of Treg. PMID- 17709885 TI - Roles of cytokines in the pathogenesis and therapy of type 1 diabetes. AB - Type 1 diabetes (T1D) results from autoimmune destruction of the insulin producing beta-cells in the pancreatic islets of Langerhans by autoreactive T helper 1 (Th1) cells characterized by their cytokine secretory products, interleukin-2 (IL-2) and interferon gamma (IFNgamma). Th1-type cytokines (IL-2 and IFNgamma) correlate with T1D, whereas Th2 (IL-4 and IL-10), Th3 (transforming growth factor beta [TGFbeta]), and T regulatory cell-type cytokines (IL-10 and TGFbeta) correlate with protection from T1D. Paradoxically, however, administrations of Th1-type cytokines (IL-2 and IFNgamma) and immunotherapies that induce Th1-type cytokine responses actually prevent T1D, at least in animal models. Therefore, immunotherapies that inhibit IL-2 production/action will block Th1 cell/cytokine-driven effector mechanisms of pancreatic islet beta-cell destruction; however, anti-IL-2 therapy will not allow immune tolerance to be established. In contrast, immunotherapies that increase IL-2 production/action may correct an immunodeficiency in IL-2 production that appears to underlie the autoimmunity of T1D, thereby restoring immune tolerance to islet beta-cells and prevention of T1D. PMID- 17709887 TI - Deleting islet autoimmunity. AB - Even though there are numerous autoantigens for type 1 diabetes, current evidence suggests that a single autoantigen, namely insulin, is responsible for the key initiating event in autoimmunity. If a single autoantigen is necessary for triggering the autoimmune process, then antigen-specific therapy to block or delete the immune response against that autoantigen before epitope spreading occurs, may become a larger focus of future immunotherapeutic strategies. In this article, we review current literature regarding insulin as an autoantigen and potential approaches to deleting insulin-reactive T cells through the use of peptide vaccines and targeted T cell receptor immunizations. PMID- 17709888 TI - The status of gene vectors for the treatment of diabetes. AB - Diabetes mellitus type 1 (DM1) represents one of the most obvious targets for successful treatment by gene transfer. The disease provides targets and methods for therapy that include suppression of autoimmunity, restoration of insulin responsiveness, functional replacement of pancreatic islets, and correction of vascular and nerve damage associated with prolonged hyperglycemia. The pathogenesis of DM1 is well understood and gene sequences are known that would support these various approaches for genetic intervention. However, a key limitation at present is the availability of efficient and reliable methods for delivery and sustained expression of the transferred DNA. Most genetic vectors are derived from viruses, and recent improvements in adenovirus-derived, lentivirus-derived, and adeno-associated virus-derived vectors suggest that these will have successful application to diabetes in the future. PMID- 17709889 TI - Improving islet transplantation by gene delivery of hepatocyte growth factor (HGF) and its downstream target, protein kinase B (PKB)/Akt. AB - Clinical studies have demonstrated that islet transplantation may be a useful procedure to replace beta cell function in patients with Type 1 diabetes. Islet transplantation faces many challenges, including complications associated with the procedure itself, the toxicity of immunosuppression regimens, and to the loss of islet function and insulin-independence with time. Despite the current successes, and residual challenges, these studies have pointed out an enormous scarcity of islet tissue that precludes the use of islet transplantation in a clinical setting on a wider scale. To address this problem, many research groups are trying to identify different islet growth factors and intracellular molecules capable of improving islet graft survival and function, therefore reducing the number of islets needed for successful transplantation. Among these growth factors, hepatocyte growth factor (HGF), a factor known to improve transplantation of a variety of organs/cells, has shown promising results in increasing islet graft survival and reducing the number of islets needed for successful transplantation in four different rodent models of islet transplantation. Protein kinase B (PKB)/Akt, a pro-survival intracellular signaling molecule is known to be activated in the beta cell by several different growth factors, including HGF. PKB/Akt has also shown promising results for improving human islet graft survival and function in a minimal islet mass model of islet transplantation in diabetic SCID mice. Increasing our knowledge on how HGF, PKB/Akt and other emerging molecules work for improving islet transplantation may provide substrate for future therapeutic approaches aimed at increasing the number of patients in which beta cell function can be successfully replaced. PMID- 17709890 TI - Vascularized composite islet-kidney transplantation in a miniature swine model. AB - Previous work from this laboratory has demonstrated that transplantation of allogeneic thymic tissue as part of a composite vascularized graft is far more successful in terms of both engraftment and long-term survival than transplantation of thymic tissue or cells alone. We have subsequently extended this concept to transplantation of allogeneic islets, comparing survival of islet cell suspensions to that of vascularized composite islet-kidneys (IK), prepared by injection of autologous islets underneath the renal capsule 2-3 months prior to allogeneic transplantation of the composite organ. We have utilized partially inbred miniature swine with defined MHC loci as the experimental large animals for this study, permitting reproducible transplantation across specific MHC barriers. Composite IK have been transplanted successfully across minor and full MHC mismatch barriers, using treatment regimens previously demonstrated to induce long-term tolerance of kidney allografts across these barriers. IK allografts containing > or =5000 islet equivalents (IE)/kg recipient body weight were found capable of reversing surgically induced diabetes, while injection of comparable numbers of purified islets via the portal vein or under the renal capsule did not. Studies are also being directed toward preparation of autologous "thymo isletkidneys" (TIK), for potential use as xenografts, in which the thymic component is intended to induce tolerance and the islets to reverse diabetic hyperglycemia. The use of both types of composite organ transplants may eventually be applicable to the treatment of type I diabetic patients suffering from end-stage diabetic nephropathy. PMID- 17709891 TI - Is the glucose-induced phosphate flush in pancreatic islets attributable to gating of volume-sensitive anion channels? AB - D-glucose and other nutrient insulin secretagogues have long been known to induce a transient increase in inorganic phosphate release from pancreatic islets, a phenomenon currently referred to as a "phosphate flush". The objective of this study was to explore the possible participation of volume-sensitive anion channels in such a process. Rat pancreatic islets were preincubated for 60 min in the presence of [32P]orthophosphate and then perifused for 90 min to measure 32P fractional outflow rate and insulin secretion. From minutes 46 to 70 inclusive either the concentration of D-glucose was increased from 1.1 to 8.3 mmol L-1 or the extracellular osmolarity was decreased by reducing the NaCl concentration by 50 mmol L-1. The increase in D-glucose concentration induced a typical phosphate flush and biphasic stimulation of insulin release. Extracellular hypoosmolarity caused a monophasic increase in both effluent radioactivity and insulin output. The inhibitor of volume-sensitive anion channels 5-nitro-2-(3 phenylpropylamino)benzoate (0.1 mmol L-1) inhibited both stimulation of insulin release and phosphate flush induced by either the increase in D-glucose concentration or extracellular hypoosmolarity. It is proposed that gating of volume-sensitive anion channels accounts for the occurrence of the phosphate flush and subsequent stimulation of insulin secretion in response to either an increase in D-glucose concentration or a decrease in extracellular osmolarity. PMID- 17709892 TI - The effect of insulin on expression of genes and biochemical pathways in human skeletal muscle. AB - To study the insulin effects on gene expression in skeletal muscle, muscle biopsies were obtained from 20 insulin sensitive individuals before and after euglycemic hyperinsulinemic clamps. Using microarray analysis, we identified 779 insulin-responsive genes. Particularly noteworthy were effects on 70 transcription factors, and an extensive influence on genes involved in both protein synthesis and degradation. The genetic program in skeletal muscle also included effects on signal transduction, vesicular traffic and cytoskeletal function, and fuel metabolic pathways. Unexpected observations were the pervasive effects of insulin on genes involved in interacting pathways for polyamine and S adenoslymethionine metabolism and genes involved in muscle development. We further confirmed that four insulin-responsive genes, RRAD, IGFBP5, INSIG1, and NGFI-B (NR4A1), were significantly up-regulated by insulin in cultured L6 skeletal muscle cells. Interestingly, insulin caused an accumulation of NGFI-B (NR4A1) protein in the nucleus where it functions as a transcription factor, without translocation to the cytoplasm to promote apoptosis. The role of NGFI-B (NR4A1) as a new potential mediator of insulin action highlights the need for greater understanding of nuclear transcription factors in insulin action. PMID- 17709893 TI - In vitro biological-to-immunological ratio of serum gonadotropins throughout male puberty in children with insulin-dependent diabetes mellitus. AB - Information on the impact of prolonged deficient glycemic control in the quality of the gonadotropin signal delivered by the pituitary gland during puberty in children with insulin-dependent diabetes mellitus (IDDM) is scarce. In the present study, we examined the impact of deficient glycemic control on bioactive LH and FSH concentrations and their corresponding biological-to-immunological (B:I) ratio in boys with poorly controlled, but systemically uncomplicated IDDM. Dual control groups comprising patients with well-controlled IDDM and healthy boys of comparable age and body mass index were included for appropriate comparisons within and between each pubertal stage. Patients with poorly controlled and well-controlled IDDM exhibited serum bioactive FSH levels and B:I FSH ratio similar to those showed by the healthy control group. In contrast, in early and mid-pubertal boys with poorly controlled IDDM bioactive LH levels were normal, but its B:I LH relationship was significantly (P < 0.05) decreased. This attenuation in the quality of the LH signal did not affect total serum T concentrations, and apparently, progression of puberty. Long-standing uncontrolled diabetes and the consequent metabolic disturbances and/or complications may aggravate the reproductive axis dysfunction and eventually provoke pubertal arrest. PMID- 17709894 TI - Effect of prolactin on inositol uptake in mouse mammary gland explants. AB - Studies were carried out to assess the role of insulin (I), cortisol (H), and prolactin (P or PRL) in regulating myoinositol (inositol) uptake in the mammary gland. Using cultured mammary gland explants from pregnant mice (12-14 days into gestation), insulin and prolactin were found to stimulate inositol uptake, while cortisol impaired inositol uptake. Optimal inositol uptake was observed when tissues were treated with all three lactogenic hormones (I, H, and PRL). Further studies were designed primarily to characterize the PRL stimulation of inositol transport. Inositol uptake in the mammary explants increased linearly for 4 h, both in IH treated tissues and those treated with IHP; distribution ratios of greater than 14 were achieved at 4 h, suggesting an active inositol transport mechanism. The PRL effect on inositol uptake is sodium-dependent, temperature dependent, and ouabain sensitive. DIDS and furosemide did not impair inositol uptake or the PRL effect on inositol uptake. PRL stimulated inositol uptake employing PRL concentrations of 10-1000 ng/ml. The PRL effect was manifested at all PRL-treatment times of 12 h or longer, but not at earlier times. PRL thus appears to be an important and essential hormone for the stimulation of inositol accumulation in milk during lactogenesis. PMID- 17709895 TI - Growth hormone reserve in adult beta thalassemia patients. AB - Reduced serum insulin-like growth factor-1 (IGF-1) and hypogonadotrophic hypogonadism are common features of adult beta-thalassemia, and warrant evaluation of the growth hormone (GH)-IGF-1 axis. The aim of this study was to determine GH reserve in beta-thalassemia patients (9 females, 7 males, 15 major, 1 intermedia), age 29.3 +/- 6.9 years, BMI 21.3 +/- 1.9 kg/m2, and in 20 age, sex and BMI-matched healthy controls, using the GH-releasing hormone (GHRH)-arginine test. The associations between peak GH response and hormonal and biochemical indices were evaluated. Using BMI-related cut-off limits for peak GH response in the GHRH-arginine test, 4/16 beta-thalassemia patients had peak GH lower than 11.5 microg/l, the cut-off limit suggested for lean subjects, and were diagnosed as GH deficient (GHD). Using 9 microg/l as the cut-off limit 2/16 patients were GHD. Reduced serum IGF-1 and IGFBP-3 were present in 69% and 19% of the patients, respectively. Peak GH did not correlate with serum IGF-1, TSH, and fT4 levels or gonadal status. Neither peak GH nor IGF-1 correlated with serum ferritin. Our findings suggest that GHD is present in up to a quarter of adult beta-thalassemia patients. The clinical benefits of GH therapy need to be determined. GHD alone does not account for the high prevalence of reduced IGF-1 in adult beta thalassemia. PMID- 17709896 TI - Interaction of testosterone with inhibin alpha and betaA subunits to regulate prostate gland growth. AB - Testosterone regulation of prostate gland growth has been shown to involve reciprocal interaction with inhibin and activin. This study was therefore conducted to correlate the effect of testosterone on prostate gland proliferation and differentiation with the level of expression of inhibin alpha and betaA subunits. Immature dogs were treated with testosterone for 0, 3, 7, and 14 days and prostate gland growth was assessed by morphological and immunohistological localization of differentiation and proliferation markers. The results showed that testosterone treatment resulted in an initial significant increase in PCNA proliferation index by days 3 and 7, followed by a significant decrease by day 14 post-treatment. Interestingly, the decrease of cell proliferation was associated with structural and biochemical changes characteristic of glandular and stromal differentiation of the prostate gland. These changes include progressive glandular ductal canalization and inter-ductal stroma differentiation which were apparent from a gradual shift from vimentin expression to vimentin and alpha actin expression. Testosterone also had a differential effect on inhibin alpha and beta subunits. Although testosterone treatment resulted in significant and constant inhibition of alpha subunit mRNA expression, it resulted in a significant increase of betaA mRNA expression by day 3, followed by a decrease by days 7 and 14. These results indicated that testosterone acts first to drive proliferation of undifferentiated prostatic cells and then to maintain a low proliferation turnover of differentiated cells. Because it has been shown that activin is an antagonistic regulator of androgens, the attenuated stimulatory effect of testosterone on cell proliferation by day 14 might be mediated, at least in part, by interplay between testosterone and activin. PMID- 17709897 TI - The effects of glutamate can be attenuated by estradiol via estrogen receptor dependent pathway in rat adrenal pheochromocytoma cells. AB - Estrogens have been suggested to exhibit neuroprotective activities against several insults including beta-amyloid and glutamate, one of the excitatory neurotransmitters in the central nervous system. In the present study, we showed that exposure to glutamate not only inhibited the cell growth of exponentially growing rat pheochromocytoma PC12 cells in a time- and dose-dependent manner, but also influenced cell adherence capacity. Glutamate-induced growth inhibition was significantly attenuated by the co-administration of estradiol in PC12 cells. Pre exposure of the PC12 cells to the estradiol was not required for protection against glutamate-induced growth inhibition. Administration of anti-estrogen ICI182,780 efficiently blocked the neuroprotective effects of estradiol. Glutamate-induced changes in cell adherence, on the other hand, were not significantly affected by estradiol. These data indicate that the neuroprotective effects of estradiol against glutamate-induced insults in PC12 cells, at least in part, involve estrogen receptor-dependent pathways. PMID- 17709898 TI - 3T3-L1 adipocytes induce dysfunction of MIN6 insulin-secreting cells via multiple pathways mediated by secretory factors in a co-culture system. AB - Pancreatic beta-cell dysfunction is an important pathological change in type 2 diabetes, which is tightly related to obesity. However, the direct role of adipose tissue in beta-cell dysfunction has not been well understood. In this study, we examined the effects of 3T3-L1 adipocytes on MIN6 insulin-secreting cells in a co-culture system. MIN6 cells used here kept most of beta-cell functions but less sensitive to glucose stimulation. Tolbutamide, the KATP channel blocker, was therefore used to stimulate insulin secretion in this report. MIN6 cells co-cultured with 3T3-L1 adipocytes had significantly reduced intracellular calcium concentration ([Ca2+]i) and lost the ability to secrete insulin in response to tolbutamide, compared to the control cells. 3T3-L1 adipocytes significantly decreased the expression of insulin, glucokinase and Kir6.2 genes but increased the expression of uncoupling protein-2 (UCP-2) in MIN6 cells after one week of co-culture, as measured by semi-quantitative RT-PCR. 3T3 L1 adipocyte-conditioned medium also significantly decreased insulin secretion and the expression of insulin, glucokinase and Kir6.2 genes in MIN6 cells. The conditioned medium also reduced tyrosine kinase activity in MIN6 cells. The inhibitor of protein tyrosine kinase, genistein, decreased the expression of glucokinase and Kir6.2 in MIN6 cells, while two free fatty acids, oleic acid and linoleic acids, were found to increase UCP-2 expression. The present study demonstrates that 3T3-L1 adipocytes directly impair insulin secretion and the expression of important genes in MIN6 cells. The effects of T3-L1 adipocytes on MIN6 cells are ascribed to secreted bioactive factors and may be mediated via multiple pathways, which include the upregulation of UCP-2 expression via free fatty acids, and downregulation of glucokinase and Kir6.2 expression via decreasing protein tyrosine kinase activity. PMID- 17709899 TI - Islet alpha-cells do not influence insulin secretion from beta-cells through cell cell contact. AB - Interactions between the endocrine cells in islets of Langerhans influence their secretory function, and disruption of islet structure results in impaired insulin secretory responses to both nutrient and non-nutrient stimuli. We have previously demonstrated that insulin-secreting MIN6 cells show enhanced secretory responses when grown as islet-like structures (pseudoislets) suggesting that homotypic cell cell interactions between beta-cells are important for normal function. We have now extended this experimental model to study the role of heterotypic interactions between insulin-expressing and glucagon-expressing cells by measuring the organization and secretory function of pseudoislets formed from MIN6 and alphaTC1 cells. The direct alpha-cell to beta-cell contact in the heterogenous MIN6/alphaTC1 pseudoislets was sufficient to enable the formation of anatomically correct islet-like structures, with a central core of MIN6 cells surrounded by a periphery of alphaTC1 cells. However, the presence of alphaTC1 cells had no detectable effect on insulin secretory responses to nutrient or non nutrient stimuli. In contrast, exogenous glucagon enhanced insulin secretion, in accordance with a paracrine role for alpha-cell-derived glucagon in the regulation of insulin secretion rather than direct, contact-mediated effects of alpha-cells on neighbouring beta-cells. PMID- 17709900 TI - Insulin like growth factor-1 (IGF-1) decreases ischemia-reperfusion induced apoptosis and necrosis in diabetic rats. AB - Previous evidence supports the view that insulin, as well as insulin like growth factor-1 (IGF-1) provides neurotropic support for neurons in the central nervous system (CNS) and peripheral nervous system (PNS). In the present study we evaluated the effects of the intravenous infusion of IGF-1 on both necrosis and apoptosis in the CNS of streptozotocin induced diabetic animals before and/or following middle cerebral artery occlusion (MCAO) with reperfusion. The lesion volume was used as an index of necrosis and the sensorimotor cortex (layers 5 and 6) as well as the CA1 and CA3 regions of the hippocampus were analyzed for apoptosis using TUNEL staining and Caspase-3 immunoreactivity. A large lesion volume was produced in diabetic animals after 2-h MCAO and 24-h reperfusion. Diabetic animals also had an elevated basal level of apoptotic cells that are bilaterally distributed. Apoptosis was further increased over basal after 2-h MCAO and 24-h reperfusion. The acute administration of IGF-1 30-min before or 2 h after MCAO followed by 24-h reperfusion decreased the lesion volume as well as the number of apoptotic cells in the cortical penumbra. Apoptosis as assessed by TUNEL and caspase-3 immunoreactivity was decreased in select sensorimotor cortex and hippocampal areas. We conclude that treatment with IGF-1 before or after ischemic insult significantly decreases both lesion volume and apoptosis in selected areas of the cortex and hippocampus. PMID- 17709901 TI - Phytosterol Pygeum africanum regulates prostate cancer in vitro and in vivo. AB - BACKGROUND: Prostate cancer is an important public health problem. It is an excellent candidate disease for chemoprevention because prostate cancer is typically slow growing and is usually diagnosed in elderly males. Pygeum africanum (Prunus africana or Rosaceae) is an African prune (plum) tree found in tropical Africa. An extract from the bark of Pygeum africanum has been used in Europe as a prevention and treatment of prostate disorders including benign prostatic hypertrophy (BPH). More recently in the USA, the phytotherapeutic preparations of Pygeum africanum and Saw palmetto have been marketed for prostate health including prostate cancer prevention and treatment. METHODS: The anti cancer potential of Pygeum africanum has been tested both in vitro (PC-3 and LNCaP cells) and in vivo (TRAMP mouse model). RESULTS: In tissue culture, ethanolic extracts (30%) of Pygeum africanum inhibited the growth of PC-3 and LNCaP cells; induced apoptosis and altered cell kinetics; down regulated ERalpha and PKC-alpha protein, and demonstrated good binding ability to both mouse uterine estrogen receptors and LNCaP human androgen receptors. TRAMP mice fed Pygeum africanum showed a significant reduction (P = 0.034) in prostate cancer incidence (35%) compared to casein fed mice (62.5%). CONCLUSION: Pygeum africanum, which is widely used in Europe and USA for treatment of BPH, has a significant role in regulation of prostate cancer both in vitro and in vivo and therefore may be a useful supplement for people at high risk for developing prostate cancer. PMID- 17709903 TI - Sustained fever resolved promptly after total thyroidectomy due to huge Hashimoto's fibrous thyroiditis. AB - We encountered a 55-year-old female patient with Hashimoto's thyroiditis who showed persistent fever, and could not find any source of fever other than the large nontender goiter. Her fever continued with positive CRP for 6 months. Although we did not assume that the inflammation was related to Hashimoto's thyroiditis, total thyroidectomy was performed for cosmetic reasons; however, fever was resolved immediately after thyroidectomy. Pathological diagnosis was Hashimoto's chronic thyroiditis. Immunohistochemical staining showed that the follicular cells were positive for IL-1alpha, IL-1beta, and TNF-alpha. We believed that fever was induced by inflammatory cytokines produced in thyroid. The case indicated that Hashimoto's thyroiditis with nontender goiter could cause idiopathic fever. PMID- 17709904 TI - Functions and oxidative stress status of leukocytes in patients with nephrotic syndrome. AB - This study was conducted to establish the functions and oxidative stress status in leukocytes of adult patients with nephrotic syndrome. Thirty adult patients with nephrotic syndrome and 32 controls were included. Phagocytosis ability, the killing ability of the micro-organism phagosited of polymorphonuclear leukocytes (PMNL) and monocytes, along with oxidative stress parameters of PMNLs were assessed. There was no statistically significant difference in phagocytosis function of PMNLs and monocytes of patients when compared to those of controls. PMNL burst activities of the patient and control groups also showed no difference; however, the monocyte burst activities of patients were significant (p = 0.012). The glutathione peroxidase (GSH-Px) activities in PMNLs of the patients with nephrotic syndrome were significantly higher (p = 0.026) when compared to those of controls. In comparison with those of the control subjects, the patients had also higher selenium levels in their PMNLs (p < 0.001). Although PMNL malonyldialdehyde (MDA) levels of the patients seem to be higher than those of controls, the difference had no statistical significance (p = 0.071). Conclusively, in the patients with nephrotic syndrome, PMNLs appear to be exposed to an oxidative stress as indicated by their increased GSH-Px activities and selenium content. However, PMNLs in nephrotic syndrome patients seem to be coping with the insulting oxidative stress, as suggested by their near-normal MDA productions. Furthermore, these data suggest that nephrotic syndrome appears not to have an influence on phagocytosis and killing abilities of granulocytes and monocytes as long as these cells can overcome the oxidative stress to which they are exposed in this disease. PMID- 17709902 TI - Anti-oxidative effect of Klotho on endothelial cells through cAMP activation. AB - Klotho, a regulatory factor implicated in countering the aging process, has been reported to ameliorate endothelial dysfunction in vivo. To clarify whether Klotho protein directly affects endothelial cell function, we studied the effects of membrane-form Klotho on manganese superoxide dismutase (Mn-SOD) expression and nitric oxide production in human umbilical vein endothelial cells (HUVEC). We incubated HUVEC with conditioned medium from COS-1 cells transfected with expression vector, pCAGGS-klotho (Klotho-CM) or a recombinant, purified 6His tagged Klotho protein. Both Klotho-CM and 6His-tagged Klotho protein enhanced Mn SOD expression by approximately two-fold, partially via activation of the cAMP signaling pathway. Furthermore, Klotho-CM increased nitric oxide production, which also contributed to the up-regulation of Mn-SOD. Using the oxidation sensitive dye dihydroethidium, we found that Klotho inhibited angiotensin II induced reactive oxygen species production in HUVEC. These findings provide new insights into the mechanisms of Klotho action and support the therapeutic potential of membrane-form Klotho to regulate endothelial function. PMID- 17709905 TI - Selected zinc metabolism parameters in premenopausal and postmenopausal women with moderate and severe primary arterial hypertension. AB - The aim of this study was to compare zinc (Zn) metabolism parameters in groups of premenopausal and postmenopausal women with moderate and severe primary arterial hypertension. The study included 38 women, of which 15 were premenopausal and 23 were postmenopausal. Postmenopausal women had a positive correlation between total (ERCt- Zn) and oubain-dependent (ERCos-Zn) rate constants of Zn efflux from lymphocyte (k = 0.52). In premenopausal women's ERCos-Zn was negatively but weakly correlated with serum Zn (Zn-s) (k = 0.35). The Zn ERCt- Zn and ERCos-Zn did not show any correlation with age, as did Zn-s. Lymphocyte Zn correlated negatively with age only in premenopausal women (k = -0.62). The renin angiotensin-aldosterone system correlated with Zn metabolism parameters. In premenopausal women, plasma renin activity and serum aldosterone showed positive correlations with lymphocyte Zn (Znl) (k = 0.63 and k = 0.41, respectively), and in postmenopausal women, it correlated negatively with Zn-s (k = -0.38) and whole aldosterone correlated negatively with ERCos-Zn (k = -0.41). Positive correlations between Zn metabolism parameters and arterial blood pressure in premenopausal women were as follows: ERCt-Zn with diastolic blood pressure (dRR) (k = 0.40) and ERCos-Zn with dRR (k = 0.47). In postmenopausal women, the correlations between ERC-t-Zn and dRR and systolic blood pressure (sRR) were negative (k = -0.53 and k = -0.63, respectively). A similar situation was observed between dRR and sRR and Zn-s (k = -0.40 and k = -0.38, respectively). The body mass index (BMI) was positively correlated with ERCt-Zn in premenopausal women (k = 0.36), whereas in postmenopausal, it was negatively correlated with ERCos-Zn (k = -0.42). For the whole group, negative correlations were seen between Zns and dRR and sRR (k = -0.36 and k = -0.39, respectively) and between ERCos-Zn and BMI (k = -0.39). The results presented show differences in Zn metabolism in arterial hypertension between premenopausal and postmenopausal women. The role of estrogens in these differences is disscused. PMID- 17709906 TI - Prediction of prostate cancer using hair trace element concentration and support vector machine method. AB - A change in the normal concentration of essential trace elements in the human body might lead to major health disturbances. In this study, hair samples were collected from 115 human subject, including 55 healthy people and 60 patients with prostate cancer. The concentrations of 20 trace elements (TEs) in these samples were measured by inductively coupled plasma-mass spectrometry. Asupport vector machine was used to investigate the relationship between TEs and prostate cancer. It is found that, among the 20 TEs, 10 (Mg P, K, Ca, Cr, Mn, Fe. Cu, Zn, and Se) are related to the risk of prostate cancer. These 10 TEs were used to build the prediction model for prostate cancer. The model obtained can satisfactorily distinguish the healthy samples from the cancer samples. Furthermore, the cross-validation by leaving-one method proved that the prediction ability of this model reaches as high as 95.8%. It is practical to predict the risk of prostate cancer using this model in the clinics. PMID- 17709907 TI - Evaluation of endemic goiter prevalence in Bulgarian schoolchildren: results from national strategies for prevention and control of iodine-deficiency disorders. AB - Iodine deficiency is a major health problem worldwide. The environment of the Balkan countries, including Bulgaria, is distinguished for its low iodine content. In 1994, the strategies for the prevention and control of iodinedeficiency disorders were actualized in Bulgaria and universal salt iodization and supplementation for the risk population groups (schoolchildren, pregnant women) were introduced. The aim of this study was to assess the effectiveness of the iodine prophylaxis in schoolchildren, living in an endemic for goiter area after the introduction of salt iodization in Bulgaria. For this purpose, the goiter prevalence and iodine status in 483 schoolchildren (274 boys and 209 girls) aged between 8 and 15 yr, living in an endemic for goiter area in Bulgaria were evaluated. Despite the normalization of iodine supply, mild iodine deficiency on the basis of goiter prevalence (16.15%) and urinary iodine excretion was found. These data indicate the need for reevaluation of the national strategy for prevention of iodine deficiency. PMID- 17709908 TI - Effects of fluoride on the intracellular free Ca2+ and Ca2+-ATPase of kidney. AB - In the present study, the effect of fluoride on intracellular free calcium ([Ca2+]i) and Ca2+-ATPase of renal cells were examined. Some paradoxical experimental results about the mechanism of fluoride toxicity were observed. In vivo, 48 Wistar rats were divided into 4 groups, and half of rats were treated with sodium fluoride (NaF) by drinking water (per liter of tap water containing 100 mg F-). Compared with the respective control, the level of [Ca2+]i of the kidney in two fluoride-treated rats obviously increased (p < 0.05); and the activity of Ca2+-ATPase in 100 mg F-/L groups with a standard diet did not significantly increase, and the enzyme activity in 100-mg F-/L group with a low calcium diet decreased significantly compared to the 100 mg F-/L group with a standard diet (p < 0.05). In vitro, renal tubular cells were cultured and respectively exposed to 1.0, 5.0, 7.5, and 12.5 mg/L fluoride in the culture medium. Results showed the significantly elevated activity of Ca2+-ATPase in the cells exposed to 1.0 and 5.0 mg/L fluoride (p < 0.05), and this enzyme activity indicated inhibitory trend in cells of the 7.5- and 12.5-mg/L fluoride-treated group. To sum up, the effect of fluoride on Ca2+-ATPase is a similar to a dose effect relationship phenomenon characterized by low-dose stimulation and high dose inhibition, and the increase of [Ca2+]i probably plays a key role on the mechanism of renal injury in fluorosis. PMID- 17709909 TI - Investigation of the effects of alpha-tocopherol on the levels of Fe, Cu, Zn, Mn, and carbonic anhydrase in rats with bleomycin-induced pulmonary fibrosis. AB - This study was designed to examine the effects of vitamin E on the levels of Zn, Mn, Cu, Fe, and carbonic anhydrase in rats with bleomycininduced pulmonary fibrosis. Twenty-one male Wistar albino rats were randomly divided into three groups: bleomycin alone, bleomycin+vitamin E, and saline alone (control group). The bleomycin group was given 7.5 mg/kg body weight (single dose) bleomycin hydrochloride intratracheally. The bleomycin+vitamin E group was also instilled with bleomycin hydrochloride but received injections of alpha-tocopherol twice a week. The control group was treated with saline alone. Animals were sacrified 14 d after intratracheal instillation of bleomycin. Tissue Zn, Mn, Cu, Fe, and carbonic anhydrase activities were measured in the lung and liver. Lung Cu, Fe, and carbonic anhydrase activity increase in both experimental groups. Zn and Mn levels decreased, except for the Mn level in the bleomycin group. Liver Zn, Mn, and Cu levels decreased in both experimental groups compared to the control group, whereas Fe and carbonic anhydrase activity increased in comparison to the control group. However, the liver tissue Fe level decreased compared to the control group. In the histopathologic assesment of lung sections in the bleomycin+vitamin E group, partial fibrotic lesions were observed, but the histopathologic changes were much less severe compared to the bleomycin-treated group. PMID- 17709911 TI - Excess calcium increases bone zinc concentration without affecting zinc absorption in rats. AB - We examined zinc (Zn) metabolism in rats given diets containing excess calcium (Ca). Rats were given phytate-free diet containing 5 g Ca/kg (control), 12.5 g Ca/kg, or 25 g Ca/kg for 4 wk in Experiment 1. The dietary treatment did not affect Zn concentration in the plasma, testis, kidney, spleen and liver; however, Zn concentration in the femur and its cortex was significantly higher in rats given diet containing 25 g Ca/kg than in other rats. Rats were given phytate-free diet containing 5 g Ca /kg or 25 g Ca /kg for 4 wk in Experiment 2. After 12-h food deprivation, rats were given a diet extrinsically labeled by 67Zn with dysprosium as a fecal marker for 4 h. Feces were collected from 1 d before administration of the labeled diet to 5 d after administration. Excess Ca did not affect the true absorption of Zn and its endogenous excretion but increased femoral Zn. These results suggest that excess Ca improves Zn bioavailability without affecting Zn absorption when diets do not contain phytate. PMID- 17709910 TI - Gender-dependent effects of selenite on the perfused rat heart: a toxicological study. AB - Gender differences are related to the manner in which the heart responds to chronic and acute stress conditions of physiological and pathological nature. Depending on dose, sodium selenite acts as an antioxidant proven to have beneficial effects in several pathological conditions G. Drasch, J. Schopfer, and G. N. Schrauzer, Selenium/cadmium ratios in human prostates: indicators of prostate cancer risk of smokers and nonsmokers, and relevance to the cancer protective effects of selenium, Biol. Trace Element Res. 103(2), 103-107 (2005); R. G. Kasseroller and G. N. Schrauzer, Treatment of secondary lymphedema of the arm with physical decongestive therapy and sodium selenite: a review, Am. J. Ther. 7(4), 273-279 (2000); G. N. Schrauzer, Anticarcinogenic effects of selenium, Cell. Mol. Life Sci. 57(13-14), 1864-1873 (2000); I. S. Palmer and O. E. Olson, Relative toxicities of selenite and selenate in the drinking water of rats, J. Nutr. 104(3), 306-314 (1974). To date, little is known about the gender dependent direct effects of toxic doses of selenite on electrophysiology of the cardiovascular system H. A. Schroeder and M. Mitchener, Selenium and tellurium in rats: effect on growth, survival and tumors, J. Nutr. 101(11), 1531-1540 (1971); G. N. Schrauzer, The nutritional significance, metabolism and toxicology of selenomethionine, Adv. Food Nutr. Res. 47, 73-112 (2003). In the present study, the effects of in vitro toxic concentrations of sodium selenite ranging from 10-6 M to 10-3 M were tested on both male and female rat heart preparations. The toxic effects seen in an electrocardiogram and left ventricular pressure were dose and sex dependent at most of the tested concentrations. The present study clearly shows that at toxic doses, stress conditions are induced by selenite, resulting in genderdependent modifications of the heart function. This modification is more pronounced in the contraction cascade of female rats. Males, on the other hand, had been much more affected in excitation-related parameters. PMID- 17709912 TI - Effects of Nigella sativa and human parathyroid hormone on bone mass and strength in diabetic rats. AB - Osteoporosis is a major complication in patients with diabetes mellitus (DM), particularly in those with insulin dependency. Recently, many therapeutic effects of Nigella sativa L. (NS) extracts have been exhibited such as anti-inflammatory, antitumor, and antidiabetic with clinical and experimental studies. Mechanical strength in the femur and vertebrae increases with human parathyroid hormone (hPTH) treatment. The aim of the present study was to test the hypothesis that combined treatment with NS and hPTH is more effective than treatment with NS or hPTH alone in improving bone mass, connectivity, and biomechanical behavior using the finite element method (FEM) in insulin-dependent diabetic rats. In the mechanical analysis, five rat bones (control, diabetic diabetic NS treated, diabetic hPTH treated, and diabetic NS + hPTH treated) have been studied for bending analysis using the finite element analysis program ANSYS. Combined treatment of NS and hPTH was more effective on bone histomorphometry and mechanical strength than treatment with NS or hPTH alone for streptozotocin induced diabetic osteopenia, which notably decreased bone volume. PMID- 17709913 TI - Involvement of oxidative stress in the impairment in biliary secretory function induced by intraperitoneal administration of aluminum to rats. AB - We have shown that aluminum (Al) induces cholestasis associated with multiple alterations in hepatocellular transporters involved in bile secretory function, like Mrp2. This work aims to investigate whether these harmful effects are mediated by the oxidative stress caused by the metal. For this purpose, the capability of the antioxidant agent, vitamin E, to counteract these alterations was studied in male Wistar rats. Aluminum hydroxide (or saline in controls) was administered ip (27 mg/kg body weight, three times a week, for 90 d). Vitamin E (600 mg/kg body weight) was coadministered, sc. Al increased lipid peroxidation (+50%) and decreased hepatic glutation levels (-43%) and the activity of glutation peroxidase (-50%) and catalase (-88%). Vitamin E counteracted these effects total or partially. Both plasma and hepatic Al levels reached at the end of the treatment were significantly reduced by vitamin E (-40% and -44%, respectively; p<0.05). Al increased 4 times the hepatic apoptotic index, and this effect was fully counteracted by vitamin E. Bile flow was decreased in Altreated rats (-37%) and restored to normality by vitamin E. The antioxidant normalized the hepatic handling of the Mrp2 substrates, rose bengal, and dinitrophenyl-S glutathione, which was causally associated with restoration of Mrp2 expression. Our data indicate that oxidative stress has a crucial role in cholestasis, apoptotic/necrotic hepatocellular damage, and the impairment in liver transport function induced by Al and that vitamin E counteracts these harmful effects not only by preventing free-radical formation but also by favoring Al disposal. PMID- 17709914 TI - Lowering asymmetric dimethylarginine--a new mechanism mediating the renoprotective effects of renin-angiotensin system inhibitors in proteinuric patients? PMID- 17709916 TI - Association of plasma adiponectin levels with oxidative stress in hemodialysis patients. AB - BACKGROUND: Recent evidence suggests that oxidative stress may be an instigator of the metabolic syndrome, and adiponectin, an adipocyte-derived polypeptide, may modulate oxidative stress, ameliorating the atherosclerotic process. AIM: Oxidative stress is increased in hemodialysis (HD) patients. We hypothesize that a relationship between plasma levels of adiponectin and markers of inflammation and oxidative stress exists. METHODS AND RESULTS: In 124 HD patients, plasma adiponectin levels and three separate oxidative stress markers, tumor necrosis factor-alpha as well as high-sensitivity C-reactive protein (hsCRP) were determined. Plasma adiponectin was significantly and negatively correlated with serum hsCRP (r = -0.247, p = 0.008) and plasma malondialdehyde (MDA) levels (r = 0.326; p < 0.001). Multiple regression analyses suggested that plasma MDA, serum HDL cholesterol levels and logarithmically transformed hsCRP were the variables independently associated with plasma adiponectin levels. CONCLUSION: Plasma adiponectin was significantly associated with plasma MDA, serum HDL cholesterol levels and serum hsCRP levels. Our results suggest the possibility that plasma adiponectin may play a role in alleviating oxidative stress in HD patients. PMID- 17709915 TI - Improving proteinuria, endothelial functions and asymmetric dimethylarginine levels in chronic kidney disease: ramipril versus valsartan. AB - BACKGROUND: The aim of this study was to find out whether the beneficial effects of the renin-angiotensin-aldosterone system (RAS) blockage in chronic kidney disease (CKD) has any relation with the alteration of asymmetric dimethylarginine (ADMA) levels. METHODS: Sixty-six nondiabetic patients with CKD and proteinuria and 36 healthy subjects were enrolled. Patients were treated with either ramipril 5 mg daily or valsartan 160 mg daily for 3 months. Proteinuria, ADMA, symmetric dimethyl arginine (SDMA), flow-mediated dilatation (FMD) and HOMA index measurements were performed both before and after the treatment. RESULTS: ADMA, SDMA, hsCRP levels, HOMA index and proteinuria of patients were significantly higher (p < 0.001 for all) and FMD, L-arginine and L-arginine/ADMA ratio in CKD were significantly lower than controls. According to the multiple regression analysis, proteinuria levels were independently related to ADMA and SDMA levels. CONCLUSION: Both drugs were equally effective in reducing elevated ADMA levels and improving endothelial dysfunction in CKD patients. PMID- 17709917 TI - The spectrum of fungal allergy. AB - Fungi can be found throughout the world. They may live as saprophytes, parasites or symbionts of animals and plants in indoor as well as outdoor environment. For decades, fungi belonging to the ascomycota as well as to the basidiomycota have been known to cause a broad panel of human disorders. In contrast to pollen, fungal spores and/or mycelial cells may not only cause type I allergy, the most prevalent disease caused by molds, but also a large number of other illnesses, including allergic bronchopulmonary mycoses, allergic sinusitis, hypersensitivity pneumonitis and atopic dermatitis; and, again in contrast to pollen-derived allergies, fungal allergies are frequently linked with allergic asthma. Sensitization to molds has been reported in up to 80% of asthmatic patients. Although research on fungal allergies dates back to the 19th century, major improvements in the diagnosis and therapy of mold allergy have been hampered by the fact that fungal extracts are highly variable in their protein composition due to strain variabilities, batch-to-batch variations, and by the fact that extracts may be prepared from spores and/or mycelial cells. Nonetheless, about 150 individual fungal allergens from approximately 80 mold genera have been identified in the last 20 years. First clinical studies with recombinant mold allergens have demonstrated their potency in clinical diagnosis. This review aims to give an overview of the biology of molds and diseases caused by molds in humans, as well as a detailed summary of the latest results on recombinant fungal allergens. PMID- 17709918 TI - Polymerase-chain-reaction-based detection of fetal rhesus D and Y-chromosome specific DNA in the whole blood of pregnant women during different trimesters of pregnancy. AB - OBJECTIVE: The aim of this study was to determine whether or not a noninvasive procedure utilizing maternal peripheral blood as the source of DNA and polymerase chain reaction (PCR) could be used to detect fetal rhesus D (RhD) status as well as fetal gender during different gestational stages of pregnancy. MATERIALS AND METHODS: Maternal blood samples were obtained from 54 RhD-negative pregnant women during the first trimester (6-13 weeks, n = 14), second trimester (14-26 weeks, n = 26) and third trimester (27-40 weeks, n = 14). Genomic DNA was extracted from the whole blood and analyzed by seminested and nested PCR for detection of DNA sequences corresponding to RhD (n = 54) and Y chromosome (n = 48) using RhD and Y chromosome-specific oligonucleotide primers, respectively. The seminested/nested PCR results were compared with the RhD status and gender of the babies after delivery. RESULTS: The sensitivity and specificity of seminested PCR for detection of fetal RhD positivity in whole blood of pregnant women were 81 and 100%, respectively, while the sensitivity and specificity of nested PCR for detection of male fetuses, using Y-chromosome-specific DNA as a marker, were 96 and 91%, respectively. There were no significant differences in the PCR results with samples obtained from women at different gestational stages of pregnancy. CONCLUSION: Seminested and nested PCRs for detection of fetal RhD and gender status, respectively, by using the blood of pregnant women during different gestational stages of pregnancy, are reliable noninvasive procedures with high sensitivity and specificity. PMID- 17709919 TI - Outcomes of primary percutaneous coronary intervention in acute myocardial infarction at Tehran Heart Center. AB - OBJECTIVE: To describe our experience of primary angioplasty in ST-segment elevation myocardial infarction. SUBJECTS AND METHODS: During a period of 2 years (April 2003 to May 2005), 83 high-risk patients presenting with acute ST-segment elevation myocardial infarction underwent primary angioplasty subject to availability of balloon dilation within 90 min of admission. In total, 73 stents were implanted; 69 were bare metal stents, while the remaining 4 were paclitaxel eluting stents. Of the 83 patients, 8 presented with cardiogenic shock. Follow-up was for a period of 9 months. All angiographic, in-hospital and clinical outcomes were recorded on a database. RESULTS: The procedure was successful in 79 of the 83 patients (95%) and unsuccessful in 4 (5%). Of these 4 patients, 3 died and 1 was treated medically. In 65 patients with zero perfusion, angioplasty was successful in 61 (93.8%), while it was completely successful (100%) in the remaining 18 patients with thrombolysis in myocardial infarction grade 3 perfusion. Vessel patency was achieved in 95% with thrombolysis in myocardial infarction grade 3 flow present in 93%. A total of 7 (8.5%) patients died while in the hospital. Of the 8 with initial cardiogenic shock on presentation, 4 (50%) died in the hospital and of the remaining 4, 1 was lost at 9-month follow-up. In hospital reocclusion and reinfarction did not occur in any patient. CONCLUSION: The results suggest that primary angioplasty is logistically feasible in our center with good clinical outcomes. PMID- 17709920 TI - Limited dose-effect relationship of adenosine for detection of atrioventricular nodal duality in patients with supraventricular tachycardias. AB - OBJECTIVE: The purpose of the study was to test the dose-effect relationship of adenosine for the diagnosis of dual atrioventricular (AV) nodal physiology in patients presenting with supraventricular tachycardia. SUBJECTS AND METHODS: The study population consisted of 57 patients (mean age 50 +/- 14 years; 36 females, 21 males) with palpitations related to supraventricular tachycardia. Adenosine was injected as bolus during sinus rhythm at rest in order to unmask dual AV nodal physiology by a PR jump on surface ECG (defined as a sudden increase by > or = 50 ms measured from the onset of the P-wave to the R-wave between two consecutive sinus beats). According to a stepwise clinical approach, adenosine was administered as bolus in incremental dosages (6 mg followed by 12 mg, if necessary up to 18 mg). Once a PR jump > or = 50 ms or a high-grade AV block was noted on surface ECG, the injection was stopped at that dose. RESULTS: A significant PR jump was noted after injection of 6 mg (n = 21, 99 +/- 30 ms) or 12 mg (n = 13, 94 +/- 35 ms), but not after 18 mg (n = 4, 35 +/- 10 ms) adenosine. Provocation of temporary first-grade AV block (n = 13) was associated with the longest increment of PR interval, whereas high-grade AV block (n = 36) produced a significantly shorter PR jump (105 +/- 35 vs. 65 +/- 40 ms, p = 0.0024). Electrophysiological study and ablation were performed in 37 highly symptomatic patients. AV nodal reentrant tachycardia was diagnosed in 33 patients and orthodromic AV reentrant tachycardia in 4 patients. CONCLUSION: The adenosine test was characterized by a reverse dose-effect relationship as far as identification of AV nodal duality was concerned. PMID- 17709921 TI - The diagnostic value of absolute neutrophil count, band count and morphologic changes of neutrophils in predicting bacterial infections. AB - OBJECTIVES: To evaluate the value of neutrophil left shift parameters and neutrophil morphologic changes in diagnosing acute bacterial infections. MATERIALS AND METHODS: Peripheral blood samples were obtained from 105 patients who had a positive culture for bacteria. Automated complete white blood cell count was performed as well as peripheral blood smear preparation. Absolute neutrophil count (ANC) and neutrophil band count were determined and the neutrophils were evaluated for morphologic changes, namely toxic granulation, vacuolation and Dohle bodies. RESULTS: Band count was less sensitive than ANC and white blood cell count in predicting bacterial infections except in the elderly and infant population. Toxic granulation in neutrophils appeared to be as sensitive as ANC in predicting bacterial infection. CONCLUSION: ANC and toxic granulation appear to be more sensitive than band count in predicting bacterial infections. However, band count has a greater sensitivity in infants and elderly patients. PMID- 17709922 TI - Therapeutic drug monitoring of gentamicin: evaluation of five nomograms for initial dosing at Al-Amiri Hospital in Kuwait. AB - OBJECTIVE: To compare five published nomograms (Thomson guidelines, Mawer nomogram, rule of eights, Hull-Sarubbi table and Dettli method) for calculating the initial gentamicin dosage regimen in a Kuwaiti population. MATERIALS AND METHODS: Based on measured peak and trough gentamicin concentrations, the elimination rate constant and volume of distribution of gentamicin were calculated for each patient (n = 56), using a modified two-point Sawchuk-Zaske method. The calculated individual set of pharmacokinetic parameters and the initial dose regimen recommended by each of the five methods were used to predict the steady-state peak and trough of gentamicin concentrations. RESULTS: The Thomson guidelines produced consistent results in predicting gentamicin concentrations within the target ranges of peak plus trough, peak only and trough only (63, 75 and 75%, respectively). The Mawer nomogram, Hull-Sarubbi table and Dettli methods achieved similar percentages of patients (46-50%) within the target ranges (5-10 mg x l(-1) for peak and 0.5-2 for trough), whereas empirical dosing and the rule of eights showed the lowest percentages of patients within the peak plus trough target range (25 and 37%, respectively). However, with respect to the underdosing target range (predicted concentration <5 mg x l(-1)), the Thomson guidelines showed that 21% of patients were underdosed. CONCLUSION: The results show that a large number of patients (37-63%) were outside the target ranges in all initial gentamicin dosing methods evaluated in this study. Therefore, serum concentration measurement can be advised to assist in the optimization of gentamicin dose selection. PMID- 17709923 TI - Bioavailability assessment of vitamin A self-nanoemulsified drug delivery systems in rats: a comparative study. AB - OBJECTIVES: To assess and compare the bioavailability of three different oral dosage forms of vitamin A in rats. The formulations included vitamin A self nanoemulsified drug delivery (SNEDD) optimized formulation-filled capsule (F1), vitamin A SNEDD optimized formulation compressed tablet (F2) and vitamin A oily solution-filled capsules without any additives (control, F3). MATERIALS AND METHODS: Bioavailability was assessed after a single oral dose of the three formulations using three groups of rats, each group comprising 6 rats. Blood samples were collected at baseline and over the next 8 h. Plasma was separated and extracted to obtain the drug, which was measured by HPLC. Statistical data analysis was performed using the Student t test and ANOVA with p < 0.05 as the minimal level of significance. RESULTS: From the pharmacokinetic parameters, both F1 and F2 showed improved bioavailability compared to F3. The values of AUC +/- SD were 3,080.7 +/- 190.2, 2,137.1 +/- 130.5 and 1,485.2 +/- 80.1 ng x h/ml for F1, F2 and F3, respectively. The Tmax was 1 h in case of F1 and F2 as compared to 1.5 h for F3. The Cmax +/- SD was 799.5 +/- 48.5, 656.2 +/- 64.4 and 425.8 +/- 33.1 for F1, F2 and F3, respectively. The increase in AUC, Cmax and Tmax was significant (p < 0.05). The bioavailability calculated from the AUC for F1 and F2 relative to F3 was 207.4 and 143.8%, respectively. The bioavailability increased almost twofold and 1.4 times for F1 and F2, respectively. CONCLUSIONS: The study showed that the newly developed vitamin A SNEDD formulations increased the rate and extent of drug absorption compared to the oily drug solution. The present investigation demonstrated that vitamin A SNEDD optimized formulations, either as filled capsules or as compressed tablets, were superior to its oily solution with regard to their biopharmaceutical characteristics. PMID- 17709924 TI - Histological and ultrastructural changes of cardiomyocytes in experimental rats with tail thrombosis following subplantar application of carrageenin. AB - OBJECTIVE: To describe histological and ultrastructural changes of cardiomyocytes in experimental rats following subplantar administration of carrageenin. MATERIAL AND METHODS: In adult rats, an acute inflammatory reaction was induced by subplantar injection of 0.1 ml of 1% sterile carrageenin solution. In a total of 10 rats, which developed gangrene of tails in 5- to 12-cm-long segments, were killed and their internal organs fixed in 10% formaldehyde solution and subsequently processed for paraffin embedding. Later, blocks of the ventricular heart tissue were refixed and reprocessed for Araldite embedding and ultrastructure observation. Similarly, the cardiac muscle of control, carrageenin injected rats which did not develop vascular thrombosis was processed. RESULTS: The cardiomyocytes of rats injected with carrageenin showed focal dystrophic alterations, enlarged mitochondria with densely packed concentrically oriented cristae, and many dense and irregularly shaped deposits with microgranular helicoid organization. Normal cardiomyocytes were observed in control rats. Complicating thrombosis of tail blood vessels leading to extensive tail necroses were also histologically confirmed. CONCLUSION: These findings demonstrate specific pathogenic effect in the cardiovascular system of the carrageenin treated rats. PMID- 17709925 TI - Serum cholesteryl ester transfer protein concentrations are associated with serum levels of total cholesterol, beta-lipoprotein and apoproteins in patients with type 2 diabetes mellitus. AB - OBJECTIVE: To investigate the role of serum cholesterol ester transfer protein (CETP) and the metabolism of various lipids including apoproteins in patients with type 2 diabetes. MATERIALS AND METHODS: The relationships between serum concentrations of CETP and various lipids and apoproteins were investigated in 193 patients with type 2 diabetes mellitus and 68 age-matched healthy subjects. Serum CETP concentrations were measured by an enzyme-linked immunosorbent assay. RESULTS: Serum CETP values were lower in diabetic patients than in healthy controls (p < 0.01). Female diabetic patients had significantly higher CETP concentrations than male patients. Serum CETP concentrations exhibited a significant positive correlation with serum concentrations of cholesterol (TC) and beta-lipoproteins in diabetic patients (r = 0.485, p = 0.013). Patients with relatively high serum concentrations of high-density lipoprotein cholesterol (HDL C) tended to have much lower CETP concentrations than patients with lower HDL-C concentrations. Serum CETP concentrations showed significant positive correlations with those of apoproteins B (Apo B; r = 0.384, p = 0.024) and E (Apo E; r = 0.341, p = 0.035). CONCLUSION: The data indicate that serum CETP is closely involved in the metabolism of TC, beta-lipoprotein, Apo B and Apo E in type 2 diabetic patients. PMID- 17709926 TI - Total hip arthroplasty in acetabular deficiency: experience in Al Razi Hospital, Kuwait. AB - OBJECTIVE: To report clinical and radiological outcomes of cemented and cementless total hip arthroplasty for primary and secondary osteoarthritis with a deficiency of acetabular bone stock. SUBJECT AND METHODS: Thirty-seven patients (16 male and 21 female) having 41 hips affected by primary and secondary acetabular bone stock defect that were operated using cemented (n = 25) and cementless (n = 16) hip replacement were followed for an average period of 37 (range 12-100) months. Bone defect was classified according to American Academy of Orthopedic Surgery criteria. Different types of bone graft techniques and metal reinforcements were used. Merle d'Aubigne clinical score was used to calculate clinical outcomes. Geometrical position of the acetabular component, cup integration, hip center and graft integration were assessed. RESULTS: The mean clinical score improved significantly from 10.6 patients preoperatively to 16.7 patients postoperatively; 95% of the cups were in the desired position and were considered integrated and the bone graft remodeled in most cases. There were 2 deep infections, 1 dislocation and 2 cases of transient neurological deficit. No significant differences in final clinical and radiological outcomes, rate of loosening and rate of complications were found between cemented and cementless acetabular replacements. CONCLUSION: The results show that reconstruction of acetabular bone deficiency can be accomplished with few complications using either a cemented or cementless acetabular component with or without grafting according to the clinical situation. PMID- 17709927 TI - Can spirometry, pulse oximetry and dyspnea scoring reflect respiratory failure in patients with chronic obstructive pulmonary disease exacerbation? AB - OBJECTIVE: To evaluate the extent to which oximetry, spirometry and dyspnea scoring can reflect hypoxemia and hypercapnia among patients admitted to the emergency department (ED) with acute exacerbations of chronic obstructive pulmonary disease. SUBJECTS AND METHODS: Spirometry, oxygen saturation by pulse oximetry (SpO2), arterial blood gas analysis and dyspnea scoring assessments were made in the ED. Correlations of these parameters were evaluated by means of Pearson's test. Pulse oximetry cutoff values to express hypoxemia were demonstrated by receiver operating characteristic (ROC) curves. RESULTS: 76 patients with a mean age of 68.0 years were included in the study. Mean spirometric values, expressed as percentages of predicted values, were forced expiratory volume in 1 s (FEV1) = 23.1 +/- 9%; forced vital capacity (FVC) = 32.8 +/- 11%, and mean FEV1/FVC = 72.4 +/- 21.6%. While there was a positive correlation between the SpO2, SaO2 and PaO2 values (r = 0.91 and 0.80, respectively), a negative correlation (r = -0.74) was observed between PaCO2 and SpO2. In determining hypoxemia, both SpO2 and FEV1 were sensitive (83.9 and 90.3%, respectively) while dyspnea scoring was the most sensitive (93.5%). In the evaluation by means of an ROC curve, a saturation of 88.5% for the pulse oximeter was the best cutoff value to reflect hypoxemia (sensitivity 95.6%, specificity 80.6%). CONCLUSION: SpO2 alone appears to be as highly specific as a combination of other tests in the evaluation of hypoxemia. A cutoff value for SpO2 of < or = 88.5% is proposed as a criterion in screening for hypoxemia. PMID- 17709928 TI - Depressive symptoms among Kuwaiti population attending primary healthcare setting: prevalence and influence of sociodemographic factors. AB - OBJECTIVES: The aim of this study was to estimate the prevalence of depressive disorders and the influence of sociodemographic characteristics on primary healthcare (PHC) setting in Kuwait. SUBJECTS AND METHODS: A cross-sectional survey was conducted in PHC setting in Kuwait using the Beck Depression Inventory second edition questionnaire (BDI II) as a screening instrument, together with a sociodemographic questionnaire. A representative sample drawn from the target population consisted of 2,320 subjects of Kuwaiti nationality randomly selected from 18 PHC centers covering all Kuwait governorates during the period from April 2003 to January 2004. The target age group was 21-64 years. Participants were asked to complete the BDI II questionnaire consisting of 21 items reflecting the depressive disorder independently. Sociodemographic data such as sex, age, marital status, children, occupation, educational status, chronic diseases and social problems were included in the questionnaire. The optimum cutoff score for BDI II was estimated. RESULTS: A total of 2,320 participants completed the questionnaire, 1,082 (46.8%) male and 1,237 (53.2%) female; 860 (37.1%) screened positive for depressive symptoms, among whom 352 (15.3%) were male and 508 (21.7%) female. Of all participants, 163 (7.0%) were severely depressed, 314 (13.5%) moderately depressed and 383 (16.5%) mildly depressed. Depressive disorder was more prevalent among women than men, young than old, more among highly educated individuals, working participants, married individuals, and parents with 3 or more children. CONCLUSION: Depressive disorder is a highly prevalent condition among Kuwaiti patients attending PHC setting. Chronic diseases and social problems are risk factors for depressive disorder. PMID- 17709929 TI - Association between an AluI polymorphism in the calcitonin receptor gene and quantitative ultrasound parameters in Korean men. AB - OBJECTIVE: The purpose of this study was to investigate the association between an AluI RFLP of the calcitonin receptor (CTR) gene and quantitative ultrasound (QUS) parameters in Korean men, and the interaction with nutrition as a lifestyle factor. MATERIALS AND METHODS: Broadband ultrasound attenuation, speed of sound and stiffness index of the calcaneus were measured using an ultrasound bone densitometer in 201 Korean men (mean age +/- SD: 51.6 +/- 11.7 years). The PCR RFLP method was used to analyze an AluI polymorphism in the CTR gene. RESULTS: In all subjects, the distribution of CC, CT and TT genotypes occurred with frequencies of 87.1, 12.4 and 0.5%, respectively. When stratified by omnivore and vegetarian groups, there was a significant association between an AluI polymorphism in the CTR gene and QUS parameters such as speed of sound and stiffness index in only vegetarian subjects. CONCLUSION: Our data suggest that the AluI polymorphism of the CTR gene can be useful as a genetic marker in the interindividual susceptibility of QUS parameters by the interaction with nutritional status as a lifestyle factor. PMID- 17709930 TI - Application of lateral arm free flap in oral and maxillofacial reconstruction following tumor surgery. AB - OBJECTIVE: To describe the application of lateral arm free flap (LAFF) in reconstruction of defects in the oral and maxillofacial regions following ablative oncological surgery. SUBJECTS AND METHODS: The study included 16 patients (13 male, 3 female, mean age 56, range 35-69 years). Sixteen LAFF were harvested to reconstruct defects caused by the dissection of malignant tumors of the oral and maxillofacial regions. The tumor was squamous cell carcinoma of the tongue (6 cases), floor of the mouth (4), retromolar area (3), inner cheek (2), and lower gingival (1). Flap sizes ranging from 5 x 7 to 6 x 9 cm were harvested using a sterile tourniquet for bloodless technique. The anastomoses were carried out using a magnifier or microscope. All donor defects were closed primarily. RESULTS: Fourteen flaps healed without venous insufficiency. One flap, in a female patient, survived with mild local microcirculatory obstruction but that of another female patient developed necrosis. There was no significant complication at the donor sites. The advantages of this flap include anatomically reliable vascular supply, accessible donor site, and the aesthetic quality of donor tissue is good. Compared with the radial artery, the posterior radial collateral artery is a nonessential vessel of the arm. The disadvantages are the relatively smaller vessel size for anastomosis and thicker subcutaneous tissue. CONCLUSIONS: For the repair of moderate-sized defects of the maxillofacial area, especially in male patients, the LAFF can be recommended. PMID- 17709931 TI - Occupationally related outbreak of chickenpox in an intensive care unit. AB - OBJECTIVE: To report occupationally related outbreak of chickenpox in intensive care unit (ICU). CASE PRESENTATION AND INTERVENTION: The index patient was a 4 year-old child who presented with a 3-day history of fever and rash and was clinically diagnosed as chickenpox encephalitis. She was admitted to an isolation room in ICU, kept on oxygen mask and given intravenous fluids, anticonvulsant, antipyretic and acyclovir. Twelve hours later, the patient was transferred to Infectious Diseases Hospital. Secondary cases were three unvaccinated ICU staff nurses who developed chickenpox 16-21 days following exposure. They were also transferred to Infectious Diseases Hospital. The affected nurses were interviewed and filled out a questionnaire. Individual immune status was verified by reviewing previous varicella zoster-IgG screening data for all ICU staff. The chickenpox case was defined according to the CDC case classification. All were treated with no complications. CONCLUSION: This report shows that adherence to isolation precautions, exclusion of susceptible staff from attending the affected patient, education, pre-employment anti-VZV-IgG screening and vaccine coverage of staff could have prevented the occurrence of this outbreak. PMID- 17709947 TI - Stress system--organization, physiology and immunoregulation. AB - Stress is defined as a state of threatened homeostasis. The principal effectors of the stress system include corticotropin-releasing hormone, arginine vasopressin, the glucocorticoids, and the catecholamines norepinephrine and epinephrine. Activation of the stress system leads to adaptive behavioral and physical changes. The principal stress hormones glucocorticoids and catecholamines affect major immune functions such as antigen presentation, leukocyte proliferation and traffic, secretion of cytokines and antibodies, and selection of the T helper (Th) 1 versus Th2 responses. A fully fledged systemic inflammatory reaction results in stimulation of the stress response, which in turn, through induction of a Th2 shift protects the organism from systemic overshooting with Th1/pro-inflammatory cytokines. Stress is often regarded as immunosuppressive, but recent evidence indicates that stress hormones influence the immune response in a less monochromatic way--systemically they inhibit Th1/pro-inflammatory responses and induce a Th2 shift, whereas in certain local responses they promote pro-inflammatory cytokine production and activation of the corticotropin-releasing hormone-mast cell-histamine axis. Through this mechanism a hyper- or hypoactive stress system associated with abnormalities of the systemic anti-inflammatory feedback and/or hyperactivity of the local pro inflammatory factors may play a role in the pathogenesis of chronic inflammation and immune-related diseases. PMID- 17709946 TI - Effects of surfactant replacement on irregular overdistension of meconium-injured lungs in rats. AB - BACKGROUND: Overdistension of the lungs is a cause of ventilator-induced lung injury. In meconium aspiration syndrome, irregular overdistension of the lungs often occurs. OBJECTIVES: We investigated whether surfactant replacement could restore the terminal airspaces in the lungs that had been distended after meconium aspiration. METHODS: Meconium aspiration was induced by injecting meconium (50 mg x kg(-1)) into the airways of adult rats anesthetized with pentobarbital and ventilated with pressure-preset mode. The animals were further ventilated with or without surfactant replacement (100 mg x kg(-1)), and the sizes of the terminal airspaces were determined after fixing the lungs at an airway pressure of 10 cm H2O on deflation. RESULTS: Approximately 75 min after aspiration (early analysis point), alveolar ducts were widened and the mean ratio of the largest terminal airspace size class (> or =63,000 microm(2)) was 38.7% (n = 7), which was significantly higher than that of controls (6%, n = 7). Three hours after the early analysis point, the ratio increased to 50.2% (n = 7, p < 0.05), but surfactant replacement reversed the ratio to 18.8% (n = 7, p < 0.05). CONCLUSIONS: In rats with meconium aspiration, surfactant replacement restored the distended terminal airspaces of the lungs and kept the spaces from irregular overdistension. PMID- 17709948 TI - HPA and immune axes in stress: involvement of the serotonergic system. AB - Chronic stress, by initiating changes in the hypothalamic-pituitary-adrenal axis and the immune system, acts as a trigger for anxiety and depression. There is experimental and clinical evidence that the rise in the concentration of pro inflammatory cytokines and glucocorticoids, which occurs in a chronically stressful situation and also in depression, contributes to the behavioural changes associated with depression. A defect in serotonergic function is associated with these hormonal and immune changes. Neurodegenerative changes in the hippocampus, prefrontal cortex and amygdalae are the frequent outcomes of the changes in the hypothalamic-pituitary-adrenal axis and the immune system. Such changes may provide evidence for the link between chronic depression and dementia in later life. PMID- 17709949 TI - Stress as a risk factor in the pathogenesis of rheumatoid arthritis. AB - Stress is now recognized as an important risk factor in the pathogenesis of autoimmune rheumatic diseases (i.e. rheumatoid arthritis) by considering that the activation of the stress response system influences the close relationships existing between the hypothalamic-pituitary-adrenal axis, the sympathetic nervous system and the immune system. The stress response results in the release of neurotransmitters (norepinephrine), hormones (cortisol) and immune cells which serve to send an efferent message from the brain to the periphery. Major life events lead to an intense release of stress mediators (large time integral of released neurotransmitters and hormones), whereas in minor life events, only short-lived surges of neurotransmitters and hormones are expected. Therefore, it is suggested that neurotransmitters such as norepinephrine or stress hormones such as cortisol might have different effects on immune/inflammatory responses at high and low concentrations present during short or extended periods of time, respectively. Long-lasting (chronic) stress may lead to proinflammatory effects because no adequate long-term responses of stress axes (anti-inflammatory) are to be expected. PMID- 17709950 TI - Stress and coping strategies in systemic lupus erythematosus: a review. AB - Systemic lupus erythematosus (SLE), a chronic and unpredictable disease accompanied by functional disability and a possible involvement of the central nervous system, leads to considerable psychological distress. A review of studies on stress and/or coping strategies in SLE since 1990 is presented. Many studies have investigated the place of major and minor stress and coping strategies in SLE morbidity (disease activity, organ damage, and physical and mental components of quality of life). Stress as a causal factor is not proved, but it seems to act as an exacerbating factor in disease activity and to have an impact on the quality of life. Coping strategies are more consistently associated with quality of life than with disease activity. Organ damage appears to be less associated with psychosocial factors than disease activity or quality of life. Despite the limitations of these studies, therapeutic interventions should be proposed to reduce psychological distress, to improve the quality of life and possibly to moderate the evolution of the disease. PMID- 17709951 TI - Cortisol circadian rhythms and stress responses in infants at risk of allergic disease. AB - Altered hypothalamic-pituitary-adrenal function associated with allergic disease has generally been thought to be secondary to the stress of chronic disease. However, recent studies suggest that altered cortisol circadian rhythm and cortisol stress hyper-responsiveness precede the inception of allergic disease and are possible links between preventive factors associated with the hygiene hypothesis and the development of allergies. Elevated endogenous cortisol responses to stressful stimuli could predispose susceptible hosts to atopy and allergic disease by biasing the developing immune system to a T helper 2 predominant immune response, greater total and allergen-specific serum immunoglobulin E responses, and/or inhibition of peripheral immune tolerance. Because glucocorticoid receptors are present throughout the human body and many genes contain glucocorticoid response elements, variances in endogenous cortisol concentrations could have an impact on the phenotypic plasticity of a wide range of immunologically active genes during early human immune development. Here, recent findings related to hypothalamic-pituitary-adrenal function in infants predisposed to developing allergic disease are discussed along with speculation regarding the potential causal role of endogenous cortisol in the inception of allergic disease. PMID- 17709952 TI - Psychological stress and the risk of diabetes-related autoimmunity: a review article. AB - The beta cell stress hypothesis suggests that any phenomenon that induces insulin resistance, and thereby extra pressure on the beta cells, should be regarded as a risk factor for type 1 diabetes (T1D). Psychological stress decreases insulin sensitivity and increases insulin resistance and may hence be important in the development/onset of T1D. The aim of the current review article was to evaluate existing empirical evidence concerning an association between psychological stress and development/onset of T1D as well as diabetes-related autoimmunity. Ten retrospective case-control studies were found. Nine studies showed a positive association between stress and development/onset of T1D in children, adolescents or adults. One study did not find an association between stress and development/onset of T1D. An association between stress and diabetes-related autoimmunity was found at 1 and 2-3 years of age in a large epidemiological study of the general population. The hypothesis that psychological stress (via beta cell stress or direct influence on the immune system) may contribute to the induction or progression of diabetes-related autoimmunity has gained some strong initial support, but is in need of further empirical verification. It seems much clearer that stress can precipitate manifest T1D, although the biological mechanisms are still not known. PMID- 17709953 TI - Stress and autoimmune thyroid diseases. AB - Autoimmune thyroid diseases (AITD) are the far most common autoimmune disorders, their prevalence in Western countries exceeding 5% of the general population. In the large majority of individual cases the clinical impact of AITD is not severe, however, their widespread diffusion renders them a significant health problem. AITD are heterogeneous in their clinical presentation: the two main forms are autoimmune thyroiditis (AT) and Graves' disease (GD). Although they probably share, at least in part, a common genetic background and may occur in the same family as well as in the same individual, they are definitely two distinct diseases both in their clinical presentation and their pathophysiology. In fact, AT causes structural thyroid damage (mainly via cell-mediated immune destruction of thyroid follicular cells) which results, as a rule, in functional impairment (hypothyroidism); however, depending on clinical variants, evolution towards hypothyroidism may be very low, or thyroid function impairment occurs after an initial phase of mild thyrotoxicosis due to relatively rapid gland destruction. GD patients have hyperthyroidism, often severe, due to autoantibody-mediated thyrotropin receptor stimulation, with thyroid cell hyperplasia and hyperfunction. Such a functional heterogeneity is a key feature for the clinical management: as a matter of fact, therapy of AITD is mainly therapy of thyroid dysfunction. Moreover, since hyperthyroidism is quite early perceived by the patient as a cause of discomfort, the timing of the natural history of GD is relatively well defined; on the other hand, AT may be asymptomatic for a long time and defining its natural history in a single patient may be difficult. In some AITD patients (mainly, but not exclusively, with GD), clinical features not directly related to thyroid dysfunction, such as orbitopathy, are present. Graves' orbitopathy is probably related, at least in part, to autoantibodies directed to thyrotropin receptor; it may be, in a minority of patients, severe and sight-threatening, and represents an independent clinical problem. PMID- 17709954 TI - Stress and disease progression in multiple sclerosis and its animal models. AB - Since the first description of multiple sclerosis (MS) by Charcot, stress has been hypothesized to be a potential trigger of relapses. In recent years, data from observational studies in MS patients have provided some support for an association between stress and MS relapses. Furthermore, studies employing the MS animal model experimental autoimmune encephalomyelitis have shown that certain stressors can exacerbate the disease if administered prior to disease induction. Several lines of research have explored the 2 major stress response systems--the hypothalamic-pituitary-adrenal axis and the autonomic nervous system--and their relation to disease course in MS and experimental autoimmune encephalomyelitis. These studies provide evidence that insensitivity of the immune system to signals from these systems may play a role in inflammatory events. These findings can be integrated into a biological model of stress response system alterations in MS. PMID- 17709955 TI - The role of psychological stress in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is an idiopathic inflammatory condition of the gastrointestinal tract whose natural history is one of periods of remission and relapse. The aetiology is complex and reflects an interaction between genes and environment. Psychological stress has long been reported by both doctors and patients as worsening disease activity in IBD. Prospective studies of the relationship between disease relapse and adverse life events have produced conflicting results, in part due to the inherent difficulties of such studies. However, several more recent analyses have suggested that both adverse life events and chronic perceived stress can contribute to disease relapse. There is also an increasing body of evidence to suggest that experimental stress can increase mucosal inflammation both in patients with IBD and in animal models of colitis. Despite this increase in understanding the pro-inflammatory effects of stress in IBD, thus far only a few limited studies have examined stress reduction as a therapeutic modality. PMID- 17709957 TI - From the brain-skin connection: the neuroendocrine-immune misalliance of stress and itch. AB - Perceived stress has long been allied with disturbances of the dynamic equilibrium established between the nervous, endocrine and immune systems, thus triggering or aggravating disease manifestation. Several common skin diseases are now acknowledged to be worsened by psychological stress, particularly immunodermatoses such as atopic dermatitis, psoriasis, seborrheic eczema, prurigo nodularis, lichen planus, chronic urticaria, alopecia areata and pruritus sine materia. Itch (pruritus) is perhaps the most common symptom associated with a majority of these inflammatory skin diseases, and acute as well as chronic stress perceptions are recognized to trigger or enhance pruritus. A wealth of mediators released systemically or locally in the skin in response to stress increase sensory innervation, upregulate the production of other pruritogenic agents, perpetuate (neurogenic) inflammation and lower the itch threshold. In the present review, we explore recent frontiers in both stress and pruritus research and portray the perpetuation of chronic skin inflammation and itch as a neuroendocrine-immune 'misalliance'. We argue that key candidate molecules of the stress response with strong pruritogenic potential, such as nerve growth factor, corticotropin-releasing hormone and substance P, and mast cells, which may be considered as 'central cellular switchboards of pruritogenic inflammation', need to be further explored systematically in order to develop more effective therapeutic combination strategies for itch management in chronic, stress vulnerable inflammatory skin diseases. PMID- 17709956 TI - Stress and wound healing. AB - Over the past decade it has become clear that stress can significantly slow wound healing: stressors ranging in magnitude and duration impair healing in humans and animals. For example, in humans, the chronic stress of caregiving as well as the relatively brief stress of academic examinations impedes healing. Similarly, restraint stress slows healing in mice. The interactive effects of glucocorticoids (e.g. cortisol and corticosterone) and proinflammatory cytokines [e.g. interleukin-1beta (IL-1beta), IL-1alpha, IL-6, IL-8, and tumor necrosis factor-alpha] are primary physiological mechanisms underlying the stress and healing connection. The effects of stress on healing have important implications in the context of surgery and naturally occurring wounds, particularly among at risk and chronically ill populations. In research with clinical populations, greater attention to measurement of health behaviors is needed to better separate behavioral versus direct physiological effects of stress on healing. Recent evidence suggests that interventions designed to reduce stress and its concomitants (e.g., exercise, social support) can prevent stress-induced impairments in healing. Moreover, specific physiological mechanisms are associated with certain types of interventions. In future research, an increased focus on mechanisms will help to more clearly elucidate pathways linking stress and healing processes. PMID- 17709958 TI - Bidirectional communication between the brain and the immune system: implications for physiological sleep and disorders with disrupted sleep. AB - This review describes mechanisms of immune-to-brain and brain-to-immune signaling involved in mediating physiological sleep and altered sleep with disease. The central nervous system (CNS) modulates immune function by signaling target cells of the immune system through autonomic and neuroendocrine pathways. Neurotransmitters and hormones produced and released by these pathways interact with immune cells to alter immune functions, including cytokine production. Cytokines produced by cells of the immune and nervous systems regulate sleep. Cytokines released by immune cells, particularly interleukin-1beta and tumor necrosis factor-alpha, signal neuroendocrine, autonomic, limbic and cortical areas of the CNS to affect neural activity and modify behaviors (including sleep), hormone release and autonomic function. In this manner, immune cells function as a sense organ, informing the CNS of peripheral events related to infection and injury. Equally important, homeostatic mechanisms, involving all levels of the neuroaxis, are needed, not only to turn off the immune response after a pathogen is cleared or tissue repair is completed, but also to restore and regulate natural diurnal fluctuations in cytokine production and sleep. The immune system's ability to affect behavior has important implications for understanding normal and pathological sleep. Sleep disorders are commonly associated with chronic inflammatory diseases and chronic age- or stress-related disorders. The best studied are rheumatoid arthritis, fibromyalgia and chronic fatigue syndromes. This article reviews our current understanding of neuroimmune interactions in normal sleep and sleep deprivation, and the influence of these interactions on selected disorders characterized by pathological sleep. PMID- 17709960 TI - For the safety and benefit of current and future patients. AB - Pathology biobanks are vital assets for medical care and treatment of current and future patients. In association with good clinical data they are also useful for biomedical research regarding the underlying mechanisms of human disease. Recent regulations have suggested the obtainment of a specific and explicit informed consent as a prerequisite for using human tissue samples with these ends in mind. However, the choice and strict use of informed consent for balancing conflicting interests associated with biobank-related research can in practice be detrimental to patient safety with regard to diagnosis, medical care and treatment. In this article I argue that a 'safety principle' should have priority and suggest how this could be implemented in clinical practice and in association with biomedical research. PMID- 17709961 TI - Biobank governance: trends and perspectives. AB - Biobanks are a challenge and topic for governance. Today, biobanks are identified as a biomedical scientific/infrastructural development that warrants a political/legal/ethical reaction with the goal to integrate biobanks into the preexisting fabric of regulation, medicine, law and society. Biobank governance is always a response to sociocultural challenges and requires the building of trust, acceptance, and careful political negotiation. Biobanks are regulated in networks of governance in which the state is one actor next to others, and the ordering and structuring of the interaction between biobanks, society, and politics operates through a variety of actors, on different levels and along particular rationalities. Such networks of governance reflect, to some extent, a postregulatory state in which governance has become a complicated architecture and field of action involving a multitude of forces and rationalities. Biobank governance is still a relatively new field of political-legal intervention and it will be crucial for the future of biobanks to establish governance regimes that appropriately link research with society and politics. PMID- 17709962 TI - Providing human tissue for research: 1996-2006. AB - This article details the authors' experience establishing infrastructure for tissue collection, storage and distribution for biomedical research, firstly within a public healthcare service and latter in the pharmaceutical industry. Access to human tissue in the context of public-private collaboration in research and development is essential to the provision of high-quality medicines and healthcare and is now supported by a new legal framework in England and Wales. Through collaborations there are opportunities for mutual benefit for patients and professionals alike. Attention to the wishes of tissue donors through informed consent at the outset ensured confidence and continued activity when so called 'organ retention scandals' emerged midway through this period. The overwhelming majority of potential donors support the use of their tissues in biomedical research irrespective of where the research is carried out. PMID- 17709963 TI - Tissue banking in a regulated environment--does this help the patient? Part 1- Legislation, regulation and ethics in the UK. AB - The difficulties with 'retained organs' in the UK have resulted in a new legislation relating to human organs, tissues, and bodies - the Human Tissue Act 2004 and the Human Tissue Act Scotland 2006 are now in place. The new laws apply to a wide range of activities including transplantation, education, clinical audit, the practice of autopsies, anatomical examination and others, including the use of human tissues in research. Pathobiology research that uses human tissues is now undertaken in a regulated environment in the UK. The details of these regulations are described and the consequences discussed. In the second part of the paper the patient's views and expectations in this new setting are forwarded. PMID- 17709964 TI - Tissue banking in a regulated environment--does this help the patient? Part 2- Patient views and expectations (including the EUROPA DONNA Forum UK position). AB - Several scandals related to tissue collection have questioned the position of patients regarding tissue banking. The Human Tissue Act in the UK is a legal framework for tissue banking that has been evaluated by the Europa Donna Forum UK, an advocacy organisation for breast cancer. Patients are well aware of the importance of clinical research and want to see it strengthened. They envisage several modalities for tissue banking. One modality is the 'patient-driven' bank where some of the individual rights are transferred to the community, research done with the tissues is partly controlled by the patients, and information regarding the results is obtained back. However, for all models proposed, the point of prime importance for patients is the issue of consent. PMID- 17709965 TI - Biobanking for epidemiological research and public health. AB - Almost all healthcare systems are currently facing fundamental challenges. New ways of organizing these systems based on novel knowledge and stakeholders' different needs are required to meet these challenges at the appropriate time. In this context, the issue of biobanking has become a specific challenge having major implications for future research and policy strategies as well as for the healthcare systems in general. Medicine is currently undergoing remarkable developments from its morphological and phenotype orientation to a molecular and genotype orientation, promoting the importance of prognosis and prediction. Yet, the discussion about the relevance of integrating genome-based information into biobanks and about the role of genome-based biobanking for epidemiological research and public health is still at the beginning. The following article contributes to this discussion by focusing on the use of genome-based biobanking for epidemiological research, surveillance systems, health policy development, individual health information management and effective health services. PMID- 17709966 TI - Biobanking for interdisciplinary clinical research. AB - Biobanking nowadays is mostly strongly determined by the specific aims of a research group in charge of the biobank, determining their own standards for the collection and annotation of samples. Often a long period is needed to build up the sample and data collections, especially when long-term follow-up data is required. Such collections need a long-term dedication and proper funding. Neglecting either sample number or annotation can result in insignificant or poor results. However, outcome of translational research does not only depend on the sample quality. In many cases it can also be improved to start the experimental design within a multidisciplinary team composed of clinicians including pathologists, molecular biologists, statisticians, bioinformaticians and tissue resource managers. Such a team, capable of careful evaluation of the numbers needed and which or what part of the samples are to be included, could help in obtaining far better results. Many lines of clinical research could benefit more efficiently from the wealth of information stored in well-preserved disease oriented tissue sample collections with the proper annotations, when the infrastructure around biobanks and new collection build-up is well organized, standardized and streamlined. Future medical research will refine its scientific questions, demanding even further refinement of corresponding clinical information. In addition, larger sample collections are needed to study for instance multifactorial diseases. Today, the samples are collected for tomorrow, therefore, improvement is needed now in standardization, automated enrichment of annotations from hospital information systems and disease registries, insight in overlapping collections of different forms of tissue banking and cooperation in national and international networks. PMID- 17709967 TI - Tumour banking: the Spanish design. AB - In the last decade the technical advances in high throughput techniques to analyze DNA, RNA and proteins have had a potential major impact on prevention, diagnosis, prognosis and treatment of many human diseases. Key pieces in this process, mainly thinking about the future, are tumour banks and tumour bank networks. To face these challenges, diverse suitable models and designs can be developed. The current article presents the development of a nationwide design of tumour banks in Spain based on a network of networks, specially focusing on its harmonization efforts mainly regarding technical procedures, ethical requirements, unified quality control policy and unique sample identification. We also describe our most important goals for the next years. This model does not correspond to a central tumour bank, but to a cooperative and coordinated network of national and regional networks. Independently from the network in which it is included, sample collections reside in their original institution, where it can be used for further clinical diagnosis, teaching and research activities of each independent hospital. The herein described 'network of networks' functional model could be useful for other countries and/or international tumour bank activities. PMID- 17709968 TI - The Genome Austria Tissue Bank (GATiB). AB - In the context of the Austrian Genome Program, a tissue bank is being established (Genome Austria Tissue Bank, GATiB) which is based on a collection of diseased and corresponding normal tissues representing a great variety of diseases at their natural frequency of occurrence from a non-selected Central European population of more than 700,000 patients. Major emphasis is put on annotation of archival tissue with comprehensive clinical data, including follow-up data. A specific IT infrastructure supports sample annotation, tracking of sample usage as well as sample and data storage. Innovative data protection tools were developed which prevent sample donor re-identification, particularly if detailed medical and genetic data are combined. For quality control of old archival tissues, new techniques were established to check RNA quality and antigen stability. Since 2003, GATiB has changed from a population-based tissue bank to a disease-focused biobank comprising major cancers such as colon, breast, liver, as well as metabolic liver diseases and organs affected by the metabolic syndrome. Prospectively collected tissues are associated with blood samples and detailed data on the sample donor's disease, lifestyle and environmental exposure, following standard operating procedures. Major emphasis is also placed on ethical, legal and social issues (ELSI) related to biobanks. A specific research project and an international advisory board ensure the proper embedding of GATiB in society and facilitate international networking. PMID- 17709969 TI - A case study on the proper use of human tissues for biomedical research at an academic pathology institution in Switzerland. AB - Any academic pathologist will sooner or later be confronted with the need to use human tissues for quality control purposes or for research projects or else with the demand for human tissue samples for research projects of external researchers. Over the last 10 years, the use of human tissues for such non diagnostic purposes has been the subject of extensive debate and wide-reaching regulations. In particular, questions of medical secrecy, safety, autonomy and anonymization have been addressed, and the role of ethical review boards defined. However, these guidelines are not uniform in all countries and unfortunately tend to suffer from a certain lack of precision, which may in part be due to the fact that they are usually edited by multiple authors with quite diverse backgrounds (physicians, lawyers, ethicists, philosophers, anthropologists, theologists or lay persons, for example). The wide spectrum of interpretations of such regulations may be embarrassing to such an extent that a continuation of academic activities with human tissues appears to many pathologists as almost impossible or even outright illegal. This paper describes a set of characteristic, recurrent situations to which an academic pathologist may be confronted and proposes simple, realistic solutions that are nevertheless in line with most current regulations. PMID- 17709970 TI - A virtual tissue bank for primary central nervous system lymphomas in immunocompetent individuals. AB - Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non Hodgkin's lymphoma with continuously increasing incidence in both immunosuppressed and immunocompetent individuals. PCNSL is a very aggressive tumor with a poor outcome, and its clinical outcome is much worse than for nodal lymphomas. Differently from lymphomas arising in lymph nodes or in other extranodal sites, the treatment of PCNSL remains very unsatisfactory. Current biologic knowledge of PCNSL is still limited and several fundamental questions remain to be answered. This is mainly due to the paucity of PCNSL material for adequate translational research. With the aim of providing biologic material to investigators interested in PCNSL, we have implemented a virtual tissue bank (VTB) for PCNSL in immunocompetent patients. After registration, the VTB is accessible via any web browser at www.ielsg.org. Only anonymous data are centralized at the website of the International Extranodal Lymphoma Study Group, whilst the pathologic material is maintained at the local pathology institutes. PMID- 17709971 TI - Legal aspects of tissue banking. AB - There exists no clear national or international consensus in key issues of tissue banking. This holds especially true for the fundamental concept of informed consent. During recent years, the harmonization of norms needed for international collaboration has made crucial progress solely in Europe, namely through legal framing. The norms relating to tissue banking are, however, under permanent construction not only in Europe but throughout the world. Consequently, anybody involved in tissue banking is well advised to observe the evolution of the legal and regulatory environment in the particular jurisdiction. PMID- 17709972 TI - Depression and Internet addiction in adolescents. AB - BACKGROUND: The aim of the study was to evaluate the relationship between depression and Internet addiction among adolescents. SAMPLING AND METHOD: A total of 452 Korean adolescents were studied. First, they were evaluated for their severity of Internet addiction with consideration of their behavioral characteristics and their primary purpose for computer use. Second, we investigated correlations between Internet addiction and depression, alcohol dependence and obsessive-compulsive symptoms. Third, the relationship between Internet addiction and biogenetic temperament as assessed by the Temperament and Character Inventory was evaluated. RESULTS: Internet addiction was significantly associated with depressive symptoms and obsessive-compulsive symptoms. Regarding biogenetic temperament and character patterns, high harm avoidance, low self directedness, low cooperativeness and high self-transcendence were correlated with Internet addiction. In multivariate analysis, among clinical symptoms depression was most closely related to Internet addiction, even after controlling for differences in biogenetic temperament. CONCLUSIONS: This study reveals a significant association between Internet addiction and depressive symptoms in adolescents. This association is supported by temperament profiles of the Internet addiction group. The data suggest the necessity of the evaluation of the potential underlying depression in the treatment of Internet-addicted adolescents. PMID- 17709973 TI - Mixed depression and the dimensional view of mood disorders. AB - BACKGROUND: Mixed depression (MxD), i.e. depression plus cooccurring noneuphoric manic/hypomanic symptoms, questions the current categorical dividing of mood disorders into bipolar disorders and depressive disorders, and supports a dimensional approach. The study aim was to test a dimensional approach to mood disorders by looking for a progressive grading of age at onset and bipolar family history loading between bipolar II disorder (BP-II) and major depressive disorder (MDD). METHODS: Consecutive 389 BP-II and 261 MDD major depressive episode outpatients were interviewed (off psychoactive drugs) with the Structured Clinical Interview for DSM-IV, the Hypomania Interview Guide (to assess intradepressive noneuphoric hypomanic symptoms), and the Family History Screen, by a mood disorder specialist psychiatrist in a private practice. BP-II and MDD MxD and non-MxD were compared on age at onset and bipolar family history loading (the diagnostic validators). A dose-response was tested between the number of intradepressive hypomanic symptoms and bipolar family history loading, and a correlation was tested between the number of intradepressive hypomanic symptoms and age at onset. RESULTS: MxD was present in 64.5% of BP-II and in 32.1% of MDD. There were significant differences in classic diagnostic validators (onset age, bipolar family history). The comparisons between BP-II and MDD MxD and non-MxD on age at onset and bipolar family history found a clear and significant grading in age at onset from BP-II MxD to MDD non-MxD (a progressive increase), and a clear and significant grading in bipolar family history loading from BP-II MxD to MDD non-MxD (a progressive decrease). A dose-response relationship was found between the number of intradepressive hypomanic symptoms and bipolar family history loading. The area under the ROC curve was small. A significant correlation was found between the number of intradepressive hypomanic symptoms and age at onset. CONCLUSIONS: The presence of MxD in a significant proportion of MDD, the progressive grading of age at onset and bipolar family history from BP-II MxD to MDD non-MxD, the dose-response relationship between intradepressive hypomanic symptoms and bipolar family history loading, and the correlation between intradepressive hypomanic symptoms and age at onset could support a dimensional approach to mood disorders (BP-II and MDD). On the other hand, the significant differences on classic diagnostic validators could support a categorical distinction. A mixed approach (dimensional and categorical) to mood disorders could be supported. PMID- 17709974 TI - Classes of disruptive behavior problems in referred adolescents. AB - BACKGROUND: Previous studies have found considerable overlap between attention/hyperactivity problems, aggressive/oppositional problems and delinquent/conduct problems in adolescents. SAMPLING AND METHODS: Mothers of 1,965 11- to 18-year-olds (1,116 boys, 849 girls), referred to mental health agencies, completed the Child Behavior Checklist (CBCL). Latent class analysis was conducted on the Attention Problems scale (representing problems with attention, impulsivity and hyperactivity), Aggressive Behavior and Rule-Breaking Behavior scales of the CBCL. RESULTS: Six latent classes were found. One of these classes contained individuals who suffered predominantly from attention problems and to a far lesser degree from aggressive or rule-breaking behaviors. The other 5 classes represented individuals with varying degrees of attention problems, aggressive behaviors and rule-breaking behaviors. CONCLUSIONS: Contrary to previous studies, the present study indicated that, in a large referred sample, problems with attention, impulsivity and hyperactivity can be considered as a diagnostic construct that should be distinguished from aggressive or rule breaking behaviors. However, the present study did not support the existence of diagnostic classes constituted by individuals who primarily suffer from aggressive behaviors or rule-breaking behaviors, and not from attention problems or hyperactivity. Implications of these findings for future research and clinical practice are discussed. The value of the study was limited by the use of parent reports only. PMID- 17709975 TI - Childhood behavioral inhibition and maternal symptoms of depression. AB - BACKGROUND: The significance of behavioral inhibition in the second year of life for the development of social phobia in later childhood was the incentive to explore whether maternal postnatal psychopathology is a predictor for behavioral inhibition in the offspring. METHOD: 101 mother-infant pairs were recruited from local obstetric units and examined for maternal psychopathology by the Symptom Checklist and the Edinburgh Postnatal Depression Scale several times during the first postnatal year. Child behavioral inhibition was assessed at 14 months in a laboratory procedure. RESULTS: Postpartum depression at 4 months measured by the Edinburgh Postnatal Depression Scale was found to be strongly associated with toddlers' fear score/behavioral inhibition at 14 months. Maternal depressive symptoms assessed by the revised 90-item Symptom Checklist at 6 weeks , 4 and 14 months were found to be related to child inhibition as well. CONCLUSIONS: Even maternal depression not reaching the level of clinical diagnosis and treatment has an impact on child behavioral development. These data should give rise to further studies on the origins of this relationship, which might be primarily genetic or interactional. PMID- 17709976 TI - Validation of a severity threshold for the Mania Rating Scale: a receiver operating characteristic analysis. AB - BACKGROUND: The aim of this study was to determine a cutoff score on the Mania Rating Scale (MRS), which easily allows identification of severe mania in a population of manic patients to be included in clinical trials of antimanic drugs. METHOD: 1,090 hospitalized patients meeting DSM-IV criteria for a manic episode were subtyped according to the specifier for severity and assessed for demographic characteristics, illness course and clinical symptomatology. Using receiver-operating characteristic (ROC) analysis, the optimal threshold for severity was determined on the MRS. RESULTS: In a French national clinical sample (n = 1,090), 851 cases were specified as severe and 239 as nonsevere (mild + moderate) mania according to DSM-IV criteria (307 without psychotic features, 544 with psychotic features). Patients with severe mania scored higher on the MRS but showed the same levels of scores on the Montgomery Asberg Depression Rating Scale compared to nonsevere cases. Many characteristics of the whole sample and of the psychotic group were found to be comparable, respectively, to those reported in recent epidemiological studies, which was particularly true for age, gender, age at onset, number of mood episodes and suicide attempts. The optimal ROC solution for separating severe from nonsevere mania was a cutoff score of 39 on the MRS. This cutoff score displayed a positive predictive value of 0.91. CONCLUSION: A cutoff score of 39 is proposed as a severity threshold for mania on the MRS by virtue of its ROC validation in a large representative sample of severe versus nonsevere manic patients whose severity was assessed according to DSM-IV subtyping. PMID- 17709977 TI - Boosting central target dose by optimizing embedded dose hot spots for gamma knife radiosurgery. AB - AIMS: To develop a boost technique for Gamma Knife radiosurgery by embedding and optimizing dose hot spots inside a conventional Gamma Knife plan. METHODS: An optimization algorithm was developed to automatically arrange the pattern and adjust the intensities of the embedded dose hot spots. We compared the treatment plans of the optimized boost technique with the conventional Gamma Knife treatment plans, where dose hot spots were scattered randomly within the target volume. RESULTS: We found the embedded boost plans significantly increased the maximum dose of the target (on average 31% or 5-6 Gy). The mean dose to the target was increased by an averaged 7.1% (1.5-2 Gy). In contrast, the dose to the adjacent normal brain was strictly maintained with the dose volume histograms differing less than 0.5% between the boost treatment plans and the conventional treatment plans. The planning effort and treatment time was comparable between the two techniques. CONCLUSION: We have demonstrated a simple and an effective technique for increasing the central target dose without affecting the normal brain sparing for Gamma Knife radiosurgery. PMID- 17709979 TI - Radiosurgery in patients with bilateral vestibular schwannomas. AB - BACKGROUND: Patients with bilateral vestibular schwannomas offer a unique opportunity to determine the effectiveness of radiosurgery. By using the untreated tumor as an internal control, one can determine whether radiosurgery was able to interrupt the natural history of the treated tumor. METHODS: From September 1998 to November 2004, 13 patients with neurofibromatosis type 2 had 14 tumors treated with radiosurgery at the University of Florida. A retrospective analysis was performed on these patients. Actuarial statistics were used to analyze local control in both the treated and untreated tumor. RESULTS: The average follow-up length was 38 months. One patient failed to send a follow-up MRI. Actuarial local control in the treated tumors was 100% at 1 year and 92% at 2 and 5 years. Only 1 of the treated tumors continued to grow. In the untreated tumors, actuarial local control was 100% at 1 year, 78% at 2 years and 21% at 5 years. None of the untreated tumors decreased in size. CONCLUSION: In all but 1 patient with follow-up data, radiosurgery successfully prevented or reversed tumor growth. Additionally, half of the untreated tumors continued to grow. This study shows that radiosurgery alters the natural history of vestibular schwannomas. PMID- 17709978 TI - Subdural electrode-associated complications: a 20-year experience. AB - BACKGROUND: Implantation of subdural strip and grid electrodes is a common methodology in the invasive evaluation of patients with medically refractory epilepsy. Although their implantation is safe, the occurrence of implantation associated complications can occasionally be troublesome. METHODS: In our current retrospective study, 185 patients undergoing subdural grid/strip implantation for invasive monitoring were examined. Their ages ranged between 16 and 48 years (mean 23.6). AdTech (Racine, Wisc., USA) strip and grid electrodes were implanted under general endotracheal anesthesia in all our cases. Duration of electroencephalographic monitoring ranged from 2 to 25 days (mean 10.8). The follow-up period ranged from 24 to 60 months (mean 44.6 months). RESULTS: The most common complication in our series was the development of postoperative epidural hematoma in 3 patients (1.6%), while 2 patients (1.1%) suffered a subdural hematoma. Two patients (1.1%) developed significant brain edema postoperatively, 2 others (1.1%) developed an infection, while 2 patients (1.1%) experienced transient aphasia. Two patients (1.1%) had fatal outcomes in our series. Interestingly, in 5 patients (2.7%) nonhabitual seizures were recorded. CONCLUSION: Thorough understanding, early identification and prompt management of potential complications can minimize the risks associated with the implantation of subdural electrodes. PMID- 17709981 TI - Safety of anterior commissure-posterior commissure-based target calculation of the subthalamic nucleus in functional stereotactic procedures. AB - The subthalamic nucleus (STN) is a common target of functional stereotactic surgeries. High-field magnetic resonance imaging and sophisticated computer systems provide precise identification of the nucleus location in stereotactic space. However, it is unclear what additional benefit these techniques provide over traditional anterior commissure-posterior commissure (AC-PC)-based standard atlas coordinate calculation methods based on the AC-PC plane. The accuracy of AC PC-based standard atlas coordinate targeting of the STN using 1.5-tesla images compared with direct visualization of the nucleus on fused 3-tesla images was examined. A retrospective examination of stereotactic images from 20 patients (40 STN targets) who underwent deep brain stimulation for Parkinson's disease was undertaken at our institution. Two methods were used to identify the STN stereotactic coordinates: (1) an AC-PC-based standard atlas coordinate calculation obtained by a series of measurements using 1.5-tesla images, and (2) a computer workstation calculation using fused 3-tesla and 1.5-tesla images. Euclidean distances between two sets of coordinates of the same target were calculated in three dimensions. Differences along individual X, Y, and Z axes were analyzed to determine whether there was a greater difference in one direction than in another. Data from the right and left sides were pooled to increase the sample power. The anterior-posterior and lateral frame tilts were compared to X, Y, and Z differences to find a correlation using linear regression. Statistical analyses were performed. The accuracy of the position of the STN calculated with state-of-the-art imaging systems was not significantly better than that obtained using traditional AC-PC-based standard atlas coordinate calculation if the frame was aligned with the AC-PC plane. The mean difference was 0.45 mm, 0.72 mm, and 0.98 mm in the X, Y, and Z axes, respectively. Therefore, it is possible to effectively target the STN for stereotactic treatment of Parkinson's disease, for instance in a situation where expensive advanced technology is unavailable. PMID- 17709980 TI - Intracerebral microvascular measurements during deep brain stimulation implantation using laser Doppler perfusion monitoring. AB - The aim of the study was to investigate if laser Doppler perfusion monitoring (LDPM) can be used in order to differentiate between gray and white matter and to what extent microvascular perfusion can be recorded in the deep brain structures during stereotactic neurosurgery. An optical probe constructed to fit in the Leksell Stereotactic System was used for measurements along the trajectory and in the targets (globus pallidus internus, subthalamic nucleus, zona incerta, thalamus) during the implantation of deep brain stimulation leads (n = 22). The total backscattered light intensity (TLI) reflecting the grayness of the tissue, and the microvascular perfusion were captured at 128 sites. Heartbeat synchronized pulsations were found at all perfusion recordings. In 6 sites the perfusion was more than 6 times higher than the closest neighbor indicating a possible small vessel structure. TLI was significantly higher (p < 0.005) and the perfusion significantly lower (p < 0.005) in positions identified as white matter in the respective MRI batch. The measurements imply that LDPM has the potential to be used as an intracerebral guidance tool. PMID- 17709982 TI - Histopathology of radiation necrosis with severe peritumoral edema after gamma knife radiosurgery for parasagittal meningioma. A report of two cases. AB - BACKGROUND: Gamma knife radiosurgery (GKS) has been an effective treatment for meningiomas. Nevertheless, it still has certain risks. We present 2 cases of parasagittal meningioma after GKS complicated with radiation necrosis and peritumoral edema. The results of histologic examination are discussed. CASE DESCRIPTION: Two cases of parasagittal meningioma received GKS. Symptomatic peritumoral edema developed 3-4 months after GKS. Both of them underwent surgical resection of their tumor afterwards. Histologic examination showed necrotic change inside the tumor and infiltration of inflammatory cells in both cases. Hyalinization of blood vessels was seen in the 2nd case. The patients had improvement of neurologic function after surgical resection. Imaging performed 3 months after surgical resection showed alleviation of brain edema. CONCLUSION: After radiosurgery peritumoral edema tends to occur in meningiomas with a parasagittal position. Radiation necrosis, infiltration of inflammatory cells, and radiation injury to the vasculature causing hyalinization of blood vessels are suggested as the underlying histopathology. PMID- 17709983 TI - Spinal accessory neuropathy after deep brain stimulation for Parkinson's disease. AB - We report a man with Parkinson's disease who developed right spinal accessory neuropathy after right subthalamic nucleus deep brain stimulator and infraclavicular pulse generator implantation. He complained of right shoulder pain and weakness in the post-operative period. He was subsequently diagnosed with a right spinal accessory nerve injury, confirmed by neuromuscular electrodiagnostic studies - electromyography (EMG) and nerve conduction (NC) -, possibly caused by a stretch injury to the nerve at the time of creation of the subcutaneous tunnel for placement of the extension lead of the deep brain stimulator system. However, he had near complete clinical resolution of the spinal accessory neuropathy within nine months after surgery. As a result of this complication, we now map the spinal accessory nerve electrophysiologically during deep brain stimulation surgery. PMID- 17709984 TI - Treatment of a facial nerve neuroma with fractionated stereotactic radiotherapy. AB - BACKGROUND: Facial nerve neuromas are extremely rare and are often mistaken for acoustic neuromas when located near the vestibular nerve. Usually presenting with facial weakness and hearing loss, facial nerve neuromas of the cerebellopontine angle have commonly been managed by surgery. We present the first reported case of a facial nerve neuroma treated with fractionated stereotactic radiotherapy (FSRT). METHODS: The patient was a 40-year-old woman who presented with tinnitus, dizziness and decreased hearing that was associated with a right intracanalicular mass on magnetic resonance imaging (MRI). She underwent a middle fossa craniotomy only to reveal a facial nerve tumor rather than an acoustic neuroma that was not resected due to the high risk of facial paralysis. Following surgery, her facial function worsened and was associated with tumor enlargement on MRI. She was referred for FSRT and received 54 Gy in daily 1.8-Gy fractions with a prescription isodose line of 90%. RESULTS: Three months after treatment she had no worsening of her pretreatment symptoms, and at the 1-year follow-up, she experienced facial weakness improvement accompanied by an absence of tumor growth on MRI. These clinical and imaging findings persisted at 48 months of follow-up. CONCLUSION: In the first report of a facial nerve neuroma treated with FSRT, this treatment resulted in excellent long-term (4-year) tumor control with improvement of pretreatment symptomatology and absence of morbidity. This report demonstrates the potential for using FSRT to treat facial nerve neuromas of the cerebellopontine angle that could otherwise be associated with significant operative morbidity. PMID- 17709985 TI - Internal carotid occlusion following gamma knife radiosurgery for cavernous sinus meningioma. AB - Gamma knife radiosurgery is a safe and effective treatment for cavernous sinus meningioma, associated with a very low morbidity. However, a high dose of radiation could lead to modifications of the vascular wall such as in radiosurgical treatment of arteriovenous malformations. We present a patient treated by gamma knife radiosurgery for a left cavernous sinus meningioma using a margin dose of 13 Gy at the 50% isodose. A complete occlusion of the intracavernous segment of the ICA occurred during the follow-up, in combination with a regression of the meningioma volume. The patient sustained no neurological deficit. We found that a hot spot of dose was administered to the intracavernous segment of the internal carotid artery, with a maximum dose of 22.3 Gy. Dose heterogeneity inside the target volume can produce hot spots of dose inside the internal carotid artery that can lead to a vascular occlusion. Therefore, we recommend shifting the hot spot during the dosimetry planning in order to reduce the incidence of such vascular injury. PMID- 17709986 TI - Posterior spinal cord stimulation in a case of painful legs and moving toes. AB - A 59-year-old woman with a 5-year history of right lower limb pain is reported. Symptoms developed initially when walking and progressively became bilateral, appeared at rest and involuntary movements of the toes became evident. A diagnosis of painful legs and moving toes was made. As several drug therapies proved unsuccessful, a therapeutic test with a tetrapolar epidural lead to stimulate the spinal cord dorsal tracts was performed. Due to the marked improvement the device and generator were implanted and she has responded satisfactorily to this therapy for the past 13 months. PMID- 17709987 TI - Successful treatment of a skull base malignant rhabdoid tumor with surgery, chemotherapy and gamma Knife-based stereotactic radiosurgery in a young child. AB - Most childhood rhabdoid tumors occur in the kidney or central nervous system but they can occur in other sites and they usually run an aggressive clinical course. We report a case of an 8-month-old boy with a right temporal bone rhabdoid tumor treated with surgery, chemotherapy and Gamma Knife-based stereotactic radiosurgery. The patient remained alive after 61 months and repeat magnetic resonance imaging (MRI) of the brain showed no evidence of recurrence. There were no obvious endocrine deficits or growth abnormalities at last follow-up. Gamma Knife-based stereotactic radiosurgery may have a role in the management of very young children with skull base tumors. PMID- 17709988 TI - Expression and function of vinculin in neuroendocrine tumors. AB - Transfection of chicken vinculin into highly malignant neuroendocrine tumor cells, vasostatin-transformed (vaso-transformed) Bon cells which expressed low levels of vinculin protein, reversed their malignant behavior and restored expression of tumor suppressor genes. Conversely, small interfering RNA (siRNA) mediated knockout of vinculin resulted in fast cell growth and augmentation of colony formation in wild-type cells. Moreover, expression of a tight junction protein, claudin 4 (CLD4), was found to be associated with vinculin expression. In the vaso-transformed Bon cells, CLD4 expression was reduced, whereas a significantly increased CLD4 expression was observed in the cells with vinculin overexpression. Furthermore, vinculin knockout brought about CLD4 downregulation in wild-type cells. However, vinculin and CLD4 expression was inversely correlated in neuroendocrine tumors, respectively. Based on these findings, we hypothesize that vinculin plays a role in growth regulation of neuroendocrine tumors. Further studies are necessary to analyze the relationship between the course of the disease, and vinculin and CLD4 expression in large tumor samples. PMID- 17709989 TI - Immunotherapy with antibody-targeted HLA class I complexes: results of in vivo tumour cell killing and therapeutic vaccination. AB - BACKGROUND: The delivery of antibody-targeted major histocompatibility complex (MHC) class I complexes containing immunogenic peptides to the surface of tumour cells allows cytotoxic T lymphocytes (CTLs) of non-tumour specificity to recognise and kill the tumour cell. Previous studies have demonstrated the activity of this system in vitro and in a simple pre-clinical model. This system has also been shown to be an effective method of expanding antigen-specific CTLs in vitro when used to target MHC class I complexes to the surface of B cells. METHODS: Mice were immunised with ovalbumin and the survival of EL4Hu20 lymphoma cells targeted with H2-D(b)/Ova complexes and control MHC complexes was compared by FACS analysis. A tumour protection assay was performed where immunised mice were injected B16Hu20 melanoma cells targeted with H2-K(b)/Ova or control complexes. T cell expansion in vivo was examined by administering B cells targeted with MHC class I/peptide complexes and assessing T cell expansion by tetramer analysis. RESULTS: In vivo killing of H2-D(b)/Ova-targeted lymphoma cells in the immunised mice was demonstrated with these cells present at only 12% of the level of the control cells. In contrast, in non-immunised mice the survival of H2-D(b)/Ova-targeted and control cells was comparable. In the tumour protection assay, injection of melanoma cells targeted with H2-K(b)/Ova complexes resulted in the development of only a solitary metastasis in each mouse. This compared to an average of 130 metastases in the control mice injected with B16Hu20 cells targeted with a control MHC peptide complex. In vivo CTL expansion was demonstrated after a single intravenous administration of Daudi B cells coated with H2-D(b)/Uty complexes produced an increase in the proportion of Uty reactive CTLs from 3.3 to 21.5%. CONCLUSION: This study supports the development of antibody-delivered MHC complexes as a method of producing CTL-mediated lysis of cancer cells in vivo. As a therapeutic vaccine, the system may provide an effective approach for expanding oligoclonal T cell responses in vivo in the treatment of malignancy and infectious diseases. PMID- 17709990 TI - Matrix metalloproteinase induction in the tumor stroma does not depend on CD147 expression in murine B16 melanoma. AB - BACKGROUND: It was conclusively demonstrated that the cell surface glycoprotein CD147 on tumor cells mediates induction of matrix metalloproteinases (MMPs) by stromal cells in humans. However, for murine models such evidence remains elusive. METHODS AND RESULTS: To address the impact of CD147 on MMP expression in the murine B16 melanoma model, we consequently stably knocked down CD147 expression in two B16 sublines. The CD147 knockdown remained stable under in vivo conditions as confirmed by immunohistochemistry. However, no differences in MMP 2, MMP-9 and MT1-MMP expression by stromal and tumor cells were detectable in CD147+ and CD147- tumors. Since the tumor microenvironment is a complex system, involving several cell types, the extracellular matrix and plethora soluble factors, we subsequently studied the role of murine CD147 in vitro. Coculture of melanoma cells with different fibroblast cell lines demonstrated that neither CD147+ nor CD147- B16 tumor cells altered the expression of MMP-2 or MMP-9 by the fibroblasts, although we could confirm the susceptibility of these fibroblasts for MMP induction. CONCLUSIONS: At least for the murine B16 melanoma model, CD147 expression on tumor cells seems not to be crucial for MMP-2, MMP-9 and MT1-MMP induction on tumor-associated stromal cells. PMID- 17709991 TI - A safeguard for dual-energy x-ray absorptiometry measurements after kyphoplasty. PMID- 17709992 TI - Poststroke and brain injury rehabilitation treatment strategies. PMID- 17709993 TI - Botulinum toxin a, evidence-based exercise therapy, and constraint-induced movement therapy for upper-limb hemiparesis attributable to stroke: a preliminary study. AB - OBJECTIVE: To determine whether the combination of botulinum toxin A (BTX-A) treatment for the upper limb and a 4-wk course of exercise therapy could improve motor function sufficiently to allow those with poststroke hemiparesis and spasticity to achieve the minimal motor criteria (MMC) to be enrolled in constraint-induced movement therapy (CIMT), and to determine the feasibility of enrolling participants into CIMT if they meet MMC after treatment with a combination of BTX-A plus exercise therapy. DESIGN: Twelve individuals received BTX-A and exercise therapy for 1 hr/day, three times per week, for 4 wks. Those who met MMC were enrolled in 2 wks of CIMT, and the rest received a home exercise program. Outcome measures included the Ashworth Scale, Wolf Motor Function Test (WMFT), the Motor Activity Log (MAL), the Box and Blocks Test (BBT), and the upper-extremity subtest of the Fugl-Meyer Assessment of Motor Function (FM-UE). RESULTS: Ashworth Scale scores declined from a mean score of 2.0-1.2 (P = 0.01). Four of 12 subjects were able to achieve MMC (P = 0.026). CIMT participants improved in the BBT, the MAL, and the WMFT compared with their own baseline. Gains achieved during CIMT receded by week 24 as spasticity returned. CONCLUSION: BTX-A plus exercise therapy shows potential to improve function for those with severe hand paresis and spasticity after stroke. Those who meet MMC may initially realize further modest gains through CIMT. However, gains are likely to recede as spasticity returns. Adding medications or modifying the therapy protocol to include activities such as functional neuromuscular stimulation or robotic training may yield a more potent effect. PMID- 17709995 TI - Muscle strength recovery in treated Guillain-Barre syndrome: a prospective study for the first 18 months after onset. AB - OBJECTIVE: To assess the recovery in muscle strength and functional capacities in subjects with Guillain-Barre syndrome (GBS) for 18 months after onset. DESIGN: Six GBS patients were treated and transferred to our rehabilitation center within the first week of recovery. RESULTS: Isometric and isokinetic strength increased significantly during the first 6 months (P < 0.01). Between 6 and 18 months, muscle strength increased less rapidly (P < 0.05). We showed a significant negative correlation between plateau period duration and knee extensors, elbow flexors muscles strength recovery (rho = -0.82; P = 0.05). At 6 months, manual muscle testing and functional independence motor total scores were close to normal levels. At 18 months, all patients satisfied the criteria for a full recovery. However, they felt difficulties after prolonged exercise. CONCLUSIONS: Until 18 months of recovery, dynamometric measures still showed significant strength improvement. This underscores the need for a minimal 24 months of clinical follow-up with an individualized rehabilitation management program. PMID- 17709994 TI - Repetitive transcranial magnetic stimulation as an adjunct to constraint-induced therapy: an exploratory randomized controlled trial. AB - OBJECTIVE: To test the potential adjuvant effect of repetitive transcranial magnetic stimulation (rTMS) on motor learning in a group of stroke survivors undergoing constraint-induced therapy (CIT) for upper-limb hemiparesis. DESIGN: This was a prospective randomized, double-blind, sham-controlled, parallel group study. Nineteen individuals, one or more years poststroke, were randomized to either a rTMS + CIT (n = 9) or a sham rTMS + CIT (n = 10) group and participated in the 2-wk intervention. RESULTS: Regardless of group assignment, participants demonstrated significant gains on the primary outcome measures: the Wolf Motor Function Test (WMFT) and the Motor Activity Log (MAL)--Amount of Use, and on secondary outcome measures including the Box and Block Test (BBT) and the MAL- How Well. Participants receiving rTMS failed to show differential improvement on either primary outcome measure. CONCLUSIONS: Although this study provided further evidence that even relatively brief sessions of CIT can have a substantial effect, it provided no support for adjuvant use of rTMS. PMID- 17709996 TI - Lesion characteristics, NIH stroke scale, and functional recovery after stroke. AB - OBJECTIVE: We examined the relationships between the National Institute of Health Stroke Scale (NIHSS) and physical, cognitive, and social participation outcomes across subpopulations of stroke survivors on the basis of cortical involvement and lesion lateralization. DESIGN: Families in Recovery from Stroke Trial participants were classified with respect to lesion lateralization (n = 274) and cortical involvement (n = 158). NIHSS scores (average 13 days after stroke) were used to predict Physical Performance Test times (PPT), limitations in activities of daily living (Augmented Barthel Index (ABI)), Instrumental Activities of Daily Living (IADL), cognitive function, depressive symptoms (Center for Epidemiologic Studies Depression scale [CES-D]), and productive, recreational, self-care, and social role activities 3 and 6 mos later. We compared the relationship between NIHSS and each outcome in stroke subgroups classified by lesion lateralization and cortical involvement. RESULTS: NIHSS predicted physical performance, activities of daily living, and IADL independence. The association between NIHSS and both PPT and IADLs was less steep for patients with cortical lesions than for patients with exclusively subcortical lesions. NIHSS predicted physical performance, activities of daily living, or IADLs similarly for right- and left hemisphere strokes, but hemisphere modified the association between NIHSS and CES D and cognitive measures. CONCLUSIONS: The NIHSS may predict outcomes in subpopulations of stroke survivors with subcortical lesions better than in patients with cortical involvement. NIHSS predicted CES-D in patients with right sided lesions but not in those with left-sided lesions. In contrast, NIHSS had little association with cognitive outcomes among patients without left-side involvement. PMID- 17709997 TI - Urinary tract infection and bacteriurua in stroke patients: frequencies, pathogen microorganisms, and risk factors. AB - OBJECTIVE: To investigate the frequencies, pathogen microorganisms involved, and possible risk factors of urinary tract infections, asymptomatic bacteriuria, and significant bacteriuria in subacute and chronic stroke patients. DESIGN: The frequencies were determined and compared for subgroups with respect to age, gender, level of education, type of lesion, side of lesion, bladder-emptying method, postvoid residual urine, ambulation-level class, and Brunnstrom recovery stage class of upper and lower extremities in 110 consecutive stroke patients. RESULTS: Frequencies were 27.3, 11.8, and 39.1% for urinary tract infections, asymptomatic bacteriuria, and significant bacteriuria, respectively. Bladder emptying method (P < 0.05), presence of postvoid residual urine >50 ml (P < 0.04), and Brunnstrom recovery stage class of upper extremity (P < 0.02) were significant factors for the frequency of urinary tract infections. Bladder emptying method, ambulation-level class, Brunnstrom recovery stage class of upper and lower extremities (P < 0.01), presence of postvoid residual urine >50 ml (P < 0.02), gender, and level of education (P < 0.05) were significant factors for the frequency of significant bacteriuria. CONCLUSIONS: Early treatment of urinary dysfunction for elimination of indwelling catheter use and high postvoid residue, early physical rehabilitation for better ambulation and hand function, patient education about prevention, and close monitoring of patients with unmodifiable risk factors may decrease the frequency of urinary tract infections and significant bacteriuria in stroke patients. PMID- 17709999 TI - The effect of providing power mobility on body weight change. AB - OBJECTIVE: To investigate whether the provision of power mobility would have an effect on body weight in adults who were first-time qualifiers for power mobility. DESIGN: This was a retrospective observational study of consecutive subjects, who served as their own controls. The medical records of 468 subjects who were approved for power mobility during a 17-mo period were reviewed. Three weight groups (12 mos before, at, and 12 mos after the power mobility evaluation) were evaluated with repeated-measures analysis of variance (ANOVA). The weight changes on subjects in different age groups (45-54, 55-64, 65-74, and >74), in geriatric vs. nongeriatric groups, and in different body mass index (BMI) groups were analyzed. RESULTS: Eighty-nine subjects met the inclusion criteria. They were obese (49.4%), and most of them were geriatric (64%). Congestive heart failure (30.34%) and chronic obstructive pulmonary disease (22.47%) were the two main presenting diagnoses. The repeated-measures ANOVA showed no significant weight change in the three studied weight groups. Similar results were seen in the age and BMI subgroups. CONCLUSIONS: There was no statistically significant weight change in adults who were first-time qualifiers and who used power mobility for 1 yr. PMID- 17710000 TI - The impact of diabetes mellitus on stroke acute rehabilitation outcomes. AB - OBJECTIVE: To examine the impact of diabetes mellitus (DM) on functional outcomes after acute rehabilitation for cerebrovascular accident (CVA). DESIGN: A retrospective research design was used to analyze outcomes in patients with a primary diagnosis of unilateral stroke (n = 367) admitted to an urban, acute rehabilitation center in the Southeastern United States. RESULTS: Multivariable hierarchical regression revealed that DM did not contribute statistically significant variance to stroke acute rehabilitation prediction models. Rehabilitation admission functioning scores, rehabilitation length of stay, age, and stroke type were significant predictors of poststroke rehabilitation motor outcomes (r2 = 0.603) and cognitive outcomes (r2 = 0.712). Diabetes also had no significant impact on acute stroke rehabilitation lengths of stay or rehabilitation discharge setting. CONCLUSIONS: Diabetes does not seem to significantly impact short-term acute rehabilitation outcomes after stroke. Persons with diabetes who suffer a stroke seem to benefit and improve during their acute rehabilitation stay at levels equivalent to peers who are not diagnosed with diabetes. Future research should examine the impact of diabetes subtypes and undiagnosed diabetes on short- and long-term outcomes. PMID- 17710001 TI - Physical medicine and rehabilitation conditions in the Astrodome clinic after hurricane Katrina. AB - OBJECTIVE: To report the physical medicine and rehabilitation (PMR) conditions seen in the Astrodome Clinic after Hurricane Katrina. DESIGN: Retrospective chart analysis from the county hospital-sponsored disaster-relief clinic in large urban city, including a study of 239 patients with 292 PMR conditions. The total number of patients seen in the Astrodome Medical Clinic was 11,245. The Astrodome database was reviewed for PMR condition diagnostic codes. A retrospective chart analysis was conducted, including date of visit, age, gender, ethnicity, and PMR diagnosis category. Descriptive statistics were obtained for the entire sample. chi2 or t tests were used to determine gender, age, or date-of-service predominance for the most common diagnostic categories. RESULTS: Mean +/- SD age was 45.7 +/- 14.3 yrs; 56% were women, 43% were men (1% unspecified), and 76% were African American. The majority (75%) of PMR conditions presented in the first week. Most frequent were swollen feet and legs (22%), leg pain and cramps (17%), headache (12%), and neck and back pain (10%). Persons with headaches were younger than those without (41.3 vs. 46.3 yrs, P = 0.048). Persons with neck and/or back pain were older than those without those conditions (51.3 vs. 44.8 yrs, P = 0.004). Women had more headaches (20.9%) than did men (6.7%, P = 0.002). There were no Caucasians with leg pain/cramps, whereas 20.2% of African Americans had this condition (P = 0.028). CONCLUSIONS: This study documents the time of clinic presentation and most frequent types of PMR conditions of patients treated in the Astrodome Clinic after a historic hurricane. Most PMR conditions were treated by PMR personnel during the first week. Thus, future disaster planning should include PMR professionals as early responders. PMID- 17710002 TI - Impairment and disability in the Astrodome after hurricane Katrina: lessons learned about the needs of the disabled after large population movements. PMID- 17710003 TI - Epidural local anesthetic plus corticosteroid for the treatment of cervical brachial radicular pain: single injection versus continuous infusion. AB - BACKGROUND: Efficacy of epidural local anesthetics plus steroids for the treatment of cervicobrachial pain is uncertain. METHODS: A prospective study randomized 160 patients with cervicobrachial pain resistant to conventional therapy. Patients were divided into 4 groups on the basis of the time between pain onset and treatment initiation: group A, 40 patients with pain onset 15 to 30 days; group B, 40 patients with pain from 31 to 60 days; group C, 40 patients, 61 to 180 days; and group D, 40 patients with pain >180 days. Patients of each group were randomized to receive an epidural block with bupivacaine and methylprednisolone at intervals of 4 to 5 days (Single injection) or continuous epidural bupivacaine every 6, 12, or 24 hours plus methylprednisolone every 4 to 5 days (Continuos epidural). The maximum duration of treatment (9 blocks in Single injection, and 30 days in Continuos epidural) was dependent on achieving Pain Control (PC) > or =80% [PC is defined by this formulae: (100) (VAS(initial) VAS(final))/VAS(initial)]. Follow-up at 1 month and 6 months compared PC and the number of pain-free hours of sleep. RESULTS: One hundred forty-one patients completed the study. The 4 groups had similar characteristics. At the 1-month and 6-month follow-up analysis based on the time between pain onset and treatment initiation showed that patients of group D, who received the Continuous epidural treatment, had significantly greater PC and significantly more pain-free hours of sleep compared with similar patients in Single injection. CONCLUSIONS: Therapy with continuous epidural local anesthetic and methylprednisolone provides better control of chronic cervicobrachial pain compared with Single injection. These results are discussed with respect to the possible mechanism of action of the drugs and may relate to the physiopathologic mechanisms associated with neuronal plasticity that result in chronic pain. PMID- 17710004 TI - Patients' perceptions of their pain condition across a multidisciplinary pain management program: do they change and if so does it matter? AB - OBJECTIVES: The primary aim of this study was to determine whether changes in cognitive processes are related to improved functional outcomes across a multidisciplinary pain management program. METHODS: A longitudinal design was employed where patients completed 6 versions of the same questionnaire at the beginning, middle, and end of the 4-week treatment program and at 1, 3, and 6 months follow-up. Seventy-six patients consented to participate in this study. Outcome was assessed using the physical and mental component scores of the Short Form Health Questionnaire. Measures of cognitive processes included the Illness Perceptions Questionnaire Revised, the Pain Catastrophizing Scale, and the Pain Vigilance and Awareness Questionnaire. Fifty-eight patients (76%) completed all 6 questionnaires. RESULTS: We found reductions in catastrophizing and beliefs about the serious consequences of pain were most strongly associated with improved physical functioning, whereas reductions in pain vigilance, emotional representations of pain, and sense of coherence about pain were the best predictors of improved mental functioning. Overall, change in cognitive processes accounted for 26% of the variance in improved physical functioning and 23% of the variance in mental functioning. DISCUSSION: These findings suggest that interventions that specifically target cognitive processes may enhance treatment effects for patients with chronic pain. PMID- 17710005 TI - Nimesulide in the treatment of postoperative pain: a double-blind, comparative study in patients undergoing arthroscopic knee surgery. AB - OBJECTIVE: To evaluate the efficacy and tolerability of nimesulide in the relief of postoperative pain after orthopedic surgery compared with naproxen and placebo. METHODS: In this multicenter, double-blind, double-dummy, randomized, parallel group study, 94 patients with at least moderate postoperative pain after arthroscopy and meniscectomy were randomized to receive nimesulide 100 mg b.i.d., naproxen 500 mg b.i.d., or placebo for a maximum of 3 days. RESULTS: Nimesulide was significantly more effective than placebo for the treatment of postoperative pain, as measured by the primary efficacy variable of summed pain intensity difference within 6 hours after first treatment (10.91 vs. 6.29). Furthermore, nimesulide also provided significantly better pain relief than naproxen on this parameter. Overall, nimesulide demonstrated superior analgesic activity compared with naproxen and placebo for the majority of secondary efficacy variables. All 3 treatments were well tolerated, with a lower number of patients reporting adverse events in the nimesulide group. Nimesulide recipients reported no gastrointestinal disorders. CONCLUSIONS: This study demonstrates that nimesulide is an effective, fast-acting and well-tolerated oral anti-inflammatory drug with a distinct analgesic activity after out-patient orthopedic surgery. PMID- 17710006 TI - Value of the magnetic resonance imaging in patients with painful lumbar spinal stenosis (LSS) undergoing lumbar epidural steroid injections. AB - OBJECTIVES: Purpose of this study is to examine the relationship between the magnetic resonance imaging (MRI) findings, pain scores, and opiates use in patients with lumbar spinal stenosis (LSS) undergoing lumbar epidural steroid (LES) injections by retrospective review of 719 patients' electronic medical records. METHODS: Reviewed were Visual Analog Scale (VAS) pain scores and opioid use before and 8 to 12 weeks after series of LES injections. The stenosis pain index (SPI) was produced by adding an assigned numerical value of severity (1=mild, 2=moderate, 3=severe) to the number of lumbar vertebral levels affected by LSS on MRI (lateral or central). RESULTS: The average age of patients was 68.4 years. There was no relationship between the pretreatment age, sex, or number of vertebral levels affected on MRI with pretreatment VAS pain scores or opioid use. The degree of LSS present on MRI, categorized as a mild, moderate, or severe, correlated clearly with initial VAS pain scores (P=0.017). The improvement in VAS pain scores after LES injections correlated well with number of levels affected (P=0.003) and the severity of stenosis (P=0.12). Positive correlation was observed between change in VAS pain score 8 to 12 weeks after the series of LES injections and the SPI (P=0.001). There were no differences found in opioid use. DISCUSSION: The improvement in VAS pain scores after LES injections correlated well with the changes in the SPI except in those patients classified on MRI as severe LSS and more than 3 lumbar levels affected. That patient group is unlikely to benefit from LES injections. PMID- 17710007 TI - Spinal mechanisms of pain control. AB - OBJECTIVES: To demonstrate initial results using Khan Kinetic Treatment (KKT) as a chronic neck pain treatment and to present pain control mechanistic theory on which the treatment is based. METHODS: A self-reported functional assessment, neck pain questionnaire, and pain medication dose were used as outcome measures for 44 matched patients randomly split into 2 groups ("treatment" and "control"). The treatment group underwent a treatment period consisting of several individual KKT treatments, whereas the control group continued conventional therapy. RESULTS: Compared with a control group, the treatment group lowered both their self-recorded neck pain scores (P=0.012) and pain medication dose (P=0.048), although current functional assessment questionnaires (range of motion, overall activity, and recreation/work activities) did not detect changes (P=0.233, 0.311, and 0.472, respectively). DISCUSSION: We address the theory of the pain control mechanisms of the device in detail. Although we await randomized placebo controlled trials and additional results from ongoing mechanistic studies, initial results show that KKT is potentially an effective treatment for chronic neck pain and may contribute to the reduction of pain relieving medication. PMID- 17710008 TI - Combination of topical EMLA with local injection of lidocaine: superior pain relief after Ferguson hemorrhoidectomy. AB - OBJECTIVE: To determine whether a combination of topical anesthetic (EMLA) and local injection with lidocaine is better than lidocaine alone for pain relief after Ferguson hemorrhoidectomy. METHODS: Sixty patients scheduled for hemorrhoidectomy were randomized into 2 groups: (1) control group (CG, n=30) received neomycin ointment (5 g), and (2) EMLA group (EG, n=30) received EMLA (5 g), both agents applied topically after surgery. Before the surgical incision was made, lidocaine (10 mL of a 1% solution) was locally injected into all 60 patients. After surgery, analgesics were provided when necessary. The visual analog scale score was recorded at 4 time points: (1) upon arrival in the postanesthesia room, (2) 2 hours after arriving in the postanesthesia room, (3) between 9 and 10 PM on the first postoperative evening, and (4) on the first postoperative morning. The frequency of meperidine requests, 1-time catheterizations for urinary retention, and patient satisfaction with postoperative pain management, were also recorded. RESULTS: The median visual analog scale scores and cumulative dosages of meperidine were significantly lower in the EG than the CG (P<0.05). Patient satisfaction with postoperative pain control was also significantly higher in the EG than the CG (P<0.01). No systemic complications occurred. DISCUSSION: EMLA is considered a breakthrough in cutaneous analgesia, capable of reducing pain in many cutaneous procedures. Because Ferguson hemorrhoidectomy has been performed for years with ongoing concerns over postoperative pain, we felt that using EMLA could lower postoperative pain intensity and the number of requests for additional medication. PMID- 17710009 TI - Factors influencing neck pain intensity in whiplash-associated disorders in Sweden. AB - OBJECTIVES: To investigate if sociodemographic and economic factors, preinjury health status, and collision factors are associated with initial neck pain intensity in whiplash-associated disorders (WAD) in Sweden. The factors of interest were demographic and socioeconomic factors, prior health, and collision factors. METHODS: A cohort study of car occupants, insured by either of 2 Swedish traffic insurers, age 18 to 74 years, who filed an injury claim and reported WAD after a motor vehicle collision (n=1187) were approached with mailed questionnaires. These contained questions about prior health, details about the collision, and symptoms after the collision. Neck pain intensity was measured on a visual analog scale and categorized into mild pain (0 to 30 mm), moderate pain (31 to 54 mm), and severe pain (55 to 100 mm). RESULTS: Low educational level [odds ratio (OR) 2.8; 95% confidence interval (CI) 1.8-4.5], being sole adult in the family (OR 1.6; 95%CI 1.1-2.2), prior neck pain (OR 2.9; 95%CI 1.4-6.2), prior headache (OR 2.2; 95%CI 0.7-6.9), prior poor general health (OR 2.6; 95%CI 1.4-4.8), and exposure to rollover collision (OR 1.9; 95%CI 1.0-3.8) were all associated with severe initial neck pain intensity. Most of these factors were also associated with moderate pain intensity. DISCUSSION: This study confirms results from a previous study that sociodemographic and economic status, preinjury health status, and collision-related factors are associated with participants' rating of initial neck pain intensity in WAD. The findings are of importance for interpreting and understanding the underlying factors of pain rating. PMID- 17710010 TI - The result of treatment on vestibular and general pain thresholds in women with provoked vestibulodynia. AB - OBJECTIVE: To correlate changes in vestibular pain thresholds to general pain thresholds in a subgroup of women with provoked vestibulodynia taking part in a treatment study. METHODS: Thirty-five women with provoked vestibulodynia were randomized to 4 months' treatment with either electromyographic biofeedback (n=17) or topical lidocaine (n=18). Vestibular and general pressure pain thresholds (PPTs) were measured and the health survey Short Form-36 (SF-36) was filled out before treatment and at a 6-month follow-up. Subjective treatment outcome and bodily pain were analyzed. Thirty healthy women of the same age served as controls for general PPTs and SF-36. RESULTS: No differences in outcome measures were observed between the 2 treatments. Vestibular pain thresholds increased from median 30 g before to 70 g after treatment in the anterior vestibule (P<0.001) and from median 20 to 30 g in the posterior vestibule (P<0.001). PPTs on the leg and arm were lower in the patients as compared with controls both before and at the 6-month follow-up. Patients reporting total cure were 3/35; 25/35 were improved. The number of patients who frequently reported of other bodily pain was reduced after the treatment. The patients had lower scores for SF-36 (General Health, Vitality) before treatment, which was restored at the 6-month follow-up. DISCUSSION: Treating provoked vestibulodynia by either topical lidocaine or electromyographic biofeedback increased vestibular pain thresholds, reduced dyspareunia, and improved bodily pain. The patients showed a general hypersensitivity to pressure pain compared with controls and in this study the hypersensitivity did not seem to be affected by treating the superficial dyspareunia. PMID- 17710011 TI - Enhanced postoperative sensitivity to painful pressure stimulation after intraoperative high dose remifentanil in patients without significant surgical site pain. AB - OBJECTIVES: This clinical study tested the hypothesis whether intraoperative high versus low dose of intravenous remifentanil resulted in postoperatively increased pain sensitivity to painful cold or pressure stimulation in eye surgery patients without significant postoperative pain. METHODS: Forty-two minor eye surgery patients were randomized to receive intraoperative high (0.4 microg/kg/min) or low (0.1 microg/kg/min) dose of intravenous remifentanil plus isoflurane over an average period of 70 minutes. Pain assessment at the surgical site, postoperative versus preoperative baseline measurements by the cold as well as the pressor test, sedation score, and withdrawal signs were evaluated 30 and 90 minutes after stop of remifentanil infusion. Patients with pain at the surgical site were excluded. RESULTS: Pressure pain tolerance thresholds at the palmar carpus of the right hand were significantly decreased in these patients after cessation of intraoperative high but not low dose of IV remifentanil. However, withdrawal latencies to cold stimulation were not significantly altered. Isoflurane concentrations were slightly higher in patients receiving the low dose of remifentanil, however, there were no significant differences in length of anesthesia and postoperative sedation. Signs of withdrawal were not observed. DISCUSSION: After high dose intravenous remifentanil our results show signs of a reduced tolerance to painful pressure but not cold stimuli distant to the surgical field. Although clinically relevant surgical pain was not reported in these patients, the demonstrated induction of hyperalgesia to painful pressure stimuli suggests a general effect in the central nervous system. PMID- 17710012 TI - Rhenium-186 hydroxyethylidenediphosphonate (186Re HEDP) for the treatment of hemophilic arthropathy: first results. AB - OBJECTIVES: The aim of this study was to evaluate the efficacy of a systemic application of rhenium-186 hydroxyethylidenediphosphonate (Re HEDP) for pain treatment in patients with hemophilic arthropathies. METHODS: Twelve patients with hemophilic arthropathy with at least 3 involved joints with persistent pain were included in this prospective study. A single dose of 15 mCi (555 MBq) Re HEDP was administered intravenously. Before and 12 weeks after treatment, pain assessment was performed using the visual analog scale (VAS). The pain status assessment included the general status, pain of all joints affected, and pain of the 3 mostly involved joints. Furthermore, quality of life was assessed. RESULTS: With regard to the 3 most involved joints, an improvement of the pain symptoms in 25 of 36 (69.4%) joints was observed. With regard to all involved joints a median of 3 joints per patient improved after Re HEDP therapy. General pain status after treatment was 2.0 VAS points lower as compared with pretreatment. The total number of involved joints remained unchanged in 7 patients, increased in 1 patient, and decreased in the remaining 4 patients. CONCLUSIONS: The results of this study show an improvement of the pain symptoms of the involved joints 12 weeks after therapy with Re HEDP in patients with hemophilic arthropathy. The only moderate success regarding a reduction of the total number of involved joints is by the fact that despite this improvement most affected joints remained still painful on a lower level after the therapy or due to newly affected joints not painful before initiation of the radionuclide therapy. PMID- 17710013 TI - Internet surveillance: content analysis and monitoring of product-specific internet prescription opioid abuse-related postings. AB - OBJECTIVES: This study describes the development of a systematic approach to the analysis of Internet chatter as a means of monitoring potentially abusable opioid analgesics. METHODS: Message boards dedicated to drug abuse were selected using specific inclusion criteria. Threaded discussions containing 48,293 posts were captured. A coding system was created to compare content of posts related to 3 opioid analgesics: Kadian, Vicodin, and OxyContin. RESULTS: The number of posts containing mentions of the target drugs were significantly different [OxyContin (1813)>Vicodin (940)>Kadian (27), P<0.001]. Analyses revealed that these differences were not simply a reflection of the availability of each product (ie, number of prescriptions written). Reliability tests indicated that the content coding system achieved good interrater reliability coefficients (average kappa across all categories=0.76, range=0.52 to 1.0). Content analysis of a sample of 234 randomly selected posts indicated that the proportion of Internet posts endorsing abuse of Kadian was statistically significantly less than OxyContin (45.5% vs. 68.4%, P=0.036, not adjusted for multiple comparisons). DISCUSSION: These results suggest that a systematic approach to postmarketing surveillance of Internet chatter related to pharmaceutical products is feasible and yields reliable information about the quantity of discussion of specific products and qualitative information regarding the nature of the discussions. Kadian was associated with fewer Internet mentions than either OxyContin or Vicodin. This investigation stands as a first attempt to establish systematic methods for conducting Internet surveillance. PMID- 17710014 TI - Change factors explaining reductions of "interference" in a multidisciplinary and an exercise prevention program for low back pain. AB - OBJECTIVES: To identify relevant changes in process variables that are associated with outcome following an exercise and a multidisciplinary secondary prevention program for low back pain. METHODS: Data from a randomized controlled clinical trial to examine the effectiveness of an exercise and a multidisciplinary prevention program were analyzed using multiple regression analyses. The specific goal was to examine the amount of variance in changes in "interference" postintervention that could be explained by prechanges to postchanges in physical and psychologic parameters, and to determine if there are interactions between physical/psychologic parameters and the program type. RESULTS: One hundred sixty two (89%) participants were included in the regression analyses. Reductions of interference at postmeasurement were explained best by reductions of pain intensity and catastrophizing in the multidisciplinary and the exercise prevention program. No significant interaction between the changes in process variables and the program type was found. The final model could explain 68.7% of variance. CONCLUSIONS: Owing to methodologic limitations, strong conclusions cannot be drawn from this study. The findings suggest that treatment success in exercise and multidisciplinary interventions might be influenced by the same change factors, namely changes in pain and psychologic factors. The results raise the question of whether the mechanism through which exercise works, is improve in physical variables, or rather a change in psychologic attributes, in that people correct their irrational cognitions by making experiences that differ from their expectations. If these findings can be confirmed in longitudinal studies with more measurement points, they would have implications for treatment refinement. PMID- 17710015 TI - Celiac plexus block: a new technique using the left lateral approach. AB - We describe a new celiac plexus block approach in a patient with cholangiocarcinoma who was referred to the Pain Clinic due to uncontrollable abdominal pain. The patient was initially programmed for a neurolytic celiac plexus block using the anterior approach with helical computerized tomography (CT) guidance. The CT scan revealed interposition of the transverse colon in the anterior approach territory, which made the anterior approach technique difficult, and also difficulty to practice the posterior approach without injuring the kidneys. We decided to attempt a left lateral atypical approach because the CT revealed the possibility of using a left lateral window to arrive to the celiac area. The left lateral access allowed us to carry out the neurolytic block using 50% alcohol without injuring any viscera. The patient tolerated the technique and was discharged without pain. No complications regarding either the punction or the block were observed. PMID- 17710016 TI - Pain relief by electrostimulation of myofascial trigger points: peripheral or central mechanisms? PMID- 17710017 TI - Atypical brown fat distribution in young males demonstrated on PET/CT. AB - The development of PET/CT has led to the recognition that metabolically active fat, referred to as "brown fat," can accumulate FDG and represents a possible source of false-positive scans in oncology patients. Numerous reports have described the typical appearance of brown fat, which most commonly presents as neck and paravertebral uptake in young female patients. Other described sites of uptake include the mediastinum and retroperitoneum. We present examples of 2 cases of atypical diffuse brown fat uptake seen in the subcutaneous fat of the thighs, abdomen, and pelvis. Both of these patients were young men and did not show uptake in the typical supraclavicular and neck fat. Although rare in our experience, knowledge of this condition may prevent misinterpretation of this finding as an infiltrative condition of the skin, such as lymphoma. PMID- 17710018 TI - PET scintigraphy of etoposide-induced pulmonary toxicity. AB - A patient with chronic myelomonocytic leukemia developed drug-induced pulmonary toxicity after using low dose oral etoposide. Because etoposide-induced pulmonary toxicity is an uncommon but serious adverse event, clinicians must be vigilant about the possibility of it, so that the optimal treatment can start as soon as possible. This report demonstrates that PET scintigraphy might be a helpful tool in the early diagnosis of drug-induced pulmonary toxicity. PMID- 17710019 TI - Tc-99m sestamibi/F-18 FDG myocardial SPECT in Takayasu arteritis with coronary artery involvement. AB - Coronary arteries may be involved in some patients with Takayasu arteritis. Evaluation of myocardial involvement due to coronary lesions may provide important information in the clinical management of these patients. We report Tc 99m sestamibi and F-18 FDG myocardial single photon emission computed tomography in 3 cases of such patients. PMID- 17710020 TI - F-18 FDG PET/CT in the management of thyroid cancer. AB - PURPOSE: There are approximately 32,000 new cases of thyroid carcinoma annually in the United States. F-18 FDG PET/CT has an established role in cancer management, including thyroid cancer, usually in patients who are thyroglobulin (Tg) positive/iodine negative. We reviewed our experience with F-18 FDG PET/CT in thyroid cancer, with an emphasis on correlation with Tg, and maximum standardized uptake values (SUV). We also analyzed the role of thyroid stimulating hormone (TSH) on PET/CT results. MATERIALS AND METHODS: This is a retrospective study (January 2003 to December 2006) of 76 patients with differentiated thyroid cancer, who had F-18 FDG PET/CT scans. There were 44 women and 32 men, with age range of 20 to 81 years (average, 51.1 +/- 18.1). The administered doses of F-18 FDG ranged from 396 to 717 MBq (15.8-19.4 mCi) (average, 566 +/- 74.8) (15.3 +/- 2). Reinterpretation of the imaging studies for accuracy and data analysis from medical records were performed. RESULTS: A total of 98 PET/CT scans were analyzed (59 patients had 1 scan, 12 patients had 2, and 5 patients had 3). PET/CT was 88.6% sensitive (95% CI: 78.-94.3) and 89.3% specific (95% CI: 71.9-97.1). Mean Tg level was 1203 ng/mL (range, 0.5-28,357) in patients with positive PET/CT and 9.72 ng/mL (range, 0.5-123.0) in patients with negative PET/CT scans (P = 0.0389). Mean SUV max was 10.8 (range, 2.5-32) in the thyroid bed recurrence/residual disease and 7.53 (range, 2.5-26.2) in metastatic lesions (P = 0.0114). Mean SUV max in recurrent/residual disease in patients with TSH 30 mIU/L was 8.1 (range, 2.6-32) (P = 0.2994). CONCLUSION: F-18 FDG PET/CT had excellent sensitivity (88.6%) and specificity (89.3%) in this patient population. Metastatic lesions were reliably identified, but were less F-18 FDG avid than recurrence/residual disease in the thyroid bed. TSH levels at the time of PET/CT did not appear to impact the FDG uptake in the lesions or the ability to detect disease. In the setting of high or rising levels of Tg, our study confirms that it is indicated to include PET/CT in the management of patients with differentiated thyroid cancer. PMID- 17710021 TI - The effect of high-dose radioiodine treatment on lacrimal gland function in patients with differentiated thyroid carcinoma. AB - PURPOSE: There are a limited number of case reports confirming the radioiodine (I 131) presence in tears and only a few case reports of lacrimal gland dysfunction after I-131 therapy. This study was designed to clarify whether lacrimal gland function can be affected by I-131 therapy. MATERIALS AND METHODS: We studied 100 eyes of 50 patients who had received high doses of I-131 for treatment of differentiated thyroid carcinoma and 100 eyes of 50 age- and sex-matched control individuals without a history of interfering conditions. The exposed group was studied at least 3 months after their last I-131 therapy. Dry eye symptoms and Schirmer test values (wetting level in millimeters per 5 minutes) of an exposed group were compared with those of an unexposed group. RESULTS: Fifty-one percent of the exposed eyes and 50% of the unexposed ones revealed at least 1 of the dry eye symptoms. There was no significant difference in symptoms between 2 groups, except for burning sensation and eye redness, which were significantly higher in the exposed eyes. A lower Schirmer test value was noted in the exposed group, 14.5 +/- 10.8 mm, when compared with that in controls, 18.2 +/- 11.0 mm (P = 0.016), and the relative risk of an abnormal Schirmer test in exposed cases to control group was 1.78 +/- 0.62. Correlation coefficient analysis showed no significant relationship between Schirmer test values and cumulative doses of administered I-131. CONCLUSIONS: Reduction in the tear secretion from lacrimal glands is seen after high-dose I-131 therapy; however, their symptoms are no greater than an unexposed population. PMID- 17710022 TI - Tc-99m ECD neuro-SPECT and diffusion weighted MRI in the detection of the anatomical extent of subacute stroke: a cautionary note regarding reperfusion hyperemia. AB - We present a case of subacute middle cerebral artery infarct, which demonstrates restricted diffusion on MRI and reperfusion hyperemia in the posterior half of the lesion on angiography. Tc-99m ethyl cysteinate dimer (ECD) SPECT obtained shortly after the MRI failed to demonstrate perfusion defects in the regions demonstrating reperfusion hyperemia on angiography, underestimating the true size of the infarct. Crossed cerebellar diaschisis is, however, present. SPECT studies obtained over the following weeks demonstrated gradual enlargement of the lesion to approximate the MRI signal changes over a 19-day period. The case presented demonstrates retention of ECD in the infarcted brain. Several studies have demonstrated that Tc-99m ECD uptake is dependent on preserved brain tissue function because tracer retention requires enzymatic esterase activity, rather than the passive, nonenergy dependent trapping of Tc-99m hexamethylpropyleneamine oxime. Hence, infarcted areas undergoing reperfusion hyperemia are unlikely to demonstrate ECD uptake. This report illustrates that MRI diffusion weighted imaging may be more accurate in demonstrating the full extent of reperfused infarcts earlier than Tc-99m ECD SPECT. SPECT in this case failed to demonstrate reduced uptake in reperfused regions of the infarct. Also, crossed cerebellar diaschisis may serve as an early marker of extensive neuronal dysfunction. PMID- 17710023 TI - A Potential Role for F-18 FDG PET/CT in Evaluation and Management of Fibrosing Mediastinitis. AB - Fibrosing mediastinitis is an uncommon benign disorder, and its pathogenesis and management remain unclear. Conventional imaging techniques (chest radiographs, CT, MRI) may suggest its diagnosis but are frequently nonspecific, and it frequently mimics a malignant process by presenting as a mediastinal mass without calcifications, encasing, and infiltrating adjacent mediastinal structures, and showing an overall aggressive behavior. The value of FDG PET imaging in this entity remains largely unknown with only a few case reports in the literature, and often, biopsy is necessary for definitive diagnosis. We report a case of biopsy proven fibrosing mediastinitis highlighting the utility of PET in the evaluation and management of the disease. PMID- 17710024 TI - Focal hepatic activity during ventilation-perfusion scintigraphy due to systemic portal shunt due to superior vena cava obstruction from histoplasmosis-induced fibrosing mediastinitis. AB - A 59-year-old woman with a history of fibrosing mediastinitis secondary to histoplasmosis diagnosed on mediastinoscopy presented with dyspnea. A ventilation perfusion scan demonstrated decreased perfusion to the entire right lung. In addition, the perfusion images demonstrated focal abnormal activity in part of the liver. On computed tomography of the chest, there was significant soft tissue opacification in the mediastinum occluding the right pulmonary artery, with passage of the injected contrast via collateral vessels to the liver. The main collateral pathway was via the right internal thoracic vein and the umbilical vein. Pulmonary angiography confirmed complete occlusion of the right pulmonary artery. PMID- 17710025 TI - Kikuchi Disease Mimicking Malignant Lymphoma on FDG PET/CT. AB - A 10-year-old girl presented with a 2-month history of intermittent fever and palpable masses in the right side of the neck. Whole body FDG PET/CT imaging was performed, showing multiple FDG-avid nodular masses in cervical and abdominal lymph nodes. The patient then underwent excision biopsy of the enlarged right cervical nymph nodes, which confirmed the diagnosis of Kikuchi disease. After steroid therapy, fever and cervical lymphadenopathy subsided. After 3 months, follow up FDG PET/CT was done, and there was no abnormality. Kikuchi disease could lead to the wrong initial diagnosis of tuberculosis or even malignant lymphoma. PMID- 17710026 TI - Hyperparathyroidism with a functioning parathyroid cyst. AB - A rare case of primary hyperparathyroidism with a functioning parathyroid cyst in whom Tc-99m MIBI scintigraphy failed to detect a parathyroid tumor is presented. A 62-year-old woman with primary hyperparathyroidism was referred for Tc-99m MIBI imaging to investigate a parathyroid adenoma. Plasma levels of intact parathyroid hormone were elevated to 2250 pg/mL. Neck ultrasonography revealed a cystic lesion measured 30 x 42 x 35 mm on the right inferior side of the thyroid gland. The cystic lesion was successfully removed at surgery. Pathologic diagnosis revealed a benign parathyroid cyst. The cyst contained clear fluid, and was lined by 1 layer of cuboidal epithelial cells. Her postoperative course was uneventful and plasma levels of intact parathyroid hormone normalized after operation. PMID- 17710027 TI - Abdominal Tuberculosis: peritoneal involvement shown by F-18 FDG PET. AB - We present a case of a right renal tumor associated with increased accumulation of F-18 FDG in the peritoneum and ileocecum on PET imaging. The FDG-PET images suggested peritoneal carcinomatosis, but the histopathology of the open biopsy proved tuberculous peritonitis. Tuberculous peritonitis should be considered as a potential interpretive pitfall in mimicking peritoneal carcinomatosis. PMID- 17710028 TI - Systemic tuberculosis presenting as an epiglottic mass detected on F-18 FDG PET/CT. AB - A 32-year-old man presented with asthenia, weight loss, cough, and dysphagia following a recent stay in Morocco. Endoscopy showed a bulky mass of the epiglottis suspected of being a malignant tumor. The patient underwent jointly an F-18 FDG PET/CT and a biopsy of the tumor. Against all expectations, biopsy revealed granulomatous inflammation with epitheloid giant cells and caeseating necrosis. These findings associated with the presence of acid-fast bacilli in the sputum smears were highly suggestive of laryngeal tuberculosis, which was confirmed later after cultivation of mycobacteria. F-18 FDG PET showed diffuse pharyngolaryngeal and lung uptake with bilateral cervical and abdominal nodes, but also one thoracic vertebral uptake. Lung CT could have revealed carcinomatous dissemination, but cavitary lesions in some pulmonary segments were more evocative of tuberculosis. Moreover, cerebral MRI showed brain tuberculomas not visualized on F-18 FDG PET/CT. The patient was treated with a 5-antituberculosis drug regimen, which improved clinical symptoms with epiglottis mass regression, and lung CT image reduction, clinching the systemic tuberculosis diagnosis. A control F-18 FDG PET/CT performed 5 months later showed disappearance of the pharyngolaryngeal and node uptake, with an improvement of lung uptake without normalization, arguing for persistent disease. Unexpected pathologic findings may be present in more than 3% of neck dissections. Although this is usually indolent, with the underlying SCC remaining the main prognostic determinate, it may significantly complicate postoperative management. PMID- 17710029 TI - Lymphoscintigraphic findings in chylous reflux in a lower extremity. AB - Lymphoscintigraphy is a useful and safe tool for the diagnostic evaluation of a swollen extremity. Unilateral leg swelling with cutaneous chylous vesicles is a common manifestation of chylous reflux. The authors present a case of chylous reflux in an 11-year-old boy who presented with swelling and skin lesions of the left lower extremity. PMID- 17710030 TI - Acute intramural hematoma of the aorta as a cause of positive FDG PET/CT. AB - Type A acute intramural hematoma (IMH) of the ascending aorta is defined as hemorrhage in the aortic wall in the absence of intimal disruption. Proximity to the adventitia may explain the higher incidence of rupture in IMH. We present a case of IMH, diagnosed by the presence of linear intense uptake of FDG on PET/CT, in a 70-year-old woman undergoing staging for colorectal cancer. There is no current role for FDG-PET in the diagnosis of IMH. This case demonstrates that incidental focal FDG activity in the wall of the aorta may indicate the life threatening diagnosis of IMH. PMID- 17710031 TI - Postlaparoscopic abdominal port-site metastasis: F-18 FDG PET/CT demonstration. AB - Laparoscopic surgery has expanded its applications to treatment of malignant neoplasms with lower morbidity and mortality compared with the ones carried by conventional procedures. With the increasing volume of this minimally invasive technique, complications such as port-site tumor seeding may have a higher occurrence. Abdominal wall metastasis has been reported with conventional cross sectional imaging. The authors present 2 cases of early detection of port-site tumor implantation by PET/CT. PMID- 17710032 TI - Unilateral Tc-99m pertechnetate breast uptake: is it always benign? AB - Although the thyroid gland is the principal organ with the ability to concentrate iodide and take up Tc-99m pertechnetate, other tissues such as choroid plexus, salivary glands, mucoid cells of stomach, and lactating breast tissue also possess this property. The lactating mammary gland can concentrate iodide, which mediated by sodium/iodine symporter (NIS) is actively transported and secreted in the milk, to supply iodide to the newborn for the biosynthesis of thyroid hormones. The authors present an uncommon case of unilateral Tc-99m breast uptake in a breast-feeding woman. PMID- 17710033 TI - Drummer's fracture of the third metatarsal bone. AB - A 14-year-old girl presented with a painful right foot. She was an elite water polo player and could recall no history of specific trauma to the foot. On close and persistent questioning, she admitted to having taken up playing the drums recently, with practice sessions of up to 4 h/d. She used the foot drum with her right foot and had noticed that this was becoming increasingly painful and prevented her playing the instrument for the last 2 days. Plain films of the foot were originally reported as normal, but revised to abnormal after the scintigraphic study. Bone scintigraphy confirmed a stress fracture of the right 3rd metatarsal bone. Stress fractures of the 3rd metatarsal bone are rare with only 2 previous reports in the literature. PMID- 17710034 TI - Intercostal muscle contraction or rib bone marrow activity?: Look for ancillary clues. AB - Diffuse and uniform FDG uptake in the ribs and the intercostal muscles might appear similar on FDG-PET images and a reliable differentiation between the two is important for accurately identifying the underlying process. The former usually suggests excessive contraction of intercostal muscles mostly due to chronic obstructive pulmonary disease, whereas the latter signifies either bone marrow stimulation or involvement by a pathologic process. At times, images may appear confusing and may be misinterpreted. However, in both clinical settings, there are additional ancillary signs, which are helpful in making a correct diagnosis. We herein present 2 case vignettes from each category in which other ancillary signs helped to distinguish FDG rib uptake from intercostal muscle uptake. PMID- 17710035 TI - F-18 FDG PET/CT following dental extraction in a patient with head and neck cancer. AB - A 48-year-old man with squamous-cell carcinoma of the left tonsillar fossa and cervical lymph node metastases was being staged before radiation and chemotherapy. The patient had periodontal disease, and extraction of 2 teeth was performed before therapy. A staging PET/CT was performed 1 week after extraction. This case demonstrates increased FDG uptake at the extraction sites, which could be potentially mistaken for metastatic lesions, especially without the fused PET/CT images. PMID- 17710036 TI - Metastatic eccrine porocarcinoma detected on FDG PET/CT. AB - Eccrine porocarcinoma is an uncommon neoplasm of the sweat gland duct and poses a significant risk of cutaneous, regional lymph node, or visceral metastases. A 62 year-old woman with a history of eccrine porocarcinoma in the left flank area underwent an F-18 FDG PET/CT scan, which revealed increased FDG uptake in left pelvic (SUV 6.34) and left axillary regions (SUV 4.02). Wide excision of left axillary and left pelvic lymph nodes was performed, and histopathologic findings were consistent with eccrine porocarcinoma. PET/CT detects metastases accurately and is helpful in the management of patients with eccrine porocarcinoma. PMID- 17710037 TI - High-grade urothelial carcinoma of the prostate on FDG PET-CT. AB - We report the PET-CT appearance of a high-grade prostatic urothelial carcinoma in a 68-year-old man with a long history of urothelial carcinoma. The patient was initially diagnosed with urothelial carcinoma in the left ureter, status postleft nephrourethrectomy. He was subsequently, 11 years later, diagnosed with low-grade urothelial carcinoma involving the bladder for which he received monthly Bacillus Calmette-Guerin treatment. Three months after the diagnosis of the bladder tumor, he was found to have biopsy-proven high-grade urothelial carcinoma of the prostate for which he was referred to have a PET-CT scan to evaluate for distant metastasis. PMID- 17710038 TI - FDG-PET is useful in staging and follow-up of primary uterine cervical lymphoma. AB - A 35-year old woman presented with vaginal bleeding. She had a normal gynecologic examination and Papanicolaou test. A CT scan of the pelvis showed a cervical mass, which on biopsy proved to be B-cell lymphoma. PET before preoperative staging demonstrated a large area of increased FDG uptake in the pelvis, corresponding to the mass seen on the CT scan. There were no other abnormal F-18 FDG avid sites. The patient received chemotherapy followed by total abdominal hysterectomy. Histopathology was consistent with large B-cell lymphoma of the uterine cervix. Posttherapy CT scan and PET scan showed no evidence of active and or residual disease. PMID- 17710040 TI - Rheumatoid lung disease as seen on PET/CT scan. AB - We present the case of a 63-year-old woman chronic smoker with a history of severe rheumatoid arthritis, who presented with dyspnea and cough. Her chest x ray film and CT scan (as part of a PET/CT scan) showed multiple lung nodules and a left pleural effusion. A PET scan (as part of a PET/CT scan) revealed no uptake in the larger lung nodules and intense left pleural uptake. The findings favored rheumatoid lung disease with rheumatoid pleural involvement, but malignant involvement was not excluded. A CT-guided lung and pleural biopsy confirmed the diagnosis of rheumatoid lung disease. On the basis of these findings, the patient was put on immunomodulators and responded to treatment. PMID- 17710039 TI - Renal metastases from follicular thyroid cancer on SPECT/CT. AB - In well-differentiated thyroid carcinoma, only a subset of patients develop distant metastases, predominantly to the lungs and the skeletal system. Only a few cases of metastatic spread to the kidneys are described in the literature. We report the case of a 64-year-old woman with a long history of follicular thyroid cancer who developed renal metastases. The lesions were detected with I-131 scintigraphy, SPECT/CT and thin-collimated contrast-enhanced CT. Subsequent surgery and histopathologic analysis of the renal lesions confirmed the diagnosis. PMID- 17710042 TI - Bariatric surgery costs and implications for hospital margins: comparing laparoscopic gastric bypass and laparoscopic gastric banding. AB - BACKGROUND: Effective cost reduction strategies require effective analyses of charges. METHODS: Costs and charges for laparoscopic gastric bypass and laparoscopic gastric banding were compared. Equipment costs, both disposable and reusable, were obtained. Data on the total charges, anesthesiology charges, and hospital charges were obtained; univariate and multivariate analyses were performed. RESULTS: Disposable equipment costs for laparoscopic gastric bypass totaled $3516.23, for laparoscopic gastric banding they were $4363; the difference stemmed from the $3195 laparoscopic band. Median total charges for the procedures differed by less than $100 (P=0.81). Hospital charges for gastric bypass were about $275 (P=0.087) more for bypass than for banding. CONCLUSIONS: Effective cost reduction strategies require cost analyses of each individual procedure; results for one procedure cannot necessarily be generalized to another procedure even if overall costs do not differ. PMID- 17710043 TI - Choice of approach for appendicectomy: a meta-analysis of open versus laparoscopic appendicectomy. AB - Although laparoscopic appendicectomy has been performed since 1983, the optimal approach for appendicectomy is still under debate. A systematic review and meta analysis of all randomized controlled trials between 1995 and 2006 was undertaken. Studies were analyzed overall and in 2 subgroups (pre-2000 and post 2000) to examine for changes in outcomes with increased laparoscopic experience. Operation time was significantly longer for laparoscopy and hospital stay was shorter. Operating time reduced markedly for laparoscopy on subgroup analysis. The risks of postoperative ileus and wound infection are lower for laparoscopy. Perhaps paradoxically, the risk of intra-abdominal abscess development is significantly raised with laparoscopy with an odds ratio of 2.26 (P=0.0002). Laparoscopic appendicectomy is a safe and effective method of treating acute appendicitis. This meta-analysis shows improvement in the outcomes of laparoscopy with increasing laparoscopic experience but open surgery appears to still confer benefits, especially in terms of intra-abdominal abscess incidence. PMID- 17710044 TI - The immunomodulatory effects of laparoscopic surgery. AB - Laparoscopic alternatives to conventional surgical procedures confer many advantages to patients including reduced postoperative pain, shortened convalescence and, perhaps, improved disease-related outcomes. The diminished degree of immune dysfunction apparent with these techniques may underpin these beneficial aspects. However, minimal access is accompanied by various ancillary anesthetic and mechanical associations (including the induction of a carbon dioxide pneumoperitoneum), which must be considered in addition to reduced tissue trauma when attempting to correlate cause with effect. Furthermore, the opportunity to establish causation between the immunomodulatory aspects of laparoscopy and subsequent clinical outcome by prospective, randomized study is difficult because of the rapid incorporation of minimal access techniques into clinical practice. Therefore, experimental in vitro and in vivo studies must be used to complement the limitations of clinical studies in this area. Although the initial investigations into the immunological effects of laparoscopy are encouraging, many of the intricacies associated with this approach still await elaboration. PMID- 17710045 TI - Laparoscopic choledochotomy in management of choledocholithiasis. AB - PURPOSE: Laparoscopic choledochotomy on patients indicated for common bile duct exploration was carried out according to an algorithm for managing choledocholithiasis. This study describes retrospectively our method and evaluates a new cystic duct biliary decompression cannula (J-tube) as an alternative to the T-tube. METHODS: Patients with confirmed choledocholithiasis (n=46) underwent laparoscopic choledochotomy. The T-tube was inserted in cases with suspected retained stones after common bile duct clearance, and the J-tube (950-mm long, 4 Fr) with a tapered and J-shaped segment at the distal end was inserted in other cases. RESULTS: Only 1 case was converted to open surgery (success rate, 97.8%); the J-tube was inserted in 30 patients and the T-tube in 15. The median operation time, hospital stay, and the interval until removal of the tube were significantly shorter with J-tube than with T-tube cases. Bile leakage after surgery occurred in 4 J-tube and 2 T-tube cases with one residual stone in each case. CONCLUSIONS: The transcystic decompression tube is easily and safely inserted with the J-kit. Among several strategies currently available for the management of choledocholithiasis, laparoscopic choledochotomy with the use of the J-tube is one of the safest and most feasible methods. PMID- 17710046 TI - Cannula site insertion technique prevents incisional hernia in laparoscopic fundoplication. AB - INTRODUCTION: Incisional hernia is a common surgical problem encountered after laparotomies. The so-called trocar-site or port-site hernia is a type of incisional one that occurs after laparoscopic procedures. It has an incidence range between 0.1% and 3%. OBJECTIVE: To evaluate our patients who underwent laparoscopic Nissen fundoplication for presence of trocar-site hernia. PATIENTS AND METHODS: This study included 405 patients who underwent laparoscopic Nissen fundoplication in Ankara University, Faculty of Medicine, Department of General Surgery, Turkey. The patients were evaluated by physical examination and anterior abdominal wall ultrasound (US). RESULTS: Trocar-site hernia was not detected in any of our cases either by physical examination or by US. CONCLUSIONS: Trocar site hernia is a rare complication of laparoscopy. It occurs at the trocar insertion site with a diameter of 10 mm or more in adult patients. Trocar insertion away from the midline can decline the incidence. PMID- 17710047 TI - A 14-year analysis of laparoscopic cholecystectomy: conversion--when and why? AB - BACKGROUND: Contraindications to laparoscopic cholecystectomy diminished over the last decade but still conversion is about 5% to 6% in elective cases and higher in acute cholecystitis. The aim of this study was to analyze the reason for conversion in all patients operated on in our department and to create strategies for critical moments, which may need conversion. METHODS: From 1990 to 2004, operations have been divided in 3 groups: primary open cholecystectomy (OC), laparoscopic cholecystectomy, and conversion. These groups were analyzed regarding the reason for conversion and postoperative complications. RESULTS: Of the 5376 patients who underwent cholecystectomy, 327 had concomitant OC without further evaluation and 544 OC (11%). Of the 4505 patients (3159 women, 1346 men) who were all started by laparoscopy 5.4% [245 patients (123 women, 3.9%; 122 men, 9.1%; P<0.05)] were converted to OC. Acute cholecystitis (29.4%), difficulties with the anatomy in Calot's triangle (17.1%), and adhesions (14.3%) have been the main reasons for conversion beside difficulties in establishing pneumoperitoneum (3.7%). CONCLUSIONS: The key scenes for conversion are the creation of the pneumoperitoneum, intra-abdominal adhesions, and difficulties in Calot's triangle, especially in acute cholecystitis. Conversion should not be seen as a complication. PMID- 17710048 TI - Laparoscopic cholecystectomy as solo surgery with the aid of a robotic camera holder: a case-control study. AB - BACKGROUND: By using robotic camera holders, a laparoscopic cholecystectomy (LC) is possible as a solo-surgeon operation. The purpose of this paper is to examine the safeness and efficiency of solo-surgeon LCs. METHODS: A series of 72 solo surgeon LCs was retrospectively compared with a control cohort (matched pairs). Efficiency and safety parameters were compared by means of equivalence tests (scope=10%). RESULTS: Nearly identical incision-suture times (means: 69.6 vs. 70.7 min) were recorded. An equivalence was also found in the cohorts for the total time in the operating room (means: 117.4 vs. 117.2 min). In terms of the rate of complications, the perioperative difference in hemoglobin, and the conversion rate, the robot cohort proved to be at least equal to the control cohort. The postoperative hospital stay was shorter for the robot cohort. CONCLUSION: Solo-surgeon LC with a robotic camera holder is an efficient and safe method. PMID- 17710049 TI - Synchronous laparoscopic resection of colorectal and renal/adrenal neoplasms. AB - Synchronous laparoscopic resections of coexisting abdominal diseases are shown to be feasible without additional postoperative morbidity. We report our experience with synchronous laparoscopic resection of colorectal carcinoma and renal/adrenal neoplasms with an emphasis on surgical and oncologic outcomes. Five patients diagnosed to have synchronous colorectal carcinoma and renal/adrenal neoplasms (renal cell carcinoma in 2 patients, adrenal cortical adenoma in 2 patients, and adrenal metastasis in 1 patient) underwent synchronous laparoscopic resection. The median operative time was 420 minutes and the median operative blood loss was 1000 mL. Three patients developed minor complications, including wound infection in 2 patients and retention of urine in 1 patient. There was no operative mortality. The median duration of hospital stay was 11 days. At a median follow up of 17.6 months, no patient developed recurrence of disease. Synchronous laparoscopic resection of colorectal and renal/adrenal neoplasms is technically feasible and safe. PMID- 17710050 TI - Evolution of clipping for thoracoscopic sympathectomy in symptomatic hyperhidrosis. AB - BACKGROUND: Severe hyperhidrosis is treated by thoracic sympathetic chain interrupting through chain transection or clipping. Our study compared the efficacy of these 2 methods. METHODS: Retrospectively, patients who underwent thoracoscopic sympathectomy from 1999 to 2005 had demographic, operative, and postoperative data analyzed. RESULTS: Fifty-four operations were performed for refractory sweating of the palm (72%), axilla (66%), foot (53%), and head/neck (19%). Thirty-seven (69%) underwent clipping; 17 (31%) underwent chain transection. There was no difference in age, sex, or blood loss. One ganglion level was interrupted in 24.1% and 2 levels in 75.4%. Bothersome compensatory hyperhidrosis occurred in 13% (5-clipping and 2-transection). One patient underwent clip removal for debilitating symptoms. Three small pneumothoraces occurred (all in the transection group); all treated expectantly. CONCLUSIONS: Thoracoscopic sympathectomy is a safe outpatient procedure. Both methods yield excellent results with minimal compensatory hyperhidrosis. Thoracoscopic sympathetic chain clipping and transection are equivalent. PMID- 17710051 TI - Laparoscopic diagnostics of acute bowel ischemia using ultraviolet light and fluorescein dye: an experimental study. AB - PURPOSE: The aim of the study was to show the diagnostic potential of laparoscopy using fluorescein dye and ultraviolet light in acute bowel ischemia. MATERIALS AND METHODS: The study involved 12 domestic pigs. Under general anesthesia, the peripheral branch of the superior mesenteric artery was embolized using polyvinyl alcohol microparticles. Two hours after the embolization, optical filters were placed into the laparoscopic set to produce ultraviolet light. Fluorescein dye was given intravenously, and the bowel was inspected. Clips were placed on the border of the ischemia that was visualized with fluorescein. Resection of the ischemic part of the bowel and anastomosis of the viable parts were carried out using laparoscopic linear cutting staplers. After 24 hours, a laparoscopic second look procedure was carried out to verify the viability of the anastomosis. RESULTS: The method was in all cases able to recognize intestinal ischemia and reliably differentiate ischemic bowel segments from viable bowel. Microscopic analysis of the ischemic specimens showed beginning ischemic changes of the bowel tissues. CONCLUSIONS: The method should be considered a valuable diagnostic procedure both for diagnostics of early stage of acute bowel ischemia and for second-look procedures. PMID- 17710052 TI - Modified Funada's gastropexy needle for mesh fixation in the subcutaneous layer using thread during laparoscopic incisional hernia repair. AB - Recent advances in laparoscopic surgery have improved the scope, ease, and effectiveness of abdominal surgery including laparoscopic abdominal incisional hernia repair using a mesh repair technique. Here, we present a new procedure for fixing mesh to the abdominal wall with thread instead of tacks, using a modified Funada's gastropexy device (Create Medic Co, Ltd, Yokohama, Japan). This modified device has 1 needle bent to cross the other, enabling the threads to be tied in the subcutaneous layer to fix the mesh to the abdominal wall. We describe how to make and use this modified device in a laparoscopic procedure. PMID- 17710053 TI - Novel laparoscopic home trainer. AB - BACKGROUND: Minimum-invasion surgery is performed by means of 2-dimensional visual feedback and without haptic sensitivity. This demands that specialty surgeons adapt to and develop new psychomotor abilities. These abilities can only be learned, developed, and maintained through training. Training technology has been divided into virtual trainers and physical trainers. The former, due to their high cost, have not had the expected academic impact, whereas the latter, although an excellent low-cost alternative, do not offer the visual handling options for refining the required psychomotor abilities. The purpose of this article is to describe the design of a box trainer which can establish a closer relationship with the visual and functional perspectives of optics during surgery, thus establishing better learning protocols. METHODS: A laparoscopic surgery trainer was designed and built based on the shape of the abdominal cavity formed during such surgery. The visual feedback is achieved with a color mini camera whose position and orientation are controlled by means of a magnetic system with 0 and 45-degree optics options. RESULTS: A trainer which allows for changes in visual perspective, for developing abilities and skills, with optics other than those of 0 degrees within a geometric space similar to that of the pneumoperitoneum has been designed. CONCLUSIONS: A training system which provides illumination and visual perspective conditions similar to those of real surgery using 0 and 45-degree optics has been designed. The training system is portable and easy to connect for training purposes. Its ports allow for various options that help to improve skills and propose new approaches. PMID- 17710054 TI - Laparoscopically assisted retrieval of lost IUCD/foreign bodies: a novel locating technique with fluoroscopic image intensifier. AB - Migration of therapeutically implanted intrauterine contraceptive devices and foreign bodies pose challenges in accurate localization and removal through the least invasive method. Laparoscopic removal is the desired method of treatment due to the lessened surgical and anesthetic morbidity and accurate and rapid localization of the devices are imperative in aiding an endoscopic removal. Difficulties in locating the device leads to prolonged intraoperative times and at times culminate in a laparotomy with its attendant increased morbidity. We present a case series where rapid and accurate localization of the devices was achieved by intraoperative usage of the fluoroscopic image intensifier. The image intensifier can view images in real time and can be used intraoperatively, increasing the diagnostic accuracy. We propose that intraoperative imaging by the fluoroscopic image intensifier is a cost effective, rapid, and accurate method of localizing a migrated contraceptive device, thus enabling optimal endoscopic treatment. PMID- 17710055 TI - The influence of minimally invasive percutaneous nephrolithotomy on renal pelvic pressure in vivo. AB - OBJECTIVE: To inspect the renal pelvic pressure during minimally invasive percutaneous nephrolithotomy (MPCNL) and to investigate whether the use of the 14 to 18-Fr percutaneous tract, 8/9.8-Fr rigid ureteroscope, and a perfusion with high pressure furnished for MPCNL results in high renal pelvic pressure. PATIENTS AND METHODS: Between July 2005 and February 2006, 76 patients were selected for renal pelvic pressure measurement during MPCNL. The renal pelvic pressure was measured by a baroceptor of the invasive blood pressure channel in a MAIDRAY PM9000 monitor, which was connected to the open-ended ureteric catheter indwelled in the renal pelvis retrogradely. The computer collected the renal pelvic pressure data each second and all the data were evaluated statistically with SPSS 12.0 software. RESULTS: During MPCNL within the 14, 16, 18, and double-16-Fr percutaneous tracts, the average renal pelvic pressures were 24.85, 16.23, 11.68, and 5.8 mm Hg, respectively. The average lasting times of renal pelvic pressure >/=30 mm Hg were 283, 96, 44, and 10 seconds, respectively. A postoperative fever >/=38 degrees C was recorded in 2 (2/12), 3 (3/30), 2 (2/21), and 1 case (1/13), respectively. CONCLUSIONS: Renal pelvic pressure generally remains lower than the level required for a backflow (30 mm Hg), during MPCNL via 14 to 18-Fr percutaneous tract. Any factor, which causes bad drainage, will result in a temporarily elevated renal pelvic pressure greater than 30 mm Hg; and multiple temporary high-pressure episodes can have a cumulative effect, which means that there will be enough backflow to cause a bacteremia. PMID- 17710056 TI - Partial laparoscopic resection of inflamed mediastinal esophageal duplication cyst. AB - We present a case of a 54-year-old woman who underwent a successful partial laparoscopic resection of a secondary inflamed esophageal duplication cyst localized in the lower posterior mediastinum. Laparoscopic approach was used for the surgical treatment of the intrathoracic esophageal duplication cyst for the first time. The standard surgical treatment uses thoracotomy or thoracoscopy, but the localization of the cyst in the lower mediastinum enables also the laparoscopic approach as it is demonstrated. Moreover, laparoscopy minimizes the risk of postoperative inflammatory complications in the pleural cavity especially after the surgery of secondary inflamed cysts. PMID- 17710057 TI - Laparoscopic treatment of paraesophageal hiatal hernia with incarceration of the pancreas and jejunum. AB - We present a successful laparoscopic treatment of paraesophageal hiatal hernia with an incarceration of the pancreas and jejunum. The patient was a 75-year-old woman who had complaints of epigastric pain and dysphasia. A chest x-ray revealed a mediastinal air-fluid level. Chest computed tomography showed intestinal contents, body and tail of the pancreas, and the splenic artery within the mediastinum. At laparoscopy, jejunum was incarcerated into the mediastinal cavity through the internal hernia of transverse mesocolon. Body and tail of the pancreas and the splenic artery were also dislocated within the hernia sac. The operation time took 115 minutes. The patient tolerated a regular diet on the first postoperative day and was discharged uneventfully. There were no recurrence or abdominal symptoms during the 29-month follow-up period. In the case of asymptomatic paraesophageal hiatal hernia with incarcerating pancreas on diagnostic imagings, elective surgical treatment is required to prevent a critical outcome. PMID- 17710058 TI - Laparoscopic repair of late-presenting Bochdalek hernia in 2 infants. AB - Laparoscopic repair was performed on 2 infants with late-presenting Bochdalek hernia. Intraoperatively, the entire small intestine was herniated in 1 case and the stomach, small intestine, and part of the colon and spleen were herniated in the other case. Laparoscopic repair of Bochdalek hernia was successfully completed in both the cases. On the basis of our experience, 4 points seem important in laparoscopic surgery for Bochdalek hernia: (1) avoiding damage to the spleen while reducing organs back into the abdominal cavity; (2) ensuring visualization of diaphragmatic defect after reducing the spleen and intestinal tract; (3) ensuring sufficient width to suture the dorsal side of the diaphragm; and (4) identifying intestinal malrotation. We believe that the fourth point represents an advantage of a laparoscopic approach, which seems superior to the thoracoscopic approach and could represent a useful therapy for Bochdalek hernia in infants and older patients. PMID- 17710059 TI - Laparoscopic Collis gastroplasty and Dor fundoplication for reflux esophagitis complicated by a penetrating ulcer and shortened esophagus: a case report. AB - The patient was a 72-year-old man, who was referred to us at the beginning of July 2005 with a chief complaint of difficulty with swallowing. After a thorough medical examination, the patient was diagnosed with a penetrating ulcer due to reflux esophagitis, lower esophageal stricture, Barrett esophagus, and shortened esophagus. After administration of a proton pump inhibitor and 2 sessions of endoscopic dilatation, esophagitis was cured and the stricture was eliminated. Subsequently, Collis gastroplasty and Dor fundoplication, which seemed appropriate to certainly avoid injuring communication with the mediastinum created by the penetrating ulcer and provide radical cure, were performed laparoscopically. The patient made a good postoperative progress, was discharged on the 11th hospital day, and is now being followed up on an outpatient basis. There have been no signs of recurrence of esophagitis, and the penetrating ulcer was cured. To our knowledge, this is the first report of simultaneous laparoscopic Collis gastroplasty and Dor fundoplication in the English literature. PMID- 17710060 TI - Minimally invasive treatment of obscure gastrointestinal bleeding using laparoscopic ultrasonography. AB - The management of patients with small bowel bleeding remains a diagnostic and therapeutic challenge because sensitive methods are lack and identifying the etiology and site of hemorrhage is essential in determining appropriate therapies. Accurate localization of small bowel lesions causing obscure bleeding is essential for the successful surgical treatment. However, if the lesions are small and intraluminal nature, it is impossible to identify the lesions by laparoscopy alone. We report a novel approach using the combination of laparoscopic surgery with laparoscopic ultrasonography, which enables successful minimally invasive treatment of obscure gastrointestinal bleeding caused by a submucosal tumor in proximal ileum. PMID- 17710061 TI - Bouveret syndrome and gallstone ileus. AB - Intestinal obstruction from gallstones is a rare complication of gallstone disease. These ectopic gallstones can cause obstruction anywhere from the duodenum to the colon and are accompanied by a cholecystoduodenal/enteric/colic fistula. We report an 81-year-old male who presented with gallstone obstruction of the duodenum who underwent attempted endoscopic fragmentation and extraction that eventually led to small bowel obstruction from an impacted fragment of the stone. He underwent successful enterolithotomy and has been asymptomatic from the cholecystoduodenal fistula. Surgery is the gold standard for the treatment of this condition but the extent of the operation remains a matter of debate. PMID- 17710062 TI - Laparoscopic radiofrequency ablation combined with laparoscopic liver resection for more than one HCC on cirrhosis. AB - The management of patients affected by more than one hepatocellular carcinoma (HCC) is still controversial but nowadays a multimodal approach to this pathology seems to be the most effective and versatile therapeutic option. When orthotopic liver transplantation is not indicated, survival-time and quality of life improvement is the goal for patients who will have a long metabolic and oncologic disease history. Combined use of minimally invasive nonsurgical treatments [percutaneous ethanol injection, radiofrequency ablation, transcutaneous arterial chemioembolization (TACE)] allows to offer to the patients the advantages of each therapeutic procedure reducing their individual side effects and complications. We consider laparoscopy as a minimally invasive procedure, which can offer the benefits of surgical treatment, by tumor removing, but with an improved postoperative course. If recurrence risk factors are present, the costs/benefits rapport can be decreased by the laparoscopic approach which offers, in addition to a radical resection, a decreased postoperative pain, reduced trauma to the abdominal wall, smaller incisions, reduced peritoneal adhesions and, in selected cases, an earlier beginning of chemiotherapy. We report the case of a patient affected by more than one HCC with a bigger lesion of 50 mm protruding from hepatic segment III, one subcapsular lesion located at segment V, and one deep lesion located at segment VII-VIII. The patient was submitted to a double laparoscopic liver resection in association with laparoscopic radiofrequency ablation. Five months later, the patient presented an early recurrence of malignancy that was treated by TACE. At 8 months from the treatment, the patient presented another multifocal recurrence and was submitted to another TACE. At 2 years from the laparoscopic procedure, the patient is in apparent good conditions with an acceptable quality of life. We think that laparoscopic resection could gain a considerable place in the multimodal treatment of cirrhotic liver with more than one HCC because, by tumor removing, it offers the benefits of surgical treatment with a lower complications rate. PMID- 17710063 TI - Laparoscopic management of a primary small bowel volvulus: a case report. AB - Primary small bowel volvulus in adults is a very rare condition, and it is defined as torsion of all or a large segment of the small intestine and its mesentery in the absence of any preexisting etiologic factors. Proper management of the patients suffering from a strangulated obstruction depends on making an early and accurate diagnosis. Timely treatment is crucial to prevent gangrene. A 49-year-old man who had a history of previous abdominal surgery was admitted to our hospital with complaints of acute abdominal pain. Simple abdominal x-ray showed multiple dilated loops of small intestine in the mid-abdomen. Enhanced abdominal computed tomography showed the distended small bowel loops and longitudinal tapering of the collapsed bowel loops. We carried out diagnostic laparoscopy to confirm the cause of suspected mechanical ileus. It revealed strangulation of the small bowel at the terminal ileum due to clockwise torsion of the bowel loop. There were no adhesions or congenital anomalies in the peritoneal cavity. The torsional segment was spontaneously reduced with minimal handling, and the strangulated portion was resected. The patient was discharged from hospital on postoperative day 6. Primary small bowel volvulus in adults is a very rare malady; if the diagnosis is uncertain, then diagnostic laparoscopy is a valuable tool for making the definitive diagnosis and administering prompt treatment. PMID- 17710064 TI - Internal herniation through the mesenteric opening after laparoscopy-assisted right colectomy: report of a case. AB - We discuss a rare complication in a patient who underwent laparoscopic colectomy. A 69-year-old woman underwent laparoscopy-assisted right colectomy for cancer of the ascending colon. Two months after the operation, bowel obstruction developed. Decompression with a long intestinal tube failed to resolve the obstruction. Thus, surgery was performed. Abdominal exploration revealed a strangulated ileal loop caused by herniation through the mesenteric opening at the anastomotic site. The mesenterium had not been sutured during the previous operation. The anastomotic segment had twisted semicircularly and adhered to the retroperitoneum, so the mesenteric opening had narrowed. PMID- 17710065 TI - Delayed colonic perforation after percutaneous radiofrequency ablation of hepatocellular carcinoma. AB - Radiofrequency ablation (RFA) is an effective treatment for hepatocellular carcinoma. Colonic perforation secondary to RFA of the liver is an uncommon complication that has been reported to have an incidence between 0.1% and 0.3%. Lesions adjacent (within 1 cm) to the colonic wall and those in patients with history of upper abdominal surgery or chronic cholecystitis are particularly at risk. More importantly, thermal injury leading to colonic perforation has proved to have a fatal outcome. We present a case of percutaneous RFA in a patient with hepatocellular carcinoma that was abutting the colonic hepatic flexure. Colonic perforation was diagnosed on the eighth day postablation when the patient was readmitted with peritonitis. PMID- 17710066 TI - Laparoscopic mesh repair of transverse rectus abdominus muscle and deep inferior epigastric flap harvest site hernias. AB - INTRODUCTION: The transverse rectus abdominus muscle (TRAM) flap is one of the treatment options for breast reconstruction. TRAM flap reconstruction donor site herniation rates range from 1% to 8.8%. Traditionally, these hernias were treated by an open primary repair with or without the addition of onlay mesh. We report laparoscopic approach to treat TRAM and deep inferior epigastric perforator flap (DIEP) harvest site hernias with mesh. CASES: We treated 5 patients, 4 from TRAM and 1 from DIEP flap harvest site hernias during the period of October 2003 to January 2006. Two of these patients underwent previous open mesh repair with recurrence. All of these patients underwent laparoscopic hernia repair using polytetrafluoroethylene dual mesh. Follow-up ranged 6 to 31 months without any recurrences. CONCLUSIONS: Laparoscopic mesh repair of ventral hernias located at TRAM and DIEP flap harvest sites can be performed safely and with a low rate of recurrence. PMID- 17710067 TI - An unusual inguinal "hernia"--the value of hernioscopic assessment. AB - The clinical diagnosis of an inguinal hernia is at times not straightforward and surprises are occasionally encountered intraoperatively. We report the case of an elderly lady who presented with a unilateral inguinal lump, which was subsequently explored using an open approach. The "sac" contained bloody ascitic fluid, which prompted diagnostic hernioscopy through the same. The patient was found to have peritoneal metastases from a primary ovarian carcinoma. This case serves to highlight the potential of hernioscopy for diagnostic biopsies and staging. PMID- 17710068 TI - Laparoscopic resection of an extra-adrenal pheochromocytoma. AB - Extra-adrenal pheochromocytomas are of rare occurrence. Since first reported laparoscopic adrenalectomy has become the gold standard in the treatment of adrenal tumors, the feasibility of laparoscopic adrenalectomy in the setting of pheochromocytoma has also been established given a careful preoperative planning. Literature on the laparoscopic treatment of extra-adrenal pheochromocytomas is lacking. We report a hypertensive 54-year-old male patient (body mass index, 26.2) with elevated urinary catecholamines and a 6-cm solid mass under the right renal hilum diagnosed after a magnetic resonance. The patient underwent complete transperitoneal laparoscopic excision of the tumor. Recovery was uneventful and final histopathologic examination showed an extra-adrenal pheochromocytoma. We believe that transperitoneal laparoscopic excision of extra-adrenal pheochromocytoma is a feasible and reproducible technique that allows for complete removal of tumoral tissue with low morbidity, shorter hospital stay, and minimal convalescence. PMID- 17710069 TI - Thoracoscopic debridement and stabilization of pyogenic vertebral osteomyelitis. AB - The role of surgical debridement and internal fixation in treatment of vertebral osteomyelitis has been evolving. The standard surgical approach to thoracolumbar vertebral osteomyelitis requiring extensive thoracotomy or retroperitoneal exposure carries significant associated morbidity and postoperative pain. Minimally invasive thoracoscopic spine surgery is designed to improve postoperative morbidity associated with the traditional open surgery. We report a case of a 70-year-old man who developed T11-T12 pyogenic vertebral osteomyelitis 3 months after undergoing posterior laminectomy and microsurgical excision of a herniated thoracic disc. The patient underwent minimally invasive thoracoscopic radical debridement and anterior spinal reconstruction and fusion. Patients with vertebral osteomyelitis may benefit from the decreased postoperative morbidity that is associated with minimally invasive thoracoscopic spinal surgery. PMID- 17710070 TI - Laparoscopic deroofing of a renal cyst: the hidden invasion. AB - Cysts of the kidney usually originate from the renal parenchyma after tubule obstruction; rarely pyelocalyceal cysts occur, originating from transitional urothelium. Neoplasia is a rare but possible complication. A 45-year-old man was found to have a cyst related to the right kidney. Computed tomography demonstrated minimal calcification in the wall (Bosniak II). Symptom-relieving percutaneous drainage yielded clear fluid; resultant cytology was negative. After rapid reaccumulation, laparoscopic deroofing was performed. No communication within the renal pelvis was detected however histology revealed transitional cell carcinoma. An open radical nephroureterectomy was performed; adjuvant chemotherapy was given. Three previous cases of malignancy in a pyelocalyceal cyst have been reported. This is the first reported after laparoscopic deroofing of a cyst. Despite widespread use of the Bosniak renal cyst classification, the management of category II cysts remains contentious. This case should serve as a warning to clinicians that seemingly benign cysts of the kidney may harbor underlying neoplasia. Intraoperative frozen section should be considered in all cases where preoperative imaging suggests Bosniak II classification. PMID- 17710071 TI - Critical GI issues for the cardiologist: new insights and understanding. Introduction. PMID- 17710072 TI - Upper GI risks of NSAIDs and antiplatelet agents: key issues for the cardiologist. AB - The use of antiplatelet/antithrombotic agents (eg, low-dose aspirin or clopidogrel) in primary or secondary intervention treatment strategies for cardiovascular disease is a common practice among cardiologists. Furthermore, these agents frequently are used concomitantly with other nonsteroidal anti inflammatory drugs (NSAIDs) that patients are taking for a wide array of rheumatologic- or orthopedic-related complaints. These therapies, however, have defined upper gastrointestinal (UGI) risks for ulcer-related injury and complications. It is important for the cardiologist to fully understand the UGI risk profiles so that each patient is evaluated as a candidate for possible preventive co-therapy with appropriate anti-ulcer medication. PMID- 17710074 TI - Use of antiplatelet agents and anticoagulants for cardiovascular disease: current standards and best practices. AB - Thrombosis superimposed on arteriosclerosis is the principal cause of mortality and morbidity in patients with arteriosclerosis. The use of antiplatelet agents and anticoagulants in the treatment of arteriosclerosis is well established, based on many large randomized trials. Aspirin is indicated for primary prevention in patients at increased risk of developing symptomatic atherosclerotic vascular disease. For patients with known vascular disease, antiplatelet therapy with aspirin is a well-established treatment. For high-risk patients such as those with acute coronary syndromes (ACS; unstable angina, myocardial infarction), dual antiplatelet therapy with aspirin and clopidogrel is indicated, based on results of the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial. Platelet glycoprotein IIb/IIIa agents are powerful inhibitors of platelet function and are also effective in ACS, but the benefit is confined to high-risk patients. Anticoagulation with heparin or low-molecular weight heparin (eg, enoxaparin) is also effective, with an approximately 50% reduction in cardiovascular events. These agents are also indicated for patients undergoing percutaneous coronary intervention. Prolonged dual antiplatelet therapy (at least 6 months) is recommended for patients receiving drug-eluting stents. The efficacy of antiplatelet therapy is thus well established in treating atherothrombosis, but aggressive therapy is associated with an increased bleeding risk. Newer agents may provide improved efficacy with a lower risk of bleeding. PMID- 17710073 TI - Strategies to reduce the GI risks of antiplatelet therapy. AB - Low-dose aspirin and other antiplatelet agents are widely used for the management of cardiovascular disease. Due to their action on cyclooxygenase, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are associated with upper gastrointestinal (GI) side effects, including ulcers and bleeding. Although the risk with low-dose aspirin alone is less than that with NSAIDs, given its widespread use, aspirin-related toxicity has become a substantial health care issue. Factors associated with an increased risk of aspirin-related upper GI complications are still being elucidated but most importantly include a prior history of ulcer or GI bleeding, aspirin dose, and concomitant use with an NSAID, anticoagulant, or additional antiplatelet drug. Various strategies are available to minimize the risk of developing upper GI side effects in patients taking aspirin. Gastroprotective agents that seem effective are prostaglandin analogues and proton pump inhibitors. Eradication of Helicobacter pylori also seems to reduce the risk of ulcers. Substitution by other antiplatelet agents such as clopidogrel alone does not seem to provide a safer alternative to low-dose aspirin for patients at high risk for GI side effects. PMID- 17710075 TI - Noncardiac chest pain. AB - The clinical approach to the patient with unexplained chest pain is complex, as the history does not clearly separate cardiac from noncardiac etiologies. After a careful work-up has excluded coronary artery disease, a systematic search for an esophageal etiology is the next step. Gastroesophageal reflux disease (GERD) is most commonly associated with noncardiac chest pain and should be the first diagnosis pursued. A therapeutic trial of antisecretory therapy with proton-pump inhibitors is the most efficient initial approach to diagnosis and therapy of GERD-related chest pain and can easily be instituted by a cardiologist familiar with the optimal use of proton-pump inhibitors. PMID- 17710076 TI - Humility and clinical trials. PMID- 17710079 TI - A decade of accomplishments: gene therapy and the ASGT. PMID- 17710083 TI - Distributing KI pills to minimize thyroid radiation exposure in case of a nuclear accident in France. PMID- 17710084 TI - Potential therapeutic applications of thyroid hormone analogs. AB - Thyroid hormone (T3 and T4) has many beneficial effects including enhancing cardiac function, promoting weight loss and reducing serum cholesterol. Excess thyroid hormone is, however, associated with unwanted effects on the heart, bone and skeletal muscle. We therefore need analogs that harness the beneficial effects of thyroid hormone without the untoward effects. Such work is largely based on understanding the cellular mechanisms of thyroid hormone action, specifically the crystal structure of the nuclear receptor proteins. In clinical studies, use of naturally occurring thyroid hormone analogs can suppress TSH levels in patients with thyroid cancer without producing tachycardia. Many thyromimetic compounds have been tested in animal models and shown to increase total body oxygen consumption, and to lower weight and serum cholesterol and triglyceride levels while having minor effects on heart rate. Alternatively, analogs that specifically enhance both systolic and diastolic function are potentially useful in the treatment of chronic congestive heart failure. In addition to analogs that are thyroid hormone receptor agonists, several compounds that are thyroid hormone receptor antagonists have been identified and tested. This Review discusses the potential application of thyroid hormone analogs (both agonists and antagonists) in a variety of human disease states. PMID- 17710085 TI - How the availability of recombinant human TSH has changed the management of patients who have thyroid cancer. AB - Recombinant human TSH (rhTSH) is used in patients who have had surgery for thyroid cancer but are at low risk of recurrence. The rhTSH is used for the preparation of postoperative administration of 3.7 GBq (100 mCi) of radioiodine for thyroid-remnant ablation and for the determination of serum thyroglobulin levels during follow-up. In these two conditions, the efficiencies of levothyroxine withdrawal and rhTSH administration are similar; however, rhTSH can be administered during levothyroxine treatment, and its use avoids the hypothyroid period induced by levothyroxine withdrawal, reduces whole body exposure after radioiodine administration, avoids potential morbidity and maintains a better quality of life compared with hormone withdrawal. PMID- 17710086 TI - Therapy insight: Body-shape changes and metabolic complications associated with HIV and highly active antiretroviral therapy. AB - Increasingly effective therapies for HIV infection are now available. These treatments, referred to collectively as highly active antiretroviral therapy, comprise various combinations of anti-HIV drugs from different drug classes. Recently, a range of metabolic complications have emerged as important toxicities in treated patients. Complications present as abnormalities of body-fat mass distribution in association with an often significant dyslipidemia and glucose homeostasis dysregulation. The body-shape changes, manifesting as peripheral lipoatrophy or central lipohypertrophy, can have a negative impact on quality of life and consequently on adherence to treatment. The combination of central lipohypertrophy, dyslipidemia and insulin resistance is associated with accelerated rates of atherosclerosis and other potentially significant long-term effects. The pathogenesis of these effects is complex and is still being actively investigated. Possible contributing factors relate to host characteristics, HIV viral parameters and specific effects of anti-HIV drugs on adipose-tissue biology and on intermediary metabolism. Management of these complications involves manipulation of the anti-HIV drugs using an understanding of their particular effects on lipid and glucose metabolism, in association with standard therapeutic interventions. Individualized approaches, taking into consideration quality-of life issues, and assessment of potential cardiovascular risks, are now an important component of effective care of HIV-infected patients. PMID- 17710089 TI - Chemical biology makes an impact. PMID- 17710087 TI - Treatment of amiodarone-associated thyrotoxicosis. AB - BACKGROUND: A 75-year-old man had a myocardial infarction complicated by poor left ventricular function and non-sustained ventricular tachycardia. He began treatment with amiodarone and 12 months later developed symptoms of thyrotoxicosis. INVESTIGATIONS: Thyroid function tests after commencement of amiodarone revealed a high-normal level of free T4 and low-normal level of free T3 with a normal serum TSH. When symptoms of thyrotoxicosis developed, significant rises in T4 and T3 levels and suppression of TSH were observed. Thyroid autoantibodies were detected and thyroid ultrasonography revealed a small multinodular goiter. DIAGNOSIS: Amiodarone-induced thyrotoxicosis (AIT) with features consistent with both AIT type I (in which thyroid antibodies and nodular goiter are present) and AIT type II (which is not responsive to thionamide therapy and eventually leads to permanent hypothyroidism). MANAGEMENT: The patient continued to be treated with amiodarone. He commenced thionamide (carbimazole) therapy but failed to improve, even after a dose increase. Glucocorticoid (prednisolone) therapy was therefore added. Combination therapy was associated with gradual clinical and biochemical improvement. The patient became persistently hypothyroid after stopping thionamide and glucocorticoid therapy and was stabilized on long-term thyroxine replacement. PMID- 17710092 TI - Synthetic biology: lessons from the history of synthetic organic chemistry. AB - The mid-nineteenth century saw the development of a radical new direction in chemistry: instead of simply analyzing existing molecules, chemists began to synthesize them--including molecules that did not exist in nature. The combination of this new synthetic approach with more traditional analytical approaches revolutionized chemistry, leading to a deep understanding of the fundamental principles of chemical structure and reactivity and to the emergence of the modern pharmaceutical and chemical industries. The history of synthetic chemistry offers a possible roadmap for the development and impact of synthetic biology, a nascent field in which the goal is to build novel biological systems. PMID- 17710090 TI - Small molecules not direct activators of caspases. PMID- 17710093 TI - Berkeley center for synthetic biology. PMID- 17710095 TI - Natural product biosynthesis moves in vitro. PMID- 17710096 TI - Targeting the spliceosome. PMID- 17710097 TI - The end defines the means in bacterial mRNA decay. PMID- 17710098 TI - Cleaving C-Hg bonds: two thiolates are better than one. PMID- 17710100 TI - Targeting virulence: a new paradigm for antimicrobial therapy. AB - Clinically significant antibiotic resistance has evolved against virtually every antibiotic deployed. Yet the development of new classes of antibiotics has lagged far behind our growing need for such drugs. Rather than focusing on therapeutics that target in vitro viability, much like conventional antibiotics, an alternative approach is to target functions essential for infection, such as virulence factors required to cause host damage and disease. This approach has several potential advantages including expanding the repertoire of bacterial targets, preserving the host endogenous microbiome, and exerting less selective pressure, which may result in decreased resistance. We review new approaches to targeting virulence, discuss their advantages and disadvantages, and propose that in addition to targeting virulence, new antimicrobial development strategies should be expanded to include targeting bacterial gene functions that are essential for in vivo viability. We highlight both new advances in identifying these functions and prospects for antimicrobial discovery targeting this unexploited area. PMID- 17710101 TI - Combating bacteria and drug resistance by inhibiting mechanisms of persistence and adaptation. AB - Antibiotics have revolutionized the treatment of infectious disease but have also rapidly selected for the emergence of resistant pathogens. Traditional methods of antibiotic discovery have failed to keep pace with the evolution of this resistance, which suggests that new strategies to combat bacterial infections may be required. An improved understanding of bacterial stress responses and evolution suggests that in some circumstances, the ability of bacteria to survive antibiotic therapy either by transiently tolerating antibiotics or by evolving resistance requires specific biochemical processes that may themselves be subject to intervention. Inhibiting these processes may prolong the efficacy of current antibiotics and provide an alternative to escalating the current arms race between antibiotics and bacterial resistance. Though these approaches are not clinically validated and will certainly face their own set of challenges, their potential to protect our ever-shrinking arsenal of antibiotics merits their investigation. This Review summarizes the early efforts toward this goal. PMID- 17710102 TI - Spinal pseudomeningocoele: a diagnostic dilemma. AB - STUDY DESIGN: Case report. OBJECTIVE: To describe the difficulty in diagnosing spinal pseudomeningocoele. SETTING: Department of Rehabilitation Medicine, University of Malaya Medical Centre, Kuala Lumpur, Malaysia. CASE REPORT: A case of progressive sacral swelling in a paraplegic man who sustained spinal cord injury 14 years ago is presented. Although his clinical features were suggestive of pseudomeningocoele, we were unable to confirm the diagnosis preoperatively. CONCLUSION: Traumatic spinal pseudomeningocoele is very rare. Even with the available modern diagnostic imaging techniques, it is still difficult to diagnose a spinal pseudomeningocoele. PMID- 17710103 TI - Thalidomide for acute treatment of neurosarcoidosis. AB - STUDY DESIGN: Case report. CLINICAL SETTING: Johns Hopkins University School of Medicine, Baltimore, MD, USA. CASE REPORT: Sarcoidosis is a multi-system granulomatous disease of unknown etiology with worldwide distribution. The involvement of the nervous system is common-neurosarcoidosis. Immune responses play an important role in the inflammatory process and granuloma formation. We report a case of neurosarcoidosis that was refractory to two courses of intravenous steroids. Upon initiation of oral thalidomide, the patient showed dramatic improvement clinically and on magnetic resonance imaging. CONCLUSION: Thalidomide is an immunomodulatory agent that acts to inhibit production of tumor necrosis factor-alpha (TNF-alpha), an important mediator in CNS inflammation, by enhancing TNF-alpha mRNA degradation. Corticosteroids have been the mainstay of treatment of neurosarcoidosis with success at halting progression of the immune process in 50% cases. Thalidomide offers unique opportunities at managing CNS inflammation due to neurosarcoidosis. DISCLOSURES: None. PMID- 17710104 TI - Morbidity of urodynamic testing in patients with spinal cord injury: is antibiotic prophylaxis necessary? AB - STUDY DESIGN: Prospective, non-randomized study. OBJECTIVES: To assess the incidence of urinary tract infection after urodynamics in patients with spinal cord injury. SETTING: Outpatient clinic of a university hospital in Germany. METHODS: Urinary tract infection and clinical symptoms in 109 consecutive outpatients with spinal cord injury following urodynamic evaluation were studied. RESULTS: Data from 72 patients were evaluable. Of these, seven patients (9.7%) developed a significant urinary tract infection. Five of these were symptomatic. Pre-existing asymptomatic bacteriuria was not associated with a higher risk for post-interventional infection. The technique of the bladder management did not correlate with urinary tract infection rates. CONCLUSION: In this study, symptomatic urinary tract infections after cystometry were not infrequent. Therefore, it seems that antibiotic prophylaxis cannot be omitted in patients with spinal cord injury undergoing urodynamic investigation. PMID- 17710105 TI - Regulatory T cells: Folate receptor 4: a new handle on regulation and memory? PMID- 17710108 TI - New perspectives on thiamine catalysis: from enzymic to biomimetic catalysis. AB - This paper is a brief review of the detailed mechanism of action of thiamine enzymes, based on metal complexes of bivalent transition and post-transition metals of model compounds, thiamine derivatives, synthesized and characterized with spectroscopic techniques and X-ray crystal structure determinations. It is proposed that the enzymatic reaction is initiated with a V conformation of thiamine pyrophosphate, imposed by the enzymic environment. Thiamine pyrophosphate is linked with the proteinic substrate through its pyrophosphate oxygens. In the course of the reaction, the formation of the "active aldehyde" intermediate imposes the S conformation to thiamine, while a bivalent metal ion may be linked through the N1' site of the molecule, at this stage. Finally, the immobilization of thiamine and derivatives on silica has a dramatic effect on the decarboxylation of pyruvic acid, reducing the time of its conversion to acetaldehyde from 330 minutes for the homogeneous system to less than 5 minutes in the heterogenous system. PMID- 17710107 TI - Factors influencing pain during transrectal ultrasonography-guided prostate biopsy. AB - We prospectively investigated the clinical parameters that influenced pain during prostate biopsies. From 12 hospitals 1781 patients were enrolled. The patients completed a visual analogue scale questionnaire for the pain during the procedure. Age, enema preparation, analgesia use and number of biopsy punctures influenced the level of pain during prostate biopsy in univariate linear regression analysis. However, multivariate analysis showed enema preparation, analgesia use and number of biopsy punctures were independent factors associated with the pain during the procedure. Our study confirmed enema preparation before biopsy and the number of biopsy punctures were associated with the pain during prostate biopsy. PMID- 17710106 TI - Influence of the docetaxel administration period (neoadjuvant or concomitant) in relation to HIFU treatment on the growth of Dunning tumors: results of a preliminary study. AB - The objective of this study was to evaluate mechanisms of the synergy between high intensity-focused ultrasound (HIFU) and docetaxel and to determine the best sequence of chemotherapy administration in relation to HIFU treatment for obtaining optimum control of tumoral growth. A total of 15 days after s.c. implantation of the tumor, 52 Copenhagen rats studied were randomized in 4 groups of 13: controls, docetaxel alone (group 1), HIFU and docetaxel concomitant (group 2) and HIFU and docetaxel administered 24 h before treatment (group 3). The number of HIFU shots was calculated in order to cover 75% of the tumor volume. The effects of docetaxel, HIFU and their interaction on tumor volumes were analyzed using a linear regression. The distributions of the tumor volumes were significantly greater in the control group than in the group 1 (P=0.002) and than in both groups 2 and 3 (P < 0.0001 and P = 0.0001). These volumes were also significantly greater in group 1 than in both groups 2 and 3 and there was no difference between the groups 2 and 3. The tumor doubling times were 7.8 days for the group 1, 43.8 days for the group 2, 16.1 days for the group 3 and 5.9 days for the controls. The mechanism of the synergy between HIFU and docetaxel on the growth of Dunning tumors is apparently multifaceted. The results are encouraging because in the two groups of rats treated with the combination of HIFU and docetaxel, the percentage of complete remission was approximately 30%. PMID- 17710109 TI - Characterization of the de novo biosynthetic enzyme of platelet activating factor, DDT-insensitive cholinephosphotransferase, of human mesangial cells. AB - Platelet activating factor (PAF), a potent inflammatory mediator, is implicated in several proinflammatory/inflammatory diseases such as glomerulonephritis, glomerulosclerosis, atherosclerosis, cancer, allergy, and diabetes. PAF can be produced by several renal cells under appropriate stimuli and it is thought to be implicated in renal diseases. The aim of this study is the characterization of DTT-insensitive cholinephosphotransferase (PAF-CPT) of human mesangial cell (HMC), the main regulatory enzyme of PAF de novo biosynthetic pathway. Microsomal fractions of mesangial cells were isolated and enzymatic activity and kinetic parameters were determined by TLC and in vitro biological test in rabbit washed platelets. The effect of bovine serum albumin (BSA), dithiothreitol (DTT), divalent cations (Mg2+ and Ca2+), EDTA, and various chemicals on the activity of PAF-CPT of HMC was also studied. Moreover, preliminary in vitro tests have been performed with several anti-inflammatory factors such as drugs (simvastatin, IFNa, rupatadine, tinzaparin, and salicylic acid) and bioactive compounds of Mediterranean diet (resveratrol and lipids of olive oil, olive pomace, sea bass "Dicentrarchus labrax," and gilthead sea bream "Sparus aurata"). The results indicated that the above compounds can influence PAF-CPT activity of HMC. PMID- 17710110 TI - PPARs Expression in Adult Mouse Neural Stem Cells: Modulation of PPARs during Astroglial Differentiaton of NSC. AB - PPAR isotypes are involved in the regulation of cell proliferation, death, and differentiation, with different roles and mechanisms depending on the specific isotype and ligand and on the differentiated, undifferentiated, or transformed status of the cell. Differentiation stimuli are integrated by key transcription factors which regulate specific sets of specialized genes to allow proliferative cells to exit the cell cycle and acquire specialized functions. The main differentiation programs known to be controlled by PPARs both during development and in the adult are placental differentiation, adipogenesis, osteoblast differentiation, skin differentiation, and gut differentiation. PPARs may also be involved in the differentiation of macrophages, brain, and breast. However, their functions in this cell type and organs still awaits further elucidation. PPARs may be involved in cell proliferation and differentiation processes of neural stem cells (NSC). To this aim, in this work the expression of the three PPAR isotypes and RXRs in NSC has been investigated. PMID- 17710112 TI - Targeted Gene Disruption of the Cyclo (L-Phe, L-Pro) Biosynthetic Pathway in Streptomyces sp. US24 Strain. AB - We have previously isolated a new actinomycete strain from Tunisian soil called Streptomyces sp. US24, and have shown that it produces two bioactive molecules including a Cyclo (L-Phe, L-Pro) diketopiperazine (DKP). To identify the structural genes responsible for the synthesis of this DKP derivative, a PCR amplification (696 bp) was carried out using the Streptomyces sp. US24 genomic DNA as template and two degenerate oligonucleotides designed by analogy with genes encoding peptide synthetases (NRPS). The detection of DKP derivative biosynthetic pathway of the Streptomyces sp. US24 strain was then achieved by gene disruption via homologous recombination using a suicide vector derived from the conjugative plasmid pSET152 and containing the PCR product. Chromatography analysis, biological tests and spectroscopic studies of supernatant cultures of the wild-type Streptomyces sp. US24 strain and three mutants obtained by this gene targeting disruption approach showed that the amplified DNA fragment is required for Cyclo (L-Phe, L-Pro) biosynthesis in Streptomyces sp. US24 strain. This DKP derivative seems to be produced either directly via a nonribosomal pathway or as a side product in the course of nonribosomal synthesis of a longer peptide. PMID- 17710114 TI - ASSESSING MEDIATED MODELS OF FAMILY CHANGE IN RESPONSE TO INFANT HOME VISITING: A TWO-PHASE LONGITUDINAL ANALYSIS. AB - The objective of this study was to assess whether a mediated model of change could account for the long-term effects of infant home-visiting services observed at ages 5 and 7 years in a high-risk cohort. Participants were 41 mothers and infants from low-income families who were referred to parent-infant home-visiting services during the first 9 months of life due to concerns about the caretaking environment. Services ended when infants reached 18 months of age. Families received between 0 and 18 months of weekly home visits based on infant age of entry into the study. During childhood (ages 5 and 7 years), teachers rated children's behavior problems using standardized instruments. Early home-visiting services accounted for positive child outcomes at 18 months, 5 years, and 7 years of age; however, earlier positive outcomes related to intervention did not account for intervention-related effects at later ages. Further inspection of the data revealed that two additional principles, one of escalating morbidity among less intensively served groups and one of generalized family problem-solving skills, were needed to account for the pattern of effects over time. We conclude that the "domino models" assessed by mediational analyses may be too simple to capture the intervention-related change processes occurring in high-risk cohorts over time. PMID- 17710111 TI - The role of peroxisome proliferator-activated receptors in pulmonary vascular disease. AB - Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily that regulate diverse physiological processes ranging from lipogenesis to inflammation. Recent evidence has established potential roles of PPARs in both systemic and pulmonary vascular disease and function. Existing treatment strategies for pulmonary hypertension, the most common manifestation of pulmonary vascular disease, are limited by an incomplete understanding of the underlying disease pathogenesis and lack of efficacy indicating an urgent need for new approaches to treat this disorder. Derangements in pulmonary endothelial-derived mediators and endothelial dysfunction have been shown to play a pivotal role in pulmonary hypertension pathogenesis. Therefore, the following review will focus on selected mediators implicated in pulmonary vascular dysfunction and evidence that PPARs, in particular PPARgamma, participate in their regulation and may provide a potential novel therapeutic target for the treatment of pulmonary hypertension. PMID- 17710115 TI - THE RELATIONSHIP QUESTIONNAIRE-CLINICAL VERSION (RQ-CV): INTRODUCING A PROFOUNDLY DISTRUSTFUL ATTACHMENT STYLE. AB - Cost-efficient prenatal assessments are needed that have the potential to identify those at risk for parent/infant relational problems. With this goal in mind, an additional attachment style description was added to the Relationship Questionnaire (Bartholomew & Horowitz, 1991), an established self-report attachment measure, to create the Relationship Questionnaire: Clinical Version (RQ-CV). The additional description represents a profoundly-distrustful attachment style: "I think it's a mistake to trust other people. Everyone's looking out for themselves, so the sooner you learn not to expect anything from anybody else the better." The RQ-CV was applied to a sample of 44 low-income mothers who had participated in a previous study of the impact of family risk factors on infant development. After first controlling for demographic risk factors and for other insecure adult attachment styles, mother's profound distrust was associated with three independent assessments of the quality of maternal interactions with the infant assessed 20 years earlier. In particular, profound-distrust was related to more hostile, intrusive, and negative behaviors toward the infant. The results are discussed within the framework of attachment theory. PMID- 17710116 TI - Homodyne scanning holography. AB - We have developed a modified version of a scanning holography microscope in which the Fresnel Zone Plates (FZP) are created by a homodyne rather than a heterodyne interferometer. Therefore, during the scanning the projected pattern on the specimen is frozen rather than varied as previously. In each scanning period the system produces an on-axis Fresnel hologram. The twin image problem is solved by a linear combination of at least three holograms taken with three FZPs with different phase values. PMID- 17710117 TI - Use of the gl1 Mutant & the CA-rop2 Transgenic Plants of Arabidopsis thaliana in the Biology Laboratory Course. PMID- 17710119 TI - Novel Materials for Low-Contrast Phantoms for Computed Tomography. AB - Acceptance testing and quality control of computed tomography (CT) scanners are of great importance. While most procedures and phantoms for testing other parameters are widely accepted, there is still discussion and uncertainty about low-contrast (LC) performance tests that measure the capability of a CT scanner to discriminate low-contrast objects. This work investigated the development of LC phantoms with available, low-cost polystyrene resin materials and some selected additives. We designed and tested phantoms with several different contrast steps by generating contrast in two different ways, one based on 'physical density difference' and the other on 'atomic number difference'. Physical density difference was achieved by adding a small amount of glycerin to the polystyrene resin, both having similar low atomic-number elements but differing in the density of their atoms. Atomic number difference was achieved by adding a small amount of iodobenzene to the resin, both having approximately the same physical density (less than 1% variation in density) but different atomic (i.e., elemental) composition. Prototypes were evaluated using a Philips Tomoscan LX system and varying beam properties. The behavior and validity of the results are discussed. PMID- 17710118 TI - Individual differences and the neural representations of reward expectation and reward prediction error. AB - Reward expectation and reward prediction errors are thought to be critical for dynamic adjustments in decision-making and reward-seeking behavior, but little is known about their representation in the brain during uncertainty and risk-taking. Furthermore, little is known about what role individual differences might play in such reinforcement processes. In this study, it is shown behavioral and neural responses during a decision-making task can be characterized by a computational reinforcement learning model and that individual differences in learning parameters in the model are critical for elucidating these processes. In the fMRI experiment, subjects chose between high- and low-risk rewards. A computational reinforcement learning model computed expected values and prediction errors that each subject might experience on each trial. These outputs predicted subjects' trial-to-trial choice strategies and neural activity in several limbic and prefrontal regions during the task. Individual differences in estimated reinforcement learning parameters proved critical for characterizing these processes, because models that incorporated individual learning parameters explained significantly more variance in the fMRI data than did a model using fixed learning parameters. These findings suggest that the brain engages a reinforcement learning process during risk-taking and that individual differences play a crucial role in modeling this process. PMID- 17710120 TI - An alternate method for using a visual discrimination model (VDM) to optimize soft-copy display image quality. AB - Researchers have developed visual discrimination models (VDMs) that can predict a human observer's ability to detect a target object superposed on an image. These models incorporate sophisticated knowledge of the properties of the human visual system. In the predictive approach, termed conventional VDM usage, two input images with and without a target are analyzed by an algorithm that calculates a just-noticeable-difference (JND) index, which is a taken as a measure of the detectability of the target. A new method of using the VDM is described, termed channelized VDM, which involves finding the linear combination of the VDM generated channels (which are not used in conventional VDM analysis) that has optimal classification ability between normal and abnormal images. The classification ability can be measured using receiver operating characteristic (ROC) or two alternative forced choice (2AFC) experiments, and in special cases they can also be predicted by signal detection theory (SDT) based model-observer methods. In this study simulated background and nodule containing regions were used to validate the new method. It was found that the channelized VDM predictions were in excellent qualitative agreement with human-observer validated SDT predictions. Either VDM method (conventional or channelized) has potential applicability to soft-copy display optimization. An advantage of any VDM-based approach is that complex effects, such as visual masking, are automatically accounted for, which effects are usually not included in SDT-based methods. PMID- 17710121 TI - From task parameters to motor synergies: A hierarchical framework for approximately-optimal control of redundant manipulators. AB - We present a hierarchical framework for approximately-optimal control of redundant manipulators. The plant is augmented with a low-level feedback controller, designed to yield input-output behavior that captures the task relevant aspects of plant dynamics but has reduced dimensionality. This makes it possible to reformulate the optimal control problem in terms of the augmented dynamics, and optimize a high-level feedback controller without running into the curse of dimensionality. The resulting control hierarchy compares favorably to existing methods in robotics. Furthermore we demonstrate a number of similarities to (non-hierarchical) optimal feedback control. Besides its engineering applications, the new framework addresses a key unresolved problem in the neural control of movement. It has long been hypothesized that coordination involves selective control of task parameters via muscle synergies, but the link between these parameters and the synergies capable of controlling them has remained elusive. Our framework provides this missing link. PMID- 17710122 TI - Steroid receptor RNA activator (SRA1): unusual bifaceted gene products with suspected relevance to breast cancer. AB - The steroid receptor RNA activator (SRA) is a unique modulator of steroid receptor transcriptional activity, as it is able to mediate its coregulatory effects as a RNA molecule. Recent findings, however, have painted a more complex picture of the SRA gene (SRA1) products. Indeed, even though SRA was initially thought to be noncoding, several RNA isoforms have now been found to encode an endogenous protein (SRAP), which is well conserved among Chordata. Although the function of SRAP remains largely unknown, it has been proposed that, much like its corresponding RNA, the protein itself might regulate estrogen and androgen receptor signaling pathways. As such, data suggest that both SRA and SRAP might participate in the mechanisms underlying breast, as well as prostate tumorigenesis. This review summarizes the published literature dealing with these two faces of the SRA gene products and underscores the relevance of this bifaceted system to breast cancer development. PMID- 17710123 TI - Evaluation of steroid hormone receptor protein expression in intact cells using flow cytometry. AB - Several methods are currently employed to evaluate expression of steroid hormone receptors in tissues and cells, including real-time reverse-transcriptase polymerase chain reaction (real-time RT-PCR) and western blot assays. These methods require homogenization of cells, thereby preventing evaluation of individual cells or specific cell types in a given tissue sample. In addition, methods such as real-time RT-PCR assess mRNA levels, which may be subject to posttranslational modifications that prevent subsequent production of functional proteins. Flow cytometry is a fluorescence-based technique commonly used to evaluate expression of cell surface and intracellular proteins. This method is especially useful as it allows for single-cell analysis and can be utilized to determine the amount of receptor expressed by individual cells. Flow cytometry is commonly used to analyze immune cell activity and determine functionality based on changes in expression of cell surface molecules, as well as intracellular proteins (such as cytokines). Here, we describe a method to identify protein expression of steroid hormone receptors by rat leukocytes from different organs (spleen, liver and thymus) using flow cytometry. We examined expression of glucocorticoid receptor (GR), androgen receptor (AR) and progesterone receptor (PR) by cells at these sites and were able to demonstrate expression of receptors, as well as the intensity of expression of each receptor. This method is useful for rapid, high throughput measurement of steroid hormone receptors at the protein level in single, intact cells and would be valuable to determine which cells are more likely to respond to steroid hormone treatment. PMID- 17710124 TI - An inhibitory sex pheromone tastes bitter for Drosophila males. AB - Sexual behavior requires animals to distinguish between the sexes and to respond appropriately to each of them. In Drosophila melanogaster, as in many insects, cuticular hydrocarbons are thought to be involved in sex recognition and in mating behavior, but there is no direct neuronal evidence of their pheromonal effect. Using behavioral and electrophysiological measures of responses to natural and synthetic compounds, we show that Z-7-tricosene, a Drosophila male cuticular hydrocarbon, acts as a sex pheromone and inhibits male-male courtship. These data provide the first direct demonstration that an insect cuticular hydrocarbon is detected as a sex pheromone. Intriguingly, we show that a particular type of gustatory neurons of the labial palps respond both to Z-7 tricosene and to bitter stimuli. Cross-adaptation between Z-7-tricosene and bitter stimuli further indicates that these two very different substances are processed by the same neural pathways. Furthermore, the two substances induced similar behavioral responses both in courtship and feeding tests. We conclude that the inhibitory pheromone tastes bitter to the fly. PMID- 17710125 TI - Extended follow-up following a phase 2b randomized trial of the candidate malaria vaccines FP9 ME-TRAP and MVA ME-TRAP among children in Kenya. AB - BACKGROUND: "FFM ME-TRAP" is sequential immunisation with two attenuated poxvirus vectors (FP9 and modified vaccinia virus Ankara) delivering the pre-erythrocytic malaria antigen ME-TRAP. Over nine months follow-up in our original study, there was no evidence that FFM ME-TRAP provided protection against malaria. The incidence of malaria was slightly higher in children who received FFM ME-TRAP, but this was not statistically significant (hazard ratio 1.5, 95% CI 1.0-2.3). Although the study was unblinded, another nine months follow-up was planned to monitor the incidence of malaria and other serious adverse events. METHODS AND FINDINGS: 405 children aged 1-6 yrs were initially randomized to vaccination with either FFM ME-TRAP or control (rabies vaccine). 380 children were still available for follow-up after the first nine months. Children were seen weekly and whenever they were unwell for nine months monitoring. The axillary temperature was measured, and blood films taken when febrile. The primary analysis was time to parasitaemia >2,500/microl. During the second nine months monitoring, 49 events met the primary endpoint (febrile malaria with parasites >2,500/microl) in the Intention To Treat (ITT) group. 23 events occurred among the 189 children in the FFM ME-TRAP group, and 26 among the 194 children in the control group. In the full 18 months of monitoring, there were 63 events in the FFM ME-TRAP group and 60 in the control group (HR = 1.2, CI 0.84-1.73, p = 0.35). There was no evidence that the HR changed over the 18 months (test for interaction between time and vaccination p = 0.11). CONCLUSIONS: Vaccination with FFM ME-TRAP was not protective against malaria in this study. Malaria incidence during 18 months of surveillance was similar in both vaccine groups. TRIAL REGISTRATION: Controlled Trials.com ISRCTN88335123. PMID- 17710126 TI - A randomised placebo-controlled trial of a traditional Chinese herbal formula in the treatment of primary dysmenorrhoea. AB - BACKGROUND: Most traditional Chinese herbal formulas consist of at least four herbs. Four-Agents-Decoction (Si Wu Tang) is a documented eight hundred year old formula containing four herbs and has been widely used to relieve menstrual discomfort in Taiwan. However, no specific effect had been systematically evaluated. We applied Western methodology to assess its effectiveness and safety for primary dysmenorrhoea and to evaluate the compliance and feasibility for a future trial. METHODOLOGY/PRINCIPAL FINDINGS: A randomised, double-blind, placebo controlled, pilot clinical trial was conducted in an ad hoc clinic setting at a teaching hospital in Taipei, Taiwan. Seventy-eight primary dysmenorrheic young women were enrolled after 326 women with self-reported menstrual discomfort in the Taipei metropolitan area of Taiwan were screened by a questionnaire and subsequently diagnosed by two gynaecologists concurrently with pelvic ultrasonography. A dosage of 15 odorless capsules daily for five days starting from the onset of bleeding or pain was administered. Participants were followed with two to four cycles for an initial washout interval, one to two baseline cycles, three to four treatment cycles, and three follow-up cycles. Study outcome was pain intensity measured by using unmarked horizontal visual analog pain scale in an online daily diary submitted directly by the participants for 5 days starting from the onset of bleeding or pain of each menstrual cycle. Overall-pain was the average pain intensity among days in pain and peak-pain was the maximal single-day pain intensity. At the end of treatment, both the overall-pain and peak-pain decreased in the Four-Agents-Decoction (Si Wu Tang) group and increased in the placebo group; however, the differences between the two groups were not statistically significant. The trends persisted to follow-up phase. Statistically significant differences in both peak-pain and overall-pain appeared in the first follow-up cycle, at which the reduced peak-pain in the Four-Agents-Decoction (Si Wu Tang) group did not differ significantly by treatment length. However, the reduced peak-pain did differ profoundly among women treated for four menstrual cycles (2.69 (2.06) cm, mean (standard deviation), for the 20 women with Four Agents-Decoction and 4.68 (3.16) for the 22 women with placebo, p = .020.) There was no difference in adverse symptoms between the Four-Agents-Decoction (Si Wu Tang) and placebo groups. CONCLUSION/SIGNIFICANCE: Four-Agents-Decoction (Si Wu Tang) therapy in this pilot post-market clinical trial, while meeting the standards of conventional medicine, showed no statistically significant difference in reducing menstrual pain intensity of primary dysmenorrhoea at the end of treatment. Its use, with our dosage regimen and treatment length, was not associated with adverse reactions. The finding of statistically significant pain reducing effect in the first follow-up cycle was unexpected and warrants further study. A larger similar trial among primary dysmenorrheic young women with longer treatment phase and multiple batched study products can determine the definitive efficacy of this historically documented formula. TRIAL REGISTRATION: Controlled Trials.com ISRCTN23374750. PMID- 17710127 TI - STAT5 is an ambivalent regulator of neutrophil homeostasis. AB - BACKGROUND: Although STAT5 promotes survival of hematopoietic progenitors, STAT5 /- mice develop mild neutrophilia. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that in STAT5-/- mice, liver endothelial cells (LECs) autonomously secrete high amounts of G-CSF, allowing myeloid progenitors to overcompensate for their intrinsic survival defect. However, when injected with pro-inflammatory cytokines, mutant mice cannot further increase neutrophil production, display a severe deficiency in peripheral neutrophil survival, and are therefore unable to maintain neutrophil homeostasis. In wild-type mice, inflammatory stimulation induces rapid STAT5 degradation in LECs, G-CSF production by LECs and other cell types, and then sustained mobilization and expansion of long-lived neutrophils. CONCLUSION: We conclude that STAT5 is an ambivalent factor. In cells of the granulocytic lineage, it exerts an antiapoptotic function that is required for maintenance of neutrophil homeostasis, especially during the inflammatory response. In LECs, STAT5 negatively regulates granulopoiesis by directly or indirectly repressing G-CSF expression. Removal of this STAT5-imposed brake contributes to induction of emergency granulopoiesis. PMID- 17710128 TI - Protistan diversity in the Arctic: a case of paleoclimate shaping modern biodiversity? AB - BACKGROUND: The impact of climate on biodiversity is indisputable. Climate changes over geological time must have significantly influenced the evolution of biodiversity, ultimately leading to its present pattern. Here we consider the paleoclimate data record, inferring that present-day hot and cold environments should contain, respectively, the largest and the smallest diversity of ancestral lineages of microbial eukaryotes. METHODOLOGY/PRINCIPAL FINDINGS: We investigate this hypothesis by analyzing an original dataset of 18S rRNA gene sequences from Western Greenland in the Arctic, and data from the existing literature on 18S rRNA gene diversity in hydrothermal vent, temperate sediments, and anoxic water column communities. Unexpectedly, the community from the cold environment emerged as one of the richest observed to date in protistan species, and most diverse in ancestral lineages. CONCLUSIONS/SIGNIFICANCE: This pattern is consistent with natural selection sweeps on aerobic non-psychrophilic microbial eukaryotes repeatedly caused by low temperatures and global anoxia of snowball Earth conditions. It implies that cold refuges persisted through the periods of greenhouse conditions, which agrees with some, although not all, current views on the extent of the past global cooling and warming events. We therefore identify cold environments as promising targets for microbial discovery. PMID- 17710129 TI - Transbilayer phospholipid movements in ABCA1-deficient cells. AB - Tangier disease is an inherited disorder that results in a deficiency in circulating levels of HDL. Although the disease is known to be caused by mutations in the ABCA1 gene, the mechanism by which lesions in the ABCA1 ATPase effect this outcome is not known. The inability of ABCA1 knockout mice (ABCA1-/-) to load cholesterol and phospholipids onto apoA1 led to a proposal that ABCA1 mediates the transbilayer externalization of phospholipids, an activity integral not only to the formation of HDL particles but also to another, distinct process: the recognition and clearance of apoptotic cells by macrophages. Expression of phosphatidylserine (PS) on the surface of both macrophages and their apoptotic targets is required for efficient engulfment of the apoptotic cells, and it has been proposed that ABCA1 is required for transbilayer externalization of PS to the surface of both cell types. To determine whether ABCA1 is responsible for any of the catalytic activities known to control transbilayer phospholipid movements, these activities were measured in cells from ABCA1-/- mice and from Tangier individuals as well as ABCA1-expressing HeLa cells. Phospholipid movements in either normal or apoptotic lymphocytes or in macrophages were not inhibited when cells from knockout and wildtype mice or immortalized cells from Tangier individuals vs normal individuals were compared. Exposure of PS on the surface of normal thymocytes, apoptotic thymocytes and elicited peritoneal macrophages from wildtype and knockout mice or B lymphocytes from normal and Tangier individuals, as measured by annexin V binding, was also unchanged. No evidence was found of ABCA1-stimulated active PS export, and spontaneous PS movement to the outer leaflet in the presence or absence of apoA1 was unaffected by the presence or absence of ABCA1. Normal or Tangier B lymphocytes and macrophages were also identical in their ability to serve as targets or phagocytes, respectively, in apoptotic cell clearance assays. No evidence was found to support the suggestion that ABCA1 is involved in transport to the macrophage cell surface of annexins I and II, known to enhance phagocytosis of apoptotic cells. These results show that mutations in ABCA1 do not measurably reduce the rate of transbilayer movements of phospholipids in either the engulfing macrophage or the apoptotic target, thus discounting catalysis of transbilayer movements of phospholipids as the mechanism by which ABCA1 facilitates loading of phospholipids and cholesterol onto apoA1. PMID- 17710130 TI - Differential drug resistance acquisition in HIV-1 of subtypes B and C. AB - BACKGROUND: Subtype C is the most prevalent HIV-1 subtype in the world, mainly in countries with the highest HIV prevalence. However, few studies have evaluated the impact of antiretroviral therapy on this subtype. In southern Brazil, the first developing country to offer free and universal treatment, subtypes B and C co-circulate with equal prevalence, allowing for an extensive evaluation of this issue. METHODS AND FINDINGS: Viral RNA of 160 HIV-1+ patients was extracted, and the protease and reverse transcriptase genes were sequenced, subtyped and analyzed for ARV mutations. Sequences were grouped by subtype, and matched to type (PI, NRTI and NNRTI) and time of ARV exposure. Statistical analyses were performed to compare differences in the frequency of ARV-associated mutations. There were no significant differences in time of treatment between subtypes B and C groups, although they showed distinct proportions of resistant strains at different intervals for two of three ARV classes. For PI, 26% of subtype B strains were resistant, compared to only 8% in subtype C (p = 0.0288, Fisher's exact test). For NRTI, 54% of subtype B strains were resistant versus 23% of subtype C (p = 0.0012). Differences were significant from 4 years of exposure, and remained so until the last time point analyzed. The differences observed between both subtypes were independent of time under rebound viremia in cases of virologic failure and of the number of HAART regimens used by treated patients. CONCLUSIONS: Our results pointed out to a lower rate of accumulation of mutations conferring resistance to ARV in subtype C than in subtype B. These findings are of crucial importance for current initiatives of ARV therapy roll-out in developing countries, where subtype is C prevalent. PMID- 17710132 TI - Haplotyping a quantitative trait with a high-density map in experimental crosses. AB - BACKGROUND: The ultimate goal of genetic mapping of quantitative trait loci (QTL) is the positional cloning of genes involved in any agriculturally or medically important phenotype. However, only a small portion (< or = 1%) of the QTL detected have been characterized at the molecular level, despite the report of hundreds of thousands of QTL for different traits and populations. METHODS/RESULTS: We develop a statistical model for detecting and characterizing the nucleotide structure and organization of haplotypes that underlie QTL responsible for a quantitative trait in an F2 pedigree. The discovery of such haplotypes by the new model will facilitate the molecular cloning of a QTL. Our model is founded on population genetic properties of genes that are segregating in a pedigree, constructed with the mixture-based maximum likelihood context and implemented with the EM algorithm. The closed forms have been derived to estimate the linkage and linkage disequilibria among different molecular markers, such as single nucleotide polymorphisms, and quantitative genetic effects of haplotypes constructed by non-alleles of these markers. Results from the analysis of a real example in mouse have validated the usefulness and utilization of the model proposed. CONCLUSION: The model is flexible to be extended to model a complex network of genetic regulation that includes the interactions between different haplotypes and between haplotypes and environments. PMID- 17710131 TI - C. elegans agrin is expressed in pharynx, IL1 neurons and distal tip cells and does not genetically interact with genes involved in synaptogenesis or muscle function. AB - Agrin is a basement membrane protein crucial for development and maintenance of the neuromuscular junction in vertebrates. The C. elegans genome harbors a putative agrin gene agr-1. We have cloned the corresponding cDNA to determine the primary structure of the protein and expressed its recombinant fragments to raise specific antibodies. The domain organization of AGR-1 is very similar to the vertebrate orthologues. C. elegans agrin contains a signal sequence for secretion, seven follistatin domains, three EGF-like repeats and two laminin G domains. AGR-1 loss of function mutants did not exhibit any overt phenotypes and did not acquire resistance to the acetylcholine receptor agonist levamisole. Furthermore, crossing them with various mutants for components of the dystrophin glycoprotein complex with impaired muscle function did not lead to an aggravation of the phenotypes. Promoter-GFP translational fusion as well as immunostaining of worms revealed expression of agrin in buccal epithelium and the protein deposition in the basal lamina of the pharynx. Furthermore, dorsal and ventral IL1 head neurons and distal tip cells of the gonad arms are sources of agrin production, but no expression was detectable in body muscles or in the motoneurons innervating them. Recombinant worm AGR-1 fragment is able to cluster vertebrate dystroglycan in cultured cells, implying a conservation of this interaction, but since neither of these proteins is expressed in muscle of C. elegans, this interaction may be required in different tissues. The connections between muscle cells and the basement membrane, as well as neuromuscular junctions, are structurally distinct between vertebrates and nematodes. PMID- 17710133 TI - A gammaherpesviral internal repeat contributes to latency amplification. AB - BACKGROUND: Gammaherpesviruses cause important infections of humans, in particular in immunocompromised patients. The genomes of gammaherpesviruses contain variable numbers of internal repeats whose precise role for in vivo pathogenesis is not well understood. METHODOLOGY/PRINCIPAL FINDINGS: We used infection of laboratory mice with murine gammaherpesvirus 68 (MHV-68) to explore the biological role of the 40 bp internal repeat of MHV-68. We constructed several mutant viruses partially or completely lacking this repeat. Both in vitro and in vivo, the loss of the repeat did not substantially affect lytic replication of the mutant viruses. However, the extent of splenomegaly, which is associated with the establishment of latency, and the number of ex vivo reactivating and genome positive splenocytes were reduced. Since the 40 bp repeat is part of the hypothetical open reading frame (ORF) M6, it might function as part of M6 or as an independent structure. To differentiate between these two possibilities, we constructed an N-terminal M6STOP mutant, leaving the repeat structure intact but rendering ORF M6 unfunctional. Disruption of ORF M6 did neither affect lytic nor latent infection. In contrast to the situation in lytically infected NIH3T3 cells, the expression of the latency-associated genes K3 and ORF72 was reduced in the latently infected murine B cell line Ag8 in the absence of the 40 bp repeat. CONCLUSIONS/SIGNIFICANCE: These data suggest that the 40 bp repeat contributes to latency amplification and might be involved in the regulation of viral gene expression. PMID- 17710135 TI - Loss of receptor on tuberculin-reactive T-cells marks active pulmonary tuberculosis. AB - BACKGROUND: Tuberculin-specific T-cell responses have low diagnostic specificity in BCG vaccinated populations. While subunit-antigen (e.g. ESAT-6, CFP-10) based tests are useful for diagnosing latent tuberculosis infection, there is no reliable immunological test for active pulmonary tuberculosis. Notably, all existing immunological tuberculosis-tests are based on T-cell response size, whereas the diagnostic potential of T-cell response quality has never been explored. This includes surface marker expression and functionality of mycobacterial antigen specific T-cells. METHODOLOGY/PRINCIPAL FINDINGS: Flow cytometry was used to examine over-night antigen-stimulated T-cells from tuberculosis patients and controls. Tuberculin and/or the relatively M. tuberculosis specific ESAT-6 protein were used as stimulants. A set of classic surface markers of T-cell naive/memory differentiation was selected and IFN-gamma production was used to identify T-cells recognizing these antigens. The percentage of tuberculin-specific T-helper-cells lacking the surface receptor CD27, a state associated with advanced differentiation, varied considerably between individuals (from less than 5% to more than 95%). Healthy BCG vaccinated individuals had significantly fewer CD27-negative tuberculin-reactive CD4 T-cells than patients with smear and/or culture positive pulmonary tuberculosis, discriminating these groups with high sensitivity and specificity, whereas individuals with latent tuberculosis infection exhibited levels in between. CONCLUSIONS/SIGNIFICANCE: Smear and/or culture positive pulmonary tuberculosis can be diagnosed by a rapid and reliable immunological test based on the distribution of CD27 expression on peripheral blood tuberculin specific T-cells. This test works very well even in a BCG vaccinated population. It is simple and will be of great utility in situations where sputum specimens are difficult to obtain or sputum-smear is negative. It will also help avoid unnecessary hospitalization and patient isolation. PMID- 17710134 TI - MHC adaptive divergence between closely related and sympatric African cichlids. AB - BACKGROUND: The haplochromine cichlid species assemblages of Lake Malawi and Victoria represent some of the most important study systems in evolutionary biology. Identifying adaptive divergence between closely-related species can provide important insights into the processes that may have contributed to these spectacular radiations. Here, we studied a pair of sympatric Lake Malawi species, Pseudotropheus fainzilberi and P. emmiltos, whose reproductive isolation depends on olfactory communication. We tested the hypothesis that these species have undergone divergent selection at MHC class II genes, which are known to contribute to olfactory-based mate choice in other taxa. METHODOLOGY/PRINCIPAL FINDINGS: Divergent selection on functional alleles was inferred from the higher genetic divergence at putative antigen binding sites (ABS) amino acid sequences than at putatively neutrally evolving sites at intron 1, exon 2 synonymous sequences and exon 2 amino acid residues outside the putative ABS. In addition, sympatric populations of these fish species differed significantly in communities of eukaryotic parasites. CONCLUSIONS/SIGNIFICANCE: We propose that local host parasite coevolutionary dynamics may have driven adaptive divergence in MHC alleles, influencing odor-mediated mate choice and leading to reproductive isolation. These results provide the first evidence for a novel mechanism of adaptive speciation and the first evidence of adaptive divergence at the MHC in closely related African cichlid fishes. PMID- 17710136 TI - Exogenous interferon-alpha and interferon-gamma increase lethality of murine inhalational anthrax. AB - BACKGROUND: Bacillus anthracis, the etiologic agent of inhalational anthrax, is a facultative intracellular pathogen. Despite appropriate antimicrobial therapy, the mortality from inhalational anthrax approaches 45%, underscoring the need for better adjuvant therapies. The variable latency between exposure and development of disease suggests an important role for the host's innate immune response. Type I and Type II Interferons (IFN) are prominent members of the host innate immune response and are required for control of intracellular pathogens. We have previously described a protective role for exogenous Type I and Type II IFNs in attenuating intracellular B.anthracis germination and macrophage cell death in vitro. METHODOLOGY AND PRINCIPAL FINDINGS: We sought to extend these findings in an in vivo model of inhalational anthrax, utilizing the Sterne strain (34F2) of B.anthracis. Mice devoid of STAT1, a component of IFN-alpha and IFN-gamma signaling, had a trend towards increased mortality, bacterial germination and extrapulmonary spread of B.anthracis at 24 hrs. This was associated with impaired IL-6, IL-10 and IL-12 production. However, administration of exogenous IFN-gamma, and to a lesser extent IFN-alpha, at the time of infection, markedly increased lethality. While IFNs were able to reduce the fraction of germinated spores within the lung, they increased both the local and systemic inflammatory response manifest by increases in IL-12 and reductions in IL-10. This was associated with an increase in extrapulmonary dissemination. The mechanism of IFN mediated inflammation appears to be in part due to STAT1 independent signaling. CONCLUSIONS: In conclusion, while endogenous IFNs are essential for control of B.anthracis germination and lethality, administration of exogenous IFNs appear to increase the local inflammatory response, thereby increasing mortality. PMID- 17710138 TI - Cause-specific excess mortality in siblings of patients co-infected with HIV and hepatitis C virus. AB - BACKGROUND: Co-infection with hepatitis C in HIV-infected individuals is associated with 3- to 4-fold higher mortality among these patients' siblings, compared with siblings of mono-infected HIV-patients or population controls. This indicates that risk factors shared by family members partially account for the excess mortality of HIV/HCV-co-infected patients. We aimed to explore the causes of death contributing to the excess sibling mortality. METHODOLOGY AND PRINCIPAL FINDINGS: We retrieved causes of death from the Danish National Registry of Deaths and estimated cause-specific excess mortality rates (EMR) for siblings of HIV/HCV-co-infected individuals (n = 436) and siblings of HIV mono-infected individuals (n = 1837) compared with siblings of population controls (n = 281,221). Siblings of HIV/HCV-co-infected individuals had an all-cause EMR of 3.03 (95% CI, 1.56-4.50) per 1,000 person-years, compared with siblings of matched population controls. Substance abuse-related deaths contributed most to the elevated mortality among siblings [EMR = 2.25 (1.09-3.40)] followed by unnatural deaths [EMR = 0.67 (-0.05-1.39)]. No siblings of HIV/HCV co-infected patients had a liver-related diagnosis as underlying cause of death. Siblings of HIV-mono-infected individuals had an all-cause EMR of 0.60 (0.16-1.05) compared with siblings of controls. This modest excess mortality was due to deaths from an unknown cause [EMR = 0.28 (0.07-0.48)], deaths from substance abuse [EMR = 0.19 ( 0.04-0.43)], and unnatural deaths [EMR = 0.18 (-0.06-0.42)]. CONCLUSIONS: HCV co infection among HIV-infected patients was a strong marker for family-related mortality due to substance abuse and other unnatural causes. To reduce morbidity and mortality in HIV/HCV-co-infected patients, the advances in antiviral treatment of HCV should be accompanied by continued focus on interventions targeted at substance abuse-related risk factors. PMID- 17710137 TI - ADaCGH: A parallelized web-based application and R package for the analysis of aCGH data. AB - BACKGROUND: Copy number alterations (CNAs) in genomic DNA have been associated with complex human diseases, including cancer. One of the most common techniques to detect CNAs is array-based comparative genomic hybridization (aCGH). The availability of aCGH platforms and the need for identification of CNAs has resulted in a wealth of methodological studies. METHODOLOGY/PRINCIPAL FINDINGS: ADaCGH is an R package and a web-based application for the analysis of aCGH data. It implements eight methods for detection of CNAs, gains and losses of genomic DNA, including all of the best performing ones from two recent reviews (CBS, GLAD, CGHseg, HMM). For improved speed, we use parallel computing (via MPI). Additional information (GO terms, PubMed citations, KEGG and Reactome pathways) is available for individual genes, and for sets of genes with altered copy numbers. CONCLUSIONS/SIGNIFICANCE: ADACGH represents a qualitative increase in the standards of these types of applications: a) all of the best performing algorithms are included, not just one or two; b) we do not limit ourselves to providing a thin layer of CGI on top of existing BioConductor packages, but instead carefully use parallelization, examining different schemes, and are able to achieve significant decreases in user waiting time (factors up to 45x); c) we have added functionality not currently available in some methods, to adapt to recent recommendations (e.g., merging of segmentation results in wavelet-based and CGHseg algorithms); d) we incorporate redundancy, fault-tolerance and checkpointing, which are unique among web-based, parallelized applications; e) all of the code is available under open source licenses, allowing to build upon, copy, and adapt our code for other software projects. PMID- 17710139 TI - Stimulus motion propels traveling waves in binocular rivalry. AB - State transitions in the nervous system often take shape as traveling waves, whereby one neural state is replaced by another across space in a wave-like manner. In visual perception, transitions between the two mutually exclusive percepts that alternate when the two eyes view conflicting stimuli (binocular rivalry) may also take shape as traveling waves. The properties of these waves point to a neural substrate of binocular rivalry alternations that have the hallmark signs of lower cortical areas. In a series of experiments, we show a potent interaction between traveling waves in binocular rivalry and stimulus motion. The course of the traveling wave is biased in the motion direction of the suppressed stimulus that gains dominance by means of the wave-like transition. Thus, stimulus motion may propel the traveling wave across the stimulus to the extent that the stimulus motion dictates the traveling wave's direction completely. Using a computational model, we show that a speed-dependent asymmetry in lateral inhibitory connections between retinotopically organized and motion sensitive neurons can explain our results. We argue that such a change in suppressive connections may play a vital role in the resolution of dynamic occlusion situations. PMID- 17710140 TI - Wrinkly-Spreader fitness in the two-dimensional agar plate microcosm: maladaptation, compensation and ecological success. AB - Bacterial adaptation to new environments often leads to the establishment of new genotypes with significantly altered phenotypes. In the Wrinkly Spreader (WS), ecological success in static liquid microcosms was through the rapid colonisation of the air-liquid interface by the production of a cellulose-based biofilm. Rapid surface spreading was also seen on agar plates, but in this two-dimensional environment the WS appears maladapted and rapidly reverts to the ancestral smooth (SM)-like colony genotype. In this work, the fitness of WS relative to SM in mixed colonies was found to be low, confirming the WS instability on agar plates. By examining defined WS mutants, the maladaptive characteristic was found to be the expression of cellulose. SM-like revertants had a higher growth rate than WS and no longer expressed significant amounts of cellulose, further confirming that the expression of this high-cost polymer was the basis of maladaptation and the target of compensatory mutation in developing colonies. However, examination of the fate of WS-founded populations in either multiple-colony or single mega colony agar plate microcosms demonstrated that the loss of WS lineages could be reduced under conditions in which the rapid spreading colony phenotype could dominate nutrient and oxygen access more effectively than competing SM/SM-like genotypes. WS-like isolates recovered from such populations showed increased WS phenotype stability as well as changes in the degree of colony spreading, confirming that the WS was adapting to the two-dimensional agar plate microcosm. PMID- 17710141 TI - Genome dynamics of short oligonucleotides: the example of bacterial DNA uptake enhancing sequences. AB - Among the many bacteria naturally competent for transformation by DNA uptake-a phenomenon with significant clinical and financial implications- Pasteurellaceae and Neisseriaceae species preferentially take up DNA containing specific short sequences. The genomic overrepresentation of these DNA uptake enhancing sequences (DUES) causes preferential uptake of conspecific DNA, but the function(s) behind this overrepresentation and its evolution are still a matter for discovery. Here I analyze DUES genome dynamics and evolution and test the validity of the results to other selectively constrained oligonucleotides. I use statistical methods and computer simulations to examine DUESs accumulation in Haemophilus influenzae and Neisseria gonorrhoeae genomes. I analyze DUESs sequence and nucleotide frequencies, as well as those of all their mismatched forms, and prove the dependence of DUESs genomic overrepresentation on their preferential uptake by quantifying and correlating both characteristics. I then argue that mutation, uptake bias, and weak selection against DUESs in less constrained parts of the genome combined are sufficient enough to cause DUESs accumulation in susceptible parts of the genome with no need for other DUES function. The distribution of overrepresentation values across sequences with different mismatch loads compared to the DUES suggests a gradual yet not linear molecular drive of DNA sequences depending on their similarity to the DUES. Other genomically overrepresented sequences, both pro- and eukaryotic, show similar distribution of frequencies suggesting that the molecular drive reported above applies to other frequent oligonucleotides. Rare oligonucleotides, however, seem to be gradually drawn to genomic underrepresentation, thus, suggesting a molecular drag. To my knowledge this work provides the first clear evidence of the gradual evolution of selectively constrained oligonucleotides, including repeated, palindromic and protein/transcription factor-binding DNAs. PMID- 17710142 TI - Speech and non-speech audio-visual illusions: a developmental study. AB - It is well known that simultaneous presentation of incongruent audio and visual stimuli can lead to illusory percepts. Recent data suggest that distinct processes underlie non-specific intersensory speech as opposed to non-speech perception. However, the development of both speech and non-speech intersensory perception across childhood and adolescence remains poorly defined. Thirty-eight observers aged 5 to 19 were tested on the McGurk effect (an audio-visual illusion involving speech), the Illusory Flash effect and the Fusion effect (two audio visual illusions not involving speech) to investigate the development of audio visual interactions and contrast speech vs. non-speech developmental patterns. Whereas the strength of audio-visual speech illusions varied as a direct function of maturational level, performance on non-speech illusory tasks appeared to be homogeneous across all ages. These data support the existence of independent maturational processes underlying speech and non-speech audio-visual illusory effects. PMID- 17710143 TI - Predicting prokaryotic ecological niches using genome sequence analysis. AB - Automated DNA sequencing technology is so rapid that analysis has become the rate limiting step. Hundreds of prokaryotic genome sequences are publicly available, with new genomes uploaded at the rate of approximately 20 per month. As a result, this growing body of genome sequences will include microorganisms not previously identified, isolated, or observed. We hypothesize that evolutionary pressure exerted by an ecological niche selects for a similar genetic repertoire in those prokaryotes that occupy the same niche, and that this is due to both vertical and horizontal transmission. To test this, we have developed a novel method to classify prokaryotes, by calculating their Pfam protein domain distributions and clustering them with all other sequenced prokaryotic species. Clusters of organisms are visualized in two dimensions as 'mountains' on a topological map. When compared to a phylogenetic map constructed using 16S rRNA, this map more accurately clusters prokaryotes according to functional and environmental attributes. We demonstrate the ability of this map, which we term a "niche map", to cluster according to ecological niche both quantitatively and qualitatively, and propose that this method be used to associate uncharacterized prokaryotes with their ecological niche as a means of predicting their functional role directly from their genome sequence. PMID- 17710144 TI - The intersexual genetic correlation for lifetime fitness in the wild and its implications for sexual selection. AB - BACKGROUND: The genetic benefits of mate choice are limited by the degree to which male and female fitness are genetically correlated. If the intersexual correlation for fitness is small or negative, choosing a highly fit mate does not necessarily result in high fitness offspring. METHODOLOGY/PRINCIPAL FINDING: Using an animal-model approach on data from a pedigreed population of over 7,000 collared flycatchers (Ficedula albicollis), we estimate the intersexual genetic correlation in Lifetime Reproductive Success (LRS) in a natural population to be negative in sign (-0.85+/-0.6). Simulations show this estimate to be robust in sign to the effects of extra-pair parentage. The genetic benefits in this population are further limited by a low level of genetic variation for fitness in males. CONCLUSIONS/SIGNIFICANCE: The potential for indirect sexual selection is nullified by sexual antagonistic fitness effects in this natural population. Our findings and the scarce evidence from other studies suggest that the intersexual genetic correlation for lifetime fitness may be very low in nature. We argue that this form of conflict can, in general, both constrain and maintain sexual selection, depending on the sex-specific additive genetic variances in lifetime fitness. PMID- 17710145 TI - Selection against spurious promoter motifs correlates with translational efficiency across bacteria. AB - Because binding of RNAP to misplaced sites could compromise the efficiency of transcription, natural selection for the optimization of gene expression should regulate the distribution of DNA motifs capable of RNAP-binding across the genome. Here we analyze the distribution of the -10 promoter motifs that bind the sigma(70) subunit of RNAP in 42 bacterial genomes. We show that selection on these motifs operates across the genome, maintaining an over-representation of 10 motifs in regulatory sequences while eliminating them from the nonfunctional and, in most cases, from the protein coding regions. In some genomes, however, 10 sites are over-represented in the coding sequences; these sites could induce pauses effecting regulatory roles throughout the length of a transcriptional unit. For nonfunctional sequences, the extent of motif under-representation varies across genomes in a manner that broadly correlates with the number of tRNA genes, a good indicator of translational speed and growth rate. This suggests that minimizing the time invested in gene transcription is an important selective pressure against spurious binding. However, selection against spurious binding is detectable in the reduced genomes of host-restricted bacteria that grow at slow rates, indicating that components of efficiency other than speed may also be important. Minimizing the number of RNAP molecules per cell required for transcription, and the corresponding energetic expense, may be most relevant in slow growers. These results indicate that genome-level properties affecting the efficiency of transcription and translation can respond in an integrated manner to optimize gene expression. The detection of selection against promoter motifs in nonfunctional regions also confirms previous results indicating that no sequence may evolve free of selective constraints, at least in the relatively small and unstructured genomes of bacteria. PMID- 17710146 TI - Tailor-made zinc-finger transcription factors activate FLO11 gene expression with phenotypic consequences in the yeast Saccharomyces cerevisiae. AB - Cys2His2 zinc fingers are eukaryotic DNA-binding motifs, capable of distinguishing different DNA sequences, and are suitable for engineering artificial transcription factors. In this work, we used the budding yeast Saccharomyces cerevisiae to study the ability of tailor-made zinc finger proteins to activate the expression of the FLO11 gene, with phenotypic consequences. Two three-finger peptides were identified, recognizing sites from the 5' UTR of the FLO11 gene with nanomolar DNA-binding affinity. The three-finger domains and their combined six-finger motif, recognizing an 18-bp site, were fused to the activation domain of VP16 or VP64. These transcription factor constructs retained their DNA-binding ability, with the six-finger ones being the highest in affinity. However, when expressed in haploid yeast cells, only one three-finger recombinant transcription factor was able to activate the expression of FLO11 efficiently. Unlike in the wild-type, cells with such transcriptional activation displayed invasive growth and biofilm formation, without any requirement for glucose depletion. The VP16 and VP64 domains appeared to act equally well in the activation of FLO11 expression, with comparable effects in phenotypic alteration. We conclude that the functional activity of tailor-made transcription factors in cells is not easily predicted by the in vitro DNA-binding activity. PMID- 17710147 TI - DNA replication stress is a determinant of chronological lifespan in budding yeast. AB - The chronological lifespan of eukaryotic organisms is extended by the mutational inactivation of conserved growth-signaling pathways that regulate progression into and through the cell cycle. Here we show that in the budding yeast S. cerevisiae, these and other lifespan-extending conditions, including caloric restriction and osmotic stress, increase the efficiency with which nutrient depleted cells establish or maintain a cell cycle arrest in G1. Proteins required for efficient G1 arrest and longevity when nutrients are limiting include the DNA replication stress response proteins Mec1 and Rad53. Ectopic expression of CLN3 encoding a G1 cyclin downregulated during nutrient depletion increases the frequency with which nutrient depleted cells arrest growth in S phase instead of G1. Ectopic expression of CLN3 also shortens chronological lifespan in concert with age-dependent increases in genome instability and apoptosis. These findings indicate that replication stress is an important determinant of chronological lifespan in budding yeast. Protection from replication stress by growth inhibitory effects of caloric restriction, osmotic and other stresses may contribute to hormesis effects on lifespan. Replication stress also likely impacts the longevity of higher eukaryotes, including humans. PMID- 17710148 TI - 3-D ultrastructure of O. tauri: electron cryotomography of an entire eukaryotic cell. AB - The hallmark of eukaryotic cells is their segregation of key biological functions into discrete, membrane-bound organelles. Creating accurate models of their ultrastructural complexity has been difficult in part because of the limited resolution of light microscopy and the artifact-prone nature of conventional electron microscopy. Here we explored the potential of the emerging technology electron cryotomography to produce three-dimensional images of an entire eukaryotic cell in a near-native state. Ostreococcus tauri was chosen as the specimen because as a unicellular picoplankton with just one copy of each organelle, it is the smallest known eukaryote and was therefore likely to yield the highest resolution images. Whole cells were imaged at various stages of the cell cycle, yielding 3-D reconstructions of complete chloroplasts, mitochondria, endoplasmic reticula, Golgi bodies, peroxisomes, microtubules, and putative ribosome distributions in-situ. Surprisingly, the nucleus was seen to open long before mitosis, and while one microtubule (or two in some predivisional cells) was consistently present, no mitotic spindle was ever observed, prompting speculation that a single microtubule might be sufficient to segregate multiple chromosomes. PMID- 17710150 TI - Optimal conservation of migratory species. AB - BACKGROUND: Migratory animals comprise a significant portion of biodiversity worldwide with annual investment for their conservation exceeding several billion dollars. Designing effective conservation plans presents enormous challenges. Migratory species are influenced by multiple events across land and sea-regions that are often separated by thousands of kilometres and span international borders. To date, conservation strategies for migratory species fail to take into account how migratory animals are spatially connected between different periods of the annual cycle (i.e. migratory connectivity) bringing into question the utility and efficiency of current conservation efforts. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report the first framework for determining an optimal conservation strategy for a migratory species. Employing a decision theoretic approach using dynamic optimization, we address the problem of how to allocate resources for habitat conservation for a Neotropical-Nearctic migratory bird, the American redstart Setophaga ruticilla, whose winter habitat is under threat. Our first conservation strategy used the acquisition of winter habitat based on land cost, relative bird density, and the rate of habitat loss to maximize the abundance of birds on the wintering grounds. Our second strategy maximized bird abundance across the entire range of the species by adding the constraint of maintaining a minimum percentage of birds within each breeding region in North America using information on migratory connectivity as estimated from stable hydrogen isotopes in feathers. We show that failure to take into account migratory connectivity may doom some regional populations to extinction, whereas including information on migratory connectivity results in the protection of the species across its entire range. CONCLUSIONS/SIGNIFICANCE: We demonstrate that conservation strategies for migratory animals depend critically upon two factors: knowledge of migratory connectivity and the correct statement of the conservation problem. Our framework can be used to identify efficient conservation strategies for migratory taxa worldwide, including insects, birds, mammals, and marine organisms. PMID- 17710149 TI - The costs, benefits, and cost-effectiveness of interventions to reduce maternal morbidity and mortality in Mexico. AB - BACKGROUND: In Mexico, the lifetime risk of dying from maternal causes is 1 in 370 compared to 1 in 2,500 in the U.S. Although national efforts have been made to improve maternal services in the last decade, it is unclear if Millennium Development Goal 5--to reduce maternal mortality by three-quarters by 2015--will be met. METHODOLOGY/PRINCIPAL FINDINGS: We developed an empirically calibrated model that simulates the natural history of pregnancy and pregnancy-related complications in a cohort of 15-year-old women followed over their lifetime. After synthesizing national and sub-national trends in maternal mortality, the model was calibrated to current intervention-specific coverage levels and validated by comparing model-projected life expectancy, total fertility rate, crude birth rate and maternal mortality ratio with Mexico-specific data. Using both published and primary data, we assessed the comparative health and economic outcomes of alternative strategies to reduce maternal morbidity and mortality. A dual approach that increased coverage of family planning by 15%, and assured access to safe abortion for all women desiring elective termination of pregnancy, reduced mortality by 43% and was cost saving compared to current practice. The most effective strategy added a third component, enhanced access to comprehensive emergency obstetric care for at least 90% of women requiring referral. At a national level, this strategy reduced mortality by 75%, cost less than current practice, and had an incremental cost-effectiveness ratio of $300 per DALY relative to the next best strategy. Analyses conducted at the state level yielded similar results. CONCLUSIONS/SIGNIFICANCE: Increasing the provision of family planning and assuring access to safe abortion are feasible, complementary and cost-effective strategies that would provide the greatest benefit within a short time frame. Incremental improvements in access to high-quality intrapartum and emergency obstetric care will further reduce maternal deaths and disability. PMID- 17710151 TI - Is bacterial persistence a social trait? AB - The ability of bacteria to evolve resistance to antibiotics has been much reported in recent years. It is less well-known that within populations of bacteria there are cells which are resistant due to a non-inherited phenotypic switch to a slow-growing state. Although such 'persister' cells are receiving increasing attention, the evolutionary forces involved have been relatively ignored. Persistence has a direct benefit to cells because it allows survival during catastrophes-a form of bet-hedging. However, persistence can also provide an indirect benefit to other individuals, because the reduced growth rate can reduce competition for limiting resources. This raises the possibility that persistence is a social trait, which can be influenced by kin selection. We develop a theoretical model to investigate the social consequences of persistence. We predict that selection for persistence is increased when: (a) cells are related (e.g. a single, clonal lineage); and (b) resources are scarce. Our model allows us to predict how the level of persistence should vary with time, across populations, in response to intervention strategies and the level of competition. More generally, our results clarify the links between persistence and other bet-hedging or social behaviours. PMID- 17710152 TI - Long-term protection against HBV chronic carriage of Gambian adolescents vaccinated in infancy and immune response in HBV booster trial in adolescence. AB - BACKGROUND: Chronic infection with hepatitis B virus (HBV) arising in childhood is associated with hepatocellular carcinoma in adult life. Between 1986 and 1990, approximately 120,000 Gambian newborns were enrolled in a randomised controlled trial to assess the effectiveness of infant HBV vaccination on the prevention of hepatocellular carcinoma in adulthood. These children are now in adolescence and approaching adulthood, when the onset of sexual activity may challenge their hepatitis B immunity. Thus a booster dose in adolescence could be important to maintain long-term protection. METHODS: Fifteen years after the start of the HBV infant vaccination study, 492 vaccinated and 424 unvaccinated children were identified to determine vaccine efficacy against infection and carriage in adolescence. At the same time, 297 of the 492 infant-vaccinated subjects were randomly offered a booster dose of HBV vaccine. Anti-HBs was measured before the booster, and two weeks and 1 year afterwards (ISRCTN71271385). RESULTS: Vaccine efficacy 15 years after vaccination was 67.0% against infection as manifest by anti-HBc positivity (95% CI 58.2-74.6%), and 96.6% against HBsAg carriage (95% CI 91.5-100%). 31.2% of participants had detectable anti-HBs with a GMC of 32 IU/l. For 168 boosted participants GMC anti-HBs responses were 38 IU/l prior to vaccination, 524 IU/l two weeks after boosting, and 101 IU/l after 1 year. CONCLUSIONS: HBV vaccination in infants confers very good protection against carriage up to 15 years of age, although a large proportion of vaccinated subjects did not have detectable anti-HBs at this age. The response to boosting persisted for at least a year. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN71271385. PMID- 17710153 TI - Biphasic Hoxd gene expression in shark paired fins reveals an ancient origin of the distal limb domain. AB - The evolutionary transition of fins to limbs involved development of a new suite of distal skeletal structures, the digits. During tetrapod limb development, genes at the 5' end of the HoxD cluster are expressed in two spatiotemporally distinct phases. In the first phase, Hoxd9-13 are activated sequentially and form nested domains along the anteroposterior axis of the limb. This initial phase patterns the limb from its proximal limit to the middle of the forearm. Later in development, a second wave of transcription results in 5' HoxD gene expression along the distal end of the limb bud, which regulates formation of digits. Studies of zebrafish fins showed that the second phase of Hox expression does not occur, leading to the idea that the origin of digits was driven by addition of the distal Hox expression domain in the earliest tetrapods. Here we test this hypothesis by investigating Hoxd gene expression during paired fin development in the shark Scyliorhinus canicula, a member of the most basal lineage of jawed vertebrates. We report that at early stages, 5'Hoxd genes are expressed in anteroposteriorly nested patterns, consistent with the initial wave of Hoxd transcription in teleost and tetrapod paired appendages. Unexpectedly, a second phase of expression occurs at later stages of shark fin development, in which Hoxd12 and Hoxd13 are re-expressed along the distal margin of the fin buds. This second phase is similar to that observed in tetrapod limbs. The results indicate that a second, distal phase of Hoxd gene expression is not uniquely associated with tetrapod digit development, but is more likely a plesiomorphic condition present the common ancestor of chondrichthyans and osteichthyans. We propose that a temporal extension, rather than de novo activation, of Hoxd expression in the distal part of the fin may have led to the evolution of digits. PMID- 17710154 TI - CD83 modulates B cell function in vitro: increased IL-10 and reduced Ig secretion by CD83Tg B cells. AB - The murine transmembrane glycoprotein CD83 is an important regulator for both thymic T cell maturation and peripheral T cell responses. Recently, we reported that CD83 also has a function on B cells: Ubiquitous transgenic (Tg) expression of CD83 interfered with the immunoglobulin (Ig) response to infectious agents and to T cell dependent as well as T cell independent model antigen immunization. Here we compare the function of CD83Tg B cells that overexpress CD83 and CD83 mutant (CD83mu) B cells that display a drastically reduced CD83 expression. Correlating with CD83 expression, the basic as well as the lipopolysaccharide (LPS) induced expression of the activation markers CD86 and MHC-II are significantly increased in CD83Tg B cells and reciprocally decreased in CD83mu B cells. Wild-type B cells rapidly upregulate CD83 within three hours post BCR or TLR engagement by de novo protein synthesis. The forced premature overexpression of CD83 on the CD83Tg B cells results in reduced calcium signaling, reduced Ig secretion and a reciprocally increased IL-10 production upon in vitro activation. This altered phenotype is mediated by CD83 expressed on the B cells themselves, since it is observed in the absence of accessory cells. In line with this finding, purified CD83mu B cells displayed a reduced IL-10 production and slightly increased Ig secretion upon LPS stimulation in vitro. Taken together, our data strongly suggest that CD83 is expressed by B cells upon activation and contributes to the regulation of B cell function. PMID- 17710155 TI - Mutational analysis of p27 (CDKN1B) and p18 (CDKN2C) in sporadic pancreatic endocrine tumors argues against tumor-suppressor function. AB - Pancreatic endocrine tumors (PETs) arise sporadically or are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome or von Hippel-Lindau syndrome. About 90% of patients with familial MEN1 display detectable MEN1 gene (menin) mutations. The cyclin-dependent kinase inhibitor p27 (CDKN1B) is a downstream target of menin and has been recently shown to be responsible for the multiple endocrine neoplasia-like syndrome in rats, where affected animals develop multiple tumors and hyperplasia in endocrine tissues, including the pancreatic islets of Langerhans. A germline nonsense truncation mutation of p27 has been recently described in a suspected MEN1 family without MEN1 mutation, raising the possibility that p27 mutation could be responsible for MEN1 phenotype. Somatic MEN1 mutations occur at low frequency in sporadic PETs; here, we subjected p27 to mutational analysis in 27 sporadic PETs. As an additional menin target, analysis of the p18 (CDKN2C) gene was included. In the p27 gene, one common polymorphism (V109G) and one novel polymorphism (g/a) in the noncoding part of exon 2 were identified. Three known polymorphisms were found in the p18 gene. These data suggest that p27 and p18 are unlikely to present classic tumor suppressor genes in sporadic PETs. PMID- 17710156 TI - Acquisition of anoikis resistance promotes the emergence of oncogenic K-ras mutations in colorectal cancer cells and stimulates their tumorigenicity in vivo. AB - Detachment from the extracellular matrix causes apoptosis of normal epithelial cells--a phenomenon called anoikis. K-ras oncogene, an established anoikis inhibitor, often occurs in colorectal carcinoma (CRC). In addition to blocking anoikis-inducing mechanisms, oncogenic K-ras can cause anoikis-unrelated changes in CRC cells, such as induction of events promoting their deregulated mitogenesis, ability to trigger angiogenesis, and so on. Thus, whether ras induced anoikis resistance of CRC cells is essential for their ability to form tumors in vivo or represents a mere epiphenomenon is unclear. We found that when poorly tumorigenic, oncogenic, K-ras-negative, anoikis-susceptible human CRC cells were cultured under anoikis-inducing conditions in vitro, they spontaneously gave rise to an anoikis-resistant cell population harboring de novo oncogenic K-ras mutations and manifesting dramatically increased tumorigenicity. We further observed that a variant of the same oncogenic K-ras-negative anoikis susceptible cells selected for increased tumorigenicity acquired de novo oncogenic K-ras mutations and manifested increased anoikis resistance. Unlike the case with anoikis, oncogenic K-ras did not rescue CRC cells from death caused by hypoxia or anticancer agents. Taken collectively, our results support the notion that ras-induced anoikis resistance of CRC cells is essential for their ability to form tumors in vivo and thus represents a potential therapeutic target. PMID- 17710158 TI - CCL2 as an important mediator of prostate cancer growth in vivo through the regulation of macrophage infiltration. AB - The ability of CCL2 to influence prostate cancer tumorigenesis and metastasis may occur through two distinct mechanisms: 1) a direct effect on tumor cell growth and function, and 2) an indirect effect on the tumor microenvironment by the regulation of macrophage mobilization and infiltration into the tumor bed. We have previously demonstrated that CCL2 exerts a direct effect on prostate cancer epithelial cells by the regulation of their growth, invasion, and migration, resulting in enhanced tumorigenesis and metastasis. Here we describe an indirect effect of CCL2 on prostate cancer growth and metastasis by regulating monocyte/macrophage infiltration into the tumor microenvironment and by stimulating a phenotypic change within these immune cells to promote tumor growth (tumor-associated macrophages). VCaP prostate cancer cells were subcutaneously injected in male SCID mice and monitored for tumor volume, CD68(+) macrophage infiltration, and microvascular density. Systemic administration of anti-CCL2 neutralizing antibodies (CNTO888 and C1142) significantly retarded tumor growth and attenuated CD68(+) macrophage infiltration, which was accompanied by a significant decrease in microvascular density. These data suggest that CCL2 contributes to prostate cancer growth through the regulation of macrophage infiltration and enhanced angiogenesis within the tumor. PMID- 17710157 TI - Validation of dynamic contrast-enhanced magnetic resonance imaging-derived vascular permeability measurements using quantitative autoradiography in the RG2 rat brain tumor model. AB - Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is widely used to evaluate tumor permeability, yet measurements have not been directly validated in brain tumors. Our purpose was to compare estimates of forward leakage K(trans) derived from DCE-MRI to the estimates K obtained using [(14)C]aminoisobutyric acid quantitative autoradiography ([(14)C]AIB QAR), an established method of evaluating blood-tumor barrier permeability. Both DCE-MRI and [(14)C]AIB QAR were performed in five rats 9 to 11 days following tumor implantation. K(trans) in the tumor was estimated from DCE-MRI using the threeparameter general kinetic model and a measured vascular input function. K(i) was estimated from QAR data using regions of interest (ROI) closely corresponding to those used to estimate K(trans). K(trans) and K(i) correlated with each other for two independent sets of central tumor ROI (R = 0.905, P = .035; R = 0.933, P = .021). In an additional six rats, K(trans) was estimated on two occasions to show reproducibility (intraclass coefficient = 0.9993; coefficient of variance = 6.07%). In vivo blood tumor permeability parameters derived from DCE-MRI are reproducible and correlate with the gold standard for quantifying blood tumor barrier permeability, [(14)C]AIB QAR. PMID- 17710159 TI - Longitudinal studies of angiogenesis in hormone-dependent Shionogi tumors. AB - Vessel size imaging was used to assess changes in the average vessel size of Shionogi tumors throughout the tumor growth cycle. Changes in R(2) and R(2)* relaxivities caused by the injection of a superparamagnetic contrast agent (ferumoxtran-10) were measured using a 2.35-T animal magnetic resonance imaging system, and average vessel size index (VSI) was calculated for each stage of tumor progression: growth, regression, and relapse. Statistical analysis using Spearman rank correlation test showed no dependence between vessel size and tumor volume at any stage of the tumor growth cycle. Paired Student's t test was used to assess the statistical significance of the differences in average vessel size for the three stages of the tumor growth cycle. The average VSI for regressing tumors (15.1 +/- 6.6 microm) was significantly lower than that for growing tumors (35.2 +/- 25.5 microm; P < .01). Relapsing tumors also had an average VSI (45.4 +/- 41.8 microm) higher than that of regressing tumors, although the difference was not statistically significant (P = .067). This study shows that VSI imaging is a viable method for the noninvasive monitoring of angiogenesis during the progression of a Shionogi tumor from androgen dependence to androgen independence. PMID- 17710160 TI - Correlation of beta-catenin localization with cyclooxygenase-2 expression and CpG island methylator phenotype (CIMP) in colorectal cancer. AB - The WNT/beta-catenin (CTNNB1) pathway is commonly activated in the carcinogenic process. Cross-talks between the WNT and cyclooxygenase-2 (COX-2 or PTGS2)/prostaglandin pathways have been suggested. The relationship between beta catenin activation and microsatellite instability (MSI) in colorectal cancer has been controversial. The CpG island methylator phenotype (CIMP or CIMP-high) with widespread promoter methylation is a distinct epigenetic phenotype in colorectal cancer, which is associated with MSI-high. However, no study has examined the relationship between beta-catenin activation and CIMP status. Using 832 population-based colorectal cancer specimens, we assessed beta-catenin localization by immunohistochemistry. We quantified DNA methylation in eight CIMP specific promoters [CACNA1G, CDKN2A(p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by real-time polymerase chain reaction (MethyLight). MSI-high, CIMP-high, and BRAF mutation were associated inversely with cytoplasmic and nuclear beta catenin expressions (i.e., beta-catenin activation) and associated positively with membrane expression. The inverse relation between beta-catenin activation and CIMP was independent of MSI. COX-2 overexpression correlated with cytoplasmic beta-catenin expression (even after tumors were stratified by CIMP status), but did not correlate significantly with nuclear or membrane expression. In conclusion, beta-catenin activation is inversely associated with CIMP-high independent of MSI status. Cytoplasmic beta-catenin is associated with COX-2 overexpression, supporting the role of cytoplasmic beta-catenin in stabilizing PTGS2 (COX-2) mRNA. PMID- 17710161 TI - c-Myc-dependent formation of Robertsonian translocation chromosomes in mouse cells. AB - Robertsonian (Rb) translocation chromosomes occur in human and murine cancers and involve the aberrant joining of two acrocentric chromosomes in humans and two telocentric chromosomes in mice. Mechanisms leading to their generation remain elusive, but models for their formation have been proposed. They include breakage of centromeric sequences and their subsequent fusions, centric misdivision, misparing between highly repetitive sequences of p-tel or p-arm repeats, and recombinational joining of centromeres and/or centromeric fusions. Here, we have investigated the role of the oncoprotein c-Myc in the formation of Rb chromosomes in mouse cells harboring exclusively telocentric chromosomes. In mouse plasmacytoma cells with constitutive c-Myc deregulation and in immortalized mouse lymphocytes with conditional c-Myc expression, we show that positional remodeling of centromeres in interphase nuclei coincides with the formation of Rb chromosomes. Furthermore, we demonstrate that c-Myc deregulation in a myc box II dependent manner is sufficient to induce Rb translocation chromosomes. Because telomeric signals are present at all joined centromeres of Rb chromosomes, we conclude that c-Myc mediates Rb chromosome formation in mouse cells by telomere fusions at centromeric termini of telocentric chromosomes. Our findings are relevant to the understanding of nuclear chromosome remodeling during the initiation of genomic instability and tumorigenesis. PMID- 17710162 TI - CITED1 expression in Wilms' tumor and embryonic kidney. AB - Wilms' tumors, or nephroblastomas, are thought to arise from abnormal postnatal retention and dysregulated differentiation of nephrogenic progenitor cells that originate as a condensed metanephric mesenchyme within embryonic kidneys. We have previously shown that the transcriptional regulator CITED1 (CBP/p300-interacting transactivators with glutamic acid [E]/aspartic acid [D]-rich C-terminal domain) is expressed exclusively in these nephrogenic progenitor cells and is downregulated as they differentiate to form nephronic epithelia. In the current study, we show that CITED1 expression persists in blastemal cell populations of both experimental rat nephroblastomas and human Wilms' tumors, and that primary human Wilms' tumors presenting with disseminated disease show the highest level of CITED1 expression. Unlike the predominantly cytoplasmic subcellular localization of CITED1 in the normal developing kidney, CITED1 is clearly detectable in the nuclear compartment of Wilms' tumor blastema. These findings indicate that CITED1 is a marker of primitive blastema in Wilms' tumors and suggest that persistent expression and/or altered subcellular localization of CITED1 in the condensed metanephric mesenchyme could play a role in Wilms' tumor initiation and pathogenesis. PMID- 17710163 TI - The ubiquitin-conjugating enzyme E2-EPF is overexpressed in primary breast cancer and modulates sensitivity to topoisomerase II inhibition. AB - We identified the ubiquitin-conjugating enzyme E2-EPF mRNA as differentially expressed in breast tumors relative to normal tissues and performed studies to elucidate its putative role in cancer. We demonstrated that overexpression of E2 EPF protein correlated with estrogen receptor (ER) negativity in breast cancer specimens and that its expression is cell cycle-regulated, suggesting a potential function for E2-EPF in cell cycle progression. However, reduction of E2-EPF protein levels by > 80% using RNAi had no significant effects on the proliferation of HeLa cervical cancer cells or ER(-) MDA-MB-231 or MDA-MB-453 breast cancer cells. Because E2-EPF protein levels were elevated during the G(2)/M phase of the cell cycle and because E2-EPF mRNA in tumor specimens was frequently coexpressed with genes involved in cell cycle control, spindle assembly, and mitotic surveillance, the possibility that E2-EPF might have a function in the cellular response to agents that induce a G(2) checkpoint or an M checkpoint was investigated. E2-EPF knockdown sensitized HeLa cells to the topoisomerase (topo) II inhibitors etoposide and doxorubicin and also increased topo IIalpha protein levels. These data suggest that combined administration of topo II-directed drugs and E2-EPF inhibitors may enhance their clinical effectiveness. PMID- 17710165 TI - Public health surveillance and the prevention of injuries in sports: what gets measured gets done. PMID- 17710166 TI - Descriptive epidemiology of collegiate men's baseball injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2003-2004. AB - OBJECTIVE: To review 16 years of National Collegiate Athletic Association (NCAA) injury surveillance data for men's baseball and identify potential areas for injury prevention initiatives. BACKGROUND: Prevention and management of collegiate baseball injuries may be facilitated through injury research aimed at defining the nature of injuries inherent in the sport. Through the NCAA Injury Surveillance System, 16 years of collegiate baseball data were collected for the academic years 1988-1989 through 2003-2004. MAIN RESULTS: College baseball has a relatively low rate of injury compared with other NCAA sports, but 25% of injuries are severe and result in 10+ days of time loss from participation. The rate of injury was 3 times higher in a game situation than in practice (5.78 versus 1.85 injuries per 1000 athlete-exposures [A-Es], rate ratio = 3.1, 95% confidence interval = 3.0, 3.3, P < .01). Practice injury rates were almost twice as high in the preseason as in the regular season (2.97 versus 1.58 per 1000 A Es, rate ratio = 1.9, 95% confidence interval = 1.8, 2.0, P < .01). A total of 10% of all game injuries occurred from impact with a batted ball, an injury rate of 0.56 injuries per 1000 game A-Es. Sliding was involved in 13% of game injuries. RECOMMENDATIONS: Proper preseason conditioning is important to reduce injuries. Athletic trainers covering practices and games should be prepared to deal with serious, life-threatening injuries from batted balls and other injury mechanisms. Further study of batted-ball injuries is warranted, and the use of breakaway bases to prevent sliding injuries should be supported in college baseball. PMID- 17710167 TI - Descriptive epidemiology of collegiate men's basketball injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2003-2004. AB - OBJECTIVE: To review 16 years of National Collegiate Athletic Association (NCAA) injury surveillance data for men's basketball and identify potential areas for injury prevention initiatives. BACKGROUND: Collegiate men's basketball is a contact sport in which numerous anatomical structures are susceptible to both acute and overuse injuries. To date, no comprehensive reporting of injury patterns in NCAA men's basketball has been published. MAIN RESULTS: The overall rate of injury was 9.9 per 1000 athlete-exposures for games and 4.3 per 1000 athlete-exposures for practices. Approximately 60% of all injuries were to the lower extremity, with ankle ligament sprains being the most common injury overall and knee internal derangements being the most common injury causing athletes to miss more than 10 days of participation. A trend of increasing incidence of injuries to the head and face was noted over the 16-year span of the study, which may be related to an observed increase in physical contact in men's basketball over the past 2 decades. RECOMMENDATIONS: These results provide the most comprehensive description of injury patterns in NCAA men's basketball to date. Many of the most common injuries seen in men's basketball, such as ankle ligament sprains and knee internal derangements, may be at least partially preventable with interventions such as taping and bracing and neuromuscular training. However, randomized controlled trials assessing the efficacy of such preventive measures among collegiate men's basketball players are clearly lacking. The increase in head and facial injuries may indicate that officials need to assess the increased tolerance for physical contact in men's basketball seen over the past 2 decades. PMID- 17710169 TI - Descriptive epidemiology of collegiate women's field hockey injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2002-2003. AB - OBJECTIVE: To review 15 years of National Collegiate Athletic Association (NCAA) injury surveillance data for women's field hockey and identify potential areas for injury prevention initiatives. BACKGROUND: Field hockey is one of the most popular sports worldwide and is growing in participation in the United States, particularly among women. From 1988-1989 to 2002-2003, participation in NCAA women's field hockey increased 12%, with the largest growth among Division III programs. In 2002- 2003, 253 colleges offered women's field hockey and 5385 women participated. MAIN RESULTS: Game injury rates showed a significant average annual 2.5% decline over 15 years, most likely fueled by drops in ankle ligament sprain, knee internal derangement, and finger fracture injuries. Despite this, ankle ligament sprains were common (13.7% of game and 15.0% of practice injuries) and a frequent cause of severe injuries (resulting in 10+ days of time-loss activity). Concussion and head laceration injuries increased over this same time, and the risk of sustaining a concussion in a game was 6 times higher than the risk of sustaining one during practice. Overall, injury rates were twice as high in games as in practices (7.87 versus 3.70 injuries per 1000 athlete-exposures, rate ratio = 2.1, 95% confidence interval = 2.0, 2.3). Most head/neck/face (71%) and hand/finger/thumb (68%) injuries occurred when the player was near the goal or within the 25-yd line and were caused by contact with the stick or ball (greater than 77% for both body sites); for 34% of head/neck/ face injuries, a penalty was called on the play. RECOMMENDATIONS: Equipment (requiring helmets and padded gloves) and rule changes (to decrease field congestion near the goal) as well as evidence-based injury prevention interventions (eg, prophylactic ankle taping/bracing, neuromuscular balance exercise programs) may be viable prevention initiatives for reducing injury rates in women's collegiate field hockey players. PMID- 17710168 TI - Descriptive epidemiology of collegiate women's basketball injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2003-2004. AB - OBJECTIVE: To review 16 years of National Collegiate Athletic Association (NCAA) injury surveillance data for women's basketball and to identify potential areas for injury prevention initiatives. BACKGROUND: The number of colleges participating in women's college basketball has grown over the past 25 years. The Injury Surveillance System (ISS) has enabled the NCAA to collect and report injury trends over an extended period of time. This has allowed certified athletic trainers and coaches to be more informed regarding injuries and to adjust training regimens to reduce the risk of injury. It also has encouraged administrators to make rule changes that attempt to reduce the risk of injury. MAIN RESULTS: From 1988-1989 through 2003-2004, 12.4% of schools across Divisions I, II, and III that sponsor varsity women's basketball programs participated in annual ISS data collection. Game and practice injury rates exhibited significant decreases over the study period. The rate of injury in a game situation was almost 2 times higher than in a practice (7.68 versus 3.99 injuries per 1000 athlete-exposures, rate ratio = 1.9, 95% confidence interval = 1.9, 2.0). Preseason-practice injury rates were more than twice as high as regular-season practice injury rates (6.75 versus 2.84 injuries per 1000 athlete-exposures, rate ratio = 2.4, 95% confidence interval = 2.2, 2.4). More than 60% of all game and practice injuries were to the lower extremity, with the most common game injuries being ankle ligament sprains, knee injuries (internal derangements and patellar conditions), and concussions. In practices, ankle ligament sprains, knee injuries (internal derangements and patellar conditions), upper leg muscle-tendon strains, and concussions were the most common injuries. RECOMMENDATIONS: Appropriate preseason conditioning and an emphasis on proper training may reduce the risk of injury and can optimize performance. As both player size and the speed of the women's game continue to increase, basketball's evolution from a finesse sport to a high-risk contact sport also will continue. The rates of concussions and other high-energy trauma injuries likely will increase. The NCAA ISS is an excellent tool for identifying new risk factors that may affect injury rates and for developing consistent injury definitions in order to improve the research and provide a source of clinically relevant data. PMID- 17710170 TI - Descriptive epidemiology of collegiate men's football injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2003-2004. AB - OBJECTIVE: To review 16 years of National Collegiate Athletic Association (NCAA) injury surveillance data for men's football and identify potential areas for injury prevention initiatives. BACKGROUND: Football is a high-velocity collision sport in which injuries are expected. Football tends to have one of the highest injury rates in sports. Epidemiologic data helps certified athletic trainers and other clinicians identify injury trends and patterns to appropriately design and institute injury prevention protocols and then measure their effects. MAIN RESULTS: During the 16-year reporting period, about 19% of the Division I, II, and III NCAA institutions sponsoring football participated in the Injury Surveillance System. The results from the 16-year study period show little variation in the injury rates over time: games averaged 36 injuries per 1000 athlete-exposures (A-Es); fall practice, approximately 4 injuries per 1000 A-Es; and spring practice, about 10 injuries per 1000 A-Es. The game injury rate was more than 9 times higher than the in-season practice injury rate (35.90 versus 3.80 injuries per 1000 A-Es, rate ratio = 9.1, 95% confidence interval = 9.0, 9.2), and the spring practice injury rate was more than 2 times higher than the fall practice injury rate (9.62 versus 3.80 injuries per 1000 A-Es, rate ratio = 2.5, 95% confidence interval = 2.5, 2.6). The rate ratio for games versus fall practices was greatest for upper leg contusions (18.1 per 1000 A-Es), acromioclavicular joint sprains (14.0 per 1000 A-Es), knee internal derangements (13.4 per 1000 A-Es), ankle ligament sprains (12.0 per 1000 A-Es), and concussions (11.1 per 1000 A-Es). RECOMMENDATIONS: Football is a complex sport that requires a range of skills performed by athletes with a wide variety of body shapes and types. Injury risks are greatest during games. Thus, injury prevention measures should focus on position-specific activities to reduce the injury rate. As equipment technology improves for the helmet, shoulder pads, and other protective devices, appropriate injury surveillance procedures should be performed to determine the effect of the new equipment on injury rates. A consistent evaluation of injury trends and patterns will assist decision makers in designing injury prevention techniques in areas that warrant the greatest attention and suggesting rule changes and modifications based on the data. PMID- 17710171 TI - Descriptive epidemiology of collegiate women's gymnastics injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2003-2004. AB - OBJECTIVE: To review 16 years of National Collegiate Athletic Association (NCAA) injury surveillance data for women's gymnastics and identify potential areas for injury prevention initiatives. BACKGROUND: In the 1988-1989 academic year, 112 schools were sponsoring varsity women's gymnastics teams, with approximately 1550 participants. By 2003-2004, the number of varsity teams had decreased 23% to 86, involving 1380 participants. Significant participation reductions during this time were particularly apparent in Divisions II and III. MAIN RESULTS: A significant annual average decrease was noted in competition (-4.0%, P < .01) but not in practice (-1.0%, P = .35) injury rates during the sample period. Over the 16 years, the rate of injury in competition was more than 2 times higher than in practice (15.19 versus 6.07 injuries per 1000 athlete-exposures; rate ratio = 2.5, 95% confidence interval [CI] = 2.3, 2.8). A total of 53% of all competition and 69% of all practice injuries were to the lower extremity. A participant was almost 6 times more likely to sustain a knee internal derangement injury in competition than in practice (rate ratio = 5.7, 95% CI = 4.5, 7.3) and almost 3 times more likely to sustain an ankle ligament sprain (rate ratio = 2.7, 95% CI = 2.1, 3.4). The majority of competition injuries (approximately 70%) resulted from either landings in floor exercises or dismounts. RECOMMENDATIONS: Gymnasts with a previous history of ankle sprain should either wear an ankle brace or use prophylactic tape on their ankles to decrease the risk of recurrent injury. Preventive efforts may incorporate more neuromuscular training and core stability programs in the off-season and preseason conditioning to enhance proper landing and skill mechanics. Equipment manufacturers are encouraged to reevaluate the design of the landing mats to allow for better absorption of forces. PMID- 17710172 TI - Descriptive epidemiology of collegiate men's ice hockey injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2003-2004. AB - OBJECTIVE: To review 16 years of National Collegiate Athletic Association (NCAA) injury surveillance data for men's ice hockey and to identify potential areas for injury prevention initiatives. BACKGROUND: The NCAA began injury surveillance of men's ice hockey during the 1988-1989 academic year. These data represent all 3 NCAA divisions; the last Division II championship, however, was held during the 1998-1999 academic year. MAIN RESULTS: The rate of injury was more than 8 times higher in games than in practices (16.27 versus 1.96 injuries per 1000 athlete exposures [A-Es], rate ratio = 8.3, 95% confidence interval [CI] = 7.9, 8.8). A significant average annual increase of 1.3% in game injury rates occurred over the sample period (P = .05), but practice rates stayed static (P = .77). Preseason practice injury rates were more than twice as high as regular-season practice rates (5.05 versus 1.94 injuries per 1000 A-Es, rate ratio = 2.6, 95% CI = 2.4, 2.9, P < .01). The majority of game and practice injuries occurred to the lower extremity. Knee internal derangement (13.5%) was the most common lower extremity injury reported for games, whereas pelvis and hip muscle strains (13.1%) were the most common injury reported during practices. Player-to-player contact was the most frequent game mechanism of injury (50.0%). The majority of injuries occurred between the blue line and face-off circles (28.0%), in the corner (23.5%), and in the neutral zone (21.4%). RECOMMENDATIONS: Preventive efforts should focus on strategies that limit player-to-player contact in the neutral zone and at the top of the offensive and defensive zones. In addition, clinicians and researchers should identify risk factors and interventions for muscle strains at the pelvis and hip region. PMID- 17710173 TI - Descriptive epidemiology of collegiate women's ice hockey injuries: National Collegiate Athletic Association Injury Surveillance System, 2000-2001 through 2003-2004. AB - OBJECTIVE: To review 4 years of National Collegiate Athletic Association (NCAA) injury surveillance data for women's ice hockey and to identify potential areas for injury prevention initiatives. BACKGROUND: The NCAA ISS prospectively collects data on injuries sustained during collegiate participation. Women's NCAA ice hockey began participation in the ISS during the 2000-2001 season. On average, over the 4 years, 15.6% of the eligible schools elected to send their injury data. MAIN RESULTS: Over the 4 years of study, the rate of injury in games was more than 5 times higher than the injury rate in practices (12.6 versus 2.5 injuries per 1000 athlete-exposures, rate ratio = 5.0, 95% confidence interval = 4.2, 6.1, P < .01). Preseason practice injury rates were almost twice as high as in-season practice rates (4.2 versus 2.3 injuries per 1000 athlete-exposures, rate ratio = 1.8, 95% confidence interval = 1.7, 2.0, P < .01). Concussions were the most common injury in both games (21.6%) and practices (13.2%). The rate of concussions in games appeared to be trending upward over the study period. The greatest number of game injuries (approximately 50%) resulted from player contact, whereas practice injuries were from either contact with another object or noncontact mechanisms. RECOMMENDATIONS: Women's ice hockey is an evolving NCAA sport. Only 4 years of ISS data are available and, therefore, data should be interpreted with caution. Women's ice hockey does not allow for formal body checking; however, approximately 50% of all game injuries were reported to result from contact with another player. Future researchers need to evaluate the effectiveness of the no-checking rule. Additional years of data collection will be required to allow the data to become more stable, and to increase attention to mechanism-of-injury issues. We anticipate that the hypothesized inconsistencies in skill level across and within the various women's teams also will be reduced as more consistently skilled players develop, allowing for more stability in the injury scenario. PMID- 17710174 TI - Descriptive epidemiology of collegiate men's lacrosse injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2003-2004. AB - OBJECTIVE: To review 16 years of National Collegiate Athletic Association (NCAA) injury surveillance data for men's lacrosse and identify potential areas for injury prevention initiatives. BACKGROUND: During the sample period, the number of sponsoring institutions and the number of participants in men's college lacrosse grew significantly. Overall, an average of 18% of NCAA institutions participated in the annual NCAA Injury Surveillance System data collection for this sport. MAIN RESULTS: Over the sample period, athletes were almost 4 times more likely to sustain injuries in games than in practices (12.58 versus 3.24 injuries per 1000 athlete-exposures [A-Es], rate ratio = 3.9, 95% confidence interval = 3.7, 4.1). Approximately half of all game (48.1%) and practice (58.7%) injuries were to the lower extremity, followed by the upper extremity (26.2% in games, 16.9% in practices), and the head and neck (11.7% in games, 6.2% in practices). In games and practices, the most common injuries were ankle ligament sprains (11.3% and 16.4%, respectively). The disparity among preseason, regular season, and postseason injuries may be due to athlete acclimatization to the rigors of the sport throughout the season. Changes in helmet design may account for the rise in the concussion rate since the 1995-1996 season. RECOMMENDATIONS: We recommend research into the mechanism of head injuries and the implications of design changes to protective helmets, as well as further investigation of the best designs for shoulder and chest protection. PMID- 17710175 TI - Descriptive epidemiology of collegiate women's lacrosse injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2003-2004. AB - OBJECTIVE: To review 16 years of National Collegiate Athletic Association injury surveillance data for women's lacrosse and identify potential areas for injury prevention initiatives. BACKGROUND: Women's lacrosse is a fast-paced, primarily noncontact sport. Participation in collegiate women's lacrosse almost doubled between the 1988-1989 and 2003-2004 seasons. Lacrosse equipment consists of sticks made of wood or a synthetic material and a hard rubber ball. Until recently, mouth guards were the only required protective equipment. MAIN RESULTS: Collegiate women's lacrosse game injury rates increased over the 16-year study period. More than 60% of all severe game injuries were lower extremity sprains and strains and knee internal derangements, most frequently the result of noncontact incidents. The most common injury scenarios by injury mechanism and player activity were no contact while ball handling (16.4%) and contact from a stick while ball handling (10.5%). Contact from a stick or a ball accounted for 5.6% and 5.2% of injuries sustained during shooting activities, respectively. Approximately 22% of all game and 12% of all practice injuries involved the head and neck. Contact from a stick accounted for the majority (56.0%) of above-the neck injuries in games; contact from the ball accounted for 20.0% of these injuries. Participants had 5 times the risk of sustaining a concussion in a game as in a practice (0.70 versus 0.15 injuries per 1000 athletic-exposures, rate ratio = 4.7, 95% confidence interval = 3.8, 6.5). RECOMMENDATIONS: To reduce the lower extremity injuries that comprise the greatest injury burden in women's lacrosse, future researchers should evaluate proprioceptive, plyometric, and balance training interventions designed specifically for female players. Other research areas of great interest involve determining whether protective eyewear (mandated in 2004) reduces injuries to the eye, orbit, and nasal area and identifying any unintended consequences of the mandate, such as increased risk of injuries to other areas of the face or more aggressive play. PMID- 17710176 TI - Descriptive epidemiology of collegiate men's soccer injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2002-2003. AB - OBJECTIVE: To review 15 years of National Collegiate Athletic Association (NCAA) injury surveillance data for men's soccer and to identify potential areas for injury prevention initiatives. BACKGROUND: The NCAA sanctioned its first men's soccer championship in 1959. Since then, the sport has grown to include more than 18 000 annual participants across 3 NCAA divisions. During the 15 years from 1988 1989 to 2002-2003, the NCAA Injury Surveillance System accumulated game and practice injury data for men's soccer across all 3 NCAA divisions. MAIN RESULTS: The injury rate was 4 times higher in games compared with practices (18.75 versus 4.34 injuries per 1000 athlete-exposures, rate ratio = 4.3, 95% confidence interval = 4.2, 4.5), and preseason practices had a higher injury rate than in season practices (7.98 versus 2.43 injuries per 1000 athlete-exposures, rate ratio = 3.3, 95% confidence interval = 3.1, 3.5). In both games and practices, more than two thirds of men's soccer injuries occurred to the lower extremities, followed by the head and neck in games and the trunk and back in practices. Although player-to-player contact was the primary cause of injury during games, most practice injuries occurred without direct contact to the injured body part. Ankle ligament sprains represented the most common injury during practices and games, whereas knee internal derangements were the most common type of severe injury (defined as 10+ days of time loss). RECOMMENDATIONS: Sprains, contusions, and strains of the lower extremities were the most common injuries in men's collegiate soccer, with player-to-player contact the primary injury mechanism during games. Preventive efforts should focus on the player-to-player contact that often leads to these injuries and greater enforcement of the rules that are in place to limit their frequency and severity. Emphasis also should be placed on addressing the high rate of first-time and recurrent ankle ligament sprains. PMID- 17710177 TI - Descriptive epidemiology of collegiate women's soccer injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2002-2003. AB - OBJECTIVE: To review 15 years of National Collegiate Athletic Association (NCAA) injury surveillance data for women's soccer and identify potential areas for injury prevention initiatives. BACKGROUND: The number of NCAA schools sponsoring women's soccer has grown tremendously, from 271 in 1988- 1989 to 879 schools in 2002-2003. During that time, the NCAA Injury Surveillance System has collected game and practice injury data for women's soccer across all 3 NCAA divisions. MAIN RESULTS: The rate of injury was more than 3 times higher in games than in practices (16.44 versus 5.23 injuries per 1000 athlete-exposures, rate ratio = 3.2, 95% confidence interval = 3.1, 3.4, P < .01), and preseason practices had an injury rate that was more than 3 times greater than the rate for in-season practices (9.52 versus 2.91 injuries per 1000 athlete-exposures, rate ratio = 3.3, 95% confidence interval = 3.1, 3.5, P < .01). Approximately 70% of all game and practice injuries affected the lower extremities. Ankle ligament sprains (18.3%), knee internal derangements (15.9%), concussions (8.6%), and leg contusions (8.3%) accounted for a substantial portion of game injuries. Upper leg muscle-tendon strains (21.3%), ankle ligament sprains (15.3%), knee internal derangements (7.7%), and pelvis and hip muscle strains (7.6%) represented most of the practice injuries. Injuries were categorized as attributable to player contact, "other contact" (eg, contact with the ball, ground, or other object), or no contact. Player-to-player contact accounted for more than half of all game injuries (approximately 54%) but less than 20% of all practice injuries. The majority of practice injuries involved noncontact injury mechanisms. Knee internal derangements, ankle ligament sprains, and concussions were the leading game injuries that resulted in 10 or more days of time lost as a result of injury. RECOMMENDATIONS: Ankle ligament sprains, knee internal derangements, and concussions are common injuries in women's soccer. Research efforts have focused on knee injuries and concussions in soccer, and further epidemiologic data are needed to determine if preventive strategies will help to alter the incidence of these injuries. Furthermore, the specific nature of the player contact leading to concussions and lower extremity injuries should be investigated. Preventive efforts should continue to focus on reducing knee injuries, ankle injuries, and concussions in women collegiate soccer players. PMID- 17710178 TI - Descriptive epidemiology of collegiate women's softball injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2003-2004. AB - OBJECTIVE: To review 16 years of National Collegiate Athletic Association (NCAA) injury surveillance data for women's softball and to identify potential areas for injury prevention initiatives. BACKGROUND: The NCAA Injury Surveillance System has tracked injuries in all divisions of NCAA softball from the 1988-1989 to the 2003-2004 seasons. This report describes what was found and why the findings are important for the safety, enhancement, and continued growth of the sport. MAIN RESULTS: Across all divisions, preseason practice injury rates were more than double the regular-season practice injury rates (3.65 versus 1.68 injuries per 1000 athlete-exposures, rate ratio = 2.2, 95% confidence interval [CI] = 2.0, 2.4, P < .01). The rate of injury in a game was 1.6 times that in a practice (4.30 versus 2.67 injuries per 1000 athlete-exposures, rate ratio = 1.6, 95% CI = 1.5, 1.7). A total of 51.2% of game injuries resulted from "other-contact" mechanisms, whereas 55% of practice injuries resulted from noncontact mechanisms. In games, ankle ligament sprains and knee internal derangements accounted for 19% of injuries. Twenty-three percent of all game injuries were due to sliding, most of which were ankle sprains. In practices, ankle ligament sprains, quadriceps and hamstring strains, shoulder strains and tendinitis, knee internal derangements, and lower back strains (combined) accounted for 38% of injuries. RECOMMENDATIONS: Ankle ligament sprains, knee internal derangements, sliding injuries, and overuse shoulder and low back injuries were among the most common conditions in NCAA women's softball. Preventive efforts should focus on sliding technique regardless of skill level, potential equipment changes, neuromuscular training programs, position-specific throwing programs, and mechanisms of low back injury. Further research is needed on the development and effects of these preventive efforts, as well as in the area of windmill-pitching biomechanics. PMID- 17710179 TI - Descriptive epidemiology of collegiate women's volleyball injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2003-2004. AB - OBJECTIVE: To review 16 years of NCAA injury surveillance data for women's volleyball and to identify potential areas for injury prevention initiatives. BACKGROUND: Participation in NCAA women's volleyball has increased greatly over the past 16 years. As with all sports, women participating in volleyball assume an inherent risk of injury each time they practice or participate in a game. In order for clinicians to better understand the risks associated with volleyball, it is critical to gather data that illustrates injury rates and patterns among volleyball athletes. Furthermore, with knowledge of injury mechanisms and risk factors comes the ability to initiate prevention strategies to minimize future injury. MAIN RESULTS: Over the past 16 years, the rate of injury in a game situation was slightly higher than in practice (4.58 versus 4.10 game injuries per 1000 athlete-exposures, rate ratio = 1.1, 95% confidence interval = -1.0, 1.2, P < .01). A total of 2216 injuries from more than 50 000 games and 4725 injuries from more than 90 000 practices were reported. The lower extremity accounted for more than 55% of all game and practice injuries, with ankle ligament sprains representing 44.1% of game injuries and 29.4% of practice injuries. Approximately 20% of all game injuries involved the upper extremity. The majority of injuries during a game situation occurred while athletes were in one of the front 3 positions. A player landing on another player and contact with the floor each accounted for 21% of game injuries. RECOMMENDATIONS: Ankle injuries appear to be the most common injuries in women's volleyball. Future preventive efforts should focus on preventing first-time ankle sprains and acute traumatic knee injuries, as well as reducing the risk of ankle sprain recurrence. PMID- 17710180 TI - Descriptive epidemiology of collegiate men's wrestling injuries: National Collegiate Athletic Association Injury Surveillance System, 1988-1989 through 2003-2004. AB - OBJECTIVE: To review 16 years of National Collegiate Athletic Association (NCAA) injury surveillance data for men's wrestling and identify potential areas for injury prevention initiatives. BACKGROUND: From 1988-1989 through 2003-2004, 17% of NCAA schools sponsoring varsity men's wrestling programs participated in annual Injury Surveillance System (ISS) data collection. MAIN RESULTS: Patterns of injury were consistent with the person-to-person, combative contact between wrestlers. The musculoskeletal system and head were the most vulnerable areas during competitions; skin infections are a continuing concern in the practice environment. The incidence of injuries in practices exhibited no significant increase over time, a positive trend that may be consistent with the influence of the recent NCAA weight management rules. RECOMMENDATIONS: Expansion of the present ISS to include indirect causes of injury, such as weight loss practices, would strengthen the analysis of data. Efforts by referees to be vigilant for potentially dangerous holds and by athletic trainers to improve wrestler and mat hygiene should be continued. PMID- 17710182 TI - Re-establishment of local populations of vectors of Chagas disease after insecticide spraying. AB - 1. Prevention of Chagas disease is mainly dependent on control of the insect vectors that transmit infection. Unfortunately, this control is not wholly successful and the vectors have been resurgent in some areas. Where re infestation has occurred, it is important to understand the dynamics of the process. We investigated how a metapopulation framework can elucidate key aspects of re-infestation and thereby contribute to more efficient disease control.2.Triatoma infestans, the main vector of Chagas disease, re-infested sites in three villages in north-west Argentina after community-wide insecticide spraying in October 1992. Ten surveys were carried out at 6-monthly intervals from November 1994 to May 1999.3. Comparisons were made of different methods of estimating the sources of dispersal and the number of sites in which bug infestations became established.4. The results indicated that (i) the number of dispersing Triatoma infestans from a given site was proportional to the number of bugs found at the site; (ii) there was a 6-month time lag between detection of a new infestation and dispersal events; (iii) the relationship between infestations and new establishments varied by season.5. Three of 156 sites at which bugs were found were estimated to be the source of more than 50% of establishment events. These three sites were the only ones with large, persistent bug populations.6.Synthesis and applications. To reduce the risk of human Chagas disease, identifying those few sites infested with large, persistent bug populations and targeting control measures at those sites should greatly improve the efficiency of vector control. The appropriate seasonal timing of vector control could also greatly increase its efficiency. Specific recommendations for the timing of insecticide spraying require further research to establish how the observed temporal pattern of bug establishment is associated with the seasonality of bug dispersal. PMID- 17710181 TI - Epidemiology of collegiate injuries for 15 sports: summary and recommendations for injury prevention initiatives. AB - OBJECTIVE: To summarize 16 years of National Collegiate Athletic Association (NCAA) injury surveillance data for 15 sports and to identify potential modifiable risk factors to target for injury prevention initiatives. BACKGROUND: In 1982, the NCAA began collecting standardized injury and exposure data for collegiate sports through its Injury Surveillance System (ISS). This special issue reviews 182 000 injuries and slightly more than 1 million exposure records captured over a 16-year time period (1988-1989 through 2003-2004). Game and practice injuries that required medical attention and resulted in at least 1 day of time loss were included. An exposure was defined as 1 athlete participating in 1 practice or game and is expressed as an athlete-exposure (A-E). MAIN RESULTS: Combining data for all sports, injury rates were statistically significantly higher in games (13.8 injuries per 1000 A-Es) than in practices (4.0 injuries per 1000 A-Es), and preseason practice injury rates (6.6 injuries per 1000 A-Es) were significantly higher than both in-season (2.3 injuries per 1000 A-Es) and postseason (1.4 injuries per 1000 A-Es) practice rates. No significant change in game or practice injury rates was noted over the 16 years. More than 50% of all injuries were to the lower extremity. Ankle ligament sprains were the most common injury over all sports, accounting for 15% of all reported injuries. Rates of concussions and anterior cruciate ligament injuries increased significantly (average annual increases of 7.0% and 1.3%, respectively) over the sample period. These trends may reflect improvements in identification of these injuries, especially for concussion, over time. Football had the highest injury rates for both practices (9.6 injuries per 1000 A-Es) and games (35.9 injuries per 1000 A Es), whereas men's baseball had the lowest rate in practice (1.9 injuries per 1000 A-Es) and women's softball had the lowest rate in games (4.3 injuries per 1000 A-Es). RECOMMENDATIONS: In general, participation in college athletics is safe, but these data indicate modifiable factors that, if addressed through injury prevention initiatives, may contribute to lower injury rates in collegiate sports. PMID- 17710184 TI - beta-Selective Glucosylation in the Absence of Neighboring Group Participation: Influence of the 3,4-O-Bisacetal Protecting System. AB - A 3,4-O-bisacetal 2,6-di-O-benzyl protected thioglucoside is converted to the corresponding glucosyl triflate with 1-benzenesulfinyl piperidine and trifluoromethanesulfonic anhydride. The moderate to excellent beta-selectivity exhibited with this glucosyl triflate with a range of alcohols is generally higher than that observed with the more electronically disarmed corresponding 3,4 O-carbonate, for which a possible reason is advanced. PMID- 17710187 TI - Continuous-Wave Operation of a 460-GHz Second Harmonic Gyrotron Oscillator. AB - We report the regulated continuous-wave (CW) operation of a second harmonic gyrotron oscillator at output power levels of over 8 W (12.4 kV and 135 mA beam voltage and current) in the TE(0,6,1) mode near 460 GHz. The gyrotron also operates in the second harmonic TE(2,6,1) mode at 456 GHz and in the TE(2,3,1) fundamental mode at 233 GHz. CW operation was demonstrated for a one-hour period in the TE(0,6,1) mode with better than 1% power stability, where the power was regulated using feedback control. Nonlinear simulations of the gyrotron operation agree with the experimentally measured output power and radio-frequency (RF) efficiency when cavity ohmic losses are included in the analysis. The output radiation pattern was measured using a pyroelectric camera and is highly Gaussian, with an ellipticity of 4%. The 460-GHz gyrotron will serve as a millimeter-wave source for sensitivity-enhanced nuclear magnetic resonance (dynamic nuclear polarization) experiments at a magnetic field of 16.4 T. PMID- 17710185 TI - A Dipolar Cycloaddition Approach Toward the Kopsifoline Alkaloid Framework. AB - Using a metal-catalyzed domino reaction as the key step, the heterocyclic skeleton of the kopsifoline alkaloid family was constructed by a 1,3-dipolar cycloaddition of a carbonyl ylide dipole derived from a Rh(II)-catalyzed reaction of a diazo ketoester across the indole pi-bond. Ring opening of the resulting 1,3 dipolar cycloadduct followed by a reductive dehydroxylation step resulted in the formation of a critical silyl enol ether necessary for the final F-ring closure of the kopsifoline skeleton. PMID- 17710188 TI - Patterns of irrigated rice growth and malaria vector breeding in Mali using multi temporal ERS-2 synthetic aperture radar. AB - We explored the use of the European Remote Sensing Satellite 2 Synthetic Aperture Radar (ERS-2 SAR) to trace the development of rice plants in an irrigated area near Niono, Mali and relate that to the density of anopheline mosquitoes, especially An. gambiae. This is important because such mosquitoes are the major vectors of malaria in sub-Saharan Africa, and their development is often coupled to the cycle of rice development. We collected larval samples, mapped rice fields using GPS and recorded rice growth stages simultaneously with eight ERS-2 SAR acquisitions. We were able to discriminate among rice growth stages using ERS-2 SAR backscatter data, especially among the early stages of rice growth, which produce the largest numbers of larvae. We could also distinguish between basins that produced high and low numbers of anophelines within the stage of peak production. After the peak, larval numbers dropped as rice plants grew taller and thicker, reducing the amount of light reaching the water surface. ERS-2 SAR backscatter increased concomitantly. Our data support the belief that ERS-2 SAR data may be helpful for mapping the spatial patterns of rice growth, distinguishing different agricultural practices, and monitoring the abundance of vectors in nearby villages. PMID- 17710189 TI - Maternal Functioning, Time, and Money: The World of Work and Welfare. AB - Numerous studies have assessed families' employment and financial stability following welfare reform. Yet little research has addressed whether welfare and work transitions are linked with other changes in family functioning. Using a representative sample of approximately 2,000 low-income urban families from the Three-City Study, analyses assessed whether mothers' welfare and employment experiences over a two-year period following welfare reform were related to changes in family well-being. Lagged regression models controlling for family characteristics and earlier levels of functioning found that moving into employment and stable employment (of 30 hours or more per week) were linked to substantial increases in income and improvements in mothers' psychological well being. Movements into employment also were associated with declines in financial strain and food insecurity. Sustained or initiated welfare receipt was related to relative declines in income, physical health, and psychological well-being, but also to improved access to medical care. In contrast, mothers' welfare and work experiences showed very limited relations to changes in the quality of parenting or of children's home environments. These patterns were similar for families with young children and those with adolescent children. Results suggest that parenting behaviors are more resistant to change than are maternal emotional and economic functioning. PMID- 17710190 TI - Predisposition to seek mental health care among Black males transitioning from foster care. AB - This study examined the predisposition to seek mental health care in the future for personal and mental health problems among Black males transitioning from the foster care system (n=74). Results of simultaneous multiple regression analysis showed that custody status, diagnosis of a DSM-IV psychiatric disorder, and emotional control contributed significantly to the prediction of Black male's predisposition to seek mental health care. Specifically, Black males who were still in foster care were more predisposed to seek mental health care, whereas those diagnosed with a DSM-IV psychiatric disorder and who adhered more to the norm of emotional control were less predisposed to seek mental health care. Implications for mental health service delivery are discussed. PMID- 17710191 TI - Evaluation of the Oral Bioavailability of Low Molecular Weight Heparin Formulated With Glycyrrhetinic Acid as Permeation Enhancer. AB - Low molecular weight heparin (LMWH) is the agent of choice for anticoagulant therapy and prophylaxis of thrombosis and coronary syndromes. However, its therapeutic use is limited due to poor oral bioavailability. The aim of this study was to investigate the oral delivery of LMWH, ardeparin formulated with 18 beta glycyrrhetinic acid (GA), as an alternative to currently used subcutaneous (sc) delivery. Drug transport through Caco-2 cell monolayers was monitored in the presence and absence of GA by scintillation counting and transepithelial electrical resistance. Regional permeability studies using rat intestine were performed using a modified Ussing chamber. Cell viability in the presence of various concentrations of enhancer was determined by MTT assay. The absorption of ardeparin after oral administration in rats was measured by an anti-factor Xa assay. Furthermore, the eventual mucosal epithelial damage was histologically evaluated. Higher ardeparin permeability (~7-fold) compared to control was observed in the presence of 0.02 % GA. Regional permeability studies indicated predominant absorption in the duodenal segment. Cell viability studies showed no significant cytotoxicity below 0.01 % GA. Ardeparin oral bioavailability was significantly increased (F(relative)/(S.C). = 13.3%) without causing any damage to the intestinal tissues. GA enhanced the oral absorption of ardeparin both in vitro and in vivo. The oral formulation of ardeparin with GA could be absorbed in the intestine. These results suggest that GA may be used as an absorption enhancer for the oral delivery of LMWH. PMID- 17710192 TI - Processing Elided Verb Phrases with Flawed Antecedents: the Recycling Hypothesis. AB - Traditional syntactic accounts of verb phrase ellipsis (e.g. "Jason laughed. Sam did [ ] too.") categorize as ungrammatical many sentences that language users find acceptable (they "undergenerate"); semantic accounts overgenerate. We propose that a processing theory, together with a syntactic account, does a better job of describing and explaining the data on verb phrase-ellipsis. Five acceptability judgment experiments supported a "VP recycling hypothesis," which claims that when a syntactically-matching antecedent is not available, the listener/reader creates one using the materials at hand. Experiments 1 and 2 used verb phrase ellipsis sentences with antecedents ranging from perfect (a verb phrase in matrix verb phrase position) to impossible (a verb phrase containing only a deverbal word). Experiments 3 and 4 contrasted antecedents in verbal versus nominal gerund subjects. Experiment 5 explored the possibility that speakers are particularly likely to go beyond the grammar and produce elided constituents without perfect matching antecedents when the antecedent needed is less marked than the antecedent actually produced. This experiment contrasted active (unmarked) and passive antecedents to show that readers seem to honor such a tendency. PMID- 17710193 TI - Children of the Affluent: Challenges to Well-Being. AB - Growing up in the culture of affluence can connote various psychosocial risks. Studies have shown that upper-class children can manifest elevated disturbance in several areas-such as substance use, anxiety, and depression-and that two sets of factors seem to be implicated, that is, excessive pressures to achieve and isolation from parents (both literal and emotional). Whereas stereotypically, affluent youth and poor youth are respectively thought of as being at "low risk" and "high risk," comparative studies have revealed more similarities than differences in their adjustment patterns and socialization processes. In the years ahead, psychologists must correct the long-standing neglect of a group of youngsters treated, thus far, as not needing their attention. Family wealth does not automatically confer either wisdom in parenting or equanimity of spirit; whereas children rendered atypical by virtue of their parents' wealth are undoubtedly privileged in many respects, there is also, clearly, the potential for some nontrivial threats to their psychological well-being. PMID- 17710194 TI - Ligament Injury, Reconstruction and Osteoarthritis. AB - PURPOSE OF REVIEW: The recent literature on the factors that initiate and accelerate the progression of osteoarthritis following ligament injuries and their treatment is reviewed. RECENT FINDINGS: The ligament-injured joint is at high risk for osteoarthritis. Current conservative (e.g. rehabilitation) and surgical (e.g. reconstruction) treatment options appear not to reduce osteoarthritis following ligament injury. The extent of osteoarthritis does not appear dependent on which joint is affected, or the presence of damage to other tissues within the joint. Mechanical instability is the likely initiator of osteoarthritis in the ligament-injured patient. SUMMARY: The mechanism osteoarthritis begins with the injury rendering the joint unstable. The instability increases the sliding between the joint surfaces and reduces the efficiency of the muscles, factors that alter joint contact mechanics. The load distribution in the cartilage and underlying bone is disrupted, causing wear and increasing shear, which eventually leads to the osteochondral degeneration. The catalyst to the mechanical process is the inflammation response induced by the injury and sustained during healing. In contrast, the inflammation could be responsible for onset, while the mechanical factors accelerate progression. The mechanisms leading to osteoarthritis following ligament injury have not been fully established. A better understanding of these mechanisms should lead to alternative surgical, drug, and tissue-engineering treatment options, which could eliminate osteoarthritis in these patients. Progress is being made on all fronts. Considering that osteoarthritis is likely to occur despite current treatment options, the best solution may be prevention. PMID- 17710195 TI - Correlates of Oral Sex and Vaginal Intercourse in Early and Middle Adolescence. AB - This study examined whether a comprehensive set of psychosocial factors was equally predictive of both adolescent vaginal intercourse and oral sex among 1,105 adolescents aged 12-16. Logistic regressions were used to examine the relationships between parental communication, religiosity, bonding to school, heavy drinking, sex expectancies, normative beliefs, and both oral sex and vaginal intercourse. Age, gender, bonding to school, heavy drinking, and negative health expectancies predicted both oral sex and vaginal intercourse. Parental communication was associated with vaginal intercourse but not oral sex. Behavior specific normative beliefs were differentially associated with oral and vaginal sex. PMID- 17710196 TI - QUALITY-CONSTANT "PRICES" FOR THE ONGOING TREATMENT OF SCHIZOPHRENIA: AN EXPLORATORY STUDY* AB - Health care expenditures have been increasing sharply in the last ten years, with spending on mental health disorders being particularly prominent. Over the same time period, a number of new antipsychotic medications have been added to the armamentarium for treatment of persons diagnosed with schizophrenia. Due in part to the sharply increased expenditures by Medicaid on mental health disorders such as schizophrenia, controversies have arisen as to the use of these more costly innovative medications, particularly their impact on the annualized cost of treating patients.Using Medicaid data on 12,864 person years from two counties in Florida over the 1994-95 to 1999-2000 time period, in this study we address three issues: (i) On a per person year basis, what is happening over time to the mental health-related costs of treating schizophrenia? (ii) How is the composition and quality of care changing over time? and (iii) Holding quality of care constant, on a per person year basis, by how much are the costs for the ongoing treatment of schizophrenia changing?We find that unadjusted for changes in quality of care over time, the annualized costs for the ongoing treatment of schizophrenia per person have increased about 0.5% per year. The composition of treatments for schizophrenia has changed substantially over this six-year time period, toward more intensive use of atypical antipsychotics, and away from psychosocial treatments. Holding treatment quality type and patient characteristics constant over time, mean treatment costs have fallen about 5.5% per year between 1994-1995 and 1999-2000. PMID- 17710197 TI - Conditional Dnmt1 deletion in dorsal forebrain disrupts development of somatosensory barrel cortex and thalamocortical long-term potentiation. AB - The transcriptional mechanisms governing the development and plasticity of somatopic sensory maps in the cerebral cortex have not been extensively studied. In particular, no studies have addressed the role of epigenetic mechanisms in the development of sensory maps. DNA methylation is one the main epigenetic mechanisms available to mammalian cells to regulate gene transcription. As demethylation results in embryonic lethality, it has been very difficult to study the role of DNA methylation in brain development. We have used cre-lox technology to generate forebrain-specific deletion of DNA methyltransferase 1 (Dnmt1), the enzyme required for the maintenance of DNA methylation. We find that demethylation of neurons in the cerebral cortex results in the failure of development of somatosensory barrel cortex. We also find that in spite of functional thalamocortical neurotransmission, thalamocortical long-term potentiation cannot be induced in slices from Dnmt1 conditional mutants. These studies emphasize the importance of DNA methylation for the development of sensory maps and suggest epigenetic mechanisms may play a role in the development of synaptic plasticity. PMID- 17710198 TI - School Based Mental Health Promotion: Nursing Interventions for Depressive Symptoms in Rural Adolescents. AB - Integrating health education and health promotion into practice is routinely done by nurses. According to a national survey, the need for mental health services has increased in over two thirds of school districts.This article describes the screening of 193 adolescents in Rural Western Pennsylvania's 9th, 10th, and 11th graders for depressive symptoms. Ten percent (N=19) of students had depressive symptoms, the majority of which were female. These students were interviewed by the research team. The outcome themes and referrals are reported as well as the discussion of implications for nurses in screening for depression and health promotion. PMID- 17710199 TI - The Extent of Cooperativity of Protein Motions Observed with Elastic Network Models Is Similar for Atomic and Coarser-Grained Models. AB - Coarse-grained elastic network models have been successful in determining functionally relevant collective motions. The level of coarse-graining, however, has usually focused on the level of one point per residue. In this work, we compare the applicability of elastic network models over a broader range of representational scales. We apply normal mode analysis for multiple scales on a high-resolution protein data set using various cutoff radii to define the residues considered to be interacting, or the extent of cooperativity of their motions. These scales include the residue-, atomic-, proton-, and explicit solvent-levels. Interestingly, atomic, proton, and explicit solvent level calculations all provide similar results at the same cutoff value, with the computed mean-square fluctuations showing only a slightly higher correlation (0.61) with the experimental temperature factors from crystallography than the results of the residue-level coarse-graining. The qualitative behavior of each level of coarse graining is similar at different cutoff values. The correlations between these fluctuations and the number of internal contacts improve with increased cutoff values. Our results demonstrate that atomic level elastic network models provide an improved representation for the collective motions of proteins compared to the coarse-grained models. PMID- 17710200 TI - Paying attention: A leap toward quality care. PMID- 17710203 TI - Homeopathy: does a teaspoon of honey help the medicine go down? PMID- 17710204 TI - Homeopathy for cancer? PMID- 17710201 TI - Adolescent development of the neural circuitry for thinking about intentions. AB - In this fMRI study, we investigated the development during adolescence of the neural network underlying thinking about intentions. A total of 19 adolescent participants (aged 12.1-18.1 years), and 11 adults (aged 22.4-37.8 years), were scanned using fMRI. A factorial design was employed with between-subjects factor age group and within-subjects factor causality (intentional or physical). In both adults and adolescents, answering questions about intentional causality vs physical causality activated the medial prefrontal cortex (PFC), superior temporal sulcus (STS), temporal poles and precuneus bordering with posterior cingulate cortex. In addition, there was a significant interaction between group and task in the medial PFC. During intentional relative to physical causality, adolescents activated part of the medial PFC more than did adults and adults activated part of the right STS more than did adolescents. These results suggest that the neural strategy for thinking about intentions changes between adolescence and adulthood. Although the same neural network is active, the relative roles of the different areas change, with activity moving from anterior (medial prefrontal) regions to posterior (temporal) regions with age. PMID- 17710205 TI - Management of single brain metastasis: a practice guideline. AB - QUESTIONS: Should patients with confirmed single brain metastasis undergo surgical resection? Should patients with single brain metastasis undergoing surgical resection receive adjuvant whole-brain radiation therapy (wbrt)? What is the role of stereotactic radiosurgery (srs) in the management of patients with single brain metastasis? PERSPECTIVES: Approximately 15%-30% of patients with cancer will develop cerebral metastases over the course of their disease. Patients identified as having single brain metastasis generally undergo more aggressive treatment than do those with multiple metastases; however, in the province of Ontario, management of patients with single brain metastasis varies. Given that conflicting evidence has been reported, the Neuro-oncology Disease Site Group (dsg) of the Cancer Care Ontario Program in Evidence-based Care felt that a systematic review of the evidence and a practice guideline were warranted. OUTCOMES: Outcomes of interest were survival, local control of disease, quality of life, and adverse effects. METHODOLOGY: The medline, cancerlit, embase, and Cochrane Library databases and abstracts published in the proceedings of the annual meetings of the American Society of Clinical Oncology (1997-2005) and American Society for Therapeutic Radiology and Oncology (1998-2004) were systematically searched for relevant evidence. The review included fully published reports or abstracts of randomized controlled trials (rcts), nonrandomized prospective studies, and retrospective studies. The present systematic review and practice guideline has been reviewed and approved by the Neuro-oncology dsg, which comprises medical and radiation oncologists, surgeons, neurologists, a nurse, and a patient representative. External review by Ontario practitioners was obtained through an electronic survey. Final approval of the guideline report was obtained from the Report Approval Panel and the Neuro oncology dsg. RESULTS: QUALITY OF EVIDENCE: The literature search found three rcts that compared surgical resection plus wbrt with wbrt alone. In addition, a Cochrane review, including a meta-analysis of published data from those three rcts, was obtained. One rct compared surgical resection plus wbrt with surgical resection alone. One rct compared wbrt plus srs with wbrt alone. Evidence comparing srs with surgical resection or examining srs with or without wbrt was limited to prospective case series and retrospective studies. BENEFITS: Two of three rcts reported a significant survival benefit for patients who underwent surgical resection as compared with those who received wbrt alone. Pooled results of the three rcts indicated no significant difference in survival or likelihood of dying from neurologic causes; however, significant heterogeneity was detected between the trials. The rct that compared surgical resection plus wbrt with surgical resection alone reported no significant difference in overall survival or length of functional independence; however, tumour recurrence at the site of the metastasis and anywhere in the brain was less frequent in patients who received wbrt as compared with patients in the observation group. In addition, patients who received wbrt were less likely to die from neurologic causes. Results of the rct that compared wbrt plus srs with wbrt alone indicated a significant improvement in median survival in patients who received srs. No quality evidence compares the efficacy of srs with surgical resection or examines the question of whether patients who receive srs should also receive wbrt. HARMS: Pooled results of the three rcts that examined surgical resection indicated no significant difference in adverse effects between groups. Postoperative complications included respiratory problems, intracerebral hemorrhage, and infection. One rct reported no significant difference in adverse effects between patients who received wbrt plus srs and those who received wbrt alone. PRACTICE GUIDELINE: TARGET POPULATION: The recommendations that follow apply to adults with confirmed cancer and a single brain metastasis. This practice guideline does not apply to patients with metastatic lymphoma, small-cell lung cancer, germ-cell tumour, leukemia, or sarcoma. RECOMMENDATIONS: Surgical excision should be considered for patients with good performance status, minimal or no evidence of extracranial disease, and a surgically accessible single brain metastasis amenable to complete excision. Because treatment in cases of single brain metastasis is considered palliative, invasive local treatments must be individualized. Patients with lesions requiring emergency decompression because of intracranial hypertension were excluded from the rcts, but should be considered candidates for surgery. To reduce the risk of tumour recurrence for patients who have undergone resection of a single brain metastasis, postoperative wbrt should be considered. The optimal dose and fractionation schedule for wbrt is 3000 cGy in 10 fractions or 2000 cGy in 5 fractions. As an alternative to surgical resection, wbrt followed by srs boost should be considered for patients with single brain metastasis. The evidence is insufficient to recommend srs alone as a single-modality therapy. QUALIFYING STATEMENTS: No high-quality data are available regarding the choice of surgery versus radiosurgery for single brain metastasis. In general, the size and location of the metastasis determine the optimal approach. The standard wbrt regimen for management of patients with single brain metastasis in the United States is 3000 cGy in 10 fractions, and this treatment is usually the standard arm in randomized studies of radiation in patients with brain metastases. Based solely on evidence, the understanding that no reason exists to choose 3000 cGy in 10 fractions over 2000 cGy in 5 fractions is correct; however, fraction size is believed to be important, and therefore 300 cGy daily (3000/10) is believed to be associated with fewer long-term neurocognitive effects than 400 cGy daily (2000/5) in the occasional long-term survivor. For that reason, many radiation oncologists in Ontario prefer 3000 cGy in 10 fractions. No data exist to either support or refute that preference; therefore, finding a resolution to this issue is not currently possible. The Neuro-oncology dsg will update the recommendations as new evidence becomes available. PMID- 17710206 TI - Ifosfamide-based combination chemotherapy in advanced soft-tissue sarcoma: a practice guideline. AB - QUESTIONS: In adult patients with inoperable locally advanced or metastatic soft tissue sarcoma, do combination chemotherapy regimens containing ifosfamide have an advantage in terms of response rate, time to progression, or survival, as compared with similar regimens without ifosfamide when used as first-line therapy? What are the adverse effects and effects on quality of life of ifosfamide-containing combination chemotherapy as compared with similar regimens without ifosfamide? PERSPECTIVES: The prognosis for patients with inoperable or meta-static soft-tissue sarcoma (sts) remains grim. Although the surgical resection of pulmonary metastases may be curative in 15%-30% of patients with isolated slow-growing metastases, most patients receive chemotherapy for palliative purposes. Ifosfamide has documented activity in patients who have received prior treatment with, or who have progressed on, doxorubicin. A number of studies have suggested a schedule and a dose-response relationship for ifosfamide in metastatic sts. Ifosfamide has also been assessed in combination with other drugs such as doxorubicin and dacarbazine (dtic); results of such studies have led some authors to suggest that polychemotherapy using "appropriate doses" of ifosfamide and doxorubicin may represent the "most effective systemic treatment" in this population. Given the limited effective therapeutic options available for patients with metastatic sts, the Sarcoma Disease Site Group (dsg) felt that a need existed to more specifically evaluate the potential benefits of ifosfamide-containing combination chemotherapy in that setting. The Sarcoma dsg developed an evidence-based series report through systematic review, evidence synthesis, and input from practitioners across Ontario. OUTCOMES: Outcomes of interest included survival, response rate, adverse events, and quality of life. METHODOLOGY: A systematic review and meta-analysis served as the evidentiary base for this clinical practice guideline. The report was reviewed and approved by the Sarcoma dsg, which comprises medical oncologists, radiation oncologists, surgeons, methodologists, and patient representatives. The results of an external review by Ontario practitioners, obtained through a mailed survey, were incorporated into this report. Final approval of the evidence-based series report was obtained from the Report Approval Panel of Cancer Care Ontario's Program in Evidence-Based Care (pebc). RESULTS: The current practice guideline reflects a combination of the draft recommendations (based on the evidence identified in a systematic review and meta-analysis) and the external feedback from Ontario practitioners and the pebc's Report Approval Panel. PRACTICE GUIDELINE: In patients with metastatic sts, the addition of ifosfamide to standard first-line doxorubicin-containing regimens is not recommended over single-agent doxorubicin. However, in patients with symptomatic, locally advanced, or inoperable sts, in whom tumour response might potentially result in reduced symptomatology or render a tumour resectable, use of ifosfamide in combination with doxorubicin is reasonable. QUALIFYING STATEMENT: In combination with a doxorubicin-containing regimen, the dose of ifosfamide should not exceed 7.5 g/m(2), given as either a split bolus or a continuous infusion. PMID- 17710207 TI - Updated recommendations from the Canadian National Consensus Meeting on HER2/neu testing in breast cancer. AB - Testing for HER2/neu in breast cancer at the time of primary diagnosis is now the standard of care. Accurate and standardized testing methods are of prime importance to ensure the proper classification of the patient's HER2/neu status. A meeting of pathologists from across Canada was convened to update the Canadian HER2/neu testing guidelines. This National HER2/neu Testing Committee reviewed the recently published American Society of Clinical Oncology/ College of American Pathologists (ASCO/CAP) guidelines for HER2/neu testing in breast cancer. The updated Canadian HER2/neu testing guidelines are based primarily on the ASCO/CAP guidelines, with some modifications. It is anticipated that widespread adoption of these guidelines will further improve the accuracy of HER2/neu testing in Canada. PMID- 17710208 TI - Phase II testing of sunitinib: the National Cancer Institute of Canada Clinical Trials Group IND Program Trials IND.182-185. AB - Sunitinib (SU11248) is an orally bioavailable inhibitor that affects the receptor tyrosine kinases involved in tumour proliferation and angiogenesis, including vascular endothelial growth factor (VEGF) receptors 1, 2, 3, and platelet-derived growth factor receptors alpha (PDGFRA) and beta (PDGFRB). Because angiogenesis is necessary for the growth and metastasis of solid tumours, and VEGF is believed to have a pivotal role in that process, SUNITINIB treatment may have broad-spectrum clinical utility. In the present article, we discuss the biologic and clinical rationales that have recently led the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group to initiate four phase ii trials testing this agent in the following four different tumour types: relapsed diffuse large cell lymphoma, malignant pleural mesothelioma, locally advanced or metastatic cervical cancer and recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. PMID- 17710209 TI - Architectures, representations and processes of language production. AB - We present an overview of recent research conducted in the field of language production based on papers presented at the first edition of the International Workshop on Language Production (Marseille, France, September 2004). This article comprises two main parts. In the first part, consisting of three sections, we review the articles that are included in this Special Issue. These three sections deal with three different topics of general interest for models of language production: (A) the general organisational principles of the language production system, (B) several aspects of the lexical selection process and (C) the representations and processes used during syntactic encoding. In the second part, we discuss future directions for research in the field of language production, given the considerable developments that have occurred in recent years. PMID- 17710210 TI - The functions of structural priming. AB - Structural priming refers to speakers' tendency to produce sentences with previously heard or produced syntactic structures. We review arguments and evidence for three common accounts of the functions of structural priming. One is that structural priming enhances fluency. Only some (reaction time and fluency measure) evidence supports this view. A second account argues that structural priming stems from implicit learning of how features of meaning are linked to syntactic configurations. We describe evidence suggesting that structural priming exhibits effects characteristic of both learning and implicitness. A third account claims that structural priming is an aspect of coordination or alignment among interlocutors. Consistent with this, some evidence shows that structural priming involves a shorter-term component that is broadly sensitive to repeated bindings of wide-ranging types of knowledge. Together, these observations suggest that structural priming is likely a multifaceted force that reflects implicit learning and, possibly independently, alignment among interlocutors. PMID- 17710211 TI - Noise and poise: Enhancement of postural complexity in the elderly with a stochastic-resonance-based therapy. AB - Pathologic states are associated with a loss of dynamical complexity. Therefore, therapeutic interventions that increase physiologic complexity may enhance health status. Using multiscale entropy analysis, we show that the postural sway dynamics of healthy young and healthy elderly subjects are more complex than that of elderly subjects with a history of falls. Application of subsensory noise to the feet has been demonstrated to improve postural stability in the elderly. We next show that this therapy significantly increases the multiscale complexity of sway fluctuations in healthy elderly subjects. Quantification of changes in dynamical complexity of biologic variability may be the basis of a new approach to assessing risk and to predicting the efficacy of clinical interventions, including noise-based therapies. PMID- 17710212 TI - Longitudinal Relations among Parental Emotional Expressivity and Sympathy and Prosocial Behavior in Adolescence. AB - Concurrent and longitudinal relations among parental emotional expressivity, children's sympathy, and children's prosocial behavior were assessed with correlations and structural equation modeling when the children were 55 months to 97 months old (n = 214; M age = 73 months, SD = 9.59) and 8 years later (n = 130; ages 150 to 195 months old, M = 171 months, SD = 10.01). Parent emotional expressivity (positive and negative) and children's sympathy were stable across time and early parent-reported sympathy predicted adolescents' sympathy and prosocial behavior. Parents' positive expressivity was positively related to sympathy and prosocial behavior, but in adolescence, this was likely due primarily to consistency over time. Early observed parental negative expressivity was negatively related to adolescents' prosocial behavior. Reported negative expressivity in childhood was negatively related to boys' sympathy in childhood and positively related to girls' sympathy behavior in adolescence. The later relation remained significant when controlling for the stability of parental expressivity and sympathy, suggesting an emerging positive relation between the variables for girls. PMID- 17710214 TI - The Mediating Role of Parenting Stress in Methadone-Maintained Mothers' Parenting. AB - OBJECTIVE: To (1) examine the subjective experience of parenting stress as a mediator between 2 distal stressors (sociodemographic risk and global psychological maladjustment), and examine the parenting of methadone-maintained mothers, and (2) identify maladaptive and adaptive parenting correlates of specific types of parenting stress. DESIGN: We analyzed baseline data from interviews conducted with 74 methadone-maintained mothers who expressed interest in a randomized clinical trial study testing the efficacy of a relational parenting intervention. Baseline measures included questionnaires on maternal psychological maladjustment, parenting stress, parenting problems, and children's maladjustment. Three series of hierarchical linear regressions were conducted to test the mediation model and specificity of associations. RESULTS: Parenting stress mediated the associations between sociodemographic risk and 2 maladaptive parenting domains (aggression and neglect) and between psychological maladjustment and all 5 parenting domains examined (aggression, neglect, affective interactions, limit setting, and autonomy), although correlations were modest. Child-focused stress was associated with higher levels of aggression, limit-setting problems, and restricted autonomy. Stress derived from the mother - child relationship was associated with higher levels of neglect and affective withdrawal. CONCLUSIONS: Although preliminary in nature, results of this study indicate the importance of understanding the role of internal mechanisms (e.g., parenting stress) in the parenting processes of addicted women and examining specific correlates of their parenting problems. PMID- 17710216 TI - Differential Behavioral Responses to Water-Borne Cues to Predation in Two Container-Dwelling Mosquitoes. AB - Larvae of the mosquito Toxorhynchites rutilus (Coquillett) prey upon other container-dwelling insects, including larvae of Aedes albopictus (Skuse), which is native to Asia but was introduced into the United States, and on the native tree hole mosquito Ochlerotatus triseriatus (Say). Previous work has established that O. triseriatus adopts low-risk behaviors in the presence of predation risk from T. rutilus. It is unknown whether introduced A. albopictus show a similar response to this predator. Behavior of fourth instars of A. albopictus or O. triseriatus was recorded in water that had held either A. albopictus or O. triseriatus larvae alone (control) and in water that had held T. rutilus larvae feeding on either A. albopictus or O. triseriatus (predation). Activity and position of larvae were recorded in 30-min instantaneous scan censuses. In response to water-borne cues to predation, O. triseriatus adopted low-risk behaviors (more resting, less feeding and movement), but A. albopictus did not change its behavior. We also tested the species specificity of the cues by recording the behavior of A. albopictus in water prepared using O. triseriatus and vice versa. O. triseriatus adopted low-risk behaviors even in predation water prepared by feeding T. rutilus with A. albopictus, but A. albopictus did not alter its behavior significantly between predation and control treatments prepared using O. triseriatus. Thus, A. albopictus does not seem to respond behaviorally to cues produced by this predator and may be more vulnerable to predation than is O. triseriatus. PMID- 17710215 TI - Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway. AB - Although pain is regarded traditionally as neuronally mediated, recent progress shows an important role of spinal glial cells in persistent pain sensitization. Mounting evidence has implicated spinal microglia in the development of chronic pain (e.g. neuropathic pain after peripheral nerve injury). Less is known about the role of astrocytes in pain regulation. However, astrocytes have very close contact with synapses and maintain homeostasis in the extracellular environment. In this review, we provide evidence to support a role of spinal astrocytes in maintaining chronic pain. In particular, c-Jun N-terminal kinase (JNK) is activated persistently in spinal astrocytes in a neuropathic pain condition produced by spinal nerve ligation. This activation is required for the maintenance of neuropathic pain because spinal infusion of JNK inhibitors can reverse mechanical allodynia, a major symptom of neuropathic pain. Further study reveals that JNK is activated strongly in astrocytes by basic fibroblast growth factor (bFGF), an astroglial activator. Intrathecal infusion of bFGF also produces persistent mechanical allodynia. After peripheral nerve injury, bFGF might be produced by primary sensory neurons and spinal astrocytes because nerve injury produces robust bFGF upregulation in both cell types. Therefore, the bFGF/JNK pathway is an important signalling pathway in spinal astrocytes for chronic pain sensitization. Investigation of signaling mechanisms in spinal astrocytes will identify new molecular targets for the management of chronic pain. PMID- 17710217 TI - Characteristics of Hidden Status Among Users of Crack, Powder Cocaine, and Heroin in Central Harlem. AB - This article analyzes hidden status among crack, powder cocaine, and heroin users and setters, in contrast to more accessible users/sellers. Several sampling strategies acquired 657 users (N=559) and sellers (N=98). Indicators of hidden status were those who (1) paid rent in full in the last 30 days, (2) used nonstreet drug procurement. (3) had legal jobs, and (4) earned $1,000 or more in legal income in the last 30 days. Nearly half had at least one indicator: approximately 16% of users/sellers had two to four indicators. In logistic regression analyses, those who had not panhandled in the last 30 days, those who had used powder cocaine in the last 30 days, and those never arrested were the most likely to have hidden status, whether the analysis predicted those having any indicators or those having two to four indicators. The four indicators begin to operationally define hidden status among users of cocaine and heroin. PMID- 17710218 TI - Linked Lives: Adult Children's Problems and Their Parents' Psychological and Relational Well-Being. AB - This study examined associations between adult children's cumulative problems and their parents' psychological and relational well-being, as well as whether such associations are similar for married and single parents. Regression models were estimated using data from 1,188 parents in the 1995 National Survey of Midlife in the United States whose youngest child was at least 19 years old. Participants reporting children with more problems indicated moderately poorer levels of well being across all outcomes examined. Single parents reporting more problems indicated less positive affect than a comparable group of married parents, but married parents reporting more problems indicated poorer parent-child relationship quality. Findings are congruent with the family life course perspective, conceptualizing parents and children as occupying mutually influential developmental trajectories. PMID- 17710219 TI - Surveying approaches to the formation of carbon-carbon bonds between a pyran and an adjacent ring. AB - We have examined several methods for the stereoselective formation of carbon carbon bonds between contiguous rings where a stereogenic center is already present. The approaches investigated were a [1,3] oxygen to carbon rearrangement of cyclic vinyl acetals, an intermolecular enolsilane addition into an in situ generated oxocarbenium ion, an intramolecular conjugate addition of tethered alkoxy enones, and epimerization of several alpha-pyranyl cycloalkanones. These routes have been found to be complementary in several cases and have enabled formation of both the trans:anti and cis:anti stereoisomers in good to excellent yields and varying diastereoselectivities. We have proven C2-C2' relative stereochemistry of 1-2 via a chemical correlation. PMID- 17710220 TI - A recyclable fluorous organocatalyst for Diels-Alder reactions. AB - Chiral fluorous imidazolidinone catalyst 2 provides consistently high enantioselectivities in Diels-Alder reactions of dienes and alpha, beta unsaturated aldehydes. The catalyst can be readily separated from the reaction products by fluorous solid-phase extraction, and recovered in excellent purity for direct reuse. PMID- 17710221 TI - Section 1-Conclusions and Recommendations. AB - The conclusions listed below are derived from scientific data presented in the review of research on ultrasound bioeffects. The recommendations detail how the medical community should respond to these conclusions. The conclusions and recommendations are divided into six parts that correspond with the papers in this journal identified as Sections 3 through 8. The background information on which these conclusions and recommendations are based may be found in those sections. PMID- 17710222 TI - DOUBLE TROUBLE IN RECOVERY: SELF-HELP FOR PEOPLE WITH DUAL DIAGNOSES. AB - Self-help is gaining increased acceptance among treatment professionals as the advent of managed care warrants the use of cost-effective modalities. Traditional "one disease-one recovery" self-help groups cannot serve adequately the needs of the dually diagnosed. This article discusses Double Trouble in Recovery (DTR), a 12-step self-help group designed to meet the special needs of those diagnosed with both a psychiatric disability and a chemical addiction, DTR differs from traditional self-help groups by offering people a safe forum to discuss their psychiatric disabilities, medication, and substance abuse. Preliminary data collected at four DTR sites in NYC indicate that DTR members have a long history of psychiatric disabilities and of substance abuse, and extensive experience with treatment programs in both areas. They are actively working on their recovery, as evidenced by their fairly intensive attendance at DTR. Recent substance use is limited, suggesting that participation in DTR (in conjunction with format treatment when needed) is having a positive effect. Most members require medication to control their psychiatric disabilities, and that alone may make attendance at "conventional" 12-step groups uncomfortable. Ratings of statements comparing DTR to other 12-step meetings suggest that DTR is a setting where members can feel comfortable and safe discussing their dual recovery needs. PMID- 17710223 TI - Proof-of-Principle to Measure Potassium in the Human Brain: A Feasibility Study. AB - We describe the results of a proof-of-principle to measure the potassium content in the human brain using the natural radioisotope (40)K that is in equilibrium with the stable isotopes of potassium, (39)K and (41)K. A fixed relationship exists between radioactive potassium and the total potassium in the brain, which in turn reflects the brain's cell mass and intracellular water compartment. Accordingly, we explored whether measurements of brain potassium could serve as possible indicators of intracellular cerebral edema. We designed, built, and then calibrated our system using a spherical phantom containing KCl salt dissolved in water at levels comparable to those in the human brain. Emitted radiation was detected using sodium iodide (Nal) and high-purity germanium (HP-Ge) detectors. Our results with phantoms and with five volunteers demonstrate the feasibility of measuring potassium at the levels normally present in human brain tissue. We plan to extend the system to detect the onset of brain edema in patients with multiple sclerosis. PMID- 17710224 TI - The structure of the nucleoside triphosphate diphosphohydrolases (NTPDases) as revealed by mutagenic and computational modeling analyses. AB - Over the last seven years our laboratory has focused on the determination of the structural aspects of nucleoside triphosphate diphosphohydrolases (NTPDases) using site-directed mutagenesis and computational comparative protein modeling to generate hypotheses and models for the hydrolytic site and enzymatic mechanism of the family of NTPDase nucleotidases. This review summarizes these studies utilizing NTPDase3 (also known as CD39L3 and HB6), an NTPDase family member that is intermediate in its characteristics between the more widely distributed and studied NTPDase1 (also known as CD39) and NTPDase2 (also known as CD39L1 and ecto ATPase) enzymes. Relevant site-directed mutagenesis studies of other NTPDases are also discussed and compared to NTPDase3 results. It is anticipated that many of the results and conclusions reached via studies of NTPDase3 will be relevant to understanding the structure and enzymatic mechanism of all the cell-surface members of this family (NTPDase1-3, 8), and that understanding these NTPDase enzymes will aid in modulating the many varied processes under purinergic signaling control. This review also integrates the site-directed mutagenesis results with a recent 3-D structural model for the extracellular portion of NTPDases that helps explain the importance of the apyrase conserved regions (ACRs) of the NTPDases. Utilizing this model and published work from Dr Guidotti's laboratory concerning the importance and characteristics of the two transmembrane helices and their movements in response to substrate, we present a speculative cartoon model of the enzymatic mechanism of the membrane-bound NTPDases that integrates movements of the extracellular region required for catalysis with movements of the N- and C-terminal transmembrane helices that are important for control and modulation of enzyme activity. PMID- 17710225 TI - (1R,2S)-Benzyl N-[3-(diisopropylaminocarbonyl)-2-phenylprop-3-enyl]carbamate. AB - The title compound, C(25)H(32)N(2)O(3), was synthesized as part of a series of related compounds using a modified Eschenmoser-Claisen rearrangement reaction. The compound is racemic and the structure features a centrosymmetric hydrogen bonded dimerization along with some aromatic stacking stabilization. PMID- 17710226 TI - TLR4-initiated and cAMP-mediated abrogation of bacterial invasion of the bladder. AB - The remarkable resistance of the urinary tract to infection has been attributed to its physical properties and the innate immune responses triggered by pattern recognition receptors lining the tract. We report a distinct TLR4 mediated mechanism in bladder epithelial cells (BECs) that abrogates bacterial invasion, a necessary step for successful infection. Compared to controls, uropathogenic type 1 fimbriated Escherichia coli and Klebsiella pneumoniae invaded BECs of TLR4 mutant mice in 10-fold or greater numbers. TLR4 mediated suppression of bacterial invasion was linked to increased intracellular cAMP levels which negatively impacted Rac-1 mediated mobilization of the cytoskeleton. Artificially increasing intracellular cAMP levels in BECs of TLR4 mutant mice restored resistance to type 1 fimbriated bacterial invasion. This finding reveals a novel function for TLR4 and another facet of bladder innate defense. PMID- 17710227 TI - Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR ABL mutations with altered oncogenic potency. AB - Molecularly targeted kinase inhibitor cancer therapies are currently administered sequentially rather than simultaneously. We addressed the potential long-term impact of this strategy in patients with chronic myelogenous leukemia (CML), which is driven by the fusion oncogene BCR-ABL. Analysis of BCR-ABL genotypes in CML patients who relapsed after sequential treatment with the ABL inhibitors imatinib and dasatinib revealed evolving resistant BCR-ABL kinase domain mutations in all cases. Twelve patients relapsed with the pan-resistant T315I mutation, whereas 6 patients developed novel BCR-ABL mutations predicted to retain sensitivity to imatinib based on in vitro studies. Three of these patients were retreated with imatinib (or the chemically related compound nilotinib) and responded; however, selection for compound mutants (2 or 3 BCR-ABL mutations in the same molecule) can substantially limit the potential effectiveness of retreating patients with inhibitors that have previously failed. Furthermore, drug-resistant mutations, when compounded, can increase oncogenic potency relative to the component mutants in transformation assays. The Aurora kinase inhibitor VX-680, currently under clinical evaluation based on its activity against the T315I mutation, is also effective against the other commonly detected dasatinib-resistant mutation in our analysis, V299L. Our findings demonstrate the potential hazards of sequential kinase inhibitor therapy and suggest a role for a combination of ABL kinase inhibitors, perhaps including VX-680, to prevent the outgrowth of cells harboring drug-resistant BCR-ABL mutations. PMID- 17710228 TI - Oncogene MYCN regulates localization of NKT cells to the site of disease in neuroblastoma. AB - Valpha24-invariant natural killer T (NKT) cells are potentially important for antitumor immunity. We and others have previously demonstrated positive associations between NKT cell presence in primary tumors and long-term survival in distinct human cancers. However, the mechanism by which aggressive tumors avoid infiltration with NKT and other T cells remains poorly understood. Here, we report that the v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN), the hallmark of aggressive neuroblastoma, repressed expression of monocyte chemoattractant protein-1/CC chemokine ligand 2 (MCP-1/CCL2), a chemokine required for NKT cell chemoattraction. MYCN knockdown in MYCN-amplified neuroblastoma cell lines restored CCL2 production and NKT cell chemoattraction. Unlike other oncogenes, MYCN repressed chemokine expression in a STAT3 independent manner, requiring an E-box element in the CCL2 promoter to mediate transcriptional repression. MYCN overexpression in neuroblastoma xenografts in NOD/SCID mice severely inhibited their ability to attract human NKT cells, T cells, and monocytes. Patients with MYCN-amplified neuroblastoma metastatic to bone marrow had 4-fold fewer NKT cells in their bone marrow than did their nonamplified counterparts, indicating that the MYCN-mediated immune escape mechanism, which we believe to be novel, is operative in metastatic cancer and should be considered in tumor immunobiology and for the development of new therapeutic strategies. PMID- 17710229 TI - Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting. AB - Clinical use of prostaglandin synthase-inhibiting NSAIDs is associated with the development of hypertension; however, the cardiovascular effects of antagonists for individual prostaglandin receptors remain uncharacterized. The present studies were aimed at elucidating the role of prostaglandin E2 (PGE2) E prostanoid receptor subtype 1 (EP1) in regulating blood pressure. Oral administration of the EP1 receptor antagonist SC51322 reduced blood pressure in spontaneously hypertensive rats. To define whether this antihypertensive effect was caused by EP1 receptor inhibition, an EP1-null mouse was generated using a "hit-and-run" strategy that disrupted the gene encoding EP1 but spared expression of protein kinase N (PKN) encoded at the EP1 locus on the antiparallel DNA strand. Selective genetic disruption of the EP1 receptor blunted the acute pressor response to Ang II and reduced chronic Ang II-driven hypertension. SC51322 blunted the constricting effect of Ang II on in vitro-perfused preglomerular renal arterioles and mesenteric arteriolar rings. Similarly, the pressor response to EP1-selective agonists sulprostone and 17-phenyltrinor PGE2 were blunted by SC51322 and in EP1-null mice. These data support the possibility of targeting the EP1 receptor for antihypertensive therapy. PMID- 17710230 TI - Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. AB - A small population of plasmacytoid DCs (pDCs) in mouse tumor-draining LNs can express the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). We show that these IDO+ pDCs directly activate resting CD4+CD25+Foxp3+ Tregs for potent suppressor activity. In vivo, Tregs isolated from tumor-draining LNs were constitutively activated and suppressed antigen-specific T cells immediately ex vivo. In vitro, IDO+ pDCs from tumor-draining LNs rapidly activated resting Tregs from non-tumor-bearing hosts without the need for mitogen or exogenous anti-CD3 crosslinking. Treg activation by IDO+ pDCs was MHC restricted, required an intact amino acid-responsive GCN2 pathway in the Tregs, and was prevented by CTLA4 blockade. Tregs activated by IDO markedly upregulated programmed cell death 1 ligand 1 (PD-L1) and PD-L2 expression on target DCs, and the ability of Tregs to suppress target T cell proliferation was abrogated by antibodies against the programmed cell death 1/PD-L (PD-1/PD-L) pathway. In contrast, Tregs activated by anti-CD3 crosslinking did not cause upregulation of PD-Ls, and suppression by these cells was unaffected by blocking the PD-1/PD-L pathway. Tregs isolated from tumor-draining LNs in vivo showed potent PD-1/PD-L-mediated suppression, which was selectively lost when tumors were grown in IDO-deficient hosts. We hypothesize that IDO+ pDCs create a profoundly suppressive microenvironment within tumor-draining LNs via constitutive activation of Tregs. PMID- 17710231 TI - A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. AB - Familial tumoral calcinosis is characterized by ectopic calcifications and hyperphosphatemia due to inactivating mutations in FGF23 or UDP-N-acetyl-alpha-D galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3). Herein we report a homozygous missense mutation (H193R) in the KLOTHO (KL) gene of a 13 year-old girl who presented with severe tumoral calcinosis with dural and carotid artery calcifications. This patient exhibited defects in mineral ion homeostasis with marked hyperphosphatemia and hypercalcemia as well as elevated serum levels of parathyroid hormone and FGF23. Mapping of H193R mutation onto the crystal structure of myrosinase, a plant homolog of KL, revealed that this histidine residue was at the base of the deep catalytic cleft and mutation of this histidine to arginine should destabilize the putative glycosidase domain (KL1) of KL, thereby attenuating production of membrane-bound and secreted KL. Indeed, compared with wild-type KL, expression and secretion of H193R KL were markedly reduced in vitro, resulting in diminished ability of FGF23 to signal via its cognate FGF receptors. Taken together, our findings provide what we believe to be the first evidence that loss-of-function mutations in human KL impair FGF23 bioactivity, underscoring the essential role of KL in FGF23-mediated phosphate and vitamin D homeostasis in humans. PMID- 17710232 TI - Essential role of sphingosine 1-phosphate receptor 2 in pathological angiogenesis of the mouse retina. AB - Sphingosine 1-phosphate (S1P), a multifunctional lipid mediator that signals via the S1P family of G protein-coupled receptors (S1PR), regulates vascular maturation, permeability, and angiogenesis. In this study, we explored the role of S1P 2 receptor (S1P2R) in normal vascularization and hypoxia-triggered pathological angiogenesis of the mouse retina. S1P2R is strongly induced in ECs during hypoxic stress. When neonatal mice were subjected to ischemia-driven retinopathy, pathologic neovascularization in the vitreous chamber was suppressed in S1p2-/- mice concomitant with reduction in endothelial gaps and inflammatory cell infiltration. In addition, EC patterning and normal revascularization into the avascular zones of the retina were augmented. Reduced expression of the proinflammatory enzyme cyclooxygenase-2 (COX-2) and increased expression of eNOS were observed in the S1p2-/- mouse retina. S1P2R activation in ECs induced COX-2 expression and suppressed the expression of eNOS. These data identify the S1P2R driven inflammatory process as an important molecular event in pathological retinal angiogenesis. We propose that antagonism of the S1P2R may be a novel therapeutic approach for the prevention and/or treatment of pathologic ocular neovascularization. PMID- 17710233 TI - Peroxisome proliferator-activated receptors and acute lung injury. AB - Peroxisome proliferator-activated receptors are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. PPARs regulate several metabolic pathways by binding to sequence-specific PPAR response elements in the promoter region of target genes, including lipid biosynthesis and glucose metabolism. Recently, PPARs and their respective ligands have been implicated as regulators of cellular inflammatory and immune responses. These molecules are thought to exert anti-inflammatory effects by negatively regulating the expression of proinflammatory genes. Several studies have demonstrated that PPAR ligands possess anti-inflammatory properties and that these properties may prove helpful in the treatment of inflammatory diseases of the lung. This review will outline the anti-inflammatory effects of PPARs and PPAR ligands and discuss their potential therapeutic effects in animal models of inflammatory lung disease. PMID- 17710234 TI - PPARs and Adipose Cell Plasticity. AB - Due to the importance of fat tissues in both energy balance and in the associated disorders arising when such balance is not maintained, adipocyte differentiation has been extensively investigated in order to control and inhibit the enlargement of white adipose tissue. The ability of a cell to undergo adipocyte differentiation is one particular feature of all mesenchymal cells. Up until now, the peroxysome proliferator-activated receptor (PPAR) subtypes appear to be the keys and essential players capable of inducing and controlling adipocyte differentiation. In addition, it is now accepted that adipose cells present a broad plasticity that allows them to differentiate towards various mesodermal phenotypes. The role of PPARs in such plasticity is reviewed here, although no definite conclusion can yet be drawn. Many questions thus remain open concerning the definition of preadipocytes and the relative importance of PPARs in comparison to other master factors involved in the other mesodermal phenotypes. PMID- 17710235 TI - The Role of PPARs in Lung Fibrosis. AB - Pulmonary fibrosis is a group of disorders characterized by accumulation of scar tissue in the lung interstitium, resulting in loss of alveolar function, destruction of normal lung architecture, and respiratory distress. Some types of fibrosis respond to corticosteroids, but for many there are no effective treatments. Prognosis varies but can be poor. For example, patients with idiopathic pulmonary fibrosis (IPF) have a median survival of only 2.9 years. Prognosis may be better in patients with some other types of pulmonary fibrosis, and there is variability in survival even among individuals with biopsy-proven IPF. Evidence is accumulating that the peroxisome proliferator-activated receptors (PPARs) play important roles in regulating processes related to fibrogenesis, including cellular differentiation, inflammation, and wound healing. PPARalpha agonists, including the hypolidipemic fibrate drugs, inhibit the production of collagen by hepatic stellate cells and inhibit liver, kidney, and cardiac fibrosis in animal models. In the mouse model of lung fibrosis induced by bleomycin, a PPARalpha agonist significantly inhibited the fibrotic response, while PPARalpha knockout mice developed more serious fibrosis. PPARbeta/delta appears to play a critical role in regulating the transition from inflammation to wound healing. PPARbeta/delta agonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPARgamma agonists. PPARgamma ligands oppose the profibrotic effect of TGF-beta, which induces differentiation of fibroblasts to myofibroblasts, a critical effector cell in fibrosis. PPARgamma ligands, including the thiazolidinedione class of antidiabetic drugs, effectively inhibit lung fibrosis in vitro and in animal models. The clinical availability of potent and selective PPARalpha and PPARgamma agonists should facilitate rapid development of successful treatment strategies based on current and ongoing research. PMID- 17710236 TI - Role of PPARs and Retinoid X Receptors in the Regulation of Lung Maturation and Development. AB - Understanding lung development has significant importance to public health because of the fact that interruptions in the normal developmental processes can have prominent effects on childhood and adult lung health. It is widely appreciated that the retinoic acid (RA) pathway plays an important role in lung development. Additionally, PPARs are believed to partner with receptors of this pathway and therefore could be considered extensions of retinoic acid function, including during lung development. This review will begin by introducing the relationship between the retinoic acid pathway and PPARs followed by an overview of lung development stages and regulation to conclude with details on PPARs and the retinoic acid pathway as they may relate to lung development. PMID- 17710238 TI - Survey of obstetrician-gynecologists about giardiasis. AB - Giardiasis is one of the most common parasitic diseases in the United States with over 15 400 cases reported in 2005. A survey was conducted by The American College of Obstetricians and Gynecologists (ACOG) in collaboration with the Centers for Disease Control and Prevention (CDC) to evaluate the knowledge of obstetricians and gynecologists regarding the diagnosis and treatment of giardiasis. The questionnaire was distributed to a random sample of 1200 ACOG fellows during February through June of 2006. Five hundred and two (42%) responded to the survey. The respondents showed good general knowledge about diagnosis, transmission, and prevention; however, there was some uncertainty about the treatment of giardiasis and which medications are the safest to administer during the first trimester of pregnancy. PMID- 17710239 TI - Xanthogranulomatous endometritis: a challenging imitator of endometrial carcinoma. AB - Xanthogranulomatous inflammation is a distinguished histopathological entity affecting several organs, predominantly the kidney and gallbladder. So far, only a small number of cases of xanthogranulomatous inflammation occurring in female genital tract have been described, most frequently affecting the endometrium and histologically characterized by replacement of endometrium by xanthogranulomatous inflammation composed of abundant foamy histiocytes, siderophages, giant cells, fibrosis, calcification and accompanying polymorphonuclear leucocytes, plasma cells and lymphocytes of polyclonal origin. We present a case of a 69-year-old female complained of post menopausal bleeding and weight loss. Clinical preliminary diagnoses were endometrial carcinoma or hyperplasia and ultrasound was supposed to be endometrial malignancy, hyperplasia or pyometra by radiologist. Histopathological examination of uterus revealed xanthogranulomatous endometritis. Since xanthogranulomatous endometritis may mimic endometrial malignancy clinically and pathologically as a result of the replacement of the endometrium and occasionally invasion of the myometrium by friable yellowish tissue composed of histiocytes, knowledge of this unusual inflammatory disease is needed for both clinicians and pathologists. PMID- 17710237 TI - The Effect of PPARalpha, PPARdelta, PPARgamma, and PPARpan Agonists on Body Weight, Body Mass, and Serum Lipid Profiles in Diet-Induced Obese AKR/J Mice. AB - Activation of peroxisome proliferator-activated receptor (PPAR) alpha, delta, and gamma subtypes increases expression of genes involved in fatty acid transport and oxidation and alters adiposity in animal models of obesity and type-2 diabetes. PPARpan agonists which activate all three receptor subtypes have antidiabetic activity in animal models without the weight gain associated with selective PPARgamma agonists. Herein we report the effects of selective PPAR agonists (GW9578, a PPARalpha agonist, GW0742, a PPARdelta agonist, GW7845, a PPARgamma agonist), combination of PPARalpha and delta agonists, and PPARpan (PPARalpha/gamma/delta) activators (GW4148 or GW9135) on body weight (BW), body composition, food consumption, fatty acid oxidation, and serum chemistry of diet induced obese AKR/J mice. PPARalpha or PPARdelta agonist treatment induced a slight decrease in fat mass (FM) while a PPARgamma agonist increased BW and FM commensurate with increased food consumption. The reduction in BW and food intake after cotreatment with PPARalpha and delta agonists appeared to be synergistic. GW4148, a PPARpan agonist, induced a significant and sustained reduction in BW and FM similar to an efficacious dose of rimonabant, an antiobesity compound. GW9135, a PPARpan agonist with weak activity at PPARdelta, induced weight loss initially followed by rebound weight gain reaching vehicle control levels by the end of the experiment. We conclude that PPARalpha and PPARdelta activations are critical to effective weight loss induction. These results suggest that the PPARpan compounds may be expected to maintain the beneficial insulin sensitization effects of a PPARgamma agonist while either maintaining weight or producing weight loss. PMID- 17710240 TI - Rapid determination of macrolide and lincosamide resistance in group B streptococcus isolated from vaginal-rectal swabs. AB - OBJECTIVE: Our objective was to assess the ability of real-time PCR to predict in vitro resistance in isolates of group B streptococcus (GBS). METHODS: The first real-time PCR assays for the genes known to confer resistance to erythromycin and clindamycin in GBS were developed. Three hundred and forty clinical GBS isolates were assessed with these assays and compared with conventional disk diffusion. RESULTS: The presence of an erythromycin ribosome methylation gene (ermB or ermTR variant A) predicted in vitro constitutive or inducible resistance to clindamycin with a sensitivity of 93% (95% CI 86%-97%), specificity of 90% (95% CI 85%-93%), positive predictive value of 76% (95% CI 67%-84%), and negative predictive value of 97% (95% CI 94%-99%). CONCLUSION: This rapid and simple assay can predict in vitro susceptibility to clindamycin within two hours of isolation as opposed to 18-24 hours via disk diffusion. The assay might also be used to screen large numbers of batched isolates to establish the prevalence of resistance in a given area. PMID- 17710241 TI - Lemierre's syndrome complicating pregnancy. AB - Lemierre's syndrome is an anaerobic suppurative thrombophlebitis involving the internal jugular vein secondary to oropharyngeal infection. There is only one previous case report in pregnancy which was complicated by premature delivery of an infant that suffered significant neurological damage. We present an atypical case diagnosed in the second trimester with a live birth at term. By reporting this case, we hope to increase the awareness of obstetricians to the possibility of Lemierre's syndrome when patients present with signs of unabating oropharyngeal infection and pulmonary symptoms. PMID- 17710242 TI - Expression of VE-Cadherin in Peritubular Endothelial Cells during Acute Rejection after Human Renal Transplantation. AB - Genes involved in acute rejection (AR) after organ transplantation remain to be further elucidated. In a previous work we have demonstrated the under-expression of VE-Cadherin by endothelial cells (EC) in AR following murine and human heart transplantation. Serial sections from 15 human kidney Banff-graded transplant biopsies were examined for the presence of VE-Cadherin and CD34 staining by immunohistochemistry (no AR (n = 5), AR grade IA (n = 5), or AR grade IIA (n = 5)). Quantification of peritubular EC staining were evaluated and results were expressed by the percentage of stained cells per surface analysed. There was no difference in CD34 staining between the 3 groups. VE-Cadherin expression was significantly reduced in AR Grade IIA when compared to no AR (P = .01) and to AR grade IA (P = .02). This study demonstrates a reduced VE-Cadherin expression by EC in AR after renal transplantation. The down-regulation of VE-Cadherin may strongly participate in human AR. PMID- 17710243 TI - Immune response regulation by leishmania secreted and nonsecreted antigens. AB - Leishmania infection consists in two sequential events, the host cell colonization followed by the proliferation/dissemination of the parasite. In this review, we discuss the importance of two distinct sets of molecules, the secreted and/or surface and the nonsecreted antigens. The importance of the immune response against secreted and surface antigens is noted in the establishment of the infection and we dissect the contribution of the nonsecreted antigens in the immunopathology associated with leishmaniasis, showing the importance of these panantigens during the course of the infection. As a further example of proteins belonging to these two different groups, we include several laboratorial observations on Leishmania Sir2 and LicTXNPx as excreted/secreted proteins and LmS3arp and LimTXNPx as nonsecreted/panantigens. The role of these two groups of antigens in the immune response observed during the infection is discussed. PMID- 17710244 TI - DNA Vaccines against Protozoan Parasites: Advances and Challenges. AB - Over the past 15 years, DNA vaccines have gone from a scientific curiosity to one of the most dynamic research field and may offer new alternatives for the control of parasitic diseases such as leishmaniasis and Chagas disease. We review here some of the advances and challenges for the development of DNA vaccines against these diseases. Many studies have validated the concept of using DNA vaccines for both protection and therapy against these protozoan parasites in a variety of mouse models. The challenge now is to translate what has been achieved in these models into veterinary or human vaccines of comparable efficacy. Also, genome mining and new antigen discovery strategies may provide new tools for a more rational search of novel vaccine candidates. PMID- 17710245 TI - Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) blocks the chemotaxis of neutrophils by inhibiting signal transduction through IL-8 receptors. AB - We investigated the impact of curcumin on neutrophils. Chemotactic activity via human recombinant IL-8 (hrIL-8) was significantly inhibited by curcumin. Curcumin reduced calcium ion flow induced by internalization of the IL-8 receptor. We analyzed flow cytometry to evaluate the status of the IL-8 receptor after curcumin treatment. The change in the distribution of receptors intracellularly and on the cell surface suggested that curcumin may affect the receptor trafficking pathway intracellulary. Rab11 is a low molecular weight G protein associated with the CXCR recycling pathway. Following curcumin treatment, immunoprecipitation studies showed that the IL-8 receptor was associated with larger amounts of active Rab11 than that in control cells. These data suggest that curcumin induces the stacking of the Rab11 vesicle complex with CXCR1 and CXCR2 in the endocytic pathway. The mechanism for antiinflammatory response by curcumin may involve unique regulation of the Rab11 trafficking molecule in recycling of IL-8 receptors. PMID- 17710246 TI - Maternal plasma procalcitonin concentrations in pregnancy complicated by preterm premature rupture of membranes. AB - OBJECTIVES: Our objective is to compare maternal plasma procalcitonin concentrations in preterm premature rupture of membranes (pPROM) and premature rupture of membranes (PROM) at term with their levels in uncomplicated pregnancy, and to determine whether these concentrations are useful in the diagnosis of pPROM cases suspected of infection and in the prediction of pPROM-to-delivery interval. STUDY DESIGN: Forty eight patients with pPROM, 30 with PROM at term, 31 healthy women at preterm gestation, and 33 healthy women at term were included. In pPROM group, analysis of procalcitonin concentrations with reference to leucocytosis, serum C-reactive protein, vaginal fluid culture, neonatal infection, histological chorioamnionitis and pPROM-to-delivery interval was carried out. RESULTS: Procalcitonin concentrations in pPROM and PROM at term cases were comparable. However, in both groups procalcitonin values were significantly higher than in healthy controls in approximate gestational age. In pPROM group, procalcitonin concentrations between the patients with and without laboratory indices of infection were comparable, as well as between patients who gave birth to newborns with and without congenital infection, and between patients with and without histological chorioamnionitis. The predictive values of procalcitonin determinations were poor. CONCLUSION: The value of maternal plasma procalcitonin determinations in the diagnostics of pPROM cases suspected of intraamniotic infection, as well as for the prediction of pPROM-to-delivery interval, newborn's infection or histological chorioamnionitis is unsatisfactory. However, procalcitonin concentrations are elevated, both in patients with preterm and term PROMs in comparison to healthy pregnants, and therefore further evaluations are necessary to establish the role of procalcitonin in the pathophysiology of pregnancy. PMID- 17710247 TI - Perinatal changes of cardiac troponin-I in normal and intrauterine growth restricted pregnancies. AB - Intrauterine growth restriction (IUGR) implies fetal hypoxia, resulting in blood flow redistribution and sparing of vital organs (brain, heart). Serum cardiac Troponin-I (cTnI), a well-established marker of myocardial ischaemia, was measured in 40 mothers prior to delivery, the doubly clamped umbilical cords (representing fetal state), and their 20 IUGR and 20 appropriate-for-gestational age (AGA) neonates on day 1 and 4 postpartum. At all time points, no differences in cTnI levels were observed between the AGA and IUGR groups. Strong positive correlations were documented between maternal and fetal/neonatal values (r > or = .498, P < or = .025 in all cases in the AGA and r > or = .615, P < or = .009 in all cases in the IUGR group). These results may indicate (a) normal heart function, due to heart sparing, in the IUGR group (b) potential crossing of the placental barrier by cTnI in both groups. PMID- 17710248 TI - Upregulation of neurotrophic factors selectively in frontal cortex in response to olfactory discrimination learning. AB - We have previously shown that olfactory discrimination learning is accompanied by several forms of long-term enhancement in synaptic connections between layer II pyramidal neurons selectively in the piriform cortex. This study sought to examine whether the previously demonstrated olfactory-learning-task-induced modifications are preceded by suitable changes in the expression of mRNA for neurotrophic factors and in which brain areas this occurs. Rats were trained to discriminate positive cues in pair of odors for a water reward. The relationship between the learning task and local levels of mRNA for brain-derived neurotrophic factor, tyrosine kinase B, nerve growth factor, and neurotrophin-3 in the frontal cortex, hippocampal subregions, and other regions were assessed 24 hours post olfactory learning. The olfactory discrimination learning activated production of endogenous neurotrophic factors and induced their signal transduction in the frontal cortex, but not in other brain areas. These findings suggest that different brain areas may be preferentially involved in different learning/memory tasks. PMID- 17710249 TI - Differential MR/GR activation in mice results in emotional states beneficial or impairing for cognition. AB - Corticosteroids regulate stress response and influence emotion, learning, and memory via two receptors in the brain, the high-affinity mineralocorticoid (MR) and low-affinity glucocorticoid receptor (GR). We test the hypothesis that MR- and GR-mediated effects interact in emotion and cognition when a novel situation is encountered that is relevant for a learning process. By adrenalectomy and additional constant corticosterone supplement we obtained four groups of male C57BL/6J mice with differential chronic MR and GR activations. Using a hole board task, we found that mice with continuous predominant MR and moderate GR activations were fast learners that displayed low anxiety and arousal together with high directed explorative behavior. Progressive corticosterone concentrations with predominant action via GR induced strong emotional arousal at the expense of cognitive performance. These findings underline the importance of a balanced MR/GR system for emotional and cognitive functioning that is critical for mental health. PMID- 17710250 TI - Role of apolipoprotein E in anxiety. AB - Anxiety is most common among Alzheimer's disease (AD) patients with an age at onset under age 65. Apolipoprotein E4 (apoE4) is a risk factor for developing AD at an earlier age and might contribute to this effect. In mice, apoE plays a role in the regulation of anxiety, which might involve histamine receptor-mediated signaling and steroidogenesis in the adrenal gland. In addition, human apoE isoforms have differential effects on anxiety in adult mice lacking apoE and probable AD patients. Compared to wild-type mice, mice lacking apoE and apoE4 mice showed pathological alterations in the central nucleus of the amygdala, which is involved in regulation of anxiety. ApoE4, but not mice lacking apoE, or apoE3 mice showed impaired dexamethasone suppression of plasma corticosterone. Understanding how apoE modulates measures of anxiety might help the developments of therapeutic targets to reduce or even prevent measures of anxiety in health and in dementing illnesses. PMID- 17710251 TI - Multimodality data integration in epilepsy. AB - An important goal of software development in the medical field is the design of methods which are able to integrate information obtained from various imaging and nonimaging modalities into a cohesive framework in order to understand the results of qualitatively different measurements in a larger context. Moreover, it is essential to assess the various features of the data quantitatively so that relationships in anatomical and functional domains between complementing modalities can be expressed mathematically. This paper presents a clinically feasible software environment for the quantitative assessment of the relationship among biochemical functions as assessed by PET imaging and electrophysiological parameters derived from intracranial EEG. Based on the developed software tools, quantitative results obtained from individual modalities can be merged into a data structure allowing a consistent framework for advanced data mining techniques and 3D visualization. Moreover, an effort was made to derive quantitative variables (such as the spatial proximity index, SPI) characterizing the relationship between complementing modalities on a more generic level as a prerequisite for efficient data mining strategies. We describe the implementation of this software environment in twelve children (mean age 5.2 +/- 4.3 years) with medically intractable partial epilepsy who underwent both high-resolution structural MR and functional PET imaging. Our experiments demonstrate that our approach will lead to a better understanding of the mechanisms of epileptogenesis and might ultimately have an impact on treatment. Moreover, our software environment holds promise to be useful in many other neurological disorders, where integration of multimodality data is crucial for a better understanding of the underlying disease mechanisms. PMID- 17710252 TI - Adaptive bayesian iterative transmission reconstruction for attenuation correction in myocardial perfusion imaging with SPECT/slow-rotation low-output CT systems. AB - OBJECTIVES: SPECT/slow-rotation low-output CT systems can produce streak artifacts in filtered backprojection (FBP) attenuation maps, impacting attenuation correction (AC) in myocardial perfusion imaging. This paper presents an adaptive Bayesian iterative transmission reconstruction (ABITR) algorithm for more accurate AC. METHODS: In each iteration, ABITR calculated a three dimensional prior containing the pixels with attenuation coefficients similar to water, then used it to encourage these pixels to the water value. ABITR was tested with a cardiac phantom and 4 normal patients acquired by a GE Millennium VG/Hawkeye system. RESULTS: FBP AC and ABITR AC produced similar phantom results. For the patients, streak artifacts were observed in the FBP and ordered-subsets expectation-maximization (OSEM) maps but not in the ABITR maps, and ABITR AC produced more uniform images than FBP AC and OSEM AC. CONCLUSION: ABITR can improve the quality of the attenuation map, producing more uniform images for normal studies. PMID- 17710253 TI - Quantitative and o(2) enhanced MRI of the pathologic lung: findings in emphysema, fibrosis, and cystic fibrosis. AB - PURPOSE: beyond the pure morphological visual representation, MR imaging offers the possibility to quantify parameters in the healthy, as well as, in pathologic lung parenchyma. Gas exchange is the primary function of the lung and the transport of oxygen plays a key role in pulmonary physiology and pathophysiology. The purpose of this review is to present a short overview of the relaxation mechanisms of the lung and the current technical concepts of T1 mapping and methods of oxygen enhanced MR imaging. MATERIAL AND METHODS: molecular oxygen has weak paramagnetic properties so that an increase in oxygen concentration results in shortening of the T1 relaxation time and thus to an increase of the signal intensity in T1 weighted images. A possible way to gain deeper insights into the relaxation mechanisms of the lung is the calculation of parameter Maps. T1 Maps based on a snapshot FLASH sequence obtained during the inhalation of various oxygen concentrations provide data for the creation of the so-called oxygen transfer function (OTF), assigning a measurement for local oxygen transfer. T1 weighted single shot TSE sequences also permit expression of the signal changing effects associated with the inhalation of pure oxygen. RESULTS: the average of the mean T1 values over the entire lung in inspiration amounts to 1199 +/- 117 milliseconds, the average of the mean T1 values in expiration was 1333 +/- 167 milliseconds. T1 Maps of patients with emphysema and lung fibrosis show fundamentally different behavior patterns. Oxygen enhanced MRT is able to demonstrate reduced diffusion capacity and diminished oxygen transport in patients with emphysema and cystic fibrosis. DISCUSSION: results published in literature indicate that T1 mapping and oxygen enhanced MR imaging are promising new methods in functional imaging of the lung and when evaluated in conjunction with the pure morphological images can provide additional valuable information. PMID- 17710254 TI - Integration of vibro-acoustography imaging modality with the traditional mammography. AB - Vibro-acoustography (VA) is a new imaging modality that has been applied to both medical and industrial imaging. Integrating unique diagnostic information of VA with other medical imaging is one of our research interests. In this work, we establish correspondence between the VA images and traditional X-ray mammogram by adopting a flexible control-point selection technique for image registration. A modified second-order polynomial, which simply leads to a scale/rotation/translation invariant registration, was used. The results of registration were used to spatially transform the breast VA images to map with the X-ray mammography with a registration error of less than 1.65 mm. The fused image is defined as a linear integration of the VA and X-ray images. Moreover, a color-based fusion technique was employed to integrate the images for better visualization of structural information. PMID- 17710255 TI - Registration of Brain MRI/PET Images Based on Adaptive Combination of Intensity and Gradient Field Mutual Information. AB - Traditional mutual information (MI) function aligns two multimodality images with intensity information, lacking spatial information, so that it usually presents many local maxima that can lead to inaccurate registration. Our paper proposes an algorithm of adaptive combination of intensity and gradient field mutual information (ACMI). Gradient code maps (GCM) are constructed by coding gradient field information of corresponding original images. The gradient field MI, calculated from GCMs, can provide complementary properties to intensity MI. ACMI combines intensity MI and gradient field MI with a nonlinear weight function, which can automatically adjust the proportion between two types MI in combination to improve registration. Experimental results demonstrate that ACMI outperforms the traditional MI and it is much less sensitive to reduced resolution or overlap of images. PMID- 17710256 TI - Investigation of Poor Academic Achievement in Children with Duchenne Muscular Dystrophy. AB - Duchenne Muscular Dystrophy (DMD) is a neurogenetic developmental disorder that presents with progressive muscular weakness. It is caused by a mutation in a gene that results in the absence of specific products that normally localize to muscle cells and the central nervous system (CNS). The majority of affected individuals have IQs within the normal range, generally with lower verbal than performance IQ scores. Prior work has demonstrated selective deficits on tests of verbal span and immediate memory. For the current study, 26 boys with DMD (and normal intellectual function) and their unaffected siblings were evaluated. Paired comparisons demonstrated that the children with DMD had significantly poorer academic achievement scores than their siblings, even though their vocabulary levels and home and educational environments were comparable. Children with DMD also had more behavioral concerns, physical disabilities, and poorer verbal memory spans. Linear regression indicated that behavioral concerns, executive function, and physical disability did not contribute substantially to academic performance, whereas performance on verbal span did. DMD presents with a selective developmental aberration in verbal span that has wide-ranging consequences on learning skills. PMID- 17710257 TI - Needle-like morphology of H2K4b polyplexes associated with increases in transfection in vitro. AB - SUMMARY: Several synthetic histidine-lysine (HK) polymers have been screened for their efficacy as carriers of nucleic acids in vitro. One branched HK polymer, H2K4b (and its derivatives), has been particularly effective as an in vitro carrier of plasmids. In this study, we investigated whether various salt conditions during formation of the H2K4b/plasmid DNA polyplex affected transfection. We compared the transfection ability of H2K4b polyplexes prepared under three conditions: 1) water, 2) water and then Opti-MEM (or 300 mM NaCl), or 3) Opti-MEM (or 150 mM NaCl). The milieu in which the H2K4b polyplexes were prepared significantly affected in vitro transfection, and conditions that resulted in highest to lowest transfection levels were as follows: water and then Opti-MEM > Opti-MEM (or 150 mM NaCl)>> water. Several biophysical properties (size and shape of polyplex, surface charge, stability) were examined for their correlation with the level of transfection by the HK carrier. Strikingly, electron micrographs showed that HK polyplexes, first formed in water and then in salt, had a needle-like morphology with a mean length of 170 nm and a width of 53 nm; these needle-like polyplexes were observed intracellularly and absorbed to the cell surface, which was in marked contrast to the spherical HK polyplexes formed in water or in Opti-MEM. Notably, these needle-like HK polyplexes entered the cell through clathrin-mediated endocytosis, in contrast to spherical polyplexes, which entered primarily through non clathrin-mediated endocytosis. PMID- 17710258 TI - Cellular impedance biosensors for drug screening and toxin detection. AB - Cell-based impedance biosensing is an emerging technology that can be used to non invasively and instantaneously detect and analyze cell responses to chemical and biological agents. This article highlights the fabrication and measurement technologies of cell impedance sensors, and their application in toxin detection and anti-cancer drug screening. We start with an introduction that describes the capability and advantages of cell-based sensors over conventional sensing technology, followed by a discussion of the influence of cell adhesion, spreading and viability during cell patterning on the subsequent impedance measurements and sensing applications. We then present an electronic circuit that models the cell electrode system, by which the cellular changes can be detected in terms of impedance changes of the circuit. Finally, we discuss the current status on using cell impedance sensors for toxin detection and anti-cancer drug screening. PMID- 17710259 TI - Review of applications of high-field asymmetric waveform ion mobility spectrometry (FAIMS) and differential mobility spectrometry (DMS). AB - High-Field Asymmetric Waveform Ion Mobility Spectrometry (FAIMS) and Differential Mobility Spectrometry (DMS) harness differences in ion mobility in low and high electric fields to achieve a gas-phase separation of ions at atmospheric pressure. This separation is orthogonal to either chromatographic or mass spectrometric separation, thereby increasing the selectivity and specificity of analysis. The orthogonality of separation, which in some cases may obviate chromatographic separation, can be used to differentiate isomers, to reduce background, to resolve isobaric species, and to improve signal-to-noise ratios by selective ion transmission. This review will focus on the applications of these techniques to the separation of various classes of analytes, including chemical weapons, explosives, biologically active molecules, pharmaceuticals and pollutants. These papers cover the period up to January 2007. PMID- 17710260 TI - Protein-nanoparticle labelling probed by surface enhanced resonance Raman spectroscopy. AB - A benzotriazole dye has been attached to a heme protein via a Michael addition and the unique potential of surface enhanced resonance Raman scattering (SERRS) to provide informative in situ recognition of more than one label on one protein demonstrated. PMID- 17710261 TI - Rapid analysis of metabolites and drugs of abuse from urine samples by desorption electrospray ionization-mass spectrometry. AB - Urine samples obtained from drug abusers were screened for drugs of abuse and their metabolites using DESI-MS and the results obtained were compared to results obtained from GC-MS experiments. The detected analyte classes included amphetamines, opiates, cannabinoids and benzodiazepines. The compounds detected were codeine, morphine, oxymorphone, 11-nor-9-carboxy-Delta(9) tetrahydrocannabinol, Delta(9)-tetrahydrocannabinol, alprazolam, temazepam, oxazepam, N-desmethyldiazepam (nordiazepam) and hydroxytemazepam. Identities of all the analytes were confirmed by tandem mass spectrometry, matching MS/MS spectra with authentic standard compounds. The concentrations of the analytes in the samples were obtained from semi-quantitative GC-MS studies and were in the range of 270-22,000 ng mL(-1). The analytes could be detected by DESI even after a hundred-fold dilution indicating that the sensitivity of DESI was more than adequate for this study. Selectivity in the DESI-MS measurements for different kinds of analytes could be increased further by optimizing the spray solvent composition: the use of an entirely aqueous solvent enhanced the signal of polar analytes, such as the benzodiazepines, whereas the use of a spray solvent with a high organic content increased the signal of less polar analytes, such as codeine and morphine. PMID- 17710262 TI - Carbon nanotube-modified microelectrodes for simultaneous detection of dopamine and serotonin in vivo. AB - Dopamine and serotonin are important neurotransmitters that interact in the brain. While dopamine is easily detected with electrochemical sensors, the detection of serotonin is more difficult because reactive species formed after oxidation can adsorb to the electrode, reducing sensitivity. Carbon nanotube treatments of electrodes have been used to increase the sensitivity, promote electron transfer, and reduce fouling. Most methods have focused on nanotube coatings of large electrodes and slower electrochemical techniques that are not conducive to measurements in vivo. In this study, we investigated carbon-fiber microelectrodes modified with single-walled carbon nanotubes for the co-detection of dopamine and serotonin in vivo. Using fast-scan cyclic voltammetry, S/N ratios for the neurotransmitters increased after nanotube coating. Electrocatalytic effects of nanotubes were not apparent at fast scan rates but faster kinetics were observed with slower scanning. Nanotube-modified microelectrodes showed significantly less fouling after exposure to serotonin than bare electrodes. The nanotube-modified electrodes were used to monitor stimulated dopamine and serotonin changes simultaneously in the striatum of anesthetized rat after administration of a serotonin synthetic precursor. These studies show that nanotube-coated microelectrodes can be used with fast scanning techniques and are advantageous for in vivo measurements of neurotransmitters because of their greater sensitivity and resistance to fouling. PMID- 17710263 TI - Multiplexed detection of ions and mRNA expression in single living cells. AB - In order to push forward into new areas of medical and biological research, new techniques must be developed that will enable a complex investigation into cellular processes. This involves investigating not only the different expression levels inside of a cell but also the ability to analyze how those expression levels are connected to one another. In order to accomplish this level of exploration, different types of analytes must be investigated simultaneously inside of single cells, thereby allowing their expression levels to be directly compared. To accomplish this, we have developed a method of detecting and monitoring mRNA expression levels and ion concentrations simultaneously inside of the same single cell. We have utilized this technique in studying the effects of an anti-cancer agent on human breast carcinoma cells. Using this approach, we are able to shed light onto the complex connections between genes and ions inside the cell that is not possible with any other existing technique. PMID- 17710264 TI - An on-chip cardiomyocyte cell network assay for stable drug screening regarding community effect of cell network size. AB - We investigate the effect of haloperidol on a four-cell and nine-cell cardiomyocyte network on an agarose microchamber array chip to evaluate a cell based model for drug screening. Using a network of cardiomyocytes whose beating intervals were stable and relatively uniform (they only fluctuated 10% from the mean beating interval), we easily observed the effect of haloperidol on the cell network beating interval 5 min after administering it. We also observed the beating interval returned to its original state 10 min after the haloperidol was washed out of the chip. Although the four-cell network showed the unstable recovery of its beating rhythm after washout of haloperidol, the nine-cell network recovered completely to the stable original beating rhythm even after a second administration of haloperidol. The results indicate the importance of the community size in cell networks used in the stable cell-based screening model. Moreover, they indicate the advantage of using direct cell-based measurements in which the amount of drug administered and the time course over which it is administered are strictly controlled for evaluating the quantitative chemical effects of drugs on cells. PMID- 17710265 TI - Subsurface probing of calcifications with spatially offset Raman spectroscopy (SORS): future possibilities for the diagnosis of breast cancer. AB - Breast calcifications are often the only mammographic features indicating the presence of a cancerous lesion. Calcium oxalate (type I) may be found in and around benign lesions, however calcium hydroxyapatite (type II) is usually found within proliferative lesions, which can include both benign and malignant pathologies. However, the composition of type II calcifications has been demonstrated to vary between benign and malignant proliferative lesions, and could be an indicator for the possible disease state. Raman spectroscopy has previously been demonstrated as a powerful tool for non-destructive analysis of tissues, utilising laser light to probe chemical composition. Raman spectroscopy is traditionally a surface technique. However, we have recently developed methods that permit its application for obtaining sample composition to clinically relevant depths of many mm. We report the first demonstration of spatially offset Raman spectroscopy (SORS) for potential in vivo breast analysis. This study evaluates the possibility of utilising SORS for measuring calcification composition through varying thicknesses of tissues (2 to 10 mm), which is about one to two orders of magnitude deeper than has been possible with conventional Raman approaches. SORS can be used to distinguish non-invasively between calcification types I and II (and carbonate substitution of phosphate in calcium hydroxyapatite) within tissue of up to 10 mm deep. This result secures the first step in taking this technique forward for clinical applications seeking to use Raman spectroscopy as an adjunct to mammography for early diagnosis of breast cancer, by utilising both soft tissue and calcification signals. Non-invasive elucidation of calcification composition, and hence type, associated with benign or malignant lesions, could eliminate the requirement for biopsy in many patients. PMID- 17710266 TI - An all-solid-state reference electrode based on the layer-by-layer polymer coating. AB - A solid-state reference electrode (SSRE) was fabricated by layering a silicone rubber (SR) film containing KCl on an AgCl surface, then a perfluorinated ionomer film, and finally a polyurethane-based membrane containing an ionophore, a lipophilic ionic additive, and a plasticizer, respectively. The addition of SiCl4 to the polyurethane-based membrane layer enhanced the strength of the membrane in an aqueous solution. The morphologies of the membranes were studied separately by SEM. The fabrication of the Ag/AgCl electrode through this layer-by-layer polymer coating improved the electrode stability enormously. In addition, the potential drift of the SSRE according to the pH of the medium was minimized by introducing a H+-ion-selective ionophore (tridodecylamine; TDDA) into the outmost polymer membrane. The cyclic voltammetric and potentiometric responses using the SSRE and a conventional reference electrode, respectively, were consistent. The SSRE exhibited little potential variation even in the case of the addition of very high concentrations of various salts, such as Na salicylate, LiCl, KCl, CaCl2, MgCl2, KNO3, NaCl, and NaHCO3. The practicability of the proposed SSRE was tested for the determination of blood pH and pCO2 in a flow cell system. The SSRE fabricated in the present study was stable over two years. PMID- 17710267 TI - Serial processing of biological reactions using flow-through microfluidic devices: coupled PCR/LDR for the detection of low-abundant DNA point mutations. AB - We have fabricated a flow-through biochip consisting of passive elements for the analysis of single base mutations in genomic DNA using polycarbonate (PC) as the substrate. The biochip was configured to carry out two processing steps on the input sample, a primary polymerase chain reaction (PCR) followed by an allele specific ligation detection reaction (LDR) for scoring the presence of low abundant point mutations in genomic DNA. The operation of the device was demonstrated by detecting single nucleotide polymorphisms in gene fragments (K ras) that carry high diagnostic value for colorectal cancers. The effect of carryover from the primary PCR on the subsequent LDR was investigated in terms of LDR yield and fidelity. We found that a post-PCR treatment step prior to the LDR phase of the assay was not essential. As a consequence, a thermal cycling microchip was used for a sequential PCR/LDR in a simple continuous-flow format, in which the following three steps were carried out: (1) exponential amplification of the gene fragments from genomic DNA; (2) mixing of the resultant PCR product(s) with an LDR cocktail via a Y-shaped passive micromixer; and (3) ligation of two primers (discriminating primer that carried the complement base to the mutation locus being interrogated and a common primer) only when the particular mutation was present in the genomic DNA. We successfully demonstrated the ability to detect one mutant DNA in 1000 normal sequences with the integrated microfluidic system. The PCR/LDR assay using the microchip performed the entire assay at a relatively fast processing speed: 18.7 min for 30 rounds of PCR, 4.1 min for 13 rounds of LDR (total processing time = ca. 22.8 min) and could screen multiple mutations simultaneously in a multiplexed format. In addition, the low cost of the biochip due to the fact that it was fabricated from polymers using replication technologies and consisted of passive elements makes the platform amenable to clinical diagnostics, where one-time use devices are required to eliminate false positives resulting from carryover contamination. PMID- 17710268 TI - A novel calibration procedure for trace analytical measurements: application to the analysis of polybrominated diphenyl ethers by GC-MS. AB - The measurement of polybrominated diphenyl ethers (PBDEs) by gas chromatography mass spectrometry (GC-MS) is highly challenging due to existence of the analytes at trace levels and the instability of the higher molecular weight PBDEs. These properties make accurate analysis especially problematic when utilising a low resolution 'bench-top' GC-electron impact (EI) mass spectrometer. We discuss the problems associated with the analyses of PBDEs on these common GC-EI-MS systems and present a novel approach to calibration in these circumstances. We propose that this 'mixed calibration procedure' allows analyses to be performed that would not be possible using traditional calibration techniques, and that the procedure may be applied to a wide range of applications throughout analytical science. PMID- 17710269 TI - Engineering of efficient phosphorescent iridium cationic complex for developing oxygen-sensitive polymeric and nanostructured films. AB - In this study, a novel phosphorescent Ir(III) complex [Ir(2-phenylpyridine)2(4,4' bis(2-(4-N,N-methylhexylaminophenyl)ethyl)-2-2'-bipyridine)Cl] (for convenience, the complex was given the synonym N-948) has been designed and synthesized, to be used as an oxygen probe. It was characterized by spectroscopic and analytical methods when incorporated in a polystyrene and nanostructured metal oxide support. N-948 is the first Ir complex in the literature with a luminescence emission at a wavelength higher than 650 nm (665 nm), with a quantum yield higher than 0.50 (0.58 +/- 0.05) and an extremely long phosphorescence lifetime (102 micros) which has been used for developing oxygen-sensitive films. In addition, the new complex shows a Stern-Volmer constant which is 20 times higher than that of other Ir complexes known from the literature when they are immobilized in polystyrene. The sensing film shows long-term stability (up to 12 months), complete reversibility of the signal quenched by oxygen and a quick response time to various oxygen concentrations (<2 s changing from 10 vol% pO2 to 90 vol% pO2). Thus, it is an interesting and promising complex for developing oxygen-selective sensors for gas analysis and the analysis of dissolved oxygen. PMID- 17710270 TI - [Evaluation of the medication dispensation system in the Tijuana General Hospital]. PMID- 17710271 TI - [Arterial pressure levels in elderly ambulatory patients]. PMID- 17710272 TI - [Mexican women with breast cancer show a high prevalence of depression and anxiety]. PMID- 17710273 TI - Streptococcus pneumoniae isolates in healthy children attending day-care centers in 12 states in Mexico. AB - OBJECTIVE: The aim of this study was to determine the prevalence of asymptomatic nasopharyngeal carriage of Streptococcus pneumoniae, which is a major factor in the transmission of this bacterium. MATERIAL AND METHODS: Nasopharyngeal cultures were performed on children attending 32 day-care centers in 12 states in Mexico. RESULTS: Streptococcus pneumoniae was isolated from the nasopharynx of 829 out of 2,777(29.9%) subjects aged two months to six years. All children lived in urban areas and 80% spent more than six hours daily in a day-care center. Streptococcus pneumoniae serotypes most frequently identified were: 19F (23%), 6B (15.6%), 23F (11.2%) and 6A (14.9%). Thirty-six percent of the isolates were susceptible to penicillin. CONCLUSIONS: Serotype distribution suggests the possible benefits that could be obtained from the heptavalent pneumococcal conjugate vaccine. PMID- 17710274 TI - [Validity and reliability of the screening questionnaire for geriatric depression used in the Mexican Health and Age Study]. AB - OBJECTIVE: To assess the validity and reliability of a geriatric depression questionnaire used in the Mexican Health and Age Study (MHAS). METHODS: The study was conducted at the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMNSZ) clinic from May 2005 to March 2006. This depression screening nine-item questionnaire was validated using the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (fourth revised version) and Yesavage's 15-item Geriatric Depression Scale (GDS-15) criteria. The instrument belongs to the MHAS, a prospective panel study of health and aging in Mexico. RESULTS: A total of 199 subjects 65 years of age and older participated in the validation process (median age= 79.5 years). MHAS questionnaire result was significantly correlated to the clinical depression diagnosis (p<0.001) and to the GDS-15 score (p<0.001). Internal consistency was adequate (alpha coefficient: 0.74). The cutoff point > or = 5/9 points yielded an 80.7% and 68.7% sensitivity and specificity respectively. The fidelity for the test retest was excellent (intra-class correlation coefficient= 0.933). Finally, the Bland and Altman agreement points indicated a difference 0.22 percent points between test retest. CONCLUSION: The MHAS questionnaire is valid and trustworthy, and allows screening in the research field for the presence of depression in the elderly. PMID- 17710275 TI - [Dietary patterns in Mexican adolescent girls. A comparison of two methods. National Nutrition Survey, 1999]. AB - OBJECTIVE: To identify dietary patterns in Mexican female adolescents by two statistic methods. MATERIAL AND METHODS: Cross-sectional study of 477 women 12 to 19 years of age -National Nutrition Survey, 1999. Dietary patterns were obtained by factor and cluster analyses. RESULTS: Three dietary patterns were identified by cluster analysis: "Urban-poor" [U] (9.7%), "Rural" [R] (47.9%), and "Western" [W] (42.3%). Pattern [U] was characterized by a sizeable intake of maize products (20%) and industrialized foods (17%). Maize products and legumes predominated in the [R] pattern (48% and 6% of total energy, respectively). In the [W] pattern, wheat products and meat contributed 19% and 10.6% of energy, respectively. Moreover, four dietary patterns were identified through factor analysis. Factor 1 had a positive loading factor on wheat products, desserts, and meat. Factor 2 was characterized by a high consumption of low-fat dairy and low-fiber breakfast cereals. Factor 3 had a high loading for sweetened beverages and industrialized foods. Factor 4 had a moderate loading on maize products and legumes. CONCLUSION: We identified dietary patterns in Mexican adolescent girls by two methods, obtaining comparable results between methods. PMID- 17710276 TI - [Obesity, body morphology, and blood pressure in urban and rural population groups of Yucatan]. AB - OBJECTIVE: To characterize body morphology and blood pressure of adults of the Mexican state of Yucatan. MATERIAL AND METHODS: Rural-urban differences in weight, height, waist, and hip circumferences, and blood pressure were analyzed in 313 urban and 271 rural subjects. RESULTS: No rural-urban differences in prevalence of obesity and overweight were found. Hypertension was marginally higher in urban subjects. Rural abnormal waist circumference was higher in young men and young women. Comparison with two national surveys and a survey in the aboriginal population (rural mixtecos) showed similar prevalence of obesity as ENSA-2000 and higher than mixtecos and ENEC-1993. Abnormal waist circumference was intermediate between ENSANUT-2006 and mixtecos and hypertension was intermediate between ENEC and mixtecos. CONCLUSION: The Maya and mestizo population of Yucatan showed a high prevalence of obesity and abnormal waist circumference not accompanied by a comparable higher hypertension frequency. This finding requires further confirmation. PMID- 17710277 TI - [Household care for ill and disabled persons: challenges for the Mexican health care system]. AB - OBJECTIVE: To identify the pattern of time devoted by members of Mexican households to providing care to ill and disabled family members. To analyze the mechanisms used by families to provide care to an ill or disabled member. MATERIAL AND METHODS: The database of the 2002 National Survey of Time Use was explored to accomplish the first objective. The second objective was accomplished by collecting primary data through in-depth interviews and focal groups in Coahuila, Sinaloa, Zacatecas, Jalisco, Oaxaca and Yucatan from June to December 2004. RESULTS: It was estimated that 1,738,756 persons spent time providing care to ill persons and 1,496,616 to disabled persons, over the reference period of the survey. There are important differences in the dedication of hours by gender and education level. Moreover, households tend to reorganize their structure to provide care to ill and disabled members. Women tend to have more responsibilities in the process. There are important differences in the care of ill and of the disabled in terms of the physical and emotional stress produced in the caregiver. CONCLUSIONS: The implications of results in the care of ill and disabled populations are highly relevant for the future of the Mexican health care system. Population aging and the increase of chronic diseases call for a reinforced relationship between institutional and household care so as to complement capacities, a situation already taking place in other countries. PMID- 17710278 TI - [Domestic water hardness and prevalence of atopic eczema in Castellon (Spain) school children]. AB - Water hardness has been associated with atopic eczema (AE) prevalence in two epidemiologic studies carried out on schoolchildren in England and Japan. OBJECTIVE: To estimate the association between the prevalence of AE and domestic water hardness. METHODS: The prevalence of AE was obtained from The International Study of Asthma and Allergies in Childhood, carried out in six towns in the province of Castellon on schoolchildren 6-7 and 13-14 years of age, using a standard questionnaire in 2002. Three zones were defined according to domestic water hardness of the six study localities: <200 mg/l, 200-250 mg/l, and >300 mg/l. A logistic regression analysis was performed. RESULTS: The lifetime prevalence of AE in schoolchildren 6-7 years of age was higher with the increment of water hardness, 28.6, 30.5 and 36.5% respectively for each zone; between zone 1 and zone 3, the adjusted odds ratios (ORa) were 1.58 (95% Confidence Intervals [CI] 1.04-2.39) (adjusted tendency test p=0.034). Prevalence of symptoms of AE within the past year were 4.7, 4.5, and 10.4%, respectively by zone; between zone 1 and zone 3, the ORa was 2.29 (95% CI 1.19-4.42) (adjusted tendency test p=0,163). For 13-14 year-old schoolchildren, tendencies to lifetime prevalence of AE at any time or in the past year were not significant. CONCLUSIONS: This study suggests that in 6-7 year-old schoolchildren, water hardness in the area where they live has some relevance to the development of the disease. PMID- 17710279 TI - [Susceptibility and insecticide resistance mechanisms in Anopheles albimanus from the southern Yucatan Peninsula, Mexico]. AB - OBJECTIVE: To diagnose susceptibility levels and insecticide resistance mechanisms in Anopheles albimanus from the southern Yucatan Peninsula (YP), Mexico. MATERIAL AND METHODS: F1 generation of An. albimanus females, collected from November to December 2005 in six villages in the Othon P. Blanco municipality in Quintana Roo and the Calakmul municipality in Campeche, were exposed to deltamethrin, DDT, pirimiphos-methyl and bendiocarb in susceptibility tests, as well as to biochemical assays in order to calculate the enzyme levels related to insecticide resistance. RESULTS: High levels of DDT and deltamethrin resistance were found in An. albimanus collected from the six villages, and a high resistance to pirimiphos-methyl was found in those from La Union, Quintana Roo. Biochemical assays showed high levels of glutathione S-transferase (GST), cytochrome P450 and esterases (with pNPA substrate) in all villages. The frequency of An. albimanus with altered acetylcholinesterase (AChE) was high in La Union (33%). CONCLUSIONS: The An. albimanus populations collected in the south of the YP are resistant to DDT and deltamethrin, whereas resistance to pirimiphos methyl was significant only in those collected from La Union. The mechanisms explaining this resistance are based on high concentrations of GST, cytochrome P450 and esterasas, the former being responsible for DDT metabolism and the others for pyrethroid metabolism. The altered AChE was the mechanism correlated to pirimiphos-methyl resistance in La Union. The results of the present study have important practical consequences for the chemical control of An. albimanus in the south of the YP. PMID- 17710280 TI - [Evaluation of the exposure to selenium in Los Altos de Jalisco, Mexico]. AB - OBJECTIVE: To evaluate the exposure to selenium in drinking water in Los Altos de Jalisco (Jalisco State Heights). MATERIALS AND METHODS: The concentration of selenium was determined in 125 water wells, and the exposure doses to selenium were estimated for babies, children and adults. RESULTS: The estimated values of the exposure doses to selenium and total intake of selenium were in the following ranges, respectively: (a) babies: 1.3-6.7 microg/kg/d and 12.6-67.2 microg/d; (b) children: 0.8-4.5 microg/kg/d and 16.8-89.6 microg/d, (c) adults: 0.6-3.0 microg/kg/d and 33.6-179.2 microg/d. CONCLUSIONS: The estimated exposure levels to selenium were higher than those recommended as optimum by international health organizations, representing a potential health risk. Nevertheless, estimated values are not high enough to produce selenosis. PMID- 17710281 TI - Review of health research on indigenous populations in Latin America, 1995-2004. AB - OBJECTIVE: To review health research conducted among indigenous populations in Latin America during the period 1995-2004. Material and methods. The search strategy was purposely broad to ensure the identification of all relevant studies indexed in the PubMed and Lilacs databases. RESULTS: Six-hundred ninety citations were included. One hundred fifty-nine (23.0%) papers dealt with indigenous populations in Central America and 509 (73.8%) papers with South American populations. Three hundred two (43.8%) of the studies were quantitative, 39 (5.7%) qualitative, 259 (37.5%) mainly based on laboratory work and 24 (3.5%) dealt with policy analyses. The most common researched theme was human biology with 200 (29.0 %) papers, followed by communicable diseases (150 papers, 21.7 %). CONCLUSIONS: There is a special need for policy studies in the field of indigenous health. An increased commitment to resources and capacity building will be the real challenge for indigenous health research in the nearest future. PMID- 17710283 TI - Prevalence and severity of dental fluorosis among students from Joao Pessoa, PB, Brazil. AB - The aim of this study was to determine the prevalence and severity of dental fluorosis among 12-15-year-old students from Joao Pessoa, PB, Brazil before starting a program of artificial fluoridation of drinking water. The use of fluoridated dentifrice was also surveyed. A sample of 1,402 students was randomly selected. However, 31 students refused to participate and 257 were not permanent residents in Joao Pessoa, thus leaving a final sample of 1,114 students. Clinical exams were carried out by two calibrated dentists (Kappa = 0.78) under natural indirect light. Upper and lower front teeth were cleaned with gauze and dried, and then examined using the TF index for fluorosis. A questionnaire on dentifrice ingestion and oral hygiene habits was applied to the students. The results revealed that fluorosis prevalence in this age group was higher than expected (29.2%). Most fluorosis cases were TF = 1 (66.8%), and the most severe cases were TF = 4 (2.2%). The majority of the students reported that they had been using fluoridated dentifrices since childhood; 95% of the participants preferred brands with a 1,500 ppm F concentration, and 40% remembered that they usually ingested or still ingest dentifrice during brushing. It was concluded that dental fluorosis prevalence among students in Joao Pessoa is higher than expected for an area with non-fluoridated water. However, although most students use fluoridated dentifrices, and almost half ingest slurry while brushing, the majority of cases had little aesthetic relevance from the professionals' point of view, thus suggesting that fluorosis is not a public health problem in the locality. PMID- 17710284 TI - Compressive strength of glass ionomer cements using different specimen dimensions. AB - The purpose of this study was to evaluate the compressive strength of two glass ionomer cements, a conventional one (Vitro Fil - DFL) and a resin-modified material (Vitro Fil LC - DFL), using two test specimen dimensions: One with 6 mm in height and 4 mm in diameter and the other with 12 mm in height and 6 mm in diameter, according to the ISO 7489:1986 specification and the ANSI/ADA Specification No. 66 for Dental Glass Ionomer Cement, respectively. Ten specimens were fabricated with each material and for each size, in a total of 40 specimens. They were stored in distilled water for 24 hours and then subjected to a compressive strength test in a universal testing machine (EMIC), at a crosshead speed of 0.5 mm/min. The data were statistically analyzed using the Kruskal Wallis test (5%). Mean compressive strength values (MPa) were: 54.00 +/- 6.6 and 105.10 +/- 17.3 for the 12 mm x 6 mm sample using Vitro Fil and Vitro Fil LC, respectively, and 46.00 +/- 3.8 and 91.10 +/- 8.2 for the 6 mm x 4 mm sample using Vitro Fil and Vitro Fil LC, respectively. The resin-modified glass ionomer cement obtained the best results, irrespective of specimen dimensions. For both glass ionomer materials, the 12 mm x 6 mm matrix led to higher compressive strength results than the 6 mm x 4 mm matrix. A higher variability in results was observed when the glass ionomer cements were used in the larger matrices. PMID- 17710285 TI - Electrochemical behavior and pH stability of artificial salivas for corrosion tests. AB - It is assumed that the compositions of artificial salivas are similar to that of human saliva. However, the use of solutions with different compositions in in vitro corrosion studies can lead dissimilar electrolytes to exhibit dissimilar corrosivity and electrochemical stability. This study evaluated four artificial salivas as regards pH stability with time, redox potentials and the polarization response of an inert platinum electrode. The tested solutions were: SAGF medium, Mondelli artificial saliva, UFRJ artificial saliva (prepared at the School of Pharmacy, Federal University of Rio de Janeiro, RJ, Brazil) and USP-RP artificial saliva (prepared at the School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, SP, Brazil). It was observed that pH variations were less than 1 unit during a 50-hour test. The SAGF medium, and the UFRJ and USP-RP solutions exhibited more oxidizing characteristics, whereas the Mondelli solution presented reducing properties. Anodic polarization revealed oxidation of the evaluated electrolytes at potentials below +600 mV SCE. It was observed that the UFRJ and USP-RP solutions presented more intense oxidation and reduction processes as compared to the Mondelli and SAGF solutions. PMID- 17710286 TI - Comparison of histometric and morphometric analyses of bone height in ligature induced periodontitis in rats. AB - The purpose of this study was to compare histologic and morphometric procedures of bone height measurement. Microscopic measurements are the most frequent methods in periodontal studies with animals, but have limited capacity to identify bone levels associated with both healthy tissues and periodontal disease. Ligatures were placed in the maxillary left second molars of 10 male 60 day-old Wistar rats for 30 days. Left and right maxillary sides of 5 rats were processed for histologic analysis (H), sectioned buccolingually, and stained with HE. The maxillae of the other 5 rats were defleshed and used for morphometric analysis (M). Histometric measurements from the cementoenamel junction to the bone crest were performed. Standardized photographs were used for morphometric analysis. The t test was used for dependent or independent samples (alpha = 0.05%). Distances from cementoenamel junction to bone crest were 0.95 +/- 0.25 and 1.07 +/- 0.30 mm for H and M, respectively. Buccal measurements were 0.92 +/- 0.16 and 1.08 +/- 0.35 mm for H and M. The values obtained using H and M for areas without ligatures were 0.44 +/- 0.15 and 0.47 +/- 0.11 mm for lingual measurements and 0.23 +/- 0.08 and 0.41 +/- 0.10 mm for buccal measurements. No significant differences were found between the two methods in the detection of bone height associated with the placement of ligatures in rats. PMID- 17710287 TI - Effects of fibrin sealer and resorbable gelatin on the repair of osseous defects in rat tibia. AB - Gelfoam - a biologically resorbable gelatin sponge - has the function of restricting hemorrhage, providing platelet rupture, and supporting fibrin threads. Beriplast - a fibrinogen-thrombin compound - is used to adhere tissues, to consolidate sutures and in hemostasis. The objective of this study was to perform a histological analysis of the effects of haemostatic agents on osseous repair. These materials were inserted into surgical sites in young rat right and left tibiae. After the observation periods of 7, 14, 30 and 45 days, according to the bioethic protocol, the animals were killed, the tibiae were removed and fixed in 10% formalin and decalcified in equal parts of formic acid and sodium citrate solutions. After routine processing, the specimens were embedded in paraffin for microtomy. Analysis of the results demonstrated that the haemostatic agents are effective in controlling hemorrhage; they stimulate osteogenesis, featuring a pattern of osseous tissue formation similar to the control pattern, although the amount of osseous trabeculae was superior, especially in the Gelfoam group in the periods of 7 and 14 days; 30 days after surgery, the delay in tissue healing in the control group in relation to the experimental groups started to decrease, and the control and experimental groups exhibited similar tissue repair after 45 days, when all the groups exhibited secondary osseous tissue. PMID- 17710289 TI - Fluoride intake from regular and low fluoride dentifrices by 2-3-year-old children: influence of the dentifrice flavor. AB - This study evaluated the fluoride intake from dentifrices with different fluoride concentrations ([F]) by children aged 24-36 months, as well as the influence of the dentifrice flavor in the amount of fluoride ingested during toothbrushing. Thirty-three children were randomly divided into 3 groups, according to the [F] in the dentifrices: G-A (523 microgF/g), G-B (1,062 microgF/g) and G-C (1,373 microgF/g). Dentifrices A and B are marketed for children, while dentifrice C is a regular product. The amount of F ingested was indirectly obtained, subtracting the amount expelled and the amount left on the toothbrush from the amount initially loaded onto the brush. The results were analyzed by ANOVA, Tukey's test and linear regression analysis (p < 0.05). Children ingested around 60% of the dentifrice loaded onto the brush, but no significant differences were seen among the groups (p > 0.05). Mean daily fluoride intake from dentifrice for G-A, G-B and G-C was 0.022(a) feminine, 0.032(a) feminine and 0.061(b) mg F/kg body weight, respectively (p < 0.01). There was a strong positive correlation (r = 0.86, p < 0.0001) between the amount of dentifrice used and the amount of fluoride ingested during toothbrushing. The results indicate the need for instructing children's parents and care givers to use a small amount of dentifrice (< 0.3 g) to avoid excessive ingestion of fluoride. The use of low-[F] dentifrices by children younger than 6 years also seems to be a good alternative to minimize fluoride intake. Dentifrice flavor did not influence the percentage of fluoride intake. PMID- 17710288 TI - Anticariogenic effect of fluoride-releasing elastomers in orthodontic patients. AB - This in vivo experimental study evaluated the efficacy of fluoride-releasing elastomers in the control of Streptococcus mutans levels in the oral cavity. Forty orthodontic patients were recruited and divided into two groups of 20. Fluoride-releasing elastomeric ligature ties (Fluor-I-Ties, Ortho Arch Co. Inc., USA) were used in the experimental group, and conventional elastomeric ligature ties (D. Morelli, Brazil), in the control group. Two initial samples of saliva were collected at a 14-day interval to determine the number of colony forming units (CFU) of Streptococcus mutans. Immediately after collecting the second sample, fluoride-releasing elastomeric ligature ties were placed in the patients of the experimental group, and conventional ligature ties, in the patients of the control group. Seven, 14 and 28 days after placement of the elastomeric ligature ties, saliva and plaque surrounding the orthodontic appliance were collected for microbiologic analysis. There were no significant differences in the number of Streptococcus mutans CFUs in saliva or plaque in the area surrounding the fluoride-releasing or conventional elastomeric ligature ties. Thus, fluoride releasing elastomeric ligature ties should not be indicated to reduce the incidence of enamel decalcification in orthodontic patients. Since there was no significant reduction in S. mutans in saliva or plaque, other means of prevention against enamel decalcification should be indicated for these patients. PMID- 17710290 TI - Effect of enamel matrix proteins on the treatment of intrabony defects: a split mouth randomized controlled trial study. AB - The objective of this split-mouth, double-blind, randomized controlled trial was to compare the clinical effect of treatment of 2- or 3-wall intrabony defects with open flap debridement (OFD) combined or not with enamel matrix proteins (EMP). Thirteen volunteers were selected with one pair of or more intrabony defects and probing pocket depth (PPD) > or = 5 mm. All individuals received instructions regarding oral hygiene and were submitted to scaling and root planing. Each participant received the two treatment modalities: test sites were treated with OFD and EMP, and control sites received only OFD. After 6 months, a significant reduction was observed in PPD for the EMP group (from 6.42 +/- 1.08 mm to 2.67 +/- 1.15 mm) and for the OFD group (from 6.08 +/- 1.00 mm to 2.00 +/- 0.95 mm) (p < 0.0001), but with no significant difference between groups (p = 0.13). A significant gain in relative attachment level (RAL) was observed in both groups (EMP: from 13.42 +/- 1.88 mm to 10.75 +/- 2.26 mm, p < 0.001; OFD: from 12.42 +/- 1.98 mm to 10.58 +/- 2.23 mm, p = 0.013), but with no significant difference between groups (p = 0.85). Gingival recession (GR) was higher in the EMP group (from 1.08 +/- 1.50 mm to 2.33 +/- 1.43 mm; p = 0.0009) than in the OFD group (from 0.66 +/- 1.15 mm to 1.16 +/- 1.33 mm; p = 0.16), but this difference was not significant (p = 0.06). In conclusion, the results showed that OFD combined with EMP was not able to improve treatment of intrabony defects compared to OFD alone. PMID- 17710291 TI - The influence of ovariectomy, simvastatin and sodium alendronate on alveolar bone in rats. AB - Bisphosphonates are currently used in the treatment of many diseases involving increased bone resorption such as osteoporosis. Statins have been widely used for the treatment of hypercholesterolemia and recent studies have shown that these drugs are also capable of stimulating bone formation. The purpose of this study was to evaluate the influence of an estrogen deficient state and the effects of simvastatin and sodium alendronate therapies on alveolar bone in female rats. Fifty-four rats were either ovariectomized (OVX) or sham operated. A month later, the animals began to receive a daily dose of simvastatin (SIN - 25 mg/kg), sodium alendronate (ALN - 2 mg/kg) or water (control) orally. Thirty-five days after the beginning of the treatment, the rats were sacrificed and their left hemimandibles were removed and radiographed using digital X-ray equipment. The alveolar radiographic density under the first molar was determined with gray-level scaling and the values were submitted to analysis of variance (alpha = 5%). Ovariectomized rats gained more weight (mean +/- standard deviation: 20.06 +/- 6.68%) than did the sham operated animals (12.13 +/- 5.63%). Alveolar radiographic density values, expressed as gray levels, were lowest in the OVX water group (183.49 +/- 6.47), and differed significantly from those observed for the groups receiving alendronate (sham-ALN: 193.85 +/- 3.81; OVX-ALN: 196.06 +/- 5.11) and from those of the sham-water group (193.66 +/- 4.36). Other comparisons between groups did not show significant differences. It was concluded that the ovariectomy reduced alveolar bone density and that alendronate was efficient for the treatment of this condition. PMID- 17710292 TI - Evaluation of the apical seal after intraradicular retainer removal with ultrasound or carbide bur. AB - There are situations in which intraradicular retainers have to be removed and replaced. The objective of this research was to evaluate the apical seal after the removal of a custom cast post and core with a carbide bur or with an ultrasound apparatus. Twenty five roots of extracted human incisors were used. They were endodontically treated and prepared to receive the posts. The posts and cores were cast with 2 types of dental alloys, CuAlZn and PdAg, and were cemented with zinc phosphate cement. After 24 hours, they were removed using the two above mentioned techniques. Then, the roots had their external surface made impermeable by two layers of cyanoacrylate adhesive, leaving only the cervical area for dye penetration. The teeth were immersed in rhodamine for 24 hours. They were then cut and observed under an optical microscope and analyzed with appropriate software (Imagelab). The results were submitted to ANOVA, and they evidenced that, regarding the alloy factor, PdAg posts presented a larger mean infiltration value (2.23 +/- 0.48 mm) as compared to the posts made of CuAlZn (1.39 +/- 0.48 mm) (p = 0.025). Regarding the technique factor, there was no significant difference (p = 0.9) between the removal of the intraradicular retainer using ultrasound (1.99 +/- 0.62 mm) or using a rotating cutting instrument (1.62 +/- 0.62 mm). Under these experimental conditions, it was possible to conclude that the degree of apical leakage was directly related to the alloy type, and it was present in both techniques used. PMID- 17710293 TI - Dental age in patients with Down syndrome. AB - The aim of this research was to evaluate dental age in 102 patients with Down Syndrome, using panoramic radiographs. A software program developed by the Discipline of Radiology, School of Dentistry of Sao Jose dos Campos, Sao Paulo State University (UNESP), was used. A table of mineralization chronology of permanent teeth among Brazilians conceived by Nicodemo, Moraes and Medici Filho was used within the software. Statistical analysis of the results showed that 70.91% of the males and 61.21% of the females presented advanced dental age. Only 32.09% of the males and 38.79% of the females presented delayed dental age. Regarding the differences between the dental and chronological ages, two thirds of the males and females presented dental age with differences of up to 12 months, which means that they can be considered to be within normal standards, whereas only 18.87% of the males and 10.21% of the females presented dental age outside normal standards, with differences of over 24 months. In conclusion, the majority of the patients with Down Syndrome were considered to be within the normal standards of mineralization chronology. PMID- 17710294 TI - Evaluation of TMJ articular eminence morphology and disc patterns in patients with disc displacement in MRI. AB - The aim of this study was to assess the shape of the temporomandibular joint (TMJ) articular eminence and the articular disc configuration and position in patients with disc displacement. TMJ magnetic resonance images (MRI) of 14 patients with bilateral disc displacement without unilateral reduction were analyzed. Articular eminence morphology was characterized as box, sigmoid, flattened, or deformed. Articular disc configuration was divided into biconcave, biplanar, biconvex, hemiconvex or folded, and its position, as "a" (superior), "b" (anterosuperior), "c" (anterior) or "d" (anteroinferior). The images were divided and the sides with disc displacement with reduction (DDWR) and without reduction (DDWOR) were compared. Regarding articular eminence shape, the sigmoid form presented the greatest incidence, followed by the box form, in the DDWR side, although this was not statistically significant. In the DDWOR side, the flattened shape was the most frequent (p = 0.041). As to disc configuration, the biconcave shape was found in 79% of the DDWR cases (p = 0.001) and the folded type predominated in 43% of the DDWOR cases (p = 0.008). As to disc position, in the DDWR side, "b" (anterosuperior position) was the most frequent (p = 0.001), whereas in the DDWOR side, "d" (anteroinferior position) was the most often observed (p = 0.001). The side of the patient with altered disc configuration and smaller shape of TMJ articular eminence seems to be more likely to develop non reducing disc displacement as compared to the contralateral side. PMID- 17710295 TI - Evaluation of some oral postradiotherapy sequelae in patients treated for head and neck tumors. AB - The aim of this study was to evaluate the oral sequelae of radiotherapy in patients treated between 1999 and 2003 for head and neck tumors. One-hundred patients (24 women, 76 men) ranging in age from 30 to 83 years (mean 59.2 years) were examined. Time since radiotherapy ranged from 1 to 72 months (mean 28 months). The total mean radiation dose received by the patients was 5,955 cGy. The evaluation protocol included anamnesis, intraoral and extraoral examination, measurement of stimulated salivary flow and salivary pH. Symptoms reported by the patients included dry mouth (68%), dysphagia (38%), and dysgeusia (30%). In 64% of the patients, the mean stimulated salivary flow rate was less than 0.7 ml/min. The mean salivary pH was 6.97 (+/- 0.714). Stimulated salivary flow increased with increasing postradiotherapy time (p < 0.05). The prevalence of mucositis was associated with higher radiation doses (p < 0.05), and the prevalence of atrophic candidiasis was related to a longer post-treatment period (p < 0.05). Two cases of recurrence of the primary tumor were detected during the study. The main effect of radiotheraphy in the head and neck region was a reduction of the salivary flow rate, even though our study demonstrated that there was a modest late improvement of the salivary flow. PMID- 17710297 TI - Polymerase chain reaction with two molecular targets in mucosal leishmaniasis' diagnosis: a validation study. AB - We validated the polymerase chain reaction (PCR) with a composite reference standard in 61 patients clinically suspected of having mucosal leishmaniasis, 36 of which were cases and 25 were non-cases according to this reference standard. Patient classification and test application were carried out independently by two blind observers. One pair of primers was used to amplify a fragment of 120 bp in the conserved region of kDNA and another pair was used to amplify the internal transcript spacers (ITS) rDNA. PCR showed 68.6% (95% CI 59.2-72.6) sensitivity and 92% (95% CI 78.9-97.7) specificity; positive likelihood ratio: 8.6 (95% CI 2.8-31.3) and negative likelihood ratio: 0.3 (95% CI 0.3-0.5), when kDNA molecular target was amplified. The test performed better on sensitivity using this target compared to the ITS rDNA molecular target which showed 40% (95% CI 31.5-42.3) sensitivity and 96% (95% CI 84.1-99.3) specificity; positive likelihood ratio: 10 (95% CI 2.0-58.8) and negative likelihood ratio: 0.6 (95% CI 0.6-0.8). The inter-observer agreement was excellent for both tests. Based upon results obtained and due to low performance of conventional methods for diagnosing mucosal leishmaniasis, we consider PCR with kDNA as molecular target is a useful diagnostic test and the ITS rDNA molecular target is useful when the aim is to identify species. PMID- 17710296 TI - Maximal bite force in young adults with temporomandibular disorders and bruxism. AB - Parafunctional habits, such as bruxism, are contributory factors for temporomandibular disorders (TMD). The aim of this study was to evaluate the maximal bite force (MBF) in the presence of TMD and bruxism (TMDB) in young adults. Twelve women (mean age 21.5 years) and 7 men (mean age 22.4 years), composed the TMDB group. Ten healthy women and 9 men (mean age 21.4 and 22.4 years, respectively) formed the control group. TMD symptoms were evaluated by a structured questionnaire and clinical signs/symptoms were evaluated during clinical examination. A visual analogical scale (VAS) was applied for stress assessment. MBF was measured with a gnatodynamometer. The subjects were asked to bite 2 times with maximal effort, during 5 seconds, with a rest interval of about one minute. The highest values were considered. The data were analyzed with Shapiro-Wilks W-test, descriptive statistics, paired or unpaired t tests or Mann Whitney tests when indicated, and Fisher's exact test (p < 0.05). TMDB women presented lower values of MBF as compared to those presented by TMDB men and by the control group. MBF for TMDB men was similar to that of the control group. The proportion of TMDB women with muscle pain and facial/teeth/head pain upon waking up was significantly higher than that of men. Control women presented significantly lower stress scores than the others. It was concluded that MBF was reduced in TMDB women, as they presented more signs and symptoms. Men presented higher MBF values than women, but TMD and bruxism did not significantly decrease MBF. Stress was not an influencing factor for TMD and bruxism in men. PMID- 17710298 TI - Rotavirus and adenovirus in Rondonia. AB - Acute gastroenteritis is one of the most common diseases in humans worldwide. Viral gastroenteritis is a global problem in infants and young children. In this study the incidence of diarrhea was assessed in 877 hospitalized children under five years old, over a period of 24 months and distributed in 470 cases of diarrhea and 407 age-matched group with other pathologies, as control group. Two antigen detection techniques based on enzyme immunoassay (EIA) and latex particles were used for detection of rotavirus and adenovirus. Rotavirus A was a major cause of gastroenteritis with 23.6% of cases, being 90% of these cases in young children. Adenovirus infections was detected by EIA with frequency of 6.4%. Rotavirus and adenovirus were detected in 10.1 and 1.7% of stools from control group, respectively. Interestingly, the frequency of the youngest children in the control group excreting Rotavirus A was comparable to that detected in stools from diarrheic children. We cannot rule out the existence of other enteric viruses because the etiology of 171 cases of diarrhea was not determined and active search for astrovirus and calicivirus was not done. This is the first study that shows the presence of enteric viruses in the infantile population from Western Brazilian Amazonia and it was important to help physicians in the treatment of viral gastroenteritis. PMID- 17710299 TI - Experimental transmission of the parasitic flagellates Trypanosoma cruzi and Trypanosoma rangeli between triatomine bugs or mice and captive neotropical bats. AB - Trypanosoma cruzi and Trypanosoma rangeli-like trypanosomes have been found in a variety of neotropical bat species. In this study, bats (Artibeus lituratus, Carollia perspicillata, Desmodus rotundus, Glossophaga soricina, Molossus molossus, Phyllostomus hastatus) were maintained under controlled conditions, and experiments were conducted to determine how they might become infected naturally with trypanosomes. All bats were first screened for existing infections by hemoculture and the examination of blood smears, and only apparently uninfected animals were then used in the experiments. Proof was obtained that the triatomine bug Rhodnius prolixus would readily feed upon some of the bats, and two species became infected after being bitten by bugs infected with T. rangeli. Some bats also became infected by ingesting R. prolixus carrying T. cruzi, or following subcutaneous or intragastic inoculation with fecal suspensions of R. prolixus containing T. cruzi. P. hastatus became infected after ingesting mice carrying T. cruzi. All of the bats studied inhabit roosts that may be occupied by triatomine bugs and, with the exception of D. rotundus, all also feed to at least some extent upon insects. These findings provide further evidence of how bats may play significant roles in the epidemiology of T. cruzi and T. rangeli in the New World tropics. PMID- 17710300 TI - More productive in vitro culture of Cryptosporidium parvum for better study of the intra- and extracellular phases. AB - The great difficulties in treating people and animals suffering from cryptosporidiosis have prompted the development of in vitro experimental models. Due to the models of in vitro culture, new extracellular stages of Cryptosporidium have been demonstrated. The development of these extracellular phases depends on the technique of in vitro culture and on the species and genotype of Cryptosporidium used. Here, we undertake the molecular characterization by polymerase chain reaction-restriction fragment length polymorphism of different Cryptosporidium isolates from calves, concluding that all are C. parvum of cattle genotype, although differing in the nucleotide at positions 472 and 498. Using these parasites, modified the in vitro culture technique for HCT-8 cells achieving greater multiplication of parasites. The HCT 8 cell cultures, for which the culture had not been renewed in seven days, were infected with C. parvum sporozoites in RPMI-1640 medium with 10% IFBS, CaCl2 and MgCl2 1 mM at pH 7.2. Percentages of cell parasitism were increased with respect to control cultures (71% at 48 h vs 14.5%), even after two weeks (47% vs 1.9%). Also, the percentage of extracellular stages augmented (25.3% vs 1.1% at 96 h). This new model of in vitro culture of C. parvum will enable easier study of the developmental phases of C. parvum in performing new chemotherapeutic assays. PMID- 17710301 TI - Genetic variability of Aedes aegypti in the Americas using a mitochondrial gene: evidence of multiple introductions. AB - To analyze the genetic relatedness and phylogeographic structure of Aedes aegypti, we collected samples from 36 localities throughout the Americas (Brazil, Peru, Venezuela, Guatemala, US), three from Africa (Guinea, Senegal, Uganda), and three from Asia (Singapore, Cambodia, Tahiti). Amplification and sequencing of a fragment of the mitochondrial NADH dehydrogenase subunit 4 gene identified 20 distinct haplotypes, of which 14 are exclusive to the Americas, four to African/Asian countries, one is common to the Americas and Africa, and one to the Americas and Asia. Nested clade analysis (NCA), pairwise distribution, statistical parsimony, and maximum parsimony analyses were used to infer evolutionary and historic processes, and to estimate phylogenetic relationships among haplotypes. Two clusters were found in all the analyses. Haplotypes clustered in the two clades were separated by eight mutational steps. Phylogeographic structure detected by the NCA was consistent with distant colonization within one clade and fragmentation followed by range expansion via long distance dispersal in the other. Three percent of nucleotide divergence between these two clades is suggestive of a gene pool division that may support the hypothesis of occurrence of two subspecies of Ae. aegypti in the Americas. PMID- 17710302 TI - Phlebotomine fauna (Diptera: Psychodidae) and species abundance in an endemic area of American cutaneous leishmaniasis in southeastern Minas Gerais, Brazil. AB - This study was undertaken to identify the phlebotomine fauna and species abundance in domiciliary and peridomiciliary (hen-house and guava-tree) environments, on a lake shore, a cultivated area of coffee and banana, and a forested area of Conceicao da Aparecida municipality, southeastern the state of Minas Gerais, to provide information for the control and epidemiological surveillance of leishmaniasis in this area. The captures were carried out monthly between May 2001 and November 2002, with automatic light and Shannon traps. A total of 1444 sand flies were captured, 951 (76.5%) with automatic light traps and 493 (23.5%) with the Shannon trap. Thirteen species were captured, the most frequent being Nyssomyia whitmani (62.7%), Migonemyia migonei (21.4%), Pintomyia fischeri (6.9%), and Evandromyia lenti (3.6%). Species abundance was determined using the automatic light traps installed in the six environments. The most abundant species according to the standardized index of species abundance were Ny. whitmani (1.0) and Mg. migonei (0.82). In view of the dominance of these two species, known vectors of cutaneous leishmaniasis in other Brazilian areas, their participation in the transmission of the disease in this county is suggested. The diversity and evenness indexes in the domicile were the lowest due to the high frequency (83%) of Ny. whitmani. The capture of Lutzomyia longipalpis, rarely recorded in the south-eastern and southern regions of Minas Gerais, is also noteworthy. PMID- 17710303 TI - Ribotyping and virulence markers of Yersinia pseudotuberculosis strains isolated from animals in Brazil. AB - Ribotyping and virulence markers has been used to investigate 68 Yersinia pseudotuberculosis strains of serogroups O:1a and O:3. The strains were isolated from clinical material obtained from healthy and sick animals in the Southern region of Brazil. Ribotypes were identified by double digestion of extracted DNA with the restriction endonucleases SmaI and PstI, separation by electrophoresis and hybridization with a digoxigenin-labeled cDNA probe. The presence of the chromosomal virulence marker genes inv, irp1, irp2, psn, ybtE, ybtP-ybtQ, and ybtX-ybtS, of the IS100 insertion sequence, and of the plasmid gene lcrF was detected by polymerase chain reaction. The strains were grouped into four distinct ribotypes, all of them comprising several strains. Ribotypes 1 and 4 presented distinct profiles, with 57.3% genetic similarity, ribotypes 2 and 3 presented 52.5% genetic similarity, and genetic similarity was 45% between these two groups (1/4 and 2/3). All strains possessed the inv, irp1, and irp2 genes. Additionally, strains of serogroup O:1a carried psn, ybtE, ybtP-ybtQ, ybtX-ybtS, and IS100. As expected lcrF was only detected in strains harboring the virulence plasmid. These data demonstrate the presence of Y. pseudotuberculosis strains harboring genotypic virulence markers in the livestock from Southern Brazil and that the dissemination of these bacteria may occur between herds. PMID- 17710304 TI - Effects of timber harvest on phlebotomine sand flies (Diptera: Psychodidae) in a production forest: abundance of species on tree trunks and prevalence of trypanosomatids. AB - The Amazon forest is being exploited for timber production. The harvest removes trees, used by sand flies as resting sites, and decreases the canopy, used as refuges by some hosts. The present study evaluated the impact of the timber harvest, the abundance of sand flies, and their trypanosomatid infection rates before and after selective logging. The study was accomplished in terra-firme production forest in an area of timber harvest, state of Amazonas, Brazil. Sand fly catches were carried out in three areas: one before and after the timber harvest, and two control areas, a nature preservation area and a previously exploited area. The flies were caught by aspiration on tree trunks. Samples of sand flies were dissected for parasitological examination. In the site that suffered a harvest, a larger number of individuals was caught before the selective extraction of timber, showing significant difference in relation to the number of individuals and their flagellate infection rates after the logging. The other two areas did not show differences among their sand fly populations. This fact is suggestive of a fauna sensitive to the environmental alterations associated with selective logging. PMID- 17710305 TI - Effect of sphingosine and phorbol-12-myristate-13-acetate on the growth and dimethylsulfoxide-induced differentiation in the insect trypanosomatid Herpetomonas samuelpessoai. AB - We investigated the effect of two modulators of protein kinase C, sphingosine and phorbol-12-myristate-13-acetate (PMA), on the growth and dimethylsulfoxide (DMSO) induced differentiation in Herpetomonas samuelpessoai. Sphingosine did not stimulate the transformation of undifferentiated-promastigotes in differentiated paramastigotes. PMA alone or in association with DMSO increased the number of paramastigotes in comparison to control cells. DMSO inhibited the parasite growth (35%) and several unusual morphological features resembling aberrant cell division were observed. Sphingosine did not significantly reduce the growth in contrast to PMA. Collectively, our results demonstrated that the reduction of the proliferation translates in an increase of the differentiation rate in the insect trypanosomatid H. samuelpessoai. PMID- 17710306 TI - The subgenus Migonemyia Galati 1995 (Diptera, Psychodidae, Phlebotominae), with description of a new species Migonemyia vaniae: a review. AB - The capture of a new species of the subgenus Migonemyia Galati, 1995 (Diptera, Psychodidae, Phlebotominae), Migonemyia vaniae sp. nov. in the Ribeira Valley, state of Sao Paulo, Brazil, together with the other two species: Mg. migonei (Franca, 1920) and Mg. rabelloi (Galati & Gomes, 1992) lead us to review this subgenus. The new species was described and illustrated. The genitalia of the two other species were also illustrated and some genital characteristics (number of setae on the gonocoxite tuft, ejaculatory ducts and pump and ducts/pump ratio; and number of setae on the tergite VIII of the females) considered important to differentiate the three species, including five populations of Mg. migonei (from Northeastern, Southeastern, and Southern Brazilian regions and of Peru) were submitted to variance analyses. The Mg. migonei population of Northeastern Brazilian region showed distinct smaller values (P < 0.05) than the other Brazilian populations studied as regarding these characteristics. The capture of both sexes of these three species in sympatry confirms the association between the sexes of Mg. rabelloi, recognised as doubtful when this species was originally described. Identification keys for male and female of the three species are presented. PMID- 17710307 TI - Distribution of dengue vectors in neighborhoods with different urbanization types of Manaus, state of Amazonas, Brazil. AB - Aedes aegypti and Ae. albopictus are vectors of dengue viruses, which cause endemic disease in the city of Manaus, capital of the state of Amazonas, Brazil. More than 53 thousand cases have been registered in this city since the first epidemic in 1998. We evaluated the hypothesis that different ecological conditions result in different patterns of vector infestation in Manaus, by measuring the infestation level in four neighborhoods with different urbanization patterns, during the rainy (April), dry (August), and transitional (November) seasons. Ae. aegypti predominated throughout the study areas and sampling periods, representing 86% of all specimens collected in oviposition traps. High frequencies of houses positive for both species were observed in all studied sites, with Ae. aegypti present in more than 84% of the houses in all seasons. Ae. albopictus, on the other hand, showed more spatial and temporal variation in abundance. We found no association between infestation level and house traits. This study highlights the homogeneity of dengue vector distribution in Manaus. PMID- 17710308 TI - T-cell responses associated with resistance to Leishmania infection in individuals from endemic areas for Leishmania (Viannia) braziliensis. AB - Subclinical or asymptomatic infection is documented in individuals living in endemic areas for leishmaniasis suggesting that the development of an appropriate immune response can control parasite replication and maintain tissue integrity. A low morbidity indicates that intrinsic factors could favor resistance to Leishmania infection. Herein, leishmanial T-cell responses induced in subjects with low susceptibility to leishmaniasis as asymptomatic subjects were compared to those observed in cured cutaneous leishmaniasis (CCL) patients, who controlled the disease after antimonial therapy. All of them have shown maintenance of specific long-term immune responses characterized by expansion of higher proportions of CD4+ as compared to CD8+ Leishmania reactive T-lymphocytes. Asymptomatic subjects had lower indexes of in vitro Leishmania induced lymphoproliferative responses and interferon-gamma (IFN-gamma) production in comparison to CCL patients. On the other hand, interleukin (IL-10) production was much higher in asymptomatics than in CCL, while no differences in IL-5 levels were found. In conclusion, long lived T-cell responses achieved by asymptomatic individuals differed from those who had developed symptomatic leishmaniasis in terms of intensity of lymphocyte activation (proliferation or IFN-gamma) and regulatory mechanisms (IL-10). The absence of the disease in asymptomatics could be explained by their intrinsic ability to create a balance between immunoregulatory (IL-10) and effector cytokines (IFN-gamma), leading to parasite destruction without producing skin tissue damage. The establishment of profiles of cell-mediated immune responses associated with resistance against Leishmania infection is likely to make new inroads into understanding the long-lived immune protection against the disease. PMID- 17710309 TI - Antioxidant activity of twenty five plants from Colombian biodiversity. AB - The antioxidant activity of the crude n-hexane, dichloromethane, and methanol extracts from 25 species belonging to the Asteraceae, Euphorbiaceae, Rubiaceae, and Solanaceae families collected at natural reserves from the Eje Cafetero Ecorregion Colombia, were evaluated by using the spectrophotometric 1,1-diphenyl 2-picrylhydrazyl (DPPH) free radical-scavenging method. The strongest antioxidant activities were showed by the methanol and dichloromethane extracts from the Euphorbiaceae, Alchornea coelophylla (IC50 41.14 mg/l) and Acalypha platyphilla (IC50 111.99 mg/l), respectively. These two species had stronger DPPH radical scavenging activities than hydroquinone (IC50 151.19 mg/l), the positive control. The potential use of Colombian flora for their antioxidant activities is discussed. PMID- 17710310 TI - Early Cretaceous trypanosomatids associated with fossil sand fly larvae in Burmese amber. AB - Early Cretaceous flagellates with characters typical of trypanosomatids were found in the gut of sand fly larvae, as well as in surrounding debris, in Burmese amber. This discovery supports a hypothesis in which free-living trypanosomatids could have been acquired by sand fly larvae in their feeding environment and then carried transtadially into the adult stage. At some point in time, specific genera were introduced into vertebrates, thus establishing a dixenous life cycle. PMID- 17710311 TI - Isolation and identification of bovine tuberculosis in a Brazilian herd (Sao Paulo). AB - Mycobacterium was verified in animals from a Brazilian dairy herd, a total of 42 samples from 30 cows were submitted to culture and the isolated strains were analyzed by two polymerase chain reaction (PCR), the first specific for species belonging to the Mycobacterium complex (MTBC) and the other for differentiating M. tuberculosis from M. bovis. Twenty seven samples (64.3%) from 18 animals (60%) were positive for mycobacteria by culture, including samples from 15 retrofaryngeal lymphnodes (55.5%), 9 prescapular lymphnodes (33.3%), 2 lungs (7.4%), and 1 liver (3.7%). All isolated colonies were confirmed by PCR to contain MTBC organisms, and were identified as M. bovis by the same methodology. PMID- 17710312 TI - First report on the occurrence of Trypanosoma rangeli Tejera, 1920 in the state of Ceara, Brazil, in naturally infected triatomine Rhodnius nasutus Stal, 1859 (Hemiptera, Reduviidae, Triatominae). AB - The aim of this work was to identify and report the occurrence of Trypanosoma rangeli and Trypanosoma cruzi in naturally infected Rhodnius nasutus (Hemiptera, Reduviidae, Triatominae) in the state of Ceara, Brazil. Triatomines feces, salivary glands, and hemolymph were collected for fresh examination, and specific detection of T. rangeli and T. cruzi DNA by polymerase chain reaction was carried out. The specific characterization of these two parasites showed the simultaneous presence of both parasites in two (7.7%) of the 26 positive insects. Our results provide further knowledge on the geographical distribution of T. rangeli in Brazil. PMID- 17710313 TI - Molecular evidence that human immunodeficiency virus type 1 dissemination in a small Brazilian city was already taking place in the early 1990s. AB - We recently performed a molecular epidemiology survey of human immunodeficiency virus type 1 (HIV-1) infection in Miracema, a small city in Southeast Brazil, and found multiple monophyletic clusters, consistent with independent introductions and spread of different viral lineages in the city. Here we apply Bayesian coalescent-based methods to the two largest subtype B clusters and estimate that the most recent common ancestors that gave rise to these two transmission chains were in circulation around 1991-1992. The finding that HIV-1 spread in this Brazilian small city was already taking place at a time Aids was considered a problem restricted to large urban centers may have important public health implications. PMID- 17710314 TI - Ki-67 is expressed in multiplying forms of Schistosoma mansoni, but not in snail host tissues. AB - Ki-67 is a protein expressed in the nucleus of several species during cell division, being absent during the GO resting phase of the cellular cycle. During attempts to disclose mitosis in the so-called " amebocyte-producing organ " in Biomphalaria glabrata infected with Schistosoma mansoni, the parasite multiplying forms appeared strongly marked for Ki-67, while the snail tissues were completely negative. These data are worth registering to complement general data on Ki-67, and to help future studies on the relationship of the parasite and of its intermediate host. PMID- 17710315 TI - Isolation and molecular identification of Leishmania (Viannia) peruviana from naturally infected Lutzomyia peruensis (Diptera: Psychodidae) in the Peruvian Andes. AB - Leishmania (Viannia) peruviana was isolated from 1/75 Lutzomyia peruensis captured during May 2006 in an endemic cutaneous leishmaniasis region of the Peruvian Andes (Chaute, Huarochiri, Lima, Peru). Sand fly gut with promastigotes was inoculated into a hamster and the remaining body was fixed in ethanol. L. (Viannia) sp. was determined by polymerase chain reaction (PCR), and Leishmania species through molecular genotyping by PCR-restriction fragment length polymorphism analyses targeting the genes cpb and hsp70, resulting L. (V.) peruviana. The infected sand fly appeared 15 days after the rains finished, time expected and useful real time data for interventions when transmission is occurring. PMID- 17710316 TI - Comparative study of the nesting behaviour of Tachysphex inconspicuus (Kirby) (Hymenoptera: Crabronidae) in two locations in southeast Brazil. AB - The nesting behaviour of the solitary wasp Tachysphex inconspicuus (Kirby) was comparatively studied based on observations made in two environmentally distinct locations in southeast Brazil: upper portions of two sandy beaches and a dirt road in a forested area. Motor patterns related to nest construction were similar in all observed wasps, but some behavioural features, which were different among the observed wasps in the two environments, seem to be constrained by ecological factors. T. inconspicuus can be behaviourally differentiated from several other species of the genus by the following combination of features: they close the nest temporarily during its provision, do not let the excavated sand to form into a mound in front of the nest entrance, construct unicellular nests, and provision the nest with cockroaches. Moreover, females T. inscospicuus use their hind legs in a peculiar way to manipulate the prey, which allows them to associate the use of the mandibles in prey transport with the possibility of excavating the temporary plug and entering the nest without releasing the prey. Chorisoneura lopesi Albuquerque, C. excelsa Albuquerque & Silva, and unidentified species of Riatia (Blattodea: Blatellidae) were found as prey and Amobia floridensis (Towsend) (Diptera: Sarcophagidae) as parasitoid of T. insconspicuus. PMID- 17710317 TI - [Bee diversity in Tecoma stans (L.) Kunth (Bignoniaceae): importance for pollination and fruit production]. AB - Tecoma stans (L.) Kunth is an exotic plant in Brazil, commonly distributed in urban areas, which is considered an invasive species in crop and pasture areas. In this study, the floral biology and the behavior of bees in flowers of T. stans from three urban areas in southeastern Brazil were investigated. In all study sites, T. stans was an important food resource to the Apoidea to 48 species of bees. Centris tarsata Smith and Exomalopsis fulvofasciata Smith (Hymenoptera: Apidae) were the effective pollinators more abundant, while Scaptotrigona depilis Moure (Hymenoptera: Apidae) was the more frequent robber species. The most part of T. stans visitors (87.5%) exploited exclusively nectar, which varied in sugar concentration depending on the day period and flower phase. In all flower stages, higher averages of nectar concentration (26.4% to 32.7%) occurred from 10 am to 2 pm. The presence of osmophore in the petals and protandry were detected. In two urban areas the number of visitors varied significantly during the day. The greatest abundance of pollinators occurred when pollen availability was higher and flowers showed receptive stigma, which could be contributing to the reproductive success of T. stans. The results indicate that the production of fruits increased in plants that received a higher number of effective pollinators. PMID- 17710318 TI - [Aquatic insects in dune lakes of the central region of the Gulf of Mexico]. AB - The aim of this study is to register the presence of aquatic insects during the rainy and dry seasons, in 15 dune lakes of the Gulf of Mexico's coastal zone. These ecosystems lodge a wealth of 62 families, 60 of them present during the rainy season and 46 during the dry period. At both times Coleoptera is the order with a greater number of families, followed by Diptera. The first one is the most diverse, but Chironomidae (Diptera) is the most abundant, representing 40% of the total number of individuals. We used high rank taxa to quantify the biodiversity based on the principle that a high number of families or genus is supposed to include a greater number of species. There were not significant differences in the alpha diversity within the same lake during the two climatic seasons. The trophic structure is dominated by the detritivorous groups (57% of scrapers, collectors, gatherers, shredders), followed by predators (38%) and herbivores (5%). These numbers indicate that dune lakes have a great amount of organic matter. The results obtained contradict our working hypothesis, thus it was rejected, in summary, because there were no important differences in family composition, abundance of individuals and trophic structure of the lakes between the rainy and dry seasons. PMID- 17710319 TI - Study of the Drosophilidae (Diptera) communities on Atlantic Forest islands of Santa Catarina State, Brazil. AB - A study of the community dynamics of Drosophilidae was carried out in six insular communities and two others on the mainland. Seasonal collections were carried out throughout two years in Santa Catarina State, southern of Brazil. The diversity index calculations show high values when compared with temperate climate communities. The sites on the mainland (Serra do Tabuleiro) presented the highest diversity, which was measured by the Diversity Index (H'). These sites are covered by primary Atlantic Forest and theoretically should have a higher variation of ecological niches. A dendogram showing the similarity between the communities, calculated by Morisita Index, points to a level of similarity equal to 60% for all communities. In this diagram, we can see two clades: one on the mainland and the other on the islands. The six island sites are grouped into one clade and separated into two subclades, one including the sites on Santa Catarina Island and the other consisting of the islands adjacent to this last and very much larger one. These groupings show the very important role of the spatial component on the prediction of the structure of the communities. This fact raises the discussion about the high complexity of the Atlantic Forest ecosystem and consequently the unpredictability of its fauna, highlighting the need of its conservation. PMID- 17710320 TI - [Mating behavior of the coffee leaf-miner Leucoptera coffeella (Guerin-Meneville) (Lepidoptera: Lyonetiidae)]. AB - Despite the importance of Leucoptera coffeella (Guerin-Meneville) in coffee production worldwide, there is a lack of information on its reproductive biology. This knowledge will help in mass rearing, as well as support the development of behavioral control techniques for this insect. The purpose of the study was to determine the periodicity of mating and male capture and describe the mating behavior L. coffeella. In laboratory, we observed the periodicity of mating with virgin couples of different ages, zero to five days after emergence. Male activity was studied in a 0.7 ha coffee plantation, cv. Catuai, where Delta traps were installed at 0.5 m above ground, using either virgin females or rubber septa lured with the synthetic sex pheromone. The sequence of mating behavior was studied by making visual observations and recorded of pairs placed on individual plastic tubes. Mating occurred between 4h and 6h of photophase, when the highest frequencies involved pairs with ages of one and three days after emergence, with peak of mating occurring in 5th hour of photophase. The young or old pairs showed significantly copulation frequency and the peak of matings advance in 1h. The highest male capture occurred at 12p.m. and 13 p.m. by traps with virgin females or traps with synthetic sex pheromone lures, respectively. L. coffeella is one insect with diurnal mating and the mating behavior was not different from what is know for other Lepidoptera species. PMID- 17710322 TI - A survey of the termite fauna (Isoptera) of an eucalypt plantation in central Brazil. AB - The termite fauna of a plantation of Eucaliptus urophylla S.T. Blake (Myrtales: Mytaceae) in Buritis, Minas Gerais, was manually sampled in 12 transects. The assemblage contained 28 species belonging to Termitidae and Rhinotermitidae. This assemblage corresponds to a subset of the native fauna of the cerrado previously present in this region. Compared to the original native fauna, it has a lower species richness, a much lower proportion of soil-feeders and a higher proportion of litter-feeders. A total of 1,600 recently cut trees were examined and only three (0.2%) had damage to the heartwood caused by Coptotermes sp. Despite the presence of a diverse termite fauna including several putative pest species, termites are not considered a significant problem to eucalypt plantations in this region. PMID- 17710321 TI - Life history and larval morphology of Eurhinus magnificus Gyllenhal (Coleoptera: Curculionidae), a new weevil to the United States. AB - Eurhinus magnificus Gyllenhal has been collected in south Florida, presumably introduced through trade with countries in its native range. Very little information has been published on the biology or taxonomy of this insect. We conducted studies to investigate various aspects of its life history and host plant associations. The pre-imaginal life stages of E. magnificus are described for the first time. Dimensions of the adult, egg, larval, and pupal stages are also provided; head capsule measurement revealed five larval instars. All life stages of E. magnificus were collected at several sites in Broward and Miami-Dade counties from the host plant Cissus verticillata (L.) Nicolson & Jarvis (Vitaceae). Eggs were laid singly within the succulent, young subterminal portion of the host plant stem, one or two occurring between two nodes. Gall formation was apparent by the first to third instar and continued to increase in size until pupation which occurred within the gall. Predators and pathogens appeared to be responsible for considerable mortality in the field; there was no evidence of parasitism of any of the life stages. Greenhouse studies were undertaken to determine E. magnificus development time and host specificity. Adult weevils attacked grape cultivars (Vitis spp.) and feeding opened the stems to fungal agents but no physical evidence of larval development was apparent on grapes. PMID- 17710323 TI - [Ultrastructure of the ovarioles of Tropidacris collaris (Stoll) (Orthoptera: Romaleidae) submitted to three photoperiods]. AB - The research evaluated the ultrastructure of the ovarioles of Tropidacris collaris (Stoll), submitted to photoperiods 10L:14D, 12L:12D and 14L:10D. Sixty nymphs (30 males and 30 females) in the last stage of development were paired in ten couples in each treatment. Thirty days after adult emergence, the females were immobilized with ethylic ether and dissected under stereomicroscope. The ovarioles were transferred to Karnovsky fixative (2.5% glutaraldehyde, 4% paraformaldehyde and 0.1 M sodium cacodylate buffer) and analyzed in transmission and scanning electron microscopes. The different photoperiods had no effect on the ovarioles' ultrastructure. Each ovariole is covered by a thick sheath constituted by a homogeneous and filamentous material. In the terminal filament, there are cells with large nuclei, some with scarce cytoplasm and projections cytoplasmatic, besides filamentous structures assuming characteristic of conjunctive tissue. In the germarium, the germ cells are big with large nuclei, scarce cytoplasm and plasma membrane containing interdigitations. The follicular cells are small with a small nucleus, yet presenting cytoplasmatic projections. In the vitellarium the follicular cells suffer modifications in their morphology varying from cubic to flat. PMID- 17710324 TI - [The genus cephalocoema serville, 1,839 (orthoptera: proscopiidae, tetanorhynchini)]. AB - The genus Cephalocoema Serville, 1,839 is revised by the study of its type species and additional ones. New species are described and synonymies are made. Each species is studied in its morphological features and genital characters, both male and female. Type localities are marked in Biogeographical regions map, which let us to get a pattern of distribution related with the habitat preferences of each species, for the whole genus. PMID- 17710325 TI - New species of Brachygasterina Macquart (Diptera: Muscidae) from high altitudes of Colombia, Ecuador and Venezuela. AB - The genus Brachygasterina Macquart (Muscidae), comprising seven species, is endemic in South America. Three new species are herein described from the highlands of Colombia, Ecuador and Venezuela. A key to the species of this genus is provided. PMID- 17710327 TI - [Development of Aphidius colemani Viereck (Hym.: Braconidae, Aphidiinae) and alterations caused by the parasitism in the host Aphis gossypii Glover (Hem.: Aphididae) in different temperatures]. AB - Aphidius colemani Viereck is among the main natural enemies used for biological control of Aphis gossypii Glover. The objective of the present study was to evaluate the development of A. colemani and the alterations caused by the parasitism in the host A. gossypii in different temperatures and to estimate the thermal requirements of the parasitoid. The experiments were carried out in controlled environmental chambers at 16, 19, 22, 25, 28 and 31 +/- 1 degrees C, 70 +/- 10% RH, and 12h photophase. Second-instar nymphs of A. gossypii were parasitized once and kept individually in glass tubes (2.5 cm x 8.5 cm), containing leaf disc of cucumber (2 cm) and 1% water/agar solution. The development time of A. colemani, from oviposition to mummies (11.9, 9.8, 7.7, 6.4 and 6.4 days) and from oviposition to adult (19.4, 16.2, 12.6, 10.5 and 10.7 days) decreased with the increase of the temperature from 16 degrees C to 25 degrees C. The rates of mummies and the emergence of the parasitoid, and its longevity also decreased with the increase of the temperature. Mummies were not produced at 31 degrees C. The lower temperature threshold of A. colemani was 5.94 degrees C and its thermal constant was 200 degrees-day. The alterations caused by the parasitoid in the A. gossypii host were minimized at 31 degrees C, where 98% of the host did not show symptoms of parasitism and produced nymphs. The temperature of 22 degrees C was optimal for the development time of A. colemani. PMID- 17710326 TI - [Biology and thermal requirements of Trichogramma atopovirilia Oatman & Platner (Hymenoptera: Trichogrammatidae) parasitizing eggs of Diaphania hyalinata L. (Lepidoptera: Pyralidae)]. AB - The development and parasitism of Diaphania hyalinata L. eggs by Trichogramma atopovirilia Oatman & Platner and its thermal requirements were studied at the temperatures of 18, 21, 24, 27, 30 and 33 degrees C. Thirty eggs of D. hyalinata were exposed to three females of T. atopovirilia for 5h at 25 degrees C and incubated at the different temperatures. The developmental time from egg exposure to adult, parasitism viability, number of adults per parasitized host egg and progeny sex ratio were monitored. The developmental time from egg to adult emergence of the parasitoid exhibited inverse relationship to the temperature, lasting 24.12 days at 18 degrees C and 7.36 days at 33 degrees C. Parasitism viability at 24, 27 and 30 degrees C was higher than 90%. The ratio of T. atapovirilia adult produced per egg and its sex ratio were not affected when using D. hialynata as host. The lowest threshold temperature (Tb) and estimated degree-days over Tb required by T. atopovirilia to develop on eggs of D. hyalinata was 11.99 degrees C and 130.42 masculine C, respectively. Considering the temperature regimes of two areas where cucurbitaces are cultivated in Bahia State (Rio Real and Inhambupe County) it was estimated that T. atopovirilia can achieve more than 32 generation per year. The results suggest that T. atopovirilia has potential to control D. hyalinata eggs with better chance of success under temperature regimes ranging from 24 to 27 degrees C that meets the suitable field conditions for cropping cucurbitaces. PMID- 17710328 TI - [Biology and non-preference for oviposition by Bemisia tabaci (Gennadius) biotype B (Hemiptera: Aleyrodidae) on cotton cultivars]. AB - The purposes of this work were to evaluate some biological aspects of Bemisia tabaci (Gennadius) biotype B at egg and nymphal stages and to evaluate the non preference for oviposition and its correlation with the number and type of trichomes on the cotton cultivars BRS Ipe, BRS 186-Precoce 3, BRS Acala, BRS Verde, BRS-200 Marrom, BRS Cedro, BRS Ita 90-2 and BRS Aroeira. The experiments were conducted in climatic chambers at 28 +/- 2 degrees C, 70% RH and photophase of 14h, and in greenhouse. Egg fertility was not affected by the cotton cultivars but survival in egg-adult period was influenced by the host plant. There was no influence of cultivars neither on the duration of egg stage, nymphs at 2nd, 3rd and 4th instars nor on the duration from egg to adult, but nymphs reared on the cultivar BRS Ipe had their 1st instar extended. Low number of eggs was detected on the cultivars BRS Aroeira, BRS Verde and BRS Ita 90-2 in both experiments with and without oviposition choice, indicating a possible mechanism of resistance, but no correlation could be established between trichome densisty and oviposition non-preference. PMID- 17710329 TI - Urban ants and transportation of nosocomial bacteria. AB - Many ant species displaying synanthropic behavior that have successfully dispersed in urban areas can cause problems in hospitals by acting as bacterial vectors. In this study, we encountered bacteria on ants collected at the Universidade Federal de Uberlandia hospital, in the campus and at households nearby. The ants were identified as Tapinoma melanocephalum (Fabricius) and Camponotus vittatus (Forel) (Hymenoptera: Formicidae) and the bacterial strains found here belong to the group of the coagulase-positive staphylococcus, coagulase-negative staphylococcus and gram negative bacilli, including antimicrobial drug-resistant strains. An investigation of the bacteria found in the ants and in the environment revealed that some ants carried non-isolated bacteria from the same environment and with high levels of resistance, evidencing the transmission potential of these insects. PMID- 17710330 TI - [Biology of Acarophenax lacunatus (Cross & Krantz) (Prostigmata: Acarophenacidae) on Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae) and Cryptolestes ferrugineus (Stephens) (Coleoptera: Cucujidae)]. AB - The aim of the present study was to assess the effect of six different temperatures on the development of Acarophenax lacunatus (Cross & Krantz) using eggs of Tribolium castaneum (Herbst) and Cryptolestes ferrugineus (Stephens) as hosts. The temperature affected the development of A. lacunatus. The largest values for the progeny (19 mites in T. castaneum and 15 mites in C. ferrugineus) were obtained at about 30 degrees C, as also observed for the net reproductive rate (Ro), which revealed that the A. lacunatus population increased 18 times in T. castaneum and 14 times in C. ferrugineus in a generation. The intrinsic rate of increase (r m) gradually increased with temperature, reaching the maximum value at 35 degrees C in T. castaneum (1,608) and C. ferrugineus (1,289). The generation time was negatively correlated with temperature, ranging from 1,60 to 4,85 days in T. castaneum and from 1,96 to 5,34 days in C. ferrugineus. These results suggest that the mite A. lacunatus may be used in programs of biological control of T. castaneum and C. ferrugineus in the tropics. PMID- 17710331 TI - [Biology of Amblyseius largoensis (Muma) (Acari: Phytoseiidae), a potential predator of Aceria guerreronis Keifer (Acari: Eriophyidae) on coconut trees]. AB - Aceria guerreronis Keifer is considered one of the main pests of coconuts around the world. Amongst the Phytoseiidae recorded on this crop, Amblyseius largoensis (Muma) has been reported in association with A. guerreronis. In order to verify whether A. largoensis feeds on A. guerreronis, the biology of this predator was evaluated on different food sources, including A. guerreronis. Three types of diet were tested [Tetranychus urticae Koch + castor bean (Ricinus communis L.) pollen + honey at 10%, A. guerreronis + pollen + honey, and only A. guerreronis], determining its development, survivorship, oviposition, sex ratio and longevity at 27 degrees C, 60 +/- 5% RH 12 h photophase. Fertility life tables were constructed. The duration of the immature phase was lower when feeding only on A. guerreronis, while fecundity was higher when feeding on a prey + pollen + honey. There was no difference in relation to survivorship of the immature stages between the three diets. Parameters of fertility life tables were higher when the diet included A. guerreronis or T. urticae + pollen + honey, although the predator was able to complete its life cycle and reproduce when feeding exclusively on A. guerreronis. The results suggest that A. largoensis preys upon A. guerreronis under natural condition and that it might play some role in the control of the latter. PMID- 17710332 TI - [Host weeds of Rhopalosiphum rufiabdominalis (Sasaki) (Hemiptera: Aphididae) in areas of irrigated rice]. AB - Rhopalosiphum rufiabdominalis (Sasaki) is an insect of world-wide distribution that damages irrigated rice. From September, 2004 to February, 2005, nymphs and adults of this aphid were collected in several host weeds of rice farms in Alegrete, Quarai and Uruguaiana, located in Western of State of Rio Grande do Sul, and Restinga Seca, in Central region of this State, Brazil. The insect was found in the root of Andropogon bicornis (West Indian foxtail), Echinochloa colona (jungle rice), Oryza sativa (volunteer rice and red-rice), Paspalum sp. (paspalum) and Soliva pterosperma (lawn burweed). PMID- 17710333 TI - [Occurrence of Amrineus cocofolius Flechtmann (Prostigmata: Eriophyidae) in coconut fruits (Cocos nucifera L.) in Cuba]. AB - The presence of the eriophyid mite, Amrineus cocofolius Flechtmann, was confirmed in association with equatorial necrotic bands on the coconut fruit epidermis, in different growth areas in the Provinces of La Habana, Granma y Guantanamo, Cuba, from February 2003 to March 2004. PMID- 17710334 TI - Megalorhipida leucodactyla (Fabricius) (Lepidoptera: Pterophoridae): first distribution record from Chile and new host plant record. AB - The presence of Megalorhipida leucodactyla (Fabricius) (Lepidoptera: Pterophoridae) in Chile is reported for the first time from the Azapa valley, northern Chile. In this locality, some immature stages of M. leucodactyla were found to be associated with Tessaria absinthioides (Hook. & Arn.) DC., Asteraceae, a new host plant record at the species, genus and family level for M. leucodactyla. PMID- 17710335 TI - Malignant tumor affects the developmental pattern of feeding larvae of Chrysomya albiceps (Wiedemann) and Chrysomya putoria (Wiedemann) (Diptera: Calliphoridae). AB - Larvae of Chrysomya albiceps (Wiedemann) and Chrysomya putoria (Wiedemann) were reared on liver tissues from a rabbit that had a malignant tumor in the thoracic cavity. Larval rearing of both blowfly species was conducted at ambient temperature. Larvae that fed on tissues from the rabbit with the tumor developed at significantly faster rates than those feeding on tissues from the control animal. PMID- 17710336 TI - First record of Diachasmimorpha longicaudata (Ashmead) (Hymenoptera: Braconidae) attacking Toxotrypana curvicauda Gerstaecker (Diptera: Tephritidae). AB - A new host record is reported for the braconid wasp Diachasmimorpha longicaudata (Ashmead) (Hymenoptera: Braconidae), parasitizing papaya fruit fly larvae Toxotrypana curvicauda Gerstaecker (Diptera: Tephritidae) in Mexico. PMID- 17710337 TI - Occurrence of Eulaema (Apeulaema) pseudocingulata Oliveira (Hymenoptera: Apidae: Euglossini) in the Platina Basin, Mato Grosso State, Brazil. AB - This study was conducted in the Chapada dos Guimaraes National Park and in the Provincia Serrana of Mato Grosso state, from May 2003 to July 2005 and involved the use of chemical baits to attract male orchid bees. A total of 498 males were captured, of which 38 were Eulaema (Apeulaema) pseudocingulata Oliveira. Twenty nine of these were collected in the national park and nine in the Provincia Serrana. E. pseudocingulata was reported as endemic to the Amazon Basin, however in the Platina Basin the species is sympatric to E. cingulata (Fabricius), a sibling species of similar morphology and color pattern but with a broader geographic distribution. PMID- 17710338 TI - [First report of parasitism of the Trichogramma bruni Nagaraja (Hymenoptera: Trichogrammatidae) in eggs of urbanus proteus (L.) (Lepidoptera: Hesperiidae) in snap beans (Phaseolus vulgaris) ( L.)]. AB - Aiming to verify the presence of eggs parasitoids of the genus Trichogramma, for using in the biological control of insects pests, were collected eggs from long tailed skipper butterfly, a lepidopteran defoliator of snap beans, which presented eggs with parasitism characteristics (dark eggs). The eggs were taken to the laboratory were 44.9% of parasitism was verified. Viability was 96.3%, with an average of 6.6 individuals per egg and a sexual ratio of 0.93. Male specimens were identified as Trichogramma bruni Nagaraja. It is the first report of parasitism in this host and culture. PMID- 17710340 TI - [Reliability of an instrument to assess the readiness of preterm infants for oral feeding]. AB - BACKGROUND: The transition from gastric to oral feeding of preterm infants is one of the greatest concerns of health professionals and therefore needs an objective criterion to support the beginning of this process. AIM: To test the reliability of an instrument that assesses the readiness of preterm infants for the transition from gastric to oral feeding. METHOD: The instrument is composed by the following items: corrected gestational age; behavioral state; global posture and tonus; lips and tongue posture; rooting, suck, bite and gag reflexes; tongue and jaw movements; tongue cupping; sucking strain; sucking and pause; maintenance sucking/pause; maintenance alert state and stress signs. The study was conducted at the Intermediate Care Unit of the Hospital de Clinicas da Faculdade de Medicina de Ribeirao Preto-University of Sao Paulo. The research sample consisted of 30 preterm infants who attended the following inclusion criteria: corrected gestational age<36 weeks and 6 days; clinically stable; absence of facial deformities; respiratory, cardiovascular, gastrointestinal and neurological disorders or syndromes that prevent or make oral feeding difficult; and not having received oral feeding of milk. The Kappa Test was used to verify interjudge reliability. RESULTS: The items that presented high reliability levels were: behavioral state, global posture and tonus, lips and tongue posture, gag reflex and maintenance of alert state. The items that presented satisfactory reliability levels were: rooting reflex, sucking and biting and jaw movement, sucking strain and sucking and pause. Only the items of tongue cupping, maintenance of sucking/pause and stress signs presented unsatisfactory reliability levels. CONCLUSION: In general, the items investigated by the assessment instrument presented adequate interjudge reliability. PMID- 17710341 TI - [Masticatory performance in adults related to temporomandibular disorder and dental occlusion]. AB - BACKGROUND: Temporomandibular disorder and mastication. AIM: To compare subjects who present temporomandibular disorders to a control group considering mastication and to analyze the related variables. METHOD: 20 subjects with temporomandibular disorder (TMD group) and 10 controls--selection based on clinical examination and anamnesis--responded to a questionnaire on the self perception of pain severity and presence of noise in the temporomandibular joints, muscle pain, otologic symptoms, headaches, and jaw opening difficulties. The subjects were also submitted to a clinical examination regarding the number of teeth and functional occlusion--measurements of jaw opening and jaw lateral excursions, occlusal interferences, occlusal contacts of the working and non working-side, and mastication evaluation. Mastication was evaluated in terms of time needed to eat a stuffed cookie, number of chewing strokes and type (unilateral or bilateral). The maximum force needed at first to break the cookie, verified with a TA-XT2 Texture Analyzer (Stable Micro Systems), was of 4341.8 g. The groups were compared using variance analysis and the correlations between variables were calculated using the Pearson product-moment test. RESULTS: Most of the control subjects presented bilateral pattern of mastication, whereas the TMD group tended to present the unilateral pattern. Masticatory type scores and laterality measurements were significantly higher in the control group. The TMD group presented higher means in terms of: age, time of chewing, number of chewing strokes and TMD severity. Chewing time and type were positively correlated with TMD severity and negatively correlated with number of occlusal interferences. CONCLUSION: In the TMD group, chewing differed from the normal physiological standard. The number of occlusal interferences and the severity of TMD were variables correlated to chewing. PMID- 17710342 TI - [Filmed sample size and pragmatic analysis in Down syndrome]. AB - BACKGROUND: Assessing language development is a complex task that requires practical and theoretical knowledge about the investigated issues. It is also important to take into account data gathering and analysis methodology, in order to achieve consistent and reliable results that mirror the subject's reality. AIM: considering the purpose of obtaining the maximum data in minimum time, without jeopardizing their quality and effectiveness, our aim is to identify the better sample's size and moment of videotaped interaction to study the pragmatic abilities of children with Down syndrome. METHOD: The communicative profile of 25 children with Down syndrome aged between 2 and 7 years were determined as proposed by Fernandes (2004). Data obtained through samples of 15 and 30 minutes were analyzed and compared. The situation analyzed provided interaction between the child and a speech-and language-therapist in play situations. To determine the statistical significance of data the tests Friedman, Wilcoxon and confidence interval were applied with a significance level of 0.05 (5%). CONCLUSION: There were no significant differences related to the obtained samples with different videotaped duration for pragmatic analysis of the communication of children with Down syndrome. PMID- 17710344 TI - [Vestibular rehabilitation in elderly patients with dizziness]. AB - BACKGROUND: The aging of the population is a natural process and is manifested by a decline in the functions of several organs. Vestibular rehabilitation (VR) is a therapeutic process that seeks to promote a significant reduction in the symptoms of the labyrinth. AIM: To verify the benefits of VR exercises through the application of the Dizziness Handicap Inventory (DHI) questionnaire--Brazilian version--pre and post rehabilitation. METHOD: Participants of this study were eight elderly patients with dizziness, ages between 63 and 82 years, three male and five female. The following procedures were carried out: medical history, otologic inspection, vestibular evaluation with vectoelectronystagmography (VENG), application of the DHI questionnaire and of the Cawthorne (1944) and Cooksey (1946) VR exercises. RESULTS: Regarding the auditory and vestibular complaints which were referred to in the medical history, the following was observed: presence of tinnitus, hearing loss, postural vertigo and of unbalance. In the evaluation of the vestibular function alterations were observed for all of the participants, mainly in the caloric test, with a prevalence of unilateral and bilateral hypofunction. In the vestibular exam the following was observed: three cases of unilateral peripheral vestibular deficit syndrome, three cases of bilateral peripheral vestibular deficit syndrome, one case of bilateral central vestibular deficit syndrome and one case of irritating bilateral central vestibular syndrome. There was a statistically significant improvement of the following aspects after VR: physical (p=0.00413), functional (p=0.00006) and emotional (p=0.03268). CONCLUSION: The VR protocol favored the improvement of life quality of the participants and was of assistance in the process of vestibular compensation. PMID- 17710343 TI - [Oral language of children with five years of experience using [corrected] cochlear implant]. AB - BACKGROUND: Cochlear implant (CI) in children. AIM: 1) to delineate a profile of receptive and expressive verbal language of children who have been using cochlear implant for five years and five years and eleven months; 2) to verify the influence of time of auditory sensorial privation in the receptive and expressive verbal language of these children. METHOD: 19 children users of CI with auditory deficiency acquired before language development, who have been using CI for 5y - 5y11m and who have an average time of sensorial privation of 3y (standard deviation of 1 year). These children were assessed using the Reynell Developmental Scales (RDLS) (Reynell e Gruber, 1990) which is composed of: Comprehension Scale (C), Expression Scale (E) and its Structure Sub-Scales (Es), Vocabulary (Ev) and Content (Ec). RESULTS: The median values and the values found for quartile 75 and quartile 25 were: .44, 57 and 54 for C; 48, 60 and 55 for E; 20, 21 and 20 for Es; 15, 19 and 17 for Ev; 15, 22 and 18 for Ec; 96, 116 and 108 for the total score. A statistical correlation between the time of sensorial privation and the score obtained for C (p=- 0.62; R=0.0044) and Ec (p=-0.48; R=0.0348) was observed. Therefore the time of sensorial privation had an influence on the overall score (p=- 0.53; R=0.0174). CONCLUSION: The language profile of children who use CI for five years is devious and similar to that of five year old hearing children regarding Expression and to that of four year old hearing regarding Comprehension; time of sensorial privation was statistically significant for the score obtained in C--receptive language--and for the score obtained in the E section (Ec)--expressive language, as well as in the overall score of RDLS. PMID- 17710345 TI - [Visual reinforcement audiometry with different sound stimuli in children]. AB - BACKGROUND: Hearing evaluation in children. AIM: To verify the Minimum Response Levels (MRL) through the use of Visual Reinforcement Audiometry (VRA) in the sound field, in 50 normal hearing children and in 25 children with hearing loss, taking into account the following variables: side of sound presentation, gender, age and type of stimulus. METHOD: VRA was performed using pure tone frequency modulation (warble) and the Sonar System. The modulated tones were produced by the Pediatric Audiometer, in the frequencies of 500, 1000, 2000 and 4000 Hz and at the intensities of 80, 60, 40 and 20 dBNA. The modulated tones were presented in a decreasing sequence of intensity and by using the stimulus-reply-visual reinforcement conditioning. The assessment procedure and analysis of response were the same when using the stimuli of the Sonar System. However, on this occasion, a sound amplification box was used. Each loudspeaker with the visual reinforcement was positioned approximately at 90 masculine azimuth to the right and the left of the child, and at a distance of approximately 50 cm. Visual reinforcement was an illuminated clown. RESULTS: No statistically significant difference was found between the MNL and the side of sound presentation. The MRL at 500 Hz and 2000 Hz, when using the Sonar System, were lower for normal hearing males. In this group, there was a decrease in the MRL with the increase in age for both stimuli. When comparing the MRL with two stimuli, there was a statistically significant difference in favor of the Sonar System, but only for the group of normal hearing children below two years of age. CONCLUSION: The MRL decrease with age independently of the stimulus and are lower when using the Sonar System. For the group of children with hearing loss no significant difference was found for any of the studied variables. PMID- 17710346 TI - [Distortion product otoacoustic emissions in infants from birth to two months]. AB - BACKGROUND: There is a need to determine parameters for the analyses of the distortion product otoacoustic emissions (DPOAE) of infants so that it can be used as a clinical criterion in auditory assessment. AIM: To describe the DPOAE records of infants from birth to two months, considering the response level, noise level and the signal to noise ratio in all frequencies; the analysis of response level according to the variables of gender, timpanometry pressure peak, state of infant during the test and distribution of the response percentile level. METHOD: 138 infants were evaluated, all of which presented no risk indicators for hearing loss and passed the hearing screening test. The parameters used were: L1=65 dB SPL and L2=50 dB SPL in the equipment ILO292-Otodynamics. RESULTS: 70 male and 68 female were evaluated, with ages between 6 to 65 days. The medians for DPOAE level for each frequency (f2) varied between 6.0 dB SPL and 16.3 dB SPL. The medians for the noise level for each frequency (f2) varied between -12.5 dB SPL and -2.1 dB SPL. The medians for the signal to noise ratio for each frequency (f2) varied between 10.5 dB SPL and 25.5 dB SPL. CONCLUSIONS: There was no statistically significant difference between genders and between ears for the response level. The timpanometry pression peak determined by three groups (between -50 and +50 daPa; <-50 daPa and >+50 daPa) indicated no influence on records of the response level. For clinical interpretation, percentile 5 can suggest hearing loss and percentile 95 can suggest normal hearing. Studies with infants who present hearing loss are considered important in order to complement the clinical criterion in case of presence of DPOAE and hearing loss. PMID- 17710347 TI - [Language and eating problems in children: co-occurrences or coincidences?]. AB - BACKGROUND: Relationship between language problems and eating disorders in children. AIM: To analyze the possible co-occurrence of these disorders taking into consideration a relationship that has structural implications, the reciprocal influences between language, body and physique. METHOD: Clinical quantitative-qualitative, based on free observations of non intentional samples of 35 children (between 1:4 and 7:0 years of age), presenting oral language problems and who were seen at a school clinic during the period of one year. One case study (J., 4:0 years old) was highlighted from the group of participants, with the importance of an emblematic scenario regarding the theoretical paradigm used in the discussion of the results. The evaluation procedure of each participant consisted of two interviews with the families, a language analysis in the dialogical context and in a play situation, and an evaluation of the oral performance. RESULTS: Language problems and eating disorders co-occurred in 100% of the cases. These were sub-divided according to age due to similarities of the symptoms. Group A (1:4 to 3:0 years of age) was composed by 10 participants (28.7%) presenting: delay in oral language development, restrictions in interaction, dysphagia or hypophagia. Group B (3:1 to 5:0 years of age) composed by 20 participants presenting: from the absence of oral language to a discursive weakness; articulatory disturbance; mastication and swallowing problems; eating idiosyncrasies and obesity. Group C (5:1 to 7:0 years of age) composed by 5 participants (14,28%) presenting: severe discursive alterations; articulatory disturbances; mastication and swallowing problems and the refusal of certain foods. CONCLUSION: The co-occurrence of oral language problems and eating disorders is not just a coincidence. Both disorders configure themselves as oral disturbances. It is suggested that speech-language pathologists investigate eating difficulties during the diagnostic process of clients with complaints and/or symptoms that have manifestations on oral language. PMID- 17710348 TI - [Botulism and dysphagia]. AB - BACKGROUND: Botulism is a severe neuroparalytic, of an acute characteristic, afebrile and is caused by the action of a toxin produced by Clostridium botulinum. This toxin links itself to the receptors of the axon membrane of the motor neurons, preventing the release of acetylcholine in the neuromuscular junction, causing flaccid paralysis of the cranial nerves and skeleton musculature. AIM: To present the speech therapy procedures adopted with a patient with botulism and who was presenting dysphagia. METHOD: A male adult, with botulism, sent for a speech-language evaluation due to the presence of difficulties when swallowing saliva. During the evaluation the following was observed: alteration in mobility, tonicity and sensibility of the organs of the Orofacial Myofunctional System (OMSs); reduction of the laryngeal movements; stasis of saliva in the oral cavity; absence of the swallowing reflex; absence of the swallowing function. Nine speech therapy sessions were carried out with the following procedures: stimulation of the OMSs--mobility, tonicity and sensibility; stimulation of the oral and pharyngeal reflexes; tests and trainings for swallowing with different food consistencies and with the help of maneuvers aiming at the protection and clearing of the airways. RESULTS: Improvement in mobility, tonicity and sensibility of the OMSs; improvement in the elevation of the larynx; re-establishment of the swallowing function without the assistance of other professionals or clinical maneuvers; vocal quality close to the normal parameters (light hypernasality and pneumophonoarticulatory incoordination). The patient was discharged from hospital and speech therapy; clinical assistance for adjustment and improvement of the OMSs was suggested. CONCLUSION: Speech therapy demonstrated to be efficient in the re-establishment of OMSs and of the swallowing function, enabling the patient to restore the adequate functionality of his orofacial myofunctional system. PMID- 17710350 TI - Management of spontaneous pneumothorax compared to British Thoracic Society (BTS) 2003 guidelines: a district general hospital audit. AB - BACKGROUND: In 1993, the British Thoracic Society (BTS) issued guidelines for the management of spontaneous pneumothorax (SP). These were refined in 2003. AIM: To determine adherence to the 2003 BTS SP guidelines in a district general hospital. METHODS: An initial retrospective audit of 52 episodes of acute SP was performed. Subsequent intervention involved a junior doctor educational update on both the 2003 BTS guidelines and the initial audit results, and the setting up of an online guideline hyperlink. After the educational intervention a further prospective re-audit of 28 SP episodes was performed. RESULTS: Management of SP deviated considerably from the 2003 BTS guidelines in the initial audit - deviation rate 26.9%. After the intervention, a number of clinical management deviations persisted (32.1% deviation rate); these included failure to insert a chest drain despite unsuccessful aspiration, and attempting aspiration of symptomatic secondary SPs. CONCLUSION: Specific tools to improve standards might include a pneumothorax proforma to improve record keeping and a pneumothorax care pathway to reduce management deviations compared to BTS guidelines. Successful change also requires identification of the total target audience for any educational intervention. PMID- 17710349 TI - [Screening versus diagnostic tests: an update in the speech, language and hearing pathology practice]. AB - BACKGROUND: Evaluation instruments, properties, selection indicators, application and validation of screening and diagnostic tests. AIM: To present some concepts concerning screening and diagnostic tests and their application according to a specific purpose. To present a few practical examples of the application of these instruments related to human communication, as well as to present validation criteria of tests in the population and criteria used for the rational selection of screening or diagnostic instruments in health programs and health services based on epidemiological concepts indexed in Scielo, Lilacs or Medline up to January 2007. CONCLUSION: Diagnostic instruments differ from screening instruments in their objectives and eligibility criteria. Sensibility and specificity are two important indicators to be considered when choosing an instrument for screening or diagnosis. Reproducibility, time required to complete the evaluation and previous preparation of patients, if needed, are also indicators to be considered when choosing an instrument. Publication and information exchange regarding the properties of evaluation instruments, used for diagnosis or screening, related to the Speech, Language and Hearing Sciences must be systematically stimulated. Besides that, improving the knowledge about methodologies and evaluation instruments under different perspectives contribute to the better use of human and financial resources. Furthermore, the elaboration of studies that promote the correct validation of screening and diagnostic instruments used in human communication disorders contributes to the increase in knowledge in the field of Speech, Language and Hearing Sciences and, indirectly, to the acknowledgement of this science, based on technical-scientific evidence, in health promotion. PMID- 17710351 TI - Promoting the use of Personal Asthma Action Plans: a systematic review. AB - OBJECTIVES: To investigate how best to encourage health professionals to promote, and for people with asthma to use, asthma action plans. METHODS: Systematic review. Randomised controlled trials published between 1960 and 2006 were searched using multiple electronic databases. Unpublished and ongoing studies were identified by contacting asthma experts internationally. Included trials reported outcome data for the promotion of action plans including issue of plans by health professionals, and patient ownership and use. RESULTS: 14 trials satisfied our study inclusion criteria. Of these, only four studies reported data for action plan use. Interventions included: education of doctors and people with asthma; telephone reinforcement; partially completed action plans and postal prompts inviting patients for general practice review; school asthma clinics; and asthma management systems (including the 3+ plan with patient recall for review and Internet-based physician monitoring). These interventions increased action plan ownership, use, or facilitation of use. Two of the highest quality papers were conducted in primary care and demonstrate the effectiveness of interventions directed at the organisation of asthma care in promoting action plan use. CONCLUSIONS: Primary care professionals could encourage the ownership and use of action plans through the implementation of proactive practice-based organisational systems, though further research is required to assess their practicality and effect on sustaining use long-term. Multi-disciplinary teams working in areas where asthma action plan ownership and use is sub-optimal should therefore consider how such interventions could be incorporated into existing practices and healthcare systems. PMID- 17710352 TI - Characteristics of patients initiating teriparatide for the treatment of osteoporosis. AB - The demographic and clinical characteristics of patients initiating teriparatide were compared with those of patients initiating bisphosphonates for the treatment of osteoporosis. In these samples of commercially insured, Medicare, and Medicaid patients, patients initiating teriparatide were older, in poorer health, and appeared to have more severe osteoporosis than patients initiating bisphosphonates. INTRODUCTION: The demographic and clinical characteristics of patients initiating teriparatide are compared with those of patients initiating bisphosphonates. METHODS: Beneficiaries (45 years and older) with at least one claim for teriparatide or a bisphosphonate from 2003 to 2005 and continuous enrollment in the previous 12 months and subsequent 6 months were identified from commercial, Medicare, and Medicaid administrative claims databases. Patients initiating teriparatide (commercial/Medicare (N = 2,218); Medicaid (N = 824)) were compared to patients initiating bisphosphonates (commercial/Medicare (N = 97,570); Medicaid (N = 77,526)) in terms of age, provider specialty, comorbidities, prior use of osteoporosis medications, fractures, BMD screening, health status, and resource utilization. RESULTS: Teriparatide patients were older and in poorer health than bisphosphonate patients. Approximately 38% of teriparatide patients in both groups had fractured in the pre-period compared to 16% of commercial/Medicare and 15% of Medicaid bisphosphonate patients. Teriparatide patients were more likely to have used osteoporosis medications in the pre-period (79.9% versus 32.1% (commercial/Medicare); 82.2% versus 19.6% (Medicaid)). CONCLUSIONS: In these samples of patients, those initiating teriparatide differed from those initiating bisphosphonates. Teriparatide patients were older, in poorer health, and appeared to have more severe osteoporosis than bisphosphonate patients. Comparisons of treatment outcomes should take these differences in patient characteristics into consideration. PMID- 17710353 TI - Changes in vertebral strength-density and energy absorption-density relationships following bisphosphonate treatment in beagle dogs. AB - We aimed to determine the effects of bisphosphonates on mechanical properties independent of changes in bone density. Our results show that at equivalent bone densities, vertebrae from beagles treated with bisphosphonate have equivalent bone strength and reduced bone energy absorption compared to those from untreated animals. INTRODUCTION: Assessing the relationship between mechanical properties and bone density allows a biomechanical evaluation of bone quality, with differences at a given density indicative of altered quality. The purpose of this study was to evaluate the strength-density and energy absorption-density relationships in vertebral bone following a one-year treatment with clinical doses of two different bisphosphonates in beagle dogs. METHODS: Areal bone mineral density (aBMD) and compressive mechanical properties (ultimate load and energy absorption) were assessed on lumbar vertebrae from skeletally mature beagle dogs treated with vehicle (VEH), alendronate (ALN), or risedronate (RIS). Relationships among properties were assessed using analyses of covariance. RESULTS: Neither treatment altered the strength-density relationship compared to VEH, suggesting increases in vertebral strength with bisphosphonate-treatment are explained by increased density. The energy absorption-density relationship was altered by ALN, resulting in significantly lower energy absorption capacity at a given aBMD compared to both VEH (-22%) and RIS (-14%). CONCLUSIONS: These data document that after adjusting for increased aBMD, vertebrae from animals treated with bisphosphonates have similar strength as those from untreated animals. Conversely, when adjusted for increased aBMD, alendronate treatment, but not risedronate treatment, significantly reduces the energy required for vertebral fracture, indicative of an alteration in bone quality. PMID- 17710354 TI - Conditions mimicking coarctation of the aorta. AB - Coarctation of the aorta is a cause of right arm hypertension in children and of heart failure in infants after ductal closure. We present two cases with these presentations that were initially thought to be coarctation of the aorta. They were subsequently diagnosed as Takayasu's arteritis in the older child and a large cerebral arteriovenous malformation in the infant. These conditions should be in the differential of right arm hypertension and of aortic flow reversal on echocardiography. PMID- 17710356 TI - Prenatal diagnosis of complete heart block and congenitally corrected transposition of the great arteries. PMID- 17710355 TI - First recanalization of a coronary artery chronic total obstruction in an 11-year old child with Kawasaki disease sequelae using the CROSSER catheter. AB - This is a case of an 11(1/2)-year-old diagnosed with Kawasaki disease at 6 months of age. Distal left main coronary aneurysm involving the proximal anterior descending and circumflex had progressed into a chronic total occlusion. We report the first application of a novel percutaneous technique using the CROSSER catheter system in a child. The CROSSER is a high-frequency mechanical vibration catheter-based technology developed to safely penetrate through calcific and noncalcific coronary artery occlusions. This is also the first Kawasaki disease patient to benefit from this technology; in this disease, coronary artery stenosis is typically associated with heavy calcification. PMID- 17710357 TI - Sensitivity and specificity of echocardiographic evidence of tamponade: implications for ventricular interdependence and pulsus paradoxus. AB - The reported sensitivity of the echocardiographic finding of right atrial collapse for the diagnosis of tamponade ranges from 50% to100%; specificities have ranged from 33% to 100%. Its sensitivity in identifying right ventricular collapse ranges from 48% to 100% whereas the specificity ranges from 72% to 100%. Collapse of either the right atrium or right ventricle is not reliable except in cases where the risk of tamponade is high, consistent with Bayes' theorem. If the patient has hypotension, tachycardia, dyspnea, increased venous pressure, and a pericardial effusion, the diagnosis of tamponade will likely be sustained. To explain pulsus paradoxus, most echocardiographic reports have invoked Dornhorst's theory that inspiratory filling of the right ventricle actively collapses the left ventricle by successfully competing for a fixed total pericardial space ("ventricular interdependence"). However, the pericardial space is not fixed in tamponade but increases with inspiration, and the right heart is much more likely to collapse than the left, given their relative thickness. Pulsus paradoxus depends on the inspiratory surge to the right heart, exaggerated by the small stroke volume of both ventricles induced by tamponade, and vascular coupling between the pulmonary and systemic beds, with a transit time of one to two heart beats. PMID- 17710358 TI - Idiopathic bilaterally diffuse arteriovenous fistulas causing severe central cyanosis. PMID- 17710359 TI - Liver metastases from colorectal cancer: imaging with superparamagnetic iron oxide (SPIO)-enhanced MR imaging, computed tomography and positron emission tomography. AB - The literature about superparamagnetic iron oxide-enhanced MR imaging, computed tomography (CT) and PET (positron emission tomography using fluorine-18 labelled fluoro-deoxy-glucose) in detection of liver metastases (LM) from colorectal cancer is reviewed in this update. Special emphasis is given to studies with surgical standard of reference allowing for the lesion-by-lesion sensitivity to be determined. Based on the review, it is concluded that state-of-the-art anatomical imaging, e.g., SPIO-enhanced MR imaging and multidetector CT (MDCT), must be considered more sensitive than PET in detection of individual LM, due to technical developments in MR imaging, such as liver specific contrast agents, modern sequences and high performance gradients, and in modern MDCT have increased the performance of these modalities. MR imaging with a liver specific contrast agent is recommended for the preoperative evaluation before liver surgery for LM because of high sensitivity and better discrimination between small LM and cysts compared to MDCT. PET or PET/CT can be used for detection of extra-hepatic tumor before liver surgery. PMID- 17710360 TI - Extramural lymphatic drainage from the thoracic esophagus based on minute cadaveric dissections: fundamentals for the sentinel node navigation surgery for the thoracic esophageal cancers. AB - In order to elucidate the lymphatic pathways from the thoracic esophagus, minute dissection of five adult cadavers, from the neck through the diaphragm, was performed. Peri-esophageal lymphatics were dissected from both the anterior and posterior aspects. The topographical differences between the right and left lymphatic drainage were revealed. The right lymphatic drainage system (RDS) was basically longitudinal and multi-stationed. Longitudinal lymphatics were relatively poorly developed in the left lymphatic drainage system (LDS), and direct drainage to the thoracic duct from the left wall of the thoracic esophagus, was frequently observed. The right uppermost thoracic paratracheal node received almost all levels of the right esophageal wall, and this node was thought to be the key node in the RDS. A contralateral lymphatic pathway was relatively frequently observed in the middle and lower thoracic esophagus. These results seemed to be in agreement with the anatomical and clinicopathological data in the literature, and might serve as a basis for sentinel node navigation surgery for the thoracic esophageal cancers. PMID- 17710361 TI - Depression in Parkinson's disease. Diffusion tensor imaging study. AB - OBJECTIVES: The pathophysiology of depression and anxiety in Parkinson's disease remains obscure. We aimed to compare the fractional anisotropy (FA) values of Parkinson's disease (PD) patients with and without depression to investigate the nature of depression in PD. METHODS: Twenty-eight patients were divided into two groups: those with depression and those without. Diagnosis of depression was made using the DSM-IV criteria. Patients in the two groups were matched for Hoehn Yahr stage. RESULTS: There were significant reductions in FA values in the bilateral frontal ROIs possibly representing anterior cingulate bundles. CONCLUSIONS: The anterior cingulate bundles play an important role in depression in PD, and some aspects of depression in PD have pathological processes in common with de novo depression. PMID- 17710362 TI - Human amniotic fluid stem cells: a new perspective. AB - The discovery of amniotic fluid stem cells initiated a new and very promising field in stem cell research. In the last four years amniotic fluid stem cells have been shown to express markers specific to pluripotent stem cells, such as Oct-4. Due to their high proliferation potential, amniotic fluid stem cell lineages can be established. Meanwhile, they have been shown to harbor the potential to differentiate into cells of all three embryonic germ layers. It will be a major aim for the future to define the potential of this new source of stem cells for therapies related to specific diseases. PMID- 17710363 TI - Differences in amino acids composition and coupling patterns between mesophilic and thermophilic proteins. AB - Thermophilic proteins show substantially higher intrinsic thermal stability than their mesophilic counterparts. Amino acid composition is believed to alter the intrinsic stability of proteins. Several investigations and mutagenesis experiment have been carried out to understand the amino acid composition for the thermostability of proteins. This review presents some generalized features of amino acid composition found in thermophilic proteins, including an increase in residue hydrophobicity, a decrease in uncharged polar residues, an increase in charged residues, an increase in aromatic residues, certain amino acid coupling patterns and amino acid preferences for thermophilic proteins. The differences of amino acids composition between thermophilic and mesophilic proteins are related to some properties of amino acids. These features provide guidelines for engineering mesophilic protein to thermophilic protein. PMID- 17710364 TI - Estimating residue evolutionary conservation by introducing von Neumann entropy and a novel gap-treating approach. AB - Evolutionary conservation derived from a multiple sequence alignment is a powerful indicator of the functional significance of a residue, and it can help to predict active sites, ligand-binding sites, and protein interaction interfaces. The results of the existing algorithms in identifying the residue's conservation strongly depend on the sequence alignment, making the results highly variable. Here, by introducing the amino acid similarity matrix, we propose a novel gap-treating approach by combining the evolutionary information and von Neumann entropies to compute the residue conservation scores. It is indicated through a series of tested results that the new approach is quite encouraging and promising and may become a useful tool in complementing the existing methods. PMID- 17710365 TI - Glycogen resynthesis and exercise performance with the addition of fenugreek extract (4-hydroxyisoleucine) to post-exercise carbohydrate feeding. AB - The purpose of this study was to determine the effect of adding fenugreek extract (FG) to post-exercise carbohydrate feeding on glycogen resynthesis and subsequent exercise performance in normoglycemic male endurance athletes. A muscle biopsy sample was obtained from the vastus lateralis from subjects prior to exercise for 5 h at 50% of peak cycling power (52.1 +/- 3.3% of VO(2) peak). A second muscle biopsy sample was obtained immediately after exercise. Immediately after and 2 h after the second biopsy subjects ingested either an oral dose of dextrose (GLU) (1.8 g x kg BW(-1)) or GLU with FG containing 1.99 +/- 0.20 mg x kg(-1) 4 hydroxyisoleucine (GLU + FG) in a randomized, cross-over, double blind design. At 4 h post-exercise a third biopsy was taken and subjects received a standardised meal along with FG or a placebo capsule. At 15 h post-exercise subjects underwent their final muscle biopsy before completing a simulated 40 km cycling time trial. There was no difference in muscle glycogen at any time between GLU and GLU + FG. Additionally, 40 km time trial performance was similar for average power output (221 +/- 28 vs. 213 +/- 16 watts) and for time to completion (69.7 +/- 3.7 vs. 70.5 +/- 2.2 min) for the GLU and GLU + FG, respectively. Despite earlier data to the contrary, the present results do not support an effect of fenugreek supplementation on glycogen resynthesis, even though this may have been the result of differences in experimental protocol. PMID- 17710367 TI - Do patients associate adverse pregnancy outcomes with folkloric beliefs? AB - Many "old wives' tales" suggest that women can contribute to adverse outcomes through their behaviors and thoughts. Women attending a Midwestern American clinic were surveyed to determine how common such beliefs are. Two hundred women rated their agreement with a set of nine such beliefs. Women with a personal history of an adverse event had beliefs similar to those without such a history. The data suggest that such beliefs do not influence a woman's experience of pregnancy loss or birth defect. PMID- 17710366 TI - Screening for maternal depression in a low education population using a two item questionnaire. AB - OBJECTIVE: To assess a two-question screening tool, the Patient Health Questionnaire-2 (PHQ-2), for identifying depressive symptomatology in economically disadvantaged mothers of children in pediatric settings and to explore risk factors associated with a positive depression screen. METHODS: A convenience sample of mothers was enrolled at an inner city well-child clinic with children age 3 days to 5 years. The PHQ-2 and Edinburgh Postnatal Depression Scale (EPDS) (as reference scale) were completed. RESULTS: Ninety-four mothers participated. Agreement of the PHQ-2 and EPDS was moderate. The sensitivity of the PHQ-2 for identifying a positive screen on the EPDS was 43.5%; the specificity was 97.2%. The sensitivity of the PHQ-2 was higher for mothers with education beyond high school compared to those with less education. Perceived lack of support with child care and having two or more children were associated with a positive screen. The rate of positive screen was similar for mothers with infants and with older children. CONCLUSION: Given the low sensitivity of the PHQ 2 in lower educated mothers, additional research in populations with varying sociodemographic characteristics is indicated. Similar rates of symptoms for mothers within and beyond the postpartum period and mothers previously screened support the need for periodic screening. PMID- 17710368 TI - Announcement of JPR Awards 2007. PMID- 17710369 TI - Identification of parental genomes and genomic organization in Aster microcephalus var. ovatus. AB - The karyotype of diploid Aster iinumae is morphologically similar to that of diploid Aster ageratoides var. ageratoides, however, its chromosome size is apparently smaller (S-type chromosomes versus L-type chromosomes, respectively). The hybrid origin of tetraploid Aster microcephalus var. ovatus (LS-type chromosomes) has previously been suggested by cytogenetics and chloroplast DNA (cp DNA) data. The cp DNA phylogeny also implies that the S-type chromosome is apomorphic, which means that genome size reduction occurred on the evolutionary way to A. iinumae. In this study, we have demonstrated that the chromosome size difference does not depend on the intensity of chromosome condensation but on the DNA content. The simultaneous genomic in situ hybridization (GISH) results show the similarity between S-type chromosomes of A. iinumae and A. microcephalus var. ovatus, and between L-type chromosomes of A. ageratoides and A. microcephalus var. ovatus, which provide additional evidence for A. microcephalus var. ovatus being a tetraploid amphidiploid produced by hybridization between S-type chromosomes and L-type chromosomes. The distribution patterns of Ty1-copia-like retrotransposons were similar in L- and S-type chromosomes. The copies of this retrotransposon dispersed uniformly on all chromosomes, and it is not yet apparent how the Ty1-copia-like retrotransposon affects the size difference between them. PMID- 17710370 TI - Safety and immunogenicity of early vaccination with two doses of tetravalent measles-mumps-rubella-varicella (MMRV) vaccine in healthy children from 9 months of age. AB - BACKGROUND: This open, randomized, controlled study [208136/018] assessed the safety and immunogenicity of early vaccination with an experimental tetravalent measles-mumps-rubella-varicella (MMRV) vaccine (GlaxoSmithKline Biologicals) compared to concomitant administration of separate licensed MMR (Priorix) and varicella (Varilrix) vaccines (MMR+V). METHODS: Vaccines were administered as a two-dose course in healthy children at 9 and 12 months of age (N = 153 in the MMRV group and N = 146 in the MMR+V group). RESULTS: The incidence of fever of any intensity (axillary temperature > or = 37.5 degrees C) during the 15 days of follow-up post-dose 1 was higher in the MMRV group than in the MMR+V group (48.3% vs 25.7%, respectively) but was low in both groups post-dose 2 (20.3% and 22.1%, respectively). The incidence of fever > 39.0 degrees C and the incidence of solicited local symptoms (pain, redness, swelling) were low ( < or = 5.3% and < or = 13.7%, respectively) in the two groups after each vaccine dose. Seroconversion rates were similar in the two groups for all vaccine antigens after each vaccine dose and were > or = 99.2% for each antigen post-dose 2. Anti measles GMT was higher in the MMRV group than in the MMR+V group after the first vaccine dose. After the second dose, slight to moderate increases in measles, mumps and rubella antibody titers and a substantial increase in varicella antibody titer were seen in both groups, leading to higher GMTs in the MMRV group compared with the MMR+V group for measles, mumps and varicella. Anti-rubella antibody GMTs were similar in the two groups post-dose 2. CONCLUSION: Early vaccination with two doses of this experimental MMRV vaccine at 9 and 12 months of age was well-tolerated and at least as immunogenic as two doses of separate licensed MMR and varicella vaccines. PMID- 17710371 TI - Brain abscess after esophageal dilatation: case report. AB - Brain abscess formation is a serious disease often seen as a complication to other diseases and to procedures. A rare predisposing condition is dilatation therapy of esophageal strictures. A case of brain abscess formation after esophageal dilatations is presented. A 59-year-old woman was admitted with malaise, progressive lethargy, fever, aphasia and hemiparesis. Six days before she had been treated with esophageal dilatation for a stricture caused by accidental ingestion of caustic soda. The brain abscess was treated with surgery and antibiotics. She recovered completely. This clinical case illustrates the possible association between therapeutic esophageal dilatation and the risk of brain abscess formation. PMID- 17710372 TI - Successful treatment of Ochroconis gallopavum infection in an immunocompetent host. AB - Ochroconis gallopavum, a dematiaceous fungus, is a rare cause disease in immunocompromised patients and epidemic encephalitis in poultry. We report the first case of active O. gallopavum pulmonary infection in an immunocompetent host with rapid and complete response to oral antifungal therapy. PMID- 17710373 TI - Acute septicemic melioidosis presenting with acute cholangitis. AB - Melioidosis is a disease prevalent in the tropics, especially in Southeast Asia. The most common clinical presentations are bacteremic pneumonia and abscess formation in various organs. Although a wide variety of disease presentations are reported for melioidosis, acute cholangitis has not been previously reported. Herein, we report a 54-year-old woman who had fever, right upper abdominal pain and jaundice 1 week after a flood caused by a typhoon in southern Taiwan. Acute cholangitis and pneumonia with septic shock caused by Burkholderia pseudomallei were subsequently diagnosed. PMID- 17710374 TI - Chemotherapy as first line treatment for oligodendroglioma. PMID- 17710375 TI - Effect of low and high dose melagatran and other antithrombotic drugs on platelet aggregation. AB - BACKGROUND: Thrombin-induced aggregation of human platelets can be completely inhibited by melagatran, the bioactive form of ximelagatran, an oral direct thrombin inhibitor. METHODS: The potential of melagatran to differentially inhibit alpha- and gamma-thrombins was tested with a synthetic thrombin substrate. Washed human platelets were also employed to determine if melagatran differentially inhibited alpha- and gamma-thrombin-induced platelet aggregation at distinct platelet thrombin receptors. In vitro studies were conducted with washed human platelets to determine thrombin-induced aggregation responses in the presence of varying doses of the anti-thrombotic drugs: melagatran, argatroban, heparin, and hirudin. RESULTS: Melagatran rapidly inhibits the hydrolysis of a thrombin chromogenic substrate within 0-1 min with alpha-, beta- and gamma thrombin being equally inhibited by high dose melagatran while alpha-thrombin was significantly more sensitive at low doses. The maximum level of melagatran inhibition of alpha- and gamma-thrombin-induced platelet aggregation requires platelets to be pre-incubated with the drug for 10-30 min. Melagatran appears to have no direct effect on the PAR-1 receptor. It does appear to have a direct effect on the GPIbalpha thrombin receptor activity as well as the PAR-4 receptor. Inhibition of platelet aggregation is dose dependent, however, at low melagatran doses (0.01-0.04 nM) platelets aggregate at significantly (P < 0.05) higher levels. The lower the level of thrombin-induced aggregation that was observed with control samples (aggregations from 10% to 39%), corresponded with a higher observed melagatran-induced stimulation with drug-treated platelets. The range of stimulation varies between several hundred percent at approximately 10% aggregation to around 20% at about 20-39% aggregation. Preliminary studies indicate that this in vitro stimulatory effect is abrogated in platelets derived from volunteers who took aspirin (81 mg/day) for 7 days. Three other anti thrombotic drugs, argatroban, heparin and hirudin, were tested with low drug levels but none were found to consistently stimulate the reaction. CONCLUSIONS: These results indicate that melagatran acts as both a direct thrombin inhibitor and indirectly by some interaction with the platelet membrane. While melagatran has been withdrawn from clinical use, its ability to differentially inhibit gamma thrombin/PAR-4 versus alpha-thrombin/PAR-1 at low doses may warrant it, or less toxic analogs to be used in the future for as yet unknown disease states involving PAR-4. PMID- 17710377 TI - Can emergency medicine physicians accurately identify i.v. t-PA eligible acute stroke patients? PMID- 17710376 TI - A two-step fermentation process for efficient production of penta-N-acetyl chitopentaose in recombinant Escherichia coli. AB - The nodC gene from Mesorhizobium loti was cloned into E. coli, leading to production of chitin oligosaccharides (COs)-mainly penta-N-acetyl-chitopentaose. A two-step fermentation procedure was then developed which gave 930 mg CO/L with a productivity of 37 mg/l.h. PMID- 17710379 TI - In vitro conservation and sustained production of breadfruit (Artocarpus altilis, Moraceae): modern technologies for a traditional tropical crop. AB - Breadfruit (Artocarpus altilis, Moraceae) is a traditionally cultivated, high energy, high-yield crop, but widespread use of the plant for food is limited by poor quality and poor storage properties of the fruit. A unique field genebank of breadfruit species and cultivars exists at the National Tropical Botanical Garden in the Hawaiian Islands and is an important global resource for conservation and sustainable use of breadfruit. However, this plant collection could be damaged by a random natural disaster such as a hurricane. We have developed a highly efficient in vitro plant propagation system to maintain, conserve, mass propagate, and distribute elite varieties of this important tree species. Mature axillary shoot buds were collected from three different cultivars of breadfruit and proliferated using a cytokinin-supplemented medium. The multiple shoots were maintained as stock cultures and repeatedly used to develop whole plants after root differentiation on a basal or an auxin-containing medium. The plantlets were successfully grown under greenhouse conditions and were reused to initiate additional shoot cultures for sustained production of plants. Flow cytometry was used to determine the nuclear deoxyribonucleic acid content and the ploidy status of the in vitro grown population. The efficacy of the micropropagation protocols developed in this study represents a significant advancement in the conservation and sustained mass propagation of breadfruit germplasm in a controlled environment free from contamination. PMID- 17710378 TI - [Optimizing dermatopathologic diagnosis with digital photography and internet. The significance of clinicopathologic correlation]. AB - Clinicopathologic correlation is the basis of a precise diagnosis. Especially in dermatopathology, the precision of a microscopic diagnosis may significantly be increased by thorough knowledge of the clinical picture. The advent of digital photography, the internet and moderately priced CDs and USB-sticks have made it possible to establish and maintain a time-saving, low-cost picture data transfer between dermatologist and dermatopathologist which is optimally suited for clinicopathologic correlation. PMID- 17710380 TI - [Gustav Klimt and the field of medicine. Painting of the medical faculty- relationship with the Zuckerkandl family]. AB - The art nouveau painter Gustav Klimt (1862-1918), a cofounder of the Vienna Secession movement, was commissioned in 1894 to prepare three ceiling paintings for the Great Hall of the University of Vienna portraying the faculties of "Philosophy," "Medicine," and "Jurisprudence." After the first public presentations of these paintings starting in 1900 fierce protests erupted since the artist had not painted a historical allegory but rather had created a modern symbolic picture in the Secessionism style. The controversy over the so-called faculty paintings escalated to the point that in 1905 Klimt irrevocably distanced himself from the commission and bought back his pictures from the state. The paintings were later purchased by the Austrian Gallery and in 1943 placed in storage in Lower Austria at the Immendorf Castle where they were destroyed by a fire in May 1945 when the German troops withdrew. Besides Klimt's preliminary sketches, only black and white photographs of the three paintings now exist as well as a color reproduction of the section depicting Hygieia from the "Medicine" painting. Due to the public rejection of the faculty paintings, Gustav Klimt broke away from official government-commissioned art and focused on private clients from among Viennese society. One of these intensive associations was with the anatomist Emil Zuckerkandl and his wife Berta, who was very active in cultural affairs. During the dispute over the faculty paintings, Zuckerkandl was one of the few university professors who signed a petition in favor of retaining the paintings. His brother, the industrialist Victor Zuckerkandl, was one of the major collectors and patrons of Secessionist art. The third brother, the well known urologist Otto Zuckerkandl (1861-1921), president of the Second and Third Congresses of the German Society of Urology in 1909 and 1911, was also in close contact with Klimt. A portrait of his wife Amalie was a work in progress between 1913 and 1917, but it remained unfinished. PMID- 17710381 TI - [Arthroscopic suturing of the rotator cuff. Placing of anchor, suturing and tying techniques]. AB - Arthroscopic reconstruction of a rotator cuff tear is a demanding technique. Besides assessment and appraisal of the different types of tears, their mobilisation and, especially, secure refixation of the soft tissue are necessary if the operation is to be successful: suture anchors must be optimally placed, and suturing must be reliably achieved while the surgical field is viewed arthroscopically. A correct technique for arthroscopic knot tying after passage of the suture thread through the tendon is also essential for the holding strength of the sutures. The way the suture thread is tied during the arthroscopic procedure needs to be tailored to the individual situation. It is essential that the operator has mastered the technique of tying nonslipping knots, by alternating holding and connecting threads with the use of a knot pusher. There is a vast number of published arthroscopic knots, and the one selected as suitable also needs to be adapted to the suture material. PMID- 17710382 TI - One single dose of etomidate negatively influences adrenocortical performance for at least 24h in children with meningococcal sepsis. AB - OBJECTIVE: To investigate the effect of one single bolus of etomidate used for intubation on adrenal function in children with meningococcal sepsis. DESIGN: Retrospective study conducted between 1997 and 2004. SETTING: University affiliated paediatric intensive care unit (PICU). PATIENTS AND PARTICIPANTS: Sixty children admitted to the PICU with meningococcal sepsis, not treated with steroids. INTERVENTIONS: Adrenal hormone concentrations were determined as soon as possible after PICU admission, and after 12h and 24h. To assess disease severity, PRISM score and selected laboratory parameters were determined. MEASUREMENTS AND MAIN RESULTS: On admission, before blood was drawn, 23 children had been intubated with etomidate, 8 without etomidate and 29 were not intubated. Children who were intubated had significantly higher disease severity parameters than those not intubated, whereas none of these parameters significantly differed between children intubated with or without etomidate. Children who received etomidate had significantly lower cortisol, higher ACTH and higher 11 deoxycortisol levels than those who did not receive etomidate. Arterial glucose levels were significantly lower in children who were intubated with etomidate than in non-intubated children. When children were intubated with etomidate, cortisol levels were 3.2 times lower for comparable 11-deoxycortisol levels. Eight children died, seven of whom had received etomidate. Within 24h cortisol/ACTH and cortisol/11-deoxycortisol ratios increased significantly in children who received etomidate, but not in children who did not, resulting in comparable cortisol/ACTH ratios with still significantly lowered cortisol/11 deoxycortisol ratios 24h after admission. CONCLUSIONS: Our data imply that even one single bolus of etomidate negatively influences adrenal function for at least 24h. It might therefore increase risk of death. PMID- 17710384 TI - Entry and intracellular location of Mycoplasma hominis in Trichomonas vaginalis. AB - The parasite Trichomonas vaginalis causes one of the most common non-viral sexually transmitted infections in humans. The coexistence of different sexually transmitted diseases in the same individual is very common, such as vaginal infections by T. vaginalis in association with Mycoplasma fermentans or Mycoplasma hominis. However, the consequences and behavior of mycoplasma during trichomonad infections are virtually unknown. This study was undertaken to elucidate whether mycoplasmas enter and leave trichomonad cells and if so how. M. hominis was analyzed in different trichomonad isolates and the process of internalization and the pathway within the parasite was studied. Parasites naturally and experimentally infected with mycoplasmas were used and transmission electron microscopy, cytochemistry and PCR analyses were performed. The results show that: (1) M. hominis enters T. vaginalis cells by endocytosis; (2) some mycoplasmas use a terminal polar tip as anchor to the trichomonad plasma membrane; (3) some trichomonad isolates are able to digest mycoplasmas, mainly when the trichomonads are experimentally infected; (4) some fresh virulent isolates are able to maintain mycoplasmas as cohabitants in the cell's interior; (5) some mycoplasmas are able to escape from the vacuole to the trichomonad cytosol, and trichomonad plasma membrane budding suggested that mycoplasmas could leave the parasite cell. PMID- 17710383 TI - Epoprostenol treatment of acute pulmonary hypertension is associated with a paradoxical decrease in right ventricular contractility. AB - OBJECTIVE: Prostacyclins have been suggested to exert positive inotropic effects which would render them particularly suitable for the treatment of right ventricular (RV) dysfunction due to acute pulmonary hypertension (PHT). Data on this subject are controversial, however, and vary with the experimental conditions. We studied the inotropic effects of epoprostenol at clinically recommended doses in an experimental model of acute PHT. DESIGN AND SETTING: Prospective laboratory investigation in a university hospital laboratory. SUBJECTS: Six pigs (36 +/- 7kg). INTERVENTIONS: Pigs were instrumented with biventricular conductance catheters, a pulmonary artery (PA) flow probe, and a high-fidelity pulmonary pressure catheter. Incremental doses of epoprostenol (10, 15, 20, 30, 40ng kg(-1) min(-1)) were administered in undiseased animals and after induction of acute hypoxia-induced PHT. MEASUREMENTS AND RESULTS: In acute PHT epoprostenol markedly reduced RV afterload (slopes of pressure-flow relationship in the PA from 7.0 +/- 0.6 to 4.2 +/- 0.7mmHg minl(-1)). This was associated with a paradoxical and dose-dependent decrease in RV contractility (slope of preload-recruitable stroke-work relationship from 3.0 +/- 0.4 to 1.6 +/ 0.2 mW s ml(-1); slope of endsystolic pressure-volume relationship from 1.5 +/- 0.3 to 0.7 +/- 0.3mmHg ml(-1)). Left ventricular contractility was reduced only at the highest dose. In undiseased animals epoprostenol did not affect vascular tone and produced a mild biventricular decrease in contractility. CONCLUSIONS: Epoprostenol has no positive inotropic effects in vivo. In contrast, epoprostenol induced pulmonary vasodilation in animals with acute PHT was associated with a paradoxical decrease in RV contractility. This effect is probably caused indirectly by the close coupling of RV contractility to RV afterload. However, data from normal animals suggest that mechanisms unrelated to vasodilation are also involved in the observed negative inotropic response to epoprostenol. PMID- 17710386 TI - Detection of avian influenza virus using an interferometric biosensor. AB - An interferometric biosensor immunoassay for direct and label-less detection of avian influenza through whole virus capture on a planar optical waveguide is described. The assay response is based on index of refraction changes that occur upon binding of virus particles to unique antigen-specific (hemagglutinin) antibodies on the waveguide surface. Three virus subtypes (two H7 and one H8) in buffer solution were tested using both monoclonal and polyclonal capture antibodies. The real-time response of the antigen-antibody interaction was measured and was shown to be concentration-dependent, with detection limits as low as 0.0005 hemagglutination units per milliliter. A simple sandwich assay was shown to further increase the biosensor response. PMID- 17710387 TI - Certification of SRM 1589a PCBs, pesticides, PBDEs, and dioxins/furans in human serum. AB - The Certificate of Analysis for SRM 1589a PCBs, Pesticides, PBDEs, and Dioxins/Furans in Human Serum has been updated to include certified concentration values for 27 polychlorinated biphenyl (PCB) congeners, three chlorinated pesticides, and four polybrominated diphenyl ether (PBDE) congeners as well as reference concentration values for 27 additional PCB congeners, six additional chlorinated pesticides, three additional PBDE congeners, and selected polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). This represents an addition of concentration values for 29 PCB congeners and for PBDE congeners that were not quantified in the previous issue of SRM 1589a. With the increased number of certified and reference concentration values for PCBs and the inclusion of certified and reference concentration values for PBDEs, this serum material will be more useful as a reference material for contaminant monitoring in human tissues and fluids. PMID- 17710385 TI - Cross-sensitization of the reinforcing effects of cocaine and amphetamine in rats. AB - RATIONALE: Cross-sensitization between cocaine and amphetamine has been demonstrated in different behavioral paradigms. There is a relative paucity of studies examining whether cross-sensitization occurs between amphetamine and cocaine when both are self-administered. OBJECTIVE: The current study was designed to test whether animals sensitized to the reinforcing effects of cocaine would show cross-sensitization of the reinforcing effects of amphetamine, using a self-administration paradigm. MATERIALS AND METHODS: Male, Sprague-Dawley rats were trained to self-administer cocaine and given limited or high exposure to cocaine under a fixed ratio (FR) 1 procedure. After the initial exposure to cocaine, animals self-administered cocaine (1.5 mg/kg per injection) under a progressive ratio (PR) procedure. Subsequently, breakpoints on a PR schedule and rates of intake on an FR schedule maintained by different doses of amphetamine were assessed. RESULTS: Animals with high initial exposure to cocaine (40 injections of 1.5 mg/kg per injection per day for 5 days) showed stable breakpoints throughout testing. Animals given limited initial cocaine exposure (20 injections of 0.75 mg/kg per injection for 1 day) produced a gradual increase in breakpoints maintained by cocaine over time (i.e., sensitization of the reinforcing effects of cocaine). When subsequently tested with amphetamine, the dose-effect curve was shifted upward in the limited-exposure group relative to the high-exposure group, suggesting cross-sensitization of the reinforcing effects of amphetamine. CONCLUSIONS: Sensitization of the reinforcing effects of cocaine resulted in cross-sensitization of the reinforcing effects of amphetamine. This phenomenon occurs even when both drugs are self-administered. PMID- 17710388 TI - Simultaneous determination of inorganic mercury, methylmercury, and total mercury concentrations in cryogenic fresh-frozen and freeze-dried biological reference materials. AB - Two speciated isotope dilution (SID) approaches consisting of a single-spike (SS) method and a double-spike (DS) method including a reaction/transformation model for the correction of inadvertent transformations affecting mercury species were compared in terms of accuracy, method performance, and robustness for the simultaneous determination of methylmercury (MeHg), inorganic mercury (iHg), and total mercury (HgT) concentrations in five biological Standard Reference Materials (SRMs). The SRMs consisted of oyster and mussel tissue materials displaying different mercury species concentration levels and different textural/matrix properties including freeze-dried (FD) materials (SRMs 1566b, 2976, and 2977) and cryogenically prepared and stored fresh-frozen (FF) materials (SRMs 1974a, 1974b). Each sample was spiked with (201)iHg (Oak Ridge National Laboratory, ORNL) and Me(202)Hg (Institute for Reference Materials and Measurements. IRMM-670) solutions and analyzed using alkaline microwave digestion, ethylation, and gas chromatography inductively coupled plasma mass spectrometry (GC/ICP-MS). The results obtained by the SS-SID method suggested that FF and FD materials are not always commutable for the simultaneous determination of iHg, MeHg, and HgT, due to potential transformation reactions resulting probably from the methodology and/or from the textural/matrix properties of the materials. These transformations can occasionally significantly affect mercury species concentration results obtained by SS-SID, depending on the species investigated and the materials considered. The results obtained by the DS SID method indicated that the two classes of materials were commutable. The simultaneous and corrected concentrations of iHg, MeHg, and HgT obtained by this technique were not found to be statistically different form the certified and reference concentration together with their expanded uncertainty budgets for the five SRMs investigated, exemplifying the robustness, the accuracy, and the improved commutability of this method compared to SS-SID measurements. PMID- 17710391 TI - Alkaliphilic and halophilic hydrocarbon-utilizing bacteria from Kuwaiti coasts of the Arabian Gulf. AB - Green animate materials from the intertidal zone of the Arabian Gulf coast accommodated more alkaliphilic and halophilic bacteria than inanimate materials. The alkaliphilic oil-utilizing bacteria, as identified by their 16S ribonucleic acid sequences, belonged to the following genera arranged in decreasing frequences: Marinobacter, Micrococcus, Dietzia, Bacillus, Oceanobacillus, and Citricoccus. The halophilic oil-utilizing bacteria belonged to the genera: Marinobacter, Georgenia, Microbacterium, Stappia, Bacillus, Isoptericola, and Cellulomonas. Most isolates could grow on a wide range of pure n-alkanes and aromatic compounds, as sole sources of carbon and energy. Quantitative gas liquid chromatographic analysis showed that individual isolates attenuated crude oil and representative pure hydrocarbons in culture. The optimum pH for most of the alkaliphilic genera was pH 10, and the optimum salinity for the halophiles ranged between 2.5 and 5% NaCl (w/v). It was concluded that as far as their microbial makeup is concerned, oily alkaline and saline intertidal areas of the Kuwaiti coasts have a self-cleaning potential. PMID- 17710392 TI - Effects of aeration intensity on formation of phenol-fed aerobic granules and extracellular polymeric substances. AB - Effect of air aeration intensities on granule formation and extracellular polymeric substances content in three identical sequential batch reactors were investigated. The excitation-emission-matrix spectra and multiple staining and confocal laser scanning microscope revealed proteins, polysaccharides, lipids, and humic substances in the sludge and granule samples. Seed sludge flocs were compacted at low aeration rate, with produced extracellular polymeric substances of 50.2-76.7 mg g(-1) of proteins, 50.2-77.3 mg g(-1) carbohydrates and 74 mg g( 1) humic substances. High aeration rate accelerated formation of 1.0-1.5 mm granules with smooth outer surface. The corresponding quantities of extracellular polymeric substances were 309-537 mg g(-1) of proteins, 61-109 mg g(-1) carbohydrates, 49-92 mg g(-1) humic substances, and 49-68 mg g(-1) lipids. Intermediate aeration rate produced 3.0-3.5 mm granules with surface filaments. Reactor failure occurred with overgrowth of filaments, probably owing to the deficiency of nutrient in liquid phase. No correlation was noted between extracellular polymeric substances composition and the proliferation of filamentous microorganisms on granule surface. PMID- 17710390 TI - MRI evaluation of tissue iron burden in patients with beta-thalassaemia major. AB - beta-Thalassaemia major is a hereditary haemolytic anaemia that is treated with multiple blood transfusions. A major complication of this treatment is iron overload, which leads to cell death and organ dysfunction. Chelation therapy, used for iron elimination, requires effective monitoring of the body burden of iron, for which serum ferritin levels and liver iron content measured in liver biopsies are used as markers, but are not reliable. MRI based on iron-induced T2 relaxation enhancement can be used for the evaluation of tissue siderosis. Various MR protocols using signal intensity ratio and mainstream relaxometry methods have been used, sometimes with discrepant results. Relaxometry methods using multiple echoes achieve better sampling of the time domain in which relaxation mechanisms take place and lead to more precise results. In several studies the MRI parameters of liver siderosis have failed to correlate with those of other affected organs, underlining the necessity for MRI iron evaluation in individual organs. Most studies have included children in the evaluated population, but MRI data on very young children are lacking. Wider application of relaxometry methods is indicated, with the establishment of universally accepted MRI protocols, and further studies, including young children, are needed. PMID- 17710393 TI - A novel enantioselective epoxide hydrolase for (R)-phenyl glycidyl ether to generate (R)-3-phenoxy-1,2-propanediol. AB - Bacillus sp. Z018, a novel strain producing epoxide hydrolase, was isolated from soil. The epoxide hydrolase catalyzed the stereospecific hydrolysis of (R)-phenyl glycidyl ether to generate (R)-3-phenoxy-1,2-propanediol. Epoxide hydrolase from Bacillus sp. Z018 was inducible, and (R)-phenyl glycidyl ether was able to act as an inducer. The fermentation conditions for epoxide hydrolase were 35 degrees C, pH 7.5 with glucose and NH(4)Cl as the best carbon and nitrogen source, respectively. Under optimized conditions, the biotransformation yield of 45.8% and the enantiomeric excess of 96.3% were obtained for the product (R)-3-phenoxy 1,2-propanediol. PMID- 17710394 TI - Adding 11C-methionine PET to the EORTC prognostic factors in grade 2 gliomas. AB - PURPOSE: The management of adult patients with grade 2 gliomas remains a challenge for the clinical neuro-oncologist. Several clinical prognostic factors appear to be as important as treatment factors in determining outcome. From the European Organisation for Research and Treatment of Cancer (EORTC) trials 22844 and 22845, a prognostic scoring system has been proposed based on the presence of unfavourable prognostic factors. The aim of the present study was to assess the additional prognostic value of (11)C-methionine (MET) measured by positron emission tomography (PET) in the setting of the EORTC prognostic scoring system. METHODS: In this retrospective review, 129 patients with supratentorial grade 2 gliomas were subjected to a PET study as part of the pre-treatment tumour investigation. One hundred and three cases were classified as low-risk patients (0-2 unfavourable factors) and 26 cases as high-risk patients (3-5 unfavourable factors) according to the EORTC criteria. MET PET was evaluated as an extra prognostic factor in both groups. RESULTS: In the high-risk group, patients with high MET uptake had a worse outcome than patients with low MET uptake. A similar trend was found for the low-risk group in patients with oligodendrocytic tumours. CONCLUSIONS: Our findings further strengthen the role of MET PET as an important prognostic tool in the management of this group of patients. PMID- 17710396 TI - Transient downregulation of monocyte-derived dendritic-cell differentiation, function, and survival during tumoral progression and regression in an in vivo canine model of transmissible venereal tumor. AB - Tumors often target dendritic cells (DCs) to evade host immune surveillance. DC injury is reported in many rodent and human tumors but seldom in tumors of other mammals. Canine transmissible venereal tumor (CTVT), a unique and spontaneous cancer transmitted by means of viable tumor cells. CTVT causes manifold damage to monocyte-derived DCs. This cancer provides an in vivo model of cancer to study the role of monocyte-derived DCs during spontaneous regression. Using flow cytometry and real-time reverse-transcription polymerase chain reactions, we compared the expression of surface molecules on monocyte-derived DCs between normal dogs and dogs with CTVT. These markers were CD1a, CD83, costimulatory factors (CD40, CD80, and CD86), and major histocompatability complex classes I and II. In immature DCs (iDCs) and lipopolysaccharide-treated mature DCs (mDCs), the surface markers were mostly downregulated during tumoral progression and regression. The tumor lowered endocytic activity of iDCs, as reflected in dextran uptake, and decreased allogeneic mixed lymphocyte reactions of mDCs. In addition, it decreased the number of monocytes in the peripheral blood by 40%. The tumor substantially impaired the efficiency with which DCs were generated from monocytes and with which mDCs were generated from iDCs. We also found that progression-phase CTVT supernatants that were cultured for 48 h and that contained protein components killed both monocytes and DCs. Additionally, DC numbers were significantly lower in the draining lymph nodes in CTVT dogs than in normal dogs. In conclusion, CTVT caused devastating damage to monocyte-derived DCs; this might be one of its mechanisms for evading host immunity. Reestablishment of monocyte-derived DC activity by the host potentially might contribute to spontaneous tumoral regression. These findings provide insight into the extent of tumoral effects on host immune systems and responses. This information is useful for developing cancer immunotherapies. PMID- 17710397 TI - Light chain myeloma in a patient with thyroid carcinoma. PMID- 17710395 TI - PET-CT enteroclysis: a new technique for evaluation of inflammatory diseases of the intestine. AB - PURPOSE: While CT/MR enteroclysis provides excellent anatomical details, it fails to provide information on metabolic activity of the inflammatory lesions of the intestine. We conceptualized a fusion of metabolic imaging techniques such as PET and an anatomical imaging modality such as CT enteroclysis to derive information both on morphological details and functional activity of lesions at the same time. PATIENTS AND METHODS: In a prospective study, we included 17 adult patients with newly diagnosed inflammatory diseases of the intestine. Low dose whole body PET-CT scan was obtained first, which began at approximately 60 min after injection of 10 mCi of (18)fluoro-deoxyglucose (FDG). Subsequently, PET-CT enteroclysis of the abdomen was performed after infusion of 2 l of 0.5% methylcellulose through a naso-jejunal catheter. RESULTS: Fourteen patients had abnormal and three had normal PET-CT enteroclysis studies. Twenty-three segments of small intestine and 27 segments of large intestine showed increased FDG uptake. The detection rate of PET-CT enteroclysis was significantly higher (total =50 segments, 23 segments of small intestine and 27 segments of large intestine) as compared with barium studies (16 segments of small intestine) and colonoscopy (17 segments of large intestine) combined together (total =33 segments). In addition PET-CT enteroclysis showed extra-luminal FDG uptake (lymph nodes in two, sacroilitis in two, and mesenteric fat proliferation in five). CONCLUSIONS: As a single investigation, PET-CT enteroclysis detects a significantly higher number of lesions both in the small and large intestine in comparison to that detected by conventional barium and colonoscopy combined together. This technique is non invasive, feasible and very promising. PMID- 17710398 TI - Pegfilgrastim compared with filgrastim after autologous peripheral blood stem cell transplantation in patients with solid tumours and lymphomas. AB - To evaluate the safety and efficacy of pegfilgrastim administered as haematological support after autologous peripheral blood stem cell transplantation, we compared 44 patients with solid tumours and lymphomas receiving a 6-mg single dose of pegfilgrastim on day +5 after transplantation to a historical control group of 25 patients receiving filgrastim 5 microg kg(-1) day(-1) starting on day +5. There were no significant differences in haematological recovery nor in the incidence and duration of neutropenic fever. Median duration of grade 4 neutropenia in the pegfilgrastim and filgrastim group was similar. The incidence of grade III-IV mucositis was lower in pegfilgrastim than in filgrastim group due to the significant difference observed among the patients with solid tumours (p = 0.00). The only adverse event considered to be cytokine related was mild to moderate bone pain occurring during haematological recovery. According to the present study design and taking into account the current prices in our institution, the cost of the two drugs was similar in both treatment groups. In conclusion, a single injection of pegfilgrastim administered at day +5 post-transplantation shows comparable safety and efficacy profiles to daily injections of filgrastim and may be cost effective. PMID- 17710399 TI - Dramatic hyperleukocytosis after treatment of myelodysplastic syndrome with pegfilgrastim and darbepoetin-alfa. PMID- 17710400 TI - In vitro cross-resistance to nucleoside analogues and inhibitors of topoisomerase 1 and 2 in acute myeloid leukemia. AB - Only about one third of all patients with acute myeloid leukemia (AML) will be cured by common chemotherapy regimens. Susceptibility towards chemotherapy either of the leukemic bulk or the leukemic stem cell is considered the major determining parameter for long-term outcome. The purpose of the present study was to investigate whether chemoresistance was correlated between different antileukemic drugs or not. We determined the lethal concentration of chemotherapy necessary to reduce viability of cells to 50% compared to untreated control (LC50) as a surrogate marker of chemotherapy susceptibility of six established chemotherapeutic agents [cytarabine (median 0.83 microg/ml), daunorubicine (0.09 microg/ml), idarubicine (0.03 microg/ml), mitoxantrone (0.05 microg/ml), etoposide (4.81 microg/ml), and topotecan (0.14 microg/ml)] in an overall number of 147 samples from consecutive patients with AML by WST-1 assay in vitro. We found that susceptibility to chemotherapy was significantly correlated between all six agents (all p values < 0.01). A homogenous response of the blast populations was significantly correlated to high chemoresistance. These data indicate that cross-resistance in AML against antileukemic drugs exists between agents with different modes of action and seems not to be mediated by drug specific resistance mechanisms but rather by more generalized death-defying features of the affected cells (e.g., inhibited apoptosis). PMID- 17710401 TI - BEAC or BEAM high-dose chemotherapy followed by autologous stem cell transplantation in non-Hodgkin's lymphoma patients: comparative analysis of efficacy and toxicity. AB - The treatment of choice for relapsed/refractory non-Hodgkin's lymphoma (NHL) consists of high-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT). Little is known, however, regarding the comparative toxicity and efficacy of various HDC regimens applied in NHL. We have retrospectively evaluated the clinical aspects of the BCNU, etoposide, cytarabine, and cyclophosphamide (BEAC) and BCNU, etoposide, cytarabine, and melphalan (BEAM) regimens for ASCT. Between April 1994 and February 2005, 97 NHL patients underwent HDC with BEAC (N = 69) or BEAM (N = 28), followed by ASCT, at the Asan Medical Center. We matched each BEAM patient with two BEAC patients having the same International Prognostic Index. Thus, 84 patients (56 BEAC and 28 BEAM) were analyzed. Median age was 40.5 years, and baseline characteristics were well balanced between the two groups. The median time to neutrophil engraftment (>500/mm(3)) was significantly longer with BEAC than with BEAM (12 vs 11 days, P = 0.001), as was the total amount of red blood cell transfusion (6.5 vs 3.7U, P = 0.037), but the median time to platelet engraftment (>20,000/mm(3)) and the total amount of platelet transfusion did not differ between the two groups. BEAM patients had significantly more frequent World Health Organization grade greater than or equal to 2 diarrhea than BEAC patients (46.4 vs 19.6%, P = 0.010), but the incidence of mucositis, nausea/vomiting, and bleeding and the number of episodes of febrile neutropenia and septicemia did not differ between the two groups. Median follow-up for survivors was 33 months in the BEAM group and 89 months in the BEAC group. Median overall survival and median event-free survival were not reached in the BEAM group and were 7.9 (95% confidence interval [CI], 1 14.8 months, P = 0.003) and 3.7 months (95% CI, 0.1-7.2 months, P = 0.001), respectively, in the BEAC group. BEAM appeared to be superior to BEAC for survival. Regimen-related toxicities were similar, except that BEAM was associated with more frequent but acceptable diarrhea. PMID- 17710402 TI - Effects of dominance on the probability of fixation of a mutant allele. AB - We consider whether the fixation probability of an allele in a two-allele diploid system is always a monotonic function of the selective advantage of the allele. We show that while this conjecture is correct for intermediate dominance, it is not correct in general for either overdominant or underdominant alleles, and that for some parameter ranges the fixation probability can initially decrease and then increase as a function of the amount of selection. We have partial results that characterize the ranges of parameters for which this happens. PMID- 17710404 TI - Serum chitotriosidase activity in sarcoidosis patients. PMID- 17710403 TI - Membrane stress is coupled to a rapid translational control of gene expression in chlorpromazine-treated cells. AB - Chlorpromazine (CPZ) is a small permeable cationic amphiphilic molecule that inserts into membrane bilayers and binds to anionic lipids such as poly phosphoinositides (PIs). Since PIs play important roles in many cellular processes, including signaling and membrane trafficking pathways, it has been proposed that CPZ affects cellular growth functions by preventing the recruitment of proteins with specific PI-binding domains. In this study, we have investigated the biological effects of CPZ in the yeast Saccharomyces cerevisiae. We screened a collection of approximately 4,800 gene knockout mutants, and found that mutants defective in membrane trafficking between the late-Golgi and endosomal compartments are highly sensitive to CPZ. Microscopy and transport analyses revealed that CPZ affects membrane structure of organelles, blocks membrane transport and activates the unfolded protein response (UPR). In addition, CPZ treatment induces phosphorylation of the translation initiation factor (eIF2alpha), which reduces the general rate of protein synthesis and stimulates the production of Gcn4p, a major transcription factor that is activated in response to environmental stresses. Altogether, our results reveal that membrane stress within the cells rapidly activates an important gene expression program, which is followed by a general inhibition of protein synthesis. Remarkably, the increase of phosphorylated eIF2alpha and protein synthesis inhibition were also detected in CPZ-treated NIH-3T3 fibroblasts, suggesting the existence of a conserved mechanism of translational regulation that operates during a membrane stress. PMID- 17710405 TI - Tumor necrosis factor alpha -308 polymorphism is associated with rheumatoid arthritis in Han population of Eastern China. AB - The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) in tumor necrosis factor alpha (TNFalpha) promoter with rheumatoid arthritis (RA) in Chinese Han population. Six SNPs at positions -238, 244, -308, -376, -857, -863 within TNFalpha promoter were genotyped in 367 unrelated RA patients and 271 healthy controls, using direct DNA sequencing method. Allelic, genotypic, and haplotypic associations of these SNPs with RA were examined. The frequencies of TNFalpha -308A allele and the haplotype GACC (in order of -238, -308, -857, -863) were significantly lower in RA patients when compared with healthy controls (P = 0.0046, P = 0.0045, respectively) but TNFalpha -308 polymorphism was not related to the clinical manifestations of RA patients. These results implied that TNFalpha gene itself or a gene in linkage disequilibrium with it might be associated with RA in Han population of Eastern China. PMID- 17710406 TI - Evidence of artemisinin production from IPP stemming from both the mevalonate and the nonmevalonate pathways. AB - The potent antimalarial sesquiterpene lactone, artemisinin, is produced in low quantities by the plant Artemisia annua L. The source and regulation of the isopentenyl diphosphate (IPP) used in the biosynthesis of artemisinin has not been completely characterized. Terpenoid biosynthesis occurs in plants via two IPP-generating pathways: the mevalonate pathway in the cytosol, and the non mevalonate pathway in plastids. Using inhibitors specific to each pathway, it is possible to resolve which supplies the IPP precursor to the end product. Here, we show the effects of inhibition on the two pathways leading to IPP for artemisinin production in plants. We grew young (7-14 days post cotyledon) plants in liquid culture, and added mevinolin to the medium to inhibit the mevalonate pathway, or fosmidomycin to inhibit the non-mevalonate pathway. Artemisinin levels were measured after 7-14 days incubation, and production was significantly reduced by each inhibitor compared to controls, thus, it appears that IPP from both pathways is used in artemisinin production. Also when grown in miconazole, an inhibitor of sterol biosynthesis, there was a significant increase in artemisinin compared to controls suggesting that carbon was shifted from sterols into sesquiterpenes. Collectively these results indicate that artemisinin is probably biosynthesized from IPP pools from both the plastid and the cytosol, and that carbon from competing pathways can be channeled toward sesquiterpenes. This information will help advance our understanding of the regulation of in planta production of artemisinin. PMID- 17710409 TI - Odor discrimination in classical conditioning of proboscis extension in two stingless bee species in comparison to Africanized honeybees. AB - Learning in insects has been extensively studied using different experimental approaches. One of them, the proboscis extension response (PER) paradigm, is particularly well suited for quantitative studies of cognitive abilities of honeybees under controlled conditions. The goal of this study was to analyze the capability of three eusocial bee species to be olfactory conditioned in the PER paradigm. We worked with two Brazilian stingless bees species, Melipona quadrifasciata and Scaptotrigona aff. depilis, and with the invasive Africanized honeybee, Apis mellifera. These three species present very different recruitment strategies, which could be related with different odor-learning abilities. We evaluated their gustatory responsiveness and learning capability to discriminate floral odors. Gustatory responsiveness was similar for the three species, although S. aff. depilis workers showed fluctuations along the experimental period. Results for the learning assays revealed that M. quadrifasciata workers can be conditioned to discriminate floral odors in a classical differential conditioning protocol and that this discrimination is maintained 15 min after training. During conditioning, Africanized honeybees presented the highest discrimination, for M. quadrifasciata it was intermediate, and S. aff. depilis bees presented no discrimination. The differences found are discussed considering the putative different learning abilities and procedure effect for each species. PMID- 17710408 TI - Muscle anatomy is a primary determinant of muscle relaxation dynamics in the lobster (Panulirus interruptus) stomatogastric system. AB - We stained sarcomere thin filaments with fluorescently labeled phalloidin, measured sarcomere and muscle length, and calculated sarcomere number in pyloric and gastric mill muscles. A wide range of sarcomere lengths (3.25-12.29 microm), muscle lengths (5.9-21.1 mm), and sarcomere numbers (648-3,036) were observed. Sarcomere number differences occurred both because of changes in sarcomere length and muscle length, and sarcomere and muscle length varied independently. This independence, the wide range of sarcomere numbers present, and the muscles being all 'slow', graded muscles allowed us to use these data to test Huxley and Neidergerke's (1954) hypothesis that muscle dynamics depend on sarcomere number. The time constants of exponential fits to contraction relaxations were used to measure muscle dynamics, and comparison of theoretical predictions and experimental results quantitatively confirm the predicted dependence. The differing dynamics of the various pyloric muscles are likely functionally important, and the dependence of muscle dynamics on sarcomere number implies that sarcomere number is likely closely regulated in these muscles. The stomatogastric system may thus be an excellent model system for studying the mechanisms regulating muscle sarcomere number. PMID- 17710410 TI - Free flight maneuvers of stalk-eyed flies: do eye-stalks affect aerial turning behavior? AB - The eyes of stalk-eyed flies (Diopsidae) are positioned at the end of rigid peduncles projected laterally from the head. In dimorphic species the eye-stalks of males exceed the eye-stalks of females and can exceed body length. Eye-stalk length is sexually selected in males improving male reproductive success. We tested whether the long eye-stalks have a negative effect on free-flight and aerial turning behavior by analyzing the morphology and free-flight trajectories of male and female Cyrtodiopsis dalmanni. At flight posture the mass-moment-of inertia for rotation about a vertical axis was 1.49-fold higher in males. Males also showed a 5% increase in wing length compared to females. During free-flight females made larger turns than males (54 +/- 31.4 vs. 49 +/- 36.2 degrees , t test, P < 0.033) and flew faster while turning (9.4 +/- 5.45 vs. 8.4 +/- 6.17 cm s(-1), ANOVA, P < 0.021). However, turning performance of both sexes overlapped, and turn rate in males even marginally exceeded turn rate in females (733 +/- 235.3 vs. 685 +/- 282.6 deg s(-1), ANCOVA, P < 0.047). We suggest that the increase in eye-span does result in an increase in the mechanical requirements for aerial turning but that male C. dalmanni are capable of compensating for the constraint of longer eye-stalks during the range of turns observed through wingbeat kinematics and increased wing size. PMID- 17710407 TI - p53 and retinoblastoma pathways in bladder cancer. AB - A majority of the aggressive, invasive bladder carcinomas have alterations in the p53 and retinoblastoma genes and pathways. Examination of the alterations in the molecules in these pathways that regulate the cell cycle and their effects on the prognosis of bladder cancer are areas of active research. While defects in the p53-Mdm2-p14 axis have been implicated in urothelial cancer, perturbations in the cyclin-dependent kinases and their inhibitors have also been extensively studied in this context. Genetic alterations of the retinoblastoma gene and aberrant post translational modifications of its protein have also been incriminated in invasive bladder cancer. This article reviews the individual prognostic roles of alterations in these molecules in the context of bladder cancer. Additionally, we review findings from recent studies that are attempting to analyze these markers in combination in an effort to construct molecular panels that can serve as more robust outcome predictors. More importantly, alterations in these molecules are now becoming enticing targets for novel therapeutics. We also review some of these agents that can restore the tumor cells' altered homeostatic mechanisms, thereby having potential in transitional cell carcinoma therapy. Future management of bladder cancer will employ validated marker panels for outcome prediction, and novel genetic and pharmacologic agents that will be able to target molecular alterations in individual tumors based on their respective profiles. PMID- 17710412 TI - Domenico Felice Cotugno and the rationale of his discovery of CSF. PMID- 17710411 TI - Is cold the new hot? Elevated ubiquitin-conjugated protein levels in tissues of Antarctic fish as evidence for cold-denaturation of proteins in vivo. AB - Levels of ubiquitin (Ub)-conjugated proteins, as an index of misfolded or damaged proteins, were measured in notothenioid fishes, with both Antarctic (Trematomus bernacchii, T. pennellii, Pagothenia borchgrevinki) and non-Antarctic (Notothenia angustata, Bovichtus variegatus) distributions, as well as non-notothenioid fish from the Antarctic (Lycodichthys dearborni, Family Zoarcidae) and New Zealand (Bellapiscis medius, Family Tripterygiidae), in an effort to better understand the effect that inhabiting a sub-zero environment has on maintaining the integrity of the cellular protein pool. Overall, levels of Ub-conjugated proteins in cold-adapted Antarctic fishes were significantly higher than New Zealand fishes in gill, liver, heart and spleen tissues suggesting that life at sub-zero temperatures impacts protein homeostasis. The highest tissue levels of ubiquitinated proteins were found in the spleen of all fish. Ub conjugate levels in the New Zealand N. angustata, more closely resembled levels measured in other Antarctic fishes than levels measured in other New Zealand species, likely reflecting their recent shared ancestry with Antarctic notothenioids. PMID- 17710413 TI - Comparison of prenatal and postnatal MRI findings in the evaluation of intrauterine CNS anomalies requiring postnatal neurosurgical treatment. AB - AIM: To assess the diagnostic capability of fetal magnetic resonance imaging (MRI) in children suspected antenatally to harbor central nervous system (CNS) defects that require immediate postnatal neurosurgical treatment. MATERIALS AND METHODS: Between 2003 and 2005, 13 fetal MRI scans were performed in mothers suspected to have fetuses with congenital CNS defects that would require surgery soon after birth. Comparisons between antenatal and postnatal scans were made with emphasis on diagnostic accuracy of antenatal examinations. RESULTS: All mothers were scanned using heavily T2-weighted fat-saturated sequences, allowing rapid acquisitions to avoid movement artefacts. Imaging quality was satisfactory in all patients. Diagnoses made antenatally were: myelomeningocele in seven, meningocele in one, diastematomyelia in one, occipital meningocele in one, and isolated hydrocephalus in three children. Of the seven children with antenatal diagnosis of myelomeningocele, one proved to have spinal lipoma postnatally. The patient who antenatally was diagnosed with meningocele proved to have spinal lipoma postnatally. These two were early antenatal MR scans. Antenatal diagnosis of hydrocephalus was made in five of the six confirmed myelomeningocele patients, which was verified postnatally. Antenatal diagnosis of Chiari II malformation was made in all six confirmed myelomeningocele patients. The antenatal diagnoses of occipital meningo-encephalocele and isolated hydrocephalus were verified postnatally. Antenatal diagnosis of diastematomyelia was not verified postnatally. CONCLUSION: Fetal MRI scanning is an effective, noninvasive method of assessing in-utero CNS abnormalities. The diagnostic accuracy has improved to allow prediction of clinical outcome and counseling for possible treatment, but is not perfect yet to allow counseling for termination of pregnancy. PMID- 17710415 TI - Prognosis of cerebellar astrocytomas in children. AB - OBJECTIVE: Our main objective is to review a large series of cerebellar astrocytomas in children and evaluate the outcome of the patients depending on astrocytoma class. The effect of astrocytoma characteristics on the children's prognosis was determined by grouping a series of cerebellar astrocytomas by their location, radiological aspect, size, and histology and determining whether this was related with outcome. MATERIALS AND METHODS: Two hundred and three children with cerebellar astrocytomas were retrospectively reviewed, and their tumors were classified by location, macroscopic radiological appearance, size, and histology. We have distinguished between patients operated before and after 1974 because of the introduction of new diagnostic (computed tomography, magnetic resonance) and more sophisticated treatment techniques after this year (microsurgery, laser, cavitron, etc). RESULTS: Our patients' results were classified according to the Lapras scale/classification as normal, with some neurological deficit but able to lead a normal life, and those with severe post surgical deficits. Recurrences and mortality were also noted. Normal or good results were obtained in 111 patients, some neurological deficit in 55, and severe deficits in nine. There were six recurrences and 22 deaths because of the disease. CONCLUSIONS: Two main factors affected prognosis. One was whether the tumor was completely resected or not; this was the treatment in most cases in this series. The second factor was the location, size, and macroscopic appearance of the tumor. The best prognosis was associated with being located in one hemisphere, being cystic, being cystic with a posterior nodule, and/or being small. PMID- 17710414 TI - Ambulation in adults with myelomeningocele. Is it possible to predict the level of ambulation in early life? AB - OBJECTIVE: The objective of this study was to evaluate the prediction of ambulation in adults with myelomeningocele from muscle strength testing and ambulation in early life. MATERIALS AND METHODS: Fifty-two myelomeningocele (MMC) individuals at the age 18-37 years at follow-up were studied. Information on muscle strength and ambulatory function in early life was retrieved from medical records. The motor levels determined by the muscle strength were used to predict ambulatory function later in life. At follow-up, a clinical examination was performed. RESULTS: Of 20 MMC individuals assessed with muscle strength within the first year of life, 7 achieved the predicted ambulatory function, 6 had a better, and 7 a poorer function. Of 32 individuals with known muscle strength at the age of 5-8 years, 10 had function as predicted, 5 a better ambulatory function, and 17 had a poorer ambulation in adult life than predicted. Good strength in quadriceps muscles gave significant better prospect for adult walking. Of the 52 participants, 41 retained their ambulation status from 5-8 years of age. CONCLUSION: For MMC individuals with motor levels L3-L5, adult ambulatory function cannot be determined from muscle strength in early life, while it to some extend can be predicted for motor levels at or above L2 and at or below S1. The majority of the participants who at the age 5-8 years were community walkers without walking aid kept that function. PMID- 17710417 TI - Comments on the article by D. Greitz "Paradigm shift in hydrocephalus research in legacy of Dandy's pioneering work: rationale for third ventriculostomy in communicating hydrocephalus". PMID- 17710418 TI - Neuropsychological screening of a group of preterm twins: comparison with singletons. AB - OBJECTS: Perform neuropsychological screening of a group of preterm twins without major brain pathology and compare it with a control group of similarly preterm children born as singletons. MATERIALS AND METHODS: Twenty-three preterm twins born at fewer than 32 weeks of gestation were tested for rapid evaluation of cognitive functions at the age of 4 years. The tests evaluated language, non verbal performances, learning and attention deficit disorders. Cognitive profiles were established. Links between perinatal factors, clinical follow-up and cognitive outcome were investigated. Their cognitive outcome was then compared with the cognitive outcome of 31 preterm singletons with the same gestational periods. CONCLUSION: The twins' neuropsychological outcome was not more marked than that of the singletons. Birth weight discordance and chorionicity were the only predictive perinatal factors with worse outcome in the twin population. PMID- 17710420 TI - Outcomes and management of rectal injuries in children. AB - In the pediatric population, rectal injuries usually occur as a result of motor vehicle collisions. There has been an increased interest in selective diversion of rectal injuries in adults and increased utilization of laparoscopy both as a diagnostic and therapeutic adjunct. The aim of the study was to review our institutional experience with rectal injuries to determine if there was a subset of patients who could be managed with selective diversion. The medical records of children admitted with a rectal injury to Hospital for Sick Children, Toronto, over the last 20 years (1984-2004) were retrospectively reviewed. Data abstraction included patient demographics, mechanism of injury, injury severity score, associated injuries, presenting symptoms, methods of diagnosis, treatment and resultant complications. Nine patients with rectal injuries were identified. The average injury severity score (ISS) was 19.3. Two patients with penetrating injuries underwent laparoscopy. Laparoscopy was able to define the intraperitoneal extension of injuries and guide the colostomy. Primary repair without a diverting colostomy was performed in 3 patients (2 intraperitoneal and 1 extraperitoneal injury) without complications. Based on the limited sample size, one should avoid making any definitive recommendations but, it appears, primary repair without fecal diversion can be performed safely in select children in spite of a longer time to surgery. Laparoscopy may be used for the immediate management of the penetrating trauma patient to rule out intraperitoneal extension, repair a perforation and guide the colostomy if necessary. PMID- 17710419 TI - The vestibulo-ocular reflex during active head motion in children and adolescents. AB - BACKGROUND: Little information is available on the performance and maturity of the vestibulo-ocular reflex (VOR) in children and adolescents during active head motion as encountered during normal locomotion. We investigated the active VOR performance in children and adolescents to determine its norm and variation with age. METHODS: We recorded the angular active VOR using an infrared eye tracker and a magnetic head tracker in 38 children, aged 8-19 years. Participants made sinusoidal head-on-body rotations in yaw (left-right) and pitch (up-down) at frequencies of about 0.5 and 2 Hz in the dark. RESULTS: Mean VOR gains, the ratios of eye to head velocities, were close to unity and were significantly higher at 2 Hz than at 0.5 Hz. VOR gains did not vary with age. CONCLUSION: The angular VOR during active head motion is functionally mature in children 8 years or older at 0.5 and 2 Hz head rotations. PMID- 17710421 TI - Retrosternal revision of jejunum interposed in the anterior sternal space for the treatment of esophageal atresia. AB - Esophageal replacement continues to be a challenging operation associated with significant morbidity. We report the case of a 5-year-old boy with esophageal atresia treated by jejunal interposition in the anterior sternal space who had revision of the interposed jejunum into the retrosternal space for cosmetic reasons. PMID- 17710422 TI - Progress on pontocerebellar hypoplasia. PMID- 17710423 TI - Autologous chondrocyte implantation for the treatment of retropatellar cartilage defects: clinical results referred to defect localisation. AB - INTRODUCTION: Although autologous chondrocyte implantation (ACI) has become well established for the treatment of full-thickness cartilage defects of the knee joint, nevertheless clinical results of retropatellar lesions are still inferior compared to those of defects located on femoral condyles. We report the clinical results obtained in 70 patients treated with ACI for full-thickness defects of the patella, with special reference to defect location and size, age, body mass index and sports activity. METHODS: At a follow-up of 38.4 months (range 14-64, follow-up rate 83.3%), patients' subjective functional knee scores (IKDC, Lysholm) were analysed, as were the results of objective examination (according to ICRS). RESULTS: Mean patient age at the time of surgery was 34.3 years (+/ 10.1). The mean Lysholm score at the time of follow-up was 73.0 (+/-22.4) and the subjective IKDC score was 61.6 (+/-21.5); normal and nearly normal clinical results according to the objective criteria of the International Cartilage Research Society (ICRS) were achieved in 67.1% of the patients, while abnormal results were achieved in 20.0% of the patients and severely abnormal results, in 12.9%. While different surgical techniques did not seem to have any significant influence on the treatment results, both defect size and defect location within the patella were found to be significantly associated with clinical outcome. The corollaries to this are that larger cartilage lesions of the patella are associated with an inferior outcome (p = 0.007) and that cartilage defects located on the lateral patellar facet are correlated with a better clinical outcome than those located on the medial facet or those involving both facets (p = 0.017). CONCLUSION: This study demonstrates that within a group of patients treated with ACI for retropatellar cartilage lesion there are significant differences in clinical outcome, which are important and should be taken into account of when a decision has to be made on whether or not ACI is indicated. PMID- 17710424 TI - The effect of dermatophytes on cytokine production by human keratinocytes. AB - Dermatophytosis (tinea) is a common disease in superficial mycoses and is generally confined to the stratum corneum in the epidermis and cutaneous appendages. The mechanisms by which dermatophytes cause dermatophytosis, however, are poorly understood. In this study, we evaluated the effect of Trichophyton mentagrophytes, T. tonsurans and T. rubrum on cytokine production by normal human epidermal keratinocytes (NHEKs). After 3-24 h of co-culture of NHEKs with each of the dermatophytes, cytokines in the supernatant were measured by enzyme-linked immunosorbent assay. Promoter activity of IL-8 was measured by chloramphenicol acetyl transferase (CAT) assay. IL-8 and GRO-alpha levels were higher in supernatants co-cultured with T. mentagrophytes isolates from animal than in those with T. mentagrophytes isolates from human, and with T. tonsurans and T. rubrum isolates. CAT expression for IL-8 promoter activity was higher in cell lysates stimulated with T. mentagrophytes isolates from animal than in those with T. mentagrophytes isolates from human, and with T. tonsurans and T. rubrum isolates. These findings suggest that dermatophytes directly induce production of cytokines at the transcriptional level by human keratinocytes, and that there are differences in their ability to induce cytokine production between the dermatophytes. PMID- 17710425 TI - Regulation of the extracellular matrix remodeling by lutein in dermal fibroblasts, melanoma cells, and ultraviolet radiation exposed fibroblasts. AB - With aging and cancer there is increased expression or activity of matrix metalloproteinases (MMPs) that degrade and remodel the structural extracellular matrix (ECM). In addition, exposure of skin to ultraviolet (UV) radiation (photoaging) leads to loss of cell viability, membrane damage, and deposition of excessive elastotic material. Lutein has antioxidant, anti-inflammatory, photoprotective, and anti-carcinogenic properties. The goal of this research was to investigate lutein's anti-aging and anti-carcinogenic effects via the regulation of the extracellular matrix remodeling. To this purpose, the effects of lutein on the expression of MMPs and their inhibitors (TIMPs, tissue inhibitors of metalloproteinases) in dermal fibroblasts (intrinsic aging) and melanoma cells were examined. Further, for lutein's photoprotective effects, the regulation of cell viability, membrane integrity, and elastin expression in the non-irradiated, and UVA or UVB radiation exposed fibroblasts were analyzed. Lutein significantly inhibited MMP-1 expression, transcriptionally, and MMP-2 protein levels in dermal fibroblasts, without altering TIMPs expression. It significantly inhibited MMP-1 expression in melanoma cells while stimulating TIMP 2. Lutein did not alter fibroblast or melanoma cell viability or membrane integrity. In ultraviolet radiation exposed fibroblasts, lutein improved cell viability, membrane integrity and inhibited elastin expression, though more significantly in the UVB exposed fibroblasts. In summary, the mechanism to lutein's anti-aging and anti-carcinogenic effects include the inhibition of MMP to TIMP ratio in dermal fibroblasts and melanoma cells, and the inhibition of cell loss, membrane damage and elastin expression in ultraviolet radiation exposed fibroblasts. PMID- 17710426 TI - Treatment of acne with intermittent and conventional isotretinoin: a randomized, controlled multicenter study. AB - Oral isotretinoin is the most effective choice in the treatment of severe acne. Application of isotretionin to acne has been expanded to treat those patients with less severe but scarring acne who are responding unsatisfactorily to conventional therapies. However, its use is associated with many side effects, some of which can result in very disastrous consequences. Data related with intermittent isotretinoin therapy is still limited. Our aim was to asses the efficacy and tolerability of two different intermittent isotretinoin courses and compare them with conventional isotretinoin treatment. In this multicenter and controlled study, 66 patients with moderate to severe cases were randomized to receive either isotretionin for the first 10 days of each month for 6 months (group 1), or each day in the first month, afterwards the first 10 days of each month for 5 months (group 2) or daily for 6 months (group 3). The drug dosage was 0.5 mg/kg/day in all groups. Patients were followed-up for 12 months. Efficacy values were evaluable for 22 patients in group 1, 19 patients in group 2, and 19 patients in group 3. Acne scores in each group were significantly lower at the end of treatment and follow-up periods (P < 0.001). When patients were evaluated separately as moderate (n = 31) and severe (n = 29), no statistically significant differences were obtained among the treatment protocols in patients with moderate acne. However, there was a significant difference between groups 1 and 3 to the response of the treatments in severe acne patients at the end of follow-up period (P = 0.013). The frequency and severity of isotretionin-related side effects were found to be lower in groups 1 and 2 compared with group 3. Intermittent isotretinoin may represent an effective alternative treatment, especially in moderate acne with a low incidence and severity of side effects. The intermittent isotretinoin can be recommended in those patients not tolerating the classical dosage. PMID- 17710427 TI - Role of transvaginal sonography in the diagnosis of retained products of conception. AB - INTRODUCTION: The aim of this study was to evaluate the criteria of endometrial thickness to detect retained products of conception following first trimester spontaneous abortion or elective pregnancy termination. METHODS: This was a retrospective study on 116 patients who underwent uterine re-evacuation with a diagnosis of retained products of conception based on clinical and sonographic findings. Pathologic reports of samples obtained during re-evacuation were reviewed for the presence of gestational tissue. Endometrial thickness determined by transvaginal sonography and certain clinical features (gestational age and interval between initial curettage and re-evacuation, which may affect presence or absence of gestational tissue, parity, indication for initial curettage) were noted. The sensitivity and specificity of sonographic measurement of endometrial thickness for detecting retained products of conception were assessed. RESULTS: Histopathologic reports confirmed the diagnosis of retained products of conception in 66 of 116 patients (56.9%). Percentage of nulliparity and the time elapsed between initial curettage and re-evacuation were significantly high in patients with retained products of conception. The sensitivity and specificity of endometrial thickness greater than 13 mm for detecting retained products of conception were 85 and 64%, respectively. CONCLUSION: An endometrial thickness of 13 mm or more, detected by transvaginal sonography, has the best diagnostic efficiency for detection of retained products of conception following first trimester spontaneous abortion or elective pregnancy termination. PMID- 17710428 TI - Psychotropic medication during pregnancy and lactation. AB - Despite the traditional notion that pregnancy is a time of joy and emotional well being, evidence suggests that it does not protect women against mental illness. Untreated mental illness carries wide-ranging repercussions for mother, child and family that often outweigh those associated with treatment. Clinical management is complex, involving competing risks to mother and offspring; the challenge lies in effectively treating mental illness, whilst minimising exposure of the child to harmful medication. The paucity of robust published evidence on which to base the principles of psychiatric care further compounds the issue. Pregnancy significantly affects plasma drug levels and immature foetal/neonatal physiology renders the child prone to damage from pharmacological agents, all of which cross the placenta/enter breast-milk to varying degrees. Risks include teratogenicity, obstetrical complications, perinatal syndromes, and long-term behavioural problems. Despite evidence that some psychotropic drugs may be safe during pregnancy, knowledge regarding the risks of antenatal exposure to medications remains far from complete. The pregnant or breastfeeding woman requires an individualised risk-benefit analysis with regard to the commencement or continuance of psychotropic medication. If treatment is deemed necessary, monotherapy at the lowest possible dose should be prescribed. More robust safety data is available for older psychotropic drugs, which should be employed in preference to newer agents with unestablished safety profiles. Pregnant/breastfeeding women should also be educated with regard to early detection of signs of drug toxicity in both themselves and their babies. Despite shared responsibility, the ultimate decision with regard to reasonable risk, and what constitutes it, rests with the informed patient. Close psychiatric monitoring and coordinated multidisciplinary care with the obstetrician and paediatrician combine with such informed patient choices to comprise the components of a holistic model of care, targeted at optimizing the complex management of women with psychiatric illness during pregnancy. PMID- 17710429 TI - The immunohistochemical evaluation of VEGF in placenta biopsies of pregnancies complicated by preeclampsia. AB - OBJECTIVE: The study was designed to determine the protein levels of vascular endothelial growth factor (VEGF) in the placenta biopsies of patients with preeclampsia and compare with normal controls. DESIGN: Prospective cohort study. METHODS: The placental biopsies were obtained from ten patients with preeclampsia and ten patients of control group at the time of delivery. Avidin-biotin peroxidase immunohistochemistry was then performed to identify levels of VEGF protein within the tissue and a semi-quantitative method was devised to score the amount of staining present in the sample. Two histopathologists who were blinded to the groups were asked to score each sample for the intensity of staining and the number of cells stained in a randomly selected per high-power fields of each sample. The resulting "H-score" was computed as a product of intensity and percent of cells stained. RESULTS: The VEGF expression was significantly higher in placenta biopsies of preeclamptic patients compared to that of controls (271.2 +/- 22.65 vs. 201.9 +/- 12.33, P = 0.000). CONCLUSION: Immunostaining of VEGF is significantly higher in placenta biopsies of patients with preeclampsia. PMID- 17710430 TI - Topical pimecrolimus does not prolong clear graft survival in a rat keratoplasty model. AB - BACKGROUND: Long-term application of topical steroids following penetrating keratoplasty is disadvantageous due to side effects (steroid response, cataract, surface disorders). In this study we investigated the efficacy of topical pimecrolimus regarding clear graft survival following allogeneic orthotopic keratoplasty in rats. METHODS: A total of 46 penetrating keratoplasties were performed using Fisher rats (allogeneic groups) and Lewis rats (syngeneic group) as donors and Lewis rats as recipients: group 1 (n = 11), allogeneic control without therapy; group 2 (n = 12), syngeneic control; group 3 (n = 11), mycophenolate mofetil (MMF) 40 mg/kg body weight; group 4 (n = 12), pimecrolimus 1% ointment twice daily. Four animals of each group were sacrificed for immunohistological evaluation on day 14. Therapy was administered for 18 days. The grafts were evaluated once every 3 days regarding opacity, oedema and vascularisation. Graft rejection was defined as total graft opacity. RESULTS: Mean rejection-free graft survival was 11.4 days in group 1 (allogeneic control), 100 days (total follow-up time) in group 2 (syngeneic control), 24.0 days in group 3 (MMF 40 mg/kg) and 11.6 days in group 4 (topical pimecrolimus). The immunohistological evaluation showed no statistically significant difference in cell infiltration of the grafts comparing groups 1 and 4. CONCLUSIONS: Topical immunosuppression with pimecrolimus does not prolong graft survival in the allogeneic keratoplasty rat model. PMID- 17710431 TI - Anaerobic performance and metabolism in boys and male adolescents. AB - Short-term maximum intensity performance, absolute and related to body mass, is lower in children than adolescents. The underlying mechanisms are not clear. We analysed Wingate Anaerobic Test (WAnT) performance and metabolism in ten boys (mean (SD); age 11.8 (0.5) years, height 1.51 (0.05) m, body mass 36.9 (2.5) kg, muscle mass 13.0 (1.0) kg) and 10 adolescents (16.3 (0.7) years, 1.81 (0.05) m, 67.3 (4.1) kg, 28.2 (1.7) kg). Related to body mass, power of flywheel acceleration (6.0 (1.6) vs. 8.1 (1.1) W kg(-1)), peak power (10.8 (0.7) vs. 11.5 (0.6) W kg(-1)), average power (7.9 (0.5) vs. 8.9 (0.7) W kg(-1)), minimum power (6.1 (0.7) vs. 6.9 (0.9) W kg(-1)) and anaerobic lactic energy (687.6 (75.6) vs. 798.2 (43.0) J kg(-1)) were lower (P < 0.05) in boys than in adolescents. Related to muscle mass the change in lactate (0.69 (0.08) vs. 0.69 (0.04) mmol kg (MM) ( 1) s(-1)) and PCr (0.60 (0.17) vs. 0.52 (0.10) mmol kg (MM) (-1) s(-1)) were not different. The corresponding oxygen uptake (1.34 (0.13) vs. 1.09 (0.13) ml kg (MM) (-1) s(-1)), total metabolic rate (132.4 (12.6) vs. 119.7 (8.5) W kg (MM) ( 1) ) and PP (30.5 (2.6) vs. 27.5 (1.7 W) kg (MM) (-1) ) were higher (P < 0.01) in boys than in adolescents. The results reflect a lower relative muscle mass combined with no differences in muscular anaerobic but fascilitated aerobic metabolism in boys. Compared with adolescents, boys' performance seemed to be significantly impaired by flywheel inertia but supported by identical brake force related to body mass. PMID- 17710432 TI - Analysis of gene expression in amyloplasts of potato tubers. AB - Gene expression in amyloplasts derived from potato tubers was analyzed at the levels of transcription, mRNA accumulation and formation of polysomes. Compared with chloroplasts, overall transcriptional activity is considerably reduced in amyloplasts. Nevertheless, several transcripts are synthesized in amyloplasts during growth of tubers. Among the transcribed amyloplast genes are the ribosomal operon and the psbA gene. Primer extension analysis provided evidence that in amyloplasts the plastid encoded RNA polymerase (PEP) is the principal RNA polymerase involved in the transcription of the rrn operon. Analysis of plastid steady state transcripts showed that there are only small differences in the levels of specific transcripts between amyloplasts and chloroplasts. With respect to the low transcription rate of the accumulating RNA-species in amyloplasts, a high stability of these transcripts is obvious. Though amyloplasts possess polysomes, specific mRNAs associated with such polysomes could not be detected. This suggests that translation could be impaired in amyloplasts, which, in turn, implies that these organelles are not suitable targets for the expression of transgenes introduced into the plastid genome by plastid transformation. PMID- 17710433 TI - SpGataE, a Strongylocentrotus purpuratus ortholog of mammalian Gata4/5/6: protein expression, interaction with putative target gene spec2a, and identification of friend of Gata factor SpFog1. AB - In the sea urchin Strongylocentrotus purpuatus, SpGataE, an ortholog of the vertebrate zinc-finger transcription factors Gata4/5/6, occupies a key position in the gene regulatory network for endomesoderm specification. We have posited that in addition to regulating gene activity required for endomesoderm specification, SpGataE also represses the expression of the aboral ectoderm specific spec2a gene in endomesoderm territories. Although the expression pattern of spgatae and its role in endomesoderm specification have been described in considerable detail, little is known about SpGataE protein accumulation and its interactions with target genes and coregulatory factors. Our purpose here was to gain further insight into the mechanisms by which SpGataE functions as a transcriptional regulator. To achieve this, we generated an anti-SpGataE antibody to determine the spatiotemporal expression pattern of SpGataE protein and establish whether it plays a role in repressing spec2a by binding to gata cis regulatory elements within the endogenous spec2a enhancer. Because Gata proteins often associate with friend of Gata (Fog) coregulators, we identified an S. purpuratus fog ortholog, spfog1, and showed that SpGataE and SpFog1 physically interacted. Spfog1 transcripts were maximal by early blastula stage but continued thereafter to be expressed at low levels. Knockdown of spfog1 using antisense morpholino oligonucleotides did not produce notable effects on endomesoderm specification or spec2a enhancer activity, suggesting that SpGataE exerts these functions independently of SpFog1. In addition to providing new information on Gata and Fog proteins in sea urchins, the anti-SpGataE antibody developed here should be a useful reagent for future analysis of SpGataE function. PMID- 17710434 TI - Intrapleural streptokinase treatment in children with empyema. AB - Our aim was to compare intrapleural streptokinase (SK) treatment and simple tube drainage in the treatment of children with complicated parapneumonic pleural effusion. A retrospective review of medical records included patient demographics, clinical presentation, biochemical and microbial studies of pleural effusion, radiographic evaluation of chest tube drainage, use of fibrinolytic agents and type of surgical intervention. During the 2.5-year period (1999-2002), 53 children (29 M, 24 F) with complicated parapneumonic effusions or empyema were identified. Closed tube drainage and antibiotic treatment were administered to patients with a diagnosis of complicated parapneumonic effusion (n = 24) until October 2000; after that time point, intrapleural streptokinase was added to this regimen (n = 29). The median age at the time of presentation was 2.5 years (range: 5 months-14.6 years). There were no significant differences in terms of clinical outcomes between the two groups. The average length of hospital stay was 19.1 +/- 5.5 and 21.9 +/- 11.2 days for the drainage and streptokinase groups, respectively; the time to afebrile state after admission was 5.8 +/- 4.1 and 7.6 +/- 7.5 days. The percentage of patients who eventually required surgical intervention was 8.3% for the drainage group and 20.6% for the streptokinase group. In conclusion, in the treatment of complicated parapneumonic effusions or empyema, the adjunctive treatment with intrapleural SK does not significantly reduce durations of fever, chest tube drainage and hospital stay, and the need for surgery, regardless of the stage of the disease, compared to simple closed tube drainage. PMID- 17710436 TI - Phlebotomus (Euphlebotomus) mascomai n. sp. (Diptera-Psychodidae). AB - A new species of sandfly is described from limestone caves in Thailand. The inclusion of this species in the subgenus Euphlebotomus is justified on the basis of characters of the male genitalia (paramere, basal lobe). The male-female gathering in the same taxon is based on ecological (cavernicolous species), morphological (length of male genital filaments and female spermathecal ducts) and molecular (homology of cytochrome b mt DNA sequences) criteria. A differential diagnosis between Phlebotomus mascomai n. sp. and P. argentipes Annandale & Brunetti, the vector of Leishmania donovani (Laveran & Mesnil) in India, is proposed based on several morphological characters like antennal formula and genitalia. PMID- 17710435 TI - Erythropoietic protoporphyria without skin symptoms-you do not always see what they feel. AB - Erythropoietic protoporphyria (EPP) is an inherited disorder of the porphyrin metabolism that often remains undiagnosed in children. We report on a 4-year-old girl who had been suffering for 1 year from recurrent painful crises affecting her hands, feet, and nose following sun exposure. Objective skin lesions were absent until the age of 6. Porphyrin analysis revealed elevated free erythrocyte protoporphyrin (FEP) levels confirming the diagnosis of EPP. This illustrates that skin lesions might be completely absent in children affected with EPP, a fact that has only been reported once previously. Because EPP can manifest with few and unspecific cutaneous symptoms or no skin lesions at all, like in this patient, the diagnosis of EPP might be delayed or missed. EPP should be excluded in all photosensitive children, especially when discomfort is disproportionate to the extent of the cutaneous lesions. The clinic, pathophysiology, diagnosis, complications, and therapy of EPP are discussed. PMID- 17710437 TI - TGF-beta in neural stem cells and in tumors of the central nervous system. AB - Mechanisms that regulate neural stem cell activity in the adult brain are tightly coordinated. They provide new neurons and glia in regions associated with high cellular and functional plasticity, after injury, or during neurodegeneration. Because of the proliferative and plastic potential of neural stem cells, they are currently thought to escape their physiological control mechanisms and transform to cancer stem cells. Signals provided by proteins of the transforming growth factor (TGF)-beta family might represent a system by which neural stem cells are controlled under physiological conditions but released from this control after transformation to cancer stem cells. TGF-beta is a multifunctional cytokine involved in various physiological and patho-physiological processes of the brain. It is induced in the adult brain after injury or hypoxia and during neurodegeneration when it modulates and dampens inflammatory responses. After injury, although TGF-beta is neuroprotective, it may limit the self-repair of the brain by inhibiting neural stem cell proliferation. Similar to its effect on neural stem cells, TGF-beta reveals anti-proliferative control on most cell types; however, paradoxically, many brain tumors escape from TGF-beta control. Moreover, brain tumors develop mechanisms that change the anti-proliferative influence of TGF-beta into oncogenic cues, mainly by orchestrating a multitude of TGF-beta-mediated effects upon matrix, migration and invasion, angiogenesis, and, most importantly, immune escape mechanisms. Thus, TGF-beta is involved in tumor progression. This review focuses on TGF-beta and its role in the regulation and control of neural and of brain-cancer stem cells. PMID- 17710438 TI - Neurogenesis of cephalic sensory organs of Aplysia californica. AB - The opisthobranch gastropod Aplysia californica serves as a model organism in experimental neurobiology because of its simple and well-known nervous system. However, its nervous periphery has been less intensely studied. We have reconstructed the ontogeny of the cephalic sensory organs (labial tentacles, rhinophores, and lip) of planktonic, metamorphic, and juvenile developmental stages. FMRFamide and serotonergic expression patterns have been examined by immunocytochemistry in conjunction with epifluorescence and confocal laser scanning microscopy. We have also applied scanning electron microscopy to analyze the ciliary distribution of these sensory epithelia. Labial tentacles and the lip develop during metamorphosis, whereas rhinophores appear significantly later, in stage 10 juveniles. Our study has revealed immunoreactivity against FMRFamides and serotonin in all major nerves. The common labial nerve develops first, followed by the labial tentacle base nerve, oral nerve, and rhinophoral nerve. We have also identified previously undescribed neuronal pathways and other FMRFamide like-immunoreactive neuronal elements, such as peripheral ganglia and glomerulus like structures, and two groups of conspicuous transient FMRFamide-like cell somata. We have further found two distinct populations of FMRFamide-positive cell somata located both subepidermally and in the inner regions of the cephalic sensory organs in juveniles. The latter population partly consists of sensory cells, suggesting an involvement of FMRFamide-like peptides in the modulation of peripheral sensory processes. This study is the first concerning the neurogenesis of cephalic sensory organs in A. californica and may serve as a basis for future studies of neuronal elements in gastropod molluscs. PMID- 17710439 TI - Alterations to network of NO/cGMP-responsive interstitial cells induced by outlet obstruction in guinea-pig bladder. AB - Interstitial cells (ICs) play a role in regulating normal bladder activity. This study explores the possibility that the sub-urothelial and muscle networks of NO/cGMP-responsive ICs are altered in animals with surgically induced outflow obstruction. In sham-operated animals, the urothelium comprised NO-stimulated cGMP-positive (cGMP(+)) umbrella cells, an intermediate layer and a basal layer that stained for nNOS. cGMP(+) sub-urothelial interstitial cells (su-ICs) were found below the urothelium. cGMP(+) cells were also associated with the outer muscle layers: on the serosal surface, on the surface of the muscle bundles and within the muscle bundles. Several differences were noted in tissues from obstructed animals: (1) the number of cGMP(+) umbrella cells and intensity of staining was reduced; (2) the intermediate layer of the urothelium consisted of multiple cell layers; (3) the su-IC layer was increased, with cells dispersed being throughout the lamina propria; (4) cGMP(+) cells were found within the inner muscle layer forming nodes between the muscle bundles; (5) the number of cells forming the muscle coat (serosa) was increased; (6) an extensive network of cGMP(+) cells penetrated the muscle bundles; (7) cGMP(+) cells surrounded the muscle bundles and nodes of ICs were apparent, these nodes being associated with nerve fibres; (8) nerves were found in the lamina propria but rarely associated with the urothelium. Thus, changes occur in the networks of ICs following bladder outflow obstruction. These changes must have functional consequences, some of which are discussed. PMID- 17710440 TI - Rat wct mutation induces a hypo-mineralization form of amelogenesis imperfecta and cyst formation in molar teeth. AB - Our previous findings have demonstrated that the rat autosomal-recessive mutation, whitish chalk-like teeth (wct), induces enamel defects resembling those of human amelogenesis imperfecta (AI) in continuously growing incisor teeth. The present study clarifies the effect of the wct mutation on the morphogenesis and calcification of rat molar teeth. Formalin-fixed maxillae obtained from animals aged 4-30 days were examined by electron probe micro-analysis (EPMA) and by immunocytochemistry for amelogenin, ameloblastin, and enamelin. There were no distinct differences in the calcium and phosphorous contents and the amount of enamel between homozygous mutant and wild-type teeth during postnatal days 4-11. Although the mineral density in the enamel matrix considerably increased in the wild-type teeth until day 15, no changes occurred in mutant teeth during days 11 30. The immunoreactivity for enamel proteins in the secretory-stage ameloblasts in mutant teeth was similar to that in the wild-type teeth, and subsequently mutant maturation-stage ameloblasts became detached from the enamel surface, resulting in odontogenic cyst formation between the enamel organ and matrix until day 7 and the expansion of the cyst around the whole tooth crown on day 15. On day 30, the erupted mutant teeth presented morphological changes such as enamel destruction and tertiary dentin formation in addition to low mineral density in the enamel. Thus, the wct mutation prevents mineral transport without disturbing the synthesis of enamel proteins in molar teeth because of the absence of maturation-stage ameloblasts, in addition to the occurrence of odontogenic cysts. PMID- 17710441 TI - Evaluation of aortic stiffness in children with chronic renal failure. AB - The measurement of aortic stiffness (As) [aortic strain (S), pressure strain elastic modulus (Ep) and pressure strain normalized by diastolic pressure (Ep*)] is suggested as an excellent marker of subclinical arterial sclerosis. We aimed to investigate the presence of As and to determine the relationship between As and some risk factors in children with chronic renal failure (CRF). Twenty-six pre-dialysis (PreD) [female/male (F/M) 7/19] patients and 23 chronic peritoneal dialysis (CPD) (F/M 13/10) patients were assessed. Twenty-nine healthy children were selected as a control group (F/M 14/15). We determined anemia, abnormal calcium/phosphate metabolism, hypertension, diastolic dysfunction, increased left ventricular mass (LVM), hypertriglyceridemia, increased stiffness (Ep, Ep*), and decreased strain (S) in the CRF (PreD and CPD) group compared with the controls (P < 0.05). Presence of renal disease, LVM and usage of angiotensin-converting enzyme inhibitor (ACE-I) in all groups; female gender, duration of disease and the usage of anti-hypertensive drug therapy in CRF patients; and LVM and LVM index in healthy children were found to be independent predictors for aortic stiffness and/or strain. In conclusion, CRF is associated with significant arterial functional abnormalities in uremic children and not controlled by dialysis treatment. These results suggest that, even in young children, uremia has a profound impact on arterial function. PMID- 17710442 TI - Safety and tolerability of velafermin (CG53135-05) in patients receiving high dose chemotherapy and autologous peripheral blood stem cell transplant. AB - GOALS OF WORK: The objective of this study was to evaluate the safety and tolerability of velafermin in patients at risk of developing severe oral mucositis (OM) from chemotherapy. MATERIALS AND METHODS: This study was a single center, open-label, single-dose escalation, phase I trial in patients undergoing high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplant (PBSCT). Velafermin was administered 24 h after stem cell infusion as a single intravenous dose infused over 15 min. Clinical safety variables were assessed and OM status scored daily for 30 days using the World Health Organization (WHO) grading scale. MAIN RESULTS: Thirty patients were treated with velafermin at doses of 0.03 (n = 10), 0.1 (n = 10), 0.2 (n = 8), or 0.33 mg/kg (n = 2). Patients were diagnosed with multiple myeloma (n = 16), non-Hodgkin's lymphoma (n = 12), acute myelogenous leukemia (n = 1), or desmoplasmic round cell tumor (n = 1). Velafermin was well tolerated at doses up to 0.2 mg/kg. There were no drug-related serious adverse events. No patient discontinued because of adverse events; however, two patients administered 0.33 mg/kg developed adverse reactions immediately after infusion of the study drug. No other patients were treated at this dose level. The most frequent (>35% of patients) treatment emergent adverse events were diarrhea, fatigue, pyrexia, vomiting, and nausea. Most adverse events were mild or moderate and resolved the same day without sequelae. Eight (27%) patients developed WHO grade 3 or 4 OM during the study; seven of these patients received high-dose melphalan as a conditioning regimen. CONCLUSION: Velafermin was well tolerated by autologous PBSCT patients at doses up to 0.2 mg/kg. PMID- 17710443 TI - Cancer-associated hypercalcemia treated with intravenous diphosphonates: a survival and prognostic factor analysis. AB - BACKGROUND: Cancer-associated hypercalcemia (CAH) is the most frequent metabolic disorder in cancer patients. We retrospectively reviewed the outcome and prognostic factors for patients with CAH being treated with standard intravenous disphosphonates. MATERIALS AND METHODS: Two hundred sixty patients were reviewed. Overall survival and prognostic factors were analyzed. Relative risks (RR) for early death (within 60 days) were assessed (Fischer exact test and logistic regression model). RESULTS: Median survival was 64 days (range, 12-1,955+). Multivariate analysis identified the following factors as poor survival predictors: serum corrected calcium >2.83 mmol/l [hazard ratio (HR) = HR 2.21], albuminemia <35.5 (HR 2.41), squamous cell carcinoma (HR 2.64), bone metastasis (HR 1.44), and liver metastasis (HR 2..22). One hundred twenty-one patients died within 60 days. For those patients, the logistic regression model identified four independent predicting factors for early death: calcemia >2.83 mmol/l (RR 5.07), hypoalbuminemia (RR 7.42), liver metastasis (RR 4.34), and squamous cell carcinomas (RR 2.21). DISCUSSION: Despite intravenous diphosphonate, CAH is still associated with poor outcome. Simple bedside parameters may estimate the risk of early deaths. PMID- 17710444 TI - Breast cancer and psychological distress: mothers' and daughters' traumatic experiences. AB - GOAL OF WORK: The objective of this exploratory retrospective study was to assess the effects of breast cancer diagnosis upon the psychological distress of adult breast cancer patients and their mothers, particularly mothers who experienced past trauma. MATERIALS AND METHODS: Four groups of mother-daughter dyads were evaluated using self-reporting measures of psychological distress [Brief Symptom Inventory (BSI)], familial support (PFS), and adjustment to cancer (MAC, IES): breast cancer patients whose mothers were Holocaust survivors (group 1), breast cancer patients with non-traumatized mothers (group 2), healthy daughters of Holocaust survivor mothers (group 3), and a control group of healthy daughters with non-traumatized mothers (group 4). MAIN RESULTS: Distress levels of both mothers and daughters in group 1 were significantly higher than distress levels of mothers and daughters in the other three groups. Daughters' distress levels in all four groups were found to be significantly related to mothers' distress levels, with the highest correlation found in both groups of cancer patients. The factors of having a clinically distressed mother and being a second-generation daughter contributed the most to predicting the clinical distress of the daughter. CONCLUSIONS: The outcomes imply that the mother's traumatic past intensifies the distressing effect of cancer diagnosis upon both the patient and her mother. The findings concerning the impact of cancer diagnosis upon the patients' non-traumatized mothers were more ambiguous. The results support the idea that in the case of breast cancer patients, a complete psychological evaluation must include not only spouses and children but also the familial background of the patient and the history of the patients' mothers. PMID- 17710445 TI - Self-reported taste and smell changes during cancer chemotherapy. AB - PURPOSE: This study explores the prevalence of self-reported taste and smell changes (TSCs) during chemotherapy and relationships between TSCs and demographic and clinical factors. MATERIALS AND METHODS: Consecutive patients who had received chemotherapy for > or =6 weeks at 11 outpatient chemotherapy units completed a questionnaire developed for this survey. RESULTS: Seventy-five percent of the 518 participants reported TSCs, with TSCs more prevalent among women and younger patients. After adjustment for age and sex, we found that patients reporting TSCs more often reported: previous smell changes, less responsibility for cooking, concurrent medication, higher educational levels, and being on sick leave. Participants reporting oral problems, nausea, appetite loss, and depressed mood more frequently reported TSCs. Diagnosis and type of chemotherapy regimen did not predict TSCs. CONCLUSION: TSCs were found to be common during cancer chemotherapy and were related to sociodemographic rather than clinical factors. TSCs were also found to be closely related to many other side effects of chemotherapy. PMID- 17710446 TI - Intra-specific and intra-sporocarp ITS variation of ectomycorrhizal fungi as assessed by rDNA sequencing of sporocarps and pooled ectomycorrhizal roots from a Quercus woodland. AB - The Internal Transcribed Spacer (ITS) regions of ribosomal DNA are widely used as markers for phylogenetic analyses and environmental sampling from a variety of organisms including fungi, plants, and animals. In theory, concerted evolution homogenizes multicopy genes so that little or no variation exists within populations or individuals. However, contrary to theory, ITS variation has been confirmed in populations and individuals from a diverse range of eukaryotes. The presence of intraspecific and intra-individual variation in multicopy genes has important implications for ecological and phylogenetic studies, yet relatively little is known about natural variation of these genes, particularly at the community level. In this study, we examined intraspecific and intra-sporocarp ITS variation by DNA sequencing from sporocarps and pooled roots from 68 species of ectomycorrhizal fungi collected at a single site in a Quercus woodland. We detected ITS variation in 27 species, roughly 40% of the taxa examined. Although intraspecific ITS variation was generally low (0.16-2.85%, mean = 0.74%), it was widespread within this fungal community. We detected ITS variation in both sporocarps and ectomycorrhizal roots, and variation was present within species of Ascomycota and Basidiomycota, two distantly related lineages within the Fungi. We discuss the implications of such widespread ITS variability with special reference to DNA-based environmental sampling from diverse fungal communities. PMID- 17710447 TI - Genetic diversity and differential in vitro responses to Ni in Cenococcum geophilum isolates from serpentine soils in Portugal. AB - Amplified fragment length polymorphism (AFLP) analysis was used to investigate the genetic diversity in isolates of the ectomycorrhizal fungus Cenococcum geophilum from serpentine and non-serpentine soils in Portugal. A high degree of genetic diversity was found among C. geophilum isolates; AFLP fingerprints showed that all the isolates were genetically distinct. We also assessed the in vitro Ni sensitivity in three serpentine isolates and one non-serpentine isolate. Only the non-serpentine isolate was significantly affected by the addition of Ni to the growth medium. At 30 microg g(-1) Ni, radial growth rate and biomass accumulation decreased to 73.3 and 71.6% of control, respectively, a highly significant inhibitory effect. Nickel at this concentration had no significant inhibitory effect on serpentine isolates, and so the fitness of serpentine isolates, as evaluated by radial growth rate and biomass yield, is likely unaffected by Ni in the field. In all isolates, the Ni concentration in the mycelia increased with increasing Ni concentration in the growth medium, but two profiles of Ni accumulation were identified. One serpentine isolate showed a linear trend of Ni accumulation. At the highest Ni exposure, the concentration of Ni in the mycelium of this isolate was in the hyperaccumulation range for Ni as defined for higher plants. In the remaining isolates, Ni accumulation was less pronounced and seems to approach a plateau at 30 microg g(-1) Ni. Because two profiles of Ni accumulation emerged among our Ni-insensitive serpentine isolates, this result suggests that different Ni detoxification pathways may be operating. The non serpentine isolate whose growth was significantly affected by Ni was separated from the other isolates in the genetic analysis, suggesting a genetic basis for the Ni-sensitivity trait. This hypothesis is further supported by the fact that all isolates were maintained on medium without added Ni to avoid carry-over effects. However, because AFLP analysis failed to distinguish between serpentine and non-serpentine isolates, we cannot conclude that Ni insensitivity among our serpentine isolates is due to evolutionary adaptation. Screening a larger number of isolates, from different geographical origins and environments, should clarify the relationships between genetic diversity, morphology, and physiology in this important species. PMID- 17710448 TI - An in vitro tissue model to study the effect of age on nucleus pulposus cells. AB - Differentiation between age (physiological) and disease-induced changes in the nucleus pulposus will facilitate our understanding of the mechanism(s) leading to the development of degenerative disc disease. The aim of this study was to develop an in vitro model that would allow the study of age-induced alterations of cell function in nucleus pulposus. Nucleus pulposus (NP) cells were isolated from intervertebral discs obtained from either calves (<9 months) or cows (>18 months). The cells were placed in culture and grown for 19 days. Although nucleus pulposus tissue was formed by the cells of the two different ages the more mature (older) cells formed less tissue as determined histologically by light microscopy. This was confirmed biochemically as the wet weight and proteoglycan content of the tissue formed by the older cells were significantly less than that of the younger tissue. The older cells accumulated less proteoglycans as determined by quantifying radioisotope incorporation. The older cells showed lower constitutive gene expression of collagen type II and aggrecan whereas collagen type I and link protein levels were similar to those of the younger cells. Metalloprotease (MMP) 13 gene and protein expression increased with age. There was no change in the levels of gene expression of MMP 2 and TIMP 1, 2, or 3 with age. Cells obtained from NP tissue harvested from younger or mature animals showed both genotypic and phenotypic differences in vitro that resulted in the inability of the older cells to reconstitute their extracellular matrix to the same extent as the younger cells. This suggests that this in vitro NP tissue model will be suitable to determine the mechanism(s) regulating age-induced changes. PMID- 17710449 TI - Validation of density functional modeling protocols on experimental bis(mu oxo)/mu-eta2:eta2-peroxo dicopper equilibria. AB - The bis(mu-oxo)/mu-eta(2):eta(2)-peroxo equilibria for seven supported Cu(2)O(2) cores were studied with different hybrid and nonhybrid density functional theory models, namely, BLYP, mPWPW, TPSS, TPSSh, B3LYP, mPW1PW, and MPW1K. Supporting ligands 3,3'-iminobis(N,N-dimethylpropylamine), N,N,N',N',N'' pentamethyldipropylenetriamine, N-[2-(pyridin-2-yl)ethyl]-N,N,N'-trimethylpropane 1,3-diamine, bis[2-(2-pyridin-2-yl)ethyl]methylamine, bis[2-(4-methoxy-2-pyridin 2-yl)ethyl]methylamine, bis[2-(4-N,N-dimethylamino-2-pyridin-2 yl)ethyl]methylamine, and 1,4,7-triisopropyl-1,4,7-triazacyclononane were chosen on the basis of the availability of experimental data for comparison. Density functionals were examined with respect to their ability accurately to reproduce experimental properties, including, in particular, geometries and relative energies for the bis(mu-oxo) and side-on peroxo forms. While geometries from both hybrid and nonhybrid functionals were in good agreement with experiment, the incorporation of Hartree-Fock (HF) exchange in hybrid density functionals was found to have a large, degrading effect on predicted relative isomer energies. Specifically, hybrid functionals predicted the mu-eta(2):eta(2)-peroxo isomer to be too stable by roughly 5-10 kcal mol(-1) for each 10% of HF exchange incorporated into the model. Continuum solvation calculations predict electrostatic effects to favor bis(mu-oxo) isomers by 1-4 kcal mol(-1) depending on ligand size, with larger ligands having smaller differential solvation effects. Analysis of computed molecular partition functions suggests that nonzero measured entropies of isomerization are likely to be primarily associated with interactions between molecular solutes and their first solvation shell. PMID- 17710450 TI - Matrix metalloproteinase-inhibitor interaction: the solution structure of the catalytic domain of human matrix metalloproteinase-3 with different inhibitors. AB - We structurally characterized the adducts of the catalytic domain of matrix metalloproteinase-3 (MMP3) with three different nonpeptidic inhibitors by solving the solution structure of one adduct [MMP3-N-isobutyl-N-(4 methoxyphenylsulfonyl)glycyl hydroxamic acid] and then by calculating structural models of the other two adducts using a reduced set of experimental NMR data, following a recently proposed procedure (Bertini et al. in J. Med. Chem. 48:7544 7559, 2005). The inhibitors were selected with the criteria of maintaining in all of them the same zinc-coordinating moiety and of selectively changing the substituents and/or the functional groups. The backbone dynamics on various time scales have been characterized as well. The comparison among these structures and with others previously reported allowed us to elucidate fine details of inhibitor receptor interactions and to develop some criteria, which could guide in optimizing the design of selective inhibitors. PMID- 17710451 TI - Kinetics and mechanism of the substitution reactions of [PtCl(bpma)]+, [PtCl(gly met-S,N,N)] and their aqua analogues with L-methionine, glutathione and 5'-GMP. AB - The substitution reactions of [PtCl(bpma)]+, [PtCl(gly-met-S,N,N)], [Pt(bpma)(H(2)O)](2+) and [Pt(gly-met-S,N,N)(H(2)O)](+) [where bpma is bis(2 pyridylmethyl)amine and gly-met-S,N,N is glycylmethionine] with L-methionine, glutathione and guanosine 5'-monophosphate (5'-GMP) were studied in aqueous solutions in 0.10 M NaClO(4) under pseudo-first-order conditions as a function of concentration and temperature using UV-vis spectrophotometry. The reactions of the chloro complexes were followed in the presence of 10 mM NaCl and at pH approximately 5, whereas the reactions of the aqua complexes were studied at pH 2.5. The [PtCl(bpma)]+ complex is more reactive towards the chosen nucleophiles than [PtCl(gly-met-S,N,N)]. Also, the aqua complexes are more reactive than the corresponding chloro complexes. The activation parameters for all the reactions studied suggest an associative substitution mechanism. The reactions of [PtCl(bpma)]+ and [PtCl(gly-met-S,N,N)] with 5'-GMP were studied by using (1)H NMR spectroscopy at 298 K. The pK (a) value of the [Pt(gly-met-S,N,N)(H(2)O)]+ complex is 5.95. Density functional theory calculations (B3LYP/LANL2DZp) show that in all cases guanine coordination to the L(3)Pt fragment (L(3) is terpyridine, bpma, diethylenetriamine, gly-met-S,N,N) is much more favorable than the thioether-coordinated form. The calculations collectively support the experimentally observed substitution of thioethers from Pt(II) complexes by N7 GMP. This study throws more light on the mechanistic behavior of platinum antitumor complexes. PMID- 17710452 TI - Three-year survival of single- and two-surface ART restorations in a high-caries child population. AB - The aim of this study was to evaluate the survival of single- and two-surface atraumatic restorative treatment (ART) restorations in the primary and permanent dentitions of children from a high-caries population, in a field setting. The study was conducted in the rainforest of Suriname, South America. ART restorations, made by four Dutch dentists, were evaluated after 6 months, 1, 2, and 3 years. Four hundred seventy-five ART restorations were placed in the primary dentition and 54 in first permanent molars of 194 children (mean age 6.09 +/- 0.48 years). Three-year cumulative survivals of single- and two-surface ART restorations in the primary dentition were 43.4 and 12.2%, respectively. Main failure characteristics were gross marginal defects and total or partial losses. Three-year cumulative survival for single-surface ART restorations in the permanent dentition was 29.6%. Main failure characteristics were secondary caries and gross marginal defects. An operator effect was found only for two-surface restorations. The results show extremely low survival rates for single- and two surface ART restorations in the primary and permanent dentitions. The variable success for ART may initiate further discussion about alternative treatment strategies, especially in those situations where choices have to be made with respect to a well-balanced, cost-effective package of basic oral health care. PMID- 17710453 TI - Spontaneous performance of wild baboons on three novel food-access puzzles. AB - Although the technical problem-solving expertise of nonhuman primates has been investigated extensively in captivity, few species have been tested in their natural habitats. Here I examine the physical cognition of wild savanna baboons (Papio anubis), a species that occupies an omnivorous foraging niche in which a variety of embedded food items are extracted and processed. Baboons were tested on three puzzles, each involving high-quality food that required removal from a novel obstruction: (1) a string-pulling puzzle in which food was hung from tree branches, (2) a twig-dipping puzzle in which food was embedded in a vertical tube, and (3) a stick-pushing puzzle in which food was contained in a horizontal conduit. The baboons failed to solve the second and third puzzles even when tools had been appropriately positioned in advance. And although they solved the first puzzle, their actions (running while holding food that was still attached to the string), suggested they did not fully comprehend the string's connective property. The baboons' performance might reflect the time constraints of life in the wild, which relative to captivity may provide fewer opportunities for the development of understanding about the physical properties of objects and their potential uses as tools. Further experiments on the physical cognition of baboons and many other primate species in their natural habitats would help test this ontogenetic hypothesis. Such field experiments would be especially fruitful if they continued to target extractive foragers like baboons: these experiments could simultaneously provide a test of phylogenetic hypotheses that invoke extractive foraging as the key stimulus for brain expansion in savanna-dwelling hominids. PMID- 17710454 TI - Delayed presentation of malrotation and midgut volvulus: imaging findings. AB - Midgut volvulus presenting outside the neonatal period often manifests with less than classic findings. One must be ever vigilant for any deviation from normal when imaging the gastrointestinal tract in these patients. Plain films often are noncontributory, and gastrointestinal imaging findings frequently are subtle and not exactly the same as those seen in classic cases in the neonatal period. Cases are presented illustrating the following: abnormal but less than classic small bowel location and configuration, malabsorption and fortuitous spiraling of a nasogastric tube, viral gastroenteritis and pseudo intussusception, intractable vomiting and dehydration with abnormal cecal position, and duodenal obstruction: pseudo SMA syndrome. Fortunately, one now can confirm one's suspicions with computed tomography and ultrasound in terms of determining whether the superior mesenteric artery and superior mesenteric vein positions are normal or reversed. PMID- 17710455 TI - Actions of snake neurotoxins on an insect nicotinic cholinergic synapse. AB - Here we examine the actions of six snake neurotoxins (alpha-cobratoxin from Naja naja siamensis, erabutoxin-a and b from Laticauda semifasciata; CM12 from N. haje annulifera, toxin III 4 from Notechis scutatus and a long toxin from N. haje) on nicotinic acetylcholine receptors in the cercal afferent, giant interneuron 2 synapse of the cockroach, Periplaneta americana. All toxins tested reduced responses to directly-applied ACh as well as EPSPs evoked by electrical stimulation of nerve XI with similar time courses, suggesting that their action is postsynaptic. Thus, these nicotinic receptors in a well-characterized insect synapse are sensitive to both long and short chain neurotoxins. This considerably expands the range of snake toxins that block insect nicotinic acetylcholine receptors and may enable further pharmacological distinctions between nAChR subtypes. PMID- 17710456 TI - Microstructural analysis of deformation-induced hypoxic damage in skeletal muscle. AB - Deep pressure ulcers are caused by sustained mechanical loading and involve skeletal muscle tissue injury. The exact underlying mechanisms are unclear, and the prevalence is high. Our hypothesis is that the aetiology is dominated by cellular deformation (Bouten et al. in Ann Biomed Eng 29:153-163, 2001; Breuls et al. in Ann Biomed Eng 31:1357-1364, 2003; Stekelenburg et al. in J App Physiol 100(6):1946-1954, 2006) and deformation-induced ischaemia. The experimental observation that mechanical compression induced a pattern of interspersed healthy and dead cells in skeletal muscle (Stekelenburg et al. in J App Physiol 100(6):1946-1954, 2006) strongly suggests to take into account the muscle microstructure in studying damage development. The present paper describes a computational model for deformation-induced hypoxic damage in skeletal muscle tissue. Dead cells stop consuming oxygen and are assumed to decrease in stiffness due to loss of structure. The questions addressed are if these two consequences of cell death influence the development of cell injury in the remaining cells. The results show that weakening of dead cells indeed affects the damage accumulation in other cells. Further, the fact that cells stop consuming oxygen after they have died, delays cell death of other cells. PMID- 17710457 TI - Mechanical properties of anterior malleolar ligament from experimental measurement and material modeling analysis. AB - In this paper, mechanical properties of the anterior malleolar ligament (AML) of human middle ear were studied through the uniaxial tensile, stress relaxation and failure tests. The digital image correlation (DIC) method was used to assess the boundary effect in experiments and calculate the strain on specimens. The constitutive behavior of the AML was described by a transversely isotropic hyperelastic model which consists of a first-order Ogden model augmented by a I(4)-type reinforcing term. The material parameters of the model were estimated and the viscoelasticity of the AML was illustrated by hysteresis phenomena and stress relaxation function. The mechanical strength of the AML was obtained through the failure test and the mean ultimate stress and stretch ratio were measured as 1.05 MPa and 1.51, respectively. Finally, a linear Young's modulus stress relationship of the AML was derived based on constitutive equation of the AML within a stress range of 0-0.5 MPa. PMID- 17710458 TI - Production of ethanol from corn stover hemicellulose hydrolyzate using Pichia stipitis. AB - Hemicellulose liquid hydrolyzate from dilute acid pretreated corn stover was fermented to ethanol using Pichia stipitis CBS 6054. The fermentation rate increased with aeration but the pH also increased due to consumption of acetic acid by Pichia stipitis. Hemicellulose hydrolyzate containing 34 g/L xylose, 8 g/L glucose, 8 g/L Acetic acid, 0.73 g/L furfural, and 1 g/L hydroxymethyl furfural was fermented to 15 g/L ethanol in 72 h. The yield in all the hemicellulose hydrolyzates was 0.37-0.44 g ethanol/g (glucose + xylose). Nondetoxified hemicellulose hydrolyzate from dilute acid pretreated corn stover was fermented to ethanol with high yields, and this has the potential to improve the economics of the biomass to ethanol process. PMID- 17710459 TI - Parametric equations to represent the profile of the human intervertebral disc in the transverse plane. AB - Computational and finite element models of the spine are used to investigate spine and disc mechanics. Subject specific data for the transverse profile of the disc could improve the geometric accuracy of these models. The current study aimed to develop a mathematical algorithm to describe the profile of the disc components, using subject-specific data points. Using data points measured from pictures of human intervertebral discs sectioned in the transverse plane, parametric formulae were derived that mapped the outer profile of the anulus and nucleus. The computed anulus and nucleus profile were a similar shape to the discs from which they were derived. The computed total disc area was similar to the experimental data. The nucleus:disc area ratios were sensitive to the data points defined for each disc. The developed formulae can be easily implemented to provide patient specific data for the disc profile in computational models of the spine. PMID- 17710460 TI - Simultaneous determination of wave speed and arrival time of reflected waves using the pressure-velocity loop. AB - In a previous paper we demonstrated that the linear portion of the pressure velocity loop (PU-loop) corresponding to early systole could be used to calculate the local wave speed. In this paper we extend this work to show that determination of the time at which the PU-loop first deviates from linearity provides a convenient way to determine the arrival time of reflected waves (Tr). We also present a new technique using the PU-loop that allows for the determination of wave speed and Tr simultaneously. We measured pressure and flow in elastic tubes of different diameters, where a strong reflection site existed at known distances away form the measurement site. We also measured pressure and flow in the ascending aorta of 11 anaesthetised dogs where a strong reflection site was produced through total arterial occlusion at four different sites. Wave speed was determined from the initial slope of the PU-loop and Tr was determined using a new algorithm that detects the sampling point at which the initial linear part of the PU-loop deviates from linearity. The results of the new technique for detecting Tr were comparable to those determined using the foot-to-foot and wave intensity analysis methods. In elastic tubes Tr detected using the new algorithm was almost identical to that detected using wave intensity analysis and foot-to foot methods with a maximum difference of 2%. Tr detected using the PU-loop in vivo highly correlated with that detected using wave intensity analysis (r (2) = 0.83, P < 0.001). We conclude that the new technique described in this paper offers a convenient and objective method for detecting Tr, and allows for the dynamic determination of wave speed and Tr, simultaneously. PMID- 17710461 TI - Extraction of fetal electrocardiogram using H(infinity) adaptive algorithms. AB - The fetal electrocardiogram (fECG) contains important information regarding the health of the fetus. However, the fECG obtained noninvasively from the abdominal surface electrical recordings of a pregnant woman are dominated by strong interference from the maternal electrocardiogram (mECG). In this paper, based on the H(infinity) principle, two adaptive algorithms are proposed for the extraction of fECG from the trans-abdominal recordings of pregnant women. The motivation behind the application of H(infinity) techniques is the fact that they are robust with respect to model uncertainties and lack of statistical information regarding noise. The proposed algorithms are applied to simulated as well as real multichannel ECG recordings and their performances are compared to that of the well-known least-mean-square (LMS) adaptive algorithm. It is found that the proposed H(infinity) based algorithms perform superior to the LMS algorithm in extracting the fECG signal. PMID- 17710462 TI - Identification of novel alpha-methoxylated phospholipid fatty acids in the Caribbean sponge Erylus goffrilleri. AB - The phospholipid fatty acid composition of the Caribbean sponge Erylus goffrilleri is described for the first time. A total of 70 fatty acids with chain lengths between 13 and 29 carbons were identified in the sponge. Methyl-branched fatty acids predominated in E. goffrilleri suggesting the presence of a considerable number of bacterial symbionts. The novel fatty acids (5Z,9Z)-2 methoxy-5,9-hexadecadienoic acid, (5Z,9Z)-2-methoxy-5,9-octadecadienoic acid, (5Z,9Z)-2-methoxy-5,9-nonadecadienoic acid, and (5Z,9Z)-2-methoxy-5,9 eicosadienoic acid are described for the first time in the literature. In addition, the iso-methyl-branched fatty acids (9Z)-2-methoxy-15-methyl-9 hexadecenoic acid and (5Z,9Z)-2-methoxy-15-methyl-5,9-hexadecadienoic acid, also identified in E. goffrilleri, were identified for the first time in nature. Based on the identified metabolites it is proposed that the unprecedented biosynthetic sequence: i-17:1Delta9 --> 2-OMe-i-17:1Delta9 --> 2-OMe-i-17:2Delta5,9 might be responsible for the biosynthesis of the novel iso-alpha-methoxylated fatty acids in E. goffrilleri. PMID- 17710464 TI - A practical guide to the isolation, analysis and identification of conjugated linoleic acid. AB - Natural and synthetic conjugated linoleic acids (CLA) are reputed to have therapeutic properties that are specific to particular geometrical and positional isomers. Analysis of these has presented unique problems that have brought forward distinctive solutions, especially the use of gas chromatography-mass spectrometry and silver-ion high-performance liquid chromatography. In the analysis of CLA present at low levels in tissue samples, it is sometimes necessary to use concentration methods. In this review, the most useful and practical methods for the isolation and analysis of CLA isomers in tissues and in commercial CLA preparations are described. PMID- 17710463 TI - Application of fatty acids for chemotaxonomy of reef-building corals. AB - Sixteen scleractinian species of six coral families (Acroporidae, Pocilloporidae, Poritidae, Faviidae, Pectiniidae, and Fungiidae) from Vietnam were analyzed for fatty acid (FA) composition. Except for the Poritidae species, total lipids of the corals had the same set of FAs, about 50% of them being unsaturated acids. Some coral families had high levels of characteristic FAs: 20:3(n-6), 20:4(n-3), and 22:6(n-3) in Pocilloporidae; 18:1(n-9) and 22:6(n-3) in Poritidae; and 18:3(n 6) and 22:5(n-3) in Faviidae. For the first time in hexacorals, unsaturated C(24) FAs (24:1(n-9), 24:2(n-6), 24:2(5,9), 24:3(5,9,17), and 24:4(n-3)) were discovered in the Poritidae species. The highest level of 18:1(n-7), odd-chain and branched FAs (7.5% in total) was detected in Sandalolitha robusta. The data obtained on the contents of ten principal C(18)-C(22) polyunsaturated FAs (PUFAs) for the 16 specimens were combined with data on the 19 reef-building coral specimens investigated previously and subjected to multidimensional scale analysis (MSA). The representative coral families (Acroporidae, Pocilloporidae, Poritidae, Faviidae, Dendrophylliidae, and Milleporidae) were separated by MSA according to the composition of their principal PUFAs. Therefore, PUFAs may serve as chemotaxonomic markers for reef-building corals at the family level. Family specific compositions of coral zooxanthellae characterized by different PUFA profiles, which affect the PUFA content of whole coral colonies, were supposed to be the probable cause of the discovered chemotaxonomic distinctions between reef building corals. PMID- 17710465 TI - Abstracts of the 43rd European Association for the Study of Diabetes (EASD) annual meeting, 18-21 September 2007, Amsterdam, The Netherlands. PMID- 17710467 TI - Manual aspiration thrombectomy with stent placement: rapid and effective treatment for phlegmasia cerulea dolens with impending venous gangrene. AB - Phlegmasia cerulea dolens is an uncommon but potentially life-threatening complication of acute deep vein thrombosis. It is an emergency and delay in treatment may cause death or loss of the patient's limb. Surgical thrombectomy is the recommended treatment in venous gangrene. Catheter-directed intrathrombus thrombolysis has been reported as successful, but it may require a lengthy infusion. Manual aspiration thrombectomy may clear the entire thrombus with no need for thrombolytic administration and provide rapid and effective treatment for patients with phlegmasia cerulea dolens with impending venous gangrene. PMID- 17710468 TI - Right renal vein aplasia associated with diverted renal venous drainage through lower pole. AB - We report a unique anomalous renal venous drainage on a 25-year-old man who had congenital absence of the right renal vein and an aberrant venous drainage through the lower pole of the kidney into the inferior vena cava. To our knowledge, this anomaly has not been previously reported in the peer-reviewed literature. State-of-the-art imaging findings are presented. PMID- 17710469 TI - Chronic contained rupture of an abdominal aortic aneurysm: from diagnosis to endovascular resolution. AB - A male patient, 69 years old, presented with fever, leucocytosis, and persistent low back pain; he also had an abdominal aortic aneurysm (AAA), as previously diagnosed by Doppler UltraSound (US), and was admitted to our hospital. On multislice computed tomography (msCT), a large abdominal mass having no definite border and involving the aorta and both of the psoas muscles was seen. This mass involved the forth-lumbar vertebra with lysis, thus simulating AAA rupture into a paraspinal collection; it was initially considered a paraspinal abscess. After magnetic resonance imaging examination and culture of the fluid aspirated from the mass, no infective organisms were found; therefore, a diagnosis of chronically contained AAA rupture was made, and an aortic endoprosthesis was subsequently implanted. The patient was discharged with decreased lumbar pain. At 12-month follow-up, no evidence of leakage was observed. To our knowledge, this is the first case of endoprosthesis implantation in a patient, who was a poor candidate for surgical intervention due to renal failure, leucocytosis and high fever, having a chronically contained AAA ruptured simulating spodylodiscitis abscess. Appropriate diagnosis and therapy resolved potentially crippling pathology and avoided surgical graft-related complications . PMID- 17710470 TI - Successful coronary stent retrieval from a pedal artery. AB - The purpose of this article is to report complications from a coronary drug eluting stent lost in the peripheral circulation. We report the case of successful retrieval of a sirolimus coronary stent from a pedal artery in a young patient who underwent coronary angiography for previous anterior myocardial infarction. Recognition of stent embolization requires adequate removal of the device to avoid unwelcome clinical sequelae. PMID- 17710471 TI - Traumatic inferior gluteal artery pseudoaneurysm and arteriovenous fistula managed with emergency transcatheter embolization. AB - We present a case of blunt trauma to the buttock resulting in an inferior gluteal artery pseudoaneurysm and arteriovenous fistula. The characteristic diagnostic features on CT angiography and digital subtraction angiography (DSA), along with the emergency percutaneous management of this traumatic vascular injury, are described. A review of the literature demonstrates inferior gluteal artery pseudoaneurysm is a rare condition, while successful treatment with glue embolization is previously unreported. PMID- 17710472 TI - Tunneled central venous catheter malpositioning. PMID- 17710473 TI - Dose perturbation caused by stents: experiments with a model 90Sr/90Y source. AB - PURPOSE: Biological effects of intravascular brachytherapy are very sensitive to discrepancies between the prescription and the applied dose. If brachytherapy is aimed at in-stent restenosis, shielding and shadowing effects of metallic stents may change the dose distribution relative to that produced by the bare source. The development of new generations of stents inspired us to a new experimental study in this field. The effect was studied for 14 stents which we have recently encountered in clinical practice. METHODS: The model source was a continuous 20 mm column of (90)Sr/(90)Y solution sealed in a 1-mm-I.D. Plexiglas capillary. The dose distribution in the Plexiglas phantom was mapped using GafChromic MD-55-2 film. The stent masses varied from 2.5 to 25 mg; the strut thicknesses, from 0.075 to 0.15 mm; and the atomic numbers of stent materials, from 24 (Cr) to 79 (Au). RESULTS: Dose perturbations depend on a variety of stent features. Local reduction of the mean dose rates near the reference distance (r(0) = 2 mm) varied from 11% to 47%. No simple correlation was found between these data and stent characteristics, but it seems that the atomic number of the stent material is less important than the strut thickness and mesh density. CONCLUSION: The results provide a warning that clinical indications for in-stent radiation therapy must always be confronted with another aspect of the patient's history: the kind of implanted stent. Intravascular brachytherapy using pure beta sources may be recommended only for patients "wearing" light, thin-strut stents. The presence of thick-strut stents is a contraindication for this modality, due to excessive dose perturbation. PMID- 17710474 TI - Early results of endovascular treatment of the thoracic aorta using the Valiant endograft. AB - Endovascular repair of the thoracic aorta has been adopted as the first-line therapy for much pathology. Initial results from the early-generation endografts have highlighted the potential of this technique. Newer-generation endografts have now been introduced into clinical practice and careful assessment of their performance should be mandatory. This study describes the initial experience with the Valiant endograft and makes comparisons with similar series documenting previous-generation endografts. Data were retrospectively collected on 180 patients treated with the Valiant endograft at seven European centers between March 2005 and October 2006. The patient cohort consisted of 66 patients with thoracic aneurysms, 22 with thoracoabdominal aneurysms, 19 with an acute aortic syndrome, 52 with aneurysmal degeneration of a chronic dissection, and 21 patients with traumatic aortic transection. The overall 30-day mortality for the series was 7.2%, with a stroke rate of 3.8% and a paraplegia rate of 3.3%. Subgroup analysis demonstrated that mortality differed significantly between different indications; thoracic aneurysms (6.1%), thoracoabdominal aneurysms (27.3%), acute aortic syndrome (10.5%), chronic dissections (1.9%), and acute transections (0%). Adjunctive surgical procedures were required in 63 patients, and 51% of patients had grafts deployed proximal to the left subclavian artery. Comparison with a series of earlier-generation grafts demonstrated a significant increase in complexity of procedure as assessed by graft implantation site, number of grafts and patient comorbidity. The data demonstrate acceptable results for a new-generation endograft in series of patients with diverse thoracic aortic pathology. Comparison of clinical outcomes between different endografts poses considerable challenges due to differing case complexity. PMID- 17710475 TI - Cardiac metastasis from invasive thymoma via the superior vena cava: cardiac MRI findings. AB - Cardiac tumors are rare, and metastatic deposits are more common than primary cardiac tumors. We present cardiac magnetic resonance imaging (MRI) findings of a 50-year-old woman with invasive thymoma. Cardiac MRI revealed a heterogeneous, lobulated anterior mediastinal mass invading the superior vena cava and extending to the right atrium. In cine images there was no invasion to the right atrial wall. PMID- 17710477 TI - Primary cutting balloon angioplasty for treatment of venous stenoses in native hemodialysis fistulas: long-term results from three centers. AB - AIM: To evaluate the technical success and patency rates following primary cutting balloon angioplasty for venous stenoses in native dialysis fistulas. METHODS: Forty-one patients (26 men, 15 women; age range 26-82 years, average age 59 years) underwent 50 (repeat procedures in 9 patients) primary cutting balloon (PCB) angioplasty procedures in three institutions by three primary operators. The indication was primary stenosis in 21 patients, recurrent lesions in 15, and immature fistulas in 5. A PCB was used alone in 17 cases, but was followed by a larger standard balloon in 33 cases. Follow-up included ultrasound, flow analysis and urea reduction ratio, and ranged from 2 to 30 months (mean 14 months). RESULTS: The technical success rate was 98%. All procedures were relatively painless. Two PCBs burst and 4 leaked, but without causing any morbidity. Nineteen fistulas were still working at last follow-up. Primary patency rates at 6, 12, and 24 months using Kaplan-Meier analysis were 88%, 73%, and 34%, respectively, and the primary assisted patencies were 90%, 75%, and 50%, respectively. CONCLUSION: PCB angioplasty has high technical success and low complication rates. The long-term patency rates are favorable for PCB angioplasty and compare favorably with other series. PMID- 17710476 TI - Retrospective study of rapid-exchange monorail versus over-the-wire technique for femoropopliteal angioplasty. AB - PURPOSE: The purpose of this study was to compare procedural outcome of rapid exchange (RX) monorail versus conventional over-the-wire (OTW) technique for femoropopliteal angioplasty. MATERIALS AND METHODS: Demographic data, procedure details, angioplasty success, and complications of 328 consecutive percutaneous transluminal angioplasties (PTAs) were collected from a prospective database and retrospectively analyzed. Procedure details included duration of fluoroscopy, area-dose product, amount of contrast agent, sheath sizes, access route, length of stenosis, presence of total occlusion, technical and anatomical success (residual stenosis < 30% in the absence of complications), need for bail-out stenting, and periprocedural complications. The RX technique alone was used in 102 of 328 cases (31%); the OTW technique, in 226 of 328 of cases (68%). RESULTS: Technical success was 98% for the RX versus 95.4% for the OTW technique (p = 0.2). A significantly greater number of stents had to be implanted due to angioplasty failure when the OTW technique was used (RX, 5.9%; OTW, 13.7%; p = 0.04). There were no significant differences in fluoroscopy time, dose-area product, or amount of contrast medium used. The RX system facilitated the use of smaller sheath sizes (5 Fr = 38% and 6 Fr = 59% for RX versus 5 Fr = 16.8% and > or = 6 Fr = 82.5% for OTW) but showed only a tendency toward lower overall complication rates (16.6% [17/102] in the RX group versus 19.9% [45/226] in the OTW group; p = 0.09). There was no effect on length of hospitalization. RX monorail systems were not associated with higher procedural costs when compared to conventional OTW technique. CONCLUSION: We conclude that RX monorail systems seem to enhance the technical success of femoropopliteal angioplasty. Although smaller sheath sizes can be used due to the lower profile of the RX systems, there is only a tendency toward lower complication rates. PMID- 17710478 TI - Comparison of intrahepatic and pancreatic perfusion on fusion images using a combined SPECT/CT system and assessment of efficacy of combined continuous arterial infusion and systemic chemotherapy in advanced pancreatic carcinoma. AB - PURPOSE: The purpose of this study was to compare intrahepatic and pancreatic perfusion on fusion images using a combined single-photon emission computed tomography (SPECT)/CT system and to evaluate the efficacy of combined continuous transcatheter arterial infusion (CTAI) and systemic chemotherapy in the treatment of advanced pancreatic carcinoma. MATERIALS AND METHODS: CTAI was performed in 33 patients (22 men, 11 women; age range, 35-77 years; mean age, 60 years) with stage IV pancreatic cancer with liver metastasis. The reservoir was transcutaneously implanted with the help of angiography. The systemic administration of gemcitabine was combined with the infusion of 5-fluorouracil via the reservoir. In all patients we obtained fusion images using a combined SPECT/CT system. Pancreatic perfusion on fusion images was classified as perfusion presence or as perfusion absent in the pancreatic cancer. Using WHO criteria we recorded the tumor response after 3 months on multislice helical CT scans. Treatment effects were evaluated based on the pancreatic cancer, liver metastasis, and factors such as intrahepatic and pancreatic perfusion on fusion images. For statistical analysis we used the chi-square test; survival was evaluated by the Kaplan Meier method (log-rank test). RESULTS: On fusion images, pancreatic and intrahepatic perfusion was recorded as hot spot and as homogeneous distribution, respectively, in 18 patients (55%) and as cold spot and heterogeneous distribution, respectively, in 15 (45%). Patients with hot spot in the pancreatic tumor and homogeneous distribution in the liver manifested better treatment results (p < 0.05 and p < 0.01, respectively). Patients with hot spot both in the pancreatic cancer and in the liver survived longer than those with cold spot in the pancreatic cancer and heterogeneous distribution in the liver (median +/- SD, 16.0 +/- 3.7 vs. 8.0 +/- 1.4 months; p < 0.05). CONCLUSIONS: We conclude that in patients with advanced pancreatic cancer, CTAI with systemic chemotherapy appeared to be effective and may prolong their survival. The development of a reservoir port system allowing for the homogeneous distribution of anticancer drugs is necessary to improve the prognosis of patients with advanced pancreatic cancer. PMID- 17710481 TI - Massive hemoperitoneum caused by rupture of an aneurysm of the marginal artery of Drummond. AB - Aneurysms of visceral arteries are uncommon and their rupture is rare. We report a case of an aneurysm of the marginal artery of Drummond, which was complicated by rupture leading to massive hemoperitoneum. A selective superior mesenteric arteriogram suggested the possibility of segmental arterial mediolysis (SAM) as a possible etiology and this was confirmed by histological examination. This is the first report of symptomatic SAM of the marginal artery of Drummond to date. This case demonstrates that the marginal artery of Drummond should be considered during the angiographic explorations for the source of hemoperitoneum. Management options are discussed. PMID- 17710479 TI - Is the routine check nephrostogram following percutaneous antegrade ureteric stent placement necessary? AB - Our aim was to review our experience with percutaneous antegrade ureteric stent (PAUS) placement and to determine if the routinely conducted check nephrostogram on the day following ureteric stent placement was necessary. Retrospective review of patients who had undergone PAUS placement between January 2004 and December 2005 was performed. There were 83 subjects (36 males, 47 females), with a mean age of 59.9 years (range, 22-94 years). Average follow-up duration was 7.1 months (range, 1-24 months). The most common indications for PAUS placement were ureteric obstruction due to metastatic disease (n = 56) and urinary calculi (n = 34). Technical success was 93.2% (96/103 attempts), with no major immediate procedure-related complications or mortalities. The Bard 7Fr Urosoft DJ Stent was used in more than 95% of the cases. Eighty-one of 89 (91.0%) check nephrostograms demonstrated a patent ureteric stent with resultant safety catheter removal. Three check nephrostograms revealed distal stent migration requiring repositioning by a goose-snare, while five others showed stent occlusion necessitating permanent external drainage by nephrostomy drainage catheter reinsertion. Following PAUS placement, the serum creatinine level improved or stabilized in 82% of patients. The serum creatinine outcome difference between the groups with benign and malignant indications for PAUS placement was not statistically significant (p = 0.145) but resolution of hydronephrosis was significantly better (p = 0.008) in patients with benign indications. Percutaneous antegrade ureteric stent placement is a safe and effective means of relief for ureteric obstruction. The check nephrostogram following ureteric stent placement was unnecessary in the majority of patients. PMID- 17710482 TI - Isolation and characterization of dibenzofuran-degrading Serratia marcescens from alkalophilic bacterial consortium of the chemostat. AB - Alkalophilic bacterial consortium developed by continuous enrichment in the chemostat in presence of 4-chlorosalicylic acid as sole source of carbon and energy contained six bacterial strains, Micrococcus luteus (csa101), Deinococcus radiothilus (csa102), csa103 (Burkholderia gladioli), Alloiococcus otilis (csa104), Micrococcus diversus (csa105), Micrococcus luteus (csa106), identified by the Biolog test method. The strains were tested for utilization of organic compounds in which one of the strains (csa101) had higher potency to utilize dibenzofuran (DF) as sole carbon and energy source identified as Serratia marcescens on the basis of 16S rDNA. The degradation of DF by bacterial strain proceeded through an oxidative route as indicated by 2,2'3-trihydroxybiphenyl, 2 hydroxy-6-(2-hydroxyphenyl)-6-oxo-2,4-hexadienoic acid, salicylic acid, and catechol, which was identified by gas chromatography-mass spectrometry. PMID- 17710483 TI - Isolation and characterization of xylitol-producing yeasts from the gut of colleopteran insects. AB - A total of 35 yeasts were isolated from the gut of beetles collected from Hyderabad city, India. Twenty of these yeasts utilized xylose as a sole carbon source but only 12 of these converted xylose to xylitol. The ability to convert xylose to xylitol varied among the isolates and ranged from 0.12 to 0.58 g/g xylose. Based on the phenotypic characteristics and phylogenetic analysis of the D1/D2 domain sequence of 26S rRNA gene, these isolates were identified as members of Pichia, Candida, Issatchenkia, and Clavispora. Strain YS 54 (CBS 10446), which was phylogenetically similar to Pichia caribbica and which formed hat-shaped ascospore characteristics of the genus Pichia, was the best xylitol producer (0.58 g xylitol/g xylose). YS 54 was also capable of producing xylitol from sugarcane bagasse hydrolysate and the efficiency of conversion was 0.32 g xylitol/g xylose after 20 cycles of adaptation in medium containing sugarcane bagasse hydrolysate. PMID- 17710484 TI - Epistasis between hyperglycemic QTLs revealed in a double congenic of the OLETF rat. AB - Glucose homeostasis is believed to be regulated by multiple genetic components, in addition to numerous external factors. It is therefore crucial to dissect and understand what roles each causative gene plays in maintaining proper glucose metabolism. In OLETF (Otsuka Long-Evans Tokushima Fatty) rat, a model of polygenic type 2 diabetes, at least 14 quantitative trait loci (QTLs) influencing plasma glucose levels were identified. In congenic strains some of the OLETF allelic variants were shown to increase glucose levels. In this study the focus was on two of the hyperglycemic loci, Nidd1/of and Nidd2/of. Congenic rats possessing OLETF genome fragment at either locus showed similar levels of mild hyperglycemia. A newly established double congenic rat showed a further aggravation of hyperglycemia. The Nidd1/of locus was also shown to function in the reduction of plasma leptin levels and fat weights, while the Nidd2/of locus led to increased plasma insulin and fat weights. Interestingly, both plasma leptin and fat weights reverted to the control levels in the double congenic rat. These results indicate that there is an epistatic interaction between the two loci. However, it is unlikely that the abnormal level of enhanced glucose homeostasis is mediated, at least not directly, by leptin or fat mass. PMID- 17710487 TI - Effectiveness of endoscopic surgery training for medical students using a virtual reality simulator versus a box trainer: a randomized controlled trial. AB - BACKGROUND: The first step toward increasing the level of patient safety in endoscopic surgery is for all endoscopic surgeons to acquire fundamental skills, including psychomotor skills, in the preoperation stage of training. The current study aimed to evaluate the effectiveness of virtual reality (VR) simulator training and box training for training the fundamental skills of endoscopic surgery. METHODS: For this study, 35 medical students at Kyushu University were divided into three groups: simulator (SIM) group (n = 20), box trainer (BOX) group (n = 20), and control group (n = 15). None of the students had any experience assisting with endoscopic surgery or any previous training for endoscopic surgery. The students in the SIM group underwent training using a VR simulator, the Procedicus MIST, 2 h per day for 2 days. The students in the BOX group underwent training using a box trainer 2 h per day for 2 days. The students in the control group watched an educational video for 30 min. The endoscopic surgical skills of all the students were evaluated before and after training with a task of suturing and knot tying using a box trainer. RESULTS: Although no significant differences were found between the three groups in the total time taken to complete the evaluation task before training, there were significant improvements in the SIM and BOX groups after training compared with the control group. Box training increased errors during the task, but simulator training did not. CONCLUSION: The findings showed that box training and VR training have different outcomes. The authors expect that the best curriculum for their training center would involve a combination that uses the merits of both methods. PMID- 17710485 TI - Efficacy of corticosteroids in the treatment of community-acquired pneumonia requiring hospitalization. AB - BACKGROUND: Recent studies suggested that administration of corticosteroids may improve clinical outcomes in patients with severe pneumonia. OBJECTIVES: The aim of this study was to assess the effectiveness of corticosteroids as an adjunctive therapy in community-acquired pneumonia (CAP) requiring hospitalization. DESIGN AND SETTING: An open label, prospective, randomized control study was conducted from September 2003 to February 2004 in a community general hospital in Japan. PATIENTS: Thirty-one adult CAP patients who required hospitalization were enrolled. MEASUREMENTS AND RESULTS: Fifteen patients received 40 mg of prednisolone intravenously for 3 days (steroid group). Sixteen patients did not receive prednisolone (control group). Both groups were also evaluated for their adrenal function. The primary endpoint was length of hospital stay. Secondary endpoints were duration of intravenous (IV) antibiotics and time required to stabilize vital signs. Both groups demonstrated similar baseline characteristics and length of hospital stay, and yet a shorter duration of IV antibiotics was observed in the steroid group (p < 0.05). In addition, vital signs were stabilized earlier in the steroid group (p < 0.05). These differences were more prominent in the moderate-severe subgroup but not as significant in the mild moderate subgroup. The prevalence of relative adrenal insufficiency (RAI) in both groups was high (43%), yet there was no difference in baseline characteristics between patients, with or without RAI. In multiple regression models, RAI seemed to have no influence on clinical courses. CONCLUSIONS: In moderate-severe CAP, administration of corticosteroids promotes resolution of clinical symptoms and reduces the duration of intravenous antibiotic therapy. PMID- 17710488 TI - Laparoscopic antireflux surgery: tailoring the hiatal closure to the size of the hiatal area. PMID- 17710490 TI - Gastrotomy closure using bioabsorbable plugs in a canine model. AB - The repair of gastric perforation commonly involves simple suture closure using an open or laparoscopic approach. An endolumenal approach using prosthetic materials may be beneficial. The role of bioprosthetics in this instance has not been thoroughly investigated, thus the authors evaluated the feasibility of gastric perforation repair using a bioabsorbable device and quantified gross and histological changes at the injury site. Twelve canines were anesthetized and underwent open gastrotomy. A 1-cm-diameter perforation was created in the anterior wall of the stomach and plugged with a bioabsorbable device. Intralumenal pH was recorded. Canines were sacrificed at one, four, six, eight, and 12 weeks. The stomach was explanted followed by gross and histological examination. The injury site was examined. The relative ability of the device to seal the perforation was recorded, as were postoperative changes. Tissue samples were analyzed for gross and microscopic tissue growth and compared to normal gastric tissue in the same animal as an internal control. A scoring system of -2 to +2 was used to measure injury site healing (-2= leak, -1= no leak and minimal ingrowth, 0= physiologic healing, +1= mild hypertrophic tissue, +2= severe hypertrophic tissue). In all canines, the bioprosthesis successfully sealed the perforation without leak under ex vivo insufflation. At one week, the device maintained its integrity but there was no tissue ingrowth. Histological healing score was -1. At 4-12 weeks, gross examination revealed a healed injury site in all animals. The lumenal portion of the plug was completely absorbed. The gross and histological healing score ranged from -1 to +1. The application of a bioabsorbable device results in durable closure of gastric perforation with physiologic healing of the injury site. This method of gastrotomy closure may aid in the evolution of advanced endoscopic approaches to perforation closure of hollow viscera. PMID- 17710489 TI - Intravenous pantoprazole utilization in a level 1 trauma center. AB - BACKGROUND: In recent years there has been a rapid increase in the use of proton pump inhibitors. Our institution has recently had several shortages of IV pantoprazole, each lasting 7-10 days. The purpose of our study was to evaluate in patient usage of IV pantoprazole. We hypothesized that hospitalized patients with upper gastrointestinal bleeding (GIB) or risk for stress ulcers inappropriately received IV pantoprazole based on current literature. METHODS: This was a retrospective study of 165 consecutive in-patients identified as receiving pantoprazole from December 2004 to March 2005. Only patients receiving IV pantoprazole were included (n = 78). Data collected included demographics, indication and dosing of pantoprazole, admitting team (surgery vs. medicine), and risk factors for stress ulcers. RESULTS: Our study population had a mean age of 54 +/- 17 years and 62% were male. Overall, 45% (35/78) of patients receiving IV pantoprazole had an appropriate indication, and 19% (15/78) received the correct dose. Of the 78 patients, 43 (55%) were treated with pantoprazole for stress ulcer prophylaxis (SUP), and 35 (45%) patients were treated for GIB. We found that none of the 43 patients treated for SUP had an appropriate indication for pantoprazole, but all of the patients with GIB (35) had an appropriate indication. Of the 35 patients treated for GIB with pantoprazole, only 40% (14/35) received the correct dose. In all cases of incorrect dosing, the patients were underdosed. CONCLUSIONS: Pantoprazole is not being prescribed appropriately for stress ulcer prophylaxis in our patient population. Even in patients appropriately receiving pantoprazole the majority were prescribed an incorrect dose. Appropriate indications and dosing of pantoprazole could eliminate the shortages seen at our institution. PMID- 17710491 TI - Building an efficient surgical team using a bench model simulation: construct validity of the Legacy Inanimate System for Endoscopic Team Training (LISETT). AB - BACKGROUND: Complex laparoscopic tasks require collaboration of surgeons as a surgical team. Conventionally, surgical teams are formed shortly before the start of the surgery, and team skills are built during the surgery. There is a need to establish a training simulation to improve surgical team skills without jeopardizing the safety of surgery. The Legacy Inanimate System for Laparoscopic Team Training (LISETT) is a bench simulation designed to enhance surgical team skills. The reported project tested the construct validity of LISETT. The research question was whether the LISETT scores show progressive improvement correlating with the level of surgical training and laparoscopic team experience or not. METHODS: With LISETT, two surgeons are required to work closely to perform two laparoscopic tasks: peg transportation and suturing. A total of 44 surgical dyad teams were recruited, composed of medical students, residents, laparoscopic fellows, and experienced surgeons. The LISETT scores were calculated according to the speed and accuracy of the movements. RESULTS: The LISETT scores were positively correlated with surgical experience, and the results can be generalized confidently to surgical teams (Pearson's coefficient, 0.73; p = 0.001). To analyze the influences of individual skill and team dynamics on LISETT performance, team quality was rated by team members using communication and cooperation characters after each practice. The LISETT scores are positively correlated with self-rated team quality scores (Pearson's coefficient, 0.39; p = 0.008). CONCLUSIONS: The findings proved LISETT to be a valid system for assessing cooperative skills of a surgical team. By increasing practice time, LISETT provides an opportunity to build surgical team skills, which include effective communication and cooperation. PMID- 17710493 TI - Security of patient and study data associated with DICOM images when transferred using compact disc media. AB - The transmission of patient and imaging data between imaging centers and other interested individuals is increasingly achieved by means of compact disc digital media (CD). These CDs typically contain, in addition to the patient images, a DICOM reader and information about the origin of the data. While equipment manufacturers attach disclaimers to these discs and specify the intended use of such media, they are often the only practical means of transmitting data for small medical, dental, or veterinary medical centers. Images transmitted by these means are used for clinical diagnosis. This has lead to a heavy reliance on the integrity of the data. This report describes attempts to alter significant patient and study data on CD media and their outcome. The results show that data files are extremely vulnerable to alteration, and alterations are not detectable without detailed analysis of file structure. No alterations to the DICOM readers were required to achieve this; changes were applied only to the data files. CDs with altered data can be readily prepared, and from the point of view of individuals viewing the images, function identically to the original manufacturer's CD. Such media should be considered unsafe where there is a potential for financial or other gain to be had from altering the data, and the copy cannot be cross-checked with the original data. PMID- 17710492 TI - Voltage-activated calcium currents in octopus cells of the mouse cochlear nucleus. AB - Octopus cells, neurons in the most posterior and dorsal part of the mammalian ventral cochlear nucleus, convey the timing of synchronous firing of auditory nerve fibers to targets in the contralateral superior paraolivary nucleus and ventral nucleus of the lateral lemniscus. The low input resistances and short time constants at rest that arise from the partial activation of a large, low voltage-activated K(+) conductance (g(KL)) and a large mixed-cation, hyperpolarization-activated conductance (g(h)) enable octopus cells to detect coincident firing of auditory nerve fibers with exceptional temporal precision. Octopus cells fire conventional, Na(+) action potentials but a voltage-sensitive Ca(2+) conductance was also detected. In this study, we explore the nature of that calcium conductance under voltage-clamp. Currents, carried by Ca(2+) or Ba(2+) and blocked by 0.4 mM Cd(2+), were activated by depolarizations positive to -50 mV and peaked at -23 mV. At -23 mV they reached 1.1 +/- 0.1 nA in the presence of 5 mM Ca(2+) and 1.6 +/- 0.1 nA in 5 mM Ba(2+). Ten micromolar BAY K 8644, an agonist of high-voltage-activated L-type channels, enhanced I(Ba) by 63 +/- 11% (n = 8) and 150 microM nifedipine, an antagonist of L-type channels, reduced the I(Ba) by 65 +/- 5% (n = 5). Meanwhile, 0.5 microM omega-Agatoxin IVA, an antagonist of P/Q-type channels, or 1 microM omega-conotoxin GVIA, an antagonist of N-type channels, suppressed I(Ba) by 15 +/- 4% (n = 5) and 9 +/- 4% (n = 5), respectively. On average 16% of the current remained in the presence of the cocktail of blockers, indicative of the presence of R-type channels. Together these experiments show that octopus cells have a depolarization-sensitive g(Ca) that is largely formed from L-type Ca(2+) channels and that P/Q-, N-, and R-type channels are expressed at lower levels in octopus cells. PMID- 17710494 TI - The open-source neuroimaging research enterprise. AB - While brain imaging in the clinical setting is largely a practice of looking at images, research neuroimaging is a quantitative and integrative enterprise. Images are run through complex batteries of processing and analysis routines to generate numeric measures of brain characteristics. Other measures potentially related to brain function - demographics, genetics, behavioral tests, neuropsychological tests - are key components of most research studies. The canonical scanner - PACS - viewing station axis used in clinical practice is therefore inadequate for supporting neuroimaging research. Here, we model the neuroimaging research enterprise as a workflow. The principal components of the workflow include data acquisition, data archiving, data processing and analysis, and data utilization. We also describe a set of open-source applications to support each step of the workflow and the transitions between these steps. These applications include DIGITAL IMAGING AND COMMUNICATIONS IN MEDICINE viewing and storage tools, the EXTENSIBLE NEUROIMAGING ARCHIVE TOOLKIT data archiving and exploration platform, and an engine for running processing/analysis pipelines. The overall picture presented is aimed to motivate open-source developers to identify key integration and communication points for interoperating with complimentary applications. PMID- 17710495 TI - Use of chewing gum in reducing postoperative ileus after elective colorectal resection: a systematic review. AB - PURPOSE: Published studies comparing the addition of chewing gum to standardized postoperative care to shorten postoperative ileus showed controversial results. This study was designed to conduct a systematic review of all relevant trials on chewing gum to reduce postoperative ileus after colorectal resection. METHODS: All published trials that compared the additional use of gum chewing with standard postoperative management were identified from Ovid MEDLINE, EMBASE, CINAHL, and All Evidence-Based Medicine Reviews between January 1991 and January 2007. The clinical outcomes were extracted and meta-analysis was performed by Forest plot review. RESULTS: Five randomized, controlled trials with 158 (94 males) patients with mean age of 61.9 years were included. Seventy-eight patients received an addition of gum chewing and 80 had standard postoperative care for colorectal resection. Operating time (P = 0.78) and blood loss (P = 0.48) were similar. All patients tolerated the gum without any side-effects. With combined standard postoperative care and gum chewing, the patients passed flatus 24.3 percent earlier (weighted mean difference, -20.8 hours; P = 0.0006) and had bowel movement 32.7 percent earlier (weighted mean difference, -33.3 hours; P = 0.0002). They were discharged 17.6 percent earlier than those having ordinary postoperative treatment (weighted mean difference, -2.4 days; P < 0.00001). The gum-chewing group was associated with similar overall postoperative complication rate (odds ratio, 0.45; P = 0.05) with individual complication showing a trend favoring gum chewing, although they were not of statistical significance. Readmission (odds ratio, 0.36; P = 0.24) and reoperation rates (odds ratio, 1.36; P = 0.83) of the two groups were similar. CONCLUSIONS: The use of gum chewing in the postoperative period is a safe method to stimulate bowel motility and reduce ileus after colorectal surgery. PMID- 17710496 TI - Multivariate analysis of predictive factors for early postoperative death after colorectal surgery in patients with colorectal cancer and synchronous unresectable liver metastases. AB - PURPOSE: Surgery of the primary tumor in patients with colorectal cancer and unresectable synchronous liver metastases remains controversial. This study was designed to evaluate predictive preoperative factors of early postoperative death (<3 months) in such patients. METHODS: This study included 80 patients who underwent colorectal resection (n = 56) or diversion stoma (n = 24) for colorectal cancer with unresectable liver metastases. Twenty-two patients (28 percent) died during the first three months after surgery with two (2.5 percent) in-hospital postoperative deaths. Analysis of predictive preoperative factors for three-month postoperative death risk was performed. RESULTS: In univariate analysis, age older than 75 years (P = 0.01), American Society of Anesthesiologists grade > II (P = 0.009), symptomatic patient (P = 0.01), bowel obstruction (P = 0.03), aspartate aminotransferase serum level >50 (1.5 N) IU/L (P = 0.008), and alkaline phosphatase >200 (2 N) IU/L (P = 0.02) were prognostic risk factors for three-month death after surgery. In multivariate analysis, age older than 75 years (relative risk = 7.9; P = 0.04) and aspartate aminotransferase serum level >50 IU/L (relative risk = 8.3; P = 0.03) were independent risk factors. CONCLUSIONS: In patients with colorectal cancer and synchronous unresectable liver metastases, the three-month mortality rate was high (28 percent). Thus, better knowledge of risk factors could help select patients who could possibly benefit from surgery. The study suggested that age older than 75 years and liver cytolysis (>1.5 N) are associated with an increased three-month postoperative death risk. In these patients, surgery should be avoided. PMID- 17710497 TI - Individual odor recognition in birds: an endogenous olfactory signature on petrels' feathers? AB - A growing body of evidence indicates that odors are used in individual, sexual, and species recognition in vertebrates, and may be reliable signals of quality and compatibility. Petrels are seabirds that exhibit an acute sense of smell. During the breeding period, many species of petrels live in dense colonies on small oceanic islands and form pairs that use individual underground burrows. Mates alternate between parental duties and foraging trips at sea. Returning from the ocean at night (to avoid bird predators), petrels must find their nest burrow. Antarctic prions, Pachyptila desolata, are thought to identify their nest by recognizing their partner's odor, suggesting the existence of an individual odor signature. We used gas chromatography and mass spectrometry to analyze extracts obtained from the feathers of 13 birds. The chemical profile of a single bird was more similar to itself, from year to year, than to that of any other bird. The profile contained up to a hundred volatile lipids, but the odor signature may be based on the presence or absence of a few specific compounds. Our results show that the odor signature in Antarctic prions is probably endogenous, suggesting that in some species of petrels it may broadcast compatibility and quality of potential mates. PMID- 17710498 TI - Recurrence and prognostic factors of ampullary carcinoma after radical resection: comparison with distal extrahepatic cholangiocarcinoma. AB - BACKGROUND: Ampullary carcinoma is often considered to have a better prognosis than distal extrahepatic cholangiocarcinoma. However, studies that directly compare the recurrence and histopathological features between the two groups are rare. METHODS: Clinicopathologic factors and the long-term outcomes of 163 patients with ampullary carcinoma after radical resection were retrospectively evaluated and compared with those of 91 patients with distal extrahepatic cholangiocarcinoma. RESULTS: Among the 163 ampullary carcinomas, T1 stage, well differentiated tumors and perineural invasion were 45 (28%), 73 (45%), and 23 (14%), respectively, whereas, only five (6%) were T1 stage, 15 (17%) were well differentiated, and 63 (69%) showed perineural invasion (p < 0.001, for all) in distal extrahepatic cholangiocarcinomas. More patients with distal extrahepatic cholangiocarcinoma had liver metastasis than ampullary carcinoma (24% vs. 10%, p = 0.004). Multivariate analysis identified venous invasion and perineural invasion as risk factors for recurrence of ampullary carcinoma after radical resection. Only lymph node involvement was identified as a risk factor for recurrence of distal extrahepatic cholangiocarcinoma by multivariate analysis. Overall five-year survival of patients with ampullary cancer was higher than that of patients with distal extrahepatic cholangiocarcinoma (68% vs. 54%; p = 0.033). In patients without lymph node metastasis, a significant difference in survival was also observed between the two groups (p = 0.049). CONCLUSION: Earlier diagnosis and the less frequent occurrence of pathological factors associated with tumor invasiveness in ampullary carcinoma than in distal extrahepatic cholangiocarcinoma may explain its association with a better prognosis. PMID- 17710499 TI - Appendiceal carcinoma with peritoneal dissemination: outcomes for the best of the best. PMID- 17710500 TI - The surgeon's role in cancer prevention. The model in colorectal carcinoma. AB - Cancer Prevention is an emerging field, capturing the old traditional concept of anticipating the development of a major disease and preventing its full impact by early detection, treatment, or aborting the tumorigenic process by a "molecular vaccine" and alleviating the full impact of the disease. Surgeons are important clinician scientists who can carry this discipline forward and develop its full potential in the clinics and in the community. Advances in molecular biology, genetics, and other technologies have permitted seminal understanding of the carcinogenic pathways and identification of targets and intermediate end points in neoplasia. In this review, we will see that we have the means of preventing significant numbers of colorectal carcinomas (CRC). PMID- 17710501 TI - Using decision tree models to depict primary care physicians CRC screening decision heuristics. AB - OBJECTIVE: The purpose of this study was to identify decision heuristics utilized by primary care physicians in formulating colorectal cancer screening recommendations. DESIGN: Qualitative research using in-depth semi-structured interviews. PARTICIPANTS: We interviewed 66 primary care internists and family physicians evenly drawn from academic and community practices. A majority of physicians were male, and almost all were white, non-Hispanic. APPROACH: Three researchers independently reviewed each transcript to determine the physician's decision criteria and developed decision trees. Final trees were developed by consensus. The constant comparative methodology was used to define the categories. RESULTS: Physicians were found to use 1 of 4 heuristics ("age 50," "age 50, if family history, then earlier," "age 50, if family history, then screen at age 40," or "age 50, if family history, then adjust relative to reference case") for the timing recommendation and 5 heuristics ["fecal occult blood test" (FOBT), "colonoscopy," "if not colonoscopy, then...," "FOBT and another test," and "a choice between options"] for the type decision. No connection was found between timing and screening type heuristics. CONCLUSIONS: We found evidence of heuristic use. Further research is needed to determine the potential impact on quality of care. PMID- 17710502 TI - The impact of perioperative dexmedetomidine infusion on postoperative narcotic use and duration of stay after laparoscopic bariatric surgery. AB - Dexmedetomidine (Precedex, Hospira, Lake Forest, IL) is an alpha-2 receptor agonist with sedative and analgesic sparing properties. This medication has not been associated with respiratory suppression, despite occasionally high levels of sedation. For 10 months, all patients undergoing a laparoscopic bariatric procedure received a dexmedetomidine infusion 30 min before the anticipated completion of the procedure (n = 34). A control group was comprised of a similar number of patients to have had laparoscopic bariatric surgery in the time period immediately before these 10 months (n = 37). All pathways and discharge criteria were identical for patients in each group. A total of 73 patients were included in this retrospective chart review. Two gastric bypass patients were excluded for complications requiring additional surgery (one bleed and one leak). Gastric bypass patients who received a dexmedetomidine infusion required fewer narcotics (66 vs 130 mg of morphine equivalents) than control patients and met discharge criteria on post-op day (POD) 1 more often (61% discharged POD 1 vs 26% discharged POD 1, p = 0.02). Vital signs and pain scores were similar in all groups. Dexmedetomidine infusion perioperatively is safe and may help to minimize narcotic requirements and decrease duration of stay after laparoscopic bariatric procedures. This may have important patient safety ramifications in a patient population with a high prevalence of obstructive sleep apnea. A well-organized prospective, randomized, double-blinded trial is necessary to confirm the benefits of dexmedetomidine suggested by this study. PMID- 17710503 TI - Can surgeons think and operate with haptics at the same time? AB - Much effort has been devoted to incorporating haptic feedback into surgical simulators. However, the benefits of haptics for novice trainees in the early stages of learning are not clear. Presumably, novices have less spare attentional resources to attend to haptic cues while learning basic laparoscopic skills. The aim of this study was to determine whether novice surgeons have adequate cognitive resources to attend to haptic information. Thirty surgical residents and attendings performed a TransferPlace task in a simulator, with and without haptics. Cognitive loading was imposed using a mental arithmetic task. Subjects performed 10 trials (five with cognitive loading and five without) with and without haptics. Results showed that all subjects performed significantly slower (27%) when they were cognitively loaded than unloaded, but equally accurately in both cases, suggesting a speed-accuracy tradeoff. On average, subjects performed 36% faster and 97% more accurately with haptics than without, even while cognitively loaded. Haptic feedback can not only enhance performance, but also counter the effect of cognitive load. This effect is greater for more experienced surgeons than less experienced ones, indicating greater spare cognitive capacity in surgeons with more experience. PMID- 17710504 TI - The outcome of laparoscopic Heller myotomy for achalasia is not influenced by the degree of esophageal dilatation. AB - In the past, a Heller myotomy was considered to be ineffective in patients with achalasia and a markedly dilated or sigmoid-shaped esophagus. Esophagectomy was the standard treatment. The aims of this study were (a) to evaluate the results of laparoscopic Heller myotomy and Dor fundoplication in patients with achalasia and various degrees of esophageal dilatation; and (b) to assess the role of endoscopic dilatation in patients with postoperative dysphagia. One hundred and thirteen patients with esophageal achalasia were separated into four groups based on the maximal diameter of the esophageal lumen and the shape of the esophagus: group A, diameter<4.0 cm, 46 patients; group B, esophageal diameter 4.0-6.0 cm, 32 patients; group C, diameter>6.0 cm and straight axis, 23 patients; and group D, diameter>6.0 cm and sigmoid-shaped esophagus, 12 patients. All had a laparoscopic Heller myotomy and Dor fundoplication. The median length of follow up was 45 months (range 7 months to 12.5 years). The postoperative recovery was similar among the four groups. Twenty-three patients (20%) had postoperative dilatations for dysphagia, and five patients (4%) required a second myotomy. Excellent or good results were obtained in 89% of group A and 91% of groups B, C, and D. None required an esophagectomy to maintain clinically adequate swallowing. These data show that (a) a laparoscopic Heller myotomy relieved dysphagia in most patients with achalasia, even when the esophagus was dilated; (b) about 20% of patients required additional treatment; (c) in the end, swallowing was good in 90%. PMID- 17710505 TI - Morbidity and mortality following multivisceral resections in complex hepatic and pancreatic surgery. AB - Complex multivisceral resections in major hepatic and pancreatic surgery are relatively infrequent, and information regarding the morbidity and mortality associated with such resections is scant. The purpose of this paper is to describe the outcomes following such aggressive surgical treatment. A retrospective review of the outcomes following multiorgan resection in the setting of major liver or pancreatic resection was conducted from 2002 until July 2006. Patients who had a major hepatic or pancreatic resection plus resection of at least one other organ were included. The primary outcome measures analyzed were the postoperative morbidity and mortality. Secondary outcomes included recurrence rates and survival. Twenty-seven patients met the inclusion criteria. There were two postoperative deaths (7%). Complications occurred in 59% of patients. Complications were minor in 26% and severe in 33%. Complications were more frequent in older patients and in patients with pancreatic resections. Mortality was significantly increased in the setting of a pancreaticoduodenectomy. These more aggressive procedures should be considered to carry a higher risk of complications, particularly in patients undergoing pancreaticoduodenectomies. Patients should be selected carefully when undertaking complex multivisceral resections in major hepatic and pancreatic surgery. PMID- 17710506 TI - Pancreatic anastomotic leakage after pancreaticoduodenectomy in 1,507 patients: a report from the Pancreatic Anastomotic Leak Study Group. AB - Several definitions for pancreatic leakage after pancreaticodoudenectomy exist, and the reported range of 2-50% underscores this variation. The goal was to determine if drain data alone was predictive of a leak and validate International Study Group on Pancreatic Fistula (ISGPF) leak criteria. Participating surgeons entered de-identified data into a web-based database designed to collect Whipple related data. Definitions used were the ISGPF definition, > or = 3 days, amylase 3x normal; and Sarr's definition, > or = 5 days, amylase 5x normal, > 30 ml. We compared how well these two definitions were at detecting a leak and its complications. There were 1,507 cases submitted from 16 international institutions. A pancreaticoduodenectomy (PPPD) was performed in 76.2%. Drain placement occurred in 98.0%. Using the ISGPF definition, the pancreatic leak rate was 26.7 and 14.3% with the Sarr definition. There were more grades A and B leaks detected by the ISGPF definition. Both determined grade C leaks equally. Both definitions correlated with an increased length of stay (LOS), need for percutaneous drains, reoperation, and delayed gastric emptying (DGE). Neither was associated with an increased risk of intensive care unit (ICU) stay or 30-day mortality. The ISGPF was able to capture more patients with clinically relevant leaks than Sarr's criteria; however, the ability to detect a leak by drain data alone is imperfect. PMID- 17710507 TI - High resolution anoscopy in the planned staged treatment of anal squamous intraepithelial lesions in HIV-negative patients. AB - Anal dysplasia (low-grade squamous intraepithelial lesions, LSIL; high-grade squamous intraepithelial lesions, HSIL) is a challenging disease for the surgeon. We reviewed 42 patients that underwent high-resolution anoscopy (HRA)-targeted surgical therapy of anal dysplasia in the past 10 years. Patients were followed up in the Anal Neoplasia Clinic with physical examination, cytology, HRA, and biopsy if indicated. Patients with disease amenable to local therapy were treated with office-based HRA-directed therapies. There were 30 men (mean age 39 years, range 21-63) and 12 women (mean age 50 years, range 31-71) included in the study. HSIL was present in 33, with four undergoing planned staged treatment due to circumferential disease. HSIL recurred in 45%, and most were re-treated successfully in-office. Progression to HSIL was seen in one patient with LSIL and to squamous cell carcinoma in one patient with HSIL despite therapy. No patients with LSIL had dysplasia at last follow-up. Minor complications occurred in three patients. HRA-targeted surgical therapy coupled with surveillance and re treatment with office-based therapies offered an effective method in controlling anal dysplasia in the immunocompetent patient. Morbidity is minimal, and our progression to cancer rate is low (2.4%). PMID- 17710508 TI - Long-term outcomes following liver transplantation for hepatic hemangioendothelioma: the UNOS experience from 1987 to 2005. AB - INTRODUCTION: Hepatic hemangioendothelioma (HEH) is a vascular neoplasm with intermediate malignant potential. Outcomes after liver transplantation have only been reported as small, single-institution experiences. The purpose of this study was to evaluate patient and allograft survivals after liver transplantation in a large, multi-institutional cohort of patients with HEH. METHODS: Using the United Network for Organ Sharing (UNOS) database, we identified 110 patients with a diagnosis of HEH who underwent 126 transplants between 1987 and 2005. Patient and allograft survivals were calculated using Kaplan-Meier survival curves. Log rank tests were used to determine the influence of study variables on outcomes. RESULTS: Of the 110 transplanted patients, 75 patients (68%) were female, 80 patients (73%) were Caucasian, and the median age was 36 years old (23%<4 y.o., 71%>18 y.o.). The 30-day posttransplant mortality rate was 2.4%. At a median patient follow-up interval of 24 months, 1- and 5-year patient and allograft survivals were 80% and 64%, and 70% and 55%, respectively. Pretransplant medical status, but not age, was found to statistically correlate with patient survival. CONCLUSION: These data indicate that survivals after transplantation for HEH are favorable. Given the propensity for recurrence after resection, these data support consideration of liver transplantation for all patients with significant intrahepatic tumor burden. PMID- 17710510 TI - Prosthetic repair of a perforated Amyand's hernia: hazardous or feasible? PMID- 17710511 TI - Soft tissue attachment on sol-gel-treated titanium implants in vivo. AB - This study was designed to examine the attachment and reactions of soft tissues to sol-gel-derived TiO2 coatings. In the first experiment, TiO2 coated and uncoated titanium cylinders were placed subcutaneously into the backs of rats for 3, 11 and 90 days. Tissue response and implant surfaces were characterized with routine light microscopy and scanning electron microscopic (SEM) analysis. In the second experiment, TiO2-coated and uncoated discs were implanted subcutaneously into the backs of rats for 14 and 21 days. The discs were pulled out from the implantation sites with a mechanical testing device using a constant speed of 5 mm/min. Rupture force was registered, after which the discs were assigned for SEM and transmission electron microscopic (TEM) analysis. All the coated implants showed immediate contact with the surrounding soft tissues without a clear connective tissue capsule. Significantly better soft tissue response was measured for all the coated compared to the uncoated cylinders (p<0.01). Higher rupture forces were measured for all coated discs, although the differences were not statistically significant. An immediate and tight connection between connective tissue fibroblasts and coatings was noticed in TEM analysis. Our study indicates that TiO2 coatings improve soft tissue attachment on a titanium surface. PMID- 17710512 TI - Recombinant biomaterials for pharmaceutical and biomedical applications. PMID- 17710513 TI - Mechanism of UVA-dependent DNA damage induced by an antitumor drug dacarbazine in relation to its photogenotoxicity. AB - PURPOSE: It has been reported that dacarbazine (DTIC) is photogenotoxic. The purpose of this study is to clarify the mechanism of photogenotoxicity induced by DTIC. MATERIALS AND METHODS: We examined DNA damage induced by UVA-irradiated DTIC using 32P-5'-end-labeled DNA fragments obtained from human genes. Formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in calf thymus DNA was measured by high performance liquid chromatograph with an electrochemical detector. Electron spin resonance (ESR) spin-trapping experiments were performed to detect radical species generated from UVA-irradiated DTIC. RESULTS: UVA-irradiated DTIC caused DNA damage at guanine residues, especially at the 5'-GGT-3' sequence in the presence of Cu(II) and also induced 8-oxodG generation in calf thymus DNA. DTIC-induced photodamage to DNA fragments was partially inhibited by catalase, whereas 8-oxodG formation was significantly increased by catalase. NaN3, a carbene scavenger, inhibited DNA damage and 8-oxodG formation in a dose-dependent manner, suggesting that carbene intermediates are involved. The ESR spin-trapping experiments demonstrated the generation of aryl radicals in the process of photodegradation of DTIC. CONCLUSION: Photoactivated DTIC generates the carbene and aryl radicals, which may induce both DNA adduct and 8-oxodG formation, resulting in photogenotoxicity. This study could provide an insight into the safe usage of DTIC. PMID- 17710514 TI - The role of permeability in drug ADME/PK, interactions and toxicity--presentation of a permeability-based classification system (PCS) for prediction of ADME/PK in humans. AB - PURPOSE: The objective was to establish in vitro passive permeability (Pe) vs in vivo fraction absorbed (fa)-relationships for each passage through the human intestine, liver, renal tubuli and brain, and develop a Pe-based ADME/PK classification system (PCS). MATERIALS AND METHODS: Pe- and intestinal fa-data were taken from an available data set. Hepatic fa was calculated based on extraction ratios of the unbound fraction of drugs (with support from animal in vivo uptake data). Renal fa (reabsorption) was estimated using renal pharmacokinetic data, and brain fa was predicted using animal in vitro and in vivo brain Pe-data. Hepatic and intestinal fa-data were used to predict bile excretion potential. RESULTS: Relationships were established, including predicted curves for bile excretion potential and minimum oral bioavailability, and a 4 Class PCS was developed: I (very high Pe; elimination mainly by metabolism); II (high Pe) and III (intermediate Pe and incomplete fa); IV (low Pe and fa). The system enables assessment of potential drug-drug transport interactions, and drug and metabolite organ trapping. CONCLUSIONS: The PCS and high quality Pe-data (with and without active transport) are believed to be useful for predictions and understanding of ADME/PK, elimination routes, and potential interactions and organ trapping/toxicity in humans. PMID- 17710515 TI - Pharmacokinetic modeling of non-linear brain distribution of fluvoxamine in the rat. AB - INTRODUCTION: A pharmacokinetic (PK) model is proposed for estimation of total and free brain concentrations of fluvoxamine. MATERIALS AND METHODS: Rats with arterial and venous cannulas and a microdialysis probe in the frontal cortex received intravenous infusions of 1, 3.7 or 7.3 mg.kg(-1) of fluvoxamine. ANALYSIS: With increasing dose a disproportional increase in brain concentrations was observed. The kinetics of brain distribution was estimated by simultaneous analysis of plasma, free brain ECF and total brain tissue concentrations. The PK model consists of three compartments for fluvoxamine concentrations in plasma in combination with a catenary two compartment model for distribution into the brain. In this catenary model, the mass exchange between a shallow perfusion limited and a deep brain compartment is described by a passive diffusion term and a saturable active efflux term. RESULTS: The model resulted in precise estimates of the parameters describing passive influx into (k in) of 0.16 min(-1) and efflux from the shallow brain compartment (k out) of 0.019 min(-1) and the fluvoxamine concentration at which 50% of the maximum active efflux (C 50) is reached of 710 ng.ml(-1). The proposed brain distribution model constitutes a basis for precise characterization of the PK-PD correlation of fluvoxamine by taking into account the non-linearity in brain distribution. PMID- 17710516 TI - One-step surface modification of poly(lactide-co-glycolide) microparticles with heparin. AB - PURPOSE: The aim of this study was to modify the surface of poly(lactide-co glycolide) (PLGA) microparticles with heparin. The heparin-coated PLGA may enhance blood and tissue compatibility of PLGA devices and provide a novel approach to deliver growth factors. MATERIALS AND METHODS: A one-step method using heparin to replace traditional emulsifiers (e.g., PVA) during emulsion solvent evaporation process was employed to surface-entrap heparin in PLGA microspheres. The emulsifying activity of heparin was modified via varying counter ion form, including univalent (Na(+), K(+), Li(+), and [Formula: see text]) and divalent (Ca(2+), Mg(2+), Ba(2+), and Zn(2+)) cations, and complexation with amino acids (Arg, Lys, Leu, Val, Gly and Glu). Surface accessible and total heparin loading were determined by a modified toluidine blue assay and elemental analysis, respectively. RESULTS: Heparin bound with univalent counter ions and amino acids exhibited emulsifying activity to varying degrees, whereas divalent heparin salts tended to cause complete aggregation of the PLGA o/w emulsion. Increasing pH (>or=7.4) of hardening medium enhanced heparin adsorption and significantly stabilized the PLGA o/w emulsion. The initial surface density of heparin on the PLGA microspheres prepared using univalent heparin salts was around 8-33 mg/m(2). Surface associated heparin desorbed quickly; potassium heparin showed the best retention, with approximately 0.2 and 0.1 mg/m(2) detected on PLGA microsphere surface following 1- and 14-day incubation in PBST at 37 degrees C, respectively. CONCLUSIONS: PLGA microparticles were successfully surface-modified with heparin. Univalent salts and amino acid complexes of heparin, as effective emulsifiers, can become surface immobilized in PLGA microspheres. PMID- 17710517 TI - Simulating pharmacokinetic and pharmacodynamic fuzzy-parameterized models: a comparison of numerical methods. AB - Statistical techniques have been traditionally used to deal with parametric variation in pharmacokinetic and pharmacodynamic models, but these require substantial data for estimates of probability distributions. In the presence of limited, inaccurate or imprecise information, simulation with fuzzy numbers represents an alternative tool to handle parametric uncertainty. Existing methods for implementing fuzzy arithmetic may, however, have significant shortcomings in overestimating (e.g., conventional fuzzy arithmetic) and underestimating (e.g., vertex method) the output uncertainty. The purpose of the present study is to apply and compare the applicability of conventional fuzzy arithmetic, vertex method and two recently proposed numerical schemes, namely transformation and optimization methods, for uncertainty modeling in pharmacokinetic and pharmacodynamic fuzzy-parameterized systems. A series of test problems were examined, including empirical pharmacokinetic and pharmacodynamic models, a function non-monotonic in its parameters, and a whole body physiologically based pharmacokinetic model. Our results verified that conventional fuzzy arithmetic can lead to overestimation of response uncertainty and should be avoided. For the monotonic pharmacokinetic and pharmacodynamic models, the vertex method accurately predicted fuzzy-valued output while incurring the least computational cost. It turned out that the choice of a suitable method for fuzzy simulation of the non-monotonic function depended on the required accuracy of the results: the vertex method was capable of eliciting an initial approximate solution with few function evaluations; for more accurate results, the transformation method was the most superior approach in terms of accuracy per unit CPU time. PMID- 17710518 TI - Synthesis and optical properties of 1-alkyl-3-methylimidazolium lauryl sulfate ionic liquids. AB - We report the synthesis of a new series of imidazolium-based halogen-free ionic liquids 1-alkyl-3-methylimidazolium lauryl sulfates. By reacting 1 methylimidazole (MIM) with butyl, hexyl, octyl, and decyl bromides and exchanging bromide ion with lauryl sulfate anion, a series of ionic liquids [RMIM][C(12)H(25)OSO(3)] were produced. The high purity of these ionic liquids was verified with (1)H-NMR, (13)C-NMR, FT-IR and mass spectrometry (MS), demonstrating the effectiveness of this synthetic approach. Solubility test of these ionic liquids showed that they are soluble in most organic solvents except nonpolar solvents such as hexane and cyclohexane. The optical properties of [BMIM]Br and [BMIM][C(12)H(25)OSO(3)], where B refers to butyl, were examined. Both ionic liquids absorbed light in the UV region, yet essentially no absorption was recorded beyond 450 nm. Furthermore, both ionic liquids showed excitation wavelength-dependent fluorescence behavior. As an example, with an excitation wavelength of 360 nm, [BMIM][C(12)H(25)OSO(3)] showed an emission band maximum at 447 nm. Increasing the excitation wavelength to 440 nm, the emission band maximum was shifted to approximately 500 nm. PMID- 17710519 TI - Acidichromism and ionochromism of luteolin and apigenin, the main components of the naturally occurring yellow weld: a spectrophotometric and fluorimetric study. AB - Luteolin and apigenin, extracted from Reseda luteola L., were spectrophotometrically and fluorimetrically studied. The spectra were investigated as a function of pH in methanol/water solutions (1/2, v/v) in the 2 12 pH range. The absorption spectra markedly shifted to the red by increasing the pH. Three acid-base dissociation steps were detected for luteolin (pK (a) = 6.9; 8.6; 10.3) and two for apigenin (pK (a) = 6.6; 9.3). Fluorescence emission was very weak or undetectable (Phi (F) < 10(-4)) in acidic solution, but increased in intensity with increasing the pH. Both molecules exhibited a great propensity towards complex formation with metal ions, with association constants on the order of 10(5)-10(7) for the first complexation step; in the presence of excess Al(3+) ions, multiple equilibria were detected. A marked fluorescence enhancement was observed upon complexation with Al(3+) ions (Phi (F) approximately 1 for luteolin and approximately 10(-2) for apigenin). PMID- 17710520 TI - A medical home center: specializing in the care of children with special health care needs of high intensity. AB - OBJECTIVE: Children with special health care needs (CSHCN) benefit from a medical home, however, a subset, those children with high intensity needs, have medical and social service issues beyond the capacity of most primary care practices. We describe a novel medical home center that is designed to meet the needs of children with special health care needs of high intensity (CSHCN-HI). MODEL OF CARE: The medical home center, U Special Kids (USK) is located at the University of Minnesota and affiliated with a tertiary medical center. USK serves CSHCN-HI throughout the state of Minnesota and, because of state supported funding for the program, children have access to the program regardless of their health insurance coverage. The team is expert at gathering an overall perspective of the child's needs, identifying gaps, accessing services and weaving together the plethora of disparate services, agencies and providers. A major goal of this model is to transition care from USK to a primary care medical home within the child's community. Transition is more likely to occur optimally once the child's complex needs are organized, the family is trained, adequate management resources are in place, and the intensity of care coordination needs are reduced. CONCLUSIONS: We propose that, in addition to a primary care medical home, CSHCN-HI benefit from a unique medical home center that can provide sufficient resources and expertise to organize their complex care coordination needs. Medical home centers, designed specifically to manage the care of children with complex high intensity medical and care coordination needs, have the potential to reduce excess health care utilization and improve patient outcomes by providing this group of children with customized, accessible and integrated services. PMID- 17710521 TI - Case report: Using an auditory trainer with caregiver video modeling to enhance communication and socialization behaviors in autism. AB - A minimally verbal child with autism was exposed to short daily sessions of watching his parents on video in conjunction with an FM auditory trainer for a period of 4 weeks. Baseline measures of verbal and social behaviors were taken pre-treatment and repeated post treatment. Results indicate substantial gains in word productions, social orienting, and increased eye contact. Results are discussed in terms of the contributions of auditory-visual processing to establishing communication and socialization in autism and early intervention effectiveness. PMID- 17710523 TI - A penis-shortening device described by the 13th century poet Rumi. PMID- 17710522 TI - Dissociation between key processes of social cognition in autism: impaired mentalizing but intact sense of agency. AB - Deficits in social cognition and interaction, such as in mentalizing and imitation behavior, are hallmark features of autism spectrum disorders. Both imitation and mentalizing are at the core of the sense of agency, the awareness that we are the initiators of our own behavior. Little evidence exists regarding the sense of agency in autism. Thus, we compared high-functioning adults with autism to healthy control subjects using an action monitoring and attribution task. Subjects with autism did not show deficits in this task, yet they showed significant mentalizing deficits. Our findings indicate a dissociation between the sense of agency and ascription of mental states in autism. We propose that social-cognitive deficits in autism may arise on a higher level than that of action monitoring and awareness. PMID- 17710524 TI - Masturbation in urban China. AB - This study examined the prevalence and sources of masturbatory practice in a nationally representative sample from China completed in the year 2000, with analysis of sources focused on 2,828 urban respondents aged 20-59. In this subpopulation, 13% (95% CI, 10-18) of women and 35% (CI, 26-44) of men reported any masturbation in the preceding year. Prevalence for people in their 20s was higher, and closer to US and European levels, especially for men. Particularly for women, masturbation not only compensated for absent partners but also complemented the high sexual interests of a subset of participants. For both women and men, practicing masturbation appeared to be a two-step process. In the first step, events such as sexual contact in childhood, early puberty, and early sex were related to sexualization and the "gateway event" of adolescent masturbation. In the second step, other factors, such as liberal sexual values and sexual knowledge, further increased the current probability of masturbation. Overall, the results suggest that masturbation is readily adopted even at more modest levels of economic and social development, that masturbation is often more than simply compensatory behavior for regular partnered sex, that masturbatory patterns are heavily influenced by early sexualization, and that a complex model is needed to comprehend masturbatory practice, particularly for women. PMID- 17710525 TI - Why housing? AB - Housing/lack of housing and HIV are powerfully linked. Housing occupies an important place in the causal chains linking poverty and inequality, and HIV risk and outcomes of infection. The articles in this Special Supplement of AIDS and Behavior confirm the impact of homelessness, and poor or unstable housing, on HIV/AIDS, and challenge scientists to test and policy makers to implement the promise of housing as an innovative response to the epidemic. In order to influence the development of policies on housing to benefit at-risk or HIV infected persons, however, proponents must justify why this association exists, and how housing can help end the epidemic as well as improve the care and health of persons living with HIV/AIDS. We introduce this supplement with a discussion of the "why" question. PMID- 17710526 TI - Correlates of condom use among sex workers and their boyfriends in three West African countries. AB - The aim of this study was to identify correlates associated with condom use at last intercourse between sex workers (SW) and their boyfriends (BF). The sample was derived as a convenience sample recruited through existing HIV prevention organizations in Benin, Guinea and Senegal. The Theory of Planned Behavior served as the conceptual framework. A total of 406 individuals (220 SW and 186 BF) participated in the study. Socio-demographic, behavioral and psychological variables were collected through a face-to-face administered questionnaire. Condom use at last intercourse was significantly associated with intention and perceived control among SW as well as their BF. With respect to intention, perceived control, attitude and moral norm explained 82 and 74% of intention of SW and BF, respectively. These results suggest that promoting condom use among SW and BF should be based primarily on the development of personal ability to overcome obstacles to condom use. PMID- 17710527 TI - Cross-national reliability of clinician-rated outcome measures in child and adolescent mental health services. AB - Clinician-rated measures are in extensive use as routine outcome measures in child and adolescent mental health services. We investigated cross-national differences and inter-rater reliability of the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA), the Children's Global Assessment Scale (CGAS) and the Global Assessment of Psychosocial Disability (GAPD). Thirty clinicians from 5 nations independently rated 20 written vignettes. The national groups afterwards established national consensus ratings. There were no cross national differences in independent scores, but there were differences in national consensus scores, which were also more severe than independent scores. The ICC for the HoNOSCA total score was 0.84, for the CGAS 0.61 and for the GAPD 0.54. These measures may usefully contribute to cross-national comparison studies. PMID- 17710528 TI - Biochemical and genetic polymorphisms for carboxylesterase and acetylesterase in grape clones of Vitis vinifera L. (Vitaceae) cultivars. AB - Native polyacrylamide gel electrophoresis (PAGE) was employed to show the highest number of esterase loci and to detect alpha- and beta-esterase polymorphisms in leaf buds of Vitis vinifera cultivars. A total of 16 esterase isozymes were detected in leaf buds from 235 plants including Italia, Rubi, Benitaka, and Brasil cultivars. Biochemical characterization of the grape esterases using ester substrates revealed alpha-, beta-, and alpha/beta-esterases with inhibitor tests distinguishing both carboxylesterases (EST-2, EST-3, EST-5, EST-6, EST-7, EST-8, EST-9, EST-10, and EST-16 isozymes) and acetylesterases (EST-4, EST-11, EST-12, EST-13, EST-14, EST-15 isozymes). No allele variation for alpha-, beta-, and alpha/beta-esterases was detected; however, EST-3 alpha-carboxylesterase was absent in 61.7% of vines, and EST-4 alpha/beta-acetylesterase was absent in one vine of Rubi cv. Null EST-3 carboxylesterase phenotype (61.7%) cannot be explained in this article, but the high genetic polymorphism in four V. vinifera clones is a positive aspect for genetic selection and development of new clones with different characteristics. PMID- 17710530 TI - Regulated shuttling of Slit-Robo-GTPase activating proteins between nucleus and cytoplasm during brain development. AB - (1) A Little information exists on the distribution of Slit-Robo-GTPase activating proteins (srGAPs), particularly about their intracellular locations, which may provide further clues to their functions. The purpose of this study is to elucidate the expression patterns of the three srGAPs in wild-type rat brains at adult and various developmental stages, and in the cultured cortical neurons. (2) Immunohistochemical method was applied to detect the distribution and localization of the srGAPs in the normal rat brains at adult and various developmental stages, and in the cultured cortical neurons using the rabbit polyclonal antibodies. (3) Immunohistochemical analysis demonstrated that the three srGAPs were mainly expressed in neurons throughout the brain. More importantly, srGAPs translocated during development by a highly regulated shuttling process between the nucleus and the cytoplasm of neurons and their expression patterns were not overlapping. In cultured cortical neurons srGAPs were found in equal amounts in the cytoplasm, nucleus, in neurites, and growth cones. When neurons were maintained in vitro for longer time, the amount of srGAPs in the nucleus strongly increased. (4) These results suggest that srGAPs are not only involved in the regulation of the Slit-Robo signal transduction, but also in neuronal development and that the translocation of srGAPs is important for their functions. PMID- 17710531 TI - Use of anti-aging herbal medicine, Lycium barbarum, against aging-associated diseases. What do we know so far? AB - Lycium barbarum (Gouqizi, Fructus Lycii, Wolfberry) is well known for nourishing the liver, and in turn, improving the eyesight. However, many people have forgotten its anti-aging properties. Valuable components of L. barbarum are not limited to its colored components containing zeaxanthin and carotene, but include the polysaccharides and small molecules such as betaine, cerebroside, beta sitosterol, p-coumaric, and various vitamins. Despite the fact that L. barbarum has been used for centuries, its beneficial effects to our bodies have not been comprehensively studied with modern technology to unravel its therapeutic effects at the biochemical level. Recently, our laboratory has demonstrated its neuroprotective effects to counter neuronal loss in neurodegenerative diseases. Polysaccharides extracted from L. barbarum can protect neurons against beta amyloid peptide toxicity in neuronal cell cultures, and retinal ganglion cells in an experimental model of glaucoma. We have even isolated the active component of polysaccharide which can attenuate stress kinases and pro-apoptotic signaling pathways. We have accumulated scientific evidence for its anti-aging effects that should be highlighted for modern preventive medicine. This review is to provide background information and a new direction of study for the anti-aging properties of L. barbarum. We hope that new findings for L. barbarum will pave a new avenue for the use of Chinese medicine in modern evidence-based medicine. PMID- 17710529 TI - Membrane organization and function of the serotonin(1A) receptor. AB - (1) The serotonin(1A) receptor is a G-protein coupled receptor involved in several cognitive, behavioral, and developmental functions. It binds the neurotransmitter serotonin and signals across the membrane through its interactions with heterotrimeric G-proteins. (2) Lipid-protein interactions in membranes play an important role in the assembly, stability, and function of membrane proteins. The role of membrane environment in serotonin(1A) receptor function is beginning to be addressed by exploring the consequences of lipid manipulations on the ligand binding and G-protein coupling of serotonin(1A) receptors, the ability to functionally solubilize the serotonin(1A) receptor, and the factors influencing the membrane organization of the serotonin(1A) receptor. (3) Recent developments involving the application of detergent-based and detergent-free approaches to understand the membrane organization of the serotonin(1A) receptor under conditions of ligand activation and modulation of membrane lipid content, with an emphasis on membrane cholesterol, are described. PMID- 17710532 TI - Effects of glucocorticoids on age-related impairments of hippocampal structure and function in mice. AB - Effects of glucocorticoids (GCs) on maze-learning performances and hippocampal morphology were observed in male C57BL/6Cr mice. Correlations between aging, GCs and maze-learning performances were also studied. (2) Eight-arm radial maze was used in maze-learning tests. Learning performance was assessed by the parameters of time of getting all the bait, number of reentry errors into the already entered arm with bait, and number of missed entries into an unbaited arm. Brain sections, 8 mum thick, were Nissl-stained with cresyl violet or stained immunocytochemically with antibodies against neurofilaments. (3) With aging, normal pyramidal cells decreased gradually in amount, and degenerating cells increased since the age of 18 months, accompanied with the maze-learning deficit. Here we have suggested that these changes were associated with the age-related deficits in adaptation tolerance of neurons to stress. In addition, the age related deficits in plasticity of hippocampal neurons to GCs in young mice (3 months of age) resulted in an increase in plasma corticosterone (CORT) concentrations, degeneration of hippocampal pyramidal cells, as well as maze learning deficits. (4) In conclusion, our data indicated that CORT caused the degeneration of hippocampal pyramidal cells and the impairment of memory. PMID- 17710533 TI - Recent development in studies of tetrahydroprotoberberines: mechanism in antinociception and drug addiction. AB - The tetrahydroprotoberberines (THPBs) are compounds isolated from Chinese herbs that possess a unique pharmacological profile as D2 dopamine receptor antagonists and D1 receptor agonists. l-Tetrahydropalmatine (l-THP) and l-stepholidine (SPD), members of the THPB family, were shown to have potential clinical use in the treatment of pain. However, their mechanism of action is not clear. In the past decades, Chinese scientists have made a great deal of effort to explore the mechanisms by which the THPBs and its analogues elicit antinociception and their potential utility in treating drug abuse. It is now clear that the antinociception produced by l-THP is related to inhibition of D(2) dopamine receptors. The present review focuses on the recent progress made in understanding the mechanisms of l-THP- and l-SPD-mediated antinociception and the sequel of drug addiction. PMID- 17710534 TI - Temporal gene expression profile in hippocampus of mice treated with D-galactose. AB - (1) Rodent chronically treated with D-galactose (D-gal) is increasingly used in pharmacological studies on aging; however, its mechanism remains unclear. The present study investigated the alterations of gene expression in the hippocampus of D-gal-treated mice. (2) C57 mice were subcutaneously injected with D-gal for 2, 4, and 8 weeks or vehicle, and then were subjected to behavioral tests. Gene expression profiles in hippocampus of each group were finally examined with cDNA microarray. (3) Both 4- and 8-week D-gal treatment led to a decrease of discrimination index in object recognition test, and 8-week D-gal-treated mice showed significant spatial learning & memory impairment in Morris water maze test. In comparison with the vehicle control group, the 2-, 4-, and 8-week D-gal treatment repressed the expression of 10, 13, and 30 genes by 2-fold or more, respectively. The early pattern was mainly characterized by down regulation of genes involved in ion transport. The delayed pattern included genes involved in protein biosynthesis, transport and signal transduction, which were highly related to synaptic functions. (4) These findings will contribute to the understanding of the mechanism of learning and memory impairment in mice treated with D-galactose. PMID- 17710535 TI - A neuroprotective herbal mixture inhibits caspase-3-independent apoptosis in retinal ganglion cells. AB - It was previously demonstrated that Menta-FX, a mixture of Panax quinquefolius L. (PQE), Ginkgo biloba (GBE), and Hypericum perforatum extracts (HPE), enhances retinal ganglion cell survival after axotomy. However, the mechanisms of neuroprotection remain unknown. The aim of this study is to elucidate the neuroprotective mechanisms of Menta-FX. Since PQE, GBE and HPE have all been observed to display anti-oxidative property, the involvement of anti-oxidation in Menta-FX's neuroprotective effect was investigated. Menta-FX lowered nitric oxide (NO) content in axotomized retinas without affecting nitric oxide synthase activity, suggesting that Menta-FX possibly exhibited a NO scavenging property. In addition, the effect of Menta-FX on the frequency of axotomy-induced nuclear fragmentation and caspase-3 activation was investigated. Menta-FX treatment significantly reduced nuclear fragmentation in axotomized retinas. Surprisingly, Menta-FX had no effect on caspase-3 activation, but selectively lowered caspase-3 independent nuclear fragmentation in axotomized retinal ganglion cells. In addition, inhibition of PI3K activity by intravitreal injection of wortmannin, a phosphoinositide-3 kinase (PI3K) inhibitor, completely abolished the neuroprotective effect of Menta-FX, indicating that Menta-FX's neuroprotective effect was PI3K-dependent. Data here suggest that Menta-FX displayed a PI3K dependent, selective inhibition on a caspase-3-independent apoptotic pathway in axotomized RGCs, thus, highlighting the potential use of herbal remedies as neuroprotective agents for other neurodegenerative diseases. PMID- 17710537 TI - Multivariate models of parent-late adolescent gender dyads: the importance of parenting processes in predicting adjustment. AB - Although parent-adolescent interactions have been examined, relevant variables have not been integrated into a multivariate model. As a result, this study examined a multivariate model of parent-late adolescent gender dyads in an attempt to capture important predictors in late adolescents' important and unique transition to adulthood. The sample for this study consisted of 151 male and 324 female late adolescents, who reported on their mothers' and fathers' parenting style, their family environment, their mothers' and fathers' expectations for them, the conflict that they experience with their mothers and fathers, and their own adjustment. Overall, the variables had significant relationships with one another. Further, the male-father, male-mother, and female-father structural equation models that were examined suggested that parenting style has an indirect relationship with late adolescents' adjustment through characteristics of the family environment and the conflict that is experienced in families; such findings were not evident for the female-mother model. Thus, the examination of parent-late adolescent interactions should occur in the context of the gender of parents and their late adolescents. PMID- 17710536 TI - Piracetam improves cognitive deficits caused by chronic cerebral hypoperfusion in rats. AB - Piracetam is the derivate of gamma-aminobutyric acid, which improves the cognition,memory,consciousness, and is widely applied in the clinical treatment of brain dysfunction. In the present experiments, we study the effects of piracetam on chronic cerebral hypoperfused rats and observe its influence on amino acids, synaptic plasticity in the Perforant path-CA3 pathway and apoptosis in vivo. Cerebral hypoperfusion for 30 days by occlusion of bilateral common carotid arteries induced marked amnesic effects along with neuron damage, including: (1) spatial learning and memory deficits shown by longer escape latency and shorter time spent in the target quadrant; (2) significant neuronal loss and nuclei condensation in the cortex and hippocampus especially in CA1 region; (3) lower induction rate of long term potentiation, overexpression of BAX and P53 protein, and lower content of excitatory and inhibitory amino acids in hippocampus. Oral administration of piracetam (600 mg/kg, once per day for 30 days) markedly improved the memory impairment, increased the amino acid content in hippocampus, and attenuated neuronal damage. The ability of piracetam to attenuate memory deficits and neuronal damage after hypoperfusion may be beneficial in cerebrovascular type dementia. PMID- 17710538 TI - A measure of cognitive and affective empathy in children using parent ratings. AB - The construct of "empathy" embodies a number of characteristics necessary for psychological health in children. Surprisingly, most research has been based solely on children and adolescent report and observational measures despite evidence that multi-informant assessment is fundamental to the accurate measurement of such constructs. We present research documenting the development and validation of a brief parent-report measure of child empathy targeted at the formative years for the development of empathic skills, through to adolescence. The Griffith Empathy Measure, adapted from the Bryant Index of Empathy, showed convergence with child ratings, and good reliability and validity across gender and age. Consistent with theoretical accounts of empathy, it was found to include affective and cognitive components that showed divergent associations with other aspects of child functioning. PMID- 17710539 TI - Limbic structures show altered glial-neuronal metabolism in the chronic phase of kainate induced epilepsy. AB - A better understanding is needed of how glutamate metabolism is affected in mesial temporal lobe epilepsy (MTLE). Here we investigated glial-neuronal metabolism in the chronic phase of the kainate (KA) model of MTLE. Thirteen weeks following systemic KA, rats were injected i.p. with [1-(13)C]glucose. Brain extracts from hippocampal formation, entorhinal cortex, and neocortex, were analyzed by (13)C and (1)H magnetic resonance spectroscopy to quantify (13)C labeling and concentrations of metabolites, respectively. The amount and (13)C labeling of glutamate were reduced in the hippocampal formation and entorhinal cortex of epileptic rats. Together with the decreased concentration of NAA, these results indicate neuronal loss. Additionally, mitochondrial dysfunction was detected in surviving glutamatergic neurons in the hippocampal formation. In entorhinal cortex glutamine labeling and concentration were unchanged despite the reduced glutamate content and label, possibly due to decreased oxidative metabolism and conserved flux of glutamate through glutamine synthetase in astrocytes. This mechanism was not operative in the hippocampal formation, where glutamine labeling was decreased. In neocortex labeling and concentration of GABA were increased in epileptic rats, possibly representing a compensatory mechanism. The changes in the hippocampus might be of pathophysiological importance and merit further studies aiming at resolving metabolic causes and consequences of MTLE. PMID- 17710540 TI - Glial expression of interleukin-18 and its receptor after excitotoxic damage in the mouse hippocampus. AB - Interleukin (IL)-18, a member of the IL-1 cytokine family, is an important mediator of peripheral inflammation and host defence responses. However, although IL-1 is a key proinflammatory cytokine in the brain, little is known about IL-18 changes in glial cells under excitotoxic neurodegeneration. In this study, we characterized the expressions of IL-18 and IL-18 receptor (IL-18R) in kainic acid (KA)-induced excitotoxicity in mouse hippocampus by immunohistochemistry and Western blotting. IL-18 immunoreactivity was found in microglia whereas IL-18R immunoreactivity was observed in astrocytes. Levels of IL-18 and IL-18R in hippocampus homogenates increased progressively from day 1 post-KA and peaked at 3 days. This study demonstrates the cellular sources of IL-18 and IL-18R, and their temporal correlations after KA-insult, and suggests roles for IL-18 and IL 18R in glial cells in response to excitotoxic damage in the hippocampus. PMID- 17710541 TI - Comparative studies on dicholesteroyl diselenide and diphenyl diselenide as antioxidant agents and their effect on the activities of Na+/K+ ATPase and delta aminolevulinic acid dehydratase in the rat brain. AB - The present study sought to evaluate the effect of a newly synthesized selenium compound, dicholesteroyl diselenide (DCDS) and diphenyl diselenide (DPDS) on the activities of delta-aminolevulinate dehydratase and Na+/K+-ATPase in the rat brain. The glutathione peroxidase mimetic activity of the two compounds as well as their ability to oxidize mono- and di- thiols were also evaluated. The antioxidant effects were tested by measuring the ability of the compounds to inhibit the formation of thiobarbituric acid reactive species and also their ability to inhibit the formation of protein carbonyls. The results show that DPDS exhibited a higher glutathione peroxidase mimetic activity as well as increased ability to oxidize di-thiols than DCDS. In addition, while DPDS inhibited the formation of thiobarbituric acid reactive species and protein carbonyls, DCDS exhibited a prooxidant effect in all the concentration range (20-167 microM) tested. Also the activities of cerebral delta-aminolevulinate dehydratase and Na+/K+ ATPase were significantly inhibited by DPDS but not by DCDS. In addition, the present results suggested that the inhibition of Na+/K+ ATPase by organodiselenides, possibly involves the modification of the thiol group at the ATP binding site of the enzyme. In conclusion, the results of the present investigation indicated that the non-selenium moiety of the organochalcogens can have a profound effect on their antioxidant activity and also in their reactivity towards SH groups from low-molecular weight molecules and from brain proteins. PMID- 17710542 TI - Anticonvulsant efficacy of drugs with cholinergic and/or glutamatergic antagonism microinfused into area tempestas of rats exposed to soman. AB - A group of antiparkinson drugs (benactyzine, biperiden, caramiphen, procyclidine, and trihexyphenidyl) has been shown to possess both anticholinergic and antiglutamatergic properties, making these agents very well suited as anticonvulsants against nerve agents. The first purpose of this study was to make a comparative assessment of the anticonvulsant potencies of the antiparkinson agents when microinfused (1 microl) into the seizure controlling area tempestas (AT) of rats 20 min before subcutaneous injection of soman (100 microg/kg). The second purpose was to determine whether cholinergic and/or glutamatergic antagonism was the effective property. The results showed that only procyclidine (6 microg) and caramiphen (10 microg) antagonized soman-induced seizures. Cholinergic, and not glutamatergic, antagonism was likely the active property, since atropine (100 microg), and scopolamine (1 microg) caused anticonvulsant effects, whereas MK-801 (1 microg), and ketamine (50 microg) did not. Soman (11 nmol) injected into AT resulted more frequently in clonic convulsions than full tonic-clonic convulsions. AT may serve as both a trigger site for soman-evoked seizures and a site for screening anticonvulsant potencies of future countermeasures. PMID- 17710543 TI - Exposure time related oxidative action of hyperbaric oxygen in rat brain. AB - Hyperbaric oxygen (HBO) is known to cause oxidative stress in several organs and tissues. Due to its high rate of blood flow and oxygen consumption, the brain is one of the most sensitive organs to this effect. The present study was performed to elucidate the relation of HBO exposure time to its oxidative effects in rats' brain cortex tissue. For this purpose, 49 rats were randomly divided into five groups. Except the control group, study groups were subjected to three atmospheres HBO for 30, 60, 90, and 120 min. Their cerebral cortex layer was taken immediately after exposure and used for analysis. Thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and nitrate-nitrite (NOX) levels were determined. TBARS and SOD levels were found to increase in a time-dependent manner. GSH-Px activity reflected an inconsistent course. NOX levels were found to be increased only in the 120 min exposed group. The results of this study suggests that HBO induced oxidative effects are strongly related with exposure time. PMID- 17710544 TI - NT-3 expression in spared DRG and the associated spinal laminae as well as its anterograde transport in sensory neurons following removal of adjacent DRG in cats. AB - Neurotrophin-3 plays an important role in survival and differentiation of sensory and sympathetic neurons, sprouting of neurites, synaptic reorganization, and axonal growth. The present study evaluated changes in expression of NT-3 in the spinal cord and L6 dorsal root ganglion (DRG), after ganglionectomy of adjacent dorsal roots in cats. NT-3 immunoreactivity increased at 3 days post-operation (dpo), but decreased at 10 dpo in spinal lamina II after ganglionectomy of L1-L5 and L7-S2 (leaving L6 DRG intact). Conversely, NT-3 immunoreactivity decreased on 3 dpo, but increased on 10 dpo in the nucleus dorsalis. Very little NT-3 mRNA signal was detected in the spinal cord, despite the changes in NT-3 expression. The above changes may be related to changes in NT-3 expression in the DRG. Ganglionectomy of L1-L5 and L7-S2 resulted in increase in NT-3 immunoreactivity and mRNA in small and medium-sized neurons, but decreased expression in large neurons of L6 DRG at 3 dpo. It is possible that increased NT-3 in spinal lamina II is derived from anterograde transport from small- and medium-sized neurons of L6 DRG, whereas decreased NT-3 immunoreactivity in the nucleus dorsalis is due to decreased transport of NT-3 from large neurons in the DRG at this time. This notion is supported by observations on NT-3 distribution in the dorsal root of L6 after ligation of the nerve root. The above results indicate that DRG may be a source of neurotrophic factors such as NT-3 to the spinal cord, and may contribute to plasticity in the spinal cord after injury. PMID- 17710545 TI - Multimodal treatments for childhood attention-deficit/hyperactivity disorder: interpreting outcomes in the context of study designs. AB - The goal of this article was to outline issues critical to evaluating the literature on incremental benefit of multiple effective treatments used together, vs. a single effective treatment, for childhood ADHD. These issues include: (1) sequencing and dosage of treatments being combined and compared; (2) difficulty drawing valid conclusions about individual components of treatment when treatment packages are employed; (3) differing results emerging from measurement tools that purportedly measure the same domain; and (4) the resultant difficulty in reaching a summary conclusion when multiple outcome measures yielding conflicting results are used. The implications of these issues for the design and conduct of future studies are discussed, and recommendations are made for future research. PMID- 17710546 TI - Cholecystectomy and the risk of colorectal adenomas. AB - Cholecystectomy has been identified as a risk factor for colorectal cancer, yet little attention has been given to the relationship between cholecystectomy and colorectal adenomas. Utilizing data collected in two large cross-sectional studies of colorectal adenoma risk factors, we examined the association between cholecystectomy and colorectal adenomas. In the adjusted logistic regression model, both men and women showed no effect of cholecystectomy on risk of colorectal adenomas (men: OR 0.67 [95% CI 0.30-1.47]; women: OR 1.46 [95% CI 0.92 2.29]). No effect was seen when examining the time since cholecystectomy for men. There was a slight association found for women who had a cholecystectomy less than 10 years prior (OR 2.02 [95% CI 1.06-3.87]) but no association was seen in women with cholecystectomy at least 10 years prior (OR 1.14 [95% CI 0.62-2.09]). Thus, we conclude that, although cholecystectomy is a risk factor for colorectal cancer, cholecystectomy is not a risk factor for colorectal adenomas. PMID- 17710547 TI - Effects of amlodipine, captopril, and bezafibrate on oxidative milieu in rats with fatty liver. AB - Oxidative stress may initiate significant hepatocyte injury in subjects with fatty liver. We characterized changes in hepatic oxidative anti-oxidative parameters in rats given a fructose-enriched diet (FED) with and without medications to reduce blood pressure or plasma triglycerides. FED rats had an increase in malondialdehyde (MDA) concentration, a reduction in alpha-tocopherol concentration, a reduction in paraoxonase (PON) activity, an increase in glutathione peroxidase (GSH-Px), and glutathione reductase (GSSG-R) activity. Amlodipine increased PON and GSH-Px, but decreased GSSG-R activity and alpha tocopherol concentration. Captopril decreased MDA concentration and the activity of both GSH-Px and GSSG-R, but increased alpha-tocopherol concentration and PON activity. Bezafibrate increased alpha-tocopherol concentration and PON activity, but decreased the activity of GSSG-R. Animals with fatty liver exhibit an increase in peroxidative stress but also a defect in anti-oxidative pathways. Drugs administered to treat hypertension and hypertriglyceridemia could lead to a variety of changes in the hepatic oxidative, anti-oxidative milieu. PMID- 17710549 TI - Is there any association between non-Hodgkin's lymphoma and primary sclerosing cholangitis/autoimmune hepatitis overlap syndrome? PMID- 17710548 TI - How adequate is digital rectal exam for prostate cancer screening at colonoscopy? Can adequacy be improved? AB - PURPOSE: Screening by digital rectal exam (DRE) has been advocated as a means of detecting early-stage prostate cancer. We sought to determine the adequacy of prostate palpation at DRE at colonoscopy, and to devise a method of improving adequacy when the gland is incompletely felt. MATERIALS AND METHODS: Adequacy of prostate palpation in the left lateral position was prospectively assessed in 200 males 40 years or older undergoing colonoscopy, and correlated with body mass index (BMI) and National Institutes of Health (NIH) weight categories. If the prostate was incompletely felt, the patient was asked to flex his knee(s) up toward his chest, and then the exam was repeated. RESULTS: The prostate was incompletely felt on initial DRE in 65 of 200 patients (32.5%). Raising the knee(s) toward the chest permitted complete palpation in 62 of those 65 cases. Incomplete palpation showed a strong correlation with BMI (P < 0.0001) and weight category: 3/36 (8.3%) for patients with normal body weight, 14/89 (15.7%) for overweight, 42/68 (61.8%) for obesity, and 6/7 (85.7%) for extreme obesity (P < 0.0001). There were 13 patients in whom no part of the prostate gland could be felt on the initial DRE, and which also correlated with NIH weight class (P < 0.0001). CONCLUSIONS: The prostate gland is often incompletely palpated at DRE in the left lateral position at colonoscopy, and shows a strong correlation with obesity. Adequacy can be dramatically improved by having the patient raise his knee(s) up toward his chest, a maneuver that takes just seconds to perform. PMID- 17710551 TI - Introduction to the Hepatic Encephalopathy Scoring Algorithm (HESA). AB - A primary obstacle to early diagnosis and treatment of hepatic encephalopathy (HE) is the lack of a well-validated, standardized assessment method. The purpose of this study was to present preliminary validity data on a new method of grading HE, the Hepatic Encephalopathy Scoring Algorithm (HESA), which combines clinical impressions with neuropsychological performances to characterize HE. Participants were 49 inpatients admitted for complications of end stage liver disease. Each participant's level of HE was graded using HESA and the West Haven Criteria (WHC) by independent raters blinded to each other's rating. A moderately strong association was found between the two grading methods (r = 0.60), and individual HESA clinical and neuropsychological indicators were good discriminators among grades. The results also suggest HESA may be more sensitive to mental status impairment in the middle grades of HE than WHC. These findings suggest HESA holds promise as a multi-method approach to grading all levels of HE. PMID- 17710550 TI - Methionine deficiency and hepatic injury in a dietary steatohepatitis model. AB - Methionine (Meth) is an essential amino acid involved in DNA methylation and glutathione biosynthesis. We examined the effect of Meth on the development of steatohepatitis. Rats were fed (five weeks) amino acid-based Meth-choline sufficient (A-MCS) or total deficient (MCD) diets and gavaged daily (two weeks) with vehicle (B-vehicle/MCD), or Meth replacement (C-Meth/MCD). To assess the effect of short-term deficiency, after three weeks one MCS group was fed a deficient diet (D-MCS/MCD). Animals fed the deficient diet for two weeks lost (29%) weight and after five weeks weighed one third as much as those on the sufficient diet, and also developed anemia (P < 0.01). Hepatic transaminases progressively increased from two to five weeks (P < 0.01), leading to severe hepatic pathology. Meth administration normalized hematocrit, improved weight (P < 0.05), and suppressed abnormal enzymes activities (P < 0.01). Meth administration improved blood and hepatic glutathione (GSH), S-adenosylmethionine (SAMe), and hepatic lesions (P < 0.01). The deficient diet significantly upregulated proinflammatory and fibrotic genes, which was ameliorated by Meth administration. These data support a pivotal role for methionine in the pathogenesis of the dietary model of Meth-choline-deficient (MCD) steatohepatitis (NASH). PMID- 17710552 TI - Neighborhood factors associated with physical activity and adequacy of weight gain during pregnancy. AB - Healthy diet, physical activity, smoking, and adequate weight gain are all associated with maternal health and fetal growth during pregnancy. Neighborhood characteristics have been associated with poor maternal and child health outcomes, yet conceptualization of potential mechanisms are still needed. Unique information captured by neighborhood inventories, mostly conducted in northern US and Canadian urban areas, has been shown to reveal important aspects of the community environment that are not captured by the demographic quantities in census data. This study used data from the Pregnancy, Nutrition, and Infection (PIN) prospective cohort study to estimate the influences of individual-level and neighborhood-level characteristics on health behaviors and adequacy of weight gain during pregnancy. Women who participated in the PIN study and who resided in Raleigh, North Carolina and its surrounding suburbs were included (n = 703). Results from a neighborhood data collection inventory identified three social constructs, physical incivilities, territoriality, and social spaces, which were hypothesized to influence maternal health behaviors. The physical incivility scale was associated with decreased odds (adjusted OR = 0.74, 95%CI = 0.57, 0.98) in participating in vigorous leisure activity before pregnancy after controlling for several individual confounders, and a crude association for decreased odds of excessive weight gain (OR = 0.79, 95%CI = 0.64, 0.98). The social spaces scale was associated with decreased odds for inadequate (adjusted OR = 0.74, 95%CI = 0.56, 0.98) and excessive (adjusted OR = 0.69, 95%CI = 0.54, 0.98) gestational weight gain. The social spaces scale was also associated with decreased odds of living greater than 3 miles from a supermarket (adjusted OR = 0.03, 95%CI = 0.00, 0.27). Territoriality was not associated with any pregnancy-related health behavior. None of the neighborhood constructs were associated with smoking or diet quality. Physical incivilities and social spaces neighborhood characteristics may be important to measure to improve our understanding of the potential mechanisms through which neighborhood environments influence health. PMID- 17710553 TI - Molecular modeling on pyruvate phosphate dikinase of Entamoeba histolytica and in silico virtual screening for novel inhibitors. AB - Pyruvate phosphate dikinase (PPDK) is the key enzyme essential for the glycolytic pathway in most common and perilous parasite Entamoeba histolytica. Inhibiting the function of this enzyme could control the wide spread of intestinal infections caused by Entamoeba histolytica in humans. With this objective, we modeled the three dimensional structure of the PPDK protein. We used templates with 51% identity and 67% similarity to employ homology-modeling approach. Stereo chemical quality of protein structure was validated by protein structure validation program PROCHECK and VERIFY3D. Experimental proof available in literature along with the in silico studies indicated Lys21, Arg91, Asp323, Glu325 and Gln337 to be the probable active sites in the target protein. Virtual screening was carried out using the genetic docking algorithm GOLD and a consensus scoring function X-Score to substantiate the prediction. The small molecule libraries (ChemDivision database, Diversity dataset, Kinase inhibitor database) were used for screening process. Along with the high scoring results, the interaction studies provided promising ligands for future experimental screening to inhibit the function of PPDK in Entamoeba histolytica. Further, the phylogeny study was carried out to assess the possibility of using the proposed ligands as inhibitors in related pathogens. PMID- 17710554 TI - Distinct repressing modules on the distal region of the SBP2 promoter contribute to its vascular tissue-specific expression in different vegetative organs. AB - The Glycine max sucrose binding protein (GmSBP2) promoter directs vascular tissue specific expression of reporter genes in transgenic tobacco. Here we showed that an SBP2-GFP fusion protein under the control of the GmSBP2 promoter accumulates in the vascular tissues of vegetative organs, which is consistent with the proposed involvement of SBP in sucrose transport-dependent physiological processes. Through gain-of-function experiments we confirmed that the tissue specific determinants of the SBP2 promoter reside in the distal cis-regulatory domain A, CRD-A (position -2000 to -700) that is organized into a modular configuration to suppress promoter activity in tissues other than vascular tissues. The four analyzed CRD-A sub-modules, designates Frag II (-1785/-1508), Frag III (-1507/-1237), Frag IV (-1236/-971) and Frag V (-970/-700), act independently to alter the constitutive pattern of -92pSBP2-mediated GUS expression in different organs. Frag V fused to -92pSBP2-GUS restored the tissue specific pattern of the full-length promoter in the shoot apex, but not in other organs. Likewise, Frag IV confined GUS expression to the vascular bundle of leaves, whereas Frag II mediated vascular specific expression in roots. Strong stem expression-repressing elements were located at positions -1485 to -1212, as Frag III limited GUS expression to the inner phloem. We have also mapped a procambium silencer to the consensus sequence CAGTTnCaAccACATTcCT which is located in both distal and proximal upstream modules. Fusion of either repressing element-containing module to the constitutive -92pSBP2 promoter suppresses GUS expression in the elongation zone of roots. Together our results demonstrate the unusual aspect of distal sequences negatively controlling tissue-specificity of a plant promoter. PMID- 17710556 TI - Glimpses of evolution: heterochromatic histone H3K9 methyltransferases left its marks behind. AB - In eukaryotes, histone methylation is an epigenetic mechanism associated with a variety of functions related to gene regulation or genomic stability. Recently analyzed H3K9 methyltransferases (HMTases) as SUV39H1, Clr4p, DIM-5, Su(var)3-9 or SUVH2 are responsible for the establishment of histone H3 lysine 9 methylation (H3K9me), which is intimately connected with heterochromatinization. In this review, available data will be evaluated concerning (1) the phylogenetic distribution of H3K9me as heterochromatin-specific histone modification and its evolutionary stability in relation to other epigenetic marks, (2) known families of H3K9 methyltransferases, (3) their responsibility for the formation of constitutive heterochromatin and (4) the evolution of Su(var)3-9-like and SUVH like H3K9 methyltransferases. Compilation and parsimony analysis reveal that histone H3K9 methylation is, next to histone deacetylation, the evolutionary most stable heterochromatic mark, which is established by at least two subfamilies of specialized heterochromatic HMTases in almost all studied eukaryotes. PMID- 17710555 TI - Expression and enzyme activity of glutathione reductase is upregulated by Fe deficiency in graminaceous plants. AB - Glutathione reductase (GR) plays an important role in the response to biotic and abiotic stresses in plants. We studied the expression patterns and enzyme activities of GR in graminaceous plants under Fe-sufficient and Fe-deficient conditions by isolating cDNA clones for chloroplastic GR (HvGR1) and cytosolic GR (HvGR2) from barley. We found that the sequences of GR1 and GR2 were highly conserved in graminaceous plants. Based on their nucleotide sequences, HvGR1 and HvGR2 were predicted to encode polypeptides of 550 and 497 amino acids, respectively. Both proteins showed in vitro GR activity, and the specific activity for HvGR1 was 3-fold that of HvGR2. Northern blot analyses were performed to examine the expression patterns of GR1 and GR2 in rice (Os), wheat (Ta), barley (Hv), and maize (Zm). HvGR1, HvGR2, and TaGR2 were upregulated in response to Fe-deficiency. Moreover, HvGR1 and TaGR1 were mainly expressed in shoot tissues, whereas HvGR2 and TaGR2 were primarily observed in root tissues. The GR activity increased in roots of barley, wheat, and maize and shoot tissues of rice, barley, and maize in response to Fe-deficiency. Furthermore, it appeared that GR was not post-transcriptionally regulated, at least in rice, wheat, and barley. These results suggest that GR may play a role in the Fe-deficiency response in graminaceous plants. PMID- 17710557 TI - A thrombin inhibitor from the gut of Boophilus microplus ticks. AB - A thrombin inhibitor was identified for the first time in the gut of the cattle tick Boophilus microplus. Here we present the partial purification and characterization of this new molecule, which was purified from the gut extract by three chromatographic steps: ion-exchange, gel filtration and affinity chromatography in a thrombin-Sepharose resin. In SDS-PAGE the inhibitor showed an apparent molecular mass of circa 26 kDa, which is different from the two thrombin inhibitors present in the saliva of this tick. The new inhibitor delays bovine plasma clotting time and inhibits both thrombin induced fibrinogen clotting and thrombin induced platelet aggregation. However, it does not interfere with thrombin amidolytic activity upon a small substrate (H-D-Phe-Pip-Arg-para nitroanilide), which does not require binding to thrombin exosites. Therefore, the inhibitor does not block thrombin active site, although it must interfere with one of the thrombin exosites. B. microplus gut thrombin inhibitor (BmGTI) is also capable of enhancing activated protein C (APC) activity upon its specific substrate (H-D-Glu-Pro-Arg-para-nitroanilide), an activity never described before among B. microplus molecules. PMID- 17710558 TI - Effect of host plants on developmental time and life table parameters of Amphitetranychus viennensis (Acari: Tetranychidae). AB - The effect of host plant species including black cherry (Prunus serotina cv. Irani), cherry (Prunus avium cv. siahe Mashhad) and apple (Malus domestica cv. shafi Abadi) was studied on biological parameters of Amphitetranychus viennensis (Zacher) in the laboratory at 25 +/- 1 degrees C, 70 +/- 10% RH and 16L: 8D photoperiod. Duration of each life stage, longevity, reproduction rate, the intrinsic rate of natural increase (rm), net reproductive rate (R0), mean generation time (T), doubling time (DT), and finite rate of increase (lambda) of the hawthorn spider mite on the three host plants were calculated. Differences in fertility life table parameters of the spider mite among host plants were analyzed using pseudo-values, which were produced by jackknife re-sampling. The results indicated that black cherry might be the most suitable plant for hawthorn spider mite due to the shorter developmental period (10.6 days), longer adult longevity (25.5 days), higher reproduction (65.6 eggs), and intrinsic rate of natural increase (0.194 females/female/day). Cherry was the least suitable host plant. To determine the effect of host shifts, the mite was transferred from black cherry onto cherry and apple. In the first generation after shifting to apple, the developmental period, reproduction and life table parameters were negatively influenced. However, population growth parameters in the first generation on cherry were actually better than after three generations on this new host. This underscores the relevance of the mites' recent breeding history for life table studies. PMID- 17710559 TI - Visualisation of plastids in endosperm, pollen and roots of transgenic wheat expressing modified GFP fused to transit peptides from wheat SSU RubisCO, rice FtsZ and maize ferredoxin III proteins. AB - The ability to target marker proteins to specific subcellular compartments is a powerful research tool to study the structure and development of organelles. Here transit sequences from nuclear-encoded, plastid proteins, namely rice FtsZ, maize non-photosynthetic ferredoxin III (FdIII) and the small subunit of RubisCO were used to target a modified synthetic GFP (S65G, S72A) to plastids. The localisations of the fusion proteins expressed in transgenic wheat plants and under the control of the rice actin promoter were compared to an untargeted GFP control. GFP fluorescence was localised to non-green plastids in pollen, roots and seed endosperm and detected in isolated leaf chloroplasts using a GFP specific antibody. Transit peptides appeared to influence the relative fluorescence intensities of plastids in different tissues. This is consistent with differential targeting and/or turnover of GFP fusion proteins in different plastid types. Replacement of GFP sequences with alternative coding regions enables immediate applications of our vectors for academic research and commercial applications. PMID- 17710560 TI - Morphological and immunocytochemical analysis of Escherichia coli-specific surface antigens in wildtype strains and in recombinant Vibrio cholerae. AB - Adhesion is the first step in the pathogenesis of enterotoxigenic Escherichia coli infections. The genes encoding the most prevalent adhesion factors CFA/I, CS3 and CS6 were cloned into Vibrio cholerae strain CVD 103-HgR and expression of fimbriae was investigated in wildtype and recombinant strains by transmission electron microscopy in conjunction with immunolabelling and negative staining. Negative staining was effective in revealing CFA/I and CS3, but not CS6. Although morphology of fimbriae differed between wildtype and recombinant strains, corresponding surface antigens were recognized by specific antibodies. The present study provides evidence that ETEC-specific fimbriae can adequately be expressed in an attenuated V. cholerae vaccine strain and that immunoelectron microscopy is a critical tool to validate the surface expression of antigens in view of their possible suitability for recombinant vaccines. PMID- 17710561 TI - Description of pharmacist interventions during physician-pharmacist co-management of hypertension. AB - OBJECTIVE: The aim of this study is to describe recommendations made by clinical pharmacists when co-managing hypertension with physicians. SETTING: Two family medicine clinics at a major teaching hospital in the mid-western United States. METHOD: This report details the specific recommendations made by pharmacists during a prospective randomized controlled clinical trial. Patients with uncontrolled hypertension were enrolled in a 9-month intensive pharmacist physician co-management study. Clinical pharmacists saw patients at baseline, 2, 4, 6, and 8 month visits. Optional visits were allowed between required visits. MAIN OUTCOME MEASURE: For this analysis, pharmacist recommendations were grouped. Physician acceptance of the pharmacists' recommendations was also evaluated. RESULTS: Data from 101 patients were included and analyzed in this study. Changes in drug therapy were recommended 267 times for these 101 patients. Most recommendations for a change in treatment involved adding a new antihypertensive medication (46.4%) or increasing a dose (33.3%). The majority of pharmacist recommendations to modify drug therapy were made at the baseline visit (41.6%), with 76.8% of recommendations made by the 2 month visit. Physicians accepted and implemented 95.9% of the 267 pharmacist recommendations to modify drug therapy. Pharmacists recommended no change in the treatment plan 361 times, most often because the patient's blood pressure (BP) had achieved the goal. Average BP decreased from 153.1+/-10.0/84.9+/-12.0 mmHg (average+/-SD) at baseline to 124.2+/-9.7/74.7+/-9.6 mmHg (P<0.001) at the end of 9 months, with 89.1% (P<0.001) of patients reaching their BP goal. CONCLUSION: Pharmacist recommendations for alterations in drug therapy generally occurred early in the course of the study and were largely to intensify therapy through higher dosages or additional medications. Pharmacist-physician co-management of BP is effective at reducing BP and improving BP control rates. PMID- 17710562 TI - Sources of information for new drugs among physicians in Thailand. AB - OBJECTIVE: To determine the sources and the types of information about new drugs that Thai doctors at a teaching hospital perceived as important before prescribing and to assess their views on their preferred sources of drug information. METHOD: There were two phases of this study, the quantitative and the qualitative components. For the quantitative study, a descriptive survey using a self-reported questionnaire was mailed. The qualitative component consisted of face-to-face interviews using a semi-structured questionnaire. MAIN OUTCOMES MEASURE: The initial sources of information about new drugs; the reliability scores for each source of information; the types of information that doctors required before prescribing new drugs; and the prescribers' views on their preferred sources. RESULTS: The general findings regarding the doctors' information sources on new drugs were consistent in both the quantitative and qualitative analyses. Conferences, medical journals, and meetings with medical representatives were the initial sources of information for new drugs. Safety and efficacy profiles of new drugs were the most common types of information considered before prescribing new medicines. Although the medical representatives were viewed as very efficient in providing information about new drugs, the interviewees perceived that the information obtained from the persons employed by the pharmaceutical companies was likely to be biased. Consequently, the physicians preferred to have an unbiased resource person who could proactively provide two-sided information for both existing and new drugs at the hospital. CONCLUSION: The information sources on new drugs most frequently used by the physicians include scientific conferences, journals and medical representatives and they yearn for unbiased information regarding safety and efficacy of the promoted drugs before prescribing the new medicines. Thus, there is a window of opportunity for hospital pharmacists to serve the unmet needs of the physicians. PMID- 17710564 TI - Helicobacter pylori infection can change the intensity of gastric Lewis antigen expressions differently between adults and children. AB - This study tested whether there were different expressions of gastric Lewis antigens between children and adults with Helicobacter pylori infection, and whether the difference was related to the infection outcome. About 68 dyspeptic children and 110 dyspeptic adults were enrolled to check H. pylori infection, its colonization density, and the related histology. Gastric Lewis antigens b (Le(b)), x (Le(x)), and sialyl-Lewis x (sialyl-Le(x)) were immunohistochemically stained and scored for the intensity. The H. pylori-infected adults, but not the children, had a lower Le(b) intensity over the antrum (p=0.019) but higher Le(b) intensity over the corpus (p=0.001) than the non-infected ones. Over the antrum, both the H. pylori-infected children and adults had a lower Le(x) and higher sialyl-Le(x) intensity than those non-infected ones (p<0.05). The H. pylori infected adults had a higher bacterial density (p=0.004) and Le(b) intensity (p=0.016) over the corpus than the H. pylori-infected children. For the H. pylori infected adults, but not children, the corpus had a higher Le(b) (p=0.038) and lower Le(x) (p=0.005) intensity than the antrum. Furthermore, the H. pylori infected adults expressed a higher Le(b) and had a higher bacterial density than those with weak Le(b) (antrum, p<0.001; corpus, p=0.001). In conclusion, H. pylori infection is associated with the intensity change of Lewis antigen expressions in the stomach. The changes of gastric Lewis antigen expressions are different between adults and children with H. pylori infection, which may exert different H. pylori colonization over the corpus between adults and children. PMID- 17710563 TI - Vibrational mode frequency calculations of chlorophyll-d for assessing (P740(+) P740) FTIR difference spectra obtained using photosystem I particles from Acaryochloris marina. AB - Acaryochloris marina is an oxygen-evolving organism that utilizes chlorophyll-d for light induced photochemistry. In photosystem I particles from Acaryochloris marina, the primary electron donor is called P740, and it is thought that P740 consist of two chlorophyll-d molecules. (P740(+)-P740) FTIR difference spectra have been produced, and vibrational features that are specific to chlorophyll-d (and not chlorophyll-a) were observed, supporting the idea that P740 consists chlorophyll-d molecules. Although bands in the (P740(+)-P740) FTIR difference spectra were assigned specifically to chlorophyll-d, how these bands shifted, and how their intensities changed, upon cation formation was never considered. Without this information it is difficult to draw unambiguous conclusions from the FTIR difference spectra. To gain a more detailed understanding of cation induced shifting of bands associated with vibrational modes of P740 we have used density functional theory to calculate the vibrational properties of a chlorophyll-d model in the neutral, cation and anion states. These calculations are shown to be of considerable use in interpreting bands in (P740(+)-P740) FTIR difference spectra. Our calculations predict that the 3(1) formyl C-H mode of chlorophyll-d upshifts/downshifts upon cation/anion formation, respectively. The mode intensity also decreases/increases upon cation/anion formation, respectively. The cation induced bandshift of the 3(1) formyl C-H mode of chlorophyll-d is also strongly dependant on the dielectric environment of the chlorophyll-d molecules. With this new knowledge we reassess the interpretation of bands that were assigned to 3(1) formyl C-H modes of chlorophyll-d in (P740(+)-P740) FTIR difference spectra. Considering our calculations in combination with (P740(+)-P740) FTIR DS we find that the most likely conclusions are that P740 is a dimeric Chl-d species, in an environment of low effective dielectric constant ( approximately 2-8). In the P740(+) state, charge is asymmetrically distributed over the two Chl-d pigments in a roughly 60:40 ratio. PMID- 17710565 TI - A novel Phex mutation with defective glycosylation causes hypophosphatemia and rickets in mice. AB - N-ethyl-N-nitrosourea (ENU) mutagenesis is a phenotype-driven approach with potential to assign function to every locus in the mouse genome. In this article, we describe a new mutation, Pug, as a mouse model for X-linked hypophosphatemic rickets (XLH) in human. Mice carrying the Pug mutation exhibit abnormal phenotypes including growth retardation, hypophosphatemia and decreased bone mineral density (BMD). The new mutation was mapped to X-chromosome between 65.4 cM and 66.6 cM, where Phex gene resides. Sequence analysis revealed a unique T-to C transition mutation resulting in Phe-to-Ser substitution at amino acid 80 of PHEX protein. In vitro studies of Pug mutation demonstrated that PHEX(pug) was incompletely glycosylated and sequestrated in the endoplasmic reticulum region of cell, whereas wild-type PHEX could be fully glycosylated and transported to the plasma membrane to exert its function as an endopeptidase. Taken together, the Pug mutant directly confirms the role of Phex in phosphate homeostasis and normal skeletal development and may serves as a new disease model of human hypophosphatemic rickets. PMID- 17710566 TI - Past mysteries and current challenges: eating disorders and trauma. PMID- 17710567 TI - Eating disorders, trauma, and comorbidity: focus on PTSD. AB - This paper reviews the relationships among eating disorders (EDs), trauma, and comorbid psychiatric disorders, with a particular focus on posttraumatic stress disorder (PTSD). There have been a number of significant conclusions in the literature, applicable to clinical practice, which are essential to the understanding of the relationships between EDs and trauma. These are summarized as follows: a) childhood sexual abuse (CSA) is a nonspecific risk factor for EDs; b) the spectrum of trauma linked to EDs has been extended from CSA to include a variety of other forms of abuse and neglect; c) trauma is more common in bulimic EDs compared to nonbulimic EDs; d) findings linking EDs with trauma have been extended to children and adolescents with EDs; e) findings linking EDs with trauma have been extended to boys and men with EDs; f) multiple episodes or forms of trauma are associated with EDs; g) trauma is not necessarily associated with greater ED severity; h) trauma is associated with greater comorbidity (including and often mediated by PTSD) in ED subjects; i) partial or subthreshold PTSD may also be a risk factor for BN and bulimic symptoms; and j) the trauma and PTSD or its symptoms must be expressly and satisfactorily addressed in order to facilitate full recovery from the ED and all associated comorbidity. PMID- 17710568 TI - Is there a link between traumatic experiences and self-injurious behaviors in eating-disordered patients? AB - To find out more about the relationship between the presence of self-injurious behavior (SIB) and a history of traumatic experiences, we studied this link in 70 patients with an eating disorder (ED). The sample showed a high frequency of SIB (38.6%), particularly in patients with bulimia nervosa. We also found high percentages of self-reported experiences of physical (32.3%) and sexual abuse (47.7%). The presence of SIB turned out to be associated with a history of physical and/or sexual abuse. Patients who had suffered interpersonal abuse before the age of 15 were more likely to develop self-destructive behaviors. In line with other investigations, we found that high levels of dissociation and self-criticism differentiated sexually abused ED patients with SIB from those without SIB. We discuss some clinical implications of our findings, with suggestions for treatment. PMID- 17710569 TI - The role of emotional abuse in the eating disorders: implications for treatment. AB - This paper addresses the clinical links between emotional abuse and the eating disorders. It is argued that the core feature of a range of abusive experiences is emotional invalidation. Emotional abuse is associated with problems in the development of emotional skills, manifesting as alexithymia, poor distress tolerance, and emotional inhibition. Cognitive-behavioral approaches are outlined for work with eating-disordered patients with a history of emotional abuse. As well as addressing the central concerns about eating, weight, and shape (using existing evidence-based methods), the focus of treatment is on addressing the conditional assumptions about the acceptability of emotions and the core beliefs that underpin the emotional difficulties. PMID- 17710570 TI - Childhood trauma, borderline personality, and eating disorders: a developmental cascade. AB - In this article, we discuss the nature and role of trauma in relationship to borderline personality disorder and eating disorders. As is clinically evident, trauma can result in a variety of psychological consequences. These consequences include both Axis I and II disorders. Among the Axis II disorders, trauma appears to heighten the risk for the development of borderline, antisocial, avoidant, paranoid, and even schizotypal personality disorders. Likewise, trauma may heighten the risk for developing an eating disorder. There appear to be complex inter-relationships among trauma, borderline personality disorder, and eating disorders. In this article, we attempt to summarize these inter-relationships. PMID- 17710571 TI - Assessment of trauma symptoms in eating-disordered populations. AB - Research suggests that individuals with eating disorders (EDs) are relatively likely to have been abused or neglected as children, or to have been victimized in adolescence or adulthood. These experiences, in turn, are often associated with a range of psychological symptoms, as well as, in some cases, a more severe or complex ED presentation. In this article, we review both generic and more trauma-specific psychological tests that can be used to (a) identify clinically relevant trauma histories in the ED patient and (b) uncover trauma-relevant symptoms that may complicate or intensify a given instance of ED. We also discuss the clinical implications of a detailed trauma assessment, including its usefulness in guiding treatment for ED-trauma patients. PMID- 17710572 TI - Treating eating disorder patients who have had traumatic experiences: a self regulatory approach. AB - Eating disorder (ED) patients are presenting with increasingly complex symptom pictures consisting of layers of potential interaction between their eating disorder, impact of their traumatic experiences, and their social environment. Consequently, clinicians are challenged to utilize approaches that efficiently and effectively organize treatment for this particular population. This paper describes an therapeutic organizational model, based on self-regulation theory, that clinically has been found to be useful and effective for working with complex, multi-symptomatic ED patients. PMID- 17710573 TI - The role of spirituality in the treatment of trauma and eating disorders: recommendations for clinical practice. AB - The relationships among trauma, eating disorders, and spirituality are complex. Both trauma and eating disorders can distance women from their own spirituality, which undermines a potentially important treatment resource. In this article, we offer suggestions based on our clinical experience for helping eating disorder patients who have suffered trauma to rediscover their faith and spirituality. We describe how spirituality can be used as a resource to assist women throughout treatment and in recovery. PMID- 17710574 TI - Development and use of quality of care indicators for obstetric care in women with preeclampsia, severe preeclampsia, and severe morbidity. AB - OBJECTIVE: To develop indicators for evaluating the quality of care in managing preeclampsia. METHODS: An expert group helped to develop and validate the following indicators for evaluating quality of care: availability of intensive care; completeness of laboratory tests; appropriateness of drug treatment at admission and before delivery (antihypertensive drugs, anticonvulsants, and dexamethasone); gestational age at which pregnancy should be interrupted; and type of delivery. By using these indicators, it was possible to evaluate the quality of care in 432 patients with preeclampsia. RESULTS: A significant percentage of patients with preeclampsia and "near misses" received low quality of care, regardless of disease severity. CONCLUSION: A number of interventions are needed to increase the quality of care to help avert maternal deaths in patients with preeclampsia. PMID- 17710575 TI - New-onset hypertension in late pregnancy and fetal growth: different associations between singletons and twins. AB - OBJECTIVE: To compare the effects of new-onset hypertension (NOH) in late pregnancy on fetal growth in singletons and twins. METHODS: A retrospective cohort study was conducted to evaluate the effect of NOH on fetal growth in 17, 720, 900 singletons and 463, 104 twins born in the United States between 1995 and 2000. RESULTS: NOH was associated with lower mean birth weight in both preterm and term singletons. Increased risk of low birth weight and decreased risk of high birth weight was associated with NOH in preterm and term singletons. NOH was associated with increased risk for small-for-gestational-age (SGA) births and decreased risk for large-for-gestational-age (LGA) births in preterm singletons, whereas it was associated with increased risk of both SGA and LGA births in term singletons. NOH was associated with higher mean birth weight in early preterm twins, and lower mean birth weight in term twins. Decreased risk for low birth weight was found in the NOH group among early preterm twins, and increased risk for low birth weight in term twins. NOH was associated with increased risk of SGA births and decreased risk for large-for-gestational-age (LGA) births in early preterm twins, while increased risk of SGA births in term twins. CONCLUSION: NOH is associated with slower fetal growth in singletons delivered at different gestational ages, but the effect varies in twins depending on gestational age at delivery with faster growth in early preterm twins. PMID- 17710576 TI - A longitudinal study using ultrasound to assess flow-mediated dilatation in normal human pregnancy. AB - OBJECTIVE: To develop normal ranges of endothelial function in normal human pregnancy to use as a screening test for preeclampsia. METHODS: In this longitudinal study, women were studied five times during pregnancy and once postpartum using flow-mediated dilatation (FMD). FMD is a noninvasive ultrasound technique used to assess endothelial function. Healthy nonpregnant women were controls. RESULTS: FMD increased non-significantly in pregnancy until 32 weeks, when it decreased significantly at 36+ weeks (n = 47). CONCLUSION: The fall in FMD in the third trimester has not been previously reported. This indicates the importance of gestational age when assessing FMD as a screening test for preeclampsia. PMID- 17710577 TI - Analysis of C-850T and G-308A polymorphisms of the tumor necrosis factor-alpha gene in Maya-Mestizo women with preeclampsia. AB - OBJECTIVE: To determine whether polymorphisms in the TNF-alpha promoter gene are associated with preeclampsia. METHODS: 105 women with preeclampsia and 200 controls were genotyped for the G-308A and C-850T polymorphisms by RFLP. Differences in allele, genotype, and haplotype frequencies between groups were assessed. RESULTS: The genotypic and allelic distribution of both polymorphisms was similar between groups. Moreover, the estimated overall pair of loci haplotype frequencies did not differ significantly. CONCLUSION: We did not find any association between these polymorphisms and the risk for preeclampsia. However, we found that both the genotypic and allelic distribution in our population differed from those reported in other populations. PMID- 17710578 TI - Angiotensin-converting enzyme insertion/deletion (ACE I/D) and angiotensin II type 1 receptor (AT1R) gene polymorphism and its association with preeclampsia in Chinese women. AB - OBJECTIVE: To investigate whether polymorphisms of angiotensin converting enzyme gene (ACE) and angiotensin II receptor type 1 gene (AT1R) are associated with etiology of preeclampsia and renal impact in women with preeclampsia. METHODS: DNA was extracted from peripheral blood of 133 patients with preeclampsia and 105 healthy pregnant women. The I/D polymorphism of the ACE gene was assessed by polymerase chain reaction, and the A1166C polymorphism of the AT(1)R gene was additionally assessed by DdeI digestion. The level of proteinuria, fasting serum urea, creatinine and uric acid were investigated according to different genotypes of ACE and AT1R genes. RESULTS: The frequency of genotypes of the ACE gene and the AT1R gene was similar in preeclampsia and normal pregnancy. DD and ID genotype predominated in patients with severe proteinuria, as well as increased serum urea and uric acid. Serum creatinine was also increased, but no significant difference was found among three genotypes. The level of proteinuria, serum uric acid, urea, and creatinine did not vary between different AT1R genotypes. Compared with patients without renal dysfunction, the frequency of DD and ID genotypes of ACE gene was much higher in those with renal dysfunction, but AC and CC genotypes of AT1R gene were not. CONCLUSION: We found no association of the two gene polymorphisms with preeclampsia. However, ACE gene I/D polymorphisms were associated with the severe proteinuria and renal dysfunction seen in preeclampsia. Preeclampsia patients carrying the D allele may be susceptible to renal dysfunction. PMID- 17710579 TI - Baroreflex control of sympathetic nerve activity in hypertensive pregnant rats with reduced uterine perfusion. AB - OBJECTIVE: Baroreflex sensitivity is reduced in women with preeclampsia. The aim of this study was to determine whether baroreflex control of renal sympathetic nerve activity (RSNA) is altered in pregnant rats with reduced uterine perfusion (a model of human preeclampsia). METHODS: Uterine perfusion was reduced in the third trimester by clipping the distal aorta and uterine branches of the ovarian arteries. RSNA baroreflex parameters were compared at term gestation in rats with reduced uterine perfusion (n = 12), in normal pregnant rats (n = 14) and in nonpregnant rats (n = 14). RESULTS: Reduced perfusion rats were hypertensive (123.6 +/- 2.3 mm Hg), and normal pregnant rats were hypotensive (97.7 +/- 2.2 mm Hg), compared with controls. In rats with reduced perfusion, the baroreflex was shifted to a higher set-point, and maximum and minimum RSNA were increased compared with normal pregnant rats. CONCLUSION: The blunted baroreflex gain of normal pregnancy is maintained in rats with reduced uterine perfusion, but a hypertensive shift in baroreflex function exists in this rat model that is associated with a reversal of the reflex maximum and minimum RSNA observed in normal pregnancy. PMID- 17710580 TI - Hemodynamic adaptation during pregnancy in chronic hypertension. AB - OBJECTIVE: To assess hemodynamic and NT-proANP changes in women with chronic hypertension during pregnancy. METHODS: Stroke volume index (SI), heart rate (HR), cardiac output index (CI), systemic vascular resistance index (SVRI), pulse wave velocity (PWV), and left cardiac work index (LCWI) were measured using whole body impedance cardiography. Systolic blood pressure (SAP), mean arterial pressure (MAP), diastolic blood pressure (DAP), and pulse pressure (PP) were also measured. Arterial compliance was defined as the SI-to-PP ratio (SI/PP). Hemodynamic parameters and NT-proANP concentrations were assessed during the early and late second trimester, the third trimester, and after delivery in 20 women with essential hypertension and 30 normotensive women. RESULTS: Arterial blood pressure, SVRI, and PWV remained higher during the whole study period in chronic hypertensive compared with healthy pregnancies. In the early second trimester, women with chronic hypertension had significantly lower SI and NT proANP concentrations than did normotensive women. CONCLUSION: The hemodynamics of chronic hypertension during pregnancy are characterized by persistent high vascular resistance. Lower SI and NT-proANP values found in chronic hypertensive pregnancies during the early second trimester may suggest a reduced intravascular volume increase during pregnancy. PMID- 17710581 TI - Plasma from women with preeclampsia has a low lipid and ketone body content--a nuclear magnetic resonance study. AB - OBJECTIVE: Using (1)H-nuclear magnetic resonance spectroscopy and chemometrics, we sought to establish the metabolic profile for preeclampsia and to identify biomarkers that would permit a distinction between women with a normal pregnancy and those suffering from preeclampsia. METHODS: Plasma samples from 11 normotensive pregnant women and 11 women with preeclampsia were analyzed. Principal component analysis was applied to differentiate between the two groups of patients. RESULTS: Lipid concentrations were found to be significantly lower in the plasma of patients suffering from preeclampsia than those in normotensive pregnant women (p = 0.031). There is also evidence to suggest that ketone body constituents may contribute to the discrimination. CONCLUSION: (1)H-nuclear magnetic resonance-based metabolic profiling can detect patients with preeclampsia. PMID- 17710582 TI - Anti-hypertensive drugs alter cytokine production from preeclamptic placentas and peripheral blood mononuclear cells. AB - OBJECTIVE: Antihypertensive drugs are administered to women with preeclampsia to control blood pressure and fluid overload. Whether they modulate placental or circulating cytokine production in women with preeclampsia is unknown. This study examines the effect of pharmacological doses of antihypertensive drugs on the production of IL-10, tumor necrosis factor alpha (TNF-alpha), and IL-6 in placental tissue and peripheral blood mononuclear cells (PBMCs) from women with preeclampsia. METHODS: Term placenta samples (n = 6) and PBMCs from whole blood (n = 6) were obtained from women with preeclampsia. Both villous explants and PBMCs were cultured with increasing concentrations of antihypertensive drugs (clonidine, diazoxide, hydralazine, and furosemide). The dose effect of drugs on the production of placental and circulating cytokines IL-10, TNF-alpha, and IL-6 was examined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our data suggest that clonidine can stimulate anti-inflammatory IL-10 production from PBMC while decreasing pro-inflammatory TNF-alpha, whereas low doses of hydralazine increased the production of IL-10, TNF-alpha, and IL-6 from preeclamptic PBMCs. There was a reduction in IL-10, TNF-alpha, and IL-6 production with increasing doses of clonidine and hydralazine by placentas in preeclampsia. IL-10, TNF alpha, and IL-6 production from preeclamptic placenta and PBMCs were inhibited by diazoxide and furosemide. CONCLUSIONS: Antihypertensive drugs may alter Th1/Th2 cytokine balance in preeclamptic tissues in vitro. PMID- 17710583 TI - Familial occurrence of gestational hypertensive disorders in a Brazilian population. AB - OBJECTIVE: To verify the occurrence of preeclampsia/eclampsia (PE/E) or gestational hypertension (GH) in first-degree relatives of Brazilian pregnant women. METHODS: A total of 485 women were enrolled in the study, and 226 were selected (75 with PE/E, 49 with GH, and 102 women with normal pregnancies). Statistical analysis was performed using Fisher's exact test. RESULTS: The frequency of families with mothers and/or sisters with PE/E was higher among the PE/E group compared to the GH and the control groups, and was statistically significant (p < 0.05). CONCLUSION: Women with PE/E have more female first-degree relatives with PE/E as observed in a Brazilian population. PMID- 17710584 TI - Some physical, pomological and nutritional properties of kiwifruit cv. Hayward. AB - In this research, several physical, pomological and nutritional properties that are important for the design of equipments for harvesting, processing, transportation, sorting, separation and packaging of kiwifruit cv. Hayward grown in the Black Sea region of Turkey were determined. The fruit characteristics ranged from 72.28 g for average fruit weight, 59.41, 46.28 and 42.87 mm for fruit length, width and thickness, 49.03 mm for the geometric mean diameter, 0.825% for sphericity and 66.52 cm(3) for the volume of fruit, respectively. The bulk density, fruit density and porosity were determined as 575.27 kg/m(3), 1,093 kg/m(3) and 47.13%. The highest coefficient of static friction was obtained on plywood as 0.190, followed by polyethylene, rubber and galvanized steel sheet as 0.173, 0.163 and 0.158, respectively. The total soluble solid content, acidity, vitamin C, ash and total nitrogen content of kiwifruit cv. Hayward were 7.32%, 1.64%, 108 mg/100g, 0.71 g/100 g and 0.84%, respectively. The fresh fruits have 1.09 mg/100g total chlorophylls and flesh color data represented as L, a and b were 57.18, 17.25 and 37.46, respectively. PMID- 17710585 TI - Proximate and mineral composition of the leaves of Momordica balsamina L.: an under-utilized wild vegetable in Botswana. AB - Proximate and mineral analyses were conducted on the leaves of Momordica balsamina L., an under-utilized wild vegetable in Botswana. The protein, fibre, fat and ash contents were 288, 37, 54 and 127 g/kg, respectively. Potassium was the most abundant mineral at 27.05 g/kg, followed by magnesium (3.82 g/kg), phosphorus (3.24 g/kg), calcium (2.22 g/kg) and sodium (0.06 g/kg). Other minerals were zinc (0.39 g/kg), manganese (0.15 g/kg) and iron (0.14 g/kg). Compared with cabbage, lettuce and spinach, this wild vegetable contained more protein and fat, while the fibre content was less. Among the minerals analysed, the leaves of M. balsamina had higher values than those reported for the exotic vegetables, except for sodium. The wild vegetable could be promoted as a protein supplement for cereal-based diets in poor rural communities, while its high potassium content could be utilized for the management of hypertension and other cardiovascular conditions. The relatively high concentrations of zinc, iron and manganese could contribute towards combating the problem of micronutrient deficiencies. PMID- 17710586 TI - Increased one week soybean consumption affects spatial abilities but not sex hormone status in men. AB - BACKGROUND: Increased soybean intake is often recommended for the prevention of hormone-dependent cancer, cardiovascular diseases and age-related cognitive decline. Although isolated phytoestrogens have shown these positive effects, the evidence for such influence of increased consumption of soybeans is lacking. AIM: To prove the effects of short-term increased soybean intake on sex hormone levels and spatial cognitive parameters in men. SUBJECTS AND METHODS: Seven young healthy men were asked to eat 900 g soybeans during 1 week. Sex hormone levels were determined in saliva and plasma, and mental rotation and spatial visualization were quantified by standard psychometric tests. All parameters were assessed before and after the study. RESULTS: Plasma estradiol, total and free testosterone, as well as salivary testosterone and estradiol remained unchained. Spatial cognitive performance was improved after increased soybean intake when considering spatial visualization (P=0.03). The results for mental rotation showed similar dynamics, but the changes were not significant. CONCLUSION: Short term increased soybean intake does not affect sex hormone status, but improves spatial cognitive performance in young healthy men. PMID- 17710587 TI - An open-label dose-response study of lymphocyte glutathione levels in healthy men and women receiving pressurized whey protein isolate supplements. AB - BACKGROUND: High-pressure treatment of whey protein may increase digestibility and bioavailability of cysteine. The purpose of the study was to determine whether total lymphocyte glutathione (gamma-glutamyl-cysteinyl-glycine [GSH]) levels (oxidized+reduced) can be augmented from three different doses of pressurized whey protein supplements in a dose-dependent manner over a 2-week period. METHODS: Eighteen healthy males and 18 healthy females were randomized into three different groups, with 31 finishing the study. Each group ingested 15, 30, or 45 g/day pressurized whey protein in the morning in bar format for 14 days. Each group was blinded to the amount of whey protein they were ingesting. Ten millilitres of blood was withdrawn before and after the 2-week period to assess blood lymphocyte levels pre and post supplementation. RESULTS: There was no change in body weight or reported physical activity levels pre and post supplementation. Pre-lymphocyte GSH levels were not significantly different between groups (3.7+/-0.7 micromol/l). Least-squares linear regression showed that the change in lymphocyte GSH levels from pre to post supplementation was affected by the amount of whey protein ingested daily (P=0.037). The group that ingested 45 g/day pressurized whey protein augmented GSH levels the most (by approximately 24%), and the group that ingested 15 g/day did not increase lymphocyte GSH levels. CONCLUSIONS: We conclude that there is a significant relationship between the dosage of supplementation and the change in lymphocyte GSH levels. Furthermore, the increase in GSH was linear with the amount of whey protein ingested. Pressurized whey protein supplementation of 45 g/day for 2 weeks can increase lymphocyte GSH by 24%. PMID- 17710588 TI - Diet during adolescence is a trigger for subsequent development of dysmenorrhea in young women. AB - Recently many young women in Japan have been restricting their dietary intake for cosmetic purposes. In this study, the relation between diet and menstrual disorders was investigated by responses to a questionnaire. Subjects ranging from 18 to 20 years old were recruited from 716 female students at Ashiya College. Dietary habits were classified into group I (having no experience with dieting), group II (those currently on a diet) and group III (those with a history of dieting). The intensity of dysmenorrhea was classified into three grades. All participants were divided into two groups as having regular or irregular menstruation. The frequency of irregular menstruation in group II was higher than that in the other groups, while group III had higher intensity of dysmenorrhea than the other groups. These findings suggest that diet during adolescence has long-lasting adverse effects on reproductive function in young women. PMID- 17710589 TI - Sugar intake, soft drink consumption and body weight among British children: further analysis of National Diet and Nutrition Survey data with adjustment for under-reporting and physical activity. AB - We investigated associations between body mass index (BMI) and intake of non-milk extrinsic sugars (NMES) and caloric soft drinks using weighed 7-day food records, nutrient intakes, BMI measurements and 7-day physical activity (PA) diaries from the UK National Dietary and Nutritional Survey of Young People (n=1,294 aged 7-18 years). NMES and caloric soft drinks (excluding 100% fruit juice) were quantified by their contribution to energy intake. BMI z-scores were calculated from UK reference curves and International Obesity Task Force (IOTF) cut-off values were used to define overweight. The BMI z-score was weakly inversely correlated with percentage energy from NMES after adjustment for under-reporting and dieting (r= 0.06, P=0.03). The percentage of energy from soft drinks was not associated with the BMI z-score or PA. After excluding under-reporters and dieters, the heaviest children (top quintile: Q5 of BMI z-scores) consumed more total energy (+1,220 kJ/day) than those in the lowest quintile (Q1), but only 60 kJ (5%) was from soft drinks. In logistic regression (adjusted for age and gender, under-reporting, and dieting), overweight was positively associated with energy intake (MJ) (odds ratio [OR]=1.58, confidence interval [CI]=1.42-1.77) and sedentary activity (h) (OR=1.11, CI=1.01-1.23), and inversely associated with moderate/vigorous activity (h) (OR=0.71, CI=0.58-0.86). In the macronutrient model, high fat and protein intake (top tertile vs lowest tertile, g/day) were positively associated with overweight (OR>2.5, P<0.001) while starch had less impact (OR=1.60, CI=1.0-2.55, P<0.05). Top tertile intakes of caloric soft drinks were weakly associated with overweight (OR=1.39, CI=0.96-2.0, P=0.08), while other sources of NMES showed no association (OR=0.81, CI=0.52-1.27, P=0.4). Risk associated with caloric soft drinks appeared non-linear with an increase in odds only for very high consumers (top quintile, mean 870 kJ/day; OR=1.67, CI=1.04-2.66, P=0.03). These data are not consistent with any specific role for NMES or caloric soft drinks in obesity among British children and adolescents, but point instead to a general role of overeating and physical inactivity. Evidence of successful interventions is urgently needed but these must use reliable measurements of exposure (diet and PA) and outcome (BMI z-score, body fat, waist circumference) and have a sufficient timescale. PMID- 17710590 TI - Nutritional composition of the commonly consumed composite dishes for the Barbados National Cancer Study. AB - PRIMARY OBJECTIVE: To provide, for the first time, the calculated nutritional composition of 32 composite dishes commonly consumed in Barbados to enable dietary intake to be calculated from a Quantitative Food Frequency Questionnaire developed specifically for this population to determine associations between diet and risk of prostate and breast cancer. METHODS AND PROCEDURES: Weighed recipes were collected in up to six different households for each of the 32 composite dishes. The average nutritional composition for these composite dishes was calculated using the US Department of Agriculture National Nutrient Database. MAIN OUTCOMES AND RESULTS: One hundred and fifty-two weighed recipes were collected for 32 composite dishes: five were fish based, two were ground beef dishes, two were chicken based, two were offal based, two were lamb dishes, one was pork based, three were rice based, three were commonly consumed home-made drinks, and the remaining were miscellaneous items. CONCLUSIONS: A total of 152 weighed recipes were collected and we provide, for the first time, nutritional composition data for 32 commonly consumed food and drink items in Barbados. Such data are essential for assessing nutrient intake and determining associations between diet and prostate and breast cancer in the Barbados National Cancer Study. PMID- 17710591 TI - Nutritional composition of commonly consumed composite dishes from the Central Province of Cameroon. AB - PRIMARY OBJECTIVE: To provide nutritional composition of 34 composite dishes commonly consumed in Cameroon, in order to enable dietary intake to be calculated from a Quantitative Food Frequency Questionnaire developed specifically for this population to determine associations between diet and diabetes. METHODS AND PROCEDURES: A total of 197 recipes were collected for 34 composite dishes. Multiple samples of each dish were collected from a range of 2-16 households in the villages of Evadoula and in the city of Yaounde. MAIN OUTCOMES AND RESULTS: The average nutritional composition for these composite dishes was calculated using the US Department of Agriculture National Nutrient Database. We provide the energy, macronutrient and micronutrient content of these foods. CONCLUSIONS: We provide, for the first time, the macronutrient and micronutrient content of 34 commonly consumed composite dishes in the Central Province of Cameroon. Such data are essential for calculating nutrient intake and determining associations between diet and diabetes and other chronic diseases. These data may also be used for nutrition interventions aimed at modifying commonly consumed composite dishes to improve dietary intake. PMID- 17710592 TI - Preparation of an edible cottonseed protein concentrate and evaluation of its functional properties. AB - Cottonseed could be used as a source of dietary protein for human food production. The cottonseed component, gossypol, is toxic, however, which has limited the potential of cottonseed in human food production. Free gossypol was removed from glanded cottonseed using a two-stage solvent extraction method utilizing aqueous and anhydrous acetone. A cottonseed protein concentrate with a low level of free gossypol and a protein content of 72.2% was obtained . The cottonseed protein concentrate had good organoleptic characteristics, and had functional properties allowing its use as a food additive. PMID- 17710593 TI - Looking for new opportunities to enhance health - time to reduce salt. PMID- 17710594 TI - An exploratory study of older adults' comprehension of printed cancer information: is readability a key factor? AB - Printed cancer information often is written at or beyond high school reading levels, despite lower average literacy abilities of the public. The objectives of this exploratory study were twofold: (1) to evaluate older adults' comprehension of breast (BC), prostate (PC), and colorectal (CC) cancer information; and (2) to determine if comprehension of BC, PC, and CC information varies according to text readability. Comprehension of printed cancer resources was evaluated with 44 community-dwelling older adults using the Cloze procedure and recall questions. Participants' comprehension scores were compared with Simple Measure of Gobbledegook (SMOG) readability scores (.05). Factors associated with lower EFS by univariate analysis were bulky disease, risk groups, and LDH level > or = 500 IU/L. By multivariate analysis only LDH level was significant. In conclusion, the treatment results in this study were similar to those of BFM group. PMID- 17710660 TI - Dysgerminoma in a child with ataxia-telangiectasia. AB - Ataxia-telangiectasia is an autosomal recessive disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, high incidence of cancer, and increased sensitivity to ionizing radiation. The authors report a case of dysgerminoma in a child with high alpha-fetoprotein, CA125 and beta-human chorionic gonadotropin, who has been followed-up for ataxia telangiectasia for 2 years. PMID- 17710658 TI - Practice of palliative sedation in children with brain tumors and sarcomas at the end of life. AB - Despite progress in the treatment of pediatric cancer, approximately 25% of these children will die of the disease. The last period of life is characterized by profound physical and psychological suffering, both of the children and their loved ones. Adequate alleviation of this suffering becomes the priority in the management of these patients. The authors retrospectively evaluated the indications, incidence, and characteristics of palliative sedation (PS) in 19 children with brain tumors (BT) and 18 with sarcomas (S) at the end of life. Twelve of the 18 S patients received PS, as did 13 of the 19 BT patients. Indications for initiation of PS for those with BT were seizures and/or pain, for those with S were pain and/or respiratory insufficiency. It was concluded that PS may be the only efficacious and safe treatment for the alleviation of suffering in these children at the end of life, despite differing indications. PMID- 17710662 TI - Pyridoxine and pyridostigmine treatment in vincristine-induced neuropathy. AB - Vincristine is a commonly used antineoplastic drug and frequently causes neurotoxicity. Here the authors report a 4-year-old boy with acute lymphoblastic leukemia in whom vincristine-induced peripheral and cranial neuropathy developed during remission induction therapy. The patient seemed to benefit from pyridoxine and pyridostigmine therapy greatly and this therapy is recommended in patients with severe vincristine-induced neuropathy. PMID- 17710663 TI - Biotinidase deficiency and juvenile myelomonocytic leukemia in a Turkish infant of consanguineous parents. AB - Here, a case is presented with two rare genetic disorders, biotinidase deficiency and juvenile myelomonocytic leukemia, in a Turkish infant. This case may serve as a reminder that the diagnosis of a genetic disorder does not exclude the possibility of a second congenital but acquired disease. PMID- 17710661 TI - Pharmacokinetics of doxorubicin and etoposide in a morbidly obese pediatric patient. AB - This case report presents the pharmacokinetics of doxorubicin and etoposide in a 14-year-old morbidly obese (body mass index: 46.3 kg/m2) male patient with Hodgkin disease. Dosing based on an adjusted body surface area resulted in a dose reduction by approximately 25% as compared to dosing based on actual body surface area. Plasma clearance of doxorubicin as well as plasma clearance and elimination rate of etoposide for this patient was comparable to pharmacokinetic data from nonobese pediatric patients. The therapy was well tolerated without any specific toxicity and a complete response was obtained after 2 scheduled courses, with the patient in complete remission 25 months after end of treatment. PMID- 17710664 TI - Got pure blood in fetal rats? AB - Have you felt frustration when fetal blood is needed for your studies in rats, or have you been concerned about fetal rat "blood" collected from decapitation? The traditional approach has been to collect fetal blood from decapitation of fetuses. The new method of collecting fetal blood is from the fetal heart, and makes it possible to obtain pure fetal blood at near-term in rodents for fetal studies. This study also demonstrated a significant difference of fetal blood oxygen levels between the traditional and new methods of blood collection. PMID- 17710665 TI - Hemoglobin-based oxygen carriers: a long road from bench to bedside. PMID- 17710666 TI - Non-alcoholic fatty liver disease. PMID- 17710667 TI - Biliary reflux and non-acid reflux are two distinct phenomena: a comparison between 24-hour multichannel intraesophageal impedance and bilirubin monitoring. AB - OBJECTIVE: Duodenogastroesophageal reflux (DGER) can greatly increase microscopic and macroscopic esophageal mucosal damage caused by acid. The aim of this study was simultaneously to assess the chemical composition of DGER by detecting bilirubin in the refluxate by means of Bilitec and describe its pH and physical properties by impedance monitoring, in order to prove that non-acid reflux and biliary reflux are two distinct phenomena. MATERIAL AND METHODS: Twenty patients with gastroesophageal reflux disease (GERD) with symptoms refractory to conventional proton-pump inhibitor (PPI) therapy or with atypical GERD symptoms were included in the study. All patients underwent upper gastrointestinal endoscopy and simultaneous Bilitec and intraeosophageal impedance (IIM) and pH monitoring. In the majority of patients (16/20), the tests were performed while assuming a standard PPI dose. RESULTS: Pathological bilirubin exposure, as defined by intraesophageal bilirubin absorbance above 0.14 for more than 3.9% of the time, was present in 9 cases, 6 of them with normal values of non-acid reflux, as detected by IIM. A pathological non-acid reflux, as defined by an IIM showing a percentage time with non-acid reflux greater than 1.4%, was observed in 5 patients, 2 of whom had no pathological biliary reflux, as detected by Bilitec. No correlation was found between the two indices, as expressed by an r-value of 0.12 (p>0.05). CONCLUSIONS: Our study confirms that biliary reflux and non-acid reflux as detected by Bilitec and by IIM, respectively, are two distinct phenomena that require different techniques in order to be assessed in humans. PMID- 17710668 TI - Reduced conscious blood flow in the stomach during non-steroidal anti inflammatory drugs administration assessed by flash echo imaging. AB - OBJECTIVE: Harmonic flash echo imaging, which is an intermittent second harmonic imaging technique, has recently been developed for the evaluation of blood flow. The present study was designed to investigate human gastric blood flow during administration of non-steroidal anti-inflammatory drugs (NSAIDs) by harmonic flash echo imaging. MATERIAL AND METHODS: Eight healthy volunteers were enrolled in the study. After an overnight fast, the volunteers were requested to drink 400 ml water and remain in the sitting position. Seven milliliters (300 mg/ml) Levovist (SHU508A) was then injected intravenously at the rate of 1 ml/s, and intermittent harmonic scanning was carried out at 1-s intervals. A similar examination was carried out one hour after each subject took an oral tablet of diclofenac sodium (50 mg). To minimize the effect of variations in acoustic attenuation among patients, the ratio of the maximum amplitude in the gastric wall to that in the portal vein was expressed as the gastric perfusion index. RESULTS: Strong ultrasonographic contrast enhancement of the gastric wall and portal vein was observed. The area under the curve was significantly reduced in the images obtained after ingestion of the diclofenac sodium tablet. The gastric perfusion index was significantly reduced from 0.617+/-0.114 to 0.480+/-0.127 in the antrum and from 0.659+/-0.103 to 0.509+/-0.107 in the lower gastric corpus after ingestion of the diclofenac sodium tablet (p<0.05). CONCLUSIONS: A reduction in the human conscious gastric transmural blood flow following ingestion of an NSAID is revealed by harmonic flash echo imaging. PMID- 17710669 TI - Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder. AB - OBJECTIVE: Sequencing efforts to discover mutations in the tyrosine kinase Kit related to systemic mast cell disorders have so far been focused mainly on only a few of the 21 exons of the encoding gene c-kit, thus considerably limiting the possibility to quantitatively reveal pathogenetic relationships. The purpose of this study was to analyze and compare the total sequence of Kit tyrosine kinase at the level of the mRNAs obtained from patients with clear systemic signs of a pathologically increased mast cell mediator release and those from healthy volunteers. MATERIAL AND METHODS: Kit encoding mRNA isolated from mast cell progenitors in peripheral blood from 17 patients with a mast cell activation disorder and from 5 healthy volunteers as well as from the human mast cell leukemia cell line HMC1 was analyzed for alterations. RESULTS: Multiple novel point mutations and six isoforms of Kit which are due to alternative mRNA splicing were detected. One isoform, the insertion of a glutamine residue at amino acid position 252, was found to be a new splice variant expressed in all patients but in none of the healthy volunteers. CONCLUSIONS: Systemic mast cell activation disorder was pathogenetically characterized by two or more alterations in the Kit tyrosine kinase providing not only a means of confirming the diagnosis, but also of assessing prognosis and of starting adequate therapeutic interventions. The insertion of Q252 appears to be pathognomic for that disease, providing a novel means for the identification of chronic non-specific gastrointestinal symptoms as manifestations of a systemic mast cell activation disorder. PMID- 17710670 TI - Breathing exercises with vagal biofeedback may benefit patients with functional dyspepsia. AB - OBJECTIVE: Many patients with functional dyspepsia (FD) have postprandial symptoms, impaired gastric accommodation and low vagal tone. The aim of this study was to improve vagal tone, and thereby also drinking capacity, intragastric volume and quality of life, using breathing exercises with vagal biofeedback. MATERIAL AND METHODS: Forty FD patients were randomized to either a biofeedback group or a control group. The patients received similar information and care. Patients in the biofeedback group were trained in breathing exercises, 6 breaths/min, 5 min each day for 4 weeks, using specially designed software for vagal biofeedback. Effect variables included maximal drinking capacity using a drink test (Toro clear meat soup 100 ml/min), intragastric volume at maximal drinking capacity, respiratory sinus arrhythmia (RSA), skin conductance (SC) and dyspepsia-related quality of life scores. RESULTS: Drinking capacity and quality of life improved significantly more in the biofeedback group than in the control group (p=0.02 and p=0.01) without any significant change in baseline autonomic activity (RSA and SC) or intragastric volume. After the treatment period, RSA during breathing exercises was significantly correlated to drinking capacity (r=0.6, p=0.008). CONCLUSIONS: Breathing exercises with vagal biofeedback increased drinking capacity and improved quality of life in FD patients, but did not improve baseline vagal tone. PMID- 17710671 TI - Antimicrobial peptides in chronic anal fistula epithelium. AB - OBJECTIVE: Anal fistulas are the result of chronic infection of an intersphincteric gland. Despite the passage through mesenchymal tissue, fistulas seldom lead to systemic infection. Antimicrobial peptides are secreted by a variety of epithelia, belonging to the innate immune system and are potential factors contributing to infection control. The aim of this study was to investigate whether epithelium is present in the fistulas and what the origin might be. MATERIAL AND METHODS: Forty-seven chronic anal fistulas from patients, excluding Crohn's disease, were compared with healthy rectal and perianal control tissue. Expression of antimicrobial peptide mRNA was analysed by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry. Tissue was further studied by cytokine and cytokeratin staining. RESULTS: Chronic anal fistulas express high levels of hBD-2 and hBD-3 and the newly identified antimicrobial peptides RNase7 and psoriasin compared to rectal mucosa from control patients. Perianal skin has almost identical levels of RNase7 and psoriasin expression to those in fistulas. IL-1b and IL-8 were the only cytokines detectable in fistulas. Fistulas are lined with squamous epithelium that expresses identical cytokeratines as skin. CONCLUSIONS: Epithelialization and local production of antimicrobial peptides in anal fistulas serve as defence mechanisms to prevent local and systemic infection by microbes from faeces passing through the fistula tract. PMID- 17710672 TI - Pro-MMP-9 is associated with poor prognosis in gastric cancer. PMID- 17710673 TI - Penetrance of the C28Y/C282Y genotype of the HFE gene. AB - OBJECTIVE: Hereditary hemochromatosis is a common genetic disease caused by accumulation of iron in the body. Most cases are homozygous for the C282Y mutation in the HFE gene, but only a minority of homozygotes will ever suffer from clinical hemochromatosis. Estimates of the penetrance of the C282Y/C282Y genotype vary greatly. The purpose of this study was to estimate the penetrance using a stringent definition, i.e. liver cirrhosis. MATERIAL AND METHODS: The results from previous phenotypic population screening for hereditary hemochromatosis were combined with findings in hospital databases in order to estimate the number of C282Y homozygotes with and without liver cirrhosis in a Norwegian county. The penetrance of the C282Y/C282Y genotype was estimated as the fraction of C282Y homozygotes with liver cirrhosis. We also calculated the expected number of male C282Y homozygotes with liver cirrhosis using figures for age-specific accumulated risk. RESULTS: The prevalence of liver cirrhosis in male homozygotes is between 3.4% and 5.0%. This figure is compatible with an accumulated risk of liver cirrhosis that increases from 0.2% at 35 years to about 10% at 65 years of age. In female homozygotes, the prevalence of liver cirrhosis is 0.3%. CONCLUSIONS: A small but significant number of Norwegian male C282Y homozygotes will contract liver cirrhosis if their hemochromatosis is not diagnosed and treated in time. The penetrance is much lower in women than in men. PMID- 17710674 TI - Efficacy of zinc administration in patients with hepatitis C virus-related chronic liver disease. AB - OBJECTIVE: Zinc supplementation has been shown to contribute to inhibition of liver fibrosis and improvement in hepatic encephalopathy. However, little is known about the anti-inflammatory effect of zinc on hepatitis C virus (HCV) related chronic liver disease (CLD). We therefore examined the effects of zinc administration on inflammatory activity and fibrosis in the liver of patients with HCV-related CLD. MATERIAL AND METHODS: Polaprezinc, a complex of zinc and l carnosine, was administrated at 225 mg/day for 6 months to 14 patients with HCV related CLD, in addition to their ongoing prescriptions. Peripheral blood cell counts, liver-related biochemical parameters, serological markers for liver fibrosis, HCV-RNA loads, and serum levels of zinc and ferritin were evaluated before and after zinc administration. RESULTS: Serum zinc concentrations were positively correlated with hepatic reserve before zinc supplementation. A significant increase in serum zinc level was observed after zinc supplementation (64+/-15 versus 78+/-26 mg/dl, p=0.0156). Treatment with polaprezinc significantly decreased serum aminotransferase levels (aspartate aminotransferase (AST): 92+/-33 versus 63+/-23 IU/l, p=0.0004; alanine aminotransferase (ALT): 106+/-43 versus 65+/-32 IU/l, p=0.0002), whereas alkaline phosphatase levels were significantly increased (305+/-117 versus 337+/-118 U/l, p=0.0020). Serum ferritin levels were significantly decreased by treatment with polaprezinc (158+/ 141 versus 101+/-80 ng/ml, p=0.0117). The reduction rate of ALT levels by polaprezinc was positively correlated with that of ferritin (r(2)=0.536, p=0.0389). There was a tendency toward a decrease in serum type IV collagen 7S levels after treatment with polaprezinc. However, administration of polaprezinc did not affect peripheral blood cell counts, other liver function tests, or HCV RNA loads. CONCLUSIONS: These findings suggest that polaprezinc exerts an anti inflammatory effect on the liver in patients with HCV-related CLD by reducing iron overload. PMID- 17710675 TI - Identification and in silico characterization of a novel compound heterozygosity associated with hereditary aceruloplasminemia. AB - BACKGROUND: Hereditary aceruloplasminemia is an adult-onset autosomal recessive disease characterized by increased iron overload in the liver, pancreas, retina, and central nervous system. So far, 45 families with cases of aceruloplasminemia have been reported world-wide and mainly missense and nonsense mutations in the ceruloplasmin gene were detected. MATERIAL AND METHODS: Here, we report the identification, clinical characterization, and in silico analysis of a novel compound heterozygosity in the ceruloplasmin gene of a 31-year-old man with iron overload. RESULTS: Increased serum ferritin levels, elevated iron saturation, as well as results of iron quantification in the liver and magnetic resonance imaging-based measurement of T2 relaxation times of the substantia nigra consistently suggested iron overload. By sequencing the ceruloplasmin gene, so far unknown nucleotide replacements G229C, and C2131A were detected in exons 2 and 12, respectively. In silico analyses showed that the resulting amino acid changes Asp58His and Gln692Lys are located at highly conserved positions. The Asp58His mutation is located on the surface of the protein, alters polarity, and may interfere with copper incorporation or ceruloplasmin trafficking. The Gln692Lys mutation is mapped to a beta-strand of domain 4 and may lead to conformational change of the cupredoxin fold. CONCLUSIONS: As causative for aceruloplasminemia, a formerly unknown compound heterozygosity in the ceruloplasmin gene was identified. In silico characterization suggests an impact on ceruloplasmin conformation and function. PMID- 17710677 TI - Characteristics of ascitic fluid in cardiac ascites. AB - OBJECTIVE: Cardiac ascites remains a rare entity with unique clinical and pathogenetic features that are not adequately recognized by clinicians. The purpose of this study was to contribute towards elucidating the nature of cardiac ascites. MATERIAL AND METHODS: We describe a series of 26 ascitic fluid samples from eight patients with cardiac ascites that were referred and further evaluated for the etiology and nature of their ascites. RESULTS: In all samples ascitic fluid was an exudate with an increased serum-ascitic fluid albumin gradient, a pattern unique in ascites. Other causes of ascites were excluded, often through a protracted differential diagnostic procedure. CONCLUSIONS: The unique pattern of cardiac ascites should allow for rapid diagnosis and characterization: The clinical implications of furosemide use in its response and biochemical properties warrant further description. PMID- 17710676 TI - Importance of cytokines, oxidative stress and expression of BCL-2 in the pathogenesis of non-alcoholic steatohepatitis. AB - OBJECTIVE: Non-alcoholic steatohepatitis (NASH) is a form of chronic hepatitis. The pathogenesis of NASH has been dealt with in only a few studies and so it has not been clearly identified yet. The purpose of this study was to investigate the roles of TNF-alpha, TGF-beta, IL-6, IL-8, malondialdehyde (MDA), nitric oxide (NO) and the expression of Bcl-2 and Bax in the pathogenesis of NASH. MATERIAL AND METHODS: The study included 92 patients, 57 of whom were diagnosed with biopsy-proven NASH, 13 with biopsy-proven hepatosteatosis and 22 with ultrasonography-diagnosed hepatosteatosis. Serum levels of TNF-alpha, TGF-beta, IL-6 and IL-8 were measured using the ELISA method. The plasma levels of NO were studied using the Griess method. Expressions of Bcl-2 and Bax were examined in paraffin blocks of liver biopsy materials by means of immunohistochemical staining. MDA levels were measured using the thiobarbituric acid method. RESULTS: No significant difference was found in the levels of TNF-alpha, TGF-beta, IL-6 or NO between the three groups (p>0.05). No difference was found in expression of Bcl-2 and expression of Bax between the biopsy-proven NASH and biopsy-proven hepatosteatosis groups (p>0.05). In the NASH group, the levels of IL-8 and MDA were found to be higher than those in the hepatosteatosis groups (p<0.05). CONCLUSIONS: The elevated levels of MDA may indicate the relationship between oxidative stress and NASH. Furthermore, IL-8 was found to be higher in the NASH group than in the hepatosteatosis group, demonstrating the importance of inflammation in the pathogenesis of NASH. PMID- 17710678 TI - Impact of observer variability on the usefulness of endoscopic images for the documentation of upper gastrointestinal endoscopy. AB - OBJECTIVE: Endoscopy is an observer-dependent diagnostic method, which, until recently, has lacked precise guidelines for written reports. There is an increasing demand for improvement in endoscopy records, which may necessitate the supplementation of image documentation. The aim of this study was to estimate interobserver as well as intra-observer variability in the assessment of images from gastroscopy. MATERIAL AND METHODS: We designed an Internet interface presenting endoscopy images, accompanied by a multiple-choice questionnaire for assessing pathology in the images. Ten images from the distal oesophagus and 10 images from the pyloric antrum were chosen. In order to study interobserver variability, physicians with varying endoscopy experience were invited to complete the questionnaire. The physicians were re-invited 5 months later to assess the same images again, this time in order to assess intra-observer variability. Kappa statistics were used for analysis of agreement. RESULTS: Initially, 13 of 20 invited physicians responded. Interobserver agreement varied between poor (kappa<0.2) and moderate (0.4 4 MOM) at mid gestation, and the control group comprised 75 randomly selected women with normal hCG levels (as well as normal alpha-fetoprotein and unconjugated estriol levels). In addition to demographic information, we collected data on fetal anomalies, chromosomal aberrations, pregnancy complications, and results of neonatal tests. RESULTS: There was a significant increase in the frequency of fetal anomalies (detected by ultrasound), low birth weight and neonatal complications in the study group. We also found an increased rate of fetal/neonatal loss proportional to the increasing levels of hCG (up to 30% in levels exceeding 7 MOM). CONCLUSION: Our study demonstrated an increased frequency of obstetric complications that was closely associated with high hCG levels. The study also raises questions about the accuracy of the Down syndrome probability equation in the presence of extremely high levels of hCG where data on the frequency of Down syndrome are severely limited. PMID- 17710781 TI - A combined approach to the molecular analysis of cystinuria: from urinalysis to sequencing via genotyping. AB - BACKGROUND: Cystinuria is an autosomal recessive disease that is manifested by kidney stones and is caused by mutations in two genes: SLC3AI on chromosome 2p and SLC7A9 on chromosome 19q. Urinary cystine levels in obligate carriers are often, but not always, helpful in identifying the causative gene. OBJECTIVES: To characterize the clinical features and analyze the genetic basis of cystinuria in an inbred Moslem Arab Israeli family. METHODS: Family members were evaluated for urinary cystine and amino acid levels. DNA was initially analyzed with polymorphic markers close to the two genes and SLC7A9 was fully sequenced. RESULTS: Full segregation was found with the marker close to SLC7A9. Sequencing of this gene revealed a missense mutation, P482L, in the homozygous state in all three affected sibs. CONCLUSIONS: A combination of urinary cystine levels in obligate carriers, segregation analysis with polymorphic markers, and sequencing can save time and resources in the search for cystinuria mutations. PMID- 17710782 TI - Chlamydia pneumoniae antibody titers and cardiac calcifications: a cross sectional serological-echocardiographic correlative study. AB - BACKGROUND: Chlamydia pneumoniae has previously been associated with higher prevalence of valvular and cardiac calcifications. OBJECTIVES: To investigate a possible association of seropositivity for C. pneumoniae and the presence of cardiac calcifications (mitral annular or aortic root calcification, and aortic valve sclerosis). METHODS: We retrospectively analyzed serological data (immunoglobulin G TWAR antibodies) from the AZACS trial (Azithromycin in Acute Coronary Syndromes), and correlated the serological findings according to titer levels with the presence of cardiac calcifications as detected by transthoracic echocardiography. RESULTS: In 271 patients, age 69 +/- 13 years, who underwent both serological and echocardiographic evaluation, we found no significant association between the "calcification sum score" (on a scale of 0-3) in seropositive compared to seronegative patients (1.56 +/- 1.15 vs.1.35 +/- 1.15, respectively, P = 0.26). The median calcification sum score was 1 (interquartile range 0-3) for the seronegative group, and 2 (interquartile range 0-3) for the seropositive group (P = 0.2757). In addition, we did not find a significant correlation of any of the individual sites of cardiac calcification and C. pneumoniae seropositivity. CONCLUSION: Our findings suggest that past C. pneumoniae infection may not be associated with the pathogenesis of valvular and cardiac calcifications. PMID- 17710783 TI - The association between anemia in infants, and maternal knowledge and adherence to iron supplementation in southern Israel. AB - BACKGROUND: Iron deficiency is the most prevalent anemia in infants and is known to be a major public health problem. OBJECTIVE: To examine mothers' knowledge and adherence with recommendations regarding iron supplementation and assess their association with the prevalence of anemia in infants. METHODS: Data on 101 infants and mothers of infants born between November 2000 and February 2001 and living in a small Jewish town in southern Israel were collected using a structured questionnaire and the infants' medical charts. Anemia was defined as serum hemoglobin less than 11 g/dl. Independent variables include socioeconomic data, mothers' knowledge, and adherence to treatment as reported by them. Chi square test was used to analyze categorical variables, t-test was used for continuous variables, and hemoglobin was tested at 9-12 months of age. RESULTS: Of the 101 infants in the study, 47% had serum hemoglobin under 11 g/dl. Of the mothers, 62 (62%) were partially or completely non-compliant with iron supplementation; 34 (34%) had low level of knowledge regarding anemia. Multivariate logistic regression analysis revealed a significant and inverse relationship between the presence of anemia and the level of maternal knowledge (odds ratio = 5.6, 95% confidence interval 1.6-9.7; P = 0.006) and reported adherence with iron supplementation (3.2, 1.1-9.7; P = 0.04) after controlling for confounding factors: maternal education, socioeconomic status, breastfeeding, and meat consumption. CONCLUSIONS: The presence of iron deficiency anemia in infants in southern Israel is inversely affected by the level of maternal knowledge of anemia and adherence to iron supplementation. Low level of knowledge is also directly related to low adherence. PMID- 17710784 TI - Obesity among Arabs and Jews in Israel: a population-based study. AB - BACKGROUND: Arabs in Israel have high morbidity and mortality from diabetes and cardiovascular disease. Obesity is a risk factor for both conditions. OBJECTIVES: To investigate the prevalence of obesity (body mass index >30 kg/m2), subjects' knowledge and behaviors, and their reports on practices of health-care professionals regarding body weight among Arabs and Jews. METHODS: The study participants (n=880) were randomly sampled from the urban population of the Hadera district in Israel. Data on demographic, socioeconomic and lifestyle characteristics; reports on height, current body weight and body weight at the age of 18 years; knowledge and behavior; and health-care professionals' practices with regard to body weight were obtained by interview. Anthropometric measurements were performed subsequently. RESULTS: Information on BMI was available on 868 participants (49% Arabs, 49% women, median age 46 years). Although the median BMI did not differ significantly between Arabs and Jews at age 18, the prevalence of current obesity was 52% in Arab women compared to 31% in Jewish women (P < 0.001), and 25% in Arab men compared to 23% in Jewish men (P = 0.6). On multivariate analysis, obesity was significantly associated with age, BMI at the age of 18 years, leisure time physical activity and cigarette smoking, but not with ethnicity. Fewer Arabs reported measuring their body weight and Arab women were less frequently advised to maintain an active lifestyle. CONCLUSIONS: The high prevalence of obesity among Arab women may be explained by lifestyle characteristics. Prevention of obesity in Arabs should be directed at women and should start preferably before adulthood. PMID- 17710785 TI - Outcome of head and other injuries among Israeli children: physical limitations and stress symptoms. AB - BACKGROUND: Head injuries, especially in young children, are frequent and may cause long-lasting impairments. OBJECTIVES: To investigate the outcome of head and other injuries caused by diverse mechanisms and of varied severity. METHODS: The study population consisted of Jews and Arabs (n=792), aged 0-17 years old, hospitalized for injuries in six hospitals in Israel. Caregivers were interviewed during hospitalization regarding circumstances of the injury and sociodemographic variables. Information on injury mechanism, profile and severity, and length of hospitalization was gathered from the medical files. Five months post-injury the caregivers were interviewed by phone regarding physical limitations and stress symptoms. RESULTS: Head injuries occurred in 60% of the children, and of these, 22.2% suffered traumatic brain injury with loss of consciousness (type 1). Among the rest, 22% of Jewish children and 28% of Arab children remained with at least one activity limitation, and no statistically significant differences were found among those with head or other injuries. The odds ratio for at least two stress symptoms was higher for children involved in transport-related injuries (OR 2.70, 95% confidence interval 1.38-5.28) than for other mechanisms, controlling for injury profile. No association was found between stress symptoms and injury severity. CONCLUSIONS: Most children had recovered by 5 months after the injury. Residual activity limitations were no different between those with head or with other injuries. Stress symptoms were related to transport-related injuries, but not to the presence of TBI or injury severity. PMID- 17710786 TI - The use of prednisone in the treatment of trichinellosis. AB - BACKGROUND: It is not entirely clear when and how steroids should be used to treat trichinellosis. OBJECTIVES: To describe the course of consecutive patients with trichinellosis treated with antihelminthic drugs with and without the addition of prednisone. METHODS: We extracted data from the hospital records of 30 patients hospitalized for trichinellosis contracted after eating poorly cooked pork that came from two wild pigs killed in the Golan Heights, and contacted them for follow-up 5-6 weeks and 6 months after hospital discharge. RESULTS: All the patients who attended a party and ingested the infected pork (100% attack rate) were hospitalized after 2-16 days (median 9 days); 29 were symptomatic and 1 patient without symptoms had creatine phosphokinase levels 17.9 times above the upper limit of normal. Twelve of 23 patients (52%) treated with antihelminthic drugs without prednisone were rehospitalized with worsening fever, increased peripheral blood eosinophil counts, but decreasing CPK values. These patients and another seven at the time of admission were treated with prednisone 40 mg/day for 5 days in addition to antihelminthic drugs for at least 14 days. All became asymptomatic within 24 hours and were asymptomatic 6 weeks and 6 months later. CONCLUSIONS: Worsening symptoms in patients treated with antihelminthic drugs alone is common. A short course of prednisone is safe and alleviates symptoms due to tissue larvae in patients with trichinellosis. PMID- 17710787 TI - Current concepts in the follow-up of patients with differentiated thyroid cancer. PMID- 17710788 TI - The human papillomavirus vaccine and its relevance in Israel. PMID- 17710789 TI - The dying patient act, 2005: Israeli innovative legislation. AB - The new Israeli Dying Patient Act is based on principles and processes that have achieved a wide consensus despite the fact that it is a very complex and emotionally loaded issue. It provides clear balancing approaches between opposing values as well as explicit mechanisms for issues that were previously not provided for in Israel or were unclear. These include mechanisms for providing autonomous patient decision making when incompetent in "real time", with legally binding advance medical directives. These include methods of verifying the real and informed wishes of the patient or the appointment of a surrogate decision maker, a national registry of advance medical directives to optimize the validity of these wishes, legally binding palliative care as a citizen's right, clear guidelines for physicians to know what is permitted and what is not in treating terminally ill patients, the appointment of a senior physician with clear directives of his or her responsibilities toward the dying patient, and dispute resolution including the innovative establishment of a National Ethics Committee composed of experts in all relevant fields. PMID- 17710790 TI - Intravenous immunoglobulin in pregnancy: a chance for patients with an autoimmune disease. PMID- 17710791 TI - Treatment of antiphospholipid syndrome in pregnancy with low doses of intravenous immunoglobulin. PMID- 17710792 TI - Hyperammonemic encephalopathy in multiple myeloma. PMID- 17710793 TI - Mycobacterial disease in a child with surface-expressed non-functional interleukin-12Rbeta1 chains. PMID- 17710794 TI - Chronic myeloid leukemia evolving after idiopathic myelofibrosis. PMID- 17710795 TI - Hyponatremia induced by amiodarone therapy. PMID- 17710797 TI - The TCM kidney-nourishing method for protection of brain in patients with diabetic encephalopathy. PMID- 17710796 TI - Imaging of oncogenic osteomalacia. PMID- 17710798 TI - Clinical research on acupuncture and moxibustion treatment of chronic atrophic gastritis. AB - OBJECTIVE: To observe the clinical therapeutic effects of acupuncture and moxibustion in treating chronic atrophic gastritis. METHODS: Patients who met the criteria were randomly divided into the treatment groups consisting of the acupuncture group (30 cases) and the acupuncture-moxibustion group (30 cases), and the control group (28 cases). After two months of treatment, observed were safety and the curative effects, through general physical check ups, routine examinations of blood, urine and feces, and symptoms, pathology and gastrin before, during and after the treatment. RESULTS: (1) The treatment groups showed significant superiorities in the improvement of symptoms, with the acupuncture moxibustion group showing the best therapeutic effects. (2) The acupuncture moxibustion group showed marked differences before and after the treatment in the improvement of glandular atrophy and intestinal metaplasia, with a total effective rate of 66.67%. (3) After the treatment, the three groups all showed marked improvement in the level of serum gastrin, with the acupuncture moxibustion group showing the best effects. CONCLUSION: Acupuncture and moxibustion have definite therapeutic effects for chronic atrophic gastritis, especially in improving the symptoms. Acupuncture or acupuncture combined with moxibustion can provide possibilities in reversing the pathologic changes of glandular atrophy and intestinal metaplasia for patients with chronic atrophic gastritis. Acupuncture-moxibustion is really an effective and safe therapy for chronic atrophic gastritis. PMID- 17710799 TI - Chronic fatigue syndrome treated by acupuncture and moxibustion in combination with psychological approaches in 310 cases. AB - OBJECTIVE: To observe clinical therapeutic effect of acupuncture and moxibustion combined with a psychological approach on chronic fatigue syndrome (CFS). METHODS: The treatment was given by acupuncture plus moxibustion combined with a psychological approach based on differentiation of symptoms and signs in 310 cases. RESULTS: Of 310 cases observed, 275 cases (88.7%) were clinically cured, 28 cases (9%) improved, and 7 cases (2.3%) failed. CONCLUSION: Acupuncture plus moxibustion combined with a psychological approach is an effective therapy for CFS. PMID- 17710801 TI - Clinical observation on 30 cases of transient cerebral ischemia attack treated with acupuncture and medication. AB - OBJECTIVE: To probe the curative effect of acupuncture and medication on transient cerebral ischemia attack. METHOD: 30 patients with transient cerebral ischemia attack in the treatment group were acupunctured at Fengchi (GB 20), Wangu (GB 12) and Tianzhu (BL 10) and given orally leech capsules and centipede capsules. 30 patients with transient cerebral ischemia attack in the control group were given intravenous drip of compound Danshen injection and orally aspirin. At the end of two treatment courses, the curative effects were evaluated and the changes in blood rheology and in 3 indexes of blood coagulation were observed before and after treatment in the 2 groups. RESULTS: The total effective rate in the treatment group was 86.7% with obvious difference as compared to the control group (P < 0.05). There were remarkable differences in blood rheology and 3 indexes of blood coagulation before and after treatment in the treatment group (P < 0.05, P < 0.01). There were remarkable differences after treatment between the 2 groups (P < 0.05). CONCLUSION: Acupuncture at Fengchi (GB 20), Wangu (GB 12) and Tianzhu (BL 10) and medication with leech capsules and centipede capsules are effective methods in treating transient cerebral ischemia attack. PMID- 17710800 TI - Effects of yixin jiangya capsules on insulin resistance and timor necrosis factor alpha in cases of primary hypertension with left ventricular hypertrophy. AB - OBJECTIVES: To observe the effects of yixin jiangya Capsules ([Chinese characters: see text] capsules for nourishing the heart and lowering blood pressure) on insulin resistance (IR) and tumor necrosis factor-alpha (TNF-alpha) in patients with primary hypertension with left ventricular hypertrophy (LVH). METHODS: Totally 93 cases were randomly divided into a control group of 31 cases taking Enalapril and a treatment group of 62 cases taking Enalapril and yixin jiangya Capsules. RESULTS: Fasting serum insulin (FSI) and TNF-alpha obviously increased and insulin sensitive index (ISI) significantly decreased in both groups before treatment as compared to those of a healthy group. After treatment, FSI, TNF-alpha and fasting blood glucose (FBG) obviously decreased and ISI remarkably increased in the treatment group, while ISI significantly increased and TNF-alpha obviously decreased in the control group. The curative effect in the treatment group was remarkably superior to that in the control group. FSI was positively related to TNF-a before treatment in both groups. CONCLUSION: FSI and TNF-alpha obviously increase and ISI significantly decreases in patients with primary hypertension with LVH. FSI and TNF-alpha influencing each other are involved in the generation and development of hypertension. Yixin jiangya Capsules can improve IR and decrease TNF-alpha. PMID- 17710802 TI - The role of different therapeutic courses in treating 47 cases of rheumatoid arthritis with acupuncture. AB - OBJECTIVE: To observe the effect of acupuncture therapeutic courses on rheumatoid arthritis. METHOD: Forty-seven patients were treated with acupuncture for 6 courses and at the end of the third and sixth course of treatment, the therapeutic effects of acupuncture on morning rigidity, swelling and pain of joints as well as rheumatoid factor (RF), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were observed. RESULT: At the end of the third course, the markedly effective rate was 34.0% for morning rigidity, 9.5% for swelling and 23.4% for pain, the RF negative-turning rate was 2.2%, and there was no significant difference (P > 0.05) in the reduction of ESR and CRP as compared to that before treatment. However, at the end of the sixth course, the markedly effective rate was 80.9% for morning rigidity, 64.3% for swelling and 87.2% for pain, the RF negative-turning rate was 26.7%, and there was a very significant difference (P < 0.01) in the reduction of ESR and CRP as compared to that before treatment. CONCLUSION: More acupuncture therapeutic courses can bring about better therapeutic results on rheumatoid arthritis. PMID- 17710803 TI - Forty cases of insomnia treated by multi-output electric pulsation and auricular plaster therapy. PMID- 17710804 TI - Clinical observation on electroacupuncture treatment of 30 cases of chronic hepatitis B. AB - OBJECTIVE: To probe into the methods and therapeutic effects of electroacupuncture (EA) on hepatitis B. METHODS: 60 hospitalized cases of mild or moderate hepatitis B were randomly divided into a treatment group (30 cases) and a control group (30 cases). EA was applied at the points selected according to the differentiation of symptoms and signs. The treatment was given once daily for 30 minutes, and 2 weeks of treatments constituted a therapeutic course, with 2-3 courses on average in the treatment group. Conventional treatment for liver protection was given in the control group. RESULTS: As compared with the control group, the duration of the treatment for recovery of the hepatic functions was significantly shorter, and the IL-8 level significantly lower in the treatment group. CONCLUSION: In treating hepatitis B, EA is effective in improving symptoms, recovering hepatic functions, and regulating immune functions to certain extent. PMID- 17710805 TI - Adolescent spasmodic torticollis treated by moxibustion--a report on 30 cases. PMID- 17710806 TI - The clustered needling, massage and cupping used for treatment of obstinate myofascitis of the back--a report of 68 cases. AB - The clustered needling, massage and cupping have been used together for treatment of myofascitis of the back with good therapeutic results through the joint effects of removing blood stasis, promoting blood circulation, dredging the channels, promoting themetabolism and the repair of the tissues, impairing and relaxing the affected muscles. PMID- 17710807 TI - Clinical experience in TCM differential treatment of fatty liver. PMID- 17710808 TI - Application of wind-expelling drugs in treatment of splenopathy and gastropathy. PMID- 17710809 TI - Treatment of male infertility. PMID- 17710810 TI - Dr. Long Wenjun's experience in auriculo-acupuncture. PMID- 17710811 TI - Experience of Dr. Ding Guangdi in treating chronic enteritis. PMID- 17710812 TI - Dr. Yu Wenqiu's experience in treating seborrheic alopecia. PMID- 17710813 TI - Experience of Dr. Zhu Peiting in treating cholelithiasis from the aspect of the liver. PMID- 17710814 TI - Effect of Xiaobailing decoction on melanocytes in vitro. AB - OBJECTIVE: To observe the effect of xiaobailing decoction ([Chinese characters: see text) on murine melanocytes in vitro and to explore the mechanism of xiaobailing Decoction in the treatment of vitiligo. METHODS: B-16F10 murine melanoma cells were cultured in 1640 medium and treated respectively with different concentrations (1 mg/ml, 2 mg/ml, 3 mg/ml) of the Chinese drug xiaobailing Decoction and its main components, the drugs for replenishing the kidney-yang, and the drugs for nourishing blood and activating blood circulation, etc. for 7 days. MMT assay was used to determine the proliferation of B-16F10 murine melanoma cells. NaOH cleavage assay was adopted to measure the melanogenesis of melanocytes. RESULTS: xiaobailing Decoction, the drugs for replenishing the kidney-yang and the drugs for nourishing blood and activating blood circulation at different concentrations significantly improved the proliferation of B-16F10 murine melanoma cells from the 3rd day to the 5th day (P < 0.05), with xiaobailing Decoction at the concentrations of 1 mg/ml having the most distinct action on promoting the proliferation of melanocytes on the 3rd day (P < 0.001); And the drugs for replenishing the kidney-yang at the concentrations of 2 mg/ml and 3 mg/ml and the drugs for nourishing blood and activating blood circulation at 3 mg/ml significantly increased melanogenesis of melanocytes (P < 0.05). CONCLUSION: Xiaobailing Decoction can promote melanocytic proliferation and melanogenesis in vitro, and it is indicated that the drugs for replenishing the kidney-yang and the drugs for nourishing blood and activating blood circulation play an important role in treating vitiligo. PMID- 17710815 TI - Effects of weiganli on the hemopoietic function of the myelosuppressed anemic mice. AB - OBJECTIVE: To study the effect of weiganli ([Chinese characters: see text]) on bone marrow hemopoiesis. METHODS: The effects of weiganli on the peripheral blood picture and the number of bone marrow nucleated cells (BMCs) were observed in myelosuppressed anemic model mice, and the effects of weiganli on the growth of colony forming unit-granulocyte macrophage (CFU-GM), colony forming unit erythroid (CFU-E), burst forming unit-erythroid (BFU-E), colony forming unit megkaryocyte (CFU-Meg) were investigated by in vitro cell culture technique. The hemopoietic stem cells (HSCs, c-kit+) in bone marrow were double stained with fluorescent antibody PE-C-Kit and FITC-CD45, and the HSCs (c-kit+) were counted by flow cytometer with CD45/SSC (side scatter) gating. RESULTS: Peripheral blood cell counts and the number of BMCs were significantly improved after weiganli administration; and bone marrow hemopoietic stem/progenitor cells were significantly increased. CONCLUSION: Weiganli can effectively promote the recovery of hemopoietic function in the myelosuppressed anemic mice. PMID- 17710816 TI - Study on relationship between the thickness of tongue fur and the expressions of apoptosis-related genes of the tongue epithelial cells in patients with diseases of the digestive system. AB - To investigate the relationship between the thickness of tongue fur, apoptosis of the tongue fur epithelial cells and expressions of apoptosis-related genes in diseases of the digestive system, apoptosis-related genes TGF-beta3, fas mRNA and protein products were detected with terminal deoxynucleotidyl transferase mediated deoxyurine triphosphate (d-UTP) nick-end labeling (TUNEL) technique, in situ hybridization, immunohistochemical methods, and image analysis technique, respectively. Results indicated that compared with the normal tongue fur, over expression of fas gene was found in the peeling fur with an increase in cell apoptosis, while a low-expression of TGF-beta3 in the thick fur with a decrease in cell apoptosis. The changes in expression levels of fas and TGF-beta3 genes, apoptosis-promoting genes in the tongue fur epithelial cells, had a similar tendency of cell apoptosis level. It is concluded that the changes in expression levels of fas and TGF-beta3 are possibly important reasons influencing apoptosis of epithelial cells of tongue fur and leading to changes in thickness of the tongue fur. PMID- 17710817 TI - A survey on acupuncture for giving up heroin and treatment of the withdrawal syndrome. AB - This paper summarizes the study of acupuncture for giving up heroin and treatment of withdrawal syndrome in China from 1995 to 2003, which includes the selection of acupoints, the evaluation of the therapeutic effects, studies of acupoints and application of relevant instruments, as well as treatment of the withdrawal syndromes of heroin with acupuncture. The therapeutic effect of acupuncture and moxibustion is definite and indispensable, especially at the time when there is no specific remedy for heroin addition. PMID- 17710818 TI - On the natural medical features of traditional Chinese medicine. AB - Heaven-human-earth Pattern (HHE) regarded as a crucial conception of traditional Chinese medicine (TCM) has been applied extensively in TCM diagnostics, etiology, acupuncture therapeutics, materia medica and herbal formula, etc. It associates closely with Chinese classic cosmology. Since ancient time of China, many cosmic phenomena have been introduced to prove or illustrate TCM theories. Moreover, the five-element theory has been proven to be in keeping with some modern approaches of life provenance and life evolution. As a result, Chinese materia medica develops in a way of a pure natural medicine. It is of great significance that by realizing the natural features, the public nowadays can understand TCM better in its scientific connotations. PMID- 17710819 TI - Selective developmental neuropsychological disorders. PMID- 17710820 TI - Tracing syndrome-specific trajectories of attention across the lifespan. AB - This paper maintains that studies of atypical attention targeting one particular age group are unlikely to be informative of syndrome-specific deficits and their developmental changes. We propose a new approach to the study of attentional deficits in genetic disorders, arguing for tracing cross-syndrome developmental trajectories from infancy through childhood to adulthood. Few studies have incorporated a developmental approach to determine whether the pattern of deficits and proficiencies remains constant across developmental time. Fewer still have included a cross-syndrome perspective to address these issues. Focusing on the cognitive domain of attention and its component parts, and using a cross-syndrome developmental perspective, the present set of studies compared the trajectories of different aspects of attention in three developmental disorders: Fragile X syndrome (FXS), Down syndrome (DS) and Williams syndrome (WS). Hitherto, these syndromes have all been reported as displaying serious "attentional deficits" above those expected in the general population. We predicted that, when one considers in greater detail subcomponent processes of attention, then ostensibly common difficulties do not necessarily emerge from common developmental pathways. We addressed this question with two studies. The first focused on inhibitory control, orienting and selective attention in infants and toddlers, and the second concentrated on selective attention, sustained attention and inhibitory control in mid-late childhood. The current results and their integration with earlier findings in adults point both to commonalities and to important syndrome-specific differences in attentional component processes, questioning whether profiles remain constant across developmental time. PMID- 17710821 TI - Heterogeneity in the patterns of neural abnormality in autistic spectrum disorders: evidence from ERP and MRI. AB - Autistic spectrum disorder (ASD) refers to a heterogeneous group of social communication problems. Research into the neural basis of ASD has revealed abnormalities in a number of different regions of the brain. However, the literature is highly inconsistent. One possible explanation for these discrepancies is differences in intelligence. Children with ASD and below average intelligence may be hypothesised to show additional or different neural abnormalities. This possibility was explored using structural magnetic resonance imaging (MRI) and event-related potentials (ERP). Two groups of children with ASD were studied, those with average or above average intelligence (high ASD group) and those with below average intelligence (low ASD group). The structural MRI data were analysed using voxel-based morphometry (VBM). Using the family-wise error threshold, results showed bilateral abnormality common to the two ASD groups in the cerebellum, fusiform gyrus and frontal cortex. In addition, a number of regions were found to be significantly different in the two ASD groups: regions of the cerebellum showed increased grey matter density bilaterally in the high ASD group, but decreased grey matter density bilaterally in the low ASD group. Further, compared to the high ASD group, additional bilateral abnormalities were found in the postcentral gyrus and regions of the dorsolateral prefrontal cortex in the low ASD group. Using the less stringent false discovery rate (FDR) threshold, differences were also seen in the medial temporal lobes. ERPs also showed differences between the two ASD groups. Whereas the ERPs of the high ASD group were not significantly different from those of the controls, the low ASD group had delayed novelty P3a responses and reduced amplitude target P3b components. These data provide convergent ERP and MRI evidence for the heterogeneity of neural abnormality in ASD in relation to variations in intelligence. PMID- 17710822 TI - ADHD and dysgraphia: underlying mechanisms. AB - Multiple complaints in the domain of writing are common among children with Attention Deficit Hyperactivity Disorder (ADHD). In this work we sought to characterize the writing disorder by studying dysgraphia in twenty 6th grade boys with ADHD and normal reading skills matched to 20 healthy boys who served as a comparison group. Dysgraphia, defined as deficits in spelling and handwriting, was assessed according to neuropsychological explanatory processes within 3 primary domains: linguistic processing, motor programming and motor kinematics. Children with ADHD made significantly more spelling errors, but showed a unique pattern introducing letter insertions, substitutions, transpositions and omissions. This error type, also known as graphemic buffer errors, can be explained by impaired attention aspects needed for motor planning. Kinematic manifestations of writing deficits were fast, inaccurate and an inefficient written product accompanied by higher levels of axial pen pressure. These results suggest that the spelling errors and writing deficits seen in children with ADHD and normal reading skills stem primarily from non-linguistic deficits, while linguistic factors play a secondary role. Recommendations for remediation include educational interventions, use of word processing and judicious use of psychostimulants. PMID- 17710823 TI - How common are symptoms of ADHD in typically developing preschoolers? A study on prevalence rates and prenatal/demographic risk factors. AB - According to the Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV - American Psychiatric Association, 1994), one of the diagnostic criteria for attention deficit hyperactivity disorder (ADHD) is the presence of symptoms of inattention and/or hyperactivity-impulsivity before the age of 7 years. In contrast to studies with older children, relatively little is known about ADHD symptoms in preschoolers. In order to address this issue, the present study was designed to investigate to what extent ADHD behaviors exist in a large community based group of preschoolers in the Netherlands. A second aim of this study was to shed light on the etiology of ADHD, by examining if and how a range of prenatal and demographic factors contribute to the prediction of ADHD behaviors in young children. Participants included 652 parents of children between the ages of 3 and 6 years. Parents were asked to complete two questionnaires: the Preschool Behavior Questionnaire (Smidts and Oosterlaan, 2005) and a background information questionnaire, specifically designed for this study. Findings from the present study show that ADHD symptoms are quite common in preschoolers, with approximately one-third of all ADHD behaviors listed in the Preschool Behavior Questionnaire being highly frequent in early childhood. It appears that hyperactive-impulsive symptoms are more common in preschoolers than inattentive behavior. For the purpose of an early identification of ADHD, this finding is particularly important, as it may be argued that inattentive behavior in preschoolers may be indicative of psychopathology. Significant predictors of ADHD behaviors included maternal smoking and alcohol, and illness of the mother during pregnancy; however, together these factors explained less than 10% of the variance. PMID- 17710825 TI - Hereditary prosopagnosia: the first case series. AB - Prosopagnosia is defined as a specific type of visual agnosia characterised by a discernible impairment in the capacity to recognise familiar people by their faces. We present seven family pedigrees with 38 cases in two to four generations of suspected hereditary prosopagnosia, detected using a screening questionnaire. Men and women are impaired and the anomaly is regularly transmitted from generation to generation in all pedigrees studied. Segregation is best explained by a simple autosomal dominant mode of inheritance, suggesting that loss of human face recognition can occur by the mutation of a single gene. Eight of the 38 affected persons were tested on the Warrington Recognition Memory Test for Faces (RMF; Warrington, 1984), famous and family faces tests, learning tests for internal and external facial features and a measure of mental imagery for face and non-face images. As a group, the eight participants scored significantly below an age- and education-matched comparison group on the most relevant test of face recognition; and all were impaired on at least one of the tests. The results provide compelling evidence for significant genetic contribution to face recognition skills and contribute to the promise offered by the emerging field of cognitive neurogenetics. PMID- 17710824 TI - Prosopagnosia without apparent cause: overview and diagnosis of six cases. AB - We compared six cases of congenital prosopagnosia to unimpaired participants using standardized test batteries, tailor-made experimental paradigms, and clinical questionnaires. Every prosopagnosic participant displayed deficits in recognizing famous faces and retaining novel faces over short periods of time. Other aspects of face perception such as judgment of emotional expression, speech reading and memory for faces and names were impaired to a lesser degree or only in single cases. No evidence was found for general visual deficits or social dysfunctions. Two of our six cases are first order relatives, and a further three report first-order relatives suffering from prosopagnosic symptoms. The results are in line with the idea of a genetic component to congenital prosopagnosia. PMID- 17710826 TI - Developmental colour agnosia. AB - Colour agnosia concerns the inability to recognise colours despite intact colour perception, semantic memory for colour information, and colour naming. Patients with selective colour agnosia have been described and the deficit is associated with left hemisphere damage. Here we report a case study of a 43-year-old man who was referred to us with a stroke in his right cerebellar hemisphere. During the standard assessment it transpired that he was unable to name coloured patches. Detailed assessment of his colour processing showed that he suffers from a selective colour agnosia. As he claimed to have had this problem all his life, and the fact that the infratentorial infarct that he had incurred was in an area far away from the brain structures that are known to be involved in colour processing, we suggest that he is the first reported case of developmental colour agnosia. PMID- 17710827 TI - Typical and atypical development of visual estimation abilities. AB - Despite the fact that developmental impairments of number skills are common, they remain sparsely investigated. We explored low-level numerical representations and their developmental trajectory in a developmental disorder, Williams syndrome (WS). Groups of WS and typically developing (TD) individuals estimated rapidly presented arrays of 5, 7, 9, and 11 dots. In comparison to the normal developmental trajectory, the ontogenesis of estimation skills in WS is both delayed and deviant. Whereas TD children's estimations became significantly more accurate and less variable over developmental time, only marginal developmental changes in estimation ability emerged across age in the WS groups. Our data highlight the importance of considering developmental changes in low-level components of numerical cognition in atypical development while at the same time emphasizing the importance of paying closer attention to quantitative changes and their functional role in typical development. PMID- 17710828 TI - Non-word repetition in children with specific language impairment: a deficit in phonological working memory or in long-term verbal knowledge? AB - In this study we investigated the effects of long-term memory (LTM) verbal knowledge on short-term memory (STM) verbal recall in a sample of Italian children affected by different subtypes of specific language impairment (SLI). The aim of the study was to evaluate if phonological working memory (PWM) abilities of SLI children can be supported by LTM linguistic representations and if PWM performances can be differently affected in the various subtypes of SLI. We tested a sample of 54 children affected by Mixed Receptive-Expressive (RE), Expressive (Ex) and Phonological (Ph) SLI (DSM-IV - American Psychiatric Association, 1994) by means of a repetition task of words (W) and non-words (NW) differing in morphemic structure [morphological non-words (MNW), consisting of combinations of roots and affixes - and simple non-words - with no morphological constituency]. We evaluated the effects of lexical and morpho-lexical LTM representations on STM recall by comparing the repetition accuracy across the three types of stimuli. Results indicated that although SLI children, as a group, showed lower repetition scores than controls, their performance was affected similarly to controls by the type of stimulus and the experimental manipulation of the non-words (better repetition of W than MNW and NW, and of MNW than NW), confirming the recourse to LTM verbal representations to support STM recall. The influence of LTM verbal knowledge on STM recall in SLI improved with age and did not differ among the three types of SLI. However, the three types of SLI differed in the accuracy of their repetition performances (PMW abilities), with the Phonological group showing the best scores. The implications for SLI theory and practice are discussed. PMID- 17710829 TI - Brain structure correlates of component reading processes: implications for reading disability. AB - Brain structures implicated in developmental dyslexia (reading disability - RD) vary greatly across structural magnetic resonance imaging (MRI) studies due to methodological differences regarding the definition of RD and the exact measurements of a specific brain structure. The current study attempts to resolve some of those methodological concerns by examining brain volume as it relates to components of proposed RD subtypes. We performed individual regression analyses on total cerebral volume, neocortical volume, subcortical volume, 9 neo-cortical structures and 2 sub-cortical structures. These analyses used three dimensions of reading, phonemic ability (PA), orthographic ability, and rapid naming (RN) ability, while accounting for total cerebral volume, age, and performance IQ (PIQ). Primary analyses included membership to a group (poor reader vs. good reader) in the analysis. The result was a significant interaction between PA and reading ability as it predicts total cerebral volume. Analyses revealed that poor readers lacked a relationship between PA and brain size, but that good readers had a significant positive relationship. This pattern of interaction was not present for the other two reading component factors. These findings bring into question the general belief that individuals with RD are at the low end of a reading ability distribution and do not have a unique disorder. Additional analyses revealed only a few significant relationships between brain size and task performance, most notably a positive correlation between orthographic ability and the angular gyrus (AG), as well as a negative correlation between RN ability and the parietal operculum (PO). PMID- 17710830 TI - Executive function following focal frontal lobe lesions: impact of timing of lesion on outcome. AB - While it is generally agreed that outcome following cerebral insult during childhood differs from that seen following similar pathology in adulthood, the specific relationship between timing of cerebral lesion and outcome, and the mechanism associated with observed neurobehavioral changes, remains controversial. Data from children with focal lesions suggests a non-linear relationship between age at injury and language function (e.g., Bates et al., 1999). With respect to executive function, animal models also demonstrate a non linear relationship, and suggest that outcome is tightly linked to underlying neuronal changes (e.g., Kolb et al., 2000). Whether these models easily translate to humans, where brain morphology, cognitive function and environmental influences are more complex, is not clear. To date, focal lesion research in children has been restricted to individual case studies or, to samples of children with lesions to regions subsuming language function, or those who have undergone hemispherectomy for the treatment of intractable epilepsy. This study aimed to build on current knowledge, investigating executive function in 38 children with focal lesions involving prefrontal cortex. Aetiology and timing of lesions was diverse. Results are consistent with animal research suggesting a non linear relationship between age at injury and outcome, with "critical periods" during development when the frontal lobes are particularly vulnerable to insult, and others when outcome is more optimal. Our findings indicate that children with prenatal lesions are at greatest risk of neurobehavioral deficits. Children with lesions sustained in middle childhood demonstrate least severe impairments across executive domains, possibly due to a period of peak synaptogenesis and dendritic arborization during this developmental stage, in keeping with animal models and research investigating frontal lobe development. PMID- 17710831 TI - The earliest behavioral expression of focal damage to human prefrontal cortex. AB - Damage to the prefrontal cortex in childhood can produce long-term impairments of emotion, behavior regulation, and executive functions, but little is known regarding the earliest expression of these impairments. We describe here detailed behavioral studies of a boy at 14 months of age ('PF1') who sustained focal damage in the right inferior dorsolateral prefrontal cortex due to resection of a vascular malformation on day 3 of life. The surgery was followed by a good medical recovery, and he reached developmental milestones at a normal rate. His neurological examination was normal, as were his mother's ratings of communication abilities, daily living skills, socialization, and motor skills. Multiple standardized laboratory paradigms were used to evaluate his behavior in structured and relatively unstructured situations designed to elicit positive and negative emotions and to place demands on attention. Relative to a comparison group of 50 age-matched boys with no neurological history, PF1 demonstrated significant impairments in the regulation of emotion and engagement of attention, particularly in unstructured conditions. These findings indicate that damage to prefrontal cortex in infancy begins to impact on emotional and cognitive development already during the first months of life. PMID- 17710832 TI - Chikungunya fever. PMID- 17710833 TI - Dengue fever and dengue haemorrhagic fever. PMID- 17710835 TI - Work culture--a tool for productive work. PMID- 17710834 TI - Working together for better health. AB - To provide effective and comprehensive care. Nurses, physicians and other health care professionals must collaborate with each other. No group can claim total authority over the other. Each profession exhibits different areas of professional competence that, when combined together, provide a continuum of care that the consumer has come to expect. The definitions of collaboration have not been structured to reflect true practice. Instead, at best, they reflect compromise, and at worst are conditioned and tailored to limit competition. PMID- 17710836 TI - Caring for carers: missing block in HIV/AIDS care. AB - To prevent or recover from burn out, learn to cultivate the methods of personal renewal, emotional self-awareness, connection with social support systems, sense of mastery and meaning in your work. Be fully present to the moment, the person, a task and competing demands common to non-workdays. To enjoy a healthy, sustainable life, let your spirit be continuously renewed. PMID- 17710837 TI - Preparation of a palliative care nurse. PMID- 17710838 TI - Nonlinear analysis of brain magnetoencephalographic activity in Alzheimer disease patients. AB - OBJECTIVES: Non-linear analysis was applied on MEG signals of Alzheimer Disease (AD) patients in order to investigate the underlying complexity of the brain dynamics. MATERIALS AND METHODS: A Single channel SQUID was used to record the MEG signals in 9 AD patients and 5 normal individuals. The magnetic activity, for each patient, was recorded from a total of 64 points of the skull (32 points from each temporal lobe). Nonlinear analysis was applied in the abnormal MEG points of the brain. RESULTS: In AD patients some recorded points were found with high amplitudes and low frequencies in magnetic activity. By applying nonlinear analysis in these records low values in the correlation dimension D of the reconstructed phase space were found. CONCLUSIONS: SQUID obtained MEG signaling from brains of AD patients showed a lower complexity compared to the brain of normal subjects. PMID- 17710839 TI - Is the Migraid device an asset in the non-pharmacologic treatment of migraine? AB - Non-pharmacologic treatment of migraine attacks is advised by guidelines to be considered. Some patients use digital massage of the temporal arteries. The Migraid device exerts a constant pressure on the temporal arteries and may be an alternative for the tiring digital massage. The present study investigates whether the new Migraid device may improve migraine symptoms. In a randomised multi-centre cross-over study the efficacy, safety and tolerability of a 1-hour use of the Migraid device at the start of the aura is compared with no-device in the treatment of migraine attacks with typical aura. Of the 134 patients who entered the study, 98 were suitable for the intention-to-treat analysis and 83 patients completed the study. Data on 94 Migraid treated and 87 non-treated attacks have been analysed. Twelve percent of patients (10/83) were pain-free at 2 hours in the Migraid group versus 1.6% (1/64) in the non-treated group (p = 0.02). After 24-hours 9.6% of patients were pain-free with the Migraid versus 0% with no treatment. After 2 hours 31.3% of patients perceived the migraine headache as severe using the Migraid versus 53.1% with no treatment. For nausea this was 6.1% and 15.6%, respectively (p = 0.01). The device was well tolerated. In conclusion, 1-hour use of the Migraid device at the start of the aura improved headache and other migraine symptoms compared to no treatment. Future research with a more appropriate control should determine whether the Migraid effects are going beyond unspecific placebo effects. PMID- 17710840 TI - Catatonia and neuroleptic malignant syndrome: two sides of a coin? AB - Catatonia was first described by Kahlbaum in 1874. Ever since, the concept of catatonia has been the focus of debate, a major point of discussion being its nosological status. The question rises whether it is to be considered a syndrome with a wide variety of causes and clinical signs or a distinct clinical entity. Since catatonia shares a number of symptoms with the neuroleptic malignant syndrome (NMS) and similar treatments can be used in both conditions, it has also been suggested that NMS and catatonia are two variants of the same disorder In this article we describe five cases of catatonia and NMS in order to approach this nosological question. The clinical similarity between both syndromes is demonstrated in our cases. On the level of pathophysiology however, catatonia and NMS are quite different, with catatonia rather being a cortical psychomotor syndrome and NMS a subcortical motor disorder. Similarities can be explained by means of well-known models of basal ganglia function. The nosological problem, however; can only be resolved when the concept of catatonia is better defined. PMID- 17710841 TI - Metastatic medulloblastoma in an adult; treatment with temozolomide. AB - Medulloblastoma is a malignant brain tumour most frequently seen in children. Treatment of this tumour type usually consists of surgery followed by radiotherapy. Relapses of medulloblastoma are sensitive to chemotherapy and treatment with chemotherapeutics in children has increased the survival rates. A medulloblastoma at adult age is extremely rare, and there is no overall accepted treatment, especially not in the case of a relapse. Recently improvement of survival was reported in patients with glioblastoma treated with a combination of radiotherapy and concomitant temozolomide. This observation encouraged us to decide to treat an adult patient with a recurrent medulloblastoma with temozolomide. This female patient showed a recurrence of a medulloblastoma 7 years after the initial presentation with metastatic spread along the neuraxis and progressive neurological deterioration. Treatment with temozolomide resulted in relief of clinical symptoms and stabilization of tumour growth for 8 months. PMID- 17710842 TI - Carotid thrombus formation and extension during anticoagulation: a case report of large vessel disease and hypercoagulable state in systemic sclerosis. AB - Systemic sclerosis (SSc) is an autoimmune multisystem disorder of connective tissue characterized by widespread vascular lesions and fibrosis. Limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dsSSC) are both subsets of SSc. The vascular component of SSc is an important part of the disease. Especially Raynaud's phenomenon and microcirculatory abnormalities are well recognized. Enhanced coagulation pathways, decreased fibrinolysis, and endothelial dysfunction probably contribute to vascular events in SSc. Macrovascular disease is not recognized as a major feature of SSc. However, several studies report an increase in large vessel disease and mortality rate attributable to cardiovascular causes. We present a patient with lcSSc with an acute embolic stroke due to a large carotid thrombus. A hypercoagulable state was suspected because of thrombus formation during oral anticoagulation and extension during intravenous heparin treatment. This is one of the few reports of large vessel disease in systemic sclerosis. The hypercoagulable state may be related to systemic sclerosis. PMID- 17710843 TI - Glomus tumor of forearm: a rare cause of neuralgia. PMID- 17710844 TI - The evolutionary developmental biology of tinkering: an introduction to the challenge. AB - Recent developments in evolutionary biology have conflicting implications for our understanding of the developmental bases of microevolutionary processes. On the one hand, Darwinian theory predicts that evolution occurs mostly gradually and incrementally through selection on small-scale, heritable changes in phenotype within populations. On the other hand, many discoveries in evolutionary developmental biology--quite a few based on comparisons of distantly related model organisms--suggest that relatively simple transformations of developmental pathways can lead to dramatic, rapid change in phenotype. Here I review the history of and bases for gradualist versus punctuationalist views from a developmental perspective, and propose a framework with which to reconcile them. Notably, while tinkering with developmental pathways can underlie large-scale transformations in body plan, the phenotypic effect of these changes is often modulated by the complexity of the genetic and epigenetic contexts in which they develop. Thus the phenotypic effects of mutations of potentially large effect can manifest themselves rapidly, but they are more likely to emerge more incrementally over evolutionary time via transitional forms as natural selection within populations acts on their expression. To test these hypotheses, and to better understand how developmental shifts underlie microevolutionary change, future research needs to be directed at understanding how complex developmental networks, both genetic and epigenetic, structure the phenotypic effects of particular mutations within populations of organisms. PMID- 17710845 TI - Tinkering: a conceptual and historical evaluation. AB - Francois Jacob's article 'Evolution and Tinkering' published in Science in 1977 is still the locus classicus for the concept of tinkering in biology. It first introduced the notion of tinkering to a wide audience of scientists. Jacob drew on a variety of different sources ranging from molecular biology to evolutionary biology and cultural anthropology. The notion of tinkering, or more accurately, the concept of bricolage, are conceptual abstractions that allow for the theoretical analysis of a wide range of phenomena that are united by a shared underlying process--tinkering, or the opportunistic rearrangement and recombination of existing elements. This paper looks at Jacob's analysis as itself an example of conceptual tinkering. It traces the history of some of its elements and sketches how it has become part of an inclusive discourse of theoretical biology and evolutionary developmental biology that emerged over the last 30 years. I will argue that the theoretical power of Jacob's analysis lies in the fact that he captured a widespread phenomenon. His conceptual analysis is thus an example of an interdisciplinary synthesis that is based on a shared process rather than a shared object. PMID- 17710846 TI - Tinkering: new embryos from old--rapidly and cheaply. AB - Marine embryos and larvae reflect distinct life histories and body plans from their adults, and are relatively simple in morphology and genetic regulation. Evolution of development to produce highly modified larval forms can be rapid among closely related species. We have studied the mechanisms by which the non feeding direct-developing larva of the sea urchin Heliocidaris erythrogramma evolved from an indirect-developing feeding larva, the pluteus. H. erythrogramma diverged within 4 million years from its sister species, H. tuberculata, which has a typical pluteus larva. Radical evolution of H. erythrogramma early development allows it to reach metamorphosis in three to four days versus the several weeks required for the pluteus. We have used embryology, cross species hybrids, and manipulation of gene expression in embryos to dissect developmental changes and the genic controls that underlie these changes. Evolution of a new larval form resulted largely from several heterochronies in which conserved regulatory pathways are shifted in timing, producing new temporal relationships to other developmental events. Other changes in gene regulation also have contributed to rapid evolution of larval features, including the origin of unexpected and novel tissue identities that transcend changes within homologous features. PMID- 17710847 TI - The relationship between development and evolution through heritable variation. AB - Darwin's theory of evolution by natural selection states that evolution occurs through the natural selection of heritable variation. Development plays the key physiological role connecting the heritable genotypes, passed from one generation to the next, to the phenotypes that are made available for selection. While at times the developmental variations underlying a selected trait may be neutral with respect to selection, it is through its effects on heritable variation that developmental tinkering affects evolution. We can gain a deeper understanding of the evolutionary process by considering the role of development in structuring variation and, through its effects on variation, structuring evolution. Both evolutionary theory and empirical studies show that features that interact in development tend to be inherited together and, hence, to evolve together. Gene mapping studies show that this modular inheritance pattern is due to modular pleiotropic gene effects, individual genes affecting a single modular unit, and that there is heritable variation in the range of features encompassed by these modules. We hypothesize that modular pleiotropic patterns are sculpted by natural selection so that functionally-and developmentally-related traits are affected by module-specific genes. PMID- 17710848 TI - Genetic networks as transmitting and amplifying devices for natural genetic tinkering. AB - Genes never act in isolation but only through webs of functional connections called 'genetic networks'. The term 'genetic network', however, embraces a number of conceptually distinct entities. These include metabolic gene networks, protein 'interactomes', transcriptional networks, and the molecularly diverse networks that underlie development. That last category is the most complex and the one of most direct relevance to morphological evolution. It will be argued here that most microevolutionary 'tinkering' involves changes in such genetic networks. Unfortunately, the conceptual and technical problems in elucidating and characterizing these networks are substantial. In consequence, relatively few developmental genetic networks, and their evolutionary alterations, have yet been characterized in any detail. Nevertheless, the generic functional properties of these networks can help explain certain aspects of evolutionary change. In particular, the ways that development genetic networks act as both transmitting and amplification devices for genetic change will be described. The relationship of these properties to the sometimes puzzlingly rapid rates of organismal evolution will be discussed. PMID- 17710849 TI - Butterfly eyespot patterns and how evolutionary tinkering yields diversity. AB - Eyespots are repeated elements in the wing pattern of butterflies. In the species rich genus of Bicyclus, all eyespots are formed by the same developmental process. Artificial selection in B. anynana has explored how readily two of the eyespots can become different to each other. There is sufficient standing genetic and developmental variation in a single stock of this species for high flexibility in the responses for eyespot size; indeed selection over 25 generations in several directions of morphospace yielded phenotypes far beyond the variability found in the whole genus. In contrast, experiments on another eyespot trait, their colour composition, indicate that comparable flexibility occurs only along the axis of least resistance in which both eyespots change in the same direction. This result is reflected in both a clear difference in the developmental regulation of eyespot size and colour composition, and in the patterns of variability among species. Such research that integrates evolutionary genetics and Evo-Devo will eventually reveal how evolutionary tinkering occurs in both genetical and developmental terms, and will also explore the consequences of differences in evolvability for patterns of diversity. PMID- 17710850 TI - Tinkering with transcription factor proteins: the role of transcription factor adaptation in developmental evolution. AB - Evolution of transcriptional regulation is often seen as being driven by the origin of transcription factor binding sites in cis-regulatory DNA. But there is strong evidence that transcriptional specificity of transcription factor proteins is determined by protein-protein interaction with other transcription factors. Here we summarize the evidence that transcription factor protein function itself is evolving and suggest that this might play an integral if not leading role in the evolution of gene regulation. PMID- 17710851 TI - Tinkering with constraints in the evolution of the vertebrate limb anterior posterior polarity. AB - Genes belonging to both HoxA and HoxD clusters are required for proper vertebrate limb development. Mice lacking all, or parts of, Hoxa and Hoxd functions in forelimbs, as well as mice with a gain of function of these genes in the early limb bud, have helped us to understand functional and regulatory issues associated with these genes, such that, for example, the tight mechanistic interdependency that exists between the production of the limb and its anterior to posterior (AP) polarity. Our studies suggest that the evolutionary recruitment of Hox gene function into growing appendages was crucial to implement hedgehog signalling, subsequently leading to the distal extension of tetrapod appendages, with an already built-in AP polarity. We propose that this process results from the evolutionary co-option, in the developing limbs, of a particular regulatory mechanism (collinearity), which is necessary to pattern the developing trunk. This major regulatory constraint imposed a polarity to our limbs as the most parsimonious solution to grow appendages. PMID- 17710852 TI - Affecting tooth morphology and renewal by fine-tuning the signals mediating cell and tissue interactions. AB - Interactions between the epithelial and mesenchymal tissue components of developing teeth regulate morphogenesis and cell differentiation, and determine key features of dentitions and individual teeth such as the number, size, shape and formation of dental hard tissues. Tissue interactions are mediated by signal molecules belonging mostly to four conserved families: transforming growth factor (TGF)beta, Wnt, fibroblast growth factor (FGF) and Hedgehog. Recent work from our laboratory has demonstrated that tooth morphology and the capacity of the teeth to grow and renew can be affected by tinkering with these signal pathways in transgenic mice. The continuous growth of the mouse incisors, as well as their subdivision into the crown and root domains, is dramatically altered by modulating a network of FGF and two TGFbeta signals, bone morphogenetic protein (BMP) and Activin. This network is responsible for the regulation of the maintenance, proliferation and differentiation of epithelial stem cells that are responsible for growth and enamel production. On the other hand, the activation of the Wnt signalling pathway induces continuous renewal of mouse teeth (which normally are not replaced), resembling tooth replacement in other vertebrates. It can be concluded that the different dental characters are quite flexible and that they are regulated by the same conserved signal pathways. These findings support the suggestions that tinkering with the signal pathways is the key mechanism underlying the morphological evolution of teeth as well as other organs. PMID- 17710854 TI - The developmental genetics of microevolution. AB - What is the relationship between variation that segregates within natural populations and the differences that distinguish species? Many studies over the past century have demonstrated that most of the genetic variation within natural populations that contributes to quantitative traits causes relatively small phenotypic effects. In contrast, the genetic causes of quantitative differences between species are at least sometimes caused by few loci of relatively large effect. In addition, most of the results from evolutionary developmental biology are often discussed as though changes at just a few important 'molecular toolbox' genes provide the key clues to morphological evolution. On the face of it, these divergent results seem incompatible and call into question the neo-Darwinian view that differences between species emerge from precisely the same kinds of variants that segregate much of the time in natural populations. One prediction from the classical model is that many different genes can evolve to generate similar phenotypes. I discuss our studies that demonstrate that similar phenotypes have evolved in multiple lineages of Drosophila by evolution of the same gene, shavenbaby/ovo. This evidence for parallel evolution suggests that svb occupies a privileged position in the developmental network patterning larval trichomes that makes it a favourable target of evolutionary change. PMID- 17710853 TI - Evolution of covariance in the mammalian skull. AB - The skull is a developmentally complex and highly integrated structure. Integration, which is manifested as covariance among structures, enables the skull and associated soft tissues to maintain function both across ontogeny within individuals and across the ranges of size and shape variation among individuals. Integration also contributes to evolvability by structuring the phenotypic expression of genetic variation. We argue that the pattern of covariation seen in complex phenotypes such as the skull results from the overlaying of variation introduced by developmental and environmental factors at different stages of development. Much like a palimpsest, the covariation structure of an adult skull represents the summed imprint of a succession of effects, each of which leaves a distinctive covariation signal determined by the specific set of developmental interactions involved. Covariance evolves either by altering the variance of one of these sequential effects or through the introduction of a novel covariance producing effect. Either way is consistent with the notion that evolutionary change occurs through tinkering. We illustrate these principles through analyses of how genetic perturbations acting at different developmental stages (embryonic, fetal, and postnatal) influence the covariance structure of adult mouse skulls. As predicted by the model, the results illustrate the intimate relationship between the modulation of variance and the expression of covariance. The results also demonstrate that covariance patterns have a complex relationship to the underlying developmental architecture, thus highlighting problems with making inferences about developmental relationships (e.g. modularity) based on covariation. PMID- 17710855 TI - The economy of tinkering mammalian teeth. AB - A central aim of evolutionary developmental research is to decipher the relative roles of ecological and molecular interactions in explaining biological diversity. Tetrapod teeth show diverse evolutionary patterns with a repeated increase in dental complexity, especially in response to herbivorous habits. Most extensively in mammals, dentition increases in complexity by elaborating morphology of individual teeth rather than increasing the number of teeth. Even though evolution of mammalian dentition is governed by ecology, recent evidence on molecular signalling suggests that many details and even some general evolutionary tendencies may be instigated by development. Specifically, iterative use of the same developmental modules, the enamel knots, may have facilitated developmentally efficient, or economical, elaboration of tooth shapes without substantially compromising the existing morphology. These kinds of developmentally influenced tendencies may be hypothesized to be typical to many organs and systems showing repeated evolutionary patterns. PMID- 17710856 TI - Pelvic skeleton reduction and Pitx1 expression in threespine stickleback populations. AB - The pelvic skeleton of threespine stickleback fish contributes to defence against predatory vertebrates, but rare populations exhibit vestigial pelvic phenotypes. Low ionic strength water and absence of predatory fishes are associated with reduction of the pelvic skeleton, and lack of Pitx1 expression in the pelvic region is evidently the genetic basis for pelvic reduction in several populations. Pelvic vestiges in most populations are larger on the left (left biased), apparently because Pitx2 is expressed only on that side. We used whole mount in situ hybridization to study Pitx1 expression in 19 populations of Gasterosteus aculeatus from lakes around Cook Inlet, Alaska, USA. As expected, specimens from six populations with full pelvic structures usually expressed Pitx1 in the limb bud; those from eight populations with left-biased pelvic reduction usually did not express it. Specimens from one of three populations with right-biased or unbiased pelvic reduction sometimes expressed Pitx1. One of two populations in which the pelvic spines (but not the girdle) are usually absent often expressed Pitx1. In terms of Jacob's 1977 'tinkering' metaphor, Pitx1 was the spare part with which natural selection usually tinkered for stickleback pelvic reduction, but it also tinkered with other genes that have smaller effects. PMID- 17710858 TI - Craniofacial variation and developmental divergence in primate and human evolution. AB - Many questions about developmental divergence in human (and non-human primate) evolution can be fruitfully explored through investigation of the extant primate phenotype. Here I discuss two approaches that use patterns of variation in extant primates to consider hypotheses of 'tinkering' both in their own lineages, and also as applied to the fossil record of human evolution. In the first, I show how comparisons of ontogenetic morphological integration in extant humans and apes can be used to consider the developmental underpinnings of the morphological change seen in the transition from the prognathic australopith face to the relatively smaller, orthognathic Homo face. In the second approach, I demonstrate how studies of craniofacial variation in hybrid baboons can be used as models for considering developmental divergence in Plio-Pleistocene primates, including fossil hominins. Of particular interest is the fact that unusual non-metric dental and sutural variation in these hybrids appears to be a sensitive indicator of evolutionary developmental divergence. Future studies would profit from focusing on the breadth and especially the overlap of morphological variation among extant primate taxa in order to determine the degree to which underlying genetic similarity in functional regions, and difference in regulatory regions, explains the variable primate phenotype. PMID- 17710857 TI - Using patterns of fin and limb phylogeny to test developmental-evolutionary scenarios. AB - Increasing fossil evidence surrounding the evolutionary origin of vertebrate limbs can be used to reconstruct the assembly of a limb ground-plan common to all tetrapods. The sequence of changes at the fin-to-limb transition can be compared to patterns of fin and limb ontogeny, and further comparisons can be made between phylogenetic changes at pectoral and pelvic levels. Such comparisons inform questions about the evolution of developmental autonomy (modularity). Limb evolution mostly concerns terminal additions and losses; from a developmental standpoint, these probably result either from minor adjustments to limb bud proportions or from the relative timing of gene expression or tissue growth. Evolutionary radiations of large clades are widely assumed to be marked by periods of rapid morphological diversification, raising further questions about the impact of restrictions imposed not only by ecology, but also by development and genetics. The early tetrapod data set is now large enough to allow initial tests of evolutionary inference to be conducted. New results are revealing novel patterns of evolutionary rate-change, encompassing the traditional notion of the fish-to-tetrapod transition and the root of the modern (crown-group) tetrapod radiation. PMID- 17710859 TI - Why has Genesys PHO been so successful over the last 12 years? PMID- 17710860 TI - Recent Supreme Court decisions are important to physicians. PMID- 17710861 TI - Innovative program helps physicians lower risk, improve care. PMID- 17710862 TI - Mastering the art of physician recruitment. PMID- 17710863 TI - The changing pomp and circumstances of medical education in Michigan. PMID- 17710864 TI - Michigan's safety nets for the uninsured enhanced by collaborations between public and private sectors. PMID- 17710865 TI - What physicians should consider when hiring a financial planner. PMID- 17710866 TI - Michigan's vaccine for children program expands its coverage. PMID- 17710867 TI - We can...we must... we will. PMID- 17710868 TI - Partial trisomy 4(q31qter) due to maternal 4;5 balanced translocation in a neonate. AB - We describe a male neonate with a duplication of 4(q31.3qter) due to unbalanced segregation of a maternal translocation (4;5)(31.3;p15.1). He has a high broad nasal bridge, large, low-set ears, epicanthal folds, long philtrum, retrognathia, high arched palate, wide-spaced nipples, bilateral single transverse palmar creases, bilateral clinodactyly of the fifth finger, right cryptorchidism, and ventricular and secundum type atrial septal defect. PMID- 17710870 TI - Elejalde syndrome: clinical and histopathological findings in an Egyptian male. AB - Elejalde syndrome is a rare disorder. An Egyptian male patient with Elejalde syndrome is presented. He had silvery hair since birth, generalized hypopigmentation, severe primary central nervous system dysfunction, and normal hematological and immunologic profiles. Magnetic resonance of the brain revealed prominent cerebellar atrophy with mild fronto-parietal cortical atrophic changes. Microscopic analysis of his hair showed melanin clumps irregularly distributed along the hair shafts, and a skin biopsy showed increased pigmentation in the basal melanocytes. The differential diagnosis of silvery hair disorders includes Elejalde syndrome, Griscelli and Chediak-Higashi syndromes. In the present report, we review the literature on Elejalde syndrome and discuss the differential diagnosis. PMID- 17710869 TI - Coexistent mosaic monosomy 21 and fragile X syndrome in a mentally retarded male patient. AB - Fragile X syndrome (FXS) is a well-recognized mental retardation syndrome with characteristic facial features and behavioural phenotype. Monosomy 21 is a rare cytogenetic aberration for which clinical features were incompletely defined since full monosomy 21 is incompatible with life. A 5-year-old male patient with FXS and low-grade mosaicism for full monosomy 21 (46,XY[96%]/45,XY,-21[4%]) is presented. He had lack of speech and severely impaired social skills, hyperactivity, stereotypical hand movements, a special interest towards moving colourful items and a short attention span for other objects around. He had macrocephaly, a rather long face, prominent occiput and prominent midface, retrognathia, down-slanting palpebral fissures, hypertelorism and cup-shaped, posteriorly rotated and low-set ears. Full monosomy in the aberrant cell line was proven by whole chromosome painting. FXS was previously reported to accompany sex chromosome aneuploidies; however, to the best of our knowledge, the present patient is the first FXS patient with an aberration involving autosomes. He contributes to the current knowledge on monosomy 21 phenotype, having dysmorphic facial findings despite the concurrent phenotypic expression of the FXS. As a last conclusion, cytogenetic analysis must be done to all mentally retarded patients with minor dysmorphic features. PMID- 17710871 TI - Children with 4q-syndrome: the parents' perspective. AB - A questionnaire survey was conducted among the parents of 32 not previously described children with 4q-syndrome, and 4 affected adult relatives. The questions related to the medical condition of the individual child and the interactions between parents and health professionals. The response rate of the survey was 58 %, and the mean age of the patients was 11.2 years. Thirty eight percent of children were diagnosed within the 1st month of life. Most parents felt severely distressed at the time of diagnosis and 66 % complained about a lack of medical information made available to them. However, parental understanding of the genetic aetiology responsible for the 4q-syndrome was overall good. Apart from a multidisciplinary team of healthcare workers, the internet and religion were named as sources of support. In all, 86 % of parents valued the experience of having a child with 4q-syndrome highly despite the difficulties involved. PMID- 17710872 TI - Precocious puberty associated with partial trisomy 18q and monosomy 11q. AB - We report a 10-years-old female patient with a partial trisomy 18q and monosomy 11q due to a maternal translocation. The phenotype of our proband is partially common with Jacobsen syndrome and duplication 18q but she has also some atypical anomalies such as precocious puberty, a retinal albinism and hypermetropia. Based on cytogenetics and FISH analysis, the karyotype of the proband was 46,XX,der(11)t(11;18)(q24;q13). To the best of our knowledge, this is the first report of precocious puberty associated with either dup(18q) or del(11q) syndromes. PMID- 17710873 TI - Associated malformations in cases with neural tube defects. AB - Infants with neural tube defects (NTDs) may have other associated congenital defects. The reported incidence and the types of associated malformations vary between different studies. The purpose of this investigation was to assess the prevalence of associated malformations in a geographically defined population. The prevalences at birth of associated malformations in infants with NTDs were collected between 1979 and 2003 on all infants born in the area covered by the registry of congenital anomalies of Northeastern France in 334,262 consecutive births. Of the 360 infants with NTDs born during this period, 20.5 % had associated malformations. Associated malformations were more frequent in infants who had encephalocele (37.5 %) than in infants with anencephaly (11.8 %) or infants with spina bifida (23.7 %). Malformations in the face (oral clefts), in the musculoskeletal system, in the renal system, and in the cardiovascular system were the most common other anomalies. In conclusion the overall prevalence of malformations, which was one in five infants, emphasizes the need for a thorough investigation of infants with NTDs. A routine screening for other malformations especially facial clefts, musculoskeletal, renal and cardiac anomalies may need to be considered in infants with NTDs, and genetic counseling seems warranted in most of these complicated cases. PMID- 17710874 TI - Maternal balanced translocation (4;21) leading to an offspring with partial duplication of 4q and 21q without phenotypic manifestations of Down syndrome. AB - We describe an 8-years old female with supernumerary chromosome der(21)t(4;21)(q25;q22) resulting in partial trisomy 4q25-qter and partial trisomy 21(pter-q22). The extra material was originated from a reciprocal balanced translocation carrier mother (4q;21q). Karyotyping was confirmed by FISH using whole chromosome painting probes for 4 and 21q and using 21q22.13-q22.2 specific probe to rule out trisomy of Down syndrome critical region. Phenotypic and cytogenetic findings were compared with previously published cases of partial trisomy 4q and 21q. Our patient had the major criteria of distal trisomy 4q namely severe psychomotor retardation, growth retardation, microcephaly, hearing impairment, specific facies (broad nasal root, hypertelorism, ptosis, narrow palpebral fissures, long eye lashes, long philtrum, carp like mouth and malformed ears) and thumbs and minor feet anomalies. In spite of detection of most of the 3 copies of chromosome 21, specific features of Down syndrome (DS) were lacked in this patient, except for notable bilateral symmetrical calcification of basal ganglia. This report represents further delineation of the phenotype-genotype correlation of trisomy 4q syndrome. It also supports that DS phenotype is closely linked to 21q22. Nevertheless, presence of basal ganglia calcification in this patient may point out to a more proximal region contributing in its development in DS, or that genes outside the critical region may influence or control manifestations of DS features. PMID- 17710875 TI - Woodhouse-Sakati syndrome: case report and symptoms review. AB - We report on a 52-year old Caucasian woman exhibiting signs of Woodhouse - Sakati syndrome and review the clinical signs and symptoms in patients reported so far. The syndrome is characterized by alopecia, mental retardation, hypogonadism, diabetes mellitus, hearing impairment, ECG changes, and by autosomal recessive inheritance. We also propose that the limited mobility of the upper extremities is one of the features of the syndrome. PMID- 17710876 TI - Prenatal diagnosis of supernumerary ring chromosome 1: case report and review of the literature. AB - A supernumerary ring chromosome was found on amniocentesis performed for advanced maternal age. A review of the literature found 34 reports of supernumerary ring chromosome I which are compared to our case. PMID- 17710877 TI - Abnormal first trimester screen in partial deletion of chromosome 6p21: a case report. AB - In this case-report we describe a 21-year-old primigravida with an abnormal first trimester screen: combined risk for Downs Syndrome was 1:90. Karyotype revealed 46,XX,del(6)(p21). Termination with Cytotec was offered because of the risk of congenital malformations and subsequent abnormalities associated with deletions in chromosome 6p. As to our knowledge no report has been written about the prenatal diagnosis of deletions on the short arm of chromosome six based on the first trimester screen. By publishing our experience we want to create awareness. This case-report shows the importance of combining prenatal screening with the biochemical tests, instead of only measuring nuchal translucency. It also shows the need for full karyotyping when invasive prenatal testing is done. PMID- 17710878 TI - Acro-cardio-facial syndrome associated with neuroepithelial cyst: a case report. AB - Acro-cardio-facial syndrome (ACFS) is a very rare genetic syndrome. Only 5 patients have been reported in the literature so far. A female neonate presented with limb abnormalities, cleft palate and congenital heart disease was diagnosed as ACFS. Her cranial magnetic resonance imaging revealed a huge cerebral neuroepithelial cyst. To our knowledge, this is the first case of ACFS in the literature associated with a neuroepithelial cyst in the brain. PMID- 17710879 TI - A nonclassified and unusual polydactyly of the foot. AB - A rare polydactyly of the foot, mixed central and pre-axial type, is described; no other dysmorphic features were present. Early surgery was performed with good results. PMID- 17710880 TI - Prenatal diagnosis of atypical facial clefting should alert amniotic band syndrome and prompt a search for associated amniotic bands and other structural anomalies. PMID- 17710882 TI - [Mitoxantrone for the treatment of Japanese patients with multiple sclerosis]. AB - We retrospectively evaluated the benefits of mitoxantrone (MITX) treatment in Japanese patients with multiple sclerosis (MS) with more than 3 relapses per year or a deterioration of more than one Expanded Disability Status Scale (EDSS) of Kurtzke score per year despite having IFN beta 1b therapy. Monthly intravenous injections of MITX, 10-12 mg/m2, for 3 months were followed by an additional treatment every 3 months. Nine patients (6 women, 3 men) with a mean age of 39 years, a mean disease duration of 3.9 years, and a mean EDSS score of 6.7 were studied. Seven patients had long spinal cord lesions (LCL-MS). Most patients tolerated the treatment, although 2 patients stopped MITX therapy after 3 injections because of severe appetite loss. The 7 patients who continued MITX therapy for more than 3 times significantly decreased their relapse rate and EDSS deterioration. The average relapse count in the year preceding initiation of MITX therapy was 4.3 (range: 3-6)/year, EDSS score increased by 2.7 (range: 1-7)/year. The average relapse count was 2.3 (range: 0-4)/year from 0 to 6 months after MITX therapy (p = 0.114), and 1.1 (range: 0-4)/year from 7 to 12 months (p = 0.285). The average EDSS deterioration was -0.4 (range -2-1) from 0 to 6 months after MITX therapy (p = 0.018), and there was no deterioration from 7 to 12 months. Most patients received granulocyte colony stimulating factor because of leukocytopenia caused by MITX. No patients showed any decrease in cardiac ejection fraction during this observation period. For Japanese MS patients, MITX therapy was very effective to suppress relapses without incurring severe adverse events. PMID- 17710881 TI - Co-occurrence of familial Mediterranean fever (FMF) heterozygote mutation and nail-patella syndrome (NPS) in 3 members of a family with LMX1B mutation analysis. PMID- 17710883 TI - [Videofluorographic assessment of swallowing function in patients with Duchenne muscular dystrophy]. AB - OBJECTIVE: To identify the characteristics of swallowing function in patients with Duchenne muscular dystrophy (DMD). METHODS: Swallowing function was evaluated using videofluorography (VF) in a cross-sectional observational study of 102 DMD patients (mean age 21.5 years) who had dysphagia or in whom dysphagia was suspected based on clinical signs. Reduced tongue movement, impaired bolus transport to the pharynx, decreased pharyngeal contraction, bolus delivery into the airway, and bolus residue at the epiglottic vallecula and at the piriform recess were qualitatively evaluated for test swallows of jelly and juice. During VF, the length of time of both the oral and pharyngeal phases of swallowing was measured in 59 patients. RESULTS: Patients started to show oral phase abnormalities in their mid-teens and pharyngeal phase abnormalities such as pharyngeal residue around age 20. Oral phase abnormalities was higher with juice than with jelly. Total oral/pharyngeal transit duration was longer with age, and total duration of hyoid maximum elevation was shorter with age. CONCLUSION: The weak positive correlation of total oral/pharyngeal transit duration and age was presumably due to gradual onset of functional abnormalities associated with deteriorated swallowing muscles starting in the teenage years. Reduced tongue movement and impaired bolus transport to the pharynx was more common in teenage DMD patients because they have limited tongue movements associated with structural abnormalities such as macroglossia and open bite. VF showed that the swallowing difficulties were more severe during the oral phase than in the pharyngeal phase in the teenage patients. The pharyngeal phase disorders such as pharyngeal residue and decreased pharyngeal contraction were seen more often in the patients in their 20s, presumably due to deterioration of swallowing muscles that becomes more apparent in the older age group. PMID- 17710884 TI - [A case presenting with both features of essential tremor and Parkinson tremor]. AB - A 78-year-old woman had postural and action tremor in hands since age of late 20's, though without much difficulty in daily living. Since age 76, she has had an increasing difficulty in walking and postural balance, with some worsening of hand shaking as well. She also noted to have head shaking, involuntary movements in the mouth, and some difficulty in swallowing. Reportedly both of her parents and her brother had hand tremor. Neurologically she had resting, postural and action tremors in hands more on the left. She also had marked rigidity in the neck and moderate cogwheel rigidity in all limbs more on the left, moderate bradykinesia, markedly stooped posture with relatively wide base, slow and small paced gait, and poor postural balance more posteriorly. Thus, it is most likely that the present case suffered from essential tremor and later developed Parkinson disease. Power spectrum analyses of surface electromyogram and accelerometer showed the peaks at 4.3 Hz for the resting tremor, and 3.1 and 5.2 Hz for the postural tremor. Furthermore, significant EEG-EMG coherence was seen at the peaks of 4.3 and 5.2 Hz, suggesting possible involvement of sensori-motor cortex for generation of both tremors. When the postural tremor was loaded with 500 g weight, the peak of power spectrum and EEG-EMG coherence showed the broader pattern with the maximal peak at 4.3 Hz, exactly the same frequency as that of the resting tremor. These findings may be explained by postulating that the 4.3 Hz peak of the resting tremor became apparent by loading because 5.2 Hz peak of the postural tremor was suppressed by the loading. The peak of the postural tremor at 3.1 Hz which was not detected by EEG-EMG coherence suggested that the tremor for 3.1 Hz was not involved to sensori-motor cortex for generation. PMID- 17710885 TI - [A clinically diagnosed lymphocytic hypophysitis presenting as recurrent meningitis]. AB - A 55-year-old woman was admitted to our hospital complaining of severe headache with fever and apparent neck stiffness. Neutrophilic pleocytosis was demonstrated in cerebrospinal fluid (CSF) and bacterial meningitis was strongly suspected, but bacterial culture of CSF was negative. After the symptoms normalized within a few days, she developed diabetes insipidus and gadolinium (Gd)-enhancement of the enlarged hypophysis and stalk was observed on cranial MRI. A Lymphocytic Hypophysitis (LH) was clinically diagnosed. Follow-up studies demonstrated spontaneous remission of serological, radiological, and CSF findings, and she was discharged on hormonal replacement therapy with desmopressin. Three months later, she returned to our hospital complaining of headache again under adenohypophysial hypofunction and expanding pituitary lesion on MRI. CSF analysis showed meningitis but there was no evidence of infection by microorganisms. Our diagnosis was relapsing LH with aseptic meningitis, and the patient was administered methylprednisolone pulse therapy, which induced rapid improvement in clinical, endocrinological, and radiological findings. This case showed a possible unique clinical presentation of LH characterized as recurrent aseptic meningitis. It is important to recognize this phenotype of LH, and to prescribe corticosteroid therapy after appropriate endocrinological and radiological studies. PMID- 17710886 TI - [Concurrence of myasthenia gravis, polymyositis, thyroiditis and eosinophilia in a patient with type B1 thymoma]. AB - We presented a 43-year-old Japanese woman who acutely developed weakness of all extremities and difficulty in swallowing and drooping of eyelids, characterized by easy fatigability at the end of December, 2005. On general physical examination, she had moderate goiter. No cervical lymphadenopathy, cardiac murmur, or skin rash was noted. Neurologically, she had blepharoptosis, more on the right, only in the upright position with easy fatigability and marked weakness in the neck flexor, trunk, and all limb muscles much more proximally than distally. She had neither muscular atrophy nor upper motor neuron sign. Laboratory data showed slight leukocytosis with eosinophilia (up to 31%), and serum creatine kinase was markedly increased to over 2,000 IU/l. TSH receptor antibody (11.9%) and anti-acetylcholine receptor antibody (46.6 nmol/L) were also increased. Edrophonium test was positive. Electrophysiologically, muscle evoked potentials by repetitive motor nerve stimulation showed 13% and 50% waning in abductor pollicis brevis and deltoid muscle, respectively, at low frequency and no waxing at high frequency. Needle EMG showed fibrillation potentials and positive sharp waves in proximal muscles. Polymyositis was diagnosed by muscle biopsy which showed infiltration of lymphocytes in the endomysium and around non necrotic muscle fibers. Upper arm muscle MRI showed multifocal high signal intensity lesions on T2-weighted images which were likely related to myositis. This finding is atypical for polymyositis. X-ray and CT of chest showed a mass lesion in the left pulmonary hilum, which was histologically diagnosed as type B1 thymoma. Thus, the present case had myasthenia gravis, polymyositis, thyroidititis and eosinophilia associated with type B1 thymoma. After the thymectomy, corticosteroid administration and immunoadsorption therapy, clinical symptoms and all laboratory abnormalities markedly improved. PMID- 17710887 TI - [Autoimmune encephalitis with anti-glutamate receptor antibody presenting as epilepsia partialis continua and action myoclonus: a case report]. AB - A 19-year-old man was admitted to our hospital with tremor and myoclonus that appeared after several episodes of consciousness disturbance and generalized convulsions. While steroid therapy resolved these symptoms, epilepsia partialis continua (EPC) and action myoclonus developed. Clobazam improved the EPC, but action myoclonus persisted. Oral tandospirone (30 mg/day) was given because 5 hydroxyindole acetic acid (5-HIAA) was markedly decreased in the cerebrospinal fluid (CSF). After 10 days of this therapy, most action myoclonus disappeared and he could perform fine motor skills. Although the MR structural images were unremarkable, cerebral SPECT showed decreased uptake in the left thalamus and bilateral frontal lobes. The antibody against glutamate receptor subunit epsilon2 was positive in the CSF. This is the first report of autoimmune encephalitis with anti-glutamate receptor antibody presenting as low level of 5-HIAA in the CSF. Tandospirone was effective for action myoclonus. PMID- 17710888 TI - [Stiff-person syndrome with elevated anti-Epstein-Barr virus antibody]. AB - Stiff-person syndrome, a relatively rare disease with a poor prognosis, presents as muscle stiffness, rigidity, and spasm. We reported a patient with this syndrome who was treated successfully. The patient was a 56-year-old Japanese man with respiratory infection-like prodromal symptoms. Episodes of painful spasm in both legs on extension and lordosis occurred spontaneously or were triggered with touch or pinprick stimuli at or below spinal level C3, and progressed subacutely. Tendon reflexes were hyperactive, Babinski's sign was positive, and vibration sense was reduced in the legs. Episodes of spasm were alleviated using diazepam. Even after discontinuing diazepam, these symptoms did not exacerbate. In this patient, although anti-glutamic acid decarboxylase (GAD) antibody was negative, anti-EB virus antibody was positive. No previous reports have described stiff person syndrome with EB virus infection. However, a few cases of this syndrome associated with viral infection were recently reported and viral gene mimicity with GAD has been postulated. Viral infection might be considered as a probable cause of this syndrome. PMID- 17710889 TI - [A case of neurolymphomatosis diagnosed with FDG-PET]. AB - A 38-year-old man with non-Hodgkin's lymphoma presented with hypesthesia and muscle weakness in the left upper limb. A lack of F-waves in left median and ulnar nerve conduction studies suggested a lesion at the proximal segments of the peripheral nerves, such as the left brachial plexus or nerve roots. Cervical magnetic resonance imaging revealed no lesions compressing nerve roots or peripheral nerves. Small and obscure uptake on the left side of the cervical nerve roots on 67Ga-scintigraphy was indistinguishable from artifact. Positron emission tomography-computed tomography (PET/CT) revealed a region of high glucose uptake in a left cervical intervertebral foramen, leading to a diagnosis of neurolymphomatosis. Neurological symptoms improved following additional chemotherapy, and the high glucose-uptake lesion disappeared. FDG-PET/CT is useful for rapid and non-invasive evaluation of neurolymphomatosis. PMID- 17710890 TI - [Usefulness of carotid ultrasonography for the early detection of moyamoya disease]. AB - We report carotid ultrasonographic findings in moyamoya disease. A 44-year-old man was admitted to our hospital because of fever, headache and nausea. Neurological examination showed neck stiffness and Kernig's sign but he was otherwise normal. Brain computed tomography showed hemorrhage in the right thalamus and the lateral ventricle. Conventional carotid ultrasonography (CCU) detected marked narrowing of the right internal carotid artery (ICA) at the proximal portion without arteriosclerosis, which fulfilled the criteria of bottle neck sign, namely, the ratio of diameter of proximal portion of ICA to that of the distal portion of common carotid artery (CCA) was less than 0.5. Additionally, CCU as well as transoral carotid ultrasonography (TOCU) showed the diameter of the ICA to be smaller than that of the external carotid artery (ECA) (diameter reversal sign). These signs strongly suggested moyamoya disease. Cerebral angiography confirmed the occlusions of intracranial ICA and moyamoya vessels. Bottle neck sign and diameter reversal sign of the carotid artery on carotid ultrasonography are useful for the early detection of moyamoya disease. PMID- 17710891 TI - [Temporal arteritis presenting with headache and abducens nerve palsy. Report of a case]. AB - A 71-year-old man visited our clinic with a 3-day history of severe throbbing headache and 1-day history of horizontal diplopia. He had had jaw claudication and pain in the neck and shoulder several days previously. His right eye was slightly esotropic and did not move laterally. There was no blepharoptosis, proptosis, lid edema, or conjunctival injection. The pupils were unremarkable. The remainder of the cranial nerve functions was intact. There was no limb weakness or sensory impairment. Superficial temporal arteries were swollen and tender on both sides. Laboratory examination showed elevated CRP level and high erythrocyte sedimentation rate. Cranial MR images were unremarkable. The cerebrospinal fluid was acellular with 45 mg/dl of protein. A diagnosis of temporal arteritis was made. Treatment with 50 mg of prednisolone brought about prompt disappearance of the headache. Right ocular movement fully recovered in 10 days. Temporal artery biopsy findings and response to corticosteroid were consistent with temporal arteritis. The motility pattern of the right eye was consistent with complete abducens nerve palsy, which is a rare manifestation of temporal arteritis. Although temporal arteritis is a rare cause of ophthalmoplegia in the elderly patients, swift diagnosis and treatment is necessary to avoid blindness. PMID- 17710892 TI - [Cancer immunotherapy using dendritic cells: current status and perspective]. PMID- 17710893 TI - [Molecular genetic alterations and their prognostic values in soft tissue sarcomas]. PMID- 17710894 TI - [Estimation of indication for living donor liver transplantation in patients with HCV and/or HBV infection]. AB - We evaluated 78 patients with chronic viral hepatitis for liver transplantation. 51 patients met our original criteria for liver transplantation, and 35 patients of them suffered from hepatocellular carcinoma (HCC). Patients with HCC were significantly older and showed higher prothrombin activity than those without HCC. Eighteen of 35 patients with HCC did not meet the Milan criteria, and they showed lower levels of total bilirubin, Child-Pugh score, and MELD score than those who met the criteria. Theses results indicate that acceptability for transplantation should be evaluated soon after the patients have become candidates for liver transplantation. In Japan, decompensated liver cirrhosis is a necessary condition for the application of public health insurance against liver transplantarion and, in cases with HCC, it is necessary to meet the Milan criteria. Application to liver transplantation should also be considered based on HCC stage such as the UNOS scoring system. PMID- 17710895 TI - Injection-site granulomas due to the administration of leuprorelin acetate for the treatment of prostatic cancer. AB - Luteinizing hormone-releasing hormone (LH-RH) analogues have become the main focus of androgen deprivation therapy for prostatic cancer. The occurrence of injection-site granulomas due to the administration of LH-RH analogues has been thought to be a rare reaction. We herein report a rare case presenting injection site granuloma due to the administration of leuprorelin acetate, mimicking metastatic nodule. A 90-year-old man presented with subcutaneous nodules at the injection-site of leuprorelin acetate 11.25 mg (for 3-month use). Ultrasound examination and computed tomography (CT) revealed two nodules in the bilateral abdominal walls mimicking metastatic nodule. Although he was surgically treated because of the possibility of malignancy, in the end, no evidence of malignancy was found. We should keep in mind that LH-RH analogues may cause injection-site granulomas mimicking metastatic nodule, and therefore we must inform patients undergoing the administration of leuprorelin acetate that it may cause injection site granuloma and thus when a patient demonstrates a subcutaneous nodule it is essential to confirm whether or not he has received an injection of the LH-RH analogue at the site of nodule. PMID- 17710896 TI - The use of potent inhalational agents for the ex- utero intrapartum treatment (exit) procedures: what concentrations? AB - The anesthetic management of a parturient undergoing ex-utero intrapartum treatment (EXIT) procedures for airway control of a newborn with a potentially life-threatening difficult airway is complex and often challenging. We herein report on the successful anesthetic management of the EXIT procedure in a 30-year old primigravida carrying a fetus with large cervical lymphangioma. General anesthesia was maintained with sevoflurane 2%, combined with continuous infusion of nitroglycerine (TNG). Although the use of high concentrations of potent inhalational agents (to keep the uterus fully relaxed) is currently recommended we believe that the use of low concentrations of potent inhalational anesthetics with continuous infusion of TNG may be a safer anesthetic strategy for these operations. PMID- 17710897 TI - Evaluation of two different epidural catheters in clinical practice. narrowing down the incidence of paresthesia! AB - Although epidural anesthesia is considered safe, several complications may occur during puncture and insertion of a catheter. Incidences of paresthesia vary between 0.2 and 56%. A prospective, open, cohort-controlled pilot study was conducted in 188 patients, ASA I-III, age 19-87 years, scheduled for elective surgery and epidural anesthesia. We evaluated a 20 G polyamide (standard) catheter and a 20 G combined polyurethane-polyamide (new) catheter. Spontaneous reactions upon catheter-insertion, paresthesia on questioning, inadvertent dural or intravascular puncture, and reasons for early catheter removal were recorded. The incidence of paresthesia reported spontaneously was 21.3% with the standard catheter and 16.7% with the new catheter. Systematically asking for paresthesia almost doubled the paraesthesia rate. Intravascular cannulation occurred in 5%. No accidental dural punctures occurred. An overall incidence of 13.3% of technical problems led to early catheter removal. The new catheter was at least equivalent to the standard regarding epidural success rate and safety : rate of paresthesia, intravascular and dural cannulation. PMID- 17710898 TI - Cystatin C in cardiac surgery. AB - Cystatin C has recently been proposed as an alternative marker of glomerular filtration rate. The study compares cystatin C and creatinine concentrations during cardiopulmonary bypass and the first 72 hours postoperatively in patients undergoing coronary artery bypass graft. Forty-nine patients with normal preoperative renal and cardiac function were scheduled for coronary artery bypass graft. Blood was sampled for creatinine and cystatin C measurements at 7 time points till 72 hours postoperatively. Glomerular filtration rate was estimated from calculated clearance using the Cockroft and Gault formula for creatinine and Larsson equation for cystatin C. The baseline values of both markers were within the normal range. Their concentrations were comparable during the whole study period. This was also the case for the calculated creatinine and cystatin C clearance. In patients with normal preoperative renal function undergoing coronary artery bypass graft, measured creatinine concentration remains a cheap and easy way of estimating renal function. PMID- 17710899 TI - Molecular genetic detection of susceptibility to malignant hyperthermia in Belgian families. AB - Malignant hyperthermia is an autosomal dominant myopathy triggered by volatile anesthetics or succinylcholine in susceptible persons. While in vitro contracture testing (IVCT) is the gold standard to establish malignant hyperthermia (MH) susceptibility, genetic analysis is increasingly used to diagnose this condition. This work aimed to determine the frequency and distribution of ryanodine receptor (RYR1) mutations in the Belgian MH-population as investigated by IVCT in our centre, as well as the discordance rates between the 2 techniques. Sequence analysis of 16 RYRI-exons in 29 selected families resulted in the detection of 10 mutations (4 Gly341Arg, 2 Arg614Leu, and 1 Cys35Arg, Arg614Cys, Arg2163Cys and Arg2435His). Discordance between IVCT and mutation analysis was observed in only 6 out of 96 individuals from 4 different families. No mutation-positive/ IVCT negative diagnosis was found. Genetic evaluation of RYR1-mutations can secure a diagnosis and aid in genetic counselling of individual family members but only in those families in which significant clinical information is present, as well as phenotyping by IVCT has been realized. PMID- 17710900 TI - First trimester anesthesia exposure and fetal outcome. A review. AB - Approximately 0.5-2% of all pregnant women undergo nonobstetric surgery during their pregnancy. This percentage does not include patients who are in the early phase of gestation and are not aware of it at the time of surgery. When pregnancy is diagnosed, the concern raises whether surgery and anesthesia during early gestation pose hazard to the developing fetus, by increasing the risk of congenital anomalies and spontaneous abortion. Literature review suggests that there is no increase in congenital anomalies at birth in women who underwent anesthesia during pregnancy. However, first trimester anesthesia exposure does increase the risk of spontaneous abortion and lower birth weight. This is more likely due to surgical manipulation and the medical condition that necessitates surgery than to the exposure to anesthesia. PMID- 17710901 TI - Morphine versus morphine-ketamine association in the management of post operative pain in thoracic surgery. AB - The aim of this study was to assess the quality of postoperative analgesia obtained with morphine-ketamine association administered in self-pain controlled analgesia, as well as the amount of morphine that has been spared. Patients who had to undergo thoracic surgery were selected. They were divided into two groups: G1 was made up of patients receiving 0.5 mg/ml of morphine associated with a placebo, with boluses of 2 ml and refractory periods of 5 minutes ; and G2 made up of patients receiving 0.5 mg/ml of ketamine associated with 0.5 mg/ml of morphine with same boluses and refractory periods. The assessment of pain at rest and on stimulation was carried out with the visual analogue scale. The response to pain and the amount of morphine spared were evaluated. Fifty patients with an average age of 34 years were selected. The assessment showed that the response to pain at rest was the same in the two groups as from the twelfth hour. On stimulation, the analgesic response was better in G2 as well as the amount of morphine spared. This study shows that the administration of ketamine in association with morphine in the post operative period procures a favourable efficiency-tolerance relationship and provides a good means of sparing morphine. PMID- 17710902 TI - Video-assisted laryngoscopy: a useful adjunct in endotracheal intubation. AB - The difficult airway is the single most important cause of anaesthesia-related morbidity and mortality and most catastrophes are due to unexpected difficulty, which are more likely in emergencies. We report a difficult airway scenario in a patient with a high energetic trauma and used several techniques for the "can't intubate, can't ventilate scenario". Eventually, successful intubation was obtained with the video-assisted laryngoscope. PMID- 17710903 TI - [How I became the first anesthesiologist in Saint Pierre Hospital in Brussels in 1947]. AB - Dr Cantinieaux Duwaerts graduated from Brussels Free University (ULB) medical school right after second world war during which she had to attend clandestine classes : The ULB was indeed forced to close in 1941 for its refusal to comply with the German occupants request to dismiss jewish teachers. She performed anesthesia first as a medical student, using ether and ethyl chloride and, when graduated, went to the Netherlands and Sweden in order to get further training in anesthesia, where she got familiar to the techniques of tracheal intubation and to the use of thiopentone and muscle relaxation. Back in Brussels in autumn 1947 she was the first and only anesthesiologist in Saint-Pierre Hospital where she started providing anesthesia for thoracic surgical procedures. At that time she had to supervise several operating rooms at the same time, leaving her patients after induction to the care of a medical student. She also worked in private clinics since the hospital was only offering her a part time job. After 1953 she dedicated herself to a full time anesthesia private practice until 1968 when she decided to retire from anesthesia : most of her surgeons had died and she found a job as medical consultant at the Royal Library. PMID- 17710904 TI - Assessing musculoskeletal performance of the back extensors following a single level microdiscectomy. AB - STUDY DESIGN: A descriptive and exploratory investigation of lumbar extensor performance in persons with a recent history of single-level microdiscectomy. OBJECTIVE: To provide a justification for and outline the procedure of assessing lumbar extensor musculature performance. BACKGROUND: The time of holding an unsupported trunk horizontally, also called the Sorensen test (ST), is often used to test the lumbar extensor endurance of healthy and patient populations, but may need to be modified for some patients. METHODS AND MEASURES: Sixty-eight participants completed a modified ST procedure, along with several questionnaires and performance measures, approximately 4 to 6 weeks after a single-level microdiscectomy. Participants were classified as either able to complete or unable to complete the final position of the modified ST procedure (trunk horizontal). RESULTS: Fifty-one point five percent of the participants could not attain the final position of the modified ST procedure due to either pain or perceived exertion. Those who could not attain the final position of the modified ST procedure had significantly lower scores (compared to those who could) on most measures. A majority (78.8%) of the participants in this study who were unable to complete the ST were correctly classified using the Fear-Avoidance Belief Questionnaire Work Subscale and a 24-hour activity questionnaire. CONCLUSION: The ability to attain the final position of the modified ST procedure was closely associated with fear-avoidance beliefs and physical activity level, suggesting that this test may be too intense (either real or perceived) for many patients within 4 to 6 weeks following a single-level microdiscectomy. PMID- 17710905 TI - Early neuromuscular electrical stimulation to optimize quadriceps muscle function following total knee arthroplasty: a case report. AB - STUDY DESIGN: Case report. BACKGROUND: Following total knee arthroplasty (TKA), restoration of normal quadriceps muscle function is rare. One month after surgery, quadriceps torque (force) is only 40% of preoperative values and quadriceps activation is only 82% of preoperative levels, despite initiating postoperative rehabilitation the day after surgery. Early application of neuromuscular electrical stimulation (NMES) offers a possible approach to minimize loss of quadriceps torque more effectively than traditional rehabilitation exercises alone. CASE DESCRIPTION: A 65-year-old female underwent a right, cemented TKA. Isometric quadriceps and hamstrings muscle torque were measured preoperatively and at 3, 6, and 12 weeks after TKA. Quadriceps muscle activation was measured using a doublet interpolation technique at the same time points. The patient participated in a traditional TKA rehabilitation program augmented by NMES, which was initiated 48 hours after surgery and continued twice a day for the first 3 weeks, and once daily for 3 additional weeks. OUTCOMES: Preoperatively, the involved quadriceps produced 75% of the torque of the uninvolved side and demonstrated only 72.9% activation. At 3, 6, and 12 weeks after TKA, quadriceps torque was greater than the preoperative values of the involved side by 16%, 29%, and 56%, respectively. Similarly, activation improved to 93.4%, 94.6%, and 93.5% at 3, 6, and 12 weeks after TKA. DISCUSSION: Mitigating quadriceps muscle weakness immediately after TKA using early NMES may improve functional outcomes, because quadriceps weakness has been associated with numerous functional limitations and an increased risk for falls. Despite presenting preoperatively with substantial quadriceps torque and activation deficits, the patient in this case demonstrated improvements in quadriceps function at all the times measured, all of which were superior to those reported in the literature. The patient also made substantial improvements in functional outcomes, including the Knee Injury and Osteoarthritis Outcome Score (KOOS), 6 minute walk test, timed up and go (TUG) test, stair-climbing test, and the SF-36 Physical Component Score. Appropriately controlled clinical trials will be necessary to determine whether such favorable outcomes following TKA are specifically attributable to the addition of NMES to the rehabilitation program. PMID- 17710906 TI - Fascicle length change of the human tibialis anterior and vastus lateralis during walking. AB - STUDY DESIGN: A single-group descriptive experimental design. OBJECTIVES: To determine the fascicle length change in the tibialis anterior (TA) and the vastus lateralis (VL) muscles during walking. BACKGROUND: The length of the muscle fibers during isometric actions and during dynamic functional activities is affected by the compliance of the tendon and aponeurosis. The TA and VL muscles have important functions both in stance and swing phases of gait. Therefore, it is important to understand the dynamics of the muscle length change as it relates to the type of muscle actions in walking. METHODS AND MEASURES: Nine healthy subjects performed treadmill walking while fascicle length, muscle activity (electromyographic signal), and joint angle (knee and ankle) were recorded. Fascicle length was measured using real-time ultrasound imaging. Fascicle length and joint angle during the gait cycle were analyzed using a repeated-measures analysis of variance. RESULTS: During the initial portion of stance, when the TA and VL muscles were active, the ankle plantar flexed and the knee joint flexed, suggesting muscle-tendon complex lengthening, but the fascicle length of both muscles remained constant (TA, P = .93; VL, P = .22). The TA muscle was again active during the initial portion of swing phase, while the ankle dorsiflexed, and the fascicle length decreased (P < .05). The VL muscle became active again at the end of swing as the knee extended, and the fascicle length decreased (P < .05). CONCLUSIONS: The lack of change in fascicle length during the initial portions of stance phase suggests a nearly isometric muscle action of the TA and VL. There is a possible interaction occurring between the fascicle and tendon in the TA and VL such that the tendon lengthens to allow joint motion and potentially to store elastic energy. PMID- 17710907 TI - Changes in pain and disability secondary to shoe lift intervention in subjects with limb length inequality and chronic low back pain: a preliminary report. AB - STUDY DESIGN: Preassessment and postassessment of treatment intervention. OBJECTIVE: To determine the changes in pain and disability secondary to shoe lift intervention for subjects with chronic low back pain (LBP) who have a limb length inequality (LLI). BACKGROUND: Previous reports have suggested that LLI may be a cause of LBP Most prior studies of lift therapy for management of LLI in patients with LBP have lacked clear guidelines for clinicians regarding the implementation of shoe lift intervention. METHODS AND MEASURES: Twelve subjects (6 male, 6 female) between the ages of 19 and 62 years with LLI (6.4-22.2 mm) and chronic LBP (1-30 years) participated. Visual analog scale pain ratings and disability questionnaire scores were acquired before and after lift intervention. Subjects determined their lift height based on resolution of LBP symptoms. RESULTS: Subjects experienced relief of general pain symptoms (P = .0006) and pain associated with standing (P= .002) following lift intervention, with minimally clinically important (MCID) reductions in general pain for 9 of 12 subjects and MCID reductions in standing pain for 8 of 10 subjects. Subjects also had less disability on the disability questionnaire (P = .001) following the intervention, with 9 of 12 subjects experiencing MCID reductions in disability. CONCLUSION: Shoe lifts may reduce LBP and improve function for patients who have chronic LBP and an LLI. Randomized controlled trials are needed to assess the efficacy of this intervention. PMID- 17710908 TI - Sex differences in clinical measures of lower extremity alignment. AB - STUDY DESIGN: Descriptive, cohort design. OBJECTIVES: To comprehensively examine sex differences in clinical measures of static lower extremity alignment (LEA). BACKGROUND: Sex differences in LEA have been included among a myriad of risk factors as a potential cause for the increased prevalence of knee injury in females. While clinical observations suggest that sex differences in LEA exist, little empirical data are available to support these sex differences or the normal values that should be expected in a healthy population. METHODS AND MEASURES: The right and left static LEA of 100 healthy college-age participants (50 males [mean +/- SD age, 23.3 +/- 3.6 years; height, 177.8 +/- 8.0 cm, body mass, 80.4 +/- 11.6 kg] and 50 females [mean +/- SD age, 21.8 +/- 2.5 years; height, 164.3 +/- 6.9 cm; body mass, 67.4 +/- 15.2 kg]) was measured. Each alignment characteristic was analyzed via separate repeated-measures analyses of variance, with 1 between-subject factor (sex) and 1 within-subject factor (side). RESULTS: There were no significant sex-by-side interactions and no differences between sides. Females had greater mean anterior pelvic tilt, hip anteversion, quadriceps angles, tibiofemoral angles, and genu recurvatum than males (P < .0001). No sex differences were observed in tibial torsion (P = .131), navicular drop (P = .130), and rearfoot angle (P = .590). CONCLUSION: Sex differences in LEA indicate that females, on average, have greater anterior pelvic tilt, thigh internal rotation, knee valgus, and genu recurvatum. These sex differences were not accompanied by differences in the lower leg, ankle, and foot. Understanding these collective sex differences in LEA may help us to better examine the influence of LEA on dynamic lower extremity function and clarify their role as a potential injury risk factor. PMID- 17710909 TI - Effects of low-voltage microamperage stimulation on tendon healing in rats. AB - STUDY DESIGN: Randomized controlled prospective experimental study. OBJECTIVES: To examine the effects of transcutaneous low-voltage microamperage stimulation (LVMAS) on the mechanical strength of Achilles tendon repair in rats at 4 weeks after injury. BACKGROUND: Understanding the effect of LVMAS on the healing of injured tendons is hampered by the lack of related experimental studies, especially from the aspect of biomechanical outcome measures. METHODS AND MEASURES: Fourteen 3-month-old male Sprague-Dawley rats received surgical transection to the medial portion of their right Achilles tendon. The rats were divided into a LVMAS group (n = 7) and control group (n = 7). From day 6 postsurgery onwards, the LVMAS group received daily treatment of transcutaneous LVMAS (2.5 V, 100 microA/cm2, 10 pulses per second, positive current) for a total of 22 sessions, while the control group received placebo LVMAS by the same investigator during that period. On day 31, the Achilles tendons were harvested for biomechanical testing for load relaxation, stiffness, and ultimate tensile strength along the longitudinal direction. RESULTS: The normalized Achilles tendon ultimate tensile strength of the LVMAS group (mean +/- SD, 110.5% +/- 25.0%) was higher than that of the control group (75.3% +/- 20.8%) (P = .014), but no significant difference was found in normalized stiffness and load relaxation between the 2 groups (P = .239 and .350, respectively). CONCLUSION: The results of this study suggest that the administration of transcutaneous LVMAS could improve healing and consequently the tensile strength of partially transected Achilles tendons of rats at 4 weeks after injury. PMID- 17710910 TI - Case series utilizing drop-out casting for the treatment of knee joint extension motion loss following anterior cruciate ligament reconstruction. AB - STUDY DESIGN: Case series. CASE DESCRIPTION: Four patients who had developed knee extension motion loss following anterior cruciate ligament reconstruction were referred to physical therapy for treatment. They were treated with drop-out casting and completed a Lower Extremity Functional Scale at baseline, at the time of application of the drop-out casting, and at discharge. OUTCOMES: Three males and 1 female with a mean age of 20.5 years (range, 18-22 years) were referred to physical therapy a mean of 31 days (range, 19-49 days) following bone-patella tendon-bone autograft anterior cruciate ligament reconstruction. The mean number of physical therapy sessions attended was 29.5 visits (range, 20-47 visits). The mean improvement in knee extension range of motion (ROM) and knee flexion ROM prior to the application of drop-out casting was 4.3 degrees (range, -1 degree to 10 degrees) and 24.3 degrees (range, 0 degree to 40 degrees), respectively. The mean improvement on the Lower Extremity Functional Scale was 10.3 points prior to drop-out casting. At time of discharge, the total mean improvement in knee extension ROM loss was 11.0 degrees (range, 4 degrees to 15 degrees), knee flexion ROM was 30.8 degrees (range, 22 degrees to 35 degrees), and Lower Extremity Functional Scale was 12 points (range, -5 to 21 points). Two of the patients were able to complete a running program without difficulty, while the other 2 patients had difficulty with higher-level activities. DISCUSSION: Despite the low incidence of knee extension ROM loss following surgery, the inability to achieve full knee extension does occur and can have debilitating consequences. When early emphasis of full passive knee extension has been inadequate, these results suggest that improving knee extension motion without inhibiting knee flexion motion is possible with the use of a drop-out cast. Future research should focus on comparison of drop-out casting to dynamic splinting, as well as the optimal frequency and duration of low-load long-duration stretching using a drop-out cast. PMID- 17710911 TI - Does evidence support the existence of lumbar spine coupled motion? A critical review of the literature. PMID- 17710913 TI - Quo vadis. PMID- 17710912 TI - The effect of anterior versus posterior glide joint mobilization on external rotation range of motion in patients with shoulder adhesive capsulitis. PMID- 17710914 TI - Uniformity of domestic wastewater effluent application in a subsurface drip distribution system. AB - An on-site wastewater treatment project with two separate drip fields was operated for 6 years and received no maintenance. The two drip fields (with different design configurations) contained pressure-compensating emitters (PC) and non-pressure-compensating emitters (NPC), respectively, and received wastewater with an average 5-day biochemical oxygen demand concentration of 23 mg/L. Flowrates of the PC emitters reduced from rated average of 3.50 to 1.00 L/h, and the average flowrate of the NPC emitters reduced from 2.00 to 1.53 L/h. The statistical uniformities were 48 and 71%, and the uniformity coefficients were 70 and 86% for PC and NPC emitters, respectively. Significant, but incomplete, recovery was achieved with field-flushing and consecutive shock chlorination treatments of 500 and 1000 mg/L. PMID- 17710915 TI - The use of active metabolism and swimming activity to evaluate the toxicity of dodecyl benzene sodium sulfonate (LAS-C12) on the Mugil platanus (Mullet) according to temperature and salinity. AB - Active metabolism and swimming activity were used to study the effects of dodecyl benzene sodium sulfonate (LAS-C12) in Mugil platanus, a species traditionally considered as estuarine. The effects of exposure to different concentrations of LAS-C12 (0.0, 1.0, 2.5, and 5.0 mg/L) on the active metabolism and swimming activity of Mugil platanus were evaluated. The active metabolism and swimming activity were estimated through experiments conducted on each of 9 possible combinations of three temperatures (35, 20, and 15 degrees C) and three salinities (35, 20, and 5 per thousand). The results show that the active metabolism increases according to the LAS-C12 concentration in all temperatures and salinities studied. At the highest tested concentration (5.0 mg/L), the active metabolism was 111%; 84.8 and 105% higher than the control, at 35 per thousand salinity at the three temperatures. However, the swimming activity decreased according to the LAS-C12 concentration in all temperatures and salinities studied. At the highest tested concentration, the swimming activity was 78.6, 73.6, and 78.7% less than the control, at 25 degrees C at the three salinities. The active metabolism and swimming activity averages, achieved in the different salinities studied, were not significantly different, as a result of the LAS-C12 concentration. PMID- 17710916 TI - Assessment of Bacillus subtilis spores as a possible bioindicator for evaluation of the microbicidal efficacy of radiation processing of water. AB - Gamma and electron-beam irradiation of Bacillus subtilis spores suspended in different types of water was studied to evaluate the inactivation of the spores and assess their possible use as a bioindicator for radiation processing. We found that the inactivation proceeded endogenously, being dose-rate-dependent and affected by oxygen. The radiation resistance of the suspended spores was found to be rather high; therefore, B. subtilis spores used as a bioindicator for efficiency of water treatment by radiation under practical conditions might result in the spores being overly conservative surrogates for pathogenic microorganisms. Moreover, the doserate dependency impedes the use of the spores as a bioindicator. Thus, B. subtilis spores cannot be recommended as a bioindicator for evaluation of the microbicidal efficacy of ionizing radiation processing of water. PMID- 17710917 TI - Kinetics of particulate organic matter removal as a response to bioflocculation in aerobic biofilm reactors. AB - Recent research has identified that the major fraction of chemical oxygen demand in domestic wastewaters is in particulate form. The research presented herein develops the kinetics of particle removal as a response to bioflocculation at the surface of aerobic biofilms. This study focuses on the removal of particles that are maintained in aqueous suspension after 30 minutes of gravity settling. It is helpful to consider the particulate organics removal process in biofilms as the sum of four steps, namely (1) external transport of the particles to the biofilm surface, (2) bioflocculation, (3) organic particulate hydrolysis, and (4) diffusion and reaction of the solubilized organics by the bacterial cells comprising the biofilm. Organic (native corn starch) and inorganic particle (Min U-Sil 10 [U.S. Silica Company, Berkeley Springs, West Virginia]) suspensions, with micronutrients, were continuously fed to a rotating disc biofilm reactor to verify a first-order kinetic expression that has been used to describe bioflocculation and to demonstrate that bioflocculation is the primary particle removal mechanism. Extracellular polymeric substances were extracted and quantified to describe the role they play in the bioflocculation process. PMID- 17710918 TI - Metal distributions in soil receiving urban pavement runoff and snowmelt. AB - Wet and dry deposition of anthropogenic metals and particulates generated from urban and traffic activities can result in contamination of urban-land-use soils. These particulate residuals encompass a wide size gradation, from 1 to greater than 10 000 microm. This study hypothesized that such contamination of surficial soils can be analyzed and explained as a function of the soil/residual granulometry. This study analyzed the gradation-based physical characteristics for 10 urban transportation land-use sites with soil/residual complexes (SRCs) located throughout metropolitan Cincinnati, Ohio, and an urban residential reference site. Particle density (rho(s)) of SRCs ranged from 2.8 to 2.1 g/cm3, with the lower particle density associated with particles less than 100 microm. For each site, specific surface area generally increased with decreasing particle size, while the predominance of total surface area was associated with the coarser size fractions, except for the clayey glacial till reference site not influenced by traffic. Cumulative analysis for lead, copper, cadmium, and zinc associated with SRCs indicated that more than 50% of the metal mass was associated with particles greater than 250 microm, with more than 80% associated with particles greater than 106 microm. Study results are similar to rainfall runoff and snowmelt distributions. Results provide guidance when considering potential fate and control of metals transported by urban drainage and are distributed across the SRC size gradation. PMID- 17710919 TI - Study of using microfiltration and reverse osmosis membrane technologies for reclaiming cooling water in the power industry. AB - A study of using dual membrane technologies, microfiltration (MF) and reverse osmosis (RO), for reclaiming blowdown of the cooling tower was conducted at ZJK power plant, Hebei province, China. The study shows that the combined MF-RO system can effectively reduce water consumption in the power industry. The results indicate that MF process is capable of producing a filtrate suitable for RO treatment and achieving a silt density index (SDI) less than 2, turbidity of 0.2 NTU. The water quality of RO effluent is very good with an average conductivity of about 40 micros/cm and rejection of 98%. The product water is suitable for injection into the cooling tower to counteract with cooling water intrusion. After adopting this system, water-saving effectiveness as expressed in terms of cycles of concentration could be increased from 2.5-2.8 times to 5 times. PMID- 17710920 TI - Degradation of nitrogen-heterocyclic compounds by anodic oxidation and electro Fenton methods. AB - This study describes the degradation of nitrogen-heterocyclic compounds (NHCs) by anodic oxidation and electro-Fenton. Using indole as a model nitrogen heterocyclic compound, the removal of indole reached 68% and 97% by anodic oxidation and electro-Fenton, respectively, while the decay of TOC was 15% and 38% correspondingly. By the analysis of ultraviolet-visible spectra and liquid chromatography/mass spectrum, the degradation mechanism of indole by electro Fenton was proposed as hydroxyl oxidation and anodic oxidation. The degradation of other NHCs including quinoline, isoquinoline and pyridine by anodic oxidation and electro-Fenton revealed the same sequence: quinoline approximately equal isoquinoline > indole >> pyridine. A significant correlation between ln k (natural logarithm of rate constants) and E(LUMO) (the energy of the lowest unoccupied molecular orbit) was obtained by quantitative structure-activity relationship analysis. Degradation of coking plant wastewater showed the removal of COD and TOC were 42% and 22% respectively after 180 min treatment by electro Fenton. PMID- 17710921 TI - Recycled and virgin plastic carriers in hybrid reactors for wastewater treatment. AB - The reduction of organic and nitrogen pollution of wastewater was investigated in two hybrid reactors and compared with the reduction obtained by using a conventional activated sludge reactor (ASR) run as a control. Both HR-1 and HR-2 were activated sludge systems where a low-density carrier, P1 (polyethylene) for HR-1 and P2 (recycled plastics) for HR-2, was added. Firstly, the three reactors were operated at 10 days Suspended Solid Retention Time (SRT(SS)), leading to a complete nitrification. Secondly, the SRT(SS) for each reactor was lowered to 3 days. Nitrification was lost for the ASR but remained complete for HR's. Respirometric techniques were used to measure fixed or suspended biomass activities for heterotrophic and autotrophic biomass. More than 90% of the autotrophic activity was found on the supports whatever the SRT(SS) used. The results may underline the role of the carrier geometry or surface characteristics on the autotrophic/heterotrophic microorganism distribution. PMID- 17710923 TI - Differential pressure in membrane channel caused by foulant capture onto spacers. AB - Feed spacers in spiral-wound reverse osmosis membrane modules are highly susceptible to deposition or attachment of suspended particulates and organic matters in the feed stream. This type of fouling can cause a significant pressure drop along the membrane channel (differential pressure) without much effect on the average permeate flux. In practical applications, membrane cleaning is often triggered when the differential pressure in a membrane channel exceeds a threshold value. A mathematical model was developed to simulate the development of differential pressure in the feed channel resulting from foulant capture by the feed spacers. Simulations were carried out to investigate and demonstrate the effect of various parameters on differential pressures in the membrane channel. Differential pressures observed in a two-stage reverse osmosis water reclamation plant were simulated with the model, and the results showed that the model could adequately describe the increase of differential pressure with operating time in the reverse osmosis plant. PMID- 17710922 TI - Wastewater disinfection by peracetic acid: assessment of models for tracking residual measurements and inactivation. AB - With its potential for low (if any) disinfection byproduct formation and easy retrofit for chlorine contactors, peracetic acid (PAA) or use of PAA in combination with other disinfectant technologies may be an attractive alternative to chlorine-based disinfection. Examples of systems that might benefit from use of PAA are water reuse schemes or plants discharging to sensitive receiving water bodies. Though PAA is in use in numerous wastewater treatment plants in Europe, its chemical kinetics, microbial inactivation rates, and mode of action against microorganisms are not thoroughly understood. This paper presents results from experimental studies of PAA demand, PAA decay, and microbial inactivation, with a complementary modeling analysis. Model results are used to evaluate techniques for measurement of PAA concentration and to develop hypotheses regarding the mode of action of PAA in bacterial inactivation. Kinetic and microbial inactivation rate data were collected for typical wastewaters and may be useful for engineers in evaluating whether to convert from chlorine to PAA disinfection. PMID- 17710924 TI - Removal of selected natural and synthetic estrogenic compounds in a Canadian full scale municipal wastewater treatment plant. AB - The effect of a full-scale municipal wastewater treatment plant (WWTP) and each of the treatment units within the stream on the removal of endocrine-disrupting compounds was evaluated by tracking 17-beta-estradiol (E2), estrone (E1), and 17 alpha-ethinylestradiol (EE2). The overall performance of the WWTP compared well with other plants, as 90.5% removal of E1+E2 and 74.9% removal of EE2 were observed. A larger fraction of EE2 entered the plant in particulate form than E1 and E2, while a lower fraction of EE2 left the plant in particulate form than soluble form. The activated sludge units reduced the concentration of E1+E2 and EE2 in the liquid phase by 88.2% and 44.6%, respectively. The UV treatment process did not reduce the amount of estrogens. The aqueous phase of the tertiary lagoon solids contained higher levels of estrogens compared with the lagoon influent. PMID- 17710925 TI - Improvement of upflow anaerobic sludge bed performance using chitosan. AB - Chitosan, with a degree of deacetylation of 85% and a molecular weight of 2.5 x 10(5) Da, yielding high flocculation efficiency (85 to 100% flocculation) and a broad flocculation region (2 to 45 mg/g suspended solids), was selected for accelerating granulation in a 30-L upflow anaerobic sludge bed (UASB) used to treat wastewater from a tropical fruit-processing industry. Compared with other studies, smaller amounts of chitosan were applied (two injections with 2 mg chitosan/g suspended solids in the reactor at each injection). Comparison with the UASB without chitosan addition, the UASB had a 24 to 37% larger particle size and a 6 to 41% longer solids retention time. In addition, the reactor performances were also enhanced. The UASB with chitosan addition had a 9 to 59% lower effluent chemical oxygen demand (COD), 4 to 10% higher COD removal, up to 35% higher biogas production rate, and a 16 to 68% lower biomass washout. The paired t-test analysis indicated that these performance parameters were significantly different (P < 0.05). PMID- 17710926 TI - Ultraviolet spectrophotometric determination of nitrate: detecting nitrification rates and inhibition. AB - Simple methods that rapidly detect nitrification inhibition are needed to enforce pretreatment programs and prevent upsets. The objective of this study was to demonstrate a rapid method for measuring nitrification inhibition by using nitrate generation rates (NGRs) coupled with direct UV detection of nitrate. The NGRs were measured with UV spectrophotometry at wavelengths between 225 and 240 nm, without chemical manipulation, and verified against ion chromatography. The method was shown to quickly and accurately measure nitrate concentrations after correcting for nitrite interference. Cadmium, hypochlorite and 1-chloro-2,4 dintrobenzene (CDNB) were tested for their ability to cause nitrification inhibition using this method. The CDNB was found to cause a correctable interference with the test, while hypochlorite provided an uncorrectable interference. Used as a batch method coupled with biotic and abiotic controls, this approach can be deployed at full-scale treatment plants as a relatively rapid (1.5 hours) means of identifying nitrification-inhibiting wastewaters. PMID- 17710927 TI - Multivariate analysis of Almendares River waters. AB - The Almendares River is the most important surface water body of the Cuban capital, Havana. In the present work, the environmental quality of waters was studied as a function of the following 14 variables: content of calcium, cadmium, iron, potassium, magnesium, manganese, sodium, nickel, zinc, chlorine, bicarbonate, and sulfate; pH; and electric conductivity parameters, which were reduced to three new variables by means of principal component analysis (PCA). The content of metal increased in waters sampled at stations located near garbage dumps and decreased inside the Ejercito Rebelde dam. The variation of the river water environmental quality with rainy and dry seasons and the differentiation of samples in three groups along the river course were obtained by PCA and corroborated by discriminant analysis. Applied statistical techniques showed their ability for environmental interpretation of limited experimental data. PMID- 17710929 TI - 'Ward managers are the key to tackling HCAIs'. PMID- 17710928 TI - Is the London NHS plan the blueprint? PMID- 17710930 TI - 'Observations are vital to recognising and responding to acute illness'. PMID- 17710931 TI - The whisleblowing dilemma. PMID- 17710932 TI - How to play the obesity mind game. PMID- 17710933 TI - Preventing skin cancer through sun protection. PMID- 17710934 TI - Sense of sight: part two. Seeing in colour, detail and depth. AB - This article is the second in a three-part series on the sense of sight. It forms part of a larger series on the special senses. The first article on sight examined the structures of the eye, the visual pathway and various disorders of the eye. This second article explores how the eye sees colour, detail and depth. PMID- 17710936 TI - Home care: keeping the Hebert family together. PMID- 17710935 TI - Assessing pain in people with dementia 2: the nurse's role. AB - This is the second in a two-part unit on dementia and pain assessment. The first part examined research on pain in people with dementia and the challenges nurses face with pain assessments. This part explores evidence on the methods and tools available to nurses and other care providers to use in pain assessment. It also outlines some practical implications. PMID- 17710937 TI - President George W. Bush proposes cutting Medicare (and Medicaid) by more than $100 billion over the next five years including excessive and disproportionate cuts to home care. PMID- 17710938 TI - Medicare's Home Health Pay-for-Performance demonstration: a preview. PMID- 17710939 TI - PPS reform: the risks of the budget neutrality adjustment. PMID- 17710940 TI - National Association for Home Care & Hospice: key legislative issues. January 2007. PMID- 17710941 TI - The managed care/Medicare advantage challenge: interface between home care and managed care fraught with tensions. PMID- 17710942 TI - Medicare hospice benefit needs to evolve. PMID- 17710944 TI - Private duty home care licensure: it's the right thing to do. PMID- 17710943 TI - Can home care agencies find their own Medicaid balance? PMID- 17710945 TI - HCTAA's public policy agenda for 110th Congress. PMID- 17710946 TI - Luck is not a strategy! PMID- 17710947 TI - Creation is tough work. AB - In the increasingly hostile ecosystem of health care, we all are startled to find ourselves in a place far from what any caregiver ever imagined could evolve from a simple desire to "take care of the sick." We have been saddled with rules, regulations, payer demands, and legislation that trumps care with politics. Even this month's publication is devoted to setting policy agendas, top legislative priorities, and the new congress seems so removed from its title of CARING. PMID- 17710948 TI - How to plan, organize, and conduct your next executive strategy retreat. PMID- 17710949 TI - Barbaro lessons. PMID- 17710950 TI - When customers are satisfied, there are no stories. PMID- 17710951 TI - A primer on e-referrals. PMID- 17710952 TI - Protecting our national security. PMID- 17710953 TI - Upping the ante again: clinical topics and the EBP process. PMID- 17710954 TI - Effect of environmental changes on noise in the NICU. AB - PURPOSE: To evaluate the effect of changes in the NICU environment on sound levels. DESIGN: A prospective quasi-experimental design evaluated sound levels in a 43-bed NICU. Decibel levels were monitored utilizing a data-logging dosimeter for 24 hours weekly over 12 months. Sound levels were also measured inside four different incubator models. SAMPLE: Forty-four 24-hour decibel recordings were obtained in one of eight randomly selected four-bed pods. In addition, a single 1 hour recording was obtained in four different models of vacant incubators. MAIN OUTCOME VARIABLE: Ambient sound levels. RESULTS: Decibel levels were analyzed to identify changes in noise levels following alterations in the NICU environment. Installation of motion-sensing motorized paper towel holders significantly increased levels at beds closest to the towel dispensers, as did thetrial of a new communication system. Decibel levels in four different incubators revealed varying noise levels. This study suggests that all environmental changes must be monitored to ensure that they reduce rather than increase noise levels. PMID- 17710955 TI - Neonatal subgaleal hemorrhage. AB - Subgaleal hemorrhages, although infrequent in the past, are becoming more common with the increased use of vacuum extraction. Bleeding into the large subgaleal space can quickly lead to hypovolemic shock, which can be fatal. Understanding of anatomy, pathophysiology, risk factors, differential diagnosis, and management will assist in early recognition and care of the infant with a subgaleal hemorrhage. PMID- 17710956 TI - Roles of long-chain polyunsaturated fatty acids in the term infant: developmental benefits. AB - Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are two long-chain polyunsaturated fatty acids (LCPUFAs) found naturally in human milk. DHA and ARA have been receiving increased attention from health care professionals and the public. Research suggests that DHA intake and status have a significant impact on visual and cognitive development in breastfed infants. For formula-fed infants, studies have shown mixed results from DHA or DHA plus ARA supplementation. There are several important differences among LCPUFA studies with term infants that may contribute to the differing results, including levels of LCPUFA added to the formula, variations in test methods, ages of infants evaluated, and sources of LCPUFA. Nevertheless, several expert groups recommend that infant formulas be supplemented with DHA and ARA. Recommendations for term infants for DHA and ARA range from 0.2 percent to 0.4 percent and from 0.35 percent to 0.7 percent of the fatty acids, respectively. PMID- 17710957 TI - Fetal nutrition and adult hypertension, diabetes, obesity, and coronary artery disease. AB - The fetal-origins-of-adult-disease hypothesis describes an adaptive phenomenon of in utero reprogramming of the undernourished fetus that predisposes the infant to increased morbidity as an adult. Studies have identified a positive association between indicators of fetal undernutrition such as low birth weight and chronic adult diseases like hypertension, diabetes, obesity, and coronary artery disease. Current research is focusing on determining other factors that may contribute to these chronic adult diseases. PMID- 17710958 TI - Sodium and potassium homeostasis. PMID- 17710959 TI - The therapeutic use of honey. AB - Honey has been shown to have antibacterial activity against a variety of species of bacteria in vitro. Although the evidence regarding the use of honey for wound treatment in neonates and infants is interesting, it is not strong. The sample sizes in the cited clinical studies are small; there were no comparison groups and no randomization. It appears that honey may be safe and useful in treating difficult-to-heal infected wounds, but double-blinded randomized controlled clinical trials with sufficient power are needed to determine the efficacy of honey in both initial wound management and secondary treatment of infected and poorly healing wounds. A comparison of different types of honey would be an important component of these trials. Currently, there is not enough evidence to recommend one type of honey over another type; however, honey and wound care experts do recommend honey for wound care, not for consumption. PMID- 17710961 TI - Keeping the wisdom at work. AB - There is a looming shortage of nurses with a diminishing pool of talent to staff the nation's NICUs. One critical strategy is to retain the talent and experience base of the older nurse. The replacement of experienced nurses is very costly to the unit and negatively impacts quality of care, patient safety, productivity, and unit cohesion. Older nurses can, do, and will make choices about where they work. Organizations have a responsibility to respond to their needs and align strategies aimed at their retention. Understanding the needs of older nurses will enable managers to better retain the staff they lead. PMID- 17710960 TI - Thyroid hormone levels in term and preterm neonates. AB - Screening for thyroid hormone levels in the first week of life is extremely important to identify infants with CH. Worldwide neonatal screening programs have been successful in decreasing childhood mental retardation related to CH by early detection and treatment. To successfully screen for CH, nurses must understand how to draw blood that will yield valid results on the metabolic screening filter paper. It is also important for the nurse to understand that thyroid levels are normally decreased in preterm infants and that regular follow-up of those low thyroid levels is crucial because levels may return to normal and eventual treatment is necessary. Early follow-up testing and treatment are essential. A thyroid scan or ultrasonography is optional and decided on by evaluating the risk benefit ratio. PMID- 17710962 TI - The role of the NNP in facilitating family-centered care. PMID- 17710963 TI - Rate of abnormal results from repeated screening tests for gestational diabetes mellitus after normal initial tests. AB - OBJECTIVE: To evaluate the rate of abnormal results of repeated screening tests for gestational diabetes mellitus when initial tests were normal and related factors. SUBJECTS: Six hundred women who had clinical risk factors for gestational diabetes mellitus (GDM) who attended the antenatal care clinic at Siriraj Hospital before 24 weeks of gestation, between January and June 2005 were recruited All had normal screening test. MATERIAL AND METHOD: All subjects were followed throughout their pregnancies. All received repeated screening and confirmatory test at 28-32 weeks ofgestation. All data of screening and confirmatory test results were collected and analyzed. RESULTS: Six hundred pregnant women who had normal screening test for GDM were enrolled Eighty-seven cases failed to take the second screening test. Of the remaining 513 cases, 154 (30.0%, 95% CI 28.2%-36.3%) had abnormal results in repeated screening tests. Among them 20 cases (3.9%) were diagnosed as GDM. Pregnant women who were > or =30 years old or had result of 50 g GCT > or =120 mg/dl had significant increased risk for abnormal repeated screening tests. CONCLUSIONS: Pregnant women with clinical risk of GDM should receive repeated screening tests when they are 28-32 weeks of gestation. Higher risk was observed among women > or =30 years old or those with a result of 50 g GCT > or =120 mg/dl. PMID- 17710965 TI - Risk assessment of preeclampsia in advanced maternal age by uterine arteries Doppler at 17-21 weeks of gestation. AB - OBJECTIVE: To assess the risk of preeclampsia development in elderly gravidarum by uterine arteries Doppler at 17-21 weeks' gestation. MATERIAL AND METHOD: Pulsatility index (PI) of the uterine arteries was measured by color Doppler transabdominal sonography in 298 elderly gravida women at 17-21 weeks of gestation. The criterion for abnormal results was PI > 95th percentile of each gestational age and/or the presence of bilateral notches. The major end point was preeclampsia. RESULTS: Ten woman (3.4%) developed preeclampsia. Two hundred and eighty-four women (95.3%) had a normal Doppler flow of uterine arteries (PI < or =95th percentile of each gestational age), and 14 woman (4.7%) had abnormal Doppler flow of uterine arteries. The sensitivity, specificity, and positive and negative predictive values for detecting preeclampsia were 20%, 95.8%, 14.3%, and 97.2%, respectively. CONCLUSION: Women with mean PI > 95th of each gestational age have a high risk of developing preeclampsia. With the high negative predictive value, this test may be useful to minimize unnecessary interventions. PMID- 17710964 TI - Challenges in the conduct of Thai herbal scientific study: efficacy and safety of phytoestrogen, pueraria mirifica (Kwao Keur Kao), phase I, in the alleviation of climacteric symptoms in perimenopausal women. AB - OBJECTIVE: To evaluate the preliminary efficacy and safety of Pueraria mirifica (Kwao Keur Kao), phytoestrogen, for the alleviation of climacteric symptoms. MATERIAL AND METHOD: Perimenopausal women attending with climacteric symptoms, such as hot flushes and night sweats, were invited to join the present study, conducted at the Menopausal Clinic, Hat Yai Regional Hospital. The patients were voluntarily enrolled and randomly received the raw material of Pueraria mirifica, oral 50 and 100 mg capsule, once daily for six months, as an open-label study. RESULTS: Of the 10 enrolled patients, 8 cases were completely evaluated. The modified Greene climacteric scale (MGCS) was satisfactorily decreased in both groups. The average scale declined from 44.1 at baseline, to be 26, 17, and 11.1 at 1-, 3-, and 6- month follow-up respectively. No other laboratory abnormalities, except one case had transiently increased the creatinine level, and one case of increased blood urea nitrogen. The mean serum estradiol was slightly increased, while the mean serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were nearly stable. CONCLUSION: Pueraria mirifica is relatively safe and preliminarily alleviates the climacteric symptoms in perimenopausal. women, but the data is insufficient to draw definite conclusions regarding the estrogenic effect. PMID- 17710966 TI - Risk factors related to group B streptococcal colonization in pregnant women in labor. AB - OBJECTIVE: To determine the risk factors related to group B streptococcal (GBS) colonization in pregnant women on admission in labor MATERIAL AND METHOD: From the 1st-30th October 2004, at the Rajavithi Hospital, 320 pregnant women, who fulfilled the specified criteria, were selected for a cross-sectional descriptive study. Swabs were cultured from the lower vagina and anorectum for GBS using Todd Hewitt broth with nalidixic acid 15 microg/ml and gentamicin 8 microg/ml only. RESULTS: Colonization was present in 58 cases (18.12%). The risk factor for GBS colonization was an older mean maternal age and a lower mean gestational age. No mothers or neonates during the study period developed a clinical infection from GBS. CONCLUSION: The risk factors for GBS colonization in pregnant women were older maternal age and lower gestational age. PMID- 17710967 TI - Risk factors of retained placenta in Siriraj Hospital. AB - OBJECTIVE: To identify risk factors associated with retained placenta after vaginal delivery. DESIGN: Case-control study. MATERIAL AND METHOD: Medical records of 234 pregnant women whose gestational age > or =28 weeks were reviewed. Cases comprised of 78 women with retained placenta after vaginal delivery and controls comprised of 156 women with spontaneous placental delivery. Associated risk factors were examined Chi-square test and logistic regression analysis were used for analysis of data. RESULTS: Cases were significantly older than controls (29.3 +/- 6.4 vs. 27.0 +/- 6.4 years respectively, p = 0.01). Cases were likely more significant than controls to have a previous history of uterine curettage (20.5% vs. 6.4% respectively, p = 0.001) and premature rupture of membranes (35.9% vs. 22.4% respectively, p = 0.029). Between the two groups, there were no differences in gestational age, parity, previous abortion, induction of labor, oxytocin, and pethidine usage. Logistic regression analysis showed that independent risk factors for retained placenta were age (adjusted OR 1.06, 95% CI 1.01-1.11), previous uterine curettage (adjusted OR 4.2, 95% CI 1.7-9.9), and PROM (adjusted OR 2.2, 95% CI 1.2-4.1). CONCLUSION: Maternal age, previous uterine curettage, and PROM were independently associated with increased risk of retained placenta. The condition should be aware of among pregnant women with such risk factors. PMID- 17710968 TI - Seizure in non-HIV cryptococcal meningitis. AB - OBJECTIVE: The authors studied the prevalence of seizure in non-HIV cryptococcal meningitis. MATERIAL AND METHOD: The records of non-HIV adult patients (age >15 years) diagnosed as cryptococcal meningitis in Srinagarind Hospital (Khon Kaen University) from 1990 to 1994 were reviewed All subjects were studied for the rate, pattern, and long-term result ofseizure. RESULTS: There were 105 cases. Eight patients (7.6%) had seizures at initial presentation. The pattern of seizure of six patients was generalized tonic-clonic seizure (GTC) and the others were focal seizure. Only one case still had seizures after treatment with conventional therapy of cryptococcal meningitis. At ten years follow up, ten cases had died, one patient still had seizures (the same case that had seizures after treatment) and one case with developed GTC after improvement of meningitis. CONCLUSION: GTC was the common pattern of seizure in non-HIV cryptococcal meningitis and mostly controlled by standard regimen of therapy for cryptococcal meningitis without any antiepileptic drugs. PMID- 17710969 TI - Clinical manifestation and survival of patients with small-cell lung cancer. AB - OBJECTIVE: To assess the clinical manifestation, diagnostic investigation, treatment, and survival of patients with small-cell lung cancer (SCLC). DESIGN: Retrospective study. MATERIAL AND METHOD: Patients with histologically and/or cytologically proven SCLC, adequate medical record for clinical history, and survival between January 1, 1999 and December 31, 2003, were reviewed. The stage of disease at presentation was based on the Veterans' Administration Lung Cancer Study Group (VALSG) staging system of limited-stage and extensive-stage disease. RESULTS: One hundred and sixteen evaluative SCLC patients were enrolled in the present study. SCLC was common in elderly men who smoked. Major symptoms were cough 81%, weight loss 72%, and dyspnea 67%. Hoarseness and superior vena cava syndrome (SVC syndrome) were present in 18% and 17% respectively. Forty-nine patients (42%) presented with limited-stage disease and 67 (58%) with extensive stage disease. Thirty patients (26%) received chemotherapy alone, 23 patients (20%) received radiotherapy alone, 33 patients (28%) received combined chemoradiotherapy, and 30 patients (26%) received supportive treatment. A chemotherapy regimen of cisplatin combined with etoposide was used in 61 of 63 patients (97%). The overall response to chemotherapy was complete remission in 12 cases (19%), and partial response in 20 cases (32%). The median survival of limited-stage disease was significantly better than those with extensive-stage disease (44 weeks vs. 22 weeks). Patients with chemotherapy treatment had significantly improved median survival in both limited-stage and extensive-stage disease. CONCLUSION: More than half of the SCLC patients presented in extensive stage disease. The majority of the patients were treated with systemic chemotherapy. Patients with limited-stage disease had better response to chemotherapy and better survival than those with extensive-stage disease. PMID- 17710970 TI - 375 childhood primary headache: clinical features, the agreement between clinical diagnosis and diagnoses using the international classification of headache disorders in Thai children. AB - OBJECTIVE: To study the clinical features of patients with headache and agreement between clinical diagnoses and ICHD II criteria diagnosis in primary headaches in Thai children. MATERIAL AND METHOD: Patients with headache who, over a 4-year period, consulted the neurological clinic, were interviewed by questionnaire, examined, diagnosed, treated, and followed up by pediatric neurologists. The result from the questionnaire was used to define the type of headache according to the ICHD II criteria. The clinical features were analyzed and clinical diagnosis was compared with diagnoses using the International Classification of Headache disorders. RESULTS: Three hundred and seventy-five primary headache patients were defined by ICHD II criteria. One hundred twenty eight (35.2%) were migraine, 47 (12.5%) were tension-type, 123 (33.3%) were probable migraine, 31 (8.3%) were probable tension-type, and 40 (10.7%) cannot be classified because the symptoms were not compatible with diagnosed criteria. Using clinical diagnosis as the standard, the sensitivity of the ICHD-based definition of migraine without aura and probable migraine was 89.96% whereas the specific was 65.09%. On the other hand, the sensitivity of the International Classification of Headache disorders-based definition of infrequent episodic tension-type and probable infrequent episodic tension-type was 56.34% whereas the specific was 87.50%. CONCLUSION: The present study shows the increase of sensitivity but decrease of the specificity of ICHD II criteria in diagnosed pediatric migraine headache. However, the duration of attack and quality of headache are still the limitation of diagnosis for pediatric headache. Therefore, the diagnosis criteria in pediatric headache should be developed distinctly from adults. PMID- 17710971 TI - Fecal alpha1--antitrypsin in healthy and intestinal-disorder Thai children. AB - OBJECTIVE: Determine the normal FA1-AT level in random wet stool of Thai children using RID and NPL, and to study the correlation between RID and NPL methods for measurement of FA1-AT. MATERIAL AND METHOD: Random stool samples were collected from healthy children and intestinal-disorders patients. Alpha1-antitrypsin (FA1 AT) in wet stool samples was measured by nephelometry (NPL) and radial immunodiffusion (RID) methods. RESULTS: Newborn infants had the highest FA1-AT level during the first day of life and declined to the same level as older children on day 3-4. Median and geometric mean of FA1-AT levels by NPL from healthy children aged 1 month-15 years was 1.23 and 1.11 mg/dL respectively. FA1 AT levels by NPL from children with severe intestinal disorders, displaying median and geometric mean at 6.77 and 12.39 mg/dL respectively, were much higher than healthy children. The RID and NPL methods showed a correlation of r = 0.87 (p < 0.01) and R2 = 0.75. CONCLUSION: Random FA1-AT assay in wet stool is a non invasive and simple test for supporting diagnosis of protein-losing enteropathy. PMID- 17710972 TI - Survival and outcome of very low birth weight infants born in a university hospital with level II NICU. AB - OBJECTIVES: Determine the survivals, neonatal outcomes to hospital discharge, and perinatal risks of death among VLBW infants born in the Thammasat University Hospital. MATERIAL AND METHOD: This was a retrospective longitudinal study. Data were colleted from medical charts of all neonates with a gestational age of more than 25 weeks and birth weight of less than 1500 grams, who were born in Thammasat University Hospital for a 3-year period between July 1st, 2003 and June 30th, 2006. Antenatal history, perinatal data, and neonatal outcome until hospital discharge were extracted and analyzed. RESULTS: Seventy-eight neonates with a birth weight between 600-1485 grams were analyzed. Survival rate of very low-birth-weight (VLBW) infants and extremely-low-birth-weight (ELBW) infants were 81% and 52% respectively. Respiratory distress syndrome (RDS) was the major cause of death. Major morbidity was found in 35% of survived infants to hospital discharge. Unfavorable outcome was documented in infants with a birth weight < 750 grams. Perinatal risks of mortality among VLBW infants included no use of antenatal steroids (p = 0.015), gestational age of <28 weeks (p = 0.012), ELBW (p < 0.001), congenital abnormalities (p = 0.002), Apgar score at 5 minute <5 (p = 0.019), needed endotracheal intubation in the delivery room (p < 0.001), and first temperature at NICU < 35.0 degrees C (p = 0.023). CONCLUSION: Overall survival and outcome among very-low-birth-weight infants born in Thammasat University Hospital is acceptable. The mortality and morbidity in extremely-low birth-weight infants remained high. A continuing audit of these measures should be encouraged. PMID- 17710973 TI - The immunological response of Thai infants to haemophilus influenzae type B polysaccharide-tetanus conjugate vaccine co-administered in the same syringe with locally produced diphtheria-tetanus-pertussis vaccine. AB - OBJECTIVE: Comparing the immunogenicity and reactogenicity of three vaccine combinations. These were GlaxoSmithKline Biologicals' (GSK) Haemophilus influenzae type b vaccine (Hib-TT, Hiberix) administered with the local Government Pharmaceutical Organization's (GPO) diphtheria-tetanus-pertussis whole cell (DTPw) vaccine, Hib-TT mixed with GPO's DTPw vaccine, or Hib-IT mixed with GSKs' DTPw vaccine (Tritanrix). MATERIAL AND METHOD: An open, randomized, controlled, single center study of three hundred and sixty infants. They were randomized into three groups to receive either Hib-TT Hiberix mix with GPOs' DTPw vaccine (group 1), Hib-TT mixed with GPO's DTPw vaccine (group 2), or Hib-TT mixed with GSKs' DTPw vaccine (Tritanrix; group 3) at two, four and six months of age. RESULT: One month after the third dose, all subjects had antibodies level against Hib polyribosylribitol phosphate (PRP) > or = 0.15 microg/ml. All 11 subjects except two (in group 2) had anti-PRP levels > or = 1.0 microg/ml. The geometric mean concentrations were similar in all three groups. Over 96% of the subjects in all three groups demonstrated an immunological response to diphtheria, tetanus, and pertussis antigens. There was no diference among the three groups in terms of severe local reaction and fever. CONCLUSION: The present study showed that the combined vaccines produced an effective antibody response with no increase in reactogenicity compared to separately administrated vaccines. PMID- 17710974 TI - The relationship of facet tropism to lumbar disc herniation. AB - SUMMARY OF BACKGROUND DATA: The association between the facet tropism and the development of lumbar disc herniation has been studied; however the results remain controversial. OBJECTIVE: To determine the association between the facet tropism and the development of lumbar disc herniation. STUDY DESIGN: A cross sectional study. MATERIAL AND METHOD: MRI of 34 patients with lumbar disc herniation was evaluated. Two orthopedic surgeons measured facet joint angle and determined the degenerative status of L3-4, L4-5, and L5-SI. Facet tropism was defined as the difference between the angle of the right and left facet more than 5 degrees. RESULTS: The average difference of facet joint angle of HNP group was higher than normal group in the same level. There was no statistically significant correlation between the facet tropism and lumbar disc herniation. CONCLUSION: These results do not indicate any relationship between the facet tropism and lumbar disc herniation. PMID- 17710975 TI - The prevalence of thrombophilia and venous thromboembolism in total knee arthroplasty. AB - BACKGROUND: Venous thromboembolism (VTE) is a common and potential serious complication in lower extremity surgeries, especially in hip and knee arthroplasty. Pulmonary embolism is one of the most fatal complications. The recognition of VTE in the lower limb has been considered as an indication for anticoagulation. Many studies have shown that thrombophilia is one factor of VTE and the most common causes are protein C, protein S and antithrombin III deficiency, factor V leiden and dysfibrinogenemia. VTE is a disease of Western populations because of well documentation of incidence and many studies about thrombophilia. In Thailand, the prevalence of VTE has been unclear. OBJECTIVE: The present prospective study evaluated the prevalence of thrombophilia and venous thromboembolism after total knee arthroplasty in patients who did not receive prophylactic treatment of VTE in Phramongkutklao Hospital. STUDY DESIGN: Descriptive prospective consecutive case studies. SETTING: The Department of Orthopedic Surgery, Phramongkutklao Hospital, Bangkok Thailand. MATERIAL AND METHOD: Blood sample was examined at 2-3 weeks before TKA for measuring the level of thrombophilia. Bilateral ascending contrast venography of the lower extremities was performed routinely between 6th-10th post operative days after total knee arthroplasty. RESULTS: The authors studied 100 patients, 94 primary TKA and 6 revisions TKA. Sixty-one (61%) were positive for deep vein thrombosis. Eleven patients with positive venograms showed bilateral DVT twelve (12%) had a proximal DVT one was protein C deficiency, nine were protein S deficiency, 18 were antithrombin III deficiency, and 36 were positive study for FDP(D-dimer), However, no one was found with factor V leiden. Odds ratio of protein S deficiency was 0.9506, Antithrombin III deficiency was 0.7376, and FDP(D-dimer) was 1.229. The protein C deficiency and factor V leiden was undetermined. CONCLUSION: Patients who have total knee arthroplasty performed are at high risk for deep venous thrombosis. Although fetal pulmonary embolism rarely occurs in Thai populations, mechanical prevention was routinely used and prophylactic regimen should be a part of management of patients who undergo total knee arthroplasty. PMID- 17710976 TI - The results of percutaneous release of trigger digits by using full handle knife 15 degrees: an anatomical hand surface landmark and clinical study. AB - OBJECTIVE: Know the results of percutaneous release of trigger digits by using full handle knife 15 degrees. MATERIAL AND METHOD: The author identified 510 cadaveric digits to find the anatomical landmark of Al pulley that relates to the knuckle and measurements of A1 pulley lengths. The proximal margin of the Al pulleys on the perpendicular line from the knuckle to the palm was in the same line in 327 (64.1%) digits, while 464 (91.0%) digits were < or =1 mm and 509 (99.8%) were < or =2 mm. The average lengths of A1 pulleys in each digit were as follows: thumb; 5.30, index finger; 6.32, middle finger; 6.58, ring finger; 6.32, and little finger 5.30 mm. The average lengths of all fingers were 6.13 mm. A further 338 digits of trigger digit in 248 patients were treated by percutaneous release by using full handle knife 15 degrees with these landmarks. RESULTS: Three hundred and thirty-eight trigger digits were treated. There was a complete resolution of symptoms in 314 digits (92.90%) when followed up 6 weeks after operation. One digit, an index finger had residual grade 1 after 3 weeks and complete resolution in 8 weeks. Three digits (0.89%), which were one thumb and two index fingers, underwent local steroid injection because of painful scar. Nineteen digits (5.62%) were stiff at proximal interphalangeal joint because of grade 4 triggering and osteoarthritis of the proximal interphalangeal joint but they increased the range of motion after 6 months. A case (0.30%) had numbness of the radial tip of the thumb, which may have been caused by injury to the radial digital nerve ofthe thumb. No one had open release of A1 pulley. CONCLUSION: This technique was a safe and effective out patient procedure on 248 patients and had a complete resolution of symptoms 92.90%. PMID- 17710977 TI - Incidence and time trend of surgical site infection in Ramathibodi Hospital during the years 2003-2005. AB - OBJECTIVE: To determine the incidence of surgical site infection (SSI) for high risk surgical procedures and any changes in the incidence of SSI during the years 2003 to 2005. MATERIAL AND METHOD: SSI surveillance data were obtained from Ramathobodi's Infection Control Committee for analysis. RESULTS: The overall 30 day incidence of SSI for 492 hepato-biliary-pancreas and colon procedures was 7.7% (38 of 492). Of the 38 SSIs, only 35 were analyzed in detail. MosI patients had SSI types I and II, 89% of SSIs were detected within 20 days after operation, and most common organisms isolated were enterococcus species, E.coli, and P. aeruginosa. SSI rate for the year 2005 (11%) was significantly higher than that of the preceding years (4-5%). CONCLUSION: Overall, SSI rates for Ramathibodi Hospital were not significantly different from those of other studies. The increased SSI rate for the year 2005 needed an explanation, but the value of the present report lies in the potential usefulness of the presented results for future prevention of SSIs. years (4-5%). CONCLUSION: Overall, SSI rates for Ramathibodi Hospital were not significantly different from those of other studies. The increased SSI rate for the year 2005 needed an explanation, but the value of the present report lies in the potential usefulness of the presented results for future prevention of SSIs. PMID- 17710978 TI - The efficacy of 5% imiquimod cream in the prevention of recurrence of excised keloids. AB - OBJECTIVE: To evaluate the efficacy of 5% imiquimod cream in the prevention of recurrence of excised keloids. MATERIAL AND METHOD: The patients with keloids that had occurred over 1 year and could be excised and primary sutured were enrolled in the study. Imiquimod 5% cream was applied to the scar 7 days after stitches removal. The patients were follow-up for recurrence and drug side effect at 4, 6, 8, 16, and 24 weeks. RESULTS: Forty-five patients enrolled to the study but only 35 patients finished the study. The keloids were at the pinnas in 22 patients, at the backs or shoulders in 7 patients, and at chest walls or necks in 6 patients. Imiquimod 5% cream was applied on the wound area 2 weeks after the operation, at alternate night for 8 weeks. The follow-up period ranged from 6 to 9 months. Ten of the treated keloids recurred (28.6% recurrent rate). The lesion at the pinna had the lowest recurrent rate (2.9% recurrent of the total patients). The highest recurrent rate occurred at the chest wall or neck (83.3% recurrent of the chest wall or neck or 14.3% of the total patients). Side effects were found in thirteen patients (37.1%). These were abrasions of the skin around the wound areas in ten patients and hyperpigmentation of the skin around the wounds in three patients. CONCLUSION: Imiquimod 5% cream could effectively prevent recurrence of the excised keloids, especially in the area that had less tension such as pinna. PMID- 17710980 TI - The Thai anesthesia incidents study (THAI Study) of perioperative death in geriatric patients. AB - BACKGROUND: The study was part of the Thai Anesthesia Incidents Study (THAI Study), a multi-centered study conducted by the Royal College of Anesthesiologists of Thailand, aiming to survey anesthetic related complications in Thailand. OBJECTIVE: Identify the incidence and factors related to perioperative death in geriatric patients. MATERIAL AND METHOD: During a 12 months period (March 1, 2003 - February 28, 2004), a prospective multicenter descriptive study conducted in 20 hospitals comprising of seven university, five tertiary, four general and four district hospitals across Thailand. Anesthesia personnel filled up patient-related data, surgical-related, and anesthesia related variables and adverse outcomes of geriatric patients (age > or =65 yr) on a structured data entry form. The data were collected during pre-anesthetic, intra-operative, and 24 hr post operative periods. RESULTS: The overall mortality was 39.3 per 10,000 anesthetics from the registry of 23,899 geriatric patients receiving anesthesia. Multiple regression analysis showed that higher American Society of Anesthesiologists (ASA) physical status grading (p < 0.001), emergency operation (p = 0.031) and current medications (p = 0.043) were factors related to 24 hr perioperative death in geriatric patients. Patient's underlying diseases and duration of operations were not significantly related to death. CONCLUSION: The present study showed an incidence of 24-hr perioperative death of 1:254 in geriatric patients receiving anesthesia, which is comparable to other countries. Mortality in elderly patients operated under anesthesia can be predicted by ASA physical status, current medications, and emergency condition. PMID- 17710979 TI - Combined spinal-epidural analgesia and epidural analgesia in labor: effect of intrathecal fentanyl vs. epidural bupivacaine as a bolus. AB - OBJECTIVE: To compare the clinical effects of intrathecal fentanyl with conventional epidural bupivacaine bolus before the same continuous epidural infusion for labor analgesia. MATERIAL AND METHOD: Fifty parturients in active labor were randomized to receive subarachnoid fentanyl 25 mcg as part of a combined spinal epidural analgesia (CSE) or bupivacaine 0.25% 10 ml incrementally into the epidural space in the epidural group. After that, 0.0625% bupivacaine with fentanyl 2 mcg/ml was infused via epidural catheter in all women at a rate of 12 ml/h. Verbal numeric pain scores (VNPS), onset time to pain relief times of additional analgesia and other side effects were recorded. RESULTS: Mean (SD) onset time to the first pain free contraction was not significantly different (7.8 +/- 4.3 min in the CSE group, 10.2 +/- 5.1 min in epidural group, p = 0.085). Most of the patients in the CSE group required additional epidural bolus dose (80% compared to 48% in the Epidural group, p = 0.038). There was no difference in motor blockage at time of delivery or mode of delivery. Significantly more women in the CSE group had pruritus (68% VS none in the epidural group, p < 0.001), all had mild degree and did not require any treatment. There was no difference in other side effects. CONCLUSION: Intrathecalfentanyl as part of CSE did not produce statistically a significant faster onset compared to epidural bupivacaine bolus. Most of the patients in the CSE group required epidural bolus after intrathecal fentanyl with a higher incidence of pruritus. PMID- 17710981 TI - Asymptomatic avascular osteonecrosis of the hip in new patients diagnosed as systemic lupus erythematosus in Ramathibodi Hospital. AB - OBJECTIVE: To determine asymptomatic avascular osteonecrosis (AVN) of the hip in new patients diagnosed as Systemic Lupus Erythematosus (SLE) in Ramathibodi Hospital. MATERIAL AND METHOD: A prospective descriptive study of new SLE patients with asymptomatic hip at the Rheumatology clinic of Ramathobodi Hospital was conducted from February 2005 to November 2005. The information of steroid and immunosuppressive drug treatment was recorded Plain film (AP and frog leg views) and MR study of both hips were analyzed. RESULTS: Twenty-two hips (II patients) were enrolled in the present study (women 100%; mean age 27.8 years; range 16 50). Four hips (2 patients, 18%) had A VN, without other abnormal imaging findigs of the hips and pelvis. Seventeen hips of nine patients hadjoint effusion; none of them had AVN. No marrow edema, secondary osteoarthritis, collapsed femoral head or pelvic insufficiency fracture in allpatients is detected. In the present study, the 2 AVN patients had longest duration of steroid treatment before MR study (105 & 99 days) and rather high cumulative dose of prednisolone or its equivalent dose (4920 & 4540 mg), compared to non-AVN patients. CONCLUSION: SLE patients without hip pain may have AVN of the hips. Joint effusion and marrow edema do not necessarily associate with early AVN, and the authors found early AVN without joint effusion. Cumulative dose and duration of steroid treatment seem to relate to AVN in the present study. However a larger number of cases, prospective clinical data, and long-term follow up will help better evaluate the prevalence of asymptomatic AVN of the hips, as well as to evaluate the benefit of MRI as a screening tool for patients at risk of AVN. PMID- 17710982 TI - Diagnostic accuracy of MRI/MRSI for patients with persistently high PSA levels and negative TRUS-guided biopsy results. AB - OBJECTIVE: To prospectively evaluate the accuracy of transrectal ultrasonographic (TRUS)-guided biopsies by using combined magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI) in patients with persistently high prostate-specific antigen (PSA) levels and negative TRUS-guided biopsy results. MATERIAL AND METHOD: Twenty-one patients (age range 50-77 years, average 61.4 years) with negative TRUS biopsy were enrolled Suspicious areas were identified by discrete low signal intensity in T2 on standard MRI. MRSI was interpreted by using spectral approach and given score of I (benign) to 5 (malignant). Suspicious voxels were localized for guided TRUS biopsy. All patients underwent sextant TRUS biopsies with up to four additional biopsies targeted at suspicious sites. Diagnostic accuracy of MRI/MRSI in patient-by patient and voxel-by-core were analyzed. RESULTS: Prostate cancer was detected in 2 of 21 patients (9.5%). The sensitivity, specificity, PPV, NPV and accuracy of combined MRI/MRSI for detection of prostate cancer were 100%, 84%, 40%, 100%, and 86%, respectively. The site of positive biopsy correlated correctly with voxels were 80%, 85%, 21%, 99% and 85% on sensitivity, specificity, PPV, NPV and accuracy, respectively. CONCLUSION: MRI/MRSI have the potential to guide biopsy to cancer foci in patients with persistently high PSA levels and prior negative TRUS biopsy results. PMID- 17710984 TI - Incidence of Helicobacter pylori recurrent infection and associated factors in Thailand. AB - OBJECTIVE: To determine the incidence of H. pylori recurrent infection after successful eradication in 4-year follow-up study, and to evaluate the influencing factors for re-infection. MATERIAL AND METHOD: Thirty-seven patients (age range 20-74 years; average 49.06 +/- 14.03 years) were recruited of which 64.9% were females. The H. pylori infection was proved to be successfully eradicated in all patients. Annually, urea breath test (UBT) was assessed to determine H. pylori status after eradication. Age, sex, eating habit, water drinking, number of children, and treatment regimens against H. pylori were recorded A breath test was also performed on the patient's spouse. RESULTS: The H. pylori recurrence occurred in 5/37 (13.51%) of patients observed There were two patients in the first year, one patient each in the second, third, and fourth year The cumulative re-infection rate was 5.41% at 1-year 8.11% at 2-year 10.81% at 3-year and 13.51% at 4-year H. pylori infection of spouse was also frequent (80%). Even if the spouse was infected, 88.89% of patients will remain uninfected after 4-years of H. pylori eradication. No influencing factor for infection recurrence was detected. CONCLUSIONS: The risk of re-infection after H. pylori eradication was low in Thai patients after 4-year follow up. Annual re-infection rate was 3.38%. No dependent factors were associated with a recurrence. PMID- 17710983 TI - Epidemiologic study of 112 osteosarcomas in Chiang Mai University Hospital, Thailand. AB - OBJECTIVE: To summarize the epidemiologic features of osteosarcoma. MATERIAL AND METHOD: One hundred and twelve cases of osteosarcoma were collected retrospectively from the Pathology Department of the Chiang Mai University Hospital, Thailand between 1995 and 2005. RESULTS: From the present study, there were 14 cases in average, annually, since 2002. Seventy-seven percent of cases were from the upper north Thailand, the region serviced by Chiang Mai University Hospital. The male:female ratio was 1.3:1 and 86% of cases occurred within the first three decades of life. The majority of cancer was found in the long bones (83%) and the majority of lesion was around the knee (68%). Conventional and telangiectatic osteosarcoma accounted for 85% and 8% of cases, respectively. CONCLUSION: The authors have summarized some epidemiologic features of osteosarcoma. The authors found the relatively high frequency of telangiectatic osteosarcoma around the upper part of north Thailand These results give an initial picture to the national health provider section for planning personnel, medical and supportive equipment, and funding for the care of osteosarcoma patients. Nationwide co-operation in registering osteosarcoma patients would provide more complete data on this tumor in Thailand and promote the establishment of standardized treatment protocols. PMID- 17710985 TI - Aerobic capacity of fifth-year medical students at Chiang Mai University. AB - OBJECTIVE: To study the level of aerobic capacity using maximal oxygen consumption (VO2max) in the fifth-year medical students at Chiang Mai University. MATERIAL AND METHOD: This was a retrospective study in which data were collected from the database of the fifth-year medical students who attended the rehabilitation medicine course at Department of Rehabilitation Medicine, Faculty of Medicine, Chiang Mai University between January 2003 and December 2004. The level of aerobic capacity was evaluated by maximal oxygen consumption (VO2max), which was calculated using sub-maximal exercise test on a bicycle ergometer (Astrand-Rhyming test). RESULTS: During two-year period, 226 medical students performed 226 Astrand-Rhyming submaximal cycle ergometer tests. The mean age was 22.3 +/- 0.7 years (range 21-26 years) and average body weight was 56.8 +/- 11.9 kg (range 30-125 kg). The number of male and female students was comparable (male 44.7% and female 55.3%). Average VO2max of the students was 38.1 +/- 8.6 ml/kg/min (range 18.5-76.7 ml/kg/min) and there was no statistical significance between sex (VO2max of male = 38.4 +/- 7.6 and female = 37.9 +/- 9.4 ml/kg/min, p 0.636). When standard VO2max value of Thai people was compared, 39.4% was categorized in low health fitness group, 40.7% was in health fitness group, and only 19.9% was in high health fitness group. However, 65% of the fifth-year medical students exercised 0-1 sessions per week (group 1), 24.3% exercised 2-4 sessions per week (group 2) and only 10. 7% exercised >4 sessions per week or everyday (group 3). Mean VO2max in group 2 (40.3 +/- 9.1 ml/kg/min) and 3 (43.2 +/- 8.4 ml/kg/min) are more than group 1 (36.5 +/- 8.4 ml/kg/min) significantly (p < 0.001 and p < 0.001 respectively) but there was no significant difference between group 2 and 3 (p = 0.16). The two most popular exercises were jogging and aerobic dance, 48.7% and 31.9% respectively. There was no significant difference of VO2max between methods ofexercise (p = 0.132) and between the single and combination of exercises (38.9 +/- 9.3 and 37.9 +/- 7.4 ml/kg/min respectively, p = 0.4). CONCLUSION: VO2max in most of the medical students was in poor to average range when compared to the standard value of Thai population. This information should prompt medical educators to address this problem, consider promoting exercise and corporate physical fitness into the medical school curriculum. PMID- 17710986 TI - The Oswestry low back pain disability questionnaire (version 1.0) Thai version. AB - OBJECTIVE: To validate the Thai version of the Oswestry low back pain disability questionnaire. MATERIAL AND METHOD: The questionnaire was translated into Thai version by two translators and some statements were adapted Back translation was performed by a language professional. The content validity was evaluated by five experts in physical medicine and rehabilitation field. The scores were calculated Then the questionnaire was completed by the patients and data calculated for Cronbach's alpha. RESULTS: Thirty-two patients who complained of acute low back pain (less than 3 months) completed the Thai version of the questionnaire. The content validity of each item ranged from 0.6-1.0 and the Cronbach's alpha of all items was 0.8107. CONCLUSION: The Thai version of the Oswestry low back disability questionnaire was qualified with good internal consistency for measuring acute low back pain in Thai patients. PMID- 17710988 TI - Evaluation of the effectiveness of a computer-based learning (CBL) program in diabetes management. AB - OBJECTIVE: Evaluate the effectiveness of a computer-based program (CBL) introduced to improve the clinical and patient history taking skills of clinical pharmacists in the area of diabetes management. This program involved a self learning approach utilizing interactive digital videos, video simulations, and audio clips. MATERIAL AND METHOD: The present study compared the pre- and post test results of two groups of final year pharmacy students. The study group used the CBL program and the control group was exposed to formal lectures and discussions. RESULTS: Eighty-three volunteers entered the present study. Forty three were constituted into the study group, and forty acted as the control group. The overall results showed that the study group post-test scores in all basic knowledge areas were significantly higher than the control group (p = 0.001). Whereas, there was no statistical difference between groups in patient history taking skills (p = 0.645). Nevertheless, the post-test scores of SOAP writing skills in the study group were statistically higher than the control group (p = 0.001). CONCLUSION: Overall, the CBL program was considered effective in the development of basic knowledge of diabetes and in the improvement of patient history taking skills. PMID- 17710987 TI - Anatomic characteristics and surgical implications of the superficial radial nerve. AB - BACKGROUND: Superficial radial nerve (SRN) that lies superficially on the radial side of the distalforearm and dorsum of the hand, can be injured by various procedures. Thus, precise knowledge in its variation is crucial. OBJECTIVE: Since there were no such data in Thai population, provide the variation data of the SRN in Thai cadavers. This is likely to be more accurate when applied in Thailand. MATERIAL AND METHOD: The authors studied the branching pattern and the course of SRN in 40 Thai cadavers. RESULTS: The extra type, replacement of SR3 by a branch of the lateral antebrachial cutaneous nerve, was found (4.7%) and the incidences of other patterns were different from those of previous reports. Moreover; asymmetry and gender difference were also demonstrated. The authors observed the higher frequencies of the SRN lying over the snuff box and first dorsal compartment of the wrist compared to other reports. The distances to important landmarks were measured and the presented data were comparable to those of other studies with no significant differences between sides or genders. CONCLUSION: These findings suggest that the different variations of the SRN among various races should be concerned during the relevant procedures. PMID- 17710989 TI - Autologous chondrocyte implantation for traumatic large cartilage defect. AB - OBJECTIVE: The authors report the immediate result (6 months) after Autologous Chondrocyte Implantation (ACI) in clinical and anatomic result with MRI. This is the first report ofACI that provides chondrocyte cells from a domestic lab. MATERIAL AND METHOD: ACI was done in a two-stage procedure, first stage via arthroscope to harvest cartilage and detect pathology. The authors found deep cartilage defect at grade 4 according ICRS, area 2.5 cm2 and near total meniscus tear. Meniscal repair and cartilage shaving were done. Harvesting 300 mg of cartilage was done in this stage. Four weeks later, the secondACl was done. Lateral para-patellar was used. Periosteum was used as chondrocyte suspension and by suture to the healthy cartilage, using prolene interrupted suture in conjunction with fibrin glue to seal the pocket after injecting the cell. Range of motion exercise started on day 2, assisted with continuous passive motion machine. Running and jumping were restricted for 9 months. RESULTS: No complication was found, full range of motion and walking was done at 7-8 weeks post operative. Visual analogue scale improved from 3 points to 0 point. MRI shows evidence of 100% filling of the repair tissue in defect site associated with hypertrophy of the repair tissue above chondral surface. CONCLUSION: Immediate result of ACI shows improvement in clinical and anatomic that present with MRI. Further follow up and case series is needed PMID- 17710990 TI - Operative results of adolescent idiopathic scoliosis in Lerdsin Hospital. AB - OBJECTIVE: Evaluate the results of the posterior instrumentation for the correction of adolescent idiopathic scoliosis (AIS) in Lerdsin Hospital. MATERIAL AND METHOD: A retrospective study was conducted to determine the effectiveness of surgical treatment of idiopathic scoliosis in Lerdsin Hospital. The pre operative, immediate post operative, and the most recent follow-up (minimum 2 years) x-ray of 17 patients were evaluated for curve correction and spinal balance. RESULT: The present study found that the curvatures in thoracic King type II and III were corrected by about 58% post operatively. The curve progressed 3 degrees (5%) at the end of 2 years. For lumbar curve in King types I and II, there was the correction of 51% and 59%. After 2 years, the curve progressed around 6 degrees (7%) and 8 degrees (14%). Trunk balance was corrected by 60% in King type III. Degrees of thoracic kyphosis was decreased about 4 degrees. CONCLUSION: Frontal and sagittal thoracic and lumbar curve correction can be satisfactorily obtained by posterior spinal correction with instrumentation. PMID- 17710991 TI - The outcome of surgical treatment for tumors of the craniocervical junction. AB - OBJECTIVE: The authors report the clinical, radiological, and surgicalfindings ofpatients with craniocervical junction tumors surgically treated in the institution over the last 8 years. MATERIAL AND METHOD: A retrospective study was performed. Clinical, radiological, and operative data were evaluated, and follow up information was obtained from outpatient examinations, and telephone interviews. RESULTS: There were 25 patients consisting of nine chordomas, eight meningiomas, three cysts, two schwannomas, one each of aneurysmal bone cyst, plasmacytoma, and metastasis. Twenty-nine operative procedures were performed, classified as 12 anterior nine posterior-lateral, and eight posterior approaches. Gross total removal was achieved in 17 cases, subtotal removal in six cases, and partial removal in two cases. Re-operation was performed in six cases. Median follow-up time was 31 months. The authors found significant improvement in Karnofsky Performance Scale scores. CONCLUSION: Appropriate surgical approaches provide successful tumor removal with less surgical morbidities, nevertheless recurrent tumors occasionally occur and so, long-term follow-up is mandatory. PMID- 17710993 TI - Specific antivenom for Bungarus candidus. AB - BACKGROUND: Bungarus candidus (Malayan krait) snake is a neurotoxin snake. Previous treatment after snakebite was mainly respiratory support until the patient had spontaneous breathing. Recently specific antivenom for the Bungarus candidus snake was produced by the Queen Saovabha Memorial Institute and distributed in June 2004. The present article is the first report on the clinical response to the specific antivenom for Bungarus candidus. OBJECTIVE: To analyze the signs and symptoms of patients after snakebite and the response of the patients after receiving specific antivenom for Bungarus candidus snake. STUDY DESIGN: Retrospective chart review. MATERIAL AND METHOD: Four cases of Bungarus candidus snakebite were identified and divided into two groups. Group I (Case 1, 2, and 3) had received specific antivenom for Bungarus candidus while group 2 (case 4) had not. Onset, signs and symptoms after snakebite, antivenom dosage, and response time after receiving antivenom were analyzed. RESULTS: The first three patients received specific antivenom for Bungarus candidus and the fourth patient did not receive any. All four patients developed neurological signs and symptoms from this neurotoxic venom. In case 1, 2, and 4, the first signs and symptoms were dyspnea, difficulty with speech, and opening the eyelids at 50 minutes (30-60 minutes). The onset ofother signs and symptoms included respiratory paralysis with intubation 3 hours (2-4 hours), full ptosis 3.66 hours (3-4 hours), mydriasis and fixedpupils 4.33 hours (4-5 hours), no response to stimuli 5.66 hours (4-10 hours), tachycardia 5.5 hours (47 hours), and hypertension 14 hours (4-24 hours). The first two patients received specific antivenom for Bungarus candidus after being bitten at 10 and 12 hours, respectively. The first clinical response in case 1, were 12 hours after receiving 16 vials, and in case 2, were 20 hours after receiving 16 vials. These were slight movement of feet phalanxes. At 40 hours after receiving specific antivenom 30 vials in case 1 and 32 vials in case 2, they were able to respond to commands, motor power changed from grade 0 to grade 1 and there was 50% elevated eyebrows. The motor power changedfrom grade I to grade 4 with 100% elevation of eyebrows from full ptosis was 65 hours after receiving specific antivenom 60 vials in case 1 and 70 hours after receiving specific antivenom 87 vials in case 2. The patients had spontaneous opening ofeyelids at 90 hours after receiving 80 vials for case I and 88 hours after receiving 87 vials for case 2. Case 2 was extubated on day 4 after the snakebite while case 1 was extubated later on day 10 because of superimposing pneumonia. The third case had delayed onset of signs and symptoms of neurotoxicity compared to the other three patients. Dyspnea, difficulty with speech, and opening eyelids occurred at 5 hours after the snakebite. No response to stimuli and respiratory paralysis occurred at 20 hours after the snakebite. His consciousness improved 10 hours after receiving 3 vials of specific antivenom. This was noted by being able to respond to commands and the motor power changed to grade 2 however, full ptosis was still present up to 24 hours. After receiving 23 vials ofspecific antivenom, he accidentally extubated himself however, he could breathe adequately using a mask with a bag. His motor power changed to grade 4 with 100% elevated eyebrows but full ptosis 34 hours after receiving 38 vials of specific antivenom. He could spontaneously open his eyelids 40 hours after receiving 38 vials specific antivenom. Cases 1, 2, and 3 had persistent mydriasis andfixed pupils until discharge. Case 4 did not receive specific antivenom for Bungarus candidus. He did not respond to stimuli 10 hours after snakebite and he was treated with respirator and symptomatic treatment. On day 2, his blood pressure dropped, he was on dopamine to raise his BP On day 3, he developed ventricular fibrillation. Defibrillation was administered and ECG returned to normal. He was given further supportive care. On day 7, he was discharged at the request of his relatives without any improvement. CONCLUSION: The patients who received specific antivenom had more rapid improvement ofsigns and symptoms comparing to the patient who did not receive the antivenon. PMID- 17710992 TI - Feasibility, safety, and mid-term efficacy of cardiac resynchronization therapy in patients with severe heart failure and ventricular conduction delay: Chulalongkorn experience. AB - BACKGROUND: Heart failure is a major and growing public health problem in developed and developing countries. Despite major advances in medical therapy, morbidity and mortality remain high. Cardiac resynchronization therapy (CRT) has been proposed as an adjunctive therapy in patients with drug-refractory heart failure and ventricular conduction delay. Short and long-term studies have demonstrated the clinical benefits of CRT. OBJECTIVE: The present study was designed to assess the feasibility, safety, and mid-term efficacy of CRT in patients with severe heart failure and ventricular conduction delay in the institute. MATERIAL AND METHOD: Ten patients with severe heart failure in New York Heart Association (NYHA) functional class III or IV with left ventricular ejection fraction (LVEF) < 35%, QRS duration >120 ms with left bundle branch block morphology received CRT At baseline, and 6 months after implantation, the following parameters were evaluated: NYHA class, QRS duration, LVEF N-terminal pro-brain natriuretic peptide (NT-pro BNP) level, 6-minute walking distance, SF 36 quality-of-life (QOL) score, and number of heart failure visit. RESULTS: All clinical parameters improved significantly at 6 months. NYHA class decreased from 3.5 +/- 0.5 to 2.4 +/- 0.7 (p < 0.01). QRS duration decreased from 145 +/- 22 ms to 126 + 6 ms (p < 0.01). LVEF increasedfrom 21 +/- 6% to 31 +/- 12% (p < 0.01). NT-pro BNP level decreased from 2503 +/- 1953 pg/ml to 767 +/- 342 pg/ml (p < 0.01). The 6-minute walking distance increased from 153 +/- 122 m to 278 +/- 128 m (p < 0.01). QOL score improved from 66 +/- 14 to 98 +/- 25 (p < 0. 01). The number of heart failure visits was reduced from 3.8 +/- 3.7 per year to 0.5 +/- 0.8 visit per year (p < 0.01). Seventy percent of patients were free of heart failure visit for one year after implantation. One patient had sudden cardiac death eleven months after implantation. There was no procedure-related mortality. One patient had left ventricular lead dislodgement 3 months after implantation. CONCLUSION: In the present study, CRT was safe and effective in improving heart failure symptom, functional status, LV function, and quality of life. CRT also reduced heart failure hospitalization in the presented severe heart failure and ventricular conduction delay patients. PMID- 17710994 TI - Diffuse pollution abatement--a key component in the integrated effort towards sustainable urban basins. AB - Water bodies are highly stressed by overdrafts of water for many purposes upstream and in the cities, and effluent domination and excessive point and diffuse pollution downstream. Pollution is also caused by the urban landscape which prefers impervious rather than porous surfaces; fast-conveyance infrastructure rather than "softer" approaches like ponds and vegetation; and stream channelization instead of natural stream courses, buffers and floodplains, and development in the floodplains. In future, the comprehensive and complex problems of urban pollution must be solved within the framework of the total hydrological cycle concept. This provides a new impetus to diffuse pollution management in urban areas. The best management practices that have been developed in the past could become key components of the new urban total hydrological cycle paradigm for solving the water shortage and pollution problems in an integrated manner, and making the urban systems hydrologically and ecologically sustainable. The paradigm will include landscape changes (less imperviousness, more green space used as buffers and groundwater recharge) as well application of the best management practices that provide water conservation, storage and reuse. PMID- 17710995 TI - Diffuse pollution in Japan: issues and perspectives. AB - Many parts of Japan have experienced rapid urbanization and industrialization over the past 50 years. This trend resulted in severe water pollution in many urban areas. To address the pollution problems, several measures such as construction of sewerage systems and enactment of laws and regulations have been undertaken. Because of these measures, the water quality has been improved to some extent. However, many water quality concerns still remain and are attributed in part to diffuse pollution. In this paper, historical progress, present situation and future aspects of diffuse pollution problems in Japan are reviewed. It is noted that solving diffuse pollution problems will require a combination of several measures including application of conventional treatment technologies and natural purification systems, implementation of appropriate policy measures, and promotion of citizen participation. PMID- 17710996 TI - Using catchment models to establish measure plans according to the Water Framework Directive. AB - A participatory modelling process (DEMO) has been developed and applied in a 350 km2 catchment in southern Sweden. The overall goal is to improve the dialogues between experts and local stakeholders by using numerical models as a platform for discussions. The study is focused on reducing nutrient load and on the development of a locally established measure plan, which is requested by the European Water Framework Directive. The HBV-NP model was chosen as it can calculate effects and costs for different allocations of several combined measures in a catchment. This paper shows the impact of including local data in the modelling process vs. using more general data. It was found that modelled diffuse nutrient pollution was highly modified when including local know-how, soft information and more detailed field investigations. Leaching from arable land was found to be 35% higher using more detailed information on for instance, agricultural practices, crop and soil distribution. Moreover, the stakeholders' acceptance of model results and reliance on experts was increased by applying the participatory process and involving stakeholders in the modelling procedure. PMID- 17710997 TI - P-pollution in a heavily urbanized river basin from point and diffuse sources: the River Ruhr case study (Germany). AB - An area-differentiated model approach (MEPhos) for the quantification of mean annual P-inputs from point and diffuse sources is presented. The following pathways are considered: artificial drainage, wash-off, groundwater outflow, soil erosion, rainwater sewers, combined sewer overflows, municipal waste water treatment plants and industrial effluents. Based on the modelling results "hot spots" for high P-loads can be localized and management option for the input reduction to surface waters proposed. The model is applied to the River Ruhr basin (4,485 km2) in Germany with contrasting natural conditions, land use patterns as well as population and industry densities. PMID- 17710998 TI - Integrated modelling of nitrate loads to coastal waters and land rent applied to catchment-scale water management. AB - The EU Water Framework Directive (WFD) requires an integrated approach to river basin management in order to meet environmental and ecological objectives. This paper presents concepts and full-scale application of an integrated modelling framework. The Ringkoebing Fjord basin is characterized by intensive agricultural production and leakage of nitrate constitute a major pollution problem with respect groundwater aquifers (drinking water), fresh surface water systems (water quality of lakes) and coastal receiving waters (eutrophication). The case study presented illustrates an advanced modelling approach applied in river basin management. Point sources (e.g. sewage treatment plant discharges) and distributed diffuse sources (nitrate leakage) are included to provide a modelling tool capable of simulating pollution transport from source to recipient to analyse the effects of specific, localized basin water management plans. The paper also includes a land rent modelling approach which can be used to choose the most cost-effective measures and the location of these measures. As a forerunner to the use of basin-scale models in WFD basin water management plans this project demonstrates the potential and limitations of comprehensive, integrated modelling tools. PMID- 17710999 TI - Riparian wetlands for enhancing the self-purification capacity of streams. AB - Best Management Practices (BMPs) are increasingly used to restore river water quality but design guidance is limited. An alternative approach to remediating diffuse pollution loads is to identify the most polluting high flows from pollutographs and hydrographs and spill these flows into riparian treatment wetlands for treatment before drainage back into the watercourse. The approach is demonstrated for two contrasting catchments in Scotland impacted by diffuse pollution. The Caw Burn receives industrial estate drainage with high suspended solids, hydrocarbons, BOD and ammoniacal-nitrogen concentrations. Applying the proposed design criteria demonstrated that the existing retrofit BMP system at the site is undersized (4950 m2) compared to the required wetland area (11,800 m2), but accommodating the additional area is likely to be expensive. The second case-study is Brighouse Bay where bathing waters are impacted by faecal indicator organisms derived primarily from livestock runoff. In this catchment the riparian wetland area required to retain runoff so that E. coli bacteria would die-off to concentrations below bathing water standards was estimated to be 3-6ha (0.5-1% of catchment area). Further refinement and testing of the design approach is required, including consideration of other factors such as vegetation type, ownership and maintenance, to develop a more holistic approach to river restoration. PMID- 17711000 TI - Nitrate in aquifers beneath agricultural systems. AB - Research from several regions of the world provides spatially anecdotal evidence to hypothesize which hydrologic and agricultural factors contribute to groundwater vulnerability to nitrate contamination. Analysis of nationally consistent measurements from the U.S. Geological Survey's NAWQA program confirms these hypotheses for a substantial range of agricultural systems. Shallow unconfined aquifers are most susceptible to nitrate contamination associated with agricultural systems. Alluvial and other unconsolidated aquifers are the most vulnerable and also shallow carbonate aquifers that provide a substantial but smaller contamination risk. Where any of these aquifers are overlain by permeable soils the risk of contamination is larger. Irrigated systems can compound this vulnerability by increasing leaching facilitated by additional recharge and additional nutrient applications. The system of corn, soybean, and hogs produced significantly larger concentrations of groundwater nitrate than all other agricultural systems because this system imports the largest amount of N fertilizer per unit production area. Mean nitrate under dairy, poultry, horticulture, and cattle and grains systems were similar. If trends in the relation between increased fertilizer use and groundwater nitrate in the United States are repeated in other regions of the world, Asia may experience increasing problems because of recent increases in fertilizer use. Groundwater monitoring in Western and Eastern Europe as well as Russia over the next decade may provide data to determine if the trend in increased nitrate contamination can be reversed. If the concentrated livestock trend in the United States is global, it may be accompanied by increasing nitrogen contamination in groundwater. Concentrated livestock provide both point sources in the confinement area and intense non-point sources as fields close to facilities are used for manure disposal. Regions where irrigated cropland is expanding, such as in Asia, may experience the greatest impact of this practice on groundwater nitrate. PMID- 17711001 TI - Using precise data sets on farming and pesticide properties to verify a diffuse pollution hydrological model for predicting pesticide concentration. AB - Verification of a diffuse pollution model involves comparing results actually observed with those predicted by precise model inputs. Acquisition of precise model inputs is, however, problematic. In particular, when the target catchment is large and substantial estimation uncertainty exists, not only model verification but also prediction is difficult. Therefore, in this study, rice farming data were collected for all paddy fields from all farmers in a catchment and pesticide adsorption and degradation rates in paddy field soil samples were measured to obtain precise model inputs. The model inputs successfully verified the model's capability to predict pesticide concentrations in river water. Sensitivity analyses of the model inputs elucidated the processes significantly affecting pesticide runoff from rice farms. Pesticide adsorption and degradation rates of the soil did not significantly affect pesticide concentrations, although pesticide discharge to river water accounted for less than 50% of the total quantity of pesticide applied to fields, possibly owing to pesticide adsorption and degradation. The timing of increases in pesticide concentrations in river water was affected mostly by the farming schedule, including the time of pesticide application and irrigation, and secondarily by rainfall events. PMID- 17711002 TI - Emission reduction by multipurpose buffer strips on arable fields. AB - In the area managed by Hollandse Delta, agriculture is under great pressure and the social awareness of the agricultural sector is increasing steadily. In recent years, a stand-still has been observed in water quality, in terms of agrochemicals, and concentrations even exceed the standard. To improve the waterquality a multi-purpose Field Margin Regulation was drafted for the Hoeksche Waard island in 2005. The regulation prescribes a crop-free strip, 3.5 m wide, alongside wet drainage ditches. The strip must be sown with mixtures of grasses, flowers or herbs. No crop protection chemicals or fertilizer may be used on the strips. A total length of approximately 200 km of buffer strip has now been laid. Besides reducing emissions, the buffer strips also stimulate natural pest control methods and encourage local tourism. Finally, the strips should lead to an improvement in the farmers' image. The regulation has proved to be successful. The buffer strips boosted both local tourism and the image of the agricultural sector. Above all, the strips provided a natural shield for emission to surface water, which will lead to an improvement of the water quality and raise the farmers' awareness of water quality and the environment. PMID- 17711003 TI - Minimization of the diffuse pollution caused by dairy farms in Cyprus through the development of guidelines for their sustainable operation. AB - This paper summarizes the work carried out for Cyprus in respect to developing guidelines on the measures that have to be taken for the reduction of the impacts caused by the operation of dairy cow farms and in a second stage, to aid the competent authorities in permitting the dairy farms under the Water and Soil Pollution Control Law. The paper includes information on the existing situation in Cyprus in regards to: (1) the operation of the farms, the production of waste and the existing practices for the management of waste, and (2) the guidelines and measures for the reduction of waste, odours and the use of waste in order to ensure the safe and sustainable operation of the farms and the management of waste. PMID- 17711004 TI - Surface discharge of heavy metals from low farmland. AB - Runoff heavy metals from farmland were examined using the field data for the summer of 2005. The observation farmland is located on lowland where the irrigation water was contaminated with the drained water from the upstream farmlands. The area of the farmland is 11.2 ha, of which 6.0 ha and 4.5 ha have been used for rice paddy fields and soybean cultivation, respectively. During the observation, heavy metal concentrations at the downstream end were usually found to be higher than those in the irrigation water. That is, the heavy metal concentrations increased due to the passage of the water through the farmland. This increase in the heavy metal concentrations is not equal to the discharge of the heavy metal because the evaporation on the surface of the paddy field and the absorption by plants makes the surface water volume small. The discharged load from the farmland generally indicates the gross surface load from the farmland. When the effects of circulation irrigation on the heavy metal concentrations are estimated, the discharged load from the farmland should be calculated as the net surface load. When the runoff heavy metals from the circulation irrigation farmland are estimated, it is important to consider the inflowing heavy metals with irrigation water. All the heavy metal types observed in this study were discharged from the farmland. The net surface loads of Cr, Fe, Cd, and Pb were 371 microg m(-2) day(-1), 14.9 mg m(-2) day(-1), 0.26 microg m(-2) day(-1), and 3.3 microm( -2) day(-1), respectively. PMID- 17711005 TI - Estimation and comparison of nitrogen loads and attenuation in agricultural catchments of Japan and Korea. AB - To help in clarifying the relationship between the time lag and attenuation of nitrogen (N) loads generated in agricultural catchments, long-term trends in activities that generate N loads and in environmental N loads were estimated in catchments in Japan and Korea dominated by non-point-source emissions. Our approach used statistical data and geographical information system software to analyze pollutant loads. The method was successful in both countries because of the availability of well-developed statistics, geographical information, and weather and water quality monitoring systems, and the accumulation of research data concerning the generation of N loads and the fate of N in soils. Comparison of environmental loads with the loads observed in river water at the outlet of each catchment revealed that: (1) the effect of changes in the environmental load in a catchment appeared almost immediately in the river water quality in Korea, but did not appear clearly even 10 years later in Japan; and (2) the strength of the attenuation appeared to be much lower in Korea than in Japan. These findings suggest that regional characteristics play important roles in the sensitivity of water quality to load-generating activities. PMID- 17711006 TI - Sorption behaviour of oxadiazon in tropical rice soils. AB - The soprtion behaviour of a pre-emergent herbicide, oxadiazon (5-tert-butyl-3 (2,4-dichloro-5-isopropoxyphenyl)-1,3,4-oxadiazol-2 (3H)-one) was investigated in tropical rice soils using a batch equilibrium method. There is no information available on the fate of oxadiazon in Bangladeshi soils; Bangladesh rice soil is a unique environment. The experiment was performed using radiolabelled (14C) oxadiazon. The sorption and desorption isotherm of oxadiazon was described using the Freundlich equation. L-type sorption isotherms were observed. The correlation coefficient (r2) was 0.995 to 0.997 and the linearity of the slope was in the range 0.96-1.07. Sorption of oxadiazon was related to organic carbon. Sorption of oxadiazon by soil was a rapid process; sorption kinetics indicated that most of the sorption occurred within two hours. Changes in sorption of oxadiazon by soils was investigated by repeated application. Sorption after the first cycle was in the range 81-92% whereas sorption capacity decreased in the following cycles. PMID- 17711007 TI - HSPF-Paddy simulation of water flow and quality for the Saemangeum watershed in Korea. AB - The Hydrological Simulation Program-FORTRAN (HSPF) is a comprehensive model that was developed to simulate many processes related to water flow and quality in watersheds of almost any size and complexity. Paddy rice fields often dominate extensive portions of the landscape in the Asian monsoon region. The hydrological and environmental conditions of paddy fields differ somewhat from those of other land uses, and HSPF may not adequately simulate watersheds in paddy farming regions. HSPF was previously modified to HSPF-Paddy; here, we examined the applicability of the modified model. The model was applied to simulate the water flow and quality of the Saemangeum watershed (2523 km2) in Korea, where paddy rice fields comprise about one-third of the total watershed area. Long-term monitoring data (5 years for water flow, 10 years for water quality) were used in the calibration and verification processes. Model performance was in the range of "very good" and "good" based on model efficiency (R2) and percent difference. The accuracy of the daily simulation was lower than that of monthly simulation for water flow. The water-quality simulation results were encouraging for this sizable watershed with mixed land uses; HSPF-Paddy proved adequate, and its application is recommended to simulate watershed processes in paddy farming regions. PMID- 17711008 TI - Modeling the effects of climate change on different land uses. AB - This study deals with the effects of the expected climate change on the hydrology of watersheds. The watershed response in terms of the water produced by the watershed has been modeled using HSPF (Hydrological Simulation Program-FORTRAN) for a time period which encompasses the first half of the twenty-first century. Climate change scenarios have been prepared based on trends expected in western Turkey and a hypothetical watershed with different land uses has been simulated. The trends have been extracted from the results of a general circulation model. The simulations have revealed that watersheds with no vegetative cover will respond to the trends in temperature and precipitation more rigorously than vegetated watersheds. Pasture or watersheds with deciduous or coniferous forests respond less to climate change due to the buffering mechanism of the vegetative cover and also due to the large quantities of water they transpire. It has also been found that monthly variations are important in predicting the future response of watersheds. While changes might seem small on a yearly scale, there are large differences in response among seasons. PMID- 17711009 TI - Application of environmental impact quotient model to Kumluca region, Turkey to determine environmental impacts of pesticides. AB - Besides the new developments in agricultural technology, intensive use of pesticides poses a great environmental hazard. The unthinking use of pesticides leads to contamination of air, water and soil. There are several pesticide risk indicator models available in the literature to assess pesticide impacts on the applicator and the ecosystem which is an important issue. This paper refers to an application of a pesticide risk indicator model, called Environmental Impact Quotient (EIQ) which was developed to measure the environmental impacts of pesticide active ingredients used in vegetable and fruit production. The application site is the Kumluca region of Turkey, which is well known for its intensive agricultural activities. As the first step in the model application, EIQ values have been calculated for 35 commonly used pesticides in Kumluca. EIO values were then turned into EIQ field use rating results based on the active ingredient percent and application rate. Furthermore, some pesticide management scenarios were evaluated to select the least detrimental pesticide by comparing EIO model results. The EIO model is an easily applied and very helpful tool for pest management practitioners and agricultural specialists. It can be used efficiently to compare different agricultural pest management strategies or programs. PMID- 17711010 TI - Applicability of modelling tools in watershed management for controlling diffuse pollution. AB - Diffuse pollution is hard to analyze, control and manage by its nature. Watershed models and Geographical Information Systems (GIS) are recently developed tools that aid analysis of diffuse sources of pollution. However, their applications are not always easy and straightforward. Turkey is a typical example of a mountainous country rich in rivers and streams. Due to the complex geomorphology, land-use and agricultural practices in most of the watersheds in Turkey, modelling, analyzing and managing diffuse pollution has been a challenge. The complex watershed structure forces the modellers to work with spatially high resolution data. Apart from the data, the models themselves may also cause operational problems. These issues and their probable solutions form the basis of the discussions in this paper. It acts as a guideline for modelling and analyzing diffuse pollution by emphasizing the referred problems and difficulties. Design of an Information Technology-based system tool for watershed and/or water quality modelling, which would be suitable for countries having watersheds with similar structure and problems to those of Turkey, is also outlined. PMID- 17711011 TI - Simultaneous estimation of model parameters and diffuse pollution sources for river water quality modeling. AB - Diffuse pollution sources along a stream reach are very difficult to both monitor and estimate. In this paper, a systematic method using an optimal estimation algorithm is presented for simultaneous estimation of diffuse pollution and model parameters in a stream water quality model. It was applied with the QUAL2E model to the South Han River in South Korea for optimal estimation of kinetic constants and diffuse loads along the river. Initial calibration results for kinetic constants selected from a sensitivity analysis reveal that diffuse source inputs for nitrogen and phosphorus are essential to satisfy the system mass balance. Diffuse loads for total nitrogen and total phosphorus were estimated by solving the expanded inverse problem. Comparison of kinetic constants estimated simultaneously with diffuse sources to those estimated without diffuse loads, suggests that diffuse sources must be included in the optimization not only for its own estimation but also for adequate estimation of the model parameters. Application of the optimization method to river water quality modeling is discussed in terms of the sensitivity coefficient matrix structure. PMID- 17711013 TI - Optimum management scheme to control nonpoint pollution in Korea. AB - Comprehensive measures to control nonpoint source were developed by the Office of the Prime Minister, Korea in March 2004. These management measures present the government's policies and directions relating to nonpoint source management by 2020. However, the government has encountered difficulties since the government implemented such policies without preparing legal and institutional arrangements associated with nonpoint source management practices. Particularly, there was no legal system to manage the workplaces and construction sites that discharge the polluted runoff. To provide legal arrangements to achieve efficient implementation of the government's nonpoint source management policies, amendments to the "Water Quality Preservation Act" were proposed in the congress in March 2005 and took effect from April 2006. Subsequently, the nationally mandated nonpoint source control system was to be applied to such industries and construction sites. This paper attempts to propose the scope of the nonpoint source control system and effective strategies applied to the construction sites and industrial workplaces in Korea. PMID- 17711012 TI - WFD and agriculture activity of the EU: first linkages between the CAP and the WFD at EU level. AB - Within the "WFD and agriculture activity" both communities agreed to co-operate during implementation of the Water Framework Directive (WFD) and further development of the Common Agricultural Policy (CAP) at EU, Commission and the Member States levels. In intensive discussions including two congresses and biannual working group meetings, seven information reports were produced. Rural Development programmes are unanimously considered to be very powerful instrument to support WFD implementation. However, limited budgets, combined with the large extent of agricultural pressures will considerably restrain the results this instrument might deliver. Limited effects are also expected from the cross compliance standards, mainly because: the standards do not cover all WFD aspects, and the existing legislation is not implemented with the same rigour in all the Member States. WFD provides additional powerful tools (River Basin Management Planning and Water Pricing discussion) to improve the situation, but the timetables of WFD and CAP do not fit each other. The activity should be continued with an intensive discussion on case and success stories in all the mentioned tools informing both policy areas for the planned evaluation of cross-compliance in 2007, and a mid-term evaluation on rural development in 2009. PMID- 17711014 TI - Assessment of uncertainty in Great Barrier Reef catchment models. AB - This paper addresses uncertainty in socio-economic and sediment-nutrient models that are being developed for the assessment of change in the Great Barrier Reef (GBR) area. The catchments draining into the GBR lagoon are sources of pollutants. The Reef Water Quality Management Plan of the Queensland Government identified sediments and nutrients transported to the GBR lagoon as the major long-term threats to the reef and inshore ecosystems and the wellbeing of the human communities. The plan clearly indicates that changes in land management are required by 2013 to reduce pollutant inputs and, at the same time, maintain or enhance the benefits from using the inland waters. Science that provides decision tools for natural resource management and improves socio-economic and biophysical understanding is required to enable managers to make better decisions. A major research activity (the Water for a Healthy Country Flagship) aims to address social, economic and biophysical outcomes of land management change in the GBR. It contains research activities that provide information for integrated model development. Currently, however, these models lack the ability to estimate the uncertainty associated with prediction. This project aims to provide statistical methods for assessing uncertainty in models of sediment transportation to the GBR. Furthermore, it provides a link between the models and the decision-making process that allows assessment of uncertainty, a step pertinent to the risk analysis of policy options. This paper describes current and ongoing approaches for assessing uncertainty using a sediment modelling example and provides a way forward for the integration of applied socio-economic and biophysical models used in the decision-making process. PMID- 17711015 TI - Effective lake basin management institutions: lessons from African lakes. AB - Weak or non-existent institutions are often cited as a major constraint facing management of many lake basins in Africa. By their nature lake basins cut across many sectoral and jurisdictional interests and therefore it is always the case that management of the basins is affected by actions within the various sectors and jurisdictions. Because of the complex nature of issues within lake basins, authority over management of lake basins is dispersed among several institutions, with no single institution having overall authority. Under these circumstances, a major challenge in lake basin management is how to ensure effective coordination among the various players. This paper reviews the situation of lake basin management at eight African lake basins and draws important lessons about lake basin management institutions. It is noted that fragmented approaches, lack of coordination across sectors, and lack of monitoring and enforcement are major institutional weaknesses. Also, it is observed that political will and commitment are essential for the management of African lake basins. PMID- 17711016 TI - The uncertain search for the diffuse silver bullet: science, policy and prospects. AB - The overwhelming importance of diffuse sources as a determinant of receiving water quality has been recognised for over 30 years. Significant research and development on techniques for reducing inputs in the riparian zone has resulted in numerous guideline documents being produced. Yet despite this research effort, and the apparently successful transfer of key results to water resource managers, the public perception in New Zealand is that the quality of receiving waters continues to decline. In this paper we examine the veracity of that perception through examination of state-of-the-environment reporting, discussions with water resource managers, and published literature. Using a case study of Lake Taupo, New Zealand as an example, we discuss the difficulties faced by water resource managers in arresting declines in water quality. We compare the reduction in potential nutrient exports possible between 'non-invasive' mitigation techniques such as riparian buffer strips, constructed and natural wetlands and source control measures such as the use of nitrification inhibitors and wintering pads. Finally, we look at options available should voluntary measures or best management practices fail to deliver the nutrient reductions that are necessary to maintain lake water quality. PMID- 17711017 TI - How participatory can participatory modeling be? Degrees of influence of stakeholder and expert perspectives in six dimensions of participatory modeling. AB - The authors are involved in a project aiming at the development of a methodology for participatory modeling as a tool for public participation in water resource management. In this paper, some examples of different degrees of stakeholder influence in six key dimensions of participatory modeling are identified and discussed. Arnstein's (A ladder of citizen participation. Journal of the American Institute of Planners, 1969, 4, 216-224) critical discussion of different degrees of "real" decision-making power is taken as a point of departure to assess possible degrees of stakeholder influence. Can we as participatory modelers be sure that we are really inviting our research objects to an equal communicative relationship where local perspectives, knowledge and priorities are respected to the same extent as central and/or expert perspectives? This paper presents an approach that could be used as a tool for structured reflection to avoid unreflective tendencies towards expert knowledge dominance and low degree of stakeholders' real influence over the process. PMID- 17711018 TI - Effectiveness of combined sewer overflow treatment for dissolved oxygen improvement in the Chicago waterways. AB - An Use Attainability Analysis (UAA) has been initiated to evaluate what water quality standards can be achieved in the Chicago Waterway System (CWS). There are nearly 200 combined sewer overflow (CSO) locations discharging to the CWS by gravity. Three CSO pumping stations also drain approximately 140 km2. Because of the dynamic nature of the CWS the DUFLOW model that is capable of simulating hydraulics and water-quality processes under unsteady-flow conditions was used to evaluate the effectiveness of water-quality improvement techniques identified by the UAA including CSO treatment. Several CSO treatment levels were applied at gravity flow CSOs to evaluate improvement in dissolved oxygen (DO). The results show that pollutant removal at CSOs improves DO to a certain degree, but it still was not sufficient to bring DO concentrations to 5 mg/L or higher for 90% of the time during wet weather at most locations on the CWS. Flow from the pumping stations results in substantial stress on DO since a huge amount of un-treated water with a high pollution load is discharged into the CWS in a short period of time at a certain location. The simulation results indicate that CSO treatment does not effectively improve DO during wet-weather periods on the CWS. PMID- 17711019 TI - Brake wear from vehicles as an important source of diffuse copper pollution. AB - In this article we show that brake wear from road traffic vehicles is an important source of atmospheric (particulate) copper concentrations in Europe. Consequently, brake wear also contributes significantly to deposition fluxes of copper to surface waters. We estimated the copper emission due to brake wear to be 2.4 kiloton per year. For comparison, the official database for Europe (without brake wear) totals 2.6 kiloton per year. In Western Europe the brake wear emissions dominate the total emission of copper. Using the spatially resolved emission data, copper distributions over Europe were calculated with the LOTOS-EUROS model. Without brake wear the model underestimates observed copper concentrations by a factor of 3, which is in accordance with other studies. Including the brake wear emissions largely removes the bias. We find that 75% of the atmospheric copper input in the North Sea may be due to brake wear. We estimate that about 25% of the total copper input in the Dutch part of the North Sea stems from brake wear. Although the estimated brake wear copper emission is associated with a large uncertainty, it significantly improves our understanding of the copper cycle in the environment. PMID- 17711020 TI - Estimation of the emission factors of PAHs by traffic with the model of atmospheric dispersion and deposition from heavy traffic road. AB - In order to consider the total atmospheric loadings of the PAHs (polycyclic aromatic hydrocarbons) from traffic activities, the emission factors of PAHs were estimated and from the obtained emission factors and vehicle transportation statistics, total atmospheric loadings were integrated and the loadings into the water body were estimated on a regional scale. The atmospheric concentration of PAHs was measured at the roadside of a road with heavy traffic in the Hiroshima area in Japan. The samplings were conducted in summer and winter. Atmospheric particulate matters (fine particle, 0.6-7 microm; coarse particle, over 7 microm) and their PAH concentration were measured. Also, four major emission sources (gasoline and diesel vehicle emissions, tire and asphalt debris) were assumed for vehicle transportation activities, the chemical mass balance method was applied and the source partitioning at the roadside was estimated. Furthermore, the dispersion of atmospheric particles from the vehicles was modelled and the emission factors of the sources were determined by the comparison to the chemical mass balance results. Based on emission factors derived from the modelling, an atmospheric dispersion model of nationwide scale (National Institute of Advanced Industrial Science and Technology - Atmospheric Dispersion Model for Exposure and Risk assessment) was applied, and the atmospheric concentration and loading to the ground were calculated for the Hiroshima Bay watershed area. PMID- 17711021 TI - Nitrogen fertilizer impact on the Wilmot watershed aquifer in Prince Edward Island, Canada. AB - The objective of this study is to estimate the soil N flux from the vadose zone to the aquifer of the Wilmot watershed (Prince Edward Island, Canada) for a typical three-year cropping rotation (barley-red clover-potato). A conceptual model estimates that 199-221 tons of N were yearly available for leaching at the watershed scale. A significant portion of this N amount was available for leaching at the end of the crop season representing 80-90% of the annual N balance. Drainage water nitrate concentrations were significantly higher after the potato-rotation year than during the crop season. Low nitrate concentrations were measured at spring thaw indicating that most of the nitrate available from the preceding potato crop season was likely leached at the end of fall or during winter. Early spring ionic exchange membrane sampling show a large availability of nitrate in soil possibly throughout winter as well, resulting from soil N mineralization and nitrification over the winter period. These findings are corroborated by the isotope natural abundance analysis of nitrate in groundwater implying that nitrifiers are significantly active during winter, as well as during the crop season, and that leaching of soil nitrates with seasonal signals takes place whenever recharge is occurring. PMID- 17711022 TI - Long-time risk of groundwater/drinking water pollution with sulphuric compounds beneath burned peatlands in Indonesia. AB - Smoke-haze episodes caused by vegetation and peat fires affect parts of Indonesia every year with significant impacts on human health and climate. The forest fires 1997/1998 were by far the largest in Indonesian history, burning between 5 and 8 million hectares before they were stopped by the monsoon rains in December 1997. Fires sprang up again in 1998 on Kalimantan when monsoon rain paused. Peat forests and peatlands are in particular severely affected. In the 1997/1998 haze event, 2.1-2.5 million hectare of peat swamp forest burnt in Indonesia. The remaining ash contains high concentrations of sulphur and sulphuric compounds which eventually leach into the groundwater, thus polluting groundwater and drinking water. The thicker the peat layer is and the higher the number of fires in the respective area the more sulphuric compounds will leach into the groundwater. Risk areas for the sulphur loads of the ash are identified. PMID- 17711023 TI - The influence of stream bed hydraulic conductivity on sustaining baseflow in rivers. AB - This study presents the results of the influence of stream bed hydraulic conductivity on baseflow sustainability by using a coupled model of surface and subsurface hydrology. The model provides a coupled solution to the dynamic interactions between a river and a surfacial aquifer and is used to numerically study the effect of stream bed conductivity on the overall system response. To achieve this objective, the model is formulated to include a one-dimensional river flow model and a two-dimensional vertically averaged groundwater flow model in an unconfined aquifer. The coupling is achieved at the river bed via a hydraulic flux that is described as a function of river bed conductivity and the gradient between river stage and groundwater head. The model incorporates the concept of simultaneous presence of the two hydrologic processes for simulating the dynamic interactions and uses a novel numerical technique to solve the two systems concurrently. These interactions are analyzed by numerical experimentation under different hydraulic conductivity conditions. The influence of hydraulic conductivity and hydraulic gradient is studied under steady and unsteady flow regimes to assess the occurrence of baseflow. The analysis also reveals critical insights into the governing mechanisms that provide and sustain the baseflow in rivers. PMID- 17711024 TI - Air-water mass transfer and tracer gases in stormwater systems. AB - Reaeration is a central quality parameter for the performance of environmental systems such as ponds receiving urban and road runoff. Tracer gases can be used to measure reaeration rates in these systems. The methods comprise injection of a volatile tracer into an environmental system and subsequently measurement of the emission of the volatile tracer. The physical basis of such methods is the existence of a constant ratio between the air-water mass transfer coefficient for oxygen and the corresponding mass transfer coefficient for the volatile tracer gas. This constant ratio is often not clearly defined in the literature due to difficulties in both experimental procedures and handling of data. In this study such methods are evaluated and an experimental procedure and a corresponding data processing procedure for a general and reliable determination of mass transfer rates are presented. Propane is selected as an example of an appropriate tracer gas and the ratio between the mass transfer coefficients of oxygen and propane is determined. PMID- 17711025 TI - Biosorption of lead(ll) and copper(ll) from stormwater by brown seaweed Sargassum sp.: batch and column studies. AB - This study evaluated the potential use of brown seaweed Sargassum sp to sequester lead and copper (Pb(II) and Cu(ll)) from urban runoff based on batch as well as column experiments. The equilibrium data exhibited Langmuir isotherms. The adsorption capacity of this seaweed was found to be 196.1 mgg(-1) and 84.0 mg g( 1) for Pb(ll) and Cu(ll), respectively, which are in good agreement with those values obtained for the aqueous solution (188.6 mg g(-1) for Pb(ll) and 86.9 mg g(-1) for Cu(II)). The functional group analysis of the seaweed using FTIR demonstrated that the carboxyl functional groups are mainly responsible for biosorption. The cation exchange capacity of the biosorbent was 2.25 meq/g. This observation suggested that ion exchange mechanism is predominantly responsible for the metal ion uptake. The column study showed that the highest bed height and the lowest flow rate result in a substantial enhancement of the metals uptake with the biosorption uptake capacities being 264.3 mg Pb(ll) g(-1) and 86.0 mg Cu(ll) g(-1). In the binary system, the biosorption capacity was observed to be 208.7 mg Pb(ll) g(-1) and 61.0 mg Cu(II) g(-1). The predicted breakthrough curves by the Thomas adsorption model gave a good fit of the experimental data with r2 ranging from 0.92 to 0.99. PMID- 17711026 TI - Budgets of major ionic species and nutrients on a dam reservoir in forested watershed. AB - To evaluate the role of a dam reservoir in the runoff of pollutant loadings from a forested watershed, the input-output budgets in the Ikuno dam reservoir had been investigated for eight years since 1996. The T-N, T-P, TOC and major ionic species in the bulk precipitation, stream water, and outflow were measured. The residence time calculated by using the data of the inflow and outflow was 0.3 year. The average precipitation was 1,772 mm during the investigation period (1996-2004). The direct deposition to water surface was less than one percentage to total loadings of nutrients and major ionic species. The ratios of output to input of TOC, TN, and TP were 1.04 to 1.42, and those of major ionic species were from 0.83 to 0.99 except for NO3(-), which was 1.12. However, the ratios of output to input of major ionic species except for NO3(-) at the Ikuno dam reservoir will be larger, and those of NO3(-), TOC, TN, and TP will be smaller, if we also include rain events. These results suggested that the dam reservoir played a role as a sink for pollutants in forested watershed, and that the pollutant loadings to downstream may decrease. PMID- 17711027 TI - Estimation of nutrient load from urban diffuse sources: experiments with runoff sampling at pilot catchments of Lake Balaton, Hungary. AB - About a quarter of the total nutrient loading of Lake Balaton (Hungary) originates from urban diffuse sources, mostly from direct shoreline watersheds. This load cannot be measured directly. Sampling of urban runoff can help improving load estimations. The dynamic processes characterizing the accumulation and washoff of contaminants suggest that randomly observed concentrations are likely under- or overestimated. The results of two recent pilot programs aimed towards achieving continuous measurement of nutrient load carried by urban runoff are introduced. Stations were implemented in two pilot catchments located on the shore of Lake Balaton. Storm event runoff was sampled automatically and manually. Discharge, precipitation and rainfall intensities were also recorded. Results proved that the more a specific pollutant is associated with solid particles, the more of its load comes from a few but large storm events, nevertheless the cumulative effect of small rainfall events is not negligible, either. Event mean concentrations of solid-related pollutants were found to be dependent on rainfall intensity. The derived empirical relationships for SS, TP and TN event mean concentrations were indeed found to be applicable for reducing the uncertainty of load estimations of these pollutants significantly, as compared to using long time average (i.e. annual mean) concentration values. PMID- 17711028 TI - The dental Blues. PMID- 17711029 TI - What you need to know about antitrust law. PMID- 17711030 TI - Injuries at work and first aid kits. PMID- 17711031 TI - Women: changing the face of dentistry. PMID- 17711032 TI - Mid-year: time to take stock. PMID- 17711033 TI - New Blues pharmacy initiatives seek to curb drug costs. PMID- 17711034 TI - Teen smoking and R-rated movies. PMID- 17711035 TI - Running on empty? Dental PAC donations are down over 50 percent this year. PMID- 17711036 TI - Blue Cross Blue Shield of Michigan's dental reorganization. PMID- 17711037 TI - EMG study of the pectoralis major (sternal portion), teres major, latissimus dorsi and deltoid medial muscles in volleyball players. AB - The pectoralis major (sternal portion), teres major, latissimus dorsi and deltoid medial muscles has been studied through in the electromyography in 8 male individuals, who practice volleyball, youth category, (age between 15 and 17 (average 16.25), right-handed, involved in volleyball for about one year. The objective was to analyze the potential of action of these muscles engaged in the volleyball movements: service, spike, pass, set and blocking with and without ball. The work was developed in the laboratory of Electromyography and Biomechanics of Posture (Physical Education Faculty - State University of Campinas - UNICAMP). To caption the muscles action potential, surface electrodes were set with conductive gel and fixed on the skin, in the center of the muscles. It was used an electromyography Lynx with 6 channels. The apparatus calibration was 3000 microV; 1199.760 Hz. The sequential experiments without ball were performed for 10 seconds, and the sequential experiments with ball in 12 seconds. RESULTS: None of the muscles presented significative difference (p > 0,05) when compared to the sequential movements executed with and without ball. When compared to the sequential movements executed without ball, the only muscles that presented significative differences (p < 0,05) were: pectoralis major / deltoid and latissimus dorsi / deltoid, for another hand when in the comparative of the movements with ball, all muscles when compared to the latissimus dorsi, presented a significance difference (p < 0,05). It is interesting to observe, that the general average and the standard deviation of the deltoid muscle (medial portion), teres major, and latis-simus dorsi were higher in the sequential movements executed without ball. PMID- 17711038 TI - Shoulder muscle strength and fatigability in patients with frozen shoulder syndrome: the effect of 4-week individualized rehabilitation. AB - The effect of 4-week individualized rehabilitation on shoulder muscle strength and fatigability was evaluated in 10 patients with frozen shoulder syndrome (FSS) in comparison of 10 age- and gender-matched healthy control subjects. Isometric maximal voluntary contraction (MVC) force of the shoulder flexors was measured by hand-held dynamometer. Isometric endurance of the shoulder muscles was characterized by endurance time and net impulse (NI) assessed during weight (30% MVC) holding in hand until exhaustion. Fatigability of deltoideus, infraspinatus and trapezius muscles during isometric endurance test was assessed by electromyogram (EMG) power spectrum median frequency (MF) slope per minute. Rehabilitation in patients with FSS consisted of exercise therapy in swimming pool and gymnasium, electrical therapy and massage. Before rehabilitation, patients with FSS had less (p < 0.05) isometric MVC force and NI during endurance test compared to the control. MF slope in patients with FSS for involved extremity was higher (p <0.05) for the deltoideus muscle and less for the infraspinatus muscle before rehabilitation compared to the controls. Shoulder pain was decreased (p < 0.05) and isometric MVC force and NI in endurance test in patients for involved extremity were increased after rehabilitation. No significant changes in endurance time and MF slope for infraspinatus and trapezius muscles in patients for involved extremity were observed after rehabilitation, whereas MF slope for deltoideus muscle was increased. It was concluded that in patients with FSS, 4-week rehabilitation decreased shoulder pain and improved MVC force of the shoulder flexors and isometric working capacity of these muscles during endurance test. PMID- 17711039 TI - The cutaneous silent period in carpal tunnel syndrome. AB - OBJECTIVES: The cutaneous silent period (CSP), a sustained voluntary contraction following a painful stimulus applied over the appropriate dermatome produces a brief period of electrical silence, may be useful if the routine nerve conduction studies and needle electromyography are insufficient to diagnose entrapment neuropathies. MATERIAL AND METHODS: To investigate whether symptomatic or asymptomatic patients with entrapment neuropathies are differed in terms of CSP, one hundred fifty four hands of 58 patient and 19 controls were studied according to the clinical and electrophysiological findings. RESULTS: CSP latency and duration could be affected in severe forms of entrapment neuropathies. However, even in patients with dysesthetic pain -which lead to the belief that small fibers may be involved-, results of electrophysiological evaluation could not support the clinical findings. CONCLUSION: In this study it was suggested that CSP studies provide no additional information in entrapment neuropathies. PMID- 17711040 TI - The influence of muscle fiber type composition on the patterns of responses for electromyographic and mechanomyographic amplitude and mean power frequency during a fatiguing submaximal isometric muscle action. AB - The purpose of this investigation was to examine the influence of muscle fiber type composition on the patterns of responses for electromyographic (EMG) and mechanomyographic (MMG) amplitude and mean power frequency (MPF) during a fatiguing submaximal isometric muscle action. Five resistance-trained (mean +/- SD age = 23.2 +/- 3.7 yrs) and five aerobically-trained (mean +/- SD age = 32.6 +/- 5.2 yrs) men volunteered to perform a fatiguing, 30-sec submaximal isometric muscle action of the leg extensors at 50% of the maximum voluntary contraction (MVC). Muscle biopsies from the vastus lateralis revealed that the myosin heavy chain (MHC) composition for the resistance-trained subjects was 59.0 +/- 4.2% Type IIa, 0.1 +/- 0.1% Type IIx, and 40.9 +/- 4.3% Type I. The aerobically trained subjects had 27.4 +/- 7.8% Type IIa, 0.0 +/- 0.0% Type IIx, and 72.6 +/- 7.8% Type I MHC. The patterns of responses and mean values for absolute and normalized EMG amplitude and MPF during the fatiguing muscle action were similar for the resistance-trained and aerobically-trained subjects. The resistance trained subjects demonstrated relatively stable levels for absolute and normalized MMG amplitude and MPF across time, but the aerobically-trained subjects showed increases in MMG amplitude and decreases in MMG MPE The absolute MMG amplitude and MPF values for the resistance-trained subjects were also greater than those for the aerobi-cally-trained subjects. These findings suggested that unlike surface EMG, MMG may be a useful noninvasive technique for examining fatigue-related differences in muscle fiber type composition. PMID- 17711041 TI - Facioscapulohumeral muscular dystrophy. Multimodal evoked potentials and electroretinogram. AB - BACKGROUND: Clinical or subclinical abnormalities of the central nervous system (CNS) have been reported in a range of primary muscle diseases, including the muscular dystrophies. PURPOSE: To ascertain by neurophysiologic techniques evidence of CNS dysfunction in a relatively large, homogeneous group of patients with facioscapulohumeral muscular dystrophy (FSHD). METHODS: Standard evoked potential (EP) and electroretinogram techniques were used to study the visual, auditory and somatosensory pathways in 20 patients with FSHD. RESULTS: Abnormal values were recorded in 70% (14/20) of patients, specifically of visual pathways (4/20), brainstem auditory pathways (4/20), median (5/20) and tibial nerve (2/20) somatosensory pathways, and of the retina (2/18). Abnormal results did not correlate with clinical parameters of patient age, disease duration and degree of weakness. CONCLUSIONS: Any process that caused CNS conduction delays was tentatively associated with FSHD. Sensorineural hearing deficit and vascular retinopathy were rare causes of abnormal EPs. Peripheral conduction delay of the arms was ascribed to mechanical factors secondary to shoulder girdle weakness. Progress in genetics and molecular pathogenesis of FSHD may shed further insight into the association between the myodystrophic process and nervous system abnormalities. PMID- 17711043 TI - Effect of voluntary contraction with electrical stimulation to antagonist muscle on agonist H-reflex. AB - OBJECTIVE: Hybrid exercise (HE) was designed to use the force generated by an electrically stimulated antagonist to provide resistance to a volitionally contracting agonist. The purpose of this study was to measure and compare the soleus H-reflex before and after HE or conventional resistance exercise (CRE). METHODS: The experiments were carried out in 18 healthy subjects (5 men and 13 women; 19-30 yr), who were divided into 2 groups of 9 for each protocol (HE or CRE). The exercise sessions lasted for 15 consecutive minutes. The soleus Hmax/Mmax was measured before and after the HE or the CRE. RESULTS: In the HE group, although there was no significant difference, the soleus Hmax/Mmax after the exercise increased compared with before the exercise (54.7 +/- 10.2% to 59.0 +/- 14.5%). On the other hand, the soleus Hmax/Mmax decreased in the CRE group (61.8 +/- 14.9% to 55.7 +/- 16.1%). In the rate of change of the soleus Hmax/Mmax, the result for the HE group was significantly higher than in the CRE group (108.0 +/- 11.7% and 89.1 +/- 8.0%, respectively) (p < 0.001). CONCLUSION: Our results show a clear difference of the neurophysiological mechanism between HE and CRE. Thus, HE might not be an alternative method for CRE. PMID- 17711042 TI - Electromyographic evaluation of the masseter and temporal muscles activity in volunteers submitted to acupuncture. AB - AIM: To assess the effect of acupuncture on the temporal and masseter muscles activity employing surface electromyography. METHODS: Thirty volunteers were evaluated according to three groups of acupuncture application: selected local points, selected points at distance and association of local and distant points. Bipolar surface electrodes were positioned bilaterally on the anterior portion of temporal muscle, as well as in the median region of masseter muscle. An electromyograph connected to a computer and a specific software registered the muscular activity before and after acupuncture, in the following experimental conditions: 1- Rest Position (RP); 2- Maximum Intercuspation Clenching (MIC); 3- Bilateral Molar Clenching with Cotton Rolls (BMCCR). The mean values obtained for the activities of the studied muscles were submitted to Analysis of Variance and Tukey complementary test. RESULTS: The electromyographic activity of the studied muscles was lower after the application of the methods of acupuncture in the Rest, and higher after the application of the acupuncture in the Maximum Intercuspation Clenching; the electromyographic activity of the temporal muscle was higher than the masseter muscle in the Rest and lower in the Bilateral molar clenching with cotton rolls; the electromyographic activity showed to be modified after the three used methods of acupuncture in the Maximum Intercuspation Clenching. In this clinical condition, the method of long-distance acupuncture was higher than the application of local needles and the associated method. CONCLUSION: Acupuncture provided alterations in the activity of the studied muscles, favoring conditions of rest and muscular tightness. PMID- 17711044 TI - [The beers criteria--an instrument to optimise the pharmacotherapy of geriatric patients]. AB - Geriatric patients represent an important population group in counselling and care of pharmacists. Despite this high need, there are only few investigations in this special patient population and derived aids for competent and practice oriented pharmaceutical care. The Beers criteria developed in the US represent an instrument to detect potentially inappropriate medication in older adults. In order to propagate in Germany a translation and adaptation to the German drug market was performed. Systematic consensus building by an expert panel will be necessary for wide acceptability. Applying the Beers criteria presents an opportunity of pharmacist to optimise the pharmacotherapy of geriatric patients. PMID- 17711045 TI - [Mumps--infectious disease with various faces]. AB - Mumps is a world-wide distributed human infectious disease. The causative agent is mumpsvirus, a single-stranded RNA virus belonging to the Paramyxoviridae. Mumpsvirus causes a variety of illnesses, which depend in part on humans' age and sex. Parotitis and meningitis as well as respiratory tract infection in children and orchitis in pubertal and postpubertal males are very common. Asymptomatic infections have also been frequently described. The treatment for mumps infection is symptomatic, there is no specific antiviral therapy. Immune prophylaxis with an attenuated life vaccine is the most important strategy of mumps prevention. During the last years, an increased number of mumps cases have been observed in several countries with a general recommendation for mumps vaccination. Young adults have been most frequently affected. The lack of immunity in this population is likely to be responsible for the increasing number of mumps cases. PMID- 17711046 TI - [Barotrauma of the middle ear. Preventive measures against aero-otitis media]. PMID- 17711047 TI - [Myrtillus beers--a new wonder drug?]. PMID- 17711048 TI - Where do we go from here? PMID- 17711049 TI - Re: Texas Dental Journal March 2007 Special Issue On Texas Dental Association Smiles Foundation. PMID- 17711050 TI - Recreational illicit drug use. PMID- 17711051 TI - Focal infection revisited. PMID- 17711052 TI - Oral and maxillofacial pathology case of the month. Hand-foot-and-mouth disease. PMID- 17711053 TI - Data archiving and backup: what you need to know. PMID- 17711054 TI - Re: JRSH olympic games special issue, 2007;127(3). PMID- 17711056 TI - A single avoidable death from injury is a tragedy, a thousand deaths is just a statistic. PMID- 17711055 TI - Playing it safe. PMID- 17711059 TI - Work-related road safety. PMID- 17711058 TI - Ten myths about injury prevention that hinder effective child safety policy making. PMID- 17711060 TI - Back pain when sitting: should everybody just sit up straight? PMID- 17711061 TI - Refugee and migrant vulnerability to injury. PMID- 17711057 TI - Preventing work-related back pain across Europe. PMID- 17711062 TI - Moving towards evidence-based healthcare for musculoskeletal injuries: featuring the work of the Cochrane Bone, joint and Muscle Trauma Group. AB - Due to their high incidence and associated morbidity and mortality, musculoskeletal injuries place an enormous burden on society. For example, in the 2004 to 2005 period 62,000 people with hip fracture accounted for 2.9% of the total number of hospital bed days in England. Between 12% and 37% of people with hip fracture die in the first year. Of the survivors, most are less mobile and many lose their independence. Soft-tissue joint injuries during sports and exercise-related activities in young adults constitute another important group. Of these, ankle sprain is the most common single injury and it predisposes people to further recurrence. Members of the Cochrane Bone, Joint and Muscle Trauma Group prepare systematic reviews (Cochrane Reviews) of the evidence for interventions used in the prevention and management of musculoskeletal injuries. These reviews serve to facilitate evidence-based decision making by policy makers, healthcare professionals and consumers, and to guide future research. This article focuses on two major groups of injuries: osteoporotic fractures and soft-tissue joint injuries, and discusses some of the fundamental issues and questions associated with the prevention and management of these. Drawing insights from relevant Cochrane Reviews, this article examines the different approaches used for preventing, and the role of surgery and immobilisation for treating, these injuries. Brief illustrations of the inherent complexity of rehabilitation are also provided. This article also gives examples of how these reviews are helping to inform healthcare choices and practice, and guide research in this area. PMID- 17711063 TI - Psychological responses to injury in competitive sport: a critical review. AB - Research has attempted to examine the psychological impact of athletic injury to assist rehabilitation personnel when treating injured athletes. Sports trainers, sports therapists, physiotherapists, medical staff and sports psychologists should be aware of psychological factors impacting on the injury experience when involved in an athlete's rehabilitation. A number of models have been proposed as useful frameworks for investigating and describing the psychological response to athletic injury. Many researchers have relied upon applying or adapting grief and cognitive appraisal models originally derived from the clinical and stress related psychology literature in an attempt to describe the psychological response to athletic injury. This article provides an overview of these models and offers a critical appraisal of this research, specifically focusing on the grief response models and the integrated model of response to sport injury and rehabilitation. Criticisms focus on the lack of research supporting a uniformed sequence of stages as a feature of response to athletic injury. Further grief criticisms centre on the absence of denial in much of the research to date. The article then focuses on the dynamic core of the integrated response to sport injury and rehabilitation model. It is argued that the interrelationships between emotional responses, behavioural responses, cognitive appraisals and recovery outcomes are not as simple as suggested in the model. PMID- 17711064 TI - Perspectives on injuries in snowboarders. AB - AIMS: Adopting effective injury prevention practices continues to be problematic within snowboarding and the participation of older individuals is associated with an appreciable injury burden. The Haddon Matrix provides an important framework for developing injury prevention interventions. Since prevention behaviour must 'fit' within individual aspirations, our study investigated the meanings and behaviours associated with snowboarding and injury prevention and then applied the findings to the established Haddon Matrix approach. METHODS: Nine, older adult recreational participants living in south-west England each contributed two interviews. These progressively focused on experiences and reflections. Verbatim transcripts were analysed and interpreted using the hermeneutic phenomenological themes of time, space, body and human relations. A further wave of analysis reinterpreted the findings in relation to the Haddon Matrix. FINDINGS: Snowboarding was conducted within a holiday when participants were seeking happiness by positively re-evaluating their lives. In a frame of connection-and disconnection, beginners (time) were concerned with being-on the slopes (body and space), while more experienced (body and time) participants blended this with being-in the mountains (space). Snowboarding is a bumps-and-bruises activity and this guided the limited prevention practices. Importantly, all prevention practices were time-limited, due to a concern for learning-by-doing within a holiday. At home, more experienced boarders paid careful attention to fitness, whereas in the resorts they actively selected the soft, off-piste areas and wore protective clothing to cushion their inevitable falls. Group experiences were associated with heightened injury risks. Being seen and judged by others helped to determine the quality of the snowboarding experience. Treatment was avoided for all but the most severe injuries. CONCLUSION: The findings confirm the exploratory value of mixing van Manen's four-dimensional approach with Haddon's well-established injury prevention framework. The diverse subjective meanings associated with snowboarding limit the potential for prevention approaches and suggest that resort-based 'injury control' may be more appropriate for addressing the spectrum of prevention in older snowboarders. PMID- 17711065 TI - The role of nurse educators in grooming future nurse leaders. AB - The authors have found in their research that too often our current nurse leaders have "fallen into" their positions, rather than choosing nursing leadership as a career path. With the impending retirements of so many nurse leaders, there is a need for a more proactive approach to ensure the next generation of nurse leaders is ready to assume the leadership of our profession. Guiding the development of a leadership mindset and promoting nursing leadership as a career choice are two important strategies. Nurse educators are in a key position to influence students and start grooming our future nurse leaders. There is no time to waste. PMID- 17711066 TI - Teaching can never be innocent: fostering an enlightening educational experience. AB - Becoming cognizant of the actual and potential oppressive dimensions of the teaching practices of nurse educators is essential in establishing a more democratic and enlightening experience for both teachers and students. Although there has been an ardent trend toward the promotion of critical thinking and reflective ability among nursing students, rarely has attention focused on the ability of nurse educators to be critically reflective of their own teaching. The authors pose key questions about the reality of nursing education today and how it can sometimes continue to reflect a philosophy that seems to contravene the notion of a more liberated approach to teaching. In that process, they reflect critically on the subtle incongruities and complexities between teachers' intentions and their practice. PMID- 17711067 TI - Gentle interruptions: transformative approaches to clinical teaching. AB - This conceptual article, drawn from the authors' shared teaching experiences and recent student and clinician evaluation data, set out to reveal and then address some common problems faced by clinical educators and nursing students in the time constrained, complex, specialized field of clinical learning. We explain and argue the benefits of transformative learning and outline specific strategies for building skills in transformative education, such as interrogating clinical routines and habits, teaching diplomacy skills, and using a process of interruption. Clinical educators can use these strategies to move beyond unwittingly serving the status quo toward consciously contributing to change. PMID- 17711068 TI - Use of the Pathfinder scaling algorithm to measure students' structural knowledge of community health nursing. AB - In nursing education, measures of structural knowledge have not been widely used to assess student learning. Some authors have suggested concept mapping as a way to measure structural knowledge, but this approach can be subjective and otherwise problematic. Pathfinder, a computer-based network scaling technique, offers an alternative, quantitative method for representing and evaluating structural knowledge. The purpose of this study was to investigate structural knowledge as a learning outcome for baccalaureate nursing students by using Pathfinder techniques. Results revealed that students' structural knowledge increased in internal consistency and became more similar to instructors' knowledge during a course in community health nursing. Students with structural knowledge that was most coherent and similar to the instructors' performed better in the course. Students' structural knowledge characteristics differentiated between high-performing and low-performing students. Findings support the use of structural knowledge representation with Pathfinder scaling techniques as a way to operationalize learning. PMID- 17711069 TI - Appreciative inquiry for leading in complex systems: supporting the transformation of academic nursing culture. AB - Increasingly complex environments in which nurse educators must function create distinct challenges for leaders in nursing education. Complexity is found in the presence of knowledge-driven economies, advancements in technology, and the blurring of campus boundaries created by online learning versus traditional classroom education. A dual bureaucracy of faculty and administration coexists in nursing education. The transformation of bureaucratic culture is a strategic challenge for academic leaders who strive to move dichotomous groups toward a collective vision of a preferred future. This article advocates for the affirmative administrative process of appreciative inquiry for academic nursing leadership, in nudging the dual bureaucracy toward transformational change. The intent and characteristics of appreciative inquiry are discussed, appreciative leadership strategies and actions are explained, methods for leading cultural paradigm shift are outlined, and an exemplar of the actualization of appreciative inquiry is presented. PMID- 17711070 TI - Academic microsystems: adapting Clinical Microsystems as an evaluation framework for community-based nursing education. AB - When an academic nursing program and clinical agency form a partnership to both educate students and effect changes in the health care of the community, evaluation presents a challenge for measuring structure, processes, and outcomes at three levels: student educational processes and outcomes; student-sensitive outcomes for the community; and the effectiveness of the partnership itself. This article describes how we adapted the Clinical Microsystems model as an Academic Microsystems model to evaluate the complementary processes and outcomes for the community and for the nursing program in a senior Community Capstone course. The Capstone is a community-based initiative in which students assess community needs, intervene appropriately, evaluate their intervention, and pass the initiative on to the next year's class. Although outcomes for students and the community were positive, the model revealed that developing the frontline microsystem of student/faculty/community nurse mentor was the key to success. PMID- 17711071 TI - Expanding educational capacity through an innovative practice-education partnership. AB - This article describes a unique demonstration project using a collaborative practice and education partnership to expand baccalaureate student education capacity by 75% in an accelerated nursing program. Components of the project include using hospital-paid (donated) master's clinicians as clinical faculty; using online course delivery for the non-clinical theory nursing courses, thereby decreasing the need for classroom space; employing a Web instructional designer to convert the existing master's nurse educator program to an online format in an effort to increase the pipeline of nursing faculty; renovating existing space to expand the nursing skills laboratory; and purchasing equipment and supplies for the simulated patient environment modules in the expanded skills laboratory space. Both formative and summative measures will be used to evaluate the project, which is expected to produce 24 additional workforce-ready baccalaureate prepared RNs in 15 months. PMID- 17711072 TI - Time requirements for implementation of the course facilitator role. AB - The purpose of this descriptive study was to identify the time requirements to implement the lead position (course facilitator) for nursing courses at a health sciences center school of nursing located in the southwestern United States. Faculty participants completed instruments dividing tasks into pre-course, within course, and post-course responsibilities. The results of this study revealed that more than 1 hour per week was spent in pre-course and post-course activities and 3.79 hours per week were spent in within-course activities. Recommendations include examining tasks requiring large amounts of time for management alternatives; developing workload expectations that accurately reflect pre course, within-course and post-course time requirements; and using course facilitators as mentors when preparing novice faculty for the course facilitator role. Although the results of this study are not generalizable, the findings represent formal assessment of a critical component of the faculty role and suggest the need for further investigation into the demands placed on nursing faculty. PMID- 17711073 TI - Using simulation to prepare students for interprofessional work in the community. PMID- 17711074 TI - A good result isn't always a good result. PMID- 17711076 TI - Nursing homes: introduction. PMID- 17711075 TI - Thomas Willis and the Oxford epidemic. PMID- 17711077 TI - Culture change in long-term care. PMID- 17711078 TI - Transitions of care: a topic for the present and future. PMID- 17711079 TI - Infections in the nursing home: a primer for the practicing physician. PMID- 17711080 TI - Nursing home physicians: roles and responsibilities. PMID- 17711081 TI - Superior sagittal sinus thrombosis. PMID- 17711082 TI - Resident and family satisfaction with nursing home care in Rhode Island: prioritizing improvement. PMID- 17711083 TI - [The influence of RS4 resistant starch on wistar rats metabolism. Biochemical and lipid indices]. AB - The influence of resistant starch RS4 on total cholesterol (TC), HDL cholesterol, triacyloglycerols (TAG) composition in blood serum and liver of rats was determined. 4 week experiment involved 32 males and 40 females laboratory Wistar rats allotted in 4 groups in each sex. Control rats were feed ad libitum with standarised synthetic diet AIN-93. In experimental groups animals were given modified feed enriched with 5% of resistant starch. monophosphate of potato starch, monophosphate of soluble potato starch and monophosphate of potato starch heated with glycne and microwaved were examined. Diet enrichment with resistant starch decerased triacyloglycerol level (TAG) while the total cholesterol (TC) level, in serum was not affected. PMID- 17711085 TI - [Hypercholesterolemic diets containing different common fats and rats plasma lipids]. AB - The aim of the study was evaluated high-fat (20% w/w), hypercholesterolemic (3% w/w) diets differing in dietary fat type (butter, margarine with stanols, margarine with rapeseed oil and sunflower oil) influence on plasma lipids profile in male Wistar rats. The results show that cholesterol enriched diets, excluding diet containing margarine with stanols, had hypercholesterolemic effects on rats. PMID- 17711084 TI - [The role of glucosinolates in the prevention of cancer--mechanisms of actions]. AB - Foods of plant origin, despite plenty of nutrients contain many non-nutrition compounds, which may prevent many diet-related non-communicable diseases, such as cancer. Plants produce thousands of phenolic compounds as secondary metabolites, such as nitrous compounds. Glucosinolates are responsible for the secretion of detoxifying enzymes that remove carcinogens for the organism. Furthermore, they activate proteins and II phase detoxifying enzymes. The compounds are very important that is why scientists are still investigating their beneficial note in cancer prevention and management. PMID- 17711086 TI - [The effect of vegetarian diet on selected biochemical and blood morphology parameters]. AB - The objective was to examine whether vegetarian diet influence biochemical parameters of blood and plasma urea in selective vegetarian group. The investigation covered 41 subject, 22 of them had been applying vegetarian diet and 19 were omnivorous. The study shows statistically significant lower values of white blood cells, % and amounts of neutrocytes and insignificant lower level of red blood cells, hemoglobine, hematocrit and platelet in vegetarian group. Significant lower plasma urea level was observed in that group. These changes indicate that high quality deficiency protein was due to vegetarian diet. PMID- 17711087 TI - [Effects of resistant starch RS4 on magnesium and iron absorption in Wistar rats]. AB - The effect of resistant starch RS4 on apparent absorption of magnesium and iron was studied in Wistar rats. The rats (4 groups male n=12 and 4 groups female n=12) were fed for 4 weeks diets: control with wheat starch (K) and 3 diets with modified resistant starches (S1, S2, S3). After an adaptation period (14 d), rats were transferred to metabolic cages. Dietary intake and faeces were monitored for 3 days. Mg and Fe levels were assessed in diets and feces by atomic absorption spectrometry. Apparent absorption of minerals was calculated as mineral intake minus fecal excretion and expressed as persentage of intake. Our results confirmed that Mg apparent absorption in female rats fed diet with resistant starch S2 was significantly increased (+37%) compared with the control group. PMID- 17711088 TI - Evaluation of antioxidant activity of amaranth (Amaranthus cruentus) grain and by products (flour, popping, cereal). AB - The objective of our study was evaluation antioxidant activity of Amaranthus cruentus grain and by-products (flour, cereals and popping). The evaluation was performed by FRAP, DPPH and ABTS methods. FRAP and ABTS assays gave comparable results, DPPH method gave lower values. Among by-products cereal had the highest activity as the least processed product. Additionally, antioxidant capacities of two cultivars of amaranth (varieties Aztek and Rawa) were compared and the influence of grain soaking on antioxidant properties was taken into account. It was found, that soaking decreased antioxidant activity of amaranth seed. PMID- 17711089 TI - Bioactive substances of garlic and their role in dietoprophylaxis and dietotherapy. AB - Garlic is characterised by medicinal properties due to the content of over 2000 biologically active substances. Numerous commercially processed garlic forms, which differ in the content of bioactive compounds, especially sulphuric, are available on the market. The knowledge of the types of bioactive substances present in garlic and its products, their changes during treatment and pro-health influence is of crucial importance to the diet supplement producers, doctors, pharmacists and consumers. Therefore, this work has aimed to characterise the most important bioactive substances of garlic, its preparations and describe in detail the role of garlic in dietoprophylaxis and dietotherapy. PMID- 17711090 TI - [The mechanisms of blood LDL-cholesterol lowering by phytosterols--a review]. AB - Daily cholesterol consumption in western countries reaches as much as 400 mg. According to the health recommendations the daily intake should not exceed 300 mg and in the case of people with cardiovascular disease it should be less than 200 mg. For 50 years it is known that phytosterols can decrease the level of cholesterol in blood. One of the mechanisms is based on the fact that phytosterols stop absorption of cholesterol in digestive tract, which results in the decrease of the concentration of cholesterol in blood. The second mechanism is based on the fact that cholesterol is pumped back out of enterocytes into the lumen of small intestine by ABC transporter and phytosterols increase this process. The above merftioned mechanisms are different than the way statins can lower cholesterol level and they are commonly used as hipocholesterolemic medicine. Because different mechanisms are implemented both statins and fitosterols can be used in therapy of hipercholeserolemia. The people taking statins who still have increased level of total cholesterol and LDL-cholesterol in blood can include phytosterols in their diet what can lead to the decrease of its level. PMID- 17711091 TI - [Energy and macronutirents intake by overweight and obese children aged 7-12]. AB - Energy and macronutrient such as protein, fat and carbonhydrate as well as anthropometric measurments were caried out in overweight and obesity children aged 7-12 (n=25) during two visits of the loss weight program for children (before and 6 weeks after dietary intervention) at the Faculty of Human Nutrition and Consumer Sciences, Warsaw Agricultural University. The study showed no significant (p > 0.05) body weight reduction expressed as body mass index (BMI), but nutrition counselling resulted in a decline in obesity prevalence in examined subject. Before nutritional counselling energy and macronutrient mean intakes from the diets of examined: children aged 7-9 y, boys 10-12 y and girls 10-12 y, were found to be: of energy (kcal): 1770, 1680, 1711 and protein: 107%, 85%, 84%; fat: 107%, 84%, 111% and carbohydrates: 81%, 57%, 67% RDA, respectively. After 6 weeks of the aplication of--low energy diet the consumption of energy and fat decreased among most of children (p < 0.05). The intakes of energy and fat need to be monitored in this group of population, since their overeating can predispose to diet-related diseases, such as cardiovascular in adulthood. PMID- 17711092 TI - Tea and coffee as the main sources of oxalate in diets of patients with kidney oxalate stones. AB - We analyzed nutritional habits of 22 stone formers with special regard to oxalate content as one of the main nutritional lithogenic factors associated with kidney stones. Daily dietary oxalate intake was 354 +/- 261 mg and 406 +/- 265 mg in men and women respectively. These values were much higher than those found by other researches. The main sources of oxalate in diets were regular tea and coffee (80 85%). Only 15-20% of oxalate was derived from other plant foods. Patients did not adhere to high fluid diet and, what is more, as common beverage they chose rich oxalate black tea. Patients' daily intake of calcium was low and didn't exceed 520 mg. Vitamin C consumption was higher than Polish Dietary Reference Intake (DRI) and vitamin B6 lower than DRI. In the management of stone patients, to lower the risk of recurrence, appropriate diet (according to the type of stone) should be provided by dietitian. PMID- 17711093 TI - [Analysis of the dependence between milk and dairy products consumption, and dental caries observed in group of children and teenagers]. AB - The aim of this research was evaluation of influence of milk and dairy products consumption on advance of dental caries observed in the group of children and teenager. The dependences between milk and dairy products (dairy beverages, cottage cheese and other kinds of cheese) consumption and advance of dental caries were analyzed. The objects of the research were 44 patients aged 7-18 years. Elements of the research were the questionnaire survey and the assessment of the patients diet. The statistical analysis was conducted using the Kolmogorov Smirnov test and Kruskall-Wallis test as far as the coefficient of correlations by Pearson. In the research it was found that cheese consumption contributes to decrease of dental caries coefficient. The need to provide children and teenagers commonly the nutritional education, concentrating on proper model of the diet and systematic consumption of milk and dairy products, was proved. PMID- 17711094 TI - [Significance of organic crops in health prevention illustrated by the example of organic paprika (Capsicumannuum)]. AB - The paprika fruits are perfect source of bioactive compounds as carotenoids (beta carotene and lutein), flavonoids and vitamin C. The aim of work was to determine the content of bioactive compounds in paprika fruits from organic and conventional cultivation. Organic and conventional paprika fruits were chemically analyzed. The results obtained showed that organic paprika contained more total and reducing sugars, vitamin C and flavonoids than conventional one. Additionally organic paprika fruits had slightly higher acidity than conventional fruits. PMID- 17711095 TI - Malnutrition, inflammation, atherosclerosis in hemodialysis patients. AB - Protein-energy malnutrition with muscle wasting occurs in a large proportion of patients with chronic renal failure and is, in addition to atherosclerosis, a strong risk factor for cardiovascular mortality in dialysis patients. There is evidence that a chronic inflammation with activation of C-reactive protein and proinfalammatory cytokines is associated with increased oxidative stress and endothelial dysfunction. Strong relations between malnutrition, inflammation and atherosclerosis in dialysis patients suggest the presence of a MIA (malnutrition, inflammation and atherosclerosis) syndrome, which is associated with high mortality rate. Thus, it could be speculated that suppression of the vicious cycle of malnutrition, inflammation and atherosclerosis would improve survival in dialysis patients. PMID- 17711096 TI - [Effect diet therapy on body weight reduction and metabolic control recommended for patients with type 2 diabetes mellitus treated with only diet]. AB - The aim of the study to assess the efficacy diet therapy recommended for patients who were recently found to have type 2 diabetes mellitus as well as the influence of the diet on metabolic control of the subjects. The study involved 35 patients of the Dietary Counseling Section of the Central Clinical Hospital of the Ministry of Internal Affairs and Administration in Warsaw. During the course of a 6-month observation, the following parameters were analyzed: body weight, BMI, WHR, indices of metabolic control, such as fasting and post-prandial glycemia, and the level of glycated hemoglobin (HbA1(c)). 6-month dietary intervention brought a decrease in body weight, and improvement in glycemia PMID- 17711097 TI - [Compliance of the diet restricted with leucine, isoleucine and valine in maple syrup urine disease (MSUD) children]. AB - The aim of this study was to evaluate the compliance of the diet with limited branched-chain amino acids (BCAA) content in long-term observation of patients with maple syrup urine disease (MSUD). The study group consisted of 7 children at age of 1.5-18 years. Nutrition evaluation was based on current diet records from 3-4 days, every 3-4 months. Energy and nutrition values of proposed daily products lists and diet records was compared with adequate references and recommendations. Energy and content of most of the nutrients in proposed daily products lists were in agreement with RDI except calcium. Diet analysis at MSUD children revealed insufficient contents of: iron, zinc, copper, vitamin B1, B2, niacin and vitamin C (often below 90% RDI). PMID- 17711098 TI - [Oat products in gluten free diet]. AB - Diagnosis of celiac disease in patent in different age is increased, but gluten free diet is only way to treat this disease. Diet without gluten cereals: wheat, rye, barley and oats is often low in many minerals, vitamins and dietary fiber, but rich in fat and sugar. Gluten free diet witch is supplemented with oats products may contains more dietary fiber, minerals, thiamine, biotin, tokopherols, tokotrienos, and unsaturated fatty acids. The majority of researches show that inclusion 20-50g/d of oat products to gluten free diet is safe for children and adults with new diagnosed and also in remission state. Simultaneously, some patients with celiac disease may intolerance to avenin. The control and assessment of gluten (wheat, rye, barley) contamination in oat products and also long term introduction of oat products to gluten free diet for patient at different age. PMID- 17711099 TI - Nutrition in pediatric patients before liver transplantation. AB - Malnutrition leading to growth failure is one of the main problems in maintainig children with chronic liver diseases. The pathogenesis of malnutrition is complex and includes reduced calorie intake, fat malabsorption, impaired protein metabolism and increased energy expenditure. The nutritional status is an important risk factor for survival post liver transplantation. Aggressive nutritional support with careful monitoring is essential, particularly where liver transplantation is considered. When the oral nutrition is inadequate, the enteral feeding with nocturnal intragastric tube should be started. In case of gastrointestinal intolerance, severe malnutrition and gastrointestinal bleeding, parenteral nutrition should be considered. PMID- 17711100 TI - [Influence of nutrition on selected metabolic cardiovascular risk factors among female residents of Krakow]. AB - The study involved influence of nutritional factors on select anthropometrical and lipid indices (total cholesterol, LDL, HDL) in female residents of Krakow who were voluntarily participating in the investigation. Only women free of diagnosed cardiovascular diseases were included. The study group consisting of 100 women aged 30-65 years, was divided into two groups: pre-menopause (PM, n=47) and after menopause (AM, n=53). The anthropometrical measurements, % of fat tissue - Tanita scale and Body Mass Index (BMI) was calculated. The energy value and the consumption of basic nutrients intake were calculated using 24-hour recalls from the day before the examination. The AM group presented higher anthropometrical and metabolic risk profile: overweight and obesity (BMI-PM = 25.51 +/- 4.16 kg/m2; AM = 28.28 +/- 4.89 kg/m2) and central adiposity type (WC-PM = 81.04 +/- 10.00 cm; AM = 86.46 +/- 11.73 cm); lipids (Total cholesterol-PM = 5.14 +/- 0.87 mmol/l, AM = 5.67 +/- 1.10 mmol/l; LDL-chol-PM = 2.98 +/- 0.90 mmol/l, AM = 3.40 +/- 0.93 mmol/l; HDL-chol-PM = 1.65 +/- 0.39 mmol/l; AM = 1.63 + 0.46 mmol/l). The irregular participation of fatty acids, proteins from plant sources and dietary fibers in daily diet were found (%Energy PM: SFA = 11.66 +/- 4.34, MUFA = 10.91 +/- 4.04, PUFA = 4.76 +/- 2.75, Keys index = 41.89 +/- 14.91; %EnergyAM: SFA = 11.48 +/- 3.86, MUFA = 11.02 +/- 4.12, PUFA = 4.89 +/- 2.92, Keys index = 40.87 +/- 14.4). Women in the AM group represented healthier nutritional behaviors. Results presented indicate that in further study concerning evaluation of nutrients consumption among women the fact of natural menopause should be considered. PMID- 17711101 TI - Nonalcoholic fatty liver disease as a feature of the metabolic syndrome. AB - The main criteria of the metabolic syndrome are obesity, insulin resistance and disturbed lipid metabolism. The same disturbances are regarded to be involved into the pathomechanism of nonalcoholic fatty liver disease which is shown by epidemiological studies and animal models. Thus NAFLD can be regarded a specific feature of the metabolic syndrome and it should be looked for in high risk populations. PMID- 17711102 TI - [The role of the ketogenic diet in the management of epilepsy]. AB - Ketogenic Diet is effective in the treatment of epilepsy in both children and adults. KD increases the effectiveness of conventional therapies and can be applied for the treatment of other diseases. Simultaneously, KD is cheaper and does not possess as many adverse effects as conventional medicine. PMID- 17711104 TI - Analysis of the intake of protein and energy by predialysis patients with chronic renal failure receiving essential amino acid ketoanologues. AB - The aim of the study was to evaluate daily dietary intake of energy and protein by predialysis patients with chronic renal failure (CRF) receiving a supplement containing essential amino acid ketoanalogues. The study was carried out on 60 patients with CRF of different etiology. Low intake of energy (88% of tested patients) and animal protein (23% of tested patients) were observed, whereas total protein level was too high (33% of tested patients). As a consequence, the analyzed diets were not properly balanced. Our data strongly suggest that constant dietician care is essential to correct protein and energy intake in patients with CRF and can protect them against malnutrition and progression of CFR. PMID- 17711103 TI - The use of glycaemic index in the prevention of cardiovascular diseases. AB - The glycaemic index concept has more and more supporters all over the world. Many years will no doubt pass before the beneficial impact of a low glycaemic index diet in the prevention of heart diseases is fully confirmed, but we already know that the risk of heart diseases is lower when we use such a diet. Additionally, the diet is consistent with the other dietary changes necessary in the prevention of heart diseases. The data resulting from epidemiological and clinical investigations show that a low GI diet facilitates body mass reduction and an improved lipid profile. However, we still need further research to learn more about many processes which influence carbohydrate and lipid metabolism and the determination of the role of various genetic and environmental factors. PMID- 17711105 TI - [The influence of dialysis's day and time shifts on selected nutrients intake by patients with end stage renal disease]. AB - The influence of dialysis's day and time shifts on selected nutrients intake was examined on 38 patients with end stage renal disease. Time shift of dialysis influenced significantly carbohydrates content all groups) and energy content (time shift II vs. III) in daily food rations. There were no differences in energy, protein, fat, carbohydrates potassium (women) and phosphorous intake between day with and without dialysis. Our data strongly suggest that constant dietician care might be essential to correct nu:ients intake and prevent possible deficiencies among patients with end stage renal disease. PMID- 17711106 TI - Selected microelements (Cr, Zn, Cu, Mn, Fe, Ni) in slimming preparations. AB - Concerning the etiopathogenesis, one can speak about the following types of obesity: primary nutritional, occurring as a result of the joint action of genetic and environmental factors, and secondary obesity--which is a symptom of e.g. metabolic diseases. It has been found out that metabolism of carbohydrates and fats in human organism is connected with some microelements, and the occurrence of obesity may indirectly be connected with the disturbances of homeostasis. The purpose of this study was determination of the content of chromium, zinc, copper, manganese, iron and nickel (elements that are involved in the processes mentioned above) in slimming preparations: Bio C.L.A., Bioslank, Chudeus-syt, Fat Burner, Slim Trio. The samples were mineralized at 450 degrees C, and the determination of elements was performed using the absorption atomic spectrometry. The determined amounts of the examined elements may be regarded as the complementary daily demand of the organism for those elements. PMID- 17711107 TI - [Analysis of nutritional habits of variously aged men and women--energy value and basic nutrients]. AB - The aim of the investigation was to compare the nutritional habits of different age groups for both genders in Wielkopolska region. Analysis of food intake was in the context of the risk of diet-related diseases. The results revealed that nutritional habits of investigated group are incompatible with commonly recognized DFRs. Difference between percentage of energy coming from carbohydrates, saccharose and protein was observed between males and females below 39. Other differences encompass nutritional density of protein for males and females aged less than 40 and general incompatibility in quantities of carbohydrates and fibre in male and female diet, regardless of age. Accordingly with the results presented above, the interference into nutritional habits of wielkopolska in considered necessary and regardless of age and gender. PMID- 17711108 TI - [Assessment of food intake and lifestyle of low physically active women. Intake of selected nutrients]. AB - In this paper food intake of low physically active women (n=100). The information about food intake were collected using 24-hour recall and diet history questionnaire. In the average food ratio the energy from fat (39.1%) and protein (13.4%) was higher and from carbohydrates was lower (47.5%) than recommended level. The intake of aterogenic nutrients was improperly high: saturated fatty acid (120% of recommendation), dietary cholesterol (137%) and animal protein (119%). PMID- 17711109 TI - Dietary supplements selected by young people exercising in fitness rooms in Krakow and environs. AB - The purpose of this study was to determine the prevalence of the use of dietary supplements among the young people exercising in fitness rooms in Krak6w and environs. In this study, 81% of the population used some form of dietary supplement; nutritional supplements were used by 21% of women and 60% of men, and were used most frequently by young people 21-25 years of age. The most popular supplement s were creatine, (20%) and HMB-beta-hydroxy-betamethylbutyrate (19%). Only 14% of the respondents asked for the opinion of qualified personnel, such as doctors, pharmacists or dieticians. PMID- 17711110 TI - [The assessment of nutritional knowledge of persons with eating disorders]. AB - The main purpose of this work was to examine the level of nutritional knowledge of persons with eating disorders. The study was performed in the group of 60 persons (30 persons diagnosed with anorexia nervosa and 30 persons with diagnosis bulimia nervosa) and 60 controls. We found that ill persons possess the higher level of nutritional knowledge than person from the control group, yet the average of correct answers amounted to 51%. Our results point to the necessity of nutritional education in persons with eating disorders. PMID- 17711112 TI - [Sodium intake including salt as its source in selected Warsaw population]. AB - The aim of study was to evaluate sodium intake by 21 women and 21 men, aged 20 31, living in Warsaw, including sodium from table salt. The study was conducted from November 2004 to March 2005. The mean sodium intake exceeded many times the recommendations. Men added more salt to meals then women, and they also ate salty products more often. The main source of sodium was salt added during preparation of meals (women) or processed food (men). The amount of sodium from products salted due to technological reasons and present naturally in foods is high enough to meet requirements for this nutrient. PMID- 17711111 TI - Food preferences of girls and nutritional value of diets and their effect on organisms of rats in terms of risk of obesity and atherosclerosis. AB - The study was conducted on 28 growing female Wistar rats, fed ad libitum for 84 days with four different diets: preferred poor, preferred rich, recommended and Labofeed B. The diet intake, feed efficiency, weight/length ratio, serum TG, TC and HDL-C levels were determined. Results were verified statistically using one way ANOVA and the Scheffe test. The poor preferred diet with predominating fruit and vegetables, in comparison to the rich preferred diet, containing sweets, lowered the risk of obesity and atherosclerosis. The recommended diet, based on the model food ration for girls aged 13-15 years, lowered the risk of these diseases too. PMID- 17711113 TI - [Vitamin intake in an average diet of Warsaw adult inhabitants]. AB - The study aimed to establish the intake of vitamins in an average diet of Warsaw adult inhabitants using 3-day records method. The consumption of vitamin B1 was about 40% lower than recommended, the intake level of vitamin C, B2, PP and B6 was about 20-30% lower than recommended, whilst, folate in the diet realized the norms only in 50%. The intake of vitamins E, A and B12 was higher than recommended. In order to ensure the proper intake of vitamin C, it is recommended to increase the intake of fruit and vegetables rich in this vitamin and their products. In order to increase the participation of vitamin B1, PP, B6 and folate in the diet, a higher consumption of vegetable and vegetable products and bread and cereal products is recommended, however, in order to supply the proper amount of vitamin B2 in the diet it is recommended to increase the intake level of milk and milk products, vegetables and bread and cereal products. PMID- 17711115 TI - Frequency of consumption of products with varying energy value by patients of a sanatorium in Ciechocinek. AB - The aim of the study was to assess the frequency of consumption of selected groups of foodstuffs with varying energy value by patients of the "Dom Zdrojowy" sanatorium in Ciechocinek (Poland). The survey included 100 persons, out of which 80% were obese individuals (OB), while the others were patients with cardiovascular diseases (CVD). Products with lowered energy value, especially cottage cheese, milk, "light" yogurt, as well as tea and coffee without sugar were on average consumed rather frequently. Obese patients, from among women constituted 80%, paid attention to fat content in their daily diet. PMID- 17711114 TI - Preliminary assessment of exposure of children and adolescents to acrylamide originating from food. AB - The objective of the tests was to make preliminary assessment of acrylamide intake from the diet in the category of children and adolescents falling into 7 18 age bracket. For the purposes of assessment the our analytical test results were used of acrylamide content in potato crisps and French fries in samples taken randomly from all over Poland, whereas the intake level was estimated on the basis of a 24-hour recalls leading by National Food and Nutrition Institute in 2000. In the population of consumers eating potato crisps and French fries the average intake of acrylamide in the population of children aged 7-13 amounted to 63.4 microg/person/day, meanwhile in adolescents population aged 14-18-- 69.5 microg/person/day. The conversion of rest results into kg of body mass showed that acrylamide intake in the children population aged 7-13 lat was 1.78 microg per kg of body mass, whereas the acrylamide intake in adolescents population aged 14-18 was 1.17 microg/kg of body mass. Due to disadvantageous health effect of acrylamide it is necessary to reduce the content of this compound in diet. PMID- 17711116 TI - [The present and past nutritional behaviours in selected country communities of Radomian region]. AB - Evaluation of the nutritional behaviours among selected country communities of Radomian region presently and over last century was carried out. The data were collected using food-consumption patterns questionnaire containing two parts: present nutritional behaviours and past one. It was found out that nutritional behaviours in the country communities changed. Increase of animal products, fruit and vegetables consumption as well as new municipal nutritional patterns was observed. Also the decrease of seasonal food consumption took place. PMID- 17711117 TI - Assessment of fruit and vegetable intake among the population of junior high school students from Olesnica. AB - The aim of this study was to assess fruit and vegetable intake among the population of junior high school students. 113 students from Junior High School No. 2 in Olesnica participated in the research. In order to assess the intake of fruit and vegetables, the method of food frequency questionnaire was used. It was stated that vegetables appearing most frequently in the diet of girls were: tomatoes, carrots, cucumbers and fresh vegetable salads, and in the meals of boys were: tomatoes, fresh vegetable salads, cucumbers and vegetable salads. Boys and girls declared that the most often consumed fruits were: apples, oranges, mandarins and bananas. The mean daily total consumption of fruit and vegetables by the junior high school students was 358.5 g/day. Compared with current dietary recommendations, intakes of fruit and vegetables were too low. PMID- 17711118 TI - Residental factors affecting nutrient intake and nutritional status of female pharmacy students in Bydgoszcz. AB - The aim of present study was to estimate nutrient intake as well as nutritional status of female pharmacy students from Bydgoszcz, and to investigate relationship of these factors with type of usual residence place during academic year The 24-hour recall method was used to evaluate dietary intake of 47 subjects. Measured values of height, body mass and four skinfolds thickness were used for calculation of BM, FFM, %FM indices. An analysis of nutritional status of studied population showed lower body mass and BMI in the sub-group of female students residing outside of their family home. In comparison to the female students living without parents percentage of energy provided by total fat (29.9%) was significantly less and percentage of energy from carbohydrate was significantly higher (55.4%) than students who reside with their parents. Elevated intake of phosphorus and retinol accompanied by inadequate intake of riboflavin, calcium, iron and copper was exhibited in both residence-type related sub-groups of investigated female pharmacy students. PMID- 17711120 TI - [The assessment of nutritional status of the selected navy warship crew]. AB - The aim of the work was the assessment of nutritional status of the ORP "PULASKI" frigate crew before long lasting training cruise. Crew of the warship consisting of 156 men, aged 22-42, underwent the nutritional status examination. The nutritional status was estimated based on the anthropometrical measurements. Body mass and body height of examined men was the base to calculate the Body Mass Index (BMI). Based on this index, using the Ferro-Luzzi classification, examined soldiers were classified into groups indicating overweight or obesity. It was observed that percentage of persons indicating overweight increased with the age. Overweight was found among 49% of examined aged up to 30, 54.3% of men aged up to 40 indicated overweight. Obesity was found among 13.5% of examined sailors aged up to 30 and among 10.9% sailors aged 40. Obesity found among sailors creates necessity to carry on large-scale prophylaxis operations including propagation of rational nutrition and healthy life style education. PMID- 17711119 TI - [Nutritional patterns versus BMI values in rural adolescents]. AB - The study was aimed at determining relationships between the daily intake of food rations, energy consumption and energy balance in adolescents differing in the BMI value. The experiment covered 280 girls and 305 boys aged 10-15 years. Somatic traits were evaluated based on measurements of body height, body mass and thickness of skinfolds (arm triceps, subscapular, abdominal), whereas energy consumption was assayed by means of a triple 24-h dietary recall interview carried out prior to examinations. Results of energy consumption assays were presented as a per cent of recommended daily intakes. In respective age categories, the children were divided into three groups based on their BMI values, i.e. thin (34.9%), normal (47.7%) and those with overweight and obesity (17.4%). A negative relationships was demonstrated between the daily frequency of food ration intake and BMI value, i.e. the thin children (BMI < or =25 ptc) were observed to more frequently consume four of five meals a day, whereas the overweight and obese children (BMI >75 ptc)--three meals a day. The study indicates also that the declared energy consumption was not always in compliance with its actual intake, namely the mean daily consumption of energy in the thin children was higher than in the children with overweight and obesity. PMID- 17711121 TI - Energy and nutritional value of diets used in patients alimentation and their assessment by patients of selected clinical department in the Military Medical Institute in Warsaw. AB - The aim of the work was laboratory assessment of energy and nutritional value of general and light diets used in patients of selected clinical department in the Military Medical Institute in Warsaw alimentation. Using questionnaire method the assessment of diets was done by patients too. Meals given to patients in hospital not always fulfilled nutritional requirements. Additional consumption of supplementary products did not always meet the requirements of proper nutrition. Half of examined patients appraised nutrition variety as good but at the same time claimed the there was not enough fruits and vegetables. PMID- 17711122 TI - Pro-health nutritional behaviors of selected group of students of the Medical University of Warsaw. AB - The aim of the study was the analysis of pro-health nutritional behaviors among 100 female students Medical University of Warsaw tested by the questionnaire method. The results of the study show that nutritional behaviors of students who learned human nutrition were significantly better in accordance with dietary guidelines. The most frequent consumed group of products were fruits and dairy products. Consumption of vegetables, number and regularity of meals had been better among dietetics students then among midwifery and nursing students. PMID- 17711123 TI - The nutritional habits among centenarians living in Warsaw. AB - The aim of the study was to determine the preferences and nutritional habits of Warsaw centenarians during their "third period" of life. The study was conducted by a questionnaire method among 29 centenarians. Most of centenarians had general good health condition. Almost 60% of centenarians performed manual labor in the past. Then they drank small amounts of alcohol irregularly. Several percent of centenarians smoked in the past. Before the age of sixty less people then at present snacked between meals. Sweets both now and in the past were preferred products, however, in the past sweets were rarely eaten by centenarians. At the present time centenarians ate more often yogurt, skim curd, fish, lean meat products, plant oils and sweets. The changes in eating habits were probably caused by civilization changes. PMID- 17711124 TI - [Consumption of fish and fishery products in Poland--analysis of benefits and risks]. AB - Fish meat content high nutritive value and essential polyunsaturated fatty acids, while low consumption of fish and fishery products in Poland. Fat meat of Baltic sea fish can also contain higher levels of dioxins and organochlorinated contaminants. Consumption of fish and fishery products in Poland ought to include different species from various catch areas. PMID- 17711125 TI - [Selected cereal products as functional elements of the diet--frequency consumption of cereal products among university students]. AB - The present study provides information about concentration of vitamins B1 and B6 in grain products as well as frequency of intake cereal products by students. Higher thiamine and vitamin B6 content was detected in the whole wheat flour. The group of 171 pupils was investigated. Frequency of cereal products consumption and choice of kind of bread intake was estimated using self-report questionnaire. The results of the study showed that respondents were more familiar with wheat bread. Most students reported the consumption of cereal products two times per day. PMID- 17711126 TI - Dietary calcium and obesity in men. AB - Increased calcium intake has been associated with lower body weight, BMI and adiposity, mostly in children, youth and women. In men results are inconclusive. In this study the relation between calcium intake and body weight and body fat in obese men was investigated. 200 men, the mean age 45.1 +/- 9.4 y, the mean BMI 33.2 +/- 4.8 kg/m2, were divided into 4 groups on the basis of their calcium/protein index. No significant differences in body weight, BMI, fat mass, percentage of body fat were found across subgroups and no significant correlations between calcium intake and body variables were stated. This study did not confirm the association between calcium intake and body weight and adiposity in men. PMID- 17711127 TI - [Dietary habits as an environmental factor of overweight and obesity]. AB - The study objective was to assess chosen environmental factors contributing to body weight increase, with special regard to dietary habits. The questionnaire survey involved 68 women and 42 men. Based on BMI, the subjects were divided into those with normal body weight, with overweight and obesity. Multivariate logistic regression analysis was performed. Weight at the age of 18 was found to be most correlated with the current body weight. Other major factors included the time of life when overweight began, alcohol consumption and earlier smoking. The dietary factors analysed: such as having something additional to eat, type of eaten snacks, night eating, no control of the caloricity value of meals in the current study may have a significant effect on the occurrence of overweight and obesity. PMID- 17711129 TI - [Nutritional education of obese adolescents aged 13-15 years]. AB - The aim of this study was the assessment of nutritional education of 13-15 year old adolescents with simple obesity in comparison to their normal weight peers. The studied group consisted of 25 obese and 31 normal weight children. The questionnaire method was used to collect the data. Obese adolescents, compared to the normal weight counterparts, showed higher level of education concerning principles of proper nutrition. Nevertheless, high level of obesity in this group of children indicates that they do not comply with these principles. The study results suggest that emphasis should be placed on the quantity of food in diet of overweight and obese adolescents. PMID- 17711128 TI - [Calcium intake and glucose and lipids concetrations in overweight and obese patients]. AB - Well-balanced diet is one of the determinants of the health and wellbeing. Inadequate nutrients' intake can promote disease development. The purpose of this study was to assess the intake of calcium, phosphorus and protein and relation between calcium intake and lipids and glucose serum concentration in patients with obesity. The studied group consisted of 57 subjects, aged 21-63 years. Dietary assessment was based on 3-d dietary record. Serum lipids concentrations were assessed by enzymatic methods, serum calcium concentrations were assessed by Vitros 250. The mean calcium intake in men was 588.8 mg/d, in women 549.3 mg/d. Calcium intake was statistically significant correlated with glucose concentration in women and men, but not with lipids concentrations. Dietary calcium intake in studied group was below the RDA. Calcium intake could be one of determinants of glucose concentration in obese persons. PMID- 17711130 TI - [Assesing the food intake in first year students of Agricultural University in Wroclaw]. AB - The aim of the paper, in which the 24-hour recall was used, was to asses the food intake of selected nutrients in first year student of Agricultural University in Wroclaw. The recommended dietary allowances for energy and basic nutrients in group of woman were particularly low, in group of man-intake of saturated fatty acids, cholesterol and animal protein was improperly high. PMID- 17711131 TI - Relative fat content in young women with normal BMI but differing in the degree of physical activity. AB - The aim of the study was to evaluate the relationship between BMI and relative body fat content. Three groups of women, aged 20-29 years and having normal BMI values, differing in the degree of practiced physical activities were studied: low activity (n=59), medium activity (n=46) and high activity (n=56). Body fat content was determined by infrared photometry (FUTREX). The percentages of women with excessive fat content (over 25%) from those 3 groups significantly differed and amounted to 44, 32 and 23, respectively. It was concluded that with increasing level of physical activities the percentage of young women with an excessive body fat content, but with BMI within normal limits, decreases. Thus, BMI ought not to be used as an indicator of body composition as it does not reflect body fat content. Individual counselling should be based on both measures, BMI and relative body fat content, taken together. PMID- 17711133 TI - Acrylamide content in heat-treated carbohydrate-rich foods in Poland. AB - The objective of the study was to determine the content of acrylamide in randomly selected samples of potato crisps and French fries using GC/MS/MS. The mean content of acrylamide in tested crisps amounted to 998 microg/kg (range from 352 to 3647 microg/kg) and was almost three times higher than in French fries--337 microg/kg (range from 88 to 799 microg/kg). Differences (even ten times) in the level of acrylamid in individual product samples, testifying the impact of raw materials and technological process running conditions on the content of acrylamide in the final product. The results of our study were close to those obtained in other countries. PMID- 17711132 TI - [Investigation of the contents of essential elements in nuts, almonds and dry fruits]. AB - Concentrations of Ca, P, Fe, Zn, Cu and Mn were determined in nuts, almonds as well as in dry fruits available on Polish market. The contents of minerals in 100 g of nuts were as follows: 55.8-261 mg Ca; 294-724 mg P; 1.11-3.06 mg Fe; 2.05 4.98 mg Zn; 0.5-1.38 mg Cu and 0.93-5.75 mg Mn. Among the analysed dry fruits, the greatest concentrations of calcium, phosphorus, zinc and cooper were recorded for figs, while apricots contained the highest levels of iron and manganese. Based on the data obtained it was possible to estimate the realization of the recommended daily intake of essential elements with the 100 g portion of analysed products for an adult person. PMID- 17711134 TI - [Fat and fatty acids chosen in chocolates content]. AB - The objective of present work was to comparison of fat and chosen fatty acid in chocolates with, approachable on national market. In the investigations on fat and fatty acids content in the milk chocolates, there were used 14 chocolates, divided into 3 groups either without, with supplements and stuffing. Crude fat content in the chocolates was determined on Soxhlet automatic apparatus. The saturated ad nsaturated acids content was determined using gas chromatographic method. Content of fat and fatty cids in chocolates were differentiation. The highest crude fat content was finding in chocolates with tuffing (31.8%) and without supplements (28.9%). The sum of saturated fatty acids content in fat above 62%) was highest and low differentiation in the chocolates without supplements. Among of saturated and unsaturated fatty acids depended from kind of chocolates dominated, palmitic, stearic, oleic and, linoleic acids. Supplements of nut in chocolates had on influence of high oleic and linoleic level PMID- 17711135 TI - Catering and gastronomy services in the rural tourism: the case of Lubuskie voivodeship. AB - In this paper we showed the results of studies about gastronomy services in the rural tourism and the range of this services using about which the respondents talked. The studies also took the feeding offer (rural dishes and regional feeding) influence for the choosing the rest offer in the countryside. In the studies took part people who live in the countryside and have homesteads and of course tourist rest in their homesteads. PMID- 17711136 TI - [Fulfilling nutrition needs in households in the context of family evolution process]. AB - The analysis of fulfilling nutrition needs on the stages of family evolution process has been recently carried out. It was based on GUS examining of households' budgets. The result was that in some households people consume not enough carbohydrate, fiber, calcium, copper and B1 vitamin. The families with children were especially endangered by low level of such ingredients. Their diets were rich in fat, cholesterol, sodium and phosphorus. PMID- 17711137 TI - [The importance of food services in nutrition of the Polish population]. AB - During last years the fast development of food service sector is noticed. In relation to this fact the purpose of this paper was to evaluate the importance of food services in the nutrition of the Polish population. It was stated on the basic of secondary data that inspire of development in the level as well as in service structure the mass feeding don't play such role as in the high developed countries. On average the Polish family spend on this purpose only about 5% of they food budget. In conclusion the continuation of food service was predicted development especially in the area of vegetarian, low fat and dietetic food. PMID- 17711138 TI - Preventing falls and eliminating injury at Ascension Health. AB - BACKGROUND: For Ascension Health's Healthcare That Is Safe strategy, eight hospitals served as alpha sites in the program to prevent falls and eliminate falls with injury. METHODS: The alpha sites implemented four key strategies: (1) assessment and re-assessment of patient risk factors for falls, (2) visual identification of patients at high risk, (3) communication of patient fall risk status, and (4) education of patients, families, and staff about fall prevention. RESULTS: The recommendations of the alpha initiative spread rapidly throughout Ascension Health and preceded measurement of the fall ratio. Even so, a 9.9% systemwide reduction in acute care fall rates from January to October 2006 was observed, and the average rate of falls with serious injury was less than 0.10 per 1,000 patient days. Compared with national rates, falls with serious injury at Ascension Health were less than 10% of the expected rate. DISCUSSION: Although it is not possible to prevent all falls in acute care facilities, decreasing the number of falls and the risk of serious injury from falls is possible. Key steps caregivers can take to prevent falls and fall injuries include establishing a trusting relationship with patients and their significant others; frequently reorienting patients to their environments, reminding those at high risk of falls not to get out of bed without help; checking on patients frequently and keeping their personal articles within reach; and protecting patients from falls at all entry points into the health care system. PMID- 17711139 TI - Applying the Toyota Production System: using a patient safety alert system to reduce error. AB - BACKGROUND: In 2002, Virginia Mason Medical Center (VMMC) adapted the Toyota Production System, also known as lean manufacturing. To translate the techniques of zero defects and stopping the line into health care, the Patient Safety Alert (PSA) system requires any employee who encounters a situation that is likely to harm a patient to make an immediate report and to cease any activity that could cause further harm (stopping the line). IMPLEMENTING THE PSA SYSTEM--STOPPING THE LINE: If any VMMC employee's practice or conduct is deemed capable of causing harm to a patient, a PSA can cause that person to be stopped from working until the problem is resolved. A policy statement, senior executive commitment, dedicated resources, a 24-hour hotline, and communication were all key features of implementation. RESULTS: As of December 2006, 6,112 PSA reports were received: 20% from managers, 8% from physicians, 44% from nurses, and 23% from nonclinical support personnel, for example. The number of reports received per month increased from an average of 3 in 2002 to 285 in 2006. Most reports were processed within 24 hours and were resolved within 2 to 3 weeks. DISCUSSION: Implementing the PSA system has drastically increased the number of safety concerns that are resolved at VMMC, while drastically reducing the time it takes to resolve them. Transparent discussion and feedback have helped promote staff acceptance and participation. PMID- 17711140 TI - Using a collaborative to reduce ventilator-associated pneumonia in Thailand. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is a serious nosocomial infection, leading to high mortality and high costs of treatment in developed and limited-resource countries. A collaborative quality improvement (QI) project was conducted in 18 secondary and tertiary care hospitals in Thailand to address the problem. METHODS: The project, conducted between February 2004 and May 2005, entailed three face-to-face meetings--two national workshops and two regional workshops (each conducted twice). Education on VAP prevention, including guidelines and the ventilator bundle, was conducted for intensive care unit staff and all relevant personnel. The collaborative's effectiveness was assessed by VAP rate, a self-administered questionnaire, and face-to-face interviews. RESULTS: Within 12 months, the pooled VAP rate decreased from 13.3 to 8.3 per 1,000 ventilator-days. The costs of antibiotic treatment for VAP decreased by more than one half. More than 80% of interviewed participants reported that the QI method could be applied effectively in their organization. DISCUSSION: VAP surveillance during this project revealed a gradual reduction of the VAP rate. The project's relative overall success appears to reflect, as reported elsewhere, a well organized program, support from hospital administrators, and workshop leaders' presentation of proven QI methods and clinical interventions. PMID- 17711141 TI - What do medical records tell us about potentially harmful co-prescribing? AB - BACKGROUND: Previous efforts document drug-drug interactions in ambulatory care. Yet little is known about medical record documentation or clinical management when interacting medications are received. METHODS: The study population was identified from the HMO Research Network's Centers for Education and Research on Therapeutics (n = 2,020,037). A random subsample of patients > or = 18 years of age with drug coverage in 2000 initiating a co-dispensing for (1) warfarin with a nonsteroidal anti-inflammatory drug (n = 97), (2) digoxin with verapamil or diltiazem (n = 100), or (3) lovastatin/simvastatin with diltiazem or verapamil (n = 89) was identified. RESULTS: The majority (63%-74%) of patients had documentation indicating receipt of both drugs during a single office visit. Documentation of risks and patient education was less common (< or = 14%, with all corresponding upper bounds of the 95% CIs < 23%). Clinical management changes were more frequently documented, ranging from 64% (95% CI: 47-81%) for lovastatin/simvastatin patients to 79% (95% CI: 60-99%) for warfarin patients. CONCLUSIONS: The findings, although indicating that clinicians are likely aware of concomitant receipt of interacting medications, call into question the adequacy of medical record documentation as well as clinical management when interacting drugs are co-prescribed in the ambulatory setting. PMID- 17711142 TI - Every error a treasure: improving medication use with a nonpunitive reporting system. AB - BACKGROUND: The fear of reprisal, combined with the additional time required for reporting, are significant disincentives to reporting of medical events. Such considerations provided an incentive for the Upstate Medical University Hospital (Syracuse, New York) to develop monitoring systems to decrease the potential for drug harm. IMPLEMENTING A NONPUNITIVE REPORTING SYSTEM: Previously, a convenient, point-based score card system for punishment and remediation led to underreporting and hindered the identification of safety improvement opportunities in medication use processes. Nursing buy-in was accomplished through careful initial negotiations that emphasized that patients were best served by learning from errors in the medication use process. The revised medication event reporting policy, as established in October 2000 for all staff, severed the link between reporting errors and performance evaluations. RESULTS: Data collected 18 months before the policy change was compared with data collected after the policy change was enacted in October 2000. The number of reports received each month increased from an average of 19 to 102 (p < .001). DISCUSSION: Substantive quality improvements in medication have been achieved by using a systematic approach to the analysis of the markedly increased number of reported medication events following the introduction of a nonpunitive reporting system. PMID- 17711143 TI - A quality improvement tool to assess self-management support in primary care. AB - BACKGROUND: Self management is an essential, central component of effective care for diabetes and other chronic illnesses, yet very few instruments exist to assess delivery or consistency of self-management support. The Assessment of Primary Care Resources and Supports for Chronic Disease Self-Management (PCRS) tool assesses both organizational infrastructure and delivery of self-management support services. METHODS: The PCRS was developed by the Robert Wood Johnson Foundation Diabetes Initiative and underwent several stages of development, including three pilot tests, review by experts, and implementation by a national quality improvement (QI) program. RESULTS: The development and testing of the instrument resulted in the current 16-item measure. Use of the PCRS in a QI collaborative with 20 diverse health care teams across the United States demonstrated that the instrument is helpful in assessing areas for improvement. DISCUSSION: Initial experience suggests that the PCRS is a user-friendly self assessment tool that primary care teams can use to assess their current capacity to support and implement consistent patient-centered self management. The initial evaluation indicates that the PCRS has acceptable psychometric properties and is applicable across different types of primary care teams and chronic illness conditions. PMID- 17711144 TI - Implementation and impact of a rapid response team in a children's hospital. AB - Like the previous two studies of RRS implementation in a children's hospital, this study--the first to use an RRT model--showed a decrease in the incidence of arrests (although not at a significant level). Low mortality rates and infrequent arrests in children's hospitals make changes in these measures insensitive indicators of the positive impact of RRT implementation. RRTs provide an immediate response for children whose clinical condition is worrisome and whose attending physicians are not immediately present. Children receive significant care through the RRT, and nurse response is very favorable to having access to fast, dependable, and knowledgeable backup 24 hours a day. The RRT program is a vital component of the safety net for children's hospitals, and RRT data provides an avenue for quality improvement efforts and further research. PMID- 17711145 TI - Unique burial practice by ancient cavemen of the Hoa Binh civilization in Vietnam. AB - The discovery of a female skeleton is reported, which can be ascribed to the Hoa Binh civilization, existing about 10,000 years before now. The most remarkable fact concerning this finding is the existence of seashells (Cyprea arabica), which were found in the eye sockets. The reasons for this in Southeast Asia so far unique burial practice are discussed. PMID- 17711146 TI - Population affinities assessed by dermatoglyphic and hemogenetic variables. AB - 13 dermatoglyphic variables have been studied in eight population samples (five smaller isolated and three larger populations) to identify the possible differences between the larger and the smaller isolated populations. The data and neighbor joining trees for the dermatoglyphic variables show distinct differences between males and females. The isolated population of the Lutheran Mountains is clearly separated from the other populations. Combining the results of dermatoglyphic and 12 hemogenetic variables (only for six populations) the male and female trees are nearly identical. The three isolated populations are clearly separated, whereas the larger ones show smaller distances. PMID- 17711147 TI - Population genetic studies in Bulgaria. AB - 17 dermatoglyphic variables have been studied in five population samples from south-central and southeastern Bulgaria. The results have been combined with 10 hemogenetic markers. The neighbor joining tree analysis showed only small genetic distances between the samples. A comparison with data of the literature, using finger patterns and pattern intensity of fingers and considering the different results for males and females, revealed no clear geographical differentiation between most of the samples studied. PMID- 17711148 TI - Age, gender and caste variations in scalp hair micro-morphological variables among Brahmins and Banias of Punjab, India. AB - A cross-sectional sample of 3136 scalp hair drawn from 392 individuals aged 10 to 60 years and belonging to the Bania (n = 201) and Brahmin (n = 191) caste groups of Punjab State of India were examined for diameters of hair shaft and medulla, scale count, medulla type, hair index, medullary index and scale-count index, employing standard procedures. The mean hair shaft diameter, medullary diameter, incidence of medullation and scale-count index was higher in males, while the mean scale count was higher in females. However, with a few exceptions, the gender differences were not statistically significant (p < 0.05). The Brahmins showed significantly (p < 0.05) higher mean values of hair shaft diameter and scale count than the Banias. The mean scale-count index was higher among the Banias. The fragmentary medulla was the most common medullary type among the Banias, while the continuous medulla was the most frequent type of medulla among the Brahmins. The frequency of medullation was significantly more among the Banias. On the average, the hair shaft diameter and diameter of medulla increased up to 30 years. Some age variations in medullation were noticed in both the caste groups. No clear age trend was noticeable in the scale count. By and large, the mean hair shaft diameter of the Banias was less than that of other populations. The mean hair shaft diameter of the Brahmin males was greater than that of the Banias, the Onges, and the Bengalees. The Brahmin females showed greater mean hair shaft diameter than that of the Banias, the Australian Aborigines, the Juangs and the Onges. Human scalp hair shows some age, gender and population variations in micro-morphological variables which have the potential of being useful for anthropological and forensic investigations. PMID- 17711149 TI - An evolutionary approach to explain the high frequency of the polycystic ovary syndrome (PCOS). AB - Infertility and sterility are worldwide phenomena with a long history. At a first glance a condition causing sterility seems to be paradox in an evolutionary sense because it contradicts the biogenetical imperative. In the present paper an evolutionary explanation for the high prevalence rate of PCOS, the most common endocrine disorder causing female infertility, is presented. The symptomatology of PCOS is described and the high prevalence rates of PCOS are explained by means of Darwinian medicine, kin selection and allomothering. PMID- 17711150 TI - Maternal age and pregnancy outcome--an anthropological approach. AB - At both extremes of reproductive phase female pregnancy outcome is described as poor. Beside a high rate of anovulatory cycles, pregnancies at these phases of the reproductive span are considered as risky for obstetric complications, and increased maternal and newborn morbidity and mortality. In the present study the associations between the age as well as somatic characteristics such as prepregnancy weight, stature, pelvic dimensions and pregnancy weight gain of 10765 women ageing between 12 and 49 years and newborn body dimensions and the mode of delivery as well as uterine child presentation were analysed. With increasing maternal age, maternal and newborn body dimensions increased significantly. Furthermore, extremely young mothers showed the lowest rates of caesarean sections, while mothers older than 40 years experienced the significantly highest rate of caesarean sections. Regarding newborn weight status, for mothers older than 35 years the highest rate of low weight newborns (< 2500 g) and the highest rate of macrosome newborns (> 4000 g) were found. Special risks were found in mothers older than 35 years, so the lower rates of ovulatory cycles during this phase of life may be interpreted as an adaptation to increased risks for complications and poor pregnancy outcome. PMID- 17711151 TI - Does physical education modify the body composition?--results of a longitudinal study of pre-school children. AB - The aim of the study is the analysis of body composition, motor development and cardiovascular parameters of preschool-children. In 2001/2002 a longitudinal study started in 17 nursery schools in Berlin. A total of 160 children out of the 264 children participated in a regular exercise programme. After 24 months of training significant differences of body composition, motor skills and cardiovascular parameters between 5 complete year old children of the intervention and the control group were observed. The results show that such an exercise programme is successful as a preventive measure to decrease the risk of obesity. PMID- 17711153 TI - Estimation of stature in Turkish adults using knee height. AB - Body height is an important clinical indicator to derive body mass index (BMI), which is a useful screening tool for both excess adiposity and malnutrition. Height measurement in the elderly may impose some difficulties and the reliability is doubtful. Stature estimation from knee height is one of the commonly used methods; nevertheless no study has been carried out so far on the Turkish population. A cross sectional anthropometric study was conducted to develop body height estimation equations by using knee height measurement for Turkish people. Measurements of height and knee height were taken according to the International Biological Programme procedures from 1422 adults (610 males, 812 females) aged 18-90 years from Ankara, the capital city of Turkey. Samples were randomly split into two sub-samples, training and validation (control group) sub-samples. Height estimation equations were developed from the knee height measurements by linear regression analysis according to age groups and sexes. Males were significantly taller and have higher knee height values than females in all age groups. Height and the knee height variables showed a gradual decrease (P 50) with aging in females and males. Evaluated knee height equations for stature estimation were tested through the validation sample and the results showed high accuracy. The study presents sex and age specific regression equations for height estimation by using the knee height measurement for Turkish adults and suggests facilitating the accurate usage of knee height. PMID- 17711152 TI - Head proportion and shape of the head of children between 2 and 7 years--results of a longitudinal study. AB - Based upon a longitudinal anthropometric study with integrated picture documentation, the head proportion and head shape of two to seven years old children will be analysed. The study was initiated in April 2002 in the administrative districts of Potsdam and Potsdam-Mittelmark (Germany). 351 boys and girls have been measured and photographed. The children shall be examined up to four years until September 2006 with a half year investigation distance. Twenty-three anthropometric dimensions have been measured including six dimensions of the head. These dimensions of the head are the head length, head breadth, auricular height, interpupillary distance, facial height and lower face height. Furthermore, digital pictures have been taken of each child. So the head of each child can be examined in a frontal view (Norma frontalis) and in a lateral view (Norma lateralis) and will be analysed relating to changing proportions of the head. The results demonstrated and discussed here are based on a longitudinal succession of photos and point out a method to make individual patterns of the changing head proportions and head shape visual on pictures. PMID- 17711154 TI - Upgrading nurse anesthesia educational requirements (1933-2006)--part 2: curriculum, faculty and students. PMID- 17711155 TI - A study comparing chloroprocaine with lidocaine for skin infiltration before intravenous catheter insertion. AB - A prospective, double-blind, mixed, crossover study was conducted to determine the perception of pain associated with intradermal lidocaine and chloroprocaine for insertion of an 18-gauge intravenous catheter. A convenience sample of 64 healthy, adult volunteers was used. Each participant received an intradermal injection of lidocaine or chloroprocaine on the dorsum of one hand followed by insertion of an 18-gauge intravenous catheter. The procedure was repeated on the opposite hand with the other anesthetic. Half of the subjects received lidocaine first, and half received chloroprocaine first. Subjects were asked to rate their pain on a 100-mm visual analogue scale immediately after injection of each local anesthetic and immediately after insertion of the catheter. A repeated analysis of variance was used to determine whether there was significant difference in pain associated with the injections and with the insertion of the catheters. There was no significant difference in the amount of pain associated with the intradermal injections (P = .955) or with insertion of an 18-gauge needle (P = .977). Both local anesthetics were effective in reducing pain from the initial injection of the local anesthetics to the insertion of the 18-gauge needle (P = .000). PMID- 17711156 TI - Anesthetic management in a pediatric patient with Noonan syndrome, mastocytosis, and von Willebrand disease: a case report. AB - This case report describes anesthetic considerations for a 6-year-old boy, admitted for adenoidectomy under general anesthesia, who had a complicated medical history, including mastocytosis, Noonan syndrome, and von Willebrand disease. Each affected the anesthetic plan and was addressed preoperatively among all surgical and anesthesia providers. Mastocytosis created a major concern, with its increased numbers of histamine-filled mast cells. Each drug that was added or eliminated from the anesthetic plan, to prevent histamine release by the activation of triggers, was considered. Patient handling and temperature control were also concerns. One of Noonan syndrome's characteristics is heart anomalies. This patient had a history of a patent foramen ovale and pulmonary stenosis; therefore, air was carefully removed from all intravenous lines and syringes. The main concern for bleeding difficulties was attributed to the history of von Willebrand disease, which results in prolonged bleeding time and can lead to delayed bleeding or serious postsurgical hemorrhage. Desmopressin was administered preoperatively to increase platelet aggregation and the von Willebrand factor level. The use of aspirin and other nonsteroidal anti inflammatory drugs was avoided. We discuss the clinical and anesthetic management of this case with a review of pertinent literature. PMID- 17711157 TI - Closed claims studies in anesthesia: a literature review and implications for practice. AB - Historically, closed malpractice claims have been used to identify and examine potential causes for adverse anesthesia outcomes. In the United States, the American Association of Nurse Anesthetists and the American Society of Anesthesiologists have compiled and analyzed such data. In all claims filed, respiratory events were most common, and the most common outcome class was brain damage or death. These findings and others led to improved practice standards, including end-tidal carbon dioxide and pulse oximetry monitoring. Although some researchers have cited closed claims studies as evidence of anesthesia risk trends, the nature of the data makes it inappropriate for calculation or comparison of risk. Further work is needed to elucidate some mechanisms of injury and to develop interventions to maximize patient safety. PMID- 17711158 TI - Anesthetic implications for surgical correction of scoliosis. AB - Patients undergoing surgical correction of scoliosis present many challenges to anesthetists because of the pathophysiologic derangements caused by the disease and the demanding nature of the anesthetic care that is required. A thorough understanding of the pathophysiology of the disease, intraoperative concerns specific to the procedure, and the efficacy of various anesthetic management techniques is required by anesthetists to optimally care for patients undergoing surgical correction of scoliosis. This literature review focuses on key considerations for anesthetists, including common comorbidities in patients with scoliosis, the need for induced hypotension, large surgical blood loss, the need for transfusion of blood and blood products, possible autologous blood donation and acute normovolemic hemodilution, patient positioning, possible intraoperative wake-up testing to assess motor function, spinal cord monitoring, and hypothermia. PMID- 17711159 TI - Update for nurse anesthetists--part 3--cyclodextrin introduction to anesthesia practice: form, function, and application. AB - Cyclodextrins, some of the select molecules exhibiting properties that are beneficial across multiple industries, are naturally occurring cyclical oligosaccharides with a lipophilic inner cavity and a hydrophilic exterior. These characteristics enable cyclodextrins to surround and bind lipophilic molecules while maintaining aqueous solubility. Agrochemistry, analytical chemistry, food, nutraceutical, and pharmaceutical industries have benefited and continue to benefit from these unique molecular properties. Though known and studied for more than 100 years, cyclodextrins have only recently been explored for specific application to anesthesia. Numerous studies exploring cyclodextrin-improved anesthetic delivery are underway. This new class of enabling molecules will enter the anesthetic arena and will require an understanding of their form, function, and application. This knowledge will facilitate anesthesia providers' optimal use of these unique molecules and the safety and efficacy associated with them. PMID- 17711160 TI - [Frans Debruyne Valedictorian Lecture. A glance about the future of urology]. PMID- 17711162 TI - [Current treatment in high risk and locally advanced prostate cancer]. AB - Treatment of locally advanced prostate cancer remains controversial. Treatment options include radical prostatectomy (PR), radiotherapy (RT) and hormonotherapy (HT). A Medline database search with key words "prostate cancer", "locally advanced", "high risk" and "treatment" in articles published during the last 15 years was done. Fifty one out of 329 papers were selected and reviewed. Selection criteria were a minimum of scientific evidence level of IIa, except for some specific level IV reference. Numerous randomized studies show that patients may benefit of a combined therapy with RT and HT. RP has shown its usefulness in selected cases of locally advanced prostate cancer. Results of long follow-up series are similar to those obtained with RT and HT. Furthermore, the possibility of clinical over staging is an argument in favour of RP. We perform an updated revision of every possible choice available in the treatment of these tumours. PMID- 17711161 TI - [Biography of Phillip Bozzini (1773-1809) an idealist of the endoscopy]. AB - Philipp Bozzini was born the 25 of May of 1773 in Mainz, Germany. The 12 of June of 1797 obtain the title of medicine doctor. From 1804 it is practically dedicated of complete to the development of its instrument, this have the approximated form of one metallic vase of 35 cm height, had in leather. In its previous face it has a circular opening that is divided vertically by a partition. In left half is the luminance source (a wax candle) and behind is a mirror, that it projects the light produced towards the interior of the corporal cavity to explore. By other half, the observer receives the reflected light and the image of the explored organ. In the later face they adapt according to the cavity diverse specula's, this allow to inspect ear, urethra, feminine bladder, rectum, uterine neck, nasal or wounds. Philipp Bozzini, profit with modest means available at the beginning of XIX century, to demonstrate to the medical world the way of endoscopes. It was with its instrument and ideas, 3/4 of century advanced to the technical and scientific possibilities of the moment. The historians are in agreement, in which this instrument, with artificial light, diverse mirrors and specula's war the beginning of a numerous family of endoscopies. PMID- 17711163 TI - [Indications, results and techniques of permanent prostate brachytherapy for localized prostate cancer]. AB - INTRODUCTION AND OBJECTIVE: Prostate brachytherapy is a first-line therapeutic approach for localized prostate cancer in selected patients. We present our experience in brachytherapy and a thorough review of the literature. MATERIALS AND METHODS: A review of the literature and evaluation of patient's selection was done. Furthermore the implantation technique, oncological results according to the different risk groups and acute and chronic complications were also analyzed. RESULTS: The biochemical relapse-free 10 year survival rate was 87-96% in low risk tumours and 63-86% in intermediate risk tumours. A total of 3-24% underwent urinary retention that required TURP in 0-8,7%. Other complications were urinary incontinence in 0-6,7%, proctitis in 0-15,5%, erectile dysfunction in 6,3-30%, rectal ulcer/fistula in 0-5,4%. CONCLUSIONS: Prostate brachytherapy is a safe and effective treatment in low and intermediate risk patients with prostate cancer. PMID- 17711164 TI - [Statistical analysis of the influence of the virus of papilloma human in the development of the vesical carcinoma]. AB - INTRODUCTION: The bladder cancer is an important disease by its morbi-mortality and its multifactorialidad. At the moment, between the possible aetiology agents that they have been indicated is the infection by the virus of papilloma human (VPH). The objective study is to analyse, by meta-analysis, the relationship between bladder cancer and infection by human papillomavirus. MATERIAL AND METHODS: We made a search in the electronic data base MEDLINE of the articles published until September of the 2004 that relate the infection of the VPH to the bladder tumors. Of 414 listed articles, we selected 38 articles. RESULTS: The articles were classified in two groups, according to they use or non methods based on the detection of the DNA. In articles based on the detection of the DNA, it was that the global proportion from the cases that had contact with the virus, through the detection of the genome was of the 19.4% (95% CI 0.160 to 0.228). Of the total of studies based on the detection of the DNA 8 were selected, to show to a group defined control, in which, the OR was investigated. If we combined the ORs, we obtain an OR estimation of 3.2 (95% CI 1.19 to 8.60) and p = 0.02. CONCLUSIONS: Most of these studies showed the relation rose at the beginning of the study. Although the majority lacked a group defined control, is possible to analyze the value of the Odds global ratio due to the homogenous behaviour of the studies with defined cases and controls affluent. This demonstrated to association between VPH and the bladder cancer. PMID- 17711165 TI - [Laparoscopic nephron sparing surgery. Initial experience]. AB - We present our initial experience in laparoscopic nephron sparing surgery. It's a technically advanced procedure requiring considerable minimally invasive expertise. This technique is particularly attractive compared to an open conventional procedure with its larger incision and associated morbidity. PMID- 17711166 TI - [The role of low urethral mucosal and submucosal blood perfusion in patients with artificial urinary sphincters]. AB - INTRODUCTION: A common complication following insertion of a bulbar AUS is recurrent incontinence, and once other causes have been ruled out, a diagnosis of urethral atrophy is then made. Urethral atrophy probably occurs to a certain degree in all patients with an AUS but the reappearance of incontinence is often attributed to inadequate pressure transfer from the cuff to the atrophic urethra. The normal urethral closure mechanism depends also on passive forces which rely on the integrity of the urethral mucosa and submucosa. MATERIAL AND METHODS: Two groups of patients with a first AUS implant which had been in place for more than 1 year were studied (n = 11). Group I consisted of continent patients (n(I) = 6) whereas Group II had significant incontinence due to urethral atrophy (n(II) = 5). Intraurethral pressures (IP) and blood flux (BF) were measured simultaneously with a micro-tip transducer and a laser Doppler flowmeter in each patient. Positional measurements were recorded proximal, within, and distal to the cuff first with the AUS deactivated and then activated. RESULTS: Group I patients exhibited similar IP and BF at all positions along the urethra. In Group II the IP was similar along the urethra but the BF within the cuff was qualitatively different (non pulsatile) and decreased significantly when compared to either side of the cuff during. DISCUSSION: Continence in patients with artificial urinary sphincters depends not only on the cuff occlusive force but is also dependent on the viability of the mucosal and submucosal tissues. For a given pressure range mucosal and submucosal blood perfusion is determinant. patients with normal blood perfusion would remain continent whereas patients with impaired perfusion would become incontinent. PMID- 17711167 TI - [Evaluation of guidelines for the assessment of success after vasectomy and needed improvements]. AB - OBJECTIVES: The evaluation of a recently established guidelines about the assessment of semen samples after vasectomy in the laboratory of the Hospital General of Albacete and to modify them to optimize the number of semen samples provided per patient but keeping in concordande with the international recommendations. PATIENTS AND METHODS: The records of seminal analysis results from vasectomies performed from January 2002 to December 2004 were reviewed. Our vasectomy guidelines are based upon those of the British Andrology Society (BAS) and those of the World Health Organization for seminal assessment. RESULTS: During the 3 years 984 patients underwent vasectomy. At follow up, 67% of them returned postvasectomy semen samples, but just 55.,5% of them get the clearance criteria; the other patient abandoned before getting them. A mean of 2 samples per patient were received, but 39.6% of them provided one and more than 23% brought more than 3 semen samples. We had 43 technical failures, 4 early recanalization (0.5%) and one late recanalization (0.1%), and 13 patients underwent revasectomy (1,7%). CONCLUSION: A high percentage of our patients failed to fulfill the clearance criteria recommended by the BAS and almost a quarter of them had to deliver more than 3 semen samples. So we find convenient to modify our guides and propose that our patients should receive 2 request forms from the practitioner for semen analysis in the 6th and the 7th month postoperatively and should return to global evaluation of both reports. In that moment most patients will be able to meet the applied criteria for success with just 2 semen samples. Those who fail to become sterile because of either technical failure or early recanalizatione may be advised to go to the urologist with just 2 semen analysis without unnecessary delay. PMID- 17711169 TI - [Comparison between the "ICIQ-UI Short Form" Questionnaire and the "King's Health Questionnaire" as assessment tools of urinary incontinence among women]. AB - INTRODUCTION: In our country there are a few available instruments to diagnose urinary incontinence (UI) from the patient's perspective. The King's Health Questionnaire (KHQ) and the "International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form" (ICIQ-UI SF) are the most widespread among that. The present study aimed to compare the clinical utility between KHQ and ICIQ-UI SF with regard to the urodynamic test. MATERIAL AND METHODS: Cross-sectional study performed in 116 women who completed the ICIQ-UI SF, the KHQ and the urodynamic test and were diagnosed according to each test. Sensibility and specificity values of symptom dimension of the ICIQ-UI SF and the KHQ were analyzed with regard to the urodynamic test. In addition, correlation scores between the both compared measures were calculated. RESULTS: Mean age (SD) of women was 54 years (SD = 13.99). KHQ and ICIQ-UI SF mean scores were 39.93 (22.11) and 13.76 (4.11), respectively. Correlation between both measures was moderated (r = 0.6; p < 0.001). Percentages of pts with symptoms suggesting Stress UI (SUI), Urge UI (UUI) and Mixed UI (MUI) according to each instrument were: 33.7, 17.3 & 49 (KHQ); 40.4, 15.4 & 44.2 (ICIQ-UI SF). Patients' distribution according to urodynamic test was: SUI 41.3%, UUI 20.2%, MUI 26.9% and 11.5% with other diagnosis. Sensibility and specificity values of both questionnaires were very similar, but feasibility was worse for the KHQ (7.76% of pts did not complete the questionnaire) than for the ICIQ-UI SF (2.59% did not complete the questionnaire). CONCLUSIONS: Because of its better feasibility, clinical use of ICIQ-UI SF is recommended against KHQ for UI evaluation. PMID- 17711168 TI - [Efficiency of a nursing clinical trial on the treatment of female urinary incontinence]. AB - INTRODUCTION: Urinary incontinence is a frequent condition in women; it is estimated that it affects between 10% and 30% of women. The most common types are stress, urgency and mixed incontinence. It is a fact that this condition affects their quality of life. OBJECTIVE: To assess the benefits of applying an integrated and standardized nursing intervention on women with a slight or moderate degree of stress, urge or mixed urinary incontinence. DESIGN: Randomized, controlled clinical trial. LOCATION: Area 6 of primary care in Madrid. PARTICIPANTS: 256 women, 128 per group. INTERVENTION: Systematized care plan for the intervention group (IG) and conventional plan for the control group (CG), depending on urinary incontinence type. RESULTS: 59% of the total sample participated; 103 participants were followed: 48 from the IG (37.5%) and 55 from the CG (42.9%). The average difference in urine loss before and after intervention was 5.7 g (n = 22) for the IG, as opposed to 1.8 g (n = 27) for the CG; this reduction was not significant (p = 0.12), 95% CI [-1.09 - 8.92]. IU degree changes were assed by means of the Sandvik scale and were grouped in "women that improved or cured" and "women that remained the same or got worse" after interention. 40.5% of the women in the IG improved or cured, as opposed to 21% of the women in the CG (p = 0.059). CONCLUSIONS: both care plans showed their efficiency to improve UI in this group of women. The mentioned improvement was greater in the IG than in the CG, with clinically relevant differences. The fact that some of the women gave up the project during the follow-up determined a power reduction of the study. PMID- 17711170 TI - [Incidence and prevalence of published studies about urolithiasis in Spain. A review]. AB - INTRODUCTION: San Antonio, Somacarrera (1977) and Rousaud-Inmark (1984) studies established the first data of incidence and prevalence about urolithiasis in Spain. Other regional or national epidemiologic details were given for several authors from 1977 to 2002. MATERIAL AND METHOD: Sixteen papers with original data about incidence or prevalence have been selected, 5 of them are about incidence, 8 about prevalence and 3 include both. Ten papers are based on poblational research (San Antonio, Martin, Pedrajas, Rousaud-Inmark, Torres, Ripa, Romero, Grases, Alapont, Aibar), 5 on subjective estimations (Sole-Balcells, Cifuentes, Puigvert, Serrallach, Conte) and one include both (Somacarrera). Seven papers are nationwide and 9 are about local areas. A map with different location studies is presented and a data register show incidence and prevalence medians. RESULTS: The Spanish median urolithiasis incidence is 0.73%, corresponding to 325,079 new cases per year; and the prevalence is 5.06%, corresponding to 2,233,214 cases. DISCUSSION: Methodologically the best epidemiologic studies about lithiasis are based on general population survey. The commonest slant is extract data from retrospective clinical registers. Most studies have significant methodological difficulties, but they reflected interest about epidemiology of stone disease in Spain. There is a concordance between Spanish results and international published data. PMID- 17711171 TI - [Spontaneous retroperitoneal hemorrhage: our experience at last 10 years]. AB - INTRODUCTION AND OBJECTIVES: Etiology, clinical features, diagnostic methods and treatment of spontaneous retroperitoneal hemorrhage were analyzed. METHODS: We report 27 cases with diagnosis of spontaneous retroperitoneal hemorrhage treated in our hospital between January 1996 and December 2005. The imaging techniques were abdominal ultrasonography, abdominal CT scan and MRI. RESULTS: The most common cause of retroperitoneal hemorrhage was renal angiomyolipoma rupture in 7 patients. Continuous flank or abdominal pain were the primary symptoms. Abdominal ultrasonography showed hematoma in 81.8% patients, but the actual etiologic diagnosis was ascertained in only 40.9% of them. Retroperitoneal hemorrhage was demonstrated by means of abdominal CT scan in all cases and bleeding origin was established in 92.6% of cases. Ten patients underwent urgent surgery while conservative treatment was attempted in the remaining 17. CONCLUSIONS: In our experience, in cases of spontaneous retroperitoneal hemorrhage, CT scan is the best imaging method to establish the diagnosis and the management of such entity although it will need to be individualized for every case because it depends on the hemodinamic situation and etiologic diagnosis. PMID- 17711172 TI - [Hypospadias repair with Snodgrass' technique]. AB - Retrospective study of 124 patients (average age: 3.8 years) with midpenile hypospadias: 48.3% (60 children), distal penile: 45.9% (57) and coronal 5.6% (7), of which the 25.8% (16) presented ventral curvature and the 4.8% (6) resulting from the complication of another previous technique. All of them were operated according to Snodgrass' technique, removing the catheter between the 6th and 7th day in most of them. The global rate of complications was of 12%: 9 fistulae (7.2%) and 6 meatal stenosis (4.8%). Aesthetic result was satisfactory in all cases, getting glans covered by foreskin in 57.3%. PMID- 17711173 TI - [The lithiasis in the upper urinary tract in children: endourological treatment]. AB - INTRODUCTION: Urolithiasis in the pediatric age is a growing problem. In the developed world they are of calcium oxalate and in the upper urinary tract. It is very similar to the presentation of lithiasis in adults, so we have to make an effort to apply the experience in this age to the children. The shock wave lithotripsy is admitted as the first treatment for this pathology in the pediatric population already. The endourological approach must be use as a common approach in this group. We present our technique and experience. MATERIAL AND METHODS: A retrospective, descriptive study of the children diagnosed of lithiasis in the upper urinary tract that were treated by an endourological technique in our centre between January 1992 and January 2005. We gathered data on: 1.) Preoperative: age, sex, clinical manifestations, size (mm) and position of the lithiasis (we divided the upper urinary tract in: renal, proximal third, medial third and distal third) 2.) Operative variable: endourological technique: percutaneus neprolithotomy or ureteroscopy. Reconversion to open surgery. 3.) Postoperative variables: time since surgery, complications and the current state of the patient (ultrasonography and renal function). RESULTS: Seven children, 4 boys and 2 girls with an age range of 2,5 to 14 years, underwent operation using an endourological technique. Lumboabdominal pain was the main clinical manifestation (4/7). The lithiasis size was 4-7mm, with the exception of a staghorn calculis. The calculis were: 5 ureteral proximal, 1 ureteral distal and one in the kidney (staghound stone). We performed one percutaneus neprolithotomy for the staghorn calculi. We removed completly the stone and had no complications. The 6 other procedures were ureteroscopies. In 3 of them we removed the calculi (4/7 success rate of 57%). The rest procedures we needed to transform in open surgery. With a following time of 1-13 years all of them are asymptomatic, and with ultrasonography and renal function in the normal limits. We did see no complications. CONCLUSION: The endourological treatment for urolithiasis in pediatric patients is possible but must be individualized in each case. With the development of new endourological material and more surgical experience this technique will be to the reach of the most of the urologists. PMID- 17711174 TI - [Renal cell carcinoma with liver extension: a report of a new case and literature review]. AB - Locally advanced renal cell carcinoma (RCC) with involvement to adjacent organs is uncommon and the prognosis is poor. Radical surgery remains the only effective treatment. We report the case of a woman with RCC and direct liver extension who was surgically treated. A literature review is made. PMID- 17711175 TI - [Staphylococcus aureus prostatic abscess and subdural empyema: a case report]. AB - INTRODUCTION AND OBJECTIVES: To report one case of prostatic abscess and subdural empyema by Staphylococcus aureus. METHODS: We describe the case of a 51 year old male patient who was diagnosed of prostatic abscess and subdural empyema by Staphilococcus aureus. We use clinical presentation and physical exploration based on rectal digital examination, as diagnostic approach method. And computerized axial tomography and transrectal ultrasonography, which allows the guided needle drainage of the abscess, as diagnostic confirmation methods. RESULTS: The clinical picture resolved with the transrectal ultrasonography guided needle aspiration of the abscess and conservative treatment with antibiotics and urinary diversion. CONCLUSIONS: Prostatic abscess is an uncommon entity nowadays. Provided the great variety of symptoms, a great degree of clinical suspicion is needed for the diagnosis, and once it is got it, immediate aggressive treatment must be initiated. Transrectal ultrasonography allows not only the diagnosis, but also the drainage of the abscess. The culture of the obtained material identifies the etiological agent and the most specific antibiotic therapy. PMID- 17711176 TI - [Multifocal renal cell carcinoma on renal allograft]. AB - Development of neoplasms after a renal transplantation is well known, but allograft neoplasms are uncommon. Diagnostics studies include routine ultrasonography, and CT. In some selective cases, if the graft is functionally salvageable and it is technically feasible, a nephron-sparing surgery should be performed. In any case, standard intervention is nephrectomy. We report a case of multifocal renal cell carcinoma diagnosed in a kidney grafted 17 years before. PMID- 17711178 TI - [Splenogonadal fusion. Report of a case]. AB - We present a new case of splenogonadal fusion in a 27 years old male. This anomaly is the result of an embryological fusion between gonad and spleen. Occasionally there is an association with other congenital alterations (peromelia). Usually it occurs in the left scrotum and, although described in both sexes, it is more frequent in males. Its only symptom is palpable tumor and this makes the surgical approach the only way to make the diagnosis. A frozen section study can avoid unnecessary radical surgery. PMID- 17711177 TI - [Cutaneous metastases of renal cell carcinoma]. AB - Renal cell carcinoma has an unknown evolution. We report a case of a man with a skin metastases from renal cell carcinoma and an unfortunate result, five years after its radical surgical treatment. We review the literature and emphasize the need of a long and exhaustive surveillance in these patients. PMID- 17711180 TI - [Reference to the article "Use of urography by magnetic resonance for the study of the urinary apparatus versus conventional urography"]. PMID- 17711179 TI - [Retroperitoneal malignant fibrous histiocytoma with contiguous organs infiltration]. AB - Retroperitoneal tumours are extremely rare neoplasms, most of them malignant. We described the case of a 48-year-old man with a large retroperitoneal mass detected during the study of a constitutional syndrome. The mass was treated surgerically and pathological diagnosis was malignant fibrous histiocytoma. Literature is reviewed and clinical features, histological findings, radiological techniques and therapeutic management are analyzed. PMID- 17711182 TI - [Ectopic (subdiafragmatic) right kidney location]. PMID- 17711181 TI - [Urinary lithiasis secundary to a foreign body]. PMID- 17711183 TI - [Shock and hematuria in elderly patient]. PMID- 17711184 TI - [Spontaneous steinstrasse resolved without treatment]. PMID- 17711186 TI - Outsourcing U.S. greenhouse-gas emissions. PMID- 17711185 TI - [Renal policystic in adults. Bilateral nephrectomy]. PMID- 17711187 TI - ESA: politics endangers science. PMID- 17711188 TI - Finding PBDEs in couches and TVs. PMID- 17711189 TI - Flying high with PBDEs. PMID- 17711190 TI - Alberta's oil sands threaten water supplies. PMID- 17711191 TI - Chemistry for a sustainable future. PMID- 17711192 TI - Adding sustainability to the engineer's toolbox: a challenge for engineering educators. PMID- 17711193 TI - Modeling the past atmospheric deposition of mercury using natural archives. AB - Historical records of mercury (Hg) accumulation in lake sediments and peat bogs are often used to estimate human impacts on the biogeochemical cycling of mercury. On the basis of studies of lake sediments, modern atmospheric mercury deposition rates are estimated to have increased by a factor of 3-5 compared to background values: i.e., from about 3-3.5 microg Hg m(-2) yr(-1) to 10-20 microg Hg m(-2) yr(-1). However, recent studies of the historical mercury record in peat bogs suggest significantly higher increases (9-400 fold, median 40x), i.e., from about 0.6-1.7 microg Hg m(-2) yr(-1) to 8-184 microg Hg m(-2) yr(-1). We compared published data of background and modern mercury accumulation rates derived from globally distributed lake sediments and peat bogs and discuss reasons for the differences observed in absolute values and in the relative increase in the industrial age. Direct measurements of modern wet mercury deposition rates in remote areas are presently about 1-4 microg m(-2) yr(-1), but were possibly as high as 20 microg Hg m(-2) yr(-1) during the 1980s. These values are closer to the estimates of past deposition determined from lake sediments, which suggests that modern mercury accumulation rates derived from peat bogs tend to overestimate deposition. We suggest that smearing of 210Pb in the uppermost peat sections contributes to an underestimation of peat ages, which is the most important reason for the overestimation of mercury accumulation rates in many bogs. The lower background mercury accumulation rates in peat as compared to lake sediments we believe is the result of nonquantitative retention and loss of mercury during peat diagenesis. As many processes controlling time-resolved mercury accumulation in mires are still poorly understood, lake sediments appear to be the more reliable archive for estimating historical mercury accumulation rates. PMID- 17711194 TI - Can mold contamination of homes be regulated? Lessons learned from radon and lead policies. AB - Increasingly, airborne mold in home environments has been linked with asthma exacerbation and other respiratory diseases in both children and adults. This problem is particularly relevanttoday, as Hurricane Katrina has resulted in water damage and mold proliferation in numerous homes on the U.S. Gulf Coast. Policies to control indoor moisture and mold can help solve problems of mold contamination and associated adverse health effects, yet very little attention has been given to developing such policies. We address the question of howto develop effective policies by deriving lessons from successful control of other home environmental contaminants; namely, radon and lead. These two agents are being controlled by a variety of policy approaches, including federal regulations and guidelines, public education, and economic incentives among home buyers and sellers. We analyze the mold problem and identify both similarities and differences with the radon and lead situations in the United States. We recommend policy approaches for controlling mold in homes that rely on home marketing incentives, building and housing codes, and maintenance and rehabilitation regulations, as well as public education initiatives. PMID- 17711195 TI - Wastes as co-fuels: the policy framework for solid recovered fuel (SRF) in Europe, with UK implications. AB - European Union (EU) member states are adopting the mechanical-biological treatment (MBT) of municipal solid waste (MSW) to comply with EU Landfill Directive (LD) targets on landfill diversion. We review the policy framework for MSW-derived solid recovered fuel (SRF), composed of paper, plastic, and textiles, in the energy-intensive industries. A comparatively high calorific value (15-18 MJ/ kg) fuel, SRF has the potential to partially replace fossil fuel in energy intensive industries, alongside MSW in dedicated combustion facilities. Attempts by the European standards organization (CEN) to classify fuel properties consider net calorific value (CV) and chlorine and mercury content. However, the particle size, moisture content, and fuel composition also require attention and future studies must address these parameters. We critically review the implications of using SRF as a co-fuel in thermal processes. A thermodynamic analysis provides insight into the technical and environmental feasibility of co-combusting SRF in coal-fired power plants and cement kilns. Results indicate the use of SRF as co fuel can reduce global warming and acidification potential significantly. This policy analysis is of value to waste managers, policy specialists, regulators, and the waste management research community. PMID- 17711196 TI - Embodied environmental emissions in U.S. international trade, 1997-2004. AB - Significant recent attention has been given to quantifying the environmental impacts of international trade. However, the United States, despite being the world's largest emitter of greenhouse gases and having large recent growth in international trade, has seen little analysis. This work uses a multi-country input-output model of the U.S. and its seven largest trading partners (Canada, China, Mexico, Japan, Germany, the UK, and Korea) to analyze the environmental effects of changes to U.S. trade structure and volume from 1997 to 2004. It is shown that increased import volume and shifting trade patterns during this time period led to a large increase in the U.S.' embodied emissions in trade (EET) for CO2, SO2, and NO(x). Methodological uncertainties, especially related to uncertainties of international currency conversion, lead to large differences in estimation of the total EET, but we estimate that the overall embodied CO2 in U.S. imports has grown from between 0.5 and 0.8 Gt of CO2 in 1997 to between 0.8 and 1.8 Gt of CO2 in 2004, representing between 9-14% and 13-30% of U.S. (2-4% to 3-7% of global) CO2 emissions in 1997 and 2004, respectively. PMID- 17711197 TI - Assessment of human exposure to polybrominated diphenyl ethers in China via fish consumption and inhalation. AB - This study examined human exposure to polybrominated diphenyl ethers (PBDEs) associated with fish consumption and inhalation in China. The median intake of sigma7 PBDEs via human milk was 48.2 ng/day for nursing infants (0-1 years old) (a range of 23.4-99.1 ng/day). For all other age groups, the median intake of sigma11 PBDEs via fish consumption was 1.7-12.9 ng/day with a range of 0.59-56.3 ng/g. Additionally, human exposure to PBDEs via inhalation was 2.7-9.2 ng/day (a range of 0.72-108 ng/day). The median total sigma11 PBDEs intakes for nursing infants (6874 and 7372 pg/ kg b.w./day for males and females, respectively) were much higher than other age groups (215-608 pg/kg b.w./ day). No significant difference in the total PBDEs intakes was found between males and females. Of the 11 PBDEs congeners, BDE-47 was predominant in the total intake for nursing infants with a mean contribution of 38%, whereas BDE-209 was the dominant congener of total intake for other age groups, varying from 44 to 61%. Currently, the PBDEs levels in Chinese consumer fish and the total intakes of PBDEs via fish consumption were at the lower end of the global range. Compared with similar studies in other countries, however, human exposure to PBDEs via inhalation in China was relatively high. Overall, estimated daily intake of total PBDEs in the Chinese population was far below the LOAEL. However, studies are needed to further understand the fate and impact of PBDEs as PBDE-containing products are still used widely in large quantities in China. PMID- 17711198 TI - Thermal analytical investigation of biopolymers and humic- and carbonaceous-based soil and sediment organic matter. AB - Improved understanding of the physical, chemical, and thermodynamic properties of soil and sediment organic matter (SOM) is crucial in elucidating sorption mechanisms of hydrophobic organic compounds (HOCs) in soils and sediments. In this study, several thermoanalytical techniques, including thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), temperature-modulated differential scanning calorimetry (TMDSC), and thermal mechanical analysis (TMA) were applied to 13 different organic materials (three woods, two humic acids, three kerogens, and five black carbons) representing a spectrum of diagenetic and/or thermal histories. Second-order thermal transition temperatures (T(t)) were identified in most materials, where the highest observed T(t) values (typically characterized as glass transition temperatures (T(g were shown to closely relate to chemical characteristics of the organic samples as influenced by diagenetic or thermal alteration. Results further suggest a positive correlation between glass transition temperature and a defined diagenetic/thermal index, where humic-based SOM (e.g., humic and fulvic acids) possess lowertransition temperatures than more "mature" carbonaceous-based SOM (i.e., kerogens and black carbons). The observed higher thermal transition temperature of aliphatic-rich Green River shale kerogen (approximately 120 degrees C) relative to that of aromatic-rich humic acids suggests that a sole correlation of aromaticity to thermal transition temperature may be inappropriate. PMID- 17711199 TI - Characterization of the polarity of natural organic matter under ambient conditions by the polarity rapid assessment method (PRAM). AB - The polarity rapid assessment method (PRAM) characterizes the polarity of aqueous natural organic matter (NOM) by quantifying the amount of material adsorbed onto different solid-phase extraction (SPE) sorbents. The analysis is performed under ambient conditions resulting in the elimination of pretreatment steps that may alterthe chemical characteristics of the NOM, allowing an accurate representation of its polarity as it exists in the environment. Additionally, analysis only requires 200 mL of sample and can be performed in 2 h. In this paper, the underlying theory of the method is presented, followed by its optimization, with emphasis on the development of conditions for the analysis of NOM in natural waters. A series of organic probe compounds showed that the most important physicochemical property describing the interaction between the NOM and the SPE sorbents was the hydrophobic surface area, allowing for the estimation of the hydrophobic character under ambient conditions. Evaluation of the effects of chemical concentration, pH, and ionic strength show that (1) concentration did not have an effect on PRAM characterization as long as the pH and ionic strength remained constant; (2) changes in pH and ionic strength resulted in considerable changes in PRAM characterization, as a result of the changes in configuration of the NOM; and (3) PRAM characterization of NOM can be completed in the concentration range of < 10 mg C/L, although this range could be expanded by evaluating the effect of concentration on a site-specific basis. Results indicate that measurement of both ultraviolet absorption and dissolved organic carbon show complementary results as they measure different aspects of NOM. PMID- 17711200 TI - Evaluation of noninvasive approach for monitoring PCB pollution of seabirds using preen gland oil. AB - Oil secreted from the preen gland (located at the base of the tail feathers) of seabirds can be collected from live birds. We determined PCB concentrations and profiles in the preen gland oil and corresponding abdominal adipose tissue collected from 30 seabirds (2 orders, 3 families, 10 genera, 13 species) to examine the utility of the oil as a monitoring medium. Samples were collected from seabirds that had died in traffic accidents or had become caught unintentionally in experimental drift nets and long-lines in the North Pacific Ocean. Significant concentrations of PCBs were detected in all oil samples, with a concentration range of 9-4834 ng/g-lipid and a geometric mean of 404 ng/ g lipid. PCBs in the oil had more lower-chlorinated congeners than those in corresponding abdominal adipose, suggesting that they had less opportunity to undergo metabolism before they were secreted from the gland. We observed a weak but significant correlation between the PCB concentrations in the oil and abdominal adipose tissue (R2 = 0.19, P < 0.05). Correcting for the metabolic loss of PCBs on the basis of congener profiles improved the correlation (R2 = 0.48, P < 0.001), implying that congener-specific determination of PCBs in the preen gland oil enables us to estimate PCB concentrations in the abdominal adipose within 1 order of magnitude difference. The differences in PCB concentrations among the 13 species are discussed in terms of dietary behavior, habitat, and migration. PMID- 17711201 TI - Influence of breastfeeding in the accumulation of polybromodiphenyl ethers during the first years of child growth. AB - The concentrations of polybromodiphenyl ethers (PBDEs) in children at birth (cord blood sera, n = 92) and at the age of 4 years (sera, n = 244) from a cohort established in Menorca Island (Balearic Island, Spain) were studied. This cohort is representative of a general European population that is fed a typical Mediterranean diet. Among the 13 congeners analyzed, BDE #47 was the most abundant in both types of samples, with mean values of 2.8 ng/g of lipid weight in cord blood sera and 2.9 ng/g of lipid weight in sera. The observed distributions of PBDEs paralleled the composition of the commercially available mixtures of pentabromodiphenyl ethers. The concentrations of most congeners were higher in females than in males, but the differences were not significant. PBDE in the sera of 4 year old children was higher among those having been fed with maternal milk than formula. The differences were statistically significant for the congeners found in higher concentrations (e.g., BDE #47 and BDE #99). This difference was consistentwith previous reports on polychlorobiphenyls or 4,4' DDE, indicating that despite the short lactation period (about 4.5 months as an average in this cohort), breastfeeding was the determining factor for the body burden of these compounds at 4 years of age. The observed increases of average body burden of total PBDEs between birth and the first 4 years of growth were 65 and 10 ng for breastfed and formula fed children, respectively. PMID- 17711202 TI - Dietary exposure of juvenile rainbow trout (Oncorhynchus mykiss) to 1,2-bis(2,4,6 tribromophenoxy)ethane: bioaccumulation parameters, biochemical effects, and metabolism. AB - Juvenile rainbow trout (Oncorhynchus mykiss) were exposed in the laboratory to an environmentally relevant dose of 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE) via their diet for 49 days, followed by 154 days of untreated food to examine bioaccumulation parameters, potential biochemical effects, and metabolic products. There was a linear increase in the amount of BTBPE in fish during the uptake phase of the experiment, and an uptake rate constant of 0.0069 +/- 0.0012 (arithmetic mean +/- 1 x standard error) nmoles per day was calculated. The elimination of BTBPE from the fish obeyed first-order depuration kinetics (r2 = 0.6427, p < 0.001) with a calculated half-life of 54.1 +/- 8.5 days. The derived biomagnification factor of 2.3 +/- 0.9 suggests that this chemical has a high potential for biomagnification in aquatic food webs. Debrominated and hydroxylated metabolites were not detected in liver extracts and suggest that either biotransformation or storage of BTBPE-metabolites in the hepatic system of fish is minor or that our exposure time frame was too short. Similar concentrations of circulating thyroid hormones, liver deiodinase enzyme activity, and thyroid glandular histology suggest that BTBPE is not a potent thyroid axis disruptor. PMID- 17711203 TI - Use of micro-XANES to speciate chromium in airborne fine particles in the Sacramento Valley. AB - While particulate matter (PM) in the atmosphere can lead to a wide array of negative health effects, the cause of toxicity is largely unknown. One aspect of PM that likely affects health is the chemical composition, in particular the transition metals within the particles. Chromium is one transition metal of interest due to its two major oxidation states, with Cr(III) being much less toxic compared to Cr(VI). Using microfocused X-ray absorption near edge structure (micro-XANES), we analyzed the Cr speciation in fine particles (diameters < or = 2.5 microm) collected at three sites in the Sacramento Valley of northern California. The microfocused X-ray beam enables us to look at very small areas on the filter with a resolution of typically 5-7 micrometers. With XANES we are able to not only distinguish between Cr(VI) and Cr(III), but also to identify different types of Cr(III) and more reduced Cr species. At all of our sampling sites the main Cr species were Cr(III), with Cr(OH)3 or a Cr-Fe, chromite-like, phase being the dominant species. Cr(VI)-containing particles were found only in the most urban site. All three sites contained some reduced Cr species, either Cr(0) or Cr3C2, although these were minor components. This work demonstrates that micro-XANES can be used as a minimally invasive analytical tool to investigate the composition of ambient PM. PMID- 17711204 TI - Brominated flame retardants in glaucous gulls from the Norwegian Arctic: more than just an issue of polybrominated diphenyl ethers. AB - Several, unregulated, current-use brominated flame retardants (BFRs), including hexabromobenzene (HBB), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), pentabromoethylbenzene (PBEB), pentabromotoluene (PBT), and hexabromocyclododecane (as total-(alpha)-HBCD), were examined in egg yolk and plasma of male and female glaucous gulls (Larus hyperboreus) from the Norwegian Arctic. Also examined were BDE209 and 38 tri- to nona-BDE congeners and brominated biphenyl (BB) 101. The HBB, BTBPE, PBEB, and PBT had high detection frequencies and variability in male and female plasma and egg yolk samples, and their concentrations ranged from nondetectable (< 0.02-0.27 ng/g wet wt) to 2.64 ng/g wet wt. The detection frequencies and range of concentrations of non-BDE BFRs were generally highest in plasma of males relative to females. Total-(alpha) HBCD concentrations were highest among the non-PBDE BFRs (up to 6.12 and 63.9 ng/g wet wt in plasma and egg yolk, respectively). Next highest was HBB with concentrations within a range comparable to the minor PBDEs monitored (e.g., BDE28, 116 and 155). Sum (sigma)38PBDE concentrations ranged from 2.49 to 54.5 ng/g wet wt in plasma and 81.2 to 321 ng/g wet wt in egg yolk. The BDE209 was virtually nondetectable, whereas six octa-BDEs (i.e., BDE196, 197, 201, 202, 203, and 205), as well as three nona-BDEs (i.e., BDE206, 207, and 208, and potential BDE209 debromination products) were found sporadically in plasma and egg yolk. The results from this study suggestthat in addition to PBDEs, several current use, non-BDE BFRs undergo long-range atmospheric transport and bioaccumulate at low levels in and are maternally transferred (to eggs) in glaucous gulls from the Norwegian Arctic. PMID- 17711205 TI - Changes in surface area and concentrations of semivolatile organic contaminants in aging snow. AB - During the winter of 1999/2000 five snowpacks at Turkey Lake Watershed east of Lake Superior were sampled immediately after falling and again after several days of aging for the analysis of specific snow surface area and the concentrations of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs). The snow surface could be determined with a relative coefficient of variation of 6% using frontal chromatography, measuring the retention of ethyl acetate, a substance with known adsorption coefficient on the ice surface. The snow surface area of fresh snow varied from 1000 to 1330 cm2/g and was higher for snow falling during colder days. The aged snow samples had consistently lower surface areas ranging from 520 to 780 cm2/g, corresponding to an average loss of half of the initial surface area during aging. The rate of loss of surface area was faster at higher temperatures. Dieldrin, alpha-HCH, and gamma-HCH were the most abundant OCPs in snowmelt water, but endosulfan, chlordane-related substances, heptachlor epoxide, pp'-DDT, pp'-DDE, and chlorinated benzenes were also consistently present. Three midwinter snowpacks that aged during relatively cold temperatures generally experienced a loss of PCBs and OCPs that was of the same order of magnitude as the observed loss of snow surface area. However, no relationship between the extent of loss and the strength of a contaminants' sorption to snow was apparent. Few significant changes in snowpack concentrations of OCPs and PCBs were observed in a snowpack that fell at relatively high temperatures and aged under colder conditions. Concentrations of OCPs and PCBs increased in a late-winter snowpack that aged while temperatures rapidly increased to above freezing. Concentrations of pp'-DDE and endosulfan-II that increased in snowpacks that saw simultaneous decreases in the levels of pp'-DDT and endosulfan-I hint at the occurrence of sunlight induced conversions in snow. While surface area decreases clearly contribute to the loss of semivolatile organic compounds from metamorphosing snowpacks, other confounding factors play a role in determining concentration changes, in particular in wet snow. PMID- 17711207 TI - Laboratory investigation of the potential for re-emission of atmospherically derived Hg from soils. AB - This paper presents data from controlled laboratory experiments focused on investigating the effect of moisture and visible and ultraviolet light on the emission and re-emission of mercury (Hg) from two soils, one with low or background Hg concentrations (14 ng g(-1)) and a soil naturally enriched in Hg (4800 ng g(-1)). Water addition was found to increase emissions from dry soils by an amount greater than that occurring during exposure to PAR or UV-A radiation, whereas UV-B and UV-C exposures facilitated the greatest release. Over all exposures, only a small percentage of Hg(ll) added in a wet spike simulating a precipitation input was released immediately after addition (< 3%). The majority of the Hg being released during all exposures was indigenous and either an original component of the soil or derived from past wet and dry deposition. Under dark and light conditions, elemental Hg was deposited to the dry low Hg containing soil. On the basis of experimental results, it is hypothesized that dry deposition of gaseous elemental Hg is an important input to low Hg soils and that light, water, and UV-A exposure promote desorption and re-emission of elemental Hg. UV-B exposure is hypothesized to promote indirect photoreduction of Hg(II) existing in the soil. The available pool and the form of Hg in the soil, as well as the chemistry of the soil, will determine the overall flux response to environmental stimulation of emissions. PMID- 17711206 TI - Platinum and palladium emissions from on-road vehicles in the Kaisermuhlen Tunnel (Vienna, Austria). AB - Total and size-segregated Pt and Pd emission factors from on-road vehicles were measured in the Kaisermuhlen Tunnel in Vienna, Austria. Aerosol sampling was performed simultaneously inside and outside the tunnel during April and May 2005. Analysis of the acid-digested aerosol samples was performed using a preconcentration procedure with subsequent on-line detection by electro-thermal atomic absorption spectrometry (ETAAS). Inside the tunnel distinctly increased Pt and Pd concentrations were found with highest levels in total suspended particulate matter samples and reduced concentrations in the size-segregated PM10 and PM2.5 samples. Emission factors were calculated from concentration differences between tunnel inside and tunnel outside samples, the distance between tunnel entrance and sampling location, the ventilation rate, and the number of vehicles passing through the tunnel. Emission rates observed for Pt ranged from 38 +/- 5.9 to 146 +/- 13 ng veh(-1) km(-1), whereas the emission factors of Pd varied between 13 +/- 2.1 and 42 +/- 4.1 ng veh(-1) km(-1). Variations in the emission rates were assumed to originate from alterations in traffic conditions. Size-segregated investigations revealed that the major part of Pt and Pd emissions were released in the coarse aerosol mode (size fraction > PM10), nevertheless a considerable fraction (approximately 12% and approximately 22% respectively) was emitted in the inhalable PM2.5 fraction. PMID- 17711208 TI - Experimental evidence of a linear relationship between inorganic mercury loading and methylmercury accumulation by aquatic biota. AB - Developing effective regulations on mercury (Hg) emissions requires a better understanding of how atmospheric Hg deposition affects methylmercury (MeHg) levels in aquatic biota. This study tested the hypothesis that MeHg accumulation in aquatic food webs is related to atmospheric Hg deposition. We simulated a range of inorganic Hg deposition rates by adding isotopically enriched Hg(II) (90.9% 202Hg) to 10-m diameter mesocosms in a boreal lake. Concentrations of experimentally added ("spike") Hg were monitored in zooplankton, benthic invertebrates, and fish. Some Hg(II) added to the mesocosms was methylated and incorporated into the food web within weeks, demonstrating that Hg(II) deposited directly to aquatic ecosystems can become quickly available to biota. Relationships between Hg(II) loading rates and spike MeHg concentrations in zooplankton, benthic invertebrates, and fish were linear and significant. Furthermore, spike MeHg concentrations in the food web were directly proportional to Hg(II) loading rates (i.e., a percent change in Hg(II) loading rate resulted in, statistically, the same percent change in MeHg concentration). This is the first experimental determination of the relationship between Hg(II) loading and MeHg bioaccumulation in aquatic biota. We conclude that changes in atmospheric Hg deposition caused by increases or decreases in Hg emissions will ultimately affect MeHg levels in aquatic food webs. PMID- 17711209 TI - Adsorptive fractionation of humic acid at air-water interfaces. AB - By using a simple bubble column, the adsorption behavior of a commercial soil humic acid (CHA) at air-water interfaces was investigated. At pH 4.0, the concentrations of the CHA exhibited clear gradients in the bubble column, and increased significantly along the column height; smaller concentration gradients were also observed at pH 6.0. These concentration profiles demonstrate the surface activity of humic acid and pH-dependent affinity toward air-water interfaces. Taking advantage of the bubble column method, we interestingly found that the adsorptive fractionation of the CHA at air-water interfaces did occur. The components with higher molecular weight and stronger UV absorptivity showed greater affinity toward air-water interfaces, despite that the fractionation pattern was reduced to a certain extent as solution pH increased. The organic carbon-normalized pyrene partition coefficient Koc values deviated from the corresponding values of original bulk solutions at both pH 4.0 and 6.0, and increased along the height of the column. Our results demonstrate the usefulness of the simple bubble column, and suggest that the adsorptive fractionation of humic acid at air-water interfaces might have implications for some natural environments and engineered systems where air-water interfaces exist extensively. PMID- 17711210 TI - Enantioselective degradation of organochlorine pesticides in background soils: variability in field and laboratory studies. AB - Variability in the enantioselective degradation of chiral organochlorine pesticides (alpha-HCH, cis- and trans-chlordane (CC and TC), and o,p'-DDT) in the field and laboratory was investigated. Background soils presumably receive the same EF signature of a compound via atmospheric deposition and then degrade that compound in a way that can vary over small spatial areas. Background soils from woodland and grassland areas were sampled to compare chiral signatures and determine the spatial variability within a few square meters. The enantiomer fractions, EF = areas of the (+)/[(+)+(-)]-enantiomers, showed variability between and within ecosystems. For example, the EF of CC varied between 0.272 and 0.558 in nine samples taken over a few square meters, and a range of 0.431 0.506 was found within depths of a few centimeters. Woodland and grassland soils were spiked with alpha-HCH, TC, CC, and o,p'-DDT, and one portion was placed in the field to monitor changes in EF under in situ conditions and the other taken to the laboratory. In general, the enantiomer degradation preferences in the laboratory paralleled those in the field, with some differences. Soil organic matter content and pH exerted a minor influence on this variability. The results of this study have implications for the use of chiral compounds to make inferences about air-soil exchange and for the mechanisms of biodegradation/ biotransformation of anthropogenic compounds in soils. PMID- 17711211 TI - Characterization of fine particle and gaseous emissions during school bus idling. AB - The particulate matter (PM) and gaseous emissions from six diesel school buses were determined over a simulated waiting period typical of schools in the northeastern U.S. Testing was conducted for both continuous idle and hot restart conditions using a suite of on-line particle and gas analyzers installed in the U.S. Environmental Protection Agency's Diesel Emissions Aerosol Laboratory. The specific pollutants measured encompassed total PM-2.5 mass (PM < or = 2.5 microm in aerodynamic diameter), PM-2.5 number concentration, particle size distribution, particle-surface polycyclic aromatic hydrocarbons (PAHs), and a tracer gas (1,1,1,2,3,3,3-heptafluoropropane) in the diluted sample stream. Carbon monoxide (CO), carbon dioxide, nitrogen oxides (NO(x)), total hydrocarbons (THC), oxygen, formaldehyde, and the tracer gas were also measured in the raw exhaust. Results of the study showed little difference in the measured emissions between a 10 min post-restart idle and a 10 min continuous idle with the exception of THC and formaldehyde. However, an emissions pulse was observed during engine restart. A predictive equation was developed from the experimental data, which allows a comparison between continuous idle and hot restart for NO(x), CO, PM2.5, and PAHs and which considers factors such as the restart emissions pulse and periods when the engine is not running. This equation indicates that restart is the preferred operating scenario as long as there is no extended idling after the engine is restarted. PMID- 17711212 TI - Quantifying the degradation and dilution contribution to natural attenuation of contaminants by means of an open system rayleigh equation. AB - Quantifying the share of destructive and nondestructive processes to natural attenuation (NA) of groundwater pollution plumes is of high importance to the evaluation and acceptance of NA as remediation strategy. Dilution as consequence of hydrodynamic dispersion may contribute considerably to NA, however, without reducing the mass of pollution. Unfortunately, tracers to quantify dilution are usually lacking. Degradation though of low-molecular-weight organic chemicals such as BTEX, chlorinated ethenes, and MTBE is uniquely associated with increases in isotope ratios for steady-state plumes. Compound-specific isotope analysis (CSIA) data are commonly interpreted by means of the Rayleigh equation, originally developed for closed systems, to calculate the extent of degradation under open system field conditions. For that reason, the validity of this approach has been questioned. The Rayleigh equation was accordingly modified to account for dilution, and showed that dilution contributed several to many times more to NA than biodegradation at a groundwater benzene plume. Derived equations also (i) underlined that field-derived isotopic enrichment factors underestimate actual values operative as a consequence of dilution, and (ii) provided a check on the lower limit of isotopic fractionation, thereby resulting in more reliable predictions on the extent of degradation. PMID- 17711213 TI - Particle-phase dry deposition and air-soil gas-exchange of polybrominated diphenyl ethers (PBDEs) in Izmir, Turkey. AB - The particle-phase dry deposition and soil-air gas-exchange of polybrominated diphenyl ethers (PBDEs) were measured in Izmir, Turkey. Relative contributions of different deposition mechanisms (dry particle, dry gas, and wet deposition) were also determined. BDE-209 was the dominating congener in all types of samples (air, deposition, and soil). Average dry deposition fluxes of total PBDEs (sigma7PBDE) for suburban and urban sites were 67.6 and 128.8 ng m(-2) day(-1), respectively. Particulate dry deposition velocities ranged from 11.5 (BDE-28) to 3.9 cm s(-1) (BDE-209) for suburban sites and 7.8 (BDE-28) to 2.8 cm s(-1) (BDE 154) for urban sites with an overall average of 5.8 +/- 3.7 cm s(-1). The highest sigma7PBDE concentration (2.84 x 10(6) ng kg(-1) dry wt) was found around an electronic factory among the 13 soil samples collected from different sites. The concentration in a bag filter dust from a steel plant was also high (2.05 x 10(5) ng kg(-1)), indicating that these industries are significant PBDE sources. Calculated net soil-air gas exchange flux of sigma7PBDE ranged from 11.8 (urban) to 23.4 (industrial) ng m(-2) day(-1) in summer, while in winter it ranged from 3.2 (urban) to 11.6 (suburban) ng m(-2) day(-1). All congeners were deposited at all three sites in winter and summer. It was estimated that the wet deposition also contributes significantly to the total PBDE deposition to soil. Dry particle, wet, and gas deposition contribute 60, 32, and 8%, respectively, to annual PBDE flux to the suburban soil. PMID- 17711214 TI - Time-variable simulation of soil vapor intrusion into a building with a combined crawl space and basement. AB - A time-variable one-dimensional model (called ViM for Vapor Intrusion Model)to predict indoor vapor concentrations in a dwelling with a combined basement and crawl space has been developed. ViM predicts vapor concentrations in each of the three compartments. Volatile chemicals that intrude into the dwelling are assumed to originate from soil, groundwater (where an attenuating plume is simulated), or ambient air. Processes included in the model are advection, diffusion, biodecay, and adsorption in the soil column; transport by diffusion and advection into individual crawl space and basement compartments; advection from each compartment into an overlying dwelling space; and exchange of ambient air and indoor air. The time-variable concentration fields are solved by first transforming the partial and ordinary differential equations into Laplace space, solving the resulting ordinary differential equations or algebraic equations, and numerically inverting those equations. This approach was an expedient way of handling the coupling between the subsurface and the dwelling. ViM was applied to a building (Building 20) located at the former Moffett Field Naval Air Station, in Mountain View, CA. The building is a former bachelor officer's quarters. The shallow groundwater beneath the building is contaminated with a number of volatile chemicals, including trichloroethene, cis-1,2-dichloroethene, and trans-1,2-dichloroethene, all of which were simulated. Using indoor air data collected in 2003-2004, and other field data collected prior to that time, the accuracy of the model's predictions was demonstrated. ViM's results were also compared against a version of the steady-state Johnson and Ettinger model (1) that was modified to accommodate a dwelling with a combined crawl space and basement (called the JEM model in this paper). The predictions from the JEM model were consistently higher than the predictions from ViM, but still near the upper range of the observed data. PMID- 17711215 TI - Multicomponent diffusion modeling in clay systems with application to the diffusion of tritium, iodide, and sodium in Opalinus Clay. AB - The hydrogeochemical transport model PHREEQC was extended with options to calculate multicomponent diffusion in free pores and in the diffuse double layer (DDL). Each solute species can be given its own tracer diffusion coefficient. The composition of the DDL is calculated with the Donnan approximation. With these options, solute species can be transported in coexisting charged and uncharged regions as may exist in clays and membranes. The model was developed to simulate in-situ tracer diffusion experiments in Opalinus Clay with tritium, iodide, and sodium. Tritium gives the formation's tortuosity factor, which applies in principle for all the neutral species. Half of the porosity is not accessible for iodide due to anion exclusion, and assumed equal to the amount of DDL-water. With this assumption, the tortuosity factor for iodide is 1.4 times higher than that for tritium. The sodium data can be matched by reducing the tortuosity factor 1.6 times relative to tritium, and by distributing the cation exchange capacity over the DDL and fixed sites that are spread heterogeneously over the model domain. The physical origin of the variable tortuosity for differently charged species is discussed. PMID- 17711216 TI - Combining model results and monitoring data for water quality assessment. AB - A Bayesian approach is used to update and improve water quality model predictions with monitoring data. The objective of this work is to facilitate adaptive management by providing a framework for sequentially updating the assessment of water quality status, to evaluate compliance with water quality standards, and to indicate if modification of management strategies is needed. Currently, most water quality or watershed models are calibrated using historical data that typically reflect conditions different from those being forecast. In part because of this, predictions are often subject to large errors. Fortunately, in many instances, postmanagement implementation monitoring data are available, although often with limited spatiotemporal coverage. These monitoring data support an alternative to the one-time prediction: pool the information from both the initial model prediction and postimplementation monitoring data. To illustrate this approach, a watershed nutrient loading model and a nitrogen-chlorophyll a model for the Neuse River Estuary were applied to develop a nitrogen total maximum daily load program for compliance with the chlorophyll a standard. Once management practices were implemented, monitoring data were collected and combined with the model forecast on an annual basis using Bayes Theorem. Ultimately, the updated posterior distribution of chlorophyll a concentration indicated that the Neuse River Estuary achieved compliance with North Carolina's standard. PMID- 17711217 TI - Use of field data to support European Water Framework Directive quality standards for dissolved metals. AB - Quality standards (QS) for dissolved metals in freshwaters have been proposed underthe European Water Framework Directive (WFD) and are based mainly upon laboratory ecotoxicity data. Uncertainties remain about laboratory-to-field extrapolation to establish QS that are neither over- nor underprotective. Freshwater benthic macroinvertebrates are a group of organisms of known sensitivity to heavy metals. We analyzed a dataset from England and Wales of dissolved metal concentrations (cadmium, chromium, copper, iron, nickel, lead, and zinc) and associated benthic invertebrate community metrics, using piecewise regression, quantile regression, and information on metal concentrations consistent with good quality status. Analysis of these field data suggests that dissolved metal QS proposed under the WFD are similar to metal concentrations in rivers associated with unimpaired benthic invertebrate assemblages in England and Wales. The only exceptions to this are QS for iron and zinc, where use of relatively large assessment factors leads to standards that are substantially below concentrations associated with impaired invertebrate assemblages in the field. PMID- 17711218 TI - Rapid identification of high particle number emitting on-road vehicles and its application to a large fleet of diesel buses. AB - Pollutant concentrations measured in the exhaust plume of a vehicle may be related to the pollutant emission factor using the CO2 concentration as a measure of the dilution factor. We have used this method for the rapid identification of high particle number (PN) emitting on-road vehicles. The method was validated for PN using a medium-duty vehicle and successfully applied to measurements of PN emissions from a large fleet of on-road diesel buses. The ratio of PN concentration to CO2 concentration, Z, in the exhaust plume was estimated for individual buses. On the average, a bus emitted about 1.5 x 10(9) particles per mg of CO2 emitted. A histogram of the number of buses as a function of Z showed, for the first time, that the PN emissions from diesel buses followed a gamma distribution, with most of the values within a narrow range and a few buses exhibiting relatively large values. It was estimated that roughly 10% and 50% of the PN emissions came from just 2% and 25% of the buses, respectively. A regression analysis showed that there was a positive correlation between Z and age of buses, with the slope of the best line being significantly different from zero. The mean Z value for the pre-Euro buses was significantly greater than each of the values for the Euro I and II buses. PMID- 17711219 TI - Immunochromatographic dipstick assay format using gold nanoparticles labeled protein-hapten conjugate for the detection of atrazine. AB - The present study describes a lateral-flow-based dipstick immunoassay format using a novel hapten-protein-gold conjugate for the rapid screening of atrazine in water samples. The immunoassay is based on the competitive inhibition, in which a newly developed hapten-protein-gold conjugate competes with the free antigen present in the sample, for the limited antibody binding sites available at test zone on dipstick membrane, housed in a plastic cartridge. The tracer used as the detection reagent was prepared by first conjugating hapten (a derivative of atrazine) molecules to a carrier protein (bovine serum albumin) via its surface lysine residues and then linking colloidal gold nanoparticles to the hapten-protein conjugate via cysteine residues of the carrier protein. The developed conjugate showed a high level of stability as it did not show any significant loss of activity even after 8 weeks of storage at ambient conditions. The color developed due to conjugate, based on competitive inhibition approach, is correlated with the concentration of atrazine sample. The sensitivity of the developed dipstick was enhanced by gold nanoparticles, as an amplification tag, presenting detection limit of atrazine in standard water samples down to 1.0 ppb level. The kit could serve as a rapid screening methodology for visual screening of atrazine contamination of water samples within 5 min of analysis time, and, when coupled with a portable colorimeter, as an inexpensive semi-quantitative assay. The method reported can be useful for screening a large number of pesticides samples in a very short time in the field. PMID- 17711220 TI - Unregulated emissions from a heavy-duty diesel engine with various fuels and emission control systems. AB - This study evaluated the effects of various combinations of fuels and emission control technologies on exhaust emissions from a heavy-duty diesel engine tested on an engine dynamometer. Ten fuels were studied in twenty four combinations of fuel and emission control technology configurations. Emission control systems evaluated were diesel oxidation catalyst (DOC), continuously regenerating diesel particulate filter (CRDPF), and the CRDPF coupled with an exhaust gas recirculation system (EGRT). The effects of fuel type and emission control technology on emissions of benzene, toluene, ethylbenzene, xylene (BTEX), and 1,3 butadiene, elemental carbon and organic carbon (EC/OC), carbonyls, polycyclic aromatic hydrocarbons (PAHs), and nitro-PAHs (n-PAHs) are presented in this paper. Regulated gaseous criteria pollutants of total hydrocarbons (THC), carbon monoxide (CO), oxides of nitrogen (NO(x)) and particulate matter (PM) emissions have been reported elsewhere. In general, individual unregulated emission with a CRDPF or an EGRT system is similar (at very low emission level) or much lower than that operating solely with a DOC and choosing a "best" fuel. The water emulsion PuriNO(x) fuel exhibited higher BTEX, carbonyls and PAHs emissions compared to other ultralow sulfur diesel (ULSD) fuels tested in this study while n-PAH emissions were comparable to that from other ULSD fuels. Naphthalene accounted for greater than 50% of the total PAH emissions in this study and there was no significant increase of n-PAHs with the usage of CRDPF. PMID- 17711221 TI - Estimation of water sampling rates and concentrations of PAHs in a municipal sewage treatment plant using SPMDs with performance reference compounds. AB - Semipermeable membrane devices (SPMDs) were exposed at ten sampling points, each representing a different stage in the treatment process, in a municipal sewage treatment plant. Differences in SPMD uptake kinetics of polycyclic aromatic hydrocarbons (PAHs) due to variations in conditions at the sampling sites were evaluated by using five performance reference compounds (PRCs) with log K(ow) values of 4.20 to 6.34. PRC release rate constants (k(e,PRC) values) were calculated for PRCs for which 50-98% of the initial amounts were lost during the sampling period. The k(e,PRC) values were high, ranging from 0.08 to 0.11 day(-1) for the studied PRCs, at sampling site W1 (raw sewage), the only sampling site where significant amounts of the PRCs with log K(ow) values > 5 were released from the SPMDs. At the other sampling sites, only PRCs with log K(ow) values between 4.20 and 4.50 were released in significant amounts. The release rates at these sites were lowest (0.04 day(-1)) at sampling site W9 (the secondary clarifier) and highest (0.18 day(-1)) at W8 (the active sludge aeration basin). Differences between sampling rates (R(s)) obtained using published laboratory calibrated data and PRC-corrected R(s) values were visualized by principal component analysis (PCA). The water concentrations of 24 studied PAHs fell substantially during the course of the sewage treatment process. However, low molecular weight PAHs were more effectively removed than high molecular weight PAHs. Significant deviations between actual and estimated water concentrations may arise unless PRC-corrected R(s) values are applied. PMID- 17711222 TI - Enhanced visible-light-induced photocatalytic disinfection of E. coli by carbon sensitized nitrogen-doped titanium oxide. AB - Nitrogen-doped titanium oxide (TiON) nanoparticle photocatalysts were synthesized by a sol-gel process, for disinfection using E. coli as target bacteria. Our work shows thatthe calcination atmosphere has strong effects on the composition, structure, optical, and antimicrobial properties of TiON nanoparticles. Powders calcinated in a flow of N2 atmosphere (C-TiON) contain free carbon residue and demonstrate different structures and properties compared to the TiON powders calcinated in air. Disinfection experiments on Escherichia coli indicate that C TiON composite photocatalyst has a much better photocatalytic activity than pure TiON photocatalyst under visible light illumination. The enhanced photocatalytic activity is related to stronger visible light absorption of the carbon-sensitized TiON. PMID- 17711223 TI - Improved adsorption of 4-nitrophenol onto a novel hHyper-cross-linked polymer. AB - In the present study we prepared a hyper-cross-linked polymeric adsorbent (NDA 701) possessing a uniquely bimodal pore size distribution for 4-nitrophenol (4 NP) adsorption from water. A macroporous polymeric adsorbent Amberlite XAD-4 and a granular activated carbon GAC-1 were chosen for comparison. NDA-701 exhibited better mechanical strength and higher capacity of 4-NP than XAD-4, which possibly resulted from its hyper-cross-linking nature and micropore structure, respectively. 4-NP adsorption isotherm onto NDA-701 is well described by the Freundlich model, and its better kinetics performance than GAC-1 resulted from its macropore structure. After adsorption NDA-701 was amenable to an entire regeneration by using NaOH solution as regenerant, whereas only approximately 75% regeneration efficiency was observed for GAC-1. Results of continuous fixed-bed runs in pilot and industrial scale demonstrated that NDA-701 is capable of completely removing 4-NP from chemical effluent with no capacity loss, and 4-NP can be readily recovered by further treatment of the concentrated regenerant solution. It is attractive that the value of the recovered 4-NP from chemical wastewater will even engender a surplus after countervailing all the operation cost during field application. PMID- 17711224 TI - Steady-state and dynamic desorption of organic vapor from activated carbon with electrothermal swing adsorption. AB - A new method to achieve steady-state and dynamic-tracking desorption of organic compounds from activated carbon was developed and tested with a bench-scale system. Activated carbon fiber cloth (ACFC) was used to adsorb methyl ethyl ketone (MEK) from air streams. Direct electrothermal heating was then used to desorb the vapor to generate select vapor concentrations at 500 ppmv and 5000 ppmv in air. Dynamic-tracking desorption was also achieved with carefully controlled yet variable vapor concentrations between 250 ppmv and 5000 ppmv, while also allowing the flow rate of the carrier gas to change by 100%. These results were also compared to conditions when recovering MEK as a liquid, and using microwaves as the source of energy to regenerate the adsorbent to provide MEK as a vapor or a liquid. PMID- 17711225 TI - Reduction of particulate matter emissions from diesel backup generators equipped with four different exhaust aftertreatment devices. AB - Diesel particulate matter (PM) reduction efficiencies for backup generators (BUGs) (> 300 kW) equipped with a diesel oxidation catalyst (DOC), DOC+fuel-borne catalyst additive combination (DOC+FBC), passive diesel particulate filter (DPF), and an active DPF were measured. Overall, the DOC and DOC+FBC technologies were found to be effective in reducing mainly organic carbon (OC) emissions (56-77%) while both DPFs showed excellent performance in reducing both elemental carbon (EC) and OC emissions (> 90%). These findings demonstrate the potential for applying DOCs to older engines where PM is dominated by the OC fraction. In most modern engine applications, where the PM consists of mainly EC, the DOC will be largely ineffective. Alternatively, passive and active DPFs are expected to be efficient for most engine technologies. Measurements of particle size distributions provided evidence of the high temperature formation of sulfate nanoparticles across the control technologies despite the use of ultralow sulfur diesel. Changes in the particle size distribution and the organic fraction of PM indicate that the OC component of PM is primarily found in the smaller sized particles. PMID- 17711226 TI - Occurrence of pharmaceuticals in river water and their elimination in a pilot scale drinking water treatment plant. AB - The occurrence of four beta blockers, one antiepileptic drug, one lipid regulator, four anti-inflammatories, and three fluoroquinolones was studied in a river receiving sewage effluents. All compounds but two of the fluoroquinolones were observed in the water above their limit of quantification concentrations. The highest concentrations (up to 107 ng L(-1)) of the compounds were measured during the winter months. The river water was passed to a pilot-scale drinking water treatment plant, and the elimination of the pharmaceuticals was followed during the treatment. The processes applied by the plant consisted of ferric salt coagulation, rapid sand filtration, ozonation, two-stage granular activated carbon filtration (GAC), and UV disinfection. Following the coagulation, sedimentation, and rapid sand filtration, the studied pharmaceuticals were found to be eliminated only by an average of 13%. An efficient elimination was found to take place during ozonation at an ozone dose of about 1 mg L(-1) (i.e., 0.2-0.4 mg of O3/ mg of TOC). Following this treatment, the concentrations of the pharmaceuticals dropped to below the quantification limits with the exception of ciprofloxacin. Atenolol, sotalol, and ciprofloxacin, the most hydrophilic of the studied pharmaceuticals, were not fully eliminated during the GAC filtrations. All in all, the treatment train was found to very effectively eliminate the pharmaceuticals from the rawwater. The only compound that was found to pass almost unaffected through all the treatment steps was ciprofloxacin. PMID- 17711227 TI - Questioning the excessive use of advanced treatment to remove organic micropollutants from wastewater. AB - Pollution from endocrine disrupting compounds and related micropollutants is widely regarded as a major environmental issue on both a regional and a global scale, largely due to concerns over risks to human and ecological health. Between 2005 and 2010, the United Kingdom is conducting a demonstration program, costing approximately 40 million (approximately $80 million atthe time of writing), to evaluate technologies to remove these compounds from wastewater. However, while such advanced treatment techniques will undoubtedly reduce the discharges of micropollutants, they will also inevitably result in large financial costs, as well as environmentally undesirable increases in energy consumption and CO2 emissions. Here we calculate the price of treating urban sewage with two of the major options specifically proposed in the U.K. demonstration program: (i) granular activated carbon and ozone and (ii) membrane filtration and reverse osmosis. Economic analysis indicates thattreating wastewater with these advanced technologies may be economically and environmentally undesirable due to the increased energy consumption and associated economic costs and CO2 emissions. Since the costs of advanced treatment of sewage would most likely have to be passed on to customers (both domestic and industrial), we propose that national demonstration programs should not only compare and contrast the most advanced treatment methods but also consider alternative techniques, such as increased sludge ages and hydraulic retention times in conjunction with nutrient removal stages and the varying redox conditions associated with them, which potentially may be almost as effective but with much lower environmental and financial costs. PMID- 17711228 TI - Factors affecting ionic liquids based removal of anionic dyes from water. AB - Liquid--liquid extraction with imidazolium based ionic liquids--[C4mim][PF6], [C6miml][PF6], [C6mim[BF4], and [C8mim][PF6--is proposed for removal of anionic dyes including methyl orange, eosin yellow, and orange G from aqueous solutions. The effects of extraction time, pH of aqueous phase, structure of the ionic liquids, temperature, and KCl concentration on the extraction efficiencies have been studied. Extraction efficiencies of dyes were strongly affected by the pH of the aqueous phase. Under the optimized pH condition, 85-99% of methyl orange, almost 100% eosin yellows, and 69% of orange G in tested water samples were transferred into the ionic liquids in a single extraction. Extraction efficiency for a given dye was found to increase with increasing temperature and increasing alkyl chain length of cation of the ionic liquids. Presence of a small amount of KCl in the aqueous phase did not considerably improve the extraction efficiency of the dyes. Thermodynamic studies revealed that the extraction process was driven by hydrophobic interaction of the anionic dyes and the ionic liquids. PMID- 17711229 TI - Inactivation of Mycobacterium avium with free chlorine. AB - The inactivation kinetics of Mycobacterium avium with free chlorine was characterized by two stages: an initial phase at a relatively fast rate followed by a slower second stage of pseudo first-order kinetics. The inactivation rate of each stage was approximately the same for all experiments performed at a certain condition of pH and temperature; however, variability was observed for the disinfectant exposure at which the transition between the two stages occurred. This variability was not a function of the initial disinfectant concentration, the initial bacterial density, or the bacterial stock. However, the transition to the second stage varied more significantly at high temperatures (30 degrees C), while lower variability was observed at lower temperatures (5 and 20 degrees C). Experiments conducted at pH values in the range of 6-9 revealed that the inactivation of M. avium was primarily due to hypochlorous acid, with little contribution from hypochlorite ion within this pH range. The inactivation kinetics was represented with a two-population model. The activation energies for the resulting pseudo first-order rate constants for the populations with fast and slow kinetics were 100.3 and 96.5 kJ/mol, respectively. The magnitude of these values suggested that for waters of relatively high pH and low temperatures, little inactivation of M. avium would be achieved within treatment plants, providing a seeding source for distribution systems. PMID- 17711230 TI - Anchored oxygen-donor coordination to iron for photodegradation of organic pollutants. AB - A photocatalyst of oxygen-donor coordination to iron, complex of 5-sulfosalicylic acid (SSA) with ferric ion, supported on resin to cycle Fe3+/Fe2+ center under visible irradiation can effectively generate *OH radicals from H2O2, leading to degradation of organic pollutants in water. The higher turnover number was achieved by this catalyst for the degradation of model compound than those reported for the general N-donor ligands catalysts. The reversible "on/ off" switching of Fe3+/Fe2+ complexation with SSA, coupled with the phenol/phenoxyl radical conversion of the o-phenoxyl moiety of SSA, produces an ideal catalytic system that separates the Fenton reaction and the followed oxidations by *OH radicals (in water phase) from the regeneration of the catalytic species, Fe (SSA)2-, which occurs on the surface of resin. This system not only inhibits the undesired destruction of the ligands by *OH radicals, improving the stability of the catalyst, but also avoids the unnecessary decomposition of H2O2 into HO2* that occurs in the homogeneous Fenton system. Therefore, the system suggests an efficient utilization of H2O2 for degradation of organic pollutants. PMID- 17711231 TI - Response of antibiotic resistance genes (ARG) to biological treatment in dairy lagoon water. AB - To explore the response of antibiotic resistance genes (ARG) to biological treatment, dairy lagoon water was incubated anaerobically or aerobically at 20 degrees C or 4 degrees C. Three conditions were compared: Antibiotic (Ab) Spiked, Ab Spiked and Killed, and Background (unamended). For Ab Spiked conditions, oxytetracycline, sulfamethoxazole, tylosin, and monensin were each added at 20 mg/L. Antibiotics and ARG were monitored using high-performance liquid chromatography/tandem mass spectrometry and quantitative real-time polymerase chain reaction, respectively. Biological degradation of antibiotics in all treatments and varied responses of different ARG was observed. Aerobic versus anaerobic treatment had no effect on tet(W), with an overall pattern of increase in the presence of antibiotics followed by decrease to initial levels. tet(O) responded differently under aerobic versus anaerobic treatment, increasing to highest levels at 4 degrees C under aerobic treatment and at 20 degrees C under anaerobic treatment before returning to initial levels. sul(I) and sul (II) showed similar patterns and increased in all Ab Spiked conditions, failing to return to initial levels at 4 degrees C and in some of the 20 degrees C treatments. ere(A) and msr(A) were lower than the other two ARG classes and remained constant in all treatments. PMID- 17711233 TI - Forging the anthropogenic iron cycle. AB - Metallurgical iron cycles are characterized for four anthropogenic life stages: production, fabrication and manufacturing, use, and waste management and recycling. This analysis is conducted for year 2000 and at three spatial levels: 68 countries and territories, nine world regions, and the planet. Findings include the following: (1) contemporary iron cycles are basically open and substantially dependent on environmental sources and sinks; (2) Asia leads the world regions in iron production and use; Oceania, Latin America and the Caribbean, Africa, and the Commonwealth of Independent States present a highly production-biased iron cycle; (3) purchased scrap contributes a quarter of the global iron and steel production; (4) iron exiting use is three times less than that entering use; (5) about 45% of global iron entering use is devoted to construction, 24% is devoted to transport equipment, and 20% goes to industrial machinery; (6) with respect to international trade of iron ore, iron and steel products, and scrap, 54 out of the 68 countries are net iron importers, while only 14 are net exporters; (7) global iron discharges in tailings, slag, and landfill approximate one-third of the iron mined. Overall, these results provide a foundation for studies of iron-related resource policy, industrial development, and waste and environmental management. PMID- 17711232 TI - Removal of heavy metals from aqueous systems with thiol functionalized superparamagnetic nanoparticles. AB - We have shown that superparamagnetic iron oxide (Fe3O4) nanoparticles with a surface functionalization of dimercaptosuccinic acid (DMSA) are an effective sorbent material for toxic soft metals such as Hg, Ag, Pb, Cd, and Tl, which effectively bind to the DMSA ligands and for As, which binds to the iron oxide lattices. The nanoparticles are highly dispersible and stable in solutions, have a large surface area (114 m2/g), and have a high functional group content (1.8 mmol thiols/g). They are attracted to a magnetic field and can be separated from solution within a minute with a 1.2 T magnet. The chemical affinity, capacity, kinetics, and stability of the magnetic nanoparticles were compared to those of conventional resin based sorbents (GT-73), activated carbon, and nanoporous silica (SAMMS) of similar surface chemistries in river water, groundwater, seawater, and human blood and plasma. DMSA-Fe3O4 had a capacity of 227 mg of Hg/g, a 30-fold larger value than GT-73. The nanoparticles removed 99 wt% of 1 mg/L Pb within a minute, while it took over 10 and 120 min for Chelex-100 and GT 73 to remove 96% of Pb. PMID- 17711234 TI - Development of a framework for quantifying the environmental impacts of urban development and construction practices. AB - To encourage sustainable development, engineers and scientists need to understand the interactions among social decision-making, development and redevelopment, land, energy and material use, and their environmental impacts. In this study, a framework that connects these interactions was proposed to guide more sustainable urban planning and construction practices. Focusing on the rapidly urbanizing setting of Phoenix, Arizona, complexity models and deterministic models were assembled as a metamodel, which is called Sustainable Futures 2100 and were used to predict land use and development, to quantify construction material demands, to analyze the life cycle environmental impacts, and to simulate future ground level ozone formation. PMID- 17711236 TI - Cell death, stress-responsive transgene activation, and deficits in the olfactory system of larval zebrafish following cadmium exposure. AB - Cadmium (Cd) is a well-described environmental pollutant known to have adverse effects in fish, including behavioral deficits. We have previously reported the development of an in vivo system that utilizes hsp70 gene activation as a measure of acute 3 h cadmium toxicity in whole living transgenic zebrafish larvae carrying a stably integrated hsp70-enhanced green fluorescent protein (eGFP) reporter gene. Here, we report that activation of this transgene in olfactory epithelium of zebrafish larvae during 96 h sublethal Cd exposure is predictive of cadmium-induced cell death, altered histological and surface organization of the epithelium, and changes in olfactory dependent behavior. The transgene is first activated in the olfactory epithelium at concentrations below those giving rise to significant defects, but exhibits a more robust response following exposure to Cd at concentrations that begin to cause significant cell death, morphological alterations, and behavioral deficits. Further, the data show that Cd-induced olfactory deficits reported previously in juvenile and adult fish can also occur during larval stages of fish development, and that such behavioral deficits are closely associated with cell death and structural alterations in the olfactory epithelium. PMID- 17711235 TI - Synthesis of plant-mediated gold nanoparticles and catalytic role of biomatrix embedded nanomaterials. AB - Growth of Sesbania seedlings in chloroaurate solution resulted in the accumulation of gold with the formation of stable gold nanoparticles in plant tissues. Transmission electron microscopy revealed the intracellular distribution of monodisperse nanospheres, possibly due to reduction of the metal ions by secondary metabolites present in cells. X-ray absorption near-edge structure and extended X-ray absorption fine structure demonstrated a high degree of efficiency for the biotransformation of Au(III) into Au(0) by planttissues. The catalytic function of the nanoparticle-rich biomass was substantiated by the reduction of aqueous 4-nitrophenol (4-NP). This is the first report of gold nanoparticle bearing biomatrix directly reducing a toxic pollutant, 4-NP. PMID- 17711237 TI - Stiffness alterations of single cells induced by UV in the presence of nanoTiO2. AB - Nanocrystalline titanium dioxide (nanoTiO2) has been reported to generate reactive oxygen species (ROS) under UV illumination. In our studies, changes in mechanical properties of human skin fibroblasts, exposed to the oxidative stress induced in the presence of nanoTiO2 and UV light, were studied using atomic force microscopy (AFM). The exposure of cells to the action of ROS was performed at low TiO2 concentration (4 microg/mL) and under illumination with low-intensity UVA (8 and 20 mW/cm2) or UVC (0.1 mW/ cm2). AFM measurements of the cell stiffness were carried out immediately after exposure of cells to the oxidative stress. The data suggest that under illumination with low-intensity UVA nanoTiO2 generates ROS, which, in turn, damage cellular and subcellular structures. This process was detected by AFM as a marked drop in the cellular stiffness of ca. 30-75%, which occurred rapidly, in the time frame of 1 min. The photo-oxidative stress inducing the decrease of cell stiffness was cancelled in the presence of a well established antioxidant, beta-carotene. The results highlight the sensitivity of AFM to detect early changes in mechanical properties of cells exposed to oxidative stress. PMID- 17711238 TI - Physiological response to persistent organic pollutants in fish from mountain lakes: analysis of CYP1A gene expression in natural populations of Salmo trutta. AB - Cytochrome p450 1A (CYP1A) gene expression in fish liver increases upon exposure to a variety of chemical compounds, including organochlorine compounds (OCs) and polycyclic aromatic hydrocarbons (PAHs). To use this physiological response as a marker of environmental impact, we developed and validated a set of primers to quantify CYP1A expression by qRT-PCR in the brown trout, Salmo trutta. These primers were used to explore the natural variability of CYP1A expression in 8 isolated populations (65 samples) from European remote lakes, in a geographical distribution encompassing the Tyrolean Alps, Pyrenees, Rila, Tatras, and Norwegian and Scottish mountains. CYP1A expression values varied more than 2 orders of magnitude among samples, with strong variations within each population. CYP1A expression values were significantly elevated in Tatras and Pyrenees fish populations, whereas the lowest median values were found in populations from the Tyrolean Alps and Rila. These values correlated with the content of different environmentally relevant pollutants in the sediments of the lakes harboring each fish population, particularly with HCB and 4,4'-DDE contents. To our knowledge, this works represents a first report of a physiological response linked to persistent organic pollutants in fish from mountain lakes. PMID- 17711239 TI - Comment on "Outside-in trimming of humic substances during ozonation in a membrane contactor". PMID- 17711240 TI - New data on malnutrition will help drive campaign. PMID- 17711241 TI - Does workforce size and mix influence patient satisfaction? PMID- 17711242 TI - Healing power of song. AB - A collection of music written more than 100 years ago led to the creation of a singing group for mental health service users and staff. The benefits are tangible. PMID- 17711243 TI - First for health. Interview by Alison Moore. AB - As director of public health for Kent County Council, Meradin Peachey is a nurse in a field where doctors have been dominant. But she has much to offer from her nursing background. PMID- 17711244 TI - Secrets and lies. PMID- 17711245 TI - Do not resuscitate: reflections on an ethical dilemma. AB - This is a reflective account of an ethical dilemma encountered while on placement on a cardiology ward. Reflection is a process which allows practitioners to reveal and expose thoughts, behaviours and feelings that are present at a particular time. All reflective models are based on the principle that purposeful reflection results in a better understanding and awareness, thus enhancing clinical practice (Driscoll and Teh 2001). The Gibbs' Reflective Cycle has been selected for its simplicity and ease of use to aid personal development. The dilemma was identified and analysed from a professional, ethical and legal perspective. Pseudonyms are used to maintain confidentiality and protect the identities of all parties involved. PMID- 17711246 TI - Measuring cholesterol levels. AB - The measurement and management of cholesterol levels are essential to reduce the risk of developing heart disease. Nursing staff play a key role in the detection and treatment of high cholesterol levels and the promotion of good nutritional health. This article focuses on the process of and rationale for cholesterol testing. PMID- 17711247 TI - Diagnosis and management of patients with Clostridium difficile-associated diarrhoea. AB - This article outlines the diagnosis, treatment and nursing management of patients with Clostridium difficile-associated diarrhoea. PMID- 17711248 TI - Reflective practice. PMID- 17711249 TI - The healing personality. PMID- 17711250 TI - Agencies offer choice and variety. PMID- 17711251 TI - All change for best results. PMID- 17711252 TI - Learning to lead. PMID- 17711253 TI - [Hope and disappointment in cancer medicine]. AB - Over the last few years fascinating new diagnostic procedures and innovative therapies with so-called "magic bullets" have been introduced into cancer medicine. However, hope stirred up by the introduction of these methods and therapies has to be rationally evaluated with regard to their success, their implementation in medical care, their compatibility with the patient's preferences and their benefit, also with regard to their high costs. PMID- 17711254 TI - [Is prevention better than healing?]. AB - Preventive and screening interventions have been met with great enthusiasm. This is due to a widespread misunderstanding of what prevention can do and what it cannot do. Initiatives for prevention or early diagnosis of disease are almost always considered beneficial. Meanwhile, however, there are many impressive examples of detrimental failures of such initiatives documented by large high quality randomised controlled trials (RCTs). These include treatment with vitamin pills to prevent cancer or cardiovascular disease or treatment of healthy women with sexual hormones which has finally turned out to be one of the biggest scandals in medicine. Systematic self-examination of the breast to detect breast cancer early does more harm than good. Most dogmas of the modern so-called healthy diet are not supported by several recently published high-quality RCTs. On the other hand, many of the promoted prevention initiatives lack evidence from high-quality RCTs such as health checks, rectal examination, screening for renal disease or diabetes, screening for colorectal cancer by coloscopy, for prostate cancer or skin cancer. Even if effective, most screening programmes will benefit only a few but harm many more, though. Harm is due to overdiagnosis and overtreatment as well as to side effects related to the investigation itself. This includes psychological and other distress related to work-up of false test results. All prevention programmes have to undergo sound scientific evaluation before they can be recommended or implemented. Ethical guidelines ask for complete, objective, unbiased, evidence-based and understandable information for potential participants of prevention programmes. Rarely is such information provided or even available. Non-participation is an explicit option for most preventive programmes and must not be penalised. PMID- 17711255 TI - [Is there any obligation to maintain and promote health?]. AB - The aim of prevention is to protect and maintain health. Several legally enforced preventive measures (e.g., use of safety belts) go undisputed mainly because of a high level of risk perception (of traffic accidents) in the population. On the other hand, obligatory measures for the prevention of chronic disease are mostly perceived as unwanted limitation of individual freedom. Due to demographic changes, pressure for technical innovation and declining revenues chronic disease, however, has become a major problem for solidarity-based health insurance schemes. In this context, new models have recently been proposed in Germany. This paper argues that these are either unpractical (risk surcharges) or directly unfair (increased financial burden on the chronically ill who did not attend free screening). PMID- 17711256 TI - [Placebo effects]. AB - The following article presents a discussion of the widely used terms placebo and placebo effect. Traditional definitions are demonstrated to be insufficient, and a new definition is proposed. The widely cited size of placebo effects is discussed and shown to be questionable, especially due to serious methodological flaws in the underlying studies. We suggest that instead of using the global term placebo effect the concept of specific context-dependent effects should be considered both in practice and research. PMID- 17711257 TI - Evaluation of complementary/alternative medicine. AB - Complementary/alternative medicine (CAM) is hugely popular. At the same time, our knowledge about CAM is woefully insufficient. Therefore it seems important to evaluate CAM and to find answers to the most pressing questions: does it work and is it safe? Despite frequently voiced arguments to the contrary, CAM can be investigated using the scientific method; occasionally standard study designs might require a degree of adaptation but there are no reasons in principle why CAM should defy science. In conclusion, rigorous evaluations of CAM are both feasible and desirable. PMID- 17711258 TI - [Imposing the truth on patients? The benefits and harms of information with the terminally ill]. AB - In this paper arguments for and against the "radical information" of seriously ill patients are confronted. In Germany, following some actual court decisions, a clear tendency favours total information as a logical condition of the so-called "informed consent". It seems indispensable before any radical (not only life threatening) intervention. However, for humanitarian reasons doctors should respect personal conditions and subjective circumstances which could influence both the extent and form of the information provided, not only in crucial situations but also in many everyday situations. Following the paternalistic tradition of Hufeland, informing the patient about the early stage of a deadly illness even seems to be rather cruel in some situations, e.g. with casual or "accidental" diagnoses, when the patient does not perceive any symptoms yet. PMID- 17711259 TI - [Physician-independent quality control of health services]. AB - Currently a physician-independent control of health services can only be managed by means of liability case law. Usually, claims are settled years after the service has been provided, based, though, on medical guidelines that have been established by the medical profession itself at the time of the provision of services. An essential factor in medical quality assurance (QA) is the involvement of the relevant physicians, which should be combined with external controls. Regarding quality in medicine, personal qualification will have to be distinguished from institutional quality and quality of healthcare, which should be ensured by internal and external QA. There is increasing pressure to publish QA results in an institution-related manner. However, the publication of results may lead to the unequal treatment of hospitals, as external QA includes only a limited number of indications (possible misjudgement of overall quality), and refers to different patient populations (no comparable treatment results). However, the publication of such outcome data will prevail in the long-term. The future vision of an external QA system comprises: 1. electronically based patient files and, derived thereof, pseudonymised data sets for QA; 2. IQWiG's participation in the definition of evidence-based indicators for quality assessment as well as the application of these indicators; 3. the full publication of results on an Internet platform. PMID- 17711260 TI - Can drug treatment prevent disease in common practice? AB - To assess whether drug treatment in common practice can prevent disease, we analysed four preventive cardiovascular randomised clinical trials (RCTs), expressing efficacy by 1-year Number Needed to Treat (NNT) in RCT and common practice effectiveness by the Disease Impact Number (DIN) in all subjects at risk and by the Population impact Number (PIN) in the entire population, based on a Swedish population survey. Adjustments were made for non-adherence. Calculations were made of alternative 1-year drug costs and number of years an average general practitioner (GP) would need to work in order to prevent one event using the actual treatment. Secondary prevention of MI by simvastatin (NNT, DIN and adjusted PIN = 37, 93 and 2657; GP work time 2.7 years; drug costs Euro 1020 - 13505), and prevention of stroke by antihypertensive treatment in high-risk subjects (elderly with systolic blood pressure > 160 mm Hg; NNT, DIN and adjusted PIN = 167, 239 and 11950; GP work time 6 years; drug costs Euro 6095 - 51567) appeared medically and economically effective. Primary prevention of MI by pravastatin (NNT, DIN and adjusted PIN 208, 2080 and 24470; GP work time 12.2 years; drug costs Euro 5736 - 117676) or by antihypertensive drug treatment in low-risk subjects (diastolic blood pressure 90-99 mm Hg) (NNT, DIN and adjusted PIN 1667, 3334 and 116982; GP work time 58.5 years; drug costs Euro 60895 - 511718) seemed ineffective and expensive. PMID- 17711261 TI - [Quality improvement potential in the pharmaceutical industry]. AB - The performance of the German pharmaceutical industry, future challenges and obstacles to quality improvement are assessed from a systems-of-innovation perspective, using appropriate innovation indicators. The current close-to-market performance indicators paint an unfavourable picture. Early R&D indicators (e.g., publications, patents), however, reveal a positive trend. A lot of obstacles to quality improvements are identified with respect to knowledge base, knowledge/technology transfer, industrial R&D processes, capital markets, market attractiveness and both regulatory and political framework conditions. On this basis, recommendations will finally be derived to improve quality in the pharmaceutical industry. PMID- 17711262 TI - Better value healthcare--the 21st century agenda. AB - Health services are faced with increasing cost pressure, and cost-effectiveness is playing a growing role in decision-making in health care. The three elements of decision-making are the evidence available, the values of the population served, and the other needs of the population. There are different types of values: those of patients, clinicians, health service managers, payers of healthcare, and industry. The sharp distinction between traditional functions in healthcare, such as "allocative efficiency" and "technical efficiency", is increasingly being broken down. The effect of this new approach is the rise of programme budgeting, with healthcare resources being allocated to different programmes of care (for example, mental health programmes), making the consequences of moving resources much clearer. Best current evidence about effectiveness and cost-effectiveness is of vital importance in clarifying the opportunities that face people who pay for or manage healthcare. PMID- 17711263 TI - [The limits of economic efficiency--medication provision and "border violations" through structures and interests]. AB - Overuse, underuse and misuse is still present in the drug provision for insured people covered by the statutory sickness funds. Beside these findings in drug utilisation characteristics the drug market offers a lot of possibilities to improve the efficiency by a better choice of useful drugs, to avoid drug analogues without additional therapeutic value and to replace expensive 'original products' by generic drugs of equivalent efficacy. But the marketing strategies and the industry dependent and often misleading drug information of the pharmaceutical companies anticipate a more efficient drug choice. Therefore it was more than necessary to establish the Institute for Quality and Efficiency in the German Health Care system to evaluate the value of new or very often prescribed drugs. The coming cost-effectiveness appraisal will help to improve patient-orientated value and efficiency of drug therapy. PMID- 17711265 TI - Ionization of linear alcohols by strong optical fields. AB - We have experimentally probed the strong-field ionization dynamics of gas-phase linear alcohols, methanol, ethanol, and 1-propanol, by irradiating them with intense, femtosecond-duration laser pulses of 800 and 400 nm wavelength. Specifically, we make high resolution measurements of the energies of electrons that are ionized by the action of the optical field. Our electron spectroscopy measurements enable us to bifurcate the dynamics into multiphoton ionization and tunneling ionization regimes. In the case of 800 nm irradiation, such bifurcation into different ionization regimes is reasonably rationalized within the framework of the adiabaticity parameter based on the original Keldysh-Faisal-Reiss model of atomic ionization, without recourse to any structure-dependent modifications to the theory. In that sense, our 800 nm spectroscopy indicates that the linear alcohols exhibit atom-like properties as far as strong field ionization dynamics in the multiphoton ionization and tunneling regimes are concerned. We also explore the limitations of this atom-like picture by making measurements with 400 nm photons wherein the ponderomotive potential experienced by the ionized electrons is much less than the photon energy; effects that are purely molecular then appear to influence the strong field dynamics. PMID- 17711264 TI - [Can rationing be fair? Ethical considerations regarding justice in the healthcare system]. AB - While economy tries to solve the problem of scarcity by rationing, i.e. increasing efficiency, ethics reflect the path of the just distribution of scarce goods, necessarily including the means of transparent and fair rationing. But how can such rationing be realised in a healthcare system? Non-medical criteria such as the patient's social function or age, though vividly discussed, are inappropriate. Only medical criteria can bring sustainable solutions. The QALY and DALY models are such an attempt. Careful reflection of these measures of quality of life and, in some aspects, accompanying rules to avoid extreme unfairness will be critical to their success. PMID- 17711266 TI - Photophysics of 1-azacarbazole dimers: a reappraisal. AB - A systematic study of 1-azacarbazole (1AZC) dissolved in 2-methylbutane (2MB) at gradually decreasing temperatures from room temperature to 77 K revealed the chromophore to exhibit four fluorescence emissions: a structured fluorescence in the UV region that is due to the 1-azacarbazole monomer, a structureless emission centered at 500 nm and assigned to the centrosymmetric dimer formed by double hydrogen bonding, an also structureless emission centered at ca. 400 nm and due to a noncentrosymmetric doubly hydrogen bonded dimer, and a fourth, structured emission at 357 and 375 nm due to a card-pack dimer. Evidence obtained from dilute solutions of 1-azacarbazole is for the first time assigned to a card-pack dimer, consistent with the photophysical behavior of carbazole in the same medium. Previously established photophysical evidence for such an interesting compound, which has been used as a model for studying light-induced double proton transfer mutational mechanisms, is completed or discussed here. The evidence obtained in this work reveals that 1AZC at a 10-4 M solution in 2MB does not exhibit doubly hydrogen bonded centrosymmetric dimer emission as the temperature decreases from room temperature up to 113 K (with a corresponding exponential increase of the solvent viscosity). At this temperature and below, however, the doubly hydrogen bonded centrosymmetric dimer emission appears. This evidence and others implemented in this work contradict the assumption of Waluk et al. that the appearance of the doubly hydrogen bonded centrosymmetric dimer is hindered by an increased viscosity of the medium. PMID- 17711267 TI - The formation of naphthalene, azulene, and fulvalene from cyclic C5 species in combustion: an ab initio/RRKM study of 9-H-fulvalenyl (C5H5-C5H4) radical rearrangements. AB - Chemically accurate ab initio Gaussian-3-type calculations of the C(10)H(9) potential energy surface (PES) for rearrangements of the 9-H-fulvalenyl radical C(5)H(5)-C(5)H(4) have been performed to investigate the formation mechanisms of polycyclic aromatic hydrocarbons (PAHs) originated from the recombination of two cyclopentadienyl radicals (c-C(5)H(5)) as well as from the intermolecular addition of cyclopentadienyl to cyclopentadiene (c-C(5)H(6)) under combustion and pyrolytic conditions. Statistical theory calculations have been applied to obtain high-pressure-limit thermal rate constants, followed by solving kinetic equations to evaluate relative product yields. At the high-pressure limit, naphthalene, fulvalene, and azulene have been shown as the reaction products in rearrangements of the 9-H-fulvalenyl radical, with relative yields depending on temperature. At low temperatures (T < 1000 K), naphthalene is predicted to be the major product (>50%), whereas at higher temperatures the naphthalene yield rapidly decreases and the formation of fulvalene becomes dominant. At T > 1500 K, naphthalene and azulene are only minor products accounting for less than 10% of the total yield. The reactions involving cyclopentadienyl radicals and cyclopentadiene have thus been shown to give only a small contribution to the naphthalene production on the C(10)H(9) PES at medium and high combustion temperatures. The high yields of fulvalene at these conditions indicate that cyclopentadienyl radical and cyclopentadiene more likely represent significant sources of cyclopentafused PAHs, which are possible fullerene precursors. Our results agree well with a low temperature cyclopentadiene pyrolysis data, where naphthalene has been identified as the major reaction product together with indene. Azulene has been found to be only a minor product in 9-H-fulvalenyl radical rearrangements, with branching ratios of less than 5% at all studied temperatures. The production of naphthalene at low combustion temperatures (T < 1000 K) is governed by the spiran mechanism originally suggested by Melius et al. At higher temperatures, the alternative C-C bond scission route, which proceeds via the formation of the cis-4 phenylbutadienyl radical, is competitive with the spiran pathway. The contributions of the previously suggested methylene walk pathway to the production of naphthalene have been calculated to be negligible at all studied temperatures. PMID- 17711268 TI - Effect of cation absorption on ionization/dissociation of cycloketone molecules in a femtosecond laser field. AB - The mass spectra of a series of cycloketone molecules, cyclopentanone (CPO), cyclohexanone (CHO), cycloheptanone (CHPO), and cyclooctanone (COO) are measured in a 788 or 394 nm laser field with 90 fs pulse duration and the intensity ranging from 5 x 10(13) W/cm(2) to 2 x 10(14) W/cm(2). At 788 nm, a dominated parent ion peak and some weak peaks from the fragment ions C(n)H(m)+ are observed for CPO and CHO (a ratio P(+)/T(+), the parent ion yield to the total ion yield, is 81.6% and 52.6%, respectively). But the extensive fragment ion peaks are observed with the greatly reduced parent ion peak for CHPO (P(+)/T(+) = 5.5%) and that are even hard to be identified for COO. These observations are interpreted explicitly in the frame of the significant resonant effect of their cation photoabsorption on ionization and dissociation of these molecules. The present work also suggests that a nonadiabatic ionization occurs with a nuclear rearrangement due to the H movement in these molecules during the ionization in an intense femtosecond laser field. PMID- 17711270 TI - Anomeric effects in the symmetrical and asymmetrical structures of triethylamine. Blue-shifts of the C-h stretching vibrations in complexed and protonated triethylamine. AB - Quantum mechanical calculations using density functional theory with the hybrid B3LYP functional and the 6-31++G(d,p) basis set are performed on isolated triethylamine (TEA), its hydrogen-bond complex with phenol, and protonated TEA. The calculations include the optimized geometries and the results of a natural bond orbital (NBO) analysis (occupation of sigma* orbitals, hyperconjugative energies, and atomic charges). The harmonic frequencies of the C-H stretching vibrations of TEA are predicted at the same level of theory. Two stable structures are found for isolated TEA. In the most stable symmetrical structure (TEA-S), the three C-C bond lengths are equal and one of the C-H bond of each of the three CH2 groups is more elongated than the three other ones. In the asymmetrical structure (TEA-AS), one of the C-C bonds and two C-H bonds of two different CH2 groups are more elongated than the other ones. These structures result from the hyperconjugation of the N lone pair to the considered sigma*(C-H) orbitals (TEA-S) or to the sigma*(C-C) and sigma*(C-H) orbitals of the CH2 groups (TEA-AS). The formation of a OH...N hydrogen bond with phenol results in a decrease of the hyperconjugation, a contraction of the C-H bonds, and blue-shifts of 28-33 cm-1 (TEA-S) or 40-48 cm-1 (TEA-AS) of the nus(CH2) vibrations. The nu(CH3) vibrations are found to shift to a lesser extent. Cancellation of the lone pair reorganization in protonated TEA-S and TEA-AS results in large blue shifts of the nu(CH2) vibrations, between 170 and 190 cm-1. Most importantly, in contrast with the blue-shifting hydrogen bonds involving C-H groups, the blue shifts occurring at C-H groups not participating in hydrogen bond formation is mainly due to a reduction of the hyperconjugation and the resulting decrease in the occupation of the corresponding sigma*(C-H) orbitals. A linear correlation is established between the C-H distances and the occupation of the corresponding sigma*(C-H) orbitals in the CH2 groups. PMID- 17711269 TI - DFT study on the nucleophilic addition reaction of water and ammonia to the thymine radical cation. AB - The nucleophilic addition reactions of water and ammonia molecules toward the C5 C6 double bond of thymine radical cations were investigated using density functional theory. We predicted that the nucleophilic addition favored the C5 site of thymine radical cations, in contrast to the previous experimental observations in bulk solution where the addition product to the C6-site was dominant. Considering the molecular orbital factors, we estimated the relative reactivity of the C5- and C6-sites of thymine radical cations for the nucleophilic addition of ammonia. We found that the C5 was more reactive than the C6 for the small-size clusters of Thy1(NH3)n+, n = 0-2, in the gas phase and even in aqueous solution, though the difference in the reactivity between the two sites became smaller as the number of ammonia molecules increased. This variation of the reactivity was attributed to the electron density redistribution within the thymine radical cations induced by the ammonia molecules as a nucleophile. We suggest that the dominance of the C6-addition product in bulk solution is mainly due to the higher stability of the C6-addition product by solvation, rather than to the higher reactivity of the C6-site for the nucleophilic addition. PMID- 17711271 TI - Theoretical investigation on the GaCl3-catalyzed ring-closing metathesis reaction of N-2,3-butadienyl-2-propynyl-1-amine: three-membered ring versus four-membered ring mechanism. AB - The gallium chloride (GaCl(3))-catalyzed ring-closing metathesis reaction mechanism of N-2,3-butadienyl-2-propynyl-1-amine has been studied at the Becke three-parameter hybrid functional combined with Lee-Yang-Parr correlation functional (B3LYP)/6-31G(d), B3LYP/6-31+G(d,p), B3LYP/6-311++G(d,p)//B3LYP/ 6 31G(d) and the second-order Moller-Plesset perturbation (MP2)/6 311++G(d,p)//B3LYP/6-31+G(d,p) levels. It was found that the final metathesis product can be yielded via a three-membered or four-membered ring mechanism. The three-membered ring pathway is favorable due to its low energy barrier at the rate determining step. The whole reaction is stepwise and strongly exothermic. PMID- 17711272 TI - Theoretical study of spectroscopic properties of dimethoxy-p-phenylene-ethynylene oligomers: planarization of the conjugated backbone. AB - The optical spectra of the dimethoxy-p-phenylene-ethynylene oligomers (up to n = 10) are calculated by DFT and TD-DFT methods. It is found that the conformational rotations around the cylindrical triple-bonded carbon links impact significantly the optical spectrum. The effective conjugation length (ECL) of the oligomer is obtained by extrapolating the HOMO-LUMO gap to infinite chain length with an alternative exponential function. The spectral shift is mainly dependent on the high pi-conjugation segment of oligomers, resulting from the planarization of the backbone. Although the rotational barrier is very low, the calculated results further indicate that rotation about the cylindrical triple bond still interrupts the conjugation of rod-like oligomers to some extent, and leads to an angle dependent HOMO-LUMO gap. The results are helpful to interpret the conformational dependent spectroscopic phenomena of p-phenyleneethynylene oligomers and polymers (PPEs) observed in ensemble and single molecule spectroscopy. PMID- 17711273 TI - Theoretical investigation on the electronic and geometric structure of GaN2+ and GaN4+. AB - The electronic and geometric structures of gallium dinitride cation, GaN2+ and gallium tetranitride cation, GaN4+ were systematically studied by employing density functional theory (DFT-B3LYP) and perturbation theory (MP2, MP4) in conjunction with large basis sets, (aug-)cc-pVxZ, x = T, Q. A total of 7 structures for GaN2+ and 24 for GaN4+ were identified, corresponding to minima, transition states, and saddle points. We report geometries and dissociation energies for all the above structures as well as potential energy profiles, potential energy surfaces, and bonding mechanisms for some low-lying electronic states. The calculated dissociation energy (De) of the ground state of GaN2+, X1Sigma+, is 5.6 kcal/mol with respect to Ga+(1S) + N2(X1Sigmag+) and that of the excited state, a3Pi, is 24.8 kcal/mol with respect to Ga+(3P) + N2(X1Sigmag+). The ground state and the first excited minimum of GaN4+ are of 1A1(C2v) and 3B1(C2v) symmetry with corresponding De of 11.0 and 43.7 kcal/mol with respect to Ga+(1S) + 2N2(X1Sigmag+) for X1A1 and Ga+(3P) + 2N2(X1Sigmag+) for 3B1. PMID- 17711274 TI - Amide-silyl ligand exchanges and equilibria among group 4 amide and silyl complexes. AB - M(NMe2)4 (M = Zr, 1a; Hf, 1b) and the silyl anion (SiButPh2)- (2) in Li(THF)2SiButPh2 (2-Li) were found to undergo a ligand exchange to give [M(NMe2)3(SiButPh2)2]- (M = Zr, 3a; Hf, 3b) and [M(NMe2)5]- (M = Zr, 4a; Hf, 4b) in THF. The reaction is reversible, leading to equilibria: 2 1a (or 1b) + 2 2 <- > 3a (or 3b) + 4a (or 4b). In toluene, the reaction of 1a with 2 yields [(Me2N)3Zr(SiButPh2)2]-[Zr(NMe2)5Li2(THF)4]+ (5) as an ionic pair. The silyl anion 2 selectively attacks the -N(SiMe3)2 ligand in (Me2N)3Zr-N(SiMe3)2 (6a) to give 3a and [N(SiMe3)2]- (7) in reversible reaction: 6a + 2 2 <--> 3a + 7. The following equilibria have also been observed and studied: 2M(NMe2)4 (1a; 1b) + [Si(SiMe3)3]- (8) <--> (Me2N)3M-Si(SiMe3)3 (M = Zr, 9a; Hf, 9b) + [M(NMe2)5]- (M = Zr, 4a; Hf, 4b); 6a (or 6b) + 8 <--> 9a (or 9b) + [N(SiMe3)2]- (7). The current study represents rare, direct observations of reversible amide-silyl exchanges and their equilibria. Crystal structures of 5, (Me2N)3Hf-Si(SiMe3)3 (9b), and [Hf(NMe2)4]2 (dimer of 1b), as well as the preparation of (Me2N)3M-N(SiMe3)2 (6a; 6b) are also reported. PMID- 17711275 TI - Characterization of a genuine iron(V)-nitrido species by nuclear resonant vibrational spectroscopy coupled to density functional calculations. AB - The characterization of high-valent iron species is of interest due to their relevance to biological reaction mechanisms. Recently, we have synthesized and characterized an [Fe(V)-nitrido-cyclam-acetato]+ complex, which has been characterized by Mossbauer, magnetic susceptibility data, and XAS spectroscopies combined with DFT calculations (Aliaga-Alcade, N.; DeBeer George, S.; Bill, E.; Wieghardt, K.; Neese, F. Angew. Chem., Int. Ed. 2005, 44, 2908-2912). The results of this study indicated that the [Fe(V)-nitrido-cyclam-acetato]+ complex is an unusual d3 system with a nearly orbitally degenerate S=1/2 ground state. Although the calculations predicted fairly different Fe-N stretching frequencies for the S=1/2 and the competing S=3/2 ground states, a direct experimental determination of this important fingerprint quantity was missing. Here we apply synchrotron based nuclear resonance vibrational scattering (NRVS) to characterize the Fe-N stretching frequency of an Fe(V)-nitrido complex and its Fe(III)-azide precursor. The NRVS data show a new isolated band at 864 cm(-1) in the Fe(V)-nitrido complex that is absent in the precursor. The NRVS spectra are fit and simulated using a DFT approach, and the new feature is unambiguously assigned to a Fe(V)-N stretch. The calculated Fe-N stretching frequency is too high by approximately 75 cm(-1). Anharmonic contributions to the Fe-N stretching frequency have been evaluated and have been found to be small (-5.5 cm(-1)). The NRVS data provided a unique opportunity to obtain this vibrational information, which had eluded characterization by more traditional vibrational spectroscopies. PMID- 17711277 TI - Different dynamics of chiral and racemic (L- and DL-) serine crystals: evidenced by incoherent inelastic neutron and Raman scattering. PMID- 17711276 TI - Terminal gold-oxo complexes. AB - In contradiction to current bonding paradigms, two terminal Au-oxo molecular complexes have been synthesized by reaction of AuCl3 with metal oxide-cluster ligands that model redox-active metal oxide surfaces. Use of K10[alpha2 P2W17O61].20H2O and K2WO4 (forming the [A-PW9O34]9- ligand in situ) produces K15H2[Au(O)(OH2)P2W18O68].25H2O (1); use of K10[P2W20O70(OH2)2].22H2O (3) produces K7H2[Au(O)(OH2)P2W20O70(OH2)2].27H2O (2). Complex 1 crystallizes in orthorhombic Fddd, with a=28.594(4) A, b=31.866(4) A, c=38.241(5) A, V=34844(7) A3, Z=16 (final R=0.0540), and complex 2 crystallizes in hexagonal P6(3)/mmc, with a=16.1730(9) A, b=16.1730(9) A, c=19.7659(15) A, V=4477.4(5) A3, Z=2 (final R=0.0634). The polyanion unit in 1 is disorder-free. Very short (approximately 1.76 A) Au-oxo distances are established by both X-ray and 30 K neutron diffraction studies, and the latter confirms oxo and trans aqua (H2O) ligands on Au. Seven findings clarify that Au and not W is present in the Au-oxo position in 1 and 2. Five lines of evidence are consistent with the presence of d8 Au(III) centers that are stabilized by the flanking polytungstate ligands in both 1 and 2: redox titrations, electrochemical measurements, 17 K optical spectra, Au L2 edge X-ray absorption spectroscopy, and Au-oxo bond distances. Variable temperature magnetic susceptibility data for crystalline 1 and 2 establish that both solids are diamagnetic, and 31P and 17O NMR spectroscopy confirm that both remain diamagnetic in solution. Both complexes have been further characterized by FT-IR, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and other techniques. PMID- 17711278 TI - Enantioselective [3+2]-cycloadditions catalyzed by a protected, multifunctional phosphine-containing alpha-amino acid. PMID- 17711279 TI - Formation of a nickel-methyl species in methyl-coenzyme m reductase, an enzyme catalyzing methane formation. PMID- 17711280 TI - Regulating gene expression in zebrafish embryos using light-activated, negatively charged peptide nucleic acids. PMID- 17711281 TI - Detection of picomole amounts of biological substrates by para-hydrogen-enhanced NMR methods in conjunction with a suitable receptor complex. PMID- 17711282 TI - Redox-mediated negative differential resistance behavior from metalloproteins connected through carbon nanotube nanogap electrodes. PMID- 17711283 TI - Biochemical and spectroscopic studies of the electronic structure and reactivity of a methyl-Ni species formed on methyl-coenzyme M reductase. PMID- 17711284 TI - Octamethyl-octaundecylcyclo[8]pyrrole: a promising sulfate anion extractant. PMID- 17711285 TI - NMR-detection of Cu(III) intermediates in substitution reactions of alkyl halides with Gilman cuprates. PMID- 17711286 TI - Fully synthetic carbohydrate HIV antigens designed on the logic of the 2G12 antibody. PMID- 17711287 TI - Palladium-catalyzed [4+3] intramolecular cycloaddition of alkylidenecyclopropanes and dienes. PMID- 17711288 TI - Highly enantioselective Michael additions in water catalyzed by a PS-supported pyrrolidine. AB - The development of a highly efficient, polymer-supported organocatalyst for the Michael addition of ketones to nitroolefins is described. A 1,2,3-triazole ring, constructed through a click 1,3-cycloaddition, plays the double role of grafting the chiral pyrrolidine monomer onto the polystyrene backbone and of providing a structural element, complementary to pyrrolidine, key to high catalytic activity and enantioselectivity. Optimal operation in water and full recyclability make the triazole linker attractive for the immobilization of organocatalysts. PMID- 17711289 TI - First asymmetric synthesis of trans-3,4-dimethyl-4-arylpiperidines. AB - The first asymmetric synthesis of the trans-3,4-dimethyl-4-arylpiperidine opioid antagonist scaffold is reported. C-3 stereochemistry was established via CBS reduction and stereoselective anti-SN2' cuprate displacement of the derived allylic phosphonate. The resultant vinyl bromide was then elaborated to the target compound by Suzuki coupling and trans-selective 4-methylation. Extension of this methodology should allow general enantioselective access to highly substituted piperidine ring systems. PMID- 17711290 TI - Synthesis of pyridazine-based scaffolds as alpha-helix mimetics. AB - The synthesis of several amphiphilic, nonpeptidic scaffolds that mimic the presentation of i, i + 3 or i + 4, and i + 7 residues of a peptide alpha-helix is described. The approach uses a pyridazine core, and the synthesis involves only a few steps and minimizes the number of C-C bond-forming reactions. The versatility of the synthesis makes it suitable for the preparation of small libraries of low molecular weight alpha-helix mimetics that could be targeted to certain protein/protein interactions. PMID- 17711292 TI - N-(2-Nitrophenyl)proline: an intramolecular hydrogen bond forming reagent for the determination of the absolute configuration of primary amines. AB - N-(2-Nitrophenyl)proline (2-NPP) amides of primary amines have a conformational preference for intramolecular hydrogen bonding. Because of the strong and selective anisotropic effects on the amine substituents, the absolute configuration of alpha-chiral primary amines can be assigned by comparing the 1H chemical shifts of diastereomeric 2-NPP amides. PMID- 17711291 TI - Substitution and cyclization reactions involving the quasi-antiaromatic 2H-indol 2-one ring system. AB - The quasi-antiaromatic 2H-indol-2-one ring system is readily generated by treating a 3-hydroxy-substituted 1,3-dihydroindol-2-one with a Lewis acid. Stepwise addition of various pi-nucleophiles to the highly reactive 2H-indol-2 one system occurs smoothly to afford substituted oxindoles. The cyclization was also carried out in an intramolecular fashion to give spiro-substituted oxindoles in good yield. PMID- 17711293 TI - Mammillarinin: a new malonylated betacyanin from fruits of Mammillaria. AB - A new betacyanin endogenously occurring in fruits of nine Mammillaria species, i.e., M. roseo-alba (Boedecker), M. donatii (Berge), M. coronata (Scheidweiler), M. karwinskiana (Martius), M. gummifera (Engelmann), M. infernillensis (Craig), M. centricirrha (Lemaire), M. krameri (Muehlenpfordt), and M. magnimamma (Haworth), was studied by means of spectroscopic techniques. The betacyanin was identified as betanidin 5-O-(6'-O-malonyl)-beta-sophoroside for which the trivial name mammillarinin is proposed. In some Mammillaria species this compound was reported as a dominating pig-ment. Except for its epimer, two other isomers of mammillarinin were tentatively identified as betanidin/isobetanidin 5-O-(4'-O malonyl)-beta-sophoroside present in the fruits as acyl migration products. PMID- 17711294 TI - Enhanced vanillin production from recombinant E. coli using NTG mutagenesis and adsorbent resin. AB - Vanillin production was tested with different concentrations of added ferulic acid in E. coli harboring plasmid pTAHEF containing fcs (feruloyl-CoA synthase) and ech (enoyl-CoA hydratase/aldolase) genes cloned from Amycolatopsis sp. strain HR104. The maximum production of vanillin from E. coli DH5alpha harboring pTAHEF was found to be 1.0 g/L at 2.0 g/L of ferulic acid for 48 h of culture. To improve the vanillin production by reducing its toxicity, two approaches were followed: (1) generation of vanillin-resistant mutant of NTG-VR1 through NTG mutagenesis and (2) removal of toxic vanillin from the medium by XAD-2 resin absorption. The vanillin production of NTG-VR1 increased to three times at 5 g/L of ferulic acid when compared with its wild-type strain. When 50% (w/v) of XAD-2 resin was employed in culture with 10 g/L of ferulic acid, the vanillin production of NTG-VR1 was 2.9 g/L, which was 2-fold higher than that obtained with no use of the resin. PMID- 17711295 TI - Pretreatment of mass spectral profiles: application to proteomic data. AB - Mass spectral profiles are influenced by several factors that have no relation to compositional differences between samples: baseline effects, shifts in mass-to charge ratio (m/z) (synchronization/alignment problem), structured noise (heteroscedasticity), and, differences in signal intensities (normalization problem). Different procedures for pretreatment of whole mass spectral profiles described by almost 50,000 m/z values are investigated in order to find optimal approaches with respect to revealing the information content in the data. In order to quantitatively assess the impact of different procedures for pretreatment of mass spectral profiles, we use factorial designs with the ratio between intergroup and intragroup (replicate) variance as response. We have examined the influence of smoothing, binning, alignment/synchronization, noise pattern, and normalization on data interpretation. Our analysis shows that the spectral profiles have to be corrected for heteroscedastic noise prior to normalization. An nth root transform, where n is a small, positive integer, is used to create a homoscedastic noise structure without destroying the linear correlation structures describing individual components when using whole mass spectral profiles. The choice of n is decided by a simple graphic procedure using replicate information. Log transform is shown to change the heteroscedastic noise structure from being dominant in high-intensity regions, to produce the largest noise in the low-intensity regions. In addition, log transform has a negative effect on the collinearity in the profiles. Factorial designs reveal strong interactions between several of the pretreatment steps, e.g., noise structure and normalization. This underlines the limited usability of looking at the different pretreatment steps in isolation. Binning turns out to be able to substitute smoothing of spectra by, for example, moving average or Savitsky-Golay, while, at the same time, reducing the data point description of the profiles by 1 order of magnitude. Thus, if the sampling density is high, binning seems to be an attractive option for data reduction without the risk of losing information accompanying the integration of profiles into peaks. In the absence of smoothing, binning should be executed prior to alignment. If binning is not performed, the order of pretreatment should be smoothing, alignment, nth root transform, and normalization. PMID- 17711296 TI - Grafting of ion-imprinted polymers on the surface of silica gel particles through covalently surface-bound initiators: a selective sorbent for uranyl ion. AB - A new ion imprinted polymer coated silica gel sorbent has been prepared using the radical "grafting from" polymerization method through surface-bound azo initiators for selective uranyl uptake. The introduction of azo initiator onto the silica surface was achieved by the reaction of surface amino groups with 4,4' azobis(4-cyanopentanoic acid chloride). The grafting step was then carried out in a stirred solution of initiator-modified silica particles in the presence of uranyl ion and functional and cross-linking monomers. The prepared sorbent was characterized using FT-IR spectroscopy, scanning electron microscopy (SEM), elemental analysis (EA), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and BET adsorption isotherm analysis. The influence of the uranyl concentration, pH, and flow rate of solution on the grafted polymer affinity has been investigated. Maximum uptake of uranyl ion was observed at a pH 3.0. The rebinding behavior of the sorbent has been successfully described by the Langmuir-Freundlich isotherm. The dynamic column capacity of sorbent and enrichment factor for uranyl ion were 52.9 +/- 3.4 micromol g(-1) and 52, respectively. It was found that imprinting results in increased affinity of the sorbent toward uranyl ion over strong competitor metal ions such as Fe(III) and Th(IV). The sorbent was repeatedly used and regenerated for 3 months without any significant decrease in polymer binding affinities. Finally the sorbent was applied to the preconcentration and determination of uranyl ion in real water samples. PMID- 17711297 TI - Surface-enhanced Raman signatures of pigmentation of cyanobacteria from within geological samples in a spectroscopic-microfluidic flow cell. AB - A simple surface-enhanced Raman spectroscopy (SERS) microflow cell was developed to investigate distributions of scytonemin pigment within cyanobacteria from samples of rock collected from an arctic desert that contained endolithic cyanobacteria. The assay, which has future potential use in a variety of applications, including astrobiology and analysis of microorganisms in remote environments, involved studying SERS spectra of bacteria from within geological samples. By using a dispersed colloidal substrate in the microfluidic device, surface enhancement of the order >10(5) was obtained for the determination of the pigment in the microorganisms when compared to the native Raman spectra. The SERS assay, which had a nM sensitivity for scytonemin, showed that the concentration of pigment was highest in samples that had experienced the highest stress environments, as a result of high doses of UV irradiation. PMID- 17711299 TI - Label-free single-nucleotide polymorphism detection using a cationic tetrahedralfluorene and silica nanoparticles. AB - We developed a simple method that is able to provide label-free sequence-specific DNA detection with single-nucleotide polymorphism (SNP) detection selectivity. This method makes use of both DNA probe immobilized silica nanoparticles and optically amplifying light harvesting molecules. The recognition is accomplished by sequence-specific hybridization between the DNA probes on the silica nanoparticles and the targets of interest. After subsequent treatment with ethidium bromide (EB), a cationic tetrahedralfluorene was added to electrostatically associate with the DNA molecules on the nanoparticle surface, leading to sensitized EB emission via fluorescence resonance energy transfer (FRET). Because of the selective response of the tetrahedralfluorene to intercalated EB, the perfectly matched DNA targets were distinctively differentiated from those with mutations. The presence of tetrahedralfluorene provides improved detection sensitivity and selectivity, as compared to the use of EB alone as a signal reporter. The demonstrated highly selective label-free detection method laid the ground work for the future development of disposable and real-time testing kits in SNP screenings. PMID- 17711298 TI - Kinetic modulation of pulsed chronopotentiometric polymeric membrane ion sensors by polyelectrolyte multilayers. AB - Polymeric membrane ion-selective electrodes are normally interrogated by zero current potentiometry, and their selectivity is understood to be primarily dependent on an extraction/ion-exchange equilibrium between the aqueous sample and polymeric membrane. If concentration gradients in the contacting diffusion layers are insubstantial, the membrane response is thought to be rather independent of kinetic processes such as surface blocking effects. In this work, the surface of calcium-selective polymeric ion-selective electrodes is coated with polyelectrolyte multilayers as evidenced by zeta potential measurements, atomic force microscopy, and electrochemical impedance spectroscopy. Indeed, such multilayers have no effect on their potentiometric response if the membranes are formulated in a traditional manner, containing a lipophilic ion exchanger and a calcium-selective ionophore. However, drastic changes in the potential response are observed if the membranes are operated in a recently introduced kinetic mode using pulsed chronopotentiometry. The results suggest that the assembled nanostructured multilayers drastically alter the kinetics of ion transport to the sensing membrane, making use of the effect that polyelectrolyte multilayers have different permeabilities toward ions with different valences. The results have implications to the design of chemically selective ion sensors since surface localized kinetic limitations can now be used as an additional dimension to tune the operational ion selectivity. PMID- 17711300 TI - Intrinsic fluorescence reports a global conformational change in the N-lobe of human serum transferrin following iron release. AB - Transferrins have been extensively studied in order to understand how they reversibly bind and release iron. Human serum transferrin (hTF) is a single polypeptide chain that folds into two lobes (N- and C-lobe); each lobe binds a single ferric ion. Iron release induces a large conformational change in each lobe. At the putative endosomal pH of 5.6, measurement of the increase in intrinsic fluorescence upon iron release from the recombinant N-lobe yields two rate constants: 8.9 min-1 and 1.3 min-1. Direct monitoring of iron release from the N-lobe at pH 5.6 (by the decrease in absorbance at 470 nm) gives a single rate constant of 9.1 min-1, definitively establishing that the faster rate constant in the fluorescent studies is due to iron release. To further elucidate the molecular basis of the intrinsic fluorescence change (and the source of the slower rate constant), we examined the contributions of the three individual tryptophan residues in the N-lobe (Trp8, Trp128, and Trp264). Three double mutants, each containing the single remaining tryptophan residue, were produced. In the iron-bound N-lobe, Trp128 and Trp264 are quenched by iron and account for almost the entire fluorescent signal when iron is released. As for the wild-type N-lobe, the fluorescence increase for each of these mutants is best fit by a double-exponential function indicating two processes. Trp8 is severely quenched under all conditions, making virtually no contribution to the signal. Additionally, a mutant lacking all three Trp residues allows assignment of the fluorescent signal completely to the three tryptophan residues and observation of the presence of one (or more) tyrosinates in the N-lobe that have physiological significance in the uptake of iron. PMID- 17711301 TI - Thermodynamics of Ni2+, Cu2+, and Zn2+ binding to the urease metallochaperone UreE. AB - The two Ni2+ ions in the urease active site are delivered by the metallochaperone UreE, whose metal binding properties are central to the assembly of this metallocenter. Isothermal titration calorimetry (ITC) has been used to quantify the stoichiometry, affinity, and thermodynamics of Ni2+, Cu2+, and Zn2+ binding to the well-studied C-terminal truncated H144*UreE from Klebsiella aerogenes, Ni2+ binding to the wild-type K. aerogenes UreE protein, and Ni2+ and Zn2+ binding to the wild-type UreE protein from Bacillus pasteurii. The stoichiometries and affinities obtained by ITC are in good agreement with previous equilibrium dialysis results, after differences in pH and buffer competition are considered, but the concentration of H144*UreE was found to have a significant effect on metal binding stoichiometry. While two metal ions bind to the H144*UreE dimer at concentrations <10 microM, three Ni2+ or Cu2+ ions bind to 25 microM dimeric protein with ITC data indicating sequential formation of Ni/Cu(H144*UreE)4 and then (Ni/Cu)2(H144*UreE)4, or Ni/Cu(H144*UreE)2, followed by the binding of four additional metal ions per tetramer, or two per dimer. The thermodynamics indicate that the latter two metal ions bind at sites corresponding to the two binding sites observed at lower protein concentrations. Ni2+ binding to UreE from K. aerogenes is an enthalpically favored process but an entropically driven process for the B. pasteurii protein, indicating chemically different Ni2+ coordination to the two proteins. A relatively small negative value of DeltaCp is associated with Ni2+ and Cu2+ binding to H144*UreE at low protein concentrations, consistent with binding to surface sites and small changes in the protein structure. PMID- 17711302 TI - LCAT can rescue the abnormal phenotype produced by the natural ApoA-I mutations (Leu141Arg)Pisa and (Leu159Arg)FIN. AB - To explain the etiology and find a mode of therapy of genetically determined low levels of high-density lipoprotein (HDL), we have generated recombinant adenoviruses expressing apolipoprotein A-I (apoA-I)(Leu141Arg)Pisa and apoA I(Leu159Arg)FIN and studied their properties in vitro and in vivo. Both mutants were secreted efficiently from cells but had diminished capacity to activate lecithin/cholesterol acyltransferase (LCAT) in vitro. Adenovirus-mediated gene transfer of either of the two mutants in apoA-I-deficient (apoA-I-/-) mice resulted in greatly decreased total plasma cholesterol, apoA-I, and HDL cholesterol levels. The treatment also decreased the cholesteryl ester to total cholesterol ratio (CE/TC), caused accumulation of prebeta1-HDL and small size alpha4-HDL particles, and generated only few spherical HDL particles, as compared to mice expressing wild-type (WT) apoA-I. Simultaneous treatment of the mice with adenoviruses expressing either of the two mutants and human LCAT normalized the plasma apoA-I, HDL cholesterol levels, and the CE/TC ratio, restored normal prebeta- and alpha-HDL subpopulations, and generated spherical HDL. The study establishes that apoA-I(Leu141Arg)Pisa and apoA-I(Leu159Arg)FIN inhibit an early step in the biogenesis of HDL due to inefficient esterification of the cholesterol of the prebeta1-HDL particles by the endogenous LCAT. Both defects can be corrected by treatment with LCAT. PMID- 17711303 TI - N-Glycosylation of the human kappa opioid receptor enhances its stability but slows its trafficking along the biosynthesis pathway. AB - We examined glycosylation of FLAG-hKOR expressed in CHO cells and determined its functional significance. FLAG-hKOR was resolved as a broad and diffuse 55-kDa band and a less diffuse 45-kDa band by immunoblotting, indicating that the receptor is glycosylated. Endoglycosidase H cleaved the 45-kDa band to approximately 38 kDa but did not change the 55-kDa band, demonstrating that the 45-kDa band is N-glycosylated with high-mannose or hybrid-type glycan. Peptide-N glycosidase F digestion of solubilized hKOR or incubation of cells with tunicamycin resulted in two species of 43 and 38 kDa, suggesting that the 43-kDa band is O-glycosylated. FLAG-hKOR was reduced to lower Mr bands by neuraminidase and O-glycosidase, indicating that the hKOR contains O-linked glycan. Mutation of Asn25 or Asn39 to Gln in the N-terminal domain reduced the Mr by approximately 5 kDa, indicating that both residues were glycosylated. The double mutant hKOR N25/39Q was resolved as a 43-kDa (mature form) and a 38-kDa (intermediate form) band. When transiently expressed, hKOR-N25/39Q had a lower expression level than the wild type. In CHO cells stably expressing the hKOR-N25/39Q, pulse-chase experiments revealed that the turnover rate constants (ke) of the intermediate and mature forms were approximately 3 times those of the wild type. In addition, the maturation rate constant (ka) of the 43-kDa form of hKOR-N25/39Q was 6 times that of the mature form of the wild type. The hKOR-N25/39Q mutant showed increased agonist-induced receptor phosphorylation, desensitization, internalization, and downregulation, without changing ligand binding affinity or receptor-G protein coupling. Thus, N-glycosylation of the hKOR plays important roles in stability and trafficking along the biosynthesis pathway of the receptor protein as well as agonist-induced receptor regulation. PMID- 17711304 TI - Characterization of the interaction of two peptides from the N terminus of the NHR domain of HIV-1 gp41 with phospholipid membranes. AB - The HIV-1 gp41 envelope glycoprotein is responsible for the membrane fusion between the virus and the target cell. According to recent models, the N-terminal coiled-coil (NHR) region of gp41 is involved in forming the interfaces between neighboring helices in the six-helix bundle, as well as in membrane binding and perturbation. In order to get new insights into the viral membrane fusion mechanism, two peptides, pFP15 and pFP23, pertaining to the first part of the gp41 NHR domain were studied regarding their structure and their ability to induce membrane leakage, aggregation, and fusion, as well as their affinity toward specific phospholipids by a variety of spectroscopic methods. Our results demonstrate that the first part of the NHR domain interacts with negatively charged phospholipid-containing model membranes, modifies the phase behavior of membrane phospholipids, and induces leakage and aggregation of liposomes, suggesting that it could be involved directly in the merging of the viral and target cell membranes working synergistically with other membrane-active regions of the gp41 glycoprotein to boost the fusion process. On the other hand, we suggest that this region of the NHR domain could be involved in the first steps of the destabilization of the HIV-1 gp41 six-helix bundle after its interaction with negatively charged phospholipid headgroups. PMID- 17711305 TI - Identification of a denitrase activity against calmodulin in activated macrophages using high-field liquid chromatography--FTICR mass spectrometry. AB - We have identified a denitrase activity in macrophages that is upregulated following macrophage activation, which is shown by mass spectrometry to recognize nitrotyrosines in the calcium signaling protein calmodulin (CaM). The denitrase activity converts nitrotyrosines to their native tyrosine structure without the formation of any aminotyrosine. Comparable extents of methionine sulfoxide reduction are also observed that are catalyzed by endogenous methionine sulfoxide reductases. Competing with repair processes, oxidized CaM is a substrate for a peptidase activity that results in the selective cleavage of the C-terminal lysine (i.e., Lys148) that is expected to diminish CaM function. Thus, competing repair and peptidase activities define the abundances and functionality of CaM in modulating cellular metabolism in response to oxidative stress, where the presence of the truncated CaM species provides a useful biomarker for the transient appearance of oxidized CaM. PMID- 17711306 TI - Structural responses to cavity-creating mutations in an integral membrane protein. AB - X-ray crystallography has been used to investigate the extent of structural changes in mutants of the purple bacterial reaction center that assemble without a particular ubiquinone or bacteriopheophytin cofactor. In the case of the bacteriopheophytin-exclusion mutant, in which Ala M149 was replaced by Trp (AM149W), the quality of protein crystals was improved over that seen in previous work by minimizing illumination, time, and temperature during the purification protocol and carrying out crystal growth at 4 degrees C after overnight incubation at 18 degrees C. The X-ray crystal structure of the AM149W mutant, determined to a resolution of 2.2 A, showed very little change in protein structure despite the absence of the bacteriopheophytin cofactor. Changes in the electron density map in the region of the cofactor binding site could be accounted for by changes in the conformation of the phytol side chains of adjacent cofactors and the presence of a buried water molecule. Residues lining the vacated binding pocket did not show any significant changes in conformation or increases in disorder as assessed through crystallographic atomic displacement parameters (B-factors). The X-ray crystal structure of a reaction center lacking the primary acceptor ubiquinone through mutation of Ala M248 to Trp (AM248W) was also determined, to a resolution of 2.8 A. Again, despite the absence of an internal cofactor only very minor changes in protein structure were observed. This is in contrast to a previous report on a reaction center lacking this ubiquinone through mutation of Ala M260 to Trp (AM260W) where more extensive changes in structure were apparent. All three mutant reaction centers showed a decrease in thermal stability when housed in the native membrane, but this decrease was smaller for the AM260W mutant than the AM248W complex, possibly due to beneficial effects of the observed changes in protein structure. The lack of major changes in protein structure despite the absence of large internal cofactors is discussed in terms of protein rigidity, the protective influence of the adaptable membrane environment, and the role of small molecules and ions as packing material in the internal cavities created by this type of mutation. PMID- 17711307 TI - Kinetic and structural analysis of mutant Escherichia coli dihydroorotases: a flexible loop stabilizes the transition state. AB - Dihydroorotase (DHOase) catalyzes the reversible cyclization of N-carbamyl-l aspartate (CA-asp) to l-dihydroorotate (DHO) in the de novo biosynthesis of pyrimidine nucleotides. Two different conformations of the surface loop (residues 105-115) were found in the dimeric Escherichia coli DHOase crystallized in the presence of DHO (PDB code 1XGE). The loop asymmetry reflected that of the active site contents of the two subunits: the product, DHO, was bound in the active site of one subunit and the substrate, CA-asp, in the active site of the other. In the substrate- (CA-asp-) bound subunit, the surface loop reaches in toward the active site and makes hydrogen bonds with the bound CA-asp via two threonine residues (Thr109 and Thr110), whereas the loop forms part of the surface of the protein in the product- (DHO-) bound subunit. To investigate the relationship between the structural states of this loop and the catalytic mechanism of the enzyme, a series of mutant DHOases including deletion of the flexible loop were generated and characterized kinetically and structurally. Disruption of the hydrogen bonds between the surface loop and the substrate results in significant loss of catalytic activity. Furthermore, structures of these mutants with low catalytic activity have no interpretable electron density for parts of the flexible loop. The structure of the mutant (Delta107-116), in which the flexible loop is deleted, shows only small differences in positions of other substrate binding residues and in the binuclear zinc center compared with the native structure, yet the enzyme has negligible activity. The kinetic and structural analyses suggest that Thr109 and Thr110 in the flexible loop provide productive binding of substrate and stabilize the transition-state intermediate, thereby increasing catalytic activity. PMID- 17711309 TI - Nonspecific protein adsorption at the single molecule level studied by atomic force microscopy. AB - Liquid tapping atomic force microscopy was used to study the nonspecific adsorption of horse spleen ferritin at a bare gold surface at single molecule resolution. The majority of ferritin molecules adsorbed irreversible on gold surfaces in accordance with the random sequential adsorption (RSA) mechanism frequently used to describe irreversible adsorption processes. However, the time resolved data also reveal events that go beyond the RSA model, i.e., lateral mobility and fragility of some molecules, resulting in desorption, chain formation, and subunit dissociation. Scanning effects of the AFM tip were observed, resulting in diminished protein coverage in the scanned area. PMID- 17711308 TI - Insight into the GTPase activity of tubulin from complexes with stathmin-like domains. AB - Microtubules are dynamically unstable tubulin polymers that interconvert stochastically between growing and shrinking states, a property central to their cellular functions. Following its incorporation in microtubules, tubulin hydrolyzes one GTP molecule. Microtubule dynamic instability depends on GTP hydrolysis so that this activity is crucial to the regulation of microtubule assembly. Tubulin also has a much lower GTPase activity in solution. We have used ternary complexes made of two tubulin molecules and one stathmin-like domain to investigate the mechanism of the tubulin GTPase activity in solution. We show that whereas stathmin-like domains and colchicine enhance this activity, it is inhibited by vinblastine and by the N-terminal part of stathmin-like domains. Taken together with the structures of the tubulin-colchicine-stathmin-like domain vinblastine complex and of microtubules, our results lead to the conclusions that the tubulin-colchicine GTPase activity in solution is caused by tubulin-tubulin associations and that the residues involved in catalysis comprise the beta tubulin GTP binding site and alpha tubulin residues that participate in intermolecular interactions in protofilaments. This site resembles the one that has been proposed to give rise to GTP hydrolysis in microtubules. The widely different hydrolysis rates in these two sites result at least in part from the curved and straight tubulin assemblies in solution and in microtubules, respectively. PMID- 17711310 TI - Molecular dynamics of a biodegradable biomimetic ionomer studied by broadband dielectric spectroscopy. AB - Broadband dielectric spectroscopy was used to investigate the bulk molecular dynamics of a recently developed biodegradable biomimetic ionomer potentially useful for biomedical applications. Isothermal dielectric spectra were gathered for a phosphoryl choline (PC)-functionalized poly(trimethylene carbonate) (PTMC) ionomer and unfunctionalized PTMC at temperatures ranging from 2 to 60 degrees C over a broad frequency range of 10(-3) to 10(6) Hz. Four relaxations were clearly identified, two of which were shown to stem from the PTMC polymer backbone. A detailed analysis showed that the formation of zwitterionic aggregates was responsible for the material's bulk functionality and that bulk conduction processes may provide useful information for assessing the PC ionomer as a candidate for drug delivery applications. Finally, it was concluded that absorbed water concentrates around the aggregates, resulting in an increased mobility of the PC end-groups. PMID- 17711311 TI - Intermolecular packing of sugar-based surfactant and phenol in a micellar phase. AB - Surfactants have been used to enhance the removal of phenol from aqueous system; therefore, the interaction between surfactants and phenol is important for selection of the surfactant and understanding the process. In this work, sugar based surfactant, n-dodecyl-beta-D-maltoside (DM), was utilized to separate phenol from aqueous solution using ultrafiltration. 2-D NMR and Cryo-TEM techniques were employed to obtain information on the orientation of phenol molecules in the micellar phase and the shape transition of the micelles. The flux was found to decrease linearly with the solute concentration and the equilibrium constant was found to be constant. 2-D NMR spectra have shown that phenol molecules reside in the palisade layer of the DM micelles with the benzene ring interacting with the hydrocarbon chain of DM molecules, especially the first methylene group. Cryo-TEM results have shown the shape transition from spherical to worm-like due to the presence of phenol. The results will help understand the interaction between surfactants and phenol and the select the optimum surfactant reagents and operational conditions for micellar enhanced ultrafiltration process. PMID- 17711312 TI - A computational study of the hydrodynamically assisted organization of DNA functionalized colloids in 2D. AB - We study computationally the self-organization of DNA-functionalized colloidal particles confined to two dimensions and subjected to a linear shear force. We show that hydrodynamic forces allow a more thorough sampling of phase space than thermal or Brownian forces alone. Two particle types are present in each of our dynamic simulations each signifying its own specific oligonucleotide sequence grafted to the particle surface: A-type and B-type. Particles are modeled as interacting via a type-specific DNA attraction where unlike-types have affinities for each other while like-types do not. The particles are small enough to feel Brownian motion while the shear adds motion to the particles. We find the formation of lines of A-type and B-type particles in simulations with an imposed shear. Simulations without imposed shear form a frustrated network with little or no linear order. An orientational distribution function, g2(r), quantifies the degree of linear order. A phase diagram is constructed, finding a linear dependence of the minimum DNA force necessary for line formation on the dimensionless shear rate. A force analysis performed on the structures shows that the lines orient perpendicular to the axis of the elongation component of the shear because it is this orientation that allows the DNA attraction to resist the shear. PMID- 17711314 TI - Double plasma treatment-induced graft polymerization of carbohydrated monomers on poly(ethylene terephthalate) fibers. AB - This study deals with the grafting of carbohydrate monomers on poly(ethylene terephthalate) fibers by double argon plasma treatment. Two monomers were used: allyl alpha-D-galactopyranoside and 2-methacryloxyethyl glucoside. The quantity of grafted carbohydrates was determined by phenol/sulfuric acid colorimetric titration. The graft density was observed to vary according to the monomer used. Allyl alpha-D-galactopyranoside yields to smaller graft densities compared to 2 methacryloxyethyl glucoside, suggesting transfer reactions occurring at the surface with allyl alpha-D-galactopyranoside. Fibers with the highest graft levels were obtained with the higher monomer concentration and the lower quantity of fiber treated in a plasma reactor. The grafting density can be modulated by the monomer concentration and mass of fiber exposed in the plasma reactor. For 0.5 mg of fibers, the graft densities for 23 and 68 mM allyl alpha-D galactopyranoside are, respectively, 18 and 35 nmol/cm2. For 0.5 mg of fibers, the graft densities for 19 and 38 mM 2-methacryloxyethyl glucoside are, respectively, 150 and 250 nmol/cm2. Comparative study without the preactivation treatment shows the efficiency of the preactivation: for a mass of fiber of 0.5 mg and a 2-methacryloxyethyl glucoside concentration of 38 mM, the grafting density without plasma pretreatment is 38 nmol/cm2. Attenuated total reflectance Fourier transform infrared spectra confirmed the anchoring of the glycopolymer onto the poly(ethylene terephthalate) surfaces. Atomic force microscopy and scanning electronic microscopy pictures indicated their morphological changes. PMID- 17711313 TI - Adsorption kinetics of carcinogens to DNA liquid crystalline gel beads. AB - Adsorption behaviors of acridine orange (AO) and biphenyl (BP) to DNA liquid crystalline gel (LCG) beads in aqueous dispersing solution have been studied theoretically and experimentally. A theoretical consideration based on nonequilibrium thermodynamics predicted that the time course of the adsorption process is expressed with a scaled equation, and a scaled number of adsorbed carcinogen molecules n is expressed with the square root of a scaled immersion time t, n proportional, variant square root t at early stage, whereas it is expressed with a power law function 1 - n proportional, variant (te - t)3/2 for n0 > 1 and an exponential equation n0 - n proportional, variant e-t/alpha tau0 for n0 > 1 at later stages of adsorption. Here, n0 is the ratio of the initial number of carcinogen molecules in the dispersing solution to the number of the sites of adsorption of carcinogen molecules in the beads, te is the scaled equilibrium time of adsorption, tau0 is a time constant for adsorption, and alpha is a constant. Observed adsorption processes for AO were well expressed by the predicted ones, and the fitting parameters n0 and tau0 increased with increasing cobalt chloride concentration CCo used for preparation of the beads, and both saturated above CCo > or = 400 mM for the adsorption of AO, whereas the adsorption processes for BP were expressed with the square root function. These results indicate that (1) the adsorption process at early stage is explained by diffusion-limited binding of the carcinogen molecules to DNA beads, and the time range of the early stage depends on the solubility (the solubility of AO in water is high whereas that of BP is low); and (2) the process at later stages depends on the balance of the numbers of adsorption sites and carcinogen molecules. PMID- 17711315 TI - Hydration in protein folding: thermal unfolding/refolding of human serum albumin. AB - Human serum albumin (HSA) is known to undergo both reversible and irreversible thermal unfolding and refolding, depending upon the experimental conditions (end temperature) at neutral pH. In this report we have used high precision densimetric and ultrasonic measurements to determine the apparent specific volume (phi v) and compressibility (phi k) of HSA at different unfolded and refolded states at two different end temperatures, 55 degrees C and 70 degrees C. The unfolded and refolded states were characterized using dynamic light scattering (DLS), circular dichroism (CD), picosecond-resolved fluorescence decay, and anisotropy of the single-tryptophan residue in HSA (Trp214). Both the unfolded states were allowed to refold by cooling wherein the former and latter processes were found to be reversible and irreversible, respectively, in nature. The results obtained from the densimetric and ultrasonic measurements reveal that the apparent specific volume and compressibility of the protein in the reversible protein unfolding process is preserved upon restoration of HSA to ambient temperature. However, a significant change in phi v and phi k occurs in the process of irreversible protein refolding (from 70 to 20 degrees C). The experimental observation is rationalized in terms of the exposure of domain IIA to an aqueous environment, resulting in the swelling of the protein to a higher hydrodynamic diameter. Our studies attempt to explore the extent of hydration associated with the structural integrity of the popular protein HSA. PMID- 17711316 TI - Effects of organic salt additives on the behavior of dimeric ("gemini") surfactants in aqueous solution. AB - The effects of a series of aromatic anions, so-called hydrotropes, on characteristic solution properties of a family of ammonium gemini surfactants with dodecyl chains were explored. The stoichiometric addition of the organic salts to the geminis can result in clear solutions or in phase separation/precipitation, depending on the detailed nature of the added counterions and on the spacer group of the gemini surfactant. Many organic anions induce synergistic effects, strongly reducing the critical micellization concentration (cmc) and the surface tension at the cmc. Furthermore, a number of combinations of organic anions and geminis exhibit thickening of their aqueous solutions. The effects of the added salts are strongly enhanced for the gemini surfactants compared to the monomeric analogue N-dodecyl-N,N,N-trimethylammonium chloride. Even anions such as benzoate may be effective for thickening, and viscoelastic solutions can be obtained with salicylate despite the relatively short alkyl chains. PMID- 17711317 TI - Electrostastic control of spontaneous curvature in catanionic reverse micelles. AB - By means of small-angle neutron scattering and conductivity measurements, we study the microstructure of octylammoniumoctanoate/octane/water catanionic reverse microemulsions with an excess of anionic or cationic surfactant. Increasing the surface charge makes the microemulsion able to incorporate much more water than in the neutral case, up to 10 water molecules per surfactant. Even with charges in the surfactant film, wormlike micelles are present in the microemulsion domain. Along water dilution lines, the classical rod-to-sphere transition due to the minimization of the curvature energy of the rigid surfactant film is observed. When temperature is decreased, a re-entrant phase transition associated with the liquid-gas equilibrium of attractive cylinders is observed. Using the framework of the Tlusty-Safran theory, attraction could originate from junctions between wormlike reverse micelles. In any case, the spontaneous curvature of the catanionic surfactant film depends on both the temperature and the net charge, whatever the sign of the latter. PMID- 17711318 TI - Di(azacrown) conjugates of 2'-O-methyl oligoribonucleotides as sequence-selective artificial ribonucleases. AB - Functionalized 2'-O-methyl oligoribonucleotides bearing two 3-(3-hydroxypropyl) 1,5,9-triazacyclododecane ligands attached via a phosphodiester linkage to a single non-nucleosidic building block have been prepared on a solid-support by conventional phosphoramidite chemistry. The branching units employed for the purpose include 2,2-bis(3-hydroxypropylaminocarbonyl)propane-1,3-diol, 2 hydroxyethyl 3'-O-(2-hydroxyethyl)-beta-D-ribofuranoside, and 2-hydroxyethyl 2'-O (2-hydroxyethyl)-beta-D-ribofuranoside. Each of these has been introduced as a phosphoramidite reagent either into the penultimate 3'-terminal site or in the middle of the oligonucleotide chain. The dinuclear Zn2+ complexes of these conjugates have been shown to exhibit enhanced catalytic activity over their monofunctionalized counterpart, the 3'-terminal conjugate derived from 2 hydroxyethyl 3'-O-(2-hydroxyethyl)-beta-D-ribofuranoside being the most efficient cleaving agent. This conjugate cleaves an oligoribonucleotide target at a single phosphodiester bond and shows turnover and 1000-fold cleaving activity compared to the free monomeric Zn2+ chelate of 1,5,9-triazacyclododecane. PMID- 17711320 TI - Preparation and preliminary evaluation of a biotin-targeted, lectin-targeted dendrimer-based probe for dual-modality magnetic resonance and fluorescence imaging. AB - A novel approach for the preparation of a biotinylated dendrimer-based MRI agent 5 is described, in which a unique disulfide bond in the core of the Gd(III)-1B4M DTPA chelated G2 PAMAM dendrimer was reduced and then attached to a maleimide functionalized biotin. The new MRI agent 5 features a well-defined dendron structure and a unique biotin functionality. Immobilization of up to four copies of biotinylated dendrimer 5 to fluorescently labeled avidin yields a supramolecular avidin-biotin-dendrimer-Gd(III) complex. Validation of the complex in mice bearing ovarian cancer tumors demonstrates that the avidin-biotin dendrimer targeting system efficiently targets and delivers sufficient amounts of chelated Gd(III) and fluorophores (e.g., Rhodamine green) to ovarian tumors to produce visible changes in the tumors by both MRI and optical imaging, respectively. Thus, the avidin-biotin-dendrimer complex may be used as a tumor targeted probe for dual-modality magnetic resonance and fluorescence imaging. PMID- 17711319 TI - Lung delivery studies using siRNA conjugated to TAT(48-60) and penetratin reveal peptide induced reduction in gene expression and induction of innate immunity. AB - The therapeutic application of siRNA shows promise as an alternative approach to small-molecule inhibitors for the treatment of human disease. However, the major obstacle to its use has been the difficulty in delivering these large anionic molecules in vivo. In this study, we have investigated whether siRNA-mediated knockdown of p38 MAP kinase mRNA in mouse lung is influenced by conjugation to the nonviral delivery vector cholesterol and the cell penetrating peptides (CPP) TAT(48-60) and penetratin. Initial studies in the mouse fibroblast L929 cell line showed that siRNA conjugated to cholesterol, TAT(48-60), and penetratin, but not siRNA alone, achieved a limited reduction of p38 MAP kinase mRNA expression. Intratracheal administration of siRNA resulted in localization within macrophages and scattered epithelial cells and produced a 30-45% knockdown of p38 MAP kinase mRNA at 6 h. As with increasing doses of siRNA, conjugation to cholesterol improved upon the duration but not the magnitude of mRNA knockdown, while penetratin and TAT(48-60) had no effect. Importantly, administration of the penetratin or TAT(48-60) peptides alone caused significant reduction in p38 MAP kinase mRNA expression, while the penetratin-siRNA conjugate activated the innate immune response. Overall, these studies suggest that conjugation to cholesterol may extend but not increase siRNA-mediated p38 MAP kinase mRNA knockdown in the lung. Furthermore, the use of CPP may be limited due to as yet uncharacterized effects upon gene expression and a potential for immune activation. PMID- 17711321 TI - Integrated pipeline for mass spectrometry-based discovery and confirmation of biomarkers demonstrated in a mouse model of breast cancer. AB - Despite their potential to impact diagnosis and treatment of cancer, few protein biomarkers are in clinical use. Biomarker discovery is plagued with difficulties ranging from technological (inability to globally interrogate proteomes) to biological (genetic and environmental differences among patients and their tumors). We urgently need paradigms for biomarker discovery. To minimize biological variation and facilitate testing of proteomic approaches, we employed a mouse model of breast cancer. Specifically, we performed LC-MS/MS of tumor and normal mammary tissue from a conditional HER2/Neu-driven mouse model of breast cancer, identifying 6758 peptides representing >700 proteins. We developed a novel statistical approach (SASPECT) for prioritizing proteins differentially represented in LC-MS/MS datasets and identified proteins over- or under represented in tumors. Using a combination of antibody-based approaches and multiple reaction monitoring-mass spectrometry (MRM-MS), we confirmed the overproduction of multiple proteins at the tissue level, identified fibulin-2 as a plasma biomarker, and extensively characterized osteopontin as a plasma biomarker capable of early disease detection in the mouse. Our results show that a staged pipeline employing shotgun-based comparative proteomics for biomarker discovery and multiple reaction monitoring for confirmation of biomarker candidates is capable of finding novel tissue and plasma biomarkers in a mouse model of breast cancer. Furthermore, the approach can be extended to find biomarkers relevant to human disease. PMID- 17711322 TI - In-depth proteomic profiling of the normal human kidney glomerulus using two dimensional protein prefractionation in combination with liquid chromatography tandem mass spectrometry. AB - The kidney glomerulus plays a pivotal role in ultrafiltration of plasma into urine and also is the locus of kidney disease progressing to chronic renal failure. We have focused proteomic analysis on the glomerulus that is most proximal to the disease locus. In the present study, we aimed to provide a confident, in-depth profiling of the glomerulus proteome. The glomeruli were highly purified from the kidney cortex from a male, 68-year-old patient who underwent nephroureterectomy due to ureter carcinoma. The patient was normal in clinical examinations including serum creatinine and urea levels and liver function, and did not receive any chemotherapy and radiotherapy. The cortical tissue was histologically normal, and no significant deposition of immunoglobulins and complement C3 was observed. We employed a novel strategy of protein separation using 1D (SDS-PAGE) and 2D (solution-phase IEF in combination with SDS-PAGE) prefractionation prior to the shotgun analysis with LC-MS/MS. The protein prefractionation produced 90 fractions, and eventually provided a confident set of identified proteins consisting of 6686 unique proteins (3679 proteins with two or more peptide matches and 3007 proteins with one peptide match), representing 2966 distinct genes. All the identified proteins were annotated and classified in terms of molecular function and biological process, compiled into 1D and 2D protein arrays, consisting of 15 and 75 sections, corresponding to the protein fractions which were defined by MW and pI range, and deposited on a Web-based database (http://www.hkupp.org). The most remarkable feature of the glomerulus proteome was a high incidence of identification of cytoskeleton-related proteins, presumably reflecting the well-developed, cytoskeletal organization of glomerular cells related to their physiological functions. PMID- 17711323 TI - The standard protein mix database: a diverse data set to assist in the production of improved Peptide and protein identification software tools. AB - Tandem mass spectrometry (MS/MS) is frequently used in the identification of peptides and proteins. Typical proteomic experiments rely on algorithms such as SEQUEST and MASCOT to compare thousands of tandem mass spectra against the theoretical fragment ion spectra of peptides in a database. The probabilities that these spectrum-to-sequence assignments are correct can be determined by statistical software such as PeptideProphet or through estimations based on reverse or decoy databases. However, many of the software applications that assign probabilities for MS/MS spectra to sequence matches were developed using training data sets from 3D ion-trap mass spectrometers. Given the variety of types of mass spectrometers that have become commercially available over the last 5 years, we sought to generate a data set of reference data covering multiple instrumentation platforms to facilitate both the refinement of existing computational approaches and the development of novel software tools. We analyzed the proteolytic peptides in a mixture of tryptic digests of 18 proteins, named the "ISB standard protein mix", using 8 different mass spectrometers. These include linear and 3D ion traps, two quadrupole time-of-flight platforms (qq TOF), and two MALDI-TOF-TOF platforms. The resulting data set, which has been named the Standard Protein Mix Database, consists of over 1.1 million spectra in 150+ replicate runs on the mass spectrometers. The data were inspected for quality of separation and searched using SEQUEST. All data, including the native raw instrument and mzXML formats and the PeptideProphet validated peptide assignments, are available at http://regis web.systemsbiology.net/PublicDatasets/. PMID- 17711324 TI - Topographical variation in metabolic signatures of human gastrointestinal biopsies revealed by high-resolution magic-angle spinning 1H NMR spectroscopy. AB - Individual and topographical variation in the metabolic profiles of multiple human gastrointestinal tract (GIT) biopsies have been characterized using high resolution magic-angle spinning (HRMAS) 1H NMR spectroscopy and pattern recognition. Samples from antrum, duodenum, jejunum, ileum, and transverse colon were obtained from 8 male and 8 female participants. Each gut region generated a highly characteristic metabolic profile consistent with the varying structural and functional properties of the tissue at different longitudinal levels of the gut. The antral (stomach) mucosa contained higher levels of choline, glycogen, phosphorylethanolamine, and taurine than other gut regions. The spatially close regions of the duodenum and jejunum were equivalent in terms of their gross biochemical composition with high levels of choline, glutathione, glycerophosphocholine (GPC), and lipids relative to other gut regions. The ileal mucosa showed poor discrimination from the duodenum and jejunum tissues and generated strong amino acids signatures but had relative low GPC signals. The colon (large intestine) was high in acetate, glutamate, inositols, and lactate and low in creatine, GPC, and taurine compared to the small intestine. These longitudinal metabolic variations in the human GIT could be attributed to functional variations in energy metabolism, osmoregulation, gut microbial activity, and oxidative protection. This work indicates that 1H HRMAS NMR studies may be of value in analyzing local metabolic variation due to pathological processes in gut biopsies. PMID- 17711325 TI - Identification and antibody-therapeutic targeting of chloramphenicol-resistant outer membrane proteins in Escherichia coli. AB - Bacterial resistance to an antibiotic may result from survival in a suddenly strong antibiotic or in sub-minimum inhibitory concentration of the drug. Their shared proteins responsible for the resistance should be potential targets for designing new drugs to inhibit the growth of the antibiotic-resistant bacteria. In the current study, comparative proteomic methodologies were used for identification of sharedly altered outer membrane proteins (OM proteins) that are responsible for chloramphenical (CAP)-resistant Escherichia coli and for survival in medium with suddenly strong CAP treatment. Six differential OM proteins and another protein with unknown location were determined to be sharedly CAP resistant-related proteins with the use of 2-DE/MS, Western blotting and gene mutant methods, in which TolC, OmpT, OmpC, and OmpW were critically altered proteins and potential targets for designing of the new drugs. Furthermore, a novel method of specific antibody combating bacterial growth was developed on these OM proteins. Only anti-TolC showed a very significant inhibition on bacterial growth in medium with CAP when antisera to TolC, OmpC, OmpT, and OmpW were separately utilized. The growth of CAP-resistant E. coli and its original strain was completely inhibited when they bound with anti-TolC and survived in 1/8 MIC of CAP. This observed result is basically the same to the finding that DeltatolC was survived in the same concentration of the antibiotic. Our study demonstrates that the enhancement of expression of antibody target with antibiotic could be very effective approach compared to using a drug alone, which highlights a potential way for treatment of infection by antibiotic-resistant bacteria. PMID- 17711326 TI - SwedCAD, a database of annotated high-mass accuracy MS/MS spectra of tryptic peptides. AB - A database of high-mass accuracy tryptic peptides has been created. The database contains 15 897 unique, annotated MS/MS spectra. It is possible to search for peptides according to their mass, number of missed cleavages, and sequence motifs. All of the data contained in the database is downloadable, and each spectrum can be visualized. An example is presented of how the database can be used for studying peptide fragmentation. Fragmentation of different types of missed cleaved peptides has been studied, and the results can be used to improve identification of these types of peptides. PMID- 17711327 TI - Survey of differentially expressed proteins and genes in jasmonic acid treated rice seedling shoot and root at the proteomics and transcriptomics levels. AB - Two global approaches were applied to develop an inventory of differentially expressed proteins and genes in rice (cv. Nipponbare) seedling grown on Murashige and Skoog medium with and without jasmonic acid (JA). JA significantly reduced the growth of shoot, root, leaf, and leaf sheath depending on JA concentration (1, 2, 5, 10, 25, and 50 microM) as compared with control. Almost 50% growth inhibition of seedling was observed with 5 microM JA. Shoots and roots of seedlings grown on 5 microM JA for 7 days were then used for proteomics and transcriptomics analyses. Two-dimensional gel electrophoresis revealed 66 and 68 differentially expressed protein spots in shoot and root, respectively, compared to their respective controls. Tandem mass spectrometry analysis of these proteins identified 52 (shoot) and 56 (root) nonredundant proteins, belonging to 10 functional categories. Proteins involved in photosynthesis (44%), cellular respiratory (11%), and protein modification and chaperone (11%) were highly represented in shoot, whereas antioxidant system (18%), cellular respiratory (17%), and defense-related proteins (15%) were highly represented in root. Transcriptomics analysis of shoot and root identified 107 and 325 induced genes and 34 and 213 suppressed genes in shoot and root, respectively. Except of unknown genes with over 57% of the total, most genes encode for proteins involved in secondary metabolism, energy production, protein modification and chaperone, transporters, and cytochrome P450. These identified proteins and genes have been discussed with respect to the JA-induced phenotype providing a new insight into the role of JA in rice seedling growth and development. KEYWORDS: phytohormone * inhibitory concentration * growth * gel-based approach * mass spectrometry * DNA microarray. PMID- 17711329 TI - Retinoid chromophores as probes of membrane lipid order. AB - There is a great need for development of independent methods to study the structure and function of membrane-associated proteins and peptides. Polarized light spectroscopy (linear dichroism, LD) using shear-aligned lipid vesicles as model membranes has emerged as a promising tool for the characterization of the binding geometry of membrane-bound biomolecules. Here we explore the potential of retinoic acid, retinol, and retinal to function as probes of the macroscopic alignment of shear-deformed 100 nm liposomes. The retinoids display negative LD, proving their preferred alignment perpendicular to the membrane surface. The magnitude of the LD indicates the order retinoic acid > retinol > retinal regarding the degree of orientation in all tested lipid vesicle types. It is concluded that mainly nonspecific electrostatic interactions govern the apparent orientation of the retinoids within the bilayer. We propose a simple model for how the effective orientation may be related to the polarity of the end groups of the retinoid probes, their insertion depths, and their angular distribution of configurations around the membrane normal. Further, we provide evidence that the retinoids can sense subtle structural differences due to variations in membrane composition and we explore the pH sensitivity of retinoic acid, which manifests in variations in absorption maximum wavelength in membranes of varying surface charge. Based on LD measurements on cholesterol-containing liposomes, the influence of membrane constituents on bending rigidity and vesicle deformation is considered in relation to the macroscopic alignment, as well as to lipid chain order on the microscopic scale. PMID- 17711328 TI - Manipulating formation and drug-release behavior of new sol-gel silica matrix by hydroxypropyl guar gum. AB - To develop biocompatible sol-gel silica matrix for the encapsulation of biomolecules or drugs, a novel water-soluble silica precursor, tetrakis(2 hydroxyethyl)orthosilicates (THEOS), was used in combination with a water-soluble polysaccharide derivative, hydroxypropyl guar gum (HPGG). We found that the introduction of HPGG could trigger and accelerate the sol-gel transition of THEOS in water and induce rapid formation of homogeneous gel matrix without the addition of any organic solvents or catalysts. Moreover, added HPGG macromolecules had a great influence on the network structure and particle dimension in the silica gel matrix, as confirmed by scanning electron microscope (SEM) observation. From the time sweep rheological measurements, it was found that a higher HPGG amount could lead to shorter gelation time for the sol-gel transition. From the strain and frequency sweep rheological experiments, it was found that the resultant silica matrix containing a higher amount of HPGG exhibited a narrower linear viscoelastic region, a higher dynamic muduli, and greater complex viscosity. In particular, the gel strength of the silica matrix could be modulated by the amount of HPGG. By investigating the controlled release of vitamin B12 from the sol-gel silica matrixes, a strong dependence of the release profile on the amount of introduced HPGG was observed. In this case, a higher HPGG amount resulted in lower release rate. PMID- 17711330 TI - Role of nonemissive quenchers for the green emission in polyfluorene. AB - The stability of fluorene-based compounds and polymers, especially at the bridged C-9 position under photoirradiation and thermal treatment, has claimed much attention. The emission of fluorenone formed by degradation of the 9-site is regarded as the origin of the low emission band at 2.2-2.3 eV in polyfluorene based conjugated materials. We have investigated the role of nonemissive quenchers such as alkyl ketones, which were also one of the products of polyfluorene degradation, for the low-energy emission in polyfluorenes. The spectral characteristics of a blend system of polyfluorene/nonemissive quencher/fluorenone are found to accord well with the kinetics of actual polyfluorene degradation. Our results indicate that strong green emission in degraded polyfluorene would be not caused only by fluorenone, but also by nonemissive quenchers for their effectively quenching bulk emission. PMID- 17711331 TI - Pressure-induced phase transitions in LiNH2. AB - In situ high-pressure Raman spectroscopy studies on LiNH2 (lithium amide) have been performed at pressures up to 25 GPa. The pressure-induced changes in the Raman spectra of LiNH2 indicates a phase transition that begins at approximately 12 GPa is complete at approximately 14 GPa from ambient-pressure alpha-LiNH2 (tetragonal, I) to a high-pressure phase denoted here as beta-LiNH2. This phase transition is reversible upon decompression with the recovery of the alpha-LiNH2 phase at approximately 8 GPa. The N-H internal stretching modes (nu([NH2]-)) display an increase in frequency with pressure, and a new stretching mode corresponding to high-pressure beta-LiNH2 phase appears at approximately 12.5 GPa. Beyond approximately 14 GPa, the N-H stretching modes settle into two shouldered peaks at lower frequencies. The lattice modes show rich pressure dependence exhibiting multiple splitting and become well-resolved at pressures above approximately 14 GPa. This is indicative of orientational ordering [NH2]- ions in the lattice of the high-pressure beta-LiNH2 phase. PMID- 17711332 TI - Thermodynamics of H in disordered Pd-Ag alloys from calorimetric and equilibrium pressure-composition-temperature measurements. AB - In this research, the thermodynamics of H2 solution and hydride formation in a series of disordered Pd-Ag alloys has been determined using both reaction calorimetry and equilibrium PH2-composition-T data. Trends of DeltaHH and DeltaSH with both H and Ag concentration have been determined. For the Pd0.76Ag0.24 alloy, which does not form a hydride phase, DeltaHH and DeltaSH both exhibit minima with H/(Pd0.76Ag0.24) followed by a linear increase of the former. A linear increase of DeltaHH is found for all of the alloys in the high H content region beyond the two-phase region or, if, there is no two-phase region, in the high H content region. DeltaHH degrees at infinite dilution of H decreases with atom fraction Ag, XAg, up to about 0.40 and then increases. Enthalpies for hydride formation/decomposition, 1/2H2(g) + dilute <--> hydride, have been determined calorimetrically for alloys which form two phases (303 K). The enthalpies for hydride formation become more exothermic with XAg while the corresponding entropy magnitudes are nearly constant, 46 +/- 2 J/K mol H. PMID- 17711333 TI - Bringing electrons and microarray technology together. AB - Low-energy secondary electrons are the most abundant radiolysis species which are thought to be able to attach to and damage DNA via formation and decay of localized molecular resonances involving DNA components. In this study, we analyze the consequences of low-energy electron impact on the ability of DNA to hybridize (i.e., to form the duplex). Specifically, single-stranded thymine DNA oligomers tethered to a gold surface are irradiated with very low-energy electrons (E = 3 eV, which is below the 7.5 eV ionization threshold of DNA) and subsequently exposed to a dye-marked complementary strand to quantify by a fluorescence method the electron induced damage. The damage to (dT)25 oligomers is detected at quite low electron doses with only about 300 electrons per oligomer being sufficient to completely preclude its hybridization. In the microarray format, the method can be used for a rapid screening of the sequence dependence of the DNA-electron interaction. We also show for the first time that the DNA reactions at surfaces can be imaged by secondary electron (SE) emission with both high analytical and spatial sensitivity. The SE micrographs indicate that strand breaks induced by the electrons play a significant role in the reaction mechanism. PMID- 17711334 TI - Poly(acrylic acid)-block-poly(L-valine): evaluation of beta-sheet formation and its stability using circular dichroism technique. AB - Secondary structure formation in four novel hybrid poly(acrylic acid)-b-poly(L valine) (PAA-b-PLVAL) block copolymers, that is, PAA(40)-PLVAL(100), PAA(80) PLVAL(100), PAA(80)-PLVAL(80), and PAA(80)-PLVAL(60), was investigated by circular dichroism. The formation of stable and well-defined beta-sheet structure in the PLVAL hydrophobic domains was observed for all the copolymers. At pH 5, PAA(80)-PLVAL(60) with the lowest PLVAL/PAA molar ratio possessed the lowest beta sheet content of 12%, and it increased to 62% for PAA(40)-PLVAL(100) system. The beta-sheet formation in the block copolymers was controlled by both random PAA PLVAL hydrogen bonds at low pH and electrostatic repulsive forces on the PAA segment at high pH; hence, the beta-sheet structure was most stable at intermediate pH. The length of PAA segments was critical in the beta-sheet solubilization and in providing sufficient shielding of the hydrophobic core from denaturing agents such as urea. PMID- 17711335 TI - Calixarene-derived fluorescent probes. PMID- 17711336 TI - Transcending binary logic by gating three coupled quantum dots. AB - Physical considerations supported by numerical solution of the quantum dynamics including electron repulsion show that three weakly coupled quantum dots can robustly execute a complete set of logic gates for computing using three valued inputs and outputs. Input is coded as gating (up, unchanged, or down) of the terminal dots. A nanosecond time scale switching of the gate voltage requires careful numerical propagation of the dynamics. Readout is the charge (0, 1, or 2 electrons) on the central dot. PMID- 17711337 TI - One-step triplex-polymerase chain reaction assay for the authentication of yellowfin (Thunnus albacares), bigeye (Thunnus obesus), and skipjack (Katsuwonus pelamis) tuna DNA from fresh, frozen, and canned tuna samples. AB - A one-step triplex-polymerase chain reaction (PCR)-based assay was developed to discriminate between three tuna species, Thunnus albacares, Thunnus obesus, and Katsuwonus pelamis, even in highly processed food samples such as canned or cooked tuna. Diagnostic nucleotides were identified by direct sequencing and alignment of part of the mitochondrial cytochrome b gene of 30 authenticated exemplars, which allowed us to evaluate intraspecific variation and the genetic distance between three tuna species. The assay relies on a one-step triplex-PCR reaction in which in a single tube species-specific amplification products are generated only in the presence of the correct template nucleic acid and the species of origin of the DNA is indicated by the distinctive size of the PCR product. The identification of tuna species can be performed with a good accuracy, low cost, and with potential automation for large-scale high-throughput screenings in small in-house laboratories. PMID- 17711338 TI - Determination of 2,3-butanediol and 2-hydroxybutanone stereoisomers in batteries of traditional balsamic vinegar. AB - The absolute quantities and the stereoisomeric ratios of R, S-2-hydroxybutanone and R, R-, S, S-, R, S ( meso)-2,3-butanediol were determined in batteries of traditional balsamic vinegar (TBV) by gas chromatography-mass spectrometry (GC MS), using a chiral capillary column, to evaluate if such parameters could be used to differentiate TBV differently aged and from different producers. Results showed that the initial amounts of 2-hydroxybutanone and 2,3-butanediol were quite variable, as a function of the producer of the vinegar; moreover, the 2 hydroxybutanone amount decreased during aging while 2,3-butanediol increased. Initially, the R-2-hydroxybutanone form prevails, and then the R/ S ratio decreased regularly during aging with some exceptions attributed to the addition of new barrels during the battery management. With regard to the 2,3-butanediol isomers, the most abundant was the R, R form, slowly transformed into the R, S and S, S isomers during aging. The GC-MS method used is easy and fast and could allow for a quick control of the maturation level of the vinegar. PMID- 17711339 TI - Antioxidant prenylated flavonoids from propolis collected in Okinawa, Japan. AB - Propolis is a resinous substance collected by honeybees from various plant sources. The composition of propolis depends upon the vegetation at the site of collection. We previously isolated four prenylated flavonoids from propolis collected in Okinawa, Japan. In this study, further fractionation of the extracts of Okinawan propolis resulted in the isolation of a new prenylated flavonoid, prokinawan, and four known compounds. The structure of prokinawan was determined by MS and NMR spectroscopic methods. Furthermore, the antioxidant activity using 1,1-diphenyl-2-picryl-hydrazyl radical scavenging and beta-carotene bleaching systems was investigated. The present study proved that the position of the geranyl or prenyl groups on the flavonoid skeleton plays an important role in exhibiting antioxidant activity. PMID- 17711340 TI - Phenolic profile of Cydonia oblonga Miller leaves. AB - Cydonia oblonga Miller leaves phenolic compounds were analyzed by reversed-phase HPLC/DAD and HPLC/UV. Qualitative and quantitative analysis of phenolics were carried out in a total of 36 samples of quince leaves from three different geographical origins of Northern (Braganca and Carrazeda de Ansiaes) and Central Portugal (Covilha) and three collection months (June, August, and October of 2006). These leaves presented a common phenolic profile composed by nine compounds: 3- O-, 4- O- and 5- O-caffeoylquinic acids, 3,5- O-dicaffeoylquinic acid, quercetin-3- O-galactoside, quercetin-3- O-rutinoside, kaempferol-3- O glycoside, kaempferol-3- O-glucoside, and kaempferol-3- O-rutinoside. 5- O caffeoylquinic acid was the major phenolic compound (36.2%), followed by quercetin 3- O-rutinoside (21.1%). Quince leaves are characterized by higher relative contents of kaempferol derivatives than fruits (pulps, peels, and seeds), especially in what concerns kaempferol-3- O-rutinoside (12.5%). C. oblonga leaves total phenolic content was very high, varying from 4.9 to 16.5 g/kg dry matter (mean value of 10.3 g/kg dry matter), indicating that these leaves can be used as a good and cheap source of bioactive constituents. Significantly differences were observed in 3- O-caffeoylquinic and 3,5- O dicaffeoylquinic acids contents, according to geographical provenance and harvesting month, suggesting a possible use of these compounds as geographical origin and/or maturity markers. PMID- 17711341 TI - Cytotoxic and antitumor activities of thiosulfinates from Allium tuberosum L. AB - In this study we isolated crude thiosulfinates from Allium tuberosum L. using CH 2Cl 2 and then with silica gel column chromatography purified S-methyl methanthiosulfinate and S-methyl 2-propene-1-thiosulfinate from the crude thiosulfinates. Subsequently, in vitro cytotoxicities against human cancer cells and in vivo antitumor activities of the thiosulfinates were investigated. Their cytotoxicities were strong in human cancer cells, in the order of S-methyl 2 propene-1-thiosulfinate, crude thiosulfinates, and S-methyl methanthiosulfinate. When thiosulfinates were administered consecutively for 7 days at 10, 30, and 50 mg/kg ip, in mice, we found significant increases in the life spans of mice that had been inoculated with Sacorma-180 tumor cells. The crude thiosulfinates also induced apoptosis in MCF-7 cancer cells. These results suggest that thiosulfinates from Allium tuberosum L. inhibit the proliferation of cancer cells via apoptosis and have antitumor activities. PMID- 17711342 TI - In vivo flavor release from gelatin-sucrose gels containing droplets of flavor compounds. AB - Gelatin-sucrose gels containing the same amount of flavor compounds present as either suspended droplets or homogenously distributed in the gel (dissolved) were eaten, and the in vivo flavor release was studied using atmospheric pressure chemical ionization-mass spectrometry. The maximum intensity of release was higher from all droplet-containing samples as compared with the dissolved sample (by a factor of 4-2500-fold). When the flavor was dispersed as a greater number of smaller droplets rather than one 1 microL droplet, the intensity of in vivo release was slightly lower. The release of 16 of the flavor compounds varied in their Log P (range 0.26-4.83) and vapor pressure (Log vapor pressure ranged from 1.09 to 1.99). The differences in release for flavors present as either droplets or dissolved in the gel matrix were strongly influenced by both of these factors. This suggested a different mechanism for flavor release from droplets as compared to the classical partition mechanism established for dissolved flavors. PMID- 17711343 TI - Withanolides from Jaborosa kurtzii. AB - Two new withanolides were isolated and characterized from the aerial parts of Jaborosa kurtzii, namely, jaborosalactone 43 (1), with a spiranoid delta-lactone at C-22, and jaborosalactone 44 (2), a 12-oxowithanolide, which may function as a biosynthetic precursor to 1. These new compounds were fully characterized by a combination of spectroscopic methods. Compound 1 showed selective phytotoxicity toward a dicotyledon species, Lactuca sativa (lettuce). PMID- 17711344 TI - Laurendecumallenes A-B and laurendecumenynes A-B, halogenated nonterpenoid C(15) acetogenins from the marine red alga Laurencia decumbens. AB - Four new halogenated nonterpenoid C(15)-acetogenins, 4:7,6:13-bisepoxy-9,10-diol 1,12-dibromopentadeca-1,2-diene (1, laurendecumallene A), 4:7,6:12-bisepoxy-9,10 diol-1,13-dibromopentadeca-1,2-diene (2, laurendecumallene B), (3Z)-6:10,7:13 bisepoxy-12-bromo-9-hydroperoxylpentadeca-3-en-1-yne (3, laurendecumenyne A), and (3Z)-6:10,9:13-bisepoxy-12-bromo-7-chloropentadeca-3-en-1-yne (4, laurendecumenyne B), together with one known halogenated C(15)-acetogenin elatenyne (5) were isolated and identified from the organic extract of the marine red alga Laurencia decumbens. Their structures and relative stereochemistry were established by means of spectroscopic analysis including UV, IR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and 1D and 2D NMR techniques. All these metabolites were submitted for the cytotoxic assay against tumor cell line A549 (human lung adenocarcinoma), but all of them were found inactive (IC(50) > 10 microg/mL). PMID- 17711345 TI - Agladupols A-E, triterpenoids from Aglaia duperreana. AB - Three new apotirucallane-type triterpenoids, agladupols A-C (1- 3), and two new tirucallane-type triterpenoids, agladupols D and E (4 and 5), along with four known compounds, were isolated from the leaves and stems of Aglaia duperreana (Meliaceae). The structures of compounds 1- 5 were elucidated by spectroscopic data. A (13)C NMR-based general rule for assignment of the C-21 configuration in the side chain of apotirucallane- and tirucallane-type triterpenoids was proposed. According to this, the relative stereochemistry of 21- O methyltoosendanpentol (1a), a known compound with the relative configurations of the stereocenters in the side chain undetermined, was completely assigned. PMID- 17711346 TI - Implications for the existence of a heptasulfur linkage in natural o benzopolysulfanes. AB - Natural o-benzopolysulfanes are often thought to exist as either the trisulfane or pentasulfane; the nomenclature has evolved around such notions. No study makes reference to the possible existence of natural o-benzoheptasulfanes. The work performed here indicates that a facile equilibration takes place between the tri , penta-, and heptasulfanes (o-C(6)H(4)S(3), o-C(6)H(4)S(5), and o-C(6)H(4)S(7)) in solution. In these simpler (unnatural) compounds, the number of sulfur atoms can be established unequivocally from their independent syntheses. The o benzopolysulfanes, even after purification, yield mixtures of compounds in solution. A similar equilibration may be anticipated for the corresponding natural products. PMID- 17711347 TI - Eujavanicols A-C, decalin derivatives from Eupenicillium javanicum. AB - Three new decalin derivatives, eujavanicols A-C (1-3), were isolated from an extract of Eupenicillium javanicum IFM 54704. Their structures were determined by chemical and spectroscopic methods. PMID- 17711348 TI - Epicoccins A-D, epipolythiodioxopiperazines from a Cordyceps-colonizing isolate of Epicoccum nigrum. AB - Epicoccins A-D (1-4), four unique epipolythiodioxopiperazines possessing unusual sulfur bridges, have been isolated from cultures of a Cordyceps-colonizing isolate of Epicoccum nigrum. The structures of these compounds were determined mainly by analysis of their NMR spectroscopic data. The relative and absolute configuration of epicoccin A (1) was established by single-crystal X-ray diffraction analysis. Epicoccin A (1) showed modest antimicrobial activity. PMID- 17711350 TI - X-ray absorption fine structure combined with X-ray fluorescence spectroscopy. Monitoring of vanadium sites in mesoporous titania, excited under visible light by selective detection of vanadium Kbeta5,2 fluorescence. AB - The photocatalytic role of vanadium doped in mesoporous TiO2 has not been clarified. Valence state-sensitive V Kbeta5,2-selecting (5462.9 eV) X-ray absorption fine structure (XAFS) was used to monitor the V sites in mesoporous TiO2 for ethanol dehydration under equilibrium in situ conditions and visible light-illumination. First, the feasibility of discriminating V(IV) sites from a 1:1 physical mixture of standard V(IV) and V(V) inorganic compounds was demonstrated, by tuning the secondary fluorescence spectrometer to 5459.0 eV. The chemical shift of V Kbeta5,2 emission between V(IV) and V(V) sites was 1.0 eV. The selection of valence states V(IV) and V(V) was 100% and 80%, respectively. The redox states for ethanol dehydration over mesoporous TiO2 excited in visible light were suggested to be V(III) and V(IV). The chemical shift between valence states V(III) and V(IV) was greater (3.2 eV). On the basis of V Kbeta5,2 emission and V Kbeta5,2-selecting XAFS spectra tuned to the V Kbeta5,2 peak, we determined that the fresh mesoporous V-TiO2 catalyst has a valence state of V(IV). The vanadium sites were partially reduced by the dissociative adsorption of ethanol under visible light, but they still stay within the emission-energy ranges for standard V(IV) compounds. These partially reduced vanadium sites were reoxidized in oxygen under visible light. Finally, direct XAFS observation of photoreduced V(III) sites was attempted by tuning the fluorescence spectrometer to 5456.3 eV for partially reduced mesoporous V-TiO2. Valence state V(III) was selected for 60% of the spectrum in the mixture of V(III) (minor) and V(IV) (dominant) valence states. PMID- 17711349 TI - A robust and convergent synthesis of dipeptide-DOTAM conjugates as chelators for lanthanide ions: new PARACEST MRI agents. AB - A generally applicable synthetic approach to dipeptide-DOTAM conjugates has been developed which is based on the peralkylation of 1,4,7,10-tetraazacyclododecane (cyclen) with protected N-iodoacetyl dipeptides. Standardized procedures were used for the alkylation, metalation, and purification of the resultant lanthanide complexes. Using this approach, we have been able to rapidly and reliably prepare and screen five different ligands each with up to six lanthanide ions. This preliminary investigation has identified several paramagnetic compounds with strong chemical exchange saturation transfer (PARACEST) properties in water at physiological temperature and pH. Extension of the synthetic approach to a wide variety of amino acids is possible. PMID- 17711351 TI - Measuring the mass of thin films and adsorbates using magnetoelastic techniques. AB - Magnetoelastic sensor techniques have the unique characteristics of being able to wirelessly detect resonant frequency shifts of a magnetoelastic foil in response to differences in the foil mass. However, the mathematical expression that links the resonant frequency shift with the change in the mass of the magnetoelastic foil is rarely reported. Furthermore, this relationship is not easy to ascertain due to potential changes in the Young's modulus of the sensor upon a change in mass loading. In this paper, we have shown that adsorption of water vapor from the gas phase by magnetoelastic ribbons coated with a two layer porous thin film (SiO2/Pt-TiO2) induces large changes in the effective Young's modulus of the sensor. We also demonstrated that the change in Young's modulus upon mass loading can be eliminated from the relationship between mass loading and shifts in resonant frequency by using a technique that we refer to as the two different length sensor method (TDLS). This methodology permits the conversion of the magnetoelastic sensor into a microbalance. From data presented in this paper, we illustrate that the sensitivity for the same sensor can range between 214 Hz/mg for mass loadings of Au to 438 kHz/mg for acetone. In the case of water adsorption, frequency shifts varies from 20.0 kHz/mg when Deltam 10 FTE GPs (6.5%), between 5-9 GPs (64.5%) and between 1-4 GPs by 29% of surveyed GPs. In June 2006 there were 31.5 FTE GPs working in Tamworth. The follow-up survey of 29 GPs revealed a significant shift in their perceptions with only 41.4% of GPs perceiving the shortage as 1-4 FTE GPs (p = 0.2), 17.2% between 5-9 GPs and 41.4% nil. No GPs in the follow-up survey perceived the shortage as >10. At the end of the 12 month study period, 8 of 17 practices were accepting new patients. CONCLUSION: GP perceptions of shortage largely reflected concurrent workforce changes that occurred during the study period where there was a 12% improvement after a prolonged period of workforce stagnation. This change drove improvements in patient access and in many GPs' minds ameliorated much of the perceived shortage. Many factors may be involved, including the increased use of practice nurses, private billing and start-up capacity. General practitioner perceptions appear to be sensitive to workforce changes, with sampled GPs working with higher patient ratios than those seen as acceptable in metropolitan areas. PMID- 17711356 TI - A suicide in an online mental health support group: reactions of the group members, administrative responses, and recommendations. AB - Suicides in online mental health support groups are inevitable. This case report of such a suicide describes the responses of the group members and the moderator and makes recommendations. Members of a large, public, mental health message board supported each other, and the moderator, a mental health professional, managed the milieu. A member joined in February 2001 and killed herself in April 2002. The initial response of the members was grief. The moderator attempted to minimize suicide contagion by not making any special announcements and to facilitate mourning by starting a memorial thread. There were no reports of self injury in response to the suicide, and the online ventilation of grief may in fact have had some preventative effect. One member went to the funeral, and gradually, the group moved on. The moderator later implemented a memorial page. The responses of online groups to suicide may, like those of real-life groups, have resuscitation, rehabilitation, and renewal phases. Diffusion of dependency, a searchable archive, and threaded, asynchronous discussion may facilitate mourning, but anonymity may increase vulnerability to false reports. A thread started in memory of a deceased member may function like a virtual memorial service. A memorial page may function like a virtual cemetery. Preliminary recommendations can be made regarding suicide prevention and responding to suicide in moderated online mental health support groups. PMID- 17711357 TI - Comparison of Internet-based and paper-based questionnaires in Taiwan using multisample invariance approach. AB - This study examines whether the Internet-based questionnaire is psychometrically equivalent to the paper-based questionnaire. A random sample of 2,400 teachers in Taiwan was divided into experimental and control groups. The experimental group was invited to complete the electronic form of the Chinese version of Center for Epidemiologic Studies Depression Scale (CES-D) placed on the Internet, whereas the control group was invited to complete the paper-based CES-D, which they received by mail. The multisample invariance approach, derived from structural equation modeling (SEM), was applied to analyze the collected data. The analytical results show that the two groups have equivalent factor structures in the CES-D. That is, the items in CES-D function equivalently in the two groups. Then the equality of latent mean test was performed. The latent means of "depressed mood," "positive affect," and "interpersonal problems" in CES-D are not significantly different between these two groups. However, the difference in the "somatic symptoms" latent means between these two groups is statistically significant at alpha = 0.01. But the Cohen's d statistics indicates that such differences in latent means do not apparently lead to a meaningful effect size in practice. Both CES-D questionnaires exhibit equal validity, reliability, and factor structures and exhibit a little difference in latent means. Therefore, the Internet-based questionnaire represents a promising alternative to the paper based questionnaire. PMID- 17711358 TI - Immersiveness and physiological arousal within panoramic video-based virtual reality. AB - In this paper, we discuss findings from a study that used panoramic video-based virtual environments (PVVEs) to induce self-reported anger. The study assessed "immersiveness" and physiological correlates of anger arousal (i.e., heart rate, blood pressure, galvanic skin response [GSR], respiration, and skin temperature). Results indicate that over time, panoramic video-based virtual scenarios can be, at the very least, physiologically arousing. Further, it can be affirmed from the results that hypnotizability, as defined by the applied measures, interacts with group on physiological arousal measures. Hence, physiological arousal appeared to be moderated by participant hypnotizability and absorption levels. PMID- 17711359 TI - Pain modulation during drives through cold and hot virtual environments. AB - Evidence exists that virtual worlds reduce pain perception by providing distraction. However, there is no experimental study to show that the type of world used in virtual reality (VR) distraction influences pain perception. Therefore, we investigated whether pain triggered by heat or cold stimuli is modulated by "warm "or "cold " virtual environments and whether virtual worlds reduce pain perception more than does static picture presentation. We expected that cold worlds would reduce pain perception from heat stimuli, while warm environments would reduce pain perception from cold stimuli. Additionally, both virtual worlds should reduce pain perception in general. Heat and cold pain stimuli thresholds were assessed outside VR in 48 volunteers in a balanced crossover design. Participants completed three 4-minute assessment periods: virtual "walks " through (1) a winter and (2) an autumn landscape and static exposure to (3) a neutral landscape. During each period, five heat stimuli or three cold stimuli were delivered via a thermode on the participant's arm, and affective and sensory pain perceptions were rated. Then the thermode was changed to the other arm, and the procedure was repeated with the opposite pain stimuli (heat or cold). We found that both warm and cold virtual environments reduced pain intensity and unpleasantness for heat and cold pain stimuli when compared to the control condition. Since participants wore a head-mounted display (HMD) in both the control condition and VR, we concluded that the distracting value of virtual environments is not explained solely by excluding perception of the real world. Although VR reduced pain unpleasantness, we found no difference in efficacy between the types of virtual world used for each pain stimulus. PMID- 17711360 TI - Digital piracy: an examination of low self-control and motivation using short term longitudinal data. AB - The purpose of the present study was to examine the link between low self control, motivation, and digital piracy. This study used short-term longitudinal data (i.e., once a week for 4 weeks) from undergraduate students (n = 292) and latent trajectory analysis. The results of this study revealed that the students had significant variability in initial levels and rates of change in digital piracy. The results indicated that whether motivation was treated as a time invariant or time-varying measure, it along with sex (i.e., being male) had a significant link with the initial levels of digital piracy and that sex and low self-control had links with the rate of change. These results are discussed, and policy implications are made. PMID- 17711361 TI - The ideal elf: identity exploration in World of Warcraft. AB - In this study, we examine the identity exploration possibilities presented by online multiplayer games in which players use graphics tools and character creation software to construct an avatar, or character. We predicted World of Warcraft players would create their main character more similar to their ideal self than the players themselves were. Our results support this idea; a sample of players rated their character as having more favorable attributes that were more favorable than their own self-rated attributes. This trend was stronger among those with lower psychological well-being, who rated themselves comparatively lower than they rated their character. Our results suggest that the game world allows players the freedom to create successful virtual selves regardless of the constraints of their actual situation. PMID- 17711362 TI - The neurobiology of virtual reality pain attenuation. AB - During the past decade, virtual reality (VR) has gained recognition as a means of attenuating pain during medical procedures. However, while investigators have examined the effects of virtual environments on level of distraction, subjective pain intensity, and brain activity, there have been only a handful of investigations into the neurobiological mechanisms associated with VR's efficacy. In an effort to explain how VR may alter pain perception and produce analgesia, as well as to guide the development of novel and improved VR pain treatments, this review aims to link the wealth of empirical data examining the neurobiology of pain to the growing field of VR. This review is separated into three main sections: (a) a brief overview of the current literature on the use of VR for the treatment of pain; (b) a review of the basic neurobiology of how pain is detected, processed, and controlled by the brain; and (c) an exploration into how current VR pain treatments may impact the pain system to produce analgesia. In addition, the future of VR for pain treatment is discussed, including how current treatments might be improved and novel ways to use VR to treat pain might be developed. Speculation on future VR interventions is based on our current understanding of how the brain processes pain and how VR appears to alter this process and produce analgesia. PMID- 17711363 TI - Factors predictive for incidence and remission of internet addiction in young adolescents: a prospective study. AB - The aim of the study is to determine the incidence and remission rates for Internet addiction and the associated predictive factors in young adolescents over a 1-year follow-up. This was a prospective, population-based investigation. Five hundred seventeen students (267 male and 250 female) were recruited from three junior high schools in southern Taiwan. The factors examined included gender, personality, mental health, self-esteem, family function, life satisfaction, and Internet activities. The result revealed that the 1-year incidence and remission rates for Internet addiction were 7.5% and 49.5% respectively. High exploratory excitability, low reward dependence, low self esteem, low family function, and online game playing predicted the emergency of the Internet addiction. Further, low hostility and low interpersonal sensitivity predicted remission of Internet addiction. The factors predictive incidence and remission of Internet addiction identified in this study could be provided for prevention and promoting remission of Internet addiction in adolescents. PMID- 17711364 TI - A study of time management: the correlation between video game usage and academic performance markers. AB - This study analyzes the correlation between video game usage and academic performance. Scholastic Aptitude Test (SAT) and grade-point average (GPA) scores were used to gauge academic performance. The amount of time a student spends playing video games has a negative correlation with students' GPA and SAT scores. As video game usage increases, GPA and SAT scores decrease. A chi-squared analysis found a p value for video game usage and GPA was greater than a 95% confidence level (0.005 < p < 0.01). This finding suggests that dependence exists. SAT score and video game usage also returned a p value that was significant (0.01 < p < 0.05). Chi-squared results were not significant when comparing time spent studying and an individual's SAT score. This research suggests that video games may have a detrimental effect on an individual's GPA and possibly on SAT scores. Although these results show statistical dependence, proving cause and effect remains difficult, since SAT scores represent a single test on a given day. The effects of video games maybe be cumulative; however, drawing a conclusion is difficult because SAT scores represent a measure of general knowledge. GPA versus video games is more reliable because both involve a continuous measurement of engaged activity and performance. The connection remains difficult because of the complex nature of student life and academic performance. Also, video game usage may simply be a function of specific personality types and characteristics. PMID- 17711365 TI - Electronic media use, reading, and academic distractibility in college youth. AB - Activities that require focused attention, such as reading, are declining among American youth, while activities that depend on multitasking, such as instant messaging (IMing), are increasing. We hypothesized that more time spent IMing would relate to greater difficulty in concentrating on less externally stimulating tasks (e.g., academic reading). As hypothesized, the amount of time that young people spent IMing was significantly related to higher ratings of distractibility for academic tasks, while amount of time spent reading books was negatively related to distractibility. The distracting nature and the context of IMing in this population are described. PMID- 17711366 TI - VR-based conversation training program for patients with schizophrenia: a preliminary clinical trial. AB - Schizophrenia is a devastating mental illness and is characterized by hallucinations and delusions as well as social skills deficits. Generally, social skills training designed to help patients develop social skills includes role playing, but this form of training has typical shortcomings, which are largely due to a trainer's difficulties to project emotion. Virtual reality (VR)-based techniques have the potential to solve these difficulties, because they provide a computer-generated but realistic three-dimensional world and humanlike avatars that can provide emotional stimuli. In this paper, we report on a method of implementing virtual environments (VEs) in order to train people with schizophrenia to develop conversational skills in specific situations, which could overcome the shortcomings of or complement conventional role-playing techniques. The paper reports the efficacy of the proposed approach in a preliminary clinical trial with 10 patients with schizophrenia. PMID- 17711367 TI - Social interactions in massively multiplayer online role-playing gamers. AB - To date, most research into massively multiplayer online role-playing games (MMORPGs) has examined the demographics of play. This study explored the social interactions that occur both within and outside of MMORPGs. The sample consisted of 912 self-selected MMORPG players from 45 countries. MMORPGs were found to be highly socially interactive environments providing the opportunity to create strong friendships and emotional relationships. The study demonstrated that the social interactions in online gaming form a considerable element in the enjoyment of playing. The study showed MMORPGs can be extremely social games, with high percentages of gamers making life-long friends and partners. It was concluded that virtual gaming may allow players to express themselves in ways they may not feel comfortable doing in real life because of their appearance, gender, sexuality, and/or age. MMORPGs also offer a place where teamwork, encouragement, and fun can be experienced. PMID- 17711368 TI - The impact of virtual reality functions of a hotel website on travel anxiety. AB - This study deals with the impact of virtual reality (VR) features that are embedded in a hotel website on travelers' anxiety. Having more information is thought to be a factor in relieving anxiety in travel. A hotel website can be a good place for gathering information about the accommodation. In this study, we posit that a hotel website with VR functions should lead to a reduction in travelers' anxiety about travel. We built a website of a hotel and used VR functions to show the exterior, the lobby, a guest room, and a restaurant through an interactive and spatial shot of the hotel images. The experiment was conducted with a premise that the subjects were about to embark on a journey to an unknown place and to stay at an unknown hotel whose website contained VR functions. The subjects were asked to play with VR functions of the hotel website and then to complete a survey with questions regarding the degree of anxiety on the travel and psychological relief that might have been perceived by the subjects. The result confirms our hypothesis that there is a statistically significant relationship between the degree of travel anxiety and psychological relief caused by the use of VR functions of a hotel website. PMID- 17711369 TI - Benefiting from social capital in online support groups: an empirical study of cancer patients. AB - With measures specific to the online cancer environment and data from an online survey of cancer patients, the current study finds support for the following model: asynchronous online communication --> social interaction --> social support --> positive health outcomes in terms of stress, depression, and coping. The findings suggest that the Internet can be a positive cyber venue for cancer patients as they confront illness, undergo treatment, and seek out support. PMID- 17711370 TI - Collaborate and share: an experimental study of the effects of task and reward interdependencies in online games. AB - Today millions of players interact with one another in online games, especially massively multiplayer online role-playing games (MMORPGs). These games promote interaction among players by offering interdependency features, but to date few studies have asked what interdependency design factors of MMORPGs make them fun for players, produce experiences of flow, or enhance player performance. In this study, we focused on two game design features: task and reward interdependency. We conducted a controlled experiment that compared the interaction effects of low and high task-interdependency conditions and low and high reward-interdependency conditions on three dependent variables: fun, flow, and performance. We found that in a low task-interdependency condition, players had more fun, experienced higher levels of flow, and perceived better performance when a low reward interdependency condition also obtained. In contrast, in a high task interdependency condition, all of these measures were higher when a high reward interdependency condition also obtained. PMID- 17711371 TI - Staging on the Internet: research on online photo album users in Taiwan with the spectacle/performance paradigm. AB - This study explores motivations of online photo album users in Taiwan and the distinctive "staging" phenomenon with media gratifications and an a priori theoretical framework, the spectacle/performance paradigm (SPP). Media drenching, performance, function and reference are "new" gratifications, which no prior research was found. These gratifications are consistent with the argument of the "diffused audience" on the Internet. This study verifies that the process-content distinction may not be applicable in the Internet setting because distinctions between the real world and the mediated world are vanishing, which is also the main argument of the SPP paradigm. PMID- 17711372 TI - Taiwanese adolescents' intention model of visiting Internet cafes. AB - This study intended to construct an intention model of visiting Internet cafes. Four hundred eighty-three Taiwanese high school students were surveyed during March 2002. The results indicated that intention increased with positive attitude toward visiting Internet cafes, the intention was only rarely affected by significant others, intention strengthened with the quantity of resources and skills perceived, and past behavior negatively influenced the intention. Three conclusions were drawn: (a) The proposed model can effectively predict adolescent intention to visit Internet cafes. (b) Past behavior was the main predictor of intention. (3) In terms of intention to visit Internet cafes, there is a strengthening of individualism and a weakening of normative influences. Finally, suggestions and recommendations were made for practice and future research. PMID- 17711373 TI - Attachment style differences in online relationship involvement: an examination of interaction characteristics and relationship satisfaction. AB - This study investigated attachment style differences in online relationships with regard to interaction characteristics and relationship satisfaction. The effect of relationship type was also taken into account in these investigations. The findings suggested that attachment style differences in interaction breadth and depth were present only in casual friendships. Preoccupied and dismissing individuals had a lower level of interaction breadth and depth than did secure and fearful individuals within this type of online relationship. A same pattern of attachment style differences was found in relationship satisfaction of casual online friendships. PMID- 17711377 TI - Immune reconstitution inflammatory syndrome associated with disseminated mycobacterial infection in patients with AIDS. AB - Restoration of the immune system after highly active antiretroviral therapy (HAART) resulting from a quantitative and qualitative process of cell immune activity recovery may evolve with adverse clinical phenomena, known as the immune reconstitution inflammatory syndrome (IRIS). It can occur in association with several opportunist infections, although most reported cases have been related to mycobacterial infection caused by Mycobacterium tuberculosis and Mycobacterium avium. We describe three clinical cases of mycobacterial infection with different presentation patterns of IRIS after HAART. In each of these patients, immune reconstitution led to clinical manifestation of a latent infection, or clinical worsening of preexisting lesions, or manifestation of new lesions in the central nervous system. Clinical aspects of IRIS are presented in the paper and clinical management options for this event are carefully discussed. PMID- 17711378 TI - TORO: ninety-six-week virologic and immunologic response and safety evaluation of enfuvirtide with an optimized background of antiretrovirals. AB - The additional 48-week optional treatment extension of the T-20 versus Optimized Regimen Only (TORO) studies evaluated long-term safety and efficacy of enfuvirtide (ENF) through week 96 in patients receiving ENF plus optimized background (OB) and patients switching to ENF plus OB from OB alone. Patient randomization was 2:1 to ENF plus OB (n = 663) and OB (n = 334), of which 89.7% and 89.8% were male, 89.3% and 88.6% were Caucasian, and median age was 41 and 42 years, respectively. HIV risk factors were comparable between the ENF plus OB and OB groups with the major factors being 65.2% versus 66.2% homosexual contact, 17.8% versus 19.8% heterosexual contact, 4.1% versus 4.8% bisexual contact, respectively, and 6.9% injection drug use in both groups. OB patients were allowed to switch to ENF plus OB at virologic failure before week 48 and required to switch at week 48 to continue in the study (n = 230). Efficacy and safety assessments were conducted for each group. At week 96, 55% of ENF plus OB subjects completed the study and 26.5% achieved a viral load of less than 400 copies per milliliter (17.5% achieved less than 50 copies per milliliter). Viral load and CD4 mean change from baseline was -2.1 and -1.1 log(10) HIV-1-RNA copies per milliliter and +166 and +116 CD4 cells/mm(3) for ENF plus OB and switch patients, respectively. No new ENF-related safety issues emerged in weeks 48-96. Injection site reactions led to discontinuation in 7% and 10% of ENF plus OB and switch patients, respectively. In conclusion, these data demonstrate durable efficacy and safety of ENF over 96 weeks and that early use of ENF in combination with other agents for the treatment of antiretroviral-experienced HIV-infected subjects is beneficial. PMID- 17711379 TI - Utility of repeat genotypic resistance testing and clinical response in patients with three class resistance and virologic treatment failure. AB - We sought to determine the utility of repeat genotypic resistance testing (GRT) and the clinical response in HIV-1-infected patients with known resistance to three of the major classes of antiretroviral drugs. The HIV-1 genetic sequences for 20 patients who had high-level 3 class resistance demonstrated on a prior GRT (3C-GRT 1) measured during the period from November 1, 2000 through July 1, 2004 were retrospectively evaluated. At the time of 3C-GRT 1, the median CD4 count and HIV-1 RNA viral load were 168 cells/mm(3) and 4.5 log copies per milliliter, respectively. The median time to the second GRT (3C-GRT 2) was 17 months. At that time, the median CD4 count and VL were 140 cells/mm(3) and 4.9 log copies per milliliter (p = 0.8 and p = 0.12, respectively). On 3C-GRT 2, all patients retained essentially identical mutations, with the exception of the loss of the M184V mutation in 6 patients. After 3C-GRT 2, all patients continued on protease inhibitor-containing highly active antiretroviral therapy (HAART) regimens. At 24 weeks after 3C-GRT 2, there was no significant change in CD4 count or HIV-1 RNA viral load (p = 0.68 and p = 0.30, respectively). Repeat GRT in patients with documented high-level 3 class resistance does not provide new or clinically useful information. Under continued antiretroviral selective pressure, the viral genetic sequences in this patient population remained stable. In addition, continuing HAART regimens containing protease inhibitors appeared to forestall further immunological and virologic deterioration in patients with multiple resistance mutations. Providers should focus on obtaining access to combinations of novel agents for patients with 3 class resistance rather than repeated GRT. PMID- 17711380 TI - Attitudes and perceptions of AIDS clinical trials group site coordinators on HIV clinical trial recruitment and retention: a descriptive study. AB - HIV-seropositive blacks, Hispanics, women of all ethnicities, and injection drug users (IDUs) have low rates of clinical trial participation. The opinions of research nurses and study coordinators as potential facilitators and barriers to access to clinical trials may contribute to this disparity. Study coordinators and research nurses from the adult AIDS Clinical Trials Group (ACTG) clinical trials units responded to an anonymous computer-based survey comprising multiple choice questions and clinical scenarios. Descriptive statistics were used to determine frequencies of responses. Recruitment rates of blacks, Hispanics, women and IDUs were mostly rated appropriate compared with the geographic region demographics. Most sites ranked white men as being the most interested in clinical trials. Sites rated their most effective interactions were with white men. Respondents felt they were less likely to enroll individuals who had missed previous clinical appointments or did not speak English. Perceptions that IDUs, Hispanics, blacks, and, to a lesser extent, women had less interest in clinical trials participation than white males may affect recruitment of the targeted populations. Interventions to improve interactions with targeted populations and to remove logistical and language barriers may improve the diversity of clinical trial participants. PMID- 17711381 TI - Adherence, drug use, and treatment failure in a methadone-clinic-based program of directly administered antiretroviral therapy. AB - Supervised dosing is a cornerstone of tuberculosis treatment. HIV treatment strategies that use directly administered antiretroviral therapy (DAART) are increasingly being assessed. In a prospective single-arm clinical trial, we enrolled methadone-maintained, HIV-infected participants to receive supervised doses of antiretroviral therapy (ART) on days when they received methadone. Other ART doses were self-administered. In this analysis we examined factors associated with retention to DAART, adherence to supervised doses, and virologic failure. Factors associated with retention to DAART were assessed with the Kaplan-Meier method and Cox proportional hazards models. Factors associated with nonadherence with supervised dosing and with virologic failure were assessed by logistic regression and techniques for longitudinal data analysis. A total of 16,453 supervised doses were administered to 88 participants over a median follow-up of 9.4 months. The median participant adherence with supervised dosing was 83%. Active drug use, determined by urine drug screens, was associated twofold increased risks of both intervention dropout and nonadherence with supervised doses. Adherence with supervised doses was strongly associated with virologic failure. Because DAART was administered only on methadone dosing days, fewer than half of the total ART doses were scheduled to be supervised in most participants. The percent of doses that was scheduled to be supervised was not associated with either adherence or with virologic failure. Given that a relatively small proportion of the total ART doses were supervised in many patients, future studies should assess how DAART affects adherence with nonsupervised doses and retention to ART. PMID- 17711382 TI - Characteristics of a sample of men who have sex with men, recruited from gay bars and Internet chat rooms, who report methamphetamine use. AB - Crystal methamphetamine is a highly addictive stimulant that initially gained popularity in the western region of the United States and has spread to all regions of the country. This study was designed to identify factors associated with methamphetamine use among men who have sex with men (MSM) in North Carolina. Participants were recruited in five gay bars and in five geographically defined Internet chat rooms concurrently in 2005 to complete a brief assessment of drug use and other risk behaviors. Of the 1189 MSM who completed the assessment, mean age was 29 years. Two thirds self-identified as black/African American or other minorities, and 25% as bisexual. Nearly 6% reported using methamphetamines during the past 30 days. In multivariable analysis, MSM who reported using methamphetamines were more likely to report higher education; health insurance coverage; inconsistent condom use during anal sex within the past 3 months; a history of sexually transmitted disease (STD) infection; positive HIV serostatus; and use of medications designed to treat erectile dysfunction. A lack of data exists on methamphetamine use among MSM in the southeastern United States, particularly in nonurban regions. Because the southeastern United States carries a disproportionate HIV, AIDS, and STD burden, our findings underscore the need for further research and intervention. PMID- 17711383 TI - The effect of perceived stigma from a health care provider on access to care among a low-income HIV-positive population. AB - Perceived stigma in clinical settings may discourage HIV-infected individuals from accessing needed health care services. Having good access to care is imperative for maintaining the health, well being, and quality of life of persons living with HIV/AIDS (PLWHAs). The purpose of this prospective study, which took place from January 2004 through June 2006, was to evaluate the relationship between perceived stigma from a health care provider and access to care among 223 low income, HIV-infected individuals in Los Angeles County. Approximately one fourth of the sample reported perceived stigma from a health care provider at baseline, and about one fifth reported provider stigma at follow up. We also found that access to care among this population was low, as more than half of the respondents reported difficulty accessing care at baseline and follow up. Perceived stigma was found to be associated with low access to care both at baseline (odds ratio [OR] = 3.29; 95% confidence interval [CI] = 1.55, 7.01) and 6-month follow up (2.85; 95% CI = 1.06, 7.65), even after controlling for sociodemographic characteristics and most recent CD4 count. These findings are of particular importance because lack of access or delayed access to care may result in clinical presentation at more advanced stages of HIV disease. Interventions are needed to reduce perceived stigma in the health care setting. Educational programs and modeling of nonstigmatizing behavior can teach health care providers to provide unbiased care. PMID- 17711384 TI - Inequality and unwillingness to care for people living with HIV/AIDS: a survey of medical professionals in Southeast China. AB - This study was aimed at assessing physicians' and physician assistants' knowledge and attitudes toward HIV/AIDS and identifying determinants of willingness to care for infected individuals in Southeast China. From May to June 2004, 454 physicians and physician assistants from 5 different medical facility levels in Fujian Province, China, undertook a survey on knowledge, attitude, behavior, and practice (KABP). Only 40.4% (95% confidence intervals: 35.9, 44.9) were willing to provide healthcare services for people living with HIV/AIDS (PLWHAs). Knowledge (p < 0.001) and attitude scores (p = 0.01) as well as the proportion of those willing to provide care (p < 0.001) significantly differed by facility level. Multivariate analysis identified supportive attitudes toward PLWHAs (p < 0.001), self-confidence in providing care (p < 0.001), and facility level as significant predictors of willingness to care for infected individuals. Village medical stations showed the most unfavorable outcomes. Enhanced education as well as specific programs promoting supportive attitudes and willingness to care is therefore required, especially among those working at lower facility levels in remote areas. PMID- 17711385 TI - Data shows long-term nevirapine efficacy and increases in good cholesterol. PMID- 17711386 TI - Treating infants early increases survival. PMID- 17711387 TI - Epigenetic control of centromere behavior. AB - The centromere is the DNA region that ensures genetic stability and is therefore of vital importance. Paradoxically, centromere proteins and centromeric structural domains are conserved despite that fact that centromere DNA sequences are highly variable and are not conserved. Remarkably, heritable states at the centromere can be propagated independent of the underlying centromeric DNA sequences. This review describes the epigenetic mechanisms governing centromere behavior, i.e., the mechanisms that control centromere assembly and propagation. A centromeric histone variant, CenH3, and histone modifications play key roles at centromeric chromatin. Histone modifications and RNA interference are important in assembly of pericentric heterochromatin structures. The molecular machinery that is directly involved in epigenetic control of centromeres is shared with regulation of gene expression. Nucleosome remodeling factors, histone chaperones, histone-modifying enzymes, transcription factors, and even RNA polymerase II itself control epigenetic states at centromeres. PMID- 17711388 TI - Chemically induced carcinogenesis affecting chromatin structure in rat hepatocarcinoma cells. AB - A new, chemically induced animal tumor cell line (HeDe) was established and characterized by its property of causing aggressively growing tumors in specific strain of rats and changes in the chromatin structure. Results show that (1) the nuclear material in nuclei of normal resting (G0) hepatocytes consists mainly of decondensed veil-like chromatin, chromosomes being clustered in six lobular domains; (2) nuclei of HeDe cells contain primarily supercoiled chromatin; or (3) the nuclear material of tumor cells undergoes apoptosis seen as apoptotic bodies. Heterogeneity of chromatin structures was expressed as contour/area ratio and was nine times higher in apoptotic cells and two times higher in tumor cells compared to resting cells. PMID- 17711389 TI - Protein disulfide isomerases from C. elegans are equally efficient at thiol disulfide exchange in simple peptide-based systems but show differences in reactivity towards protein substrates. AB - Although the formation of disulfide bonds is an essential process in every living organism, only little is known about the mechanisms in multicellular eukaryotic systems. The reason for this uncertainty is that in addition to the well-known key enzyme protein disulfide isomerase (PDI), several PDI-like proteins are present in the ER of metazoans. In total, there are now 18 PDI-family members in the human endoplasmic reticulum, with different domain architectures and active site chemistries. To understand why multicellular organisms express multiple proteins with similarity to the archetypal mammalian PDI, the properties of three PDIs from the nematode C. elegans were investigated. Here the authors demonstrate that PDI-1, PDI-2, and PDI-3 show comparable kinetic properties in catalyzing thiol:disulfide exchange reactions in two simple peptide-based assays. However, the three enzymes exhibited clear differences in their reactivity towards protein substrates. The authors therefore propose that the three PDIs can catalyze similar thiol-disulfide exchange reactions in a substrate, but due to differences in substrate binding, they can direct a folding polypeptide chain onto different folding pathways and hence fulfil distinct and different functions in the organism. PMID- 17711390 TI - Sepsis: redox mechanisms and therapeutic opportunities. PMID- 17711391 TI - T lymphocyte trafficking: a novel target for neuroprotection in traumatic brain injury. AB - Infiltration of T lymphocytes is a key feature in transplant rejection and in several autoimmune disorders, but the role of T lymphocytes in traumatic brain injury (TBI) is largely unknown. Here we studied trafficking of immune cells in the brain after experimental TBI. We found that scavenging of reactive oxygen species (ROS) at the endothelial level dramatically reduced the infiltration of activated T lymphocytes. Immune cell infiltration was studied 12 h to 7 days after controlled cortical contusion in rats by ex vivo propagation of T lymphocytes (TcR+, CD8+), neutrophils (MPO+), and macrophages/microglia (ED-1+) from biopsies taken from injured cortex and analyzed by flow cytometry, as well as by quantitative immunohistochemistry. T lymphocyte and neutrophil infiltration peaked at 24 h and macrophages/microglia at 7 days post-injury. Pretreatment with 2-sulfophenyl-N-tert-butyl nitrone (S-PBN) produced a dramatic reduction of TcR+ T lymphocytes and a significantly smaller attenuation of neutrophil infiltration at 24 h post-injury, but did not affect CD8+ T lymphocytes or macrophages/microglia. S-PBN significantly reduced the expression of the endothelial adhesion molecules ICAM-1 and VCAM at 24 h for following TBI. We conclude that ROS inhibition at the endothelial level influenced T lymphocyte and neutrophil infiltration following TBI. We submit that the reduction of T lymphocyte infiltration is a key feature in improving TBI outcome after S-PBN treatment. Our data suggest that targeting T lymphocyte trafficking to the injured brain at the microvascular level is a novel concept of neuroprotection in TBI and warrants further exploration. PMID- 17711392 TI - Deficits in novelty exploration after controlled cortical impact. AB - Experimental models of traumatic brain injury (TBI) have been utilized to characterize the behavioral derangements associated with brain trauma. Several studies exist characterizing motor function in the controlled cortical impact (CCI) injury model of TBI, but less research has focused on how CCI affects exploratory behavior. The goal of this study was to characterize deficits in three novelty exploration tasks after the CCI. Under anesthesia, 37 adult male Sprague Dawley rats received CCI (2.7 mm and 2.9 mm; 4 m/sec) over the right parietal cortex or sham surgery. For days 1-6 post-surgery, the beam balance and beam walking tasks were used to assess motor deficits. The Open Field, Y-Maze, and Free Choice Novelty (FCN) tasks were used to measure exploratory deficits from days 7-14 post-surgery. Injured rats displayed a significant, but transient, deficit on each motor task (p < 0.0001). Open Field results showed that injured rats had lower activity levels than shams (p < 0.0001), displayed less habituation to the task, and had more anxiety related behaviors (thigmotaxis) across days (p < 0.0001). Y-maze results suggest that injured rats spent less time in the novel arm versus the familiar arms when compared to shams (p < 0.0001). For FCN, injured rats were less active (p < 0.05) and spent less time and had fewer interactions with objects in the novel environment compared to shams (p < 0.05). These results suggest that several ethological factors contribute to exploratory deficits after CCI and can be effectively characterized with the behavioral tasks described. Future work will utilize these tasks to evaluate the neural substrates underlying exploratory deficits after TBI. PMID- 17711393 TI - Perfusional deficit and the dynamics of cerebral edemas in experimental traumatic brain injury using perfusion and diffusion-weighted magnetic resonance imaging. AB - The aim of this work was to characterize edema dynamics, cerebral blood volume, and flow alterations in an experimental model of brain trauma using quantitative diffusion and perfusion magnetic resonance imaging (MRI). Associated with an influx of water in the intracellular space 1-5 h post-trauma as demonstrated by the 40% reduction in apparent diffusion coefficient, a 70-80% reduction in cerebral blood flow was measured within the lesioned region. Transient hypoperfusion (40-50%) was also observed in the non-traumatized contralateral hemisphere, although there was no evidence of edema formation. After the initial cytotoxic edema, a clear evolution toward extracellular water accumulation was observed, demonstrated by an increase in apparent diffusion coefficient. PMID- 17711394 TI - Plasma von Willebrand factor levels correlate with clinical outcome of severe traumatic brain injury. AB - Biochemical markers of cellular stress/injury have been proposed to indicate outcome after head injury. The aim of the present study was to determine whether plasma von Willebrand factor (VWF) levels correlate with primary outcome and with clinical variables in severe traumatic brain injury (TBI). Forty-four male patients, victims of severe TBI, were analyzed. Clinical outcome variables of severe TBI comprised survival and neurological assessment using the Glasgow Outcome Scale (GOS) at intensive care unit (ICU) discharge. Computerized tomography (CT) scans were analyzed according to Marshall CT classification. Three consecutive venous blood samples were taken: first sample (11.4 +/- 5.2 h after trauma, mean +/- SD), and 24 h and 7 days later. The result of mean plasma VWF concentration was significantly higher in the TBI group (273 U/dL) than in the control group (107 U/dL; p < 0.001). Severe TBI was associated with a 50% mortality rate. Nonsurvivors presented significantly higher APACHE II scores than survivors (nonsurvivors mean, 18.8; survivors mean, 12.7; p < 0.001), and also presented higher scores in Marshall CT classification (nonsurvivors mean, 4.6; survivors mean, 2.7; p < 0.05). There was a significant positive correlation between plasma levels at second plasma sampling and scores in Marshall CT classification (p < 0.05). The sensitivity of plasma VWF concentration in predicting mortality according to the cut-off of 234 U/dL was 64%, with a specificity of 68%. Therefore, VWF increases following severe TBI may be a marker of unfavorable outcome. PMID- 17711395 TI - Time course of intracranial hypertension after traumatic brain injury. AB - High intracranial pressure (HICP) may be a very early event after traumatic brain injury (TBI), but in most cases, especially when contusions and edema develop over time, HICP will worsen over succeeding days. This study describes the incidence and severity of elevated intracranial pressure (ICP) after TBI and attempts to document its time course. In this prospective study, 201 TBI patients in whom ICP was monitored for more than 12 h were evaluated. ICP was measured, digitalized, and analyzed after manual filtering. The number of episodes of HICP and the mean ICP value for every 12-h interval were calculated. When monitoring was concluded, the highest mean ICP collected in every patient was identified. A total of 21,000 h of ICP monitoring were recorded. Active treatment to prevent or reduce HICP was used in 200 patients. HICP was documented in 155 cases. Half of the patients had their highest mean ICP during the first 3 days after injury, but many showed delayed ICP elevation, with 25% showing highest mean ICP after day 5. In these cases, HICP was significantly worse and required more intense therapies. PMID- 17711396 TI - Serum and cerebrospinal fluid magnesium in severe traumatic brain injury outcome. AB - Serum magnesium concentration has a neuroprotective effect in experimental models of traumatic brain injury (TBI). This study was designed to assess the relationship between initial serum magnesium, cerebrospinal fluid (CSF) magnesium, neurological outcome and the efficacy of magnesium replacement therapy (MgSO4). A retrospective analysis was performed on a prospectively collected dataset from 216 patients admitted during 1996-2006 to the University of Pittsburgh Medical Center with severe TBI. Admission serum and CSF magnesium were dichotomized into low and normal magnesium concentration groups for serum and normal and high concentration groups for CSF. A logistic-regression analysis was performed with 6-month Glasgow Outcome Scale (GOS) scores as outcome variable. The outcome of a subset of 31 patients who presented with low serum magnesium and who were rapidly corrected within 24 h of admission was also analyzed. Low initial serum magnesium was measured in 56.67% of all patients. Patients with an initial serum magnesium of <1.3 mEq/L were 2.37 times more likely to have a poor outcome (CI: 1.18-4.78, p = 0.016). The prognostic significance of depressed serum magnesium remained, even in patients whose serum magnesium levels were corrected within 24 h (OR = 11.03, CI: 1.87-68.14, p = 0.008). Patients with an initial high CSF magnesium were 7.63 more likely to have a poor outcome (p = 0.05). Elevated CSF magnesium correlated with depressed serum magnesium only in patients with poor outcome (p = 0.013). Patients with low serum magnesium and high CSF magnesium are most likely to have poor outcome after severe TBI. Rapid correction of serum magnesium levels does not reverse the prognostic value of these markers. PMID- 17711397 TI - Head injury mortality in a geriatric population: differentiating an "edge" age group with better potential for benefit than older poor-prognosis patients. AB - A comparison of outcomes between different modes of head-injury treatment in the elderly has important bearing on questions of cost-effectiveness and medical ethics. Here, we have examined rates of mortality in elderly head-trauma victims to determine whether it is valid to differentiate an "edge" age group of younger elderly patients, 65-74 years of age, from older elderly patients, considering possible benefit from intensive treatment and surgical intervention. We collected data from 1926 cases of head trauma and separated them into three age groups: 14 64 years, 65-74 years, and 75 years or older. We then compared these groups with respect to cause of injury, severity of injury, and whether or not treatment included either admission to an Intensive Care Unit (ICU) or surgical intervention. We found that road traffic accidents were the major cause of head injury in the younger age group, whereas in the elderly falls predominated. Mortality was higher in the elderly in all the head injury severity subgroups. Young subjects with a Glasgow Coma Scale (GCS) score of less than or equal to 8 tended to benefit from ICU treatment whereas patients 75 and over did not, regardless of their severity of injury. For these patients who were in the 65-74 age group, the data suggested that some benefit was likely. Patients 75 and older were significantly less likely to survive surgical intervention than younger patients. We conclude that it is valid to treat patients in the age group 65-74 years as a separate group from those patients 75 and older. Patients in this younger subset of the elderly may benefit from ICU treatment or surgical intervention. However, the patients in our older subset of elderly patients clearly did not, and they had a significantly higher risk of surgical mortality. PMID- 17711398 TI - Focal photothrombotic lesion of the rat motor cortex increases BDNF levels in motor-sensory cortical areas not accompanied by recovery of forelimb motor skills. AB - Brain infarct triggers neurodegeneration that often shades spontaneous plasticity, occurring in the areas related anatomically and functionally to the infarcted structures. Neurotrophins which promote neuronal survival and plasticity, may protect neurons and enhance remodeling of the remaining circuits, leading to restoration of function. In particular, the crucial role of brain derived neurotrophic factor (BDNF) in cortical function is well documented. Since BDNF was implicated in the mechanism of postinfarct recovery, we investigated whether focal photothrombosis in the motor cortex of adult rats modifies cortical BDNF protein levels in a time- and region-dependent fashion. In parallel, we aimed to establish, which cortical cells respond with altered BDNF expression and whether these alterations are reflected by forelimb motor skill impairment and recovery, evaluated up to 1 month postinfarct. The distribution of BDNF protein was visualized immunohistochemically and BDNF tissue levels were evaluated with enzyme-linked immunosorbent assay (ELISA). Ipsilateral to the infarct, an increase in BDNF levels occurred both in injured and neighboring regions already 24 h after photothrombosis. This increase was sustained up to postlesion day 7 in the motor cortex and reduced at 28 days. No BDNF changes were detected in homotopic regions of the contralateral cortex. The time-course of enhanced neurotrophic expression was paralleled by bilateral deficits in skilled reaching, which was the only clear and measurable motor impairment observed in the study. We conclude that the spontaneous increase of BDNF is not sufficient to protect neurons from degeneration in the lesion proximity whereas plasticity reported in the adjacent regions may be attributable to enhanced BDNF-related stimuli, which do not counteract the impairment of skilled reaching but might be, at least in part, responsible for the absence of deficits in other functional/behavioral tests. PMID- 17711400 TI - New rat model for diffuse brain injury using coronal plane angular acceleration. AB - A new experimental model was developed to induce diffuse brain injury (DBI) in rats through pure coronal plane angular acceleration. An impactor was propelled down a guide tube toward the lateral extension of the helmet fixture. Upon impactor-helmet contact, helmet and head were constrained to rotate in the coronal plane. In the present experimental series, the model was optimized to generate rotational kinematics necessary for concussion. Twenty-six rats were subjected to peak angular accelerations of 368 +/- 30 krad/sec2 (mean +/- standard deviation) with 2.1 +/- 0.5-msec durations. Following rotational loading, unconsciousness was defined as time between reversal agent administration and return of corneal reflex. All experimental rats demonstrated transient unconsciousness lasting 8.8 +/- 3.7 min that was significantly longer than control rats. Macroscopic damage was noted in 51% of experimental animals: 38% subarachnoid hemorrhage, and 15% intraparenchymal lesion. Microscopic analysis indicated no evidence of axonal swellings at sacrifice times of 24, 48, 72, and 96 h. All rats survived rotational loading without skull fracture. Injuries were classified as concussion based on transient unconsciousness, scaled biomechanics, limited macroscopic damage, and minimal histological abnormalities. The experimental methodology remains adjustable, permitting investigation of increasing DBI severities through modulation of model parameters, and inclusion of further functional and histological outcome measures. PMID- 17711399 TI - Neuroprotective effects of the Ras inhibitor S-trans-trans-farnesylthiosalicylic acid, measured by diffusion-weighted imaging after traumatic brain injury in rats. AB - Ras proteins play a role in receptor-mediated signaling pathways and are activated after traumatic brain injury. S-trans-trans-farnesylthiosalicylic acid (FTS), a synthetic Ras inhibitor, acts primarily on the active, GTP-bound form of Ras and was shown to improve neurobehavioral outcome after closed head injury (CHI) in mice. To gain a better understanding of the neuroprotective mechanism of FTS, we used diffusion-weighted imaging (DWI) in a rat model of CHI. Apparent diffusion coefficients (ADC) and transverse relaxation times (T2) were measured in injured rat brains after treatment with vehicle or FTS (5 mg/kg). Neuroprotection by FTS was also assessed in terms of the neurological severity score. One week after injury, significantly better recovery was observed in the FTS-treated rats than in the controls (p = 0.0191). T2 analysis of the magnetic resonance images revealed no differences between the two groups. In contrast, they differed significantly in ADC, particularly at 24 h post-CHI (p < 0.05): in the vehicle-treated rats ADC had decreased to approximately 26% below baseline, whereas it had increased to about 10% above baseline in the FTS-treated rats. As the magnitude of ADC reduction is strongly linked to blood perfusion deficit, these results suggest that the neuroprotective mechanism of FTS might be related to an improvement in cerebral perfusion. We propose that FTS, which is currently being tested in humans for anti-cancer indications, should also be considered as a new strategy for the management of head injury. PMID- 17711401 TI - Local administration of the poly(ADP-ribose) polymerase inhibitor INO-1001 prevents NAD+ depletion and improves water maze performance after traumatic brain injury in mice. AB - Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme best known for its role in DNA repair and as a mediator of NAD+ depletion and energy failure-induced cell death. We tested the effect of the potent and selective ideno-isoquinolone PARP-1 inhibitor INO-1001 after controlled cortical impact (CCI) in mice. Anesthetized adult male mice were subjected to moderate CCI (velocity 6 m/sec, depth 1.2 mm) or sham-injury. Immediately after CCI or sham-injury mice received either INO 1001 (1.6 mg/kg) or vehicle via intracerebral injection (5 microl over 5 min) in a randomized fashion. At 2 h, contused brain tissue was dissected and NAD+ levels were measured. Separate mice underwent neuropathological outcome tests that included spatial memory acquisition (Morris water maze days 14-20), and assessment of contusion volume and hippocampal cell death at day 21. Local treatment with INO-1001 preserved brain NAD+ levels 2 h after CCI (vehicle = 67 +/- 7.6, INO-1001 = 95.8 +/- 4.4 % uninjured hemisphere; n = 6/group, p = 0.03). In the Morris water maze, treatment with INO-1001 reduced the latency to find the hidden platform and increased the time spent in the target quadrant versus vehicle after CCI (n = 11/group, p < or = 0.05). Histological damage did not differ between vehicle and INO-1001-treated mice after CCI. Treatment with INO 1001 prevented NAD+ depletion and improved outcome, although modestly, identifying PARP-mediated energy failure as a contributor to the pathological sequelae of TBI. Further study testing the effects of PARP inhibitors is warranted, specifically in models of brain injury where energy failure is seen. PMID- 17711402 TI - Early changes in deep vein diameter and biochemical markers associated with thrombi formation after spinal cord injury in mice. AB - Spinal cord injury (SCI) is associated with the development of deep venous thrombosis (DVT) in the lower limbs and, hence, with rapidly increasing risks of cardiovascular and pulmonary complications soon after trauma. However, specific mechanisms underlying DVT formation following SCI are poorly understood. Here, we studied in mice, employing in vivo confocal microscopy, changes in deep vein size over 4 weeks after spinal cord transection (Tx). Changing levels of biochemical markers that may be associated with DVT formation were also examined. The results showed decreased concentrations of cholesterols, triglycerides, and low-density lipoprotein (LDL), but not of high-density lipoproteins (HDL) and platelets. Concentrations of creatinine, bilirubin, glucose, albumin, total protein and uric acid did not significantly change. In turn, the femoral and saphenous veins underwent a large increase (>1.5-fold) in diameter throughout the entire period studied. Overall, this study reveals that a profound change in deep vein size and, an unsuspected decrease in triglyceride and LDL levels, occur as early as at one week post-Tx in mice. This indicates, given the well-documented risk of DVT formation soon after SCI, that deep vein enlargement, but not lipoprotein level changes, may constitute an early event contributing to venous stasis and thrombi formation in paralyzed individuals. PMID- 17711404 TI - Regulation of Cidea protein stability by the ubiquitin-mediated proteasomal degradation pathway. AB - Cidea, one of three members of the CIDE (cell-death-inducing DNA-fragmentation factor-45-like effector) family of proteins, is highly enriched in brown adipose tissue, in which it plays a critical role in adaptive thermogenesis and fat accumulation. Cidea-null mice have increased energy expenditure with resistance to high-fat-diet-induced obesity and diabetes. However, little is known as to how the Cidea protein is regulated. In the present study we show that Cidea is a short-lived protein as measured by cycloheximide-based protein chase experiments in different cell lines or in differentiated brown adipocytes. Proteasome inhibitors specifically increased the stability of both transfected and endogenous Cidea protein. Furthermore, Cidea protein was found to be polyubiquitinated when overexpressed in different culture cells as well as in differentiated mature brown adipocytes. Extensive mutational analysis of individual lysine residues revealed that ubiquitinated lysine residues are located in the N-terminal region of Cidea, as alteration of these lysine residues to alanine (N-5KA mutant) renders Cidea much more stable when compared with wild type or C-terminal lysine-less mutant (C-5KA). Furthermore, K23 (Lys23) within the N-terminus of the Cidea was identified as the major contributor to its polyubiquitination signal and the protein instability. Taken together, the results of our study demonstrated that the ubiquitin-proteasome system confers an important post-translational modification that controls the protein stability of Cidea. PMID- 17711405 TI - Improving institutional fairness to live kidney donors: donor needs must be addressed by safeguarding donation risks and compensating donation costs. AB - The number of kidney transplants from live donors is increasing worldwide, yet donor needs have not been satisfactorily addressed in either developed or developing countries. This paper argues that unmet donor needs are unfair to live kidney donors in two ways. First, when safeguards against the risks of donation are insufficient, live donation can impair the donor's health and thus his or her fair opportunities to access jobs and offices and to function as a free and equal citizen more generally. Secondly, when the financial costs of donation are not fully compensated, operational fairness (associated with the nephrectomy event) is compromised for the donor. The donor assumes the risks of a nontherapeutic intervention--for the good of the recipient and society--and should not have to incur costs for donating. Based on a systematic analysis of unmet donor needs in developed and developing countries, context-relative measures to improve institutional fairness to live kidney donors are delineated in this paper. The identified ways of safeguarding donation risks and compensating donation costs are not merely means to removing disincentives for donation and increasing donation rates. They are essential for preserving institutional fairness in the health care of the live kidney donor. PMID- 17711406 TI - The 'Blind Innsbruck Ostomy', a cutaneous enterostomy for long-term histologic surveillance after small bowel transplantation. AB - Intestinal transplantation has evolved into an established treatment for patients with intestinal failure. Although acute rejection episodes are reversible, late onset and chronic rejections remain major prognostic factors. We describe here our experience with endoscopic and histologic long-term monitoring through a cutaneous enterostomy. Between 1989 and 2003, 24 intestinal transplants were performed. After revascularization and reconstruction of proximal intestinal continuity, a side-to-end ileo-enterostomy was performed 20 cm from the stoma and the terminal allograft ileostomy left in the abdominal wall. Approximately after 2 months, in eight patients (nine transplants), the stoma was excluded from the gastrointestinal continuity, allowing ongoing endoscopy and histologic examination. Of 280 forceps biopsies, 64 (23%) were performed through the 'blind ostomy'. Eleven acute allograft rejections were diagnosed between days 3 and 51, with two episodes in three cases. Through the 'blind ostomy', a late mild acute rejection was diagnosed in five instances, three to 37 months after transplantation. In all these patients, basal immunosuppression was intensified. Chronic rejection was seen in three cases 4-26 months after transplantation. In one of the three patients, chronic rejection was diagnosed from the excluded blind enterostomy. A long-term cutaneous enterostomy, even if disconnected from the intestinal continuity, enables simple long-term monitoring of small bowel allografts. PMID- 17711407 TI - Timing and value of protocol biopsies in well-matched kidney transplant recipients--a clinical and histopathologic analysis. AB - The role and timing of protocol biopsies after kidney transplantation are controversial. We changed our protocol biopsy policy and compared the predictive value of biopsies at different time-points. Protocol biopsies at 6 months (n = 45) were obtained during 2001-2004, and at 3 and 12 months from 2004 (n = 41). Donor biopsy was available from 70 patients. Histopathologic changes were described with chronic allograft damage index (CADI) and Banff 1997. Follow-up was for 18 months. Chronic allograft nephropathy (CAN) was present in 12%, 51%, and 34% and borderline or subclinical rejection in 9.8%, 8.9%, and 7.3% of patients at 3, 6, and 12 months. CAN at 6 and 12 months was associated with reduced graft function (P = 0.001). Semiquantitative CADI scores at all time points significantly correlated with glomerular filtration rate (GFR) at 18 months. Strongest correlation existed with CADI at 12 months (P < 0.001). Change in CADI between 0-6 and 0-12 months, but not between 0-3 and 3-12 months, correlated with GFR at 18 months (P = 0.03, P = 0.01). Subclinical rejections were rare and chronic changes mild at 3 months. In our well-matched population, the predictive value of a biopsy at 3 months was inferior to biopsies at 6 or 12 months, both of which were effective in predicting long-term graft function. PMID- 17711409 TI - A polymorphic variant in the MHC2TA gene is not associated with systemic lupus erythematosus. AB - Single-nucleotide polymorphisms (SNPs) in the major histocompatibility complex class II transactivator (MHC2TA) gene encoding the class II transactivator have been associated with multiple sclerosis, rheumatoid arthritis, and myocardial infarction in the Swedish population. We used a case-control approach to investigate the prevalence of a relevant variant in Swedish systemic lupus erythematosus (SLE) cohorts to determine whether SLE shares the same MHC2TA susceptibility allele as the other diseases. No differences were observed between cases and control subjects at either the allele or genotype levels. Furthermore, no significant correlations were found when comparing different clinical and serological SLE phenotypes. This particular polymorphism rs3087456 of the MHC2TA gene does not appear to influence genetic susceptibility to SLE in the Swedish population. We conclude that our data support neither allelic nor genotype association between the MHC2TA SNP and SLE. PMID- 17711410 TI - Cytokine gene polymorphisms in Colombian patients with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) patients exhibit alterations in cytokine production that may be relevant to SLE pathogenesis. There is evidence that cytokine gene polymorphisms control cytokine production; thus, these polymorphisms may be associated with SLE or its clinical manifestations. To establish the association of tumor necrosis factor alpha (TNF-alpha), transforming growth factor (TGF) beta1, interleukin (IL)-10, and IL-6 gene polymorphisms in Colombian SLE patients and their clinical manifestations, 120 SLE patients and 102 healthy controls were studied. Single nucleotide polymorphisms were studied by sequence-specific primers polymerase chain reaction (SSP-PCR) at: TNFalpha-308 (G/A), TGFbeta1 codon 10 (C/T) and codon 25 (G/C), IL 10 -1082 (G/A), -819 (C/T) and -592 (C/A), and IL-6 + 174 (G/C). Human leukocyte antigen (HLA)-DRbeta1 was typed by SSP-PCR. SLE patients had increased frequency of allele C at TGFbeta1 codon 25 (P = 0.0001, odds ratio (OR): 4.25, 95% confidence interval (CI): 2.17-8.35) and allele A at TNFalpha-308 (P = 0.0004 OR: 3.9, 95% CI: 1.65-5.80) compared with healthy controls. There was higher frequency of GC genotype at TGFbeta1 codon 25 in SLE patients (P < 0.0001). Extended genotypic analysis showed that SLE patients have decreased frequency of TNFalphaLow/TGFbeta1High (0.50) compared with healthy controls (0.80) (P < 0.0001). No association was found between these polymorphisms and SLE clinical manifestations except for Sm and Ro autoantibodies that were associated with TNFalpha allele A. There is an association between TNFalpha-308A/TGFbeta1 codon 25C with SLE susceptibility in Colombian population. This association may result in a highly inflammatory response with a decrease regulatory function mediated by TNFalpha and TGFbeta1, respectively. The TNFalpha-308A/TGFbeta1 25C genotype may be one component of genetic susceptibility to SLE in Colombian population. PMID- 17711408 TI - Transplantation tolerance: lessons from experimental rodent models. AB - Immunological tolerance or functional unresponsiveness to a transplant is arguably the only approach that is likely to provide long-term graft survival without the problems associated with life-long global immunosuppression. Over the past 50 years, rodent models have become an invaluable tool for elucidating the mechanisms of tolerance to alloantigens. Importantly, rodent models can be adapted to ensure that they reflect more accurately the immune status of human transplant recipients. More recently, the development of genetically modified mice has enabled specific insights into the cellular and molecular mechanisms that play a key role in both the induction and maintenance of tolerance to be obtained and more complex questions to be addressed. This review highlights strategies designed to induce alloantigen specific immunological unresponsiveness leading to transplantation tolerance that have been developed through the use of experimental models. PMID- 17711411 TI - New HLA-C alleles identified in minority populations. AB - Twenty new human leukocyte antigen C alleles identified in 2200 minority individuals characterized by sequence-based typing. PMID- 17711412 TI - Enhanced phosphorus nutrition in monocots and dicots over-expressing a phosphorus responsive type I H+-pyrophosphatase. AB - Plants challenged by limited phosphorus undergo dramatic morphological and architectural changes in their root systems in order to increase their absorptive surface area. In this paper, it is shown that phosphorus deficiency results in increased expression of the type I H+-pyrophosphatase AVP1 (AVP, Arabidopsis vacuolar pyrophosphatase), subsequent increased P-type adenosine triphosphatase (P-ATPase)-mediated rhizosphere acidification and root proliferation. Molecular genetic manipulation of AVP1 expression in Arabidopsis, tomato and rice results in plants that outperform controls when challenged with limited phosphorus. However, AVP1 over-expression and the resulting rhizosphere acidification do not result in increased sensitivity to AlPO4, apparently because of the enhancement of potassium uptake and the release of organic acids. Thus, the over-expression of type I H+-pyrophosphatases appears to be a generally applicable technology to help alleviate agricultural losses in low-phosphorus tropical/subtropical soils and to reduce phosphorus runoff pollution of aquatic and marine environments resulting from fertilizer application. PMID- 17711413 TI - Heat shock factor 1 is a key regulator of the stress response in Chlamydomonas. AB - We report here on the characterization of heat shock factor 1 (HSF1), encoded by one of two HSF genes identified in the genome of Chlamydomonas reinhardtii. Chlamydomonas HSF1 shares features characteristic of class A HSFs of higher plants. HSF1 is weakly expressed under non-stress conditions and rapidly induced by heat shock. Heat shock also resulted in hyperphosphorylation of HSF1, and the extent of phosphorylation correlated with the degree of induction of heat shock genes, suggesting a role for phosphorylation in HSF1 activation. HSF1, like HSFs in yeasts, forms high-molecular-weight complexes, presumably trimers, under non stress, stress and recovery conditions. Immunoprecipitation of HSF1 under these conditions led to the identification of cytosolic HSP70A as a protein constitutively interacting with HSF1. Strains in which HSF1 was strongly under expressed by RNAi were highly sensitive to heat stress. 14C-labelling of nuclear encoded proteins under heat stress revealed that synthesis of members of the HSP100, HSP90, HSP70, HSP60 and small HSP families in the HSF1-RNAi strains was dramatically reduced or completely abolished. This correlated with a complete loss of HSP gene induction at the RNA level. These data suggest that HSF1 is a key regulator of the stress response in Chlamydomonas. PMID- 17711414 TI - PRMT11: a new Arabidopsis MBD7 protein partner with arginine methyltransferase activity. AB - Plant methyl-DNA-binding proteins (MBDs), discovered by sequence homology to their animal counterparts, have not been well characterized at the physiological and functional levels. In order better to characterize the Arabidopsis AtMBD7 protein, unique in bearing three MBD domains, we used a yeast two-hybrid system to identify its partners. One of the interacting proteins we cloned is the Arabidopsis arginine methyltransferase 11 (AtPRMT11). Glutathione S-transferase pull-down and co-immunoprecipitation assays confirmed that the two proteins interact with each other and can be co-isolated. Using GFP fluorescence, we show that both AtMBD7 and AtPRMT11 are present in the nucleus. Further analyses revealed that AtPRMT11 acts as an arginine methyltransferase active on both histones and proteins of cellular extracts. The analysis of a T-DNA mutant line lacking AtPRMT11 mRNA revealed reduced levels of proteins with asymmetrically dimethylated arginines, suggesting that AtPRMT11, which is highly similar to mammalian PRMT1, is indeed a type I arginine methyltransferase. Further, AtMBD7 is a substrate for AtPRMT11, which post-translationally modifies the portion of the protein-containing C-terminal methylated DNA-binding domain. These results suggest the existence of a link between DNA methylation and arginine methylation. PMID- 17711416 TI - A hydraulic signal in root-to-shoot signalling of water shortage. AB - Photosynthesis and biomass production of plants are controlled by the water status of the soil. Upon soil drying, plants can reduce water consumption by minimizing transpiration through stomata, the closable pores of the leaf. The phytohormone abscisic acid (ABA) mediates stomatal closure, and is the assigned signal for communicating water deficit from the root to the shoot. However, our study does not support ABA as the proposed long-distance signal. The shoot response to limited soil water supply is not affected by the capacity to generate ABA in the root; however, the response does require ABA biosynthesis and signalling in the shoot. Soil water stress elicits a hydraulic response in the shoot, which precedes ABA signalling and stomatal closure. Attenuation of the hydraulic response in various plants prevented long-distance signalling of water stress, consistent with root-to-shoot communication by a hydraulic signal. PMID- 17711415 TI - Computer-vision analysis of seedling responses to light and gravity. AB - Measuring the effects of mutation, natural variation or treatment on the development of plant form is often complicated by the shapes, dynamics or small size of the organismal structures under study. This limits accuracy and throughput of measurement and thereby limits progress toward understanding the underlying gene networks and signaling systems. A computer-vision platform based on electronic image capture and shape-analysis algorithms was developed as an alternative to the mostly manual methods of measuring seedling development currently in use. The spatial and temporal resolution of the method is in the range of microns and minutes, respectively. The algorithm simultaneously quantifies apical hook opening and inhibition of hypocotyl elongation during photomorphogenesis of Arabidopsis thaliana seedlings. It can determine when and where gravitropic curvature develops along the root axis in A. thaliana and Medicago truncatula seedlings. Novel features of gravitropic curvature development were discovered as a result of the high resolution. The computer vision algorithms developed and demonstrated here could be used to study mutant phenotypes in detail, to form the basis of a high-throughput screening platform, or to quantify natural variation in a population of plants. PMID- 17711417 TI - Mature monomeric forms of Hop stunt viroid resist RNA silencing in transgenic plants. AB - Viroids, small non-coding pathogenic RNAs, are able to induce RNA silencing, a phenomenon that has been associated with the pathogenesis and evolution of these small RNAs. It has been recently suggested that viroids may resist this plant defense mechanism. However, the simultaneous degradation of non-replicating full length viroid RNA, and the resistance of mature forms of viroids to RNA silencing, have not been experimentally demonstrated. Transgenic Nicotiana benthamiana plants expressing a dimeric form of Hop stunt viroid (HSVd) that have the capability to cleave and circularize this viroid RNA were used to address this question. A reporter construct, consisting of a full-length HSVd RNA fused to GFP-mRNA, was agroinfiltrated in these plants and its expression was suppressed. Interestingly, both circular and linear HSVd molecules were stable and able to traffic through grafts in these restrictive conditions, indicating that the mature forms of HSVd are able, in some way, to resist the RNA-silencing mechanism. The observation that a full-length HSVd RNA fused to GFP-mRNA, but not circular and/or linear viroid forms, was fully susceptible to RNA degradation strongly suggests that structures adopted by the free mature monomer protect the pathogenesis-associated forms of the viroid from RNA silencing. PMID- 17711418 TI - Robust stimulation of TrkB induces delayed increases in BDNF and Arc mRNA expressions in cultured rat cortical neurons via distinct mechanisms. AB - In cultures of rat cortical neurons, we found that stimulation of tyrosine receptor kinase B (TrkB) with brain-derived neurotrophic factor (BDNF) induced a biphasic expression of BDNF exon IV-IX mRNA, which became obvious 1-3 h (primary induction) and 24-72 h (delayed induction) after the stimulation, and characterized the delayed induction in relation to the mRNA expression of activity-regulated cytoskeleton-associated protein (Arc). Withdrawal of BDNF from the medium after stimulation for 3 h allowed the delayed induction, which was caused at the transcriptional level and dependent upon the initial contact between exogenously added BDNF and TrkB, the effect of which was time- and dose dependent. The primary induction was controlled by the extracellular signal regulated kinase/mitogen-activated protein kinase (ERK/MAPK) whereas the secondary induction by the calcium (Ca(2+)) signaling pathway. The enhanced Arc or Zif268 mRNA expression was controlled by activation of the ERK/MAPK pathway, both of which were repressed by blocking the binding of endogenously synthesized BDNF to TrkB. Thus, robust stimulation of TrkB autonomously induces delayed BDNF mRNA expression in an activity-dependent manner in rat cortical neurons, resulting in the stimulation of Arc mRNA expression through endogenously synthesized BDNF, the process being orchestrated by the Ca(2+) and ERK/MAPK signaling pathways. PMID- 17711420 TI - Low-molecular-weight post-translationally modified microcins. AB - Microcins are a class of ribosomally synthesized antibacterial peptides produced by Enterobacteriaceae and active against closely related bacterial species. While some microcins are active as unmodified peptides, others are heavily modified by dedicated maturation enzymes. Low-molecular-weight microcins from the post translationally modified group target essential molecular machines inside the cells. In this review, available structural and functional data about three such microcins--microcin J25, microcin B17 and microcin C7-C51--are discussed. While all three low-molecular-weight post-translationally modified microcins are produced by Escherichia coli, inferences based on sequence and structural similarities with peptides encoded or produced by phylogenetically diverse bacteria are made whenever possible to put these compounds into a larger perspective. PMID- 17711419 TI - Identification of a domain in the delta subunit (S238-V264) of the alpha4beta3delta GABAA receptor that confers high agonist sensitivity. AB - We have expressed the alpha4beta3delta and alpha4beta3gamma2L subtypes of the rat GABAA receptor in Xenopus oocytes and have investigated their agonist activation properties. GABA was a more potent agonist of the alpha4beta3delta receptor (EC50 approximately 1.4 micromol/L) than of the alpha4beta3gamma2L subtype (EC50 approximately 27.6 micromol/L). Other GABAA receptor agonists (muscimol, 4,5,6,7 tetrahydroisoxazolo[5,4-c]pyridin-3-ol, imidazole-4-amino acid) displayed similar subtype selectivity. The structural determinants underlying these differences have been investigated by co-expressing chimeric delta/gamma2L subunits with alpha4 and beta3 subunits. A stretch of amino acids in the delta subunit, S238 V264, is shown to play an important role in determining both agonist potency and the efficacies of full or partial agonists. This segment includes transmembrane domain 1 and the short intracellular loop that leads to the second transmembrane domain. The effects of the competitive antagonists, bicuculline and SR95531, and the channel blocker, picrotoxin, were not significantly affected by the incorporation of chimeric subunits. As the delta and gamma2L subunits have not been previously implicated directly in agonist binding, we suggest that the effects are likely to arise from changes in the transduction mechanisms that link agonist binding to channel activation. PMID- 17711421 TI - The distribution, density and three-dimensional histomorphology of Pacinian corpuscles in the foot of the Asian elephant (Elephas maximus) and their potential role in seismic communication. AB - Both Asian (Elephas maximus) and African (Loxodonta africana) elephants produce low-frequency, high-amplitude rumbles that travel well through the ground as seismic waves, and field studies have shown that elephants may utilize these seismic signals as one form of communication. Unique elephant postures observed in field studies suggest that the elephants use their feet to 'listen' to these seismic signals, but the exact sensory mechanisms used by the elephant have never been characterized. The distribution, morphology and tissue density of Pacinian corpuscles, specialized mechanoreceptors, were studied in a forefoot and hindfoot of Asian elephants. Pacinian corpuscles were located in the dermis and distal digital cushion and were most densely localized to the anterior, posterior, medial and lateral region of each foot, with the highest numbers in the anterior region of the forefoot (52.19%) and the posterior region of the hindfoot (47.09%). Pacinian corpuscles were encapsulated, had a typical lamellar structure and were most often observed in large clusters. Three-dimensional reconstruction through serial sections of the dermis revealed that individual Pacinian corpuscles may be part of a cluster. By studying the distribution and density of these mechanoreceptors, we propose that Pacinian corpuscles are one possible anatomic mechanism used by elephants to detect seismic waves. PMID- 17711422 TI - A new prey-detection mechanism for kiwi (Apteryx spp.) suggests convergent evolution between paleognathous and neognathous birds. AB - Kiwi (Apterygidae: Apteryx spp.) are traditionally assumed to detect their soil dwelling invertebrate prey using their sense of smell. The unique position of the nares at the tip of the bill and the enlarged olfactory centres in the brain support this assumption. However, studies designed to show the importance of olfaction in prey-detection by Apteryx have provided equivocal results. Another family of probing birds, the Scolopacidae, detect their buried prey using specialised vibration and pressure-sensitive mechanoreceptors embedded in pits in the bill-tip. We found that aspects of the foraging patterns of Apteryx mantelli are like those of scolopacid shorebirds, suggesting that Apteryx may be using a similar prey-detection mechanism. We examined specimens of all five Apteryx species and conducted a morphological and histological examination of the bill of A. mantelli. We discovered that Apteryx possess an arrangement of mechanoreceptors within pits similar to that in Scolopacidae species and may therefore be able to localise prey using a similar vibrotactile sense. We suggest that this sense may function in conjunction with, or be dominant over, olfaction during prey-detection. The Apterygidae and the Scolopacidae are members of the two different super-orders of birds: the Paleognathae and the Neognathae, respectively. Therefore we cite the similar bill-tip anatomy of these two families as an example of convergent evolution across a deep taxonomic divide. PMID- 17711423 TI - Culture of HepG2 liver cells on three dimensional polystyrene scaffolds enhances cell structure and function during toxicological challenge. AB - Cultured cells are dramatically affected by the micro-environment in which they are grown. In this study, we have investigated whether HepG2 liver cells grown in three dimensional (3-D) cultures cope more effectively with the known cytotoxic agent, methotrexate, than their counterparts grown on traditional two dimensional (2-D) flat plastic surfaces. To enable 3-D growth of HepG2 cells in vitro, we cultured cells on 3-D porous polystyrene scaffolds previously developed in our laboratories. HepG2 cells grown in 3-D displayed excellent morphological characteristics and formed numerous bile canaliculi that were seldom seen in cultures grown on 2-D surfaces. The function of liver cells grown on 3-D supports was significantly enhanced compared to activity of cells grown on 2-D standard plasticware. Unlike their 2-D counterparts, 3-D cultures were less susceptible to lower concentrations of methotrexate. Cells grown in 3-D maintained their structural integrity, possessed greater viability, were less susceptible to cell death at higher levels of the cytotoxin compared to 2-D cultures, and appeared to respond to the drug in a manner more comparable to its known activity in vivo. Our results suggest that hepatotoxicity testing using 3-D cultures might be more likely to reflect true physiological responses to cytotoxic compounds than existing models that rely on 2-D culture systems. This technology has potential applications for toxicity testing and drug screening. PMID- 17711424 TI - New light on old shoulders: palaeopathological patterns of arthropathy and enthesopathy in the shoulder complex. AB - Rotator cuff disease represents the most common cause of modern shoulder pain and disability. Much of the clinical literature on rotator cuff disease focuses on subacromial impingement and supraspinatus tendinopathy, although other patterns of lesions are also recognised. Rotator cuff disease has received relatively little attention in palaeopathological literature, but signs relating to subacromial impingement have been reported. Given the variety and patterns of lesions that are recognized clinically as rotator cuff disease, this study aimed to investigate whether a similarly wide range of lesions could be identified in human skeletal remains. Degenerative changes in surfaces around the shoulder were recorded in a sample of 86 skeletons. The resultant data were assessed using both simple descriptive statistics and exploratory factor analysis. Degenerative changes characteristic of modern subacromial impingement formed a minor underlying pattern in the data. The predominant underlying variable in the data represented an association between lesser tuberosity, bicipital sulcus and glenohumeral degenerative changes. This pattern reflects recent reports in the clinical literature highlighting the prevalence of subscapularis tendinopathy, and also supports a pathoaetiological model of progression from subscapularis to long head of biceps to glenohumeral involvement. The degenerative changes seen at the non-articular, fibrocartilaginous entheses on the humeral tuberosities were similar to those seen in subchondral bone in osteoarthritis. PMID- 17711425 TI - Modulation of amyloid-beta-induced and age-associated changes in rat hippocampus by eicosapentaenoic acid. AB - The age-related deficit in long-term potentiation (LTP) in the dentate gyrus is positively correlated with hippocampal concentration of the pro-inflammatory cytokine, interleukin-1beta (IL-1beta). Previous evidence also indicates that the inhibition of LTP induced by intracerebroventricular injection of amyloid-beta(1 40) (Abeta) is accompanied by increased hippocampal IL-1beta concentration and IL 1beta-stimulated signalling, specifically activation of the stress-activated protein kinase, c-jun N-terminal kinase (JNK). We considered that the underlying age-related neuroinflammation may render older rats more susceptible to Abeta administration and, to investigate this, young, middle-aged and aged rats were injected intracerebroventricularly with Abeta or vehicle. Hippocampal IL-1beta concentration, JNK phosphorylation, expression of the putative Abeta receptor, Receptor for advanced glycation end products (RAGE) and the microglial cell surface marker, CD40 were assessed. We report that Abeta inhibited LTP in a concentration-dependent manner in young rats and that this was accompanied by concentration-dependent increases in hippocampal IL-1beta and expression of phosphorylated JNK, RAGE and CD40. While 20 micromol/L Abeta exerted no significant effect on LTP in young rats, it inhibited LTP in middle-aged and aged rats and the increased vulnerability of aged rats was associated with increased IL-1beta concentration. Treatment of rats with eicosapentaenoic acid attenuated the inhibitory effect of 60 micromol/L Abeta on LTP in young rats and the effect of 20 micromol/L Abeta in middle-aged and aged rats. We present evidence which indicates that the effect of eicosapentaenoic acid may be linked with its ability to stimulate activation of peroxisome proliferator-activated receptor gamma. PMID- 17711426 TI - Transcellular biosynthesis of cysteinyl leukotrienes in rat neuronal and glial cells. AB - Leukotrienes are mediators of inflammation that belong to a family of lipids derived from arachidonic acid by the action of 5-lipoxygenase. Leukotrienes have been detected in the central nervous system in association with different pathological events, but little is known about their biosynthesis or function in the brain. When rat neurons and glial cells in primary culture were stimulated with the calcium ionophore, no significant biosynthesis of leukotrienes was detected using liquid chromatography/mass spectrometry (LC/MS) techniques. However, when exogenous LTA(4) was added to these cultured cells, both neurons and glia were able to synthesize LTC(4). Activated neutrophils are known to supply LTA(4) to other cells for transcellular biosynthesis of cysteinyl leukotrienes. Since neutrophils can infiltrate brain tissue after stroke or traumatic brain injury, we examined whether neutrophils play a similar role in the central nervous system. When peripheral blood neutrophils were co-cultured with rat neurons, glia cells, and then stimulated with calcium ionophore, a robust production of LTC(4), LTD(4), and LTE(4) was observed, revealing that neurons and glia can participate in the transcellular mechanism of leukotriene biosynthesis. The formation of LTC(4) through this mechanism may be relevant in the genesis and progression of the inflammatory response as a result of brain injury. PMID- 17711427 TI - Death effector activation in the subventricular zone subsequent to perinatal hypoxia/ischemia. AB - Perinatal hypoxia/ischemia (H/I) is the leading cause of neurological injury resulting from birth complications and pre-maturity. Our studies have demonstrated that this injury depletes the subventricular zone (SVZ) of progenitors. In this study, we sought to reveal which cell death pathways are activated within these progenitors after H/I. We found that calpain activity is detected as early as 4 h of reperfusion and is sustained for 48 h, while caspase 3 activation does not occur until 8 h and peaks at 24 h post-insult. Activated calpains and caspase 3 co-localized within precursors situated in the lateral aspects of the SVZ (which coincides with progenitor cell death), whereas neither enzyme was activated in the medial SVZ (which harbors the neural stem cells that are resilient to this insult). These studies reveal targets for neuroprotective agents to protect precursors from cell death towards the goal of restoring normal brain development after H/I. PMID- 17711428 TI - Assessment of endothelial function in Alzheimer's disease: is Alzheimer's disease a vascular disease? AB - OBJECTIVES: To compare endothelial function of people with Alzheimer's disease (AD) with that of people without. DESIGN: Case-control study. SETTING: Geriatric medicine outpatient clinic of a university hospital. PARTICIPANTS: Twenty-five patients with AD who were free of vascular risk factors and 24 healthy elderly controls were enrolled. Exclusion criteria were diabetes mellitus, hypertension, dyslipidemia, evident stroke, smoking, documented coronary artery disease, history of myocardial infarction, heart failure, acute or chronic infection, malignancy, peripheral artery disease, renal disease, rheumatologic diseases, alcohol abuse, and certain drugs that may affect endothelial function. Both groups underwent comprehensive geriatric assessment and neuropsychiatric assessment. MEASUREMENTS: Endothelial function was evaluated according to flow mediated dilation (FMD) from the brachial artery. RESULTS: Mean age +/- standard deviation was 78 +/- 5.9 in the group with AD (11 female and 14 male) and 72.1 +/ 5.8 in the control group (9 female and 11 male). Multiple linear regression analysis revealed that FMD was significantly lower in patients with AD (median 3.45, range 0-7) than controls (median 8.41, range 1-14) (P < .001), independent of age. It was also found that FMD values were inversely correlated with the stage of the disease as determined according to the Clinical Dementia Rating scale (r=-0.603, P < .001). CONCLUSION: Endothelial function is impaired in patients with AD. Endothelial function was worse in patients with severe AD. These findings provide evidence that vascular factors have a role in the pathogenesis of AD. PMID- 17711429 TI - Re: Venice Chart international consensus document on atrial fibrillation ablation. PMID- 17711430 TI - Treatment of pyridostigmine-induced AV block with hyoscyamine in a patient with myasthenia gravis. AB - Myasthenia gravis is an autoimmune disorder of the nervous system typically mediated by antibodies against the nicotinic acetylcholine receptor at the neuromuscular junction. Treatment of myasthenia gravis frequently involves the use of cholinesterase inhibitors such as pyridostigmine. Treatment with these agents has been associated with bradycardia and syncope requiring pacemaker implantation. We report a case of a 60-year-old man with a 1-year history of myasthenia gravis treated with pyridostigmine who presented with syncope due to high degree AV block. Before committing the patient to a permanent pacemaker, a trial of medical therapy with hyoscyamine was attempted. Hyoscyamine is a muscarinic antagonist commonly used to block cholinergic side effects associated with pyridostigmine without reducing its efficacy at the neuromuscular junction. Treatment with hyoscyamine resulted in complete resolution of AV block, thereby avoiding pacemaker implantation. PMID- 17711431 TI - Gastric hypomotility following epicardial vagal denervation ablation to treat atrial fibrillation. AB - We report a case of a 55-year-old man with vagal paroxysmal atrial fibrillation (AF) who was submitted to selective epicardial and endocardial atrial vagal denervation with the objective of treating AF. Radiofrequency pulses were applied on epicardial and endocardial surface of the left atrium close to right pulmonary veins (PVs) and also on epicardial surface close to left inferior PV. Following the procedure, patient presented with symptoms of gastroparesis, which was documented on CT scan and gastric emptying scintigraphy. Symptoms were transient and the patient recovered completely. PMID- 17711432 TI - Novel electrode design for potentially painless internal defibrillation also allows for successful external defibrillation. AB - BACKGROUND: Implantable cardioverter defibrillators (ICDs) save lives, but the defibrillation shocks delivered by these devices produce substantial pain, presumably due to skeletal muscle activation. In this study, we tested an electrode system composed of epicardial panels designed to shield skeletal muscles from internal defibrillation, but allow penetration of an external electric field to enable external defibrillation when required. METHODS AND RESULTS: Eleven adult mongrel dogs were studied under general anesthesia. Internal defibrillation threshold (DFT) and shock-induced skeletal muscle force at various biphasic shock strengths were compared between two electrode configurations: (1) a transvenous coil placed in the right ventricle (RV) as cathode and a dummy can placed subcutaneously in the left infraclavicular fossa as anode (control configuration) and (2) RV coil as cathode and the multielectrode epicardial sock with the panels connected together as anode (sock connected). External DFT was also tested with these electrode configurations, as well as with the epicardial sock present, but with panels disconnected from each other (sock-disconnected). Internal DFT was higher with sock-connected than control (24 +/- 7 J vs. 16 +/- 6 J, P < 0.02), but muscle contraction force at DFT was greatly reduced (1.3 +/- 1.3 kg vs. 10.6 +/- 2.2 kg, P < 0.0001). External defibrillation was never successful, even at 360 J, with sock-connected, while always possible with sock-disconnected. CONCLUSION: Internal defibrillation with greatly reduced skeletal muscle stimulation can be achieved using a novel electrode system that also preserves the ability to externally defibrillate when required. This system may provide a means for painless ICD therapy. PMID- 17711433 TI - Cardiac resynchronization: is electrical synchrony relevant? PMID- 17711434 TI - "Thinking outside the box". PMID- 17711435 TI - Radiofrequency ablation of complex fractionated atrial electrograms (CFAE): preferential sites of acute termination and regularization in paroxysmal and persistent atrial fibrillation. AB - INTRODUCTION: Complex fractionated atrial electrograms (CFAE) have been described as a new target for ablation of atrial fibrillation (AF). This prospective study evaluates the acute effects of CFAE ablation in patients with paroxysmal or persistent AF and analyzes the preferential anatomic sites where these effects occur. METHODS AND RESULTS: Ablation of CFAE was performed in 66 symptomatic patients (mean age of 58 +/- 12 years) with paroxysmal (n = 36) or persistent AF (n = 30). Termination or regularization of AF during ablation of CFAE was achieved in 56 of 66 patients (84%), with termination in 28 of 66 patients (42%) and regularization of AF in 28 of 66 patients (42%). Ablation of CFAE showed no effect in 10 of 66 patients (16%). Termination of AF occurred at 53 sites and AF regularization at 81 sites. The preferential sites of AF termination or regularization were found around the pulmonary veins (termination n = 15; regularization n = 22), at the anterior wall (termination n = 14; regularization n = 19) and at the interatrial septum (termination n = 8; regularization n = 17). CONCLUSION: Termination or regularization of AF was achieved acutely in 84% of patients by ablation of CFAE. The preferential sites of AF termination or regularization were found around the pulmonary veins, at the anterior wall of the LA and at the interatrial septum. These findings may have implications for future ablation concepts. PMID- 17711436 TI - Autonomic and pharmacological responses of idiopathic ventricular tachycardia arising from the left ventricular outflow tract. AB - BACKGROUND: It is well recognized that the mechanism of idiopathic ventricular tachycardia (VT) arising from the right ventricular outflow tract (RVOT) is mostly due to cyclic AMP-mediated triggered activity. The mechanism of VT arising from the left ventricular outflow tract (LVOT) has not been well clarified whether it is the same as VT of RVOT. METHODS: We studied autonomic modulations and pharmacological interventions on VT/premature ventricular contractions (PVCs) from LVOT to explore its possible mechanism in six patients (age: 49 +/- 14, three males). None of them had structural heart diseases. RESULTS: Isoproterenol application easily induced VT and/or PVCs from LVOT. Valsalva maneuvers suppressed isoproterenol-induced VT in two and PVCs in two, and carotid sinus massage (CSM) suppressed PVCs in one patient. Adenosine triphosphate inhibited both VT and PVCs in all six patients. Propranolol, lidocaine, and procainamide eliminated VT/PVCs in four, three, and four patients, respectively. Verapamil terminated VT in one and PVCs in another one patient, but aggravated PVCs to VT in one patient. CONCLUSION: The results suggest that the mechanism of VT from LVOT is mostly due to cAMP-mediated triggered activity as similar to that in VT from RVOT. PMID- 17711437 TI - The VA relationship after differential atrial overdrive pacing: a novel tool for the diagnosis of atrial tachycardia in the electrophysiologic laboratory. AB - INTRODUCTION: Despite recent advances in clinical electrophysiology, diagnosis of atrial tachycardia (AT) originating near Koch's triangle remains challenging. We sought a novel technique for rapid and accurate diagnosis of AT in the electrophysiologic laboratory. METHODS: Sixty-two supraventricular tachycardias including 18 ATs (10 ATs arising from near Koch's triangle), 32 atrioventricular nodal reentrant tachycardias (AVNRTs), and 12 orthodromic reciprocating tachycardias (ORTs) were studied. Overdrive pacing during the tachycardia from different atrial sites was performed, and the maximal difference in the postpacing VA intervals (last captured ventricular electrogram to the earliest atrial electrogram of the initial beat after pacing) among the different pacing sites was calculated (delta-VA interval). RESULTS: The delta-VA intervals were >14 ms in all AT patients and <14 ms in all AVNRT/ORT patients, and thus, the delta-VA interval was diagnostic for AT with the sensitivity, specificity, and positive and negative predictive values all being 100%. When the diagnostic value of the delta-VA interval and conventional maneuvers were compared for differentiating AT from atypical AVNRT, both a delta-VA interval >14 ms and "atrial-atrial-ventricular" response after overdrive ventricular pacing during the tachycardia were diagnostic. However, the "atrial-atrial-ventricular" response criterion was available in only 52% of the patients because of poor ventriculoatrial conduction. CONCLUSIONS: The delta-VA interval was useful for diagnosing AT irrespective of patient conditions such as ventriculoatrial conduction. PMID- 17711438 TI - Focal arrhythmia confined within the coronary sinus and maintaining atrial fibrillation. AB - INTRODUCTION: The coronary sinus (CS) is a complex structure comprising a mesh of circumferential muscular fibers with oblique connections to both atria. We describe further evidence for the clinical importance of CS arrhythmogenicity in maintaining atrial fibrillation (AF) in humans. METHODS: Since January 2004, following a sequential approach, the CS and the inferior left atrium were ablated in 144 patients with symptomatic drug refractory AF. Patients were included for analysis when this step resulted in the electrical dissociation of the CS from both atria with restoration of sinus rhythm, but with continued arrhythmic activity in the CS. The electrophysiologic mechanism of the confined arrhythmia was considered as focal activity (automaticity or triggered activity) by the presence of electrograms spanning less than 75% of the cycle length in the CS. RESULTS: After restoration of sinus rhythm, four male patients (3% of the patients, three persistent and one permanent AF) were identified in whom arrhythmia continued within the CS. Repetitive activity confined to the disconnected CS was inconsistent in occurrence, as well as in duration (1 sec to 15 min) and cycle length (from 158 to 380 ms). For all four patients, electrogram mapping of the entire CS was compatible with a focal mechanism. In two patients, bursts alternating with slow dissociated activity suggested automaticity. In one patient, local activity consistently coupled to the previous sinus beat favored triggered activity. CONCLUSIONS: This study provides evidence that the CS may be a potential source of focal rapid activity maintaining AF. PMID- 17711439 TI - Response to cardiac resynchronization therapy predicts survival in heart failure: a single-center experience. AB - OBJECTIVE: To determine whether survival after cardiac resynchronization therapy (CRT) is related to improvement in clinical or echocardiographic parameters. BACKGROUND: In clinical trials, CRT improved symptoms, left ventricular (LV) structure, function, and survival. In clinical practice, response to CRT is highly variable and whether survival benefit is confined to those patients who experience improvement in clinical status or cardiac structure and function is unclear. METHODS: This is a single-center study of patients receiving clinically indicated CRT between January 2002 and December 2004. RESULTS: Of 309 patients (age 68 +/- 11 years, 83% male) receiving CRT at our institution during the study period, 174 returned for follow-up and 127 had repeat echocardiography. Baseline clinical characteristics and survival were similar among those who did or did not return for follow-up. In paired analyses, New York Heart Association (NYHA) class (-0.56 +/- 0.07, p < 0.0001), ejection fraction (EF, 6.3 +/- 0.7%, P < 0.0001), LV dimension (-2.7 +/- 0.6 mm, P < 0.0001), pulmonary artery systolic pressure (PASP, -4.6 +/- 1.3 mm Hg, P = 0.0007), and MR severity grade (-0.20 +/- 0.05, P = 0.0002) improved after CRT. Survival after CRT was associated with decrease in NYHA class (risk ratio [RR]= 0.43, P = 0.0004), increase in EF (RR = 0.94, P = 0.02), and decrease in PASP (RR = 0.96, P = 0.03). Change in EF and NYHA class were correlated (r = -0.46, P < 0.0001) and, adjusting for this covariance, change in NYHA (P = 0.04) but not EF (P = 0.12) was associated with improved survival. CONCLUSION: Patients who experience improved symptoms, ventricular function, and/or hemodynamics have better survival after CRT. These data enhance understanding of the relationship between CRT clinical response and survival benefit in clinical practice. PMID- 17711440 TI - In vivo effects of mutant HERG K+ channel inhibition by disopyramide in patients with a short QT-1 syndrome: a pilot study. AB - INTRODUCTION: Quinidine has been evaluated in patients with a short QT-1 syndrome caused by an IKr gain-of-function mutation of HERG. Recently, in vitro data with disopyramide showed an even stronger effect on the N588K mutant current. The aim of the present study was to test the in vivo effects of disopyramide in patients with short QT-1 syndrome caused by a N588K mutation in HERG. METHODS AND RESULTS: Repetitive ECGs were recorded in two female patients with short QT-1 syndrome with a N588K-HERG mutation off drugs, on oral quinidine, and on oral disopyramide. One patient underwent exercise testing on drugs to determine the QT interval to heart rate relation, whereas the QT interval was calculated to the peak of the T wave in lead V3. In the same patient, drug-induced changes in ventricular effective refractory periods were determined by programmed ventricular stimulation via the ICD lead. Disopyramide increased the QT interval from QTc 329 ms/QTc 315 ms, respectively, off drugs to QTc 358 ms/QTc 333 ms in both patients and restored the heart rate dependence of the QT interval toward normal subjects (-0.39 ms/bpm off drugs, -0.58 ms/bpm on disopyramide vs. 1.29 +/ 0.33 ms/bpm in normal subjects). The ventricular effective refractory period increased under disopyramide by 40 ms. CONCLUSION: These preliminary observations suggest that oral disopyramide may be a suitable alternative to quinidine for prolonging the QT interval and ventricular effective refractory periods in patients with short QT-1 syndrome. Further studies of this pharmacologic approach are warranted. PMID- 17711441 TI - Validation of the frequency spectra obtained from the noncontact unipolar electrograms during atrial fibrillation. AB - INTRODUCTION: Noncontact mapping (NCM) can record virtual unipolar electrograms (Egs) from multiple sites simultaneously; therefore, it has the potential to perform simultaneous frequency mapping during atrial fibrillation (AF). The aim of this study was to validate the frequency spectra of the noncontact unipolar Egs in both atria. METHODS: This study enrolled 12 patients (age = 61 +/- 16 years) with paroxysmal or persistent AF who underwent catheter ablation guided by NCM. Noncontact and contact unipolar Egs were recorded simultaneously. The cross correlation of the Eg morphology, activation time difference of the time-domain signals, and resultant frequency spectra were compared via dominant frequency (DF) and magnitude-squared coherence (MSC). RESULTS: A total of 159 sites were analyzed during AF. The variables that independently predicted a higher correlation between the contact and noncontact electrogram morphology were a smaller activation timing difference P < 0.01), smaller distance of the mapping sites to the array center (P = 0.01), and higher atrial voltage (P = 0.03). However, the average MSC of the frequency band within the physiologic range of AF (2 to 15 Hz) was only affected by the activation timing difference (P = 0.002). The DF value between the contact and noncontact unipolar signals correlated well with each other throughout the right atria and left atria in 94% of the mapping sites (r = 0.87, P < 0.001). CONCLUSION: The accuracy of the noncontact unipolar Eg morphology decreased when the mapping sites harbored a smaller atrial voltage and longer distance to the array center. The DF difference between the contact and noncontact unipolar Eg was not affected by the distance to the array center. PMID- 17711442 TI - Increasing gap junction coupling reduces transmural dispersion of repolarization and prevents torsade de pointes in rabbit LQT3 model. AB - INTRODUCTION: Increased transmural dispersion of repolarization (TDR) contributes importantly to the development of torsades de pointes (TdP) in long QT syndrome (LQTS). Intercellular electrical coupling via gap junctions plays an important role in maintaining TDR in both normal and diseased hearts. This study examined the effects of antiarrhythmic peptide AAP10, a gap junction enhancer, on TDR and induction of TdP in a rabbit LQT3 model. METHODS AND RESULTS: An arterially perfused rabbit left ventricular preparation and sea anemone toxin II (ATX-II, 20 nM) were used to establish a LQT3 model. Transmural ECG as well as action potentials from both endocardium and epicardium were simultaneously recorded. Changes in nonphosphorylated connexin43 (Cx43) were measured by immunoblotting. Compared with the control group, the QT interval, TDR, early afterdepolariztion (EAD), R-on-T extrasystole, and TdP increased sharply with augmented nonphosphorylated Cx43 in the LQT3 group (P < 0.001 for both). Interestingly, compared with the LQT3 group, 500 nM AAP10 reduced QT interval, TDR (P < 0.001 for both), and prevented EAD, R-on-T extrasystole, and TdP (P = 0.003, P = 0.001, P = 0.02) with a parallel decrease in nonphosphorylated Cx43 in the presence of ATX-II (P < 0.001). CONCLUSION: Gap junction enhancer AAP10 is capable of abbreviating the QT interval, reducing TDR, and suppressing TdP in a rabbit LQT3 model probably via its effect by preventing dephosphorylation of Cx43. These data suggest that increasing intercellular coupling may reduce TDR and, therefore, prevent TdP in LQTS. PMID- 17711443 TI - Molecular epidemiological study of hepatitis B virus in Thailand based on the analysis of pre-S and S genes. AB - AIMS: This study was undertaken to determine the prevalence and characteristics of hepatitis B virus (HBV) genotypes, antigen subtypes, "a" determinant variants and pre-S gene mutations circulating on a large scale in Thailand. METHODS: The sequences of the Pre-S1, Pre-S2 and S regions were determined in serum samples of 147 HBsAg and HBV DNA-positive subjects who had been enrolled from the nationwide seroepidemiological survey conducted on 6213 individuals in 2004. RESULTS: The results showed that genotypes C, B and A accounted for 87.1%, 11.6% and 1.3%, respectively. The distribution of the HBV antigen subtypes was: adr (84.4%), adw (14.2%) and ayw (1.4%). Regarding the "a" determinant, 2/43 (4.65%) and 2/104 (1.92%) samples of vaccinated and non-vaccinated subjects, respectively, displayed mutations, all ofwhich were Thr126Asn. Sequencing analysis showed the pre-S mutations in 14 (9.5%) samples, with pre-S2 deletion as the most common mutant (4.1%) followed by pre-S2 start codon mutation (2.9%), both pre-S2 deletion and start codon mutation (2.0%), and pre-S1 deletion (0.7%). The pre-S mutations were associated with older age and higher mean serum HBsAg level. CONCLUSION: This study demonstrated that HBV genotype/subtype C/adr and B/adw were the predominant strains circulating in Thailand. The "a" determinant variants seemed to be uncommon, and might not be attributed to vaccine-induced mutation. PMID- 17711444 TI - EMA-CO chemotherapy for high-risk gestational trophoblastic neoplasia: a clinical analysis of 54 patients. AB - This study was designed to analyze the outcomes of chemotherapy for high-risk gestational trophoblastic neoplasia (GTN) with EMA-CO regimen as primary and secondary protocol in China. Fifty-four patients with high-risk GTN received 292 EMA/CO treatment cycles between 1996 and 2005. Forty-five patients were primarily treated with EMA-CO, and nine were secondarily treated after failure to other combination chemotherapy. Adjuvant surgery and radiotherapy were used in the selected patients. Response, survival and related risk factors, as well as chemotherapy complications, were retrospectively analyzed. Thirty-five of forty five patients (77.8%) receiving EMA-CO as first-line treatment achieved complete remission, and 77.8% (7/9) as secondary treatment. The overall survival rate was 87.0% in all high-risk GTN patients, with 93.3% (42/45) as primary therapy and 55.6% (5/9) as secondary therapy. The survival rates were significantly different between two groups (chi(2)= 6.434, P =0.011). Univariate analysis showed that the metastatic site and the number of metastatic organs were significant risk factors, but binomial distribution logistic regression analysis revealed that only the number of metastatic organs was an independent risk factor for the survival rate. No life-threatening toxicity and secondary malignancy were found. EMA-EP regimen was used for ten patients who were resistant to EMA-CO and three who relapsed after EMA-CO. Of those, 11 patients (84.6%) achieved complete remission. We conclude that EMA-CO regimen is an effective and safe primary therapy for high-risk GTN, but not an appropriate second-line protocol. The number of metastatic organs is an independent prognostic factor for the patient with high-risk GTN. EMA-EP regimen is a highly effective salvage therapy for those failing to EMA-CO. PMID- 17711446 TI - Ki67 and cyclin A as prognostic factors in early breast cancer. What are the optimal cut-off values? AB - AIMS: To find the optimal cut-off values for cyclin A and Ki67 in early breast cancer tumours and to evaluate their prognostic values. METHODS AND RESULTS: Tissue microarray (TMA) slides were constructed from 570 T1-4 N0-1 M0 breast cancer tumours. The TMA slides were stained for cyclin A and Ki67 using immunohistochemistry with commercial antibodies. To investigate the optimal cut off values for cyclin A, Ki67 average and maximum values the material was split into two parts at cut-offs defined by dividing it into deciles. For each cut-off value the relative risk (RR) for metastasis-free survival (MFS) and overall survival (OS) was calculated comparing patients with high versus low cyclin A or Ki67 expression. When using a cut-off value around the seventh decile, cyclin A and Ki67 score correlated with the highest RR ratio for MFS in the chemotherapy naive subgroup. Among patients having received adjuvant chemotherapy, no statistically significant differences in MFS or OS were found. CONCLUSIONS: The optimal cut-off value for cyclin A average is 8% and for cyclin A maximum value 11%; for Ki67 the corresponding values are 15% and 22%. Additional studies are needed to verify these results. PMID- 17711445 TI - Reversal of expression of 15-lipoxygenase-1 to cyclooxygenase-2 is associated with development of colonic cancer. AB - AIMS: Two different pathways of linoleic acid (LA) metabolism have opposite effects on the development of colonic cancer: a protumoral prostaglandin cascade metabolized by cyclooxygenase (COX)-2, and an antitumoral peroxisome proliferator activated receptor (PPAR)-gamma ligands metabolized by 15-lipooxygenase (LOX)-1. The aim was to examine the switching of the two LA metabolic pathways in colonic adenomas and carcinomas. MATERIALS AND METHODS: The expression of 15LOX-1 mRNA and COX-2 protein was examined in 54 adenomas, 21 pTis carcinoma-in-adenoma lesions and 36 pT3/p Stage II carcinomas of the colon by in-situ hybridization and immunohistochemistry, respectively. RESULTS: 15LOX-1 expression was found in 89% (48 of 54) of adenomas, 43% (nine of 21) of adenomas and 10% (two of 21) of carcinomas in carcinoma-in-adenoma lesions, but not in pT3 carcinomas (P < 0.0001). In contrast, COX-2 production was found in 11% (six of 54) of adenomas, 52% (11 of 21) of adenomas and 71% (15 of 21) of carcinomas in carcinoma-in adenoma lesions, and 92% (33 of 36) of pT3 carcinomas (P < 0.0001). Concurrence of 15LOX-1 down-regulation and COX-2 up-regulation was found in 6% (three of 54) of adenomas, 33% (seven of 21) of adenomas and 71% (15 of 21) of carcinomas in carcinoma-in-adenoma lesions, and 92% (33 of 36) of pT3 carcinomas (P < 0.0001). CONCLUSIONS: These results suggest that switching of LA metabolism by reversal of the expression of 15LOX-1 and COX-2 is associated with acquisition of malignant potential in colonic neoplasia. PMID- 17711447 TI - Immunohistochemistry for beta-catenin in the differential diagnosis of spindle cell lesions: analysis of a series and review of the literature. AB - AIMS: Nuclear staining for beta-catenin by immunohistochemistry is being used increasingly to diagnose desmoid tumours (deep fibromatoses), especially where the differential diagnosis includes other abdominal spindle cell neoplasms. This study aimed to define the prevalence of beta-catenin positivity in desmoid tumours and other morphologically similar spindle cell neoplasms. METHOD AND RESULTS: Nuclear beta-catenin expression was evaluated by immunohistochemistry in 270 soft tissue tumours. Nuclear immunopositivity was detected in 80% of cases of sporadic desmoid fibromatosis (24/30) and in 67% of tumours in patients with familial adenomatous polyposis (8/12). Nuclear positivity was also present in 14/25 superficial fibromatoses (56%), 3/10 low-grade myofibroblastic sarcomas (30%), 5/23 solitary fibrous tumours (22%), 1/5 infantile fibrosarcomas (20%), 1/18 desmoplastic fibroblastomas (6%) and 1/21 gastrointestinal stromal tumours (5%). No nuclear immunoreactivity was present in neurofibromas (0/26), schwannomas (0/25), nodular fasciitis (0/19), leiomyosarcomas (0/16), inflammatory myofibroblastic tumours (0/12), fibromas of tendon sheath (0/9), lipofibromatoses (0/5), Gardner fibromas (0/4), calcifying aponeurotic fibromas (0/4) or fibromatosis colli (0/1). CONCLUSION: Nuclear staining for beta-catenin is supportive, but not definitive, of the diagnosis of desmoid fibromatosis. No significant difference in immunoreactivity was observed between sporadic and familial desmoid fibromatoses. beta-Catenin negativity does not preclude the diagnosis of fibromatosis. PMID- 17711448 TI - Distribution and significance of the oesophageal and gastric cardiac mucosae: a study of 131 operation specimens. AB - AIMS: To clarify the distribution and significance of the oesophageal and gastric cardiac mucosae at the oesophago-gastric junction (EGJ). METHODS AND RESULTS: Oesophagectomy specimens from 131 consecutive patients with middle and upper thoracic oesophageal cancer were examined. The surgically resected specimens including the EGJ were cut into 5 mm thick serial sections and examined histopathologically for the length of the oesophageal and gastric cardiac mucosae and the incidence of columnar epithelial islands (CEIs). We also determined the presence of short-segment Barrett's oesophagus (SSBE) and goblet cell metaplasia in SSBE. Oesophageal cardiac mucosa was found in 125 cases (95%) and gastric cardiac mucosa was found in all cases. The mean length of the oesophageal and gastric cardiac mucosa was 4 mm (range 1-26 mm) and 13 mm (range 2-64 mm), respectively. CEIs were found in 75 cases (57%). SSBE was found in 70 cases (53%), among which goblet cell metaplasia was found in 28 cases (21%). No long segment Barrett's oesophagus was found. The mean length of oesophageal cardiac mucosa (6 mm) and gastric cardiac mucosa (17 mm) in SSBE was significantly greater than that (3 mm and 8 mm, respectively) in non-SSBE cases (P < 0.0001 and P < 0.0001). The incidence (69%) of CEIs in SSBE was significantly higher than that (44%) in non-SSBE cases (P = 0.005). CONCLUSIONS: Oesophageal and gastric cardiac mucosae were found frequently. Oesophageal cardiac glands and CEIs might play an important role in the development of SSBE. PMID- 17711449 TI - Increased cytoplasmic level of migfilin is associated with higher grades of human leiomyosarcoma. AB - AIMS: Leiomyosarcomas (LMS) are malignant neoplasms composed of cells that exhibit distinct smooth muscle differentiation. The molecular and cytogenetic features of LMS are complex and no consistent aberrations have been reported to date. Mitogen inducible gene-2 (Mig-2), kindlin and migfilin are recently identified cell-matrix adhesion proteins. The aim was to determine the expression and distribution of these proteins in human smooth muscle tumours of somatic soft tissue. METHODS AND RESULTS: Immunohistochemistry was performed on a human LMS tissue microarray and on sections of human leiomyomas (LM) and normal smooth muscle. Migfilin was barely detectable in normal smooth muscle cells, whereas increased levels of migfilin were observed in the majority of LM and LMS. Furthermore, the cytoplasmic level of migfilin was strongly associated with higher tumour grades. Additionally, the cytoplasmic levels of migfilin and Mig-2 were correlated with each other, suggesting an association between the two in the cytoplasm. Kindlin was expressed in normal smooth muscle, LM and LMS, and its level did not correlate with tumour grade. CONCLUSIONS: Our results suggest a role for cytoplasmic migfilin in the progression of LMS and identify cytoplasmic migfilin as a potentially important biological marker for human LMS progression. PMID- 17711451 TI - Effects of maternal strain on ethanol responses in reciprocal F1 C57BL/6J and DBA/2J hybrid mice. AB - Variations in maternal behavior, either occurring naturally or in response to experimental manipulations, have been shown to exert long-lasting consequences on offspring behavior and physiology. Despite previous research examining the effects of developmental manipulations on drug-related phenotypes, few studies have specifically investigated the influence of strain-based differences in maternal behavior on drug responses in mice. The current experiments used reciprocal F1 hybrids of two inbred mouse strains (i.e. DBA/2J and C57BL/6J) that differ in both ethanol (EtOH) responses and maternal behavior to assess the effects of maternal environment on EtOH-related phenotypes. Male and female DBA/2J and C57BL/6J mice and their reciprocal F1 hybrids reared by either DBA/2J or C57BL/6J dams were tested in adulthood for EtOH intake (choice, forced), EtOH induced hypothermia, EtOH-induced activity and EtOH-induced conditioned place preference (CPP). C57BL/6J and DBA/2J mice showed differences on all EtOH responses. Consistent with previous reports that maternal strain can influence EtOH intake, F1 hybrids reared by C57BL/6J dams consumed more EtOH during forced exposure than did F1 hybrids reared by DBA/2J dams. Maternal strain also influenced EtOH-induced hypothermic responses in F1 hybrids, producing differences in hybrid mice that paralleled those of the inbred strains. In contrast, maternal strain did not influence EtOH-induced activity or CPP in hybrid mice. The current findings indicate that maternal environment may contribute to variance in EtOH-induced hypothermia and EtOH intake, although effects on EtOH intake appear to be dependent upon the type of EtOH exposure. PMID- 17711450 TI - The brain 5-HT1A receptor gene expression in hibernation. AB - Hibernation is a unique physiological state characterized by profound reversible sleep-like state, depression in body temperature and metabolism. The serotonin 5 hydroxytryptamine(1A) (5-HT(1A)) receptor gene sequence in typical seasonal hibernator, ground squirrel (Spermophilus undulatus), was specified. It was found that the fragment encoding the fifth transmembrane domain showed 93.6% of homology with the analogous fragment of the mouse and rat genes and displayed 88.5% homology with the human 5-HT(1A) receptor gene. Using primers designed on the basis of obtained sequence, the expression of 5-HT(1A) receptor gene in the brain regions in active, entering into hibernation, hibernating and coming out of hibernation ground squirrels was investigated. Significant structure-specific changes were revealed in the 5-HT(1A) messenger RNA (mRNA) level in entry into hibernation and in arousal. An increase in the 5-HT(1A) gene expression was found in the hippocampus during the prehibernation period and in ground squirrels coming out of hibernation, thus confirming the idea of the hippocampus trigger role in the hibernation. Significant decrease in 5-HT(1A) receptor mRNA level in the midbrain was found in animals coming out of hibernation. There was no considerable changes in 5-HT(1A) receptor mRNA level in different stages of sleep wake cycle in the frontal cortex. Despite drastically decreased body temperature in hibernating animals (about 37 degrees C in active and 4-5 degrees C in hibernation), 5-HT(1A) receptor mRNA level in all examined brain regions remained relatively high, suggesting the essential role of this 5-HT receptor subtype in the regulation of hibernation and associated hypothermia. PMID- 17711452 TI - The ptsP gene encoding the PTS family protein EI(Ntr) is essential for dimethyl sulfone utilization by Pseudomonas putida. AB - Many bacteria living in soil have developed the ability to use a wide variety of organosulfur compounds. Pseudomonas putida strain DS1 is able to utilize dimethyl sulfide as a sulfur source via a series of oxidation reactions that sequentially produce dimethyl sulfoxide, dimethyl sulfone (DMSO2), methanesulfonate, and sulfite. To isolate novel genes involved in DMSO2 utilization, a transposon-based mutagenesis of DS1 was performed. Of c. 10,000 strains containing mini-Tn5 inserts, 11 mutants lacked the ability to utilize DMSO2, and their insertion sites were determined. In addition to the cysNC, cysH, and cysM genes involved in sulfate assimilation, the ptsP gene encoding the phosphoenolpyruvate:sugar phosphotransferase system (PTS) family protein EI(Ntr) was identified, which is necessary for DMSO2 utilization. Using quantitative reverse transcriptase polymerase chain reaction analysis, it was demonstrated that the expression of the sfn genes, necessary for DMSO2 utilization, was impaired in the ptsP disruptant. To the authors' knowledge, this is the first report of a PTS protein that is involved in bacterial assimilation of organosulfur compounds. PMID- 17711453 TI - Cloning and characterization of a haloarchaeal heat shock protein 70 functionally expressed in Escherichia coli. AB - The Hsp70 molecular chaperone machine is constituted by the 70-kDa heat shock protein Hsp70 (DnaK), cochaperone protein Hsp40 (DnaJ) and a nucleotide-exchange factor GrpE. Although it is one of the best-characterized molecular chaperone machines, little is known about it in archaea. A 5.2-kb region containing the hsp70 (dnaK) gene was cloned from Natrinema sp. J7 strain and sequenced. It contained the Hsp70 chaperone machine gene locus arranged unidirectionally in the order of grpE, hsp70 and hsp40 (dnaJ). The hsp70 gene from Natrinema sp. J7 was overexpressed in Escherichia coli BL21 (DE3). The recombinant Hsp70 protein was in a soluble and active form, and its ATPase activity was optimally active in 2.0 M KCl, whereas NaCl had less effect. In vivo, the haloarchaeal hsp70 gene allowed an E. coli dnak-null mutant to propagate lambda phages and grow at 42 degrees C. The results suggested that haloarchaeal Hsp70 should be beneficial for extreme halophiles survival in low-salt environments. PMID- 17711454 TI - Effects of inoculation with plant growth-promoting rhizobacteria on resident rhizosphere microorganisms. AB - Plant growth-promoting rhizobacteria (PGPR) are exogenous bacteria introduced into agricultural ecosystems that act positively upon plant development. However, amendment reproducibility as well as the potential effects of inoculation upon plant root-associated microbial communities can be sources of concern. To address these questions, an understanding of mutual interactions between inoculants and resident rhizosphere microorganisms is required. Mechanisms used by PGPR can be direct or indirect; the former entails the secretion of growth regulators and the latter occurs through the production of antimicrobial compounds that reduce the deleterious effects of phytopathogens. The different modes of action may lead to different relationships between an inoculant and root microbial communities. Rhizobacterial communities are also affected by the plant, engineered genes, environmental stresses and agricultural practices. These factors appear to determine community structure more than an exogenous, active PGPR introduced at high levels. PMID- 17711455 TI - Manganese affects the production of laccase in the basidiomycete Ceriporiopsis subvermispora. AB - The authors have previously identified and characterized lcs, a gene encoding laccase in the white-rot basidiomycete Ceriporiopsis subvermispora. In this work, the effect of Mn2+ in the production of extracellular laccase in liquid cultures of this fungus has been assessed. It was observed that at low (0-10 microM) concentrations of Mn2+, high titers of lcs-mRNA were obtained, whereas at high (160-194 microM) concentrations of this metal ion, transcripts levels decreased markedly. This phenomenon was observed at different days of growth. On the other hand, Cu2+ or Ag+, but not Zn2+ or Cd2+, led to an accumulation of lcs transcripts only in cultures grown in the absence of Mn2+. A dramatic increase in lcs transcript levels was also obtained with syringic acid, a lignin-related aromatic compound. This effect was more pronounced in cultures lacking Mn2+. In the course of these studies it was observed that Mn2+ stimulates mycelium growth. Thus, although extracellular laccase activity appeared higher in cultures containing 160 or 194 microM Mn2+, i.e. when lcs transcripts were lower, a correlation between lcs-mRNA levels and enzymatic activity was observed when values of the latter were corrected by the amount of mycelium present in the cultures. PMID- 17711456 TI - Genome sequence of Streptococcus mutans bacteriophage M102. AB - Bacteriophage M102 is a lytic phage specific for serotype c strains of Streptococcus mutans, a causative agent of dental caries. In this study, the complete genome sequence of M102 was determined. The genome is 31,147 bp in size and contains 41 ORFs. Most of the ORFs encoding putative phage structural proteins show similarity to those from bacteriophages from Streptococcus thermophilus. Bioinformatic analysis indicated that the M102 genome contains an unusual lysis cassette, which encodes a holin and two lytic enzymes. PMID- 17711457 TI - Heterogeneous rRNAs are differentially expressed during the morphological development of Streptomyces coelicolor. AB - It is generally assumed that all mature rRNA molecules assembled into ribosomes within a single cell are identical. However, sequence analysis of Streptomyces coelicolor genome revealed that it harbors six copies of divergent rRNA operons that may express and constitute three and five different kinds of small subunit (SSU) and large subunit (LSU) rRNA molecules, respectively, in a single cell. Phylogenetic analyses of the LSU rRNA genes and the internal transcribed spacer between SSU and LSU genes indicated that the LSU gene of rrnA and rrnE operons might be the result of interspecies recombination between rRNA genes in closely related streptomycetes. Profiling of rRNA species using primer extension analysis showed that heterogeneous rRNA transcripts are expressed and assembled into ribosomes in the cell. As the cells developed from germination to sporulation, the relative amount of LSU rRNA molecules derived from three rRNA operons (rrnA, D, and E) gradually decreased from approximately 85% to approximately 60%, whereas the distribution of LSU rRNA molecules from two other operons (rrnB and F) and rrnC operon gradually increased from approximately 10% to approximately 20% of the total LSU rRNA. These findings indicate that heterogeneous rRNA molecules are differentially expressed during the life cycle of this developmentally complex microorganism. PMID- 17711458 TI - Contribution of SPI-4 genes to the virulence of Salmonella enterica. AB - Salmonella pathogenicity island-4 (SPI-4) is a 27-kb region that carries six genes designated siiABCDEF. SiiC, SiiD, and SiiF form a type I secretion apparatus for the secretion of SiiE, a huge (approximately 600 kDa) protein contributing to the colonization of the bovine intestines. Here it is shown that loss of SPI-4 attenuates the oral virulence of Salmonella enterica serovars Typhimurium and Enteritidis in mice. Fifty percent lethal doses were elevated in both serovars upon the loss of SPI-4. Moreover, delta SPI-4 mutants were outcompeted in systemic organs by their wild-type strains in a cochallenge model. Contribution of SPI-4 to virulence appeared less pronounced in the S. Enteritidis strain, which was justified by lower levels of the secreted protein SiiE in this strain in comparison with S. Typhimurium. Competition assays with isogenic mutants lacking individual genes of the island showed that all six genes were required for full virulence of S. Typhimurium. Delta siiA and delta siiB mutants were, nevertheless, able to secrete SiiE to culture supernatants. The amount of secreted SiiE was, however, reduced in these two mutants compared with the wild type strain. Furthermore, a down-regulation of SiiE levels is shown in structural and regulatory lipopolysaccharide mutants exhibiting the deep-rough phenotype. PMID- 17711459 TI - Genetically engineered Fusarium as a tool to evaluate the effects of environmental factors on initiation of trichothecene biosynthesis. AB - Fusarium graminearum was engineered for expression of enhanced green fluorescent protein gene (egfp) as a reporter regulated in a manner similar to Tri5, a key pathway gene in trichothecene biosynthesis. Using the transgenic fungus, it was found that the reporter gene was induced to express in aerial hyphae developed on trichothecene noninducing medium YG solidified by agar. Unexpectedly, the transcriptional activation of egfp was markedly suppressed by adding NaCl that does not significantly affect fungal growth. As suggested by these findings, wild type F. graminearum that formed aerial hyphae on YG agar plates produced trichothecenes and the production was effectively suppressed by adding 1% NaCl to the agar. To evaluate the effects of abiotic stress on the expression of trichothecene biosynthesis (Tri) genes, a sensitive plate assay was established using GYEP medium (which very weakly induces trichothecene production) solidified with gellan gum. Using this assay, triazole fungicides were shown to cause transcriptional activation of egfp at sublethal concentrations. Indeed, trichothecene production significantly increased when F. graminearum was grown in rice medium (which moderately induces trichothecene) amended with low doses of tebuconazole. The real-time monitoring system described here may help predict the risks of trichothecene contamination by the fungus under various environmental conditions. PMID- 17711460 TI - A case with atypical childhood occipital epilepsy "Gastaut type": an ictal migraine manifestation with a good response to intravenous diazepam. AB - We report the history of a 14-year-old girl with atypical childhood occipital epilepsy "Gastaut type" whose first generalized tonic-clonic seizure was preceded by migraine without aura and followed by a status migrainosus. This status lasted for 3 days despite standard analgesic therapy. An EEG recording revealed an occipital status epilepticus during her migraine complaints. Seven minutes after intravenous administration of 10 mg diazepam under continuous EEG recording, a suppression of the epileptiform discharges over the right occipital was seen, while the headache subsided 3 min later. After precise questioning about the circumstances that possibly could have led to these events, it appeared that she had played for hours with a play station on the new color TV and she had visited an exhibition of Matisse and Bonnard with bright colors and contrast-rich text. Standardized extensive intermittent photic stimulation (IPS), 2 days after the status migrainosus, evoked besides asymmetrical right-sided driving, green spots in her left visual field, while in the EEG sharp waves were recorded over the right parietotemporal region. After further IPS with 20 Hz (eye closure), she started complaining of a light pulsating headache right occipitally and in the EEG right parietotemporal sharp-waves were seen. This lasted for about 10 min. Later, an interictal routine EEG was normal except for some theta over the right temporooccipital area. The most likely diagnosis is an atypical form of occipital epilepsy "Gastaut type." We would therefore advocate recording EEGs with photic stimulation in patients with atypical migraneous features. PMID- 17711461 TI - Anticonvulsant effects of carbamazepine on spontaneous seizures in rats with kainate-induced epilepsy: comparison of intraperitoneal injections with drug-in food protocols. AB - PURPOSE: The present study evaluated the effectiveness of intraperitoneal (IP) injections and oral administration of carbamazepine (CBZ) in food on the frequency of spontaneous motor seizures in rats with kainate-induced epilepsy. The purpose was to develop a convenient drug-in-food approach for continuous, long-term administration of potential antiepileptic drugs (AEDs). METHODS: Single IP injections of CBZ (10-100 mg/kg) were compared to vehicle injections via six AED-versus-vehicle tests using a repeated-measures, crossover protocol. Similar protocols were used with CBZ-containing or control food pellets. RESULTS: CBZ significantly reduced motor seizure frequency at 30 and 100 mg/kg after single IP injections, and these doses completely blocked motor seizures during a 6-h postdrug epoch in 25% and 70% of the animals, respectively. Single administrations of 30 mg/kg and 100 mg/kg CBZ in food also significantly reduced motor seizures, and blocked seizures in 33% and 89% of the rats, respectively. CBZ administered in food three times per day (100 mg/kg x3 CBZ in food) continuously blocked nearly all motor seizures over a 5-day period, and completely suppressed motor seizures in 50% of the animals tested. CONCLUSIONS: CBZ strongly suppresses spontaneous motor seizures, and single doses of CBZ in food are as effective as IP injections in rats with kainate-induced epilepsy. CBZ administered regularly in food continuously blocks nearly all motor seizures, and may provide a relatively simple method to test AEDs in chronic models of epilepsy. PMID- 17711462 TI - Are psychiatric adverse events of antiepileptic drugs a unique entity? A study on topiramate and levetiracetam. AB - PURPOSE: To investigate the hypothesis that some patients with epilepsy are generally prone to develop psychiatric adverse events (PAEs) during antiepileptic drug (AED) therapy irrespective of the mechanism of action of the drugs. METHODS: From a large case registry of patients prescribed topiramate (TPM) and levetiracetam (LEV), data of patients who had a trial with both drugs were analyzed. Demographic and clinical variables of those who developed PAEs with both drugs (group 1) were compared with those who did not (group 2). Subsequently, from the whole case registry, psychopathological features, demographic, and clinical variables of patients developing PAEs with TPM were compared with those of patients developing PAEs with LEV. RESULTS: The case registry included over 800 patients. Among 108 patients having a trial with both drugs, we identified 9 patients in group 1 and 71 in group 2. Previous psychiatric history, family psychiatric history and history of febrile convulsions showed to be significant clinical correlates. Comparing patients who developed PAEs with LEV with those who developed PAEs with TPM, there were no differences in epilepsy related variables. Well-defined DSM-IV disorders were more frequent with TPM than with LEV. Seizure freedom was associated with psychosis. CONCLUSIONS: This study suggests that a subgroup of patients is generally prone to develop PAEs during AED therapy, despite different pharmacological properties of the AEDs. A particular clinical profile and relevant variables have been identified. PMID- 17711463 TI - Effects of migration on the genetic covariance matrix. AB - In 1996, Schluter showed that the direction of morphological divergence of closely related species is biased toward the line of least genetic resistance, represented by g(max), the leading eigenvector of the matrix of genetic variance covariance (the G-matrix). G is used to predict the direction of evolutionary change in natural populations. However, this usage requires that G is sufficiently constant over time to have enough predictive significance. Here, we explore the alternative explanation that G can evolve due to gene flow to conform to the direction of divergence between incipient species. We use computer simulations in a mainland-island migration model with stabilizing selection on two quantitative traits. We show that a high level of gene flow from a mainland population is required to significantly affect the orientation of the G-matrix in an island population. The changes caused by the introgression of the mainland alleles into the island population affect all aspects of the shape of G (size, eccentricity, and orientation) and lead to the alignment of g(max) with the line of divergence between the two populations' phenotypic optima. Those changes decrease with increased correlation in mutational effects and with a correlated selection. Our results suggest that high migration rates, such as those often seen at the intraspecific level, will substantially affect the shape and orientation of G, whereas low migration (e.g., at the interspecific level) is unlikely to substantially affect the evolution of G. PMID- 17711465 TI - Constraints on the origin and maintenance of genetic kin recognition. AB - Kin-recognition mechanisms allow helping behaviors to be directed preferentially toward related individuals, and could be expected to evolve in many cases. However, genetic kin recognition requires a genetic polymorphism on which recognition is based, and kin discriminating behaviors will affect the evolution of such polymorphism. It is unclear whether genetic polymorphisms used in kin recognition should be maintained by extrinsic selection pressures or not, as opposite conclusions have been reached by analytical one-locus models and simulations exploring different population structures. We analyze a two-locus model in a spatially subdivided population following the island model of dispersal between demes of finite size. We find that in the absence of mutation, selection eliminates polymorphism in most cases, except with extreme spatial structure and low recombination. With mutation, the population may reach a stable limit cycle over which both loci are polymorphic; however, the average frequency of conditional helping can be high only under strong structure and low recombination. Finally, we review evidence for extrinsic selection maintaining polymorphism on which kin recognition is based. PMID- 17711464 TI - Interaction between parental care and sibling competition: parents enhance offspring growth and exacerbate sibling competition. AB - Species with elaborate parental care often also show intense sibling competition over resources provided by parents, suggesting joint evolution of these two traits. Despite this, the evolution of elaborate parental care and the evolution of intense sibling competition are often studied separately. Here, we examine the interaction between parental food provisioning and sibling competition for resources through the joint manipulation of the presence or absence of parents and brood size in a species with facultative parental care: the burying beetle Nicrophorus vespilloides. The effect of the interaction between the presence or absence of parents and brood size was strong; brood size had a strong effect on growth when parents provided care, but no effect when parents were absent. As in previous studies, offspring grew faster when parents were present than when parents were absent, and offspring grew faster in smaller broods than in larger broods. Our behavioral observations showed that brood size had a negative effect on both the amount of time parents spent providing resources to individual offspring and the offspring's effectiveness of begging, confirming that the level of sibling competition increased with brood size. Furthermore, offspring in larger broods shifted more from begging toward self-feeding as they grew older compared to offspring in small broods. Our study provides novel insights into the joint evolution of parental care and sibling competition, and the evolution of offspring begging signals. We discuss the implications of our results in light of recent theoretical work on the evolution of parental care, sibling competition, and offspring begging signals. PMID- 17711466 TI - An experimental test of character displacement's role in promoting postmating isolation between conspecific populations in contrasting competitive environments. AB - Ecological character displacement takes place when two closely related species co occur in only part of their geographical range, and selection to minimize competition between them promotes divergence in resource-use traits in sympatry but not in allopatry. Because populations sympatric with the heterospecific competitor will experience a different competitive environment than conspecific populations in allopatry, conspecific populations from these two competitive environments will also diverge in resource traits as an indirect consequence of interspecific ecological character displacement. Ultimately, ecologically dependent postmating isolation may arise between conspecific populations from these divergent competitive environments if offspring produced by matings between them are competitively inferior in either type of competitive environment. Yet, there are no direct tests of character displacement's role in initiating such postmating isolation. Here, we present a test by comparing the phenotypes and performances of spadefoot toad tadpoles produced from between-competitive environment (BCE) matings versus those produced from within-competitive environment (WCE) matings. When raised with naturally occurring competitors, BCE offspring grew significantly less and were significantly smaller than WCE offspring. BCE offspring generally performed worse even when raised alone, suggesting that they may have harbored intrinsic genetic incompatibilities. Moreover, the difference in growth and body size of BCE versus WCE offspring was significantly greater when each was raised with competitors than when each was raised alone, suggesting that BCE tadpoles were competitively inferior to WCE tadpoles. Presumably, this enhanced difference arose because BCE tadpoles produced an intermediate resource-use phenotype that is less well adapted to either competitive environment. Because larval size is under strong, positive, directional selection, reduced growth and size of BCE offspring may diminish gene flow between populations in divergent competitive environments, thereby generating postmating isolation. Thus, postmating isolation between conspecific populations, and possibly even speciation, may arise as a by-product of interactions between species. PMID- 17711467 TI - Evidence of local adaptation to coarse-grained environmental variation in Arabidopsis thaliana. AB - Plants can achieve an appropriate phenotype in particular conditions either constitutively or plastically, depending in part on the grain size of the environmental conditions being considered. Coarse-grained environmental variation should result in selection for local adaptation and no selection on plasticity to novel levels of the coarse-grained environmental factors. We tested the hypotheses that natural populations of the well-studied model system Arabidopsis thaliana are locally adapted to spatially coarse-grained environmental variation, and that the photoperiodic regime per se is at least partially responsible for that local adaptation, by exposing natural populations to photoperiodic regimes characteristic of their native and foreign (novel) environments. We also tested the hypothesis that plasticity to novel photoperiodic regimes should appear random. We found that populations showed evidence of local adaptation at a spatially coarse grain, although not to photoperiodic regime per se. We also found that the plasticities to novel photoperiodic regimes appeared random and did not generally show evidence of adaptive divergence. Our study highlights the need for caution in extrapolating from the finding of local adaptation to the causes of local adaptation. PMID- 17711470 TI - Maternal body size as an evolutionary constraint on egg size in a butterfly. AB - Genetic and developmental constraints have often been invoked to explain patterns of existing morphologies. Yet, empirical tests addressing this issue directly are still scarce. We here set out to investigate the importance of maternal body size as an evolutionary constraint on egg size in the tropical butterfly Bicyclus anynana, employing an artificial two-trait selection experiment on simultaneous changes in body and egg size (synergistic and antagonistic selection). Selection on maternal body size and egg size was successful in both the synergistic and the antagonistic selection direction. Yet, responses to selection and realized heritabilities varied across selection regimes: the most extreme values for pupal mass were found in the synergistic selection directions, whereas in the antagonistic selection direction realized heritabilities were low and nonsignificant in three of four cases. In contrast, for egg size the highest values were obtained in the lines selected for low pupal mass. Thus, selection on body size yielded a stronger correlated response in egg size than vice versa, which is likely to bias (i.e., constrain), if weakly, evolutionary change in body size. However, it seems questionable whether this will prevent evolution toward novel phenotypes, given enough time and that natural selection is strong. Correlated responses to selection were overall weak. Egg and larval development times tended to be associated with changes in maternal size, whereas variation in pupal development times weakly tended to follow variation in egg size. Lifetime fecundity was similar across selection regimes, except for females simultaneously selected for large body mass and small egg size, exhibiting increased fecundity. Multiple regressions showed that lifetime fecundity and concomitantly reproductive investment were primarily determined by longevity, as expected for an income breeder, whereas egg size was primarily determined by pupal mass. Evidence for a phenotypic trade-off between egg size and number was weak. PMID- 17711468 TI - The likelihood node density effect and consequences for evolutionary studies of molecular rates. AB - Many molecular phylogenies show longer root-to-tip path lengths in species-rich groups, encouraging hypotheses linking cladogenesis with accelerated molecular evolution. However, the pattern can also be caused by an artifact called the node density effect (NDE): this effect occurs when the method used to reconstruct a tree underestimates multiple hits that would have been revealed by extra nodes, leading to longer root-to-tip path lengths in clades with more terminal taxa. Here we use a twofold approach to demonstrate that maximum likelihood and Bayesian methods also suffer from the NDE known to affect parsimony. First, simulations deliberately mismatching the simulation and reconstruction models show that the greater the model disparity, the greater the gap between actual and reconstructed tree lengths, and the greater the NDE. Second, taxon sampling manipulation with empirical data shows that NDE can still be present when using optimized models: across 12 datasets, 70 out of 109 sister path comparisons showed significant evidence of NDE. Unless the model fairly accurately reconstructs the real tree length-and given the complexity of real sequence evolution this may be uncommon -- it will consistently produce a node density artifact. At commonly encountered divergence levels, a 10% underestimation of tree length results in > or = 80% of simulated phylogenies showing a positive NDE. Bayesian trees have a slight but consistently stronger effect. This pervasive methodological artifact increases apparent rate heterogeneity, and can compromise investigations of factors influencing molecular evolutionary rate that use path lengths in topologically asymmetric trees. PMID- 17711472 TI - Density-dependent self-fertilization and male versus hermaphrodite siring success in an androdioecious plant. AB - Models of mating-system evolution emphasize the importance of frequency-dependent interactions among mating partners. It is also known that outcross siring success and the selfing rate in self-compatible hermaphrodites can be density dependent. Here, we use array experiments to show that the mating system (i.e., the outcrossing rate) and the siring success of morphs with divergent sex allocation strategies are both density dependent and frequency dependent in androdioecious populations of the wind-pollinated, annual plant Mercurialis annua. In particular, the outcrossing rate is a decreasing function of the mean interplant distance, regulated by a negative exponential pollen fall-off curve. Our results indicate that pollen dispersed from a male inflorescence are over 60% more likely to sire outcrossed progeny than equivalent pollen dispersed from hermaphrodites, likely due to the fact that males, but not hermaphrodites, disperse their pollen from erect inflorescence stalks. Because of this difference, and because males of M. annua produce much more pollen than hermaphrodites, the presence of males in the experimental arrays reduced both the selfing rate and the outcross siring success of hermaphrodites. We use our results to infer a density threshold below which males are unable to persist with hermaphrodites but above which they can invade hermaphroditic populations. We discuss our findings in the context of a metapopulation model, in which males can only persist in well-established populations but are excluded from small, sparse populations, for example, in the early stages of colonization. PMID- 17711473 TI - Cuckoo parasitism and productivity in different magpie subpopulations predict frequencies of the 457bp allele: a mosaic of coevolution at a small geographic scale. AB - The level of defense against great spotted cuckoo (Clamator glandarius) parasitism in different European populations of magpie (Pica pica) depends on selection pressures due to parasitism and gene flow between populations, which suggests the existence of coevolutionary hot spots within a European metapopulation. A mosaic of coevolution is theoretically possible at small geographical scales and with strong gene flow, because, among other reasons, plots may differ in productivity (i.e., reproductive success of hosts in the absence of parasitism) and defensive genotypes theoretically should be more common in plots of high productivity. Here, we tested this prediction by exploring the relationship between parasitism rate, level of defense against parasitism (estimated as both rejection rate and the frequency of the 457bp microsatellite allele associated with foreign egg rejection in magpies), and some variables related to the productivity (average laying date, clutch size, and number of hatchlings per nest) of magpies breeding in different subpopulations. We found that both estimates of defensive ability (egg rejection rate and frequency of the 457bp allele) covaried significantly with between-plot differences in probability of parasitism, laying date, and number of hatchlings per nest. Moreover, the parasitism rate was larger in more productive plots. These results confirm the existence of a mosaic of coevolution at a very local geographical scale, and the association between laying date and number of hatchlings with variables related to defensive ability and the selection pressure arising from parasitism supports the prediction of coevolutionary gradients in relation to host productivity. PMID- 17711471 TI - Transforming the dilemma. AB - How does natural selection lead to cooperation between competing individuals? The Prisoner's Dilemma captures the essence of this problem. Two players can either cooperate or defect. The payoff for mutual cooperation, R, is greater than the payoff for mutual defection, P. But a defector versus a cooperator receives the highest payoff, T, where as the cooperator obtains the lowest payoff, S. Hence, the Prisoner's Dilemma is defined by the payoff ranking T > R > P > S. In a well mixed population, defectors always have a higher expected payoff than cooperators, and therefore natural selection favors defectors. The evolution of cooperation requires specific mechanisms. Here we discuss five mechanisms for the evolution of cooperation: direct reciprocity, indirect reciprocity, kin selection, group selection, and network reciprocity (or graph selection). Each mechanism leads to a transformation of the Prisoner's Dilemma payoff matrix. From the transformed matrices, we derive the fundamental conditions for the evolution of cooperation. The transformed matrices can be used in standard frameworks of evolutionary dynamics such as the replicator equation or stochastic processes of game dynamics in finite populations. PMID- 17711474 TI - Comparative genomics identifies a cis-regulatory module that activates transcription in specific subsets of neurons in Ciona intestinalis larvae. AB - The larval nervous system of the ascidian Ciona intestinalis exhibits an abstract form of the vertebrate nervous system. The Ci-Galphai1 gene, which encodes a G protein alpha subunit, is specifically expressed in distinct sets of neurons in C. intestinalis larvae, including papillar neurons of the adhesive organ, ocellus photoreceptor cells, and cholinergic and GABAergic neurons in the central nervous system (CNS). A GFP reporter gene driven by the 4.2-kb 5' flanking region of Ci Galphai1 recapitulated the endogenous gene expression patterns. Comparative genomic analysis of the Galphai1 gene between C. intestinalis and Ciona savignyi identified an 87-bp highly conserved non-coding sequence located between -3176 and -3090 bp upstream of the gene. Deletion of this conserved upstream sequence resulted in the complete loss of reporter expression in the central nervous system, while reporter expression in the adhesive organ and mesenchyme cells remained unaffected. The conserved upstream sequence can activate gene expression from basal promoters in the brain vesicle, although it requires additional cis regulatory sequences to fully activate the CNS-specific gene expression. These results suggest that different types of central neurons share a common transcriptional activation mechanism that is different from that of papillar neurons. PMID- 17711475 TI - Adhesive papillae on the brachiolar arms of brachiolaria larvae in two starfishes, Asterina pectinifera and Asterias amurensis, are sensors for metamorphic inducing factor(s). AB - It has been hypothesized by Barker that starfish brachiolaria larvae initiate metamorphosis by sensing of metamorphic inducing factor(s) with neural cells within the adhesive papillae on their brachiolar arms. We present evidence supporting Barker's hypothesis using brachiolaria larvae of the two species, Asterina pectinifera and Asterias amurensis. Brachiolaria larvae of these two species underwent metamorphosis in response to pebbles from aquaria in which adults were kept. Time-lapse analysis of A. pectinifera indicated that the pebbles were explored with adhesive papillae prior to establishment of a stable attachment for metamorphosis. Microsurgical dissections, which removed adhesive papillae, resulted in failure of the brachiolaria larvae to respond to the pebbles, but other organs such as the lateral ganglia, the oral ganglion, the adhesive disk or the adult rudiment were not required. Immunohistochemical analysis with a neuron-specific monoclonal antibody and transmission electron microscopy revealed that the adhesive papillae contained neural cells that project their processes towards the external surface of the adhesive papillae and they therefore qualify as sensory neural cells. PMID- 17711476 TI - A new triple staining method for double in situ hybridization in combination with cell lineage tracing in whole-mount Xenopus embryos. AB - To analyze cell to cell interaction effects on cell differentiation, we developed a new triple staining method for double in situ hybridization with cell lineage tracing in whole-mount Xenopus embryos. The method provides high color contrast views, and also enabled us to examine inside the embryos. Wild-type embryos whose blastomere(s) had been injected with a cell lineage tracer were cultured, fixed, hemisectioned when necessary, and first served for the double in situ hybridization, with two sequential chromogenic reactions. They were postfixed, and the labeled cells were retraced immunohistochemically. Finally, the pigment of the embryos was bleached to obtain a clear view. We applied this method to a blastomere transplantation experiment to examine whether the spatial gene expression patterns along the anteroposterior axis can be induced by cell to cell interactions. The presumptive organizer of a 32-cell embryo was replaced by the labeled presumptive epidermis of another synchronous embryo. The resultant triple stained late gastrula showed quite similar anteroposterior expression patterns of gsc and Xbra to those of a normal embryo in the axial mesoderm derived from the transplanted presumptive epidermis, indicating that cell to cell interactions had induced these patterns. PMID- 17711477 TI - Prevalence of OPG and IL-1 gene polymorphisms in chronic periodontitis. AB - AIM: To investigate the association of polymorphisms in the osteoprotegerin (OPG) and interleukin 1 (IL-1) genes with chronic periodontitis (CP). MATERIAL AND METHODS: One hundred and ninety-four individuals (97 CP patients, 97 controls) were genotyped for the OPG polymorphisms Lys3Asn and Met256Val and for the IL-1 polymorphisms IL-1A (-889C/T) and IL-1B (+3953C/T). RESULTS: The homozygous variants coding for Lys3 were present at a higher frequency, whereas Asn3 and Met256 were present at a lower frequency in CP patients/controls (Lys3: 31%/25%, Asn3: 23%/32% and Met256: 66%/73%). Heterozygosity for Lys3Asn was observed at a higher frequency in CP patients/controls (46%/43%). Homozygosity for the Val256 genotype was observed in two CP patients (one in controls). Met256Val heterozygosity was more prevalent in CP patients/controls (32%/20%). All differences were statistically not significant between CP patients and controls. In contrast, both IL-1 polymorphisms were statistically significant. The heterozygous variant for IL-1A was present in 32% of the CP patients and in 20% of the controls (homozygosity (patients/controls) CC: 10%/21% and TT: 55%/33%). Heterozygosity for IL-1B was observed in 37% of the CP patients versus 34% in the controls (homozygosity (patients/controls) CC: 26%/57% and TT: 37%/9%). CONCLUSION: While the association between the IL-1 polymorphisms and CP was confirmed, no association between the OPG polymorphisms and CP could be found. PMID- 17711478 TI - Incomplete adherence to an adjunctive systemic antibiotic regimen decreases clinical outcomes in generalized aggressive periodontitis patients: a pilot retrospective study. AB - AIM: The objective of this study was to explore the effect of incomplete adherence to the prescribed antibiotic regimen, amoxicillin and metronidazole, in the non-surgical treatment of generalized aggressive periodontitis (GAP). METHODS: This retrospective study included 18 GAP subjects who received a conventional course of full-mouth non-surgical periodontal treatment using machine-driven and hand instruments and an adjunctive course of systemic antibiotics (500 mg amoxicillin and 500 mg metronidazole three times a day for 7 days). Clinical parameters were collected at baseline and at 2 months post treatment. Self-reported adherence to the prescribed medication regimen was recorded at 2 months. RESULTS: All clinical parameters, except for the mean clinical attachment level (CAL) in sites with initial probing pocket depth (PPD) < or = 3 mm, improved at 2 months in all subjects. PPD reduction was 3.7 mm [95% confidence interval (CI) 3.2, 4.3 mm] in deep pockets (> or = 7 mm) and 2.2 mm (95% CI 1.9, 2.4 mm) in moderate pockets (4-6 mm), while CAL gain was 2.2 mm (95% CI 1.7, 2.6 mm) and 1.2 mm (95% CI 0.8, 1.5 mm), respectively. However, only 11 subjects (61.1%) reported full adherence to the medication. In deep pockets (> or = 7 mm), the difference between an adherent and non-adherent/partially adherent subject was 0.9 mm (95% CI 0.1, 1.7 mm, ancova, p=0.027) in PPD reduction and 0.8 mm (95% CI -0.2, 1.9, p=0.129) in CAL gain at 2 months. In moderate pockets (4-6 mm) this difference was smaller in magnitude: 0.4 mm (95% CI 0.1, 0.9 mm, p=0.036) in PPD reduction and 0.2 mm (95% CI -0.3, 0.9 mm, p=0.332) in CAL gain. CONCLUSIONS: Within the limits of this design, these data suggest that incomplete adherence to a 7-day adjunctive course of systemic metronidazole and amoxicillin is associated with decreased clinical outcomes in subjects with generalized aggressive periodontitis. PMID- 17711479 TI - A community-based epidemiological study of periodontal disease in Keelung, Taiwan: a model from Keelung community-based integrated screening programme (KCIS No. 18). AB - AIMS: To estimate the prevalence and severity of periodontal disease (PD) in the Taiwanese population aged 35-44 years and to investigate the association between demographic factors and PD. MATERIALS AND METHODS: Between 2003 and 2005, residents of Keelung of the appropriate age were invited to screening. The community periodontal index (CPI) and loss of attachment (LA) index were used to measure the periodontal status at subject (prevalence) and sextant levels (severity). Basic demographic information was also collected by a questionnaire. RESULTS: Of 8462 enrollees, 94.8% had some signs of PD, of whom 29.7% had periodontal pockets >3 mm and 35% LA >3 mm. Calculus was the most common problem in terms of both prevalence (49.6%) and severity (affecting an average of 3.0 sextants per person). Risk factors for poor periodontal status (as measured by CPI) were older age (odds ratio, OR: 1.44), male gender (OR: 2.70), low education level (OR: 1.40), and being a manual worker (OR: 1.51). Similar findings were observed for LA. CONCLUSION: The prevalence of PD in 35-44-year-olds was found to be high in this large community-based study of screening for PD with CPI and LA. Poorer periodontal health was observed in males, the less educated, and manual workers. PMID- 17711480 TI - Toll-like receptor 2 contributes to antibacterial defence against pneumolysin deficient pneumococci. AB - Toll-like receptors (TLRs) are pattern recognition receptors that recognize conserved molecular patterns expressed by pathogens. Pneumolysin, an intracellular toxin found in all Streptococcus pneumoniae clinical isolates, is an important virulence factor of the pneumococcus that is recognized by TLR4. Although TLR2 is considered the most important receptor for Gram-positive bacteria, our laboratory previously could not demonstrate a decisive role for TLR2 in host defence against pneumonia caused by a serotype 3 S. pneumoniae. Here we tested the hypothesis that in the absence of TLR2, S. pneumoniae can still be sensed by the immune system through an interaction between pneumolysin and TLR4. C57BL/6 wild-type (WT) and TLR2 knockout (KO) mice were intranasally infected with either WT S. pneumoniae D39 (serotype 2) or the isogenic pneumolysin deficient S. pneumoniae strain D39 PLN. TLR2 did not contribute to antibacterial defence against WT S. pneumoniae D39. In contrast, pneumolysin-deficient S. pneumoniae only grew in lungs of TLR2 KO mice. TLR2 KO mice displayed a strongly reduced early inflammatory response in their lungs during pneumonia caused by both pneumolysin-producing and pneumolysin-deficient pneumococci. These data suggest that pneumolysin-induced TLR4 signalling can compensate for TLR2 deficiency during respiratory tract infection with S. pneumoniae. PMID- 17711482 TI - Detection of diverse SCCmec variants in methicillin-resistant Staphylococcus aureus and comparison of SCCmec typing methods. AB - Non-duplicate methicillin-resistant Staphylococcus aureus (MRSA) isolates (n = 436), collected from four hospitals located in three Korean cities between 2001 and 2005, were investigated by SCCmec typing and multilocus sequence typing (MLST). Variations within SCCmec, especially type II, were detected in 165 (37.8%) isolates, and these variants were characterised using four different SCCmec typing methods. The predominant SCCmec type was a type II variant that differed from type II by the absence of a pUB110 insertion. MLST analysis showed that most of the isolates carrying SCCmec variants belonged to ST5. PMID- 17711481 TI - The lysine- and glutamic acid-rich protein KERP1 plays a role in Entamoeba histolytica liver abscess pathogenesis. AB - The parasite Entamoeba histolytica colonizes the large bowel where it may persist as an asymptomatic luminal gut infection, which changes to virulence. Parasite invasion of the intestine leads to dysentery and spreads to the liver, where amoebae form abscesses. We took advantage of changes in virulence that occurs after long-term in vitro culture of E. histolytica strains. Using microarrays, we concluded that virulence correlates with upregulation of key genes involved in stress response, including molecular chaperones, ssp1 and peroxiredoxin; as well as the induction of unknown genes encoding lysine-rich proteins. Seven of these were retained with respect to their lysine content higher than 25%. Among them, we found KERP1, formerly identified as associated to parasite surface and involved in the parasite adherence to host cells. Experimentally induced liver abscesses, using molecular beacons and protein analysis, allowed us to draw a parallel between the intricate upregulation of kerp1 gene expression during abscess development and the increased abundance of KERP1 in virulent trophozoites. Following its characterization as a marker for the progression of infection, KERP1 was also seen to be a virulence marker as trophozoites affected in kerp1 expression by an antisense strategy were unable to form liver abscesses. PMID- 17711483 TI - Outbreak of Legionnaires' disease in immunosuppressed patients at a cancer centre: usefulness of universal urine antigen testing and early levofloxacin therapy. AB - This report describes an outbreak of Legionnaires' disease in severely immunosuppressed patients hospitalised at a cancer centre. Universal urine antigen testing and early levofloxacin therapy appeared to lower case fatality rates in comparison with previous reports concerning this high-risk population. This diagnostic and therapeutic strategy should be considered when facing a nosocomial outbreak of Legionnaires' disease in immunosuppressed hosts. PMID- 17711484 TI - Evaluation of human antibody responses to diphtheria toxin subunits A and B in various age groups. AB - This study aimed to evaluate human antibody responses to diphtheria toxin subunits in various age groups. Antibodies against the intact diphtheria toxin and the diphtheria toxin subunits A and B were evaluated in 1319 individuals using a double-antigen ELISA. Although high levels of protection (83.6%, 95% CI 79.2-87.4) were found in children and adolescents, the middle-aged adult population was less protected (28.8%, 95% CI 24.3-33.6). An increase in age was associated with a decrease in the frequency of protected individuals in the 0-39 year age group (p <0.001). Anti-subunit B levels correlated well (p <0.01) with levels of antibodies against the intact toxin. In children aged < or =16 years, the intervals at which the peaks in geometric mean titres of anti-subunit B antibodies were observed were found to correlate with the ages at which booster doses are administered. Overall, males appeared to be more protected than females (OR 1.67, 95% CI 1.34-2.08, p <0.001). A small group of individuals had antibody levels of > or =0.1 IU/mL against the intact toxin, but did not have protective antibody against subunit B. Determination of anti-subunit B antibody levels should help in evaluating the effectiveness of diphtheria boosters and other aspects of diphtheria immunity. PMID- 17711486 TI - Dynamic colonisation by different Pneumocystis jirovecii genotypes in cystic fibrosis patients. AB - Although asymptomatic carriers of Pneumocystis jirovecii with cystic fibrosis (CF) have been described previously, the molecular epidemiology of P. jirovecii in CF patients has not yet been clarified. This study identified the distribution and dynamic evolution of P. jirovecii genotypes based on the mitochondrial large subunit (mt LSU) rRNA gene. The mt LSU rRNA genotypes of P. jirovecii isolates in 33 respiratory samples from CF patients were investigated using nested PCR and direct sequencing. Three different genotypes were detected: 36.3% genotype 1 (85C/248C); 15.1% genotype 2 (85A/248C); 42.4% genotype 3 (85T/248C); and 6% mixed genotypes. Patients studied during a 1-year follow-up period showed a continuous colonisation/clearance cycle involving P. jirovecii and an accumulative tendency to be colonised with genotype 3. PMID- 17711485 TI - Tuberculosis and Legionella pneumophila pneumonia in a patient receiving anti tumour necrosis factor-alpha (anti-TNF-alpha) treatment. PMID- 17711487 TI - Suppression of lipopolysaccharide- and tumour necrosis factor-alpha-induced interleukin (IL)-8 expression by glucocorticoids involves changes in IL-8 promoter acetylation. AB - There is accumulating evidence that the transrepressional effect of glucocorticoids in down-regulating proinflammatory gene expression might be regulated by an action on histone acetylation. To investigate this, we studied the effect of two glucocorticoids (dexamethasone and triamcinolone acetonide) on reducing lipopolysaccharide (LPS)- and tumour necrosis factor (TNF)-alpha-induced interleukin (IL)-8 release in a monocytic cell line and two lymphocytic cell lines (HUT-78 and Jurkat). The effect of the histone deacetylase inhibitor trichostatin A (TSA) on LPS- and TNF-alpha-induced IL-8 release and its repression by glucocorticoids was also examined. LPS and TNF-alpha induced IL-8 release in all three cell lines and this induction was inhibited by both dexamethasone and triamcinolone. Pretreatment of cells with TSA enhanced basal and LPS- and TNFalpha-stimulated IL-8 release in all three cell lines. TSA also attenuated the inhibitory effect of glucocorticoids on stimulated IL-8 release. Chromatin immunoprecipitation assays confirmed that LPS and TNF-alpha enhanced histone acetylation at the IL-8 promoter and that this was inhibited by triamcinolone in all three cell types. Changes in histone acetylation at the IL-8 are important in its regulation by proinflammatory and anti-inflammatory agents, and modulation of this activity may have therapeutic potential in inflammatory conditions. PMID- 17711488 TI - Demonstration of autoantibodies to recombinant human sulphite oxidase in patients with chronic liver disorders and analysis of their clinical relevance. AB - It has been shown previously that sera from patients with cholestatic liver diseases react with sulphite oxidase (SO) prepared from chicken liver. In order to analyse this reactivity and the clinical relevance of anti-SO antibodies in more detail, we produced human recombinant SO. Human recombinant SO (60 kDa) was expressed in Escherichia coli and applied to enzyme-linked immunosorbent assay and Western blot. Sera from patients with autoimmune liver disorders [primary biliary cirrhosis (PBC) n = 96; autoimmune hepatitis (AIH) n = 77; primary sclerosing cholangitis (PSC) n = 39], and from patients with other hepatic (n = 154) and non-hepatic chronic inflammatory disorders (n = 113) were investigated. Highest incidence and activities of IgG-anti-SO antibodies were observed in PSC patients. Nine of 16 untreated (56%) and four of 23 PSC patients treated with ursodeoxycholic acid (UDCA) (17%) were positive. Antibody activity decreased significantly during UDCA treatment. Five per cent of PBC and 9% of AIH patients, but also 15% of patients with alcoholic liver disease, were IgG anti-SO-positive. In patients with viral hepatitis and non-hepatic disorders they could be hardly detected. Anti-SO antibodies are further anti-mitochondrial antibodies in chronic liver diseases. They occur predominantly in PSC, and UDCA treatment seams to decrease antibody activity. Whether these antibodies are primary or secondary phenomena and whether they are related to the aetiology or pathogenesis, at least in a subgroup of patients with chronic liver diseases, has still to be evaluated. PMID- 17711489 TI - Indoleamine 2,3-dioxygenase activity is increased in patients with systemic lupus erythematosus and predicts disease activation in the sunny season. AB - Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-degrading enzyme which suppresses T lymphocyte activity. IDO activity can be determined by relating kynurenine, the main metabolite of tryptophan, to tryptophan (kyn/trp). We have demonstrated recently that systemic lupus erythematosus (SLE) is activated during the sunny season as measured by the European Consensus Lupus Activity Measurement Index (ECLAM) activity score. Our aim here was to establish whether IDO-dependent mechanisms are involved in the activation process of SLE. Kyn/trp was measured by reverse-phase high-performance liquid chromatography (HPLC) in 33 (30 female, three male) SLE patients in winter, spring and summer and in 309 healthy control subjects. At the same time-points the SLE patients were examined by a rheumatologist and a dermatologist and the activity of SLE assessed by the ECLAM score. IDO activity was higher in SLE patients than in healthy subjects. There was no seasonal variation in IDO activity in SLE patients and it did not correlate with the ECLAM activity score in winter. However, there was a significant correlation between IDO activity and the ECLAM score both in spring and in summer. High IDO activity in winter predicted subsequent activation of SLE in spring and summer. Our results indicate that IDO-dependent immunosuppressive mechanisms are activated in SLE patients. Exposure to sunlight or another factor causing seasonal variation in SLE activity leads to insufficiency of this suppression in a subgroup of patients, causing activation of SLE. High IDO activity in winter predicts activation of SLE in the sunny season. PMID- 17711490 TI - Low mannose-binding lectin (MBL) levels in neonates with pneumonia and sepsis. AB - We investigated whether deficiency of mannose-binding lectin (MBL), a component of innate immunity, is associated with neonatal pneumonia and sepsis during the first 72 h, i.e. early onset, and during the first month after birth. In 88 neonatal intensive care patients (71 premature), MBL2 genotype and MBL plasma levels at birth were determined prospectively by Taqman analysis and enzyme linked immunosorbent assay, respectively. Thirty-five neonates (40%) had low, i.e. /=3 months) in 86% and continued at the time of the survey in 55% and presented typically as severe short-lasting attacks provoked by physical stress, bending or coughing. Non-steroidal anti-inflammatory drugs were effective in most cases. Depression (usually mild) occurred in 24% of the respondents, being significantly more common in prolonged postoperative headache patients. The operation doubled the prevalence of headache (from 32% to 64%). Headache after acoustic neuroma operation appears to be a specific subgroup of postcraniotomy headache. PMID- 17711495 TI - Interictal executive dysfunction in migraineurs without aura: relationship with duration and intensity of attacks. AB - Subjects with migraine are at increased risk of subcortical white matter lesions (WML). Reports of cognitive testing in adults with migraine have yielded inconsistent results. We performed a cross-sectional study to assess whether migraine without aura (MwA) is associated with impairment in executive functioning, a typical cognitive correlate of subcortical WML. Forty-five subjects with MwA and 90 controls, matched for age and education, underwent a cognitive battery of tests evaluating executive functions. The following migraine characteristics were collected: age at onset and length of migraine history, and frequency, duration and intensity of attacks. Subjects with MwA performed significantly lower than controls in tests evaluating complex, multifactorial executive functions. After multiple adjustments, the duration and intensity of migraine attacks significantly predicted cognitive disturbances. In the interictal phase of MwA there is evidence of mild executive dysfunction. The cumulative effects of repeated migraine attacks on prefronto-cerebellar loop probably account for our results. PMID- 17711496 TI - Laparoscopy in the management of closed loop sigmoid volvulus. AB - OBJECTIVE: To investigate the feasibility and surgical outcome of elective laparoscopic surgery for acute closed loop sigmoid volvulus. METHOD: A prospectively electronic database of colorectal laparoscopic procedures identified nine consecutive patients with sigmoid volvulus managed by colonoscopic decompression followed by same admission laparoscopic recto sigmoidectomy. RESULTS: Between January 2001 and February 2007, nine patients, ASA I (one), II (four), III (four) with sigmoid volvulus were treated: seven were women. Their age distribution was 37-87 years (median 64). The volvulus was the first episode in one patient, the second episode for four and the third (or more) for the remainder. The median operation time was 115 min (45-145). No anastomosis was de-functioned. Postoperative analgesia was parenteral paracetamol (eight) supplemented by 10 mg oral morphine in one case; a ninth patient received patient controlled parenteral morphine for 36 h. Complications included: ileus (one), myocardial infarct (one) and wound infection (one). There was one death on day 32 from a brainstem infarct. Seven had an uncomplicated recovery. The median postoperative stay was 4 days (2-32). CONCLUSION: Laparoscopic recto sigmoidectomy postcolonoscopic decompression is a good option for patients with sigmoid volvulus. Surgical complications are minimal and recovery is quick. PMID- 17711497 TI - Prospective, case-matched study of heated and humidified carbon dioxide insufflation in laparoscopic colorectal surgery. AB - PURPOSE: Laparoscopic colorectal surgery is often prolonged and may cause hypothermia. It is uncertain if heated and humidified carbon dioxide (CO(2)) in laparoscopic colorectal surgery is beneficial. This is a prospective case-matched study on the use of heated and humidified CO(2) in patients undergoing laparoscopic colorectal surgery. METHOD: Twenty consecutive patients undergoing laparoscopic colorectal surgery with heated (36 degrees C) and humidified (95%) CO(2) were compared with 20 consecutive patients using standard CO(2) (30.2 degrees C). All procedures were performed by a single surgeon in an institution. The changes in core temperature during surgery, visual quality of images and the short-term clinical outcome were documented. RESULTS: The core temperature fell during surgery in both groups. Although the fall of core temperature was more in the control group, it was not statistically significant (P > 0.05). The passage of flatus was more delayed in heated and humidified group (P = 0.004), but it did not affect the hospital discharge. All the other parameters, including the quality of visual images and the postoperative pain, were similar in both groups. CONCLUSIONS: Despite better temperature maintenance (nonsignificant), pneumoperitoneum using heated and humidified CO(2) gas did not appear to have any clinical benefits in laparoscopic colorectal surgery. PMID- 17711498 TI - Stress and burnout among colorectal surgeons and colorectal nurse specialists working in the National Health Service. AB - BACKGROUND: It has been suggested that changes to the organization of the National Health Service (NHS) and clinical practices in dealing with cancer are associated with increased stress and burnout in healthcare professionals. The aim of this study, therefore, was to evaluate stress and burnout in colorectal surgeons (surgeons) and colorectal clinical nurse specialists (nurses) working in the NHS. METHOD: A list of all consultant surgeons and nurses was obtained from The Association of Coloproctology of Great Britain and Ireland. Participants were sent a questionnaire booklet consisting of standardized measures [General Health Questionnaire (GHQ), Maslach Burnout Inventory (MBI), Coping Questionnaire] and various ad hoc questions to obtain information about demographics, cancer workload and job satisfaction. Independent predictors of clinically significant distress and burnout were identified using logistic regression. RESULTS: Four hundred and fifty-five surgeons and 326 nurses were sent booklets. The response rate was 55.6% in surgeons and 54.3% in nurses. The mean age of the nurses was lower than that of surgeons (42.8 vs 47.7, P < 0.001). Psychiatric morbidity was similar in the surgeons and nurses as assessed using the GHQ (30.2% and 30.3% respectively). On the MBI, compared with nurses, surgeons had significantly higher levels of depersonalization (17.4%vs 7.4%, P = 0.003) and lower personal accomplishment (26.6%vs 14.2%, P = 0.002). Seventy-seven per cent of surgeons and 63.4% of nurses stated their intention to retire before the statutory retirement age. Coping strategies, especially those in which respondents isolated themselves from friends and family, were associated with higher psychiatric morbidity and burnout. Dissatisfaction with work, intention to retire early, intention to retire as soon as affordable and poor training in communication and management skills were also significantly associated with high GHQ scores and burnout in both groups. DISCUSSION: We found high levels of psychiatric morbidity and burnout in this national cohort of surgeons and nurses working in the NHS. However, psychiatric morbidity and burnout were unrelated to cancer workload. Nurses have lower burnout levels than surgeons and this may be related to their different working practices, responsibilities and management structure. PMID- 17711499 TI - Investigation to predict faecal continence in patients undergoing reversal of a defunctioning stoma (Porridge enema test). AB - OBJECTIVE: A defunctioning stoma is often performed in cases of major anorectal surgery or sphincter injury. This study aimed to assess the Porridge enema (PE) test as a tool to evaluate function prior to stoma closure. METHOD: Thirty-eight patients underwent PE test at a median of 12.5 months after stoma formation prior to consideration of stoma closure. Outcome was assessed by immediate leakage after PE test on lying, standing, walking and the ability to hold the enema for 30 min. Patients available for follow-up were divided into two groups: group 1 (n = 20) patients with stoma closure performed and group 2 (n = 10) patients where the stoma remains. Eight patients were excluded from analysis as the stoma had not been reversed for reasons unrelated to continence. The results of other investigations performed in these patients were analysed. Finally, we studied the agreement in the interpretation of the test by two investigators blinded to the patient's group and each other's interpretation and to functional results after the stoma was reversed. RESULTS: Anorectal physiology testing and imaging assessment of the anal sphincters was not statistically different between the two groups. There was a significant difference in the percentage of patients in each group that had enema leakage in: lying position (P = 0.002), standing position (P = 0.013), walking (P = 0.002) and ability to defer for 30 min (P = 0.005). There was a good correlation in the interpretation of PE test results by two investigators. Among patients whose stoma was closed and who were evaluated functionally, 55% were fully continent. CONCLUSION: This report suggests that the PE test is a promising tool as part of evaluation of anorectal function prior to stoma reversal. PMID- 17711500 TI - Conservative management resulting in complete resolution of a double intussusception in an adult haemophiliac. AB - Acute abdominal pain in haemophiliacs should be approached as haemorrhage until proven otherwise. With advancements in factor repletion and coagulopathic management a conservative approach should be considered. We describe a case of double colo-colonic intussusception lead by an intramural haematoma occurring spontaneously and resolving with conservative management in a young haemophiliac. This demonstrates that intussusception in these cases may be transient, and does not require surgical intervention. PMID- 17711501 TI - Epidermal growth factor receptor in colorectal carcinoma: correlation with clinico-pathological prognostic factors. AB - OBJECTIVE: This study was undertaken to determine the relationship between epidermal growth factor receptor (EGFR) status in primary colorectal cancer (CRC) to different clinico-pathological prognostic factors. METHOD: Seventy-nine primary CRC were studied using four scoring systems: 1- EGFR pharmDx score, 2- score modified from the Hercept test [J Histo cytochem, 52 (2004) 893], 3- two additive scores with different cutoff points [Mod Pathol, 11 (1998) 155], 4- two multiplicative scores with different cutoff points [Ann Oncol, 16 (2005) 102]. RESULTS: More than 10% membranous EGFR reactivity was identified in 46.8% (37/79) of the tumours. The intensity was classified as mild, moderate and strong representing 8.9%, 20.3% and 17.7% respectively. Strong correlation was found between the EGFR pharmDx and the proposed scores, at different cutoff points (P < 0.01). A strong correlation was found between EGFR expression, advanced clinical stage (P < 0.01), nodal involvement (P < 0.01) and lympho-vascular invasion (LV) (P < 0.05) in category I factors, poorly differentiated tumours in IIA (P < 0.05), infiltrative border configuration in IIB (P < 0.01), perineural invasion (PN) in III (P < 0.01), and larger tumours in IV (P < 0.01). Heterogenous staining was present in 46.3% of tumours and was associated with an increased score, LV and PN invasion and advanced clinical stage (P < 0.05). CONCLUSION: Using a cut-off point of 10%, similar results with different scoring systems were obtained, representing standardization for EGFR interpretation. EGFR expression is correlated with conventional clinico-pathological prognostic factors. PMID- 17711502 TI - Cellular localization and functional characterization of the equilibrative nucleoside transporters of antitumor nucleosides. AB - Nucleoside transporters play an important role in the disposition of nucleosides and their analogs. To elucidate the relationship between chemosensitivity to antitumor nucleosides and the functional expression of equilibrative nucleoside transporters (ENT), we established stable cell lines of human fibrosarcoma HT 1080 and gastric carcinoma TMK-1 that constitutively overexpressed green fluorescent protein-tagged hENT1, hENT2, hENT3 and hENT4. Both hENT1 and hENT2 were predictably localized to the plasma membrane, whereas hENT3 and hENT4 were localized to the intracellular organelles. The chemosensitivity of TMK-1 cells expressing hENT1 and hENT2 to cytarabine and 1-(3-C-ethynyl-beta-D ribopentofuranosyl) cytosine increased markedly in comparison to that of mock cells. However, no remarkable changes in sensitivity to antitumor nucleosides were observed in cell lines that expressed both hENT3 and hENT4. These data suggest that hENT3 and hENT4, which are mainly located in the intracellular organelles, are not prominent nucleoside transporters like hENT1 and hENT2, which are responsible for antitumor nucleoside uptake. PMID- 17711503 TI - ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol 3 kinase isoforms. AB - Class I phosphatidylinositol 3 kinases (PI3K) phosphorylate phosphatidylinositol 4,5-bisphosphate to generate phosphatidylinositol 3,4,5-trisphosphate. These molecules play an important role in fundamental cellular responses. Four isoforms of class I PI3K are known to have different functions, and abnormalities in their activities have been related to various diseases such as cancer and inflammation. We previously identified a novel PI3K inhibitor, ZSTK474, which showed potent antitumor activity in vivo against a human cancer xenograft without observable toxicity. However, the mode of its molecular action was not investigated in detail. Our previous study only suggested that ZSTK474 possibly competes with ATP for the ATP-binding pocket of PI3Kgamma. In the present study, we have used an in vitro homogenous time-resolved fluorescence kinase assay to examine whether ZSTK474 is indeed an ATP-competing inhibitor of PI3K, and also to determine whether the inhibitory activity of ZSTK474 was isoform-specific. Lineweaver-Burk plot analysis revealed that ZSTK474 inhibits all four PI3K isoforms in an ATP competitive manner. Among all of the PI3K isoforms, PI3Kdelta was inhibited most potently by ZSTK474 with a K(i) of 1.8 nM, and the other isoforms were inhibited at higher doses. We have also used a kinase activity ELISA to determine whether ZSTK474 inhibits mammalian target of rapamycin, a key kinase acting downstream of PI3K to promote protein synthesis and cell proliferation. Even at a concentration of 100 microM, ZSTK474 inhibited mammalian target of rapamycin activity rather weakly. These results indicate that ZSTK474 is an ATP-competitive pan-class I PI3K inhibitor. PMID- 17711505 TI - Identification of cell proliferation-associated epitope on CD98 oncoprotein using phage display random peptide library. AB - CD98 is known as a cell surface antigen expressed in proliferating normal tissues and in almost all tumor cells. Although the function of CD98 is not yet fully elucidated, it is suggested that CD98 is concerned functionally in lymphocyte activation, cell proliferation, and malignant transformation. Monoclonal antibody against human CD98 heavy chain (h.c.), termed HBJ127, shows inhibition of lymphocyte activation and tumor cell growth in vitro. These observations suggest that the epitope recognized by HBJ127 may be crucial for CD98 function. In the present study, the authors investigated the epitope recognized by HBJ127 using a phage display random heptapeptide library. Approximately 2.4 x 10(4)-fold amplification of eluted phage titer was obtained after three rounds of panning of the phage library against HBJ127. Seven different heptapeptide sequences were isolated from 30 randomly selected clones of the post-panning phage population. A homology search using ClustalW identified the peptide sequence corresponding to (442)AFS(444) of human CD98 h.c. It was also found that (443)F is a human specific amino acid by comparing sequences of human, rat, and mouse origin. Reduced reactivity of HBJ127 was detected against the phenylalanine-substituted peptide but not detected against the alanine or serine-substituted one. It has been identified that HBJ127 reacts only with human species and the HBJ127 epitope position is predicted in 418-529 of human CD98 h.c. From these results and observations, it was estimated that (442)AFS(444) of human CD98 h.c. may be the HBJ127 epitope. Moreover, (443)F may be critical for the binding of HBJ127 against human CD98 h.c. PMID- 17711504 TI - GM3 synthase gene is a novel biomarker for histological classification and drug sensitivity against epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. AB - Expression of gangliosides and alterations in their composition have been observed during cell proliferation and differentiation and in certain cell cycle phases, brain development and cancer malignancy. To investigate the characteristics of GM3 synthase, SAT-I mRNA and ganglioside GM3 expression levels in lung cancer, we examined the expression levels of SAT-I mRNA as well as GM3 in 40 tumor tissues surgically removed from non-small cell lung cancer patients. Adenocarcinoma tissues expressed SAT-I mRNA levels that were significantly higher than those of squamous and other carcinomas (P < 0.0001). Moreover, the SAT-I mRNA levels were high in the bronchioalveolar carcinoma subtype and low in the solid and mucin subtypes of adenocarcinomas (P = 0.049, 0.049 and 0.013, respectively). To clarify the relationship between SAT-I mRNA and epidermal growth factor receptor (EGFR)-tyrosine kinase (TK) inhibitor sensitivity, we carried out drug sensitivity tests for the EGFR-TK inhibitors gefitinib and AG1478 using eight adenocarcinoma cell lines expressing no EGFR mutations. The IC(50) values for gefitinib and AG1478 decreased dramatically with increasing SAT I mRNA levels (R(2) = 0.81 and 0.59, respectively), representing a wide range of drug sensitivities among adenocarcinoma cell lines. To explore a possible mechanism of how GM3 could enhance the sensitivity to EGFR-TK inhibitors, the SAT I gene was introduced stably into a GM3-negative clone of murine 3LL lung cancer cells to produce GM3-reconstituted clones. We found an increase in EGFR protein levels and gefitinib sensitivity in GM3-reconstituted cells, suggesting the involvement of GM3 in the turnover of EGFR protein. Therefore, it is highly expected that, by measuring the expression levels of SAT-I mRNA in lung biopsy samples from non-small cell lung cancer patients, enhanced pathological identification and individualized chemotherapeutic strategies can be established for the appropriate use of EGFR-TK inhibitors. PMID- 17711506 TI - LKB1 gene mutations in Japanese lung cancer patients. AB - Mutation of the LKB1 gene (also known as STK11) is regarded as a cause of Peutz Jeghers syndrome. In Caucasian patients, LKB1 somatic mutations occur in approximately one-third of lung adenocarcinomas. The aim of the present study was to examine the LKB1 gene in Japanese patients with lung cancer and to evaluate its clinical and pathological implications. We sequenced the LKB1 gene in 22 lung cancer cell lines and 100 Japanese patients with lung cancer (including 81 adenocarcinomas, 14 squamous cell carcinomas and five other histological types) who had undergone curative pulmonary resection. We also determined expression levels of the LKB1 gene by quantitative real-time reverse transcription polymerase chain reaction and correlated these results with the clinical and pathological features of patients. Among the 22 cell lines, four had mutations and three of these were in adenocarcinoma cells. Of 100 primary lung cancers, only three had LKB1 gene mutations (3%). All of them were male smokers with adenocarcinomas. Hence, when confined to this subset of patients, the mutation frequency was 9% (3/33). No significant correlation was observed between the expression level of LKB1 and patient clinicopathological features. In conclusion, LKB1 gene mutations were relatively rare in Japanese patients with lung cancer compared with Caucasian patients. LKB1 gene mutations appear to be frequent in male, smoking patients of Caucasian origin, in contrast to EGFR or HER2 mutations that are frequent in non-smoking, female patients of Asian origin. PMID- 17711508 TI - A critical appraisal of the classification of urothelial tumours: time for a change, but not the change proposed. PMID- 17711507 TI - Biological and therapeutic significance of MUC1 with sialoglycans in clear cell adenocarcinoma of the ovary. AB - A monoclonal antibody (mAb) MY.1E12 was applied to detect MUC1 with sialylated glycans in a total of 55 formalin-fixed, paraffin-embedded surgical specimens of ovarian clear cell adenocarcinomas. A reverse correlation between the binding levels of this mAb and patient survival was demonstrated. To examine the role of MUC1 in ovarian clear cell carcinomas, two cDNA encoding MUC1 were transfected into ES-2 ovarian clear cell carcinoma cells. By comparing these cells, the role of MUC1 in tumorigenicity, chemosensitivity and survival under anoikis conditions were assessed. The results indicate that MUC1 expressed on ovarian clear cell carcinoma cells is causally involved in the malignant behavior. PMID- 17711509 TI - Role of Rho-kinase in contractions of ureters from rabbits with unilateral ureteric obstruction. AB - OBJECTIVE: To investigate the expression of two isoforms of Rho-kinase (ROCK) and its functional role in the pathophysiological control of smooth muscle contraction in rabbits with unilateral ureteric obstruction (UUO). MATERIAL AND METHODS: Left UUO was created in 14 rabbits and eight other rabbits (controls) had sham operations. After 2 weeks all the rabbits were killed. Ureteric strips suspended in an organ bath were used for functional studies and the effects of Y 27632, a specific inhibitor of Rho-kinase, on spontaneous contractions and electrical field stimulation (EFS; 50 V, 1 ms, 16 Hz, for 20 s), carbachol- (10( 7)-10(-4)m), phenylephrine- (10(-7)-10(-4)m) and KCl- (50 mm) induced contractions were analysed. Western blotting was used to determine expression levels of Rho-kinase protein in the ureters of UUO and control rabbits. RESULTS: In the functional analysis, the contractions induced by EFS, KCl, phenylephrine and carbachol in the ureteric strips from rabbits with UUO were significantly greater than those from the control rabbits. Y-27632 considerably suppressed the ureter contractile responses in both UUO and control rabbits. Western blot analysis showed that both ROCK-1 and ROCK-2 proteins were expressed in the rabbit ureter. In accordance with the functional studies, the expression levels of both ROCK-1 and ROCK-2 were significantly greater in the ureters of UUO rabbits than in the controls. CONCLUSIONS: Y-27632 suppressed ureteric contractions in the rabbits with UUO. Western blot analysis also confirmed greater expression levels of ROCK-1 and ROCK-2 in the ureters of UUO rabbits. It is important to elucidate by which mechanisms the Rho-kinase pathway affects ureteric function after obstruction. PMID- 17711510 TI - Increased expression of transient receptor potential vanilloid subfamily 1 in the bladder predicts the response to intravesical instillations of resiniferatoxin in patients with refractory idiopathic detrusor overactivity. AB - OBJECTIVES: To investigate the correlation of transient receptor potential vanilloid subfamily 1 (TRPV1) mRNA expression levels and the clinical outcome of intravesical resiniferatoxin treatment in patients with idiopathic detrusor overactivity (IDO), as such treatment with vanilloids can be effective for DO. PATIENTS AND METHODS: In all, 28 patients with IDO refractory to anticholinergics were enrolled and treated with four weekly intravesical instillations of 10 nm resiniferatoxin. Eleven patients having ureteroscopic surgery served as controls. Two bladder wall biopsies were taken from the posterior wall by rigid cystoscopy. TRPV1 expression in the bladder wall samples was determined by individual quantitative reverse transcription-polymerase chain reaction, and immunohistochemical staining. Responders to the therapy were defined as those with an improvement in an urgency scale by >/=1, and with improved general satisfaction. Baseline TRPV1 expression was compared between responders, nonresponders and controls. RESULTS: At 3 months, 14 patients (50%) were responders and in the other 14 the treatment failed (nonresponders). Bladder biopsies were available in seven responders and 11 nonresponders. Transcript levels before treatment correlated significantly with the therapeutic effect of resiniferatoxin (P = 0.004), with higher TRPV1 mRNA expression in responders (median 1.50, range 0.89-2.78) than nonresponders (0.74, 0.34-1.32). Responders also had higher TRPV1 expression levels than a control group (P = 0.067), but the TRPV1 transcript levels of nonresponders were not significantly different from those of the control (P = 0.367). CONCLUSION: Successful intravesical resiniferatoxin treatment is closely associated with the over-expression of TRPV1 in the bladder mucosa and submucosa in patients with IDO. PMID- 17711511 TI - Tissue-resonance interaction method for the noninvasive diagnosis of prostate cancer: analysis of a multicentre clinical evaluation. AB - OBJECTIVE: To determine, in a multicentre prospective study, the accuracy of the tissue-resonance interaction method (TRIMprob, new technology developed for the noninvasive analysis of electromagnetic anisotropy in biological tissues) in the diagnosis of prostate cancer. PATIENTS AND METHODS: Two hundred patients (mean age 67.4 years) scheduled to have prostatic biopsies (because of a prostate specific, PSA, antigen level of >/=4 ng/mL or a suspicious digital rectal examination, DRE) were preliminarily examined while unaware of their clinical details using TRIMprob in five different centres. The final diagnosis obtained with TRIMprob was compared with the final histological diagnosis after extended biopsies. RESULTS: Of the 188 evaluable patients (mean PSA level 9.3 ng/mL, sd 8.8; mean prostate volume 62.0 mL, sd 32.4), 61 (32.4%) had a positive biopsy for adenocarcinoma of the prostate. The overall sensitivity, specificity, positive predictive value, negative predictive value (NPV) and accuracy of TRIMprob were 80%, 51%, 44%, 84% and 60%, respectively. The prostate cancer detection rate after biopsy was significantly higher in patients with a positive examination (49/111, 44%) than in patients with a negative TRIMprob (12/77, 15%; P < 0.001). When TRIMprob results were combined with DRE findings the sensitivity and NPV both increased to 92%. CONCLUSION: TRIMprob seems to be a useful tool in the diagnosis of prostate cancer and can increase the accuracy of PSA or DRE results. The high NPV suggests that this new technology might be useful to reduce the indications for prostatic biopsy or repeated series of biopsies in patients suspected of having prostate cancer. PMID- 17711512 TI - Repeat retroperitoneal lymph-node dissection after chemotherapy for metastatic testicular germ cell tumour. AB - OBJECTIVES: To examine the operative findings, histopathology and clinical outcome of patients undergoing repeat retroperitoneal lymph node dissection (RPLND) after initial chemotherapy and RPLND (PC-RPLND) for metastatic testicular germ cell tumour (GCT), as a small proportion relapse or have residual disease after incomplete resection in the lung, retrocrural or pelvic nodes, and retroperitoneum. PATIENTS AND METHODS: Between September 1992 and May 2006, 359 patients had PC-RPLND under the care of one surgeon, 54 of which were repeat procedures. We compared the long-term outcome between those having primary and those having repeat PC-RPLND. RESULTS: The median (range) time from original to repeat surgery was 2.4 (0.25-26.5) years, and the median follow-up after the repeat procedure was 5.8 (0.08-12.9) years. There was no difference in survival between patients requiring only one PC-RPLND and those having a repeat procedure (P = 0.592). The most frequent sites of recurrent disease were: behind the great vessels/para-aortic areas (38, 46%), in the suprahilar region (18, 18%), in the retrocrural area (16, 19%), in the pelvic nodes (10, 12%) and in the lung (one, 1%). The most common pathological findings in the repeat PC-RPLNDs were differentiated teratoma (19, 35%), malignant teratoma undifferentiated (nine, 17%), adenocarcinoma (eight, 15%) and necrotic tissue (five, 9.2%). CONCLUSION: Although a small proportion of patients with metastatic GCT might require repeat PC-RPLND, there is no difference in survival between this group and those having one PC-RPLND. However, to avoid cancer recurrence and reoperation, it is crucial that the first PC-RPLND is careful and complete, preferably done in a centre with expertise in this procedure. PMID- 17711513 TI - Interferon-gamma sensitizes hepatitis B virus-expressing hepatocarcinoma cells to 5-fluorouracil through inhibition of hepatitis B virus-mediated nuclear factor kappaB activation. AB - Nuclear factor (NF)-kappaB is important for immune responses and cell survival; however, abnormal activation of NF-kappaB is linked with many types of diseases, including hepatocellular carcinoma (HCC). Our previous report indicated that hepatitis B virus (HBV) induces NF-kappaB activation through NF-kappaB-inducing kinase (NIK), and this can be blocked specifically by interferon (IFN)-gamma. In the present study, we report that HBV expression in HCC cell lines induces drug resistance against 5-fluorouracil (5-FU). This drug resistance was abolished by inhibition of NF-kappaB activation through small interfering RNA-mediated NIK 'knockdown' and IFN-gamma treatment. In addition to the reduced NF-kappaB activation and drug resistance, the upregulated growth arrest- and DNA damage inducible protein 45beta (Gadd45beta) in HBV-expressing HCC cell lines was downregulated by the small interfering RNA-mediated NIK knockdown and IFN-gamma treatment. The overexpression of Gadd45beta in HCC cell lines also induces drug resistance against 5-FU. Based on our data, we suggest that IFN-gamma treatment might be helpful for chemotherapy in HBV-integrated HCC through inhibition of the NIK-mediated NF-kappaB activation and downregulation of the NF-kappaB target gene Gadd45beta. PMID- 17711514 TI - Toll-like receptor 2 -196 to 174del polymorphism influences the susceptibility of Japanese people to gastric cancer. AB - Toll like receptors (TLR) play important roles in the signaling of many pathogen related molecules and endogenous proteins associated with immune activation. The 196 to -174del polymorphism affects the TLR2 gene and alters its promoter activity. We investigated the influence of the TLR2-196 to -174del polymorphism on the occurrence of non-cardiac gastric cancer (NCGC) in a Japanese population. The study was carried out with 289 patients with NCGC, 309 non-cancer patients with abdominal discomfort and 146 healthy controls. The -196 to -174del TLR2 polymorphism was investigated using the allele-specific polymerase chain reaction method in all of the subjects. The -196 to -174del/del genotype of TLR2 showed a significantly higher frequency in NCGC patients than in healthy controls (adjusted odds ratio [OR] = 6.06; 95% confidence interval [CI] = 1.86-19.72). Similarly, the frequency of the -196 to -174del/del genotype was significantly higher among NCGC patients than in non-cancer patients (adjusted OR = 2.02; 95% CI = 1.22-3.34). The same genotype was associated with an increased risk of both intestinal (OR = 2.00, 95% CI = 1.12-3.60) and diffuse-type (OR = 2.05; 95% CI = 1.11-3.79) histopathology. There were no significant associations between TLR2 genotypes and tumor stage and anatomical location. Our data suggest that the -196 to -174del/del genotype of TLR2 may increase the risk of gastric cancer in the Japanese population. PMID- 17711515 TI - Inhibition of caspase-dependent spontaneous apoptosis via a cAMP-protein kinase A dependent pathway in neutrophils from sickle cell disease patients. AB - Sickle cell disease (SCD) is a chronic inflammatory condition characterized by high leucocyte counts, altered cytokine levels and endothelial cell injury. As the removal of inflammatory cells by apoptosis is fundamental for the resolution of inflammation, we aimed to determine whether the leucocyte apoptotic process is altered in SCD. Neutrophils from SCD individuals showed an inhibition of spontaneous apoptosis when cultured in vitro, in the presence of autologous serum for 20 h. Intracellular cyclic adenosine monophosphate (cAMP) levels were approximately twofold increased in SCD neutrophils; possible cAMP-upregulating factors present in SCD serum include interleukin-8, granulocyte-macrophage colony stimulating factor and prostaglandin. Accordingly, co-incubation of SCD neutrophils with KT5720, a cAMP-dependent protein kinase (PKA) inhibitor, abrogated increased SCD neutrophil survival. Caspase-3 activity was also significantly diminished in SCD neutrophils cultured for 16 h and this activity was restored when cells were co-incubated with KT5720. BIRC2 (encoding cellular inhibitor of apoptosis protein 1, cIAP(1)), MCL1 and BAX expression were unaltered in SCD neutrophils; however, BIRC3 (encoding the caspase inhibitor, cIAP(2)), was expressed at significantly higher levels. Thus, we report an inhibition of spontaneous SCD neutrophil apoptosis that appears to be mediated by upregulated cAMP-PKA signalling and decreased caspase activity. Increased neutrophil survival may have significant consequences in SCD; contributing to leucocytosis, tissue damage and exacerbation of the chronic inflammatory state. PMID- 17711517 TI - Aplasia cutis associated with coarctation of the aorta: could this be an incomplete form of Adams-Oliver syndrome? PMID- 17711516 TI - Childhood acute lymphoblastic leukaemia simulating multifocal osteomyelitis. PMID- 17711518 TI - Recurrence of classical juvenile pityriasis rubra pilaris in adulthood: report of a case. PMID- 17711519 TI - Admissions to a U.K. teaching hospital with nonnecrotizing lower limb cellulitis show a marked seasonal variation. PMID- 17711520 TI - Novel homozygous nonsense TMC8 mutation detected in patients with epidermodysplasia verruciformis from a Brazilian family. PMID- 17711521 TI - Histone deacetylase inhibitors preferentially augment transient transgene expression in human dermal fibroblasts. AB - BACKGROUND: Skin is an attractive target for gene therapy. However, low efficiency of gene transfection has been a major problem. Histone deacetylase (HDAC) inhibitors have been reported to increase transgene expression in malignant cells. OBJECTIVES: We have estimated how much HDAC inhibitors might increase transgene expression in HaCaT cells, normal human epidermal keratinocyte (NHEK) cells, normal human dermal fibroblast (NHDF) cells and also in stratified cultured epidermal sheets that mimic the structure of the skin. METHODS: After treatment with each HDAC inhibitor [trichostatin A, FK228 and cyclic hydroxamic acid-containing peptide 31 (CHAP31)], transient transgene expression in HaCaT, NHEK and NHDF cells and stratified cultured epidermal sheets was compared with that of respective controls without treatment. Reactivation of transgene expression using HDAC inhibitors in HaCaT cells stably expressing the transgene was also studied. RESULTS: All HDAC inhibitors equally increased transient transgene expression by 2-fold in NHEK cells, 20-fold in NHDF cells and 6-fold in HaCaT cells when compared with untreated cells. This augmented expression continued for 72 h in all cell lines maintained under each HDAC inhibitor. In cells stably expressing the transgene, only CHAP31 reactivated transgene expression. In stratified cultured epidermal sheets, CHAP31 most effectively improved transient transgene expression. CONCLUSIONS: HDAC inhibitors are most efficient at amplifying transient transgene expression in NHDF cells. This suggests that NHDF cells may be most suitable as transgene targets for transient gene transfection using HDAC inhibitors. Specific HDAC inhibitors may not prove so useful for treating genetic dermatoses requiring cells stably expressing the correct gene, but may be advantageous in treating nonhealing cutaneous wounds or cancer. PMID- 17711522 TI - Giant genital variant of folliculosebaceous cystic hamartoma: successful management by CO2 laser and acitretin therapy. PMID- 17711523 TI - C16 laminin peptide increases angiotropic extravascular migration of human melanoma cells in a shell-less chick chorioallantoic membrane assay. AB - BACKGROUND: As distinct from intravascular dissemination, extravascular migratory metastasis (EVMM) has been described as a potential additional mechanism of melanoma spread in which tumour cells migrate along the external surfaces of vessels. Recent experimental studies strongly suggest a correlation of angiotropism of melanoma cells with EVMM. Angiotropic melanoma cells are linked to the endothelium by an amorphous matrix confirmed to contain laminin. OBJECTIVES: To investigate whether laminin plays a role in this extravascular mechanism of tumour spread. METHODS: We tested the effect of the C16 laminin peptide on melanoma spread in a shell-less chick chorioallantoic membrane model. RESULTS: After 3 days, green fluorescent protein-expressing melanoma cells were observed spreading along or in the immediate proximity of vessels. The C16 laminin peptide significantly lengthened the distance of extravascular, angiotropic migration of melanoma cells. Histopathology confirmed the angiotropism of melanoma cells without intravasation, compatible with that observed with human angiotropic melanoma. CONCLUSIONS: The results of this study suggest that the C16 laminin gamma1 chain peptide has angiotropic, extravascular migration-promoting activity on human melanoma cells, and might be a molecular target for preventing melanoma metastasis. PMID- 17711524 TI - High frequency of contact allergy to gold in patients with endovascular coronary stents. AB - BACKGROUND: Stent implantation is an effective method for treatment of atherosclerotic disease. Factors predisposing to in-stent restenosis are still largely unknown. Contact allergy to metal ions eluted from the stent has been suggested to be a risk factor. OBJECTIVES: To explore whether there is a possible induction of contact allergy to metals used in stents among patients with a stainless steel stent containing nickel (Ni stent) and patients with a gold plated stent (Au stent). METHODS: Adults (n = 484) treated with coronary stent implantation participated in the study with patch testing. The study design was retrospective and cross-sectional with no assessment of contact allergy before stenting. Age- and sex-matched patch-tested patients with dermatitis (n = 447) served as controls. RESULTS: Of Au-stented patients, 54 of 146 (37%) were allergic to gold compared with 85 of 447 (19%) controls (P < 0.001). Within the stented population there were no statistically significant differences in contact allergy to gold or nickel between Ni-stented and Au-stented patients. In multivariate models where other risk factors for contact allergy to gold were considered, the Au stent showed a trend towards statistical significance (odds ratio 1.43, 95% confidence interval 0.95-2.16; P = 0.09). CONCLUSIONS: As the frequency of contact allergy to gold is higher in stented patients independent of stent type it suggests a previous sensitization. However, several pieces of circumstantial evidence as well as statistical analysis indicate the possibility of sensitization in the coronary vessel by the Au stent. Ni stents and Au stents should not be ruled out as risk factors for induction of contact allergy to these metals. PMID- 17711525 TI - Late presentation of erythropoietic protoporphyria: case report and genetic analysis of family members. AB - Erythropoietic protoporphyria (EPP) is an inherited disorder of haem biosynthesis caused by decreased activity of the enzyme ferrochelatase (FECH), which catalyses the insertion of iron into protoporphyrin, the last step in haem biosynthesis. Development of clinically overt EPP usually requires inheritance of a severe FECH mutation trans to a low-expression FECH variant (FECH IVS3-48C), which is present in 13% of the U.K. population. Reduced FECH activity leads to accumulation of protoporphyrin in various tissues. An excess amount of free protoporphyrin in the skin causes photosensitivity. EPP usually presents in early childhood or infancy, with painful burning and pruritus within minutes of light exposure. Onset of symptoms in adults is rare and often associated with acquired somatic mutation of the FECH gene secondary to haematological malignancy. Here we describe a patient with EPP, in whom the presenting clinical symptom, night-time itch, did not appear until middle age and who had an asymptomatic sister with the same FECH genotype. PMID- 17711527 TI - Paradoxical effects of beta-estradiol on epidermal permeability barrier homeostasis. AB - BACKGROUND: Previous studies have demonstrated that sex hormones modulate epidermal permeability barrier homeostasis, and when the balance of these hormones is altered at menopause or during the menstrual cycle, skin sensitivity or barrier function is changed. OBJECTIVES: To observe the direct effects of sex hormones on epidermal homeostasis. METHODS: We examined the effects of topical application of sex hormones on permeability barrier recovery after tape stripping in the hairless mouse. To avoid the influence of systemic hormonal alteration, we employed male animals. RESULTS: Application of androgen (testosterone or androsterone) delayed the barrier recovery, and the delay was overcome by co application of beta-estradiol. Progesterone also delayed the barrier recovery, but in this case the delay was enhanced by beta-estradiol. CONCLUSIONS: These results suggest that changes in sex hormone balance might be associated with the skin dysfunction that often occurs during menopause, and at certain points during the menstrual cycle. PMID- 17711526 TI - Clinical features and natural course of Behcet's disease in 661 cases: a multicentre study. AB - BACKGROUND: Behcet's disease (BD) is a systemic inflammatory disease with unpredictable exacerbations and remissions. The natural course of BD is not fully known. OBJECTIVES: We aimed retrospectively to determine the occurrence of the symptoms in chronological order. We also evaluated the influence of the treatment and follow-up on the clinical severity and tried to identify the factors determining severe organ involvement. METHODS: Six hundred and sixty-one patients were involved in this multicentre study. The symptoms of the disease were recorded retrospectively in the time order of the manifestations in each patient. RESULTS: Oral ulcers were the most common manifestation (100%), followed by genital ulcers (85.3%), papulopustular lesions (55.4%), erythema nodosum (44.2%), skin pathergy reaction (37.8%), and articular (33.4%) and ocular involvement (29.2%). Oral ulcers were the most common onset manifestation (88.7%). The mean +/- SD duration between the onset symptom and the fulfilment of diagnostic criteria was calculated to be 4.3 +/- 5.7 years. The clinical severity score was significantly increased in the noncompliant treatment group compared with the compliant group with the passage of time (P < 0.001). The frequency of ocular involvement and genital ulcers was significantly higher in patients whose disease onset was at < 40 years. Genital ulcers, ocular involvement, papulopustular lesions, thrombophlebitis and skin pathergy reaction were found to be significantly more frequent in males. CONCLUSIONS: Mucocutaneous lesions are the hallmarks of the disease, and especially oral ulcers precede other manifestations. The increase in clinical severity score is more pronounced in patients without regular treatment and follow-up. Male sex and a younger age at onset are associated with more severe disease. PMID- 17711528 TI - Functional redundancy of extracellular matrix protein 1 in epidermal differentiation. AB - BACKGROUND: Extracellular matrix protein 1 (ECM1) is a secreted protein expressed in skin. Its dermatological relevance has been highlighted by the discovery of loss-of-function mutations in ECM1 in patients with lipoid proteinosis (LiP). OBJECTIVES: To determine the role of ECM1 in epidermal differentiation by examining gene and protein expression of epidermal differentiation markers in individuals with LiP and histological assessment of transgenic mouse skin that overexpresses Ecm1a in basal or suprabasal epidermis. METHODS: Subconfluent, confluent and postconfluent LiP and control keratinocyte cultures were analysed by Northern and Western blotting for differences in expression of differentiation markers. Expression of these markers was analysed in skin of patients with LiP by immunohistochemistry. To study effects of Ecm1 overexpression on epidermal differentiation, transgenic mice were generated under control of either a keratin 14 or an involucrin promoter. RESULTS: No differential expression of the different markers analysed was observed in LiP keratinocytes compared with controls. No histological differences were found in Ecm1-overexpressing mouse skin compared with wild-type. CONCLUSIONS: Absence of ECM1 does not lead to differences in epidermal differentiation. Moreover, overexpression of Ecm1a in vivo does not exert dramatic effects on epidermal structure. Collectively, these findings suggest no role of ECM1 in epidermal differentiation. PMID- 17711530 TI - Infliximab, as sole or combined therapy, induces rapid clearing of erythrodermic psoriasis. PMID- 17711529 TI - Ceramide analogue 14S24 selectively recovers perturbed human skin barrier. AB - BACKGROUND: Topical ceramide application is an effective therapeutic approach in skin disorders with disturbed barrier function, including atopic dermatitis and psoriasis. OBJECTIVES: To evaluate ceramide analogue N-tetracosanoyl-(l)-serine tetradecyl ester (14S24) using a novel ex vivo model. METHODS: Freshly excised human skin was disrupted by lipid extraction, tape stripping and sodium lauryl sulphate (SLS) treatment. Barrier perturbation was evaluated by the measurement of transepidermal water loss (TEWL), skin hydration and the penetration of model compound, theophylline (TH), assessed by microdialysis. The effect of topical 5% 14S24 was compared with a commercial formulation containing a skin lipid mixture (LR) and control formulation with no skin lipids (L). RESULTS: Both LR and 14S24 produced significant recovery of TEWL and TH penetration in extracted and tape stripped skin with 14S24 being significantly more effective. In SLS-treated skin, 14S24 decreased TEWL but not TH penetration; LR was inactive. L improved skin hydration but not barrier characteristics. Weak correlation between TEWL and TH penetration was observed in extracted and tape-stripped skin but not in SLS treated skin. CONCLUSIONS: Cutaneous microdialysis can serve as a useful tool for the evaluation of skin barrier recovery by topical formulations ex vivo whereas TEWL may not be an appropriate measure of skin barrier function in such studies. The excellent barrier repair activity of 14S24 could be beneficial in skin disorders with ceramide deficiency. PMID- 17711532 TI - Photoageing: mechanism, prevention and therapy. AB - Photoageing is the superposition of chronic ultraviolet (UV)-induced damage on intrinsic ageing and accounts for most age-associated changes in skin appearance. It is triggered by receptor-initiated signalling, mitochondrial damage, protein oxidation and telomere-based DNA damage responses. Photodamaged skin displays variable epidermal thickness, dermal elastosis, decreased/fragmented collagen, increased matrix-degrading metalloproteinases, inflammatory infiltrates and vessel ectasia. The development of cosmetically pleasing sunscreens that protect against both UVA and UVB irradiation as well as products such as tretinoin that antagonize the UV signalling pathways leading to photoageing are major steps forward in preventing and reversing photoageing. Improved understanding of the skin's innate UV protective mechanisms has also given rise to several novel treatment concepts that promise to revolutionize this field within the coming decade. Such advances should not only allow for the improved appearance of skin in middle age and beyond, but also greatly reduce the accompanying burden of skin cancer. PMID- 17711533 TI - Skin disease is common in rural Nepal: results of a point prevalence study. AB - BACKGROUND: Skin problems are the commonest reason for people accessing healthcare services in Nepal but there is little information about the prevalence of skin disease. OBJECTIVES: To perform a point prevalence study of skin disease in the Terai region of Nepal. METHODS: Five villages were randomly selected in Bara District in the Terai region of Nepal, and 878 people were examined. RESULTS: The number of individuals identified as having a skin disease was 546. The point prevalence of identifiable skin abnormalities was 62.2% (546 of 878) (with 95% exact confidence intervals 58.9-65.4%). A wide range of dermatoses was identified. The six most prevalent were dermatophyte infections (11.4%), followed by pityriasis versicolor (8.9%), acne (7.7%), melasma (6.8%), eczema (5.6%) and pityriasis alba (5.2%). Overall, treatable skin infections and infestations were by far the commonest skin diseases identified. CONCLUSIONS: Our study has demonstrated a very high point prevalence (62.2%) of skin disease in rural Nepal. This study represents the first formal survey of skin disease in Nepal and demonstrates a large burden of disease, in particular treatable infections. PMID- 17711531 TI - Cold urticaria: tolerance induction with cold baths. PMID- 17711534 TI - A scoring system for mucosal disease severity with special reference to oral lichen planus. AB - BACKGROUND: To date, there is only weak evidence for the superiority of any interventions over placebo for the palliation of symptomatic oral lichen planus (LP). Further research involving large placebo-controlled, randomized clinical trials is needed. These will require carefully selected and standardized outcome measures. OBJECTIVES: To formulate a scoring system for intraoral LP. METHODS: One hundred and fifty-six patients with biopsy-confirmed LP were scored at the first and subsequent visits according to (i) extent of site involvement, (ii) disease activity at each site and (iii) an overall pain score as reported by the patient. Overall differences between clinical variants of LP were analysed using the Kruskal-Wallis test and pairwise differences by the Mann-Whitney U-test. Clinical sensitivity (Wilcoxon signed-rank test) was assessed by scoring patients before and after treatment (n = 23). RESULTS: Reticular LP (n = 48) was the commonest single type of clinical presentation, followed by ulcerative (n = 30), atrophic (n = 22), desquamative (n = 18) and plaque (n = 1). The median severity and activity scores were 13/6 (reticular), 39/20 (ulcerative), 20/9 (atrophic) and 23/11 (desquamative). Two or more clinical variants were seen in 37 cases. Statistical significance was observed for differences between clinical variants (P < 0.0001) and variation in scores (P < 0.01) when ulcerative LP was compared with all other types. Clinical sensitivity was statistically significant (P < 0.01), while reproducibility was high and allowed the response to therapy to be easily assessed. CONCLUSIONS: It is suggested that this scoring system is easy to use, reproducible and sensitive enough to detect clinical responses to therapy. PMID- 17711535 TI - Different angiotensin-converting enzyme inhibitors have similar clinical efficacy after myocardial infarction. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Treatment with an angiotensin converting enzyme (ACE) inhibitor benefits many patients with cardiovascular disease. ACE inhibitors are generally assumed to be equally effective, but this has never been fully verified in clinical trials. WHAT THIS STUDY ADDS: Studying the association among ACE inhibitors after myocardial infarction demonstrated similarity in clinical outcome and supports a dosage-response relationship. Therefore, for long-term benefits for patients who need treatment with an ACE inhibitor, a focus of treatment at the recommended dosage is most important and not which ACE inhibitor is used. AIM: Therapy with angiotensin-converting enzyme (ACE) inhibitors is common after myocardial infarction (MI). Given the lack of randomized trials comparing different ACE inhibitors, the association among ACE inhibitors after MI in risk for mortality and reinfarction was studied. METHODS: Patients hospitalized with first-time MI (n = 16,068) between 1995 and 2002, who survived at least 30 days after discharge and claimed at least one prescription of ACE inhibitor, were identified using nationwide administrative registries in Denmark. RESULTS: Adjusted Cox regression analysis demonstrated no differences in risk for all-cause mortality, but patients using captopril had higher risk of reinfarction (hazard ratio 1.18, 95% confidence interval 1.05, 1.34). However, following adjustment for differences in used dosages, all ACE inhibitors had similar clinical efficacy. Risk of all-cause mortality: trandolapril (reference) 1.00, ramipril 0.97 (0.89, 1.05), enalapril 1.04 (0.95, 1.150), captopril 0.95 (0.83, 1.08), perindopril 0.98 (0.84, 1.15) and other ACE inhibitors or angiotensin II receptor blockers (ARB) 1.06 (0.94, 1.19). Reinfarction: trandolapril (reference) 1.00, ramipril 0.98 (0.89, 1.08), enalapril 1.04 (0.92, 1.17), captopril 1.05 (0.89, 1.25), perindopril 0.96 (0.81, 1.14) and other ACE inhibitors or ARB 0.99 (0.86, 1.14). Furthermore, the association between ARBs and clinical events was similar to ACE inhibitors (trandolapril reference): all cause mortality 0.99 (0.84, 1.16) and recurrent MI 0.99 (0.83, 1.19). CONCLUSIONS: Our results suggest a class effect among ACE inhibitors when used in comparable dosages. Focus on treatment at the recommended dosage is therefore most important, and not which ACE inhibitor is used. PMID- 17711537 TI - Exposure-response analysis reveals that clinically important toxicity difference can exist between bioequivalent carbamazepine tablets. AB - AIMS: To assess whether, using the current regulatory criteria, therapeutically important differences can exist between bioequivalent carbamazepine (CBZ) tablets. A secondary goal was to demonstrate quantitatively the relationship between the risk of neurological adverse effects to orally ingested CBZ and the rate of absorption. METHODS: Results of a bioequivalence study by Olling et al. (Biopharm Drug Dispos 1999; 20: 19-28) were reanalysed. Following an exploratory data analysis step, a mixed-effect pharmacokinetic-pharmacodynamic (PK-PD) model was built to describe the dependence of adverse events on the CBZ concentration. RESULTS: Rapid development of tolerance was demonstrated for most neurological adverse effects, with a characteristic half-life of 02.29 h and an initial EC50 of 2.33 mg l(-1). The resulting tolerance PK-PD model was characterized further using the tools and terminology of sensitivity analysis. It was demonstrated that the maximum concentration (C(max)) exhibits poor PK and PD sensitivities, and that clinically significant differences can exist between formulations which otherwise comply with the bioequivalence requirements. In contrast, another PK metric, the partial AUC, was a much better marker of the early neurological adverse events observable during the absorption phase of the drug. CONCLUSIONS: In clinical and regulatory considerations, the development of acute tolerance for adverse effects of CBZ must be taken into account. Partial AUC reflects more sensitively the risk of adverse events than C(max). Instead of the current trend of tightening of the bioequivalence criteria for narrow therapeutic index drugs, the use of alternative, more sensitive PK metrics is proposed. PMID- 17711538 TI - Overview of model-building strategies in population PK/PD analyses: 2002-2004 literature survey. AB - AIMS: A descriptive survey of published population pharmacokinetic and/or pharmacodynamic (PK/PD) analyses from 2002 to 2004 was conducted and an evaluation made of how model building was performed and reported. METHODS: We selected 324 articles in Pubmed using defined keywords. A data abstraction form (DAF) was then built comprising two parts: general characteristics including article identification, context of the analysis, description of clinical studies from which the data arose, and model building, including description of the processes of modelling. The papers were examined by two readers, who extracted the relevant information and transmitted it directly to a MySQL database, from which descriptive statistical analysis was performed. RESULTS: Most published papers concerned patients with severe pathology and therapeutic classes suffering from narrow therapeutic index and/or high PK/PD variability. Most of the time, modelling was performed for descriptive purposes, with rich rather than sparse data and using NONMEM software. PK and PD models were rarely complex (one or two compartments for PK; E(max) for PD models). Covariate testing was frequently performed and essentially based on the likelihood ratio test. Based on a minimal list of items that should systematically be found in a population PK-PD analysis, it was found that only 39% and 8.5% of the PK and PD analyses, respectively, published from 2002 to 2004 provided sufficient detail to support the model building methodology. CONCLUSIONS: This survey allowed an efficient description of recent published population analyses, but also revealed deficiencies in reporting information on model building. PMID- 17711539 TI - Inter-expert agreement of seven criteria in causality assessment of adverse drug reactions. AB - AIMS: To evaluate agreement between five senior experts when assessing seven causality criteria and the probability of drug causation. METHODS: A sample of 31 adverse event-drug pairs was constituted. For each pair, five experts separately assessed (i) the probability of drug causation, which was secondarily divided into seven causality levels: ruled out (0-0.05), unlikely (0.06-0.25), doubtful (0.26-0.45), indeterminate (0.46-0.55), plausible (0.56-0.75), likely (0.76 0.95), and certain (0.96-1); and (ii) seven causality criteria. To test discrepancies between experts, the kappa index was used. RESULTS: The agreement of the five experts was very poor (kappa = 0.05) for the probability of drug causation. Among the seven levels of causality, only 'doubtful' showed a significant rate of agreement (kappa = 0.32, P < 0.001). For all criteria, the kappa index was significant except for the item 'risk(s) factor(s)' (kappa = 0.09). Agreement between experts was good (0.64, P < 0.001) only for the criterion 'reaction at site of application or toxic plasma concentration of the drug or validated test'. However, the rate of agreement with kappa indices of the causality criteria ranged from 0.12 to 0.38. CONCLUSIONS: This study confirms that in the absence of an operational procedure, agreement between experts is low. This should be considered when designing a causality assessment method. In particular, criteria inducing a low level of agreement should have their weight reduced. PMID- 17711540 TI - Plasma concentrations of fluticasone propionate and budesonide following inhalation: effect of induced bronchoconstriction. AB - AIMS: To determine whether and to what extent bronchoconstriction affects plasma concentrations of fluticasone and budesonide following inhalation. METHODS: Twenty people with mild asthma inhaled 1000 microg fluticasone (Accuhaler) plus 800 microg budesonide (Turbohaler) on two visits. On one occasion, prior to drug inhalation, FEV(1) was decreased by at least 25% using inhaled methacholine. Plasma drug concentrations were measured for each drug over 5 h and area under the plasma concentration-time curve (AUC(0,5 h)) compared between visits. RESULTS: The mean difference in FEV(1) prior to drug inhalation on the 2 days was 33%. AUC(0,5 h) values for fluticasone and budesonide were lower by a median of 60% (IQR 36-75) and 29% (IQR 2-44), respectively, when administered following bronchoconstriction; the reduction was greater for fluticasone than for budesonide, P = 0.007. CONCLUSIONS: The lower plasma concentrations of fluticasone and, to a lesser extent, budesonide seen when the drugs were inhaled following induced bronchoconstriction, is likely to reflect variations that will occur with fluctuations in airway caliber in asthma. PMID- 17711541 TI - Sheathotomy in complicated cases of branch retinal vein occlusion. AB - PURPOSE: To report the clinical experience and results of using a microsurgical technique to decompress the arteriovenous connection in complicated branch retinal vein occlusion (BRVO) combined with haemorrhage, oedema and ischaemia. METHODS: We carried out a retrospective, non-randomized, interventional case study of the surgical sheathotomy decompression procedure. We enrolled 12 patients (seven women, five men; median age 64 years) with BRVO and decreased visual acuity (VA) caused by haemorrhage, oedema and ischaemia. The mean duration of thrombosis was 7 months (2-15 months). The patients were examined for pre- and postoperative best corrected VA (BCVA), intraocular pressure (IOP) and fundus photography. Ten patients were examined with fluorescein angiography and eight with ocular coherence tomography (OCT). Postoperative progression of cataract was recorded, as were other complications. The mean follow-up time was 20 months (8 39 months). RESULTS: Best corrected VA had improved in nine patients, was unchanged in one patient and had deteriorated in two patients at the last follow up. Noted complications were venous haemorrhage at surgery in five patients, retinal detachment in one patient and progression of cataract in four patients. CONCLUSIONS: Microsurgical treatment with sheathotomy of BRVO is a technically feasible procedure with few complications. Postoperative increased reperfusion could explain the resolution of macular haemorrhage, oedema and ischaemia, and may improve visual function in patients with this common vascular eye disease. PMID- 17711542 TI - True polycoria or pseudo-polycoria? PMID- 17711543 TI - Peribulbar poloxamer for ocular drug delivery. AB - PURPOSE: The use of biopolymers in peribulbar injection for controlled drug delivery provides alternative options to eyedrops and intravitreal or surgical methods. Polymerizable biopolymers are especially likely to have a role because of their particular properties. In liquid form, they can be easily injected into the target site and, after polymerization, they provide a prolonged and controlled release of the drug. This study was undertaken to demonstrate the suitability of a thermopolymerizable biopolymer poloxamer (Lutrol F127) for peribulbar injections and controlled drug release. METHODS: The toxicity of injected poloxamer compounds was evaluated by visual inspection and histological and immunohistochemical tissue evaluation. The release of marker substances such as 5(6)-carboxyfluorescein (376 Da) or fluorescein isothiocyanate-dextran (FITC dextran) (4-40 kDa) from poloxamer was used to simulate drug release and penetration into the eye using in vivo fluorometry. RESULTS: According to our clinical and pathological analyses, poloxamer was well tolerated in peribulbar injections and did not cause acute toxicity at the site of injection. The marker compounds were released from the site of injection during the first 24 hours. CONCLUSIONS: Although poloxamer appears to be suitable for peribulbar injections, a more prolonged period of dissolution is desirable for clinical purposes. PMID- 17711544 TI - Functional and anatomical investigations in racemose haemangioma. AB - PURPOSE: To determine the vascular morphology of racemose haemangioma and related functional alterations in arteriovenous (AV) malformation type 3. METHODS: A 17 year-old patient with unilateral racemose haemangioma received a full ophthalmic examination including Snellen visual acuity (VA) and Goldmann visual field. The central vision was investigated by scanning laser ophthalmoscope (SLO) and multifocal electroretinogram (mfERG). The ocular haemodynamics were examined by fluorescence angiography and Doppler ultrasound. The tomographic contour of the vascular architecture was visualized using B-scan ultrasound, Stratus optical coherence tomography (OCT) and three-dimensional Heidelberg retina tomograph (3D HRT II). RESULTS: The VA of the patient's right eye was reduced to 20/400 and her visual field was constricted concentrically. Microperimetry revealed a small central field with good central fixation. The mfERG demonstrated reduced amplitudes of the central retina. On fluorescein angiography, there was a fast filling of the retinal branches related to the racemose vessels. Doppler ultrasound confirmed a significantly changed haemodynamic flow in the racemose vessels. Ultrasound, OCT and HRT demonstrated a prominent optic nerve head. CONCLUSION: The racemose haemangioma led to a marked visual field defect. Racemose haemangiomas are associated with severe changes in the haemodynamics of the retinal vasculature. PMID- 17711545 TI - Dichotomy of food and inhalant allergen sensitization in eosinophilic esophagitis. AB - BACKGROUND: Eosinophilic esophagitis (EE) is an emerging condition where patients commonly present with symptoms of gastroesophageal reflux disease and fail to respond adequately to anti-reflux therapy. Food allergy is currently recognized as the main immunological cause of EE; recent evidence suggests an etiological role for inhalant allergens. The presence of EE appears to be associated with other atopic illnesses. OBJECTIVES: To report the sensitization profile of both food and inhalant allergens in our EE patient cohort in relation to age, and to profile the prevalence of other allergic conditions in patients with EE. METHOD: The study prospectively analyzed allergen sensitization profiles using skin prick tests to common food allergens and inhalant allergens in 45 children with EE. Patch testing to common food allergens was performed on 33 patients in the same cohort. Comorbidity of atopic eczema, asthma, allergic rhinitis and anaphylaxis were obtained from patient history. RESULTS: Younger patients with EE showed more IgE and patch sensitization to foods while older patients showed greater IgE sensitization to inhalant allergens. The prevalence of atopic eczema, allergic rhinitis and asthma was significantly increased in our EE cohort compared with the general Australian population. A total of 24% of our cohort of patients with EE had a history of anaphylaxis. CONCLUSION: In children with EE, the sensitization to inhalant allergens increases with age, particularly after 4 years. Also, specific enquiry about severe food reactions in patients presenting with EE is strongly recommended as it appears this patient group has a high incidence of anaphylaxis. PMID- 17711546 TI - Esomeprazole-induced DRESS syndrome. Studies of cross-reactivity among proton pump inhibitor drugs. PMID- 17711547 TI - IgE-mediated type-I-allergy against red wine and grapes. PMID- 17711548 TI - Influence of rituximab therapy on hepatitis C virus RNA concentration in kidney transplant patients. PMID- 17711549 TI - Nonviral gene delivery with indoleamine 2,3-dioxygenase targeting pulmonary endothelium protects against ischemia-reperfusion injury. AB - Pulmonary endothelial dysfunction induced by inflammation and inflammation associated reactive oxygen species is a central component in the pathophysiology of lung transplant ischemia-reperfusion (IR) injury. Indoleamine-2,3-dioxygenase (IDO) is a unique cytosolic enzyme possessing both immune modulating and antioxidant properties. This study investigated whether enhanced pulmonary endothelial IDO activity by a targeted nonviral gene transfer approach ameliorates lung IR injury. Orthotopic syngeneic lung transplants were performed in Lewis rats. A human IDO (hIDO)-expressing plasmid driven by an endothelial cell-specific endothelin-1 promoter was generated and intravenously delivered to donor lung using cationic polymer polyethylenimine. This nonviral gene transfer approach augmented hIDO expression specifically in endothelial cells within lung grafts. Importantly, enhanced IDO activity induced by the hIDO transgene prevented endothelial cell apoptosis, reduced vascular permeability and leukocyte extravasation, and consequently improved graft function and histologic appearance. Furthermore, our in vitro studies showed that increased IDO activity in endothelial cells protected its mitochondrial function and ultrastructure from oxidative stress through stabilization of intracellular redox status. The approach used in these experiments has properties that could eliminate the inherent side effects associated with viral vectors and/or antibody-directed targeted therapy, and thus may represent a potential therapeutic strategy against lung IR injury in patients. PMID- 17711550 TI - Gadolinium is not the only trigger for nephrogenic systemic fibrosis: insights from two cases and review of the recent literature. AB - Nephrogenic systemic fibrosis (NSF) is an emerging fibrosing disease with serious consequences in patients with acute and chronic kidney disease including solid organ and renal transplant recipients. It has recently been linked to gadolinium exposure. Almost all recently reported cases of NSF were found to be preceded by gadolinium administration, which led the FDA to issue a warning against the use of gadolinium in patients with moderate-to-severe reduction in the glomerular filtration rate. We report two organ transplant recipients who developed NSF and in whom extensive record review failed to document any prior gadolinium exposure. We then critically review the recently published literature linking NSF and gadolinium and we propose other possible triggers. We conclude that gadolinium is not the only trigger for NSF, and that the search for other triggers should be sought. We believe that this information is an important addition to the NSF literature, such that the definitive etiology and pathogenesis of NSF can be researched. PMID- 17711551 TI - Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway. AB - Carbon monoxide (CO) provides protection against oxidative stress via anti inflammatory and cytoprotective actions. In this study, we tested the hypothesis that a low concentration of exogenous (inhaled) CO would protect transplanted lung grafts from cold ischemia-reperfusion injury via a mechanism involving the mitogen-activated protein kinase (MAPK) signaling pathway. Lewis rats underwent orthotopic syngeneic or allogeneic left lung transplantation with 6 h of cold static preservation. Exposure of donors and recipients (1 h before and then continuously post-transplant) to 250 ppm CO resulted in significant improvement in gas exchange, reduced leukocyte sequestration, preservation of parenchymal and endothelial cell ultrastructure and reduced inflammation compared to animals exposed to air. The beneficial effects of CO were associated with p38 MAPK phosphorylation and were significantly prevented by treatment with a p38 MAPK inhibitor, suggesting that CO's efficacy is at least partially mediated by activation of p38 MAPK. Furthermore, CO markedly suppressed inflammatory events in the contralateral naive lung. This study demonstrates that perioperative exposure of donors and recipients to CO at a low concentration can impart potent anti-inflammatory and cytoprotective effects in a clinically relevant model of lung transplantation and support further evaluation for potential clinical use. PMID- 17711552 TI - The impact of aprotinin on renal function after liver transplantation: an analysis of 1,043 patients. AB - Renal dysfunction is frequently seen after orthotopic liver transplantation (OLT). Aprotinin is an antifibrinolytic drug which reduces blood loss during OLT. Recent studies in cardiac surgery suggested a higher risk of postoperative renal complications when aprotinin is used. The impact of aprotinin on renal function after OLT, however, is unknown. In 1,043 adults undergoing OLT, we compared postoperative renal function in patients who received aprotinin (n = 653) or not (n = 390). Using propensity score stratification (C-index 0.82) and multivariate regression analysis, aprotinin was identified as a risk factor for severe renal dysfunction within the first week, defined as increase in serum creatinine by >or= 100% (OR = 1.97, 95% CI = 1.14-3.39; p = 0.02). No differences in renal function were noted at 30 and 365 days postoperatively. Moreover, no significant differences were found in the need for renal replacement therapy (OR = 1.52, 95% CI = 0.94-2.46; p = 0.11) or in 1-year patient survival rate (OR = 1.14, 95% CI = 0.73-1.77; p = 0.64) in patients who received aprotinin or not. In conclusion, aprotinin is associated with a higher risk of transient renal dysfunction in the first week after OLT, but not with a higher need for postoperative renal replacement therapy or an increased risk of mortality. PMID- 17711553 TI - Immunosuppression minimization in pediatric transplantation. AB - The greatest benefit of immunosuppression minimization for children may lie in improving patient morbidity, by the elimination of the inherent side effects of steroid and calcineurin inhibitors (CNI). The newer generation of powerful induction and maintenance immunosuppressants offers an option for selected immunosuppression minimization strategies, some of which have been shown to also reduce graft morbidity. Steroid minimization and avoidance in single-center uncontrolled trials have shown early promise and the availability of data from an ongoing randomized, prospective, controlled trial of steroid avoidance in children will provide necessary data to support a practice change for steroid elimination in children. Calcineurin inhibitor minimization and addition of mycophenolate mofetil (MMF) or sirolimus have shown variable improvements in renal function, though suboptimal efficacy and safety with the currently proposed regimes have limited their application. Randomized, prospective studies of steroid and calcineurin inhibitor minimization and/or avoidance are warranted to clearly confirm the short and long-term safety and efficacy of alternative immunosuppression combinations. Linked pharmacokinetic and mechanistic studies within these trials will allow for optimizing drug dosing and monitoring. This article reviews published experience to date with steroid and calcineurin minimization in pediatric renal transplantation and discusses the risks and benefits of these approaches. PMID- 17711554 TI - Occupational asthma and rhinitis caused by eugenol in a hairdresser. PMID- 17711555 TI - Allergy to turnip seeds in a bird fancier. PMID- 17711556 TI - Detection of natural killer T cells in the sinus mucosa from asthmatics with chronic sinusitis. AB - BACKGROUND: Chronic sinusitis (CS) with asthma generally exhibits a high degree of sinus tissue eosinophilia and recurrence often occurs even after surgical therapy. However, the cause has not yet been fully clarified. AIMS OF THE STUDY: To elucidate the pathogenesis of this refractory disease, we examined the infiltration of natural killer T (NKT) and type 1 helper T (Th1)/type 2 helper T (Th2) cells, and the cytokine expression in the sinus mucosa. METHODS: Sinus mucosal specimens were obtained surgically from 16 CS patients with nasal polyps. The NKT cells, Th1/Th2 cells and the expression of IL-4, IL-5, IL-13 and IFN gamma were examined by a polymerase chain reaction or flow cytometry. Nasal mucosal specimens from six other patients with allergic rhinitis (AR) were examined in a similar manner. RESULTS: The NKT cells were detected to varying degrees in the sinus mucosa from asthmatic CS patients, but neither in the nonasthmatics nor in the nasal mucosa from the patients with AR. The Th2 cells and Th2 cytokines were expressed at significantly higher levels in the sinus mucosa from the CS patients with asthma in comparison to those without asthma. However, the Th1 cell infiltration and IFN-gamma expression were not different between these groups. CONCLUSION: Natural killer T cells may, therefore, play important roles in the enhanced Th2 cytokine expression and increased infiltration of Th2 cells and eosinophils observed in the sinus mucosa from asthmatic CS patients through MHC-independent mechanisms. PMID- 17711557 TI - The role of the intestinal microbiota in the development of atopic disorders. AB - The prevalence of atopic diseases, including eczema, allergic rhinoconjunctivitis and asthma, has increased worldwide, predominantly in westernized countries. Recent epidemiological studies and experimental research suggest that microbial stimulation of the immune system influences the development of tolerance to innocuous allergens. The gastrointestinal microbiota composition may be of particular interest, as it provides an early and major source of immune stimulation and seems to be a prerequisite for the development of oral tolerance. In this review the observational studies of the association between the gut microbiota and atopic diseases are discussed. Although most studies indicated an association between the gut microbiota composition and atopic sensitization or symptoms, no specific harmful or protective microbes can be identified yet. Some important methodological issues that have to be considered are the microbiological methods used (traditional culture vs molecular techniques), the timing of examining the gut microbiota, the definition of atopic outcomes, confounding and reverse causation. In conclusion, the microbiota hypothesis in atopic diseases is promising and deserves further attention. To gain more insight into the role of the gut microbiota in the etiology of atopy, large-scale prospective birth cohort studies using molecular methods to study the gut microbiota are needed. PMID- 17711558 TI - Familial Mediterranean Fever in Lebanon: founder effects for different MEFV mutations. AB - Haplotype analysis of 376 Familial Mediterranean Fever (FMF) patients and 100 controls from Lebanon was performed using 4 microsatellite loci to study founder effects for the five most frequent mutations within the MEFV gene (M694V, M694I, V726A, M680I and E148Q). Each of these mutations was associated with a particular haplotype that was less frequent among controls, confirming that they have probably arisen from unique mutation events and that the carrier chromosomes derived from a common ancestor. The estimated ages of the most recent common ancestor for each of the 5 mutations, using the ESTIAGE program, were 7000, 8500, 15000, 23000 and 30000 years for M694V, M694I, V726A, M680I and E148Q, respectively. Varying the mutation rate at one of the markers led to younger age estimates, but the mutation E148Q remained the oldest one. Comparison of haplotype distributions among the different Lebanese religious groups confirmed that Muslim sub-populations (Shiites and Sunnites) as well as Christian ones, including Armenians who were formerly settled in the South-Eastern part of Asia Minor (Cilicia), are all derived from an ancient common ancestral population in which most of the MEFV mutations were already present with their respective associated haplotypes. PMID- 17711559 TI - Assessment of alcohol consumption among hepatitis C-positive people receiving opioid maintenance treatment using direct ethanol metabolites and self-report: a pilot study. AB - This study was conducted to identify the alcohol consumption among hepatitis C positive people receiving opioid maintenance therapy using self-report and biomarkers. A total of 49 people (28 male, 21 female) were hepatitis C virus (HCV) positive and were included. The alcohol use disorder identification test (AUDIT) and self-reported ethanol intake in the last 28 days were assessed. In addition to gamma-glutamyl-transferase (GGT) and mean corpuscular volume (MCV), ethyl glucuronide (EtG) and ethyl sulphate (EtS) were determined in serum and urine (UEtG, UEtS, SEtG) using liquid chromatography/tandem mass-spectroscopy (LC/MS-MS) with deuterated internal standards. Abstinence from alcohol was reported for the last 28 days by 13 participants and for the last 7 days by 22. AUDIT was > 8 in 27 cases. The maximum values were 34.8 mg/l for UEtG, 5.3 mg/l for UEtS and 0.15 for SEtG. Among the 19 UEtG positives, 8 had not reported any ethanol intake in the 7 days prior to the study. Six participants reported intake of up to 320 g of ethanol in the last 7 days, but were negative for SEtG, UEtG and UEtS. Self-reported ethanol intake in the last 28 days correlated with AUDIT score (r = 0.733, P < 0.001), with the direct ethanol metabolites and MCV. In this population, abstinence and episodic heavy drinking are more common than in the general population. Episodic heavy drinking is a significant cause of acute risk in this population. Results from biomarker testing could indicate cases of under- as well as over-reporting of alcohol consumption. Further research on the diagnostic accuracy of direct ethanol metabolites, including the use of phosphatidylethanol (PEth), in this setting is needed. PMID- 17711560 TI - Caenorhabditis elegans integrates food and reproductive signals in lifespan determination. AB - Dietary restriction extends lifespan and inhibits reproduction in many species. In Caenorhabditis elegans, inhibiting reproduction by germline removal extends lifespan. Therefore, we asked whether the effect of dietary restriction on lifespan might proceed via changes in the activity of the germline. We found that dietary restriction could increase the lifespan of animals lacking the entire reproductive system. Thus, dietary restriction can extend lifespan independently of any reproductive input. However, dietary restriction produced little or no increase in the long lifespan of animals that lack germ cells. Thus, germline removal and dietary restriction may potentially activate lifespan-extending pathways that ultimately converge on the same downstream longevity mechanisms. In well-fed animals, the somatic reproductive tissues are generally completely required for germline removal to extend lifespan. We found that this was not the case in animals subjected to dietary restriction. In addition, in these animals, loss of the germline could either further lengthen lifespan or shorten lifespan, depending on the genetic background. Thus, nutrient levels play an important role in determining how the reproductive system influences longevity. PMID- 17711561 TI - Calorie restriction extends the chronological lifespan of Saccharomyces cerevisiae independently of the Sirtuins. AB - Calorie restriction (CR) extends the mean and maximum lifespan of a wide variety of organisms ranging from yeast to mammals, although the molecular mechanisms of action remain unclear. For the budding yeast Saccharomyces cerevisiae reducing glucose in the growth medium extends both the replicative and chronological lifespans (CLS). The conserved NAD(+)-dependent histone deacetylase, Sir2p, promotes replicative longevity in S. cerevisiae by suppressing recombination within the ribosomal DNA locus and has been proposed to mediate the effects of CR on aging. In this study, we investigated the functional relationships of the yeast Sirtuins (Sir2p, Hst1p, Hst2p, Hst3p and Hst4p) with CLS and CR. SIR2, HST2, and HST4 were not major regulators of CLS and were not required for the lifespan extension caused by shifting the glucose concentration from 2 to 0.5% (CR). Deleting HST1 or HST3 moderately shortened CLS, but did not prevent CR from extending lifespan. CR therefore works through a Sirtuin-independent mechanism in the chronological aging system. We also show that low temperature or high osmolarity additively extends CLS when combined with CR, suggesting that these stresses and CR act through separate pathways. The CR effect on CLS was not specific to glucose. Restricting other simple sugars such as galactose or fructose also extended lifespan. Importantly, growth on nonfermentable carbon sources that force yeast to exclusively utilize respiration extended lifespan at nonrestricted concentrations and provided no additional benefit when restricted, suggesting that elevated respiration capacity is an important determinant of chronological longevity. PMID- 17711562 TI - Effect of 3 g of intravenous paracetamol on post-operative analgesia, platelet function and liver enzymes in patients undergoing tonsillectomy under local anaesthesia. AB - BACKGROUND: Paracetamol is often given as an adjunctive analgesic to reduce opioid-related adverse effects but its optimal dose is unknown. We studied the analgesic effect and safety of a single 3-g intravenous (i.v.) dose of paracetamol in adults. METHODS: One hundred and seven patients undergoing tonsillectomy under local anaesthesia were randomly allocated to receive i.v. 3 g of paracetamol, 75 mg of diclofenac or placebo prior to surgery. The consumption of post-operative morphine using a patient-controlled analgesia-device was quantified for 6 h. Platelet aggregation and the concentrations of paracetamol, liver aminotransferases, glutathione transferase alpha 1-1 (GSTA1-1) and thromboxane B(2) were measured. RESULTS: During the first hours after surgery, both paracetamol and diclofenac reduced (P < 0.05) the consumption of morphine but had no effect thereafter. The values for the 6-h cumulative consumption of morphine in patients given paracetamol (18.7 +/- 13.8 mg), diclofenac (16.1 +/- 9.9 mg) and placebo (22.0 +/- 12.1 mg) did not differ. Paracetamol had no effect on platelet aggregation, which was impaired only by diclofenac in response to arachidonic acid (P < 0.005). Both paracetamol (P < 0.01) and diclofenac (P < 0.005) inhibited the release of thromboxane B(2) at 1 h but they did not affect serum aminotransferase and GSTA1-1 levels. One patient given paracetamol displayed a transient increase in GSTA1-1 and liver aminotransferases. CONCLUSION: During the initial hours after tonsillectomy, the administration of 3 g of i.v. paracetamol and 75 mg of diclofenac reduced the consumption of morphine. Both drugs also reduced the release of thromboxane B(2) from activated platelets but only diclofenac had a negative effect on platelet aggregation. In sensitive individuals, large doses of paracetamol may disturb the hepatocellular integrity. We do not recommend the use of i.v. doses of paracetamol higher than 1 g. PMID- 17711563 TI - Combined photoplethysmographic monitoring of respiration rate and pulse: a comparison between different measurement sites in spontaneously breathing subjects. AB - BACKGROUND: The non-invasive photoplethysmographic (PPG) signal reflects blood flow and volume in a tissue. The PPG signal shows variation synchronous with heartbeat (PPGc), as used in pulse oximetry, and variations synchronous with breathing (PPGr). PPGr has been used for non-invasive monitoring of respiration with promising results. Our aim was to investigate PPG signals recorded from different skin sites in order to find suitable locations for parallel monitoring of variations synchronous with heartbeat and breathing. METHODS: PPG sensors were applied to the forearm, finger, forehead, wrist and shoulder on 48 awake healthy volunteers. From these sites, seven PPG signals were simultaneously recorded during normal spontaneous breathing over 10 min. Capnometry served as respiration and electrocardiogram (ECG) as pulse reference signals. PPG signals were compared with respect to power spectral content and squared coherence. RESULTS: Forearm PPG measurement showed significantly higher power within the respiratory region of the power spectrum [median (quartile range) 42 (26)%], but significantly lower power within the cardiac region [9 (10)%] compared with the other skin sites. PPG finger measurement showed the opposite; in transmission mode, the power within the respiratory region was significantly lower [4 (10)%] and within the cardiac region significantly higher [45 (25)%] than the other sites. PPGc coherence values were generally high [>0.96 (0.08)], and PPGr coherence values lower [0.83 (0.35)-0.94 (0.17)]. CONCLUSION: Combined PPG respiration and pulse monitoring is possible, but there are significant differences between the respiratory and cardiac components of the PPG signal at different sites. PMID- 17711564 TI - A study of blood glucose in paediatric laparoscopy. AB - BACKGROUND: There are few studies on stress responses to laparoscopic surgery in children. This study was conducted to assess the blood glucose levels in children undergoing laparoscopy. We also studied the effect of two different intravenous (i.v.) solutions on blood glucose in open and laparoscopic procedures. METHODS: One hundred and twenty healthy children, aged 2-12 years, undergoing either open or laparoscopic surgery, were randomized to receive either dextrose normal saline (DS) or Ringer's lactate peri-operatively (RL). All patients had blood glucose measurements performed immediately after induction but prior to the i.v. infusion of any fluid. Blood glucose was again measured 1 h after induction in the open cases and 1 h after insufflation in the laparoscopy cases. RESULTS: In the groups, baseline blood glucose values were comparable. In all groups, blood glucose concentrations increased from the immediate post-induction (baseline) values. When RL was infused, the 1-h blood glucose was higher in the laparoscopy group as compared with the open group. However, when DS was infused the difference between the 1-h blood glucose in the open and laparoscopic procedures was not statistically significant. In the laparoscopy group, the 1-h blood glucose value was significantly higher in the patients receiving dextrose solution. CONCLUSION: Laparoscopic procedures in children are associated with a rise in blood glucose levels similar to open surgery. The hyperglycaemic response was more pronounced when dextrose-containing solutions were infused peri operatively. PMID- 17711565 TI - Severe head injury: control of physiological variables, organ failure and complications in the intensive care unit. AB - BACKGROUND: In patients with severe head injury, control of physiological variables is important to avoid intracranial hypertension and secondary injury to the brain. The aims of this retrospective study were to evaluate deviations of physiological variables and the incidence of extracranial complications in patients with severe head injury. We also studied if these deviations could be related to outcome. PATIENTS AND METHODS: One hundred and thirty-three patients were included during a 5-year period (1998-2002). Deviations from treatment goals for the following physiological variables were studied: blood pressure, haemoglobin, blood sugar, serum sodium, serum albumin and temperature. Extra cerebral organ complications were also recorded as well as outcome at 6 months. RESULTS: The median age was 32 years (range; 1-88 years). Median Glasgow Coma Scale (GCS) before intubation was 6 (range; 3-14). The frequencies of severe deviations from the desired values of the physiological variables for at least one treatment day were: hypotensive episodes (systolic BP < 90 mmHg) - 20%, anaemia (hgb < 8 g/dL) - 22%, blood glucose > 10 mmol/l - 26%, serum sodium concentration < 130 mmol/l - 10%, serum albumin < 25 g/l(-1)- 31% and hyperthermia > 39 degrees C - 24%. Pneumonia was diagnosed in 71% and Acute Lung Injury (ALI)/Adult Respiratory Distress Syndrome (ARDS) in 26% of the patients. Other complications such as severe sepsis (6%), renal failure (1.5%), a coagulation disorder (6%) and liver failure (one patient) were infrequent. Age, GCS, hypotension during the first day of treatment, elevated blood sugar and low albumin predicted an unfavourable outcome. CONCLUSIONS: Deviations of key physiological variables and pulmonary complications were frequent in patients suffering from severe head injury. During intensive care treatment, hypotension, elevated blood sugar and hypoalbuminemia are possible independent predictors of an unfavourable outcome. PMID- 17711566 TI - Prevention of withdrawal movement associated with injection of rocuronium in children: comparison of remifentanil, alfentanil and fentanyl. AB - BACKGROUND: We compared the efficacy of remifentanil, alfentanil and fentanyl in reducing withdrawal movement associated with the injection of rocuronium in children. METHODS: In total, 164 ASA physical status I or II pediatric patients, aged 1-14 years, were randomly assigned to four treatment groups: group C received saline; group R, remifentanil 1 microg/kg; group A, alfentanil 10 micro/kg; and group F, fentanyl 2 microg/kg. Treatments were injected over 30 s, followed by thiopental 5 mg/kg. At 90 s after the start of the study drug injection, rocuronium 0.6 mg/kg was injected over 10 s. The patient's response to the injection of rocuronium was graded on a four-point scale in a double-blinded manner. RESULTS: The incidence of withdrawal movement was 89.5% in group C, 70.3% in group F, 36.3% in group A and 7.2% in group R. The incidence of generalized movement (grade 4) was 86.9% in group C, 58.5% in group F, 15.9% in group A and 2.4% in group R. CONCLUSION: Remifentanil, alfentanil and fentanyl all reduced the incidence of withdrawal movement when administered 90 s before the injection of rocuronium compared with saline. Remifentanil was the most effective, followed by alfentanil. Fentanyl was less effective but significantly different from the saline in reducing withdrawal movement in children. PMID- 17711567 TI - Evaluation of pre-hospital trauma triage criteria: a prospective study at a Danish level I trauma centre. AB - BACKGROUND: The aim of the present study was to evaluate the precision of our trauma triage protocol [based on the American College of Surgeons, Committee on Trauma (ACS COT)] in identifying severely injured defined as an injury severity score (ISS) > 15. Our hypothesis was that isolated mechanism-of-injury criteria were responsible for a significant over-triage leading to over-use of our trauma team. METHODS: DESIGN: A prospective cohort study. SETTING: A level I trauma centre, Aarhus, Denmark. PATIENTS AND PARTICIPANTS: Among all injured patients admitted during a 6-month period in 2003 we identified severely injured. During the study period, trauma team activations were consecutively registered and triage criteria were prospectively collected. Sensitivity, specificity, positive predictive value, over-triage and under-triage were calculated. RESULTS: Out of 15,162 patients in the emergency department, 848 injured patients were included and 59 (7%) were severely injured. We had 242 trauma team activations with 54 (22%) severely injured. Sensitivity was 92%, specificity 76%, giving an over triage of 24% and an under-triage of 8%. The positive predictive value was 22%. Among 60 patients with mechanism-of-injury as the only criterion, five were severely injured in contrast to 12 out of 20 patients with mechanism-of-injury combined with physiological and/or anatomical criteria. CONCLUSION: The positive predictive value of our triage protocol was low, only 22%. This was mainly as a result of a significant over-triage from isolated mechanism-of-injury criteria. We recommend revision of the triage protocol and reallocation of our trauma team resources. PMID- 17711568 TI - Correlation between structure and temperature in prokaryotic metabolic networks. AB - BACKGROUND: In recent years, an extensive characterization of network structures has been made in an effort to elucidate design principles of metabolic networks, providing valuable insights into the functional organization and the evolutionary history of organisms. However, previous analyses have not discussed the effects of environmental factors (i.e., exogenous forces) in shaping network structures. In this work, we investigate the effect of temperature, which is one of the environmental factors that may have contributed to shaping structures of metabolic networks. RESULTS: For this, we investigate the correlations between several structural properties characterized by graph metrics like the edge density, the degree exponent, the clustering coefficient, and the subgraph concentration in the metabolic networks of 113 prokaryotes and optimal growth temperature. As a result, we find that these structural properties are correlated with the optimal growth temperature. With increasing temperature, the edge density, the clustering coefficient and the subgraph concentration decrease and the degree exponent becomes large. CONCLUSION: This result implies that the metabolic networks transit with temperature as follows. The density of chemical reactions becomes low, the connectivity of the networks becomes homogeneous such as random networks and both the network modularity, based on the graph-theoretic clustering coefficient, and the frequency of recurring subgraphs decay. In short, metabolic networks undergo a change from heterogeneous and high-modular structures to homogeneous and low-modular structures, such as random networks, with temperature. This finding may suggest that the temperature plays an important role in the design principles of metabolic networks. PMID- 17711572 TI - Simultaneous chromophobe renal cell carcinoma and squamous renal cell carcinoma. AB - Chromophobe renal cell carcinoma (CHRC) is a neoplasm of the kidney with clinicopathologic peculiarities that seems to be of better prognosis than conventional renal cell carcinoma. Classical and eosinophilic types are the two histological variants recorded. Also, it has been described in association with carcinoma of collecting ducts, conventional renal cell carcinoma and sarcomatoid renal cell carcinoma. Squamous renal carcinoma is a very rare neoplasm with a malignant course. We describe a case of simultaneous chromophobe renal cell carcinoma with squamous cell carcinoma, finding which, to the best of our knowledge, has not previously been reported. PMID- 17711571 TI - Evaluation of 3D-Jury on CASP7 models. AB - BACKGROUND: 3D-Jury, the structure prediction consensus method publicly available in the Meta Server http://meta.bioinfo.pl/, was evaluated using models gathered in the 7th round of the Critical Assessment of Techniques for Protein Structure Prediction (CASP7). 3D-Jury is an automated expert process that generates protein structure meta-predictions from sets of models obtained from partner servers. RESULTS: The performance of 3D-Jury was analysed for three aspects. First, we examined the correlation between the 3D-Jury score and a model quality measure: the number of correctly predicted residues. The 3D-Jury score was shown to correlate significantly with the number of correctly predicted residues, the correlation is good enough to be used for prediction. 3D-Jury was also found to improve upon the competing servers' choice of the best structure model in most cases. The value of the 3D-Jury score as a generic reliability measure was also examined. We found that the 3D-Jury score separates bad models from good models better than the reliability score of the original server in 27 cases and falls short of it in only 5 cases out of a total of 38. We report the release of a new Meta Server feature: instant 3D-Jury scoring of uploaded user models. CONCLUSION: The 3D-Jury score continues to be a good indicator of structural model quality. It also provides a generic reliability score, especially important for models that were not assigned such by the original server. Individual structure modellers can also benefit from the 3D-Jury scoring system by testing their models in the new instant scoring feature http://meta.bioinfo.pl/compare_your_model_example.pl available in the Meta Server. PMID- 17711570 TI - The influence of smoking and other risk factors on the outcome after radiochemotherapy for anal cancer. AB - BACKGROUND: Smoking is an important risk factor for the development of cancer. Smoking during radiochemotherapy therapy may have a negative influence on prognosis. We evaluated the effect of smoking during radiochemotherapy on the outcome for patients with anal cancer. METHODS: Sixty-eight patients (34 smokers, 34 non-smokers) treated by radiochemotherapy for anal cancer were analysed. The effect of smoking during radiochemotherapy and other risk factors (gender, T- and N category, tumor site, dose, therapy protocol) on disease-specific survival (DSS), local control (LC) and colostomy free survival (CFS) was evaluated. RESULTS: There was a significant difference in age and male:female ratio between the two groups. With a median follow up of 22 months (max. 119) DSS, LC, and CFS were 88%, 84% and 84%. A significant difference in local control between smokers (S) and non-smokers (NS) was found (S 74% vs. NS 94%, p = .03). For DSS and CFS a difference in terms of outcome between smokers and non-smokers was seen (DSS: S 82% vs. NS 96%, p = .19, CFS: S 75% vs. 91%, p = .15), which did not reach statistical significance. In multivariate analyses only gender had a significant association with LC and T category with CFS. The other risk factors did not reach statistical significance. CONCLUSION: Even though our evaluation reached statistical significance only in univariate analysis, we suggest, that the role of smoking during radiochemotherapy for anal cancer should not be ignored. The potential negative effect on prognosis should be explained to patients before therapy. PMID- 17711569 TI - Circulating Bmi-1 mRNA as a possible prognostic factor for advanced breast cancer patients. AB - INTRODUCTION: Deregulation of Polycomb member Bmi-1 is involved in cell proliferation and human oncogenesis. Modulation of Bmi-1 is found in several tumor tissues, including primary breast carcinomas; however, analysis of Bmi-1 in plasma of cancer patients has not been reported. This is the first study that evaluates Bmi-1 in plasma by using a large series of primary breast carcinomas to investigate the presence at diagnosis of detectable Bmi-1 mRNA in plasma and possible correlations between this event and a series of clinical-pathological parameters of the tumors. METHODS: Bmi-1 expression levels were quantified in plasma of 111 breast cancer patients and in 20 healthy controls by real-time quantitative polymerase chain reaction. RESULTS: Cancer patients with the presence of Bmi-1 mRNA in plasma had higher levels of Bmi-1 expression than healthy controls with Bmi-1 mRNA in plasma. The higher expression levels of Bmi-1 correlated with well-established markers of poor clinical outcome in breast cancer such as positive p53 immunostaining and negative progesterone receptors. Moreover, we described for the first time a statistically significant correlation between Bmi-1 expression in plasma of breast cancer patients and disease-free and overall survival in advanced stages. CONCLUSION: Our results suggest that levels of Bmi-1 expression may be a surrogate marker of poor prognosis and may become clinically useful as noninvasive diagnostic markers. PMID- 17711573 TI - Occipitoparietal contributions to recognition memory: stimulus encoding prompted by verbal instructions and operant contingencies. AB - BACKGROUND: Many human neuroimaging investigations on recognition memory employ verbal instructions to direct subject's attention to a stimulus attribute. But do the same or a similar neurophysiological process occur during nonverbal experiences, such as those involving contingency-shaped responses? Establishing the spatially distributed neural network underlying recognition memory for instructed stimuli and operant, contingency-shaped (i.e., discriminative) stimuli would extend the generality of contemporary domain-general views of recognition memory and clarify the involvement of declarative memory processes in human operant behavior. METHODS: Fifteen healthy adults received equivalent amounts of exposure to three different stimulus sets prior to neuroimaging. Encoding of one stimulus set was prompted using instructions that emphasized memorizing stimuli (Instructed). In contrast, encoding of two additional stimulus sets was prompted using a GO/NO-GO operant task, in which contingencies shaped appropriate GO and NO-GO responding. During BOLD functional MRI, subjects completed two recognition tasks. One required passive viewing of stimuli. The second task required recognizing whether a presented stimulus was a GO/NO-GO stimulus, an Instructed stimulus, or novel (NEW) stimulus. Retrieval success related to recognition memory was isolated by contrasting activation from each stimulus set to a novel stimulus (i.e., an OLD > NEW contrast). To explore differences potentially related to source memory, separate contrasts were performed between stimulus sets. RESULTS: No regions reached supralevel thresholds during the passive viewing task. However, a relatively similar set of regions was activated during active recognition regardless of the methods and included dorsolateral and ventrolateral prefrontal cortex, right inferior and posterior parietal regions and the occipitoparietal region, precuneus, lingual, fusiform gyri and cerebellum. Results also showed the magnitude of the functional response in the occipitoparietal region was inversely correlated with reaction times (RTs), such that the largest functional response and slowest RTs occurred to Instructed stimuli and the smallest functional response and fastest RTs occurred to GO stimuli, with effects to NO-GO stimuli intermediate. The inverse relation was also present bilaterally in the parahippocampus and hippocampus. Comparisons between stimulus sets also revealed regional differences potentially related to source memory. CONCLUSION: Recognition of stimuli previously associated with instructions and operant contingencies (i.e., discriminative stimuli) generally recruited similar inferior frontal and occipitoparietal regions and right posterior parietal cortex, with the right occipitoparietal region showing the largest effect. These findings suggest domain-general views of recognition memory may be applicable to understanding the neural correlates of control exerted by discriminative stimuli and suggest declarative memory processes are involved in human operant behavior. PMID- 17711574 TI - Necrotising colitis related to clozapine? A rare but life threatening side effect. AB - We report here a case of a 34-year-old gentleman who developed right-sided necrotising colitis after clozapine usage. Anticholinergic activity is believed to the cause. We believe that in patients who have been consuming medications known to have an association with necrotising colitis, constipation with concomitant increasing abdominal pain, distension and fever should be treated with a strong index of suspicion. Consideration of necrotising colitis should prompt expeditious resection of the affected colonic segment. PMID- 17711575 TI - Genome-wide polysomal analysis of a yeast strain with mutated ribosomal protein S9. AB - BACKGROUND: The yeast ribosomal protein S9 (S9) is located at the entrance tunnel of the mRNA into the ribosome. It is known to play a role in accurate decoding and its bacterial homolog (S4) has recently been shown to be involved in opening RNA duplexes. Here we examined the effects of changing the C terminus of S9, which is rich in acidic amino acids and extends out of the ribosome surface. RESULTS: We performed a genome-wide analysis to reveal effects at the transcription and translation levels of all yeast genes. While negligible relative changes were observed in steady-state mRNA levels, a significant number of mRNAs appeared to have altered ribosomal density. Notably, 40% of the genes having reliable signals changed their ribosomal association by more than one ribosome. Yet, no general correlations with physical or functional features of the mRNA were observed. Ribosome Density Mapping (RDM) along four of the mRNAs with increased association revealed an increase in ribosomal density towards the end of the coding region for at least two of them. Read-through analysis did not reveal any increase in read-through of a premature stop codon by the mutant strain. CONCLUSION: The ribosomal protein rpS9 appears to be involved in the translation of many mRNAs, since altering its C terminus led to a significant change in ribosomal association of many mRNAs. We did not find strong correlations between these changes and several physical features of the mRNA, yet future studies with advanced tools may allow such correlations to be determined. Importantly, our results indicate an accumulation of ribosomes towards the end of the coding regions of some mRNAs. This suggests an involvement of S9 in ribosomal dissociation during translation termination. PMID- 17711576 TI - Hypernatremic dehydration, diabetes insipidus, and cerebral venous sinus thrombosis in a neonate: a case report. PMID- 17711577 TI - Thottapalayam virus is genetically distant to the rodent-borne hantaviruses, consistent with its isolation from the Asian house shrew (Suncus murinus). AB - Thottapalayam (TPM) virus belongs to the genus Hantavirus, family Bunyaviridae. The genomes of hantaviruses consist of three negative-stranded RNA segments (S, M and L) encoding the virus nucleocapsid (N), glycoprotein (Gn, Gc), and polymerase (L) proteins, respectively. The genus Hantavirus contains predominantly rodent borne viruses, with the prominent exception of TPM virus which was isolated in India in 1964 from an insectivore, Suncus murinus, commonly referred to as the Asian house shrew or brown musk shrew. Analysis of the available TPM virus S (1530 nt) RNA genome segment sequence and the newly derived M (3621 nt) and L (6581 nt) segment sequences demonstrate that the entire TPM virus genome is very unique. Remarkably high sequence differences are seen at the nucleotide (up to S 47%, M - 49%, L - 38%) and protein (up to N - 54%, Gn/Gc - 57% and L - 39%) levels relative to the rodent-borne hantaviruses, consistent with TPM virus having a unique host association. PMID- 17711578 TI - Production of Recombinant Peanut Allergen Ara h 2 using Lactococcus lactis. AB - BACKGROUND: Natural allergen sources can supply large quantities of authentic allergen mixtures for use as immunotherapeutics. However, such extracts are complex, difficult to define, vary from batch to batch, which may lead to unpredictable efficacy and/or unacceptable levels of side effects. The use of recombinant expression systems for allergen production can alleviate some of these issues. Several allergens have been tested in high-level expression systems and in most cases show immunereactivity comparable to their natural counterparts. The gram positive lactic acid bacterium Lactococcus lactis is an attractive microorganism for use in the production of protein therapeutics. L. lactis is considered food grade, free of endotoxins, and is able to secrete the heterologous product together with few other native proteins. Hypersensitivity to peanut represents a serious allergic problem. Some of the major allergens in peanut have been described. However, for therapeutic usage more information about the individual allergenic components is needed. In this paper we report recombinant production of the Ara h 2 peanut allergen using L. lactis. RESULTS: A synthetic ara h 2 gene was cloned into an L. lactis expression plasmid containing the P170 promoter and the SP310mut2 signal sequence. Flask cultures grown overnight showed secretion of the 17 kDa Ara h 2 protein. A batch fermentation resulted in 40 mg/L recombinant Ara h 2. Purification of Ara h 2 from the culture supernatant was done by hydrophobic exclusion and size separation. Mass spectrometry and N-terminal analysis showed a recombinant Ara h 2 of full length and correctly processed by the signal peptidase. The immunological activity of recombinant Ara h 2 was analysed by ELISA using antibodies specific for native Ara h 2. The recombinant Ara h 2 showed comparable immunereactivity to that of native Ara h 2. CONCLUSION: Recombinant production of Ara h 2 using L. lactis can offer high yields of secreted, full length and immunologically active allergen. The L. lactis expression system can support recombinant allergen material for immunotherapy and component resolved allergen diagnostics. PMID- 17711579 TI - Molecular portrait of cisplatin induced response in human testis cancer cell lines based on gene expression profiles. AB - BACKGROUND: Testicular germ cell tumors (TGCTs) respond well to cisplatin-based chemotherapy and show a low incidence of acquired resistance compared to most somatic tumors. The reasons for these specific characteristics are not known in detail but seem to be multifactorial. We have studied gene expression profiles of testicular and colon cancer derived cell lines treated with cisplatin. The main goal of this study was to identify novel gene expression profiles with their functional categories and the biochemical pathways that are associated with TGCT cells' response to cisplatin. RESULTS: Genes that were differentially expressed between the TGCT cell lines vs the (somatic) HCT116 cell line, after cisplatin treatment, were identified using the significance analysis of microarrays (SAM) method. The response of TGCT cells was strikingly different from that of HCT116, and we identified 1794 genes that were differentially expressed. Functional classification of these genes showed that they participate in a variety of different and widely distributed functional categories and biochemical pathways. Database mining showed significant association of genes (n = 41) induced by cisplatin in our study, and genes previously reported to by expressed in differentiated TGCT cells. We identified 37 p53-responsive genes that were altered after cisplatin exposure. We also identified 40 target genes for two microRNAs, hsa-mir-372 and 373 that may interfere with p53 signaling in TGCTs. The tumor suppressor genes NEO1 and LATS2, and the estrogen receptor gene ESR1, all have binding sites for p53 and hsa-mir-372/373. NEO1 and LATS2 were down regulated in TGCT cells following cisplatin exposure, while ESR1 was up-regulated in TGCT cells. Cisplatin-induced genes associated with terminal growth arrest through senescence were identified, indicating associations which were not previously described for TGCT cells. CONCLUSION: By linking our gene expression data to publicly available databases and literature, we provide a global pattern of cisplatin induced cellular response that is specific for testicular cancer cell lines. We have identified cisplatin-responsive functional classes and pathways, such as the angiogenesis, Wnt, integrin, and cadherin signaling pathways. The identification of differentially expressed genes in this study may contribute to a better understanding of the unusual sensitivity of TGCT to some DNA-damaging agents. PMID- 17711580 TI - Effect of discriminative plant-sugar feeding on the survival and fecundity of Anopheles gambiae. AB - BACKGROUND: A previous study showed for Anopheles gambiae s.s. a gradation of feeding preference on common plant species growing in a malaria holoendemic area in western Kenya. The present follow-up study determines whether there is a relationship between the mosquito's preferences and its survival and fecundity. METHODS: Groups of mosquitoes were separately given ad libitum opportunity to feed on five of the more preferred plant species (Hamelia patens, Parthenium hysterophorus, Ricinus communis, Senna didymobotrya, and Tecoma stans) and one of the less preferred species (Lantana camara). The mosquitoes were monitored daily for survival. Sugar solution (glucose 6%) and water were used as controls. In addition, the fecundity of mosquitoes on each plant after (i) only one blood meal (number of eggs oviposited), and (ii) after three consecutive blood meals (proportion of females ovipositing, number of eggs oviposited and hatchability of eggs), was determined. The composition and concentration of sugar in the fed-on parts of each plant species were determined using gas chromatography. Using SAS statistical package, tests for significant difference of the fitness values between mosquitoes exposed to different plant species were conducted. RESULTS AND CONCLUSION: Anopheles gambiae that had fed on four of the five more preferred plant species (T. stans, S. didymobotrya, R. communis and H. patens, but not P. hysterophorus) lived longer and laid more eggs after one blood meal, when compared with An. gambiae that had fed on the least preferred plant species L. camara. When given three consecutive blood-meals, the percentage of females that oviposited, but not the number of eggs laid, was significantly higher for mosquitoes that had previously fed on the four more preferred plant species. Total sugar concentration in the preferred plant parts was significantly correlated with survival and with the proportion of females that laid eggs. This effect was associated mainly with three sugar types, namely glucose, fructose, and gulose. Except for P. hysterophorus, the results suggest that feeding by mosquitoes on preferred plant species under natural conditions results in higher fitness-related benefits, and that the sugar content in preferred plant parts is largely responsible for these effects. PMID- 17711581 TI - Automated smoother for the numerical decoupling of dynamics models. AB - BACKGROUND: Structure identification of dynamic models for complex biological systems is the cornerstone of their reverse engineering. Biochemical Systems Theory (BST) offers a particularly convenient solution because its parameters are kinetic-order coefficients which directly identify the topology of the underlying network of processes. We have previously proposed a numerical decoupling procedure that allows the identification of multivariate dynamic models of complex biological processes. While described here within the context of BST, this procedure has a general applicability to signal extraction. Our original implementation relied on artificial neural networks (ANN), which caused slight, undesirable bias during the smoothing of the time courses. As an alternative, we propose here an adaptation of the Whittaker's smoother and demonstrate its role within a robust, fully automated structure identification procedure. RESULTS: In this report we propose a robust, fully automated solution for signal extraction from time series, which is the prerequisite for the efficient reverse engineering of biological systems models. The Whittaker's smoother is reformulated within the context of information theory and extended by the development of adaptive signal segmentation to account for heterogeneous noise structures. The resulting procedure can be used on arbitrary time series with a nonstationary noise process; it is illustrated here with metabolic profiles obtained from in-vivo NMR experiments. The smoothed solution that is free of parametric bias permits differentiation, which is crucial for the numerical decoupling of systems of differential equations. CONCLUSION: The method is applicable in signal extraction from time series with nonstationary noise structure and can be applied in the numerical decoupling of system of differential equations into algebraic equations, and thus constitutes a rather general tool for the reverse engineering of mechanistic model descriptions from multivariate experimental time series. PMID- 17711583 TI - Quantitative analysis of mutation and selection pressures on base composition skews in bacterial chromosomes. AB - BACKGROUND: Most bacterial chromosomes exhibit asymmetry of base composition with respect to leading vs. lagging strands (GC and AT skews). These skews reflect mainly those in protein coding sequences, which are driven by asymmetric mutation pressures during replication and transcription (notably asymmetric cytosine deamination) plus subsequent selection for preferred structures, signals, amino acid or codons. The transcription-associated effects but not the replication associated effects contribute to the overall skews through the uneven distribution of the coding sequences on the leading and lagging strands. RESULTS: Analysis of 185 representative bacterial chromosomes showed diverse and characteristic patterns of skews among different clades. The base composition skews in the coding sequences were used to derive quantitatively the effect of replication-driven mutation plus subsequent selection ('replication-associated pressure', RAP), and the effect of transcription-driven mutation plus subsequent selection at translation level ('transcription-associate pressure', TAP). While different clades exhibit distinct patterns of RAP and TAP, RAP is absent or nearly absent in some bacteria, but TAP is present in all. The selection pressure at the translation level is evident in all bacteria based on the analysis of the skews at the three codon positions. Contribution of asymmetric cytosine deamination was found to be weak to TAP in most phyla, and strong to RAP in all the Proteobacteria but weak in most of the Firmicutes. This possibly reflects the differences in their chromosomal replication machineries. A strong negative correlation between TAP and G+C content and between TAP and chromosomal size were also revealed. CONCLUSION: The study reveals the diverse mutation and selection forces associated with replication and transcription in various groups of bacteria that shape the distinct patterns of base composition skews in the chromosomes during evolution. Some closely relative species with distinct base composition parameters are uncovered in this study, which also provides opportunities for comparative bioinformatic and genetic investigations to uncover the underlying principles for mutation and selection. PMID- 17711582 TI - CD117 immunoexpression in canine mast cell tumours: correlations with pathological variables and proliferation markers. AB - BACKGROUND: Cutaneous mast cell tumours are one of the most common neoplasms in dogs and show a highly variable biologic behaviour. Several prognosis tools have been proposed for canine mast cell tumours, including histological grading and cell proliferation markers. CD117 is a receptor tyrosine kinase thought to play a key role in human and canine mast cell neoplasms. Normal (membrane-associated) and aberrant (cytoplasmic, focal or diffuse) CD117 immunoexpression patterns have been identified in canine mast cell tumours. Cytoplasmic CD117 expression has been found to correlate with higher histological grade and with a worsened post surgical prognosis. This study addresses the role of CD117 in canine mast cell tumours by studying the correlations between CD117 immunoexpression patterns, two proliferation markers (Ki67 and AgNORs) histological grade, and several other pathological variables. RESULTS: Highly significant (p < 0,001) correlations were found between CD117 immunostaining patterns and histological grade, cell proliferation markers (Ki67, AgNORs) and tumoral necrosis. Highly significant (p < 0,001) correlations were also established between the two cellular proliferation markers and histological grade, tumour necrosis and epidermal ulceration. A significant correlation (p = 0.035) was observed between CD117 expression patterns and epidermal ulceration. No differences were observed between focal and diffuse cytoplasmic CD117 staining patterns concerning any of the variables studied. CONCLUSION: These findings highlight the key role of CD117 in the biopathology of canine MCTs and confirm the relationship between aberrant CD117 expression and increased cell proliferation and higher histological grade. Further studies are needed to unravel the cellular mechanisms underlying focal and diffuse cytoplasmic CD117 staining patterns, and their respective biopathologic relevance. PMID- 17711584 TI - Proteomic analyses of retina of excitatory amino acid carrier 1 deficient mice. AB - BACKGROUND: Excitatory amino acid carrier 1 (EAAC1) is a glutamate transporter found in neuronal tissues and is extensively expressed in the retina. EAAC1 plays a role in a variety of neural functions, but its biological functions in the retina has not been fully determined. The purpose of this study was to identify proteins regulated by EAAC1 in the retina of mice. To accomplish this, we used a proteomics-based approach to identify proteins that are up- or down-regulated in EAAC1-deficient (EAAC1-/-) mice. RESULTS: Proteomic analyses and two-dimensional gel electorphoresis were performed on the retina of EAAC1-/- mice, and the results were compared to that of wild type mice. The protein spots showing significant differences were selected for identification by mass spectrometric analyses. Thirteen proteins were differentially expressed; nine proteins were up regulated and five proteins were down-regulated in EAAC1-/- retina. Functional clustering showed that identified proteins are involved in various cellular process, e.g. cell cycle, cell death, transport and metabolism. CONCLUSION: We identified thirteen proteins whose expression is changed in EAAC-/- mice retinas. These proteins are known to regulate cell proliferation, death, transport, metabolism, cell organization and extracellular matrix. PMID- 17711585 TI - Patterns and correlates of physical activity: a cross-sectional study in urban Chinese women. AB - BACKGROUND: Inactivity is a modifiable risk factor for many diseases. Rapid economic development in China has been associated with changes in lifestyle, including physical activity. The purpose of this study was to investigate the patterns and correlates of physical activity in middle-aged and elderly women from urban Shanghai. METHODS: Study population consisted of 74,942 Chinese women, 40-70 years of age, participating in the baseline survey of the Shanghai Women's Health Study (1997-2000), an ongoing population-based cohort study. A validated, interviewer-administered physical activity questionnaire was used to collect information about several physical activity domains (exercise/sports, walking and cycling for transportation, housework). Correlations between physical activity domains were evaluated by Spearman rank-correlation coefficients. Associations between physical activity and socio-demographic and lifestyle factors were evaluated by odds ratios derived from logistic regression. RESULTS: While more than a third of study participants engaged in regular exercise, this form of activity contributed only about 10% to daily non-occupational energy expenditure. About two-thirds of women met current recommendations for lifestyle activity. Age was positively associated with participation in exercise/sports and housework. Dietary energy intake was positively associated with all physical activity domains. High socioeconomic status, unemployment (including retirement), history of chronic disease, small household, non-smoking status, alcohol and tea consumption, and ginseng intake were all positively associated with exercise participation. High socioeconomic status and small household were inversely associated with non-exercise activities. CONCLUSION: This study demonstrates that physical activity domains other than sports and exercise are important contributors to total energy expenditure in women. Correlates of physical activity are domain-specific. These findings provide important information for research on the health benefits of physical activity and have public health implications for designing interventions to promote participation in physical activity. PMID- 17711586 TI - Classification of a moderately oxygen-tolerant isolate from baby faeces as Bifidobacterium thermophilum. AB - BACKGROUND: Bifidobacteria are found at varying prevalence in human microbiota and seem to play an important role in the human gastrointestinal tract (GIT). Bifidobacteria are highly adapted to the human GIT which is reflected in the genome sequence of a Bifidobacterim longum isolate. The competitiveness against other bacteria is not fully understood yet but may be related to the production of antimicrobial compounds such as bacteriocins. In a previous study, 34 Bifidobacterium isolates have been isolated from baby faeces among which six showed proteinaceous antilisterial activity against Listeria monocytogenes. In this study, one of these isolates, RBL67, was further identified and characterized. RESULTS: Bifidobacterium isolate RBL67 was classified and characterized using a polyphasic approach. RBL67 was classified as Bifidobacterium thermophilum based on phenotypic and DNA-DNA hybridization characteristics, although 16S rDNA analyses and partial groEL sequences showed higher homology with B. thermacidophilum subsp. porcinum and B. thermacidophilum subsp. thermacidophilum, respectively. RBL67 was moderately oxygen-tolerant and was able to grow at pH 4 and at a temperature of 47 degrees C. CONCLUSION: In order to assign RBL67 to a species, a polyphasic approach was used. This resulted in the classification of RBL67 as a Bifidobacterium thermophilum strain. To our knowledge, this is the first report about B. thermophilum isolated from baby faeces since the B. thermophilum strains were related to ruminants and swine faeces before. B. thermophilum was previously only isolated from animal sources and was therefore suggested to be used as differential species between animal and human contamination. Our findings may disapprove this suggestion and further studies are now conducted to determine whether B. thermophilum is distributed broader in human faeces. Furthermore, the postulated differentiation between human and animal strains by growth above 45 degrees C is no longer valid since B. thermophilum is able to grow at 47 degrees C. In our study, 16S rDNA and partial groEL sequence analysis were not able to clearly assign RBL67 to a species and were contradictory. Our study suggests that partial groEL sequences may not be reliable as a single tool for species differentiation. PMID- 17711587 TI - Experiences of refugees and asylum seekers in general practice: a qualitative study. AB - BACKGROUND: There has been much debate regarding the refugee health situation in the UK. However most of the existing literature fails to take account of the opinions of refugees themselves. This study was established to determine the views of asylum seekers and refugees on their overall experiences in primary care and to suggest improvements to their care. METHODS: Qualitative study of adult asylum seekers and refugees who had entered the UK in the last 10 years. The study was set in Barnet Refugee Walk in Service, London. 11 Semi structured interviews were conducted and analysed using framework analysis. RESULTS: Access to GPs may be more difficult for failed asylum seekers and those without support from refugee agencies or family. There may be concerns amongst some in the refugee community regarding the access to and confidentiality of professional interpreters. Most participants stated their preference for GPs who offered advice rather than prescriptions. The stigma associated with refugee status in the UK may have led to some refugees altering their help seeking behaviour. CONCLUSION: The problem of poor access for those with inadequate support may be improved by better education and support for GPs in how to provide for refugees. Primary Care Trusts could also supply information to newly arrived refugees on how to access services. GPs should be aware that, in some situations, professional interpreters may not always be desired and that instead, it may be advisable to reach a consensus as to who should be used as an interpreter. A better doctor-patient experience resulting from improvements in access and communication may help to reduce the stigma associated with refugee status and lead to more appropriate help seeking behaviour. Given the small nature of our investigation, larger studies need to be conducted to confirm and to quantify these results. PMID- 17711588 TI - MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system. AB - BACKGROUND: MicroRNA (miRNA) encoding genes are abundant in vertebrate genomes but very few have been studied in any detail. Bioinformatic tools allow prediction of miRNA targets and this information coupled with knowledge of miRNA expression profiles facilitates formulation of hypotheses of miRNA function. Although the central nervous system (CNS) is a prominent site of miRNA expression, virtually nothing is known about the spatial and temporal expression profiles of miRNAs in the brain. To provide an overview of the breadth of miRNA expression in the CNS, we performed a comprehensive analysis of the neuroanatomical expression profiles of 38 abundant conserved miRNAs in developing and adult zebrafish brain. RESULTS: Our results show miRNAs have a wide variety of different expression profiles in neural cells, including: expression in neuronal precursors and stem cells (for example, miR-92b); expression associated with transition from proliferation to differentiation (for example, miR-124); constitutive expression in mature neurons (miR-124 again); expression in both proliferative cells and their differentiated progeny (for example, miR-9); regionally restricted expression (for example, miR-222 in telencephalon); and cell-type specific expression (for example, miR-218a in motor neurons). CONCLUSION: The data we present facilitate prediction of likely modes of miRNA function in the CNS and many miRNA expression profiles are consistent with the mutual exclusion mode of function in which there is spatial or temporal exclusion of miRNAs and their targets. However, some miRNAs, such as those with cell-type specific expression, are more likely to be co-expressed with their targets. Our data provide an important resource for future functional studies of miRNAs in the CNS. PMID- 17711589 TI - Greater incidence of depression with hypnotic use than with placebo. AB - BACKGROUND: Although it has been claimed that insomnia causes an increased risk for depression, adequate controlled trials testing this hypothesis have not been available. This study contrasted the incidence of depression among subjects receiving hypnotics in randomized controlled trials versus those receiving placebo. METHODS: The incidence of depression among patients randomized to hypnotic drugs or placebo was compiled from prescribing information approved by the United States Food and Drug Administration (FDA) and from FDA New Drug Application documents. Available data for zolpidem, zaleplon, eszopiclone, and ramelteon were accessed. RESULTS: Data for 5535 patients randomized to a hypnotic and for 2318 randomized to placebo were compiled. The incidence of depression was 2.0% among participants randomized to hypnotics as compared to 0.9% among those randomized in parallel to placebo (p < 0.002). CONCLUSION: Modern hypnotics were associated with an increased incidence of depression in data released by the FDA. This suggests that when there is a risk of depression, hypnotics may be contra indicated. Preventive treatments such as antidepressant drugs, cognitive behavioral therapy, or bright light might be preferred. Limitations in the FDA data prevented a formal meta-analysis, and there was a lack of information about drop-out rates and definitions of depression. Trials specifically designed to detect incident depression when treating insomnia with hypnotic drugs and better summarization of adverse events in trials submitted to the FDA are both necessary. PMID- 17711590 TI - Kinematics and muscle activity of individuals with incomplete spinal cord injury during treadmill stepping with and without manual assistance. AB - BACKGROUND: Treadmill training with bodyweight support and manual assistance improves walking ability of patients with neurological injury. The purpose of this study was to determine how manual assistance changes muscle activation and kinematic patterns during treadmill training in individuals with incomplete spinal cord injury. METHODS: We tested six volunteers with incomplete spinal cord injury and six volunteers with intact nervous systems. Subjects with spinal cord injury walked on a treadmill at six speeds (0.18-1.07 m/s) with body weight support with and without manual assistance. Healthy subjects walked at the same speeds only with body weight support. We measured electromyographic (EMG) and kinematics in the lower extremities and calculated EMG root mean square (RMS) amplitudes and joint excursions. We performed cross-correlation analyses to compare EMG and kinematic profiles. RESULTS: Normalized muscle activation amplitudes and profiles in subjects with spinal cord injury were similar for stepping with and without manual assistance (ANOVA, p > 0.05). Muscle activation amplitudes increased with increasing speed (ANOVA, p < 0.05). When comparing spinal cord injury subject EMG data to control subject EMG data, neither the condition with manual assistance nor the condition without manual assistance showed a greater similarity to the control subject data, except for vastus lateralis. The shape and timing of EMG patterns in subjects with spinal cord injury became less similar to controls at faster speeds, especially when walking without manual assistance (ANOVA, p < 0.05). There were no consistent changes in kinematic profiles across spinal cord injury subjects when they were given manual assistance. Knee joint excursion was approximately 5 degrees greater with manual assistance during swing (ANOVA, p < 0.05). Hip and ankle joint excursions were both approximately 3 degrees lower with manual assistance during stance (ANOVA, p < 0.05). CONCLUSION: Providing manual assistance does not lower EMG amplitudes or alter muscle activation profiles in relatively higher functioning spinal cord injury subjects. One advantage of manual assistance is that it allows spinal cord injury subjects to walk at faster speeds than they could without assistance. Concerns that manual assistance will promote passivity in subjects are unsupported by our findings. PMID- 17711591 TI - Isokinetic eccentric exercise can induce skeletal muscle injury within the physiologic excursion of muscle-tendon unit: a rabbit model. AB - BACKGROUND AND PURPOSE: Intensive eccentric exercise can cause muscle damage. We simulated an animal model of isokinetic eccentric exercise by repetitively stretching stimulated triceps surae muscle-tendon units to determine if such exercise affects the mechanical properties of the unit within its physiologic excursion. METHODS: Biomechanical parameters of the muscle-tendon unit were monitored during isokinetic eccentric loading in 12 rabbits. In each animal, one limb (control group) was stretched until failure. The other limb (study group) was first subjected to isokinetic and eccentric cyclic loading at the rate of 10.0 cm/min to 112% (group I) or 120% (group II) of its initial length for 1 hour and then stretched to failure. Load-deformation curves and biomechanical parameters were compared between the study and control groups. RESULTS: When the muscle-tendon unit received eccentric cyclic loading to 112%, changes in all biomechanical parameters - except for the slope of the load-deformation curve - were not significant. In contrast, most parameters, including the slope of the load-deformation curve, peak load, deformation at peak load, total energy absorption, and energy absorption before peak load, significantly decreased after isokinetic eccentric cyclic loading to 120%. CONCLUSION: We found a threshold for eccentrically induced injury of the rabbit triceps surae muscle at between 12% and 20% strain, which is within the physiologic excursion of the muscle-tendon units. Our study provided evidence that eccentric exercise may induce changes in the biomechanical properties of skeletal muscles, even within the physiologic range of the excursion of the muscle-tendon unit. PMID- 17711592 TI - A cluster of Candida krusei infections in a haematological unit. AB - BACKGROUND: Candida krusei infections are associated with high mortality. In order to explore ways to prevent these infections, we investigated potential routes for nosocomial spread and possible clonality of C. krusei in a haematological unit which had experienced an unusually high incidence of cases. METHODS: We searched for C. krusei contamination of the hospital environment and determined the level of colonization in patients and health care workers. We also analyzed the possible association between exposure to prophylactic antifungals or chemotherapeutic agents and occurrence of C. krusei. The C. krusei isolates found were genotyped by pulsed-field electrophoresis method in order to determine possible relatedness of the cases. RESULTS: Twelve patients with invasive C. krusei infection and ten patients with potentially significant infection or mucosal colonization were documented within nine months. We were unable to identify any exogenic source of infection or colonization. Genetic analysis of the isolates showed little evidence of clonal transmission of C. krusei strains between the patients. Instead, each patient was colonized or infected by several different closely related genotypes. No association between medications and occurrence of C. krusei was found. CONCLUSION: Little evidence of nosocomial spread of a single C. krusei clone was found. The outbreak may have been controlled by cessation of prophylactic antifungals and by intensifying infection control measures, e.g. hand hygiene and cohorting of the patients, although no clear association with these factors was demonstrated. PMID- 17711593 TI - Determinants of the range of drugs prescribed in general practice: a cross sectional analysis. AB - BACKGROUND: Current health policies assume that prescribing is more efficient and rational when general practitioners (GPs) work with a formulary or restricted drugs lists and thus with a limited range of drugs. Therefore we studied determinants of the range of drugs prescribed by general practitioners, distinguishing general GP-characteristics, characteristics of the practice setting, characteristics of the patient population and information sources used by GPs. METHODS: Secondary analysis was carried out on data from the Second Dutch Survey in General Practice. Data were available for 138 GPs working in 93 practices. ATC-coded prescription data from electronic medical records, census data and data from GP/practice questionnaires were analyzed with multilevel techniques. RESULTS: The average GP writes prescriptions for 233 different drugs, i.e. 30% of the available drugs on the market within one year. There is considerable variation between ATC main groups and subgroups and between GPs. GPs with larger patient lists, GPs with higher prescribing volumes and GPs who frequently receive representatives from the pharmaceutical industry have a broader range when controlled for other variables. CONCLUSION: The range of drugs prescribed is a useful instrument for analysing GPs' prescribing behaviour. It shows both variation between GPs and between therapeutic groups. Statistically significant relationships found were in line with the hypotheses formulated, like the one concerning the influence of the industry. Further research should be done into the relationship between the range and quality of prescribing and the reasons why some GPs prescribe a greater number of different drugs than others. PMID- 17711594 TI - Design of the Endobronchial Valve for Emphysema Palliation Trial (VENT): a non surgical method of lung volume reduction. AB - BACKGROUND: Lung volume reduction surgery is effective at improving lung function, quality of life, and mortality in carefully selected individuals with advanced emphysema. Recently, less invasive bronchoscopic approaches have been designed to utilize these principles while avoiding the associated perioperative risks. The Endobronchial Valve for Emphysema PalliatioN Trial (VENT) posits that occlusion of a single pulmonary lobe through bronchoscopically placed Zephyr endobronchial valves will effect significant improvements in lung function and exercise tolerance with an acceptable risk profile in advanced emphysema. METHODS: The trial design posted on Clinical trials.gov, on August 10, 2005 proposed an enrollment of 270 subjects. Inclusion criteria included: diagnosis of emphysema with forced expiratory volume in one second (FEV1) < 45% of predicted, hyperinflation (total lung capacity measured by body plethysmography > 100%; residual volume > 150% predicted), and heterogeneous emphysema defined using a quantitative chest computed tomography algorithm. Following standardized pulmonary rehabilitation, patients were randomized 2:1 to receive unilateral lobar placement of endobronchial valves plus optimal medical management or optimal medical management alone. The co-primary endpoint was the mean percent change in FEV1 and six minute walk distance at 180 days. Secondary end-points included mean percent change in St. George's Respiratory Questionnaire score and the mean absolute changes in the maximal work load measured by cycle ergometry, dyspnea (mMRC) score, and total oxygen use per day. Per patient response rates in clinically significant improvement/maintenance of FEV1 and six minute walk distance and technical success rates of valve placement were recorded. Apriori response predictors based on quantitative CT and lung physiology were defined. CONCLUSION: If endobronchial valves improve FEV1 and health status with an acceptable safety profile in advanced emphysema, they would offer a novel intervention for this progressive and debilitating disease. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00129584. PMID- 17711595 TI - Effectiveness of compression stockings to prevent the post-thrombotic syndrome (the SOX Trial and Bio-SOX biomarker substudy): a randomized controlled trial. AB - BACKGROUND: Post thrombotic syndrome (PTS) is a burdensome and costly complication of deep venous thrombosis (DVT) that develops in 20-40% of patients within 1-2 years after symptomatic DVT. Affected patients have chronic leg pain and swelling and may develop ulcers. Venous valve disruption from the thrombus itself or thrombus-associated mediators of inflammation is considered to be a key initiating event for the development of venous hypertension that often underlies PTS. As existing treatments for PTS are extremely limited, strategies that focus on preventing the development of PTS in patients with DVT are more likely to be effective and cost-effective in reducing its burden. Elastic compression stockings (ECS) could be helpful in preventing PTS; however, data on their effectiveness are scarce and conflicting. METHODS/DESIGN: The SOX Trial is a randomized, allocation concealed, double-blind multicenter clinical trial. The objective of the study is to evaluate ECS to prevent PTS. A total of 800 patients with proximal DVT will be randomized to one of 2 treatment groups: ECS or placebo (inactive) stockings worn on the DVT-affected leg daily for 2 years. The primary outcome is the incidence of PTS during follow-up. Secondary outcomes are severity of PTS, venous thromboembolism (VTE) recurrence, death from VTE, quality of life and cost-effectiveness. Outcomes will be evaluated during 6 clinic visits and 2 telephone follow ups. At baseline, 1 and 6 months, blood samples will be obtained to evaluate the role of inflammatory mediators and genetic markers of thrombophilia in the development of PTS (Bio-SOX substudy). DISCUSSION: The SOX Trial will be the largest study and the first with a placebo control to evaluate the effectiveness of ECS to prevent PTS. It is designed to provide definitive data on the effects of ECS on the occurrence and severity of PTS, as well as DVT recurrence, cost-effectiveness and quality of life. This study will also prospectively evaluate the predictive role of biomarkers that are reflective of putative underlying pathophysiological mechanisms in the development of clinical PTS. As such, our results will impact directly on the care of patients with DVT. TRIAL REGISTRATION: NCT00143598 and ISRCTN71334751. PMID- 17711597 TI - Abortion-seeking behaviour among Nigerian women. AB - This study used data from a community-based survey to examine women's experiences of abortion in Nigeria. Fourteen percent of respondents reported that they had ever tried to terminate a pregnancy, and 10% had obtained an abortion. The majority of women who sought an abortion did so early in the pregnancy. Forty-two percent of women who obtained an abortion used the services of a non-professional provider, a quarter experienced complications and 9% sought treatment for complications from their abortions. Roughly half of the women who obtained an abortion used a method other than D&C or MVA. The abortion prevalence and conditions under which women sought abortions varied by women's socio-demographic characteristics. Because abortion is illegal in Nigeria except to save the woman's life, many women take significant risks to terminate unwanted pregnancies. Reducing the incidence of unwanted pregnancy and unsafe abortion can significantly impact the reproductive health of women in Nigeria. PMID- 17711596 TI - Extensive genomic diversity and selective conservation of virulence-determinants in enterohemorrhagic Escherichia coli strains of O157 and non-O157 serotypes. AB - BACKGROUND: Enterohemorrhagic Escherichia coli (EHEC) O157 causes severe food borne illness in humans. The chromosome of O157 consists of 4.1 Mb backbone sequences shared by benign E. coli K-12, and 1.4 Mb O157-specific sequences encoding many virulence determinants, such as Shiga toxin genes (stx genes) and the locus of enterocyte effacement (LEE). Non-O157 EHECs belonging to distinct clonal lineages from O157 also cause similar illness in humans. According to the 'parallel' evolution model, they have independently acquired the major virulence determinants, the stx genes and LEE. However, the genomic differences between O157 and non-O157 EHECs have not yet been systematically analyzed. RESULTS: Using microarray and whole genome PCR scanning analyses, we performed a whole genome comparison of 20 EHEC strains of O26, O111, and O103 serotypes with O157. In non O157 EHEC strains, although genome sizes were similar with or rather larger than O157 and the backbone regions were well conserved, O157-specific regions were very poorly conserved. Around only 20% of the O157-specific genes were fully conserved in each non-O157 serotype. However, the non-O157 EHECs contained a significant number of virulence genes that are found on prophages and plasmids in O157, and also multiple prophages similar to, but significantly divergent from, those in O157. CONCLUSION: Although O157 and non-O157 EHECs have independently acquired a huge amount of serotype- or strain-specific genes by lateral gene transfer, they share an unexpectedly large number of virulence genes. Independent infections of similar but distinct bacteriophages carrying these virulence determinants are deeply involved in the evolution of O157 and non-O157 EHECs. PMID- 17711598 TI - The effects of temperature on the distribution and establishment of Echinoparyphium recurvatum metacercariae in Lymnaea peregra. AB - The establishment and distribution of Echinoparyphium recurvatum metacercariae in the second intermediate host, Lymnaea peregra, were investigated at a temperature range of 5-29 degrees C. Preliminary studies on the survival and infectivity of E. recurvatum cercariae showed that both parameters were temperature dependent. No cercarial transmission occurred at 5 or 10 degrees C. Nevertheless, the transmission efficiency (1/H0) indicated that transmission was temperature independent in the temperature range 17-25 degrees C and was much lower than in previous studies using this host-parasite system. These differences were attributed to low cercarial densities used in this study. The effect of temperature on encystment site choice (mantle cavity, kidney, pericardium) by metacercariae showed that the mantle cavity was the prime site of encystment, followed by the pericardium and the kidney. Temperatures at the lower and upper ranges (14 and 29 degrees C), however, caused a significant reduction in encystment in the mantle cavity but not in the pericardium or kidney. The importance of cercarial densities, the physiological mechanisms influencing metacercarial distribution and their implications for parasite transmission to the definitive host are discussed. PMID- 17711599 TI - Point prevalence of gastrointestinal helminthiasis in ruminants in southern Punjab, Pakistan. AB - The present study was carried out to determine the prevalence of gastrointestinal helminthiasis in ruminants in an irrigated area of lower Punjab (Pakistan). For this purpose, 100 faecal samples were collected from sheep, goats, cattle and buffaloes. Parasitological procedures including direct and indirect methods (sedimentation and floatation) and coproculture were used for the identification of helminths. The overall prevalence of helminthiasis was 51% in cattle, 47% in buffaloes, 62% in sheep and 52% in goats, with nematodes being the most common helminths. The prevalence of helminths was higher in young animals compared with adults in cattle (P < 0.0001), buffaloes (P < 0.0001), sheep (P < 0.059) and goats (P = 0.010). The prevalence of different species of helminths also varied in different age groups, with Toxocara vitulorum being higher in calves than adults both in cattle (P = 0.017) and buffaloes (P < 0.0001). Sex-wise prevalence of helminths was higher in males than females for buffaloes (P < 0.0001) and sheep (P = 0.014) in contrast to cattle and goats. PMID- 17711600 TI - Screening of gap junction antagonists on dye coupling in the rabbit retina. AB - Many cell types in the retina are coupled via gap junctions and so there is a pressing need for a potent and reversible gap junction antagonist. We screened a series of potential gap junction antagonists by evaluating their effects on dye coupling in the network of A-type horizontal cells. We evaluated the following compounds: meclofenamic acid (MFA), mefloquine, 2-aminoethyldiphenyl borate (2 APB), 18-alpha-glycyrrhetinic acid, 18-beta-glycyrrhetinic acid (18-beta-GA), retinoic acid, flufenamic acid, niflumic acid, and carbenoxolone. The efficacy of each drug was determined by measuring the diffusion coefficient for Neurobiotin (Mills & Massey, 1998). MFA, 18-beta-GA, 2-APB and mefloquine were the most effective antagonists, completely eliminating A-type horizontal cell coupling at a concentration of 200 muM. Niflumic acid, flufenamic acid, and carbenoxolone were less potent. Additionally, carbenoxolone was difficult to wash out and also may be harmful, as the retina became opaque and swollen. MFA, 18-beta-GA, 2-APB and mefloquine also blocked coupling in B-type horizontal cells and AII amacrine cells. Because these cell types express different connexins, this suggests that the antagonists were relatively non-selective across several different types of gap junction. It should be emphasized that MFA was water-soluble and its effects on dye coupling were easily reversible. In contrast, the other gap junction antagonists, except carbenoxolone, required DMSO to make stock solutions and were difficult to wash out of the preparation at the doses required to block coupling in A-type HCs. The combination of potency, water solubility and reversibility suggest that MFA may be a useful compound to manipulate gap junction coupling. PMID- 17711602 TI - How robust is a neural circuit? AB - Design in engineering begins with the problem of robustness-by what factor should intrinsic capacity exceed normal demand? Here we consider robustness for a neural circuit that crosses the retina from cones to ganglion cells. The circuit's task is to represent the visual scene at many successive stages, each time by modulating a stream of stochastic events: photoisomerizations, then transmitter quanta, then spikes. At early stages, the event rates are high to achieve some critical signal-to-noise ratio and temporal bandwidth, which together set the information rate. Then neural circuits concentrate the information and repackage it, so that nearly the same total information can be represented by modulating far lower event rates. This is important for spiking because of its high metabolic cost. Considering various measurements at the outer and inner retina, we conclude that the "safety factors" are about 2-10, similar to other tissues. PMID- 17711601 TI - Laminin deficits induce alterations in the development of dopaminergic neurons in the mouse retina. AB - Genetically modified mice lacking the beta2 laminin chain (beta2null), the gamma3 laminin chain (gamma3 null), or both beta2/gamma3 chains (compound null) were produced. The development of tyrosine hydroxylase (TH) immunoreactive neurons in these mouse lines was studied between birth and postnatal day (P) 20. Compared to wild type mice, no alterations were seen in gamma3 null mice. In beta2 null mice, however, the large, type I TH neurons appeared later in development, were at a lower density and had reduced TH immunoreactivity, although TH process number and size were not altered. In the compound null mouse, the same changes were observed together with reduced TH process outgrowth. Surprisingly, in the smaller, type II TH neurons, TH immunoreactivity was increased in laminin-deficient compared to wild type mice. Other retinal defects we observed were a patchy disruption of the inner limiting retinal basement membrane and a disoriented growth of Muller glial cells. Starburst and AII type amacrine cells were not apparently altered in laminin-deficient relative to wild type mice. We postulate that laminin-dependent developmental signals are conveyed to TH amacrine neurons through intermediate cell types, perhaps the Muller glial cell and/or the retinal ganglion cell. PMID- 17711604 TI - Apolipoprotein E genotype and lifetime cognitive decline. AB - OBJECTIVE: The relationship of apolipoprotein E (APOE) genotype to lifetime cognitive decline was examined over 22 years in a large community-based population study. METHOD: The sample for the present study was derived from follow-up of a probability sample of the adult household residents of East Baltimore. From the Baltimore cohort of the Epidemiologic Catchment Area Study, genotype data were collected on 818 participants at the study's fourth wave between 2003 and 2004. Participants were administered the Mini-mental State Examination (MMSE) at all four study waves. Three tests of verbal learning - immediate recall, delayed recall, and word recognition - were completed at waves 3 and 4. The 659 participants for whom genetic data were available had also completed cognitive testing at all time points. Test scores and changes in these scores were examined by APOE genotype group (x/x or 4/x) in younger and older subcohorts defined by age at wave 4 (< or > or = age 65). RESULTS: Cross sectional wave 4 scores on all four cognitive tasks were lower in APOEepsilon4 carriers when compared to non-carriers. In longitudinal univariate models epsilon4 carriers in the younger cohort demonstrated a greater annual rate of decline on a delayed recall task and MMSE. After adjusting for covariates only the decline in the delayed recall task was significant. CONCLUSION: We report an association between APOE genotype and decline in delayed recall and possibly MMSE over this extended time period limited to younger individuals. The lack of an association between APOE and decline in older individuals is likely to be the result of survival bias. Although a clear association exists between APOE genotype and cognitive decline or dementia in late life, these findings suggest that over the lifespan the relationship between APOE and cognitive decline is more complicated. PMID- 17711605 TI - The effects of old age and distraction on the assessment of prospective memory in a simulated naturalistic environment. AB - BACKGROUND: The ability to remember to complete future intentions, prospective memory, often begins to fail in old age. The aim of the present study was to examine the sensitivity of a computer-based procedure using naturalistic stimuli to age-related increases in forgetting under conditions of high (increased visual and auditory noise) or low distraction. METHODS: Participants were tested in a virtual shopping precinct constructed from linked photographs, sounds, and video segments. Groups of 32 older and younger persons completed two concurrent memory tasks while moving along the street. In one task, participants were given errands to complete with an accessible checklist, in the other, they were required to remember to respond to three different targets that appeared repeatedly. RESULTS: The results confirmed previous findings that older adults have difficulty remembering future intentions, even on a self-paced task using naturalistic stimuli, and showed that this was accentuated in noisy environments. CONCLUSIONS: Older persons have particular difficulty remembering in noisy environments, and results from testing in the clinic may underestimate the practical memory problems experienced by older adults with mild cognitive impairments. The findings provide encouragement for the construction of computer-generated environments to measure functional deficits in cognition. PMID- 17711603 TI - Dopaminergic modulation of tracer coupling in a ganglion-amacrine cell network. AB - Many retinal ganglion cells are coupled via gap junctions with neighboring amacrine cells and ganglion cells. We investigated the extent and dynamics of coupling in one such network, the OFF alpha ganglion cell of rabbit retina and its associated amacrine cells. We also observed the relative spread of Neurobiotin injected into a ganglion cell in the presence of modulators of gap junctional permeability. We found that gap junctions between amacrine cells were closed via stimulation of a D(1) dopamine receptor, while the gap junctions between ganglion cells were closed via stimulation of a D(2) dopamine receptor. The pairs of hemichannels making up the heterologous gap junctions between the ganglion and amacrine cells were modulated independently, so that elevations of cAMP in the ganglion cell open the ganglion cell hemichannels, while elevations of cAMP in the amacrine cell close its hemichannels. We also measured endogenous dopamine release from an eyecup preparation and found a basal release from the dark-adapted retina of approximately 2 pmol/min during the day. Maximal stimulation with light increased the rate of dopamine release from rabbit retina by 66%. The results suggest that coupling between members of the OFF alpha ganglion cell/amacrine cell network is differentially modulated with changing levels of dopamine. PMID- 17711607 TI - For debate: is the influence of the pharmaceutical industry on prescribing, research and publication in the field of psychogeriatrics excessive? PMID- 17711606 TI - Dose form modification - a common but potentially hazardous practice. A literature review and study of medication administration to older psychiatric inpatients. AB - BACKGROUND: Many older patients have difficulty in swallowing their tablets and capsules. Dose form modification, by crushing tablets or opening capsules, is often used by nurses to administer such medication. METHODS: Electronic searches of five literature databases on tablet crushing and capsule opening were carried out. A review of medication incident reports involving tablet crushing from the U.K. National Reporting and Learning System (NRLS) was also undertaken. An observational study of medication administration on two long-stay wards for older mentally ill inpatients was carried out in a large psychiatric hospital. RESULTS: Only 17 incidents involving tablet crushing were reported to NRLS in 13 months. In the observational study, the administration of 1257 oral doses of medication at 36 medication rounds was observed. Tablets were crushed or capsules opened for 25.5% (266/1045) of solid oral doses. For 44.0% (117/266) of these doses the tablet crushing had not been authorized by the prescriber. For 4.5% (12/266) of doses crushing was specifically contra-indicated by the manufacturer. In 57.5% (153/266) of doses, tablet crushing was avoidable by the correct use of more suitable preparations. Crushing caused contamination, spillage and hygiene problems. CONCLUSIONS: Although tablet crushing and capsule opening are common practices, they are rarely reported as causing patient harm. Tablet crushing can often be avoided by the use of more suitable preparations. Crushing tablets and opening capsules are contra-indicated for some preparations. Older patients' medication may benefit from review by a pharmacist in order to optimize safe medication administration. Where tablet crushing is unavoidable, attention to cleanliness, contamination and spillage are necessary. PMID- 17711608 TI - Yes, industry influence is excessive. PMID- 17711611 TI - Factors related to inbreeding components from isonymy in an urban population: Aranjuez (Spain). AB - An isonymic analysis has been carried out using a sample of 1529 reconstituted families residing during 1870-1964 in Aranjuez, an urban area situated south of Madrid, Spain. The random, non-random and total-components inbreeding coefficients from isonymy were obtained and the various combinations of surnames compared in order to infer the patri- or matrilocal pattern of residence. Throughout the period studied the random component of inbreeding (F(r)) has not changed, in contrast to the non-random component (F(n)), thus suggesting the latter could be responsible for the reduction of total inbreeding. Using several methodological approaches (biplot analysis, alpha, nu and percentage of immigrants) the predominance of the immigration of grooms was interpreted in terms of Aranjuez as a matrilocal pattern of residence. From this study it can also be concluded that surnames provided by reconstituted families are good estimators of inbreeding and migration. PMID- 17711609 TI - Is the influence of the pharmaceutical industry on prescribing, research and publication in the field of psychogeriatrics excessive? - No. PMID- 17711612 TI - Physiological effects of dietary fructans extracted from Agave tequilana Gto. and Dasylirion spp. AB - Recent data reported that inulin-type fructans extracted from chicory roots regulate appetite and lipid/glucose metabolism, namely, by promoting glucagon like peptide-1 (GLP-1) production in the colon. The Agave genus growing in different regions of Mexico also contains important amounts of original fructans, with interesting nutritional and technological properties, but only few data report their physiological effect when added in the diet. Therefore, we decided to evaluate in parallel the effect of supplementation with 10 % agave or chicory fructans on glucose and lipid metabolism in mice. Male C57Bl/6J mice were fed a standard (STD) diet or diet supplemented with Raftilose P95 (RAF), fructans from Agave tequilana Gto. (TEQ) or fructans from Dasylirion spp. (DAS) for 5 weeks. The body weight gain and food intake in mice fed fructans-containing diets were significantly lower than the ones of mice fed the STD diet, TEQ leading to the lowest value. Serum glucose and cholesterol were similarly lower in all fructans fed groups than in the STD group and correlated to body weight gain. Only RAF led to a significant decrease in serum TAG. As previously shown for RAF, the supplementation with agave fructans (TEQ and DAS) induced a higher concentration of GLP-1 and its precursor, proglucagon mRNA, in the different colonic segments, thus suggesting that fermentable fructans from different botanical origin and chemical structure are able to promote the production of satietogenic/incretin peptides in the lower part of the gut, with promising effects on glucose metabolism, body weight and fat mass development. PMID- 17711613 TI - Are research priorities in Latin America in line with the nutritional problems of the population? AB - OBJECTIVE: Concordance of nutritional research priorities with the related burden of disease is essential to develop cost-effective interventions to address the nutritional problems of populations. The present study aimed to evaluate whether nutrition research priorities are in agreement with the population's nutritional problems in Latin America. DESIGN: The epidemiological profile was contrasted with the research priorities and research produced by academic institutions for each country. Qualitative analysis of research production by type of contribution to problem solving was also conducted. SETTINGS: Nine Latin American countries. RESULTS: Obesity (high body mass index (BMI)) and micronutrient deficiencies (anaemia) emerged as key problems, followed by stunting, breast-feeding/lactation and low birth weight. Wasting in children and women (low BMI) was uncommon. Concordance of ranked research priorities with the epidemiological profile of the country was generally good for nutrition-related chronic diseases, micronutrients and low birth weight, but not for undernutrition, stunting and breast-feeding. Studies on the efficacy and effectiveness of interventions were uncommon. CONCLUSIONS: The present research agenda insufficiently supports the goal of public health nutrition, which is to ensure the implementation of cost-effective nutrition programmes and policies. A more rational approach to define research priorities is needed. PMID- 17711614 TI - Differential ability and attainment in language and arithmetic of Dutch primary school pupils. AB - BACKGROUND: In preschool and primary education, pupils differ in many abilities and competences (giftedness). Yet mainstream educational practice seems rather homogeneous in providing age-based or grade-class subject matter approaches. AIMS: To clarify whether pupils scoring initially at high ability level do develop and attain differently at school with respect to language and arithmetic compared with those displaying other initial ability levels. To investigate whether specific individual, family, or educational variables covary with the attainment of these different types of pupils in school. SAMPLES: Data from the large-scale PRIMA cohort study including a total of 8,258 Grades 2 and 4 pupils from 438 primary schools in The Netherlands. METHODS: Secondary analyses were carried out to construct gain scores for both language and arithmetic proficiency and a number of behavioural, attitudinal, family, and educational characteristics. The pupils were grouped into four different ability categories (highly able, able, above average, average or below average). Further analyses used Pearson correlations and analyses of variance both between- and within ability categories. Cross-validation was done by introducing a cohort of younger pupils in preschool and grouping both cohorts into decile groups based on initial ability in language and arithmetic. RESULTS: Highly able pupils generally decreased in attainment in both language and arithmetic, whereas pupils in average and below-average groups improved their language and arithmetic scores. Only with highly able pupils were some educational characteristics correlated with the pupils' development in achievement, behaviour, and attitudes. CONCLUSIONS: Preschool and primary education should better match pupils' differences in abilities and competences from their start in preschool to improve their functioning, learning processes, and outcomes. Recommendations for educational improvement strategies are presented at the end of the article. PMID- 17711615 TI - Clients' experience of case formulation in cognitive behaviour therapy for psychosis. AB - OBJECTIVES: Case formulation (CF) is considered essential to the practice of cognitive behaviour therapy, and crucial when working with more complex problems such as psychosis. Several claims are made for the beneficial impact of CF on clients, although little empirical research has been conducted. DESIGN: The study used content analysis methodology to assess clients' experience of the CF process in cognitive behaviour therapy for psychosis. In addition, therapists ranked seven documented benefits for them of CF. METHOD: Thirteen clients and their respective therapists were interviewed 2-3 weeks after shared written formulation. RESULTS: Overall, clients' reactions to CF were cognitively, behaviourally, and emotionally complex, and subject to change over time. Therapists reported that they found the CF to be most useful in increasing their understanding of their clients. CONCLUSIONS: Formulation is a complex process for clients, and future research into CF faces methodological challenges. PMID- 17711616 TI - Effect of omalizumab on the need for rescue systemic corticosteroid treatment in patients with moderate-to-severe persistent IgE-mediated allergic asthma: a pooled analysis. AB - BACKGROUND: Allergic asthma is an immunoglobulin E (IgE)-mediated disease characterized by frequent exacerbations following exposure to relevant allergens that leads to the development of chronic airway inflammation. Omalizumab, an anti IgE antibody, reduces asthma exacerbation and hospitalization rates in patients with IgE-mediated allergic asthma. We investigated the effect of omalizumab on asthma outcomes in a retrospective pooled analysis of data from phase III clinical trials in patients (>or= 12 years) with moderate-to-severe persistent IgE-mediated allergic asthma. METHODS: Systemic corticosteroid bursts and physician and patient overall assessments of asthma control were assessed in patients who received add-on omalizumab or current asthma therapy (control). The association of physician and patient overall assessments with the number of steroid bursts were also evaluated. RESULTS: The analysis encompassed 4308 patients with moderate-to-severe persistent IgE-mediated allergic asthma (93% met GINA 2002 criteria for severe persistent asthma) from seven clinical trials. The number of systemic corticosteroid bursts was significantly lower in omalizumab treated patients than in the control group (relative risk [95% CI]: 0.57 [0.48 0.66], p < 0.001). In addition, 58.5% of omalizumab recipients had complete/marked improvement in asthma control according to the physician's overall assessment (responders) vs. 36.9% in the control group (p < 0.001). Similarly, 64.2% of omalizumab patients vs. 43.9% of control patients had complete/marked improvement according to the patient's overall assessment (p < 0.001). There were statistically significant associations between systemic corticosteroid bursts and physician (Goodman-Kruskal gamma [95% CI]: 0.32 [0.26 0.38]) and patient (gamma [95% CI]: 0.29 [0.23-0.36]) overall assessments. This pooled analysis has limitations as it was not pre-specified. CONCLUSIONS: Omalizumab therapy reduced the need for systemic corticosteroid bursts and improved effectiveness of asthma treatment as judged by both physicians and patients. PMID- 17711617 TI - Methodological considerations in using claims databases to evaluate persistence with bisphosphonates for osteoporosis. AB - OBJECTIVE: To demonstrate that retrospective analyses of medication persistence require careful methodological approaches to assure accuracy and consistency across various types of databases. Bisphosphonates (BPs) are used as an example because of the availability of diverse dosing options that can create a unique set of challenges for persistence analyses. METHODS: Reports of BP persistence were compared for methodological approaches, including data source, duration of follow-up, allowed gap for persistence, and presentation of results. MAIN OUTCOME MEASURES: Medication persistence. RESULTS: Comparisons among reports of BP persistence for weekly and monthly formulations revealed inconsistent definitions and a variety of methods. Persistence analyses varied greatly, particularly in allowed gaps and adjustment for demographic and clinical characteristics that affected results. Persistence with weekly dosing was 179-249 days, with 24-78% remaining on treatment at 1 year. Analyses of persistence with monthly treatment was complicated by the variety of gap lengths (30-90 days). The studies reviewed had many limitations, including lack of an established threshold for efficacy, inadequacy of information in databases, and potential biases in case selection (treatment-naive or experienced). CONCLUSIONS: The limitations of published studies reveal the need for a more consistent approach to medication persistence analyses using claims databases to allow for comparison across reports. The analysis plan should present definitions of all terms, details of all methods and types of adjustments needed for demographic and clinical characteristics, as well as specify allowed gaps between refills. These approaches would improve clinical utility of data describing BP persistence and its impact on fracture risk. PMID- 17711618 TI - The serotonin transporter and 5HT2A receptor in rat brain after localized lesions. AB - OBJECTIVES: Post-stroke depression and depression after traumatic brain lesion are most often seen when the lesion includes frontal areas. The development of depression may include the serotonergic system because selective serotonin reuptake inhibitors (SSRIs) can be used to treat the depression. The purpose of the present study was to examine whether serotonin transporter density or 5HT2A serotonin receptor density is changed in specific brain areas following anterior or posterior lesions in the two hemispheres. METHODS: Localized heat-induced brain lesions were induced in rats, and the densities of the serotonin transporter and 5HT2A receptor were measured by quantitative autoradiography in eight and 15 different brain areas, respectively. RESULTS: A decrease in serotonin transporter density was detected in some frontal rat brain areas, and an increase in serotonin transporter density was detected in the right median raphe nucleus. No change was detected for 5HT2A receptor density. PMID- 17711619 TI - Recurrent ADEM versus MS: differential diagnostic criteria. PMID- 17711620 TI - CCR7 expression on peripheral blood lymphocytes is up-regulated following treatment of multiple sclerosis with interferon-beta. AB - A prospective study of the expression of the chemokine receptor CCR7 was performed in 11 relapsing-remitting multiple sclerosis (MS) patients during 12 months of interferon-beta (IFNbeta) treatment. The results show increased expression of CCR7 on peripheral blood lymphocytes (PBL) of MS patients receiving IFNbeta treatment as well as lymphocytes from healthy subjects treated with IFNbeta in vitro. Our results suggest that in addition to modulating the expression of adhesion molecules, the mode of action of IFNbeta also involves the control of the chemokine receptor CCR7. The net effect is a key change in the control of lymphocyte traffic between immune organs and the central nervous system (CNS) and a shift from CCR7 negative effector T cells to CCR7 positive central memory T cells. PMID- 17711621 TI - [An overview of hepatocellular carcinoma research]. PMID- 17711622 TI - [An analysis of annexin II related to HCC metastatic ability]. AB - OBJECTIVE: To use a glycemic method to screen hepatocellular carcinoma (HCC) metastasis related aberrant 1-6 fucosylated glycoproteins, and to analyze the metastasis-related alterations of annexin II. METHODS: 2-DE coupled with lectin affinity blot, lectin affinity precipitation followed by MALDI-TOF-MS/MS was established to screen glycoproteins related to HCC metastasis. Immunofluorescence analysis, Western blot and real-time PCR were performed on higher and lower metastatic HCC cell lines to detect the protein expression levels and mRNA levels of annexin II. RESULTS: The Lens culinaris agglutinin (LCA) affinity glycoprotein profiles from MHCC97-L and MHCC97-H cells were differentially displayed when compared with Hep3B. Annexin II was identified by MALDI-TOF-MS/MS and its increased core-fucosylation was associated with HCC metastasis and it was confirmed. In addition, we found that annexin II was distributed in the cytoplasm and it had higher protein and gene expressions in MHCC97-L and MHCC97-H cells than in Hep3B cells. CONCLUSION: Our results suggest that the increase of annexin II and its expression levels, and the increase of core-fucosylation might all be related to HCC metastatic ability. PMID- 17711623 TI - [Expressions of phosphorylated-Smad2 and PTEN in hepatocellular carcinomas and adjacent liver tissues]. AB - OBJECTIVE: To investigate the expressions of phosphorylated Smad2 (P-Smad2) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) in hepatocellular carcinoma (HCC) tissues. METHODS: The expressions of P-Smad2 and PTEN were detected using Envision immunohistochemical technique in 31 cases of HCC tissues, 25 cases of HCC adjacent liver tissues and 13 cases of non-hepatocellular carcinoma tissues. RESULTS: The positive expression and staining intensity of PTEN in the cytoplasm of HCC cells (64.5%, 4.19+/-3.31) was significantly lower than those of the cells of the cancer adjacent tissues and non-cancerous tissues (96.0%, 7.88+/-0.93; 100%, 7.77+/-0.93). The staining intensity of PTEN in the cytoplasm of Edmondson pathologic grade III HCC cells was lower than those of the Edmondson grade I. The expression of PTEN was negatively correlated with intrahepatic vascular cancer thrombi (r=-0.43) and the expression of PTEN in the nuclei or cytoplasm of liver cells was negatively correlated with the liver disease progressions (r=-0.34). The positive rate and expression intensity of phosphorylated Smad2 in nuclei of HCC cells were the same as those in cancer adjacent and non-tumor liver tissues. The expression was mostly in the nucleus and cytoplasm of Edmondson grade I HCC cells, cancer adjacent liver tissue cells and non-tumor liver tissues, but its expression was only in the nuclei of Edmondson grade II and III HCC cells. The phosphorylated Smad2 expression appeared in the nuclei and in the cytoplasm of liver cells and it was positively correlated with the severity of the tumor pathology (r=0.22). Spearman correlation analysis revealed a significant inverse correlation between PTEN and phosphorylated Smad2 in HCC tissues (r=-0.73). CONCLUSIONS: The aberrant expressions of PTEN and phosphorylated Smad2 and their interaction may play an important role in the pathogenesis of hepatocellular carcinoma. PMID- 17711624 TI - [Proteomic analysis of mitochondrial proteins in hydroxycamptothecin-treated SMMC 7721 cells]. AB - OBJECTIVE: To investigate the differentially expressed mitochondrial proteins in hydroxycamptothecin (HCPT)-treated SMMC-7721 cells by comparative proteomic analysis. METHODS: Apoptosis of SMMC-7721 cells were induced by using HCPT and their mitochondria were isolated with a mitochondria isolation kit for cultured cells. Three different solubility protein fractions were extracted with ReadyPrep Sequential Extraction Kit and were separated by two-dimensional gel electrophoresis (2-DE). PDQuest software was used to differentiate mitochondrial proteins between control cells and HCPT-treated cells. Matrix assisted laser desorption/ionization time of flying mass spectrometry (MALDI-TOF-MS) was used to identify some of the different proteins. RESULTS: Highly purified mitochondria and high resolution 2-DE patterns of the proteins were obtained. Forty-four mitochondrial protein spots from the HCPT-treated cells showed different expressions compared to those of the control cells. Twenty of the different protein spots were analyzed by MALDI-TOF-MS. CONCLUSION: Differently expressed mitochondrial proteins in HCPT-treated cells and control cells were obtained in this study. This will be of help to understand the mechanism by which HCPT induces cell apoptosis. PMID- 17711625 TI - [An analysis of the pathohistology of liver tissues, clinical features and prognostic factors of chronic hepatitis B virus carriers]. AB - OBJECTIVE: To study the correlations between clinical features and liver pathohistological changes of chronic hepatitis B virus (HBV) carriers and to discuss the factors which may influence the prognosis. METHODS: Ninety HBV carriers who had liver biopsies were enrolled in this study. RESULTS: (1) The mean follow-up period of the patients was 118 weeks. (2) Fifty-four patients (60.0%) had G1 hepatitis and 21 (23.3%) had G2 hepatitis. The fibrosis stages were graded as S1(42) and S2(21). (3) There were significant age differences among S0, S1 and S2. (4) There were significant differences in aminotransferase levels between patients who had a normal liver histology and those who had mild hepatitis. (5) The grades of liver inflammation were not correlated with the titers of HBeAg and HBV DNA in sera. The stages of liver fibrosis were not correlated with the titers of HBVDNA in sera. Most of the HBeAg negative patients progressed to S2. (6) There were significant differences in spleen dimensions measured by ultrasonography between S0, S1 and S2 patients. (7) During the follow up period serum aminotransferase (ALT) levels remained normal in 60 patients (group A); 22 patients had transient elevations (group B), and 8 patients had persistent increases (group C). There were significant differences of the ratios of S0 and S2 cases among patients in groups A, B and C. (8) Age and fibrosis stages were predictive factors of liver cirrhosis. CONCLUSIONS: Most chronic HBV carriers had mild inflammatory histological changes in their livers and also had different degrees of liver fibrosis. This follow-up study shows that some of those carriers should have had antiviral therapy. PMID- 17711626 TI - [Clinical significance of intrahepatic hepatitis B core antigen (+) in patients with chronic hepatitis B]. AB - OBJECTIVE: This study aimed to assess the clinical significance of intrahepatic hepatitis B core antigen (HBcAg) (+) in patients with chronic hepatitis B (CHB). METHODS: 200 CHB patients were prospectively studied using fluorescence quantitative PCR (FQ-PCR), combined PCR with fluorescence probe hybridization technique, to determine serum HBV DNA. Serum HBeAg was measured quantitatively. Liver biopsies were performed and immunohistochemistry stained liver slides were examined in all the cases. Correlation analyses were performed. RESULTS: Based on the HBV DNA levels, the patients were divided into 5 groups: group A (<3 log10 copies/ml) n=20, group B (>or=3 log10 copies/ml-<5 log10 copies/ml) n=13, group C (>or=5 log10 copies/ml-<6 log10 copies/ml) n=24, group D (>or=6 log10 copies/ml <8 log10 copies/ml) n=116, and group E (>or=8 log10 copies/ml) n=27, and 87.5% of the CHB patients were intrahepatic HBcAg (+). The rate of HBcAg (+) was 55.0% (11/20) in group A, 53.8% (7/13) in group B, 75.0% (19/24) in group C, 96.6% (112/116) in group D, and 100% (27/27) in group E. A strong correlation was found between the rate of HBcAg (+) and the level of serum HBV DNA (r=0.80). This type of association also appeared between serum HBV DNA levels and HBeAg (+) (r=0.47). Of 20 CHB patients who were serum HBV DNA negative, 25% (5) were HBeAg (+), and 55% (11) were HBcAg (+), whereas 15 patients were both HBV DNA (-) and HBeAg (-), and 46.7% (7) were HBcAg (+). CONCLUSIONS: Intrahepatic HBcAg (+) in CHB patients might be more reliable in reflecting HBV replication. Determination of HBcAg (+) may have clinical significance for evaluating the efficacy of antiviral therapy and for predicting the therapeutic responses to different antiviral agents. PMID- 17711627 TI - [Changes of RANTES levels in livers of patients with chronic hepatitis B: the clinical significance and the possible mechanisms]. AB - OBJECTIVES: To study the relationship between intra-hepatic levels of regulated on activation, normal T-cell expressed and secreted (RANTES) and the disease severity and liver inflammatory degrees in patients with chronic hepatitis B and the possible mechanism of the changes of intra-hepatic levels of RANTES. METHODS: The expression of RANTES of the livers was studied using immunohistochemical stainings and morphometric quantitative measurements in liver specimens from 10 normal subjects and 64 patients with chronic hepatitis B with different degrees of liver inflammation and different clinical severity. The expressions of RANTES protein and mRNA in cell line HepG2, HepG2.2.15 and HepG2 treated with 10 ng/ml TNFa at different times were quantified by ELISA and one-step RT-PCR. RESULTS: The expression of RANTES of the livers in patients was significantly higher than that in the normal controls. Hepatic RANTES levels increased significantly and the increases were parallel to the increases of the severity of the hepatitis, from mild, moderate to severe hepatitis (the positive units were 3.7+/-1.5, 15.6+/-6.9, 24.0+/-4.0, 37.9+/-11.1, respectively) and from G0 degree to G4 degrees of liver inflammation (the positive units were 3.7+/-1.5, 15.0+/-5.7, 21.6+/-5.9, 30.3+/-8.2, 40.9+/-12.3, respectively). The expressions of RANTES protein and mRNA of HepG2.2.15 were higher than that of HepG2. RANTES protein and mRNA were induced in HepG2 by TNFa. CONCLUSION: RANTES may have an important role in the pathogenesis of chronic hepatitis B. The elevation of hepatic RANTES may be caused by hepatitis B virus and TNFa. PMID- 17711628 TI - [The effects of endothelial progenitor cell transplantation in carbon tetrachloride induced hepatic fibrosis rats]. AB - OBJECTIVES: To study the effects of rat endothelial progenitor cell (EPC) transplantation on hepatic fibrosis in carbon tetrachloride (CCl4) induced hepatic fibrosis rats. METHODS: Hepatic fibrosis was developed in 24 healthy female SD rats by feeding them 25% CCl4/olive oil for 8 weeks. Eight of them were sacrificed at the end of the 8 weeks. The rats were subdivided into a EPCs transplanting group (n=8) and a saline control group (n=8). After the EPCs were isolated and cultured for 9 days, the cells were injected into the portal veins of the rats in the EPCs transplanting group. Four weeks later all of the rats were sacrificed. The blood biochemical parameters from the serum were examined. The degree of liver fibrosis was evaluated by reading Masson staining liver slides and by detecting the expression of a-SMA and collagen III. RESULTS: Compared with the saline control group, hepatic activity index (HAI), levels of ALT, AST and TBil in the serum were all lower in the EPCs transplanting group, but the level of Alb was higher and the expression of a-SMA and collagen III were lower. Compared with the 8 week hepatic fibrosis group, the levels of ALT, AST and TBil in the serum of the EPCs transplanting group were all lower. In the saline control group, the serum levels of ALT, AST and TBil were higher, the level of Alb was lower, and the expressions of a-SMA and Collagen III were higher. CONCLUSION: In hepatic fibrosis rats, transplantation of rat EPCs could minimize the hepatic fibrosis process and the injuries. PMID- 17711629 TI - [A clinico-pathological analysis of HCV infection in post-liver transplantation patients]. AB - OBJECTIVE: To investigate the pathological characteristics of HCV infection after liver transplantation. METHODS: This is a retrospective analysis of the clinico pathological changes of 73 liver biopsies obtained from 61 patients who had HCV infection (including HCV recurrence and reinfection) after liver transplantation in our center from September 2000 to September 2006. RESULTS: Abnormal enzyme test results due to HCV infection happened on the 9th to the 1553rd post transplantation surgery day. The serum HCV RNA level was higher than 10(5) copies/ml in 19 cases and between 10(2)-10(5) copies/ml in the other 42 cases. The histological changes in the transplanted livers were hepatocellular degeneration, necrosis and apoptosis, portal infiltrations and fibrosis. They were classified into two stages (early stage and late stage) according to the onset of fibrosis which appeared within 90 days or later after their transplantation in our study. The incidence of predominant portal infiltrates and liver fibrosis in early stage and late stage was 5.7% (2/35) and 94.7% (36/38) (chi2=54.34, P<0.01) and 2.9% (1/35) and 97.4% (37/38) (chi2=61.47, P<0.01) respectively. CONCLUSIONS: Pathological features of early stage and late stage hepatitis C infection in transplanted livers are different and they are also different from that in native livers. Liver biopsies are important in clinical staging, evaluation of the severity, and differential diagnosis of post transplantation HCV infection. PMID- 17711630 TI - [Differentiation of adult mouse mesenchymal stem cells into hepatocytes cultured in a conditioned culture medium of injured hepatocytes]. AB - OBJECTIVE: To establish a method through which murine bone marrow mesenchymal stem cells (MSCs) can be induced into hepatocytes in vitro. METHODS: A conditioned medium of injured hepatocytes (with CCl4 in vivo) was used to culture the isolated MSCs. The differentiated cells were identified by morphological observation, reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence assay (for AFP, Albumin, and CK18) and periodic acid schiff reaction (PAS) for glycogen. RESULTS: The differentiated cells showed characteristics of hepatocytes. PT-PCR detected AFP mRNA on day 5 and it increased gradually until day 15, and then decreased; CK18 mRNA was detected on day 10; TAT was detected on day 20. Immunofluorescence assay for AFP, albumin and CK18 showed positive staining reactions on day 20. PAS positive glycogen granules appeared in the cytoplasm of the differentiated cells. CONCLUSION: MSCs of adult mice cultured in a conditioned medium of injured hepatocytes can differentiate into hepatocytes. This method can be used in further studying of the mechanism of transdifferentiation of MSCs into hepatocytes. PMID- 17711631 TI - [A study on the transdifferentiation of adipose mesenchymal stem cells into hepatocytes]. AB - OBJECTIVE: To investigate the possibility of transdifferentiation of adipose mesenchymal stem cells (AMSCs) into hepatocytes. METHODS: Human omentum adipose tissue was dispersed with collagenase I. Cells collected were cultured in a DMEM F12 medium containing 2% FBS supplemented with 20 ng/ml HGF, 10 ng/ml FGF4, 1xITS and 0.1 micromol/L dexasmison. The cells of the control group were also cultured in the same kind of medium but without any cytokines serving as a control. The expression of hepatic transcriptional factors such as GATA4 and HNF1 were checked by RT-PCR. At the end of the induction, hepatocyte markers were analysed by flow cytometry, and cytokeratin expressions were examined using cyto immunofluorescence methods. RESULTS: AMSCs grew like fibroblasts and were passaged easily. Most of the third passaged AMSCs were positive against anti CD29, anti-CD44 antibodies, but negative for the anti-CD34 and anti-CD45 ones. The hepatic transcriptional factor was expressed gradually to higher levels during the induction time. AFP and Alb positive cells were 30.0% and 17.8% of the total cultured cells, and the rate of cells positive to the two markers was 6.9%. The inducted cells were positive for CK18 and CK19 antibodies at the end of the induction. The cells in the control group were negative when checked by these methods. CONCLUSIONS: AMSCs could be directed to differentiate into hepatocytes in vitro by a cytokine cocktail with a low concentration FBS culture system. PMID- 17711633 TI - [Clinical values of genetic markers in diagnosing hepatocellular carcinoma]. PMID- 17711632 TI - [Common linear B-cell epitopes in human hepatitis B virus core protein and woodchuck hepatitis virus core protein]. AB - OBJECTIVE: To search for and verify some common B cell epitopes in the core proteins of woodchuck hepatitis virus and human hepatitis B virus. METHODS: Monoclonal antibodies against both core proteins of woodchuck hepatitis virus (WHV) and human hepatitis B virus (HBV) were prepared by inoculating Balb/c mice with denatured recombination WHV and HBV core proteins. ELISA and immunoblotting assays for WHcAg and HBcAg were carried out by using these antibodies. Immunohistochemistry was carried out with liver tissue sections of both WHV infected woodchucks and chronic HBV-infected patients. The epitopes were mapped with the mouse mAbs (6D1 and 1H4) by using a panel of 24 16mer overlapping peptides covering the entire WHcAg. The amino acid sequences of WHcAg and HBcAg were compared. RESULTS: Cross-reactions were observed between mAbs (6D1 and 1H4) and WHcAg and between Mabs and HBcAg/HBcAg in ELISA and immunoblotting assay. Liver tissue sections of both WHV-infected woodchucks and chronic HBV-infected patients could be stained specifically by mAbs. The epitopes were mapped at aa1-8 (6D1) and aa125-140 (1H4) of the core proteins of both WHV and HBV by using ELISA assay. WHcAg and HBcAg share similar amino acids sequences at aa1-8 and aa125-140 respectively. CONCLUSION: The core proteins of woodchuck hepatitis virus and human hepatitis B virus share common linear B cell epitopes which span aa1-8 and aa125-140 respectively. PMID- 17711634 TI - [Early treatments of hepatocellular carcinoma]. PMID- 17711635 TI - [Advances and prospects of radiotherapy for recurrent hepatocellular carcinoma]. PMID- 17711636 TI - [A study on transcription regulation of human alpha 2(I) procollagen gene by FoxH 1]. PMID- 17711637 TI - [Fractionate and collect hepatocyte canalicular membrane vesicles of rats and study their transportation functions in vitro]. PMID- 17711638 TI - [The expressions of platelet-derived growth factor beta receptor and p-ERK1/2 in livers of rats with experimental hepatic fibrosis]. PMID- 17711639 TI - [Relationships between changes of endostatin expressions and the degrees of fibrosis in estrogen interfered experimental rat liver fibrosis]. PMID- 17711640 TI - [High expressions of tissue transglutaminase in human hepatocellular carcinomas]. PMID- 17711641 TI - [Influence of plasma exchange on serum cytokines in patients with acute liver failure]. PMID- 17711642 TI - [Misdiagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome: a case report]. PMID- 17711643 TI - [A case of portal vein cavernous transformation treated with a live donor liver transplantation]. PMID- 17711644 TI - [Hepatic sarcoidosis with severe jaundice leading to cirrhosis: a case report]. PMID- 17711646 TI - [Understanding guidelines of the diagnosis and treatment in liver failure]. PMID- 17711645 TI - [Analysis of 4 cases with graft-versus-host disease after liver transplantation]. PMID- 17711647 TI - [Nuclear factor-kB and hepatocellular carcinoma]. PMID- 17711648 TI - [Targeted therapy of liver fibrosis]. PMID- 17711649 TI - [Evidence-based management of non-ST-segment elevation acute coronary artery syndrome]. PMID- 17711650 TI - [Hot topics of percutaneous coronary intervention in 2006]. PMID- 17711651 TI - [Guideline for diagnosis and treatment of patients with unstable angina and non ST-segment elevation myocardial infarction]. PMID- 17711652 TI - [Procedural success and 10-month outcome between Cypher and TAXUS drug-eluting stents for the treatment of in-stent restenosis]. AB - OBJECTIVE: To compare the procedural success and 10-month outcome between sirolimus-eluting stent (Cypher stent) and paclitaxel-eluting stent (TAXUS stent) for the treatment of in-stent restenosis lesions. METHODS: Patients with in-stent restenosis treated with drug-eluting stents (DES) from December 2002 to March 2005 were included in this study and 10 months post stenting follow-up data were reported. RESULTS: A total of 253 patients with 262 in-stent restenosis lesions were treated with 176 Cypher and 132 TAXUS stents. There were 29 total occlusion, 143 > or = 90% stenosis and 90 < 90% stenosis lesions. Target lesion type distributions were as follows: 9 type A, 45 type B1, 73 type B2 and 135 type C lesions. The mean diameter in Cypher group (2.96 +/- 0.27) mm was smaller than that of TAXUS (3.05 +/- 0.35 mm, P = 0.041) and mean DES length was similar between the two groups (23.31 +/- 6.68 mm vs. 23.56 +/- 6.54 mm, P = 0.745). Procedural success rate of DES implantation was 100% for both Cypher and TAXUS groups. MACE rate during hospitalization was similar between the two groups. At 10-month follow up, MACE rate was significantly higher in TAXUS group than that in Cypher group (16.0% vs. 6.7% P = 0.031) and angiographic in-stent restenosis rate tended also higher in TAXUS group than that in Cypher group (29.4% vs. 14.0%, P = 0.075). CONCLUSION: Procedural success rate was similar between Cypher and TAXUS groups and the angiographic and clinical outcome at 10 months was better in Cypher DES group than in TAXUS DES group. PMID- 17711653 TI - [Incidence of in-hospital upper gastrointestinal haemorrhage post percutaneous coronary interventions in the drug eluting stent era: a single center experience]. AB - OBJECTIVE: To observe the incidence and the predictors of upper gastrointestinal haemorrhage (UGH) in patients underwent percutaneous coronary interventions (PCI). METHODS: UGH occurred in 21 out of 2279 PCI patients (0.92%). The clinical characteristics, procedural and prognostic status of all UGH patients were analyzed. RESULTS: The incidence of UGH was significantly higher in patients aged more than 70 years, female, diabetes mellitus, peptic ulcer history, admission with ACS than patients without above factors. Platelet glucoprotein IIb/IIIa receptor antagonist use during the procedure and primary PCI also contributed to the development of UGH. Hospitalization time was significantly longer in patients with UGH compared with patients without UGH (13.8 versus 5.1 days, P < 0.001). The total MACCEs including myocardial infarction, TVR and death rate in patients with UGH were higher than that in patients without UGH (23.0% versus 9.3%, P < 0.01). Stepdown multivariate logistic regression analysis revealed that age more than 70 years (OR 2.23, 95% CI 1.01 - 4.13, P < 0.01), admission with acute coronary syndrome (OR 1.91, 95% CI 0.57 - 2.52, P < 0.05) and history of peptic ulcer (OR 1.02, 95% CI 0.17 - 2.25, P < 0.05) were the predictors of in-hospital UGH post PCI. CONCLUSION: Age more than 70 years, admission with ACS and peptic ulcer history were closely related to the development of in-hospital UGH post PCI and hospitalization was prolonged in UGH patients. PMID- 17711654 TI - [Very late stent thrombosis after implantation of sirolimus eluting coronary stents]. AB - OBJECTIVE: To analyze the clinical date of 4 patients who developed very late stent thrombosis after implantation of sirolimus eluting stents. METHODS: From Oct. 2002 to Aug. 2006, 835 sirolimus eluting stents were implanted in 612 patients. From Jan. 2006 to Aug. 2006, very late thrombosis in sirolimus eluting stents occurred in 4 patients (0.65%), and which caused acute myocardial infarction in anterior wall. Emergency percutaneous coronary interventions (PCIs) were performed in 4 patients immediately after re-admission. The clinical date of the 4 cases were analyzed retrospectively. RESULTS: These 4 patients were male with the age of 40-69 years. Very late stent thrombosis occurred 31-37 months after successful implantation of sirolimus eluting stents. Application of clopidogrel was stopped 7-12 months after first stents implantation. Aspirin was continued in 3 patients, while the other patient discontinued taking aspirin 18 moths before thrombosis occurred. Emergency coronary angiogram showed that sirolimus eluting stents in LADs were all occlude by thrombosis with TIMI 0 flow. All 4 patients survived after successfully primary PCIs. CONCLUSIONS: Our report presents evidence of very late thrombosis in sirolimus eluting coronary stents, and more careful and prolonged flow-up was required in patients after implantation of drug eluting stents. PMID- 17711655 TI - [Procedural success rate and short-term outcomes of percutaneous interventional therapy for severe subclavian artery stenosis in 152 patients]. AB - OBJECTIVE: To evaluate the safety and efficacy of percutaneous transluminal angioplasty (PTA, with or without stents) for the treatment of patients with subclavian artery stenosis. METHODS: Using the brachial (n = 25), radial (n = 3), femoral (n = 96), or combined (n = 28) approach, PTA was performed in consecutive 152 [bilateral n = 27, unilateral n = 125, 88 male, aged 17 approximately 82 (58 +/- 16) years old] subclavian artery stenosis patients with 179 lesions. Stenosis was caused by atheroma in 114 of 152 patients (75%) and by aortoarteritis in the other patients (25%). The indications for intervention were arm claudication in 130 of 152 patients (85.5%), subclavian steal in 138 of 152 patients (90.8%), blue finger syndrome in 2 of 152 patients (1.3%), coronary steal syndrome in 2 of 162 patients (1.3%), or anticipated coronary artery bypass grafting using the internal mammary artery in 10 asymptomatic patients (6.6%). All patients were followed up for at least 9 months after procedure. RESULTS: PTA was succeeded in 142 of 152 patients (93.4%) and procedural success rate was 100% in 133 stenotic lesions (diameter reduction 70% approximately 99%) and 78.2% in total occlusive lesions (36/46). Stents were deployed in 145 of 169 lesions. In the 142 patients successfully treated with PTA, the percent diameter stenosis was reduced from (90 +/- 8)% to (6 +/- 8)%, and lesions diameter improved from (1.0 +/- 0.9) mm to (7.0 +/- 0.5) mm (all P values < 0.001). No severe procedure related complications were observed. During 9 months follow-up in these 142 patients with successful PTA, sustained clinical improvement was seen in 135 patients and restenosis occurred in 7 patients with aortoarteritis (n = 4) and atheroma (n = 3). CONCLUSIONS: Percutaneous transluminal angioplasty is effective and safe for the treatment of subclavian artery stenosis. PMID- 17711656 TI - [Association between serum adiponectin and mean blood pressure]. AB - OBJECTIVE: To investigate the relationship between serum adiponectin and mean blood pressure (BP). METHODS: A total of 187 subjects were divided into four groups according to BP levels: optimal blood pressure group (n = 38), high normal blood pressure group (n = 50), treated hypertension group (n = 54) and untreated hypertension group (n = 45). Serum adiponectin and microalbuminuria were detected by radioimmunology assay. Insulin resistant index defined as HOMA-IR and urinary concentration of microalbuminuria/urinary concentration of creatinine defined as albumin creatinine ratio (ACR) were calculated. RESULTS: (1) Serum adiponectin decreased in proportion to BP increase and the serum adiponectin level was significantly higher in treated hypertension group than untreated hypertension group. (2) Correlation analysis showed that adiponectin concentration was negatively correlated with mean blood pressure (P < 0.01). (3) Multivariate regression analysis revealed that mean blood pressure and HOMA-IR were independent predictors of serum adiponectin level. CONCLUSIONS: Mean blood pressure was the main determinant of serum adiponectin level and negatively correlated to serum adiponectin level. PMID- 17711657 TI - [Comparison of low-dose dobutamine echocardiography and dual-isotope emission simultaneous myocardial perfusion acquisition for myocardial viability assessment]. AB - OBJECTIVE: To compare the value of low-dose dobutamine echocardiography (LDDE) and dual-isotope emission simultaneous myocardial perfusion acquisition (technetium-99-m-tetrofosmin/fluorine 18-fluorodeoxy-glucose) single-photon emission computed tomography (DISA-SPECT) for myocardial viability assessment in patients with acute myocardial infarction (MI). METHODS: LDDE and DISA-SPECT were performed in 44 patients within 5-10 days after onset of first acute MI and percutaneous coronary intervention was made thereafter. A 16-segment semi quantitative scoring model was adopted for both techniques. Wall motion improvement at follow-up (3 months after acute MI) compared with baseline before dobutamine infusion derived from two dimensional images was used as golden criteria for myocardial viability. RESULTS: The sensitivity, specificity, diagnostic accuracy, positive and predictive values for identification of viable myocardium were 77%, 82%, 79%, 82% and 77%, respectively by LDDE and 85%, 62%, 74%, 71% and 79%, respectively by DISA. No difference was found between LDDE and DISA for identifying viable myocardium in hypokinetic segments (74.1% vs. 77.6%, P > 0.05) but less viable myocardium was detected by LDDE than DISA in akinetic segments (29% vs. 53%, P < 0.01). CONCLUSIONS: Sensitivity was higher while specificity was lower on detecting viable myocardium by DISA compared to LDDE. Combined use of the two techniques could improve viable myocardium detection in patients with acute MI. PMID- 17711658 TI - [Variations of pulmonary venous drainage and venous ostium index detection in atrial fibrillation patients prior to radiofrequency catheter ablation by MDCT pulmonary venography]. AB - OBJECTIVE: To evaluate variations of pulmonary venous drainage and venous ostium index (VOI) in patients with atrial fibrillation (AF) prior to radio-frequency catheter ablation (RFCA) by MDCT pulmonary venography. METHODS: 16-detector row CT pulmonary venography was performed in 64 AF patients referred to RFCA from June, 2005 to May, 2006. Variations in pulmonary venous drainage were observed in volume render imagines. Anterior-posterior and superior-inferior diameters of pulmonary venous ostium were measured on maximum intensity projection images. VOI derived from left superior, left inferior, right superior, right inferior pulmonary veins and variations in pulmonary venous drainage were calculated. RESULTS: Classic pulmonary veins anatomy was found in 11 patients (17.18%), early branching veins in 45 patients (70.31%), left common ostium in 5 patients (7.81%), right common ostia in 1 patient, right accessory (middle) pulmonary vein in 5 patients (7.81%) and left accessory (middle) pulmonary vein in 1 patient (1.56%). VOI of homolateral pulmonary veins and bilateral superior pulmonary veins were similar (P > 0.05) while there was a significant difference on VOIs derived from left superior and right inferior; two inferior, left inferior versus right superior veins (P < 0.05). Right inferior pulmonary venous ostium was most rounded and had the highest index (0.88) and left inferior pulmonary venous ostium was most oval and had the lowest index (0.72). CONCLUSION: Multidetector row CT pulmonary venography (MDCT-PV) could provide valuable informations on pulmonary venous anatomy in AF patients referred to RFCA and should be used as a routine examination prior to the operation. PMID- 17711659 TI - [Transcoronary ablation of septal hypertrophy versus dual-chamber cardiac pacing for the treatment of aged patients with hypertrophic obstructive cardiomyopathy]. AB - OBJECTIVE: To compare the safety and efficacy of transcoronary ablation of septal hypertrophy (TASH) versus dual-chamber cardiac pacing (PM) for the treatment of aged > 60 years old) patients with hypertrophic obstructive cardiomyopathy (HOCM). METHODS: Medically uncontrolled symptomatic aged patients with hypertrophic obstructive cardiomyopathy (HOCM, n = 23) were treated by transcoronary ablation of septal hypertrophy (TASH, n = 15) or dual-chamber cardiac pacing (PM, n = 8) and followed up for 24 months. Two patients needed permanent pacemaker after TASH were excluded from the analysis. RESULTS: NYHA class improved from 3.2 +/- 0.7 to 1.5 +/- 0.5 and from 3.0 +/- 0.1 to 1.9 +/- 0.6 and general symptomatic score decreased from 5.9 +/- 1.6 to 1.8 +/- 0.7 and from 4.5 +/- 1.3 to 2.3 +/- 1.6 post TASH or PM treatments, respectively (all P < 0.01 vs. baseline). The decrease of left ventricular outflow pressure gradient (PG) was (80.0 +/- 35.5) mm Hg (1 mmHg = 0.133 kPa) and (49.3 +/- 37.7) mmHg post TASH and PM treatments respectively (all P < 0.05 vs. baseline) and the PG decrease was more significant in TASH group compared to PM group (P < 0.01). Interventricular septal thickness was significantly reduced post TASH [(22 +/- 4) mm vs. (17 +/- 3) mm, P < 0.05] and remained unchanged in PM group. Three patients with paroxysmal atrial fibrillation (2 patients in TASH group and 1 in PM group) developed chronic atrial fibrillation during the follow-up. CONCLUSIONS: Both therapeutic approaches-TASH and PM implantation, significantly reduced PG and significantly improved NYHA class and general symptomatic score in aged symptomatic patients with HOCM. TASH was superior to PM in terms of PG decrease and general symptomatic score improvement. PMID- 17711660 TI - [Association between preoperative pulmonary hypertension and postoperative right ventricular function in heart transplant patients]. AB - OBJECTIVE: To observe the relationship between preoperative pulmonary artery pressure and postoperative right ventricular function in heart transplant patients. METHOD: A total of 54 heart transplant patients were divided to two groups: group I (n = 34): preoperative pulmonary arterial systolic pressure (sPAP) > or = 45 mm Hg (1 mm Hg = 0.133 kPa) [(60 +/- 12) mm Hg]; group II (n = 20): sPAP < 45 mm Hg [(25 +/- 9) mm Hg]. Cardiac index (CI), pulmonary circulation resistance (PVR) and CVP were measured preoperatively and up to 60 hours post operation by Swan-Ganz catheter. The extent of tricuspid regurgitation at preoperation and 3, 7, 14, 21, 30 days post operation was evaluated by bedside echocardiography. Postoperative pulmonary hypertension was treated by diuresis, nitrates, Ilomedin 20 and hemofiltration (CRRT). RESULT: All patients survived the operation. Preoperative PVR was significantly higher in group I patients than that of group II patients [(358 +/- 150) dyn x s(-1) x cm(-5) vs. (140 +/- 68) dyn x s(-1) x cm(-5), P < 0.01]. Right heart insufficiency early post operation was more often in group I patients than that in group II patients (70.6% vs. 35.0%, P < 0.05). The PVR was higher and tricuspid regurgitation extent severer in group II than group I early post operation and were similar 30 days post operation. CONCLUSION: Post operative right heart insufficiency was associated to preoperative pulmonary hypertension in heart transplant patients. PMID- 17711661 TI - [The clinical features and outcomes of immunoglobulin light-chain amyloidosis with heart involvement]. AB - OBJECTIVE: To analyze the clinical features and outcomes of patients with immunoglobulin light-chain amyloidosis (AL) who had heart involvement. METHODS: Clinical features and outcomes of AL amyloidosis patients with heart involvement in the past 7 years in our hospital were retrospectively analyzed. RESULTS: Cardiac involvement was seen in 36 out of the 60 AL patients (60%). The clinical manifestations of cardiac amyloidosis included heart failure (50%), low QRS voltage (47.2%) and pseudomyocardial infarction (33.3%) in electrocardiography, as well as thickening of ventricular wall (63.9%), echo of granular sparkling texture (11.1%), atria dilation (33.3%) and diastolic dysfunction (30.6%) in echocardiography. The prognosis was poor, with a median survival time of 13.9 months. CONCLUSION: Patients of AL amyloidosis with cardiac involvement are not rare. Thickening of ventricular wall and diastolic dysfunction are the most common characteristics. Special attention should be paid to this disease. PMID- 17711662 TI - [In vivo cardiac magnetic resonance imaging of superparamagnetic iron oxides labeled mesenchymal stem cells in swines]. AB - OBJECTIVE: To explore the feasibility of magnetic resonance imaging (MR) on detecting transplanted nanometer small superparamagnetic iron oxides (SPIO) labeled mesenchymal stem cells (MSCs) in swine model with acute myocardial infarction (MI). METHODS: MSCs isolated from swine were incubated with nanometer SPIO for 24 hours and the third-passage MSCs were labeled with DNA dye 4'-6 diamidino-2-phenylindole (DAPI) and aliphatic red fluorescent dye PKH(26)-GL. Presence of small particles of SPIO in MSCs was assessed by Prussian Blue staining and electron microscopy. Three animals in each group received SPIO labeled MSCs (5 x 10(5); 1 x 10(6); 2 x 10(6)) and MSCs without SPIO (1 x 10(6)) injections into the infarcted myocardium approximately 1 hour following left anterior descending coronary artery. MRI (1.5-T) was performed 20 to 24 hours post infarction in all animals and the animals were subsequently sacrificed for histology 1 hour post MRI. RESULTS: In vitro Prussian Blue staining and electron microscopy examination revealed numerous iron particles in the cytoplasm of MSCs. Low signal intensity spots with the scanning T(2)(*)WI-Flash 2d sequence were detected in all SPIO-MSCs but not in SPIO-negative-MSCs injected myocardial sites in vivo with the clinical 1.5 T scanner. Prussian blue, DAPI and PKH(26) positive cells were detected histologically in sections corresponding to low signal intensity spots area shown on MRI. CONCLUSION: Magnetically labeled MSCs transplanted in myocardial ischemia area of swine can be visualized in vivo with a clinical 1.5-T MRI and could be used for tracking SPIO-MSCs clinically. PMID- 17711663 TI - [Autologous bone marrow mononuclear cells and peripheral endothelial progenitor cells differentiation in myocardial ischemia reperfusion injury region in swine]. AB - OBJECTIVE: To investigate the differentiation status of autologous bone marrow mononuclear cells (BM-MNC) and peripheral endothelial progenitor cells (EPC) transplanted into myocardial ischemia reperfusion injury region in swine. METHODS: BM-MNC marked with PKH26 (n = 9), EPC marked with CM-DiI (n = 7), phosphate buffer saline (control, n = 7) were transplanted into myocardial ischemia reperfusion injury region of swine by intracoronary artery injection. Specimens were harvested 4 weeks after injection for histological analysis (HE, immunochemical stain for vWF, alpha-sarcomeric-actin and fibronectin antibody). Cell differentiation was observed under transmission electronmicroscope. RESULTS: The number of small blood vessels was similar between BM-MNC group and EPC group (13.39 +/- 6.96/HP vs.12.39 +/- 4.72/HP, P < 0.05), but was significantly higher than that of control group (P < 0.05). Responsive intensity of immunochemical stain for fibronectin antibody was significantly lower in BM-MNC and EPC groups than that in control group. Responsive intensity of immunochemical stain for alpha-sarcomeric-actin antibody was similar among the three groups. Cluster cells were observed in one swine from BM-MNC group which might relate to the proliferation of stem cells in situ. Immature endothelial cells and myocytes were also detected by transmission electronmicroscope in BM-MNC and EPC group. CONCLUSION: BM-MNC and EPC transplanted into myocardial ischemia reperfusion injury region in swine stimulated the formation of blood vessels and inhibited fibrogenesis. PMID- 17711664 TI - [The effects of shRNA targeting angiotensin II type 1 receptor on blood pressure and AT1R mRNA expression in spontaneously hypertensive rats]. AB - OBJECTIVE: To investigate the effects of retroviral vector containing shRNA targeting rat angiotensin II type 1 receptor (AT1R) gene (Ad5-AT1R-shRNA) on blood pressure and AT1R mRNA expression in spontaneously hypertensive rats (SHR). METHODS: Retroviral vector containing shRNA targeting rat AT1R gene was constructed and propagated further in 293 cells. SHR rats were randomly divided into SHR + Ad5-AT1R-shRNA (1.7 x 10(9) TCID(50)/ml) group and SHR (Ad5-EGFP, 7.9 x 10(9) TCID(50)/ml, n = 11 each) and 11 male Wistar-Kyoto rats (WKY) serve as normal controls (Ad5-EGFP, 7.9 x 10(9) TCID(50)/ml). Systolic blood pressure was measured before and after single intravenous injection of Ad5-AT1R-shRNA or Ad5 EGFP. Heart, liver, kidney, aorta and adrenal gland were removed after blood pressure measurement. Tissue Ad5-AT1R-shRNA expression was detected with fluorescence microscope and AT1R mRNA in liver, kidney and aorta was measured by fluorescence quantitative PCR. RESULTS: Ad5-AT1R-shRNA significantly reduced blood pressure compared with controls (-29 mm Hg, 1 mm Hg = 0.133 kPa, P < 0.05) 24 hours after single injection and this antihypertensive effect could last for 5 to 7 days. Ad5-AT1R-shRNA expression detected with fluorescence microscope was significantly increased in heart, liver, kidney, aorta and adrenal gland post Ad5 AT1R-shRNA injection. AT1R mRNA in kidney and aorta (0.086 +/- 0.014, 0.051 +/- 0.023) were significantly decreased in Ad5-AT1R-shRNA treated rats compared with SHR control rats (0.362 +/- 0.042, 0.463 +/- 0.045, P < 0.01). CONCLUSION: The results indicate that Ad5-AT1R-shRNA could inhibit the tissue AT1R mRNA expression and produce prolonged antihypertensive effects in SHR rats. PMID- 17711665 TI - [Fluid shear stress upregulated endothelial nitric oxide synthase gene expression and nitric oxide formation in human endothelial progenitor cells]. AB - OBJECTIVE: To observe the effect of fluid shear stress on the eNOS gene expression and NO production in endothelial progenitor cells (EPCs). METHODS: The peripheral blood mononuclear cells from healthy volunteers were inducted into EPCs and divided into stationary group (0 dyn/cm(2), 1 dyn/cm(2) = 0.1 Pa), low flow shear stress group (5 dyn/cm(2)), medium-flow shear stress group (15 dyn/cm(2)) and high-flow shear stress group (25 dyn/cm(2)). The effects of shear stress on the endothelial nitric oxide synthase (eNOS) gene expression and nitric oxide (NO) production in human EPCs were measured. RESULTS: Typical "spindle shaped" appearance was shown in EPCs derived from peripheral blood mononuclear cells and were positively labeled by acetylated-LDL, lectin, FLK-1 and vWF. After 4 hours treatment with various shear stresses, the ratio of eNOS/beta-actin mRNA expression by human EPCs in low, medium and high-flow shear stress group was 0.364, 0.505 and 0.548 respectively, which was significantly higher than that in stationary group (0.183, all P < 0.05) and the NO secretion in human EPCs in low, medium and high-flow shear stress group was also significantly higher than that in stationary group (all P < 0.05). CONCLUSION: Fluid shear stress enhances the eNOS mRNA expression and NO secretion in human EPCs, therefore, shear stress could potentiate the repair efficacy of EPCs for endothelial injury. PMID- 17711670 TI - [Case in dual right coronary arteriography complicated by right atrium fistula]. PMID- 17711671 TI - [Re-occurred acute myocardial infarction caused by very late thrombosis 36 months after implantation of sirolimus eluting stent: a case report]. PMID- 17711672 TI - [Percutaneous coronary intervention for two acute myocardial infarction patients with isolated single coronary artery anomaly]. PMID- 17711673 TI - [The formation of aneurysm of apex after the occlusion of ventricular septal defect]. PMID- 17711674 TI - [Acute myocardial infarction due to infective endocarditis: a case report]. PMID- 17711675 TI - [Catheter ablation of anteroseptal accessory pathway in the non-coronary aortic sinus]. PMID- 17711676 TI - [Congestive heart failure complicated with hypothyroidism: five cases experience]. PMID- 17711677 TI - [Current research on the role of endothelial progenitor cell in acceleration of endothelialization and prevention of post-stenting restenosis]. PMID- 17711678 TI - [Arrhythmias and KCNE gene family encoding the potassium channels]. PMID- 17711680 TI - [Aimed at the current situation in China, to develop the guidelines for dyslipidemia and implement it into clinical practice]. PMID- 17711681 TI - [Actively explores the global cardiometabolic risk assessment]. PMID- 17711682 TI - [Chinese guidelines on prevention and treatment of dyslipidemia in adults]. PMID- 17711683 TI - [The second multi-center survey of dyslipidemia management in China: goal attainment rate and related factors]. AB - OBJECTIVE: To assess the current status in dyslipidemia management in China. METHODS: We recruited 2306 patients who received lipid-lowering drugs between January 1, 2004 and February 28, 2006, and maintained on the treatment for at least 2 months, from 21 provincial level hospitals and 6 prefecture and country level hospitals. The goal attainment rate was defined as the percentage of patients reaching cholesterol goals recommended by the updated Adult Treatment Panel III (ATPIII) of the National Cholesterol Education Program and the new Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults. RESULTS: (1) Among 2094 patients who met guidelines' criteria for initiating drug therapy, there were 80% patients treated in provincial level hospitals, 60% aged 60 years and above, 57% hyperlipidemia, 15% with normal lipids values, 68% coronary heart disease and other atherosclerotic diseases, 75% hypertensive, 80% high or very high risk patients, 84% statin-users and 83% referred to diet change. (2) According to ATPIII 2004, overall 34% patients attained the LDL-C goal. The goal attainment rates was 85%, 78%, 61%, 31% and 22% for patients at low risk, moderate, moderate high, high and very high risk respectively (P for trends < 0.001). According to the new Chinese guidelines, the goal attainment rate was 50% for overall patients and was 91%, 77%, 49% and 38% for patients at low risk, moderate, high and very high risk respectively (P for trend < 0.001). (3) The goal attainment rate was 51% for patients using combination therapy, 35% for those using statins, 23% for those using fibrates, 24% for those using niacin, 28% for those using other lipid-lowering medications (P < 0.001). (4) Among 1808 patients treated with statins, a multi-variable Logistic regression analysis showed that the dosage of statins (high vs. low dose, OR = 1.72, 95% CI: 1.15 - 2.58), risk of patients (very high vs. low risk, OR = 0.02, 95% CI: 0.01 - 0.03), baseline LDL-C [every 0.259 mmol/L (10 mg/dl) increase, OR = 0.83, 95% CI: 0.80 - 0.86] and sex (women vs. men, OR = 0.77, 95% CI: 0.60 - 0.99) were major factors that affected goal attainment. CONCLUSIONS: The characteristics of target patients taking lipid-lowering drugs have changed significantly in China and were used not only for lipid lowering but also for other purposes, which is well in accordance with current guidelines. However, current clinical management of dyslipidemia in China is still far behind the desirable goals derived both Chinese guidelines and the updated ATPIII guidelines, especially for high and very high risk patients. To further improve the clinical management of dyslipidemia, it is necessary to strengthen the choice of drugs and dosage, new drug development to allow better and safer combination therapy, intensive therapeutic lifestyle changes, patient health education, etc. PMID- 17711684 TI - [Cut offs and risk stratification of dyslipidemia in Chinese adults]. AB - OBJECTIVE: To establish cut offs and risk stratification of dyslipidemia in Chinese adults. METHODS: Data from 2 widely cited studies: the PRC-US Collaborative Study of Cardiovascular and Cardiopulmonary Epidemiology and the China Multi-Provincial Cardiovascular Cohort Study, with a total of 40 719 Chinese adults, age 35 to 64 at baseline, about half men and half women, followed up for a total of 345 140.5 person years, were used to analyze the relationship between dyslipidemia and ischemic cardiovascular diseases (ICVD, including coronary heart events and ischemic stroke events) using a common data analysis protocol co-developed by the scientists from the 2 studies. The relative risk was estimated with the Cox proportional hazard model adjusting for other conventional cardiovascular risk factors. The 10-year absolute risk of ICVD for a 50 years-old person at different risk factor combinations was used to develop the risk stratification. RESULTS: (1) There was a continuous linear relationship between baseline TC (or LDL-C) and ICVD risk without a threshold; (2) The incidence (absolute risk) of ICVD was similar for LDL-C < 3.37 mmol/L (130 mg/dl) and for TC < 5.18 mmol/L (200 mg/dl); and similar for LDL-C < 4.14 mmol/L (160 mg/dl) and for TC < 6.22 mmol/L (240 mg/dl); (3) The absolute ICVD risk for TC > or = 6.22 mmol/L (240 mg/dl) was slightly less but close to that for grade 1 hypertension; (4) ICVD risk increased as HDL-C decreased; (5) No significant association was found between baseline TG and subsequent ICVD; (6) At any TC level, the absolute ICVD risk for those having only hypertension was higher than that for those having 3 other risk factors. CONCLUSION: The cut offs for diagnosis of dyslipidemia in Chinese adults can refer to those used in relevant international guidelines: TC < 5.18 mmol/L (200 mg/dl) [or LDL-C < 3.37 mmol/L (130 mg/dl)] as normal, TC 5.18 - 6.19 mmol/L (200 - 239 mg/dl) [or LDL-C 3.37 - 4.12 mmol/L (130 - 159 mg/dl)] as borderline high, and TC > or = 6.22 mmol/L (240 mg/dl) [or LDL-C > or = 4.14 mmol/L (160 mg/dl)] as high; HDL-C < 1.04 mmol/L (40 mg/dl) as low, 1.04 - 1.53 mmol/L (40 - 59 mg/dl) as normal and > or = 1.55 mmol/L (60 mg/dl) as optimal. In risk stratification scheme, hypertension plays a role that equals to that of any other 3 risk factors. PMID- 17711686 TI - [Myocardial blush grade, ST-segment elevation resolution and prognosis in acute myocardial infarction patients with or without diabetes mellitus post primary percutaneous coronary intervention]. AB - OBJECTIVES: To investigated the prognosis of primary percutaneous coronary intervention (PCI) in acute myocardial infarction patients with or without diabetes mellitus (DM) in terms of myocardial blush grade (MBG) and ST-segment elevation resolution (STR). METHODS: MBG and STR were measured in AMI patients with (n = 95) and without (n = 192) diabetes mellitus after successful primary PCI. RESULTS: Post-procedural TIMI grade 3 flow (>95%) were similar between two groups. Compared to non-DM patients, DM patients were more likely to have absent myocardial perfusion (MBG 0/1, 56.0% vs. 41.1%, P = 0.019) and absent STR (43.2% vs. 30.7%, P = 0.038). MACE rate was also higher in DM patients than that in non DM patients during follow-up (27.4% vs. 16.1%, P = 0.025). Multivariate analysis showed DM was an independently factor related to the risk of poor prognosis (RR 1.83, 95% CI 1.04 - 3.36], P = 0.01). CONCLUSION: Despite similar TIMI-3 flow after primary PCI, DM patients are more likely to have abnormal myocardial perfusion as assessed by both incomplete STR and reduced MBG and poor prognosis compared to non-DM patients. Poor prognosis in DM patients with AMI post PCI might be related to more disturbed micro-vascular perfusion. PMID- 17711685 TI - [Serum lipid profile changes of the adults in Shanghai communities]. AB - OBJECTIVE: To explore the adult lipid profile of Huayang community from 1998 to 2000 and Caoyang communities in 2001. METHODS: Representative serum samples of 5628 adults (aged 20 - 95 years) were obtained in Huayang and Caoyang communities during 1998.9 and 2001.11. Standard epidemiology questionnaire, physical check ups and serum lipids data were analyzed. RESULTS: After standardization to Chinese census statistics of 2000, the age-and sex-standardized means of total cholesterol, HDL-C, LDL-C and triglycerides of the two communities (Huayang vs. Caoyang) were 5.01 mmol/L vs. 4.43 mmol/L, 1.28 mmol/L vs. 1.32 mmol/L, 3.37 mmol/L vs. 2.99 mmol/L, 1.97 mmol/L vs. 1.60 mmol/L respectively, and the age- and sex- standardized prevalence of dyslipidemia was 52.9% vs. 25.1%, and the prevalence for borderline dyslipidemia was 76.0% vs. 56.2%, respectively. The decreasing order of dyslipidemia prevalence of the two communities was: elevated TG, decreased HDL-C, elevated LDL-C and TC. The standardized proportions of optimal HDL-C level were only 15.7% and 16.1% in Huayang and Caoyang respectively which was much lower than these of TG, LDL and TC. CONCLUSIONS: The standardized prevalence of adult dyslipidemia and borderline dyslipidemia in the two communities were high. Dyslipidemia of the two communities was TG and decreased. PMID- 17711687 TI - [Prevalence of abnormal glucose regulation in patients with chronic ischemic heart failure]. AB - OBJECTIVE: To investigate the prevalence of diabetes mellitus (DM) and glucose abnormalities in patients with ischemic chronic heart failure (CHF). METHODS: A total of 1004 hospitalized eligible patients from 52 hospitals in 7 Chinese cities were included in this study. RESULTS: In this survey, 420 out of 1004 patients had DM history (41.8%), 175 patients were newly diagnosed as DM (17.4%), 208 patients (20.7%) had impaired glucose tolerance (IGT). NYHA grade increases in proportion to severity of abnormal glucose metabolism [(r(s)) = 0.17, P = 0.001]. After adjustment of age and other factors, logistic regression analyses showed risk of suffering severe CHF symptoms (NYHA III/IV) increases with the severity of abnormal glucose metabolism: OR, 1.2, 95% CI: 0.7 - 1.7 in patients with IGT; 1.4, 95% CI: 0.9 - 2.1 in the newly diagnosed DM patients and 1.7, 95% CI: 1.2 - 2.4 in the DM history group, respectively. CONCLUSIONS: High prevalence of abnormal glucose metabolism was observed in patients with chronic ischemic hear failure and the severity of abnormal glucose metabolism was closely related to NYHA symptom grade. PMID- 17711688 TI - [Coronary artery lesion comparison between Chinese and Australian patients with coronary artery disease]. AB - OBJECTIVE: To compare coronary lesion characteristics by coronary angiography (CAG) between yellows and whites. METHODS: CAG results of 3021 Chinese patients, defined as yellows, from Nanjing and 3230 Australian patients, defined as whites, from Sydney were analyzed. The coronary artery lesion was evaluated by the number and location of coronary lesion and Gensini scores. RESULTS: (1) Coronary stenosis was diagnosed in 69.4% Chinese patients and 75.5% in Australians. The involved coronary arteries were left anterior descending branch, right coronary artery, left circumflex branch and left main coronary artery in a descending order in both Chinese and Australians. (2) The incidences of three-vessel disease and left main disease of yellows were significantly lower than that of whites in both male (29.8% vs. 34.0% and 9.6% vs. 14.2%) and female patients (15.8% vs. 26.2% and 4.9% vs. 11.6%) respectively, all P < 0.05. (3) There was an age dependent Gensini scores increase in both yellows and whites patients and Gensini scores at age 40 and more of whites were significantly higher than those of yellows in comparable age groups. CONCLUSION: The incidences of three-vessel disease and left main disease as well as Gensini score were significantly higher in Australian patients than those of Chinese patients. PMID- 17711689 TI - [Comparison of plasma low-density lipoprotein and oxidized low-density lipoprotein levels with coronary lesion severities in patients with coronary artery disease]. AB - OBJECTIVE: To explore the relationship between plasma low-density lipoprotein (LDL) and oxidized low-density lipoprotein (ox-LDL) levels and the severity of coronary atherosclerosis. METHODS: Fasting plasma ox-LDL was measured by enzyme linked immunosorbent assay and plasma LDL was measured by biochemical autoanalyser in 31 patients with coronary artery spasm (CAS group, chest pain with positive acetylcholine provocation test but without significant coronary artery stenosis), 35 patients with stable angina pectoris (SAP group) and 24 healthy persons (control group). RESULTS: Plasma LDL levels were similar between CAS and SAP groups but significantly higher than that in control group. Plasma ox LDL levels significantly increased in proportion to coronary lesion severities [SAP (575 +/- 219 microg/L) > CAS (299 +/- 117 microg/L) > control (218 +/- 35 microg/L)]. In SAP group, plasma ox-LDL level was also significantly higher in multi-vessel disease group than that in single-vessel disease group (672 +/- 92 vs. 462 +/- 72 microg/L, P < 0.05). CONCLUSION: Plasma ox-LDL but not LDL level is significantly correlated to the severity of coronary atherosclerosis and should therefore be the focused therapy target in patients with coronary artery disease. PMID- 17711690 TI - [A survey of factors influencing prognosis and control rate for patients with hypertension in mainland China]. AB - OBJECTIVE: To observe the risk factor stratification and prevalence of target organ damage in hypertensive patients before therapy and blood pressure control rate after 4 or 12 weeks antihypertensive drug therapy. METHODS: In this prospective survey, data on cardiovascular risk factors, target organ damage and concomitant disease were collected in 26 655 hypertensive patients. Among them 26 325 and 3457 patients were recruited for antihypertensive drug therapy for 4 and 12 weeks, respectively and blood pressure control rate was determined. RESULTS: The sedentary lifestyle, smoking, high body mass index, dyslipidemia were found in 52.5%, 34.4%, 31.8%, 24.5%, and microproteinuria, left ventricular hypertrophy, coronary artery disease and diabetes in 21.0%, 23.6%, 20.1%, 26.7% hypertensive patients, respectively. The average systolic and diastolic pressures were 158 +/- 14 mm Hg and 94 +/- 11 mm Hg and 3.2%, 22.2%, 21.1% and 53.3% patients were defined as low, medium, high and very high risk patients in risk stratification to quantify prognosis. There were 77.2%, 20.4% and 2.4% systolic and diastolic, isolated systolic and isolated diastolic hypertensive patients respectively. The goal blood pressure control rate was 50.2% and 56.7% respectively after 4 and 12 weeks antihypertensive drug therapy. The control rate in patients complicated with diabetes and renal disease was significantly lower than patients without them and systolic pressure control rate was remarkably lower than diastolic pressure control rate. Majority patients required 2 or more antihypertensive drugs for effective pressure control (1.5 drug per patients in average in both 4 or 12 weeks groups). CONCLUSION: The prevalence of risk factors, target organ damage and concomitant disease were high in Chinese patients with hypertension and comprehensive interventions were indicated. To reach goal blood pressure control in patients with hypertension, follow up intensifying and drug therapy guidance are required within the context of usual medical care. PMID- 17711691 TI - [Diver CE versus Guardwire Plus for thrombectomy during primary angioplasty for inferior myocardial infarction]. AB - OBJECTIVE: In this randomized prospective single-center study, we compared the efficacy of adjunctive thrombectomy using Diver CE device (Linvatec, Italy) versus Guardwire Plus device (Medtronic, USA) before percutaneous coronary intervention (PCI) in patients with <12 h acute inferior myocardial infarction (AIMI) and Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 to 1. The primary end point was the magnitude of ST-segment resolution after PCI. METHODS: A total of 122 patients (61 in Diver CE group and 61 in Guardwire Plus group) were studied. The magnitude of ST-segment resolution, myocardial blush grade and slow flow or no re-flow 1 h after PCI were measured in study patients. RESULTS: Baseline characteristics were similar between groups: age (59.6 +/- 14 years vs. 60.1 +/- 13 years), males (82% vs. 84%), diabetes (31% vs. 28%), previous coronary artery disease (25% vs. 23%), onset-to-angiogram (350 +/- 185 min vs. 345 +/- 180 min), and glycoprotein IIb/IIIa inhibitor use (11% vs. 13%, all P > 0.05). The magnitude of ST-segment resolution was also similar in these two groups: ST-segment resolution > 70% (57% vs. 59%, P > 0.05). Slow flow/no reflow rate (8% vs. 7%), TIMI flow grade 3 (95% vs. 97%) and myocardial blush grade 3 (70% vs. 72%) post PCI were not different in the groups (all P > 0.05). Left ventricle ejection fraction (0.54 +/- 0.12 vs. 0.53 +/- 0.11), death (3% vs. 3%), re-myocardial infarction (2% vs. 0) and target vessel revascularization (2% vs. 2%) at one month post PCI were comparable (all P > 0.05). CONCLUSION: Efficacy of removing thrombus burden with Diver CE device or Guardwire Plus device was similar in patients with < 12 h acute inferior myocardial infarction. PMID- 17711692 TI - [Pulmonary hypertension caused by Sjogren's Syndrome: a case report]. PMID- 17711693 TI - [Effects of amiodarone on funny current I(f) channel gene expression in neonatal rat ventricular myocytes]. AB - OBJECTIVE: To analysis the effect of amiodarone on funny current (I(f)) and hyperpolarization-activated cation channel (HCN) gene expressions of the neonatal rat ventricular myocytes. METHODS: Ventricular myocytes of 1 - 3 days-old rats were isolated and cultured. The cardiomyocytes were treated by amiodarone (0.01, 0.1, 1, 10, 100 micromol/L) for 3 hours or amiodaron (10 micromol/L) for 0, 0.5, 1, 3, 6 hours. The I(f) and HCN 1 - 4 gene expressions were measured through the whole-cell configuration of the patch-clamp technique and real-time quantitative polymerase chain reaction (real-time PCR) using SYBR Green PCR kit. RESULTS: (1) HCN1, HCN2, HCN3 and HCN4 represented (0.23 +/- 0.01)%, (83.58 +/- 0.04)%, (0.79 +/- 0.01)% and (15.44 +/- 0.01)% of total HCN mRNA, respectively. (2) Amiodaron resulted in a dose-dependent I(f) [(3.1 +/- 0.9)%, (9.7 +/- 2.4)%, (36.7 +/- 5.8)%, (80.3 +/- 1.8)% and (85.9 +/- 3.1)%, respectively at -145 mV, IC(50) (1.32 +/- 0.28) micromol/L], HCN2 [(2.1 +/- 0.8)%, (8.9 +/- 3.6)%, (30.1 +/- 4.2)%, (78.3 +/- 3.6)% and (81.1 +/- 1.9)%, respectively] and HCN4 decrease [(0.5 +/- 0.2)%, (2.1 +/- 2.6)%, (8.8 +/- 3.2)%, (60.1 +/- 4.6)% and (59.6 +/- 6.5)%, respectively]. (3) Amiodaron (10 micromol/L) also induced a time-dependent I(f) [(1.1 +/- 0.1)%, (12.6 +/- 2.3)%, (80.6 +/- 2.2)% and (80.1 +/- 2.1)%, respectively], HCN2 [(1.0 +/- 0.1)%, (9.8 +/- 3.9)%, (82.9 +/- 4.6)% and (83.9 +/ 1.7)%, respectively] and HCN4 decrease [(0.1 +/- 0.1)%, (1.9 +/- 1.1)%, (59.4 +/ 7.8)% and (60.9 +/- 3.1)%, respectively]. However, HCN1 and HCN3 expressions were not affected by amiodaron treatment. CONCLUSION: Current density of I(f) and the expression of HCN2 and HCN4 were decreased by amiodaron which might be the possible antiarrhythmic working mechanisms of amiodaron. PMID- 17711694 TI - [Effects of aldosterone on inducible nitric oxide synthase/nitric oxide pathway in aortic adventitia]. AB - OBJECTIVE: To evaluate the effect and related mechanisms of aldosterone (ALD) on inducible nitric oxide synthase (iNOS) activity and nitric oxide (NO) production in aortic adventitia. METHODS: Aortic adventitias from SD rats were incubated for 6 hours with various protocols: buffer alone (control), ALD (10(-8) mol/L - 10( 6) mol/L), ALD + spironolactone (10(-5) mol/L, ALD + SP), ALD + RU486 (10(-5) mol/L), LPS 10 ng/ml (LPS), ALD + LPS (10 ng/ml), ALD + LPS + SP (10(-5) mol/L), and ALD + LPS + RU486. Nitrate/nitrite (NOx), an index of NO production, was measured by Greiss Reaction. iNOS activity was determined by isotope-labeled L arginine convertion rate. RESULTS: (1) NOx production and iNOS activity were similar between ALD and control groups (P > 0.05). NOx production was significantly reduced while iNOS activity remained unchanged in the ALD (10(-6) mol/L) + SP group compared to ALD (10(-6) mol/L) group. NOx production by 10(-7) mol/L and 10(-6) mol/L ALD increased by 50.0% and 58.7% respectively (P < 0.01) and iNOS activity was also significantly increased (P < 0.01) in ALD + RU486 group than that in ALD group. (2) LPS significantly increased the NOx production and iNOS activity (P < 0.01) and these effects were not augmented by adding ALD to LPS (P > 0.05) and SP significantly blocked and RU486 significantly enhanced the effects by LSP and ALD on NOx production and iNOS activity (P < 0.05). CONCLUSION: Aldosterone has a dual effect on iNOS/NO through mineralocorticoid receptor and glucocorticoid receptor pathway. PMID- 17711695 TI - [Effects of metoprolol on cardiac function and myocyte calcium regulatory protein expressions in rabbits with experimental heart failure]. AB - OBJECTIVE: To investigate the effects of metoprolol on cardiac function and myocyte calcium regulatory protein expressions in rabbits with heart failure. METHODS: Rabbit heart failure model was established by aortic insufficiency induced volume overload followed 14 days later by pressure overload induced by abdominal aorta constricting (HF, n = 11), another 8 rabbits with heart failure were treated with metoprolol (ME) for 6 weeks, sham-operated rabbits (n = 11) served as control. Cardiac function was measured by echocardiography at the end of study. Caffeine-induced calcium transients of myocytes loaded by Fluo-3/AM were observed under Laser scanning confocal microscope. Calcium regulatory protein expression was determined by Western blot analysis. RESULTS: Compared to control animals, the ejection fractions [EF, (45.7 +/- 3.0)% vs. (72. 6 +/- 5.0)%, P < 0.01] and the amplitude of caffeine-induced calcium transients [(16.0 +/- 3.5) FI vs. (43.5 +/- 6.2) FI, P < 0.01] were significantly decreased while its time to peak was significantly prolonged [(129.8 +/- 14.5) s vs. (52.2 +/- 7.4) s, P < 0.01] in HF rabbits. The RyR2 (0.106 +/- 0.007 vs. 0.203 +/- 0.021, P < 0.01) and the ratio of SERCA2a and NCX (1.22 +/- 0.23 vs. 1.96 +/- 0.12, P < 0.01) were also significantly reduced in myocytes of HF rabbits. Metoprolol significantly attenuated the decrease of EF [(60.2 +/- 5.1)%], the amplitude of calcium transient [(32.8 +/- 5.4) FI], the RyR2 expression (0.164 +/- 0.016) and the ratio of SERCA2a and NCX (1.68 +/- 0.17, all P < 0.05 vs. HF rabbits) and attenuated the increase of the time to peak of caffeine-induced calcium transients [(91.4 +/- 10.9) s, P < 0.05 vs. HF rabbits]. CONCLUSION: Metoprolol could improve the cardiac function possibly by preventing the alterations of calcium regulatory proteins and increasing calcium transients in failing heart. PMID- 17711696 TI - [Bone marrow derived endothelial cells promote healing of acute intimal injury in carotid arteries of rabbits]. AB - OBJECTIVE: To investigate the effect of bone marrow derived endothelial cells implantation on healing of acute injured intima. METHODS: Mononuclear cells derived from bone marrow were differentiated to endothelial cells. The cells were labeled with bromodeoxyuridine. Carotids injuring was induced by a balloon in 40 rabbits, endothelial cell suspension (2 x 10(6)/ml, n = 20) or PBS (2 ml, n = 20) was infused to injured arteries. The intima covered area was tested by Evan's Blue staining. The average intima thickness and media thickness were observed 7 and 14 days post procedure by histological assay. The immunofluorescent staining was performed for testing the BrdU labeled-cells, and these cells were detected under a fluorescent microscope. RESULTS: Intima covered area rate was significant higher (54.1% +/- 8.2% vs. 30.0% +/- 5.5% at day 7, and 81.8% +/- 6.0% vs. 63.6% +/- 8.4% at day 14, all P < 0.05) and the intima thickness and media thickness were significantly reduced in the endothelial cell suspension group. CONCLUSION: The bone marrow derived endothelial cell promoted healing post intima injury in this model compared to PBS group (all P < 0.05). PMID- 17711700 TI - [Urotensin II and atherosclerosis]. PMID- 17711702 TI - [Acute compartment syndrome in a patient after transradial access for percutaneous cardiac intervention]. PMID- 17711703 TI - [Bone marrow stem cell administration for acute myocardial infarction]. PMID- 17711705 TI - [Evaluation of myocardial viability with 201Tl/18F-FDG DISA-SPECT technique in patients with acute myocardial infarction after emergent intracoronary autologous bone marrow mononuclear cells transplantation]. AB - OBJECTIVE: To evaluate the myocardial viability with (201)Tl/(18)F-FDG DISA-SPECT technique in patients with acute myocardial infarction underwent emergent intracoronary autologous bone marrow mononuclear cells (BM-MNC) transplantation. METHODS: Patients with first acute myocardial infarction underwent emergent percutaneous coronary intervention (PCI) were randomized in a 1:1 ratio to either intracoronary transplantation of autologous BM-MNC (n = 20) or to sodium chloride concluding heparin (control, n = 20) via a micro infusion catheter group immediately after PCI. Change in global left ventricular function (LVEF measured by echocardiography) and the myocardial viability detected by (201)Tl/(18)F-FDG DISA-SPECT from baseline and 6-months post transplantation were analyzed. RESULTS: Left ventricular ejection fraction (LVEF) was improved in both groups and the absolute increase (DeltaLVEF) in BM-MNC group was significantly higher than that in control group (7.6% +/- 2.8% vs. 3.0% +/- 2.8%, P < 0.001). In addition, the absolute decrease of myocardial infusion defect detected by (201)Tl SPECT was more significant in BM-MNC group than that in control group (6.7% +/- 3.0% vs. 2.6% +/- 2.6%, P < 0.001) and the number of mismatched segments (indicating viable myocardium) detected by (18)F-FDG SPECT in border zone was also significantly higher in BM-MNC group than that in control group. CONCLUSION: Improved myocardial viability and reduced myocardial infusion defect post emergent intracoronary transplantation of autologous BM-MNC in patients with acute myocardial infarction could be detected by (201)Tl/(18)F-FDG DISA-SPECT technique. PMID- 17711707 TI - [Supravalvular aortic stenosis on 2 cases of mother and daughter]. PMID- 17711706 TI - [Effect of intracoronary adenovirus vector encoding hepatocyte growth factor gene on hematopoietic stem cells mobilization in patients with extensive coronary heart disease]. AB - OBJECTIVE: To investigate the effect of intracoronary adenovirus vector encoding hepatocyte growth factor gene (Ad(5)-HGF) on hematopoietic stem cells mobilization in patients with extensive coronary heart disease. METHODS: Patients with extensive coronary heart disease were treated with intracoronary infusion of adenovirus vector encoding hepatocyte growth factor (Ad(5)-HGF 5 x 10(9) pfu) gene plus stent implantation (n = 9) or equal physiological saline plus stent implantation (n = 9). Angioplasty and stent implantation was performed according to standard clinical practice by the femoral approach and blood samples were drawn from each patient at baseline before PCI, 6 to 24 hours and 6 days post procedure. The number of CD34(+), CD38(+) and CD117(+) cells in peripheral blood was analyzed by flow cytometer. RESULTS: The number of circulating CD34(+) cells in Ad(5)-HGF gene treatment group 6 hours after procedure and the number of circulating CD117(+) cells 6 days post procedure were significantly higher in Ad(5)-HGF gene treatment group than those in the control group (0.104 +/- 0.082 vs. 0.022 +/- 0.012, P = 0.021) and (0.058 +/- 0.058 vs. 0.012 +/- 0.009, P = 0.034), respectively. CONCLUSION: Intracoronary administration of Ad(5)-HGF could mobilize hematopoietic stem cells into peripheral blood and the consequent role of this observation on myocardial regeneration warrants further detailed studies. PMID- 17711708 TI - [Cardiac function changes post stem cell perfusion in isolated apolipoprotein-E gene deficiency murine heart]. AB - OBJECTIVE: This study assessed cardiac function changes post embryonic stem cells (ESCs) perfusion at different concentrations in the isolated apolipoprotein-E gene deficiency (apo E-/-) and wild type (WT) hearts. METHODS: apo E-/- and WT mice hearts were isolated and retrogradely perfused (Langendorff model) and ESCs were infused with different concentrations (Low dose group: 1.0 x 10(6) cells, high dose group: 2.5 x 10(6) cells). Hemodynamic parameters including coronary flow (CF), heart rate (HR), dp/dtmax, dp/dtmin, left ventricular end diastolic pressure (LVEDP), were recorded after stabilization period and at before, 5 min, 15 min and 30 min after cell perfusions. The number of cells in the transudate was counted. RESULTS: Cardiac function parameters were similar before cell perfusion in apo E-/- and WT hearts. Cardiac function was significantly impaired after low dose cell perfusion in apo E-/- hearts while remained unchanged in WT hearts with the exception of lowered HR. Cardiac function was also significantly impaired after high dose cell perfusion in both apo E-/- and WT hearts, especially in apo E-/- murine hearts. Most of the cells perfused into the heart were expelled after 30 min (63.2% - 77.0%). CONCLUSION: ESCs perfusion into an isolated heart, especially in the atherosclerosis-prone hearts, in the Langed off model impaired cardiac function in a concentration-dependent manner. PMID- 17711709 TI - [Ischemia-induced bone marrow-derived endothelial progenitor cells mobilization impairment in diabetic mice]. AB - OBJECTIVE: To determine whether ischemia-induced bone marrow-derived EPCs mobilization is impaired in diabetic mice and the association with vascular endothelial growth factor (VEGF) release post ischemia. METHODS: C57Bl/6 mice were injected with 40 mg x kg(-1) x d(-1) streptozotocin for 5 days to induce diabetes and mice with fasting glucose > 10 mmol/L were included to DM group, control mice were injected with placebo. Two months later, hindlimb ischemia was induced by left femoral artery dissection and ligation. The ischemia was visualized by tetrazolium dye staining and pre-mortem angiography. The percentage of c-Kit(+)/Sca-1(+)/flk-1(+) early EPCs in peripheral blood mononuclear cells (PBMCs) was detected by flow cytometric analysis on days 0 (pre-ligation), 1, 3, 5, 7 and 14 days post-ligation. The plasma VEGF level was measured with a standardized ELISA-Kit. RESULTS: Circulating EPCs number was significantly lower in diabetic mice than that in control mice (0.60% +/- 0.03% vs. 0.95% +/- 0.09%, P < 0.001) and the plasma VEGF was undetectable in all animals before ligation Similar EPCs kinetics following induction of hindlimb ischemia were shown in both groups. However, EPCs mobilization was significantly impaired in diabetic mice compared with control mice within 3 days post ischemia (day 1: 1.16% +/- 0.20% vs. 1.80% +/- 0.32%, P < 0.05; day 3: 1.38% +/- 0.34% vs. 2.37% +/- 0.52%, P < 0.05). In parallel, plasma VEGF increase post ischemia was significantly less in diabetic mice than that in control mice (day 1: 73.1 pg/ml +/- 18.6 pg/ml vs. 128.5 pg/ml +/- 44.2 pg/ml, P < 0.05). CONCLUSION: Our data suggest that ischemia induced bone marrow-derived EPCs mobilization is impaired in diabetic mice, which may be related to the insufficient release of plasma VEGF post ischemia. PMID- 17711710 TI - [Effects of intracoronary or intravenous tirofiban administration in patients with acute ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention]. AB - OBJECTIVE: To compare the effects on MACE of intracoronary or intravenous tirofiban bolus administration in patients with acute ST-elevation myocardial infarction (STEMI). METHODS: A total of 60 consecutive STEMI patients ready to receive primary PCI were randomly assigned to intracoronary tirofiban bolus (10 microg/kg) prior to the first balloon inflation (Group IC) or to intravenous tirofiban bolus at the same dose prior to coronary angiography (Group IV), followed by a 36-hours IV tirofiban (0.15 microg . kg(-1) . min(-1)) infusion for all patients. Clinical and angiographic features between 2 groups before and after PCI were analyzed. RESULTS: Fifty-four out of 60 STEMI patients accomplished the study. Group IC was superior to Group IV in terms of TIMI flow grade, TIMI myocardial perfusion grade, ST-segment resolution, the distal embolism of IRA immediately after PCI and ejection fraction at 5 - 7 days after the PCI. The in-hospital MACE rate and bleeding complications were similar between the groups while, the combined incidence of MACE during follow-up was significantly lower in the Group IC compared with Group IV (7.1% versus 30.8%; P = 0.02). CONCLUSION: Intracoronary bolus application of tirofiban is associated with superior clinical prognosis compared with the standard intravenous bolus application of tirofiban in patients with STEMI undergoing primary PCI. PMID- 17711711 TI - [Clinical and angiographic outcome in coronary artery disease patients with type II diabetes mellitus undergoing elective bare-metal stenting or drug-eluting stenting]. AB - OBJECTIVE: To compare the clinical and angiographic outcome in patients with type II diabetes mellitus undergoing drug-eluting stent (DES) or bare-metal stent (BMS). METHODS: A total of 139 consecutive diabetic patients (114 males) with coronary disease who underwent successful elective percutaneous coronary intervention with DES (n = 83 with 151 lesions) or BMS (n = 56 with 70 lesions) on native coronary arteries from April 2004 to August 2005 at our institution were included in this study. All patients were treated according to guidelines and coronary angiography was repeated at 6 months post procedure in all patients. Aspirin (300 mg/d) and clopidogrel (75 mg/d) were administered till 6 months after the procedure. RESULTS: There were 42.5% C type by ACC/AHA and 19.0% total occlusion lesions. The average stent length of each lesion was 26.53 +/- 14.72 mm, and mean reference diameter was 2.80 +/- 0.43 mm. Baseline characteristics were similar between DES and BMS groups except lower mean reference vessel diameter in DES than that of BMS group (2.71 +/- 0.41 mm vs. 2.98 +/- 0.53 mm, P < 0.001). The in stent restenosis rate at 6 months (10.6% vs. 38.6%, P < 0.001) and in-segment late loss (0.24 +/- 0.56 mm vs. 0.91 +/- 0.77 mm, P < 0.001) were significantly lower in DES group than those of BMS group. The target lesion revascularization (TLR) incidence was also significantly lower in DES group compared to BMS group (8.6% vs. 30.0%, P < 0.001). However, 4 late in-stent thrombosis were seen in DES group and none in BMS group of DES (P = 0.148). CONCLUSION: DES implantation in patients with diabetes mellitus is associated with lower in-stent restenosis and TLR rates compared to BMS implantation 6 months after procedure and attention should be paid on late in-stent thrombosis after DES implantation. PMID- 17711712 TI - [Serum high-sensitivity C-reactive protein level in patients with coronary heart disease complicating with or without metabolic syndrome]. AB - OBJECTIVE: To observe the relationship between serum high-sensitivity C-reactive protein (hs-CRP) level and coronary artery lesion in patients with coronary heart disease (CHD) complicating with or without metabolic syndrome. METHODS: CHD was confirmed in 170 out of 227 patients who were admitted into Peking union hospital because of chest pain by coronary artery angiography (CAG). Metabolic syndrome was diagnosed in 79 out of 170 CHD patients (MS group) and the relationship between serum hs-CRP level and coronary lesion was compared to CHD patients without metabolic syndrome (non-MS group). RESULTS: The number of CHD patients who had type B and C coronary stenosis and the serum level of hs-CRP was significantly higher in MS group than those in non-MS group, especially in patients with the serum level of hs-CRP > 3.5 mmol/L. CONCLUSION: For CHD patients complicating metabolic syndrome, hs-CRP is a reliable marker to predict the severity of coronary artery lesion. PMID- 17711713 TI - [The effects after withdrawal of simvastatin on brachial artery endothelial function in patient with coronary heart disease or risk factors]. AB - OBJECTIVE: Landmark trials have demonstrated that statins can reduce the risk of coronary events. Despite the widespread use of statins in the settings of primary and secondary prevention of CHD, withdrawal of statins is a frequent problem in clinical practice. Several recent clinical studies have suggested that withdrawal of statin therapy might be associated with an increase in thrombotic vascular events and the onset of acute coronary syndromes. However, the effects of discontinuing of statins treatment on endothelial function and underlying mechanism are unknown. Objectives We investigated the effects after withdrawal of simvastatin on brachial artery endothelial function in patients unreached cholesterol target with coronary heart disease (CHD) or CHD risk factors. METHODS: We included 33 patients with established CHD or CHD risk factors, whose serum cholesterol did not achieve NCEP target level. They were administered simvastatin (20 mg) for 4 weeks. Endothelial dependent flow-mediated vasodilation (FMD) was assessed in the brachial artery using high-resolution ultrasound at baseline, after 4 weeks of simvastatin and after termination of therapy 1 week. We evaluated fasting serum lipid profiles and vasoactive substances simultaneously, included nitric oxide (NO), endothelin (ET), 6-keto-PGF1(alpha) and thromboxane B(2) (TXB(2)), which were measured as plasma prostacyclin and TXA(2) respectively. RESULTS: Simvastatin treatment reduced low density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels and improved endothelial-dependent vasodilation in patients after 4 weeks. Withdrawal of simvastatin, however, FMD showed a significant reduction [(4.82 +/- 0.71)% vs (11.51 +/- 0.87)%, P < 0.01], that remained in low level after 1 week, and the FMD were even lower than the baseline values [(4.82 +/- 0.71)% vs (5.89 +/- 0.65)%, P < 0.01]. After terminating simvastatin treatment, serum NO and plasma 6 keto-PGF1(alpha) levels decreased, as well as plasma ET and serum LDL-C levels increased. But there was no significant difference between plasma TXB(2) levels before and after withdrawal of simvastatin (P > 0.05). Overall, there were significant positive correlations between withdrawal-induced changes in FMD and serum NO level (r = 0.674, P = 0.004), whereas no correlations were shown between the changes in FMD and serum LDL-C level (r = -0.414, P = 0.083). CONCLUSIONS: Abrupt withdrawal of simvastatin therapy resulted in the significant adverse impact on brachial artery endothelial function in patients unreached cholesterol target with CHD or CHD risk factors. Termination of therapy may suppress endothelial NO production and impair endothelial function that is independent of lipid-lowering effect. PMID- 17711715 TI - [Safety and efficacy comparison of myocardial contrast enhancement-guided and angio-pressure-guided transcoronary ablation of septal hypertrophy for patients with hypertrophic obstructive cardiomyopathy]. AB - OBJECTIVE: To compare the safety and efficacy of myocardial contrast enhancement (MCE)-guided and angio-pressure (AP)-guided transcoronary ablation of septal hypertrophy (TASH) for patients with hypertrophic obstructive cardiomyopathy (HOCM). METHODS: TASH was performed under MCE-guide (n = 47, group I) or AP-guide (n = 25, group II) for drug-refractory patients with HOCM. Myocardial perfusion imaging (MPI) data as well as other clinical data were compared. RESULTS: TASH both under MCE-guide or AP-guide resulted in similar and significant reduction of left ventricular outflow tract gradient (PG) and associated with significant symptom improvement (all P < 0.001). Dosage of ethanol use, peak-level of CK-MB and ablated myocardial area and incidence of arrhythmia were also similar between the two groups.Similar left ventricular/atrial dimension changes post TASH were observed in the 2 groups during follow-up. However, the first selected septal vessels were changed under MCE in 6 patients. CONCLUSIONS: Our data demonstrated that the MCE-guided TASH was not superior to AP-guided TASH in safety and efficacy. However, MCE-guided TASH can avoid the misplace of ethanol to avoid innocent myocardial ablation. PMID- 17711714 TI - [Association of the MspI polymorphism of cytochrome P4501A1 gene and smoking to the susceptibility to coronary artery disease]. AB - OBJECTIVE: To investigate the association of MspI polymorphism of Cytochrome P4501A1 (CYP1A1) gene and smoking to the susceptibility to coronary artery disease (CAD). METHODS: The genotypes of CYP1A1 MspI site were detected using the methods of polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) in 349 cases with CAD and 404 non-CAD as controls. CAD diagnosis was confirmed by coronary angiograms. Genetic risk of CYP1A1 genotypes was analyzed by smoking index (SI). RESULTS: The frequency of the predominant homozygotes TT, heterozygotes TC and the rare homozygotes CC in CAD group were not different with that of the controls (chi(2) = 3.224, P = 0.200). But in the smokers, the frequency of CC in CAD group was higher than that of non-CAD group (P = 0.002), while its odds ratio was 3.142 [95% confidence interval (CI) 1.481 - 6.668]. The odds ratio of genotype CC and heterozygote TC was 2.215 (95% CI 1.087 - 4.510) in the low dose cigarette smoking group, and was 1.407 (95% CI 0.709 - 2.791) in the high dose cigarette smoking group. CONCLUSION: Both MspI polymorphism of CYP1A1 gene and smoking exposure promote the development of CAD. PMID- 17711716 TI - [Prognostic value of ventricular longitudinal systolic velocities and maximal oxygen consumption in patients with dilated cardiomyopathy]. AB - OBJECTIVE: To compare the prognostic value of regional longitudinal ventricular systolic velocities with that of maximal oxygen consumption (VO(2max)) in patients with dilated cardiomyopathy (DCM). METHODS: VO(2max) derived from cardiopulmonary exercise tests and regional longitudinal ventricular systolic velocities obtained from tissue Doppler imaging were compared in 18 DCM patients with cardiac events (death, cardiac transplantation, hospitalization, group A) and 24 patients without cardiac events (group B). Peak velocities during isovolumic contraction (is) and ejection (ez) were interrogated at the mitral or tricuspid annulus (site 1), at the mid parts of the walls (site 3, at the level of papillary muscle), and at the midpoints (site 2) between sites 1 and 3 of interventricular septum (S), lateral wall of LV (L) and of RV (R) in apical 4 chambers view. RESULTS: R1is, R2is, R2ez, R3is, S1is, S1ez, S2ez, L1is, L1ez and L2ez of group A were significantly lower than those in group B (all P < 0.05). Independent of VO(2max), high sensitivity and specificity were shown for R3ez, S1ez, L1ez, L1is, L2is and L3is in predicting cardiac events of DCM patients. CONCLUSION: LV and RV systolic velocities could independently predict cardiac events in DCM patients. PMID- 17711717 TI - [Clinical characterization and outcome of patients with noncompaction of ventricular myocardium]. AB - OBJECTIVE: To analyze the clinical features and outcome of patients with noncompaction of ventricular myocardium (NVM). METHODS: Clinical manifestations, electrocardiograms and echocardiographies data were analyzed in 18 patients with NVM. Mean follow-up period was (11 +/- 5) months. RESULTS: The patients aged from 1.5 to 71 years, 66.7% patients were males, familial history was observed in 2 cases, congestive heart failure was present in 14 cases, thromboembolic event occurred in 1 patient, arrhythmia induced syncopes were diagnosed in 2 patients and 1 patient was asymptomatic. Abnormal electrocardiograms were observed in all patients, including premature ventricular beats (7 cases), heart block (4 cases), and atrial fibrillations (4 cases). Echocardiographies showed that noncompaction of ventricular myocardium localized in the left ventricle in 17 patients, and right ventricle in 1 patient. The extension of noncompaction myocardium was predominantly at the apex (72%). N/C was 2.3 - 3.1. EF was less than 50% in 15 patients. Hypokinetic movements were observed in both noncompacted and compacted segments. During the follow-up, 1 patient with congestive heart failure received heart transplantation. ICD was implanted in one patient due to ventricular tachycardia. One patient suffered from sudden cardiac death. CONCLUSIONS: The most common clinical presentations of NVM are congestive heart failure, cardiac arrhythmias, and thromboembolism. Echocardiography is considered as the best tool for the diagnosis of NVM. ICD, heart transplantation and anticoagulation therapy could improve the prognosis of patients with NVM in selected cases. PMID- 17711718 TI - [Same genotype and different phenotypes in a family with PRKAG2 gene mutation]. AB - OBJECTIVE: The gamma(2) subunit of AMP-activated protein kinase (PRKAG2) located in chromosome 7 plays an important role in regulating metabolic pathways, and patients with PRKAG2 mutations are associated with familial ventricular pre excitation, hypertrophic cardiomyopathy and AV block. We observed the difference on the phenotypes in a large family with same PRKAG2 mutation. METHOD: Direct DNA sequence was performed to screen the exons and exon-intron boundaries of PRKAG2 gene in a large family with 13 affected persons detected by electrocardiography (ECG). RESULTS: Sinus bradycardia, short PR interval, right bundle bunch block (RBBB), complete AV block, atrial flutter, atrial fibrillation and sudden cardiac death were identified in this family. Hypertrophic cardiomyopathy was found in one family member. Genetic analysis revealed a missense mutation (Arg302Glu) in all affected family members. This mutation was previous described in patients with Wolff-Parkinson-White (WPW) syndrome and hypertrophic cardiomyopathy. CONCLUSIONS: Besides WPW syndrome and hypertrophic cardiomyopathy, PRKAG2 mutations are responsible also for a diverse phenotypes. PRKAG2 gene mutation should be suspected with familial occurrence of RBBB, sinus bradycardia, and short PR interval. PMID- 17711719 TI - [Outcome of endovascular stent graft placement in patients with acute thoracic aortic syndromes]. AB - OBJECTIVE: To evaluate the outcome of endovascular stent graft placement in patients with acute thoracic aortic syndromes. METHODS: Emergency stent-graft implantations were performed in 57 patients with acute thoracic aortic syndromes from May 2001 to December 2005 (45 Stanford B aortic dissections, 9 acute penetrating aortic ulcers or pseudoaneurysms. 3 traumatic thoracic aneurysms). The clinical data, efficacy and follow-up results were analyzed. RESULTS: Procedures were successful in all patients. Type I endoleaks were evidenced in 5 patients and ascending aortic dissection occurred in 1 patient during operation, 5 patients with acute penetrating aortic ulcer complicating with coronary artery disease received successful PCI immediately post endovascular stent graft placement. Adynamia in extremities occurred in 1 patient and recovered two days later post anisodamine and mcnicol treatments. Left vertebral artery ischemia was found in 1 patient due to coated subclavian artery by stent-graft and the patient recovered spontaneously after two days lethargy without special treatment. The mean ICU time after surgery was 3.5 days (1 - 8 days) and the mean hospitalization time was 10 days. The mean follow-up time was 25.30 +/- 13.1 months (1 - 47 months). Two patients died within 30 days after operation, 1 patient died of rupture of the ascending aortic dissection (7 days post operation), 1 patient died of acute renal failure at the 2nd day post operation. One patient died of empsyxis 3 months after procedure, 1 patient died at the 4th month post procedure for unknown reason, 1 patient received second stent-graft implantation because of a newly formed endoleak at the proximal end of the stent graft, 5 patients received second stent-graft implantation because of newly formed leaks at the remote end of the stent-graft. No paraplegia or stent migration or stenosis was observed during the follow up period. Total mortality during hospitalization and follow-up was 7.0%. CONCLUSION: Patients with acute thoracic aortic syndrome could be effectively and safely treated by coated stent graft endovascular placement. PMID- 17711724 TI - [Effect of early and non-early controlled-release of arsenic-trioxide eluting stents on restenosis inhibition in a canine model]. AB - OBJECTIVE: To observe the safety and efficacy of early or non-early controlled release arsenic-trioxide (As(2)O(3))-eluting stents on reducing in-stent neointimal hyperplasia. METHODS: Bare stents, stents coated with polybutyl methacrylate/Nano silica (containing 200 microg of As(2)O(3) per stent or not), stents coated with polybutyl methacrylate/Nano silica inside (containing 200 microg of As(2)O(3) per stent or not) and poly-lactide-co-glycolide (PLGA) outside were deployed with mild oversizing in left anterior descending (LAD) and circumflex coronary arteries (LCX)of 30 canines (n = 6, 12 stents for each group). RESULTS: The mean injury scores were similar in all groups at 4 weeks post stents implantation while the mean neointimal thickness, neointimal area and degree of stenosis were significantly reduced and the lumen area significantly increased in canines receiving single coating stents containing As(2)O(3) compared with single or double coating stents and bare stents groups (all P < 0.01). These effects were further enhanced in canines implanted with double coating stents containing As(2)O(3) (all P < 0.01 vs. single coating stents containing As(2)O(3)). No intraintimal hemorrhage, medial and adventitial necrosis, aneurysm, thrombosis, inflammatory cells infiltration were observed in all stenting groups. CONCLUSIONS: Controlled-release As(2)O(3)-eluting stents resulted in a significant inhibition of neointimal hyperplasia in the canine coronary arteries 4 weeks after stents implantation and the effects is more significant with controlled-release of As(2)O(3) at non-early stage than that at early stage. PMID- 17711723 TI - [Effects of the total flavone of radix puerariae on apoptotic cell and apoptotic related-gene in atherosclerotic plaques of apoE gene deficiency mice]. AB - OBJECTIVE: To investigate the anti atherosclerosis effect and related mechanisms of total flavone of radix puerariae (TFRP) on atherosclerotic plaques in apoE gene deficiency (apoE-/-) mice. METHODS: apoE-/- mice were treated with saline, TFRP 15 mg . kg(-1). d(-1) or TFRP 85 mg . kg-1. d-1 (n = 8 each group) respectively per gavage for 12 weeks. The apoptotic cells in atherosclerotic plaques were then detected by TUNEL analysis, transmission electron microscope (TEM). The expression of CD-68, SMA and Caspase-3 were determined by immunochemical methods. RESULTS: Early macrophage apoptosis signs were observed under TEM, TUNEL-positive and CD-68 positive cells were found in lipid cores of atherosclerotic plaques. TFRP significantly reduced the number of apoptotic cells in a dose-dependent manner [(0.38 +/- 0.17)%, (1.95 +/- 1.02)%, (10.50 +/- 5.89)%, respectively, P < 0.01] in atherosclerotic plaques. TFRP treatment also significantly reduced the immune expression of Caspase-3 protein in a dose dependent manner. CONCLUSION: TFRP significantly attenuated the development of advanced atherosclerotic plaques in a dose-dependent manner which might related to down-regulated expression of Caspase-3 protein and reduced macrophage apoptotic cells in atherosclerotic plaques post TFRP treatment. PMID- 17711725 TI - [The effect of anthocyanins on cholesterol efflux from mouse peritoneal macrophage-derived foam cells and its possible molecular mechanism]. AB - OBJECTIVE: To investigate the potential role of anthocyanins on modulating cholesterol efflux in mouse peritoneal macrophage-derived foam cells and related molecular mechanisms. METHODS: The macrophages were isolated from pathogen-free NIH mice and were loaded with 50 microg/ml oxLDL for 24 hours, newly formed foam cells were then treated with anthocyanins (cyanidin-3-glucoside, Cy-3-g; or peonidin-3-glucoside, Pn-3-g) at the concentrations of 1 micromol/L, 10 micromol/L, 100 micromol/L for 0 to 36 hours, respectively. The enzymatic fluorescent method was used to determine cholesterol content in culture medium. ABCA1 expressions at mRNA and protein level were detected by real-time PCR and confocal microscope. RESULTS: Cholesterol efflux of macrophage-derived foam cells increased in a time- and dose-dependent manner post anthocyanins treatment. ABCA1 expressions at mRNA and protein levels were also significantly enhanced after anthocyanins treatment in these cells and these effects could be blocked by co treatment with DIDS, an inhibitor of the transport activities of ABCA1 and blocker of apoAI-mediated cholesterol efflux. CONCLUSION: These data demonstrate that anthocyanins induce cholesterol efflux from mouse peritoneal macrophage derived foam cells via regulating ABCA1 expression. PMID- 17711726 TI - [Genetic analysis of the familial noncompaction ventricular myocardium with sick sinus syndrome]. PMID- 17711727 TI - [Infective endocarditis after transcatheter closure of a ventricular septal defect]. PMID- 17711729 TI - [Trans-fatty acids and cardiovascular diseases]. PMID- 17711731 TI - Relatively light general anesthesia is more effective than fluid expansion in reducing the severity of epinephrine-induced hypotension during functional endoscopic sinus surgery. AB - BACKGROUND: Epinephrine infiltration of the nasal mucosa causes hypotension during functional endoscopic sinus surgery (FESS) under general anesthesia. A prospective randomized-controlled study was designed to determine whether relatively light general anesthesia is superior to fluid expansion in reducing epinephrine-induced hypotension during FESS. METHODS: Ninety patients undergoing elective FESS under general anesthesia were randomly assigned to three groups with 30 patients in each. Each patient received local infiltration with adrenaline-containing (5 microg/ml) lidocaine (1%, 4 ml) under different conditions. For Group I, anesthesia was maintained with propofol 2 microg/ml and rimifentanil 2 ng/ml by TCI. Group II (control group) and Group III received propofol 4 microg/ml and rimifentanil 4 ng/ml, respectively. In Groups I and II, fluid expansion was performed with hetastarch 5 ml/kg within 20 minutes; hetastarch 10 ml/kg was used in Group III. Mean arterial pressure (MAP) and heart rate (HR) were recorded at 30-second-intervals for 5 minutes after the beginning of local infiltration. Simultaneously, the lowest and the highest MAP were recorded to calculate the mean maximum increase or decrease percent in MAP for all patients in each group. Data analysis was performed by chi(2) test, one-way analysis of variance, or one-way analysis of covariance. RESULTS: Hemodynamic changes, particularly a decrease in MAP accompanied by an increase in HR at 1.5 minutes (P < 0.05), were observed in all groups. The mean maximum decrease in MAP below baseline was 14% in Group I, 24% in Group III and 26% in Group II. There were statistically significant differences between Group I and Groups II and III (P < 0.05). The mean maximum increase in MAP above baseline was 9% in Group I, 6% in Group III and 2% in Group II. CONCLUSION: Relatively light general anesthesia can reduce the severity of epinephrine-induced hypotension more effectively than fluid expansion during FESS under general anesthesia. PMID- 17711732 TI - Early diagnosis and treatment of acute or subacute spinal epidural hematoma. AB - BACKGROUND: Despite low morbidity, acute or subacute spinal epidural hematoma may develop quickly with a high tendency to paralysis. The delay of diagnosis and therapy often leads to serious consequences. In this study we evaluated the effects of a series of methods for the diagnosis and treatment of the hematoma in 11 patients seen in our hospital. METHODS: Of the 11 patients (8 males and 3 females), 2 had the hematoma involving cervical segments, 2 cervico-thoracic, 4 thoracic, 1 thoraco-lumbar, and 2 lumbar. Three patients had quadriplegia, including one with central cord syndrome; another had Brown-Sequard's syndrome; and the other seven had paraplegia. Five patients were diagnosed at our hospitals within 3 - 48 hours after appearance of symptoms, and 6 patients were transferred from community hospitals within 21 - 106 hours after development of symptoms. Key dermal points, key muscles and the rectal sphincter were determined according to the American Spinal Injury Society Impairment Scales as scale A in two patients, B in 5 and C in 4. Emergency MRI in each patient confirmed that the dura mater was compressed in the spinal canal, with equal intensity or hyperintensity on T(1) weighted image and mixed hyperintensity on T(2) weighted image. Preventive and curative measures were taken preoperatively and emergency operation was performed in all patients. Open laminoplasty was done at the cervical and cervico thoracic segments, laminectomy at the thoracic segments, laminectomy with pedicle screw fixation at the thoraco-lumbar and lumbar segments involving multiple levels, and double-sided laminectomy with the integrity of articular processes at the lumbar segments involving only a single level. During the operation, special attention was given to hematoma evacuation, hemostasis and drainage tube placement. RESULTS: Neither uncontrollable hemorrhage nor postoperative complications occurred. All patients were followed up for 1 - 6 years. A marked difference was noted between postoperative and preoperative scales (u = 3.66, P < 0.01). Most patients recovered after therapy, but the recovery of patients treated at our hospitals was superior to that of those transferred from community hospitals (t = 2.95, P < 0.05). Of the patients treated at our hospitals, 4 were cured and 1 was upgraded with scale from A to D, whereas none of those transferred from community hospitals recovered completely, even one remained scale C. CONCLUSIONS: Physical examination plus MRI is essential to early diagnosis of acute or subacute spinal epidural hematoma. Preventive and curative measures including emergency operation are helpful to the recovery of patients' nerve function. PMID- 17711734 TI - Associations of blood pressure and arterial compliance with occupational noise exposure in female workers of textile mill. AB - BACKGROUND: There are few studies on the arterial compliance of noise exposure. The purpose of this study was to understand the relationship between hearing loss, blood pressure and arterial compliance of female workers who exposed to occupational noise in a textile mill. METHODS: The noise levels in the workplace were measured with a HS6288 sound level meter. Cumulated noise exposure (CNE) was calculated according to the noise intensity and the exposure period. Hearing ability and arterial compliance were measured in 618 noise exposed workers. The database was set up with EpiData and the statistical analysis was performed with SAS software 9.1.3. RESULTS: The noise levels were 80.1dB (A) to 113.5dB (A), of which the levels at 92.5% of the noise monitoring sites were over the national standard. The incidence of high frequency hearing loss (HFHL) was 24.43% and language frequency hearing impairment (LFHI) was 0.81%. The incidence of hypertension was 7.93%. Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) in the high frequency hearing loss group were significantly higher than those in the normal hearing group (P < 0.05), while C(1) (large artery compliance) and C(2) (small artery compliance) were significantly lower (P < 0.05). The high frequency hearing threshold (HFHT) of the hypertension group was significantly higher than in the normal blood pressure group (P < 0.05), while C(1) and C(2) were significantly lower (P < 0.05). C(1) and C(2) had a negative correlation with HFHT, SBP, DBP, mean of arterial pressure (MAP), pulse pressure (PP) and pulse rate (PR) (P < 0.05). The multiple regression analyses showed that blood pressure and PR were the main influencing factors on C(1) and C(2). LFHT was an influence on C(2) and HFHT on C(1). CONCLUSIONS: Textile mill noise pollution is very serious and has an obvious influence on worker's auditory function. The female workers with low artery compliance or with high blood pressure might be suffering from hearing loss; those with noise induced hearing loss might be suffering from hypertension if she is constantly exposed to loud industrial noise. PMID- 17711736 TI - Molecular epidemic survey on co-prevalence of scrub typhus and marine typhus in Yuxi city, Yunnan province of China. AB - BACKGROUND: Human rickettsioses are worldwide zoonoses and it is not easy to differentiate them from other infectious diseases because of their atypical manifestation. In recent years the number of patients with fever of unknown causes from Hongta District CDC, Yuxi city of Yunnan Province has been increasing significantly in the summer. Diagnosis of scrub typhus was made by local clinicians. In order to ascertain the disease, we undertook a laboratory investigation for such patients from August 18 to 26, 2005. METHODS: Active surveillance was conducted by Hongta District CDC Yuxi city of Yunnan Province from 2002 to 2004 and basic data were obtained from cases confirmed according to clinical definitions. Average incidences and town-level incidences were calculated during the study periods. Blood samples were analyzed by PCR and serological test. Based on the groEL gene sequences a paired general outer primers (Gro-1 and Gro-2) targeting typhus, spotted fever as well as scrub typhus and two paired inner primers (SF1, SR2 and TF1, TR2) for typhus together with spotted fever and scrub typhus, respectively, were designed to perform a multiplex-nested PCR. Serological assay was carried out by indirect immunofluorescence assay with 7 different rickettsial antigens, i.e., R.mossori, R.sibirica, R.conorii, O.tsutsugamushi, B.quintana, B.henselae and Coxilella burnetii phase II Ag. RESULTS: Epidemiological surveillance showed that from 2002 to 2004, the average incidences of the scrub typhus or scrub typhus with murine typhus were 222.1/10(5), 204.3/10(5) and 109.6/10(5), respectively. Of 13 blood samples taken during acute stage of illness, 6 showed the amplified products for scrub typhus and the sequenced products showed 100%, 99%, 99%, 99%, 99%, 99% similarity to O.tsutsugamushi Karp but they shared the same deduced amino acid sequences, which indicated 100% identity with the heat shock protein of the O.tsutsugamushi Karp strain. Five yielded PCR products for murine typhus and their corresponding nucleotide sequences exhibited 100%, 100%, 99%, 99% and 99% similarity to R. mossori Wilmington and the analyses of predicted amino acid sequences indicated 100%, 100%, 98%, 98% and 98% identity with the heat shock protein of R. mossori Wilmington strain. Of the 8 PCR positive patients, 3 showed a co-infection of scrub typhus with murine typhus. All the 13 serum samples from febrile patients were positive against O. tsutsugamushi and 8 of them were positive against R. mossori. All of the 8 paired specimens had four-fold elevation of antibody against O. tsutsugamushi, and seroconversion for typhus was demonstrated in 3 paired serum samples. Another finding in the study was that a high seropositive prevalence (76.9%) of Q fever was detected. CONCLUSION: It's confirmed that co-prevalence of scrub typhus with murine typhus are occurring in Yuxi city of Yunnan province, China. Other rickettsial diseases also need to be investigated in these areas. PMID- 17711737 TI - A therapeutic anti-CD4 monoclonal antibody inhibits T cell receptor signal transduction in mouse autoimmune cardiomyopathy. AB - BACKGROUND: T cell immune abnormalities in patients with dilated cardiomyopathy (DCM) has been intensively studied over the past 10 years. Our previous study has suggested that immunization of mice with the peptides derived from human adenine nucleotide translocator (ANT) result in the production of autoantibodies against the ANT and histopathological changes similar to those in human DCM. The ANT peptides can induce autoimmune cardiomyopathy like DCM in Balb/c mice. In this study we aimed to focus on the molecular mechanism of T cells in the autoimmune cardiomyopathy mouse model by detecting the expression of the two T cell signaling molecules. METHODS: The ANT peptides were used to cause autoimmune cardiomyopathy in Balb/c mice. Anti-L3T4 or rat anti-mouse IgG was administered to the mice (n = 6 in each group) simultaneously immunized with ANT. ELISA analysis was used to detect autoantibodies against the ANT peptides and the percentages of interferon-gamma and interleukin-4 producing cells among splenic CD4(+) lymphocytes was determined by using flow cytometry analysis. The expression of CD45 in spleen T cells was determined by immunohistochemistry and the mRNAs of T cell signaling molecules were detected by real-time PCR. RESULTS: Treatment of ANT immunized Balb/c mice with anti-CD4 mAb caused a reduction in the gene expression of P56lck and Zap-70 and a lower level of CD45 expression by spleen T cells. Also, a reverse of the Th1/Th2 ratio that results in the reduced production of antibodies against ANT was found in the anti-CD4 monoclonal antibodies (mAb) group. Whereas irrelevant antibody (rat anti-mouse IgG) did not suppress T cell signaling molecules nor inhibit CD45 expression, and control antibody mice did not show any significant differences compared with the DCM group. CONCLUSION: The results show that anti-CD4 mAb is a powerful inhibitor of the early initiating events of T cell receptor (TCR) signal transduction in mouse autoimmune dilated cardiomyopathy. PMID- 17711738 TI - Screening of aplastic anaemia-related genes in bone marrow CD4+ T cells by suppressive subtractive hybridization. AB - BACKGROUND: CD4(+) T cells play a crucial role in the pathogenesis of aplastic anaemia. However, the mechanisms of over-proliferation, activation, infiltration of bone marrow and damage to haematopoietic cells of CD4(+) T cells in aplastic anaemia are unclear. Therefore, we screened differentially expressed genes of bone marrow CD4(+) T cells of aplastic anaemia patients and normal donors by suppressive subtractive hybridization to investigate the pathogenesis of aplastic anaemia. METHODS: The bone marrow mononuclear cells of a first visit aplastic anaemia patient and a healthy donor of the same age and sex were isolated using lymphocyte separating medium by density gradient centrifugation. With the patients as "tester" and donor as "driver", their CD4(+) T cells were separated with magnetic bead sorting and a cDNA library established by suppressive subtractive hybridization. Then 15 of the resulting subtracted cDNA clones were randomly selected for DNA sequencing and homological analysis. With semiquantitative RT-PCR, bone marrow samples from 20 patients with aplastic anaemia and 20 healthy donors assessed the expression levels of differentially expressed genes from SSH library. RESULTS: PCR detected 89 clones in the library containing an inserted fragment of 100 bp to 700 bp. Among 15 sequenced clones, 12 were known genes including 3 repeated genes. Compared with normal donors, there were 9/12 genes over-expressed in bone marrow CD4(+) T cells of patients with aplastic anaemia. The effects of these genes included protein synthesis, biology oxidation, signal transduction, proliferative regulation and cell migration. Not all these genes had been reported in the mechanisms of haematopoietic damage mediated by CD4(+) T cells in aplastic anaemia. CONCLUSIONS: Screening and cloning genes, which regulate functions of CD4(+) T cells, are helpful in elucidating the mechanisms of over proliferation, activation, infiltrating bone marrow and damaging haematopoietic cells of CD4(+) T cells in aplastic anaemia. PMID- 17711739 TI - Human vascular smooth muscle cells and endothelial cells cocultured on polyglycolic acid (70/30) scaffold in tissue engineered vascular graft. AB - BACKGROUND: Current prosthetic, small diameter vascular grafts showing poor long term patency rates have led to the pursuit of other biological materials. Biomaterials that successfully integrate into surrounding tissue should match not only the mechanical properties of tissues, but also topography. Polyglycolic acid (70/30) has been used as synthetic grafts to determine whether human vascular smooth muscle cells and endothelial cells attach, survive and secrete endothelin and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha). METHODS: Endothelial cells and smooth muscle cells were isolated from adult human great saphenous vein. They were seeded on polyglycolic acid scaffold in vitro separately to grow vascular patch (Groups A and B respectively) and cocultured in vitro to grow into vascular patch (Group C). Smooth muscle cells and endothelial cells were identified by immunohistochemical analysis and growth of cells on polyglycolic acid was investigated using scanning electron microscopy. The levels of endothelin and 6 keto-PGF1alpha in the culturing solutions were examined by radioimmunology to measure endothelial function. RESULTS: Seed smooth muscle cells adhered to polyglycolic acid scaffold and over 28 days grew in the interstices to form a uniform cell distribution throughout the scaffold. Then seed endothelial cells formed a complete endothelial layer on the smooth muscle cells. The levels of endothelin and 6-keto-prostaglandin F1 alpha in the culturing solution were (234 +/- 29) pg/ml and (428 +/- 98) pg/ml respectively in Group C and (196 +/- 30) pg/ml and (346 +/- 120) pg/ml in Group B; both significantly higher than in Groups A and D (blank control group, all P < 0.05). CONCLUSIONS: Cells could be grown successfully on polyglycolic acid and retain functions of secretion. Our next step is to use human saphenous vein smooth muscle cells and endothelial cells to grow tubular vascular grafts in vitro. PMID- 17711740 TI - Anti-tumor effects of polybutylcyanoacrylate nanoparticles of diallyl trisulfide on orthotopic transplantation tumor model of hepatocellular carcinoma in BALB/c nude mice. AB - BACKGROUND: Hepatocellular carcinoma (HCC) ranked the second among the causes of cancer mortality in China since the 1990s. Up to now, medication still plays an important role in the treatment of HCC. The therapies based on the allicin as a potential chemopreventive analog although is in its infancy at the present time, may have a significant role in the future management of HCC. Diallyl trisulfide (DATS) is a natural compound derived from garlic. In this study, we investigated the inhibitory effects of hepatic targeted polybutylcyanoacrylate nanoparticles of diallyl trisulfide (DATS-PBCA-NP) on orthotopic transplanted HepG2 hepatocellular carcinoma in nude mice. METHODS: DATS-PBCA-NP were detected by transmission electron microscope (TEM) and high-performance liquid chromatography (HPLC). The orthotopic transplantation HCC models were established by implanting HCC HepG2 xenograft bits under the envelope of the mice liver. Successful models (n = 29) were divided into 4 groups: normal saline (NS), empty nanoparticles (EN), DATS and DATS-PBCA-NP were intravenously administered to the mice respectively for 2 weeks. In vivo antitumor efficacy was evaluated by the measurement of tumor volume. Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay and protein levels of apoptosis and cell proliferation proteins by immunoblotting in tumor tissues were performed to elucidate the possible mechanism. RESULTS: DATS-PBCA-NP possessed smooth and round appearance, dispersed well, and released in vitro in accord with double phase kinetics model. DATS-PBCA-NP changed the tissue/organ distribution of DATS in vivo. The successful rate of tumor implantation was 100%. Intravenous administration of DATS-PBCA-NP significantly retarded the growth of orthotopically transplanted hepatoma in BALB/c nude mice (compared with the other three groups, all P < 0.05) without causing weight loss (P > 0.05). TUNEL staining showed that the tumors from DATS-PBCA-NP treated mice exhibited a markedly higher apoptotic index compared with control tumors. Western blot analysis of tumor tissue revealed that the down-regulated expression of proliferation cell nuclear antigen (PCNA) and Bcl-2 proteins in DATS-PBCA-NP group, and there were no significant differences in the expression of Fas, FasL and Bax proteins among the four groups (P > 0.05). CONCLUSIONS: DATS-PBCA-NP has good prolonged release effect in vivo and hepatic-targeted activity, and significant anti-tumor effect on the orthotopic transplantation HCC model in mice in association with the suppression of proliferation and the induction of apoptosis of tumor cells. These advantages are probably due to their liver targeting characteristics and consequently bring a higher anti-tumor activity. PMID- 17711741 TI - Hydrogen sulfide facilitates carotid sinus baroreceptor activity in anesthetized male rats. AB - BACKGROUND: It has been reported that hydrogen sulfide (H(2)S) could relax vascular smooth muscle by direct activation of K(ATP) channels and hyperpolarization of the membrane potential. Recently, our study has shown that H(2)S facilitated carotid baroreflex. This study was conducted to investigate the effect of H(2)S on carotid baroreceptor activity (CBA). METHODS: The functional curve of carotid baroreceptor (FCCB) was constructed and the functional parameters of carotid baroreceptor were measured by recording sinus nerve afferent discharge in anesthetized male rats with perfused isolated carotid sinus. RESULTS: H(2)S (derived from NaHS) 25, 50 and 100 micromol/L facilitated CBA, which shifted FCCB to the left and upward. There was a marked increase in peak slope (PS) and peak integral value of carotid sinus nerve charge (PIV) in a concentration-dependent manner. Pretreatment with glibenclamide (20 micromol/L), a K(ATP) channel blocker, the above effects of H(2)S on CBA were abolished. Pretreatment with Bay K8644 (an agonist of calcium channels, 500 nmol/L) eliminated the role of H(2)S on CBA. An inhibitor of cystathionine gamma-lyase (CSE), DL-propargylglycine (PPG, 200 micromol/L) inhibited CBA in male rats and shifted FCCB to the right and downward. CONCLUSIONS: Our results suggest that exogenous H(2)S exerts a facilitatory role on isolated CBA through opening K(ATP) channels and further closing the calcium channels in vascular smooth muscle. Endogenous H(2)S may activate CBA in vivo. PMID- 17711742 TI - hTERT-targeted E. coli purine nucleoside phosphorylase gene/6-methylpurine deoxyribose therapy for pancreatic cancer. AB - BACKGROUND: Pancreatic cancer is one of the most common tumors and has a 5-year survival for all stages of less than 5%. Most patients with pancreatic cancer are diagnosed at an advanced stage and therefore are not candidates for surgical resection. In recent years, investigation into alternative treatment strategies for this aggressive disease has led to advances in the field of gene therapy for pancreatic cancer. E. coli purine nucleoside phosphorylase/6-methylpurine deoxyribose (ePNP/MePdR) is a suicide gene/prodrug system where PNP enzyme cleaves nontoxic MePdR into cytotoxic membrane-permeable compounds 6-methylpurine (MeP) with high bystander activity. hTERT is expressed in cell lines and tissues for telomerase activity. In this study we examined the efficacy of ePNP under the control of hTERT promoter sequences and assessed the selective killing effects of the ePNP/prodrug MePdR system on pancreatic tumors. METHODS: Recombinant pET-PNP was established. The protein of E. coli PNPase was expressed and an antibody to E. coli PNPase was prepared. Transcriptional activities of hTERT promoter sequences were analyzed using a luciferase reporter gene. A recombinant phTERT ePNP vector was constructed. The ePNP/MePdR system affects SW1990 human pancreatic cancer cell lines in vitro. RESULTS: The hTERT promoter had high transcriptional activity and conferred specificity on cancer cell lines. The antibody to E. coli PNPase was demonstrated to be specific for the ePNP protein. The MePdR treatment induced a high in vitro cytotoxicity on the sole hTERT-ePNP producing cell lines and affected SW1990 cells in a dose-dependent manner. CONCLUSIONS: The hTERT promoter control of the ePNP/MePdR system can provide a beneficial anti-tumor treatment in pancreatic cancer cell lines including a good bystander killing effect. PMID- 17711743 TI - Lipopolysaccharide induces apoptosis of cytotrophoblasts by activating an innate immune reaction in vitro. AB - BACKGROUND: Enhanced apoptosis of cytotrophoblasts in early pregnancy is associated with high risk of intrauterine growth retardation and preeclampsia, which are two common pregnant complications. Its etiological factors remain unclear. Cytotrophoblasts share some traits with innate immune cells and may show response to lipopolysaccharide. This study was conducted to demonstrate whether lipopolysaccharide has apoptosis-inducing effects on cytotrophoblast and the role of innate immune reaction in this process. METHODS: Cytotrophoblasts were isolated from early pregnant villous tissues and cultured with serum-free medium. Subsequently, cytotrophoblasts were treated with lipopolysaccharide at the concentrations of 0 (control), 25, 50, 100 and 200 ng/ml for 24 hours. Apoptosis of cytotrophoblasts was determined by light microscopy, Hoechst 33258 DNA staining with a fluorescent microscope, transmission electron microscope and annexin V-fluorescein isothiocyanate-conjugated/propidium iodide (PI) staining with flow cytometry. Then expression of caspase-3 was detected by Western blot. Confocal immunofluorescence technique was used to detect tumor necrosis factor alpha expression in cytotrophoblasts. The levels of tumor necrosis factor alpha in the culture medium were detected by enzyme-linked immunosorbent assay. RESULTS: Under light, fluorescence microscope and transmission electron microscope, characteristic alternations of apoptosis in cytotrophoblasts were observed after lipopolysaccharide treatment. Flow cytometry results showed that lipopolysaccharide significantly increased apoptosis indexes of cytotrophoblasts. Significant statistical differences were found in the above groups (P = 0.01). The mean relative densities of bands corresponding to caspase-3 were significantly increased in groups treated with lipopolysaccharide, as compared with the normal control (P < 0.001). Tumor necrosis factor a expression was found to increase in cytotrophoblasts by confocal immunofluorescence technique and in culture medium by enzyme-linked immunosorbent assay after lipopolysaccharide treatment. A positive correlation was found between tumor necrosis factor a expression and apoptosis indexes of cytotrophoblasts (r = 0.747, P < 0.001). CONCLUSION: Apoptosis of cytotrophoblasts could be induced by lipopolysaccharide, in which innate immune reaction is the important mechanism. PMID- 17711745 TI - Application of occluders in endovascular repair of aortic aneurysms. PMID- 17711744 TI - Transmission models of tuberculosis in heterogeneous population. AB - OBJECTIVE: To review the transmission models of tuberculosis in heterogeneous population. DATA SOURCES: The data used in this review were adopted mainly from the studies of models of tuberculosis reported from 1995 to 2006. STUDY SELECTION: Relevant literature on transmission models of tuberculosis in heterogeneous populations are referenced. RESULTS: Casual/random factors and genetic factors are the main reasons for epidemics of tuberculosis in recent years. Mass public transport is playing the primary role in casually close contact which can facilitate the transmission of tuberculosis. Genetic susceptibility not only varies endemic prevalence levels, but also drastically alters the effects of treatment for tuberculosis patients. Detailed studies further exhibit that casual contact and genetic factor are responsible for over 30% - 40% of the total new cases in recent years. The prevalence of tuberculosis could double (from 33% to 60%) if a genetically susceptible phenotype is present in only 30% of the population. And some challenges have emerged along with these exciting results. CONCLUSIONS: Casual/random contact, public transport and genetic susceptibility are responsible for most new tuberculosis cases and a wide variation in endemic tuberculosis levels between regions. Hence, the transmission model of tuberculosis in a heterogeneous population can provide more clues to underlying mechanism of tuberculosis transmission than in a homogeneous population. However, many challenges remain for us in understanding transmission of disease. PMID- 17711746 TI - Idiopathic membranous nephropathy complicated with malignant hypertension: a case report. PMID- 17711747 TI - Facemask therapy with miniplate implant anchorage in a patient with maxillary hypoplasia. PMID- 17711748 TI - Liver transplantation in a patient with situs inversus: a case report. PMID- 17711749 TI - An unusual presentation of tuberculosis in pregnancy. PMID- 17711751 TI - Terminal ileum perforation: a rare complication of intestinal endometriosis. PMID- 17711752 TI - Neurilemmoma of a seminal vesicle. PMID- 17711753 TI - Schwannoma of the lateral nasal wall: two case reports and review of the literature. PMID- 17711754 TI - Endoscopic surgical treatment of pleomorphic adenoma of the inferior nasal turbinate. PMID- 17711755 TI - Ewing's sarcoma/primitive neuroectodermal tumour of the mandible: report of a rare case and review of the literature. PMID- 17711756 TI - Giant neonatal cervical teratoma associated with facial clefts--a rare association. PMID- 17711757 TI - Cacosmia secondary to an olfactory groove meningioma. PMID- 17711758 TI - Recurrent inflammatory myofibroblastic tumour of the larynx: a clinicopathologic diagnostic dilemma. PMID- 17711759 TI - Successful multimodal treatment of a carcinosarcoma of the masticator space. PMID- 17711760 TI - Triple ossicular fixation and semicircular canal malformations. PMID- 17711761 TI - Contamination of post-endoscopic sinus surgery sinus cavities with Pasteurella multocida. PMID- 17711762 TI - Unusual congenital laryngeal web in an 11-year-old child. PMID- 17711763 TI - Infectious causes of bilateral facial nerve palsy. PMID- 17711764 TI - Spontaneous resolution of a traumatic laryngocele. PMID- 17711765 TI - Malignant peripheral nerve sheath tumour of the paranasal sinus. PMID- 17711767 TI - Non-nutritive swallowing and respiration coordination among states of alertness in adult sheep. AB - Swallowing is a powerful inhibitor of respiration. Its coordination with respiration is therefore crucial to avoid aspiration and apnea. The aim of this study was to determine the coordination between non-nutritive swallowing (NNS) and phases of the respiratory cycle, including the assessment of the effect of states of alertness in adult sheep. Six animals were surgically instrumented under general anesthesia to record electroencephalography, electro-oculography (state of alertness), diaphragmatic electromyography (EMG), nasal flow (respiration), esophageal EMG, and the thyroarytenoid muscle (NNS). Our results revealed that (1) the highest NNS frequency is observed in rapid eye movement (REM) sleep, especially for bursts of NNS; (2) while NNS begins mainly during inspiration in all states of alertness, REM sleep, however, is responsible for an increase in the proportion of NNS beginning in expiration; (3) the link between inspiration and NNS is not affected by rumination. In conclusion, the link between NNS and inspiration in adult sheep is similar to that of lambs but contrary to previous reports on NNS induced by water in humans. Whether these differences are related to interspecies differences or the experimental techniques clearly needs further studies on spontaneous NNS in humans. PMID- 17711768 TI - Randomized control trial of fluorescence-guided surgical excision of nonmelanotic cutaneous malignancies. AB - OBJECTIVE: Protoporphyrin IX (PpIX) is an endogenous photosensitizer commonly used in photodynamic therapy. This study sought to assess if PpIX fluorescence can be applied clinically to improve the delineation and excision of nonmelanotic cutaneous malignancies. DESIGN: Prospective, randomized control trial. SETTING: A tertiary care skin cancer clinic. METHODS: Fifty-one individuals with 65 cutaneous nonmelanotic cervicofacial malignancies were randomized into two groups. The control group was offered surgical excision with surgeon-delineated excision margins. The study group had their excision margins delineated while under fluorescence. MAIN OUTCOME MEASURES: The delineated lesion borders, proposed excision margins, and projected lesion-free areas were compared among the two groups. Pathologic resection margins and completeness of excision were also assessed. RESULTS: Excisions performed using fluorescence delineation were 20% narrower (p < .01) and 17% shorter (p < .04), with 35% less lesion-free skin excised (p < .005). All lesions excised using photodelineation had clear pathologic resection margins. A significant number of lesions excised via the traditional approach required reexcision owing to pathologically positive peripheral margins (p < .001). Follow-up at 2 years revealed no lesion recurrence among the study group and one recurrence within the control group. CONCLUSION AND SIGNIFICANCE: The results demonstrate a reliable and novel application for photodynamic photodelination and support its application in the excision of nonmelanotic cutaneous malignancies. PMID- 17711770 TI - Tonsillectomy and biopsy for asymptomatic asymmetric tonsillar enlargement: are we right? AB - OBJECTIVE: The aim of this study was to evaluate the incidence of malignancy in patients with clinically asymmetrical tonsils and who are otherwise asymptomatic. DESIGN: Retrospective review of our experience based on case note review, carried out in a district general hospital setting during a period of two years. MATERIAL AND METHODS: 142 patients who had undergone tonsillectomy and biosy were included in the study. Histological studies of all these patients obtained and correlated with the clinical findings. RESULTS: None of the patients with asymmetric enlargement of tonsils but are otherwise asymptomatic had shown histological evidence of malignancy. However all the 3 patients with associated suspicious symptoms in the presence of asymmetric tonsils were diagnosed as having tonsillar malignancy. CONCLUSION: Tonsillar asymmetry in the absence of other associated risk factors may not indicate malignancy and a period of watchful waiting is considered appropriate prior to any surgical intervention. PMID- 17711769 TI - Return to home, school, and sports after electrosurgical adenoidectomy: when is it safe? AB - OBJECTIVE: To determine when it is safe for healthy children to return to home, school, and sports after uncomplicated electrosurgical adenoidectomy (EA). DESIGN: (1) A survey of Canadian otolaryngologists (COs) regarding their EA complication rates and their opinions regarding best practice standards for patient care after EA. (2) Informal retrospective analysis of approximately 200 children who have been allowed to resume sports 3 days after uncomplicated EA. RESULTS: (1) Thirteen COs responded to the survey. The total estimated EA cases performed were 8617 over 10 years. Four patients were known to have bled mildly; none required reoperation. Eleven of 13 COs supported discharge home 2 hours after uncomplicated EA if other standard discharge criteria were met. Seven of 13 COs supported a return to school the next day if the child had returned to his or her usual state of health; however, 2 COs suggested 7 to 10 days at home. Four of 13 COs supported a return to sports 3 days after uncomplicated EA. (2) None of the 200 children who had been allowed to resume sports 3 days after uncomplicated EA have had any known bleeding. At least 10 toddlers have actually engaged in unplanned strenuous exercise within 4 to 6 hours of EA without adverse effect. CONCLUSIONS: Considerable variation exists in Canada in terms of current practice standards regarding return to home, school, and sports after uncomplicated EA. Survey data suggest that, after uncomplicated EA, it is safe for healthy children to return home after 2 hours and to school the next day. Preliminary data suggest that it may be safe for children to resume sports 3 days after uncomplicated EA; however, ideally, this should be studied prospectively, on a large scale. PMID- 17711771 TI - Endoscopic dacryocystorhinostomy with a T-type ventilation tube. AB - BACKGROUND: The aim of this article is to present a different endoscopic dacryocystorhinostomy technique and its results on patients with blockage of the nasolacrimal drainage system. METHODS: Eleven patients (seven female and four male) who had chronic epiphora with the diagnosis of chronic nasolacrimal duct blockage were operated on using T-type ventilation tubes. Oral antibiotics, nasal steroids, oral antihistamines, and antibiotic eyedrops were given to all cases. The ventilation tubes were removed 3 months after surgery. RESULTS: Of 11 cases, 9 patients had unilateral and 2 patients had bilateral blockage. Eleven sides of nine patients were symptom free (85% success rate), and two patients had decreased continuation in complaints. Granulation tissue occurred in two revision patients. CONCLUSION: Endoscopic dacryocystorhinostomy using a T-type ventilation tube is an easy and cost-effective alternative and has low complication rates in the management of patients with nasolacrimal duct obstruction. PMID- 17711772 TI - Significance and mechanism of microsatellite instability in laryngeal squamous cell carcinoma. AB - OBJECTIVE: To evaluate the significance and mechanism of microsatellite instability (MSI) in laryngeal squamous cell carcinoma (LSCC). METHODS: We investigated the expression frequency and clinical significance of MSI in 50 LSCC patients. The status of MSI was evaluated by using microdissection, polymerase chain reaction, single-strand length polymorphism, and silver staining. Five markers on chromosomes 1p, 3p, 5q, 9p, and 17p were used. Two of the six components of mismatch repair (MMR)-hMLH1 and hMSH2-were investigated by an immunohistochemical approach. RESULTS: The informative case numbers of the five markers (D17S796, D3S3544, D5S656, D1S375, D9S162) were 44, 42, 45, 44, and 40 in all 50 cases, respectively. The incidence of MSI on D17S796 (TP53) was 20.5% (9 of 44), on D3S3544 (FHIT) was 14.3% (6 of 42), on D5S656 (APC) was 31.1% (14 of 45), on D1S375 (BCAR3) was 20.5% (9 of 44), and on D9S162 (CDKN2A) was 15.0% (6 of 40). Although there was no relationship between MSI status and age, gender, smoking history, tumour location, tumour differentiation, and T stage (p > .05), there was a strong relationship between MSI and relapse condition (p < .01). Also, MSI status correlated with MMR expression to some degree (p < .01). But it was common that negative and positive staining of MMR coexisted on the same slide. CONCLUSION: MSI and abnormal MMR may contribute to the carcinogenesis of a subset of LSCC. MSI may be a characteristic signal of tumour recurrence. PMID- 17711773 TI - Rounding of the inferior rectus muscle as an indication of orbital floor fracture with periorbital disruption. AB - OBJECTIVE: To determine if rounding of the inferior rectus muscle on coronal computed tomographic (CT) scans predicts disruption of the periorbita in orbital floor fractures and therefore predicts delayed enophthalmos. DESIGN: Cadaveric study with CT scan analysis. SETTING: Cadaveric laboratory and CT scanner at a tertiary care hospital in London, Ontario. METHODS: Each orbit of each cadaveric head was randomly assigned to have either intact or disrupted periorbita. Progressively larger orbital floor fractures were made and CT scans were taken before fractures and after each fracture to assess the shape of the inferior rectus muscle. Measurements were made of the length of the long and short axis of the inferior rectus muscle using CT analysis software. The short to long axis ratio was then compared. MAIN OUTCOME MEASURES: Change in the short to long axis ratio of the inferior rectus muscle and correlation of the ratio with intact and disrupted periorbita. RESULTS: Orbital floor fractures measuring 1 x 1 cm show an increase in the short to long axis ratio (rounding) of the inferior rectus muscle only if the periorbita is disrupted. Orbital floor fractures measuring 2 x 2 cm show rounding of the inferior rectus muscle regardless of whether the periorbita is intact or disrupted; however, the degree of rounding is greater if the periorbita is disrupted. CONCLUSIONS: For small orbital floor fractures, rounding of the inferior rectus muscle predicts periorbital disruption. This may therefore represent an indication for early surgical repair to prevent delayed enophthalmos. PMID- 17711774 TI - Risk of damage to hearing from personal listening devices in young adults. AB - OBJECTIVE: To investigate the effects of personal listening device use on hearing in young listeners. METHODS: Conventional frequency audiometry (0.5-8 kHz) and extended high-frequency audiometry (10-20 kHz) were performed on 120 personal listening device users and 30 normal-hearing young adults. RESULTS: The hearing thresholds in the 3 to 8 kHz frequency range were significantly increased in the personal listening device listeners. The frequency range of the increased thresholds became broad as the exposure duration was increased. Impaired hearing was detected in 14.1% (34 of 240 ears) of ears (> 25 dB HL in one or more frequencies in 0.5-8 kHz). The hearing thresholds of extended high-frequency audiometry in personal listening device users could also be increased even if their hearing thresholds in conventional frequency audiometry were normal. CONCLUSION: Our results suggest that long-term use of personal listening devices can impair hearing function The data also indicate that extended high-frequency audiometry is a sensitive method for early detection of noise-induced hearing loss. PMID- 17711775 TI - Clavipectoral osteomyocutaneous free flap in oromandibular reconstruction. AB - INTRODUCTION: Mandibular reconstruction continues to challenge most head and neck reconstructive surgeons despite the tremendous advances in surgical and fixation techniques. We recently described the clavipectoral osteocutaneous flap for mandibular reconstruction. This flap encompasses the clavicle and the clavicular head of the pectoralis major with overlying skin. OBJECTIVES: The purpose of this article is to report our prospective clinical experience with the use of clavipectoral osteocutaneous flap in the reconstruction of oromandibular defects. STUDY DESIGN: Prospective case series. METHODS: Five patients with significant mandibular defects underwent reconstruction using the newly described clavipectoral flap. All patients had shoulder range of motion testing preoperatively and at 3 and 6 months postoperatively. Panorex and bone scans were obtained on the seventh postoperative day. RESULTS: All five flaps survived. The transferred clavicles demonstrated good vascularity on the postoperative bone scans. The shoulder morbidity was minimal, with all patients resuming their preoperative level of activity. CONCLUSIONS: The clavipectoral flap has bone and soft tissue components that are especially suited for composite mandibular defects, but it should be used as a second-line flap owing to the short pedicle and the regular need for vein grafts. PMID- 17711776 TI - To "EE" or not to "EE". AB - OBJECTIVE: To assess whether /i:/ ("ee") is the best sound to use during indirect laryngoscopy to produce the optimal view of the larynx. DESIGN: Prospective study. SETTING: District general hospital otolaryngology outpatient clinic. PATIENTS: Eighty-seven patients from a general otolaryngology clinic with no laryngeal or pharyngeal symptoms or pathology. MAIN OUTCOME MEASURES: The views obtained during indirect laryngoscopy and vocalization of /i:/ ("ee"), /ei/ ("ay"), /[see text]/ ("err"), /a:/ ("ah"), and /ea/ ("air") were graded according to a laryngoscopy grading system. RESULTS: The greatest number of adequate views of the larynx was achieved by using the sounds /i:/ and /[see text]/. There was no significant difference between /i:/ and /[see text]/ (p = .740), but there were significant differences between /i:/ and /ei/ (p = .019), /i:/ and /a:/ (p = .00000), and /i:/ and /ea/ (p = .00013). CONCLUSION: For the optimal view of the larynx during indirect laryngoscopy, we recommend the use of the sounds /i:/ ("ee") and /[see text]/ ("err"). PMID- 17711777 TI - Oxygen sensitivity of reporter genes: implications for preclinical imaging of tumor hypoxia. AB - Reporter gene techniques have been applied toward studying the physiologic phenomena associated with tumor hypoxia, a negative prognostic indicator. The purpose of this study was to assess the potential adverse effects of hypoxic conditions on the effectiveness of four commonly used reporter genes: Renilla luciferase, monomeric red fluorescent protein, thymidine kinase, and lacZ. Tumor forming A375 cells expressing a trifusion reporter consisting of Renilla luciferase, monomeric red fluorescent protein, and thymidine kinase were subjected to decreasing oxygen tensions and assayed for reporter expression and activity. A375 cells expressing beta-galactosidase were similarly exposed to hypoxia, with activity of the reporter monitored by cleavage of the fluorescent substrate 7-hydroxy-9H-(1,3-dichloro-9,9-dimethylacridin-2-one)-beta-galactoside (DDAOG). Generation of signal in in vivo tumor models expressing bioluminescent or beta-galactosidase reporters were also examined over the course of hypoxic stresses, either by tumor clamping or the antivascular agent 5,6 dimethylxanthenone-4-acetic acid (DMXAA). Our findings indicate that bioluminescent and fluorescent reporter activity are decreased under hypoxia despite minimal variations in protein production, whereas beta-galactosidase reporter activity per unit protein was unchanged. These results demonstrate that combining beta-galactosidase with the DDAOG optical probe may be a robust reporter system for the in vivo study of tumor hypoxia. PMID- 17711778 TI - Fluorescence lifetime imaging system for in vivo studies. AB - In this article, a fluorescence lifetime imaging system for small animals is presented. Data were collected by scanning a region of interest with a measurement head, a linear fiber array with fixed separations between a single source fiber and several detection fibers. The goal was to localize tumors and monitor their progression using specific fluorescent markers. We chose a near infrared contrast agent, Alexa Fluor 750 (Invitrogen Corp., Carlsbad, CA). Preliminary results show that the fluorescence lifetime for this dye was sensitive to the immediate environment of the fluorophore (in particular, pH), making it a promising candidate for reporting physiologic changes around a fluorophore. To quantify the intrinsic lifetime of deeply embedded fluorophores, we performed phantom experiments to investigate the contribution of photon migration effects on observed lifetime by calculating the fluorescence intensity decay time. A previously proposed theoretical model of migration, based on random walk theory, is also substantiated by new experimental data. The developed experimental system has been used for in vivo mouse imaging with Alexa Fluor 750 contrast agent conjugated to tumor-specific antibodies (trastuzumab [Herceptin]). Three-dimensional mapping of the fluorescence lifetime indicates lower lifetime values in superficial breast cancer tumors in mice. PMID- 17711779 TI - In vivo resolution of multiexponential decays of multiple near-infrared molecular probes by fluorescence lifetime-gated whole-body time-resolved diffuse optical imaging. AB - The biodistribution of two near-infrared fluorescent agents was assessed in vivo by time-resolved diffuse optical imaging. Bacteriochlorophyll a (BC) and cypate glysine-arginine-aspartic acid-serine-proline-lysine-OH (Cyp-GRD) were administered separately or combined to mice with subcutaneous xenografts of human breast adenocarcinoma and slow-release estradiol pellets for improved tumor growth. The same excitation (780 nm) and emission (830 nm) wavelengths were used to image the distinct fluorescence lifetime distribution of the fluorescent molecular probes in the mouse cancer model. Fluorescence intensity and lifetime maps were reconstructed after raster-scanning whole-body regions of interest by time-correlated single-photon counting. Each captured temporal point-spread function (TPSF) was deconvolved using both a single and a multiexponental decay model to best determine the measured fluorescence lifetimes. The relative signal from each fluorophore was estimated for any region of interest included in the scanned area. Deconvolution of the individual TPSFs from whole-body fluorescence intensity scans provided corresponding lifetime images for comparing individual component biodistribution. In vivo fluorescence lifetimes were determined to be 0.8 ns (Cyp-GRD) and 2 ns (BC). This study demonstrates that the relative biodistribution of individual fluorophores with similar spectral characteristics can be compartmentalized by using the time-domain fluorescence lifetime gating method. PMID- 17711780 TI - Imaging collagen in intact viable healthy and atherosclerotic arteries using fluorescently labeled CNA35 and two-photon laser scanning microscopy. AB - We evaluated CNA35 as a collagen marker in healthy and atherosclerotic arteries of mice after both ex vivo and in vivo administration and as a molecular imaging agent for the detection of atherosclerosis. CNA35 conjugated with fluorescent Oregon Green 488 (CNA35/OG488) was administered ex vivo to mounted viable muscular (uterine), elastic (carotid), and atherosclerotic (carotid) arteries and fresh arterial rings. Two-photon microscopy was used for imaging. CNA35/OG488 labeling in healthy elastic arteries was compared with collagen type I, III, and IV antibody labeling in histologic sections. For in vivo labeling experiments, CNA35/OG488 was injected intravenously in C57BL6/J and apolipoprotein E(-/-) mice. Ex vivo CNA35/OG488 strongly labeled collagen in the tunica adventitia, media, and intima of muscular arteries. In healthy elastic arteries, tunica adventitia was strongly labeled, but labeling in tunica media and intima was prevented by endothelium and elastic laminae. Histology confirmed the affinity of CNA35 for type I, III, and IV collagen in arteries. Strong CNA35/OG488 labeling was found in atherosclerotic plaques. In vivo applied CNA35/OG488 minimally labeled the tunica intima of healthy carotid arteries. Atherosclerotic plaques in apolipoprotein E(-/-) mice exhibited large uptake. CNA35/OG488 imaging in organs revealed endothelium as a limiting barrier for in vivo uptake. CNA35/OG488 is a good molecular imaging agent for atherosclerosis. PMID- 17711782 TI - Improved in vivo whole-animal detection limits of green fluorescent protein expressing tumor lines by spectral fluorescence imaging. AB - Green fluorescent protein (GFP) has been used for cell tracking and imaging gene expression in superficial or surgically exposed structures. However, in vivo murine imaging is often limited by several factors, including scatter and attenuation with depth and overlapping autofluorescence. The autofluorescence signals have spectral profiles that are markedly different from the GFP emission spectral profile. The use of spectral imaging allows separation and quantitation of these contributions to the total fluorescence signal seen in vivo by weighting known pure component profiles. Separation of relative GFP and autofluorescence signals is not readily possible using epifluorescent continuous-wave single excitation and emission bandpass imaging (EFI). To evaluate detection thresholds using these two methods, nude mice were subcutaneously injected with a series of GFP-expressing cells. For EFI, optimized excitation and emission bandpass filters were used. Owing to the ability to separate autofluorescence contributions from the emission signal using spectral imaging compared with the mixed contributions of GFP and autofluorescence in the emission signal recorded by the EFI system, we achieved a 300-fold improvement in the cellular detection limit. The detection limit was 3 x 10(3) cells for spectral imaging versus 1 x 10(6) cells for EFI. Despite contributions to image stacks from autofluorescence, a 100-fold dynamic range of cell number in the same image was readily visualized. Finally, spectral imaging was able to separate signal interference of red fluorescent protein from GFP images and vice versa. These findings demonstrate the utility of the approach in detecting low levels of multiple fluorescent markers for whole-animal in vivo applications. PMID- 17711781 TI - Cardiac micro-computed tomography for morphological and functional phenotyping of muscle LIM protein null mice. AB - The purpose of this study was to investigate the use of micro-computed tomography (micro-CT) for morphological and functional phenotyping of muscle LIM protein (MLP) null mice and to compare micro-CT with M-mode echocardiography. MLP null mice and controls were imaged using both micro-CT and M-mode echocardiography. For micro-CT, we used a custom-built scanner. Following a single intravenous injection of a blood pool contrast agent (Fenestra VC, ART Advanced Research Technologies, Saint-Laurent, QC) and using a cardiorespiratory gating, we acquired eight phases of the cardiac cycle (every 15 ms) and reconstructed three dimensional data sets with 94-micron isotropic resolution. Wall thickness and volumetric measurements of the left ventricle were performed, and cardiac function was estimated. Micro-CT and M-mode echocardiography showed both morphological and functional aspects that separate MLP null mice from controls. End-diastolic and -systolic volumes were increased significantly three- and fivefold, respectively, in the MLP null mice versus controls. Ejection fraction was reduced by an average of 32% in MLP null mice. The data analysis shows that two imaging modalities provided different results partly owing to the difference in anesthesia regimens. Other sources of errors for micro-CT are also analyzed. Micro-CT can provide the four-dimensional data (three-dimensional isotropic volumes over time) required for morphological and functional phenotyping in mice. PMID- 17711783 TI - Targeting and cellular trafficking of magnetic nanoparticles for prostate cancer imaging. AB - Antibody-conjugated iron oxide nanoparticles offer a specific and sensitive tool to enhance magnetic resonance (MR) images of both local and metastatic cancer. Prostate-specific membrane antigen (PSMA) is predominantly expressed on the neovasculature of solid tumors and on the surface of prostate cells, with enhanced expression following androgen deprivation therapy. Biotinylated anti PSMA antibody was conjugated to streptavidin-labeled iron oxide nanoparticles and used in MR imaging and confocal laser scanning microscopic imaging studies using LNCaP prostate cancer cells. Labeled iron oxide nanoparticles are internalized by receptor-mediated endocytosis, which involves the formation of clathrin-coated vesicles. Endocytosed particles are not targeted to the Golgi apparatus for recycling but instead accumulate within lysosomes. In T(1)-weighted MR images, the signal enhancement owing to the magnetic particles was greater for cells with magnetic particles bound to the cell surface than for cells that internalized the particles. However, the location of the particles (surface vs internal) did not significantly alter their effect on T(2)-weighted images. Our findings indicate that targeting prostate cancer cells using PSMA offers a specific and sensitive technique for enhancing MR images. PMID- 17711784 TI - An alternative solution to our shortage of nurses, physicians, pharmacists, and other health care providers? PMID- 17711785 TI - Are statins safe? PMID- 17711786 TI - Understanding the new Medicare enrollment rules: obtaining and maintaining active Medicare enrollment. PMID- 17711787 TI - Understanding defining characteristics of assisted living. PMID- 17711788 TI - Beliefs about physical activity--focus group results of Chinese community elderly in Seattle and Taipei. AB - The purpose of this study was to identify the beliefs about physical activity held by Chinese immigrant older adults in Seattle and to compare them with the beliefs held by Chinese elderly in Taipei. Researchers conducted 2 focus groups of Chinese older adults to explore their behavioral beliefs, normative beliefs, and perceived control beliefs. The first group included 10 elderly recruited from the Chinese Information and Service Center in Seattle, Washington. The second group included 14 elderly adults recruited from a health center in Taipei, Taiwan. This study used a qualitative study design, and deductive content analysis was used for analyzing information gathered. The results showed that Chinese immigrant older adults in Seattle had positive attitudes toward physical activity and that, compared with the group in Taipei, the group in Seattle perceived more positive social and environmental supports. The factors influencing Chinese older adults' physical activity and behaviors both in Seattle and in Taipei are discussed. PMID- 17711789 TI - A study of Family Councils in nursing homes. AB - Families can remain actively involved in the care of their residents by participating in a Family Council within the nursing home (NH). A Family Council is an independent, self-determining group of NH residents' families and friends and often includes a nursing facility liaison. PROBLEM: Less than half of NHs has an active council. PURPOSE: To determine the presence, characteristics, and impact of Family Councils. METHOD: A descriptive study was conducted. Mailed surveys to NH administrators and personal interviews of Family Council members were included in this study. The survey was mailed to administrators in all 60 licensed NHs in a metropolitan county in the southwestern United States. RESULTS: Sixteen NH administrators responded, with 12 (75%) of the 16 reporting the presence of an active Family Council. Three administrators provided the name of a member of their facility's Family Council who were interviewed by telephone. Both the survey and personal interview results supported the positive effect of active Family Councils to provide mutual support, empower its members, and advocate change to improve the residents' quality of life. PMID- 17711790 TI - Assessment and treatment of sleep disorders in the older adult. PMID- 17711791 TI - Heterologous expression and characterization of the recombinant bradykinin B2 receptor using the methylotrophic yeast Pichia pastoris. AB - The human bradykinin subtype 2 receptor (B(2)R), a member of class A GPCRs, was heterologously expressed in the methylotrophic yeast Pichia pastoris. The recombinant receptor was produced as a fusion protein with affinity tags and it was expressed at a level of 3.5 pmol/mg of total membrane protein. [(3)H]Bradykinin binding analysis revealed that the recombinant receptor binds to its endogenous ligand bradykinin with high affinity (K(d)=0.87+/-0.1 nM), similar to the native receptor. Enzymatic deglycosylation revealed that the recombinant B(2)R was produced in a glycosylated form. Immunogold staining of the Pichia cells expressing B(2)R suggested that the recombinant receptor was localized intracellularly and it was not present in the plasma membrane. The data presented here should facilitate isolation of the recombinant receptor for structural studies. PMID- 17711792 TI - Brainstem excitability is increased in subjects with palmomental reflex. AB - BACKGROUND/PURPOSE: The palmomental reflex (PMR) is a brief contraction of the mentalis muscles caused by a scratch over the thenar eminence, i.e. a brainstem reflex to afferents of upper limb. Using electrophysiologic methods, we studied the characteristics of brainstem excitability in PMR subjects. METHODS: Ten healthy PMR subjects were included in the study. Brainstem excitability was assessed with electrical stimulation at the trigeminal nerve, median nerve, ulnar nerve, and sural nerve with recordings at the mentalis muscles. A comparison was made by the probability between the mechanical scratch and the electrical stimulation to evoke the visible muscle contraction of mentalis. RESULTS: An electrical stimulus was able to elicit mentalis muscle responses (MMR(electrical)) in all the subjects if the stimulus was of sufficient strength. Using electrical stimulation, the median nerve at the wrist was the best site to evoke MMR(electrical). However, in PMR subjects, the probability of MMR(electrical) to median nerve stimulation was less than that of MMR(scratch), i.e. the clinical findings of PMR. Significantly lower thresholds and higher amplitudes were noted in PMR subjects only when the median nerve was stimulated. The onset latency did not show any difference between the two groups despite the stimulation sites. CONCLUSION: The facial motor neurons to median nerve stimulation are more sensitive in PMR subjects. In healthy PMR subjects, this indicates that the excitability increases only in the specific neuronal circuits between the lower cervical spinal cord and the facial motor nucleus in the rostral medulla. MMR(electrical) is a physiologic phenomenon, and PMR is a sign of increased brainstem excitability. PMID- 17711793 TI - Revision in reference ranges of peripheral total leukocyte count and differential leukocyte percentages based on a normal serum C-reactive protein level. AB - BACKGROUND/PURPOSE: A higher total leukocyte count is a predictor of all-cause mortality and cardiovascular morbidity. The currently used reference range for peripheral total leukocyte count is wide (4.5-11.0 x 10(9)/L) and is associated with a low sensitivity in identifying non-infectious chronic diseases. We attempt to revise it based on a normal serum C-reactive protein (CRP) level. METHODS: Study subjects were participants in a health check program at our hospital between 2000 and 2002. Those whose leukocyte analysis had been checked with the Sysmex Cell Counter NE-9000 were enrolled. RESULTS: Significantly positive relationships between CRP level and total leukocyte count, neutrophil percentage, and monocyte percentage were found in all subjects (n = 14,114; p < 0.0001). In contrast, CRP level had a significantly inverse correlation with lymphocyte percentage (p < 0.0001). A proposed new reference range for total leukocyte count was estimated based on the data in the normal CRP level group (CRP < 0.1 mg/dL; n = 4839). To rest on the essence of statistics that the range of [mean +/- 2 standard deviations] contains approximately the middle 95% of observations in a sampled population, a new reference range for total leukocyte count was accordingly estimated to be 3.11-8.83 x 10(9)/L. CONCLUSION: In view of the abundant evidence showing that a higher peripheral total leukocyte count is harmful to health, a down-correction of its upper reference range from the currently used 11.0 x 10(9)/L to the proposed 8.83 x 10(9)/L, based on a normal CRP level, should allow more abnormal health conditions to be identified and promote the usefulness of peripheral leukocyte analysis. PMID- 17711794 TI - Computer simulation of hemodynamic changes after right lobectomy in a liver with intrahepatic portal vein aneurysm. AB - BACKGROUND/PURPOSE: Intrahepatic portal vein aneurysm is rare and its natural history is unknown. A 22-year-old healthy man, who wished to donate part of his liver to his diseased father, was incidentally diagnosed to have an intrahepatic portal vein aneurysm. The surgical decision of performing live donor hepatectomy for such a patient is normally difficult. We combined modern imaging reconstruction technologies with scientific computing as a new modality to foresee the risks of surgical complications. METHODS: Cross-sectional computed tomography images were used to reconstruct the three-dimensional image of portal vein distribution using the 3D-Doctor v3.5 software. The reconstructed images were further employed to generate surface and interior meshes with CFX software. Simulated hemodynamic changes in velocity, pressure, and wall stress were determined for the right lobectomy case pre- and postoperatively. RESULTS: The simulation results indicated that aneurismal pressure would be elevated significantly to 12.03 mmHg after operation. The left segmental portal venous blood flow would increase from 2.95- to 4.25-fold. The area near the branch point of one left segmental portal vein, which supplies blood to liver segment 4, and the portal vein aneurysm would endure high shear stress gradient. The resulting elevated aneurismal pressure may cause the thin wall to enlarge and rupture, while the high shear stress gradient would lead to vascular endothelial cell injury. Living donor surgery was not recommended hemodynamically based on the simulated results. CONCLUSION: Scientific computing and modern imaging technologies can be applied together to aid surgeons to make the best decision in difficult clinical situations. PMID- 17711795 TI - Usefulness of drug eluting stent in percutaneous coronary intervention--a single center experience in Taiwan. AB - BACKGROUND/PURPOSE: Drug eluting stents (DES) have been shown to reduce in-stent restenosis rate and target vessel revascularization in large clinical trials. However, the safety and efficacy of DES use in the Taiwanese population has not been reported. We designed this trial to analyze the clinical results in patients using DES in a single tertiary center. METHODS: We retrospectively analyzed the clinical data of all patients treated at National Taiwan University Hospital, Taipei, Taiwan, with sirolimus- or paclitaxel-eluting stents between September 2003 and January 2005. RESULTS: A total of 585 patients (466 men, 119 women; mean age, 64.5 +/- 11.2 years) were enrolled. Meanwhile, 205 sirolimus- and 717 paclitaxel-eluting stents were implanted, with a mean of 1.6 stents per patient. Half (50.2%) of the stents were placed in the left anterior descending artery. Among the enrolled patients, 41.8% had diabetes mellitus, 25% had a diagnosis of acute coronary syndrome, and 10.7% was treated with primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Overall 8-month target vessel revascularization, major adverse cardiac event rate, and cardiac death rate were 8.8%, 9.7% and 2.5%, respectively. There was no difference in clinical events between sirolimus- and paclitaxel-eluting stents. The overall subacute stent thrombosis rate was 1.36%, significantly lower than that in patients who presented with acute coronary syndrome (4%). CONCLUSION: The use of DES in the Taiwanese population yielded comparable results as those in large clinical trials. Subacute stent thrombosis rate was higher in acute coronary syndrome. The safety of DES in these situations should be further clarified. PMID- 17711796 TI - Cost-effectiveness of highly active antiretroviral therapy for HIV infection in Taiwan. AB - BACKGROUND/PURPOSE: Since the late 1980s, the Taiwanese government has provided all HIV-infected citizens with free access to antiretroviral therapy. Recently, there is controversy as to whether or not free access to expensive highly active antiretroviral therapy (HAART) should be continued for HIV-infected patients. This study aimed to evaluate the cost-effectiveness of HAART therapy. METHODS: HAART-associated improvement in survival was obtained by analyzing the follow-up data of all HIV-positive patients identified during April 1984 to March 1997 (pre HAART era) and May 1997 to April 2003 (HAART era) in Taiwan. Data on quality of life in HIV-positive patients was obtained from a cross-sectional survey of 224 patients using standard gamble method and World Health Organization Quality of Life-BREF instrument. Information regarding the cost of HAART was obtained from the National Health Insurance (NHI). RESULTS: In 2000, the average annual NHI expenditure on HAART per HIV-positive patient receiving HAART was NT$210,018 (US$6177, at an exchange rate of 34.0 NT$/US$). In the AIDS group, the cost was NT$176,441 (US$5189) per life year gained and NT$241,700 (US$7109) per quality adjusted life year gained. For non-AIDS patients, the corresponding costs were NT$226,156 (US$6652) and NT$332,582 (US$9782), respectively. These estimates have not yet included the additional cost savings from HAART-associated reduction in hospitalization and use of antimicrobial agents for opportunistic infections, and the additional life years gained from the reduction in HIV transmission under the universal availability of HAART. CONCLUSION: HAART for HIV infection is cost effective, especially when the societal and epidemiologic factors are considered. We recommend that the policy of providing free HAART to all HIV-infected citizens be continued. PMID- 17711797 TI - Predictors of therapeutic response to beta-blockers in patients with heart failure in Taiwan. AB - BACKGROUND/PURPOSE: Chinese are more sensitive to beta-blockers than Caucasians. However, data regarding beta-blocker therapy in heart failure (HF) patients in Taiwan are lacking. We aimed to evaluate the improvement of left ventricular function and the potential predictors of response to beta-blocker therapy in Taiwanese HF patients. METHODS: We enrolled 34 HF patients with baseline left ventricular ejection fraction (LVEF) 0.05) or hemodynamic profiles. CONCLUSION: DEX (10 mg, IV) 5 minutes prior to fentanyl injection reduces the incidence of FIC and can be an ideal premedicant for general anesthesia induction. PMID- 17711799 TI - Prognosis of Taiwanese patients with isolated optic neuritis after intravenous methylprednisolone pulse therapy. AB - BACKGROUND/PURPOSE: To evaluate the clinical manifestations, prognosis, recurrence rate and development of multiple sclerosis between papillitis group and retrobulbar group in Taiwanese patients with isolated acute optic neuritis (AON) after treatment with intravenous methylprednisolone pulse therapy. METHODS: We retrospectively reviewed patients with AON who had received intravenous methylprednisolone pulse therapy. These patients were classified into retrobulbar or papillitis groups. Demographic characteristics, responsiveness to pulse therapy, recurrence rate and incidence of multiple sclerosis were compared between these two groups. RESULTS: Of the 43 patients enrolled in this study, 19 patients (44%) were in the retrobulbar group and 24 patients (56%) were in the papillitis group. Seven cases (16%) showed periventricular plaque on magnetic resonance imaging (MRI). Among these seven patients, five developed definite or probable multiple sclerosis. The incidence of multiple sclerosis in patients with positive brain MRI findings was significantly higher than in patients with negative MRI findings (p = 0.002). There was no statistical difference in final visual acuity between the two group (p = 0.353). Sixteen patients suffered from recurrence of AON (21% in the papillitis group and 58% in the retrobulbar group, p = 0.029). Two patients (8%) in the papillitis group and six patients (32%) in the retrobulbar group developed multiple sclerosis (p = 0.061) with a mean interval of 21.6 +/- 11.2 months. CONCLUSION: AON in Taiwan has a relatively lower percentage of development of multiple sclerosis than in Western countries. The presence of periventricular plaque on MRI is significantly associated with the later development of multiple sclerosis. The retrobulbar group had a stronger association with recurrence and development of multiple sclerosis. PMID- 17711800 TI - Esophageal adenocarcinoma arising from Barrett's epithelium in Taiwan. AB - The prevalence of Barrett's esophagus (BE) in Eastern countries is rising to match the prevalence in the West. However, a corresponding trend of BE-associated adenocarcinoma has yet to be observed in Asia. Historically, adenocarcinoma complicating BE has been considered a rare event in Taiwan. In the present report, we collected three Taiwanese cases of esophageal adenocarcinoma arising from BE. The first case was a 37-year-old man with an advanced cancer that developed on pre-existing BE after a 3-year interval without endoscopic surveillance. The second case was a 63-year-old man who presented with odynophagia and was found to have an ulcerative tumor centered on the characteristic Barrett's mucosa. The final case was a 44-year-old man who presented with gradual-onset dysphagia and weight loss, without typical reflux symptom. Our report emphasizes the need for an updated epidemiologic study to determine the incidence of BE-associated adenocarcinoma in Taiwan. PMID- 17711801 TI - Alpha-fetoprotein-producing pancreatic acinar cell carcinoma. AB - A 47-year-old man with chronic hepatitis B had progressive elevated alpha fetoprotein of 2 years' duration. A pancreatic tail tumor, instead of liver tumor, was detected. He underwent elective distal pancreatectomy and splenectomy and the pathology turned out to be acinar cell carcinoma of the pancreas. Serum level of alpha-fetoprotein returned to normal soon after surgery. No cancer recurrence was noted after 3 years of follow-up. Alpha-fetoprotein is commonly used as a tumor marker to screen for hepatocellular carcinoma in high-risk patients. However, elevated alpha-fetoprotein could occur in a much rarer disease, acinar cell carcinoma of the pancreas. PMID- 17711802 TI - Lipoma of the palatine tonsil. AB - Lipomas are benign tumors composed of mature fat cells. They occur frequently in subcutaneous tissue but rarely in the upper aerodigestive tract. Tonsillar lipomas are rare. To our knowledge, there are only six documented cases in the English literature. Here, we present the case of a 46-year-old Taiwanese female with a submerged oval yellowish mass in her left palatine tonsil. She received tonsillectomy and the pathologic diagnosis was tonsillar lipoma. The clinical presentation, management and literature review are also presented. PMID- 17711803 TI - Rapidly progressive pancreatic lipomatosis in a young adult patient with transfusion-dependent myelodysplastic syndrome. AB - Pancreatic lipomatosis is defined as deposition of fat cells in pancreatic parenchyma. Although the etiology of this condition is still unclear, it is not uncommon in the elderly, obese individuals, and a variety of transfusion dependent hematologic diseases such as beta-thalassemia major. Pancreatic lipomatosis associated with transfusion-dependent myelodysplastic syndrome (MDS) has never been reported. We present a 17-year-old male patient with transfusion dependent MDS. He received transfusion of a total of 345 units of blood in a period of 18 months but without iron chelating agent. Progressive fatty replacement of the pancreas parenchyma was found by a series of computed tomography images over seven hospital admissions due to repeated infections. Bone marrow biopsy revealed hemosiderin deposition. Because of his poor response to induction chemotherapy, stem cell transplantation was suggested, but the patient died of sepsis before the therapeutic procedure could take place. Although most patients with pancreatic lipomatosis have neither clinical symptoms nor abnormal laboratory data, it may cause endocrine and exocrine pancreas dysfunction. In this reported case, mild exocrine dysfunction was noted on the last admission. Clinicians should be cautious of hemosiderin deposition after large amount of blood transfusion and chelating therapy should be given to avoid iron overload. PMID- 17711805 TI - Clinical experience of percutaneous endoscopic gastrostomy in Taiwanese patients- 310 cases in 8 years. AB - Although percutaneous endoscopic gastrostomy (PEG) has become a popular method for long-term tube feeding worldwide, there are only a few reports about its application in Taiwan. From May 1997 to May 2005, we performed 302 PEG insertions successfully in 310 attempts (97.4% success rate) using modified Ponsky's pull method with 24-Fr feeding tubes. All the patients received PEG for tube feeding except for two patients with cancerous peritonitis for decompression. The underlying diseases in these 308 patients who received PEG for tube feeding were 161 cerebrovascular accidents (52.3%), 62 head and neck cancers (20.1%), 21 cases of Parkinsonism (6.8%), and others. There were 11 major complications (3.6%) and 57 minor complications (18.9%). Ten patients (3.3%) died within 30 days after PEG insertion. However, no procedure-related mortality occurred. In conclusion, PEG is an effective method for tube feeding and drainage with a high success rate. PEG insertion was often indicated for patients with dysphagia caused by cerebrovascular accident, head and neck cancer, and Parkinsonism in Taiwan. It is a relatively safe procedure, with a 3.6% rate of major complications and 18.9% rate of minor complications. PMID- 17711804 TI - Bilateral neuralgic amyotrophy presenting with left vocal cord and phrenic nerve paralysis. AB - This article reports the difference between neuralgic amyotrophy and neuropathy caused by chemotherapy and radiation treatment which manifested with severe shoulder pain followed by marked weakness of bilateral upper arms and involvement of cranial nerves. A 62-year-old man presented with acute severe neuropathic pain at the left shoulder, bilateral shoulder weakness, hoarseness of voice from vocal cord palsy, and respiratory insufficiency from left diaphragm palsy, which all occurred sequentially over a 1-month period. The diagnosis of neuralgic amyotrophy was supported and differentiated from tumor-induced and radiation induced neuropathy by clinical presentation, electrophysiologic and imaging studies. Unlike previous reports of the onset of neuralgic amyotrophy being associated with initiation of radiation treatment in cancer patients, this report demonstrates that neuralgic amyotrophy can occur at any point of the malignant disease process after radiation and chemotherapy. PMID- 17711806 TI - Psychological distress, life stressors, and social support in new immigrants with HIV. AB - The expression of psychological distress is culture-dependent. Ethiopian Jewish immigrants' expression of distress is anchored in their unique culture. The authors' aim in this study was to assess the psychological distress of HIV positive (HIV+) Ethiopian Jewish immigrants in Israel, using a culture-based tool, and to examine the relations of psychological distress, psychosocial variables, and T lymphocyte subset counts and viral load. Participants were 56 HIV+ patients. The authors assessed psychological distress by the self-report questionnaire, which they adjusted for the Ethiopian immigrants (SRQ-E). The authors also assessed adherence to treatment regimen, number of life stressors, and degree of perceived social support, T lymphocyte subset counts, and viral load in plasma. The overall level of psychological distress was in the high range of the SRQ-E scale and was considerably higher in men than in women. Psychological distress was related to more life stressors and lower perceived social support. Women reported having more social support, had better T(CD4+) lymphocyte count and T(CD4+)/T(CD8+) ratio, and lower viral load than did men. Better HIV indicators were related to shorter duration of HIV+ since diagnosis, better adherence, and more social support, but not to psychological distress. The culture-based tool allowed identification of the high degree of psychological distress among the HIV+ Ethiopian immigrants. Researchers need to assess the adaptability of culture-based questionnaires to determine psychological distress in HIV+ patients. PMID- 17711807 TI - The relation between cumulative fatigue and marital status in Japanese workers. AB - The authors' aim in this study was to clarify the influence of marital status on mental and physical fatigue symptoms. For 5,582 men and 484 women workers, the authors determined odds ratios of marital status using positive findings of 8 subscales on the Cumulative Fatigue Symptoms Index (CFSI) as dependent variables and other potential covariates as independent variables by logistic regression analysis. In men, the odds ratios for decreased vitality, physical disorders, decreased willingness to work, anxiety, and depressive feelings of CFSI were significantly higher in the unmarried group. In women, the odds ratios on CFSI for decreased vitality and decreased willingness to work were likewise significantly higher. The results verified that unmarried status was more associated with fatigue than was married status and being overworked. PMID- 17711808 TI - Intention to encourage complementary and alternative medicine among general practitioners and medical students. AB - The authors' goal was to identify factors explaining intention to encourage a patient to follow complementary and alternative medicine (CAM) treatment among general practitioners (GPs), fourth-year medical students, and residents in family medicine. They surveyed 500 GPs and 904 medical students via a self administered mailed questionnaire that they based on the Theory of Planned Behavior. Respondents expressed a neutral level of intention to encourage CAM approach. Variables explaining 75% of variance of intention of all participants were: moral norm, beta=0.34, p<.0001; perceived behavioral control, beta=0.29, p<.0001; attitude, beta=0.22, p<.0001; descriptive norm, beta=0.13, p<.0001; and professional status, (GPs, beta=-0.07, p<.0001; residents, beta=-0.07, p<.0001). Facilitating conditions and developing a better perception of control over perceived obstacles could help enhance health-care practitioners' intentions to use CAM. Also, a clear position on the part of the medical community would help to define a professional norm in line with the moral norm. PMID- 17711809 TI - Does money really matter? The effects of fiscal margin on quality of care in military treatment facilities. AB - This study was prompted by an escalating interest in the quality of healthcare provided within the United States. The authors hypothesized that one determinant of quality is the adequacy of financial resources available to the healthcare organization. The authors addressed their question by using data from two Defense Department sources: the 2003 Health Care Survey of Defense Department Beneficiaries (HCSDB) and 1999-2003 data from the Department of Defense Medical Expense Performance Reporting System (MEPRS). The authors used a measure of military treatment facility fiscal margin to predict seven Consumer Assessment of Health Plan Satisfaction (CAHPS) quality dimensions. Regression analysis and multilevel modeling are the primary statistical methods. Results indicate a significant and positive association between organizational financial strength and quality outcomes. This finding indicates that organizations with more financial flexibility may be more adept at meeting or exceeding patient care expectations. PMID- 17711810 TI - Ethical triage and scarce resource allocation during public health emergencies: tenets and procedures. AB - Public health emergencies may result in mass casualties and a surge in demand for hospital-based care. Healthcare standards may need to be altered to respond to an imbalance between demands for care and resources. Clinical decisions that involve triage and scarce resource allocation may present unique ethical challenges. To address these challenges, the authors detailed tenets and procedures to guide triage and scarce resource allocation during public health emergencies. The authors propose health care organizations deploy a Triage and Scarce Resource Allocation Team to over-see and guide ethically challenging clinical decision making during a crisis period. The authors' goal is to help healthcare organizations and clinicians balance public health responsibilities and their duty to individual patients during emergencies in as equitable and humane a manner as possible. PMID- 17711811 TI - John Kane: member, board of directors, GetWellNetwork. Interview by Dennis S. Palkon and Jason R. Alyesh. PMID- 17711812 TI - The impact of provider and environmental factors on the outcomes of urgent tracheal intubation at a large teaching hospital. PMID- 17711813 TI - Assistance in dying: Part III. Implications for managers, physicians, and HSOs. PMID- 17711815 TI - Larval rearing environment affects several post-copulatory traits in Drosophila melanogaster. AB - In Drosophila melanogaster, accessory gland proteins (Acps) that a male transfers during mating affect his reproductive success by altering the female's behaviour and physiology. To test the role of male condition in the expression of Acps, we manipulated the pre-adult environment and examined adult males for relative transcript abundance of nine Acps, and for post-copulatory traits that Acps influence. Larval culture density had no effect on any measured trait. Larval nutrient availability impacted the number of sperm transferred and stored, the male's ability to induce refractoriness in his mate, but relative transcript abundance of only a single Acp (Acp36DE). Reduced male body size due to low yeast levels affected sperm competition. Our data indicate that some female-mediated post-copulatory traits (induced refractoriness and sperm transfer and storage) might be influenced by the male's developmental environment, but relative expression of most Acps and some traits they influence (P1') are not. PMID- 17711816 TI - Interspecies physiological variation as a tool for cross-species assessments of global warming-induced endangerment: validation of an intrinsic determinant of macroecological and phylogeographic structure. AB - Global warming is now recognized as the dominant threat to biodiversity because even protected populations and habitats are susceptible. Nonetheless, current criteria for evaluating species' relative endangerment remain purely ecological, and the accepted conservation strategies of habitat preservation and population management assume that species can mount ecological responses if afforded protection. The insidious threat from climate change is that it will attenuate or preclude ecological responses by species that are physiologically constrained; yet, quantitative, objective criteria for assessing relative susceptibility of diverse taxa to warming-induced stress are wanting. We explored the utility of using interspecies physiological variation for this purpose by relating species' physiological phenotypes to landscape patterns of ecological and genetic exchange. Using a salamander model system in which ecological, genetic and physiological diversity are well characterized, we found strong quantitative relationships of basal metabolic rates (BMRs) to both macroecological and phylogeographic patterns, with decreasing BMR leading to dispersal limitation (small contemporary ranges with marked phylogeographic structure). Measures of intrinsic physiological tolerance, which vary systematically with macroecological and phylogeographic patterns, afford objective criteria for assessing endangerment across a wide range of species and should be incorporated into conservation assessment criteria that currently rely exclusively upon ecological predictors. PMID- 17711817 TI - Function of weaponry in females: the use of horns in intrasexual competition for resources in female Soay sheep. AB - In many species, females show reduced expression of a trait that is under sexual selection in males, and this expression is thought to be maintained through genetic associations with the male phenotype. However, there is also the potential for the female trait to convey an advantage in intrasexual conflicts over resources. We tested this hypothesis in a feral population of Soay sheep, in which males and females have a polymorphism for horn development, producing either full (normal horned), reduced (scurred) or no (polled, females only) horns. During the lambing period, females who possessed horns were more likely to initiate and win aggressive interactions, independent of age, weight and birthing status. The occurrence of aggression was also context dependent, decreasing over the lambing period and associated with local density. Our results demonstrate that a trait that confers benefits to males during intrasexual competition for mates may also be used by females in intrasexual competition over resources: males use weaponry to gain mates, whereas females use weaponry to gain food. PMID- 17711818 TI - Range and severity of a plant disease increased by global warming. AB - Climate change affects plants in natural and agricultural ecosystems throughout the world but little work has been done on the effects of climate change on plant disease epidemics. To illustrate such effects, a weather-based disease forecasting model was combined with a climate change model predicting UK temperature and rainfall under high- and low-carbon emissions for the 2020s and 2050s. Multi-site data collected over a 15-year period were used to develop and validate a weather-based model forecasting severity of phoma stem canker epidemics on oilseed rape across the UK. This was combined with climate change scenarios to predict that epidemics will not only increase in severity but also spread northwards by the 2020s. These results provide a stimulus to develop models to predict the effects of climate change on other plant diseases, especially in delicately balanced agricultural or natural ecosystems. Such predictions can be used to guide policy and practice in adapting to effects of climate change on food security and wildlife. PMID- 17711820 TI - Reciprocal relationships among alcohol use, risk perception, and sexual victimization: a prospective analysis. AB - OBJECTIVE: The authors' purpose in this study was to assess longitudinally the relationships among alcohol use, risk perception, and sexual victimization. PARTICIPANTS: Three hundred and seventy-two women from 2 midsized universities made up the sample. METHODS: Participants filled out questionnaires regarding history of sexual victimization, alcohol use, and perceived personal risk for sexual assault in the following 2 months. The authors then reassessed participants at 2 follow-up periods. RESULTS: The pattern of results suggested that that the relationship between alcohol use and sexual victimization was complex and that alcohol use may moderate the relation between history of victimization and revictimization for women with sexual assault histories. In particular, results indicated an increase in risk for sexual revictimization with increases in alcohol use for women with a history of sexual victimization. The data did not, however, support a reciprocal relationship between sexual assault and drinking (eg, in that a sexual victimization during one time period did not predict drinking behaviors in subsequent time periods). CONCLUSIONS: These results underscore the importance of both alcohol and sexual assault programming on college campuses. PMID- 17711821 TI - What predicts adjustment among college students? A longitudinal panel study. AB - OBJECTIVE: Researchers have previously reported that law students and medical students experience significant distress during their first year. The authors suspected that freshmen undergraduates might experience similar distress in their transition to college. PARTICIPANTS: They surveyed 242 undergraduate freshmen at the beginning and end of their first year. METHODS: The authors asked participants about their physical health, alcohol use and smoking habits, stress levels, perfectionism, self-esteem, coping tactics, optimism, extroversion, and psychological adaptation to college. RESULTS: Data replicated the declines reported in law and medical students' psychological and physical health. Negative coping tactics and perfectionism predicted poorer physical health and alcohol use at the end of the year; however, optimism and self-esteem predicted better physical and psychological outcomes. CONCLUSION: Future researchers should investigate steps that college administrators can take to help to alleviate some of these problems, such as offering workshops on stress relief to incoming freshmen. PMID- 17711823 TI - Holistic wellness as a means to developing a lifestyle approach to health behavior among college students. AB - OBJECTIVE: The authors examined the influence of a holistic model of wellness on activity level among obese and sedentary college students. PARTICIPANTS: They recruited 41 participants for an 11-week program. METHODS: Participants were required to record daily walking totals and complete 5 bimonthly classes where principles of holistic wellness were discussed. Pre- and posttest values of activity level (walking activity, cardiovascular training, general activity, and resistance training) and pre- and posttest knowledge and self-efficacy related to principles of holistic wellness. Participants also completed a 1-month followup. RESULTS: Participants who completed the program reported increases in general exercise activity, resistance training, and walking behavior, as well as self efficacy and knowledge concerning principles of holistic wellness. The authors also observed decreases in participants' body fat and body mass. CONCLUSIONS: Relevance to adherence of exercise behavior and a lifestyle approach to health are discussed. Future directions and limitations are highlighted. PMID- 17711822 TI - A qualitative study of attitudes, beliefs, and practices among 40 undergraduate smokers. AB - OBJECTIVE: Because little is known about college-age smokers, the authors conducted a qualitative study to better understand this population. PARTICIPANTS: Forty college student smokers from 12 Pacific Northwest colleges participated in the study. METHODS: The authors identified themes and built models to ascertain important factors related to smoking and smoking cessation. Four models emerged: smoking facilitators, smoking barriers, cessation facilitators, and cessation barriers. RESULTS: The authors observed physical, psychological, and social influences across models, and social influences were strongly associated with both smoking and cessation. Many smokers were unlikely to define themselves as regular smokers. Most smokers had made prior quit attempts. CONCLUSIONS: College students are a unique category of smoker and colleges can play a role in helping them achieve cessation. PMID- 17711824 TI - The prevalence of physical activity maintenance in a sample of university students: a longitudinal study. AB - The health and financial costs of physical inactivity are staggering. Few researchers have assessed the prevalence of physical activity at the level needed to gain health benefits. OBJECTIVE: The author's purpose in this longitudinal study was to assess the prevalence of university students who maintained physical activity at the level necessary for health gains for at least 1 month. PARTICIPANTS: University students (N = 392) from 2 campuses participated in this 1-month study. METHODS: The author administered a survey to the same group of students at baseline and 1 month later to assess the prevalence of students who met and maintained the physical activity guideline for health (PAGH). RESULTS: Thirty-five percent of students maintained the PAGH for 1 month. CONCLUSION: The majority of students in this study were insufficiently physically active. Given that insufficient physical activity may lead to serious health concerns, interventions are needed to improve activity maintenance in this population. PMID- 17711825 TI - Osteoporosis knowledge and attitudes: a cross-sectional study among college-age students. AB - OBJECTIVE: The authors' purpose in this study was to investigate the influence of knowledge of osteoporosis, attitudes regarding osteoporosis, and knowledge of dietary calcium on dairy product intake in both male and female college-age students. PARTICIPANTS: The authors conducted this cross-sectional study on 911 men and women enrolled in 2 demographically similar universities. METHODS: A modified osteoporosis knowledge questionnaire assessed participant's general osteoporosis knowledge and perceived disease risk. RESULTS: The authors found that knowledge of osteoporosis and calcium did not significantly influence dairy product intake. Attitude regarding osteoporosis was a significant predictor of dairy product intake in men but was not significant for the women. CONCLUSIONS: The authors recommend development and implementation of educational programs designed to increase awareness of calcium-rich food sources as well as other risk factors of this crippling disease. PMID- 17711826 TI - An exploratory study of differences in self-esteem, kinship social support, and coping responses among African American ACOAs and Non-ACOAs. AB - The author sought to identify differences in kinship social support, self-esteem, and coping responses between African American college students who identify themselves as adult children of alcoholics (ACOAs) and adult children of nonalcoholics (non-ACOAs) at 2 separate universities. The results indicate that there were no differences in levels of self-esteem, kinship social support, and coping responses among ACOAs and non-ACOAs. The author addresses implications for practice, policy, and research. PMID- 17711827 TI - Life change and spirituality among a college student cohort. AB - OBJECTIVE: Because college marks a time when life-change is typically high, the authors designed this study to determine whether life-change was related to degree of spirituality, the "directing" component of health, among a college student cohort. PARTICIPANTS AND METHODS: The sample group, consisting of 180 northeastern US undergraduate college students, completed the 48-item Life Attitude Profile-Revised (LAP-R) and the Schedule of Recent Experience (SRE) in the fall semester of 2004. RESULTS: Findings indicate that college students who reported experiencing higher levels of life change, both positive and negative, also scored lower on spirituality. Nevertheless, these students had scores indicative of a higher desire to find spirituality, even though their motivation to do so was low. CONCLUSIONS: Although life changes among college students likely will remain high, lower spirituality can be enhanced; therefore, interested health educators are encouraged to help students increase their degree of spirituality. PMID- 17711828 TI - Relational commitment and threats to relationship maintenance goals: influences on condom use. AB - OBJECTIVE: The authors examined the effects of relational commitment (high commitment versus low commitment) and relationship maintenance goals (high threat versus low threat) on decisions to request the use of a condom. METHODS: The authors conducted a 2-part study using a survey of responses to hypothetical scenarios and decisions in actual relationships. RESULTS: Results indicated that people with high relational commitment were less likely to request a condom than were people with low relational commitment. People who perceived threats to relationship maintenance goals if a condom was requested were less likely to request a condom than were people who did not perceive threats to relationship maintenance goals. CONCLUSIONS: Findings from this study highlight the influence that relational threats and commitment levels have on condom use decision making. PMID- 17711829 TI - Health value, perceived social support, and health self-efficacy as factors in a health-promoting lifestyle. AB - During their college years, students may adopt healthpromoting lifestyles that bring about long-term benefits. OBJECTIVE AND PARTICIPANTS: The purpose of this study was to explore the roles of health value, family/friend social support, and health self-efficacy in the health-promoting lifestyles of a diverse sample of 162 college students. METHODS: Participants completed an Assessment Battery consisting of the following instruments: (1) a demographic questionnaire, (2) the Multi-Dimensional Support, (3) the Value on Health Scale, (4) the Self-Rated Abilities for Health Practices, (5) the Health-Promoting Lifestyle Profile II, and (6) the Marlowe-Crowne Social Desirability Scale. RESULTS: Correlational analyses indicated that health value, perceived family/friend social support, and health self-efficacy were significantly associated with engagement in a health promoting lifestyle. An analysis of covariance (ANCOVA) revealed that health value and health self-efficacy significantly predicted the level of engagement in a health-promoting lifestyle. Perceived family/friend social support was not significant in the model. As age increased, level of perceived family/friend social support decreased. CONCLUSION: Present findings suggest that health interventions programs focus on assessing and increasing health self-efficacy and health value of these youth. College health professionals can design and evaluate the effectiveness of such health-promoting interventions. PMID- 17711830 TI - Gambling as an emerging health problem on campus. AB - OBJECTIVE: The authors documented the prevalence of gambling and correlates to health among undergraduates. METHODS: The authors analyzed data from a health habit questionnaire (gambling questions included) given to students enrolled in a university-required course. RESULTS: Gambling and problems with gambling were more frequent among men than women regardless of venue. Athletes more frequently bet on sports and played games of chance, had gambling debt, and sought help for gambling than did nonathletes. More than 50% of fraternity members gambled and had a higher prevalence of gambling debt than did other men. Several gambling practices were correlated with failure to use seatbelts, driving or riding with someone under the influence, and using drugs (including cigarettes). Twice as many students who had gambling problems reported considering or attempting suicide than did those who did not report gambling problems, and gambling was correlated with depression. CONCLUSION: These results indicate that gambling is correlated with high-risk health behaviors and indicates the need for intervention for college students with gambling problems. PMID- 17711831 TI - Concurrent niche and neutral processes in the competition-colonization model of species coexistence. AB - The importance of neutral dynamics is contentiously debated in the ecological literature. This debate focuses on neutral theory's assumption of fitness equivalency among individuals, which conflicts with stabilizing fitness that promotes coexistence through niche differentiation. I take advantage of competition-colonization trade-offs between species of aquatic micro-organisms (protozoans and rotifers) to show that equalizing and stabilizing mechanisms can operate simultaneously. Competition trials between species with similar colonization abilities were less likely to result in competitive exclusion than for species further apart. While the stabilizing mechanism (colonization differences) facilitates coexistence at large spatial scales, species with similar colonization abilities also exhibited local coexistence probably due to fitness similarities allowing weak stabilizing mechanisms to operate. These results suggest that neutral- and niche-based mechanisms of coexistence can simultaneously operate at differing temporal and spatial scales, and such a spatially explicit view of coexistence may be one way to reconcile niche and neutral dynamics. PMID- 17711833 TI - Estimating dinosaur maximum running speeds using evolutionary robotics. AB - Maximum running speed is an important locomotor parameter for many animals predators as well as prey-and is thus of interest to palaeobiologists wishing to reconstruct the behavioural ecology of extinct species. A variety of approaches have been tried in the past including anatomical comparisons, bone scaling and strength, safety factors and ground reaction force analyses. However, these approaches are all indirect and an alternative approach is to create a musculoskeletal model of the animal and see how fast it can run. The major advantage of this approach is that all assumptions about the animal's morphology and physiology are directly addressed, whereas the exact same assumptions are hidden in the indirect approaches. In this paper, we present simple musculoskeletal models of three extant and five extinct bipedal species. The models predict top speed in the extant species with reasonably good agreement with accepted values, so we conclude that the values presented for the five extinct species are reasonable predictions given the modelling assumptions made. Improved musculoskeletal models and better estimates of soft tissue parameters will produce more accurate values. Limited sensitivity analysis is performed on key muscle parameters but there is considerable scope for extending this in the future. PMID- 17711832 TI - Transmission stage investment of malaria parasites in response to in-host competition. AB - Conspecific competition occurs in a multitude of organisms, particularly in parasites, where several clones are commonly sharing limited resources inside their host. In theory, increased or decreased transmission investment might maximize parasite fitness in the face of competition, but, to our knowledge, this has not been tested experimentally. We developed and used a clone-specific, stage specific, quantitative PCR protocol to quantify Plasmodium chabaudi replication and transmission stage densities in mixed-clone infections. We co-infected mice from two strains with an avirulent and virulent parasite clone and found competitive suppression of in-host (blood-stage) parasite densities and generally corresponding reductions in transmission stage production, with the virulent clone obtaining overall competitive superiority. In response to competitive suppression, there was little evidence of any alteration in transmission stage investment, apart from a small reduction by one of the two clones in one of the two host strains. This alteration did not result in a competitive advantage, although it might have reduced the disadvantage. This study supports much of the current literature, which predicts that conspecific in-host competition will result in a competitive advantage and positive selection for virulent clones and thus the evolution of higher virulence. PMID- 17711834 TI - The risk of establishment of aquatic invasive species: joining invasibility and propagule pressure. AB - Invasive species are increasingly becoming a policy priority. This has spurred researchers and managers to try to estimate the risk of invasion. Conceptually, invasions are dependent both on the receiving environment (invasibility) and on the ability to reach these new areas (propagule pressure). However, analyses of risk typically examine only one or the other. Here, we develop and apply a joint model of invasion risk that simultaneously incorporates invasibility and propagule pressure. We present arguments that the behaviour of these two elements of risk differs substantially--propagule pressure is a function of time, whereas invasibility is not--and therefore have different management implications. Further, we use the well-studied zebra mussel (Dreissena polymorpha) to contrast predictions made using the joint model to those made by separate invasibility and propagule pressure models. We show that predictions of invasion progress as well as of the long-term invasion pattern are strongly affected by using a joint model. PMID- 17711835 TI - Spatial adaptations for plant foraging: women excel and calories count. AB - We present evidence for an evolved sexually dimorphic adaptation that activates spatial memory and navigation skills in response to fruits, vegetables and other traditionally gatherable sessile food resources. In spite of extensive evidence for a male advantage on a wide variety of navigational tasks, we demonstrate that a simple but ecologically important shift in content can reverse this sex difference. This effect is predicted by and consistent with the theory that a sexual division in ancestral foraging labour selected for gathering-specific spatial mechanisms, some of which are sexually differentiated. The hypothesis that gathering-specific spatial adaptations exist in the human mind is further supported by our finding that spatial memory is preferentially engaged for resources with higher nutritional quality (e.g. caloric density). This result strongly suggests that the underlying mechanisms evolved in part as adaptations for efficient foraging. Together, these results demonstrate that human spatial cognition is content sensitive, domain specific and designed by natural selection to mesh with important regularities of the ancestral world. PMID- 17711836 TI - Evolution of parasite virulence when host responses cause disease. AB - The trade-off hypothesis of virulence evolution rests on the assumption that infection-induced mortality is a consequence of host exploitation by parasites. This hypothesis lies at the heart of many empirical and theoretical studies of virulence evolution, despite growing evidence that infection-induced mortality is very often a by-product of host immune responses. We extend the theoretical framework of the trade-off hypothesis to incorporate such immunopathology and explore how this detrimental aspect of host defence mechanisms affects the evolution of pathogen exploitation and hence infection-induced mortality. We argue that there are qualitatively different ways in which immunopathology can arise and suggest ways in which empirical studies can tease apart these effects. We show that immunopathology can cause infection-induced mortality to increase or decrease as a result of pathogen evolution, depending on how it covaries with pathogen exploitation strategies and with parasite killing by hosts. Immunopathology is thus an important determinant of whether public and animal health programmes will drive evolution in a clinically beneficial or detrimental direction. Immunopathology complicates our understanding of disease evolution, but can nevertheless be readily accounted for within the framework of the trade off hypothesis. PMID- 17711837 TI - Negative plant-soil feedbacks may limit persistence of an invasive tree due to rapid accumulation of soil pathogens. AB - Soil organisms influence plant species coexistence and invasion potential. Plant soil feedbacks occur when plants change soil community composition such that interactions with that soil community in turn may positively or negatively affect the performance of conspecifics. Theories predict and studies show that invasions may be promoted by stronger negative soil feedbacks for native compared with exotic species. We present a counter-example of a successful invader with strong negative soil feedbacks apparently caused by host-specific, pathogenic soil fungi. Using a feedback experiment in pots, we investigated whether the relative strength of plant-soil feedbacks experienced by a non-native woody invader, Sapium sebiferum, differed from several native tree species by examining their performance in soils collected near conspecifics ('home soils') or heterospecifics ('away soils') in the introduced range. Sapium seedlings, but no native seedlings, had lower survival and biomass in its home soils compared with soils of other species (negative feedback'). To investigate biotic agents potentially responsible for the observed negative feedbacks, we conducted two additional experiments designed to eliminate different soil taxa ('rescue experiments'). We found that soil sterilization (pot experiment ) or soil fungicide applications (pot and field experiments) restored Sapium performance in home soil thereby eliminating the negative feedbacks we observed in the original experiment. Such negative feedbacks apparently mediated by soil fungi could have important effects on persistence of this invader by limiting Sapium seedling success in Sapium dominated forests (home soils) though their weak effects in heterospecific (away) soils suggest a weak role in limiting initial establishment. PMID- 17711838 TI - Chemical deterrent enables a socially parasitic ant to invade multiple hosts. AB - Social parasites are involved in a coevolutionary arms race, which drives increasing specialization resulting in a very narrow host range. The Formicoxenus ants are a small group of social parasites with a xenobiotic lifestyle. Formicoxenus quebecensis and Formicoxenus provancheri are highly specialized ants using chemical mimicry to blend into their respective Myrmica ant host colonies. However, Formicoxenus nitidulus is unique in being able to survive in over 11 different ant host species. We observed that when live or dead F. nitidulus adults are seized by their host they are immediately dropped undamaged, despite possessing a cuticular hydrocarbon profile that differs markedly from its host. Hexane extracts of the F. nitidulus cuticle made previously acceptable prey items unattractive to their Formica host, indicating a chemical deterrent effect. This is the first time that a social parasite has been shown to exploit the generalized deterrence strategy to avoid host aggression over long periods of time. This supports the idea that coevolved and generalist diseases or parasites require fundamentally different defence mechanisms. We suggest that F. nitidulus uses its cuticular chemistry, possible alkadienes, as a novel deterrent mechanism to allow it to switch hosts easily and so become a widespread and abundant social parasite. PMID- 17711839 TI - Habitat assessment ability of bumble-bees implies frequency-dependent selection on floral rewards and display size. AB - Foraging pollinators could visit hundreds of flowers in succession on mass flowering plants, yet they often visit only a small number--potentially saving the plant from much self-pollination among its own flowers (geitonogamy). This study tests the hypothesis that bumble-bee (Bombus impatiens) residence on a particular plant depends on an assessment of that plant's reward value relative to the overall quality experienced in the habitat. In a controlled environment, naive bees were given experience in a particular habitat (all plants having equal nectar quality or number of rewarding flowers), and we tested whether they learn about and adaptively exploit a new habitat type. Bees' residence on a plant (number of flowers probed per visit) was eventually invariant to a doubling of absolute nectar quality and increased only slightly with a doubling of absolute flower number in the habitat. These results help to explain why pollinators are quick to leave highly rewarding plants and suggest that the fitness of rewarding plant traits will often be frequency dependent. One implication is that geitonogamy may be a less significant constraint on the evolution of rewarding traits than generally supposed. PMID- 17711840 TI - Probabilistic participation in public goods games. AB - Voluntary participation in public goods games (PGGs) has turned out to be a simple but effective mechanism for promoting cooperation under full anonymity. Voluntary participation allows individuals to adopt a risk-aversion strategy, termed loner. A loner refuses to participate in unpromising public enterprises and instead relies on a small but fixed pay-off. This system leads to a cyclic dominance of three pure strategies, cooperators, defectors and loners, but at the same time, there remain two considerable restrictions: the addition of loners cannot stabilize the dynamics and the time average pay-off for each strategy remains equal to the pay-off of loners. Here, we introduce probabilistic participation in PGGs from the standpoint of diversification of risk, namely simple mixed strategies with loners, and prove the existence of a dynamical regime in which the restrictions ono longer hold. Considering two kinds of mixed strategies associated with participants (cooperators or defectors) and non participants (loners), we can recover all basic evolutionary dynamics of the two strategies: dominance; coexistence; bistability; and neutrality, as special cases depending on pairs of probabilities. Of special interest is that the expected pay off of each mixed strategy exceeds the pay-off of loners at some interior equilibrium in the coexistence region. PMID- 17711841 TI - Character displacement among bat-pollinated flowers of the genus Burmeistera: analysis of mechanism, process and pattern. AB - Coexisting plants that share pollinators can compete through interspecific pollen transfer. A long-standing idea holds that divergence in floral morphology may reduce this competition by placing pollen on different regions of the pollinator's bodies. However, surprisingly little empirical support for this idea exists. Burmeistera is a diverse neotropical genus that exhibits wide interspecific variation in the degree to which the reproductive parts are exserted outside the corolla. Coexisting Burmeistera share bats as their primary pollinators, and the degree of exsertion determines the site of pollen deposition on the bats' heads. Here we study the mechanism, process and pattern of floral character displacement for assemblages of coexisting Burmeistera. Flight cage experiments with bats and pairs of Burmeistera species demonstrate that the greater the divergence in exsertion length, the less pollen transferred interspecifically. Null model analyses of exsertion lengths for 19 species of Burmeistera across 18 sites (each containing two to four species) demonstrate that observed assemblage structure is significantly overdispersed relative to what would be expected by chance. Local evolution, rather than ecological sorting, appears to be the primary process driving this pattern of overdispersion because local adaptation of the nine widespread species accounts for a large portion of the observed pattern. Taken together, results of this study provide strong support for the idea that competition through interspecific pollen transfer can drive character displacement in plants. PMID- 17711842 TI - What are the consequences of being left-clawed in a predominantly right-clawed fiddler crab? AB - Male fiddler crabs (genus Uca) have an enlarged major claw that is used during fights. In most species, 50% of males have a major claw on the left and 50% on the right. In Uca vocans vomeris, however, less than 1.4% of males are left clawed. Fights between opponents with claws on the same or opposite side result in different physical alignment of claws, which affects fighting tactics. Left clawed males mainly fight opposite-clawed opponents, so we predicted that they would be better fighters due to their relatively greater experience in fighting opposite-clawed opponents. We found, however, that (i) a left-clawed male retains a burrow for a significantly shorter period than a size-matched right-clawed male, (ii) when experimentally displaced from their burrow, there is no difference in the tactics used by left- and right-clawed males to obtain a new burrow; however, right-clawed males are significantly more likely to initiate fights with resident males, and (iii) right-clawed residents engage in significantly more fights than left-clawed residents. It appears that left-clawed males are actually less likely to fight, and when they do fight they are less likely to win, than right-clawed males. The low-level persistence of left-clawed males is therefore unlikely to involve a frequency-dependent advantage associated with fighting experience. PMID- 17711843 TI - The rise and fall of species: implications for macroevolutionary and macroecological studies. AB - Knowing the geographic extents of species is crucial for understanding the causes of diversity distributions and modes of speciation and extinction. Species geographic ranges are often viewed as approximately constant in size in geological time, even though climate change studies have shown that historical and modern species geographic distributions are not static. Here, we use an extensive global microfossil database to explore the temporal trajectories of geographic extents over the entire lifespan of marine nannoplankton, diatom, planktic foraminifer and radiolarian species. We show that geographic extents are not static over geological time-scales. Temporal trajectories of species geographic ranges are asymmetric: the rise is quicker than the fall. We propose that once a species has overcome its initial difficulties in geographic establishment, it rises to its peak geographic extent. However, once this peak value is reached, it will also have a maximal number of species to interact with. The negative of these biotic interactions could then cause a gradual geographic decline. We discuss the multiple implications of our findings with reference to macroecological and macroevolutionary studies. PMID- 17711844 TI - Pseudomonas syringae type III effector AvrPtoB is phosphorylated in plant cells on serine 258, promoting its virulence activity. AB - The Pseudomonas syringae pv. tomato protein AvrPtoB is translocated into plant cells via the bacterial type III secretion system. In resistant tomato leaves, AvrPtoB acts as an avirulence protein by interacting with the host Pto kinase and eliciting the host immune response. Pto-mediated immunity requires Prf, a Pto interacting protein with a putative nucleotide-binding site and a region of leucine-rich repeats. In susceptible tomato plants, which lack either Pto or Prf, AvrPtoB acts as a virulence protein by promoting P. syringae pv. tomato growth and enhancing symptoms associated with bacterial speck disease. The N-terminal 307 amino acids of AvrPtoB (designated AvrPtoB(1-307)) are sufficient for these virulence activities and for Pto-mediated avirulence. We report that AvrPtoB is phosphorylated by a Pto- and Prf-independent kinase activity that is conserved in several plant species, including tomato (Solanum lycopersicum), Nicotiana benthamiana, and Arabidopsis thaliana. AvrPtoB(1-307) was phosphorylated in tomato protoplasts, and mass spectrometry identified serine 258 as the major in vivo phosphorylation site of this protein. An alanine substitution of Ser(258) resulted in the loss of virulence and the diminution of avirulence activity of AvrPtoB(1-307), whereas a phosphomimetic S258D mutant had activities similar to wild type AvrPtoB(1-307). These observations suggest that AvrPtoB has evolved to mimic a substrate of a conserved plant kinase, leading to enhancement of its virulence and avirulence activities in the host cell. PMID- 17711845 TI - Fidelity and processivity of reverse transcription by the human mitochondrial DNA polymerase. AB - We have characterized, by transient-state kinetic methods, the polymerase and exonuclease activities of the human mitochondrial DNA polymerase (pol gamma) during reverse transcription, employing a synthetic oligonucleotide consisting of a DNA primer and an RNA template. In comparison with the kinetic parameters observed with a DNA template, the rate of correct deoxynucleotide incorporation was reduced 25-fold (5.5+/-0.2 s(-1)), whereas the dissociation constant (Kd) for nucleotide binding was increased 4-fold (12+/-1 microm). In addition, discrimination against mismatches was reduced approximately 20-fold to only 15,000 on average. The proofreading exonuclease favored the removal of an incorrect nucleotide (0.0021+/-0.0002 s(-1) for correct versus 0.034+/-0.004 s( 1) for incorrect), and the partitioning between incorporation beyond a mismatch (5.5x10(-5)+/-0.4x10(-5) s(-1)), and exonuclease removal of that mismatch favors removal of the mismatch. These data suggest that the "reverse transcriptase activity" of mitochondrial polymerase could be physiologically relevant. However, the enzyme stalls and is unable to efficiently incorporate beyond a single nucleotide with an RNA template. Additionally, we present a refined method for calculating net discrimination, which more accurately describes the contributions of correct and incorrect incorporation. The biological and biotechnological significance of these results are discussed. PMID- 17711846 TI - The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. AB - The maintenance of homeostasis throughout an organism's life span requires constant adaptation to changes in energy levels. The AMP-activated protein kinase (AMPK) plays a critical role in the cellular responses to low energy levels by switching off energy-consuming pathways and switching on energy-producing pathways. However, the transcriptional mechanisms by which AMPK acts to adjust cellular energy levels are not entirely characterized. Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites. Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. Using a genome-wide microarray analysis, we identify a set of target genes that are regulated by FOXO3 when phosphorylated at these six regulatory sites in mammalian cells. The regulation of FOXO3 by AMPK may play a crucial role in fine tuning gene expression programs that control energy balance and stress resistance in cells throughout life. PMID- 17711848 TI - DNA binding suppresses human AIF-M2 activity and provides a connection between redox chemistry, reactive oxygen species, and apoptosis. AB - Human AIF-M2 is an unusual flavoprotein oxidoreductase that binds DNA, nicotinamide coenzyme, and the modified flavin 6-hydroxy-FAD. Using multiple solution methods to investigate the redox chemistry and binding interactions of AIF-M2, we demonstrate that binding of DNA and coenzyme to AIF-M2 is mutually exclusive. We also show that DNA binding does not perturb the redox chemistry of AIF-M2, but it has significant effects on the reduction kinetics of the 6-hydroxy FAD cofactor by NAD(P)H. Based on quantitative analysis of ligand binding and redox chemistry, we propose a model for the function of AIF-M2. In this model, DNA binding suppresses the redox activity of AIF-M2 by preventing the binding of the reducing coenzyme NAD(P)H. This DNA-mediated suppression of AIF-M2 activity is expected to lower cellular levels of superoxide and peroxide, thereby lessening survival signaling by Ras, NF-kappaB, or AP-1, as suggested from knock out studies of the related AIF in human colon cancer cell lines. We show marked differences between AIF-M2 and AIF. DNA and coenzyme binding activity is retained in the C-terminal deletion mutant AIF-M2-(Delta319-613), whereas DNA binds to the C-terminal D3 domain of AIF. Our work provides the first analysis of AIF-M2 ligand interactions and redox chemistry and identifies an important mechanistic connection between coenzyme and DNA binding, redox activity, and the apoptotic function of AIF-M2. Through its DNA binding activity, we suggest that AIF-M2 lessens survival cell signaling in the presence of foreign (e.g. bacterial and (retro)viral) cytosolic DNA, thus contributing to the onset of apoptosis. PMID- 17711849 TI - Identification and characterization of human cdc7 nuclear retention and export sequences in the context of chromatin binding. AB - The Cdc7 serine/threonine kinase activates the initiation of DNA replication by phosphorylating MCM proteins that are bound to the origins of DNA replication. We reported previously that human Cdc7 nuclear import is mediated directly by importin-beta through its binding to the Cdc7 nuclear localization sequence (NLS). Here, we report that human Cdc7 nuclear localization is regulated by two additional elements: nuclear retention (NRS) and export sequences (NES). Cdc7 proteins imported into the nucleus are retained in the nucleus by associating with chromatin, for which NRS-(306-326) is essential. Importantly, this binding appears to be specific to the origin of DNA replication, because the binding of wild-type Cdc7 to origin is 2.4-fold higher than to non-origin DNA. Furthermore, an NRS-defective Cdc7 mutant could not be retained in the nucleus, although it was imported into the nucleus normally. Together, our data suggest that NRS plays an important role in the activation of DNA replication by Cdc7. The Cdc7 proteins unassociated with chromatin are bound by CRM1 via two NES elements: NES1 at 458 467 within kinase insert III, and NES2 at 545-554 within the kinase IX domain. The primary function of the Cdc7-CRM1 association may be to translocate nuclear Cdc7 to the cytoplasm. However, the binding of CRM1 with Cdc7 at NES2 raises an interesting possibility that CRM1 may also down-regulate Cdc7 by masking its kinase domain. PMID- 17711847 TI - Structure-function analysis of the WIP role in T cell receptor-stimulated NFAT activation: evidence that WIP-WASP dissociation is not required and that the WIP NH2 terminus is inhibitory. AB - WASP and its binding partner WIP play important roles in T cells both in actin polymerization and in interleukin-2 transcription. Aberrations thereof contribute to the pathology of Wiskott-Aldrich syndrome (WAS). To directly evaluate the cooperativity of WIP and WASP in interleukin-2 transcription, we investigated how the WIP-WASP complex regulates NF-AT-mediated gene transcription. We developed an improved model system for analysis, using WIP and WASP cotransfection into Jurkat cells, in which strong induction of NFAT reporter activation is observed with anti-T cell receptor (TCR) antibody without the phorbol 12-myristate 13-acetate usually used previously. Using this system, our findings contradict a prevailing conceptual model of TCR-induced WIP-WASP dissociation by showing in three ways that the WIP-WASP complex mediates TCR-induced NFAT activation without dissociation. First, phosphorylation of WIP Ser(488) does not cause dissociation of the WIP-WASP complex. Second, WIP-WASP complexes do not dissociate demonstrably after TCR stimulation. Third, a fusion protein of WIP to WASP efficiently mediates NFAT activation. Next, our studies clarify that WIP stabilization of WASP explains otherwise unexpected results in TCR-induced NFAT activation. Finally, we find that the NH(2) terminus of WIP is a highly inhibitory region for TCR-mediated transcriptional activation in which at least two elements contribute: the NH(2)-terminal polyproline and the NH(2)-terminal actin-binding WH2 domain. This suggests that WIP, like WASP, is subject to autoinhibition. Our data indicate that the WIP-WASP complex plays an important role in WASP stabilization and NFAT activation. PMID- 17711850 TI - Retrophosphorylation of Mkk1 and Mkk2 MAPKKs by the Slt2 MAPK in the yeast cell integrity pathway. AB - In Saccharomyces cerevisiae, a variety of stresses and aggressions to the cell wall stimulate the activation of the cell wall integrity MAPK pathway, which triggers the expression of a series of genes important for the maintenance of cell wall homeostasis. This MAPK module lies downstream of the Rho1 small GTPase and protein kinase C Pkc1 and consists of MAPKKK Bck1, MAPKKs Mkk1 and Mkk2, and the Slt2 MAPK. In agreement with previous reports suggesting that Mkk1 and Mkk2 were functionally redundant, we show here that both Mkk1 and Mkk2 alone or even chimerical proteins constructed by interchanging their catalytic and regulatory domains are able to efficiently maintain signal transduction through the pathway. Both Mkk1 and Mkk2 are phosphorylated in vivo concomitant to activation of the cell integrity pathway. Interestingly, hyperphosphorylation of the MEKs required not only the upstream components of the pathway, but also a catalytically competent Slt2 MAPK downstream. Active Slt2 purified from yeast extracts was able to phosphorylate Mkk1 and Mkk2 in vitro. We have mapped Ser(50) as a direct phosphorylation target for Slt2 in Mkk2. However, substitution of all (Ser/Thr) Pro canonical MAPK target sites with alanine did not totally abrogate Slt2 dependent Mkk2 phosphorylation. Mutation or deletion of a conserved MAPK-docking site at the N-terminal extension of Mkk2 precluded its interaction with Slt2 and negatively affected retrophosphorylation. Our data show that the cell wall integrity MAPKKs are targets for their downstream MAPK, suggesting the existence of complex feedback regulatory mechanisms at this level. PMID- 17711851 TI - Identification of a redox-sensitive cysteine in GCP60 that regulates its interaction with golgin-160. AB - Golgin-160 is ubiquitously expressed in vertebrates. It localizes to the cytoplasmic side of the Golgi and has a large C-terminal coiled-coil domain. The noncoiled-coil N-terminal head domain contains Golgi targeting information, a cryptic nuclear localization signal, and three caspase cleavage sites. Caspase cleavage of the golgin-160 head domain generates different fragments that can translocate to the nucleus by exposing the nuclear localization signal. We have previously shown that GCP60, a Golgi resident protein, interacts weakly with the golgin-160 head domain but has a strong interaction with one of the caspase generated golgin-160 fragments (residues 140-311). This preferential interaction increases the Golgi retention of the golgin-160 fragment in cells overexpressing GCP60. Here we studied the interaction of golgin-160-(140-311) with GCP60 and identified a single cysteine residue in GCP60 (Cys-463) that is critical for the interaction of the two proteins. Mutation of the cysteine blocked the interaction in vitro and disrupted the ability to retain the golgin-160 fragment at the Golgi in cells. We also found that Cys-463 is redox-sensitive; in its reduced form, interaction with golgin-160 was diminished or abolished, whereas oxidation of the Cys-463 by hydrogen peroxide restored the interaction. In addition, incubation with a nitric oxide donor promoted this interaction in vitro. These findings suggest that nuclear translocation of golgin-160-(140-311) is a highly coordinated event regulated not only by cleavage of the golgin-160 head but also by the oxidation state of GCP60. PMID- 17711852 TI - PGAP1 knock-out mice show otocephaly and male infertility. AB - A palmitate linked to the inositol in glycosylphosphatidylinositol (GPI) is removed in the endoplasmic reticulum immediately after the conjugation of GPI with proteins in most cells. Previously, we identified PGAP1 (post GPI attachment to proteins 1) as a GPI inositoldeacylase that removes the palmitate from inositol. A defect in PGAP1 caused a delay in the transport of GPI-anchored proteins (GPI-APs) from the endoplasmic reticulum to the cell surface in Chinese hamster ovary cells, although the cell-surface expression of GPI-APs in the steady state was normal. Nevertheless, in most cells, GPI-APs undergo deacylation. To elucidate the biological significance of PGAP1 in vivo, we established PGAP1 knock-out mice. Most PGAP1 knock-out mice showed otocephaly, a developmental defect, and died right after birth. However, some survived with growth retardation. Male knock-out mice showed severely reduced fertility despite the capability of ejaculation. Their spermatozoa were normal in number, motility, and ability to ascend the uterus, but were unable to go into the oviduct. In vitro, PGAP1-deficient spermatozoa showed weak attachment to the zona pellucida and a severely diminished rate of fertilization. Therefore, an extra acyl chain in GPI anchors caused severe deleterious effects to development and sperm function. PMID- 17711853 TI - T-cell intracellular antigen-1 (TIA-1)-induced translational silencing promotes the decay of selected mRNAs. AB - Gene array analysis revealed that a subset of mRNAs overexpressed in macrophages lacking the destabilizing factor TTP are also overexpressed in macrophages lacking the translational silencer TIA-1. We confirmed that a representative transcript, apobec-1, is significantly stabilized in cells lacking TIA-1. Tethering TIA-1 to a reporter transcript also promotes mRNA decay, suggesting that TIA-1-mediated translational silencing can render mRNA susceptible to the decay machinery. TIA-1-mediated decay is inhibited by small interfering RNAs targeting components of either the 5'-3' (e.g. DCP2) or the 3'-5' (e.g. exosome component Rrp46) decay pathways, suggesting that TIA-1 renders mRNA susceptible to both major decay pathways. TIA-1-mediated decay is inhibited by cycloheximide and emetine, drugs that stabilize polysomes, but is unaffected by puromycin, a drug that disassembles polysomes. These results suggest that TIA-1-induced polysome disassembly is required for enhanced mRNA decay and that TIA-1-induced translational silencing promotes the decay of selected mRNAs. PMID- 17711854 TI - Site-specific binding affinities within the H2B tail domain indicate specific effects of lysine acetylation. AB - Acetylation of specific lysines within the core histone tail domains plays a critical role in regulating chromatin-based activities. However, the structures and interactions of the tail domains and the molecular mechanisms by which acetylation directly alters chromatin structures are not well understood. To address these issues we developed a chemical method to quantitatively determine binding affinities of specific regions within the individual tail domains in model chromatin complexes. Examinations of specific sites within the H2B tail domain indicate that this tail contains distinct structural elements and binds within nucleosomes with affinities that would reduce the activity of tail-binding proteins 10-50-fold from that deduced from peptide binding studies. Moreover, we find that mutations mimicking lysine acetylation do not cause a global weakening of tail-DNA interactions but rather the results suggest that acetylation leads to a much more subtle and specific alteration in tail interactions than has been assumed. In addition, we provide evidence that acetylation at specific sites in the tail is not additive with several events resulting in similar, localized changes in tail binding. PMID- 17711855 TI - Structural characterization of the human androgen receptor ligand-binding domain complexed with EM5744, a rationally designed steroidal ligand bearing a bulky chain directed toward helix 12. AB - Antiandrogens are commonly used to treat androgen-dependent disorders. The currently used drugs unfortunately possess very weak affinity for the human AR (hAR), thus indicating the need to develop new high-affinity steroidal antiandrogens. Our compounds are specially designed to impede repositioning of the mobile carboxyl-terminal helix 12, which blocks the ligand-dependent transactivation function (AF-2) located in the AR ligand-binding domain (ARLBD). Using crystal structures of the hARLBD, we first found that H12 could be directly reached from the ligand-binding pocket (LBP) by a chain positioned on the C18 atom of an androgen steroid nucleus. A set of 5alpha-dihydrotestosterone-derived molecules bearing various C18 chains were thus synthesized and tested for their capacity to bind hAR and act as antagonists. Although most of those having very high affinity for hAR were agonists, several very potent antagonists were obtained, confirming the structural importance of the C18 chain. To understand the role of the C18 chain in their agonistic/antagonistic properties, the structure of the hARLBD complexed with one of these agonists, EM5744, was determined at a 1.65-A resolution. We have identified new interactions involving Gln(738), Met(742), and His(874) that explain both the high affinity of this compound and the inability of its bulky chain to prevent the repositioning of H12. This structural information will be helpful to refine the structure of the chains placed on the C18 atom to obtain efficient H12-directed steroidal antiandrogens. PMID- 17711856 TI - Cell shape-dependent Control of Ca2+ influx and cell cycle progression in Swiss 3T3 fibroblasts. AB - The ability of adherent cells such as fibroblasts to enter the cell cycle and progress to S phase is strictly dependent on the extent to which individual cells can attach to and spread on a substratum. Here we have used microengineered adhesive islands of 22 and 45 mum diameter surrounded by a nonadhesive substratum of polyhydroxyl methacrylate to accurately control the extent to which individual Swiss 3T3 fibroblasts may spread. The effect of cell shape on mitogen-evoked Ca2+ signaling events that accompany entry into the cell cycle was investigated. In unrestricted cells, the mitogens bombesin and fetal calf serum evoked a typical biphasic change in the cytoplasmic free Ca2+ concentration. However, when the spreading of individual cells was restricted, such that progression to S phase was substantially reduced, both bombesin and fetal calf serum caused a rapid transient rise in the cytoplasmic free Ca2+ concentration but failed to elicit the normal sustained influx of Ca2+ that follows Ca2+ release. As expected, restricting cell spreading led to the loss of actin stress fibers and the formation of a ring of cortical actin. Restricting cell shape did not appear to influence mitogen-receptor interactions, nor did it influence the presence of focal adhesions. Because Ca2+ signaling is an essential component of mitogen responses, these findings implicate Ca2+ influx as a necessary component of cell shape-dependent control of the cell cycle. PMID- 17711857 TI - Bone morphogenetic protein 2 functions via a conserved signaling pathway involving Wnt4 to regulate uterine decidualization in the mouse and the human. AB - A critical role of progesterone (P) during early pregnancy is to induce differentiation of the endometrial stromal cells into specialized decidual cells that support the development of the implanting embryo. The P-induced signaling pathways that participate in the formation and function of the decidual cells remain poorly understood. We report here that the expression of the bone morphogenetic protein 2 (BMP2), a morphogen belonging to the TGFbeta superfamily, is induced downstream of P action in the mouse uterine stroma during decidualization. To determine the function of BMP2 during this differentiation process, we employed a primary culture system in which undifferentiated stromal cells isolated from pregnant mouse uterus undergo decidualization. When recombinant BMP2 was added to these stromal cultures, it markedly advanced the differentiation program. We also found that siRNA-mediated silencing of BMP2 expression in these cells efficiently blocked the differentiation process. Gene expression profiling experiments identified Wnt4 as a downstream target of BMP2 regulation in stromal cells undergoing decidualization. Attenuation of Wnt4 expression by siRNAs greatly reduced stromal differentiation in vitro, indicating that it is a key mediator of BMP2-induced decidualization. We also observed a remarkable induction in the expression of BMP2 in human endometrial stromal cells during decidualization in vitro in response to steroids and cAMP. Addition of BMP2 to these cultures led to a robust enhancement of Wnt4 expression and stimulated the differentiation process. Collectively, our studies uncovered a unique conserved pathway involving BMP2 and Wnt4 that mediates P-induced stromal decidualization in the mouse and the human. PMID- 17711858 TI - The MIT domain of UBPY constitutes a CHMP binding and endosomal localization signal required for efficient epidermal growth factor receptor degradation. AB - We have identified and characterized a Microtubule Interacting and Transport (MIT) domain at the N terminus of the deubiquitinating enzyme UBPY/USP8. In common with other MIT-containing proteins such as AMSH and VPS4, UBPY can interact with CHMP proteins, which are known to regulate endosomal sorting of ubiquitinated receptors. Comparison of binding preferences for the 11 members of the human CHMP family between the UBPY MIT domain and another ubiquitin isopeptidase, AMSH, reveals common interactions with CHMP1A and CHMP1B but a distinct selectivity of AMSH for CHMP3/VPS24, a core subunit of the ESCRT-III complex, and UBPY for CHMP7. We also show that in common with AMSH, UBPY deubiquitinating enzyme activity can be stimulated by STAM but is unresponsive to its cognate CHMPs. The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. This is functionally significant as an MIT-deleted UBPY mutant is unable to rescue its binding partner STAM from proteasomal degradation or reverse a block to epidermal growth factor receptor degradation imposed by small interfering RNA-mediated depletion of UBPY. PMID- 17711859 TI - Intrinsic signaling functions of the beta4 integrin intracellular domain. AB - A key issue regarding the role of alpha6beta4 in cancer biology is the mechanism by which this integrin exerts its profound effects on intracellular signaling, including growth factor-mediated signaling. One approach is to evaluate the intrinsic signaling capacity of the unique beta4 intracellular domain in the absence of contributions from the alpha6 subunit and tetraspanins and to assess the ability of growth factor receptor signaling to cooperate with this domain. Here, we generated a chimeric receptor composed of the TrkB extracellular domain and the beta4 transmembrane and intracellular domains. Expression of this chimeric receptor in beta4-null cancer cells enabled us to assess the signaling potential of the beta4 intracellular domain alone or in response to dimerization using brain-derived neurotrophic factor, the ligand for TrkB. Dimerization of the beta4 intracellular domain results in the binding and activation of the tyrosine phosphatase SHP-2 and the activation of Src, events that also occur upon ligation of intact alpha6beta4. In contrast to alpha6beta4 signaling, however, dimerization of the chimeric receptor does not activate either Akt or Erk1/2. Growth factor stimulation induces tyrosine phosphorylation of the chimeric receptor but does not enhance its binding to SHP-2. The chimeric receptor is unable to amplify growth factor-mediated activation of Akt and Erk1/2, and growth factor-stimulated migration. Collectively, these data indicate that the beta4 intracellular domain has some intrinsic signaling potential, but it cannot mimic the full signaling capacity of alpha6beta4. These data also question the putative role of the beta4 intracellular domain as an "adaptor" for growth factor receptor signaling. PMID- 17711860 TI - Co-receptor requirements for fibroblast growth factor-19 signaling. AB - FGF19 is a unique member of the fibroblast growth factor (FGF) family of secreted proteins that regulates bile acid homeostasis and metabolic state in an endocrine fashion. Here we investigate the cell surface receptors required for signaling by FGF19. We show that betaKlotho, a single-pass transmembrane protein highly expressed in liver and fat, induced ERK1/2 phosphorylation in response to FGF19 treatment and significantly increased the interactions between FGF19 and FGFR4. Interestingly, our results show that alphaKlotho, another Klotho family protein related to betaKlotho, also induced ERK1/2 phosphorylation in response to FGF19 treatment and increased FGF19-FGFR4 interactions in vitro, similar to the effects of betaKlotho. In addition, heparin further enhanced the effects of both alphaKlotho and betaKlotho in FGF19 signaling and interaction experiments. These results suggest that a functional FGF19 receptor may consist of FGF receptor (FGFR) and heparan sulfate complexed with either alphaKlotho or betaKlotho. PMID- 17711862 TI - Generation of multipotential mesendodermal progenitors from mouse embryonic stem cells via sustained Wnt pathway activation. AB - Pluripotent embryonic stem cells (ESCs) are capable of differentiating into cell types belonging to all three germ layers within the body, which makes them an interesting and intense field of research. Inefficient specific differentiation and contamination with unwanted cell types are the major issues in the use of ESCs in regenerative medicine. Lineage-specific progenitors generated from ESCs could be utilized to circumvent the issue. We demonstrate here that sustained activation of the Wnt pathway (using Wnt3A or an inhibitor of glycogen synthase kinase 3beta) in multiple mouse and human ESCs results in meso/endoderm-specific differentiation. Using monolayer culture conditions, we have generated multipotential "mesendodermal progenitor clones" (MPC) from mouse ESCs by sustained Wnt pathway activation. MPCs express increased levels of meso/endodermal and mesendodermal markers and exhibit a stable phenotype in culture over a year. The MPCs have enhanced potential to differentiate along endothelial, cardiac, vascular smooth muscle, and skeletal lineages than undifferentiated ESCs. In conclusion, we demonstrate that the Wnt pathway activation can be utilized to generate lineage-specific progenitors from ESCs, which can be further differentiated into desired organ-specific cells. PMID- 17711863 TI - Identification of novel autoxidation products of the omega-3 fatty acid eicosapentaenoic acid in vitro and in vivo. AB - Increased intake of fish oil rich in the omega-3 fatty acids eicosapentaenoic acid (EPA, C20:5 omega-3) and docosahexaenoic acid (DHA, C22:6 omega-3) reduces the incidence of human disorders such as atherosclerotic cardiovascular disease. However, mechanisms that contribute to the beneficial effects of fish oil consumption are poorly understood. Mounting evidence suggests that oxidation products of EPA and DHA may be responsible, at least in part, for these benefits. Previously, we have defined the free radical-induced oxidation of arachidonic acid in vitro and in vivo and have proposed a unified mechanism for its peroxidation. We hypothesize that the oxidation of EPA can be rationally defined but would be predicted to be significantly more complex than arachidonate because of the fact that EPA contains an addition carbon-carbon double bond. Herein, we present, for the first time, a unified mechanism for the peroxidation of EPA. Novel oxidation products were identified employing state-of-the-art mass spectrometric techniques including Ag(+) coordination ionspray and atmospheric pressure chemical ionization mass spectrometry. Predicted compounds detected both in vitro and in vivo included monocylic peroxides, serial cyclic peroxides, bicyclic endoperoxides, and dioxolane-endoperoxides. Systematic study of the peroxidation of EPA provides the basis to examine the role of specific oxidation products as mediators of the biological effects of fish oil. PMID- 17711861 TI - Glycogen synthase kinase-3beta induces neuronal cell death via direct phosphorylation of mixed lineage kinase 3. AB - Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase member that activates the c-Jun N-terminal kinase (JNK) pathway. Aberrant activation of MLK3 has been implicated in neurodegenerative diseases. Similarly, glycogen synthase kinase (GSK)-3beta has also been shown to activate JNK and contribute to neuronal apoptosis. Here, we show a functional interaction between MLK3 and GSK-3beta during nerve growth factor (NGF) withdrawal-induced cell death in PC-12 cells. The protein kinase activities of GSK-3beta, MLK3, and JNK were increased upon NGF withdrawal, which paralleled increased cell death in NGF deprived PC-12 cells. NGF withdrawal-induced cell death and MLK3 activation were blocked by a GSK-3beta-selective inhibitor, kenpaullone. However, the MLK family inhibitor, CEP-11004, although preventing PC-12 cell death, failed to inhibit GSK 3beta activation, indicating that induction of GSK-3beta lies upstream of MLK3. In GSK-3beta-deficient murine embryonic fibroblasts, ultraviolet light was unable to activate MLK3 kinase activity, a defect that was restored upon ectopic expression of GSK-3beta. The activation of MLK3 by GSK-3beta occurred via phosphorylation of MLK3 on two amino acid residues, Ser(789) and Ser(793), that are located within the C-terminal regulatory domain of MLK3. Furthermore, the cell death induced by GSK-3beta was mediated by MLK3 in a manner dependent on its phosphorylation of the specific residues within the C-terminal domain by GSK 3beta. Taken together, our data provide a direct link between GSK-3beta and MLK3 activation in a neuronal cell death pathway and identify MLK3 as a direct downstream target of GSK-3beta. Inhibition of GSK-3 is thus a potential therapeutic strategy for neurodegenerative diseases caused by trophic factor deprivation. PMID- 17711864 TI - BK channels are linked to inositol 1,4,5-triphosphate receptors via lipid rafts: a novel mechanism for coupling [Ca(2+)](i) to ion channel activation. AB - Glioma cells prominently express a unique splice variant of a large conductance, calcium-activated potassium channel (BK channel). These channels transduce changes in intracellular calcium to changes of K(+) conductance in the cells and have been implicated in growth control of normal and malignant cells. The Ca(2+) increase that facilitates channel activation is thought to occur via activation of intracellular calcium release pathways or influx of calcium through Ca(2+) permeable ion channels. We show here that BK channel activation involves the activation of inositol 1,4,5-triphosphate receptors (IP(3)R), which localize near BK channels in specialized membrane domains called lipid rafts. Disruption of lipid rafts with methyl-beta-cyclodextrin disrupts the functional association of BK channel and calcium source resulting in a >50% reduction in K(+) conductance mediated by BK channels. The reduction of BK current by lipid raft disruption was overcome by the global elevation of intracellular calcium through inclusion of 750 nm Ca(2+) in the pipette solution, indicating that neither the calcium sensitivity of the channel nor their overall number was altered. Additionally, pretreatment of glioma cells with 2-aminoethoxydiphenyl borate to inhibit IP(3)Rs negated the effect of methyl-beta-cyclodextrin, providing further support that IP(3)Rs are the calcium source for BK channels. Taken together, these data suggest a privileged association of BK channels in lipid raft domains and provide evidence for a novel coupling of these Ca(2+)-sensitive channels to their second messenger source. PMID- 17711865 TI - Medicare prescription drug benefit progress report: findings from a 2006 national survey of seniors. AB - A national survey in 2006 found that Part D secured drug coverage for most seniors who were without it in 2005, prior to the Medicare drug benefit. Seniors without drug coverage in 2006 generally fell into two groups: those in relatively good health and those potentially difficult to reach. Compared with seniors covered through employer plans or the Department of Veterans Affairs, Part D enrollees had higher out-of-pocket spending and greater cost-related nonadherence. Low-income subsidies offered protection against high out-of-pocket spending; without them, one-third of Part D enrollees at or below 150 percent of poverty paid more than $100 a month for their medications. PMID- 17711867 TI - The work of Committee 2 of ICRP on internal dosimetry. AB - Over the last few years Committee 2 of ICRP has been responsible for preparing a series of publications giving dose coefficients for intakes of radionuclides by members of the public. The last report in this series covers doses to the offspring in mothers' milk and should be issued in 2005. The emphasis of work on internal dosimetry is now concerned with occupational exposure. It is intended to replace Publications 30 and 68 that give biokinetic data and dose coefficients for intakes of radionuclides and Publications 54 and 78 that give information for bioassay interpretation, with a single series of publications. The first report of the series is expected to cover radionuclides of the elements addressed in the publications on dose coefficients for members of the public. It will also take into account new recommendations from the Commission. Subsequent publications will cover additional elements. A supporting Guidance Document is also being developed that will give more comprehensive advice on the interpretation of bioassay data. The need for this document was identified following recent interlaboratory comparisons that have shown wide variations in the way monitoring data can be interpreted in different laboratories. PMID- 17711866 TI - Methotrexate combined with isoniazid treatment for latent tuberculosis is well tolerated in patients with rheumatoid arthritis: experience from an urban arthritis clinic. AB - OBJECTIVES: Reactivation of Mycobacterium tuberculosis (TB) is a significant problem with all available tumour necrosis factor (TNF) antagonists when used to treat rheumatoid arthritis (RA), psoriatic arthritis, psoriasis and other inflammatory diseases. Concerns have been raised regarding the appropriate management of patients with latent TB (LTB) exposure (or active TB infection) before initiating TNF antagonists as the safety data of combined treatment with two potentially hepatotoxic medications, methotrexate (MTX) and isoniazid (INH), is lacking. The goal of this study was to investigate the toxicity of MTX and INH treatment in patients with RA before initiating TNF antagonists. METHODS: To investigate the toxicity of MTX and INH treatment in patients with RA we performed a retrospective chart review of patients seen at the Bellevue Hospital Arthritis Clinic in New York City between 2002 and 2006. Forty-four patients who were concomitantly treated with both drugs were included. The primary outcome investigated was increase in liver function tests (LFT). RESULTS: Transient increases in LFT were seen in 11% of patients, but in no case was this more than twice the upper limit of normal values. All abnormal LFT resolved spontaneously without intervention. In addition, no patient has developed signs or symptoms of TB reactivation. CONCLUSIONS: The use of INH for LTB was well tolerated in patients with RA on a background regimen of MTX. While the risks and benefits of all treatment must always be considered, in our experience the additive risk of INH to MTX in terms of hepatotoxicity was low. None the less it is prudent to follow LFT closely on patients taking this combination. PMID- 17711868 TI - An operational approach for aircraft crew dosimetry: the SIEVERT system. AB - The study of naturally occurring radiation and its associated risk is one of the preoccupations of bodies responsible for radiation protection. Cosmic particle flux is significantly higher on-board the aircraft that at ground level. Furthermore, its intensity depends on solar activity and eruptions. Due to their professional activity, flight crews and frequent flyers may receive an annual dose of some millisieverts. This is why the European directive adopted in 1996 requires the aircraft operators to assess the dose and to inform their flight crews about the risk. The effective dose is to be estimated using various experimental and calculation means. In France, the computerised system for flight assessment of exposure to cosmic radiation in air transport (SIEVERT) is delivered to airlines for assisting them in the application of the European directive. This professional service is available on an Internet server accessible to companies with a public section. The system provides doses that consider the routes flown by aircraft. Various results obtained are presented. PMID- 17711869 TI - The right choice: extremity dosemeter for different radiation fields. AB - Measurements of weakly penetrating radiation in personal dosimetry present problems in the design of suitable detectors and in the interpretation of their readings. For the measurement of the individual beta radiation dose, personal dosemeters for the fingers/tips are required. LiF:Mg,Cu,P is a promising thermoluminescent (TL) material which allows the production of thin detectors with sufficient sensitivity. Dosimetric properties of two different types of extremity dosemeters, designed to measure the personal dose equivalent Hp(0.07), have been compared: LiF:Mg,Ti (TLD100) and LiF:Mg,Cu,P (TLD700H). A type test for energy response for photon and beta radiation according to ISO 4037-3 and ISO 6980 was carried out and the results for both dosemeters were compared. Simultaneous measurements with both types of dosemeters were performed at workplaces, where radiopharmaceuticals containing different radioisotopes are prepared and applied. Practices in these fields are characterized by handling of high activities at very small distances between source and skin. The results from the comparison of the two-dosemeter types are presented and analysed with respect to different radiation fields. Experiments showed a satisfactory sensitivity for the thinner dosemeter (TLD 700H) for detecting beta radiation at protection levels and a good energy response. PMID- 17711870 TI - Microsomal epoxide hydrolase, glutathione S-transferase P1, traffic and childhood asthma. AB - BACKGROUND: Microsomal epoxide hydrolase (EPHX1) metabolises xenobiotics including polyaromatic hydrocarbons (PAHs). Functional variants at this locus have been associated with respiratory diseases. The effects of EPHX1 variants may depend upon exposures from tobacco smoke and traffic emissions that contain PAHs as well as variants in other enzymes in the PAH metabolic pathway such as glutathione S-transferase (GST) genes. A study was undertaken to investigate associations of variants in EPHX1, GSTM1, GSTP1 and GSTT1 with asthma and the relationships between asthma, EPHX1 metabolic phenotypes and exposure to sources of PAHs. METHODS: Odds ratios (ORs) and 95% confidence intervals (CIs) were computed to estimate the associations of genetic variants and exposures with asthma phenotypes using data from 3124 children from the Children's Health Study. RESULTS: High EPHX1 activity was associated with an increased risk for lifetime asthma (OR 1.51, 95% CI 1.14 to 1.98) which varied by GSTP1 Ile105Val genotype and by residential proximity to major roads (p for interaction = 0.006 and 0.03, respectively). Among children with GSTP1 105Val/Val genotype, those who had high EPHX1 phenotype had a fourfold (95% CI 1.97 to 8.16) increased risk of lifetime asthma than children with low/intermediate EPHX1 phenotype. Among children living within 75 metres of a major road, those with high EPHX1 activity had a 3.2-fold (95% CI 1.75 to 6.00) higher lifetime asthma risk than those with low/intermediate activity. The results were similar for current, early persistent and late onset asthma. Children with high EPHX1 phenotype, GSTP1 Val/Val genotype who lived <75 metres from a major road were at the highest asthma risk. CONCLUSION: EPHX1 and GSTP1 variants contribute to the occurrence of childhood asthma and increase asthma susceptibility to exposures from major roads. PMID- 17711871 TI - Airway inflammation in the elite athlete and type of sport. AB - BACKGROUND: The prevalence of asthma and bronchial hyper-responsiveness is greater in elite athletes than in the general population, and its association with mild airway inflammation has recently been reported. OBJECTIVE: To study the relationship between the type of sport practised at the highest levels of competition (on land or in water) and sputum induction cell counts in a group of healthy people and people with asthma. MATERIAL AND METHODS: In total, 50 athletes were enrolled. Medical history, results of methacholine challenge tests and sputum induced by hypertonic saline were analysed RESULTS: Full results were available for 43 athletes, who were classified by asthma diagnosis and type of sport (land or water sports). Nineteen were healthy (10 land and 9 water athletes) and 24 had asthma (13 land and 11 water athletes). Although the eosinophil counts of healthy people and people with asthma were significantly different (mean difference 3.1%, 95% CI 0.4 to 6.2, p = 0.008), analysis of variance showed no effect on eosinophil count for either diagnosis of asthma or type of sport. However, an effect was found for neutrophil counts (analysis of variance: F = 2.87, p = 0.04). There was also a significant correlation between neutrophil counts and both duration of training and bronchial hyper responsiveness among athletes exposed to water (Spearman's rank correlations, 0.36 and 0.47, p = 0.04 and 0.04, respectively). CONCLUSIONS: Elite athletes who practice water sports have mild neutrophilic inflammation, whether or not asthma is present, related to the degree of bronchial hyper-reactivity and the duration of training in pool water. PMID- 17711872 TI - Echocardiographic characterisation of left ventricular geometry of professional male tennis players. AB - BACKGROUND: The cardiac characteristics of various types of athletes have been defined by echocardiography. Athletes involved in predominately static exercise, such as bodybuilders, have been found to have more concentric hypertrophy, whereas those involved in dynamic exercise, such as long distance runners, have more eccentric hypertrophy. Tennis at the elite level is a sport that is a combination of static and dynamic exercise. OBJECTIVE: To characterise left ventricular geometry including left ventricular hypertrophy by echocardiography in male professional tennis players. DESIGN: Retrospective study of screening echocardiograms that were performed on male professional tennis players. SETTING: All echocardiograms were performed at the Mayo Clinic (Jacksonville, Florida, USA) between 1998-2000. PARTICIPANTS: A total of 41 male professional tennis players, with a mean age of 23. RESULTS: Left ventricular hypertrophy was present in 30 of 41 subjects (73%, 95% CI: 57%-86%). The majority of players manifested eccentric hypertrophy (n = 22, 54%). Concentric hypertrophy (n = 9, 22%) and normal geometry (n = 7, 17%) were encountered with similar frequency. Only 7% (n = 3) manifested concentric remodelling. The mean thickness of both the interventricular septum and the posterior wall was 11.0 mm. The mean LVEDd was 55 mm. The mean RWT was 0.41. The mean LVMI was 130 gm/m2 and the mean EF was 64%. Five of the 41 subjects had an abnormal septal thickness of 13 mm. CONCLUSION: This was the first study to specifically describe the full range of echocardiographically-determined left ventricular geometry in professional male tennis players. The majority of subjects exhibited abnormal geometry, predominantly eccentric hypertrophy. PMID- 17711873 TI - Randomized trial of two physiotherapy interventions for primary care back and neck pain patients: cost effectiveness analysis. AB - OBJECTIVES: To assess the cost-effectiveness of a brief physiotherapy pain management approach using cognitive-behavioural principles (Solution-Finding Approach) when compared with a commonly used traditional method of physical therapy (McKenzie Approach). METHODS: Economic evaluation conducted alongside a randomized trial. The study related incremental differences in costs and benefits associated with the Solution Finding and McKenzie approaches over 12 months. Costs were measured in UK pounds sterling. Benefit was measured as health-related quality of life using the EQ-5D, which was used to estimate patient-specific quality adjusted life years (QALYs). RESULTS: The McKenzie treatment required, on average, one extra physiotherapist visit (4.15 vs 3.10). Over a 12-month period, Solution Finding was associated with a lower per patient cost of pound-24.4 (95% CI pound-49.6 to 0.789 pounds). The mean difference in QALYs between the two groups was -0.020 (95% CI -0.057 to 0.017); favouring those receiving McKenzie. Relating incremental mean costs and QALYs gave an incremental cost effectiveness ratio of 1220 pounds (-24.4/-0.020) suggesting the McKenzie treatment is cost effective. CONCLUSIONS: Results suggest that the additional cost associated with the McKenzie treatment when compared with the Solution Finding Approach may be worth paying, given the additional benefit the approach seems more likely to provide. Further research is needed to assess the extent to which the difference in physiotherapy visits between the two strategies is generalizable to other treatment settings. PMID- 17711875 TI - A novel Fe deficiency-responsive element (FeRE) regulates the expression of atx1 in Chlamydomonas reinharditii. AB - We investigated the promoter region of atx1, which encodes a copper chaperone in response to iron deficiency induction. Deletion analysis of the promoter region from the 5' and 3' ends revealed that the -532/-461 and -320/-276 regions were necessary and sufficient for iron deficiency-inducible expression. Further deletion analysis showed that two of the Fe deficiency-responsive elements (FeREs) localized within the -532/-511 and -306/-276 regions, in which AtxFeRE1 at -529/-515 (GTCGCACTGGCATGT) and AtxFeRE2 at -300/-286 (GCAGCGATGGCATTT) had been identified, respectively, with a conserved sequence of GNNGCNNTGGCATNT, differing from all known FeREs found in other organisms. PMID- 17711874 TI - Association of the long allele of the 5-HTTLPR polymorphism with compulsive craving in alcohol dependence. AB - AIMS: Various studies have reported a role of the serotonin transporter-linked polymorphic region (5-HTTLPR) in alcoholism. METHOD: The present study investigated an association of this polymorphism with obsessive-compulsive alcohol craving in 124 male patients admitted for alcohol detoxification treatment. RESULTS: We found significantly higher compulsive craving in patients with the long allele of the 5-HTTLPR polymorphism [at admission: analysis of variance (ANOVA): F = 3.48, P = 0.034, general linear model: F = 3.92, P = 0.023; after 7 days: ANOVA: F = 3.12, P = 0.049]. CONCLUSIONS: Our results suggest that the long variant of the 5-HTTLPR polymorphism is associated with higher compulsive alcohol craving at the beginning of alcohol withdrawal. PMID- 17711876 TI - Plants utilize isoprene emission as a thermotolerance mechanism. AB - Isoprene is a volatile compound emitted from leaves of many plant species in large quantities, which has an impact on atmospheric chemistry due to its massive global emission rate (5 x 10(14) carbon g year(-1)) and its high reactivity with the OH radical, resulting in an increase in the half-life of methane. Isoprene emission is strongly induced by the increase in isoprene synthase activity in plastids at high temperature in the day time, which is regulated at its gene expression level in leaves, while the physiological meaning of isoprene emission for plants has not been clearly demonstrated. In this study, we have functionally overexpressed Populus alba isoprene synthase in Arabidopsis to observe isoprene emission from transgenic plants. A striking difference was observed when both transgenic and wild-type plants were treated with heat at 60 degrees C for 2.5 h, i.e. transformants revealed clear heat tolerance compared with the wild type. High isoprene emission and a decrease in the leaf surface temperature were observed in transgenic plants under heat stress treatment. In contrast, neither strong light nor drought treatments showed an apparent difference. These data suggest that isoprene emission plays a crucial role in a heat protection mechanism in plants. PMID- 17711877 TI - Cell-surface transglutaminase undergoes internalization and lysosomal degradation: an essential role for LRP1. AB - Tissue transglutaminase functions as a protein crosslinking enzyme and an integrin-binding adhesion co-receptor for fibronectin on the cell surface. These activities of transglutaminase and the involvement of this protein in cell-matrix adhesion, integrin-mediated signaling, cell migration and matrix organization suggest a precise and efficient control of its cell-surface expression. We report a novel mechanism of regulation of surface transglutaminase through internalization and subsequent lysosomal degradation. Constitutive endocytosis of cell-surface transglutaminase depends on plasma membrane cholesterol and the activity of dynamin-2, and involves both clathrin-coated pits and lipid rafts or caveolae. Furthermore, the key matrix ligands of transglutaminase, fibronectin and platelet-derived growth factor, promote its endocytosis from the cell surface. Our results also indicate that transglutaminase interacts in vitro and on the cell surface with the major endocytic receptor, low-density lipoprotein receptor-related protein 1, and demonstrate the requirement for this receptor in the endocytosis of transglutaminase. Finally, a deficiency of this endocytic receptor or blockade of endo-lysosomal function upregulate transglutaminase expression on the cell surface, leading to increased cell adhesion and matrix crosslinking. These findings characterize a previously unknown pathway of transglutaminase internalization and degradation that might be crucial for regulation of its adhesive and signaling functions on the cell surface and reveal a novel functional link between cell-matrix adhesion and endocytosis. PMID- 17711878 TI - Poliovirus infection blocks ERGIC-to-Golgi trafficking and induces microtubule dependent disruption of the Golgi complex. AB - Cells infected with poliovirus exhibit a rapid inhibition of protein secretion and disruption of the Golgi complex. Neither the precise step at which the virus inhibits protein secretion nor the fate of the Golgi complex during infection has been determined. We find that transport-vesicle exit from the endoplasmic reticulum (ER) and trafficking to the ER-Golgi intermediate compartment (ERGIC) are unaffected in the poliovirus-infected cell. By contrast, poliovirus infection blocks transport from the ERGIC to the Golgi complex. Poliovirus infection also induces fragmentation of the Golgi complex resulting in diffuse distribution of both large and small vesicles throughout the cell. Pre-treatment with nocodazole prevents complete fragmentation, indicating that microtubules are required for poliovirus-induced Golgi dispersion. However, virally induced inhibition of the secretory pathway is not affected by nocodazole, and Golgi dispersion was found to occur during infection with mutant viruses with reduce ability to inhibit protein secretion. We conclude that the dispersion of the Golgi complex is not in itself the cause of inhibition of traffic between the ERGIC and the Golgi. Instead, these phenomena are independent effects of poliovirus infection on the host secretory complex. PMID- 17711879 TI - Evaluation of accuracy of drug interaction alerts triggered by two electronic medical record systems in primary healthcare. AB - This article presents a study to evaluate the accuracy of drug interaction (DI) alerts triggered by two electronic medical record (EMR) systems in primary healthcare. A scenario-based software architecture analysis methodology (SAAM) was used with drug-drug interaction (DDI) pairs in hypothetical patient scenarios. A literature search identified common drugs used in the management of conditions in the elderly population. Three reference programs determined the level of severity of drug interactions, and a common severity rating scale was adapted. The EMR systems showed a limited potential to identify 'severe' clinically significant DDIs and considerable probability for triggering spurious alerts. This may explain the overriding of DI alerts and the interruption of the workflow of users of EMR systems. Reasons for EMR system deficiency included unavailable updates or programming, database functioning discrepancies, and controversies in the clinical evidence. PMID- 17711880 TI - Mobile case-based decision support for intelligent patient knowledge management. AB - Hospitals everywhere are integrating health data using electronic health record (EHR) systems, and disparate and multimedia patient data can be input by different caregivers at different locations as encapsulated patient profiles. Healthcare institutions are also using the flexibility and speed of wireless computing to improve quality and reduce costs. We are developing a mobile application that allows doctors to efficiently record and access complete and accurate real-time patient information. The system integrates medical imagery with textual patient profiles as well as expert interactions by healthcare personnel using knowledge management and case-based reasoning techniques. The application can assist other caregivers in searching large repositories of previous patient cases. Patients' symptoms can be input to a portable device and the application can quickly retrieve similar profiles which can be used to support effective diagnoses and prognoses by comparing symptoms, treatments, diagnosis, test results and other patient information. PMID- 17711881 TI - Supporting information technology across health boards in New Zealand: the role of learning in adapting to complex change. AB - This article describes a study of a major change management project involving the establishment of a shared services organization to align the information services functions for two district health boards in New Zealand. The research uncovered a capability crisis that many people experienced when they realized the magnitude of the task they were involved in. Not everyone experienced the crisis and it seems that learning, especially in a complex healthcare environment, plays an important role in reducing the negative impact of change. PMID- 17711882 TI - Assessing the quality of websites providing information on multiple sclerosis: evaluating tools and comparing sites. AB - The quality of health information available on the Internet has proved difficult to assess objectively. The Internet's growing popularity as a source of health information, accompanied by the lack of regulation of websites, has resulted in research that has developed and tested tools to evaluate health website quality. However, only a few studies have tested the validity and reliability of these tools. There is a lack of consensus about appropriate indicators with which to operationalize the concept of quality health information. This study aimed to contribute to this research by testing the validity and reliability of existing tools, through their application to websites that provided information about multiple sclerosis. Furthermore, a specific tool for evaluating multiple sclerosis information was developed, contributing to the debate about suitable criteria for measuring the ;quality' of health information on the web. PMID- 17711883 TI - How consumers search for health information. AB - To date most of the research concerning consumer health information has focused on trust and quality of health information websites. In this research, we observed 48 consumers searching for four health-related topics (some of their own choosing) using Google. Using transaction logs, video screen capture, retrospective verbal protocols and self-reported questionnaires, we examined holistically the consumer's search process. Results indicate significant problems in query formulation and in making efficient selections from results lists. PMID- 17711886 TI - Making the diagnosis of systemic lupus erythematosus in children and adolescents. AB - Approximately 15% of patients with systemic lupus erythematosus (SLE) will have the onset of their disease in childhood or adolescence. Due to the broad range of possible clinical features of SLE, the diagnosis may be difficult to make in a general pediatric or community setting. The common symptoms of SLE in children and adolescents include fever, fatigue, weight loss, arthritis, rash and renal disease. SLE is more common in non-Caucasian ethnic groups and should be considered in the differential diagnosis of a multisystem disease in these patients. In this article, the classification criteria for SLE are discussed, and an approach to making an accurate and timely diagnosis of this disease is considered. PMID- 17711887 TI - Distinctive clinical features of pediatric systemic lupus erythematosus in three different age classes. AB - It is estimated that around 20% of patients with systemic lupus erythematosus (SLE) have their onset in childhood but there have been conflicting data about the prevalence and severity of the clinical features in different age classes. We conducted this study to analyse the clinical features of patients with pediatric SLE (pSLE) with onset in infancy, prepubertal and postpubertal age. The charts of patients followed at the Department of Pediatrics, University of Padua, who met the criteria for SLE diagnosis, were reviewed. Patients were divided into three groups based on age at disease onset: group A, patients < or =2 years old, group B patients aged between 2 and 10 years, group C patients between 11 and 16 years of age. The clinical and laboratory characteristics of each group were compared. Forty-two patients with pSLE entered the study: 2 were diagnosed before the age of 2 years, 11 between 2 and 10 years and 29 between 10 and 16 years. Eleven more patients with infantile (onset <2 years) SLE (iSLE) were found by a systematic literature search on PubMed and EmBASE and added for analysis to the group A. The female preponderance was significant only in postpubertal patients (F:M = 6.3: 1) whereas the other two groups presented a similar F:M ratio (1.2: 1). In comparison with the other two groups, iSLE showed a significantly higher prevalence of cardiovascular and pulmonary involvement, anemia and thrombocytopenia and a shorter disease duration at time of diagnosis. The postpubertal group showed a higher frequency of musculoskeletal involvement and leukopenia. In prepubertal patients there was no female preponderance and the frequency of clinical features was intermediate between infantile and postpubertal patients. Complement fractions level, antinuclear antibodies (ANA), anti-dsDNA, anti-cardiolipin antibodies and lupus anti-coagulant autoantibodies were not significantly different in the three groups. In general, the prevalence of internal organs involvement in pSLE seems to decrease with age. In infants, SLE is more severe than in the following ages. Postpubertal patients have a strong female preponderance and more specific signs of disease at onset. Prepubertal patients have an intermediate disease severity and no gender predilection. PMID- 17711888 TI - Familial lupus and antiphospholipid syndrome. AB - The occurrence of systemic lupus erythematosus (SLE) in several members of a family has spurred intense efforts to identify susceptibility genes predisposing to the disease. As a result, a number of candidate association genes in different ethnic groups have been identified, and some genes have been linked to specific lupus manifestations. Particularly where familial disease occurs in childhood, and especially when it occurs prior to puberty, complement deficiencies and other immunologic defects should be explored. Evidence of other forms of autoimmunity, including autoimmune thyroiditis and antiphospholipid syndrome (APS), is common in families with SLE. Familial APS is uncommon in the absence of other thrombophilic defects, but occasionally is seen with apparent autosomal dominant inheritance. Thus far, no firm gene associations have been identified for APS, in part because of the rarity of multiplex families to study. A search for other familial causes of thrombotic disease should be performed when APS occurs in more than one family member. PMID- 17711890 TI - Unusual neurologic manifestations (I): Parkinsonism in juvenile SLE. AB - A girl with neuropsychiatric lupus demonstrated Parkinsonian features soon after commencing risperidone. The single photon emission computed tomography scan showed hyperperfusion of the basal ganglia. Symptoms abated with the addition of dopaminergic agents to immunosuppressive therapy. The literature on juvenile Parkinsonism in lupus has been reviewed. PMID- 17711889 TI - Neuropsychiatric involvement in pediatric systemic lupus erythematosus. AB - Neuropsychiatric (NP) manifestations are found in approximately 25% of children and adolescents with pediatric SLE (pSLE). In 70% of those, NP involvement will occur within the first year from the time of diagnosis. Headaches (66%), psychosis (36%), cognitive dysfunction (27%) and cerebrovascular disease (24%) are the most common presentations. The support of a psychiatrist is often required. Anti-phospholipid antibodies are associated with distinct NP disease entities and may be implicated in the pathogenesis of several manifestations of NP-pSLE including chorea, cerebrovascular disease and seizures. The role of novel auto-antibodies and imaging modalities is currently explored. The treatment of NP pSLE is not based on prospective studies; however, an immunosuppressive combination therapy consisting of high doses of prednisone and a second line agent such as cyclophosphamide or azathioprine is commonly suggested for children with NP-pSLE. The role of novel therapies is currently studied. The outcome of children with NP-pSLE is relatively good. The overall survival is 95-97%, 20% of children experience a disease flare during childhood and 25% have evidence of permanent neuropsychiatric damage. PMID- 17711891 TI - Unusual neurologic manifestations (II): posterior reversible encephalopathy syndrome (PRES) in the context of juvenile systemic lupus erythematosus. AB - Posterior reversible encepalopathy syndrome (PRES), or reversible posterior leukoencephalopathy, is a neurologic condition characterized by recognizable pattern of altered mental status, headache, visual changes and seizures in association with findings indicating a predominantly posterior leucoencephalopathy on imaging studies. It has rarely been described in children. We report two cases of pediatric systemic lupus erythematosus (SLE) complicated by PRES and review the literature. PMID- 17711892 TI - Bone status in juvenile systemic lupus erythematosus. AB - Osteoporosis is a well-recognized major health problem in adult patients with systemic lupus erythematosus (SLE). Children and adolescents with SLE, however are at even higher risk of developing osteoporosis later in life, since they develop the disease before achieving peak bone mass, which serves as a 'bone bank' for the rest of life. There is still a paucity of studies on bone mass in pediatric SLE, but those studies available provide evidence of reduced bone mass in this age group. A frequency of osteopenia of 40% measured by dual energy X-ray absorptiometry at one or more skeletal sites has been reported, and the lumbar spine is most seriously affected. Peak bone mass seems to be lower in childhood onset SLE patients compared to healthy controls, and there are no signs of catch up of bone mass in young adult patients with a history of pediatric SLE. Glucocorticoid therapy has been found to have a major negative effect on bone mass in these patients, thus the importance of keeping corticosteroid doses down to the lowest possible dose whenever possible. Interestingly, studies of oral alendronate therapy in children with rheumatic childhood diseases have shown promising results with increases of 15-33% during one year of treatment with no major side effects reported. Finally, there is a hope that new biologic therapies, which are more specific and steroid-sparing, will also have a beneficial effect on bone health in SLE in the future. PMID- 17711893 TI - Macrophage activation syndrome in juvenile systemic lupus erythematosus: an under recognized complication? AB - Macrophage activation syndrome (MAS) is a life-threatening complication of rheumatic diseases that is thought to be caused by the activation and uncontrolled proliferation of T lymphocytes and macrophages, leading to widespread haemophagocytosis and cytokine overproduction. It is seen most commonly in systemic juvenile idiopathic arthritis, but is increasingly recognized also in juvenile systemic lupus erythematosus (J-SLE). Recognition of MAS in patients with J-SLE is often challenging because it may mimic the clinical features of the underlying disease or be confused with an infectious complication. This review summarizes the characteristics of patients with J-SLE associated MAS reported in the literature or seen by the authors and analyses the distinctive clinical, diagnostic and therapeutic issues that the occurrence of MAS may raise in patients with J-SLE. PMID- 17711894 TI - Gonadal functioning and preservation of reproductive fitness with juvenile systemic lupus erythematosus. AB - Increased survival of children with juvenile systemic lupus erythematosus (jSLE) and improved prognosis have led to a change in the long-term health issues arising for jSLE patients. Preservation of gonadal functioning and fertility are of increasing importance for young adults with jSLE. Events during childhood, such as exposure to alkylating agents, may compromise the reproductive potential. Even in the absence of gonadotoxic therapies, fertility may be decreased through organs specific involvement with jSLE. Strategies to preserve the reproductive potential of girl and boys with jSLE are discussed. PMID- 17711895 TI - Contraception in adolescents with systemic lupus erythematosus. AB - In the management of adolescents with systemic lupus erythematosus (SLE), sexual activity and prevention of unwanted pregnancies are important topics. Many contraceptive methods are available nowadays. Oral contraceptives (OCs) are the preferred choice among adolescents in general. However, the use of these medications in adolescents with SLE raises serious concerns, particularly the risk of thrombotic events from estrogen exposure and the impact of these medications on lupus activity. In this article, different contraceptive methods available are reviewed and their application in adolescents with SLE is discussed. In conclusion, OCs are the methods of choice in adolescents with stable disease and no antiphospholipid antibodies (aPL) detected. In patients with aPL, fewer options are available, and the selection of the preferred form of contraception should be made on an individual basis. PMID- 17711896 TI - Lupus in adolescence. AB - Juvenile systemic lupus erythematosus (JSLE) represents 15-20% of all SLE cases. The leading presenting symptoms of JSLE are constitutional and not specific such as fatigue, headache, weight loss or mood swings. They are also encountered in healthy adolescents, which explains frequent diagnosis delay. The frequency of irreversible damage is high in JSLE and involves especially the renal, musculoskeletal and neuropsychiatric systems. Although the overall prognosis has markedly improved, thanks to earlier diagnosis and new therapeutic approaches, cardiovascular, hematological events and chronic renal failure remain severe, and constitute the main disease-related causes of death. Treatment is based on hydroxycloroquine and corticosteroids. Immunosuppressive agents must be discussed to decrease the duration of corticosteroids use. New drugs and monoclonal antibodies targeting B-cells and B-cell related cytokines are being evaluated with encouraging results. Management of JSLE has to challenge three objectives: controlling disease progression, obtaining patient's adherence to treatment, and preventing consequences of medication side effects on growth, puberty, development and fertility. Patients' quality of life and psychosocial development have also to be taken into account, as well as the organization of a successful transition from paediatric to adult care. PMID- 17711897 TI - Systemic lupus erythematosus in the young: the importance of a transition clinic. AB - The objective of this report is to focus on the problems of patients with childhood onset systemic lupus erythematosus (SLE) at the age of transition to an adult care Unit. SLE is a multisystem disease characterised by diffuse internal organ involvement and by the presence of antinuclear and anti DNA antibodies. Central nervous system and renal damage are the main complications especially in children. Transition in health-care is a multifaceted, active process that attends to the medical, psychosocial and educational-vocational needs of adolescents when they move from child to adult-oriented lifestyles and systems. Lack of institutional support and difficulty in communicating and in identifying adult specialists are the major concerns in a transition care Unit. Psychosocial matters can make this change dramatic and hard for young people and their families. Patients with juvenile-onset SLE require specialised and multidisciplinary care when entering a transition clinic; physicians need to focus on preventing long-term complications of SLE, including atherosclerosis, obesity, osteoporosis and their treatment. We report on our experience in a cohort of patients with juvenile SLE cared for at our transition clinic over last six years. PMID- 17711898 TI - Management of dyslipidemia in children and adolescents with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an independent risk factor for atherosclerosis, placing children and adolescents with SLE at great risk for developing cardiovascular sequelae, including myocardial infarction, in adulthood. Dyslipidemia and other traditional cardiac risk factors occur frequently in pediatric SLE and are often under-recognized and under-treated. Two dyslipidemia patterns are evident in pediatric SLE. Active disease is characterized by elevated triglycerides (TG) and low high density lipoprotein (HDL). With SLE treatment HDL and TG often normalize, while total cholesterol and low density lipoprotein (LDL) rise. The complex pathophysiology of dyslipidemia in SLE involves cytokines, autoantibodies, disease activity, medications, diet, and physical activity level, as well as other factors. Routine screening for dyslipidemia with fasting lipid profiles is indicated for children and adolescents with SLE. If lipoprotein levels are abnormal, first line therapy involves diet and exercise interventions for a minimum of six months. For persistent dyslipidemia, several pharmacologic therapies are available. Hydroxychloroquine, a common treatment for SLE, can improve lipid profiles and should be considered for all patients with SLE. Statins and bile acid sequestrants are typically added first for dyslipidemia, while niacin and fibrates are reserved for refractory disease and optimally prescribed in a multidisciplinary lipid clinic. Future research is needed to further illuminate the mechanisms of dyslipidemia in pediatric SLE with well designed clinical trials to determine the safest and most effective interventions to correct lipid profiles and prevent atherosclerosis. PMID- 17711899 TI - Antiphospholipid antibodies in pediatric systemic lupus erythematosus and the antiphospholipid syndrome. AB - The antiphospholipid syndrome (APS) is recognized increasingly as the most common acquired hypercoagulation state of autoimmune etiology and may occur as an isolated clinical entity (primary APS) or in association with an underlying systemic disease, particularly systemic lupus erythematosus (SLE). The major differences between pediatric and adult APS include absence of common acquired risk factors for thrombosis, absence of pregnancy-related morbidity, increased incidence of infection-induced antibodies, differences in cut-off values for determination of aPL and specific factors regarding long-term therapy in children. APS in children has been largely reported in patients with arterial or venous thromboses and less frequently in association with neurological or hematological manifestations. The presence of aPL in pediatric SLE can modify the disease expression and may be an important predictor of the development of irreversible organ damage. Two recently established international registries of neonates and children with APS provide a good opportunity to conduct large, prospective studies on the clinical significance of aPL and long-term outcome of pediatric APS. PMID- 17711900 TI - Infant perinatal thrombosis and antiphospholipid antibodies: a review. AB - Perinatal thrombosis in infants born to mothers with antiphospholipid antibodies (aPL) is a rare event, but with risk of death or severe sequelae. We analysed 16 infants with such perinatal thrombosis reported in the literature in the last 20 years. Thromboses were arterial (13/16), mostly strokes (8/16). Hydrops fetalis with left renal vein thrombosis was associated to a lupus anticoagulant (LA) present only in the child. Risk factors additional to aPL: either prenatal (preeclampsia and/or intra-uterine growth retardation) or perinatal (asphyxia, sepsis, arterial or venous catheter and congenital thrombophilia) were present (one to four of them) in nine out of the 14 evaluable babies. aPL were the only risk factor found in five full term babies who suffered from stroke in four cases and from renal thrombosis in another. Eleven of these infants with aPL in their serum presented a neonatal APS with the same antibody (LA or aCL IgG) found in neonates and their mothers, while the other infants had thrombosis with aPL only in their mother's blood. aCL IgM was only found in one neonate who suffered from sepsis. Thrombosis treatments were diverse. This analysis suggests that women with aPL should be investigated for other thrombophilic risk factors and that aPL should be detected systematically at birth in the offspring of mothers with APS. PMID- 17711901 TI - Congenital heart block: clinical features and therapeutic approaches. AB - Isolated congenital heart block is strongly associated with anti-Ro antibodies. It occurs in 2% of anti-Ro antibody positive pregnancies with a recurrence rate of 17-19%. Mortality is high in the first year of life (12-41%) and is predominantly due to dilated cardiomyopathy. A prolonged QTc occurs in 15-22% of cases and minor structural defects such as atrial septal defects and patent arterial ducts are well recognized. The 'mechanical' PR interval can now be measured in utero allowing for the detection of first-degree heart block. Both first and second-degree heart block detected in utero respond to therapy with fluorinated steroids. Complete congenital heart block is not reversible. Progression from a normal PR interval to complete heart block can occur within a week. IVIG is under investigation for the prevention of recurrence of congenital heart block, while dexamethasone should not be used for this purpose due to unacceptable toxicity. Data on the use of fluorinated steroids for established complete heart block is conflicting, although their use in cases where there is evidence of hydrops, poor ventricular function or both is not controversial. PMID- 17711902 TI - Selective IgA deficiency in children and adults with systemic lupus erythematosus. AB - The objective of this study was to determine the frequency and clinical characteristics of selective IgA deficiency (SIgAD) in children and adults with systemic lupus erythematosus (SLE), and evaluate potential differences in presentation and course of the SLE. IgA deficiency was defined as a serum IgA concentration < or =0.01 mg/mL determined on two sera by radial diffusion. SLE was classified by the 1982 criteria of the American College of Rheumatology. Seventy-seven children with SLE followed prospectively for > or =20 years and 152 adults surveyed during a one-year period were assayed for serum IgA levels. Disease characteristics were compared among the deficient patients and the IgA normal patients. Twelve patients with SIgAD were identified: 1) Juvenile(J)-SLE: four children with juvenile onset (< or =18 years) and four others encountered as adults; and 2) Adult(A)-SLE: four patients with adult onset. No significant differences were found in clinical presentation or course except for a possible increase in recurrent infections and the observation that there were only two African-Americans. Five patients had received blood transfusions with no reactions; three of these patients had serum anti-IgA antibodies. One pediatric patient developed low levels of IgA (/=10 ng of cancer cell DNA and in CRC stool with a range of native human DNA amounts from 4 to 832 ng. Without MBD enrichment, methylated vimentin was not detected in the enriched stools and was detected in only 1 cancer stool with high human DNA (832 ng). In stools from healthy individuals methylated vimentin was not detected, with or without MBD enrichment. CONCLUSIONS: MBD capture increases assay sensitivity for detecting methylated DNA markers in stool. Applied clinical studies for stool cancer screening are indicated. PMID- 17712003 TI - Second-trimester reference intervals for thyroid tests: the role of ethnicity. AB - BACKGROUND: Thyroid function changes during pregnancy, complicating the diagnosis of thyroid disorders. Maternal thyroid dysfunction has been associated with a variety of adverse outcomes. We evaluated thyroid function test results by ethnicity and week of gestation during the 2nd trimester of pregnancy. METHODS: We collected 3064 blood specimens in serum tubes from Asians (13%), blacks (22%), Hispanics (23%), and whites (42%). We measured thyroid-stimulating hormone (TSH), total and free thyroxine (TT4 and FT4), total and free triiodothyronine (TT3 and FT3), thyroglobulin autoantibodies (TgAb), and thyroid peroxidase autoantibodies (TPOAb) by use of an ARCHITECT i2000(SR) (Abbott Diagnostics). The TSH reference interval was calculated for samples negative for both TgAb and TPOAb and reference intervals for TT4, FT4, TT3, and FT3 in antibody-negative samples with normal TSH. RESULTS: Serum samples were positive for TgAb in 10.6%, 1.8%, 6.2%, 6.5%, and 5.9% of Asian, black, Hispanic, white, and combined groups, respectively. Samples were positive for TPOAb in 12.4%, 4.1%, 11.8%, 12.3%, and 10.4% of the same groups, respectively. The nonparametric reference intervals for all participants were 0.15-3.11 mIU/L (TSH), 9.3-15.2 pmol/L (0.72-1.18 ng/dL; FT4), 89.0-176.3 nmol/L (6.90-13.67 mug/dL; TT4), 3.82-5.96 pmol/L (2.48-3.87 pg/mL; FT3), and 1.82-3.68 nmol/L (118-239 ng/dL; TT3). CONCLUSIONS: Blacks had lower prevalences of TgAb and TPOAb positivity and of increased serum TSH. The prevalence of TgAb and TPOAb positivity was highest in Asians. Whites had the highest prevalence of increased TSH. The lower and upper reference limits of TT3 were significantly lower for Asians. Reference intervals for women in the 2nd trimester were different from those of nonpregnant individuals. PMID- 17712004 TI - Quantification of diphtheria toxin mediated ADP-ribosylation in a solid-phase assay. AB - BACKGROUND: Because of reduced vaccination programs, the number of diphtheria infections has increased in the last decade. Diphtheria toxin (DT) is expressed by Corynebacterium diphtheriae and is responsible for the lethality of diphtheria. DT inhibits cellular protein synthesis by ADP-ribosylation of the eukaryotic elongation factor 2 (eEF2). No in vitro system for the quantification of DT enzymatic activity exists. We developed a solid-phase assay for the specific detection of ADP-ribosylation by DT. METHODS: Solid phase-bound his-tag eEF2 is ADP-ribosylated by toxins using biotinylated NAD(+) as substrate, and the transferred biotinylated ADP-ribose is detected by streptavidin-peroxidase. DT enzymatic activity correlated with absorbance. We measured the amount of ADP ribosylated eEF2 after precipitation with streptavidin-Sepharose. Quantification was done after Western blotting and detection with anti-his-tag antibody using an LAS-1000 System. RESULTS: The assay detected enzymatically active DT at 30 ng/L, equivalent to 5 mU/L ADP-ribosylating activity. Pseudomonas exotoxin A (PE) activity was also detected at 100 ng/L. We verified the assay with chimeric toxins composed of the catalytic domain of DT or PE and a tumor-specific ligand. These chimeric toxins revealed increased signals at 1000 ng/L. Heat-inactivated DT and cholera toxin that ADP-ribosylates G-proteins did not show any signal increase. CONCLUSIONS: The assay may be the basis for the development of a routine diagnostic assay for the detection of DT activity and highly specific inhibitors of DT. PMID- 17712006 TI - T-cell regulatory gene CTLA-4 polymorphism/haplotype association with autoimmune pancreatitis. AB - BACKGROUND: Autoimmune pancreatitis (AIP) is a distinct disease entity of chronic pancreatitis. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a key negative regulator of the T-cell immune response, and its gene is highly polymorphic. Many positive associations between cytotoxic T-lymphocyte-associated protein 4 (CTLA4) single-nucleotide polymorphisms and various autoimmune diseases have been identified. We investigated possible genetic associations of CTLA4 in a Chinese population with AIP. METHODS: We performed genotyping for CTLA4 (49 A/G, 318 C/T, and CT60 A/G) and tumor necrosis factor (TNF)-alpha promoter (-857 C/T, 863 C/A, and -1031 C/T) by use of PCR sequence-specific primers and direct sequencing, respectively, in 46 patients with AIP, 78 patients with chronic calcifying pancreatitis (CCP), and 200 healthy individuals. RESULTS: We found a significant increase in CTLA4 49A carriers in patients with AIP compared with healthy individuals (78.3% vs 48%; P <0.0001). The frequency of CTLA4 49A was also significantly higher in patients with AIP compared with CCP (78.3% vs 37.1%; P <0.0001). CTLA4 49A conferred a higher risk of AIP [with CCP, odds ratio (OR) 7.20; P <0.0001]. The -318C/+49A/CT60G haplotype was associated with a higher susceptibility to AIP (OR 8.53; P = 0.001). The TNF-alpha promoter -863A was associated with extrapancreatic involvement in patients with AIP. CONCLUSION: CTLA-4 49A polymorphism and -318C/+49A/CT60G haplotype are associated with AIP in a Chinese population. PMID- 17712005 TI - Plasma free metanephrine measurement using automated online solid-phase extraction HPLC tandem mass spectrometry. AB - BACKGROUND: Quantification of plasma free metanephrine (MN) and normetanephrine (NMN) is considered to be the most accurate test for the clinical chemical diagnosis of pheochromocytoma and follow-up of pheochromocytoma patients. Current methods involve laborious, time-consuming, offline sample preparation, coupled with relatively nonspecific detection. Our aim was to develop a rapid, sensitive, and highly selective automated method for plasma free MNs in the nanomole per liter range. METHODS: We used online solid-phase extraction coupled with HPLC tandem mass spectrometric detection (XLC-MS/MS). Fifty microliters plasma equivalent was prepurified by automated online solid-phase extraction, using weak cation exchange cartridges. Chromatographic separation of the analytes and deuterated analogs was achieved by hydrophilic interaction chromatography. Mass spectrometric detection was performed in the multiple reaction monitoring mode using a quadrupole tandem mass spectrometer in positive electrospray ionization mode. RESULTS: Total run-time including sample cleanup was 8 min. Intra- and interassay analytical variation (CV) varied from 2.0% to 4.7% and 1.6% to 13.5%, respectively, whereas biological intra- and interday variation ranged from 9.4% to 45.0% and 8.4% to 23.2%. Linearity in the 0 to 20 nmol/L calibration range was excellent (R(2) > 0.99). For all compounds, recoveries ranged from 74.5% to 99.6%, and detection limits were <0.10 nmol/L. Reference intervals for 120 healthy adults were 0.07 to 0.33 nmol/L (MN), 0.23 to 1.07 nmol/L (NMN), and <0.17 nmol/L (3-methoxytyramine). CONCLUSIONS: This automated high-throughput XLC MS/MS method for the measurement of plasma free MNs is precise and linear, with short analysis time and low variable costs. The method is attractive for routine diagnosis of pheochromocytoma because of its high analytical sensitivity, the analytical power of MS/MS, and the high diagnostic accuracy of free MNs. PMID- 17712007 TI - HPLC method for plasma vitamin K1: effect of plasma triglyceride and acute-phase response on circulating concentrations. AB - BACKGROUND: The plasma concentration of vitamin K(1) (phylloquinone) is the most reliable index for assessing vitamin K status. Our aim was to analytically validate an HPLC method for quantifying phylloquinone in plasma and to examine the effect of plasma triglyceride concentration on the phylloquinone reference interval. We also examined the effect of acute-phase response on phylloquinone concentration in plasma. METHODS: Phylloquinone was extracted from fasting plasma samples by deproteinization and C18 solid-phase extraction, separated by reversed phase HPLC, and detected fluorometrically after postcolumn reduction with a platinum catalyst. We synthesized a novel internal calibrator, docosyl naphthoate. RESULTS: The recovery of phylloquinone was >90%. Between-run imprecision was 8.7%-9.0%, and within-run imprecision was 3.8%-7.0%. The linearity was up to 44.8 nmol/L, limit of detection 0.08 nmol/L, and limit of quantification 0.14 nmol/L. The correlation between plasma phylloquinone and triglyceride concentrations was r = 0.7 in the reference population. The 95% reference interval for the phylloquinone:triglyceride ratio was 0.20 to 2.20 nmol/mmol. Plasma concentrations of C-reactive protein were significantly increased, whereas triglyceride and phylloquinone but not the phylloquinone:triglyceride ratio were transiently decreased >50% after surgery. CONCLUSION: Phylloquinone population reference intervals should be expressed as a ratio of the triglyceride concentration. Phylloquinone concentrations in plasma are decreased in acute-phase response and, unless corrected for plasma triglyceride concentration, are unlikely to be a reliable index of vitamin K status. PMID- 17712008 TI - Spurious conclusions on analog free thyroxine assay performance. PMID- 17712009 TI - A recommended improvement for specifying and estimating serum creatinine performance. PMID- 17712010 TI - Presence of the hemochromatosis S65C mutation leads to failure of amplification in a multiplex C282Y/H63D PCR. PMID- 17712012 TI - Measurements of free hemoglobin and hemolysis index: EDTA- or lithium-heparinate plasma? PMID- 17712013 TI - Hemoglobin Hagley Park: a novel (alpha82Ala-->Thr) substitution identified in an infant with severe hemolytic anemia. PMID- 17712014 TI - Comparison of the diagnostic accuracy of BNP and NT-proBNP in acute and chronic heart failure. PMID- 17712016 TI - Genetic factors for warfarin dose prediction. PMID- 17712017 TI - Evaluation of analytical performance of the Siemens ADVIA TnI ultra immunoassay. PMID- 17712018 TI - Midtrimester amniotic fluid adiponectin in normal pregnancy. PMID- 17712019 TI - Should meta-analyses of interventions include observational studies in addition to randomized controlled trials? A critical examination of underlying principles. AB - Some authors argue that systematic reviews and meta-analyses of intervention studies should include only randomized controlled trials because the randomized controlled trial is a more valid study design for causal inference compared with the observational study design. However, a review of the principal elements underlying this claim (randomization removes the chance of confounding, and the double-blind process minimizes biases caused by the placebo effect) suggests that both classes of study designs have strengths and weaknesses, and including information from observational studies may improve the inference based on only randomized controlled trials. Furthermore, a review of empirical studies suggests that meta-analyses based on observational studies generally produce estimates of effect similar to those from meta-analyses based on randomized controlled trials. The authors found that the advantages of including both observational studies and randomized studies in a meta-analysis could outweigh the disadvantages in many situations and that observational studies should not be excluded a priori. PMID- 17712020 TI - Identification and analysis of internal promoters in Caenorhabditis elegans operons. AB - The current Caenorhabditis elegans genomic annotation has many genes organized in operons. Using directionally stitched promoterGFP methodology, we have conducted the largest survey to date on the regulatory regions of annotated C. elegans operons and identified 65, over 25% of those studied, with internal promoters. We have termed these operons "hybrid operons." GFP expression patterns driven from internal promoters differ in tissue specificity from expression of operon promoters, and serial analysis of gene expression data reveals that there is a lack of expression correlation between genes in many hybrid operons. The average length of intergenic regions with putative promoter activity in hybrid operons is larger than previous estimates for operons as a whole. Genes with internal promoters are more commonly involved in gene duplications and have a significantly lower incidence of alternative splicing than genes without internal promoters, although we have observed almost all trans-splicing patterns in these two distinct groups. Finally, internal promoter constructs are able to rescue lethal knockout phenotypes, demonstrating their necessity in gene regulation and survival. Our work suggests that hybrid operons are common in the C. elegans genome and that internal promoters influence not only gene organization and expression but also operon evolution. PMID- 17712022 TI - Glycemic index, dietary fiber, and risk of type 2 diabetes in a cohort of older Australians. PMID- 17712021 TI - A new approach to estimate parameters of speciation models with application to apes. AB - How populations diverge and give rise to distinct species remains a fundamental question in evolutionary biology, with important implications for a wide range of fields, from conservation genetics to human evolution. A promising approach is to estimate parameters of simple speciation models using polymorphism data from multiple loci. Existing methods, however, make a number of assumptions that severely limit their applicability, notably, no gene flow after the populations split and no intralocus recombination. To overcome these limitations, we developed a new Markov chain Monte Carlo method to estimate parameters of an isolation-migration model. The approach uses summaries of polymorphism data at multiple loci surveyed in a pair of diverging populations or closely related species and, importantly, allows for intralocus recombination. To illustrate its potential, we applied it to extensive polymorphism data from populations and species of apes, whose demographic histories are largely unknown. The isolation migration model appears to provide a reasonable fit to the data. It suggests that the two chimpanzee species became reproductively isolated in allopatry approximately 850 Kya, while Western and Central chimpanzee populations split approximately 440 Kya but continued to exchange migrants. Similarly, Eastern and Western gorillas and Sumatran and Bornean orangutans appear to have experienced gene flow since their splits approximately 90 and over 250 Kya, respectively. PMID- 17712023 TI - Mediterranean diet inversely associated with the incidence of metabolic syndrome: the SUN prospective cohort. PMID- 17712024 TI - Vinegar ingestion at bedtime moderates waking glucose concentrations in adults with well-controlled type 2 diabetes. PMID- 17712025 TI - Osteoprotegerin: a novel independent marker for silent myocardial ischemia in asymptomatic diabetic patients. AB - OBJECTIVE: We sought to evaluate osteoprotegerin, an inhibitor of osteoclastogenesis involved in atherosclerosis, and other novel risk factors as predictive markers of silent myocardial ischemia (SMI). RESEARCH DESIGN AND METHODS: A total of 465 consecutive diabetic patients with more than one additional risk factor were evaluated for SMI using stress myocardial perfusion imaging (MPI). We studied the association of SMI (positive stress electrocardiogram and/or abnormal MPI) with osteoprotegerin, other novel risk factors (lipoprotein[a], homocysteine, adiponectin, C-reactive protein, and fibrinogen), and conventional risk factors (total, LDL, and HDL cholesterol and triglycerides). RESULTS: A total of 92 patients were diagnosed with SMI. Of the six novel markers, osteoprotegerin was the only one associated with SMI; the relative risk (RR) of SMI in patients with osteoprotegerin values above the 75th percentile was 3.19 (95% CI 1.99-5.18; P < 0.001) in comparison with those with osteoprotegerin below the 75th percentile. In univariate analyses, the other plasma markers significantly associated with SMI were higher triglycerides (P = 0.04) and lower HDL cholesterol (P = 0.02). The association of osteoprotegerin with SMI remained significant after correcting for other variables associated with SMI at P < 0.15 in univariate analysis (RR 3.95 [95% CI 2.21-7.06]; P < 0.0001). The association of osteoprotegerin with SMI was observed in male (P < 0.0001) and female (P = 0.03) patients, in type 1 (P = 0.002) and type 2 (P = 0.0004) diabetic patients, in patients with (P = 0.0004) or without (P = 0.03) nephropathy, and in patients without (P < 0.0001) but not with (P = 0.2) peripheral arterial disease. CONCLUSIONS: Osteoprotegerin measurement, together with other conventional factors, can help to better define the diabetic population with an increased likelihood for SMI. PMID- 17712026 TI - Does waist circumference predict diabetes and cardiovascular disease beyond commonly evaluated cardiometabolic risk factors? AB - OBJECTIVE: While the measurement of waist circumference (WC) is recommended in current clinical guidelines, its clinical utility was questioned in a recent consensus statement. In response, we sought to determine whether WC predicts diabetes and cardiovascular disease (CVD) beyond that explained by BMI and commonly obtained cardiometabolic risk factors including blood pressure, lipoproteins, and glucose. RESEARCH DESIGN AND METHODS: Subjects consisted of 5,882 adults from the 1999-2004 National Health and Nutrition Examination Survey, which is nationally representative and cross-sectional. Subjects were grouped into sex-specific WC and BMI tertiles. Blood pressure, triglycerides, LDL and HDL cholesterol, and glucose were categorized using standard clinical thresholds. Logistic regression analyses were used to calculate the odds for diabetes and CVD according to WC tertiles. RESULTS: After controlling for basic confounders, the medium and high WC tertiles were more likely to have diabetes and CVD compared with the low WC tertile (P < 0.05). After inclusion of BMI and cardiometabolic risk factors in the regression models, the magnitude of the odds ratios were attenuated (i.e., for diabetes the magnitude decreased from 6.54 to 5.03 for the high WC group) but remained significant in the medium and high WC tertiles for the prediction of diabetes, though not for CVD. CONCLUSIONS: WC predicted diabetes, but not CVD, beyond that explained by traditional cardiometabolic risk factors and BMI. The findings lend critical support for the recommendation that WC be a routine measure for identification of the high-risk, abdominally obese patient. PMID- 17712027 TI - Symptoms of diabetes and their association with the risk and presence of diabetes: findings from the Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD). AB - OBJECTIVE: The American Diabetes Association (ADA) lists seven symptoms of diabetes; however, it is not known how specific these symptoms are for initial diagnosis of type 2 diabetes. The Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD) examined prevalence of ADA symptoms and their association with diabetes diagnosis. RESEARCH DESIGN AND METHODS: SHIELD is a 5-year observational study of individuals with or at risk for diabetes diagnosis. Following an initial screening phase, follow-up questionnaires were mailed to a stratified random sample of individuals (n = 22,001) with type 1 or type 2 diabetes or at high (three to five risk factors) or low (zero to two risk factors) risk for diabetes. Individuals reported whether they experienced each ADA symptom, as well as symptoms unrelated to diabetes. RESULTS: A total of 15,794 questionnaires were returned (response rate 71.8%). All ADA symptoms were reported more frequently in type 2 diabetes than in low- and high-risk groups (P < 0.0001 for each). Multivariable logistic regression analyses found that each ADA symptom other than irritability was significantly associated with type 2 diabetes, as was erectile/sexual dysfunction. However, 48% of type 1 diabetic and 44% of type 2 diabetic respondents reported no ADA symptom in the previous year. CONCLUSIONS: Occurrence of ADA symptoms alone may not adequately identify those who should be evaluated for type 2 diabetes. Longitudinal data from SHIELD will evaluate whether combinations of symptoms or addition of other symptoms can better identify individuals for evaluation. PMID- 17712028 TI - Oral health knowledge, attitude, and practices and sources of information for diabetic patients in Lahore, Pakistan. PMID- 17712029 TI - Behavior of insulin resistance and its metabolic correlates in prepubertal children: a longitudinal study (EarlyBird 32). PMID- 17712031 TI - Impact of steady-state lopinavir plasma levels on plasma lipids and body composition after 24 weeks of lopinavir/ritonavir-containing therapy free of thymidine analogues. AB - OBJECTIVES: To study the impact of lopinavir/ritonavir-containing therapy on plasma lipids and body fat of HIV-infected adults and to assess whether lopinavir plasma levels at steady state are correlated with plasma lipids and body fat after 24 weeks. METHODS: Patients had their antiretroviral therapy switched to an antiretroviral regimen containing lopinavir/ritonavir plus one or two non thymidine analogues. Body composition was assessed by dual energy X-ray absorptiometry at baseline and at week 24 and an intensive pharmacokinetic (PK) 12 h profile was performed at week 2. RESULTS: Twenty-six patients were included. Plasma triglycerides (from 206 mg/dL to 261 mg/dL, P = 0.09) and total cholesterol (from 201 to 206 mg/dL, P = 0.03) increased from baseline to week 24. There was a significant rise in total fat (from 10.9 to 11.9 kg, P = 0.02) and limb fat (from 3.8 to 4.4 kg, P = 0.02) from baseline to week 24. We did not find any correlation between PK lopinavir levels and changes over time for triglycerides, cholesterol or body fat composition. CONCLUSIONS: There was an increase in plasma triglycerides and total cholesterol levels and a gain in both total and limb fat at 24 weeks, but these changes were not correlated with lopinavir plasma levels. PMID- 17712030 TI - Aberrant epigenetic regulation could explain the relationship of paternal age to schizophrenia. AB - The causal mechanism underlying the well-established relation between advancing paternal age and schizophrenia is hypothesized to involve mutational errors during spermatogenesis that occur with increasing frequency as males age. Point mutations are well known to increase with advancing paternal age while other errors such as altered copy number in repeat DNA and chromosome breakage have in some cases also been associated with advancing paternal age. Dysregulation of epigenetic processes may also be an important mechanism underlying the association between paternal age and schizophrenia. Evidence suggests that advancing age as well as environmental exposures alter epigenetic regulation. Errors in epigenetic processes, such as parental imprinting can have serious effects on the offspring both pre- and postnatally and into adulthood. This article will discuss parental imprinting on the autosomal and X chromosomes and the alterations in epigenetic regulation that may lead to such errors. PMID- 17712032 TI - The association of DNA repair gene polymorphisms with the development and progression of renal cell carcinoma. AB - BACKGROUND: DNA repair enzymes repair some of the DNA damage associated with risk factors for renal cell carcinoma (RCC), including smoking. DNA repair gene polymorphisms modulate the repair capacity and might influence individual risk and progression of RCC. We examined associations between functional polymorphisms and risk, clinicopathologic characteristics and survival of RCC. PATIENTS AND METHODS: The study groups comprised 215 RCC patients and 215 age- and gender matched healthy controls. Polymorphisms in xeroderma pigmentosum complementation groups C, D and G and X-ray repair cross-complementing groups 1 and 3 genes were genotyped. RESULTS: No significant differences in DNA repair genotype were observed between RCC cases and controls. In all patients, however, greater numbers (> or =3) of total variant alleles in all DNA repair genes studied were associated with less frequent venous extension (P = 0.0079). In smokers, some genotypes were associated with characteristics of RCC (Ps < or = 0.0067) and smokers with greater numbers of total variant alleles had improved overall survival (P = 0.040). CONCLUSION: These results suggest that DNA repair gene polymorphisms may not influence RCC susceptibility, but that some of them may influence RCC progression, especially in smokers, possibly due to altered DNA repair capacity by these polymorphisms. PMID- 17712034 TI - Interface pressures produced by two different types of lymphedema therapy devices. AB - BACKGROUND AND PURPOSE: Sequential compression is used to manage lymphedema, but little is known about pressures delivered to the therapeutic targets. This study characterized actual pressures delivered by a traditional compression pump (Lympha Press [LP]) and one using an alternate compression pattern (Flexitouch [FT]). SUBJECTS: Ten adults who were healthy volunteered to participate in the study. METHODS: Pressure-time along the forearm was measured using a 256-pressure sensor array during the pressure cycling of each device. Device assessments were separated by at least 48 hours. RESULTS: Pressure patterns and magnitudes produced by the 2 devices differed considerably. The FT pressure pattern displayed a rapid rise and fall, progressing from the wrist toward the elbow. The LP pressure rose slower and was sustained at a higher level during its inflation cycle. Pressures delivered with the LP were significantly greater than those delivered with the FT. DISCUSSION AND CONCLUSION: The pressure patterns and magnitudes on treated limbs depend on the device. These differences should be considered before selecting a device for a specific patient. PMID- 17712035 TI - Aging and Down syndrome: implications for physical therapy. AB - The number of people over the age of 60 years with lifelong developmental delays is predicted to double by 2030. Down syndrome (DS) is the most frequent chromosomal cause of developmental delays. As the life expectancy of people with DS increases, changes in body function and structure secondary to aging have the potential to lead to activity limitations and participation restrictions for this population. The purpose of this update is to: (1) provide an overview of the common body function and structure changes that occur in adults with DS as they age (thyroid dysfunction, cardiovascular disorders, obesity, musculoskeletal disorders, Alzheimer disease, depression) and (2) apply current research on exercise to the prevention of activity limitations and participation restrictions. As individuals with DS age, a shift in emphasis from disability prevention to the prevention of conditions that lead to activity and participation limitations must occur. Exercise programs appear to have potential to positively affect the overall health of adults with DS, thereby increasing the quality of life and years of healthy life for these individuals. PMID- 17712033 TI - Repeated-slip training: an emerging paradigm for prevention of slip-related falls among older adults. AB - Falls frequently cause injury-related hospitalization or death among older adults. This article reviews a new conceptual framework on dynamic stability and weight support in reducing the risk for falls resulting from a forward slip, based on the principles of motor control and learning, in the context of adaptation and longer-term retention induced by repeated-slip training. Although an unexpected slip is severely destabilizing, a recovery step often is adequate for regaining stability, regardless of age. Consequently, poor weight support (quantified by reduction in hip height), rather than instability, is the major determinant of slip-related fall risk. Promisingly, a single session of repeated slip training can enhance neuromechanical control of dynamic stability and weight support to prevent falls, which can be retained for several months or longer. These principles provide the theoretical basis for establishing task-specific adaptive training that facilitates the development of protective strategies to reduce falls among older adults. PMID- 17712036 TI - Game-based exercises for dynamic short-sitting balance rehabilitation of people with chronic spinal cord and traumatic brain injuries. AB - BACKGROUND AND PURPOSE: Goal-oriented, task-specific training has been shown to improve function; however, it can be difficult to maintain patient interest. This report describes a rehabilitation protocol for the maintenance of balance in a short-sitting position following spinal cord and head injuries by use of a center of-pressure-controlled video game-based tool. The scientific justification for the selected treatment is discussed. CASE DESCRIPTION: Three adults were treated: 1 young adult with spina bifida (T10 and L1-L2), 1 middle-aged adult with complete paraplegia (complete lesion at T11-L1), and 1 middle-aged adult with traumatic brain injury. All patients used wheelchairs full-time. OUTCOMES: The patients showed increased motivation to perform the game-based exercises and increased dynamic short-sitting balance. DISCUSSION: The patients exhibited increases in practice volume and attention span during training with the game based tool. In addition, they demonstrated substantial improvements in dynamic balance control. These observations indicate that a video game-based exercise approach can have a substantial positive effect by improving dynamic short sitting balance. PMID- 17712037 TI - Altered microRNA expression in human heart disease. AB - MicroRNAs are recently discovered regulators of gene expression and are becoming increasingly recognized as important regulators of heart function. Genome-wide profiling of microRNAs in human heart failure has not been reported previously. We measured expression of 428 microRNAs in 67 human left ventricular samples belonging to control (n = 10), ischemic cardiomyopathy (ICM, n = 19), dilated cardiomyopathy (DCM, n = 25), or aortic stenosis (AS, n = 13) diagnostic groups. miRNA expression between disease and control groups was compared by ANOVA with Dunnett's post hoc test. We controlled for multiple testing by estimating the false discovery rate. Out of 428 microRNAs measured, 87 were confidently detected; 43 were differentially expressed in at least one disease group. In supervised clustering, microRNA expression profiles correctly grouped samples by their clinical diagnosis, indicating that microRNA expression profiles are distinct between diagnostic groups. This was further supported by class prediction approaches, in which the class (control, ICM, DCM, AS) predicted by a microRNA-based classifier matched the clinical diagnosis 69% of the time (P < 0.001). These data show that expression of many microRNAs is altered in heart disease and that different types of heart disease are associated with distinct changes in microRNA expression. These data will guide further studies of the contribution of microRNAs to heart disease pathogenesis. PMID- 17712039 TI - Nicotine responses in hypersensitive and knockout alpha 4 mice account for tolerance to both hypothermia and locomotor suppression in wild-type mice. AB - Nicotinic receptors containing the alpha 4 subunit (alpha 4* nAChRs) have high sensitivity and are widely expressed in the central nervous system, yet their contributions to behavioral tolerance, a hallmark of nicotine dependence, are unclear. To evaluate the contribution of alpha 4* and non-alpha 4 nAChRs in the development of tolerance to hypothermia and locomotor suppression, alpha 4 knockout (KO), hypersensitive Leu9'Ala alpha 4 knock-in, and wild-type (WT) mice received daily nicotine injections, and their behaviors were compared. Repeated selective activation of alpha 4* nAChRs in Leu9'Ala mice produced profound tolerance to hypothermia over 7 days, whereas no tolerance was observed in alpha 4 KO animals. The summed time course and temperature response (after appropriate normalizations) from these two mutant mouse strains resembled the time course of WT tolerance. In addition, daily selective activation of alpha 4* nAChRs elicited locomotor activation in Leu9'Ala mice, but nicotine suppressed activity in alpha 4 KO mice and this did not change with daily drug exposure. Again, appropriately combined responses from the two mutant strains resembled the biphasic nicotine induced activity in WT animals. Thus, by analyzing nicotinic responses in two complementary mouse lines, one lacking alpha 4* nAChRs, the other expressing hypersensitive alpha 4* nAChRs, one can accurately separate non-alpha 4 nAChR responses from alpha 4 nAChR responses, and one can also account for WT tolerance to both hypothermia and locomotor suppression. Our study suggests a new paradigm for bridging the gap between genetic manipulation of a single receptor and whole animal behavioral studies and shows that activation of alpha 4* nAChRs is both necessary and sufficient for the expression of tolerance. PMID- 17712038 TI - Transcriptional profiling of genes that are regulated by the endoplasmic reticulum-bound transcription factor AIbZIP/CREB3L4 in prostate cells. AB - The androgen-regulated protein androgen-induced bZIP (AIbZIP) is a bZIP transcription factor that localizes to the membrane of the endoplasmic reticulum (ER). The physiological role of AIbZIP is unknown, but other ER-bound transcription factors such as ATF6 and SREBPs play a crucial role in the regulation of protein processing and lipid synthesis, respectively. In response to alterations in the intracellular milieu, ATF6 and SREBPs are processed to their transcriptionally active forms by regulated intramembrane proteolysis. In humans, AIbZIP mRNA is expressed in several organs including the pancreas, liver, and gonads, but it is especially abundant in prostate epithelial cells. We therefore used LNCaP human prostate cancer cells as a model to identify stimuli that lead to AIbZIP activation and define the transcriptional targets of AIbZIP. In LNCaP cells, AIbZIP was processed to its transcriptionally active form by drugs that deplete ER calcium stores (i.e., A23187 and caffeine), but it was unaffected by an inhibitor of protein glycosylation (tunicamycin). To identify AIbZIP-regulated genes, we generated LNCaP cell lines that conditionally express the processed form of AIbZIP and used Affymetrix microarrays to screen for AIbZIP regulated transcripts. Selected genes (n = 48) were validated by Northern blot hybridization. The results reveal that the downstream targets of AIbZIP include genes that are implicated in protein processing (e.g., BAG3, DNAJC12, KDELR3). Strikingly, a large number of AIbZIP-regulated transcripts encode proteins that are involved in transcriptional regulation, small molecule transport, signal transduction, and metabolism. These results suggest that AIbZIP plays a novel role in cell homeostasis. PMID- 17712040 TI - Ammonia excretion in rainbow trout (Oncorhynchus mykiss): evidence for Rh glycoprotein and H+-ATPase involvement. AB - Branchial ammonia transport in freshwater teleosts is not well understood. Most studies conclude that NH(3) diffuses out of the gill and becomes protonated to NH(4)(+) in an acidified gill boundary layer. Rhesus (Rh) proteins are new members of the ammonia transporter superfamily and rainbow trout possess genes encoding for Rh30-like1 and Rhcg2. We identified seven additional full-length trout Rh cDNA sequences: one Rhag and two each of Rhbg, Rhcg1, and Rh30-like. The mRNA expression of Rhbg, Rhcg1, and Rhcg2 was examined in trout tissues (blood, brain, eye, gill, heart, intestine, kidney, liver, muscle, skin, spleen) exposed to high external ammonia (HEA; 1.5 mmol/l NH(4)HCO(3), pH 7.95, 15 degrees C). Rhbg was expressed in all tissues, Rhcg1 was expressed in brain, gill, liver, and skin, and Rhcg2 was expressed in gill and skin. Brain Rhbg and Rhcg1 were downregulated, blood Rh30-like and Rhag were downregulated, and skin Rhbg and Rhcg2 were upregulated with HEA. After an initial uptake of ammonia into the fish during HEA, excretion was reestablished, coinciding with upregulations of gill Rh mRNA in the pavement cell fraction: Rhcg2 at 12 and 48 h, and Rhbg at 48 h. NHE2 expression remained unchanged, but upregulated H(+)-ATPase (V-type, B-subunit) and downregulated carbonic anhydrase (CA2) expression and activity were noted in the gill and again expression changes occurred in pavement cells, and not in mitochondria-rich cells. Together, these results indicate Rh glycoprotein involvement in ammonia transport and excretion in the rainbow trout while underscoring the significance of gill boundary layer acidification by H(+) ATPase. PMID- 17712041 TI - Platelet-endothelial cell adhesion molecule-1-directed endothelial targeting of superoxide dismutase alleviates oxidative stress caused by either extracellular or intracellular superoxide. AB - Targeting of the antioxidant enzyme catalase to endothelial cells protects against vascular oxidative stress induced by hydrogen peroxide (H(2)O(2))(Am J Physiol 285:L283-L292, 2003; Nat Biotechnol 21:392-398, 2003; Am J Physiol 293:L162-L169, 2007). However, another reactive oxygen species, superoxide anion, is also involved in many forms of vascular oxidative stress, including ischemia/reperfusion, hypertension, and inflammation. To protect endothelium against superoxide attack, we designed and tested antibody-directed targeting of superoxide dismutase (SOD) to the endothelial surface determinant, platelet endothelial cell adhesion molecule (PECAM)-1. We synthesized anti-PECAM/SOD conjugates that retained 70% of enzymatic activity (superoxide anion dismutation) and specifically bound to endothelial cells, but not PECAM-negative cells. The effect of anti-PECAM/SOD delivery to cells was tested in two distinct models of oxidative stress induced by either extracellular or intracellular generation of superoxide anion. In the first model, anti-PECAM/SOD, but not unconjugated SOD, protected endothelial cells against injury caused by superoxide produced in the medium by hypoxanthine-xanthine oxidase. At the optimal dose, anti-PECAM/SOD provided up to 40 to 50% protection against cell death in this model. In the second model, anti-PECAM/SOD at the optimal dose provided complete protection against necrosis caused by paraquat-induced intracellular superoxide generation. Endothelial targeting of SOD represents a new molecular antioxidant approach that could be used for the management of vascular oxidative stress. PMID- 17712042 TI - Preprocedural statin therapy in percutaneous coronary intervention. AB - OBJECTIVE: To review the published literature regarding the effectiveness of preprocedural statin therapy for the prevention of cardiac events after percutaneous coronary intervention (PCI). DATA SOURCES: Searches of MEDLINE (1966 May 2007) and Cochrane Database (1993-May 2007) were conducted using the search terms statins, HMG-CoA reductase inhibitors, percutaneous coronary intervention, and myocardial necrosis. Limits included articles written in English with human subjects. Additional data were identified through bibliographic reviews. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were evaluated. Trials and studies were eligible for inclusion if they evaluated the effectiveness of preprocedural statin therapy for the prevention of cardiac events after PCI. DATA SYNTHESIS: Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) provide benefits relative to morbidity and mortality as primary and secondary prevention of cardiovascular events. In addition to lowering concentrations of low-density lipoprotein cholesterol, statins have documented pleiotropic effects including plaque stabilization as well as reductions in inflammation, platelet activation/adhesion, thrombosis, and oxidative stress. One retrospective analysis, 4 prospective observational studies, and 3 randomized controlled trials evaluating preprocedural statin therapy for the prevention of cardiac events after PCI were reviewed. Included studies were limited by small sample sizes (N = 153-5052), short durations of follow-up (24 h-21 mo), use of surrogate markers of myocardial necrosis, various degrees of coronary disease and procedure-specific factors, and lack of consistent choice of agent, dose, and duration of statin therapy. Despite these limitations, the data suggest reduced post-PCI myocardial necrosis with preprocedural statin therapy when given before elective PCI in stable patients, as well as when given before PCI in patients with recent acute coronary syndrome. CONCLUSIONS: There is growing evidence that preprocedural statin therapy reduces the incidence of post-PCI myocardial necrosis. The appropriate regimen (drug, dose, duration of treatment before the procedure), as well as the predictive role of concomitant disease states (eg, hyperlipidemia), requires further investigation. PMID- 17712043 TI - Sensitivity of patient outcomes to pharmacist interventions. Part I: systematic review and meta-analysis in diabetes management. AB - BACKGROUND: Pharmacists participate in managing diabetes therapy. Despite many reviews, few have quantified the impact of pharmacists' interventions. OBJECTIVES: To identify outcomes sensitive to pharmacists' interventions and quantify their impact through critical literature review. METHODS: All original research describing the impact of pharmacists' interventions in the management of diabetic pharmacotherapy was sought in International Pharmaceutical Abstracts, MEDLINE, Embase, Cochrane Register, and Cumulative Index to Nursing & Allied Health Literature from inception through 2006. Two independent reviewers identified articles, compared results, and settled differences through consensus. The Downs-Black scale was used to assess quality. Data included intervention type, patient numbers, demographics, study characteristics, instruments used, data compared, and outcomes reported. A random-effects meta-analysis combined amenable results. RESULTS: Of 302 articles identified, 108 involved pharmacists' interventions; 36 addressed diabetes (14 medical clinics, 11 community pharmacies, 7 ambulatory care clinics, 4 hospital wards, 1 physician's office, 1 prison, and 3 in both medical clinics and community pharmacies; 1 did not describe its practice site). Research designs included randomized (n = 18) and nonrandomized (n = 9) controlled trials, pre- and postobservational cohorts (n = 2), retrospective cohort study (n = 1), chart reviews (n = 5), and database study (n = 1). Diabetes education (69%) and medication management (61%) were the most frequently used interventions. Mean +/- SD quality was 62 +/- 11% (fair). Fifty one (69%) study results were sensitive. Meta-analysis of data from 2247 patients in 16 studies found a significant reduction in hemoglobin A1C (A1C) levels in the pharmacists' intervention group (1.00 +/- 0.28%; p < 0.001) but not in controls (0.28 +/- 0.29%; p = 0.335). Pharmacists' interventions further reduced A1C values 0.62 +/- 0.29% (p = 0.03) over controls. CONCLUSIONS: A1C is sensitive to pharmacists' interventions. Several potentially sensitive outcomes were identified, but too few studies were available for quantitative summaries. More research is needed. PMID- 17712044 TI - The HBS1L-MYB intergenic region on chromosome 6q23.3 influences erythrocyte, platelet, and monocyte counts in humans. AB - Common sequence variants situated between the HBS1L and MYB genes on chromosome 6q23.3 (HMIP) influence the proportion of F cells (erythrocytes that carry measurable amounts of fetal hemoglobin). Since the physiological processes underlying the F-cell variability are thought to be linked to kinetics of erythrocyte maturation and differentiation, we have investigated the influence of the HMIP locus on other hematologic parameters. Here we show a significant impact of HMIP variability on several types of peripheral blood cells: erythrocyte, platelet, and monocyte counts as well as erythrocyte volume and hemoglobin content in healthy individuals of European ancestry. These results support the notion that changes of F-cell abundance can be an indicator of more general shifts in hematopoietic patterns in humans. PMID- 17712045 TI - Proteinase 3, the Wegener autoantigen, is externalized during neutrophil apoptosis: evidence for a functional association with phospholipid scramblase 1 and interference with macrophage phagocytosis. AB - Proteinase 3 (PR3), a serine proteinase contained in neutrophil azurophilic granules, is considered a risk factor for vasculitides and rheumatoid arthritis when expressed on the outer leaflet of neutrophil plasma membrane and is the preferred target of antineutrophil cytoplasm autoantibodies (ANCA) in Wegener granulomatosis. ANCA binding to PR3 expressed at the surface of neutrophils activates them. Evidence is provided that neutrophil apoptosis induced significantly more membrane PR3 expression without degranulation (but no enhanced membrane CD35, CD66b, CD63, myeloperoxidase, or elastase expression). This observation was confirmed on cytoplasts, a model of granule-free neutrophils. We hypothesized that PR3 could interact with proteins involved in membrane flip-flop (eg, phospholipid scramblase 1 [PLSCR1]). PR3-PLSCR1 interaction in neutrophils was demonstrated by confocal microscopy and coimmunoprecipitation. In the RBL-2H3 rat mast-cell line stably transfected with PR3 or its inactive mutant (PR3S203A), PR3 externalization depended on PLSCR1, as shown by less PR3 externalization in the presence of rPLSCR1 siRNA, but independently of its serine-proteinase activity. Finally, apoptosis-externalized PR3 decreased the human macrophage phagocytosis rate of apoptotic PR3 transfectants. Therefore, in addition to ANCA binding in vasculitis, the proinflammatory role of membrane PR3 expression may involve interference with macrophage clearance of apoptotic neutrophils. PMID- 17712046 TI - The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia. AB - We report the molecular and cytogenetic characterization of a novel variant of acute promyelocytic leukemia (APL). The bone marrow showed 88% hypergranular promyelocytes, and the karyotype was 47,XY,+22 [5]/46,XY[30]. Fluorescence in situ hybridization (FISH) indicated disruption and deletion of the 5'-end of the RARA gene. Treatment with all-trans retinoic acid, idarubicin, and arsenic trioxide induced cytogenetic complete remission without morphologic evidence of residual leukemia. The diagnostic marrow was negative for PML-RARA transcripts by reverse transcription-polymerase chain reaction (RT-PCR), but an atypical product was observed. Sequencing showed partial homology to the PRKAR1A gene, encoding the regulatory subunit type I-alpha of cyclic adenosine monophosphate-dependent protein kinase. RT-PCR using specific primers for PRKAR1A and RARA amplified 2 transcript splice variants of a PRKAR1A-RARA fusion gene, and PRKAR1A and RARA FISH probes confirmed the fusion. This novel PRKAR1A-RARA gene rearrangement is the fifth variant APL in which the RARA partner gene has been identified and the second known rearrangement of PRKAR1A in a malignant disease. This trial was registered at www.actr.org.au with the Australian Clinical Trials Registry as number 12605000070639. PMID- 17712047 TI - JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. AB - Few investigators have evaluated the usefulness of the JAK2 V617F mutation for explaining the phenotypic variations and for predicting the risk of major clinical events in primary myelofibrosis (PMF). In a transversal survey we assayed by allele-specific polymerase chain reaction (PCR) the JAK2 V617F mutational status in 304 patients with PMF. Multiple DNA samples were collected prospectively from 64 patients, and a highly sensitive quantitative PCR was used as a confirmatory test. In a longitudinal prospective study we determined the progression rate to clinically relevant outcomes in 174 patients who had JAK2 mutation determined at diagnosis. JAK2 V617F was identified in 63.4% of patients. None of the V617F-negative patients who were sequentially genotyped progressed to become V617F positive, whereas progression rate from heterozygous to homozygous mutation was 10 per 100 patient-years. JAK2 V617F mutation contributed to hemoglobin, aquagenic pruritus, and platelet count variability, whereas homozygous mutation was independently associated with higher white blood cell count, larger spleen size, and greater need for cytoreductive therapies. Adjusting for conventional risk factors, V617F mutation independently predicted the evolution toward large splenomegaly, need of splenectomy, and leukemic transformation. We conclude that JAK2 V617F genotype should be considered in any future risk stratification of patients with PMF. PMID- 17712048 TI - Caspase-cleaved HPK1 induces CD95L-independent activation-induced cell death in T and B lymphocytes. AB - Life and death of peripheral lymphocytes is strictly controlled to maintain physiologic levels of T and B cells. Activation-induced cell death (AICD) is one mechanism to delete superfluous lymphocytes by restimulation of their immunoreceptors and it depends partially on the CD95/CD95L system. Recently, we have shown that hematopoietic progenitor kinase 1 (HPK1) determines T-cell fate. While full-length HPK1 is essential for NF-kappaB activation in T cells, the C terminal fragment of HPK1, HPK1-C, suppresses NF-kappaB and sensitizes toward AICD by a yet undefined cell death pathway. Here we show that upon IL-2-driven expansion of primary T cells, HPK1 is converted to HPK1-C by a caspase-3 activity below the threshold of apoptosis induction. HPK1-C selectively blocks induction of NF-kappaB-dependent antiapoptotic Bcl-2 family members but not of the proapoptotic Bcl-2 family member Bim. Interestingly, T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of the CD95/CD95L system but involving caspase-9. Knock down of HPK1/HPK1-C or Bim by small interfering RNA shows that CD95L-dependent and HPK1/HPK1-C-dependent cell death pathways complement each other in AICD of primary T cells. Our results define HPK1-C as a suppressor of antiapoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent AICD of lymphocytes. PMID- 17712051 TI - Re: Neurologic complications associated with intrathecal liposomal cytarabine given prophylactically in combination with high-dose methotrexate and cytarabine to patients with acute lymphocytic leukemia. PMID- 17712049 TI - Macrophages prevent the differentiation of autoreactive B cells by secreting CD40 ligand and interleukin-6. AB - Activation of the innate immune system promotes polyclonal antibody secretion to eliminate invading pathogens. Inherent in this process is the potential to activate autoreactive B cells and induce autoimmunity. We showed previously that TLR-stimulated dendritic cells and macrophages regulate B cell tolerance to Smith antigen, in part through the secretion of interleukin-6 (IL-6). In this manuscript, we show that neutralization of IL-6 fails to abrogate macrophage mediated repression and identify soluble CD40 ligand (CD40L) as a second repressive factor secreted by macrophages. CD40L selectively repressed Ig secretion by chronically antigen-experienced (anergic) immunoglobulin transgenic and nontransgenic B cells but not by transiently stimulated B cells. The importance of macrophages in maintaining B cell tolerance was apparent in lupus prone MRL/lpr mice. Compared with C57BL/6 mice, macrophages from MRL/lpr mice were significantly less efficient at repressing immunoglobulin secretion coincident with diminished IL-6 and CD40 ligand production. These data indicate that macrophages regulate autoreactive B cells by secreting repressive factors that prohibit terminal differentiation of B cells. The regulation of autoreactive B cells by macrophages is diminished in lupus-prone mice suggesting a role in autoimmunity. PMID- 17712052 TI - Therapeutic drug monitoring in CML patients on imatinib. PMID- 17712054 TI - Defining acute renal failure: the RIFLE criteria. AB - Acute renal failure is common among critically ill patients and carries significant morbidity and mortality. The reported incidence and the attributed morbidity and mortality of acute renal failure vary widely, largely owing to the use of a wide variety of definitions for acute renal failure. Until recently, no consensus existed about how to best define, characterize, and study acute renal failure. This lack of a standard definition has been a major impediment to the progress of clinical and basic research in this field. This review outlines some of the physiologic principles that may help us better understand and define acute renal failure and describes the RIFLE criteria (an acronym comprising Risk, Injury, and Failure; and Loss, and End-stage kidney disease), a recent consensus method of defining and stratifying acute renal failure. Also discussed are many of the challenges and controversies associated with achieving consensus and developing a classification for acute renal dysfunction. PMID- 17712055 TI - Lumbar puncture and brain herniation in acute bacterial meningitis: a review. AB - There has been controversy regarding the risk of cerebral herniation caused by a lumbar puncture (LP) in acute bacterial meningitis (ABM). This review discusses in detail the issues involved in this controversy. Cerebral herniation occurs in about 5% of patients with ABM, accounting for about 30% of the mortality. In many reports, LP is temporally strongly associated with this event of herniation and is most likely causative based on pathophysiologic arguments. Although a computed tomography (CT) scan of the head is useful to find contraindications to an LP, a normal CT scan in ABM does not mean that an LP is safe. Clinical signs of "impending" herniation are the best predictors of when to delay an LP because of the risk of precipitating herniation, even with a normal CT scan. Some of these clinical signs to be considered are deteriorating level of consciousness (particularly to a Glasgow Coma Scale of 75% of prescription-related events were performed electronically. Prescribers at e prescribing sites spent less time writing, but time-savings were offset by increased computer tasks. After adjusting for site, prescriber and prescription type, e-prescribing tasks took marginally longer than hand written prescriptions (12.0 seconds; -1.6, 25.6 CI). Nursing staff at the e-prescribing sites spent longer on computer tasks (5.4 minutes/hour; 0.0, 10.7 CI). E-prescribing was not associated with an increase in combined computer and writing time for prescribers. If carefully implemented, e-prescribing will not greatly disrupt workflow. PMID- 17712089 TI - Medication administration discrepancies persist despite electronic ordering. AB - Background Up to 38% of inpatient medication errors occur at the administration stage. Although they reduce prescribing errors, computerized provider order entry (CPOE) systems do not prevent administration errors or timing discrepancies. This study determined the degree to which CPOE medication orders matched actual dose administration times. METHODS At a 658-bed academic hospital with CPOE but lacking electronic medication administration charting, authors randomly selected adult patients with eligible medication orders from historical 1999-2003 CPOE log files. Retrospective manual chart audits compared expected (from CPOE) and actual timing of medication administrations. Outcomes included: dose omissions, median lag times between ordered and charted administrations, unauthorized doses, wrong dose errors, and the rate of nurses' medication schedule shifting. RESULTS Dose omissions occurred in 756 of 6019 (12.6%) audited administration opportunities; only 313 of the omissions (5.2% of opportunities) were unexplained. Wrong doses and unexpected doses occurred for 0.1% and 0.7% of opportunities, respectively. Median lag from expected first dose to actual charted administration time was 27 minutes (IQR 0-127). Nursing staff shifted from ordered to alternate administration schedules for 10.7% of regularly scheduled recurring medication orders. Chart review identified reasons for dose omissions, delays, and dose shifting. CONCLUSION Inpatient CPOE orders are legible and conveyed electronically to nurses and the pharmacy. Nonetheless, ward-based medication administrations do not consistently occur as ordered. Medication administration discrepancies are likely to persist even after implementing CPOE and bar-coded medication administration unless recommended interventions are made to address issues such as determining the true urgency of medication administration, avoiding overlapping duplicative medication orders, and developing a safe means for shifting dosing schedules. PMID- 17712090 TI - Patient web services integrated with a shared medical record: patient use and satisfaction. AB - OBJECTIVES: This study sought to describe the evolution, use, and user satisfaction of a patient Web site providing a shared medical record between patients and health professionals at Group Health Cooperative, a mixed-model health care financing and delivery organization based in Seattle, Washington. DESIGN: This study used a retrospective, serial, cross-sectional study from September 2002 through December 2005 and a mailed satisfaction survey of a random sampling of 2,002 patients. MEASUREMENTS: This study measured the adoption and use of a patient Web site (MyGroupHealth) from September 2002 through December 2005. RESULTS: As of December 2005, 25% (105,047) of all Group Health members had registered and completed an identification verification process enabling them to use all of the available services on MyGroupHealth. Identification verification was more common among patients receiving care in the Integrated Delivery System (33%) compared with patients receiving care in the network (7%). As of December 2005, unique monthly user rates per 1,000 adult members were the highest for review of medical test results (54 of 1,000), medication refills (44 of 1,000), after-visit-summaries (32 of 1,000), and patient-provider clinical messaging (31 of 1,000). The response rate for the patient satisfaction survey was 46% (n = 921); 94% of survey respondents were satisfied or very satisfied with MyGroupHealth overall. Patients reported highest satisfaction (satisfied or very satisfied) for medication refills (96%), patient-provider messaging (93%), and medical test results (86%). CONCLUSION: Use and satisfaction with MyGroupHealth were greatest for accessing services and information involving ongoing, active care and patient-provider communication. Tight integration of Web services with clinical information systems and patient-provider relationships may be important in meeting the needs of patients. PMID- 17712091 TI - Using electronic medical records to enhance detection and reporting of vaccine adverse events. AB - We implemented an automated vaccine adverse event surveillance and reporting system based in an ambulatory electronic medical record to improve underreporting and incomplete reporting that prevails in spontaneous systems. This automated system flags potential vaccine adverse events for the clinician when a diagnosis is entered, prompts clinicians to consider the vaccine as a cause of the condition, and facilitates reporting of suspected adverse events to the Vaccine Adverse Event Reporting System (VAERS). During five months, a total of 33,420 vaccinations were administered during 14,466 encounters. There were 5,914 follow up contacts by vaccinees within 14 days of the vaccination visits; 686 (11.6%) generated an alert. Clinicians submitted VAERS reports for 23 of these (0.69 per 1,000 vaccine doses), which is almost 6 times the dose-based reporting rate to VAERS. (1) Clinician surveys indicated that it took a minimal amount of time to respond to the alerts. Of those who felt that an alert corresponded to an actual vaccine adverse event, the majority used the reporting feature to file a VAERS report. We believe that elicited surveillance via real time prompts to clinicians holds substantial promise. By coupling simplified reporting with the initial prompt, clinicians can consider and report a vaccine adverse event electronically in a few moments during the office visit. PMID- 17712092 TI - The value of patient self-report for disease surveillance. AB - OBJECTIVE: To determine the accuracy of self-reported information from patients and families for use in a disease surveillance system. DESIGN: Patients and their parents presenting to the emergency department (ED) waiting room of an urban, tertiary care children's hospital were asked to use a Self-Report Tool, which consisted of a questionnaire asking questions related to the subjects' current illness. MEASUREMENTS: The sensitivity and specificity of three data sources for assigning patients to disease categories was measured: the ED chief complaint, physician diagnostic coding, and the completed Self-Report Tool. The gold standard metric for comparison was a medical record abstraction. RESULTS: A total of 936 subjects were enrolled. Compared to ED chief complaints, the Self-Report Tool was more than twice as sensitive in identifying respiratory illnesses (Rate ratio [RR]: 2.10, 95% confidence interval [CI] 1.81-2.44), and dermatological problems (RR: 2.23, 95% CI 1.56-3.17), as well as significantly more sensitive in detecting fever (RR: 1.90, 95% CI 1.67-2.17), gastrointestinal problems (RR: 1.10, 95% CI 1.00-1.20), and injuries (RR: 1.16, 95% CI 1.08-1.24). Sensitivities were also significantly higher when the Self-Report Tool performance was compared to diagnostic codes, with a sensitivity rate ratio of 4.42 (95% CI 3.45-5.68) for fever, 1.70 (95% CI 1.49-1.93) for respiratory problems, 1.15 (95% CI 1.04-1.27) for gastrointestinal problems, 2.02 (95% CI 1.42-2.87) for dermatologic problems, and 1.06 (95% CI 1.01-1.11) for injuries. CONCLUSIONS: Disease category assignment based on patient-reported information was significantly more sensitive in correctly identifying a disease category than data currently used by national and regional disease surveillance systems. PMID- 17712093 TI - Collection of cancer stage data by classifying free-text medical reports. AB - Cancer staging provides a basis for planning clinical management, but also allows for meaningful analysis of cancer outcomes and evaluation of cancer care services. Despite this, stage data in cancer registries is often incomplete, inaccurate, or simply not collected. This article describes a prototype software system (Cancer Stage Interpretation System, CSIS) that automatically extracts cancer staging information from medical reports. The system uses text classification techniques to train support vector machines (SVMs) to extract elements of stage listed in cancer staging guidelines. When processing new reports, CSIS identifies sentences relevant to the staging decision, and subsequently assigns the most likely stage. The system was developed using a database of staging data and pathology reports for 710 lung cancer patients, then validated in an independent set of 179 patients against pathologic stage assigned by two independent pathologists. CSIS achieved overall accuracy of 74% for tumor (T) staging and 87% for node (N) staging, and errors were observed to mirror disagreements between human experts. PMID- 17712095 TI - Depression and physical function: results from the aging and longevity study in the Sirente geographic area (ilSIRENTE Study). AB - Depression in older persons represents a major issue because of its relevant prevalence and the associated higher risk of adverse health-related events. The aim of this study was to evaluate the relationship of depressive symptoms with measures of physical performance, muscle strength, and functional status. Data are from baseline evaluation of the ilSIRENTE Study (n = 364). Physical performance was assessed using the Short Physical Performance Battery and the 4 meter walking test. Muscle strength was measured by hand-grip strength. Functional performance was assessed using Basic and Instrumental Activities of Daily Living. Depression was defined by analyzing the different depressive manifestations included in the Minimum Data Set for Home Care Form: verbal expression of sad and/or anxious mood and demonstrated signs of mental distress. Analyses of covariance and linear regressions were performed to evaluate the relationship between depression and physical function. Participants with depression showed significantly worse results in all of the physical function tests. Subjects with depression presented significantly lower adjusted mean results for the 4-meter walking test (0.41 m/s; SE, 0.03) and the Short Physical Performance Battery score (5.68; SE, 0.38) compared with those without depression (0.50 m/s; SE, 0.01 and 6.93; SE, 0.21; all P < .01, respectively). Participants with depressed mood also presented a higher number of impaired instrumental activities of daily living (3.69; SE, 0.25) compared with participants with less than 3 depressive symptoms (2.85; SE, 0.14; P = .005). No significant difference was reported for the hand-grip strength and the Basic Activities of Daily Living scale. In conclusion, physical performance and functional status measures are significantly and negatively influenced by the presence of depression in community-dwelling older persons aged 80 years and older. PMID- 17712094 TI - Topological analysis of large-scale biomedical terminology structures. AB - OBJECTIVE: To characterize global structural features of large-scale biomedical terminologies using currently emerging statistical approaches. DESIGN: Given rapid growth of terminologies, this research was designed to address scalability. We selected 16 terminologies covering a variety of domains from the UMLS Metathesaurus, a collection of terminological systems. Each was modeled as a network in which nodes were atomic concepts and links were relationships asserted by the source vocabulary. For comparison against each terminology we created three random networks of equivalent size and density. MEASUREMENTS: Average node degree, node degree distribution, clustering coefficient, average path length. RESULTS: Eight of 16 terminologies exhibited the small-world characteristics of a short average path length and strong local clustering. An overlapping subset of nine exhibited a power law distribution in node degrees, indicative of a scale free architecture. We attribute these features to specific design constraints. Constraints on node connectivity, common in more synthetic classification systems, localize the effects of changes and deletions. In contrast, small-world and scale-free features, common in comprehensive medical terminologies, promote flexible navigation and less restrictive organic-like growth. CONCLUSION: While thought of as synthetic, grid-like structures, some controlled terminologies are structurally indistinguishable from natural language networks. This paradoxical result suggests that terminology structure is shaped not only by formal logic based semantics, but by rules analogous to those that govern social networks and biological systems. Graph theoretic modeling shows early promise as a framework for describing terminology structure. Deeper understanding of these techniques may inform the development of scalable terminologies and ontologies. PMID- 17712096 TI - Characterization of the lipid profile in dementia and depression in the elderly. AB - The purpose of the study was to examine the association of plasma lipid concentrations with changes in cognitive function and depressive states in elderly Greek individuals. The study population consisted of 3 groups: A) 37 subjects with dementia, B) 33 subjects with depression, and C) 33 controls. All individuals were screened with the Mini-Mental State Examination (MMSE), the Geriatric Depression Scale (GDS), and an evaluation of their psychiatric state. Lipid profile was assessed in all subjects, and the results were statistically evaluated at P < .05 level of significance. Groups A and B had significantly lower levels of total plasma cholesterol and HDL cholesterol than group C (P < .01). Triglyceride levels did not differ significantly between groups A and C, although they were significantly higher in group B. The results of this study suggest that an association does exist between the plasma concentration of cholesterol and HDL-C and depression and/or cognitive impairment. Further studies are required to explore the significance of these observations and establish if lipid levels could serve as markers for diagnostic and therapeutic purposes. PMID- 17712098 TI - Depression in Primary Progressive Aphasia. AB - Primary Progressive Aphasia (PPA) is a clinical dementia syndrome in which language functions decline over time while other cognitive domains remain relatively preserved for at least 2 years. Because PPA patients suffer progressive interference with communication despite relatively preserved memory, reasoning, and insight, there is reason to believe they may experience depression. Geriatric Depression Scale (GDS) scores from PPA patients and normal controls were compared, the relationship between GDS and neuropsychological test scores was examined, and responses to items on the GDS were explored and grouped by the GDS factor structure. A significant proportion of PPA patients scored in the clinically depressed range. Although PPA patients as a group were not clinically depressed, they reported more symptoms of depression than controls, and the number of symptoms correlated with severity of naming impairment in depressed PPA patients. Symptoms of social withdrawal and lack of mental and physical energy were most common, suggesting that patients with PPA should be evaluated for depression so that they may be appropriately treated. PMID- 17712097 TI - Depressive symptoms and cognitive change in older Mexican Americans. AB - To examine the association between presence of clinically relevant depressive symptoms (Center for Epidemiologic Studies Depression Scale [CES-D] score >or= 16) and subsequent cognitive function (Mini-Mental State Examination [MMSE]) over a 7-year period in older Mexican Americans, a prospective cohort study was performed. Five south-western states contributed data to the Hispanic Established Populations for Epidemiologic Studies of the Elderly. Participants included 2812 noninstitutionalized Mexican Americans aged 65 and older followed from 1993-1994 until 2000-2001. Cognitive change was assessed using the MMSE at baseline and at 2, 5, and 7 years of follow-up. Independent variables were sociodemographics, CES D >or= 16, medical conditions (hypertension, diabetes, coronary artery disease, and stroke), and activities of daily living (ADL) status. A general linear mixed model was used to estimate cognitive change. There was a cross-sectional association between CES-D >or= 16 and lower MMSE score (estimate = -0.48; standard error [SE] = 0.15; P < .01), independent of age, gender, education, marital status, time of interview, ADL limitations, vision impairment, and medical conditions. In the fully adjusted longitudinal model, subjects with clinically relevant depressive symptoms had a greater decline in MMSE score over 7 years than those without clinically relevant depressive symptoms (estimate = 0.17; SE = 0.05; P < .001), adjusting for sociodemographics, ADL and medical conditions. Each point increase in the CES-D score was associated with a decline of 0.010 point in MMSE score per year (SE = 0.002; P < 0.0001), adjusting for relevant confounders. Presence of clinically relevant depressive symptoms was associated with subsequent decline in cognitive function over 7 years in older Mexican Americans, independent of demographic and health factors. PMID- 17712099 TI - Antidepressant treatment of veterans with Parkinson's disease and depression: analysis of a national sample. AB - We examined the impact of comorbid Parkinson's disease (PD) on depression treatment. Using national Veterans Affairs (VA) databases, fiscal year 2002 data were examined for 283 273 elderly males seen for depression. We compared 2 matched depression groups, one with (N = 7868) and one without (N = 7868) PD. In the 12-month period following a depression-related clinic visit, PD and non-PD patients were equally likely to fill an antidepressant prescription (77.8% vs. 77.4%), most commonly for a selective serotonin re-uptake inhibitor (SSRI) (62.9% vs 62.6%). Depressed PD patients had slightly higher rates of newer non-SSRI use (20.6% vs 19.2%, P < .05) and lower rates of tricyclic antidepressant use (7.4% vs 8.9%, P < .001). The presence of a PD diagnosis appears to have little impact on the frequency and type of antidepressant treatment. Efforts to improve the care of depressed PD patients should focus instead on improving recognition, ensuring adequacy of treatment, and evaluating the efficacy of existing antidepressants. PMID- 17712100 TI - Symptom profile of delirium in older people with and without dementia. AB - Clinical profiles of delirium in 717 older people with and without dementia age 75 years and older in 4 different types of care were studied. Delirium and dementia were diagnosed according to DSM-IV criteria. Delirious demented participants (n = 135) had more often had previous delirium episodes and were more often being treated with analgesics compared to delirious participants without dementia (n = 180). The clinical profile of delirium in the participants with dementia was more frequently characterized by aggressivity, latency in reaction to verbal stimuli, restlessness and agitation, delusions, anxiousness, hallucinations, and a poorer orientation and recognition. Delirium among demented participants more often had a fluctuating course during the day and was more common in the evening and at night. In conclusion, clinical profiles of delirium in participants with and without dementia are different, which might indicate a different etiology or pathophysiology, or both, and a need for different treatment strategies. PMID- 17712101 TI - Survival of ethnic Chinese with Alzheimer's disease: a 5-year longitudinal study in Taiwan. AB - Survival time and mortality risk factors in patients with Alzheimer's disease (AD) have been documented in Western countries, but comparable information on the ethnic Chinese is scarce. We consecutively recruited 159 AD patients and 145 control subjects from the Memory Clinic of Taipei Veterans General Hospital. After admission to the study, each subject received clinical, neuropsychological, and psychiatric evaluation and apolipoprotein E genotyping. Survival status was followed for 5 years. Forty-six AD patients (28.9%) and 3 control subjects (2.1%) died during the 5-year follow-up period. The mean survival time for AD patients was 4.48 years (SD = 0.1 years) after the time of enrollment. Among individuals with AD, those with severe disease, older patients, and those experiencing hallucinations were at greater risk for increased mortality. As expected, AD shortened life expectancy in these patients. The factors found to correlate with a shorter life span may suggest effective health care strategies for AD patients. PMID- 17712102 TI - Clozapine for treatment-resistant agitation in dementia. AB - Few studies have examined the potential role of clozapine in treatment of agitation in dementia patients who have previously failed to respond to standard pharmacotherapy. We conducted a systematic chart review of all elderly patients admitted to our inpatient unit between 2001 and 2004. Of them, 16 dementia patients were treated with clozapine for treatment-resistant agitation, and their charts were blindly rated by 3 clinicians on the Clinical Global Impression (CGI) Scale, Brief Agitation Rating Scale (BARS), and the Cohen-Mansfield Agitation Inventory-Short Form (CMAI-SF). Overall, clozapine therapy seemed beneficial in treatment-resistant agitation in dementia patients. PMID- 17712103 TI - Cyclops lesions that occur in the absence of prior anterior ligament reconstruction. AB - Loss of full extension after anterior cruciate ligament (ACL) reconstruction, with development of an audible and palpable "clunk" with terminal extension was first described by Jackson and Schaefer as "cyclops syndrome." This syndrome, which is the result of a fibrous nodule (termed a cyclops nodule), has recently been described in patients who have sustained ACL injury but have not undergone reconstructive surgery. From 2001 to 2006, the authors identified 10 patients (five women and five men, ages 27-76 years) with cyclops nodules seen at magnetic resonance (MR) imaging. All patients had a history of trauma but no history of ACL reconstruction. The cyclops lesions had a mean size of 16 x 12 x 11 mm, with 90% of them located just anterior to the distal ACL. MR imaging showed a well defined, somewhat heterogeneous soft-tissue nodule with a signal intensity typically similar to that of skeletal muscle. The authors suspect that the cause of cyclops lesions that occur in the absence of ACL reconstruction is similar to that suggested in the classic postoperative patient. Cyclops syndrome should be suspected in any patient in whom an ACL nodule is identified at MR imaging, and similarly a cyclops nodule should be considered as a possible cause of loss of extension in any patient who has sustained ACL injury. Movies available at http://radiographics.rsnajnls.org/cgi/content/full/e26/DC1. PMID- 17712104 TI - Adiponectin receptor 1 variants associated with lower insulin resistance in African Americans. AB - Adiponectin has been shown to have a role in insulin resistance. However, little is known about the contribution of genetic variation in the adiponectin receptor 1 gene (ADIPOR1) in this regard. We hypothesized that variation in ADIPOR1 would be associated with significant changes in insulin resistance and tested this hypothesis in a cohort of 483 African-American adolescents. Seven single nucleotide polymorphisms (SNPs) of ADIPOR1 spanning from the promoter to the 3' untranslated region were genotyped. We analyzed single SNPs and haplotypes for associations with insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] in the full cohort as well as lean (BMI < 85%) and non-lean (BMI >or= 85%) subsets. There was no evidence of ADIPOR1 variant effects on HOMA IR in the full cohort or in the lean subset. However, in the non-lean subset, SNP +5843 (A allele), and haplotypes including SNPs -8505/-5692/+3002/+5843 (ATTA and AGTG) showed significant associations with decreased HOMA-IR after adjustment for sex, puberty, adiponectin, and waist z-score. Our findings suggest not only that ADIPOR1 variants influence insulin resistance in the presence of adiposity, but also that these variants and haplotypes are protective in African Americans. PMID- 17712105 TI - High childhood obesity in an Australian population. AB - OBJECTIVE: The objective was to determine the prevalences of overweight and obesity in regional Australian children and to examine the association between BMI and indicators of socioeconomic status (SES). RESEARCH METHODS AND PROCEDURES: Regionally representative cross-sectional survey of 2184 children, 4 to 12 years of age, was conducted, and the socio-demographic characteristics of their parents from regional Victoria, Australia, 2003 to 2004, were obtained. RESULTS: The prevalences of overweight and obesity were 19.3 +/- 0.8% (proportion +/- standard error) and 7.6 +/- 0.6%, respectively, using international criteria, and the proportion of overweight/obese girls was significantly higher than that of boys (29.6 +/- 1.4% vs. 23.9 +/- 1.3%, chi2 = 9.01, p = 0.003). Children from households of lower SES had higher odds of being overweight/obese; lower SES was defined by lower paternal education (adjusted odds ratio, 1.18; 95% confidence interval, 1.08 to 1.30) and lower area-level SES (adjusted odds ratio, 1.13; 95% confidence interval, 1.02 to 1.25), adjusted for age, gender, height, and clustering by school. DISCUSSION: The prevalences of overweight and obesity are increasing in Australian children by about one percentage point per year. This equates to approximately 40,000 more overweight children each year, placing Australian children among those at highest risk around the world. In addition, girls are more likely to be overweight, and there is a general trend for children of lower SES to be at even greater risk of overweight and obesity. PMID- 17712106 TI - BMI and waist circumference as indicators of health among Samoan women. AB - OBJECTIVE: High rates of obesity and chronic disease make establishment of effective indicators of risk for chronic disease important. The objective was to examine adequacy of anthropometric cut-off points as indicators of risk for chronic disease among Samoan women in Hawaii. RESEARCH METHODS AND PROCEDURES: A cross-sectional survey of 55 Samoan women 18 to 28 years of age that included blood lipids, cholesterol, and glucose (including after a 2-hour oral glucose test); anthropometry (weight, height, waist circumference); and DXA of body composition. RESULTS: Using the Centers for Disease Control and Prevention (CDC)/World Health Organization (WHO) cut-off points for BMI, 22% of women were overweight and 58% were obese. Cholesterol, lipid, and glucose values were all linearly related to DXA body fat, BMI, and waist circumference. BMI and waist circumference at WHO/NIH cut-off points predicted levels of blood lipids and glucose that indicate elevated risk for disease. DISCUSSION: WHO/NIH cut-off points for BMI and waist circumference reflect risk indicators of chronic disease among young Samoan women in Hawaii. PMID- 17712107 TI - Adiposity, physical activity, and physical fitness among children from Aragon, Spain. AB - OBJECTIVE: The main purpose of this study was to determine the relationship between physical activity (PA) levels and adiposity. The secondary purpose was to assess the effect of physical fitness and living area on adiposity. RESEARCH METHODS AND PROCEDURES: A cross-sectional study was carried out in a regional representative sample of 1068 children 7 to 12 years of age. Anthropometric and physical fitness values (including BMI, aerobic capacity, strength levels, velocity assessment, and flexibility) were measured in all children. RESULTS: The prevalence of being overweight and obese in the entire sample was 31% and 6%, respectively. No difference between urban and rural children was found. The proportion of boys who were classified as overweight and obese was similar in physically active and sedentary (non-physically active) groups. However, physically active girls tended to show lower obesity prevalence compared with their sedentary counterparts (p = 0.06). In girls, the sum of the 6 skinfolds thickness (SSF) measurements was lower in the physically active group when compared with the non-physically active group (p < 0.05); however, this effect was not observed in boys. Multiple regression analysis revealed that the level of physical activity (PA) had a significant effect on BMI and SSF in boys but not in girls, while maximal oxygen uptake (VO2max) was significantly related to adiposity in both sexes. DISCUSSION: Regular participation in at least 2 hours per week of sports activities on top of the compulsory education program is associated with better physical fitness and lower whole body adiposity. In the children included in our study, among all physical fitness variables, VO2max showed the strongest relationship with BMI and fat mass assessed by means of skinfold measurements. PMID- 17712109 TI - The measurement of resting metabolic rate in preschool children. AB - OBJECTIVE: This study examined the repeatability of measuring resting metabolic rate (RMR) in preschool children and the effect of different calculation protocols. RESEARCH METHODS AND PROCEDURES: Eleven children (4 females and 7 males) participated in the project. They were recruited through advertisements in local schools and community centers. Resting metabolic rate was measured on 3 occasions over a 2-week period, each after an overnight fast and each lasting approximately 20 to 25 minutes. Results were compared using repeated-measures ANOVA to check for repeatability, and a number of methods of calculating RMR were assessed. RESULTS: Repeatability of RMR measurements was good (coefficient of variation of replicates, 6.8%), with no significant difference between days of measurement. The lowest RMR measurement was obtained when the first 10 minutes were excluded and periods during which large activity was observed were excluded. This measurement was, on average, 4% lower than averaging the measurements after the first 5 minutes, including body movements. DISCUSSION: This study suggests that RMR can be measured in preschool children and that the best method for calculating RMR in these subjects is to exclude periods when large body movements occur and the first 10 minutes of the measurement period. Only a single measurement of RMR is needed to obtain a reliable estimate. PMID- 17712108 TI - The influence of weight loss on serum osteoprotegerin concentration in obese perimenopausal women. AB - OBJECTIVE: To assess the influence of weight reduction therapy on serum osteoprotegerin (OPG) concentration in obese patients and compare these results with normal-weight controls. RESEARCH METHODS AND PROCEDURES: Forty-three obese women (BMI, 36.7 +/- 4.1 kg/m2; mean age, 50.1 +/- 4.5 years) were studied. The control group consisted of 19 normal-weight women (BMI, 24.2 +/- 2.1 kg/m2; mean age, 53.8 +/- 5.2 years). In all patients, serum concentrations of OPG, C telopeptide of type I collagen containing the cross-linking site (CTX), osteocalcin, parathormone, 25-(OH)-D3 (vitamin D), and total calcium and phosphorus were assessed before and after a 3-month weight reduction therapy. RESULTS: In obese subjects, serum concentrations of OPG, 25-(OH)-D3, osteocalcin, total calcium, and phosphorus were significantly lower, and serum concentration of parathormone was significantly higher, before weight reduction therapy in comparison with normal-weight controls. After weight reduction, a significantly higher serum concentration of 25-(OH)-D3 and CTX and significantly lower concentration of OPG were found. DISCUSSION: Serum concentration of OPG was significantly lower in obese patients in comparison with normal-weight controls. Weight reduction therapy resulted in further decrease in OPG serum concentrations. Therefore, OPG cannot be treated as a protective factor from bone loss in obese patients. PMID- 17712110 TI - Deep subcutaneous adipose tissue: a distinct abdominal adipose depot. AB - OBJECTIVE: Abdominal visceral (VAT) and subcutaneous adipose tissue (SAT) display significant metabolic differences, with VAT showing a functional association to metabolic/cardiovascular disorders. A third abdominal adipose layer, derived by the division of SAT and identified as deep subcutaneous adipose tissue (dSAT), may play a significant and independent metabolic role. The aim of this study was to evaluate depot-specific differences in the expression of proteins key to adipocyte metabolism in a lean population to establish a potential physiologic role for dSAT. RESEARCH METHODS AND PROCEDURES: Adipocytes and preadipocytes were isolated from whole biopsies taken from superficial SAT (sSAT), dSAT, and VAT samples obtained from 10 healthy normal weight patients (7 women and 3 men), with a mean age of 56.4 +/- 4.04 years and a mean BMI of 23.1 +/- 0.5 kg/m2. Samples were evaluated for depot-specific differences in insulin sensitivity using adiponectin, glucose transport protein 4 (GLUT4), and resistin mRNA and protein expression, glucocorticoid metabolism by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) expression, and alterations in the adipokines leptin and tumor necrosis factor-alpha (TNF-alpha). RESULTS: Although no regional differences in expression were observed for adiponectin or TNF-alpha, dSAT whole biopsies and adipocytes, while intermediary to both sSAT and VAT, reflected more of the VAT expression profile of 11beta-HSD1, leptin, and resistin. Only in the case of the intracellular pool of GLUT4 proteins in whole biopsies was an independent pattern of expression observed for dSAT. In an evaluation of the homeostatic model, dSAT 11beta-HSD1 protein (r = 0.9573, p = 0.0002) and TNF-alpha mRNA (r = 0.8210, p = 0.0236) correlated positively to the homeostatic model. DISCUSSION: Overall, dSAT seems to be a distinct abdominal adipose depot supporting an independent metabolic function that may have a potential role in the development of obesity associated complications. PMID- 17712111 TI - 1Alpha,25-dihydroxyvitamin D3 modulation of adipocyte reactive oxygen species production. AB - OBJECTIVE: We have previously shown 1alpha,25-dihydroxyvitamin D3 [1alpha,25 (OH)2D3] to inhibit mitochondrial uncoupling protein 2 (UCP2) expression in adipocytes and that in vivo suppression of calcitriol levels with calcium-rich diets increases UCP2 expression. Because UCP2 plays a significant role in the clearance of reactive oxygen species (ROS), we studied the effect of calcitriol on ROS production and ROS-induced adipocyte proliferation. RESEARCH METHODS AND PROCEDURES: ROS production in human and murine adipocytes was stimulated by high glucose (30 mM) or H2O2 (100 nM). RESULTS: Both approaches resulted in increased ROS production by 27% to 100% (p < 0.05) and increased cell proliferation by 15% to 39% (p < 0.03). These effects were augmented by the addition of mitochondrial uncoupling inhibitor guanosine 5'-diphosphate (GDP; 100 microM) or 1alpha,25 (OH)2D3 (10 nM) and attenuated by UCP2 overexpression, suggesting that inhibition of mitochondrial uncoupling suppresses clearance of ROS and increases adipocyte proliferation. The addition of alpha +/- tocopherol (1 microM) inhibited cell proliferation in adipocytes treated with either H2O2 or high glucose, indicating that ROS plays a major role in the regulation of cell proliferation in adipocytes. Moreover, stimulation of ROS with high glucose and H2O2 resulted in a 2- to 5-fold increase in adipocyte intracellular calcium ([Ca2+]i; p < 0.001), and calcium channel antagonism (nifedipine, 10 microM) suppressed ROS induced calcium influx and cell proliferation, indicating that [Ca2+]i may also regulate ROS production and exert a mitogenic effect in adipocytes. DISCUSSION: These data support a role of 1alpha,25-(OH)2D3, UCP2, and [Ca2+]i in the regulation of adipocyte ROS production. PMID- 17712112 TI - 11Beta-HSD type 1 expression in human adipose tissue: impact of gender, obesity, and fat localization. AB - OBJECTIVE: Pre-receptor amplification of glucocorticoids is, in part, determined by the isoenzymes 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 and type 2, interconverting inert cortisone and active cortisol. Increased tissue activity of cortisol may play a part in features of the metabolic syndrome. Our objective was to compare 11beta-HSD1 gene expression in different fat depots (visceral, subcutaneous abdominal, and subcutaneous gluteal) in lean and obese men and women. RESEARCH METHODS AND PROCEDURES: A cross-sectional study design was used for healthy patients undergoing minor abdominal surgery (lean men, 10), minor gynecological surgery (lean woman, 10), or gastric banding operations (obese men, 10; and obese women, 10). Gene expressions of 11beta-HSD1 in adipose tissue samples were determined by real-time reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Lean women had lower 11beta-HSD1 gene expression in subcutaneous adipose tissue compared with men (62% lower, p < 0.01), whereas no significant difference was found between obese men and women. 11Beta-HSD1 mRNA in human adipose tissue was higher in obese subjects compared with lean subjects in both women and men and in both subcutaneous and visceral adipose tissue. No difference in mRNA expression of 11beta-HSD1 between visceral and subcutaneous adipose tissue or between subcutaneous adipose tissue from different depots was found. CONCLUSIONS: 11Beta-HSD1 in adipose tissue is increased in obesity in both women and men, and may contribute to the associated metabolic syndrome. As 11beta-HSD1 expression in lean women was found to be significantly lower than in lean males, the up-regulation associated with obesity may be relatively more devastating in women than in men, and may help explain the higher relative risk of cardiovascular disease in women suffering from the metabolic syndrome. PMID- 17712113 TI - Adipokine and insulin profiles distinguish diabetogenic and non-diabetogenic obesities in mice. AB - OBJECTIVE: To use longitudinal profiling of plasma adipokines to distinguish diabetogenic vs. non-diabetogenic obesity syndrome in two new mouse models of polygenic obesity. RESEARCH METHODS AND PROCEDURES: Male mice of the NONcNZO5 strain develop a polygenic obesity syndrome uncomplicated by diabetes, whereas NONcNZO10 males develop a comparable polygenic obesity that precipitates type 2 diabetes. A multiplex immunoassay for simultaneous measurement of insulin and a panel of mouse adipokines (leptin, resistin, adiponectin, interleukin-6, tumor necrosis factor alpha, macrophage chemoattractant protein-1, plasminogen activator inhibitor-1) were used to profile longitudinal changes in these strains between 4 and 16 weeks of age that might distinguish the non-diabetogenic vs. diabetogenic obesity (diabesity). RESULTS: Both strains became adipose, with NONcNZO5 males attaining a higher mean body weight with a higher percentage fat content. Weight gain in NONcNZO5 was accompanied by a transient peak in plasma insulin (PI) at 8 weeks followed by a decline into normal range, with normoglycemia maintained throughout. In contrast, NONcNZO10 showed no early PI secretory response because both body weight and plasma glucose increased between 4 and 8 weeks. Only after 12 weeks, with hyperglycemia established, was a delayed PI secretory response observed. Neither plasma leptin nor adiponectin concentrations significantly differentiated the two syndromes over time. However, repeated measures ANOVA showed that NONcNZO10 males maintained significantly higher plasma concentrations of two adipokines, resistin and plasminogen activator inhibitor-1, and the pro-inflammatory cytokine/adipokine macrophage chemoattractant protein-1. DISCUSSION: Longitudinal profiling of PI and adipokines in two new mouse models developing moderate obesity demonstrated that specific marker signatures differentiated a non-diabetogenic obesity from a diabetogenic obesity. PMID- 17712114 TI - Overeating by young obesity-prone and lean rats caused by tastes associated with low energy foods. AB - OBJECTIVE: Childhood obesity is a prominent health problem that may involve early learning about tastes and the energy content of foods. We tested the hypothesis that food tastes predictive of low energy content cause overeating in young animals. RESEARCH METHODS AND PROCEDURES: Juvenile and adolescent (4- and 8-week old) male JCR:LA-cp lean (+/cp or +/+) and obesity-prone (cp/cp) rats were given sweet (saccharin) and salty (sodium chloride) gelatin cubes made with starch (high caloric) or no starch (low caloric) for 16 days of taste conditioning. After 10 hours of food deprivation, rats received pre-meals with flavors that had been paired or unpaired with high caloric content during taste conditioning, followed immediately by measurement of chow intake at regular meals. RESULTS: Our findings show that both lean (+/cp) and obesity-prone (cp/cp) juvenile rats ate more regular chow after a pre-meal with a flavor associated with low caloric value than after a similar pre-meal with a flavor predictive of high caloric content. This effect occurred with juvenile rats but not with adolescents. DISCUSSION: Data from our study indicate that the subversion of the relationship between taste and caloric content disrupts the normal physiological and behavioral energy balance of juvenile rats, resulting in overeating that is independent of genetic disposition for obesity. PMID- 17712116 TI - Macrophage-colony stimulating factor in obese adipose tissue: studies with heterozygous op/+ mice. AB - OBJECTIVE: We examined the gene expression of macrophage-colony stimulating factor (M-CSF) in mice with diet-induced obesity and in genetically obese mice. We also examined the effect of decreased M-CSF signaling on the susceptibility to obesity and macrophage recruitment into the adipose tissue of mice. RESEARCH METHODS AND PROCEDURES: The adipose tissue from mice with diet-induced obesity, obese KKA(y) mice, and ob/ob obese mice was used for RNA preparation. Production of M-CSF and monocyte chemoattractant protein-1 (MCP-1) was examined by quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. The op/+ heterozygous mice, with decreased functional M-CSF expression, were placed on a high-fat diet or crossed with KKA(y) mice to study the susceptibility to obesity. The gene expression of macrophage markers in adipose tissue was examined. RESULTS: The expression of M-CSF was not significantly changed in mice on a high-fat diet or in either type of genetic obesity (KKA(y) or ob/ob mice). No change in the degree of obesity or macrophage related gene expression (F4/80, CD68, and MCP-1) in the adipose tissue was observed in op/+ mice compared with +/+ control mice, which were either treated with a high-fat diet or crossed with KKA(y) mice. DISCUSSION: This study demonstrated that there was no significant change in the expression of M-CSF in the adipose tissue from obese mice and only a minor phenotypic change, such as macrophage infiltration, in the adipose tissue from op/+ mice, suggesting that M CSF does not play a major role in macrophage recruitment in the adipose tissue of obese mice. PMID- 17712115 TI - Extreme obesity reduces bone mineral density: complementary evidence from mice and women. AB - OBJECTIVE: To evaluate the effects of body adiposity on bone mineral density in the presence and absence of ovarian hormones in female mice and postmenopausal women. RESEARCH METHODS AND PROCEDURES: We assessed percentage body fat, serum leptin levels, and bone mineral density in ovariectomized and non-ovariectomized C57BL/6 female mice that had been fed various calorically dense diets to induce body weight profiles ranging from lean to very obese. Additionally, we assessed percentage body fat and whole body bone mineral density in 37 overweight and extremely obese postmenopausal women from the Women's Contraceptive and Reproductive Experiences study. RESULTS: In mice, higher levels of body adiposity (>40% body fat) were associated with lower bone mineral density in ovariectomized C57BL/6 female mice. A similar trend was observed in a small sample of postmenopausal women. DISCUSSION: The complementary studies in mice and women suggest that extreme obesity in postmenopausal women may be associated with reduced bone mineral density. Thus, extreme obesity (BMI > 40 kg/m2) may increase the risk for osteopenia and osteoporosis. Given the obesity epidemic in the U.S. and in many other countries, and, in particular, the rising number of extremely obese adult women, increased attention should be drawn to the significant and interrelated public health issues of obesity and osteoporosis. PMID- 17712118 TI - Amylin and its relation to insulin and lipids in obese children before and after weight loss. AB - OBJECTIVE: There are limited data concerning the relationships between amylin, weight status, lipids, insulin, and insulin resistance in obese humans. Therefore, the aim was to study these relationships in cross-sectional and longitudinal analyses. RESEARCH METHODS AND PROCEDURES: Fasting amylin, insulin, glucose, triglycerides, low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol, and percentage body fat based on skinfold measurements were determined in 37 obese children (median age, 11.5 years) and compared with 16 lean children of the same age and gender. Furthermore, we analyzed the changes of these variables in the obese children after participating in a one-year weight loss intervention program. RESULTS: Obese children had significantly (p < 0.01) higher amylin, triglycerides, LDL-cholesterol, and insulin levels as compared with the lean children. In multiple linear regression analysis, amylin was significantly (p < 0.05) correlated to insulin and triglycerides, but not to age, gender, pubertal stage, or BMI. Changes of amylin correlated significantly (p < 0.001) to changes of insulin (r = 0.54) and triglycerides (r = 0.49), but not to changes of BMI or percentage body fat. Substantial weight loss in 17 children led to a significant (p < 0.05) decrease of amylin, triglycerides, and insulin, in contrast to the 20 children without substantial weight loss. CONCLUSION: Amylin levels were related to insulin concentrations in both cross-sectional and longitudinal analyses, suggesting a relationship between amylin and insulin secretion. Amylin levels were reversibly increased in obesity and related to triglyceride concentrations. PMID- 17712117 TI - C57BL/6J and A/J mice fed a high-fat diet delineate components of metabolic syndrome. AB - OBJECTIVE: The aim of this study was to assess the suitability of A/J and C57BL/6J mice of both sexes as models of some components of the human metabolic syndrome (MetS) under nutritional conditions more comparable with the actual worldwide diet responsible for the increased incidence of the MetS. RESEARCH METHODS: We fed large cohorts (n = 515) of two strains of mice, A/J and the C57BL/6J, and of both sexes a high-fat diet (HFD; 60% fat) that, in contrast with most previous reports using saturated fats, was enriched in mono- and polyunsaturated fatty acids, thus more closely mimicking most Western diets, or a control diet (10% fat), for 20 weeks. RESULTS: In sharp contrast to previous reports, weight gain and hyperleptinemia were similar in both strains and sexes. Hyperinsulinemia, glucose tolerance, insulin resistance, and hypercholesterolemia were observed, although with important differences between strains and sexes. A/J males displayed severely impaired glucose tolerance and insulin resistance. However, in contrast with C57BL6/J mice, which displayed overt type 2 diabetes, A/J mice of both sexes remained normoglycemic. DISCUSSION: With important differences in magnitude and time course, the phenotypic and metabolic characteristics of both strains and both sexes on this HFD demonstrate that these models are very useful for identifying the mechanisms underlying progression or resistance to subsequent type 2 diabetes. PMID- 17712119 TI - Growth hormone and ghrelin secretion in severely obese women before and after bariatric surgery. AB - OBJECTIVE: The objective was to evaluate ghrelin and growth hormone (GH) interactions and responses to a growth hormone-releasing hormone (GHRH)/arginine test in severe obesity before and after surgically-induced weight loss. RESEARCH METHODS AND PROCEDURES: Our study population included 11 severely obese women 39 +/- 12 years of age, with a mean BMI of 48.6 +/- 2.4 kg/m2, re-studied in a phase of stabilized body weight, with a BMI of 33.4 +/- 1.2 kg/m2, 18 months after having successfully undergone biliopancreatic diversion (BPD). A GHRH/arginine test was performed before and 18 months after BPD to evaluate ghrelin and GH interactions. Active ghrelin, measured by radioimmunoassay (RIA), and GH, measured by chemiluminescence assay, were assayed before and after the GHRH/arginine test. RESULTS: Fasting serum GH levels and GH area under the curve (AUC) significantly increased from 0.2 +/- 0.05 ng/mL to 1 +/- 0.3 ng/mL (p < 0.05) and from 514.76 +/- 98.7 ng/mL for 120 minutes to 1957.3 +/- 665.1 ng/mL for 120 minutes after bariatric surgery (p < 0.05), respectively. Although no significant change in fasting ghrelin levels was observed (573 +/- 77.9 before BPD vs. 574.1 +/- 32.7 after BPD), ghrelin AUC significantly increased from 3253.9 +/- 2180.9 pg/mL for 120 minutes to 1142.3 +/- 916.4 pg/mL for 120 minutes after BPD (p < 0.05). Fasting serum insulin-like growth factor (IGF)-1 concentration did not change significantly (133.6 +/- 9.9 ng/mL before vs. 153.3 +/- 25.2 ng/mL after BPD). DISCUSSION: Our study demonstrates that the mechanisms involved in ghrelin and GH secretion after the secretagogue stimulus (GHRH/arginine) are consistent with patterns observed in other populations. PMID- 17712120 TI - Impact of obesity on left ventricular mass and function in subjects with chronic volume overload. AB - OBJECTIVE: Previous studies evaluated the effect of obesity on left ventricular (LV) mass and systolic function in healthy subjects and in patients with coexistent chronic LV pressure overload due to hypertension, but no data exist regarding subjects with underlying volume overload. This study assessed the impact of overweight-obesity on LV mass and systolic function in patients with coexistent chronic LV volume overload. RESEARCH METHODS AND PROCEDURES: In 885 subjects with degenerative aortic regurgitation, a common cause of LV volume overload, LV mass, ejection fraction, and myocardial contractility were determined by echocardiography. RESULTS: LV mass was greater in overweight (193.5 +/- 54.2 g) and further increased in obese subjects (208.4 +/- 63.6 g) in comparison with normal-weight patients (177.7 +/- 54.9 g) (p < 0.0001), and these differences were still evident after adjustment for LV workload, gender, and body size. Despite no differences in ejection fraction, LV myocardial contractility was lower in overweight (92.6 +/- 14.8%) and obese subjects (91.7 +/- 14.4%) than normal-weight individuals (95.6 +/- 16.0%) (p = 0.0058). The magnitudes of these effects were not different from those found in age-, gender-, and body size matched controls, suggesting additive interaction, rather than synergistic, between overweight-obesity and the underlying condition of volume overload. Multivariate analysis showed that BMI independently predicted LV mass and that the negative effect on LV myocardial contractility was mediated by LV hypertrophy. DISCUSSION: Overweight and obesity are associated with LV hypertrophy and contractile impairment in patients with underlying chronic LV volume overload. PMID- 17712122 TI - Genome-wide scan of plasma cholecystokinin in baboons shows linkage to human chromosome 17. AB - OBJECTIVE: Cholecystokinin (CCK) is known to inhibit food intake and is an important signal for controlling meal volume, indicating a possible role in weight regulation. Our objective was to investigate genetic influences on plasma CCK in baboons. RESEARCH METHODS AND PROCEDURES: Subjects were 376 baboons (males = 113, females = 263) from the Southwest National Primate Research Center, housed at the Southwest Foundation for Biomedical Research, San Antonio, Texas. Anthropometric and biochemical parameters were analyzed. Genetic effects on plasma CCK were estimated by the maximum likelihood-based variance components method implemented in the software program SOLAR (Sequential Oligogenic Linkage Analysis Routines). RESULTS: Male baboons (32.7 +/- 6 kg) were much heavier than females (20.2 +/- 4 kg). Similarly, mean (+/- standard deviation) plasma CCK values were also higher in male baboons (13.8 +/- 6 pM) than female baboons (12.5 +/- 4 pM). Significant heritabilities were observed for plasma CCK (0.14 +/- 0.1, p < 0.05), body weight (h2 = 0.62 +/- 0.15, p < 10(-8)), and glucose (h2 = 0.68 +/- 0.17, p < 10(-7)). A genome-wide scan of plasma CCK detected a strong signal for a quantitative trait locus (QTL) on chromosome 17p12-13 [logarithm of the odds (LOD) = 3.1] near marker D17S804. Suggestive evidence of a second QTL was observed on chromosome 4q34-35 (LOD = 2.3) near marker D4S2374. DISCUSSION: A substantial contribution of additive genetic effects to the variation in plasma levels of CCK was demonstrated in baboons. The identification of a QTL for plasma CCK on chromosome 17p is significant, as several obesity-related traits such as BMI, leptin, adiponectin, and acylation stimulating protein have already been mapped to this region. PMID- 17712121 TI - NPY5R antagonism does not augment the weight loss efficacy of orlistat or sibutramine. AB - OBJECTIVE: Central counter-regulatory mechanisms, including those related to the orexigenic hormone neuropeptide Y (NPY), may limit the weight loss observed with conventional pharmacological monotherapy. This study evaluated whether blockade of the NPY Y5 receptor (NPY5R) with the selective antagonist MK-0557 potentiates sibutramine and orlistat weight loss effects. RESEARCH METHODS AND PROCEDURES: Obese patients (497, BMI 30 to 43 kg/m2) were randomized to 1 of 5 treatment arms [placebo, n = 101; sibutramine 10 mg/d, n = 100; MK-0557 1 mg/d plus sibutramine 10 mg/d, n = 98; orlistat 120 mg TID, n = 99; MK-0557 1 mg/d plus orlistat 120 mg TID, n = 99] in conjunction with a hypocaloric diet for 24 weeks. The all patients-treated population, imputing missing data using last observation carried forward, was used to assess weight loss from baseline. RESULTS: The study was completed by 71% of patients in placebo, 76% in sibutramine alone, 79% in MK-0557 + sibutramine, 69% in orlistat alone, and 76% in MK-0557 + orlistat groups. Least squares (LS) mean difference [95% confidence interval (CI)] in weight change from baseline between MK-0557 + sibutramine and sibutramine alone was -0.1 (-1.6, 1.4) kg (p = 0.892) and between MK-0557 + orlistat and orlistat alone was -0.9 (-2.4, 0.6) kg (p = 0.250). Sibutramine alone induced a LS mean weight loss of -5.9 ( 6.9, -4.9) kg vs. -4.6 (-5.7, -3.6) kg for orlistat (p = 0.097). There were no serious drug-related adverse events and MK-0557 was well tolerated. DISCUSSION: Blockade of the NPY5R with the potent antagonist MK-0557 did not significantly increase the weight loss efficacy of either orlistat or sibutramine monotherapy. PMID- 17712123 TI - Single nucleotide polymorphisms at the adiponectin locus and risk of coronary heart disease in men and women. AB - OBJECTIVE: The objective was to examine the association of 5 common single nucleotide polymorphisms (SNPs) at the adiponectin locus with risk of coronary heart disease (CHD) in men and women. METHODS AND PROCEDURES: We genotyped five common SNPs in the adiponectin gene (rs266729, -11365C>G; rs822395, -4034A>C; rs822396, -3964A>G; rs2241766, +45T>G; and rs1501299, +276G>T) in men (Health Professionals Follow-up Study) and women (Nurses' Health Study) in a nested case control setting. Among participants free of cardiovascular disease at baseline, 266 men and 249 women developed non-fatal myocardial infarction or fatal CHD during 6 and 8 years of follow-up, respectively. In addition, 564 men had coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty. Using risk set sampling, controls were selected 2:1 matched on age, smoking, and date of blood draw. RESULTS: The -4034CC genotype was related to an increased risk of non-fatal myocardial infarction or fatal CHD compared with the AA genotype [relative risk (RR), men, 1.69; 95% confidence interval (CI), 0.99 to 2.89; women, 2.04; 95% CI, 1.20 to 3.49); however, this genotype was not related to risk of coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty or to plasma adiponectin levels. Other SNPs or haplotypes defined by the 5 SNPs were not consistently related to risk of CHD in men and women or to plasma adiponectin levels. DISCUSSION: Our study does not support the hypothesis that these 5 common SNPs in the adiponectin gene play an important role in the development of CHD among men and women, although we cannot exclude an association between the -4034CC genotype and risk of CHD. PMID- 17712124 TI - Evidence of linkage and association with body fatness and abdominal fat on chromosome 15q26. AB - OBJECTIVE: In the present study, we undertook a two-step fine mapping of a 20 megabase region around a quantitative trait locus previously reported on chromosome 15q26 for abdominal subcutaneous fat (ASF) in an extended sample of 707 subjects from 202 families from the Quebec Family Study. RESEARCH METHODS AND PROCEDURE: First, 19 microsatellites (in addition to the 7 markers initially available on 15q24-q26; total = 26) were genotyped and tested for linkage with abdominal total fat, abdominal visceral fat, and ASF assessed by computed tomography and with fat mass (FM) using variance component-based approach on age- and sex-adjusted phenotypes. Second, 16 single nucleotide polymorphisms (SNPs) were genotyped and tested for association using family-based association tests. RESULTS: After the fine mapping, the peak logarithm of odds ratio (LOD) score (marker D15S1004) increased from 2.79 to 3.26 for ASF and from 3.52 to 4.48 for FM, whereas for abdominal total fat, the peak linkage (marker D15S996) decreased from 2.22 to 1.53. No evidence of linkage was found for abdominal visceral fat. Overall, for genotyped SNPs, three variants located in the putative MCTP2 gene were significantly associated with FM and the three abdominal fat phenotypes (p 30), and independent variables assessed included individual level variables (age, education, income, smoking status, sex, black race, and Hispanic ethnicity), and zip code level variables (percentage black, percentage Hispanic, percentage with more than a high school education, retail density, establishment density, employment density, population density, the presence of a supermarket, intersection density, median household income, and density of fast food outlets). RESULTS: After controlling for individual level factors, median household income [relative risk (RR) = 0.992; 95% confidence interval (CI) = 0.990, 0.994], population density (RR = 0.98; 95% CI = 0.972, 0.990), employment density (RR = 1.004; 95% CI = 1.001, 1.009), establishment density (RR = 0.981 95% CI = 0.964, 0.999), and the presence of a supermarket (RR = 0.893; 95% CI = 0.815, 0.978) were associated with obesity risk. Fast food establishment density was poorly associated with obesity risk. DISCUSSION: Where one lives may affect obesity status. Given the influence of the presence of a supermarket on obesity risk, efforts to address food access might be a priority for reducing obesity. PMID- 17712131 TI - Climate amenity and BMI. AB - OBJECTIVES: Our goal was to examine the relationship between BMI and climate amenable for physical activity at the county level in the U.S. RESEARCH METHODS AND PROCEDURES: Using Geographic Information Systems tools and 6-year National Oceanic and Atmospheric Administration station hourly weather records, an index of amenable climate was derived for all U.S. counties. This index was linked to individual BMI in a multi-level analysis that accounted for other individual characteristics from the 2002 survey of the Behavioral Risk Factor Surveillance System. RESULTS: There was an inverse relationship between climate amenable to physical activity and BMI at the county level after controlling for individual risk factors, county road density, and median household income and unemployment rate. Residents in high climate-amenity counties tended to have a lower BMI. DISCUSSION: The contribution of less amenable climate to overweight and obesity in the U.S. is likely to be substantial because it cuts across wide geographic areas. Health promotion strategies that promote mixed land use or other urban design conducive to walking and other physical activities should consider broader environmental disamenities to mitigate their influence. Strategies for outdoor physical activity should also be tailored for people of different racial groups and educational backgrounds due to observed differences in their response to climate amenity. PMID- 17712132 TI - Erythrocyte hyperaggregation in obesity: determining factors and weight loss influence. AB - OBJECTIVE: To compare erythrocyte aggregation (EA) in patients with severe obesity without other cardiovascular risk factors with a control group, using the Myrenne and the Sefam aggregometers, and to evaluate the effect of weight loss on this parameter. RESEARCH METHODS AND PROCEDURES: This was a longitudinal, clinical intervention study of a very low-calorie diet for 4 weeks followed by a low-calorie diet for 2 months. In 67 severely obese patients, an anthropometric and analytical evaluation [plasmatic lipids, fibrinogen (Fbg), and EA] was performed at baseline and 3 months after diet. The same determinations were performed in 67 normal-weight volunteers. EA was measured with the Myrenne MA1, which determines EA at stasis (EA0) and at a low shear of 3 seconds(-1) (EA1), and the Sefam aggregometer, which determines aggregation index at 10 seconds(-1) (IA10), aggregation time (Ta), and disaggregation threshold (gammaD). Insulin resistance (IR) was calculated by homeostasis model assessment. RESULTS: Obese patients showed higher Fbg levels, EA0, EA1, IA10, and gammaD values, and lower Ta values. Differences between obese patients and control group for EA0, EA1, Ta, IA10, and gammaD disappeared after adjusting for BMI or for homeostasis model assessment but were maintained after adjusting for Fbg or low-density lipoprotein cholesterol. Obese patients with IR showed higher EA0 and EA1 values. After weight loss, EA1 showed a significant improvement. DISCUSSION: Obese patients show increased EA. Erythrocyte hyperaggregation does not seem to be related to a high Fbg level or to an abnormal lipid profile but to IR. Hyperagreggation improves after weight loss. PMID- 17712133 TI - Fatness, fitness, and insulin sensitivity among 7- to 9-year-old children. AB - OBJECTIVE: The purpose of this study was to examine the relationships among fatness and aerobic fitness on indices of insulin resistance and sensitivity in children. RESEARCH DESIGN AND METHODS: A total of 375 children (193 girls and 182 boys) 7 to 9 years of age were categorized by weight as normal-weight, overweight, or obese and by aerobic fitness based on a submaximal physical working capacity test (PWC). Fasting blood glucose (GLU) and insulin (INS) were used to calculate various indices of insulin sensitivity (GLU/INS), the homeostasis model assessment (HOMA), and the quantitative insulin sensitivity check index (QUICKI). Surrogate measures of pancreatic beta cell function included the insulinogenic index (INS/GLU) and the HOMA estimate of pancreatic beta-cell function (HOMA %B). RESULTS: Insulin sensitivity and secretion variables were significantly different between the normal-weight children and the overweight and obese subjects. Fasting insulin (FI), HOMA, QUICKI, and INS/GLU were significantly different between the overweight and obese subjects. Likewise, the high fitness group possessed a better insulin sensitivity profile. In general, the normal-weight-high fit group possessed the best insulin sensitivity profile and the obese-unfit group possessed the worst insulin sensitivity profile. Several significant differences existed among the six fat-fit groups. Of particular note are the differences within BMI groups by fitness level and the comparison of values between the normal-weight-unfit subjects and the overweight and obese subjects with high fitness. CONCLUSIONS: The results indicate that aerobic fitness attenuates the difference in insulin sensitivity within BMI categories, thus emphasizing the role of fitness even among overweight and obese children. PMID- 17712134 TI - Trust in scientific experts on obesity: implications for awareness and behavior change. AB - OBJECTIVE: To explore the relationship between public trust in scientific experts on obesity and public attention to nutrition recommendations, to investigate trust as a predictor of weight-related behaviors, and to identify the sociodemographic characteristics associated with high and low trust in scientific experts on obesity. RESEARCH METHODS AND PROCEDURES: This analysis used survey data from two sources: 1) a 2005 Harvard School of Public Health Obesity Survey (N = 2033), and 2) the 2004 General Social Survey (N = 2812). Five outcome measures were used. Three were used to explore trust as a predictor of attention and weight-related behaviors. Two were used to identify the sociodemographic predictors of trust. Logistic regression analysis was used to model the outcome variables. RESULTS: Trust in scientific experts was the strongest predictor of public attention to nutritional recommendations from scientific experts, but it was not directly related to weight-related behaviors. Public attention was significantly associated with two weight-related behaviors: tracking fruit and vegetable intake and exercise. Women and more educated individuals had significantly higher odds of trusting scientific experts. Characteristics associated with distrust in scientific experts included Hispanic race and older age (over 50). DISCUSSION: Public health experts should work toward building trust as an important step in stemming the obesity epidemic. Further, more research is necessary to better understand the factors driving trust in scientific experts on obesity. A deeper insight in this area will certainly be of great benefit to obesity-related risk communication and potentially lead to positive behavior change. PMID- 17712135 TI - The relationship between relative weight and school attendance among elementary schoolchildren. AB - OBJECTIVE: To determine the relationship between relative weight and school attendance among elementary schoolchildren. RESEARCH METHODS AND PROCEDURES: A total of 1069 fourth to sixth graders from nine elementary schools in the inner city of Philadelphia, PA, were part of an ongoing randomized control trial to assess prevention strategies for obesity. The mean rate of students eligible for free/reduced meals was 82.9 +/- 11.5%. Weight was measured in the second semester of the academic year. Absentee data for the entire academic year were recorded by homeroom teachers. Participants were classified into relative weight categories described by the Institute of Medicine: underweight, normal-weight, overweight, and obese. RESULTS: ANOVA showed that overweight children were absent significantly more than normal-weight children (12.2 +/- 11.7 days vs.10.1 +/- 10.5 days) (p < 0.05). Linear regression showed that the obese category remained a significant contributor to the number of days absent even after adjusting for age, race/ethnicity, and gender. DISCUSSION: These data suggest that in addition to the medical and psychosocial consequences of being overweight, heavier children have greater risk for school absenteeism than their normal-weight peers. As the rate of childhood obesity increases, parallel increases in school absenteeism should be expected. PMID- 17712137 TI - Signals on the move: chemokine receptors and organogenesis in zebrafish. AB - The chemokine SDF1 (stromal cell-derived factor 1) directs cell migration in many different contexts, ranging from embryogenesis to inflammation. SDF1a is the guidance cue for the zebrafish lateral line primordium, a tissue that moves along the flank of the embryo and deposits cells that form mechanosensory organs. The SDF1a receptor CXCR4b acts in cells at the leading edge of the primordium to direct its migration. Two new studies show that a second SDF1 receptor, CXCR7, is required only in the trailing cells of the primordium, and they explore how these two receptors orchestrate migration of the primordium. CXCR4b and CXCR7 are expressed in complementary domains, possibly through mutual repression in which each receptor inhibits expression of the other. These studies illustrate how the entire primordium can respond to a single signal, yet generate cell type-specific responses by using different receptors. PMID- 17712138 TI - Methods for pseudopodia purification and proteomic analysis. AB - Directional cell migration requires the formation of a dominant pseudopodium in the direction toward which the cell migrates. When a migratory cell is stimulated with a chemoattractant or extracellular matrix (ECM) gradient, it responds with localized amplification of signals on the side facing the gradient. The signals mediate reorganization of the actin-myosin cytoskeleton, leading to morphological polarization of the cell and pseudopodium extension. To identify these signals, we developed an approach to biochemically isolate the pseudopodium from the cell body using 3.0-micrometer porous filters for large-scale quantitative proteomic and phosphoproteomic analysis. Here, we detail the methodology for pseudopodium purification and proteomic analysis. This model system should be widely applicable for the analysis of the pseudopodium proteome from various migratory cell lines, including primary and cancer cell lines stimulated with a diverse array of chemoattractants, ECM proteins, or both. PMID- 17712139 TI - Filopodia: the fingers that do the walking. AB - Filopodia are actin-based structures composed of parallel bundles of actin filaments and various actin-associated proteins, and they play important roles in cell-cell signaling, guidance toward chemoattractants, and adhesion to the extracellular matrix. Two mechanisms for the formation of filopodia have been suggested, each using different sets of actin-regulating proteins, creating some controversy in the field. New molecules, some of unknown functions, have also been implicated in filopodium formation, suggesting that other possible mechanisms of filopodium formation exist. We discuss established and novel proteins that mediate the formation and dynamics of filopodia, different mechanisms of filopodium formation, and the various functions that distinct filopodia perform. PMID- 17712140 TI - Cadherins, RhoA, and Rac1 are differentially required for stretch-mediated proliferation in endothelial versus smooth muscle cells. AB - Abnormal mechanical forces can trigger aberrant proliferation of endothelial and smooth muscle cells, as observed in the progression of vascular diseases such as atherosclerosis. It has been previously shown that cells can sense physical forces such as stretch through adhesions to the extracellular matrix. Here, we set out to examine whether cell-cell adhesions are also involved in transducing mechanical stretch into a proliferative response. We found that both endothelial and smooth muscle cells exhibited an increase in proliferation in response to stretch. Using micropatterning to isolate the role of cell-cell adhesion from cell-extracellular matrix adhesion, we demonstrate that endothelial cells required cell-cell contact and vascular endothelial cadherin engagement to transduce stretch into proliferative signals. In contrast, smooth muscle cells responded to stretch without contact to neighboring cells. We further show that stretch stimulated Rac1 activity in endothelial cells, whereas RhoA was activated by stretch in smooth muscle cells. Blocking Rac1 signaling by pharmacological or adenoviral reagents abrogated the proliferative response to stretch in endothelial cells but not in smooth muscle cells. Conversely, blocking RhoA completely inhibited the proliferative response in smooth muscle cells but not in endothelial cells. Together, these data suggest that vascular endothelial cadherin has an important role in mechanotransduction and that endothelial and smooth muscle cells use different mechanisms to respond to stretch. PMID- 17712141 TI - The route of administration (enteral or parenteral) affects the conversion of isotopically labeled L-[2-15N]glutamine into citrulline and arginine in humans. AB - BACKGROUND: Glutamine exhibits numerous beneficial effects in experimental and clinical studies. It has been suggested that these effects may be partly mediated by the conversion of glutamine into citrulline and arginine. The intestinal metabolism of glutamine appears to be crucial in this pathway. The present study was designed to establish the effect of the feeding route, enteral or parenteral, on the conversion of exogenously administered glutamine into citrulline and arginine at an organ level in humans, with a focus on gut metabolism. METHODS: Sixteen patients undergoing upper gastrointestinal surgery received an IV or enteral (EN) infusion of L-[2-(15)N]glutamine. Blood was sampled from a radial artery and from the portal and right renal vein. Amino acid concentrations and enrichments were measured, and net fluxes of [(15)N]-labeled substrates across the portal drained viscera (PDV) and kidneys were calculated from arteriovenous differences and plasma flow. RESULTS: Arterial [(15)N]glutamine enrichments were significantly lower during enteral tracer infusion (tracer-to-tracee ratio [labeled vs unlabeled substrate, TTR%] IV: 6.66 +/- 0.35 vs EN: 3.04 +/- 0.45; p < .01), reflecting first-pass intestinal metabolism of glutamine during absorption. Compared with IV administration, enteral administration of the glutamine tracer resulted in a significantly higher intestinal fractional extraction of [(15)N]glutamine (IV: 0.15 +/- 0.03 vs EN: 0.44 +/- 0.08 micromol/kg/h; p < .01). Furthermore, enteral administration of the glutamine tracer resulted in higher arterial enrichments of [(15)N]citrulline (TTR% IV: 5.52 +/- 0.44 vs EN: 8.81 +/- 1.1; p = .02), and both routes of administration generated a significant enrichment of [(15)N]arginine (TTR% IV: 1.43 +/- 0.12 vs EN: 1.68 +/- 0.18). This was accompanied by intestinal release of [(15)N]citrulline across the PDV, which was higher with enteral glutamine (IV: 0.38 +/- 0.07 vs EN: 0.72 +/- 0.11 micromol/kg/h; p = .02), and subsequent [(15)N]arginine release in both groups. CONCLUSIONS: In humans, the gut preferably takes up enterally administered glutamine compared with intravenously provided glutamine. The route of administration, enteral or IV, affects the quantitative conversion of glutamine into citrulline and subsequent renal arginine synthesis in humans. PMID- 17712142 TI - Intestinal polymeric immunoglobulin receptor is affected by type and route of nutrition. AB - BACKGROUND: Secretory immunoglobulin A (SIgA) prevents adherence of pathogens at mucosal surfaces to prevent invasive infection. Polymeric immunoglobulin receptor (pIgR) is located on the basolateral surface of epithelial cells and binds dimeric immunoglobulin A (IgA) produced by plasma cells in the lamina propria. This IgA-pIgR complex is transported apically, where IgA is exocytosed as SIgA to the mucosal surface. Our prior work shows that mice fed intragastric (IG, an elemental diet model) and IV parenteral nutrition (PN) solution have reduced intestinal T and B cells, SIgA, and interleukin-4 (IL-4) compared with mice fed chow or a complex enteral diet (CED). Prior work also demonstrates a reduction in IgA transport to mucosal surfaces in IV PN-fed mice. Because IL-4 up-regulates pIgR production, this work studies the effects of these diets on intestinal pIgR. METHODS: Male Institute of Cancer Research (ICR) mice were randomized to chow (n = 11) with IV catheter, CED (n = 10) or IG PN (n = 11) via gastrostomy and IV PN (n = 12) for 5 days. CED and PN were isocaloric and isonitrogenous. Small intestine was harvested for pIgR and IL-4 assays after mucosal washing for IgA. IgA and IL-4 levels were analyzed by enzyme-linked immunosorbent assay and pIgR by Western blot. RESULTS: Small intestinal pIgR expression, IgA levels, and IL-4 levels decreased significantly in IV PN and IG PN groups. CONCLUSIONS: Lack of enteral stimulation affects multiple mechanisms responsible for decreased intestinal SIgA levels, including reduced T and B cells in the lamina propria, reduced Th-2 IgA-stimulating cytokines, and impaired expression of the IgA transport protein, pIgR. PMID- 17712143 TI - Effects of lymphotoxin beta receptor blockade on intestinal mucosal immunity. AB - BACKGROUND: Mucosal addressin cellular adhesion molecule-1 (MAdCAM-1) directs lymphocyte migration into gut-associated lymphoid tissue (GALT) through Peyer's patches (PPs). Parenteral nutrition (PN) impairs mucosal immunity by reducing PPs MAdCAM-1 expression, T and B cells in GALT, and intestinal and respiratory immunoglobulin (Ig) A levels. We previously showed that PN reduces lymphotoxin beta receptor blockade (LTbetaR) in PPs and intestine, and that stimulation with LTbetaR agonist antibodies reverses these defects. To confirm that LTbetaR regulates transcription of MAdCAM-1 message and more fully understand the effects of LTbetaR on MAdCAM-1 function within the mucosal immune system, we studied the effect of LTbetaR blockade with a chimeric LTbetaR Ig-fusion protein on MAdCAM-1 mRNA levels, PP lymphocyte mass and IgA levels in the intestinal and respiratory tracts. METHODS: Mice were cannulated and killed 3 days after receiving chow + control Ig, chow + LTbetaR-Ig fusion protein (100 microg IV), or PN + control Ig. The PPs of half of the animals were processed for lymphocyte count, and the other half were processed for complementary DNA and subsequent polymerase chain reaction (PCR). mRNA levels of MAdCAM-1 were determined by real-time PCR; intestinal and respiratory IgA levels were measured by ELISA. RESULTS: PN significantly reduced PP lymphocyte mass, MAdCAM-1 mRNA, and intestinal IgA. As anticipated, LTbetaR blockade significantly decreased PP cells and MAdCAM-1 mRNA, but not intestinal IgA because chow feeding was maintained. Both LTbetaR blockade and PN decreased nasal IgA, but not significantly. CONCLUSIONS: LTbetaR blockade in chow animals significantly reduces transcription of MAdCAM-1 gene and PPs lymphocyte mass. These data implicate inadequate LTbetaR signaling as a major mechanism for decreased GALT cells with lack of enteral stimulation, and further establish the role of LTbetaR in the mucosal immune system. PMID- 17712144 TI - Effect of thiol-containing molecule cysteamine on the induction of inducible nitric oxide synthase in hepatocytes. AB - BACKGROUND: Cysteamine, which is a known antioxidant and anti-inflammatory agent, is believed to be a key regulator of essential metabolic pathways in organisms. Cysteamine has beneficial effects in liver damaged by a variety of insults. During liver injury, inducible nitric oxide synthase (iNOS) is induced by lipopolysaccharide or proinflammatory cytokines, leading to excessive nitric oxide (NO) production. Accumulated evidence indicates that NO is an important factor associated with hepatic dysfunction. We examined whether cysteamine influences the induction of iNOS in hepatocytes. METHODS: Primary cultured rat hepatocytes were treated with interleukin (IL)-1beta in the presence and absence of cysteamine. NO production, iNOS induction, and iNOS signal were analyzed. RESULTS: IL-1beta stimulated the inhibitory protein kappaB (IkappaB)/nuclear factor kappaB (NFkappaB) pathway, resulting in the activation of NFkappaB (nuclear translocation and DNA binding), which was followed by the induction of iNOS and NO production. The addition of IL-1beta and cysteamine (1-4 mmol/L) markedly inhibited NO production, with a maximal effect at 4 mmol/L (80%-90% inhibition). Cysteamine also decreased the levels of iNOS protein and mRNA. Transfection experiments revealed that cysteamine decreased the transactivation activity of the iNOS promoter. An electrophoretic mobility shift assay demonstrated that cysteamine inhibited the activation of NFkappaB. Furthermore, cysteamine decreased the mRNA levels of the NFkappaB subunit p65 but increased those of the inhibitory protein IkappaB. CONCLUSIONS: These findings suggest that cysteamine inhibits iNOS induction at the step of NFkappaB activation. Further study is necessary to define the molecular basis of this effect of cysteamine on the regulation of NFkappaB and its pharmacologic implications. PMID- 17712145 TI - Effect of active hexose correlated compound on the production of nitric oxide in hepatocytes. AB - BACKGROUND: Active hexose correlated compound (AHCC) is a "complex compound" containing polysaccharides. AHCC has been reported to improve the prognosis of postoperative hepatocellular carcinoma patients. However, the molecular mechanism of this improvement is not fully understood. In the diseased liver, nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS) is considered to be a causal factor for various hepatopathies. In this study, the possibility of AHCC regulation of NO production by iNOS was pursued as a potential liver-protecting mechanism. METHODS: Primary cultured rat hepatocytes were treated with interleukin-1beta (IL-1beta) in the presence or absence of AHCC. NO production, iNOS induction, and iNOS signal were analyzed. RESULTS: IL-1beta stimulated iNOS induction through the activation of nuclear factor kappaB (NFkappaB), leading to NO production. The addition of AHCC inhibited NO production, showing >80% inhibition at 8 mg/mL. AHCC also decreased the levels of iNOS protein and mRNA. However, AHCC influenced neither the degradation of inhibitory protein kappaB (IkappaB) nor the activation of NFkappaB stimulated by IL-1beta. Transfection experiments with an iNOS promoter-luciferase construct (iNOS-Luc) revealed that AHCC had no effect on the transactivation activity of the iNOS promoter. By contrast, AHCC inhibited the activity of iNOS-Luc containing a 3'untranslated region (UTR) with adenosine and uridine (AU)-rich elements, which shows the stabilizing activity of iNOS mRNA. CONCLUSIONS: Results indicated that AHCC inhibits the induction of iNOS at the level of transcription, causing a decrease in NO production in hepatocytes. AHCC seems to decrease the levels of iNOS mRNA by reducing mRNA stabilization rather than inhibiting its synthesis. PMID- 17712146 TI - Tip position of long-term central venous access devices used for parenteral nutrition. AB - BACKGROUND: Venous thrombosis is a potential postplacement complication of a central venous access device (VAD). Improper catheter tip position is a predisposing factor, especially when the device is used to administer parenteral nutrition (PN). American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) guidelines recommend that a central VAD used for PN be placed with its tip in the superior vena cava (SVC) adjacent to the right atrium (RA). The purpose of this study is to determine the prevalence of improper central VAD tip position and factors associated with malpositioning. METHODS: All adult patients with a longterm VAD (ie, tunneled central venous catheter, peripherally inserted central catheter [PICC], or implanted port) placed before the current admission who were scheduled to receive PN also received chest x-rays to evaluate position of the catheter tip. Position was determined by a staff radiologist. A catheter with its tip ranging from the middle third of the SVC to the RA was considered acceptable; a catheter with its tip in any other position was considered malpositioned. Subjects with multiple VADs or multiple evaluations for the same catheter had the first placement and last evaluation considered. A logistic regression analysis was used to study the univariable and multivariable associations of these factors with tip malposition. RESULTS: Data were collected for catheters in 124 patients, including 74 tunneled catheters (71 Hickman, 2 Broviac, 1 Groshong), 38 PICCs, and implanted ports. Most of the catheters were placed for (81.9%) or chemotherapy (14.5%). Median catheter duration was 1.6 months at time of evaluation. Of 138 catheters studied, 15.9% (95% confidence interval, 10.2-23.1) were malpositioned at time of evaluation. According to univariable analysis, factors associated with malpositioned catheters included shorter catheter duration (p = .001), greater number of lumens (p = .029), venous entry site on the arm (p <.001) and catheters placed at institutions other than Cleveland Clinic (p = .007). Additionally, PICCs were likely to be malpositioned at time of evaluation compared with other long-term VADs combined (34.2% vs 9.0%; p < .001). CONCLUSIONS: A high percentage of long-term VADs improperly positioned for PN in the present study. were more likely to be malpositioned at time of evaluation compared with tunneled catheters and implanted These findings suggest the tip position of long-term should be confirmed before infusing PN. PMID- 17712147 TI - Autopsy tissue trace elements in 8 long-term parenteral nutrition patients who received the current U.S. Food and Drug Administration formulation. AB - Iron, zinc, copper, manganese, chromium, and selenium levels were measured in autopsy tissues of 8 people with short bowel syndrome who received home parenteral nutrition (HPN) and the U.S. Food and Drug Administration (FDA) approved trace element formulation for an average duration of 14 years (range, 2 21). Iron, zinc, copper, manganese and selenium were measured by inductively coupled plasma methods; chromium, by graphite furnace atomic absorption spectrometry. The levels in the 4 tissues studied, heart, skeletal muscle, liver, and kidney, were compared with levels in 45 controls who died without chronic gastrointestinal disorders. Results showed normal HPN patient values for iron and selenium, mild elevation of zinc, and major elevations of copper, manganese, and chromium. The implications of these results for trace-element supplements in long term PN adult patients are discussed, and the need for reformulation of commercially available multi-trace element products in the United States is stressed. PMID- 17712148 TI - Oral antibiotics attenuate bowel segment reversal-induced systemic inflammatory response and body weight loss in massively bowel-resected rats. AB - BACKGROUND: Using a massively bowel-resected rat model, our previous study demonstrated that small bowel segment reversal stimulates jejunal hyperplasia but may also increase the possibility of bacterial translocation and the elevation of circulating white blood cells and serum interleukin-6 that may reduce the whole body anabolism. The aim of this study is to investigate whether oral antibiotics might attenuate the inflammatory responses and might therefore facilitate the beneficial effects of bowel segment reversal. METHODS: Male Wistar rats (approximately 270 g) underwent a 70% small bowel resection with (REV group) or without (CON group) a 3-cm small bowel segment reversal, or underwent a sham operation (SHAM group). After surgeries, half of the animals in the REV group were given oral clindamycin plus amoxicillin (50 plus 50 mg/kg/d, ANT group) for 3 weeks. RESULTS: Oral antibiotics administration significantly attenuated the decreases in feeding efficiency (g of body weight/100 kcal diet) and increases in the circulation of white blood cells, serum nitric oxide, and interleukin-6 (1 way ANOVA, p < .05), which are associated with bowel segment reversal. In addition, antibiotics significantly increased serum concentrations of insulin like growth factor-I, significantly decreased the total numbers of bacteria in the intestine, and tended to reduce the extent of jejunal hyperplasia in rats with bowel segment reversal. CONCLUSIONS: Our results suggest that oral antibiotics may be used as an adjuvant to attenuate the inflammatory responses and to enhance the anabolic responses in massively bowel-resected patients with bowel segment reversal. PMID- 17712149 TI - Subjective global assessment in the clinical setting. AB - BACKGROUND: Our goal was nutrition assessment in hospitalized patients of an internal medicine service. METHODS: Ours was a longitudinal, prospective, and observational study. Four hundred twelve patients participated in this study using the Subjective Global Assessment (SGA). We used chi(2) for univariate and logistic regression. RESULTS: Of 412 patients, 47.6% presented with malnutrition: 38.8% with moderate malnutrition (group B), and 8.58% with severe malnutrition (group C). Malnutrition was related to male patients older than 65 years, oncologic and infectious diseases, and length of hospitalization. CONCLUSIONS: Malnutrition incidence in an internal medical service is high. There is remarkable lack of interest in hospitalized patients' nutrition state. Results show similarities to other studies from Latin America. PMID- 17712150 TI - Feeding the open abdomen. AB - BACKGROUND: The purpose of this study was to determine if early enteral nutrition improves outcome for trauma patients with an open abdomen (OA). METHODS: Retrospective review was used to identify 78 patients who required an OA for >or=4 hospital days, survived, and had available nutrition data. Demographic data and nutrition data comprising enteral nutrition initiation day and daily % target goal were collected. Patients were divided into 2 groups: early enteral feeding (EEN), initiated 4 days). Outcomes included infectious complications, early closure of the abdominal cavity (<8 days from original celiotomy), and fistula formation. RESULTS: Fifty three of 78 (68%) patients were men, with a mean age of 35 years; 74% had blunt trauma. Forty-three of 78 (55%) patients had EEN, whereas 35 of 78 (45%) had LEN. There was no difference with respect to demographics, injury severity, or infectious complication rates. Thirty-two of 43 (74%) patients with EEN had early closure of the abdominal cavity, whereas 17 of 35 (49%) patients with late feeding had early closure (p = .02). Four of 43 (9%) patients with EEN demonstrated fistula formation, whereas 9 of 35 (26%) patients with late feeding formed fistulae (p = .05). The EEN group had lower hospital charges (p = .04) by more than $50,000. CONCLUSIONS: EEN in the OA was associated with (1) earlier primary abdominal closure, (2) lower fistula rate, (3) lower hospital charges. PMID- 17712151 TI - Influence of adding fish oil to parenteral nutrition on gut-associated lymphoid tissue. AB - BACKGROUND: Lack of enteral nutrition reduces gut-associated lymphoid tissue (GALT) mass and function, a mechanism underlying the increased morbidity of infectious complications in severely injured or critically ill patients. Strategies to restore parenteral nutrition (PN)-induced changes of GALT mass and function have been pursued. However, the influences of adding fish oil to PN on gut immunity remain to be clarified. METHODS: Male Institute of Cancer Research (ICR) mice (n = 50) were randomized to 4 groups: ad libitum chow (chow), fat free PN (fat (-)-PN), PN + fish oil (FO-PN), and PN + safflower oil (SO-PN). The PN groups were given isocaloric and isonitrogenous PN solutions. The FO- and SO-PN groups received 20% of total calories from fat emulsions. After 5 days of feeding, lymphocytes from Peyer's patches (PPs), the intraepithelial space (IE), and the lamina propria (LP) of the entire small intestine were isolated. GALT lymphocyte numbers and phenotypes (CD4+, CD8+, alphabetaTCR+, gammadeltaTCR+, B220+ cells) were determined. Immunoglobulin A (IgA) levels of small intestinal washings were also measured by enzyme-linked immunosorbent assay. Another set of mice (n = 24) was used to determine plasma fatty acid compositions after feeding. RESULTS: Lymphocyte numbers from PPs and the LP and intestinal IgA levels were significantly lower in the PN groups than in the chow group, with no significant differences between any 2 PN groups. The FO- and SO-PN groups showed moderate recovery of IE cell numbers compared with the fat (-)-PN group. Omega-3 and omega 6 fatty acid levels were increased with fish and safflower oil additions, respectively, compared with the fat (-)-PN group. CONCLUSIONS: Adding fish oil to PN does not exacerbate PN-induced GALT changes but rather partially reverses these changes, with increased plasma omega-3 fatty acid levels. PMID- 17712152 TI - Dietary gangliosides enhance in vitro glucose uptake in weanling rats. AB - BACKGROUND: The intestine adapts to environmental stimuli, such as modifications in dietary lipids. Dietary lipids modify brush border membrane (BBM) permeability and nutrient transporter activities. Gangliosides (GANG) are glycolipids present in human milk, but they are present only in low amounts in infant formula. Exogenous GANG are incorporated into cell membranes and increase their permeability. This study was undertaken to determine if feeding a 0.2% GANG enriched diet for 2 weeks alters in vitro intestinal sugar absorption in weanling rats compared with an isocaloric control diet or diet enriched with polyunsaturated long-chain fatty acids. METHODS: In vitro uptake of 34-96 mm glucose and fructose and morphological measurements were assessed on intestinal tissue of weanling rats. Western blotting, immunohistochemistry, Northern blotting, and reverse transcription-polymerase chain reaction were performed to determine the mRNA and protein abundance of the sugar transporters SGLT-1, GLUT2 and GLUT5. RESULTS: Feeding GANG did not alter the rates of animal weight gain or intestinal morphology. GANG did not affect fructose uptake. Depending on the concentration of glucose, GANG increased jejunal uptake of higher concentrations of glucose by approximately 20%-60%. There were no changes in GLUT5 or GLUT2 protein or mRNA abundance. Similarly, there were no changes in SGLT-1 mRNA and protein abundance, as determined by Northern and Western blotting. However, using immunohistochemistry, SGLT-1 was lower in GANG than in controls. CONCLUSIONS: The results of this study suggest that the enhanced uptake of glucose that results from feeding 0.2% GANG for 2 weeks to weanling rats may be regulated posttranslationally. Clearly any adjustment of the content of GANG in infant formula must be studied carefully. PMID- 17712154 TI - ASPEN statement on parenteral nutrition standardization. AB - In response to questions regarding use of standardized parenteral nutrition (PN) formulations, the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) developed a Task Force to address some of these issues. A.S.P.E.N. envisions standardized PN as a broader issue rather than simply using a standardized, commercially available PN product. A standardized process for PN must be explored in order to improve patient safety and clinical appropriateness, and to maximize resource efficiency. A standardized process may include use of standardized PN formulations (including standardized, commercial PN products) but also includes aspects of ordering, labeling, screening, compounding, and administration of PN. A safe PN system must exist which minimizes procedural incidents and maximizes the ability to meet individual patient requirements. Using clinicians with nutrition support therapy expertise will contribute to that safe PN system. The purpose of this statement is to present the published literature associated with standardized PN formulations, to provide recommendations, and to identify areas in need of future research. PMID- 17712153 TI - Advanced glycation and lipoxidation end products--amplifiers of inflammation: the role of food. AB - BACKGROUND: High levels of glycated and lipoxidated proteins and peptides in the body are repeatedly associated with chronic diseases. These molecules are strongly associated with activation of a specific receptor called RAGE and a long lasting exaggerated level of inflammation in the body. METHODS: PubMed reports over 5000 papers plus >13,500 articles about the related HbA(1c), most of them published in the past 5 years. Most of the available abstracts have been read and approximately 800 full papers have been studied. RESULTS: RAGE, a member of the immunoglobulin superfamily of cell surface molecules and receptor for advanced glycation end products, known since 1992, functions as a master switch, induces sustained activation of nuclear factor kappaB (NFkappaB), suppresses a series of endogenous autoregulatory functions, and converts long-lasting proinflammatory signals into sustained cellular dysfunction and disease. Its activation is associated with high levels of dysfunctioning proteins in body fluids and tissues, and is strongly associated with a series of diseases from allergy and Alzheimers to rheumatoid arthritis and urogenital disorders. Heat treatment, irradiation, and ionization of foods increase the content of dysfunctioning molecules. CONCLUSIONS: More than half of the studies are performed in diabetes and chronic renal diseases; there are few studies in other diseases. Most of our knowledge is based on animal studies and in vitro studies. These effects are worth further exploration both experimentally and clinically. An avoidance of foods rich in deranged proteins and peptides, and the consumption of antioxidants, especially polyphenols, seem to counteract such a development. PMID- 17712155 TI - The great demographic trap. PMID- 17712156 TI - Job satisfaction and career commitment among nursing assistants providing Alzheimer's care. AB - As part of a statewide dementia-specific training collaborative, data were collected from nursing assistants and aides who provide paid Alzheimer's care. This study explored the relevance of previous education and practical experiences to specific constructs associated with worker recruitment and retention. Direct care providers with prior training in gerontology and geriatrics had lower levels of extrinsic job satisfaction and career resilience than those without this kind of continuing education. Program participants who were currently or previously the primary caregiver for a friend or relative with Alzheimer's disease had higher levels of intrinsic job satisfaction but lower levels of career resilience than those with no informal caregiving experience. Current or previous informal caregiving experience may enhance intrinsic job satisfaction by increasing personal commitment to pursue formal care work and providing a kind of inoculation against the demoralization that is too often suffered in these very challenging jobs. PMID- 17712157 TI - Impact of a multimodal rehabilitative intervention on demented patients and their caregivers. AB - Alzheimer's disease is becoming a social, political, and economic issue as a result of both the growing number of people affected and the enormous economic, social, and emotional costs involved in caring for Alzheimer's patients. The aim of this study is to evaluate the effects of a multimodal intervention program for patients with Alzheimer's disease and their caregivers. The study was conducted on a sample of 32 subjects: 16 Alzheimer's patients and their caregivers. The results obtained after the multimodal rehabilitation program showed that the Alzheimer's patients had a more stable cognitive status and improved mood. Regarding the psychoeducational program, the results demonstrate the efficacy of such interventions in terms of increasing and preserving the caregivers' coping skills and enhancing their perception of the value of support groups. PMID- 17712158 TI - Depressed mood in informal caregivers of individuals with mild cognitive impairment. AB - This study estimates the prevalence of depressed mood in caregivers of individuals with mild cognitive impairment (MCI) and assesses whether demographics, stressors, intrapsychic strain, and gain are associated with depressed mood. A secondary analysis of baseline data from the Alzheimer's Disease Cooperative Study MCI trial was conducted using a cross-sectional, correlational design. Descriptive statistics to estimate the prevalence of caregiver depressed mood and univariate and block-wise logistic regression analyses were used. The prevalence of depressed mood in 769 caregivers was 24.6% (95% confidence interval, 21.5-27.7). The odds of being depressed were significantly higher in younger, nonspousal caregivers with less education, who cared for MCI patients with lower activities of daily living functioning, and who perceived greater relational deprivation, higher levels of self-loss, and personal gain. Controlling for relevant variables, relational deprivation and caregiver education continued to be significantly associated with depressed mood. Relational deprivation may be important for future interventions. PMID- 17712159 TI - Preserved implicit memory in dementia: a potential model for care. AB - A growing body of evidence supports the presence of a preserved implicit memory (PIM) system for persons with Alzheimer's disease (AD). This article describes a new approach to dementia care, the PIM model, which translates evidence from implicit memory research into a practice model of dementia care. The PIM model predicts that function can be sustained longer for persons with AD through interventions and environments that activate an individual's PIM. Activation of PIM can occur with perceptual priming of familiar objects and reinforcement of learned motor skill memories within tasks. This practice model provides a new framework for planning and implementing dementia care that may preserve function for persons with Alzheimer's dementia. PMID- 17712160 TI - Progressive nonfluent aphasia associated with a new mutation V363I in tau gene. AB - Reported here is a new missense mutation V363I in exon 12 of the microtubule associated protein tau (MAPT) gene associated with progressive nonfluent aphasia, with onset at the age of 69 years in a woman. Although near mute, she maintained complex activities and had no discernible deficits outside of language until the age of 75 years, when progressive gait and swallowing disturbances appeared. There was a history of late-onset aphasia and apraxia in her father. All of her children were asymptomatic adults, but psycholinguistic abnormalities were detected in those bearing the mutation, consisting of difficulties in comprehension, both reading (symbol discrimination and comprehension of oral spelling) and oral (matching sentences to pictures and comprehension of locative relationships). A mutation-bearing sibling showed no abnormalities at 70 years old, consistent with the limited penetrance expected in late-onset disease. The mutation, corresponding to a highly conserved residue in the fourth tubulin binding repeat, was not present in 194 normal individuals with the same genetic background. PMID- 17712161 TI - Cognition and amyotrophic lateral sclerosis (ALS). AB - Amyotrophic lateral sclerosis (ALS) is classically described as a pure motor disease; however, there is growing evidence of a range of cognitive impairment. Cognitive abnormalities include deficiencies in frontal executive skills, varying from mild deficits to meeting criteria for diagnosis of frontotemporal dementia (FTD). Cognitive impairment occurs in sporadic and familial forms of ALS. Patients may present with cognitive deficits before, after, or at the onset of motor neuron disease. Structural and functional imaging studies have shown extramotor cortical degeneration corresponding to levels of frontal executive impairment on neuropsychologic testing. In addition, ALS and a subset of FTD patients display common pathological findings on immunohistochemistry staining. It is believed that these disorders represent a continuum between motor and nonmotor cortical degeneration. The purpose of this article is to review the literature on cognitive deficits in ALS. Identifying changes in cognition is critical for physicians and caregivers of ALS patients, as cognitive decline may interfere with patient compliance. Diagnosis and treatment of cognitive symptoms in ALS patients may improve quality of life. PMID- 17712162 TI - A Quick Test for Cognitive Speed: a measure of cognitive speed in dementia with Lewy bodies. AB - The purpose of this article is to investigate how patients with dementia with Lewy bodies (DLB) perform on A Quick Test for Cognitive Speed (AQT) compared with patients with Alzheimer's disease (AD) and age- and sex-matched controls and to see whether this test might be helpful in distinguishing DLB from AD at comparable cognitive levels. Twenty-three patients with DLB, 18 patients with AD, and 24 controls were included. The time in seconds to complete the AQT was recorded for the 3 independent study groups according to standard directives. The DLB patients had significantly longer reading times than the AD patients at equivalent and relatively high Mini-Mental State Examination levels. We suggest that slow performance on the AQT at relatively high Mini-Mental State Examination levels could be one way of distinguishing DLB from AD. This may have clinical implications for treatment as well as for understanding the neuropathological properties of the disease. PMID- 17712163 TI - Apoptotic gene expression in Alzheimer's disease hippocampal tissue. AB - Alzheimer's disease (AD) is the major cause of dementia, accounting for 50% to 70% of the late-onset patients, with 17 to 20 million affected. It is characterized by neurofibrillary tangles, neuronal loss, and amyloid plaques in tissues of the cortex, hippocampus, and amygdala. Apoptosis or programmed cell death appears in the progression of AD. In this study, we investigated the gene expression of 14 apoptotic genes (E2F1, p21/WAF, ICE-LAP3, Fas Antigen, CPP-32, GADD153, ICE-beta, c-Fos, c-Jun, Bax-alpha, Bcl-2, Bcl-(x)L, BAK, and p53) in 5 normal and 6 AD human hippocampal tissues, using reverse transcription-polymerase chain reaction. Our results show an upregulation of gene expression in AD patients for c-Fos and BAK. ICE-beta, c-Jun, Bax-alpha, Bcl-x(L), p53, and GADD153 were found to be upregulated in some AD samples but were not detected or downregulated in other AD or normal samples. No gene expression was found for E2F1 , p21/WAF, ICE-LAP3, Fas Antigen, CPP32, or Bcl-2. These results indicate significant increases in c-Fos , c-Jun, and Bak; therefore, we suggest that these genes may be critical in the apoptotic cascades of AD. PMID- 17712164 TI - Enhanced response of neurons in rat somatosensory cortex to stimuli containing temporal noise. AB - Sensory stimuli under natural conditions often consist of a temporally irregular sequence of events, contrasting with the periodic sequences commonly used as stimuli in the laboratory. These experiments compared the responses of neurons in rat barrel cortex with trains of whisker movements with different frequencies; each train possessed either a periodic or an irregular, "noisy" temporal structure. Periodic stimulus trains were composed of a sequence of 21 whisker deflections separated by 20 equal interdeflection intervals (IDIs). Noisy trains were matched for mean IDI but included intervals shorter and longer than the mean IDI. Cortical responses were equivalent for periodic and noisy stimuli for frequencies up to 10 Hz. Above 10 Hz, temporal noise led to a larger response magnitude, and this effect was amplified as deflection frequency increased. Noise also caused a sharpening of the temporal precision of response to the individual deflections of the stimulus train. Cortical neurons thus appear to be "tuned" to respond in a different way to stimuli characterized by temporal unpredictability. As a consequence, perceptual judgments that depend on somatosensory cortical firing rate may be affected by the presence of temporal noise. PMID- 17712165 TI - Literature review: visual search by children with and without ADHD. AB - OBJECTIVE: To summarize the literature that has employed visual search tasks to assess automatic and effortful selective visual attention in children with and without ADHD. METHOD: Seven studies with a combined sample of 180 children with ADHD (M age = 10.9) and 193 normally developing children (M age = 10.8) are located. RESULTS: Using a qualitative approach, the authors find no group difference in automatic search, but results are variable for effortful serial search. Using a novel, graphical approach, the authors find that the ADHD group demonstrated less efficient serial search. This overall effect is explored as a function of search display complexity. Children with ADHD search less efficiently at the lowest and highest levels of display complexity. CONCLUSION: Children with ADHD show impairments in aspects of their effortful visual selective attention, as measured by visual search. PMID- 17712166 TI - ADHD symptoms and associated psychopathology in a community sample of adolescents from the European north of Russia. AB - OBJECTIVE: To assess the prevalence of ADHD symptoms and their relationship to psychopathology in adolescents from the European North of Russia. METHOD: The prevalence of ADHD symptoms is assessed by teacher reports in 536 adolescents. Internalizing and externalizing problems are assessed by teacher ratings and student self-reports. RESULTS: Prevalence of individual ADHD symptoms ranges between 3.3% and 35%. Only 8.9% of boys and 3.6% of girls have positive ratings on six items in either inattention or hyperactivity subtype. These adolescents fare significantly worse regarding externalizing but not internalizing problems. Compared to girls with ADHD, boys with ADHD report higher levels of violent and nonviolent delinquency and are described by teachers as having more conduct problems. Possible ADHD status is associated with depressive symptoms in boys but not in girls. CONCLUSION: The estimates of ADHD prevalence rates obtained in this study are similar to those of other countries, suggesting the need for identification and treatment of the disorder. Evaluation of associated disruptive behavior disorders and depression, particularly in boys, is warranted. PMID- 17712167 TI - Development of a new psychosocial treatment for adult ADHD. AB - OBJECTIVE: The purpose of this study was to assess the effectiveness of a new manualized group Meta-Cognitive Therapy (MCT) for adults with ADHD that extends the principles and practices of cognitive-behavioral therapy to the development of executive self-management skills. METHOD: Thirty adults diagnosed with ADHD completed an 8- or 12-week program designed to target impairments in time management, organization, and planning skills. Treatment efficacy was measured using pre- and posttreatment self-report standardized measures (CAARS-S:L & Brown ADD Scales). RESULTS: General linear modeling revealed a robust significant posttreatment decline on the CAARS DSM-IV Inattentive symptom scale (p < .001) as well as improvement on the Brown ADD Scales (p < .001). CONCLUSION: The findings indicate that participants in the MCT program showed marked improvement with respect to core ADHD symptoms of inattention, as well as executive functioning skills, suggesting that this program has promise as a treatment for meta cognitive deficits in adults with ADHD. PMID- 17712168 TI - Attention problems and hyperactivity as predictors of college grade point average. AB - OBJECTIVE: This study examined the relative contributions of measures of attention problems and hyperactivity to the prediction of college grade point average (GPA). METHOD: A sample of 316 students enrolled in introductory psychology and sociology classes at a southeastern university completed the BASC 2 Self-Report of Personality College Form. Scores on the attention problems scale and the hyperactivity scale of the BASC-2 were entered into a regression equation as predictors of cumulative GPA. RESULTS: Each of the independent variables made a significant contribution to the prediction of GPA. Attention problem scores alone explained 7% of the variability in GPAs. The addition of hyperactivity scores to the equation produced a 2% increase in explanatory power. CONCLUSION: The implications of these results for assessing symptoms of inattention and hyperactivity in college students are discussed. PMID- 17712171 TI - Sustained and focused attention deficits in adult ADHD. AB - OBJECTIVE: To examine the specificity of deficits in focused attention and sustained attention in adults with ADHD and to evaluate the effect of comorbidity. METHOD: Twenty-eight adults with ADHD without comorbidity were compared with 28 ADHD outpatients with comorbidity. Two control groups were used: 68 adults referred for ADHD but with another psychopathology rather than ADHD (non-ADHD) and 28 healthy controls. All participants completed attention tests of the Amsterdam Neuropsychological Tasks program. RESULTS: Both ADHD groups demonstrated a sustained attention deficit relative to the control groups, as indicated by a disproportionate deterioration of speed fluctuation with time-on task reflecting temporal lapses in attention. Only the ADHD+ group showed focused attention deficits in that they were less able to ignore irrelevant information. CONCLUSION: These findings show that adults with ADHD have specific deficits in sustained attention. Additional deficits in focused attention are confined to outpatients with ADHD and comorbidity. PMID- 17712172 TI - Adjustment to college in students with ADHD. AB - OBJECTIVE: To examine college adjustment in students reporting an ADHD diagnosis and the effect of medication treatment on students' adjustment. METHOD: 1,648 first-semester freshmen attending a public and a private university completed a Web-based survey to examine their adjustment to college. RESULTS: Compared with 200 randomly selected control students, 68 students with ADHD reported more academic concerns and depressive symptoms. This was explained by higher rates of inattentive symptoms among students with ADHD and was unrelated to hyperactive impulsive symptoms. Among students with ADHD, medication treatment was not related to better adjustment or diminished ADHD symptoms. The contribution of inattention to academic concerns and depressive symptoms remained significant when controlling for personality traits. CONCLUSION: Students with ADHD experience greater academic performance concerns and depressive symptoms during the transition to college. Medication treatment did not appear to diminish ADHD symptoms nor enhance students' adjustment. PMID- 17712173 TI - The experience of receiving a diagnosis and treatment of ADHD in adulthood: a qualitative study of clinically referred patients using interpretative phenomenological analysis. AB - OBJECTIVE: To evaluate the psychological impact of receiving a diagnosis of ADHD in adulthood and treatment with medication and to examine how diagnosis and treatment with medication changes an individual's self-perception and view of the future. METHOD: Participants were eight individuals diagnosed with ADHD at a tertiary service. Semistructured interviews were conducted and the data were analyzed according to the principles of Interpretative Phenomenological Analysis. RESULTS: Three master themes emerge from the analysis: Participants engage in a (a) review of the past, particularly how they feel different from others, (b) the emotional impact of the diagnosis, and (c) consideration of the future. These themes suggest a six-stage model of psychological acceptance of a diagnosis of ADHD: (a) relief and elation, (b) confusion and emotional turmoil, (c) anger, (d) sadness and grief, (e) anxiety, and (f) accommodation and acceptance. CONCLUSION: The model indicates an important role for psychological treatment, which should begin at the point of diagnosis. Cognitive behavioral techniques will help clients diagnosed with ADHD in adulthood cope with the adjustment process. Adults should be taught skills to anticipate future hurdles and challenges and apply appropriate coping strategies. PMID- 17712175 TI - Distribution of endothelin-converting enzyme-1 and neutral endopeptidase in human endometrium. AB - The expression of endothelin-1 (ET-1), which has been proposed to have a potential autocrine/paracrine role, varies during the menstrual cycle, and therefore, ET-1 may be involved in the cyclic change of the human endometrium. However, neither the synthesis nor the degradation of ET-1 in the endometrium has been determined in detail. We investigated endothelin-converting enzyme-1 (ECE 1), which converts big-ET-1 to active ET-1, and neutral endopeptidase (NEP), which cleaves and inactivates ET-1 in human endometrium in vivo and in vitro. Western blot analysis demonstrated that the change in the expression of ECE-1 during the menstrual cycle differed from that of NEP in the endometrium. ECE-1 was expressed by endometrial epithelial cells, whereas NEP was predominantly expressed by stromal cells in vivo and in vitro. In conclusion, our results suggest that spacio-temporal expression of two endopeptidases, ECE-1 and NEP, involved in the synthesis and degradation of ET-1, might regulate ET-1 action in human endometrium. PMID- 17712176 TI - Interaction of membrane skeletal protein, protein 4.1B and p55, and sodium bicarbonate cotransporter1 in mouse renal S1-S2 proximal tubules. AB - Our recent studies demonstrated the localization of protein 4.1B, a member of the 4.1 skeletal membrane proteins, to the basolateral membranes of the S1-S2 renal proximal tubules. In the present studies, we investigated the presence of binding partners that could form a molecular complex with the 4.1B protein. Immunohistochemistry revealed the localization of p55, a membrane-associated guanylate kinase, and the sodium bicarbonate cotransporter1 (NBC1), to the basolateral membrane domain of S1-S2 in mouse renal proximal tubules. Using immunoprecipitation of kidney lysates with anti-p55 antibody, a positive band was blotted with anti-4.1B antibody. GST fusion proteins including the NBC1 and 4.1B regions were confirmed to bind with each other by electrophoresis after mixing. Both NBC1- and 4.1B-specific bands were detected in renal protein mixtures immunoprecipated by either anti-4.1B- or NBC1-specific antibodies. It is likely that NBC1, 4.1B, and p55 form a molecular complex in the basolateral membrane of the kidney S1-S2 proximal tubules. We propose that the 4.1B-containing membrane skeleton may play a role in regulating the Na(+) and HCO(3)(-) reabsorption in S1 S2 proximal tubules. PMID- 17712177 TI - YKL-40 protein expression in the early developing human musculoskeletal system. AB - YKL-40 is a growth factor for chondrocytes and fibroblasts. The aim was to evaluate YKL-40 expression in the musculoskeletal system during early human development. We studied sections from 15 human embryos [weeks 5.5-8; 7- to 31-mm crown-rump length (CRL)] and 68 fetuses (weeks 9-14; 33- to 105-mm CRL) for YKL 40 protein expression by immunohistochemistry. YKL-40 mRNA expression was evaluated in two human embryos (days 41 and 51). Initially YKL-40 is expressed in all germ layers: ecto-, meso-, and endoderm. YKL-40 mRNA and protein expression are found in tissues of the ecto-, meso-, and endoderm, and YKL-40 protein expression is present during development of cartilage, bone, joints, and muscles. At the cellular level, YKL-40 protein expression is high in tissues characterized by rapid proliferation, marked differentiation, and undergoing morphogenetic changes. Examples of rapid cell proliferation include the chondrogenic inner layer of perichondrium and the osteogenic inner layer of periosteum. Differences in YKL-40 expression during differentiation are found in the chondrogenic and osteogenic cell lineages. The initial shaping of cartilage and bone models and joints is concomitant with a strong outline of YKL-40-positive cells. This indicates that YKL-40 is associated with cell proliferation, differentiation, and tissue morphogenesis during development of the human musculoskeletal system. PMID- 17712178 TI - Planar spindle orientation and asymmetric cytokinesis in the mouse small intestine. AB - A major feature of epithelial cell polarity is regulated positioning of the mitotic spindle within the cell. Spindles in cells of symmetrically expanding tissues are predicted to align parallel to the tissue plane. Direct measurement of this alignment has been difficult in mammalian tissues. Here, we analyzed the position of spindles in intact mouse intestinal epithelium using microtubule immunofluorescence and three-dimensional confocal imaging. Mitotic cells were identified in the proliferative zone of intestinal crypts. Spindle angle relative to the apical cell surface was determined either by direct measurement from confocal images or with a computational algorithm. Angles averaged within 10 degrees of parallel to the apical surface in metaphase and anaphase cells, consistent with robust planar spindle positioning, whereas spindles in prometaphase cells showed much greater angle variability. Interestingly, cytokinetic furrows appeared to extend from the basal cell surface toward the apical surface. This type of image analysis may be useful for studying the regulation of spindle position during tissue remodeling and tumor formation. PMID- 17712180 TI - Preventing kernicterus: a wake-up call. PMID- 17712179 TI - Evidence that the ZNT3 protein controls the total amount of elemental zinc in synaptic vesicles. AB - The ZNT3 protein decorates the presynaptic vesicles of central neurons harboring vesicular zinc, and deletion of this protein removes staining for zinc. However, it has been unclear whether only histochemically reactive zinc is lacking or if, indeed, total elemental zinc is missing from neurons lacking the Slc30a3 gene, which encodes the ZNT3 protein. The limitations of conventional histochemical procedures have contributed to this enigma. However, a novel technique, microprobe synchrotron X-ray fluorescence, reveals that the normal 2- to 3-fold elevation of zinc concentration normally present in the hippocampal mossy fibers is absent in Slc30a3 knockout (ZNT3) mice. Thus, the ZNT3 protein evidently controls not only the "stainability" but also the actual mass of zinc in mossy fiber synaptic vesicles. This work thus confirms the metal-transporting role of the ZNT3 protein in the brain. PMID- 17712181 TI - Placing preterm infants for sleep: first prone, then supine. PMID- 17712182 TI - Drug misuse during pregnancy and fetal toxicity. PMID- 17712183 TI - Are postnatal steroids ever justified to treat severe bronchopulmonary dysplasia? PMID- 17712185 TI - Antenatal diagnosis and postnatal treatment of intrapulmonary arteriovenous malformation. PMID- 17712184 TI - Is nitric oxide effective in preterm infants? PMID- 17712187 TI - Asymmetrical crying facies in monozygotic twins. PMID- 17712186 TI - Life-threatening bleeding from thymic cysts in a newborn. PMID- 17712188 TI - How has research in the past 5 years changed my clinical practice. AB - This article discusses how research in the past 5 years into management strategies influencing respiratory outcomes has changed (or not changed) the author's clinical practice. Changes include using inhaled nitric oxide but no longer systemic pulmonary vasodilators in term born infants with pulmonary hypertension. Use of postnatal steroids is now restricted to systemic administration in infants with severe respiratory failure and who are ventilator dependent beyond 2 weeks of age. Infants with bronchopulmonary dysplasia, unless they have pulmonary hypertension, are maintained at oxygen saturation levels of 90-92% rather than >/=95%. Supine sleeping is instituted in prematurely born infants without contraindications several weeks prior to neonatal discharge to reinforce to parents the importance of supine sleeping their baby at home. Further research is required to identify the optimal respiratory support strategy, particularly for very immature infants. PMID- 17712189 TI - Neonatal gastric perforation following inadvertent connection of oxygen to the nasogastric feeding tube. PMID- 17712190 TI - Impact of common genetic variation on neonatal disease and outcome. AB - The main aim of identifying gene-environment interactions is to provide insight into mechanisms of disease development and to identify patients with an inherent vulnerability to certain conditions. This in turn may allow patients to be targeted with individualised treatment based on the knowledge of their inborn susceptibility to specific conditions. This review describes the possible effects of common genetic variation on outcome in various conditions affecting the neonate. It focuses predominantly on studies of positive association rather than non-association to illustrate this potential influence and to highlight the potential for further study and intervention. The shortcomings of published association studies and the place of such studies in future research are also discussed. PMID- 17712192 TI - Newborn with intermittent grunting in the first hours after delivery. PMID- 17712193 TI - Dr Edith Potter (1901 1993) of Chicago: pioneer in perinatal pathology. AB - Following in the footsteps of Billard and Ballantyne, Edith Potter founded from the 1930s onwards the modern subspecialty of perinatal pathology. Her name is eponymously linked with the facial characteristics of infants with bilateral renal agenesis. PMID- 17712194 TI - N-terminal pro-B-type natriuretic peptide as a marker of ductal haemodynamic significance in preterm infants: a prospective observational study. PMID- 17712191 TI - Neonatal nasal intermittent positive pressure ventilation: what do we know in 2007? AB - Although neonatal nasal intermittent positive pressure ventilation (NIPPV) is widely used today, its place in neonatal respiratory support is yet to be fully defined. Current evidence indicates that NIPPV after extubation of very premature infants reduces the rate of reintubation. However, much is still not known about NIPPV including its mechanisms of action. It may improve pulmonary mechanisms, tidal volume and minute ventilation but more studies are required to confirm these findings. There is some evidence that NIPPV marginally improves gas exchange. More research is needed to establish which device is best, what settings to use or whether to use synchronised rather than non-synchronised NIPPV, and about the way to wean NIPPV. Future studies should enrol sufficient infants to detect uncommon serious complications and include long-term follow up to determine important neurodevelopment and pulmonary outcomes. PMID- 17712195 TI - Free-flow oxygen delivery using a T-piece resuscitator. PMID- 17712196 TI - Routine mechanical ventilation for transferred neonates with duct-dependent congenital heart disease. PMID- 17712198 TI - Revascularization of thrombus-laden lesions in AMI--the burden on the interventionalist. PMID- 17712197 TI - Feasibility of sequential thrombus aspiration and filter distal protection in the management of very high thrombus burden lesions. AB - BACKGROUND: A series of thrombectomy and distal filter devices have been developed to limit distal embolization during percutaneous coronary interventions (PCI). OBJECTIVE: To evaluate the feasibility of the combined use of thrombus aspirating catheters and distal filter devices in patients at high risk of no reflow. METHODS: Thrombus aspiration (TA) and distal filter protection (DFP) were sequentially used in a series of patients undergoing urgent PCI within 48 hours of acute myocardial infarction (MI). Inclusion criteria were: (1) occlusion of the infarct-related artery; (2) at least 2 out of the 6 Yip's classification features of high thrombus burden. Coronary angiograms were evaluated off-line to assess thrombus score, coronary flow and distal embolization in different phases of the procedure. RESULTS: TA followed by DFP prior to balloon dilatation or stent implantation was successfully performed in 20 patients with acute MI due to occlusion of de novo lesions (80%) or in-stent thrombosis (20%) located in a native coronary artery (90%) or a saphenous vein graft (10%). TA was associated with a significant acute reduction of TS and improvement of coronary flow (TIMI grade from 0.7 +/- 0.8 to 1.6 +/- 1.1; p = 0.004 and CTFC from 83 +/- 29 to 52 +/ 36; p = 0.006). This facilitated the deployment of DFP, which did not induce significant flow modification (TIMI grade: 2.3 +/- 0.9 pre-DFP placement vs. 2.2 +/- 1.0 post-DFP placement; p = 0.20; CTFC: 32 +/- 28 pre-DFP placement vs. 35 +/ 28 post-DFP placement; p = 0.47). Post-PCI angiography revealed a 90% TIMI 3 flow rate and 47% MBG 3 rate with only 1 case of angiographically evident distal embolization. CONCLUSIONS: Sequential use of TA and DFP may be successfully used during PCI in patients at very high risk of distal embolization. However, the possible benefits of such an approach should be weighted with the increased complexity of the procedure. Further evaluations of the clinical efficacy of this approach are needed. PMID- 17712199 TI - Coronary stenting with M-Guard: feasibility and safety porcine trial. AB - M-Guard is an ultra-thin polymer mesh sleeve attached to the external stent surface. It is designed to minimize distal embolization during coronary, renal, carotid and vein graft stenting. The polymer net could also serve as a platform for more uniform drug delivery. AIM: To evaluate coronary M-Guard stent deliverability and safety (stent thrombosis and restenosis) in comparison to bare metal stents (BMS) in a porcine model of percutaneous coronary interventions (PCIs). METHODS: Under general anesthesia using percutaneous technique, 6 swine received a total of 18 coronary stents: 5 BMS and 13 M-Guard-BMS. Quantitative coronary angiography (QCA) was obtained immediately prior to and post-PCI, and at 30 days post-stenting. At 30 days, all animals were sacrificed and hearts were sent to a core lab for coronary histology and histomorphometry. Primary endpoints were 30-day QCA percent diameter stenosis, late luminal loss and minimal luminal diameter (MLD). Secondary endpoints were procedural success, 30-day mortality and stent thrombosis. Exploratory endpoints were histology and histomorphometric analysis performed at 30 days on M-Guard stented segments. RESULTS: All stents were delivered successfully. There were no procedural complications or porcine morbidity or mortality at 30 days. The M-Guard and BMS displayed similar results of MLD, late luminal loss and percent diameter stenosis at 1 month. CONCLUSION: When compared to BMS, PCI with M-Guard-BMS is feasible, safe and yields similar inflammatory and restenotic response. PMID- 17712200 TI - Short- and long-term clinical outcomes of coronary drug-eluting stent recipients presenting with chronic renal disease. AB - BACKGROUND: Randomized trials of drug-eluting stents (DES) excluded patients with severe renal insufficiency. We sought to evaluate the impact of baseline renal function on clinical outcomes in recipients of coronary DES. METHODS: We retrospectively reviewed our hospital databases to identify consecutive patients who underwent DES implantations between May 2003 and December 2004, subgrouped among 4 ranges of glomerular filtration rate (GFR) between > or = 90 ml per minute and < 30 ml per minute, in 30 ml per minute decrements, and 1 group treated with long-term dialysis. Clinical follow up was obtained at 6 months, 1 year and annually thereafter. RESULTS: Our study group included 2,758 patients with long-term outcomes recorded over a mean follow up of 706 +/- 273 days. The rates of in-hospital adverse events increased significantly as GFR decreased, though no major adverse event occurred among the dialyzed patients. Actuarial survival analyses up to 2 years revealed significant between-groups differences in rates of major adverse cardiac events (MACE) and death (both p < 0.001), while the differences in target vessel revascularization (TVR) rates did not reach statistical significance (p = 0.069). By Cox regression analysis, a GFR < 60 ml per minute remained a significant predictor of 2-year mortality (p < 0.001) and MACE (p < 0.001), but not TVR (p = 0.839). CONCLUSIONS: In conclusion, low rates of TVR were observed over 2 years in DES recipients with a wide range of renal function. Low rates of TVR were countered by high rates of death and MACE among renally insufficient patients over the long term. PMID- 17712201 TI - PCI in CKD: A-OK? PMID- 17712202 TI - Intra-aortic counterpulsation does not improve coronary flow early after PCI in a high-risk group of patients: observations from a randomized trial to explore its mode of action. AB - The intra-aortic balloon pump (IABP) is the most commonly used temporary cardiac assist device. The precise role and the mechanism of any benefit in high-risk patients undergoing percutaneous coronary intervention (PCI) have not been fully determined. We hypothesized that the use of an IABP following PCI in high-risk non-shocked patients would immediately increase coronary blood flow, tissue perfusion and hence preserve left ventricular function. METHODS: Predefined high risk, but non-shocked, patients were randomized to either an IABP or no IABP following PCI. Angiography was performed pre-PCI, immediately post-PCI and 10 minutes after the completion of the procedure. TIMI flow grade (TFG), TIMI frame count (TFC) and myocardial blush grade (MBG) were measured. Echocardiographic wall motion index (WMI) was measured on days 1 and 30 following PCI. RESULTS: Of 33 patients, 17 received IABP and 16 did not. At final angiography, the TFG was 2.8 +/- 0.7 and 2.9 +/- 0.3 (p = 0.6), the TFC was 19.9 +/- 23 and 16.9 +/- 16.9 (p = 0.7), and the MBG was 2.5 +/- 0.9 and 2.5 +/- 0.7 (p = 0.9) in the IABP and the no-IABP arms. The WMI on day 1 was 1.7 +/- 0.4 and 1.7 +/- 0.4 (p = 0.7), and on day 30, it was 1.5 +/- 0.4 and 1.5 +/- 0.4 (p = 0.9). There was no difference in the total sum of ST-segment elevation prior to PCI (12.6 +/- 7.7 vs. 13.5 +/- 7.9; p = 0.8), nor in the summed ST change in subsequent electrocardiograms (ECGs) to 48 hours in both of the groups. CONCLUSION: Whether an IABP is of any benefit in non-shocked, but high-risk, patients undergoing PCI remains to be established, but any potential benefit does not appear to be associated with early improvement in coronary flow. Whether the insertion of an IABP improves coronary flow beyond 10 minutes is not known. However, the IABP did not significantly affect subsequent left ventricular wall motion index or ECG ST segment resolution in this study. PMID- 17712203 TI - Is it time to burst the "balloon" for high-risk patients? PMID- 17712204 TI - Cost-effectiveness of the radial versus femoral artery approach to diagnostic cardiac catheterization. AB - BACKGROUND: The radial approach to cardiac catheterization is increasingly popular due to shorter procedural and recovery times and greater patient comfort. METHODS: Comparative cost analysis between radial or femoral (with or without closure device) approaches were performed. RESULTS: Radial (R), femoral (F), and femoral with a closure device (F +/- C) approaches were used in 70, 62 and 49 consecutive cases, respectively. Group R had higher access equipment cost (93.0 dollars +/- 9.5 vs. 40.5 dollars) in group F (p < 0.001), but lower catheter cost (19.7 dollars +/- 12.7 vs. 31.1 dollars +/- 9.3; p < 0.001) than Group F, and lower contrast cost (26.9 dollars +/- 17.0 vs. 42.9 dollars +/- 25.0) in Group F +/- C (p < 0.001). There was a lower postprocedure recovery cost (185.2 dollars +/- 52.7) in Group R compared to 337.5 dollars +/- 59.0 in Group F (p < 0.001) and 208 dollars +/- 70.4 in Group F +/- C (p < 0.001), with a median recovery time of 126.0 +/- 36.0 minutes in group R vs. 240.0 +/- 42.0 minutes, and 150.0 +/- 48.0 minutes in groups F and F +/- C, respectively (both p < 0.05). The total variable procedural cost, which includes approach-dependent equipment and recovery room stay, was significantly lower in the Radial group than in the Femoral group (369.5 dollars +/- 74.6 vs. 446.9 dollars +/- 60.2 and 553.4 dollars +/- 81.0; p < 0.001). CONCLUSION: The radial artery approach to diagnostic cardiac catheterization is clearly more cost effective than the femoral approach, with or without the use of a femoral closure device. PMID- 17712205 TI - Cost-effectiveness of transradial coronary access. PMID- 17712206 TI - A life-saving procedure for treatment of massive pulmonary air embolism. AB - We present an unusual case of massive pulmonary air embolism during permanent pacemaker implantation. Head down position, precordial thumb and cardiac massage must be done immediately after the diagnosis of this life threatening condition. If these maneuvers are not successful, air suctioning with a large-lumen guiding catheter may be effective and life saving. PMID- 17712207 TI - Percutaneous septal cryoablation for the treatment of hypertrophic cardiomyopathy. PMID- 17712208 TI - Percutaneous coronary intervention of chronic saphenous vein graft occlusion: a potential new paradigm. PMID- 17712209 TI - Spontaneous dissection of the left main coronary artery treated with percutaneous coronary stenting. AB - Spontaneous coronary artery dissection is a rare and often fatal cause of acute myocardial ischemia occurring predominantly in young or middle-aged and otherwise healthy patients. We report a case of spontaneous dissection of the left main coronary artery in a young woman who was successfully treated with percutaneous coronary stent implantation. PMID- 17712210 TI - Microcoil embolization of distal coronary artery perforation without reversal of anticoagulation: a simple, effective approach. PMID- 17712211 TI - Use of Tandem Heart as a temporary hemodynamic support option for severe pulmonary artery hypertension complicated by cardiogenic shock. AB - The TandemHeart is a recently-introduced percutaneous ventricular assist device that may be used for short-term hemodynamic support. Its utility has been shown for assisting the left ventricle in a variety of high-risk percutaneous interventions, in helping the left ventricle recover from myocarditis, in cardiomyopathies and in cardiogenic shock following acute coronary syndromes. Limited data exist on its applications in patients with right ventricular failure. We report our experience, possibly the first human case description, of a patient in cardiogenic shock secondary to severe pulmonary artery hypertension where the TandemHeart was used as a short-term hemodynamic support tool. PMID- 17712212 TI - Triple wire technique for removal of fractured angioplasty guidewire. AB - Device fracture or dislodgement is an infrequent complication of percutaneous coronary intervention. While uncommon, there are a number of well-described complications including perforation, thrombosis and arrhythmia. Several percutaneous retrieval techniques have been previously utilized. We describe the use of three standard 0.014 inch angioplasty guidewires to simply and effectively remove a fractured guidewire located within a distal coronary artery. Various methods of management available in cases of device dislodgement or fracture are discussed, as is the potential mechanism of guidewire fracture. PMID- 17712213 TI - Successful stenting of bilateral multiple renal arteries in a patient with renovascular hypertension. AB - We describe the use of stenting in multiple renal arteries with severe ostial stenoses. A 62-year-old male with long-standing arterial hypertension despite treatment with multiple antihypertensive medications and mild renal impairment, appeared to have 5 renal arteries, 4 of which had severe ostial stenoses. Successful stent implantation of these 4 lesions was performed in one session. At 3-month follow up, the patient did well with adequate blood pressure control. In conclusion, stenting of ostial stenoses in multiple renal arteries appears to be a feasible and useful option in patients with renovascular hypertension. PMID- 17712214 TI - Percutaneous aortic valvuloplasty as a bridge to a high-risk percutaneous coronary intervention. AB - We describe a novel approach of using percutaneous aortic valvuloplasty as a bridge to percutaneous coronary intervention in a patient with refractory congestive heart failure, severe aortic stenosis, severe left ventricular dysfunction and severe 3-vessel coronary artery disease who was not a surgical candidate for aortic valve replacement and coronary artery bypass grafting. PMID- 17712216 TI - Successful endovascular renal artery aneurysm exclusion using the Venture catheter and covered stent implantation: a case report and review of the literature. AB - Renal artery aneurysms are rare vascular anomalies in which rupture is associated with devastating consequences. Only a few reported cases involved percutaneous treatment. Recently, technological advances have expanded indications for percutaneous treatment of such complex peripheral lesions. Despite this, certain anatomical settings such as extreme vessel tortuosity or angulation of the afferent vessel continue to pose challenges. New steerable devices may play a crucial role in those cases where conventional techniques have failed. We report a case of successful percutaneous treatment of a renal artery aneurysm and stenosis in a young male using the Venture catheter. PMID- 17712215 TI - Anterolateral myocardial infarction induced by coronary-subclavian-vertebral steal syndrome successfully treated with stenting of the subclavian artery. AB - A female patient with graft-dependent coronary circulation presented with vertebrobasilar insufficiency and NSTEMI (Non-ST-Elevation Myocardial Infarction) related to a 100 percent stenosis of the left subclavian artery. Our review of the medical literature indicates that this is the first reported case in which a patient presented with an anterolateral NSTEMI and dizziness with subsequent angiographic evidence of both coronary subclavian and vertebral subclavian steal syndromes successfully treated with angioplasty and stenting of the left subclavian artery without any intervention in the coronary arterial tree. PMID- 17712217 TI - Usefulness of the SafeCut Dual Wire PTCA catheter for the treatment of calcified lesions. AB - Calcified lesions are a cause of stent underexpansion, which significantly increases the subsequent risks of restenosis and stent thrombosis, even when drug eluting stents are used. In this report, we describe how a novel balloon catheter, the SafeCut Dual Wire percutaneous transluminal coronary angioplasty catheter, enabled adequate dilatation in a calcified lesion that was unresponsive to conventional balloon catheters. PMID- 17712218 TI - Introduction: The use of animal research in developing treatments for human motor disorders: brain-computer interfaces and the regeneration of damaged brain circuits. PMID- 17712219 TI - Animal care and use issues in movement disorder research. AB - Animal models of movement disorders can present special challenges for the research institutions that use them. Such models often affect the animals' ability to ambulate and perform normal body functions, and these potential effects on health and well-being mandate additional steps to ensure humane animal care and use. Indeed, the appropriate level of care for these models may call for actions that go beyond what is required or considered standard for other protocols. A proactive team approach to animal use protocol development and animal management is important. Through the commitment and involvement of the entire team-researchers, facility personnel, and institutional animal care and use committee members--institutions that use these valuable models can ensure both the fulfillment of research objectives and the implementation of the best practices for animal care. Among the most commonly used animal models of movement disorder are models of stroke, brain and spinal cord injury, dystonia, Parkinson's disease, and Huntington's disease. Despite their relatively wide use, there is very little in the literature that describes the specific needs of individual models and the challenges those needs may present in today's regulatory environment. In this article, we discuss animal use considerations and provide the available animal care information on specific models. Interested readers are also referred to the additional information in the accompanying articles in this issue of ILAR Journal. PMID- 17712220 TI - Stem cells, regenerative medicine, and animal models of disease. AB - The field of stem cell biology and regenerative medicine is rapidly moving toward translation to clinical practice, and in doing so has become even more dependent on animal donors and hosts for generating cellular reagents and assaying their potential therapeutic efficacy in models of human disease. Advances in cell culture technologies have revealed a remarkable plasticity of stem cells from embryonic and adult tissues, and transplantation models are now needed to test the ability of these cells to protect at-risk cells and replace cells lost to injury or disease. With such a mandate, issues related to acceptable sources and controversial (e.g., chimeric) models have challenged the field to provide justification of their potential efficacy before the passage of new restrictions that may curb anticipated breakthroughs. Progress from the use of both in vitro and in vivo regenerative medicine models already offers hope both for the facilitation of stem cell phenotyping in recursive gene expression profile models and for the use of stem cells as powerful new therapeutic reagents for cancer, stroke, Parkinson's, and other challenging human diseases that result in movement disorders. This article describes research in support of the following three objectives: (1) To discover the best stem or progenitor cell in vitro protocols for isolating, expanding, and priming these cells to facilitate their massive propagation into just the right type of neuronal precursor cell for protection or replacement protocols for brain injury or disease, including those that affect movement such as Parkinson's disease and stroke; (2) To discover biogenic factors -compounds that affect stem/progenitor cells (e.g., from high-throughput screening and other bioassay approaches)--that will encourage reactive cell genesis, survival, selected differentiation, and restoration of connectivity in central nervous system movement and other disorders; and (3) To establish the best animal models of human disease and injury, using both small and large animals, for testing new regenerative medicine therapeutics. PMID- 17712221 TI - Nonhuman primate models of Parkinson's disease. AB - Nonhuman primate (NHP) models of Parkinson's disease (PD) play an essential role in the understanding of PD pathophysiology and the assessment of PD therapies. NHP research enabled the identification of environmental risk factors for the development of PD. Electrophysiological studies in NHP models of PD identified the neural circuit responsible for PD motor symptoms, and this knowledge led to the development of subthalamic surgical ablation and deep brain stimulation. Similar to human PD patients, parkinsonian monkeys are responsive to dopamine replacement therapies and present complications associated with their long-term use, a similarity that facilitated the assessment of new symptomatic treatments, such as dopaminergic agonists. New generations of compounds and novel therapies that use directed intracerebral delivery of drugs, cells, and viral vectors benefit from preclinical evaluation in NHP models of PD. There are several NHP models of PD, each with characteristics that make it suitable for the study of different aspects of the disease or potential new therapies. Investigators who use the models and peer scientists who evaluate their use need information about the strengths and limitations of the different PD models and their methods of evaluation. This article provides a critical review of available PD monkey models, their utilization, and how they compare to emerging views of PD as a multietiologic, multisystemic disease. The various models are particularly useful for representing different aspects of PD at selected time points. This conceptualization provides clues for the development of new NHP models and facilitates the clinical translation of findings. As ever, successful application of any model depends on matching the model to the scientific question to be answered. Adequate experimental designs, with multiple outcome measures of clinical relevance and an appropriate number of animals, are essential to minimize the limitations of models and increase their predictive clinical validity. PMID- 17712223 TI - Rat models of upper extremity impairment in stroke. AB - Stroke remains the leading cause of adult disability, with upper extremity motor impairments being the most prominent functional deficit in surviving stroke victims. The development of animal models of upper extremity dysfunction after stroke has enabled investigators to examine the neural mechanisms underlying rehabilitation-dependent motor recovery as well as the efficacy of various adjuvant therapies for enhancing recovery. Much of this research has focused on rat models of forelimb motor function after experimentally induced ischemic or hemorrhagic stroke. This article provides a review of several different methods for inducing stroke, including devascularization, photothrombosis, chemical vasoconstriction, and hemorrhagia. We also describe a battery of sensorimotor tasks for assessing forelimb motor function after stroke. The tasks range from measures of gross motor performance to fine object manipulation and kinematic movement analysis, and we offer a comparison of the sensitivity for revealing motor deficits and the amount of time required to administer each motor test. In addition, we discuss several important methodological issues, including the importance of testing on multiple tasks to characterize the nature of the impairments, establishing stable baseline prestroke motor performance measures, dissociating the effects of acute versus chronic testing, and verifying lesion location and size. Finally, we outline general considerations for conducting research using rat models of stroke and the role that these models should play in guiding clinical trials. PMID- 17712222 TI - Animal models of Huntington's disease. AB - Huntington's disease (HD) is a neurological disorder caused by a genetic mutation in the IT15 gene. Progressive cell death in the striatum and cortex, and accompanying declines in cognitive, motor, and psychiatric functions, are characteristic of the disease. Animal models of HD have provided insight into disease pathology and the outcomes of therapeutic strategies. Earlier studies of HD most often used toxin-induced models to study mitochondrial impairment and excitotoxicity-induced cell death, which are both mechanisms of degeneration seen in the HD brain. These models, based on 3-nitropropionic acid and quinolinic acid, respectively, are still often used in HD studies. The discovery in 1993 of the huntingtin mutation led to the creation of newer models that incorporate a similar genetic defect. These models, which include transgenic and knock-in rodents, are more representative of the HD progression and pathology. An even more recent model that uses a viral vector to encode the gene mutation in specific areas of the brain may be useful in nonhuman primates, as it is difficult to produce genetic models in these species. This article examines the aforementioned models and describes their use in HD research, including aspects of the creation, delivery, pathology, and tested therapies for each model. PMID- 17712224 TI - Rat models of traumatic spinal cord injury to assess motor recovery. AB - Devastating motor, sensory, and autonomic dysfunctions render long-term personal hardships to the survivors of traumatic spinal cord injury (SCI). The suffering also extends to the survivors' families and friends, who endure emotional, physical, and financial burdens in providing for necessary surgeries, care, and rehabilitation. After the primary mechanical SCI, there is a complex secondary injury cascade that leads to the progressive death of otherwise potentially viable axons and cells and that impairs endogenous recovery processes. Investigations of possible cures and of ways to alleviate the hardships of traumatic SCI include those of interventions that attenuate or overcome the secondary injury cascade, enhance the endogenous repair mechanisms, regenerate axons, replace lost cells, and rehabilitate. These investigations have led to the creation of laboratory animal models of the different types of traumatic human SCI and components of the secondary injury cascade. However, no particular model completely addresses all aspects of traumatic SCI. In this article, we describe adult rat SCI models and the motor, and in some cases sensory and autonomic, deficits that each produces. Importantly, as researchers in this area move toward clinical trials to alleviate the hardships of traumatic SCI, there is a need for standardized small and large animal SCI models as well as quantitative behavioral and electrophysiological assessments of their outcomes so that investigators testing various interventions can directly compare their results and correlate them with the molecular, biochemical, and histological alterations. PMID- 17712225 TI - Monkey models of recovery of voluntary hand movement after spinal cord and dorsal root injury. AB - The hand is unique to the primate and manual dexterity is at its finest in the human (Napier 1980), so it is not surprising that cervical spinal injuries that even partially block sensorimotor innervation of the hand are frequently debilitating (Anderson 2004). Despite the clinical need to understand the neuronal bases of hand function recovery after spinal and/or nerve injuries, relatively few groups have systematically related subtle changes in voluntary hand use following injury to neuronal mechanisms in the monkey. Human and macaque hand anatomy and function are strikingly similar, which makes the macaque the favored nonhuman primate model for the study of postinjury dexterity. In this review of monkey models of cervical spinal injury that have successfully related voluntary hand use to neuronal responses during the early postinjury months, the focus is on the dorsal rhizotomy (or dorsal rootlet lesion) model developed and used in our laboratory over the last several years. The review also describes macaque monkey models of injuries to the more central cervical spine (e.g., hemisection, dorsal column) that illustrate methods to assess postlesion hand function and that relate it to neurophysiological and neuroanatomical changes. Such models are particularly important for understanding what the sensorimotor pathways are capable of, and for assessing the outcome of therapeutic interventions as they are developed. PMID- 17712226 TI - Learning-based animal models: task-specific focal hand dystonia. AB - Dystonia is a disabling, involuntary disorder of movement that leads to writhing, twisting end-range movements or abnormal postures. Inadequate inhibition could account for excessive excitation and near synchronous co-contractions of agonists and antagonists. Dystonia may be generalized or specific, affecting only one part of the body or involving only a well-learned task (e.g., writing, keyboarding, golfing, playing a musical instrument). Task-specific and other focal dystonias are considered idiopathic, with multiple factors such as genetics, anatomy, physiology, psychology, environment, and behavioral characteristics contributing to the development of symptoms. This article provides detailed descriptions of two behavioral animal models (a primate [owl monkey] model and a rodent [Sprague Dawley rat] model) developed to study the effect of excessive repetition as a potential etiology of focal hand dystonia (FHd). The hypothesis is that repetitive, near simultaneous hand movements can degrade the topographic representations of the hand on the somatic sensory and motor cortices, creating the involuntary movements characteristic of dystonia. While animal studies permit the opportunity for greater control to determine efficacy, the findings must always be confirmed by clinical studies to evaluate sensitivity and specificity of diagnosis and effectiveness of treatment in the home, work, and personal environment. This article presents a review of the etiology and clinical implications for intervention strategies from animal and clinical studies that support learning-based mechanisms for FHd. Other animal models are also briefly reviewed. PMID- 17712227 TI - Keratinocyte chemoattractant (KC)/human growth-regulated oncogene (GRO) chemokines and pro-inflammatory chemokine networks in mouse and human ovarian epithelial cancer cells. AB - Chronic inflammation is an important underlying condition for ovarian tumor development, growth and progression. Since chemokine networks are activated by inflammation, patterns of chemokine gene expression were investigated in ovarian cancer cells. Chemokine specific microarrays were performed after mouse (ID8) and human (SKOV-3) ovarian surface epithelial cancer cells were exposed to the inflammatory agent bacterial endotoxin lipopolysaccharide (LPS, 10 microg/ml) and pro-inflammatory cytokines interleukin-1beta (IL-1, 10 ng/ml) and tumor necrosis factor-alpha (TNF, 10 ng/ml). In the mouse ID8 cells, LPS, IL-1 and TNF led to robust upregulation of keratinocyte chemoattractant (KC) chemokines CXCL1/2, mouse homologues of human growth-regulated oncogenes (GRO). Other chemokines, interferong inducible protein (IP)-10 (CXCL10), CCL7 and CCL20 were moderately upregulated. ID8 cells constitutively expressed CXCL16 and CCL2, but only CCL2 expression was enhanced by LPS, IL-1 and TNF. In the human SKOV-3 cells, LPS had no effect on chemokines expression due to the absence of the LPS receptor, toll like receptor 4 (TLR4). However, IL-1 and TNF induced GROalpha/beta (CXCL1/2) in human SKOV-3 cells in a similar manner as observed with mouse ID8 cells. In SKOV 3 cells, IL-8 (CXCL8) was highly expressed and other chemokines GROgamma (CXCL3) and CCL20 were moderately expressed in response to IL-1 and TNF. The nuclear factor-kappaB (NF-kappaB) is a known mediator of cytokine and chemokines signaling. The NFkappaB inhibitor BAY 11-7082 attenuated expression of inflammatory-induced chemokines in the mouse and human ovarian cancer cells. Taken together, the results indicate that KC/GRO chemokines are the principal chemokines induced by LPS and pro-inflammatory cytokines IL-1 and TNF via NFkappaB signaling in ovarian surface epithelial cancer cells. PMID- 17712229 TI - Phosphoinositides control epithelial development. AB - Epithelial organs consist on layers of cubical cells that separate different compartments. They form a physical barrier that allows the regulated transports of certain molecules and ions. To perform this and other functions epithelial cells require to be highly polarized. The molecular mechanisms that integrate cellular polarity with epithelial architecture are poorly understood. Using a three-dimensional model of epithelial morphogenesis, we have recently reported a molecular mechanism for the formation of the apical membrane and the central lumen.(1) This molecular pathway is initiated by the membrane segregation of phosphoinositides at the apical domain. Apically localized phosphatidylinositol(4,5)-bisphosphate [PtdIns(4,5)P2] recruits the scaffolding protein Annexin2 and the GTPase Cdc42 to generate the apical plasma membrane domain and the central lumen. PMID- 17712228 TI - The therapeutic potential of survivin promoter-driven siRNA on suppressing tumor growth and enhancing radiosensitivity of human cervical carcinoma cells via downregulating hTERT gene expression. AB - Human telomerase is a ribonucleoprotein complex composed of two subunits, an RNA component (hTR) and a human telomerase reverse transcriptase component (hTERT). The activation of telomerase, a process regulated by the human telomerase reverse transcriptase (hTERT), is a crucial step during cellular immortalization and malignant transformation. hTERT is overexpressed in most malignant cells but undetectable in most normal somatic cells. To explore its possibility as a therapeutic target for human cervical carcinoma, we developed a novel tumor specific RNA interference system targeting hTERT by using the survivin promoter and investigated the effects of it on the proliferation, apoptosis and radiosensitivity in human cervical carcinoma cells (HeLa). The treatment of HeLa cells by hTERT gene RNAi not only could inhibit the proliferation of human cervical carcinoma cells (HeLa), but also could enhance the radiosensitivity of those cells via downregulation of their mRNA and protein expression. Therefore, survivin promoter-driven siRNA expression vector targeting hTERT may have potential use in radiosensitization therapy with targeted tumor gene silencing effect in human cervical carcinomas. PMID- 17712231 TI - Strategies for development of universal vaccines against meningococcal serogroup B disease: the most promising options and the challenges evaluating them. AB - A vaccine inducing protection against most of the circulating variants of serogroup B meningococcal strains is not yet available. A number of plausible options are currently under investigation. A conjugate vaccine based on a modified capsular polysaccharide might well work, but has safety concerns from molecular mimicry between group B sialic acid and human tissue. Recently, however, the group B capsule has been shown to contain de-N-acetyl sialic acid residues that do not cross react with normal host tissues and can then be the target of bactericidal antibodies. Potentially, this polysaccharide structure could form the basis of a safe and protective group B vaccine. Outer membrane vesicles (OMVs) from Neisseria lactamica avoid the immunodominant and highly strain specific immune response against the PorA protein, and are reported to elicit cross reactive protection in mice against lethality from challenge with meningococcal group B bacteria. However, the serum antibody responses lack bactericidal activity, and the mechanisms of protection are unknown. A number of universal, cross-reactive antigens have been identified through "reverse vaccinology" and successfully tested as recombinant protein vaccines. Promising results have also been demonstrated using OMV vaccines prepared from strains engineered for upregulation of conserved, cross-reactive antigens. This approach takes advantage of experience gained with conventional wild-type OMV vaccines and the large number of new antigens identified through sequencing the genome of N. meningitidis. Initial studies show that the traditional use of detergents to decrease toxicity by extraction of lipopolysaccharides (LPS) should, if possible, be omitted in order to avoid extraction of important lipoproteins. In the absence of detergent extraction, clinical OMV formulations with acceptable toxicity may still be achieved by constructing vaccine production strains with genetically detoxified LPS. Thus, a MenB vaccine might be designed based on non-cross reactive capsular antigens, OMV vaccines from genetically modified strains, recombinant proteins or a combination of these approaches. Given all of the recent data available and experience gained, the possibility for development of a universal vaccine for prevention of group B meningococcal disease looks promising. For evaluation of vaccine formulations relying on cross-reactive proteins, selection of strains for representation of the global epidemiological situation will be of outmost importance. Defining criteria for establishing and revising such strain collections is currently ongoing and will be a key element in developing and evaluating new protein based vaccines in the time to come. PMID- 17712232 TI - Predicting completed suicide. PMID- 17712230 TI - Cardiac progenitors and the embryonic cell cycle. AB - Despite the critical importance of proper cell cycle regulation in establishing the correct morphology of organs and tissues during development, relatively little is known about how cell proliferation is regulated in a tissue-specific manner. The control of cell proliferation within the developing heart is of considerable interest, given the high prevalence of congenital cardiac abnormalities among humans, and recent interest in the isolation of cardiac progenitor populations. We therefore review studies exploring the contribution of cell proliferation to overall cardiac morphology and the molecular mechanisms regulating this process. In addition, we also review recent studies that have identified progenitor cell populations within the adult myocardium, as well as those exploring the capability of differentiated myocardial cells to proliferate post-natally. Thus, the exploration of cardiomyocyte cell cycle regulation, both during development as well as in the adult heart, promises to yield many exciting and important discoveries over the coming years. PMID- 17712233 TI - AACAP 2005 Research Forum: speeding the adoption of evidence-based practice in pediatric psychiatry. AB - OBJECTIVES: At the 2005 Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), the Academy's Workgroup on Research conducted a Research Forum entitled "Increasing Research Literacy Through the Adoption of Evidence-Based Practice (EBP) in Pediatric Psychiatry." METHOD: Forum participants focused on speeding the adoption of EBP across five areas: EBP as the preferred heuristic for teaching research literacy, use of EBP in training programs, dissemination of EBP in clinical practice, EBP in partnership with industry, and EBP as a framework for developing practice guidelines. RESULTS: EBP provides an easy-to-understand method for accessing and evaluating the research literature and then applying this information to decisions about patient care. Although EBP has been gaining greater visibility in pediatric psychiatry, it is far from the preferred heuristic. To move the field toward fully embracing EBP will require greater understanding of what EBP is (and is not), educating mental health professionals in EBP skills, access to EBP resources, and a commitment to apply EBP to the conceptualization and design of research protocols and practice guidelines. CONCLUSIONS: Pediatric psychiatry would benefit from a principled commitment to follow other areas of medicine in adopting EBP. PMID- 17712234 TI - Treating comorbid anxiety and aggression in children. AB - OBJECTIVE: The aim of the study was to evaluate the effectiveness of an intervention that targeted both anxious and aggressive behaviors in children with anxiety disorders and comorbid aggression by parent report. METHOD: The effects of a cognitive-behavioral therapy intervention targeting comorbid anxiety and aggression problems were compared with a standard cognitive-behavioral therapy intervention targeting anxiety only. The study was conducted over a period of 2 years, and 69 families were included, with participating children ranging in age from 8 to 14 years. Intervention effects were evaluated at posttreatment and 3 months following treatment. RESULTS: An intent-to-treat analysis identified few significant differences between conditions in level of improvement following treatment and at follow-up, with the exception of parent-reported stress, anxiety, and depression, which improved in the anxiety treatment condition. Both treatment programs led to significant reductions in parent-reported child externalizing and internalizing problems and child-reported internalizing problems and to improved parenting practices. CONCLUSIONS: Comorbidity did not appear to significantly affect treatment outcome for anxiety disorders, and combining existing treatments to address comorbid problems did not enhance treatment effectiveness. Further trials are required to assess the effectiveness of an expanded combined treatment program that allows adequate time to address both internalizing and externalizing problems. PMID- 17712235 TI - Atomoxetine treatment for pediatric patients with attention-deficit/hyperactivity disorder with comorbid anxiety disorder. AB - OBJECTIVE: Research suggests 25% to 35% of children with attention deficit/hyperactivity disorder (ADHD) have comorbid anxiety disorders. This double-blind study compared atomoxetine with placebo for treating pediatric ADHD with comorbid anxiety, as measured by the ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-PI) and the Pediatric Anxiety Rating Scale (PARS). METHOD: Patients (ages 8-17 years) meeting DSM-IV criteria for ADHD and generalized anxiety disorder, separation anxiety disorder, and/or social phobia were randomized to 12 weeks of atomoxetine (n = 87) or placebo (n = 89). ADHDRS-IV-PI and PARS total scores were analyzed using analysis of covariance last observation carried forward and repeated-measures analyses. RESULTS: Sixty-six patients in each group completed the study. Mean ADHDRS-IV-PI total score improved significantly for atomoxetine (n = 55; -10.5, SD 10.6) relative to placebo (n = 58; -1.4, SD 8.3; p < .001). Mean PARS total score also improved significantly for atomoxetine (n = 55; -5.5, SD 4.8) relative to placebo (n = 58; -3.2, SD 5.0; p = .011). CONCLUSIONS: Atomoxetine was efficacious in reducing ADHD symptoms in patients who have ADHD with comorbid anxiety and was well tolerated. There was also a significant reduction in independently assessed anxiety symptoms using both clinician-rated and self-rated measures, which merits further investigation. Results support consideration of atomoxetine for the treatment of ADHD in youths who have ADHD with comorbid anxiety disorder. CLINICAL TRIAL REGISTRATION INFORMATION: The LYBP study, on which this article is based, was not registered at clinicaltrials.gov because the last patient visit occurred before July 1, 2005. Results, however, are publicly posted at lillytrials.com and clinicalstudyresults.org. The unique study ID at both sites is 6477a. PMID- 17712236 TI - High-dose atomoxetine treatment of ADHD in youths with limited response to standard doses. AB - OBJECTIVE: To assess the utility and tolerability of higher than standard atomoxetine doses to treat attention-deficit/hyperactivity disorder (ADHD). METHOD: Two randomized, double-blind trials of atomoxetine nonresponders ages 6 to 16 years were conducted comparing continued treatment with same-dose atomoxetine to treatment using greater than standard efficacious doses (study 1: up to 3.0 mg . kg . day; study 2: up to 2.4 mg . kg . day). RESULTS: The primary outcome measure for both studies was mean ADHD Rating Scale (ADHD RS) total score. For study 1 (N = 122), decreases in ADHD RS total scores were not significantly different between treatment groups (mean change [SD]: continued same dose, -8.9 [11.2]; high dose, -9.8 [13.1]; p = .595). Likewise, for study 2 (N = 125), treatment groups did not differ (mean change [SD]: continued same dose, -6.2 [12.2]; high dose, -8.9 [10.0], p =.110). Tolerability was not significantly different between the continued same-dose and high-dose groups. CONCLUSIONS: These studies provide evidence that current dose recommendations are appropriate for most patients, suggesting no systematic advantage to increasing atomoxetine doses beyond current guidelines. In both studies, continued treatment, whether at a higher dose or the previous dose, was associated with improved outcomes in patients who demonstrated incomplete/inadequate response to acute ADHD treatment, although without a placebo arm, we cannot rule out the possibility that expectancy played a role in symptom improvement. PMID- 17712237 TI - Long-term effects of methylphenidate transdermal delivery system treatment of ADHD on growth. AB - OBJECTIVE: To examine the long-term effects of the methylphenidate transdermal system (MTS) on the growth of children being treated for attention deficit/hyperactivity disorder. METHOD: Height, weight, and body mass index (BMI) were measured in 127 children ages 6 to 12 at longitudinal assessments for up to 36 months of treatment with MTS. These data were compared with norms provided by the Centers for Disease Control and Prevention. RESULTS: MTS treatment was associated with small but significant delays in growth for height, weight, and BMI. The latter two indices were affected in a dose-dependent manner. Children who had not received prior stimulant therapy and children who entered the study with above-average height, weight, and BMI were most likely to experience growth deficits during the trial. Effects on all parameters of growth were most apparent during the first year of treatment, and attenuated over time. CONCLUSIONS: Consistent with prior studies of methylphenidate, our results suggest that treatment with MTS can lead to reductions in expected height, weight, and BMI that show some attenuation over the course of treatment. Growth of patients with attention-deficit/hyperactivity disorder treated with MTS should be closely monitored, but in this study, deficits in growth in relation to MTS treatment were not a significant clinical concern for most children. PMID- 17712238 TI - Who is at greatest risk of adverse long-term outcomes? The Finnish From a Boy to a Man study. AB - OBJECTIVE: To study associations between comorbid psychopathology and long-term outcomes in a large birth cohort sample from age 8 to early adulthood. METHOD: The sample included long-term outcome data on 2,556 Finnish boys born in 1981. The aim was to study the impact of early childhood psychopathology types (externalizing versus internalizing versus both) and informant sources (self report versus parent/teacher reports) on young adult outcomes, based on data from a military registry of psychiatric diagnosis, a police registry on criminal and drug offenses, and self-reported problems in late adolescence and early adulthood. RESULTS: Children with combined conduct and internalizing problems at age 8 had the worst outcomes and highest risk of subsequent psychiatric disorders, criminal offenses, and self-reported problems at follow-up, with 62% of these boys manifesting psychiatric disorders, committing criminal offenses, or both at follow-up. Although these children included only 4% of the sample, they were responsible for 26% of all criminal offenses at follow-up. In contrast, children with conduct problems without internalizing problems and those with attention problems had much less severe but nonetheless elevated levels of risk of antisocial personality disorder and criminal offenses. Long-term outcomes for these two groups were substantially better than for children with combined conduct and internalizing problems. Children with "pure" emotional problems had an elevated risk only of similar emotional problems at follow-up. CONCLUSIONS: The subjective suffering and long-term burden to society is especially high among children with comorbid conduct and internalizing problems in childhood. A major challenge for child and adolescent psychiatric, education, and social services is to develop effective intervention strategies focusing on these children. Additional longitudinal epidemiological studies of this comorbidity group are needed, and, if replicated, such findings will have important implications for future diagnostic classification systems (DSM-V). PMID- 17712239 TI - Mental health and functional outcomes of maternal and adolescent reports of adolescent depressive symptoms. AB - OBJECTIVE: To assess the value of maternal and self-ratings of adolescent depression by investigating the extent to which these reports predicted a range of mental health and functional outcomes 4 years later. The potential influence of mother's own depressed mood on her ratings of adolescent depression and suicidal ideation on adolescent outcome was also tested. METHOD: A longitudinal population-based study of 842 adolescents ages 11 to 16 at the baseline assessment and 15 to 20 at follow-up (62% retention). RESULTS: Both mother- and adolescent-rated depressive symptoms predicted future depression, antisocial behavior, impairment, health service use, and regular tobacco use in the adolescent. The odds ratios obtained for maternal and adolescent ratings of depressive symptoms as predictors of future psychopathology were not significantly different. Mothers' own depressive symptoms were not significantly associated with adolescent depression, health service use, or substance use at follow-up. Depression that was accompanied by adolescent-rated suicidal thoughts was significantly more strongly associated with impairment at follow-up than depression alone. CONCLUSIONS: It is possible to obtain clinically useful information on adolescent depression from the child's mother. However, information on suicidal ideation was rarely endorsed by mothers, suggesting that maternal report of adolescent suicidal thoughts shows less sensitivity than adolescent report. PMID- 17712240 TI - Parental expressed emotion and adolescent self-injury. AB - OBJECTIVE: This study examined the relationship between parental expressed emotion (EE) and adolescent self-injurious thoughts and behaviors (SITB), as well as potential mediators and moderators of this relationship. METHOD: Thirty-six adolescents ages 12 to 17 years recruited from the community (2004-2005) provided data. Parents of the adolescents completed the Five-Minute Speech Sample, a performance-based measure of EE, and adolescents completed interviews and rating scales assessing SITB, mental disorders, and related constructs. RESULTS: Analyses revealed that high parental EE was associated with each type of SITB assessed: suicide ideation, suicide plans, suicide attempts, and non-suicidal self-injury. Analyses also revealed that one specific component of EE (i.e., parental criticism) was strongly associated with SITB, whereas the other (i.e., emotional overinvolvement) was not and that the relationship between EE and SITB was not explained by the presence of mental disorders. Finally, a moderation model was supported in which the relationship between parental criticism and SITB was especially strong among adolescents with a self-critical cognitive style. CONCLUSIONS: This study indicates that parental criticism is significantly associated with SITB and suggests one specific pathway through which the family may influence adolescent SITB. Future research is needed to replicate these findings and examine the direction of these relationships. PMID- 17712241 TI - A one-session human immunodeficiency virus risk-reduction intervention in adolescents with psychiatric and substance use disorders. AB - OBJECTIVE: To explore change in human immunodeficiency virus (HIV) risk among teens in outpatient treatment for substance use disorders (SUDs). METHOD: From December 2002 to August 2004, 50 adolescents (13-19 years) with major depressive disorder, conduct disorder, and one or more non-nicotine SUD completed the Teen Health Survey (THS) at the beginning and end of 16 weeks of outpatient cognitive behavioral SUD treatment, which included a one-session HIV intervention. Changes in THS scale scores and specific item responses targeted by the intervention were assessed with paired t tests and Wilcoxon signed rank tests. RESULTS: Pre/post mean THS scores significantly improved for two subscales: Measures of HIV Information (14.8-17.6; p < .001) and Beliefs about Condom Use (17.6-18.5; p < .05). Analyses of specific items showed trends for improvement in intentions to carry condoms and in the number of teens who obtained condoms. Not all of the risks targeted by the intervention showed significant change, but no change was observed in any area that was not specifically targeted. CONCLUSIONS: Results from this preliminary study are consistent with the need for specific assessment and targeted intervention to reduce HIV risk in outpatient adolescent SUD treatment. PMID- 17712243 TI - Autonomic reactivity of children to separation and reunion with foster parents. AB - OBJECTIVE: To determine whether foster children showed different autonomic nervous system activity on separation and reunion than control children. Autonomic nervous system activity in foster children was examined in relation to time in placement and disinhibited attachment. METHOD: The sample included 60 foster and 50 control children between 2 and 7 years of age who participated with their caregivers in a modified Strange Situation. Heart rate, respiratory sinus arrhythmia (RSA), and pre-ejection period were monitored continuously. Foster caregivers reported disinhibited symptoms on the Disturbances of Attachment Interview. RESULTS: The Strange Situation elicited less RSA reactivity in foster children. Differences in RSA, heart rate, and pre-ejection period responses on the specific separation and reunion episodes were not significant. RSA responses on separation from the stranger and on reunion with the foster caregiver were partly explained by time in placement and disinhibited attachment. CONCLUSIONS: Early experiences of relationship disruptions in foster children as well as short placements may have an impact on children's adaptation to environmental and relational challenges. Stable placement may facilitate adaptive affect regulation, except for children with disinhibited symptoms. PMID- 17712242 TI - The sounds of silence: language, cognition, and anxiety in selective mutism. AB - OBJECTIVES: To determine whether oral language, working memory, and social anxiety differentiate children with selective mutism (SM), children with anxiety disorders (ANX), and normal controls (NCs) and explore predictors of mutism severity. METHOD: Children ages 6 to 10 years with SM (n = 44) were compared with children with ANX (n = 28) and NCs (n = 19) of similar age on standardized measures of language, nonverbal working memory, and social anxiety. Variables correlating with mutism severity were entered in stepwise regressions to determine predictors of mute behavior in SM. RESULTS: Children with SM scored significantly lower on standardized language measures than children with ANX and NCs and showed greater visual memory deficits and social anxiety relative to these two groups. Age and receptive grammar ability predicted less severe mutism, whereas social anxiety predicted more severe mutism. These factors accounted for 38% of the variance in mutism severity. CONCLUSIONS: Social anxiety and language deficits are evident in SM, may predict mutism severity, and should be evaluated in clinical assessment. Replication is indicated, as are further studies of cognition and of intervention in SM, using large, diverse samples. PMID- 17712245 TI - Case report: "Purely" psychiatric presentation of multiple sclerosis in an adolescent boy. AB - We present the case of a 14-year-old Hispanic boy with a 6-month history of a psychotic disorder necessitating several hospitalizations who was incidentally found to have multiple sclerosis with no physical findings. Neuropsychological assessment has revealed impairments in word-finding, bilateral fine motor skills, and attention. Imaging and laboratory studies have supported the diagnosis of multiple sclerosis. Steroid and immunomodulating therapy has not significantly affected psychiatric symptoms. He has had poor response to psychotropic medications as well. We discuss the implications of multiple sclerosis as the cause of this patient's psychiatric illness. PMID- 17712244 TI - A psychometric evaluation of the CDRS and MADRS in assessing depressive symptoms in children. AB - OBJECTIVE: This study compared the psychometric properties of the Children's Depression Rating Scale-Revised (CDRS-R) and the Montgomery-Asberg Depression Rating Scale (MADRS) in children with major depressive disorder. METHOD: Children (N = 96; ages 8 to 11 years inclusive) with nonpsychotic major depressive disorder were enrolled. Participants were part of a multisite, outpatient, randomized, placebo-controlled, 9-week trial of fluoxetine (10 mg/day for the first week and 20 mg/day thereafter). The CDRS-R and MADRS were completed based on clinician interviews with both parents and children. Classic test theory and item response theory analyses were conducted. RESULTS: The MADRS and CDRS-R total scores were correlated at baseline (r = 0.51) and at study exit (r = 0.85). Cronbach's alpha was .86 (CDRS-R) and .82 (MADRS) at exit. The effect sizes for change from baseline to exit between the fluoxetine and placebo groups were 0.78 (CDRS-R) and 0.61 (MADRS). There was agreement between the CDRS-R and MADRS in the declaration of treatment response (50% improvement from baseline to exit) in 84.2% of children. Test information function favored the CDRS-R. CONCLUSIONS: The CDRS-R showed greater effect size for differentiating drug and placebo and better test information than the MADRS in this study of depressed children. PMID- 17712246 TI - The use of movies to facilitate family engagement in psychiatric hospitalization. PMID- 17712247 TI - Antidepressant management in the context of suicidal ideation. PMID- 17712250 TI - Size matters: EQ-5D in transition. PMID- 17712251 TI - Evaluating equivalency between response systems: application of the Rasch model to a 3-level and 5-level EQ-5D. AB - BACKGROUND: Expansion of the EQ-5D health state classifier to 5 levels (EQ-5D-5L) has been proposed to improve discriminative and evaluative properties, but current preference-based algorithms were developed for a 3-level (EQ-5D-3L) structure. The objectives were to examine equivalency of meaning between 3L and 5L response systems, and to psychometrically derive a system of weights that facilitate conversion of 3L preference-based algorithms to a 5L system. METHODS: Rasch models were used to examine the equivalency of the 3L and 5L systems using 2 datasets where health status was assessed using the 3L and 5L: a Dutch study of primarily hypothetical health state assessments and a US-based multicenter study of 423 cancer patients. Category-specific mean values of latent person parameters (using maximum likelihood estimation) for the levels of the 3L and 5L systems were estimated. RESULTS: Means on the latent continuum pertaining to level 3 in the 5L system and level 2 in the 3L (some problems) were similar for both datasets, suggesting equivalence of these levels. Extremes of the 5L response structure consistently broadened the measurement continuum. By anchoring "no problems" as 0 disutility, disutility weights from EQ-5D-3L were transformed into weights for EQ-5D-5L using ratios of logit distances between person means for 5L and 3L calibrated for each dimension using the Rasch model. CONCLUSIONS: This study illustrates the rich potential for modern psychometric techniques both to examine equivalency when health status measures are modified as well as to inform preference-based measurement systems using existing value sets. PMID- 17712252 TI - The effects of interventions on health-related quality of life among persons with diabetes: a systematic review. AB - BACKGROUND: Health-related quality of life (HRQL) is increasingly used to measure the outcomes of interventions among people with chronic diseases. OBJECTIVES: To assess the effect of interventions for adults with diabetes on HRQL, as measured by the Short Form (SF)-36 questionnaire. RESEARCH DESIGN: The systematic review was conducted using the methods of the Cochrane Collaboration. Studies reporting SF-36 scores before and after an intervention focused on adults with diabetes were obtained from searches of multiple bibliographic databases. The mean changes and standardized mean differences between pre- and post-intervention were reported as outcome measures. Pooled estimates were obtained using random effects models. RESULTS: : We identified 33 studies examining a wide range of interventions, including diabetes education and behavioral modifications (15 studies), pharmacotherapy (11 studies), and surgery (7 studies). Interventions generally demonstrated improvement in HRQL. When all available profile scores were examined together, the ranges of mean changes in scores were as follows: surgery for treating diabetes comorbidities, 15.0 to 42.0 point improvement; surgery for treating diabetes complications, -13.0 to 37.9; pharmacotherapy using insulin to optimize glycemic control, -4.6 to 27.6; pharmacotherapy for treating comorbidities, 3.8 to 33.2; pharmacotherapy for treating complications, -2.6 to 14.6. Pooled effects from 5 randomized controlled trials of educational interventions demonstrated significantly improved physical function [3.4 (95% CI, 0.1-6.6)] and mental health [4.2 (95% CI, 1.8-6.6)], and a decrease in bodily pain [3.6 (95% CI, 0.6-6.7)]. CONCLUSIONS: A variety of interventions can improve HRQL among adults with diabetes, but the magnitude of effects varied with the interventions. The mechanism of these changes needs to be further examined in the future research. PMID- 17712254 TI - Differences between symptom-specific and general survey questions of unmet need in measuring insurance and racial/ethnic disparities in access to care. AB - OBJECTIVE: To examine differences in insurance and racial/ethnic disparities in access to care between a single-item measure of general unmet medical need and a multi-item measure of symptom-specific unmet medical need. DATA SOURCE: The 2003 Community Tracking Study Household Survey, which included both a single question about any unmet medical needs over the last year, and a measure of unmet medical need keyed to the recent occurrence of 1 of 15 symptoms that a panel of physicians considered serious enough to warrant seeking medical care. STUDY DESIGN/METHODS: We constructed 3 measures of unmet need (general perceived unmet need, perceived unmet need for a specific new symptom, and actual unmet need for the new symptom). We used multivariate logistic regression analysis to determine whether the measures have similar implications for access disparities by insurance status and by race/ethnicity, while controlling for income, health, and other sociodemographic characteristics. PRINCIPAL FINDINGS: Uninsured people are consistently more likely than privately insured people to have unmet medical needs across the 3 measures of unmet need, and these differences were not due to differences in the perceived need for care. However, racial/ethnic disparities were apparent only for the symptom-specific measures of unmet need, and not the general measure of unmet need. CONCLUSIONS: Using a symptom-specific measure of unmet medical need is probably not worth the added survey complexity and cost if the primary objective is to measure access disparities by insurance coverage. However, a general measure of unmet medical needs may not adequately capture racial/ethnic disparities in access. PMID- 17712253 TI - On the assessment of preferences for health and duration: maximal endurable time and better than dead preferences. AB - BACKGROUND: Several studies revealed difficulties with the valuation and analysis of health states deemed worse than dead. These problems may be linked to maximal endurable time (MET) preferences, the phenomenon that for severe states better than dead (BTD), shorter durations are often preferred to longer durations. OBJECTIVE: To test the association between the duration of health states and their valuation. METHODS: A representative sample of 123 Dutch respondents (age range, 18-45 years) valued 5 EQ-5D health states. With a straightforward method using BTD preferences, respondents indicated whether a state of a certain duration is better, equal to, or worse than dead. To validate these BTD preferences, MET preferences (whether a longer duration of a health state is better, equal, or worse than a shorter duration) were collected. RESULTS: BTD and MET preferences were strongly related (P < 0.001). For severe health states, although still judged as better than dead, BTD preferences curved downwards with increasing duration. Such curved BTD patterns occurred in 28% of the respondents, especially for more severe states (P < 0.001). CONCLUSIONS: BTD preferences revealed that the value of moderate and severe states declines with increasing duration, suggesting that health and duration interact. For states worse than dead versus states better than dead, traditional valuation techniques have the drawback that different preference questions are used. Using BTD preferences, however, a single simple preference question can assess states better than dead, as well as states worse than dead. PMID- 17712255 TI - Investigating differential item functioning by chronic diseases in the SF-36 health survey: a latent trait analysis using MIMIC models. AB - OBJECTIVES: Differential item functioning (DIF) is present when respondents of unique subgroups endorse certain items differently given the respondents have the same underlying ability. This study investigates the presence of DIF regarding chronic illnesses among items of the physical functioning (PF) and mental health (MH) domains of the SF-36 health survey. METHODS: Multiple indicators multiple causes (MIMIC) model was applied to data extracted from the Kaiser Permanente database for members who completed the SF-36 during 1994-1995 (N = 7538). DIF effects were evaluated for sociodemographic variables and for indicators of 5 chronic conditions: hypertension, rheumatic conditions, diabetes, respiratory diseases, and depression. An iterative strategy with backward selection was applied to build DIF models, which were estimated by weighted least squares. The Hochberg procedure was applied to P values for multiple tests. RESULTS: After controlling for the selected covariates and the latent ability, DIF was present in 3 items for hypertension, one for respiratory diseases, and one for diabetes. Adjusting for DIF did not modify the overall pattern of exogenous variables' effects on PF or MH, except Hispanic and other ethnicity on PF, education on MH became insignificant; and black ethnicity on PF, old ages and other ethnicity on MH became significant. CONCLUSIONS: Considering the number of items and disease subgroups compared, the presence of DIF was minimal among items of the PF and MH domains of the SF-36. DIF had little effect on comparisons of sociodemographic or disease groups. PMID- 17712256 TI - Evaluating chronic disease for heterogeneous populations: the case of arthritis. AB - BACKGROUND: Cost-effectiveness evaluation for health care programs often involves the use of quality-adjusted life-year (QALY) estimates to measure morbidity losses from health conditions. Current techniques for measuring morbidity losses are often subjective, inflexible, impractical, and subject to bias. OBJECTIVE: We sought to examine the impact of population heterogeneity on QALY values for arthritis sufferers by estimating an alternative health-adjusted life-year (HALY) measure based on self-assessed health status. RESEARCH DESIGN: We present a feasible approach for the assessment of improved QALY estimates for chronic conditions affecting heterogeneous populations. An ordered probit model, using data from the National Health Interview Survey (NHIS), is used to calculate expected HALY losses from arthritis for distinct population subgroups. These measures are used to scale existing QALY measures that have been calculated for distinct homogeneous populations. RESULTS: : We find that QALY losses from chronic arthritis vary by age, time since onset, and type of arthritis. When we apply these results to prevention programs aimed at reducing the incidence of Salmonella enteritidis infections (and the resulting reactive arthritis sequelae), we find that age-invariant QALYs underestimate the true discounted lifetime QALY losses from arthritis by 15%. CONCLUSIONS: Our results indicate that a failure to account for population heterogeneity can lead to biased health loss estimates. The modified HALY measure presented here can be used to help inform policymakers faced with heterogeneous populations. PMID- 17712257 TI - Quality of diabetes care among cancer survivors with diabetes. AB - BACKGROUND: Among patients with chronic medical conditions, unrelated conditions are often undertreated. OBJECTIVE: To compare the quality of diabetes care delivered to diabetic patients with and without cancer in a large regional integrated delivery system. DESIGN: Observational cohort study using propensity score methods to control for baseline differences between diabetic patients with and without a history of cancer. SUBJECTS: A total of 5773 Kaiser Northern California members with diabetes and previous cancer and 23,092 members with diabetes and no previous cancer. MEASURES: : Nine measures of diabetes technical quality and clinical outcomes in 2003. RESULTS: : Relative to diabetic patients without cancer, those with cancer had higher adjusted rates of HbA1c testing (66.3% vs. 64.4%; P = 0.02), HbA1c control (73.4% vs. 70.9%; P < 0.001), and urine microalbumin testing (59.1% vs. 55.2%; P < 0.001) but lower rates of low density lipoprotein (LDL) cholesterol control (40.7% vs. 42.2%; P = 0.02) and statin use if LDL >100 mg/dL (76.7% vs. 80.6%; P < 0.001). The groups had similar rates of LDL cholesterol testing, dilated retinal examinations, blood pressure control, and angiotensin converting enzyme (ACE) inhibitor use for hypertension (all P >/= 0.20). CONCLUSIONS: Despite the potential for cancer-related services to compete with delivery of diabetes care, diabetic patients with cancer received care of generally similar quality relative to diabetic patients without cancer in this integrated delivery system. Nevertheless, the quality of diabetes care delivered to all patients could be improved, particularly the control of LDL cholesterol and blood pressure. Combining data from electronic disease registries has the potential for monitoring quality of care delivered to patients with more than 1 major medical illness. PMID- 17712258 TI - Agreement between self-reports and medical records was only fair in a cross sectional study of performance of annual eye examinations among adults with diabetes in managed care. AB - BACKGROUND: Despite consensus about the importance of measuring quality of diabetes care and the widespread use of self-reports and medical records to assess quality, little is known about the degree of agreement between these data sources. OBJECTIVES: To evaluate agreement between self-reported and medical record data on annual eye examinations and to identify factors associated with agreement. RESEARCH DESIGN AND SUBJECTS: Data from interviews and medical records were available for 8409 adults with diabetes who participated in the baseline round of the Translating Research Into Action for Diabetes (TRIAD) Study. MEASURES: Agreement between self-reports and medical records was evaluated as concordance and Cohen's kappa coefficient. RESULTS: Self-reports indicated a higher performance of annual dilated eye examinations than did medical records (75.9% vs. 38.8%). Concordance between the data sources was 57.9%. Agreement was only fair (kappa coefficient = 0.25; 95% confidence interval, 0.23-0.26). Nearly two-thirds (64.6%) of discordance was due to lack of evidence in the medical record to support self-reported performance of the procedure. After adjustment, agreement was most strongly related to health plan (chi = 977.9, df = 9; P < 0.0001), and remained significantly better for 3 of the 10 health plans (P < 0.00001) and for persons younger than 45 years of age (P = 0.00002). CONCLUSIONS: The low level of agreement between self-report and medical records suggests that many providers of diabetes care do not have easily available accurate information on the eye examination status of their patients. PMID- 17712259 TI - Development of a measure of clinical information systems expectations and experiences. AB - BACKGROUND/OBJECTIVES: The purpose of this study is to describe the development and initial psychometric properties of a measure of expectations and experiences regarding the impact of clinical information systems on work process and outcomes. RESEARCH DESIGN: Basic item analysis, confirmatory factor analysis, cross-validation factor analyses, and reliability analysis were used to assess the psychometric properties of the scale. SUBJECTS: The initial validation sample included registered nurses from a large Midwestern rural referral hospital that implemented electronic medical records and computerized provider order entry systems. Nurses from 3 other hospitals were used to cross-validate the factor structure of the scale. MEASURES: The scale assesses respondents' perceptions related to communication changes, changes in selected work behaviors, perceptions of the implementation strategy, and the impact on quality of patient care. The instrument can be used to assess perceptions before and after implementation. RESULTS: Confirmatory factor analysis generally supported the a priori factor structure for both expectations and experiences regarding the clinical information system. The consistency of the fit to the factor models was also high across the cross-validation samples. The scales demonstrated acceptable internal consistency in all the samples. CONCLUSIONS: Our findings suggest that the measure of clinical information systems expectations and experiences offers a valid and reliable tool for assessing the perceived impact of new clinical technology on work process and outcomes. This instrument can be useful before and after technology implementation by assisting in the identification of staff perceptions and concerns, thus allowing for targeted interventions to address these issues. PMID- 17712260 TI - Overall quality of life and difficulty paying for ostomy supplies in the Veterans Affairs ostomy health-related quality of life study: an exploratory analysis. AB - PURPOSE: To explore whether there was a significant relationship between difficulty paying for ostomy supplies and overall quality of life among a sample of ostomates receiving care from the Veterans Health Administration (VHA). METHODS: The data were collected as part of the Veterans Affairs (VA) Ostomy Health-Related Quality of Life Study, in which 511 respondents (239 cases, 272 controls) completed a survey instrument that included the modified City of Hope Quality of Life (mCOH-QOL) Ostomy questionnaire, SF-36V, and sociodemographic items. Responses from the 239 cases (ie, patients with intestinal stomas) were used in this analysis. The modified City of Hope Quality of Life Ostomy questionnaire item, "How good is your overall quality of life?," was the dependent variable for this analysis. The primary independent variable was the response (yes/no) to the item, "If you pay for any of the (ostomy) costs, is it difficult for you?" A hierarchical regression model was used to examine whether difficulty paying was significantly related to overall quality of life after adjusting for age, income, race/ethnicity, and physical health. RESULTS: After accounting for the proportion of variance explained by age, income, race/ethnicity, and physical health, the additional proportion of variance explained by difficulty paying was statistically significant. Individuals reporting difficulty paying had a roughly 1 point lower (ie, beta-coefficient = 1.052; SE = 0.481) overall quality of life score on the 11-point scale. CONCLUSIONS: We found a significant association between difficulty paying for ostomy supplies and overall quality of life. Although the cross-sectional study design does not allow causal inference, the results suggest a relationship that merits further examination. PMID- 17712261 TI - Access to osteoporosis treatment is critically linked to access to dual-energy x ray absorptiometry testing. AB - OBJECTIVE: To determine if inequities in access to osteoporosis investigation [dual-energy x-ray absorptiometry (DXA) testing] and treatment (bisphosphonate, calcitonin, and/or raloxifene) exist among older women in a region with universal health care coverage. METHODS: Community-dwelling women aged 65-89 years residing within 2 regions of Ontario, Canada were randomly sampled. Data were collected by standardized telephone interview. Potential correlates of DXA testing (verified by physician records), and current treatment were grouped by type as: "predisposing characteristics," "enabling resources," or "need factors" based on hypothesized relationships formulated before data collection. Variables associated with each outcome independent of "need factors" identified inequities in the system. RESULTS: Of the 871 participants (72% response rate), 55% had been tested by DXA and 20% were receiving treatment. Using multiple variable logistic regression to adjust for need factors, significant inequities in access to DXA testing existed by age, health beliefs, education, income, use of preventive health services, region, and provider sex. DXA testing mediated access to treatment; 34% of those having had a DXA were treated compared with 2% of those who did not. Among women with osteoporosis, correctly reporting that their DXA test indicated osteoporosis and higher perceived benefits of taking pharmacological agents for osteoporosis were associated with treatment. CONCLUSIONS: Significant inequities in access to fracture prevention exist in a region with universal health care coverage. Improved access to DXA and better communication to patients of both their DXA results and the benefits of treatment has the potential to reduce the burden of osteoporosis. PMID- 17712262 TI - Assessment of the clinical management of fragility fractures and implications for the new HEDIS osteoporosis measure. AB - BACKGROUND: Rates of screening for and treatment of osteoporosis have been low, even among those with fractures who are at greatest risk for new fractures. OBJECTIVE: The objective of this study was to examine trends in the clinical management of patients with fragility fractures to provide baseline data for future assessments of the impact of the new Health Plan Employer Data and Information Set (HEDIS) measure. RESEARCH DESIGN: The MarketScan Medicare Supplemental and Coordination of Benefits (COB) database was used to examine adherence to the 2004 HEDIS guidelines by measuring the percent of women age 67 and older who were screened and/or treated after a fracture from 2000 through 2005. Clinical, demographic, and provider characteristics were assessed to determine the correlates of being screened and treated. RESULTS: The overall unadjusted percent of women screened and treated remains low, with just 10.2% screened and 12.9% treated in 2005. Multivariate analyses, which controlled for fracture location, patient characteristics, physician specialty, and region indicated small, albeit statistically significant, increases in treatment and screening over time. Women fracturing in 2005 were 27% more likely to be screened and 15% more likely to receive treatment relative to those fracturing in the year 2000. CONCLUSIONS: Although our study found some improvements in the screening for and treatment of osteoporosis among Medicare beneficiaries with a fragility fracture from 2000 through 2005, the overall percent of women screened and/or treated remained low. These data provide a baseline for assessing the impact of the new HEDIS measure in the coming years. PMID- 17712263 TI - The medical license number accurately identifies the prescribing physician in a large pharmacy claims database. AB - BACKGROUND: Medical license numbers that identify physicians in pharmacy claims data are used increasingly for both research and quality improvement efforts; however, little is known about how well this information identifies the physician who wrote the prescription. We studied the accuracy of the medical license number in data from a state-run drug benefit plan by assessing its consistency with 2 external sources of data. METHODS: We studied a cohort of new users of osteoporosis medications who participated in Medicare and a state-run pharmaceutical benefit program. The medical license number from the prescription data were merged with the American Medical Association's (AMA) Masterfile to determine if the physician on the pharmacy claim existed in the AMA directory and practiced in the area under study. The prescription data were then merged with Medicare Part B data to determine if the physician on the prescription had an outpatient visit with the patient who received the medication. RESULTS: Of the 40,002 index prescriptions, 38,671 (96.7%) were written by physicians or doctors of osteopathy. Of those, 38,618 (99.9%) could be matched to the AMA Masterfile of which 37,375 (98%) had a local address. Of the AMA-matched prescriptions with a valid Unique Physician Identification Number (UPIN), 28,888 (96.1%) could be matched to Medicare Part B data, indicating that the physician whose license number appeared on the prescription had at least 1 outpatient visit with the patient who received the medication. CONCLUSIONS: The state medical license number in the pharmacy claims dataset studied seems to identify the prescribing physician with a high degree of accuracy. PMID- 17712264 TI - Regulating drugs for effectiveness and safety: a public health perspective. PMID- 17712265 TI - Development of effective connectivity for narrative comprehension in children. AB - A large-scale study of narrative comprehension using functional MRI was performed involving children of ages 5-18 years old using a recently published method, multivariate autoregressive modeling, modified for multi subject analyses to investigate effective connectivity and its development with age. Feedback networks were found during a narrative processing task and involved effective connectivity from Broca's area and the medial aspect of the superior frontal gyrus to the posterior aspects of the superior temporal gyrus bilaterally. The effective connectivity from Broca's area to the superior temporal gyrus in the left hemisphere was shown to increase with age. The results demonstrate the feasibility of performing multi subject multivariate autoregressive modeling analyses to investigate effective connectivity in the absence of an a priori model. PMID- 17712266 TI - The human pyramidal syndrome Redux. AB - Experimental studies in nonhuman primates have questioned the selectivity of pyramidal tract damage in giving rise to the classical pyramidal syndrome in humans, characterized by permanent spastic hemiplegia (PSH). According to this view, concomitant injury of extrapyramidal pathways is necessary for the development of both hemiplegia and spasticity. In this study we used conventional magnetic resonance imaging and diffusion tensor imaging tractography to characterize the anatomical correlates of PSH in a patient with a rare and discrete unilateral lesion of the medullary pyramid. Our findings support the hypothesis that damage confined to the medullary pyramid/pyramidal tract is sufficient to produce PSH. In contrast to nonhuman primates, the human 'pyramidal' and 'pyramid' syndromes are equivalent clinico-anatomic concepts. PMID- 17712267 TI - Learning by doing: an fMRI study of feedback-related brain activations. AB - Extracting meaningful information from the positive and negative outcomes of actions is a key requirement for learning. To define the neural correlates of feedback processing, rapid event-related functional magnetic resonance imaging was used in an associative learning paradigm in normal human volunteers. Positive (compared with negative) feedback was associated with activations in the ventral striatum, midbrain and anterior and posterior cingulate cortex. No activations were seen for the comparison negative >positive feedback. Blood oxygenation level dependent responses from the midbrain and the anterior cingulate cortex showed a phasic increase in response to positive feedback, whereas a decrease in response was seen for negative feedback. These results underscore the role of the reward system in feedback learning. PMID- 17712268 TI - Asymmetries of cortical thickness: effects of handedness, sex, and schizophrenia. AB - Sex, handedness, and disease processes in schizophrenia may affect the magnitude and/or direction of structural brain asymmetries. Using MRI data from 67 healthy (30 men, 10 nondextral) and 84 schizophrenia patients (60 men, 16 nondextral), cortical thickness asymmetries were compared at high spatial resolution. Within group asymmetries were observed in sensorimotor, perisylvian, and parahippocampal cortices (leftward) and in anterior mesial frontal cortices (rightward). Asymmetry patterns were similar across diagnosis and sex, although some regional asymmetry increases were observed in men. Hand preference (dextrality) significantly influenced regional asymmetries in parietal association and dorsomedial frontal cortices (false discovery rate-corrected), where medial frontal regions showed diagnosis by dextrality effects (uncorrected). Thus, dextrality relates to cortical thickness asymmetries, although schizophrenia may differentially affect asymmetry patterns across handedness. PMID- 17712269 TI - NRG induces membrane targeting of Galphaz in muscle: implication in myogenesis. AB - The neuregulins (NRGs) constitute a family of trophic factors that are known to play critical roles during neural development. We recently reported that Gbeta subunit regulates NRG-mediated signaling and gene transcription in cultured C2C12 myotubes. In this study, we demonstrated that NRG treatment of C2C12 myotubes stimulates a rapid translocation of Galphaz protein to the plasma membranes. In addition, Galphaz protein is localized to the postsynaptic regions at adult neuromuscular junctions and is prominently expressed in rat skeletal muscle during early postnatal stages. Interestingly, we found that expression of the constitutively activated Galphaz in C2C12 myoblasts attenuates myogenic differentiation. Taken together, our observations reveal an unanticipated role of Galphaz in mediating the actions of NRG during neural development. PMID- 17712270 TI - Neural basis of syntactic processing of simple sentences in Japanese. AB - This study used event-related functional magnetic resonance imaging to investigate the neural basis underlying the sequential involvement of syntactic processing in the course of sentence comprehension. In experiments, a noun, case particle, and verb were presented one by one, constituting simple sentences in Japanese. Participants judged whether the sentence was syntactically correct (syntactic judgment) or whether the particle and verb had the same vowel (phonological judgment). During particle presentation, greater activation in the left inferior frontal gyrus was observed during syntactic judgment than during phonological judgment. Presentation of verbs subsequently activated the left dorsal prefrontal cortex and medial superior frontal areas in the same comparison. Our findings indicate that these regions are sequentially recruited in the syntactic processing of simple sentences in Japanese. PMID- 17712271 TI - Effects of Notch-1 signalling pathway on differentiation of marrow mesenchymal stem cells into neurons in vitro. AB - In this study, the putative involvement of the Notch-1 signaling pathway in the neuronal differentiation of bone marrow mesenchymal stem cells (BMSCs) was investigated through RNA interference (RNAi). We found that mNotch-1shRNA could efficiently block expression of Notch-1 in BMSCs. After induction, immunohistochemistry, reverse transcriptase-PCR and Western blot analyses, all indicated that the expression of neuron-specific markers such as neuron-specific enolase and neurofilament 200 was much higher in mNotch-1shRNA BMSCs than that in control groups, whereas the expression of glial fibrillary acidic protein was lower in mNotch-1shRNA BMSCs. The percentage of apoptotic cells in mNotch-1shRNA BMSCs, however, was significantly higher than that in control groups. These data indicate that Notch signaling plays a role in the differentiation of BMSCs into neurons in vitro. Pharmacological or genetic interference with Notch signaling may provide a novel method to obtain neurons for therapeutic use. PMID- 17712272 TI - Amygdala activation in affective priming: a magnetoencephalogram study. AB - We employed magnetoencephalography (MEG) to examine amygdala activity during a linguistic affective priming task. The experimental design included positive and negative word pairs. Using synthetic aperture magnetometry in the analysis of MEG data, we identified a left amygdala power increase in the theta frequency range during priming involving negative words. We found that the amygdala displayed a time-dependent intensification in responsiveness to negative stimuli, specifically between 150 and 400 ms after target presentation. This study provides evidence for theta power changes in the amygdala and demonstrates that the analysis of brain oscillations provides a powerful tool to explore mechanisms implicated in emotional processing. PMID- 17712273 TI - Noun-verb naming in aphasia: a voxel-based lesion-symptom mapping study. AB - Single case and anatomo-correlative studies of aphasic participants have indicated that lesions in temporal regions cause predominant noun impairment, whereas lesions in frontal areas affect verb processing. These studies, however, relied mostly on arbitrary cut-offs, grouping participants according to whether or not they showed a noun or a verb deficit. Here, instead, we applied a recent anatomo-correlation technique, voxel-based lesion symptom mapping (VLSM) to a group of 16 left-hemisphere stroke participants tested on noun and verb naming tasks. Behavioral and lesion data were collected continuously without establishing a priori two different groups of participants. Noun naming was associated with regions located in the left superior temporal areas, whereas verb naming involved a larger region extending from the left prefrontal to the superior temporal areas. The differences and similarities of the two networks are discussed. PMID- 17712274 TI - 2R, 4R-APDC decreases cell proliferation in the dentate gyrus of adult rats: the effect of 2R, 4R-APDC on cell proliferation. AB - This study investigated the effects of group II metabotropic glutamate receptor agonist, 2R, 4R-4-aminopyrrolidine-2,4-dicarboxylate (2R, 4R-APDC), on cell proliferation in the dentate gyrus of adult rats. 2R, 4R-APDC at a dose of 1 and 10 nmol/day resulted in decreased bromodeoxyuridine immunoreactive cells in the dentate gyrus. In addition, we found that APDC treatment had no effect on the number of BrdU+ and GFAP(+)-labeled cells or BrdU+ and NeuN(+)-labeled cells compared with controls. These data suggest that group II metabotropic glutamate receptor is an important site for glutamate's regulation on cell proliferation in the dentate gyrus, but 2R, 4R-APDC had no effects on newborn cell's ability to differentiate into neurons or astrocytes. PMID- 17712275 TI - Grafted neural stem cells increase the life span and protect motoneurons in pmn mice. AB - In this study, we have grafted neural stem cells (NSCs) into the lumbar spinal cord of a mouse mutant that has a specific loss of motoneurons (progressive motor neuronopathy/pmn). A small number of grafted cells ( approximately 3000) increased the life span of the mice by 56%. The improved survival was accompanied by a rescue of host motoneurons, a stabilization in the weight and an increase in the size of the muscle fibers. The grafted NSCs were small and round and exhibited no neural markers, suggesting that they remained in an undifferentiated state. Thus grafting of NSCs in a mouse model with motoneuron degeneration exerts a neuroprotective effect. PMID- 17712276 TI - Elevated spectroscopic glutamate/gamma-amino butyric acid in rats bred for learned helplessness. AB - The theory of depression is dominated by the monoamine hypothesis but there is increasing evidence that beyond monoamines, glutamate (Glu) and gamma aminobutyric acid (GABA) play an essential role in the pathogenesis of depression. In this study, the effect of alterations of GABA and Glu were investigated in the congenital learned helplessness paradigm. Proton magnetic resonance spectroscopy is an important monitoring tool to bridge the findings in clinical and preclinical studies. We found increased Glu/GABA ratios in the hippocampus and prefrontal cortex of placebo-treated (saline intraperitoneally) congenital learned helplessness rats versus wild-type rats, and a treatment induced (desipramine 10 mg/kg intraperitoneally or electroconvulsive shock) decrease of this monoamine ratio in both brain regions. Our results corroborate previous findings of an amino-acid influence on the pathomechanisms of mood disorders. PMID- 17712277 TI - Imaging the attentional blink: perceptual versus attentional limitations. AB - Imaging studies of conscious perception using techniques such as masking often show increased neural responses in object processing regions of the brain, and accompany increased awareness of the stimulus. Imaging studies of the attentional blink, an effect where conscious awareness of the stimulus is suppressed through reduction of attentional resources, has tended to show the opposite neural response. This study examines changes in stimulus parameters such that either attention or perceptual information is limited. Findings show that under conditions of limited attention but reduced perception the BOLD response reveals increased activity when the stimulus cannot be reported; however, under conditions of reduced perception but normal attention, more activity is revealed on trials when the stimulus can be reported. PMID- 17712278 TI - Extinction of conditioned blink responses by cerebello-olivary pathway stimulation. AB - Learning of classically conditioned eyeblink responses depends on mechanisms within the cerebellum. It has been suggested that climbing fibres from the inferior olive transmit the unconditioned stimulus signal to the cerebellum. We have previously shown that the pathway from the deep cerebellar nuclei to the inferior olive inhibits olivary activity. It is known that repeated presentation of the conditioned stimulus on its own leads to extinction of the conditioned response. If the unconditioned stimulus signal is transmitted to the cerebellum via the inferior olive - climbing fibre system then stimulation of the nucleo olivary pathway just before the unconditioned stimulus in a trained animal should lead to extinction. The results from this investigation confirm this. PMID- 17712279 TI - Brain activation in patients with congenital bilateral hearing impairment. AB - Twelve patients with idiopathic, congenital, symmetric, moderate-to-severe sensorineural hearing loss participated in this study. Functional magnetic resonance imaging was performed while speech sounds were presented to each patient monaurally. Notable blood oxygenation level-dependent responses were clustered mainly in the superior temporal gyrus and transverse temporal gyrus of both hemispheres during right and left ear stimulation. In addition, the middle temporal gyrus of the right hemisphere was activated during right ear stimulation. The activation pattern was very similar to that of participants with normal hearing. Thus, as long as peripheral acoustic stimulation has not been totally absent from childhood, the classical activation pattern can be elicited in patients with congenital bilateral hearing impairment. PMID- 17712280 TI - No relation between 2D : 4D fetal testosterone marker and dyslexia. AB - It has been suggested that high levels of prenatal testosterone exposure are implied in the aetiology of dyslexia and its frequently co-occurring sensory problems. This study examined 2D : 4D digit ratio (a marker of fetal testosterone exposure) in dyslexic and normal reading children. No group differences in 2D : 4D were observed. Digit ratio did not show the postulated relation with reading, spelling, phonological ability, speech perception, auditory processing and visual processing. These findings challenge the validity of theories that allocate a prominent role to fetal testosterone exposure in the aetiology of dyslexia and its sensory impairments. PMID- 17712281 TI - Accumbal dopamine D2 receptors are important for sensorimotor gating in C3H mice. AB - One operational measure of sensorimotor gating that is deficient in many psychiatric disorders is prepulse inhibition (PPI) of the startle response. To investigate the role of dopamine D1 and D2 receptors within the nucleus accumbens (NAC) in sensorimotor gating in mice, we infused dopamine D1 and D2 receptor agonists (dihydrexidine and quinpirole respectively) directly into the NAC and measured the effects on PPI and on prepulse facilitation. Quinpirole infusions increased PPI and attenuated prepulse facilitation, whereas dihydrexidine had no effects. These results stand in contrast to data after systemic injections in mice and rats and intra-accumbal infusions in rats, suggesting that the role of dopamine D2 receptors within the NAC in mice differs from their role in rats. PMID- 17712282 TI - [123I]FP-CIT striatal binding in early Parkinson's disease patients with tremor vs. akinetic-rigid onset. AB - We performed [123I]FP-CIT/SPECT in 20 drug-naive Parkinson's disease (PD) patients, 10 with unilateral akinesia/rigidity at onset (arPD) and 10 with additional tremor-at-rest (tPD), to evaluate whether resting tremor at onset is associated with differences in striatal dopamine transporter binding. Patients of the two cohorts were matched for age, disease duration (<3 years) and severity of non-tremor motor symptoms; 31 healthy participants served as controls. Mean striatal dopamine transporter binding reduction in PD patients vs. controls was 42% for arPD and 50% for tPD; mean ipsilateral striatum and caudate nucleus uptake values were lower by 12 and 24%, respectively, in tPD than arPD. We conclude that widespread degeneration of the nigrostriatal dopaminergic pathway might be necessary for the development of parkinsonian tremor-at-rest. PMID- 17712283 TI - Relationship between P50 suppression and the cortical silent period. AB - Deficient inhibitory neurotransmission has been demonstrated in schizophrenia through electroencephalography (e.g. P50 suppression) and transcranial magnetic stimulation (e.g. short-interval cortical inhibition and the cortical silent period). It is not known whether these inhibitory paradigms are related despite evidence suggesting that both are coordinated through gamma-aminobutyric acid inhibitory neurotransmission. We explored the relationship between P50 suppression, short-interval cortical inhibition and the cortical silent period in 21 healthy participants using previously published methods. P50 suppression was significantly correlated with cortical silent period (r=-0.49, P=0.02) but not with short-interval cortical inhibition. As both P50 suppression and the cortical silent period have been linked to gamma-aminobutyric acidB receptor-mediated inhibitory neurotransmission, these data highlight the importance of this receptor subtype in the pathophysiology of schizophrenia. PMID- 17712284 TI - The neural basis of risky decision-making in a blackjack task. AB - To investigate the neural substrates of risky decision making in gambling tasks, we recorded event-related potentials while participants engaged in a modified blackjack game. We focused on the high-conflict condition (probability of losing approximately 50%) and low-conflict condition (probability of losing approximately 20%). We were also interested in the difference between risky and conservative responses under high-conflict conditions. In the 220-320 and 500-600 ms time windows, high-conflict conditions elicited more negative event-related potential deflections than low-conflict conditions. In the latter time window, risky conditions elicited more negative event-related potential deflections than conservative conditions. The N2 (220-320 ms) and N500 (500-600 ms) provide evidence for the dissociation of neural circuits between perceptual and response conflicts. PMID- 17712286 TI - Cancer stem cells: the root of the problem. PMID- 17712285 TI - Alteration of brain metabolites in young alcoholics without structural changes. AB - Using proton magnetic resonance spectroscopy and magnetic resonance imaging, we investigated concentrations of various brain metabolites, including glutamate, and measured brain volumes and neuropsychological performances in 13 recently abstinent young alcoholic men compared with 18 controls. No differences were found in volumetric variables between groups (intracranial volume, white matter, grey matter, anterior cingulate, insula, hippocampus, and amygdala). For the anterior cingulate, choline and creatine levels in the patient group were significantly lower than controls, and the glutamate to creatine ratio was significantly increased. These were correlated with altered short-term memory functions. Thus, neurochemical changes can occur even in the brains of young alcoholic men lacking brain atrophy. PMID- 17712287 TI - American Pediatric Society presidential address 2007: Robust complex networks in health, disease and international pediatric research. PMID- 17712290 TI - Importance of age and postimplantation experience on speech perception measures in children with sequential bilateral cochlear implants. AB - OBJECTIVES: Clinical trials in which children received bilateral cochlear implants in sequential operations were conducted to analyze the extent to which bilateral implantation offers benefits on a number of measures. The present investigation was particularly focused on measuring the effects of age at implantation and experience after activation of the second implant on speech perception performance. STUDY DESIGN: Thirty children aged 3 to 13 years were recipients of 2 cochlear implants, received in sequential operations, a minimum of 6 months apart. All children received their first implant before 5 years of age and had acquired speech perception capabilities with the first device. They were divided into 3 age groups on the basis of age at time of second ear implantation: Group I, 3 to 5 years; Group II, 5.1 to 8 years; and Group III, 8.1 to 13 years. Speech perception measures in quiet included the Multisyllabic Lexical Neighborhood Test (MLNT) for Group I, the Lexical Neighborhood Test (LNT) for Groups II and III, and the Hearing In Noise Test for Children (HINT-C) sentences in quiet for Group III. Speech perception in noise was assessed using the Children's Realistic Intelligibility and Speech Perception (CRISP) test. Testing was performed preoperatively and again postactivation of the second implant at 3, 6, and 12 months (CRISP at 3 and 9 mo) in both the unilateral and bilateral conditions in a repeated-measures study design. Two-way repeated measures analysis of variance was used to analyze statistical significance among device configurations and performance over time. SETTING: US Multicenter. RESULTS: Results for speech perception in quiet show that children implanted sequentially acquire open-set speech perception in the second ear relatively quickly (within 6 mo). However, children younger than 8 years do so more rapidly and to a higher level of speech perception ability at 12 months than older children (mean second ear MLNT/LNT scores at 12 months: Group I, 83.9%; range, 71 96%; Group II, 59.5%; range, 40-88%; Group III, 32%; range, 12-56%). The second ear mean HINT-C score for Group III children remained far less than that of the first ear even after 12 months of device use (44 versus 89%; t, 6.48; p<0.001; critical value, 0.025). Speech intelligibility for spondees in noise was significantly better under bilateral conditions than with either ear alone when all children were analyzed as a single group and for Group III children. At the 9 month test interval, performance in the bilateral configuration was significantly better for all noise conditions (13.2% better for noise at first cochlear implant, 6.8% better for the noise front and noise at second cochlear implant conditions, t=2.32, p=0.024, critical level=0.05 for noise front; t=3.75, p<0.0001, critical level=0.05 for noise at first implant; t=2.73, p = 0.008, critical level=0.05 for noise at second implant side). The bilateral benefit in noise increased with time from 3 to 9 months after activation of the second implant. This bilateral advantage is greatest when noise is directed toward the first implanted ear, indicating that the head shadow effect is the most effective binaural mechanism. The bilateral condition produced small improvements in speech perception in quiet and for individual Group I and Group II patient results in noise that, in view of the relatively small number of subjects tested, do not reach statistical significance. CONCLUSION: Sequential bilateral cochlear implantation in children of diverse ages has the potential to improve speech perception abilities in the second implanted ear and to provide access to the use of binaural mechanisms such as the head shadow effect. The improvement unfolds over time and continues to grow during the 6 to 12 months after activation of the second implant. Younger children in this study achieved higher open-set speech perception scores in the second ear, but older children still demonstrate bilateral benefit in noise. Determining the long-term impact and cost effectiveness that results from such potential capabilities in bilaterally implanted children requires additional study with larger groups of subjects and more prolonged monitoring. PMID- 17712291 TI - Transdermal rotigotine (Neupro) for Parkinson's disease. PMID- 17712292 TI - Low-dose transdermal estrogens. PMID- 17712294 TI - A precision translation stage for reproducing measured target volume motions. AB - The development of 4D imaging, treatment planning and treatment delivery methods for radiation therapy require the use of a high-precision translation stage for testing and validation. These technologies may require spatial resolutions of 1 mm, and temporal resolutions of 2-30 Hz for CT imaging, electromagnetic tracking, and fluoroscopic imaging. A 1D programmable translation stage capable of reproducing idealized and measured anatomic motions common to the thorax has been design and built to meet these spatial and temporal resolution requirement with phantoms weighing up to 27 kg. The stage consists of a polycarbonate base and table, driven by an AC servo motor with encoder feedback by means of a belt coupled precision screw. Complex motions are possible through a programmable motion controller that is capable of running multiple independent control and monitoring programs concurrently. Programmable input and output ports allow motion to be synchronized with beam delivery and other imaging and treatment delivery devices to within 2.0 ms. Average deviations from the programmed positions are typically 0.2 mm or less, while the average typical maximum positional errors are typically 0.5 mm for an indefinite number of idealized breathing motion cycles and while reproducing measured target volume motions for several minutes. PMID- 17712296 TI - Image-guided helical tomotherapy for localized prostate cancer: technique and initial clinical observations. AB - The purpose of the present study was to implement a technique for daily computed tomography (CT)-based image-guided radiation therapy and to report observations on treatment planning, imaging, and delivery based on the first 2 years of clinical experience. Patients with previously untreated stage T1-T3 biopsy-proven adenocarcinoma of the prostate were considered eligible for treatment with daily CT-guided helical tomotherapy. The prostate was targeted daily using megavoltage CT (MVCT) images that were fused with treatment-planning CT images based on anatomic alignments. All patients were treated at 2 Gy per fraction to 76-78 Gy (mean: 76.7 Gy). As part of this study, 33 prostate patients were planned, imaged, and treated with a total of 1266 CT-guided fractions. The prostate, rectum, bladder, femoral heads, and pubis symphysis were visible in one or more slices for all 1266 MVCT image sets. The typical range of measured prostate displacement relative to a 3-point external laser setup in this study was 2-10 mm [3.4 mm standard deviation (SD)] in the anterior-posterior direction, 2-8 mm (3.7 mm SD) in the lateral direction, and 1-6 mm (2.4 mm SD) in the superior-inferior direction. The obese patients in this study had a substantially larger lateral variation (8.2 mm SD) attributable to mobility of skin marks. The prostate, seminal vesicles, rectum, and bladder anatomy were used to position the patient relative to the desired treatment position without the use of implanted markers. Acute toxicities were within the expected range given the number of patients treated and the dose level. PMID- 17712295 TI - Comparing computed tomography localization with daily ultrasound during image guided radiation therapy for the treatment of prostate cancer: a prospective evaluation. AB - In the present paper, we describe the results of a prospective trial that compared isocenter shifts produced by BAT Ultrasound (Nomos, Sewicky, PA) to those produced by a computed tomography (CT) unit in the treatment room to aid in positioning during image-guided radiation therapy. The trial included 15 consecutive patients with localized prostate cancer. All patients underwent CT and MR simulation immobilized supine in an Alpha Cradle and were treated with intensity-modulated radiation therapy. BAT Ultrasound was used daily to correct for interfraction motion by obtaining shift in the x, y, and z directions. Two days per week during therapy, CT scans blinded to the ultrasound shifts were obtained and recorded. We analyzed 218 alignments from the 15 patients and observed a high level of correlation between the CT and ultrasound isocenter shifts (correlation coefficients: 0.877 anterior-posterior, 0.842 lateral, and 0.831 superior-inferior). The systematic differences were less than 1 mm, and the random differences were approximately 2 mm. The average absolute differences, including both systemic and random differences, were less than 2 mm in all directions. The isocenter shifts generated by using a CT unit in the treatment room correlate highly with shifts produced by the BAT Ultrasound system. PMID- 17712297 TI - Commissioning experience with cone-beam computed tomography for image-guided radiation therapy. AB - This paper reports on the commissioning of an Elekta cone-beam computed tomography (CT) system at one of the first U.S. sites to install a "regular," off the-shelf Elekta Synergy (Elekta, Stockholm, Sweden) accelerator system. We present the quality assurance (QA) procedure as a guide for other users. The commissioning had six elements: (1) system safety, (2) geometric accuracy (agreement of megavoltage and kilovoltage beam isocenters), (3) image quality, (4) registration and correction accuracy, (5) dose to patient and dosimetric stability, and (6) QA procedures. The system passed the safety tests, and agreement of the isocenters was found to be within 1 mm. Using a precisely moved skull phantom, the reconstruction and alignment algorithm was found to be accurate within 1 mm and 1 degree in each dimension. Of 12 measurement points spanning a 9x9x15-cm volume in a Rando phantom (The Phantom Laboratory, Salem, NY), the average agreement in the x, y, and z coordinates was 0.10 mm, -0.12 mm, and 0.22 mm [standard deviations (SDs): 0.21 mm, 0.55 mm, 0.21 mm; largest deviations: 0.6 mm, 1.0 mm, 0.5 mm] respectively. The larger deviation for the y component can be partly attributed to the CT slice thickness of 1 mm in that direction. Dose to the patient depends on the machine settings and patient geometry. To monitor dose consistency, air kerma (output) and half-value layer (beam quality) are measured for a typical clinical setting. Air kerma was 6.3 cGy (120 kVp, 40 mA, 40 ms per frame, 360-degree scan, S20 field of view); half value layer was 7.1 mm aluminum (120 kV, 40 mA). We suggest performing items 1, 2, and 3 monthly, and 4 and 5 annually. In addition, we devised a daily QA procedure to verify agreement of the megavoltage and kilovoltage isocenters using a simple phantom containing three small steel balls. The frequency of all checks will be reevaluated based on data collected during about 1 year. PMID- 17712298 TI - Radiation shielding for gamma stereotactic radiosurgery units. AB - Shielding calculations for gamma stereotactic radiosurgery units are complicated by the fact that the radiation is highly anisotropic. Shielding design for these devices is unique. Although manufacturers will answer questions about the data that they provide for shielding evaluation, they will not perform calculations for customers. More than 237 such units are now installed in centers worldwide. Centers installing a gamma radiosurgery unit find themselves in the position of having to either invent or reinvent a method for performing shielding design. This paper introduces a rigorous and conservative method for barrier design for gamma stereotactic radiosurgery treatment rooms. This method should be useful to centers planning either to install a new unit or to replace an existing unit. The method described here is consistent with the principles outlined in Report No. 151 from the U.S. National Council on Radiation Protection and Measurements. In as little as 1 hour, a simple electronic spreadsheet can be set up, which will provide radiation levels on planes parallel to the barriers and 0.3 m outside the barriers. PMID- 17712299 TI - Quantitative assessment of four-dimensional computed tomography image acquisition quality. AB - The purpose of the present work was to describe the development and validation of a series of tests to assess the quality of four-dimensional (4D) computed tomography (CT) imaging as it is applied to radiation treatment planning. Using a commercial respiratory motion phantom and a programmable moving platform with a CT phantom, we acquired 4D CT datasets on two commercial multislice helical CT scanners that use different approaches to 4D CT image reconstruction. Datasets were obtained as the platform moved in various patterns designed to simulate breathing. Known inserts in the phantom were contoured, and statistics were generated to evaluate properties important to radiation therapy--namely, accuracy of phase-binning, shape, volume, and CT number. Phase-binning accuracy varied by as much as 5% for a 4D procedure in which images were reconstructed and then binned, but exhibited no variation for a 4D procedure in which projections were binned before reconstruction. The magnitude of geometric distortion was found to be small for both approaches, as was the magnitude of volume error. Partial volume effects in the direction perpendicular to the transverse planes of reconstruction affected volume accuracy, however. Computed tomography numbers were reproduced accurately, but 4D images exhibited more variation in CT number than static CT images did. Characterization of such properties can be used to better understand and optimize the various parameters that affect 4D CT image quality. PMID- 17712300 TI - Effect of skull shape approximations in Gamma Knife dose calculations. AB - Doses in Leksell GammaPlan (Elekta, Stockholm, Sweden) are calculated for each shot by summing the contribution from the 201 radiation beams emitted by the Gamma Knife (Elekta), weighted for attenuation in the tissue traversed. The patient's head is modeled based on 24 skull measurements, from which the depth to the calculation point is determined for each beam. The limited number of measurement points associated with this approach can result in substantial discrepancies between the skull model used for dose calculations and the actual skull contour from computed tomography or magnetic resonance data. A review of 24 patients found that differences between the actual and approximated skull shape gave treatment time errors as large as 4.1%, although in most instances, the errors were less than 1%. The conclusion was that the Leksell GammaPlan head model provides a quick and convenient approach for specifying the shape of the patient's head in all but extreme cases, where discrepancies as large as approximately 5% can result. PMID- 17712301 TI - TG-43U1 parameterization of elongated RadioCoil 103Pd brachytherapy sources. AB - Recently, to eliminate problems associated with seed type sources, RadioMed Corporation (Tyngsboro, MA) introduced RadioCoil 103Pd sources for interstitial prostate implants. The RadioCoil sources are available in integral lengths ranging from 1.0 cm to 6.0 cm. In this project, dosimetric characteristics of these sources were determined following the TG-43U1 recommendations, with consideration of our recent publication on the evaluation of two-dimensional anisotropy function for elongated brachytherapy sources. Dosimetric parameters of these sources were determined experimentally in Solid Water (Gammex RMI, Middleton, WI) and theoretically using Monte Carlo simulation in Solid Water and liquid water. Per the TG-43U1 protocol, the consensus of these results would be used for their clinical applications. PMID- 17712302 TI - A survey on planar IMRT QA analysis. AB - Quality assurance (QA) systems for intensity-modulated radiation therapy (IMRT) have become standard tools in modern clinical medical physics departments. However, because formalized industry standards or recommendations from professional societies have yet to be defined, methods of IMRT QA analysis vary from institution to institution. Understanding where matters stand today is an important step toward improving the effectiveness of IMRT QA and developing standards. We therefore conducted an IMRT QA survey. This particular survey was limited to users of an electronic two-dimensional diode array device, but we took care to keep the questions as general and useful as possible. The online survey polled institutions (one survey per institution) on a collection of questions about methods of IMRT QA. The topics were general to the IMRT QA analysis methods common to all IMRT systems; none of the questions was vendor- or product specific. Survey results showed that a significant proportion of responding institutions (32.8%) use the single-gantry-angle composite method for IMRT QA analysis instead of field-by-field analysis. Most institutions perform absolute dose comparisons rather than relative dose comparisons, with the 3% criterion being used most often for the percentage difference analysis, and the 3 mm criterion for distance-to-agreement analysis. The most prevalent standard for acceptance testing is the combined 3% and 3 mm criteria. A significant percentage of responding institutions report not yet having standard benchmarks for acceptance testing-specifically, 26.6%, 35.3%, and 67.6% had not yet established standard acceptance criteria for prostate, head and neck, and breast IMRT respectively. This survey helps in understanding how institutions perform IMRT QA analysis today. This understanding will help to move institutions toward more standardized acceptance testing. But before standards are defined, it would be useful to connect the conventional planar QA analyses to their resulting impact on the overall plan, using clinically relevant metrics (such as estimated deviations in dose-volume histograms). PMID- 17712303 TI - Duplicating a tandem and ovoids distribution with intensity-modulated radiotherapy: a feasibility study. AB - Brachytherapy plays an important role in the definitive treatment of cervical cancers by radiotherapy. In the present study, we investigated whether sliding window intensity-modulated radiation therapy (IMRT) can achieve a pear-shaped distribution with a similar sharp dose falloff identical to that of brachytherapy. The computed tomography scans of a tandem and ovoid patient were pushed to both a high dose rate (HDR) and an IMRT treatment planning system (TPS) after the rectum, bladder, and left and right femoral heads had been outlined, ensuring identical structures in both planning systems. A conventional plan (7 Gy in 5 fractions, defined as the average dose to the left and right point A) was generated for HDR treatment. The 150%, 125%, 100%, 75%, 50%, and 25% isodose curves were drawn on each slice and then transferred to the IMRT TPS. The 100% isodose envelope from the HDR plan was the target for IMRT planning. A 7-field IMRT plan using 6-MV X-ray beams was generated and compared with the HDR plan using isodose conformity to the target and 125% volume, dose-volume histograms, and integral dose. The resulting isodose distribution demonstrated good agreement between the HDR and IMRT plans in the 100% and 125% isodose range. The dose falloff in the HDR plan was much steeper than that in the IMRT plan, but it also had a substantially higher maximum dose. Integral dose for the target, rectum, and bladder were found to be 6.69 J, 1.07 J, and 1.02 J in the HDR plan; the respective values for IMRT were 3.47 J, 1.79 J, and 1.34 J. Our preliminary results indicate that the HDR dose distribution can be replicated using a standard sliding-window IMRT dose delivery technique for points lying closer to the three-dimensional isodose envelope surrounding point A. Differences in radiobiology and patient positioning between the two techniques merit further consideration. PMID- 17712304 TI - Daily quality assurance phantom for ultrasound image guided radiation therapy. AB - A simple phantom was designed, constructed, tested, and clinically implemented for daily quality assurance (QA) of an ultrasound-image-guided radiation therapy (US-IGRT) system, the Restitu Ultrasound system (Resonant Medical, Montreal, QC). The phantom consists of a high signal echogenic background gel surrounding a low signal hypoechoic egg-shaped target. Daily QA checks involve ultrasound imaging of the phantom and segmenting of the embedded target using the automated tools available on the US-IGRT system. This process serves to confirm system hardware and software functions and, in particular, accurate determination of the target position. Experiments were conducted to test the stability of the phantom at room temperature, its tissue-mimicking properties, the reproducibility of target position measurements, and the usefulness of the phantom as a daily QA device. The phantom proved stable at room temperature, exhibited no evidence of bacterial or fungal invasion in 9 months, and showed limited desiccation (resulting in a monthly reduction in ultrasound-measured volume of approximately 0.2 cm3). Furthermore, the phantom was shown to be nearly tissue-mimicking, with speed of sound in the phantom estimated to be 0.8% higher than that assumed by the scanner calibration. The phantom performs well in a clinical setting, owing to its light weight and ease of operation. It provides reproducible measures of target position even with multiple users. At our center, the phantom is being used for daily QA of the US-IGRT system with clinically acceptable tolerances of +/-1 cm3 on target volume and +/-2 mm on target position. For routine daily QA, this phantom is a good alternative to the manufacturer-supplied calibration phantom, and we recommended that that larger phantom be reserved for less frequent, more detailed QA checks and system calibration. PMID- 17712305 TI - Commissioning and acceptance testing of a CyberKnife linear accelerator. AB - Acceptance testing and commissioning of a CyberKnife robotic stereotactic radiosurgery system was performed in April 2006. The CyberKnife linear accelerator produces a photon beam of 6 MV nominal energy, without the use of a flattening filter. Clinically measured tissue-phantom ratios, off-center ratios, and output factors are presented and compared with similar data from other CyberKnife sites throughout the United States. In general, these values agreed to within 2%. PMID- 17712306 TI - Lag correction model and ghosting analysis for an indirect-conversion flat-panel imager. AB - Cone-beam digital tomosynthesis (CBDT) is a new approach that was recently proposed for rapid tomographic imaging of soft-tissue targets in the radiotherapy treatment room. One of the potential problems in implementing CBDT using, for example, megavoltage (MV) X rays is the possibility of artifacts caused by image lag and ghosting of the X-ray detector used. In the present work, we developed a model to correct for image lag with indirect-conversion flat-panel imagers (FPIs) used for MV-CBDT. This model is based on measurement and analysis of image lag in an indirect-conversion FPI irradiated with a 6-MV X-ray beam. Our results demonstrated that image lag is amenable to correction. In addition, we measured the ghosting effect for an indirect-conversion FPI and found it to be insignificant. PMID- 17712310 TI - Sensitivity of epidermal growth factor receptor and ErbB2 exon 20 insertion mutants to Hsp90 inhibition. AB - The mature epidermal growth factor receptor (EGFR) neither associates with nor requires the molecular chaperone heat-shock protein 90 (Hsp90). Mutations in EGFR exons 18, 19, and 21 confer Hsp90 chaperone dependence. In non-small cell lung cancer (NSCLC), these mutations are associated with enhanced sensitivity to EGFR inhibitors in vitro and with clinical response in vivo. Although less prevalent, insertions in EGFR exon 20 have also been described in NSCLC. These mutations, however, confer resistance to EGFR inhibitors. In NSCLC, exon 20 insertions have also been identified in the EGFR family member ErbB2. Here, we examined the sensitivity of exon 20 insertion mutants to an Hsp90 inhibitor currently in the clinic. Our data demonstrate that both EGFR and ErbB2 exon 20 insertion mutants retain dependence on Hsp90 for stability and downstream-signalling capability, and remain highly sensitive to Hsp90 inhibition. Use of Hsp90 inhibitors should be considered in NSCLC harbouring exon 20 insertions in either EGFR or ErbB2. PMID- 17712309 TI - Obesity and mental disorders in the general population: results from the world mental health surveys. AB - OBJECTIVES: (1) To investigate whether there is an association between obesity and mental disorders in the general populations of diverse countries, and (2) to establish whether demographic variables (sex, age, education) moderate any associations observed. DESIGN: Thirteen cross-sectional, general population surveys conducted as part of the World Mental Health Surveys initiative. SUBJECTS: Household residing adults, 18 years and over (n=62 277). MEASUREMENTS: DSM-IV mental disorders (anxiety disorders, depressive disorders, alcohol use disorders) were assessed with the Composite International Diagnostic Interview (CIDI 3.0), a fully structured diagnostic interview. Obesity was defined as a body mass index (BMI) of 30 kg/m(2) or greater; severe obesity as BMI 35+. Persons with BMI less than 18.5 were excluded from analysis. Height and weight were self-reported. RESULTS: Statistically significant, albeit modest associations (odds ratios generally in the range of 1.2-1.5) were observed between obesity and depressive disorders, and between obesity and anxiety disorders, in pooled data across countries. These associations were concentrated among those with severe obesity, and among females. Age and education had variable effects across depressive and anxiety disorders. CONCLUSIONS: The findings are suggestive of a modest relationship between obesity (particularly severe obesity) and emotional disorders among women in the general population. The study is limited by the self-report of BMI and cannot clarify the direction or nature of the relationship observed, but it may indicate a need for a research and clinical focus on the psychological heterogeneity of the obese population. PMID- 17712312 TI - Increasing incidence of childhood leukaemia: a controversy re-examined. AB - We provide evidence of a gradual increase in the incidence of childhood leukaemia over the twentieth century from examination of trends in both incidence and mortality in England and Wales. We conclude that much of the recorded increase is likely to be real. PMID- 17712311 TI - Antitumour and biological effects of letrozole and GnRH analogue as primary therapy in premenopausal women with ER and PgR positive locally advanced operable breast cancer. AB - Preoperative endocrine therapy is effective in postmenopausal patients with breast cancers expressing oestrogen receptor. We investigated the activity of primary therapy with letrozole in combination with GnRH analogue in premenopausal women with T2-T4 N0-N2 breast cancer, whose tumours expressed oestrogen and progesterone receptors. We measured the expression of molecular factors involved in responsiveness to endocrine agents including ERalpha, EGFR, HER2, MAP kinases (and phosphorylated forms) ER-beta1, both at initial biopsy and at the time of surgery. Thirty-five patients were included and 32 patients were evaluable for response. Sixteen patients (50%, 95% CI 32-68%) obtained a partial response, 16 patients were stable. One patient showed pathological complete response (3%, 95% CI 0-16%). Response was significantly associated with younger age (P<0.05) and a longer duration of treatment (P<0.05). Treatment significantly decreased ERalpha p-Ser(118) and upregulated ER-beta1, independently of response. No or negligible overexpression of EGFR was observed at baseline or after treatment in this population. Preoperative letrozole and GnRH analogue are effective in premenopausal women. A biological response in terms of downregulation of phosphorylated ERalpha was observed in all patients. Future investigations might focus on treatments of longer duration. PMID- 17712313 TI - Treatment with imatinib improves drug delivery and efficacy in NSCLC xenografts. AB - Imatinib, an inhibitor of PDGF-Rbeta and other tyrosine kinase receptors, has been shown to decrease microvessel density and interstitial fluid pressure in solid tumours, thereby improving subsequent delivery of small molecules. The purpose of this study was to test whether pretreatment with imatinib increases the efficacy of traditional chemotherapy in mice bearing non-small cell lung carcinoma xenografts, and to investigate the effects of imatinib on liposomal drug delivery. Efficacy treatment groups included (n=9-10): saline control, imatinib alone (oral gavage, 100 mg kg(-1) x 7 days), docetaxel alone (10 mg kg( 1) i.p. 2 x /week until killing), and imatinib plus docetaxel (started on day 7 of imatinib). Tumours were monitored until they reached four times the initial treatment volume (4 x V) or 28 days. A separate experiment compared tumour doxorubicin concentrations (using high performance liquid chromatography) 24 h after treatment with liposomal doxorubicin alone (6 mg kg(-1) i.v., n=9) or imatinib plus liposomal doxorubicin (n=16). Imatinib plus docetaxel resulted in significantly improved antitumour efficacy (0/10 animals reached 4 x V by 28 days) when compared to docetaxel alone (3/9 reached 4 x V, P=0.014) or imatinib alone (9/10 reached 4 x V, P=0.025). Pretreatment with imatinib also significantly increased tumour concentrations of liposomal doxorubicin. Overall, these preclinical studies emphasise the potential of imatinib as an adjunct to small molecule or liposomal chemotherapy. PMID- 17712315 TI - mGluR7 facilitates extinction of aversive memories and controls amygdala plasticity. AB - Formation and extinction of aversive memories in the mammalian brain are insufficiently understood at the cellular and molecular levels. Using the novel metabotropic glutamate receptor 7 (mGluR7) agonist AMN082, we demonstrate that mGluR7 activation facilitates the extinction of aversive memories in two different amygdala-dependent tasks. Conversely, mGluR7 knockdown using short interfering RNA attenuated the extinction of learned aversion. mGluR7 activation also blocked the acquisition of Pavlovian fear learning and its electrophysiological correlate long-term potentiation in the amygdala. The finding that mGluR7 critically regulates extinction, in addition to acquisition of aversive memories, demonstrates that this receptor may be relevant for the manifestation and treatment of anxiety disorders. PMID- 17712314 TI - Genome-wide gene expression profiling suggests distinct radiation susceptibilities in sporadic and post-Chernobyl papillary thyroid cancers. AB - Papillary thyroid cancers (PTCs) incidence dramatically increased in the vicinity of Chernobyl. The cancer-initiating role of radiation elsewhere is debated. Therefore, we searched for a signature distinguishing radio-induced from sporadic cancers. Using microarrays, we compared the expression profiles of PTCs from the Chernobyl Tissue Bank (CTB, n=12) and from French patients with no history of exposure to ionising radiations (n=14). We also compared the transcriptional responses of human lymphocytes to the presumed aetiological agents initiating these tumours, gamma-radiation and H(2)O(2). On a global scale, the transcriptomes of CTB and French tumours are indistinguishable, and the transcriptional responses to gamma-radiation and H(2)O(2) are similar. On a finer scale, a 118 genes signature discriminated the gamma-radiation and H(2)O(2) responses. This signature could be used to classify the tumours as CTB or French with an error of 15-27%. Similar results were obtained with an independent signature of 13 genes involved in homologous recombination. Although sporadic and radio-induced PTCs represent the same disease, they are distinguishable with molecular signatures reflecting specific responses to gamma-radiation and H(2)O(2). These signatures in PTCs could reflect the susceptibility profiles of the patients, suggesting the feasibility of a radiation susceptibility test. PMID- 17712316 TI - Beta-amyloid expression, release and extracellular deposition in aged rat brain slices. AB - Alzheimer's disease (AD) is characterized by beta-amyloid plaques, tau pathology, cholinergic cell death and inflammation. The aim of this study was to investigate whether beta-amyloid is generated, released and extracellularly deposited in organotypic brain slices. In developing slices, no amyloid-precursor protein (APP) was detectable; however, there was a strong upregulation in aging slices. In such slices, rat beta-amyloid(1-42) and -(1-40) peptides were found using four sequence-specific antibodies. APP and beta-amyloid were expressed in neurons and to a lesser extent in astrocytes. Beta-amyloid was secreted into the medium. Beta amyloid was located extracellularly when aging slices were incubated with medium at pH 6.0 including apolipoprotein E4 (ApoE4). It is concluded that aging organotypic brain slices express beta-amyloid and that acidosis induces cell death with efflux of beta-amyloid and extracellular depositions, which is triggered by ApoE4. This novel in vitro model may enable us to investigate further the pathological cascade for AD and may be useful to explore future therapeutics. PMID- 17712317 TI - Do patients with ACS aged 90 years or older receive the same standard of care as younger patients? PMID- 17712318 TI - Does remote monitoring improve outcome in patients with chronic heart failure? PMID- 17712319 TI - Body mass index as a risk factor for incident hypertension. PMID- 17712320 TI - Type 1 iodothyronine deiodinase is the major source of circulating T3 in hyperthyroidism: implications for therapy. PMID- 17712321 TI - Does androgen suppression plus radiation therapy lead to changes in penile length in prostate cancer patients? PMID- 17712322 TI - Can response to TACE predict survival after liver transplantation in patients with hepatocellular carcinoma? PMID- 17712323 TI - How safe is intravenous sedation with midazolam and fentanyl for pediatric gastrointestinal endoscopy? PMID- 17712324 TI - Does emergency colectomy reduce mortality in patients with Clostridium difficile associated disease? PMID- 17712325 TI - Risk of serious bacterial infection: treatment with anti-TNF versus methotrexate. PMID- 17712326 TI - Diffusion tensor MRI for the differentiation of Parkinson's disease and multiple system atrophy. PMID- 17712327 TI - Clinical assessment of progressive supranuclear palsy over time: new rating scale validated. PMID- 17712328 TI - Cyclophosphamide plus steroids for membranous nephropathy with nephrotic syndrome: long-term outcomes. PMID- 17712329 TI - How high is the risk of ANCA-associated vasculitis recurring after renal transplantation? PMID- 17712330 TI - Safe selection of genetically manipulated human primary keratinocytes with very high growth potential using CD24. AB - Stable and safe corrective gene transfer in stem keratinocytes is necessary for ensuring success in cutaneous gene therapy. There have been numerous encouraging preclinical approaches to cutaneous gene therapy in the past decade, but it is only recently that a human volunteer suffering from junctional epidermolysis bullosa could be successfully grafted using his own non-selected, genetically corrected epidermal keratinocytes. However, ex vivo correction of cancer-prone genetic disorders necessitates a totally pure population of stably transduced stem keratinocytes for grafting. Antibiotic selection is not compatible with the need for full respect for natural cell fate potential and avoidance of immunogenic response in vivo. In order to surmount these problems, we developed a strategy for selecting genetically modified stem cell keratinocytes. Driving ectopic expression of CD24 (a marker of post-mitotic keratinocytes) at the surface of clonogenic keratinocytes permitted their full selection. Engineered keratinocytes expressing CD24 and the green fluorescent protein (GFP) tracer gene were shown to retain their original growth and differentiation potentials both in vitro and in vivo over 300 generations. Also, they did not exhibit signs of genetic instability. Using ectopic expression of CD24 as a selective marker of genetically modified human epidermal stem cells appears to be the first realistic approach to safe cutaneous gene therapy in cancer-prone disease conditions. PMID- 17712331 TI - An immunocompetent murine model for oncolysis with an armed and targeted measles virus. AB - An immunocompetent model is required to test therapeutic regimens for clinical trials with the oncolytic measles virus (MV). Toward developing this model, a retargeted MV that enters murine colon adenocarcinoma cells forming tumors in syngeneic C57BL/6 mice was generated. Since MV infection tends to be less efficient in murine than in human cells, the targeted virus was also armed with the prodrug convertase, purine nucleoside phosphorylase (PNP), and named MV-PNP antiCEA. We have shown before that in cultured cells, infection with this virus activated the prodrug, 6-methylpurine-2'-deoxyriboside (MeP-dR), causing extensive cytotoxicity. When injected intratumorally (IT), MV-PNP-antiCEA inhibited subcutaneous tumor growth marginally, but subsequent administration of the prodrug enhanced the oncolytic effect. Systemic delivery of MV-PNP-antiCEA alone had no substantial oncolytic effects, but in combination with the prodrug it was therapeutic, revealing synergistic effects between virus and prodrug. Immunosuppression with cyclophosphamide (CPA) retarded the appearance of MV neutralizing antibodies and enhanced oncolytic efficacy: survival was 100%, with 9 out of 10 animals going into complete remission. This immunocompetent murine model facilitates the testing of therapeutic regimens for clinical trials. PMID- 17712332 TI - Interactions between human plasma components and a xenogenic adenovirus vector: reduced immunogenicity during gene transfer. AB - By the time we are adolescents most of us have been in contact with several of the >50 human adenovirus (HAd) serotypes. These common subclinical infections lead to an efficient anti-adenovirus cross-reacting adaptive immunity. During gene therapy, the ubiquitous anti-adenovirus humoral response and complement activation will modify and dictate vector biodistribution, as well as the response to the virion and transgene(s). In this study, we assayed the interactions of a xenogenic adenovirus derived from canine serotype 2 (CAV-2) with naturally occurring human antibodies (Abs) and the complement system. In our cohort, we found class G immunoglobulins (Igs) that recognized the intact CAV-2 virion and the external virion proteins. However, the majority of donors had low or no neutralizing Abs, class A, or class M Igs. Purified anti-HAd serotype 5 Abs also recognized CAV-2 virion proteins. In addition, in spite of the presence of anti-CAV-2 IgGs, CAV-2 poorly activated the classical and alternative complement cascades. This atypical response was due to a block upstream of the component 3 (C3) convertase and interplay between the component 1 (C1) inhibitor, the C1q C1r2-C1s2 complex and CAV-2. Our data demonstrate that some xenogenic adenovirus vectors, like CAV-2, could lead to notably different outcomes following systemic delivery. PMID- 17712333 TI - Inhibition of enterovirus 71 in virus-infected mice by RNA interference. AB - Enterovirus 71 (EV71) is the main causative agent of hand, foot, and mouth disease (HFMD) in young children. It is often associated with neurological complications and has caused high mortality levels in recent outbreaks in the Asia Pacific region. Currently, there is no effective antiviral therapy against EV71 infections. In this study, we have evaluated and compared the efficacies of three different forms of small interfering RNAs (siRNAs) in inhibiting EV71 replication in a murine model. We have shown that both synthetic 19-mer siRNAs and plasmid-borne short hairpin RNAs (shRNAs) targeted at the conserved 3D(pol) region were able to inhibit EV71 infections in suckling mice when delivered with or without lipid carrier via the systemic route. The treated mice did not exhibit hind limb paralysis and weight loss, as was observed in untreated mice. EV71 replication was significantly reduced as revealed by real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blot. In addition, no evidence of interferon (IFN) induction was detected in the intestinal tissues harvested from the mice as a result of siRNA administration. However, the chemically synthesized 29-mer shRNA did not protect the suckling mice from EV71 infections despite being more potent in the in vitro system. Our results indicate that RNA interference (RNAi) may be a promising therapeutic approach for fighting EV71 infections. PMID- 17712334 TI - Intracellular trafficking of a fiber-modified adenovirus using lipid raft/caveolae endocytosis. AB - Most adenoviral vectors (HAdvs) elaborated for gene therapy are derived from serotype 5 viruses that use clathrin-coated vesicle endocytosis for cell entry. However, it appears that adenoviral vectors are able to take advantage of lipid raft/caveolae endocytosis to infect cells. In vivo targeting of a therapeutic gene to specific cells by vector engineering has become a major focus of gene therapy research. Yet, modification of adenoviral tropism, especially fiber gene engineering, can induce deficient intracellular trafficking of the viral particle, with a shift in subcellular localization resulting in extensive exocytosis. In this study we demonstrate that uptake of a fiber-modified adenovirus using lipid raft/caveolae endocytosis leads to non-altered intracellular trafficking without endosomal retention. Moreover, activation of lipid raft structures by this vector leads to the formation of "mega-caveosomes". These results demonstrate that, by forcing adenoviruses to take advantage of a non-clathrin, non-classical endocytic pathway, it is possible to compensate for the deficiency in endosomolysis that is associated with the use of some of the fiber-modified adenoviral constructs. Moreover, it renders such vectors ideal candidates for infecting human coxsackie and adenoviruses receptor (hCAR) negative cells. PMID- 17712335 TI - Promoting peace through science. PMID- 17712336 TI - TSLP-mediated fetal B lymphopoiesis? PMID- 17712338 TI - Probing the 'labyrinth' linking the innate and adaptive immune systems. PMID- 17712339 TI - T(H)-17 differentiation: of mice and men. PMID- 17712340 TI - Regula'ten' the gut. PMID- 17712341 TI - Cytoplasmic double-stranded DNA sensor. PMID- 17712342 TI - Holding antigen where B cells can find it. PMID- 17712344 TI - Multiple sclerosis: a complicated picture of autoimmunity. AB - Understanding of autoimmune diseases, including multiple sclerosis, has expanded considerably in recent years. New insights have been provided by not only animal models but also studies of patients, often in conjunction with experimental therapies. It is accepted that autoimmune T cells mediate the early steps of new multiple sclerosis lesions, and although uncertainties remain about the specific targets of autoreactive T cells, several studies indicate myelin antigens. Recent findings obtained with both animal models and patients with multiple sclerosis indicate involvement of a T helper cell with a T(H)-17 phenotype, in contrast to previous data indicating that T helper type 1 cells are critical. Evidence has also been presented for CD8(+) and regulatory T cell populations, although their involvement remains to be established. Despite evidence supporting the idea that autoreactive T cells are involved in disease induction, cells of myeloid lineage, antibodies and complement as well as processes intrinsic to the central nervous system seem to determine the effector stages of tissue damage. Careful analysis of the alterations in immune processes should further advance knowledge of the relationship between the inflammatory component of this disease and the more diffuse degeneration of progressive multiple sclerosis. PMID- 17712346 TI - Facilitated acquisition but not persistence of responding for a cocaine-paired conditioned reinforcer following sensitization with cocaine. AB - Sensitization has been hypothesized to increase the incentive salience of drug paired conditioned stimuli and in the present study the ability of a sensitizing pretreatment with cocaine to increase responding for a drug-paired conditioned reinforcer was tested. In support of the incentive-sensitization hypothesis, sensitized rats earned more presentations of a drug-paired conditioned reinforcer during acquisition of a new response for this stimulus. By comparison, sensitization had no effect on the number of CSs earned during reversal of the contingency or following pretreatment with d-amphetamine. During reversal learning, however, sensitized rats were impaired in the extinction of the inappropriate response once the contingent CS was no longer available following presses on that lever. The results are discussed with reference to a possible role of increased incentive salience of a drug-paired CS to the formation of a habit. PMID- 17712347 TI - Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers. AB - Atypical antipsychotics have been linked to a higher risk for glucose intolerance, and consequentially the development of type 2 diabetes mellitus (DM2). We have therefore set out to investigate the acute effects of oral administration of olanzapine and ziprasidone on whole body insulin sensitivity in healthy subjects. Using the standardized hyperinsulinemic euglycemic clamp technique we compared whole body insulin sensitivity of 29 healthy male volunteers after oral intake of either olanzapine 10 mg/day (n = 14) or ziprasidone 80 mg/day (n = 15) for 10 days. A significant decrease (p<0.001) in whole body insulin sensitivity from 5.7 ml/h/kg ( = mean, SM = 0.4 ml/h/kg) at baseline to 4.7 ml/h/kg ( = mean, SM = 0.3 ml/h/kg) after oral intake of olanzapine (10 mg/day) for 10 days was observed. The ziprasidone (80 mg/day) group did not show any significant difference (5.2+/-0.3 ml/h/kg baseline vs 5.1+/-0.3 ml/h/kg) after 10 days of oral intake. Our main finding demonstrates that oral administration of olanzapine but not ziprasidone leads to a decrease in whole body insulin sensitivity in response to a hyperinsulinemic euglycemic challenge. Our finding is suggestive that not all atypical antipsychotics cause acute direct effects on glucose disposal and that accurate determination of side effect profile should be performed when choosing an atypical antipsychotic. PMID- 17712345 TI - Regulatory mechanisms of fear extinction and depression-like behavior. AB - Human anxiety is frequently accompanied by depression, and when they co-occur both conditions exhibit greater severity and resistance to treatment. Little is known, however, about the molecular processes linking these emotional and mood disorders. Based on previously reported phosphorylation patterns of extracellular signal-regulated kinase (ERK) in the brain, we hypothesized that ERK's upstream activators intertwine fear and mood regulation through their hippocampal actions. We tested this hypothesis by studying the upstream regulation of ERK signaling in behavioral models of fear and depression. Wild-type and ERK1-deficient mice were used to study the dorsohippocampal actions of the putative ERK activators: mitogen-activated and extracellular signal-regulated kinase (MEK), protein kinase C (PKC), and cAMP-dependent protein kinase (PKA). Mice lacking ERK1 exhibited enhanced fear extinction and reduced depression caused by overactivation of ERK2. Both behaviors were reversed by inhibition of MEK, however the extinction phenotype depended on hippocampal, whereas the depression phenotype predominantly involved extrahippocampal MEK. Unexpectedly, inhibition of PKC accelerated extinction and decreased depression by ERK-independent mechanisms, whereas inhibition of PKA did not produce detectable molecular or behavioral effects in the employed paradigm. These results indicate that, contrary to fear conditioning but similar to mood stabilization, extinction of fear required upregulation of MEK/ERK and downregulation of ERK-independent PKC signaling. The dissociation of these pathways may thus represent a common mechanism for fear and mood regulation, and a potential therapeutic option for comorbid anxiety and depression. PMID- 17712348 TI - Mapping callosal morphology in early- and late-onset elderly depression: an index of distinct changes in cortical connectivity. AB - There is some evidence of corpus callosum abnormalities in elderly depression, but it is not known whether these deficits are region-specific or differ based on age at onset of depression. Twenty-four patients with early-onset depression (mean age = 68.00, SD+/-5.83), 22 patients with late-onset depression (mean age = 74.50, SD+/-8.09) and 34 elderly control subjects (mean age = 72.38; SD+/-6.93) were studied. Using 3D MRI data, novel mesh-based geometrical modeling methods were applied to compare the midsagittal thickness of the corpus callosum at high spatial resolution between groups. Neuropsychological correlates of midsagittal callosal area differences were additionally investigated in a subsample of subjects. Depressed patients exhibited significant callosal thinning in the genu and splenium compared to controls. Significant callosal thinning was restricted to the genu in early-onset patients, but patients with late-onset depression exhibited significant callosal thinning in both the genu and splenium relative to controls. The splenium of the corpus callosum was also significantly thinner in subjects with late- vs early-onset depression. Genu and splenium midsagittal areas significantly correlated with memory and attention functioning among late onset depressed patients, but not early-onset depressed patients or controls. Circumscribed structural alterations in callosal morphology may distinguish late- from early-onset depression in the elderly. These findings suggest distinct abnormalities of cortical connectivity in late- and early-onset elderly depression with possible influence on the course of illness. Patients with a late onset of depression may be at higher risk of illness progression and eventually dementia conversion than early-onset depression, with potentially important implications for research and therapy. PMID- 17712349 TI - Early auditory sensory processing deficits in mouse mutants with reduced NMDA receptor function. AB - Cognitive deficits in schizophrenia include impairments at automatic, preattentive stages of sensory information processing. These deficits are evident in the prepulse inhibition- (PPI) and habituation of the auditory startle response paradigm, the paired tone paradigm in the EEG, and the peak recovery function of auditory evoked potentials (AEP). Administration of NMDA receptor antagonists reliably disrupts PPI and habituation of the startle, but not gating of AEPs in rodents. In the peak recovery paradigm, patients with schizophrenia and primates treated with NMDA receptor antagonists show reduced maximal response at long interstimulus intervals (ISI), but normal responses at short ISIs. Thus reduced NMDA receptor signalling may underlie alterations in these paradigms observed in schizophrenia. We tested the paradigms mentioned in mouse mutants with reduced expression of the NR1 subunit of the NMDA receptor (N = 15) and their wild-type littermates (N = 16). The NR1 mutant mice showed impaired habituation and PPI of the auditory startle response, as well as impaired gating in the paired tone paradigm. Deficits between the two gating measures did not correlate, corroborating previous evidence that these paradigms measure distinct processes. In the peak recovery paradigm, the NR1 mutants showed increased responses of the AEPs P1 and N1 at short ISIs but no difference between groups were observed at long ISIs. In conclusion, the NR1 hypomorphic mice modelled sensory and sensorimotor gating and startle habituation deficits observed in schizophrenia, but failed to model alterations in the peak recovery function. PMID- 17712350 TI - Modafinil: a review of neurochemical actions and effects on cognition. AB - Modafinil (2-[(Diphenylmethyl) sulfinyl] acetamide, Provigil) is an FDA-approved medication with wake-promoting properties. Pre-clinical studies of modafinil suggest a complex profile of neurochemical and behavioral effects, distinct from those of amphetamine. In addition, modafinil shows initial promise for a variety of off-label indications in psychiatry, including treatment-resistant depression, attention-deficit/hyperactivity disorder, and schizophrenia. Cognitive dysfunction may be a particularly important emerging treatment target for modafinil, across these and other neuropsychiatric disorders. We aimed to comprehensively review the empirical literature on neurochemical actions of modafinil, and effects on cognition in animal models, healthy adult humans, and clinical populations. We searched PubMed with the search term 'modafinil' and reviewed all English-language articles for neurochemical, neurophysiological, cognitive, or information-processing experimental measures. We additionally summarized the pharmacokinetic profile of modafinil and clinical efficacy in psychiatric patients. Modafinil exhibits robust effects on catecholamines, serotonin, glutamate, gamma amino-butyric acid, orexin, and histamine systems in the brain. Many of these effects may be secondary to catecholamine effects, with some selectivity for cortical over subcortical sites of action. In addition, modafinil (at well-tolerated doses) improves function in several cognitive domains, including working memory and episodic memory, and other processes dependent on prefrontal cortex and cognitive control. These effects are observed in rodents, healthy adults, and across several psychiatric disorders. Furthermore, modafinil appears to be well-tolerated, with a low rate of adverse events and a low liability to abuse. Modafinil has a number of neurochemical actions in the brain, which may be related to primary effects on catecholaminergic systems. These effects are in general advantageous for cognitive processes. Overall, modafinil is an excellent candidate agent for remediation of cognitive dysfunction in neuropsychiatric disorders. PMID- 17712351 TI - Females do not express learned helplessness like males do. AB - Women are more likely than men to suffer from stress-related mental disorders, such as depression. In the present experiments, we identified sex differences in one of the most common animal models of depression, that of learned helplessness. Male and female rats were trained to escape a mild footshock each day for 7 days (controllable stress). Each rat was yoked to another rat that could not escape (uncontrollable stress), but was exposed to the same amount of shock. One day later, all stressed rats and unstressed controls were tested on a more difficult escape task in a different context. Most males exposed to uncontrollable stress did not learn to escape and were therefore helpless. In contrast, most females did learn to escape on the more difficult escape task, irrespective of whether they had been exposed to controllable or uncontrollable stress. The sex differences in helplessness behavior were not dependent on the presence of sex hormones in adulthood, because neither ovariectomy of females nor castration of males abolished them. The absence of helplessness in females was neither dependent on organizational effects of testosterone during the day of birth, because masculinized females did not express helplessness as adults. Thus, sex differences in helplessness behavior are independent of gonadal hormones in adulthood and testosterone exposure during perinatal development. Learned helplessness may not constitute a valid model for depressive behavior in women, at least as reflected by the response of female rats to operant conditioning procedures after stressful experience. PMID- 17712352 TI - Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder. AB - LY354740, a potent and selective mGlu (metabotropic glutamate receptor)2/3 agonist, has shown efficacy in the treatment of generalized anxiety disorder (GAD). LY544344 is a LY354740 prodrug that increases LY354740 bioavailability. This 8-week study was designed to evaluate the efficacy, safety, and tolerability of LY544344 in the treatment of GAD. Participants had a diagnoses of GAD, baseline Hospital Anxiety and Depression Scale anxiety subscale scores > or = 10, and moderate illness severity. Patients were randomized to double-blind treatment with LY544344 16 mg b.i.d. (n = 28), LY544344 8 mg b.i.d. (n = 36), or placebo (n = 44). LY544344 16 mg b.i.d.-treated patients showed significantly greater improvement from baseline in Hamilton Anxiety and Clinical Global Impression Improvement scores, as well as response and remission rates compared with placebo treated patients. LY544344 was well tolerated and there were no significant differences in the incidence of treatment-emergent adverse events among the three treatment groups. However, the trial was discontinued early based on findings of convulsions in preclinical studies. In conclusion, the findings of this study support the potential efficacy of mGlu2/3 receptor agonist agents in the treatment of GAD. Additional studies will be needed to further assess the toxicological and clinical profile of LY354740/LY544344. PMID- 17712353 TI - Differential effects of nucleus accumbens core, shell, or dorsal striatal inactivations on the persistence, reacquisition, or reinstatement of responding for a drug-paired conditioned reinforcer. AB - Drug-paired conditioned reinforcers can maintain persistent instrumental responding, thus providing a model of some aspects of long-term drug addiction. The purpose of the present study was to investigate the effects of inactivating the dorsal striatum (DStr), nucleus accumbens (NAcc) core, or NAcc shell on different types of responding, each maintained by drug-paired conditioned reinforcers. Inactivations were achieved by infusing a combination of baclofen and muscimol prior to (1) persistent responding for a drug-paired conditioned reinforcer, (2) reacquisition of this instrumental response after extinction by omission of the contingent conditioned stimulus (CS), or (3) CS (cue)-induced reinstatement of the original (and different) instrumental response that had previously delivered cocaine. Inactivation of the DStr attenuated persistent responding for a cocaine-paired conditioned reinforcer, as well as its reacquisition after extinction of this response, while the only effect of inactivation of the NAcc shell was to increase CS (cue)-induced reinstatement of the extinguished instrumental response that had previously delivered cocaine. Inactivation of the NAcc core affected all measures of responding maintained by drug-paired conditioned reinforcers. These results are discussed with reference to the neural systems involved in different aspects of responding maintained by drug-paired conditioned reinforcers. PMID- 17712355 TI - Attitudes regarding carrier testing in incompetent children: a survey of European clinical geneticists. AB - The aim of this study is to gather information from European clinical geneticists about their practices and attitudes with regard to carrier testing in incompetent children. European clinical institutes where genetic counseling is offered to patients have been contacted. One hundred and seventy-seven of the 287 eligible respondents, corresponding to a response rate of 63%, completed the questionnaire. For all autosomal recessive and X-linked disorders studied, the majority of the respondents were very unwilling or unwilling to provide a carrier test to a 6-year-old asymptomatic child on parental request (range 73-91%). The results of the Wilcoxon-Mann-Whitney U test indicated that for almost all disorders, respondents from Eastern and Southern European countries are more willing to provide a carrier test to a 6-year-old asymptomatic child than respondents from Western and Northern European countries. The Spearman's rank correlation coefficients showed that when a clinical geneticist was unwilling to perform such a test, he/she mostly disagreed that parental uncertainty and anxiety was a good reason to perform a carrier test, he/she mostly disagreed that parents should have the right to decide about such a test, he/she mostly agreed that future autonomy and the confidentiality of genetic information is violated if this test is performed. Overall, the survey showed an adherence to existing recommendations and guidelines regarding carrier testing in incompetent minors. However, for every condition studied, a group of clinical geneticists was willing or very willing to provide a carrier test to a 6-year-old child on parental request. PMID- 17712354 TI - Delineation of large deletions of the MECP2 gene in Rett syndrome patients, including a familial case with a male proband. AB - Comprehensive genetic screening programs have led to the identification of pathogenic methyl-CpG-binding protein 2 (MECP2) mutations in up to 95% of classical Rett syndrome (RTT) patients. This high rate of mutation detection can partly be attributed to specialised techniques that have enabled the detection of large deletions in a substantial fraction of otherwise mutation-negative patients. These cases would normally be missed by the routine PCR-based screening strategies. Here, we have identified large multi-exonic deletions in 12/149 apparently mutation-negative RTT patients using multiplex ligation-dependent probe amplification (MLPA). These deletions were subsequently characterised using real-time quantitative PCR (qPCR) and long-range PCR with the ultimate aim of defining the exact nucleotide positions of the breakpoints and rearrangements. We detected an apparent deletion in one further patient using MLPA; however, this finding was contradicted by subsequent qPCR and long-range PCR results. The patient group includes an affected brother and sister with a large MECP2 deletion also present in their carrier mother. The X chromosome inactivation pattern of all female patients in this study was determined, which, coupled with detailed clinical information, allowed meaningful genotype-phenotype correlations to be drawn. This study reaffirms the view that large MECP2 deletions are an important cause of both classical and atypical RTT syndrome, and cautions that apparent deletions detected using high-throughput diagnostic techniques require further characterisation. PMID- 17712356 TI - New genetic evidence supports isolation and drift in the Ladin communities of the South Tyrolean Alps but not an ancient origin in the Middle East. AB - The Alps are one of the most significant geographical barriers in Europe and several isolated Swiss and Italian valleys retain the distinctive Ladin and Romansch languages, alongside the modern majority of Italian and German languages. Linguistically, Ladin belongs to the Romance languages, but some studies on mitochondrial DNA (mtDNA) variation have suggested a major Middle Eastern component to their genealogical origin. Furthermore, an observed high degree of within-population diversity has been interpreted as reflecting long standing differentiation from other European populations and the absence of a major bottleneck in Ladin population history. To explore these issues further, we examined Y chromosome and mtDNA variation in two samples of Ladin speakers, two samples of German speakers and one sample of metropolitan Italian speakers. Our results (1) indicate reduced diversity in the Ladin-speaking and isolated German speaking populations when compared to a sample of metropolitan Italian speakers, (2) fail to identify haplotypes that are rare in other European populations that other researchers have identified, and (3) indicate different Middle Eastern components to Ladin ancestry in different localities. These new results, in combination with Bayesian estimation of demographic parameters of interest (population size, population growth rate, and Palaeolithic/Neolithic admixture proportions) and phylogeographic analysis, suggest that the Ladin groups under study are small genetically isolated populations (subject to strong genetic drift), having a predominantly European ancestry, and in one locality, may have a greater Palaeolithic component to that ancestry than their neighbours. PMID- 17712357 TI - AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. AB - The SNF1/AMP-activated protein kinase (AMPK) family maintains the balance between ATP production and consumption in all eukaryotic cells. The kinases are heterotrimers that comprise a catalytic subunit and regulatory subunits that sense cellular energy levels. When energy status is compromised, the system activates catabolic pathways and switches off protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. Surprisingly, recent results indicate that the AMPK system is also important in functions that go beyond the regulation of energy homeostasis, such as the maintenance of cell polarity in epithelial cells. PMID- 17712358 TI - Autophagy: from phenomenology to molecular understanding in less than a decade. AB - In 2000, it was suggested to me that "Autophagy will be the wave of the future; it will become the new apoptosis." Few people would have agreed at the time, but this statement turned out to be prophetic, and this process of 'self-eating' rapidly exploded as a research field, as scientists discovered connections to cancer, neurodegeneration and even lifespan extension. Amazingly, the molecular breakthroughs in autophagy have taken place during only the past decade. PMID- 17712359 TI - Nucleophosmin mutations in acute myeloid leukemia in children. PMID- 17712361 TI - Obesity cardiomyopathy: diagnosis and therapeutic implications. AB - Obesity is associated with an increased risk of heart failure. Apparently healthy obese individuals can, however, exhibit subclinical left ventricular dysfunction. The use of myocardial imaging techniques to detect this subclinical change could have important management implications with respect to initiating prophylactic therapy. In this Review, we evaluate possible pharmacologic and nonpharmacologic strategies for treating obesity cardiomyopathy in the context of currently understood mechanisms, including myocardial remodeling and small vessel disease, and more speculative mechanisms such as insulin resistance, and activation of the renin-angiotensin-aldosterone and sympathetic nervous systems. PMID- 17712362 TI - Antiangiogenic therapy for normalization of atherosclerotic plaque vasculature: a potential strategy for plaque stabilization. AB - Angiogenesis within human atherosclerotic plaques has an important role in plaque progression as immature blood vessels leak red blood cells and inflammatory mediators into the plaque center. Accumulation of free cholesterol from red blood cell membranes potentially increases the size of the necrotic core and triggers a chain of events that promote plaque destabilization. Antiangiogenic agents have been shown to prune some tumor vessels and 'normalize' the structure and function of the remaining vasculature, thereby improving the access of chemotherapeutic agents to tumors. We propose that antiangiogenic therapy can similarly stabilize vulnerable 'rupture-prone' plaques by pruning and normalizing immature intraplaque vessels, preventing further intraplaque hemorrhage. This normalization would limit necrotic core enlargement, further luminal narrowing and the degree of inflammation. Such normalization has been realized using vascular endothelial growth factor antagonists for the treatment of cancer and age-related macular degeneration. The development of this novel approach to prevent plaque progression might add to the armamentarium of preventive measures for acute myocardial infarction, stroke and sudden cardiac death. PMID- 17712363 TI - Surgery insight: Septal myectomy for obstructive hypertrophic cardiomyopathy--the Mayo Clinic experience. AB - Septal myectomy has been the gold standard treatment for the relief left ventricular outflow tract obstruction and cardiac symptoms in both adults and children with obstructive hypertrophic cardiomyopathy. In almost all circumstances, abnormalities of the mitral valve and subvalvar mitral apparatus can be managed without the need for mitral valve replacement, and other cardiac lesions can be repaired simultaneously. In the current era, the operative mortality for isolated septal myectomy at an experienced center is low in both children and adults (approximately 1%). Excellent late results with myectomy are gratifying: 90% of patients improve by at least one NYHA class, and improvements persist in most individuals on late follow-up. Late survival in patients with obstructive hypertrophic cardiomyopathy who undergo myectomy exceeds that of patients who do not receive surgical treatment and, in addition, myectomy may be associated with reduced long-term risk of sudden cardiac death. These results should serve as a basis for comparison with newer nonsurgical treatment regimens. PMID- 17712364 TI - The total absence of atrial automaticity in a child with sinus node dysfunction. AB - BACKGROUND: A routine sports evaluation identified constant alternation between a junctional and idioventricular rhythm in a 9-year-old child. During exercise testing, electrography demonstrated that the child was in junctional rhythm without any apparent P waves, and had a reduced increase in heart rate. Endocardial atrial pacing captured the atrium and demonstrated that atrioventricular conduction was normal, but the recovery time of the ectopic rhythm was very long. Three-dimensional electrophysiological mapping revealed 1:1 retrograde homogeneous conduction through the right atrium. INVESTIGATIONS: Electrocardiography, Holter monitoring, echocardiography, exercise stress testing, atrial pacing, three-dimensional electroanatomical mapping of the right atrium and genetic testing. DIAGNOSIS: Sinus node dysfunction. MANAGEMENT: Pacemaker implantation was postponed until a later stage in the patient's development. PMID- 17712365 TI - Degree of polarization as a criterion to obtain the nine bilinear constraints between the Mueller-Jones matrix elements. AB - The degree of polarization is employed as a criterion to find the nine independent relations among the elements of the Mueller-Jones matrix. This procedure is applied by considering a previously determined, physically realizable Mueller matrix. On the other hand, the nine bilinear constrains are obtained by directly measuring the degree of polarization from an outgoing beam of light from an optical system by considering nine incident states of light taken from the Poincare sphere. For practical purposes, all the incident polarization states must be scanned from the Poincare sphere in order to satisfy the over-polarization and the over-gain conditions, respectively, for the physical realizability of the Mueller matrix. PMID- 17712366 TI - Approach for reconstructing anisoplanatic adaptive optics images. AB - Atmospheric turbulence corrupts astronomical images formed by ground-based telescopes. Adaptive optics systems allow the effects of turbulence-induced aberrations to be reduced for a narrow field of view corresponding approximately to the isoplanatic angle theta(0). For field angles larger than theta(0), the point spread function (PSF) gradually degrades as the field angle increases. We present a technique to estimate the PSF of an adaptive optics telescope as function of the field angle, and use this information in a space-varying image reconstruction technique. Simulated anisoplanatic intensity images of a star field are reconstructed by means of a block-processing method using the predicted local PSF. Two methods for image recovery are used: matrix inversion with Tikhonov regularization, and the Lucy-Richardson algorithm. Image reconstruction results obtained using the space-varying predicted PSF are compared to space invariant deconvolution results obtained using the on-axis PSF. The anisoplanatic reconstruction technique using the predicted PSF provides a significant improvement of the mean squared error between the reconstructed image and the object compared to the deconvolution performed using the on-axis PSF. PMID- 17712367 TI - Self-mixing interference effects of microchip Nd:YAG laser with a wave plate in the external cavity. AB - We present the optical feedback characteristics of a single-mode Nd:YAG laser with a wave plate in the external cavity. The laser intensities of the two orthogonal directions, which are both modulated by the change of external cavity length, have a phase difference due to the birefringence effect of the wave plate. When threshold intensity is introduced, a period of intensity fringe can be divided into four equal zones. Each zone corresponds to lambda/8 displacement of the external feedback reflector. The direction of displacement can be discriminated by the sequence of these four zones. This phenomenon provides a potential displacement sensor with directional discrimination and high resolution of eighth wavelength compared with the traditional optical feedback. PMID- 17712368 TI - High-efficiency fast scintillators for "optical" soft x-ray arrays for laboratory plasma diagnostics. AB - Scintillator-based "optical" soft x-ray (OSXR) arrays have been investigated as a replacement for the conventional silicon (Si)-based diode arrays used for imaging, tomographic reconstruction, magnetohydrodynamics, transport, and turbulence studies in magnetically confined fusion plasma research. An experimental survey among several scintillator candidates was performed, measuring the relative and absolute conversion efficiencies of soft x rays to visible light. Further investigations took into account glass and fiber-optic face-plates (FOPs) as substrates, and a thin aluminum foil (150 nm) to reflect the visible light emitted by the scintillator back to the optical detector. Columnar (crystal growth) thallium-doped cesium iodide (CsI:Tl) deposited on an FOP, was found to be the best candidate for the previously mentioned plasma diagnostics. Its luminescence decay time of the order of approximately 1-10 micros is thus suitable for the 10 micros time resolution required for the development of scintillator-based SXR plasma diagnostics. A prototype eight channel OSXR array using CsI:Tl was designed, built, and compared to an absolute extreme ultraviolet diode counterpart: its operation on the National Spherical Torus Experiment showed a lower level of induced noise relative to the Si-based diode arrays, especially during neutral beam injection heated plasma discharges. The OSXR concept can also be implemented in less harsh environments for basic spectroscopic laboratory plasma diagnostics. PMID- 17712369 TI - Systematic design of an anastigmatic lens axicon. AB - We present an analytical method for systematic optical design of a double-pass axicon that shows almost no astigmatism in oblique illumination compared to a conventional linear axicon. The anastigmatic axicon is a singlet lens with nearly concentric spherical surfaces applied in double pass, making it possible to form a long narrow focal line of uniform width. The front and the back surfaces have reflective coatings in the central and annular zones, respectively, to provide the double pass. Our design method finds the radii of curvatures and axial thickness of the lens for a given angle between the exiting rays and the optical axis. It also finds the optimal position of the reflecting zones for minimal vignetting. This method is based on ray tracing of the real rays at the marginal heights of the aperture and therefore is superior to any paraxial method. We illustrate the efficiency of the method by designing a test axicon with optical parameters used for a prototype axicon, which was manufactured and experimentally tested. We compare the optical characteristics of our test axicon with those of the experimental prototype. PMID- 17712370 TI - Dispersion relations for testing the validity of linear and nonlinear optical spectra. AB - We exploit efficient dispersion relations, which were developed for terahertz spectroscopy, to show their validity for testing linear and nonlinear optical spectra. As an example, we deal with the measured data for complex reflectivity of a KCl crystal and complex nonlinear susceptibility of a polysilane. It is suggested that the spectral data presented in the literature both for the KCl and the polysilane are consistent with the presented spectra analysis method. PMID- 17712371 TI - Optical characterization of hybrid antireflective coatings using spectrophotometric and ellipsometric measurements. AB - A hybrid antireflective coating combining homogeneous layers and linear gradient refractive index layers has been deposited using different techniques. The samples were analyzed optically based on spectrophotometric and spectroscopic ellipsometry measurements under different angles of incidence in order to precisely characterize the coatings. The Lorentz-Lorenz model has been used to calculate the refractive index of material mixtures in gradient and constant index layers of the coating. The obtained refractive index profiles have been compared with the targeted ones to detect errors in processes of deposition. PMID- 17712372 TI - Reflective diffractive beam splitter for laser interferometers. AB - The first realization of a reflective 50/50 beam splitter based on a dielectric diffraction grating suitable for high-power laser interferometers is reported. The beam splitter is designed to operate at a wavelength of 1064 nm and in s polarization. To minimize the performance degradation of the device that is due to fabrication fluctuations, during the design process special attention was paid to achieve high fabrication tolerances especially of groove width and depth. Applying this beam splitter to high-power laser interferometers, such as future gravitational wave detectors, will avoid critical thermal lensing effects and allow for the free choice of substrate materials. PMID- 17712373 TI - Estimation of the phase error in interferometric measurements by evaluation of the speckle field intensity. AB - Intensities recorded with CCD or CMOS sensors represent spatially averaged values of the intensity across the area of a pixel. In this work we investigate the influence of spatial averaging in interferograms on the evaluated phase from an object wave with well resolved, fully developed speckles. Based on an analytical description of the averaging process, a procedure is developed to create a quality map for the evaluated phase, in order to give an estimation of the expected error at each point. The proposed method uses only the local intensity distribution of the object wave for the qualification of the phase values. The theoretical results are tested and verified by means of numerically generated objective and subjective speckle fields. PMID- 17712374 TI - Adaptive aperture defocused digital speckle photography. AB - Speckle photography can be used to monitor deformations of solid surfaces. Its measuring characteristics, such as range or lateral resolution, depend heavily on the optical recording and illumination setup. I show how, by the addition of two suitably perforated masks, the effective optical aperture of the system may vary from point to point of the surface, accordingly adapting the range and resolution to local requirements. Furthermore, by illuminating narrow areas, speckle size can be chosen independently from the optical aperture, thus lifting an important constraint on the choice of the latter. The technique, which I believe to be new, is described within the framework of digital defocused speckle photography under normal collimated illumination. Mutually limiting relations between the range of measurement and the spatial frequency resolution turn up both locally and when the whole surface under study is considered. They are deduced and discussed in detail. Finally, experimental results are presented. PMID- 17712375 TI - Uneven fringe projection for efficient calibration in high-resolution 3D shape metrology. AB - A novel uneven fringe projection technique is presented whereby nonuniformly spaced fringes are generated at a digital video projector to give evenly spaced fringes in the measurement volume. The proposed technique simplifies the relation between the measured phase and the object's depth independent of pixel position. This method needs just one coefficient set for calibration and depth calculation. With uneven fringe projection the shape data are referenced to a virtual plane instead of a physical reference plane, so an improved measurement with lower uncertainty is achieved. Further, the method can be combined with a radial lens distortion model. The theoretical foundation of the method is presented and experimentally validated to demonstrate the advantages of the uneven fringe projection approach compared with existing methods. Measurement results on a National Physical Laboratory (UK) "step standard" confirm the measurement uncertainty using the proposed method. PMID- 17712376 TI - Spatial fringe pattern analysis using the two-dimensional continuous wavelet transform employing a cost function. AB - We present a novel ridge extraction algorithm for use with the two-dimensional continuous wavelet transform to extract the phase information from a fringe pattern. A cost function is employed for the detection of the ridge. The results of the proposed algorithm on simulated and real fringe patterns are illustrated. Moreover, the proposed algorithm outperforms the maximum ridge extraction algorithm and it is found to be robust and reliable. PMID- 17712377 TI - Optimization of doubly Q-switched lasers with both an acousto-optic modulator and a GaAs saturable absorber. AB - A doubly Q-switched laser with both an acousto-optic (AO) modulator and a GaAs saturable absorber can obtain a more symmetric and shorter pulse with high pulse peak power, which has been experimentally proved. The key parameters of an optimally coupled doubly Q-switched laser with both an AO modulator and a GaAs saturable absorber are determined, and a group of general curves are generated for what we believe is the first time, when the single-photon absorption (SPA) and two-photon absorption (TPA) processes of GaAs are combined, and the Gaussian spatial distributions of the intracavity photon density and the initial population-inversion density as well as the influence of the AO Q-switch are considered. These key parameters include the optimal normalized coupling parameter, the optimal normalized GaAs saturable absorber parameters, and the normalized parameters of the AO Q-switch, which can maximize the output energy. Meanwhile, the corresponding normalized energy, the normalized peak power, and the normalized pulse width are given. The curves clearly show the dependence of the optimal key parameters on the parameters of the gain medium, the GaAs saturable absorber, the AO Q-switch, and the resonator. Sample calculations for a diode-pumped Nd3+:YVO4 laser with both an AO modulator and a GaAs saturable absorber are presented to demonstrate the use of the curves and the relevant formulas. PMID- 17712378 TI - Shack-Hartmann sensor improvement using optical binning. AB - We present a design improvement for a recently proposed type of Shack-Hartmann wavefront sensor that uses a cylindrical (lenticular) lenslet array. The improved sensor design uses optical binning and requires significantly fewer detector pixels than the corresponding conventional or cylindrical Shack-Hartmann sensor, and so detector readout noise causes less signal degradation. Additionally, detector readout time is significantly reduced, which reduces the latency for closed loop systems and data processing requirements. We provide simple analytical noise considerations and Monte Carlo simulations, we show that the optically binned Shack-Hartmann sensor can offer better performance than the conventional counterpart in most practical situations, and our design is particularly suited for use with astronomical adaptive optics systems. PMID- 17712379 TI - Optical properties of micrometer size water droplets studied by cavity ringdown spectroscopy. AB - Optical extinction by homogeneous, pure water droplets of 30 to 70 microm diameter produced by a vibrating orifice aerosol generator has been studied by pulsed cavity ringdown (CRD) spectroscopy at lambda=560 nm under ambient conditions. Experimental sensitivity of better than 1% achieved in measurements of CRD times enabled detection of changes in laser light losses per pass due to changes in the number and size of particles within the laser beam volume. By systematically changing the droplet size in the cavity while recording the CRD time, a periodic modulation in the value of the loss per pass was observed. The modulation is caused by the oscillatory nature of the extinction efficiency, which was subsequently inferred and compared with the results of theoretical calculations based on Mie theory. PMID- 17712380 TI - Stimulated photorefractive backscatter leading to six-wave mixing and phase conjugation in iron-doped lithium niobate. AB - The generation of multiple waves during near-oblique incidence of a 532 nm weakly focused beam on photorefractive iron-doped lithium niobate in a typical reflection geometry configuration is studied. It is shown that these waves are produced through two-wave coupling (self-diffraction) and four-wave mixing (parametric diffraction). One of these waves, the stimulated photorefractive backscatter produced from parametric diffraction, contains the self-phase conjugate. The dynamics of six-wave mixing and its dependence on crystal parameters, angle of incidence, and pump power are analyzed. What we believe to be a novel order analysis of the interaction equations provides further insight into experimental observations in the steady state. The quality of the backscatter is evaluated through image restoration, interference experiments, and visibility measurement. Reduction of two-wave coupling may significantly improve the quality of the self-phase conjugate. PMID- 17712382 TI - Atmospheric electromagnetic pulse propagation effects from thick targets in a terawatt laser target chamber. AB - Generation and effects of atmospherically propagated electromagnetic pulses (EMPs) initiated by photoelectrons ejected by the high density and temperature target surface plasmas from multiterawatt laser pulses are analyzed. These laser radiation pulse interactions can significantly increase noise levels, thereby obscuring data (sometimes totally) and may even damage sensitive probe and detection instrumentation. Noise effects from high energy density (approximately multiterawatt) laser pulses (approximately 300-400 ps pulse widths) interacting with thick approximately 1 mm) metallic and dielectric solid targets and dielectric-metallic powder mixtures are interpreted as transient resonance radiation associated with surface charge fluctuations on the target chamber that functions as a radiating antenna. Effective solutions that minimize atmospheric EMP effects on internal and proximate electronic and electro-optical equipment external to the system based on systematic measurements using Moebius loop antennas, interpretations of signal periodicities, and dissipation indicators determining transient noise origin characteristics from target emissions are described. Analytic models for the effect of target chamber resonances and associated noise current and temperature in a probe diode laser are described. PMID- 17712381 TI - Millimeter- and submillimeter-wave characterization of various fabrics. AB - Transmission measurements of 14 fabrics are presented in the millimeter-wave and submillimeter-wave electromagnetic regions from 130 GHz to 1.2 THz. Three independent sources and experimental set-ups were used to obtain accurate results over a wide spectral range. Reflectivity, a useful parameter for imaging applications, was also measured for a subset of samples in the submillimeter-wave regime along with polarization sensitivity of the transmitted beam and transmission through doubled layers. All of the measurements were performed in free space. Details of these experimental set-ups along with their respective challenges are presented. PMID- 17712383 TI - Comparison between a model-based and a conventional pyramid sensor reconstructor. AB - A model of a non-modulated pyramid wavefront sensor (P-WFS) based on Fourier optics has been presented. Linearizations of the model represented as Jacobian matrices are used to improve the P-WFS phase estimates. It has been shown in simulations that a linear approximation of the P-WFS is sufficient in closed-loop adaptive optics. Also a method to compute model-based synthetic P-WFS command matrices is shown, and its performance is compared to the conventional calibration. It was observed that in poor visibility the new calibration is better than the conventional. PMID- 17712384 TI - Particle shape as revealed by spectral depolarization. AB - Through a series of numerical simulations we explore some scatter effects due to nonspherical particles. Specifically, we examine the link between the aspect ratio of randomly oriented, prolate spheroidal particles and the resulting linear depolarization of the scattered light in the forward and backscatter directions. The particular objective is to detect the presence of randomly oriented particles that have a systematic size and aspect ratio. Calculations show that the spectral behavior of the linear depolarization reveals the aspect ratio of the scattering particles. The concept is demonstrated using the size, shape, and refractive index of the spore form of Bacillus globigii (BG). PMID- 17712385 TI - Modeling biological fluorescence emission spectra using Lorentz line shapes and nonlinear optimization. AB - Using the Levenberg-Marquardt nonlinear optimization algorithm and a series of Lorentzian line shapes, the fluorescence emission spectra from BG (Bacillus globigii) bacteria can be accurately modeled. This method allows data from both laboratory and field sources to model the return signal from biological aerosols using a typical LIF (lidar induced fluorescence) system. The variables found through this procedure match individual fluorescence components within the biological material and therefore have a physically meaningful interpretation. The use of this method also removes the need to calculate phase angles needed in autoregressive all-pole models. PMID- 17712386 TI - Differential phase-contrast BioCD biosensor. AB - Common-path differential phase-contrast interferometry measures the spatial gradient of surface dipole density on a bio-optical compact disk (BioCD) and is sensitive to small changes in dipole density following molecular binding of target molecules out of solution. The recognition molecules are antibody IgG proteins that are deposited in periodic patterns on the BioCD using soft lithography or photolithography on the silanized silica surfaces of dielectric mirrors. Spatial carrier-wave sideband demodulation extracts the slowly varying protein envelope that modulates the protein carrier frequency. The experimental interferometric profilometry has surface height sensitivity down to 20 pm averaged over a lateral scale of 70 microm with a corresponding scaling mass sensitivity limit of 1.5 pg/mm. Under the conditions of an IgG immunoassay with background changes caused during incubation, the scaling mass sensitivity is approximately 7 pg/mm. A saturated reverse immunoassay performed with IgG at 100 ng/ml showed false positive and false negative rates of 0.2%. PMID- 17712387 TI - Study on the quality of interference fringes from a pulsed UV source for application in a biprism based fiber Bragg grating writing. AB - This paper presents a study on the quality of interference fringes formed from a pulsed UV (255 nm, 5.6 kHz, and 40 ns) source for an application in writing fiber Bragg gratings (FBGs). The interference fringes of separation of about 8 microm, formed by a biprism of apex angle 2 degrees , were studied for their contrast, evolution of contrast, and positional and intensity stability over a period of 5 min (over 10(6) pulses). Second harmonic UV (255 nm) sources of different spatial coherence and pointing stability characteristics were employed as the inputs. It is established that the UV fringes contrast and interference pattern stability with time is largely controlled by the optical resonator geometry of the fundamental wavelength (510 nm) copper vapor laser (CVL) oscillator. In particular, the generalized diffraction filtered resonator (GDFR) CVL produced the highest quality second harmonic beam with the highest fringes contrast and stability. The implications of these results were studied by employing these UV sources for the fabrication of the C-band FBGs by a 24 degrees apex angle biprism. PMID- 17712388 TI - Analysis of a spatially dispersive displacement sensor utilizing an AlGaInP chip. AB - We present a demonstration and analysis of an industrialized design of a spatially dispersive displacement sensor, which is composed of an AlGaInP gain chip in visible range, optical assembly, and a spectrum analyzer. The sensor utilizes the spatial dispersion of focus from the optical assembly and wavelength spectrum's deviation induced by the displacement of the target. As a result, the sensor delivers a quick and simple way of measuring displacement. By adapting the magnification and resolution of the optical assembly, a displacement sensor with a middle measurement range, ~10 microm, was obtained. However, we should note that 25 nm resolution is limited by the bandwidth and temperature fluctuation of the gain chip. PMID- 17712389 TI - [Solid pseudopapilar pancreatic tumors: report of 7 cases and review of the literature]. AB - INTRODUCTION: The cystic tumors of the pancreas represent an uncommon entity and the less frequent type among them is the solid pseudopapillary tumor of the pancreas. Its main difference lies in the fact that this type of tumor is more frequent in young patients. Solid pseudopapillary tumors are generally tumors of large size and the majority of them have a benign behavior. MATERIAL AND METHOD: During a period of three years, seven patients with this neoplasia underwent surgery. Six patients (86%) were females and just one was a male, all of them between the ages of 11 and 37. None of these cases showed metastasis and there were no signs of malignancy reported in the pathological anatomy. The average tumor size was 8 cm and the head of the pancreas was the most frequent location (57%). Of the resections performed in these patients, three were middle pancreatectomies, two were distal pancreatectomies one was a duodenopancreatectomy and one was duodenum preserving head resection of the pancreas. DISCUSSION: The solid pseudopapillary tumors are uncommon tumors which are generally benign or premalignant neoplasias. Nevertheless, 9% of them can behave like carcinomas; therefore, these tumors should not be ignored. PMID- 17712391 TI - [Clinical aspects in polyps of the colon]. AB - INTRODUCTION: The colonics polyps according to their number, size, location, age of presentation and mainly, according to their histology, have the potentiality of malignant degeneration, which makes of a continuous study and pursuit susceptible. OBJECTIVES: To evaluate the relation between the histologic type of the colon polyps, its location, the degree of dysplasia, the size, its possible commitment by carcinoma, the age, sex and the handling that has occurred them, in a series of 684 patients of the National Institute of Enfermedades Neoplasicas (INEN) between the 1 of January from 1974 to the 31 of March of the 2004. MATERIAL AND METHODS: The revision of clinical histories of 840 patients with the diagnosis of colon polyp was made who attended the service of Gastroenterology of the INEN between the 1 of January from 1974 to the 31 of March of 2004 and a card predesigned for each clinical history filled. The study is of observational, analytical type and of cross section. 1162 resecteds polyps evaluated themselves in this period. 156 patients by diagnosis related to cancer and familiar adenomatouspoliposis did not include themselves. The final sample was of 684 patients, in whom it was 1057 polyps. Other endoscopic findings were: internal hemorrhoids (172), colonic diverticulosis (50), anal fissure (4), and nonspecific ulcerative colitis (2). The statistical processing was made with program SPSS 12. For the qualitative variables the method of the Chi-square was used, for the quantitative variables analyzed the average, the rank and the variance. RESULTS: 1057 polyps extirpated, by means of the endoscopy polipectomy were 1016, with colectomy were 32 and with transanal resection without colectomy they 9. Within the histology of the 1057 polyps, 331 was briefed (31.3%) that were hyperplasic, 448 (42.4%) adenomas, 278 (26.3%) others and 35 (8.2%) adenocarcinomas on adenomas. The average age was of 50 years, was no significant difference with sex. The location but frequence of the adenomas was in the left colon (76.6%). Adenocarcinoma (carcinomas on adenomas), was present mainly in polyps villous type, with dysplasia severe and greater to 10 mm. Nevertheless, in smaller polyps of 5mm with dysplasia severe, was a polyp invaded by cancer, that represents the 0,8% of millimetric polyps. The made handling was mainly endoscopic, with 96% of the resected polyps this way, also slogan transanal resection and segmental colonic resection. The colectomy was necessary in 3% of all the made interventions, dysplasia severe or carcinoma was made in adenomatous polyps with, and in greater percentage in greater polyps of 20 mm (53%). The single polipectomy was sufficient in the level of invasion Haggitt 0. In patients with level of invasion Haggitt 1 and 2, the single polipectomy was the election treatment. On the other hand, in polyps with level of invasion Haggitt 3 and 4, the colectomy was the election treatment. One briefed two complications, one of perforation and peritonitis and another one of digestive hemorrhage loss (both: 0.29%), without mortality events. CONCLUSIONS: The Evaluation of colonic polyps in INEN is predominantly by endoscopy. The polyps are more frequent over the 50 years and have preferred location in the left colon. The carcinoma is more probable with severe dysplasia and greater size of the adenoma. All polyps, from the millimetric ones, including the hyperplasic, must be considered marks of neoplasia and extirpated in its totality. PMID- 17712392 TI - [Cytomegalovirus in ulcerative colitis in "Hospital Nacional 2 de Mayo"]. AB - The association between cytomegalovirus and ulcerative colitis has been reported by many authors, but the exact pathogenesis of this relationship remains unclear. We reviewed all ulcerative colitis cases whose diagnosis were made in Hospital dos de Mayo, during period 2000-2005, these cases were evaluated for Cytomegalovirus using inmunohistochemistry, also we described histological features of our cases. CMV was identified in 22.2% of all cases, none of them had been treated with inmunosuppressants previously, histological activity was reported in all positive cases and 42.8% negative cases for CMV; Crypt architectural abnormality was the most often histological finding, and the frequency of ulcerative colitis was 1.5 per year. Our findings are similar to those reported by foreign authors and is consistent with theory which maintains inflammatory changes of UC would help CMV's activation without using inmunosuppressants. PMID- 17712393 TI - [Microscopic colitis: pathogenesis]. AB - INTRODUCTION: Microscopic colitis (MC) is a chronic inflammatory process observed in colon biopsies of patients with chronic aqueous diarrhea. It is called microscopic because diagnosis is determined by histological studies since the microscopic characteristics of the colon endoscopy are normal. Two patterns exist: Lymphocytic Microscopic Colitis and Collagenous Microscopic Colitis. Etiology is unknown, and the proposed pathogenic mechanisms indicate an immunological phenomenon. Based on this, the authors of this study hypothesize that lymphocytic infiltration of the lamina propria could be related to cytotoxic lymphocytes CD8 as causative agents of colon tissue damage. OBJECTIVES: Prove hypothesis of immunological pathogenesis of MC. APPARATUS AND METHODS: Thirty eight (38) patients with diagnosed MC were recruited for the last four years in the Pathology Laboratory at Ricardo Palma University. Twenty two (22) colon biopsies with the most severe histological lesions were selected. These biopsies were obtained from 17 patients: 5 patients had 2 biopsies in 2 colonoscopy sessions. Biopsies were fixed in neutral formaldehyde, processed through the paraffin inclusion method, and stained with hematoxiline-eosine and Masson trichromic to distinguish collagenous tissue. Immunohistochemistry was conducted in 4- or 5-micron-thick histological sections processed through the immunoperoxidase method. RESULTS: Nineteen (19) biopsies corresponded to Lymphocytic MC and 3 to Collagenous MC. Lymphocytic MC showed intraepithelial lymphocytosis, dystrophic epithelial damage in the areas of lymphocytic infiltration, lamina propria inflammation with lymphocytes and plasma cells, and normal basement membrane. Collagenous MC showed thickened basement membrane due to the presence of a collagenous band, mild to moderate intraepithelial lymphocytosis, vacuolization,and frequent detachment of protective epithelium. Twenty two (22) biopsies were positive in the immunohistochemical studies. PMID- 17712394 TI - [Choledocolithiasis predictors in high-risk population subjected to endoscopic retrograde pancreatocholangiography at "Hospital Nacional Arzobispo Loayza"]. AB - INTRODUCTION: The choledocholithiasis is a frequent complication of gallstone disease. The endoscopic retrograde cholangiopancreatography (ERCP) is suitable for its diagnosis and treatment. That approach has both significative morbility and mortality so others methods of diagnosis have been proposed such as intraoperatorycholangiography (IOC) and magnetic resonance cholangiography (MRC), reserving ERCP only for therapy purpose. OBJECTIVES: Verify the utility of choledocholithiasis predictors described in literature MATERIAL AND METHODS: This study is a correlational observational transversal prospective approach. It was performed at the Arzobispo Loayza Hospital from August 2004 to January 2005. Many clinical, biochemical and ecographyc predictors of choledocholithiasis were analyzed in 151 patient underwent to ERCP. In all peopleunder study and analyzing separately patients underwent to cholecystectomy or not previous to ERCP, it was identified some risk factors for choledocholithiasis by means of both univariate and multivariate analysis. RESULTS: The univariate analysis showed a relationships among age, icterus, cholangytis, direct bilirrubin, amylase, lactic deshidrogenasa, ductal dilatation (>8 mm) and choledocholithiasis. In all groups, the multivariate analysis determined that ductal dilatation by ecography was the unique predictor for choledocholithiasis in the group of patients postoperated. CONCLUSIONS: None single indicator was able to predict with accuracy the choledocholithiasis. However, the parameters described in the literature are useful in our country. PMID- 17712395 TI - [Study of urease test or breath test (BT) and correlation with gastric biopsy to detect helicobacter pylori (Hp) in dyspeptic patients at "Hospital Nacional Cayetano Heredia hospital" (HNCH)--Lima]. AB - OBJECTIVE: To establish the utility of the IPEN ureasa test or breath test with C14, in the detection of Helicobacter pylori infection in dyspeptic patients at the HNCH. MATERIAL AND METHODS: 31 dyspeptic patients that attended the outpatient GI clinic during September 2004 were included. All of them had an upper endoscopy, gastric biopsies, and a Breath Test with C14, done at the IPEN (Peruvian Institute of Nuclear Energy). The diagnosis of HP infection was based on the histopathology report. RESULTS: Of the 31 Breath Test, one was a false negative and in 30 there was a good correlation with the biopsies results, 23 demonstrated the HP infection and in 7 this was not present. CONCLUSION: The IPEN Breath Test showed in this study a sensibility of 96.6% and a specificity of 100%, demonstrating that is a very useful diagnostic tool for HP infection. PMID- 17712396 TI - [Functional gastrointestinal diseases and Rome III]. AB - In 2006 have appeared the new criteria of the digestive functional diseases, In brief the Rome Criteria in tribute to the first conference of experts in Rome in 1998. The criteria were displayed in the DDW of Los Angeles and have been denominating criteria of Rome III. They include 6 great groups of diseases in adults, 7 in newborn and nursing groups in and 3 in children and adolescents. It is a effort to make the criteria more practical for daily clinical use. Major changes are in the time of duration of symptoms that has lowered single to 6 months, and the presence of annoyances is of last the 3 months; and he is not indispensable that the annoyances are daily in these periods. The other great challenge of Rome III, is a of redefinition of dyspepsia or be more useful for the practical doctor. The following months will indicate to us since all the changes will benefit the use and acceptance of the new criteria of Rome III of the functional digestive diseases. PMID- 17712397 TI - [Chronic angioedema and blastocystis hominis infection]. AB - The presence of urticaria associated with Blastocystic Hominis infection has been described in very few studies. To the best of our knowledge, no cases of chronic angioedema associated with Blastocystic hominis have been published. The clinical and immunological data of a patient with said association is presented. In the last 5 years, a 21 year old woman suffered episodic spells of angioedema which affected her lips, face and upper limbs accompanied by recurring urticaria. The patient continually used antihistamines and corticoids. Laboratory and immunological tests were normal. Blastocystic hominis in faeces was identified on three occasions. The angioedema and urticaria, as well as the intestinal infection, were successfully treated with paramomycin sulphate. The angiodema and urticaria continue in remission after 24 months of followup care. This case helps to encourage studies to establish an association between the infection by Blastocystis hominis and the presence of chronic angioedema which does not respond to standard treatment, as this condition can seriously affect the quality of life of sufferers. PMID- 17712398 TI - [Bochdalek's hernia in a mentally retarded adolescent]. AB - Bochdalek hernia is a congenital defect of the lateral posterior or vertebral lumbar region on the left side of diaphragm, caused by a foramen on it, through which viscera displaced from abdomen to pleural cavity. This is a pathology frequently observed in just born babies but rarely found in teenagers or adults. In world medical history only 100 cases in adults have been reported. We present a case of a 16 years old male patient with moderate mental retard who suddenly suffered from convulsions; this was the second time it happened, because the first time (3 months ago) he showed the same clinical picture but with no further complications. Anticonvulsives were administered to the patient in the general hospital E.R., but immediately after that, he had uncontrollable and frequent nausea, vomits and regurgitation when eating. He also showed anxiety, desperation and even aggressiveness. He was also very thirsty. Three days later the patient was transferred to the gastroenterology unit where we observed the symptoms above mentioned. He also presented sialorrhea. After many difficulties to find the diagnosis due to the patient's problems to communicate even with his relatives help, we decided to perform a surgery. Endoscopy showed total occlusion of the gastric-esophagus connection and an abdomen and thorax X-r showed an abnormal image with hydro aerial level in nearly all left hemithorax. The surgical findings showed total displacement of stomach, spleen, part of the small intestine, ascending colon, cecum, appendix and proximal part of transverse colon to the left hemithorax. Surgical corrections were performed. The clinical case resolved satisfactorily. The late age of the patient, type and treatment are discussed. PMID- 17712399 TI - [Pancreatic cancer and peripancreatic tuberculous lymphadenitis, a case report and literature review]. AB - Pancreatic tuberculosis and peripancreatic tuberculous lymphadenitis are rare conditions mainly affecting young women, and often occur in endemic areas and immunocompromised patients. The presentation of this condition could be similar to a malign neoplasm. However, coexistence of both pathologies is still very rare and just one case has been reported. A case of synchronism of peripancreatic tuberculous lymphadenitis and pancreatic adenocarcinoma in a 79-year-old woman is presented. PMID- 17712400 TI - Chemotherapy in Androgen-Independent Prostate Cancer (AIPC): What's next after taxane progression? AB - SummaryProstate cancer is the most common non-cutaneous cancer in the United States. Although most are diagnosed at earlier stages of disease, a significant number of patients will eventually progress to metastatic androgen-independent prostate cancer (AIPC) and will receive chemotherapy. The benefit of chemotherapy in overall survival has been demonstrated in studies utilizing docetaxel. However, duration of response is short and therapeutic options are limited after taxane failure. There is a need for effective chemotherapeutic agents in the second-line setting, either alone or in combination. Some of these regimens may also ultimately translate to the front-line chemotherapeutic setting as an alternative or perhaps in combination with a taxane. PMID- 17712401 TI - HIV-1 protease and reverse transcriptase control the architecture of their nucleocapsid partner. AB - The HIV-1 nucleocapsid is formed during protease (PR)-directed viral maturation, and is transformed into pre-integration complexes following reverse transcription in the cytoplasm of the infected cell. Here, we report a detailed transmission electron microscopy analysis of the impact of HIV-1 PR and reverse transcriptase (RT) on nucleocapsid plasticity, using in vitro reconstitutions. After binding to nucleic acids, NCp15, a proteolytic intermediate of nucleocapsid protein (NC), was processed at its C-terminus by PR, yielding premature NC (NCp9) followed by mature NC (NCp7), through the consecutive removal of p6 and p1. This allowed NC co-aggregation with its single-stranded nucleic-acid substrate. Examination of these co-aggregates for the ability of RT to catalyse reverse transcription showed an effective synthesis of double-stranded DNA that, remarkably, escaped from the aggregates more efficiently with NCp7 than with NCp9. These data offer a compelling explanation for results from previous virological studies that focused on i) Gag processing leading to nucleocapsid condensation, and ii) the disappearance of NCp7 from the HIV-1 pre-integration complexes. We propose that HIV-1 PR and RT, by controlling the nucleocapsid architecture during the steps of condensation and dismantling, engage in a successive nucleoprotein-remodelling process that spatiotemporally coordinates the pre-integration steps of HIV-1. Finally we suggest that nucleoprotein remodelling mechanisms are common features developed by mobile genetic elements to ensure successful replication. PMID- 17712402 TI - Cellular immune responses induced with dose-sparing intradermal administration of HIV vaccine to HIV-uninfected volunteers in the ANRS VAC16 trial. AB - OBJECTIVE: The objective was to compare the safety and cellular immunogenicity of intradermal versus intramuscular immunization with an HIV-lipopeptide candidate vaccine (LIPO-4) in healthy volunteers. METHODOLOGY: A randomized, open-label trial with 24 weeks of follow-up was conducted in France at six HIV-vaccine trial sites. Sixty-eight healthy 21- to 55-year-old HIV-uninfected subjects were randomized to receive the LIPO-4 vaccine (four HIV lipopeptides linked to a T helper-stimulating epitope of tetanus-toxin protein) at weeks 0, 4 and 12, either intradermally (0.1 ml, 100 microg of each peptide) or intramuscularly (0.5 ml, 500 microg of each peptide). Comparative safety of both routes was evaluated. CD8+ T-cell immune responses to HIV epitopes (ELISpot interferon-gamma assay) and tetanus toxin-specific CD4+ T-cell responses (lymphoproliferation) were assessed at baseline, two weeks after each injection, and at week 24. RESULTS AND CONCLUSION: No severe, serious or life-threatening adverse events were observed. Local pain was significantly more frequent after intramuscular injection, but local inflammatory reactions were more frequent after intradermal immunization. At weeks 2, 6, 14 and 24, the respective cumulative percentages of induced CD8+ T cell responses to at least one HIV peptide were 9, 33, 39 and 52 (intradermal group) or 14, 20, 26 and 37 (intramuscular group), and induced tetanus toxin specific CD4+ T-cell responses were 6, 27, 33 and 39 (intradermal), or 9, 46, 54 and 63 (intramuscular). In conclusion, intradermal LIPO-4 immunization was well tolerated, required one-fifth of the intramuscular dose, and induced similar HIV specific CD8+ T-cell responses. Moreover, the immunization route influenced which antigen-specific T-cells (CD4+ or CD8+) were induced. TRIAL REGISTRATION: ClinicalTrials.gov NCT00121121. PMID- 17712403 TI - Transmission heterogeneity and control strategies for infectious disease emergence. AB - BACKGROUND: The control of emergence and spread of infectious diseases depends critically on the details of the genetic makeup of pathogens and hosts, their immunological, behavioral and ecological traits, and the pattern of temporal and spatial contacts among the age/stage-classes of susceptible and infectious host individuals. METHODS AND FINDINGS: We show that failing to acknowledge the existence of heterogeneities in the transmission rate among age/stage-classes can make traditional eradication and control strategies ineffective, and in some cases, policies aimed at controlling pathogen emergence can even increase disease incidence in the host. When control strategies target for reduction in numbers those subsets of the population that effectively limit the production of new susceptible individuals, then control can produce a flush of new susceptibles entering the population. The availability of a new cohort of susceptibles may actually increase disease incidence. We illustrate these general points using Classical Swine Fever as a reference disease. CONCLUSION: Negative effects of culling are robust to alternative formulations of epidemiological processes and underline the importance of better assessing transmission structure in the design of wildlife disease control strategies. PMID- 17712405 TI - A threshold value for the time delay to TB diagnosis. AB - BACKGROUND: In many communities where TB occurs at high incidence, the major force driving the epidemic is transmission. It is plausible that the typical long delay from the onset of infectious disease to diagnosis and commencement of treatment is almost certainly the major factor contributing to the high rate of transmission. METHODOLOGY/PRINCIPAL FINDINGS: This study is confined to communities which are epidemiologically relatively isolated and which have low HIV incidence. The consequences of delays to diagnosis are analyzed and the existence of a threshold delay value is demonstrated. It is shown that unless a sufficient number of cases are detected before this threshold, the epidemic will escalate. The method used for the analysis avoids the standard computer integration of systems of differential equations since the intention is to present a line of reasoning that reveals the essential dynamics of an epidemic in an intuitively clear way that is nevertheless quantitatively realistic. CONCLUSIONS/SIGNIFICANCE: The analysis presented here shows that typical delays to diagnosis present a major obstacle to the control of a TB epidemic. Control can be achieved by optimizing the rapid identification of TB cases together with measures to increase the threshold value. A calculated and aggressive program is therefore necessary in order to bring about a reduction in the prevalence of TB in a community by decreasing the time to diagnosis in all its ramifications. Intervention strategies to increase the threshold value relative to the time to diagnosis and which thereby decrease disease incidence are discussed. PMID- 17712404 TI - CSF metabolic and proteomic profiles in patients prodromal for psychosis. AB - BACKGROUND: The initial prodromal state of psychosis (IPS) is defined as an early disease stage prior to the onset of overt psychosis characterized by sub threshold or more unspecific psychiatric symptoms. Little is known regarding the biochemical changes during this period. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the metabolic/proteomic profiles of cerebrospinal fluid (CSF) of first-onset drug naive paranoid schizophrenia patients (n = 54) and individuals presenting with initial prodromal symptoms (n = 24), alongside healthy volunteers (n = 70) using proton nuclear magnetic resonance ((1)H-NMR) spectroscopy and surface enhanced laser desorption ionization (SELDI) mass spectrometry, respectively. Partial least square discriminant analysis (PLS-DA) showed that 36%/29% of IPS patients displayed proteomic/metabolic profiles characteristic of first-onset, drug naive schizophrenia, i.e., changes in levels of glucose and lactate as well as changes in a VGF-derived peptide (VGF23-62) and transthyretin protein concentrations. However, only 29% (n = 7) of the investigated IPS patients (who to date have been followed up for up to three years) have so far received a diagnosis of schizophrenia. The presence of biochemical alterations in the IPS group did not correlate with the risk to develop schizophrenia. CONCLUSIONS/SIGNIFICANCE: Our results imply that schizophrenia-related biochemical disease processes can be traced in CSF of prodromal patients. However, the biochemical disturbances identified in IPS patients, at least when measured at a single time point, may not be sufficient to predict clinical outcome. PMID- 17712406 TI - Estimating individual and household reproduction numbers in an emerging epidemic. AB - Reproduction numbers, defined as averages of the number of people infected by a typical case, play a central role in tracking infectious disease outbreaks. The aim of this paper is to develop methods for estimating reproduction numbers which are simple enough that they could be applied with limited data or in real time during an outbreak. I present a new estimator for the individual reproduction number, which describes the state of the epidemic at a point in time rather than tracking individuals over time, and discuss some potential benefits. Then, to capture more of the detail that micro-simulations have shown is important in outbreak dynamics, I analyse a model of transmission within and between households, and develop a method to estimate the household reproduction number, defined as the number of households infected by each infected household. This method is validated by numerical simulations of the spread of influenza and measles using historical data, and estimates are obtained for would-be emerging epidemics of these viruses. I argue that the household reproduction number is useful in assessing the impact of measures that target the household for isolation, quarantine, vaccination or prophylactic treatment, and measures such as social distancing and school or workplace closures which limit between household transmission, all of which play a key role in current thinking on future infectious disease mitigation. PMID- 17712407 TI - Considering the case for biodiversity cycles: re-examining the evidence for periodicity in the fossil record. AB - We re-examine the evidence for a 62 million year (Myr) periodicity in biodiversity throughout the Phanerozoic history of animal life reported by, as well as related questions of periodicity in origination and extinction. We find that the signal is robust against variations in methods of analysis, and is based on fluctuations in the Paleozoic and a substantial part of the Mesozoic. Examination of origination and extinction is somewhat ambiguous, with results depending upon procedure. Origination and extinction intensity as defined by may be affected by an artifact at 27 Myr in the duration of stratigraphic intervals. Nevertheless, when a procedure free of this artifact is implemented, the 27 Myr periodicity appears in origination, suggesting that the artifact may ultimately be based on a signal in the data. A 62 Myr feature appears in extinction, when this same procedure is used. We conclude that evidence for a periodicity at 62 Myr is robust, and evidence for periodicity at approximately 27 Myr is also present, albeit more ambiguous. PMID- 17712408 TI - Combining phylogeography with distribution modeling: multiple Pleistocene range expansions in a parthenogenetic gecko from the Australian arid zone. AB - Phylogenetic and geographic evidence suggest that many parthenogenetic organisms have evolved recently and have spread rapidly. These patterns play a critical role in our understanding of the relative merits of sexual versus asexual reproductive modes, yet their interpretation is often hampered by a lack of detail. Here we present a detailed phylogeographic study of a vertebrate parthenogen, the Australian gecko Heteronotia binoei, in combination with statistical and biophysical modeling of its distribution during the last glacial maximum. Parthenogenetic H. binoei occur in the Australian arid zone and have the widest range of any known vertebrate parthenogen. They are broadly sympatric with their sexual counterparts, from which they arose via hybridization. We have applied nested clade phylogeographic, effective migration, and mismatch distribution analyses to mitochondrial DNA (mtDNA) sequences obtained for 319 individuals sampled throughout the known geographic ranges of two parthenogenetic mitochondrial lineages. These analyses provide strong evidence for past range expansion events from west to east across the arid zone, and for continuing eastward range expansion. Parthenogen formation and range expansion events date to the late Pleistocene, with one lineage expanding from the northwest of its present range around 240,000 years ago and the second lineage expanding from the far west around 70,000 years ago. Statistical and biophysical distribution models support these inferences of recent range expansion, with suitable climatic conditions during the last glacial maximum most likely limited to parts of the arid zone north and west of much of the current ranges of these lineages. Combination of phylogeographic analyses and distribution modeling allowed considerably stronger inferences of the history of this complex than either would in isolation, illustrating the power of combining complementary analytical approaches. PMID- 17712409 TI - Computer-aided lead optimization: improved small-molecule inhibitor of the zinc endopeptidase of botulinum neurotoxin serotype A. AB - Optimization of a serotype-selective, small-molecule inhibitor of botulinum neurotoxin serotype A (BoNTA) endopeptidase is a formidable challenge because the enzyme-substrate interface is unusually large and the endopeptidase itself is a large, zinc-binding protein with a complex fold that is difficult to simulate computationally. We conducted multiple molecular dynamics simulations of the endopeptidase in complex with a previously described inhibitor (K(i) (app) of 7+/ 2.4 microM) using the cationic dummy atom approach. Based on our computational results, we hypothesized that introducing a hydroxyl group to the inhibitor could improve its potency. Synthesis and testing of the hydroxyl-containing analog as a BoNTA endopeptidase inhibitor showed a twofold improvement in inhibitory potency (K(i) (app) of 3.8+/-0.8 microM) with a relatively small increase in molecular weight (16 Da). The results offer an improved template for further optimization of BoNTA endopeptidase inhibitors and demonstrate the effectiveness of the cationic dummy atom approach in the design and optimization of zinc protease inhibitors. PMID- 17712410 TI - Homosexual women have less grey matter in perirhinal cortex than heterosexual women. AB - Is sexual orientation associated with structural differences in the brain? To address this question, 80 homosexual and heterosexual men and women (16 homosexual men and 15 homosexual women) underwent structural MRI. We used voxel based morphometry to test for differences in grey matter concentration associated with gender and sexual orientation. Compared with heterosexual women, homosexual women displayed less grey matter bilaterally in the temporo-basal cortex, ventral cerebellum, and left ventral premotor cortex. The relative decrease in grey matter was most prominent in the left perirhinal cortex. The left perirhinal area also showed less grey matter in heterosexual men than in heterosexual women. Thus, in homosexual women, the perirhinal cortex grey matter displayed a more male-like structural pattern. This is in accordance with previous research that revealed signs of sex-atypical prenatal androgenization in homosexual women, but not in homosexual men. The relevance of the perirhinal area for high order multimodal (olfactory and visual) object, social, and sexual processing is discussed. PMID- 17712412 TI - Marburg virus infection detected in a common African bat. AB - Marburg and Ebola viruses can cause large hemorrhagic fever (HF) outbreaks with high case fatality (80-90%) in human and great apes. Identification of the natural reservoir of these viruses is one of the most important topics in this field and a fundamental key to understanding their natural history. Despite the discovery of this virus family almost 40 years ago, the search for the natural reservoir of these lethal pathogens remains an enigma despite numerous ecological studies. Here, we report the discovery of Marburg virus in a common species of fruit bat (Rousettus aegyptiacus) in Gabon as shown by finding virus-specific RNA and IgG antibody in individual bats. These Marburg virus positive bats represent the first naturally infected non-primate animals identified. Furthermore, this is the first report of Marburg virus being present in this area of Africa, thus extending the known range of the virus. These data imply that more areas are at risk for MHF outbreaks than previously realized and correspond well with a recently published report in which three species of fruit bats were demonstrated to be likely reservoirs for Ebola virus. PMID- 17712411 TI - Epidermal stem cells are defined by global histone modifications that are altered by Myc-induced differentiation. AB - Activation of Myc induces epidermal stem cells to exit their niche and differentiate into sebocytes and interfollicular epidermis, a process that is associated with widespread changes in gene transcription. We have identified chromatin modifications that are characteristic of epidermal stem cells and investigated the effects of Myc activation. Quiescent stem cells in the interfollicular epidermis and the hair follicle bulge had high levels of tri methylated histone H3 at lysine 9 and H4 at lysine 20. Chromatin in both stem cell populations was hypoacteylated at histone H4 and lacked mono-methylation of histone H4 at lysine 20. Myc-induced exit from the stem cell niche correlated with increased acetylation at histone H4 and transiently increased mono methylation at lysine 20. The latter was replaced by epigenetic modifications that are largely associated with chromatin silencing: di-methylation at histone H3 lysine 9 and histone H4 lysine 20. These modifications correlated with changes in the specific histone methyltransferases Set8 and Ash-1. The Myc-induced switch from mono- to di-methylated H4K20 required HDAC activity and was blocked by the HDAC inhibitor trichostatin A (TSA). TSA treatment induced a similar epidermal phenotype to activation of Myc, and activation of Myc in the presence of TSA resulted in massive stimulation of terminal differentiation. We conclude that Myc induced chromatin modifications play a major role in Myc-induced exit from the stem cell compartment. PMID- 17712413 TI - High cooperativity of the SV40 major capsid protein VP1 in virus assembly. AB - SV40 is a small, non enveloped DNA virus with an icosahedral capsid of 45 nm. The outer shell is composed of pentamers of the major capsid protein, VP1, linked via their flexible carboxy-terminal arms. Its morphogenesis occurs by assembly of capsomers around the viral minichromosome. However the steps leading to the formation of mature virus are poorly understood. Intermediates of the assembly reaction could not be isolated from cells infected with wt SV40. Here we have used recombinant VP1 produced in insect cells for in vitro assembly studies around supercoiled heterologous plasmid DNA carrying a reporter gene. This strategy yields infective nanoparticles, affording a simple quantitative transduction assay. We show that VP1 assembles under physiological conditions into uniform nanoparticles of the same shape, size and CsCl density as the wild type virus. The stoichiometry is one DNA molecule per capsid. VP1 deleted in the C-arm, which is unable to assemble but can bind DNA, was inactive indicating genuine assembly rather than non-specific DNA-binding. The reaction requires host enzymatic activities, consistent with the participation of chaperones, as recently shown. Our results demonstrate dramatic cooperativity of VP1, with a Hill coefficient of approximately 6. These findings suggest that assembly may be a concerted reaction. We propose that concerted assembly is facilitated by simultaneous binding of multiple capsomers to a single DNA molecule, as we have recently reported, thus increasing their local concentration. Emerging principles of SV40 assembly may help understanding assembly of other complex systems. In addition, the SV40-based nanoparticles described here are potential gene therapy vectors that combine efficient gene delivery with safety and flexibility. PMID- 17712415 TI - Efficient construction of an inverted minimal H1 promoter driven siRNA expression cassette: facilitation of promoter and siRNA sequence exchange. AB - BACKGROUND: RNA interference (RNAi), mediated by small interfering RNA (siRNA), is an effective method used to silence gene expression at the post transcriptional level. Upon introduction into target cells, siRNAs incorporate into the RNA-induced silencing complex (RISC). The antisense strand of the siRNA duplex then "guides" the RISC to the homologous mRNA, leading to target degradation and gene silencing. In recent years, various vector-based siRNA expression systems have been developed which utilize opposing polymerase III promoters to independently drive expression of the sense and antisense strands of the siRNA duplex from the same template. PRINCIPAL FINDINGS: We show here the use of a ligase chain reaction (LCR) to develop a new vector system called pInv-H1 in which a DNA sequence encoding a specific siRNA is placed between two inverted minimal human H1 promoters (approximately 100 bp each). Expression of functional siRNAs from this construct has led to efficient silencing of both reporter and endogenous genes. Furthermore, the inverted H1 promoter-siRNA expression cassette was used to generate a retrovirus vector capable of transducing and silencing expression of the targeted protein by>80% in target cells. CONCLUSIONS: The unique design of this construct allows for the efficient exchange of siRNA sequences by the directional cloning of short oligonucleotides via asymmetric restriction sites. This provides a convenient way to test the functionality of different siRNA sequences. Delivery of the siRNA cassette by retroviral transduction suggests that a single copy of the siRNA expression cassette efficiently knocks down gene expression at the protein level. We note that this vector system can potentially be used to generate a random siRNA library. The flexibility of the ligase chain reaction suggests that additional control elements can easily be introduced into this siRNA expression cassette. PMID- 17712414 TI - The Princeton Protein Orthology Database (P-POD): a comparative genomics analysis tool for biologists. AB - Many biological databases that provide comparative genomics information and tools are now available on the internet. While certainly quite useful, to our knowledge none of the existing databases combine results from multiple comparative genomics methods with manually curated information from the literature. Here we describe the Princeton Protein Orthology Database (P-POD, http://ortholog.princeton.edu), a user-friendly database system that allows users to find and visualize the phylogenetic relationships among predicted orthologs (based on the OrthoMCL method) to a query gene from any of eight eukaryotic organisms, and to see the orthologs in a wider evolutionary context (based on the Jaccard clustering method). In addition to the phylogenetic information, the database contains experimental results manually collected from the literature that can be compared to the computational analyses, as well as links to relevant human disease and gene information via the OMIM, model organism, and sequence databases. Our aim is for the P-POD resource to be extremely useful to typical experimental biologists wanting to learn more about the evolutionary context of their favorite genes. P POD is based on the commonly used Generic Model Organism Database (GMOD) schema and can be downloaded in its entirety for installation on one's own system. Thus, bioinformaticians and software developers may also find P-POD useful because they can use the P-POD database infrastructure when developing their own comparative genomics resources and database tools. PMID- 17712416 TI - Candidate genes for expansion and transformation of hematopoietic stem cells by NUP98-HOX fusion genes. AB - BACKGROUND: Hox genes are implicated in hematopoietic stem cell (HSC) regulation as well as in leukemia development through translocation with the nucleoporin gene NUP98. Interestingly, an engineered NUP98-HOXA10 (NA10) fusion can induce a several hundred-fold expansion of HSCs in vitro and NA10 and the AML-associated fusion gene NUP98-HOXD13 (ND13) have a virtually indistinguishable ability to transform myeloid progenitor cells in vitro and to induce leukemia in collaboration with MEIS1 in vivo. METHODOLOGY/PRINCIPAL FINDINGS: These findings provided a potentially powerful approach to identify key pathways mediating Hox induced expansion and transformation of HSCs by identifying gene expression changes commonly induced by ND13 and NA10 but not by a NUP98-Hox fusion with a non-DNA binding homedomain mutation (N51S). The gene expression repertoire of purified murine bone marrow Sca-1+Lin- cells transduced with retroviral vectors encoding for these genes was established using the Affymetrix GeneChip MOE430A. Approximately seventy genes were differentially expressed in ND13 and NA10 cells that were significantly changed by both compared to the ND13(N51S) mutant. Intriguingly, several of these potential Hox target genes have been implicated in HSC expansion and self-renewal, including the tyrosine kinase receptor Flt3, the prion protein, Prnp, hepatic leukemia factor, Hlf and Jagged-2, Jag2. Consistent with these results, FLT3, HLF and JAG2 expression correlated with HOX A cluster gene expression in human leukemia samples. CONCLUSIONS: In conclusion this study has identified several novel Hox downstream target genes and provides important new leads to key regulators of the expansion and transformation of hematopoietic stem cells by Hox. PMID- 17712417 TI - Detection of novel amplicons in prostate cancer by comprehensive genomic profiling of prostate cancer cell lines using oligonucleotide-based arrayCGH. AB - BACKGROUND: The purpose of this study was to prove the feasibility of a longmer oligonucleotide microarray platform to profile gene copy number alterations in prostate cancer cell lines and to quickly indicate novel candidate genes, which may play a role in carcinogenesis. METHODS/RESULTS AND FINDINGS: Genome-wide screening for regions of genetic gains and losses on nine prostate cancer cell lines (PC3, DU145, LNCaP, CWR22, and derived sublines) was carried out using comparative genomic hybridization on a 35,000 feature oligonucleotide microarray (arrayCGH). Compared to conventional chromosomal CGH, more deletions and small regions of gains, particularly in pericentromeric regions and regions next to the telomeres, were detected. As validation of the high-resolution of arrayCGH we further analyzed a small amplicon of 1.7 MB at 9p13.3, which was found in CWR22 and CWR22-Rv1. Increased copy number was confirmed by fluorescence in situ hybridization using the BAC clone RP11-165H19 from the amplified region comprising the two genes interleukin 11 receptor alpha (IL11-RA) and dynactin 3 (DCTN3). Using quantitative real time PCR (qPCR) we could demonstrate that IL11 RA is the gene with the highest copy number gain in the cell lines compared to DCTN3 suggesting IL11-RA to be the amplification target. Screening of 20 primary prostate carcinomas by qPCR revealed an IL11-RA copy number gain in 75% of the tumors analyzed. Gain of DCTN3 was only found in two cases together with a gain of IL11-RA. CONCLUSIONS/SIGNIFICANCE: ArrayCGH using longmer oligonucleotide microarrays is feasible for high-resolution analysis of chomosomal imbalances. Characterization of a small gained region at 9p13.3 in prostate cancer cell lines and primary prostate cancer samples by fluorescence in situ hybridization and quantitative PCR has revealed interleukin 11 receptor alpha gene as a candidate target of amplification with an amplification frequency of 75% in prostate carcinomas. Frequent amplification of IL11-RA in prostate cancer is a potential mechanism of IL11-RA overexpression in this tumor type. PMID- 17712418 TI - Yersinia pestis evolution on a small timescale: comparison of whole genome sequences from North America. AB - BACKGROUND: Yersinia pestis, the etiologic agent of plague, was responsible for several devastating epidemics throughout history and is currently of global importance to current public heath and biodefense efforts. Y. pestis is widespread in the Western United States. Because Y. pestis was first introduced to this region just over 100 years ago, there has been little time for genetic diversity to accumulate. Recent studies based upon single nucleotide polymorphisms have begun to quantify the genetic diversity of Y. pestis in North America. METHODOLOGY/PRINCIPAL FINDINGS: To examine the evolution of Y. pestis in North America, a gapped genome sequence of CA88-4125 was generated. Sequence comparison with another North American Y. pestis strain, CO92, identified seven regions of difference (six inversions, one rearrangement), differing IS element copy numbers, and several SNPs. CONCLUSIONS/SIGNIFICANCE: The relatively large number of inverted/rearranged segments suggests that North American Y. pestis strains may be undergoing inversion fixation at high rates over a short time span, contributing to higher-than-expected diversity in this region. These findings will hopefully encourage the scientific community to sequence additional Y. pestis strains from North America and abroad, leading to a greater understanding of the evolutionary history of this pathogen. PMID- 17712420 TI - Development of sensory, motor and behavioral deficits in the murine model of Sanfilippo syndrome type B. AB - BACKGROUND: Mucopolysaccharidosis (MPS) IIIB (Sanfilippo Syndrome type B) is caused by a deficiency in the lysosomal enzyme N-acetyl-glucosaminidase (Naglu). Children with MPS IIIB develop disturbances of sleep, activity levels, coordination, vision, hearing, and mental functioning culminating in early death. The murine model of MPS IIIB demonstrates lysosomal distention in multiple tissues, a shortened life span, and behavioral changes. PRINCIPAL FINDINGS: To more thoroughly assess MPS IIIB in mice, alterations in circadian rhythm, activity level, motor function, vision, and hearing were tested. The suprachiasmatic nucleus (SCN) developed pathologic changes and locomotor analysis showed that MPS IIIB mice start their daily activity later and have a lower proportion of activity during the night than wild-type controls. Rotarod assessment of motor function revealed a progressive inability to coordinate movement in a rocking paradigm. Purkinje cell counts were significantly reduced in the MPS IIIB animals compared to age matched controls. By electroretinography (ERG), MPS IIIB mice had a progressive decrease in the amplitude of the dark adapted b-wave response. Corresponding pathology revealed shortening of the outer segments, thinning of the outer nuclear layer, and inclusions in the retinal pigmented epithelium. Auditory-evoked brainstem responses (ABR) demonstrated progressive hearing deficits consistent with the observed loss of hair cells in the inner ear and histologic abnormalities in the middle ear. CONCLUSIONS/SIGNIFICANCE: The mouse model of MPS IIIB has several quantifiable phenotypic alterations and is similar to the human disease. These physiologic and histologic changes provide insights into the progression of this disease and will serve as important parameters when evaluating various therapies. PMID- 17712419 TI - Prefrontal cortex and somatosensory cortex in tactile crossmodal association: an independent component analysis of ERP recordings. AB - Our previous studies on scalp-recorded event-related potentials (ERPs) showed that somatosensory N140 evoked by a tactile vibration in working memory tasks was enhanced when human subjects expected a coming visual stimulus that had been paired with the tactile stimulus. The results suggested that such enhancement represented the cortical activities involved in tactile-visual crossmodal association. In the present study, we further hypothesized that the enhancement represented the neural activities in somatosensory and frontal cortices in the crossmodal association. By applying independent component analysis (ICA) to the ERP data, we found independent components (ICs) located in the medial prefrontal cortex (around the anterior cingulate cortex, ACC) and the primary somatosensory cortex (SI). The activity represented by the IC in SI cortex showed enhancement in expectation of the visual stimulus. Such differential activity thus suggested the participation of SI cortex in the task-related crossmodal association. Further, the coherence analysis and the Granger causality spectral analysis of the ICs showed that SI cortex appeared to cooperate with ACC in attention and perception of the tactile stimulus in crossmodal association. The results of our study support with new evidence an important idea in cortical neurophysiology: higher cognitive operations develop from the modality-specific sensory cortices (in the present study, SI cortex) that are involved in sensation and perception of various stimuli. PMID- 17712421 TI - Natural variation in the thermotolerance of neural function and behavior due to a cGMP-dependent protein kinase. AB - Although it is acknowledged that genetic variation contributes to individual differences in thermotolerance, the specific genes and pathways involved and how they are modulated by the environment remain poorly understood. We link natural variation in the thermotolerance of neural function and behavior in Drosophila melanogaster to the foraging gene (for, which encodes a cGMP-dependent protein kinase (PKG)) as well as to its downstream target, protein phosphatase 2A (PP2A). Genetic and pharmacological manipulations revealed that reduced PKG (or PP2A) activity caused increased thermotolerance of synaptic transmission at the larval neuromuscular junction. Like synaptic transmission, feeding movements were preserved at higher temperatures in larvae with lower PKG levels. In a comparative assay, pharmacological manipulations altering thermotolerance in a central circuit of Locusta migratoria demonstrated conservation of this neuroprotective pathway. In this circuit, either the inhibition of PKG or PP2A induced robust thermotolerance of neural function. We suggest that PKG and therefore the polymorphism associated with the allelic variation in for may provide populations with natural variation in heat stress tolerance. for's function in behavior is conserved across most organisms, including ants, bees, nematodes, and mammals. PKG's role in thermotolerance may also apply to these and other species. Natural variation in thermotolerance arising from genes involved in the PKG pathway could impact the evolution of thermotolerance in natural populations. PMID- 17712422 TI - Utrophin up-regulation by an artificial transcription factor in transgenic mice. AB - Duchenne Muscular Dystrophy (DMD) is a severe muscle degenerative disease, due to absence of dystrophin. There is currently no effective treatment for DMD. Our aim is to up-regulate the expression level of the dystrophin related gene utrophin in DMD, complementing in this way the lack of dystrophin functions. To this end we designed and engineered several synthetic zinc finger based transcription factors. In particular, we have previously shown that the artificial three zinc finger protein named Jazz, fused with the appropriate effector domain, is able to drive the transcription of a test gene from the utrophin promoter "A". Here we report on the characterization of Vp16-Jazz-transgenic mice that specifically over-express the utrophin gene at the muscular level. A Chromatin Immunoprecipitation assay (ChIP) demonstrated the effective access/binding of the Jazz protein to active chromatin in mouse muscle and Vp16-Jazz was shown to be able to up-regulate endogenous utrophin gene expression by immunohistochemistry, western blot analyses and real-time PCR. To our knowledge, this is the first example of a transgenic mouse expressing an artificial gene coding for a zinc finger based transcription factor. The achievement of Vp16-Jazz transgenic mice validates the strategy of transcriptional targeting of endogenous genes and could represent an exclusive animal model for use in drug discovery and therapeutics. PMID- 17712423 TI - Expressed sequence tags as a tool for phylogenetic analysis of placental mammal evolution. AB - BACKGROUND: We investigate the usefulness of expressed sequence tags, ESTs, for establishing divergences within the tree of placental mammals. This is done on the example of the established relationships among primates (human), lagomorphs (rabbit), rodents (rat and mouse), artiodactyls (cow), carnivorans (dog) and proboscideans (elephant). METHODOLOGY/PRINCIPAL FINDINGS: We have produced 2000 ESTs (1.2 mega bases) from a marsupial mouse and characterized the data for their use in phylogenetic analysis. The sequences were used to identify putative orthologous sequences from whole genome projects. Although most ESTs stem from single sequence reads, the frequency of potential sequencing errors was found to be lower than allelic variation. Most of the sequences represented slowly evolving housekeeping-type genes, with an average amino acid distance of 6.6% between human and mouse. Positive Darwinian selection was identified at only a few single sites. Phylogenetic analyses of the EST data yielded trees that were consistent with those established from whole genome projects. CONCLUSIONS: The general quality of EST sequences and the general absence of positive selection in these sequences make ESTs an attractive tool for phylogenetic analysis. The EST approach allows, at reasonable costs, a fast extension of data sampling from species outside the genome projects. PMID- 17712425 TI - Evidence for a minimal eukaryotic phosphoproteome? AB - BACKGROUND: Reversible phosphorylation catalysed by kinases is probably the most important regulatory mechanism in eukaryotes. METHODOLOGY/PRINCIPAL FINDINGS: We studied the in vitro phosphorylation of peptide arrays exhibiting the majority of PhosphoBase-deposited protein sequences, by factors in cell lysates from representatives of various branches of the eukaryotic species. We derived a set of substrates from the PhosphoBase whose phosphorylation by cellular extracts is common to the divergent members of different kingdoms and thus may be considered a minimal eukaryotic phosphoproteome. The protein kinases (or kinome) responsible for phosphorylation of these substrates are involved in a variety of processes such as transcription, translation, and cytoskeletal reorganisation. CONCLUSIONS/SIGNIFICANCE: These results indicate that the divergence in eukaryotic kinases is not reflected at the level of substrate phosphorylation, revealing the presence of a limited common substrate space for kinases in eukaryotes and suggests the presence of a set of kinase substrates and regulatory mechanisms in an ancestral eukaryote that has since remained constant in eukaryotic life. PMID- 17712424 TI - Sequential logic model deciphers dynamic transcriptional control of gene expressions. AB - BACKGROUND: Cellular signaling involves a sequence of events from ligand binding to membrane receptors through transcription factors activation and the induction of mRNA expression. The transcriptional-regulatory system plays a pivotal role in the control of gene expression. A novel computational approach to the study of gene regulation circuits is presented here. METHODOLOGY: Based on the concept of finite state machine, which provides a discrete view of gene regulation, a novel sequential logic model (SLM) is developed to decipher control mechanisms of dynamic transcriptional regulation of gene expressions. The SLM technique is also used to systematically analyze the dynamic function of transcriptional inputs, the dependency and cooperativity, such as synergy effect, among the binding sites with respect to when, how much and how fast the gene of interest is expressed. PRINCIPAL FINDINGS: SLM is verified by a set of well studied expression data on endo16 of Strongylocentrotus purpuratus (sea urchin) during the embryonic midgut development. A dynamic regulatory mechanism for endo16 expression controlled by three binding sites, UI, R and Otx is identified and demonstrated to be consistent with experimental findings. Furthermore, we show that during transition from specification to differentiation in wild type endo16 expression profile, SLM reveals three binary activities are not sufficient to explain the transcriptional regulation of endo16 expression and additional activities of binding sites are required. Further analyses suggest detailed mechanism of R switch activity where indirect dependency occurs in between UI activity and R switch during specification to differentiation stage. CONCLUSIONS/SIGNIFICANCE: The sequential logic formalism allows for a simplification of regulation network dynamics going from a continuous to a discrete representation of gene activation in time. In effect our SLM is non-parametric and model-independent, yet providing rich biological insight. The demonstration of the efficacy of this approach in endo16 is a promising step for further application of the proposed method. PMID- 17712426 TI - Prevalence of same-sex sexual behavior and associated characteristics among low income urban males in Peru. AB - BACKGROUND: Peru has a concentrated HIV epidemic in which men who have sex with men are particularly vulnerable. We describe the lifetime prevalence of same-sex sexual contact and associated risk behaviors of men in Peru's general population, regardless of their sexual identity. METHODS AND RESULTS: A probability sample of males from low-income households in three Peruvian cities completed an epidemiologic survey addressing their sexual risk behavior, including sex with other men. Serum was tested for HSV-2, HIV, and syphilis. Urine was tested for chlamydia and gonorrhea. A total of 2,271 18-30 year old men and women were contacted, of whom 1,645 (72.4%) agreed to participate in the study. Among the sexually experienced men surveyed, 15.2% (85/558, 95% CI: 12.2%-18.2%) reported a history of sex with other men. Men ever reporting sex with men (MESM) had a lower educational level, had greater numbers of sex partners, and were more likely to engage in risk behaviors including unprotected sex with casual partners, paying for or providing compensated sex, and using illegal drugs. MESM were also more likely to have had previous STI symptoms or a prior STI diagnosis, and had a greater prevalence of HSV-2 seropositivity. CONCLUSIONS: Many low-income Peruvian men have engaged in same-sex sexual contact and maintain greater behavioral and biological risk factors for HIV/STI transmission than non-MESM. Improved surveillance strategies for HIV and STIs among MESM are necessary to better understand the epidemiology of HIV in Latin America and to prevent its further spread. PMID- 17712427 TI - Low numbers of FOXP3 positive regulatory T cells are present in all developmental stages of human atherosclerotic lesions. AB - BACKGROUND: T cell mediated inflammation contributes to atherogenesis and the onset of acute cardiovascular disease. Effector T cell functions are under a tight control of a specialized T cell subset, regulatory T cells (Treg). At present, nothing is known about the in situ presence of Treg in human atherosclerotic tissue. In the present study we investigated the frequency of naturally occurring Treg cells in all developmental stages of human atherosclerotic lesions including complicated thrombosed plaques. METHODOLOGY: Normal arteries, early lesions (American Heart Association classification types I, II, and III), fibrosclerotic plaques (types Vb and Vc) and 'high risk' plaques (types IV, Va and VI) were obtained at surgery and autopsy. Serial sections were immunostained for markers specific for regulatory T cells (FOXP3 and GITR) and the frequency of these cells was expressed as a percentage of the total numbers of CD3+ T cells. Results were compared with Treg counts in biopsies of normal and inflammatory skin lesions (psoriasis, spongiotic dermatitis and lichen planus). PRINCIPLE FINDINGS: In normal vessel fragments T cells were virtually absent. Treg were present in the intima during all stages of plaque development (0.5-5%). Also in the adventitia of atherosclerotic vessels Treg were encountered, in similar low amounts. High risk lesions contained significantly increased numbers of Treg compared to early lesions (mean: 3.9 and 1.2%, respectively). The frequency of FOXP3+ cells in high risk lesions was also higher compared to stable lesions (1.7%), but this difference was not significant. The mean numbers of intimal FOXP3 positive cells in atherosclerotic lesions (2.4%) was much lower than those in normal (24.3%) or inflammatory skin lesions (28%). CONCLUSION: Low frequencies of Treg in all developmental stages of human plaque formation could explain the smoldering chronic inflammatory process that takes place throughout the longstanding course of atherosclerosis. PMID- 17712428 TI - A sex-specific metabolite identified in a marine invertebrate utilizing phosphorus-31 nuclear magnetic resonance. AB - Hormone level differences are generally accepted as the primary cause for sexual dimorphism in animal and human development. Levels of low molecular weight metabolites also differ between men and women in circulating amino acids, lipids and carbohydrates and within brain tissue. While investigating the metabolism of blue crab tissues using Phosphorus-31 Nuclear Magnetic Resonance, we discovered that only the male blue crab (Callinectes sapidus) contained a phosphorus compound with a chemical shift well separated from the expected phosphate compounds. Spectra obtained from male gills were readily differentiated from female gill spectra. Analysis from six years of data from male and female crabs documented that the sex-specificity of this metabolite was normal for this species. Microscopic analysis of male and female gills found no differences in their gill anatomy or the presence of parasites or bacteria that might produce this phosphorus compound. Analysis of a rare gynandromorph blue crab (laterally, half male and half female) proved that this sex-specificity was an intrinsic biochemical process and was not caused by any variations in the diet or habitat of male versus female crabs. The existence of a sex-specific metabolite is a previously unrecognized, but potentially significant biochemical phenomenon. An entire enzyme system has been synthesized and activated only in one sex. Unless blue crabs are a unique species, sex-specific metabolites are likely to be present in other animals. Would the presence or absence of a sex-specific metabolite affect an animal's development, anatomy and biochemistry? PMID- 17712433 TI - Chronic septic bursitis caused by dematiaceous fungi. PMID- 17712434 TI - Hydatid disease of the lumbar spine: combined surgical and medical treatment--a case report. PMID- 17712429 TI - Sterility and gene expression in hybrid males of Xenopus laevis and X. muelleri. AB - BACKGROUND: Reproductive isolation is a defining characteristic of populations that represent unique biological species, yet we know very little about the gene expression basis for reproductive isolation. The advent of powerful molecular biology tools provides the ability to identify genes involved in reproductive isolation and focuses attention on the molecular mechanisms that separate biological species. Herein we quantify the sterility pattern of hybrid males in African Clawed Frogs (Xenopus) and apply microarray analysis of the expression pattern found in testes to identify genes that are misexpressed in hybrid males relative to their two parental species (Xenopus laevis and X. muelleri). METHODOLOGY/PRINCIPAL FINDINGS: Phenotypic characteristics of spermatogenesis in sterile male hybrids (X. laevis x X. muelleri) were examined using a novel sperm assay that allowed quantification of live, dead, and undifferentiated sperm cells, the number of motile vs. immotile sperm, and sperm morphology. Hybrids exhibited a dramatically lower abundance of mature sperm relative to the parental species. Hybrid spermatozoa were larger in size and accompanied by numerous undifferentiated sperm cells. Microarray analysis of gene expression in testes was combined with a correction for sequence divergence derived from genomic hybridizations to identify candidate genes involved in the sterility phenotype. Analysis of the transcriptome revealed a striking asymmetric pattern of misexpression. There were only about 140 genes misexpressed in hybrids compared to X. laevis but nearly 4,000 genes misexpressed in hybrids compared to X. muelleri. CONCLUSIONS/SIGNIFICANCE: Our results provide an important correlation between phenotypic characteristics of sperm and gene expression in sterile hybrid males. The broad pattern of gene misexpression suggests intriguing mechanisms creating the dominance pattern of the X. laevis genome in hybrids. These findings significantly contribute to growing evidence for allelic dominance in hybrids and have implications for the mechanism of species differentiation at the transcriptome level. PMID- 17712435 TI - Staphylococcus lugdunensis osteomyelitis: a case report. PMID- 17712436 TI - Late recurrent Salmonella sacroiliac osteomyelitis with psoas abscess in a non sickle cell adult: case report. PMID- 17712430 TI - Condensin I reveals new insights on mouse meiotic chromosome structure and dynamics. AB - Chromosome shaping and individualization are necessary requisites to warrant the correct segregation of genomes in either mitotic or meiotic cell divisions. These processes are mainly prompted in vertebrates by three multiprotein complexes termed cohesin and condensin I and II. In the present study we have analyzed by immunostaining the appearance and subcellular distribution of condensin I in mouse mitotic and meiotic chromosomes. Our results demonstrate that in either mitotically or meiotically dividing cells, condensin I is loaded onto chromosomes by prometaphase. Condensin I is detectable as a fuzzy axial structure running inside chromatids of condensed chromosomes. The distribution of condensin I along the chromosome length is not uniform, since it preferentially accumulates close to the chromosome ends. Interestingly, these round accumulations found at the condensin I axes termini colocalized with telomere complexes. Additionally, we present the relative distribution of the condensin I and cohesin complexes in metaphase I bivalents. All these new data have allowed us to propose a comprehensive model for meiotic chromosome structure. PMID- 17712437 TI - Gemella morbillorum septic arthritis of the knee and infective endocarditis. PMID- 17712438 TI - Synthesis of inorganic nanomaterials. AB - Synthesis forms a vital aspect of the science of nanomaterials. In this context, chemical methods have proved to be more effective and versatile than physical methods and have therefore, been employed widely to synthesize a variety of nanomaterials, including zero-dimensional nanocrystals, one-dimensional nanowires and nanotubes as well as two-dimensional nanofilms and nanowalls. Chemical synthesis of inorganic nanomaterials has been pursued vigorously in the last few years and in this article we provide a perspective on the present status of the subject. The article includes a discussion of nanocrystals and nanowires of metals, oxides, chalcogenides and pnictides. In addition, inorganic nanotubes and nanowalls have been reviewed. Some aspects of core-shell particles, oriented attachment and the use of liquid-liquid interfaces are also presented. PMID- 17712439 TI - INDOLPhos: novel hybrid phosphine-phosphoramidite ligands for asymmetric hydrogenation and hydroformylation. AB - Hybrid bidentate phosphine-phosphoramidite ligands are prepared in a modular 2 step sequence and their rhodium complexes display high selectivity in rhodium catalysed hydrogenation and hydroformylation reactions. PMID- 17712441 TI - Crystal formation and growth during the hydrothermal synthesis of beta-Ni(OH)2 in one-dimensional nano space. AB - Hydrothermal synthesis of beta-Ni(OH)(2) was performed inside uniform carbon coated nanochannels of an anodic aluminium oxide film. The time course of crystal formation and growth of Ni(OH)(2) in such one-dimensional nano space was observed using transmission electron microscopy (TEM), and the changes in the number and size of crystals with the hydrothermal reaction period were quantitatively analyzed using the TEM images. Moreover, the effect of the channel size (25, 100 and 300 nm in diameter) on the crystal growth was examined. In the early stage of the reaction, the crystal formation and growth of beta-Ni(OH)(2) in the one dimensional channels took place in the same manner as in conventional hydrothermal synthesis. However, except for the 300 nm-channels, further crystal growth was hampered by the spatial restriction, and it allowed only the growth toward the channel axis. In the case of the 25 nm-channels, many Ni(OH)(2) crystals of less than 40 nm formed initially, but slowly disappeared except for a few that grew larger at the expense of the small crystals. This finding clearly indicates that the crystal growth of Ni(OH)(2) during the whole hydrothermal process was governed by the Ostwald ripening. With this mechanism and the spatial restriction, single crystals of beta-Ni(OH)(2) nanorods with a length of over 150 nm were finally formed. PMID- 17712440 TI - Use of 1,10-phenanthroline in diiron dithiolate derivatives related to the [Fe Fe] hydrogenase active site. AB - Treatment of [Fe(2)(micro-pdt)(CO)(6)] (pdt = S(CH(2))(3)S) with 1,10 phenanthroline (phen) in refluxing toluene affords the asymmetric complex [Fe(2)(micro-pdt)(CO)(4)(phen)] (1); the protonation of with HBF(4).OEt(2) in CD(2)Cl(2) at 203 K has been monitored by (1)H NMR. PMID- 17712443 TI - Organic-inorganic hybrid materials constructed from inorganic lanthanide sulfate skeletons and organic 4,5-imidazoledicarboxylic acid. AB - Five different types of the lanthanide sulfate-carboxylates family, [La(2)(SO(4))(Himdc)(2)(H2O)2] , [Gd(2)(SO(4))(2)(Himdc)(H2O)3].H2O , [Ln(2)(SO(4))(2)(Himdc)(H2O)(3)].H2O (Ln = Gd3a, Eu3b), [Eu(6)Cu(SO(4))(6)(Himdc)(4)(H2O)(14)] , and [Ln(Himc)(SO(4))(H2O)] (Ln = Eu5a, Gd5b, Tb5c, Dy5d, Er5e); H(2)imc = 4-imidazolecarboxylic acid, H(3)imdc = 4,5 imidazoledicarboxylic acid) have been obtained by hydrothermal reactions of Ln(2)O(3), transition metal sulfates and H(3)imdc at 170 degrees C and characterized by means of elemental analyses, IR, TG analysis, luminescence spectroscopy and single crystal X-ray diffraction. The 3D structure of 1 is constructed from alternately linkages of organic {La(Himdc)} layers and inorganic {La(2)O(2)(SO(4))} layers, with the La atoms as hinges. 2 and 3a/3b both contain alternately arranged 1D left- and right-handed helical {Ln(imdc)} chains bridged by SO(4)(2-) anions to form a 3D framework with 1D rectangle-like channels along the b axis. The structural differences of 2 and 3a/3b lie in the linkages of the SO(4)(2-) anions. Complex 4 consists of 2D tubular Eu-sulfate layers pillared by {Cu(Himdc)(2)} units to generate a 3D network. Complexes 5a-5e possess 2D bamboo raft-like layer structures based on helical tubes. Interestingly, H(2)imc comes from the in-situ decarboxylation of H(3)imdc in the hydrothermal reactions. The luminescence properties of the complexes 3a, 4, 5a 5c, 5d were investigated in solid state at room temperature. PMID- 17712442 TI - Cyclometalated iridium and platinum complexes as singlet oxygen photosensitizers: quantum yields, quenching rates and correlation with electronic structures. AB - Photophysical properties are reported for a series of cyclometalated platinum and iridium complexes that can serve as photosensitizers for singlet oxygen. The complexes have the formula (C;N)(2)Ir(O;O) or (C;N)Pt(O;O) where C;N is a monoanionic cyclometalating ligand such as 2-(phenyl)pyridyl and 2 (phenyl)quinolyl, and O;O is the ancillary ligand acetylacetonate (acac) or dipivaloylmethane (dpm). Also examined were a series of (N;N)PtMe(2) complexes where N;N is a diimine such as 2,2'-bipyridyl. In general, the cyclometalated complexes are excellent photosensitizers for the production of singlet oxygen, while the (N;N)PtMe(2) complexes were ineffective at this reaction. Quantum yields of singlet oxygen production range from 0.9-1.0 for the cyclometalated Pt complexes and 0.5-0.9 for Ir complexes. Luminescence quenching and singlet oxygen formation of the Ir complexes occurs from a combination of electron and energy transfer processes, whereas the Pt complexes only react by energy transfer. For Ir complexes with low emission energy, physical deactivation of the triplet excited state becomes competitive with energy transfer to ground state dioxygen. The rates of singlet oxygen quenching for the complexes presented here are in the range 6 x 10(6)-2 x 10(7) M(-1) s(-1) for Pt complexes and 2 x 10(5)-2 x 10(7) M( 1) s(-1) for Ir complexes, respectively. Differences in the efficiency of both forming and quenching singlet oxygen between the Ir and Pt cyclometalates are believed to come about from the more exposed coordination geometry in the latter species. PMID- 17712444 TI - Synthesis, photophysical and photochemical properties of substituted zinc phthalocyanines. AB - The synthesis, photophysical and photochemical properties of the 4-({3,4,5-tris [2-(2-ethoxyethoxy)ethyloxy]benzyl}oxy) and 4-({3,4,5-tris-[2-(2 ethoxyethoxy)ethyloxy]benzyl}thio) zinc(ii) phthalocyanines are reported for the first time. The new compounds have been characterized by elemental analysis, IR, (1)H and (13)C NMR spectroscopy, electronic spectroscopy and mass spectra. General trends are described for photodegradation, singlet oxygen, fluorescence and triplet excited state quantum yields, and triplet state and fluorescence lifetimes of these compounds in dimethylsulfoxide (DMSO). The fluorescence of the complexes was quenched by benzoquinone (BQ). The effects of the substitution on the photophysical and photochemical parameters of the zinc(II) phthalocyanines (6, 7 and 8) are also reported. Photophysical and photochemical properties of phthalocyanine complexes are very useful for PDT applications. The substituted Zn(II) phthalocyanines showed high triplet and singlet oxygen quantum yields. High singlet oxygen quantum yields are very important for Type II mechanism. Thus, these complexes show potential as Type II photosensitizers. PMID- 17712445 TI - Construction of trinuclear iridium clusters through ancillary ortho-carborane-1,2 diselenolato ligands, with simultaneous iridium-induced B-H activation. AB - The reaction of the 16-electron "pseudo-aromatic" complex Cp*Ir[Se2C2(B10H10)] (1, Cp* = eta5-C5Me5) with [Ir(cod)(micro-OC2H5)]2 leads to the trinuclear iridium complexes {(cod)Ir[Se2C2(B10H8)(OC2H5)]}Ir{[Se2C2(B10H10)]IrCp*} (2), {(cod)Ir[Se2C2(B10H8)(OC2H5)]}Ir{[Se2C2(B10H9)]IrCp*} (3), {Cp*Ir[Se2C2(B10H9)]}{IrSe(2)[C2(B10H9)(OC2H5)]}{[Se2C2(B10H10)] IrCp*} (4) and one mononuclear complex Cp*Ir[Se2C2(B10H8)(OC2H5)(2)] (5). The reactivity of 2 was investigated and revealed that transformation from 2 to 3 occurred thermally in solution. The transoid complex 2 (with the carborane diselenolato units in trans position) can be converted in nearly 90% yield to the cisoid complex 3. In complexes 2, 3, two diselenolato carborane ligands bridge the Ir(3) core, which consists of Ir-Ir metal bonds. Compared with transoid 2, the cisoid 3 contains two iridium-boron bonds. Complex 4 consists of three different coordination environment carborane ligands (Ir-B(cluster): {Cp*Ir[Se2C2(B10H9)]}, O B(cluster): {[Se2C2(B10H9)](OC2H5)}, and intact carborane: {Cp*Ir[Se2C2 (B10H10)]}) without the presence of a metal-metal bond. Analogous reaction of 1 with [Ir(cod)(micro-OCH(3))](2) results in formation of the trinuclear complex {Cp*Ir[Se2C2(B10H9)]}{IrSe(2)[C2(B10H9)(OCH3)]}{[Se2C2(B10H10)]IrCp*} (6) and mononuclear complex Cp*Ir[Se2C2(B10H8)(OCH3)(2)] (7). The structures of 2, 3, 4, 5, 6 and 7 have been determined by crystallographic studies. PMID- 17712446 TI - Carboxylate lability as a factor in the Rh2(carboxylate)4-catalysed cyclopropenation and cyclopropanation of alkynes and alkenes. AB - The mechanism of Rh(2)(carboxylate)(4)-catalysed cyclopropenation and cyclopropanation via two different pathways has been investigated computationally. The two pathways either (a) conserve the Rh(2)O(8) framework, with initial coordination of CH(2)N(2) and further reaction occurring at an axial acceptor site, or (b) allow dechelation of carboxylate to liberate an equatorial site for activation of bound CH(2)N(2.) Calculations on the system in question [Rh(2)(formate)(4), CH(2)N(2), C(2)H(4) or C(2)H(2)] show that both pathways are equally favoured. The importance of coordinated solvent in determining the reaction pathway is demonstrated. PMID- 17712447 TI - A minimalist approach to understanding the efficiency of mononuclear Zn(II) complexes as catalysts of cleavage of an RNA analog. AB - Mononuclear complexes between Zn(2+) and the following four macrocycles were prepared: 1,4,7,10-tetraazacyclododecane (1), 1-oxa-4,7,10-triazacyclododecane (2), 1,5,9-triazacyclododecane (3) and 1-hydroxyethyl-1,4,7-triazacyclononane (4). The pH rate profiles of values of the observed second-order rate constant log (k(Zn))(app) for Zn(X)(OH(2))-catalyzed cleavage (X = 1, 2, 3 and 4) of 2 hydroxypropyl-4-nitrophenyl phosphate (HpPNP) show downward breaks centered at the pK(a) for ionization of the respective zinc bound water. At low pH, where the rate acceleration for the catalyzed reaction is largest, the stabilizing interaction between the catalyst and the bound transition state is 5.7, 7.4, 7.4 and 5.9 kcal mol(-1) for the reactions catalyzed by Zn(1)(OH(2)), Zn(2)(OH(2)), Zn(3)(OH(2)) and Zn(4)(OH(2)), respectively. The interactions between the metal cation and the macrocycle cause either a modest increase or reduction in transition state stabilization compared with 6.6 kcal mol(-1) stabilization for catalysis by Zn(OH(2))(6). The best Zn(II)-macrocycle catalysts are those for which the interactions between the metal ion and macrocycle are the weakest. Inhibition studies show that each of the four catalysts form complexes with phosphate and oxalate dianions with a much higher affinity than diethyl phosphate monoanion, consistent with stronger interaction of the catalysts with the transition state dianion compared with the substrate monoanion HpPNP. The pH dependence of methyl phosphate inhibition of Zn(2) catalyzed cleavage of HpPNP shows that only the Zn(2)(OH(2)) species binds the inhibitor. This result is consistent with a mechanism that has Zn(2)(OH(2)) as the active catalytic species. PMID- 17712448 TI - Protonation, electrochemical properties and molecular structures of halogen functionalized diiron azadithiolate complexes related to the active site of iron only hydrogenases. AB - Diiron complexes [{(micro-SCH2)2NCH2C6H4X}{Fe(CO)2L}2] (L = CO, X = 2-Br, 1; 2-F, 2; 3-Br, 3; L = PMe(3), X = 2-Br, 4) were prepared as biomimetic models of the iron-only hydrogenase active site. The N-protonated species [(NH)]+ClO(4)(-), [(NH)](+)ClO(4)(-) and the micro-hydride diiron complex [4(FeHFe)]+PF(6)(-) were obtained in the presence of proton acids and well characterized. The protonation process of 4 was studied by in-situ IR and NMR spectroscopy, which suggests the formation of the diprotonated species [4(NH)(FeHFe)](2+) in the presence of an excess of proton acid. The molecular structures of 1, [(NH)]+ClO(4)(-), 4 and [4(FeHFe)]+PF(6)(-) were determined by X-ray crystallography. The single-crystal X-ray analysis reveals that an intramolecular H...Br contact (2.82 A) in the crystalline state of [1(NH)]+ClO(4)(-). In the presence of 1-6 equiv of the stronger acid HOTf, complex 1 is readily protonated on the bridged-N atom and can electrochemically catalyze the proton reduction at a relatively mild potential (ca.-1.0 V). Complex 4 is also electrocatalytic active at -1.4 V in the presence of HOTf with formation of the micro-hydride diiron species. PMID- 17712449 TI - Hydrodefluorination of pentafluoropyridine at rhodium using dihydrogen: detection of unusual rhodium hydrido complexes. AB - The pentafluoropyridyl complex [Rh(4-C5NF4)(PEt3)3] (3) reacts with H2 to give initially the dihydrido complex cis-mer-[Rh(H)2(4-C5NF4)(PEt3)3] (6). Within a few hours 2,3,5,6-tetrafluoropyridine as well as two rhodium(III) complexes mer [Rh(H)3(PEt3)3] (mer-) and fac-[Rh(H)3(PEt3)3] (fac-) are formed. A catalytic C-F activation process for the formation of 2,3,5,6-tetrafluoropyridine starting from pentafluoropyridine and dihydrogen using 3 as a catalyst has been developed. Reaction of [RhH(PEt3)3] (1) with hydrogen affords fac-[Rh(H)3(PEt3)3] (fac-7) and mer-[Rh(H)3(PEt3)3] (mer-7) in a ratio of 1 : 7.25 at 193 K. The latter complex represents the first mononuclear rhodium compound bearing trans-hydrides. PMID- 17712450 TI - Bowl adamanzanes--bicyclic tetraamines: syntheses and crystal structures of complexes with cobalt(III) and chelating coordinated oxo-anions. AB - Seven cobalt(III) complexes of the macrobicyclic tetraamine ligand [2(4).3(1)]adamanzane ([2(4).3(1)]adz) are reported along with the crystal structure of six of these complexes. The solid state and solution structures are discussed, and a detailed assignment of the NMR spectra of the sulfato complex is provided. Four of the seven complexes contain a chelate coordinating oxo-anion (sulfate, formiate, nitrate, carbonate). Equilibration of these species with the corresponding diaqua complex is generally slow. The rates of equilibration in 5 mol dm(-3) perchloric acid at 25 degrees C have been measured, yielding half lives of 20 min, 10 min and 3 h for the sulfato, formiato and carbonato species respectively. The corresponding reaction for the nitrato complex occurs with a half life of less than 3 min. The concentration acid dissociation constant for the Co([2(4).3(1)]adz)(HCO(3))(2+) ion has been measured to K(a) = 0.33 mol dm( 3) [25 degrees C, I = 2 mol dm(-3)] and K(a) = 0.15 mol dm(-3) [25 degrees C, I = 5 mol dm(-3)]. The propensity for coordination of sulfate was found to be large enough for a quantitative conversion of the carbonato complex to the sulfato complex to occur in 3 mol dm(-3) triflic acid containing a small sulfate contamination. On this basis the decarboxylation in 5 mol dm(-3) triflic acid of the corresponding cobalt(III) carbonato complex of the larger macrobicyclic tetraamine ligand [3(5)]adz was reinvestigated and found to lead to the sulfato complex as well. The difference in exchange rate of the oxo-anion ligands for the cobalt(III) complexes of the two adamanzane ligands is discussed and attributed to fundamental differences in the molecular structure where an inverted configuration of the secondary non-bridged amine groups is seen for the complexes of the larger [3(5)]adz ligand. The high affinity for chelating coordination of oxo-anions for these two cobalt(iii)-adamanzane-moieties is rationalised on basis of the N-Co-N angles. N-Co-N angles are compared for a series of adamanzane complexes, and the structural consequences are discussed. PMID- 17712451 TI - Polymerization of methyl methacrylate catalyzed by nickel complexes with hydroxyindanone-imine ligands. AB - A series of new hydroxyindanone-imine ligands [PhN=CC2H3(CH3)C6H2(CH3)OH] (HL1) and [ArN=CC2H3(CH3)C6H2(R)OH] (Ar = 2,6-i-Pr(2)C(6)H(3), R = Me (HL2), R = H (HL3), and R = Cl (HL4)) were synthesized and characterized. Reactions of hydroxyindanone-imines with Ni(OAc)(2).4H(2)O result in the formation of the trinuclear hexa(indanone-iminato)tri(nickel(II)) complex Ni(3)[PhN=CC2H3(CH3)C6H2(CH3)O](6) (1) and the mononuclear bis(indanone iminato)nickel(II) complexes Ni[ArN=CC2H3(CH3)C6H2(R)O](2) (Ar = 2,6-i Pr(2)C(6)H(3), R = Me (2), R = H (3), and R = Cl (4)). All nickel complexes were characterized by their IR, NMR spectra and elemental analyses. In addition, X-ray structure analyses were performed for complexes 1 and 2. After being activated with methylaluminoxane (MAO), these nickel(II) complexes can be used as catalysts for the polymerization of methyl methacrylate (MMA) to produce syndiotactic-rich PMMA. Catalytic activities and the degree of syndiotacticity of PMMA have been investigated for various reaction conditions. PMID- 17712453 TI - Autoionization at the surface of neat water: is the top layer pH neutral, basic, or acidic? AB - Autoionization of water which gives rise to its pH is one of the key properties of aqueous systems. Surfaces of water and aqueous electrolyte solutions are traditionally viewed as devoid of inorganic ions; however, recent molecular simulations and spectroscopic experiments show the presence of certain ions including hydronium in the topmost layer. This raises the question of what is the pH (defined using proton concentration in the topmost layer) of the surface of neat water. Microscopic simulations and measurements with atomistic resolution show that the water surface is acidic due to a strong propensity of hydronium (but not of hydroxide) for the surface. In contrast, macroscopic experiments, such as zeta potential and titration measurements, indicate a negatively charged water surface interpreted in terms of preferential adsorption of OH(-). Here we review recent simulations and experiments characterizing autoionization at the surface of liquid water and ice crystals in an attempt to present and discuss in detail, if not fully resolve, this controversy. PMID- 17712454 TI - Formation and properties of metal clusters isolated in helium droplets. AB - The unique conditions forming atomic and molecular complexes and clusters using superfluid helium nanodroplets have opened up an innovative route for studying the physical and chemical properties of matter on the nanoscale. This review summarizes the specific characteristics of the formation of atomic clusters partly generated far from equilibrium in the helium environment. Special emphasis is on the optical response, electronic properties as well as dynamical processes which are mostly affected by the surrounding quantum matrix. Experiments include the optical induced response of isolated cluster systems in helium under quite different excitation conditions ranging from the linear regime up to the violent interaction with a strong laser field leading to Coulomb explosion and the generation of highly charged atomic fragments. The variety of results on the outstanding properties in the quantum size regime highlights the peculiar capabilities of helium nanodroplet isolation spectroscopy. PMID- 17712455 TI - A unified scheme for the calculation of differentiated and undifferentiated molecular integrals over solid-harmonic Gaussians. AB - Utilizing the fact that solid-harmonic combinations of Cartesian and Hermite Gaussian atomic orbitals are identical, a new scheme for the evaluation of molecular integrals over solid-harmonic atomic orbitals is presented, where the integration is carried out over Hermite rather than Cartesian atomic orbitals. Since Hermite Gaussians are defined as derivatives of spherical Gaussians, the corresponding molecular integrals become the derivatives of integrals over spherical Gaussians, whose transformation to the solid-harmonic basis is performed in the same manner as for integrals over Cartesian Gaussians, using the same expansion coefficients. The presented solid-harmonic Hermite scheme simplifies the evaluation of derivative molecular integrals, since differentiation by nuclear coordinates merely increments the Hermite quantum numbers, thereby providing a unified scheme for undifferentiated and differentiated four-center molecular integrals. For two- and three-center two electron integrals, the solid-harmonic Hermite scheme is particularly efficient, significantly reducing the cost relative to the Cartesian scheme. PMID- 17712456 TI - Theoretical analysis of the hydrogen bond of imidazolium C(2)-H with anions. AB - The intermolecular interaction energies of ion pairs of imidazolium-based ionic liquids were studied by MP2/6-311G level ab initio calculations. Although the hydrogen bond between the C(2) hydrogen atom of an imidazolium cation and anion has been regarded as an important interaction in controlling the structures and physical properties of ionic liquids as in the cases of conventional hydrogen bonds, the calculations show that the nature of the C(2)-H...X interaction is considerably different from that of conventional hydrogen bonds. The interaction energies of the imidazolium cation with neighboring anions in the four crystals of ionic liquids were calculated. The size of the interaction is determined mainly by the distance between the imidazolium ring and anion. The calculated interaction energy is nearly inversely proportional to the distance, which shows that the charge-charge interaction is the dominant interaction in the attraction. The orientation of the anion relative to the C(2)-H bond does not greatly affect the size of the interaction energy. Calculated interaction energy potentials of 1,3-dimethylimidazolium tetrafluoroborate ([dmim][BF(4)]) complexes show that the C(2)-H bond does not prefer to point toward a fluorine atom of the BF(4). This shows that the C(2)-H...X hydrogen bond is not essential for the attraction. PMID- 17712457 TI - Automated parameter optimization in modeling absorption spectra and resonance Raman excitation profiles. AB - An automated method is described for optimizing the molecular parameters in simultaneous modeling of optical absorption spectra and resonance Raman excitation profiles. The method utilizes a previously developed Fortran routine that calculates absorption spectra and Raman excitation profiles for polyatomic molecules in solution from a model for the potential energy surfaces and spectral broadening mechanisms. It is combined here with an optimization routine from the commercial MATLAB package that iteratively adjusts the parameters of the molecular model to minimize the least-squared error between calculated and experimental spectra. Optimizations that typically require days to weeks of human time when performed interactively can be accomplished automatically in less than an hour of computer time. The method can handle large molecules (we show results for as many as 23 Raman-active modes) and mixtures of spectral broadening mechanisms (lifetime, Brownian oscillator, and inhomogeneous), and is robust toward noise or missing data points. PMID- 17712458 TI - Coordination and solvation of copper ion: infrared photodissociation spectroscopy of Cu(+)(NH(3))(n) (n = 3-8). AB - Coordination and solvation structures of the Cu(+)(NH(3))(n) ions with n = 3-8 are studied by infrared photodissociation spectroscopy in the NH-stretch region with the aid of density functional theory calculations. Hydrogen bonding between NH(3) molecules is absent for n = 3, indicating that all NH(3) molecules are bonded directly to Cu(+) in a tri-coordinated form. The first sign of hydrogen bonding is detected at n = 4 through frequency reduction and intensity enhancement of the infrared transitions, implying that at least one NH(3) molecule is placed in the second solvation shell. The spectra of n = 4 and 5 suggest the coexistence of multiple isomers, which have different coordination numbers (2, 3, and 4) or different types of hydrogen-bonding configurations. With increasing n, however, the di-coordinated isomer is of growing importance until becoming predominant at n = 8. These results signify a strong tendency of Cu(+) to adopt the twofold linear coordination, as in the case of Cu(+)(H(2)O)(n). PMID- 17712459 TI - Kinetics and products from reaction of Cl radicals with dioctyl sebacate (DOS) particles in O(2): a model for radical-initiated oxidation of organic aerosols. AB - The reaction of Cl radicals with bis (2-ethylhexyl) sebacate (also known as dioctyl sebacate, DOS) particles in the presence of O(2) is studied as a model of radical-initiated oxidation of organic aerosols. The uptake coefficient as measured from the rate of loss of DOS is gamma(DOS) = 1.7 (+/-0.3) indicating that a radical chain is operative. It is observed that nearly all of the detected products, accounting for 86% (+/-12%) of the reacted DOS, remain in the particles indicating that they are not efficiently volatilized. Correspondingly, the particles do not decrease in volume even after 60% of the DOS has reacted; upon further reaction the volume does decrease by up to 20%. Additionally, the mass of a DOS film increases with reaction indicating that the density increases. The two primary products identified are the ketone (38 +/- 10% yield) and alcohol (14 +/- 4% yield) resulting from reactions of alkylperoxy radicals originating from DOS oxidation. The fact that the ketone/alcohol ratio is >1 implies that the Russell mechanism, the typical fate of alkylperoxy radicals in liquids whereby both a ketone and an alcohol are generated, is not the only source of ketones. In fact, the ketone yield demonstrates a Langmuir-Hinshelwood type dependence on the O(2) concentration indicating that 44% (+/-8%) of the ketone is created from the reaction of alkoxy radicals with O(2) at the surface of the particles (at 20% O(2)). While this is a common reaction in the gas phase, it is generally not considered to occur in organic solvents. Furthermore, the appearance of gas-phase H(2)O(2) suggests that peroxy radicals react to form two ketones and H(2)O(2)via the Bennett and Summers mechanism. The absence of aldehyde products, both in the gas phase and in the particles, indicates that beta-scission of the alkoxy radicals is not significant. The results of this study suggest that organic aerosols in the troposphere are efficiently oxidized by gas-phase radicals but that their chemical transformation does not lead to their removal through volatilization. PMID- 17712460 TI - Synthesis and characterization of nickel nanoparticles dispersed in imidazolium ionic liquids. AB - The diameter and size-distribution of Ni nanoparticles prepared by the decomposition of [bis(1,5-cyclooctadiene)nickel(0)] organometallic precursor dissolved in 1-alkyl-3-methylimidazolium N-bis(trifluoromethanesulfonyl) amide ionic liquids depend on the length of the alkyl side-chain of the imidazolium ring. The increase of the organization range order of the ionic liquid that increases with that of the alkyl side-chain (from n-butyl to n-hexadecyl) induces the formation of nanoparticles with a smaller diameter and size-distribution. The cubic fcc Ni nanoparticles with 4.9 +/- 0.9 to 5.9 +/- 1.4 nm in mean diameter and monomodal size-distribution thus prepared are probably composed of a small cap layer of NiO around a core of Ni metal. The contribution of the oxide layer also depends on the medium i.e. the metal oxide ratio increases in salts containing four to eight carbons on their side-chains and then decreases as the number of carbons increases. The Ni nanoparticles dispersed in the ionic liquids are active catalysts for the hydrogenation of olefins under relatively mild reaction conditions. PMID- 17712461 TI - In situ monitoring of desilication of MFI-type zeolites in alkaline medium. AB - In situ pH and Attenuated Total Reflection (ATR) infrared techniques have been successfully applied in order to gain insights into the dissolution process connected to mesopore formation occurring upon alkaline treatment of ZSM-5 zeolites. Online pH measurements reveal a similar consumption of OH(-) ions in the initial stage of the reaction independent of the Si/Al ratio of the zeolite. In view of the greatly different mesoporosity development, the extraction of polymeric silica entities is anticipated, its structure depending on the framework Si/Al ratio. In agreement, ATR-IR experiments have confirmed dissolution of polymeric silicon-containing species that in the course of the alkaline treatment disintegrate into smaller entities. A direct relation between the type of porosity developed and the process of silicon extraction as measured in the liquid phase cannot be drawn. PMID- 17712462 TI - Adenosine deaminase activity in serum of patients with hepatitis -- a useful tool in monitoring clinical status. AB - BACKGROUND AND PURPOSE: The evaluation of adenosine deaminase (ADA) activity in sera of patients with hepatitis should be considered a useful tool in the monitoring of their clinical status. In this study, we aimed to determine the relationship between viral load, transaminase levels, and serum ADA levels in hepatitis B virus (HBV)- and hepatitis C virus (HCV)-infected patients. METHODS: Seventy three patients with hepatitis B, 71 patients with hepatitis C and 40 healthy individuals were included. Patients with HBV and HCV infections were classified into 3 groups according to viral load. Serum ADA levels were investigated by colorimetric assays. RESULTS: Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and ADA levels of HBV- and HCV-infected patients were higher than those of the control group. These differences were statistically significant for the levels of all enzymes in HCV-infected patients (p<0.05), and all except AST (p>0.05) in HBV-infected patients. ADA levels of HBV infected patients with high viral loads were higher than those in HBV-infected patients with intermediate and low viral loads, and the difference was detectably significant between patients with high and intermediate viral loads. Evaluation of HCV-infected patients according to viral load showed no statistically significant relationship between viral load and serum ADA, ALT, and AST levels (p>0.05). HBV- and HCV-infected patients with high ALT and AST levels showed statistically significantly higher levels of ADA than patients with normal ALT and AST levels (p<0.001). CONCLUSIONS: We suggest that serum ADA levels are associated more with the level of serum transaminases than viral load in HBV- and HCV-infected patients. In the treatment of patients with hepatitis, serum ADA levels should be considered a useful tool for the monitoring of liver condition. PMID- 17712463 TI - Epidemiology of respiratory syncytial virus infection in northern Taiwan, 2001 2005 -- seasonality, clinical characteristics, and disease burden. AB - BACKGROUND AND PURPOSE: Respiratory syncytial virus (RSV) is an important pathogen in children less than 2 years old. However, there is limited epidemiological data about RSV infection in Taiwan. This study aimed to investigate the clinical, epidemiological, virological, and economical aspects of RSV infections in Taiwan. METHODS: We collected data of children with positive RSV respiratory specimens at the Laboratory of Virology, National Taiwan University Hospital, between January 2001 and December 2005. Medical charts were reviewed retrospectively. RESULTS: 892 children in whom acute bronchiolitis was the predominant diagnosis (60.7%) were enrolled. Compared with those without underlying disease (n = 630), children with underlying disease (n = 262) were older (11 vs 9 months), required longer oxygen therapies (7 vs 4 days), were more likely to have lower respiratory tract involvement (96.2% vs 92.3%) and intensive care unit stays (49.0% vs 9.4%), endotracheal intubations (21.0% vs 2.0%), ribavirin use (35.0% vs 1.4%), and had higher medical costs (US$ 1250 vs 688), and nosocomial infection (24.8% vs 1.0%). Compared with those without endotracheal intubation (n = 824), cases requiring endotracheal intubation (n = 68) had higher rates of underlying diseases (80.9% vs 25.1%), especially congenital heart diseases (45.6% vs 8.1%), chronic lung disease (13.2% vs 3.2%) and neurological disorders (17.6% vs 3.5%). There was a biennial pattern with peaks in the spring and fall. Medical cost was estimated to be US$ 250,000 annually in our hospital. CONCLUSION: In children with underlying diseases, RSV infection is associated with significant morbidity, and even mortality. Nosocomial infections appear to be an important cause of RSV transmission. The seasonality of RSV infections in Taiwan showed a biennial pattern with peaks in spring and fall. PMID- 17712464 TI - A cluster of adenovirus serotype 3 infections in children in northern Taiwan: clinical features and laboratory findings. AB - BACKGROUND AND PURPOSE: To define clinical manifestations and laboratory findings of adenovirus serotype 3 infections in children. METHODS: A total of 499 children diagnosed with adenovirus infections based on throat virus cultures were treated in Chang Gung Children's Hospital from January 2004 to May 2005. Serotypes were determined in 197 strains, of which majority were serotype 3 (n = 147; 107 inpatients and 40 outpatients). Demographics, clinical presentations, and laboratory findings of the inpatients and demographics only of the outpatients were evaluated. RESULTS: The mean age was 4 years and 7 months (range, 5 months to 12 years). Adenovirus serotype 3 infections were identified in 74.6% of the 197 children examined between January 2004 and May 2005. The mean time lag between specimen collection and a positive culture result was 8.3 days. The 3 most common symptoms were fever (100.0%), cough (87.9%), and rhinorrhea (73.8%). The mean duration of fever was 6 days, and the mean duration before admission was 4 days. The mean length of hospital stay was 5.4 days. The 3 most common diagnoses were tonsillitis/pharyngitis (43.0%), pneumonia/bronchopneumonia (32.7%), and acute otitis media (6.5%). Fifteen children had documented bacterial coinfection. Leukopenia (white blood cell [WBC] <5000/mm3) was noted in 2 patients (2.1%) and leukocytosis (WBC > or =15,000/mm3) in 28 patients (30.4%). Of the 92 children with serum C-reactive protein level measurements, 74 children (80.4%) had a serum C-reactive protein level >40 mg/L. Although 69 (64.0%) of the 107 hospitalized children never received antibiotic therapy, the outcomes were excellent. CONCLUSION: By recognizing that children with adenoviral infections may present with prolonged high fever, leuokocytosis, and elevated C-reactive protein levels, mimicking symptoms of bacterial infections, clinicians will be able to avoid the unnecessary prescription of antibiotics to these patients. PMID- 17712465 TI - Molecular epidemiology of community-acquired methicillin-resistant Staphylococcus aureus bacteremia in a teaching hospital. AB - BACKGROUND AND PURPOSE: Methicillin-resistant Staphylococcus aureus (MRSA) is a key nosocomial pathogen globally. Community-acquired MRSA (CA-MRSA) infections have become a growing problem in recent years. The purpose of this 4-year retrospective study was to analyze the molecular epidemiology and susceptibility pattern of isolates from adults (> or =18 years of age) with CA-MRSA bacteremia in northern Taiwan. METHODS: Molecular epidemiology of CA-MRSA isolates was analyzed by pulsed-field gel electrophoresis. Antimicrobial susceptibility was tested by the disk diffusion method and the minimal inhibitory concentration was determined by Etest. RESULTS: Thirty eight patients with CA-MRSA bacteremia were enrolled. Thirty one CA-MRSA isolates were available for further molecular typing and susceptibility testing. A total of 13 distinct genotypes were identified and 48.4% (15/31) of the isolates were found to belong to genotype A. Genotype A CA MRSA isolates were closely associated with the nosocomial strains. All CA-MRSA isolates were multidrug resistant (19.4% susceptible to clindamycin and 25.8% to trimethoprim-sulfamethoxazole) and consistent susceptibility was only observed to glycopeptides, rifampin, and linezolid. CONCLUSIONS: This study demonstrated that although CA-MRSA genotypes were heterogeneous, the predominant genotype that was circulating in our community was genotype A. Also, the multidrug resistance of CA MRSA might be connected to the spreading of nosocomial strains in the community. PMID- 17712466 TI - Endocarditis: impact of methicillin-resistant Staphylococcus aureus in hemodialysis patients and community-acquired infection. AB - BACKGROUND AND PURPOSE: Staphylococcus aureus endocarditis showed an increase in the 1990s compared to the 1980s. In order to characterize the clinical and laboratory features of S. aureus endocarditis, we retrospectively reviewed the medical charts of patients diagnosed with endocarditis in the 5-year-period between 2000 and 2005. METHODS: From August 2000 to August 2005, 22 patients with a definite diagnosis of infective endocarditis (IE) caused by S. aureus were reviewed. RESULTS: Of the 22 patients reviewed, 16 cases were caused by methicillin-resistant S. aureus (MRSA) while the causative agent in the other 6 cases was methicillin-susceptible S. aureus (MSSA). Patients with MRSA infections were more likely to show hospital-acquired infections, hemodialysis and ventilator dependence, septic shock, impaired initial renal function, persistent bacteremia, and a higher 3-month mortality rate. MSSA infections in patients were more likely to be community-acquired, and show intravenous drug use and longer days of fever prior to admission. Three patients with MRSA endocarditis, however, presented community-acquired infections. The mortality rate of MRSA endocarditis in hemodialysis patients was 90% (9/10). CONCLUSIONS: MRSA IE is more common than MSSA IE and is associated with a significantly poorer prognosis, especially in patients undergoing hemodialysis. Although most cases of MRSA IE are hospital acquired, we noticed 3 cases of community-acquired MRSA IE. As MRSA IE has been noticed in the community and hemodialysis patients in recent years, and is associated with higher mortalities, strategies for its prevention and management are warranted. PMID- 17712467 TI - An outbreak of methicillin-resistant Staphylococcus aureus infection in patients of a pediatric intensive care unit and high carriage rate among health care workers. AB - BACKGROUND AND PURPOSE: Methicillin-resistant Staphylococcus aureus (MRSA) has been the leading cause of nosocomial infections in many hospitals. To investigate the impact of carriage by health care workers (HCWs) on patient transmission, surveillance culture was performed following an outbreak of MRSA in a pediatric intensive care unit (PICU). METHODS: Isolates from 61 HCWs and 10 environmental sites were collected. Pulsed-field gel electrophoresis (PFGE) and antibiogram analysis were performed to determine the clonal relationship between isolates and potential routes of transmission. RESULTS: The overall carriage rate of HCWs was 67.2% (41/61) for S. aureus and 26.2% (16/61) for MRSA. One MRSA was isolated from the 10 environmental sites sampled. Two major MRSA clusters were identified based on the PFGE patterns. Isolates with indistinguishable PFGE patterns (pulsotype A) were found in all patient isolates from the outbreak, from several HCWs plus the environmental isolate; all were resistant to ciprofloxacin, clindamycin, erythromycin, gentamicin, tetracycline, and trimethoprim sulfamethoxazole. Interestingly, the isolate from a patient who had prolonged hospitalization in PICU had PFGE patterns (pulsotype B) distinct from the strains involved in the outbreak. This strain was susceptible to ciprofloxacin and trimethoprim-sulfamethoxazole, and was also found in several HCWs. Thus, there appeared to be 2 main MRSA clones circulating in the PICU of our hospital. CONCLUSIONS: Person-to-person and environment-to-person (or vice versa) transmissions are documented in this study. Strict hand washing before and after patient contact must be enforced and closely monitored, as it is the principal preventive measure in containing the spread of MRSA. To prevent the emergence of vancomycin-resistant MRSA and the further transmission of multidrug-resistant organisms, implementation of periodic and routine active surveillance cultures as part of infection control measures may also be evaluated. PMID- 17712468 TI - Necrotizing fasciitis in a medical center in northern Taiwan: emergence of methicillin-resistant Staphylococcus aureus in the community. AB - BACKGROUND AND PURPOSE: Necrotizing fasciitis (NF) is a rapidly progressive life threatening infection. It is located in the deep fascia, with secondary necrosis of the subcutaneous tissues requiring urgent surgical and medical therapy. Staphylococcus aureus is, historically, a very uncommon cause of NF, but we have recently noted an increasing number of these infections being caused by community acquired methicillin-resistant S. aureus (CA-MRSA). METHODS: The medical records of 53 patients diagnosed with NF between January 2001 and December 2005 were reviewed. A standardized instrument was used to abstract information from the medical records of each patient. RESULTS: S. aureus monomicrobial infection accounted for 37.7% (20/53) of the causal organisms noted. Of the 20 strains of S. aureus, 8 were methicillin-sensitive S. aureus and 12 were MRSA. In the 12 patients with MRSA infection, 7 had CA-MRSA. All patients with NF caused by CA MRSA had no serious coexisting conditions or risk factors. All CA-MRSA isolates were susceptible to ciprofloxacin, trimethoprim-sulfamethoxazole, and vancomycin in vitro. All were cured after surgical intervention and medical treatment. CONCLUSIONS: For patients with severe invasive NF caused by CA-MRSA, glycopeptides may be prescribed as an empirical treatment until susceptibility results. The prognosis of NF caused by CA-MRSA was good after adequate surgical and antimicrobial treatment. PMID- 17712469 TI - Factors that affect sputum conversion and treatment outcome in patients with Mycobacterium avium-intracellulare complex pulmonary disease. AB - BACKGROUND AND PURPOSE: To investigate factors that might affect the sputum conversion and treatment outcome of Mycobacterium avium-intracellulare complex (MAC) pulmonary disease. METHODS: This retrospective study reviewed 46 patients diagnosed with MAC pulmonary disease at the Chang Gung Memorial Hospital at Linkou between July 1998 and February 2005. The diagnosis was based on the American Thoracic Society criteria for diagnosis of disease due to non tuberculous mycobacteria of 1997. RESULTS: Of the 46 patients reviewed, 30 were men and 16 women, with a mean age of 64.39 years (range, 28-87 years). Thirty one patients had preexisting lung diseases, including history of pulmonary tuberculosis in 23 patients. Follow-up of sputum cultures could be traced in 28 patients, and sputum conversion was found in 17 patients. Of the 28 patients, 9 were treated with anti-MAC drugs for <5 months or with a regimen not containing at least 2 anti-MAC drugs. These treatment regimens were significantly associated with failure of sputum conversion to culture negativity (adjusted odds ratio [OR], 16.83; 95% confidence interval [CI], 1.16-245.06; p=0.039). Eleven of the remaining 19 patients were treated with an anti-MAC regimen containing clarithromycin for >5 months. However, there was no statistically significant association between sputum conversion and clarithromycin-containing anti-MAC regimens (OR, 0.42; 95% CI, 0.08-2.16; p=0.435). CONCLUSIONS: MAC pulmonary disease often occurs in the context of preexisting lung disease, especially pulmonary tuberculosis. Patients tend to be older. Inappropriate treatment might lead to failure of sputum conversion. Treatment with rational combination regimens for at least 5 months could be necessary for sputum conversion. PMID- 17712470 TI - Clinical features and complications of viridans streptococci bloodstream infection in pediatric hemato-oncology patients. AB - BACKGROUND AND PURPOSE: Viridans streptococci (VS) are part of the normal flora of humans, but are fast emerging as pathogens causing bacteremia in neutropenic patients. The clinical features, outcomes, and antibiotic susceptibilities of VS bloodstream infections in children with hemato-oncological diseases are reported in this study. METHODS: A retrospective chart review of pediatric patients (< or =18 years) diagnosed with VS infections between January 1998 and December 2004 was conducted at the National Taiwan University Hospital. RESULTS: Among the 26 episodes noted in 25 pediatric patients, the incidence rate of VS bacteremia was found to be significantly higher in pediatric patients with acute myeloid leukemia compared with other hemato-oncological conditions. Most of the patients had profound neutropenia related to chemotherapy for a median of 5 days on the day of positive blood culture. Eight of the 25 patients had undergone stem cell transplantations. Streptococcus mitis was the most common bloodstream isolate and only 12 (44%) of the 27 isolated strains of VS were penicillin-susceptible. Empirical antibiotic treatments were not effective in half of the episodes, but did not affect overall mortality. Isolated bacteremia (63%) and pneumonia (22%) were the two leading clinical presentations. Complications were recognized more frequently in patients with pneumonia. Hypotension and mechanical ventilation each developed in 8 patients (31%). The overall mortality rate was 23%. CONCLUSIONS: Penicillin non-susceptible VS infection has emerged as a threat in children with hemato-oncological diseases, especially those with acute myeloid leukemia. S. mitis is the most common spp. of VS causing bacteremia in children and is associated with serious complications. The development of pneumonia resulted in clinical complications and higher mortality. Empirical antibiotic treatments with activity against the infecting strains did not reduce the overall mortality rate in this study. PMID- 17712471 TI - Community-onset candidemia at a university hospital, 1995-2005. AB - BACKGROUND AND PURPOSE: Although not all candidemias are hospital-acquired, data on clinical epidemiology for the community-onset candidemia are limited. This retrospective study was conducted to describe predisposing factors and outcomes of community-onset candidemias. METHODS: Medical records of patients who were admitted to the National Taiwan University Hospital between January 1, 1995 and May 31, 2005 and had Candida isolated from their blood in the outpatient setting and/or within 48 h of hospitalization (community-onset) were reviewed. RESULTS: A total of 56 episodes of candidemia were reviewed, which included 8 episodes (14.3%) of true community-acquired candidemia occurring in patients with no record of hospitalization within the previous 30 days and without histories of invasive procedures either just before or at the time of admission, and 48 episodes (85.7%) that were health care-associated. The latter included 24 episodes (42.9%) in patients recently discharged from hospitals (within 2-30 days of current admission), 23 episodes (41.1%) associated with invasive procedures and/or central intravascular lines placed for outpatient therapy, and 1 episode (1.8%) in patients admitted from nursing homes. Gastrointestinal bleeding (46.4%), immunosuppressive therapy (42.9%) and previous antibiotics use (37.5%) were the most common predisposing factors. Diabetes was the single most important predisposing factor in true community-acquired candidemia (62.5%) and had a significantly higher prevalence among these patients than in those with health care-associated candidemias (p=0.035). Candida albicans was the most common isolate (39.7%), followed by Candida tropicalis (22.4%) and Candida glabrata (17.2%). The overall case fatality rate was 55.4% (31/56), and 58.1% (18/31) of this was attributable to candidemia. Multivariate analysis identified higher severity score and lack of antifungal therapy as having an independent and adverse influence on outcome. CONCLUSIONS: Up to 85.7% of community-onset candidemias are health care-associated. There is a conceptual and practical need for a new classification for the spectrum of acquisition of infection, wherein the new category of health care-associated infection will have implications for the selection of empirical therapy. PMID- 17712472 TI - Immune response to ovalbumin following bisphenol A administration in mice fed with a low level of dietary protein. AB - BACKGROUND AND PURPOSE: We have previously shown that bisphenol A (BPA) augments T-helper (Th) 1 activity with no significant effects on an established oral tolerance to ovalbumin (OVA) in mice fed with a normal protein diet. The present study aimed to examine the effect of BPA on the immune response in a mouse model maintained on a very low protein diet (5% casein). METHODS: Mice were fed on a 5% protein diet, together with either OVA (OVA-fed) or water (water-fed), immunized intraperitoneally with OVA at 3-week intervals and administered BPA between the 2 immunizations. A week after the last immunization, animals were sacrificed and examined by enzyme-linked immunosorbent assay for serum titers of total immunoglobulin E (IgE), OVA-specific IgE, immunoglobulin G (IgG), IgG1, IgG2a, and the production of interferon-gamma, interleukin (IL)-4, and IL-12. RESULTS: In both BPA-treated and non-treated animals, OVA feeding resulted in lower titers of total and OVA-specific IgE, and OVA-specific IgG (p<0.05). There were higher levels of interferon-gamma (p<0.05), IL-4, and IL-12 (p<0.05) in animals with OVA tolerance following BPA treatment. However, IL-12 production was augmented only in BPA-treated water-fed animals (p<0.01). CONCLUSION: BPA administration in mice fed with a low level of dietary protein augmented Th1 cytokines more profoundly in the animals with OVA tolerance than in the non-tolerant animals. PMID- 17712473 TI - Fifteen-year experience of children with Henoch-Schonlein purpura in southern Taiwan, 1991-2005. AB - BACKGROUND AND PURPOSE: Although Henoch-Schonlein purpura (HSP) is the most common cause of systemic vasculitis in children, long-term and large-scale Taiwanese studies on HSP are rare. We reviewed the records of 107 Taiwanese pediatric patients diagnosed with HSP at our institution between 1991 and 2005. METHODS: The first clinical manifestations, laboratory findings, and outcome evaluations of the patients were analyzed. Data were grouped according to the presence of fever and upper respiratory tact infection (URI) as a presenting symptom and also by gender. Chi-squared test was used for statistical analysis. RESULTS: The children had a mean age of 6.2 +/- 2.5 years (range, 2 to 13 years), with a male-to-female ratio of 1.0:0.7. Main clinical symptoms included skin rashes (95.3%), gastrointestinal (GI) symptoms (72.0%), joint involvement (46.7%), and kidney involvement (28.0%). The most common first manifestations were skin rashes (56.1%), GI symptoms (35.5%), and joint involvement (12.1%). There was no significant association between first manifestations and fever presence or gender. However, the non-URI patients had a significantly higher incidence of GI problems than the URI group (p=0.01). Fever as a symptom was not associated with elevation of C-reactive protein (p=0.45). Immunoglobulin A levels were within the normal range. No chronic renal failure or end-stage renal disease was detected, and overall the prognosis of patients was good. CONCLUSIONS: The categories used did not predict the expression of HSP, with the exception of an association between absence of URI and GI manifestations. Overall, HSP showed a good prognosis. PMID- 17712474 TI - Chronic inflammatory demyelinating polyneuropathy associated with intestinal tuberculosis. AB - Chronic inflammatory demyelinating polyneuropathy (CIDP) is an increasingly common but under-recognized neurological disorder. It is immune mediated, and usually has a relapsing and remitting course. However, the initial presentation may be rapid. It can be associated with significant morbidity and mortality, particularly if there is a delay in diagnosis and treatment. It has been associated with both infective and non-infective etiologies. We present a case of CIDP associated with ileocecal tuberculosis (TB), presenting with progressive motor weakness and significant weight loss. The patient's symptoms improved to some extent with intravenous immunoglobulin and steroid, but improved significantly after being started on anti-TB therapy. However, his symptoms relapsed when he stopped his anti-TB treatment prematurely whilst continuing the immunosuppressive therapy. Upon resuming the anti-TB therapy, he made a good recovery. CIDP associated with TB has only been reported once. Our case highlights the need to consider TB in patients with neurological disorders. PMID- 17712475 TI - Relationship between chromatin organization, mRNAs profile and human male gamete quality. AB - Spermiogenesis is a complex process leading to the formation of motile spermatozoa characterized by a highly stable chromatin compaction that transfers the paternal genome into the oocyte. It is commonly held that these haploid cells are devoid of transcriptional and translational activities and that the transcripts represent remnants of stored mRNAs. Recently, the chromatin organization of mature spermatozoa has been revisited as a double nucleoprotamine nucleohistone structure possessing less-condensed regions sensitive to nuclease activity, which could be implicated in the expression of genes involved in the early embryo development. The existence of a complex population of mRNAs in human sperm is well-documented, but their role is not yet elucidated. Evidence for a latent transcriptional capacity and/or a potential de novo translation in mature spermatozoa from fertile men are essential for understanding the last steps of sperm maturation, such as capacitation and acrosome reaction. As such, we have documented the relationship between sperm quality and the distribution of sperm RNAs by showing divergent levels of transcripts encoding for proteins involved in either nuclear condensation (protamines 1 and 2) or in capacitation (eNOS and nNOS, c-myc) or in motility and sperm survival (aromatase) between low and high motile sperm issued from the same sample. Therefore, analyzing the profile of mRNAs could be helpful either as a diagnostic tool for evaluating male fertility after spermatogenesis or for prognosis use for fertilization. PMID- 17712476 TI - Current perspectives on pyospermia: a review. AB - Pyospermia is an abnormal laboratory finding of high concentration of white blood cells in human ejaculates during infertility workup. The role of pyospermia and its impact on fertility is an important consideration in the management of infertility. Etiology, pathogenesis, diagnostic modalities and the management of pyospermia are reviewed in this paper. Current use of antibiotics and the intrinsic production of antioxidants in the management of pyospermia are also discussed in this review. PMID- 17712477 TI - Ectopic expression of neurotrophic peptide derived from saposin C increases proliferation and upregulates androgen receptor expression and transcriptional activity in human prostate cancer cells. AB - AIM: To determine the effects of the functional domain of saposin C (neurotrophic peptide [NP]) on androgen receptor (AR) expression and transcriptional activity. METHODS: We constructed DNA vectors expressing NP or a chimeric peptide of the viral TAT transduction domain and NP (TAT-NP) using gene cloning technology. The effects of ectopic expression of NP or TAT-NP on cell growth were examined by 3 (4, 5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Reverse transcription-polymerase chain reaction (RT-PCR), Western blot, transient transfection and reporter gene assays were used to determine the effects of NP on AR expression and activation. RESULTS: NP stimulated proliferation of androgen responsive LNCaP cells in the absence of androgens. RT-PCR and Western blot analyses showed that ectopic expression of NP resulted in induction of AR gene expression, and that the NP-stimulated expression of AR could be synergistically enhanced in the presence of androgens. Furthermore, reporter gene assay results showed that NP could enhance AR transactivation by increasing androgen-inducible gene reporter activity. CONCLUSION: We provided evidence that ectopic expression of saposin C-originated NP could upregulate AR gene expression and activate the AR transcriptional function in an androgen-independent manner in prostate cancer cells. PMID- 17712478 TI - Interactions among age, adiposity, bodyweight, lifestyle factors and sex steroid hormones in healthy Singaporean Chinese men. AB - AIM: To examine the inter-relationships among age, lifestyle factors, anthropometric parameters, percent body fat and steroid hormone parameters in 531 healthy Singaporean Chinese men aged between 29 and 72 years old. METHODS: Various lifestyle parameters were quantified through a survey, and testosterone (T), estradiol (E2), dehydroepiandrosterone sulphate (DHEAS) and sex hormone binding globulin (SHBG) were measured using established methods. Anthropometric parameters were collected and computed, and percent body fat (Siri) was measured using the DEXA scanner. RESULTS: SHBG, DHEAS, bioavailable-T (Bio-T), E2, Siri, Ht, W/H, W/Ht and work stress were independently correlated with age. Using multivariate analyses and adjusting for age and other related factors, exercise, smoking and alcohol consumption have positive impacts on androgen levels and body composition. However, black and green tea consumption was associated with negative effects on body composition and with higher levels of E2 and Free Estradiol Index (FEI). Men with shorter sleep duration had significantly lower T levels as compared to those with 6 h or more of nightly sleep. Higher T levels were associated with lower levels of adiposity and other indices of adiposity, whereas higher E2 levels were related to higher levels of adiposity. Men with higher DHEAS were significantly taller and heavier than those with low DHEAS levels. CONCLUSION: The study showed the close interactions among the gonadal/adrenal and metabolic compartments, with age being a key determinant in their interactions. Lifestyle factors such as exercise, smoking, sleeping and alcohol and tea consumption might play significantly roles in determining the status of health in men. PMID- 17712479 TI - NFAT2 is implicated in corticosterone-induced rat Leydig cell apoptosis. AB - AIM: To investigate the activation of the nuclear factor of activated T cells (NFAT) and its function in the corticosterone (CORT)-induced apoptosis of rat Leydig cells. METHODS: NFAT in rat Leydig cells was detected by Western blotting and immunohistochemical staining. Cyclosporin A (CsA) was used to evaluate potential involvement of NFAT in the CORT-induced apoptosis of Leydig cells. Intracellular Ca(2+) was monitored in CORT-treated Leydig cells using Fluo-3/AM. After the Leydig cells were incubated with either CORT or CORT plus CsA for 12 h, the levels of NFAT2 in the nuclei and in the cytoplasm were measured by semi quantitative Western blotting. The role of NFAT2 in CORT-induced Leydig cell apoptosis was further evaluated by observing the effects of NFAT2 overexpression and the inhibition of NFAT2 activation by CsA on FasL expression and apoptosis. RESULTS: We found that NFAT2 was the predominant isoform in Leydig cells. CsA blocked the CORT-induced apoptosis of the Leydig cells. The intracellular Ca(2+) level in the Leydig cells was significantly increased after the CORT treatment. The CORT increased the level of NFAT2 in the nuclei and decreased its level in the cytoplasm. CsA blocked the CORT-induced nuclear translocation of NFAT2 in the Leydig cells. Both CORT-induced apoptosis and FasL expression in the rat Leydig cells were enhanced by the overexpression of NFAT2 and antagonized by CsA. CONCLUSION: NFAT2 was activated in CORT-induced Leydig cell apoptosis. The effects of NFAT2 overexpression and the inhibition of NFAT2 activation suggest that NFAT2 may potentially play a pro-apoptotic role in CORT-induced Leydig cell apoptosis through the up-regulation of FasL. PMID- 17712480 TI - Distribution profiles of transient receptor potential melastatin-related and vanilloid-related channels in prostatic tissue in rat. AB - AIM: To investigate the expression and distribution of the members of the transient receptor potential (TRP) channel members of TRP melastatin (TRPM) and TRP vanilloid (TRPV) subfamilies in rat prostatic tissue. METHODS: Prostate tissue was obtained from male Sprague-Dawley rats. Reverse transcription polymerase chain reaction (RT-PCR) and quantitative real-time polymerase chain reaction (PCR) were used to check the expression of all TRPM and TRPV channel members with specific primers. Immunohistochemistry staining for TRPM8 and TRPV1 were also performed in rat tissues. RESULTS: TRPM2, TRPM3, TRPM4, TRPM6, TRPM7, TRPM8, TRPV2 and TRPV4 mRNA were detected in all rat prostatic tissues. Very weak signals for TRPM1, TRPV1 and TRPV3 were also detected. The mRNA of TRPM5, TRPV5 and TRPV6 were not detected in all RT-PCR experiments. Quantitative real-time RT PCR showed that TRPM2, TRPM3, TRPM4, TRPM8, TRPV2 and TRPV4 were the most abundantly expressed TRPM and TRPV subtypes, respectively. Fluorescence immunohistochemistry indicated that TRPM8 and TRPV1 are highly expressed in both epithelial and smooth muscle cells. CONCLUSION: Our results demonstrate that mRNA or protein for TRPM1, TRPM2, TRPM3, TRPM4, TRPM6, TRPM7, TRPM8, TRPV1, TRPV2, TRPV3 and TRPV4 exist in rat prostatic tissue. The data presented here assists in elucidating the physiological function of TRPM and TRPV channels. PMID- 17712481 TI - Localization of AKAP4 and tubulin proteins in sperm with reduced motility. AB - AIM: To perform screening, related to A-kinase anchoring proteins 4 (AKAP4) and tubulin proteins, in spermatozoa with absent or severely reduced motility in order to detect the status of the fibrous sheath and the axonemal structure. METHODS: An immunocytochemical study of tubulin, used as a positive control, and AKAP4 was carried out to detect the presence and the distribution of these proteins in different sperm samples. The morphological characteristics of sperm were studied by transmission electron microscope (TEM) and the results were elaborated using a formula reported in previous studies. PCR was carried out on DNA extracted from peripheral blood lymphocytes to analyse partial sequences of the Akap4 and Akap3 genes. RESULTS: Immunolabelling of tubulin and AKAP4 showed different patterns, which led us to divide the patients into groups. In group I, the absence of AKAP4 and tubulin was revealed, although these patients did not show alterations in the Akap4/Akap3 binding site. TEM evaluation highlighted that a high presence of necrosis was associated with total sperm immotility. In group II, a regular AKAP4 and tubulin signal was present, although motility was reduced and TEM analysis revealed the presence of immaturity. In group III, in which a weak AKAP4 label associated with normal tubulin staining and reduced motility was observed, a severe disorganization of the fibrous sheath was highlighted by TEM. CONCLUSION: While the role of AKAP4 in sperm motility is unclear, absent or weak AKAP4-labelling seems to be associated with absent or weak sperm motility. PMID- 17712482 TI - Effect of genistein on acrosome reaction and zona pellucida binding independent of protein tyrosine kinase inhibition in bull. AB - AIM: To investigate if the phytoestrogen, genistein, affects essential functions of cryopreserved bovine spermatozoa. METHODS: The effect of genistein upon motility was assessed by computer-assisted motion analysis. Hemizona assay was performed to detect the ability of spermatozoa binding to the zona pellucida. The inducibility of the acrosome reaction using progesterone and ZP3-6 peptide was analysed by fluorescein-conjugated Pisum sativum agglutinin (FITC-PSA)/Hoechst 33258 double staining. Capacitation after incubation with genistein was assessed by the chlortetracycline (CTC) assay. Immunoblots showed the pattern of protein tyrosine phosphorylation of cryopreserved bovine spermatozoa. RESULTS: Immunodetection of tyrosine-phosphorylated proteins showed that genistein did not affect tyrosine phosphorylation in cryopreserved bovine spermatozoa. However, genistein significantly reduced the progesterone- and ZP3-6 peptide-mediated induction of the acrosome reaction and led to a dose-dependent inhibition of sperm-zona pellucida binding; while sperm motility and capacitation were not affected by this phytoestrogen, as indicated by computer-assisted sperm motion analysis and the CTC assay, respectively. CONCLUSION: Our results suggest that in cryopreserved bovine spermatozoa, genistein affects a protein tyrosine phosphorylation-independent signal transduction pathway that is involved in sperm capacitation, the acrosome reaction and sperm-zona pellucida binding. PMID- 17712483 TI - 17beta-estradiol stimulates proliferation of spermatogonia in experimental cryptorchid mice. AB - AIM: To investigate whether estrogen stimulates the proliferation of spermatogonia or induces spermatogenesis in cryptorchid mice. METHODS: Mice were surgically rendered cryptorchid, then treated with different doses of 17beta estradiol (E2) s.c. once a day. Mice were killed at sexual maturity (45 days of age), and histological analysis and immunofluorescence were performed. Serum follicle stimulating hormone (FSH), estradiol, testosterone and luteinizing hormone (LH) were measured. RESULTS: Low doses of E2 had no notable effect on spermatogonia, but at higher doses, E2 stimulated the proliferation of spermatogonia. CONCLUSION: E2 has a dose-related mitogenic effect on spermatogonia. PMID- 17712484 TI - Outcome of repeated micro-surgical testicular sperm extraction in patients with non-obstructive azoospermia. AB - AIM: To evaluate the outcome of repetitive micro-surgical testicular sperm extraction (mTESE) attempts in non-obstructive azoospermia (NOA) cases, in relation to patients' initial testicular histology results. METHODS: A total of 68 patients with NOA in whom mTESE had been performed in previous intracytoplasmic sperm injection (ICSI) attempts were reviewed. RESULTS: Among the 68 patients with NOA, the first mTESE yielded mature sperm for ICSI in 44 (64%) (Sp(+)), and failed in the remaining 24 (36%) (Sp(-)). Following their first trial, 24 patients decided to undergo a second mTESE. Of these 24 patients, no spermatozoa were obtained in 5 patients, and Sp(+) but no fertilization/pregnancy were achieved in 19. In these 24 cases, mTESE was successively repeated for two (n = 24), three (n = 4) and four (n = 1) times. The second attempt yielded mature sperm in 3/5 patients from the Sp- group and 16/19 patients from the Sp(+) group. At the third and fourth trials, 4/4 and 1/1 of the original Sp(+) patients were Sp(+) again, respectively. Distribution of main testicular histology included Sertoli cell-only syndrome (16%), maturation arrest (22%), hypospermatogenesis (21%) and focal spermatogenesis (41%). Overall, in repetitive mTESE, 24/29 (82%) of the attempts were finally Sp(+). CONCLUSION: Repeated mTESE in patients with NOA is a feasible option, yielding considerably high sperm recovery rate. In patients with NOA, mTESE may safely be repeated one or more times to increase sperm retrieval rate, as well as to increase the chance of retrieving fresh spermatozoa to enable ICSI. PMID- 17712485 TI - AZF microdeletions and partial deletions of AZFc region on the Y chromosome in Moroccan men. AB - AIM: To evaluate for the first time the frequency of Y chromosome microdeletions and the occurrence of the partial deletions of AZFc region in Moroccan men, and to discuss the clinical significance of AZF deletions. METHODS: We screened Y chromosome microdeletions and partial deletions of the AZFc region of a consecutive group of infertile men (n = 149) and controls (100 fertile men, 76 normospermic men). AZFa, AZFb, AZFc and partial deletions of the AZFc region were analyzed by polymerase chain reaction (PCR) according to established protocols. RESULTS: Among the 127 infertile men screened for microdeletion, four subjects were found to have microdeletions: two AZFc deletions and two AZFb+AZFc deletions. All the deletions were found only in azoospermic subjects (4/48, 8.33%). The overall AZFc deletion frequency was low (4/127, 3.15%). AZF microdeletions were not observed in either oligoasthenoteratozoospermia (OATS) or the control. Partial deletions of AZFc (gr/gr) were observed in a total of 7 of the 149 infertile men (4.70%) and 7 partial AZFc deletions (gr/gr) were found in the control group (7/176, 3.98%). In addition, two b2/b3 deletions were identified in two azoospermic subjects (2/149, 1.34%) but not in the control group. CONCLUSION: Our results suggest that the frequency of Y chromosome AZF microdeletions is elevated in individuals with severe spermatogenic failure and that gr/gr deletions are not associated with spermatogenic failure. PMID- 17712486 TI - Gene expression changes of urokinase plasminogen activator and urokinase receptor in rat testes at postnatal stages. AB - AIM: To investigate the gene expression changes of urokinase plasminogen activator (uPA)/urokinase receptor (uPAR) in rat testes at postnatal stages and explore the effects of uPA/uPAR system on the rat spermatogenesis. METHODS: The mRNAs of uPA and uPAR in rat testes were measured by using real-time quantitative polymerase chain reaction (PCR) at postnatal days 0, 5, 10, 15, 21, 28, 35, 42, 49 and 56, respectively. RESULTS: The tendencies of uPA and uPAR mRNA expression were similar at most postnatal stages except for D(0). The expression of uPAR mRNA in rats testes was relatively higher than that of uPA at postnatal D(0), and both were decreased until D(21), increased obviously at postnatal D(28), reached a peak at postnatal D(35), then declined sharply at postnatal D(42) and retained at a low level afterwards. CONCLUSION: The uPA/uPAR system may be strongly linked to spermiation and spermatogenesis via regulating germ cell migration and proliferation, as well as promoting the spermiation and detached residual bodies from the mature spermatids. PMID- 17712487 TI - Semen parameters in men with spinal cord injury: changes and aetiology. AB - AIM: To assess the changes in semen parameters in men with spinal cord injury (SCI) and the possible causes of these changes. METHODS: The study included 45 subjects with SCI. Semen retrieval was done by masturbation (2), vigorous prostatic massage (n = 13), penile vibratory stimulation (n = 13) or electroejaculation (n = 17). RESULTS: The semen of men with SCI showed normal volume (2.3 +/- 1.9 mL) and sperm count (85.0 X 10(6) +/- 83.8 X 10(6)/mL) with decreased motility (11.6% +/- 0.1%), vitality (18.5% +/- 5.2%) and normal forms (17.5% +/- 3.4%), and pus cells has been increased (6.0 X 10(6) +/- 8.2 X 10(6)/mL). Total (13.4 +/- 9.9 vs. 7.1 +/- 6.8) and progressive (4.4 +/- 3.9 vs.2.2 +/- 2.1) motility were significantly higher in subjects with lower scrotal temperatures. There was no statistical significant difference between electroejaculation and penile vibratory stimulation groups as regards any of the semen parameters. Subjects'age, infrequent ejaculation, injury duration and hormonal profile showed no significant effect on semen parameters. CONCLUSION: The defining characteristics of the seminogram in men with SCI are normal volume and count with decreased sperm motility, vitality and normal forms, and the increased number of pus cells. The most acceptable cause of the deterioration of semen is elevated scrotal temperature. PMID- 17712488 TI - Protease activated receptor 2 and epidermal growth factor receptor are involved in the regulation of human sperm motility. AB - AIM: To investigate mechanisms of tryptase-induced reduction of sperm motility and explore whether epidermal growth factor receptor (EGF-R) and protease activated receptor 2 (PAR-2)- associated pathways are involved. METHODS: Fresh semen was collected from healthy donors (n = 15). Semen parameters and quality were assessed in accordance with the World Health Organization (WHO) criteria. Swim-up sperm were fixed and subjected to immunocytochemistry and immunoelectronmicroscopy with specific antibodies directed against PAR-2 and EGF R. Protein extractions from swim-up spermatozoa were analyzed by Western blotting with antibodies for both receptors. Motility of spermatozoa was evaluated by computer-assisted semen analysis. RESULTS: Immunocytochemistry found PAR-2 and EGF-R in approximately 30% of examined human ejaculated spermatozoa. Both receptors were localized in the plasma membrane. Like tryptase, the PAR-2 synthetic agonist SLIGKV reduced sperm motility, and this effect was inhibited by application of two specific EGF-R pathway blockers (AG1478 and PD168393). CONCLUSION: The observed reduction of sperm motility by tryptase through the PAR 2 receptor involves EGF-R pathways. PMID- 17712489 TI - Inhibition of telomerase with human telomerase reverse transcriptase antisense increases the sensitivity of tumor necrosis factor-alpha-induced apoptosis in prostate cancer cells. AB - AIM: To investigate the effect of inhibition of telomerase with human telomerase reverse transcriptase (hTERT) antisense on tumor necrosis factor-alpha (TNF alpha)-induced apoptosis in prostate cancer cells (PC3). METHODS: Antisense phosphorothioate oligodeoxynucleotide (AS PS-ODN) was synthesized and purified. Telomerase activity was measured using the telomeric repeat amplification protocol (TRAP) and polymerase chain reaction enzyme-linked immunoassay (PCR ELISA). hTERT mRNA was measured by reverse transcription PCR (RT-PCR) assay and gel-image system. hTERT protein was detected by immunochemistry and flow cytometry. Cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5 Diphenyltetrazolium (MTT) assay. Cell apoptosis was observed by morphological method and determined by flow cytometry. RESULTS: The telomerase activity decreased with time after hTERT AS PS-ODN treatment. The levels of hTERT mRNA decreased with time after hTERT AS PS-ODN treatment, which appeared before the decline of the telomerase activity. The percentage of positive cells of hTERT protein declined with time after hTERT AS PS-ODN treatment, which appeared after the decline of hTERT mRNA. There was no difference in telomerase activity, hTERT mRNA and protein levels between hTERT sense phosphorothioate oligodeoxynucleotide (S PS-ODN) and the control group. The cell viability decreased with time after hTERT AS PS-ODN combined with TNF-alphatreatment. The percentage of apoptosis increased with time after hTERT AS PS-ODN combined with TNF-alpha treatment. There was no difference in cell viability and the percentage of apoptosis between hTERT S PS-ODN and the control group. CONCLUSION: hTERT AS PS-ODN can significantly inhibit telomerase activity by downregulating the hTERT mRNA and protein expression, and inhibition of telomerase with hTERT antisense can enhance TNF-alpha-induced apoptosis of PC3 cells. PMID- 17712490 TI - Urine versus brushed samples in human papillomavirus screening: study in both genders. AB - AIM: To investigate whether urine is a good medium for screening and whether there is a correlation between the amount of extracted DNA and human papillomavirus (HPV)-positivity. METHODS: In the present study, 30 first-voided urine (FVU) specimens and 20 urethroglandular swabs using cervex-brushes from male partners of HPV-positive patients, and 31 FVU specimens and 100 liquid-based cervix cytology leftovers sampled with cervix-brushes from HPV-positive women were examined for the presence of beta-globin. Oncogenic HPV were detected using type-specific PCR. RESULTS: beta-globin was found in all the brushed samples, whereas it was found in only 68.9% of the FVU specimens. HPV-PCR was positive in 60.0% of the male brushes, in 29% of the female brushes and in 0% of the male FVU specimens. DNA concentration was, respectively, 0.9998 ng/microL, 37.0598 ng/microL and 0.0207 ng/microL. CONCLUSION: Urine is not a good tool for HPV detection, probably because the low DNA concentration reflects a low amount of collected cells. beta-globin is measurable in FVU by real time quantitative PCR, but the DNA concentration is lower compared to brush sampling for both genders. beta-globin-positivity of urethral and cervical swabs is 100%, showing a higher mean concentration of DNA, leading to a higher detection rate of HPV. This is the first article linking DNA-concentration to the presence of HPV. PMID- 17712491 TI - Comparisons of voided urine cytology, nuclear matrix protein-22 and bladder tumor associated antigen tests for bladder cancer of geriatric male patients in Taiwan, China. AB - AIM: To compare the results of bladder tumor associated antigen (BTA TRAK), nuclear matrix protein 22 (NMP 22) and voided urine cytology (VUC) in detecting bladder cancer. METHODS: A total of 135 elderly male and 50 healthy volunteers enrolled in this study were classified into three groups: (i) 93 patients with bladder cancer; (ii) 42 patients with urinary benign conditions; and (iii) 50 healthy volunteers. BTA TRAK and NMP 22 kits were used to detect bladder cancer. Voided urine cytology was used to compare the sensitivity and specificity of the screening tests. RESULTS: The sensitivity and specificity of cytology, BTA TRAK and NMP 22 were 24% and 97%, 51% and 73%, 78% and 73%, respectively. The level of NMP 22 increased with tumor grading. The BTA TRAK kit has the lowest sensitivity among the screening tests. The NMP 22 with the best sensitivity can be an adjunct to cytology for evaluating bladder cancer. CONCLUSION: The NMP 22 test has a better correlation with the grading of the bladder cancer than BTA TRAK. As cytology units are typically not available in hospitals or in outpatient clinics, NMP 22 might be a promising tool for screening bladder cancer. PMID- 17712492 TI - Outcome of implanting penile prosthesis for treating erectile dysfunction: experience with 42 cases. AB - AIM: To report a short-time result of three-piece inflatable penile prosthesis (IPP) implantation on treating patients with organic erectile dysfunction (ED). METHODS: Three-piece IPPs were implanted in 42 Chinese patients with ED refractory to systemic treatment between May 2002 and May 2004. The etiologies of ED were neurogenic (28 with paraplegia and seven with traumatic nervi-erigentes injury); congenital venous leakage (5 cases), fibrosis of corpus cavernosum (1case) and Klinefelter's syndrome (1 case). The follow-up period ranged from 24 to 57 months. RESULTS: Implantation procedures were successfully performed upon all 42 patients. The length of implanted prosthesis was from 13 cm to 18 cm, and the diameter was 1 cm. The implanted prosthesis was made by the Medical Instrumentation Company of Muping (Muping, Shandong, China). Localized infection occurred in only one patient and mechanical complications occurred in five patients. Coitus could be performed in 41 cases (97.6%). Three patients with congenital venous leakage made their spouses pregnant after implantation. CONCLUSION: Implantation of three-piece IPP is an effective and safe modality for treating patients with ED. It can be well accepted by Chinese patients because of its efficacy. PMID- 17712493 TI - Higher frequency of Yq microdeletions in sperm DNA as compared to DNA isolated from blood. AB - AIM: To determine if Yq microdeletion frequency and loci of deletion are similar in two tissues (blood and sperm) of different embryological origin. METHODS: The present study included 52 infertile oligozoospermic cases. In each case, DNA was isolated from blood and sperms and polymerase chain reaction (PCR) microdeletion analysis was done from genomic DNA isolated from both the tissues. The PCR products were analyzed on a 1.8% agarose gel. PCR amplifications found to be negative were repeated at least three times to confirm the deletion of a given marker. RESULTS: Only 1 case harbored microdeletion in blood DNA, whereas 4 cases harbored microdeletion in sperm DNA. CONCLUSION: The frequency of Yq microdeletions is higher in germ cells as compared to blood. As the majority of infertile couples opt for assisted reproduction procreation techniques (ART), Yq microdeletion screening from germ cells is important to understand the genetic basis of infertility, to provide comprehensive counseling and most adapted therapeutics to the infertile couple. PMID- 17712494 TI - Scrotal aggressive angiomyxoma mimicking inguinal hernia. PMID- 17712500 TI - An application of item response mixture modelling to psychosis indicators in two large community samples. AB - OBJECTIVE: Previous research has suggested that psychosis is better described as a continuum rather than a dichotomous entity. This study aimed to describe the distribution of positive psychosis-like symptoms in two large community samples using an item response mixture model. METHOD: An item response mixture model was used to explain the pattern of psychosis-like symptom endorsement. This model incorporated two elements. First, a continuous non-normal latent variable to explain the observed pattern of data. Second, a categorical latent variable to explain the variation in the continuous non-normal latent variable. RESULTS: For both samples, representing broadly and narrowly defined psychosis, the best fitting model was a four-class solution. In both cases, the classes differed quantitatively rather than qualitatively. CONCLUSIONS: The analysis showed that psychosis-like symptoms at the population level could be best explained by four classes that appeared to represent an underlying continuum. PMID- 17712501 TI - Risk of readmission in compulsorily and voluntarily admitted patients. AB - OBJECTIVES: The aim of this study is to examine relationships between hospital admission legal status (voluntary, psychiatrist-ordered, and court ordered), length of stay and risk of hospital readmission. METHODS: The records (1994-2005) of all consecutive admissions (n = 16,016) to one inpatient mental health facility were reviewed. Patients (n = 6,656) were classified into 3 groups at first admission: voluntary (n = 5,442), psychiatrist-ordered (n = 1,067) and court ordered (n = 147). RESULTS: The probability of readmission of the court ordered and psychiatrist-ordered groups were significantly lower than that of voluntarily admitted patients (P < 0.05). The length of stay at first admission was significantly longer for the court-ordered group than for the others (P < 0.001). As compared with the other groups, court ordered-patients were significantly younger (P < 0.001), had attained fewer years of education (P < 0.001) and included a lower percentage of immigrants (P < 0.05). Significant differences were found in the mean morality age of the three groups (P < 0.005). CONCLUSIONS: As compared with psychiatrist-ordered and voluntarily admitted patients, court ordered patients have a lower probability for hospital readmission, possibly related to longer length of stay. PMID- 17712502 TI - Polychlorinated biphenyls (PCBs) in PM10 surrounding a chemical industrial zone in Shanghai, China. AB - In order to gain comprehensive understanding of status, properties and sources of PCBs pollution at an industrial area in Shanghai, PM10 were collected during the period November 2004-September 2005. The results showed that the mean value of total PCBs in the industrial area was 2,017.22 pg m(-3). Three dioxin-like PCB congeners had a mean value of TEQ of 0.24 pg-TEQ m(-3). The concentrations of PCBs at all sites were higher in colder months than in warmer months. SigmaPCB concentrations were correlated positively with SO2, NO2 and OCPs, while negatively with polycyclic aromatic hydrocarbons (PAHs), ambient temperature, rainfall and wind speed. It could be concluded that the area had been contaminated by PCBs from a local source. PMID- 17712504 TI - Effects of increasing levels of nickel contamination on structure of offshore nematode communities in experimental microcosms. AB - A microcosm experiment was used to examine the effects of nickel on offshore nematode communities of a Tunisian coastal zone (Southwestern Mediterranean Sea). Sediments were contaminated with three nickel concentrations [low (250 ppm), medium (550 ppm) and high (900 ppm)], and effects were examined after 30 days. Results showed significant differences between nematode assemblages from undisturbed controls and those from nickel treatments. Most univariates measures, including diversity and species richness, decreased significantly with increasing level of Ni contamination. Results from multivariate analyses of the species abundance data demonstrated that responses of nematode species to the nickel treatments were varied: Leptonemella aphanothecae was eliminated at all the nickel doses tested and seemed to be intolerant species to nickel contamination; Daptonema normandicum, Neochromadora trichophora and Odontophora armata which significantly increased at 550 ppm nickel concentration appeared to be "opportunistic" species at this dose whereas Oncholaimus campylocercoides and Bathylaimus capacosus which increased at all doses tested (250, 550 and 900 ppm) seemed to be "nickel-resistant" species. PMID- 17712503 TI - Fatty acid profile in milk from goats, Capra aegagrus hircus, exposed to perchlorate and its relationship with perchlorate residues in human milk. AB - Polyunsaturated fatty acids (PUFA) in milk are vital for normal growth and development of infant mammals. Changes in fatty acid composition were observed in milk fat from goats dosed with perchlorate (0.1 and 1 mg/kg body weight/day) for 31 days, but the effect was not persistent. Adaptation may be induced in these goats to compensate for the perchlorate effect. In an analysis of fatty acid composition in human milk samples, a weak negative correlation was observed between perchlorate concentrations and total PUFA in 38 human milk samples. PMID- 17712505 TI - Acute toxicity of deltamethrin for freshwater mussel, Unio elongatulus eucirrus bourguignat. AB - In this study, the acute toxicity of deltamethrin, contaminating aquatic ecosystems as a pollutant, on freshwater mussel, Unio elongatulus eucirrus, was examined. Deltamethrin was applied at concentrations of 1, 2, 3, 4, 5, 6, 7, 8, 16 and 32 mg L(-1). The 1, 24, 48, 72 and 96 h LC(50) values of deltamethrin for freshwater mussels were determined as 10.07, 8.99, 8.09, 7.30 and 6.60 mg L(-1), respectively. There were significant differences in LC(10-90) values obtained for different times of exposure. The results show that deltamethrin is moderately toxic for freshwater mussel and it should be used with caution in agriculture to protect natural waters from contamination. PMID- 17712506 TI - Polyaromatic hydrocarbons (PAHs) and metal evaluation after a diesel spill in Oaxaca, Mexico. AB - Pollution in the marine environment due to a diesel spill takes days to months to complete natural remediation owing to its low volatility. Metal and PAH contamination caused by an accidental diesel spill were studied. V, Ni and Hg levels increased immediately after the spill, while PAH levels decreased after 1 month (79.4-7.6 microg kg(-1)). At the diesel spill point, fluoranthene exceeded acute and chronic levels, although most of the PAHs were within the range of low effects. In fish body burden, the highest bioaccumulation factor (2.63 for naphthalene) was related to the lower molecular weight PAHs. PMID- 17712507 TI - Effect of fluidizing agents on paclitaxel penetration in cervical cancerous monolayer membranes. AB - The aim of this study was to compare modulation of paclitaxel penetration in cancerous and normal cervical monolayers by four fluidizing agents: PCPG (9:1 DPPC:PG), PCPE (9:1 DPPC:DOPE), ALEC (7:3 DPPC:PG) and Exosurf (13.5:1.5:1.0 DPPC:hexadecanol:tyloxapol). Presence of the fluidizing agents improved drug penetration significantly. PCPG and PCPE were promising penetration enhancers. PCPG 0.1% caused 3.8- and 1.7-fold higher maximum increments in surface pressure due to drug penetration, (Delta pi)(max), than the control in cancerous and normal monolayers, respectively, at 20 mN/m. In cancerous monolayer at 20 mN/m, presence of 0.1%, 0.5%, 1%, 5% and 10% PCPE produced 3.4-, 5.7-, 7.4-, 9.6- and 9.8-fold higher drug penetration compared to the control monolayer without PCPE, respectively. In cancerous monolayer at 20 mN/m, PCPG and PCPE liposomes having 1 mg lipid gave 2.1 and 3.6 times higher (Delta pi)(max )compared to the control, respectively. Further, the liposomal drug penetration was found to be directly proportional to the liposomal lipid content. The effect of the fluidizing agents was confirmed by increased calcein release from model cervical cancer liposomes. These results may have implications in using the above biocompatible lipids and surfactants as penetration enhancers along with anticancer drugs or as carriers for liposomal formulations of anticancer drugs for improved membrane penetration. PMID- 17712508 TI - Neuronavigation guided surgery for parenchymal neurocysticercosis in two patients. AB - Neurocysticercosis is a rare disease in the Baltic area while it is common in the endemic regions. Two patients with serologically negative parenchymal neurocysticercosis from our neurosurgical department who underwent extirpation of the cystic lesions with neuronavigation guided surgery are reported in this paper. Though most publications propose medical treatment with albendazole and praziquantel for parenchymal neurocysticercosis, surgery can be an option for diagnosis and treatment in conjunction with cysticidal medication if the diagnosis is unclear particularly in non-endemic areas. PMID- 17712509 TI - Diffusion tensor imaging and white matter tractography in patients with brainstem lesions. AB - BACKGROUND: Diffusion tensor imaging (DTI) and white matter tractography (WMT) are promising techniques for estimating the course, extent, and connectivity patterns of the white matter (WM) structures in the human brain. In this study, we investigated the ability of DTI and WMT to visualize white matter tract involvement for the preoperative surgical planning and postoperative assessment of brainstem lesions. METHODS: Preoperative and postoperative DTI data (echo planar, 1.5T) were retrospectively analyzed in 10 patients with brainstem lesions (3 diffuse, 7 focal). WMT applying a tensor deflection algorithm was used to reconstruct WM tracts adjacent to the lesions. Reconstructed tracts included corticospinal tracts and medial lemnisci. The clinical and imaging follow-up data were also compared and analyzed. FINDINGS: WMT revealed a series of tract alteration patterns including deviation, deformation, infiltration, and apparent tract interruption. WMT reconstructions showed that the major WM tracts were preserved during surgery and improved in position and appearance postoperatively. These findings correlated with the improvement or preservation of neurological function as determined by clinical assessment. CONCLUSIONS: Compared with the information provided by conventional MR imaging, DTI and WMT provided superior quantification and visualization of lesion involvement in eloquent fibre tracts of the brainstem. Moreover, DTI and WMT were found to be beneficial for white matter recognition in the neurosurgical planning and postoperative assessment of brainstem lesions. PMID- 17712510 TI - Novel entry point for intraoperative ventricular puncture during the transsylvian approach. AB - OBJECTIVE: In dealing with cases of oedematous brain, relaxation during the transsylvian approach to supratentorial aneurysms has been accomplished by ventricular drainage by using the anatomic point defined by Dr. Paine. However, we have experienced patient complications when using this point. We propose a novel anatomic point to reduce catheter-related complications and facilitate adequate ventricular puncture during ruptured aneurysm operations. METHODS: Ten patients underwent aneurysmal neck clipping for ruptured aneurysm by means of the transsylvian approach. The use of a novel anatomic point for intraoperative drainage was examined using a neuronavigation system. RESULTS: Using the novel point of entry for ventricular cannulation proved to be reliable for puncture and reduced chance of malpositioning. CONCLUSION: Secure intraoperative ventricular cannulation is reliably achieved by pointing the catheter approximately 2 cm beyond a line extending from the anterior limb of the triangle described by Paine. This technique reduces injury to the deep brain and enhances preciseness and safety of ventricular cannulation. PMID- 17712511 TI - Primary CNS lymphoma treated with combined intra-arterial ACNU and radiotherapy. AB - OBJECT: To assess whether nimustine (ACNU), a drug that can cross the blood brain barrier, combined with radiotherapy, improved the survival of patients with primary central nervous system lymphoma (PCNSL). CLINICAL MATERIALS AND METHODS: Between 1995 and 2005, we treated 63 immunocompetent PCNSL patients with combination therapy consisting of intra-arterial ACNU (100 mg/m(2)) and whole brain radiotherapy (36-50 Gy). Their median age was 60 years (range 28-81). The median follow-up was 24 months. FINDINGS: With this regimen we achieved a complete response rate of 75% (43 of 57 patients). Kaplan-Meier estimates for median progression-free survival and median overall survival were 26 and 39 months, respectively. The 3- and 5-year survival rates were 51% (95% confidence interval [CI], 36-65%) and 32% (95% CI, 17-47%), respectively. By multivariate analysis, age (<60 vs. > or =60 years) was the only statistically significant prognostic factor; the WBRT dose, sex, and number of tumors were not significant prognostic factors in this study. Myelosuppression was the most frequent side effect, 60% of patients experienced grade 3-4 leukopenia. Late neurotoxicity as a result of treatment was observed in 14 of 43 patients (34%) and higher age (>60) was associated with a high risk of neurotoxicity. CONCLUSION: The intra-arterial administration of ACNU combined with radiation therapy yielded a high response rate at acceptable toxicity levels in younger patients with PCNSL. However, late neurotoxicity was a serious complication in patients above 60 years of age. PMID- 17712512 TI - Extra-arachnoidal cranio-cervical decompression for syringomyelia associated with Chiari I malformation in adults: technique assessment. AB - BACKGROUND: The osteo-dural decompression of the cerebellar tonsils at the cranio cervical junction is generally considered the most effective treatment for syringomyelia-Chiari I complex. However much controversy concerning a great number of surgical adjuvants to the standard bony decompression is still present. In this work an extra-arachnoidal cranio-cervical decompression (CCD) without duroplasty is described and the surgical results are reported. METHOD: Between 2000 and 2005, 24 adult patients underwent surgery for symptomatic syringomyelia Chiari I complex not associated with hydrocephalus. In all cases, the surgical procedure consisted of a limited suboccipital craniectomy and laminectomy of C1 (when necessary C2 as well) followed by dural opening leaving the arachnoid membrane intact. The dura mater is left open and stitched laterally to the muscles. FINDINGS: With a mean clinical long term follow-up of 44 months (range, 12-78 mo), neurological disturbances improved in 21 of 24 patients (87.5%) as result of extra-arachnoidal CCD. The postoperative complications occurred when the arachnoid was accidentally violated (4 cases, 16.6%). The complications included aseptic meningitis (one patient), nucal pseudomeningocele (two patients) and postoperative hydrocephalus requiring a ventriculoperitoneal shunt (one patient). Finally, one patient received an additional C2 laminectomy in order to obtain symptoms improvement and syrinx shrinkage. Postoperative MRI studies demonstrated that the syrinx decreased in size or collapsed in 20 patients (83.3%) and stabilized in 4 (16.7%). CONCLUSIONS: The extra-arachnoidal CCD is a safe and effective treatment for syringomyelia associated with Chiari I malformation in adults without intraoperative evidence of adhesive arachnoiditis. However a larger number of patients and longer follow-up will be necessary to determine the efficacy of extra-arachnoidal CCD. PMID- 17712513 TI - Gamma knife radiosurgery for intracranial haemangioblastomas. AB - BACKGROUND: The results of gamma knife radiosurgery for haemangioblastomas were retrospectively studied to assess the efficacy for tumour growth control and clarify the clinical indications for gamma knife radiosurgery in these tumours. METHODS: The medical records of 22 patients with 67 tumours, 12 men and 10 women aged 20-73 years (mean 51.9 years), who underwent gamma knife radiosurgery for haemangioblastomas between January 1993 and January 2006, were retrospectively reviewed. Ten patients with 54 lesions had von Hippel-Lindau disease. The mean tumour volume was 1.69 cm(3) (range 0.0097-16.4 cm(3)). Nineteen patients had undergone 1-4 open surgery procedures (mean 1.5) before gamma knife radiosurgery. Tumours without a cystic component, (the solid type), were found in 54 lesions and tumours associated with cyst, (the mural nodule with cyst type), in 13 lesions. The marginal dose was 8-30 Gy (mean 14.0 Gy). FINDINGS: Follow-up magnetic resonance (MR) imaging was performed at 9-146 months (mean 63 months). The control rate for tumour growth was 83.6%. The only factor affecting tumour growth control was the presence of a cystic component at the time of gamma knife radiosurgery in both univariate and multivariate analysis. No complication such as radiation-induced peritumoural oedema or radiation necrosis occurred. CONCLUSION: The presence of cystic components at the time of gamma knife radiosurgery was the only factor significantly correlated with unfavourable tumour growth control by gamma knife radiosurgery for haemangioblastomas. Gamma knife radiosurgery is effective for solid type tumours, even if the marginal dose is relatively low. Surgical removal is recommended for mural nodule with cyst type tumours, when possible. PMID- 17712514 TI - Illustrations of neurosurgical techniques in early period of Ottoman Empire by Serefeddin Sabuncuoglu. AB - BACKGROUND: Serefeddin Sabuncuoglu (A.D. 1385-1468) was the author of the first illustrated surgery atlas Cerrahiyyetu'l Haniyye (Imperial Surgery), which was written in Turkish in 1465. The purpose of this report is to present his unique contribution to modern neurological surgery. METHODS: Cerrahiyyetu'l Haniyye consists of 412 pages in three chapters, in which there are a total of 191 sections dealing with a variety of surgical specialties, including neurosurgery. In each section of the book, a sentence written in rhyme and meter gives the diagnosis, classification and surgical technique in detail. Serefeddin Sabuncuoglu describes medical and surgical management of neurological diseases such as spinal trauma, epilepsy, migraine, facial palsy, hemiplegia, low back pain, cranial fracture, hydrocephalus and abscesses of the head in his textbook. CONCLUSIONS: Serefeddin Sabuncuoglu was a great surgeon in Turkish medical history and the sections on neurological diseases in Cerrahiyyetu'l Haniyye are of great importance in neurosurgery. Today, he is justified as a pioneer of surgery, an investigator and a medical illustrator in the early period of Ottoman Empire. His atlas is a modification of original contributions from earlier treatises. PMID- 17712515 TI - Radial nerve repair using an autologous denatured muscle graft: comparison with outcomes of nerve graft repair. AB - BACKGROUND: The efficiency of denatured muscle grafting in nerve repair has been confirmed in experimental models and animals. The first clinical trials to repair digital nerves and mixed sensory-motor nerves were encouraging regarding sensory recovery but motor recovery was poor, probably because of delayed repair. We present the functional outcome of repair of motor nerves using denatured muscle graft and compare the results with those using standard nerve graft techniques. METHODS: This prospective study included 9 radial nerve defects repaired with denatured muscle grafts and 23 radial nerve defects repaired using nerve grafts. Missile induced nerve injury, mid-arm level of lesion, a nerve gap smaller than 6 cm, and a preoperative interval of less than 5 months were characteristics shared by all patients. None of the patients had concomitant vascular injury, severe scarring, or significant soft tissue damage in the region of nerve repair. Motor recovery was estimated with 0-5 points, at least 4.7 years after surgery, according to the BMRC scale. RESULTS: A successful outcome (>or=M3) was achieved in 7 out of the 9 patients treated using a muscle graft and in 21 out of the 23 patients treated using nerve grafts (P > 0.05). Excellent recovery and the clinically significant re-establishment of thumb extension (M5 grade) were never achieved in the patients treated using muscle grafts. The average motor score was significantly better in patients treated with nerve grafts than in those who received muscle grafts (3.8 +/- 0.9 and 3.2 +/- 0.8; P = 0.035). With the patients who received muscle grafts, an inverse correlation existed between motor recovery and the length of the nerve gap (P = 0.017). CONCLUSIONS: Denatured muscle grafts can be useful for bridging short radial nerve defects, but the quality of recovery is significantly worse than after nerve graft repair. Even if relatively short nerve defects are bridged with denatured muscle grafts, the outcomes correlate inversely with the length of the gap. PMID- 17712516 TI - Review of language organisation in bilingual patients: what can we learn from direct brain mapping? AB - Although the majority of people worldwide are bilingual, the brain representation of language in bilingual persons is still a matter of debate. Since the beginning of the studies conducted on bilinguals, most authors denied that learning a new language requires a new semantic processing or the involvement of new cortical areas. In this paper, we review neurosurgical studies using direct electrocortical or subcortical stimulation techniques for brain mapping in bilingual subjects and compare this data with that obtained from other brain mapping methods. The authors focused on the most controversial issue whether multiple languages are represented in common or distinct cerebral areas. Seven direct brain mapping studies from different teams focused on bilingualism and multilingualism. All these studies showed that even if cerebral representation of language in multilingual patients could be grossly located in the same cortical region, it was possible to individualise distinct language-specific areas by direct cortical stimulation in the dominant frontal and temporo-parietal regions. Task- and language-specific sites were also described, demonstrating an important specialisation of some cortical areas. Using subcortical stimulation, some authors were able to find specific white matter tracts for different languages. Finally, all authors recommend in bilingual patients who need brain mapping for neurosurgical purpose to test all languages in which the subjects are fluent. PMID- 17712517 TI - Gravity-aided trans-falcine removal of a contralateral subcortical ependymoma. AB - The transfalcine approach is a variant of the interhemispheric approach which provides exposure of the medial surface of the contralateral hemisphere through a falx incision. Gravity can be used as a natural retractor. We report a 32-year old woman with an ependymoma of the medial surface of the left Rolandic area that was completely removed through a contralateral gravity-aided, image-guided transfalcine approach. The contralateral transfalcine approach can be a good option for lesions presenting at the interhemispheric fissure especially those associated with perilesional oedema and avoids the risks of a transparenchymal dissection and retraction of a swollen hemisphere. PMID- 17712518 TI - Pellagra: a rare complication of anorexia nervosa. AB - Pellagra is a potentially fatal, nutritional disease with cutaneous, gastrointestinal, and neuropsychiatric manifestations. Because of the diversity of pellagra's signs and symptoms, diagnosis is difficult without an appropriate index of suspicion. A case of pellagra in a 14-year-old girl with anorexia nervosa is presented. Signs and symptoms of pellagra were resolved after niacin therapy and dietary treatment. PMID- 17712519 TI - C-ANCA positive systemic vasculitis in a patient with rheumatoid arthritis treated with infliximab. AB - The advent of anti-tumour necrosis factor (TNF) agents to treat inflammatory arthritis has dramatically changed the management of patients in the last few years. Other possible indications for these agents are currently being explored in preliminary studies. However, whether this therapy can be safely and efficaciously applied to other inflammatory disorders requires further case controlled studies. Since these agents are increasingly used in the last 7 years, there has been the expected emergence of reports on uncommon side effects. The literature on the side effects of anti-TNF agents has focused on infective complications and development of autoantibodies. Reports concerning vasculitis have been contradictory, with TNF blockade being implicated in both the development and treatment of vasculitis. We present the first published report of necrotising crescentic glomerulonephritis associated with positive antineutrophil cytoplasmic antibody in a man receiving treatment with infliximab for rheumatoid arthritis. We discuss the literature and potential causal mechanisms. PMID- 17712520 TI - Hydrodynamic screening of star polymers in shear flow. AB - The mutual effects of the conformations of a star polymer in simple shear flow and the deformation of the solvent flow field are investigated by a hybrid mesoscale simulation technique. We characterize the flow field near the star polymer as a function of its functionality (arm number) f . A strong screening of the imposed flow is found inside the star polymer, which increases with increasing f . To elucidate the importance of hydrodynamic screening, we compare results for hydrodynamic and random solvents. The dependence of the polymer orientation angle on the Weissenberg number shows a power law behavior with super universal exponent --independent of hydrodynamic and excluded-volume interactions. In contrast, the polymer rotation frequency changes qualitatively when hydrodynamic interactions are switched on. PMID- 17712521 TI - Confined ferrofluid droplet in crossed magnetic fields. AB - When a ferrofluid drop is trapped in a horizontal Hele-Shaw cell and subjected to a vertical magnetic field, a fingering instability results in the droplet evolving into a complex branched structure. This fingering instability depends on the magnetic field ramp rate but also depends critically on the initial state of the droplet. Small perturbations in the initial droplet can have a large influence on the resulting final pattern. By simultaneously applying a stabilizing (horizontal) azimuthal magnetic field, we gain more control over the mode selection mechanism. We perform a linear stability analysis that shows that any single mode can be selected by appropriately adjusting the strengths of the applied fields. This offers a unique and accurate mode selection mechanism for this confined magnetic fluid system. We present the results of numerical simulations that demonstrate that this mode selection mechanism is quite robust and "overpowers" any initial perturbations on the droplet. This provides a predictable way to obtain patterns with any desired number of fingers. PMID- 17712522 TI - Phase behavior of a suspension of hard spherocylinders plus ideal polymer chains. AB - We study isotropic-isotropic and isotropic-nematic phase transitions of fluid mixtures containing hard spherocylinders (HSC) and added non-adsorbing ideal polymer chains using scaled particle theory (SPT). First, we investigate isotropic-nematic (I -N phase coexistence using SPT in the absence of polymer. We compare the results obtained using a Gaussian form of the orientational distribution function (ODF) to minimize the free energy versus minimizing numerically. We find that formal numerical minimization gives results that are much closer to computer simulation results. In order to describe mixtures of HSC plus ideal chains we studied the depletion of ideal chains around a HSC. We analyze the density profiles of ideal chains near a hard cylinder and find the depletion thickness delta is a function of the ratio of the polymer's radius of gyration R(g) and the cylinder radius R(c). Our results are compared with a common approximation in which the depletion thickness is taken equal to the radius of gyration of the polymer chain. We incorporate the correct depletion thickness into SPT and find that for R (g)/R (c) < 1.56 using ideal chains gives phase transitions at smaller polymer concentrations, whereas for R (g)/R (c) > 1.56 , which is a common experimental situation, the phase transitions are found at larger polymer concentrations with respect to delta = R (g) . The differences are significant, especially for R (g) >> R (c) , so we can conclude it is essential to take into account the properties of ideal polymer chains and the resulting depletion near a cylinder. Finally, we present phase diagrams for rod polymer mixtures which could be realized under experimental conditions. PMID- 17712523 TI - Active membranes studied by X-ray scattering. AB - In view of recent theories of "active" membranes, we have studied multilamellar phospholipid membrane stacks with reconstituted transmembrane protein bacteriorhodopsin (BR) under different illumination conditions by X-ray scattering. The light-active protein is considered as an active constituent which drives the system out of equilibrium and is predicted to change the collective fluctuation properties of the membranes. Using X-ray reflectivity, X-ray non specular (diffuse) scattering, and grazing incidence scattering, we find no detectable change in the scattering curves when changing the illumination condition. In particular the intermembrane spacing d remains constant, after eliminating hydration-related artifacts by design of a suitable sample environment. The absence of any observable non-equilibrium effects in the experimental window is discussed in view of the relevant parameters and recent theories. PMID- 17712524 TI - Domain-induced budding in buckling membranes. AB - We present a phase field model on buckling membranes to analyze phase separation and budding on soft membranes. By numerically integrating dynamic equations, it turns out that the formation of caps is greatly influenced by the presence of a little excess area due to the surface area constraint. When cap-shaped domains are created, domain coalescence is mainly observed not between domains with same budding directions, but between domains with opposite budding directions, because the bending energy between two domains is larger in the former case. Although we do not introduce spontaneous curvature like Helfrich model, we obtain some suggestions related to the slow dynamics of the phase separation on vesicles. PMID- 17712526 TI - Isoform-specific functions of Akt in cell motility. PMID- 17712525 TI - Gravity-controlled asymmetrical transport of auxin regulates a gravitropic response in the early growth stage of etiolated pea (Pisum sativum) epicotyls: studies using simulated microgravity conditions on a three-dimensional clinostat and using an agravitropic mutant, ageotropum. AB - Increased expression of the auxin-inducible gene PsIAA4/5 was observed in the elongated side of epicotyls in early growth stages of etiolated pea (Pisum sativum L. cv. Alaska) seedlings grown in a horizontal or an inclined position under 1 g conditions. Under simulated microgravity conditions on a 3D clinostat, accumulation of PsIAA4/5 mRNA was found throughout epicotyls showing automorphosis. Polar auxin transport in the proximal side of epicotyls changed when the seedlings were grown in a horizontal or an inclined position under 1 g conditions, but that under clinorotation did not, regardless of the direction of seed setting. Accumulation of PsPIN1 and PsPIN2 mRNAs in epicotyls was affected by gravistimulation, but not by clinorotation. Under 1 g conditions, auxin transport inhibitors made epicotyls of seedlings grown in a horizontal or inclined position grow toward the proximal direction to cotyledons. These inhibitors led to epicotyl bending toward the cotyledons in seedlings grown in an inclined position under clinorotation. Polar auxin transport, as well as growth direction, of epicotyls of the agravitropic mutant ageotropum did not respond to various gravistimulation. These results suggest that alteration of polar auxin transport in the proximal side of epicotyls regulates the graviresponse of pea epicotyls. PMID- 17712527 TI - A new synthesis in epigenetics: towards a unified function of DNA methylation from invertebrates to vertebrates. AB - DNA methylation is generally limited to CpG doublets located at the gene promoter with an involvement in gene silencing. Surprisingly, two recent papers showed an extensive methylation affecting coding portions of transcriptionally active genes in human and plants prompting a rethink of DNA methylation in eukaryotes. Actually, gene body methylation is not surprising since it has been repeatedly reported in invertebrates, where it interferes with transcriptional elongation preventing aberrant transcription initiations. As a whole, the published data suggest that the most ancestral function of DNA methylation is the control of genes that are susceptible to transcriptional interference and not to gene silencing. The recruitment of DNA methylation for silencing represents a successive tinkered use. In view of this additional function, the invertebrate vertebrate transition has been accompanied by new constraints on DNA methylation that resulted in the strong conservation of the DNA methylation machinery in vertebrates and in the non-viability of mutants lacking DNA methylation. PMID- 17712528 TI - Phosphorylation and activation of the atypical kinase p53-related protein kinase (PRPK) by Akt/PKB. AB - p53-related protein kinase (PRPK), the human homologue of yeast Bud32, belonging to a small subfamily of atypical protein kinases, is inactive unless it is previously incubated with cell lysates. Here we show that such an activation of PRPK is mediated by another kinase, Akt/PKB, which phosphorylates PRPK at Ser250. We show that recombinant PRPK is phosphorylated in vitro by Akt and its phospho form is recognized by a Ser250-phospho-specific antibody; that cell co transfection with Akt along with wild-type PRPK, but not with its Ser250Ala mutant, results in increased PRPK phosphorylation; and that the phosphorylation of p53 at Ser15, the only known substrate of PRPK, is markedly increased by co transfection of Akt with wild-type PRPK, but not PRPK dead mutant, and is abrogated by cell treatment with the Akt pathway inhibitor LY294002. Our data disclose an unanticipated mechanism by which PRPK can be activated and provide a functional link between this enigmatic kinase and the Akt signaling pathway. PMID- 17712530 TI - Trace element balance is changed in infected organs during acute Chlamydophila pneumoniae infection in mice. AB - Most infectious diseases are accompanied by changed levels of several trace elements in the blood. However, sequential changes in trace elements in tissues harbouring bacterial infections have not been studied. In the present study the respiratory pathogen Chlamydophila pneumoniae (C. pneumoniae), adapted to C57BL/6J mice, was used to study whether the balance of trace elements is changed in infected organs. Bacteria were quantitatively measured by real-time PCR in the blood, lungs, liver, aorta, and heart on days 2, 5, and 8 of the infection. Concentrations of 13 trace elements were measured in the liver, heart, and serum by inductively coupled plasma mass-spectrometry (ICP-MS). Infected mice developed expected clinical signs of disease and bacteria were found in lungs, liver, and heart on all days. The number of bacteria peaked on day 2 in the heart and on day 5 in the liver. The copper/zinc (Cu/Zn) ratio in serum increased as a response to the infection. Cu increased in the liver but did not change in the heart. Iron (Fe) in serum decreased progressively, whereas in the heart it tended to increase, and in the liver it progressively increased. C. pneumoniae may thus cause a changed trace element balance in target tissues of infection that may be pivotal for bacterial growth. PMID- 17712531 TI - An investigation of hemopexin redox properties by spectroelectrochemistry: biological relevance for heme uptake. AB - Hemopexin (HPX) has two principal roles: it sequesters free heme in vivo for the purpose of preventing the toxic effects of this moiety, which is largely due to heme's ability to catalyze free radical formation, and it transports heme intracellularly thus limiting its availability as an iron source for pathogens. Spectroelectrochemistry was used to determine the redox potential for heme and meso-heme (mH) when bound by HPX. At pH 7.2, the heme-HPX assembly exhibits E (1/2) values in the range 45-90 mV and the mH-HPX assembly in the range 5-55 mV, depending on environmental electrolyte identity. The E (1/2) value exhibits a 100 mV positive shift with a change in pH from 7.2 to 5.5 for mH-HPX, suggesting a single proton dependent equilibrium. The E (1/2) values for heme-HPX are more positive in the presence of NaCl than KCl indicating that Na(+), as well as low pH (5.5) stabilizes ferro-heme-HPX. Furthermore, comparing KCl with K(2)HPO(4), the chloride salt containing system has a lower potential, indicating that heme HPX is easier to oxidize. These physical properties related to ferri-/ferro-heme reduction are both structurally and biologically relevant for heme release from HPX for transport and regulation of heme oxygenase expression. Consistent with this, when the acidification of endosomes is prevented by bafilomycin then heme oxygenase-1 induction by heme-HPX no longer occurs. PMID- 17712529 TI - The surgical management of cataract: barriers, best practices and outcomes. AB - Cataract is the leading cause of blindness in the world. Cataract surgery has been shown by multiple studies to be one of the most cost-effective health interventions, and leads to a dramatic increase in quality of life and productivity for many patients. Though there has been marked improvement in the last several decades, surgical delivery services in developing nations are still suboptimal, and a large backlog in cataract cases continues to grow. To decrease this backlog, barriers to surgery, such as direct and indirect patient costs, geographic access to surgical facilities and surgeons, cultural factors, and patient education, must be addressed. In particular, access to services by women and rural patients needs to be improved. It is clear that extracapsular techniques are cost-effective and lead to better post-operative outcomes than intracapsular cataract extraction with aphakic correction. In addition, monitoring surgical outcomes is essential for improving the quality of surgical services. However, other issues regarding the delivery of cataract surgical services, including the role of average power intraocular lenses and the role of non-physician surgeons, are yet unresolved. Information about the true cost of surgery, including costs of surgeon training, equipment, and patient outreach programs, is needed so that the goal of self-sustaining programs may be obtained. PMID- 17712532 TI - A message emerging from development: the repression of mitochondrial beta-F1 ATPase expression in cancer. AB - Mitochondrial research has experienced a considerable boost during the last decade because organelle malfunctioning is in the genesis and/or progression of a vast array of human pathologies including cancer. The renaissance of mitochondria in the cancer field has been promoted by two main facts: (1) the molecular and functional integration of mitochondrial bioenergetics with the execution of cell death and (2) the implementation of (18)FDG-PET for imaging and staging of tumors in clinical practice. The latter, represents the bed-side translational development of the metabolic hallmark that describes the bioenergetic phenotype of most cancer cells as originally predicted at the beginning of previous century by Otto Warburg. In this minireview we will briefly summarize how the study of energy metabolism during liver development forced our encounter with Warburg's postulates and prompted us to study the mechanisms that regulate the biogenesis of mitochondria in the cancer cell. PMID- 17712534 TI - Tyrosine kinase inhibitors and anti-angiogenic therapies in kidney cancer. AB - Renal cell carcinoma (RCC) is a heterogeneous disease as reflected in its presentation and clinical course, pathological subtypes, nuclear grades and molecular biology. Emerging data indicate that renal tumors express a variety of molecular tumor markers and unique patterns of gene expression. Clinically the disease behaves quite heterogeneously, with courses ranging from indolent to highly aggressive. Surgical monotherapy or as part of a multimodal approach remains the standard of care for most cases of RCC. Radical or partial nephrectomy is associated with a 5-year cancer specific survival (CSS) of 85-97% for pT1 tumors. Unfortunately, 20% of patients have either locally advanced or node positive (N+) RCC while another 22% have metastatic RCC (mRCC) at presentation. Unlike the outcomes in early localized disease, survival rates for N+ patients are poor and patients with mRCC are rarely cured despite aggressive multimodal therapy. Classic cytotoxic chemotherapy has repeatedly been shown to have little effect and only 5-20% of patients with mRCC respond to immunologic agents such as interferon and/or interleukin. Cytoreductive nephrectomy with systemic immunotherapy is associated with few cures with median survivals of 12 24 months. Recent advances in our understanding of the molecular origins and pathways of RCC have led to the development of more effective targeted therapies. Here we review the molecular pathways that define the pertinent therapeutic targets in RCC and the clinical data for these new and promising agents. PMID- 17712533 TI - Mechanisms of tumor growth and metastasis in head and neck squamous cell carcinoma. AB - The formation and progression of head and neck squamous cell carcinoma (HNSCC) is multisystemic and involves the immune system, vascularization, and dissemination. Immune involvement includes the subversion of anti-tumor defenses. Vascularization involves both angiogenesis and vasculogenesis. Dissemination involves local tumor invasion as well as distant metastasis through processes including angiogenesis and lymphangiogenesis. Current studies in the dysregulation of various processes, including genetic stability, angiogenesis, lymphangiogenesis, immune regulation, and immune function, are opening opportunities for the development of targeted tumor therapies. The interrelationship of these processes in HNSCC development will be explored in this review. PMID- 17712536 TI - [Pathophysiology of heart failure]. AB - Chronic heart failure is a clinical syndrome and the final common pathway of different cardiac diseases. Heart failure is accompanied by activation of the renin-angiotensin-aldosterone-system and the adrenergic nervous system. In addition, recent data emphasize important roles of maladaptive intracellular signaling pathways, decreased capillary density, altered calcium handling, metabolic changes, genetic polymorphisms, and programmed cell death in the failing heart. In this context, traditional pathophysiological concepts, e. g. concerning the role of cardiac hypertrophy, had to be given up. Thus, an increasingly complex scenario emerges with interdependent changes on the biochemical, molecular, metabolic, and cellular level. Novel therapeutic strategies may soon be based on these new pathophysiological concepts. PMID- 17712537 TI - [Liver toxicity of paracetamol]. PMID- 17712538 TI - [Nutrition of critically ill patients in intensive care]. AB - A concept for combined enteral and parenteral nutrition for critically ill patients is described in which endogenous substrate production during the acute phase of illness is taken into consideration and hyperalimentation is avoided. The nutritional goal is defined by multiplication of the base rate, i.e. body weight (BW) in kg as delivery rate in ml/h (wedge 24 kcal/kg BW/24 h), with a target factor, which varies between 0.2 and 1.8. An equivalent composition of enteral and parenteral nutrition allows a transition between both forms without problems. Simultaneously, immunologic aspects of nutrition are considered as well and both forms of nutrition are complemented by immune-modulating substrates such as glutamine and antioxidants. PMID- 17712539 TI - [Preoperative risk evaluation in heart failure]. AB - The primary target in preoperative risk evaluation is not to classify patients as operable or inoperable but rather to reduce perioperative morbidity and mortality. Indications for perioperative diagnostic and therapeutic procedures are mostly the same as for patients without subsequent non-cardiac surgery. However, the time schedule often depends on cofactors such as urgency and severity of surgical interventions. Perioperative risk management requires exceedingly good communication and collaboration between surgeons, anesthesiologists and internists and offers the chance to diagnose and treat perioperative risk factors in a justifiable time and cost context. PMID- 17712540 TI - Salt glands in the Jurassic metriorhynchid Geosaurus: implications for the evolution of osmoregulation in Mesozoic marine crocodyliforms. AB - The presence of salt-excreting glands in extinct marine sauropsids has been long suspected based on skull morphology. Previously, we described for the first time the natural casts of salt-excreting glands in the head of the Jurassic metriorhynchid crocodyliform Geosaurus araucanensis from the Tithonian of the Vaca Muerta Formation in the Neuquen Basin (Argentina). In the present study, salt-excreting glands are identified in three new individuals (adult, a sub-adult and a juvenile) referable to the same species. New material provides significant information on the salt glands form and function and permit integration of evolutionary scenarios proposed on a physiological basis in extant taxa with evidence from the fossil record. G. araucanensis represents an advanced stage of the basic physiological model to marine adaptations in reptiles. G. araucanensis salt glands were hypertrophied. On this basis, it can be hypothesized that these glands had a high excretory capability. This stage implies that G. araucanensis (like extant pelagic reptiles, e.g. cheloniids) could have maintained constant plasma osmolality even when seawater or osmoconforming prey were ingested. A gradual model of marine adaptation in crocodyliforms based on physiology (freshwater to coastal/estuarine to estuarine /marine to pelagic life) is congruent with the phylogeny of crocodyliforms based on skeletal morphology. The fossil record suggests that the stage of marine pelagic adaptation was achieved by the Early Middle Jurassic. Salt gland size in the juvenile suggests that juveniles were, like adults, pelagic. PMID- 17712541 TI - Genetic dissection of grain yield in bread wheat. II. QTL-by-environment interaction. AB - The grain yield of wheat is influenced by genotype, environment and genotype-by environment interaction. A mapping population consisting of 182 doubled haploid progeny derived from a cross between the southern Australian varieties 'Trident' and 'Molineux', was used to characterise the interaction of previously mapped grain yield quantitative trait locus (QTL) with specific environmental covariables. Environments (17) used for grain yield assessment were characterised for latitude, rainfall, various temperature-based variables and stripe rust infection severity. The number of days in the growing season in which the maximum temperature exceeded 30 degrees C was identified as the variable with the largest effect on site mean grain yield. However, the greatest QTL-by-environmental covariable interactions were observed with the severity of stripe rust infection. The rust resistance allele at the Lr37/Sr38/Yr17 locus had the greatest positive effect on grain yield when an environment experienced a combination of high stripe rust infection and cool days. The grain yield QTL, QGyld.agt-4D, showed a very similar QTL-by-environment covariable interaction pattern to the Lr37/Sr38/Yr17 locus, suggesting a possible role in rust resistance or tolerance. Another putative grain yield per se QTL, QGyld.agt-1B, displayed interactions with the quantity of winter and spring rainfall, the number of days in which the maximum temperature exceeded 30 degrees C, and the number of days with a minimum temperature below 10 degrees C. However, no cross-over interaction effect was observed for this locus, and the 'Molineux' allele remained associated with higher grain yield in response to all environmental covariables. The results presented here confirm that QGyld.agt-1B may be a prime candidate for marker assisted selection for improved grain yield and wide adaptation in wheat. The benefit of analysing the interaction of QTL and environmental covariables, such as employed here, is discussed. PMID- 17712542 TI - Complex mutational patterns and size homoplasy at maize microsatellite loci. AB - Microsatellite markers have become one of the most popular tools for germplasm characterization, population genetics and evolutionary studies. To investigate the mutational mechanisms of maize microsatellites, nucleotide sequence information was obtained for ten loci. In addition, Single-Strand Conformation Polymorphism (SSCP) analysis was conducted to assess the occurrence of size homoplasy. Sequence analysis of 54 alleles revealed a complex pattern of mutation at 8/10 loci, with only 2 loci showing allele variation strictly consistent with stepwise mutations. The overall allelic diversity resulted from changes in the number of repeat units, base substitutions, and indels within repetitive and non repetitive segments. Thirty-one electromorphs sampled from six maize landraces were considered for SSCP analysis. The number of conformers per electromorph ranged from 1 to 7, with 74.2% of the electromorphs showing more than one conformer. Size homoplasy was apparent within landraces and populations. Variation in the amount of size homoplasy was observed within and between loci, although no differences were detected among populations. The results of the present study provide useful information on the interpretation of genetic data derived from microsatellite markers. Further efforts are still needed to determine the impact of these findings on the estimation of population parameters and on the inference of phylogenetic relationships in maize investigations. PMID- 17712543 TI - Development and validation of a Viviparous-1 STS marker for pre-harvest sprouting tolerance in Chinese wheats. AB - Pre-harvest sprouting (PHS) of wheat reduces the quality of wheat grain, and improving PHS tolerance is a priority in certain wheat growing regions where conditions favorable for PHS exist. Two new Viviparous-1 allelic variants related to PHS tolerance were investigated on B genome of bread wheat, and designated as Vp-1Bb and Vp-1Bc, respectively. Sequence analysis showed that Vp-1Bb and Vp-1Bc had an insertion of 193-bp and a deletion of 83-bp fragment, respectively, located in the third intron region of the Vp-1B gene. The insertion and deletion affected the expression level of the Vp1 at mature seed stage, more correctly spliced transcripts were observed from the genotypes with either insertion or deletion than that of the wild type. Based on these insertions and deletions, a co-dominant STS marker of Vp-1B gene was developed and designated as Vp1B3, which in most cases could amplify either 845 or 569-bp fragment from the tolerant cultivars, and 652-bp from the susceptible ones. This Vp1B3 marker was mapped to chromosome 3BL using a set of Chinese Spring nulli-tetrasomic and ditelosomic lines. A total of 89 white-grained Chinese wheat cultivars and advanced lines, were used to validate the relationship between the polymorphic fragments of Vp1B3 and PHS tolerance. Statistical analysis indicated that Vp1B3 was strongly associated with PHS tolerance in this set of Chinese germplasm, suggesting that Vp1B3 could be used as an efficient and reliable co-dominant marker in the evaluation of wheat germplasm for PHS tolerance and marker-assisted breeding for PHS tolerant cultivars. PMID- 17712544 TI - Detection of seed dormancy QTL in multiple mapping populations derived from crosses involving novel barley germplasm. AB - Seed dormancy is one of the most important traits in germination process to control malting and pre-harvest sprouting in barley (Hordeum vulgare L.). EST based linkage maps were constructed on seven recombinant inbred (RI) and one doubled haploid (DH) populations derived from crosses including eleven cultivated and one wild barley strains showing the wide range of seed dormancy levels. Seed dormancy of each RI and DH line was estimated from the germination percentage at 5 and 10 weeks post-harvest after-ripening periods in 2003 and 2005. Quantitative trait loci (QTLs) controlling seed dormancy were detected by the composite interval mapping procedure on the RI and DH populations. A total of 38 QTLs clustered around 11 regions were identified on the barley chromosomes except 2H among the eight populations. Several QTL regions detected in the present study were reported on similar positions in the previous QTL studies. The QTL on at the centromeric region of long arm of chromosome 5H was identified in all the RI and DH populations with the different degrees of dormancy depth and period. The responsible gene of the QTL might possess a large allelic variation among the cross combinations, or can be multiple genes located on the same region. The various loci and their different effects in dormancy found in the barley germplasm in the present study enable us to control the practical level of seed dormancy in barley breeding programs. PMID- 17712546 TI - Consensus statement on the worldwide standardisation of the HbA1c measurement. PMID- 17712545 TI - Effect of macrophage migration inhibitory factor (MIF) gene variants and MIF serum concentrations on the risk of type 2 diabetes: results from the MONICA/KORA Augsburg Case-Cohort Study, 1984-2002. AB - AIMS/HYPOTHESIS: Macrophage migration inhibitory factor (MIF) is a central mediator of innate immunity. Our aim was to investigate the triangular association between MIF genotypes, circulating MIF concentrations and incident type 2 diabetes, and to use a Mendelian randomisation approach to assess the causal role of MIF. METHODS: Using a case-cohort design within the population based MONICA/KORA Augsburg Study, based on 502 individuals with incident type 2 diabetes (293 men, 209 women) and 1,632 non-cases (859 men, 773 women), we determined MIF serum levels at baseline and genotyped four MIF single nucleotide polymorphisms (SNPs). RESULTS: The C allele of SNP rs1007888 (3.8 kb 3' of the translation termination codon) was associated with increased circulating MIF. MIF genotype rs1007888CC was associated with an increased risk of type 2 diabetes in women [hazard ratio (95% CI) 1.74 (1.02-2.97)], but not in men [1.17 (0.75 1.81)]. Elevated MIF serum levels were associated with higher type 2 diabetes risk also only in women [HR (95% CI) 1.95 (1.15-3.29) comparing extreme quartiles after multiple adjustment], but not in men (p for interaction 0.039). The association between MIF levels and incident type 2 diabetes was significantly higher in obese women (111 cases, 147 non-cases) compared with non-obese women (98 cases, 626 non-cases; p for BMI interaction 0.0002). CONCLUSIONS/INTERPRETATION: The consistent triangular relationship between genotypes, serum levels and incident type 2 diabetes in women indicates that MIF may play a causal role in the aetiology of type 2 diabetes and that elevated MIF levels confer a higher disease risk. PMID- 17712547 TI - Fatty acid-induced mitochondrial uncoupling in adipocytes as a key protective factor against insulin resistance and beta cell dysfunction: a new concept in the pathogenesis of obesity-associated type 2 diabetes mellitus. AB - Type 2 diabetes is associated with excessive food intake and a sedentary lifestyle. Local inflammation of white adipose tissue induces cytokine-mediated insulin resistance of adipocytes. This results in enhanced lipolysis within these cells. The fatty acids that are released into the cytosol can be removed by mitochondrial beta-oxidation. The flux through this pathway is normally limited by the rate of ADP supply, which in turn is determined by the metabolic activity of the adipocyte. It is expected that the latter does not adapt to an increased rate of lipolysis. We propose that elevated fatty acid concentrations in the cytosol of adipocytes induce mitochondrial uncoupling and thereby allow mitochondria to remove much larger amounts of fatty acids. By this, release of fatty acids out of adipocytes into the circulation is prevented. When the rate of fatty acid release into the cytosol exceeds the beta-oxidation capacity, cytosolic fatty acid concentrations increase and induce mitochondrial toxicity. This results in a decrease in beta-oxidation capacity and the entry of fatty acids into the circulation. Unless these released fatty acids are removed by mitochondrial oxidation in active muscles, these fatty acids result in ectopic triacylglycerol deposits, induction of insulin resistance, beta cell damage and diabetes. Thiazolidinediones improve mitochondrial function within adipocytes and may in this way alleviate the burden imposed by the excessive fat accumulation associated with the metabolic syndrome. Thus, the number and activity of mitochondria within adipocytes contribute to the threshold at which fatty acids are released into the circulation, leading to insulin resistance and type 2 diabetes. PMID- 17712548 TI - The tibialis tendon as a valuable anterior cruciate ligament allograft substitute: biomechanical properties. AB - The study evaluates the biomechanical properties of single-strand and single-loop tibialis (anterior and posterior) tendon allografts. A comparison was made with bone-patellar tendon-bone (BPTB) allografts. Sixty-four tendon allografts were evaluated in this study. Sixteen of these were single-strand tibialis anterior (TA) and 16 single-strand tibialis posterior (TP) tendons. Sixteen single-loop TA and TP tendons were also tested. The fourth group was composed of 16 BPTB allografts. The biomechanical properties determined were maximal load, stiffness, cross-sectional area and elongation. The results of this study showed that the maximal load of the single-loop tibialis tendons (1,553 +/- 62 N) was greater than of the BPTB (1,139 +/- 99 N), TA (776 +/- 43 N) and TP (888 +/- 64 N) tendons. The stiffness of the single-loop tibialis tendons (236 +/- 10 N/mm) was also greater than of the BPTB (168 +/- 13 N/mm), TA (60 +/- 2 N/mm) and TP (73 +/ 5 N/mm) tendons. The cross-sectional area of the BPTB tendons was 67 +/- 5 mm(2), of the single-loop tibialis tendons 36 +/- 2 mm(2), of the TA tendons 20 +/- 1 mm(2), and of the TP tendons 23 +/- 1 mm(2). The elongation of the single loop tibialis tendons and of the BPTB tendons was almost similar (7 +/- 0.4 mm). The same applied to the TA and TP tendons (14 +/- 0.6 mm). The results of this in vitro mechanical study suggest that fresh-frozen single-loop TA and TP tendons, and BPTB allografts are an acceptable substitute for hamstrings in anterior cruciate ligament reconstruction. PMID- 17712550 TI - Analysis of O-glycan heterogeneity in IgA1 myeloma proteins by Fourier transform ion cyclotron resonance mass spectrometry: implications for IgA nephropathy. AB - IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis. In IgAN, IgA1 molecules with incompletely galactosylated O-linked glycans in the hinge region (HR) are present in mesangial immunodeposits and in circulating immune complexes. It is not known whether the galactose deficiency in IgA1 proteins occurs randomly or preferentially at specific sites. We have previously demonstrated the first direct localization of multiple O-glycosylation sites on a single IgA1 myeloma protein by use of activated ion-electron capture dissociation (AI-ECD) Fourier transform ion cyclotron resonance (FT-ICR) tandem mass spectrometry. Here, we report the analysis of IgA1 O-glycan heterogeneity by use of FT-ICR MS and liquid chromatography FT-ICR MS to obtain unbiased accurate mass profiles of IgA1 HR glycopeptides from three different IgA1 myeloma proteins. Additionally, we report the first AI-ECD fragmentation on an individual IgA1 O glycopeptide from an IgA1 HR preparation that is reproducible for each IgA1 myeloma protein. These results suggest that future analysis of IgA1 HR from IgAN patients and normal healthy controls should be feasible. PMID- 17712551 TI - Evaluation of limited sampling strategies for tacrolimus. AB - OBJECTIVE: In literature, a great diversity of limited sampling strategies (LSS) have been recommended for tacrolimus monitoring, however proper validation of these strategies to accurately predict the area under the time concentration curve (AUC0-12) is limited. The aim of this study was to determine whether these LSS might be useful for AUC prediction of other patient populations. METHODS: The LSS from literature studied were based on regression equations or on Bayesian fitting using MWPHARM 3.50 (Mediware, Groningen, the Netherlands). The performance was evaluated on 24 of these LSS in our population of 37 renal transplant patients with known AUCs. The results were also compared with the predictability of the regression equation based on the trough concentrations C0 and C12 of these 37 patients. Criterion was an absolute prediction error (APE) that differed less than 15% from the complete AUC0-12 calculated by the trapezoidal rule. RESULTS: Thirteen of the 18 (72%) LSS based on regression analysis were capable of predicting at least 90% of the 37 individual AUC0-12 within an APE of 15%. Additionally, all but three LSS examined gave a better prediction of the complete AUC0-12 in comparison with the trough concentrations C0 or C12 (mean 62%). All six LSS based on Bayesian fitting predicted <90% of the 37 complete AUC0-12 correctly (mean 67%). CONCLUSIONS: The present study indicated that implementation of LSS based on regression analysis could produce satisfactory predictions although careful evaluation is necessary. PMID- 17712553 TI - Distribution of free and esterified ergosterols in the medicinal fungus Ganoderma lucidum. AB - The fruiting bodies, spores, and lipid from the spores of Ganoderma lucidum have been widely used for medicinal purpose in China. Ergosterol content may be a suitable marker for evaluating the quality of ganoderma spore and ganoderma spore lipid (GSL) products. A gradient reversed-phase high-performance liquid chromatography method was developed for the simultaneous determination of free and esterified ergosterols in G. lucidum. The contents of free and esterified ergosterols in the different parts (the stipe, pileus, tubes, and spores) of G. lucidum and GSL were determined. The results showed that total ergosterol levels in the stipe, pileus, tubes, and spores of G. lucidum were between 0.8 and 1.6 mg/g. The relative abundances of free to esterified ergosterol were different in the different parts of G. lucidum. The spores and the tubes, the hymenophore tissue that contains the spore-producing cells, have a considerably higher percentage of ergosteryl esters (41.9 and 39.7% of total ergosterol) in comparison with the pileus and stipe tissues (3.6 and 6.2%). PMID- 17712552 TI - High concordance between self-reported medication and official prescription database information. AB - OBJECTIVE: We set out to compare the agreement between self-reported psychotropic medication use and information obtained from the administrative prescription database of the Social Insurance Institution of Finland. We compared the point prevalence of psychotropic medication use, and self-reported vs. register-based information on antipsychotic medication dosage. METHODS: The study population consisted of 905 participants from a population-based genetic study of schizophrenia, of whom 366 had schizophrenia spectrum disorder, 56 had bipolar spectrum disorder, and 483 were unaffected family members. Current medication use was obtained by interview and from the prescription reimbursement database. Agreement between data sources was compared using Cohen's kappa statistic and correlation coefficients. RESULTS: The agreement between the two sources was generally good. Kappa values were best for lithium use (0.96; p < 0.0001), followed by antipsychotics (0.87; p < 0.0001) and antidepressants (0.77; p < 0.0001). Agreement was lowest for benzodiazepines (0.42; p < 0.0001). Correlation between antipsychotic medication dose estimates was 0.79 (95% CI 0.76-0.81). CONCLUSION: The concordance between self-reported psychotropic medication use and information obtained from an official prescription database was good for most psychotropic drugs. More studies are needed to replicate results with other forms of medication and patient groups. PMID- 17712549 TI - A pharmacological analysis of mice with a targeted disruption of the serotonin transporter. AB - RATIONALE: Partial or complete ablation of serotonin transporter (SERT) expression in mice leads to altered responses to serotonin receptor agonists and other classes of drugs. OBJECTIVES: In the current report, we review and integrate many of the major behavioral, physiological, and neurochemical findings in the current literature regarding pharmacological assessments made in SERT mutant mice. RESULTS: The absence of normal responses to serotonin reuptake inhibiting (SRI) antidepressants in SERT knockout (-/-) mice demonstrates that actions on SERT are a critical principle mechanism of action of members of this class of antidepressants. Drugs transported by SERT, (+)-3,4 methylenedioxymethamphetamine (MDMA) and 1-methyl-4-(2'-aminophenyl)-1,2,3,6 tetrahydropyridine (2'-NH(2)-MPTP), are also inactive in SERT -/- mice. Temperature, locomotor, and electrophysiological responses to various serotonin receptor agonists, including 8-hydroxy-2-(di-n-propylamino)-tetraline (8-OH DPAT), ipsapirone, and RU24969, are reduced in SERT -/- mice, despite comparatively lesser reductions in Htr1a and Htr1b binding sites, G-proteins, and other signaling molecules. SERT -/- mice exhibit an approximately 90% reduction in head twitches in response to the Htr2a/2c agonist (+/-)-1-(2,5-dimethoxy-4 iodophenyl)-2-aminopropane (DOI), associated with a profound reduction in arachidonic acid signaling, yet only modest changes in Htr2a and Htr2c binding sites. SERT -/- mice also exhibit altered behavioral responses to cocaine and ethanol, related to abnormal serotonin, and possibly dopamine and norepinephrine, homeostasis. CONCLUSIONS: Together, these studies demonstrate a complex and varied array of modified drug responses after constitutive deletion of SERT and provide insight into the role of serotonin, and in particular, its transporter, in the modulation of complex behavior and in the pharmacological actions of therapeutic agents and drugs of abuse. PMID- 17712554 TI - A new esterase showing similarity to putative dienelactone hydrolase from a strict marine bacterium, Vibrio sp. GMD509. AB - Vibrio sp. GMD509, a marine bacterium isolated from eggs of the sea hare, exhibited lipolytic activity on tributyrin (TBN) plate, and the gene representing lipolytic activity was cloned. As a result, an open reading frame (ORF) consisting of 1,017 bp (338 aa) was found, and the deduced amino acid sequence of the ORF showed low similarity (< 20%) to alpha/beta hydrolases such as dienelactone hydrolases and esterase/lipase with G-X(1)-S-X(2)-G sequence conserved. Phylogenetic analysis suggested that the protein belonged to a new family of esterase/lipase together with various hypothetical proteins. The enzyme was overexpressed in Escherichia coli and purified to homogeneity. The purified enzyme (Vlip509) showed the best hydrolyzing activity toward p-nitrophenyl butyrate (C(4)) among various p-nitrophenyl esters (C(2) to C(18)), and optimal activity of Vlip509 occurred at 30 degrees C and pH 8.5, respectively. Kinetic parameters toward p-nitrophenyl butyrate were determined as K (m) (307 muM), k (cat) (5.72 s(-1)), and k (cat)/K (m) (18.61 s(-1) mM(-1)). Furthermore, Vlip509 preferentially hydrolyzed the S-enantiomer of racemic ofloxacin ester. Despite its sequence homology to dienelactone hydrolase, Vlip509 showed no dienelactone hydrolase activity. This study represents the identification of a novel lipolytic enzyme from marine environment. PMID- 17712555 TI - Evaluation of radial-sequence imaging in detecting acetabular labral tears at hip MR arthrography. AB - OBJECTIVE: In recent years, radial imaging has been advocated for improved visualization of the acetabular labrum in magnetic resonance arthrography of the hip. The purpose of this study was to investigate whether radial imaging demonstrates labral tears not visible on standard imaging planes. METHODS: Fifty four consecutive magnetic resonance (MR) arthrograms of the hip that included radial imaging over 2 years were retrospectively analyzed by two radiologists. Standard imaging planes and radial imaging were reviewed for identification of labral tears in four specific areas of the labrum: anterosuperior, posterosuperior, anteroinferior, and posteroinferior. The standard imaging sequences include fat-saturated spin-echo T1-weighted images in the coronal and oblique axial planes, non-fat-saturated T1-weighted images in the coronal and sagittal planes, and T2-weighted sequence in the axial plane. Radial imaging was performed as previously described using fat-saturated T1-weighted sequences. RESULTS: Using standard imaging planes, 50 anterosuperior, 31 posterosuperior, 10 anteroinferior, and 9 posteroinferior labral tears were detected in 54 MR arthrograms of the hip. Using radial sequences alone, 44 anterosuperior, 25 posterosuperior, 9 anteroinferior, and 5 posteroinferior labral tears were detected. In all four areas of the labrum, the radial imaging did not show any labral tear not seen on standard imaging planes. DISCUSSION: In MR arthrography of the hip, radial imaging did not reveal any additional labral tears. Standard imaging planes sufficiently demonstrate all acetabular labral tears. PMID- 17712557 TI - Contribution of HIF-1alpha or HIF-2alpha to erythropoietin expression: in vivo evidence based on chromatin immunoprecipitation. AB - Circulating erythropoietin (EPO) is mainly produced by the kidneys and mediates erythrogenesis in bone marrow and nonhematopoietic cell survival. EPO is also produced in other tissues where it functions as a paracrine. Moreover, the hypoxic induction of EPO is known to be mediated by HIF-1alpha and HIF-2alpha, but it remains obscure as to which of these two mediators mainly contributes to EPO expression. Thus, we designed in vivo experiments to evaluate the contributions made by HIF-1alpha and HIF-2alpha to EPO expression. In mice exposed to mild whole body hypoxia, HIF-1alpha and HIF-2alpha were both induced in all tissues examined. However, EPO mRNA was expressed in kidney and brain, but not in liver and lung. Likewise, chromatin immunoprecipitation (CHIP) analyses demonstrated that HIF-1alpha or HIF-2alpha binding to the EPO gene increased under hypoxic conditions only in kidney and brain. A comparison of CHIP data and EPO mRNA levels suggested that, during mild hypoxia, renal EPO transcription is induced equally by HIF-1alpha and HIF-2alpha, but that brain EPO is mainly induced during hypoxia by HIF-2alpha. Thus, HIF-1alpha and HIF-2alpha appear to contribute to EPO expression tissue specifically. PMID- 17712556 TI - Ultrasound of the small joints of the hands and feet: current status. AB - The aim of this article was to review the current status of ultrasound imaging of patients with rheumatological disorders of the hands and feet. Ultrasound machines with high-resolution surface probes are readily available in most radiology departments and can be used to address important clinical questions posed by the rheumatologist and sports and rehabilitation physician. There is increasing evidence that ultrasound detects synovitis that is silent to clinical examination. Detection and classification of synovitis and the early detection of bone erosions are important in clinical decision making. Ultrasound has many advantages over other imaging techniques with which it is compared, particularly magnetic resonance. The ability to carry out a rapid assessment of many widely spaced joints, coupled with clinical correlation, the ability to move and stress musculoskeletal structures and the use of ultrasound to guide therapy accurately are principal amongst these. The use of colour flow Doppler studies provides a measure of neovascularisation within the synovial lining of joints and tendons, and within tendons themselves, that is not available with other imaging techniques. Disadvantages compared to MRI include small field of view, poor image presentation, and difficulty in demonstrating cartilage and deep joints in their entirety. Contrast-enhanced magnetic resonance provides a better measure of capillary permeability and extracellular fluid than does ultrasound. The ability to image simultaneously multiple small joints in the hands and feet and their enhancement characteristics cannot be matched with ultrasound, though future developments in 3-D ultrasound may narrow this gap. Magnetic resonance provides a more uniform and reproducible image for long-term follow-up studies. PMID- 17712558 TI - Genetic polymorphisms of methylenetetrahydrofolate reductase and promoter methylation of MGMT and FHIT genes in diffuse large B cell lymphoma risk in Middle East. AB - Diffuse large B cell lymphoma (DLBCL) is one of the most common non-Hodgkin's lymphoma types. Methylenetetrahydrofolate reductase (MTHFR) balances the pool of folate coenzymes in one carbon metabolism of deoxyribonucleic acid (DNA) synthesis and methylation; both are implicated in carcinogenesis of many types of cancer including lymphoma. Two common variants in the MTHFR gene (C677T and A1298C) have been associated with reduced enzyme activity, thereby making MTHFR polymorphisms a potential candidate as a cancer-predisposing factor. The O6 methylguanine DNA methyltransferase (MGMT) and fragile histidine triad (FHIT) genes are transcriptionally silenced by promoter hypermethylation in DLBCL. These genetic differences are highly race specific and have never been screened in the Saudi DLBCL patients. We conducted a hospital-based case-control study including 160 DLBCL cases and 511 Saudi control samples analyzing the MTHFR C677T and A1298C functional polymorphisms by the restriction fragment length polymorphism method and their association with MGMT and FHIT genes promoter hypermethylation. Our data demonstrated that Saudi individuals carrying MTHFR genotype 1298CC (p < 0.001) and the 1298C allele (p = 0.012) had 4.23 and 1.73-fold higher risk of developing DLBCL, respectively. Additionally, combined genotype CCCC (MTHFR 677CC + MTHFR 1298CC) was associated with 3.489-fold, and CTCC (MTHFR 677 CT + 1298CC) was related to 9.515-fold higher risk, compared with full MTHFR enzyme activity. No significant association between MTHFR variant genotypes and methylation of MGMT and FHIT genes were observed. Our findings suggested that polymorphisms of MTHFR enzyme genes might be associated with the individual susceptibility to develop DLBCL. Additionally, the results indicated that MTHFR variants were not related to MGMT or FHIT hypermethylation in DLBCL. PMID- 17712559 TI - Analysis of molecular markers in three different tomato cultivars exposed to ozone stress. AB - Three differentially expressed cDNAs have been isolated from ozone treated tomato seedlings. Their level of expression after ozone exposure has been analysed in three tomato cultivars with different sensitivity to ozone (Nikita, Alisa Craig and Valenciano). These comparative analyses have been extended to a number of genes involved in antioxidative, wounding or pathogenesis responses, showing several differences among cultivars that could be related with their different sensitivity to ozone. Gene response to ozone was affected not only by the period and dose of ozone exposure (short time or chronic), but also by growth conditions (controlled growth chamber or field). Comparison of gene expression patterns puts on evidence the needing of validation in field of experiments performed with plants grown under controlled conditions. Our results suggest that changes in genes expression, observed after ozone treatment in field, are affected by additional factors related to environmental clues. PMID- 17712560 TI - Genetic transformation of sweet orange with the coat protein gene of Citrus psorosis virus and evaluation of resistance against the virus. AB - Citrus psorosis is a serious viral disease affecting citrus trees in many countries. Its causal agent is Citrus psorosis virus (CPsV), the type member of genus Ophiovirus. CPsV infects most important citrus varieties, including oranges, mandarins and grapefruits, as well as hybrids and citrus relatives used as rootstocks. Certification programs have not been sufficient to control the disease and no sources of natural resistance have been found. Pathogen-derived resistance (PDR) can provide an efficient alternative to control viral diseases in their hosts. For this purpose, we have produced 21 independent lines of sweet orange expressing the coat protein gene of CPsV and five of them were challenged with the homologous CPV 4 isolate. Two different viral loads were evaluated to challenge the transgenic plants, but so far, no resistance or tolerance has been found in any line after 1 year of observations. In contrast, after inoculation all lines showed characteristic symptoms of psorosis in the greenhouse. The transgenic lines expressed low and variable amounts of the cp gene and no correlation was found between copy number and transgene expression. One line contained three copies of the cp gene, expressed low amounts of the mRNA and no coat protein. The ORF was cytosine methylated suggesting a PTGS mechanism, although the transformant failed to protect against the viral load used. Possible causes for the failed protection against the CPsV are discussed. PMID- 17712561 TI - Construction and functional characteristics of tuber-specific and cold-inducible chimeric promoters in potato. AB - The improvement of processing quality of potato products (fries and chips) demands less accumulation of reducing sugars (glucose and fructose) in cold stored potato (Solanum tuberosum) tubers. Control of gene expression to achieve this requires promoters with specificity to tubers as well as inducible activity under low temperatures. Here we use overlapping extension PCR to construct two chimeric promoters, pCL and pLC, to control gene expression in a tuber-specific and cold-inducible pattern. This combined different combinations of the LTRE (low temperature responsive element) from Arabidopsis thaliana cor15a promoter and the TSSR (tuber-specific and sucrose-responsive sequence) from potato class I patatin promoter. The cold-inducible and tuber-specific activities of the chimeric promoters were investigated by quantitative analysis of GUS activity in transgenic potato cultivar E3 plants. The results showed that the cis-elements, LTRE and TSSR, played responsive roles individually or in combination. pCL with the TSSR closer to the TATA-box showed substantially higher promoter activity than pLC with the LTRE closer to the TATA-box at either normal (20 degrees C) or low temperature (2 degrees C), suggesting that the promoter activity was closely associated with the position of the two elements. The chimeric promoter pCL with tuber-specific and cold-inducible features may provide valuable tool for controlling the expression of gene constructs designed to lower the formation of reducing sugars in tubers stored at low temperature and to improve the processing quality of potato products. PMID- 17712562 TI - Cold tolerance of an Antarctic nematode that survives intracellular freezing: comparisons with other nematode species. AB - Panagrolaimus davidi is an Antarctic nematode with very high levels of cold tolerance. Its survival was compared with that of some other nematodes (P. rigidus, Rhabditophanes sp., Steinernema carpocapsae, Panagrellus redivivus and Ditylenchus dipsaci) in both unacclimated samples and those acclimated at 5 degrees C. Levels of recrystallization inhibition in homogenates were also compared, using the splat-cooling assay. The survival of P. davidi after the freezing of samples was notably higher than that of the other species tested, suggesting that its survival ability is atypical compared to other nematodes. In general, acclimation improved survival. Levels of recrystallization inhibition were not associated with survival but such a relationship may exist for those species that are freezing tolerant. PMID- 17712563 TI - The cationic composition and pH in the moulting fluid of Porcellio scaber (Crustacea, Isopoda) during calcium carbonate deposit formation and resorption. AB - Before moulting, terrestrial isopods resorb calcium carbonate (CaCO(3)) from the posterior cuticle and store it in sternal deposits. These consist mainly of amorphous calcium carbonate (ACC) spherules that develop within the ecdysial space between the anterior sternal epithelium and the old cuticle. Ions that occur in the moulting fluid, including those required for mineral deposition, are transported from the hemolymph into the ecdysial space by the anterior sternal epithelial cells. The cationic composition of the moulting fluid probably affects mineral deposition and may provide information on the ion-transport activity of the sternal epithelial cells. This study presents the concentrations of inorganic cations within the moulting fluid of the anterior sternites during the late premoult and intramoult stages. The most abundant cation is Na(+) followed by Mg(2+), Ca(2+) and K(+). The concentrations of these ions do not change significantly between the stages whereas the mean pH changed from 8.2 to 6.9 units between mineral deposition in late premoult, and resorption in intramoult, respectively. Measurements of the transepithelial potential show that there is little driving force for passive movements of calcium across the anterior sternal epithelium. The results suggest a possible role of magnesium ions in ACC formation, and a contribution of pH changes to CaCO(3) precipitation and dissolution. PMID- 17712565 TI - Fatty acid signatures of stomach oil and adipose tissue of northern fulmars (Fulmarus glacialis) in Alaska: implications for diet analysis of Procellariiform birds. AB - Procellariiforms are unique among seabirds in storing dietary lipids in both adipose tissue and stomach oil. Thus, both lipid sources are potentially useful for trophic studies using fatty acid (FA) signatures. However, little is known about the relationship between FA signatures in stomach oil and adipose tissue of individuals or whether these signatures provide similar information about diet and physiology. We compared the FA composition of stomach oil and adipose tissue biopsies of individual northern fulmars (N = 101) breeding at three major colonies in Alaska. Fatty acid signatures differed significantly between the two lipid sources, reflecting differences in dietary time scales, metabolic processing, or both. However, these signatures exhibited a relatively consistent relationship between individuals, such that the two lipid sources provided a similar ability to distinguish foraging differences among individuals and colonies. Our results, including the exclusive presence of dietary wax esters in stomach oil but not adipose tissue, are consistent with the notion that stomach oil FA signatures represent lipids retained from prey consumed during recent foraging and reflect little metabolic processing, whereas adipose tissue FA signatures represent a longer-term integration of dietary intake. Our study illustrates the potential for elucidating short- versus longer-term diet information in Procellariiform birds using different lipid sources. PMID- 17712564 TI - Studies on a PMCA-like protein in the outer mantle epithelium of Anodonta cygnea: insights on calcium transcellular dynamics. AB - Early studies on the outer mantle epithelium (OME) cells of the freshwater bivalve Anodonta cygnea (Linnaeus, 1758) revealed high ionic calcium concentrations by electrophysiological methods and subsequently a high tendency to reach an intracellular toxic condition. This toxicity could be neutralized by specific mechanisms in the cytosol of OME cells of A. cygnea. The present immunocytochemistry studies of OME cells by light and transmission electron microscopy (TEM) clearly showed a positive reaction of an antibody directed against the human plasma membrane Ca(2+)-ATPase 1 (PMCA-1) in the cytoplasm of OME cells. Also, western blot analysis of different fractions of OME cells with anti human PMCA-1 and C28R2 antibodies confirmed the presence of a PMCA-like protein with an unusual topographical localization and a molecular weight of only 70-80 kDa. These results lead us to speculate that this PMCA-like protein is distributed either in the plasma membrane or in the entire cytosol, where it eventually regulates intracellular calcium levels. Interestingly, the antibody reactions showed seasonal variations, being highest in OME samples prepared during summer when A. cygnea live under natural acidosis and absent in samples taken in winter conditions, which is in accordance with the seasonal variation of shell calcification rates. During winter, PMCA-1 antibody reaction was also detected in OME cells of animals kept only under experimentally induced acidosis conditions. Therefore, we assume that a functional role for this PMCA-like protein in the intracellular calcium regulation of OME cells during the mineralization of the shells of A. cygnea can be speculated. PMID- 17712566 TI - ICP and CPP: excellent predictors of long term outcome in severely brain injured children. AB - OBJECTIVE: To determine the predictive powers of intracranial pressure (ICP) and cerebral perfusion pressure (CPP) amongst severely brain injured children. MATERIALS AND METHODS: ICP and CPP were recorded from thirty-five severely brain injured children who were prospectively recruited after admission to paediatric intensive care. Twenty-five suffered traumatic brain injury (TBI) and ten suffered non-TBI. Peak ICP and minimum CPP recorded for each patient during their admission were related to 5 year Glasgow Outcome Scale outcome. Receiver operator characteristic curves determined that the optimum threshold for unfavourable outcome prediction was >or=40 mmHg for ICP and or =150 eggs per gram were selected on each of three farms (n = 150 total sheep) which were randomly allocated to one of five groups. Groups were treated with febantel, levamisole, ivermectin, or moxidectin while the fifth group acted as the control group. A FEC reduction test (FECRT) was conducted on each animal and the mean FEC of each treatment group was compared to that of the control group within farm. Resistance was declared when percentage reduction (R) <95% and the lower 95% confidence interval was <90%. Levamisole (mean R = 89%) resistance was found on all farms and ivermectin (mean R = 93%) resistance was found on two of the three farms. Posttreatment larval cultures showed the presence of Teladorsagia (Ostertagia) circumcincta and Trichostrongylus spp. larvae. Febantel (mean R = 96%) and moxidectin (mean R = 100%) remained effective. This study suggests that drug resistance in sheep gastrointestinal trichostrongyles is present in central Italy and a potential problem which would justify a broader nationwide geographical investigation. PMID- 17712572 TI - Biologically Fe2+ oxidizing fluidized bed reactor performance and controlling of Fe3+ recycle during heap bioleaching: an artificial neural network-based model. AB - The performance of a biological Fe(2+) oxidizing fluidized bed reactor (FBR) was modeled by a popular neural network-back-propagation algorithm over a period of 220 days at 37 degrees C under different operational conditions. A method is proposed for modeling Fe(3+) production in FBR and thereby managing the regeneration of Fe(3+) for heap leaching application, based on an artificial neural network-back-propagation algorithm. Depending on output value, relevant control strategies and actions are activated, and Fe(3+) production in FBR was considered as a critical output parameter. The modeling of effluent Fe(3+) concentration was very successful, and an excellent match was obtained between the measured and the predicted concentrations. PMID- 17712571 TI - PCR-based determination of internal transcribed spacer (ITS) regions of ribosomal DNA of giant intestinal fluke, Fasciolopsis buski (Lankester, 1857) Looss, 1899. AB - Fasciolopsis buski, the zoonotic intestinal flukes of pigs in South and Southeast Asia, is commonly prevalent in regions across Northeast India. Populations of the fluke collected from different parts of the region exhibit variations in morphology. The main objective of our study was to provide molecular characterization of the parasite so as to supplement morphological criteria, using ribosomal DNA cluster (rDNA), which is flanked by more conserved internal transcribed spacer (ITS) regions. We describe herein the ITS sequences of the parasite collected from swine hosts of Assam region. The ITS sequences of both egg and adult origins were found to be identical in length and composition. Phylogenetically, F. buski resembles closely the other members of family Fasciolidae, showing significant expectation value in the alignment. The results corroborate that the ITS sequences are not stage specific and are conserved through different stages of development of the fluke, and thus could be used as species markers. PMID- 17712573 TI - Use of chemotherapy at the end of life in a Portuguese oncology center. AB - GOALS OF WORK: Chemotherapy plays a major role in the treatment of cancer. However, it is sometimes thought of as being taken too far, being used in many cases close to death. The purpose of this study is to determine the proximity of chemotherapy use to the patient's death in our hospital. MATERIALS AND METHODS: This study comprised the analysis of the charts of 1,064 patients aged over 16 years with solid tumors who died in 2002 and were treated at the Porto Section of the Portuguese Institute of Oncology. MAIN RESULTS: Four hundred ten of the 1,064 patients (39%) underwent chemotherapy. Fifty-two percent of those that underwent chemotherapy did so in the last 6 months of their lives, 31% in the last 3 months, 13% in the last month, and 3% in the last week. In the context of the total cohort of 1,064, the percentages of those that underwent chemotherapy was 20, 12, 5, and 1%, respectively. By multivariate analysis, age <65 years, breast and lung cancers, and metastases were positively associated with chemotherapy; kidney cancer and comorbidity were associated with a lower probability of undergoing chemotherapy. Three hundred sixty-one patients (34%) were admitted to the palliative care unit of the hospital. CONCLUSION: It was concluded that in this hospital, chemotherapy is not used as close to death as often as most professionals feel and the literature reports. There are various possible explanations for this discrepancy; one of them may be the influence of health care systems. It would be useful to see what is happening in other countries with different health care systems. PMID- 17712574 TI - Correlation of cervical endplate strength with CT measured subchondral bone density. AB - Cervical interbody device subsidence can result in screw breakage, plate dislodgement, and/or kyphosis. Preoperative bone density measurement may be helpful in predicting the complications associated with anterior cervical surgery. This is especially important when a motion preserving device is implanted given the detrimental effect of subsidence on the postoperative segmental motion following disc replacement. To evaluate the structural properties of the cervical endplate and examine the correlation with CT measured trabecular bone density. Eight fresh human cadaver cervical spines (C2-T1) were CT scanned and the average trabecular bone densities of the vertebral bodies (C3 C7) were measured. Each endplate surface was biomechanically tested for regional yield load and stiffness using an indentation test method. Overall average density of the cervical vertebral body trabecular bone was 270 +/- 74 mg/cm3. There was no significant difference between levels. The yield load and stiffness from the indentation test of the endplate averaged 139 +/- 99 N and 156 +/- 52 N/mm across all cervical levels, endplate surfaces, and regional locations. The posterior aspect of the endplate had significantly higher yield load and stiffness in comparison to the anterior aspect and the lateral aspect had significantly higher yield load in comparison to the midline aspect. There was a significant correlation between the average yield load and stiffness of the cervical endplate and the trabecular bone density on regression analysis. Although there are significant regional variations in the endplate structural properties, the average of the endplate yield loads and stiffnesses correlated with the trabecular bone density. Given the morbidity associated with subsidence of interbody devices, a reliable and predictive method of measuring endplate strength in the cervical spine is required. Bone density measures may be used preoperatively to assist in the prediction of the strength of the vertebral endplate. A threshold density measure has yet to be established where the probability of endplate fracture outweighs the benefit of anterior cervical procedure. PMID- 17712575 TI - Flexible non-fusion scoliosis correction systems reduce intervertebral rotation less than rigid implants and allow growth of the spine: a finite element analysis of different features of orthobiom. AB - The orthobiom non-fusion scoliosis correction system consists of two longitudinal rods, polyaxial pedicle screws, mobile and fixed connectors and a cross connector. The mobile connectors can move along and around the rod, thus allowing length adaptation during growth. The aim of this study was to determine the effects of different features of this novel implant on intervertebral rotations, to calculate the movement of the mobile connectors along the rods for different loading cases and to compare the results with those of a rigid implant construct. A finite element analysis was performed using six versions (M1-M6) of a three dimensional, nonlinear model of a spine ranging from T3 to L2. The models were loaded with pure moments of 7.5 N m in the three main anatomical planes. First, the validated intact model (M1) was studied. Then, the orthobiom implant system was inserted, bridging the segments between T4 and L1 (M2). The effect of pedicle screws only in every second vertebrae was investigated (M3). For comparison, three connection variations of screws and rods were investigated: (1) an implant with rigid screws and mobile connectors (M4), (2) an implant with non-locking polyaxial screws and fixed connectors (M5) and (3) a completely rigid implant construct (M6). For flexion, extension and lateral bending, intervertebral rotation was reduced at all implant levels due to the implants. A rigid implant construct (M6) and an implant with non-locking polyaxial screws and fixed connectors (M5) led to the strongest reduction of intervertebral rotation. The orthobiom non-fusion implant system (M2, M3) allowed much more intervertebral rotation than a rigid implant (M6). Differences in intervertebral rotations were small when polyaxial screws were placed at every second level only (M3) instead of at every level (M2). For axial rotation, intervertebral rotation was strongly reduced by a rigid implant construct (M6) and by an implant with rigid screws and mobile connectors (M4). For rotation, an implant with non-locking polyaxial screws (M2, M3, M5) led to nearly the same intervertebral rotations as in an intact spine without an implant (M1). The predicted maximum translation of the mobile connectors along the rod was 4.2 mm for extension, 3.1 mm for lateral bending, 1.6 mm for flexion and 0.8 mm for axial rotation. The movement of the connectors was highest for those closest to the ends of the rods. With rigid screws, the maximum translation was significantly reduced. This study, conducted under a load-controlled loading protocol, showed that intervertebral rotation was reduced much less by the non-fusion orthobiom system than by a rigid implant. The mobile connectors moved considerably along the rod when the spine was bent. It can be expected that the connectors also move along the rod as the adolescent grows, possibly leaving the discs intact until the patient is fully grown. PMID- 17712576 TI - Significant correlation between cerebrospinal fluid nitric oxide concentrations and neurologic prognosis in incomplete cervical cord injury. AB - In animal models of spinal cord injury (SCI), inducible NO (nitric oxide) synthase is expressed in the spinal cord immediately after sustaining SCI. Excessive NO production has cytotoxic effects and induces neuronal apoptosis, causing neural degeneration and neurodysfunction in the spinal cord. Little is known, however, about the relationship between NO(x) (NO metabolites: nitrite and nitrate) levels in the cerebrospinal fluid (CSF) and neurologic severity or recovery in clinical cases. The objective of the present study was to examine the correlation between CSF NO(x) levels and neurologic severity or recovery in SCI. Twenty-five patients with incomplete cervical cord injury (CCI) were examined. Eight cases were treated conservatively (non-operated group). Seventeen cases underwent surgical intervention (operated group). NO(x) levels in the CSF were measured using the Griess method. The severity of the neurologic impairment was assessed using Frankel's classification and the American Spinal Injury Association motor score (ASIA MS). The degree of neurologic recovery was assessed using Frankel's classification and the ASIA motor recovery percentage (MRP). There was no significant difference in the NO(x) levels between the CCI group (NO(x) levels: 5.9 +/- 0.7 microM) and the 36 control subjects (1 volunteer and 35 patients without neurologic disorders, NO(x) levels: 4.9 +/- 0.3 microM). There was no significant difference in NO(x) levels and MRP between the non operated group and the operated group. The NO(x) levels in total SCI group were significantly correlated with the ASIA MS and MRP. There was a significant correlation between CSF NO(x) levels and neurologic severity or recovery in incomplete CCI. PMID- 17712577 TI - Midterm outcome after unilateral approach for bilateral decompression of lumbar spinal stenosis: 5-year prospective study. AB - The aim of our study is to evaluate the results and effectiveness of bilateral decompression via a unilateral approach in the treatment of degenerative lumbar spinal stenosis. We have conducted a prospective study to compare the midterm outcome of unilateral laminotomy with unilateral laminectomy. One hundred patients with 269 levels of lumbar stenosis without instability were randomized to two treatment groups: unilateral laminectomy (Group 1), and laminotomy (Group 2). Clinical outcomes were assessed with the Oswestry Disability Index (ODI) and Short Form-36 Health Survey (SF-36). Spinal canal size was measured pre- and postoperatively. The spinal canal was increased to 4-6.1-fold (mean 5.1 +/- SD 0.8-fold) the preoperative size in Group 1, and 3.3-5.9-fold (mean 4.7 +/- SD 1.1 fold) the preoperative size in Group 2. The mean follow-up time was 5.4 years (range 4-7 years). The ODI scores decreased significantly in both early and late follow-up evaluations and the SF-36 scores demonstrated significant improvement in late follow-up results in our series. Analysis of clinical outcome showed no statistical differences between two groups. For degenerative lumbar spinal stenosis unilateral approaches allowed sufficient and safe decompression of the neural structures and adequate preservation of vertebral stability, resulted in a highly significant reduction of symptoms and disability, and improved health related quality of life. PMID- 17712578 TI - Endovascular repair of iliac artery injury complicating lumbar disc surgery. AB - Vascular injury as a complication of disc surgery was first reported in 1945 by Linton and White. It is a rare but potentially fatal complication. The high mortality rate (40-100%) is attributed to a combination of rapid blood loss and the failure to recognise the cause of the deteriorating patient. Early diagnosis and treatment is essential. Treatment has traditionally been by open vascular surgical repair, however with modern imaging and endovascular techniques, minimally invasive treatment should be considered first line in patients who are stable. We present the case of a 51-year-old woman who sustained common iliac artery injury during lumbar spinal surgery that was treated successfully using a covered stent. PMID- 17712580 TI - Ultrahigh-resolution study on Pyrococcus abyssi rubredoxin: II. Introduction of an O-H...Sgamma-Fe hydrogen bond increased the reduction potential by 65 mV. AB - The effect of D-H...S(gamma)-Fe hydrogen bonding on the reduction potential of rubredoxin was investigated by the introduction of an O-H...S(gamma)-Fe hydrogen bond on the surface of Pyrococcus abyssi rubredoxin. The formation of a weak hydrogen bond between Ser44-O(gamma) and Cys42-S(gamma) in mutant W4L/R5S/A44S increased the reduction potential by 56 mV. When side effects of the mutation were taken into account, the contribution of the additional cluster hydrogen bond to the reduction potential was estimated to be +65 mV. The structural analysis was based on ultrahigh-resolution structures of oxidized P. abyssi rubredoxin W4L/R5S and W4L/R5S/A44S refined to 0.69 and 0.86 A, respectively. PMID- 17712581 TI - Effect of alpha-domain substitution on the structure, property and function of human neuronal growth inhibitory factor. AB - Human metallothionein-3 (hMT3), also named human neuronal growth inhibitory factor (hGIF), is attractive due to its distinct neuronal growth inhibitory activity, which is not shown by other human MT isoforms. It has been reported that the neuronal growth inhibitory activity arises from the N-terminal beta domain rather than its C-terminal alpha-domain. However, previous bioassay results have shown that the single beta-domain is less effective at inhibiting the neuron growth than that in intact hMT3 on a molar basis, which suggests that the alpha-domain is indispensable to the neuronal growth inhibitory activity of hMT3. In order to confirm this assumption, we constructed two domain-hybrid mutants, the beta(MT3)-beta(MT3) mutant and the beta(MT3)-alpha(MT1) mutant, and investigated their structural and metal binding properties by UV-vis spectroscopy, CD spectroscopy, pH titration, DTNB reaction, EDTA reaction, etc. The results showed that stability of the Cd(3)S(9) cluster of the beta(MT3) beta(MT3) mutant decreased significantly while the Cd(3)S(9) cluster of the beta(MT3)-alpha(MT1) mutant had a similar stability and solvent accessibility to that of hMT3. Interestingly, the bioassay results showed that the neuronal growth inhibitory activity of the beta(MT3)-beta(MT3) mutant decreased significantly, while the beta(MT3)-alpha(MT1) mutant showed similar inhibitory activity to hMT3. Based on these results, we conclude that the alpha-domain is indispensable and plays an important role in modulating the stability of the metal cluster in the beta-domain by domain-domain interactions, thus influencing the bioactivity of hMT3. PMID- 17712582 TI - Genomic analysis reveals widespread occurrence of new classes of copper nitrite reductases. AB - Recently, the structure of a Cu-containing nitrite reductase (NiR) from Hyphomicrobium denitrificans (HdNiR) has been reported, establishing the existence of a new family of Cu-NiR where an additional type 1 Cu (T1Cu) containing cupredoxin domain is located at the N-terminus (Nojiri et al. in Proc. Natl. Acad. Sci. USA 104:4315-4320, 2007). HdNiR retains the well-characterised coupled T1Cu-type 2 Cu (T2Cu) core, where the T2Cu catalytic site is also built utilising ligands from neighbouring monomers. We have undertaken a genome analysis and found the wide occurrence of these NiRs, with members clustering in two groups, one showing an amino acid sequence similarity of around 80% with HdNiR, and a second group, including the NiR from the extremophile Acidothermus cellulolyticus, clustering around 50% similarity to HdNiR. This is reminiscent of the difference observed between the blue (Alcaligenes xylosoxidans) and green (Achromobacter cycloclastes and Alcaligenes faecalis) NiRs which have been extensively studied and may indicate that these also form two distinct subclasses of the new family. Genome analysis also showed the presence of Cu-NiRs with a C terminal extension of 160-190 residues containing a class I cytochrome c domain with a characteristic beta-sheet extension. Currently no structural information exists for any member of this family. Genome analysis suggests the widespread occurrence of these novel NiRs with representatives in the alpha, beta and gamma subclasses of the Proteobacteria and in two species of the fungus Aspergillus. We selected the enzyme from Ralstonia pickettii for comparative modelling and produced a plausible structure highlighting an electron transfer mode in which the cytochrome c haem at the C-terminus can come within 16-A reach of the T1Cu centre of the T1Cu-T2Cu core. PMID- 17712583 TI - Rifampin as adjuvant treatment of Gram-positive bacterial infections: a systematic review of comparative clinical trials. AB - We reviewed the bibliographic evidence from comparative trials regarding the role of rifampin as adjuvant treatment in the treatment of Gram-positive infections [PubMed (1/1950-7/2006)]. Only studies reporting comparative outcome data in patients treated with an antibiotic regimen with the addition or not of rifampin were included. Eight comparative studies were identified [all were randomized controlled trials (RCTs)], five reporting on infections caused by staphylococci (S. aureus in 97% of patients) and three by streptococci. There was no statistically significant difference in mortality between the treatment arms (with and without rifampin) in any of the included studies. Clinical cure was achieved more commonly (p < 0.05) in the rifampin treatment arm in 3/8 studies; in staphylococcal infections of orthopedic stable implants and in beta-hemolytic streptococcal pharyngitis in children (one RCT each), and in one RCT that reported on patients with various staphylococcal infections. However, no statistically significant difference in cure of the infection between the two groups was found after pooling data from two RCTs (121 patients) that reported on patients with various staphylococcal infections (odds ratio = 0.57; 95% confidence interval 0.27-1.17). No differences were noted between the two groups regarding relapse of infection or adverse events. There is only limited evidence from comparative trials regarding the role of rifampin as adjuvant therapeutic agent for infections caused by Gram-positive bacteria, not allowing for definitive conclusions on this important management question. More controlled trials are necessary for better evaluation of this practice. PMID- 17712584 TI - Biobleaching of banana fibre pulp using Bacillus subtilis C O1 xylanase produced from wheat bran under solid-state cultivation. AB - A cellulase-free xylanase produced by Bacillus subtilis C 01 from wheat bran under solid-state cultivation was tested for its efficacy in biobleaching of raw banana fibre and banana pulp obtained through a mechanical pulping process. Banana pulp samples treated with crude xylanase (450 nkat g(-1) pulp) resulted in a 19.6% increase in the brightness as compared to untreated pulp. The presence of chromophores, hydrophobic compounds and an increased reducing sugar (10.79 mg g( 1) pulp) quantity in the bleached solution after enzymatic treatment indicated the removal of materials that were absorbed at 237 nm from the banana pulp. PMID- 17712585 TI - No influence of increased intake of orange and blackcurrant juices and dietary amounts of vitamin E on paraoxonase-1 activity in patients with peripheral arterial disease. AB - BACKGROUND: Paraoxonase-1 (PON1) is an antioxidative enzyme associated with HDL and its serum activity is associated with risk of cardiovascular disease. The interindividual variation in PON1 activity is partly determined by genetic factors, such as polymorphisms in the PON1 gene, but also by dietary factors like the antioxidants. AIM OF THE STUDY: We examined the effect of antioxidant-rich orange and blackcurrant juices and vitamin E supplement on PON1 activity in patients with peripheral arterial disease. Furthermore, we studied whether genetic polymorphisms in the PON1 gene predicted the change in PON1 activity. METHODS: The study was designed as a cross-over trial with 48 participants who received two of the four possible treatments: (1) 250 ml orange juice and 250 ml blackcurrant juice; (2) 15 mg vitamin E; (3) 250 ml orange juice and 250 ml blackcurrant juice and 15 mg vitamin E; or (4) control/placebo (energy-equivalent sugar-containing beverage). The treatments were given for 28 days, separated by a 4-week wash-out period. RESULTS: The PON1 activity was not affected by juice or vitamin E supplement neither was there evidence of synergetic effects. However, a statistically significant interaction was observed between treatment and PON1 genotype, such that PON1 activity increased after juice alone in patients carrying the PON1 L55-allele. Results need to be interpreted with care since the study population was relatively small. CONCLUSION: Consumption of orange and blackcurrant juice and vitamin E supplement does not affect the activity of PON1 in patients with peripheral arterial disease. However, a gene-diet interaction may be present. PMID- 17712586 TI - Modulation of folate uptake in cultured human colon adenocarcinoma Caco-2 cells by dietary compounds. AB - Folate is a water-soluble B vitamin with a crucial role in the synthesis and methylation of DNA and in the metabolism of several amino acids. In the present study we investigated whether beverages like wine, beer and tea, or some of their specific constituents, affect the intestinal uptake of (3)H-folic acid or (3)H methotrexate (an antifolate). All tested beverages significantly inhibited the uptake of (3)H-folic acid by Caco-2 cells. Most of these beverages, with the exception of wines (not tested), also inhibited (3)H-methotrexate uptake in these cells. Additionally, ethanol, when tested separately, inhibited the uptake of both compounds. Some of the tested phenolic compounds, namely myricetin, epigallocatechin gallate (EGCG) and isoxanthohumol, markedly inhibited (3)H-folic acid uptake. Myricetin and EGCG also had a concentration-dependent inhibitory effect upon the uptake of (3)H-methotrexate by Caco-2 cells. Resveratrol, quercetin and kaempferol were able to inhibit the transport of both compounds, but only in the concentration of 100 microM. In conclusion, dietary constituents may impact on intestinal folate uptake, as here shown for phenolic compounds. PMID- 17712587 TI - Comparative effects of fatty acids on endothelial inflammatory gene expression. AB - BACKGROUND: Endothelial dysfunction may be related to adverse effects of some dietary fatty acids (FAs). Although in vitro studies have failed to show consistent findings, this may reflect the diverse experimental protocols employed and the limited range of FAs and end points studied. AIMS: To investigate the effect of dietary FA type (saturated, monounsaturated, n-6 and n-3 polyunsaturated fatty acids), concentration, incubation time and cell stimulation state, on a broad spectrum of endothelial inflammatory gene expression. METHODS: Using human umbilical vein endothelial cells, with and without stimulation (+/-10 ng/ml TNFalpha), the effects of arachidonic (AA), docosahexaenoic (DHA), eicosapentaenoic (EPA), linoleic (LA), oleic (OA) and palmitic acids (PA) (10, 25 and 100 microM), on the expression of genes encoding a number of inflammatory proteins and transcription factors were assessed by quantitative real time RT PCR. RESULTS: Individual FAs differentially affect endothelial inflammatory gene expression in a gene-specific manner. EPA, LA and OA significantly up-regulated MCP-1 gene expression compared to AA (p = 0.001, 0.013, 0.008, respectively) and DHA (p < 0.0005, = 0.004, 0.002, respectively). Furthermore, cell stimulation state and FA incubation time significantly influenced reported FA effects on gene expression. CONCLUSION: The comparative effects of saturated, monounsaturated, n 6 and n-3 polyunsaturated FAs on endothelial gene expression depend on the specific FA investigated, its length of incubation, cell stimulation state and the gene investigated. These findings may explain existing disparity in the literature. PMID- 17712588 TI - Low incidence of restrictive valvulopathy in patients with Parkinson's disease on moderate dose of pergolide. AB - Restrictive valvular heart disease (VHD) has recently been reported in Parkinson's disease (PD) patients treated with ergot dopamine agonists. The aim of the present study was to detect valvular changes in our patients and to investigate their relationship to long-term use of pergolide. We examined 90 patients (mean age 60.8 +/- SD 9.5 years) with PD, average duration 10.0 +/- 5.1 years. Mean pergolide dose was 2.93 +/- 0.75 (range 0.75 to 5) mg per day. 36 subjects (mean age 55.0 +/- 12.8 years) served as controls. All subjects underwent transthoracic echo-Doppler examination. Valve morphology was rated as normal, fibrotic, restrictive, or degenerative. In addition, the mitral tenting area (TA) and tenting distance (TD) were assessed. In 40 out of 90 (45%) PD patients and in 13 out of 36 (36%) controls, mild mitral regurgitation was observed. In 1 PD patient, a moderate mitral regurgitation was recorded. However, no case of restrictive VHD was found. Neither the TA (1.44 +/- 0.24 cm(2) vs 1.33 +/- 0.44 cm(2)) nor the TD (0.73 +/- 0.10 cm vs. 0.72 +/- 0.30 cm) differed from controls. There were no correlations between the current or cumulative dose of pergolide and TA or TD. Discrete fibrotic changes on valves were found in 10 out of 90 (11%) patients. Degenerative changes of valves were found in 11 (12%) patients and in 7 (19 %) controls. Thus in contrast to earlier findings of restrictive VHD in up to one-third of PD patients on pergolide, we did not find any significant heart disease. We only observed mild to moderate mitral regurgitation and clinically insignificant valvular fibrosis. A possible reason for such a discrepancy is that the daily doses of pergolide in our patients were inferior to those reported previously. In conclusion, the prevalence of restrictive VHD has been lower than expected in our patients with PD, probably in relation to moderate daily doses of pergolide. PMID- 17712589 TI - Retrospective analysis of dual-phase MDCT and follow-up EUS/EUS-FNA in the diagnosis of pancreatic cancer. AB - BACKGROUND: The optimal approach for detecting small pancreatic tumors is uncertain. We compared multidetector CT (MDCT) with follow-up endoscopic ultrasonography (EUS) without or with fine-needle aspiration (EUS-FNA) for diagnosing pancreatic cancer. METHODS: Patients with suspicion of pancreatic cancer who underwent dual-phase MDCT and follow-up EUS were retrospectively reviewed. This consisted of scoring MDCT scans independently by three radiologists on a 1-5 scale of certainty, determining whether a stent was present, scoring EUS reports regarding presence of a mass and analyzing EUS-FNA results. RESULTS: A total of 117 patients underwent MDCT and EUS. ROC values for MDCT were 0.85, 0.87, and 0.91. There was no significant difference in the accuracy of EUS and MDCT. Follow-up EUS (99%) was significantly more sensitive than MDCT (89% and 93%), as interpreted by two radiologists. Follow-up EUS was statistically significantly more sensitive than MDCT (96% vs. 70%) for one radiologist for tumors < 2 cm. Specificity of EUS was 50%, and sensitivity of EUS FNA was 82%. Negative predictive value of EUS-FNA was significantly less in patients with (21%) than without (70%) biliary stents. CONCLUSIONS: Follow-up EUS improves lesion detection over MDCT alone. Close follow-up/repeat biopsy should be considered if FNA is negative, but EUS is positive. PMID- 17712590 TI - Differentiation of ampullary tumor from benign papillary stricture by thin section multidetector CT. AB - The objective of this paper was to determine the criteria for differentiation of ampullary tumor from benign papillary stricture using thin-section multidetector CT images. Multidetector CT images with 2.5 mm slice-thickness in 57 consecutive patients (24 with ampulla of Vater tumor and 33 with benign papillary stricture) with extrahepatic duct dilatation due to ampullary obstruction were reviewed retrospectively. The papilla/papillary mass was evaluated regarding size, homogeneity of enhancement, attenuation value, and the diameters of extrahepatic duct and main pancreatic duct were measured. The measurability, enhancement pattern, the attenuation value of papilla/papillary mass on portal venous phase, and the maximum diameters of extrahepatic duct and main pancreatic duct were different between two groups. Multiple logistic regression analysis showed the papilla/papillary mass size was the only independently differentiating variable of ampullary tumor from benign stricture (P = 0.016) with an odds ratio of 2.424 (95% confidence interval, 1.179-4.903). The most appropriate cutoff value of papilla/papillary mass size was 12.3 mm with 91.7% sensitivity, 92.3% specificity, and 92.0% accuracy. Ampullary tumor and benign papillary stricture could be effectively differentiated by thin-section multidetector CT based on papilla/papillary mass size. PMID- 17712591 TI - Guidelines for deep venous thrombosis prophylaxis during laparoscopic surgery. PMID- 17712592 TI - Laparoscopic approaches to resection of suspected gastric gastrointestinal stromal tumors based on tumor location. AB - BACKGROUND: Surgical resection of gastric gastrointestinal stromal tumor (GIST) should be optimized to achieve a negative pathologic surgical margin while limiting the extent of stomach volume loss. Careful identification of exact gastric tumor location using preoperative computed tomography (CT) scans and gastroscopy should allow for selection of a specific operative approach. METHODS: This retrospective case series involved 12 patients (7 men and 5 women; mean age, 60.5 years) with suspected gastric GIST undergoing tumor resection at Fletcher Allen Health Care, a university medical center, from January 2005 to August 2006. The main outcome measures were pathologic resection margins, operative time, estimated blood loss (EBL), morbidity, and duration of hospital stay. RESULTS: The 12 patients were separated into three groups on the basis of tumor location as follows: type 1 (fundus/greater curvature, n = 5), type 2 (prepyloric/antrum, n = 3), and type 3 (lesser curvature/perigastroesophageal junction, n = 4). Preoperative imaging (CT scan and/or endoscopy) used to identify tumor location accurately predicted the operative approach before surgery for 11 of the12 patients. The surgical approach was selected solely by tumor location as follows: type 1 (laparoscopic partial gastrectomy [LPG]), type 2 (laparoscopic distal gastrectomy [LDG]), and type 3 (laparoscopic transgastric resection [LTG]). Nine patients had a final pathologic diagnosis of GIST. The average tumor size was 4.6 cm, but this did not influence procedure selection. Histologic margins were microscopically negative in all patients. The LPG and LTG approaches had similar outcomes in terms of estimated blood loss (EBL; 80 vs 100 ml) and hospital stay (3.4 vs 3.3 days; p = 0.0198), but LTG had longer operative times (236 vs 180 min). The LDG procedure had longer operative times, greater EBL, and a longer hospital stay. The operative morbidity was 17%, and there was no operative mortality. CONCLUSION: The selection of an operative technique for resection of gastric submucosal tumors can be based on preoperative identification of tumor location, for better definition of both the extent of gastric resection and the technical complexity of the laparoscopic procedure. PMID- 17712593 TI - New laparoscopic double-stapling technique. AB - BACKGROUND: Laparoscopic surgery for colon cancer has been shown by several randomized, controlled trials to be an acceptable alternative to open surgery; however, laparoscopic rectal surgery has not been evaluated in a randomized trial. One of the most serious problems associated with laparoscopic rectal surgery are bowel clamping, irrigation, and transection of the rectum, and laparoscopic rectal surgery has not been as reliable as open rectal surgery. MATERIALS AND METHODS: We present our new technique, the laparoscopic double stapling technique, which eliminates these problems. This technique uses curved Doyen forceps introduced through the wound just above pubis symphysis for clamping the rectal wall at the anal side of the tumor. An endolinear stapler (length 60 mm) is inserted through the same wound, applied at the rectal wall parallel and caudal to the Doyen forceps, and transects the rectum under pneumoperitoneum. We used this technique for eight cases of rectal surgery. RESULTS AND DISCUSSION: The laparoscopic double-stapling technique provided secure bowel clamping and rectal irrigation. The number of cartridges used in laparoscopic double-stapling technique cases was not more than 2, with an average of 1.6 per patient. None of the laparoscopic double-stapling technique cases experienced major complications. CONCLUSION: We consider that many cases of rectal cancer that are suitable for laparoscopic low anterior resection can undergo laparoscopic surgery by using this technique, which will improve the quality of rectal surgery. PMID- 17712594 TI - Subcutaneous fissurotomy: a novel procedure for chronic fissure-in-ano. a review of 109 cases. AB - PURPOSE: The constant presence of a narrow subcutaneous tract extending caudad to chronic fissures-in-ano is reported. The efficacy of surgically unroofing this tract (subcutaneous fissurotomy) without sphincterotomy was evaluated. METHODS: By using a narrow-gauge, hooked probe, a constant, midline subcutaneous tract was identified extending from the caudad aspect of chronic anal fissures. These tracts are present within the sentinel tag, when present, and extend up to 1 cm caudad to the fissure in the subcutaneous plane. A proximal connection with the dentate line in the submucous plane also was identified. Surgically unroofing the tract (subcutaneous fissurotomy) resulted in significant widening of the distal anal canal, rendering internal sphincterotomy unnecessary. A 32-month prospective evaluation of this new technique was performed. Inclusion criteria included patients with chronic anal fissures that had failed conservative therapy, including topical agents. In each case, the tract was identified and surgically laid open along its entire length. No internal sphincterotomy was performed in any patient. Postoperatively, patients were instructed to apply topical 10 percent metronidazole t.i.d. The need for repeat surgery and/or subsequent internal sphincterotomy was recorded. RESULTS: A total of 109 patients were enrolled during the study period. Median follow-up was 12 months. During the study period, two patients (1.8 percent) required repeat surgery for persistent symptoms at 3 and 12 months postoperatively. No change in continence was reported in any patient. CONCLUSIONS: Laying open the subcutaneous tract has a very high success rate and a low incidence of repeat surgery. This finding introduces a new debate relating to the etiology of fissure-in-ano and makes routine internal sphincterotomy unnecessary. PMID- 17712595 TI - Muscle fibers from senescent mice retain excitation-contraction coupling properties in culture. AB - In the present study, we test the hypothesis that mouse skeletal muscle in culture retains the fundamental properties of excitation-sarcoplasmic reticulum Ca(2+) release coupling reported for young-adult (3-4 mo) and senescent (22-23) mice. Dissociated flexor digitorum brevis (FDB) muscles from young-adult and senescent mice were cultured for 7 d in a serum-free medium. During this period, the overall morphology of cultured fibers resembled that exhibited by acutely dissociated cells. In addition, survival analysis revealed that more than 70% of the fibers from both young and old mice remained suitable for electrophysiological studies during this same culture period. Charge movement and intracellular Ca(2+) recordings in FDB fibers, voltage clamped in the whole cell configuration of the patch-clamp technique, reproduced the maximal values, and voltage dependence similarly displayed by acutely dissociated cells for both parameters in young-adult and senescent mice. The analysis of the dihydropyridine receptor by immunoblots confirmed, in the culture system, the age-dependent decrease in the expression of this protein. In conclusion, FDB fibers from young adult and old mice retain the excitation-contraction coupling phenotype during the course of a week in serum-free medium culture. PMID- 17712597 TI - Guanine tetrad and palindromic sequence play critical roles in the RNA dimerization of bovine foamy virus. AB - Retroviruses are unique in having a diploid genome. However, the RNA sequences and structures that link the two RNA molecules are different. To identify the dimer linkage site of bovine foamy virus (BFV), complementary DNAs were used to interfere with RNA dimerization of BFV. We found that two sites, designated SI and SII, within a 53-base RNA fragment, were essential for BFV dimerization in vitro. SI consists of a potential guanine tetrad (GGGGC), which overlaps the primer binding site, while SII contains 15 nucleotides including a palindromic sequence, UCCCUAGGGA. Masking either of the sites completely abolished RNA dimer formation. Furthermore, a deletion of SII was introduced into a BFV infectious DNA clone; we found that deletion of SII significantly increased expression of BFV transactivator Borf-1. Interestingly, we also found that this deletion abolished viral infectivity. These results suggest that dimerization might play a unique role in the BFV life cycle. PMID- 17712596 TI - Surgical management of gallbladder carcinoma: a review. AB - Gallbladder cancer is a relatively unusual, but often lethal malignancy. Surgical management has historically been palliative only; however, with the advancement of techniques in hepatobiliary surgery, varying extents of surgical intervention have been advocated for cure. This article reviews the current approach to the surgical management of gallbladder cancer and discusses the rationale for an aggressive approach to this disease. PMID- 17712598 TI - Analysis of the entire genomes of fifteen torque teno midi virus variants classifiable into a third group of genus Anellovirus. AB - Recently, we identified a novel human virus with a circular DNA genome of 3.2 kb, tentatively designated as torque teno midi virus (TTMDV), with a genomic organization resembling those of torque teno virus (TTV) of 3.8-3.9 kb and torque teno mini virus (TTMV) of 2.8-2.9 kb. To investigate the extent of genomic variability of TTMDV genomes, the full-length sequence was determined for 15 TTMDV isolates obtained from viremic individuals in Japan. The 15 TTMDV isolates comprised 3175-3230 bases and shared 67.0-90.3% identities with each other, and were only 68.4-73.0% identical to the 3 reported TTMDV isolates over the entire genome. TTMDV possessed a genomic organization with four open reading frames (ORF1-ORF4) with characteristic sequence motifs and stem and loop structures with high GC content, similar to TTV and TTMV. The total of 18 TTMDV genomes differed by up to 60.7% from each other in the amino acid sequence of ORF1 (658-677 amino acids), but segregated phylogenetically into the same cluster, which was distantly related to the TTVs and TTMVs. These results indicate that TTMDV with a circular DNA genome of 3.2 kb, has an extremely high degree of genomic variability, and is classifiable into a third group in the genus Anellovirus. PMID- 17712599 TI - Analysis of the activation mechanism of the guinea-pig Histamine H1-receptor. AB - The Histamine H(1)-receptor (H1R), belonging to the amine receptor-class of family A of the G-protein coupled receptors (GPCRs) gets activated by agonists. The consequence is a conformational change of the receptor, which may involve the binding-pocket. So, for a good prediction of the binding-mode of an agonist, it is necessary to have knowledge about these conformational changes. Meanwhile some experimental data about the structural changes of GPCRs during activation exist. Based on homology modeling of the guinea-pig H1R (gpH1R), using the crystal structure of bovine rhodopsin as template, we performed several MD simulations with distance restraints in order to get an inactive and an active structure of the gpH1R. The calculations led to a Phe6.44/Trp6.48/Phe6.52-switch and linearization of the proline kinked transmembrane helix VI during receptor activation. Our calculations showed that the Trp6.48/Phe6.52-switch induces a conformational change in Phe6.44, which slides between transmembrane helices III and VI. Additionally we observed a hydrogen bond interaction of Ser3.39 with Asn7.45 in the inactive gpH1R, but because of a counterclockwise rotation of transmembrane helix III Ser3.39 establishes a water-mediated hydrogen bond to Asp2.50 in the active gpH1R. Additionally we simulated a possible mechanism for receptor activation with a modified LigPath-algorithm. PMID- 17712602 TI - A Cre/loxP-mediated self-activating gene excision system to produce marker gene free transgenic soybean plants. AB - Marker-gene-free transgenic soybean plants were produced by isolating a developmentally regulated embryo-specific gene promoter, app1, from Arabidopsis and developing a self-activating gene excision system using the P1 bacteriophage Cre/loxP recombination system. To accomplish this, the Cre recombinase gene was placed under control of the app1 promoter and, together with a selectable marker gene (hygromycin phosphotransferase), were cloned between two loxP recombination sites. This entire sequence was then placed between a constitutive promoter and a coding region for either beta-glucuronidase (Gus) or glyphosate acetyltransferase (Gat). Gene excision would remove the entire sequence between the two loxP sites and bring the coding region to the constitutive promoter for expression. Using this system marker gene excision occurred in over 30% of the stable transgenic events as indicated by the activation of the gus reporter gene or the gat gene in separate experiments. Transgenic plants with 1 or 2 copies of a functional excision-activated gat transgene and without any marker gene were obtained in T0 or T1 generation. This demonstrates the feasibility of using developmentally controlled promoters to mediate marker excision in soybean. PMID- 17712601 TI - Characterization of Arabidopsis thaliana genes encoding functional homologues of the yeast metal chaperone Cox19p, involved in cytochrome c oxidase biogenesis. AB - The Arabidopsis thaliana genome contains two nearly identical genes which encode proteins showing similarity with the yeast metal chaperone Cox19p, involved in cytochrome c oxidase biogenesis. One of these genes (AtCOX19-1) produces two transcript forms that arise from an alternative splicing event and encode proteins with different N-terminal portions. Both AtCOX19 isoforms are imported into mitochondria in vitro and are found attached to the inner membrane facing the intermembrane space. The smaller AtCOX19-1 isoform, but not the larger one, is able to restore growth on non-fermentable carbon sources when expressed in a yeast cox19 null mutant. AtCOX19 transcript levels increase by treatment with copper or compounds that produce reactive oxygen species. Young roots and anthers are highly stained in AtCOX19-1::GUS plants. Expression in leaves is only observed when cuts are produced, suggesting an induction by wounding. Infection of plants with the pathogenic bacterium Pseudomonas syringae pv. tomato also induces AtCOX19 gene expression. The results suggest that AtCOX19 genes encode functional homologues of the yeast metal chaperone. Induction by biotic and abiotic stress factors may indicate a relevant role of this protein in the biogenesis of cytochrome c oxidase to replace damaged forms of the enzyme or a more general role in the response of plants to stress. PMID- 17712600 TI - Arabidopsis CBF5 interacts with the H/ACA snoRNP assembly factor NAF1. AB - The conserved protein CBF5, initially regarded as a centromere binding protein in yeast and higher plants, was later found within nucleoli and in Cajal bodies of yeast and metazoa. There, it is assumed to be involved in posttranscriptional pseudouridinylation of various RNA species that might be important for RNA processing. We found EYFP-labeled CBF5 of A. thaliana to be located within nucleoli and Cajal bodies, but neither at centromeres nor somewhere else on chromosomes. Arabidopsis mutants carrying a homozygous T-DNA insertion at the CBF5 locus were lethal. Yeast two-hybrid and mRNA expression analyses demonstrated that AtCBF5 is co-expressed and interacts with a previously uncharacterized protein containing a conserved NAF1 domain, presumably involved in H/ACA box snoRNP biogenesis. The homologous yeast protein has been shown to contribute to RNA pseudouridinylation. Thus, AtCBF5 might have an essential function in RNA processing rather than being a kinetochore protein. PMID- 17712603 TI - The DNA-binding domain as a functional indicator: the case of the AraC/XylS family of transcription factors. AB - The AraC/XylS family of transcription factors, which include proteins that are involved in the regulation of diverse biological processes, has been of considerable interest recently and has been constantly expanding by means of in silico predictions and experimental analysis. In this work, using a HMM based on the DNA binding domain of 58 experimentally characterized proteins from the AraC/XylS (A/X), 1974 A/X proteins were found in 149 out of 212 bacterial genomes. This domain was used as a template to generate a phylogenetic tree and as a tool to predict the putative regulatory role of the new members of this family based on their proximity to a particular functional cluster in the tree. Based on this approach we assigned a functional regulatory role for 75% of the TFs dataset. Of these, 33.7% regulate genes involved in carbon-source catabolism, 9.6% global metabolism, 8.3% nitrogen metabolism, 2.9% adaptation responses, 8.9% stress responses, and 11.7% virulence. The abundance of TFs involved in the regulation of metabolic processes indicates that bacteria have optimized their regulatory systems to control energy uptake. In contrast, the lower percentage of TFs required for stress, adaptation and virulence regulation reflects the specialization acquired by each subset of TFs associated with those processes. This approach would be useful in assigning regulatory roles to uncharacterized members of other transcriptional factor families and it might facilitate their experimental analysis. PMID- 17712604 TI - Seasonal variation of microbial populations and biomass in Tatachia grassland soils of Taiwan. AB - To investigate the seasonal variations of microbial ecology in grassland of Tatachia forest, soil properties, microbial populations, microbial biomass, and 16S rDNA clone library analysis were determined. The soil had temperatures 6.6 18.4 degrees C, pH 3.6-5.1, total organic carbon 1.11-10.68%, total nitrogen 0.18 0.78%, and C/N ratios 3.46-20.55. Each gram of dry soil contained bacteria, actinomycetes, fungi, cellulolytic, phosphate-solubilizing microbes, and nitrogen fixing microbes 4.54 x 10(4) to 3.79 x 10(7), 3.43 x 10(2) to 2.17 x 10(5), 5.74 x 10(3) to 3.76 x 10(6), 1.97 x 10(3) to 1.34 x 10(6), 8.49 x 10(2) to 5.59 x 10(5), and 3.86 x 10(2) to 3.75 x 10(5) CFU, respectively. Each gram of soil contained 117-2,482 microg of microbial biomass carbon, 23-216 microg of microbial biomass nitrogen and 9-29 microg of DNA. The microbial populations, microbial biomass, and DNA decreased stepwise with the depth of soil, and they had low values in winter seasons. The microbial populations, microbial biomass carbon, microbial biomass nitrogen, and DNA at the BW2 horizon were 8.42-17.84, 19.26-64.40, 16.84-61.11, and 31.03-46.26% of those at the O horizon, respectively. When analyzing 16S rDNA library, members of Proteobacteria, Acidobacteria, Actinobacteria, Bacteroidetes, Chloroflexi, Firmicutes, candidate division TMI, candidate division TM7, Gammatimonadetes, and Verrucomicrobia were identified. Members of Proteobacteria (44.4%) and Acidobacteria (33.3%) dominated the clone libraries. Within the phylum Proteobacteria, alpha-, beta-, and gamma Proteobacteria were most numerous, followed by delta-Proteobacteria. PMID- 17712605 TI - Spider mite (Acari: Tetranychidae) mitochondrial COI phylogeny reviewed: host plant relationships, phylogeography, reproductive parasites and barcoding. AB - The past 15 years have witnessed a number of molecular studies that aimed to resolve issues of species delineation and phylogeny of mites in the family Tetranychidae. The central part of the mitochondrial COI region has frequently been used for investigating intra- and interspecific variation. All these studies combined yield an extensive database of sequence information of the family Tetranychidae. We assembled this information in a single alignment and performed an overall phylogenetic analysis. The resulting phylogeny shows that important patterns have been overlooked in previous studies, whereas others disappear. It also reveals that mistakes were made in submitting the data to GenBank, which further disturbed interpretation of the data. Our total analysis clearly shows three clades that most likely correspond to the species T. urticae, T. kanzawai and T. truncatus. Intraspecific variation is very high, possibly due to selective sweeps caused by reproductive parasites. We found no evidence for host plant associations and phylogeographic patterns in T. urticae are absent. Finally we evaluate the application of DNA barcoding. PMID- 17712606 TI - Intrauterine growth retardation and placental vacuolization as presenting features in a case of GM1 gangliosidosis. AB - Diagnosis of GM1 gangliosidosis (OMIM 230500) is usually based on the presence of physical signs of storage such as coarse facial features, corneal clouding, cherry red macula, hepatosplenomegaly and skeletal dysostosis. More rarely it can present as nonimmune hydrops. We describe a male patient with GM1 gangliosidosis born to healthy first-cousin parents of Indian Asian descent. The disease was recognized on the basis of diffuse vacuolization of cyto- and syncytiotrophoblasts, stromal cells and amniocytes on histological analysis of the placenta. The placental examination was prompted by the prenatal detection of intrauterine growth retardation (IUGR) and oligohydramnios at 32 weeks of gestation. The diagnosis of GM1 gangliosidosis was supported by both biochemical and molecular data. The beta-galactosidase enzymatic activity on leukocytes was severely reduced, while the neuraminidase activity on fibroblasts was normal, thereby excluding galactosialidosis. The molecular analysis of the beta galactosidase gene (GLB1) revealed a previously unreported splicing mutation (IVS1+2 insT) in homozygous state. Our case further illustrates the value of histological examination of the placenta in the diagnosis of lysosomal storage disorders and shows that either hydrops or IUGR can be presenting features of GM1 gangliosidosis in the neonatal period. PMID- 17712608 TI - Is ethical expertise possible? AB - Services of ethics committees are nowadays commonly used in such various spheres of life as health care, public administration, business, law, engineering, and scientific research. It is taken that as their members have expertise in ethics, these committees can have valuable contributions to make in solving practical moral problems. It has, however, also been maintained that it is simply absurd to claim that one has some special knowledge and skills in moral matters; in connection with moral questions there is no expertise to be had. In this paper, I assess this criticism of the use of ethics committees and ethics consultants. I argue that there is no sufficient reason to reject the possibility of ethical expertise. PMID- 17712607 TI - Active bovine selenophosphate synthetase 2, not having selenocysteine. AB - During the course of studying selenocysteine (Sec) synthesis mechanisms in mammals, we prepared selenophosphate synthetase (SPS) from bovine liver by 4-step chromatography. In the last step of chromatography of hydroxyapatite, we found a protein band of molecular mass 33 kDa on SDS-PAGE, consistent with the pattern of SPS activity that was indirectly manifested by [(75)Se]Sec production activity; however, we could not detect significant Se content in this active fraction. We also found a clear band of 33 kDa by Western blotting with antibody against a common peptide (387-401) in SPS2. We detected selenophosphate as the product of this active enzyme in the reaction mixture, composed of ATP, [(75)Se]H(2)Se and SPS. Chemically synthesized selenophosphate plays a role in Sec synthesis, not the addition of this enzyme. These results support that the product of SPS2 is selenophosphate itself. During this investigation, the probable sequence of bovine SPS2 not having Sec was reported in the blast information and the molecular mass was near with the protein in this report. Thus, bovine active SPS2 of molecular mass 33 kDa does not contain Sec. PMID- 17712610 TI - Quality of life among Turkish immigrants in Sweden. AB - OBJECTIVES: To assess quality of life among Turkish immigrants in Sweden by using the WHOQOL-100 scale and to evaluate the domains' contribution to explain the variance in the quality of life of the immigrants. Our hypothesis was QOL among Turkish immigrants in Sweden are better than Turkish people who are living in their home country. MATERIAL AND METHODS: This study was performed in the districts of Stockholm where Turkish immigrants have mostly settled. With the help and guidance of the Turkish Association, a sample of 520 participants was selected. We collected the demographic data by printed questionnaires, and to measure the quality of life, we used the WHOQOL-100 scale Turkish version. For analysis, we used the SPSS V.13.0 and R package programs, variance analyses, and Bayesian regression. RESULTS: The quality of life among the sample of Turkish immigrants was found to be moderate, but higher than the sample of the Turkish population. The quality of life of male immigrants was found to be higher than for females. Swedish-born Turks had better quality of life perceptions. CONCLUSION: Turkish immigrants' quality of life perceptions were better than those of the Turkish sample. The best scores were received from the third generation. The first generation and female immigrants need attention in order to receive higher quality of life perceptions. PMID- 17712609 TI - Immanuel Kant, his philosophy and medicine. AB - The article examines the statements made by Immanuel Kant with reference to medicine as well as the impact of his philosophy on medicine. It describes the initial reaction of Kantian philosophy on medicine in the late 18th and early 19th century and its influence in the late 20th century. PMID- 17712611 TI - Perinatal disparities for black mothers and their newborns. AB - OBJECTIVES: In the United States, significant ethnic and racial health and healthcare disparities exist among our most vulnerable populations, new mothers and newborns. We sought to determine disparities in socioeconomic status, perinatal health, and perinatal healthcare for black mothers and their newborns cared for in well-baby nurseries compared with white mother/baby pairs in Pennsylvania. METHODS: A retrospective analysis of a merged data set containing birth and clinical discharge records was conducted. Perinatal data from 44,105 black mothers and their singleton newborns, > or = 35 weeks gestational age cared for in Pennsylvania well-baby nurseries from 1998-2002 were compared with 88,210 white mother/baby pairs. RESULTS: Black mothers were younger and were much more likely to receive Medicaid or be uninsured compared with white mothers. They were less likely to be college-educated, married, or have prenatal care beginning in the first trimester. Infants born to black mothers were less likely to be delivered via Cesarean section, but were more likely to be born between 35 and 38 weeks gestation and be of low birth weight. CONCLUSIONS: Numerous significant disparities exist for black mothers and their newborns cared for in well-baby nurseries in Pennsylvania. Since most newborns are cared for in this setting as opposed to intensive care environments, recognition of the differences that exist for this group when compared to well newborns of white mothers can help to improve healthcare and its delivery to this population. Federal and local initiatives must continue efforts to eliminate racial disparities. PMID- 17712612 TI - Interpregnancy primary care and social support for African-American women at risk for recurrent very-low-birthweight delivery: a pilot evaluation. AB - OBJECTIVES: Very-low-birthweight (VLBW) delivery accounts for the majority of neonatal mortality and the black-white disparity in infant mortality. The risk of recurrent VLBW is highest for African-Americans of lower socioeconomic status. This study explores whether the provision of primary health care and social support following a VLBW delivery improves subsequent child spacing and pregnancy outcomes for low-income, African-American women. METHODS: This pilot study of mixed prospective-retrospective cohort design enrolled African-American women who qualified for indigent care and delivered a VLBW infant at a public hospital in Atlanta from November 2003 through March 2004 into the intervention cohort (n (1) = 29). The intervention consisted of coordinated primary health care and social support for 24 months following the VLBW delivery. A retrospective cohort was assembled from consecutive women meeting the same eligibility criteria who delivered a VLBW infant during July 2001 through June 2002 (n (2) = 58). The number of pregnancies conceived within 18 months of the index VLBW delivery and the number of adverse pregnancy outcomes for each cohort was compared with Poisson regression. RESULTS: Women in the control cohort had, on average, 2.6 (95% CI: 1.1-5.8) times as many pregnancies within 18 months of the index VLBW delivery and 3.5 (95% CI: 1.0-11.7) times as many adverse pregnancy outcomes as women in the intervention cohort. CONCLUSIONS: This small, pilot study suggests that primary health care and social support for low-income, African-American women following a VLBW delivery may enhance achievement of a subsequent 18-month interpregnancy interval and reduce adverse pregnancy outcomes. PMID- 17712613 TI - Health of children adopted from Ethiopia. AB - OBJECTIVES: Since 2000, American families have adopted 1,700 children from Ethiopia. Little is known about the health and development of these children. PATIENTS AND METHODS: Retrospective chart review of the arrival health status of all 50 (26F:24M) children from Ethiopia/Eritrea seen in the International Adoption Clinic. RESULTS: Prior to adoption, most children resided with relatives; 36% were >18 months old prior to entry into care. More than 50% were true orphans, often due to HIV. Arrival age ranged from 3 months to 15 years (mean +/- SD 4 years +/- 43.8 months). At arrival, growth z scores were near average (weight -.59, height -.64, head circumference -.09); significantly better than adopted children Guatemala, China, or Russia seen in our clinic. However, some Ethiopian children were significantly growth delayed (WAZ < or =-2, 8%, HAZ 12%, HCZ 18%). Age at adoption did not relate to growth delays. Medical issues on arrival included intestinal parasites (53%, [14% with > or =3 types]), skin infections (45%), dental caries (25%), elevated liver transaminases (20%), latent tuberculosis (18%), and hepatitis B (2%). Age-appropriate vaccines had been administered in 15-77% of children (depending on specific vaccine). Behavior problems were uncommon. Gross/fine motor and cognitive skills were approximately 86% of expected for age. Age correlated inversely with developmental scores for cognition (r = -.49, P = .003). Five children had age reassignments. CONCLUSIONS: Ethiopian/Eritean adoptees differ from other groups of internationally adopted children: they reside for relatively long periods of time with relatives prior to institutionalization, often have uncertain ages, exhibit few behavioral problems at arrival, have better growth, and may have less severe developmental delays. Whether these differences at arrival predict better outcomes for the Ethiopian/Eritrean children is unknown. PMID- 17712614 TI - The prevalence of live birth Down syndrome in the region of Primorsko-goranska County in Croatia, 1996-2005: the impact of screening and amniocentesis. AB - OBJECTIVES: To investigate the prevalence of live birth Down syndrome (DS) in the region of Primorsko-goranska County (PGC) in Croatia from 1996 to 2005 and to evaluate the impact of second-trimester maternal serum screening (MSS) and amniocentesis on live birth DS prevalence. METHODS: Study was based on databases from the Department of Gynecology and Obstetrics, University Hospital Centre Rijeka, the Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, and the Croatian National Institute of Public Health. The regional policy of prenatal diagnosis for DS includes amniocentesis for pregnant women aged 35 or over and MSS for younger women. We estimated live birth and total prevalence of DS and measured the proportion of pregnant women using MSS and amniocentesis. Trends of live birth and total prevalence of DS were tested by linear regression analysis. RESULTS: The live birth prevalence of DS was 1.4/1000 in the period 1996-2005. A decreasing, but nonsignificant, trend of prevalence was observed over time (P = 0.577). Women aged 35 or over represented 11.6% of all pregnant women included in the study. The proportion of women who had MSS was 33.9%. The proportion who underwent amniocentesis was 6.1%. CONCLUSIONS: No marked decrease in prevalence of live birth DS was observed in the region of PGC during the last 10 years. The usage of MSS and amniocentesis was too low to have any significant impact on live birth DS prevalence. Women's, as well as physician's, knowledge and attitudes towards prenatal diagnosis of DS should be evaluated. PMID- 17712615 TI - Effort levels of national maternal and neonatal health programs: 2005 measures and six year trends. AB - OBJECTIVE: To assess efforts by national programs in developing countries to improve maternal and neonatal health in 2005 in the context of the six-year trend. METHODS: A total of 14 components of effort based upon 81 questionnaire items were measured for 49-55 countries in 1999, 2002, and 2005, covering about 85% of the developing world's population. A standard questionnaire was completed by 10-25 experts in each country, with all questionnaires analyzed centrally and results returned to each country. The 2005 round includes new items and analysis for malaria and newborn interventions. FINDINGS: An overall index of effort showed no significant improvement over the six-year period. The patterns of effort across the 14 components were quite similar in the three rounds, supporting the usefulness of the methodology while also confirming the consistency of non-improvement. Rural access to services, in essentially all countries, is very inferior to urban access. Effort scores for antenatal and neonatal care were among the highest while those for health center capacities were among the lowest. CONCLUSION: Effort levels by maternal health programs in developing countries remain seriously deficient. Even by the standard set by the best scoring countries the ratings show only about 75% of maximum effort achieved. The overall average is just above half of maximum effort, at about 56% in all three years, whether countries are weighted equally or by their population sizes. PMID- 17712617 TI - What do I have to lose? Effects of a psycho-educational intervention on cancer patient preference for resuscitation. AB - This original empirical study examined effects of a psycho-educational intervention on cancer patients' knowledge, concern, and preferences for cardiopulmonary resuscitation (CPR). We examined message framing as one factor that might impact subsequent decision making. In addition, we examined personality and coping style as predictors and moderators of patients' reactions to an informational intervention. As hypothesized, participants initially underestimated CPR complications and overestimated survival rates. The intervention significantly increased concern, improved knowledge, and decreased preference for CPR, particularly for participants receiving both numerical and descriptive information. Message framing of survival data did not uniquely affect CPR preference. Higher optimism predicted less increase in concern about CPR, and higher hope predicted greater decrease in preference for CPR. More approach coping related to increased concern about CPR and decreased preference for CPR. PMID- 17712618 TI - Anger suppression, ironic processes and pain. AB - Whether anger suppression exerts a causal influence on pain experience, and the mechanisms of such an influence, are not well understood. We report two experimental studies that examine the hypothesis that anger suppression paradoxically increases cognitive accessibility of anger, in turn coloring perceptions of succeeding pain in an anger-congruent fashion. The results of two experimental studies largely confirmed these predictions. Study 1 revealed that participants instructed to suppress emotions during anger-provocation experienced greater cold-pressor pain than those in the control condition. This difference was confined to perception of anger-specific qualities of pain. Study 2 replicated key findings of Study 1, but also provided partial evidence for increased cognitive accessibility of anger tied to anger suppression through self report and modified dot-probe methodologies. Implications and limitations of these findings are discussed. PMID- 17712616 TI - Tryptophan, adenosine, neurodegeneration and neuroprotection. AB - This review summarises the potential contributions of two groups of compounds to cerebral dysfunction and damage in metabolic disease. The kynurenines are oxidised metabolites of tryptophan, the kynurenine pathway being the major route for tryptophan catabolism in most tissues. The pathway includes quinolinic acid - an agonist at N-methyl-D-aspartate (NMDA) receptors, kynurenic acid -- an antagonist at glutamate and nicotinic receptors, and other redox active compounds that are able to generate free radicals under many physiological and pathological conditions. The pathway is activated in immune-competent cells, including glia in the central nervous system, and may contribute substantially to delayed neuronal damage following an infarct or metabolic insult. Adenosine is an ubiquitous purine that can protect neurons by suppressing excitatory neurotransmitter release, reducing calcium fluxes and inhibiting NMDA receptors. The extent of brain injury is critically dependent on the balance between the two opposing forces of kynurenines and purines. PMID- 17712619 TI - Patterns of sedentary behaviour and physical activity among adolescents in the United Kingdom: Project STIL. AB - The purpose of this study was to use ecological momentary assessment to investigate the patterning of physical activity and sedentary behaviours in UK adolescents and to examine if different lifestyle groups differ on key explanatory variables. A total of 1,371 (38% boys, mean age 14.7 years) adolescents completed diaries every 15 min for 3 weekdays outside of school hours and 1 weekend day. Cluster analysis yielded five-cluster solutions for both boys and girls to explain the grouping of sedentary behaviours and physical activity. The clusters demonstrated that adolescents engage in many leisure time behaviours but have one activity that predominates. Active adolescents spend more time outside and more time with their friends. Few demographic and environmental variables distinguished between clusters. The findings suggest a potential need for different behavioural targets in interventions to reduce sedentary behaviour in sub groups of the adolescent population. Further research is required to examine the modifiable determinants of different sedentary lifestyles among young people. PMID- 17712620 TI - The effectiveness of respondent driven sampling for recruiting males who have sex with males in Dhaka, Bangladesh. AB - This paper evaluates the effectiveness of respondent driven sampling (RDS) to sample males who have sex with males (MSM) in Dhaka, Bangladesh. A major objective for conducting this survey was to determine whether RDS can be a viable sampling method for future routine serologic and behavioral surveillance of MSM as well as other socially networked, hard to reach populations in Bangladesh. We assessed the feasibility of RDS (survey duration; MSM social network properties; number and types of initial recruits) to recruit a diverse group of MSM, the efficacy of an innovative technique (systematic coupon reduction) to manage the implementation and completion of the RDS recruitment process and reasons why MSM participated or did not participate. The findings provide useful information for improving RDS field techniques and demonstrate that RDS is an effective sampling method for recruiting diverse groups of MSM to participate in HIV related serologic and behavioral surveys in Dhaka. PMID- 17712621 TI - Glutamate receptor 6 gene (GluR6 or GRIK2) polymorphisms in the Indian population: a genetic association study on autism spectrum disorder. AB - Autism is a neurodevelopmental disorder with early manifestation. It is a multifactorial disorder and several susceptible chromosomal regions for autism are identified through genome scan studies. The gene coding for glutamate receptor 6 (GluR6 or GRIK2) has been suggested as a candidate gene for autism based on its localization in the autism specific region on chromosome 6q21 and the involvement of receptor protein in cognitive functions like learning and memory. Despite its importance, so far no studies have been carried out on possible involvement of GluR6 with autism in the Indian population. Therefore in the present study, we have performed genetic analysis of three markers of GluR6 (SNP1: rs2227281, SNP2: rs2227283, SNP3: rs2235076) for possible association with autism through population, and family-based (TDT and HHRR) approaches. DSM-IV criteria and CARS/ADI-R have been utilized for diagnosis. Genotyping analysis for the SNPs has been carried out in 101 probands with autism spectrum disorder, 180 parents and 152 controls from different regions of India. Since the minor allele frequency of SNP3 was too low, the association studies have been carried out only for SNP1 and SNP2. Even though two earlier studies have shown association of these markers with autism, the present case-control and TDT, as well as HHRR analyses have not demonstrated any biased transmission of alleles or haplotypes to the affected offspring. Thus our results suggest that these markers of GluR6 are unlikely to be associated with autism in the Indian population. PMID- 17712622 TI - PMS777, a bis-interacting ligand for PAF receptor antagonism and AChE inhibition, attenuates PAF-induced neurocytotoxicity in SH-SY5Y cells. AB - (1) HIV-1 and viral proteins-evoked chronic brain inflammation, which is characterized by microglial activation, is the pivotal neuropathogenesis of HIV-1 associated dementia (HAD). Platelet-activating factor (PAF), mainly released from activated microglia and acts as a high potent inflammatory mediator and a neurotoxin, is indicated to be a principle initiator of neuroinflammation, neuronal dysfunction, and apoptosis related to HAD. Thus, bis-interacting ligands of acetylcholinesterase (AChE) inhibition and PAF receptor antagonism would be of great interest in the therapeutic potential of HAD not only for improvement of cognitive performance, but also for disease-modifying. (2). We have previously reported that a novel tetrahydrofuran-derived bis-interacting ligand PMS777 had satisfying potencies for PAF receptor blockade and AChE inhibition, and markedly improved cholinergic dysfunction-induced cognitive impairment in mice. Continuing with our research, we further investigated the neuroprotective activities of PMS777 on PAF-triggered neuronal injury in human neuroblastoma SH-SY5Y cells. (3) The bis-interacting ligand PMS777 (10 muM) obviously alleviated PAF-induced cell apoptosis in SH-SY5Y cells. Pretreatment with PMS777 also markedly inhibited intracellular Ca(2+) overload, down-regulation of anti-apoptotic bcl-2 mRNA, stimulation of pro-apoptotic bax mRNA expression and activation of caspase-3 pathway. Also, PMS777 could fine-tune pro-inflammatory cyclooxygenase-2 (cox-2) mRNA expression in PAF-treated cells. (4) These results suggest that PMS777 possesses a neuroprotective profile via anti-apoptotic/inflammatory signaling and warrant further investigations in connection with the potential value of this compound in HAD treatment. PMID- 17712623 TI - Overexpressed alpha-synuclein regulated the nuclear factor-kappaB signal pathway. AB - Alpha-synuclein is a presynaptic protein which is implicated in some neurodegenerative disorders including Parkinson's disease, dementia with Lewy bodies, multiple systems atrophy, and Hallervorden-Spatz disease, and its overexpression contributes to the loss of dopaminergic neurons. Although the role of alpha-synuclein in these paradigms has been widely documented, its exact function is still elusive. And the dysfunction of the transcription factor nuclear factor (NF-kappaB) also exists in many neurodegenerative diseases. In this reason the purpose of this study was to investigate the molecular mechanism of alpha-synuclein's toxicity and its association with NF-kappaB by MTT assay, Western blot method, and luciferase assay. Results showed that overexpressed alpha-synuclein and 1-methyl-4-phenylpyridinium (MPP(+)) suppressed the SH-SY5Y cell viability and attenuate NF-kappaB-mediated luciferase expression significantly. Moreover, the impairment function was enhanced with the increase of alpha-synuclein protein level. We also found that overexpressed alpha synuclein localized both in the cytoplasms and nuclei, down-regulated the anti apoptotic Bcl-2 expression and up-regulated the pro-apoptotic glycogen synthase kinase 3beta (GSK3beta) protein level. In conclusion, all these findings mentioned above suggested that alpha-synuclein shared some toxic functional homology with neurotoxin MPP(+), and the proapoptotic effects of alpha-synuclein might be mediated at least in part by the impairment of NF-kappaB signaling pathway which involves GSK3beta. PMID- 17712624 TI - Neuroprotective effects of cactus polysaccharide on oxygen and glucose deprivation induced damage in rat brain slices. AB - 1. The neuroprotective effect of cactus polysaccharide (CP) on oxygen and glucose deprivation (OGD) and reoxygenation (REO)-induced damage in the cortical and hippocampal slices of rat brain was investigated. 2. Cell viability was evaluated by using the 2, 3, 5-triphenyl tetrazolium chloride (TTC) method. The fluorescence of propidium iodide (PI) staining was used for quantification of cellular survival, and lactate dehydrogenase (LDH) activity in incubation medium was assessed by LDH assay to evaluate the degree of injury. 3. The OGD ischemic condition significantly decreased cellular viability and increased LDH release in the incubation medium. CP (0.2 mg/l approximately 2 mg/l) protected brain slices from OGD injury in a dosage dependent manner as demonstrated by increased A 490 value of TTC, decreased PI intensity and LDH release. At the above concentration, CP also prevented the increase of nitric oxide (NO) content and inducible nitric oxide synthase (iNOS) activity induced by OGD. 4. CP can protect the brain slices (cortical and hippocampus) against injury induced by OGD. Its neuroprotective effect may be partly mediated by the NO/iNOS system induced by OGD insult. PMID- 17712626 TI - The role of TNF-alpha and its receptors in the production of beta-1,4 galactosyltransferase I mRNA by rat primary type-2 astrocytes. AB - beta-1,4-galactosyltransferase I (beta-1,4-GalT I) plays an important role in the synthesis of the backbone structure of adhesion molecules involved in leukocyte endothelial cell interaction. The expression of beta-1,4-GalT I mRNA increased in primary human endothelial cells after exposure to tumor necrosis factor-alpha (TNF-alpha). In the central nervous system (CNS), astrocytes play a pivotal role in immunity as immunocompetent cells by secreting cytokines and inflammatory mediators, there are two types of astrocytes. Type-1 astrocytes can secrete TNF alpha when stimulated with Lipopolysaccharide (LPS), while the responses of type 2 astrocytes during inflammation are unknown. So we examined the expression change of beta-1,4-GalT I mRNA in type-2 astrocytes after exposure to TNF-alpha and LPS. Real-time PCR showed that TNF-alpha or LPS affected beta-1,4-GalT I mRNA expression in a time- and dose-dependent manner. RT-PCR analysis revealed that TNFR1 and TNFR2 were present in normal untreated type-2 astrocytes, and that TNF alpha, TNFR1 and TNFR2 increased in type-2 astrocytes after exposure to TNF-alpha or LPS. Immunocytochemistry showed that TNFR1 was expressed in the cytoplasm, nucleus and processes of normal untreated type-2 astrocytes, and distributed mainly in the cytoplasm and processes after exposure to LPS. TNFR2 was mainly expressed in the nucleus of normal untreated type-2 astrocytes, and distributed mainly in the processes of type-2 astrocytes after exposure to LPS. Both anti TNFR1 and anti-TNFR2 antibodies suppressed beta-1,4-GalT I mRNA expression induced by TNF-alpha or LPS. From these results, we conclude that TNF-alpha signaling via both TNFR1 and TNFR2 translocated from nucleus to cytoplasm or processes is sufficient to induce beta-1,4-GalT I mRNA. In addition, we observed that not only exogenous TNF-alpha but also TNF-alpha produced by type-2 astrocytes affected beta-1,4-GalT I mRNA production in type-2 astrocytes. These results suggest that an autocrine loop involving TNF-alpha contributes to the production of beta-1,4-GalT I mRNA in response to inflammation. PMID- 17712625 TI - Neuroprotective mechanism of taurine due to up-regulating calpastatin and down regulating calpain and caspase-3 during focal cerebral ischemia. AB - AIMS: Taurine as an endogenous substance possesses a number of cytoprotective properties. In the study, we have evaluated the neuroprotective effect of taurine and investigated whether taurine exerted neuroprotection through affecting calpain/calpastatin or caspase-3 actions during focal cerebral ischemia, since calpain and caspase-3 play central roles in ischemic neuronal death. METHODS: Male Sprague-Dawley rats were subjected to 2 h of middle cerebral artery occlusion (MCAo), and 22 h of reperfusion. Taurine was administrated intravenously 1 h after MCAo. The dose-responses of taurine to MCAo were determined. Next, the effects of taurine on the activities of calpain, calpastatin and caspase-3, the levels of calpastatin, microtubule-associated protein-2 (MAP-2) and alphaII-spectrin, and the apoptotic cell death in penumbra were evaluated. RESULTS: Taurine reduced neurological deficits and decreased the infarct volume 24 h after MCAo in a dose-dependent manner. Treatment with 50 mg/kg of taurine significantly increased the calpastatin protein levels and activities, and markedly reduced the m-calpain and caspase-3 activities in penumbra 24 h after MCAo, however, it had no significant effect on mu-calpain activity. Moreover, taurine significantly increased the MAP-2 and alphaII spectrin protein levels, and markedly reduced the ischemia-induced TUNEL staining positive score within penumbra 24 h after MCAo. CONCLUSIONS: Our data demonstrate the dose-dependent neuroprotection of taurine against transient focal cerebral ischemia, and suggest that one of protective mechanisms of taurine against ischemia may be blocking the m-calpain and caspase-3-mediated apoptotic cell death pathways. PMID- 17712627 TI - Pituicyte stellation is prevented by RhoA-or Cdc42-dependent actin polymerization. AB - Our aim was to shed light on different steps leading from metabotropic receptor activation to changes in cell shape, such as those that characterize the morphological plasticity of neurohypophysial astrocytes (pituicytes). Using explant cultures of adult rat pituicytes, we have previously established that adenosine A1 receptor activation induces stellation via inhibition of RhoA monomeric GTPase and subsequent disruption of actin stress fibers. Here, we rule out RhoA phosphorylation as a mechanism for that inhibition. Rather, our results are more consistent with involvement of a GTPase-activating protein (GAP). siRNA and pull-down experiments suggest that a step downstream of RhoA might involve Cdc42, another GTPase of the Rho family. However, RhoA activation, e.g., in the presence of serum, induces stress fibers, whereas direct Cdc42 activation appears to confine actin within a submembrane - i.e., cortical - network, which also prevents stellation. Therefore, we propose that RhoA may activate Cdc42 in parallel with an effector, such as p160Rho-kinase, that induces and maintains actin stress fibers in a dominant fashion. Rac1 is not involved in the stellation process per se but appears to induce a dendritogenic effect. Ultimately, it may be stated that pituicyte stellation is inducible upon mere actin depolymerization, and preventable upon actin organization, be it in the form of stress fibers or in a cortical configuration. PMID- 17712628 TI - Effects of electro-acupuncture on PDGF expression in spared dorsal root ganglion and associated dorsal horn subjected to partial dorsal root ganglionectomy in cats. AB - The effects of electro-acupuncture (EA) on the expression of platelet derived growth factor (PDGF) in spared dorsal root ganglion (DRG) and associated dorsal horns were evaluated in cats subjected to bilateral removal of L1-L5 and L7-S2 DRG, while sparing L6 DRG and were demonstrated using Immunohistochemistry, Western blot and RT-PCR techniques. On the acupunctured side, there was a significant increase in the total number of PDGF positive neurons. Large neurons of the L6 DRG at 7 days post operation (dpo), and small to medium-sized neurons at 14 dpo, as well as in the lamina II of the L6 spinal cord at 14 dpo was observed. The expression of PDGF protein increased significantly in the L6 DRG at 7 and 14 dpo and in the dorsal horn of the L6 spinal cord at 14 dpo while the upregulation of PDGF mRNA was seen at 3 dpo in the L6 DRG and the dorsal horn of the L3 and L6 spinal cord. These findings demonstrate that intrinsic PDGF has been upregulated in cats subjected to partial dorsal root ganglionectomy following EA, indicating endogenous PDGF is involved in promoting spinal plasticity following EA. PMID- 17712629 TI - Reduced hippocampal cell differentiation in the subgranular zone of the dentate gyrus in a rat model of type II diabetes. AB - It has recently been reported that diabetes mellitus is strongly associated with neurodegenerative and functional disorders of the central nervous system. In the present study, we investigated the changes in proliferating neurons in the dentate gyrus of type II diabetic rats using doublecortin (DCX), a marker of progenitors differentiating into neurons. At 4 weeks after birth, there were no differences in the blood glucose levels of Zucker diabetic fatty (ZDF) rats or Zucker lean control (ZLC) rats. DCX-immunoreactive neurons were detectable in the subgranular zone of the dentate gyrus in both the ZDF and ZLC rats; however, DCX immunoreactivity was higher in the ZLC rats than in the ZDF rats. At 12 weeks after birth, the blood glucose level was significantly increased by 400 mg/dl in the ZDF rats, but the blood glucose level in the ZLC rats was only slightly increased by 152.3 mg/dl. DCX immunoreactivity was significantly decreased in 12 week-old rats in comparison to 4-week-old rats. Some DCX-immunoreactive neurons were detectable in the subgranular zone of the dentate gyrus in the ZLC rats. However, only a few DCX-immunoreactive neurons were observed in the ZDF rats, and the DCX-immunoreactive neurons in the ZDF rats did not show fully developed processes. These results suggest that DCX-immunoreactive neurons were significantly decreased in an age-dependent manner and that DCX-immunoreactive neurons were also reduced in diabetic rats. In addition, the reduction in DCX immunoreactive neurons in age matched rats may be associated with type II diabetes. PMID- 17712631 TI - Therapeutic vitamin A doses increase the levels of markers of oxidative insult in substantia nigra and decrease locomotory and exploratory activity in rats after acute and chronic supplementation. AB - Vitamin A is known to regulate some central nervous system (CNS)-associated functions. Vitamin A at high doses has been demonstrated to be beneficial in the treatment of some diseases, for instance acute promyelocytic leukemia. However, vitamin A and its naturally occurring metabolites (retinoids) are known to alter neuronal function, inducing behavioral disorders. Here we provide an evidence to indicate that vitamin A supplementation, at both therapeutic and excessive doses, induces oxidative stress in the rat substantia nigra. Vitamin A supplementation induced lipid peroxidation, protein carbonylation, and oxidation of protein thiol groups, as well as change in catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activity. Surprisingly, locomotory and exploratory activity of rats were decreased after acute and chronic vitamin A supplementation. Therefore, we may conclude from our results that vitamin A supplementation is prooxidant to the rat substantia nigra and effective in altering behavior. PMID- 17712632 TI - Rapid decrease of GAD 67 content before the convulsion induced by hyperbaric oxygen exposure. AB - Exposure to hyperbaric oxygen (HBO) can lead to seizures, the etiology of which is not completely understood. Glutamic acid decarboxylase (GAD) plays a very important role in maintaining excitatory-inhibitory balance of the central nervous system (CNS). In the present study we investigated the effects of HBO on the activity and content of GAD in vivo and in primarily cultured neurons to probe in detail its effect on the formation of convulsion induced by HBO exposure. The results obtained from in vivo and in vitro experiments were identical. In the latent period before the onset of seizure, the GAD activity followed a rise-and-fall pattern with the prolongation of HBO exposure. At the time of the onset of seizure, GAD activity descended to the normal level. Besides, in the latent period, GAD content also reduced. Such reduction came from a GAD subtype, GAD67, while the content of another GAD subtype, GAD65, remained almost unchanged. Our investigations indicated that GAD is indeed an enzyme highly sensitive to the effect of HBO exposure. The rapid reduction in GAD67 content may be very closely related to seizures induced by HBO exposure. PMID- 17712630 TI - Characteristics of GABA release induced by free radicals in mouse hippocampal slices. AB - The release of the inhibitory neurotransmitter GABA is generally enhanced under potentially cell-damaging conditions. The properties and regulation of preloaded [3H]GABA release from mouse hippocampal slices were now studied in free radical containing medium in a superfusion system. Free radical production was induced by 0.01% of H2O2 in the medium. H2O2 markedly potentiated GABA release, which was further enhanced about 1.5-fold by K+ stimulation (50 mM). In Ca2+-free media this stimulation was not altered, indicating that the release was mostly Ca2+ independent. Moreover, omission of Na+ increased the release, suggesting that it is mediated by Na+-dependent transporters operating outwards, a conception confirmed by the enhancement with GABA homoexchange. Inhibition of the release with the ion channel inhibitors diisothiocyanostilbene-2,2'-disulphonate and 4 acetamido-4'-isothiocyanostilbene-2,2'-disulphonate indicates that Cl(-) channels also participate in the process. This release was not modified by the adenosine receptor (A1 and A2a) agonists and ionotropic glutamate receptor agonists kainate, N-methy-D: -aspartate and 2-amino-3-hydroxy-5-methyl-4 isoxazolepropionate, whereas the agonists of metabotropic glutamate receptors of group I [(S)-3,5-dihydroxyphenylglycine] and of group II [(2R,4R)-4 aminopyrrolidine-2,4-dicarboxylate] enhanced it by receptor-mediated mechanisms, the effects being abolished by their respective antagonists. The group III agonist L+-2-amino-4-phosphonobutyrate reduced the evoked GABA release, but this was not affected by the antagonist. Furthermore, the release was reduced by activation of protein kinase C by 4 beta-phorbol 12-myristate 13-acetate and by inhibition of tyrosine kinase by genistein and of phoshoplipase by quinacrine. On the other hand, increasing cGMP levels with the phosphodiesterase inhibitor zaprinast, selective for PDE5, 6 and 9, and NO production with the NO-generating compounds hydroxylamine, sodium nitroprusside and S-nitroso-N-penicillamine enhanced the release. The regulation of GABA release induced by free radical production proved thus to be rather complex. Under potentially cell-damaging conditions, the potentiation of GABA release may be a mechanism to counteract hyperactivity and reduce the effects of excitatory amino acid release. On the other hand, reduction of GABA release could be harmful and contribute to excitotoxic damage and neuronal degeneration. PMID- 17712634 TI - Influence of E. coli strain Nissle 1917 (EcN) on intestinal gas dynamics and abdominal sensation. AB - E. coli strain Nissle 1917 (EcN) is a probiotic clinically used with various indications. However, especially at the beginning of treatment, some patients report abdominal bloating. In a prospective, randomized, double-blind study in 30 healthy individuals we assessed the influences of EcN on intestinal gas dynamics and abdominal sensation. After one week without medication volunteers orally received 2.5-25 x 10(9) colony-forming units of EcN or placebo per day for 21 days. EcN was well tolerated and did not significantly affect abdominal symptoms, stool frequency or stool consistency. During gas challenge at different days no difference in the perception scores (range from 0 = no perception to 6 = pain) was observed between the two groups: the mean perception score was 1.2 (SD 0.2) in the EcN group and 1.4 (SD 0.2) in the placebo group. EcN had no relevant influence on intestinal gas dynamics. PMID- 17712633 TI - Biological treatment for liver tumor and new potential biomarkers. AB - The search for effective and efficacious therapy for liver tumor was started many years ago and is still ongoing. Despite all of the surgical advances, much work needs to be done to improve understanding of the biology of the tumor and its treatment. The rules of hepatic surgery are changing because of two recent major trends: (1) technical simplification, and (2) the endeavor to treat an increasing number of patients. T lymphocytes are potent cellular effectors of the immune system and possess a memory that responds to rechallenge by the same antigen. Being more specific and less toxic than chemotherapy, tumor infusion could be an ideal adjuvant therapy for patients with primary and secondary liver malignancies. Moreover, tumor cell vaccines have demonstrated efficacy in terms of minimal residual disease and are being investigated, but the requirement for an adequate supple of autologos tumor may limit the general applicability of these approaches. Various studies have demonstrated the aberrant expression of germ-cell proteins called cancer-testis (CT) antigens in liver neoplastic cells. Their selective normal-tissue expression makes them ideal antigens for immune targeting of malignant disease. Specific expression of CT antigens also suggests their application as tumor markers to detect circulating hepatocellular carcinoma (HCC) cells, as an adjuvant diagnostic tool, and as indicators for recurrence and prognosis. Biological therapy is now generating more clinical trials. More studies need to be performed and further experiments need to be done, although currently this seems a valid pathway for the treatment of liver cancer. Cytoreduction treatment of liver tumor and the vaccine might be the future of the treatment of primary and secondary liver tumor. PMID- 17712636 TI - Examination of gender in pathologic grooming behaviors. AB - Trichotillomania and pathologic skin picking are pathologic versions of grooming behaviors. Although mentioned in the psychiatric literature for decades, little is known about how gender influences clinical presentation of these behaviors. Seventy-seven adult subjects (12 men) with trichotillomania or pathologic skin picking were examined on a variety of clinical measures including symptom severity, functioning, and comorbidity. There were more similarities than differences between men and women with these behaviors. Some significant differences, however, were that men with grooming disorders had a later age of onset of the behaviors, had greater functional impairment due to the behaviors, and were more likely to suffer from a co-occurring anxiety disorder. This study suggests that gender may be an important clinical factor when assessing and treating these disorders. Further research is needed to validate our findings and identify whether treatments should be specially tailored differently for men and women with grooming disorders. PMID- 17712635 TI - TNF microsatellite alleles in Brazilian Chagasic patients. AB - To evaluate the tumor necrosis factor (TNF) a-e microsatellite polymorphism in Chagasic patients, we studied 162 patients stratified according to the major clinical variants (cardiac, digestive, digestive plus cardiac, and indeterminate forms) and 221 healthy controls. TNF microsatellite alleles were typed using genomic DNA amplified with specific primers. Statistical analyses were performed using the GENEPOP and ARLEQUIN softwares and the two-tailed Fisher exact test. The TNFa2, TNFa7, TNFa8, TNFb2, TNFb4, TNFd5, TNFd7, and TNFe2 alleles were overrepresented, whereas the TNFb7 and TNFd3 alleles were underrepresented when clinical variants of Chagas' disease or the patient group as a whole were compared with controls. Twelve TNF haplotypes were associated with susceptibility to or protection against Chagas' disease, considered as a whole or stratified into clinical variants. Many of these haplotypes encompassed the above-described susceptibility/protective alleles. These results indicate that the TNF chromosomal region is relevant for Chagas' disease development. PMID- 17712639 TI - Is there a future for obstetrics? NFYOG addresses the challenges ahead for trainees. PMID- 17712637 TI - Environment and origin of disease. PMID- 17712640 TI - Hormone replacement therapy and ovarian cancer risk--any news? PMID- 17712641 TI - Transduction patterns and efficiencies in rabbit uterine tissues after intraluminal uterine adenovirus administration vary with the reproductive cycle. AB - BACKGROUND: The options for destroying the full thickness of endometrium are very limited, relying mainly on surgical endometrial ablation. A nonsurgical, safe method would benefit many women in clinical settings. This study was undertaken to investigate the potential of gene therapy to transfect and destroy endometriun at different stages of the reproductive cycle in rabbits. METHODS: We used adenoviruses carrying the LacZ (AdvLacZ) marker gene, indicating the transfection efficiency, and adenoviruses carrying thymidine kinase (AdvTK) followed by intravenous ganciclovir therapy as a potential treatment for excess endometrial growth. Ganciclovir was given intravenously after AdvTK treatment. Adenoviruses were injected intraluminally into the uterus of nonpregnant, pseudopregnant, and pregnant New Zealand White rabbits (n=25). RESULTS: After AdvLacZ gene transfer into the uterus of intact rabbits, transduced cells were observed in uterine muscle and endometrial stroma. In pseudopregnant and pregnant rabbits the endometrium was proliferative and transduction was restricted to endometrial epithelium. However, no treatment effect was observed after AdvTK gene therapy although the transduction with AdvLacZ was clearly detectable. CONCLUSIONS: It is concluded that the transduction pattern of uterine tissues varies significantly with the reproductive cycle. Secondly, although the transduction efficiency was relatively high in the endometrial epithelium, the effect of the AdvTK and ganciclovir treatment was poor and not sufficient for clinical applications. PMID- 17712642 TI - Serum markers of macrophage activation in pre-eclampsia: no predictive value of soluble CD163 and neopterin. AB - BACKGROUND: Alternatively activated macrophages expressing the CD163 and CD206 surface receptors are the dominant immune-cell type found in the placenta. The placental number and distribution of macrophages is altered in pre-eclampsia, and the generalised inflammatory reaction associated with pre-eclampsia might lead to shedding of soluble CD163 into the circulation. METHODS: Serum samples from 18 women with pre-eclampsia and 90 normal pregnancies were obtained from a longitudinal study of 955 pregnant women at Randers County Hospital, Denmark. sCD163 and Neopterin were measured by ELISA on samples collected in weeks 18, 28, 32, and 38 of pregnancy. RESULTS: sCD163 levels in pregnancy (2-3 mg/l) were similar to previously measured levels in non-pregnant women, and did not increase from week 18 to 38. There was a tendency towards higher sCD163 in week 38 in pre eclamptic women compared to healthy women. Neopterin increased throughout pregnancy in both healthy (from median 5.4 to 6.7 nmol/l, p<0.0001) and pre eclamptic women (from 5.0 to 8.0 nmol/l, p<0.0001), but there were no differences between groups at any time-point. sCD163 correlated to neopterin in both the control (r=0.25, p<0.0001) and in the pre-eclampsia group (r=0.32, p=0.011). C reactive protein was higher in pre-eclampsia than in healthy pregnancies by week 38 (159 versus 91 nmol/l, p=0.0189). CONCLUSIONS: The macrophage serum-markers sCD163 and neopterin are not pre-symptomatic nor prognostic markers for pre eclampsia. PMID- 17712643 TI - Comparative study of conservative and surgical management for symptomatic moderate and severe hydronephrosis in pregnancy: a prospective randomized study. AB - BACKGROUND: To analyze the role of different measures in the treatment of acute moderate or severe symptomatic hydronephrosis in pregnancy. METHODS: Of the 18,130 women delivering at our institution between January 2000 and December 2004, 93 patients were admitted due to symptomatic hydronephrosis. Among these, 50 patients were diagnosed with moderate or severe hydronephrosis, and were randomly treated with conservative measures (25 patients) or double pigtail stent insertion (25 patients). Renal sonography, urinalysis, serum creatinine levels, white blood cell counts, and urine culture were done in all patients at first visit. The clinical and perinatal outcomes of the two groups were compared. RESULTS: The incidence of symptomatic hydronephrosis in pregnancy was 0.5% in our institution (93/18,130). The majority of the moderate or severe hydronephrosis (88%) cases were diagnosed after the first trimester. There were no statistically significant differences in the fetal body weight, Apgar score, preterm labor, and hospitalization day between the two groups. Among those receiving conservative treatment, five patients (5/25, 20%) failed to respond and were subsequently treated by double pigtail stent insertion successfully, compared with the surgical group, in which all patients were successfully relieved by double pigtail stent (p=0.018). Four patients receiving double pigtail stent insertion complained of stent discomfort and flank pain after the procedure (16%). CONCLUSION: Double pigtail stent insertion is effective for the treatment of moderate or severe symptomatic hydronephrosis in pregnancy, and showed a lower failure rate than the conservative treatment. However, due to the complications and discomfort with surgical treatment, conservative treatment should still be the first choice. PMID- 17712644 TI - Association of pre-pregnancy maternal body mass and maternal weight gain to newborn outcomes in twin pregnancies. AB - BACKGROUND: The rate of twin gestations is now about 3% of all pregnancies. The study objective was to investigate the association between twin pregnancy newborn outcomes and maternal weight. METHODS: Birth certificate information of 1,342 sets of live-born twin deliveries collected in a regional perinatal data system from a contiguous eight-county area in upstate New York was studied. RESULTS: The obese maternal pre-pregnancy BMI category was correlated with an increased odds ratio of a "Type I" (both a > or =36-week gestation and a > or =2,500-g average twin weight) newborn outcome (adjusted OR 1.92; 95% CI: 1.43, 2.56). For total maternal weight gain, there was an increased odds ratio of having a Type I newborn outcome with >25 kg weight gain (adjusted OR 2.24; 95% CI: 1.51, 3.33). CONCLUSIONS: Based on this population-based study, we conclude that both maternal pre-pregnancy BMI and total maternal weight gain are associated with twin newborn outcomes. PMID- 17712645 TI - Management of primary abdominal pregnancy: twelve years of experience in a medical centre. AB - BACKGROUND: The aim of this study was to evaluate our institution's 12-year experience in managing primary abdominal pregnancy by laparotomy or laparoscopy. METHODS: We identified 11 cases of primary abdominal pregnancy treated at our institution between January 1994 and December 2005, and separated the cases into 2 groups based on type of surgical management. The outcome measures we evaluated were operative time, blood loss and duration of hospital stay. In addition, the incidence rates for all types of ectopic pregnancy were recorded. Analysis excluded secondary abdominal pregnancy. RESULTS: Of the 11 primary abdominal pregnancies, 6 were treated with laparotomy and 5 with laparoscopy. The laparoscopy group had significantly better results in operative time, blood loss and hospital stay (p<0.05). The difference in gestational age was not significant (p=0.141), even after excluding the patient whose abdominal pregnancy was only identified after cesarean delivery. CONCLUSION: Our experience shows a trend toward better management of primary abdominal pregnancy with laparoscopy. These patients had shorter operative time, reduced blood loss, and fewer days in hospital then patients treated with laparotomy. Choice of management should depend on the patient's condition, gestational age of the pregnancy, and the physician's clinical experience. PMID- 17712646 TI - Precision, consistency, and reproducibility of blood pressure in diabetic and non diabetic pregnancy: the appraisal of repeated measurements. AB - A monitor (Spacelab 90207) was compared with sphygmomanometric blood pressure (BP) with respect to reproducibility and variations on precision and consistency. Some 133 women with type 1 diabetes mellitus and 59 non-diabetic women were recruited. During pregnancy, systolic BP was between 6 and 12 mmHg higher in the oscillometric than the auscultatory readings, and diastolic BP was between 1 and 2.6 mmHg. The association of difference with the mean BP disappeared with progression of pregnancy and the repetition of measurements in diabetic pregnancy. The precision, reproducibility, and trend of association over the scale of measurement were improved in the repeated compared to individual measurements, whereas consistency did not improve. PMID- 17712647 TI - Non-clinical determinants of planned cesarean delivery in cases of term breech presentation in France. AB - BACKGROUND: To explore non-clinical maternal and institutional factors associated with the decision for planned cesarean in cases of breech presentation at term in France, where planned vaginal delivery are recommended by the French College of Gynecologists and Obstetricians (CNGOF) when conditions are optimal. METHODS: The analysis included 6,080 women with a live fetus in breech presentation at term, from the PREMODA prospective survey, in 138 French maternity units between 1 June 2001 and 31 May 2002. Women with previous cesarean sections were excluded. The analysis to identify risk factors for planned cesarean used a multilevel logistic model. RESULTS: The planned cesarean rate was 63.5%. The maternal factors most strongly associated with a decision for planned cesarean were parity (adjusted OR: 2.56 (2.29-2.88)) and maternal age > or =35 years (ORa: 1.38 (1.18-1.61)). No association was found between institutional factors, such as maternity size and level of care, although a centre effect was documented (p<0.001). CONCLUSION: The variation in planned cesarean rates between maternity units was not associated with their structural characteristics, but was related to a characteristic specific to each centre, and, thus, suggests that despite the current guidelines in France, obstetricians have diverse opinions about the best mode of delivery for breech presentations. PMID- 17712648 TI - Ultrastructural alterations in human decidua in miscarriages compared to normal pregnancy decidua. AB - BACKGROUND: Pregnant endometrial stroma, an immunologically privileged site in the female reproductive system, is enriched by decidual and natural killer (NK) cells. Since the cellular microenvironment in early pregnancy from the decidual tissues of normal and miscarriage cases has gained importance, with special emphasis on cell-to-cell contacts, we aimed to document the plastic structure of the cellular milieu in normal and miscarriage decidua. METHODS: Endometrial biopsies were obtained from women after legal curettage or women who had been treated by curettage after miscarriage. Samples were analysed in a light microscope (LM), a scanning electron microscope (SEM) and a transmission electron microscope (TEM). RESULTS: Decidual cells possess several polyploidic protrusions on cell membranes. NK cells were distributed among decidual cells. Decidual cells were found to develop gap junctions in the interfaces between each other. Their cytoplasms were also found to possess well-developed protein synthesising organelles. Decidual cells obtained from miscarriages showed a moderate degree of degeneration and, in between, a decreased number of junctional complexes. Mononuclear cell infiltration was found to be significantly low. CONCLUSION: We conclude that decidual cells during early pregnancy build a series of miniature cell-cell contacts to assemble a proper endometrial milieu. In contrast, in miscarriage samples, those intercellular communications seem lacking, associated with an increased number of NK cells, a phenomenon which obviously alters proper implantation and leads to the induction of embryonic disgenesis and miscarriage. PMID- 17712649 TI - Norwegian midwives and doctors have increased cesarean section rates. AB - BACKGROUND: Increasing cesarean section (CS) rates over the last 3 decades may, in part, be explained by improved obstetric procedures, but socio-economic factors also play a major role. Much attention has been given to professionals' attitudes to operative delivery, and several studies have been performed to clarify the issue. The present study explored CS rates among Norwegian doctors and midwives, compared to other professionals with an education of 17-18 years (doctors) and 15-16 years (midwives). METHODS: Data on mode of delivery notified to the Medical Birth Registry of Norway for 1969-1998 (n=1,733,665) were linked with data on formal education from Statistics Norway. CS rates and crude and adjusted odds ratios (ORs) were calculated for the observation period. RESULTS: Female doctors and midwives had higher CS rates; the crude ORs were 1.18 (95% CI: 1.12-1.28) for doctors, and 1.35 (95% CI: 1.21-1.49) for midwives. Adjusted for age and birth order, the ORs were 1.22 (95% CI: 1.12-1.33) for doctors and 1.14 (95% CI: 1.03-1.27) for midwives. CONCLUSION: From 1969 to 1998, Norwegian female doctors and midwives had higher CS rates than other professionals with an education of comparable duration. PMID- 17712650 TI - Sense of coherence and symptoms of post-traumatic stress after emergency caesarean section. AB - BACKGROUND: In this study of women who had undergone an emergency caesarean section (EmCS), the aim was to examine the associations between, on the one hand, the new mother's sense of coherence (SOC) and obstetric and demographic variables a few days postpartum, and on the other hand, post-traumatic stress symptoms 3 months' postpartum. METHODS: In a prospective study, 122 Swedish- or English speaking new mothers completed 2 self-assessment questionnaires, at 2 days and 3 months after an EmCS. To measure SOC, we used the Sense of Coherence Scale (SOC 13), and to measure reactions to traumatic events, the Impact of Event Scale (IES 15). RESULTS: Independent risk factors associated with post-traumatic stress symptoms were: imminent fetal asphyxia as an indication for the operation, and low SOC in the woman. The group of women with low SOC were those with an intense fear of childbirth during pregnancy, immigrants, and socially underprivileged women. CONCLUSIONS: Symptoms of post-traumatic stress following EmCS are associated both with the new mother's personal coping style and with the circumstances of the event. We recommend that women who belong to groups who more often report a low SOC or who had imminent asphyxia as an indication for the operation should be offered support and follow-up. PMID- 17712651 TI - Post-cesarean surgical site infections according to CDC standards: rates and risk factors. A prospective cohort study. AB - OBJECTIVES: The aim of this study was to document the true incidence of post cesarean surgical site infections (SSI), according to the definition of the US Centers for Disease Control and Prevention (CDC), and to identify independent risk factors for infection. DESIGN: Prospective population-based cohort study in Norway. Setting. Sykehuset Asker og Baerum HF, a secondary community hospital, associated with the University of Oslo (UiO), Norway, accounting for 2,000 deliveries per year. Participants. All cesarean deliveries during a 12-month period from September 2003. Main outcome measures. Rate and risk factors for SSI. RESULTS: The total rate of SSI was 8.9%, with an observation period of 30 days post-operatively, compared to 1.8% registered at hospital discharge. The total response rate was 100%. There was no significant difference in SSI rate in elective or emergency cesarean section (CS), respectively. All SSI were superficial. We found 2 significant independent risk factors: operating time > or =38 min and body mass index (BMI) >30. CONCLUSION: The rate of SSI is underestimated if the observation time is limited to the hospital stay. Operating time exceeding 38 min substantially increases the risk of SSI. The finding of no significant difference in SSI rate between elective and emergency CS should lead to a different approach concerning the use of antibiotics: subgroup at risk (operating time > or =38 min and BMI >30) may benefit from antibiotics in relation to the operation, whether the CS is an emergency or elective operation. PMID- 17712652 TI - Mid-pregnancy maternal plasma levels of interleukin 2, 6, and 12, tumor necrosis factor-alpha, interferon-gamma, and granulocyte-macrophage colony-stimulating factor and spontaneous preterm delivery. AB - BACKGROUND: Few studies have investigated the relationship between inflammation and spontaneous preterm delivery (sPTD) in women before preterm labour. The authors examine whether mid-pregnancy plasma cytokine levels are associated with sPTD, and whether associations vary by maternal age, body mass index, prior preterm delivery, or gravidity. METHODS: This case-control study was nested within the Danish National Birth Cohort, a cohort of women with 101,042 pregnancies from 1997 to 2002. Included in this study are 61 women delivering at 24-29 weeks, 278 delivering at 30-33 weeks, 334 delivering at 34-36 weeks, and 1,125 delivering at > or =37 weeks. Maternal plasma interleukin (IL)-2, IL-6, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and granulocyte macrophage colony-stimulating factor (GM-CSF) at 25 weeks' gestation were measured using multiplex flow cytometry. RESULTS: For IL-2, TNF-alpha, and GM CSF, the proportion of women with levels >75th or >90th percentile did not differ by gestational age at delivery. IFN-gamma >90th percentile was associated with an increased risk of delivering at 30-33 weeks (crude odds ratio (cOR): 1.56; 95% confidence interval (CI): 1.07-2.30), while IFN-gamma >75th percentile and IL-6 >75th percentile were associated with an increased risk of delivering at 34-36 weeks (cOR: 1.32; 95% CI: 1.01-1.73); estimates changed little after adjusting for confounders. There was no effect-measure modification by maternal factors. CONCLUSION: Elevated mid-pregnancy plasma IL-2, TNF-alpha, and GM-CSF did not appear to be associated with an increased risk of sPTD, while elevated IFN-gamma and IL-6 levels were weakly associated with moderate and late sPTD. The value of using mid-pregnancy cytokines in predicting spontaneous preterm delivery appears limited. PMID- 17712653 TI - Knowledge, attitudes and prescribing pattern of emergency contraceptives by health care workers in Kampala, Uganda. AB - BACKGROUND: Health care workers (HCWs) play an important role in making emergency contraceptives (ECs) available to clients. They can influence accessibility positively through counselling, prescribing or advocating the use of ECs. However, in some settings, HCWs have been blamed for unfavourable attitudes and lack of accurate information. Objective. To assess the knowledge, attitudes and prescribing pattern of EC by HCWs in Kampala district, Uganda. METHODS: The total number of health units at different levels of health care delivery in Kampala (894) was obtained. Probability proportional to size (PPS) technique of sampling was applied. Some 247 HCWs completed a self-administered questionnaire on their knowledge about EC, including methods, mechanism of action, prescription of EC, sources of information, attitudes towards EC, and if and how it should be made available. RESULTS: Of the HCWs, 80% had knowledge of ECs. However, 1 in every 4 was not sure about the time limit within which EC is effective. A total of 50% of the participants had obtained information from a physician (26.4%) or from a training school (24%). The Yuzpe regimen was the most commonly mentioned and prescribed method of EC. The HCWs attitudes to EC were generally positive, and it was suggested that the community should be informed and sensitised about EC. There was a significant difference between having had a family planning educational update or not in the last year and knowledge of EC (p=0.005). CONCLUSION: Most HCWs were aware of EC, but some lacked important knowledge on its use or available methods. RECOMMENDATION: HCWs should have regular (annual) in-service training in reproductive health issues, such as counselling on EC. This will enable them to keep up to date with the current evidence-based recommendations in the field of contraceptive technology. PMID- 17712655 TI - A prospective, randomised, controlled trial comparing 3 hour and 24 hour postoperative removal of bladder catheter and vaginal pack following vaginal prolapse surgery. AB - BACKGROUND: The aim of this prospective, randomised, study was to determine whether or not there was a higher incidence of bleeding, reoperation, urinary retention or bacterial count in the urine, depending on whether urinary catheter and vaginal pack was removed 3 h or 24 h after vaginal prolapse surgery. METHODS: Some 136 women were randomised into Group 1 (removal of catheter and vaginal pack after 3 h), and Group 2 (removal of catheter and vaginal pack after 24 h). Data on postoperative bleeding, reoperation, and urinary retention were collected. Preoperatively, day after operation, and 14 days after operation, a urine culture was performed. RESULTS: There was no tendency towards more bleeding with early removal of vaginal pack and urinary catheter. No patients in either group were reoperated during the first 48 postoperative hours. Three patients in Group 1 required sterile intermittent catheterisation postoperatively, however, only once in 2 patients. There was a trend towards a higher postoperative bacterial count in patients in Group 2 (p=0.306). CONCLUSION: We recommend removing the vaginal pack and urinary catheter after 3 h with careful monitoring of the patient's voiding. PMID- 17712654 TI - One or two day mifepristone-misoprostol interval for second trimester abortion. AB - METHODS: A retrospective 2-year cohort study of 127 women, with gestation between 13 and 24 weeks and a live fetus, seeking induced abortion. The aim was to compare the effect of a 1-day and a 2-day interval between oral mifepristone (200 mg) and vaginal misoprostol (400 microg) every 3 h. RESULTS: The time to fetal expulsion was longer (9.8 versus 7.5 h; p<0.01) in the 1-day than in the 2-day group, but the median number of applications were identical and abortion occurred in 98% within 24 h in both groups The time to abortion was longer in women with a gestation of 17-22 weeks compared to women with lower gestation (10.2 versus 6.8 h; p<0.001), and longer in nulliparae than in parous women (10.0 versus 6.7 h; p<0.001). CONCLUSION: The combined regimen of mifepristone and misoprostol is effective in the second trimester, and the interval between the drugs can be reduced allowing individualised patient care. PMID- 17712656 TI - Preventive treatment of intrauterine device-induced menstrual blood loss with tranexamic acid in Chinese women. AB - OBJECTIVES: To investigate whether tranexamic acid (Transamin) therapy reduces the amount of menstrual blood loss (MBL) and occurrence of menorrhagia after intrauterine device (IUD) insertion. METHODS: Some 175 Chinese women attending for IUD insertion were equally assigned into 2 Transamin groups (1,000 and 500 mg, twice daily) and a placebo group. Their MBL was recorded with a pictorial chart in 3 subsequent menstrual cycles after insertion, while the MBL of 64 patients, collecting used sanitary towels, was also measured by an alkaline hematin method. RESULTS: A significant decline in post-insertion MBL and occurrence of menorrhagia was found in the 2 Transamin groups compared with the placebo group (p<0.05), whereas the difference in the results from the pictorial chart score was not statistically significant between the 1 g group and placebo group. CONCLUSION: Transamin treatment with a generally recommended dosage can effectively reduce the amount of IUD-induced MBL and prevent menorrhagia in Chinese women. A lower dosage than recommended (50% of recommended dosage) may have a similar preventive effect. PMID- 17712657 TI - Clinical and urodynamic parameters associated with history of urinary tract infections in women. AB - OBJECTIVES: To evaluate the association of various clinical and urodynamic variables with history of urinary tract infections (UTIs) in women. METHODS: A prospective study of 2,081 women referred to a urogynecologic clinic between June 2000 and November 2005 for investigation of lower urinary tract symptoms. RESULTS: Some 144 women reported history of UTI(s) within the last year from the visit to the clinic, and 91 had recurrent episodes (> or =3 per year). The multivariable analysis showed that urge incontinence (odds ratio (OR) = 2.23, 95% confidence interval (CI): 1.46-3.42), suprapubic pain (OR = 4.12, 95% CI: 2.21 7.67), and low maximum flow rate during voiding cystometry (OR = 0.96, 95% CI: 0.94-0.98) associated with UTIs. CONCLUSIONS: Our results suggest that urodynamic testing does not help in identifying specific urogynecologic mechanisms that could improve medical and/or surgical management or prevent recurrent UTI. PMID- 17712658 TI - Which factors influenced the result of a tension free vaginal tape operation in a single teaching hospital? AB - BACKGROUND: Tension free vaginal tape (TVT) has proven to be successful. Nevertheless, complications of the TVT have been reported. The aim of this study was to describe factors that might influence the efficacy and safety of the TVT procedure in our clinic. METHODS: Medical records of all patients who underwent TVT surgery between 1 January 2001 and 1 May 2004 were reviewed. To achieve subjective follow-up, in 2004 and 2005, we sent all patients standardised validated questionnaires. Data were analysed with SPSS. RESULTS: A total of 198 TVT procedures were performed. In 75 cases (37.9%), the procedure was combined with vaginal prolapse surgery. Complications were found in 19.7% of all TVT procedures. Most patients (71%) returned the questionnaire. Median follow-up was 27 months (range: 9-49). Subjective success rate was 73%. Logistic regression analysis showed that success rate of the TVT procedure was not influenced by any of the factors we studied. Complications were not more common in patients who had undergone prior incontinence or prolapse surgery. Concomitant prolapse surgery with the TVT, however, was found to be the only risk factor for complications, mainly prolonged catheterisation. CONCLUSIONS: In this study, we found no factor that influenced the success rate of the TVT. In the literature, the experience of the surgeon is marked as a factor influencing the success rate. We, therefore, gradually reduced the number of gynecologists who perform TVT. Concomitant prolapse surgery, however, was shown to be an independent risk factor for complications. Therefore, we prefer to 'separate' prolapse and incontinence surgery. PMID- 17712659 TI - 'See and treat' regime by LEEP conisation is a safe and time saving procedure among women with cytological high-grade squamous intraepithelial lesion. AB - BACKGROUND: Assess the value of colposcopic evaluation preceding loop electrosurgical excision procedure (LEEP) conisation of cytological high grade squamous intraepithelial lesion (HSIL), and study risk factors for recurrence. METHODS: Consecutive follow-up among women undergoing LEEP conisation from January 2001 to December 2004. RESULTS: Some 528 LEEP conisations were performed because of suspected or verified cervical dysplasia. On classified samples, cytology, punch biopsy and histopathology of the cone specimen showed cervical intraepithelial neoplasia (CIN)2 or a higher degree in 48.5, 36.2 and 58.6%, respectively. Sensitivity for HSIL out of cytology and colposcopically directed punch biopsy was 74.4 and 73.3%, respectively. Likewise, among 286 women with all 3 samples, positive and negative predictive value for HSIL in Papanicolaou (Pap) smear and punch biopsy was 78.5, 73.2% and 60.3, 63.6%, respectively. Positive cone margins were found in 16.8%. Residual/recurrent disease, defined as any grade of dysplasia at cytological follow-up, was found among 9.4%. Significant risk for recurrent/residual disease was found among those with positive marginal status. Median time from colposcopy to conisation was 2 months. CONCLUSIONS: An immediate colposcopically-guided LEEP conisation after HSIL Pap smear may be a safe and time saving strategy. Positive cone margins are a risk factor for residual/recurrent disease. PMID- 17712660 TI - Effect of steroid administration and plasmapheresis to prevent fetal congenital heart block in patients with systemic lupus erythematosus and/or Sjogren's syndrome. PMID- 17712661 TI - Extraperitoneal laparoscopic para-aortic lymphadenectomy as a diagnostic procedure for lymph node recurrence of gynaecological cancers. PMID- 17712663 TI - Fear of childbirth can be treated, and cesarean section on maternal request avoided. PMID- 17712666 TI - Exploring the relation between human papilloma virus and larynx cancer. AB - Human papilloma virus (HPV) has a role in benign and malignant pathology of the larynx. In this review we present the biological and epidemiological aspects related to these issues. PMID- 17712667 TI - Optical coherence tomography as an orientation guide in cochlear implant surgery? AB - CONCLUSION: With optical coherence tomography (OCT) it is basically possible to reveal parts of the cochlear morphology without opening its enveloping membranes. Thus, it may serve as a helpful guide for the surgeon to localize the scala tympani precisely before opening the fluid-filled inner ear to insert the electrode array. OBJECTIVE: To improve anatomical orientation in cochlear implant surgery before definitively opening the fluid-filled inner ear. The question was whether a new imaging technique, OCT, might provide information about the site of the underlying inner ear structures (scala tympani, scala vestibuli) and could, consequently, guide the surgeon towards the scala tympani. MATERIALS AND METHODS: In a preliminary study, OCT was carried out on human temporal bone preparations, in which a cochleostomy ('fenestration') was performed leaving the endosteum and the fluid-filled inner ear intact. OCT was applied via a prototype of a specially equipped operating microscope. The mode of OCT used in this context was spectral domain (SD)-OCT. RESULTS: On scans, which can be read analogous to B-mode sonography, OCT provides information about structures on the inner surface of the partly exposed but still intact membranous cochlear lining - such as scala tympani or scala vestibuli. PMID- 17712668 TI - Noise protection with N-acetyl-l-cysteine (NAC) using a variety of noise exposures, NAC doses, and routes of administration. AB - CONCLUSION: These studies extend previous work on N-acetyl-l-cysteine (NAC) and noise, showing protection with NAC against a high-kurtosis noise, showing protection with NAC at low doses, as well as protection by oral gavage. The studies further reveal the potential for the use of NAC in a clinical population exposed to noise. OBJECTIVE: To extend previous work on NAC protection from noise, the current study examined the effectiveness of NAC against a high kurtosis noise that combined continuous and impact noise, tested the effectiveness of NAC at varying doses, and tested NAC when administered by gavage. MATERIALS AND METHODS: Chinchillas were tested for auditory brainstem responses (ABRs) at five frequencies before and at three time points after one of three noise exposures: high-kurtosis (2 h, 108 dB L(eq)), impulse (75 pairs of 155 dB pSPL impulses), or continuous (4 kHz octave band, 105 dB SPL for 6 h). Animals were treated with NAC or saline vehicle before and after noise. RESULTS: The NAC was protective against the high-kurtosis noise both at low doses and when given orally by gavage. PMID- 17712669 TI - Temporal bone investigations on landmarks for conventional or endosteal insertion of cochlear electrodes. AB - CONCLUSION: Our anatomical findings place special emphasis on the requirement to follow an infero-anterior approach to the round window, to expose the scala tympani safely for 'normal' cochlear implantation. It is also known how easily the basilar membrane may be accidentally damaged, despite exercising considerable caution in the approach used. With regard to an 'endosteal electrode' it can be stated that there are no really specific indicators to locate the spiral ligament, or each of the scalae, on the lateral aspect of the tissue layer encasing the cochlea. For the concept of an endosteal electrode, however, the soft tissue layer of the lateral aspect of the cochlea is considered to be sufficiently thick to serve as a physical barrier between the electrode and the inner ear fluid. OBJECTIVES: To re-evaluate surgical techniques of gaining access to the scala tympani for cochlear implantation (cochleostomy, 'fenestration'). There are two reasons for this study. First, recent publications show that in a significant number of patients the electrode array was unintentionally inserted into the 'wrong' scala (sc. vestibuli). Second, dealing with an alternative concept proposed by Lehnhardt for patients with residual hearing ('endosteal electrode'), the anatomical site of the spiral ligament should be known. In a study on human temporal bones the topography of the middle and inner ear is revised with regard to the presence of anatomical or surgical landmarks that may guide the surgeon. MATERIALS AND METHODS: Anatomical examinations were performed on 10 temporal bones (5 fresh specimens and 5 fixed in formalin), in which the bone of the promontory was carefully milled. The consistency of identification and the relative location of specific surgical indicators or landmarks such as 'blue lines' and 'gray lines' were evaluated for 10 temporal bones. Furthermore, the projection of the lateral attachment of the basilar membrane on the promontory was determined with regard to round window anatomy. RESULTS: In all cases, a major blue line indicated the lateral aspect of the basal cochlear turn while milling the promontorial bone. In a limited number of cases (20%), an additional gray line potentially indicated the spiral ligament before the last shell of bone was removed. In 80% of the cases it was possible to remove the bony layer and leave the endosteum intact as a precondition for a potential endosteal electrode insertion. In addition, through the examination of these models, the relative anatomical location of structures, such as the scala vestibuli, scala tympani, spiral ligament, and basilar membrane, is reviewed. PMID- 17712670 TI - Prediction of upper respiratory tract bacteria in acute otitis media. AB - CONCLUSIONS: Thorough otomicroscopical examination of the tympanic membrane in acute otitis media (AOM) might distinguish AOM episodes caused by different bacteria. It thus might be a way to select appropriate treatment for each patient without raising the number of dangerous complications. OBJECTIVES: The aim of this study was to see if it might be possible to predict the causative bacterium by judging the otomicroscopical appearance of the tympanic membrane in episodes of AOM. PATIENTS AND METHODS: The study was prospective. Patients suffering from non-perforated AOM were included. The tympanic membrane was photographed. A prediction of the causative bacterium was made and tympanocentesis was performed. Effusion from the middle ear and a nasopharyngeal swab were obtained for bacterial culturing. The causative bacteria were categorized into gram-positive (Streptococcus pneumoniae and S. pyogenes) or gram-negative (non-typable Haemophilus influenzae and Moraxella catarrhalis). RESULTS: A total of 82 patients were included in the study. A correct prediction was made in 47/63, a false prediction in 16/63 (kappa 0.48, p<0.001). PMID- 17712671 TI - Piezoelectric bone surgery in otosclerosis. AB - CONCLUSION: This test of the Piezosurgery medical device for osteoplasty of the external auditory duct posterior wall and stapedotomy highlighted the advantages of this device. The device's accuracy and selectivity render it superior to conventionally rotating instruments in otologic surgery. The precise nature of the instrument allows exact, clean, and smooth cut geometries during surgery, without any visible injury to the adjacent soft tissue. OBJECTIVE: The aim of this work was to test the Piezosurgery device as a new and alternative method to conventional bone tissue management in otologic surgery and in particular in stapedotomy and the external auditory duct posterior wall. MATERIALS AND METHODS: The Piezosurgery medical device is a piezoelectric ultrasonic bone-cutting surgical instrument designed to perform sharp cutting actions. The equipment consists of two piezoelectric hand-pieces and two insets that are connected to a main unit, which supplies power and has holders for the hand-piece and irrigation fluids. Piezosurgery uses low frequency ultrasonic waves (24.7-29.5 kHz), the applied power can be modulated between 2.8 and 16 W, and the machine is programmed in accordance with the density of the bone cut. The micro-vibrations that are created in the piezoelectric hand-piece cause the inserts to vibrate linearly between 60 and 210 microm and allow a selective cut of mineralized tissues without trauma to soft tissues. The interoperative irrigation cools down the bone surface and make the operating site blood-free. Twenty patients affected by otosclerosis underwent treatment utilizing the device. RESULTS: In all the patients treated, the characteristics of the ultrasonic frequencies allowed rapid and easy intraoperative management, without any visible injury to the adjacent soft tissue. No side effects were detected. PMID- 17712672 TI - Intratympanic treatment of acute acoustic trauma with a cell-permeable JNK ligand: a prospective randomized phase I/II study. AB - OBJECTIVES: Intratympanic administration of a cell-permeable JNK ligand has been shown to prevent hearing loss after acute acoustic trauma in animal models. CONCLUSIONS: Functional and morphological analysis of the treated ears revealed that AM-111 had an excellent otoprotective effect, even when administered hours after the noise exposure. Blocking the signal pathway with D-JNKI-1 is therefore a promising way to protect the morphological integrity and physiological function of the inner ear in various conditions involving acute sensorineural hearing loss. SUBJECTS AND METHODS: For the first application of AM-111 in humans, we organized a clinical phase I/II trial in patients with acute acoustic trauma after exposure to firecrackers in Berlin and Munich on New Year's Eve 2005/2006. We randomly selected 11 patients for intratympanic treatment with AM-111 at a concentration of 0.4 mg/ml or 2 mg/ml within 24 h after noise exposure. Pure tone audiometry and otoacoustic emissions were assessed before treatment and on days 3 and 30 thereafter. RESULTS: Based on clinical experience and on a calculation using an empirically derived exponential hearing recovery function AM-111 seems to have had a therapeutic effect. A total of 13 adverse events were reported in 5 study participants. None of the adverse events were serious or severe. PMID- 17712673 TI - Beneficial auditory and cognitive effects of auditory brainstem implantation in children. AB - CONCLUSION: This preliminary study demonstrates the development of hearing ability and shows that there is a significant improvement in some cognitive parameters related to selective visual/spatial attention and to fluid or multisensory reasoning, in children fitted with auditory brainstem implantation (ABI). The improvement in cognitive paramenters is due to several factors, among which there is certainly, as demonstrated in the literature on a cochlear implants (CIs), the activation of the auditory sensory canal, which was previously absent. The findings of the present study indicate that children with cochlear or cochlear nerve abnormalities with associated cognitive deficits should not be excluded from ABI implantation. OBJECTIVES: The indications for ABI have been extended over the last 10 years to adults with non-tumoral (NT) cochlear or cochlear nerve abnormalities that cannot benefit from CI. We demonstrated that the ABI with surface electrodes may provide sufficient stimulation of the central auditory system in adults for open set speech recognition. These favourable results motivated us to extend ABI indications to children with profound hearing loss who were not candidates for a CI. This study investigated the performances of young deaf children undergoing ABI, in terms of their auditory perceptual development and their non-verbal cognitive abilities. PATIENTS AND METHODS: In our department from 2000 to 2006, 24 children aged 14 months to 16 years received an ABI for different tumour and non-tumour diseases. Two children had NF2 tumours. Eighteen children had bilateral cochlear nerve aplasia. In this group, nine children had associated cochlear malformations, two had unilateral facial nerve agenesia and two had combined microtia, aural atresia and middle ear malformations. Four of these children had previously been fitted elsewhere with a CI with no auditory results. One child had bilateral incomplete cochlear partition (type II); one child, who had previously been fitted unsuccessfully elsewhere with a CI, had auditory neuropathy; one child showed total cochlear ossification bilaterally due to meningitis; and one child had profound hearing loss with cochlear fractures after a head injury. Twelve of these children had multiple associated psychomotor handicaps. The retrosigmoid approach was used in all children. Intraoperative electrical auditory brainstem responses (EABRs) and postoperative EABRs and electrical middle latency responses (EMLRs) were performed. Perceptual auditory abilities were evaluated with the Evaluation of Auditory Responses to Speech (EARS) battery - the Listening Progress Profile (LIP), the Meaningful Auditory Integration Scale (MAIS), the Meaningful Use of Speech Scale (MUSS) - and the Category of Auditory Performance (CAP). Cognitive evaluation was performed on seven children using the Leiter International Performance Scale - Revised (LIPS-R) test with the following subtests: Figure ground, Form completion, Sequential order and Repeated pattern. RESULTS: No postoperative complications were observed. All children consistently used their devices for >75% of waking hours and had environmental sound awareness and utterance of words and simple sentences. Their CAP scores ranged from 1 to 7 (average =4); with MAIS they scored 2-97.5% (average =38%); MUSS scores ranged from 5 to 100% (average =49%) and LIP scores from 5 to 100% (average =45%). Owing to associated disabilities, 12 children were given other therapies (e.g. physical therapy and counselling) in addition to speech and aural rehabilitation therapy. Scores for two of the four subtests of LIPS-R in this study increased significantly during the first year of auditory brainstem implant use in all seven children selected for cognitive evaluation. PMID- 17712674 TI - Experimental comparative study in rabbits of three different ways of cartilage graft fixation: suture, gelatin-resorcin-formaldehyde and butyl-2-cyanoacrylate. AB - CONCLUSION: The compound gelatin-resorcin-formaldehyde (GRF) was a better stabilizing material for cartilage grafts in rabbits than butyl-2-cyanoacrylate. GRF was also better than the suture when comparing fixation of cartilage to the periosteum and inflammatory reaction. OBJECTIVE: Cartilage grafting is an interesting option for refinements on rhinoplasties. The objective of this study was to compare butyl-2-cyanoacrylate to GRF and suture to determine the efficacy of these methods in restraining grafted cartilage in rabbits. MATERIALS AND METHODS: Fifteen male adult New Zealand rabbits underwent surgery with the aim of collecting six auricular cartilage grafts from each animal. Two of these grafts in each animal were glued together with butyl-2-cyanoacrylate, two were glued together with compound GRF, and two were sewn together with nylon suture. These sandwich grafts were then glued or sutured to the periosteum of the glabella. After 2, 6, and 12 weeks, groups of five animals were sacrificed and histological analysis for inflammation was performed. Cartilage graft migration, adhesion, and deformities of the grafts were also evaluated. RESULTS: There was less migration of the cartilages glued with GRF than with cyanoacrylate and suture. GRF showed statistically less inflammatory reaction and angiogenesis than the other two methods. The three methods showed a tendency to decrease of fibrosis, inflammation, and angiogenesis as weeks passed. There was no detachment or deformity in the cartilage sandwiches sutured to the glabella's periostium. The majority of detached and deformed cartilages were those glued with cyanoacrylate. The number of detached cartilages was directly related to the number of deformed cartilages. The data were statistically significant (p<0.05). PMID- 17712675 TI - Neurotransmitter candidates in the vomeronasal organ of the rat. AB - CONCLUSION: The rich supply of nerve fibres containing neurotransmitters, particularly those containing SP and CGRP, is suggested to be a prerequisite for the recognition of chemical irritants as part of a chemical sense. OBJECTIVE: The present study was designed to examine the distribution of different neurotransmitter candidates in the vomeronasal organ (VNO) of rats. MATERIALS AND METHODS: The distribution of neurotransmitter candidates was studied in the vomeronasal organ of the rat using immunocytochemistry. RESULTS: The neuronal marker protein gene product 9.5 revealed a very rich supply of nerve fibres within and beneath the sensory epithelium, around blood vessels and glands. A moderate supply of nerve fibres containing tyrosine hydroxylase and neuropeptide Y was mostly seen close to blood vessels. Numerous nerve fibres containing nitric oxide synthase and vasoactive intestinal peptide were seen around blood vessels and in the subepithelial layer, with occasional fibres within the epithelium. Only few fibres located in the subepithelial layer contained pituitary adenylate cyclase activating peptide. Nerve fibres containing substance P and in particular calcitonin gene-related peptide were abundant in and beneath the epithelium and scattered in the submucosal layers around blood vessels. PMID- 17712676 TI - Complex evaluation of pain after tonsillectomy. AB - CONCLUSION: Postoperative odynophagia should be assessed by a variety of methods including visual analogue scale (VAS) pain scores (subjective), clinical data (objective qualitative) and surface electromyography (sEMG; objective quantitative). sEMG might be used for quantitative evaluation of odynophagia when aggravation or hysteria-conversion reaction is suspected. Tonsillectomy affects muscle activity significantly by involving additional muscles in deglutition. OBJECTIVES: Complex evaluation of post tonsillectomy odynophagia was used for objective assessment of complaints of operated patients. PATIENTS AND METHODS: Parameters evaluated for 50 randomly chosen operated adults included VAS pain score, clinical data, and the EMG data such as the timing, electric amplitude and graphic patterns of muscular activity during deglutition. We investigated masseter (MS), infrahyoid (INF) and submental-submandibular (SUB) muscles. The results were compared with a normative database. The patients were first tested 12 h after surgery and were monitored for 30 days. The sEMG data were compared with VAS pain score with regard to changes in clinical condition of the patients. RESULTS: Signs of clinical recovery after tonsillectomy did not always correspond with the VAS pain score evolution. sEMG was more in concord with clinical recovery than VAS. Electric activity of MS and LSM was significantly higher among the patients in comparison with a normative database (p<0.005). PMID- 17712677 TI - Safety and usefulness of an electric knife during surgery for parotid benign tumor: postoperative facial paresis and its risk factors. AB - CONCLUSION: The incidence of facial nerve paresis was not high compared with previously reported incidences using conventional operative techniques, showing the safety of the use of an electric knife in this operative technique. An electric knife is provided in almost all operating rooms and no special apparatus is necessary for this technique. BACKGROUND: Since the glandular tissue of the parotid gland is rich in blood flow, safe and accurate protection of the nerve is often made difficult due to bleeding during parotid surgery. Therefore, we developed a technique in which glandular tissue is cut using an electric knife, which is provided in almost all operating rooms. PATIENTS AND METHODS: In this study, the safety and usefulness of an electric knife in parotid surgery were confirmed by evaluating patients with parotid benign tumor who underwent surgery using an electric knife. The subjects were 135 patients with parotid benign tumors. RESULTS: Postoperative facial nerve paresis developed in 36 (26.6%) of the 135 patients but was transient in all cases. Depending on the tumor site, transient paresis was observed in 8 of the 13 patients with tumors in the deep lobe but in 28 (22.9%) of the 122 patients with tumors in the superficial lobe. The mean recovery time from facial nerve paresis was 6.1 weeks. PMID- 17712678 TI - Inducible nitric oxide synthase expression in various laryngeal lesions in relation to carcinogenesis, angiogenesis, and patients' prognosis. AB - CONCLUSIONS: The inducible nitric oxide synthase (iNOS) expression leading to vascular endothelial growth factor (VEGF) overexpression may be useful as a factor for predicting recurrence after initial treatment and prognosis in laryngeal squamous cell carcinoma (SCC). OBJECTIVE: We analyzed expression of iNOS, p53, and VEGF in various laryngeal lesions. MATERIALS AND METHODS: The study samples consisted of 63 SCC, 20 dysplasia, 7 polyp, and 5 normal epithelium of the larynx. The expression of iNOS, p53, and VEGF was identified by immunohistological methods. RESULTS: No positive immunostaining for iNOS, p53, and VEGF was observed in normal epithelium and polyps. In contrast, with the progression from mild/moderate dysplasia to severe dysplasia to carcinoma, their expression levels increased. In dysplasia, there was a significant positive correlation among expression of iNOS, p53, and VEGF. In SCC, iNOS expression correlated with VEGF overexpression and microvessel density, but not with p53 overexpression. In SCC, the expression of iNOS and VEGF significantly increased in patients who developed local recurrence and/or metastases after initial treatments. Kaplan-Meier analysis showed that disease-free survival was significantly shorter in patients with iNOS or VEGF expression. Multivariate analysis showed expression of iNOS and VEGF as independent indicators for poor disease-free survival. PMID- 17712679 TI - Recurrence in patients with oral and oropharyngeal squamous cell carcinoma: human papillomavirus and other risk factors. AB - CONCLUSIONS: The results confirm that tumour stage influences the risk of recurrence/second primary tumour (SPT). High-risk human papillomavirus (HPV) infected patients have a significantly higher risk of recurrence/SPT compared with high-risk HPV-negative patients. High alcohol consumption was associated with a higher risk of recurrence/SPT. In this study, the competing risk of death in intercurrent disease (DICD) was given special consideration. OBJECTIVES: The aim of the present study was to evaluate whether any of the factors which were found to increase the risk of oral and oropharyngeal squamous cell carcinoma (OOSCC) in previous analyses (smoking tobacco, alcohol, high-risk HPV infection, oral hygiene, missing teeth and dentures) have an influence on recurrence or the occurrence of a new SPT of OOSCC within the first 3 years following diagnosis. PATIENTS AND METHODS: One hundred and twenty-eight consecutive cases with planned curative treatment, who were part of a population-based case-control study carried out in southern Sweden between September 2000 and January 2004, were included. Only patients for whom the intention was curative treatment were eligible. The cases were followed to the first event of recurrence/SPT, death, loss to follow-up, 30 June 2005 or a maximum of 3 years. Time to the first event of recurrence/SPT was analysed by cumulative incidence, where DICD was a competing risk. Regression was performed on cause-specific hazard rates. RESULTS: After a median follow-up time of 22 months (range 0-36 months), 30 recurrences, 2 SPT, 12 lost to follow-up and 21 deaths before recurrence or SPT were observed. Tumour stage was associated with both a higher risk of recurrence/SPT and of DICD. In univariate analysis, patients with tonsillar carcinoma had a significantly higher risk of recurrence/SPT than patients with carcinoma at other sites, but there was no difference according to site in multivariate analyses. High alcohol consumption was associated with a higher risk of recurrence/SPT, but not of DICD. There was no increased risk of recurrence/SPT related to smoking, but there was an association between smoking and DICD. High-risk HPV-positive cases had a higher risk of recurrence/SPT, but a lower risk of DICD compared with high-risk HPV-negative cases. This seemingly higher risk should be interpreted by taking the competing risk of DICD into account. PMID- 17712680 TI - The incidence of tonsillar cancer in Sweden is increasing. AB - CONCLUSIONS: The incidence of tonsillar cancer in Sweden is increasing, particularly among men. Risk factors other than smoking may have contributed to the observed secular trend in men. In women, however, smoking can be a part of the explanation. Further studies to look at changes in other environmental factors, such as human papilloma virus (HPV) infection, are clearly warranted. OBJECTIVES: Head and neck cancer is related to smoking habits and smoking has decreased substantially during the last 30 years in Sweden. However, there is suspicion that the incidence of tonsillar cancer has increased in the last 30 years as it has in the USA and Finland, in spite of reduced prevalence of known risk factors. The time trends of oral and oropharygeal cancer have been studied in Sweden, but not tonsillar cancer specifically. SUBJECTS AND METHODS: We used the Swedish Cancer Registry to assess the secular trend of incidence of tonsillar cancer in Sweden since 1960. For comparison we investigated the incidence of other oral cancers and lung cancer, which are also smoking-related. The prevalence of smoking was investigated for reference. Age-standardized incidence rates were calculated and linear regression was used to evaluate secular trends. RESULTS: The incidence of tonsillar cancer increased by 2.6% per year in men and 1.1% in women. No similar increase was seen in the other oral cancers. For lung cancer there was a decrease in the incidence in men, but in women the incidence is still increasing. PMID- 17712681 TI - Primary tumours of the facial nerve: diagnostic and surgical treatment experience in Chinese PLA General Hospital. AB - CONCLUSIONS: The commonest manifestation of facial nerve tumours was facial paralysis, followed by hearing loss. During tumour resection facial nerve continuity should be maintained and reconstructed in one stage wherever possible. If this is not a viable option, second-stage surgery should be performed as soon as possible after surgery. OBJECTIVE: To summarize the clinical characteristics of tumours of the facial nerve and discuss their diagnosis and treatment. PATIENTS AND METHODS: Twenty-two cases of primary facial nerve tumours were reviewed. These cases were confirmed pathologically and treated in the Chinese PLA General Hospital during the period 1986-2003, where the clinical manifestations, diagnosis and treatment of this series were analysed. RESULTS: Among the 22 cases, 14 were facial neurilemmomas, 6 were facial neurofibromas and 2 were facial nerve haemangiomas. The commonest presenting symptom in all cases was facial paralysis (14/22) followed by hearing loss (10/22). Facial paralysis was also the commonest sign of a facial nerve tumour (18/22), followed by a swollen mass in the tympanic cavity (8/22) and a swollen mass in the external auditory canal (5/22). The 22 tumours were totally resected surgically. The function of the facial nerve was normal (grade I) in two cases where the integrity of the nerve was preserved during the operation, grade II in one case and grade III in another case where it was possible to maintain partial continuity of the facial nerve. The facial nerve was reconstructed in one stage when the tumours were resected, with facial-great auricular-facial nerve cable grafting (10 cases) and facial-lateral femoral cutaneous-facial nerve cable grafting (1 case). The facial nerve function consequently recovered to grade II IV. The second stage facial-hypoglossal nerve anastomosis was carried out in two cases, and facial function consequently recovered to grade II in one case at 3 years and grade III in another with 2 years follow-up. In five cases, the facial nerve remained discontinuous and the facial nerve function showed no recovery (grade VI). PMID- 17712682 TI - The significance of assessing the perineural vascular plexus for locating the facial nerve in microsurgery of the ear. AB - CONCLUSIONS: The perineural vascular plexus is a reliable indicator for the detection of the horizontal segment of the facial nerve in surgery for otologists and neurologists. OBJECTIVE: To evaluate the validity and reliability of the perineural vascular plexus for locating the facial nerve in microsurgery of the ear to avoid iatrogenic facial paralysis. PATIENTS AND METHODS: Our study group comprised 311 patients who underwent tympanoplasty or facial nerve decompression from July 2002 to July 2005. The validity of using the perineural vascular plexus to locate the facial nerve was observed and assessed. RESULTS: The perineural vascular plexus was well differentiated on the horizontal mesotympanic segment of the nerve in 95.8% of patients. The 95% confidence interval was 93.6-98.0%. PMID- 17712683 TI - Base of tongue neurilemmoma: excision by transoral laser microsurgery. AB - Benign and malignant tumors of the tongue base can be removed by various surgical approaches. A rare case of neurilemmoma of the base of the tongue removed by transoral laser microsurgery (TLM) is presented. Schwannomas in this area usually present as a slow-growing, painless mass on the tongue surface. In this case, fiberoptic examination and magnetic resonance imaging were crucial as first step studies to elucidate the biology of the lesion. PMID- 17712684 TI - Early diagnosis of otosclerosis: possible role of VEMPs. PMID- 17712685 TI - Is AIDS chronic or terminal? The perceptions of persons living with AIDS and their informal support partners. AB - Viewed as a terminal disease just a decade ago, HIV/AIDS is now often characterized as a chronic yet manageable disease. The goal of this study is to assess the perceptions of the course of the disease among persons living with AIDS and their informal support partners and to identify the themes that distinguish the differing perceptions of the epidemic. The findings from this research reveal that 41% of persons living with AIDS and 39% of their informal support partners perceive AIDS as chronic. By contrast, 37% of persons living with AIDS and 39% of the informal support partners perceive AIDS to be terminal rather than chronic. Among persons living with HIV/AIDS, those with lower levels of education and higher levels of perceived race-based discrimination were significantly more likely to view AIDS as a terminal rather than chronic condition. In addition, informal support partners in poor health were significantly more likely than others to view AIDS as terminal rather than chronic. Content analyses of the qualitative data revealed five broad themes related to the specific perceptions of AIDS, including medications, personal experience, cure, time/eventuality and education. The implications of these findings are discussed. PMID- 17712686 TI - Gender relations in the context of HIV/AIDS in rural South Africa. AB - As part of the Microbicides Development Programme, we conducted formative research to explore gender relations at a site in rural KwaZulu-Natal. We were interested in gender relations and in assessing their implications for emerging female initiated and controlled HIV prevention methods in the form of microbicides. Eleven focus group discussions were conducted with men and women in the community. Participants were asked about decision making about sex, family planning and the use of condoms in heterosexual relationships. Findings suggest that gender relations in the context of HIV are complex. The findings suggest that both men and women feel that the final decision about child-bearing and the use of contraceptives and rests with women since they are the ones who bear the burden of child care. This implies that it is feasible for couples to use women initiated and controlled methods of HIV prevention. PMID- 17712687 TI - To determine factors in an initiation of a same-sex relationship in rural China: using ethnographic decision model. AB - The sexual behaviour and HIV risks among Chinese MSM in rural areas are grossly under-researched. The aims of this study were to explore the process and formation as well as the factors in an initiation of sexual relationship or act in among MSM in this cultural setting. Twenty-four in-depth interviews and observation were conducted in Dali prefecture in two field visits in 2004 and the data were analysed using grounded theory and an ethnographic decision model. We found their sexual relationship can be understood as a negotiation process with self, family and society, some of which (e.g. emotional and physical needs; rationalization in choosing partners) are common in all MSM groups while others (e.g. sex hierarchy or role of family) are geographically and culturally more unique or prominent for rural China. By better understanding of these decision processes, more effective and target-orientated intervention programmes can be implemented fighting against HIV/AIDS in this sexually marginalized sub-group of the population. PMID- 17712688 TI - The social epidemiology of HIV transmission among African American women who use drugs and their social network members. AB - Despite 15 years of prevention efforts, recent increases in HIV infection have been documented for Black women in the US. Little is known about the role played by HIV status disclosure in high HIV prevalence communities. 180 Black women who used drugs in the past 30 days were recruited between May 2002 and May 2004 in New York City. Women were administered a structured network questionnaire and HIV serotested. Risk practices, HIV status disclosure within networks and mixing patterns by known HIV status are examined. Most (85%) women had used crack in the past 30 days; 48 (27%) had injected drugs, 65 (36%) reported anal sex, and 99 (55%) reported sex work at some time. Forty (22%) women were HIV-seropositive; 29 (16%) knew their seropositive status. Of high risk individual behaviours, only a history of sex work was associated with an HIV-seropositive status [(aOR=3.0; 95%CI: 1.3-7.3), p=.01]. Few (7%) of 600 network members disclosed an HIV positive status, although 73% were sex or drug use partners. Women who knew themselves to be HIV-infected were more likely than other women to report HIV infected network members [(OR=1.5; 95%CI: 1.1-6.4), p=.03]. However, only 51% of network members disclosed an HIV status and women disclosed to 50% of their network members. In a context of high background HIV prevalence and low levels of HIV status disclosure, serodiscordant mixing patterns likely facilitate transmission. PMID- 17712689 TI - Coping with AIDS-related bereavement in KwaZulu-Natal, South Africa. AB - This qualitative study explored how South Africans view and cope with AIDS related loss. In-depth interviews were conducted with a purposive sample of 18 bereaved adults living in KwaZulu-Natal, a province that has been severely impacted by the HIV/AIDS epidemic. Data were analysed according to the conventions of qualitative research. Participants felt quite powerless and accepted AIDS-related deaths as a part of their life. They tried to reframe their loss as something positive; constructing meaning from their loss. Coping strategies included: suppressing emotions; seeking comfort and strength from one's spiritual beliefs; and maintaining an optimistic attitude about the future. These themes are consistent with research on coping with AIDS-related bereavement in the West. Further research is needed to confirm these themes in the South African context using culturally appropriate measures. Future interventions must be tailored to the local context and must take into consideration the limited availability of funds for mental health services in South Africa. PMID- 17712690 TI - Local understanding of an HIV vaccine and its relationship with HIV-related stigma in the Dominican Republic. AB - The purpose of this study was to explore local perceptions and experiences regarding vaccines in general and HIV vaccines and vaccine trials in the Dominican Republic. In-depth interviews were carried out with 25 participants representing two study groups: (1) individuals considered at high risk for HIV infection including female sex workers and male STI clinic attendees and (2) individuals considered at low risk of HIV infection including women and men recruited at a general outpatient clinic. Across the groups, participants often characterized vaccines in general as having both preventive and curative properties. In turn, one of the most salient concerns regarding the receipt of an HIV vaccine was the fear that one would be labelled 'HIV positive' and stigmatized, as the vaccine may be perceived as a cure for those already infected. These findings suggest the importance of individual and community level education to clarify the nature and mechanisms of the given HIV vaccine being tested. Social support and counselling services should also accompany HIV vaccine trials and distribution plans to assist individuals in determining if and how they communicate their participation and/or receipt of an HIV vaccine to others and manage potential negative social reactions. PMID- 17712691 TI - Health-seeking behaviour for sexually transmitted infections and HIV testing among female sex workers in Vietnam. AB - This qualitative study was conducted to explore health-seeking behaviour for sexually transmitted infections (STIs) and HIV testing among female sex workers (FSWs) in the cities of Hanoi and Da Nang, Vietnam. Data were gathered from in depth interviews, focus groups and participant observation. Results suggest that women's decision to seek STI treatment and HIV testing is influenced by the complex interplay of personal risk perceptions, social relationships and community discourse. The women exhibited adequate knowledge of HIV while their knowledge of STIs was limited. They demonstrated high-risk perceptions of HIV, but they showed little concern for STIs. Most women sought treatment at pharmacies when they noticed symptoms of the genital tract. Their decision to seek care in health facilities and HIV testing was hampered by the high costs of treatment, judgmental attitudes of service providers, and a lack of information on testing services. Future interventions need to focus on strengthening knowledge of STIs and the STI-HIV association, and increasing awareness of HIV counselling and testing services. Training for STI service providers including pharmacies and private practitioners on sex-worker friendly and non-judgmental services and counselling skills should be emphasized to provide timely diagnosis and treatment of STIs, and to refer women to HIV testing. PMID- 17712692 TI - Knowledge and attitudes of nursing students toward patients living with HIV/AIDS (PLHIV): a Turkish perspective. AB - The aim of this study was to assess the knowledge and attitudes towards HIV/AIDS of nursing students in Turkey. HIV/AIDS has become one of the most serious health problems in the world. It is important to understand nursing students' knowledge and attitudes towards people living with HIV (PLHIV) because the educational preparation of nurses has been known to affect the attitudes of the nurse and the effectiveness of the care provided to PLHIV. The study was conducted with 227 nursing students from the School of Health in Antalya, Turkey during the calendar year 2005/2006. Qualitative and quantitative methods were both used to collect data for the study. Analysis of variance, t-test, Mann-Whitney U-test, Kruskal Wallis and inductive methods were used in data analysis. The majority of nursing students in this study had a moderate level of HIV/AIDS knowledge. Students correctly answered 64.4% of HIV/AIDS-related questions in the questionnaire (Mean 28.99; SD 7.03 out of 45 points). Scores increased parallel with student grade (F=26.925; p=0.000) and age (chi2 (K-W)=35.117; p=0.000). Fear of being infected and feelings of pity and empathy were the feelings most commonly indicated by the students. Students who had previous experience in caring for an AIDS patient and had known someone with HIV/AIDS were willing to care for PLHIV. Results underline the need to strengthen education on all aspects of HIV/AIDS. To improve nursing students willingness to care for PLHIV, particular emphasis should be placed on the training of nursing students as skilled nursing staff with humane attitudes towards PLHIV. PMID- 17712693 TI - Using the theory of planned behaviour to understand the motivation to learn about HIV/AIDS prevention among adolescents in Tigray, Ethiopia. AB - Various studies indicate that school- or university-based HIV prevention curricula can reduce the prevalence of sexual risk behaviour among adolescent youth in Sub-Saharan Africa. However, effective HIV/AIDS prevention education may be problematic, if the needs of youth are not served adequately. To date, little attention has been given to the motivation of youth to learn about HIV/AIDS and about their preferences for HIV/AIDS curriculum design options. The aim of this study was to get insight into the determinants of the motivation of youth to learn about HIV/AIDS prevention and to assess their curriculum design preferences. Students from a university in Tigray, Ethiopia, filled out a structured questionnaire, which assessed demographics, variables that according to the Theory of Planned Behaviour are related to the motivation to learn, and their preferences for independent, carrier and integrated HIV/AIDS curriculum designs. On average, participants were highly motivated to learn about HIV/AIDS. Motivation to learn was primarily related to social norms and was not related to self-efficacy to discuss HIV/AIDS in class. The often discussed reluctance to discuss sexuality and condom use in curricula in Sub-Saharan Africa, seems to be more related to existing negative social norms, than to lack of self-efficacy. Participants revealed a high preference for the independent, carrier and integrated curriculum design options. However, students with a higher motivation to learn about HIV/AIDS were more attracted to the independent course design. PMID- 17712694 TI - HIV-related traumatic stress symptoms in AIDS caregiving family dyads. AB - This study assesses HIV-related traumatic stress symptoms in 135 AIDS caregiving family dyads in which the caregiver is a midlife or older mother or wife, and the care-recipient is her HIV-infected adult son or husband. Symptoms of HIV-related traumatic stress can be reliably measured in these dyads, with both caregivers and care-recipients reporting avoidant and intrusive thoughts. Among care recipients, high symptoms are associated with high daily living assistance requirements, low dyadic adjustment, and high constriction of social activities. Among caregivers, high symptoms of traumatic stress are associated with being HIV positive, feeling overloaded by caregiving demands, and perceiving high levels of HIV stigma. Caregiving mothers and wives may feel traumatized 'courtesy' of their loved one's HIV infection, the caregiving scenario, or the resultant caregiving stress. PMID- 17712695 TI - Care centre visits to married people living with HIV: an indicator for measuring AIDS-related stigma & discrimination. AB - We tested whether observation of the presence and relationship of attendants (i.e. those that accompany upon admission) and visitors to a sample of 230 (128 male, 102 female) married HIV-positive people in an HIV care centre provides an indicator of caregiving, AIDS-related stigma and discrimination. Sensitivity to gender, location (urban vs. rural), age (<35 yrs vs. >35) and source of infection (spouse vs. non-spouse) were factors considered to modulate AIDS-related stigma and assess discrimination. HIV-positive people were accompanied by their spouse (53%), mother (14%), father (7%), with only 7% attending alone. Immediate family most commonly accompanied on admission (80%), but visitors were mainly from the 'extended' family (32%) with many receiving no visitors (48%). Females (11%) were more likely than males to attend alone (11% vs. 4%; p<0.05). No effect of location, age or infector was obtained. Females were more likely to be visited by their mother (14% vs. 6%; p<0.01) and non-immediate family (39% vs. 27%; p<0.05) than males were. In contrast, fathers (0% vs. 6%; p <0.05) and spouses were less likely (3% vs. 10%; p<0.05) to visit females than males. No effect of location or age upon visitation was obtained. Non-spouse infected persons were less likely than spouse-infected to be visited by their spouse (3% vs. 10%; p<0.05) but more likely to receive 'extended' family visitation (43% vs. 24%; p<0.01). Spouse infected persons had a higher rate of no visitors than persons not infected by their spouse (54% vs. 40%; p<0.05). Observation of the presence and relationship of attendants and visitors to HIV-positive people has potential as an indicator of caregiving AIDS-related stigma and discrimination. The measure appears particularly sensitive to the gender of the HIV-positive person. Such a measure may aid healthcare professionals to focus resources such as relational counselling upon the family and close friends of people experiencing AIDS-related stigma and discrimination, with the aim of improving the provision of care within the community. PMID- 17712696 TI - Comprehension of sexual situations and its relationship to risky decisions by young adults. AB - This research examines the nature of the relationship between comprehension of sexual situations and decisions about risky sexual behaviour by young adults. Participants were 56 heterosexual students from Brooklyn College, NY, located in a community with a relatively high prevalence of HIV/AIDS. They read a sexual encounter scenario and verbally responded to open-ended questions and made decisions about condom use. The responses were recorded, transcribed and analysed. Prior beliefs were evaluated based on participants' initial responses to the scenario. High and low risk individuals showed a specific set of beliefs about safer sex practices, and they processed information differently during comprehension of the sexual situation. Low-risk individuals focused on cues that show "risks of unprotected sex", with the goal of not taking any risks. High-risk individuals processed given information as emotionally related, with the goal of 'immediate pleasure' in the situation. These processing variables influenced the young adults' decisions to practice (or not) safer sex behaviour. Educational interventions need to be tailored for different patterns of behaviour. The goal of a customization approach is to intervene at appropriate weak links in the decision-making process, including any contradictory or unjustified beliefs, to promote safer sex behaviour. PMID- 17712697 TI - Quality of life in HIV-positive Brazilians: application and validation of the WHOQOL-HIV, Brazilian version. AB - The importance of Quality of Life (QOL) evaluation is a recognized outcome in HIV related studies. The objective of this study was to test the psychometric properties of the Brazilian version of the WHOQOL-HIV. The QOL of 308 HIV infected men and women was assessed in the different HIV disease severity stages. Women, younger (<35 years) and married patients were associated with a lower QOL. Psychometric properties of the Brazilian version of WHOQOL-HIV were evaluated: reliability, construct validity, discriminant and concurrent validity. Cronbach alpha was above 0.70 in 27 of the 31 facets of the WHOQOL-HIV and ranged between 0.32 and 0.65 in the remaining four facets. Better QOL scores occurred in early stages of the infection (asymptomatic and symptomatic groups) while the AIDS group showed worse scores in all domains of WHOQOL-HIV, with statistically significant differences in early stages. The correlation between the domains and overall QOL was statistically significant (r>0.5; p<0.01). The Brazilian version of the WHOQOL-HIV adequately discriminated between the QOL of individuals in the different stages of HIV infection, in the expected direction and demonstrated satisfactory reliability and concurrent validity in this study. It would appear to be a useful tool to assess the subjective QOL in people living with HIV and AIDS. PMID- 17712698 TI - Sex work and risk behaviour among HIV-negative gay men. AB - Gay men who engage in sex work may be at increased risk through risk behaviour outside the context of sex work. Among participants in the Health in Men (HIM) cohort of HIV-seronegative gay men in Sydney, 19.7% had ever engaged in sex work. Five percent reported being paid for sex in a six-month period during the study (2001-2006); a minority (18.3%) of these current sex workers reported unprotected anal intercourse (UAI) with clients and 62.0% reported UAI with any casual partners. The practice of sex work itself may not represent increased risk for HIV transmission but sex workers in this study were, nonetheless, at markedly increased risk in other aspects of their lives. PMID- 17712699 TI - Return to post-test counselling by out-of-treatment injecting drug users participating in a cross-sectional survey in north Vietnam. AB - Return to post-test counselling is essential for optimal individual and public health impact of voluntary counselling and testing (VCT) services. Our study assessed factors associated with return to post-test counselling among 309 out-of treatment injecting drug users who underwent VCT as part of a cross-sectional survey in Bac Ninh, Vietnam during August and September 2003. The overall return rate to post-test counselling was 54% (n=167). While participants in the rural study district were significantly less likely (chi2=5.8; p<0.05) to return compared with participants in the town centre (42.7 versus 58.1%), return rates did not significantly vary by age, perception of personal HIV risk, HIV serostatus diagnosed by the study, counsellor, history of HIV testing or prior knowledge of HIV status. In a multivariate analysis, higher return rate was associated with residence in Bac Ninh town centre (adjusted OR=1.9; CI=1.1-3.1). Of HIV-positive participants (n=131), 45% (n=59) did not return to collect test results. In view of the findings it is crucial to address risk perception and benefits of collecting test results during pre-test counselling sessions in order to maximize the desired impact of community-based VCT services targeting IDUs in Vietnam. PMID- 17712700 TI - Characteristics of bisexually active men in the Seropositive Urban Mens' Study (SUMS). AB - Characteristics of bisexually-active men were compared with those of their homosexually-active counterparts in a study of HIV-seropositive men who have sex with men (MSM). Men who had had sex with women in the prior year were younger and more likely to be African American than those reporting sex only with men. They reported higher levels of internalised homophobia and less participation in the gay community. They tended to be recruited through friend referral rather than public sex environments or AIDS service organisations. However, they did not seek sex partners from different venues than other participants. Implications for HIV transmission risk-reduction interventions for this population are discussed. PMID- 17712705 TI - The well-being of subjects and other parties in genetic research and testing. PMID- 17712706 TI - Grappling with groups: protecting collective interests in biomedical research. AB - Strategies for protecting historically disadvantaged groups have been extensively debated in the context of genetic variation research, making this a useful starting point in examining the protection of social groups from harm resulting from biomedical research. We analyze research practices developed in response to concerns about the involvement of indigenous communities in studies of genetic variation and consider their potential application in other contexts. We highlight several conceptual ambiguities and practical challenges associated with the protection of group interests and argue that protectionist strategies developed in the context of genetic research will not be easily adapted to other types of research in which social groups are placed at risk. We suggest that it is this set of conceptual and practical issues that philosophers, ethicists, and others should focus on in their efforts to protect identifiable social groups from harm resulting from biomedical research. PMID- 17712707 TI - Understanding risks and benefits in research on reproductive genetic technologies. AB - Research protocols must have a reasonable balance of risks and anticipated benefits to be ethically and legally acceptable. This article explores three characteristics of research on reproductive genetic technologies that complicate the assessment of the risk-benefit ratio for such research. First, a number of different people may be affected by a research protocol, raising the question of who should be considered to be the subject of reproductive genetic research. Second, such research could involve a wide range of possible harms and benefits, making the evaluation and comparison of those harms and benefits a challenging task. Finally, the risk-benefit ratio for this type of research is difficult to estimate because such research can have unpredictable, long-term implications. The article aims to facilitate the assessment of risk-benefit ratios in research on reproductive genetic technologies by proposing and defending some guidelines for dealing with each of these complicating factors. PMID- 17712708 TI - The changing face of "misidentified paternity". AB - Advances in genetic research and technology can have a profound impact on identity and family dynamics when genetic findings disrupt deeply held assumptions about the nuclear family. Ancestry tracing and paternity testing present parallel risks and opportunities. As these latter uses are now available over the internet directly to the consumer, bypassing the genetic counselor, consumers need adequate warning when making use of these new modalities. PMID- 17712709 TI - Using the Best Interests Standard to decide whether to test children for untreatable, late-onset genetic diseases. AB - A new analysis of the Best Interests Standard is given and applied to the controversy about testing children for untreatable, severe late-onset genetic diseases, such as Huntington's disease or Alzheimer's disease. A professional consensus recommends against such predictive testing, because it is not in children's best interest. Critics disagree. The Best Interests Standard can be a powerful way to resolve such disputes. This paper begins by analyzing its meaning into three necessary and jointly sufficient conditions showing it: 1. is an "umbrella" standard, used differently in different contexts, 2. has objective and subjective features, 3. is more than people's intuitions about how to rank potential benefits and risks in deciding for others but also includes evidence, established rights, duties and thresholds of acceptable care, and 4. can have different professional, medical, moral and legal uses, as in this dispute. Using this standard, support is given for the professional consensus based on concerns about discrimination, analogies to adult choices, consistency with clinical judgments for adults, and desires to preserve of an open future for children. Support is also given for parents' legal authority to decide what genetic tests to do. PMID- 17712711 TI - Linking children's neuropsychological processing of emotion with their knowledge of emotion expression regulation. AB - Understanding of emotions has been shown to develop between the ages of 4 and 10 years; however, individual differences exist in this development. While previous research has typically examined these differences in terms of developmental and/or social factors, little research has considered the possible impact of neuropsychological development on the behavioural understanding of emotions. Emotion processing tends to be lateralised to the right hemisphere of the brain in adults, yet this pattern is not as evident in children until around the age of 10 years. In this study 136 children between 5 and 10 years were given both behavioural and neuropsychological tests of emotion processing. The behavioural task examined expression regulation knowledge (ERK) for prosocial and self presentational hypothetical interactions. The chimeric faces test was given as a measure of lateralisation for processing positive facial emotion. An interaction between age and lateralisation for emotion processing was predictive of children's ERK for only the self-presentational interactions. The relationships between children's ERK and lateralisation for emotion processing changes across the three age groups, emerging as a positive relationship in the 10-year-olds. The 10-years-olds who were more lateralised to the right hemisphere for emotion processing tended to show greater understanding of the need for regulating negative emotions during interactions that would have a self-presentational motivation. This finding suggests an association between the behavioural and neuropsychological development of emotion processing. PMID- 17712712 TI - Evolution of hemispheric specialisation of antagonistic systems of management of the body's energy resources. AB - Excellent and rich reviews of lateralised behaviour in animals have recently been published indexing renewed interest in biological theorising about hemispheric specialisation and yielding rich theory. The present review proposes a new account of the evolution of hemispheric specialisation, a primitive system of "management of the body's energy resources". This model is distinct from traditionally evoked cognitive science categories such as verbal/spatial, analytic/holistic, etc., or the current dominant neuroethological model proposing that the key is approach/avoidance behaviour. Specifically, I show that autonomic, immune, psychomotor, motivational, perceptual, and memory systems are similarly and coherently specialised in the brain hemispheres in rodents and man. This energy resource management model, extended to human neuropsychology, is termed here the "psychic tonus" model of hemispheric specialisation. PMID- 17712713 TI - Fixation and attention control in lateralised target detection and free recall with words. AB - The purpose of the present study was to test the hypothesis that lateralised target detection in the visual modality would produce results similar in magnitude, reliability, and validity to those obtained in the auditory modality with an analogue task. Thus, it was expected that it would produce laterality effects that are larger, more reliable, and more valid than those obtained in a free recall task. The claim that target detection provides its own attention control also led to the hypothesis that the magnitude of laterality effects should be affected by fixation control in free recall but not target detection. A total of 349 right-handed participants completed a word recognition task with either free recall or target detection with or without fixation control. Only the finding that free recall was generally more reliable than target detection went contrary to the hypotheses. This finding is interpreted as reflecting a consistent attentional bias that stems from task requirements. In general, the results suggest that target detection without fixation control has much potential as a measure of perceptual asymmetries in the visual modality. PMID- 17712714 TI - A note on motor laterality in plains zebras (Equus burchellii) and impalas (Aepyceros melampus). AB - This observational field study used intermittent still photography to examine the distribution of motor laterality in images of two African grazing quadruped species: plains zebras (Equus burchellii) and impalas (Aepyceros melampus). Zebra images (n=708) had a laterality index of -6.21 and a Z-score of -1.65 (p=.098). Impala images (n=318) had a laterality index of -18.87 and a Z-score of -3.36 (p=.0008). The weak left motor bias in zebras aligns with that reported in domestic horses using a related method. PMID- 17712715 TI - A note on asymmetric use of the forelimbs during feeding in the European green toad (Bufo viridis). AB - European green toads (Bufo viridis) were tested for one-sided forelimb lateralisation during prey ingestion, i.e., when pushing food into the mouth. Results showed that toads preferentially used their left forelimb to help themselves in the ingestion of living larvae. It is argued that previous failure to reveal lateralisation in tests in which B. viridis toads wiped a foreign object off their snout was due to prevalent activation of grooming behaviour; in contrast, lateralisation seems clear when specifically associated with feeding behaviour. PMID- 17712716 TI - Asymmetry of flight and escape turning responses in horses. AB - We investigated whether horses display greater reactivity to a novel stimulus presented in the left compared to the right monocular visual field, and whether a population bias exists for escape turning when the same stimulus was presented binocularly. Domestic horses (N=30) were tested on three occasions by a person opening an umbrella five metres away and then approaching. The distance each horse moved away before stopping was measured. Distance was greatest for approach on the left side, indicating right hemisphere control of flight behaviour, and thus followed the same pattern found previously in other species. When order of monocular presentation was considered, an asymmetry was detected. Horses tested initially on the left side exhibited greater reactivity for left approach, whereas horses tested on the right side first displayed no side difference in reactivity. Perhaps left hemisphere inhibition of flight response allowed horses to learn that the stimulus posed no threat and this information was transferred to the right hemisphere. No population bias existed for the direction of escape turning, but horses that turned to the right when approached from the front were found to exhibit longer flight distances than those that turned to the left. PMID- 17712717 TI - MTHFR C677T polymorphism and osteoporotic fractures. AB - The C677T (rs1801133) polymorphism of MTHFR (methylenetetrahydrofolate reductase) has been associated with the risk of cardiovascular events, and also with osteoporosis in some studies. However, the results are controversial. Our objective was to determine the relationship of the polymorphism with osteoporotic fractures by means of a case-control study. C677T was analyzed in 823 subjects (365 controls, 136 with vertebral fractures and 322 with hip fracture) by using a Taqman assay. The distribution of MTHFR genotypes was similar in patients and controls. In comparison with TC/CC genotypes, the age-adjusted OR for hip fractures of the TT genotype was 1.0 (95% confidence interval 0.6-1.7) in women and 0.7 (0.3-1.8) in men. The OR for vertebral fractures was 0.8 (0.4-1.7) in women and 1.7 (0.4-6.7) in men. A meta-analysis combining these data with previous reports confirmed the lack of association between MTHFR and fractures, with an OR of 1.1 (0.7-1.9, p=0.65) for vertebral fractures and 1.2 (0.7-2.0; p=0.45) for peripheral fractures, but there was significant heterogeneity among the results of individual studies, particularly about peripheral fractures. In conclusion, the C677T polymorphism of the MTHFR gene does not appear to be associated with the overall risk of osteoporotic fractures. However, given the heterogeneity of the results of published studies, further investigations are needed to evaluate its influence in specific population subgroups. PMID- 17712718 TI - Quantitative real-time PCR for the measurement of 11beta-HSD1 and 11beta-HSD2 mRNA levels in tissues of healthy dogs. AB - The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) exists in two isoforms, 11beta-HSD1 and 11beta-HSD2. 11beta-HSD1 generates active cortisol from cortisone and appears to be involved in insulin resistant states. 11beta-HSD2 protects the mineralocorticoid receptor from inappropriate activation by glucocorticoids and is important to prevent sodium retention and hypertension. The purposes of the present study were to develop two real-time PCR assays to assess 11beta-HSD1 and 11beta-HSD2 mRNA expression and to evaluate the tissue distribution of the two isoforms in dogs. Thirteen different tissues of 10 healthy dogs were evaluated. Both real-time PCR assays were highly specific, sensitive and reproducible. Highest 11beta-HSD1 mRNA expression was seen in liver, lung, and renal medulla; highest 11beta-HSD2 mRNA expression in renal cortex, adrenal gland, and renal medulla. Higher 11beta-HSD1 than 11beta-HSD2 mRNA levels were found in all tissues except adrenal gland, colon, and rectum. Our results demonstrate that the basic tissue distribution of 11beta-HSD1 and 11beta-HSD2 in dogs corresponds to that in humans and rodents. In a next step 11beta-HSD1 and 11beta-HSD2 expression should be assessed in diseases like obesity, hypercortisolism, and hypertension to improve our knowledge about 11beta-HSD activity, to evaluate the dog as a model for humans and to potentially find new therapeutic options. PMID- 17712719 TI - Effect of immunosuppressive and other drugs on the cortisol-cortisone shuttle in human kidney and liver. AB - BACKGROUND: Impaired 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) has been suggested in patients with hypertension or renal disease, where it may contribute to sodium retention and hypertension. 11beta-HSD1, which is expressed predominantly in liver and adipose tissue, influences glucose homeostasis and fat distribution by altering intracellular cortisol (F) concentrations. We tested immunosuppressive drugs that cause hypertension, and substances that interfere with steroidogenesis or influence glucose homeostasis for their ability to influence the inhibition of 11beta-HSD isozymes. METHODS: For inhibition experiments, we used microsomes prepared from unaffected parts of human liver segments and resected human kidney cortex because of hepatocarcinoma or renal cell cancer. The inhibitory potency of several compounds was evaluated in concentrations from 10(-9)-10(-5) mol/l. RESULTS: Only sirolimus, but not cyclosporine A, tacrolimus, mycophenolate mofetil, or azathioprine showed a slight inhibition of 11beta-HSD2 activity. None of the drugs that inhibit steroidogenesis (suramine, mitotane, etomidate, and aminogluthethimide) or steroid metabolism (rifampicine) influenced 11beta-HSDs, nor did ginsenoides Re, Rc, and Rb1. Among sulfonylureas, only gliclazide decreased significantly 11beta HSD1 activity. CONCLUSIONS: Increased blood pressure due to immunosuppressive drugs is probably not caused by direct inhibition of 11beta-HSD2. An additional glucose lowering effect of sulfonylurea gliclazide may be due to its ability to inhibit 11beta-HSD1. PMID- 17712720 TI - Regulation of human MC2-R gene expression by CREB, CREM, and ICER in the adrenocortical cell line Y1. AB - The MC2-Receptor (melanocortin 2 receptor, MC2-R) is a Gs-protein coupled receptor that is upregulated by its own ligand ACTH and by forskolin. The mechanisms regulating MC2-R expression are still unclear. We therefore investigated the role of the stimulatory transcription factors CREB and CREM and the inhibitory factor ICER for regulation of human MC2-R expression. We cotransfected mouse adrenocortical Y1 cells with luciferase reporter gene vectors containing full length and deleted human MC2-R promoter constructs with expression plasmids for CREB, CREBS133A, CREMtau, CREMtauS117A, or ICER. Direct protein-DNA interaction was investigated by EMSA. Wild type CREB did not significantly affect promoter activity due to high endogenous CREB activity. However, CREBS133A decreased forskolin stimulated MC2-R promoter activity by 48+/ 5% (mean+/-SEM) while unstimulated values remained unchanged. CREMtau moderately increased basal and forskolin stimulated luciferase activity in a dose-dependent manner (maximum effect 252+/-24% and 186+/-13% VS. control vector, respectively). While this effect required the full length promoter, cAMP stimulation was retained in shorter constructs. ICER reduced basal luciferase activity in Y1 cells by 17+/-28%, but completely abolished forskolin stimulation. Although 5' deletion constructs mapped the minimum promoter region required for ICER effect to the shortest -64/+40 construct, direct protein DNA interaction in this promoter region could not be identified by EMSA. Moreover, mutation of the SF-1 binding sites, which retained ICER dependent inhibition, excluded SF-1 to be required for this effect. We conclude from these data that transcription factors of the CREB/CREM/ATF family have a moderate effect on human MC2-R promoter activity, but seem to play a minor role in transmitting stimulation of the cAMP pathway to increased MC2-R expression. PMID- 17712721 TI - Circadian and age-dependent expression patterns of GLUT2 and glucokinase in the pancreatic beta-cell of diabetic and nondiabetic rats. AB - Alterations in glucose sensing are well-known in both humans and animal models of non-insulin-dependent diabetes mellitus. However, the circadian- and age dependent expression of glucose-sensing genes has not previously been investigated in vivo. In the present paper, we show a progressive loss of beta cell GLUT2-mRNA and, by immunocytochemistry, a gain of soluble, cytoplasmic GLUT2 protein in Goto-Kakizaki rat islets. We report that GLUT2-mRNA shows significant diurnal variation, which is stronger in metabolically healthy rats. We also demonstrate the significant diurnal variation of glucokinase-mRNA, with higher levels in the pancreas of 6-week-old Goto-Kakizaki rats than in Wistar rats. This leads to a maximum glucose phosphorylation capacity in-phase with food intake, enhanced glucose-stimulated insulin secretion, and prevents postprandial hyperglycemia. Perfusion experiments showed a reduction in glucose-stimulated insulin secretion in Goto-Kakizaki rat islets with an impaired first phase. Hyperglycemia and hypoinsulinemia in newborn and up to 3-week-old Goto-Kakizaki rats are thus probably due to reduced pancreatic beta-cell content, reduced beta cell insulin content and impaired glucose sensing. The de-compensation of the metabolic situation in 42-week-old Goto-Kakizaki rats is likely to be caused by beta-cell destruction accompanied by negligible accumulation of GLUT2 in the cell membrane and further reduction of glucokinase expression. PMID- 17712722 TI - Discoidin domain receptor 2 impairs insulin-stimulated insulin receptor substrate 1 tyrosine phosphorylation and glucose uptake in 3T3-L1 adipocytes. AB - Differentiation of preadipocytes into functional adipocytes depends on early proliferative events (mitotic clonal expansion) and extracellular matrix interactions. We report that discoidin domain receptor (DDR) 2, a novel adhesion receptor, is expressed in 3T3-L1 preadipocytes and is downregulated during the early phase of adipogenesis. DDR2 overexpression (DDR2-L1 preadipocytes) reduced subconfluent proliferation by 56% (p<0.001) and insulin-stimulated tyrosine phosphorylation of insulin receptor substrate (IRS)-1 by 34% (p<0.05). The mitotic clonal expansion phase of differentiating confluent DDR2-L1 preadipocytes was impaired by approximately 25% (p<0.05). Although induction of peroxisome proliferator-activated receptor gamma, fatty acid synthase, and adiponectin was not altered, the resulting adipocytes were 55% larger (p<0.05), and contained 66% more triacylglycerol (p<0.01). The induction of CCAAT/enhancer binding protein alpha was reduced by 37% (p<0.05), correlating with a similar reduction in insulin-stimulated IRS-1 tyrosine phosphorylation and glucose transport in DDR2 L1 adipocytes (decreases of 22% and 27%, respectively; p<0.05 for both). Our data show that DDR2 is expressed in adipose cells and that its overexpression leads to insulin resistance. PMID- 17712723 TI - The administration of oleoyl-estrone to lactating dams induces selective changes in the normal growth pattern of their pups. AB - To determine the effects of oleoyl-estrone treatment on the lactating dams and on the growth pattern of developing rats, female Wistar rats were randomly divided into two groups after delivery. One group received a daily gavage of 0.2 mL sunflower oil containing 10 micromol oleoyl-estrone/kg (treated group) and the other received a daily intragastric gavage of 0.2 mL sunflower oil (control group). Treatment was carried out during the first 15 days of lactation. Dams were killed on days 1, 15 or 20 after delivery and pups were sacrificed on days 1, 15, 20 or 30. Treated dams showed a transient decrease in food intake, significant lower lipid content than control dams, with a parallel maintenance of protein content and no appreciative changes in plasmatic parameters. However, a significant increase in brown adipose tissue mass was detected in treated group. Pups from treated dams showed a decrease in their growth rate that was reflected in the lower adipose tissue mass in different locations, except in the case of brown adipose tissue and, that continued after cessation of treatment. Thus, treatment affects dams in a selective way that does not coincide with a simple food restriction model. PMID- 17712724 TI - Plasma galanin, vasopressin, and oxytocin in patients with Addison's disease. AB - Galanin is colocalized with adrenocorticotrophin (ACTH) in the human pituitary and with corticotrophin releasing hormone, arginine, vasopressin, and oxytocin in the hypothalamus. Galanin, vasopressin, and oxytocin influence the secretion of pituitary ACTH. The aim of this study was to investigate if the endogenous stimulation of ACTH release in Addison's disease was reflected in plasma galanin, vasopressin, and oxytocin. ACTH, galanin, vasopressin, and oxytocin were measured in plasma from 14 patients with Addison's disease, one patient with Nelson's syndrome, and 14 healthy controls. Eight patients had elevated plasma ACTH whereas six patients and all controls had ACTH levels within the reference-range. There was no difference in galanin or vasopressin between patients and controls or between samples with low or high ACTH concentrations. In contrast, oxytocin was higher in patients with elevated plasma ACTH compared to patients and controls with normal or low ACTH. No relation was found between galanin or oxytocin and age or sex. A tendency towards lower vasopressin with increasing age was found among the men (p=0.057). The highest ACTH and galanin levels were found in the patient with Nelson's syndrome. In conclusion, increased plasma ACTH was not reflected in elevated plasma galanin or vasopressin. In contrast, elevated ACTH levels were accompanied by higher oxytocin levels. PMID- 17712725 TI - Immune-mediated activation of the endocannabinoid system in visceral adipose tissue in obesity. AB - The aim of the study was to investigate if the endocannabinoid system (ECS) is activated in visceral adipose tissue and if adipose tissue inflammation affects the ECS activation state. Therefore, expression of fatty acid amide hydrolase (FAAH), cannabinoid receptor 1 (Cb1), adiponectin, and tumor necrosis factor (TNF)-alpha was compared in visceral adipose tissue from 10 normal-weight (BMI 24.4+/-1.1 kg/m2) and 11 obese subjects (BMI 37.6+/-13.6 kg/m2) using quantitative RT-PCR, and gene expression changes were analyzed after in vitro stimulation of visceral adipose tissue with TNF-alpha. The data demonstrate that the ECS is activated in obese visceral adipose tissue as shown by decreased FAAH, Cb1, and adiponectin expression. Obesity-related ECS activation is accompanied by elevated expression of the pro-inflammatory cytokine TNF-alpha, which in turn stimulates ECS activation in vitro. Our data show a strong association between adipose tissue inflammation and ECS activation in obesity, and indicate that a pro-inflammatory state may directly activate the ECS. PMID- 17712727 TI - The relationship of serum lipoprotein lipase mass with fasting serum apolipoprotein B-48 and remnant-like particle triglycerides in type 2 diabetic patients. AB - BACKGROUND: There have been no previous reports showing specifically the relation between lipoprotein lipase (LPL) and apolipoprotein (apo) B-48 or remnant metabolism. In this study, we have clarified the relationships of LPL mass in pre heparin with serum apo B-48 measured by enzyme-linked immunosorbent assay, triglycerides (TG), and remnant-like particle triglycerides (RLP-TG). MATERIAL AND METHODS: Seventy-nine type 2 diabetic subjects [age, 55+/-13; body mass index (BMI), 25+/-5.0 kg/m2; fasting plasma glucose (FPG), 7.39+/-2.22 mmol/l, HbA1c, 6.5+/-1.3%, total cholesterol (TC), 5.36+/-1.09 mmol/l, TG, 2.32+/-2.53 mmol/l; HDL-C, 1.22+/-0.44 mmol/l; serum LPL mass, 45+/-22 ng/ml; apo B-48, 6.6+/-6.3 microg/ml] were recruited in this study. Fasting serum apo B-48 were measured by ELISA using anti-human apo B-48 monoclonal antibodies (MoAb) and LPL mass by ELISA using anti-bovine milk LPL MoAb. RLP-TG levels were measured using monoclonal antibodies to apo B-100 and apo A-1. RESULTS: There was no relationship of LPL mass to age, BMI, FPG, and HbA1c. Serum LPL mass was correlated inversely with TG (r=-0.529 p<0.0001) and positively with HDL-C (r=0.576, p<0.0001). Also, LPL mass showed inverse correlations with apo B-48 (r= 0.383 p<0.0001) and RLP-TG (r=-0.422 p<0.0001, n=51). Multiple regression analysis with TG, apo B-48, or RLP-TG as dependent variables, and age, gender, BMI, plasma glucose, and LPL mass as independent variables showed that LPL mass was associated independently with TG, apo B-48, or RLP-TG. CONCLUSION: The decrease in LPL protein mass could cause an increase in serum apo B-48 and RLP-TG levels, which is related to the retardation of remnant metabolism. PMID- 17712726 TI - The satiety factor apolipoprotein A-IV modulates intestinal epithelial permeability through its interaction with alpha-catenin: implications for inflammatory bowel diseases. AB - INTRODUCTION: Apolipoprotein A-IV (apoA-IV), an intestinally and cerebrally synthesized satiety factor and anti-atherogenic plasma apolipoprotein, was recently identified as an anti-inflammatory protein. In order to elucidate whether intestinal apoA-IV exerts similar repair function as its hepatic homologue apolipoprotein A-V (apoA-V), apoA-IV-interactive proteins were searched and in vitro functional studies were performed with apoA-IV overexpressing cells. ApoA-IV was also analyzed in the intestinal mucosa of patients with inflammatory bowel diseases (IBD), together with other genes involved in epithelial junctional integrity. METHODS: A yeast-two-hybrid screening was used to identify apoA-IV interactors. ApoA-IV was overexpressed in Caco-2 and HT-29 mucosal cells for colocalization and in vitro epithelial permeability studies. Mucosal biopsies from quiescent regions of colon transversum and terminal ileum were subjected to DNA-microarray analysis and pathway-related data mining. RESULTS: Four proteins interacting with apoA-IV were identified, including apolipoprotein B-100, alpha1 antichymotrypsin, cyclin C, and the cytosolic adaptor alpha-catenin, thus linking apoA-IV to adherens junctions. Overexpression of apoA-IV was paralleled with a differentiated phenotype of intestinal epithelial cells, upregulation of junctional proteins, and decreased paracellular permeability. Colocalization between alpha-catenin and apoA-IV occurred exclusively in junctional complexes. ApoA-IV was downregulated in quiescent mucosal tissues from patients suffering from IBD. In parallel, only a distinct set of junctional genes was dysregulated in non-inflamed regions of IBD gut. CONCLUSIONS: ApoA-IV may act as a stabilizer of adherens junctions interacting with alpha-catenin, and is likely involved in the maintenance of junctional integrity. ApoA-IV expression is significantly impaired in IBD mucosa, even in non-inflamed regions. PMID- 17712728 TI - Hyperinsulinemia does not acutely enhance adrenal androgen production in women or men. PMID- 17712729 TI - Internalization of sex hormone binding globulin into fibroblast 3T3 cells. PMID- 17712730 TI - When neuropediatrics meets odontology. PMID- 17712731 TI - Lessons to learn from rare inborn errors of metabolism. PMID- 17712732 TI - Further evidence for a somatic KRAS mutation in a pilocytic astrocytoma. AB - Astrocytomas are the most common brain tumors of childhood. However, knowledge of the molecular etiology of astrocytomas WHO grade I and II is limited. Germline mutations in the Ras-guanosine triphosphatase-activating protein, neurofibromin, in individuals with neurofibromatosis type I predispose to pilocytic astrocytomas. This association suggests that constitutive activation of the Ras signaling pathway plays a fundamental role in astrocytoma development. We screened 25 WHO I and II astrocytomas for mutations of PTPN11, NRAS, KRAS, and HRAS genes and identified the somatic G12A KRAS mutation in one pilocytic astrocytoma. These data suggest that Ras is rarely mutated in these tumors. Analyzed astrocytomas without mutations in Ras or neurofibromin may harbor mutations in other proteins of this pathway leading to hyperactive Ras signaling. PMID- 17712733 TI - Ataxia, delayed dentition and hypomyelination: a novel leukoencephalopathy. AB - We present four children, three of them boys, affected with an identical clinical pattern consisting of early-onset ataxia, delayed dentition, hypomyelination and cerebellar atrophy. Dental radiographs showed variable absence of succedaneous teeth. Proton MR spectroscopy in one child showed elevated white matter myo inositol. As the clinical and radiological picture in these patients is identical to that of four cases described earlier, we suggest that this disorder with ataxia, delayed dentition and hypomyelination (ADDH) represents a new entity. With the characteristic tooth abnormalities it should be straightforward to identify new patients in order to facilitate the search for the underlying genetic defect. PMID- 17712734 TI - Motor outcome at the age of one after perinatal hypoxic-ischemic encephalopathy. AB - OBJECTIVE: The aim of this report is to describe the motor outcome in one year old children who were born at full-term with perinatal hypoxic-ischemic encephalopathy (HIE). Relationships between motor ability tests and neurological examination at one year, and between these tests and neonatal brain magnetic resonance imaging (MRI) were investigated. PARTICIPANTS AND METHODS: 32 surviving children, born full-term with perinatal HIE, are included in this report. All children had a neonatal MRI. At one year, motor ability was assessed with the Alberta Infant Motor Scale and the Bayley Scales of Infant Development (2nd version). Neurological examinations included the neurological optimality score (NOS). RESULTS: At one year, 14 children (44%) had normal motor ability, nine (28%) had mildly delayed, and nine had significantly delayed motor ability. The NOS ranged from 14.6-27 points. All children with normal motor ability had (near) optimal NOS, however, not all children with high NOS had normal motor ability. Eleven children (34%) had normal neonatal MRI; at one year, six of them had normal, and five had mildly delayed motor ability. Eight children with normal motor ability showed abnormalities on neonatal MRI. CONCLUSION: Neonatal brain MRI does not predict motor outcome at one year. Motor ability tests and neurological examinations should be used in a complementary manner to describe outcome after HIE. PMID- 17712735 TI - Ethylmalonic encephalopathy: clinical and biochemical observations. AB - Ethylmalonic encephalopathy (EE) is a rare, recently defined inborn error of metabolism which affects the brain, gastrointestinal system and peripheral blood vessels and is characterized by a unique constellation of clinical and biochemical features. A 7-month-old male, who presented with psychomotor retardation, chronic diarrhea and relapsing petechiae is described with the objective of highlighting the biochemical and neuroradiological features of this disorder as well as the effect of high-dose riboflavin therapy. Urinary organic acid analysis revealed markedly increased excretion of ethylmalonic acid, isobutyrylglycine, 2-methylbutyrylglycine and isovalerylglycine. Acylcarnitine analysis in dried blood spots showed increased butyrylcarnitine. Short-chain acyl CoA dehydrogenase (SCAD) activity in muscle was normal as were mitochondrial OXPHOS enzyme activities in cultured skin fibroblasts. In skeletal muscle the catalytic activity of complex II was decreased. Brain MRI revealed bilateral and symmetrical atrophy in the fronto-temporal areas, massive enlargement of the subarachnoid spaces and hyperdensities on T (2) sequences of the basal ganglia. Mutation analysis of the ETHE1 gene demonstrated homozygosity for the Arg163Gly mutation, confirming the diagnosis of EE at a molecular level. On repeat MRI, a significant deterioration was seen, correlating well with the clinical deterioration of the patient. PMID- 17712736 TI - Is ethosuximide a risk factor for generalised tonic-clonic seizures in absence epilepsy? AB - The occurrence of generalised tonic-clonic seizures (GTCS) was investigated in patients with absence epilepsy (AE), evaluating the opinion that ethosuximide does not protect against GTCS. Our retrospective study included 238 patients with absences and generalised 3-Hz spike waves (SW). We analysed the efficacy of antiepileptic drugs (AED) and the occurrence of GTCS before, during and after treatment. We surveyed family history, treatment delay and EEG findings. Family history of epilepsy was positive in 28%. Children with 3-Hz SW lasting >10 s suffered less frequently from GTCS (p=0.002). Photosensitivity (3-Hz SW during photic stimulation) recorded in 47 children was more frequent in juvenile AE (p=0.0001), but not associated with higher rates of GTCS. GTCS occurred in 27 children (11%) before treatment, in 14 (5.8%) during treatment and in 8 (4.8%) after tapering AED. Valproate and ethosuximide monotherapy were equally effective on absences, carrying the same low risk of GTCS during treatment (2 valproate, 1 ethosuximide). Most GTCS occurred on drug combinations considered effective against GTCS. Risk factors for relapses after tapering AED were photosensitivity (p=0.002) and GTCS during treatment (p=0.02). GTCS are rare in patients with typical AE. Our data do not support the current opinion that ethosuximide is inefficacious on GTCS in AE. PMID- 17712737 TI - Congenital cataract, ataxia, external ophthalmoplegia and dysphagia in two siblings. A Marinesco-Sjogren-like syndrome. AB - Marinesco-Sjogren syndrome (MSS) is an autosomal recessive multiorgan disorder with clinical and genetic heterogeneity. The key features of MSS include cerebellar ataxia, early bilateral cataracts, delayed motor development, and to a varying degree mental retardation. The syndrome was recently mapped to chromosome 5q31, and loss-of-function mutations in the SIL1 gene have been identified as the primary pathology. Here, we describe two German siblings with clinical characteristics resembling those seen in many cases of MSS except that a marked cerebellar atrophy was not detectable in our patients. In addition, both patients presented with external ophthalmoplegia and paralytic dysphagia. Sequencing of all 10 exons of the SIL1 gene did not detect any SIL1 mutation in our patients. PMID- 17712738 TI - Predictive value of neurodevelopmental assessment versus evaluation of general movements for motor outcome in preterm infants with birth weights <1500 g. AB - PURPOSE: The aim of this study was to make a comparison of predictive values of neurodevelopmental assessment and evaluation of videotaped spontaneous movements of premature infants for motor outcome. METHODS: We performed a prospective longitudinal study of 103 VLBW infants, 96 (455-1490 g, 24-35 weeks gestational age) including (a) a neurodevelopmental assessment based on criteria by Amiel Tison/Grenier at 40 weeks postconceptional age, 3 and 20 months corrected age; (b) an evaluation of general movements with fidgety character, based on criteria by Prechtl, at 3 months; and (c) a standardized testing using the Griffiths Developmental Motor Scale at 20 months. We calculated sensitivity, specificity and predictive values for each method. RESULTS: For predicting motor outcome, the assessment of general movements (GM) had a positive predictive value of 89% and negative predictive value of 84%; neurodevelopmental assessment (NA) at 40 weeks had a positive predictive value of 33% and negative predictive value of 88%, respectively, with similar results for neurodevelopmental assessment at age 3 months. CONCLUSIONS: Normal motor outcome of VLBW infants may be accurately predicted by clinical neurodevelopmental assessment, but for adverse outcomes, evaluation of general movements (fidgety movements) is superior. GM assessment has a high predictive value, especially for CP, but it needs to be complemented by NA for non-CP outcomes. It is a simple, repeatable and non-intrusive technique, and may be a valuable method for the early detection of central nervous system impairment in VLBW infants in routine follow-up. PMID- 17712739 TI - Progressive unilateral hemispheric atrophy in an infant with neurofibromatosis. AB - INTRODUCTION: Cerebrovascular diseases are rarely seen in neurofibromatosis type 1. These include vascular occlusive disease, moyamoya vessels, aneurysms, arteriovenous malformations and fistulae. CASE REPORT: We describe the case of an infant with genetically proven neurofibromatosis type 1 and progressive brain hemiatrophy over months, due to primary narrowing of intracranial carotid artery branches, as demonstrated by successive brain imaging. She presented with refractory seizures and a progressive hemiparesis associated with developmental delay. Surgical material from hemispherotomy done at 18 months showed severe abnormalities of the small vessels. CONCLUSION: Cerebrovascular changes seen in neurofibromatosis can be diffuse and progressive, with secondary hemiparesis, epilepsy and developmental delay. PMID- 17712740 TI - Familial spinal neurofibromatosis. AB - Familial spinal neurofibromatosis (FSNF) is a rare localized subtype of NF1 which shows neurological symptomatology during adult life. Only a few families have been reported to date. We describe a family in which three members in two generations, mother, son and daughter, were affected. The patients, aged 48, 22 and 18 years, had spinal bilateral neurofibromas affecting all spinal roots. Spinal symptoms were not present in any of the patients. However, the son had generalized nerve sheath tumors that caused important signs of peripheral neuropathy. The daughter also had benign tumors that involved the left optic nerve and chiasm and the left cerebellar hemisphere. The spinal neurofibromas underwent an important growth in size between 20 and 22 years of age. A specific mutation G848R, 2542 G > C in NF1 exon 16 was present in all three patients. PMID- 17712741 TI - Bugging the bugs: novel approaches in the strategic management of resistant Staphylococcus aureus infections. PMID- 17712742 TI - Microbiology of antibiotic resistance in Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) isolates came into existence soon after the introduction of methicillin. Historically, MRSA isolates have been associated with nosocomial infections and rapidly developed resistance to multiple drug classes. However, in recent years, different strains with unique phenotypes have emerged in the community, and the reservoir of community associated MRSA is rapidly expanding. Community-associated pathogens are likely to cause life-threatening systemic infections, especially in children and elderly individuals, and may also cause serious skin and soft-tissue infections in healthy individuals. Compared with nosocomial strains, community-associated MRSA isolates are associated with increased virulence and currently are more likely to be susceptible to a variety of antibiotics. The epidemiological and microbiological differences between community-associated and nosocomial MRSA infections necessitate different strategies to prevent and treat the 2 types of infections. Vancomycin nonsusceptibility in S. aureus is on the increase, further complicating therapy. PMID- 17712743 TI - Epidemiology of staphylococcal resistance. AB - An understanding of the prevalence of resistant Staphylococcus aureus and the risk factors for infection with resistant isolates is essential to help clinicians choose appropriate antibiotic therapy. Selection pressure due to prior and inappropriate antibiotic use of any kind seems to be the main driving force behind the increasing rates of multidrug resistance in methicillin-resistant S. aureus (MRSA) strains. Resistance to glycopeptide antibiotics in MRSA has also emerged in recent years, along with increased use of vancomycin to treat serious infections due to MRSA. Infections due to MRSA are associated with significantly increased morbidity, mortality, length of hospital stay, and costs, compared with infections due to methicillin-susceptible S. aureus, despite adjustment for disease severity and initially appropriate antibiotic treatment. Improvements in the preparation and dissemination of antibiograms, along with adequate public reporting of MRSA trends, are needed to address the challenge of choosing appropriate initial antibiotic treatment for MRSA infections. PMID- 17712744 TI - Principles of antibiotic therapy in severe infections: optimizing the therapeutic approach by use of laboratory and clinical data. AB - The increasingly daunting problem of antimicrobial resistance has led to an intense focus on optimization of antibiotic therapy, with simultaneous goals of improving patient outcomes and minimizing the contribution of that therapy to making the available antibiotics obsolete. Although even appropriate antibiotic therapy drives resistance, inappropriate therapy may also have adverse effects on the individual patient, as well as on the bacterial ecology. Recent research has validated the benefit of intelligent utilization of both microbiological data and clinical assessment in the empirical selection of initial broad-spectrum therapy and in further guidance of therapeutic decisions throughout the course of illness by use of a systems approach. Thus, the optimal approach to the critically ill patient with infection involves the initiation of aggressive broad-spectrum empirical therapy followed by timely responses to microbiological and clinical results as they become available. An appropriate response to this information often involves de-escalation of therapy or even its discontinuation. PMID- 17712745 TI - Alternatives to vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. AB - Vancomycin remains the reference standard for the treatment of systemic infection caused by methicillin-resistant Staphylococcus aureus (MRSA). However, as a result of limited tissue distribution, as well as the emergence of isolates with reduced susceptibility and in vitro resistance to vancomycin, the need for alternative therapies that target MRSA has become apparent. New treatment options for invasive MRSA infections include linezolid, daptomycin, tigecycline, and quinupristin/dalfopristin. Additionally, a number of new anti-MRSA compounds are in development, including novel glycopeptides (dalbavancin, telavancin, and oritavancin), ceftobiprole, and iclaprim. The present article will review clinical issues surrounding the newly marketed and investigational agents with activity against MRSA. PMID- 17712746 TI - Limitations of vancomycin in the management of resistant staphylococcal infections. AB - Vancomycin is effective against methicillin-resistant Staphylococcus aureus and has been widely used in the past few years. However, several recent reports have highlighted the limitations of vancomycin, and its role in the management of serious infections is now being reconsidered. Vancomycin treatment failure rates are associated with an increase in the minimum inhibitory concentration as well as a decrease in the rate of bacterial killing. The intrinsic limitations of vancomycin also include poor tissue penetration, particularly in the lung; relatively slow bacterial killing; and the potential for toxicity. In addition, intermediate-level vancomycin resistance has emerged among staphylococci, as have rare cases of fully resistant strains. Because of these problems, when using vancomycin, it is probably prudent to carefully establish the diagnosis, test for antimicrobial susceptibility, and monitor serum trough concentrations to ensure adequate dosing. PMID- 17712747 TI - Drug-drug interaction between itraconazole and efavirenz in a patient with AIDS and disseminated histoplasmosis. AB - Although there is a presumed drug-drug interaction between itraconazole and nonnucleoside reverse-transcriptase inhibitors, the medical literature lacks such documentation. We describe a drug-drug interaction between itraconazole and efavirenz in a patient with disseminated histoplasmosis and acquired immunodeficiency syndrome (AIDS). The drug combination resulted in persistently elevated urinary Histoplasma antigen levels and subtherapeutic plasma itraconazole concentrations. Changing treatment from efavirenz to a protease inhibitor was accompanied by improvements in the desired urinary Histoplasma antigen level and plasma itraconazole concentration. PMID- 17712748 TI - Pasteurella multocida sepsis and meningitis in 2-month-old twin infants after household exposure to a slaughtered sheep. AB - This article outlines 2 cases of Pasteurella multocida sepsis and meningitis in 2 month-old twins after their father was exposed to a sheep during a sacrifice celebration at home. These cases emphasize the necessity of respecting basic hygiene rules and the danger involved in animal sacrifice without suitable professional structure. PMID- 17712749 TI - Fulminant mulch pneumonitis: an emergency presentation of chronic granulomatous disease. AB - BACKGROUND: Chronic granulomatous disease (CGD) is associated with multiple and recurrent infections. In patients with CGD, invasive pulmonary infection with Aspergillus species remains the greatest cause of mortality and is typically insidious in onset. Acute fulminant presentations of fungal pneumonia are catastrophic. METHODS: Case records, radiograph findings, and microbiologic examination findings of patients with CGD who had acute presentations of dyspnea and diffuse pulmonary infiltrates caused by invasive fungal infection were reviewed and excerpted onto a standard format. RESULTS: From 1991 through 2004, 9 patients who either were known to have CGD or who received a subsequent diagnosis of CGD presented with fever and new onset dyspnea. Eight patients were hypoxic at presentation; bilateral pulmonary infiltrates were noted at presentation in 6 patients and developed within 2 days after initial symptoms in 2 patients. All patients received diagnoses of invasive filamentous fungi; 4 patients had specimens that also grew Streptomyces species on culture. All patients had been exposed to aerosolized mulch or organic material 1-10 days prior to the onset of symptoms. Cases did not occur in the winter. Five patients died. Two patients, 14 years of age and 23 years of age, who had no antecedent history of recognized immunodeficiency, were found to have p47(phox)-deficient CGD. CONCLUSIONS: Acute fulminant invasive fungal pneumonia in the absence of exogenous immunosuppression is a medical emergency that is highly associated with CGD. Correct diagnosis has important implications for immediate therapy, genetic counseling, and subsequent prophylaxis. PMID- 17712750 TI - Reduction of invasive aspergillosis incidence among immunocompromised patients after control of environmental exposure. AB - BACKGROUND: The objective of the study was to assess the impact of the relocation of an adult hematological intensive care unit on invasive aspergillosis (IA) incidence. METHODS: A quasi-experimental study, including a control group and an intervention group that both underwent pretest and posttest evaluations, was conducted in the 3 adult hematological intensive care units (each composed of 14 single rooms) in a university hospital from 14 April 2005 through 1 February 2006. One of these units was relocated from the main building to an adjoining modular construction. In this unit, 4 rooms were equipped with laminar airflow before relocation; all rooms were equipped with positive pressure isolation after relocation. The 2 other units (control group), each containing 8 rooms with laminar airflow, did not undergo environmental modification. The diagnostic criteria for IA were based on the criteria of the European Organization for Research and Treatment of Cancer. RESULTS: In total, 356 hospitalized patients were included. Of the 21 cases of IA, 18 were nosocomial, and 3 were of undetermined origin. In the relocated unit, the incidence of IA decreased from 13.2% (9 patients) before relocation to 1.6% (1 patient) after relocation (P=.018). Eight of the 9 patients with IA before relocation stayed in rooms without specific air treatment. The rate of IA did not change in the control group. Patient characteristics were similar in each unit before and after relocation. CONCLUSION: We detected a straightforward association between environmental modification and decreased IA incidence, which emphasizes the use of an environmental strategy, including high-efficiency air filtration, in the prevention of IA. PMID- 17712751 TI - Prosthetic joint infection due to rapidly growing mycobacteria: report of 8 cases and review of the literature. AB - BACKGROUND: Prosthetic joint infection (PJI) due to rapidly growing mycobacteria (RGM) is only occasionally encountered in clinical practice. Therefore, the optimal clinical management for this condition is unknown. METHODS: The medical records of patients who had PJI due to RGM during 1969-2006 were reviewed to summarize its clinical characteristics, treatment, and outcome. RESULTS: Eight patients developed 9 episodes of PJI (7 episodes involving the knee and 1 each involving the hip or elbow) due to RGM at a median of 312 weeks (range, 1-170 weeks) after prosthesis implantation. Patients presented with joint pain (7 patients), joint swelling (7 patients), and fever (3 patients), accompanied by an elevated erythrocyte sedimentation rate (median, 70.5 mm/h) and C-reactive protein level (median, 6 mg/dL). Mycobacterium chelonae (n=3), Mycobacterium abscessus (n=2), Mycobacterium fortuitum (n=3), and Mycobacterium smegmatis (n=1) were isolated from the 9 infected joints. Seven of 9 prostheses were resected, whereas 2 were retained after surgical debridement. Six of 8 patients received > or = 1 active antimicrobial agent for at least 6 months. During a median follow up period of 33 weeks (range, 2.6-326 weeks) after surgical intervention, no clinical or microbiological relapses were observed. Reimplantation was performed successfully for 2 of 6 patients who underwent resection arthroplasty. The 2 patients with retained prosthesis continued to receive prolonged courses of suppressive antimicrobial therapy. CONCLUSIONS: RGM is a rare cause of PJI that should be suspected in patients with negative results of routine bacterial cultures. The combination of resection arthroplasty and antimicrobial therapy is the preferred approach. However, in cases involving retained prosthetic components, RGM infection may be suppressed with lifelong courses of effective antibiotic therapy. PMID- 17712752 TI - Spread and epidemiology of Clostridium difficile polymerase chain reaction ribotype 027/toxinotype III in The Netherlands. AB - BACKGROUND: After reports of emerging outbreaks in Canada and the United States, Clostridium difficile-associated disease (CDAD) due to polymerase chain reaction ribotype 027 was detected in 2 medium-to-large hospitals in The Netherlands in 2005. METHODS: National surveillance was initiated to investigate the spread and the epidemiology of CDAD. Microbiologists were asked to send strains recovered from patients with a severe course of CDAD or recovered when an increased incidence of CDAD was noted. A standardized questionnaire was used to collect demographic, clinical, and epidemiological patient data. Strains were characterized by polymerase chain reaction ribotyping, toxinotyping, the presence of toxin genes, and antimicrobial susceptibility. RESULTS: During the period from February 2005 through November 2006, 1175 stool samples from 863 patients were sent from 50 health care facilities. Of these patients, 218 (25.3%) had CDAD due to ribotype 027, and 645 patients (74.7%) had CDAD due to other ribotypes, mainly 001 (17.8%) and 014 (7.2%). Polymerase chain reaction ribotype 027 was more frequently present in general hospitals than in academic hospitals (odds ratio [OR], 4.38; 95% confidence interval [CI], 1.60-12.0). Outbreaks of CDAD were observed in 10 hospitals and in 1 nursing home. Patients infected with ribotype 027 were significantly older (OR, 2.18; 95% CI, 1.43-3.33), and significantly more patients used fluoroquinolones (OR, 2.88; 95% CI, 1.01-8.20), compared with those who were infected with other ribotypes. Clear trends were observed for more severe diarrhea (OR, 1.99; 95% CI, 0.83-4.73), higher attributable mortality (6.3% vs. 1.2%; OR, 3.30; 95% CI, 0.41-26.4), and more recurrences (OR, 1.44; 95% CI, 0.94-2.20). CONCLUSIONS: Ribotype 027 was found in 20 (18.3%) of 109 hospitals in The Netherlands, with a geographic concentration in the western and central parts of the country. The clinical syndrome in patients with CDAD differed on the basis of ribotype. Thus, early recognition of the ribotype has benefits. PMID- 17712754 TI - In pursuit of ventilator-associated pneumonia prevention: the right path. PMID- 17712753 TI - Effectiveness of an educational program to reduce ventilator-associated pneumonia in a tertiary care center in Thailand: a 4-year study. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is considered to be an important cause of infection-related death and morbidity in intensive care units (ICUs). We sought to determine the long-term effect of an educational program to prevent VAP in a medical ICU (MICU). METHODS: A 4-year controlled, prospective, quasi-experimental study was conducted in an MICU, surgical ICU (SICU), and coronary care unit (CCU) for 1 year before the intervention (period 1), 1 year after the intervention (period 2), and 2 follow-up years (period 3). The SICU and CCU served as control ICUs. The educational program involved respiratory therapists and nurses and included a self-study module with preintervention and postintervention assessments, lectures, fact sheets, and posters. RESULTS: Before the intervention, there were 45 episodes of VAP (20.6 cases per 1000 ventilator days) in the MICU, 11 (5.4 cases per 1000 ventilator-days) in the SICU, and 9 (4.4 cases per 1000 ventilator-days) in the CCU. After the intervention, the rate of VAP in the MICU decreased by 59% (to 8.5 cases per 1000 ventilator-days; P=.001) and remained stable in the SICU (5.6 cases per 1000 ventilator-days; P=.22) and CCU (4.8 cases per 1000 ventilator-days; P=.48). The rate of VAP in the MICU continued to decrease in period 3 (to 4.2 cases per 1000 ventilator days; P=.07), and rates in the SICU and CCU remained unchanged. Compared with period 1, the mean duration of hospital stay in the MICU was reduced by 8.5 days in period 2 (P<.001) and by 8.9 days in period 3 (P<.001). The monthly hospital antibiotic costs of VAP treatment and the hospitalization cost for each patient in the MICU in periods 2 and 3 were also reduced by 45%-50% (P<.001) and 37%-45% (P<.001), respectively. CONCLUSIONS: A focused education intervention resulted in sustained reductions in the incidence of VAP, duration of hospital stay, cost of antibiotic therapy, and cost of hospitalization. PMID- 17712755 TI - The effectiveness of a 9-month regimen of isoniazid alone versus 3- and 4-month regimens of isoniazid plus rifampin for treatment of latent tuberculosis infection in children: results of an 11-year randomized study. AB - BACKGROUND: A 9-month course of isoniazid monotherapy is currently recommended for the treatment of latent tuberculosis infection (LTBI) and has been shown to be effective in both children and adults. Reduced compliance with this regimen has forced physicians to explore shorter regimens. The aim of this study was to compare 3- and 4-month combination regimens of isoniazid plus rifampin with a 9 month regimen of isoniazid monotherapy for the treatment of LTBI in children. METHODS: This prospective, randomized, controlled study was conducted over an 11 year period (1995-2005). In period 1 (1995-1998), 232 patients received isoniazid therapy for 9 months (group A), and 238 patients received isoniazid and rifampin for 4 months (group B). In period 2 (1999-2002), 236 patients were treated with isoniazid and rifampin for 4 months (group C), and 220 patients received the same regimen for 3 months (group D). All patients were observed for > or = 3 years. RESULTS: Overall compliance with treatment was good, but patients who received isoniazid monotherapy were less compliant than were those who received short course combination therapy (P=.011, for group A vs. group B; P=.510, for group C vs. group D). No patient in any group developed clinical disease during the follow-up period. New radiographic findings suggestive of possible active disease were more common in patients who received isoniazid monotherapy (24%) than in those treated with shorter regimens (11.8%, 13.6%, and 11% for groups B, C, and D, respectively; P=.001 for group A vs. group B; P=.418 for group C vs. group D). Serious drug-related adverse effects were not detected. CONCLUSIONS: Short-course treatment with isoniazid and rifampin for 3-4 months is safe and seems to be superior to a 9-month course of isoniazid monotherapy. PMID- 17712756 TI - Hypercytokinemia and hyperactivation of phospho-p38 mitogen-activated protein kinase in severe human influenza A virus infection. AB - BACKGROUND: We postulate that hypercytokinemia plays a role in immunopathogenesis of severe human influenza. METHODS: We prospectively studied 39 consecutive patients who were hospitalized with severe influenza A virus infection. On laboratory confirmation of the diagnosis, paired acute-phase (obtained at hospital admission) and convalescent-phase (obtained >10 days after hospital admission) plasma samples were collected for assay of 11 cytokines and chemokines (interleukin [IL] 1 beta; IL-6; IL-10; IL-12p70; tumor necrosis factor alpha; IL 8; monokine induced by interferon [IFN]-gamma; IFN-inducible protein 10; monocyte chemoattractant protein 1; regulated upon activation, normal T cell-expressed and secreted; and IFN-gamma) using cytometric bead-array analysis and enzyme-linked immunosorbent assay. Simultaneously, virus concentration in the acute-phase nasopharyngeal aspirate was determined using real-time quantitative reverse transcriptase polymerase chain reaction. Intracellular signaling molecules regulating lymphocyte activation, phospho-p38 mitogen-activated protein kinase and phospho-extracellular signal-regulated protein kinase in CD4+ and CD8+ T lymphocytes were studied in the acute-phase samples using flow cytometric analysis and were compared with results for samples from healthy control subjects. RESULTS: Statistically significant increases in plasma IL-6 (3.7-fold increase), IL-8 (2.6-fold increase), IFN-induced protein 10 (4.9-fold increase), and monokine induced by IFN-gamma (2.3-fold increase) concentrations were detected during acute illness (P < .01 for all, by Wilcoxon signed-rank test); the highest concentrations were observed on symptom days 3 and 4. Corresponding plasma cytokine and chemokine concentrations and nasopharyngeal viral loads showed statistically significant correlations (rho = 0.41, 0.49, 0.54, and 0.46, respectively; P < or = .01). Phospho-p38 mitogen-activated protein kinase expression in CD4+ lymphocytes was increased, correlating with cytokine concentrations (e.g., for IFN-induced protein 10, rho = 0.78; P < .01); phospho extracellular signal-regulated protein kinase was suppressed. Advanced age and comorbidity were associated with aberrant IL-6, IL-8, and monokine induced by IFN gamma responses (P < .05, by Mann-Whitney U test). An elevated IL-6 concentration was independently associated with prolonged hospitalization (hospitalization for >5 days; P = .02), adjusted for age, comorbidity, and virus load. CONCLUSIONS: Hypercytokinemia (of proinflammatory and T helper 1 cytokines) is detected in severe influenza, correlating with clinical illness and virus concentration. Hyperactivation of phospho-p38 mitogen-activated protein kinase (in T helper cells) is possibly involved. Early viral suppression may attenuate these potentially deleterious cytokine responses. PMID- 17712757 TI - Postinfective fatigue syndrome is not associated with altered cytokine production. AB - Peripheral blood specimens and clinical data were obtained over a 12-month period from subjects in the Dubbo Infection Outcomes Study to examine cytokine production in postinfective fatigue syndrome. Ex vivo production of 8 cytokines was examined in 22 case patients and in 42 control subjects who recovered promptly. No significant differences were found. Ongoing production of the cytokines examined does not play a role in postinfective fatigue syndrome. PMID- 17712759 TI - A young man with pyomyositis and bullous disease. PMID- 17712758 TI - Prevalence and long-term effects of occult hepatitis B virus infection in HIV infected women. AB - Occult hepatitis B virus (HBV) infection is of concern in human immunodeficiency virus (HIV)-infected persons. We observed that 2% of 400 HIV-infected women with antibodies to hepatitis B core antigen alone had occult HBV infection (i.e., detectable HBV DNA in the absence of HBV surface antigen). CD4 cell counts of <200 cells/mm3 were more common among occult HBV-infected women than among those without occult HBV infection. Aminotransferase levels did not appear to be associated with being positive for HBV DNA. PMID- 17712760 TI - Group a streptococcal disease in long-term care facilities: descriptive epidemiology and potential control measures. AB - Group A streptococci (GAS) are an important cause of severe, life-threatening illness among the elderly population, particularly those individuals residing in long-term care facilities (LTCFs). Outbreaks of GAS infection are potentially devastating in this vulnerable population and often require large-scale control efforts involving LTCF staff, public health officials, and infectious diseases practitioners. Although multiple outbreaks of GAS infection in LTCFs have been described in the medical literature, this topic has not been reviewed for 15 years, and there is a need for updated guidance on how to approach GAS infection outbreak control. We reviewed published documents on GAS infection in LTCFs to describe the current understanding of the disease's epidemiology in this setting, identify techniques for outbreak investigation and prevention, and expose areas where additional research is needed. We highlight well-accepted prevention and control strategies that can be employed during investigation and control of GAS infection outbreaks in LTCFs. PMID- 17712761 TI - Back to the future: using aminoglycosides again and how to dose them optimally. AB - Gram-negative organisms have become increasingly resistant to both beta-lactam antibiotics and fluoroquinolones. Consequently, aminoglycoside antibiotics have undergone a resurgence in use. Because of the known toxicities of aminoglycoside antibiotics, clinicians have avoided their use, unless no other alternatives were extant. Over the past 2 decades, we have learned much about the relationship between aminoglycoside exposure and the likelihood of a good clinical outcome or the occurrence of nephrotoxicity. For example, minimum inhibitory concentration values > or = 2.0 mg/L lead to unacceptably low probabilities of a good clinical outcome, and infrequent administration of doses (i.e., intervals of 24 h and longer intervals for patients with compromised renal function) plays a central role in minimizing the likelihood of toxicity. Using these new insights, we suggest ways of evaluating the dose and schedule of administration of aminoglycosides in empirical therapy to obtain the highest likelihood of an efficacious and nontoxic therapy. PMID- 17712762 TI - Tipranavir: a new option for the treatment of drug-resistant HIV infection. AB - Tipranavir is a recently approved nonpeptidic protease inhibitor specifically developed for the management of human immunodeficiency virus (HIV) infection in treatment-experienced patients with protease inhibitor-resistant infection. It is active against a wide range of drug-resistant laboratory- and patient-derived isolates. Tipranavir requires pharmacokinetic boosting by ritonavir (200 mg) to achieve therapeutic levels with twice-daily dosing and must be administered with food for optimal absorption. It is a potent protease inhibitor with a unique drug resistance profile that offers advantages in the management of cases of multidrug resistant HIV infection. Tipranavir (in combination with ritonavir) is both an inhibitor and inducer of cytochrome p450, with significant potential for drug drug interactions, and therefore, it must be used cautiously when administered to patients who are receiving other drugs. Evolution of drug resistance after treatment failure with tipranavir is complex and is not yet fully understood. There is limited overlap in the resistance mutations that predict response to tipranavir and another new protease inhibitor, darunavir, which is active against drug-resistant isolates. Tipranavir is associated with elevations in alanine aminotransferase and aspartate aminotransferase levels, as well as elevated cholesterol and triglyceride levels, and can cause the typical gastrointestinal adverse effects associated with all protease inhibitors. PMID- 17712764 TI - Antiretroviral drug dosing errors in HIV-infected patients undergoing hemodialysis. AB - BACKGROUND: Several studies have revealed the frequency of antiretroviral (ARV) drug prescription errors. We analyzed highly active antiretroviral therapy (HAART) prescribing practices for human immunodeficiency virus (HIV)-infected patients undergoing hemodialysis in France. METHODS: Prescribed ARV drug doses in our cohort (consisting of all HIV-infected patients who underwent hemodialysis from 1 January 2002 and were prospectively followed up until 1 January 2004) were compared with the recommended doses for patients undergoing hemodialysis. The log rank test was used to compare the outcomes among different groups of treated patients. RESULTS: One hundred seven of the 129 patients in our cohort received a total of 317 ARV drugs, 59% of which were improperly prescribed. The dosing was too low for 18% of the patients and too high for 39% of the patients. Twenty eight patients (26%) did not receive any of their ARV drugs at the recommended dose. The lowest prescribed dose (8% of the daily recommended dose) was observed with indinavir and zidovudine, and the highest prescribed dose (1000% of the recommended dose) was observed with stavudine. Among patients who received HAART, those who were prescribed an insufficient dose of a protease inhibitor had more severe HIV disease and worse 2-year survival than did the other patients (mean rate of survival+/-standard deviation, 79.5%+/-7.5% vs. 95.4%+/-2.6%, respectively; P<.02). For dialyzable ARV drugs, the delay between ARV drug receipt by the patients and dialysis sessions was not respected in 9% of cases, and in 73% of cases, it was not known whether the patients took the ARV drugs before or after dialysis sessions. CONCLUSION: This is, to our knowledge, the first study to show a significant association between ARV drug prescription errors and survival in patients undergoing dialysis. PMID- 17712763 TI - Superiority of directly administered antiretroviral therapy over self administered therapy among HIV-infected drug users: a prospective, randomized, controlled trial. AB - BACKGROUND: Directly administered antiretroviral therapy (DAART) is one approach to improve treatment adherence among human immunodeficiency virus (HIV)-infected drug users. METHODS: In this randomized, controlled trial (ClinicalTrials.gov identifier, NCT00367172), the biological outcomes of a 6-month community intervention of DAART were compared with those of self-administered therapy among HIV-infected drug users. Patients randomized to receive DAART received supervised therapy 5 days per week from workers in a mobile health care van. The primary outcome, using an intention-to-treat approach, was the proportion of patients achieving either a reduction in HIV-1 RNA level of > or = 1.0 log10 copies/mL or an HIV-1 RNA level < or = 400 copies/mL at 6 months. Secondary outcomes included the mean change from baseline in HIV-1 RNA level and CD4+ T lymphocyte count. RESULTS: Of the 141 patients who met the entry criteria, 88 were randomized to receive DAART, and 53 were randomized to receive self-administered therapy; 74 (84%) of 88 of the patients randomized to receive DAART accepted the intervention. Of the 74 patients who initiated DAART, 51 (69%) completed the full 6-month intervention. At the end of 6 months, a significantly greater proportion of the DAART group achieved the primary outcome (70.5% vs. 54.7; P=.02). Additionally, compared with patients receiving self-administered therapy, patients receiving DAART demonstrated a significantly greater mean reduction in HIV-1 RNA level (-1.16 log10 copies/mL vs. -0.29 log10 copies/mL; P=.03) and mean increase in CD4+ T lymphocyte count (+58.8 cells/microL vs. -24.0 cells/microL; P=.002). CONCLUSIONS: This randomized, controlled trial was, to our knowledge, the first to demonstrate the effectiveness of DAART at improving 6-month virologic outcomes among drug users. These results suggest that DAART should be more widely available in HIV treatment programs that target drug users who have poor adherence to treatment. PMID- 17712765 TI - Long-term nonprogression of HIV infection in children: evaluation of the ANRS prospective French Pediatric Cohort. AB - BACKGROUND: Some children who are infected with human immunodeficiency virus type 1 (HIV-1) during the perinatal period remain asymptomatic for very long periods in the absence of antiretroviral treatment, as is the case for some adults. Our objective was to estimate the proportion of children who developed neither symptoms nor major immunological perturbations to the age of > or = 10 years in a prospective cohort of infected children who had been observed since birth. METHODS: The ongoing prospective French Pediatric Cohort includes 568 HIV-1 infected children. Here, we report the follow-up data for all 348 HIV-1-infected children who were born before 1 January 1994. Children with long-term nonprogression of infection (LTNPs) were defined as HIV-1-infected children who had been observed for at least 10 years, never received antiretroviral treatment other than zidovudine monotherapy, never developed symptoms of Centers for Disease Control and Prevention clinical category C or B, and had a CD4+ cell percentage of < 25% no more than once during follow-up. Other definitions were compared. RESULTS: The Kaplan-Meier estimate of long-term nonprogression was 2.4% (95% confidence interval, 1.1%-4.6%) at 10 years of age, and 7 children were classified as LTNPs. The Kaplan-Meier estimates decreased slightly with age, to 1.8% at 12 years of age and 1.4% at 14 years of age. Plasma HIV-1 replication rates were low (< 1000 copies RNA/mL) for 2 of the 7 LTNPs at the age of 10 years (0.6% of the total denominator). None of the routinely measured maternal or perinatal markers were significantly linked to long-term nonprogression, with the exception of the mother's Centers for Disease Control and Prevention clinical category at the time of delivery. CONCLUSIONS: Approximately 2% of children who were infected during the perinatal period displayed no immunological or clinical progression by the age of 10 years. This figure is close to that reported for adults in studies that have used similar definitions. PMID- 17712766 TI - Prevalence of hepatitis B and C virus infections in children infected with HIV. AB - We evaluated the prevalence and transmission mode of hepatitis B and C in an inner-city, pediatric cohort of human immunodeficiency virus (HIV)-infected persons, as well as the demographic characteristics of the cohort. Hepatitis B or C was found in 13 (5.8%) of 228 children. This analysis suggests that chronic hepatitis is prevalent and should be routinely screened for in the pediatric HIV infected population. PMID- 17712768 TI - Tenosynovitis and vascular disorders associated with Chikungunya virus-related rheumatism. PMID- 17712769 TI - Diabetes mellitus and pyogenic liver abscess: risk and prognosis. PMID- 17712770 TI - Preventing vertical hepatitis C virus transmission. PMID- 17712771 TI - Promoting retention in care: an effective model in an antiretroviral treatment service in South Africa. PMID- 17712772 TI - Lack of cross-hepatotoxicity between voriconazole and posaconazole. PMID- 17712773 TI - Structure of an anti-cholera toxin antibody Fab in complex with an epitope derived D-peptide: a case of polyspecific recognition. AB - The structure of a complex of the anti-cholera toxin antibody TE33 Fab (fragment antibody) with the D-peptide vpGsqhyds was solved to 1.78 A resolution. The D peptide was derived from the linear L-peptide epitope VPGSQHIDS by a stepwise transformation. Despite the very similar amino acid sequence-the only difference is a tyrosine residue in position 7-there are marked differences in the individual positions with respect to their contribution to the peptide overall affinity as ascertained by a complete substitutional analysis. This is reflected by the X-ray structure of the TE33 Fab/D-peptide complex where there is an inverted orientation of the D-peptide as compared with the known structure of a corresponding complex containing the epitope L-peptide, with the side chains establishing different contacts within the binding site of TE33. The D- and L peptide affinities are comparable and the surface areas buried by complex formation are almost the same. Thus the antibody TE33 provides a typical example for polyspecific binding behavior of IgG family antibodies. PMID- 17712774 TI - Mapping correlated membrane pulsations and fluctuations in human cells. AB - The cell membrane and cytoskeleton are dynamic structures that are strongly influenced by the thermo-mechanical background in addition to biologically driven mechanical processes. We used atomic force microscopy (AFM) to measure the local membrane motion of human foreskin fibroblasts (HFFs) which were found to be governed by random and non-random correlated mechanical processes. Interphase cells displayed distinct membrane pulsations in which the membrane was observed to slowly contract upwards followed by a recovery to its initial position. These pulsations occurred one to three times per minute with variable amplitudes (20 100 pN) separated by periods of random baseline fluctuations with amplitudes of <20 pN. Cells were exposed to actin and microtubule (MT) destabilizing drugs and induced into early apoptosis. Mechanical pulsations (20-80 pN) were not prevented by actin or MT depolymerization but were prevented in early apoptotic cells which only displayed small amplitude baseline fluctuations (<20 pN). Correlation analysis revealed that the cell membrane motion is largely random; however several non-random processes, with time constants varying between approximately 2 and 35 s are present. Results were compared to measured cardiomyocyte motion which was well defined and highly correlated. Employing automated positioning of the AFM tip, interphase HFF correlation time constants were also mapped over a 10 microm2 area above the nucleus providing some insights into the spatial variability of membrane correlations. Here, we are able to show that membrane pulsations and fluctuations can be linked to physiological state and cytoskeletal dynamics through distinct sets of correlation time constants in human cells. PMID- 17712775 TI - The NTA-His6 bond is strong enough for AFM single-molecular recognition studies. AB - There is a need in current atomic force microscopy (AFM) molecular recognition studies for generic methods for the stable, functional attachment of proteins on tips and solid supports. In the last few years, the site-directed nitrilotriacetic acid (NTA)-polyhistidine (Hisn) system has been increasingly used towards this goal. Yet, a crucial question in this context is whether the NTA-Hisn bond is sufficiently strong for ensuring stable protein immobilization during force spectroscopy measurements. Here, we measured the forces between AFM tips modified with NTA-terminated alkanethiols and solid supports functionalized with His6-Gly-Cys peptides in the presence of Ni2+. The force histogram obtained at a loading rate of 6600 pN s(-1) showed three maxima at rupture forces of 153 +/- 57 pN, 316 +/- 50 pN and 468 +/- 44 pN, that we attribute primarily to monovalent and multivalent interactions between a single His6 moiety and one, two and three NTA groups, respectively. The measured forces are well above the 50-100 pN unbinding forces typically observed by AFM for receptor-ligand pairs. The plot of adhesion force versus log (loading rate) revealed a linear regime, from which we deduced a kinetic off-rate constant of dissociation, k(off) approximately 0.07 s(-1). This value is in the range of that estimated for the multivalent interaction involving two NTA, using fluorescence measurements, and may account for an increased binding stability of the NTA-His6 bond. We conclude that the NTA His6 system is a powerful, well-suited platform for the stable, oriented immobilization of proteins in AFM single-molecule studies. PMID- 17712778 TI - A lifelong dedication to cytometry--a tribute to Guenter Valet. PMID- 17712779 TI - Cytometry in malaria: moving beyond Giemsa. PMID- 17712782 TI - The need for reorientation toward cost-effective prediction: comments on 'Evaluating the added predictive ability of a new marker: From area under the ROC curve to reclassification and beyond' by Pencina et al., Statistics in Medicine (DOI: 10.1002/sim.2929). PMID- 17712783 TI - Noninvasive measurement of the cerebral blood flow response in human lateral geniculate nucleus with arterial spin labeling fMRI. AB - To date, functional magnetic resonance imaging (fMRI) studies of the lateral geniculate nucleus (LGN) have primarily focused on measures of the blood oxygenation level dependent (BOLD) signal. Arterial spin labeling (ASL) is an MRI method that can provide direct measures of functional cerebral blood flow (CBF) changes. Because CBF is a well-defined physiological quantity that contributes to BOLD contrast, CBF measures can be used to improve the quantitative interpretation of fMRI studies. However, due in part to the low intrinsic signal to-noise ratio of the ASL method, measures of functional CBF changes in the LGN are challenging and have not previously been reported. In this study, we demonstrate the feasibility of using ASL fMRI to measure the CBF response of the LGN to visual stimulation on a 3 T MRI system. The use of background suppression and physiological noise reduction techniques allowed reliable detection of LGN activation in all five subjects studied. The measured percent CBF response during activation ranged from 40 to 100%, assuming no interaction between the left and right LGN. PMID- 17712784 TI - Dynamics of event-related causality in brain electrical activity. AB - A new method (Event-Related Causality, ERC) is proposed for the investigation of functional interactions between brain regions during cognitive processing. ERC estimates the direction, intensity, spectral content, and temporal course of brain activity propagation within a cortical network. ERC is based upon the short time directed transfer function (SDTF), which is measured in short EEG epochs during multiple trials of a cognitive task, as well as the direct directed transfer function (dDTF), which distinguishes direct interactions between brain regions from indirect interactions via brain regions. ERC uses new statistical methods for comparing estimates of causal interactions during prestimulus "baseline" epochs and during poststimulus "activated" epochs in order to estimate event-related increases and decreases in the functional interactions between cortical network components during cognitive tasks. The utility of the ERC approach is demonstrated through its application to human electrocorticographic recordings (ECoG) of a simple language task. ERC analyses of these ECoG recordings reveal frequency-dependent interactions, particularly in high gamma (>60 Hz) frequencies, between brain regions known to participate in the recorded language task, and the temporal evolution of these interactions is consistent with the putative processing stages of this task. The method may be a useful tool for investigating the dynamics of causal interactions between various brain regions during cognitive task performance. PMID- 17712785 TI - Cortical dynamics of word recognition. AB - While functional neuroimaging studies have helped elucidate major regions implicated in word recognition, much less is known about the dynamics of the associated activations or the actual neural processes of their functional network. We used intracerebral electroencephalography recordings in 10 patients with epilepsy to directly measure neural activity in the temporal and frontal lobes during written words' recognition, predominantly in the left hemisphere. The patients were presented visually with consonant strings, pseudo-words, and words and performed a hierarchical paradigm contrasting semantic processes (living vs. nonliving word categorization task), phonological processes (rhyme decision task on pseudo-words), and visual processes (visual analysis of consonant strings). Stimuli triggered a cascade of modulations in the gamma-band (>40 Hz) with reproducible timing and task-sensitivity throughout the functional reading network: the earliest gamma-band activations were observed for all stimuli in the mesial basal temporal lobe at 150 ms, reaching the word form area in the mid fusiform gyrus at 200 ms, evidencing a superiority effect for word like stimuli. Peaks of gamma-band activations were then observed for word-like stimuli after 400 ms in the anterior and middle portion of the superior temporal gyrus (BA 38 and BA 22 respectively), in the pars triangularis of Broca's area for the semantic task (BAs 45 and 47), and in the pars opercularis for the phonological task (BA 44). Concurrently, we observed a two-pronged effect in the prefrontal cortex (BAs 9 and 46), with nonspecific sustained dorsal activation related to sustained attention and, more ventrally, a strong reflex deactivation around 500 ms, possibly due to semantic working memory reset. PMID- 17712786 TI - Selective activation around the left occipito-temporal sulcus for words relative to pictures: individual variability or false positives? AB - We used high-resolution fMRI to investigate claims that learning to read results in greater left occipito-temporal (OT) activation for written words relative to pictures of objects. In the first experiment, 9/16 subjects performing a one-back task showed activation in > or =1 left OT voxel for words relative to pictures (P < 0.05 uncorrected). In a second experiment, another 9/15 subjects performing a semantic decision task activated > or =1 left OT voxel for words relative to pictures. However, at this low statistical threshold false positives need to be excluded. The semantic decision paradigm was therefore repeated, within subject, in two different scanners (1.5 and 3 T). Both scanners consistently localised left OT activation for words relative to fixation and pictures relative to words, but there were no consistent effects for words relative to pictures. Finally, in a third experiment, we minimised the voxel size (1.5 x 1.5 x 1.5 mm(3)) and demonstrated a striking concordance between the voxels activated for words and pictures, irrespective of task (naming vs. one-back) or script (English vs. Hebrew). In summary, although we detected differential activation for words relative to pictures, these effects: (i) do not withstand statistical rigour; (ii) do not replicate within or between subjects; and (iii) are observed in voxels that also respond to pictures of objects. Our findings have implications for the role of left OT activation during reading. More generally, they show that studies using low statistical thresholds in single subject analyses should correct the statistical threshold for the number of comparisons made or replicate effects within subject. PMID- 17712787 TI - Stature and sexual stature dimorphism in Sweden, from the 10th to the end of the 20th century. AB - Mean stature in a population has been observed to vary with living conditions. If, and how, this affects sexual dimorphism in stature is not fully understood. We analyzed stature data from Swedish populations from the 10th to the end of the 20th century to investigate if male stature is more plastic than female stature in response to environmental changes. Further, we examined if there, as a consequence of this, exists an allometric relationship between male and female stature that is not caused by genetic factors, coupling greater stature with greater dimorphism. We found no significant change in stature from the 10th century to the 17th century, but a clear increase in both male and female stature during the 20th century, most likely because of improved living conditions. Regression analyses revealed no consistent change in sexual stature dimorphism over time for any of the time periods, including the 20th century. Further, we found no significant allometric relationship between male and female stature, and could consequently not identify any significant relationship between stature and stature dimorphism. Thus, contrary to previous suggestions, the regressions did not provide support for the assertion that male stature is more sensitive to environmental changes than female stature, nor that stature dimorphism increases with increasing stature. PMID- 17712788 TI - The African contribution to the present-day population of the Azores Islands (Portugal): analysis of the Y chromosome haplogroup E. AB - Among the settlers that, from 1432 onwards, arrived to the Azores Islands were individuals of North and sub-Saharan African origin. A previous study of markers of the Y chromosome revealed that haplogroup E is the second more frequent in the Azores (13%). Since this haplogroup is heterogeneous and may contain subtypes of African or non-African origin, we analyzed an extended sample of 319 Azoreans, originating from the three groups of islands (Eastern, Central, and Western), to evaluate the African contribution to the present-day population of the Azores. Samples belonging to the E clade were distributed into six haplogroups, from which the most frequent was E3b1a, representing 47.2% of the E chromosomes (6.3% of the total sample). The sub-Saharan haplogroup E3a was found in 7.1% of E chromosomes (0.9% of the total), corresponding to the highest frequency reported so far in a Portuguese population. No significant differences were detected in the haplogroup distribution among groups of islands, as well as between Azores and most of other European populations compared. The present-day representation of sub-Saharan lineages in Azores, although reduced, is higher than in other Portuguese populations, where the demographic representation of sub-Saharan slaves is reported as similar. PMID- 17712789 TI - Diversity and relationship between Iranian ethnic groups: human dopamine transporter gene (DAT1) VNTR genotyping. AB - The 40-bp VNTR polymorphism in the 3' untranslated region of the human DAT1 (dopamine transporter 1) was analyzed in the Iranian ethnic groups in order to examine the influence of geographical and linguistic affiliation on the genetic affinities among the Iranian population. A total of 449 subjects belonging to nine ethnic groups from the Iranian population were included in the study. The screening of 898 chromosomes showed five alleles (6, 7, 8, 9, 10, and 11), of which allele 10 revealed the highest frequency in most regions. Allele 8 was predominant in one ethnicity and occurred more frequently in the center of Iran. This study shows that the DAT1 distribution in Iran has a different pattern from those in other studies, which can contribute to an understanding of differentiation and diversity of Iranian ethnic groups. This polymorphism could represent the genetic diversity among the various ethnic groups of Iran. PMID- 17712790 TI - Cardiovascular fitness in adolescents: the influence of sexual maturation status the AVENA and EYHS studies. AB - The purposes were: (1) to determine the influence of sexual maturation status and body composition by comparing cardiovascular fitness (CVF) level in two adolescent populations from the south and the north of Europe; (2) to describe the associations between CVF and sexual maturation status in adolescence. A total of 1,867 Spanish adolescents from the AVENA study and 472 from the Swedish part of the EYHS were selected for this report (aged 14-16 years). CVF (expressed by the maximal oxygen consumption) was estimated from 20 m shuttle run test in the AVENA study and from a maximal ergometer cycle test in the EYHS. Sexual maturation status was classified according to Tanner stages. Body fat percentage (BF%) was estimated from skinfold thicknesses. Expressing CVF in different ways (in absolute value and in relation to weight or fat free mass; FFM) resulted in two different results with regard to CVF interpretation and comparison between the study populations. A higher CVF, as expressed in relation to FFM, was observed in the Spanish when compared to Swedish adolescents (P = 0.001). However, after adjusting for both sexual maturation status and BF%, the difference disappeared in males, while it remained significant in females (P = 0.001). CVF was negatively associated with sexual maturation status in males (P = 0.001). However, after adjusting for BF%, the association disappeared in males, while it was significant in females (P = 0.05). These results suggest that for CVF comparisons and interpretation in adolescent populations, sexual maturation status and BF%, as well as the way to express the CVF, should be taken into account. PMID- 17712791 TI - Monitoring serum hepatitis C virus (HCV) RNA in patients with HCV-infected CD20 positive B-cell lymphoma undergoing rituximab combination chemotherapy. AB - Several studies have shown that the frequency of hepatitis C virus (HCV) infection is high in patients with B-cell non-Hodgkin's lymphoma (NHL). In these studies, liver dysfunction during chemotherapy has been demonstrated, but changes in HCV ribonucleic acid (RNA) levels during chemotherapy have not been well documented. In this study, we monitored serum HCV RNA levels and liver function in five HCV-infected patients with B-cell NHL undergoing treatment with rituximab combination chemotherapy. Increased HCV RNA levels during or after the chemotherapy were observed in all five patients, and a significant increase in transaminases was seen in one case. In this case, serum HCV RNA level dramatically decreased at the time of the increase of transaminases, and this suggested that the cause of liver damage was an immune reaction against hepatocytes with HCV and not any anticancer drug induced liver toxicity. Monitoring of serum HCV RNA levels and transaminases may be helpful to understand the cause of liver dysfunction in patients receiving chemotherapy. However, increases of HCV viral load were not associated with the occurrence of liver dysfunction in this study. Further studies will be necessary to investigate more fully the relationship between changes in HCV viral load and liver function during chemotherapy for HCV-infected patients. PMID- 17712792 TI - Comparison of gene expression profiles in erythroid-like cells derived from mouse embryonic stem cells differentiated in simple and co-culture systems. AB - The feeder layer and the presence of specific growth factors are thought to induce the differentiation of embryonic stem cells (ESCs) in culture. The aim of this study was to evaluate the effect of erythropoietin (EPO) on the differentiation of ESCs into erythroid colonies in simple and co-culture systems. Embryoid bodies were dissociated and replated in semisolid medium in simple culture or in a co-culture system with bone-marrow stromal cells (BMSCs), both in the presence or absence of EPO. Colony assays, benzidine staining, and ultrastructural studies were carried out until day 10 of culture. Expression of the epsilon globin, betaH1 globin, runt-related transcription factor 1 (RUNX1), betamajor globin, and erythropoietin receptor (EPOR) genes was evaluated using semi-quantitative RT-PCR. A comparison with the corresponding controls showed that colony size increased in both systems (P 90% ovarian cancers, labeled with fluorescein, and an alpha-FR antibody labeled with antimouse-phycoerythrin have been used to label tumor cells, with a CD45-phycoerythrin-cyanine5 antibody used to exclude white blood cells from the analysis. The method was optimized using human carcinoma cell lines (JEG-3, IGROV-1, and KB cells). Calibrated beads were used to quantify the number of antibodies bound per cell. The triple antibody protocol successfully measured alpha-FR expression levels in cell lines spiked with blood. Tumor cells were obtained from ascites in 25 patients with relapsed ovarian cancer. In each case sufficient cells were harvested to identify an epithelial cell population to estimate the number of binding sites/cell. All the samples contained a single population of BerEP4, alpha-FR positive cells between 5x10(3) and 5x10(5) antibody binding sites/cell. The method can be used to determine the number of anti-alpha-FR antibodies bound per epithelial cell in ascites from patients with ovarian carcinoma. The results obtained were reproducible and the method could be applied to specimens that had been stored at -80 degrees C. PMID- 17712799 TI - Immunolocalization of the high-mobility group N2 protein and acetylated histone H3K14 in early developing parthenogenetic bovine embryos derived from oocytes of high and low developmental competence. AB - This study investigated differences in the distribution of acetylated histone H3 at Lysine 14 (H3K14ac) and the High-Mobility Group N2 (HMGN2) protein in the chromatin of early- (before 24 hr) and late-cleaved (after 24 hr) bovine embryos derived from small- (1-2 mm) and large-follicles (4-8 mm). The presence of HMGN2 and H3K14ac has been associated with different nuclear functions including chromatin condensation, transcription, DNA replication and repair. In vitro matured oocytes were parthenogenetically activated (PA) and cultured in synthetic oviduct fluid medium. Early- and late-cleaved embryos were fixed at 36, 50, 60, 70 and 80 hr after PA to detect the presence of H3K14ac and HMGN2. The rates of nuclear maturation (81.1% vs. 58.7%), early cleavage (46.9% vs. 38.9%), and development to blastocyst stage (34.3% vs. 18.9%) were higher (P < 0.05) in oocytes derived from large- compared to small follicles. The proportion of positively stained nuclei at 50 and 60 hr after PA was higher for both H3K14ac (27.2% vs. 4.8% and 64.3% vs. 30%) and HMGN2 (47% vs. 21.3% and 60.6% vs. 46%) in early versus late cleaved embryos derived from small- versus large-follicles, respectively. However, the rate of positive nuclei in early-cleaved embryos from small-versus large-follicles was similar for HMGN2 (87% vs. 93%) but lower for H3K14ac (51% vs. 64.4%) at 80 hr after PA. These data suggest that less developmentally competent embryos derived from small follicles had an altered chromatin remodeling process at the early stages of development compared to those derived from large follicles that are more competent to support development to blastocyst stage. PMID- 17712802 TI - Novel bulky esters of cellulose. AB - Novel bulky esters of cellulose were synthesized homogeneously, applying the solvent systems DMA/LiCl or DMSO/TBAF, by conversion of the biopolymer with aryl polyester dendrons. The carboxylic acid moieties were efficiently activated in situ with CDI or the acid chloride was applied. Cellulose esters with DS values of up to 0.7 were obtained. The functionalization pattern was analyzed by different NMR spectroscopic techniques indicating that not only position 6 (primary hydroxyl group) but also the secondary one at position 2 was included in the reaction. PMID- 17712803 TI - Processing and characterization of waxy maize starch films plasticized by sorbitol and reinforced with starch nanocrystals. AB - Nanocomposites films have been processed from a filler and a matrix having the same nature, i.e. waxy maize starch. The filler consists of nanoplatelet-like starch particles obtained as an aqueous suspension by acid hydrolysis of starch granules and the matrix was prepared by plasticization and disruption of starch granules with water and sorbitol. Nanocomposite films were obtained by casting and evaporating the mixture of the aqueous suspension of starch nanocrystals with the gelatinized starch. The resulting films were conditioned before testing and the effect of accelerated ageing in moist atmosphere was investigated. The thermal properties of the nanocomposite films were determined from DSC measurements and the mechanical characterization was performed in both the linear and nonlinear range. PMID- 17712804 TI - Polymer-controlled, bio-inspired calcium phosphate mineralization from aqueous solution. AB - Nowadays, the majority of the commercially available calcium phosphate materials is fabricated by 'classical' materials science approaches, i.e., from rather poorly defined slurries or from organic solvents, often at high temperatures and pressures. Bioinspired precipitation of inorganics with (polymeric) additives from aqueous solution, on the other hand, enables the synthesis of intriguing inorganic or organic/inorganic materials that are often much more closely related to biological structures. This article discusses approaches for the fabrication of bio-inspired calcium phosphate hybrid materials by precipitation from aqueous solution. The article focuses on polymers and related self-assembling structures for the design of CaP/organic hybrids and pure CaP with crystal structures and morphologies regulated by the respective additive. PMID- 17712805 TI - Direct visualization of enantiospecific substitution of chiral guest molecules into heterochiral molecular assemblies at surfaces. PMID- 17712806 TI - Return to the RNAi world: rethinking gene expression and evolution (Nobel Lecture). PMID- 17712807 TI - Push-pull molybdenum trisdithiolenes allow rapid nonconventional binding of ethylene at ligand sulfur atoms. PMID- 17712808 TI - A cheap, efficient, and environmentally benign synthesis of the versatile catalyst methyltrioxorhenium (MTO). PMID- 17712809 TI - In vitro synthesis of new enniatins: probing the alpha-D-hydroxy carboxylic acid binding pocket of the multienzyme enniatin synthetase. PMID- 17712810 TI - Cannabis and endocannabinoids: 'the old man and the teenagers'. PMID- 17712811 TI - History of cannabis and its preparations in saga, science, and sobriquet. AB - Cannabis sativa L. is possibly one of the oldest plants cultivated by man, but has remained a source of controversy throughout its history. Whether pariah or panacea, this most versatile botanical has provided a mirror to medicine and has pointed the way in the last two decades toward a host of medical challenges from analgesia to weight loss through the discovery of its myriad biochemical attributes and the endocannabinoid system wherein many of its components operate. This study surveys the history of cannabis, its genetics and preparations. A review of cannabis usage in Ancient Egypt will serve as an archetype, while examining first mentions from various Old World cultures and their pertinence for contemporary scientific investigation. Cannabis historians of the past have provided promising clues to potential treatments for a wide array of currently puzzling medical syndromes including chronic pain, spasticity, cancer, seizure disorders, nausea, anorexia, and infectious disease that remain challenges for 21st century medicine. Information gleaned from the history of cannabis administration in its various forms may provide useful points of departure for research into novel delivery techniques and standardization of cannabis-based medicines that will allow their prescription for treatment of these intractable medical conditions. PMID- 17712812 TI - Phytocannabinoids in Cannabis sativa: recent studies on biosynthetic enzymes. PMID- 17712814 TI - Cannabidiol--recent advances. AB - The aim of this review is to present some of the recent publications on cannabidiol (CBD; 2), a major non-psychoactive constituent of Cannabis, and to give a general overview. Special emphasis is laid on biochemical and pharmacological advances, and on novel mechanisms recently put forward, to shed light on some of the pharmacological effects that can possibly be rationalized through these mechanisms. The plethora of positive pharmacological effects observed with CBD make this compound a highly attractive therapeutic entity. PMID- 17712813 TI - On the pharmacological properties of Delta9-tetrahydrocannabinol (THC). AB - Cannabis is one of the first plants used as medicine, and the notion that it has potentially valuable therapeutic properties is a matter of current debate. The isolation of its main constituent, Delta9-tetrahydrocannabinol (THC), and the discovery of the endocannabinoid system (cannabinoid receptors CB1 and CB2 and their endogenous ligands) made possible studies concerning the pharmacological activity of cannabinoids. This paper reviews some of the most-important findings in the field of THC pharmacology. Clinical trials, anecdotal reports, and experiments employing animal models strongly support the idea that THC and its derivatives exhibit a wide variety of therapeutic applications. However, the psychotropic effects observed in laboratory animals and the adverse reactions reported during human trials, as well as the risk of tolerance development and potential dependence, limit the application of THC in therapy. Nowadays, researchers focus on other therapeutic strategies by which the endocannabinoid system might be modulated to clinical advantage (inhibitor or activator of endocannabinoid biosynthesis, cellular uptake, or metabolism). However, emerging evidence highlights the beneficial effects of the whole cannabis extract over those observed with single components, indicating cannabis-based medicines as new perspective to revisit the pharmacology of this plant. PMID- 17712815 TI - From active ingredients to the discovery of the targets: the cannabinoid receptors. PMID- 17712816 TI - Medicinal chemistry endeavors around the phytocannabinoids. AB - Over the past 50 years, a considerable research in medicinal chemistry has been carried out around the natural constituents of Cannabis sativa L. Following the identification of Delta9-tetrahydrocannabinol (Delta9-THC) in 1964, critical chemical modifications, e.g., variation of the side chain at C3 and the opening of the tricyclic scaffold, have led to the characterization of potent and cannabinoid receptor subtype-selective ligands. Those ligands that demonstrate high affinity for the cannabinoid receptors and good biological efficacy are still used as powerful pharmacological tools. This review summarizes past as well as recent developments in the structure-activity relationships of phytocannabinoids. PMID- 17712817 TI - Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. AB - Cannabis sativa L. has been utilized for treatment of pain and sleep disorders since ancient times. This review examines modern studies on effects of Delta9 tetrahydrocannabinol (THC) and cannabidiol (CBD) on sleep. It goes on to report new information on the effects on sleep in the context of medical treatment of neuropathic pain and symptoms of multiple sclerosis, employing standardized oromucosal cannabis-based medicines containing primarily THC, CBD, or a 1 : 1 combination of the two (Sativex). Sleep-laboratory results indicate a mild activating effect of CBD, and slight residual sedation with THC-predominant extracts. Experience to date with Sativex in numerous Phase I-III studies in 2000 subjects with 1000 patient years of exposure demonstrate marked improvement in subjective sleep parameters in patients with a wide variety of pain conditions including multiple sclerosis, peripheral neuropathic pain, intractable cancer pain, and rheumatoid arthritis, with an acceptable adverse event profile. No tolerance to the benefit of Sativex on pain or sleep, nor need for dosage increases have been noted in safety extension studies of up to four years, wherein 40-50% of subjects attained good or very good sleep quality, a key source of disability in chronic pain syndromes that may contribute to patients' quality of life. PMID- 17712818 TI - The toxicology of cannabis and cannabis prohibition. AB - The acute side effects caused by cannabis use are mainly related to psyche and cognition, and to circulation. Euphoria, anxiety, changes in sensory perception, impairment of memory and psychomotor performance are common effects after a dose is taken that exceeds an individually variable threshold. Cannabis consumption may increase heart rate and change blood pressure, which may have serious consequences in people with heart disease. Effects of chronic use may be induction of psychosis and development of dependency to the drug. Effects on cognitive abilities seem to be reversible after abstinence, except possibly in very heavy users. Cannabis exposure in utero may have negative consequences on brain development with subtle impairment of cognitive abilities in later life. Consequences of cannabis smoking may be similar to those of tobacco smoking and should be avoided. Use by young people has more detrimental effects than use by adults. There appear to be promising therapeutic uses of cannabis for a range of indications. Use of moderate doses in a therapeutic context is usually not associated with severe side effects. Current prohibition on cannabis use may also have harmful side effects for the individual and the society, while having little influence on prevalence of use. Harm is greatest for seriously ill people who may benefit from a treatment with cannabis. This makes it difficult to justify criminal penalties against patients. PMID- 17712820 TI - Blocking the cannabinoid receptors: drug candidates and therapeutic promises. AB - The CB1 and CB2 cannabinoid receptors have been described as two prime sites of action for endocannabinoids. Both the localization and pharmacology of these two G-protein-coupled receptors are well-described, and numerous selective ligands have been characterized. The physiological effects of Cannabis sativa (cannabis) and a throughout study of the endocannabinoid system allowed for the identification of several pathophysiological conditions--including obesity, dyslipidemia, addictions, inflammation, and allergies--in which blocking the cannabinoid receptors might be beneficial. Many CB1 receptor antagonists are now in clinical trials, and the results of several studies involving the CB1 antagonist lead compound rimonabant (SR141716A) are now available. This review describes the pharmacological tools that are currently available and the animal studies supporting the therapeutic use of cannabinoid receptor antagonists and inverse agonists. The data available from the clinical trials are also discussed. PMID- 17712821 TI - Discovery and isolation of anandamide and other endocannabinoids. PMID- 17712822 TI - Biosynthetic pathways of the endocannabinoid anandamide. AB - Anandamide (=N-arachidonoylethanolamine) is the first discovered endocannabinoid, and belongs to the class of bioactive, long-chain N-acylethanolamines (NAEs). In animal tissues, anandamide is principally formed together with other NAEs from glycerophospholipid by two successive enzymatic reactions: 1) N-acylation of phosphatidylethanolamine to generate N-acylphosphatidylethanolamine (NAPE) by Ca2+-dependent N-acyltransferase; 2) release of NAE from NAPE by a phosphodiesterase of the phospholipase D type (NAPE-PLD). Although these anandamide-synthesizing enzymes were poorly understood until recently, our cDNA cloning of NAPE-PLD in 2004 enabled molecular-biological approaches to the enzymes. NAPE-PLD is a member of the metallo-beta-lactamase family, which specifically hydrolyzes NAPE among glycerophospholipids, and appears to be constitutively active. Mutagenesis studies suggested that the enzyme functions through a mechanism similar to those of other members of the family. NAPE-PLD is widely expressed in animal tissues, including various regions in rat brain. Its expression level in the brain is very low at birth, and remarkably increases with development. Analysis of NAPE-PLD-deficient mice and other recent studies revealed the presence of NAPE-PLD-independent pathways for the anandamide formation. Furthermore, calcium-independent N-acyltransferase was discovered and characterized. In this article, we will review recent progress in the studies on these enzymes responsible for the biosynthesis of anandamide and other NAEs. PMID- 17712823 TI - The multiple pathways of endocannabinoid metabolism: a zoom out. PMID- 17712824 TI - Fatty acid amide hydrolase: from characterization to therapeutics. AB - Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme within the amidase-signature family that terminates the action of several endogenous lipid messengers, including oleamide and the endocannabinoid anandamide. The hydrolysis of such messengers leads to molecules devoid of biological activity, and, therefore, modulates a number of neurobehavioral processes in mammals, including pain, sleep, feeding, and locomotor activity. Investigations into the structure and function of FAAH, its biological and therapeutic implications, as well as a description of different families of FAAH inhibitors are the topic of this review. PMID- 17712819 TI - Human cannabinoid pharmacokinetics. PMID- 17712825 TI - Tuning the stacking properties of C3-symmetrical molecules by modifying a dipeptide motif. AB - C3-symmetrical molecules are described which consists of a 1,3,5 benzenetricarboxamide core extended with dipeptide fragments bearing peripheral mesogenic groups. Small structural modifications in the dipeptide fragment have been performed to demonstrate their influence on the stability of the stacks and on the order within the self-assemblies formed. Seven C3-symmetrical discs have been investigated, all with different combinations of glycine, L- and/or D phenylalanine in the dipeptide fragments. Characterization of these discotics in the neat state using differential scanning calorimetry (DSC), X-ray diffraction (XRD) and polarized optical microscopy (POM) and in solution with circular dichroism (CD), UV-visible spectroscopy, low-concentration proton nuclear magnetic resonance and IR spectroscopy reveals that there is a clear trend in the stack stability, going from the glycine-phenylalanine motifs to the phenylalanine phenylalanine ones. The combination of a larger hydrophobic core, more confinement of space and the possibility of additional pi-pi interactions leads to more stable stacks. Surprisingly, the weakest stacks consist of discotics of which the center is extended with L-phenylalanyl-glycines and not of discotics of which the center is extended with the glycyl-L-phenylalanine sequences. Furthermore, the XRD investigations show that it is difficult to form well ordered self-assemblies in the neat state. And, CD measurements point out that some of the discs have a very complex energy landscape in solution. These observations suggest that small differences in the balance between the secondary interactions originating from the benzenetricarboxamide core and the dipeptide fragments, have a strong influence on the order within the stack. From these results it can be concluded that subtle modifications in the peptide fragments of the discs cause significant changes in the stacking properties, stressing the importance of understanding the self-assembly mechanism of each discotic in order to clarify its self-assembly behavior. PMID- 17712826 TI - Carbohydrates as synthetic tools in organic chemistry. AB - While amino acids, terpenes and alkaloids have found broad application as tools in stereoselective organic synthesis, carbohydrates have only lately been recognised as versatile starting materials for chiral auxiliaries, reagents, ligands and organocatalysts. The structural diversity of carbohydrates and the high density of functional groups offer a wide variety of opportunities for derivatization and tailoring of synthetic tools to a specific problem. PMID- 17712827 TI - Protein side chains facilitate Mg/Al exchange in model protein binding sites. AB - Among the most frequent protein binding sites served by Mg(II), we identify those which have higher affinity towards Al(III). We also estimate the free energies of metal exchange for all these binding sites taking into account solvent effects explicitly. The obtained results show that thermodynamically favored Mg(II)/Al(III) exchange reactions take place at a number of these metal binding sites, which could possibly be related to some dysfunctions of Mg(II)-dependent biological processes. Additionally, they shed light on the molecular basis of the toxicity of Al(III) in living organisms. PMID- 17712829 TI - A simple pathway to the synthesis of magnetic nanoparticles with immobilized metal ions for the fast removal of microcystins in water. PMID- 17712828 TI - A cryptophane biosensor for the detection of specific nucleotide targets through xenon NMR spectroscopy. PMID- 17712830 TI - Structural identification of DNA adducts derived from 3-nitrobenzanthrone, a potent carcinogen present in the atmosphere. AB - 3-Nitrobenzanthrone is a powerful bacterial mutagen and carcinogen to mammals. To obtain precise information on DNA-adduct formation by 3-nitrobenzanthrone, a number of DNA adducts, including N-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone (13 a), 2-(2'-deoxyguanosin-N2-yl)-3-aminobenzanthrone (14 a), N-(2' deoxyadenosin-8-yl)-3-aminobenzanthrone (15 a), 2-(2'-deoxyadenosin-N6-yl)-3 aminobenzanthrone (16 a), and their N-acetylated counterparts 13 b, 14 b, 15 b, and 16 b were synthesized by palladium-catalyzed aryl amination of the corresponding nucleoside and bromobenzanthrone derivatives. Among these DNA adducts, DNA adducts 13 a, 13 b, 14 a, 14 b, and 16 a were identified in the reaction mixture of nucleosides (2'-deoxyguanosine, 2'-deoxyadenosine, or DNA) with N-acetoxy-3-aminobenzanthrone or N-acetyl-N-acetoxy-3-aminobenzanthrone, both of which are recognized as activated metabolites of 3-nitrobenzanthrone. The formation of these multiple DNA adducts may help explain the potent mutacarcinogenicity of 3-nitrobenzanthrone. PMID- 17712831 TI - A DFT study on the mechanism of Rh2(II,II)-catalyzed intramolecular amidation of carbamates. AB - The potential-energy surfaces of the reactions of dirhodium tetracarboxylate (Rh2(II,II)) catalyzed nitrene (NR) insertion into C-H bonds were examined by a DFT computational study. A pure Becke exchange functional (B88) rather than a hybrid exchange functional (B3, BHandH) was found to be appropriate for the calculation of the energy difference between the singlet and triplet Rh2(II,II) NH nitrene species. Rh2(II,II)-NR1 (R1 = (S)-2-methyl-1-butylformyl) is thermodynamically more favorable with a free energy lower than that of Rh2(II,II) N(PhI)R1. The singlet and triplet states of Rh2(II,II)-NR1 have similar stability. Singlet Rh2(II,II)-NR1 undergoes a concerted NR insertion into the C-H bond with simultaneous formation of the N-H and N-C bonds during C-H bond cleavage; triplet Rh2(II,II)-NR1 undergoes H atom abstraction to produce a diradical, followed by subsequent bond formation by diradical recombination. The singlet pathway is favored over the triplet in the context of the free energy of activation and leads to the retention of the chirality of the C atom in the NR insertion product. The reactivities of the C-H bonds toward the nitrene-insertion reaction follow the order tertiary > secondary > primary. Relative reaction rates were calculated for the six reaction pathways examined in this work. PMID- 17712832 TI - Monoglyceride lipase as an enzyme hydrolyzing 2-arachidonoylglycerol. PMID- 17712833 TI - The N-acylethanolamine-hydrolyzing acid amidase (NAAA). AB - Bioactive N-acylethanolamines, including the endocannabinoid anandamide and anti inflammatory N-palmitoylethanolamine, are hydrolyzed to fatty acids and ethanolamine in animal tissues by the catalysis of fatty acid amide hydrolase (FAAH). We recently cloned cDNA of N-acylethanolamine-hydrolyzing acid amidase (NAAA), another enzyme catalyzing the same reaction, from human, rat, and mouse. NAAA reveals no sequence homology with FAAH and belongs to the choloylglycine hydrolase family. The most striking catalytic property of NAAA is pH optimum at 4.5-5, which is consistent with its immunocytochemical localization in lysosomes. In rat, NAAA is highly expressed in lung, spleen, thymus, and intestine. Notably, the expression level of NAAA is exceptionally high in rat alveolar macrophages. The primary structure of NAAA exhibits 33-35% amino acid identity to that of acid ceramidase, a lysosomal enzyme hydrolyzing ceramide to fatty acid and sphingosine. NAAA actually showed a low, but detectable ceramide-hydrolyzing activity, while acid ceramidase hydrolyzed N-lauroylethanolamine. Thus, NAAA is a novel lysosomal hydrolase, which is structurally and functionally similar to acid ceramidase. These results suggest a unique role of NAAA in the degradation of N acylethanolamines. PMID- 17712834 TI - Genetic polymorphisms of the endocannabinoid system. AB - Disturbances in the endocannabinoid system has been linked to diseases and conditions such as Parkinson's, schizophrenia, pain, energy metabolism, immune modulation, and bone density. Since the early 1990s, a number of genetic polymorphisms in the genes and proteins of the endocannabinoid system have been characterized. Currently identified genetic polymorphisms of the endocannabinoid system are reviewed here with particular consideration given to polymorphisms linked to drug and alcohol abuse, schizophrenia, other mental disorders, and energy metabolism. PMID- 17712835 TI - The N-acylethanolamine-mediated regulatory pathway in plants. AB - While cannabinoids are secondary metabolites synthesized by just a few plant species, N-acylethanolamines (NAEs) are distributed widely in the plant kingdom, and are recovered in measurable, bioactive quantities in many plant-derived products. NAEs in higher plants are ethanolamides of fatty acids with acyl-chain lenghts of C12-C(18) and zero to three C=C bonds. Generally, the most-abundant NAEs found in plants and vertebrates are similar, including NAE 16 : 0, 18 : 1, 18 : 2, and 18 : 3. Like in animal systems, NAEs are formed in plants from N acylphosphatidylethanolamines (NAPEs), and they are hydrolyzed by an amidase to yield ethanolamine and free fatty acids (FFA). Recently, a homologue of the mammalian fatty acid amide hydrolase (FAAH-1) was identified in Arabidopsis thaliana and several other plant species. Overexpression of Arabidopsis FAAH (AtFAAH) resulted in plants that grew faster, but were more sensitive to biotic and abiotic insults, suggesting that the metabolism of NAEs in plants resides at the balance between growth and responses to environmental stresses. Similar to animal systems, exogenously applied NAEs have potent and varied effects on plant cells. Recent pharmacological approaches combined with molecular-genetic experiments revealed that NAEs may act in certain plant tissues via specific membrane-associated proteins or by interacting with phospholipase D-alpha, although other, direct targets for NAE action in plants are likely to be discovered. Polyunsaturated NAEs can be oxidized via the lipoxygenase pathway in plants, producing an array of oxylipin products that have received little attention so far. Overall, the conservation of NAE occurrence and metabolic machinery in plants, coupled with the profound physiological effects of elevating NAE content or perturbing endogenous NAE metabolism, suggest that an NAE-mediated regulatory pathway, sharing similarities with the mammalian endocannabinoid pathway, indeed exists. PMID- 17712836 TI - New players in the cytokine orchestra of inflammatory bowel disease. AB - In both Crohn's disease (CD) and ulcerative colitis, the pathologic process is almost certainly driven by an aberrant local immune response directed against normal components of the bacterial microflora. Mucosal immune cells interact with nonimmune cells such as epithelial cells and fibroblasts to promote tissue damage; cytokines are essential mediators of this cross talk. Accumulating evidence now suggests that interleukin-21 (IL-21), the newest member of the common gamma-chain-dependent cytokine family, is a key component of the inflammatory cascade. IL-21 is highly produced by activated CD4+ lymphocytes in the inflamed gut of patients with CD, where it contributes to sustaining the ongoing Th1 inflammation. IL-21 also increases the secretion of extracellular matrix-degrading enzymes by fibroblasts and of MIP-3alpha by epithelial cells. Two other cytokines, IL-27 and IL-32, may also be important in the inflammatory pathways that operate in IBD. PMID- 17712837 TI - Lamivudine resistance and exacerbation of hepatitis B in infliximab-treated Crohn's disease patient. PMID- 17712838 TI - Isolation of flagellated bacteria implicated in Crohn's disease. AB - BACKGROUND: Serologic expression cloning has identified flagellins of the intestinal microbiota as immunodominant antigens in experimental colitis in mice and in individuals with Crohn's disease (CD). The present study was done to identify the microbial source of such flagellins. METHODS: Using a variety of isolation and culture approaches, a number of previously unknown flagellated bacteria were isolated. Based on 16S ribosomal DNA sequences, these bacteria fall into the family Lachnospiraceae of the phylum Firmicutes. RESULTS: Serum IgG from patients with CD and from mice with colitis reacted to the flagellins of these bacteria, and only their flagellins, whereas serum IgG from controls did not. The sequence of these flagellins demonstrate conserved amino- and carboxy-terminal domains that cluster phylogenetically and have a predicted 3D structure similar to Salmonella fliC, including an intact TLR5 binding site. The flagellin of 1 of these bacteria was likely O-glycosylated. CONCLUSIONS: The conserved immune response in both mouse and human to these previously unknown flagellins of the microbiota indicate that they play an important role in host-microbe interactions in the intestine. PMID- 17712839 TI - Irritable pouch syndrome is associated with depressiveness and can be differentiated from pouchitis by quantification of mucosal levels of proinflammatory gene transcripts. AB - BACKGROUND: Pouchitis and irritable pouch syndrome (IPS) are 2 of the most frequent sequelae of ileal pouch-anal anastomosis (IPAA) after restorative proctocolectomy in patients with ulcerative colitis. These complications can compromise the gain in health-related quality of life (HRQOL) substantially. The pathophysiological mechanisms underlying IPS and the predictors of HRQOL in IPS have not been studied so far. METHODS: In IPAA patients in remission (n = 10), patients with pouchitis (n = 18) and patients with IPS (n = 15) symptoms, endoscopical and histological patterns, anxiety and depressiveness (Hospital Anxiety and Depression Scale HADS), and HRQOL scores (Inflammatory Bowel Disease Questionnaire, IBDQ-D) were assessed. Mucosal expression of 5 proinflammatory gene transcripts (MRP-14, IL-1beta, IL-8, MIP-2alpha, and MMP-1) were quantified using real-time polymerase chain reaction. RESULTS: Clinical symptoms and HRQOL differed significantly (P < 0.01) between patients in remission on the one hand and those with pouchitis or IPS on the other. However, between IPS and pouchitis no such differences could be found. Depressiveness scores differed between IPS and patients in remission (P = 0.05). HRQOL in IPS was predicted by depressiveness (P < 0.001). Cytokine transcripts discriminated between pouchitis and IPS (P < 0.01), whereas between IPS patients and asymptomatic patients no such differences were observed. CONCLUSIONS: Patients with IPS and pouchitis cannot be differentiated by clinical symptoms or HRQOL, which is associated with depressiveness in IPS patients. IPS is a noninflammatory sequela in IPAA patients that shares clinical features with IBD. Quantification of mucosal proinflammatory gene transcripts differentiates objectively and simply between IPS and pouchitis. PMID- 17712840 TI - Genome-wide association scans identify multiple confirmed susceptibility loci for Crohn's disease: lessons for study design. AB - The last 12 months have seen unprecedented progress in identifying the susceptibility genes that predispose to common disease in general and Crohn's disease in particular. Success has derived from the new technique of genome-wide association scanning in large panels of cases and controls. This has itself been made possible by the sequencing of the human genome,12 development of a map of common human haplotype structure (HapMap),3 and advances in genotyping technologies permitting ascertainment of hundreds of thousands of genetic variants in multiple individuals. Several previously unsuspected pathways particularly relating to innate immunity and the early host response to bacteria have been revealed as key determinants of Crohn's disease susceptibility. These will provide a solid foundation for directed functional and translational research. Further, the wealth of confirmed association data coming from unbiased surveys of the genome provided by genome-wide association scans provide several key pointers regarding design and analysis of inflammatory bowel disease genetics studies in the future. PMID- 17712841 TI - Looking for leukemia clues in of all places....meconium! PMID- 17712842 TI - Reliability and validity of ICARS in focal cerebellar lesions. AB - To evaluate the therapies for cerebellar diseases appropriate neurological assessment methods to measure severity of ataxia are required. Reliability and validity of the semiquantitative International Cooperative Ataxia Rating Scale (ICARS) has recently been examined in patients with degenerative ataxias. We evaluated reliability (internal consistency), criterion-related validity and internal construct validity of ICARS for the first time in patients with focal cerebellar lesions (68 patients with surgical lesions and 68 patients with ischemic lesions). For comparison 45 patients with degenerative cerebellar ataxia were included. We found an excellent Cronbach's alpha as a measurement for internal consistency which was independent from underlying disease. Criterion related validity was high. Total ICARS score mirrored clearly the immediate postsurgical worsening and the improvement during the first 3 months after focal surgical and ischemic lesions, whereas in chronic state of focal and degenerative cerebellar disorders ICARS score remained nearly unchanged. Principal component analysis in patients with focal lesions revealed five distinct and clinically meaningful factors which corresponded to the four ICARS subscores and reflected the laterality of kinetic functions. In degenerative disorders, however, the items for the subscore "kinetic function" loaded to more than one factor. Total ICARS score seems to be a useful and valid measurement to describe the time course of ataxia in patients with focal and degenerative disorders affecting primarily the cerebellum. Validity of subscores however is good in focal, but not in degenerative disorders. PMID- 17712843 TI - Assessment of psychiatric complications in Parkinson's disease: The SCOPA-PC. AB - The objective of this study was to develop a clinimetric sound scale that addresses both psychotic and compulsive complications in Parkinson's disease (PD). The SCales for Outcomes in PArkinson's disease-Psychiatric Complications (SCOPA-PC) was developed by modifying the items of the Parkinson Psychosis Rating Scale (PPRS) and including an item on compulsive behavior in PD. To evaluate the validity of the SCOPA-PC, 106 PD patients were assessed. A subsample of 43 patients was assessed for interrater and test-retest reliability. Construct validity was evaluated using the Neuropsychiatric Inventory (NPI) and the South Oaks Gambling Scale (SOGS). Interrater and test-retest reliability for the total score was 0.95 and 0.91 (intraclass correlation coefficient), respectively. For the items, the interrater reliability ranged from 0.62 to 0.96 (weighted kappa) and the test-retest reliability ranged from 0.54 to 0.88 (weighted kappa). Cronbach's alpha was 0.68. The correlation between the SCOPA-PC total score and the NPI was 0.41. The correlation between SCOPA-PC items and NPI items that addressed similar constructs ranged from 0.34 to 0.68, whereas the correlation between the item on compulsive behavior and the SOGS was 0.49. In conclusion, the SCOPA-PC is a reliable, valid, and easily-administered semistructured questionnaire for both psychotic and compulsive complications in PD. PMID- 17712844 TI - Different cerebral cortical areas influence the effect of subthalamic nucleus stimulation on parkinsonian motor deficits and freezing of gait. AB - Inconsistent response in freezing of gait (FOG) with levodopa treatment or STN DBS makes the pathogenesis difficult to understand. We studied brain areas associated with the expression of STN DBS effect on parkinsonian motor deficits and FOG. Ten Parkinson's disease patients with typical FOG were included. One month before STN DBS, we performed [(18)F]-deoxyglucose PET scans and measured the UPDRS motor and modified FOG (mFOG) scores during levodopa off and on periods. At two months after STN DBS, same rating scores were measured. The percentage improvement of mFOG and UPDRS motor scores by STN DBS during levodopa off period was calculated. We searched for brain areas in which glucose metabolism correlated with the improvement of mFOG and UPDRS motor scores by DBS. During levodopa off period, STN DBS improved the UPDRS motor scores by 32.3% and the mFOG scores by 56.6%. There was no correlation between the improvements of both scores. The improvement of UPDRS motor score by DBS correlated with the metabolic activities of rostral supplementary motor area (Brodmann's area 8; BA8), anterior cingulate cortex (BA32), and prefrontal cortex (BA9). On the other hand, there was a positive correlation between the improvement of mFOG score by DBS and the metabolic activity of the parietal, occipital, and temporal sensory association cortices. In conclusion, dysfunction of different cerebral cortical areas limits the beneficial effects of DBS on parkinsonian motor deficits and FOG. PMID- 17712845 TI - A large Italian family with Gilles de la Tourette syndrome: clinical study and analysis of the SLITRK1 gene. AB - Our objective was to report the clinical characteristics and to investigate the role of SLITRK1 gene in a large Italian family with Tourette syndrome (TS). The diagnosis of TS and chronic motor tics (CMT) was made according to "The Tourette Syndrome Classification Study Group" (1993). Psychiatric diagnoses were made by administering the Structured Clinical Interview for DSM and the Yale-Brown Obsessive Compulsive Scale. Genetic study included direct sequencing and copy number analysis of the SLITRK1 gene, and haplotype analysis. We found tics or other behavioral manifestations in 15 subjects. Of these, 5 received a diagnosis of definite TS, 5 were classified as having definite CMT, 2 had definite nonspecific tic disorder, and 3 patients had obsessive-compulsive disorder without motor or phonic tics. Tics mainly involved the craniocervical district. Many patients with tics had coexisting psychiatric disorders, especially obsessive-compulsive disorder, performed poorly at school and had social problems. Direct sequencing and copy number analysis of the SLITRK1 gene, and haplotype analysis suggested that the SLITRK1 locus was not involved in this family. In conclusion, the distinctive clinical features in this family are the motor tics mainly involving the face and the neck and the severe coexisting psychiatric disorders. The negative results of the SLITRK1 analysis point to genetic heterogeneity in TS. PMID- 17712846 TI - Acute ataxia, Graves' disease, and stiff person syndrome. AB - Stiff person syndrome (SPS) has been associated with autoimmune diseases, such as Type 1 diabetes mellitus and autoimmune thyroid disease (Hashimoto's thyroiditis), among others. The association of SPS with hyperthyroidism is extremely rare. We describe a patient with uncontrolled Graves' disease and undiagnosed SPS, who presented initially with acute ataxia simulating a cerebrovascular accident. Initiation of immunosuppressive therapy dramatically improved the patient's Graves' disease within 2 weeks but the neurological symptoms were not alleviated after a follow-up period of 3 years. PMID- 17712847 TI - Isolated navicular fracture presenting as stiff limb syndrome: a case report. PMID- 17712848 TI - Coffee and tea consumption and the risk of Parkinson's disease. AB - Several prospective studies have assessed the association between coffee consumption and Parkinson's disease (PD) risk, but the results are inconsistent. We examined the association of coffee and tea consumption with the risk of incident PD among 29,335 Finnish subjects aged 25 to 74 years without a history of PD at baseline. During a mean follow-up of 12.9 years, 102 men and 98 women developed an incident PD. The multivariate-adjusted (age, body mass index, systolic blood pressure, total cholesterol, education, leisure-time physical activity, smoking, alcohol and tea consumption, and history of diabetes) hazard ratios (HRs) of PD associated with the amount of coffee consumed daily (0, 1-4, and > or = 5 cups) were 1.00, 0.55, and 0.41 (P for trend = 0.063) in men, 1.00, 0.50, and 0.39 (P for trend = 0.073) in women, and 1.00, 0.53, and 0.40 (P for trend = 0.005) in men and women combined (adjusted also for sex), respectively. In both sexes combined, the multivariate-adjusted HRs of PD for subjects drinking > or = 3 cups of tea daily compared with tea nondrinkers was 0.41 (95% CI 0.20 0.83). These results suggest that coffee drinking is associated with a lower risk of PD. More tea drinking is associated with a lower risk of PD. PMID- 17712849 TI - Pharmacokinetics of itraconazole after intravenous and oral dosing of itraconazole-cyclodextrin formulations. AB - The current research evaluated and compared the efficacy of hydroxybutenyl-beta cyclodextrin (HBenBCD) and hydroxypropyl-beta-cyclodextrin (HPBCD) as enhancers of itraconazole solubility and oral bioavailability. At 10 wt% cyclodextrin, 17 fold and 3.8-fold increases in itraconazole aqueous solubility were observed in the presence of HBenBCD and HPBCD, respectively. Significant differences in the dissolution of itraconazole in the presence of these two cyclodextrins were also observed. Itraconazole pharmacokinetics is known to exhibit a significant food effect. However, testing in biorelevant media indicated that no food effects should be observed after oral administration of itraconazole:HBenBCD complexes. Formulations of itraconazole with HBenBCD were prepared and these complexes, along with the commercial forms of itraconazole with and without HPBCD (Sporanox) were administered to male Sprague-Dawley rats by oral and intravenous routes. Intravenous administration of itraconazole formulated with HBenBCD resulted in a higher AUC relative to Sporanox. When administered as oral solutions, the itraconazole:HBenBCD formulation provided higher oral bioavailability than the Sporanox oral solution. When administered as solid formulations, the itraconazole:HBenBCD solid formulation provided a 2x increase in oral bioavailability relative to the Sporanox solid formulation. No food effects were observed with the itraconazole:HBenBCD solid dosage forms. Drug/metabolite ratios were dependent upon the dosage form. PMID- 17712850 TI - Biochemical investigation of active intracellular transport of polymeric gene delivery vectors. AB - To design safe, efficient synthetic gene therapy vectors, it is desirable to understand the intracellular mechanisms that facilitate their delivery from the cell surface to the nucleus. Elements of the cytoskeleton and molecular motor proteins are known to play a pivotal role in most intracellular active transport processes. The actin depolymerizer cytochalasin D and microtubule effectors colchicine and paclitaxel were used to evaluate the function of these components of the cytoskeleton in the trafficking of polyethylenimine (PEI)-DNA complexes. In addition, ATPase inhibitors erythro-9[3-(2-hydroxynonyl)] adenine (EHNA), vanadate, adenylylimidodiphosphate (AMP-PNP), and rose bengal lactone (RBL), which have inhibitory activity against dynein and kinesin, were used to examine to the effects of these molecular motors on PEI-DNA delivery. Disruption of microfilaments decreased the delivery efficiency of PEI polyplexes 60-80%, though cytochalasin D did not significantly inhibit uptake. Depolymerization of microtubules by colchicine decreased transfection efficiency by 75%. Microtubule stabilization with paclitaxel, however, facilitated a 20-fold increase in gene expression. Treatment with EHNA and vanadate caused 50% and 80% decreases in transfection efficiency, respectively. Transfection efficiency was also decreased by RBL (80%) and AMP-PNP (98%). Our findings confirm the importance of microfilament- and microtubule-based active transport of PEI-DNA complexes. Further, the strong decrease in transfection efficiency caused by ATPase inhibitors that possess inhibitory activity against kinesin implies an unexpected role for these motors in gene delivery. PMID- 17712852 TI - Embouchure dystonia and tremor in a professional windpipe "Nadaswaram" player. PMID- 17712851 TI - Psychogenic camptocormia. AB - Camptocormia describes a severe forward-flexion at the waist. Originally used in reference to a conversion disorder seen in military personel (Souques and Rosanoff-Saloff, Rev Neurol 1915, 22, 937; Rosen and Frymoyer, Spine 1985, 10, 325; Miller and Forbes, Br J Psychiatry 1990, 157, 765; Perez-Sales, Arch Phys Med Rehabil 1990, 71, 1078; Sinel and Eisenberg, Rev Rhum Mal Osteoartic 1992, 59, 169; Miller and Forbes, Mil Med 1990, 155, 561; Belgrano and Giordano, Rev Neurol 1947, 79, 25-35), the term has been adapted to describe severely flexed postures observed in Parkinson disease (Djaldetti et al., Mov Disord 1999, 14, 443), other basal ganglia disorders (Nieves et al., Mov Disord 2001, 16, 177; Reichel et al., Nervenarzt 2001, 72, 281), and muscular disease (Delcey et al., Rev Med Intern 2002, 23, 144; Van Gerpen, Mov Disord 2001, 16, 358). Although rare, psychogenic camptocormia is seen in civilian populations, presenting diagnostic challenges. We describe a patient whose initial history and examination suggested a psychogenic etiology for his camptocormic posture. A multidisciplinary approach elucidated the patient's motivations and emotional state, and has been helpful in management of this patient. PMID- 17712853 TI - Prone positioning for head and neck reconstructive surgery. AB - Certain head and neck surgical cases require the patient to be positioned prone. Such positioning carries with it an attendant subset of risks and complications not otherwise encountered in more traditional supine positioning. Gaining awareness of these risks and complications, and developing proactive positioning strategies, will enable the surgical team to position the patient optimally for the procedure and provide for every consideration of patient safety. This article consists of a specific literature review of those issues directly related to the anatomical and physiological concerns arising from prone positioning. Particular attention is paid to the cardiopulmonary, renal, ophthalmologic, and neurological vulnerabilities unique to this position. Proper planning by the surgical team and utilization of the correct equipment are a necessity. A tailored approach to the needs of the individual patient and an intimate awareness of the potential pitfalls will contribute to better outcomes when using the prone position. PMID- 17712854 TI - Dissection of the submuscular recess (sublevel IIb) in squamous cell cancer of the upper aerodigestive tract: prospective study and systematic review of the literature. AB - BACKGROUND: Selective neck dissection is commonly used to clear occult neck metastases in the N0 neck. The aim of this study was to identify the incidence of occult metastases in lymph nodes of sublevel IIb (submuscular recess; SMR) in upper aerodigestive tract squamous cell carcinoma in the setting of clinically and radiologically staged N0 necks and to perform a systematic review of the literature on the incidence of metastases in this setting. METHODS: We conducted a prospective study of 50 neck dissections and systematic review of the literature. RESULTS: (A) Prospective study: Tissue dissected out from the SMR was sent separately for histopathologic analysis. Between 0 and 7 nodes were harvested from sublevel IIb. One patient had a metastatic node in sublevel IIb with extracapsular spread in the ipsilateral neck. No other positive nodes were detected. Sixteen necks showed occult metastases at other levels. (B) Systematic review: The review identified 14 articles with 903 necks suitable for inclusion. The overall incidence of metastatic disease at this sublevel in the context of an N0 neck from any site is 2.0% (18 of 903). The incidence of occult metastatic disease in sublevel IIb for oral cavity, oropharyngeal, and laryngeal cancer is 3.9% (11 of 279), 5.2% (5 of 96), and 0.4% (1 of 230) patients, respectively. Contralateral positive nodes (0.9%) and isolated metastases (0.3%) at this sublevel were rare. CONCLUSION: Nodal metastases are uncommon in the SMR even in the presence of positive nodes in adjacent sublevel IIa. There appears to be no advantage in performing contralateral SMR dissection in N0 necks and in laryngeal primaries. PMID- 17712855 TI - Pure akinesia with gait freezing: a third clinical phenotype of progressive supranuclear palsy. AB - The clinical syndrome of pure akinesia has most often been associated with progressive supranuclear palsy (PSP) and is characterized by difficulty initiating gait and "freezing" during walking, writing and speaking. Similar syndromes have been described under the rubrics of primary progressive freezing gait and primary gait ignition failure. We investigated the specificity of the clinical syndrome of pure akinesia with gait freezing (PAGF) for PSP-tau pathology. Among 749 patients archived at the QSBB, only 7 fulfilled proposed diagnostic criteria of: gradual onset of freezing of gait or speech; absent limb rigidity and tremor; no sustained response to levodopa; and no dementia or ophthalmoplegia in the first 5 years of disease. In these cases detailed pathological examination was performed. PSP was the pathological diagnosis in six patients, and Parkinson's disease (PD) in the seventh. As defined, this syndrome had a positive predictive value of 86% for PSP-tau pathology. In the cases with PSP there were no additional features of coexistent vascular or PD and the median PSP-tau score was 3, reflecting relative mild tau load. The clinical syndrome of PAGF appears to have a high specificity for PSP-tau pathology. This relatively uncommon presentation of PSP-tau pathology has less severe tau accumulation than in the more common, "classic" PSP clinical phenotype: Richardson's disease. PMID- 17712856 TI - Freezing of gait affects quality of life of peoples with Parkinson's disease beyond its relationships with mobility and gait. AB - The aim of this study was to examine the association between freezing of gait (FOG) and quality of life (QoL) in patients with Parkinson's disease (PD). PD patients (n = 118) completed the PDQ-39 (QoL) and FOG-Q questionnaires. Disease severity was assessed by the Hoehn and Yahr (H&Y) staging and the Unified Parkinson's Disease Rating Scale (UPDRS). The relations between those parameters were assessed using regression models. 66 men and 52 women (mean age 65.8 +/- 10.2 years, UPDRS total score 48.4 +/- 17.1, disease duration 8.5 +/- 5.8 years, H&Y stage 2.7 +/- 0.8) participated. FOG severity had a significant effect on QoL (P < 0.0015), accounting for disease severity assessed by UPDRS. Specifically, FOG severity was correlated with all the dimensions of the PDQ-39 except for stigma and social support, as follows: with mobility, bodily discomfort, activity of daily living (ADL) (P < 0.005 in all), with emotional, communication, and cognition (P < 0.05 in all). FOG severity (FOG-Q) was also found to affect a modified PDQ total score, without the mobility aspect (P = 0.0081). FOG should be viewed as a highly important symptom with regard to QoL of PD patients beyond its effect on gait and mobility. On the basis of the present results, special attention should be given to FOG in the treatment of patients with PD. PMID- 17712858 TI - Patients with adult-onset dystonic tremor resembling parkinsonian tremor have scans without evidence of dopaminergic deficit (SWEDDs). AB - We present the clinical details and dopamine transporter SPECT scan results of 10 patients with arm tremor, including a rest component and reduced arm swing on the affected side, in whom the possibility of PD had been raised. All patients had signs of dystonia or components of their arm tremor that were compatible with dystonic tremor, and none had true akinesia with fatiguing or decrement, even after a mean follow-up period of 5.8 years. All patients had normal dopamine transporter SPECT scans. Clinicians should be aware that primary adult-onset dystonia can present with an asymmetric resting arm tremor, with impaired arm swing and sometimes also facial hypomimia or a jaw tremor, but without evidence of true akinesia. Given the important consequences of misdiagnosing such patients as PD, in cases with diagnostic uncertainty functional imaging should be considered. Among patients suspected of PD, dystonic tremor may be one cause of SWEDDs (Scans Without Evidence of Dopaminergic Deficit). PMID- 17712857 TI - Genetic analysis of SCA 2 and 3 repeat expansions in essential tremor and atypical Parkinsonism. AB - Anecdotal reports suggest that patients with spinocerebellar ataxia (SCA 2) patients can present with postural tremor with ataxia. We determined the prevalence of SCA2 and SCA3 mutations in a cohort of ET and atypical Parkinsonism patients. A total of 277 subjects comprising of 177 ET and 100 atypical Parkinsonism were examined. We identified one positive case of SCA3 among those who were diagnosed with ET, yielding a prevalence of 0.5%, but a zero prevalence among our atypical Parkinsonism patients. No study subjects carried an abnormal SCA2 repeat expansion. Our study highlights that SCA3 can present initially with ET symptoms, expanding the spectrum of genetic diseases that can be associated with ET-like phenotype. Routine screening for SCA2 and SCA3 in ET and atypical Parkinsonism patients may not be cost effective. However, in the long-term follow up of patients who present with an ET phenotype, clinicians should be vigilant for other neurological signs, which may be point to an alternate diagnosis. PMID- 17712859 TI - Cause of death in Wilson disease. AB - Before 1948, all patients with Wilson disease died shortly after diagnosis. In 1948, BAL (dimercaprol) was introduced as a possible effective treatment, to be followed by penicillamine (1955), zinc salts (1961), trientine (1969), liver transplantation (1982), and tetrathiomolybdate (1984). Despite this wide range of therapeutic options, patients still die. This article examines the cause of death in 67 patients (33 men, 34 women) out of a series of 300 seen between 1948 and 2000. Patients were classified according to their presentation as neurological, 32 patients, hepatic 11, mixed hepatic/neurological 10, hemolytic, 6, and "sibling biopsy " 8. Diagnostic failure was the principal cause of death but there were multiple other causes of which the principal was poor compliance and the development of malignant disease after 10 years of follow-up. The development of new symptoms should alert the physician to the possibility of a new pathology. PMID- 17712860 TI - NTP-CERHR expert panel report on the reproductive and developmental toxicity of hydroxyurea. PMID- 17712861 TI - Locomotion of fish epidermal keratocytes on spatially selective adhesion patterns. AB - Cell migration results from forces generated by assembly, contraction, and adhesion of the cytoskeleton. To address how these forces integrate in space and time, novel assays are required that allow spatial separation of the different force categories. We used micro-contact printing of fibronectin on glass substrates to study the effect of adhesion patterns on fish epidermal keratocytes locomotion. Cells migrated at similar speeds on homogeneously adhesive substrates and on patterns with 5 microm-wide adhesive stripes interleaved by non-adhesive stripes with a width varied between 5 and 13 microm. The leading edge protruded on adhesive stripes and lagged behind on non-adhesive stripes. On patterns with non-adhesive stripes wider than 13 microm cells halted, although the lamellipodium did not collapse. High correlation was found between the widths of protruding and lagging edge segments and the widths of the underlying stripes. We explain our data by the force balances between actin polymerization, contraction and adhesion on fibronectin stripes; and between actin polymerization, contraction and lamellipodium-internal elastic tension on non-adhesive stripes. We tested our model further by blocking lamellipodium actin network contraction and polymerization. In both experiments we observed that cells eventually lost their ability to move. However, the two perturbations induced distinct morphological responses. The data suggested that forces powering forward motion of keratocytes are largely associated with network assembly whereas contraction maintains cell polarity. This study establishes spatially selective adhesion substrates and cell morphological readouts as a means to elucidate the mechanical balance between substrate adhesion and cytoskeleton-internal tension in cell migration. PMID- 17712862 TI - A novel algesic peptide derived from skin secretions of the frog Amolops loloensis. AB - Several algesic agents including bradykinin and tachykinin have been identified from skin secretions of amphibians. They may act in defensive roles against aggressors. In this study, a novel peptide named Amolos with an amino acid sequence of FLPIVGAKL and isolated from skin secretion of the frog Amolops loloensis, is shown to strengthen nociceptive responses induced by inflammatory factors and strongly inhibit the contraction of isolated ileum. A synthetic peptide based on the sequence obtained showed characterization data identical to those of the isolated material, confirming its structure. These two types of responses seem to be a part of the defensive functions against predators or aggressors. The current results suggest that pharmacological molecules in amphibian skins not only act as innate defense mechanisms against microorganisms but also exert other defensive physiological functions against other aggressors. PMID- 17712863 TI - Long-term retention of gadolinium in tissues from nephrogenic systemic fibrosis patient after multiple gadolinium-enhanced MRI scans: case report and implications. AB - Nephrogenic systemic fibrosis (NSF) is a painful and debilitating fibrosing disorder of the skin and systemic tissues. It is associated with exposure to Gd, used in MRIs and MRAs, in patients with renal insufficiency. We here present an illustrative example of a young patient who underwent multiple Gd-enhanced scans, both before and after developing severe NSF. We examined biopsy tissues for quantification of detectable insoluble Gd deposits using automated scanning electron microscopy/energy dispersive X-ray spectroscopy. High concentrations of Gd associated with calcium and phosphorus in skin persisted even 3 years after the last exposure to Gd. Such long-term retention of Gd raises further concerns about the utility and safety of Gd-based contrast agents. Residual Gd chelates, after initial and rapid renal clearance, can dissociate into insoluble, toxic Gd(3+) that precipitates with tissue anions. Bone serves as a site for Gd storage. Subsequent clearance and mobilization from such stores may explain the variable latency of onset of NSF. We hypothesize that long-term persistence and slow release of Gd(3+) from bone stores can be a cause for concern of Gd associated toxicity with long latency. PMID- 17712864 TI - Phage phiC31 integrase-mediated genomic integration and long-term gene expression in the lung after nonviral gene delivery. AB - BACKGROUND: Phage phiC31 integrase has emerged as a potent tool for achieving long-term gene expression in different tissues. The present study investigated the activity of phiC31 integrase in murine lungs. METHODS: Transfections in murine alveolar epithelial (MLE12) cells were performed with Lipofectamine 2000. For in vivo gene delivery, DNA was complexed with polyethylenimine (PEI) and PEI DNA complexes were injected intravenously into mice. Expression of luciferase in mice was monitored by in vivo bioluminsecence imaging. Genomic integration and integration into a previously described 'hotspot' were confirmed by polymerase chain reaction (PCR). RESULTS: phiC31 integrase mediated intramolecular recombination between wild-type attB and attP sites in MLE12 cells. Long-term gene expression could be observed in MLE12 cells in the presence of integrase without any selection pressure. Long-term expression of luciferase after intravenous injection of PEI-DNA complexes could be observed only in the lungs of mice which were co-injected with the integrase-encoding plasmid. Increased amounts of integrase plasmid and administration of a second dose had no effect on the level of luciferase expression achieved with a single dose, which was three orders of magnitude lower than the values observed on 'day 1' post application. Genomic integration of the transgene in the mouse lungs was confirmed by PCR. Seven out of the fifteen treated mice showed integration at the mpsL1 site, a previously described 'hot spot' from liver. CONCLUSIONS: These results provide evidence for the activity of phiC31 integrase in lungs but also emphasize the need for optimization of the system to maintain long-term gene expression at high levels. PMID- 17712865 TI - Opioid receptor-like 1 (ORL1) receptor binding and the biological properties of Ac-Arg-Tyr-Tyr-Arg-Ile-Arg-NH2 and its analogs. AB - Hexapeptides such as Ac-Arg-Tyr-Tyr-Arg-Ile-Lys-NH(2) and Ac-Arg-Tyr-Tyr-Arg-Trp Arg-NH(2) have been isolated from a combinatorial peptide library as small peptide ligands for the opioid peptide-like 1 (ORL1) receptor. To investigate the detailed structural requirements of hexapeptides, 25 analogs of these hexapeptides, based on the novel analog Ac-Arg-Tyr-Tyr-Arg-Ile-Arg-NH(2) (1), were synthesized and tested for their ORL1 receptor affinity and agonist/antagonist activity on mouse vas deferens (MVD) tissues. Analog 1 and its Cit(6)-analog (10) were found to possess high affinity to the ORL1 receptor, comparable to that of nociceptin/orphanin FQ, and exhibited potent antagonist activity (pA(2) values of 7.77 for 1 and 7.51 for 10, which are higher than that of [NPhe(1)]nociceptin(1-13)-NH(2) (6.90) on MVD assay. It was also found that the amino acid residue in position 5 plays a key role in agonist/antagonist activity, i.e. an L-configuration aliphatic amino acid is required for potent antagonist activity, while a nonchiral or D-configuration residue produces potent agonist activity. These lines of evidence may provide insight into the mechanisms controlling agonist/antagonist switching in the ORL1 receptor, and may also serve to help developing more potent ORL1 agonists and antagonists. PMID- 17712866 TI - Soft shell resins for solid-phase peptide synthesis. AB - Soft shell (SS) resins with a lightly or noncross-linked shell layer were prepared by reducing the amount of cross-linking agent, divinylbenzene (DVB), during seed suspension polymerization from polystyrene (PS) resin. These SS resins have a lower swelling volume than that produced by normal cross-linking. Despite its lower swelling, however, SS (10-00) resin, which consists of the 1% DVB-cross-linked core and the noncross-linked surface layer, showed higher efficiency in peptide synthesis compared with 1% DVB-PS resin and other SS resins. PMID- 17712867 TI - Hafnium: stepping into the limelight! PMID- 17712868 TI - Organocuprate cross-coupling: the central role of the copper(III) intermediate and the importance of the copper(I) precursor. PMID- 17712869 TI - Enzyme-responsive PARACEST MRI contrast agents: a new biomedical imaging approach for studies of the proteasome. AB - Proteases are important biomarkers for many biological processes and are popular targets for therapeutics investigations. A protease can be detected by monitoring changes in the paramagnetic chemical exchange saturation transfer (PARACEST) effect of a MRI contrast agent that serves as a substrate for the protease. To translate this type of responsive PARACEST MRI contrast agent to in vivo applications, the sensitivity, timing, specificity and validation of the response of the agent must be evaluated. This report demonstrates that PARACEST MRI contrast agents can be used to detect nanomolar concentrations of proteases, can be designed to preferentially detect the protease caspase-3 relative to caspase 8, and can be detected within the 15 min time frame of typical MRI studies. The response can be validated using an unresponsive PARACEST MRI contrast agent as a control. A survey of the MEROPS database shows that this approach may also be applied to detect other proteases, and therefore may represent a new platform technology for studies of the proteasome. PMID- 17712871 TI - Ask the doctors. I am a man in my early forties and just had a heart attack. Fortunately, I survived, but I have a brother two years younger than me as well as three small children. I am concerned that they may be at risk as well. What advice should I give them, if any? PMID- 17712870 TI - Clinical significance of the presence of amniotic fluid 'sludge' in asymptomatic patients at high risk for spontaneous preterm delivery. AB - OBJECTIVES: To determine the clinical significance of the presence of amniotic fluid (AF) 'sludge' among asymptomatic patients at high risk for spontaneous preterm delivery. METHODS: This retrospective case-control study included 281 patients with (n = 66) or without (n = 215) AF 'sludge', who underwent transvaginal ultrasound examination between 13 and 29 completed weeks of gestation. Patients with threatened preterm labor, multiple gestation, fetal anomalies, placenta previa or uterine contractions were excluded. RESULTS: The prevalence of AF 'sludge' in the study population was 23.5% (66/281). The rates of spontaneous preterm delivery at < 28 weeks, < 32 weeks, < 35 weeks and < 37 weeks of gestation were 14.7% (29/197), 21.3% (46/216), 28.7% (62/216) and 42.1% (91/216), respectively. Patients with 'sludge' had: (1) a higher rate of spontaneous preterm delivery at < 28 weeks (46.5% (20/43) vs. 5.8% (9/154); P < 0.001), < 32 weeks (55.6% (25/45) vs. 12.3% (21/171); P < 0.001) and < 35 weeks (62.2% (28/45) vs. 19.9% (34/171); P < 0.001); (2) a higher frequency of clinical chorioamnionitis (15.2% (10/66) vs. 5.1% (11/215); P = 0.007), histologic chorioamnionitis (61.5% (40/65) vs. 28% (54/193); P < 0.001) and funisitis (32.3% (21/65) vs. 19.2% (37/193); P = 0.03); (3) a higher frequency of preterm prelabor rupture of membranes (PROM) (39.4% (26/66) vs. 13.5% (29/215); P < 0.001), lower gestational age at preterm PROM (median 24.7 (interquartile range (IQR), 22.3 28.1) weeks vs. 32.3 (IQR, 27.7-34.8) weeks; P < 0.001); and (4) shorter median ultrasound-to-delivery interval ('sludge' positive 127 days (95% CI, 120-134 days) vs. 'sludge' negative 161 days (95% CI, 153-169 days); P < 0.001) and ultrasound-to-preterm PROM interval ('sludge' positive 23 days (95% CI, 7-39 days) vs. 'sludge' negative 57 days (95% CI, 38-77 days); P = 0.003) than those without 'sludge'. AF 'sludge' was an independent explanatory variable for the occurrence of spontaneous preterm delivery at < 28 weeks, < 32 weeks and < 35 weeks, preterm PROM, microbial invasion of the amniotic cavity (MIAC) and histologic chorioamnionitis. Moreover, the combination of a cervical length < 25 mm and 'sludge' conferred an odds ratio of 14.8 and 9.9 for spontaneous preterm delivery at < 28 weeks and < 32 weeks, respectively. CONCLUSIONS: AF 'sludge' is an independent risk factor for spontaneous preterm delivery, preterm PROM, MIAC and histologic chorioamnionitis in asymptomatic patients at high risk for spontaneous preterm delivery. Furthermore, the combination of 'sludge' and a short cervix confers a higher risk for spontaneous preterm delivery at < 28 weeks and < 32 weeks than a short cervix alone. PMID- 17712872 TI - Ask the doctors. I have been reading a lot about sleep apnea lately and I think my husband has it. He does have heart disease. Do you think his sleep apnea could be causing it? PMID- 17712873 TI - Crura ultrastructural alterations in patients with hiatal hernia: a pilot study. PMID- 17712874 TI - Proceedings of the Triennial Reproduction Symposium presented at the ADSA-ASAS Joint Annual Meeting. Minneapolis, Minnesota, USA. July 2006. PMID- 17712875 TI - Effects of early use of pioglitazone in combination with metformin in patients with newly diagnosed type 2 diabetes. AB - BACKGROUND: Type 2 diabetes is characterised by a progressive decline in HbA1c control over time. Early combination therapy, rather than sequential introduction of individual oral glucose-lowering agents, has been proposed to prevent this gradual rise in HbA1c. This observational study assessed the effect of early dual combination oral glucose-lowering therapies within 6 months of diagnosis in newly diagnosed, drug-naive patients with type 2 diabetes. PATIENTS AND METHODS: This was an observational, open-label, non-randomised study in newly diagnosed patients with type 2 diabetes, aged 35-70 years, with HbA1c levels > 8.0% at diagnosis or > 7.0% at the 3-6-month follow-up. Patients were allocated to dietary management alone if the HbA1c level was 7.0-8.0% at diagnosis. Metformin combined with gliclazide, repaglinide, or pioglitazone was given at diagnosis if the HbA1c was > 8.0%. Similar treatments were introduced at 3-6 months if the HbA1c was > 7.0%. Over a 3-year period, HbA1c was measured at 3-monthly intervals. All patients underwent regular dietetic review. Target HbA1c was < or = 7.0%. RESULTS: 416 patients were considered eligible for inclusion, with a mean (+/- SD) age of 54.1 +/- 9.2 years, BMI of 33.5 +/- 6.1 kg/m2, and baseline HbA1c of 8.6 +/- 1.7%. A mixed model analysis of variance on the 178 patients who started with combination therapy, either immediately or after a 3-6 month period on diet, showed that metformin plus gliclazide, repaglinide, or pioglitazone was associated with a gradual increase in HbA1c values. Amongst those patients treated with the metformin/pioglitazone combination there was an estimated 0.1% increase in HbA1c/year. This was much less pronounced than the rises seen in HbA1c/year of 0.5% with the metformin/gliclazide and metformin/repaglinide combinations. CONCLUSIONS: This preliminary analysis of an observational, non randomised, open-label ongoing study has shown that early use of combination therapy at time of diagnosis or within the first 3-6 months following diagnosis with metformin plus pioglitazone in newly diagnosed type 2 diabetes results in a slower deterioration in glycaemic control than that with metformin combined with either gliclazide or repaglinide. This may be due to the beta-cell protective properties of pioglitazone. These results need to be confirmed by further studies with a more robust design and methodology. PMID- 17712876 TI - Update on emerging infections: news from the Centers for Disease Control and Prevention. Update to CDC's Sexually Transmitted Diseases Treatment Guidelines, 2006: fluoroquinolones no longer recommended for treatment of gonococcal infections. PMID- 17712877 TI - "Poachers and dabblers?": ASA president's incautious comment riles emergency physicians. PMID- 17712878 TI - The cost of koi: evidence-based design in emergency medical facilities. PMID- 17712879 TI - No faulty-gene carrier need apply. PMID- 17712880 TI - Evidence-based emergency medicine/systematic review abstract. Should anticholinergic drugs be used for neuroleptic-induced acute akathisia? PMID- 17712881 TI - Climbing the cardiology career ladder: France. Interview by Barry Shurlock. PMID- 17712882 TI - The discussion about the NTI. PMID- 17712883 TI - Chain reaction? PMID- 17712885 TI - Well fit? PMID- 17712884 TI - Quitting time. PMID- 17712886 TI - Lost soul. PMID- 17712887 TI - Supporting mum. PMID- 17712889 TI - Fifth column. An outsider's view of what goes on inside mental health services. PMID- 17712888 TI - High aims. PMID- 17712890 TI - Welfare writes. A fair sickness test would be the single biggest carrot they could offer people. PMID- 17712891 TI - Outside the box. The main advantage of thinking small is that you can see the results--a smile really is a smile. PMID- 17712892 TI - Listening to deaf people. PMID- 17712893 TI - Making DREEM come true. PMID- 17712894 TI - Art for mental health's sake. PMID- 17712895 TI - You need to have been there. PMID- 17712896 TI - Judge imposes two-year sentence; says treatment needs likely better met in federal prison. PMID- 17712897 TI - Ex-professional football player guilty of two counts of aggravated sexual assault. PMID- 17712898 TI - Human Rights Tribunal rejects application to dismiss discrimination complaint. PMID- 17712899 TI - Appeal Court finds assisted contraception regulations do not discriminate against lesbians and gay men. PMID- 17712900 TI - $6 million settlement in medical negligence case. PMID- 17712901 TI - Mexico: Supreme Court rules discharge of HIV-positive troops unconstitutional. AB - On 27 February 2007, Mexico's National Supreme Court of Justice ruled unconstitutional an article of the Social Security Institute Law for the Armed Forces that required HIV-positive service men and women to be discharged. The ruling came as the Court determined a group of 11 cases brought by HIV-positive ex-military personnel requesting constitutional injunctions against their dismissals from the armed forces. PMID- 17712902 TI - Europe: Court finds lack of medical assistance in Russian detention facility to be in violation of human rights. PMID- 17712903 TI - Australia: coroner recommends prisoners be given access to sterile syringes. PMID- 17712904 TI - Criminal law and HIV/AIDS: four new cases. PMID- 17712905 TI - UK: Bournemouth court imposes three-and-a-halfyear sentence for reckless HIV transmission. PMID- 17712906 TI - South Africa: inmate who refuses ARVs will get hearing about whether he can die at home. PMID- 17712907 TI - China: hospital to compensate 19 people infected with HIV through blood transfusions. PMID- 17712908 TI - Putting "sleepdriving" and new safety warning in perspective. PMID- 17712910 TI - Limiting the hurt of a broken hip. PMID- 17712909 TI - Type 2 diabetes drug boom: is newer better? PMID- 17712911 TI - Research update: the benefits of folate. PMID- 17712912 TI - Who pays for ED drugs? PMID- 17712913 TI - Can exercise cause osteoarthritis (OA) of the knee? PMID- 17712914 TI - WHO Collaborating Center for Patient Safety's nine life-saving Patient Safety Solutions. PMID- 17712915 TI - Clinical trials of amyloid-based therapies for Alzheimer's disease. PMID- 17712916 TI - Measuring disease modification in Alzheimer's disease. PMID- 17712917 TI - Comorbidity and diagnosis of ADHD. PMID- 17712918 TI - Treatment of adult ADHD and comorbid disorders. PMID- 17712919 TI - Dentists receive tangible benefits for pro bono dental care. PMID- 17712920 TI - Diagnostic quiz. Case No. 1: metastatic carcinoma. PMID- 17712921 TI - The FDA's past five years: sowing seeds of success. PMID- 17712922 TI - Prepare now for the 2007 hurricane season. PMID- 17712923 TI - Diagnostic quiz. Case No. 1: central lipoma of bone. PMID- 17712925 TI - Board of Dentistry says "Best Dentists" lists are violation of advertising laws and rules. PMID- 17712924 TI - Know the do's and don'ts of dental advertising. PMID- 17712926 TI - Diagnostic quiz. Case No. 1: central giant cell granuloma. PMID- 17712927 TI - Mind your business manners. Research suggests that business etiquette affects human resources, your practice and your bottom line. PMID- 17712928 TI - Anne McLaren 1927-2007. PMID- 17712929 TI - Children's oral health. PMID- 17712930 TI - Position of the American Dietetic Association: oral health and nutrition. AB - It is the position of the American Dietetic Association that nutrition is an integral component of oral health. The American Dietetic Association supports the integration of oral health with nutrition services, education, and research. Collaboration between dietetics and dental professionals is recommended for oral health promotion and disease prevention and intervention. Scientific and epidemiological data suggest a lifelong synergy between nutrition and the integrity of the oral cavity in health and disease. Oral health and nutrition have a synergistic bidirectional relationship. Oral infectious diseases, as well as acute, chronic, and terminal systemic diseases with oral manifestations, impact the functional ability to eat as well as diet and nutrition status. Likewise, nutrition and diet may affect the development and integrity of the oral cavity as well as the progression of oral diseases. As we advance in our discoveries of the links between oral and nutrition health, practitioners of both disciplines must learn to provide screening, baseline education, and referral to each other as part of comprehensive client/patient care. Dietetics practice requires registered dietitians to provide medical nutrition therapy that incorporates a person's total health needs, including oral health. Inclusion of both didactic and clinical practice concepts that illustrate the role of nutrition in oral health is essential in both dental and dietetic education programs. Collaborative endeavors between dietetics and dentistry in research, education, and delineation of health provider practice roles are needed to ensure comprehensive health care. The multifaceted interactions between diet, nutrition, and oral health in practice, education, and research in both dietetics and dentistry merit continued, detailed delineation. PMID- 17712931 TI - NIH announces phase III clinical trial of creatine for Parkinson's disease. PMID- 17712932 TI - [Enhancement of di-n-butyl phthalate on the estrogenic activities of esters of p hydroxybenzoic acid]. AB - OBJECTIVE: To studied the estrogenicity of single propylparaben (PP), butylparaben (BP), di-n-butyl phthalate (DBP), and their joint treatment. METHODS: Estrogenicity was studied using the uterotrophic assay of immature female Wistar rats. Animals were subcutaneously (sc) treated for three consecutive days with single PP, BP, DBP and their joint treatment. Estrogenic activity effects were identified through the ratio of uterus/body weight. RESULTS: Estrogenic activities of PP and BP was detected, the lowest observed effect level (LOEL) of PP and BP were 400mg/kg and 200mg/ kg, respectively, estrogenic activity of DBP was not detected at the doses of 400mg/kg and 100mg/kg. In the equal effect dosage joint treatment of PP and BP, uterus proliferation effects were observed at the doses of 1 and 1/2 LOEL, but the effect was not observed at the doses of 1/4 LOEL. In the joint treatment with DBP increased uterus proliferation effects of PP or BP were observed at matches of 100mg/kg PP(1/4LOEL) + 400mg/kg DBP, 200mg/kg PP(1/2LOEL) + 400mg/kg DBP and 100mg/kg BP(1/2LOEL) + 400mg/kg DBP. CONCLUSION: It was suggested that the DBP could have potential enhancing action to estrogenic activities of PP or BP, and the estrogenic activity of PP enhancement by DBP could be stronger than that of BP. PMID- 17712933 TI - [Effect of nerve growth factor on mitochondrion dysfunction of motor neuron induced by 2,5-hexanedione]. AB - OBJECTIVE: To explore the effect of nerve growth factor (NGF) on mitochondrion dysfunction of motor neuron induced by 2,5-hexanedione (2,5-HD). METHODS: VSC4.1 cells (a cell line from motor neuron) were incubated 2,5-HD at the doses of 10mmol/L and 20mmol/L. VSC4.1 were incubated with 20mmol/L 2,5-HD for 12 hours and then 2,5-HD and serum were removed and same cells were cultured with NGF contained medium. The cell viability was measured by MTF method. The mitochondrion membrane potential (Delta psi m) was detected by Rho-123 and expression of NGF protein was detected by immunofluorescence and flow cytometry. RESULTS: VSC4.1 cells were treated with 2,5-HD at doses of 10mmol/L and 20mmol/L for 12 hours, when compared with the control group, the VSC4.1 cell viabilities decreased 17% and 23% , and expressions of NGF of VSC4.1 cells also decreased (33.5% , 34%), and levels of mitochondrion membrane potential (Delta psi m) of VSC4. 1 cells decreased from 39.36 to 29.57 and 23.80, respectively. 50 and 100ng/ml NGF were added into the culture medium when VSC4.1 cells were treated with 2,5-HD at the doses of 20mmol/L for 12h. The viabilities increased 6.38% and 23.40%. Mitochondria membrane potential of VSC4.1 cells increased(from 26.03 to 30.18 and 31.50). CONCLUSION: The improvement of the mitochondrion dysfunction induced by 2,5-HD could be associated the mitochondrion membrane potential (Delta psi m) increased by NGF. PMID- 17712934 TI - [Effects of 2,2', 4,4' -tetrabromodiphenyl ethers on oxidative stress and DNA damage in SH-SY5Y cells]. AB - OBJECTIVE: To investigate the effects of 2, 2', 4,4 '-polybrominated diphenyl ethers (PBDE-47) on SH-SY5Y cells were oxidative stress and DNA damage in human neuroblastoma cells (SH-SY5Y cells). METHODS: cultured in DMEM supplemented with 10% fetal bovine serum at 37 degrees C in a humidified incubator with 95% air and 5% CO2. The rate of cellular survivors, LDH leakage, contents of MDA and GSH, activity of SOD, and DNA damage were measured after exponentially growing cells were incubated with 1, 2, 4, 6, 8 and 10 microg/ml PBDE-47 for 24 hours in vitro. RESULTS: The rate of cellular survivors in the low dose PBDE-47-treated groups (l microg/ml and 2 microg/ml) were higher than the control group (P <0.05), but those in the high dose PBDE-47-treated groups (4, 6, 8 and 10 microg/ml) were significantly lower than the control group (P < 0.05). Compared with the control group, the GSH content were significantly decreased (P < 0.05) and DNA tail moment were significantly increased with increasing PBDE-47 concentrations. The MDA content in the high PBDE-treated groups (4, 8 and 10 microg/ml) were notably higher than the control group and increased with increasing PBDE-47 concentrations (P < 0.05). In the high PBDE-treated groups (4, 6, 8 and l0 microg/ml), the LDH leakage were markedly higher and the SOD activity were markedly lower than the control group (P < 0.05). The percentage of DNA in the tail in the high PBDE-treated groups (6,8 and 10 microg/ml) were visibly higher than the control group (P < 0.05). CONCLUSION: PBDE-47 could induce oxidative stress and DNA damage in SH-SY5Y cells. The oxidative stress may play an important role in the DNA damage induced by PBDE-47. PMID- 17712935 TI - [Effects of volatile organic compounds on brain amino acid neurotransmitter in mice]. AB - OBJECTIVE: Study adverse effects of volatile organic compounds volatile organic compounds (VOCs) on brain amino acid neurotransmitter in mice. METHODS: Four groups of mouse were respectively exposed to 0, low, middle and high concentration of VOCs for two hours every day for 30 days. The content of brain amino acid neurotransmitter was determined. RESULTS: The result showed that the content of Glu and ASP in brain of VOCs -exposed mouse decreased and GABA and Gly increased compared with that of control. CONCLUSION: The memory impair in mice induced by exposing VOCs may relate to the chang of content of amino acid neurotransmitter. PMID- 17712936 TI - [Relationship between reactive oxygen species and apoptosis in HepG2 cells induced by sodium selenite]. AB - OBJECTIVE: To investigate the mechanism of sodium selenite-induced apoptosis in HepG2 cells. METHODS: HepG2 cells were treated with 0,2.5,5,10 and 20 micromol/L sodium selenite for different time, and NAC (5 micromol) was added simultaneously with selenite (10 micromol/L). Then the cell viability was detected by MTT, and the fluorescent intensity of ROS and the apoptosis rate was determined by flow cytometry. RESULTS: Compared with the control group, the levels of ROS were increased after HepG2 was treated with 5, 10 and 20 micromol/L sodium selenite for one hour, and the cell viability decreased after 12 hours, and the apoptosis rate of HepG2 was increased. After NAC was added with selenite, ROS was effectively inhibited. Subsequently cell viability was increased and the cell apoptosis rate was decreased. CONCLUSION: ROS may play a crucial role in sodium selenite-decreased cell viability and -induced apoptosis in HepG2 cells. PMID- 17712937 TI - [Effects of serum starvation and contact inhibition on the cell cycle G0 synchronization of the human embryonic lung fibroblast]. AB - OBJECTIVE: To compare the effects of two different cell cycle G0 stage synchronization methods in the human embryonic lung fibroblast and re-entry into the cell cycle. METHODS: Cell cycle synchronization was achieved by serum starvation and contact inhibition. Which were identified by flow cytometry. Cell morphologic character were also analyzed. Detection cell cycle distribution change after serum starvation(0.5% serum) for 48h then serum re-stimulation 24h, growth in contact inhibition 72h and subsequent passage 0-24h respectively. RESULTS: Serum starvation 48h could well synchronize HELF in G0 stage. Re stimulated by serum 16h cell re-entered cycle and S increased to peak at 20h, G2 increased to peak at 24h. Growth in contact inhibition 72h could synchronize 83.36% cell in G0. Cells re-entered cycle after passage 13h and S increased to peak at 22h, G2 increased to peak at 25h. CONCLUSION: Serum starvation 48h and growth in confluence 72h both can synchronize HELF in G0 stage effectively. Cells could re-enter cell cycle 16h after re-stimulated by serum or 13h after passage respectively. Serum starvation method was better than contact inhibition. PMID- 17712938 TI - [Monitoring of aerosol microorganisms in the air of hospital sewage treated by membrane biological reactor]. AB - OBJECTIVE: To monitor aerosols exhaling into the air from the process of hospital sewage treated by membrane biological reactor (MBR). METHODS: The aerosol microorganisms under negative pressure, normal pressure and partially open status of MBR a hospital sewage treatment station were determined, and were emphasized on their quantity and particle size distribution using Andersen sampler. RESULTS: Under negative pressure status, the average concentrations of the bacteria and fungi in the workshop, were lower than those of normal pressure and partially open status. Obviously, the bacteria concentrations (388 CFU/m3) in the air treated by high efficiency air filter were lower than the bacteria concentration (8039 CFU/m3) in the off-gas without treatment, the removal rates were up to 95.2%. CONCLUSION: Under negative pressure status, the off-gas of MBR treated by high efficiency air filter could lead to secondary pollution to ambient air. PMID- 17712939 TI - [Study and evaluation of effect on the parameters of heterotrophic plate counts in drinking water in distribution networks]. AB - OBJECTIVE: To study of effect on conditions and parameters of heterotrophic plate counts. METHODS: chlorine, turbidity, total ferric, total organic carbon etc of distribution network were determinted in a northern city in China. RESULTS: HPC (heterotrophic plate counts) got from R2A medium with longer culture time can reflect the real situation of bacteria in drinking water well. Water temperature was positively related with HPC. Free chlorine was better negatively related with HPC. The results of turbidity and total ferric were better positively related with HPC. TOC content was positively related with HPC. CONCLUSION: There are many parameters affecting dringing water quality especially in the residential area with complex water power condition, it can't be represented by one parameter and it should be thought about with all parameters synthetically. PMID- 17712940 TI - [Study on the method for determination of pentachlorophenol in water]. AB - OBJECTIVE: To establish a method for sensitive and rapid determination of pentachlorophenol (PCP) in different water. METHODS: Based on the actual national standard detection method of PCP, gas chromatographic conditions and quantitative method were modified and optimized. The modified method was used for the determination of pentachlorophenol in samples from natural water, output water and tap water. RESULTS: A modified method for the detection of PCP in drinking water samples was developed with the conditions of gas chromatography as follows: the capillary column was used for separation and tribromophenol (TBP) as internal standard for quantification, the linear range were 0.1 - 10 microg/L, and the correlation coefficient was 0.9999. The limit of detection was 4.5 ng/L. Recoveries were between 90.1% and 98.4%, and RSD was less than 4.1% . CONCLUSION: The proposed method is a sensitive and accurate method for trace analysis of PCP in different water. PMID- 17712941 TI - [Development and performance evaluation for a solid phase adsorption gas sampler of ammonia in indoor air]. AB - OBJECTIVE: To develop a solid phase adsorption gas sampler, which was suitable for collection and analysis of ammonia in indoor air. METHODS: This solid phase adsorption gas sampler was composed of two parts, a support part made of a glass tube, an absorbent part in glass tube made of fiber coated ammonia absorbent. For its performance, established a method for sampling ammonia in indoor air with the gas sampler was evaluated. The associated samples were determinated with indophenol blue photometric method. RESULTS: For the solid phase adsorption gas sampler, the collection efficiency was 97.96% , and the desorption efficiency was 97.91% . The variation coefficients of sampling was 3.72% ( n = 10). The recovery rates varied from 95.84% to 103.28% . The above method was compared with the standard method, the results showed no significant difference between two methods. CONCLUSION: This solid phase adsorption gas sampler could be used for sampling and determination ammonia in indoor air. PMID- 17712942 TI - [Demethylation in the promoter region of MTHFR gene and its mRNA expression in cultured human vascular smooth muscle cells induced by homocysteine]. AB - OBJECTIVE: To investigate the effect of homocysteine (Hey) on the methylation modification of 5, 10- methylenetetrahydrofolate reductase(MTHFR) gene promoter and its mRNA expression in cultured human vascular smooth muscle cells (HVSMCs). METHODS: HVSMCs from umbulical arteries were isolated and cultured in DMEM/F12 medium, which clinic-relevant and very high homocysteine concentrations (0,30,100,200,500 and 1000 micromol/L) were added for 72h treatment. Methylation specific polymerase chain reaction(MS-PCR) was performed to catalyze the methylation pattern of the MTHFR promoter region, semiquantitative RT-PCR was used to detect the MTHFR mRNA expression after Hcy treatment. RESULTS: The homocysteine induced demethylation in the promoter region of MTHFR gene at all concentrations of Hcy, the methylation pattern in MTHFR gene displayed significant hypomethylation and the MTHFR mRNA expression demonstrated obvious upregulation as well. CONCLUSION: The homocysteine could induce demethylation in the promoter region of MTHFR gene in HVSMCs and upregulate the MTHFR mRNA expression. PMID- 17712943 TI - [Mechanism of protective effects of procyanidins on liver injury induced by alcohol in mice]. AB - OBJECTIVE: To study the mechanism of protective effects of procyanidins on liver injury model induced by alcohol in mice. METHODS: Mice were divided into 3 groups to set up the model of liver injury induced by alcohol in mice: the group of liver injury induced by alcohol, the group of procyanidins with low doses (100mg/kg), the group of procyanidins with high doses(300mg/kg). Then established normal group of control. The model of liver injury induced by alcohol in mice was used to investigate the protective effects at low and high doses procyanidins in serum indicated by alanine aminotransferase (ALT), asparate aminotransferase (AST) and in liver homogenate indicated by malonaldehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS). The levels of Cu,Zn-SOD mRNA in hepatic tissue and toll like receptor 4 (TLR4) mRNA were determined by using reverse transcription polymerase chain reaction (RT-PCR) technique. RESULTS: The procyanidins with low and high doses could reduce ALT, MDA, ROS content and increase SOD level, up-regulate the expression of Cu, Zn-SOD mRNA and down regulate the expression of TLR4 mRNA. CONCLUSION: Mechanism of the protective effects on liver injuries of mice induced by alcoholmay be associated with promoting the expression of Cu, Zn-SOD and suppressing the expression of TLR4 mRNA. PMID- 17712944 TI - [Study on antioxidative activities of Psidium guajava Linn leaves extracts]. AB - OBJECTIVE: To study the antioxidative activities of the extracts from Psidium guajava Linn leaves (PGL). METHODS: The PGL was submersed with distilled water, 65% ethanol and 95% ethanol respectively. The 3 extracts were obtained after the solutions were filtered, concentrated and dried. The scavenging rate to hydroxyl radicals and inhibiting rate to lipid peroxidation were analyzed for the 3 extracts. Their contents of total flavonoids were determined by ultraviolet spectrophotometry, and the components of total flavonoids were primarily identified by high performance liquid chromatography (HPLC) and ultraviolet visible absorption spectrometry (UV). RESULTS: The extracts from distilled water, 65% ethanol and 95% ethanol respectively showed effects on scavenging hydroxyl radicals and inhibiting lipid peroxidation in the dose-dependent manner, had 50% effective concentration (EC50) on scavenging hydroxyl radicals of 0.63, 0.47 and 0.58g/L, had EC50 on inhibiting lipid peroxidation of 0.20, 0.035, 0.18g/L and had total flavonoids contents of 3.28, 30.71 and 55.98g/kg respectively. CONCLUSION: The aquatic and the ethanol extracts from PGL possess the potential antioxidative activities in the study. The flavonoids may be one of their antioxidative components. PMID- 17712945 TI - [Analysis of phytosterol contents in Chinese plant food and primary estimation of its intake of people]. AB - OBJECTIVE: To analyze the phytosterol content in plant food commonly consumed in China, and to estimate the intake of phytosterols in Chinese people. METHODS: More than 160 types of plant food in 7 kinds were chosen as samples. The contents of beta-sitosterol, campesterol, stigmasterol, beta-sitostanol, campestanol were analyzed by GC methods and the total phytosterols were calculated. The intake of phytosteols in Chinese people was estimated using the data of "Survey on the Status of Nutrition and Health of the Chinese People" in 2002. RESULTS: The contents of phytosterols in edible oils, nuts, and soybeans were higher than those in other plant food. In cereals, phytosterol contents of wheat flour were much higher than those of rice, the refinements of cereals may decrease the phytosterol contents. The phytosterol contents in vegetables and fruits were lower. The total intake of phytosterols in Chinese people was estimated to be 322.41mg/day, in which 40% may be of edible oil origin and 40% may be of cereal origin. CONCLUSION: The results indicated that in the current dietary pattern, increase the intake of wheat, soybean, vegetable and fruit would enhance the phytosterol intake in Chinese. PMID- 17712946 TI - [Distribution of serum folic acid level of patient suffered mild and moderate hypertension in six cities in China]. AB - OBJECTIVE: To describe distribution of serum folic acid concentrations and differences among age, gender groups and geography in Chinese population with mild-to-moderate hypertension. METHODS: 455 subjects aged 28 to 75 years were randomly recruited from six cities in China. Serum folic acid concentrations were measured by electrochemiluminescence. RESULTS: (1)The mean of serum folic acid in male (12.39nmol/L) was lower than that in female (14.61nmol/L) (P <0.01). The folic acid deficiency rate and lower folic acid rate in male were also significantly higher than those in female (P < 0.05). (2) Subjects from Nanjing city could have relatively higher level in serum of folic acid (P < 0.05), when compared with those from other cities. Additionally, there were no differential distributions of folic acid levels among different age groups. CONCLUSION: Serum folic acid distribution in Chinese mild-to-moderate hypertensive patients could have gender and geography differences. PMID- 17712947 TI - [Effects of resistant starch, fat and protein on rates of starch hydrolysis in vitro]. AB - OBJECTIVE: To evaluate the effects of resistant starch, fat, and protein on rates of starch hydrolysis in vitro. METHODS: By an orthogonal experimental design, starch hydrolysis rates of nine test foods composed of different levels of restsistant starch, fat, protein were measured according to Englyst' s method. The starch hydrolysis curve were obtained and the release index of reduce sugar were analyzed by variance analysis. RESULTS: The release index of reduce sugar decreased significantly with the amount of fat and RS increased (P < 0.05). The first affecting factor on the release index of reduce sugar within 2 hours was fat, the second one was RS, and the last one was protein The optimum of the release index of reduce sugar within 2 hours was as follow: 0% RS, 0% fat and 20% protein. CONCLUSION: The addition of RS and fat could significantly decrease the hydrolysis rates of starch. PMID- 17712948 TI - [Effect of calcium supplementation on absorption rates of zinc and iron in 12-17 years old adolescents]. AB - OBJECTIVE: To study the effect of calcium supplementation on absorption rate of zinc and iron by calcium metabolic balance study. METHODS: A total of 80 students (12-17 years old) were selected randomly from 320 subjects who had been supplemented with calcium supplementation for one year. 10 boys and 10 girls were randomly selected from each calcium supplementation group to attend a 10-day metabolic balance study. Samples of foods, feces and urine were collected. Calcium, zinc and iron in samples were measured with ICP-AES. RESULTS: There were significant differences of calcium intake, but were no differences of iron and zinc intake for 4 groups. The apparent absorption rate of calcium, iron and zinc in boys and girls were 69.4%, 12.5%, 29.9% and 46.4%, 20.9%, 35.3%, respectively. Absorption rates of iron were associated with pubertal stages. There were no significant differences of absorption of calcium, iron and zinc for 4 groups. Apparent absorption rates of calcium, iron and zinc seemed higher (75.3%, 23.2% and 36.4%) when the level of calcium intake were 600 - 800mg/d in boys. CONCLUSION: There were no significant effects on absorption rate of iron and zinc when the level of calcium intake was 1400mg/d in 12-17 years old Chinese adolescents. Absorption rates of calcium, iron and zinc seemed higher when the level of calcium intake was 600 - 800mg/d in boys. PMID- 17712949 TI - [Effects of compound coarse grain on the disordered lipid metabolism in rats]. AB - OBJECTIVE: To explore the effects of different feeds, including rice, flour and the compound coarse grain on the disordered lipid metabolism in rats. METHODS: 40 male SD rats were divided into 4 groups, including the negative control group, the hyperlipemic control group, the rice-flour group and the compound coarse grain group. All 4 group rats were given different feeds for 10 weeks, body weights were weighted, serum TC, TG and HDL-C contents were determined and liver pathology were observed. RESULTS: When compared with the negative control group, the disordered lipid metabolism model was successfully made in hyperlipemic control group. When compared with the hyperlipemic control group, the serum TG and TC contents significantly declined and HDL-C significantly increased in the compound coarse grain group. Moreover, the conditions of liver cell fatty degeneration in compound coarse grain group were slight. CONCLUSION: Compound coarse grain could improve the lipid metabolism in rats. PMID- 17712950 TI - [Relationship of ghrelin and obesity induced by high-fat diet in rats]. AB - OBJECTIVE: To explore the effects of expression and secretion of ghrelin on high fat diet induced obesity in rats. METHODS: Forty male SD rats were randomly divided into high-fat diet group (n = 30) and chow fed control group (n = 10), and given either high-fat diet or chow for twelve weeks. Then the high-fat diet group was subdivided into dietary induced obesity (DIO) and dietary induced obesity resistant (DIR) group according to the final body weight. Fasting plasma ghrelin were determined by RIA. Reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the expression of preproghrelin mRNA in gastric tissue. RESULTS: Cumulative caloric intake, body weight in DIO group were significantly higher than those in DIR and control group. Both fasting plasma ghrelin concentration and the preghrelin expression in gastric tissue were significantly lower in DIO group than in DIR and control group. CONCLUSION: Lower expression and secretion of ghrelin were closely associated with high-fat diet induced obesity and their higher caloric intake. PMID- 17712951 TI - [Gene expression of hormone sensitive lipase and lipoprotein lipase in obesity prone and obesity-resistant rats induced by high-fat diet]. AB - OBJECTIVE: To explore the gene expression of hormone sensitive lipase (HSL) and lipoprotein lipase (LPL) between obesity-prone (OP) and obesity-resistant (OR) rats induced by a high-fat diet. METHODS: Eighty male Sprague-Dawley (SD) rats were fed with a high-fat diet for 5 weeks, then OP and OR rats were selected according to their body weight gain. All the rats were fed with basic diet for another 10 weeks, the rats were then sacrificed, and serum samples were collected. To discuss the function of HSL and LPL during the formation of obesity or obesity resistance, RT-PCR was used to compare the gene expression of HSL and LPL in white adipose tissue. RESULTS: At the end of the 5th week, when compared with OR rats, the gene expression of HSL in white adipose tissue was lower in OP rats, but the gene expression of LPL was higher in OP rats. After switched to basic diet for 10 weeks, HSL gene expression had no difference between OP and OR rats, but LPL gene was still highly expressed in OP rats. CONCLUSION: The formation of obesity prone rats may be associated with decreased HSL gene expression and increased LPL gene expression, which promote adipose synthesis and inhibit lipolysis. Highly expressed HSL gene may be associated with high fat diet, while increased LPL gene expression is the specific change of OP rats. PMID- 17712952 TI - [Analysis on the influence factors of parental participation in prevention and control of smoking among secondary school students]. AB - OBJECTIVE: To identify the influence factors of parental participation in tobacco control among adolescents. METHODS: In a cross-sectional survey, self administered questionnaires were used to collect data about smoking-related information from 2851 students and their parents in six secondary schools. The method of Ordinal Regression was applied to select significant influence factors. RESULTS: A total of 2617 pairs of valid questionnaires were included in final analysis. The portion of parents with V level participation was highest (46.4%), followed by IV level at 33.4%, III level at 13.4%, II level at 4.9% and I level at 1.9%. The mothers' participation was significant (P < 0.05) higher than fathers'. With Ordinal Regression, ten variables were selected as significant influence factors that could predict parental participation. Eight of them were associated with high parental participation and ranked as follows according to odds ratio: high education level, ever tried to quit smoking, correct attitudes to image and psychological effects of smoking, level of knowledge about respiratory diseases and cancers caused by cigarette smoking, correct attitudes to bans of smoking, having a male child, correct attitudes to smoking and personal interaction, and correct attitudes to health damage of smoking. On the contrary, two variables had significant association with low parental participation: current smoking and ages of parents. CONCLUSION: The parents with lower education level, older age, daughters and current smoking are comparatively inactive in tobacco control among adolescents. Health promotion family is proposed as an effective way to increase their participation. As a result, the prevalence of smoking among adolescents in China will be under control in some extent. PMID- 17712953 TI - [Regional correlation analysis of birth defects in Heshun county, Shanxi Province]. AB - OBJECTIVE: To study the regional correlation analysis of birth defects in Heshun county, Shanxi province from 1997 to 2001. METHODS: Exploratory data analysis, especially the parallel coordinate plot (PCP) method, and geographic information system were used to analysis the regional correlation of birth defects. In this paper, we selected 1997 to 2001 five groups variables of birth defects to plot the PCP. RESULTS: Yangguangzhan and Hengling have stronger positive correlation on the region. Liyang and Niuchuan have weak correlation. Yixing and Songyan have no correlation and other towns have no positive correlation on the region. CONCLUSION: The results indicate that this studied region has the regional correlation of birth defects. PMID- 17712954 TI - [Effect of musculoskeletal disorders on the occupational activity and health of health professional]. AB - OBJECTIVE: To study the effect of musculoskeletal disorders(MSD) on the occupational activity and health of health professional. METHODS: Anatomical diagram and affected occupational activity or ability and health of 334 health professionals were inspected by means of a questionnaire survey in a city. RESULTS: The response rates of the survey was 99.5% . Among them, 308 health professionals (92.2%) experienced and MSD in the previous 12 months, was 72.2%, 59.9% and 59.9% of MSD on the neck, shoulder and lower back sites, respectively. Fifty-six percent of their symptoms lasted more than 24 hours, in which 23.0% interfered with their occupational work ability and 15.9% required medical treatment. MSD of the hand/wrist( OR = 3.1,95% CI 1.6 - 6.4, P < 0.01) and MSD of the shoulders (OR = 2.6, 95% CI 1.4 - 4.7, P < 0.01) were the most likely to last longer than 24 hours. MSD of the lower back (OR = 2.7, 95 CI 1.6 -4.7, P <0.01), upper legs (OR = 2.4, 95% CI 1.1 -5.0, P <0.05) and hand/wrist (OR = 2.2,95% CI 1.3 - 3.9, P < 0.01) were commonly associated with a reduction of work ability. Medical teatment was 2.8 times more likely (OR = 2.8,95% CI 1.5 - 5.4, P < 0.01) and 2.1 time more likely (OR = 2.1, 95% CI 1.1 - 4.0, P < 0.05) to have been sought for MSD of the lower back and kness, respectively. Females were five times more likely to report MSD at any body site( OR = 52.95,95 % CI 1.3 - 21.0, P < 0.05). CONCLUSION: It was suggested that MSD could be important cause of occupational activity disability and sickness of health professionals. PMID- 17712955 TI - [Study of relationship between arsenic methylation and skin lesion in a population with long-term high arsenic exposure]. AB - OBJECTIVE: To investigate the difference of arsenic metabolism in populations with long-term high arsenic exposure and explore the relationship between arsenic metabolism diversity and skin lesion. METHODS: 327 residents in an arsenic polluted village were voluntarily enrolled in this study. Questionnaire survey and medical examination were carried out to learn basic information and detect skin lesions. Urinary inorganic and methylated arsenic were speciated by high performance liquid chromatography combined with hydride-generation atomic fluorescence spectrometry. Total arsenic concentration in hair was determined with DDC-Ag method. RESULTS: Hair arsenic content of studied polutions was generally high, but no significant difference were found among the studied four groups. MMA and DMA concentration in urine increased with studied polution age, and were positively related with skin lesion grade. The relative proportion of MMA in serious skin lesion group was significantly higher than in other 3 groups, while DMA/MMA ratio was significantly lower than control and mild group. The relative proportion of MMA was positively related with skin lesion grade, DMA/ MMA ratio was negatively related with skin lesion grade. Males could have higher arsenic cumulation and lower methylation capacity than those of females. The population of above 40 years old may have higher methylation capacity than those of adults below 40yeas old. Smokers and drinkers seemed lower methylation capacity than those of non-smokers and non-drinkers respectively. CONCLUSION: The methylation of arsenic could affect by several factors, including age gender, smoking and drinking. Arsenic methylation copacity mey be associated with skin lesion induced by arsenic exposure. PMID- 17712956 TI - [Changes of the certain genotoxicities in workers occupationally exposed to arsenic]. AB - OBJECTIVE: To study the changes of genotoxicities of workers occupationally exposed to arsenic in a mill of Yunnan Province. METHODS: The micronucleated cell and micronucleus frequency, comet rate and tail length of lymphocyte in comet assay from peripheral blood, urinary total and organic arsenic were detected and evaluated in 40 workers (exposure group), and also local people who did not contact with any poison obviously (control group). RESULTS: The micronucleated cell and micronucleus frequencies, the comet rate and tail length of lymphocyte in exposure groups were all more higher than those of controls (P < 0.01). The urinary total and organic arsenic concentrations in exposure groups were more higher than those of controls (all lower than 0.02mg/L for controls). The increased tendencies of micronucleated cells and micronucleus frequencies with the products of organic arsenic concentrations and service length were found in exposure groups(r(s) = 0.356, P = 0.024, r(s) = 0.347, P = 0.028). CONCLUSION indicated that arsenic could induce the damage of chromosome and DNA in lymphocyte of peripheral blood in workers occupationally exposed to arsenic. PMID- 17712958 TI - [Effects of arsenic in drinking water on children's intelligence]. AB - OBJECTIVE: To study the effect of high concentration arsenic in drinking water on children's intelligence. METHODS: Pupils in Hangjinhou Qi were selected as subjects. Arsenic in drinking water and urine was determined. These subjects were divided into control( < 0.05mg/L, group A), mild exposure (0.05 - 0.1mg/L, group B) and heavy exposure group(> or = 0.1 mg/L, group C), according to arsenic concentration in drinking water. The Chinese combined Raven' s test was applied to evaluate the intelligence of children. In addition, the questionnaire survey was conducted to find out information, such as general information of households, source of drinking water, health of subjects and their parents, education of parents, etc. RESULTS: The boys' average intelligence quotients (IQ) were 99.4 (group A), 96.5 (group B), 94.9 (group C). On the other hand, average IQs of girls were 101.3 (group A), 98.3 (group B) and 94.2 (group C) in the sequence from high to low. When other factors were adjusted, the average intelligence quotient of girls who exposured to arsenic higher than 0.1 mg/L were significantly decreased, compared with control groups, while boys' IQ did not show so. CONCLUSION: Children's ingested the dring water contaminating arsenic ( > 1.0mg/L) for the long run probably could have adverse effect on their intelligence development in some degree. Girls' IQ seemed more susceptible to arsenic. PMID- 17712957 TI - [Analysis of risk factors of skin lesions from burning high-arsenic-contaminating coal in southern Shanxi Province]. AB - OBJECTIVE: To explore risk factors of the patients with skin lesions from burning high-arsenic-contaminated coal in southern Shanxi Province. METHODS: An epidemiological cross-sectional study was conducted in two villages of Hanbin District, Ankang City, Shanxi Province, where 198 participants were randomly selected. The parts of factors which were not significantly different were rejected via the single variable analysis and the collinear relationships were removed between the other factors using principal components analysis, and then the major risk factors of the skin lesions from burning high-arsenic-contaminated coal were obtained from stepwise logistic regression. RESULTS: The single variable analysis showed that 11 influential variables were significantly associaed with coal-burning-arsenic-associated skin lesions, while principal component and logistic regression analysis showed that 6 variables could be the principal, which were period of burning arsenic-contaminating coal, ege, the arsenic content in blood, resident duration, the arsenic content in urine and hair, respectively. CONCLUSION: The results suggested that the major risk factors of the skin lesions related to burning coal-contaminating arsenic should be period of burning arsenic-contaminating coal, age, the arsenic content in blood, resident duration, the arsenic content in urine and hair. PMID- 17712959 TI - [Effect of high iodine concentration in drinking water on thyroid function of elementary school student in Tianjin]. AB - OBJECTIVE: To study the effect of high iodine concentration in drinking water on thyroid function of elementary school student in Tianjin. METHODS: According to the water monitoring results and determination standard of iodine concentration excess area, urine iodine level and thyroid condition of elementary students were tested in the area with high and low water iodine concentration. Meanwhile the condition of iodized salt intaked students' family was inspected. RESULTS: The content of urine iodine and goiter rate of students in the area with high water iodine concentration were significantly higher than those with low water iodine concentration. But the iodine concentration of edible salt in students' family in the area with high water iodine concentration were significantly lower than those of students' family with low water iodine concentration. CONCLUSION: High water iodine concentration could impact thyroid function of elementary students in Tianjin. PMID- 17712960 TI - [Explore of plateau period of amino acid metabolism kinetics]. AB - OBJECTIVE: To explore the plateau period of the enrichment of stable isotope for amino acid metabolism kinetics using the method of stable isotope tracer. METHODS: Selecting 5 healthy adults as subject, all of them were given 13C labeled leucine for 3 hours by their cutaneous veins on day 6 after 5 days adaption period. The respired air was collected during the course of infusion and 1 hour after infusion to determine the enrichment of 13C. RESULTS: The 13C enrichment in the respired air was at a higher level in 1 hour before infusion end and it will decrease immediately after the infusion end. CONCLUSION: It was suggested that one hour before infusion end is the optimal time for sampling in the study of metabolism kinetics of amino acid. PMID- 17712961 TI - [Effects of complementary food supplements on respiratory infections and diarrhea of infants and young children in poor rural]. AB - OBJECTIVE: To investigate the effect of complementary food supplements with protein and multi-micronutrients on respiratory infections and diarrhea of infants and yound children in poor rural China. METHODS: In 5 poor county of Gansu Province, 1478 children aged 4 - 12 months were enrolled and divided into two groups. In addition to the usual home-made complementary food, all the children were fed one package of either formula I or formula II per day, usual home-made complementary food, all the children were fed one package of either formula I or formula II per day, protein and micronutrient were supplemented in formula I group. Every 6 months, a massive dose of vitamin A was protein and micronutrient were supplemented in formula I group. Every 6 months, a massive dose of vitamin A was supplemented to all children, weight and height measurements have been done every 3 months until they were 24 months old. RESULTS: During the follow-up of 12 months supplementation, prevalence of respiratory infection and diarrhea reduce significantly compared with baseline survey (P < 0.0001), there is no difference between the two group at the same survey, lasting time of respiratory infection is shortened in formula I group, and medical cost of disease in the two groups Complementary food supplements, with large-dose vitamin A, reduce prevalence of reduced significantly. CONCLUSION: Complementary food supplements, with large-dose vitamin A, reduce prevalence of respiratory infections, diarrhea and medical cost of those diseases. PMID- 17712962 TI - [Geographic information system based spatial analysis on chronic arsenic poisoning in a tin mining area, Thailand]. AB - OBJECTIVE: To explore the spatial features of arsenic contamination and its association with chronic arsenic poisoning in a tin mining area of Thailand. METHODS: Geographic information system(GIS) was built up with integration of arsenic concentration in varied environmental media and occurring location data of chronic arsenism patients. Then, the spatial interpolation (IDW), buffer zoning, query and rank correlation analysis were applied. RESULTS: Groundwater and surface farming land were classified according to local environmental arsenic standards; the relative risk areas were identified. The incidence of chronic arsenic poisoning was significantly correlated with arsenic level in groundwater and soil type (P < 0.05), and insignificantly related with water soluble arsenic in soil (P > 0.05). CONCLUSION: The arsenic content in drinking water could be critical to chronic arsenic poisoning. The soil type could be an important factor affecting such poisoning. Trend analysis in GIS could provide a valuable tool for understanding the pollution situation and disease surveillance. PMID- 17712963 TI - [Studies on DNA damage of the neuron cell in rat offspring induced by cypermerthrin and methylparathrion during embryo exposure]. AB - OBJECTIVE: To explore DNA damage of rat's brain prenatal exposure to mixed pesticides of cypermerthrin and methylparathrion. METHODS: 48 pregnant Wistar rats were divided into 4 groups. During the 1st to 15th day of gestation, all rats were force fed with mixed pesticides of cypermerthrin plug methylparathrion. The dosage of the two pesticides were (0, 1/300, 1/95 and 1/30) LD50, respectively. The brains of 24 embryos at the gestation day 16th (6 each group) and 24 rat offspring (6 each group) at the 30-day-old after birth were taken out respectively, and the single cell gel electrophoresis (SCGE or comet assay) was utilized to access DNA damage. RESULTS: At the exposure does of 1/95LD50 and 1/30LD50, the mixed pesticides could induce the neuron cell DNA strain rupture of the neuron cell of embryos remarkably (P < 0.05), while the high dose could induce the DNA damage in brain of 30-day-old rats (P < 0.05). The DNA damage in brain neurons of rat offspring was more severe with increased doses of mixed pesticides (correlation analysis: DNA damage at embryos, r = 0.836, P = 0.000). Especially at dose of 1/95 LD50, 1/30 LD50, the DNA damage in brain of the 30-day old rats was more severe than the embryo rats (F = 15.81, P < 0.0001). CONCLUSION: Prenatally exposed to mixed pesticides of cypermerthrin plus methyl parathion could cause neuron cell DNA damage. At the lower level, DNA damage of the neuron of rat offspring could be repaired, but the repair was difficult at the higher level. PMID- 17712964 TI - [Effects of taurine on tumor necrosis factor expression of lung in rats treated by silica]. AB - OBJECTIVE: To evaluate the effects of taurine on the expression of tumor necrosis factor-alpha (TNF-alpha) protein of lung in rats treated by silica. METHODS: 144 Wistar rats were randomly divided into three experimental groups: saline instilled with a control diet (saline-treated group), silica-instilled with a control diet (silica-treated group), and silica-instilled with a diet containing 2.5% taurine (taurine-treated group). There were 48 rats in every experimental group. Rats were treated by direct tracheal instillation of silica into rat lungs exposed surgically. 8 rats in every experimental group were killed at each at 6 time points (1, 3, 7, 14, 21 and 28 day) respectively. The taurine concentration of serum were analyzed by means of HPLC. The expression of TNF-alpha protein in paraffin-embedded lung sections with Streptavidin/ peroxidase(SP) immunohistochemistry on tissue microarray were measured by image-pro Plus. RESULTS: The concentration of taurine in serum of taurine-treated group were significantly elevated when compared with saline-treated and silica-treated groups (P < 0.05, P < 0.01). After instillation of silica, TNF-alpha positive area percent of the lung was elevated in silica-treated rats when compared with the corresponding saline-treated group, peaking at 7 days, and elevated by 6.57% and 2.37% at 7 days and 14 days respectively (P < 0.01 or P < 0.05). Taurine treatment significantly decreased silica-elevated TNF-alpha positive area percent by 3.52 at 7 day (P < 0.05). CONCLUSION: Treatment with taurine can effectively attenuate the pathological expression of TNF-alpha protein of lung in rats induced by silica. PMID- 17712965 TI - [Study on determination of the xenoestrogens 4-nonylphenol and bisphenol A in vegetables using gas chromatography- mass spectrometry]. AB - OBJECTIVE: To develop a simple and sensitive GC/MS method for the determination of 4-nonylphenol (4-NP) and bisphenol A (BPA) from vegetables. METHODS: After smashed, the samples were extracted using ultrasonic extraction, and CH cartridge was used to clean the impurity, then desorbed with dichloromethane, the elution was chemically dried with anhydrous sodium sulphate and a silylation step was carried out with N,O-bis(trimethylsilyl) -trifluoroacetamide (BSTFA) to enhance the selectivity and sensitivity of the detection. Then the derivation were identified and quantified by GC-MS. RESULTS: The linear range is from 10 to 500 microg/L for two target compounds with the correlation coefficient of 0.999, and the limit of detection(LOD) is 0.1microg/kg (4-NP) and 0.02 microg/kg (BPA), respectively. The spiked recoveries of two target compounds are ranged from 85.0% - 105.1%, and the precision are both below 10%. CONCLUSION: This method has fairly high sensitivity and good precision, it can be used to detect the trace amount of 4-NP and BPA from vegetables. PMID- 17712966 TI - [Effect of parathyroid hormone and 1,25-(OH)2-D3 on the expression of the mRNA of calbindin D9k in Caco-2 cells]. AB - OBJECTIVE: To study the effect of parathyroid hormone (PTH) on the expression of the mRNA of calbindin D9k(CaBP-D9k) in Caco-2 Cells and whether PTH influences the effect of 1,25-(OH)2-D3 on the expression of calbindin mRNA in Caco-2 Cells. METHODS: Caco-2 cells were used as the model of human small intestinal enterocytes. Caco-2 cells were treated 5, 10, 20, 40 and 80 min at the dose of 10(-8), 10(-9) and 10(-12) mol/L PTH, another groups of Caco-2 cells were treated for 2, 4, 8, 16 and 24h at the dose of 10(-8) mol/L 1,25-(OH)2-D3 alone. The other groups of Caco-2 cells were treated for 2, 4, 8, 16 and 24h at the dose of 10(-8) mol/L 1,25-(OH)2-D3 plus at the dose of 10(-8), 10(-9) and 10(-12) mol/L of PTH respectively. 0.1% ethanol solutions were used as the vehicle for the later two groups. The expression of calbindin D9k mRNA was determined by RT-PCR (the level of GAPDH was taken as internal control). RESULTS: The expressions of calbindin D9k mRNA were more higher than those of blank controls when Caco-2 cells were treated at the dose of 10(-8) mol/L 1,25-(OH)2-D3 for 2, 4, 8, 16 and 24h, the expressions of CaBP-D9k mRNA were higher than those of vehicle. The increases of CaBP-D9k mRNA levels caused by 10(-8) mol/L 1,25-(OH)2-D3 plus PTH were more lower than those caused by 1,25-(OH)2-D3 alone. CONCLUSION: 10(-8) and 10(-12) mol/L PTH probably caused increase on the expression of CaBP-D9k mRNA in short period (1 - 20min). 10(-8) mol/L 1,25-(OH)2-D3 increases CaBP-D9k mRNA levels in Caco-2 cells. PTH may inhibit or counteract the increase in CaBP-D9k mRNA caused by 1,25-(OH)2-D3 in Caco-2 cells. PMID- 17712967 TI - [Preliminary study on rapid test of Enterohemorrhagic E. coli O157 by PCR immunochromatographic test]. AB - OBJECTIVE: To establish a new method named PCR- immunochromatographic test (PCR ICT) for rapid test of Enterohemorrhagic E. coli(EHEC) O157. METHODS: The specific hemolysin gene segment (hlyAB) was used as an indicator for EHEC screening. According to the gene squences of hlyAB, the specific probe was designed and labeled by digoxin while the primers were quoted and the former one was labeled with biotin. The amplification products were detected by colloid gold ICT stripes. RESULTS: 5 strains of EHEC O157: H7 were analyzed by the method which show positive stripes, and 5 strains of common E. coli non-EHEC and 5 strains of other which all show negative results. 43 export food samples of iced shrimp meat, iced shellfish meat, iced chicken and iced pork. The results were all negetive which concordant with those of agar gel electrophoresis and culture medium methods. CONCLUSION: The new developed PCR-ICT may be rapid and convenient for screening EHEC, it could save time and labour compared with agar gel electrophoresis. PMID- 17712968 TI - [Determination of total N-nitroso compounds in sausage on the market]. AB - OBJECTIVE: To survey the polluted level of total N-nitroso compounds (TNOC) in sausage on the market by the method established for the determination of TNOC in the sausage. METHODS: The method of chemical fission-thermal energy analyzer was based on the previous method for the determination of TNOC in biological fluids which could distinguish between thermo-labile compounds and acid-labile compounds (TAC). Thirty-two samples of sausage were selected by a random sample procedure on the market. Chemical fission-thermal energy analyzer was used in the analysis of TNOC in the samples. RESULTS: The results showed that nitrate from the sample was effectively removed by AG1-X8 anion exchange resin, and did not affected detection of N-nitroso compounds (NOC). 0.2% HCl/HAc was optimum concentration for TAC, and did not decompose unstable nitrosamides. Spiked with NOC mixture, the recovery in the sausage was 86% (83% -89%). The detection limit of this method was 6.6 microg(N-NO)/kg with 5.9% the relative standard deviation. TNOC detection rate and the average levels in the sausage were 93.8% and 49.09 microg/kg (95% Cl 39.15 - 126.35 microg/kg), respectively. CONCLUSION: This method may be veracity and could be repeated and could use for determination of TNOC in sausage. PMID- 17712970 TI - [Application of pressure-driven membrane technologies for the removal of arsenic from drinking water]. AB - Endemic arsenism caused by ingestion of arsenic-bearing drinking water has been an important public health problem in China. The experimental results of arsenic removal from drinking water by press-driven membrane technologies in recent years are introduced in this paper. Arsenic removal efficiencies and its influencing factors are mainly discussed. It is put forward the idea that coagulation/microfiltration process should be the hotspot in recent study in China due to its high arsenic removal efficiency, low energy consumption and high water recovery. PMID- 17712969 TI - [Application of ELISA for microcystins detection]. AB - Microcystins (MCs) may be group of closely related toxic cyclic heptapeptides produced by common cyanobacteria (blue-green algae). Their toxicity could be associated with specific inhibition of intracellular protein phosphatases type-1 and type-2A (PP1 and PP2A, respectively). There are some methods for analyzing and detecting MCs in aquatic environment, such as HPLC, LC-MS, PPIA, and ELISA. This review introduces advances on MCs determined by enzyme-linked immunosorbent assay (ELISA), and estimates the prospective development of ELISA for monitoring MCs in natural waters. PMID- 17712971 TI - Galactic spiral structure. PMID- 17712972 TI - Tensile water. PMID- 17712973 TI - The now and future role of Sigma Xi. PMID- 17712974 TI - Should we teach "modern" mathematics? An affirmation from a founder of Bourbaki of the principles of the new curricula in mathematics. PMID- 17712975 TI - Toward a national science policy. PMID- 17712976 TI - Stalking the Arctic whale. PMID- 17712977 TI - Science and the American Society. PMID- 17712978 TI - After the supernova, what? PMID- 17712979 TI - Large numbers, cosmology, and Gamow. PMID- 17712981 TI - Energy: planning for the future. PMID- 17712980 TI - Some views of the energy crisis. PMID- 17712982 TI - Energy sources and conversion techniques. PMID- 17712983 TI - Is autism partly a consolidation disorder? AB - Computational modeling has been useful for understanding processes of encoding and consolidation in cortical structures. In particular, this work suggests a role of neuromodulators in setting dynamics for consolidation processes during different stages of waking and sleep. Because autistic individuals show symptoms of a cognitive nature coupled with a high prevalence of comorbid conditions such as epileptiform discharge during sleep and sleep disorders, it is possible that autism could involve a breakdown in consolidation processes, which are essential to build effective cognitive representations of the environment on the basis of individual experiences. In this article, theories of consolidation during different stages of waking and sleep and the role of different neuromodulators in these consolidation processes are reviewed in conjunction with different features of autism, which may be understood in the context of these theories. PMID- 17712984 TI - Food for thought: fluctuations in brain extracellular glucose provide insight into the mechanisms of memory modulation. AB - Extensive evidence indicates that peripheral or direct central glucose administration enhances cognitive processes in rodents and humans. These behavioral findings suggest that glucose acts directly on the brain to regulate neural processing, a function that seems incompatible with the traditional view that brain glucose levels are high and invariant except under extreme conditions. However, recent data suggest that the glucose levels of the brain's extracellular fluid are lower and more variable than previously supposed. In particular, the level of glucose in the extracellular fluid of a given brain area decreases substantially when a rat is performing a memory task for which the brain area is necessary. Together with results identifying downstream effects of such variance in glucose availability, the evidence leads to new thinking about glucose regulation of brain functions including memory. PMID- 17712985 TI - The nucleus accumbens and reward: neurophysiological investigations in behaving animals. AB - The nucleus accumbens (Acb) is a crucial component of the brain reward system. This report reviews electrophysiological studies that examined Acb cell firing during goal-directed behaviors for natural reinforcers (food, water, sucrose) and drugs of abuse (cocaine, heroin, ethanol). Studies that examined the role of environmental stimuli and operant contingencies on Acb activity during behavior are also explored. Given the extensive literature that links dopamine in the Acb with drug reinforcement, experiments are considered that examined the influence of dopamine in modulating Acb cell firing during drug-seeking behaviors. Finally, because the Acb is one neural substrate of a larger brain reward circuit, the influence of afferent input (hippocampus and prefrontal cortex) on Acb cell firing during behavior is also discussed. These findings provide a unique insight into the cellular mechanisms underlying reward-related processing and goal directed behaviors and reveal a level of functional organization in the Acb not identified by other experimental approaches. PMID- 17712986 TI - The neural correlates of navigation: do head direction and place cells guide spatial behavior? AB - Head direction (HD) and place cells are thought to represent the neural correlates of processes underlying navigation. At present, however, a large gap exists in our knowledge as to how the firing characteristics of HD and place cells relate to performance in a navigational task. The purpose of this review is to evaluate critically the current evidence that such a relationship exists by examining the studies that have directly addressed this issue. The results of these studies are consistent with the notion that behavior and perceived orientation (as represented in the firing of HD and place cells) can be independently controlled by different cues but, under certain conditions, are controlled by the same cue(s). Much work, however, remains to be done to clarify the role of the HD and place cell systems in the neurobiology of spatial cognition and navigation. PMID- 17712987 TI - Immune-mediated diseases: where do we stand? AB - The progress in basic immunology during the past 50-60 years has been associated with the emergence of clinical immunology as a new discipline in the 1970s. It was defined as the application of basic immunology principles to the diagnosis and treatment of patients with diseases in which immune-mediated mechanisms play an etiological role. Immune-mediated diseases such as autoimmune diseases, allergic diseases, and asthma are important health challenges in the United States and worldwide. For instance, autoimmune diseases afflict 5-8% of the US population; asthma and allergic diseases combined represent the sixth leading cause of chronic illness and disability in the United States and the leading cause among children. As shocking as these numbers and other data in this chapter are, they cannot adequately reflect the physical and emotional devastation to individuals, families, and communities coping with hundreds of immune-mediated disorders nor do they capture the enormous deleterious impact of these diseases on the economies of countries, nations, and indeed entire planet. PMID- 17712988 TI - The four most common pediatric immunodeficiencies. AB - Other than the physiologic hypogammaglobulinemia of infancy, 80% of the confirmed immunodeficiencies consist of four syndromes: transient hypogammaglobulinemia of infancy (THI), IgG subclass deficiency, partial antibody deficiency with impaired polysaccharide responsiveness (IPR), and selective IgA deficiency IgAD. None are life threatening, all can be readily managed, and many recover spontaneously. An exact incidence of these disorders is not known. A summary of immunodeficiency registries in four countries listed IgAD in 27.5% of the patients, IgG subclass deficiency in 4.8%, and THI in 2.3%. The 1999 US survey of primary immunodeficiencies conducted by the Immune Deficiency Foundation found that 17.5% of these patients had IgAD and 24% had IgG subclass deficiency, while THI and IPR were not listed. The Jeffrey Modell Foundation (2005) survey of their global centers in 2004 reported IgAD in 15.5%, subclass deficiencies in 8%, and THI in 2% of their patients. PMID- 17712989 TI - Immune dysregulation, polyendocrinopathy, enteropathy, X-linked inheritance: model for autoaggression. AB - Patients with the rare X-linked syndrome, immune dysregulation, polyendocrinopathy, enteropathy (IPEX) may present early in life with type I diabetes, hyperthyroidism, chronic enteropathy, villous atrophy, dermatitis, autoimmune hemolytic anemia, and antibody- induced neutropenia and thrombocytopenia. Of the reported families with IPEX, most affected boys died before the age of 3 years of malabsorbtion, failure to thrive, infections, or other complications. Characteristic findings at autopsy include lymphocytic infiltrates affecting the lungs, endocrine organs, such as pancreas and thyroid and skin, and increased lymphoid elements in lymph nodes and spleen. Although symptomatic therapy with immunosuppressive drugs provides some beneficial effects, the only curative treatment is hematopoietic stem cell transplantation. PMID- 17712990 TI - DiGeorge syndrome/velocardiofacial syndrome: the chromosome 22q11.2 deletion syndrome. AB - Chromosome 22q11.2 deletion (CH22qD) syndrome is also known as DiGeorge syndrome or velocardiofacial syndrome. This deletion syndrome is extremely common with nearly one in 4000 children being affected. Recent advances and a holistic approach to patients have improved the care and well-being of these patients. This review will summarize advances in understanding the health needs and immune system of patients with CH22qD syndrome. Patients will most often need interventions directed at maximizing function for many organ systems but can ultimately have a high level of functioning. PMID- 17712991 TI - Leukocyte adhesion deficiencies: molecular basis, clinical findings, and therapeutic options. AB - Leukocyte trafficking from bloodstream to tissue is important for the continuous surveillance for foreign antigens, as well as for rapid leukocyte accumulation at sites of inflammatory response or tissue injury. Leukocyte interaction with vascular endothelial cells is a pivotal event in the inflammatory response and is mediated by several families of adhesion molecules. The crucial role of the beta2 integrin subfamily in leukocyte emigration was established after leukocyte adhesion deficiency (LAD) I was discovered. Patients with this disorder suffer from life-threatening bacterial infections, and in its severe form, death usually occurs in early childhood unless bone marrow transplantation is performed. The LAD II disorder clarifies the role of the selectin receptors and their fucosylated ligands. Clinically, patients with LAD II suffer from a less severe form of disease, resembling the moderate phenotype of LAD I. LAD III emphasizes the importance of the integrin activation phase in the adhesion cascade. Although the primary defect is still unknown, it is clear that all hematopoietic integrin activation processes are defective, which lead to severe infection as observed in LAD I and to marked increase tendency for bleeding problems. PMID- 17712992 TI - Nijmegen breakage syndrome. AB - Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disease, characterized by microcephaly, growth retardation, immunodeficiency, chromosome instability, radiation sensitivity, and a strong predisposition to lymphoid malignancy. The gene responsible for the development of this syndrome (NBS1) was mapped on chromosome 8q21. The product of this gene--nibrin--is a protein with 95 kDa molecular weight (p95). The same mutation in the NBS1 gene (deletion 657del5) was detected in most of the evaluated patients. In this chapter, we describe the analysis of the literature and our results on clinical and immunological features and genetic evaluation of 21 NBS patients. PMID- 17712993 TI - Neutrophil activity in chronic granulomatous disease. AB - The killing of microorganisms by neutrophils causes degranulation of azurophilic, specific, and gelatinase granules into the formed phagolysosomes. During the degranulation process, increased surface expression of CD63 (localized in the azurophilic granules of resting neutrophils) and CD66b/CD67 (from specific granules) can be detected. This results from the fusion of the granule membrane, containing these markers, with a plasma membrane. Release of granule content into the phagolysosomes or the extracellular environment occurs not only upon proper cell activation but also upon tissue injury. We compared expression of degranulation markers on neutrophils from chronic granulomatous disease (CGD) patients and healthy volunteers. Surface expression of CD63 in non-stimulated and phorbol 12-myristate 13-acetate (PMA)-stimulated neutrophils, bactericidal activity of serum, and alpha-defensins level (HNP 1-3) in plasma of CGD patients were significantly higher in comparison with healthy volunteers. At the same time, the levels of intracellular HNP 1-3 in CGD neutrophils were lower than in normal neutrophils. Thus, our data revealed augmented degranulation of azurophilic neutrophil granules in CGD, which might play a role in tissue destruction observed in this disease. PMID- 17712994 TI - Mycobacterial infections in primary immunodeficiency patients. AB - Primary immunodeficiencies (PID) are a diverse group of hereditary diseases leading to the impaired immune response that creates high susceptibility to mycobacterium infection. High susceptibility to mycobacterial infections of patients suffering from defects of phagocytosis and combined immunodeficiencies can be explained by predominant participation of macrophages and T lymphocytes in the specific immune response. Mycobacterium tuberculosis, Bacille Calmette Guerin, and non-tuberculosis mycobacterium (NTM) may cause a severe disease in patients with PIDs. We report here our results of the clinical features of mycobacterium infection presentations in 36 patients with various PIDs. PMID- 17712995 TI - SLE 1, 2, 3...genetic dissection of lupus. AB - Systemic lupus erythematosus (SLE) is a chronic and complex autoimmune disease of unknown etiology, characterized by the presence of widespread immunological abnormalities and multiorgan injury. An important advance over the past decade has been our understanding of how different genetic loci (or genes) may dictate specific immune abnormalities in lupus. "Genetic dissection" has unveiled some of the mystery enshrouding lupus pathogenesis. It appears that there are at least two distinct events leading to disease. The first involves a breach in the adaptive immune system and the second involves a dysregulation of innate immunity. Co-ordinate dysregulation of both checkpoints is necessary for full blown lupus to ensue. The challenge ahead is to understand how these two checkpoints are regulated in human SLE, and to devise therapeutic strategies that target both checkpoints. PMID- 17712996 TI - Network of myeloid and plasmacytoid dendritic cells in atopic dermatitis. AB - Atopic dermatitis (AD) presents as a chronic relapsing skin disease with high prevalence in children. The typical distributed skin lesions make the clinical diagnosis of AD very simple and clear-cut in most of the cases. In contrast, the underlying mechanisms leading to the manifestation of AD are more than complex and consist of genetic components combined with various deficiencies on the level of innate and adaptive immune mechanisms. Challenged by this puzzle, scientific approaches of the last years have made considerable progress in gaining insights into the mechanisms, which cause AD. AD is a biphasic inflammatory skin disease characterized by an initial phase predominated by Th2 cytokines which switches into a second, more chronic Th1-dominated eczematous phase. Two different dendritic cell (DC) subtypes bearing the high-affinity receptor for IgE (FcepsilonRI) have been identified in the epidermal skin of AD patients: FcepsilonRIhigh Langerhans cells (LCs) and FcepsilonRIhigh inflammatory dendritic epidermal cells (IDECs). These two DC subtypes are believed to contribute distinctly to the biphasic nature and the outcome of T cell responses in AD. In contrast, plasmacytoid DCs, which play an important role in the defence against viral infections, have been shown to bear the high-affinity receptor for IgE too but are nearly absent from the epidermal skin lesions of AD patients. In light of recent developments, the picture emerges that different IgE-receptor bearing DC subtypes in the blood and skin of AD patients play a pivotal role in the complex network of DCs, which is highlighted in this review. PMID- 17712997 TI - Peptide-based therapy in lupus: promising data. AB - Systemic lupus erythematosus (SLE) is a multisystem chronic inflammatory disease of multifactorial aetiology, characterized by inflammation and damage of various tissues and organs. Current treatments of the disease are mainly based on immunosuppressive drugs such as corticosteroids and cyclophosphamide. Although these treatments have reduced mortality and morbidity, they cause a non-specific immune suppression. To avoid these side effects, our efforts should focus on the development of alternative therapeutic strategies, which consist, for example in specific T cell targeting using autoantigen-derived peptides identified as sequences encompassing major epitopes. PMID- 17712998 TI - Reduced number and function of CD4+CD25highFoxP3+ regulatory T cells in patients with systemic lupus erythematosus. AB - CD4+CD25+ regulatory T cells (Tregs) play an important role in maintaining tolerance to self-antigens controlling occurrence of autoimmune diseases. Recently, it has been shown that the transcription factor forkhead box P3 (FoxP3) is specifically expressed on CD4+CD25+ T cells. FoxP3 has been described as the master control gene for the development and function of Tregs. We characterized CD4+CD25+CTLA-4+FoxP3+ T cells in 43 patients with systemic lupus erythematosus (SLE). Twenty of them comprised a group of newly admitted patients with the first manifestations of the disease, and the second group included patients that were treated with cytostatics and steroids. The results revealed a significant decrease in CD4+CD25+ and CD4+CD25high T cells numbers in patients from group I compared with control and group II patients. Coexpression of FoxP3 on CD4+CD25+ T cells was significantly reduced in both groups regardless the therapy. The ability of Tregs to suppress proliferation of autologous CD8+ and CD4+ T cells was significantly reduced in both groups of patients compared to healthy donors. Our data revealed impaired production of Tregs in SLE patients that can be partly restored by conventional treatments. PMID- 17712999 TI - Role of altered expression of HLA class I molecules in cancer progression. AB - HLA class I antigens play a key role in immune recognition of transformed and virally infected cells via binding to the peptides of "non-self" or aberrantly expressed proteins and subsequent presentation of the newly formed "HLA-I peptide" complex to T lymphocytes. Consequently, a chain of immune reactions is initiated leading to tumor cell elimination by cytotoxic T cells. Altered tumor expression of HLA class I is frequently observed in various types of malignancies. It represents one of the main mechanisms used by cancer cells to evade immunosurveillance. Because of immune selection, HLA class I-negative variants escape and lead to tumor growth and metastatic colonization. Loss or downregulation of HLA class I antigens on tumor cell surface is a factor that limits clinical outcome of peptide-based cancer vaccines aimed to increasing specific anti-tumor activity of cytotoxic T lymphocytes. Thus, gaining more knowledge regarding frequency of HLA class I defect, its tissue specificity, and underlying molecular mechanisms may help designing appropriate therapeutic strategies in cancer treatment. Here, we describe various types of HLA class I alterations found in different malignancies and molecular mechanisms that underlie these defects. We also discuss a correlation between HLA class I defects cancer progression in melanoma patients with poor clinical response to autologous vaccination. PMID- 17713000 TI - Intrathymic selection: new insight into tumor immunology. AB - Central tolerance to self-antigens is formed in the thymus where deletion of clones with high affinity to "self" takes place. Expression of peripheral antigens in the thymus has been implicated in T cell tolerance and autoimmunity. During the last years, it has been shown that medullary thymic epithelial cells (mTECs) are the unique cell type expressing a diverse range of tissue-specific antigens. Promiscuous gene expression is a cell autonomous property of thymic epithelial cells and is maintained during the entire period of thymic T cell output. The array of promiscuously expressed self-antigens was random and included well-known targets for cancer immunotherapy, such as alpha-fetoprotein, P1A, tyrosinase, and gp100. Gene expression in normal tissues may result in tolerance of high-avidity cytotoxic T lymphocyte (CTL), leaving behind low avidity CTL that cannot provide effective immunity against tumors expressing the relevant target antigens. Thus, it may be evident that tumor vaccines that targeted the tumor-associated antigens should be inefficient due to the loss of high-avidity T cell clones capable to be stimulated. Stauss with colleagues have described a strategy to circumvent immunological tolerance that can be used to generate high-avidity CTL against self-proteins, including human tumor-associated antigens. In this strategy, the allorestricted repertoire of T cells from allogenic donor is used as a source of T cell clones with high avidity to tumor antigens of recipient for adoptive immunotherapy. Then, the T cell receptor (TCR) genes isolated from antigen-specific T cells can be exploited as generic therapeutic molecules for antigen-specific immunotherapy. PMID- 17713001 TI - Crosstalk between apoptosis and antioxidants in melanoma vasculogenic mimicry. AB - The concept of "vasculogenic mimicry" (VM) was introduced to describe the unique ability of highly aggressive tumor cells to form capillary-like structure (CLS) and matrix-rich patterned network in three-dimensional cultures that mimic embryonic vasculogenic network. Here, we provide the experimental evidence that CLS structure formation requires apoptotic cell death through activation of caspase-dependent mechanism. Our results indicate that the formation of CLS is also related to the reactive oxygen species (ROS) levels. PMID- 17713002 TI - Immunological role of dendritic cells in cervical cancer. AB - Cervical cancer is the second most frequent gynecological malignancy in the world. Human papillomavirus (HPV) infection is the primary etiologic agent of cervical cancer. However, HPV alone is not sufficient for tumor progression. The clinical manifestation of HPV infection depends also on the host's immune status. Both innate and adaptive immunity play a role in controlling HPV infection. In untransformed HPV-infected keratinocytes, the innate immunity is induced to eliminate the invading HPV pathogen through sensitization to HPV-related proteins by epithelial-residing Langerhans cells (LCs), macrophages, and other immune cells. Once the HPV infection escapes from initial patrolling by innate immunity, cellular immunity becomes in charge of killing the HPV-infected keratinocytes of the uterine cervix through systemic immune response developing by dendritic cells (DCs) in the regional lymphoid organs or through local immune response developing by LCs in the cervix. Thereby, DC/LC plays a critical role in eliciting innate and adaptive cellular immune responses against HPV infection. HPV-associated cervical malignancies might be prevented or treated by induction of the appropriate virus-specific immune responses in patients. Encouraging results from experimental vaccination systems in animal models have led to several prophylactic and therapeutic vaccine clinical trials. PMID- 17713003 TI - Sensitizing tumor cells to immune-mediated cytotoxicity. AB - The molecular basis underlying tumor destruction in vivo by specific antitumor CD8+ T cells remains unclear. We propose that the local production of certain tumor necrosis factor (TNF)-family members (death ligands) may be more important for tumor destruction in vivo than previously thought. Also, the apoptotic response of some tumor cells to the TNF-family member TRAIL can be augmented by the proteasome inhibitor bortezomib (Velcade). Thus, bortezomib may sensitize tumor cells to T cell-mediated cytotoxicity and could potentially improve the beneficial effects of immunotherapy. PMID- 17713004 TI - Inhibition of dendritic cell generation and function by serum from prostate cancer patients: correlation with serum-free PSA. AB - Tumor produces a number of immunosuppressive factors that block maturation of dendritic cells (DCs). Here, we demonstrated that endogenous factors presented in the serum of patients with prostate cancer (CaP) inhibited the generation of functionally active DCs from CD14+ monocytes in vitro. We have shown a significant inhibitory potential of serum obtained from patients with CaP and benign prostate hyperplasia benign prostatic hyperplasia (BPH) when compared with serum from healthy volunteers. As assessed by flow cytometry, expression of CD83, CD86, and CD40 molecules was strongly inhibited by CaP and BPH serum. In addition, these DCs were weak stimulators of allogeneic T cell proliferation when compared with DCs produced in the presence of healthy volunteer serum. Statistical analysis of the results revealed a positive relationship between the inhibition of expression of DC markers CD83 and CD80 and the levels of serum-free prostate-specific antigen (PSA). These data suggest that the DC system may be impaired in CaP patients. PMID- 17713005 TI - Alarmins initiate host defense. AB - In response to infection and/or tissue injury, cells of the host innate immune system rapidly produce a variety of structurally distinct mediators (we elect to call alarmins) that not only function as potent effectors of innate defense but also act to alarm the immune system by promoting the recruitment and activation of host leukocytes through interaction with distinct receptors. Alarmins are capable of activating antigen-presenting cells (APCs) and enhancing the development of antigen-specific immune responses. Here, we discuss the characteristics of several alarmins, a variety of potential alarmin candidates and potential implications of alarmins. PMID- 17713006 TI - Gangliosides as immunomodulators. AB - Gangliosides are glycosphingolipids expressed at the outer leaflet of the plasmatic membrane of cells from vertebrate organisms. These molecules exert diverse biological functions including modulation of the immune system responses. Aberrant expression of gangliosides has been demonstrated on malignant cells. Besides expression on tumor cell membranes, gangliosides are also shed in the tumor microenvironment and eventually circulate in patients blood. Gangliosides derived from tumors posses the capability to affect the immune system responses by altering the function of lymphocytes and antigen-presenting cells and promoting tumor growth. These molecules can be considered as tumor weapons directed to attack and destroy immunosurveillance mechanisms devoted to control cancer progression. PMID- 17713007 TI - Functional changes of macrophages induced by dimeric glycosaminylmuramyl pentapeptide. AB - Under the influence of dimeric glucosaminylmuramyl pentapeptide (diGMPP), a component of bacterial cell wall, macrophages undergo certain changes similar to those associated with dendritic cell (DC) maturation. The effect of diGMPP on DCs resulted in maturation and expression of CD83. Macrophages treated with diGMPP displayed reduced phagocytic activity and elevated ability to kill ingested bacteria. Reduced phagocytosis may be due to phenotypic changes that occur in macrophages during the maturation process, such as reduced expression of receptors that mediate ingesting of microorganisms (CD16, CD64, and CD11b). Down regulated expression of pattern-recognizing receptors (TLR2, TLR4, and CD206) was accompanied by elevated expression of antigen-presenting (HLA-DR) and costimulating molecules (CD86 and CD40), similar to alterations observed in maturating DCs. In addition, diGMPP treatment of macrophages resulted in enhanced synthesis of IL-12, TNF-alpha, and IL-1beta. PMID- 17713008 TI - Myeloid-derived suppressor cells. AB - The development of tumor-specific T cell tolerance is largely responsible for tumor escape. Accumulation of myeloid-derived suppressor cells (MDSCs) in animal tumor models as well as in cancer patients is involved in tumor-associated T cell tolerance. In recent years, it has become increasingly evident that MDSCs bring about antigen-specific T cell tolerance by various mechanisms, which is the focus of this chapter. PMID- 17713009 TI - The lytic NK cell immunological synapse and sequential steps in its formation. AB - Natural killer (NK) cells are lymphocytes of the innate immune system that are critical in host defense. They are best known for their ability to mediate cytotoxicity, which involves a coordinated series of events resulting in the directed secretion of lytic granules onto a target cell. This process requires the formation of an immunological synapse in NK cells. The NK cell immunological synapse involves the reorganization of the actin cytoskeleton and clustering of certain cell surface receptors in the NK cell at the interface with the target cell. The lytic NK cell immunological synapse, specialized for mediating cytotoxicity, is further distinguished by the polarization of lytic granules, which are then secreted through this region onto the target cell. These events unfold in a definitive sequence and lead to critical checkpoints that provide regulatory control at specific stages in the formation of the NK cell lytic synapse. PMID- 17713010 TI - Infective, neoplastic, and homeostatic sequelae of the loss of perforin function in humans. AB - Perforin, a pore-forming protein toxin synthesized and stored in the cytoplasmic vesicles of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, is secreted when these effector lymphocytes encounter virus-infected or neoplastic cells. Perforin is encoded by a single-copy gene and is critical for immune homeostasis and defense of the organism against intracellular sepsis. A complete deficiency of perforin expression in either mice or humans is associated with a syndrome of immune insufficiency and severely deregulated lymphoid homeostasis. Humans who inherit inactivating mutations of perforin or defects in various parts of the cellular machinery that delivers perforin to the target cell suffer from familial hemophagocytic lymphohistiocytosis (FHL), a fatal condition necessitating bone marrow transplantation, usually in infancy. In mice, a high incidence of spontaneous B cell lymphoma has also been noted as the animals age. Across human populations, a number of polymorphisms that result in measurable, but suboptimal CTL activity have been noted, and some of these predispose to attenuated FHL or susceptibility to infectious disease, but in many cases, to no discernible disease predisposition. This chapter discusses the significance of human perforin polymorphisms, particularly those associated with diseases other than FHL, and recent advances in our understanding of perforin biology and function. PMID- 17713011 TI - Natural killer T (NKT) cell subsets in chlamydial infections. AB - Natural killer T (NKT) cells are a newly identified unique subset of cells that express both alphabeta T cell receptor and NK cell markers. We investigated the role of NKT cells in modulating adaptive T cell responses in chlamydial infections using human-disease-related chlamydial species. Our study provides in vivo evidence that even closely related pathogens may activate different functional NKT subsets, which can further polarize CD4+ and CD8+ cells in adaptive immune responses. PMID- 17713012 TI - Memory T cells in allograft rejection. AB - T cell repertoire of many humans contains high frequencies of memory T cells specific for alloantigens. The increasing evidence implicates these cells as a barrier to allograft survival and to the induction of transplantation tolerance. This review discusses several aspects of memory T cell immunobiology pertinent to their role in transplantation. PMID- 17713013 TI - Differences in dendritic cell activation and distribution after intravenous, intraperitoneal, and subcutaneous injection of lymphoma cells in mice. AB - Dendritic cells (DCs) are key antigen-presenting cells (APCs) for initiating immune responses. However, in recent years, several groups have shown the defective function of DCs in tumor-bearing mice and in cancer patients. Our aim was to study the effects of lymphoma on DC differentiation and maturation and to assess the input of the tumor microenvironment and intravasation of tumor cells on DC precursors. EL-4 lymphoma cells were administrated via different routes (intraperitoneal, subcutaneous, and intravenous) and DC phenotype was investigated. Bone marrow-derived DCs and APCs obtained from the spleen were examined by flow cytometry, and immunohistochemical analysis of lymphoma, lungs, livers, and spleens was also performed. Intravenous administration of lymphoma cells induced suppression of DC differentiation and maturation assessed as a significant decrease of the IAb, CD80, CD86, CD11b, and CD11c expression on DCs and IAb on splenic APCs. Upregulation of APC differentiation was observed in animals after subcutaneous and intraperitoneal administration of lymphoma cells determined as increased expression of CD40 and CD86 in spleen APCs. These data suggest that the development of antitumor immune response might differ in the host receiving tumor vaccines via different injection routes. PMID- 17713014 TI - Role of IL-1-mediated inflammation in tumor angiogenesis. AB - Angiogenesis, or generation of new blood vessels from pre-existing vessels, is an integral part of many physiological or pathological processes, including tumor growth. Physiological angiogenesis is a complex process controlled by different proangiogenic as well as antiangiogenic factors. For angiogenic induction, the balance between these pro- and antiangiogenic factors in the microenvironment has to shift in favor of proangiogenic factors, either by upregulation of these pro angiogenic factors or by downregulation of angiogenic inhibitors. Proinflammatory cytokines, such as IL-1 and TNFa, were found to be major proangiogenic stimuli of both physiological and pathological angiogenesis. The IL-1 family consists of pleiotropic proinflammatory and immunoregulatory cytokines, namely, IL-1alpha and IL-1beta, and one antagonistic protein, the IL-1 receptor antagonist (IL-1Ra), which binds to IL-1 receptors without transmitting an activation signal and represents a physiological inhibitor of preformed IL-1. Previously, we described an important role for microenvironment IL-1, mainly IL-1beta, in tumor angiogenesis. In this chapter, we analyze the role of microenvironment host- and tumor cell-derived IL-1 on angiogenesis and the role of inflammation in pathological angiogenesis. PMID- 17713015 TI - New approaches for monitoring CTL activity in clinical trials. AB - We have developed a modification of the ELISPOT assay that measures Granzyme B (GrB) release from cytotoxic T lymphocytes (CTLs). The GrB ELISPOT assay is a superior alternative to the 51Cr-release assay since it is significantly more sensitive and provides an estimation of cytotoxic effector cell frequency. Additionally, unlike the IFN-gamma ELISPOT assay, the GrB ELISPOT directly measures the release of a cytolytic protein. We report that the GrB ELISPOT can be utilized to measure ex vivo antigen-specific cytotoxicity of peripheral blood mononuclear cells (PBMCs) from cancer patients vaccinated with a peptide-based cancer vaccine. We compare the reactivity of patients' PBMCs in the GrB ELISPOT, with reactivity in the tetramer, IFN-gamma ELISPOT and chromium (51Cr)-release assays. Differences in immune response over all assays tested were found between patients, and four response patterns were observed. Reactivity in the GrB ELISPOT was more closely associated with cytotoxicity in the 51Cr-release assay than the tetramer or IFN-gamma ELISPOT assays. We also optimized the GrB ELISPOT assay to directly measure immune responses against autologous primary tumor cells in vaccinated cancer patients. A perforin ELISPOT assay was also adapted to evaluate peptide-stimulated reactivity of PMBCs from vaccinated melanoma patients. Modifications of the ELISPOT assay described in this chapter allow a more comprehensive evaluation of low-frequency tumor-specific CTLs and their specific effector functions and can provide a valuable insight into immune responses in cancer vaccine trials. PMID- 17713016 TI - Serum levels of soluble HLA and IL-2R molecules in patients with urogenital chlamydia infection. AB - Cellular immunity plays a central role in immune response to chlamydial infection, and soluble forms of immune cell membrane antigens take part in the regulation of immune response. Using an immunoenzymatic method, we determined serum levels of soluble HLA molecules (sHLA-I and sHLA-DR) and soluble CD25 molecules (sCD25) in patients with genital chlamydial infection. Specimens from patients with nonspecific inflammation of the urogenital tract were studied and healthy volunteers served as controls. We revealed that serum levels of sHLA-DR and sCD25 increased 3.5- and 2.3-fold, respectively, during chlamydial infection, while the levels of sHLA-I were not changed. Nonspecific inflammation of the urogenital tract was characterized by a 1.5-fold increase in sHLA-I, a 1.6-fold decrease in sCD25, and no changes of sHLA-DR levels in comparison with healthy volunteers. We concluded that Th1 immune responses might dominate during genital chlamydial infection contrary to the state of nonspecific inflammation of urogenital tract. PMID- 17713017 TI - Evaluation of suspected immunodeficiency. AB - The clinical utility and capacity to evaluate immunologic function has evolved significantly over the past few decades. This chapter summarizes screening methods and more sophisticated approaches to assess the immune system when there is a suspicion of an immune deficiency. PMID- 17713018 TI - Frequently ill children. AB - Frequently ill children (FIC) show persistence of infection in the nasopharynx, disbiosis of intestinal flora, and concomitant and allergic diseases. As per our results, FIC with acute respiratory diseases (ARD) frequency of 6-15 times a year plus chronic infection foci at the age of 2-15 y/o at the remission period have heterogeneous nature of immune system disorders. It depends on the age, frequency of ARD, and chronic infection foci. About 20-50% of children have low number of T cells and 70% of children have high number of activated T cells. About 5-23% of children have low level of serum IgG or IgA, while low level of saliva IgA has been determined in 94% of children and low synthesis of IFN-alpha in 80% and of IFN-gamma in 30% of children. About 50% of kids have high level of common IgE (160-220 ME/ml) and diagnostic sensitization to various allergens. In contrast, only 25% of children with ARD frequency of 4-6 times a year without chronic infection foci had low synthesis of IFN-alpha, 30% had low IgA level in saliva, and 8.3% had low IgA level in serum. After vaccination against hepatitis B, antibody level to HBs-Ag and time of their circulation at FIC had been lower than in children with ARD frequency of 4-6 times a year. Examination of FIC at the remission period showed polymorphism of natural and adaptive immunity disorders associated with the immune system developmental delay and subsequent forming of chronic infection foci being an aggravating factor for these disorders. PMID- 17713019 TI - Evaluation of bactericidal activity of human biological fluids by flow cytofluorimetry. AB - The ability of biological fluids to kill microbes is an important feature of the human immune system. Following incubation of fluorescein isothiocyanate-labeled Staphylococcus aureus with biological specimens and subsequent staining with propidium iodide, the proportions of killed bacteria were estimated by flow cytometry. FACScan is a simple, quick and reliable method to evaluate bactericidal activity of biological fluids. The results of the cytometric method correlated well with the results of the classic microbiological method. The proposed method is highly informative for evaluating bactericidal activity of sera in immunocompromised patients. PMID- 17713020 TI - Rational development of antigen-specific therapies for type 1 diabetes. AB - Administration of autoantigens, especially via the mucosal route, can induce tolerance under certain circumstances. In autoimmune diabetes, mucosal vaccination with autoantigens was frequently effective in restoring tolerance in mice but has not yet succeeded in humans. Furthermore, in some instances, autoimmunity can be precipitated upon autoantigen administration. We will here briefly discuss the underlying reasons and delineate which efforts should be made in the future to rationally translate antigen-specific immunotherapy, for example, by establishing better assays to reduce the risk for possible adverse events in humans. PMID- 17713021 TI - Interleukin-7 immunotherapy. AB - IL-7 is a member of the common gamma-chain family of cytokines sharing a common gamma-chain in their receptor. Beyond its long-established pivotal role in immune development, it has been more recently recognized as a critically important regulator of peripheral naive and memory T cell homeostasis while its role in postdevelopment thymic function remains at best, poorly defined, and controversial. Its multiple immune-enhancing properties, most notably in the maintenance of T cell homeostasis, make it a very attractive candidate for immunotherapy in a wide variety of clinical situations. Following many years of rich preclinical data in murine and simian models, IL-7 is now emerging in human phase I trials as a very promising immunotherapeutic agent. Human in vivo data discussed here are derived from the phase I study initiated at the National Cancer Institute in collaboration with Cytheris, Inc., in a cohort of subjects with incurable malignancy. PMID- 17713022 TI - Transmembrane interactions as immunotherapeutic targets: lessons from viral pathogenesis. AB - Multichain immune recognition receptors (MIRRs) represent a family of structurally related but functionally different surface receptors expressed on different cells of the immune system. A distinctive and common structural characteristic of MIRR family members is that the extracellular recognition domains and intracellular signaling domains are located on separate subunits. How extracellular ligand binding triggers MIRRs and initiates intracellular signal transduction processes is not clear. A novel model of immune signaling, the Signaling Chain HOmoOLigomerization (SCHOOL) model, suggests possible molecular mechanisms and reveals the MIRR transmembrane interactions as universal therapeutic targets for a variety of MIRR-mediated immune disorders. Intriguingly, these interactions have been recently shown to play an important role in human immunodeficiency virus and cytomegalovirus pathogenesis. In this chapter, I demonstrate how the SCHOOL model, together with the lessons learned from viral pathogenesis, can be used practically for rational drug design and the development of new therapeutic approaches to treat a variety of seemingly unrelated disorders, such as T cell-mediated skin diseases and platelet disorders. PMID- 17713023 TI - Tumor cell vaccines. AB - This chapter reviews the history of tumor cell vaccines, both autologous and allogeneic, as well as adjuvants used with tumor cell vaccines. The chapter discusses various tumor cell modifications that have been tested over the years. The immune response to tumor vaccines is briefly described, as are some methods of immune monitoring after vaccine therapy. Finally, there is a description of various tumor cell-based vaccines that have been tested in clinical trials. PMID- 17713024 TI - T cell tolerance to tumors and cancer immunotherapy. AB - It is widely recognized that the immune system plays a role in cancer progression and that some tumors are inherently immunogenic. The identification of tumor associated antigens (TAAs) has stimulated research focused on immunotherapies to mediate the regression of established tumors. Cancer-specific immunity has traditionally been aimed at activating CD8+ cytotoxic T lymphocytes (CTLs) directed against major histocompatibility complex (MHC) class I-binding peptide epitopes. Other approaches utilize T cell adoptive therapy where autologous, tumor-specific T cells propagated in vitro are transferred back into recipients. However, these strategies have met with limited success in part due to the regulatory mechanisms of T cell tolerance, which poses a considerable challenge to cancer immunotherapy. Our laboratory utilizes the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model, a murine model of prostate cancer, to study mechanisms of T cell tolerization to tumor antigens. We previously demonstrated that upon encounter with their cognate antigen in the tumor microenvironment, naive T cell become tolerized. Our ongoing studies are testing whether provision of CD4+ T cells can enhance tumor immunity by preventing CD8+ T cell tolerance. A greater understanding of the interaction between various tumor-specific T cell subsets will facilitate the design of novel approaches to stimulate a more potent antitumor immune response. PMID- 17713025 TI - Herpes simplex virus: treatment with antimicrobial peptides. AB - The herpes virus infection represents a significant challenge for public health. The innate immunity plays an important role in herpes simplex virus (HSV) elimination. The innate antiviral immunity has not been comprehensively studied. The recent investigations demonstrate that Toll-like receptors are actively involved in the virus recognition. The complement and natural antibodies, as well as cytokines and antimicrobial peptides, are the first molecules to bind to virions. In this chapter, some mechanisms of the innate antiviral immunity are discussed and treatment regimens are proposed. The complex of native cytokines and antimicrobial peptides (CCAP or Superlymph) proved to inhibit the virus reproduction in vitro. Protegrines, as a CCAP component, were active against the virus. Considering all the data, we conclude that the complex of native cytokines and antimicrobial peptides produces both immunomodulating and antiviral effects. PMID- 17713026 TI - Vaccine containing natural TLR ligands protects from Salmonella typhimurium infection in mice and acute respiratory infections in children. AB - It has been shown that a single parenteral administration of vaccine containing bacterial ligands for TLRI, TLR2, TLR4, TLR6, and TLR9 in mice induced rapid (24 h after administration) and effective (100%), but short-term (96 h) protection against lethal challenge with Salmonella typhimurium. Repeated mucosal applications of this vaccine stimulated long-term (up to 9 months) protection against acute respiratory infections in children of preschool age. PMID- 17713027 TI - Lymphocyte subpopulations in melanoma patients treated with dendritic cell vaccines. AB - The main goal of cancer immunotherapy is to induce or boost tumor-specific effector cells able to eliminate or reduce tumor progression. In this study, we characterized lymphocyte phenotypes in melanoma patients receiving dendritic cell (DC)-based vaccinotherapy. We found that several biological markers served as unfavorable prognostic factors for patients' response to therapy. This included decrease of CD4+ and CD8+ lymphocyte levels, 10% and higher increase of CD16+CD3+CD8+ lymphocyte population, and increase of CD16+CD8+perforin+ T lymphocytes, especially in combination with decreased levels of CDI6+CD8( )perforin+ and CD8+CD16(-)perforin+ cells. Increase in CD8+CD16(-)perforin+ T lymphocytes with normal levels of CD16+CD8(-)perforin+ cells and the absence of CD16+CD8+perforin+ and regulatory lymphocytes were shown to be the positive prognostic markers for patients' response to DC vaccines. PMID- 17713028 TI - Cell technologies in immunotherapy of cancer. AB - Tumor growth is accompanied by active immune reactions even on the early stages. Vaccine therapy implies the use of single antigen or combination of antigens, either with or without adjuvants, for the modulation of immune response. N.N. Petrov Institute of Oncology joined the field of antitumor vaccine therapy and related cellular technologies in 1998. The following activities are held: (1) Optimization of the preparation of autologous and allogeneic antitumor vaccines and development of tumor cell culture bank for the experiments on allogeneic vaccination. (2) Clinical evaluation of autologous vaccine therapy by (a) bone marrow precursors of dendritic cells (DCs), which are loaded with tumor lysates; (b) genetically modified tumor cells; (c) intact tumor cells used in combination with various adjuvants (BCG, IL-1beta, and IL-1beta combined with low doses of cyclophosphamide) in patients with disseminated melanoma, metastatic kidney cancer, and colorectal cancer. Total 117 patients have received non-modified vaccine (48 patients: 2-6 intracutaneous BCG injections; 54 patients: 4-6 intracutaneous IL-1beta injections; 15 patients: up to 6 injections of IL-1beta in combination with low doses of cyclophosphamide). Clinical trial of genetically modified vaccine included 59 patients (clinical results: I PR (partial response) / 8 SD (disease stabilization)--melanoma, 2 PR/ 2 MR (minimal response) / 3 SD- renal cancer). Vaccine prepared from tumor cell-activated DC bone marrow precursors was administered to 18 patients (clinical results: 2 MR and 6 SD). PMID- 17713029 TI - Therapeutic potential of cannabinoid-based drugs. AB - Cannabinoid-based drugs modeled on cannabinoids originally isolated from marijuana are now known to significantly impact the functioning of the endocannabinoid system of mammals. This system operates not only in the brain but also in organs and tissues in the periphery including the immune system. Natural and synthetic cannabinoids are tricyclic terpenes, whereas the endogenous physiological ligands are eicosanoids. Several receptors for these compounds have been extensively described, CB1 and CB2, and are G protein-coupled receptors; however, cannabinoid-based drugs are also demonstrated to function independently of these receptors. Cannabinoids regulate many physiological functions and their impact on immunity is generally antiinflammatory as powerful modulators of the cytokine cascade. This anti-inflammatory potency has led to the testing of these drugs in chronic inflammatory laboratory paradigms and even in some human diseases. Psychoactive and nonpsychoactive cannabinoid-based drugs such as Delta9 tetrahydrocannabinol, cannabidiol, HU-211, and ajulemic acid have been tested and found moderately effective in clinical trials of multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain. Furthermore, although clinical trials are not yet reported, preclinical data with cannabinoid-based drugs suggest efficacy in other inflammatory diseases such as inflammatory bowel disease, Alzheimer's disease, atherosclerosis, and osteoporosis. PMID- 17713030 TI - Micro- and nanoparticle-based vaccines for hepatitis B. AB - The incredible success of vaccinations in contributing to public health is undeniable. In fact, vaccines are the most cost-effective public health tool for disease prevention because their cost is less than the combined costs of treatment, hospitalization, and time loss from work. However, despite the availability of vaccines, cost per dose is a factor limiting the success of global vaccination campaigns, as are the limitations imposed by the need of delivering multiple vaccine doses. A number of approaches are being tested particularly for the delivery of subunit vaccines, and in recent years, a number of groups have devoted their efforts to develop nano/microparticles prepared from biodegradable and biocompatible polymers as vaccine delivery systems with the goal of inducing both humoral and cellular immune responses. Some important properties of biodegradable polymers are their documented safety history, biocompatibility, and an ability to provide controlled time/rate of antigen release and polymer degradation. The most extensively studied polymer used for encapsulating vaccine antigens is poly (lactide-co-glycolide acid) (PLGA). This chapter deals in brief with efforts targeting the use of PLGA micro-and nanoparticles for the delivery of hepatitis B surface antigen. PMID- 17713031 TI - Mast cells, T cells, and inhibition by luteolin: implications for the pathogenesis and treatment of multiple sclerosis. AB - Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) mainly mediated by Th1, but recent evidence indicates that Th2 T cells, mostly associated with allergic reactions, are also involved. Mast cells are involved in allergic and inflammatory reactions because they are located perivascularly and secrete numerous proinflammatory cytokines. Brain mast cells are critically placed around the blood-brain barrier (BBB) and can disrupt it, a finding preceding any clinical or pathological signs of MS. Moreover, mast cells are often found close to MS plaques, and the main MS antigen, myelin basic protein (MBP), can activate human cultured mast cells to release IL-8, TNF-alpha, tryptase, and histamine. Mast cells could also contribute to T cell activation since addition of mast cells to anti-CD3/anti-CD28 activated T cells increases T cell activation over 30-fold. This effect requires cell-to-cell contact and TNF, but not histamine or tryptase. Pretreatment with the flavone luteolin totally blocks mast cell stimulation and T cell activation. Mast cells could constitute a new unique therapeutic target for MS. PMID- 17713032 TI - Ignore FDA reform at your peril. PMID- 17713034 TI - Competitive acquisition program: let the bidding begin. PMID- 17713033 TI - Transparency initiatives spark interest. PMID- 17713035 TI - Guiding the way to wellness. PMID- 17713036 TI - Examine the evidence. PMID- 17713037 TI - Achieving value-driven health care. PMID- 17713038 TI - Operation transformation. Interview by Laronda Famodu. PMID- 17713039 TI - [What comes to mind with this ECG?]. PMID- 17713040 TI - [How motivation or organ donation be increased? (interview by Maria Weiss)]. PMID- 17713041 TI - [Can the illness be due to the tetanus vaccination?]. PMID- 17713042 TI - [Operation in size XXL format--surgeons must adapt to more obese patients]. PMID- 17713043 TI - [Do obese patients need higher dosages? (interview by Dr. Judith Neumaier)]. PMID- 17713044 TI - [Treatment of knee osteoarthritis: what is useful and what is nonsense?]. PMID- 17713045 TI - [Pathogenesis of knee osteoarthrist]. AB - More than 20% of the population of over 60-year olds suffers from degenerative joint diseases of the lower extremities. The cause of primary osteoarthritis of the knee is still unknown. A multifactorial genesis is presumed that includes genetic, nutritional, hormonal and age-related factors. On the other hand, secondary osteoarthritis is a sequela of predisposing factors. The most frequent are axial deformities, pre-existing conditions or injuries. Pre-osteoarthritis appears as dysplasias and dystopias (abnormal presentation) of the patella and axial misalignments, incongruities and joint damage after fractures. The result is the mechanical destruction of the cartilage that, in turn, initiates a vicious circle of further cartilage loss. PMID- 17713046 TI - [Clinical picture and diagnosis of knee osteoarthritis]. AB - The principal symptom of osteoarthritis of the knee is pain. As the disease progresses, attack-like symptoms with knee pain, effusion, activated osteoarthritis, increasing restriction in knee mobility and reduced walking range occur more frequently. Secondarily joint malalignments also develop. Activities such as climbing stairs or sitting for long periods with bent legs are named as sources of pain for patients with patellofemoral osteoarthritis. Medial and/or lateral osteoarthritis of the knee is very probable when the pain is described as being more lateral or medial. The standard x-ray should always be taken AP and from the side. Axial images of the patella and tangential images of the patellofemoral joint are also made for assessing the centring of the patella and for evaluating retropatellar osteoarthritis. For planning the therapy, x-rays of the knee joint AP while standing or of the entire leg while standing are essential. PMID- 17713047 TI - [Conservative Therapy of Knee Osteoarthritis]. AB - Many highly effective measures as well as orthopaedic aids are available for the conservative therapy of knee osteoarthritis. When appropriately implemented for the stage of the disease,they can clearly alleviate the patient's symptoms. However, physiotherapy, physical therapy, balneotherapy and the usual conservative treatment options are not capable of stopping the progression of knee osteoarthritis. Other conservative therapeutic options such as magnetic field therapy, pulse signal therapy, radiotherapy, radiosynoviorthesis, acupuncture and drug therapies improve symptoms to different extents. For this reason, their application should always be critically evaluated. PMID- 17713048 TI - [Surgical treatment of knee osteoarthritis]. AB - Surgery for knee osteoarthritis is indicated if the clinical subjective symptoms in conjunction with radiological findings can no longer be adequately treated by conservative measures. Fundamentally, the treatment procedures are differentiated between joint preserving interventions (arthroscopy, knee revision, if necessary with meniscal debridement, partial synovectomy, osteophyte removal, cartilage surgery with microfracturing, autologous chrondrocyte transplantation, mosaic plasty or spacer implantation), corrective osteotomies near the knee joint and joint replacing procedures (knee endoprostheses or knee fusion [arthrodesis]). PMID- 17713049 TI - [Acupuncture in pain therapy]. AB - The neurobiological mechanisms of acupuncture have been investigated in many cases and provide plausible explanatory approaches for its effectiveness. However, only some of these mechanisms depend on the ,,point-specifity". Evaluation following evidence-based medicine criteria shows level 1 evidence for the efficacy of acupuncture for post-operative dental pain as well as for nausea and vomiting. In addition there are positive results for the efficacy of acupuncture for treating headaches, lumbar spine pain, temporomandibular dysfunction, fibromyalgia, osteoarthritis of the knee and epicondylitis. Acupuncture can be part of a multimodal therapeutic concept for chronic pain disorders with biopsychosocial components. PMID- 17713050 TI - [Glucagon-like peptide 1 (GLP-1)]. AB - GLP-1 receptor agonists such as exenatide are a group of new therapeutic agents that mimic the gut-derived incretin hormone GLP-1. These drugs stimulate insulin secretion while suppressing glucagon secretion, inhibit gastric motility, reduce appetite and hence, food intake. This group of drugs also induce reduction in fasting and postprandial glucose concentrations, HbA1c and ultimately lead to weight loss. The drugs are administered subcutaneously (exenatide twice daily). The most common side effect is mild nausea. Although short-term studies are promising, long-term clinical studies are needed to determine the benefits of this approach for the treatment of type 2 diabetes. PMID- 17713051 TI - [Lip laceration]. PMID- 17713052 TI - [Effective also in Bechterew disease]. PMID- 17713054 TI - [Practice check brings clarity: how do I compare with my colleagues?]. PMID- 17713053 TI - [Combination therapy with oral antidiabetics]. PMID- 17713055 TI - [Specialists worry about their sinecure--general practitioners as champions in case reimbursement]. PMID- 17713056 TI - The right thing to do. PMID- 17713057 TI - The real threats to dentistry. PMID- 17713058 TI - Philadelphia dentists help make 2007 Give Kids a Smile Day successful. PMID- 17713059 TI - Is Pennsylvania spending a fair share of health care expenditures for dental services? PMID- 17713060 TI - American Academy of Pediatric Dentistry and American Academy of Pediatrics issue co-endorsed sedation guidelines. PMID- 17713061 TI - Corrole-based applications. AB - Despite of the many similarities between corroles and porphyrins, the chemistry of the former remained undeveloped for decades because of severe synthetic obstacles. The recent discoveries of facile methodologies for the synthesis of triarylcorroles and the corresponding metal complexes allowed for their utilization in various fields. This survey reveals many examples where corroles were used as the key components in catalysis, sensing of gaseous molecules and medicine-oriented research. The focus in all these cases was on the special features of corroles: stabilization of high valent transition metal ions, unique photophysical properties, large NH acidity, facile synthetic manipulation and distinct catalytic properties. The latter aspect includes several examples of reactions that are not catalyzed by any non-corrole metal complex, such as the iron-based aziridination by Chloramine-T, the clean disproportionation of peroxynitrite, and the very facile N-H activation of amines. PMID- 17713062 TI - Phthalocyanines: old dyes, new materials. Putting color in nanotechnology. AB - Phthalocyanines are versatile building blocks for fabricating materials at the nanometer scale. These colored macrocycles exhibit fascinating physical properties which arise from their delocalized pi-electronic structure. This article describes why these molecules are targets for different scientific purposes and technological applications. PMID- 17713063 TI - Anisotropic fluorescent materials via self-organization of perylenedicarboximide. AB - In this communication, we report the self-organization of a perylenedicarboximide to produce materials that exhibit dichroic (direction-dependent) absorption and anisotropic fluorescence emission of visible light. PMID- 17713064 TI - Lewis vs. Bronsted-basicities of diiron dithiolates: spectroscopic detection of the "rotated structure" and remarkable effects of ethane- vs. propanedithiolate. AB - The new complexes Fe2(S2CnH2n)(CO)2(dppv)2 (n = 2, 3; dppv = cis-1,2-C2H2(PPh2)2) form adducts with AlBr3 and B(C6F5)3, which adopt the "rotated structure" proposed for the active site of the Fe-only hydrogenases--the propanedithiolate is significantly more Lewis basic due to nonbonded interactions between the dithiolate strap and the ligands on Fe. PMID- 17713065 TI - Liquid crystal formation of RecA-DNA filamentous complexes. AB - Spontaneous optical birefringence of RecA-bound linear and closed circular single stranded DNA filaments, as well as RecA self-assembled polymer, was observed in aqueous buffer solutions, which demonstrates the formation of lyotropic liquid crystalline phases. PMID- 17713066 TI - Sensor technologies based on a cellulose supported platform. AB - A simple approach to sensor development based on encapsulating a probe molecule in a cellulose support followed by regeneration from an ionic liquid solution is demonstrated here by the codissolution of cellulose and 1-(2-pyridylazo)-2 naphthol in 1-butyl-3-methylimidazolium chloride followed by regeneration with water to form strips which exhibit a proportionate (1 : 1) response to Hg(II) in aqueous solution. PMID- 17713067 TI - Luminescent metallogels of platinum(II) terpyridyl complexes: interplay of metal...metal, pi-pi and hydrophobic-hydrophobic interactions on gel formation. AB - A series of platinum(II) terpyridyl complexes has been demonstrated to show gelation properties driven by Pt...Pt and pi-pi interactions in addition to hydrophobic-hydrophobic interactions; counter-anions have been found to affect strongly the colour of the metallogel. PMID- 17713068 TI - Au-silica nanoparticles by "reverse" synthesis of cores in hollow silica shells. AB - Core-silica shell nanoparticles were prepared in a "reverse" manner by nucleation and growth of Au cores within hollow silica nanospheres. PMID- 17713069 TI - A novel three-dimensional heterometallic compound: templated assembly of the unprecedented planar "Na within [Cu4]" metalloporphyrin-like subunits. AB - A 3D heterometallic compound, [Cu4Na4(TzDC)4(H2O)7]n (H3TzDC = 1,2,3-triazole-4,5 dicarboxylic acid), which contains unprecedented planar "Na within [Cu4]" metalloporphyrin-like subunits, was synthesized by hydrothermal reactions involving in situ formation of the ligand and templated assembly of the metalloporphyrin-like subunits. PMID- 17713070 TI - Unusual nickel-mediated C-S cleavage of alkyl and aryl sulfoxides. AB - The first examples of transition metal mediated C-S cleavage of sulfoxides containing sp2- and sp3-hybridized carbon bonds attached to the sulfur atom and the first example of a structurally characterized complex featuring an oxygen bound sulfinyl ligand are presented. PMID- 17713072 TI - Mesoporous TiO2/SiO2 composite nanofibers with selective photocatalytic properties. AB - Mesoporous TiO2/SiO2 composite nanofibers with a diameter of 100-200 nm and silica shell thickness of 5-50 nm have been fabricated by a sol-gel combined two capillary co-electrospinning method; the composite nanofibers exhibited selective photocatalytic activity based on the decomposition of Methylene Blue, Active Yellow and Disperse Red. PMID- 17713071 TI - Mupirocin H, a novel metabolite resulting from mutation of the HMG-CoA synthase analogue, mupH in Pseudomonas fluorescens. AB - Mutation of the HMG-CoA synthase encoding mupH gene in Pseudomonas fluorescens gives rise to a new metabolite formed from a truncated polyketide intermediate, providing in vivo evidence for the roles of mupH and cognate genes found in several "AT-less" and other bacterial PKS gene clusters responsible for the biosynthesis of diverse metabolites containing acetate/propionate derived side chains. PMID- 17713073 TI - Unusual regioselective mercuration of metalloporphyrins and its potential applications. AB - The reaction of Hg(CF3CO2)2 with metalloporphyrins produces mercurated porphyrins regioselectively, the reaction, surprisingly occurring at the most hindered betaB position; this behavior is in marked contrast to the usual electrophilic substitution reactions of porphyrins, whose reactions produce meso-substituted porphyrins; the obtained mercurated porphyrins are active to transition metal catalyzed coupling reactions, such as the Mizoroki-Heck reaction. PMID- 17713074 TI - Lithium dimer formation in the Li-conducting garnets Li(5+x)Ba(x)La(3-x)Ta2O12 (0 < x < or =1.6). AB - The garnet system Li(5+x)Ba(x)La(3-x)Ta2O12 shows an unprecedented Li+ content (x < or = 1.6) and short Li-Li distances of ca 2.44 A between majority occupied sites suggesting that the high Li+ mobility requires a complex cooperative mechanism. PMID- 17713075 TI - Room temperature ionic liquids: new solvents for Schrock's catalyst and removal using polydimethylsiloxane membranes. AB - A room temperature ionic liquid was used as the solvent for metathesis reactions with the Schrock catalyst and a new method to facilitate separation between small molecules and ionic liquids using polydimethylsiloxane thimbles is reported. PMID- 17713076 TI - Archaeosomes based on synthetic tetraether-like lipids as novel versatile gene delivery systems. AB - Novel cationic liposomes, termed "archaeosomes", based on mixtures of neutral/cationic bilayer-forming lipids and archaeobacterial synthetic tetraether type bipolar lipids show efficient in vitro gene transfection properties and represent a new approach for modulating the lipidic membrane fluidity of the complexes they form with DNA. PMID- 17713077 TI - Tautomeric polymorphism in omeprazole. AB - Crystalline omeprazole exists as solid solutions of two tautomers in a continuous composition range, and this raises questions pertaining to the definition of the term polymorph. PMID- 17713078 TI - The first trialkylphosphane telluride complexes of Ag(I): molecular, ionic and supramolecular structural alternatives. AB - The structures of the first phosphane telluride complexes of silver(I), obtained from i-Pr3PTe (1) with AgNMs2 [Ms = SO2CH3] and with AgSbF6, reveal the superior coordinating ability of 1, particularly as a bridging ligand, compared with related i-Pr3PS and i-Pr3PSe ligands. PMID- 17713079 TI - Non-heme iron(II) complexes are efficient olefin aziridination catalysts. AB - Iron(II) complexes of polydentate nitrogen donor ligands catalyze the rapid aziridination of olefins by PhINTs. PMID- 17713080 TI - Grignard reagents in ionic solvents: electron transfer reactions and evidence for facile Br-Mg exchange. AB - Grignard reagents form persistent solutions in phosphonium ionic liquids possessing O-donor anions and these solutions are excellent reaction media for electron transfer processes and transmetallation reactions. PMID- 17713081 TI - Novel unsymmetrically pi-elongated porphyrin for dye-sensitized TiO2 cells. AB - A novel naphthyl-fused zinc porphyrin carboxylic acid has been synthesized and employed successfully in a dye-sensitized TiO2 solar cell, with a power conversion efficiency of 4.1%, which is improved by 50% relative to the unfused porphyrin reference cell. PMID- 17713082 TI - Facile preparation and electrochemical properties of cubic-phase Li4Mn5O12 nanowires. AB - Single crystalline Li4Mn5O12 nanowires with cubic phase were prepared in a large scale by a simple molten salt route without using any surfactant as template; the nanowires exhibited high storage capacity and coulombic efficiency as cathode materials for lithium-ion batteries. PMID- 17713083 TI - Halogen-magnesium exchange on unprotected aromatic and heteroaromatic carboxylic acids. AB - The magnesiation of halogenated aromatic and heteroaromatic carboxylic acids is accomplished by their treatment with MeMgCl in the presence of LiCl and subsequent reaction with i-PrMgCl.LiCl; the resulting double-magnesiated species react with a variety of electrophiles in up to 97% yield. PMID- 17713084 TI - Promiscuous zinc-dependent acylase-mediated carbon-carbon bond formation in organic media. AB - A zinc-dependent acylase, D-aminoacylase from Escherichia. Coli, displays a promiscuous activity to catalyze the carbon-carbon bond formation reaction of 1,3 dicarbonyl compounds to methyl vinyl ketone in organic media. PMID- 17713085 TI - Two-photon degradable supramolecular assemblies of linear-dendritic copolymers. AB - Micelles of dendritic-linear copolymers have been developed to release a payload after infrared stimulus. PMID- 17713086 TI - A reassignment of the EPR spectra previously attributed to Cu@C60. AB - EPR spectra attributed to the endohedral metallofullerene Cu@C60 are better explained by the previously characterized Cu(II) dithiocarbamate family of compounds. PMID- 17713087 TI - Ovarian tissue cryopreservation--new opportunity to preserve fertility in female cancer patients. AB - INTRODUCTION: Malignant disease and the therapy are major factors that may result in complete loss of fertility. There are several strategies for fertility preservation in fertile women faced with cancer. A modern and potentially effective method of reproductive function protection is ovarian tissue cryopreservation. MATERIALS AND METHODS: This paper summarizes the medical and scientific knowledge in this interesting multidisciplinary medical field. Furthermore, the authors' own experience with this novel and interesting method of ovarian tissue protection is presented. Ovarian tissue was obtained during laparoscopic surgery in five nuliparous women (aged 19-33) with a diagnosis of lymphoma before chemotherapy from 2004 to 2006. After laboratory preparation, tissue was frozen by a slow cooling technique and stored in liquid nitrogen. RESULTS: In total 75 women with malignant lymphoma before chemotherapy were referred to our center for consultation--68 chose ovarian inactivation by GnRH analogues during chemotherapy, two IVF cycles with embryo or oocyte cryopreservation and five ovarian tissue cryopreservation. In these five women one to two slices of ovarian cortex from both ovaries were recovered. Totally 20 cryotubes with three pieces of tissue in each were cryopreserved. In no case was metastasis of cancer cells found by histological evaluation. CONCLUSIONS: Cryopreservation of ovarian tissue represents an effective alternative or addition to the cryopreservation of embryos or oocytes for women at risk of premature ovarian failure due to chemotherapy. Reproductive function protection requires close cooperation between oncology departments and assisted reproduction centers. PMID- 17713088 TI - Improved survival for stage IIIC ovarian cancer patients treated at the Norwegian Radium Hospital between 1984 and 2001. AB - BACKGROUND: The aim of this study was to evaluate the treatment of FIGO Stage IIIC patients who were primarily treated completely or partially at the Norwegian Radium Hospital (NRH) during a 15-year period in order to discover possibilities for improvement of prognosis of advanced ovarian cancer. MATERIALS AND METHOD: A retrospective study based on record information from all patients with epithelial ovarian cancer Stage IIIC treated at NRH from 1985-2000, in total 776 patients. RESULTS: We found age, amount of residual tumour after surgery for primary treatment and type of chemotherapy to be the most significant prognostic factors for overall survival. During the last 5-year period primary surgery was increasingly centralised, and surgery was improved with lymph node staging and use of paclitaxel. Survival was significantly better during the last 5-year period and after macroscopic radical surgery. Also progression-free survival was better with no macroscopic tumour remaining. INTERPRETATION: Improved survival during the last 5-year period is partly attributed to improved surgery and partly to the addition of paclitaxel. We believe that further centralisation of primary surgery for advanced ovarian cancer can contribute to a better prognosis. PMID- 17713089 TI - Efficacy of c-erbB-2 antisense oligonucleotide transfection on uterine endometrial cancer HEC-1A cell lines. AB - OBJECTIVE: Antigene therapy targeting only one oncogene has made much progress although it still has some limitations. To explore the potential for antigene therapy in uterine endometrial cancer, we examined the in vitro inhibitory effects of liposmal anti-sense phosphorothioate oligonucleotides targeting c-erbB 2 in the human uterine endometrial cancer HEC-1A cell line. METHODS: 1) To detect c-erbB-2 protein expression on HEC-1A cell membranes by immunohisto- chemistry. 2) To assay cellular growth inhibition by MTT after transfecting 0.1-0.6 microM ASODN. 3) To observe cellular and ultra-structural changes under transmission electron microscope and to assay the cellular apoptotic rate by flow cytometry and c-erbB-2 mRNA, and protein expression by RT-PCR and Western blot after transfecting 0.3 microM ASODN. RESULTS: 1) c-erbB-2 protein expression was positive on HEC-1A cell membranes. 2) With the increase of the transfecting ASODN concentration from 0.1-0.6 microM, HEC-1A cellular growth inhibition was also enhanced. The results of MTT showed that when the transfecting concentration of ASODN was 0.3 microM, the HEC-1A cellular growth inhibition rate was 50% while when the transfecting concentration of ASODN was 0.6 microM, the HEC-1A cell growth inhibition rate was 75%. 3) When the concentration of transfecting ASODNs was 0.3 microM, there were obvious vacuolar degenerations in the plasma of HEC-1A cells, disappearance of organelle and nuclear structure and obvious shrinkage of nuclei under transmission electron microscope. The cellular apoptotic rate was 62.80%, while c-erbB-2 mRNA and protein expression were 47.18% and 33.60%, respectively, compared with those of the normal control cells. CONCLUSION: Transfecting c-erbB-2 ASODNs can obviously suppress the mRNA and protein expression in HEC-1A cells, cause cellular apoptosis and inhibit cell growth. It may be a more useful gene therapy for endometrial cancer. PMID- 17713090 TI - Granulocytic sarcoma involving the uterus and right fallopian tube with negative endometrial biopsy. AB - Granulocytic sarcoma is an extramedullary tumor associated with acute myelogenous leukemia (AML) and it is rarely seen in the female genital tract. We report an unusual case of granulocytic sarcoma of the uterus and fallopian tube in an AML patient who presented with vaginal bleeding and persistent abdominal pain. She was under chemotherapy. Biopsy did not reveal the diagnosis. After laparoscopic examination, hysterectomy with bilateral salpingo-oophorectomy was performed. Pathology showed atypical myeloid cells infiltrating the muscle bundles which was consistent with granulocytic sarcoma involving the uterus and right fallopian tube. Immunohistochemistry confirmed the diagnosis. The patient is in complete remission for AML and being followed-up for granulocytic sarcoma. Granulocytic sarcoma of the uterus and fallopian tube is very rare, and in AML patients with abnormal uterine bleeding but negative endometrial biopsy it should still be considered in the differential diagnosis. PMID- 17713091 TI - Irradiation reduces bleomycin sensitivity in cervical squamous cancer cells in vitro. AB - PURPOSE OF INVESTIGATION: The study was performed to examine how bleomycin (BLM) and peplomycin (PEM) should be effectively used in radiotherapy for cervical squamous cancer patients. METHODS: The effects of BLM on radiosensitivity and the effects of radiation on the sensitivity to BLM of cancer cells were investigated using the radiosensitive human cervical squamous cell carcinoma cell line ME180. RESULTS: BLM treatment did not affect radiosensitivity. However, irradiation significantly reduced cell BLM sensitivity in a dose-dependent manner. There was no significant difference in BLM sensitivity and PEM sensitivity between cells concurrently irradiated and those treated with BLM or PEM 8 h before or 8 h after irradiation. CONCLUSION: Since sensitivity to BLM is reduced during irradiation, BLM should be administered to cervical cancer patients as an adjuvant chemotherapeutic drug after completion of radiotherapy. PMID- 17713092 TI - MMAC tumor supressor gene expression in ovarian endometriosis and ovarian adenocarcinoma. AB - OBJECTIVE: The aim of this study was to investigate the role of MMAC1 protein in the relationship between ovarian endometriosis and clear cell and endometrioid type ovarian adenocarcinomas. METHODS: A total of 63 subjects who underwent surgery for a pelvic tumoral mass, 30 of whom were diagnosed with grade 1 to 3 ovarian adenocarcinoma and 33 of whom were diagnosed with grade 1 to 4 endometriosis during histopathological examination were included in this study. The mean age for subjects with ovarian endometrioid type adenocarcinoma was 51.8 +/- 12.4, whereas the mean age for subjects with ovarian clear cell type adenocarcinoma was 59.5 +/- 13.7. Ovarian carcinomas were graded in accordance with the FIGO 1989 grading system. The mean age for subjects with endometriosis was 37 +/- 11.9. New sections were obtained from paraffin blocks in the archives of Ege University, School of Medicine, Department of Pathology onto lysinated slides and immunohistochemical staining by using mouse monoclonal antibody (MMAC1, 28H6 clone, Novocastra, UK) as MMAC antibody was applied in order to determine MMAC1 protein. Brown staining on the nucleus was considered as positive immunoreactivity. Immunoreactive staining was evaluated as percentage staining over the whole preparative. RESULTS: Of the 63 subjects included in the immunohistochemical study, ovarian endometrioid adenocarcinoma was identified in 18 subjects, while 12 subjects were diagnosed with ovarian clear cell adenocarcinoma and 33 subjects with ovarian endometriosis. No significant relationships were observed between age and MMAC immune staining in the ovarian endometrioid adenocarcinoma (r = -0.41, p = 0.08) and ovarian endometriosis (r = 0.12, p = 0.50) groups, whereas a significant relationship was observed in the ovarian clear cell adenocarcinoma group (r = 0.631, p = 0.02). No significant relationships were observed between CA125 levels and MMAC immune staining in the ovarian endometrioide adenocarcinoma (r = 0.056, p = 0.82), ovarian endometriosis (r = 0.21, p = 0.36) and ovarian clear cell adenocarcinoma (r = 0.363, p = 0.24) groups. No correlations were observed between endometriosis stages and the MMAC immune staining (r = -0.17, p = 0.92). There was no correlation between mean diameter of endometrioma and MMAC immune staining (r = -0.230, p = 198). Mean endometrioma diameter was 5.7 +/- 3.5 (1-15.5). No correlations were detected between MMAC immune staining and ovarian endometrioide adenocarcinoma or ovarian clear cell adenocarcinoma stage (r = -0.22, p = 0.37; r = 0.44, p = 0.14, respectively). No significant relationships with respect to MMAC immune staining were detected between the endometriosis and ovarian clear cell adenocarcinoma groups (p = 0.05) and between the ovarian clear cell adenocarcinoma and ovarian endometrioid adenocarcinoma groups (p = 0.27). A significant relationship with respect to MMAC immune staining was observed between ovarian endometrioide adenocarcinoma and endometriosis groups (p = 0.001). CONCLUSION: Immunohistochemical determination of MMAC defective protein expressions could be considered for utilization as a new, simple and useful technique in determination of endometriosis patients with increased risk of malignant transformation, patients where early surgical treatment would be necessary and patients that should be subjected to follow-up controls with a higher frequency. PMID- 17713093 TI - Preneoplastic and neoplastic cervical lesions as detected in Cytoblock sections: the importance of sampling women with bleeding symptoms. AB - PURPOSE OF INVESTIGATION: The purpose was to use cervical samples to prepare Cytoblocks and use the subsequent paraffin sections for additional immunostaining in our studies on angiogenesis. METHODS: Between January and April 2006, 261 women with bleeding complaints were selected of which 85 had gone to their general practitioner (GP) because of postcoital bleeding. The 261 cervical samples were processed by the Shandon Cytoblock Preparation System. On the subsequent prepared Papanicolaou-stained paraffin sections a histological diagnosis was rendered on the minibiopsies. RESULTS: In all (pre)invasive cases, the paraffin sections contained numerous cancerous minibiopsies. The (pre)invasive cases had many Ki-67 positive nuclei displaying an S-phase staining pattern. In the Ki-67 stained sections, the glandular architecture of the two AIS cases and the two adenocarcinoma cases was highlighted. CONCLUSION: Histologic paraffin sections provided enough minibiopsies to allow concise diagnosis including evaluation of proliferation. Signs of cervical angiogenesis, including postcoital bleeding, can be a strong argument to prepare cytoblocks from samples collected by sampling brushes. PMID- 17713094 TI - Primary ovarian angiosarcoma--review of the literature and report of a case with coexisting chylothorax. AB - BACKGROUND: Primary ovarian angiosarcoma is a very rare gynaecologic malignancy with poor prognosis and uncertain, up-to-date, treatment options. Its exact diagnosis is challenging for surgeons and difficult for pathologists. There are only a few cases reported in the international literature. CASE: We report a case of primary pure ovarian angiosarcoma with coexisting chylothorax which is, to the best of our knowledge, the first reported case. An extensive review of the literature analyzing all clinical and pathological parameters related to this condition is presented. RESULT: In spite of all therapeutic efforts, surgical and medical, prognosis of ovarian angiosarcoma remains very poor in most cases. CONCLUSION: Primary ovarian angiosarcoma is a rare and aggressive malignancy. The report of such cases is interesting in order to exchange knowledge and experience, and possibly to further improve our diagnostic and therapeutic capabilities. PMID- 17713095 TI - The role of p53, Bcl-2 and Ki-67 in premalignant cervical lesions and cervical cancer. AB - PURPOSE: The aim of this study was to determine the role of p53, Bcl-2 and Ki-67 expression in the carcinogenesis of cervical carcinoma and aggressiveness of cervical intraepithelial neoplasia (CIN). METHODS: The pathology specimens of 63 patients with a diagnosis of normal squamous epithelium (22 cases), CIN I (14), CIN II (5), CIN III (8) and squamous cell carcinoma (14) were evaluated immunohistochemically for the expression of p53, Bcl-2 and Ki-67 in paraffin sections. RESULTS: The expression of p53 and Ki-67 increased proportionally to the grade of CIN and cervical cancer, but only the increase of p53 expression was statistically significant (p = 0.002). There was no significant correlation between Bcl-2 expression and premalignant and malignant cervical lesions. CONCLUSION: p53 expression may have a role in the carcinogenesis of squamous cell cervical carcinoma whereas Bcl-2 expression has no role. Ki-67 expression can not be used in determining the aggressiveness of CIN lesions. PMID- 17713096 TI - Laparoscopic oophorectomy either with or without hysterectomy for early breast cancer. AB - OBJECTIVES: The aim of this study was to assess the surgical results, complications and pathological findings of laparoscopic ovarian ablation either with or without hysterectomy in women with early-stage breast cancer (BC). METHODS: Ninety women in early breast cancer stage who underwent laparoscopic bilateral salpingo-oophorectomy (BSO) either with or without hysterectomy were identified in a retrospective study conducted between January 2000 and December 2006. Tamoxifen antiestrogen therapy was used prior to hysterectomy. RESULTS: Forty-eight consecutive patients underwent laparoscopic hysterectomy with bilateral salpingo-oophorectomy and 42 with ovarian ablation only. The mean operative time for the laparoscopic hysterectomy and bilateral salpingo oophorectomy or BSO alone was 82 min and 47.8 min, respectively. Blood loss was minimal in both groups (range: 20-250 ml). The rate of postoperative complications was very low (4.4%). One of all ovaries removed by laparoscopy showed ovarian breast carcinoma metastasis. Histopathologic examination revealed concomitant findings of leiomyoma, adenomyosis or endometrial abnormalities in 64.5% of hysterectomy specimens. CONCLUSION: Our experience with ovarian ablation either with or without hysterectomy confirmed that the use of a minimally invasive technique is feasible. We assume that ovarian ablation and hysterectomy is an appropriate treatment for premenopausal women at risk (BRCA positive) or for patients with concomitant benign uterine pathology, treated with tamoxifen in first-line therapy. Removing the uterus allows women to take only estrogens rather than combination HRT. Further investigation into the indications of disease where laparoscopic ablative surgery is appropriate in the management of early breast cancer is needed. PMID- 17713097 TI - Epidemiological overview on the effectiveness of mass screening for female cancer in Umbria, Italy. AB - Using incidence, survival and mortality we tried to verify the effectiveness of mass-screening interventions for cervical uterine, breast, and colorectal cancer in females. Mortality data concern the period from 1978-2002. Incident cases derived from an ad hoc survey for 1978-1982 data and from the RTUP from 01/01/1994 to 31/12/2002. Relative survival rates were calculated for 1978-1982, 1994-1997 and 1998-2002 time intervals. All standardized mortality figures showed a steady trend. Incidence rates concerning cervical uterine cancer showed a decrease starting from the 1978-1982 period, whereas those for breast cancer had a constant increasing trend, and those for colorectal cancer increased up to 1997 1999 and later remained constant. For breast cancer the 5-year survival rate increased about 15% compared to the first period, for colon cancer there was less of an increase and the increase for cervical uterine cancer survival was only for the 1998-2002 period compared to the former ones. With constant incidence rates, improvement in survival from cervical uterine cancer may be due to a high number of cancer cases detected at an early stage. The effect of breast cancer screening on incidence is evident, though differences still did not influence mortality and survival. Colorectal cancer epidemiology can be considered as a prescreening pattern. Mortality, incidence and survival data allow a good overview for the effectiveness of screening procedures. PMID- 17713098 TI - Comparison of human papillomavirus testing and cervical cytology with colposcopic examination and biopsy in cervical cancer screening in a cohort of patients with Sjogren's syndrome. AB - OBJECTIVE: The purpose of this study was to evaluate women with Sjogren Syndrome by using cervical cytology, colposcopic examination and HPV-DNA testing and to compare these findings with those obtained from the control group. METHOD: A total of 100 women, who were referred to Ege University, School of Medicine, Department of Obstetrics and Gynecology for cervical cytological screening between September 2004 and March 2005 and 33 of whom had Sjogren syndrome were included in this study. The patients were informed and subjected to cervical cytology, colposcopic examination and HPV-DNA testing. Colposcopic biopsy and endocervical canal curettage were carried out in cases of suspicious colposcopic examination and cytological findings. The findings obtained from 33 women with Sjogren syndrome and 67 subjects in the control group were compared. RESULTS: Normal cervical cytology was detected in five women (5.7%), while suspicious cervical cytology was reported in 62 women (92.5%) in the control group. The prevalence of normal cytology in patients with Sjogren syndrome was 93.9% (n = 31), where 6.1% (n = 2) of the women had suspicious cervical cytology findings. HPV-DNA findings were negative in 66 women (98.5%) in the control group, where the test result of one women (1.5%) was positive. HPV-DNA findings of patients with Sjogren syndrome were positive in one women (3%) and negative in 32 (97%). Colposcopic findings were normal in 63 women (94%) in the control group, where abnormal colposcopic findings were observed in four women (6%). Normal colposcopic findings were observed in 32 women (97%) with Sjogren syndrome, while pathological findings were recorded in one woman (3%). Suspicious cervical cytology, positive findings at colposcopic examination and biopsy and positive HPV-DNA tests were observed together in only one 40-year-old woman who was diagnosed with Sjogren syndrome for a period of four years. Prevalence of dyspareunia and vaginal dryness (atrophic vaginitis) symptoms were observed in Sjogren syndrome and control groups as 36.3% and 22.3%, respectively. CONCLUSION: No significant differences were observed between Sjogren syndrome and the control group who were evaluated by using cervical cytology, colposcopic examination and HPV-DNA tests. A higher prevalence of dyspareunia and vaginal dryness were observed in patients with Sjogren syndrome, yet this difference was not considered as significant with respect to either colposcopic or histopathological findings. PMID- 17713099 TI - Transnipple pyramidectomy in pathological nipple discharge: an original minimal surgery technique in a series of 80 cases. AB - Pathologic nipple discharge presents a diagnostic dilemma as no one diagnostic test has proven clearly superior to any other in the differentiation of benign versus malignant conditions. This is a clinical study of 80 patients with unilateral suspicious nipple discharge whose complete investigation included histological evaluation. A transnipple approach was used to identify, get to and excise the breast tissue suspicious of having caused the pathological discharge, with a pyramide-shaped tissue dissection (pyramidectomy). Specimens satisfactory for histological evaluation were obtained in all cases. Breast cancer was detected in six cases, papillomatosis in four, papillomas in 30, fibrocystic changes in five, ductal ectasia in 31 and non specific findings in four cases. There were no intraoperative complications and functional and healing-esthetic recovery was very good in all cases. It is concluded that transnipple pyramidectomy is a useful technique for a reliable diagnosis of pathologic nipple discharge. PMID- 17713100 TI - Correlation between squamous intraepithelial lesions (SILs) and bacterial vaginosis. AB - Bacterial vaginosis (BV) is a condition that seldom occurs in prepuberal girls or postmenopausal women, suggesting a hormonal component in its aetiology. The precise mechanisms by which BV arises are not fully understood. One proposed mechanism suggests that carcinogenic nitrosamines act either independently or via human papilloma virus (HPV). Human papillomavirus is known to be associated with the development of squamous intraepithelial lesion (SIL). Still today the relationship between BV and SIL is debated. Many confounding factors regarding the relationship between BV and SIL include the presence of HPV and/or other sexually transmitted diseases. In a case-controlled study the correlation between BV, SIL and the presence of HPV was evaluated. BV was diagnosed according to standard criteria: vaginal pH > 4.5; positive amine test or 'whiff' test; presence of clue cells and abnormal discharge. High risk-HPV testing by PCR was performed. X2 Pearson analysis was applied for statistical evaluation of data. The results of the study have shown that BV is not associated with SIL. PMID- 17713101 TI - Analysis of vaginal recurrences in stage I endometrial adenocarcinoma. AB - OBJECTIVE: To determine the risk of vaginal recurrence in Stage 1 endometrial cancer and treatment morbidity associated with different therapeutic approaches MATERIAL AND METHODS: Between 1995 and 2005, 341 patients with clinical Stage I endometrial cancer were treated at Istanbul Medical Faculty. One hundred and forty-four women were included in this study as the follow-ups and records were complete. The patients with no myometrial invasion received no further therapy following hysterectomy. When there was superficial myometrial invasion postoperative vaginal vault radiation was used, and if deep myometrial invasion was present, external pelvic radiation was given. RESULTS: Overall 5-year survival rate for all patients with Stage I disease was 80%. Nine patients (6.25%) developed recurrent disease, three of whom had vaginal recurrences. All three vaginal recurrences were small and diagnosed at routine follow-up exam within 51 months of primary therapy. CONCLUSION: This selective treatment protocol for patients with Stage I endometrial cancer avoided radiation entirely in 38% of the patients while achieving a very low rate of vaginal recurrence and good overall survival. PMID- 17713102 TI - Tuberculosis mimicking cervical carcinoma--case report. AB - Tuberculosis is a chronic bacterial infection that primarily results in pulmonary disease. Although there are several reported cases of extra-pulmonary tuberculosis, very few reports have described this disease in the female genital tract. We present a case involving a 67-year-old woman who presented with vaginal discharge, abdominal discomfort, and a pelvic mass in 2006. Clinically, cervical carcinoma was suspected, but pathologic diagnosis eventually revealed tuberculosis of the cervix. Tuberculosis is associated with a significant inflammatory reaction, which may mimic a gynecologic malignancy on exam or with diagnostic imaging. Despite the rare incidence, tuberculosis of the cervix should be considered in the differential diagnosis when cervical carcinoma is initially suspected. PMID- 17713103 TI - Rectal carcinoma after radiotherapy for cervical carcinoma in patients with a family history of colorectal carcinoma: report of two cases. AB - Rectal carcinoma is a rare, but well documented late complication of pelvic irradiation. Little is known about the factors predisposing to the development of radiation-associated rectal carcinoma. We present two patients who developed rectal carcinoma 17 and 26 years after radiotherapy for carcinoma of the uterine cervix. In one patient, mutation in exon 4 of the hMLH1 gene was detected. Radiation-associated rectal carcinoma represents a rare late toxicity of radiotherapy for cervical carcinoma that may occur in patients with a family history of colorectal carcinoma, including hereditary non-polyposis colorectal cancer. PMID- 17713104 TI - Impressive remission of locally advanced malignant peritoneal mesothelioma treated with combination of radiotherapy and intraperitoneal paclitaxel. AB - BACKGROUND: The results of treatment of malignant peritoneal mesothelioma are quite unsatisfactory, especially in the later stages of the disease, regardless of the treatment modality employed. CASE: We report a case of locally advanced malignant peritoneal mesothelioma, in which the combination of radiotherapy and intraperitoneal paclitaxel was beneficial for long-term disease stabilization. A 71-year-old woman presented with abdominal pain. Abdominal ultrasound and magnetic resonance imaging confirmed the presence of a mass with both cystic and solid components with moderate ascites. Serum CA-125 concentration was 727 IU/ml. At exploratory laparotomy, a large mass originating from the pouch of Douglas was found. A total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed with partial excision of the mass and involved the peritoneum of the pouch of Douglas. The histologic study showed malignant peritoneal mesothelioma. One year and five months after surgery, significant progression of the residual tumor with increasing ascites was noted. Radiotherapy to the whole pelvis with 45 Gy in 25 fractions was given over five weeks together with intraperitoneal paclitaxel (60 mg/m2) instillation, which was repeated every three weeks. The patient received eight cycles of paclitaxel instillation over seven months. The compliance of the patient was excellent under therapy and her general condition improved significantly one and half year with a marked regression of the tumor masses after this treatment. CONCLUSION: The combination of radiotherapy and intraperitoneal paclitaxel seems suitable in palliative settings primarily aimed at improving the quality of life. PMID- 17713105 TI - Recurrent angiomyofibroblastoma of the vagina: a case report. AB - Angiomyofibroblastoma is a rare tumour of the superficial soft tissue of the pelvis and perineum. It is considered to be a slowly growing benign tumour. In the literature no evidence of recurrence has been reported up to eight years following local excision. We report a recurrent case of this tumour with no evidence of malignant transformation. PMID- 17713106 TI - Symptom management in a patient with end-stage ovarian cancer: case report. AB - Bowel obstruction is a common complication in patients with far advanced abdominal or pelvic cancer. In patients with recurrent or advanced disease, where options for curative treatment have been exhausted, palliation of symptoms with minimal additional morbidity is the aim of therapy. Owing to the difficulties inherent in conducting perspective randomized trials, clinicians face a significant challenge in managing terminally ill obstructed patients. We evaluated the case of a woman with ovarian cancer. Clinically, the objective of the study was to focus attention on the most up-to-date evidence concerning the treatment of malignant bowel obstruction. PMID- 17713107 TI - Buschke-Lowenstein tumor and pregnancy: a case report. AB - Buschke-Lowenstein tumor is a giant condyloma acuminatum that arises on the male and female anogenital region. It is considered a histologically benign tumor but carries a risk of malignant transformation. Early diagnosis and treatment are advised and the choice of treatment is crucial. We present a case of a 31-year old pregnant woman with myasthenia gravis affected by Buschke-Lowenstein tumor. PMID- 17713108 TI - Difficulties in achieving optimal cytoreduction in primary peritoneal carcinoma management. AB - Primary peritoneal carcinoma (PPC) occurs mostly in older women and rarely in women under 50 years of age. The mean age of patients with PPC in our study was 65.5 years. We present the clinical and demographic data, management of cases and the results of six women who underwent exploratory laparotomy between January 2003 and August 2006. PMID- 17713109 TI - [Protein biomarkers in experimental models and in clinical care of traumatic brain injury]. AB - Traumatic brain injury is the leading cause of mortality in Hungary in the population under 40 years of age. In Western societies, like the United Sates, traumatic brain injury represents an extreme social-economic burden, expected to become the third leading cause of mortality until 2020. Despite its' epidemiological significance, experimental therapeutic modalities developed in the last few decades did not prove efficient in the clinical care of severe traumatic brain injury. The reason for such a lack of success in terms of translating experimental results to clinical treatment at least partially could be explained by the paucity and the low sensitivity and specificity of clinical parameters endowing us to monitor the efficacy of the therapy. The drive for finding clinical parameters and monitoring tools that enable us to monitor treatment efficacy as well as outcome focused recent attention on biomarkers (and) surrogate markers that are based on rational pathological processes associated with/operant in traumatic brain injury. This review summarizes those biomarkers that could purportedly be used to monitor the treatment of the severely head injured while also providing information on salvageability facilitating the conduction of more rationally designed clinical studies. PMID- 17713110 TI - [Statin drugs decrease the plasma level of coenzyme Q10 (ubiquinone) in the organism]. AB - In this paper the authors review the relationship and the possible interaction between the HMG-CoA reductase inhibitors (statins) and the CoQ10 (ubiquinone) based on the current literature. The statins are widely used in the clinical practice. Inhibiting the synthesis of mevalonic acid they decrease the plasma cholesterol level. Since mevalonic acid is also required for ubiquinone synthesis statins could influence ubiquinone metabolism. Many studies confirmed the relationship between statin therapy and lower plasma ubiquinone level. Much less data are available about the tissue concentration changes of ubiquinone during statin therapy. The authors try to summarise the consequences of the interaction between statin therapy and ubiquinone metabolism. PMID- 17713112 TI - [Social insurance costs of hospital treatment of stroke in Hungary, 2003-2005]. AB - Our aim was to assess the social insurance costs of hospital treatments for acute stroke in Hungary between 2003 and 2005. We studied how much burden stroke patients impose on the financer (National Health Insurance Fund Administration) in acute and chronic hospital admissions. We extracted the data of "new" stroke patients (ICD-10: 160-64 diagnosis) hospitalized in May 2003 from the database of the financer. We analyzed active and chronic hospital treatment costs of these patients in the period of 12 months before the stroke and in the following first and second 12 months. Data were collected by sex and age (age groups: 25-44, 45 64, over 65). We studied patients hospitalized in May 2003 with the ICD-10: 160 64 main diagnosis but not being treated with the same diagnosis in the previous 24 months. In the first 12 months of the active care the burden of the disease was (male vs. female) 65+: 254.6 vs. 205.8; 45-64: 341.4 vs. 280.5; 25-44: 370.1 vs. 306.1 thousand HUF per patient. In the second 12 months the costs were 50.6 vs. 36.2; 24.2 vs. 32.6; 27.6 vs. 24.8 thousand HUF respectively. In the first year following the episode the costs of the chronic hospital treatment were (age groups as above) 23.3 vs. 31.3; 28.9 vs. 22.2; 22.8 vs. 22.5 thousand HUF A year later the chronic hospital costs were 9.0 vs. 10.9; 6.7 vs. 12.2; 1.4 vs. 38.1 thousand HUF respectively. Average costs of stroke are higher in the case of males as are in the case of females, 364.8 vs. 303.0 thousand HUF in the first 24 months. The remarkable difference results from active hospital treatment costs (331.5 vs. 262.1 thousand HUF), while the discrepancy is smaller in the chronic hospital care (33.3 vs. 40.9 thousand HUF). PMID- 17713111 TI - [Investigation of the effect of vinpocetine on cerebral blood flow and cognitive functions]. AB - INTRODUCTION: Vinpocetine has been widely used in the treatment of ischaemic cerebrovascular diseases and dementias of vascular type. Chronic cerebral hypoperfusion plays an important role in the development of certain types of dementia. In consequence of complex mode of action vinpocetine plays a significant role in the improvement of cerebral hypoperfusion. The symptoms of mild cognitive impairment considered as "predementia" are similar to those of dementia, although milder. AIMS: The authors investigated the characteristics of the blood flow parameters of patients with ischemic stroke and mild cognitive impairment both in resting conditions or following chemical stimulus as well as they investigated the severity of mental deterioration in the two patient groups. In a pilot study the authors examined the influence of 12-week long oral vinpocetine therapy on the blood flow parameters and cognitive functions in the two patient groups. METHODS: The authors studied the blood flow velocity of a. cerebri media in resting conditions and after 30 sec of breath holding with transcranial Doppler before treatment and after a 12-week long oral vinpocetine treatment. At the same time psychometric tests (MMSE, ADAS-Cog) were used in order to examine cognitive functions, while the general condition of the patients were scored by Clinical Global Impression (CGI) scale. RESULTS: After a 12-week long oral vinpocetine treatment the increase of blood flow velocity in resting conditions compared to the baseline values was significant in the vascular group. The percent increase of mean velocity after the breath holding TCD test showed a significant increase compared to the baseline in both patient groups. The authors found a significant improvement of cognitive functions after a 12-week long oral vinpocetine therapy using psychometric tests. The improvement was identical in both groups. The general condition of patients improved significantly according to both the investigator's and the patients' opinion; patients with mild cognitive impairment judged the improvement higher. CONCLUSIONS: Vinpocetine improved the cerebrovascular reserve capacity in both patient groups and favourably influenced the cognitive status and general condition of patients with chronic hypoperfusion. The authors recommend the use of vinpocetine for the treatment of patients with mild cognitive impairment. PMID- 17713113 TI - [Mortality of hospitalized stroke patients in Hungary; 2003-2005]. AB - The aim of our research was to assess the incidence and the 12- and 24-month mortality of hospitalized stroke in Hungary. We analyzed the rate of mortality after stroke and compared it to the standard mortality rate of the population. To assess the incidence we extracted the data of "new" stroke patients (ICD-10 diagnoses: 160-64) hospitalized in May 2003 from the database of the National Health Insurance Fund Administration. We regarded those as "new" patients who had not been treated with these primary or secondary diagnoses in the previous 24 months. Data were collected by sex and age (age groups: 25-44, 45-64, 65 and over). We analyzed the patients' survival on the basis of their April 2004 and April 2005 data. The incidence of the "new" hospitalized stroke patients was higher in men than in women; the incidence in the age group of 65 and over was 2112/100.000 in males and 1582/100.000 in females, the corresponding values in the 45-64 age group were 623 vs. 366 per 100.000, respectively. In 2003 more than 42 thousand "new" stroke patients were hospitalized in Hungary of whom over 10 thousand died in the first year, followed by a further 2 thousand in the second year. Women's survival is more favourable than men's: in the first year it is 71.47% vs. 69.24% (65+ group), and 88.18% vs. 83.16% (45-64 group); in the second year the corresponding values are 66.95% vs. 61.62% (65+), and 85.45% vs. 80.90% (45-64), respectively. The risk of death in the first year after stroke, compared to the standard population, is 5.17-fold in women and 4.70-fold in men in the total sample, and 10-15-fold in the 45-64 group. There are large differences by gender, particularly in men of the working age groups (25-44, 45-64), whose mortality is twice as high as that of women of the same age. PMID- 17713114 TI - A case of frontotemporal lobar degeneration with ubiquitin-positive intraneuronal inclusions. AB - The case of a 57-year-old man is reported who has been treated several times because of his relatively expedite mental decline which has begun four years before his death. His first complaints were forgetfulness, mild changes in his behaviour, confusion and difficulty in speech. The neuropsychiatric examinations displayed a mild difficulty in naming and sometimes comprehension of words, although his speech was grammatically correct. Furthermore the patient presented a very severe decrease in short term memory with dementia and confusion. These symptoms together with the results of CT and test examinations established the diagnosis of Alzheimer's disease. Finally pneumonia afflicted the patient during the last hospitalization and he died. Histopathological examinations of the brain showed a severe, mainly temporofrontal atrophy caused by an extensive cortical neuronal loss and gliosis without neurofibrillary degenerations and senile plaques which characterize the Alzheimer's disease. Tau-positivity Pick- and Lewy bodies may not be found. The loss of neurons associated in some places with spongiosity of laminar form. The ubiquitin-positive intracytoplasmic inclusions proved to be the most characteristic feature in the swollen neurons. These mainly occurred in the gray matter of the mediobasal part of the temporal lobe. The positivity of GFAP immunocytochemistry revealed a definite astrocytosis in the affected parts of the gray matter. In the temporal and frontal cortex scattered ballooned cells (achromatic or Pick cells) were seen in alpha B-crystallin immunohistochemistry. These findings confirmed the diagnosis of the case of frontotemporal lobar degeneration with ubiquitin-positive intraneuronal inclusions (FTLD-U) without tau-positivity. The separation of the different forms in the group of the frontotemporal dementias is recommended by means of the modern immunocytochemical examinations. PMID- 17713115 TI - [Functional MRI at 1 Tesla. Basic paradigms and clinical application]. AB - AIM OF THE STUDY: To perform functional MRI experiments at low magnetic field, and to set up routine protocol to help the planning of neurosurgical operations and the examination of epilepsy patients. METHODS: An optimized 2D EPI sequence was applied to yield functional MR images in basic paradigms such as finger tapping and internal word generation. Further, activation was induced also by a task involving mental navigation based on the retrieval of individually familiar visuo-spatial knowledge. RESULTS: Low resolution (matrix of 64x64) functional MR images satisfactorily visualized moto-sensor strip and speech centers. In the mental navigation task bilateral activation of the hippocampal formation was observed. Determination of motor area was also performed in an epilepsy patient whose seizure focus had been found in the area of pre- and post-central gyrus. The dislocation of the motor cortex was demonstrated. CONCLUSION: Functional MR images with fine quality can be obtained in basic paradigms even at low magnetic field if MR imaging parameters and paradigms are optimized. PMID- 17713116 TI - [DYT1 positive generalised dystonia: a case study of two siblings]. AB - The early-onset generalised dystonia is a dyskinetic movement disorder with a wide variety in phenotype and poor response to pharmacological treatment. A mutation on the DYT1 gene is responsible for the disease in more than 50% of cases with typical early-onset dystonia beginning in a limb. We describe the medical history of two brothers with first signs of focal dystonia at age 12 starting with right side lower limb dystonia of the older brother and writers cramp of the younger one. In both over a period of 6 and 10 years dystonia generalised. The negative results of MRI, electrophysiological testing and muscle biopsy corroborate the diagnosis of primary dystonia. The DNA from the older patient was tested for the 3 bp deletion in exon 5 of the DYT1 gene by restriction enzyme. The positive result confirmed the diagnosis of early-onset primary dystonia. A short synopsis of routine molecular genetic tests indications and treatment options is outlined. PMID- 17713118 TI - [Relationship between alpha-synuclein and Parkinson's disease]. AB - Alpha-synuclein(SNCA) is a major component of Lewy bodies. Lewy bodies were appeared in some neurodegenerative disorders known as Alzheimer's disease or Parkinson's disease. Recently SNCA multiplications were reported in several autosomal familial Parkinson's disease (ADPD). In two triplication pedigree, the double expression level of alpha-synuclein was reported in both peripheral blood and brain. And the some affected patients in SNCA multiplication family also had more severe prognosis than sporadic patients. They were suffered from cognitive decline and severe parkinsonism. Mainly triplication patients were showed severe prognosis compared to duplication patients. They had young onset and non responsiveness to levodopa. On the other hand, duplication patients had milder course similar with sporadic cases. These analysis were suggested that the gain of function mechanism on SNCA could cause severe dementia like diffuse Lewy bodies and high amount of Lewy bodies in brain. And the differences of length between triplication and duplication also might be influenced on clinical aspects. In this review, we described about the clinical and genetic aspects of alpha-synuclein, not only SNCA multiplication but also mis-sense mutation of SNCA. PMID- 17713117 TI - [Molecular genetics of Parkinson's disease]. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder in the world. The occurrence of PD is largely sporadic, while several families with Mendelian segregation of PD have been reported. PD is thought to be caused by mitochondrial dysfunction, oxidative stress and inflammation based on multiple genetic and environmental factors, resulting in the apoptosis of dopaminergic cells. Six causal genes for Mendelian inherited PD have been identified to date, which indicate the importance of the ubiquitin-proteasome pathway in the molecular pathogenesis of dopaminergic cell death. Recent studies have also indicated the involvement of genetic factors in the pathogenesis of sporadic PD. Many association studies on candidate genes have examined the relationship between PD and polymorphisms; We identified a-synuclein as a definite susceptibility gene for sporadic PD. Since 2001, significant linkage to several loci have been reported in samples of affected sibling pairs. With the recent advances in human genome analyses, genome-wide association studies by SNP chip are being performed to identify susceptibility genes and to establish tailor-made medicine for PD. PMID- 17713119 TI - [Molecular genetics of PINK1]. AB - PTEN-induced putative kinase 1 (PINK1) is a causative gene for autosomal recessive early onset parkinsonism. Mutations in PINK1 were identified originally in PARK6-linked parkinsonism families from Italy and Spain. PINK1 contains 8 exons spanning 1.8 kb, and encodes a protein of 581 amino acids with a mitochondrial targeting motif and a serine-threonine protein kinase domain. Until now PINK1-mutation positive parkinsonism is the second frequent one next to parkin among autosomal recessive parkinsonism. Most of reported mutations were distributed throughout the serine-threonine protein kinase domain. Thus, loss of function of kinase activity of PINK1 is the most probable disease mechanism. The clinical phenotype of PINK1 -mutation positive parkinsonism is similar to that of parkin mutation positive parkinsonism. Single heterozygous mutations of PINK1 have been also identified sporadic Parkinson's disease (PD) patients. The presence of dopamine hypometabolism in asymptomatic mutation carriers suggests that single heterozygous mutations of PINK1 are risk factors for developing parkinsonism. In addition, some functional data have been shown that PINK1 protein may function as neuroprotective roles for mitochondria. Recent biochemical and morphological studies using drosophila melanogaster suggested that Parkin and PINK1 share a common pathway to maintain mitochondrial function and that PINK1 functions upstream of Parkin. Moreover, co-expression of double mutations of PINK1 and DJ-1 in cultured cells from one family with heterozygous mutations, enhanced susceptibility to MPP+ (1-methyl-4-phenylpyridinium ion) induced cell death. These data suggest that PINK1, parkin, and/or DJ-1 could play an important role to maintain mitochondrial functions. In the other word, the mitochondrion is a good target for elucidating the pathogenesis of not only sporadic form but also monogenic form of PD. PMID- 17713120 TI - [Clinical molecular genetics for PARK8 (LRRK2)]. AB - Parkinson's disease (PD) is an etiologically heterogeneous disorder characterized by parkinsonism (bradykinesia, resting tremor, rigidity, and postural instability) with good response to L-dopa. PD is the second most prevalent neurodegenerative disorder after Alzheimer disease. Although the majority of PD cases are sporadic, 5-10% of PD is monogenic form of PD as familial PD (FPD). Multifactorial genetic-environmental interaction has been thought in PD pathogenesis, although these interactions are still poorly understood. In 2004, LRRK2 was identified as the causative gene for PARK8 originally mapped in the large Japanese Sagamihara family with late-onset autosomal dominant PD (ADPD). Patients with LRRK2 mutations account for approximately 2-13% of ADPD and 0.5-3% of sporadic PD. Genetically, LRRK2 mutations have been distributed worldwide with some ethnic differences by single founder effect such as G2019S, R1441G, and G2385R variants. LRRK2 G2385R was reported to be a risk factor for sporadic PD in Asia. Clinically, most patients with LRRK2 mutations develop typical idiopathic PD, however, variable clinical features and pathologies such as diffuse Lewy body disease, multiple system atrophy, progressive supranuclear palsy, and amyotrophic lateral sclerosis have been reported. Although Lewy bodies have been considered as a pathological hallmark for sporadic PD classically, some FPD and sporadic PD patients with heterozygous LRRK2 mutations or homozygous parkin mutations have no Lewy bodies. On the other hand, LRRK2 was reported as a component of Lewy bodies. Based on the variability, multifunction of LRRK2 such as phosphorylation of other proteins, especially, alpha-synuclein and tau, have been suggested. As interaction of Parkin and LRRK2 was reported, interaction and intersection among the autosomal-recessive or autosomal-dominant PD proteins could be involved in some common pathways, and LRRK2 may play an important role as a key FPD gene product. Identification of PARK8 and LRRK2 has given meaningful insights in not only PD but also numerous neurodegenerative disorders such as synucleinopathies and tauopathies with or without Lewy bodies. PMID- 17713121 TI - [Pathology of familial Parkinson's disease]. AB - Studies of familial forms of Parkinson's disease (PD) have identified a growing number of genes that derive from the loci given the nomenclature PARK1-PARK13 (OMIM 168600). The alpha-synuclein gene has been implicated in rare autosomal dominant PD because of either mis-sense mutations (PARK1) or gene multiplications (PARK4). Moreover, UCHL1 (PARK5), LRRK2 (PARK8) and HTRA2 (PARK13) have been identified as causative genes for autosomal dominant PD, whereas parkin (PARK2), PINK1 (PARK6), DJ-1 (PARK7) and ATP13A2 (PARK9) have been identified as causative genes for autosomal recessive PD. Neuropathological examination of the kindreds of PARK1/4 showed Lewy body pathology ranging from classic PD to diffuse Lewy body disease. The pathological findings of PARK3 are similar to those of classic PD. In contrast, autopsies of patients with PARK2 showed nigral cell loss without Lewy bodies, although exceptions have been reported. Several kindreds of PARK8 included cases with Lewy body pathology, tau pathology, or with nigral cell loss in the absence of obvious protein deposition. Ubiquitin-positive inclusions that are negative for alpha-synuclein and tau are also seen in some cases. Moreover, widespread Lewy body pathology was also reported in several cases of familial Alzheimer's disease with presenilin-1 mutations. PMID- 17713122 TI - [Amusia]. AB - This report reviewed recent cases of amusia and drew the following conclusions. First, amusia is an ill-defined condition. The classical definition restricted amusia to musical disorders caused by brain lesions. By the end of the last century, however, some researchers included developmental or innate musical disorders in amusia. Second, although recent case reports were based on the classical schema of amusia, there have been an increasing number of case studies that have described more restricted and specific symptoms, such as receptive amusia for harmony or musical alexia for rhythm notation. Third, although we can now obtain more accurate information about the brain lesions, we have not taken advantage of this information. Traditionally, it has been thought that the pitch element of vocal performance is referred to the right frontal or temporal lobe. Lastly, the relationship between musical function and degenerative disease deserves attention. Degenerative diseases can cause either a musical deficit or, paradoxically, improve musical function. For example, the musical competence of some patients improved after selective atrophy of the left hemisphere. In conclusion, recent ideas concerning the relationship between music and the brain have been derived from patients with brain damage, developmental disorders, and degenerative diseases. However, there is a missing link with respect to amusia. We know a lot about the cognitive aspect of music, but the 'true' function of music from an evolutionary perspective, something that is lacking in amusia, is not known. PMID- 17713123 TI - [Questionnaire survey to investigate correspondence of medical doctors and dentists in Japan for antithrombotic therapy at surgeries or biopsy]. AB - PURPOSE: We examined correspondence of doctors and dentists at the time of surgeries or biopsy in patients treated with antithrombotics by questionnaire survey. METHODS: We investigated management of antithrombotic therapy at dental extraction, biopsy or polypectomy under an endoscope, an operation of a cataract, pacemaker implantation by questionnaire survey for doctors and dentists in 64 national hospital organization hospitals (NHO-hospital) and doctors in 163 hospitals participated in the Japan Multicenter Stroke Investigators' Collaboration (J-MUSIC) study. We compared the results between NHO-hospitals and J-MUSIC hospitals. RESULT: The doctor questionary survey got an answer from 103 institutions (63%) out of the 163 J-MUSIC hospitals and 26 institutions (40%) out of 64 NHO-hospitals. The dental extraction under continuation of warfarin therapy in patients with past history of stroke and non-valvular atrial fibrillation or mechanical heart valves was accepted in 35% and 45%, respectively. They were 58% and 69%, respectively in J-MUSIC hospitals and were significantly higher than those in NHO-hospital (p = 0.031 and p = 0.023, respectively). There were no significant differences in antithrombotic management strategies in correspondence to the biopsy, polypectomy or pacemaker implantation between the two groups of hospitals. Continuation of the antithrombotic therapy at surgery to cataracta was more frequent in J-MUSIC hospitals than in NHO-hospitals (nonvalvular atrial fibrillation 48% vs 22% p = 0.015, mechanical heart valve 51% vs 30% p = 0.059). Experience of stroke due to transient withdrawal of warfarin (69% vs 27%, p = 0.0005) and antiplatelet (59% vs 31%, p = 0.022) therapies were more frequently seen in the J-MUSIC hospitals than in the NHO-hospitals. The dentist questionary survey got an answer from 30 institutions (44%) out of the NHO-hospitals. The acceptance rates of dental extraction under continuation of warfarin or antiplatelet therapies were 53% and 60%, respectively. CONCLUSION: It is suggested that constant consensus is provided with a medical institution as for the biopsy, polypectomy, and pacemaker implantation without a difference being seen in both medical institution groups. However, acceptance rate under antithrombotic therapy at dental extraction or surgery for cataracta was higher in the J-MUSIC hospitals than in the NHO-hospitals, which may be due to lack of the consensus to antithrombotic therapy for those surgeries and higher rate of doctors' experience of stroke after withdrawal of antithrombotic therapy in J MUSIC hospitals. PMID- 17713124 TI - [Cerebral peduncle infarction with pure dysarthria--case report]. AB - A 82 year-old male having a long history of hypertension was admitted for dysarthria. Neurological examination revealed dysarthria with mild disturbance of left-sided soft palate elevation. No lingual palsy nor facial weakness were noted. No motor weakness in the upper and lower extremities was noted. Diffusion weighted image and T2 weighted image revealed a small high signal lesion localized in the medial one-third of the left cerebral peduncle. There were bilateral stenotic lesions of the posterior cerebral artery at P1 portion in intracranial magnetic resonance angiography. Pure dysarthria can be caused by disruption of the supranuclear fiber of glossopharyngeal and vagal nerve nucleus in the corticobulbar tract, which can be localized in the medial portion of the cerebral peduncle. PMID- 17713125 TI - [Operative case of isomorphic astrocytoma]. AB - Diffuse astrocytomas are classified as WHO Grade II tumors. Recently, a subtype presenting with better prognosis has been proposed, and it is known as "isomorphic astrocytoma." A clinical case that we encountered was believed to be categorized as this subtype; it has been presented in this report. The patient was a 20-year-old male with a chief complaint of intractable epileptic seizures. He experienced his first attack at 16 years of age in July 2001, and it was a generalized seizure. Anticonvulsants prescribed by a previous doctor had no effect on controlling the seizures. MRI performed in March 2004 showed a lesion approximately 2.0 cm in diameter in the left temporal lobe. The patient was referred to our institution for further investigation of the lesion and therapy. Electroencephalography and magnetoencephalography were used to assess the lesion at seizure focus. The tumor was resected under awake surgery. The pathological diagnosis was diffuse astrocytoma, but this tumor was considered to be the isomorphic subtype. Some parts of the tumor showed a relatively high MIB-1 labeling index (LI) of 9.2%, and additional 50-Gy radiotherapy was performed. The postoperative course was uneventful and despite decreasing the anticonvulsant dosage, he has remained seizure free. Isomorphic astrocytoma is characterized by prolonged epileptic seizures, a low MIB-1 LI, and better prognosis. In our case, since the MIB-1 LI was higher in some parts of the tumor, the appropriate therapy for WHO Grade II tumors was performed. However, this case was considered representative of isomorphic astrocytoma. No reports of this tumor subtype have been previously described in Japan. Therefore, this report is the first case of isomorphic astrocytoma reported to Japanese literature. PMID- 17713126 TI - [Clinical efficacy of blood flow interruption using the HyperForm in right vertebral arteriovenous fistula--case report]. AB - A 44-year-old male with right vertebral arteriovenous fistula accompanied with tinnitus, underwent endovascular treatment using GDC. A digital subtraction angiography clearly showed one fistula flowed from the right vertebral artery (VA) to the vertebral venous plexus, while the right VA close to the fistula was interupped with HyperForm. The tip of the micro catheter was placed in the vertebral venous plexus through fistula from the right VA, and the vertebral venous plexus around the fistula was embolized with 4 GDCs. Blood flow of the right VA was maintained. Follow-up angiography undertaken 6 months after the operation didn't show the recurrence of arteriovenous fistula. PMID- 17713127 TI - [Case of 69-year-old woman with steroid responsive recurrent myelitis: pathological findings of the spinal cord biopsy]. PMID- 17713128 TI - [Marshall Hall Lectures on the nervous system and its diseases. 1836]. PMID- 17713129 TI - Can differences in the ability to recognize words cease to have an effect under certain reading conditions? AB - In this study, we aimed to ascertain whether it is possible to create reading contexts that eliminate the impact of word recognition on reading comprehension and permit pupils with reading disabilities (RD) to attain a level of comprehension similar to that of their peers without RD. Specifically, the study compared a traditional reading situation with one of reading with aids (joint reading). In both situations, pupils' comprehension level was assessed by means of a summary and a series of inferential questions, and we controlled the effect on comprehension of word recognition, previous knowledge, rhetorical competence, and working memory. The results showed that the aids provided during reading do not eliminate the effect of word recognition, but they do permit readers with RD to attain a comprehension level similar to that of their peers. PMID- 17713130 TI - Timed essay writing: implications for high-stakes tests. AB - The majority of high-stakes tests from elementary school through postsecondary education include the timed impromptu essay as a measure of writing performance. For adolescents with writing disorders, this type of evaluation often presents a significant barrier. The purpose of the current study was twofold. First, we investigated the influence of handwritten, typed, and typed/edited formats of an expository essay on the quality scores received by students with (n = 65) and without (n = 65) dyslexia. Second, we examined the contribution of spelling, handwriting, fluency, and vocabulary complexity to the quality scores that students with and without dyslexia received on the same writing task. Analyses indicated that vocabulary complexity, verbosity, spelling, and handwriting accounted for more variance in essay quality scores for writers with dyslexia than for their typically achieving peers. Both group and individual student outcomes are reported to better understand the needs of struggling writers with dyslexia. Implications for assessment, instruction, and accommodations are discussed with an eye toward reform efforts that target improved teaching and learning. PMID- 17713131 TI - Evaluation of the double-deficit hypothesis subtype classification of readers in Spanish. AB - The double-deficit hypothesis acknowledges both phonological processing deficits and serial naming speed deficits as two dimensions associated with reading disabilities. The purpose of this study was to examine these two dimensions of reading as they were related to the reading skills of 29 Spanish average readers and poor readers (mean age 9 years 7 months) who met the criteria for either single phonological deficit (PD), double deficit (DD), or no deficit. DD children were the slowest readers and had the weakest orthography processing skills. No significant differences were found between PD and DD groups on word and pseudoword reading. Word reading and reading comprehension skills were average or above average in the three studied groups. As in previous studies in transparent orthographies, word reading was not a salient problem for Spanish poor readers, whereas for the DD group, reading speed and orthographic recognition skills were significantly affected. PMID- 17713132 TI - Attributes of effective and efficient kindergarten reading intervention: an examination of instructional time and design specificity. AB - A randomized experimental design with three levels of intervention was used to compare the effects of beginning reading interventions on early phonemic, decoding, and spelling outcomes of 96 kindergartners identified as at risk for reading difficulty. The three instructional interventions varied systematically along two dimensions--time and design of instruction specificity--and consisted of (a) 30 min with high design specificity (30/H), (b) 15 min with high design specificity plus 15 min of non-code-based instruction (15/H+15), and (c) a commercial comparison condition that reflected 30 min of moderate design specificity instruction (30/M). With the exception of the second 15 min of the 15/H+15 condition, all instruction focused on phonemic, alphabetic, and orthographic skills and strategies. Students were randomly assigned to one of the three interventions and received 108 thirty-minute sessions of small-group instruction as a supplement to their typical half-day kindergarten experience. Planned comparisons indicated findings of statistical and practical significance that varied according to measure and students' entry-level performance. The results are discussed in terms of the pedagogical precision needed to design and provide effective and efficient instruction for students who are most at risk. PMID- 17713133 TI - The influence of instruction modality on brain activation in teenagers with nonverbal learning disabilities: two case histories. AB - Teenagers with nonverbal learning disabilities (NLD) have difficulty with fine motor coordination, which may relate to the novelty of the task or the lack of "self-talk" to mediate action. In this study, we required two teenagers with NLD and two control group teenagers to touch the thumb of each hand firmly and accurately to the fingertips of the same hand, in an order specified by verbal or tactile instruction. Brain activity patterns (measured using functional magnetic resonance imaging) suggest that unlike control participants, the NLD participants used internalized speech to facilitate the novel task only when instructions were verbal. NLD participants also showed activity in a more widely distributed network of neural structures. These findings provide preliminary evidence for remediation strategies that encourage internal speech. PMID- 17713134 TI - Significant predictors of test anxiety among students with and without learning disabilities. AB - In the present study, the relationship between students with and without learning disabilities (LD) and different aspects of test anxiety was examined on a new multidimensional measure of test anxiety. A sample of 774 elementary and secondary school students--195 students with LD and 579 students not identified with LD--completed the Test Anxiety Inventory for Children and Adolescents (TAICA), a new multidimensional measure of test anxiety for elementary and secondary school students in Grades 4 through 12. Examination of the factor structure of the TAICA scores across LD status to determine whether accurate test score interpretation was possible revealed that the majority of the coefficient of congruence values between each pair of six corresponding factors of the TAICA (Cognitive Obstruction/ Inattention, Performance Enhancement/Facilitation Anxiety, Physiological Hyperarousal, Social Humiliation, Worry, and Lie) and the Total Test Anxiety factor were above .90, and the salient variable similarity index values were statistically significant, suggesting that the factor structure of the TAICA was similar across groups. The results of seven multiple regression analyses revealed that LD predicted higher Cognitive Obstruction/Inattention and Worry scores and lower Performance Enhancement/Facilitation Anxiety and Lie scores. Implications of the findings for school personnel who work with students with LD are discussed. PMID- 17713135 TI - Age at first intercourse and HPV immunization. AB - The licence of the first human papillomavirus vaccine (HPV) has important implications for the most appropriate age for a mandatory immunization. In this paper data taken from a recent study show that more than 10% of the Italian women report having already had a sexual intercourse by the age of 15. There is thus sufficient evidence to recommend administration of the HPV vaccine to all girls by the age of 12. PMID- 17713137 TI - Improvements on a total mercury determination absorption spectrophotometry detection method in human hair using graphite-furnace atomic. AB - In this work, a methodology for the determination of total mercury in human hair is presented. This methodology is an improvement of a previous technique which has been reported by Chen et al. in 2002. This previous work was based on an acid digestion, C, cartridge clean-up, a 2,3-dimercaptopropane-1-sulfonate complexing agent, solid phase extraction and a graphite furnace atomic absorption spectrophotometric determination. In the present study, the complexing agent has been replaced by the ammonium pyrrolidine dithiocarbamate followed by a liquid liquid extraction and the clean-up has been avoided in order to obtain a less expensive and less time consuming methodology. PMID- 17713136 TI - Molecular epidemiology of measles in Liguria, Italy: a tool for the elimination of the infection. PMID- 17713138 TI - Mother to child transmission of hepatitis C virus in a province of northern Italy. AB - INTRODUCTION: Study reports of mother to child transmission of hepatitis C virus (HCV) have shown transmission rates ranging from 3 to 37%, according to maternal viremia and HIV-1 coinfection. The present study evaluated the prevalence of the HCV infection in the general population and the incidence of vertical transmission, from women who delivered in the Obstetric Clinic of the Hospital of Parma from January 1st 1996 to 31st 2001 December. METHODS: Mothers and children were tested for the presence of HCV-RNA within one week after delivery. Children were considered to be infected when they were found positive at least twice for viral RNA or antibodies were still detectable at the end of the follow-up period (18 months) in blood. RESULTS: Out of 13,025 women, 110 (0.8%) were found positive for anti-HCV antibodies; 72 of them (65.4%) were HCV-RNA positive. All 110 children were positive for anti-HCV antibodies in the first blood sample (time 0); 8 of them were HCV-RNA positive. Three children were still viremic at the end of the follow-up whereas 5 showed a clearance. No significant differences were found between viremic and nonviremic children with respect to gestational week, maternal alanine aminotransferase (ALT) levels and newborns weight at birth. CONCLUSION: This investigation shows that vertical transmission may occur in a general obstetric population despite a low prevalence of HCV-positive subjects. PMID- 17713139 TI - Assessment of the efficacy of Umonium38 on multidrug-resistant nosocomial pathogens. AB - INTRODUCTION: We investigated the efficacy of a biocide Umonium38 on multidrug resistant strains by comparison with a chloride derivative (Decs). METHODS: In vitro susceptibility tests were performed by agar diffusion disk and results were interpreted according to Clinical and Laboratory Standards Institute (CLSI). In vitro antibacterial efficacy of Umonium38 and Decs over selected strains was evaluated according to European Standards protocol with or without organic substance. RESULTS: In vitro tests with Umoniumnr at 2.5% concentration demonstrated an overall drop in microbial and yeast charges after 5 min. contact without organic substance. The same results were obtained in presence of organic substance. In vitro tests with chloride derivative at 5% without organic substance also resulted in overall drop in bacterial and mycotic charges. Conversely, in presence of organic substance, the hypochlorite reduced the initial 10 UFC/ml to 10 UFC/ml for all bacterial strains with a decrease of 4 log except for Enterococcus faecalis and Candida albicans whose reduction was 2 and 1 log units respectively. DISCUSSION: The organic substance in water requires large use of oxidising disinfectants (chloride, ozone) implying in the need for higher than-standard concentrations. The disinfecting effect of chloride is only visible when the "requirement" of organic substance has been met. By contrast, Umonium38 behaves like a powerful biocide even in presence of organic substance, as it is not "consumed" by possible organic residues. CONCLUSIONS: Umonium38 resulted beneficial and effective. It is to be stressed, however, that all these experiments were in vitro tests and still requires validation from a correct use of clinical practice. PMID- 17713140 TI - FMECA methodology applied to two pathways in an orthopaedic hospital in Milan. AB - INTRODUCTION: Adverse events pose a challenge to medical management: they can produce mild or transient disabilities or lead to permanent disabilities or even death; preventable adverse events result from error or equipment failure. METHODS: IRCCS Istituto Ortopedico Galeazzi implemented a clinical risk management program in order to study the epidemiology of adverse events and to improve new pathways for preventing clinical errors: a risk management FMECA-FMEA pro-active analysis was applied either to an existing clinical support pathway or to a new process before its implementation. RESULTS: The application of FMEA FMECA allowed the clinical risk unit of our hospital to undertake corrective actions in order to reduce the adverse events and errors on high-risk procedure used inside the hospitals. PMID- 17713142 TI - Quality pays. PMID- 17713141 TI - Occurrence of salmonella and Listeria spp. on retail poultry products in south Italy and comparison of conventional and rapid methods for their detection. AB - Salmonella and Listeria spp. are frequently detected in poultry meats. Conventional isolation and identification methods to detect these microrganisms in food are laborious and time-consuming. In the present study the occurrence of Salmonellae and Listeriae on 362 samples of retail poultry in Caserta, South Italy was evaluated and standard microbiological and rapid methods were compared. Furthermore, the samples were collected and analyzed twice a week, on Monday and Friday to establish their possible variability from storage. Both methods showed a strong contamination of samples by Listeria spp. (about 50% for both methods) with 12% Listeria monocytogenes while the contamination of Salmonella was poorer (14-15%). The two procedures showed a good agreement for the detection of Listeriae while the sensitivity of the Rapid test for Salmonellae was poorer (75%). Data about sampling on Monday and Friday highlighted a significant increase in Listeria spp. at the end of the week. PMID- 17713144 TI - What is your diagnosis? Cutaneous larva migrans. PMID- 17713143 TI - Acquired zinc deficiency in full-term newborns from decreased zinc content in breast milk. AB - Zinc deficiency occurs in children when the demand for zinc exceeds its supply. Malnutrition, prematurity, total parenteral nutrition dependence, and burns increase the demand for zinc, whereas congenital malabsorption syndromes represent clinical situations where less zinc is supplied to the growing child. Clinical recognition of acral eczematous lesions, alopecia, and gastrointestinal tract symptoms in settings of the aforementioned medical history often lead to the diagnosis. Zinc deficiency in healthy, full-term, breast-fed infants can occur. The cause of these deficiencies has been attributed to decreased zinc levels in maternal breast milk. We present a case of acquired zinc deficiency in a healthy breast-fed infant, with a review of the English language literature of reported cases. PMID- 17713145 TI - Oral trimethoprim/sulfamethoxazole in the treatment of acne vulgaris. AB - Oral trimethoprim/sulfamethoxazole (TMP-SMX) is approved by the US Food and Drug Administration for the treatment of urinary tract infections, shigellosis, acute otitis media in pediatric patients, and Pneumocystis carinii pneumonia. TMP-SMX has been used off label in dermatology to treat various skin conditions, including acne vulgaris and other skin and soft tissue infections, especially those infections caused by methicillin-resistant Staphylococcus aureus. PMID- 17713146 TI - What's eating you? Bees, part 1: characteristics, reactions, and management. AB - Bee stings are common in the United States. We review the characteristics of bumblebees, honeybees, and Africanized honeybees; the types and pathophysiology of sting reactions; and the medical management and prevention of bee stings. In part 2 of this series, we will discuss the use of venom immunotherapy, the diagnosis of systemic mastocytosis that initially presents as anaphylaxis, and the efficacy of immunotherapy in patients with mastocytosis. PMID- 17713147 TI - Cutaneous lymphoid hyperplasia: a case report and brief review of the literature. AB - Cutaneous lymphoid hyperplasia (CLH) is considered a benign lymphoid reactive process that results from various antigenic stimuli and may have potential for progression to overt lymphoma. CLH lesions may closely resemble lymphoma both clinically and histologically. We present a case of a 54-year-old woman who spontaneously developed lesions of unknown cause consistent with CLH. We also review the literature and discuss the etiology, clinical features, diagnosis, and management of CLH. PMID- 17713148 TI - Acquired perforating dermatosis associated with primary biliary cirrhosis and hashimoto thyroiditis. AB - Acquired perforating dermatosis (APD) is an uncommon skin eruption of unclear etiology that most often is associated with diabetes mellitus or chronic renal insufficiency. There are rare reports of APD in association with liver disease or thyroid disease. We report a case of APD in a patient with both primary biliary cirrhosis and Hashimoto thyroiditis in the absence of diabetes mellitus and chronic renal insufficiency. The patient had a partial response to narrowband UVB phototherapy. PMID- 17713149 TI - Idiopathic thrombocytopenic purpura with black oral mucosal lesions. AB - Idiopathic thrombocytopenic purpura (ITP) is an acquired autoimmune disorder in which autoantibodies are made against platelets, causing accelerated platelet destruction. History and physical examination are most often normal except for petechiae, commonly seen in the lower extremities. Hemorrhagic bullae of mucous membranes can indicate the presence of severe thrombocytopenia. We report a case of ITP in a 33-year-old man who presented with insidious onset of black oral mucosal lesions. PMID- 17713150 TI - Erythromelanosis follicularis faciei et colli: case reports of bilateral lesions in 2 females. AB - Erythromelanosis follicularis faciei et colli (EFFC) is a rare disorder of unknown etiology characterized by the clinical triad of well-demarcated erythema, hyperpigmentation, and follicular plugging on the face. For many years, it was thought to be a disease occurring in males with ethnical cutaneous pigmentation. There are less than 50 cases reported in the literature, most of which are males. We describe bilateral EFFC in 2 females. PMID- 17713151 TI - Can sun protection knowledge change behavior in a resistant population? AB - The future skin cancer statistics for the youth of the United States are staggering. Traditional educational programs are currently the mainstay to foster sun protective awareness for this high-risk, sun-worshipping population. This study was designed to monitor high school students for both short-term and long term changes in knowledge and attitude, as well as for any change in behavior, following a standard sun protection intervention. Our results demonstrated that although students had an increase in knowledge, it was insufficient to change their behavior. PMID- 17713152 TI - Ketoconazole gel 2% in the treatment of moderate to severe seborrheic dermatitis. AB - Seborrheic dermatitis traditionally has been treated with topical steroids. In current practice, however, antifungal agents such as ketoconazole often are used because Malassezia yeasts are thought to play a role in the disease pathogenesis. Ketoconazole gel 2% has been developed for the once-daily treatment of seborrheic dermatitis. This gel is almost invisible after application, unlike ketoconazole cream, and may offer advantages in patient acceptance and adherence to treatment. Three randomized, double-blinded, vehicle-controlled, multicenter, parallel-group phase 3 studies evaluated the efficacy and tolerability of ketoconazole gel 2% compared with a vehicle gel in more than 900 subjects with moderate to severe seborrheic dermatitis who applied treatment for 14 days and were followed for an additional 14 days. Two of these studies also compared a combination gel containing ketoconazole 2% and desonide 0.05%, each active gel individually, and a vehicle control. Subjects were considered effectively treated if the erythema and scaling as well as investigator global assessment (IGA) scores decreased to 0 (or 1 if the baseline score was > or =3) by day 28. Pooled data from these studies showed that the proportion of effectively treated subjects was significantly greater in the ketoconazole gel 2% treatment group compared with the vehicle group (P < .001). The comparison of the combination gel to its individual components revealed that the efficacy of ketoconazole alone was comparable to the combination gel as well as desonide gel alone for up to 2 weeks after the end of treatment. These data suggest that once-daily ketoconazole gel 2% is an effective treatment for seborrheic dermatitis and a viable alternative to the ketoconazole cream 2% formulation. PMID- 17713153 TI - Quadruple nucleoside therapy with zidovudine, lamivudine, abacavir and tenofovir in the treatment of HIV. AB - Highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality in HIV-infected patients. However, problems such as short-term or long-term toxicity and the development of drug resistance could necessitate a change in the therapy regimen. Whereas various HAART options with low pill burden and favourable long-term tolerability profiles are available for naive patients, treatment of experienced patients tends to be more complex and remains a challenge. Treatment with class sparing nucleoside-only regimens could be an option in this context, but the combination of zidovudine (AZT), lamivudine (3TC) and abacavir (ABC) has shown to be inferior in terms of virological efficacy compared with the standard regimen. More promising data were obtained when AZT, 3TC and ABC were intensified with tenofovir (TDF), resulting in a quadruple nucleoside therapy. This regimen has demonstrated comparable potency to a standard regimen with AZT, 3TC and efavirenz in treatmentnaive patients. Additionally, it has shown to be an efficient treatment option especially in moderately pretreated patients. This is accredited to the potency of the single components and the antagonistic selection pressure of AZT and TDF. The presence of L210W, or at least two of the mutations 41L, 67N, 70R, 215F/Y or 219Q/E, at or before baseline seems to be a predictor of non-response, whereas the presence of M184V does not impede virological response and might even be advantageous. This review summarizes current data on the combined use of AZT, 3TC, ABC and TDF in regard to virological and immunological outcome as well as genotypic predictors of response. PMID- 17713154 TI - Impact of early viral kinetics on T-cell reactivity during antiviral therapy in chronic hepatitis B. AB - BACKGROUND: The patterns of hepatitis B viral dynamics during different antiviral therapies and the associated changes in HBV-specific T-cell reactivity are not well defined. METHODS: We investigated the impact of early viral load decline on virus-specific T-cell reactivity in 30 hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B randomized to monotherapy with adefovir dipivoxil (ADV) or in combination with emtricitabine (ADV/FTC). Viral kinetics were analysed by mathematical modelling. T-cell reactivity to HBV core and/or surface antigens and natural killer T cell frequency were tested longitudinally, baseline to week 48, using EliSPOT assays and/or flow cytometry. RESULTS: Mathematical modelling of early HBV kinetics identified two subsets of patients: 11 fast responders (undetectable viraemia by week 12; eight on ADV/FTC three on ADV) and 19 slow responders who remained viremic (six on ADV/FTC 13 on ADV). The rate of infected hepatocyte loss was higher in fast than in slow responders (P = 0.0007), and correlated inversely with pre-treatment levels of intrahepatic covalently closed circular HBV DNA. The frequency of HBV core-specific CD4+ T cells increased significantly only in fast responders, peaking between week 16 and 24, while the HBV surface-specific CD4+ T-cells increased in both subsets. These changes in CD4+ T-cell reactivity were transient however, and no increase in HBV-specific CD8+ T-cells was observed. By week 48, HBeAg seroconversion occurred only in 3/30 (10%) patients. CONCLUSIONS: Early viraemia clearance facilitates recovery of virus-specific CD4+ T-cell reactivity, but appears insufficient to establish clinically relevant antiviral immunity. PMID- 17713156 TI - Resistance profiling of hepatitis C virus protease inhibitors using full-length NS3. AB - BACKGROUND: The NS3 protease of hepatitis C virus (HCV) is a prime target for anti-HCV drugs but resistance towards inhibitors of the enzyme is likely to emerge because of mutations in the viral genome that modify the structure of the protein. Enzyme inhibition data supporting this is limited to studies with few compounds and analysis performed with truncated NS3. EXPERIMENTAL: The potential of HCV acquiring resistance towards NS3 protease inhibitors and the structural features associated with resistance has been explored with a series of inhibitors and by using full-length NS3 protease/helicase variants with amino acid substitutions (A156T, D168V and R155Q) in the protease domain. RESULTS: The A156T and D168V substitutions did not influence the kinetic properties of the protease, whereas the R155Q substitution reduced the catalytic efficiency 20 times, as compared with the wild type. Inhibition studies revealed that these substitutions primarily affected the potency of compounds which effectively inhibit the wild type enzyme, and had little effect on weak or moderate inhibitors. As a consequence, all compounds had similar inhibitory potencies to the substituted enzyme variants. An exception was VX-950, which inhibited the D168V enzyme more efficiently than the wild type. For this inhibitor, the present data correlated better with replicon data than data from assays with truncated enzyme. CONCLUSIONS: These results have provided a structural basis for designing inhibitors that may be less susceptible to resistance by three known mutations, and suggest that the present variants of full-length NS3 constitute effective models for resistance profiling of NS3 protease inhibitors. PMID- 17713155 TI - DNA polymerase mutations in drug-resistant herpes simplex virus mutants determine in vivo neurovirulence and drug-enzyme interactions. AB - Mutations in the thymidine kinase and DNA polymerase genes of herpes simplex virus (HSV) might confer resistance to antiviral drugs, particularly in immunocompromised patients who suffer from chronic and/or disseminated lesions. The patterns of cross-resistance and neurovirulence in mice of several DNA polymerase mutants selected under pressure of foscarnet (PFA) and different acyclic nucleoside phosphonates (ANPs), including (S)-3-hydroxy-2 phosphonylmethoxypropyl (HPMP) derivatives of adenine (HPMPA) and cytosine (HPMPC, cidofovir) and 2-phosphonylmethoxyethyl (PME) derivatives of adenine (PMEA) and 2,6-diaminopurine (PMEDAP), were investigated. The mutants were derived from the HSV-1 strain KOS following either single or multiple steps of selection with PFA (V714M, A719V, 5724N and T821M), PMEA (S724N, L802F and R959H), PMEDAP (Q618H, S724N, S724N+D1070N), HPMPC (V573M, R700M and K960R) or HPMPA (W998L, L1007M and 11028T). These amino acid substitutions were located in different subdomains of the HSV-1 DNA polymerase, either in conserved or non conserved regions. The sensitivity of the mutants to a new class of ANPs, the 6 (2-[phosphonomethoxy]alkoxy)pyrimidines HPMPO-DAPy and PMEO-DAPy, was investigated. Cross-resistance between the HPMP derivatives and HPMPO-DAPy, on the one hand, and between the PME derivatives and PMEO-DAPy, on the other hand, was observed. Different degrees of cross-resistance between PME derivatives, PMEO DAPy, PFA and acyclovir were noticed. The mutants ranged from exhibiting near wild-type neurovirulence (V714M, A719V, 5724N and L1007M) to significant attenuation (Q618H, S724N+D1070N, L802F, R700M, K960R, W998L and 11028T) or higher levels of attenuation (V573M). It appears that drug-resistant mutants arising under the pressure of HPMP derivatives have the lowest levels of neurovirulence. PMID- 17713157 TI - Safety, pharmacokinetics and immune effects in normal volunteers of CPG 10101 (ACTILON), an investigational synthetic toll-like receptor 9 agonist. AB - CPG 10101 (ACTILON) is a novel potent and selective unmethylated cytidine phosphate-guanosine (CpG)-containing oligodeoxynucleotide agonist of Toll-like receptor 9 (TLR9) being developed for the treatment of chronic infections such as HCV. OBJECTIVES AND METHODS: In this randomized, double-blind, placebo-controlled Phase I study in 48 normal volunteers, we investigated the safety, pharmacokinetic parameters and immune effects of subcutaneous administration of CPG 10101. Five sequential escalating doses from 0.25 to 20 mg were administered twice, 14 days apart. In addition, a 4 mg dose was administered twice weekly for four weeks. RESULTS: A maximum tolerated dose was not reached and the adverse event profile was consistent with the known immunostimulatory effects of TLR9 agonists, mostly consisting of injection site reactions or flu-like symptoms that were generally mild in intensity. CPG 10101 induced interferons, cytokines and chemokines in a pattern consistent with the biology of TLR9. The most sensitive marker was IP-10/CXCL10, whose induction was detected in some subjects even at the 0.25 mg dose. Some cytokines showed transient circulating levels, while the levels of others such as the antiviral cytokine 2',5'-oligoadenylate synthetase were sustained for several days. CONCLUSION: This study warrants further investigation of CPG 10101 for the treatment of chronic infections such as HCV. PMID- 17713158 TI - Substitutions due to antiretroviral toxicity or contraindication in the first 3 years of antiretroviral therapy in a large South African cohort. AB - INTRODUCTION: The patterns and reasons for antiretroviral therapy (ART) drug substitutions are poorly described in resource-limited settings. METHODS: Time to and reason for drug substitution were recorded in treatment-naive adults receiving ART in two primary care treatment programmes in Cape Town. The cumulative proportion of patients having therapy changed because of toxicity was described for each drug, and associations with these changes were explored in multivariate models. RESULTS: Analysis included 2,679 individuals followed for a median of 11 months. Median CD4+ T-cell count at baseline was 85 cells/microl. Mean weight was 59 kg, mean age was 32 years and 71% were women. All started non nucleoside reverse transcriptase inhibitor-based ART (60% on efavrienz) and 75% started on stavudine (d4T). After 3 years, 75% remained in care on-site, of whom 72% remained on their initial regimen. Substitutions due to toxicity of nevirapine (8% by 3 years), efavirenz (2%) and zidovudine (8%) occurred early. Substitutions on d4T occurred in 21% of patients by 3 years, due to symptomatic hyperlactataemia (5%), lipodystrophy (9%) or peripheral neuropathy (6%), and continued to accumulate over time. Those at greatest risk of hyperlactataemia or lipodystrophy were women on ART > or =6 months, weighing > or =75 kg at baseline. DISCUSSION: A high proportion of adult patients are able to tolerate their initial ART regimen for up to 3 years. In most instances treatment-limiting toxicities occur early, but continue to accumulate over time in patients on d4T. Whilst awaiting other treatment options, the risks of known toxicities could be minimized through early identification of patients at the highest risk. PMID- 17713160 TI - The influence of HIV infection and antiretroviral therapy on the mitochondrial membrane potential of peripheral mononuclear cells. AB - OBJECTIVES: Clinical disorders occurring in HIV-infected patients on antiretroviral therapy (ART) have been linked to mitochondrial dysfunction, for example, lactic acidosis and lipodystrophy. Mitochondrial membrane potential (delta psi m) is the most direct measure of the state of energization of the mitochondria. We analysed delta psi m, of peripheral blood mononuclear cells (PBMCs) in HIV-negative, healthy subjects (n=8), HIV-infected, treatment-naive patients (n=30), and HIV-infected patients on ART (n=58). The influence of ART was analysed in six patients who started their first regimen. METHODS: The delta psi m of PBMC was measured by flow cytometry using the dye JC-1. RESULTS: The delta psi m was significantly lower in HIV-infected patients than in HIV-negative controls. This difference was detected in both treated (P = 0.0001) and untreated patients (P = 0.001). The delta psi m of PBMCs was highly correlated with CD4+ T cell count in therapy-naive patients (P = 0.002, r = 0.546) and in treated patients (P = 0.028, r = 0.288). The delta psi m increased significantly in therapy-naive patients after starting ART (P = 0.001). Patients with lipoatrophy had significantly lower delta psi m than patients without lipodystrophy or with lipohypertrophy (P = 0.023). CONCLUSIONS: In HIV-infected persons delta psi m is significantly reduced. Patients with lipoatrophy have significantly reduced delta psi m. This is the first study showing that the delta psi m of PBMCs is highly correlated with CD4+ T-cell count in HIV infection. PMID- 17713159 TI - A novel mutation pattern emerging during lamivudine treatment shows cross resistance to adefovir dipivoxil treatment. AB - AIMS: This study was conducted to clarify the resistance profile of a novel mutation pattern emerging during lamivudine (3TC) therapy and showing cross resistance to adefovir dipivoxil (ADV) in a patient with chronic hepatitis B. METHODS AND RESULTS: Successful suppression of hepatitis B virus (HBV) replication by sequential therapy of 9 MU thrice weekly interferon (IFN) and 3TC was followed by genotypical resistance detected at month 28 of therapy (month 19 of lamivudine treatment). ADV was added to 3TC therapy on month 44 of antiviral treatment. Neither alanine aminotransferase normalization nor a stable decrease in HBV viral load was observed, although ADV was used for more than 40 months. The HBV pol region was amplified from serum samples obtained before and after ADV treatment. The complete genome was cloned into a TA vector. PCR products and 7-10 clones from each cloned vector were sequenced. A novel mutation, A181S, in the reverse transcriptase gene leading to a conversion of W172C in the overlapping surface antigen gene was detected along with a M2041 mutation. The complete genome comprising the A181S+M2041 pattern was cloned into an expression vector and its in vitro susceptibility to 3TC, ADV, tenofovir (PMPA), clevudine (L-FMAU) and emtricitabine (FTC) were determined in transiently transfected Huh7 cells. This mutation pattern displayed more than 1000-fold resistance to the nucleoside analogues 3TC and FTC and approximately sixfold resistance to L-FMAU, while it confers 28.23- and 5.57-fold resistance for the nucleotide analogues ADV and PMPA, respectively. CONCLUSION: A new mutation pattern, A181S+M2041, arising under lamivudine treatment confers cross-resistance to ADV both in vivo and in vitro. PMID- 17713161 TI - Dynamics of apoptotic activity during antiviral treatment of patients with chronic hepatitis C. AB - INTRODUCTION: Cell death during antiviral therapy of patients with chronic hepatitis C is not well understood. METHODS: In the present study, apoptotic activity was monitored by quantification of apoptotic cytokeratin-18 neoepitopes in serum from patients with chronic hepatitis C before and 4, 12, 24 and 48 weeks after initiation of antiviral therapy with pegylated interferon-alpha2a and ribavirin and was compared with viral kinetic parameters. RESULTS: After 4 weeks of treatment apoptotic activity decreased significantly compared with baseline. Later during treatment, however, apoptotic activity increased again to levels similar to baseline. Alanine aminotransferase (ALT) activity also showed a significant decrease at week 4 compared with baseline but, in contrast to apoptotic activity, ALT remained at a reduced level during the treatment period. Baseline apoptotic activity was inversely correlated with the infected cell loss while an increase of apoptotic activity within the first 4 treatment weeks compared with baseline was positively correlated with the infected cell loss. CONCLUSIONS: Apoptosis appears to be an important form of cell death during interferon-alpha-based treatment and is associated with infected cell loss and underestimated by ALT activity. PMID- 17713162 TI - Pharmacokinetics of darunavir/ritonavir and TMC125 alone and coadministered in HIV-negative volunteers. AB - OBJECTIVE: To evaluate the pharmacokinetics of TMC125 (etravirine) and darunavir (DRV) with low-dose ritonavir (DRV/r). DESIGN: Open-label, randomized, two-way crossover Phase I trial. METHODS: Thirty-two HIV-negative volunteers were randomized 1:1 to two panels. All received TMC125 100 mg twice daily for 8 days and, after 14 days washout, DRV/r 600/100 mg twice daily for 16 days. During days 9-16, TMC125 100 or 200 mg twice daily was coadministered (Panel I or II, respectively). RESULTS: Twenty-three volunteers completed the trial. With DRV/r coadministration, mean exposure (area under the plasma concentration-time curve from 0 to 12 h [AUC12h) to TMC125 given as 100 mg twice daily was decreased by 37%; maximum and minimum plasma concentrations (Cmax and Cmin) were decreased by 32% and 49%, respectively. For TMC125 200 mg twice daily coadministered with DRV/r, AUC12h, Cmax and Cmin of TMC125 were 80%, 81% and 67% greater, respectively, versus TMC125 100 mg twice daily alone. DRV pharmacokinetics were unchanged except a 15% increase in AUC12h when given with TMC125 200 mg twice daily. CONCLUSIONS: No clinically relevant changes in DRV pharmacokinetics were observed when combined with TMC125; therefore DRV dose adjustment is not required. Coadministration of TMC125 100 mg twice daily with DRV/r decreased TMC125 exposure by 37%. The increase of TMC125 exposure by 80% when given as 200 mg twice daily reflects the higher dose and the interaction with DRV/r. The magnitude of this interaction is comparable to TMC125 interactions with other boosted PIs observed in Phase IIb trials in HIV-1-infected patients. As these trials demonstrated TMC125 efficacy, no dose adjustment of TMC125 is needed when combined with DRV/r. PMID- 17713163 TI - Serum alpha-foetoprotein level predicts treatment outcome in chronic hepatitis C. AB - OBJECTIVES: To analyse the association between serum alpha-foetoprotein (AFP) levels and sustained virological response (SVR) in treated patients. METHODS: One hundred patients with chronic hepatitis C were treated with pegylated interferon alpha-2a plus ribavirin for 48 weeks. The primary endpoint was SVR. Linear regression analysis was performed to identify clinical, biological, and histological factors affecting baseline AFP levels. The association between pretreatment serum AFP and SVR was assessed by multivariate logistic regression analysis. RESULTS: Of 100 patients, 95 were infected with genotype 4, one with genotype 1, and four with undetermined genotype. The median serum AFP level was 4.5 ng/ml and AFP values ranged from 1.2 to 49.8 ng/ml. In multivariate analysis, higher fibrosis stage and higher steatosis score were independently associated with higher serum AFP levels. SVR rate was 61.0% (61/100), and was lower for patients with AFP levels above rather than below the median value (40.8% versus 80.4%, respectively, P < 0.001). In multivariate analysis, including adjustment for age, gender, body mass index, steatosis score, fibrosis stage, ALT level, haemoglobin level, clotting time, HCV RNA viral load, and treatment dose received, a baseline serum AFP level above the median value was associated with a lower SVR rate (OR [95% CI]=0.10 [0.03-0.42], P < 0.001). None of the seven patients with increased (above 15 ng/ml) pretreatment AFP achieved SVR. CONCLUSIONS: In this study, higher baseline serum AFP levels independently predicted a lower SVR rate among patients with chronic hepatitis C. If confirmed with genotypes other than 4, these findings would suggest adding serum AFP to the list of factors predictive of treatment response. PMID- 17713164 TI - Effect of ribavirin on the hepatitis C virus (JFH-1) and its correlation with interferon sensitivity. AB - BACKGROUND: The consensus therapy for chronic hepatitis C infection is based on a synergistic combination of pegylated interferon and ribavirin. The therapy leads to a sustained virological response in around 60% of infected patients. The mechanism by which this synergy occurs has not yet been elucidated. Several mechanisms of action have been proposed; one suggests that ribavirin, which is a nucleoside analogue, is incorporated into the RNA strand and generates an increase in the error rate. Such an accumulation of mutations would threaten the integrity of the virus's genetic information. METHODS: The effects of ribavirin on the new infectious hepatitis C virus cell culture (HCVcc) system were investigated using Huh-7 cells. Cells were cultured for 1 month in either 0 microM, 20 microM or 50 microM ribavirin. The HCV interferon sensitivity and the NS5A quasispecies were analysed. RESULTS: An increase in the mutation rate in the HCV NS5A gene was observed when the infected cells were treated with 50 microM ribavirin for 1 month. Amino acid sequence analysis revealed that ribavirin exerts an increase in G to A transition events as predicted by its mutagenic effect and a selective pressure on the HCV NS5A sequence. Furthermore, ribavirin treatment modified the efficacy of interferon (IFN) treatment. The IFN half inhibition concentration (IC50) was significantly lower for viruses obtained after 1 month's exposure to 50 microM ribavirin than for viruses cultured in the absence of ribavirin. CONCLUSIONS: Ribavirin's mutagenic effect could explain in part its synergistic action with interferon. PMID- 17713165 TI - Virological response to different combination regimes of peginterferon alpha-2b and lamivudine in hepatitis B e antigen positive chronic hepatitis B. AB - OBJECTIVE: To investigate whether simultaneous commencement of peginterferon alpha-2b and lamivudine treatment has more potent hepatitis B virus (HBV) DNA suppression than staggered regimes. METHODS: Thirty HBeAg-positive chronic hepatitis B patients were randomized in 1:1:1 ratio to 32-week peginterferon started simultaneously with lamivudine (group 1), eight weeks before lamivudine (group 2) or eight weeks after commencement of lamivudine (group 3). All patients received lamivudine until week 104. RESULTS: At week 52, the log HBV DNA reduction in group 1 (6.38) was more profound than that in group 2 (3.43, P = 0.022) and tended to be superior to that in group 3 (4.44, P = 0.060). HBeAg seroconversion developed in six (67%) patients in group 1, three (33%) patients in group 2 (P = 0.35 versus group 1) and one (10%) patient in group 3 (P = 0.037 versus group 1). At week 104, the log HBV DNA reduction in group 1 (6.13) versus that in group 2 (5.24) and group 3 (5.15) was insignificantly different. Lamivudine resistance was found in four (14%) patients at week 104. There was 1.22 and 2.52 median log reduction in covalently closed circular DNA and total intrahepatic HBV DNA, respectively, at week 104, but there was no difference among the three groups. At 24 weeks post-treatment, sustained HBeAg seroconversion was observed in five (56%), three (33%) and four (40%) of the patients in groups 1, 2 and 3, respectively (P > 0.05). CONCLUSIONS: Simultaneous commencement of peginterferon and lamivudine tend to provide more profound viral suppression than staggered regimes in the early phase of treatment. PMID- 17713166 TI - Abacavir plasma pharmacokinetics in the absence and presence of atazanavir/ritonavir or lopinavir/ritonavir and vice versa in HIV-infected patients. AB - BACKGROUND: Significant interactions between abacavir and other antiretrovirals have not been reported. This study investigated the steady-state plasma pharmacokinetics of abacavir when co-administered with atazanavir/ritonavir or lopinavir/ritonavir in HIV-infected individuals. METHODS: HIV-infected subjects on abacavir (600 mg once daily) plus two nucleoside reverse transcriptase inhibitors (NRTIs) (excluding tenofovir) underwent a 24 h pharmacokinetic assessment for plasma abacavir concentrations. Atazanavir/ritonavir (300/100 mg once daily; arm (1) or lopinavir/ritonavir (400/100 mg twice daily; arm (2) were then added and the 24 h pharmacokinetic assessment repeated. Arm 3 included subjects stable on atazanavir/ritonavir or lopinavir/ritonavir and two NRTIs (excluding tenofovir or abacavir). These patients underwent a pharmacokinetic assessment for atazanavir/ritonavir or lopinavir/ritonavir concentrations on day 1, abacavir (600 mg once daily) was then added to the regimen and the pharmacokinetic assessment repeated. Within-subject changes in drug exposure were evaluated by geometric mean (GM) ratios and 95% confidence intervals (CI). RESULTS: Twenty-four patients completed the study. GM (95% CI) abacavir area under the curve (AUC) was 18,621 (15,900-21,807) and 15,136 (13,339-17,174) ng.h/ml without and with atazanavir/ritonavir and 15,136 (12,298-18,628) and 10,471 (9,270-11,828) ng.h/ml without and with lopinavir/ritonavir. GM (95% CI) atazanavir AUC without and with abacavir was 26,915 (13,252-54,666) and 28,840 (19,213-43,291) ng.h/ml; lopinavir AUC without and with abacavir was 60,253 (48,084-75,509) and 63,096 (48,128-82,718) ng.h/ml. CONCLUSIONS: No changes in atazanavir or lopinavir exposures were observed following the addition of abacavir; however, decreases in abacavir plasma exposure of 17% and 32% were observed following the addition of atazanavir/ritonavir or lopinavir/ritonavir, respectively. PMID- 17713167 TI - Effect of transporter modulation on the emergence of nelfinavir resistance in vitro. AB - BACKGROUND: HIV drug resistance is of increasing concern and could result from inadequate drug potency, poor therapy adherence and the existence of pharmacological sanctuary sites for viral replication. One contributing factor to the generation of such sites could be drug efflux transporters, which have been shown capable of effluxing HIV protease inhibitors from cells. METHODS: In this 'proof-of-concept' study, the ability of the efflux transport inhibitor verapamil to modulate the intracellular accumulation of radiolabelled nelfinavir (NFV) and the antiviral effect of NFV was assessed in MT4 cells. Wild-type virus was then serially passaged with increasing concentrations of NFV with and without verapamil and resistance mutations monitored by sequencing of the viral protease gene. RESULTS: The cellular accumulation ratio of 3H-NFV was 116.8 +/- 9.7 in controls and was significantly increased to 149.8 +/- 24.5 following incubation with verapamil (P < 0.05, n=4). The EC50 of NFV was decreased in MT4 cells in the presence of verapamil from 8.5 11.3 nM to 4.4 +/- 0.8 nM (P < 0.001, n=6). Of the 24 isolates passaged without verapamil, 21 carried the D30N mutation at detectable levels. Of the 23 passaged with verapamil, 14 carried the mutation (odds ratio = 4.5; P < 0.05). CONCLUSIONS: These results suggest that 'intracellular boosting' of PIs is achievable through inhibition of drug efflux proteins in vitro and that such boosting has the ability to enhance suppression of viral replication, slowing the emergence of resistance mutations. PMID- 17713168 TI - Declining prevalence of HIV-1 drug resistance in treatment-failing patients: a clinical cohort study. AB - OBJECTIVES: A major barrier to successful viral suppression in HIV type 1 (HIV-1) infected individuals is the emergence of virus resistant to antiretroviral drugs. We explored the evolution of genotypic drug resistance prevalence in treatment failing patients from 1999 to 2005 in a clinical cohort. PATIENTS AND METHODS: Prevalence of major International AIDS Society-USA HIV-1 drug resistance mutations was measured over calendar years in a population with treatment failure and undergoing resistance testing. Predictors of the presence of resistance mutations were analysed by logistic regression. RESULTS: Significant reductions of the prevalence of resistance to all three drug classes examined were observed. This was accompanied by a reduction in the proportion of treatment-failing patients. Independent predictors of drug resistance were the earlier calendar year, prior use of suboptimal nucleoside analogue therapy, male sex and higher CD4 levels at testing. CONCLUSIONS: In a single clinical cohort, we observed a decrease in the prevalence of resistance to all three examined antiretroviral drug classes over time. If this finding is confirmed in multicentre cohorts it may translate into reduced transmission of drug-resistant virus from treated patients. PMID- 17713169 TI - Allergic contact dermatitis to synthetic rubber following breast augmentation. AB - Allergic reactions associated with silicone injection and implant were examined in a 50-year-old woman with a granulomatous reaction following breast silicone gel prosthesis rupture who developed a delayed hypersensitivity to rubber compounds. Patch tests with SIDAPA, dental, and rubber series as well as open tests with latex, silicone and non silicone tubes, open application test with silicone gel, and skin prick test for aero and food-allergens were performed. Total and specific serum IgE measured by CAP-FEIA. Skin tests revealed a delayed type hypersensitivity to thioureas, thiuram mixture and platinum. Specific IgE to natural rubber latex were found. Allergic contact dermatitis from thioureas, thiurams and platinum might be under-diagnosed, as they are not tested as part of the standard patch test series. Clinicians should consider this diagnosis in patients submitted to several cosmetic treatments. PMID- 17713170 TI - Allergies associated with body piercing and tattoos: a report of the Allergy Vigilance Network. AB - Body piercing and tattooing are increasingly common. As well as the risk of infection and scarring, allergic reactions are also reported. This is the first multi-centre study to assess the frequency of consultations for allergy. Of the 138 allergologists who answered our two questionnaires, 7.9% reported allergic reactions associated with body piercing and 18.9% identified allergies associated with temporary henna-based tattoos. Contact eczema, rhinitis and urticaria were related to nickel allergy. Contact eczema, generalized eczema, pruritus and edema were caused by tattoos. In 20 out of 28 cases, sensitization to para phenylenediamine (PPD) was observed. The authors review the literature, underscoring the risk of serious allergy to PPD, the need for long-term monitoring of the risk of skin lymphocytoma, the difficulties met during treatment and the necessity of regulating tattooing and body piercing practices. PMID- 17713171 TI - Drug allergy and asthma. AB - The prevalence of drug induced asthma in a series of 347 patients with drug induced adverse effects has been evaluated corresponding to 10% of drug adverse effects always due to NSAIDS. PMID- 17713172 TI - The asthma rhinitis link. AB - The reports and similarities between rhinitis and asthma are presented--common triggers, common inflammatory mechanisms and incidence of association of both diseases are analysed. Personal data on the frequency of asthma in rhinitis and of rhinitis in asthma are presented. The effect of nasal provocations tests in peak expiratory flow in patients with and without rhinitis is compared being greater in presence of nasal allergy. Finally the ARIA recommendations are discussed. PMID- 17713173 TI - Drug allergy and pollinosis. A short report. AB - 2 series of patients with pollinosis and drug allergy studied 10 years apart and comprising 115 cases are presented. In both series grass pollens and parietaria are as usual the most common cause of pollinosis but Parietaria was more common in the first series. Beta-lactams were the major cause of drug allergy in the first group, supersed by NSAID in the second group. Rhinitis was the more frequent symptom on pollinosis and urticaria/angioedema on drug allergy. PMID- 17713174 TI - Use of new "barrier socks" in contact allergic dermatitis. AB - We present the case of a fifty-year-old construction worker with contact allergic dermatitis in his feet. Given the limited results obtained with a costly topical therapy, we tried, for first time, using completely breathable "barrier socks", which solved the persistent problem in a matter of days. In addition to the improvement in the patient's quality of life and the renewed possibility of his wearing protective shoes, a net reduction in the costs incurred with topical therapy was also obtained. PMID- 17713175 TI - AstraZeneca launches a smarter approach to asthma management in Europe. PMID- 17713176 TI - Contesting the dominance of emotional labour in professional nursing. AB - PURPOSE: The main intension of this paper is to challenge the dominance of emotional labour in professional nursing. DESIGN/METHODOLOGY/APPROACH: The article begins by evaluating the central conceptual and definitional aspects of emotional labour, emotion work and emotional work. The purpose of this discussion is to argue against the false public and private dichotomy that has plagued emotional labour and emotion work. Second, it is proposed that the central and helpful defining aspects of emotional labour and emotion work are Marx's concepts of exchange-value and use-value. These defining attributes are used in conjunction with other re-conceptualisations, which unite these terms in order to create more encompassing constructs that are useful for focusing on the waged and unwaged aspects of professional nurses' emotional work response behaviours. Finally, the use of emotional labour in professional nursing is contested on the grounds that the construct has limited theoretical and empirical utility for researching the complex nature of professional nurses' emotional work response behaviours. FINDINGS: It is recommended that a more robust encompassing concept needs to be developed, which accurately reflects the nature and complexity of professional nurses' waged and unwaged emotional work response behaviours, as they are important overlooked facets of behaviour that can be theoretically related to professional nurses' contextual performance. ORIGINALITY/VALUE: The paper provides a better understanding of professional nurses' emotional work response behaviours, which benefit nursing research and practice by drawing on other areas of theory and research. PMID- 17713177 TI - An examination of the stages of change construct for health promotion within organizations. AB - PURPOSE: The purpose of this research is to examine the organizational stages of change construct of the transtheoretical model of behavior change. DESIGN/METHODOLOGY/APPROACH: Data on organizational and individual stages of change for tobacco reduction, physical activity promotion, and heart healthy eating promotion were collected from service provider, senior management, and board level members of provincial health authorities across three data collection periods. FINDINGS: Results revealed significant correlations between individual and organizational stages of change for management level respondents, but inconsistent relationships for service providers and no significant correlations for board level respondents. There were no significant differences between respondent levels for organizational stage of change for any of the promotion behaviors. In general, changes in stage failed to predict whether there was a belief in an organization's capability of addressing any of the health promotion activities. There was also a large amount of variance between individual respondents for most health authorities in their reported organizational stages of change for physical activity and healthy eating. PRACTICAL IMPLICATIONS: Based on the results of the present study it is concluded that there is little evidence that the organizational stages of change construct is valid. The evidence indicates that assessing individual readiness within an organization may be as effective as asking individuals to report on organizational stages of readiness. ORIGINALITY/VALUE: This paper reports on the validity of the organizational stages of change construct in a health promotion context and provides information for those who are considering using it. PMID- 17713178 TI - Fault-lines between policy and practice in local partnerships. AB - PURPOSE: The purpose of this study is to explore gaps between policy and practice in relation to the involvement of voluntary and community sector (VCS) members in local strategic partnerships (LSPs), using the example of inequalities in health. DESIGN/METHODOLOGY/APPROACH: Documentary analysis; semi-structured interviews with VCS representatives from a sample of LSPs in one region of England; semi structured interviews with key researchers and national stakeholders. FINDINGS: National policy imperatives to expand the role of the VCS in decision-making and to make LSPs an important avenue for addressing inequalities in health are not always translated into practice. VCS members are at the sharp end of tensions in LSPs between thematic and neighbourhood approaches, local views and strategic priorities and between democratic and participatory approaches to decision making. Effective engagement in addressing inequalities in health requires a strategic approach across the LSP which is reflected in the priorities of each of the constituent partnerships. RESEARCH LIMITATIONS/IMPLICATIONS: This is a snapshot of LSPs at one point in time and local interviews are restricted to one region of England. PRACTICAL IMPLICATIONS: The article illustrates good practice and barriers to VCS involvement in addressing inequalities in health through LSPs. This is relevant to a range of public health partnerships. ORIGINALITY/VALUE: The views of VCS members on addressing inequalities in health through LSPs have not previously been researched, despite their key role. Lessons are relevant for multi-agency strategic partnerships with a public health focus in England and internationally. PMID- 17713179 TI - Bridging the gap? A critical analysis of the development of the Patient Advice And Liaison Service (PALS). AB - PURPOSE: The creation of the Patient Advice and Liaison Service (PALS) was part of a range of measures to make the NHS more patient-centred. The purpose of this paper is to present a critical analysis of PALS through examining the impact on major stakeholder groups. DESIGN/METHODOLOGY/APPROACH: The paper starts by examining the drivers for reform and the significance of PALS in the wider policy context. Key issues for implementation are then discussed including access to information, independence, cultural change in the health service and relationships with the voluntary sector. Research literature on the provision of advice in health care settings is drawn on. FINDINGS: Taking a critical perspective, the paper argues that the current model of PALS can never succeed in bridging the gap between users and the health service and will end up merely defending service interests. It concludes by arguing for an alternative model of development based on fostering strong partnerships with the community and voluntary sector. PRACTICAL IMPLICATIONS: This paper highlights critical issues for service development and delivery, including examining the impact on service users and the voluntary sector. ORIGINALITY/VALUE: PALS is a very significant development in the health care provision, operating at the interface between the service and the public and yet its development has attracted little critical comment. This paper provides a comprehensive analysis of the new service and proposes an alternative model of development. PMID- 17713180 TI - Creating complex health improvement programs as mindful organizations: from theory to action. AB - PURPOSE: The purpose of this paper is to identify ways for organizationally complex, community-based health improvement initiatives to avoid "failures" with regard to client outcomes. DESIGN/METHODOLOGY/APPROACH: Organizational research on errors, failures and high reliability organizations led Weick and Sutcliffe to articulate five strategies for organizational mindfulness: preoccupation with failure, reluctance to simplify, sensitivity to operations, commitment to resilience, and deference to expertise. Using this framework, one US federally funded health initiative to reduce infant mortality and pre-term birth and a corresponding locally implemented program are analyzed. Experience with both over a five year period is the basis for this case study. FINDINGS: Mindlessness actions were found to occur at both the federal and local levels, despite the possibility of enacting mindfulness strategies at federal and local levels. PRACTICE IMPLICATIONS: To create health care initiatives and programs in ways that prevent disastrous outcomes, such as infant death and preterm births, can be achieved through application of the mindfulness strategies. ORIGINALITY/VALUE: The evidence-based approach of organizational mindfulness previously has not been applied to health programs. Yet, this analysis demonstrates its usefulness in identifying ways in which these semi-autonomous organizations could avoid "failures" for their program clients. PMID- 17713181 TI - Strategic behaviour of institutional providers in mental handicapped care in the Netherlands. AB - PURPOSE: The purpose of this paper is to describe an inventory of the strategic responses of institutional providers of mental handicapped care to the strengthening of consumer choice through a personal care budget (PCB). DESIGN/METHODOLOGY/APPROACH: Semi structured interviews were conducted among 26 providers covering 52 per cent of the total market volume of about 100,000 clients annually. FINDINGS: A representative number of providers was included; on average a percentage below the national average of PCB users was found to be served. Of the 26 providers, 16 indicated adaption to their strategy in response to expected consumer empowerment The actual deployment of this response in the organisations seemed not to be very thorough or explicit. Surprisingly, as a growing part of PCB-clients choose alternative providers, no concerns were raised concerning the possible emergence of new service providers. ORIGINALITY/VALUE: Although the market share of PCB users is growing fast and existing providers do not seem to absorb this accordingly, a lack of market analysis and strategic behaviour of the traditional providers in response to this development was found. Based on this research growth of market shares of disruptive service providers can very well be anticipated. PMID- 17713182 TI - Back to the future in NHS reform. AB - PURPOSE: In the mid 1990s the NHS "did" competition, in the mid 2000s the NHS is "doing" choice. This paper aims to cut through the rhetoric, highlight the differences and parallels between then and now and identify if these differences will have a different or the same impact on local services. DESIGN/METHODOLOGY/APPROACH: Following a review of literature from the 1990s, a qualitative research study is used to examine the impact of competition and markets in the 1990s. The discussion examines the implications of this study for current system reform. FINDINGS: Patient choice recreates many of the features of the internal market, but despite concerns at the time, the internal market did not have a significant impact on services. It is likely that patient choice will similarly have a limited impact. RESEARCH LIMITATIONS/IMPLICATIONS: The research is a case study confined to Day Surgery in one part of the North of England. ORIGINALITY/VALUE: The paper reminds academics and practitioners what happened last time the NHS attempted to introduce a market-based system. PMID- 17713183 TI - Why sexual health promotion misses its audience: men who have sex with men reading the texts. AB - PURPOSE: Sexual health promotion aimed at men who have sex with men (MSM) is not achieving its objective of reducing the incidence of new infections of sexually transmitted diseases, notably HIV/AIDS, in the MSM population. The paper aims to raise awareness of possible unintended consequences when using visual culture and advertising techniques in the field of sexual (and other) health promotion and public health messages. DESIGN/METHODOLOGY/APPROACH: Using critical textual analysis and drawing on visual culture methodology the approach is to critique current practice and suggest alternative ways to approach gay men's sexual health which are not predicated on a "model" gay man. FINDINGS: Men who have sex with men (MSM) are constructed through sexual health promotion (SHP) literature as young, hedonistic and irrational which may serve to distance the very audience it seeks to attract and address. What may at first appear to be a targeted and helpful initiative to raise awareness may inadvertently have the simultaneous and unanticipated effect of "selling" unsafe sex rather than promoting safe sex. This is because, first, the use of sexual imagery designed to attract attention works in unanticipated ways. Second, MSM are constructed through the images and language used in ways that may be at best unhelpful and potentially quite harmful. RESEARCH LIMITATIONS/IMPLICATIONS: There are many different approaches and interventions in this field and the criticisms here may not be applicable to many of the other sources of health promotion awareness campaigns. Future research could certainly be conducted in other fields of health promotion and public health issues such as obesity, drug and alcohol abuse and smoking cessation. PRACTICAL IMPLICATIONS: Health promotion practice should beware of depicting their audience in stereotypical ways. MSM could be constructed far more positively as role models to be followed instead of bad examples to be avoided. ORIGINALITY/VALUE: The methodology is new to this field and the findings provide an original basis for criticism of advertising techniques which have until now formed the basis of this type of public awareness-raising. PMID- 17713184 TI - Outsourcing in private healthcare organisations: a Greek perspective. AB - PURPOSE: The purpose of this paper is to present a study carried out to investigate the extent of outsourcing, the decision-making process, the impact of outsourcing, and the future trend of outsourcing in private healthcare organisations in Greece. DESIGN/METHODOLOGY/APPROACH: A survey instrument was designed and mailed to a random sample of 100 private healthcare organisations in Greece. A total of 25 usable questionnaires were received, representing a response rate of 25 percent. The survey instrument focused on the extent to which private healthcare organisations outsource services, the decision-making process for choosing an external service provider, the impact of outsourcing, and the future trend of outsourcing. FINDINGS: Private healthcare organisations in Greece outsource a variety of activities. Cost savings, customisation, and customer satisfaction are the main factors affecting the outsourcing decision. The cooperation with a contract service provider has led to an improvement in customer satisfaction and to a cost reduction. Most users are highly satisfied with the performance of these companies and believe that there will be a future increase in the usage of these services. PRACTICAL IMPLICATIONS: The paper provides a framework regarding outsourcing in private healthcare organisations. ORIGINALITY/VALUE: This research fills the gap in the area of outsourcing in private healthcare organisations in Greece. PMID- 17713185 TI - Contributing to the wellbeing of primary health care workers in PNG. AB - PURPOSE: The purpose of this paper is to investigate how organisational frames of reference, which are neither not appropriately communicated nor supported, affect the wellbeing of workers. DESIGN/METHODOLOGY/APPROACH: A review of the literature is used to develop a new model linking ambiguous frames of reference with reduced levels of workers' wellbeing. This is then tested using data collected in a study involving primary health care workers in Papua New Guinea (PNG). FINDINGS: This paper finds that, for these particular workers, the model linking ambiguous frames of reference and reduced worker wellbeing is valid. RESEARCH LIMITATIONS/IMPLICATIONS: The paper shows that there is a need for further research into a variety of areas including the importance of frames of reference to worker wellbeing, the significance of reference groups to organisational frames of reference and the consequences of reduced worker wellbeing in developing countries. PRACTICAL IMPLICATIONS: In this paper, recommendations for changes to current PNG primary health care management practices, including ensuring the support for as well as communicating the organisational frame of reference, are discussed. ORIGINALITY/VALUE: The paper shows that the experiences of these particular primary health care workers not only demonstrates the validity of the new model but also brings a unique perspective to the field of worker wellbeing, which up until now has been dominated by research conducted in western countries. PMID- 17713186 TI - Leadership transmission: a muddled metaphor? AB - PURPOSE: The purpose of this paper is to examine critically the concept of "leadership transmission", considering what theoretical and practical value this metaphor brings to the healthcare modernization agenda. DESIGN/METHODOLOGY/APPROACH: The paper develops understanding of the transmission metaphor, whilst theoretical perspectives on leadership are reviewed, including debates, which shed light on the concept by focusing on the phenomenon of distributed or dispersed leadership. FINDINGS: The transmission metaphor is perhaps misleading, by implying that "leadership can be caught" like a disease. However, defining leadership in terms of influence, a novel typology of transmission processes is introduced; top down (one-way), inter-organizational (bi-lateral), and dispersed (multi-directional). Recent research suggests that organizational changes are often led by the spontaneous concertive action of staff at all levels, not just by senior elite groups. The way in which dispersed influence processes arise, unfold, and are transmitted into organizational outcomes can be understood through theoretical narratives, which capture event sequences and combinations of factors unfolding over time in a given context. Given the scale and pace of the change agenda, healthcare modernization may indeed depend on widely dispersed leadership. PRACTICAL IMPLICATIONS: It is therefore necessary to establish the conditions in which leadership transmission is encouraged, to recognize, support, and develop the "unsung heroes" who assume change leadership positions, and to widen the agenda and coverage of NHS leadership development programmes. ORIGINALITY/VALUE: There is currently no other commentary, empirical or theoretical, academic or professional, which examines critically the concept of leadership transmission, while exploring the nature of this perspective, and its theoretical and practical value. PMID- 17713187 TI - Organizational leadership and its relationship to regional health authority actions to promote health. AB - PURPOSE: The purpose of this paper is to examine organizational leadership and its relationship to regional health authority actions to promote health. DESIGN/METHODOLOGY/APPROACH: Through use of four previously developed measures of Perceived Organizational Leadership for Health Promotion, this paper focused on leadership as a distributed entity within regional health authority (RHA) jurisdictions mandated to address the health of the population in the province of Alberta, Canada. FINDINGS: First, examination of differentials between organizational levels (i.e. board members, n = 30; middle/senior management, n = 58; and service providers, n = 56) on ratings of the four leadership measures revealed significant differences. That is, board members tended to rate leadership components significantly higher than service providers and middle/senior managers: from across all 17 RHAs; and in low health promotion capacity and high health promotion capacity RHAs. Second, regression analyses identified that the leadership measures "Practices for Organizational Learning" and "Wellness Planning" were positively associated with health authority actions on improving population heart health (heart health promotion). The presence of a "Champion for Heart Health Promotion" and the leadership measures "Workplace Milieu" and "Organization Member Development" were also positively associated with health authority actions for health promotion. A subsidiary aim revealed low to moderate positive relationships of the dimensions of Leadership, Infrastructure and Will to Act with one another, as proposed by the Alberta Model on "Organizational Capacity Building for Health Promotion." ORIGINALITY/VALUE: This paper, conducted on the baseline dataset (n = 144) of the "Alberta Heart Health Project's Dissemination Phase", represents a rare effort to examine leadership at a collective organizational level. PMID- 17713188 TI - System characteristics of healthcare organizations conducting successful improvements. AB - PURPOSE: In a previous study, based on a survey to all clinical department and primary care center managers in Sweden, it was concluded that the prevailing general improvement strategy is characterized by: drivers for improvement are staff needs; patients and data are not as important; improvements mainly focus on administrative routines and stress management; improvements are mainly reached, by writing guidelines, and conducting meetings; the majority of managers perceive outcomes from this strategy as successful. The purpose of current research in this paper is to investigate whether there is any other improvement strategy at play in Swedish health care. DESIGN/METHODOLOGY/APPROACH: Data from the study of all Swedish managers were stratified into two populations based on an instrument predicting successful improvement. One population represented organizations with exceptionally high probability of successful imrpovement and remaining organizations represented the general improvement strategy. FINDINGS: The paper finds that organizations with high probability for successful change differed from the comparison population at the p = 0.05 level in many of the surveyed characteristics. They put emphasis on patient focus, measuring outcomes, feedback of data, interorganizational collaboration, learning and knowledge, communication/information, culture, and development of administration and management. Thus these organizations center their attention towards behavioral changes supported by data. PRACTICAL IMPLICATIONS: Organizations predicted to conduct successful improvement apply comprehensive improvement strategies as suggested in the literature. Such actions are part of the Patient Centered Task Alignment strategy and it is suggested that this concept has managerial implications as well, as it might be useful in further studies on improvement work in health care. ORIGINALITY/VALUE: This paper provides empirically based findings on a successful improvement strategy that can aid research-informed policy decisions on organizational improvement strategies. PMID- 17713189 TI - Integrated care pathways: pathways to change in health care? AB - PURPOSE: The purpose of this paper is to demonstrate that, if teams in healthcare focus on the patient using the framework of a care pathway, change can occur without the overt need to "manage" it directly. DESIGN/METHODOLOGY/APPROACH: In this paper the relevant literature is reviewed and it is demonstrated that if this approach is used it also provides a means for addressing difficult professional and organisational issues that are often unresolved in broader projects of organisational change. This is not presented as a panacea or the solution to all change projects, rather the contention here is that it is one means among many that can be used to bring about important changes in practice. FINDINGS: The paper finds that care pathways represent a useful tool, which teams can use to work through the contextual and practical issues involved in changing practice. ORIGINALITY/VALUE: The paper describes the development of integrated care pathways, which can be regarded as a fortunate fusion of managerial and professional concerns. PMID- 17713190 TI - Nurse retention strategies: advice from experienced registered nurses. AB - PURPOSE: The purpose of the paper is to explore the insights of experienced nurses regarding initiatives they believe would effectively retain nurses like themselves in the nursing profession. DESIGN/METHODOLOGY/APPROACH: As part of a qualitative investigation into the perceptions of nurses regarding issues affecting their profession, experienced nurses were asked to describe what retention strategies they would recommend to policy-makers. A total of 16 semi structured interviews were conducted with long-term nurses in a health region in western Canada. FINDINGS: The paper found that seven retention strategies were commonly mentioned by the participants. The qualitative mode of inquiry allowed the nurses to convey the context, attitudes and feelings behind their recommendations. RESEARCH LIMITATIONS/IMPLICATIONS: The work environments and accompanying retention policies experienced by nurses vary widely according to the specific employment context As is typical with qualitative research, the findings of this study cannot be considered as generalizable to all nurses in all health care settings. PRACTICAL IMPLICATIONS: The results of this paper provide a deeper understanding of the attitudes, emotions and contextual issues behind the nurse retention strategies seen as most appropriate by the target audience of long-term nurses. ORIGINALITY/VALUE: While there is much literature advocating the implementation of nurse retention strategies, very little evidence has been presented from a qualitative lens. It is necessary to directly listen to the voices of those impacted by policies in order to better appreciate how such policies are perceived from a bottom-up perspective. PMID- 17713191 TI - Organisational justice and employee perceptions on hospital management. AB - PURPOSE: The purpose to clarify what kind of managerial challenges employees experience regarding organisational justice in hospitals. DESIGN/METHODOLOGY/APPROACH: This exploratory study of 8,971 employees working in 14 hospitals and examines the concept of organisational justice in management with qualitative and quantitative methods. FINDINGS: An inductive content analysis of the comments revealed five integrative frames describing challenges in hospital management at respondents' workplaces. These frames should be regarded as major managerial challenges in hospitals. These findings illustrate important antecedents of organisational justice and suggest that work units tend to share the same perceptions of justice. They also reveal that individually produced comments reflect collective experiences in organisational justice. Further, the results indicate that problems in management and policies are often experienced in a complex way, and people making justice judgements do not separate procedural and interactional factors. RESEARCH LIMITATIONS/IMPLICATIONS: Although the commentators producing qualitative data represented many organisational hierarchy levels, the results should not be generalised to apply to horizontal, informal social relationships. PRACTICAL IMPLICATIONS: This paper gives useful information regarding challenges in human resources management in hospitals. ORIGINALITY/VALUE: The paper suggests that people making fairness judgements do not make a distinction between procedural and interpersonal factors. Instead, they use any information available to judge the righteousness of the management events. This paper serves to guide hospital managers towards a better understanding of the importance of organisational justice and its collective nature. PMID- 17713192 TI - Clarifying concerns about doctors' clinical performance: what is the contribution of assessment by the National Clinical Assessment Service? AB - PURPOSE: The UK National Clinical Assessment Service (NCAS) provides local NHS bodies with advice and support in relation to concerns about individual doctors and dentists and in some cases also conducts a detailed assessment of practitioner performance. The purpose of this paper is to identify the contribution of NCAS performance assessment to clarifying concerns about clinical performance through comparison of concerns suspected at initial referral with those identified at assessment. DESIGN/METHODOLOGY/APPROACH: In the paper a sample of 50 NCAS medical cases, performance issues reported at the point of referral to NCAS and those identified at assessment were grouped into five broad domains (clinical care, behaviour, health, education and training, organisation). Concerns identified at assessment were compared with those reported at referral for each domain of concern. Conclusions and recommendations following assessment were also reviewed. FINDINGS: Within each domain, some concerns noted at referral were confirmed; others were challenged or redefined. In all areas, but particularly in respect of the work environment, new concerns were identified for the first time at assessment. In 20 percent of cases, the concerns identified at referral were not borne out at assessment. In 12 percent of cases the issues revealed at assessment were more serious than anticipated. PRACTICAL IMPLICATIONS: Findings indicate that the NCAS assessment process provides a more accurate and comprehensive "diagnosis" of performance issues, enabling more appropriate recommendations for "treatment" and helping to differentiate between potentially remediable and more fundamental problems. ORIGINALITY/VALUE: There is currently little published evidence about the contribution of this type of performance assessment programme to clarifying performance issues. PMID- 17713193 TI - [Dietary risk assessment for pesticide residues in food of plant origin during the plant protection product's registration process]. AB - One of the main goals of risk assessment during registration of plant protection product is to approve (or not) the proposed Maximum Residue Levels (MRLs) derived from the field trials conducted under Good Agricultural Practice (GAP). Generally, risk assessment at this stage is based on comparison of potential long and short-term dietary intake of given pesticide with two earlier established outputs of hazard characterisation, i.e. Acceptable Daily Intake - ADI and Acute Reference Dose--ARfD. The first estimate of long-term hazard, which overestimates the risk, is comparing the Theoretical Maximum Daily Intake (TMDI) to the ADI of the pesticide. TMDI is based on assumption that all food products consumed over the lifetime of the consumer contain residues at level of MRL. Afterwards, the ADI is compared against International/National Estimated Daily Intake (IEDI/NEDI). I(N)EDI values provide a "best estimate" of dietary intake as they take into account residues in edible portions at level of median residue values from supervised trials. In case of short-term dietary exposure to acute toxic pesticides, the intake is compared to ARfD. The calculation of International/National Estimated Short-Term Intake IESTI/NESTI) requires single day consumption data for the 97.5th percentile for each subgroups of consumers (so called "large portions") together with typical unit weight, and percentage of edible portion for each commodity as well as high, and median residue levels derived from the field trials. Additionally, in intake calculations for commodities with unit weight over 25 g, the variability factor (from 3 to 10) has been introduced, which reflects the possible high deposition of a pesticide on the individual unit, even when the quantified residue level in composite sample is relatively low. PMID- 17713194 TI - [Sudan and other illegal dyes--food adulteration]. AB - As foodstuffs adulterated by illegal dyes, such as Sudan I, II, III IIV, para Red, have appeared on the European Union market, the emergency measures to eliminate this problem have been taken. The illegal dyes are added to dried, ground chilli, curry, curcuma and to palm oil. These products are imported from countries outside the E.U. The adulteration concerns also ready to eat products which contain the ingredients mentioned above. Apart from the adulteration, the presence of illegal dyes in foodstuffs can be a threat to consumer's health. In 2003-2005 three Commission Decisions on emergency measures regarding some products which can contain illegal dyes were published. Since May 2003 to March 2006, 651 notifications on food adulteration by illegal dyes were sent to the RASFF system. As a result of the taken measures, the number of notifications have decreased. The possibility of food adulteration by illegal dyes different from the ones which are used now are considered. This is the reason why the continuation of food control and cooperation between official control authorities and food producers are necessary. PMID- 17713195 TI - [Arsenic, cadmium, lead and mercury in king bolete Boletus edulis and tolerance limits]. AB - In the article are reviewed and discussed available data on arsenic, cadmium, lead and mercury content of the fruiting bodies of king bolete. The values of cadmuim concentration of the fruiting bodies of king bolete collected from the areas unpoluted with metals and metaloids in Poland and other European countries usually are greater than an actual tolerance limits set by E.U. law for 0.2 mg/kg wet weight in cultivated mushrooms. Analogically, as is for cadmium also content of lead to be sometimes greater than tolerance limit of 0.3 mg/kg w.w. set in EU for cultivated mushrooms. The fruiting bodies of king bolete usually are also relatively rich in mercury at concentration much greater when compared to tolerance limit set earlier in Poland (in E.U. there is no tolerance limit for mercury in mushrooms). In the case of cadmium it can bee agreed, that this element content of pooled samples of the fruiting bodies of king bollete collected from unpolluted regions usually will not exceed a value of 20 mg/kg d.m., while at polluted areas will exceed a value of 20 mg/kg d.m. In the case of mercury it can bee agreed, that this element content of pooled samples of the fruiting bodies of king bollete collected from unpolluted regions usually will not exceed a value of 5 mg/kg d.m., while at polluted areas will exceed a value of 5 mg/kg d.m. In the case of lead it can be agreed, that this element content of some percent of pooled samples of the fruiting bodies of king bolete collected from unpoluted regions will sometimes exceed an actual the EU tolerance limit of 0.3 mg/kg w.w. as set only or cultivated mushrooms. In the case of arsenic it can be agreed, that total arsenic contant of some percent of pooled samples of the fruiting bodies of king bolete collected from unpoluted regions will exceed value of 0.50 mg/kg d.m. PMID- 17713196 TI - [A comparison of N-nitrosodimethylamine contents in selected meat products]. AB - Nitrosamines are know as the most potent group of carcinogens. Approximately 300 of these compounds have been tested, and about 90% of them have been found to be carcinogenic in laboratory animals. N-nitrosodimethylamine causes liver cancer, whereas some of tobacco specific nitrosamines causes lung cancer. Volatile N nitrosamines induce tumors in a variety of human organs, including the tongue, esophagus, lung, pancreas, liver, kidney and bladder. They are formed during reaction of secondary or tertiary amino compounds and nitrite or nitrogen oxides. Nitrosamines occurs as contaminants in many foodstuff including food and beverages: beers, cheeses, sausages, smoked and pickled foods. They are formed during frying, smoking and food preserved with pickling salt. These compounds can also be produced in man and other mammals under the acidic conditions in the stomach. The present study was carried out to determine level of N nitrosodimethylamine in selected 13 meat products. The extraction procedure was based on Raoul's method, ie. on two consecutive extraction-concentration step using extrelut and florisil columns. The level of N-nitrosodimethylamine was varied from 0.049 mg/kg to 16.47 mg/kg. The highest level of NDMA was found in smoked sausage. PMID- 17713197 TI - [Macro- and microelements in canned sprats]. AB - The content of macro- and microelements and toxic metals in the most popular canned sprat was described in this paper. The research included the following canned sprat: sprat in tomato, smoked and steamed sprat in oil. The following analyses were carried out: content of calcium, phosphorus, potassium, magnesium, copper, zinc, iron, manganese, chromium, selenium, fluorine, iodine, cadmium, lead, mercury and arsenic. Fluorine, iodine, selenium, and calcium and phosphorous are provided to customer organism in large amount by canned sprat, however canned sprat cannot be considered as a source of copper, chromium, and manganese. On the base of assessment data one canned sprat (weight 170 g) provides to customer organism more than 50% recommended daily intake of calcium and phosphorus, 85-233% fluorine, 62.5% iodine, 43% recommended selenium, more than 25% zinc, about 15% daily intake of magnesium, potassium and iron. It was found that all of the analyzed canned sprat contained relatively low content of cadmium, lead, mercury and arsenic, thus confirming the established safety standards. PMID- 17713198 TI - [Organoleptic analysis of food packaging]. AB - The basic rules for the organoleptic analysis of food contact materials and food packaging and the criteria of their assessment was presented. According to the EU legislation food contact materials can not release their constituents into the food in quantities that can be harmful for the consumers and/or can change the organoleptic characteristics of food. Conformity of food contact materials and food packaging with the regulation for overall and specific migration and organoleptic characteristics should be shown by their performance in relevant tests. The standardised method for the organoleptic analysis of the food contact materials does not exist in the UE. Member States use the own methods published as national standards. For sensory analysis of foreign taste and odour Poland uses the triangle method according to Polish Standard PN-87/O-79114. Some countries use Robinson test according to German Standard DIN 10955. These two tests are basing on the same principle. Food contact materials and food packaging, which give negative results in sensory analysis can not be used in direct contact with food, even though all testing parameters in overall and specific migration were fulfil the requirements for the permissible limits. PMID- 17713199 TI - [Dioxins in agricultural soil of Poland]. AB - Total PCDDs concentration ranged from 6.8 to 41 pg g d.w. and for PCDFs from 3.9 to 19 pg/g d.w. with total toxic equivalency within a range 0.023-5.9 pg TEQ/g d.w. A somewhat elevated concentrations of PCDDs and PCDFs were found in the samples collected from the south of Poland in the vicinity of highly industrialized regions known for former extensive mining industry of hard coal and metallurgy, as well as for regions with high rates of urbanization in central Poland and in the vicinity of the western border of the country. Nevertheless, if consider homologue specific pattern of PCDDs and PCDFs no major differences were noted between spatially scattered sampling sites. In all samples highly chlorinated PCDDs/DFs dominated (12345678-OcCDD, 1234678-HpCDD, 12346789-OcCDF, 1234789-HpCDF, 1234678-HpCDF were found in all investigated soils). Their similar pattern can suggest that formation of these chemicals occur in similar conditions. Energy production and fossil fuel co-fired power boilers, chemical industry, metallurgical industry are probably the main sources in industrial regions, however heating of houses by small stoves and hard coal with added household wastes, and former use of agrochemical formulations consisting byimpurities of PCDD/F may also play important role at rural sites. The particularly elevated concentrations of OcCDF in some samples might be connected to the former production and use of highly chlorinated polychlorinated biphenyl formulation--Chlorofen. PMID- 17713200 TI - Sewage sludge open-air drying affects on keratinolytic, keratinophilic and actidione-resistant fungi. AB - The study was to demonstrate the effect of sewage sludge open-air drying on the quantitative and qualitative composition of keratinolytic/keratinophilic and actidione-resistant fungi. The sludge was being dried for up to thirty days (on average fourteen days) at 25-30'C. The composition of these fungi was determined with the hair baiting method along with the dilution method, using the Wiegand medium supplemented with chloramphenicol (100 mgiL) and actidione (500 mg/L). The open-air drying altered the composition of keratinolytic fungi and considerably increased the population of keratinophilic and actidione-resistant fungi in the sludge. This phenomenon can be explained with that the drying process was associated with slow sludge moisture decrease, sludge laceration due to crumbling and the subsequent improvement of sludge aeration and organic matter biodegradation conditions. A considerable increase of fungal populations can be expected in sludges being dried in drying beds at wastewater treatment plants and in sludge-amended soils. Two sludge opportunistic fungi, i.e. Microsporum gypseum and Pseudallescheria boydii, require special attention from the epidemiological point of view. Sludge land applications may increase the number of these fungi in the environment and the subsequent risk to public health posed by them. PMID- 17713201 TI - [Nutritional knowlegde, lifestyle and food groups intake in the group of the first year students of Agricultural University in Wroclaw]. AB - In this paper, the level of nutritional knowledge, lifestyle and food group intake was assessed in the first year students of Agricultural University in Wroclaw, by using nutritional questionnaire. Generally, the level of knowledge of principles of rational nutrition was particularly low. Inadequate low intake of cereal, milk, meat products, potatoes, fruit and vegetables was noticed in group of women. Too high intake of meat products, eggs and plant fat was observed in the group of men. PMID- 17713202 TI - [Some nutritional habits of pregnant women]. AB - The aim of the project was to evaluate diets of pregnant women. The research, whose tool was a voluntary questionnaire, was undertaken in 2005, among a group of a hundred randomly chosen pregnant women ranging in age from 23 to 32. A great degree of inappropriateness of their diets was revealed: too low intake of vegetables, fruit, dairy produce, proteins. Of all the women surveyed, a low percentage introduced folic acid (27%) and products rich in iron (17%) into their diets. The women stated that they both had limited coffee intake and started drinking milk. PMID- 17713203 TI - Screening of the European Union New Chemicals Database concerning an aquatic exposure threshold of no concern. PMID- 17713204 TI - Mineralization and plant uptake of 14C-labeled nonylphenol, nonylphenol tetraethoxylate, and nonylphenol nonylethoxylate in biosolids/soil systems planted with crested wheatgrass. AB - Microcosm experiments (duration, 150 d) were conducted to evaluate the mineralization and plant uptake of [14C]nonylphenol (NP), [14C]nonylphenol tetraethoxylate (NPE4), and [14C]nonylphenol nonylethoxylate (NPE9) in a soil/biosolids (99.5:0.5 w/w) environment planted with crested wheatgrass (Agropyron cristatum). Three initial nominal concentrations (6, 24, and 47 mg/kg dry wt) each of NP, NPE4, and NPE9 were examined along with unplanted and unplanted poisoned controls. Phenol (22 mg/kg) also was evaluated as a more degradable reference compound. The biosolids were obtained from a municipal treatment plant, and the loamy sand soil was freshly collected. Mineralization ranged from 7% for NP to 53% for phenol, and no enhancement was observed in the planted systems. For NP, NPE4, and NPE9, 14C foliar tissues concentrations were proportional to exposure concentrations but were 10-fold lower than the root concentrations and two- to threefold lower than the soil concentrations. Bioconcentration factors (BCFs) based on 14C measurements ranged from 0.31 (mg compound/kg dry plant/ mg compound/kg dry soil) for systems spiked with NP to 0.52 for systems spiked with NPE9. Results of the NP analysis (initial concentration, 47 mg/ kg) showed a 90% decrease in the soil concentration and an average BCF of 1.0. The lower BCF calculated from the 14C analysis likely resulted from the presence of NP transformation products in the soil that are less available or are translocated by the plants but quantified by the combustion/liquid scintillation counting procedure. PMID- 17713205 TI - Nontarget deposition and losses of oxamyl in surface runoff from flatwoods citrus production areas. AB - Pesticide export from citrus production areas is a concern in the Indian River Lagoon drainage basin (Florida, USA). These studies evaluated nontarget deposition and losses of the insecticide oxamyl from typical flatwoods citrus production areas in South Florida. Deposition was estimated with the use of Teflon spray targets placed across nontarget water furrows during spray applications. After oxamyl applications, surface water runoff events were generated with an overhead irrigation system to simulate relatively low intensity rainfall. Results indicated that 0.3 to 20.0% of the applied active ingredient landed on nontarget water furrow surfaces and that the majority of oxamyl loss occurs in runoff events shortly following application. Mean concentrations were greater during the first runoff events, ranging from 34.7 to 47.0 microg/L. Total losses during the first several hours of each set of runoff events ranged from 0.1 to 3.8% of the total active ingredient applied. Similar losses can be expected when rainfall occurs shortly after application for other pesticides with similar chemical properties and application methods. PMID- 17713206 TI - Identification of potentially toxic compounds in complex extracts of environmental samples using gas chromatography-mass spectrometry and multivariate data analysis. AB - In this study, we examined 31 samples of varying chemical composition, including samples of soils from gasworks, coke production sites, and sites where wood preservatives were heavily used; ash and soot from municipal solid waste incinerators; antiskid sand; and dust from areas with heavy road traffic. The samples were comprehensively chemically characterized, especially their polycyclic aromatic compound contents, using gas chromatography-time-of-flight mass spectrometry, whereas their biological effects were assessed using dehydrogenase activity, root growth (Hordeum vulgare), reproduction of springtails (Folsomia candida), algal growth (Desmodesmus subspicatus), germinability (Sinapis alba), Vibrio fischeri, DR-CALUX, and Ames Salmonella assays. The number of compounds detected in the samples ranged from 123 to 527. Using the multivariate regression technique of partial-least-squares projections to latent structures, it was possible to find individual compounds that exhibited strong correlations with the different biological responses. Some of the results, however, indicate that a broader chemical characterization may be needed to identify all the compounds that may cause the measured biological responses. PMID- 17713207 TI - Synergism between the toxicity of chlorophenols and iron complexes. AB - Synergistic interactions could prove to be relevant when evaluating the toxicity of environmental pollutants in a complex mixture, especially when organic and inorganic substances co-occur at concentrations currently considered to be low toxic or sublethal. Escherichia coli cells (SR-9 strain) were used as a model system for studying the cellular toxicity of environmental pollutants. Exposure of bacterial cells to a combination of pentachlorophenol (PCP) and a positively charged complex of iron or copper caused a dramatic inhibition of growth and an increase in cell death. Incubation of bacterial cells with PCP and either ferric 1,10-phenanthroline complex [Fe3+(OP)3]3+ (500 and 5 microM, respectively) or cupric-1,10-phenanthroline complex [Cu2+(OP)2]2+ (400 and 0.05 microM, respectively) showed two and four log units of cell death, respectively, in 30 min. In contrast, only minor amounts of cell death were observed with each component alone. Similar effects have been shown for other positively charged complexes of transition metals and for other biocides. The observed synergism was associated with the formation of novel noncharged and lipophilic ternary complexes, which contain PCP anions (or other polychlorinated anions) and the iron (or copper) complex. The ternary complexes demonstrated effective transport of their components into the cells. PMID- 17713208 TI - Effects of copper on sulfate reduction in bacterial consortia enriched from metal contaminated and uncontaminated sediments. AB - The effects of copper amendments on bacterial sulfate reduction in enrichment cultures obtained from two types of freshwater sediment were examined. Sulfate reducing bacterial (SRB) consortia were enriched from pond sediment with no known history of metal contamination (uncontaminated) and from reservoir sediment with a well-documented history of metal contamination (metal-contaminated). The rates and extent of sulfate reduction in each sediment type in the absence of added copper were indistinguishable. With amendments of 0.8 mg/L copper, no inhibitory effects on sulfate reduction were observed in either consortium type. At 8.0 mg/L copper, activity in uncontaminated SRB consortia was significantly inhibited, as evidenced by a delay in and decreased rate of sulfate reduction; sulfidogenesis in metal-contaminated consortia was apparently unaffected. When the dissolved copper concentration was 30.0 mg/L, sulfidogenic activity in pond sediment consortia was completely inhibited. The rate of sulfate reduction temporarily decreased in the metal-contaminated enrichments but recovered after a short time. In active microcosms, copper was precipitated as CuS. The results of this study suggest that SRB from metal-contaminated environments have a markedly higher metal tolerance than those enriched from uncontaminated environments. The most significant inference from this work is that metal sulfide formation alone does not explain observed differences in metal tolerance between SRB consortia enriched from uncontaminated sediments and those that are derived from metal contaminated sediments. PMID- 17713209 TI - Using an internal standard method to determine Henry's law constants. AB - An internal standard method is developed for the measurement of thermodynamic Henry's law constants (H). In this method, a mixture of the analytes and an internal standard is prepared and used to make a standard solution (organic solvent) and a dilute aqueous solution. Both the standard solution and the headspace samples above the aqueous solution at partitioning equilibrium in closed containers are subject to gas chromatographic (GC) analysis. Subsequently, the values of H for the analytes can be calculated from the known H of the internal standard and the GC peak-area ratios. Only approximate values of the concentrations of the compounds, the GC injection volumes, and the vapor-phase to liquid-phase volume ratios in the closed containers are needed in this approach. The method works particularly well for compounds that are highly soluble in water or that have low vapor pressures. Experimentally determined values of H are reported for some low-molecular-weight aldehydes, ketones, and nitriles, and their temperature dependencies are examined. The results also are compared with literature values. The applicability of this new approach is limited to compounds that have dimensionless H on the order of 10(-3) or less. PMID- 17713210 TI - Relationship between mutagenicity and reactivity or biodegradability for nitroaromatic compounds. AB - Although many studies have reported that nitroaromatics such as 2,4,6 trinitrotoluene (TNT) have strong mutagenicity, the mechanism of mutagenic activity in these compounds has not yet been reported. We examined the mutagenicity versus reactivity and biodegradation by bacteria using TNT and its analogs (1,3,5-trinitrobenzene [TNB], 2,4,6-trinitroaniline [TNA], 2,4,6-trinitro phenol [TNP], N,2,4,6-tetranitro-N-methyl-aniline [tetryl], 2,4-dinitrotoluene [24DNT], and 2,6-dinitrotoluene [26DNT]). Aromatic compounds harboring three nitro groups (except TNP) have high mutagenicity, judging from the results of the umu test using luminescent bacteria (Salmonella typhimurium strain TA1535/pTL210). Single-electron reduction potentials for these chemicals were 530, -555, -565, -575, -640, -674, and -764 mV for TNA, tetyl, TNT, TNB, 24DNT, 26DNT, and TNP, respectively, indicating that trinitro-aromatics (except TNP) were more reducible than other compounds. Pseudomonas sp. strain TM15, which was isolated from TNT-contaminated soils in the Yamada Green Zone, Kitakyushu City, Japan, could efficiently biotransform TNT, TNB, TNA, and tetryl; 24DNT, 26DNT, and TNP were less biodegradable. This strain converted all TNT analogs into reduction products; nitro groups were reduced to amino groups. We revealed that the mutagenicity of nitroaromatics correlate with reactivity and biodegradability. This finding may contribute to the elucidation of mutagenic expression of nitroaromatic compounds in organisms. PMID- 17713211 TI - Metal-phytoplankton interactions: modeling the effect of competing ions (H+, Ca2+, and Mg2+) on uranium uptake. AB - The influence of pH and hardness cation concentrations on uranium uptake by a green alga, Chlamydomonas reinhardtii, was investigated through short-term exposure experiments. Uranium uptake at pH 5 and at pH 7 was measured over a large concentration range (0.020-2.0 microM 233U), and the effects of hardness cations were studied over environmentally pertinent concentration ranges (approximately 0.05-2 mM) at a constant uranium concentration (0.25 microM). Calcium and magnesium inhibited uranyl uptake, but the influence of pH was more complex than anticipated. The equilibrium biotic ligand paradigm of metal bioavailability predicts that two distinct phenomena of antipathetic effect will influence uranium availability as pH is varied. Increasing pH reduces the concentration of protons, thus reducing competition for the physiologically active sites, whereas the concomitant complexation by carbonates and hydroxides reduces the free uranyl activity. Maximum uranium uptake rates observed at pH 7, however, were far greater than those observed at pH 5, suggesting a noncompetitive inhibition of metal transport by protons. Modeling on the basis of our results strongly suggests that cells grown and exposed at pH 7 have either a greater internalization rate of uranyl or a higher number of transport sites compared with cells grown and exposed at pH 5. We thus conclude that the simple proton-metal competition described by the biotic ligand model cannot successfully depict uranium-algae interactions. The development of an appropriate model incorporating the influence of protons to predict metal uptake and toxicity will be more challenging than anticipated. PMID- 17713212 TI - Bioremediation of benzene, ethylbenzene, and xylenes in groundwater under iron amended, sulfate-reducing conditions. AB - Elevated concentrations of sulfide in groundwater (approximately 63 mg S(2-)/L in water and 500 mg dissolved H2S/L dissipating from the wellhead) at a field site near South Lovedale (OK, USA) were inhibiting the activity of sulfate-reducing bacteria (SRB) that are known to degrade contaminants, including benzene, toluene, ethylbenzene, and xylenes. Elevated concentrations of these contaminants, except for toluene, also were present in this groundwater. Microcosms were established in the laboratory using groundwater and sediment collected from the field site and amended with various nutrient, substrate, and inhibitor treatments. All microcosms initially were amended with FeCl2 to induce FeS precipitation and, thereby, to reduce aqueous sulfide concentrations. Complete removal of benzene, ethylbenzene, and m+p-xylenes (BEX; o-xylene not detected) was observed within 39 d in treatments with various combinations of nutrient and substrate amendments, including treatments with no amendments (other than FeCl2). This indicates that the elevated concentration of sulfide is the only limiting factor to BEX biodegradation at this site under anaerobic conditions and that treating the groundwater with FeCl2 may be a simple remedy to both facilitate and enhance BEX degradation by the indigenous SRB population. PMID- 17713213 TI - Enantiomeric composition of chiral polychlorinated biphenyl atropisomers in dated sediment cores. AB - Enantiomer fractions (EFs) of seven chiral polychlorinated biphenyls (PCBs) were measured in dated sediment cores of Lake Hartwell (SC, USA) and Lake Ontario (USA) to detect, quantify, and gain insight regarding microbial reductive dechlorination of PCBs in lake sediments with high and low concentrations, respectively. Lake Hartwell sediments had high total PCBs (5-60 microg/g), with significantly nonracemic EFs that generally were consistent with those from previous laboratory microcosm reductive dechlorination experiments using sediments from these sites. Thus, stereoselective reductive dechlorination had occurred in situ, including at total PCB concentrations of less than the threshold of approximately 30 to 80 microg/g suggested as being necessary for reductive dechlorination. Enantiomer fractions of PCBs 91, 95, 132, and 136 in Lake Hartwell cores were significantly correlated both with concentrations of those individual congeners and with total PCB concentration for some sites. This result indicates that enantioselective microbial dechlorination activity increases with higher concentrations within sediments for these congeners. Enantiomer composition reversed with depth for PCBs 91, 132, and 176, suggesting that multiple microbial populations may be present within the same core that are enantioselectively dechlorinating PCBs. Such observations indicate that concentration and time are not the only factors affecting biotransformation, complicating prediction of enantioselectivity. Comparison of EFs with dates suggested biotransformation half-lives of approximately 30 years, which is on the same time scale as sequestration by burial. In contrast, Lake Ontario sediments (maximum total PCBs, 400 ng/g) had racemic or near-racemic amounts of most congeners throughout the core profile, which is consistent with achiral indicators suggesting no microbial biotransformation within Lake Ontario sediments. Thresholds for reductive dechlorination may exist, but they would be at concentrations of less than 30 to 80 microg/g. PMID- 17713214 TI - Sorption of male hormones by soils and sediments. AB - This paper reports the sorption of two male hormones, testosterone and androstenedione, by four soil and sediment samples at both equilibrium and rate limiting conditions. Unlike prior studies, androstenedione was studied independently of testosterone. Apparent sorption equilibrium is achieved in one to two weeks when the initial aqueous hormone concentrations (C0) at 10,000 microg/L (approximately 30% of their solubility limits [S(w)]) and two to three weeks when the C(0) is 300 microg/L (less than 1% of S(w)). The Freundlich model parameter n ranged from 0.698 to 0.899 for all soil-solute systems indicating nonlinear sorption isotherms. Isotherm nonlinearity leads to an inverse correlation between single-point organic carbon-normalized sorption distribution coefficients (K(oc)) and equilibrium androgen concentration (C(e)). When C(e)S(w) = 0.012, the log K(oc) values for testosterone and androstenedione on the various sorbents ranged from 6.18 to 6.75 and 6.83 to 6.04, respectively, compared to 6.30 to 6.80 and 6.16 to 6.92 when C(e)/S(w) = 0.004. This study suggests that male hormones may exhibit slow rates of sorption over 14 d or longer and that soils and sediments may have greater sorption distribution coefficients when concentrations fall into the ng/L range. PMID- 17713215 TI - Environmental estrogens suppress hormones, behavior, and reproductive fitness in male fathead minnows. AB - This study explored the possibility that environmental estrogens in sewage effluent may reduce the reproductive fitness of adult male fish by suppressing their reproductive behaviors, including their ability to compete for nests and females. Male fathead minnows (Pimephales promelas) were exposed for three weeks to either blank control, effluent released by a sewage treatment plant (STPE), waterborne estradiol (E2), or a synthetic androgen (methyltestosterone [MT]). Afterward, fish were placed with females and a nest, and their behavior was monitored for 5 d in either the presence or the absence of a competing (unexposed control) male. Males exposed to either the STPE or E2 (approximately 50 ng/L, a level chosen to mimic the estrogenic content of the STPE) had elevated levels of circulating vitellogenin (p < 0.05) and lower levels of 11-ketotestosterone (KT; p < 0.05). Nearly all STPE- and E2-exposed males spawned successfully in the absence of a competing male, but in both cases, exposed males suffered nearly total reproductive failure when they had to compete. Conversely, males exposed to MT (approximately 50 ng/L) outcompeted control males. Behavioral observations suggested that subtle differences in agonistic behaviors, typically associated with circulating androgens (i.e., KT), were responsible. We speculate that male fish exposed to estrogenic effluent in the field are less likely to reproduce successfully within large populations of wild fish, thereby causing abnormal and potentially detrimental patterns of gene flow within those populations. PMID- 17713216 TI - Comparison of the estrogenic activities of seawater extracts from Suruga Bay, Japan, based on chemical analysis or bioassay. AB - The present study compared estrogenicity measured by in vitro bioassay and estrogenicity estimated by the chemical analysis of seawater from Suruga Bay, Japan. Nonylphenol, bisphenol A, estrone, 17beta-estradiol, nonhydroxy polycyclic aromatic hydrocarbons, and hydroxy polycyclic aromatic hydrocarbons, some of which show estrogenic activity, were selected as the target compounds. The yeast two-hybrid system was used to evaluate the estrogenic activities of seawater and chemicals with or without rat liver S9. Concentrations of estrogenic compounds in seawater were measured by chemical analysis using gas chromatography/ mass spectrometry. The main estrogenic compounds in seawater were estrone (< or = 9.2 ng/L), bisphenol A (< or = 1,070 ng/L), and nonylphenol (< or = 276 ng/L). The highest estrogenic activities in seawater were observed near a sewage treatment plant, but the predicted potencies based on the chemistry data were higher than those observed experimentally for the estrogenic activity in seawater. The estrogenicity measured by bioassay was raised considerably after S9 treatment; this observation was limited to the zone of freshwater immediately adjacent to the wastewater outfall. PMID- 17713217 TI - Quantification and associated variability of induced vitellogenin gene transcripts in fathead minnow (Pimephales promelas) by quantitative real-time polymerase chain reaction assay. AB - Ecological risk assessors have a growing need for sensitive and rapid indicators of environmental exposures in aquatic ecosystems resulting from natural and synthetic estrogen-like compounds. Investigators developing subcellular exposure markers in traditional sentinel organisms must be vigilant about inherent variability of analyses, especially regarding regulatory and policy statements. Here, we report a quantitative real-time polymerase chain reaction (QPCR) assay for the detection of vitellogenin transcripts environmentally triggered in fathead minnows (Pimephales promelas). We demonstrate that our QPCR assay exhibits little inter- or intra-assay variability (21.7 and 11.9%, respectively). This method appears to be robust in terms of variability stemming from extrinsic sources, indicating that it may be readily transferable to laboratories having the requisite equipment. Our primary focus in development of this method derived from the observation that transcriptional responses of the vitellogenin gene (vtg) in fathead minnows demonstrated high biological variability between identically treated individuals, even under controlled laboratory conditions (coefficient of variation, > 100%). This variability was not seen in other genes from the same RNA preparations that we examined, suggesting that it is specific to the vitellogenin response. Our data and those of others suggest that variability in vtg expression is common to a number of aquatic vertebrates, which is indicative of genetic causation. Despite a relatively high degree of variability in vtg transcription, this method is sensitive enough to detect exposures of 5.0 ng 17alpha-ethinylestradiol (EE2)/L within 24 h of exposure, and it has the ability to discriminate 10.0 and 5.0 ng EE2/L within 48 h. The vitellogenin QPCR assay is a highly sensitive, comparatively rapid, and inexpensive method for the detection and characterization of exposure to environmental estrogens and estrogen mimics. PMID- 17713218 TI - Flow cytometry as a tool to study phytotoxic modes of action. AB - The objective of the present investigation was to provide a diagnostic tool for the analysis of phytotoxic interactions between environmental contaminants and algae by application of flow cytometry. Therefore, an experimental design was developed consisting of synchronized Scenedesmus vacuolatus cell populations at defined cell-cycle stages, short-term exposure against different inhibitors with known molecular targets, and fluorochrome labeling of different metabolic processes. To discriminate cells with compromised metabolic processes from intact and metabolically inactive cells, references for every fluorochrome were defined using control and heat-treated populations. The experimental results showed that fluorescence markers are able to detect disturbance of specific cellular characteristics, such as membrane integrity, chlorophyll synthesis, and degradation. A differentiation of impacts on specific metabolic process caused by the reference inhibitors in concentration-dependent patterns could be seen using flow-cytometric fluorochrome analysis. These findings were compared with effects observed for N-phenyl-2-naphthylamine (PNA), a sediment contaminant of high phytotoxicity but unclear mode of action. Rhodamine 123 and cyano-ditolyl tetrazolium chloride detected significant metabolic changes for relevant exposures against PNA, thus pointing to compromised mitochondrial activity and changes in membrane potential as causes of phytotoxicity. PMID- 17713219 TI - Heavy metal contamination status of Japanese cranes (Grus japonensis) in east Hokkaido, Japan--extensive mercury pollution. AB - Japanese cranes (Grus japonensis) of eastern Hokkaido, Japan, and migrants between the Amur River basin and the eastern China-Korea Peninsula, live around fresh and brackish wetlands. Only a few thousand cranes are confirmed to exist in the world, so they are under threat of extinction. To understand the adverse effects of metal accumulation, we measured concentrations of three heavy metals in the liver, kidney, and muscle of 93 Japanese cranes from Hokkaido. The cranes were classified into six categories according to their sex and three life stages. Cadmium and mercury (Hg: total mercury) showed age-dependent but not sex dependent accumulation in the liver and kidney. Twenty cranes showed 30 microg/g or higher levels of Hg in dry tissue and five adult cranes had more than 100 microg/g in their livers or kidneys. Cadmium concentrations were generally lower in all samples. Two adult cranes showed extremely high lead levels of more than 30 microg/g in their livers, suggesting lead poisoning. These results have highlighted the widespread and high levels of Hg pollution in Japanese cranes in Hokkaido, Japan. PMID- 17713220 TI - Bioaccumulation and biotransformation of 61 polychlorinated biphenyl and four polybrominated diphenyl ether congeners in juvenile American kestrels (Falco sparverius). AB - This study examined the bioaccumulation and dietary retention of 61 polychlorinated biphenyl (PCB) and four polybrominated diphenyl ether (PBDE) congeners in juvenile American kestrels (Falco sparverius). American kestrels were exposed to contaminants via egg injection and daily gavage dosing over the posthatch-to-fledgling period. Retention factors for PCBs were dependent on chemical hydrophobicity and chlorine substitution patterns and ranged from less than 1 to 16.4% for PCBs having vicinal hydrogen substitutions at meta-, para- carbons on at least one of the phenyl rings and between 13.2 and 81.5% for congeners containing chlorine substitutions at 4,4'-, 3',4,5'-, 3,4',5-, or 3,3',5,5'-positions. These results indicate that juveniles are capable of biotransforming PCBs according to the same structure-activity rules as adults. A toxicokinetic model, initially parameterized using adult toxicokinetic parameters, was used to describe concentration trends in juveniles over time. The adult model overestimated PCB concentrations but provided an adequate fit when elimination rate constants were increased by a factor of 12.7. Retention factors for the PBDE congeners 2,2',4,4'-tetrabromodiphenyl ether (BDE 47), 2,2',4,4',6 pentabromodiphenyl ether (BDE 100), 2,2',4,4',5-pentabromodiphenyl ether (BDE 99), and 2,2',4,4',5,5'-hexabromodiphenyl ether (BDE 153) were from 7.8 to 45.3% of the total dose. The retention of BDE 47 was similar that observed for readily cleared PCBs, whereas the remaining PBDEs exhibited retention factors consistent with those of persistent PCBs. Half-lives for PBDEs in juveniles were estimated to range from 5.6 to 44.7 d. Assuming differences in PBDE toxicokinetics between juveniles and adults similar to those measured for PCBs, adult American kestrel PBDE half-lives are expected to range from 72 to 572 d. PMID- 17713221 TI - Effects of acid-volatile sulfide on metal bioavailability and toxicity to midge (Chironomus tentans) larvae in black shale sediments. AB - Metal bioavailability and toxicity to aquatic organisms are greatly affected by variables such as pH, hardness, organic matter, and sediment acid-volatile sulfide (AVS). Sediment AVS, which reduces metal bioavailability and toxicity by binding and immobilizing metals as insoluble sulfides, has been studied intensely in recent years. Few studies, however, have determined the spatial variability of AVS and its interaction with simultaneously extracted metals (SEM) in sediments containing elevated concentrations of metals resulting from natural geochemical processes, such as weathering of black shales. We collected four sediment samples from each of four headwater bedrock streams in northcentral Arkansa (USA; three black shale-draining streams and one limestone-draining stream). We conducted 10 d acute whole-sediment toxicity tests using the midge Chironomus tentans and performed analyses for AVS, total metals, SEMs, and organic carbon. Most of the sediments from shale-draining streams had similar total metal and SEM concentrations but considerable differences in organic carbon and AVS. Zinc was the leading contributor to the SEM molar sum, averaging between 68 and 74%, whereas lead and cadmium contributed less than 3%. The AVS concentration was very low in all but two samples from one of the shale streams, and the sum of the SEM concentrations was in molar excess of AVS for all shale stream sediments. No significant differences in mean AVS concentrations between sediments collected from shale-draining or limestone-draining sites were noted (p > 0.05). Midge survival and growth in black shale-derived sediments were significantly less (p < 0.001) than that of limestone-derived sediments. On the whole, either SEM alone or SEM-AVS explained the total variation in midge survival and growth about equally well. However, survival and growth were significantly greater (p < 0.05) in the two sediment samples that contained measurable AVS compared with the two sediments from the same stream that contained negligible AVS. PMID- 17713222 TI - Metal uptake by Lolium perenne in contaminated soils using a four-step approach. AB - Most research dealing with soil (solution) speciation and metal uptake by plants has focused on the relationships between a certain bioavailable fraction in the soil and metal uptake by aboveground parts of the plants. Here, a new approach to interpretation of metal uptake is presented that considers four steps: First, the metal concentration in the soil solution is related to the total metal content of the soil. Second, the metal adsorption to the root surface is related to the metal concentration in the soil solution. Third, the metal content in the roots is related to the adsorption of metal ions to the root surface. Fourth, the metal content in the shoots is related to the metal content in the roots. For grass grown on 10 different soils, it is shown that the metal adsorption to the root surface is pH-dependently related to the free or total metal concentration in the soil solution. The metal content in the roots depends linearly on the metal adsorption at the root surface, whereas the metal content in the shoots depends on the metal content in the roots, either linearly (Zn) or reaching a maximum (Cu, Pb, and Cd). For the Ni content in the shoots as a function of the root content, the relation is pH dependent, probably because of the competition effects of Ca. The pH of the soil has to be taken into account when CaCl2 extractions are used as a basis for risk assessment toward plants. PMID- 17713223 TI - Agricultural intensity and landscape structure: influences on the macroinvertebrate assemblages of small streams in northern Germany. AB - The present study aimed to relate aquatic macroinvertebrate community composition to agricultural intensity and landscape structure. A total of 360 streams were investigated within the Aller river basin in northern Germany. The study area is typical of central German arable agricultural regions, but the small streams were of low dilution potential. These streams were characterized for abiotic parameters (including modeled potential for diffuse inputs from agricultural sources) and macroinvertebrate communities, with data collected over a 17-year period. Spray drift potential did not correlate with community composition. In contrast, the relative index of runoff potential (RP) was negatively correlated with various measures of taxonomic richness and abundance. Community composition also was correlated with environmental parameters, including stream width, clay content of sediment, and presence of dead wood in sediment. The abundance of sensitive species decreased significantly during the main period of agrochemical use at sites of high RP but completely recovered by the following spring. Long term decreased taxonomic richness and a shift to ecologically robust species also were observed at sites of high RP. The results suggest that long-term alterations in community measures probably were associated with factors related to runoff input. Nevertheless, the community composition remained reasonably rich and even. Landscape structure also appeared to influence community structure. Abundance of sensitive species remained significantly enhanced, even at sites of high RP, when forested reaches were present in upstream reaches. These probably provided a source of organisms for downstream recolonization and amelioration of effects at high RP. PMID- 17713224 TI - Reducing bioavailability and phytotoxicity of 2,4-dinitrotoluene by sorption on K smectite clay. AB - Smectite clays demonstrate high affinities for nitroaromatics that strongly depend on the exchangeable cation. The K-smectites have high affinities for nitroaromatics, but Ca-smectites do not. Here we evaluate the ability of K smectite to attenuate the bioavailability and hence toxicity of 2,4 dinitrotoluene (2,4-DNT) to the aquatic plant duckweed. In the absence of K smectite, 2,4-DNT was highly toxic to duckweed. Small amounts of K-smectite reduced toxicity substantially, presumably by reducing 2,4-DNT bioavailability via sorption. PMID- 17713225 TI - Mitochondrial control region variation in bank voles (Clethrionomys glareolus) is not related to Chernobyl radiation exposure. AB - Three previous studies at Chernobyl, Ukraine, documented elevated mitochondrial DNA diversity in bank voles (Clethrionomys glareolus) from radioactively contaminated sites. Little evidence was found to link patterns of diversity in contaminated areas to radiation exposure, but the experimental design precluded discriminating among alternative explanations for elevated diversity in exposed groups. Reference sites selected for the studies were relatively distant from contaminated sites and, additionally, were separated from contaminated sites by large river systems; thus, we hypothesized that differences among sites were correlated with geographic isolation rather than with radiation exposure. For the present study, we added three reference sites, which were selected based on minimal radioactive contamination, proximity to contaminated sites, and absence of obvious barriers to dispersal. We hypothesized that neighboring reference sites should exhibit levels and patterns of diversity similar to those of contaminated sites if the previously detected differences were, in fact, caused by geographic isolation. Indeed, levels of diversity in nearby reference sites are comparable to levels in contaminated sites. Additionally, nearby reference sites contain several haplotypes not observed at other study sites. Our results suggest that levels of diversity in contaminated regions are more plausibly explained by ecological and historical factors than by increased mutational pressure resulting from exposure to Chernobyl radiation. PMID- 17713226 TI - Combined use of biomarkers and in situ bioassays in Daphnia magna to monitor environmental hazards of pesticides in the field. AB - The aim of this investigation was to evaluate toxicity effects of pesticides in aquatic invertebrates using in situ bioassays with the local species, Daphnia magna. Investigations were carried out in the Delta del Ebro (northeast Spain) during the main growing season of rice (May-August). Measures of energy consumption (i.e., algal grazing) and of specific biochemical responses (biomarkers) were conducted in individuals transplanted at four stations, including a clean site upstream of the affected area and the three main channels that collect and drain the water from the rice fields into the sea. Seventeen pesticides were analyzed in water by on-line solid-phase extraction-liquid chromatography-tandem mass spectrometry. The results obtained indicated high levels of pesticides in water, with peak values of 487 microg/L for bentazone, 8 microg/L for methyl-4-chlorophenoxyacetic acid, 5 microg/L for propanil, 0.8 microg/L for molinate, and 0.7 microg/L for fenitrothion. Measured biological responses denoted severe effects on grazing rates; a strong inhibition of cholinesterases and carboxylesterases, which are specific biomarkers of organophosphorous and carbamate pesticides; and altered patterns of the antioxidant enzyme catalase and the phase II metabolizing enzyme glutathione S transferase. Correlation analysis with pesticide residue levels converted to toxic units relative to its acute 48-h median lethal concentration of D. magna indicated significant and negative coefficients between the dominant pesticide residues and the observed biological response, thus denoting a clear cause-and effect relationship. The results emphasize the importance of considering specific (biomarkers) as well as more generalized and ecologically related (grazing) in situ responses to identify and evaluate biological effects of environmental contaminants in the field. PMID- 17713227 TI - The dynamics of change. PMID- 17713228 TI - Google's geospatial organizing principle. PMID- 17713230 TI - 3D documents. PMID- 17713229 TI - An immersive musical instrument prototype. PMID- 17713231 TI - Content-based 3D object retrieval. PMID- 17713232 TI - Structural shape prototypes for the automatic classification of 3D objects. PMID- 17713233 TI - Navigation and discovery in 3D CAD repositories. PMID- 17713235 TI - A virtual environment for decision support in ship damage control. PMID- 17713234 TI - Managing complex augmented reality models. PMID- 17713236 TI - Representing interwoven surfaces in 2-1/2D drawings. PMID- 17713237 TI - Climbing longs peak: the steep road to the future of OpenGL. PMID- 17713239 TI - DM programming moves from the Internet to mobile phones for added impact. PMID- 17713238 TI - Understanding and realizing presence in the Presenccia project. PMID- 17713240 TI - New centers aim to provide DM-style, multidisciplinary care to people with ADD/ADHD. PMID- 17713241 TI - Medicaid programs find opportunities for improvement in complex patient populations. PMID- 17713242 TI - Broad-based coalition aims to make chronic disease a top priority for policymakers and presidential candidates. PMID- 17713243 TI - [A medical ultrasonic image filtering method based on morphological reconstruction]. AB - Speckle is the main reason which declines the quality of medical ultrasonic images. In this paper, the initial condition for the Downhill filter, a morphological reconstruction algorithm, is modified and applied in the speckle reduction. Firstly, the initial area and start position as the mark image was determined in the marker image. Then the modified Downhill filter was used in the ultrasonic marker image. The results showed that, in comparison with the other three filters, this modified Downhill filter, while maintaining the integrity of the contour,could reduce the speckle in the regions of cavity efficiently and rapidly. PMID- 17713244 TI - [Numerical simulation on evolution and control of spiral wave in heart]. AB - In this paper, the numerical simulation for evolution and control of spiral waves in 2D cardiac excitable media is performed; it can be represented as modified FitzHugh-Nagumo (FHN) model by selecting suitable parameter values. When the plane wave being cut, the system can evolve into a spiral wave. The excitability of media can produce effect on the stability of spiral wave. When the excitability is greater than the critical value, the spiral wave core and period tend towards infinity and disappear. The drifting ways of spiral wave tip are different (meandering) in various driving frequencies when one spiral wave is driven by uniform periodic small current. When period T is below or above the resonance period of spiral wave, the spiral wave is in its pedaflower or pediflower orbit, and if the driving period precisely equals the resonance period, the spiral wave tip drifts along a straight line. PMID- 17713245 TI - [Method of localization of microelectrode in the globus pallidus during pallidotomy for Parkinson's disease]. AB - Intraoperative analysis of the position of microelectrode in the globus pallidus only depends on experiences and subjective interpretation of microeletrode recording discharge of neurons during pallidotomy for Parkinson's disease. In this paper is reported a method for objective localization of microeletrode during neurosurgery. This method uses the factor of interspike interval based on microelectrode recordings. It is effective for identifying the change of the globus pallidal organism along the microelectrode pathway and the departure or deviation of the needle-pathway. The classification is consistent with the anatomic structures and the results of neurosurgery. This method can be used as a guide in pallidotomy. Globus pallidus. PMID- 17713246 TI - [An experimental study of energy controllable steep pulse in the treatment of rat with subcutaneous transplantive tumor]. AB - This experimental study was designed to investigate the effects and the expressions of microvessel density (MVD), vascular endothelial growth factor (VEGF) on the transplanted tumor in the rat model with Walker-256 after energy controllable steep pulse(ECSP). The experiment revealed that the steep pulse electrical field has better effect on tumor, compared with the control. The positive cell staining intensity of VEGF in the control group was significantly higher than that in ECSP group (P < 0.05). The number of MVD in the tumor tissues of ECSP group was significantly lower than that of tumor control group (P < 0.05). These results showed that ECSP could inhibit the growth and angiogenesis of tumor and its pathway is to down-regulate the expression of VEGF possibly. PMID- 17713248 TI - [Segmentation of ultrasonic medical image based on a symmetric region growing algorithm]. AB - A method based on a symmetric region growing algorithm is presented for the segmentation of ultrasonic medical image. The method divides into three steps. First, according to the characteristic of the ultrasonic medical images, an adaptive weighted median filter is used to suppress speckle noise. Then, scan the digital image from the first row and grow regions from each scanned point by applying the growth criteria and combination criteria until all image pixels have been scanned. Examine the resulting regions using the seed criteria. If any point of a region satisfies the criteria for the region of interest region, assign the region to the resulting segmented image. The effectiveness of this method and a group of growth criteria as well as combination criteria applicable to ultrasonic medical image have been obtained by cardiac ultrasound image segmentation experiments. The experiment result shows that this method is good in the performance of the segmention of cardiac ultrasonic medical image. PMID- 17713247 TI - [Synchronization analysis of ECoG and EHG from eplieptiform discharges rats]. AB - The mechanisms leading to the occurrence of seizures in humans are still poorly understood. It is widely accepted, however, that the process of seizure generation is closely associated with an abnormal synchronization of neurons. In order to investigate this process, we have studied synchronization between different regions of the brain from intracranial EEG recordings of Pilocarpine induced epileptic rat by Synchronization likelihood (SL). It was found that during the state of transition from non-epileptiform discharges to continuous epileptiform discharges, synchronization between left-ECoG and left-EHG was significantly strengthened, and similar change had taken place between right-ECoG and right-EHGd; left-ECoG; and right-ECoG and left-EHG and right-EHG (P < 0.05). During the state of transition from continuous-epileptiform discharges to period epileptiform discharges, the synchronization was significantly weakened between left-ECoG and left-EHG, and similar change was noted between left-EHG and right EHG (P < 0.01). The results showed that SL might be used to assess the dynamics of synchronization and it might be helpful to understanding the mechanisms involving the origin of epileptiform discharge. PMID- 17713249 TI - [Extracting and analyzing rabbit somatosensory evoked potential on the basis of continuous wavelet transform and multi-resolution analysis]. AB - This study was directed at extracting the rabbit somatosensory evoked potential (SEP), locating and analyzing the waveform of rabbit SEP. The rabbit was narcotized and stimulated by 0.5 Hz electric pulse. Potential of scalp was sampled at 3.764 Hz. Rabbit somatosensory evoked potential was extracted by one dimension multi-resolution analysis, and continuous wavelet transform (CWT) was employed to locate and analyze the wave of SEP. The study results showed that Single-trail SEP can be extracted by Daubechies wavelet, when wavelet transform result of single-trail was compared with the result of averaged SEP. Wave component of SEP can be located precisely through the method of continuous wavelet transform. Frequency feature of SEP can also be analyzed by CWT. The technique of continuous wavelet transform, which can project a one-dimension signal into a two-dimension time-frequency space, shows good application prospect of processing medical electronic signal. PMID- 17713250 TI - [The heartbeat modes in modified Ikeda phase resetting model]. AB - In this paper are proposed four heartbeat models which correspond to two different positions of the ectopic pacemaker and two coupling styles of the sinus and ectopic pacemakers. The models computed are based on the modified Ikeda phase resetting model. Most of the heartbeat modes are periodic; they exhibit "Arnold's tongue" structure in parameter plane of perturbing frequency and strength. When the ectopic pacemaker is located in the ventricle, there are bistable dynamic modes. The abnormal hearbeat rhythms of bigeminy and trigeminy in clinical medicine have been observed when coupling strength is weaker in odd resetting or refractory time is longer in even resetting. PMID- 17713251 TI - [SVM-aided cancer diagnosis based on the concentration of the macroelement and microelement in human blood]. AB - Support vector machine (SVM) has shown its excellent learning and generalization ability for the binary classification of real problems and has been extensively employed in many areas. In this paper, SVM, K-Nearest Neighbor, Decision Tree C4.5 and Artificial Neural Network were applied to identify cancer patients and normal individuals using the concentrations of 6 elements including macroelements (Ca, Mg) and microelements (Ba, Cu, Se, Zn) in human blood. It was demonstrated, by using the normalized features instead of the original features, the classification performances can be improved from 91.89% to 95.95%, from 83.78% to 93.24%, and from 90.54% to 94.59% for SVM, K-NN and ANN respectively, whereas that of C4.5 keeps unchangeable. The best average accuracy of SVM with linear dot kernel by using 5-fold cross validation reaches 95.95%, and is superior to those of other classifiers based on K-NN (93.24%), C4.5 (79.73%), and ANN (94.59%). The study suggests that support vector machine is capable of being used as a potential application methodology for SVM-aided clinical cancer diagnosis. PMID- 17713252 TI - [A study of manometry of esophageal varices based on computer vision]. AB - Non-invasive manometry of esophageal varices is a cynosure of researchers. This paper develops a method based on computer vision. Experiments results reveal that correct pressure value can be got quickly. PMID- 17713253 TI - [Multifractal analysis of genomes sequences' CGR graph]. AB - To describe the fractal feature of CGR (Chaos-game representation) graph of genomes sequences, a multifractal theory is presented in the analysis. By studying the effect of three probability sets on the scale invariance range, the probability set with the best scale invariance is chosen, and then the smooth general dimension spectrum and multifractal spectrum are calculated. The experimental result shows that the probability set composed of the relative probability has the best scale-invariance performance. The scale invariance has three different variance regions, which indicate that genomes sequence segments with different lengths have different distribution rules. It is concluded that the multifractal method is effective for describing the fractal feature of CGR graph of genomes sequences. PMID- 17713254 TI - [Research of ventricular late potentials detection based on approximate entropy analysis]. AB - We present an analysis method of electrocardiogram (ECG) to determine patients' ventricular late potentials (VLPs) characteristics by means of wavelet packet transform and entropy (ApEn). The results indicate that the patients with VLPs tend to have higher ApEn values than do those without. So ApEn can be used as an indicator and a BP neural network for distinguishing between the two patient groups. The experiment result shows that this method has higher distinguishability. PMID- 17713255 TI - [A real-time flow velocity estimation applied to ultrasound color display]. AB - In this paper the theory of autocorrelation algorithm for color flow mapping is analyzed and a new way for ultrasound color flow velocity estimation and real time display is proposed. The method sets up a mapping table which directly relates to the dynamic display range and has only 256 entries using an inverse mapping method instead of calculating the arctangent value directly. This method is ideal for software implementation and offers an interactive way to the user for changing the dynamic range of flow velocity and thus to increasing the display resolution. PMID- 17713256 TI - [Treatment of bone defect in hip revision]. AB - To investigate the option of treatments for bone defect in femoral revision after total hip replacement (THR), 29 patients (29 hips) who had undergone hip replacement 13.7 years previously were hospitalized again to undergo revisions. 3 patients were given cement protheses and the other 24 patients were given non cement protheses. In 3 cases were used Synergy+Reflection protheses, and in the others were used CLS +ALLOFIT. All of the patients have got primary healing without early infection symptoms post-operatively. We have been following up 25 cases (25 hips) for 58 months averagely. All the hip joints functioned well. Harris score increased from preoperative 36.8 to postoperative 93.2. In our experience, if there exist significant bone defect in acetabular bone and the coverage of the cup by the graft is more than 80%, bone graft is not needful. If the coverage is between 50% and 80%, bone grains combining bone segment grafts are needful. If the coverage is less than 50%, bone segment grafts be likely to give good effect. In summary, compacted bone grains grafts combining allograft osintegumentale plate could gain satisfactory outcome for femoral bone defect. PMID- 17713257 TI - [Characterization and histocompatibility of acellular bone collagen matrices]. AB - A processing technique has been developed to prepare acellular bone collagen matrix (ABCM) and ABCM-PDLLA composite materials. The properties of these materials were characterized through several different methods. The histocompatibility of the materials were investigated by ELISA (enzyme linked immunosorbent assay) test and healing the defection of New Zealand white rabbit bilateral radius. The spectroscopy indicated that the major inorganic and organic components of the bone blocks were carbonated hydroxyapatite and collagen respectively,and the fatty and cellular components were. completely eliminated. The test results also revealed that the materials had good mechanical property and well-internnected pore structure, and the addition of PDLLA increased the strength of the materials. The ELISA results demonstrated that the materials had low immunogenicity in short order, and the degree of immune response caused by ABCM was greater than that by ABCM-PDLLA. All of the grafts exhibited good osteoconductive ability and a new bone form after the creeping substitution. In conclusion, two kinds of materials with good histocompatibility have been prepared, and owing to its good mechanical performance and low immunogenicity, ABCM-PDLLA is a better candidate for bone substitute and bone tissue engineering scaffold when compared with single ABCM. PMID- 17713258 TI - [Effects of fluid shear stress on bone resorption in rat osteoclasts]. AB - This study was aimed to assess the effects of fluid shear stress on the bone resorption in rat osteoclasts. The osteoclasts were derived from the lumbar vertebrae marrow cells which were isolated from the 6-month-old female Sprague Dawley rats, cultured on the slide at 1 x 10(6) cell/ml, and induced with 1, 25 (OH)2 Dihydroxyvitamin D3. The slide containing osteoclasts was taken out on day 7 after culture and then put into the flow chamber. The loads of fluid shear stress applied to the osteoclasts were 5.97, 11.36, 16.08 and 20.54 dyne/cm2, respectively, for 30 minutes. The osteoclasts unloading fluid shear stress were used as control. The bone resorptive pits were studied by light microscopy and scanning electron microscopy. The tartrate-resistant acid phosphatase (TRAP) secreted by osteoclasts was detected with ultraviolet spectrophotometry. The results showed that fluid shear stress can increase the activity of TRAP and significantly increase the number and area of bone resorptive pits made by osteoclasts,and the effect of fluid shear stress on the bone resorption of osteoclasts is the same as that on the activity of TRAP. The reaction of the osteoclasts to the fluid shear stress in this study also suggested that the bone resorption of osteoclasts be increased in a magnitude of fluid shear stress dependent manner, and that the changes of TRAP activity be closely related to the changes of the number and area of resorptive pits of the osteoclasts. PMID- 17713259 TI - [Finite element method and computational fluid dynamics used in the analysis of a stent]. AB - Stent implantation can cause thrombus, vessel injury and blood flow disturbance which are considered as the main causes of instent restenosis. In order to investigate the influence of stent implantation on vessel wall and blood flow, we used finite element method (FEM) and computational fluid dynamics (CFD) in this work. The results showed that the implantation of the stent could cause vessel injury and flow stagnation. The instant recoil of the implanted stent is much more than that of the stent itself (12.3% versus 3.1%). In conclusion, FEM and CFD can help illustrate and quantify some biomechanical characteristics for the optimization of stent design. PMID- 17713260 TI - [3D finite element analysis of bone stress around distally osseointegrated implant for artificial limb attachment]. AB - Using the CT data, we have constructed the finite element models of human femur distally amputated at high-position, middle-position and low-position, along with distally osseointegrated implant under the maximal load during a normal walking cycle. Results of finite element analysis revealed: the maximal stress of implant is produced near the exit of the amputated limb, where the fatigue breakpoint caused by cyclic stress would take place. With the ascending of truncated position, the peri-implant interfacial stress of bone increases. There is severe stress-shielding at the bone-implant interface, and there is concentration of stress at the end of implant and at the 3/4 point of femur, which would lead to bone loss and bone resorption and would shorten the longevity of implant. The results also showed that the curvature of natural bone has notable effect on the stress distribution, which should not be neglected. These data may provide reliable reference for the design and research of osseointegarted artificial limb. PMID- 17713261 TI - [Design and construction of pulsatile-flow-cultivation system for the tissue engineering heart valve]. AB - A plane, three-dimensional chamber of pulsatile-flow-cultivation and the liquid store chamber connected by medical silica gel tube were designed and constructed by ourselves according to the design principle. The rotator pump of cardiopulmonary bypass unit was acted as the power source. The mixed gas containing 5% CO2 and 95% air was supplied through the ventilation orifice of the liquid store chamber. The temperature of these components was stabilized by thermostatic waterbath. The test of biomechanics and biological compatibility for the system was carried out by cultures experiment during two weeks. The results of the experiment showed that there was no leak in the pulsatile-flow-cultivation components in which the concentration of CO2 was controlled about 5%+1%, the temperature at 37 +/- 1 degree C, and the value of pH between 6.8 and 7.5. The flow rate of the system could be adjusted exactly between 0.125 L/min and 6.0 L/min. The endothelial cells on the viable homograft valve increased about 10 times after being cultured for 2 weeks. The cultures of cell and mould taken from the leaf and Dacron cloth of homograft valve were reported to be negative. The results of the experiment demonstrated that there was satisfactory homeostasis of these components in effective modeling pulsatile-flow-field for the implantation cells cultured, proliferated, and remodeled under the condition inferior or superior to physiological level in vitro. The system can meet the need for study of pulsatile-flow-cultivation and tissue engineering heart valve constructed in vitro. PMID- 17713262 TI - [Biomechanical evaluation on the primary stability of cervical spine instrumented with aliform type cervical intervertebral fusion cage]. AB - We sought to test the primary stability offered by aliform cervical intervertebral fusion cage (ACIFC) and to evaluate its biomechanical effect. The anterior cervical spinal fusion procedures with ACIFC were simulated in ABAQUS software. The angular range of motion (ROM) and the stress distribution were quantified to assess the primary stability and the biomechanical relation of the cervical spines. The ROM decreased by 25y and when it was compared with the noninstrumented, a significant difference was seen (P < 0.01). As the ACIFC has the function of pullout resistance and provides good environment for spinal fusion, it can supply enough primary stability for the anterior cervical spinal fusion. PMID- 17713263 TI - [A mathematical model of 3-dimensional excursive movement of the mandible on Hanau articulator]. AB - Aiming at filling the vacancy in the study about mandibular movement, which mainly focuses on the field of biology at present, this study builds a mathematical model of 3-dimensional excursive movement of the mandible on Hanau articulator from the viewpoint of spatial mechanisms and analytical geometry. On the basis of the theory of spatial mechanisms, the freedom of motion of Hanau articulator is analyzed, and a hypothesis of constraints is presented, the objective of which is to restrict the mandibular movement. Based on the theory of analytical geometry, a series of mathematical expressions are derived to describe the 3-dimensional movement of the mandible mounted on the articulator. With the geometrical parameters of the articulator, these mathematical equations are solved by programming in Matlab 6.5 (a language for technical computing) and VC + +6.0. Therefore, the spatial path of the arbitrary point on the mandible can be precisely described when the upper body of Hanau articulator is guided along a specific direction. This study proves that the included angle between the plane of orientation and occlusal plane is positively related to the inclination of condylar guidance and incisal guidance, therefore, provides a theoretical foundation for Hanau's laws of articulation and the Hanau Quint. The future of dentistry is basically connected with the use of computer technology. This study will be useful for the further research of the dynamic occlusion to improve dental restorative procedures by realizing future replacement of the mechanical articulator with a virtual one. PMID- 17713264 TI - [Effects of defibrillation in the multiple-lead cardiac defibrillation systems on left ventricular function in animal model]. AB - This study evaluates the immediate effects of the endocardial electrical defibrillation delivered by two transvenous defibrillation systems on left ventricular (LV) function in the animal model. Automatic cardiac defibrillation systems with bipolar leads (group I) and tripolar leads (group II) were placed in the hearts of 10 dogs (group I) and 10 pigs (group II),respectively. Transesophageal echocardiography with two dimensional image, M-mode and pulse Doppler were performed at baseline and after several episodes of defibrillation (DF). Each animal in group 1 underwent 4 DF with 64 Joules; the animals in group2 underwent an average of 8 DF with a total of 210 Joules. LV fractional area contraction, isovolumic relaxation time, and both ratios of velocities and time velocity integrals in transmitral Doppler flow E and A waves exhibited no significant change after the shocks. This study suggests that the repeated low energy electrical countershocks delivered by two transvenous defibrillation systems do ndt cause LV global systolic and/or diastolic dysfunction. PMID- 17713265 TI - [Preparation and characterization of quantum dots-peptides bioconjugations and their specificity related to recognizing tumor cells]. AB - Water-soluble CdTe quantum dots synthesized in aqueous solution have been conjugated with peptide LyP-1 using N-Succinimidyl 3-[2-pyridyldithio]-propionate (SPDP) as a cross-linking reagent. Capillary electrophoresis (CE), UV-Vis absorption and photoluminescent (PL) spectra suggested that the peptide had been successfully linked to the QDs. The QDs-peptides conjugates could specifically recognize the lung adenoma cancer cells (SPCA-1), but did not recognize promyelocytic leukemia cells (HL-60). PMID- 17713266 TI - [The degradation performance of chitin short fiber reinforced polycaprolactone composite in vitro]. AB - We have investigated the degradation of pure Polycaprolactone (PurePCL) and chitin short fiber reinforced Polycaprolactone composite (SFRP) in vitro in order to provide useful scientific basis for clinical application. PurePCL, SFRP and DL PLA were immersed in 0.9% NaCL solution for periods of 2, 4, 8, 12, 16 and 24 weeks. Then pH values in immersing solution, weight loss and mechanical properties of tested materials were measured and SEM was used to study the change of the materials in the process of degradation. It was shown that the initial strength of SFRP was much higher than that of PurePCL. In the process of degradation of SFRP, the pH values maintained weak acid or remianed neutral. The rate of weight loss of SFRP was faster than that of PurePCL, but slower than that of DL-PLA. The strength and modulus of SFRP did not change much in 24 weeks, compared with the initial ones. In conclusion, the composites have excellent properties and may be optimal for clinical use in reconstruction of chest wall defects as well as in internal fixation of bone fracture. PMID- 17713267 TI - [Effect of proteins pre-coating on bone marrow mesenchymal cells retention and proliferation on decellular bovine pericardium]. AB - To observe the growth of rat bone marrow mesenchymal cells (BMMCs) on decellular bovine pericardia in vitro and to investigate the effect of proteins pre-coating on cells retention and proliferation, bovine pericardia were decellularized using trypsin, DNase and Triton X-100 respectively. Then three proteins (fibronetin (FN), gelatin, collagen I) were coated on the surfaces of the bovine pericardia separately. BMMCs were harvested from rat thighbone marrow , then expanded and seeded onto decellular bovine pericardia with the proteins pre-coated . Decelluar bovine pericardia without coating were used as controls. The retention and growth of BMMSCs were observed by Hochest staining and analyzed by MTT method. It was shown that the retention and proliferation of BMMCs on FN group and gelatin group were significantly enhanced comparing with those on collagen I group and control group (P < 0.001). There was no significant difference between FN group and gelatin group (P > 0.05), nor between collagen I group and control group (P > 0.05). We conclude that the retention and proliferation of seeding cells on FN and gelatin could be significantly improved on decellular bovine pericardia (DBP) but not on collagen I. PMID- 17713268 TI - [Experiment and analyse on the effect of magnetic nanoparticles upon relaxation time of proton in molecular recognition by MRI]. AB - To research on the effect of three different magnetic nanoparticles upon relaxation time of proton. The detection by magnetic resonance imaging (MRI) indicates that there is the effect of marked difference to right control experiment and to analyze the difference from theory. The result discloses that will be able to perform the experiment of molecular recognition using magnetic nanoparticles later. PMID- 17713269 TI - [Synthesis and properties of poly(hydroxyethyl methacrylate) hydrogel for IOL materials]. AB - Poly (hydroxyethyl methacrylate) (PHEMA) hydrogel for intraocular lens (IOL) materials was synthesized by solution polymerization using 2-hydroxyethyl methacrylate (HEMA) as raw material, ammonium persulfate and sodium pyrosulfite (KPS/SMBS) as catalyst, and trietyleneglycole dimethacrylate (TEGDMA) as cross linking additive. Effects of reaction time, temperature, dosage of catalyst and cross-linking additive on mechanical strength and the equilibrium water content (EWC) of the PHEMA hydrogel were systematically investigated and their structure and optical property were also characterized. The experimental results showed that the optimum conditions for preparing PHEMA hydrogel are: catalyst 0.5 wt%, cross-linking additive 1.0 wt%, reaction temperature 40 degrees C, reaction time 36 h. Under the optimum conditions, the tensile strength of PHEMA hydrogel prepared is as high as 0.57 MPa, hardness of Shore A is 23.0, EWC is over 40%, and light transmittance is over 97%. PMID- 17713270 TI - [Pilot study of a cell membrane like biomimetic drug-eluting coronary stent]. AB - A novel bioinspired phospholipid copolymer has been synthesized by the radical polymerization of poly2-Methacryloyloxyethylphosphorylcholine (MPC), stearyl methacrylate (SMA), hydroxypropyl methacrylate (HPMA) and trimethoxysilylpropyl methacrylate (TSMA). Contact angle results indicated that the coating surface rearranged to get a more hydrophilic surface at the polymer/water interface. The membrane mimic phosphorylcholine coating surface could resist the platelet adhesion and prolong plasma recalcification time significantly. Rapamycin was used as model drugs to prepare drug-eluting coating. The animal experiments showed that this novel drug-eluting stent could effectively prevent the phenomena of restenosis. PMID- 17713271 TI - [The drug release properties of poly (acrylamide-co-itaconate vinylbenzylglycosylallylamide) hydrogels]. AB - Sugar-containing monomer vinylbenzylglycosylallyamide (VBG) was synthesized by vinylbenzyl amine and delta-gluconolactone in dimethylformamide(DMF) solution. The sugar-based hydrogel was prepared by free radical crosslinking copolymerization of VBG, itaconic acid (IA) and acrylamide (AM). The release properties of Aspirin from xerogels matrices and from hydrogel in different pH solutions and different concentration NaCl solutions were studied respectively. The release mechanism of Aspirin was further confirmed by evaluating the n value in Peppas equation. The results indicated that the drug release increased with the increase of pH values and with the decrease of NaCl concentration. PMID- 17713272 TI - [Studies on the morphology and structure of electrospun poly (3 hydroxybutyrate)/soya protein isolates fibers]. AB - Ultra-fine Poly(3-hydroxybutyrate)/soya protein isolates fibers were prepared via electrospinning technique. The structure and morphology of the electrospun fibers were determined by scanning electron microscope (SEM), thermal analysis (DSC-TGA) and optical micrographs. The effects of melt stability, concentration,electrical potential and the distance between the spinning tip and the collector upon the morphology of electrospun fibers were also discussed. The results showed that glycerin was surface active agent in the melt PHB/soya protein blends. It was also found that electrospinning process promotes the crystallation ,which may be caused by the orientation of molecule chains due to electrical force stretching. PMID- 17713273 TI - [Application of fibrin glue in facial nerve repair]. AB - This animal experiment was aimed to apply fibrin in facial nerve repair and to quest for technical improvements in facial surgery. In each of 15 healthy large ear white rabbits, a unilateral 5 mm intratemporal facial nerve gap was created, the proximal and distal stumps were inserted into chitin tube, 1 ml autologous fibrin glue was applied around the anastomotic zone, and no suture was employed. At 3 months and 5 months after opertion, electrophysioligical study was performed. Compared with normal nerves, the regenerating nerves in both the chitin tube bridged group and the perineurium suture group had longer incubation period, lower amplitude, slower nerve-muscle conduction velocity at 3 months postoperatively. The differences were distinctly significant (P < 0.01). Although being decreased at 5 months after operation, the differences were still statistically significant (P < 0.05). There were no significant differences between the chitin tube bridged group and perineurium suture group at 3 months and 5 months, respectively. The study suggests that facial nerve repair using fibrin glue and chitin tube has the advantages of being easier,faster and more stable. PMID- 17713274 TI - [Posterior atlantoaxial fixation using vertex multiaxial screw system]. AB - This study aims to assess the effectiveness and advantages of Vertex multiaxial screw system in use for stabilizing the atlanto-axial junction. The entry point of the atlas was located 18-20 mm lateral to the midline and 2.0 mm superior to the inferior border of posterior arch, and the direction of screw was chosen to be about 10 degrees medial to the sagittal plane and about 5 degrees cephalad to the transverse plane. In odontoid vertebra (C2), the direction of the drill bit was guided directly by the medial and superior aspect of the individual C2 pedicle. All screws were placed properly without incidence of nerve or blood vessel injury, and no complication appeared in operation and after surgery. All cases were followed up for an average of 9 months, all cases achieved well reposition and fixation of atlantoaxial joint, average JOA grade was 9.6 before preoperation and 15.9 after operation. Fixation of the atlantoaxial complex using Vertex multiaxial screw system seemed to be a reliable technique and should be considered a good alternative in atlantoaxial fusion. The technique could be used in young patiens. PMID- 17713275 TI - [Expression and purification of recombinant human cytochrome C in Escherichia coli]. AB - Cytochrome C plays important roles in electron transferring, oxidative stress and apoptosis. In this study, soluble cytochrome C was accumulated in cytoplasm of E. coli by utilizing the co-expression of human cytochrome c and yeast heme lyase from a single plasmid. After ultrasonic disruption of the bacteria, a lot of contaminated proteins were discarded by addition of 350 g/L ammonium sulfate into the supernatant. Then the recombinant human cytochrome C was purified to 80% homogeneity after two times cation exchange chromatography on SP-Sepharose Fast Flow. Yields of cytochrome C greater than 10 mg per liter culture were attained. This efficient system for producing human cytochrome C is helpful for us to understand the roles of this protein in biological processes and therapy of human diseases relevant to apoptosis and oxidative stress. PMID- 17713276 TI - [The killing effect of focused ultrsound activating protoporphyrin IX on S180 cells]. AB - The killing effect on S180 cells was studied using the combination of protoporphyrin IX and focused ultrasound at the frequency of 2.2 MHz and different intensities. Cell viability was determined by trypan blue exclusion test, morphology changes were evaluated by means of scanning electron microscopy and transmission electron microscopy after ultrasonic exposure. The results indicated that protoporphyrin IX(PPIX) alone showed no significant effect on S180 cells when compared with that of control group. Ultrasound alone and ultrasound combined with PPIX groups showed some anti-tumor effect, which became more noticeable as the ultrasound intensity and PPIX concentration increased, and when the concentration of PPIX increased to 120 microM, the ultrasound combined with PPIX exerted a more significant anti-tumor effect than did the ultrasound alone in the same experiment. PMID- 17713277 TI - [The effect of CPAP on the structure and function of upper airway of mini pig with OSAS]. AB - This study sought to assess the effect of CPAP on the structure and function of upper airway of mini pig with OSAS induced by altitude hypoxia. 12 adult male mini pigs were randomly assigned to 2 groups, named A and B. The mini pigs in group A were treated with altitude hypoxia 6 h per day for 22 days, and then with CPAP 6 h per day for 30 days. The mini pigs in group B were treated with altitude hypoxia only. Pharyngeal CT scanning and respiratory pressure testing were performed after the treatments . At last all mini pigs were sacrificed and their pharyngeal tissue was acquired for pathological examination. Result of pharyngeal CT scanning showed that, in group A, both of transverse diameters of pharyngeal cave in anterior and posterior areas of hyoid bone increased significantly after CPAP treatment (P < 0.05), while the pharyngeal longitudinal diameters exhibited no significant change (P > 0.05). The thickness of pharyngeal posterior wall of the anterior areas of hyoid bone increased significantly (P < 0.05) after CPAP, while the thickness of the lateral wall displayed no significant change. The pharyngeal longitudinal diameters of group A after CPAP were shorter than those of group B, and the transverse diameters were longer than those of group B, but these differences were not statistically significant (P > 0.05). The pharyngeal posterior walls in soft palate area and anterior area of hyoid bone after CPAP were significantly thicker than those of group B (P < 0.05), but there were no significant differences between the two groups as far as lateral wall thickness was concerned (P > 0.05). After CPAP treatment, the pharyngeal inspiration pressure in group A decreased significantly (P < 0.05), and the pressure was significantly lower than that of group B. Microscopic findings showed that the epithelium was proliferated partly after CPAP treatment. The muscle fibers of group A became fatter and were arranged disorderly with unclear transverse striation. The dropsied and congestive subcutaneous tissues were also infiltrated with inflammatory cells. These pathological changes were more obvious in group B. The results suggested that CPAP treatment could normalize the structure and function of pharyngeal tissue in OSAS mini pigs. PMID- 17713278 TI - [Construction and expression of the prokaryotic expression vector of MTB cfpl0 esat6 fusion gene]. AB - To begin with, we constructed cfp10-esat6 fusion gene and its prokaryotic expression vector and had it express in E. coli. By GeneSOEing techniques, a fusion gene was constructed by splicing cfpl0 gene and esat6 gene, and then was cloned into pGEX-4T-1 plasmid. Secondly, we constructed the prokaryotic expression recombinant plasmid pGcfp10-esat6. After identification with restriction enzyme analysis, PCR and nucleotide sequencing analysis, The E. coli BL21 containing the recombinant plasmid was induced by IPTG (Isopropy-beta-D thiogalatoside). The fusion protein CFP10-ESAT6 with GST-tag about 42 kDa was expressed and purified with GST-fusion protein purification kit,The expression of cfp10-esat6 fusion gene was subsequently detected by SDS-polyacrylamine gel electrophoresis and Western-blot analysis. The sequence of cfp10 and esat6 in recombinant plasmid was consistent with that of GenBank report. The fusion protein existed in cytoplasm in soluble form and represented about 40% total bacterial protein of E. coil. The fusion protein was purified and the purity reached 90%. Its antigenicity was confirmed by Western-blotting. The prokaryotic expression vector (pGcfp1o-esat6) was constructed successfully, and the fusion protein CFP10-ESAT6 was obtained. This study provided an experimental basis for potential application of the recombinant CFP10-ESAT6 in the diagnosis of tuberculosis. PMID- 17713279 TI - [Adipogenic potential of bone marrow mesenchymal stem cells derived from ovariectomized rats]. AB - In order to study the effect of ovariectomy on the capacity of rat MSCs' differentiation into adipocytes, we established the animal models of osteoporosis by performing ovariectomy on the 3-months-old and 6-month-old female SD rats. Then MSCs were isolated from these rats by means of the density-gradient centrifugation method. After adipogenic induction (ADI), lipid droplets were detected by oil red O staining, and the mRNA level of lipoprotein lipase(LPL) was measured by RT-PCR assay. The experiments included 8 groups: (1) MSCs from 3 month-old rats (MSCs 3control); (2) MSCs from 3-month-old ovariectomized rats (MSCs 3ovx); (3) MSCs from 6-month-old rats (MSCs 6control); (4) MSCs from 6 month-old ovariectomized rats (MSCs 6ovx); (5) MSCs from 3-month-old rats with ADI (MSCs ADI 3control); (6) MSCs from 3-month-old ovariectomized rats with ADI (MSCs ADI 3ovx); (7) MSCs from 6-month-old rats with ADI (MSCs ADI 6control); 8) MSCs from 6-month-old ovariectomied rats with ADI (MSCs ADI 6ovx). The results showed that the number of lipid droplets and expression level of LPL mRNA in MSCs ADI 3ovx and MSCs ADI 6ovx were higher than those in MSCs ADI 3control and MSCs ADI 6control, respectively; that the number of lipid droplets and expression level of LPL mRNA in MSCs ADI 6control were higher than those in MSCs ADI 3control respectively. The results of this study suggested that the adipogenic potential of MSCs from both aged and ovariectomied osteoporotic rats were augmented. PMID- 17713280 TI - [The intervention effect of traditional Chinese medicine on meningeal nuclear factor expression of rats suffering from migraine]. AB - This animal experiment was made to probe into the mechanism by which traditional Chinese medicine interferes with the meningeal nuclear factor of rats suffering from migraine. The adult SD rats were selected, and the Cristina Tassorelli method was adopted for the preparation of the migraine models, which were classified into the normal group, model group and traditional Chinese medicine group respectively, and the latter two groups were further divided, in terms of intervals, into 0.5 h, 1.5 h, 2.5 h and 4 h groups, with the model group as control. Real-time quantitative RT-PCR technology was employed to test and measure the gene expression of meningeal nuclear factor of rats. The results showed that when the level of NF-kappaB mRNA expression in the model group was compared with that in 0.5 h group, 1.5 h group and 2.5 h group, there was no significant difference (P > 0.05), but when compared with that in the 4h group, there was significant difference (P < 0.05). Intervention by traditional Chinese medicine in the gene expression of meningeal nuclear factor of model rats suffering from migraine can restrain at different degree the expression of abnormally increasing miningeal nuclear factor NF-kappaB mRNA, which suggests that the intervention by traditional Chinese medicine may enable improvement and treatment of the obstacle of the constriction and dilation system of cerebral blood vessels through restraining excessive expression of meningeal NF-kappaB genes. This conclusion could serve as a theoretical basis for developing traditional Chinese medicine, which takes the NF-kappaB as the target point and the treatment time window, and have underpins an objective approach to the clinical treatment of migraine. PMID- 17713281 TI - [A primary study using the method of average positive stained area percentage to measure the immunohistochemistry results]. AB - With the help of computer image analysis system, we used the method of average positive stained area percentage APSAP to evaluate the slice immunohistochemistry result. Then we compared the evaluation result with the result of manual counting. Conformity between the two methods was verified. These data indicated that the method of was in accord with manual counting to a great extent. Moreover, the theory basis, advantages and disadvantages of the method were discussed in this paper. PMID- 17713282 TI - [Association between polymorphisms of HIF-1alpha C1772T and G1790A and hypoxic acclimation in high altitude in Tibetans]. AB - In this study the blood sample was collected from eighty-six athletes in Tibetan mountaining team and Tibetan mountaining sports school and ninety healthy Han nationality people in Guangdong province, and genomic DNA was extracted from peripheral leukocyte. The allele frequency distribution and the genotypes combination distribution of hypoxia-inducible factor-la gene (HIF-1alpha)exonl2 C1772T and G1790A were examined by restriction fragment length polymorphism PCR (PCR-RFLP) in order to evaluate the association of single nucleotide polymorphisms (SNPs) of HIF-1alpha C1772T and G1790A with hypoxic acclimation in high altitude in Tibetans. The results indicated that the genotype frequency of HIF-1alpha C1772T in Tibetan and in Han nationality was 13.95% versus 16.67% in genotype CC, 38.37% versus 41.11% in genotype CT and 47.68% versus 42.22% in genotype TT. No significant difference in CC, CT and TT genotype frequency of HIF 1alphaC1772T was shown between Tibetans and Han nationality respectively, while GA genotype frequency of HIF-la G1790A in Tibetans was higher than that in Han nationality. The GA genotype of HIF-1alpha G1790A may be involved in the hypoxic acclimation of high altitude , and it is worth of deep-going investigation. PMID- 17713283 TI - [Construction and expression of anti-GD2/anti-CD16 single-chain bispecific antibody]. AB - This study sought to construct a recombinant vector that expresses anti-GD2/anti CD16 bispecific single-chain antibody(sc-BsAb), and to assess its biological activities. The anti-GD2 gene and the anti-CD16 gene (NM3E2) were obtained using PCR amplification technique, and then the fusion gene was constructed by overlapping PCR. The sc-BsAb gene was subcloned into the pET-22b(+) plasmid from the pMD18-T easy vector by digestion with NcoI, Hind III restriction endonucleases, whose sites exist in both the vectors. Then the combinant plasmids were transferred into E. coli BL21 (DE3). The expression product in the periplasmic was analyzed by both SDS-PAGE and Western blot technique, then was purified with Ni2+ -NTA superflow affinity chromatography. It was demonstrated that the linker in the sc-BsAb fusion protein is SerGly4Ser. and the molecular is 53 KD. PMID- 17713284 TI - [Recommendation of a highly sensitive method for measuring hemoglobin in hemolytic test]. AB - In this paper is recommended a highly sensitive and reagent-safe method to determine plasma heamoglobin (FHb) in viscacha hemolytic test. The 2,4 dichlorophenol method (2,4-DCP) of Trinder reaction has been improved. The performance of 2,4-DCP is verified. The sensitivity of 2,4-DCP is 2.39 times that of phenol method. It is well used with run precision and day-to-day precision. The reaction color is stable. The reference value FHb is 1-36.7 mg/L. Sodium citric is an excellent anticoagulant liquid to keep erythrocyte. The 2,4-DCP method is neither carcinogenic nor poisonous;it is suitable for viscacha hemolytic test in clinical and biomedical engineering. PMID- 17713285 TI - [Comparison between gene therapy and gradual release carrier for bone morphogenetic protein-2 in repairing bone defects]. AB - To compare the effects between gene therapy and gradual release carrier for bone morphogenetic protein-2 (BMP-2) in repairing bone defects, bone defects for 15 mm were created.on the bilateral radius in rabbits and treated with four kinds of implantations, ie, composite of transgeneic MSCs and PLA/PCL (Group A), composite of MSCs and gradual release carrier for BMP-2 (Group B), composite of MSCs and PLA/PCL (Group C), and PLA/PCL alone (Group D). After 4, 8, and 12 weeks of the operations, X-ray, histological examination, biomechanics analysis, and bone density measurement were conducted. Results showed that both osteoblasts and mesenchymal cells displayed strongly positive expression of BMP-2 in Group A after 4 weeks of the operation, the speed and quality of bone formation in Group A were much better than those in Group B. After 12 weeks of the operations, bone defects were completely repaired in Group A. BMP-2 gene therapy is really a good method to repair segmental bone defects. PMID- 17713286 TI - [Parameter optimization of body surface laplacian electrodes in bioelectricity detection]. AB - In this article, some details about the parameter optimization of body surface Laplacian electrodes are presented theoretically and practically. The influence of these parameters on the performance of the electrodes is studied to derive some rules which have to be obeyed during the design. An evaluation routine based on relative error analysis and the noise level of amplifier is prompted. Furthermore, the paper particularly indicates that, it would be helpful to reduce the relative error when assuming that the effective radius b is equal to the inner radius r(i) of the ring electrode. Finally, we suggest that in the presence of weak bioelectrical signals, the effective radius of the electrodes should be reasonably increased in order to improve signal-to-noise ratio (SNR). PMID- 17713287 TI - [Initial study on the characterization of atrial fibrillation in epicardial mapping]. AB - Atrial fibrillation (AF) is a complex and dangerous arrhythmia. The treatment method is still unefficient because of its unknown mechanism. The purpose of our research is to detect the electrical activity on the atria surface and therefore find the optimal technique to characterize AF for clinical application. All kinds of maps are presented clearly and the activity of sinus or AF rhythm can be seen quite differently. The active isopotential map can display the dynamic electrical conduction of the atrium as a movie. Sequentially the vectorgraph shows the direction of depolarization at every moment. Finally statistical results are also very useful for analysis on AF. Statistics of exciting frequency and correlation area show great difference in various channels during AF. "Source" or "sink" may be estimated by interval variance statistics. This study demonstrates the flexibility of the system in AF research. The statistical results can also be adopted to clearly express the characteristics of AF. PMID- 17713288 TI - [Experimental research for dielectric spectroscopy of normal human platelets]. AB - The dielectric spectroscopy of human platelets was measured within the frequency range of 100 KHz-100 MHz, and the dielectric numerical characters of human platelets in response to AC electric field were analyzed. We measured the AC impedance of normal human platelets with the impedance technique in the frequency domain for the first time. The experimental data were used to draw a relationship curve between the frequency of electric field and permittivity or conductivity, and then the dielectric spectrum and the Cole-Cole plots of human platelets were established and then, the characteristics of dielectric response of human platelets were decided, which demonstrated the dependence of permittivity and conductivity of human platelets upon frequency, and showed two characteristic frequencies of the dielectric spectroscopy of human platelets: the first characteristic frequency f(C1) = 6.66 MHz; the second characteristic frequency f(C2) = 9.81 MHz. PMID- 17713289 TI - [Effects of nanotopography for biomaterials on cell behaviors]. AB - The topography structure of biomaterial is one of the most important factors which affect cells' behaviors, including cell adhesion, proliferation, differentiation and apoptosis. With the development of nanobiology and technology, it is well known that cells could sense and respond to the nanotopography of material's substratum with "contact guidance", and the nanotopography of the substratum has potential application and significance to tissue regeneration and rehabilitation. In this article, various methods to constitute nanotopography including polymer demixing, electrospinning, electron beam lithography as well as chemical grafting were reviewed, the effects of nanotopography on cells' growth behavior and reconstruction of extracellular matrix were analyzed, and the important functions of nanotopography construction to the cell-material interaction at the molecular and cellular level were discussed. PMID- 17713290 TI - [Research advances in new treatment of heart failure]. AB - The treatments for heart failure were developed rapidly in recent years ; new therapeutic techniques such as cytokine therapy, gene therapy and pacemaker therapy have been developed respectively. This paper reviews the mechanisms, therapeutic effect and limitation of these new techniques, and the future work in this research field is also discussed. PMID- 17713291 TI - [A review of studies on hair follicle dermal sheath cells]. AB - The dermal sheath surrounding the outside of the hair follicle maintains and regenerates the dermal papilla, a necessary component for hair regeneration. Dermal sheath cells participate in skin wound healing and have some characteristics of adult stem cells such as immuneprivilege, multiple differentiation and plasticity. It is likely that dermal sheath cells will be the new cynosure in the research on wound healing and tissue engineering. Here we review the studies of hair follicle dermal sheath in present years. PMID- 17713292 TI - [Self-assembled monolayers as model systems to study the relation between biocompatibity and surface chemistry of biomaterials]. AB - The surface properties of biomaterials are essentially important to their biocompatibility. The complexity of surface composition and structure of biomaterials bring out the problem that it is difficult to make fully clear how the surface chemical properties and the structures of biomaterials control the biological reactions between the surfaces and proteins and/or cells. The structure of self-assembled monolayers (SAMs) is well established and SAMs have the characteristics of which a variety of functional groups and molecules can be introduced, either before or after the monolayer is formed, and diversified spectroscopy monitoring can be used to characterize SAMs and changes after their interactions with proteins or cells. Thus, SAMs are suitable model substrates for the study of the relationship between the surface chemical properties and biocompatibility of biomaterials. This paper reviews the researches on SAMs as models to study the absorption of proteins, cell adhesion and proliferation on materials, and the influences of both surface chemical functional groups and motion of molecular chains on hemocompatibility of biomaterials. PMID- 17713293 TI - [Advance of study on apoptosis inducer of several types of natural drug]. AB - Along with the deep-going researches on mechanism of apoptosis, the apoptosis inducers as anticancer drugs have been the hot points of researches for new drugs. In this paper are reviewed a number of related articles on the progress in cell apoptosis inducers including the derivative anthraquinone, saponin, flavonids and terpines. The mechanisms are analyzed and discussed. The researches into the molecular mechanisms of inducer can provide the theoretical basis for discovering new compound, and can find out the apoptosis inducers with high efficiency and low toxicity. There is hope of developing apoptosis inducers into safe and effectual anticancer drugs. PMID- 17713294 TI - [Progress of study in auditory event-related potentials of novel events]. AB - This is a review of the progress in the study on auditory event-related potentials (ERP) of novel events. Several cognitive problems about the novelty ERP response on brain and the experiment methods are introduced. The mismatch negative potential (MMN) reflects the detection of deviant events, and MMN is related with the novelty P3. Familiarity and attention influence the novelty ERP response. Experiments results showed that the amplitude of ERPs in the frontal area was reduced with the enhancement of familiarity, while that in the parietal area had little change. Attention was helpful in increasing the amplitude of ERPs, and could make the corresponding brain area active. The functional significance of the response of ERP was discussed also. PMID- 17713295 TI - [Current progress of research on measuring sphygmus information]. AB - Based on summarizing the physical features to describe the sphygmus information in traditional Chinese medicine (TCM), this paper surveys the methodologies of sphygmus measuring, such as single-probe measurement and multi-probe measurement based on pressure sensors, as well as measurement methods based on non-pressure sensors. It is concluded that to achieve the comprehensiveness on the sphygmus information measurement and analysis, researchers need to do further studies of the underlying mechanism and the information properties of the sphygmus. In addition, the sphygmus system should be modeled physically and mathematically. PMID- 17713296 TI - [Mechanism of PUFA in regulating of gene expression]. AB - Polyunstaurated fatty acids (PUFAs) not only are essential component of cells in maintaining function and composing organelle, but also control gene transcription of enzymes which are involved in differentiation, growth and metabolism in organisms. Resent studies have been shown that PUFA interact directly with nuclear receptors such as PPARs, LXR, HNF-4, other mechanism are indirect and rest with transcription factors such as SREBP. PUFA affect cell function through diverse pathways. The roles of such factors and PUFA in mediating the nuclear effects are addressed in order to elucidate the mechanism of PUFA in regulating gene expression. Further understanding of gene mechanism of regulation at the level of molecule would prompt the development of nutrition, health and medical treatment. PMID- 17713298 TI - Type 2 diabetes and Hispanic culture: two kinds of insulin resistance. PMID- 17713297 TI - Type 2 diabetes: the end of clinical inertia. PMID- 17713299 TI - Human ehrlichiosis: clinical and ecological challenges. PMID- 17713301 TI - Psychiatric manifestations of thyroid disease. PMID- 17713300 TI - Metabolic effects of the atypical antipsychotics. PMID- 17713302 TI - Association of race and gender with use of antiretroviral therapy among HIV infected individuals in the Southeastern United States. AB - BACKGROUND: Women and minorities continue to account for a higher proportion of AIDS incidence and mortality than their male and white counterparts. This study examined whether race and gender were associated with antiretroviral use among HIV-infected individuals in the southeastern US. METHODS: Multivariate regression analyses were used to identify whether race and gender predicted use of a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) from 1996 to 2000 among individuals receiving HIV primary care. RESULTS: Female gender and nonwhite race were significantly associated with a lower likelihood of being prescribed a PI or NNRTI at baseline. At the follow-up measure three years later, fewer individuals of minority race and female gender were prescribed a PI or NNRTI; however, these differences had declined and were no longer statistically significant. CONCLUSIONS: Efforts are needed to improve prompt access to advances in HIV therapeutics for women and minorities and to address continued disparities in HIV care by race and gender. PMID- 17713303 TI - Is it Clostridium difficile infection or something else? A case-control study of 352 hospitalized patients with new-onset diarrhea. AB - BACKGROUND: Clostridium difficile-associated diarrhea (CDAD) is a leading cause of nosocomial diarrhea in the United States, and may be associated with significant morbidity and occasional mortality. Diarrhea is also very common among hospitalized patients and is often related to a variety of factors not related to C difficile infection. METHODS: We performed a retrospective case control study at a tertiary care community medical center to delineate factors that are predictive of CDAD among hospitalized patients with new-onset diarrhea (ie, not present at the time of admission). Controls were selected based on negative C difficile toxin test(s) (CDTTs) (> 95% by cytotoxic assay), presence on the same ward as the patients with first positive CDTT, and hospitalization around the same period as the positive cases. RESULTS: The study involved 352 patients (88 cases and 264 controls). In univariate analysis, age 75 years or greater, exposure to cefazolin or levofloxacin during the 4-week period preceding CDTT, and hospitalization for 7 days or greater before CDTT were significantly associated with a positive test; male gender and prior ceftriaxone exposure nearly reached statistical significance. Multivariate logistic regression analysis revealed age 75 years or greater (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.3-3.7), hospitalization for 7 days or more (OR 2.3, 95% CI 1.3 3.8], and prior exposure to cefazolin (OR 3.5, 95% CI 1.6-7.5) or levofloxacin (OR 2.1, 95% CI 1.2-3.7) as independent predictors of a positive CDTT; male gender nearly achieved statistical significance (OR 1.6, 95% CI 0.9-2.7). CONCLUSIONS: Among hospitalized patients with diarrhea who underwent testing for C difficile toxin, age 75 years or older, hospitalization for 7 days or greater, and recent exposure to cefazolin or levofloxacin were important predictors of a positive CDTT. These findings may help in the initiation of early presumptive treatment for CDAD, and appropriate isolation of higher risk patients before results become available. In addition, consideration of these risk factors may help in deciding whether a CDTT should be repeated when the first test is negative. Our study also supports more judicious use of antibiotics, particularly cefazolin and levofloxacin, in reducing the risk of CDAD in hospitalized patients. PMID- 17713304 TI - Diabetes-related lower extremity amputation rates fall significantly in South Carolina. AB - BACKGROUND: The aims of this study are to compare the diabetes-related lower extremity amputation (LEA) rate trend in South Carolina (SC) to that of the United States (US) and to determine changes in LEA rates in SC according to age, race, gender, and amputation METHODS: National Hospital Discharge Survey (NHDS) and SC hospital discharge data for 1996 to 2002 were analyzed. ICD-9-CM codes identified all diabetic patients and occurrences of LEA. Linear regression was used to compare the LEA rate trends between SC and the US. RESULTS: LEA rates are decreasing throughout the study period. The slope is greater in SC compared with US (US slope = -0.00082; SC slope = -0.0015; P = 0.002), signifying a decrease in LEA rates of 1.5/1000 per year in SC and 0.8/1000 per year in the US. Furthermore, LEA rate decreases in SC are significant throughout all ages, races, genders, and amputation levels. CONCLUSIONS: Diabetes-related LEA rates are decreasing in SC more rapidly than in the US. Ongoing community-level education may be assisting in the favorable trends. PMID- 17713305 TI - Patient complaints and malpractice risk in a regional healthcare center. AB - OBJECTIVE: To study the association between physicians' complaint records and their risk management experiences in a regional healthcare center. DATA SOURCES: Patient complaints about physicians in a large border state medical center's hospital and outpatient clinics were recorded and coded. The study period was from January 2001 through December 2003. These records were linked to the counterpart physicians' data covered by the institutions' risk management plan through June 2004. STUDY DESIGN AND DATA COLLECTION: All physicians at the institution who had contact with patients during the study period were identified as surgeons or non-surgeons. Complaints for these physicians were recorded by the institution's Office of Patient Relations (OPR) and independently coded using a standardized protocol to characterize the nature of the problem and to uniquely identify the person complained about. The complaint records were then linked to the risk management files (RMFs) for the defined physician cohort. In addition, these data were supplemented with clinical service values (RVUs) which were available for 338 members (76%) of the 445 member cohort. PRINCIPAL FINDINGS: Both patient complaints and risk management events were higher for surgeons than for non-surgeons. This was true for the number of RMFs, those involving expenditures, and for lawsuits. Logistic regression was used to assess the effects of complaint counts, practice type and volume of clinical activity. All were statistically significant in predicting the number of RMF openings, RMF openings with expenditures and lawsuits. Predictive concordance was 75% or greater for each of the three risk management outcomes. CONCLUSIONS: Expressions of patient dissatisfaction and practice type are significantly related to risk management experiences in a regional medical center. Associations of risk management experiences with volume of clinical activity (RVUs) for surgeons in the regional medical center environment were not as strong as those found in a similar study reported from an academic medical center. PMID- 17713306 TI - The management of post traumatic stress disorder (PTSD) in the primary care setting. AB - Recent geopolitical events, including the terrorist attacks on the United States on September 11, 2001, and ongoing military operations in Iraq, have raised awareness of the often severe psychological after-effects of these and other types of traumatic events. Post traumatic stress disorder (PTSD) represents the most severe of these sequelae. PTSD is an under-recognized and under-treated chronic anxiety disorder associated with significant psychosocial morbidity, substance abuse, and a number of other negative health outcomes. Fortunately, the biologic underpinnings of this complex disorder and new advances in treatment are being realized. Early detection by primary care providers and rapid initiation of treatment are the keys to successful management of the disorder. PMID- 17713307 TI - Treating the whole patient for optimal management of type 2 diabetes: considerations for insulin therapy. AB - Primary care physicians are responsible for providing healthcare to most patients with type 2 diabetes. In this role, it is critical that physicians utilize a whole-patient treatment approach that includes lifestyle modifications and pharmacotherapy aimed to achieve glycemic control, in addition to the management of any comorbid conditions or risk factors for cardiovascular complications of diabetes. Due to the progressive nature of the disease, most patients with type 2 diabetes will eventually require insulin to achieve and maintain glycemic control, because of both increased insulin resistance and diminished secretory capacity of the pancreatic beta cells. Thus, physicians need to be knowledgeable about and comfortable with the use of insulin, as well as with educating patients and discussing any potential barriers to insulin therapy. The use of a stepwise approach--beginning with basal insulin therapy and adding prandial insulin if necessary--is simple, effective, and appropriate for use in many patients. PMID- 17713308 TI - Addressing cultural barriers to the successful use of insulin in Hispanics with type 2 diabetes. AB - Hispanics experience a higher rate of diabetes than non-Hispanic whites and tend to have worse glycemic control and a greater risk of diabetes-related complications. Once oral antidiabetic agents become insufficient, insulin plays an important role in achieving glycemic goals. However, many Hispanic patients are resistant to initiating insulin therapy or hesitant to increase doses, as necessary, to control their glucose levels. Barriers to insulin therapy include socioeconomic issues (eg, cost, insurance status), language difficulties, poor health literacy, and cultural beliefs that impact the patient-provider relationship and negatively affect patients' perceptions of diabetes and insulin. Healthcare providers can help overcome these issues and improve patient-provider communication by practicing culturally competent care. Implementation of a simple titration regimen using once-daily basal insulin may enable Hispanic patients to maintain glycemic control and improve outcomes. PMID- 17713309 TI - Henoch-Schonlein purpura: a review article. AB - Henoch-Schonlein purpura (HSP) is the most common vasculitis of childhood. Although HSP is typically a disease of children, adult cases have been described. HSP can affect multiple organs with a characteristic rash present in all patients. Most cases resolve with symptomatic treatment, but serious complications can occur such as renal failure. Primary care physicians should be well aware of the disease because the true incidence is probably underestimated. PMID- 17713311 TI - New onset diabetes with ketoacidosis attributed to quetiapine. AB - A 45-year-old man with paranoid schizophrenia with delusions was transferred from a group home for treatment of diabetic ketoacidosis (DKA). Six months before this episode, he had been hospitalized in an inpatient psychiatric institution and treated with valproic acid and quetiapine 400 mg with normal blood sugars recorded. The patient was treated for diabetic ketoacidosis, and all outpatient medications were discontinued. Insulin resistance is commonly cited as the mechanism for hyperglycemia, a theory supported by the efficacy of insulin- sensitizing medications in reported cases. Although antipsychotic- associated DKA is uncommon, hyperglycemia associated with these medications is commonplace. Analysis of case series have not identified risk factors for hyperglycemia or diabetic ketoacidosis within this population. Considering the incidence and unpredictability of hyperglycemia associated with quetiapine and atypical antipsychotics, clinicians should initiate intensive monitoring in patients, including weight, hyperglycemia, and dyslipidemia. PMID- 17713310 TI - Ehrlichiosis: making the diagnosis in the acute setting. AB - Human monocytic ehrlichiosis (HME) is a tick-borne disease transmitted during the summer months in the mid-Atlantic, southeastern and south-central United States. A large proportion of patients presenting with ehrlichiosis must be hospitalized because of the severity of their presenting signs, symptoms and lab abnormalities. We report a case of HME presenting with negative serologies and positive DNA PCR for Ehrlichia chaffeensis during the acute illness. The patient was empirically treated with doxycycline before the availability of diagnostic test results and had a rapid recovery. This report summarizes the common findings of ehrlichiosis on presentation, diagnostic strategies, and treatment options. This case emphasizes the importance of considering tick-borne diseases in the differential diagnosis for patients presenting with nonspecific febrile syndromes in endemic areas and using the clinical scenario to determine whether empiric treatment for a tick-borne disease is necessary. Delaying treatment while awaiting confirmatory tests is unnecessary, and may result in a less favorable patient outcome. PMID- 17713312 TI - A challenging case of syndrome of inappropriate secretion of antidiuretic hormone in an elderly patient secondary to quetiapine. AB - Hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is an uncommon complication of treatment with centrally acting drugs including selective serotonin reuptake inhibitors (SSRIs) and antipsychotic medications. Antipsychotics are commonly used for the treatment of behavioral and psychiatric symptoms in elderly patients with dementia, and the use of those agents is increasing. Here, we report an elderly man who developed hyponatremia after treatment with medications for depression and agitation. PMID- 17713313 TI - Additional evidence of the abuse potential of quetiapine. AB - Quetiapine is an atypical antipsychotic agent approved by the FDA for the treatment of schizophrenia, acute mania, and bipolar depression. Recently, reports of medication abuse, particularly intranasal and i.v. abuse, have been described. Three cases of oral misuse of quetiapine are presented and clinical implications are discussed. Clinicians should exercise caution when prescribing quetiapine to patients at risk for substance abuse. PMID- 17713314 TI - "Thyrotoxic psychosis" associated with subacute thyroiditis. AB - Severe psychiatric derangements are a rare manifestation of Graves disease or toxic goiter. An 18-year-old male college student was hospitalized with depression and psychotic behavior. He was found to have thyrotoxicosis due to subacute thyroiditis, as evidenced by a reduced radioactive iodine uptake, elevated thyroglobulin level, and spontaneous remission into a hypothyroid phase. His behavioral abnormalities resolved with progressive normalization of thyroid function. To our knowledge, this is the first reported case of the self-limited condition of subacute thyroiditis causing 'thyrotoxic psychosis' and serves to remind clinicians of this association when treating patients in clinical practice. PMID- 17713315 TI - Multiglandular parathyroid carcinoma: a case report and brief review. AB - A 53-year-old man with no past medical history was admitted with complaints of hematuria, flank and abdominal pain of one week duration. He also complained of an enlarging new neck mass one month before presentation. The laboratory assessment showed a calcium level of 17.3 mg/dL (normal 8.5-10.5 mg/dL), serum albumin 2.9 g/dL (normal 3.0-5.0 g/dL), serum creatinine 3.4 mg/dL (normal 0.5 1.2 mg/dL). A neck ultrasound showed a complicated left neck mass. He was hydrated for one week with improvement in his labs, showing a decrease in serum calcium to 9.3 mg/dL and a serum creatinine of1.8 mg/dL. He underwent a total thyroidectomy and parathyroidectomy. The pathology showed multiglandular parathyroid carcinoma. It is important for the physician and surgeon dealing with primary hyperparathyroidism to look for parathyroid carcinoma. A better knowledge and understanding of this condition would aid in early diagnosis and possibly increase the survival rate. PMID- 17713316 TI - Rapid development of an axillary mass in an adult: a case of cystic hygroma. AB - Cystic hygroma is a congenital anomaly of lymphatic origin, which mainly develops during childhood. Its development in adulthood, however, has been proposed to be related to several predisposing factors such as trauma, infection, tumor growth or iatrogenic stimuli. The development of cystic hygroma in the extremities of adults is extremely rare and moreover, its development in the axillary region has, to our knowledge, been reported only once in the literature. We describe an unusual case of a cystic hygroma which developed rapidly in the axillary region of a female patient in the absence of any predisposing factor. The diagnostic workup and the need for surgical excision of the mass to obtain an accurate, histologic diagnosis is presented. PMID- 17713317 TI - An overlooked differential diagnosis of acute chest pain. PMID- 17713318 TI - An unusual case of nonhealing leg ulcer in a diabetic patient. PMID- 17713319 TI - Life-threatening complications of an extremely rare tumor of the kidney: adult type primary renal ganglioneuroblastoma. PMID- 17713320 TI - Pisa syndrome: acute and tardive forms. PMID- 17713321 TI - Self-poisoning with pet medications. PMID- 17713322 TI - Treating osteoarthritis in the elderly: should recent data on NSAIDs change our way of practice? PMID- 17713323 TI - Patient's page. Managing post traumatic stress disorder. PMID- 17713324 TI - Constrictive bronchiolitis after treatment of colon cancer with 5-fluorouracil. AB - Constrictive bronchiolitis (CB) is a rare disease with unclear etiology. We report a 37-year-old female with CB who developed progressive dyspnea and cough after completing a course of 5-fluorouracil (5-FU) for colon cancer. The patient had evidence of irreversible obstructive lung disease and lung biopsy showed typical findings of chronic inflammation, submucosal thickening and obliteration of bronchioles. To the best of our knowledge this is the first reported case of CB after treatment with 5-FU. PMID- 17713325 TI - Effects of levofloxacin and doxycycline on interleukin-6 production of Chlamydia trachomatis-infected human synovial fibroblasts. AB - BACKGROUND: A large amount (80,000-100,000 pg/ml) of interleukin-6 (IL-6) was detected in cultures of human synoviocytes infected with Chlamydia trachomatis. In this study, we investigated the effect of antibiotics on the IL-6 production of C. trachomatis-infected human fibroblast-like synovial cells (HFLS). METHODS: The minimum inhibitory concentrations of levofloxacin and doxycycline against C. trachomatis were determined in either HFLS or HeLa 229 cells. The number of live Chlamydia was also examined. IL-6 in the supernatants of infected cultures was quantified by capture ELISA. RESULTS: The production of IL-6 was suppressed to as low as 1,800 pg/ml in the infected HFLS treated with levofloxacin or doxycycline immediately or early after infection. In HFLS treated with levofloxacin and doxycycline, the IL-6 levels decreased to 37,000 and 21,000 pg/ml, respectively, 48 h after infection, and levofloxacin was thus found to be less effective than doxycycline. In addition, the number of viable C. trachomatis in the infected cultures treated with levofloxacin 24 h after infection was higher than when treated with doxycycline. CONCLUSIONS: The early administration and proper selection of antibiotics is important for the suppression of inflammatory cytokine production. These findings indicate that antibiotic therapy will not only work in treating infections but might also be useful in treating reactive arthritis secondary to the infection. PMID- 17713326 TI - Establishment of a single-dose irinotecan model of gastrointestinal mucositis. AB - BACKGROUND: Irinotecan is a common cytotoxic agent used in advanced colorectal cancers. However, a major clinical problem with this cytotoxic is that it causes gastrointestinal mucositis manifest by severe diarrhoea. To date there is no established single dose of irinotecan in rats to enable determination of changes occurring following administration. Therefore, the primary aim of this study was to determine a single dose of irinotecan that induced reproducible gastrointestinal mucositis in DA rats. The secondary aim was to determine if the presence of tumour altered the development of mucositis. METHODS: Eighty-eight rats were divided into two groups, 44 received tumours and 44 remained tumour naive. These were randomized to receive a single dose of irinotecan at 150, 200, 250 or 300 mg/kg. Two control groups of rats received either no treatment or 2 doses of 150 mg/kg irinotecan, shown previously to induce reproducible gastrointestinal mucositis. Rats were monitored closely for incidence and severity of diarrhoea, and mortality, before being killed 48 and 144 h following treatment. RESULTS: Rats administered 250 and 300 mg/kg of irinotecan all developed diarrhoea, and this was associated with high mortality rates (up to 100%). Necropsies revealed that many of these rats had duodenal perforations and fatty lysis consistent with peritonitis. The lower doses of 150 and 200 mg/kg irinotecan also caused diarrhoea, but were not associated with high mortality rates. Histopathological examination confirmed small and large intestinal damage in all rats that received irinotecan, regardless of dose. Tumour-bearing rats had worse diarrhoea and higher mortality compared to tumour-naive rats. CONCLUSIONS: We find that a single dose of 200 mg/kg irinotecan causes reproducible gastrointestinal mucositis as measured by levels of diarrhoea, and small and large intestinal histology. Importantly this dose has a low mortality. The response to irinotecan is more pronounced in tumour-bearing rats. PMID- 17713327 TI - What our eyes see is not necessarily what our heart feels. PMID- 17713328 TI - Assessment of aortic valve area in aortic stenosis using cardiac magnetic resonance tomography: comparison with echocardiography. AB - BACKGROUND: Cardiac magnetic resonance tomography (CMR) is a new imaging technique capable of imaging the aortic valve with high resolution. We assessed the aortic valve area (AVA) in patients with aortic stenosis (AS) using CMR and compared the results to those obtained by transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE). METHODS: Forty-two patients (36% female, 71 +/- 8 years) symptomatic for AS underwent TTE followed by TEE to determine the AVA; the continuity equation was used with TTE and the planimetry technique with TEE. In 26 of these patients, the AVA was additionally obtained by CMR planimetry. RESULTS: The mean AVA derived by TTE, TEE and CMR were 0.74 +/- 0.27, 0.87 +/- 25 and 0.97 +/- 0.30 cm(2), respectively. The mean absolute differences in AVA were 0.13 +/- 0.19 cm(2) for TTE vs. TEE, 0.21 +/- 0.25 cm(2) for TTE vs. CMR and 0.05 +/- 0.11 cm(2) for CMR vs. TEE. CONCLUSION: There is a good agreement between CMR and the echocardiographic determination of the AVA. If multicenter, large-scale studies confirm these observations, CMR could serve as a noninvasive alternative to TTE/TEE for the assessment of AVA in AS. PMID- 17713329 TI - Left ventricular functional analysis using 64-slice multidetector row computed tomography: comparison with left ventriculography and cardiovascular magnetic resonance. AB - OBJECTIVE: The progress in computed tomography (CT) has improved temporal resolution and shortened the acquisition time. We compared cardiac function using 64-slice CT with left ventriculography (LVG) and cardiovascular magnetic resonance (CMR). METHODS: A head-to-head comparison between CT, LVG and CMR was performed in 41 patients. In global LV function, CMR served as the reference. Regional wall motion was compared in a 5-point scoring system. RESULTS: CT had excellent intra- and interobserver reproducibility. Ejection fraction, end diastolic and end-systolic volumes by CT were closely correlated with CMR (r = 0.95, 0.96 and 0.98, respectively), while LVG underestimated LV volumes (p < 0.01). The standard deviation of ejection fraction difference between CT and CMR was significantly lower than that between LVG and CMR (p = 0.0015). In regional function, there were good agreements of 94.8% (kappa = 0.82) between CT and LVG and 94.5% (kappa = 0.84) between CT and CMR. The intermethod agreements in mild hypokinesis using CT tended to be lower. CONCLUSION: An excellent correlation was observed between CT and CMR in the LV function over a wide range of heart rates. However, even though 64-slice CT tended to be less sensitive in detecting mild hypokinesis, it still showed excellent concordance in advanced regional abnormalities. PMID- 17713330 TI - Sudden cardiac death in the young. Calling for new tools. PMID- 17713332 TI - Assessment of the ozone-mediated killing of bacteria in infected dentine associated with non-cavitated occlusal carious lesions. AB - The ability of ozone to kill micro-organisms associated with non-cavitated occlusal caries was investigated. The occlusal surfaces were treated with ozone (n = 53) or air (n = 49) for 40 s, and the underlying infected dentine was exposed. There was no significant difference between the number of bacteria recovered from the ozone-treated and the control sites (p > 0.1). Treatment of the exposed dentine with ozone resulted in a just significant (p = 0.044) reduction in bacterial counts. Ozone treatment of non-cavitated occlusal lesions for 40 s failed to significantly reduce the numbers of viable bacteria in infected dentine beneath the demineralized enamel. PMID- 17713333 TI - The antibacterial activity of plant extracts containing polyphenols against Streptococcus mutans. AB - The minimum inhibitory concentrations (MIC) of commercially available and 70% aqueous propanone (P70) extracts from plants chosen for polyphenol content on Streptococcus mutans and other bacteria were determined using a standard susceptibility agar dilution technique to investigate their potential use as anticariogenic agents. The effects on adhesion of S. mutans to glass were also studied. The lowest MICs were for the P70 extracts of red grape skin (0.5 mg ml( 1)) and green tea and sloe berry skin (2 mg ml(-1)). The commercial extracts generally had a lower activity with a minimum MIC of 2 mg ml(-1) for tea extracts, grape seed extracts and Pynogenol (extract of maritime pine). All other extracts had MICs of > or = 4 mg ml(-1). Unfermented cocoa had greater antimicrobial activity than fermented cocoa and the activity of the fractionated extract increased with the extent of epicatechin polymerization. Epicatechin polymer had an MIC of 1 mg ml(-1) and an MBC of 64 mg ml(-1). Selected extracts were tested against other oral bacteria and showed activity against gram-positive organisms. P70 extracts of unfermented cocoa, epicatechin polymer fraction, green tea and red grape seed were bacteriostatic and prevented acid production when added at the MIC to cultures of S. mutans grown in a chemically defined medium supplemented with either glucose or sucrose. There was a reduction in viability which was greater when added to washed cells, but there were some viable cells after 24 h. The extracts also reduced adherence of S. mutans to glass. PMID- 17713334 TI - Effect of a fluoridated food item on enamel in situ. AB - After the consumption of food items prepared with fluoridated salt elevated fluoride concentrations can be observed in saliva, whereby enamel mineralization is supposed to be positively affected. The aim of this double-blind (with respect to fluoride), placebo-controlled, randomized, cross-over study was to evaluate the effects of the consumption of either a fluoridated (effect) or a placebo food item on the mineral content of sound and pre-demineralized human enamel in situ. During both phases of the study 8 enamel specimens in each of 10 intraoral appliances were positioned, either recessed or flush with the acrylic surface. One of the flanges was brushed twice daily with fluoride-free toothpaste prior to the storage of the appliance in sucrose solution. The subjects were asked to refrain from other sources of fluorides except for the consumption of either a highly fluoride-containing (0.5 mg) or a placebo cookie (3 times daily) during the respective study phase. Mineral content and lesion depth were measured in the enamel specimens and fluoride concentrations in saliva and urine. Significantly increased urinary and salivary (immediately after food consumption) fluoride concentrations compared to baseline were observed during the effect phase. In the absence of fluorides more pronounced demineralization was observed, especially for the recessed specimens of both surface conditions. Brushing was shown to inhibit demineralization, particularly during the placebo phase. In conclusion, fluorides added to food items seem to be efficacious to inhibit enamel demineralization in plaque-covered enamel but might be less effective if oral hygiene is adequate. PMID- 17713335 TI - Assessment of autofluorescence to detect the remineralization capabilities of sodium fluoride, monofluorophosphate and non-fluoride dentifrices. A single-blind cluster randomized trial. AB - The purpose of the study was to determine if longitudinal measurements of enamel autofluorescence (quantitative light-induced fluorescence, QLF) could detect differences in remineralization of early enamel caries on buccal surfaces of anterior teeth following supervised daily brushing with either sodium fluoride (NaF; 1,450 ppm F), sodium monofluorophosphate (MFP; 1,450 ppm F) dentifrices or a herbal, non-fluoride placebo dentifrice. The study was a pragmatic cluster randomized controlled trial with schools as the unit of randomization. Twenty-one schools in Chengdu, China, comprised the clusters; 296 children with at least 1 visible white-spot lesion were examined using QLF at baseline and after 3 and 6 months. Each of the 21 clusters was randomly assigned 1 of the 3 dentifrices, and the children brushed under supervision once per day for 2 min. The primary outcome measure was deltaQ (product of fluorescence loss and area) at a 5% threshold after 6 months of product use. A multi-level model was fitted to the data at the site level, taking into account the hierarchical structure with baseline deltaQ, age and sex as covariates. After 3 months there was a significant difference between the MFP group and placebo (p = 0.02) and after 6 months between the NaF group (p = 0.002), MFP group (p < 0.001) and the placebo. QLF methodology could detect, within 3- and 6-month periods of supervised brushing, a difference in remineralization between fluoride-containing and non fluoride-containing dentifrices. Typically lesions in all 3 treatment groups demonstrated improvement. Groups receiving fluoride experienced a more rapid and more substantial remineralization than those in the placebo group. PMID- 17713336 TI - Low-fluoride dentifrices with reduced pH: fluoride concentration in whole saliva and bioavailability. AB - This double-blind study assessed the fluoride (F) concentration in whole saliva and F bioavailability after the use of low-F dentifrices with reduced pH. Whole saliva was collected from 10 volunteers after brushing with: experimental dentifrices (pH 5.5) 275, 550 and 1,100 ppm F; commercial 500 ppm F, pH 6.9 and a 'gold standard' 1,100 ppm F, pH 6.5. To analyze F bioavailability, 9 volunteers ingested weights of four dentifrices equivalent to 2 mg F: 1,500 ppm F/MFP/CaCO3, pH 9.5; 1,100 ppm F/NaF/silica, pH 5.5; 1,100 ppm F/NaF/silica, pH 7.0 and 1,100 ppm F/NaF/silica, pH 6.5 ('gold standard'). Ductal saliva and urine were collected. F was analyzed by electrode. Data were tested using ANOVA and Tukey's post hoc test (p < 0.05). The 550 ppm F/pH 5.5 dentifrice was similar to the 'gold standard' in its effect on whole saliva F concentration. The area under the curve of ductal saliva F concentration x time and urinary F excretion rates did not differ among the dentifrices. The results show that acidic low-F dentifrices are effective in increasing salivary F concentration and pH reduction does not seem to affect their F bioavailability. PMID- 17713337 TI - A cluster randomised controlled trial to evaluate the effectiveness of fluoride varnish as a public health measure to reduce caries in children. AB - This cluster randomised controlled study assessed the effectiveness of twice yearly applications of fluoride varnish as a public health measure to reduce dental caries in children living in relatively deprived communities. The test (n = 334) and control (n = 330) children in 2 school years (unit of randomisation) attended 24 state primary schools and were 6-8 years of age at the start. Good baseline balance was found. Duraphat varnish was applied at school on 5 occasions over 26 months, by dental therapists. A combined visual and fibre-optic transillumination examination included all surfaces of primary and first permanent molars at baseline and after 26 months for small and large enamel and dentine lesions. At the final examination the only statistically significant difference was in the caries increment for small enamel lesions in the primary dentition, with the test children having fewer lesions. This study failed to demonstrate that the twice-yearly application of fluoride varnish provided at school reduced dental caries in children living in this community. The low level of response and a lower than expected caries increment had a major impact on the effectiveness of the intervention, since the children who participated were least likely to have benefited from the programme, whereas those who might have benefited did not consent. PMID- 17713338 TI - Effect of addition of citric acid and casein phosphopeptide-amorphous calcium phosphate to a sugar-free chewing gum on enamel remineralization in situ. AB - Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) has been shown to remineralize enamel subsurface lesions in situ. The aim of this study was to investigate the effects of CPP-ACP in a fruit-flavoured sugar-free chewing gum containing citric acid on enamel remineralization, and acid resistance of the remineralized enamel, using an in situ remineralization model. The study utilized a double-blind, randomized, crossover design with three treatments: (i) sugar free gum (2 pellets) containing 20 mg citric acid and 18.8 mg CPP-ACP, (ii) sugar free gum containing 20 mg citric acid alone, (iii) sugar-free gum not containing CPP-ACP or citric acid. Ten subjects were instructed to wear removable palatal appliances, with 4 half-slab insets of human enamel containing demineralized subsurface lesions and to chew gum (2 pellets) for 20 min 4 times per day for 14 days. At the completion of each treatment the enamel half-slabs were removed and half of the remineralized lesion treated with demineralization buffer for 16 h in vitro. The enamel slabs (remineralized, acid-challenged and control) were then embedded, sectioned and subjected to microradiography to determine the level of remineralization. Chewing with gum containing citric acid and CPP-ACP resulted in significantly higher remineralization (13.0 +/- 2.2%) than chewing with either gum containing no CPP-ACP or citric acid (9.4 +/- 1.2%) or gum containing citric acid alone (2.6 +/- 1.3%). The acid challenge of the remineralized lesions showed that the level of mineral after acid challenge was significantly greater for the lesions exposed to the gum containing CPP-ACP. PMID- 17713339 TI - Noninvasive control of dental caries in children with active initial lesions. A randomized clinical trial. AB - The aim of this study was to investigate whether DMFS increment can be decreased among children with active initial caries by oral hygiene and dietary counseling and by using noninvasive preventive measures. Except for mentally disabled and handicapped children attending special schools, all 11- to 12-year-olds in Pori, Finland, with at least one active initial caries lesion were invited to participate in the study and were then randomized into two groups. Children in the experimental group (n = 250) were offered an individually designed patient centered preventive program aimed at identifying and eliminating factors that had led to the presence of active caries. The program included counseling sessions with emphasis on enhancing use of the children's own resources in everyday life. Toothbrushes, fluoride toothpaste and fluoride and xylitol lozenges were distributed to the children. They also received applications of fluoride/chlorhexidine varnish. The children in the control group (n = 247) received basic prevention offered as standard in the public dental clinics in Pori. For both groups, the average follow-up period was 3.4 years. A community level program of oral health promotion was run in Pori throughout this period. Mean DMFS increments for the experimental and control groups were 2.56 (95% CI 2.07, 3.05) and 4.60 (3.99, 5.21), respectively (p < 0.0001): prevented fraction 44.3% (30.2%, 56.4%). The results show that by using a regimen that includes multiple measures for preventing dental decay, caries increment can be significantly reduced among caries-active children living in an area where the overall level of caries experience is low. PMID- 17713340 TI - Prevalence of approximal caries in posterior teeth in 15-year-old Swedish teenagers in relation to their caries experience at 3 years of age. AB - The aim of the present investigation was to study the prevalence of approximal caries lesions and fillings in posterior teeth at 15 years of age in a prospectively followed Swedish population (n = 568), with special reference to their caries experience at the age of 3 years. Only approximal surfaces were recorded, since all children in the Community of Jonkoping have had fissure sealing performed on all caries-free permanent molars. At 15 years of age, the mean number of approximal tooth surfaces with initial caries lesions (D(i)a), manifest caries lesions and fillings (D(m)Fa) and total caries experience and fillings (D(i + m)Fa)--recorded on bitewing radiographs--was 2.78 , 0.45 and 3.23, respectively. One third of the adolescents had no approximal caries or fillings; the D(i)a constituted 86% of the D(i + m)Fa. Children with manifest caries at 3 years of age had a higher risk of developing approximal caries in their permanent teeth than caries-free children at the same age (41 vs. 17%). Furthermore, children who were caries-free at 3 years of age were more likely to remain caries-free at 15 years of age compared to children with manifest caries (37 vs. 17%). All these differences were statistically significant (p < 0.001). Additionally, early childhood caries experience (developed before 3 years of age) had a greater predictive value than late childhood caries experience (developed between 3 and 6 years of age) concerning approximal caries at 15 years of age. PMID- 17713342 TI - Temporal relationship between sucrose-associated changes in dental biofilm composition and enamel demineralization. AB - The aim of this study was to investigate the temporal relationship between changes in biofilm composition and enamel demineralization following exposure to sucrose. A crossover blind study was conducted in situ in three phases, during which 12 volunteers, divided into three groups, subjected enamel slabs 8 times/day to water (negative control), 10% glucose + 10% fructose (active control) or 20% sucrose solution. Biofilms accumulated for 3, 7 and 14 days were collected and analyzed biochemically and microbiologically, and mineral loss from enamel (deltaZ) was evaluated. Significantly higher deltaZ was found in the sucrose group after 7 days. However, on the 3rd day, lactobacilli, insoluble extracellular polysaccharide (EPS) and intracellular polysaccharide were significantly higher, and the calcium, inorganic phosphorus and fluoride concentrations in the biofilm were significantly lower in the sucrose group than in the negative controls. The only significant difference compared to glucose + fructose treatment was a higher insoluble EPS concentration. The data suggest that, although sucrose induces significant enamel demineralization only after 7 days of biofilm accumulation, changes in the biofilm composition are observed earlier. PMID- 17713341 TI - Approximal secondary caries lesion progression, a 20-week in situ study. AB - There is no consensus about the definition and progression of outer and wall lesions in secondary caries. In this study we investigated whether lesion progression is influenced by an adjacent composite restoration and whether wall lesions develop at the composite-tooth interface. In order to study the appearance and progression of approximal primary caries lesions and lesions next to composite restorations, 16 samples were placed in a full denture of each of 8 subjects. Each denture housed 4 restored and 4 unrestored enamel samples and similarly 8 dentin samples. All samples were distributed over 2 sample holders, in each of which 4 approximal spaces were simulated. Every 4 weeks the sample holders were microradiographed using transversal wavelength independent microradiography and lesion depth was measured. At the end of the study, after 20 weeks, the lesion depth of the outer lesions was 0-350 microm for enamel and 0 750 microm for dentin. The estimated difference in progression between secondary and primary lesions (1.1 microm/4 weeks, 95% CI: -9.2 to 11.4 microm) was not statistically significant (p = 0.83). Secondary outer lesions appeared and progressed as primary caries lesions. No clear wall lesions were found next to composite, but they were observed next to acrylic resin. PMID- 17713343 TI - Microbiota of plaque microcosm biofilms: effect of three times daily sucrose pulses in different simulated oral environments. AB - AIM: To explore the Ecological Plaque Hypothesis for dental caries. To test modification of the microbiota of dental plaque microcosm biofilms by sucrose pulsing during growth in two different simulated oral fluids, and with a urea induced plaque pH elevation. METHODS: Plaque microcosm biofilms were cultured in an 'artificial mouth' with and without 6-min 5% w/v sucrose pulses every 8 h in an environment of continuously supplied saliva-like defined medium with mucin (DMM), or basal medium mucin (BMM, a high-peptone-yeast extract oral fluid analogue), and also in DMM + 10 mmol/l urea, with sucrose pulsing. Forty plaque species were quantified by checkerboard DNA:DNA hybridization analysis. RESULTS: Sucrose pulsing extended rapid plaque growth in DMM and BMM, inducing major microbiota changes in DMM but not in BMM. In DMM, some streptococci and lactobacilli were unaffected while others implicated in caries, together with Candida albicans and Capnocytophaga gingivalis, increased. Aerobic, microaerophilic and major anaerobic species decreased. Elevation of the pH(max) from 6.4 to 7.0 had almost no effect on the microbiota. BMM plaques were distinct from DMM plaques with particularly low levels of Candida albicans and Actinomyces. CONCLUSIONS: Modest sucrose exposure in a saliva-like environment causes profound changes in the developmental self-organization of plaque microcosms, supporting the Ecological Plaque Hypothesis. Nevertheless, there is significant stability in microbial composition with varying pH near neutrality. Increases in levels of specific bacteria in response to sucrose could be characteristic of organisms particularly important in caries. PMID- 17713344 TI - The effect of saliva derived from different individuals on the erosion of enamel and dentine. A study in vitro. AB - The aim of this study was to determine if saliva from 14 subjects afforded different levels of protection to human enamel and dentine against erosion in vitro. Test specimens were exposed for 2 h to saliva and control specimens to water for 2 h followed by citric acid for 10 min. This cycle was carried out 12 times. Tissue loss measured by contact profilometry was highly significantly different between subjects. Erosion was significantly reduced by pre-treatment with saliva from 7 subjects (enamel) or 6 subjects (dentine). Saliva from 1 subject resulted in significantly more enamel erosion than control. CONCLUSION: Saliva from different donors affords different levels of protection against erosion. PMID- 17713345 TI - Surgical therapeutic index of tension-free vaginal tape and transobturator tape for stress urinary incontinence. AB - BACKGROUND/AIMS: The aim of this study was to obtain the surgical therapeutic index (STI) of tension-free vaginal tape (TVT) and transobturator tape (TOT) and compare it with the previously obtained result of Burch colposuspension. METHODS: The study population consisted of 121 patients who were diagnosed as having stress urinary incontinence, underwent TVT or TOT between January 1, 2000 and June 30, 2005 and were followed up for at least 1 year. Patients with detrusor overactivity, urinary tract infection, intrinsic sphincter deficiency and pelvic organ prolapse more than stage II according to the POP-Q system were excluded. The cure and complication rates were investigated, and the STI (median percent cure rate/median percent complication rate) of each operation was calculated. RESULTS: Of the 121 patients, 61 underwent TVT and 60 received TOT. Patient characteristics and the results of preoperative urodynamic studies showed no significant difference between the two groups. The STI of TOT (2.72, 4.08, 4.23, 5.29) was higher than that of Burch colposuspension (1.19, 2.27, 2.89, 3.53) and TVT (2.77, 3.69, 3.23, 3.17) irrespective of follow-up months (at 1, 3, 6, 12 months). CONCLUSION: TOT seems to be a more suitable surgical procedure for stress urinary incontinence with urethral hypermobility. PMID- 17713347 TI - Abstracts of the 32nd Annual Meeting of the European Thyroid Association, September 1-5, 2007, Leipzig, Germany. PMID- 17713346 TI - Changes in hemostatic variables induced by estrogen replacement therapy: comparison of transdermal and oral administration in a crossover-designed study. AB - AIM: The purpose of this study was to determine the changes of biochemical risk factors for thromboembolisms using different administration routes of early estrogen replacement therapy. METHODS: In a 12-week prospective, randomized crossover trial, estradiol was administered orally (2 mg daily) or transdermally (0.05 mg daily). Forty-five healthy early postmenopausal women were included into the study within 12 weeks after hysterectomy and oophorectomy. Forty-one women (age 49 +/- 6 years) completed the study, and their data were analyzed. The hemocoagulation parameters were determined prior to beginning of the study and at the end of each treatment period, separated by a 1-week washout period. RESULTS: After oral therapy, the average tissue factor pathway inhibitor levels decreased statistically significantly (p < 0.0001) from 87.5 +/- 39.1 to 68 +/- 37.49 ng/ml. The plaminogen activator inhibitor-1 levels also decreased statistically significantly (p = 0.001) after the oral estrogen therapy from 11.39 +/- 12.02 to 5.0 +/- 5.27 IU/l. These changes were also significant when compared with the nonsignificant changes after the transdermal therapy. No significant changes occurred in the levels of D-dimers. After both treatment methods, the antithrombin III and fibrinogen levels decreased, but within their physiological ranges. CONCLUSIONS: Oral administration of estrogen statistically significantly reduced the tissue factor pathway inhibitor and plasminogen activator inhibitor-1 levels when compared with the transdermal route. These changes cannot be unambiguously considered risky, and the zero change of D-dimers suggests that there was no activation of the coagulation cascade. We consider the neutral effect of the transdermal therapy more beneficial. PMID- 17713348 TI - Frequency-dependent phenotype modulation of vascular smooth muscle cells under cyclic mechanical strain. AB - Phenotype transformation of vascular smooth muscle cells (VSMCs) is known to be modulated by mechanical strain. The present study was designed to investigate how different frequencies of mechanical strain affected VSMC phenotype. VSMCs were subjected to the strains of 10% elongation at 0, 0.5, 1 and 2 Hz for 24 h using a Flexercell strain unit. VSMC phenotype was assessed by cell morphology, measurement of two-dimensional cell area, Western blotting for protein and RT-PCR for mRNA expression of differentiation markers. Possible protein kinases involved were evaluated by Western blotting with their specific antibodies. The strains at certain frequencies could induce a contractile morphology in VSMC with almost perpendicular alignment to the strain direction. The strains also regulated protein and mRNA expression of several differentiation markers, as well as the activation of extracellular signal-regulated kinases (ERKs), p38 MAP kinase and protein kinase B (Akt) in a frequency-dependent manner. Furthermore, the inhibition of the p38 pathway could block the frequency-induced phenotype modulation of VSMCs, but not inhibition of ERK or Akt pathways. These results indicate that the frequency of cyclic strain can result in the differentiated phenotype of VSMCs, and it is mediated at least partly by the activation of the p38 pathway. PMID- 17713349 TI - The effects of statins on the progression of atherosclerotic renovascular disease. AB - BACKGROUND/AIMS: The aim was to examine the influence of statin therapy on the natural history of atherosclerotic renal artery stenosis (RAS). METHODS: Our hospital atherosclerotic renovascular disease (ARVD) database was analysed for patients who underwent repeat renal angiography during clinical follow-up. Patients with >or=1 RAS lesion and >or=4 months between baseline and repeat renal angiography were analysed. 79 patients were included. Baseline renal arterial anatomy was classified as normal, 50% RAS or renal artery occlusion. RESULTS: Mean follow-up time between angiograms was 27.8 +/- 22.3 (4.0 101.9) months. Progression of RAS occurred in 28 (23%) vessels, regression in 14 (12%) and no significant change in 79 (65%). Multivariate regression analysis showed that baseline proteinuria >0.6 g/day increased the risk of progressive disease (relative risk, RR, 3.8; 95% confidence interval, CI, 1.2-12.1), treatment with statin reduced the risk of progression (RR 0.28; 95% CI 0.10 0.77). 14 renal arteries from 12 patients showed RAS regression with a greater proportion on statin [statin treatment 10 (83%) versus no statin treatment 2 (17%), p = 0.001]. Change in estimated glomerular filtration rate (eGFR) per year was not different between statin- and no-statin-treated groups. CONCLUSIONS: Progression or development of RAS was significantly less likely to occur with statin therapy. Delta eGFR did not correlate with progression of RAS, reflecting the importance of intrarenal injury in the aetiology of renal dysfunction. Our results suggest statin therapy can alter the natural history of ARVD. PMID- 17713350 TI - Three-dimensional echocardiographic analysis of left ventricular function during hemodialysis. AB - BACKGROUND: The effects of hemodialysis (HD) on left ventricular (LV) function have been studied by various echocardiographic techniques (M-mode, 2D echocardiography). These studies are hampered by a low accuracy of measurements because of geometric assumptions regarding LV shape. Three-dimensional echocardiography (3DE) overcomes this limitation. METHODS: We tested the feasibility of 3DE assessment of LV function during HD. Conventional biplane Simpson rule (BSR) and single plane area length method (SPM) for LV function analysis were used as a reference. RESULTS: 12 HD patients were studied and in 10 (83%) a total of 80 3D datasets were acquired. In 3 patients, one dataset (4%) was of insufficient quality and excluded from analysis. Correlation between SPM, BSR and 3DE for calculation of end-diastolic (EDV, r = 0.89 and r = 0.92, respectively), end-systolic volume (ESV, r = 0.92 and r = 0.93, respectively) and for ejection fraction (EF, r = 0.90 and r = 0.88, respectively) was moderate. Limits-of-agreement results for EDV and ESV were poor with confidence intervals larger than 30 ml. Both 2DE methods underestimated end-diastolic and end-systolic volume, while overestimating ejection fraction. CONCLUSION: 3DE is feasible for image acquisition during HD, which opens the possibility for accurate and reproducible measurement of LV function during HD. This may improve the assessment of the acute effect of HD on LV performance, and guide therapeutic strategies aimed at preventing intradialytic hypotension. PMID- 17713351 TI - Dose requirements among hemodialysis patients treated with darbepoetin-alpha or epoetin-beta. AB - BACKGROUND/AIMS: In a cohort of hemodialysis patients, we evaluated the hypothesis that weekly administration of intravenous (IV) darbepoetin-alpha (DA) was associated with lower total erythropoiesis-stimulating agent (ESA) requirements as compared to a regimen of multiple subcutaneous (SC) doses per week of epoetin-beta (EB). METHODS: We studied 1,159 hemodialysis patients who were treated exclusively with either IV DA or SC EB across a network of Portuguese clinics during 2004. Linear regression was used to assess the adjusted relationship between the ESA regimen and weekly ESA requirements over the period of observation. Generalized estimating equations were applied in order to model the population average effects of the correlated mean weekly ESA dose for each individual. We also calculated propensity scores for the receipt of DA and assessed the relationship between ESA type and dose requirement within each quintile of the score. RESULTS: The adjusted dose of IV DA, when expressed as a proportion of the dose used in EB-treated patients, did not differ from the dose administered to EB recipients (0.961, 95% CI 0.904, 1.021). A similar relationship was observed within each propensity score quintile. CONCLUSIONS: Hemodialysis patients who received IV DA had dose requirements that were similar to their counterparts who were treated with SC EB. A once-weekly dosing regimen and avoidance of SC administration enhance the attractiveness of DA as an alternative to traditional ESAs. The potential for unmeasured confounding, restriction to a population that was treated with a single ESA preparation and application of a 200 IU:1 mug EB:DA dose conversion are important limitations of this study. PMID- 17713352 TI - Effect of the COX-2 inhibitor celecoxib on behavioural and immune changes in an olfactory bulbectomised rat model of depression. AB - BACKGROUND: The olfactory bulbectomised (OBX) rat model is a chronic model of depression in which behavioural and neuroimmunoendocrine changes are reversed only after chronic antidepressant treatment. The cyclooxygenase 2 (COX-2) inhibitor celecoxib has been shown to improve the depressive symptoms in patients with major depression. METHODS: The association between blood and brain immunological and behavioural changes in chronic treatment with COX-2 inhibitor was explored in the OBX rats and their sham-operated controls. RESULTS: The OBX group showed significantly higher locomotor activity than the other groups in the first 5 min in the open field. In the home cage emergence test, the OBX group showed a significantly shorter latency period compared to the sham group (z = 3.192, p = 0.001) but there was no difference between the other three groups. In the hypothalamus, the OBX group had a significantly higher interleukin 1beta (IL 1beta) concentration than the OBX + celecoxib group (z = -1.89, p = 0.05) as well as a significantly higher IL-10 concentration (z = -1.995, p = 0.046). In the prefrontal cortex, the OBX group showed significantly higher concentrations of tumour necrosis factor alpha (z = -2.205, p = 0.028) and IL-1beta (z = -3.361, p = 0.001) than the OBX + celecoxib group, but a significantly lower concentration of IL-10 (p = -3.361, p = 0.001) than the OBX + celecoxib group. CONCLUSIONS: The results of this study supported the potential therapeutic role of the COX-2 inhibitor celecoxib. It is possible that the behavioural changes following the chronic administration of celecoxib to the OBX rats are associated with an attenuation of the increase in the pro-inflammatory cytokines in the brain. PMID- 17713353 TI - Effect of sleep deprivation on the corticosterone secretion in an experimental model of autoimmune disease. AB - OBJECTIVE: Sleep disturbances have been observed in a number of chronic inflammatory conditions, such as systemic lupus erythematosus. Previous results from our laboratory showed that when NZB/NZWF1 mice, an experimental model of lupus, are submitted to sleep deprivation (SD), they exhibit an earlier onset of the disease. Sleep disturbances have far-reaching effects on the endocrine and immune system, changes that may be linked to disease manifestation. Immunoendocrine communication via the hypothalamic-pituitary-adrenal axis has been proposed as an important modulatory factor for the development of autoimmune disease. We hypothesized here that corticosterone (CORT) could be involved in earlier onset of the disease in sleep-deprived NZB/NZWF1 mice. METHODS: The profile of CORT secretion was measured immediately after the end of SD (platform method) and during the development of the disease. Also, we analyzed the effects of SD on CORT secretion of Swiss albino mice, which do not present immune alterations. RESULTS: The results showed that NZB/NZWF1 mice exhibited a CORT response to SD similar to Swiss albino mice. However, CORT levels remained elevated throughout the whole period of evaluation. There was an increase in circulating levels of CORT in the NZB/NZWF1 mice as the disease progressed, but this effect was more evident in the sleep-deprived mice. CONCLUSION: According to these results, we suggest that elevated CORT levels are involved in the earlier onset of the disease. PMID- 17713354 TI - Botulinum toxin therapy in the ovalbumin-sensitized rat. AB - OBJECTIVE: The aim of this study was to determine whether intranasal administration of botulinum toxin type A (BTX-A) could relieve the typical symptoms of allergic rhinitis (AR) and alter substance P (SP)- and vasoactive intestinal peptide (VIP)-immunoreactive (IR) expression in nasal mucosa of AR animals sensitized with ovalbumin (OVA). METHODS: AR was induced by intraperitoneal injection of OVA followed by its repeated intranasal instillation in female Wistar rats. Some AR animals were intranasally treated with a cotton strip containing BTX-A (10 U per nostril) for 1 h. After BTX-A treatment, OVA was repeatedly instilled in AR and AR + BTX-A groups every 2 days for 10 days. Subsequently, nasal symptoms were evaluated, and nasal secretions collected. Finally, the nasal mucosae of all animals were prepared for histological and immunohistochemical assessment. RESULTS: BTX-A administration alleviated typical AR symptoms including rhinorrhea, nasal itching and sneezing, and subsequent intranasal repeated challenge with OVA did not trigger AR symptoms. After BTX-A treatment, inflammatory histological characteristics within the nasal mucosa of AR animals were absent, but atrophy of serous glands was observed. BTX-A decreased dense SP-IR and VIP-IR cells and fibers within and beneath the epithelium, around blood vessels and close to serous glands in AR animals. CONCLUSION: Local BTX-A treatment is an effective method to reduce AR symptoms. BTX-A decreased the excessive SP-IR and VIP-IR expression induced by OVA. Therefore, BTX-A may affect the nasal mucosa via the suppression of neuropeptides, playing a major role in autonomous mucosal innervation in the pathophysiology of AR. PMID- 17713355 TI - Impact of gender and menstrual cycle phase on plasma cytokine concentrations. AB - OBJECTIVE: The lifetime prevalence of major depression is twice as high in females as in males. Depression is known to increase at periods where there are changes in gonadal hormones. We examined pro- and anti-inflammatory cytokine levels during the normal menstrual cycle of healthy females compared to similar time points in healthy males. METHODS: Plasma concentrations of interleukin (IL) 4, IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNF-alpha) and soluble IL-6 receptor (sIL-6R) were measured with enzyme-linked immunosorbent assays in healthy females during the normal ovulatory menstrual cycle and also in males at similar time points. RESULTS: The luteal phase of the menstrual cycle is associated with increased production of sIL-6R, IL-4 and TNF-alpha compared to the early follicular phase. No change was observed in IL-6, IL-8 and IL-10 concentration throughout the menstrual cycle. We found IL-4 positively correlated with oestrogen while TNF-alpha positively correlated with progesterone. Females were found to have significantly higher concentrations of TNF-alpha and sIL-6R across all phases of the menstrual cycle, compared to males across similar time points. CONCLUSION: The normal menstrual cycle is associated with increased production of sIL-6R, IL-4 and TNF-alpha in the luteal phase compared to the early follicular phase. Females have significantly higher concentrations of sIL 6R and TNF-alpha at all time points across the menstrual cycle than males. PMID- 17713356 TI - Beta-adrenergic receptor blockade attenuates the exercise-induced suppression of TNF-alpha in response to lipopolysaccharide in rats. AB - Stressful exercise has been found to reduce the proinflammatory cytokine response to lipopolysaccharide (LPS). In this study, we aimed to determine whether receptor antagonists for corticosterone or catecholamines would increase the LPS induced tumor necrosis factor-alpha (TNF-alpha) response after exhaustive exercise. Female F344 rats were randomly assigned to one of five groups: control (vehicle), RU-486 (glucocorticoid receptor antagonist, 30 mg/kg)-, propranolol [nonselective beta-adrenergic receptor (AR) blockade, 30 mg/kg]-, atenolol (beta(1)-AR blockade, 30 mg/kg)-, or ICI 118551 (beta(2)-AR blockade, 30 mg/kg) treated groups. Each antagonist was given intraperitoneally 30 min prior to exercise or control period. Exercised rats ran until exhaustion on a treadmill at gradually increasing speeds, from 10 to 36 m/min at 15% grade. Immediately postexercise or control period all rats were injected with LPS (1 mg/kg, i.v.). Plasma TNF-alpha was reduced by prior exercise to approximately 10% of that of sedentary controls (p < 0.01). Plasma TNF-alpha concentration in exercised RU-486 treated rats was significantly different than that of nonexercised rats (19.2%, p < 0.01) and not different from exercised rats. However, pretreatment of rats with the nonselective beta-AR blocker propranolol almost completely reversed the exercise-induced suppression of plasma TNF-alpha in response to LPS. beta(1)-AR pretreatment almost completely attenuated the exercise-induced suppression of LPS induced plasma TNF-alpha while beta(2)-antagonism had a partial effect. These results indicate that exercise-induced catecholamines, acting through beta-ARs (especially the beta(1)-AR), are responsible for the exercise-induced suppression of plasma TNF-alpha after LPS administration. PMID- 17713358 TI - Mini-incision for pediatric cochlear implantation with a MED-EL device. AB - OBJECTIVE: Minimal invasive approaches have been described for cochlear implantation. However, the number of reports about minimal invasive approaches for MED-EL devices is sparse. In this technical note, we describe our pediatric cochlear implantation and incision techniques for MED-EL devices. METHODS: Among 92 cochlear implantations performed between November 2002 and November 2006, there were 32 consecutive pediatric cochlear implantations with MED-EL devices which were performed between July 2005 and October 2006. In our technique, standard posterior tympanotomy and cochleostomy were performed after 4- to 5-cm mini-incisions in the postauricular region. However, suture fixations were not used for the implant receiver nor its electrode. RESULTS: There were 14 girls and 18 boys with a mean age of 3.9 years. The mean follow-up duration was 5.8 months. No flap necrosis, hematoma or infection, nor implant migration, extrusion or breakdown were encountered. Revision surgery was performed in 3 patients due to cochlear ossification, perilymph leakage and extracochlear implantation. CONCLUSION: MED-EL implantation can be performed using small incisions without suture fixation of the receiver and its electrode. PMID- 17713357 TI - Expression and secretion of CXCL8 (IL-8), release of tryptase and transcription of histidine decarboxylase mRNA by anti-IgE-activated human umbilical cord blood derived cultured mast cells. AB - Activation of cytokine receptors and alterations in cytokines are thought to play important roles in neuronal dysfunction and in the pathogenesis of the nervous system diseases. CXCL8 (IL-8) is a CXC chemokine with chemotactic and inflammatory properties. Chemokines control mast cell infiltration in several inflammatory diseases, including stress and neurological dysfunctions. Using isolated human umbilical cord blood-derived cultured mast cells (HUCMC) from hematopoietic stem cells CD34+, mast cells were immunologically activated with anti-IgE at concentrations of 1, 5, 10 and 20 microg/ml leading to the dose dependent production of IL-8 (p < 0.05). The increase in IL-8 mRNA expression was also noted when the cells were treated with anti-IgE at 10 microg/ml for 6 h. Immunologically activated HUCMC provoked the generation of tryptase in a dose- and time-dependent manner. We also found increased histidine decarboxylase (HDC) expression in activated HUCMC after 6 h of incubation, a rate-limiting enzyme responsible for the generation of histamine from histidine. Taken together, these results confirm that anti-IgE-activated mast cells release inflammatory mediators including CXCL8, a CXC chemokine which regulates several biological effects of mast cells, e.g. chemoattraction, and possibly causes cell arrest. PMID- 17713359 TI - Effectiveness and side effects of one-stage laser-assisted uvuloplasty in primary rhonchopathy. AB - The aim of this study is to evaluate the results of laser-assisted uvuloplasty (LAUP) in terms of effect on snoring and side effects. The case report study is based on the analysis of questionnaires with a visual analog scale (VAS) describing the severity of snoring before and 6-26 months after operation and questions regarding postoperative course. The group of patients consisted of 73 patients with primary rhonchopathy. The average preoperative VAS score was 8.36; it decreased to an average of 3.98 postoperatively (p = 0.001). No improvement was reported by 12% of patients, improvement of 4 and more of the VAS scale was reported by 67% of patients. The majority (58%) of patients reported postoperative pain for up to 10 days. Bothersome sensations persisted in 15% of patients. No predictive factors for the success of treatment were found. LAUP diminished snoring in 88% of patients. A major drawback was the postoperative pain. Further studies looking for predictive factors are needed. PMID- 17713360 TI - An improved mouse model of atopic dermatitis and suppression of skin lesions by an inhibitor of Tec family kinases. AB - BACKGROUND: Atopic dermatitis is a chronic or chronically relapsing, pruritic inflammatory skin disease. The incidence of atopic dermatitis has dramatically increased during the past three decades in industrialized countries. We attempted to develop an improved method to induce an animal model of atopic dermatitis and to use it to evaluate the efficacy of a Tec family kinase inhibitor. METHODS: We treated dermatitis-prone inbred mice, NC/Nga, by repetitive epicutaneous applications of a house dust mite allergen and staphylococcal enterotoxin B to induce atopic dermatitis-like skin lesions. RESULTS: We established a highly efficient protocol to induce skin lesions in NC/Nga mice, which were histologically and immunologically similar to human atopic dermatitis. Similar to human patients, serum IgE levels were increased in dermatitis-induced mice. Consistent with the proposed roles of infiltrated immune cells in the pathogenesis of human atopic dermatitis, skin lesions were treatable with terreic acid, an inhibitor of Tec family kinases, as well as dexamethasone. CONCLUSIONS: We established a highly efficient, highly reproducible protocol to induce skin lesions in NC/Nga mice and successfully applied it to show the efficacy of terreic acid in treating skin lesions. This mouse model of atopic dermatitis will be useful to study the pathogenetic processes of atopic dermatitis and to evaluate the efficacy of drug candidates. PMID- 17713361 TI - Analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis in Japan from 2000 to 2006. AB - BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse drug reactions with high mortality. METHODS: To present the current clinical characteristics and treatment of SJS and TEN in Japan, we retrospectively analyzed reports of SJS and TEN published in medical journals from 2000 to 2006. RESULTS: Fifty-two cases of SJS (19 males and 33 females; mean age, 45.2 years) and 65 cases of TEN (31 males and 34 females; mean age, 45.7 years) were reported. Thirty-six cases of SJS (69.2%) and all cases of TEN were caused by drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and anticonvulsant drugs. Hepatitis was the most common organ involvement in both SJS and TEN. Renal dysfunction and respiratory disorders were also involved in some cases. The major complication was sepsis, but in only 1.9% of SJS and 10.8% of TEN. Most cases were treated systemically with corticosteroids, and 42 cases (80.8%) of SJS and 39 cases (60.0%) of TEN were treated with corticosteroids alone. Plasmapheresis and/or immunoglobulin therapy was combined with corticosteroid therapy in some cases. The mortality rates for patients with SJS and TEN were 1.9% and 6.2%, respectively. The mortality in TEN decreased remarkably from 21.6% (58/269) during the previous 17 years (1981 to 1997). CONCLUSIONS: Improvement of treatment may be one of the reasons for the decrease in mortalities of both SJS and TEN. PMID- 17713362 TI - Symptoms of allergic rhinitis in women during early pregnancy are associated with higher prevalence of allergic rhinitis in their offspring. AB - BACKGROUND: Epigenetic control of gene expression profiles is a ubiquitous mechanism during cell differentiation, organogenesis and chronic inflammatory reactions. Recent studies have shown that allergen exposure during very early pregnancy increases bronchial hypersensitivity in offspring in a murine model of bronchial asthma. However, no such phenomena were reported in humans. In the present study, the role of epigenetic control in the onset of allergic diseases was investigated. METHODS: A total of 400 pairs of mothers with physician diagnosed allergic rhinitis (AR) and their offspring (age 7-18 months) who participated in a large-scale medical check-up were enrolled in this retrospective cohort study. Family history of allergic diseases and the presence or absence of AR symptoms during pregnancy were inquired about using a self answered questionnaire. A logistic regression model adjusted for age, gender, birth month and father's history of allergic diseases was statistically analyzed. RESULTS: Offspring whose mothers had any AR symptoms during early pregnancy showed a significantly higher adjusted odds ratio for the onset of AR in offspring than those whose mothers had no symptoms during pregnancy (adjusted Odds Ratio: 6.26, p = 0.036). However, the symptoms of AR during late pregnancy showed no effects on the odds ratio. In contrast, the presence or absence of AR symptoms during early or late pregnancy showed no association with the prevalence of food allergy, atopic dermatitis or asthma in offspring. CONCLUSIONS: Our results suggest the presence of possible epigenetic mechanisms regulating the onset of AR in humans presumably through increased organ-specific hypersensitivity. PMID- 17713364 TI - Respiratory muscle weakness in patients with critical illness neuromyopathies: A practical assessment. PMID- 17713365 TI - Modulation of the sepsis inflammatory response by resuscitation: The missing link between cytopathic and hypoxic hypoxia? PMID- 17713366 TI - The need for a registry renaissance in neurocritical care. PMID- 17713367 TI - The team works 24/7. PMID- 17713368 TI - Pulmonary hypertension in the intensive care unit: Critical role of the right ventricle. PMID- 17713369 TI - Size matters to a model's fit. PMID- 17713370 TI - Not a panacea. PMID- 17713371 TI - Positive blood cultures or Gram-negative pathogens with ventilator-associated pneumonia: What's the real killer? PMID- 17713372 TI - Is simple bedside glucose assessment prognostic in calcium channel blocker overdose? PMID- 17713373 TI - Rapid response systems: Is it the team or the system that is working? PMID- 17713374 TI - Closing the gap between knowledge and behavior: Mission impossible? PMID- 17713375 TI - Developing new strategies in severe traumatic shock: Small continuous steps are likely to result in progress. PMID- 17713376 TI - Kidney in sepsis. PMID- 17713377 TI - Administration of exogenous cytochrome c as a novel approach for the treatment of cytopathic hypoxia. PMID- 17713378 TI - Understanding the role of stress proteins in acute lung injury: Closer to the answer, but not there yet. PMID- 17713379 TI - Cerebral microcirculation during cardiopulmonary resuscitation: Polarized light at the end of the tunnel? PMID- 17713380 TI - Permissive hypercapnia: Balancing risks and benefits in the peripheral microcirculation. PMID- 17713381 TI - Pathology of mechanical and gap junctional co-coupling at the intercalated disc: Is sepsis a junctionopathy? PMID- 17713382 TI - Sepsis, oxidative stress, and brain injury. PMID- 17713384 TI - Rapid response system: Let's not get carried away! PMID- 17713386 TI - Interpretation of acid-base disorders. PMID- 17713387 TI - "A rose by any other name"? Toward a common terminology in simulation education and assessment. PMID- 17713389 TI - Metabolic support in sepsis and multiple organ failure. PMID- 17713390 TI - Metabolic support in sepsis and multiple organ failure: more questions than answers ... AB - The metabolic support of critically ill patients is a relatively new topic of active research and discussion, and surprisingly little is known about the effects of critical illness on metabolic physiology and activity. The metabolic changes seen in critical illness are highly complex, and how and when to treat them are only just beginning to be determined. Studies have demonstrated that the acute phase and the later phase of critical illness behave differently from a metabolic point of view for many organs, and while many of the alterations in metabolism seen during early critical illness may be appropriate and beneficial responses to cellular stress, whether this is true for all the metabolic alterations in all forms of critical illness is unclear. Currently we face more questions than answers, and further study is needed to elucidate the various components of the metabolic response to acute and chronic critical illness and to develop better techniques to assess and monitor these changes so that we can determine which therapeutic approaches should be used in what combinations and in which patients. PMID- 17713391 TI - Mitochondrial function in sepsis: acute phase versus multiple organ failure. AB - OBJECTIVE: To describe temporal changes in mitochondrial function during the septic process, including the recovery phase. DESIGN: Literature review. SUBJECTS: Clinical studies and laboratory models. MAIN RESULTS: Biochemical and ultrastructural mitochondrial abnormalities have been recognized in in vivo, ex vivo, and in vitro laboratory models of sepsis for >30 yrs. Short-term models show variable effects on mitochondrial function and structure; this is likely related to differences in model design, including species, organs studied, degree of septic insult, and degree of resuscitation. Longer-term models more consistently reveal mitochondrial dysfunction and damage. There is a rebound increase in oxygen consumption and resting energy expenditure in the recovery phase of sepsis. This could reflect mitochondrial recovery (biogenesis) that may restore the energy supply needed to fuel restorative metabolic processes and enable patient survival. CONCLUSION: Mitochondrial dysfunction seems to be intrinsically involved in the pathogenesis of multiple organ failure. As a consequence of a progressive decrease in energy availability, metabolism must decrease or the cell will die. The interplay between adenosine 5'-triphosphate supply and demand, dictated by the degree of mitochondrial dysfunction and the level of metabolic shutdown (analogous to a hibernation-type response), seems to be crucial in determining outcome. Further studies are needed to confirm this hypothesis. PMID- 17713392 TI - Mitochondrial function in sepsis: respiratory versus leg muscle. AB - Patients with sepsis-induced multiple organ failure often experience muscle fatigue in both locomotive and respiratory muscles. Muscle fatigue extends intensive care unit stay, mostly in the form of prolonged weaning from the ventilator, and the recovery period after intensive care unit treatment due to general muscle fatigue. Muscle mitochondria are the main determinant of muscle fatigue and fatigability. Derangements in mitochondrial function in locomotive muscles have been described extensively both in animal models and patients with sepsis. Also, in respiratory muscle, mitochondrial function and content are impaired during sepsis. However, in septic patients with multiple organ failure, in locomotive muscle, lower levels of energy-rich compounds accompany the decreased mitochondrial content, whereas in respiratory muscle, the decreased mitochondrial content has no effect on cellular energy metabolism. PMID- 17713393 TI - Mitochondrial function and substrate availability. AB - Carbohydrates and lipid oxidations support energy metabolism by distinct pathways exhibiting similarities and differences. Alterations of energy metabolism during sepsis are well recognized; however, failure of oxygen or substrate supply is not a prominent cause. The occurrence of a "mitochondrial cytopathy" induced by sepsis explains some of these abnormalities, which may represent a "metabolic hibernation," a potential strategy of defense during the very acute phase of the illness. Our view of the involvement of mitochondrial metabolism in cell signaling has evolved considerably. Because of the structure of the respiratory chain, the way electrons are provided (upstream or downstream of complex 1 [i.e., nicotinamide adenine dinucleotide {reduced form} or flavin adenine dinucleotide {reduced form}]) plays an important role in the regulation of several functions, including the yield of adenosine triphosphate synthesis and the production of reactive oxygen species. Moreover, the modern view of energy channeling and compartmentation in the cell may open attractive hypotheses regarding the changes in cellular energy distribution in pathologic states, such as sepsis. PMID- 17713394 TI - Hemigramicidin-TEMPO conjugates: novel mitochondria-targeted antioxidants. AB - Reactive oxygen species (ROS) are reactive, partially reduced derivatives of molecular oxygen. ROS are important in the pathogenesis of a wide range of acute pathologic processes, including ischemia/reperfusion injury, sepsis, and shock. Accordingly, effective ROS scavengers might be useful therapeutic agents for these conditions. Since mitochondria are the primary sites for ROS production within cells, it seems reasonable that targeting ROS scavengers to these organelles could be a particularly effective strategy. Indeed, a number of compounds or classes of compounds have been described that are based on this concept. One approach consists of coupling a payload--the portion of the molecule with ROS-scavenging activities--to a targeting moiety--the portion of the molecule that promotes selective accumulation within mitochondria. For example, the payload portion of XJB-5-131 consists of a stable nitroxide radical, which has been extensively investigated as a cytoprotective agent in a number of experimental models of oxidative stress. The targeting portion of XJB-5-131 consists of a portion of the membrane-active cyclopeptide antibiotic, gramicidin S. The gramicidin segment was used to target the nitroxide payload to mitochondria because antibiotics of this type have a high affinity for bacterial membranes and because of the close relationship between bacteria and mitochondria. In a rat model of hemorrhagic shock, delayed treatment with XJB-5 131 has been shown to prolong survival time in the absence of resuscitation with blood or a large volume of crystalloid fluid. Compounds like XJB-5-131 warrant further evaluation for the treatment of hemorrhagic shock as well as other acute conditions associated with increased mitochondrial production of ROS. PMID- 17713395 TI - Cytochrome c oxidase dysfunction in sepsis. AB - Sepsis, the principal cause of death in critically ill patients, is associated with impaired oxygen extraction by tissues. One possible explanation is the development of mitochondrial dysfunction and ineffective oxygen utilization. This abnormality has been termed cytopathic hypoxia. This may be caused by an abnormality in the transport of electrons down the cytochrome chain on the mitochondrial inner membrane. In this article we review our studies on abnormalities in the function of complex IV (cytochrome oxidase), the final electron acceptor in this chain. In addition, we provide evidence that administration of cytochrome c may overcome these abnormalities and provide a novel therapeutic alternative. PMID- 17713396 TI - Role of fat metabolism in burn trauma-induced skeletal muscle insulin resistance. AB - OBJECTIVE: Review current evidence on the role of fat in post-trauma insulin resistance, in reference to new studies with peroxisome proliferating activating receptor-alpha agonists. DESIGN: Review. SETTING: University laboratory. PATIENTS: Thirty pediatric burn trauma patients. INTERVENTIONS: Fourteen days of peroxisome proliferating activating receptor-alpha agonist immediately following burn trauma. MEASUREMENTS AND MAIN RESULTS: We measured glucose metabolism and fat metabolism via tracer methodology and intracellular measurements. Insulin stimulated glucose uptake is impaired following burn trauma, as is intracellular insulin signaling, palmitate oxidation, and mitochondrial oxidative capacity. Furthermore, levels of intracellular lipids are increased. Two weeks of peroxisome proliferating activating receptor-alpha treatment significantly reverses these pathologic changes incurred from burn injury. CONCLUSIONS: Severe burn injury seriously affects multiple aspects of glucose and fat metabolism within the muscle, which can adversely affect clinical outcomes. Treatment with a peroxisome proliferating activating receptor-alpha drug may be a potential new therapeutic option. PMID- 17713397 TI - Experimental animal models of muscle wasting in intensive care unit patients. AB - The muscle wasting and loss of muscle function associated with critical illness and intensive care have significant negative consequences for weaning from the respirator, duration of hospital stay, and quality of life for long periods after hospital discharge. There is, accordingly, a significant demand for focused research aiming at improving our understanding of the mechanisms underlying the impaired neuromuscular function in intensive care unit (ICU) patients. However, the study of generalized muscle weakness in critically ill ICU patients is further complicated by the coexistence of multiple independent factors, such as different primary diseases, large variability in pharmacologic treatment, collection of muscle samples several weeks after admission to the ICU, and exposure to causative agents. This has led to the design of specific animal models mimicking ICU conditions. These models have often been used to study the mechanisms underlying the paralysis and muscle wasting associated with acute quadriplegic myopathy in ICU patients. This short review aims at presenting existing and recently introduced experimental animal models mimicking the conditions in the ICU (i.e., models designed to determine the mechanisms underlying the muscle wasting associated with ICU treatment). PMID- 17713398 TI - Mitochondria, endoplasmic reticulum, and alternative pathways of cell death in critical illness. AB - Dying cells are distinguished by their biochemical and morphologic traits and categorized into three subtypes: apoptosis, oncosis (necrosis), and cell death with autophagy. Each of these types of cell death plays critical roles in tissue morphogenesis during normal development and in the pathogenesis of human diseases. Given that tissue homeostasis is controlled by the intricate balance between degeneration and regeneration, it is essential to understand the mechanisms of different forms of cell death to establish and improve therapeutic interventions for prevention and rescue of these cell death-related disorders. Critical illness, including sepsis, trauma, and burn injury, is often complicated by multiple organ dysfunction syndrome and is accompanied by increased cell death in parenchymal and nonparenchymal tissues. Accumulating evidence suggests that augmented cell death plays an important role in the organ failure in critical illness. We discuss possible therapeutic approaches for prevention of cell death, particularly apoptotic cell death. PMID- 17713399 TI - Tight blood glucose control: what is the evidence? AB - In two large, randomized studies, maintenance of normoglycemia with intensive insulin therapy largely prevented morbidity and reduced mortality of critically ill patients. Recently, questions have been raised about the efficacy and safety of this therapy. These issues are systematically addressed and discussed with the evidence available from these and other studies. The available studies show that an absolute reduction in risk of hospital death of 3% to 4% is to be expected from intensive insulin therapy in an intention-to-treat analysis. Future studies designed to confirm a statistically significant survival benefit should be adequately powered, with inclusion of >or=5,000 patients. When patients are treated with intensive insulin therapy for >3 days, the absolute reduction in the risk of death increases to approximately 8%. Insulin therapy also improves morbidity, more so when continued for >3 days. Strict blood glucose control to normoglycemia (<110 mg/dL) is required to obtain the most clinical benefit, but this inherently increases the risk of hypoglycemia. It remains unclear whether short hypoglycemic episodes are truly harmful for these patients. In conclusion, demonstration of the clinical benefits of intensive insulin therapy depends on the quality of blood glucose control and the statistical power of the studies. PMID- 17713400 TI - Clinical experience with tight glucose control by intensive insulin therapy. AB - OBJECTIVE: To describe the current status and the clinical data related to the effects of tight glucose control by intensive insulin therapy in critically ill patients. DESIGN: Review article. SETTING: University hospital. PATIENTS: Medical and surgical critically ill patients in whom a correlation between blood glucose and outcome variables were searched. INTERVENTIONS: Tight glucose control by intensive insulin therapy. MEASUREMENTS AND MAIN RESULTS: In contrast to the decreases in mortality and to low severity of adverse effects reported when insulin rate was titrated to keep blood glucose between 80 and 110 mg/dL, the benefits were not confirmed in multicenter prospective studies. Retrospective data found an association between a mean blood glucose level of <140-150 mg/dL and improved outcome. Currently unanswered issues include the optimal target for blood glucose, the effects of high blood glucose variability, the risks and hazards of hypoglycemia, and the potential influence of the underlying disorder on the effects of tight glucose control. CONCLUSIONS: Recommendations regarding the practical aspects of tight glucose control by intensive insulin therapy cannot be presently issued. An intermediate target level for blood glucose of 140 180 mg/dL seems to be associated with the lowest risk-to-benefit ratio. PMID- 17713401 TI - Glucose metabolism and catecholamines. AB - Until now, catecholamines were the drugs of choice to treat hypotension during shock states. Catecholamines, however, also have marked metabolic effects, particularly on glucose metabolism, and the degree of this metabolic response is directly related to the beta2-adrenoceptor activity of the individual compound used. Under physiologic conditions, infusing catecholamine is associated with enhanced rates of aerobic glycolysis (resulting in adenosine triphosphate production), glucose release (both from glycogenolysis and gluconeogenesis), and inhibition of insulin-mediated glycogenesis. Consequently, hyperglycemia and hyperlactatemia are the hallmarks of this metabolic response. Under pathophysiologic conditions, the metabolic effects of catecholamines are less predictable because of changes in receptor affinity and density and in drug kinetics and the metabolic capacity of the major gluconeogenic organs, both resulting from the disease per se and the ongoing treatment. It is also well established that shock states are characterized by a hypermetabolic condition with insulin resistance and increased oxygen demands, which coincide with both compromised tissue microcirculatory perfusion and mitochondrial dysfunction. This, in turn, causes impaired glucose utilization and may lead to inadequate glucose supply and, ultimately, metabolic failure. Based on the landmark studies on intensive insulin use, a crucial role is currently attributed to glucose homeostasis. This article reviews the effects of the various catecholamines on glucose utilization, both under physiologic conditions, as well as during shock states. Because, to date (to our knowledge), no patient data are available, results from relevant animal experiments are discussed. In addition, potential strategies are outlined to influence the catecholamine-induced effects on glucose homeostasis. PMID- 17713402 TI - Effect of insulin on the inflammatory and acute phase response after burn injury. AB - After a severe burn, the liver plays a pivotal role by modulating inflammatory processes, metabolic pathways, immune functions, and the acute phase response. Therefore, liver integrity and function are important for recovery. A thermal injury, however, causes hepatic damage by inducing hepatic edema, fatty infiltration, hepatocyte apoptosis, and metabolic derangements associated with insulin resistance and impaired insulin signaling. In preliminary studies, we found that these pathophysiological processes are related to hepatic inflammation, altered intracellular signaling, and mitochondrial dysfunction. We hypothesize that modulation of these processes with insulin could improve hepatic structure and function and, therefore, outcome of burned and critically ill patients. Insulin administration improves survival and decreases the rate of infections in severely burned and critically ill patients. Here, we show that insulin administration decreases the synthesis of proinflammatory cytokines and signal transcription factors and improves hepatic structure and function after a severe burn injury; insulin also restores hepatic homeostasis and improves hepatic dysfunction postburn via alterations in the signaling cascade. PMID- 17713403 TI - Insulin and the burned patient. AB - Severe burns lead to insulin resistance, which is associated with hyperglycemia and muscle wasting. Investigators showed relatively recently that control of hyperglycemia with intensive insulin treatment is associated with improved outcomes for those in the intensive care unit, including patients with severe burns. In this article, we review the actions of insulin in terms of glycemic control and muscle metabolism, biochemical and clinical effects of insulin treatment in the severely burned, and the vagaries of glucose control. PMID- 17713404 TI - Substrate utilization in sepsis and multiple organ failure. AB - Sepsis and multiple organ failure are characterized by an excessive release of inflammatory mediators and a marked stimulation of stress hormones. These in turn have profound effects on energy and substrate metabolism: energy expenditure is generally increased, and increased lipolysis and fat oxidation are observed. Net protein breakdown occurs and leads to accelerated wasting. Most of these effects can be produced in healthy humans by administration of bacterial endotoxin or by tumor necrosis factor-alpha. Hyperlactatemia is a hallmark of sepsis and critical illness, and its severity is related to mortality. An increased lactate production, possibly secondary to activation of Na-K adenosine 5'-triphosphatase and to muscle mitochondrial dysfunction, is involved. Lactate production by immune cells and wound tissue may also play a role. Long-chain, n-3 polyunsaturated fatty acids have anti-inflammatory effects that may be beneficial in sepsis. They also decrease the stimulation of stress hormones induced by bacterial endotoxin, possibly through an effect exerted at the level of the central nervous sytem. Their use in patients with sepsis does not lead to adverse metabolic effects. PMID- 17713405 TI - Feeding critically ill patients: what is the optimal amount of energy? AB - Hypermetabolism and malnourishment are common in the intensive care unit. Malnutrition is associated with increased morbidity and mortality, and most intensive care unit patients receive specialized nutrition therapy to attenuate the effects of malnourishment. However, the optimal amount of energy to deliver is unknown, with some studies suggesting that full calorie feeding improves clinical outcomes but other studies concluding that caloric intake may not be important in determining outcome. In this narrative review, we discuss the studies of critically ill patients that examine the relationship between dose of nutrition and clinically important outcomes. Observational studies suggest that achieving targeted caloric intake might not be necessary since provision of approximately 25% to 66% of goal calories may be sufficient. Randomized controlled trials comparing early aggressive use of enteral nutrition compared with delayed, less aggressive use of enteral nutrition suggest that providing increased calories with early, aggressive enteral nutrition is associated with improved clinical outcomes. However, energy provision with parenteral nutrition, either instead of or supplemental to enteral nutrition, does not offer additional benefits. In summary, the optimal amount of calories to provide critically ill patients is unclear given the limitations of the existing data. However, evidence suggests that improving adequacy of enteral nutrition by moving intake closer to goal calories might be associated with a clinical benefit. There is no role for supplemental parenteral nutrition to increase caloric delivery in the early phase of critical illness. Further high-quality evidence from randomized trials investigating the optimal amount of energy intake in intensive care unit patients is needed. PMID- 17713406 TI - Glutamine: mode of action in critical illness. AB - A recent editorial in Critical Care Medicine was titled "Glutamine, a life-saving nutrient, but why?" (2003; 31:2555-2556). This review will attempt to utilize new understanding of gene-nutrient interactions and molecular medicine to address potential mechanisms by which glutamine may be lifesaving after critical illness and injury. Recent meta-analysis data reveal that glutamine seems to exert a beneficial effect on mortality in critically ill patients. However, this effect seems to be dose and route dependent. The questions that remain to be answered are in what settings and via what method of administration does this phamaconutrient show optimal benefit? It is likely that examination of the molecular mechanisms by which glutamine exerts its effects will lead to an understanding of how best to utilize glutamine as both a pharmacologic and a nutritional agent. Clearly, clinical critical illness leads to a marked deficiency in glutamine that is correlated with mortality in the intensive care unit setting. It makes obvious sense that the deficiency of this vital stress nutrient should be replaced. In addition, recent laboratory data reveal glutamine may act via mechanisms independent of its role as a metabolic fuel. These include enhanced stress protein response, attenuation of the inflammatory response, improved tissue metabolic function, and attenuation of oxidant stress. Present data indicate that glutamine functions as a metabolic fuel and "stress-signaling molecule" after illness and injury. Thus, deficiencies observed in critical illness demand replacement for both pharmacologic and metabolic optimization. Presently, randomized, multicenter, clinical trials utilizing glutamine as a pharmacologic and a nutritional agent are ongoing. PMID- 17713407 TI - Exogenous glutamine: the clinical evidence. AB - We know that critically ill patients suffering from undernutrition with a limited nutritional reserve have a poorer outcome. Furthermore, having a low body mass index has been shown to be an independent predictor of excess mortality in multiple organ failure. Therefore, nutritional support has gained increasing interest in critical illness with the hope of preventing or attenuating the effects of malnutrition. A negative nitrogen balance is the characteristic metabolic feature in critical illness, with the major protein loss derived from skeletal muscle. In particular, glutamine concentrations are rapidly reduced in plasma and muscle. Over the last 20 yrs or so, increasing evidence is emerging to support the use of glutamine supplementation in critical illness. Clinical trials have found a mortality and morbidity advantage with glutamine supplementation. The advantage appears to be greater the more glutamine is given and greater again when given parenterally. Various modes of action have been postulated. Glutamine seems to have an effect on the immune system, antioxidant status, glucose metabolism, and heat shock protein response. However, the benefit of exogenous glutamine on morbidity and mortality is not universally accepted. This review critically appraises the current clinical evidence regarding glutamine supplementation in critical illness. PMID- 17713408 TI - Exogenous glutamine--compensating a shortage? AB - There is still insufficient knowledge about in vivo glutamine metabolism and the regulation of glutamine homeostasis, particularly during metabolic stress. A shortage of glutamine is associated with a poor outcome, whereas for septic patients in the intensive care unit an increased availability of glutamine can prevent mortality and morbidity. Cellular defense mechanisms depend on normal glutamine availability to respond adequately to challenges presented. In clinical practice, treatment of plasma glutamine depletion improves outcome for the critically ill patient. An increased metabolic need for glutamine must be met with an increased consumption of glutamine. Ordinary food is not a sufficient supply of glutamine for the patient with multiple organ failure in the intensive care unit, but that is also true for several other nutrients. It is, therefore, debatable whether an exogenous supply of glutamine should be regarded as a pharmacologic treatment or whether this just represents physiology in stressed states. If a glutamine shortage requires substitution, supplementation to the normal concentration is compensation of a shortage, and the effect is physiological. PMID- 17713409 TI - Exogenous arginine in sepsis. AB - Sepsis is a severe condition in critically ill patients and is considered an arginine deficiency state. The rationale for arginine deficiency in sepsis is mainly based on the reduced arginine levels in sepsis that are associated with the specific changes in arginine metabolism related to endothelial dysfunction, severe catabolism, and worse outcome. Exogenous arginine supplementation in sepsis shows controversial results with only limited data in humans and variable results in animal models of sepsis. Since in these studies the severity of sepsis varies but also the route, timing, and dose of arginine, it is difficult to draw a definitive conclusion for sepsis in general without considering the influence of these factors. Enhanced nitric oxide production in sepsis is related to suggested detrimental effects on hemodynamic instability and enhanced oxidative stress. Potential mechanisms for beneficial effects of exogenous arginine in sepsis include enhanced (protein) metabolism, improved microcirculation and organ function, effects on immune function and antibacterial effects, improved gut function, and an antioxidant role of arginine. We recently performed a study indicating that arginine can be given to septic patients without major effects on hemodynamics, suggesting that more studies can be conducted on the effects of arginine supplementation in septic patients. PMID- 17713410 TI - Use of exogenous arginine in multiple organ dysfunction syndrome and sepsis. AB - Given the multiple biological, metabolic, and pharmacologic effects of supplemental arginine, much effort has been devoted to defining its role in numerous clinical conditions. Herein, we review the multiple pathways of arginine metabolism with its various enzyme systems; the effect of arginine on nutrition, healing, and immune system; and its clinical use. Sepsis has been postulated to be an arginine-deficient state and/or a syndrome with elevated levels of nitric oxide. So-called immunonutritional formulations containing various nutritional components have been used most often, yet the effects often are attributed to arginine alone. Such conclusions led to guidelines recommending against the use of arginine-supplemented diets in critically ill patients. While caution in the face of a lack of evidence for benefit in sepsis is commended, well-defined studies examining arginine monotherapy in the context of full nutritional support should be carried out so as to define the possible clinical uses of arginine in critically ill and septic patients. PMID- 17713411 TI - Specific amino acids in the critically ill patient--exogenous glutamine/arginine: a common denominator? AB - OBJECTIVE: Glutamine and arginine are both used as nutritional supplements in critically ill patients. Although glutamine has been shown to be beneficial for the metabolically stressed patient, considerations about arginine supplementation are not unanimously determined. Our aim is to review the current knowledge on the possible interplay between glutamine and arginine generation in the stressed patient and to elaborate on whether these amino acids may function as a common denominator. Because glutamine can be given by the parenteral and enteral routes, possible different actions on the metabolic fate (e.g., generation of citrulline) with both routes are analyzed. DATA SOURCE: A summary of data on the clinical effect of glutamine and arginine metabolism is given, incorporating data on glutamine and arginine supplementation. Differences between the route of administration, parenteral or enteral, and the molecular form of supplied glutamine, free or as dipeptide, on citrulline generation by the gut and production of arginine are discussed. RESULTS: Glutamine and arginine influence similar organ systems; however, they differ in their targets. For example, glutamine serves as fuel for the immune cells, increases human leukocyte antigen DR expression on monocytes, enhances neutrophil phagocytosis, and increases heat shock protein expression. Arginine affects the immune system by stimulating direct or indirect proliferation of immune cells. This indirect effect is possibly mediated by nitric oxide, which also enhances macrophage cytotoxicity. Furthermore, glutamine serves as a precursor for the de novo production of arginine through the citrulline-arginine pathway. Glutamine has shown to be beneficial in the surgical and critically ill patient, whereas arginine supplementation is still under debate. The route of glutamine administration (parenteral or enteral) determines the effect on citrulline and on the de novo arginine generation. There is a marked difference between the administration of free glutamine and dipeptide enterally or parenterally. Splanchnic extraction of the hydrolyzed glutamine in mice when administering the dipeptide enterally is higher compared with administering free glutamine from the enteral site. In patients, splanchnic extraction of the dipeptide given enterally is 100% when comparing supplementation of the dipeptide intravenously. CONCLUSIONS: The beneficial effects of free glutamine or dipeptide may depend on the route of administration but also on the metabolic fate of amino acids generated (e.g., citrulline, arginine). Glutamine serves as a substrate for de novo citrulline and arginine synthesis. More research needs to be done to establish the direct clinical relevance of the different metabolic pathways. Future perspectives might include combining enteral and parenteral routes of administrating free glutamine or dipeptide. PMID- 17713412 TI - Antioxidant therapy in critical care--is the microcirculation the primary target? AB - This review presents the rationale for the therapeutic use of antioxidants in treating critically ill patients; it is not a systematic review of the clinical evidence that has been assessed recently by others. Clinical and nonclinical evidence is presented to support the notion that natural antioxidants are of therapeutic value in treating cardiovascular shock. Oxidative stress is a major promoter and mediator of the systemic inflammatory response. The microcirculation is particularly susceptible to oxidative stress that causes hemodynamic instability, leading to multiple organ failure due to systemic inflammatory response syndrome. Vitamin C is the antioxidant used experimentally to demonstrate oxidative stress as a key pathophysiologic factor in septic shock. Pharmacologic studies reveal that vitamin C (as ascorbate), at supraphysiologic doses, significantly affects the bioavailability of nitric oxide during acute inflammation, including inhibiting nitric oxide synthetase induction. Parenteral high-dose vitamin C inhibits endotoxin-induced endothelial dysfunction and vasohyporeactivity in humans and reverses sepsis-induced suppression of microcirculatory control in rodents. In severe burn injury, in both animals and patients, parenteral high-dose vitamin C significantly reduces resuscitation fluid volumes. Therefore, a significant body of pharmacologic evidence and sound preliminary clinical evidence supports the biological feasibility of using the exemplary antioxidant, vitamin C, in the treatment of the critically ill. PMID- 17713414 TI - Glutathione metabolism in sepsis. AB - Sepsis is characterized by severe redox imbalance. Glutathione plays a major role in cellular defenses against oxidative and nitrosative stress. There is limited information on the response of glutathione synthesis in human sepsis. This review proposes a critical analysis of available data on potential factors affecting glutathione synthesis in sepsis. Glutathione is synthesized from its constituent amino acids--glutamate, cysteine, and glycine. Cysteine availability and the activity of the enzyme glutamate cysteine ligase are rate-limiting for glutathione synthesis. Glutathione synthetic capacity is increased in liver and other tissues during the acute phase of experimental sepsis. Potential mechanisms for glutamate cysteine ligase activation in sepsis involve a decreased ratio of reduced/oxidized glutathione as well as the effects of reactive oxygen species, nitric oxide species, proinflammatory cytokines, heat shock proteins, and physical inactivity. Glutathione synthesis can be impaired by cysteine depletion, protein-energy malnutrition, hyperglycemia, glucocorticoid at pharmacologic doses, and decreased secretion of anterior pituitary hormones (growth hormones, thyrotropin, gonadotropins), as often observed in prolonged critical illness. PMID- 17713413 TI - Antioxidant supplementation in sepsis and systemic inflammatory response syndrome. AB - OBJECTIVE: Summarize the current knowledge about oxidative stress-related organ dysfunction in inflammatory and septic conditions, and its potential prevention and treatment by antioxidants in critically ill patients, focusing on naturally occurring antioxidants and clinical trials. STUDY SELECTION: PubMed, MEDLINE, and personal database search. SYNTHESIS: Plasma concentrations of antioxidant micronutrients are depressed during critical illness and especially during sepsis. The causes of these low levels include losses with biological fluids, low intakes, dilution by resuscitation fluids, as well as systemic inflammatory response syndrome-mediated redistribution of micronutrients from plasma to tissues. Numerous clinical trials have been conducted, many of which have shown beneficial effects of supplementation. Interestingly, among the candidates, glutamine, glutathione, and selenium are linked with the potent glutathione peroxidase enzyme family at some stage of their synthesis and metabolism. CONCLUSIONS: Three antioxidant nutrients have demonstrated clinical benefits and reached level A evidence: a) selenium improves clinical outcome (infections, organ failure); b) glutamine reduces infectious complication in large-sized trials; and c) the association of eicosapentaenoic acid and micronutrients has significant anti-inflammatory effects. Other antioxidants are still on the clinical benchmark level, awaiting well-designed clinical trials. PMID- 17713415 TI - Metabolism modulators in sepsis: the abnormal pituitary response. AB - OBJECTIVE: Summarize the current knowledge on the role of the hypothalamic pituitary axis in the development of sepsis. DESIGN: Review article. METHOD: We systematically searched for relevant articles in MEDLINE and Embase (up to December 2006) using the following search terms: sepsis or septic shock or septicemia or endotoxemia and pituitary gland or hypothalamus. We also retrieved relevant references from selected articles. RESULTS: During sepsis, the pituitary gland is activated via blood-borne proinflammatory cytokines and through a complex interaction between the autonomic nervous system and the immune cells. Sepsis elicits a very reproducible pattern of pituitary hormone secretion, with plasma adrenocorticotropin and prolactin increasing within a few minutes following the insult, and with a rapid inhibition of secretion of luteinizing and thyroid-stimulatory hormone but not of follicle-stimulating hormone. Growth hormone secretion also is stimulated. Nitric oxide is a key mediator in the activation of the hypothalamic-pituitary axis and in excess nitric oxide is the main factor accounting for abnormal pituitary response. Low adrenocorticotropin and vasopressin levels are likely the most deleterious consequences of the abnormal pituitary response, because they will contribute to shock and progression of inflammation with subsequent multiple organ failure and death. CONCLUSIONS: Sepsis is associated with major changes in the hypothalamic pituitary axis. The manipulation of the pituitary function during sepsis is a major challenge for the next decade. PMID- 17713417 TI - Vasopressin in septic shock. PMID- 17713416 TI - Role of glucocorticoids in the molecular regulation of muscle wasting. AB - OBJECTIVE: To review glucocorticoid-regulated molecular mechanisms of muscle wasting. DESIGN: Review of recent literature describing the role of glucocorticoids in the regulation of proteolytic mechanisms, transcription factors, and nuclear cofactors in skeletal muscle during various catabolic conditions. MAIN RESULTS: Catabolic doses of glucocorticoids induce muscle atrophy both in vivo and in vitro by stimulating protein breakdown and inhibiting protein synthesis. Signaling pathways that regulate muscle protein synthesis at the translational level are inhibited by glucocorticoids. Glucocorticoids increase the expression and activity of the ubiquitin-proteasome pathway, a major proteolytic mechanism of muscle atrophy. The expression and activity of muscle wasting-related transcription factors, including C/EBPbeta and delta and Forkhead box O 1, 3, and 4, as well as the nuclear cofactor p300, are up-regulated by glucocorticoid excess. CONCLUSIONS: Muscle wasting in various catabolic conditions is, at least in part, regulated by glucocorticoids. The role of glucocorticoids in muscle wasting is complex and reflects regulation at the molecular level of multiple mechanisms influencing both synthesis and degradation of muscle proteins. PMID- 17713418 TI - Metabolism modulators in sepsis: propranolol. AB - Sepsis is accompanied by an enormous increase in catecholamine expression, leading to metabolism of lipids and glucose, changes in cardiovascular output, immunomodulatory effects, and changes in protein metabolism, all of which push the body into a catabolic state. Deleterious beta-adrenoceptor controlled responses to stress and sepsis are well documented; therefore, it would seem appropriate to use propranolol under such circumstances. There are arguments both for and against the use of beta-adrenoceptor blockade during episodes of stress and infection. The definition of sepsis itself is a clinical one in most cases. There are guidelines concerning the diagnosis of sepsis (systemic inflammatory response syndrome [SIRS] in the presence of significant infection). However, when the cause of SIRS is not infection, for example, in burn patients, is it not possible, and indeed preferable, to tackle the stress response in a more aggressive fashion? The effects of SIRS on the body are myriad and have been defined and illustrated in many fine reviews. The effects of sepsis on the body, as well, have been discussed in the world literature and are beyond the scope of this article. In this article we attempt to demonstrate the effects of sepsis (SIRS plus infection) on whole body metabolism, outline the mediators of these changes, and then show the ability of propranolol to attenuate the changes seen. PMID- 17713419 TI - Metabolic modulators following trauma sepsis: sex hormones. AB - BACKGROUND: The development of metabolic perturbations following severe trauma/sepsis leading to decreased energy production, hyperglycemia, and lipolysis is often rapid. Gender is increasingly recognized as a major factor in the outcome of patients suffering from trauma/sepsis. Moreover, sex hormones influence energy, glucose, and lipid metabolism. Metabolic modulators, such as peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha, which are required for mitochondrial energy production and fatty acid oxidation, are regulated by the estrogen receptor-beta and consequently contribute to cardioprotection following trauma hemorrhage. Additionally, sex steroids regulate inflammatory cytokines that cause hypermetabolism/catabolism via acute phase response, leading to increased morbidity and mortality. MEASUREMENTS: This article examines the following: (1) the evidence for gender differences; (2) energy, glucose, and lipid metabolism and the acute phase protein response; (3) the mechanisms by which gender/sex hormones affect the metabolic modulators; and (4) the tissue-specific effect of sex hormone receptors and the effect of genomic and nongenomic pathways of sex hormones following trauma. RESULTS AND CONCLUSIONS: The available information indicates that sex steroids not only modulate the immune/cardiovascular responses but also influence various metabolic processes following trauma. Thus, alteration or modulation of the prevailing hormone milieu at the time of injury appears to be a novel therapeutic adjunct for improving outcome after injury. PMID- 17713421 TI - Antiretroviral therapy for advanced naive HIV-infected patients: current status and comparison of two different management strategies. PMID- 17713420 TI - Restoration of hormonal action and muscle protein. AB - This review focuses on the effects of restoring hormonal levels and/or influence on muscle protein metabolism in the stressed state. We have highlighted our clinical experience in the administration of anabolic and anticatabolic agents in stressed clinical populations, primarily adult and pediatric burn injury, as well as patients undergoing elective hip arthroplasty. Our previous experience entails the administration of anabolic hormones, such as testosterone and its derivatives, growth hormone, insulin-like growth factor-1 combined with its binding protein 3, and insulin. Current efforts focus on the administration of anticatabolic agents to reduce the effects of hypercortisolemia. Muscle protein metabolism was determined by stable isotope methodology. Our results indicate that normalization of anabolic hormone concentrations or amelioration of hormonal resistance restores the effects of feeding on skeletal muscle protein metabolism. Anabolic hormone administration results in a more favorable muscle protein balance in severely burned patients. Amelioration of hypercortisolemia in the stressed state leads to an improvement in protein kinetics. To summarize, alterations in hormonal influence that accompany stress states favor the loss of muscle protein. Restoration or normalization of hormonal influence improves muscle protein kinetics and ameliorates the loss of muscle nitrogen. To restore hormonal influence, clinicians should consider reestablishing anabolic stimuli and reducing catabolic stimuli. PMID- 17713422 TI - Antiretroviral treatment strategies and immune reconstitution in treatment-naive HIV-infected patients with advanced disease. AB - Treatment-naive advanced HIV-infected patients have a lower life expectancy than those treated early with highly active antiretroviral therapy (HAART). Early treatment allows greater immunological recovery, a reduction of AIDS progression, a reduced risk of related illnesses, and lower mortality compared with HAART initiation in advanced disease. Given the numbers with advanced disease worldwide and the high cost of care, strategies encouraging early detection may be life saving and cost effective. Factors associated with increased clinical progression include higher baseline HIV viral load and older age, emphasizing the need for early viral load suppression. HAART initiation faces many challenges; interactions between antiretroviral agents and drugs used to treat life threatening opportunistic infections may cause subtherapeutic antiretroviral exposure and the development of resistance or supratherapeutic levels resulting in adverse effects. Immune reconstitution inflammatory syndrome can be another cause of suboptimal outcomes. The management of patients with advanced HIV infection should include rapid short-term immune reconstitution to limit the risk of disease progression plus aggressive antiviral treatment to achieve rapid virological suppression. Clear evidence on the optimal regimen and agents to use to target advanced HIV disease is lacking. Therefore, antiretroviral treatment for these patients has to be carefully tailored to the individual according to many variables. PMID- 17713423 TI - Late diagnosis of HIV infection: epidemiological features, consequences and strategies to encourage earlier testing. AB - A substantial proportion of HIV-infected individuals do not present for HIV testing until late in infection; these individuals are often ill, have a high mortality risk, and are less likely to respond to treatment when initiated. Furthermore, late presentation means that opportunities to reduce onward transmission, either by reducing high-risk behaviours or by reducing an individual's infectivity, are missed. The proportion of HIV-infected individuals who present late has remained relatively stable over the past decade, despite several attempts to encourage earlier diagnosis. Late presenters tend to be those at lower perceived risk of infection, those who are not routinely offered HIV testing, and are often from marginalized groups. Strategies that encourage earlier testing, including routine HIV testing in healthcare settings where high risk individuals attend frequently, the availability of HIV testing services in non-medical settings, and partner notification schemes or peer-led projects to encourage high-risk individuals to attend for testing, may all increase the proportion of HIV-infected individuals who are aware of their HIV status, thus helping to control the spread of the epidemic. This review summarizes recent evidence on the epidemiology of late presentation and its impact on clinical progression, and describes several key strategies that may encourage earlier diagnosis. PMID- 17713424 TI - Optimal timing and best antiretroviral regimen in treatment-naive HIV-infected individuals with advanced disease. AB - The introduction of highly active antiretroviral therapy (HAART) in developed countries has achieved a good control of HIV infection. Despite this, a delayed HIV diagnosis makes it necessary to start antiretroviral treatment in individuals with severe impairment of their immunological function. Very often, this is accompanied by an opportunistic infection that needs to be treated, with a consequent complication of management because of overlapping toxicities and pharmacokinetic interactions with antiretroviral drugs, and a greater pill burden. All this could impair adherence and reconstitution of the immune function with a paradoxical clinical worsening in some patients, especially if the CD4 cell count is below 50 cells/microl. The best antiretroviral regimen and the best timing for starting antiretroviral therapy in treatment-naive patients with advanced infection have not yet been established. Recommendations for the clinical management of advanced HIV disease come from panels of experts in the therapy of opportunistic infections and antiretroviral treatment, and they advise starting combined antiretroviral therapy 2-4 weeks after initiating treatment of the opportunistic infection. Many patients have been successfully treated with a pharmacologically enhanced (boosted) protease inhibitor (mainly lopinavir/ritonavir)-based regimens. The efficacy of non-nucleoside reverse transcriptase inhibitor-based regimens for the treatment of very immunosuppressed patients has been tested in few clinical trials during the HAART era. Some cohort studies and randomized clinical trials support the use of efavirenz-based antiretroviral therapy for the treatment of advanced HIV-1-infected patients; however, recent randomized controlled data suggest, in a moderately advanced HIV population, a better CD4 cell recovery for lopinavir-ritonavir than for efavirenz treated patients, but a greater virological suppression in the efavirenz arm. Further randomized clinical trials are needed in order to determine whether the efficacy, tolerability and the immunological reconstitution of efavirenz-based therapy can match that achieved with lopinavir/ritonavir or other current boosted protease inhibitor regimens in advanced patients. PMID- 17713425 TI - Protocols and mechanisms for remote ischemic preconditioning: a novel method for reducing ischemia reperfusion injury. AB - Ischemia reperfusion injury (IRI) results in damage to local and remote organs. Remote ischemic preconditioning (RIPC) is a strategy to protect against IRI by inducing a prior brief period(s) of IRI to an organ remote from that undergoing sustained injury. RIPC has been shown to protect organs against IRI; however, the protocols and mechanisms for RIPC are unclear. For this review, a Medline/Pubmed search (January 1985 to January 2007) was conducted and all relevant articles were included. RIPC protocols are organ and species specific and both humoral and neurogenic pathways are involved in triggering intracellular signal pathways for protection. PMID- 17713426 TI - Understanding FOXP3: progress towards achieving transplantation tolerance. AB - Regulatory T cells (Treg) suppress immune responses, making them an exciting therapeutic target for achieving operational transplant tolerance. Recent observations have identified forkhead box P3 (FOXP3) as a master gene required for the development and function of Treg. Improving our understanding of FOXP3 may facilitate methods for identifying and generating Treg. PMID- 17713427 TI - Cultural barriers to kidney transplantation: a new frontier. PMID- 17713428 TI - A modest approach to a new frontier: commentary on Danovitch. PMID- 17713430 TI - Live donor liver transplantation for acute liver failure. AB - BACKGROUND: Acute liver failure (ALF) carries a high mortality unless urgent orthotopic liver transplantation (OLT) is performed on time. Live donors are utilized to treat this irreversible condition first in pediatric cases and then in adults. Herein, we aimed to report our experience with live donors for ALF in a country of a deceased donor organ donation rate is only 1.5 per million people. METHODS: Among the 245 live donor liver transplantations (LDLT) performed from June 1999 to December 2005, 14 of them (6%) were performed for ALF in 8 pediatric and 6 adult cases. Right lobes were harvested for the adult cases whereas left lateral segments were harvested for pediatric cases, except one child transplanted with a right lobe graft. The etiology of the disease was; acute hepatitis B in four cases, hepatitis A in three cases, Wilson disease two cases, autoimmune hepatitis in two cases, and was unknown in three cases. RESULTS: Three year graft and patient survival is 79% for these series. Five of the six adult patients and six of the eight pediatric cases survived after transplantation. There was not any donor mortality or major morbidity. CONCLUSIONS: LDLT offers a safe and effective modality of treatment for ALF for both pediatric and adult patients to overcome the problem of organ shortage especially in countries where the chance of receiving an organ from a deceased donor is low. PMID- 17713429 TI - Replacement of calcineurin-inhibitors with sirolimus as primary immunosuppression in stable cardiac transplant recipients. AB - BACKGROUND: Calcineurin-inhibitor (CNI) nephrotoxicity is a major cause of morbidity and mortality after cardiac transplantation. The aim of this study was to assess over 2 years the safety and effect on renal function of withdrawal of CNI immunosuppression and replacement with sirolimus (SRL) in stable cardiac transplant recipients. METHODS: CNI was substituted with SRL in 78 cardiac transplant recipients (SRL group) of whom 58 (group A) had CNI-induced renal impairment (glomerular filtration rate [GFR] <50 mL/min) and 20 (group B) had preserved renal function (GFR >50 mL/min). Fifty-one patients (CNI group) with renal impairment (GFR < or =50 mL/min) maintained on CNI served as controls. Secondary immunosuppressants were unchanged. RESULTS: In the SRL group, GFR increased from 47.0+/-18.0 to 61.2+/-22.2 ml/min (P=0.0001) 24 months after SRL initiation. In Group A, GFR increased from 40.5+/-12.7 to 53.9+/-19.8 mL/min (P<0.0001). In Group B, GFR increased marginally from 67.2+/-15.8 to 83.5+/-27.8 mL/min (P=0.10). In the CNI group, GFR declined from 40.5+/-14.0 mL/min to 36.4+/ 12.5 mL/min (P=0.23) after 24 months of follow up. There was no significant difference in cardiac rejection or cardiac allograft function. In SRL group, proteinuria increased from 299+/-622 mg/day to 517+/-795 mg/day (P=0.0002) 12 months after SRL initiation and then stabilized; it did not differ from CNI group at 24 months (637+/-806 vs. 514+/-744 mg/day, P=0.39). Uric acid decreased from 7.6+/-2.4 to 6.2+/-1.9 mg/dL (P=0.0007) in the SRL group. CONCLUSIONS: Graduated substitution of CNI with SRL in cardiac transplant recipients is safe and improves renal function, without cardiac compromise. PMID- 17713431 TI - The effect of etanercept on cardiac transplant recipients: a study of TNFalpha antagonism and cardiac allograft hypertrophy. AB - Cardiac allograft hypertrophy is associated with persistent expression of cardiac tumor necrosis factor (TNF)-alpha. We investigated whether TNFalpha antagonism would impact allograft hypertrophy. EFECT (EFfect of Etanercept on Cardiac Transplantation) was a randomized, controlled, double-blind trial evaluating the effect of etanercept versus placebo treatment immediately posttransplant. The primary end-point was change in left ventricular (LV) mass after 6 months. Secondary endpoints included degree of collagen deposition at 6 months and incidence of adverse events. Forty-nine patients were randomized to either etanercept or placebo. LV mass increased significantly in both arms at 6 months, with a smaller increase in the etanercept group (19% vs. 33%, P=ns). Myocardial collagen content increased in the placebo, but not the etanercept, group (+39.8%, P<0.08 vs. -7.0%, P=NS). Allograft hypertrophy develops posttransplant with a corresponding increase in extracellular matrix. Etanercept appeared to decrease LV hypertrophy by decreasing extracellular matrix deposition. PMID- 17713432 TI - Living donor liver transplantation in children with congenital heart disease. AB - BACKGROUND: The occurrence of congenital heart disease (CHD) with congenital biliary disease is uncommon. Our aim is to present our experience in living donor liver transplantation (LDLT) as treatment for end-stage liver disease (ESLD) in children with CHD. METHODS: A review of transplant records from June 1994 to December 2004 was performed. Twenty-three LDLT (13 males, 10 females) recipients were diagnosed to have both CHD and ESLD. RESULTS: CHD diagnoses were made preoperatively using transthoracic two-dimensional color flow Doppler echocardiography. The mean age was 22.3 months. There were 20 (87%) biliary atresia, two (9%) neonatal hepatitis, and one (4%) glycogen storage disease patients. Isolated CHD associated with ESLD included atrial septal defect (11, 48%), pulmonary stenosis (including 2 Alagille syndrome; 4, 17%), patent foramen ovale (4, 17%), ventricular septal defect (1, 4%), and mitral valve prolapse (1, 4%). Complex CHD included atrial septal defect + patent ductus arteriosus + patent foramen ovale (1, 4%), and atrial septal defect + pulmonary stenosis (1, 4%). The median Child's and Pediatric End-stage Liver Disease scores were 9, and 17, respectively. In all, 70% presented with varying degrees of pulmonary congestion pretransplant. There were no perioperative cardiac complications. Posttransplant, the patent foramen ovale in four recipients and atrial septal defect in four recipients closed spontaneously; and two recipients with pulmonary stenosis had their stenoses resolved spontaneously. The overall rejection rate was 17%. There was no mortality. The overall recipient and graft survivals at 1 and 5 years were both 100%. CONCLUSION: LDLT is a safe procedure in a select group of ESLD patients with CHD. PMID- 17713433 TI - Accuracy to estimate rates of decline in glomerular filtration rate in renal transplant patients. AB - BACKGROUND: We examined the use of the Cockroft Gault (C-G) test, Modified Diet in Renal Disease 2 (MDRD2) test, and inverse serum creatinine (Delta1/Scr) to estimate rates of decline in renal transplant function using isotope glomerular filtration rate (GFR) as a reference test. METHODS: Percent changes in estimated GFR (DeltaeGFR) were compared to simultaneous changes in isotope GFR (DeltaiGFR) in 72 patients. RESULTS: The number of iGFR was 508 with a mean of 7.15+/-3.15 scans per patient. There was a decline in iGFR of 16.14+/-21.37 ml/min over the study duration of 88.9+/-57.6 months. DeltaeGFR and Delta1/Scr correlated significantly with DeltaiGFR. Accuracy to predict DeltaiGFR from the eGFRs was limited to <65% concordance within 30% range from changes in iGFR. Slope analyses showed a significantly lower percent annual loss in mean iGFR of 6.03% than that of the C-G of 8.62% and MDRD2 of 8.96% (P<0.001). The within patient variability measured from the standard deviation (ml/min) of root mean square of 4.69 for iGFR was significantly higher than that for C-G and MDRD2 of 2.46 and 2.94, respectively. iGFR and eGFR at first observation correlated significantly (P<0.001) with last observation. CONCLUSIONS: iGFR is significantly more variable within patient than the other predictors, and the two estimators predict the iGFR with a high sensitivity but low specificity. This is a clinically reasonable combination. Predicted percent of annual loss in iGFR appears to be smaller than that using the two estimators. PMID- 17713434 TI - The changing pattern of humoral rejection in cardiac transplant recipients. AB - BACKGROUND: Most humoral rejection (HR) episodes occur early after cardiac transplantation and are associated with hemodynamic compromise and poor prognosis. Late cases of HR (>6 months after transplant) have been reported. We examined the differences in clinical characteristics and outcomes in patients presenting with HR in the early (<6 months) and late transplant periods. METHODS: A retrospective chart review was performed of all cases of HR at a single large transplant center from January 1, 1995 to March 1, 2006. RESULTS: A total of 37 adult transplants had biopsy-proven HR; 13 patients had early HR and 24 patients had HR a mean of 5 yr after transplantation (range, 7 months to 17 yrs). Treatment for HR included plasmapheresis, cyclophosphamide, and rituximab. The age of the early and late humoral rejecters was similar (58+/-14 vs. 50+/-14 yrs; P=0.12). There was a trend toward more women in the early HR group (54% vs. 33%). Use of left ventricular assist devices was similar (38% vs. 33%). Early rejecters were more likely to have positive cross-matches (46% vs. 8%; P<0.01). Patients with late HR had a coexistent diagnosis of malignancy, or significant recent infection in 50% vs. 8% for early HR, suggesting an activation of a nonhuman leukocyte antigen antibody-mediated immune response to an acute illness. One-year survival after the diagnosis of HR was 78% for the both groups (P=NS). CONCLUSIONS: Humoral rejection occurs now more frequently in patients with remote transplants and is commonly associated with the presence of malignancy or infection. PMID- 17713435 TI - Asialoerythropoietin has strong renoprotective effects against ischemia reperfusion injury in a murine model. AB - BACKGROUND: The renoprotective effect of erythropoietin (EPO) and the nonhematopoietic EPO, asialoEPO was investigated in a murine ischemia-reperfusion injury (I/R) model. METHODS: I/R was created by clamping the right renal pedicle for 60 min after left nephrectomy. Balb/c mice were divided into four groups (n=15 in each group): sham operation (Sham), vehicle treatment (Vehicle), EPO treatment (EPO), and asialoEPO treatment (AsialoEPO). EPO and asialoEPO were given at a dose of 500 IU/kg 30 min before I/R. Plasma creatinine (Cr), survival, and the number of apoptotic cells were analyzed. Protein expression was analyzed by Western blotting. RESULTS: Plasma Cr level was not significantly different at 6 hr after I/R. At 24 hr after I/R, the Cr (mg/dL) levels in Sham, Vehicle, EPO, and asialoEPO were 0.13+/-0.01, 1.24+/-0.70, 0.24+/-0.08, and 0.25+/-0.13, respectively (P<0.05). The numbers of apoptotic cells in these groups were 0.1+/ 0.1, 98.9+/-42.6, 3.3+/-0.7, and 2.9+/-1.6, respectively (P<0.05). Western blotting revealed that in kidney tissue of mice treated with EPO and asialoEPO, p38-MAPK and the proapoptotic molecule Bad was decreased, and the antiapoptotic molecules Bcl-xL and XIAP were increased. Survival rates at 7 days after I/R injury in the Sham, Vehicle, EPO, and AsialoEPO groups were 100%, 21.4%, 23.1%, and 53.8%, respectively (P=0.05). CONCLUSION: EPO and asialoEPO attenuated renal dysfunction caused by I/R in mouse kidney at the same level, but only asialoEPO improved survival. PMID- 17713436 TI - Association between toll-like receptor polymorphisms and the outcome of liver transplantation for chronic hepatitis C virus. AB - BACKGROUND: Experimental models suggest that immune cells recognize hepatitis C virus (HCV) through toll-like receptor (TLR)-2 and TLR4. We assessed the association between the single nucleotide polymorphism in genes that encode for these receptors and the outcome of liver transplantation for chronic HCV. METHODS: A historical cohort of 92 liver transplant patients with chronic HCV were screened for TLR2 Arg753Gln and TLR4 Asp299Gly and Thr399Ile polymorphisms. The results were correlated with the predefined composite primary outcome of cirrhosis, retransplantation, and death. Statistical analysis was performed using Kaplan-Meier estimation and Cox proportional hazard model. RESULTS: The mean patient age was 49+/-9 years. Sixty percent were male and 84% were white. Twelve (13%) patients had TLR2 Arg753Gln and 32 (35%) had TLR4 Asp299Gly and/or Thr399Ile polymorphism. During the mean follow-up period of 32 months after liver transplantation, the composite primary outcome occurred in 19 (24%) of 80 patients without TLR2 polymorphism, one (14%) of seven patients with heterozygous TLR2 polymorphism, and in all five (100%) patients with homozygous TLR2 polymorphism (P=0.0007). Time-to-event analysis showed a significant association between homozygous TLR2 polymorphism and the primary outcome (P<0.0001). After adjusting for donor age and azathioprine use, homozygous TLR2 mutation (RR 5.20 [1.65-13.9]; P=0.007) remained associated with the primary outcome. TLR4 polymorphisms were not associated with primary outcome. CONCLUSION: Homozygous TLR2 Arg753Gln polymorphism is associated with allograft failure and mortality after liver transplantation for chronic HCV. The potential clinical relevance of this observation should encourage studies to assess its biologic mechanism. PMID- 17713437 TI - Rosiglitazone attenuates transplant arteriosclerosis after allogeneic aorta transplantation in rats. AB - BACKGROUND: Transplant arteriosclerosis is a leading cause of chronic transplant dysfunction and is characterized by occlusive neointima formation in intragraft arteries. Development of transplant arteriosclerosis is refractory to conventional immunosuppressive drugs and adequate therapy is not available. In this study, we determined the efficacy of the synthetic peroxisome proliferator activated receptor (PPAR)-gamma agonist rosiglitazone to attenuate the development of transplant arteriosclerosis in rat aortic allografts. METHODS: Lewis aortic allografts were transplanted into Brown Norway recipient rats. Recipient rats received either approximately 5 mg rosiglitazone/day (starting 1 week before transplantation until the end of the experiment) or were left untreated. Transplant arteriosclerosis was quantified using morphometric analysis. Alloreactivity was measured in vitro using mixed lymphocyte reactions. Regulatory T cell frequency and function were analyzed using flow cytometry and in vitro suppression assays, respectively. Intragraft gene expression was analyzed using real-time polymerase chain reaction. Finally, medial and neointimal vascular smooth muscle cell proliferation was analyzed in vitro. RESULTS: Rosiglitazone significantly reduced transplant arteriosclerosis development 8 weeks after transplantation (P<0.01 vs. nontreated). Rosiglitazone reduced T cell alloreactivity which was not mediated through modulation of CD4+CD25+FoxP3+ regulatory T cells. Reduced development of transplant arteriosclerosis coincided with reduced intragraft expression of stromal-derived factor-1alpha and platelet-derived growth factor receptor-beta. Finally, rosiglitazone reduced growth-factor-driven proliferation of both medial and neointimal vascular smooth muscle cells in vitro, which was not mediated through PPARgamma. CONCLUSION: PPARgamma agonists may offer a new therapeutic strategy in clinical transplantation to attenuate the development of transplant arteriosclerosis and thereby chronic transplant dysfunction. PMID- 17713438 TI - Alloimmunization to red cell antigens in liver and multivisceral transplant patients. AB - BACKGROUND: Alloimmunization to red blood cell (RBC) antigens can significantly impact transfusion support of patients undergoing solid-organ transplantation. This study evaluated the incidence of clinically significant RBC alloantibodies (abs) in 2000 consecutive adults receiving liver (OLTX), intestinal (ITX) or multivisceral (MVT) transplants. METHODS: From January 1991 to May 2006, 2000 patients underwent OLTX (n=1892), MVT (n=74), or ITX (n=34). Blood sample for serologic investigation was submitted to the transfusion service no later than 4 hr before surgery. The presence of clinically significant RBC abs before transplant with subsequent transfusion requirements, the incidence of delayed transfusion reactions, and de novo abs after transplant were evaluated. RESULTS: One hundred fifteen patients (5.75%) had clinically significant RBC abs before transplant, with 56.7% directed against Rh system antigens. Forty-six (40%) had multiple abs. A mean of 18 packed RBC units (U) were transfused per patient. Patients requiring >20 U (n=34) or those with multiple abs received antigen negative units for the first 5-10 U when antibody was still present, switched to antigen-unscreened units during massive blood loss and returned to antigen negative units for the last 5-10 U transfused. Twelve patients (0.6%) developed de novo abs posttransplant. Twenty-two (1.1%) had delayed serologic transfusion reaction. All patients were successfully managed without delay in initiation of surgery or hemolytic complications. CONCLUSION: RBC alloimmunization can present a special challenge to solid-organ transplantation. Early serologic testing of the recipient pretransplant and prompt communication between the transfusion service and transplant team facilitates successful transfusion management of these patients. PMID- 17713439 TI - Human leukocyte antigen class I epitopes: update to 103 total epitopes, including the C locus. AB - BACKGROUND: Epitopes of human leukocyte antigen (HLA) are the sites to which the antibodies bind. We identify here 103 HLA class I epitopes shared by groups of class I antigens. In particular, our emphasis was on identifying epitopes exclusive to the C-locus antigens or interlocus epitopes among A, B, and C antigens. The use of monoclonal antibodies or alloantibodies eluted from HLA recombinant single antigen cell lines tested with a panel of single antigen beads have proved very useful in the identification of the epitopes. METHODS: Alloantibodies absorbed onto then eluted from HLA single antigen cell lines and monoclonal antibodies were tested with a panel of 95 A-, B-, and C- single antigen beads and the HLA specificities determined. Each epitope was defined by amino acids shared exclusively by the positive antigens for each antibody. RESULTS: In addition to the 58 A and B class I epitopes identified in an earlier study, we add 45 more new A, B, C epitopes including, for the first time, epitopes found on C locus antigens. CONCLUSION: Beads bearing single antigens tested with monoclonal or eluted alloantibodies proved very powerful in identifying epitopes shared among HLA antigens. These epitopes are the targets of the antibodies. Antibody specificities to non-donor-specific antigens, often found in sera of transplant patients, can now be understood as reactions to epitopes shared with the donor specific antigens. The importance of identifying these epitopes is that they may be the "transplantation antigens" responsible for antibody-mediated transplant rejection. PMID- 17713440 TI - Impact of simultaneous pancreas and kidney transplantation on cardiovascular risk factors in patients with type 1 diabetes mellitus. AB - We retrospectively investigated the impact of pancreas transplantation on cardiovascular disease risk factors in patients with type 1 diabetic end-stage renal disease (ESRD). Two cohorts of patients, 44 simultaneous pancreas and kidney transplant patients (SPK) and 30 kidney transplant-alone patients (KTA), were included. Univariate and multivariate analyses were performed. Compared with KTA patients, SPK patients had significantly lower mean arterial pressure (88.5+/ 12.7 vs. 98.2+/-13.0 mmHg, P=0.002), lower pulse pressure (51.6+/-15.1 vs. 61.4+/ 15.6 mmHg, P=0.008), lower low-density lipoprotein cholesterol (83.5+/-20.6 vs. 99.2+/-32.5 mg/dl, P=0.02), and required fewer lipid-lowering medications (31.8% vs. 60.0%, P=0.02). Compared with pretransplant values, only SPK patients showed significant improvement in both blood pressure and total cholesterol. We conclude that SPK significantly improves blood pressure and dyslipidemia compared with KTA in type 1 diabetic ESRD patients. PMID- 17713441 TI - Long-term tolerance to kidney allografts in a preclinical canine model. AB - Durable immune tolerance supporting vascularized allotransplantation offers the possibility of extending graft survival and avoiding harmful complications of chronic immunosuppression. Immune tolerance to renal allografts was induced in a preclinical canine model through engraftment of donor hematopoietic cells using a combination of low-dose total body irradiation and a short course of immunosuppression. Subsequently, donor renal allografts were transplanted accompanied by bilateral native nephrectomies. With 5-year follow up, we found normal renal function in all recipients and no histological evidence of acute or chronic rejection. This tolerance does not extend universally to donor skin grafts, however, with two of four animals rejecting delayed donor skin grafts. Hematopoietic chimerism produces durable and robust immune tolerance to kidney allografts, although incomplete tolerance to donor skin grafting. PMID- 17713442 TI - Lack of cross-species transmission of porcine endogenous retrovirus (PERV) to transplant recipients and abattoir workers in contact with pigs. AB - This study investigated the potential transmission of porcine endogenous retrovirus (PERV) to solid-organ transplant recipients and abattoir workers in contact with pigs. Blood samples were obtained from volunteer healthy blood donors (Group A; n=33); pig-breeding farmers who had undergone a liver transplant (Group B; n=14); and pig abattoir workers (Group C; n=49). A second blood sample was obtained 1 year after the first sample from 10 of the abattoir workers (Group D). Tests included investigation for PERV-DNA, PERV-RNA, pig-specific mitochondrial DNA, a quantitative detection of PERV nucleic acids, and antibodies to PERV by two different Western Blots. All polymerase chain reaction and Western Blots assays were negative for PERV or antibodies to PERV. Therefore, the risks of cross-species transmission of PERV appear to be negligible for immunocompetent individuals and allotransplant recipients, even if they are in close and repeated contact with live pigs or pig tissues. PMID- 17713443 TI - Similar outcome after unrelated allogeneic peripheral blood stem cell transplantation compared with bone marrow in children and adolescents. AB - This study compares children and adolescents with hematological malignancies undergoing allogeneic stem cell transplantation (ASCT) with unrelated donors receiving either bone marrow (BM, n=39) or peripheral blood stem cells (PBSCs, n=35). Age and other characteristics were comparable in the two groups. All patients were given conventional conditioning and antithymocyte globulin (ATG). Graft-versus-host disease prophylaxis consisted of cyclosporine plus methotrexate or prednisolone. After PBSC, engraftment of neutrophils and platelets were more rapid. The incidences of acute and chronic graft-versus-host disease were similar in the two groups. In the two groups, other outcome variables, such as transplant related mortality, overall survival, and relapse-free survival, were the same. Patients given BM tended to have more relapses (P=0.1) and patients given PBSC tended to have more incidences of infectious death. Four cases of EBV-lymphomas were found among patients receiving PBSC, whereas no case was seen in patients given BM (P=0.1). We found no differences in transplant-related mortality and survival in children and adolescents receiving BM or PBSC from unrelated donors. More rapid engraftment and a trend for less relapses in patients given PBSC grafts was noted. PMID- 17713444 TI - Role of PECAM-1 in acute rejection of fully major histocompatibility complex class II-mismatched cardiac allografts in mice. AB - The aim of this study was to determine the role of platelet-endothelial cell adhesion molecule (PECAM) in acute rejection of vascularized whole organ allografts in vivo. Hearts were transplanted between BALB/c, PECAM-1(-/-), or C57BL/6 wild-type mice. Grafts were harvested on the day of rejection or after 120 days and were analyzed histologically. BALB/c allografts survived significantly longer in PECAM-1(-/-) recipients compared to wild-type controls (8.3+/-0.4 vs. 6.4+/-0.8 days; P<0.05). Survival of PECAM-1(-/-) allografts in BALB/c recipients did not differ from that of wild-type-derived transplants (12.2+/-3.0 vs. 9.3+/-0.7; P>0.05). In all allografts, histology showed massive monomorphonuclear leukocyte infiltration, indicating parenchymal rejection. Immunohistochemistry confirmed in all transplants a preserved donor endothelial phenotype. Our data indicate a subtle role of nonendothelial PECAM-1 in acute allograft rejection. Although deletion of PECAM-1 could not prevent rejection, it should be further evaluated as a therapeutic target in more complex settings with concomitant immunosuppression or during chronic rejection. PMID- 17713445 TI - Acute cellular allograft rejection in homozygous CCR5 Delta32 patients after renal transplantation. PMID- 17713446 TI - Induction of regional collateral sprouting following muscle denervation. AB - OBJECTIVES/HYPOTHESIS: Anecdotal clinical findings suggest that denervated muscle may regain modest functional recovery via spontaneous collateral sprouts from intact adjacent nerve fibers. The current study evaluates the conditions needed for the denervated masseter muscle to induce axonal sprouting from the facial nerve. We hypothesize that epineurial injury is required to induce collateral sprouting toward a neighboring denervated muscle. STUDY DESIGN: Twelve thy1 yellow fluorescent protein-16 (thy1-YFP-16) transgenic mice whose axons express yellow fluorescent protein were allocated into six groups, with four degrees of facial nerve injury (intact, crush, transection, removed segment) with or without masseter denervation. METHODS: Animals underwent serial in vivo imaging analyses under the fluorescent microscope weekly for 5 or 7 weeks and were subsequently perfused for analysis. Masseter muscle acetylcholine receptors (AChRs) were stained with Alexa Fluor 594 conjugated alpha-bungarotoxin, and whole mounts were imaged with confocal microscopy. RESULTS: In groups with intact or crushed facial nerves, no evidence of collateral sprouting was demonstrated. Mice with transected facial nerve branches or removed segments demonstrated sprouting from the proximal stump into the denervated masseter. Staining of the AChRs confirmed that new neuromuscular junctions were established between the facial nerve and the denervated masseter. CONCLUSIONS: This study suggests that epineurial injury is required to stimulate axonal sprouting into adjacent denervated muscle. Nerves with compromised epineurium may be useful in promoting neo-neurotization after muscle denervation. PMID- 17713447 TI - Organ preservation surgery for advanced unilateral glottic and subglottic cancer. AB - OBJECTIVES: Functional surgery of unilateral T(2b) to T3 glottic cancer and cricoid chondrosarcoma is possible using the technique of tracheal autotransplantation. The objective of this paper is to report the functional and oncologic outcome of 24 consecutive patients treated with this technique between 2001 and 2007. METHODS: Seventeen patients, of whom nine were previously irradiated, had unilateral glottic cancer with impaired mobility of the vocal fold. Clinical staging was T(2b) to (3)N(0). Seven patients had a chondrosarcoma of the cricoid cartilage. In a first operation, an extended hemilaryngectomy was performed, and a radial forearm flap, comprising a distal fascial and a proximal skin component, was transferred to the neck. The fascial paddle was wrapped around the upper 4-cm segment of cervical trachea, and the skin paddle was used for temporary closure of the extended hemilaryngectomy defect. The definitive reconstruction was performed after 2 to 3 months and consisted of removal of the skin paddle from the laryngeal defect and a transplantation of a patch of revascularized cervical trachea to reconstruct the laryngeal defect. RESULTS: Swallowing and speech were restored after the first operation. The glottic and subglottic airway lumen was restored during the second operation. The tracheostomy could be closed in 20 patients. After a median follow-up period of 33 (range, 1-66) months or almost 3 years, 23 patients remained free of tumor recurrence. CONCLUSIONS: Tracheal autotransplantation can be recommended as a functional treatment for selected T(2b) to T(3) glottic cancers and for unilateral chondrosarcomas of the cricoid cartilage. The technique is oncologically robust while resulting in good postoperative function. PMID- 17713448 TI - Airway reconstruction with carrier-free cell sheets composed of autologous nasal squamous epithelium. AB - OBJECTIVES/HYPOTHESIS: Although skin has been the most effective graft material for reconstructing the airway lumen, the use of squamous epithelium has many problems. If autologous airway squamous epithelium could differentiate into mucociliary epithelium after in vivo grafting, it could be an answer to these problems. In this study, we wanted to examine whether carrier-free nasal epithelial cell sheets composed of autologous squamous epithelium could be used as a substitute for skin in airway luminal reconstruction in three maxillectomy patients. STUDY DESIGN: In vitro biochemical experiments with in vivo applications. METHODS: We cultured nasal squamous epithelium from three maxillary cancer patients prior to maxillectomy. These squamous cell sheets were grafted on the forearm free flap, and, after maxillectomy, the surgical defect was reconstructed with a prefabricated myocutaneous radial forearm free flap with the cultured nasal squamous epithelium. At 1 and 3 month intervals after the reconstructive surgery, the cultured cell grafted area was investigated with histologic phenotype, comparing the skin grafted area. RESULTS: The autologous nasal squamous epithelial cell sheet differentiated into mucociliary epithelium without the crust or mucus stagnation that is usually observed in cases in which skin graft is used for airway reconstruction. CONCLUSIONS: We suggest that autologous cultured nasal squamous epithelium, which differentiates into mucociliary epithelium after in vivo grafting, can be used as a clinically relevant substitute for skin graft in airway luminal reconstruction. PMID- 17713449 TI - Minimally invasive single-stage multilevel treatment for obstructive sleep apnea/hypopnea syndrome. AB - OBJECTIVES: To assess subjective and objective improvement after single-stage multilevel minimally invasive treatment for obstructive sleep apnea/hypopnea syndrome (OSAHS). STUDY DESIGN: A retrospective review of a prospective dataset of patients treated in a tertiary care referral center. METHODS: Charts of 145 patients with mild/moderate OSAHS treated with a single-stage multilevel minimally invasive technique were reviewed to abstract pre- and posttreatment symptoms and polysomnographic data. One hundred twenty-two patients had minimum follow-up of 6 (range, 6-23) months and complete data available for analysis. All patients studied had three-level treatment that included nasal surgery, palatal stiffening by Pillar implant technique, and radiofrequency volume reduction of the tongue base. Primary outcomes included change from baseline in apnea/hypopnea index (AHI). Secondary outcomes included change in Epworth Sleepiness Scale (ESS) and bed-partner assessed snoring visual analogue scale (VAS, 0-10), pain levels, narcotic use, and complications. RESULTS: Mean AHI decreased from 23.2 +/- 7.6 preoperatively to 14.5 +/- 10.2 postoperatively (P < .0001). Classical "cure" was achieved in 54 (47.5%) patients. Mean ESS decreased from 9.7 +/- 3.9 preoperatively to 6.9 +/- 3.3 postoperatively (P < .0001). Mean snoring VAS decreased from 9.4 +/- 0.9 preoperatively to 3.2 +/- 2.4 postoperatively (P <. 0001). CONCLUSION: Polysomnographic respiratory parameters, ESS, and snoring VAS significantly improved in patients with mild/moderate OSAHS treated with single stage multilevel minimally invasive surgery. Multilevel minimally invasive single stage surgery is a valid option for selected patients with mild/moderate OSAHS with the understanding that they may require secondary treatment. PMID- 17713450 TI - Oncostatin-M enhances osteoinduction in a rabbit critical calvarial defect model. AB - INTRODUCTION: Oncostatin-M (OSM) is a member of the interleukin-6 family of cytokines with controversial roles in bone homeostasis. Evidence supports a role in bone regulation, but the balance between healing promotion and acceleration of bone destruction is unclear. It is also uncertain as to whether these varied responses may be dose dependent or related to interactions with other growth factors within the bone microenvironment. OBJECTIVE: To determine whether OSM enhances osteoinduction in a rabbit critical calvarial defect model and whether there is a dose response curve. HYPOTHESIS: OSM enhances osteoinduction, and there is a dose response curve favoring lower doses over higher doses. STUDY DESIGN: Controlled animal study using arms of increasing concentrations of OSM in an inactive demineralized bone matrix (DBM) carrier to assess the degree of osteoinduction through standard histomorphometric analysis and a variant of the radiodensitometry technique. METHODS: Twenty-five skeletally mature New Zealand white rabbits were randomized into control and experimental arms. Incremental doses of OSM (30 microg, 100 microg, and 300 microg/g) in an inactivated guanidine-extracted DBM (Gu-DBM) carrier were implanted into a critically sized (13 mm) calvarial defect. Arms of carrier alone and no carrier served as controls. The animals were sacrificed at 4 weeks, and histomorphometry and radiodensitometry analyses were then performed. RESULTS: All OSM arms showed a statistically significant increase in bone formation and bone density compared with either control arm. There was also a statistically significant increase in bone area by histomorphometry between each OSM group, showing an inverse relationship to dose. Radiodensitometry analysis confirmed a significant bone density difference when comparing experimental groups with controls and also showed a significant difference between the low dose and the higher doses of OSM. It failed to show any significance between the higher two doses when compared with each other. CONCLUSIONS: OSM enhances osteoinduction in vivo and will close a critically sized calvarial defect in a rabbit model when delivered in a Gu-DBM carrier. There appears to be an inverse dose relationship with new bone formation. PMID- 17713451 TI - Vocal fold immobility: a longitudinal analysis of etiology over 20 years. AB - OBJECTIVES: To determine the current etiology of vocal fold immobility, identify changing trends over the last 20 years, and compare results to historical reports. STUDY DESIGN: The present study is a retrospective analysis of all patients seen within a tertiary care institution between 1996 and 2005 with vocal fold immobility. The results were combined with a previous study of patients within the same institution from 1985 through 1995. Results were compared to the literature. METHODS: The medical records of all patients assigned a primary or additional diagnostic code for vocal cord paralysis were obtained from the electronic database. RESULTS: Eight hundred twenty-seven patients were available for analysis (435 from the most recent cohort), which is substantially larger than any reported series to date. Vocal fold immobility was most commonly associated with a surgical procedure (37%). Nonthyroid surgeries (66%), such as anterior cervical approaches to the spine and carotid endarterectomies, have surpassed thyroid surgery (33%) as the most common iatrogenic causes. These data represent a change from historical figures in which extralaryngeal malignancies were considered the major cause of unilateral immobility. Thyroidectomy continues to cause the majority (80%) of iatrogenic bilateral vocal fold immobility and 30% of all bilateral immobility. CONCLUSIONS: This 20-year longitudinal assessment revealed that the etiology of unilateral vocal fold immobility has changed such that there has been a shift from extralaryngeal malignancies to nonthyroid surgical procedures as the major cause. Thyroid surgery remains the most common cause of bilateral vocal fold immobility. PMID- 17713452 TI - The variant type of preauricular sinus: postauricular sinus. AB - OBJECTIVE: Preauricular sinuses (PAS) are common congenital malformations that usually occur at the anterior margin of the ascending limb of the helix, but the positions of PAS and directions on the fistular tracts are rarely posterior to the external auditory canal (EAC), which presents as a postauricular swelling. We named these cases as the variant type of PAS ('postauricular sinuses'), and compared their clinical manifestations with those of the classical type. STUDY DESIGN: A retrospective study. METHODS: We retrospectively reviewed the charts of patients who had undergone preauricular fistulectomy from 2002 to 2006. These patients were then categorized into two groups according to the position of the preauricular sinus sac. The classical group was defined as the group of patients with sacs located on the (superior) anterior to the EAC, and the variant group as those whose sacs are located on the posterior site of the EAC. We analyzed the incidence, previous histories, clinical manifestations, recurrence rates, and surgical techniques of the variant type of preauricular sinuses and compared them with those of the classical type. RESULTS: Eleven (10.9%) of 101 patients were diagnosed with preauricular sinuses of the variant type. The male to female ratios of the classical and the variant groups were 44:46 and 7:4, respectively. The average age of the patients was approximately 11 to 13 years in both groups. All variant types of preauricular sinuses showed preauricular pits located posterior to the imaginary line that connects the tragus with the posterior margin of the ascending limb of the helix, unlike the classical type. Most (72.8%) of the fistular tracts of the variant type were directed in the posterior middle direction from the pits. The variant types were operated with a dual approach using preauricular and retroauricular incisions, unlike the classical type, and the recurrence rate was 0% (compared with 2.2% in the classical type). CONCLUSION: Frequent postauricular infected swellings may indicate the presence of the variant type of preauricular sinuses. The variant type of preauricular sinuses presenting in the postauricular area were found to have an unusual location of the fistula pit that was positioned posterior to the imaginary tragal extended line. A comprehensive physical examination of the preauricular pits should be performed to avoid incomplete excision of the variant types. PMID- 17713453 TI - Paradigm shifts in GI disease management: new information, new opportunities. Introduction. PMID- 17713454 TI - Role of antibiotics in the management of inflammatory bowel disease: a review. AB - The current model of pathogenesis for inflammatory bowel disease (IBD) is a dysregulated immune system that is triggered by an environmental factor in a genetically susceptible individual. Although much about this model remains unproven, it is believed that bacteria are often the environmental factor driving the inflammatory response. This is supported by indirect evidence that antibiotics are of benefit in the treatment of Crohn's disease (CD) and pouchitis, and observations that enteric infections may result in activation of ulcerative colitis disease activity. In CD, limited studies have demonstrated that metronidazole, ciprofloxacin, and rifaximin improve clinical disease activity, and this is more pronounced in the treatment of colonic disease and for perianal fistulas (with metronidazole and ciprofloxacin). In addition, limited evidence supports the use of metronidazole in the prevention of recurrence after resection in CD. Antibiotics have not shown substantial benefit in the treatment of ulcerative colitis, but a variety of antimicrobial agents have a definite role in the treatment of acute and recurrent or chronic pouchitis. The absence of specifically identified organisms that are primarily responsible for the observed clinical picture remains the challenge to confirming the relationship between bacteria and IBD. A proposal for future therapies is provided that might include a combination therapy aimed at both a reduction in pathogenetic bacteria and immune modulation to achieve the most durable remission of disease. PMID- 17713455 TI - New issues in infectious diarrhea. AB - Infectious diarrhea remains a leading cause of both mortality and morbidity worldwide. Novel organisms recently have been described as causes of previously undiagnosed diarrhea. In addition, changes in epidemiologic trends of known pathogens, such as Clostridium difficile, are occurring, including multiple outbreaks of a newly recognized epidemic strain associated with increased severity of cases and poor response to current antibiotics. Given rising resistance rates, new antimicrobial agents are being studied. Rifaximin is a nonabsorbable, gut-selective antibiotic recently approved by the US Food and Drug Administration for the treatment of travelers' diarrhea caused by noninvasive Escherichia coli. This novel antibiotic has also shown promise in the prevention of travelers' diarrhea, as well as a host of other gastrointestinal disorders. Development of a vaccine against diarrheagenic organisms is of high global importance but has been a challenge, owing to the multiple causative serotypes of E. coli and other organisms. PMID- 17713456 TI - Bacterial concepts in irritable bowel syndrome. AB - An overlap of symptoms in irritable bowel syndrome (IBS) exists across subtype groups. Symptoms include intestinal gas, diarrhea, dyspepsia, bloating, abdominal pain, and constipation. The unifying symptom may be excessive intestinal gas as a by-product of intestinal microbial fermentation. Abnormal fermentation of food takes place when gut microbes expand proximally into the small intestine instead of being confined predominantly to the colon. Such proximal expansion of indigenous gut microbes or small intestinal bacterial overgrowth (SIBO) may lead to activation of host mucosal immunity and an increase in intestinal permeability to result in flu-like extra-intestinal symptoms that accompany the classic IBS symptoms of altered bowels. The presence of methane on lactulose breath testing is associated with constipation-predominant IBS. Antibiotic therapy may be appropriate to treat underlying SIBO in IBS patients. Seventy-five percent improvement of IBS symptoms was reported in a double-blind, placebo-controlled study once antibiotics succeeded in treating bacterial overgrowth. Once a good clinical response and normalization of the lactulose breath test are achieved, a prokinetic agent may be used to stimulate phase III of interdigestive motility to delay relapse of bacterial overgrowth. PMID- 17713457 TI - Antibiotics in the management of hepatic encephalopathy: an evidence-based review. AB - Hepatic encephalopathy (HE) is an increasingly prevalent and debilitating condition that occurs in functional hepatic insufficiency. It is marked by fluctuating neuropsychiatric and cognitive impairment, which can be severe and life threatening. Hepatic encephalopathy is a diagnosis of exclusion; thus, it is challenging to diagnose definitively and to investigate in clinical trials. High response rates in the placebo arms of well-conducted studies demonstrate that the most effective treatment for HE is the correction of known precipitating triggers. However, pharmacological therapies may also be helpful. Although the precise pathogenesis remains unknown, bacterially derived neurotoxins from enteric flora likely play an important role. Based on this hypothesis and on accumulating clinical experience documented in randomized trials, oral antibiotics have emerged as an important treatment adjunct. This article addresses the qualities of an ideal antibiotic and reviews the literature on 4 antibiotics used to treat HE: neomycin, metronidazole, vancomycin, and rifaximin, with the most promising of these drugs appearing to be rifaximin. Unfortunately, most studies of the treatment of HE are difficult to interpret due to small sample sizes, methodological flaws, vulnerability to bias, and the intrinsic challenges of studying HE. Many studies have erroneously concluded that treatments are equivalent simply because no significant difference between treatment arms was detected. Consequently, the literature generally lacks definitive data from large, randomized, placebo-controlled trials. Nevertheless, the data suggest that minimally absorbed antibiotics are emerging as a safe and effective approach for the treatment of HE. PMID- 17713462 TI - Oxygen and glucose deprivation-induced changes in astrocyte membrane potential and their underlying mechanisms in acute rat hippocampal slices. AB - Accumulating evidence indicates a significant astrocytic involvement in cerebral ischemia neuropathology, but little is known about the immediate astrocytic responses to ischemia insults in terms of electrophysiology and their pathologic implications. We show that astrocytes in acute rat hippocampal slices responded reversibly to more than 30 mins oxygen and glucose deprivation (OGD) treatment with depolarized membrane potentials (V(m)) in whole-cell current clamp recording. This depolarization was multiphasic, showing an initial approximately 11 mins small-amplitude depolarization plateau, followed by a 6-mins accelerated depolarization, and then a second plateau. Oxygen and glucose deprivation-induced astrocyte V(m) depolarization was only marginally inhibited, approximately 10%, by inhibition of ionotropic glutamate, gamma-aminobutyric acid, purinergic receptors, and glutamate transporters presumed to be present on astrocytes in situ, suggesting increase in extracellular [K(+)] was primarily responsible for the astrocytic V(m) change. The V(m) depolarization was five-fold greater when glycolysis was inhibited by iodoacetate in a short 8 mins OGD treatment, suggesting glycolytic ATP is critical in maintaining extracellular K(+) homeostasis in the early phase of OGD. Addition of oxidative metabolism inhibitors had much less effect. Cessation of OGD was always followed by a rapid and transient 9 mV astrocyte V(m) hyperpolarization relative to the control V(m) that was inhibited by ouabain, indicating a reactively enhanced Na(+)/K(+)-ATPase activity in post-OGD reperfusion. Altogether, hippocampal astrocytes appear to be electrophysiologically more resistant to acute ischemia insults as compared with neurons, and this should allow astrocytes to rescue endangered neurons in the face of acute ischemia insults via their various homeostatic functions. PMID- 17713464 TI - Increased cortical cell loss and prolonged hemodynamic depression after traumatic brain injury in mice lacking the IP receptor for prostacyclin. AB - Prostacyclin is the major arachidonic acid metabolite of the vascular endothelium and is produced mainly via the cyclooxygenase-2 pathway. By acting on the prostacyclin (IP) receptor on platelets and vascular smooth muscle cells, prostacyclin exerts vasodilatory and antiaggregative/antiadhesive effects. Previous studies have shown that prostacyclin production increases after brain trauma, but the importance of prostacyclin for posttraumatic hemodynamic alterations and neuron survival has not been investigated. This study evaluated if endogenous prostacyclin plays a role in the pathophysiologic process in the brain after brain trauma. This was performed by comparing prostacyclin (IP) receptor-deficient (IP(-/-)) mice and mice with functional IP receptor (IP(+/+)) after a controlled cortical injury regarding contusion volume, cerebral blood flow ([(14)C]iodoantipyrine autoradiography), number of perfused capillaries (fluorescein isothiocyanate-dextran fluorescence technique), the transfer constant (K(i)) for [(51)Cr]EDTA, and brain water content (wet vs dry weight) in the injured and contralateral cortex. Contusion volume was increased in IP(-/-) mice compared with IP(+/+) mice. Three hours after trauma, cortical blood flow was decreased in the injured cortex of both groups and the reduction in blood flow in the cortex of the IP(-/-) mice persisted from 3 to 24 h, whereas blood flow approached normal values in the IP(+/+) mice after 24 h. No differences could be detected between the two genotypes regarding other hemodynamic parameters. We conclude that the prostacyclin IP receptor is beneficial for neuron survival after brain trauma in mice, an effect that may be mediated by improved cortical perfusion. PMID- 17713463 TI - Acute plasmalemma permeability and protracted clearance of injured cells after controlled cortical impact in mice. AB - Cell death after traumatic brain injury (TBI) evolves over days to weeks. Despite advances in understanding biochemical mechanisms that contribute to posttraumatic brain cell death, the time course of cell injury, death, and removal remains incompletely characterized in experimental TBI models. In a mouse controlled cortical impact (CCI) model, plasmalemma permeability to propidium iodide (PI) was an early and persistent feature of posttraumatic cellular injury in cortex and hippocampus. In cortical and hippocampal brain regions known to be vulnerable to traumatic cell death, the number of PI+ cells peaked early after CCI, and increased with increasing injury severity in hippocampus but not cortex (P<0.05). Propidium iodide labeling correlated strongly with hematoxylin and eosin staining in injured cells (r=0.99, P<0.001), suggesting that plasmalemma damage portends fatal cellular injury. Using PI pulse labeling to identify and follow the fate of a cohort of injured cells, we found that many PI+ cells recovered plasmalemma integrity by 24 h and were terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling negative, but nonetheless disappeared from injured brain by 7 days. Propidium iodide-positive cells in dentate gyrus showed significant ultrastructural damage, including plasmalemma and nuclear membrane damage or overt membrane loss, in all cells when examined by laser capture microdissection and transmission electron microscopy 1 to 24 h after CCI. The data suggest that plasmalemma damage is a fundamental marker of cellular injury after CCI; some injured cells might have an extended window for potential rescue by neuroprotective strategies. PMID- 17713465 TI - Focal segmental glomerulosclerosis in a patient homozygous for a CD2AP mutation. AB - Focal segmental glomerulosclerosis (FSGS) is a histologic diagnosis in several kidney diseases characterized by proteinuria and a severe decrease in kidney function. Mutations in several genes were found in patients with primary FSGS, one of which is a CD2-associated protein CD2AP (originally referred to as CMS). This gene encodes an adaptor protein that plays a role in endocytosis, cell motility, and cell survival. Mice deficient in Cd2ap (the mouse homolog) die due to kidney failure, while heterozygous mice develop lesions similar to those of FSGS patients. In the kidney, CD2AP regulates the actin cytoskeleton. The only previously described patient with CD2AP mutation had a severely truncated protein. In this study, we describe a patient with a novel mutation resulting in a premature stop codon yielding a protein truncated by only 4%. This shortened CD2AP protein displays a significantly decreased F-actin binding efficiency in vitro with no expression of the mutated allele in the patient's lymphocytes. Heterozygous expression of the CD2AP mutation in both parents did not lead to any kidney pathology, as both have normal glomerular filtration rates and no proteinuria. PMID- 17713467 TI - Disease targets and strategies for the therapeutic modulation of endogenous neural stem and progenitor cells. AB - Neural stem cells, able to self-renew and give rise to both neurons and glia, line the cerebral ventricles of the adult human brain. Humans also harbor lineage restricted neuronal progenitors in the hippocampus and glial progenitor cells in both the gray and white matter of the forebrain. These various stem and progenitor cell types may provide targets for pharmacotherapy for a variety of disorders of the central nervous system. Each resident progenitor phenotype may be mobilized and induced to differentiate in vivo by the actions of both exogenous growth factors and small molecule modulators of progenitor-selective signaling pathways. This strategy may be particularly efficacious in neurodegenerations such as Huntington's disease, in which lost neurons may be replenished through the directed induction of progenitor cells lining the ventricular wall of the affected striatum. Similarly, the mobilization of glial progenitor cells may permit the introduction of new oligodendrocytes to demyelinated regions of adult white matter. Our rapidly increasing understanding of the molecular control of progenitor cell mobilization and differentiation should provide a wealth of new opportunities for recruiting endogenous progenitors as a means of treating neurological disease. PMID- 17713466 TI - Estrogen receptor genotypes, menopausal status, and the lipid effects of tamoxifen. AB - Tamoxifen induces important changes in serum lipid profiles in some women; however, little information is available to predict which women will experience improved lipid profiles during tamoxifen therapy. As part of a multicenter prospective observational trial in 176 breast cancer patients, we tested the hypothesis that tamoxifen-induced lipid changes were associated with genetic variants in candidate target genes (CYP2D6, ESR1, and ESR2). Tamoxifen lowered low-density lipoprotein cholesterol (P<0.0001) by 23.5 mg/dl (13.5-33.5 mg/dl) and increased triglycerides (P=0.006). In postmenopausal women, the ESR1-XbaI and ESR2-02 genotypes were associated with tamoxifen-induced changes in total cholesterol (P=0.03; GG vs GA/AA) and triglycerides (P=0.01; gene-dose effect), respectively. In premenopausal women, the ESR1-XbaI genotypes were associated with tamoxifen-induced changes in triglycerides (P=0.002; gene-dose effect) and high-density lipoprotein (P=0.004; gene-dose effect). Our results suggest that estrogen receptor genotyping may be useful in predicting which women would benefit more from tamoxifen. PMID- 17713468 TI - Finding a liability-free space in which personalized medicine can bloom. AB - Personalized medicine uses genetic and other screening tests to predict a patient's response to specific drug and biologic therapies (together "drugs"), with the aim of choosing a treatment that will provide benefits while avoiding drug-related harms. There are two schools of thought on how tort liability may affect personalized medicine, i.e., whether fear of lawsuits will tend to accelerate progress or slow it down. Tort suits include product liability suits against manufacturers and negligence suits against physicians and other providers of health-related services. PMID- 17713469 TI - The emerging role of pharmacogenomics in biologics. AB - Biologics can be seen as "designer" drugs whose mode of action in a specific disease mechanism is frequently well understood, making it often possible to predict better efficacy and safety profiles for biologics when compared with small molecule drugs. Biologics have been approved for the treatment of major disease classes, such as inflammatory disease, cardiovascular disease, and cancer. However, as it is true for small molecule drugs, often only a fraction of the treated population responds to biologics, and clinical markers for prediction of efficacy are seldom available. It is reasonable to expect that the use of genetic or genomic markers will contribute to improving the prediction of safety and efficacy of both biologics and small molecule drugs. In this paper, we will review the differences between biologics and small molecule drugs, focusing on studies highlighting the relevance of genetic and genomic information on safety and efficacy issues in therapies with biologics. The potential impact of these studies on the promotion of personalized medicine and on regulatory decisions will also be discussed. PMID- 17713470 TI - The education potential of the pharmacogenetics and pharmacogenomics knowledge base (PharmGKB). AB - The pharmacogenetics and pharmacogenomics knowledge base (PharmGKB, http://www.pharmgkb.org) is a publicly available internet resource dedicated to the integration, annotation, and aggregation of pharmacogenomic knowledge. PharmGKB is a repository for pharmacogenetic and pharmacogenomic data, and curators provide integrated knowledge in terms of gene summaries, pathways, and annotated literature. Although PharmGKB is primarily directed toward catalyzing new research, it also has utility as a source of information for education about pharmacogenomics. PMID- 17713471 TI - Lopinavir-ritonavir dramatically affects the pharmacokinetics of irinotecan in HIV patients with Kaposi's sarcoma. AB - The coadministration of protease inhibitors with anticancer drugs in the management of human immunodeficiency virus-related malignancies can cause potential drug-drug interactions. The effect of lopinavir/ritonavir (LPV/RTV) on the pharmacokinetics of irinotecan (CPT11) has been investigated in seven patients with Kaposi's sarcoma. Coadministration of LPV/RTV reduces the clearance of CPT11 by 47% (11.3+/-3.5 vs 21.3+/-6.3 l/h/m(2), P=0.0008). This effect was associated with an 81% reduction (P=0.02) of the AUC (area under the curve) of the oxidized metabolite APC (7-ethyl-10-[4-N-(5-aminopentanoic-acid)-1 piperidino]-carbonyloxycamptothecin). The LPV/RTV treatment also inhibited the formation of SN38 glucuronide (SN38G), as shown by the 36% decrease in the SN38G/SN38 AUCs ratio (5.9+/-1.6 vs 9.2+/-2.6, P=0.002) consistent with UGT1A1 inhibition by LPV/RTV. This dual effect resulted in increased availability of CPT11 for SN38 conversion and reduced inactivation on SN38, leading to a 204% increase (P=0.0001) in SN38 AUC in the presence of LPV/RTV. The clinical consequences of these substantial pharmacokinetic changes should be investigated. PMID- 17713472 TI - Inter-rater reliability of a classification system for hospital adverse drug event reports. AB - Hospital pharmacovigilance systems frequently classify adverse drug event (ADE) reports on various axes such as severity and type of outcome in an attempt to better detect changes in the frequency of certain types of ADEs. The aim of this study was to measure the inter-observer reliability of an ADE classification system. Two pharmacists and two internal medicine physicians reviewed 150 pharmacist-generated ADE reports and used a structured form to classify reports on four domains: the presence or absence of process measures leading to ADE; the individual who initiated the process that potentially leads to ADE; the severity of ADE; and whether the ADE was related to dose. There was wide variation in inter-observer reliability of different elements in a classification system for ADEs. Agreement on specific processes associated with ADEs ranged from poor to moderate, which limits the ability to target accurately processes to improve drug utilization. PMID- 17713473 TI - Germline polymorphisms in EGFR and survival in patients with lung cancer receiving gefitinib. AB - The purpose of this study was to evaluate associations between germline epidermal growth factor receptor (EGFR) variants involved in transcriptional regulation and overall survival in white patients with non-small-cell lung cancer (NSCLC) treated with the EGFR tyrosine kinase inhibitor, gefitinib. Of 175 consecutive patients treated with oral gefitinib (250 mg/day), 170 (median age: 67 years; 72% men) were evaluable for genotyping and survival. Fifty-five patients (33%) had stable disease and 17 (10%) had an objective response. The most common of four haplotypes was G-C (EGFR*1) at the EGFR -216G>T and -191C>A loci (frequency, 0.45). After adjusting for performance status, previous platinum-containing chemotherapy and occurrence of skin rash or diarrhea during the first treatment cycle in patients with performance status 0 or 1 (N=139), the absence of EGFR*1 was associated with significantly better survival (hazard ratio: 0.54; 95% confidence interval: 0.32-0.91; P=0.015). The results may help identify patients with NSCLC who can benefit from gefitinib treatment. PMID- 17713474 TI - Physical and cognitive performance and burden of anticholinergics, sedatives, and ACE inhibitors in older women. AB - Polypharmacy, common in older people, confers both risk of adverse outcomes and benefits. We assessed the relationship of commonly prescribed medications with anticholinergic and sedative effects to physical and cognitive performance in older individuals. The study population comprised 932 moderately to severely disabled community-resident women aged 65 years or older who were participants in the Women's Health and Aging Study I. A scale based on pharmacodynamic principles was developed and utilized as a measure of drug burden. This was related to measures of physical and cognitive function. After adjusting for demographics and comorbidities, anticholinergic drug burden was independently associated with greater difficulty in four physical function domains with adjusted odds ratios (95% confidence interval (CI)) of 4.9 (2.0-12.0) for balance difficulty; 3.2 (1.5 6.9) for mobility difficulty; 3.6 (1.6-8.0) for slow gait; 4.2 (2.0-8.7) for chair stands difficulty; 2.4 (1.1-5.3) for weak grip strength; 2.7 (1.3-5.4) for upper extremity limitations; 3.4 (1.7-6.9) for difficulty in activities of daily living; and 2.4 (95% CI, 1.1-5.1) for poor performance on the Mini-Mental State Examination. Sedative burden was associated only with impaired grip strength (3.3 (1.5-7.3)) and mobility difficulty (2.4 (1.1-5.3)). The burden of multiple drugs can be quantified by incorporating the recommended dose regimen and the actual dose and frequency of drug taken. Anticholinergic drug burden is strongly associated with limitations in physical and cognitive function. Sedative burden is associated with impaired functioning in more limited domains. The risk associated with exposure of vulnerable older women to drugs with anticholinergic properties, and to a lesser extent those with sedative properties, implies that such drugs should not be used in this patient group without compelling clinical indication. PMID- 17713475 TI - Expression of inosine monophosphate dehydrogenase type I and type II after mycophenolate mofetil treatment: a 2-year follow-up in kidney transplantation. AB - The objective of the study was to evaluate the effect of mycophenolate mofetil (MMF) on the regulation of inosine monophosphate dehydrogenase (IMPDH) during the first 2 years after renal transplantation. Twelve patients were enrolled, and 10 h time-course evaluations of the effects of MMF were regularly performed during the study. IMPDH activity and gene expression were measured in whole blood and in mononuclear cells, respectively. Type I IMPDH (IMPDH-I) mRNA was increased during the first 3 months following transplantation and reached its maximal level during acute rejection episodes, whereas type II IMPDH mRNA was stable. Furthermore, although no alteration in the predose samples was observed, patients with prolonged MMF treatment exhibited an increase in the induction potency of both IMPDH activity and gene expression. In vitro experiments confirmed that IMPDH-I is inducible, but preferentially in monocytes than in lymphocytes. This finding suggests that the measurement of IMPDH mRNAs may provide reliable information to predict acute rejection. PMID- 17713476 TI - Safety, tolerability, and pharmacokinetics of raltegravir after single and multiple doses in healthy subjects. AB - Raltegravir is a novel human immunodeficiency virus-1 integrase inhibitor with potent in vitro activity (95% inhibitory concentration (IC95)=33 nM in 50% human serum). Three double-blind, randomized, placebo-controlled, pharmacokinetic, safety, and tolerability studies were conducted: (1) single-dose escalation study (10-1,600 mg), (2) multiple-dose escalation study (100-800 mg q12 h x 10 days), and (3) single-dose female study (400 mg). Raltegravir was rapidly absorbed with a terminal half-life (t1/2) approximately 7-12 h. Approximately 7-14% of raltegravir was excreted unchanged in urine. Area under the curve (AUC)(0 infinity) was similar between male and female subjects. After multiple-dose administration, steady state was achieved within 2 days; there was little to modest accumulation of raltegravir. Trough levels were >33 nM for dose levels of 100 mg and greater. Raltegravir is generally well tolerated at doses of up to 1,600 mg/day given for up to 10 days and exhibits a pharmacokinetic profile supportive of twice-daily dosing with multiple doses of 100 mg and greater achieving trough levels >33 nM. PMID- 17713477 TI - Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. AB - Genetic imprinting, found in flowering plants and placental mammals, uses DNA methylation to yield gene expression that is dependent on the parent of origin. DNA methyltransferase 3a (Dnmt3a) and its regulatory factor, DNA methyltransferase 3-like protein (Dnmt3L), are both required for the de novo DNA methylation of imprinted genes in mammalian germ cells. Dnmt3L interacts specifically with unmethylated lysine 4 of histone H3 through its amino-terminal PHD (plant homeodomain)-like domain. Here we show, with the use of crystallography, that the carboxy-terminal domain of human Dnmt3L interacts with the catalytic domain of Dnmt3a, demonstrating that Dnmt3L has dual functions of binding the unmethylated histone tail and activating DNA methyltransferase. The complexed C-terminal domains of Dnmt3a and Dnmt3L showed further dimerization through Dnmt3a-Dnmt3a interaction, forming a tetrameric complex with two active sites. Substitution of key non-catalytic residues at the Dnmt3a-Dnmt3L interface or the Dnmt3a-Dnmt3a interface eliminated enzymatic activity. Molecular modelling of a DNA-Dnmt3a dimer indicated that the two active sites are separated by about one DNA helical turn. The C-terminal domain of Dnmt3a oligomerizes on DNA to form a nucleoprotein filament. A periodicity in the activity of Dnmt3a on long DNA revealed a correlation of methylated CpG sites at distances of eight to ten base pairs, indicating that oligomerization leads Dnmt3a to methylate DNA in a periodic pattern. A similar periodicity is observed for the frequency of CpG sites in the differentially methylated regions of 12 maternally imprinted mouse genes. These results suggest a basis for the recognition and methylation of differentially methylated regions in imprinted genes, involving the detection of both nucleosome modification and CpG spacing. PMID- 17713478 TI - UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. AB - The trithorax and the polycomb group proteins are chromatin modifiers, which play a key role in the epigenetic regulation of development, differentiation and maintenance of cell fates. The polycomb repressive complex 2 (PRC2) mediates transcriptional repression by catalysing the di- and tri-methylation of Lys 27 on histone H3 (H3K27me2/me3). Owing to the essential role of the PRC2 complex in repressing a large number of genes involved in somatic processes, the H3K27me3 mark is associated with the unique epigenetic state of stem cells. The rapid decrease of the H3K27me3 mark during specific stages of embryogenesis and stem cell differentiation indicates that histone demethylases specific for H3K27me3 may exist. Here we show that the human JmjC-domain-containing proteins UTX and JMJD3 demethylate tri-methylated Lys 27 on histone H3. Furthermore, we demonstrate that ectopic expression of JMJD3 leads to a strong decrease of H3K27me3 levels and causes delocalization of polycomb proteins in vivo. Consistent with the strong decrease in H3K27me3 levels associated with HOX genes during differentiation, we show that UTX directly binds to the HOXB1 locus and is required for its activation. Finally mutation of F18E9.5, a Caenorhabditis elegans JMJD3 orthologue, or inhibition of its expression, results in abnormal gonad development. Taken together, these results suggest that H3K27me3 demethylation regulated by UTX/JMJD3 proteins is essential for proper development. Moreover, the recent demonstration that UTX associates with the H3K4me3 histone methyltransferase MLL2 (ref. 8) supports a model in which the coordinated removal of repressive marks, polycomb group displacement, and deposition of activating marks are important for the stringent regulation of transcription during cellular differentiation. PMID- 17713480 TI - Magnetoelectrics: is CdCr2S4 a multiferroic relaxor? AB - Materials showing simultaneous ferroelectric and magnetic ordering are attracting a great deal of interest because of their unusual physics and potential applications. Hemberger et al. have reported relaxor-like dielectric properties and colossal magnetocapacitance (in excess of 500%) for the cubic spinel compound CdCr2S4 and related isomorphs, concluding that CdCr2S4 is a multiferroic relaxor. We argue here, however, that their results might also be explained by a conductive artefact. PMID- 17713479 TI - IgH class switching and translocations use a robust non-classical end-joining pathway. AB - Immunoglobulin variable region exons are assembled in developing B cells by V(D)J recombination. Once mature, these cells undergo class-switch recombination (CSR) when activated by antigen. CSR changes the heavy chain constant region exons (Ch) expressed with a given variable region exon from Cmu to a downstream Ch (for example, Cgamma, Cepsilon or Calpha), thereby switching expression from IgM to IgG, IgE or IgA. Both V(D)J recombination and CSR involve the introduction of DNA double-strand breaks and their repair by means of end joining. For CSR, double strand breaks are introduced into switch regions that flank Cmu and a downstream Ch, followed by fusion of the broken switch regions. In mammalian cells, the 'classical' non-homologous end joining (C-NHEJ) pathway repairs both general DNA double-strand breaks and programmed double-strand breaks generated by V(D)J recombination. C-NHEJ, as observed during V(D)J recombination, joins ends that lack homology to form 'direct' joins, and also joins ends with several base-pair homologies to form microhomology joins. CSR joins also display direct and microhomology joins, and CSR has been suggested to use C-NHEJ. Xrcc4 and DNA ligase IV (Lig4), which cooperatively catalyse the ligation step of C-NHEJ, are the most specific C-NHEJ factors; they are absolutely required for V(D)J recombination and have no known functions other than C-NHEJ. Here we assess whether C-NHEJ is also critical for CSR by assaying CSR in Xrcc4- or Lig4 deficient mouse B cells. C-NHEJ indeed catalyses CSR joins, because C-NHEJ deficient B cells had decreased CSR and substantial levels of IgH locus (immunoglobulin heavy chain, encoded by Igh) chromosomal breaks. However, an alternative end-joining pathway, which is markedly biased towards microhomology joins, supports CSR at unexpectedly robust levels in C-NHEJ-deficient B cells. In the absence of C-NHEJ, this alternative end-joining pathway also frequently joins Igh locus breaks to other chromosomes to generate translocations. PMID- 17713485 TI - Indentured labour. PMID- 17713487 TI - Technology trap. PMID- 17713486 TI - Innovation versus science? PMID- 17713489 TI - Ocean circulation noisy, not stalling. PMID- 17713492 TI - Journal presents a mathematical conundrum. PMID- 17713490 TI - Oldest gorilla ages our joint ancestor. PMID- 17713493 TI - Fleece myth hints at golden age for Georgia. PMID- 17713494 TI - Is baby DVD research Mickey Mouse science? PMID- 17713495 TI - More biologists but tenure stays static. PMID- 17713496 TI - Let down by the statistics. PMID- 17713497 TI - Hope for axed cancer-prevention trial. PMID- 17713499 TI - A change of gear at Siemens. PMID- 17713502 TI - RNA interference: hitting the on switch. PMID- 17713503 TI - Africa conservation: making room. PMID- 17713504 TI - Puns can be baffling, so keep headlines simple. PMID- 17713505 TI - Berlin shows how natural history can pull the crowds. PMID- 17713506 TI - Religion: Islamic science fading before colonialism. PMID- 17713507 TI - Scientists should unite against threat from religion. PMID- 17713508 TI - Drop 'higher' and 'lower' to raise descriptive standards. PMID- 17713509 TI - Summing up The Simpsons. PMID- 17713510 TI - Regions unite to challenge inequalities in Brazil. PMID- 17713511 TI - Puns: wimp or macho, not a particle of offence is meant. PMID- 17713517 TI - Neuroscience: obsessed with grooming. PMID- 17713518 TI - Quantum physics: wave goodbye. PMID- 17713520 TI - Economics: age, health and wealth. PMID- 17713521 TI - Materials science: stirring stuff. PMID- 17713522 TI - Evolutionary biology: structure in mutualistic networks. PMID- 17713523 TI - Materials science: embedded shells decalcified. PMID- 17713524 TI - Earth science: old diamonds and the upper crust. PMID- 17713525 TI - Obituary: Daniel Koshland (1920-2007). PMID- 17713526 TI - Integrating molecular and network biology to decode endocytosis. AB - The strength of network biology lies in its ability to derive cell biological information without a priori mechanistic or molecular knowledge. It is shown here how a careful understanding of a given biological pathway can refine an interactome approach. This permits the elucidation of additional design principles and of spatio-temporal dynamics behind pathways, and aids in experimental design and interpretation. PMID- 17713527 TI - Progressive field-state collapse and quantum non-demolition photon counting. AB - The irreversible evolution of a microscopic system under measurement is a central feature of quantum theory. From an initial state generally exhibiting quantum uncertainty in the measured observable, the system is projected into a state in which this observable becomes precisely known. Its value is random, with a probability determined by the initial system's state. The evolution induced by measurement (known as 'state collapse') can be progressive, accumulating the effects of elementary state changes. Here we report the observation of such a step-by-step collapse by non-destructively measuring the photon number of a field stored in a cavity. Atoms behaving as microscopic clocks cross the cavity successively. By measuring the light-induced alterations of the clock rate, information is progressively extracted, until the initially uncertain photon number converges to an integer. The suppression of the photon number spread is demonstrated by correlations between repeated measurements. The procedure illustrates all the postulates of quantum measurement (state collapse, statistical results and repeatability) and should facilitate studies of non classical fields trapped in cavities. PMID- 17713529 TI - Gap junction adhesion is necessary for radial migration in the neocortex. AB - Radial glia, the neuronal stem cells of the embryonic cerebral cortex, reside deep within the developing brain and extend radial fibres to the pial surface, along which embryonic neurons migrate to reach the cortical plate. Here we show that the gap junction subunits connexin 26 (Cx26) and connexin 43 (Cx43) are expressed at the contact points between radial fibres and migrating neurons, and acute downregulation of Cx26 or Cx43 impairs the migration of neurons to the cortical plate. Unexpectedly, gap junctions do not mediate neuronal migration by acting in the classical manner to provide an aqueous channel for cell-cell communication. Instead, gap junctions provide dynamic adhesive contacts that interact with the internal cytoskeleton to enable leading process stabilization along radial fibres as well as the subsequent translocation of the nucleus. These results indicate that gap junction adhesions are necessary for glial-guided neuronal migration, raising the possibility that the adhesive properties of gap junctions may have an important role in other physiological processes and diseases associated with gap junction function. PMID- 17713528 TI - Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. AB - Obsessive-compulsive disorder (OCD) is an anxiety-spectrum disorder characterized by persistent intrusive thoughts (obsessions) and repetitive actions (compulsions). Dysfunction of cortico-striato-thalamo-cortical circuitry is implicated in OCD, although the underlying pathogenic mechanisms are unknown. SAP90/PSD95-associated protein 3 (SAPAP3; also known as DLGAP3) is a postsynaptic scaffolding protein at excitatory synapses that is highly expressed in the striatum. Here we show that mice with genetic deletion of Sapap3 exhibit increased anxiety and compulsive grooming behaviour leading to facial hair loss and skin lesions; both behaviours are alleviated by a selective serotonin reuptake inhibitor. Electrophysiological, structural and biochemical studies of Sapap3-mutant mice reveal defects in cortico-striatal synapses. Furthermore, lentiviral-mediated selective expression of Sapap3 in the striatum rescues the synaptic and behavioural defects of Sapap3-mutant mice. These findings demonstrate a critical role for SAPAP3 at cortico-striatal synapses and emphasize the importance of cortico-striatal circuitry in OCD-like behaviours. PMID- 17713530 TI - No extreme bipolar glaciation during the main Eocene calcite compensation shift. AB - Major ice sheets were permanently established on Antarctica approximately 34 million years ago, close to the Eocene/Oligocene boundary, at the same time as a permanent deepening of the calcite compensation depth in the world's oceans. Until recently, it was thought that Northern Hemisphere glaciation began much later, between 11 and 5 million years ago. This view has been challenged, however, by records of ice rafting at high northern latitudes during the Eocene epoch and by estimates of global ice volume that exceed the storage capacity of Antarctica at the same time as a temporary deepening of the calcite compensation depth approximately 41.6 million years ago. Here we test the hypothesis that large ice sheets were present in both hemispheres approximately 41.6 million years ago using marine sediment records of oxygen and carbon isotope values and of calcium carbonate content from the equatorial Atlantic Ocean. These records allow, at most, an ice budget that can easily be accommodated on Antarctica, indicating that large ice sheets were not present in the Northern Hemisphere. The records also reveal a brief interval shortly before the temporary deepening of the calcite compensation depth during which the calcite compensation depth shoaled, ocean temperatures increased and carbon isotope values decreased in the equatorial Atlantic. The nature of these changes around 41.6 million years ago implies common links, in terms of carbon cycling, with events at the Eocene/Oligocene boundary and with the 'hyperthermals' of the Early Eocene climate optimum. Our findings help to resolve the apparent discrepancy between the geological records of Northern Hemisphere glaciation and model results that indicate that the threshold for continental glaciation was crossed earlier in the Southern Hemisphere than in the Northern Hemisphere. PMID- 17713531 TI - Northern Hemisphere forcing of climatic cycles in Antarctica over the past 360,000 years. AB - The Milankovitch theory of climate change proposes that glacial-interglacial cycles are driven by changes in summer insolation at high northern latitudes. The timing of climate change in the Southern Hemisphere at glacial-interglacial transitions (which are known as terminations) relative to variations in summer insolation in the Northern Hemisphere is an important test of this hypothesis. So far, it has only been possible to apply this test to the most recent termination, because the dating uncertainty associated with older terminations is too large to allow phase relationships to be determined. Here we present a new chronology of Antarctic climate change over the past 360,000 years that is based on the ratio of oxygen to nitrogen molecules in air trapped in the Dome Fuji and Vostok ice cores. This ratio is a proxy for local summer insolation, and thus allows the chronology to be constructed by orbital tuning without the need to assume a lag between a climate record and an orbital parameter. The accuracy of the chronology allows us to examine the phase relationships between climate records from the ice cores and changes in insolation. Our results indicate that orbital-scale Antarctic climate change lags Northern Hemisphere insolation by a few millennia, and that the increases in Antarctic temperature and atmospheric carbon dioxide concentration during the last four terminations occurred within the rising phase of Northern Hemisphere summer insolation. These results support the Milankovitch theory that Northern Hemisphere summer insolation triggered the last four deglaciations. PMID- 17713532 TI - Hadean diamonds in zircon from Jack Hills, Western Australia. AB - Detrital zircons more than 4 billion years old from the Jack Hills metasedimentary belt, Yilgarn craton, Western Australia, are the oldest identified fragments of the Earth's crust and are unique in preserving information on the earliest evolution of the Earth. Inclusions of quartz, K feldspar and monazite in the zircons, in combination with an enrichment of light rare-earth elements and an estimated low zircon crystallization temperature, have previously been used as evidence for early recycling of continental crust, leading to the production of granitic melts in the Hadean era. Here we present the discovery of microdiamond inclusions in Jack Hills zircons with an age range from 3,058 +/- 7 to 4,252 +/- 7 million years. These include the oldest known diamonds found in terrestrial rocks, and introduce a new dimension to the debate on the origin of these zircons and the evolution of the early Earth. The spread of ages indicates that either conditions required for diamond formation were repeated several times during early Earth history or that there was significant recycling of ancient diamond. Mineralogical features of the Jack Hills diamonds such as their occurrence in zircon, their association with graphite and their Raman spectroscopic characteristics-resemble those of diamonds formed during ultrahigh-pressure metamorphism and, unless conditions on the early Earth were unique, imply a relatively thick continental lithosphere and crust-mantle interaction at least 4,250 million years ago. PMID- 17713533 TI - A new species of great ape from the late Miocene epoch in Ethiopia. AB - With the discovery of Ardipithecus, Orrorin and Sahelanthropus, our knowledge of hominid evolution before the emergence of Pliocene species of Australopithecus has significantly increased, extending the hominid fossil record back to at least 6 million years (Myr) ago. However, because of the dearth of fossil hominoid remains in sub-Saharan Africa spanning the period 12-7 Myr ago, nothing is known of the actual timing and mode of divergence of the African ape and hominid lineages. Most genomic-based studies suggest a late divergence date-5-6 Myr ago and 6-8 Myr ago for the human-chimp and human-gorilla splits, respectively-and some palaeontological and molecular analyses hypothesize a Eurasian origin of the African ape and hominid clade. We report here the discovery and recognition of a new species of great ape, Chororapithecus abyssinicus, from the 10-10.5-Myr-old deposits of the Chorora Formation at the southern margin of the Afar rift. To the best of our knowledge, these are the first fossils of a large-bodied Miocene ape from the African continent north of Kenya. They exhibit a gorilla-sized dentition that combines distinct shearing crests with thick enamel on its 'functional' side cusps. Visualization of the enamel-dentine junction by micro-computed tomography reveals shearing crest features that partly resemble the modern gorilla condition. These features represent genetically based structural modifications probably associated with an initial adaptation to a comparatively fibrous diet. The relatively flat cuspal enamel-dentine junction and thick enamel, however, suggest a concurrent adaptation to hard and/or abrasive food items. The combined evidence suggests that Chororapithecus may be a basal member of the gorilla clade, and that the latter exhibited some amount of adaptive and phyletic diversity at around 10-11 Myr ago. PMID- 17713534 TI - Non-random coextinctions in phylogenetically structured mutualistic networks. AB - The interactions between plants and their animal pollinators and seed dispersers have moulded much of Earth's biodiversity. Recently, it has been shown that these mutually beneficial interactions form complex networks with a well-defined architecture that may contribute to biodiversity persistence. Little is known, however, about which ecological and evolutionary processes generate these network patterns. Here we use phylogenetic methods to show that the phylogenetic relationships of species predict the number of interactions they exhibit in more than one-third of the networks, and the identity of the species with which they interact in about half of the networks. As a consequence of the phylogenetic effects on interaction patterns, simulated extinction events tend to trigger coextinction cascades of related species. This results in a non-random pruning of the evolutionary tree and a more pronounced loss of taxonomic diversity than expected in the absence of a phylogenetic signal. Our results emphasize how the simultaneous consideration of phylogenetic information and network architecture can contribute to our understanding of the structure and fate of species-rich communities. PMID- 17713535 TI - Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells. AB - Immunoglobulin-A has an irreplaceable role in the mucosal defence against infectious microbes. In human and mouse, IgA-producing plasma cells comprise approximately 20% of total plasma cells of peripheral lymphoid tissues, whereas more than 80% of plasma cells produce IgA in mucosa-associated lymphoid tissues (MALT). One of the most biologically important and long-standing questions in immunology is why this 'biased' IgA synthesis takes place in the MALT but not other lymphoid organs. Here we show that IgA class-switch recombination (CSR) is impaired in inducible-nitric-oxide-synthase-deficient (iNOS-/-; gene also called Nos2) mice. iNOS regulates the T-cell-dependent IgA CSR through expression of transforming growth factor-beta receptor, and the T-cell-independent IgA CSR through production of a proliferation-inducing ligand (APRIL, also called Tnfsf13) and a B-cell-activating factor of the tumour necrosis factor (TNF) family (BAFF, also called Tnfsf13b). Notably, iNOS is preferentially expressed in MALT dendritic cells in response to the recognition of commensal bacteria by toll like receptor. Furthermore, adoptive transfer of iNOS+ dendritic cells rescues IgA production in iNOS-/- mice. Further analysis revealed that the MALT dendritic cells are a TNF-alpha/iNOS-producing dendritic-cell subset, originally identified in mice infected with Listeria monocytogenes. The presence of a naturally occurring TNF-alpha/iNOS-producing dendritic-cell subset may explain the predominance of IgA production in the MALT, critical for gut homeostasis. PMID- 17713536 TI - p15Ink4b is a critical tumour suppressor in the absence of p16Ink4a. AB - The CDKN2b-CDKN2a locus on chromosome 9p21 in human (chromosome 4 in mouse) is frequently lost in cancer. The locus encodes three cell cycle inhibitory proteins: p15INK4b encoded by CDKN2b, p16INK4a encoded by CDKN2a and p14ARF (p19Arf in mice) encoded by an alternative reading frame of CDKN2a (ref. 1). Whereas the tumour suppressor functions for p16INK4a and p14ARF have been firmly established, the role of p15INK4b remains ambiguous. However, many 9p21 deletions also remove CDKN2b, so we hypothesized a synergistic effect of the combined deficiency for p15INK4b, p14ARF and p16INK4a. Here we report that mice deficient for all three open reading frames (Cdkn2ab-/-) are more tumour-prone and develop a wider spectrum of tumours than Cdkn2a mutant mice, with a preponderance of skin tumours and soft tissue sarcomas (for example, mesothelioma) frequently composed of mixed cell types and often showing biphasic differentiation. Cdkn2ab-/- mouse embryonic fibroblasts (MEFs) are substantially more sensitive to oncogenic transformation than Cdkn2a mutant MEFs. Under conditions of stress, p15Ink4b protein levels are significantly elevated in MEFs deficient for p16Ink4a. Our data indicate that p15Ink4b can fulfil a critical backup function for p16Ink4a and provide an explanation for the frequent loss of the complete CDKN2b-CDKN2a locus in human tumours. PMID- 17713539 TI - Tissue preparation: Tissue issues. PMID- 17713537 TI - The effects of molecular noise and size control on variability in the budding yeast cell cycle. AB - Molecular noise in gene expression can generate substantial variability in protein concentration. However, its effect on the precision of a natural eukaryotic circuit such as the control of cell cycle remains unclear. We use single-cell imaging of fluorescently labelled budding yeast to measure times from division to budding (G1) and from budding to the next division. The variability in G1 decreases with the square root of the ploidy through a 1N/2N/4N ploidy series, consistent with simple stochastic models for molecular noise. Also, increasing the gene dosage of G1 cyclins decreases the variability in G1. A new single-cell reporter for cell protein content allows us to determine the contribution to temporal G1 variability of deterministic size control (that is, smaller cells extending G1). Cell size control contributes significantly to G1 variability in daughter cells but not in mother cells. However, even in daughters, size-independent noise is the largest quantitative contributor to G1 variability. Exit of the transcriptional repressor Whi5 from the nucleus partitions G1 into two temporally uncorrelated and functionally distinct steps. The first step, which depends on the G1 cyclin gene CLN3, corresponds to noisy size control that extends G1 in small daughters, but is of negligible duration in mothers. The second step, whose variability decreases with increasing CLN2 gene dosage, is similar in mothers and daughters. This analysis decomposes the regulatory dynamics of the Start transition into two independent modules, a size sensing module and a timing module, each of which is predominantly controlled by a different G1 cyclin. PMID- 17713543 TI - Splenectomy: a new treatment option for ALL tumors expressing Hox-11 and a means to test the stem cell hypothesis of cancer in humans. PMID- 17713544 TI - Lack of a relationship between the common 8q24 variant rs6983267 and risk of chronic lymphocytic leukemia. PMID- 17713545 TI - FOXP3+ regulatory T cells in cutaneous T-cell lymphomas: association with disease stage and survival. AB - FOXP3 is a unique marker for CD4+CD25+ regulatory T cells (Tregs). In solid tumours, high numbers of Tregs are associated with a poor prognosis. Knowledge about the implications of Tregs for the behaviour of haematological malignancies is limited. In this study, skin biopsies from 86 patients with mycosis fungoides (MF) and cutaneous T-cell lymphoma (CTCL) unspecified were analysed for the expression of FOXP3 on tumour cells and tumour-infiltrating Tregs. Labelling of above 10% of the neoplastic cells was seen in one case classified as an aggressive epidermotropic CD8+ cytotoxic CTCL. In the remaining 85 cases, the atypical neoplastic infiltrate was either FOXP3 negative (n=80) or contained only very occasional weakly positive cells (n=5). By contrast, all biopsies showed varying numbers of strongly FOXP3+ tumour-infiltrating Tregs. MF with early or infiltrated plaques had significantly higher numbers of FOXP3+ Tregs than CTCL unspecified or advanced MF with tumours or transformation to large cell lymphoma. An analysis of all patients demonstrated that increasing numbers of FOXP3+ Tregs were associated with improved survival in both MF and CTCL unspecified. In conclusion, our data indicate that the presence of FOXP3+ Tregs in CTCL is associated with disease stage and patient survival. PMID- 17713547 TI - The DC-derived protein DC-STAMP influences differentiation of myeloid cells. PMID- 17713546 TI - Aplidin synergizes with cytosine arabinoside: functional relevance of mitochondria in Aplidin-induced cytotoxicity. AB - Aplidin (plitidepsin) is a novel marine-derived antitumor agent presently undergoing phase II clinical trials in hematological malignancies and solid tumors. Lack of bone marrow toxicity has encouraged further development of this drug for treatment of leukemia and lymphoma. Multiple signaling pathways have been shown to be involved in Aplidin-induced apoptosis and cell cycle arrest in G1 and G2 phase. However, the exact mechanism(s) of Aplidin action remains to be elucidated. Here we demonstrate that mitochondria-associated or -localized processes are the potential cellular targets of Aplidin. Whole genome gene expression profiling (GEP) revealed that fatty acid metabolism, sterol biosynthesis and energy metabolism, including the tricarboxylic acid cycle and ATP synthesis are affected by Aplidin treatment. Moreover, mutant MOLT-4, human leukemia cells lacking functional mitochondria, were found to be resistant to Aplidin. Cytosine arabinoside (araC), which also generates oxidative stress but does not affect the ATP pool, showed synergism with Aplidin in our leukemia and lymphoma models in vitro and in vivo. These studies provide new insights into the mechanism of action of Aplidin. The efficacy of the combination of Aplidin and araC is currently being evaluated in clinical phase I/II program for the treatment of patients with relapsed leukemia and high-grade lymphoma. PMID- 17713548 TI - Detection of an MPLW515 mutation in a case with features of both essential thrombocythemia and refractory anemia with ringed sideroblasts and thrombocytosis. PMID- 17713549 TI - Classification of myeloproliferative disorders in the JAK2 era: is there a role for red cell mass? PMID- 17713550 TI - Reply to 'Male preponderance in chronic lymphocytic leukemia utilizing IGHV1-69.' When size of the sample matters. PMID- 17713551 TI - Clinical characteristics and outcomes in patients with t(8;21) acute myeloid leukemia in Japan. PMID- 17713552 TI - Congenital transfusion-dependent anemia and thrombocytopenia with myelodysplasia due to a recurrent GATA1(G208R) germline mutation. PMID- 17713553 TI - T cells from patients with polycythemia vera elaborate growth factors which contribute to endogenous erythroid and megakaryocyte colony formation. AB - In the present study, we report that media conditioned by polycythemia vera (PV) CD3+ cells promote BFU-E and CFU-Mk colony formation by both cord blood and PV peripheral blood CD34+ cells in the absence of exogenous cytokines and promoting megakaryocyte proplatelet formation. CD3+ cells constitutively produce elevated levels of IL-11, while stimulation with the addition of phytohemagglutinin (PHA) increased GM-CSF levels in most of the patients with PV. Anti-IL-11-neutralizing antibody partially inhibited the formation of BFU-E and CFU-Mk colonies promoted by PV CD3+ cell-conditioned media. Although IL-11 is not produced by normal T cells, real-time PCR and flow cytometric analysis showed that IL-11 was upregulated in the CD3+ cells of most PV patients as compared to normal CD3+ cells. In addition, a greater percentage of BFU-E colonies formed by PV CD34+ cells in the presence of PV CD3+ cell-conditioned media alone were JAK2V617F positive as compared with that induced by EPO. We conclude that dysregulated production of soluble growth factor(s), including IL-11 and GM-CSF by PV T cells, contributes to the in vitro formation of erythroid colonies in the absence of exogenous cytokines by PV CD34+ cells and likely plays a role in sustaining hematopoiesis in PV. PMID- 17713554 TI - Combined single nucleotide polymorphism-based genomic mapping and global gene expression profiling identifies novel chromosomal imbalances, mechanisms and candidate genes important in the pathogenesis of T-cell prolymphocytic leukemia with inv(14)(q11q32). AB - T-cell prolymphocytic leukemia (T-PLL) is a rare aggressive lymphoma derived from mature T cells, which is, in most cases, characterized by the presence of an inv(14)(q11q32)/t(14;14)(q11;q32) and a characteristic pattern of secondary chromosomal aberrations. DNA microarray technology was employed to compare the transcriptomes of eight immunomagnetically purified CD3+ normal donor-derived peripheral blood cell samples, with five highly purified inv(14)/t(14;14) positive T-PLL blood samples. Between the two experimental groups, 734 genes were identified as differentially expressed, including functionally important genes involved in lymphomagenesis, cell cycle regulation, apoptosis and DNA repair. Notably, the differentially expressed genes were found to be significantly enriched in genomic regions affected by recurrent chromosomal imbalances. Upregulated genes clustered on chromosome arms 6p and 8q, and downregulated genes on 6q, 8p, 10p, 11q and 18p. High-resolution copy-number determination using single nucleotide polymorphism chip technology in 12 inv(14)/t(14;14)-positive T PLL including those analyzed for gene expression, refined chromosomal breakpoints as well as regions of imbalances. In conclusion, combined transcriptional and molecular cytogenetic profiling identified novel specific chromosomal loci and genes that are likely to be involved in disease progression and suggests a gene dosage effect as a pathogenic mechanism in T-PLL. PMID- 17713555 TI - Human telomerase is regulated by erythropoietin and transforming growth factor beta in human erythroid progenitor cells. AB - Telomerase catalytic subunit (hTERT) exerts important cellular functions including telomere homeostasis, genetic stability, cell survival and perhaps differentiation. However, the nature of external or internal signals, which regulate hTERT expression in tissues, remains poorly understood. Thus, whereas it has been described that hTERT gene is regulated along the differentiation of primitive myeloid progenitors, the effect of specific cytokines on telomerase expression in each myeloid lineage is currently unknown. Based on these considerations, we have investigated hTERT expression in erythroid cells treated with erythropoietin (EPO) and transforming growth factor beta (TGFbeta), as putative positive and negative regulators, respectively. We describe here that EPO activates hTERT gene transcription in in vitro-expanded primary erythroid precursors as well as in UT7 erythroleukemia cells. In UT7 cells, this study shows also that EPO acts through a JAK2/STAT5/c-myc axis. In contrast, TGFbeta blocks EPO signaling downstream of c-myc induction through a Smad3-dependent mechanism. Finally, hTERT appears to be efficiently regulated by EPO and TGFbeta in an opposite way in erythropoietic cells, arguing for a role of telomerase in red blood cell production. PMID- 17713556 TI - Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production. AB - The inhibitory receptor FcgammaRIIb regulates B-cell functions. Genetic studies have associated Fcgr2b polymorphisms and lupus susceptibility in both humans and murine models, in which B cells express reduced FcgammaRIIb levels. Furthermore, FcgammaRIIb absence results in lupus on the appropriate genetic background, and lentiviral-mediated FcgammaRIIb overexpression prevents disease in the NZM2410 lupus mouse. The NZM2410/NZW allele Fcgr2b is, however, located in-between Sle1a and Sle1b, two potent susceptibility loci, making it difficult to evaluate Fcr2b(NZW) independent contribution. By using two congenic strains that each carries only Sle1a (B6.Sle1a(15-353)), or Fcr2b(NZW) in the absence of Sle1a or Sle1b (B6.Sle1(111-148)), we show that the Fcr2b(NZW) allele does not upregulate its expression on germinal center B cells and plasma cells, as does the C57BL/6 allele on B6.Sle1a(15-353) B cells. Furthermore, in the absence of the flanking Sle1a and Sle1b, Fcr2b(NZW) does not produce an autoimmune phenotype, but is associated with an increased number of class-switched plasma cells. These results show that while a lower level of FcgammaRIIb does not by itself induce the development of autoreactive B cells, it has the potential to amplify the contribution of autoreactive B cells induced by other lupus-susceptibility loci by enhancing the production of class-switched plasma cells. PMID- 17713559 TI - Food for the gods. PMID- 17713560 TI - Two channels for one job. AB - The study by Rieg et al. is the first to examine potassium handling in BK(-/-) mice, thereby addressing many unanswered questions regarding the separate roles of BK and ROMK channels in renal potassium secretion. This Commentary is an interpretation and opinion of their results, by two researchers who have been studying BK and ROMK, respectively, as potassium secretory channels in the distal nephron. PMID- 17713557 TI - Genes at human chromosome 5q31.1 regulate delayed-type hypersensitivity responses associated with Leishmania chagasi infection. AB - Visceral leishmaniasis (VL) caused by Leishmania chagasi is endemic to northeast Brazil. A positive delayed-type hypersensitivity skin test response (DTH+) is a marker for acquired resistance to disease, clusters in families and may be genetically controlled. Twenty-three single nucleotide polymorphisms (SNPs) were genotyped in the cytokine 5q23.3-q31.1 region IRF1-IL5-IL13-IL4-IL9-LECT2-TGFBI in 102 families (323 DTH+; 190 DTH-; 123 VL individuals) from a VL endemic region in northeast Brazil. Data from 20 SNPs were analyzed for association with DTH+/- status and VL using family-based, stepwise conditional logistic regression analysis. Independent associations were observed between the DTH+ phenotype and markers in separate linkage disequilibrium blocks in LECT2 (OR 2.25; P=0.005; 95% CI=1.28-3.97) and TGFBI (OR 1.94; P=0.003; 95% CI=1.24-3.03). VL child/parent trios gave no evidence of association, but the DTH- phenotype was associated with SNP rs2070874 at IL4 (OR 3.14; P=0.006; 95% CI=1.38-7.14), and SNP rs30740 between LECT2 and TGFBI (OR 3.00; P=0.042; 95% CI=1.04-8.65). These results indicate several genes in the immune response gene cluster at 5q23.3-q31.1 influence outcomes of L. chagasi infection in this region of Brazil. PMID- 17713561 TI - Balanced calcitriol treatment to make children grow. AB - Short stature is an important clinical problem in children with chronic kidney disease. Calcitriol is used as standard therapy to control secondary hyperparathyroidism, but its effect on linear growth remains controversial. Sanchez and He report multiple effects of calcitriol on chondrocyte proliferation and maturation that might help to clarify this controversy. PMID- 17713562 TI - The making of a bone in blood vessels: from the soft shell to the hard bone. AB - Vascular calcification, particularly of the medial layer of arteries, is one of the key determinants of survival in patients with chronic kidney disease. This abnormality is not merely a simple process of precipitation of calcium and phosphate but also includes several mechanisms similar to those of bone formation within the vessel wall. PMID- 17713563 TI - Can we do better than a single estimated GFR threshold when screening for chronic kidney disease? AB - The Modification of Diet in Renal Disease (MDRD) equation has been used to screen for and diagnose chronic kidney disease (CKD). A fixed estimated glomerular filtration rate cutoff point has been advocated by the National Kidney Foundation to diagnose CKD. However, data derived from healthy individuals challenge this approach and suggest that age- and gender-specific reference values may be more useful in the screening setting. PMID- 17713565 TI - The Case | Acute paraplegia with anuric ARF. Occlusive aortic thrombus with ischemia of spinal cord and kidneys. PMID- 17713566 TI - Obstructive nephropathy and renal failure not improving after ureteral catheterization. PMID- 17713567 TI - Adeno-associated virus-mediated expression and constitutive secretion of NPY or NPY13-36 suppresses seizure activity in vivo. AB - Neuropeptide Y (NPY) is a 36-amino-acid peptide that attenuates seizure activity following direct infusion or adeno-associated virus (AAV)-mediated expression in the central nervous system. However, NPY activates all NPY receptor subtypes, potentially causing unwanted side effects. NPY13-36 is a C-terminal peptide fragment of NPY that primarily activates the NPY Y2 receptor, thought to mediate the antiseizure activity. Therefore, we investigated if recombinant adeno associated virus-mediated expression and constitutive secretion of NPY or NPY13 36 could alter limbic seizure sensitivity. Rats received bilateral piriform cortex infusions of AAV vectors that express and constitutively secrete full length NPY (AAV-FIB-NPY) or NPY13-36 (AAV-FIB-NPY13-36). Control rats received no infusion, as we have previously shown that vectors expressing and secreting reporter genes like GFP (AAV-FIB-EGFP), as well as vectors expressing peptides that lack secretion sequences (AAV-GAL) have no effect on seizures. One week later, all animals received kainic acid (10 mg kg(-1), intraperitoneally), and the latencies to wet dog shakes and limbic seizure behaviors were determined. Although both control and vector-treated rats developed wet dog shake behaviors with similar latencies, the latencies to class III and class IV limbic seizures were significantly prolonged in both NPY- and NPY13-36-treated groups. Thus, AAV mediated expression and constitutive secretion of NPY and NPY13-36 is effective in attenuating limbic seizures, and provides a platform for delivering therapeutic peptide fragments with increased receptor selectivity. PMID- 17713569 TI - Clinical and molecular characterization of patients at risk for hereditary melanoma in southern Brazil. AB - Melanoma is the most dangerous of all common skin cancers, due to its propensity to metastasize. Therefore, identification of at-risk populations may allow early detection of disease at a curable stage. In Europe and North America, between 8 14% of melanoma patients have a family history of the disease, and a subset of these individuals possess germline mutations in the CDKN2A gene, which encodes the p16(INK4A) and p14(ARF) tumor suppressors. We identified 30 patients (29 families) from Southern Brazil, who had a family history of melanoma and/or pancreatic cancer; or a personal history of multiple primary melanoma. We screened this cohort for mutations in the CDKN2A and CDK4 genes, and detected two functional mutations: a G-34T transversion in 5'untranslated region; and a M53I alteration encoded in exon 2. Both mutants have been previously associated with melanoma and demonstrate founder effects. We conclude that germline mutations of CDKN2A occur in the Brazilian population, and that these mutations likely originated in Europe. PMID- 17713568 TI - GCV modulates the antitumoural efficacy of a replicative adenovirus expressing the Tat8-TK as a late gene in a pancreatic tumour model. AB - Replication-competent adenoviruses carrying the herpes simplex thymidine kinase (TK) gene have shown contradictory evidence with regard to their antitumoural efficacy in combination with ganciclovir (GCV) treatment. We generated a replication-competent adenovirus carrying Tat8-TK, a modified form of the TK gene, under the control of the adenoviral major late promoter (AdRGDTat8-TK-L). Pancreatic cancer cell lines with different sensitivity to the TK/GCV system were infected with AdRGDTat8-TK-L, both in the presence and absence of GCV, and tested for treatment efficacy. We observed that, although the presence of GCV reduced viral replication in all infected cell lines, in three out of four GCV significantly enhanced the efficacy of the virotherapy. Interestingly, the cytotoxicity of the AdRGD-Tat8-TK-L/GCV was found more potent than that of a first generation AdTK/GCV system. In tumour xenografts from BxPC-3 and NP-18 pancreatic cells, both AdRGDTat8-TK-L and AdRGDTat8-TK-L/GCV treatment showed antitumoural activity. In BxPC-3 tumours scheduling of virus and prodrug was a key factor to determine the outcome of the therapy. Importantly, the addition of GCV enhanced the antitumoural effect of AdRGDTat8-TK-L only when applied in two rounds of virus+GCV. Interestingly, in spite of interfering with viral replication in vitro, GCV treatment of NP-18 tumours did not compromise the antitumoural efficacy of the AdRGDTat8-TK-L adenovirus. Thus, our results show that the combination therapy of a replicative adenovirus and the Tat8-TK/GCV suicide system can prove beneficial, when the appropriate regimen of virus and GCV is applied. PMID- 17713570 TI - Epidemiologic support for melanoma heterogeneity using the Surveillance, Epidemiology, and End Results Program. PMID- 17713571 TI - IL-21 enhances antitumor responses without stimulating proliferation of malignant T cells of patients with Sezary syndrome. AB - IL-21, a common gamma-chain cytokine secreted by activated CD4+ T cells, influences both humoral and cell-mediated immune responses through the regulation of T, B, dendritic, and natural killer (NK) cells. Sezary syndrome is an advanced form of cutaneous T-cell lymphoma, a clonally derived malignancy of CD4+ T cells that is characterized by profound defects in host cellular immune function. As a modulator of both innate and adaptive immune responses, IL-21 could play an important role in augmenting cell-mediated immunity in these patients. Normal donor and Sezary syndrome patient peripheral blood mononuclear cells were cultured with IL-21 and tested for CD8+ T- and NK-cell activation, NK-cell cytotoxicity, and tumor cell proliferation and apoptosis. IL-21 resulted in a modest increase in CD8+ T- and NK-cell activation, associated with a marked increase in cytolytic activity against both K562 and malignant CD4+ T-cell targets. Although IL-21 failed to demonstrate pro-apoptotic effects on the malignant CD4+ T cells, it is noteworthy that it had no demonstrable proliferative effects on these cells. Thus, IL-21 may play an important role in enhancing the host immune response of Sezary syndrome patients through the increased cytolytic activity of T and NK cells. PMID- 17713572 TI - Deficiency of PPARbeta/delta in the epidermis results in defective cutaneous permeability barrier homeostasis and increased inflammation. AB - In cultured human keratinocytes or murine epidermis, peroxisome proliferator activated receptor beta/delta (PPARbeta/delta) (NR1C2) activators (1) stimulate keratinocyte differentiation; (2) decrease keratinocyte proliferation; (3) accelerate permeability barrier repair; (4) increase epidermal lipid synthesis; and (5) reduce cutaneous inflammation. Since these results suggest that PPARbeta/delta could play an important role in cutaneous homeostasis, we assessed here the skin phenotype of mice deficient in PPARbeta/delta. Gross cutaneous abnormalities were not evident, and both stratum corneum (SC) skin hydration and surface pH were normal. However, the epidermis was thickened and proliferating cell nuclear antigen (PCNA) staining was increased, indicating increased cell proliferation. No change in apoptosis was observed but the expression of differentiation markers, such as filaggrin, involucrin, and loricrin, was slightly increased in PPARbeta/delta(-/-) mice. Although basal permeability barrier function was normal, PPARbeta/delta knockout (KO) mice show a significant delay in barrier recovery rates following acute barrier disruption by either acetone treatment or tape-stripping. Delayed barrier recovery correlated with decreased production and secretion of lamellar bodies (LBs), and with reduced numbers of extracellular lamellar membranes in the SC. Finally, PPARbeta/delta KO mice displayed increased inflammation in response to 12-O-tetradecanoylphorbol-13 acetate (TPA) treatment. Together, these results further demonstrate that PPARbeta/delta in the epidermis: (1) is required for permeability barrier homeostasis; (2) regulates keratinocyte proliferation; and (3) modulates cutaneous inflammation. PMID- 17713573 TI - Upregulation of the human alkaline ceramidase 1 and acid ceramidase mediates calcium-induced differentiation of epidermal keratinocytes. AB - Extracellular calcium (Ca2+(o)) potently induces the growth arrest and differentiation of human epidermal keratinocytes (HEKs). We report that Ca2+(o) markedly upregulates the human alkaline ceramidase 1 (haCER1) in HEKs; and its upregulation mediates the Ca2+(o)-induced growth arrest and differentiation of HEKs. haCER1 is the human ortholog of mouse alkaline ceramidase 1 that we previously identified. haCER1 catalyzed the hydrolysis of very long-chain ceramides to generate sphingosine (SPH). This in vitro activity required Ca2+. Ectopic expression of haCER1 in HEKs decreased the levels of D-e-C(24:1)-ceramide and D-e-C(24:0)-ceramide but elevated the levels of both SPH and its phosphate (S1P), whereas RNA interference-mediated knockdown of haCER1 caused the opposite effects on the levels of these sphingolipids in HEKs. Similar to haCER1 overexpression, Ca2+(o) increased the levels of SPH and S1P, and this was attenuated by haCER1 knockdown. haCER1 knockdown also inhibited the Ca2+(o) induced growth arrest of HEKs and the Ca2+(o)-induced expression of keratin 1 and involucrin in HEKs. In addition, the acid ceramidase (AC) was also upregulated by Ca2+(o); and its knockdown attenuated the Ca2+(o)-induced expression of keratin 1 and involucrin in HEKs. These results strongly suggest that upregulation of haCER1 and AC mediates the Ca2+(o)-induced growth arrest and differentiation of HEKs by generating SPH and S1P. PMID- 17713575 TI - Chromatin and chromatin-modifying proteins in adipogenesis. AB - Long considered scarcely more than an uninteresting energy depot, adipose tissue has recently achieved star status. Far from being mere fat droplets, the adipocytes secrete a number of hormones and bioactive peptides, collectively known as adipokines, which participate in the regulation of a variety of functions, from haemostasis to angiogenesis to energy balance. Adipose tissue constitutes a bona-fide endocrine organ whose main dysfunctions, obesity and lipodystrophy, are related to the development of diabetes, hypertension, or dyslipidemia. The renewed interest in this tissue has prompted an escalation in the number of studies focusing on every aspect of the biology of the adipose cell, in the belief that a detailed knowledge of the mechanisms involved in the differentiation and function of adipocytes may contribute new therapeutical approaches to the treatment of such alarming medical problems. Adipogenesis is the result of an intertwined network of transcription factors and coregulators with chromatin-modifying activities that together, are responsible for the establishment of the gene expression pattern of mature adipocytes. Although the exquisitely regulated transcription factor cascade controlling adipogenesis has been extensively studied, the role of chromatin and chromatin-modifying proteins has become apparent only in recent times. PMID- 17713574 TI - Chronic eczematous eruptions of the elderly are associated with chronic exposure to calcium channel blockers: results from a case-control study. AB - It has been suggested that chronic eczematous eruptions of the elderly could be associated with chronic drug exposure. To determine the drugs associated with these eruptions, we conducted a case-control study on 102 cases and 204 controls. Cases were consecutive patients older than 60 years presenting with an eczematous eruption that had evolved continuously or recurrently for more than 3 months without a reliable cause. Two controls were matched to each case on age, sex, in/outpatient origin, and center. Information about drug exposure was obtained from patients and their pharmacists. Drug use for more than 3 months within the year preceding the eruption was compared between cases and controls. An association was found between calcium channel blockers (CCB) and eczema, with a matched OR (odds ratio) of 2.5 (95% CI (confidence interval): 1.3-4.6). To ascertain the course of patients after CCB withdrawal, two ancillary studies were performed on 74 patients with eczematous eruptions from our department before the case-control study period, and on 101 patients registered in the French "Pharmacovigilance" database. Healing of these eruptions after CCB withdrawal occurred in 83 and 68% of these cases, respectively. The long-term use of CCB is a risk factor for chronic eczematous eruptions of the elderly. PMID- 17713576 TI - HIPK2: a multitalented partner for transcription factors in DNA damage response and development. AB - Protein phosphorylation is a widely diffuse and versatile post-translational modification that controls many cellular processes, from signal transduction to gene transcription. The homeodomain-interacting protein kinases (HIPKs) belong to a new family of serine-threonine kinases first identified as corepressors for homeodomain transcription factors. Different screenings for the identification of new partners of transcription factors have indicated that HIPK2, the best characterized member of the HIPK family, is a multitalented coregulator of an increasing number of transcription factors and cofactors. The aim of this review is to describe the different mechanisms through which HIPK2 regulates gene transcription. PMID- 17713577 TI - Nucleosome organization and targeting of SWI/SNF chromatin-remodeling complexes: contributions of the DNA sequence. AB - Chromatin organization within the nuclear compartment is a fundamental mechanism to regulate the expression of eukaryotic genes. During the last decade, a number of nuclear protein complexes with the ability to remodel chromatin and regulate gene transcription have been reported. Among these complexes is the SWI/SNF family, which alters chromatin structure in an ATP-dependent manner. A considerable effort has been made to understand the molecular mechanisms by which SWI/SNF catalyzes nucleosome remodeling. However, limited attention has been dedicated to studying the role of the DNA sequence in this remodeling process. Therefore, in this minireview, we discuss the contribution of nucleosome positioning and nucleosome excluding sequences to the targeting and activity of SWI/SNF complexes. This discussion includes results from our group using the rat osteocalcin gene promoter as a model. Based on these results, we postulate a model for chromatin remodeling and transcriptional activation of this gene in osteoblastic cells. PMID- 17713578 TI - Negotiating the nucleosome: factors that allow RNA polymerase II to elongate through chromatin. AB - Initiation by RNA polymerase II (Pol II) involves a host of enzymes, and the process of elongation appears similarly complex. Transcriptional elongation through chromatin requires the coordinated efforts of Pol II and its associated transcription factors: C-terminal domain kinases, elongation complexes, chromatin modifying enzymes, chromatin remodeling factors, histone chaperones (nucleosome assembly factors), and histone variants. This review examines the following: (i) the consequences of the encounter between elongating Pol II and a nucleosome, and (ii) chromatin remodeling factors and nucleosome assembly factors that have recently been identified as important for the elongation stage of transcription. PMID- 17713579 TI - Histone H3K4 demethylases are essential in development and differentiation. AB - Lysine histone methylation is one of the most robust epigenetic marks and is essential for the regulation of multiple cellular processes. The methylation of Lys4 of histone H3 seems to be of particular significance. It is associated with active regions of the genome, and in Drosophila it is catalyzed by trithorax group proteins that have become paradigms of developmental regulators at the level of chromatin. Like other histone methylation events, H3K4 methylation was considered irreversible until the identification of a large number of histone demethylases indicated that demethylation events play an important role in histone modification dynamics. However, the described demethylases had no strictly assigned biological functions and the identity of the histone demethylases that would contribute to the epigenetic changes specifying certain biological processes was unknown. Recently, several groups presented evidence that a family of 4 JmjC domain proteins results in the global changes of histone demethylation, and in elegant studies using model organisms, they demonstrated the importance of this family of histone demethylases in cell fate determination. All 4 proteins possess the demethylase activity specific to H3K4 and belong to the poorly described JARID1 protein family. PMID- 17713581 TI - CHD proteins: a diverse family with strong ties. AB - Chromodomain/helicase/DNA-binding domain (CHD) proteins have been identified in a variety of organisms. Despite common features, such as their chromodomain and helicase domain, they have been described as having multiple roles and interacting partners. However, a common theme for the main role of CHD proteins appears to be linked to their ATP-dependent chromatin-remodeling activity. Their actual activity as either repressor or activator, and their cell or gene specificity, is connected to their interacting partner(s). In this minireview, we attempt to match the members of the CHD family with the presence of structural domains, cofactors, and cellular roles in the regulation of gene expression, recombination, genome organization, and chromatin structure, as well as their potential activity in RNA processing. PMID- 17713580 TI - How many remodelers does it take to make a brain? Diverse and cooperative roles of ATP-dependent chromatin-remodeling complexes in development. AB - The development of a metazoan from a single-celled zygote to a complex multicellular organism requires elaborate and carefully regulated programs of gene expression. However, the tight packaging of genomic DNA into chromatin makes genes inaccessible to the cellular machinery and must be overcome by the processes of chromatin remodeling; in addition, chromatin remodeling can preferentially silence genes when their expression is not required. One class of chromatin remodelers, ATP-dependent chromatin-remodeling enzymes, can slide nucleosomes along the DNA to make specific DNA sequences accessible or inaccessible to regulators at a particular stage of development. While all ATPases in the SWI2/SNF2 superfamily share the fundamental ability to alter DNA accessibility in chromatin, they do not act alone, but rather, are subunits of a large assortment of protein complexes. Recent studies illuminate common themes by which the subunit compositions of chromatin-remodeling complexes specify the developmental roles that chromatin remodelers play in specific tissues and at specific stages of development, in response to specific signaling pathways and transcription factors. In this review, we will discuss the known roles in metazoan development of 3 major subfamilies of chromatin-remodeling complexes: the SNF2, ISWI, and CHD subfamilies. PMID- 17713582 TI - Che-1/AATF, a multivalent adaptor connecting transcriptional regulation, checkpoint control, and apoptosis. AB - Che-1/AATF (Che-1) was originally characterized as an interacting protein for RNA polymerase II. In addition to transcriptional regulation, the evidence suggests that Che-1 has a viral factor-like S phase promoting role in counteracting Rb repression to facilitate E2F-dependent transactivation during G1-S transition. Recently, Che-1 was found to play an important role in the DNA damage response and cell-cycle checkpoint control. Genetic studies in mice revealed that Che-1 is essential for preimplantation development and the establishment of embryonic gene expression. Importantly, several findings showed that Che-1 participates in inhibiting apoptotic process. Thus, Che-1 emerges as an important adaptor that connects transcriptional regulation, cell-cycle progression, checkpoint control, and apoptosis. PMID- 17713583 TI - Noncoding but nonexpendable: transcriptional regulation by large noncoding RNA in eukaryotes. AB - Genome sequencing and annotation has advanced our understanding of genome organization and gene structure but initially only allowed predictions of how many genes might be present. Mechanisms such as alternative splicing reveal that these predictions only scratch the surface of the true nature of the transcriptome. Several thousand expressed partial gene fragments have been cloned but were considered transcriptional noise or cloning artifacts. We now know that genomes are indeed expressed at much higher levels than was previously predicted, and much of the additional transcription maps to intergenic regions, intron sequences, and untranslated regions of mRNAs. These transcripts are expressed from either the sense or the antisense strand and can be confirmed by conventional techniques. In addition to the already established roles for small RNAs in gene regulation, large noncoding RNAs (ncRNAs) are also emerging as potent regulators of gene expression. In this review, we summarize several illustrative examples of gene regulatory mechanisms that involve large ncRNAs. We describe several distinct regulatory mechanisms that involve large ncRNAs, such as transcriptional interference and promoter inactivation, as well as indirect effects on transcription regulatory proteins and in genomic imprinting. These diverse functions for large ncRNAs are likely to be only the first of many novel regulatory mechanisms emerging from this growing field. PMID- 17713584 TI - Characterization of breast cancer by array comparative genomic hybridization. AB - Cancer progression is due to the accumulation of recurrent genomic alterations that induce growth advantage and clonal expansion. Most of these genomic changes can be detected using the array comparative genomic hybridization (CGH) technique. The accurate classification of these genomic alterations is expected to have an important impact on translational and basic research. Here we review recent advances in CGH technology used in the characterization of different features of breast cancer. First, we present bioinformatics methods that have been developed for the analysis of CGH arrays; next, we discuss the use of array CGH technology to classify tumor stages and to identify and stratify subgroups of patients with different prognoses and clinical behaviors. We finish our review with a discussion of how CGH arrays are being used to identify oncogenes, tumor suppressor genes, and breast cancer susceptibility genes. PMID- 17713587 TI - Quantification of the impact of feature selection on the variance of cross validation error estimation. AB - Given the relatively small number of microarrays typically used in gene expression-based classification, all of the data must be used to train a classifier and therefore the same training data is used for error estimation. The key issue regarding the quality of an error estimator in the context of small samples is its accuracy, and this is most directly analyzed via the deviation distribution of the estimator, this being the distribution of the difference between the estimated and true errors. Past studies indicate that given a prior set of features, cross-validation does not perform as well in this regard as some other training-data-based error estimators. The purpose of this study is to quantify the degree to which feature selection increases the variation of the deviation distribution in addition to the variation in the absence of feature selection. To this end, we propose the coefficient of relative increase in deviation dispersion (CRIDD), which gives the relative increase in the deviation distribution variance using feature selection as opposed to using an optimal feature set without feature selection. The contribution of feature selection to the variance of the deviation distribution can be significant, contributing to over half of the variance in many of the cases studied. We consider linear discriminant analysis, 3-nearest-neighbor, and linear support vector machines for classification; sequential forward selection, sequential forward floating selection, and the t-test for feature selection; and k-fold and leave-one-out cross-validation for error estimation. We apply these to three feature-label models and patient data from a breast cancer study. In sum, the cross-validation deviation distribution is significantly flatter when there is feature selection, compared with the case when cross-validation is performed on a given feature set. This is reflected by the observed positive values of the CRIDD, which is defined to quantify the contribution of feature selection towards the deviation variance. PMID- 17713585 TI - Mre11-Rad50-Nbs1 is a keystone complex connecting DNA repair machinery, double strand break signaling, and the chromatin template. AB - The Mre11-Rad50-Nbs1 (MRN) complex is providing paradigm-shifting results of exceptional biomedical interest. MRN is among the earliest respondents to DNA double-strand breaks (DSBs), and MRN mutations cause the human cancer predisposition diseases Nijmegen breakage syndrome and ataxia telangiectasia-like disorder (ATLD). MRN's 3-protein multidomain composition promotes its central architectural, structural, enzymatic, sensing, and signaling functions in DSB responses. To organize the MRN complex, the Mre11 exonuclease directly binds Nbs1, DNA, and Rad50. Rad50, a structural maintenance of chromosome (SMC) related protein, employs its ATP-binding cassette (ABC) ATPase, Zn hook, and coiled coils to bridge DSBs and facilitate DNA end processing by Mre11. Contributing to MRN regulatory roles, Nbs1 harbors N-terminal phosphopeptide interacting FHA and BRCT domains, as well as C-terminal ataxia telangiectasia mutated (ATM) kinase and Mre11 interaction domains. Current emerging structural and biological evidence suggests that MRN has 3 coupled critical roles in DSB sensing, stabilization, signaling, and effector scaffolding: (1) expeditious establishment of protein- nucleic acid tethering scaffolds for the recognition and stabilization of DSBs; (2) initiation of DSB sensing, cell-cycle checkpoint signaling cascades, and establishment of epigenetic marks via the ATM kinase; and (3) functional regulation of chromatin remodeling in the vicinity of a DSB. PMID- 17713588 TI - The formula of grangeat for tensor fields of arbitrary order in N dimensions. AB - The cone beam transform of a tensor field of order m in n >/= 2 dimensions is considered. We prove that the image of a tensor field under this transform is related to a derivative of the n-dimensional Radon transform applied to a projection of the tensor field. Actually the relation we show reduces for m = 0 and n = 3 to the well-known formula of Grangeat. In that sense, the paper contains a generalization of Grangeat's formula to arbitrary tensor fields in any dimension. We further briefly explain the importance of that formula for the problem of tensor field tomography. Unfortunately, for m > 0, an inversion method cannot be derived immediately. Thus, we point out the possibility to calculate reconstruction kernels for the cone beam transform using Grangeat's formula. PMID- 17713589 TI - The wavelet-based cluster analysis for temporal gene expression data. AB - A variety of high-throughput methods have made it possible to generate detailed temporal expression data for a single gene or large numbers of genes. Common methods for analysis of these large data sets can be problematic. One challenge is the comparison of temporal expression data obtained from different growth conditions where the patterns of expression may be shifted in time. We propose the use of wavelet analysis to transform the data obtained under different growth conditions to permit comparison of expression patterns from experiments that have time shifts or delays. We demonstrate this approach using detailed temporal data for a single bacterial gene obtained under 72 different growth conditions. This general strategy can be applied in the analysis of data sets of thousands of genes under different conditions. PMID- 17713590 TI - Clustering time-series gene expression data using smoothing spline derivatives. AB - Microarray data acquired during time-course experiments allow the temporal variations in gene expression to be monitored. An original postprandial fasting experiment was conducted in the mouse and the expression of 200 genes was monitored with a dedicated macroarray at 11 time points between 0 and 72 hours of fasting. The aim of this study was to provide a relevant clustering of gene expression temporal profiles. This was achieved by focusing on the shapes of the curves rather than on the absolute level of expression. Actually, we combined spline smoothing and first derivative computation with hierarchical and partitioning clustering. A heuristic approach was proposed to tune the spline smoothing parameter using both statistical and biological considerations. Clusters are illustrated a posteriori through principal component analysis and heatmap visualization. Most results were found to be in agreement with the literature on the effects of fasting on the mouse liver and provide promising directions for future biological investigations. PMID- 17713591 TI - A novel signal processing measure to identify exact and inexact tandem repeat patterns in DNA sequences. AB - The identification and analysis of repetitive patterns are active areas of biological and computational research. Tandem repeats in telomeres play a role in cancer and hypervariable trinucleotide tandem repeats are linked to over a dozen major neurodegenerative genetic disorders. In this paper, we present an algorithm to identify the exact and inexact repeat patterns in DNA sequences based on orthogonal exactly periodic subspace decomposition technique. Using the new measure our algorithm resolves the problems like whether the repeat pattern is of period P or its multiple (i.e., 2P, 3P, etc.), and several other problems that were present in previous signal-processing-based algorithms. We present an efficient algorithm of O(NL(w) log L(w)), where N is the length of DNA sequence and L(w) is the window length, for identifying repeats. The algorithm operates in two stages. In the first stage, each nucleotide is analyzed separately for periodicity, and in the second stage, the periodic information of each nucleotide is combined together to identify the tandem repeats. Datasets having exact and inexact repeats were taken up for the experimental purpose. The experimental result shows the effectiveness of the approach. PMID- 17713592 TI - Theoretical investigation of halogen-oxygen bonding and its implications in halogen chemistry and reactivity. AB - Trends in the properties of normal valent and multivalent halogen-oxygen bonding are examined for the isomers of the halogen polyoxide families of the types (YXO2) and (YXO3), Y = Cl, Br, I, H, CH(3), X = Cl, Br, I. A qualitative model is formulated on the relationship between the X-O bond distance variations, the ionic character of the bonding, and the degree of halogen valence. The relative stability and enthalpy of formation of each species are also suggested to correlate with the ionic nature of the X-O bonding and the electrostatic character of the Y, YO fragments. In the model presented, halogen hypervalence is interpreted to be the result of partial p --> d promotion of lone-pair valence electrons followed by the formation of two, four, or six additional pd hybrid bonds around the halogen atom. PMID- 17713593 TI - Gene selection for multiclass prediction by weighted Fisher criterion. AB - Gene expression profiling has been widely used to study molecular signatures of many diseases and to develop molecular diagnostics for disease prediction. Gene selection, as an important step for improved diagnostics, screens tens of thousands of genes and identifies a small subset that discriminates between disease types. A two-step gene selection method is proposed to identify informative gene subsets for accurate classification of multiclass phenotypes. In the first step, individually discriminatory genes (IDGs) are identified by using one-dimensional weighted Fisher criterion (wFC). In the second step, jointly discriminatory genes (JDGs) are selected by sequential search methods, based on their joint class separability measured by multidimensional weighted Fisher criterion (wFC). The performance of the selected gene subsets for multiclass prediction is evaluated by artificial neural networks (ANNs) and/or support vector machines (SVMs). By applying the proposed IDG/JDG approach to two microarray studies, that is, small round blue cell tumors (SRBCTs) and muscular dystrophies (MDs), we successfully identified a much smaller yet efficient set of JDGs for diagnosing SRBCTs and MDs with high prediction accuracies (96.9% for SRBCTs and 92.3% for MDs, resp.). These experimental results demonstrated that the two-step gene selection method is able to identify a subset of highly discriminative genes for improved multiclass prediction. PMID- 17713595 TI - A spiderless arachnophobia therapy: comparison between placebo and treatment groups and six-month follow-up study. AB - We describe a new arachnophobia therapy that is specially suited for those individuals with severe arachnophobia who are reluctant to undergo direct or even virtual exposure treatments. In this therapy, patients attend a computer presentation of images that, while not being spiders, have a subset of the characteristics of spiders. The Atomium of Brussels is an example of such an image. The treatment group (n = 13) exhibited a significant improvement (time x group interaction: P = .0026) when compared to the placebo group (n = 12) in a repeated measures multivariate ANOVA. A k-means clustering algorithm revealed that, after 4 weeks of treatment, 42% of the patients moved from the arachnophobic to the nonarachnophobic cluster. Six months after concluding the treatment, a follow-up study showed a substantial consolidation of the recovery process where 92% of the arachnophobic patients moved to the nonarachnophobic cluster. PMID- 17713594 TI - A role for excitatory amino acids in diabetic eye disease. AB - Diabetic retinopathy is a leading cause of vision loss. The primary clinical hallmarks are vascular changes that appear to contribute to the loss of sight. In a number of neurodegenerative disorders there is an appreciation that increased levels of excitatory amino acids are excitotoxic. The primary amino acid responsible appears to be the neurotransmitter glutamate. This review examines the nature of glutamatergic signaling at the retina and the growing evidence from clinical and animal model studies that glutamate may be playing similar excitotoxic roles at the diabetic retina. PMID- 17713596 TI - Detection of elevated signaling amino acids in human diabetic vitreous by rapid capillary electrophoresis. AB - Elevated glutamate is implicated in the pathology of PDR. The ability to rapidly assess the glutamate and amino acid content of vitreous provides a more complete picture of the chemical changes occurring at the diabetic retina and may lead to a better understanding of the pathology of PDR. Vitreous humor was collected following vitrectomies of patients with PDR and control conditions of macular hole or epiretinal membrane. A capillary electrophoresis method was developed to quantify glutamate and arginine. The analysis is relatively fast (<6 minutes) and utilizes a poly(ethylene)oxide and sodium dodecylsulfate run buffer. Both amino acid levels show significant increases in PDR patients versus controls and are comparable to other reports. The levels of vitreal glutamate vary inversely with the degree of observed hemorrhage. The results demonstrate a rapid method for assessment of a number of amino acids to characterize the chemical changes at the diabetic retina to better understand tissue changes and potentially identify new treatments. PMID- 17713597 TI - Pharmacotherapies for diabetic retinopathy: present and future. AB - Diabetic retinopathy remains a major cause of worldwide preventable blindness. Measures to avoid blindness include medical management (control of blood sugar, blood pressure, and serum lipids) and ocular management (laser photocoagulation and pars plana vitrectomy). Adjunctive pharmacologic therapies (intravitreal triamcinolone acetonide and anti-vascular endothelial growth factor agents) have shown early promise in the treatment of both diabetic macular edema and proliferative diabetic retinopathy. Other medications under investigation include the fluocinolone acetonide implantable device, extended-release dexamethasone implant, oral ruboxistaurin, and intravitreal hyaluronidase. PMID- 17713598 TI - The amphioxus SoxB family: implications for the evolution of vertebrate placodes. AB - Cranial placodes are regions of thickened ectoderm that give rise to sense organs and ganglia in the vertebrate head. Homologous structures are proposed to exist in urochordates, but have not been found in cephalochordates, suggesting the first chordates lacked placodes. SoxB genes are expressed in discrete subsets of vertebrate placodes. To investigate how placodes arose and diversified in the vertebrate lineage we isolated the complete set of SoxB genes from amphioxus and analyzed their expression in embryos and larvae. We find that while amphioxus possesses a single SoxB2 gene, it has three SoxB1 paralogs. Like vertebrate SoxB1 genes, one of these paralogs is expressed in non-neural ectoderm destined to give rise to sensory cells. When considered in the context of other amphioxus placode marker orthologs, amphioxus SoxB1 expression suggests a diversity of sensory cell types utilizing distinct placode-type gene programs was present in the first chordates. Our data supports a model for placode evolution and diversification whereby the full complement of vertebrate placodes evolved by serial recruitment of distinct sensory cell specification programs to anterior pre-placodal ectoderm. PMID- 17713599 TI - Superoxide anion radical scavenging activities of herbs and pastures in northern Japan determined using electron spin resonance spectrometry. AB - Free radicals are not only destructive to the living cells but also reduce the quality of animal products through oxidation. As a result the superoxide anion radical (O2-), one of the most destructive reactive oxygen species, is a matter of concern for the animal scientists as well as feed manufacturers to ensure the quality of product to reach consumers demand. The superoxide anion radical scavenging activities (SOSA) of water and MeOH extracts of 2 herbs and 9 pasture samples collected from lowland and highland swards were determined against a 5,5 dimethyl-1-pyroline-N-oxide-O2-spin adduct based on a hypoxanthine-xanthine oxidase reaction using electron spin resonance spectrometry. Both the water and MeOH extracted SOSA differed among the herbs and pastures. Species and altitudinal variations were observed between extraction methods. The herbs were higher in both water and MeOH extracted SOSA than the pastures except for water extracts of one pasture, white clover (Trifolium repens L.). Among the pastures, quackgrass (Agrophyron repens L.) showed higher SOSA in both the MeOH and water extracts, and timothy (Phleum pretense L.) showed higher MeOH extracted SOSA. It is apparent that the kind and amount of antioxidants differ among herbs and pastures. Animal health and quality of animal products could be improved by adequate selection and combining of herbs and pastures having higher SOSA. PMID- 17713600 TI - Inhibition by natural dietary substances of gastrointestinal absorption of starch and sucrose in rats and pigs: 1. Acute studies. AB - Rapid gastrointestinal absorption of refined carbohydrates (CHO) is linked to perturbed glucose-insulin metabolism that is, in turn, associated with many chronic health disorders. We assessed the ability of various natural substances, commonly referred to as "CHO blockers," to influence starch and sucrose absorption in vivo in ninety-six rats and two pigs. These natural enzyme inhibitors of amylase/sucrase reportedly lessen breakdown of starches and sucrose in the gastrointestinal tract, limiting their absorption. To estimate absorption, groups of nine SD rats were gavaged with water or water plus rice starch and/or sucrose; and circulating glucose was measured at timed intervals thereafter. For each variation in the protocol a total of at least nine different rats were studied with an equal number of internal controls on three different occasions. The pigs rapidly drank CHO and inhibitors in their drinking water. In rats, glucose elevations above baseline over four hours following rice starch challenge as estimated by area-under-curve (AUC) were 40%, 27%, and 85% of their internal control after ingesting bean extract, hibiscus extract, and l-arabinose respectively in addition to the rice starch. The former two were significantly different from control. L-Arabinose virtually eliminated the rising circulating glucose levels after sucrose challenge, whereas hibiscus and bean extracts were associated with lesser decreases than l-arabinose that were still significantly lower than control. The glucose elevations above baseline over four hours in rats receiving sucrose (AUC) were 51%, 43% and 2% of control for bean extract, hibiscus extract, and L-arabinose, respectively. Evidence for dose-response of bean and hibiscus extracts is reported. Giving the natural substances minus CHO challenge caused no significant changes in circulating glucose concentrations, indicating no major effects on overall metabolism. A formula combining these natural products significantly decreased both starch and sucrose absorption, even when the CHO were given simultaneously. These results support the hypothesis that the enzyme inhibitors examined here at reasonable doses can safely lower the glycemic loads starch and sucrose. PMID- 17713601 TI - Inhibition by natural dietary substances of gastrointestinal absorption of starch and sucrose in rats 2. Subchronic studies. AB - Acute oral consumption of various natural inhibitors of amylase (bean and hibiscus extracts) and sucrase (L-arabinose) reduce absorption of starch and sucrose respectively in rats and pigs measured by lessened appearance of circulating glucose levels. The present subchronic study was designed to determine whether these selected inhibitors of gastrointestinal starch and sucrose absorption (so-called "carb blockers") remain effective with continued use and to assess their metabolic influences after prolonged intake. Sprague Dawley rats were gavaged twice daily over nine weeks with either water or an equal volume of water containing a formula that included bean and hibiscus extracts and L-arabinose. To estimate CHO absorption, control and treated Sprague Dawley rats were gavaged with either water alone or an equal volume of water containing glucose, rice starch, sucrose, or combined rice starch and sucrose. Circulating glucose was measured at timed intervals over four hours. The ability to decrease starch and sucrose absorption use. No toxic effects (hepatic, renal, hematologic) were evident. Blood chemistries revealed significantly lower circulating glucose levels and a trend toward decreased HbA1C in the nondiabetic rats receiving the natural formulation compared to control. Subchronic administration of enzyme inhibitors was also associated with many metabolic changes including lowered systolic blood pressure and altered fluid-electrolyte balance. We postulate that proper intake of natural amylase and sucrase inhibitors may be useful in the prevention and treatment of many chronic disorders associated with perturbations in glucose-insulin homeostasis secondary to the rapid absorption of refined CHO. PMID- 17713602 TI - The role of actin and microtubule networks in plasmid DNA intracellular trafficking. AB - This work is focused on the function of the microtubule and actin networks in plasmid DNA transport during liposomal transfection. We observed strong binding of plasmid DNA-lipid complexes (lipoplexes) to both networks and directional long range motion of these lipoplexes along the microtubules. Disruption of either of these networks led to the cessation of plasmid transport to the nucleus, a decreased mobility of plasmids, and accumulation of plasmid DNA in large aggregates at the cell periphery. Our findings show an indispensable but different role of both types of cytoskeleton, actin and microtubular, in the processes of gene delivery. PMID- 17713603 TI - Evaluation of HI-6 oxime: potential use in protection of human acetylcholinesterase inhibited by antineoplastic drug irinotecan and its cyto/genotoxicity in vitro. AB - The function of acetylcholinesterase (AChE) is the rapid hydrolysis of the neurotransmitter acetylcholine (ACh), which is involved in the numerous cholinergic pathways in both the central and the peripheral nervous system. Therefore, AChE measurement is of high value for therapy management, especially during the course of intoxication with different chemicals or drugs that inhibit the enzyme. Pyridinium or bispyridinium aldoximes (oximes) are able to recover the activity of the inhibited enzyme. Since their adverse effects are not well elucidated, in this study the efficiency of HI-6 oxime in protection and/or reactivation of human erythrocyte AChE inhibited by the antineoplastic drug irinotecan as well as its cyto/genotoxicity in vitro were investigated. HI-6 was effective in protection of AChE and increased its activity up to 30%; the residual activity after irinotecan inhibition was 7%. Also, it reactivated the enzyme previously inhibited by 50% irinotecan (4.6 microg/ml) applied at 1/4 of the IC50 value. The tested concentrations of HI-6 exhibited acceptable genotoxicity towards white blood cells, as estimated by the alkaline comet assay, DNA diffusion assay and cytogenetic endpoints (structural chromosome aberrations and cytokinesis-block micronucleus assay). The results obtained warrant the further investigation of HI-6 in vivo, as well as its development for possible application in chemotherapy. PMID- 17713604 TI - Amyloid beta enhances cytosolic phospholipase A2 level and arachidonic acid release via nitric oxide in APP-transfected PC12 cells. AB - Cytosolic phospholipase A2 (cPLA2) preferentially liberates arachidonic acid (AA), which is known to be elevated in Alzheimer's disease (AD). The aim of this study was to investigate the possible relationship between enhanced nitric oxide (NO) generation observed in AD and cPLA2 protein level, phosphorylation, and AA release in rat pheochromocytoma cell lines (PC12) differing in amyloid beta secretion. PC12 control cells, PC12 cells bearing the Swedish double mutation in amyloid beta precursor protein (APPsw), and PC12 cells transfected with human APP (APPwt) were used. The transfected APPwt and APPsw PC12 cells showed an about 2.8 and 4.8-fold increase of amyloid beta (Abeta) secretion comparing to control PC12 cells. An increase of NO synthase activity, cGMP and free radical levels in APPsw and APPwt PC12 cells was observed. cPLA2 protein level was higher in APPsw and APPwt PC12 cells comparing to PC12 cells. Moreover, phosphorylated cPLA2 protein level and [3H]AA release were also higher in APP-transfected PC12 cells than in the control PC12 cells. An NO donor, sodium nitroprusside, stimulated [3H]AA release from prelabeled cells. The highest NO-induced AA release was observed in control PC12 cells, the effect in the other cell lines being statistically insignificant. Inhibition of cPLA2 by AACOCF3 significantly decreased the AA release. Inhibitors of nNOS and gamma-secretase reduced AA release in APPsw and APPwt PC12 cells. The basal cytosolic [Ca2+](i) and mitochondrial Ca2+ concentration was not changed in all investigated cell lines. Stimulation with thapsigargin increased the cytosolic and mitochondrial Ca2+ level, activated NOS and stimulated AA release in APP-transfected PC12 cells. These results indicate that Abeta peptides enhance the protein level and phosphorylation of cPLA2 and AA release by the NO signaling pathway. PMID- 17713606 TI - Microfluidic platforms for lab-on-a-chip applications. AB - We review microfluidic platforms that enable the miniaturization, integration and automation of biochemical assays. Nowadays nearly an unmanageable variety of alternative approaches exists that can do this in principle. Here we focus on those kinds of platforms only that allow performance of a set of microfluidic functions--defined as microfluidic unit operations-which can be easily combined within a well defined and consistent fabrication technology to implement application specific biochemical assays in an easy, flexible and ideally monolithically way. The microfluidic platforms discussed in the following are capillary test strips, also known as lateral flow assays, the "microfluidic large scale integration" approach, centrifugal microfluidics, the electrokinetic platform, pressure driven droplet based microfluidics, electrowetting based microfluidics, SAW driven microfluidics and, last but not least, "free scalable non-contact dispensing". The microfluidic unit operations discussed within those platforms are fluid transport, metering, mixing, switching, incubation, separation, droplet formation, droplet splitting, nL and pL dispensing, and detection. PMID- 17713607 TI - A virtual valve for smooth contamination-free flow switching. AB - We present a channel geometry that allows for clean switching between different inlets of a microchip without any contamination of the inlets or the downstream flow. We drive this virtual valve with a pneumatic pressure setup that minimizes disturbance of the downstream flow during the switching procedure by simultaneous variation of the pressures applied to the different inlets. We assess the efficiency of the setup by spectroscopic measurement of downstream dye concentrations, and demonstrate its practical utility by sequentially constructing multiple layers of alginate hydrogel. The method is potentially useful for a whole series of further applications, such as changing perfusion liquids for cell culture and cell analysis, metering, chemical-reaction initiation and multi-sample chromatography, to name a few. PMID- 17713608 TI - Dielectrophoresis switching with vertical sidewall electrodes for microfluidic flow cytometry. AB - A novel dielectrophoresis switching with vertical electrodes in the sidewall of microchannels for multiplexed switching of objects has been designed, fabricated and tested. With appropriate electrode design, lateral DEP force can be generated so that one can dynamically position particulates along the width of the channel. A set of interdigitated electrodes in the sidewall of the microchannels is used for the generation of non-uniform electrical fields to generate negative DEP forces that repel beads/cells from the sidewalls. A countering DEP force is generated from another set of electrodes patterned on the opposing sidewall. These lateral negative DEP forces can be adjusted by the voltage and frequency applied. By manipulating the coupled DEP forces, the particles flowing through the microchannel can be positioned at different equilibrium points along the width direction and continue to flow into different outlet channels. Experimental results for switching biological cells and polystyrene microbeads to multiple outlets (up to 5) have been achieved. This novel particle switching technique can be integrated with other particle detection components to enable microfluidic flow cytometry systems. PMID- 17713609 TI - Hierarchical aqueous self-assembly of C60 nano-whiskers and C60-silver nano hybrids under continuous flow. AB - The ubiquitous starch-iodine complex can be used to organize hydrophobic fullerene C(60) in water into nano-whiskers shrouded by the biopolymer, and are approximately 5-8 nm in cross section, and 250-350 nm in length, as a hierarchical self assembly process. The preformed starch-iodine complex reacts with solid pristine C(60) affording nano-whiskers with iodine surrounding the fullerene array, the iodine then being removed on treatment with ascorbic acid. The hydrophobic surface of the nano-whiskers of C(60) can be coated with silver metal in a controlled way using 'soft energy' spinning disc processing. PMID- 17713610 TI - Raman acoustic levitation spectroscopy of red blood cells and Plasmodium falciparum trophozoites. AB - Methods to probe the molecular structure of living cells are of paramount importance in understanding drug interactions and environmental influences in these complex dynamical systems. The coupling of an acoustic levitation device with a micro-Raman spectrometer provides a direct molecular probe of cellular chemistry in a containerless environment minimizing signal attenuation and eliminating the affects of adhesion to walls and interfaces. We show that the Raman acoustic levitation spectroscopic (RALS) approach can be used to monitor the heme dynamics of a levitated 5 microL suspension of red blood cells and to detect hemozoin in malaria infected cells. The spectra obtained have an excellent signal-to-noise ratio and demonstrate for the first time the utility of the technique as a diagnostic and monitoring tool for minute sample volumes of living animal cells. PMID- 17713611 TI - Micro fluid segment technique for screening and development studies on Danio rerio embryos. AB - The applicability of micro fluid segments for studying the behaviour of multicellular systems, in particular embryonic development, has been investigated. It was found that eggs from the zebrafish Danio rerio can be introduced into micro fluid segments without serious damage by using perfluoromethyldecalin (PP9) as the carrier liquid and Teflon (PTFE) as the tube material. The development processes of fish embryos were observed over a time period of 80 hours, until hatching time. After five days, the fish larvae were brought out of the micro fluid segments and transferred into breeding reservoirs. Effects of the membrane-damaging anionic surfactant sodium dodecyl sulfate (SDS) alone and SDS with the addition of CuCl(2) (copper(II) chloride) were investigated. By analyzing different end points, we found inhibiting and also supporting effects on the development of the embryos. Low SDS concentrations with and without copper(II) ions were supportive, while higher SDS concentrations led to negative impacts on the development of the embryos. The results showed that automated micro screening processes with complex biological systems can be performed using microfluidic systems and are applicable for future toxicological and drug screening studies. PMID- 17713612 TI - Single cell epitaxy by acoustic picolitre droplets. AB - The capability to encapsulate single to few cells with micrometre precision, high viability, and controlled directionality via a nozzleless ejection technology using a gentle acoustic field would have great impact on tissue engineering, high throughput screening, and clinical diagnostics. We demonstrate encapsulation of single cells (or a few cells) ejected from an open pool in acoustic picolitre droplets. We have developed this technology for the specific purpose of printing cells in various biological fluids, including PBS and agarose hydrogels used in tissue engineering. We ejected various cell types, including mouse embryonic stem cells, fibroblasts, AML-12 hepatocytes, human Raji cells, and HL-1 cardiomyocytes encapsulated in acoustic picolitre droplets of around 37 microm in diameter at rates varying from 1 to 10,000 droplets per second. At such high throughput levels, we demonstrated cell viabilities of over 89.8% across various cell types. Moreover, this ejection method is readily adaptable to other biological applications, such as extracting data from single cells and generating large cell populations from single cells. The technique described in the current study may also be applied to investigate stem cell differentiation at the single cell level, to direct tissue printing, and to isolating pure RNA or DNA from a single cell at the picolitre level. Overall, the techniques described have the potential for widespread impact on many high-throughput testing applications in the biological and health sciences. PMID- 17713613 TI - nDEP microwells for single-cell patterning in physiological media. AB - We present a novel technique to accurately position single cells on a substrate using negative dielectrophoresis and cell-substrate adhesion. The cells are suspended in physiological media throughout the patterning process. We also verify the biocompatibility of this method by demonstrating that the patterned cells proliferate and show normal morphology. We calculate the temperatures and transmembrane potential that cells in the device experience and compare them to physiologically acceptable levels described in previous studies. PMID- 17713614 TI - Building up longitudinal concentration gradients in shallow microchannels. AB - We demonstrate a compact and low consumption (60 nL) method for generating concentration gradients along microchannels with shallow parabolic cross sections. The regimes of dispersion at work in such systems and the resulting concentration fields are described theoretically and experimentally. Experiments are performed in PDMS (polydimethylsiloxane) microchannels actuated by integrated valves. Detailed comparison between theory and experiment for the "short time" and "long time" regimes leads to excellent agreement. The system is used to successfully set up a series of isolated microchambers with mixtures of increasing solute concentrations, which may be a first step towards devices for screening. PMID- 17713615 TI - DNA mutation detection with chip-based temperature gradient capillary electrophoresis using a slantwise radiative heating system. AB - A simple and robust chip-based temperature gradient capillary electrophoresis (TGCE) system was developed for DNA mutation/single-nucleotide polymorphism (SNP) analysis using a radiative heating system. Reproducible, stable and uniform temperature gradients were established along a 3 cm length of the electrophoretic separation channel using a single thermostated aluminium heater plate. The heater was slightly slanted relative to the plane of the glass chip at 0.2-1.3 degrees by inserting thin spacers between the plate and chip at one end to produce differences in radiative heating that created the temperature gradient. On-chip TGCE analyses of 4 mutant DNA model samples amplified from plasmid templates, each containing a single base substitution, with a wide range of melting temperatures, showed that mutations were successfully detected under a wide temperature gradient of 10 degrees C and within a short gradient region of about 3 cm (3.3 degrees C cm(-1) gradient). The radiative heating system was able to establish stable spatial temperature gradients along short microfluidic separation channels using simple peripheral equipment and manipulation while ensuring good resolution for detecting a wide range of mutations. Effectiveness of the system was demonstrated by the successful detection of K-ras gene mutations in 6 colon cancer cell lines. PMID- 17713616 TI - Planar optofluidic chip for single particle detection, manipulation, and analysis. AB - We present a fully planar integrated optofluidic platform that permits single particle detection, manipulation and analysis on a chip. Liquid-core optical waveguides guide both light and fluids in the same volume. They are integrated with fluidic reservoirs and solid-core optical waveguides to define sub-picoliter excitation volumes and collect the optical signal, resulting in fully planar beam geometries. Single fluorescently labeled liposomes are used to demonstrate the capabilities of the optofluidic chip. Liposome motion is controlled electrically, and fluorescence correlation spectroscopy (FCS) is used to determine concentration and dynamic properties such as diffusion coefficient and velocity. This demonstration of fully planar particle analysis on a semiconductor chip may lead to a new class of planar optofluidics-based instruments. PMID- 17713618 TI - Development of a nanomechanical biosensor for analysis of endocrine disrupting chemicals. AB - A nanomechanical transducer is developed to detect and screen endocrine disrupting chemicals (EDCs) combining fluidic sample injection and delivery with bioreceptor protein functionalized microcantilevers (MCs). The adverse affects of EDCs on the endocrine system of humans, livestock, and wildlife provides strong motivation for advances in analytical detection and monitoring techniques. The combination of protein receptors, which include estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER-beta), as well as monoclonal antibodies (Ab), with MC systems employing modified nanostructured surfaces provides for excellent nanomechanical response sensitivity and the inherent selectivity of biospecific receptor-EDC interactions. The observed ranking of binding interaction of the tested EDCs with ER-beta is diethylstilbestrol (DES) > 17-beta estradiol > 17-alpha-estradiol > 2-OH-estrone > bisphenol A > p,p' dichlorodiphenyldichloroethylene (p,p'-DDE) with measurements exhibiting intra day RSDs of about 3%. A comparison of responses of three EDCs, which include 17 beta-estradiol, 17-alpha-estradiol, and 2-OH-estrone, with ER-beta and ER-alpha illustrates which estrogen receptor subtype provides the greatest sensitivity. Antibodies specific to a particular EDC can also be used for analyte specific screening. Calibration plots for a MC functionalized with anti-17-beta-estradiol Ab show responses in the range of 1 x 10(-11) through 1 x 10(-7) M for 17-beta estradiol with a linear portion extending over two orders of magnitude in concentration. PMID- 17713617 TI - Controlled delivery of proteins into bilayer lipid membranes on chip. AB - The study and the exploitation of membrane proteins for drug screening applications requires a controllable and reliable method for their delivery into an artificial suspended membrane platform based on lab-on-a-chip technology. In this work, a polymeric device for forming lipid bilayers suitable for electrophysiology studies and biosensor applications is presented. The chip supports a single bilayer and is configured for controlled protein delivery through on-chip microfluidics. In order to demonstrate the principle of protein delivery, the potassium channel KcsA was reconstituted into proteoliposomes, which were then fused with the suspended bilayer on-chip. Fusion of single proteoliposomes with the membrane was identified electrically. Single channel conductance measurements of KcsA in the on-chip bilayer were recorded and these were compared to previously published data obtained with a conventional planar bilayer system. PMID- 17713619 TI - Photodefinable polydimethylsiloxane (PDMS) for rapid lab-on-a-chip prototyping. AB - In this paper, we introduce a new and simple method of patterning polydimethylsiloxane (PDMS) directly using benzophenone as a photoinitiator. The photodefinable PDMS mixture (photoPDMS) is positive-acting and only sensitive to light below 365 nm, permitting processing under normal ambient light. Features of the order of 100 microm, which are sufficiently small for most microfluidic applications, were successfully fabricated using this novel process. A parametric study of process parameters was performed to optimize the fabrication. As a demonstration, microfluidic channels of varying dimensions were successfully fabricated using this process and experimentally characterized using fluorescence microscopy. To further demonstrate photoPDMS potential, thin (<30 microm) free standing films with through patterns were fabricated and successfully used as shadow masks. The photoPDMS process completely eliminates the need for a master, permits processing under normal ambient light conditions, and makes fabrication fast and simple. This process for rapid prototyping of low-cost, disposable LOCs can be accomplished without cleanroom facilities and thus can be employed for a wide range of applications. PMID- 17713620 TI - A simple polysilsesquioxane sealing of nanofluidic channels below 10 nm at room temperature. AB - We present a simple sealing method to fabricate nanofluidic channels, where plasma treated polysilsesquioxane (PSQ) thin film on a rigid support is used to bond to a hydrophilic glass surface permanently at room temperature. This method shows precise dimension control below 10 nm with easy experimental setup. Using this method, one dimensional confined shallow nanochannels with a depth as small as 8 nm and an aspect ratio of <4 x 10(-5), two dimensional confined nanochannel arrays, and integrated nano/microchannel devices with a micro-to-nano interface have been demonstrated. Smooth transfer of DNA fragments from microchannel to nanochannel through the interface area was observed. PMID- 17713621 TI - An automated method for in vitro anticancer drug efficacy monitoring based on cell viability measurement using a portable photodiode array chip. AB - An integrated circuit (IC) bipolar semiconductor photodiode array (PDA) microchip system coupled with light emitting diodes (LEDs) was used for rapid, automated cell viability measurements and high-throughput drug efficacy monitoring. Using the absorption property of trypan blue dye against the red light emitted by LEDs, we determined the effect of three anticancer drugs, viz., camptothecin (CAM), sodium salicylate (Na-Sal) and naringenin (Nar) on the cell viability of human promyelocytic leukemia cells (HL-60) and human embryonic kidney cells (HEK-293). Cell viabilities were measured based on the relative reduction in the photo responses of the photodiodes, covered with known concentration of trypan blue stained cells. The developed method offers greater sensitivity and hence an excellent estimation of cell viability, but without all the hassle of conventional methods. Flow cytometric measurement and confocal microscopy were applied as complementary techniques for further validation of the results. The work presented here has important implications with regard to high-throughput measurement of optimal concentrations of different drugs against different cell lines in vitro. PMID- 17713622 TI - Real-time detection of lymphocytes binding on an antibody chip using SPR imaging. AB - We demonstrate the use of SPR imaging for the detection of site-specific binding of either B or T lymphocyte populations on an electrochemically-grafted antibody array. PMID- 17713623 TI - Design and fabrication of chemically robust three-dimensional microfluidic valves. AB - A current problem in microfluidics is that poly(dimethylsiloxane) (PDMS), used to fabricate many microfluidic devices, is not compatible with most organic solvents. Fluorinated compounds are more chemically robust than PDMS but, historically, it has been nearly impossible to construct valves out of them by multilayer soft lithography (MSL) due to the difficulty of bonding layers made of "non-stick" fluoropolymers necessary to create traditional microfluidic valves. With our new three-dimensional (3D) valve design we can fabricate microfluidic devices from fluorinated compounds in a single monolithic layer that is resistant to most organic solvents with minimal swelling. This paper describes the design and development of 3D microfluidic valves by molding of a perfluoropolyether, termed Sifel, onto printed wax molds. The fabrication of Sifel-based microfluidic devices using this technique has great potential in chemical synthesis and analysis. PMID- 17713625 TI - [On the 90th anniversary of the Instituto Nacional de Salud]. PMID- 17713624 TI - Flow characterization of a microfluidic device to selectively and reliably apply reagents to a cellular network. AB - A three-dimensional microfluidic device has been successfully fabricated and the flow streams characterized for eventual use in studying communication in an in vitro network of nerve cells. The microfluidic system is composed of two layers of channels: a lower layer for the delivery of pharmacological solutions and an upper layer of channels used to direct the flow of the pharmacological solution streams and perfuse the cells with media and nutrients. Flow profiles have been characterized with computational fluid dynamics simulations, confocal fluorescence microscopy, and carbon-fiber amperometry, which have been used to map changes in flow profiles at different bulk flow rates. Ultimately, the microfluidic system and incorporated cell network will show how networked neurons adapt, compensate, and recover after being exposed to different chemical compounds. PMID- 17713626 TI - [Make your own diagnosis: part one]. PMID- 17713627 TI - Tuberculosis in patients treated with tumor necrosis factor-alpha antagonists living in an endemic area. Is the risk worthwhile? AB - Tumor necrosis factor alpha antagonists (TNFA) are biological agents to treat chronic inflammatory and autoimmune diseases. However, their use is associated with an increased rate of tuberculosis, endemic mycoses, and intracellular bacterial infections. Since tuberculosis is moderately to highly endemic in Colombia, the risk of these infections in patients treated with TNFAs may be higher than previously reported in Colombia. Recently, four patients have developed tuberculosis during TNFA therapy. Tuberculosis appeared between 3 to 24 months after initiation of TFNA therapy and was independent of previous tuberculin skin test status. A review of the relevant literature and recommendations are presented as guides for surveillance and prophylaxis on a country-wide basis. PMID- 17713628 TI - [Impact of the new definitions in the prevalence of the metabolic syndrome in an adult population at Bucaramanga, Colombia]. AB - INTRODUCTION: The prevalence of metabolic syndrome depends on the criteria used for its classification. Three criteria in common use are those from International Diabetes Federation (IDF), the Adult Treatment Panel (ATP-III) or its update (ATP IIIa). OBJECTIVE: The prevalence statistic for generated metabolic syndrome was compared on the basis of each of the three criteria in an adult population. MATERIALS AND METHODS: The sample consisted of 155 teachers and employees in the school of medicine. The average age was 40.9; 54.2% were men. The three criteria were applied and the prevalences were compared with the Wilcoxon test and Cohen's kappa. RESULTS: Metabolic syndrome prevalence generated by each criterion was as follows: ATP-III was 12.3% (95%CI 7.5-18.5), ATP-IIIa was 34.8% (95%CI 27.4-42.9) and IDF 32.9% (95%CI 25.6--40.9). The prevalence indicated by ATP-III was lower than the ATP-IIIa or IDF prevalences (p < 0,001); however those of ATPIII-a and IDF were similar (p=0,083). Poor agreement was seen between ATP-III and ATP-IIIa (k=0.414, IC95% 0.409-0.420), and between ATP-III and IDF (k=0.374, IC95% 0.368 0.379); however, very good agreement was obtained between ATP-IIIa and IDF (k=0.957, IC95% 0.950-0.963). CONCLUSION: The new definitions for metabolic syndrome, ATP-IIIa and IDF, increase the prevalence statistic by three times. This occurred despite the inclusion in IDF of an obesity factor in the criteria set. PMID- 17713629 TI - [Perceived urgency of medical condition and use of health care services in Medellin, Colombia, 2005-2006]. AB - INTRODUCTION: Medellin has a population of 2.1 million and has 47 acute care hospitals that provide emergency health care services. Perceived seriousness of a medical condition in addition to accessibility and availability of care may influence the use of health care services in the region. OBJECTIVES: A broad spectrum survey was conducted to rate the urgency of a health condition as perceived by the patient and how that patient proceeded to make use of health care services. MATERIALS AND METHODS: The cross sectional survey was conducted, using door-to-door personal interviews in 1,442 homes from 70 neighborhoods. RESULTS: Of the 612,689 individuals interviewed, 533,718 (87,11%) reported that they have had a medical emergency. Respiratory difficulties were the most frequent reason for visiting a health care facility as reported by 113,153 (21.2%) of the participants. Of the 532,718 visits reported, 501,558 (93.97%) led to a hospital admission. Of the 21,042 visits not leading to an admission, 42.0% were considered as non-urgent by the hospital staff. Visits admissions reports were missing, 11.118 (2.08%). CONCLUSIONS: In Medellin, the incidence of medical emergencies leading to a health care facility visit is high. The high prevalence of respiratory emergencies and other conditions that can be managed outside the emergency service indicates the need for a pre-hospital emergency service. PMID- 17713630 TI - DNA microarray analysis reveals metastasis-associated genes in rat prostate cancer cell lines. AB - INTRODUCTION: The molecular and cellular mechanisms involved in prostate cancer progression towards a hormone-independent and highly invasive, metastatic phenotype, are not well understood. Cell lines with different metastatic potential, when analyzed by microarray techniques, offer valuable tools for identifying genes associated with the metastatic phenotype. OBJECTIVES: Gene expression profiles were compared for two rat prostate cancer cell lines with differing metastatic abilities in order to better characterized molecular underpinnings of the prostate cancer metastatic process. MATERIALS AND METHODS: Affymetrix arrays were used to analyze gene expression of two rat prostate cancer cell lines, MAT-LyLu and G. Microarray data were analyzed using pathway and functional group analysis. A selected set of genes was subjected to real-time polymerase chain reaction for validating the microarray data. RESULTS: Microarray data analysis revealed differential expression of genes from a number of signaling and metabolic pathways. Overexpression was detected in 48 genes and underexpression in 59 genes of the MAT-LyLu line compared to the standard G line. Genes were grouped into functional categories, including epithelial-extracellular matrix interaction, cell motility, cell proliferation, and transporters, among others. Many of these genes were not previously associated to prostate cancer metastasis. CONCLUSIONS: Many genes with altered expression associated with a metastatic prostate cancer phenotype were identified. Further validation of these genes in human prostate samples will determine their usefulness as biomarkers for early diagnosis of recurrence or metastasis of prostate cancer, as well as potential therapeutic targets for this disease. PMID- 17713631 TI - [Polymorphisms of the pfmdr1 gene in field samples of Plasmodium falciparum and their association with therapeutic response to antimalarial drugs and severe malaria in Colombia]. AB - INTRODUCTION: The pfmdr1 gene of Plasmodium falciparum has been described as a gene conferring resistance to several antimalarial drugs. In particular, polymorphisms on specific codons have been associated with resistance and treatment failure with cloroquine, amodiaquine and mefloquine. However, the role of these polymorphisms in treatment response to antimalarials remains unexplored in Colombia. Furthermore, the relationship of these polymorphisms to severe malaria is unknown. OBJECTIVE: This work studied the association of the Asn 86Tyr and Asp1246Tyr pfmdr1 polymorphisms with response to cloroquine, amodiaquine and mefloquine treatment in three municipalities of Antioquia, and severe malaria cases from the municipality Tumaco. MATERIALS AND METHODS: The polymorphisms were assessed by nucleic acid amplification followed by restriction length polymorphism analysis. RESULTS: The wild-type codon Asn 86 was detected in 97% of the clinical samples from the treatment response study. No association was detected between this polymorphism and treatment failure to the three antimalarials administered. The 1246Tyr polymorphism was detected with a higher frequency in the samples from Antioquia 92% (130/141) than in those from Tumaco 22% (20/89). However, again, no association was found between the presence of a specific polymorphism and the presence of severe malaria in the municipality of Tumaco. CONCLUSIONS: The 86Tyr and 1246Tyr polymorphisms of the pfmdr1 gene are not useful as predictors of treatment failure or severe malaria in the municipalities studied. In addition, we report for the first time, the presence of the mutant codon 86Tyr in field samples in South America. PMID- 17713632 TI - [Body composition assessment by anthropometry and bioelectrical impedance]. AB - INTRODUCTION: Anthropometry and electric impedance methods are widely used for body composition assessment. However the evidence is unclear whether the results obtained from the two methods can be compared. OBJECTIVE: Two methods are compared for assessment of body composition; anthropometry and electric impedance. MATERIALS AND METHODS: Body composition was measured in 70 women; aged 22 to 56 and 53 men; aged 24 to 54, using anthropometry (Durning/Womersley and Jackson/Pollock skinfolds equations) and electric impedance (foot to foot electric impedance) to obtain percentage body fat. RESULTS: The mean percentage body fat was significant higher with Durning/Womersley (25.2%) than Jackson/Pollock (20.1%) and electric impedance (19.3%) for men (p<0.001). The mean percentage body fat was significant higher with Durning/Womersley (36.9%) than Jackson/Pollock (31.0%) and electric impedance (27.6%) for women (p<0.001). Correlation coefficient was high when two methods were compared (r>0.77) however, the concordance between methods to classify obesity subjects was low (K<0.5). CONCLUSIONS: The percentages obtained from the anthropometry method were higher than the bioelectrical impedance method. A significant difference was found between methods applied in men and women, and therefore these methods are not comparable. PMID- 17713633 TI - [Evaluation of ICT malaria immunochromatographic Binax NOW ICT P.f/P.v test for rapid diagnosis of malaria in a Colombian endemic area]. AB - INTRODUCTION: One of the strategies to reduce malarial morbidity and mortality is to make an early diagnosis, using simple rapid tests which are highly sensitive and specific. Furthermore, the tests must be easy to perform and understand by local people in such a way that a suitable and prompt antimalarial treatment is guaranteed. OBJECTIVE: The sensitivity and specificity was determined for the immuno-chromographic malaria dipstick (ICT Pf/Pv) test for the rapid diagnosis of malaria in Turbo, Antioquia. MATERIALS AND METHODS: The sample consisted of 171 patients distributed into two groups: the first group was 118 patients with acute febrile syndrome compatible with malaria to which ICT Pf/Pv and thick smears were applied simultaneously; a second group was 53 patients with positive diagnosis by thick smear, with follow-up on the 4th and 7th days after beginning treatment. RESULTS: Sensitivity and specificity of the ICT Pf/Pv test for Plasmodium falciparum infections were 54.2% (95%CI: 52.0-53.4%) and 93.6% (95%CI: 93.1 94.2%), respectively. In addition, for Plasmodium vivax the sensitivity and specificity were 80% (95%CI: 77.9-82.1%) and 100% (95%CI: 99.5-100%); there was a 21.4% loss of sensitivity for P. falciparum 21.4% and a 33% loss for P. vivax malaria with parasitaemias under 500 parasites/ul. For the confirmatory test, ICT Pf/Pv showed a global sensitivity of 71.6% with 20.7% false positive and 5.6% false negative results. During follow-up, ICT showed 36% and 34% false positive results for day 4 and 7, respectively. CONCLUSIONS: The ICT Pf/Pv test has a poor sensitivity for P. falciparum malaria and its capacity to detect parasitemias under 500 parasites/ul is minimal. As a confirmatory test, the ICT Pf/Pv has a good sensitivity for P. falciparum. Its use for patient follow-up is not recommended. PMID- 17713634 TI - [Characterization of two typhoid fever outbreaks in Apartado, Antioquia, 2005]. AB - INTRODUCTION: The characterization of typhoid fever outbreaks is important because it is necessary to find the source of the infection and development control measures. OBJECTIVE: A typhoid fever outbreak is described from Apartado and the Salmonella Typhi isolates characterized by phenotypic and genotypic methods. MATERIALS AND METHODS: From 44 patients, 15 blood cultures and 7 stools cultures were recovered. Phenotypic identification of isolates was done by biochemical and serological tests, and antibiotic susceptibility was tested. Genes hilA, invA and the IS200 marker were evaluated by polymerase chain reaction; pulsed field gel electrophoresis was used for the XbaI gene. Eight water samples were examined by polymerase chain reaction and culture methods in order to isolate Salmonella spp. RESULTS: Fifteen patients were confirmed for typhoid fever, 13 by blood cultures and two by stools cultures. All S. Typhi isolates were susceptible to the antimicrobials tested. The presence of hilA, invA and IS200 were confirmed by polymerase chain reaction in all isolates. The pulsed field gel electrophoresis method grouped 10 isolates in COINJPP.X01.0035 pattern, three in COINJPPX01.0002, one in COINJPP.X01.0012 and one in COINJPPX01.0037. Water isolates were negatives for Salmonella spp. CONCLUSIONS: Pulsed field gel electrophoresis discriminated the isolates in two outbreaks. Initially the cases were described as only one outbreak, by epidemiological criteria and phenotypic test. Additionally two isolates with different clonal origin were discriminated, indicating that they were unrelated to the other cases. It was not possible to confirm the infection source from water samples. PMID- 17713635 TI - [Cholinesterases in total blood measured with a semiquantitative technique, and plasma or erythrocyte cholinesterases measured with quantitative techniques]. AB - INTRODUCTION: An equivalence model which allows comparison of blood cholinesterase values, measured by Lovibond (semiquantitative technique), and Michel, EQM, Monotest (erythrocyte and plasma cholinesterases) values measured by quantitative techniques is required. OBJECTIVE: The performance of Lovibond (Edson tintometric and Limperos & Ranta techniques) were compared with quantitative techniques. MATERIALS AND METHODS: The experimental design was descriptive, cross-sectional, and prospective. From a working population (18-59 years) in Valle de Aburra and Near East of Antioquia. 827 representative samples were chosen for their lack of exposure to cholinesterase-inhibiting plaguicides and affiliated to the Social Security System. RESULTS: (1) 827 workers were classified by Lovibond in four categories: 821 values with 75% of cholinesterase activity or greater (categories 75, 87.5 and 100%) and 6 with cholinesterase activity smaller than 75%. (2) With each quantitative method, the mean values of erythrocyte and plasmatic cholinesterase corresponding to the four values obtained with Lovibond were statistically different to each other. (3) The mean values of each quantitative technique increased when increased the tintometric method value. (4) Lovibond classified the low enzymatic erythrocyte activity very poorly (61-73%), but the classification of the low enzymatic plasma activity was almost completely in error (94-96%). CONCLUSION: The values of erythrocyte or plasma cholinesterase were adequately estimated by both the quantitative techniques of Michel and EQM and by Lovibond, but only when the enzymatic activity is normal. Lovibond, however, had a poor capacity to designate as "low" the values that were low according to the quantitative tests. PMID- 17713637 TI - [Make your own diagnosis: part two]. PMID- 17713636 TI - [Production and characterization of a polyclonal antibody against rabies virus phosphoprotein]. AB - INTRODUCTION: The expression of recombinant viral proteins has been a useful tool to study molecular biology and pathogenesis of virus infections. Because commercial specific antibodies to rabies virus phosphoprotein (P) are currently unavailable, these antibodies must be generated de novo in order to study the role of P protein during the infectious process. OBJECTIVE: A polyclonal antibody was produced and characterized for use against the phosphoprotein (P) of rabies virus. The antibody was raised in rabbits with a recombinant viral phosphoprotein (P) produced in Escherichia coli. MATERIALS AND METHODS: Gene P coding for the viral phosphoprotein (P) was amplified by RT-PCR and cloned into the expression vector PinPoint Xa-1 T. The recombinant protein P was expressed in Escherichia coli, purified by affinity chromatography and used to produce a polyclonal antibody anti-P. The antibody anti-P was purified and characterized by immunocytochemistry, immunofluorescence, fluorometric CELL-ELISA and Western blotting. RESULTS: The recombinant viral phosphoprotein was successfully expressed as a 50 kd biotinylated fusion protein which corresponds to the whole protein P of rabies virus. The polyclonal antibody raised against this recombinant protein P was able to detect with high specificity, protein P in cultures of sensorial neurons infected with rabies virus. CONCLUSIONS: The P protein obtained from heterologous expression in Escherichia coli became a specific antigen that was used to produce a polyclonal antibody capable of detecting native P protein in rabies virus infected cells. PMID- 17713638 TI - [Detection of Aedes albopictus (Skuse) (Diptera: Culicidae) in the city of Cali, Valle del Cauca, Colombia]. AB - INTRODUCTION: Aedes albopictus is the second most important dengue virus vector in the Asian southeast after Aedes aegypti. Its entrance into the Americas occurred in 1985, and laboratory studies performed show its potential as a vector in this continent as well. In Colombia, this species has been reported in Leticia (Amazonas) in 1998 and Buenaventura (Valle del Cauca) in 2001. The latest discoveries show that this mosquito continues to advance toward the country's interior. OBJECTIVE: To inform that the presence of A. albopictus is documented in the city of Cali, Valle del Cauca, Colombia. MATERIALS AND METHODS: Since 2002, weekly sampling has been performed using larval traps located at seventeen stations. The identification of the A. albopictus species, was carried out in the Unidad de Entomologia, Laboratorio de Salud Publica Departamental. These identifications were confirmed in the Entomology Laboratory at Universidad del Valle and the National Institute of Health in Bogota. RESULTS: From April to June of 2006, larvae of A. albopictus were found in six sampling stations located between northwest and northeast of Cali, one of them in the suburban area of the Yumbo city. CONCLUSION: The control of A. aegypti and A. albopictus must be integrated into a single program. The surveillance in the cities and nearest departments must be intensified with the objective of limiting the advancement of A. albopictus. PMID- 17713640 TI - [Therapeutic approach to Staphylococcus aureus bacteremia]. AB - Staphylococcus aureus is an important human pathogen, responsible for 11-33% of the bacteremias acquired in the hospital setting and nearly 50% of those acquired in the community at large. The epidemiology of S. aureus bacteremia is discussed, with an special emphasis on the situation in Colombia and the resistance mechanisms against the major drug groups used for the treatment. The clinical keys and laboratory support for the appropriate clinical approaches are presented together with the therapeutic strategies for the treatment of patients with S. aureus bacteremia. PMID- 17713639 TI - [The role of toll-like receptors in viral infections: HIV-1 as a model]. AB - The toll-like receptors are an essential component of the innate and adaptive immune response. They are responsible for the recognition of different pathogens agents and trigger responses directed at eliminating the pathogens as well as the development of immunological long-term memory. During viral infections, several different toll-like receptors are activated. These generally induce a protective immune response, but at the same time, can also be part of the pathogenic mechanisms of the viral infection. One of the viral infections in which toll-like receptors participate is the HIV-1 infection. Here, several receptors are activated to develop antiviral responses mediated by interferon type I; however virus replication and spreading dissemination are also favoured by signals derived from stimulation of the toll-like receptors. Individuals co-infected with opportunistic microorganisms are particularly affected, promoting the progression of HIV-1 infection. An integral understanding of the behavior of toll-like receptors during viral infections will allow the design of prophylactic and/or therapeutic strategies, based on the modulation of the expression and function of these receptors. Agonists of these receptors can be used effectively to control these viral infections. PMID- 17713641 TI - In vitro mating of Colombian isolates of the Cryptococcus neoformans species complex. AB - INTRODUCTION: Within the Cryptococcus neoformans species complex, two species and five serotypes are recognized: C. neoformans (var. grubii, serotype A; var. neoformans, serotype D and a hybrid, serotype AD) and C. gattii (serotypes B and C). Mating types a and alpha are designated by a single locus, with the mating type alpha being most prevalent in serotype A and D strains. OBJECTIVE: To evaluate the ability of Colombian isolates of the C. neoformans species complex to mate in vitro with tester strains of the opposite mating type. MATERIALS AND METHODS: Fifty three clinical isolates were included in this study, 33 C. neoformans var. grubii serotype A, 4 C. neoformans var. neoformans serotype D, all mating type alpha, and 16 C. gattii, 13 serotype B (mating type a) and 3 serotype C (mating type alpha), were mixed on V8 juice agar, using a modified method, with the appropriate tester strains to determine the mating types in vitro. RESULTS: Mating studies revealed that 9 of 33 (27.3%) serotype A isolates and 6 of 13 (46.2%) serotype B isolates were able to mate. Clamp connections and basidia with basidiospores were observed microscopically, indicating that the mating process had occurred. All mating competent serotype A strains were mating type alpha and the serotype B mating competent strains were mating type a. CONCLUSION: This is the first report of the determination of the mating ability of Colombian Cryptococcus neoformans isolates to mate in vitro with appropriate tester strains, which is of great importance to study the propagation of the fungus around the globe. PMID- 17713642 TI - The emergence of YMDD mutants precedes biochemical flare by 19 weeks in lamivudine-treated chronic hepatitis B patients: an opportunity for therapy reevaluation. AB - Given the loss of therapeutic efficacy associated with the development of resistance to lamivudine (LMV) and the availability of new alternative treatments for chronic hepatitis B patients, early detection of viral genotypic resistance could allow the clinician to consider therapy modification before viral breakthrough and biochemical relapse occur. To this end, 28 LMV-treated patients (44 +/- 12 years; 24 men), on their first therapy schedule, were monitored monthly at four Brazilian centers for the emergence of drug resistance using the reverse hybridization-based INNO-LiPA HBV DR assay and occasionally sequencing (two cases). Positive viral responses (HBV DNA clearance) after 6, 12, and 18 months of therapy were achieved by 57, 68, and 53% of patients, while biochemical responses (serum alanine aminotransferase normalization) were observed in 82, 82, and 53% of cases. All viral breakthrough cases (N = 8) were related to the emergence of YMDD variants observed in 7, 21, and 35% of patients at 6, 12, and 18 months, respectively. The emergence of these variants was not associated with viral genotype, HBeAg expression status, or pretreatment serum alanine aminotransferase levels. The detection of resistance-associated mutations was observed before the corresponding biochemical flare (41 +/- 14 and 60 +/- 15 weeks) in the same individuals. Then, if highly sensitive LMV drug resistance testing is carried out at frequent and regular intervals, the relatively long period (19 +/- 2 weeks) between the emergence of viral resistance and the onset of biochemical relapse can provide clinicians with ample time to re-evaluate drug therapy. PMID- 17713643 TI - Breathing pattern, thoracoabdominal motion and muscular activity during three breathing exercises. AB - The objective of the present study was to evaluate breathing pattern, thoracoabdominal motion and muscular activity during three breathing exercises: diaphragmatic breathing (DB), flow-oriented (Triflo II) incentive spirometry and volume-oriented (Voldyne) incentive spirometry. Seventeen healthy subjects (12 females, 5 males) aged 23 +/- 5 years (mean +/- SD) were studied. Calibrated respiratory inductive plethysmography was used to measure the following variables during rest (baseline) and breathing exercises: tidal volume (Vt), respiratory frequency (f), rib cage contribution to Vt (RC/Vt), inspiratory duty cycle (Ti/Ttot), and phase angle (PhAng). Sternocleidomastoid muscle activity was assessed by surface electromyography. Statistical analysis was performed by ANOVA and Tukey or Friedman and Wilcoxon tests, with the level of significance set at P < 0.05. Comparisons between baseline and breathing exercise periods showed a significant increase of Vt and PhAng during all exercises, a significant decrease of f during DB and Voldyne, a significant increase of Ti/Ttot during Voldyne, and no significant difference in RC/Vt. Comparisons among exercises revealed higher f and sternocleidomastoid activity during Triflo II (P < 0.05) with respect to DB and Voldyne, without a significant difference in Vt, Ti/Ttot, PhAng, or RC/Vt. Exercises changed the breathing pattern and increased PhAng, a variable of thoracoabdominal asynchrony, compared to baseline. The only difference between DB and Voldyne was a significant increase of Ti/Ttot compared to baseline. Triflo II was associated with higher f values and electromyographic activity of the sternocleidomastoid. In conclusion, DB and Voldyne showed similar results while Triflo II showed disadvantages compared to the other breathing exercises. PMID- 17713644 TI - Ambient particulate air pollution from vehicles promotes lipid peroxidation and inflammatory responses in rat lung. AB - Oxidative stress plays a major role in the pathogenesis of particle-dependent lung injury. Ambient particle levels from vehicles have not been previously shown to cause oxidative stress to the lungs. The present study was conducted to a) determine whether short-term exposure to ambient levels of particulate air pollution from vehicles elicits inflammatory responses and lipid peroxidation in rat lungs, and b) determine if intermittent short-term exposures (every 4 days) induce some degree of tolerance. Three-month-old male Wistar rats were exposed to ambient particulate matter (PM) from vehicles (N = 30) for 6 or 20 continuous hours, or for intermittent (5 h) periods during 20 h for 4 consecutive days or to filtered air (PM <10 microm; N = 30). Rats continuously breathing polluted air for 20 h (P-20) showed a significant increase in the total number of leukocytes in bronchoalveolar lavage compared to control (C-20: 2.61 x 105 +/- 0.51;P-20: 5.01 x 105 +/- 0.81; P < 0.05) and in lipid peroxidation ([MDA] nmol/mg protein: C-20: 0.148 +/- 0.01; P-20: 0.226 +/- 0.02; P < 0.05). Shorter exposure (6 h) and intermittent 5-h exposures over a period of 4 days did not cause significant changes in leukocytes. Lipid damage resulting from 20-h exposure to particulate air pollution did not cause a significant increase in lung water content. These data suggest oxidative stress as one of the mechanisms responsible for the acute adverse respiratory effects of particles, and suggest that short-term inhalation of ambient particulate air pollution from street with high automobile traffic represents a biological hazard. PMID- 17713645 TI - Are birth weight and maternal smoking during pregnancy associated with malnutrition and excess weight among school age children? AB - In the late 1980's child malnutrition was still prevalent in Brazil, and child obesity was beginning to rise in the richest regions of the country. To assess the extent of the nutritional transition during the period and the influence of birth weight and maternal smoking on the nutritional condition of schoolchildren, we estimated the prevalence of excess weight and malnutrition in a cohort of Brazilian schoolchildren from 1987 to 1989. We calculated the body mass index (BMI) of 8- to 10-year-old schoolchildren born in Ribeirao Preto in 1978/79. We considered children with a BMI <5th percentile (P5) to be malnourished, children with P5 > or = BMI or = P85 to be overweight. We evaluated the association of these nutritional disorders with birth factors (infant weight, sex, preterm delivery, number of pregnancies, maternal smoking during pregnancy, marital status, and schooling) and type of school using nominal logistic regression. A total of 2797 schoolchildren were evaluated. There was a significant prevalence of malnutrition (9.5%) and excess weight already tended to increase (15.7%), while 6.4% of the children were obese. Excess weight was more prevalent among children attending private schools (odds ratio, OR = 2.27) and firstborn children (OR = 1.69). Maternal smoking during pregnancy protected against malnutrition (OR = 0.56), while children with lower birth weight were at higher risk for malnutrition (OR = 4.23). We conclude that a nutritional transition was under way while malnutrition was still present, but excess weight and related factors were already emerging. PMID- 17713646 TI - Therapeutic effects of Sophora moorcroftiana alkaloids in combination with albendazole in mice experimentally infected with protoscolices of Echinococcus granulosus. AB - The objective of the present study was to determine if the combination of alkaloids from Sophora moorcroftiana seeds and albendazole might be effective in the treatment of experimental echinococcosisin female NIH mice (6 weeks old and weighing 18-20 g, N = 8 in each group) infected withprotoscolices of Echinococcus granulosus. Viable protoscolices (N = 6 x 10(3)) were cultured in vitro in 1640 medium and mortality was calculated daily. To determine the in vivo efficacy, mice were inoculated intraperitoneally with viable protoscolices and then treated once daily by gavage for three months with the alkaloids (50 mg kg-1 day-1) and albendazole (50 mg kg-1 day-1), separately and in combination (both alkaloids at 25 mg kg-1 day-1 and albendazole at 25 mg kg-1 day-1). Next, the hydatid cysts collected from the peritoneal cavity of the animals were weighed and serum IL-4, IL-2, and IgE levels were analyzed. Administration of alkaloids to cultured protoscolices showed significant dose- and time-dependent killing effects. The weight of hydatid cysts was significantly decreased upon treatment with each drug (P < 0.01), but the decrease was more prominent and the rate of hydatid cyst growth inhibition was much higher (76.1%) in the group receiving the combined treatments (18.3 +/- 4.6 mg). IL-4 and total IgE were decreased (939 +/- 447 pg/mL and 2.03 +/- 0.42 IU/mL, respectively) in serum from mice treated with alkaloids and albendazole compared with the untreated control (1481 +/- 619 pg/mL and 3.31 +/- 0.37 IU/mL; P < 0.01). These results indicate that S. moorcroftiana alkaloids have protoscolicidal effects and the combination of alkaloids and albendazole has significant additive effects. PMID- 17713647 TI - The effect of sun exposure on 25-hydroxyvitamin D concentrations in young healthy subjects living in the city of Sao Paulo, Brazil. AB - The range of 25-hydroxyvitamin D (25OHD) concentration was determined in a young healthy population based on bone metabolism parameters and environmental and behavioral aspects. We studied 121 healthy young volunteers (49 men, 72 women) living in Sao Paulo (23 masculine 34' south latitude) belonging to three occupational categories: indoor workers (N = 28), medical school students (N = 44), and resident physicians (N = 49). Fasting morning blood samples were collected once from each volunteer from August 2002 to February 2004, and 25OHD, total calcium, albumin, alkaline phosphatase, phosphorus, creatinine, intact parathyroid hormone, osteocalcin, and type I collagen carboxyterminal telopeptide were measured. Data are reported as means +/- SD. Mean subject age was 24.7 +/- 2.68 years and mean 25OHD level for the entire group was 78.7 +/- 33.1 nM. 25OHD levels were lower (P < 0.05) among resident physicians (67.1 +/- 27.0 nM) than among students (81.5 +/- 35.8 nM) and workers (94.0 +/- 32.6 nM), with the last two categories displaying no difference. Parathyroid hormone was higher (P < 0.05) and osteocalcin was lower (P < 0.05) among resident physicians compared to non-physicians. Solar exposure and frequency of beach outings showed a positive association with 25OHD (P < 0.001), and summer samples presented higher results than winter ones (97.8 +/- 33.5 and 62.9 +/- 23.5 nM, respectively). To define normal levels, parameters such as occupational activity, seasonality and habits related to solar exposure should be taken into account. Based on these data, we considered concentrations above 74.5 nM to be desired optimal 25OHD levels, which were obtained during the summer for 75% of the non-physicians. PMID- 17713649 TI - Is there an association between T102C polymorphism of the serotonin receptor 2A gene and urinary incontinence? AB - The regulation of bladder function is influenced by central serotonergic modulation. Several genetic polymorphisms related to serotonin control have been described in the literature. T102C polymorphism of the serotonin receptor 2A gene (5-HT2A) has been shown to be associated with certain diseases such as non-fatal acute myocardial infarction, essential hypertension, and alcoholism. In the present study, we examined the association between 5-HT2A gene polymorphism and urinary incontinence in the elderly. A case-control study was performed in 298 elderly community dwellers enrolled in the Gravatai-GENESIS Project, Brazil, which studies gene-environmental interactions in aging and age-related diseases. Clinical, physical, biochemical, and molecular analyses were performed on volunteers. 5-HT2A genotyping was determined by PCR-RFLP techniques using the HpaII restriction enzyme. The subjects had a mean age of 68.05 +/- 6.35 years (60 100 years), with 16.9% males and 83.1% females. The C allele frequency was 0.494 and the T allele frequency was 0.506. The CC genotype frequency was 21.78%, the CT genotype frequency was 55.24% and the TT genotype frequency was 22.98%. We found an independent significant association between the TT genotype (35.7%) and urinary incontinence (OR = 2.06, 95%CI = 1.16-3.65). Additionally, urinary incontinence was associated with functional dependence and systolic hypertension. The results suggest a possible genetic influence on urinary incontinence involving the serotonergic pathway. Further investigations including urodynamic evaluation will be performed to better explain our findings. PMID- 17713648 TI - Dendritic thickness: a morphometric parameter to classify mouse retinal ganglion cells. AB - To study the dendritic morphology of retinal ganglion cells in wild-type mice we intracellularly injected these cells with Lucifer yellow in an in vitro preparation of the retina. Subsequently, quantified values of dendritic thickness, number of branching points and level of stratification of 73 Lucifer yellow-filled ganglion cells were analyzed by statistical methods, resulting in a classification into 9 groups. The variables dendritic thickness, number of branching points per cell and level of stratification were independent of each other. Number of branching points and level of stratification were independent of eccentricity, whereas dendritic thickness was positively dependent (r = 0.37) on it. The frequency distribution of dendritic thickness tended to be multimodal, indicating the presence of at least two cell populations composed of neurons with dendritic diameters either smaller or larger than 1.8 microm ("thin" or "thick" dendrites, respectively). Three cells (4.5%) were bistratified, having thick dendrites, and the others (95.5%) were monostratified. Using k-means cluster analysis, monostratified cells with either thin or thick dendrites were further subdivided according to level of stratification and number of branching points: cells with thin dendrites were divided into 2 groups with outer stratification (0 40%) and 2 groups with inner (50-100%) stratification, whereas cells with thick dendrites were divided into one group with outer and 3 groups with inner stratification. We postulate, that one group of cells with thin dendrites resembles cat beta-cells, whereas one group of cells with thick dendrites includes cells that resemble cat alpha-cells. PMID- 17713650 TI - The husk fiber of Cocos nucifera L. (Palmae) is a source of anti-neoplastic activity. AB - In the present study, we investigated the in vitro anti-tumoral activities of fractions from aqueous extracts of the husk fiber of the typical A and common varieties of Cocos nucifera (Palmae). Cytotoxicity against leukemia cells was determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Cells (2 x 10(4)/well) were incubated with 0, 5, 50 or 500 microg/mL high- or low-molecular weight fractions for 48 h, treated with MTT and absorbance was measured with an ELISA reader. The results showed that both varieties have almost similar antitumoral activity against the leukemia cell line K562 (60.1 +/- 8.5 and 47.5 +/- 11.9% for the typical A and common varieties, respectively). Separation of the crude extracts with Amicon membranes yielded fractions with molecular weights ranging in size from 1-3 kDa (fraction A) to 3-10 kDa (fraction B) and to more than 10 kDa (fraction C). Cells were treated with 500 microg/mL of these fractions and cytotoxicity was evaluated by MTT. Fractions ranging in molecular weight from 1-10 kDa had higher cytotoxicity. Interestingly, C. nucifera extracts were also active against Lucena 1, a multidrug-resistant leukemia cell line. Their cytotoxicity against this cell line was about 50% (51.9 +/- 3.2 and 56.3 +/- 2.9 for varieties typical A and common, respectively). Since the common C. nucifera variety is extensively cultured in Brazil and the husk fiber is its industrial by-product, the results obtained in the present study suggest that it might be a very inexpensive source of new antineoplastic and anti multidrug resistant drugs that warrants further investigation. PMID- 17713651 TI - Probing the SERCA1a sarcoplasmic reticulum Ca2+-ATPase phosphorylation-site mutant D351E with inorganic phosphate. AB - The expression of sarcoplasmic reticulum SERCA1a Ca2+-ATPase wild-type and D351E mutants was optimized in yeast under the control of a galactose promoter. Fully active wild-type enzyme was recovered in yeast microsomal membrane fractions in sufficient amounts to permit a rapid and practical assay of ATP hydrolysis and phosphoenzyme formation from ATP or Pi. Mutant and wild-type Ca2+-ATPase were assayed for phosphorylation by Pi under conditions that are known to facilitate this reaction in the wild-type enzyme, including pH 6.0 or 7.0 at 25 degrees C in the presence of dimethylsulfoxide. Although glutamyl (E) and aspartyl (D) residue side chains differ by only one methylene group, no phosphoenzyme could be detected in the D351E mutant, even upon the addition of 40% dimethylsulfoxide and 1 mM 32Pi in the presence of 10 mM EGTA and 5 mM MgCl2. These results show that in the D351E mutant, increasing hydrophobicity of the site with inorganic solvent was not a sufficient factor for the required abstraction of water in the reaction of E351 with Pi to form a glutamylphosphate (P-E351) phosphoenzyme moiety. Mutation D351E may disrupt the proposed alignment of the reactive water molecule with the aspartylphosphate (P-D351) moiety in the phosphorylation site, which may be an essential alignment both in the forward reaction (hydrolysis of aspartylphosphate) and in the reverse reaction (abstraction of water upon formation of an aspartylphosphate intermediate). PMID- 17713652 TI - Cytotoxic and DNA-topoisomerase effects of lapachol amine derivatives and interactions with DNA. AB - The cytotoxic activity of amino (3a-e), aza-1-antraquinone (4a-e) lapachol derivatives against Ehrlich carcinoma and human K562 leukemia cells was investigated. Cell viability was determined using MTT assay, after 48 (Ehrlich) or 96 h (K562) of culture, and vincristine (for K562 leukemia) and quercetin (for Ehrlich carcinoma) were used as positive controls. The results showed dose dependent growth-inhibiting activities and that the amino derivatives were active against the assayed cells, whereas the 4a-e derivatives were not. The allylamine derivative 3a was the most active against Ehrlich carcinoma, with IC50 = 16.94 +/ 1.25 microM, and against K562 leukemia, with IC50 = 14.11 +/- 1.39 microM. The analogous lawsone derivative, 5a, was also active against Ehrlich carcinoma (IC50 = 23.89 +/- 2.3 microM), although the 5d and 5e derivatives showed lower activity. The interaction between 3a-d and calf thymus DNA was investigated by fluorimetric titration and the results showed a hyperchromic effect indicating binding to DNA as presented of ethidium bromide, used as positive control. The inhibitory action on DNA-topoisomerase II-a was also evaluated by a relaxation assay of supercoiled DNA plasmid, and the etoposide (200 microM) was used as positive control. Significant inhibitory activities were observed for 3a-d at 200 microM and a partial inhibitory action was observed for lapachol and methoxylapachol. PMID- 17713653 TI - Synthesis and secretion of transferrin by a bovine trabecular meshwork cell line. AB - The trabecular meshwork (TM) is the main outflow pathway in the mammalian eye. Oxidative damage to TM cells has been suggested to be an important cause of impairment of TM functions, leading to deficient drainage of aqueous humor, with deleterious consequences to the eye. Transferrin, a metalloprotein involved in iron transport, has been characterized as an intrinsic eye protein. Since transferrin is implicated in the control of oxidative stress, the objective of the present study was to determine if a bovine TM cell line (CTOB) synthesizes and secretes transferrin. The CTOB cell line was cultured in the presence of 35S methionine and the incubation medium was submitted to immunoprecipitation. Total RNAs from CTOB and isolated bovine TM (freshly isolated, incubated or not) were subjected to the reverse transcription-polymerase chain reaction and the amplification products were sequenced. Also, both CTOB and histological TM preparations were processed for transferrin immunolocalization. A labeled peptide of about 80 kDa, the expected size for transferrin, was immunopurified from CTOB samples obtained from the incubation assays. The reverse transcription-polymerase chain reaction and sequencing experiments detected the presence of transferrin mRNA in CTOB and isolated bovine TM. Reactivity to antibodies against transferrin was observed both in CTOB and TM. The results obtained in all of these experiments indicated that the TM is capable of synthesizing and secreting transferrin. The possible implications for the physiology of the eye are discussed. PMID- 17713654 TI - Comparative effects of organic and inorganic mercury on in vivo dopamine release in freely moving rats. AB - The present study was carried out in order to compare the effects of administration of organic (methylmercury, MeHg) and inorganic (mercury chloride, HgCl 2 ) forms of mercury on in vivo dopamine (DA) release from rat striatum. Experiments were performed in conscious and freely moving female adult Sprague Dawley (230-280 g) rats using brain microdialysis coupled to HPLC with electrochemical detection. Perfusion of different concentrations of MeHg or HgCl 2 (2 microL/min for 1 h, N = 5-7/group) into the striatum produced significant increases in the levels of DA. Infusion of 40 microM, 400 microM, or 4 mM MeHg increased DA levels to 907 +/- 31, 2324 +/- 156, and 9032 +/- 70% of basal levels, respectively. The same concentrations of HgCl 2 increased DA levels to 1240 +/- 66, 2500 +/- 424, and 2658 +/- 337% of basal levels, respectively. These increases were associated with significant decreases in levels of dihydroxyphenylacetic acid and homovallinic acid. Intrastriatal administration of MeHg induced a sharp concentration-dependent increase in DA levels with a peak 30 min after injection, whereas HgCl 2 induced a gradual, lower (for 4 mM) and delayed increase in DA levels (75 min after the beginning of perfusion). Comparing the neurochemical profile of the two mercury derivatives to induce increases in DA levels, we observed that the time-course of these increases induced by both mercurials was different and the effect produced by HgCl 2 was not concentration-dependent (the effect was the same for the concentrations of 400 microM and 4 mM HgCl 2 ). These results indicate that HgCl 2 produces increases in extracellular DA levels by a mechanism differing from that of MeHg. PMID- 17713655 TI - Melatonin prevents inflammation and oxidative stress caused by abdominopelvic and total body irradiation of rat small intestine. AB - We investigated the day-night differences in intestinal oxidative-injury and the inflammatory response following total body (TB) or abdominopelvic (AP) irradiation, and the influence of melatonin administration on tissue injury induced by radiation. Rats (male Wistar, weighing 220-280 g) in the irradiated groups were exposed to a dose of 8 Gy to the TB or AP region in the morning (resting period - 1 h after light onset) or evening (activity span - 13 h after light onset). Vehicle or melatonin was administered immediately before, immediately after and 24 h after irradiation (10, 2.0 and 10 mg/kg, ip, respectively) to the irradiated rats. AP (P < 0.05) and TB (P < 0.05) irradiation applied in the morning caused a significant increase in thiobarbituric acid reactive substance (TBARS) levels. Melatonin treatment in the morning (P < 0.05) or evening (P < 0.05) decreased TBARS levels after TB irradiation. After AP irradiation, melatonin treatment only in the morning caused a significant decrease in TBARS levels (P < 0.05). Although we have confirmed the development of inflammation after radiotherapy by histological findings, neither AP nor TB irradiation caused any marked changes in myeloperoxidase activity in the morning or evening. Our results indicate that oxidative damage is more prominent in rats receiving TB and AP irradiation in the morning and melatonin appears to have beneficial effects on oxidative damage irrespective of the time of administration. Increased neutrophil accumulation indicates that melatonin administration exerts a protective effect on AP irradiation-induced tissue oxidative injury, especially in the morning. PMID- 17713656 TI - Pattern of Wnt ligand expression during chick eye development. AB - The dorsoventral axis of the eye is determined prior to optic cup invagination. A variety of signaling pathways have been implicated in the maintenance of the optic dorsoventral axis, including, but not limited to, bone morphogenetic protein 4, Sonic Hedgehog and retinoic acid. Here, we investigated the possible contribution of Wnt ligands to the establishment or maintenance of the optic axis by analyzing their expression pattern during early chick optic development. We performed in situ hybridization of Wnt-1, Wnt-3a, Wnt-4, and Wnt-5a during the optic vesicle, early optic cup and established optic cup stages and focused our analysis on the optic region. Our data showed that Wnt-5a, but none of the others, is expressed in the dorsal region of the eye starting from the Hamburger and Hamilton stage 14 (HH14). These results are supported by cryosections of the labeled optic region, which further reveal that Wnt-5a is expressed only in the dorsal retinal pigmented epithelium. Thus, we propose that Wnt-5a is a marker for dorsal retinal pigmented epithelium in chick embryos from HH14 to HH19. PMID- 17713657 TI - Social inequality and perinatal health: comparison of three Brazilian cohorts. AB - The objective of the present study was to estimate and compare social inequality in terms of three indicators, i.e., low birth weight (LBW), preterm birth (PTB) and small for gestational age (SGA) birth, in three birth cohorts. Two cohorts were from the city of Ribeirao Preto, where data were collected for all 6748 live born singletons in 1978/79 and for one third of live born singletons (2846) in 1994. The third cohort consisted of 2443 singletons born in Sao Luis over a period of one year (1997/98). In Ribeirao Preto, LBW and PTB rates increased in all social strata from 1978/79 to 1994. Social inequalities regarding LBW and PTB disappeared since the increase in these rates was more accelerated in the groups with higher educational level. The percentage of SGA infants increased over the study period. Social inequality regarding SGA birth increased due to a more intense increase in SGA births in the strata with lower schooling. In Sao Luis, in 1997/98 there was no social inequality in LBW or PTB rates, whereas SGA birth rate was higher in mothers with less schooling. We speculate that the more accelerated increase in medical intervention, especially due to the increase in cesarean sections in the more privileged groups, could be the main factor explaining the unexpected increase in LBW and PTB rates in Ribeirao Preto and the decrease or disappearance of social inequality regarding these perinatal indicators in the two cities. PMID- 17713658 TI - Leptin levels in different forms of Chagas' disease. AB - Leptin is produced primarily by adipocytes. Although originally associated with the central regulation of satiety and energy metabolism, increasing evidence indicates that leptin may be an important mediator in cardiovascular pathophysiology. The aim of the present study was to investigate plasma leptin levels in patient with Chagas' heart disease and their relation to different forms of the disease. We studied 52 chagasic patients and 30 controls matched for age and body mass index. All subjects underwent anthropometric, leptin and N terminal pro-brain natriuretic peptide (NT-proBNP) measurements and were evaluated by echocardiography, 12-lead electrocardiogram (ECG), and chest X-ray. All patients had fasting blood samples taken between 8:00 and 9:00 am. Chagasic patients were divided into 3 groups: group I (indeterminate form, IF group) consisted of 24 subjects with 2 positive serologic reactions for Chagas' disease and no cardiac involvement as evaluated by chest X-rays, ECG and two-dimensional echocardiography; group II (showing ECG abnormalities and normal left ventricular systolic function, ECG group) consisted of 14 patients; group III consisted of 14 patients with congestive heart failure (CHF group) and left ventricular dysfunction. Serum leptin levels were significantly lower (P < 0.001) in the CHF group (1.4 +/- 0.8 ng/mL) when compared to the IF group (5.3 +/- 5.3 ng/mL), ECG group (9.7 +/- 10.7 ng/mL), and control group (8.1 +/- 7.8 ng/mL). NT-proBNP levels were significantly higher (P < 0.001) in the CHF group (831.8 +/- 800.1 pg/mL) when compared to the IF group (53.2 +/- 33.3 pg/mL), ECG group (83.3 +/- 57.4 pg/mL), and control group (32 +/- 22.7 pg/mL). Patients with Chagas' disease and an advanced stage of CHF have high levels of NT-ProBNP andlow plasma levels of leptin. One or more leptin-suppressing mechanisms may operate in chagasic patients. PMID- 17713659 TI - Male gonadal function, prolactin secretion and lactotroph population in an experimental model of cirrhosis. AB - Liver cirrhosis, a highly prevalent chronic disease, is frequently associated with endocrine dysfunctions, notably in the gonadal axis. We evaluated lactotroph population by immunohistochemistry, gonadotropins and prolactin by immunoradiometric assay and testosterone and estradiol by radioimmunoassay in adult male Wistar rats with cirrhosis induced by carbon tetrachloride. No significant difference in mean +/- SEM percentages of lactotrophs was found between cirrhotic animals and controls (N = 12, mean 18.95 +/- 1.29%). Although there was no significant difference between groups in mean serum levels of prolactin (control: 19.2 +/- 4 ng/mL), luteinizing hormone (control: 1.58 +/- 0.43 ng/mL), follicle-stimulating hormone (control: 19.11 +/- 2.28 ng/mL), estradiol (control: 14.65 +/- 3.22 pg/mL), and total testosterone (control: 138.41 +/- 20.07 ng/dL), 5 of the cirrhotic animals presented a hormonal profile consistent with hypogonadism, all of them pointing to a central origin of this dysfunction. Four of these animals presented high levels of estradiol and/or prolactin, with a significant correlation between these two hormones in both groups (r = 0.54; P = 0.013). It was possible to detect the presence of central hypogonadism in this model of cirrhotic animals. The hyperestrogenemia and hyperprolactinemia found in some hypogonadal animals suggest a role in the genesis of hypogonadism, and in the present study they were not associated with lactotroph hyperplasia. PMID- 17713661 TI - Early life, current socioeconomic position and serum lipids in young adulthood of participants in a cohort study initiated in 1978/1979. AB - The association between socioeconomic position (SEP) and serum lipids has been little studied and the results have been controversial. A total of 2063 young adults born in 1978/79 were evaluated at 23-25 years of age in the fourth follow up of a cohort study carried out in Ribeirao Preto, SP, Brazil, corresponding to 31.8% of the original sample. Total serum cholesterol (TC), triglycerides, high density cholesterol (HDL cholesterol) and low-density cholesterol (LDL cholesterol) were analyzed according to SEP at birth and during young adulthood. SEP was classified into tertiles of family income and a cumulative score of socioeconomic disadvantage was created. TC was 11.85 mg/100 mL lower among men of lower SEP in childhood (P < 0.01) but no difference was found in women, whereas it was 8.46 lower among men (P < 0.01) and 8.21 lower among women of lower SEP in adulthood (P < 0.05). Individuals of lower SEP had lower LDL and HDL cholesterol, with small differences between sexes and between the two times in life. There was no association between SEP and triglyceride levels. After adjustment of income at one time point in relation to the other, some associations lost significance. The greater the socioeconomic disadvantage accumulated along life, the lower the levels of TC, LDL and HDL cholesterol (P < 0.05). The socioeconomic gradient of TC and LDL cholesterol was inverse, representing a lower cardiovascular risk for individuals of lower SEP, while the socioeconomic gradient of HDL cholesterol indicated a lower cardiovascular risk for individuals of higher SEP. PMID- 17713660 TI - Low expression of antigen-presenting and costimulatory molecules by lung cells from tuberculosis patients. AB - Costimulatory and antigen-presenting molecules are essential to the initiation of T cell immunity to mycobacteria. The present study analyzed by immunocytochemistry, using monoclonal antibodies and alkaline phosphatase-anti alkaline phosphatase method, the frequency of costimulatory (CD86, CD40, CD40L, CD28, and CD152) and antigen-presenting (MHC class II and CD1) molecules expression on human lung cells recovered by sputum induction from tuberculosis (TB) patients (N = 22) and non-TB controls (N = 17). TB cases showed a statistically significant lower percentage of HLA-DR+ cells than control subjects (21.9 +/- 4.2 vs 50.0 +/- 7.2%, P < 0.001), even though similar proportions of TB cases (18/22) and control subjects (16/17, P = 0.36) had HLA-DR-positive-stained cells. In addition, fewer TB cases (10/22) compared to control subjects (16/17) possessed CD86-expressing cells (P = 0.04; OR: 0.05; 95%CI = 0.00-0.51), and TB cases expressed a lower percentage of CD86+ cells (P = 0.04). Moreover, TB patients with clinically limited disease ( pound1 lobe) on chest X-ray exhibited a lower percentage of CD86-bearing cells compared to patients with more extensive lung disease (>1 lobe) (P = 0.02). The lower expression by lung cells from TB patients of HLA-DR and CD86, molecules involved in antigen presentation and activation of T cells, may minimize T cell recognition of Mycobacterium tuberculosis, fostering an immune dysfunctional state and active TB. PMID- 17713662 TI - Do socioeconomic factors explain why maternal smoking during pregnancy is more frequent in a more developed city of Brazil? AB - The prevalence of smoking during pregnancy in Ribeirao Preto, a rich Brazilian city, was significantly higher (21.4%) than in Sao Luis (5.9%), a less developed city. To assess which variables explain the difference in prevalence of smoking during pregnancy, data from two birth cohorts were used, including 2846 puerperae from Ribeirao Preto, in 1994, and 2443 puerperae from Sao Luis, in 1997/98. In multivariable analysis, risk of maternal smoking during pregnancy was higher in Sao Luis for mothers living in a household with five or more persons (OR = 1.72, 95%CI = 1.12-2.64), aged 35 years or older (OR = 1.98, 95%CI = 0.99-3.96), who had five or more children (OR = 2.10, 95%CI = 1.16-3.81), and whose companion smoked (OR = 2.20, 95%CI = 1.52-3.18). Age of less than 20 years was a protective factor (OR = 0.55, 95%CI = 0.33-0.92). In Ribeirao Preto there was association with maternal low educational level (OR = 2.18, 95%CI = 1.30-3.65) and with a smoking companion (OR = 3.25, 95%CI = 2.52-4.18). Receiving prenatal care was a protective factor (OR = 0.24, 95%CI = 0.11-0.49). Mothers from Ribeirao Preto who worked outside the home were at a higher risk and those aged 35 years or older or who attended five or more prenatal care visits were at lower risk of smoking during pregnancy as compared to mothers from Sao Luis. Smoking by the companion reduced the difference between smoking rates in the two cities by 10%. The socioeconomic variables in the model did not explain the higher prevalence of smoking during pregnancy in the more developed city. PMID- 17713664 TI - Factors associated with infant and adolescent mortality. AB - Few studies have described factors associated with infant and adolescent mortality since birth. We report here mortality during a 20-year period in a birth cohort from Ribeirao Preto in order to identify birth variables that influenced mortality among infants and children between 10 and 19 years of age, the main causes of death, and the influence of social inequality at birth on death. Mothers were interviewed shortly after delivery. Social, biological and demographic information was collected, and mortality up to 19 years of age was investigated in registry systems. Of the 6748 liveborn singletons born in the municipality from 1978 to 1979, 343 died before or when 19 years of age were completed. Most of the cohort mortality (74.9%) occurred during the first year of life and 19.6% occurred from 10 to 19 years. Mortality was higher among boys. Preterm birth (hazard ratio, HR = 7.94) and low birth weight (HR = 10.15) were strongly associated with infant mortality. Other risk factors for infant mortality were: maternal age (3)35 years (HR = 1.74), unskilled manual occupation of family head (HR = 2.47), and for adolescent mortality: unskilled manual occupation of family head (HR = 9.98) and male sex (HR = 6.58). "Perinatal conditions" were the main causes of deaths among infants and "external causes" among adolescents, especially boys. Socioeconomic factors at birth, represented by occupation, influenced adolescent mortality due to external causes, which was higher among boys (7:1). The influence of social inequality at birth on death, measured by occupation, was greater in adolescence than in infancy. PMID- 17713663 TI - Anti-tumor necrosis factor-a for the treatment of steroid-refractory acute graft versus-host disease. AB - Allogeneic stem cell transplantation has been increasingly performed for a variety of hematologic diseases. Clinically significant acute graft-versus-host disease (GVHD) occurs in 9 to 50% of patients who receive allogeneic grafts, resulting in high morbidity and mortality. There is no standard therapy for patients with acute GVHD who do not respond to steroids. Studies have shown a possible benefit of anti-TNF-a (infliximab)for the treatment of acute GVHD. We report here on the outcomes of 10 recipients of related or unrelated stem cell transplants who received 10 mg/kg infliximab, iv, once weekly for a median of 3.5 doses (range: 1-6) for the treatment of severe acute GVHD and who were not responsive to standard therapy. All patients had acute GVHD grades II to IV (II = 2, III = 3, IV = 5). Overall, 9 patients responded and 1 patient had progressive disease. Among the responders, 3 had complete responses and 6 partial responses. All patients with cutaneous or gastrointestinal involvement responded, while only 2 of 6 patients with liver disease showed any response. None of the 10 patients had any kind of immediate toxicity. Four patients died, all of them with sepsis. Six patients are still alive after a median follow-up time of 544 days (92-600) after transplantation. Considering the severity of the cases and the bad prognosis associated with advanced acute GVHD, we find our results encouraging. Anti-TNF-a seems to be a useful agent for the treatment of acute GVHD. PMID- 17713665 TI - Do early life factors influence body mass index in adolescents? AB - The association between early life factors and body mass index (BMI) in adulthood has been demonstrated in developed countries. The aim of the present study was to assess the influence of early life factors (birth weight, gestational age, maternal smoking, and social class) on BMI in young adulthood with adjustment for adult socioeconomic position. A cohort study was carried out in 1978/79 with 6827 mother-child pairs from Ribeirao Preto city, located in the most developed economic area of the country. Biological, economic and social variables and newborn anthropometric measurements were obtained shortly after delivery. In 1996, 1189 males from this cohort, 34.3% of the original male population, were submitted to anthropometric measurements and were asked about their current schooling on the occasion of army recruitment. A multiple linear regression model was applied to determine variables associated with BMI. Mean BMI was 22.7 (95%CI = 22.5-23.0). After adjustment, BMI was 1.22 kg/m(2) higher among infants born with high birth weight ( > or = 4000 g), 1.21 kg/m(2) higher among individuals of low social class at birth and 0.69 kg/m(2) higher among individuals whose mothers smoked during pregnancy (P < 0.05). The association between social class at birth and BMI remained statistically significant (P < 0.05) even after adjustment for adult schooling. These findings suggest that early life social influences on BMI were more important and were not reversed by late socioeconomic position. Therefore, prevention of overweight and obesity should focus not only on changes in adult life styles but also on factors such as high birth weight. PMID- 17713666 TI - Inadequate utilization of prenatal care in two Brazilian birth cohorts. AB - Data for two birth cohorts from two Brazilian municipalities, Ribeirao Preto in 1994 and Sao Luis in 1997/1998, were used to identify and compare factors associated with inadequate utilization of prenatal care and to identify factors capable of explaining the differences observed between the two cities. Prenatal care was defined as adequate or inadequate according to the recommendations of the Brazilian Ministry of Health. The chi-square test and Poisson regression were used to compare differences in the inadequacy of prenatal care utilization. The percentage of inadequacy was higher in Sao Luis (34.6%) than in Ribeirao Preto (16.9%). Practically the same variables were associated with inadequacy in both cities. Puerperae with lower educational level, without a companion or cohabiting, who delivered in public health units, younger than 20 years, multiparae and smokers, with low family income presented higher percentages of inadequate prenatal care utilization. However, the effects of some variables differed between the two cities. The risk for inadequate use of prenatal care was higher for women attended in the public health sector in Sao Luis and for cohabiting women in Ribeirao Preto. The effect of the remaining factors studied did not differ between cities. The category of admission accounted for 57.0% of the difference in the inadequate use of prenatal care between cities and marital status accounted for 45.3% of the difference. Even after adjustment for all variables, part of the difference in the inadequacy of prenatal care utilization remained unexplained. PMID- 17713667 TI - Why are the rates of cesarean section in Brazil higher in more developed cities than in less developed ones? AB - The objective of the present study was to investigate factors associated with cesarean sections in two cities located in different regions of Brazil and to determine factors that explain the higher cesarean section rate in the more developed city, Ribeirao Preto, compared to the less developed one, Sao Luis. Data from two cohort studies comprising 2846 women in Ribeirao Preto in 1994, and 2443 women in Sao Luis in 1997/1998 were used. Adjusted and non-adjusted risk estimates were calculated using a Poisson regression model. The cesarean section rate was 33.7% in Sao Luis and 50.8% in Ribeirao Preto. Adjusted analysis in a joint sequential model revealed a 51% higher risk of cesarean section in Ribeirao Preto compared to Sao Luis (prevalence rate ratio (PRR) = 1.51). Adjustment for category of hospital admission reduced the PRR to 1.09, i.e., this variable explained 82% of the difference in the cesarean section rate between the two cities. Adjustment for the variable "the same physician for prenatal care and delivery" reduced the PRR to 1.07, with the "physician" factor explaining 86% of the difference between rates. When simultaneously adjusted for the two variables, the PRR decreased to 1.05, with these two variables explaining 90% of the difference in the cesarean section rate between the two cities, and the difference was no longer significant. The difference in the cesarean section rate between the two Brazilian cities, one more and one less developed, was mainly explained by the physician factor and, to a lesser extent, by the category of hospital admission. PMID- 17713668 TI - Racial inequalities and perinatal health in the southeast region of Brazil. AB - Few studies are available about racial inequalities in perinatal health in Brazil and little is known about whether the existing inequality is due to socioeconomic factors or to racial discrimination per se. Data regarding the Ribeirao Preto birth cohort, Brazil, whose mothers were interviewed from June 1, 1978 to May 31, 1979 were used to answer these questions. The perinatal factors were obtained from the birth questionnaire and the ethnic data were obtained from 2063 participants asked about self-reported skin color at early adulthood (23-25 years of age) in 2002/2004. Mothers of mulatto and black children had higher rates of low schooling (< or = 4 years, 27.2 and 38.0%) and lower family income (< or = 1 minimum wage, 28.6 and 30.4%). Mothers aged less than 20 years old predominated among mulattos (17.0%) and blacks (14.0%). Higher rates of low birth weight and smoking during pregnancy were observed among mulatto individuals (9.6 and 28.8%). Preterm birth rate was higher among mulattos (9.5%) and blacks (9.7%) than whites (5.5%). White individuals had higher rates of cesarean delivery (34.9%). Skin color remained as an independent risk factor for low birth weight (P < 0.001), preterm birth (P = 0.01), small for gestational age (P = 0.01), and lack of prenatal care (P = 0.02) after adjustment for family income and maternal schooling, suggesting that the racial inequalities regarding these indicators are explained by the socioeconomic disadvantage experienced by mulattos and blacks but are also influenced by other factors, possibly by racial discrimination and/or genetics. PMID- 17713669 TI - Profile of three Brazilian birth cohort studies in Ribeirao Preto, SP and Sao Luis, MA. AB - We describe three birth cohort studies, respectively carried out in 1978/79 and 1994 in Ribeirao Preto, a city located in the most developed region of Brazil, and in 1997/98 in Sao Luis, a city located in a less developed region. The objective of the present report was to describe the methods used in these three studies, presenting their history, methodological design, objectives, developments, and difficulties faced along 28 years of research. The first Ribeirao Preto study, initially perinatal, later encompassed questions regarding the repercussions of intrauterine development on future growth and chronic adult diseases. The subjects were evaluated at birth (N = 6827), at school age (N = 2861), at the time of recruitment for military service (N = 2048), and at 23/25 years of age (N = 2063). The study of the second cohort, which started in 1994 (N = 2846), permitted comparison of aspects of perinatal health between the two groups in the same region, such as birth weight, mortality and health care use. In 1997/98, a new birth cohort study was started in Sao Luis (N = 2443), capital of the State of Maranhao. The 1994 Ribeirao Preto cohort and the Sao Luis cohort are in the second phase of joint follow-up. These studies permit comparative temporal analyses in the same place (Ribeirao Preto 1978/79 and 1994) and comparisons of two contrasting populations regarding cultural, economic and sociodemographic conditions (Ribeirao Preto and Sao Luis). PMID- 17713672 TI - Roles of calcium and IP3 in impaired colon contractility of rats following multiple organ dysfunction syndrome. AB - The purpose of the present study was to explore changes in rat colon motility, and determine the roles of calcium and inositol (1,4,5)-triphosphate (IP3) in colon dysmotility induced by multiple organ dysfunction syndrome (MODS) caused by bacteria peritonitis. The number of stools, the contractility of the muscle strips and the length of smooth muscle cells (SMC) in the colon, the concentration of calcium and IP3 in SMC, and serum nitric oxide were measured. Number of stools, fecal weight, IP3 concentration in SMC and serum nitric oxide concentration were 0.77 +/- 0.52 pellets, 2.51 +/- 0.39 g, 4.14 +/- 2.07 pmol/tube, and 113.95 +/- 37.89 micromol/L, respectively, for the MODS group (N = 11) vs 1.54 +/- 0.64 pellets, 4.32 +/- 0.57 g, 8.19 +/- 3.11 pmol/tube, and 37.42 +/- 19.56 micromol/L for the control group (N = 20; P < 0.05). After treatment with 0.1 mM acetylcholine and 0.1 M potassium chloride, the maximum contraction stress of smooth muscle strips, the length of SMC and the changes of calcium concentration were 593 +/- 81 and 458 +/- 69 g/cm(3), 48.1 +/- 11.8 and 69.2 +/- 15.7 microM, 250 +/- 70 and 167 +/- 48%, respectively, for the control group vs 321 +/- 53 and 284 +/- 56 g/cm(3), 65.1 +/- 18.5 and 87.2 +/- 23.7 microM, 127 +/ 35 and 112 +/- 35% for the MODS group (P < 0.05). Thus, colon contractility was decreased in MODS, a result possibly related to reduced calcium concentration and IP3 in SMC. PMID- 17713670 TI - Genomic analysis of Brazilian patients with Fabry disease. AB - Fabry disease is an X-linked lysosomal disorder due to a-galactosidase A deficiency that causes storage of globotriaosylceramide. The gene coding for this lysosomal enzyme is located on the long arm of the X chromosome, in region Xq21.33-Xq22. Disease progression leads to vascular disease secondary to involvement of kidney, heart and the central nervous system. Detection of female carriers based solely on enzyme assays is often inconclusive. Therefore, mutation analysis is a valuable tool for diagnosis and genetic counseling. Many mutations of the a-galactosidase A gene have been reported with high genetic heterogeneity, being most mutations private found in only one family. The disease is panethnic, and estimates of incidence range from about 1 in 40,000 to 60,000 males. Our objective was to describe the analysis of 6 male and 7 female individuals belonging to 4 different Fabry disease families by automated sequencing of the seven exons of the alpha-galactosidase gene. Sequencing was performed using PCR fragments for each exon amplified from DNA extracted from peripheral blood. Three known mutations and one previously described in another Brazilian family were detected. Of 7 female relatives studied, 4 were carriers. Although the present study confirms the heterogeneity of mutations in Fabry disease, the finding of the same mutation previously detected in another Fabry family from our region raises the possibility of some founder effect, or genetic drift. Finally, the present study highlights the importance of molecular analysis for carrier detection and genetic counseling. PMID- 17713673 TI - Food consumption by young adults living in Ribeirao Preto, SP, 2002/2004. AB - There is evidence showing a close relationship between diet and the occurrence of non-communicable chronic diseases. The present study assessed food consumption in a 2002/2004 cohort of young adults born in 1978/79 in Ribeirao Preto, SP, Brazil. The composition of the habitual diet consumed by a sample of 2063 individuals aged 23-25 years was analyzed using a validated semi-quantitative food frequency questionnaire based on studies of prevention of non-communicable chronic diseases. The Dietsys software was used for dietary calculations. In terms of WHO/2003 recommendations, there was a high mean daily consumption of energy from fat (consumption: 35.4%; recommendation: 15-30%), a low mean intake of energy from carbohydrates (47.5%; 55-75%) and a low mean consumption of total fibers (15.2 g; >25 g). Mean intake of energy from fatty acids (10%; <10%) and protein (15.6%; 10-15%) was within recommended limits. When compared to the recommendations of the food pyramid adapted to the Brazilian population, adequate intake was observed only regarding the meat group (consumption: 1.9 portions; recommended: 1-2). There was a low consumption of vegetables (2.9; 4-5), fruits (1.2; 3-5), breads (3.6; 6-9), and dairy products (1.7; 3), with excessive fat and sugar intake (5.7; 1-2). We conclude that the inadequate food consumption observed in this young population may be associated with the development of excess weight and may contribute to the triggering of non-communicable chronic diseases. PMID- 17713674 TI - The use of stem cells for the treatment of autoimmune diseases. AB - Autoimmune diseases constitute a heterogeneous group of conditions commonly treated with anti-inflammatory, immunosuppressant and immunomodulating drugs, with satisfactory results in most cases. Nevertheless, some patients become resistant to conventional therapy. The use of high doses of drugs in such cases results in the need for bone marrow reconstitution, a situation which has stimulated research into the use of hematopoietic stem cells in autoimmune disease therapy. Stem cell transplantation in such diseases aims to destroy the self-reacting immune cells and produce a new functional immune system, as well as substitute cells for tissue damaged in the course of the disease. Significant results, such as the reestablishment of tolerance and a decrease in the recurrence of autoimmune disease, have been reported following stem cell transplantation in patients with autoimmune disease in Brazil and throughout the world. These results suggest that stem cell transplantation has the potential to become an important therapeutic approach to the treatment of various autoimmune diseases including rheumatoid arthritis, juvenile idiopathic arthritis, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, Crohn's disease, autoimmune blood cytopenias, and type I diabetes mellitus. PMID- 17713679 TI - Current situation of Chagas disease in Central America. AB - Chagas disease in Central America is known since 1913 when the first human case was reported in El Salvador. The other Central American countries reported their first cases between 1933 and 1967. On October 1997 was launched the Central American Initiative for Chagas Disease Control (IPCA). The objectives of this sub regional Initiative are: (1) the elimination of Rhodnius prolixus in Central America; (2) the reduction of the domiciliary infestation of Triatoma dimidiata; and (3) the elimination of the transfusion transmission of Trypanosoma cruzi. Significant advancements being close to the elimination of R. prolixus in Central America and the control of the transfusion transmission has been a transcendent achievement for the sub-region. The main challenges that the IPCA will have in the close future are: developing effective strategies for control and surveillance of T. dimidiata; and surveillance of other emerging triatominae species like R. pallescens, T. nitida, and T. ryckmani. PMID- 17713680 TI - Access to diagnosis and treatment of Chagas disease/infection in endemic and non endemic countries in the XXI century. AB - In this article, Medicos Sin Fronteras (MSF) Spain faces the challenge of selecting, piecing together, and conveying in the clearest possible way, the main lessons learnt over the course of the last seven years in the world of medical care for Chagas disease. More than two thousand children under the age of 14 have been treated; the majority of whom come from rural Latin American areas with difficult access. It is based on these lessons learnt, through mistakes and successes, that MSF advocates that medical care for patients with Chagas disease be a reality, in a manner which is inclusive (not exclusive), integrated (with medical, psychological, social, and educational components), and in which the patient is actively followed. This must be a multi-disease approach with permanent quality controls in place based on primary health care (PHC). Rapid diagnostic tests and new medications should be available, as well as therapeutic plans and patient management (including side effects) with standardised flows for medical care for patients within PHC in relation to secondary and tertiary level, inclusive of epidemiological surveillance systems. PMID- 17713681 TI - Social, epidemiological, and control determinants of Chagas disease in American Southern Cone--working group. PMID- 17713687 TI - Current clinical research environment: focus on psychiatry. AB - The introduction of international guidelines on Good Clinical Practices (GCP) in 1996, immediately followed by the publication of Resolution CNS 196/96 in Brazil, created a great opportunity for Brazilian research centers to participate in international trials. Such studies must be strictly monitored in order to assure compliance with the regulations, as well as with the standards of patient safety. Clear agreement among the investigator, the sponsor and the institution carrying out the study must be previously defined in order to avoid any conflicts of interest during or after the study. Operational aspects, such as the time needed to gain regulatory approval of the study design, strategies for patient recruitment/retention and appropriate logistics, are also important. In 2005, the Brazilian National Clinical Research Network was established, bringing together a number of research centers in teaching hospitals. The objective was to subsidize public clinical research with state-of-the-art practices and appropriate technical/scientific training programs. The development of research protocols that prioritize public health care needs in Brazil is other fundamental goal of this network. This article addresses general aspects of clinical research, as well as some specific issues in psychiatry. Improving the health and quality of life of the global population is certainly the major objective of all of the work done in this area. PMID- 17713688 TI - [Quality of life in individuals with obsessive-compulsive disorder: a review]. AB - OBJECTIVE: Obsessive-compulsive disorder affects between 1.6 and 3.1% of the population. Due to the distress caused by obsessive-compulsive disorder leading to disability as well as the prevalence of the disease, there has been an increase in the number of studies focusing on the general well-being of patients by assessing quality of life. METHOD: A literature review of the studies that investigated the quality of life of patients with obsessive-compulsive disorder was performed. The search was carried out in the following database: Medline, SciELO and PsychoInfo, and the following key-words were used "quality of life" and "obsessive-compulsive disorder". Twenty-seven articles about the topic were selected. The results from this study describe the areas most severely affected by the disorder as well as the relationship between obsessive-compulsive disorder and quality of life. In addition, the effects of the treatment on the patients' quality of life are presented. RESULTS: The social and familial relationships and the occupational performance (capacity to work and study) were the areas most severely affected by the disorder, and, although there was an improvement with the treatment, these areas remain at a poor level of performance. The obsessions were associated with the most significant impairment of the quality of life if compared to the compulsions (rituals). CONCLUSIONS: Results from the selected studies suggest that obsessive-compulsive disorder patients have an impairment of quality of life. The level of impairment is similar to that of schizophrenic patients. Future studies with different designs are necessary so that more consistent results can be established. PMID- 17713689 TI - The role of hyperventilation: hypocapnia in the pathomechanism of panic disorder. AB - OBJECTIVE: The authors present a profile of panic disorder based on and generalized from the effects of acute and chronic hyperventilation that are characteristic of the respiratory panic disorder subtype. The review presented attempts to integrate three premises: hyperventilation is a physiological response to hypercapnia; hyperventilation can induce panic attacks; chronic hyperventilation is a protective mechanism against panic attacks. METHOD: A selective review of the literature was made using the Medline database. Reports of the interrelationships among panic disorder, hyperventilation, acidosis, and alkalosis, as well as catecholamine release and sensitivity, were selected. The findings were structured into an integrated model. DISCUSSION: The panic attacks experienced by individuals with panic disorder develop on the basis of metabolic acidosis, which is a compensatory response to chronic hyperventilation. The attacks are triggered by a sudden increase in (pCO2) when the latent (metabolic) acidosis manifests as hypercapnic acidosis. The acidotic condition induces catecholamine release. Sympathicotonia cannot arise during the hypercapnic phase, since low pH decreases catecholamine sensitivity. Catecholamines can provoke panic when hyperventilation causes the hypercapnia to switch to hypocapnic alkalosis (overcompensation) and catecholamine sensitivity begins to increase. CONCLUSION: Therapeutic approaches should address long-term regulation of the respiratory pattern and elimination of metabolic acidosis. PMID- 17713691 TI - [Treatment-resistant mood disorders]. AB - OBJECTIVE AND METHOD: Mood disorders are the most prevalent psychiatric disorders. Despite new insights and advances on the neurobiological basis and therapeutic approaches for bipolar disorders and recurrent depression, elevated prevalence of recurrence, persistent sub-syndromal symptoms and treatment resistance are challenging aspects and need to be urgently addressed. The objective of this literature review is to evaluate the current concepts of treatment resistance and refractoriness in mood disorders. RESULTS: Genetic factors, misdiagnosis, use of inappropriate pharmacological approaches, non compliance and biological/psychosocial stressors account for dysfunctions in mood regulation, thus increasing the prevalence of refractory mood disorders. Regarding available treatments, the use of effective doses during an adequate period followed by augmentation with a second and/or third agent, and finally switching to other agent are steps frequently necessary to optimize efficacy. However, in the treatment-resistant paradigm, drugs mimicking standard strategies, which target preferentially the monoaminergic system, can present reduced therapeutic effects. Thus, the search for new effective treatments for mood disorders is critical to decreasing the overall morbidity secondary to treatment resistance. CONCLUSION: Emerging strategies targeting brain plasticity pathways or 'plasticity enhancers', including antiglutamatergic drugs, glucocorticoid receptor antagonists and neuropeptides, have been considered promising therapeutic options for difficult-to-treat mood disorders. PMID- 17713692 TI - Validity of a frustration-induction procedure. AB - OBJECTIVE: To test a reliable and easily administered frustration-induction procedure for experimental research. METHOD: One hundred volunteers (81 women, mean age +/- SD 34.2 +/- 8 years) physically and psychiatrically healthy submitted to the frustration induction procedure were prevented from reaching reward level scores. Subjective aggressiveness feelings related to frustration were self-rated in a 13-item visual analogue scale before and after the procedure. RESULTS: Significant increases in aggressiveness-related feelings were detected in 12 of the 13 items. This was consistent with the observed overt behavior of the subjects during the task. CONCLUSIONS: The frustration-induction procedure is a simple, easy to administer frustration-induction procedure that can be used in experimental studies in normal subjects. PMID- 17713694 TI - WHOQOL-BREF psychometric properties in a sample of smokers. AB - OBJECTIVE: To study the World Health Organization Quality of Life Instrument Bref psychometric properties in a sample of smokers. It is a self-administered instrument to evaluate quality of life. It contains 26 questions allocated to 4 domains: Social, Psychological, Physical and Environmental, there are 2 questions related to the Global domain. METHOD: The sample was formed by 276 tobacco users selected at random. The instruments applied were: World Health Organization Quality of Life Instrument Bref, Fagerstrom Test for Nicotine Dependence, and Medical Outcomes Study Short-Form 36-item. The statistical analysis was accomplished up by ANOVA, Cronbach's alpha, Pearson's Coefficient and Multiple Regression. RESULTS: The World Health Organization Quality of Life Instrument Bref presented good reliability (Cronbach's alpha 0.9207), converging validation (0.382 Al > Zn > Ni > Cu > Mn > Co > Cr > Pb and Cd, while for Biscuits it was Al > Fe > Zn > Ni > Mn > Co > Cr > Pb > Cu and Cd. PMID- 17713712 TI - Effects of pentachlorophenol on Galba pervia, Tubifex sinicus and Chironomus plumousus larvae. AB - The 24-h median lethal concentrations of pentachlorophenol to Chironomus plumousus, Tubifex sinicus and Galba pervia were 0.302, 0.977 and 0.293 mg/L, respectively. Bioconcentration factors of C. plumousus, T. sinicus and G. pervia to pentachlorophenol were 108, 367 and 85 at 0.02 mg/L pentachlorophenol, respectively. As pentachlorophenol concentration increased, the G. pervia egg hatching rates became lower, and the total hatched time became longer. Pentachlorophenol teratogenesis was demonstrated by observing the deformation of C. plumousus larvae mentum. PMID- 17713714 TI - Which bone mass measures discriminate adolescents who have fractured from those who have not? AB - This study of 415 adolescent children examined the association between four different measures of bone mass and prevalent fracture (N = 160 children). DXA measures and calcaneal ultrasound (but not radial ultrasound or metacarpal index) were associated with upper limb fracture, suggesting heel ultrasound is also a discriminator of fractures in children. INTRODUCTION: The aim of the study was to describe the association between different measures of bone mass and prevalent fracture in adolescents. METHODS: A total of 415 adolescents (150 girls and 265 boys), mean age 16.3 years were examined. Dual energy X-ray absorptiometry (DXA) measures were performed at hip, spine, radius and total body. Calcaneal bone ultrasound attenuation (BUA), speed of sound (SOS), and stiffness were assessed by a Sahara densitometer. Radial ultrasound SOS was assessed by a Sunlight 8000P machine. Metacarpal index was calculated from a left hand X-ray. Prevalent fractures were assessed by questionnaire. RESULTS: A total of 160 adolescents (39%) reported at least one previous fracture (106 upper limb, 53 lower limb, one other for first fracture). Significantly lower DXA measures, heel BUA, and heel stiffness was observed in those with a history of upper limb fracture (all P < 0.05). Despite significant correlations between all the bone mass measures, radial ultrasound and metacarpal index did not discriminate those with fracture from those without. Similar associations were present for number of fractures. No bone measure was able to discriminate lower limb fracture. CONCLUSIONS: Both calcaneal quantitative ultrasound and DXA are able to discriminate adolescents with a history of upper limb fracture from those without. PMID- 17713715 TI - Association of interferon-gamma gene polymorphism (+874A) with arthritis manifestation in SLE. AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which genetic factors strongly influence susceptibility. Cytokines such as the interferon-gamma (IFNG) gene play a key role in controlling the immunity and inflammation, and therefore their polymorphisms may affect these genes' expression levels among individuals. We investigated the frequency of IFNG gene intron (+874) polymorphism, previously reported to be associated with IFNG production, in SLE patients compared to a control group. This population-based case-control study includes 154 SLE patients and 154 healthy control subjects with similar ethnic backgrounds. The genotyping was determined by polymerase chain reaction sequence-specific primer method and using the Chi-squared test for analyzing the association between this single-nucleotide polymorphism and SLE. The allele frequencies of the IFNG (+874) gene polymorphism were not significantly different between SLE patients and control subjects (72.7 vs 77%). However, there was a significant association between A dominance model of inheritance with arthritis (odds ratio = 7.64, 95% confidence interval = 1.56 41.64, P = 0.006, P(c) = 0.03). The result suggested that the +874 intron polymorphism of IFNG can be used as the marker for SLE susceptibility with arthritis in the Thai population. PMID- 17713716 TI - Autoantibodies to novel membrane and cytosolic antigens of the lachrymal gland in primary Sjogren's syndrome. AB - Sjogren's syndrome (SS) is a prototypical systemic autoimmune disease, where autoimmune processes lead to the dysfunction of the exocrine glands. The key feature of the disease is autoimmune exocrinopathy, causing reduced tear secretion and subsequent keratoconjunctivitis sicca (KCS). The aim of this study was to investigate the connection between the presence of autoantibodies to lachrymal gland antigens and the reduced tear production in patients with primary SS. Ninety-nine patients, 90 women and 9 men, were investigated in the study. Twenty healthy young women served as controls. Enzyme-linked immunosorbent assay (ELISA) and Western blotting were applied to detect autoantibodies to antigen fractions prepared from the human lachrymal gland membrane and cytosolic fractions. Autoantibodies of the IgG, IgA and IgM isotypes to the lachrymal membrane and cytosolic fractions were detected in about one third (27%) of the patients with primary SS. IgA antobodies to the membrane and cytosolic fractions occurred most frequently in SS patients. A significant difference was found in the presence of IgA antibodies to the membrane lachrymal fraction between patients and controls given in ELISA indices (1.23 +/- 0.3 vs 1 +/- 0.19, p < 0.001). IgG, IgA, and IgM isotypes of autoantibodies directed to the membrane lachrymal fraction of 200-180, 120-116, 80-70, 58, 50, 48.5, 40 and 28.8 kDa were also identified in patients. Membrane IgG antibody levels showed a positive correlation (R = 0.998; p = 0.045) with the clinical loss of secretory function (Schirmer's test values). Positive correlation was found between membrane IgM and anti-SS-A levels (R = 0.962; p = 0.038) and also between cytosolic IgM antibodies and anti-SS-A levels (R = 0.982; p = 0.018). IgG, IgA and IgM types of autoantibodies may play a role in the development of the impaired lachrymal secretion and therefore may be involved in the pathogenesis of KCS. PMID- 17713717 TI - Use of tissue Doppler imaging to identify and manage systemic diseases. AB - In systemic diseases such as amyloidosis, sarcoidosis, Friedreich's ataxia, Fabry's disease and muscular dystrophy the clinician has to judge the presence and the amount of cardiac involvement. In most of these patients conventional echocardiographic parameters are not sensitive enough to detect sub-clinical dysfunction. Tissue Doppler imaging and in addition strain rate imaging has proven to be very sensitive for the assessment of myocardial dysfunction. This review explores the impact of these new techniques to identify and to manage cardiac aspects of the different systemic diseases. PMID- 17713718 TI - Influence of aminophylline on the anticonvulsive action of gabapentin in the mouse maximal electroshock seizure threshold model. AB - Accumulating evidence indicates that aminophylline [theophylline(2) x ethylenediamine] markedly attenuates the anticonvulsant action of conventional antiepileptic drugs in experimental animal models of epilepsy and evokes severe seizure activity in patients treated with this methylxanthine. The objective of this study was to determine the influence of acute (single) and chronic (twice daily for 14 consecutive days) treatments with aminophylline on the anticonvulsant potential of gabapentin (a second-generation antiepileptic drug) in the mouse maximal electroshock seizure threshold model. Additionally, the effects of acute and chronic administration of aminophylline on the adverse effect potential of gabapentin in terms of motor coordination impairment were assessed in the chimney test. To evaluate pharmacokinetic characteristics of interaction between drugs, total brain concentrations of gabapentin and theophylline were estimated with high-pressure liquid chromatography and fluorescence polarization immunoassay, respectively. Results indicated that gabapentin (at doses of 75 and 100 mg/kg, i.p.) increased the threshold for electroconvulsions in mice. Aminophylline in non-convulsive doses of 50 and 100 mg/kg (i.p.), both in acute and chronic experiments, did not attenuate the anticonvulsant potential of gabapentin in the maximal electroshock seizure threshold test in mice. Similarly, aminophylline at a dose of 100 mg/kg had no impact on the adverse effect potential of gabapentin in the chimney test. Pharmacokinetic evaluation of total brain concentrations of gabapentin and theophylline revealed no significant changes in total brain concentrations of the drugs after both, acute and chronic applications of aminophylline in combination with gabapentin. The data show that aminophylline did not alter the ability of gabapentin to protect mice against seizures induced by electroconvulsive shock. The observed interaction between gabapentin and aminophylline in both acute and chronic experiments was pharmacodynamic in nature. PMID- 17713719 TI - Reduced availability of serotonin transporters in obsessive-compulsive disorder correlates with symptom severity - a [11C]DASB PET study. AB - Reduced availability of brainstem serotonin transporters (5-HTT) has been observed in vivo in obsessive-compulsive disorder (OCD). However, results vary and may be influenced by competition with endogenous serotonin. Using positron emission tomography (PET) and [11C]DASB, a specific 5-HTT ligand that showed no competition with serotonin for 5-HTT binding in vitro, we tested the hypothesis that 5-HTT availability is reduced in OCD patients and correlated with OCD severity. METHODS. 5-HTT availability in the thalamus and the midbrain was measured in nine drug-free OCD patients and compared with 19 healthy controls, matched for the individual combination of 5-HTT genotype, gender and smoking status. OCD severity was assessed with the Yale-Brown obsessive compulsive scale (Y-BOCS). RESULTS. 5-HTT availability was significantly reduced in the thalamus and midbrain of OCD patients. Age and 5-HTT in the thalamus explained 83% of OCD severity in patients that were drug-free for at least 1 year. CONCLUSION. This PET study confirms a central role of the serotonergic system, particularly the thalamus in the pathogenesis of obsessive compulsive disorder. PMID- 17713720 TI - A supratentorial primitive neuroectodermal tumor in an adult: a case report and review of the literature. AB - Supratentorial primitive neuroectodermal tumors (sPNET) occurring in adults are rare. Only 56 such cases have been previously reported. This report documents a 56-year-old male who presented with the chief complaint of right facial palsy. Magnetic resonance imaging (MRI) revealed left frontal and bilateral periventricular lesions. Surgery was performed for the frontal mass, which was histologically diagnosed to be sPNET. An immunohistochemistry assay for CD99, and a fluorescence in situ hybridization (FISH) assay for t(11;22) translocation revealed this PNET to be a central PNET. This case was the first case to detect a central PNET using both immunohistochemistry and the FISH assay in adult sPNET. Though radiation therapy was performed, an MRI performed 2.5 months after the surgery revealed a regrowth of the tumor. The patient died 5 months after surgery. This case report is accompanied by a review of 57 cases of adult sPNET. PMID- 17713721 TI - In vitro formation of lacuna structure by human dermal fibroblasts co-cultured with porcine chondrocytes on a 3D biodegradable scaffold. AB - Dermal fibroblasts (DF) possess chondrogenic differentiation potential but whether DF, or a subpopulation of DF, can form a typical cartilage structure in culture is unknown. In this study, human DF were co-cultured with porcine articular chondrocytes on a biodegradable scaffold of polylactic acid/polyglycolic acid. Histological analysis demonstrated that some DFs can be induced to form cartilage lacuna structure showing the existence of a chondrogenic subpopulation of human DF. Moreover, the 3D-co-culture system can serve as an optimal model for directing stem cell differentiation in vitro. PMID- 17713722 TI - Management of the Neck after Treatment with Radiation with or without Chemotherapy. PMID- 17713723 TI - Lenalidomide in myeloma. AB - The standard treatment approach to symptomatic myeloma consists of induction therapy, consolidation with high-dose chemotherapy and autologous hematopoietic stem cell transplantation in appropriate patients, maintenance therapy, and salvage therapy. Salvage therapy is of particular importance because not all patients respond to primary therapy, and relapse is virtually universal in responding patients. Newer agents such as thalidomide, bortezomib, and lenalidomide are very active in patients with relapsed or refractory disease. Their use singly and in combination results in excellent cytoreduction including complete remissions in patients relapsing - even after extensive prior therapy. These novel agents have been usually used as salvage therapy in patients relapsing after standard treatment options including transplantation; a setting in which they are thought to improve survival. However, there is an increasing trend to start using them early in the course of the disease; for induction therapy. While early deployment of these agents is certainly associated with high response rates, evidence that this improves long-term outcome (survival) in patients who subsequently undergo intensive therapy and transplantation is lacking. Toxicity, expense, and possible long-term consequences on the biology of the disease (for example, development of refractory relapse) remain a concern. The most appropriate use of newer agents such as lenalidomide is as salvage therapy of relapsed or refractory disease, and their use as part of induction therapy should be confined to clinical trials until additional data and long-term follow-up are available. PMID- 17713725 TI - Axillary lymph node echo-guided fine-needle aspiration cytology enables breast cancer patients to avoid a sentinel lymph node biopsy. Preliminary experience and a review of the literature. AB - PURPOSE: For many years, the status of the axillary lymph nodes has been determined by an axillary lymphadenectomy. However, a sentinel lymph node biopsy has been shown to effectively replace the need for an axillary lymphadenectomy in order to determine the axillary staging. This study presents the preliminary results regarding the efficacy of fine-needle aspiration cytology (FNAC) to identify metastatic axillary lymph nodes in the pre-operative phase. METHODS: One hundred lymph nodes from 100 patients with histologically and cytologically confirmed breast cancer (cT1-2 cN0) underwent echo-guided FNAC. The diagnostic accuracy (sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV]) for the axillary metastases was evaluated based on the histological findings of either a sentinel lymph node biopsy or an axillary lymphadenectomy as a reference standard. RESULTS: It was possible to avoid a sentinel lymph node biopsy in 30% of the cases; the sensitivity was 68%, specificity 100%, PPV 100%, and NPV 65%. Echo-guided FNAC of the axillary lymph nodes should thus be included among the regular diagnostic procedures of presurgical staging. CONCLUSION: This simple, inexpensive, and minimally invasive technique makes it possible to avoid the additional cost of a sentinel lymph node biopsy while also sparing the patient the stress of undergoing a second surgery. PMID- 17713726 TI - Review of acute pulmonary embolism in a general hospital. AB - PURPOSE: Acute pulmonary embolism (APE) is a serious cardiovascular disease associated with high mortality rates. We analyzed the clinical characteristics, treatment, and outcome of patients with APE in a general hospital in Japan. METHODS: The subjects were 14 patients with APE: 6 with out-of-hospital onset and 8 with in-hospital onset. RESULTS: The incidence of APE in hospitalized patients was 0.03% (95% confidence interval, 0.01%-0.05%). Eight patients suffered shock and three patients suffered cardiac arrest. Advanced age, deep vein thrombus (DVT), cancer, fracture, obesity, and surgery were common risk factors. In the hospitalized patients, surgery was a major risk factor: APE developed perioperatively in five (63%) of eight patients. Nine patients were treated with heparin alone, three were treated with thrombolysis, and two underwent surgical embolectomy for right heart thrombi. Three of the patients who suffered shock died during hospitalization and another died of recurrence 2 months after the first episode. Overall in-hospital and 3-month mortality rates were 21% and 29%, respectively, and the in-hospital mortality rate of the patients with shock was 38%. CONCLUSION: Acute pulmonary embolism was associated with high mortality rates and surgery was the most common risk factor predisposing to APE in hospitalized patients. Thus, standardized prophylaxis against DVT is essential for patients undergoing surgery. PMID- 17713724 TI - Impact of smoking status on the biological behavior of lung cancer. AB - Cigarette smoking is the most established risk factor for lung carcinogenesis; however, its effects on the progression of lung cancer are still unclear. We reviewed the clinical investigations on this issue, which imply that smoking status is a treatment predictor and prognostic factor for several subtypes of lung cancer. Moreover, gene alterations and various protein expressions of tumor progression were recognized more frequently in the tumor tissues of smokers than in those of the never smokers. A cellular analysis revealed that tobacco-specific chemical compounds cause genetic or epigenetic alterations, modulate expressions of large numbers of genes that include molecules related to proliferation, invasion and metastasis, and deteriorate anti-tumor immunity. Our findings suggest that smoking promotes the progression of lung cancer, and that elucidating the molecular mechanisms may help to clarify the therapeutic targets. PMID- 17713727 TI - Staple line reinforcement with fleece-coated fibrin glue (TachoComb) after thoracoscopic bullectomy for the treatment of spontaneous pneumothorax. AB - BACKGROUND: We investigated the cause of pneumothorax recurrence after thoracoscopic surgery and the effectiveness of staple line reinforcement with fleece-coated fibrin glue (TachoComb) in the prevention of postoperative pneumothorax recurrence. METHODS: From April 3, 1992 to the end of December 2005, thoracoscopic bullectomy was performed on 499 patients of primary spontaneous pneumothorax. The causes of recurrence were investigated on 39 patients on the basis of surgical observations, preoperative chest computed tomography, and so on. The most common cause was new bulla formation (37 cases), 19 of which were apparently related to the staple line (within 1 cm of the staple lines) and 15 of which were not related to the staple line. After 2000, we stopped using forceps to grasp lungs and we have reinforced the staple line by applying fleece-coated fibrin glue. RESULTS: The staple line reinforced with fleece-coated fibrin glue, or sprayed with fibrin glue solution and the untreated group (bullectomy only with staples) were compared, and the recurrence rates were 1.22%, 7.25%, and 10.00%, respectively (P = 0.0006021). CONCLUSIONS: The recurrence rate after thoracoscopic bullectomy with fleece-coated fibrin glue was significantly lowered and we consider this procedure to be the treatment of choice for the management of spontaneous pneumothorax. PMID- 17713728 TI - The variations in the immunologic features and interleukin-6 levels for the surgical treatment of cardiac myxomas. AB - PURPOSE: In this study, we propose the existence of a relationship between cardiac myxomas and the immunologic features or interleukin-6 (IL-6), while also considering the optimal treatment of cardiac myxoma, especially "familial myxoma." METHODS: In a 19-year period at our hospital, 20 patients underwent 21 operations for cardiac myxomas. The immunologic features and the IL-6 levels were measured pre-operatively in 13 cases and post-operatively in 10 cases. A case of "familial myxoma" was diagnosed based on molecular genetic analyses. RESULTS: No patients died in the hospital. The tumor size correlated with the preoperative IL 6 and/or alpha1-globulin values (P < 0.05). In addition, all of the immunologic features and IL-6 levels normalized by 4 weeks after surgery. "Familial myxoma" demonstrated recurrence without showing increases in either the immunologic features, inflammatory signs, or serum IL-6 levels. CONCLUSIONS: Patients with cardiac myxoma should therefore be operated on immediately because the possibility that the tumor size might be large when IL-6 and/or alpha1-globulin values are high. In addition, cases of "familial myxoma" require careful observation and periodic echocardiography after surgery to identify any possible recurrence. Recently, molecular genetic analyses are therefore considered to be an important diagnostic tool for cardiac myxoma, especially "familial myxoma." Our "familial myxoma" case demonstrated a C769T PRKAR1a mutation, which has also been observed in other cases of "familial myxoma." PMID- 17713729 TI - Medium- and long-term results of jejunal pouch reconstruction after a total and proximal gastrectomy. AB - PURPOSE: We developed several kinds of jejunal (J)-pouch reconstruction after a gastrectomy for gastric cancer. The aim of this study was to investigate the advantages of these methods. METHODS: As for the treatment of malignant gastric diseases at stage II or earlier, we employed the J-pouch reconstruction (Roux-en Y method: JPRY, or J-pouch interposing: JPI) following a total gastrectomy. We also used JPI after a proximal gastrectomy for early gastric cancer located in the upper third of the stomach. RESULTS: Out of a total of 80 patients, JPRY was performed in 40 patients and JPI in 40. No anastomotic leaks were associated with the use of an automatic stapler. The stapler (Endo GIA; U.S. Surgical, Norwalk, CT, USA) with a 60-mm-long white cartridge minimized bleeding from the anastomotic site and reduced the operative time. While two patients died of recurrence, all other patients are alive and well for a maximum of 15 years after surgery. The motility of the J pouch was satisfactory after both surgical procedures, as measured by the bile regurgitation test or the transit test employing radiopaque markers. The mean percentage of the radiopaque markers eliminated from the J pouch 1 h after breakfast was 7.5% in the JPRY group and 0% 33% in the JPI group. After another hour, the corresponding percentage was 19.5% in the JPRY group and 14%-60% in the JPI group. CONCLUSION: Our procedures for J pouch reconstruction are considered to result in a favorable postoperative quality of life and prognosis. J-pouch reconstruction is therefore advantageous in terms of operative morbidity, postoperative clinical signs, symptoms, and dietary status. PMID- 17713730 TI - Retroperitoneal abscess resulting from perforated acute appendicitis: analysis of its management and outcome. AB - BACKGROUND: Acute appendicitis may become life threatening if it is complicated by retroperitoneal abscess. To the best of our knowledge, only case reports have been documented; thus, we analyzed the published experiences and reviewed this issue. MATERIALS AND METHODS: In addition to two patients treated at our institution, a PubMed search identified 22 cases of acute appendicitis, complicated by retroperitoneal abscess, reported by 18 authors between 1955 and 2005. The patients' characteristics, onset of symptoms, timing and methods of diagnosis and management, and outcome are reviewed and analyzed. RESULTS: Most of the patients were adults (21/24, 87.5%), of whom seven were older than 65 years. None of the patients presented with the classical symptoms of acute appendicitis at the onset of the disease, and less than half (9/24) reported abdominal pain. The average interval between the onset of symptoms and diagnosis was 16 days, and the most effective diagnostic tool was computed tomography. Pathogens were usually polymicrobial, and appendectomy followed by adequate drainage of the abscess was the best treatment. The mortality rate was 16.7% (4/24), and all deaths were caused by profound sepsis. According to the available data, the average hospital stay was 27.3 days for the survivors. CONCLUSION: The formation of complicated retroperitoneal abscesses involving thigh, psoas muscle, perinephric space, or even the lateral abdominal wall is a serious complication of perforated acute appendicitis. An intra-abdominal pathological abnormality cannot be excluded in a patient presenting without abdominal symptoms. The mortality rate can only be reduced by a high index of suspicion, accurate diagnosis, and appropriate treatment. PMID- 17713732 TI - Skin necrosis after intravenous calcium chloride administration as a complication of parathyroidectomy for secondary hyperparathyroidism: report of four cases. AB - Intravenous (i.v.) calcium chloride is usually given to treat symptomatic hypocalcemia; however, the extravasation of calcium solution may cause soft tissue and skin necrosis. After parathyroidectomy and autotransplantation for secondary hyperparathyroidism associated with end-stage renal failure, i.v. calcium infusion is often necessary to treat severe postoperative hypocalcemia. We reviewed 371 patients who underwent parathyroidectomy for secondary hyperparathyroidism between January 2000 and June 2005, 96 of whom received i.v. calcium postoperatively for symptomatic hypocalcemia. We report the cases of three (3%) of our own patients and of one patient referred to our hospital, who suffered skin necrosis after i.v. calcium solution administration. These reports show that i.v. calcium should be administered into large veins, or via a central line, and diluted in an appropriate volume of solution. Moreover, the calcium solution infusion should be ceased if the patient complains of tenderness over the injection site. If skin necrosis develops, we suggest early debridement and a simple split thickness skin graft to repair the skin defect. We report our experience to remind surgeons of the danger of calcium chloride injection and to discuss ways of preventing and treating this complication. PMID- 17713731 TI - Stable gastric pentadecapeptide BPC 157 in trials for inflammatory bowel disease (PL-10, PLD-116, PL14736, Pliva, Croatia) heals ileoileal anastomosis in the rat. AB - PURPOSE: Gastric pentadecapeptide BPC 157 (BPC 157), which has been shown to be safe in clinical trials for inflammatory bowel disease (PL-10, PLD-116, PL14736, Pliva, Croatia), may be able to cure intestinal anastomosis dehiscence. This antiulcer peptide shows no toxicity, is limit test negative, and a lethal dose is not achieved. It is stable in human gastric juice. In comparison with other standard treatments it is more effective for ulcers and various wounds, and can be used without a carrier needed for other peptides, both locally and systemically (i.e., perorally, parenterally). We studied the effectiveness of BPC 157 for ileoileal anastomosis healing in rats. METHODS: We assessed ileoileal anastomosis dehiscence macroscopically, histologically, and biomechanically (volume [ml] infused through a syringe-perfusion pump system (1 ml/10 s), and pressure [mmHg] to leak induction [catheter connected to a chamber and a monitor, at 10 cm proximal to anastomosis]), at 1, 2, 3, 4, 5, 6, 7, and 14 days. BPC 157 (10 microg, 10 ng, 10 pg/kg i.p. (or saline [5 ml/kg]) was first administered after surgery, while it was last given 24 h before either assessment or sacrifice. RESULTS: Throughout the experiment, both higher doses of BPC 157 were shown to improve all parameters of anastomotic wound healing. The formation of adhesions remained slight, the blood vessels were filled with blood, and a mild intestinal passage obstruction was only temporarily observed. Anastomosis without leakage induces markedly higher volume and pressure values, with a continuous increase toward healthy values. From day 1, edema was markedly attenuated and the number of granulocytes decreased, while from days 4 or 5 necrosis decreased and granulation tissue, reticulin, and collagen formation substantially increased, thus resulting in increased epithelization. CONCLUSION: This study showed BPC 157 to have a beneficial effect on ileoileal anastomosis healing in the rat. PMID- 17713733 TI - Primary epithelioid angiosarcoma of the male breast: report of a case. AB - We report a case of primary epithelioid angiosarcoma of the male breast. The patient was a 20-year-old Chinese man who presented with a huge tumor just below the left nipple. Histopathological examination and immunohistochemical analysis confirmed a diagnosis of primary epithelioid angiosarcoma of the male breast, without axillary lymph node metastasis. We review the relevant literature on this rare malignant tumor. PMID- 17713734 TI - Thoracoscopic resection of middle mediastinal noninvasive thymoma: report of a case. AB - We performed thoracoscopic resection of a middle mediastinal noninvasive thymoma in a 69-year-old woman. Chest computed tomography on admission showed a tumor, 75 x 48 x 32 mm in size, and pathological examination revealed a spindle-cell, noninvasive thymoma, of type A according to the World Health Organization classification, and stage I according to the Masaoka staging system. Thymomas are prone to ectopic occurrence, and should be considered in the differential diagnosis of middle mediastinum tumors. PMID- 17713735 TI - Pulmonary inverted Schneiderian papilloma causing high serum levels of carcinoembryonic antigen and squamous cell carcinoma-associated antigen: report of a case. AB - We report a rare case of inverted Schneiderian papilloma causing exceedingly high serum levels of carcinoembryonic antigen (CEA) and squamous cell carcinoma associated antigen (SCC). A 74-year-old man presented with a 6-month history of a productive cough, bloody sputa, and dyspnea. Chest computed tomography showed massive infiltration in the lower lobe with multiple focal soft tissue densities. Blood biochemical analysis revealed a serum CEA level of 107.0 ng/ml (normal <5.0 ng/ml), and an SCC level of 373.0 ng/ml (normal <1.5 ng/ml). Squamous papilloma was diagnosed by histological examination of a bronchoscopic biopsy specimen. To alleviate the patient's symptoms and refine the diagnosis, we performed a right lower lobectomy. The lower lobe of the lung was filled with mucinous sputa and very fragile papillary tumors of various sizes. Microscopic examination revealed papillary growth of stratified epithelial cells with massive mucin production. No nuclear abnormality or invasion of the basal membrane of the tumor cells was observed. Postoperatively, the patient's symptoms resolved quickly, and the serum levels of CEA and SCC decreased to 6.4 ng/ml and 1.7 ng/ml, respectively, within 3 months. PMID- 17713736 TI - Inflammatory aneurysm of the ascending aorta: report of a case. AB - Inflammatory aortic aneurysms are found most commonly in the infrarenal abdominal aorta. We report the case of a 78-year-old man with an inflammatory aortic aneurysm of the ascending aorta, which is extremely unusual. Surgery revealed that the ascending aorta was adherent to the superior vena cava and pulmonary artery, but a dissection membrane was not found. The wall of the ascending aorta was up to 20 mm thick with perianeurysmal fibrosis. Pathologic examination revealed an inflammatory aneurysm with adventitia remarkably thickened by fibrotic tissue and infiltrated by lymphocytes and plasma cells. Our search of the literature found only seven other cases of an inflammatory ascending aortic aneurysm. Preoperative diagnosis was very difficult in most of these cases; however, improved scanning techniques using multidetector row computed tomography may allow the differential diagnosis of this clinical entity. PMID- 17713738 TI - Adult cecoanal intussusception caused by cecum cancer: report of a case. AB - We report a case of cecoanal intussusception caused by cecum cancer in a 29-year old woman. The patient presented to our hospital with a mass protruding from the anus. We manually pushed the mass back into the rectum and performed a gastrograffin enema, which showed a cup-shaped filling defect in the rectum. The defect was moved back to oral side with the pressure of the enema, revealing a tumor originating in the cecum. Colonoscopy showed a protrusion, 5 x 3 cm in size, in the cecum. Laparotomy confirmed that the tumor originated at the bottom of the appendix in the cecum. We performed partial resection of the cecum containing the tumor and appendix. The pathological finding was submucosal adenocarcinoma in adenoma. Cecoanal intussusception is extremely rare and, to our knowledge, this adult case represents the first report documented in the world scientific literature. PMID- 17713737 TI - Pseudoaneurysm of the popliteal artery complicated by peroneal mononeuropathy in a 4-year-old child: report of a case. AB - Pseudoaneurysms of the popliteal artery (PPA) rarely occur in children. In fact, we found only 10 cases reported in the medical literature. We report the case of a 4-year-old boy who presented with a painful palpable mass in the right popliteal fossa. He also had mild, painless right foot-drop and difficulty toe walking on the same side. The diagnosis of a PPA was based on the findings of triplex ultrasound and computed tomographic-angiography. We attributed the cause of the lesion to blunt trauma, which he had suffered 2 years earlier. Thorough preoperative evaluation excluded the possibility of a self-immune process or a bone tumor in the region. Neurological examination demonstrated a mild, isolated, peripheral mononeuropathy of the right peroneal nerve. Thus, we performed surgical repair using an autologous reversed great saphenous vein graft. The patient had an uneventful postoperative course and his peripheral neuropathy and foot-drop resolved completely within 1 month after surgery. Now, after 3 years of follow-up, the patient has a patent graft and a fully functioning limb. PPAs are rare, especially in children, and trauma is the predominating underlying cause. PPAs should be treated immediately after diagnosis because their complications are associated with high rates of functional impairment and even limb loss. PMID- 17713739 TI - Mucinous cystadenocarcinoma of the appendix invading the ascending colon with fistula formation: report of a case. AB - Based on colonoscopy findings, we made a preoperative diagnosis of primary mucinous cystadenocarcinoma of the appendix with features of a submucosal tumor (SMT) in the ascending colon. A 59-year-old woman who presented with right lower quadrant abdominal pain underwent colonoscopy, which revealed an SMT with three nodules covered with mucus in the ascending colon. Examination of colonoscopic biopsy specimens indicated "very" well-differentiated adenocarcinoma with mucus lakes. Abdominal computed tomography showed irregular wall thickness from the cecum to the ascending colon. The adjacent appendix had an enhanced wall and unclear border against the ascending colon. Thus, we performed right hemicolectomy, with good results. Histopathological examination revealed mucinous cystadenocarcinoma of the appendix, invading the ascending colon with fistula formation. Appendiceal tumors can manifest with a variety of colonoscopic features, and curative surgical resection should be attempted even if there is fistula formation. PMID- 17713741 TI - Surgical strategy for advanced gastric cancer with a concomitant thoracoabdominal aortic aneurysm requiring arterial reconstruction of the visceral branches. AB - A 70-year-old man who presented with hematemesis was found to have advanced gastric cancer concomitant with a thoracoabdominal aortic aneurysm (TAAA), which involved all branches of the visceral arteries. The patient underwent the following staged operations: first, radical resection of the advanced gastric cancer with simultaneous reconstruction of the visceral branches, followed 1 month later by endovascular aortic replacement of the TAAA. He recovered uneventfully and was discharged without any paralytic complications or sign of graft infection. PMID- 17713740 TI - Mesenchymal hamartoma of the liver accompanied by a daughter nodule: report of a case. AB - Mesenchymal hamartoma of the liver (MHL) is an uncommon benign tumor found primarily in children younger than 2 years of age. We report a rare case of MHL with a daughter nodule and atypical histological findings in a 14-month-old girl. On admission, computed tomography, magnetic resonance imaging, and angiography showed a solid hypovascular mass with a central cystic area in the liver. Laparotomy revealed a tumor, 8 cm in size, occupying segment 5 and parts of segments 4 and 6 of the liver, and a small nodule, 10 mm in size, in segment 7. Thus, we performed a partial hepatic resection (S4-6) and tumor extirpation (S7). The histological findings of both tumors were the same, but atypical of MHL. Recent studies on the pathogenesis of this tumor have found neoplastic features such as genetic anomalies and malignant transformation. These findings suggest that the conventional approach of completely resecting the tumor whenever possible is the best treatment. PMID- 17713742 TI - Life close to the thermodynamic limit: how methanogenic archaea conserve energy. AB - Methane-forming archaea are strictly anaerobic, ancient microbes that are widespread in nature. These organisms are commonly found in anaerobic environments such as rumen, anaerobic sediments of rivers and lakes, hyperthermal deep sea vents and even hypersaline environments. From an evolutionary standpoint they are close to the origin of life. Common to all methanogens is the biological production of methane by a unique pathway currently only found in archaea. Methanogens can grow on only a limited number of substrates such as H(2) + CO(2), formate, methanol and other methyl group-containing substrates and some on acetate. The free energy change associated with methanogenesis from these compounds allows for the synthesis of 1 (acetate) to a maximum of only 2 mol of ATP under standard conditions while under environmental conditions less than one ATP can be synthesized. Therefore, methanogens live close to the thermodynamic limit. To cope with this problem, they have evolved elaborate mechanisms of energy conservation using both protons and sodium ions as the coupling ion in one pathway. These energy conserving mechanisms are comprised of unique enzymes, cofactors and electron carriers present only in methanogens. This review will summarize the current knowledge of energy conservation of methanogens and focus on recent insights into structure and function of ion translocating enzymes found in these organisms. PMID- 17713743 TI - [Active middle ear implants: more than "just" a hearing aid]. PMID- 17713745 TI - Expression profiles of the genes associated with metabolism and transport of amino acids and their derivatives in rat liver regeneration. AB - Amino acids (AA) are components of protein and precursors of many important biological molecules. To address effects of the genes associated with metabolism and transport of AA and their derivatives during rat liver regeneration (LR), we firstly obtained the above genes by collecting databases data and retrieving related thesis, and then analyzed their expression profiles during LR using Rat Genome 230 2.0 array. The LR-associated genes were identified by comparing the gene expression difference between partial hepatectomy (PH) and sham-operation (SO) rat livers. It was approved that 134 genes associated with metabolism of AA and their derivatives and 26 genes involved in transport of them were LR associated. The initially and totally expressing number of these genes occurring in initial phase of LR (0.5-4 h after PH), G0/G1 (4-6 h after PH), cell proliferation (6-66 h after PH), cell differentiation and structure-function reconstruction of liver tissue (72-168 h after PH) were respectively 76, 17, 79, 5 and 162, 89, 564, 195, illustrating that these LR-associated genes were initially expressed mainly in initial stage, and functioned in different phases. Frequencies of up-regulation and down-regulation of them being separately 564 and 357 demonstrated that genes up-regulated outnumbered those down-regulated. Categorization of their expression patterns into 22 types implied the diversity of cell physiological and biochemical activities. According to expression changes and patterns of the above-mentioned genes in LR, it was presumed that histidine biosynthesis in the metaphase and anaphase, valine metabolism in the anaphase, and metabolism of glutamate, glutamine, asparate, asparagine, methionine, alanine, leucine and aromatic amino acid almost were enhanced in the whole LR; as for amino acid derivatives, transport of neutral amino acids, urea, gamma aminobutyric acid, betaine and taurine, metabolism of dopamine, heme, S adenosylmethionine, thyroxine, and biosynthesis of hydroxyproline, nitric oxide, orinithine, polyamine, carnitine, selenocysteine were augmented during the entire liver restoration. Above results showed that metabolism and transport of AA and their derivates were necessary in liver regeneration. PMID- 17713746 TI - Beneficial impact of L-carnitine in liver: a study in a rat model of syndrome X. AB - The present study was designed to explore whether L-carnitine (CA) regulates insulin signaling and modulates the changes in liver in a well-characterized insulin resistant rat model. Adult male Wistar rats were divided into 4 groups. Groups I and IV animals received starch-based control diet, while groups II and III rats were fed a high fructose-diet (60 g/100 g). Groups III and IV animals additionally received CA (300 mg/kg/day i.p). After a period of 60 days hepatic tyrosine phosphorylation status was determined by assaying protein tyrosine phosphatase (PTP) and protein tyrosine kinase (PTK) activities. Oxidative damage was monitored by immunohistochemical localization of 4-hydroxynonenal (4-HNE), 3 nitrotyrosine (3-NT) and dinitrophenol (DNP)-protein adducts. In addition protein kinase C beta II (PKC beta II) expression, propidium iodide staining of isolated hepatocytes and histology of liver tissue were determined to examine liver integrity. Fructose-fed rats displayed reduced insulin action, increased expression of PKC beta II, altered histology, fragmentation of hepatocyte nuclear DNA, and accumulation of oxidatively modified proteins. Simultaneous treatment with CA alleviated the abnormalities associated with fructose feeding. In summary the data suggest that elevated oxidative damage and PKC expression could in part induce insulin resistance and CA has beneficial impact on liver during insulin resistance with modulatory effects at the post-receptor level. PMID- 17713744 TI - Amino acids supply in culture media is not a limiting factor in the matrix synthesis of engineered cartilage tissue. AB - Increased amino acid supplementation (0.5 x, 1.0 x, and 5.0 x recommended concentrations or additional proline) was hypothesized to increase the collagen content in engineered cartilage. No significant differences were found between groups in matrix content or dynamic modulus. Control constructs possessed the highest compressive Young's modulus on day 42. On day 42, compared to controls, decreased type II collagen was found with 0.5 x, 1.0 x, and 5.0 x supplementation and significantly increased DNA content found in 1.0 x and 5.0 x. No effects were observed on these measures with added proline. These results lead us to reject our hypothesis and indicate that the low collagen synthesis in engineered cartilage is not due to a limited supply of amino acids in media but may require a further stimulatory signal. The results of this study also highlight the impact that culture environment can play on the development of engineered cartilage. PMID- 17713748 TI - [Arthroscopic treatment of posterior shoulder instability: technique and results]. AB - Posterior shoulder instability occurs in approximately 2-5% of all cases of shoulder instability and treatment is still challenging. Open capsular plication procedures are described, but significant complications and risks have been reported in the literature. Arthroscopy has led to a better understanding of the pathoanatomy of posterior shoulder instability in recent years. We present our operative technique and the results of arthroscopic posterior shoulder stabilisation for the management of posterior shoulder instability. Sixteen patients with posterior shoulder instability were treated by arthroscopic posterior stabilisation from January 2004 to March 2005. There were 11 male and 5 female patients. The mean age was 24 (15-45) years. Nine patients had a unidirectional posterior instability. Seven patients had a predominantly posterior instability based on a multidirectional instability. Fourteen patients were evaluated after a mean follow-up of 12 (6-18) and 20 (14-26) months. Stability, range of motion and function were assessed using the Rowe score. The average Rowe score improved from pre-operative 32 (20-40) points to post operative 87 (40-100) points after the first follow-up and 90 (40-100) points after the second follow-up. Furthermore subjective shoulder function was evaluated using a visual analog scale. The average score improved from pre operative 3 (0-6) points to post-operative 8 (4-10) points after the first and second follow-up. At the first follow-up 93% of the patients had a stable shoulder; 85% had a stable shoulder after arthroscopic stabilisation at the second follow-up. Arthroscopic treatment for posterior shoulder instability is a demanding procedure. Due to a special operative technique with specific instruments soft tissue pathologies found in this type of instability such as capsular redundancy and labral tears can be addressed. Our results show that it can be used as an effective tool for the treatment of posterior shoulder instability. PMID- 17713747 TI - [Hypertension and cardiac failure]. AB - Arterial hypertension is the leading cause of mortality and morbidity with a worldwide prevalence of 26%. Aging increases the incidence of arterial hypertension. Arterial hypertension is the prime example for a chronic disease with asymptomatic beginning, creeping course and fatal outcome. Arterial hypertension is a major cardiovascular risk factor and leads to vascular as well as myocardial manifestations: coronary artery disease, hypertensive microvascular disease, concentric left ventricular hypertrophy as well as perivascular and interstitial fibrosis. In the late stages of the disease, hypertrophy and cardiac failure develop. Arterial hypertension is the leading cause of coronary artery disease and cardiac failure, and coronary artery disease is the cause of heart failure in 50% of cases. Various non-invasive and invasive procedures are available for screening and follow-up. The primary therapeutic target is to reverse cardiac manifestations of arterial hypertension using specific therapeutic algorithms as well as lowering blood pressure. This article covers the pathophysiology of arterial hypertension and cardiac failure, clinical symptoms, diagnostic options and therapeutical goals as well as medicinal options. PMID- 17713749 TI - [Injury prevention as the physician's challenge]. AB - In Germany, more than 9 million individuals yearly sustain injuries and more than 30,000 fatal injuries. Based on estimations, preventive measures could avoid more than one half of all accidents and could influence the other half of the accidents such that the injuries caused are minor. The aim of an initiative of the Study Group on Injury Prevention of the German Trauma Society (DGU) is a complete inventory of all prevention programs from different expert groups in Germany. A synopsis of the gathered knowledge should serve as a basis for further interdisciplinary preventive measures. The consistent interdisciplinary orientation of this program is a special characteristic including trauma surgery, orthopedics, pediatric surgery, pediatrics, sociology, legal medicine, psychology, sports medicine, geriatrics, anesthesiology, and others. Special attention was also directed to the age groups of children/adolescents and the elderly. PMID- 17713751 TI - Do anthropogenic transports facilitate stored-product pest moth dispersal? A molecular approach. AB - Stored-product moths cause large economic damage in food processing industries and storage facilities. Control of indoor pests is currently dealt with locally, and control strategies seldom include different mills or cooperative industries in joint efforts to reduce infestations. In colder climates where conditions hinder flight dispersal of stored-product moths, we hypothesize that human transport between mills will facilitate dispersal. Albeit considered intuitive, this hypothesis has so far never been tested. Male moths from three mills (populations) in southern Sweden and Denmark were collected and by using amplified fragment length polymorphism (AFLP) pair-wise F(st) values were calculated. Cluster (population) origins of the genotypes were computed by using a model-based method, structure. The results suggest that known transportation of flour between two mills generate genetically more similar populations of the economically important stored-product moth, Ephestia kuehniella (Zell.) (Lepidoptera; Pyralidae), compared to the third mill, with another distribution area, but situated geographically in between the other mills. The structure model placed the sampled genotypes to belong to either two or five original populations, with a higher probability of two original populations. The third mill was consistently different from the other two mills independent of the models' calculated number of populations. Although the study was restricted to three mills and one transportation route, it highlights the possibility that transportation of food products promotes genetic mixing (i.e. dispersal) of insect pest populations. Including cooperating mills in control (or monitor) strategy schemes against stored-product pest insects would therefore be a more effective action, rather than to treat each mill separately. PMID- 17713750 TI - Measurement of flow speed in the channels of novel threadlike structures on the surfaces of mammalian organs. AB - There have been several reports on novel threadlike structures (NTSs) on the surfaces of the internal organs of rats and rabbits since their first observation by Bonghan Kim in 1963. To confirm this novel circulatory function, it is necessary to observe the flow of liquid through the NTS as well as the structurally corroborating channels in the NTS. In this article, we report on the measurement of the flow speed of Alcian blue solution in the NTSs on the organ surfaces of rabbits, and we present electron microscopic images depicting the cribrous cross-section with channels. The speed was measured as 0.3 +/- 0.1 mm/s, and the flow distance was up to 12 cm. The flow was unidirectional, and the phase contrast microscopic images showed that the NTSs were strongly stained with Alcian blue. The ultrastructure of the NTSs revealed by cryo-scanning electron microscopy and high-voltage electron microscopy showed that (1) there were cell like bodies and globular clumps of matter inside the sinus of the channel with thin strands of segregated zones which is a microscopic evidence of the liquid flow, (2) the sinuses have wall structures surrounded with extracellular matrices of collagenous fibers, and (3) there exists a cribriform structure of sinuses. To understand the mechanism for the circulation, a quantitative analysis of the flow speed has been undertaken applying a simplified windkessel model. In this analysis, it was shown that the liquid flow through the NTSs could be due to peristaltic motion of the NTS itself. PMID- 17713752 TI - [Multiple sclerosis and Epstein-Barr virus : new developments and perspectives]. AB - Data from studies of twins and migrants with multiple sclerosis (MS) imply environmental factors in the development of MS. In this respect, increasing evidence indicates that Epstein-Barr virus (EBV) plays a unique role as an infectious risk factor for MS. A nearly 100% seroprevalence of antibodies to EBV in patients with MS, elevated EBV antibody titers years before clinical onset of the disease, and an increased risk for MS after symptomatic primary EBV infection (infectious mononucleosis) suggest an association of MS with a previous infection with EBV. However, the precise mechanisms through which EBV may contribute to MS are still unclear. Currently discussed potential mechanisms are outlined. The notion of a persisting (possibly immunological) change caused during the acute phase of primary EBV infection and subsequently leading to permanently elevated MS risk appears compatible with several aspects of the association found between MS and EBV. PMID- 17713753 TI - [Nephrogenic systemic fibrosis as an adverse drug reaction of gadolinium-based contrast media for magnetic resonance imaging]. AB - Nephrogenic systemic fibrosis (NSF) was first described as nephrogenic fibrosing dermopathy (NFD), a disease occurring exclusively in patients with severe renal insufficiency. Recently NSF was recognised to be a very rare adverse drug reaction (ADR) of gadolinium-based contrast media for magnetic resonance imaging (MRI). Over 200 million applications of gadolinium-based contrast agents have been performed worldwide, including about 80 million of Magnevist and 33 million of Omniscan. Cases of NSF have been reported so far only for Omniscan (180 including 77 from the EU), for Magnevist (78 including 9 from the EU, 4 of which were also exposed to Omniscan) and for OptiMARK, which is not authorized in the EU. Because of this risk an EU-wide contraindication was ordered for patients with severe renal failure for the use of Omniscan (gadodiamid), which is one of eight gadolinium-based substances authorized in Germany and the EU and which has the highest risk potential, and just recently also for Magnevist (gadopentetate dimeglumine). Whether similar measures will be implemented for other gadolinium based substances, for which no cases of NSF have been reported, but a risk potential may exist, is still under discussion. PMID- 17713754 TI - [Indications and contraindications for contrast-enhanced MRI and CT during pregnancy]. AB - There are no reports about negative effects on the fetus of the application of gadolinium-containing contrast media to pregnant mothers. Iodine-containing contrast media may lead to a transient hypothyroidism in the newborn. This will be detected with certainty by the neonatal TSH screening. Iodine- or gadolinium containing contrast media may be used in pregnant women if indispensable. In the gut of breastfed children less than 1% of the recommended pediatric doses of contrast media are found after both types of contrast media have been given to their mothers. Therefore there are no reasons against the use of contrast media during the nursing period. PMID- 17713755 TI - Genetic dissection of grain yield in bread wheat. I. QTL analysis. AB - Grain yield forms one of the key economic drivers behind a successful wheat (Triticum aestivum L.) cropping enterprise and is consequently a major target for wheat breeding programmes. However, due to its complex nature, little is known regarding the genetic control of grain yield. A doubled-haploid population, comprising 182 individuals, produced from a cross between two cultivars 'Trident' and 'Molineux', was used to construct a linkage map based largely on microsatellite molecular makers. 'Trident' represents a lineage of wheat varieties from southern Australia that has achieved consistently high relative grain yield across a range of environments. In comparison, 'Molineux' would be rated as a variety with low to moderate grain yield. The doubled-haploid population was grown from 2002 to 2005 in replicated field experiments at a range of environments across the southern Australian wheat belt. In total, grain yield data were recorded for the population at 18 site-year combinations. Grain yield components were also measured at three of these environments. Many loci previously found to be involved in the control of plant height, rust resistance and ear-emergence were found to influence grain yield and grain yield components in this population. An additional nine QTL, apparently unrelated to these traits, were also associated with grain yield. A QTL associated with grain yield on chromosome 1B, with no significant relationship with plant height, ear-emergence or rust resistance, was detected (LOD > or =2) at eight of the 18 environments. The mean yield, across 18 environments, of individuals carrying the 'Molineux' allele at the 1B locus was 4.8% higher than the mean grain yield of those lines carrying the 'Trident' allele at this locus. Another QTL identified on chromosome 4D was also associated with overall gain yield at six of the 18 environments. Of the nine grain yield QTL not shown to be associated with plant height, phenology or rust resistance, two were located near QTL associated with grain yield components. A third QTL, associated with grain yield components at each of the environments used for testing, was located on chromosome 7D. However, this QTL was not associated with grain yield at any of the environments. The implications of these findings on marker-assisted selection for grain yield are discussed. PMID- 17713756 TI - Haplotype analysis of vernalization loci in European barley germplasm reveals novel VRN-H1 alleles and a predominant winter VRN-H1/VRN-H2 multi-locus haplotype. AB - In barley, variation in the requirement for vernalization (an extended period of low temperature before flowering can occur) is determined by the VRN-H1, -H2 and H3 loci. In European cultivated germplasm, most variation in vernalization requirement is accounted for by alleles at VRN-H1 and VRN-H2 only, but the range of allelic variation is largely unexplored. Here we characterise VRN-H1 and VRN H2 haplotypes in 429 varieties representing a large portion of the acreage sown to barley in Western Europe over the last 60 years. Analysis of genotype, intron I sequencing data and growth habit tests identified three novel VRN-H1 alleles and determined the most frequent VRN-H1 intron I rearrangements. Combined analysis of VRN-H1 and VRN-H2 alleles resulted in the classification of seventeen VRN-H1/VRN-H2 multi-locus haplotypes, three of which account for 79% of varieties. The molecular markers employed here represent powerful diagnostic tools for prediction of growth habit and assessment of varietal purity. These markers will also allow development of germplasm to test the behaviour of individual alleles with the aim of understanding the relationship between allelic variation and adaptation to specific agri-environments. PMID- 17713758 TI - The highly toxic oxyanion tellurite (TeO (3) (2-) ) enters the phototrophic bacterium Rhodobacter capsulatus via an as yet uncharacterized monocarboxylate transport system. AB - The facultative phototroph Rhodobacter capsulatus takes up the highly toxic oxyanion tellurite when grown under both photosynthetic and respiratory growth conditions. Previous works on Escherichia coli and R. capsulatus suggested that tellurite uptake occurred through a phosphate transporter. Here we present evidences indicating that tellurite enters R. capsulatus cells via a monocarboxylate transport system. Indeed, intracellular accumulation of tellurite was inhibited by the addition of monocarboxylates such as pyruvate, lactate and acetate, but not by dicarboxylates like malate or succinate. Acetate was the strongest tellurite uptake antagonist and this effect was concentration dependent, being already evident at 1 microM acetate. Conversely, tellurite at 100 microM was able to restrict the acetate entry into the cells. Both tellurite and acetate uptakes were energy dependent processes, since they were abolished by the protonophore FCCP and by the respiratory electron transport inhibitor KCN. Interestingly, cells grown on acetate, lactate or pyruvate showed a high level resistance to tellurite, whereas cells grown on malate or succinate proved to be very sensitive to the oxyanion. Taking these data together, we propose that: (a) tellurite enters R. capsulatus cells via an as yet uncharacterized monocarboxylate(s) transporter, (b) competition between acetate and tellurite results in a much higher level of tolerance against the oxyanion and (c) the toxic action of tellurite at the cytosolic level is significantly restricted by preventing tellurite uptake. PMID- 17713757 TI - [Imaging in evaluating rotator cuff tears]. AB - Diagnostic imaging in a patient with shoulder pain should be used only after a comprehensive clinical evaluation of the shoulder. X-ray and ultrasonography are the basic diagnostic tools; computed tomography and magnetic resonance imaging (MRI) should be used only with certain indications. Ultrasonography and MRI have comparable accuracy for identifying and measuring full-thickness rotator cuff tears, but the accuracy for identifying partial-thickness still needs to be improved. MR arthrography has significantly improved sensitivity and specificity for partial-thickness tears of the cuff. Only ultrasound provides a real-time examination tool during shoulder movements. Moreover, dynamic ultrasonography can assess the contraction patterns of the supraspinatus and infraspinatus muscles, which may improve decision making in the treatment of shoulder diseases. In depicting fatty atrophy of the supraspinatus and infraspinatus muscles, MRI remains the reference standard. MRI should not be used as a diagnostic screening tool in patients with chronic shoulder pain because it does not appear to significantly affect treatment or outcome. PMID- 17713759 TI - Properties of Bacillus anthracis spores prepared under various environmental conditions. AB - Bacillus anthracis makes highly stable, heat-resistant spores which remain viable for decades. Effect of various stress conditions on sporulation in B. anthracis was studied in nutrient-deprived and sporulation medium adjusted to various pH and temperatures. The results revealed that sporulation efficiency was dependent on conditions prevailing during sporulation. Sporulation occurred earlier in culture sporulating at alkaline pH or in PBS than control. Spores formed in PBS were highly sensitive towards spore denaturants whereas, those formed at 45 degrees C were highly resistant. The decimal reduction time (D-10 time) of the spores formed at 45 degrees C by wet heat, 2 M HCl, 2 M NaOH and 2 M H(2)O(2) was higher than the respective D-10 time for the spores formed in PBS. The dipicolinic acid (DPA) content and germination efficiency was highest in spores formed at 45 degrees C. Since DPA is related to spore sensitivity towards heat and chemicals, the increased DPA content of spores prepared at 45 degrees C may be responsible for increased resistance to wet heat and other denaturants. The size of spores formed at 45 degrees C was smallest amongst all. The study reveals that temperature, pH and nutrient availability during sporulation affect properties of B. anthracis spores. PMID- 17713760 TI - Lack of evidence for reduced prefrontal cortical serotonin and dopamine efflux after acute tryptophan depletion. AB - RATIONALE: Acute tryptophan depletion (ATD) is a widely used method to study the role of serotonin (5-HT) in affect and cognition. ATD results in a strong but transient decrease in plasma tryptophan and central 5-HT synthesis and availability. Although its use is widespread, the evidence that the numerous functional effects of ATD are caused by actual changes in 5-HT neuronal release is not very strong. Thus far, decreases in 5-HT efflux (thought to reflect synaptic release) were only reported after chronic tryptophan depletion or when ATD was combined with blockade of 5-HT reuptake. OBJECTIVE: With the current experiment, we aimed to study the validity of the method of ATD by measuring the extent to which it reduces the efflux of 5-HT (and dopamine) in the prefrontal cortex in the absence of reuptake blockage. MATERIALS AND METHODS: We simultaneously measured in freely moving animals plasma tryptophan via a catheter in the jugular vein and 5-HT and DA efflux in the medial prefrontal cortex through microdialysis after ATD treatment. RESULTS: ATD reduced plasma tryptophan to less than 30% of control, without affecting 5-HT or DA efflux in the prefrontal cortex, indicating that even strong reductions of plasma tryptophan do not necessarily result in decreases in central 5-HT efflux. CONCLUSION: The present experiment showed that reductions in plasma tryptophan, similar to values associated with behavioural effects, do not necessarily reduce 5-HT efflux and suggest that the cognitive and behavioural effects of ATD may not be (exclusively) due to alterations in 5-HT release. PMID- 17713761 TI - Application of high-performance liquid chromatography-tandem mass spectrometry with a quadrupole/linear ion trap instrument for the analysis of pesticide residues in olive oil. AB - This article describes the development of an enhanced liquid chromatography-mass spectrometry (LC-MS) method for the analysis of pesticides in olive oil. One hundred pesticides belonging to different classes and that are currently used in agriculture have been included in this method. The LC-MS method was developed using a hybrid quadrupole/linear ion trap (QqQ(LIT)) analyzer. Key features of this technique are the rapid scan acquisition times, high specificity and high sensitivity it enables when the multiple reaction monitoring (MRM) mode or the linear ion-trap operational mode is employed. The application of 5 ms dwell times using a linearly accelerating (LINAC) high-pressure collision cell enabled the analysis of a high number of pesticides, with enough data points acquired for optimal peak definition in MRM operation mode and for satisfactory quantitative determinations to be made. The method quantifies over a linear dynamic range of LOQs (0.03-10 microg kg(-1)) up to 500 microg kg(-1). Matrix effects were evaluated by comparing the slopes of matrix-matched and solvent-based calibration curves. Weak suppression or enhancement of signals was observed (<15% for most-80 of the pesticides). A study to assess the identification criteria based on the MRM ratio was carried out by comparing the variations observed in standard vs matrix (in terms of coefficient of variation, CV%) and within the linear range of concentrations studied. The CV was lower than 15% when the response observed in solvent was compared to that in olive oil. The limit of detection was < or =10 microg kg(-1) for five of the selected pesticides, < or =5 microg kg(-1) for 14, and < or =1 microg kg(-1) for 81 pesticides. For pesticides where additional structural information was necessary for confirmatory purposes-in particular at low concentrations, since the second transition could not be detected-survey scans for enhanced product ion (EPI) and MS3 were developed. PMID- 17713762 TI - Apparent diffusion coefficient in vasogenic edema and reactive astrogliosis. AB - INTRODUCTION: Distinguishing between vasogenic edema and reactive astrogliosis may be difficult in some instances. This study was performed to test the hypothesis that diffusion-weighted (DW) imaging with apparent diffusion coefficient (ADC) maps can be used to differentiate these two types of changes. METHODS: The study population included 11 patients with perilesional vasogenic edema and 11 patients with gliosis examined with conventional MR imaging and DW imaging. The signal intensities of conventional pulse sequences and ADC values were calculated in regions of interest placed in the hyperintense edematous or gliotic regions and compared with those of normal-appearing white matter. Signal intensity ratios and ADC values in gliosis were compared with those in vasogenic edema using the Mann-Whitney U-test. RESULTS: While considerable overlap was present for signal intensity ratios on conventional MR images, areas of gliosis demonstrated significantly higher ADC values (1.76 +/- 0.09 x 10(-3) mm(2)/s) than areas of vasogenic edema (1.35 +/- 0.06 x 10(-3) mm(2)/s; P < 0.0001) without overlap. CONCLUSION: ADC values are helpful in differentiating reactive gliosis from vasogenic edema. PMID- 17713763 TI - The state of the art in the analysis of two-dimensional gel electrophoresis images. AB - Software-based image analysis is a crucial step in the biological interpretation of two-dimensional gel electrophoresis experiments. Recent significant advances in image processing methods combined with powerful computing hardware have enabled the routine analysis of large experiments. We cover the process starting with the imaging of 2-D gels, quantitation of spots, creation of expression profiles to statistical expression analysis followed by the presentation of results. Challenges for analysis software as well as good practices are highlighted. We emphasize image warping and related methods that are able to overcome the difficulties that are due to varying migration positions of spots between gels. Spot detection, quantitation, normalization, and the creation of expression profiles are described in detail. The recent development of consensus spot patterns and complete expression profiles enables one to take full advantage of statistical methods for expression analysis that are well established for the analysis of DNA microarray experiments. We close with an overview of visualization and presentation methods (proteome maps) and current challenges in the field. PMID- 17713764 TI - What can gallium-68 PET add to receptor and molecular imaging? PMID- 17713765 TI - The efficacy of whole-body FDG-PET or PET/CT for autoimmune pancreatitis and associated extrapancreatic autoimmune lesions. AB - PURPOSE: The aim of this study was to evaluate retrospectively the efficacy of whole-body (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) for autoimmune pancreatitis (AIP) and associated extrapancreatic autoimmune lesions. METHODS: Whole-body FDG-PET or PET/computed tomography (CT) findings were reviewed in six patients with AIP. The initial PET scans were performed 1 h and 2 h after FDG injection in all six patients. Follow-up PET scans were performed during or following steroid therapy in five patients and in one patient who did not have steroid therapy. RESULTS: The initial PET scans revealed intense FDG uptake by AIP in all six patients. The maximum standardized uptake value (SUVmax) increased in four patients and was stable in two patients. The intense uptake in the pancreas disappeared during or following steroid therapy in five patients and in one patient who showed spontaneous remission of AIP. Abnormal FDG uptake by extrapancreatic autoimmune diseases was observed in five of the six patients: sclerosing sialadenitis (n = 5), lymphadenopathy (n = 5), retroperitoneal fibrosis (n = 2), interstitial nephritis (n = 2) and sclerosing cholecystitis (n = 1). Abnormal FDG uptake disappeared in the salivary glands (n = 4), lymph nodes (n = 4), retroperitoneum (n = 2), kidneys (n = 1) and gallbladder (n = 1) during or following steroid therapy and remained in the salivary glands and lymph nodes of a spontaneous remission patient. CONCLUSION: These results suggest that whole body FDG-PET may be useful for detecting AIP and associated extrapancreatic autoimmune lesions and for monitoring their disease activity but that dual time point imaging may not be useful for differentiating malignancy from AIP. PMID- 17713766 TI - The impact of 18F-FDG PET/CT in patients with liver metastases. AB - PURPOSE: The aim of this study was to assess the performance of (18)F fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) versus dedicated contrast-enhanced CT (CECT) in the detection of metastatic liver disease. METHODS: All patients that presented to our Institution with suspected metastatic liver disease who underwent (18)F-FDG PET/CT and CECT within 6 weeks of each other, were retrospectively analyzed, covering a 5-year period. One hundred and thirty-one patients (67 men, 64 women; mean age 62) were identified. Seventy-five had colorectal carcinoma and 56 had other malignancies. The performance of CECT and that of (18)F-FDG-PET/CT in detecting liver metastases were compared. The ability of each to detect local recurrence, extrahepatic metastases and to alter patient management was recorded. The final diagnosis was based on histology, clinical and radiological follow-up (mean 23 months). RESULTS: In detecting hepatic metastases, (18)F-FDG-PET/CT yielded 96% sensitivity and 75% specificity, whilst CECT showed 88% sensitivity and 25% specificity. (18)F-FDG-PET/CT and CECT were concordant in 102 out of 131 patients (78%). In the colorectal group (18)F-FDG-PET/CT showed 94% sensitivity and 75% specificity, whilst CECT had 91% sensitivity and 25% specificity. In the noncolorectal group (18)F-FDG-PET/CT showed 98% sensitivity and 75% specificity whilst CECT had 85% sensitivity and 25% specificity. Overall, (18)F-FDG-PET/CT altered patient management over CECT in 25% of patients. CECT did not alter patient management over (18)F-FDG-PET/CT alone in any patients. CONCLUSION: (18)F FDG-PET/CT performed better in detecting metastatic liver disease than CECT in both colorectal and noncolorectal malignancies, and frequently altered patient management. The future role of CECT in these patients may need to be re-evaluated to avoid potentially unnecessary duplication of investigation where (18)F-PET/CT is readily available. PMID- 17713767 TI - Spatial orientation in the bushcricket Leptophyes punctatissima (Phaneropterinae; Orthoptera): III. Peripheral directionality and central nervous processing of spatial cues. AB - We examined peripheral and central nervous cues underlying the ability of the bushcricket Leptophyes punctatissima to orient to elevated and depressed sound sources broadcasting the female acoustic reply. The peripheral spatial directionality of the ear was measured physiologically using monaural preparations of an auditory interneuron (T-fibre). In the azimuth, maximal interaural intensity differences of 18 dB occur between ipsi- and contralateral stimulation. With increasing elevation or depression of the sound sources, IIDs decrease systematically and reach zero with the source exactly above or below the preparation. Bilateral, simultaneous recordings of the activity of the pair of interneurons allowed determining the binaural discharge differences which occur in response to the extremely short (1 ms) female reply. These discharge differences are large (four action potentials/stimulus) and reliable in the azimuth with lateral stimulation, and decrease gradually with more frontal stimulation. With elevation and depression of sound sources these differences again decrease to one action potential/stimulus at 60 degrees or 75 degrees elevation, and lateral stimulus angles of about 60 degrees . We also calculated the reliability with which a receiver could correctly determine the location of the sound source. We discuss these quantitative measures in relation to the spatial phonotactic behaviour of male L. punctatissima. PMID- 17713768 TI - Mechanoreception by cuticular sensilla on the pectines of the scorpion Pandinus cavimanus. AB - On the pectines of scorpions, several types of cuticular receptors are located. Of these receptors, only the chemo- and mechanosensory peg sensilla have been studied so far while the response characteristics of the long, straight hair sensilla are unknown. As these sensilla protrude in the walking direction and to the ground, we assume that these receptors are most likely involved in observed reflex behaviours. The sensilla constitute rather robust shafts, comparable to other touch-receptors. Their innervation pattern reveals that 5-6 sensory cells are associated with one sensillum. It was possible to record up to three different spike classes (units) which could be distinguished by size, response characteristics and conduction velocity. Two units were analysed in more detail. The response characteristics showed two phasic units, one large and one small, coding the velocity of a stimulus. One medium-sized unit showed phasic-tonic characteristics, coding also the duration of a stimulus. Taking together the morphological and electrophysiological results, we suggest that these sensilla belong to the group of long hair sensilla distributed all over the scorpion body. Furthermore, their response characteristics and the timing between sensory and motor activity within the pectine nerve enable them to be involved in reflex behaviours. PMID- 17713769 TI - Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. AB - Pathological TDP-43 is the major disease protein in frontotemporal lobar degeneration characterized by ubiquitin inclusions (FTLD-U) with/without motor neuron disease (MND) and in amyotrophic lateral sclerosis (ALS). As Guamanian parkinsonism-dementia complex (PDC) or Guamanian ALS (G-PDC or G-ALS) of the Chamorro population may present clinically similar to FTLD-U and ALS, TDP-43 pathology may be present in the G-PDC and G-ALS. Thus, we examined cortical or spinal cord samples from 54 Guamanian subjects for evidence of TDP-43 pathology. In addition to cortical neurofibrillary and glial tau pathology, G-PDC was associated with cortical TDP-43 positive dystrophic neurites and neuronal and glial inclusions in gray and/or white matter. Biochemical analyses showed the presence of FTLD-U-like insoluble TDP-43 in G-PDC, but not in Guam controls (G C). Spinal cord pathology of G-PDC or G-ALS was characterized by tau positive tangles as well as TDP-43 positive inclusions in lower motor neurons and glial cells. G-C had variable tau and negligible TDP-43 pathology. These results indicate that G-PDC and G-ALS are associated with pathological TDP-43 similar to FTLD-U with/without MND as well as ALS, and that neocortical or hippocampal TDP 43 pathology distinguishes controls from disease subjects better than tau pathology. Finally, we conclude that the spectrum of TDP-43 proteinopathies should be expanded to include neurodegenerative cognitive and motor diseases, affecting the Chamorro population of Guam. PMID- 17713770 TI - Internal fixation of traumatic diastasis of pubic symphysis: is plate removal essential? AB - INTRODUCTION: Internal fixation of the traumatic diastasis of symphysis pubis is an integral part of the definitive management of pelvic ring injuries. Both functional outcome and long term physiological effects of plate retention have not been clearly addressed and no specific indications regarding implant removal have been proposed in the literature. MATERIALS AND METHODS: We reviewed 74 patients (18 females and 56 males), with an average age of 40.6 (16-75) years, who underwent open reduction and internal fixation (ORIF) of the pubic symphysis. Except from the demographic data many other parameters like suprapubic pain, sexual disturbance, impotence and dyspareunia were taken under consideration. Furthermore, any correlation between implant failure and functional impairment was recorded and the subject of implant removal in pregnant women was examined. Health outcome was assessed according to EuroQol 5-D (EQ-5D) questionnaire. Mean follow up: 41.7 (28-89) months. RESULTS: Suprapubic pain was present in ten patients. Three men developed neurogenic impotence and one woman had deep dyspareunia. None of these symptoms were related to implant status. Three of the four females who had uncomplicated pregnancy in the post-stabilization period had the plate in situ. Implant failure was seen in four patients but they remained asymptomatic. EQ-5D questionnaire revealed high satisfaction scores among young women and men of all age groups. CONCLUSION: This study supports the view that routine removal of the plate is not essential. The issue of whether the implant needs to be removed in women of childbearing age requires further investigation. PMID- 17713771 TI - Outcome after open reduction and angular stable internal fixation for supra intercondylar fractures of the distal humerus: preliminary results with the LCP distal humerus system. AB - INTRODUCTION: Fractures of the distal humerus are complex injuries that can be effectively treated with open reduction and internal fixation (ORIF). The new LCP distal humerus system allows angular stable fixation of these complex fractures with anatomically preshaped plates. The aim of the study was to evaluate operative reposition, fracture healing, and pain, function and patient satisfaction after open reduction with an angular stable fixation. METHODS: Fourteen patients with a mean age of 55.2 years (21-83) were treated with open reduction and angular stable internal fixation. Two patients were lost to follow up (1 died, one refused to be reevaluated). AO classification showed 12 C fractures (1 x C 1.1; 1 x C 1.3; 4 x C 2.2; 4 x C 3.2; 2 x C 3.3) and 2 B fracture (B 2.3 and B 3.3). 5 fractures were open fractures (4 x II degrees , 1 x I degrees ). The clinical and radiographic follow up (Mayo elbow performance score (MEPS), Dash Score, elbow anterior-posterior and lateral view X-rays, and flexion and extension force as % of contralateral side at 90 degrees flexion) were performed postoperatively. Mean follow up was 10 months. RESULTS: Radiographically, complete union was achieved in all patients. There were no cases of primary malposition or secondary dislocation. Complications were: (1) delayed union after olecranon osteotomy, (2) transient ulnar nerve irritation. Clinical MEPS results were good to excellent with a mean of 91 +/- 11.7 points. The mean DASH Score was 18.5 +/- 11.5 points. Mean flexion was 121 +/- 20.9, mean extension deficit was 17.9 degrees +/- 10.3. Mean flexion force was 75.3% +/- 26.7 and mean extension force was 70.7 % +/- 24.9. CONCLUSION: Treatment of supra intercondylar fractures of the distal humerus is challenging. Anatomically preshaped angular stable implants facilitate operative reduction and stabilization of the fracture and may allow early postoperative rehabilitation. Clinical and radiological results are promising, with good range of motion and flexion and extension force. PMID- 17713772 TI - Dislocation of the elbow with fractures of the coronoid process and radial head. AB - INTRODUCTION: The aim of the study was to evaluate the factors relevant to prognosis after operative treatment of an elbow dislocation/fracture involving the coronoid process and the radial head. In 30-50% of cases, elbow dislocations are accompanied by concomitant bony injuries. Here, the ulnar coronoid process and the radial head are particularly crucial to the stability of the elbow joint. MATERIALS AND METHODS: In a retrospective study, 27 out of 37 patients who were treated surgically in our clinic between 1990 and 1999 for elbow dislocation with involvement of the coronoid process and the radial head were examined after an average of 36 months. RESULTS: According to the criteria of the Morrey Score, 2 patients achieved an extremely good therapeutic result, 10 patients a good therapeutic result and 12 patients a moderate therapeutic result. A poor result was achieved in three cases. CONCLUSION: Elbow dislocations with involvement of the ulnar coronoid process and the radial head are complex injuries and their surgical treatment and aftercare need to be handled by a skilled and experienced traumatologist. In this process, the precondition for regaining a stable joint with good function is, above all, early, exercise-stable fixation and/or reconstruction of the coronoid process and early functional mobilization of the joint. PMID- 17713773 TI - Diagnostic and therapeutic problems of giant cell tumor in the proximal femur. AB - Primaly giant cell tumor of bone (GCT) in the proximal femur is relatively rare, and can prove difficult to diagnose, and can require therapeutic methods. Subjects comprised 10 patients (8 males, 2 females). Mean patient age was 27.5 years, and mean follow-up was 89.9 months. Tumors in the present study were limited to H1 and H2 according to the International Society of Limb Salvage (ISOLS) system. All patients received surgical treatment only. Second surgery after preoperative open biopsy was performed for two patients, while the remaining eight patients received excisional biopsy to determine treatment methods using rapid intraoperative pathological examination of frozen sections. The mean functional score was 28.2 out of 30 (93.9%). Local recurrence was observed in two patients. The long-term follow-up reveals that one of the important problem is pre-operative diagnosis. Excisional biopsy is effective for surgery of GCT in the proximal femur. PMID- 17713774 TI - Arthroscopy prior to osteotomy around the knee? AB - INTRODUCTION: Osteotomy around the knee is well established in orthopaedic surgery in cases of congenital/posttraumatic leg deformities with mono compartment osteoarthritis of the knee. However, there is no consensus whether there should be an arthroscopy prior to osteotomy in the same operative session, either for diagnostic or therapeutic reasons. PATIENTS AND METHODS: This prospective study included 340 cases of osteotomy around the knee with a routine arthroscopy. During arthroscopy indication for osteotomy was checked first. Then cartilage status was determined to modify type and degree of correction osteotomy accordingly. Finally therapeutic procedures were performed in cases of intraarticular pathologies. RESULTS: Indication was rejected in 47 cases with ten patients receiving endoprosthetic treatment. In 157 cases the degree of correction was modified, in eleven cases the level of osteotomy. Under the 330 non-endoprothetic sessions there were 316 arthroscopies with therapeutic treatments. CONCLUSION: This study could demonstrate that arthroscopy in the same session is indispensable, to check the indication for osteotomy, to modify type and degree of correction according to cartilage status and to perform therapeutic procedures. PMID- 17713775 TI - Foreign body reaction due to polyethylene's wear after implantation of an interspinal segment. AB - Different interspinous implants are used as minimal invasive intervention in the management of degenerative disorders of the lumbar spine. We present a case with foreign body reaction due to polyethylene's wear after a device for intervertebral assisted motion (DIAM) implantation. We conclude that the polyethylene interspinous devices can cause biological response, therefore; the surgeons and the companies should carefully watch their patients following application of such devices. PMID- 17713776 TI - Acute promyelocytic leukemia: an unusual cause showing prolonged disseminated intravascular coagulation after placental abruption. AB - BACKGROUND: Disseminated intravascular coagulation (DIC) caused by placental abruption usually improves rapidly after prompt delivery and adequate anti-DIC treatment. CASE: A 30-year-old nulliparous woman suffered from placental abruption at the 25th week of pregnancy, and emergent cesarean section was done immediately. She exhibited DIC, which continued even after termination of the pregnancy and anti-DIC treatment. She also showed neutropenia. We closely observed her, and at the 58th day postpartum, blast cells appeared in the peripheral blood and she was diagnosed with acute promyelocytic leukemia (APL). Induction chemotherapy was done successfully. The close observation after delivery enabled us to make the prompt diagnosis/treatment, leading to the complete remission. CONCLUSION: APL should be added to the list of differential diagnosis when DIC persists even after prompt delivery and appropriate anti-DIC treatment after placental abruption. PMID- 17713777 TI - Long-term impact of the women's health initiative on HRT. AB - OBJECTIVE: To evaluate the long-term trends in the HRT following the results of the WHI, which were made public in July 2002. STUDY DESIGN: An observational cohort study was performed from prescription data of estrogen containing products ordered from Tripler Army Medical Center between July 1999 and July 2005. We used automated pharmacy data to identify all estrogen products dispensed to active duty soldiers, dependent wives, and retirees during the study period. Differences in prescription rate were compared between groups using a Student's t-test. RESULTS: A total of 71,592 prescriptions were written for HRT. Prescriptions decreased from 1,272/month at the start of the study to 493/month at the conclusion of the study. Prior to July 2002 OBGYNs were the first to decrease their prescribing rate of estrogen, and this decrease was greater than other specialties analyzed. The frequency of HRT prescriptions decreased after July 2002 while the percentage of patients who filled HRT prescriptions increased from 68 to 72%. CONCLUSIONS: We have found a significant decrease in prescriptions after release of the WHI initiative results. With this decrease in prescribing rate of HRT we found that a greater percentage of women actually filled their prescriptions perhaps indicating greater certainty in their choice. PMID- 17713778 TI - Haemoperitoneum from corpus luteal rupture in a patient with protein S deficiency receiving anticoagulant therapy. PMID- 17713779 TI - Neonatal blood is more resistant to oxidative stress induced by stable nitroxide radicals than adult blood. AB - Neonate erythrocytes are more susceptible to oxidizing drugs than adults; however, there are controversial reports in the literature regarding the total antioxidant capacity of neonate blood. Stable nitroxide radicals (NRs) are reduced by blood and some other biological materials to the corresponding hydroxylamines. The kinetics of the nitroxide's disappearance using electron paramagnetic resonance (EPR) spectroscopy, provides useful biochemical and biophysical information about the antioxidant properties of biological systems. In order to investigate the antioxidant properties in the newborn's blood, we applied this novel method on 38 umbilical vein blood samples and 40 healthy adults. The NR, 5-Dimethylaminonaphthalene-1-sulfonyl-4-amino-2,2,6,6, tetramethyl-piperidine-oxyl (R), was used for this purpose. Ascorbate is the only known natural antioxidant that reduces R. We found that the reduction rates of R in neonate's whole blood are significantly higher (P < 0.001) than the reduction rates of R in adult's whole blood. However, there were no significant differences in the antioxidant capacity between the two groups. Newborn's blood has significantly higher ability to deal with oxidative stress, caused by R, in comparison with adult blood. We suggest that the system that responds to the recycling of ascorbate is more efficient in neonate blood than in adult's blood. PMID- 17713780 TI - A unique congenital mullerian anomaly: Robert's uterus. PMID- 17713781 TI - Analytic view to concordance between electrocochleography and caloric test in Meniere's disease. AB - We aimed to investigate if there is a concordance between summation potential (SP)/action potential (AP) ratio and unilateral weakness in patients with definite-Meniere's disease. There were two groups, a group of unilateral definite Meniere patients who received no treatment and another group of control subjects. Twenty-six patients were identified as complying with the defined criteria. Fifteen healthy subjects with no hearing and balance disorders were assigned to the control group. Arithmetic mean of the four-tone average of thresholds at 0.5, 1, 2, and 3 or 4 kHz, SP/AP ratio and degree of unilateral weakness were calculated. The number of patients was tabulated based on the presence of abnormal SP/AP ratio and unilateral weakness. Co-occurrence of unilateral weakness and elevated-SP/AP ratio was investigated with reference to the stage of the disease. A correlation was sought among pure-tone average, SP/AP ratio and degree of unilateral weakness in a pair-wise manner. Unilateral weakness and abnormal SP/AP ratio were identified in 53.8% and 38.4% of the patients, respectively. Co-occurrence of unilateral weakness and abnormal SP/AP ratio was observed in 34.6% of the patients. However, it was noticed that this co occurrence gradually increased when the disease progressed. Mean SP/AP ratio also gradually increased as the stage progressed. Of pair-wise correlations among pure tone average, SP/AP ratio and degree of unilateral weakness, a weak correlation (r = 0.383) was found only between SP/AP ratio and degree of unilateral weakness with marginal significance (P = 0.053). We concluded that co-occurrence of unilateral weakness and elevated SP/AP ratio increases when the disease progresses. This co-occurrence is less encountered in earlier stages. This difference might be resulted from a difference in distension capability of the endolymphatic space of the cochlea and the vestibule. Albeit weak, there was a correlation between mean SP/AP ratio and degree of unilateral weakness, which suggests that the disease parallelly disturbs the lateral semicircular or cochlear functions especially in advanced stages. PMID- 17713782 TI - Long-term results with tracheoesophageal voice prosthesis: primary versus secondary TEP. AB - The aim of this study was to evaluate the influence of timing of tracheoesophageal puncture (TEP)with indwelling voice prosthesis insertion regarding long-term success rate and postoperative complication. We conducted a Retrospective clinical study at tertiary academic center. There were 75 patients with primary TEP (80.6%) and 18 with secondary TEP (19.3%). Long-term success rate was 81.7%, with 80.0% in primary TEP and 88.9% in secondary TEP. No significant difference in Harrison-Robillard-Schultz Rating Scale success assessment were observed between patients with primary and secondary TEP (P = .596). The use of postoperative radiotherapy did not significantly influence the success rate. The age of patients who were older or younger than 60 years significantly influence the success rate in primary TEP (P = .012). The higher rate of complications in primary TEP was not statistically significant. These findings suggest that primary and secondary TEP are equally safe and effective procedures. Primary TEP should be preferred because of avoiding a second surgical intervention and allowing early voice restoration with a considerable psychological impact. PMID- 17713783 TI - Cadmium translocation and accumulation in developing barley grains. AB - Soil cadmium (Cd) contamination has posed a serious problem for safe food production and become a potential agricultural and environmental hazard worldwide. In order to study the transport of Cd into the developing grains, detached ears of two-rowed barley cv. ZAU 3 were cultured in Cd stressed nutrient solution containing the markers for phloem (rubidium) and xylem (strontium) transport. Cd concentration in each part of detached spikes increased with external Cd levels, and Cd concentration in various organs over the three Cd levels of 0.5, 2, 8 microM Cd on 15-day Cd exposure was in the order: awn > stem > grain > rachis > glume, while the majority of Cd was accumulated in grains with the proportion of 51.0% relative to the total Cd amount in the five parts of detached spikes. Cd accumulation in grains increased not only with external Cd levels but the time of exposure contrast to stem, awn, rachis and glume. Those four parts of detached spike showed increase Cd accumulation for 5 days, followed by sharp decrease till day 10 and increase again after 12.5 days. Awn-removal and stem-girdling markedly decreased Cd concentration in grains, and sucrose or zinc (Zn) addition to the medium and higher relative humidity (RH) also induced dramatic reduction in Cd transport to developing grains. The results indicated that awn, rachis and glume may involve in Cd transport into developing grains, and suggested that Cd redistribution in maturing cereals be considered as an important physiological process influencing the quality of harvested grains. Our results suggested that increasing RH to 90% and Zn addition in the medium at grain filling stage would be beneficial to decrease Cd accumulation in grains. PMID- 17713784 TI - The expression of genes coding for auxin carriers in different tissues and along the organ can explain variations in auxin transport and the growth pattern in etiolated lupin hypocotyls. AB - Novel cDNA clones encoding putative auxin influx and efflux carriers have been isolated and characterized from etiolated lupin (Lupinus albus L) hypocotyls. The full length of LaAUX1 and LaPIN1 and the partial length of LaPIN3 were obtained and the deduced amino acid sequence revealed a high degree of identity with the corresponding auxin carrier proteins from several species. The expression of these genes depended on the tissue, the hypocotyl zone and seedling age. LaAUX1 and LaPIN3 were expressed in stele and outer tissues, while LaPIN1 was restricted to the stele. From the above-mentioned results and taking into account the role proposed for the efflux carrier PIN1, it is suggested that LaPIN1 could mediate the basipetal auxin transport already described in this organ. LaAUX1 might facilitate auxin influx in the transport cells. The expression of the three genes decreased down the hypocotyl. The basipetally decreasing gradient in the expression of LaPIN1 coincides with previous results showing a similar gradient in the intensity and polarity of auxin transport. The decisive role ascribed to PIN1 in polar auxin transport due to its localization in the basal end of transporting cells and the existence of such a gradient in the expression of LaPIN1 support the hypothesis of a barrier effect (generated by decreasing auxin transport) previously proposed by our research group as being responsible for the auxin gradient, which controls the growth pattern in etiolated lupin hypocotyls. PMID- 17713786 TI - Behavioral and energetic costs of group membership in a coral reef fish. AB - Animals in social aggregations often spend more time foraging than solitary conspecifics. This may be a product of the relative safety afforded by aggregations: group members can devote more time to foraging and less time to antipredator behaviors than solitary animals (the "risk reduction" effect). All else being equal, risk reduction should result in higher food intake for grouped animals. However, intragroup competition may force group members to spend more time foraging in order to obtain the same food ration as solitary individuals (the "resource competition" effect). We compared these opposing explanations of foraging time allocation in a coral reef fish, bluehead wrasse (Thalassoma bifasciatum). Aggregations of juvenile bluehead wrasse experience safety-in numbers, and preliminary observations suggested that juveniles in aggregations spent more time foraging for copepods in the water column than solitary juveniles. However, the risk reduction and resource competition hypotheses are indistinguishable on the basis of behavioral observations alone. Therefore, we collected behavioral, dietary, and growth data (using otolith growth rings) for bluehead wrasse at multiple reefs around a Caribbean island. Despite spending more time foraging in the water column, grouped fish did not capture more prey items and had slower growth rates than solitary fish. Thus, the increased foraging time of grouped fish appears to reflect resource competition, not risk reduction. This competition may limit the size and frequency of aggregations among juvenile bluehead wrasse, which have been shown to experience reduced mortality rates in larger groups. Bluehead wrasse recruits also spent less time foraging but grew faster at sites where planktonic copepod prey were more abundant. This suggests the possibility that large-scale spatiotemporal variability in the abundance of planktonic copepods over coral reefs may produce corresponding variability in the dynamics of reef fish populations. PMID- 17713785 TI - Evidence for a role of caveolin-1 in neurokinin-1 receptor plasma-membrane localization, efficient signaling, and interaction with beta-arrestin 2. AB - This study was focused on the relationship between the plasma-membrane localization of neurokinin-1 receptor (NK1-R) and its endocytic and signaling properties. First, we employed electron paramagnetic resonance (EPR) to study the domain structure of HEK-293 cells and NK1-R microlocalization. EPR spectra and the GHOST condensation routine demonstrated that NK1-R was distributed in a well ordered domain of HEK-293 cells possibly representing lipid raft/caveolae microdomains, whereas the impairment of caveolae changed the NK1-R plasma membrane distribution. Internalization and second messenger assays combined with bioluminescence resonance energy transfer were employed subsequently to evaluate the functional importance of the NK1-R microlocalization in lipid raft/caveolae microdomains. The internalization pattern was delineated through the use of dominant-negative mutants (DNM) of caveolin-1 S80E (Cav1 S80E), dynamin-1 K44A (Dyn K44A), and beta-arrestin (beta-arr 319-418) and by means of cell lines that expressed various endogenous levels of beta-arrestins. NK1-R displayed rapid internalization that was substantially reduced by DNMs of dynamin-1 and beta arrestin and even more profoundly in cells lacking both beta-arrestin1 and beta arrestin2. These internalization data were highly suggestive of the predominant use of the clathrin-mediated pathway by NK1-R, even though NK1-R tended to reside constitutively in lipid raft/caveolae microdomains. Evidence was also obtained that the proper clustering of the receptor in these microdomains was important for effective agonist-induced NK1-R signaling and for its interaction with beta arrestin2. PMID- 17713787 TI - Richness-productivity relationships between trophic levels in a detritus-based system: significance of abundance and trophic linkage. AB - Most theoretical and empirical studies of productivity-species richness relationships fail to consider linkages among trophic levels. We quantified productivity-richness relationships in detritus-based, water-filled tree-hole communities for two trophic levels: invertebrate consumers and the protozoans on which they feed. By analogy to theory for biomass partitioning among trophic levels, we predicted that consumer control would result in richness of protozoans in the lower trophic level being unaffected by increases in productivity, whereas richness of invertebrate consumers would increase with productivity. Our data were consistent with this prediction: consumer richness increased linearly, but protozoan richness was unrelated to changes in productivity. The productivity richness relationships for all taxa combined were not necessarily consistent with relationships within each trophic level. We used path analysis to investigate the mechanisms that may produce the observed responses of trophic levels to changes in productivity. We tested the importance of the direct effect of productivity on richness and the indirect effect of productivity mediated by effects on total abundance. For protozoans, only direct effects of productivity on richness were important, but both direct and indirect effects of productivity on richness were important for invertebrates. Protozoan richness was strongly affected by top-down impacts of abundance of invertebrates. These results are consistent with theory on biomass partitioning among trophic levels and suggest a strong link between richness and abundance within and between trophic levels. Understanding how trophic level interactions determine productivity-richness relationships will likely be necessary in order for us to achieve a comprehensive understanding of the determinants of diversity. PMID- 17713788 TI - Parasites boost productivity: effects of mistletoe on litterfall dynamics in a temperate Australian forest. AB - The importance of litter in regulating ecosystem processes has long been recognised, with a growing appreciation of the differential contribution of various functional plant groups. Despite the ubiquity of mistletoes in terrestrial ecosystems and their prominence in ecological studies, they are one group that have been overlooked in litter research. This study evaluated the litter contribution from a hemiparasitic mistletoe, Amyema miquelii (Lehm. ex Miq.) Tiegh., in an open eucalypt forest (Eucalyptus blakelyi, E. dwyeri and E. dealbata), at three scales; the forest stand, single trees and individual mistletoes. Litter from mistletoes significantly increased overall litterfall by up to 189%, the amount of mistletoe litter being proportional to the mistletoe biomass in the canopy. The high litter input was due to a much higher rate of mistletoe leaf turnover than that of host trees; the host litterfall and rate of leaf turnover was not significantly affected by mistletoe presence. The additional litter from mistletoes also affected the spatial and temporal distribution of litterfall due to the patchy distribution of mistletoes and their prolonged period of high litterfall. Associated with these changes in litterfall was an increase in ground litter mass and plant productivity, which reflects similar findings with root-parasitic plants. These findings represent novel mechanisms underlying the role of mistletoes as keystone resources and provide further evidence of the importance of parasites in affecting trophic dynamics. PMID- 17713789 TI - Contact networks and transmission of an intestinal pathogen in bumble bee (Bombus impatiens) colonies. AB - In socially living animals, individuals interact through complex networks of contact that may influence the spread of disease. Whereas traditional epidemiological models typically assume no social structure, network theory suggests that an individual's location in the network determines its risk of infection. Empirical, especially experimental, studies of disease spread on networks are lacking, however, largely due to a shortage of amenable study systems. We used automated video-tracking to quantify networks of physical contact among individuals within colonies of the social bumble bee Bombus impatiens. We explored the effects of network structure on pathogen transmission in naturally and artificially infected hives. We show for the first time that contact network structure determines the spread of a contagious pathogen (Crithidia bombi) in social insect colonies. Differences in rates of infection among colonies resulted largely from differences in network density among hives. Within colonies, a bee's rate of contact with infected nestmates emerged as the only significant predictor of infection risk. The activity of bees, in terms of their movement rates and division of labour (e.g., brood care, nest care, foraging), did not influence risk of infection. Our results suggest that contact networks may have an important influence on the transmission of pathogens in social insects and, possibly, other social animals. PMID- 17713790 TI - Annual variation in maternal age and calving date generate cohort effects in moose (Alces alces) body mass. AB - A general feature of the demography of large ungulates is that many demographic traits are dependent on female body mass at early ages. Thus, identifying the factors affecting body mass variation can give important mechanistic understanding of demographic processes. Here we relate individual variation in autumn and winter body mass of moose calves living at low density on an island in northern Norway to characteristics of their mother, and examine how these relationships are affected by annual variation in population density and climate. Body mass increased with increasing age of their mother, was lower for calves born late in the spring, decreased with litter size and was larger for males than for female calves. No residual effects of variation in density and climate were present after controlling for annual variation in mother age and calving date. The annual variation in adult female age structure and calving date explained a large part (71-75%) of the temporal variation in calf body mass. These results support the hypotheses that (a) body mass of moose calves are affected by qualities associated with mother age (e.g. body condition, calving date); and (b) populations living at low densities are partly buffered against temporal fluctuations in the environment. PMID- 17713791 TI - Epidemiology of a Daphnia brood parasite and its implications on host life history traits. AB - Parasites influence host life-history traits and therefore might crucially shape host populations in natural systems. In a series of laboratory experiments, we studied the impact of an oomycete brood parasite on its Daphnia (waterflea) host. We asked whether Daphnia dump the infected brood and subsequently are able to reproduce again as was occasionally observed in a preliminary study. No viable offspring developed from infected clutches, but 78% of the infected females produced healthy offspring after releasing the infected brood while molting. Neither those offsprings' development success nor their mothers' reproductive potential was affected by the brood parasite. However, infected Daphnia had a reduced life-span and suffered an increased susceptibility to another parasite, an unidentified bacterium. Additionally, we studied the prevalence of this brood parasite and the unidentified bacterium in a natural Daphnia assemblage in a pre alpine lake, across changing demographic and environmental conditions. The brood parasite epidemic seemed to be host-density dependent. Our results show that the brood parasite's impact on the host population is enhanced when combined with the unidentified bacterium. PMID- 17713792 TI - Resource distribution influences mating system in the bobuck (Trichosurus cunninghami: Marsupialia). AB - Mammalian mating systems are thought to be shaped by the spatial distribution and abundance of key resources, which in turn influence the spacing behaviour of individuals. In particular, female home range size is predicted to reflect the availability of key resources. We documented the availability and distribution of food and shelter resources for two neighbouring populations of bobucks, or mountain brushtail possums, Trichosurus cunninghami, that were characterised by different mating systems: our "forest population" was socially monogamous, whereas the "roadside population" was polygynous. Both silver wattle, Acacia dealbata, the main food resource for bobucks, and den-trees, which provided shelter, occurred at significantly higher density at the roadside site. The pattern of distribution of these two resources also differed between the sites. Both food and den-trees were scattered evenly throughout the roadside habitat. In contrast, den-trees were located predominantly at one end of the forest site, while silver wattle trees were located at the other. There was no significant difference in the amount of silver wattle, or in the number of den-trees, located within the home ranges of individual females at the two sites. However, forest females had home ranges, on average, almost three times the size of those of roadside females. At the roadside site, the size of female home ranges varied inversely with the density of silver wattle, indicating that these females ranged over as large an area as necessary to gain access to sufficient silver wattle trees. There was no such relationship among forest females. These populations provide a clear example of resource distribution determining female home range size. This influenced the number of female home ranges a male's home range overlapped with, which in turn determined the mating system. Such clear links between resource availability and mating system have not previously been established in a marsupial. PMID- 17713793 TI - Metabolic flux and robustness analysis of glycerol metabolism in Klebsiella pneumoniae. AB - The knowledge of the mechanism of flux distribution will benefit understanding cell physiology and regulation of metabolism. In this study, the measured fluxes obtained under steady-state conditions were used to estimate intracellular fluxes and identify the robustness of branch points of the anaerobic glycerol metabolism in Klebsiella pneumoniae for the production of 1,3-propanediol by metabolic flux analysis. The biomass concentration increased as NADH(2)/NAD(+) decreased at low initial concentration and inversed at high initial glycerol concentration. The flux distribution revealed that the branch points of glycerol and dihydroxyacetonephosphate were rigid to the environmental conditions. However, the pyruvate and acetyl coenzyme A metabolisms gave cells the flexibility to regulate the energy and intermediate fluxes under various environmental conditions. Additionly, it was found that the formation rate of ethanol and the ratio of pyruvate dehydrogenase to pyruvate formate lyase appeared visible fluctuations at high glycerol uptake rate. PMID- 17713795 TI - Adjacent vertebral failure after vertebroplasty: a biomechanical study of low modulus PMMA cement. AB - PMMA is the most common bone substitute used for vertebroplasty. An increased fracture rate of the adjacent vertebrae has been observed after vertebroplasty. Decreased failure strength has been noted in a laboratory study of augmented functional spine units (FSUs), where the adjacent, non-augmented vertebral body always failed. This may provide evidence that rigid cement augmentation may facilitate the subsequent collapse of the adjacent vertebrae. The purpose of this study was to evaluate whether the decrease in failure strength of augmented FSUs can be avoided using low-modulus PMMA bone cement. In cadaveric FSUs, overall stiffness, failure strength and stiffness of the two vertebral bodies were determined under compression for both the treated and untreated specimens. Augmentation was performed on the caudal vertebrae with either regular or low modulus PMMA. Endplate and wedge-shaped fractures occurred in the cranial and caudal vertebrae in the ratios endplate:wedge (cranial:caudal): 3:8 (5:6), 4:7 (7:4) and 10:1 (10:1) for control, low-modulus and regular cement group, respectively. The mean failure strength was 3.3 +/- 1 MPa with low-modulus cement, 2.9 +/- 1.2 MPa with regular cement and 3.6 +/- 1.3 MPa for the control group. Differences between the groups were not significant (p = 0.754 and p = 0.375, respectively, for low-modulus cement vs. control and regular cement vs. control). Overall FSU stiffness was not significantly affected by augmentation. Significant differences were observed for the stiffness differences of the cranial to the caudal vertebral body for the regular PMMA group to the other groups (p < 0.003). The individual vertebral stiffness values clearly showed the stiffening effect of the regular cement and the lesser alteration of the stiffness of the augmented vertebrae using the low-modulus PMMA compared to the control group (p = 0.999). In vitro biomechanical study and biomechanical evaluation of the hypothesis state that the failure strength of augmented functional spine units could be better preserved using low-modulus PMMA in comparison to regular PMMA cement. PMID- 17713794 TI - Cost-effectiveness evaluation of an RCT in rehabilitation after lumbar spinal fusion: a low-cost, behavioural approach is cost-effective over individual exercise therapy. AB - Recently, Christensen et al. reported the clinical effects of a low-cost rehabilitation program equally efficient to a relatively intensive program of individual, physiotherapist-guided exercise therapy. Yet, the low-cost approach is not fully supported as an optimal strategy until a full-scale economic evaluation, including extra-hospital effects such as service utilization in the primary health care sector and return-to-work, is conducted. The objective of this study was to conduct such evaluation i.e. investigate the cost-effectiveness of (1) a low-cost rehabilitation regimen with a behavioural element and (2) a regimen of individual exercise therapy, both in comparison with usual practice, from a health economic, societal perspective. Study design was a cost effectiveness evaluation of an RCT with a 2-year follow-up. Ninety patients having had posterolateral or circumferential fusion (indicated by chronic low back pain and localized pathology) were randomized 3 months after their spinal fusion. Validated pain- and disability index scales were applied at baseline and at 2 years postoperative. Costs were measured in a full-scale societal perspective. The probability of the behavioural approach being cost-effective was close to 1 given pain as the prioritized effect measure, and 0.8 to 0.6 (dependent on willingness to pay per effect unit) given disability as the prioritized effect measure. The probability of the exercise therapy approach being cost-effective was modest due to inferior effectiveness. Results proved robust to relevant sensitivity analysis although a differentiated cost effectiveness ratio between males and females was suspected. In conclusion, a simple behavioural extension, of setting up group meetings for patients, to a regimen with a strict physiotherapeutic focus was found cost-effective, whereas the cost-effectiveness of increasing frequency and guidance of a traditional physiotherapeutic regimen was unlikely in present trial setting. PMID- 17713797 TI - The studies on substrate, product and inhibitor binding to a wild-type and neuronopathic form of human acid-beta-glucosidase. AB - Gaucher disease is a lysosomal storage disorder caused by deficiency of human acid beta-glucosidase. Recent x-ray structural elucidation of the enzyme alone and in the presence of its inhibitor was done, which provided an excellent template for further studies on the binding of substrate, product and inhibitor. To draw correlations between the clinical manifestation of the disease driven by point mutations, L444P and L444R, and the placement and function of putative S binding sites, the presented theoretical studies were undertaken, which comprised of molecular dynamics and molecular docking methods. The obtained results indicate the D443 and D445 residues as extremely important for physiological functionality of an enzyme. They also show, although indirectly, that binding of the substrate is influenced by an interplay of E235 and E334 residues, constituting putative substrate binding site, and the region flanked by D435 and D445 residues. PMID- 17713796 TI - En bloc resection of a C4 chordoma: surgical technique. AB - The prognosis of aggressive benign and low-grade malignant tumors in the spine as in the limbs, seems to be mostly related to the feasibility of en bloc resection, while in the treatment of high-grade malignant tumors the protocols of treatment include the combination of chemotherapy, radiation and surgery. Indications, criteria of feasibility and surgical technique are extensively reported for the thoracic and lumbar spine. In the cervical spine few cases are reported of resection, due not only to anatomical constraint, but also to the rarity of finding a tumor accomplishing the criteria of feasibility. A case of double approach vertebrectomy finalized to remove en bloc the body of C4 for a stage IA chordoma is reported. The first stage was posterior, aiming to remove the posterior healthy elements by piecemeal technique. The anterior approach consisted of contemporary right and left prevascular presternocleidomastoid approaches The specimen was submitted for the histological study of the margins, which resulted tumor-free. This technical note is finalized to confirm that en bloc resection of the vertebral body through total vertebrectomy is feasible in the midcervical spine by double approaches, provided the tumor involves only layers B and C, maximum extension sectors 5-8. PMID- 17713798 TI - Theoretical study on binding of S100B protein. AB - S100B protein is one of the factors involved in the down-regulation of tumor suppressor protein p53, a transcription activator that signals for cycle arrest and apoptosis. As the inactivation of normal p53 functions is found in over half of human cancers, restoration of normal p53 functions through the destruction or prevention of S100B--p53 complexes represents a possible approach for the development of anti-cancer drugs. The aim of this work was to propose the S100B binding interface through an examination of the literature and use of molecular modeling (MM) techniques with AutoDock program and the AMBER force field. We propose two residues in the S100B binding pocket (Val56, Phe76) and two residues on the protein surface (Val52, Ala83) are essential for ligand binding. The data presented here indicate that interactions with these four residues are necessary for a reduction in the incidence of the S100B--p53 complex. Additionally, we have tried to explain a mechanism for the action of pentamidine, the best-known S100B ligand, and have proposed two S100B--pentamidine structures. The results presented here may be useful for the efficient design of new S100B ligands. PMID- 17713800 TI - Insect genomes: challenges and opportunities for neuroscience. PMID- 17713799 TI - Window manipulation in diagnosis of body packing using computed tomography. AB - Body packing refers to the internal concealment of narcotics, usually within the gastrointestinal tract. This is important to recognise for clinical and forensic reasons. Imaging is often helpful, particularly because an accurate history is unusual. Furthermore, clinical examination and urine screens are often unreliable. Plain abdominal radiography and ultrasonography have been used with limited success. Thus, the use of alternative modalities, such as computed tomography (CT), is becoming more widespread. Although there have been no large trials, one false-negative has been reported. We report the case of a body packer whose CT appeared normal with standard abdominal windowing (level 40/width 400). However, on manipulation of the windowing (level -175/width 600), paraffin and heroin packages became conspicuous within the colon. We suggest that the simple step of reviewing images on wider than standard abdominal windows may be helpful in the detection of ingested illicit packages of fatty density within the bowel. PMID- 17713801 TI - Prediction of extracellular matrix stiffness in engineered heart valve tissues based on nonwoven scaffolds. AB - The in vitro development of tissue engineered heart valves (TEHV) exhibiting appropriate structural and mechanical characteristics remains a significant challenge. An important step yet to be addressed is establishing the relationship between scaffold and extracellular matrix (ECM) mechanical properties. In the present study, a composite beam model accounting for nonwoven scaffold-ECM coupling and the transmural collagen concentration distribution was developed, and utilized to retrospectively estimate the ECM effective stiffness in TEHV specimens incubated under static and cyclic flexure conditions (Engelmayr Jr et~al. in Biomaterials 26(2):175-187 2005). The ECM effective stiffness was expressed as the product of the local collagen concentration and the collagen specific stiffness (i.e., stiffness/concentration), and was related to the overall TEHV effective stiffness via an empirically determined scaffold-ECM coupling parameter and measured transmural collagen concentration distributions. The scaffold-ECM coupling parameter was determined by flexural mechanical testing of polyacrylamide gels (i.e., ECM analogs) of variable stiffness and associated scaffold-polyacrylamide gel composites (i.e., engineered tissue analogs). The transmural collagen concentration distributions were quantified from fluorescence micrographs of picro-sirius red stained TEHV sections. As suggested by a previous structural model of the nonwoven scaffold (Engelmayr Jr and Sacks in J Biomech Eng 128(4):610-622, 2006), nonwoven scaffold-ECM composites did not follow a traditional rule of mixtures. The present study provided further evidence that the primary mode of reinforcement in nonwoven scaffold-ECM composites is an increase in the number fiber-fiber bonds with a concomitant increase in the effective stiffness of the spring-like fiber segments. Simulations of potential ECM deposition scenarios using the current model indicated that the present approach is sensitive to the specific time course of tissue deposition, and is thus very suitable for studies of ECM formation in engineered heart valve tissues. PMID- 17713803 TI - Atorvastatin decreases triacylglycerol-associated risk of vascular events in coronary heart disease patients. AB - High triacylglycerol (TAG) levels may predict vascular risk. The effect of a statin-induced reduction in TAG levels, irrespective of HDL-C increase, on clinical outcome has not yet been addressed by an endpoint study in patients with coronary heart disease (CHD). The GREACE study compared usual with structured care aimed at achieving LDL-C = 100 mg/dL (2.6 mmol/L) by dose titration with atorvastatin. All patients had CHD and were followed for 3 years. This post hoc analysis of GREACE examines the effect of statins on TAG levels and their relation with cardiovascular disease (CVD) events in all patients and in the subgroup of patients with metabolic syndrome (MetS). Baseline TAG levels >150 mg/dL (1.7 mmol/L) were predictive of subsequent CVD events [cardiac mortality, non-fatal myocardial infarction (MI), unstable angina (UA), revascularisation, congestive heart failure (CHF), and stroke] only in statin untreated patients. Stepwise regression analysis showed that with every 20% statin-related TAG reduction there was a decrease in CVD risk by 12% (HR 0.88, 95% CI 0.75-0.95, P = 0.007) in the structured care group vs. the usual care group, by 8% (HR 0.92, 95% CI 0.81-0.97, P = 0.02) in all statin treated patients vs. the untreated ones and by 15% (HR 0.85, 95% CI 0.65-0.94, P = 0.005) in those with MetS treated with a statin vs. those untreated. Using the same analysis but only taking into consideration vascular events (cardiac mortality, non-fatal MI, UA, revascularisation, and stroke) there was a 18% (HR = 0.82, 95% CI 0.57-0.96, P = 0.03) decrease in risk in the MetS (+) patients treated with a statin vs. those not on a statin, and a decrease in risk by 16% (HR = 0.84, 95% CI 0.53-1.07, P = 0.08), when only hard vascular endpoints (cardiac mortality, non-fatal MI, and stroke) were considered. TAG levels are predictive of subsequent CVD events in statin untreated CHD patients. Statin (mainly atorvastatin)-induced decrease in TAG levels was related to a significant reduction in subsequent CVD events. This benefit was more pronounced in CHD MetS (+) patients. PMID- 17713802 TI - Important differences exist in the dose-response relationship between diet and immune cell fatty acids in humans and rodents. AB - Omega-3 polyunsaturated fatty acids (n-3 PUFA) are noted for their ability to diminish inflammatory and immune responses in vitro and in a variety of animal based models of autoimmunity and inflammation. Yet, recent systematic reviews suggest that the evidence for these fatty acids having beneficial effects on inflammation or autoimmunity in humans is equivocal. A possible explanation for these disappointing and somewhat paradoxical findings emerged from the analyses described in this review. The available data on the changes in immune cell fatty acid profiles in mice, rats and humans, fed various forms and amounts of n-3 PUFA are summarized and displayed graphically. The dose-response curves generated provide new insights into the relationship between dietary n-3 PUFA and immune cell fatty acid profiles. The author suggests that the poor predictive value of most in vitro as well as many animal trials may, in part, be a consequence of the frequent adoption of experimental conditions that create differences in immune cell fatty acid profiles that far exceed what is possible in free-living humans through dietary intervention. Recommendations for improving the preclinical value of future in vitro and animal-based studies with n-3 PUFA are provided. PMID- 17713805 TI - [Oculomotor, trochlear, and abducens nerve palsies]. AB - Patients with oculomotor, trochlear, or abducens nerve palsies mainly complain of binocular double vision, but sometimes merely of blurred vision or vertigo. The clinical signs comprise strabismus, pathologic head posture, and disturbed saccades. The characteristic motility deficits are picked up by measuring the strabismic angles at different directions of gaze. Documentation of all three spatial strabismic components is advantageous. Nonparetic strabismus and orbital diseases are important differential diagnoses. Conclusions about the cause of a palsy can be drawn from the time course of double vision, the character of associated headaches, the patient's general risk factors, and the examination of vicinal structures. Imaging studies are indicated when the ischemic nature of the palsy is in doubt. Therapeutic strategies include prisms, occlusion, and eye muscle surgery. PMID- 17713804 TI - Bioequivalence of Docosahexaenoic acid from different algal oils in capsules and in a DHA-fortified food. AB - Docosahexaenoic acid (DHA), a long-chain omega-3 fatty acid, is important for eye and brain development and ongoing visual, cognitive, and cardiovascular health. Unlike fish-sourced oils, the bioavailability of DHA from vegetarian-sourced (algal) oils has not been formally assessed. We assessed bioequivalence of DHA oils in capsules from two different algal strains versus bioavailability from an algal-DHA-fortified food. Our 28-day randomized, placebo-controlled, parallel group study compared bioavailability of (a) two different algal DHA oils in capsules ("DHASCO-T" and "DHASCO-S") at doses of 200, 600, and 1,000 mg DHA per day (n = 12 per group) and of (b) an algal-DHA-fortified food (n = 12). Bioequivalence was based on changes in plasma phospholipid and erythrocyte DHA levels. Effects on arachidonic acid (ARA), docosapentaenoic acid-n-6 (DPAn-6), and eicosapentaenoic acid (EPA) were also determined. Both DHASCO-T and DHASCO-S capsules produced equivalent DHA levels in plasma phospholipids and erythrocytes. DHA response was dose-dependent and linear over the dose range, plasma phospholipid DHA increased by 1.17, 2.28 and 3.03 g per 100 g fatty acid at 200, 600, and 1,000 mg dose, respectively. Snack bars fortified with DHASCO-S oil also delivered equivalent amounts of DHA on a DHA dose basis. Adverse event monitoring revealed an excellent safety and tolerability profile. Two different algal oil capsule supplements and an algal oil-fortified food represent bioequivalent and safe sources of DHA. PMID- 17713807 TI - Temperature- and pH-induced structural changes in the membrane of the hyperthermophilic archaeon Aeropyrum pernix K1. AB - The influence of pH and temperature on the structural organization, fluidity and permeability of the hyperthermophilic archaeon membrane was investigated in situ by a combination of electron paramagnetic resonance (EPR) and fluorescence emission spectroscopy. For EPR measurements, Aeropyrum pernix cells, after growing at different pHs, were spin-labeled with the doxyl derivative of palmitic acid methylester (MeFASL(10,3)). From the EPR spectra maximal hyperfine splitting (2A (max)) and empirical correlation time (tau (emp)), which are related to mean membrane fluidity, were determined. The mean membrane fluidity increases with temperature and depends on the pH of the growth medium. Computer simulation of the EPR spectra shows that membrane of A. pernix is heterogeneous and consists of the regions characterized with three different types of motional characteristics, which define three types of membrane domains. Order parameter and proportion of the spin probes in the three types of domains define mean membrane fluidity. The fluidity changes of the membrane with pH and temperature correlate well with the ratio between the fluorescence emission intensity of the first and third bands in the vibronic spectra of pyrene, I(1)/I(3). At pH 7.0 a decrease of I(1)/I(3) from 2.0 to 1.2, due to the penetration of pyrene into the nonpolar membrane region, is achieved at temperatures above 65 degrees C, the lower temperature limit of A. pernix growth. PMID- 17713808 TI - Different positively selected sites at the gametophytic self-incompatibility pistil S-RNase gene in the Solanaceae and Rosaceae (Prunus, Pyrus, and Malus). AB - In this work we perform a comparative study on the location of positively selected sites (those likely responsible for defining specificity differences) at the S-RNase gene, the pistil component of the gametophytic self-incompatibility system. For Plantaginaceae and Rosaceae (Prunus and Pyrus/Malus) this is the first study of this kind. A clear sign of positive selection was observed for 13, 17, and 27 amino acid sites in Solanaceae, Prunus, and Pyrus/Malus, respectively, using two different methodologies. In Plantaginaceae no clear positively selected sites were identified. Possible reasons for this result are discussed. Indirect experimental evidence suggests that the identified positively selected amino acid sites play a role in specificity determination. The percentage of positively selected sites is similar in Solanaceae and Rosaceae but the location of those sites is different. PMID- 17713809 TI - Studies on the genotoxicity of endosulfan in different tissues of fresh water fish Mystus vittatus using the comet assay. AB - Endosulfan, a widely used organochlorine pesticide, is readily bio-accumulative in fishes and can be indirectly harmful to human populations. Limited efforts have been made to study long-term genotoxic effects of endosulfan in different tissues of fish using gentoxicity biomarkers. Therefore, the current investigation was undertaken to detect single-cell DNA strand breaks induced by endosulfan in the fresh water teleost fish Mystus vittatus using the comet assay. The LC(50) value of technical grade endosulfan was first determined for the fish species in a semistatic system, and on the basis of the LC(50) value, the sublethal and nonlethal concentrations were determined. The DNA damage was measured in gill, kidney, and erythrocytes as the percentage of DNA in comet tails of fish specimens exposed to the sublethal and nonlethal concentrations of endosulfan. In general, significant effects (p < 0.01) from both concentration and time of exposure were observed in exposed fishes. It was found that all the tissues at all concentrations exhibited the highest DNA damage on day 1, after which there was a nonlinear decline in the percentage of tail DNA. The comparison of DNA damage among the tissues at different concentrations could not show the sensitivity of particular tissue to endosulfan. The current study explored the utility of the comet assay for in vivo laboratory studies using fish species to screen the genotoxic potential of chemical agents. PMID- 17713810 TI - Effects of the fungicide benomyl on earthworms in laboratory tests under tropical and temperate conditions. AB - Soil organisms play a crucial role in the terrestrial ecosystem. Plant protection products (PPPs) are known to affect soil organisms and might have negative impacts on soil functions influenced by these organisms. Little research has been performed to date on the impact of PPPs on tropical soil ecosystems. Therefore, in this study it was investigated whether the effects of the fungicide benomyl (chosen as a model substance) differ between tropical and temperate regions and whether data generated under temperate conditions can be used for the Environmental Risk Assessment (ERA) in tropical regions. The effect of benomyl on earthworms was evaluated in acute and chronic laboratory tests modified for tropical conditions. These tests were performed at two temperatures (20 degrees C and 28 degrees C) and with two strains (temperate and tropical) of the compost worm Eisenia fetida. The fungicide was spiked in two natural and two artificial soils. In addition to the organization for economic cooperation and development (OECD) artificial soil, a tropical artificial soil (TAS), containing a tropical fern product (xaxim) instead of peat, was developed in this study. The results from the laboratory tests and a literature review showed that the effects of benomyl were, on average, lower under tropical conditions (LC(50): 450-630 mg active ingredient (a.i.)/kg; EC(50): 0.8-12.9 mg a.i./kg) than under temperate conditions (LC(5)0: 61-67 mg a.i./kg; EC(50): 1.0-1.6 mg a.i./kg) by a maximum factor of 10.3 (acute tests) and 12.9 (chronic tests). This result might be caused by an increased degradation of benomyl, and/or its first metabolite carbendazim, at higher temperatures, but a different sensitivity of the two worm strains cannot be ruled out. Despite the lower toxicity under tropical conditions and assuming comparable application rates, a preliminary assessment confirms the risk of benomyl to soil invertebrates under both conditions. PMID- 17713811 TI - Heavy metal levels in ribbon snakes (Thamnophis sauritus) and anuran larvae from the Mobile-Tensaw River Delta, Alabama, USA. AB - The Mobile-Tensaw River Delta (MTD) drains more than 75% of the state of Alabama and leads into Mobile Bay and the Northern Gulf of Mexico. Although it is a relatively healthy watershed, the MTD is potentially impacted by inputs of contaminants such as heavy metals. The levels of lead, copper, cadmium, and mercury were measured in whole body samples of Eastern Ribbon Snakes (Thamnophis sauritus) collected from the MTD. Lead, copper, and cadmium levels were also measured in anuran larvae (Rana catesbeiana, R. clamitans, and Hyla cinerea). These organisms were chosen because they are abundant in the MTD and are underrepresented in environmental contaminant biomonitoring studies. Ribbon snakes had significantly lower levels of lead, copper, and cadmium compared to whole body levels in anuran larvae, indicating that these metals were not biomagnifying through upper trophic levels. Copper and mercury levels were significantly correlated with age/growth indices in ribbon snakes. Although detectable levels of all metals were found in anuran larvae and ribbon snakes, these levels appear to be less than body burdens that would be associated with toxic effects. Populations of ribbon snakes in our particular collection sites within the MTD appear to be at minimal risk of exposure to toxic levels of metals. However, the MTD contains low- and high-impact areas, and other populations within this watershed could be at higher risk of exposure to heavy metals. We found the Eastern Ribbon Snake to be an excellent snake model for contaminant biomonitoring because of its abundance, reasonable size, and ease of collection. PMID- 17713812 TI - Observation of gastro-esophageal reflux by MRI: a feasibility study. AB - PURPOSE: To evaluate the feasibility of detecting and measuring gastro-esophageal reflux (GER) with esophageal MR fluoroscopy in patients suffering from heartburn. MATERIALS AND METHODS: Twenty patients with heartburn underwent esophageal MR fluoroscopy. The T1-FFE sequence was applied for MR imaging. We examined the frequency and the level of GER on MR images. Based on the MRI observations, patients were classified into four MRI grades (grade 1-4). Endoscopic findings were categorized into five grades (grade 0 to D). The overall MRI grade, Carlsson's questionnaire score, and endoscopic findings were compared. RESULTS: GER was observed with MR fluoroscopy in 19 of 20 patients. GER was observed only several times in three patients, and much more frequently in the remaining 16 patients. Elevated levels of GER reached the lower, middle-to-upper esophagus, and the hypopharynx. The observed MRI grades were grade 1 = 1 patient, grade 2 = 3 patients, grade 3 = 2 patients, and grade 4 = 13 patients. There was no statistical correlation between the questionnaire score and the MRI grade. Also, there was no correlation between the grade of endoscopic findings and MRI grade. Six patients demonstrated continuous reflux on MRI did not show mucosal injury at endoscopy. CONCLUSION: Esophageal MR fluoroscopy may be a useful diagnostic tool for GERD for its ability to show GER, even in patients with no mucosal injury, and for suggesting the cause of the reflux. PMID- 17713813 TI - Biodegradation of ethametsulfuron-methyl by Pseudomonas sp. SW4 isolated from contaminated soil. AB - A soil bacterium SW4, capable of degrading the sulfonylurea herbicide ethametsulfuron-methyl (ESM), was isolated from the bottom soil of a herbicide factory. Based on physiological characteristics, biochemical tests and phylogenetic analysis of the 16S rRNA gene sequence, the strain was identified as a Pseudomonas sp. The total degradation of ESM in the medium containing glucose was up to 84.6% after 6 days of inoculation with SW4 strain. The inoculation of strain SW4 to soil treated with ESM resulted in a higher degradation rate than in noninoculated soil regardless of the soil sterilized or nonsterilized. Five metabolites of ESM degradation were analyzed by liquid chromatography/mass spectrometry. Based on the identified products, strain SW4 seemed to degrade ESM after two separate and different pathways: one leads to the cleavage of the sulfonylurea bridge, whereas the other to the dealkylation and opening of the triazine ring of ESM. PMID- 17713814 TI - PilJ localizes to cell poles and is required for type IV pilus extension in Pseudomonas aeruginosa. AB - Twitching motility allows Pseudomonas aeruginosa to respond to stimuli by extending and retracting its type IV pili (TFP). PilJ is a protein necessary for this surface-associated twitching motility and bears high sequence identity with Escherichia coli methyl-accepting chemotaxis proteins (MCP). Here, we report that whereas wild-type P. aeruginosa PAO1 cells have extended pili at a single pole, pilJ mutant cells have shortened pili often at both poles despite normal levels of pilin accumulation, suggesting that PilJ is required for full TFP assembly/extension. Using yellow fluorescent protein fusions (pilJ-yfp), both plasmid born and in-frame chromosomal constructs, we determined that PilJ localizes to both poles of the cell. Overexpression of pilJ-yfp resulted in the protein accumulating between the poles. PMID- 17713815 TI - Biosorption and bioreduction of trivalent aurum by photosynthetic bacteria Rhodobacter capsulatus. AB - Biosorption has been shown to be an eco-friendly approach to remove heavy metal ions. In this study, the photosynthetic bacteria Rhodobacter capsulatus was screened and found to have strong ability to adsorb Au(III). The maximum specific uptake of living cells was over 92.43 mg HAuCl(4)/g dry weight of cell in the logarithmic phase. Biosorpion ability would be enhanced by an acidic environment. As the main cations, during biosorption the quantity of Mg(2+) exchanged was more than Na(+). Biosorbed Au(III) could be reduced by carotenoid and enzymes embedded and/or excreted by R. capsulatus, which might be the mechanism of photosynthtic bacteria metal tolerance. PMID- 17713816 TI - Replication of Legionella pneumophila in floating biofilms. AB - Biofilms are a major source of human pathogenic Legionella pneumophila in aquatic systems. In this study, we investigated the capacity of L. pneumophila to colonize floating biofilms and the impact of Acanthamoeba castellanii on the replication of biofilm-associated Legionella. Biofilms were grown in Petri dishes and consisted of Aeromonas hydrophila, Escherichia coli, Flavobacterium breve, and Pseudomonas aeruginosa. Six hours following inoculation, Legionella were detected in floating biofilms in mean concentrations of 1.4 x 10(4) cells/cm(2 )(real-time polymerase chain reaction) and 8.3 x 10(2) CFU/cm(2 )(culture). Two way analysis of variance tests and fluorescent in situ hybridization clearly proved that increased biofilm-associated L. pneumophila concentrations were the result of intracellular replication in A. castellanii. Forty-eight hours after the introduction of A. castellanii in the Petri dishes, 90 +/- 0.8% of the amoebae (infection rate) were completely filled with highly metabolic active L. pneumophila (mean infection intensity). PMID- 17713817 TI - Management of biliary tract disease during pregnancy: a decision analysis. AB - BACKGROUND: The appropriate management of biliary tract disease during pregnancy is uncertain. Although laparoscopic cholecystectomy can be performed safely during pregnancy, the timing and indications for this surgical intervention have not been firmly established. METHODS: We constructed a Markov decision analytic model that incorporates maternal well-being and fetal outcome into a choice between nonoperative management (NM) and laparoscopic cholecystectomy (LC) for pregnant women with biliary tract disease (BTD). Our model cycles through weeks of pregnancy for a cohort of 200 gravid women presenting with biliary tract disease in both the first and second trimesters. Weekly state probabilities and utilities for fetal outcome were derived from the literature, while weekly utilities for disease and operative states were estimated in consultation with obstetricians. We cycled the model from 6 to 42 weeks and from 19 to 42 weeks to simulate first and second trimester presentations. Outcomes are expressed in quality pregnancy weeks (QPWs). One QPW is the utility of a normal healthy week of pregnancy. RESULTS: A comprehensive search of the literature yielded a fetal death rate following LC for biliary tract disease of 2.2% and following NM of 7%. Relapse rates were found to be trimester dependent and estimated to be 55%, 55%, and 40% in the first, second, and third trimester, respectively. For a hypothetical cohort of 100 women presenting with biliary tract disease in their first trimester, LC generated 12,800 QPWs compared with 12,400 QPWs for NM, an average gain of 4 QPWs per woman. For the cohort of women entering the model in the second trimester, 11,600 QPWs were accrued by the LC group and 11,400 QPWs by the NM group, an average gain of 2 QPWs per woman. These findings were sensitive only to changes in fetal death rates under the two treatment arms. CONCLUSIONS: Laparoscopic cholecystectomy is superior to nonoperative management for pregnant women presenting in the first or second trimester with biliary tract disease. PMID- 17713819 TI - Metastatic Merkel cell carcinoma in the rectum: report of a case. AB - Merkel cell carcinoma is a rare, aggressive skin malignancy of neuroendocrine origin with predominant occurrence in the elderly males. Approximately 50 percent of patients with Merkel cell carcinoma develop distant metastasis at some point during the disease course; hence, Merkel cell carcinoma always has a poor prognosis. Distant metastasis has never been disclosed in the rectum to the best of our knowledge. We present a 76-year-old male with clinical manifestation of massive hematochezia and final diagnosis of metastatic Merkel cell carcinoma in the rectum. We conclude that radical resection of rectal metastatic Merkel cell carcinoma is important in the management strategy of a patient with recurrence and lymph node metastases. PMID- 17713818 TI - Antifouling activity of bromotyrosine-derived sponge metabolites and synthetic analogues. AB - Eighteen brominated sponge-derived metabolites and synthetic analogues were analyzed for antilarval settlement of Balanus improvisus. Only compounds exhibiting oxime substituents including bastadin-3 (4), -4 (1), -9 (2), and -16 (3), hemibastadin-1 (6), aplysamine-2 (5), and psammaplin A (10) turned out to inhibit larval settling at 1 to 10 microM. Analogues of hemibastadin-1 (6) were synthesized and tested for structure activity studies. Debromohemibastadin-1 (8) inhibited settling of B. improvisus, albeit at lower concentrations than hemibastadin-1 (6). Both 6 and 8 also induced cyprid mortality. 5,5' dibromohemibastadin-1 (7) proved to be nontoxic, but settlement inhibition was observed at 10 microM. Tyrosinyltyramine (9), lacking the oxime function, was not antifouling active and was non-toxic at 100 microM. Hemibastadin-1 (6) and the synthetic products showed no general toxicity when tested against brine shrimp larvae. In contrast to the lipophilic psammaplin A (10), the hydrophilic sulfated psammaplin A derivative (11) showed no antifouling activity even though it contains an oxime group. We therefore hypothesize that the compound needs to cross membranes (probably by diffusion) and that the target for psammaplin A lies intracellularly. PMID- 17713820 TI - Phenolic chemistry of coast live oak response to Phytophthora ramorum infection. AB - Since the mid 1990s, Phytophthora ramorum has been responsible for the widespread mortality of tanoaks, as well as several oak species throughout California and Oregon forests. However, not all trees die, even in areas with high disease pressure, suggesting that some trees may be resistant to the pathogen. In this study, the chemical basis of host resistance was investigated. Three field experiments were carried out in California between December 2004 and September 2005. The levels of nine phenolic compounds (gallic acid, catechin, tyrosol, a tyrosol derivative, ellagic acid, and four ellagic acid derivatives) extracted from the phloem of trees that had been either artificially inoculated with P. ramorum or trees putatively infected with P. ramorum (based on canker symptoms) were quantified by high-performance liquid chromatography (HPLC). Significant differences in phenolic profiles were found between phloem sampled from the active margins of cankers, healthy phloem from asymptomatic trees, and phloem sampled 60 cm away from canker sites, although the magnitude and direction of the responses was not consistent across all experiments. Concentrations of gallic acid, tyrosol, and ellagic acid showed the greatest differences in these different tissues, but varied considerably across treatments. Gallic acid and tyrosol were tested in in vitro bioassays and showed strong dose-dependent inhibitory effects against P. ramorum, P. cinnamomi, P. citricola, and P. citrophthora. These results suggest that phloem chemistry varies in response to pathogen infection in California coast live oak populations and that changes in phloem chemistry may be related to apparently resistant phenotypes observed in the field. PMID- 17713821 TI - Histological aggressiveness of fluorodeoxyglucose positron-emission tomogram (FDG PET)-detected incidental thyroid carcinomas. AB - BACKGROUND: We previously reported a high incidence of primary thyroid cancer in fluorodeoxyglucose positron-emission tomogram (FDG-PET)-detected incidental thyroid abnormalities. The aim of our study was to determine if these FDG-PET detected thyroid malignancies represent a more-aggressive variant of primary thyroid carcinoma. MATERIALS AND METHODS: All patients that underwent operative intervention for FDG-PET-detected incidental thyroid abnormalities were identified (June 2003 to April 2006). Patients with a diagnosis of primary thyroid carcinoma on final histopathology were included in the study. The patient demographics and histopathological findings were analyzed to identify adverse prognostic features. RESULTS: In 11,500 patients, 17,250 FDG-PET scans were performed; 377 of these patients (3.2% of patients and 2.1% of FDG-PET scans) had findings positive for thyroid abnormality. Of the 32 patients that underwent operative intervention, 22 patients with a final diagnosis of primary thyroid malignancy were included in the study. A greater number of patients [12 patients, (54%)] were noted to harbor poor prognostic variants of primary thyroid carcinoma on final histopathology [tall-cell variant: 11 patients (50%) and poorly differentiated thyroid carcinoma: 1 patient (4%)]. Extra-thyroidal extension (ETE) was noted in the majority of patients [14 patients (63%)]. In patients with tall cell variant on final histopathology, the rate of ETE was even higher [10 patients (90%)]. CONCLUSION: Thyroid malignancies incidentally detected on FDG PET scan harbor a high rate of unfavorable prognostic features and may represent a more-aggressive variant of primary thyroid carcinoma. These patients need to be subjected to further investigation with a view to possible operative intervention. PMID- 17713822 TI - Para-aortic involvement and interest of para-aortic lymphadenectomy after chemoradiation therapy in patients with stage IB2 and II cervical carcinoma radiologically confined to the pelvic cavity. AB - BACKGROUND: Pelvic radiation therapy with concomitant chemotherapy (PCRT) is the standard treatment of stage IB2/II cervical carcinoma. The impact of concomitant chemotherapy on positive para-aortic nodes (PA+), however, remains unknown. The aim of this study was twofold: to evaluate the rate of histological PA+ after PCRT and to determine the survival of patients with PA+. METHODS: Patients fulfilling the following inclusion criteria were studied: (1) stage IB2/II cervical carcinoma, (2) histological subtype: squamous cell, adenocarcinoma or an adenosquamous tumor, (3) exclusion of patients with radiological PA+ (CT scan/MRI), (4) pelvic external radiation therapy of 45 Gy with concomitant chemotherapy (cisplatin 40 mg/m2/week) + utero-vaginal brachytherapy, and (5) completion surgery after the end of PCRT including at least a para-aortic lymphadenectomy. RESULTS: Seventy-three patients (16 stage IB2, 57 stage II) treated between 1998 and 2004 fulfilled all the inclusion criteria. PA+ after PCRT were observed in 13 patients (18%) with a median of five (range, 2-22) positive nodes. Overall and disease-free survival at 24 months in patients with PA+ was 40% and 17%. Only two patients with PA+ are currently alive and in remission. CONCLUSIONS: The rate of PA+ remains high after PCRT in patients treated for stage IB2/II cervical carcinoma. Furthermore, the survival rate of patients with PA+ is very low. These important results suggest that detection of PA + at the time of completion surgery (after PCRT) is not beneficial for improving survival. PMID- 17713824 TI - Ureteroscopic holmium laser cutting for inadvertently sutured drainage tube (report of five cases). AB - The aim of this paper is to report a simple solution for inadvertently sutured drainage tube after urological surgery and discuss the different managements according to different types of this embarrassing complication. From September 2001 to January 2007, five inadvertently sutured drainage tubes were treated with ureteroscopic holmium laser cutting for the suture. All drainage tubes were removed after the operation without other complications. Holmium laser cutting via ureteroscope is a simple solution for the embarrassing problem of inadvertently sutured drainage tube. It can save the patient from undergoing another open surgery. PMID- 17713823 TI - Effects of neoadjuvant therapy on perioperative morbidity in elderly patients undergoing esophagectomy for esophageal cancer. AB - BACKGROUND: The use of cytoreductive therapy followed by surgery is preferred by many centers dealing with locally advanced esophageal cancer. However, the potential for increase in mortality and morbidity rates has raised concerns on the use of chemoradiation therapy, especially in elderly patients. The aim of this study was to assess the effects of induction therapy on postoperative mortality and morbidity in elderly patients undergoing esophagectomy for locally advanced esophageal cancer at a single institution. METHODS: Postoperative mortality and morbidity of patients > or = 70 years old undergoing esophagectomy after neoadjuvant therapy, between January 1992 and October 2005 for cancer of the esophagus or esophagogastric junction, were compared with findings in younger patients also receiving preoperative cytoreductive treatments. RESULTS: 818 patients underwent esophagectomy during the study period. The study population included 238 patients < 70 years and 31 > or = 70 years old undergoing esophageal resection after neoadjuvant treatment. Despite a significant difference in comorbidities (pulmonary, cardiological and vascular), postoperative mortality and morbidity were similar irrespective of age. CONCLUSIONS: Elderly patients receiving neoadjuvant therapies for cancer of the esophagus or esophagogastric junction do not have a significantly increased prevalence of mortality and major postoperative complications, although cardiovascular complications are more likely to occur. Advanced age should no longer be considered a contraindication to preoperative chemoradiation therapy preceding esophageal resection in carefully selected fit patients. PMID- 17713825 TI - The effect of low level laser irradiation on adult human adipose derived stem cells. AB - This study investigated the effect of low level laser irradiation on primary cultures of adult human adipose derived stem cells (ADSC) using a 635-nm diode laser, at 5 J/cm(2) with a power output of 50.2 mW and a power density of 5.5 mW/cm(2). Cellular morphology did not appear to change after irradiation. Using the trypan blue exclusion test, the cellular viability of irradiated cells increased by 1% at 24 h and 1.6% at 48 h but was not statistically significant. However, the increase of cellular viability as measured by ATP luminescence was statistically significant at 48 h (p < 0.05). Proliferation of irradiated cells, measured by optical density, resulted in statistically significant increases in values compared to nonirradiated cells (p < 0.05) at both time points. Western blot analysis and immunocytochemical labeling indicated an increase in the expression of stem cell marker beta1-integrin after irradiation. These results indicate that 5 J/cm(2) of laser irradiation can positively affect human adipose stem cells by increasing cellular viability, proliferation, and expression of beta1-integrin. PMID- 17713826 TI - Rescue therapy with anti-CD20 treatment in neuroimmunologic breakthrough disease. PMID- 17713827 TI - Ocular myasthenia revisited: insights from pseudo-internuclear ophthalmoplegia. AB - Ocular myasthenia can mimic central disorders of eye movements. We compared horizontal saccades in two patients with myasthenia gravis who presented as pseudo-internuclear ophthalmoplegia (pseudo-INO), two patients with true INO due to multiple sclerosis (MS), and five healthy subjects. In myasthenics, peak velocity of horizontal saccades was similar to, or greater than, controls; in MS patients, adducting saccades were slower than controls. Differences between the peak velocity of abducting and adducting eyes for each saccade were similar to controls for myasthenic pseudo-INO, but greater than controls for true INO. Using the technique of phase-plane analysis, in which eye velocity is plotted against eye position, we found that initial components of abducting and adducting saccades in the myasthenics were as conjugate as controls, even though later components of myasthenic saccades were highly and variably disjunctive. Conversely, phase planes of saccades in true INO showed disjunctive early components of abducting and adducting saccades. Two hypotheses have been offered to account for preservation of fast saccades despite reduced range of eye movements in ocular myasthenia. The first is intrasaccadic neuromuscular fatigue, which is variable over time. Our finding that initial components of saccades were consistently conjugate in the myasthenics gives support to a second hypothesis: selective sparing of pale global fibers, which are important for generating highspeed eye movements, and which are unique amongst extraocular fibers in possessing well developed synaptic folding. PMID- 17713838 TI - The nucleotide sequence and genome organization of Magnaporthe oryzae virus 1. AB - Magnaporthe oryzae virus 1 (MoV1) found in Magnaporthe oryzae, the pathogenic fungus responsible for rice blast, is a small icosahedral virus with a nonsegmented double-stranded RNA genome. The viral genome has two open reading frames (ORF 1 and 2). The deduced amino acid sequences of both ORF 1 and ORF 2 show a significant similarity to those of capsid protein and RdRp, respectively, of members of the family Totiviridae. Both a comparison of genome organization and phylogenic analysis have indicated that MoV1 is closely related to some of the totiviruses that infect filamentous fungi. These results suggest that MoV1 belongs to the family Totiviridae. PMID- 17713839 TI - Do oral contraceptives act as mood stabilizers? Evidence of positive affect stabilization. AB - Previous research has suggested that oral contraceptives (OCs) may provide a stabilizing effect on affect. The present study examined whether OC users and nonusers differ in their affect reactivity in response to four laboratory mood induction procedures. A sample of 107 undergraduate students (40 OC users, 36 nonusers, and 31 men) completed the Positive and Negative Affect Schedule (PANAS) before and after completing a series of four mood-induction procedures (i.e., positive affect, jealousy, social ostracism, and parental feelings affect inductions). OC users experienced a blunted positive affect response to the tasks when compared with nonusers and men. Women who used OCs for less than two years showed the lowest positive affect reactivity. The groups did not differ in terms of negative affect reactivity. The results suggest that hormonal contraceptives may reduce the degree of positive affect change that women experience in response to environmental events. Possible mechanisms for an OC-induced positive affect stabilization effect are discussed. PMID- 17713840 TI - Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis. AB - The mammalian target of rapamycin (mTOR) is a controller of cell growth with multiple effects on cancer development and progression. Being closely linked to key oncogenic pathways that regulate tumor cell growth and cell cycle progression, mTOR integrates the cellular response to mitogenic and growth stimuli. Rapamycin and its analogs temsirolimus and everolimus are specific inhibitors of mTOR that exert suppressive effects on proliferation, invasion, and metastasis and induce apoptosis of tumor cells. Apart from the direct effects of mTOR inhibitors on tumor cells, rapamycin and its analogs have potent antiangiogenic properties related to the suppression of vascular endothelial growth factor signal transduction. While the use of mTOR inhibitors as a monotherapy seems to be insufficient to effectively control tumor progression in most tumor entities, combination with tyrosine kinase inhibitors or cytotoxic agents might potentiate the antitumoral effects of mTOR inhibition. In a clinical setting, mTOR inhibitors show an acceptable safety profile over a wide dose range. Currently, mTOR inhibitors are tested in multiple trials in combination with other agents in various cancer entities in intermittent schedules to avoid immunosuppression. However, lacking adequate surrogate and response parameters, the most effective biological dosing schedules remain to be defined. Considering these apparent limitations, the full clinical potential of this promising class of drugs is at risk to be missed by applying them inadequately. PMID- 17713841 TI - Estrogen delays the progression of salt-induced cardiac hypertrophy by influencing the renin-angiotensin system in heterozygous proANP gene-disrupted mice. AB - Left ventricular hypertrophy is considered an independent risk factor for cardiac morbidity and mortality, and many studies have shown that women have a lower incidence of left ventricular hypertrophy even after correcting for numerous risk factors. This cardio-protective effect seen in women has been attributed to estrogen, which likely modulates specific growth-promoting systems such as the renin-angiotensin system, and in turn may lead to the prevention of left ventricular hypertrophy. Furthermore, the underlying mechanisms responsible are poorly understood. The aim of the present study was to examine the effect of estrogen in relation to its impact on the development of left ventricular hypertrophy through its interaction with the renin-angiotensin system by using the proANP heterozygous (ANP +/-) mouse as a model of salt-sensitive cardiac hypertrophy. Male, female ANP +/- mice and also ovariectomized female ANP +/- mice treated with oil or estrogen, were fed either a normal or high-salt diet. All four groups exhibited a general suppression of the renin-angiotensin system under the high salt challenge. However, after the 5-week treatment period, marked left ventricular hypertrophy was noted only in the male and oil-injected ovariectomized female ANP +/- mice treated with high salt. Collectively, we provide direct evidence that the differences in cardiac hypertrophy between genders in ANP +/- mice is attributed to estrogen. Furthermore, estrogen may play a key role in slowing down the progression of salt-induced left ventricular hypertrophy in ANP +/- mice, in part, independent of the classical systemic renin angiotensin system and possibly through other pathways. PMID- 17713842 TI - Alternol inhibits proliferation and induces apoptosis in mouse lymphocyte leukemia (L1210) cells. AB - Alternol is a novel compound purified from the fermenting products by microorganisms named as Alternaria alternata var. monosporus from the bark of Yew. In this study, we tested its effect on mouse lymphocyte leukemia L1210 cells. Alternol was found to inhibit the proliferation and induce apoptosis in L1210 cells. When the cells were treated with Alternol, chromatin condensation and phosphatidylserine externalization were observed with the down-regulation of the pro-survival gene Bcl-2 and the activation of caspase-3, caspase-9, but not caspase-8. Moreover, exposure of cells to Alternol resulted in a significant increase in reactive oxygen species (ROS) and mitochondrial transmembrane potential (DeltaPsim) depolarization. Taken together, these results demonstrate that Alternol is a potent agent in inducing L1210 cells to apoptosis, which involve caspase activation and ROS generation. PMID- 17713843 TI - Effect of polymerization degree of calcium polyphosphate on its microstructure and in vitro degradation performance. AB - Preparation, characterization and in vitro study of a series of calcium polyphosphate (CPP) with different polymerization degree were reported. A series of CPP with different polymerization degree were prepared by controlling calcining time. Average polymerization degree was analyzed by liquid state 31P nuclear magnetic resonance (NMR). The microstructure was observed by scanning electric microscope (SEM). X-ray diffraction (XRD) analysis was used to demonstrate that polymerization degree would not affect the crystal system and space group of CPP. The results showed that polymerization degree increased with the increase of calcining time. Degradation studies were performed during 32 days in physiological saline solution (aqueous solution, 0.9 wt.%NaCl) to assess the effect of polymerization degree on the degradation velocity of the samples. It was also shown that the degradation velocity of CPP (polymerization degree=13) doubles than another two samples (polymerization degree=9,19). The results in the present study may be able to provide some fundamental data for controlling CPP degradation. PMID- 17713845 TI - Temperature-dependent time-resolved fluorescence study of cinchonine alkaloid dication. AB - Photo induced excited state dynamical processes of cinchonine alkaloid dication (C(++)) have been studied over a wide range of temperature using steady state and nanosecond time-resolved fluorescence spectroscopic techniques. The temperature dependent fluorescence studies of C(++) clearly indicate the existence of two distinct emitting species having their own characteristic decay rates. The shorter-lived species shows a usual temperature dependence with increasing non radiative deactivation at higher temperatures, while the longer-lived species show features resembling to the excited state solvent relaxation process with a large solvent relaxation time (tau(r) approximately 6 ns). The species emitting in the lower energy side, having longer decay time is found to be more sensitive towards chloride ion quenching and has a charge transfer character. Further, concentration quenching with decrease in tau(r) of long lived species shows the possibility of energy migration along with solvent relaxation in C(++). PMID- 17713844 TI - Genetically engineered block copolymers: influence of the length and structure of the coiled-coil blocks on hydrogel self-assembly. AB - PURPOSE: To explore the relationship between the structure of block polypeptides and their self-assembly into hydrogels. To investigate structural parameters that influence hydrogel formation and physical properties. METHODS: Three ABA triblock and two AB diblock coiled-coil containing polypeptides were designed and biologically synthesized. The triblock polypeptides had two terminal coiled-coil (A) domains and a central random coil (B) segment. The coiled-coil domains were different in their lengths, and tyrosine residues were incorporated at selected solvent-exposed positions in order to increase the overall hydrophobicity of the coiled-coil domains. The secondary structures of these polypeptides were characterized by circular dichroism and analytical ultracentrifugation. The formation of hydrogel structures was evaluated by microrheology and scanning electron microscopy. RESULTS: Hydrogels self-assembled from the triblock polypeptides, and had interconnected network microstructures. Hydrogel formation was reversible. Denaturation of coiled-coil domains by guanidine hydrochloride (GdnHCl) resulted in disassembly of the hydrogels. Removal of GdnHCl by dialysis caused coiled-coil refolding and hydrogel reassembly. CONCLUSIONS: Protein ABA triblock polypeptides composed of a central random block flanked by two coiled coil forming sequences self-assembled into hydrogels. Hydrogel formation and physical properties may be manipulated by choosing the structure and changing the length of the coiled-coil blocks. These self-assembling systems have a potential as in-situ forming depots for protein delivery. PMID- 17713846 TI - Segmented frequency-domain fluorescence lifetime measurements: minimizing the effects of photobleaching within a multi-component system. AB - This study introduces a newly developed frequency segmentation and recombination method for frequency-domain fluorescence lifetime measurements to address the effects of changing fractional contributions over time and minimize the effects of photobleaching within multi-component systems. Frequency segmentation and recombination experiments were evaluated using a two component system consisting of fluorescein and rhodamine B. Comparison of experimental data collected in traditional and segmented fashion with simulated data, generated using different changing fractional contributions, demonstrated the validity of the technique. Frequency segmentation and recombination was also applied to a more complex system consisting of pyrene with Suwannee River fulvic acid reference and was shown to improve recovered lifetimes and fractional intensity contributions. It was observed that photobleaching in both systems led to errors in recovered lifetimes which can complicate the interpretation of lifetime results. Results showed clear evidence that the frequency segmentation and recombination method reduced errors resulting from a changing fractional contribution in a multi component system, and allowed photobleaching issues to be addressed by commercially available instrumentation. PMID- 17713847 TI - Preparing Child Care Health Consultants to address childhood overweight: a randomized controlled trial comparing web to in-person training. AB - OBJECTIVES: Child care centers have recently become targets for overweight prevention efforts directed at young children. Child Care Health Consultants (CCHCs), who provide consultation to these centers, receive little training on the basic nutrition and physical activity principles important for the promotion of child healthy weight. Traditional approaches, such as in-person training, are limited in their ability to disseminate health information to a geographically diverse population of health professionals. The purpose of this study was to determine if web-based training is as effective as in-person training. METHODS: A randomized controlled trial was conducted between August 2005 and June 2006 with 50 CCHCs. Web-based and in-person trained CCHCs were compared to each other and to controls. The main outcome of this study was performance on a test of nutrition knowledge related to childhood overweight measured by a 28-item multiple choice test administered pre- and post-training. RESULTS: Results from the ANCOVA model suggest that web trained CCHCs performed similarly to in-person trained CCHCs on the knowledge test (P < .0001). Additionally, both training groups improved significantly compared to controls (P < .0001 for each group). CONCLUSIONS: This study found no significant differences in post-training knowledge between in-person and web trained Child Care Health Consultants. Scores on the post-training knowledge test were within 0.5 points for the in-person and web trained groups. These results demonstrate that web-based instruction is as effective as in-person training on improving basic nutrition and physical activity knowledge for promoting healthy weight in preschool children. PMID- 17713849 TI - Maternal mortality in Argentina: a closer look at women who die outside of the health system. AB - OBJECTIVES: To assess maternal mortality among women who died outside health institutions. To use the technique of verbal autopsy to identify maternal deaths and to obtain qualitative information about the determinants of maternal death using the "three delays" model. METHODS: Subjects were women aged 10-49 who died outside of a health institution during 2002 in five Argentine provinces with maternal mortality ratios above the national average. Cases were identified through the national and provincial registries, and data were collected using verbal autopsies, where the relatives of the deceased are interviewed. RESULTS: Of 252 completed verbal autopsies, 15 maternal deaths and five late maternal deaths were found. Hemorrhage was the most common cause of maternal death. Seventy-nine percentage of women who died of maternal causes experienced at least one delay in accessing care, with delays in seeking assistance as the most common, followed by delays in accessing and receiving quality care. CONCLUSIONS: Maternal causes of death are equally prevalent among women who die outside the health system as among those who die within it, but avoidable deaths are still a problem. Interventions to improve understanding of "alarm signals" (serious symptoms) and improved access and quality of care are necessary to reduce maternal mortality. PMID- 17713848 TI - Pre-pregnancy body mass index, gestational weight gain, and other maternal characteristics in relation to infant birth weight. AB - OBJECTIVES: Infant birth weight is influenced by modifiable maternal pre pregnancy behaviors and characteristics. We evaluated the relationship among pre pregnancy body mass index (BMI), gestational weight gain, and infant birth weight, in a prospective cohort study. METHODS: Women were enrolled at < or =20 weeks gestation, completed in-person interviews and had their medical records reviewed after delivery. Infant birth weight was first analyzed as a continuous variable, and then grouped into Low birth weight (LBW) (<2,500 g), normal birth weight (2,500-3,999 g), and macrosomia (> or =4,000 g) in categorical analysis. Pre-pregnancy BMI and gestational weight gain were categorized based on Institute of Medicine BMI groups and gestational weight gain guidelines. Associations among infant birth weight and pre-pregnancy BMI, gestational weight gain, and other factors were evaluated using multivariate regression. Risk ratios were estimated using generalized linear modeling procedures. RESULTS: Pre-pregnancy BMI was independently and positively associated with infant birth weight (beta = 44.7, P = 0.001) after adjusting for confounders, in a quadratic model. Gestational weight gain was positively associated with infant birth weight (beta = 19.5, P < 0.001). Lower infant birth weight was associated with preterm birth (beta = 965.4, P < 0.001), nulliparity (beta = -48.6, P = 0.015), and female babies (beta = -168.7, P < 0.001). Less than median gestational weight gain was associated with twice the risk of LBW (RR = 2.04, 95% CI 1.34-3.11). Risk of macrosomia increased with increasing pre-pregnancy BMI and gestational weight gain (P for linear trend <0.001). CONCLUSIONS: These findings support the need to balance pre pregnancy weight and gestational weight gain against the risk of LBW and macrosomia among lean and obese women, respectively. PMID- 17713850 TI - Effects of visual erotic stimulation on vibrotactile detection thresholds in men. AB - This study examined the effects of sexual arousal on vibration detection thresholds in the right index finger of 30 healthy, heterosexual males who reported no sexual dysfunction. Vibrotactile detection thresholds at frequencies of 30, 60, and 100 Hz were assessed before and after watching erotic and control videos using a forced-choice, staircase method. A mechanical stimulator was used to produce the vibratory stimulus. Results were analyzed using repeated measures analysis of variance. After watching the erotic video, the vibrotactile detection thresholds at 30, 60, and 100 Hz were significantly reduced (p < .01). No changes in thresholds were detected at any frequency following exposure to the non-erotic stimulus. The results show that sexual arousal resulted in an increase in vibrotactile sensitivity to low frequency stimuli in the index finger of sexually functional men. PMID- 17713852 TI - The therapeutic effects of tyrosine hydroxylase gene transfected hematopoetic stem cells in a rat model of Parkinson's disease. AB - AIMS: To investigate the therapeutic effects of tyrosine hydroxylase (TH) transfected neuronal stem cells derived from bone marrow stem cells (NdSCs-D BMSCs) on Parkinson's disease (PD) through different transplantation protocols, including microinjection into the cerebral ventricles (CV) and the striatum (ST). METHODS: After identification by enzyme digestion, the constructed plasmid pEGFP C2-TH was transfected into 8-day-cultured NdSCs-D-BMSCs by electroporation resulting in the coexpression of green fluorescent protein (GFP) and TH. The TH transfected cells were injected into either the right ST or CV of PD rats. The changes in locomotor activity of PD rats and the migration of transplanted cells in cerebral tissue were monitored and cerebral DA levels were assayed by high performance liquid chromatography (HPLC). RESULTS: Five days after plasmid pEGFP C2-TH transfection into NdSCs-D-BMSCs GFP was expressed in 62.1% of the cells and the rate of co-expression with TH was 83.5%. Ten weeks following transplantation, the symptoms of PD rats in both groups were significantly improved and DA levels were restored to 46.6% and 33% of control. The transferred cells showed excellent survival rates in PD rat brains and distant migration was observed. CONCLUSION: Both CV and ST transplantation of TH-transfected NDSCs-D-BMSCs has obvious therapeutic effects on PD rats. This study could provide evidence for future transplantation route selection, possibly leading to stem cell transplantation through lumbar puncture. PMID- 17713853 TI - The role of 3-O-methyldopa in the side effects of L-dopa. AB - Long-term treatment of L-dopa for Parkinson's disease (PD) patients induces adverse effects, including dyskinesia, on-off and wearing-off symptoms. However, the cause of these side effects has not been established to date. In the present study, therefore, 3-O-methyldopa (3-OMD), which is a major metabolite of L-dopa, was tested to determine whether it plays a role in the aforementioned adverse effects. The effects of 3-OMD on the dopaminergic nervous system in the brain were investigated, by examining behavioral, biochemical, and cellular changes in male Sprague-Dawley rats and catecholamine-producing PC12 neuronal cells. The results revealed that the intracerebroventricular (icv) injection of 1 micromol of 3-OMD impaired locomotor activities by decreasing movement time (MT), total distance (TD), and the number of movement (NM) by 70, 74 and 61%, respectively. The biochemical analysis results showed that a single administration of 1 micromole of 3-OMD decreased the dopamine turnover rate (DOPAC/DA) by 40.0% in the rat striatum. 3-OMD inhibited dopamine transporter and uptake in rat brain striatal membranes and PC12 cells. The subacute administration of 3-OMD (5 days, icv) also significantly impaired the locomotor activities and catecholamine levels. 3-OMD induced cytotoxic effects via oxidative stress and decreased mitochondrial membrane potential in PC12 cells, indicating that 3-OMD can damage neuronal cells. Furthermore, 3-OMD potentiated L-dopa toxicity and these toxic effects induced by both 3-OMD and L-dopa were blocked by vitamin E (alpha tocopherol) in PC12 cells, indicating that 3-OMD may increase the toxic effects of L-dopa to some extent by oxidative stress. Therefore, the present study reveals that 3-OMD accumulation from long-term L-dopa treatment may be involved in the adverse effects of L-dopa therapy. Moreover, L-dopa treatment might accelerate the progression of PD, at least in part, by 3-OMD. PMID- 17713854 TI - Effects of Nigella sativa and its major constituent, thymoquinone on sciatic nerves in experimental diabetic neuropathy. AB - The aim of this study was designed to investigate the possible beneficial effects of Nigella sativa (NS) and thymoquinone (TQ) on histopathological changes of sciatic nerves in streptozotocin-induced diabetic rats. The rats were randomly allotted into one of four experimental groups: A (control), B (diabetic untreated), C (diabetic treated with NS) and D (diabetic treated with TQ); each group contain ten animals. B, C and D groups received streptozotocin (STZ) to induce diabetes. The rats in NS and TQ treated groups were given NS (in a dose of 400 mg/kg body weight) and TQ (50 mg/kg body weight) once a day orally by using intra-gastric intubation for 12 weeks starting 2 days after STZ injection, respectively. Blood and tissue samples were obtained for biochemical and histopathological investigation. The treatment of both NS and TQ caused a sharp decrease in the elevated serum glucose (P < 0.01, 0.05, respectively), and an increase in the lowered serum insulin concentrations (P < 0.01, 0.05, respectively), in STZ-induced diabetic rats. STZ induced a significant decrease in the area of insulin immunoreactive beta-cells (P < 0.0001). NS (P < 0.001) and TQ (P < 0.01) treatment resulted in increased area of insulin immunoreactive beta cells significantly. To date, no histopathological changes of sciatic nerves in STZ induced diabetic rats by NS and TQ treatment have been reported. In this study, histologic evaluation of the tissues in diabetic animals treated with TQ and especially NS showed fewer morphologic alterations. Myelin breakdown decreased significantly after treatment with NS and TQ. The ultrastructural features of axons also showed remarkable improvement. We believe that further preclinical research into the utility of NS and TQ may indicate its usefulness as a potential treatment on peripheral neuropathy (PN) in STZ induced diabetic rats. PMID- 17713855 TI - Novel biodegradable stents for benign esophageal strictures following endoscopic submucosal dissection. AB - The application of metallic stents for benign stenosis is limited due to long term complications. We report here the results of the implantation of a novel biodegradable poly-L-lactic acid (PLLA) esophageal stent in two patients with benign esophageal stenosis after endoscopic submucosal dissection (ESD). Case 1 was a 64-year-old man who received ESD for an early squamous esophageal cancer in the middle esophagus. The mucosal defect was seven-eighths of the circumference, and the distal margin of the resection scar formed the stenosis. After balloon dilatation, the PLLA esophageal stent was endoscopically placed; for 6 months, he has not experienced any symptoms of re-stenosis. Case 2 consisted of a 62-year old man who developed an early squamous esophageal cancer in the middle esophagus. The lesion was resected by ESD, and the mucosal defect was seven eighths of the circumference. The resection scar formed the stenosis, and the PLLA esophageal stent was endoscopically placed. He also has not experienced any symptoms of re-stenosis for 6 months. In conclusion, the PLLA esophageal stent provides a new possibility for the management of benign esophageal strictures after ESD. Due to the biodegradable features of this stent, longer term studies are necessary to investigate the relationship between the expected disappearance of the stent and the patency of the stricture. PMID- 17713857 TI - Potent induction of TNF-alpha during interaction of immune effectors with oral tumors as a potential mechanism for the loss of NK cell viability and function. AB - The inhibitory role of TNF-alpha on survival of naive and IL-2 treated NK cells has been demonstrated in the past. However, its effect on the function of these cells against tumor cells, in particular against oral tumors has not been established. We investigated the significance of secreted TNF-alpha in death and functional loss of splenocytes and NK cells in ex-vivo cultures with oral tumors. Oral tumors trigger potent secretion of TNF-alpha by human and murine immune effectors. Absence of TNF-alpha increases the cytotoxic activity and secretion of IFN-gamma by IL-2 treated splenocytes and NK cells in co-cultures with MOK L2D1+/p53-/- oral tumor cells. IL-2 treated splenocytes and NK cells from TNF alpha -/- mice survive and proliferate more when compared to cells from TNF-alpha +/+ mice. Cell death induced by F. nucleatum, an oral bacteria, in TNF-alpha -/- splenocytes are considerably lower than that induced in TNF-alpha +/+ splenocytes where potent release of TNF-alpha is reproducibly observed. Addition of exogenous rTNF-alpha to IL-2 treated splenocytes and NK cells decreased survival and function of splenocytes and NK cells obtained from TNF-alpha -/- mice against oral tumors. These findings suggest that potent induction of TNF-alpha during interaction of immune effectors with oral tumors and/or oral bacteria is an important factor in decreasing the function and survival of cytotoxic immune effectors. Strategies to neutralize TNF-alpha may be beneficial in the treatment of oral cancers. PMID- 17713856 TI - Effects of the Communities That Care model in pennsylvania on youth risk and problem behaviors. AB - We undertook the first broad-scale quasi-experimental evaluation of youth outcomes in communities using the Communities That Care program (Hawkins, J. D., & Catalano, R. F., Jr. San Francisco, CA, USA: Jossey-Bass Inc, Publishers, 1992a), which targets adolescent problem behaviors. We evaluated 15 risk factors and 6 outcomes (substance use and delinquent behaviors) for 38,107 youth in 2001 and 98,436 youth in 2003 in Pennsylvania schools. Multilevel analyses compared student reports in communities with CTC programs to comparable communities without CTC, while controlling for level of poverty in the community. Results favored the CTC communities at greater than chance levels in terms of lower rates of some risk factors and outcomes. In a follow-up analysis, CTC community grade cohorts were included only if the grade cohort was expected to benefit from a CTC sponsored program (based on timing of program implementation and target age of the program). Evidence of CTC effects for grade cohorts that received evidence based programs was even stronger. These findings suggest that community coalitions can affect adolescent public health problems at a population level, especially when evidence-based programs are utilized. PMID- 17713858 TI - Cytogenetic analysis of four species of Pseudis (Anura, Hylidae), with the description of ZZ/ZW sex chromosomes in P. tocantins. AB - Pseudis paradoxa paradoxa, P. p. platensis, P. bolbodactyla, P. fusca and P. tocantins were analyzed cytogenetically by conventional chromosomal staining, C banding, silver staining and fluorescent in situ hybridization with an rDNA probe. Pseudis tocantins chromosomes were also stained with distamycin A/DAPI. All of the species had a diploid number of 2n = 24 chromosomes and the nucleolar organizer region (NOR) was located on pair 7. However, the karyotypes could be differentiated based on the morphology of chromosomal pairs 2 and 8, the region that the NORs occupied on the long arms of the homologous of pair 7, and the pattern of heterochromatin distribution. The subspecies P. p. paradoxa and P. p. platensis had identical karyotypes. Heteromorphism in NOR size was seen in P. p. paradoxa, P. p. platensis, P. bolbodactyla and P. fusca. Heteromorphic sex chromosomes (ZZ/ZW) were identified in P. tocantins. The W chromosome was subtelocentric and larger than the metacentric Z chromosomes. The differences observed in the C-banding pattern and in the position of the NOR on the sex chromosomes suggested that inversions and heterochromatinization were responsible for the morphological differentiation of these chromosomes. PMID- 17713859 TI - Interactions among phytophagous mites, and introduced and naturally occurring predatory mites, on strawberry in the UK. AB - In choice test experiments on strawberry leaf disc arenas the phytoseiid mites Neoseiulus californicus and N. cucumeris were more effective than Typhlodromus pyri as predators of the phytophagous mites Tetranychus urticae and Phytonemus pallidus. There were no preferences shown for either prey by any of these predators. In multiple predator leaf disc experiments both Phytoseiulus persimilis and N. cucumeris significantly reduced numbers of T. urticae eggs and active stages; this effect was seen when the two species were present alone or in combination with other predator species. Neoseiulus californicus was less effective at reducing T. urticae numbers, and T. pyri was not effective; no interaction between predator species was detected in these experiments. When T. urticae alone was present as prey on potted plants, P. persimilis and N. californicus were the only phytoseiids to significantly reduce T. urticae numbers. These two predator species provided effective control of T. urticae when P. pallidus was also present; however, none of the predators reduced numbers of P. pallidus. There were no significant negative interactions when different species of predators were present together on these potted plants. In field experiments, releases of both P. persimilis and N. cucumeris significantly reduced T. urticae numbers. However, there was a significant interaction between these predator species, leading to poorer control of T. urticae when both species were released together. These results show the importance of conducting predator/prey feeding tests at different spatial scales. PMID- 17713860 TI - Mapping nitrate leaching to upper groundwater in the sandy regions of The Netherlands, using conceptual knowledge. AB - The European Community asks its Member States to provide a comprehensive and coherent overview of their groundwater chemical status. It is stated that simple conceptual models are necessary to allow assessments of the risks of failing to meet quality objectives. In The Netherlands two monitoring networks (one for agriculture and one for nature) are operational, providing results which can be used for an overview. Two regression models, based upon simple conceptual models, link measured nitrate concentrations to data from remote sensing images of land use, national forest inventory, national cattle inventory, fertiliser use statistics, atmospheric N deposition, soil maps and weather monitoring. The models are used to draw a nitrate leaching map and to estimate the size of the area exceeding the EU limit value in the early 1990s. The 95% confidence interval for the fraction nature and agricultural areas where the EU limit value for nitrate (50 mg/l) was exceeded amounted to 0.77-0.85 while the lower 97.5% confidence limit for the fraction agricultural area where the EU limit value was exceeded amounted to 0.94. Although the two conceptual models can be regarded as simple, the use of the models to give an overview was experienced as complex. PMID- 17713861 TI - Association of angiotensin-converting enzyme (ACE) gene insertion-deletion polymorphism with spondylarthropathies. AB - Low back pain (LBP) is a common medical problem. Interaction between genetic and environmental factors predisposes individuals to LBP even at an early age. Inflammatory back pain or spondylarthropathies include ankylosing spondylitis (AS), psoriatic arthritis (PSA), reactive arthritis enteropathic and undifferentiated arthropathies. Angiotensin-converting enzyme (ACE) plays an important role in circulatory homeostasis, physiology of vasculature and inflammation. The insertion-deletion (I/D) polymorphism of the ACE gene has been shown to determine the plasma and tissue levels of ACE especially in the synovial fluid. The aim of this study was to investigate an association between ACE gene I/D polymorphism and inflammatory back pain (spondylarthropathies) secondary to ankylosing spondylitis (AS), psoriatic arthritis, inflammatory bowel disease and undifferentiated spondylarthropathies. The prevalence of ACE gene I/D polymorphism genotypes was determined in 63 patients with inflammatory back pain by polymerase chain reaction (PCR) and compared with that in 111 healthy controls. Of the 63 patients studied, 45 (71.4%) were with AS, 13 (20.6%) were with PSA, 4 (6.3%) were with reactive arthropathy and 1 (1.6%) manifested undifferentiated arthropathy. There were 43 males and 20 females. Mean age of patients was 39.0+/-11.36 years, age at onset of spondylarthropathy was 27.7+/ 7.49 years and disease duration was 10.3+/-7.74 months. The controls were selected to match with the patients group in terms of gender ratio, age and ethnicity. The ACE gene polymorphism showed an overall significant difference between patients and controls (p=0.050). When the ID and II genotype frequency was combined and compared with that for DD genotype amongst patient and control groups, a considerably higher incidence was detected for ID and II genotypes than the DD genotype in spondylarthropathy patients compared to that in the controls (p=0.036). This study showed a significant association of the I-allele of ACE gene I/D polymorphism with spondylarthropathy in Kuwaiti Arabs. PMID- 17713862 TI - [Again every summer: burn injuries from barbecue grills]. PMID- 17713863 TI - [Influenza: acceptance of vaccination by healthcare personnel. Evaluation of the influenza season 2006/2007]. AB - BACKGROUND AND OBJECTIVE: Since 1988 the recommendations of the Standing Committee on Vaccination (STIKO) at the Robert Koch Institute has explicitly designated healthcare workers (HCW) as persons that should be vaccinated against influenza. However, the acceptance rate of influenza vaccination within medical personnel is low. This account describes reasons why the vaccination rate remains inadequate and how it could be improved. METHODS: At the University Hospital Frankfurt an anonymized questionnaire regarding the attitude towards influenza vaccination was distributed in the course of a vaccination campaign in 2006/2007. 1,052 healthcare workers among 4,080 healthcare workers (2,715 females/ [66.5%]; 1,365 males [ 33.5%] were vaccinated against influenza (35.8%), 628 females and 419 males, while gender was not recorded for five. Most of the participants (76.2%) were between 20 and 49 years old. RESULTS: An extensive information campaign achieved an increase in the influenza vaccination rate. Nevertheless significant vaccination gaps still exist. A mere 25.8% of personnel participated in the influenza vaccination campaign. CONCLUSION: In spite of an extensive vaccination campaign and a significantly increased vaccination rate of the personnel (3.5% in 2001/2002; 25.8% in 2006/2007), the acceptance of influenza vaccination remains low. Long-term measures are required to obtain better rates for preventive vaccine protection against influenza. PMID- 17713864 TI - [Complete remission of relapsed mixed cellularity Hodgkin's disease treated with rituximab]. AB - INTRODUCTION: Cure rates of Hodgkin's disease (HD) with chemotherapy and/or radiotherapy are high. However, a few patients are refractory to treatment or relapse. We describe a patient with mixed cellularity (MC)-type HD with frequent relapses. As all Hodgkin's or Hogan-Reed-Sternberg (HRS) cells expressed CD20, treatment with the anti-CD20 monoclonal antibody rituximab was given. HISTORY AND ADMISSION FINDINGS: A 55-year-old man presented with cervical lymphadenopathy. Biopsy revealed HD of MC type in stage IVA (Ann Arbor classification). Complete remission (CR) was achieved after six cycles of doxorubicin-bleomycin-vinblastin dacarbazine (ABVD) and cyclophosphamid-vincristine-procarbazine-prednison (COPP) regimens. The first relapse occurred 12 months later and was treated with DEXA BEAM and autologous peripheral blood stem cell transplantation. 7 years later, the patient relapsed again. Histology confirmed the initial diagnosis. Staging revealed a stage IVA. A partial remission was induced with two further DEXA-BEAM cycles (dexamethasone, BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea], ectoposide, ara-C, melphalan). 4 months later, the disease progressed. Despite treatment with gemcitabine there was no response. As all Hogan-Reed-Sternberg (HRS) cells were CD20 positive, rituximab (monoclonal antibodies) was given at a dose of 375 mg/m2 once a week for 4 weeks in an outpatient setting. RESULTS: Treatment was well tolerated. A complete remission was achieved 2 months later. No infectious episodes occurred. After 30 months, the patient relapsed again. A second treatment with rituximab yielded another complete remission which was maintained for 20 months. CONCLUSION: HRS cells are derived from germinal center B-cells in more than 90% of cases, B-cell markers being present in 80% of classical HD. CD20 expressions vary from 21-80%. A few patients with HD treated with rituximab have been reported. Most of these cases had lymphocyte-predominant HD. In our patient the safety and efficacy of rituximab in relapsed CD20-positive classical HD of an MC type was demonstrated to achieve long-lasting remission. PMID- 17713865 TI - [Type IV-allergy due to corticosteroids. Rare and paradoxical]. AB - HISTORY AND CLINICAL FINDINGS: A 48-year-old woman developed a skin rash after taking glucocorticoids. INVESTIGATIONS: Positive patch tests revealed type IV allergy (delayed reaction) to several glucocorticoids. In addition an eczema-like rash was produced by an oral provocation test with triamcinolone, although the patch test for this drug had been negative. TREATMENT AND COURSE: We recommended avoidance of the positively-tested corticosteroids and issued a corresponding allergy pass. CONCLUSION: Type IV allergy to glucocorticoids is rare but should be considered whenever patients develop a skin rash after the use of corticosteroids. PMID- 17713866 TI - [Carcinoma of the pancreas: summary of guidelines 2007, issued jointly by 15 German specialist medical societies]. PMID- 17713867 TI - [Erroneous electrode connection]. PMID- 17713869 TI - [Pericardiocentesis]. PMID- 17713868 TI - [Lung and autoimmune disease--therapy]. AB - Pulmonary manifestations of autoimmune diseases are treated depending on the involved lung structure and the underlying disorder. In this review the therapeutic approach in the case of vascultitis, rheumatoid arthritis and connective tissue disease will be presented. PMID- 17713870 TI - [Workplace harassment by hospital doctors. Decision of the Rheinland-Pfalz labor court from October 4, 2005]. PMID- 17713871 TI - Identification of Dryopteris crassirhizoma and the adulterant species based on cpDNA rbcL and translated amino acid sequences. AB - Dry rhizome of Dryopteris crassirhizoma Nakai (Dryopteridaceae), also known as Guan Zhong, is a traditional Chinese herbal medicine used in the treatment of viral disease. But the dry rhizomes of Woodwardia JAPONICA (L. f.) Sm., OSMUNDA JAPONICA Thunb. and Cyrtomium fortunei J. Sm. are also used as Guan Zhong in local areas. The adulterants are similar to Dryopteris crassirhizoma. It is difficult to identify the botanical origin of these herbs. In our study, sequences of the cpDNA RBCL gene were determined and analyzed for Dryopteris crassirhizoma and adulterant species, where nineteen molecular markers had been determined. Also, amino acid sequences translated from the RBCL gene were analyzed and four important molecular markers were detected. Based on cpDNA RBCL and translated amino acid sequences, Dryopteris crassirhizoma can easily be distinguished from the other three fern species. PMID- 17713872 TI - In vitro antiviral effect of meroditerpenes isolated from the Brazilian seaweed Stypopodium zonale (Dictyotales). AB - The meroditerpenoids atomaric acid (1), epitaondiol (2) and the peroxylactone of 5'a-desmethyl-5'-acetylatomaric acid (3) were isolated from the Brazilian brown alga Stypopodium zonale collected in two localities (Buzios and Marataizes, RJ and ES States). These compounds showed strong anti-HSV-1 activity in vitro but neither of them inhibited the transcriptase reverse enzyme of HIV-1. PMID- 17713873 TI - Sage extract rich in phenolic diterpenes inhibits ultraviolet-induced erythema in vivo. AB - The leaves of sage (Salvia officinalis L., Lamiaceae) contain high amounts of phenolic diterpenes such as carnosol and carnosic acid. These compounds display antioxidant and anti-inflammatory effects in vitro. Here, we have investigated the anti-inflammatory potency of a sage extract (SE) rich in phenolic diterpenes in vivo using the ultraviolet (UV) erythema test. In a prospective randomised double-blind placebo-controlled study, test areas on the backs of 40 healthy volunteers were irradiated with the 1.5-fold minimal erythema dose. Subsequently, the test areas were treated occlusively with 2% SE in a hydrophilic ointment, compared to 1% hydrocortisone and 0.1% betamethasone as positive controls, and the vehicle alone as placebo. Erythema values were measured photometrically prior to irradiation and after 48 hours. Compared to placebo, SE significantly reduced the ultraviolet-induced erythema, to a similar extent as hydrocortisone. These data suggest that SE might be useful in the topical treatment of inflammatory skin diseases. PMID- 17713874 TI - Mangiferin identified in a screening study guided by neuraminidase inhibitory activity. AB - A screening study on neuraminidase inhibitory constituents was carried out, and activity-guided fractionations of three plants, Gouania obtusifolia, Zizyphus cambodiana, and Mangifera odorata, led to the isolation of eleven compounds (1 11). Mangiferin was identified as a significant neuraminidase inhibitor. PMID- 17713875 TI - Cudraflavanone A, a flavonoid isolated from the root bark of Cudrania tricuspidata, inhibits vascular smooth muscle cell growth via an Akt-dependent pathway. AB - In previous studies of the root bark of Cudrania tricuspidata, various isoprenylated xanthones and flavonoids were isolated, some of which have anticancer, hepatoprotective, and antiperoxidative activities. Cytokines and growth factors are involved in the regulation of vascular smooth muscle cells (VSMCs) in atherosclerotic plaques. To assess whether cudraflavanone A isolated from the root bark of C. tricuspidata may be useful in the prevention of atherosclerosis or restenosis after angioplasty, we investigated the ability of cudraflavanone A to inhibit VSMCs growth under 25 ng/mL platelet-derived growth factor BB (PDGF-BB)-stimulated conditions. Cudraflavanone A (0.1-1 microM) significantly inhibited PDGF-BB-induced cell numbers in a concentration-dependent manner. The antigrowth effects of cudraflavanone A on VSMCs were also examined in [3H]-thymidine incorporation and cell cycle assays. Consistent with the inhibitory effect on cell number, PDGF-BB-stimulated [3H]-thymidine incorporation and cell cycle progression in VSMCs was also concentration-dependently reduced by cudraflavanone A. Furthermore, PDGF-BB markedly activated PDGF-beta receptor (PDGF-Rbeta) tyrosine kinase activity, leading to activation of intracellular signals required for VSMC growth. However, PDGF-BB-induced this kinase activity was not affected by cudraflavanone A. PDGF-BB also increased the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), Akt, and phospholipase C gamma (PLCgamma)1, which are important signaling molecules in cell growth. Cudraflavanone A (0.1-1 microM) suppressed PDGF-BB-stimulated Akt activation, which is involved in cell survival, but had no effect on the activation of ERK1/2 and PLCgamma1. Selective modification of Akt activation by cudraflavanone A in VSMCs may suppress intimal thickening after angioplasty and plaque formation in atherosclerosis. These results suggest that cudraflavanone A from C. tricuspidata inhibits PDGF-BB-induced rat aortic VSMC growth via an Akt-dependent pathway. PMID- 17713876 TI - [Predictors of nodal metastasising in laryngeal squamous cell carcinomas as decision support for neck dissection: comprehensive analysis of literature]. AB - BACKGROUND: A subset of advanced laryngeal squamous cell carcinomas (SCC) does not metastasize in regional lymph nodes (pN0). However, more than 30 % of tumors without signs of metastasizing in the clinical examination (cN0) show occult metastases. The guidelines of the German ENT-Society intend the extent of neck dissection (ND) depending on clinical stage of tumor and lymph nodes. If laryngeal surgery is followed by an adjuvant radiation/chemotherapy, ND is not always necessary. Histomorphological, immunohistochemical, or molecular parameters with predictive value for nodal metastasizing could support the planning for ND, especially in patients with cN0. METHODS: Within the last 20 years there were many publications concerning this problem. Herein, we analyzed the results of 455 publications. We have chosen studies regarding the predictive value of tumor stage, grading, peritumorous inflammation, invasion of lymphatic vessels, angioneogenesis, proliferation, overexpression of p53 or cyclin D1, inhibitors of cyclin-dependent kinases, growth factors, apoptosis, cell-adhesion, nm23, metalloproteinases, DNA/ploidy as well as tumor genetics. RESULTS: All examined parameters did not allow a fail-safe prediction of the risk for nodal metastasizing. CONCLUSIONS: Up to now, reliable predictors do not exist. The investigation of above mentioned parameters in pre-operative tumor biopsies is not helpful for the planning of ND in the stage cN0 (out of T1). PMID- 17713877 TI - [Relevance of psychosocial factors in speech rehabilitation after laryngectomy]. AB - BACKGROUND: Often it is assumed that psychosocial and sociodemographic factors cause the success of voice rehabilitation after laryngectomy. Aim of this study was to analyze the association between these parameters. METHODS: Based on tumor registries of six ENT-clinics all patients were surveyed, who were laryngectomized in the years before (N = 190). Success of voice rehabilitation has been assessed as speech intelligibility measured with the postlaryngectomy telephone-intelligibility-test. For the assessment of the psychosocial parameters validated and standardized instruments were used if possible. Statistical analysis was done by multiple logistic regression analysis. RESULTS: Low speech intelligibility is associated with reduced conversations (OR 0.970) and social activity (OR 1.049). Patients are more likely to talk with esophageal voice when their motivation for learning the new voice was high (OR 7.835) and when they assessed their speech therapist as important for their motivation (OR 4.794). The risk to communicate merely by whispering is higher when patients live together with a partner (OR 5.293), when they talk seldomly (OR 1.017) and when they are not very active in social contexts (OR 0.966). CONCLUSIONS: Psychosocial factors can only partly explain how voice rehabilitation after laryngectomy becomes a success. Speech intelligibility is associated with active communication behaviour, whereas the use of an esophageal voice is correlated with motivation. It seems that the gaining of tracheoesophageal puncture voice is independent of psychosocial factors. PMID- 17713878 TI - [Image-guided minimal-invasive cochlear implantation--experiments on cadavers]. AB - BACKGROUND: The accuracy of navigation systems can be improved significantly by using high-resolution flat panel-based Volume Computed Tomography (fpVCT) so that new surgical therapeutic concepts become feasible. A navigation-guided minimally invasive cochleostomy places highest requirements on the accuracy of intraoperative navigation. METHODS: A flat-panel Volume Computed Tomograph (fpVCT) was used to scan four human temporal bones. The isometric voxel size was 200 microm. The preoperative planning was used to define an optimized drilling channel from the mastoid surface to the round window niche and the scala tympani providing a safety margin to critical anatomical structures such as facial nerve, chorda tympani, sigmoid sinus and posterior wall of auditory canal. The canal was drilled hand-operated with a navigated drill following the previously planned trajectory. Afterwards the drilled canal was imaged by fpVCT. Conventional dissection including mastoidectomy and posterior tympanotomy assured correct localization of the cochleostomy. RESULTS: Path planning took an average of 54 minutes (range 35-85 minutes). Installation took an average of 16 minutes (range 14-19 minutes). The drilling procedure itself took an average of 7.75 min (range 5-12 minutes.) The RMSE-values varied between 0.1 and 0.2 mm (Table 1). All four specimens showed a cochleostomy located at the scala tympani anterior inferior to the round window. The chorda tympani was damaged in one specimen--this was preoperatively planned as a narrow facial recess was encountered. The time needed for planning and system-installation could be reduced continuously. CONCLUSIONS: This feasibility study demonstrates that using current image-guided surgery technology in combination with fpVCT allows drilling of a minimally invasive channel to the cochlea with loco typico cochleostomy. The necessary accuracy of intraoperative navigation can be achieved by use of fpVCT (technical accuracy between 0.1 and 0.2 mm). Our results demonstrate the feasibility of a navigation guided minimally-invasive cochleostomy loco typico. While we are enthused by this preliminary work, we recognize the barriers which exist in translation to clinical application. These include surgical issues (e.g. control of unexpected bleeding) and electrode issues (e.g. development of insertion tools). PMID- 17713880 TI - [Gastroenterology as an interdisciplinary challenge]. PMID- 17713879 TI - [Spontaneous tongue necrosis consecutive to rheumatoid hyperviscosity syndrome. A case report and literature review]. AB - BACKGROUND: Because the tongue is an organ known for its excellent blood supply, ischaemic lingual necrosis is extremely rare within clinical everyday life. Acute lingual circulatory disturbances can result from impairment of venous drainage or more often from ischaemic arterial occlusion. Due to permanent function loss of the tongue, apparent lingual necrosis may lead to severe mutilation of the patient. While vasculitis of the lingual arteries in temporal arteritis is said to be the most frequent causation of tongue necrosis, diagnosing the underlying disease of lingual ischaemia may sometimes be challenging for the clinician. PATIENTS AND METHODS: We present the first reported case of a spontaneous lingual necrosis in a patient with rheumatoid arthritis, due to polyclonal gammopathy with extensive hyperviscosity syndrome and local vasculitis. RESULTS: Clinical symptoms, diagnosis and therapy of tongue necrosis are presented in a case report. Besides an overview on the disorder of hyperviscosity syndrome, the discussion will illustrate pathogenetic, diagnostic and therapeutic considerations of lingual ischaemia. The international medical literature is reviewed to summarize the causes of tongue necroses that are described up to now. The particular importance of temporal arteritis Horton for the otolaryngologist in general and for the development of lingual necrosis in particular is highlighted. CONCLUSIONS: Apart from the presentation of the first reported case of lingual necrosis in rheumatoid hyperviscosity syndrome, the intention of this article is to draw the clinician's attention on the fundamental aspects of lingual ischaemia and of temporal arteritis. PMID- 17713881 TI - [Economic effects of "molecular" medicine]. PMID- 17713882 TI - [Quality of care and health economics in occupationally acquired hepatitis C in German health care workers between 1993 and 2004]. AB - BACKGROUND AND OBJECTIVE: Data for quality of care and health economics in patients with occupationally acquired hepatitis C are lacking in Germany. The aim of this study was to analyse quality and economics of health care in occupationally acquired hepatitis C recognized by the Employees Compensation Boards between 1993 and 2000 in the area of Cologne and Bochum, Germany. METHODS: Results for 192 patients (146 women and 46 men, mean age 42 +/- 10 years) were analysed, using a standardized evaluation form. In addition to direct medical costs and diagnostic and therapeutic performance, disability days and benefit payments were also analysed. The observational period was from 01.01.1993 to 31.07.2004. Disability benefits were considered from 1983 onwards. RESULTS: HCV genotype 1 accounted for 79 % of infections. 112 patients (58 %) received antiviral treatment at least once. There were no differences in treatment rates between patients with prognostically favorable genotypes (2/3) and those with unfavorable HCV types (1/4) (59 % v. 60 %) or patients with low and those with advanced fibrosis (61 % v. 64 %). A sustained virological response was achieved in 53 % of treated patients. Disability days were more frequent in patients receiving antiviral treatment (214 v. 67 days). The cost of medication made up a major part of health care expenditure (mean of i 13,279 per patient). In addition, total disability benefits of i 6,933,789 were paid out between 1983 and 2004. CONCLUSION: Occupationally acquired hepatitis C is a major health-economic burden in Germany. Quality of health care corresponded to guidelines at any one time and sustained virological response was in the range of large controlled trials. However, 69 % of the patients remain chronically infected and are at risk for disease progression and transmission. PMID- 17713883 TI - [Hepatitis B associated polyarteriitis nodosa with cerebral vasculitis]. AB - HISTORY AND ADMISSION FINDINGS: A 53-year-old male was admitted with an acute brainstem syndrome. He developed a severe fluctuating psychosis. Because of the worsening neurological symptoms he was admitted to our neurological clinic five months after onset of the disease. On admission he showed signs of a productive psychosis in addition to akinetic-rigid parkinsonism and cerebellar symptoms. INVESTIGATIONS: Laboratory tests revealed a HBeAg-negative hepatitis B. The initial neuroradiolgical studies showed multiple supratentorial and periventricular ischemic and hemorrhagic lesions. MR-angiography and conventional cerebral angiography demonstrated multiple irregularities of the intracranial vessels and vascular occlusions, findings which were compatible with cerebral vasculitis. DIAGNOSIS, THERAPY AND COURSE: The laboratory and neuroradiological studies indicated a hepatitis B-associated polyarteriitis nodosa and cerebral vasculitis. He was given oral immunsuppressive therapy (prednisolone 60 mg daily) and virostatic drug (lamivudine 100 mg daily). When the steroid dosis was reduced to 40 mg prednisolon a severe relapse of the encephalopathy occurred which was treated with the atypical antipsychotic drug risperidon, 3 mg daily, and intravenous methylprednisolone plus plasmaphereses. Later he was given prednisolone (60 mg daily) and lamivudine (100 mg daily) again which has so far stabilized the clinical course. CONCLUSION: The main treatment of the rare hepatitis B-associated polyarteriitis nodosa with cerebral vasculitis consists of oral steroids in combination with antiviral drugs. Depending on the course of the disease an escalating steroid pulse administration and plasmaphereses should be considered. PMID- 17713884 TI - [Subcutaneous anal fistula, combined with an anal thrombosis]. PMID- 17713885 TI - [Methotrexate-induced pneumonitis in a woman with Crohn's disease]. AB - HISTORY AND ADMISSION FINDINGS: A 36-year-old woman (BMI 37,2 kg m (-2)) with steroid-dependent Crohn's disease presented with stomatitis (aphthous ulcers), retrosternal pain and dry cough after 10 weeks of methotrexate treatment. INVESTIGATIONS: Initially the C-reactive protein (CRP) was elevated, the blood gas analysis was normal, as were computed tomography (CT) and gastroscopy. Lung function tests showed restrictive partial respiratory failure. As pneumonia was suspected antibiotic treatment with ceftriaxone was started as well as topical antimycotic therapy with amphotericin B. However, within a few days the patient developed severe partial respiratory insufficiency. DIAGNOSIS, TREATMENT AND COURSE: The CT-scan showed extensive ground-glass infiltrates, bronchoalveolar lavage revealed CD3 (+) and CD8 (+) lymphocytosis. Methotrexate-induced pneumonitis was diagnosed. Methotrexate administration was discontinued, high dose steroid application was started and ventilatory support given. These measures achieved full recovery. CONCLUSION: Methotrexate-induced pneumonitis can be a relevant complication in Crohn's disease. Abnormal ventilation is an early sign and should lead to further investigation. PMID- 17713886 TI - [Short bowel syndrome: which remedy, which nutrition and which surgical options?]. PMID- 17713887 TI - [Strategies for monitoring patients with Barrett's esophagus--pro]. PMID- 17713888 TI - [Strategies for monitoring patients with Barrett's esophagus--contra]. PMID- 17713889 TI - [Crohn's disease--infliximab, adalimumab and certolizumab-pegol: clinical value of anti-TNF-alpha treatment]. AB - Therapeutic antibodies against TNF-alpha are an important therapeutic innovation in recent years in treating complicated Crohn's disease. Chimeric infliximab fully human produced Adalimumab and Certolizumab-Pegol, a humanized, PEGylated anti-TNF-alpha antibody Fab'fragment, are therapeutic antibodies against TNF. All three antibodies have a rapid onset of action, with two thirds of the patients with refractory Crohn's disease showing an initial clinical response to the anti TNFalpha treatment and only 20-30 % develops a lasting remission. Clinical benefits include closure of draining fistulas and reduction of chronic glucocorticoid medication. When considering an anti TNF-alpha therapy a long term strategy is needed and a systematic maintenance treatment should be developed. The antibodies recognize different epitopes but have a complementary mode of action. Does one antibody fail, especially after an initial clinical response, a second antibody can still show an effect. More recent anti TNF-alpha antibodies can be applied without an azathioprine comedication. Severe side effects like an increase risk of infection and malignancies are a class effect and closely linked to the mode of action. When patients are properly selected, the clinical benefit outweighs the side effects. Before starting an immunosuppressive therapy or an anti-TNF-alpha therapy screening for latent tuberculosis is mandatory. An abscess has to be excluded. Due to the high risk of infection any symptoms which might be a sign of complications during therapy should result in a thorough diagnostic examination. Patients should be documented in registries. PMID- 17713890 TI - [German guidelines on diagnosis and therapy of hepatitis B]. AB - Therapeutic option for hepatitis B virus infection have significantly improved in recent years. Moreover, new insights in the natural history of hepatitis B required an update of current national guidelines. Therefore, the German network of competence on viral hepatitis (Hep-Net) has revised guidelines on diagnosis and treatment og HBV incetion in cooperation with the national societies for Gastroenterology, Pathology, Virology, and Pediatric Gastroenterology. Important alterations concern the indication for antiviral therapy considering an HBV viremia of 104 copies/ml (2000 IU/ml) as a critical level. Moreover, specific recommendations how to prevent and to treat antiviral drug resistance are given. Finally, the importance of HBV in the context of organ and bone marrow transplantation, treatment of coinfections and children and prophylaxis of HBV is covered. PMID- 17713891 TI - Atomic partitioning of the dissociation energy of the P-O(H) bond in hydrogen phosphate anion (HPO4(2-)): disentangling the effect of Mg2+. AB - This paper has three goals: (1) to provide a first step in understanding the atomic basis of the role of magnesium in facilitating the dissociation of the P-O bond in phosphorylated biochemical fuel molecules (such as ATP or GTP), (2) to compare second-order Moller-Plesset perturbation theory (MP2) results with those obtained at the more economical density functional theory (DFT) level for a future study of larger more realistic models of ATP/GTP, and (3) to examine the calculation of atomic total energies from atomic kinetic energies within a Kohn Sham implemention of DFT, as compared to ab initio methods. A newly described method based on the quantum theory of atoms in molecules (QTAIM), which is termed the "atomic partitioning of the bond dissociation energy" (APBDE), is applied to a simple model of phosphorylated biological molecules (HPO42-). The APBDE approach is applied in the presence and in the absence of magnesium. It is found that the P-O(H) bond in the magnesium complex is shorter, exhibits a higher stretching frequency, and has a higher electron density at the bond critical point than in the magnesium-free hydrogen phosphate anion. Though these data would seem to suggest a stronger P-O(H) bond in the magnesium complex compared to the magnesium-free case, the homolytic breaking of the P-O(H) bond in the complex is found to be easier, i.e., has a lower BDE. This effect is the result of the balance of several atomic contributions to the BDE induced by the magnesium cation, which stabilizes the dissociation product more than it stabilizes the intact model molecule. PMID- 17713892 TI - Theoretical calculation of the photodetachment spectra of XAuY- (X, Y = Cl, Br, and I). AB - The photodetachment spectra of the title molecules have been calculated, taking electron correlation and spin-orbit coupling into account and employing improved relativistic effective core potentials for gold and the halogen atoms. The calculated spectra have been compared with existing experimental spectra. The spin-orbit splitting of several degenerate electronic states has been calculated. The composition of the spin-orbit eigenstates are analyzed in terms of scalar relativistic electronic states. A comparison of the relative position of peaks in the calculated photodetachment spectra of the title molecules has been made. PMID- 17713893 TI - Thermodynamical study of the thermoelectric effect for magnesium silicide. AB - The thermoelectric effect of magnesium silicide is studied by using a thermodynamical method in the presence of an electric field. The thermoelectric potential is evaluated from the partial derivative of free energy with respect to charge in which the free energy is calculated at the B3LYP/6-31G(d,p) level of density functional theory. This free energy is also utilized to determine the average dipole moment from which the polarizability, alpha; molar polarization, Psi; and dielectric constant can be computed. The present calculation for the dielectric constant (approximately 24-20) is in very good agreement with the experimental value (20). This accurate dielectric constant can be used to derive the relation of the thermoelectric potential with respect to temperature, from which the thermoelectric power or the Seebeck coefficients are calculated. The present result shows good agreement with experiment measurement for the Seebeck coefficients. In comparison, that calculation from the energy band structure theory is far off from the experimental values. PMID- 17713894 TI - Stairway to the conical intersection: a computational study of the retinal isomerization. AB - The potential-energy surface of the first excited state of the 11-cis-retinal protonated Schiff base (PSB11) chromophore has been studied at the density functional theory (DFT) level using the time-dependent perturbation theory approach (TDDFT) in combination with Becke's three-parameter hybrid functional (B3LYP). The potential-energy curves for torsion motions around single and double bonds of the first excited state have also been studied at the coupled-cluster approximate singles and doubles (CC2) level. The corresponding potential-energy curves for the ground state have been calculated at the B3LYP DFT and second order Moller-Plesset (MP2) levels. The TDDFT study suggests that the electronic excitation initiates a turn of the beta-ionone ring around the C6-C7 bond. The torsion is propagating along the retinyl chain toward the cis to trans isomerization center at the C11=C12 double bond. The torsion twist of the C10-C11 single bond leads to a significant reduction in the deexcitation energy indicating that a conical intersection is being reached by an almost barrierless rotation around the C10-C11 single bond. The energy released when passing the conical intersection can assist the subsequent cis to trans isomerization of the C11=C12 double bond. The CC2 calculations also show that the torsion barrier for the twist of the retinyl C10-C11 single bond adjacent to the isomerization center almost vanishes for the excited state. Because of the reduced torsion barriers of the single bonds, the retinyl chain can easily deform in the excited state. Thus, the CC2 and TDDFT calculations suggest similar reaction pathways on the potential energy surface of the excited state leading toward the conical intersection and resulting in a cis to trans isomerization of the retinal chromophore. According to the CC2 calculations the cis to trans isomerization mechanism does not involve any significant torsion motion of the beta-ionone ring. PMID- 17713895 TI - Global inorganic source of atmospheric bromine. AB - A few bromine molecules per trillion (ppt) causes the complete destruction of ozone in the lower troposphere during polar spring and about half of the losses associated with the "ozone hole" in the stratosphere. Recent field and aerial measurements of the proxy BrO in the free troposphere suggest an even more pervasive global role for bromine. Models, which quantify ozone trends by assuming atmospheric inorganic bromine (Bry) stems exclusively from long-lived bromoalkane gases, significantly underpredict BrO measurements. This discrepancy effectively implies a ubiquitous tropospheric background level of approximately 4 ppt Bry of unknown origin. Here, we report that I- efficiently catalyzes the oxidation of Br- and Cl- in aqueous nanodroplets exposed to ozone, the everpresent atmospheric oxidizer, under conditions resembling those encountered in marine aerosols. Br- and Cl-, which are rather unreactive toward O3 and were previously deemed unlikely direct precursors of atmospheric halogens, are readily converted into IBr2- and ICl2- en route to Br2(g) and Cl2(g) in the presence of I . Fine sea salt aerosol particles, which are predictably and demonstrably enriched in I- and Br-, are thus expected to globally release photoactive halogen compounds into the atmosphere, even in the absence of sunlight. PMID- 17713896 TI - Design and evaluation of naphthol- and carbazole-containing fluorescent sigma ligands as potential probes for receptor binding studies. AB - Some 3,3-dimethyl-1-(3-naphthylpropyl)piperidine and 1-cyclohexyl-4-(3 naphthylpropyl)piperazine derivatives, structurally containing naphthol as a fluorescent moiety, were prepared for being potentially used as fluorescent sigma ligands. Structurally related analogs were also prepared, where the naphthalene nucleus was replaced by the fluorescent carbazole moiety and chain length was varied. For all compounds the in vitro affinities toward sigma receptors and Delta8-Delta7 sterol isomerase site were measured, and the fluorescent properties were determined. Compound 19 gave the best results both for sigma receptor affinities (sigma1, Ki = 6.78 nM and sigma2, Ki = 26.4 nM) and fluorescence features; thus, it was chosen for in vitro saturation binding analysis at sigma receptors. The good results obtained in such assay suggested that the fluorescent compound 19 could be used instead of a radioligand in "green" binding assays. PMID- 17713897 TI - Cisplatinum and transplatinum complexes with benzyliminoether ligands; synthesis, characterization, structure-activity relationships, and in vitro and in vivo antitumor efficacy. AB - New benzyliminoether derivatives [PtCl2{N(H)=C(OMe)CH2Ph}2] of cis (1a, 1b) and trans (2a, 2b) geometry were prepared and characterized by means of elemental analysis, multinuclear NMR and FT-IR techniques, and X-ray crystallography; this latter was carried out for 1b. The cytotoxic properties of these new platinum(II) complexes were evaluated in terms of cell growth inhibition against a panel of different types of human cancer cell lines. cis-[PtCl2{E-N(H)=C(OMe)CH2Ph}2] (1a) was significantly more potent than cisplatin against all tumor cell lines tested, showing IC50 values from about 2- to 17-fold lower than the reference compound. Chemosensitivity tests performed on cisplatin-sensitive and -resistant cell lines have demonstrated that complex 1a is able to overcome cisplatin resistance. Analyzing the mechanism by which complex 1a led to cell death, we have found that it induced apoptosis in a dose-dependent manner, accompanied by the activation of caspase-3. The in vivo studies carried out using two transplantable tumor models (L1210 leukemia and Lewis lung carcinoma) showed that derivative 1a induced a remarkable antitumor activity in both tumor models, as measured by prolonged survival and reduced tumor mass compared to control groups. PMID- 17713898 TI - Phenylimidazole derivatives of 4-pyridone as dual inhibitors of bacterial enoyl acyl carrier protein reductases FabI and FabK. AB - FabI and FabK are bacterial enoyl-acyl carrier protein (ACP) reductases that catalyze the final and rate-limiting step of bacterial fatty acid biosynthesis (FAS) and are potential targets of novel antibacterial agents. We have reported 4 pyridone derivative 3 as a FabI inhibitor and phenylimidazole derivative 5 as a FabK inhibitor. Here, we will report phenylimidazole derivatives of 4-pyridone as FabI and FabK dual inhibitors based on an iterative medicinal chemistry and crystallographic study of FabK from Streptococcus pneumoniae/compound 26. A representative compound 6 showed strong FabI inhibitory (IC50 = 0.38 microM) and FabK inhibitory (IC50 = 0.0045 microM) activities with potent antibacterial activity against S. pneumoniae (MIC = 0.5 microg/mL). Since elevated MIC value was observed against S. pneumoniae mutant possessing one amino acid substitution in FabK, the antibacterial activity of the compound was considered to be due to the inhibition of FabK. Moreover, this compound showed no significant cytotoxicity (IC50 > 69 microM). These results support compound 6 as a novel agent for the treatment of bacterial infections. PMID- 17713901 TI - Significance of water molecules in the inhibition of cylin-dependent kinase 2 and 5 complexes. AB - Interest in CDK2 and CDK5 has stemmed mainly from their association with cancer and neuronal migration or differentiation related diseases and the need to design selective inhibitors for these kinases. In the present paper, eight Molecular Dynamics (MD) simulations are carried out to examine the importance of structure and dynamics of water in the active site of both CDK2 and CDK5 complexes with roscovitine and indirubin analogues. Together with previous results, the current work shows a highly conserved water-involved hydrogen bonding (HB) network in both CDK2- and CDK5-indirubin combinations to complete information from the X-ray crystallography. The simulations suggest the importance of such a network for combining the inhibitor to the host protein as well as the significance of using an activated CDK as a template when designing new inhibitors. Different binding patterns of roscovitine in CDK2 and CDK5 are detected during the simulations because of the different binding conformations of the group on the C2 side chain, which might offer a clue toward finding highly selective inhibitors with regards to CDK2 and CDK5. PMID- 17713902 TI - Tripodal bis(imidazole) thioether copper(I) complexes: mimics of the Cu(M) site of copper hydroxylase enzymes. AB - Tripodal bis(imidazole) thioether ligands, (N-methyl-4,5-diphenyl-2 imidazolyl)2C(OR)C(CH3)2SR' (BIT(OR,SR'); R = H, CH3; R' = CH3, C(CH3)3, C(C6H5)3), have been prepared, offering the same N2S donor atom set as the CuM binding site of the hydroxylase enzymes, dopamine beta hydroxylase and peptidylglycine hydroxylating monooxygenase. Isolable copper(I) complexes of the type [(BIT(OR,SMe))Cu(CO)]PF6 (3a and 3b) are produced in reactions of the respective tripodal ligands 1a (R = H) and 1b (R = Me) with [Cu(CH3CN)4]PF6 in CH2Cl2 under CO (1 atm); the pyramidal structure of 3a has been determined crystallographically. The infrared (IR) nu(CO)'s of 3a and 3b (L = CO) are comparable to those of the Cu(M)-carbonylated enzymes, indicating similar electronic character at the copper centers. The reaction of [(BIT(OH,SMe))Cu(CH3CN)]PF6 (2a) with dioxygen produces [(BIT(O,SOMe))2Cu2(DMF)2](PF6)2 (4), whose X-ray structure revealed the presence of bridging BIT-alkoxo ligands and terminal -SOMe groups. In contrast, oxygenation of 2b (R = Me) affords crystallographically defined [(BIT(OMe,SMe))2Cu2(mu-OH)2](OTf)2 (5), in which the copper centers are oxygenated without accompanying sulfur oxidation. Complex 5 in DMF is transformed into five-coordinate, mononuclear [CuII(BIT(OMe,SMe))(DMF)2](PF6)2 (6). The sterically hindered BIT(OR,SR') ligands 9 and 10 (R' = t-Bu; R = H, Me) and 11 and 12 (R' = CPh3; R = H, Me) were also prepared and examined for copper coordination/oxygenation. Oxygenation of copper(I) complex 13b derived from the BIT(OMe,SBu-t) ligand is slow, relative to 2b, producing a mixture of (BIT(OMe,SBu-t))2Cu2(mu-OH)2-type complexes 14b and 15b in which the -SBu-t group is uncoordinated; one of these complexes (15b) has been ortho-oxygenated on a neighboring aryl group according to the X-ray analysis and characterization of the free ligand. Oxygenation of the copper(I) complex derived from BIT(OMe,SCPh3) ligand 12 produces a novel dinuclear disulfide complex, [(BIT(OMe,S)2Cu2(mu OH)2](PF6)2 (17), which is structurally characterized. Reactivity studies under anaerobic conditions in the presence of t-BuNC indicate that 17 is the result of copper(I)-induced detritylation followed by oxygenation of a highly reactive copper(I)-thiolate complex. PMID- 17713903 TI - Spin-state energetics and spin-crossover behavior of pseudotetrahedral cobalt(III)-imido complexes. The role of the tripodal supporting ligand. AB - DFT calculations have underscored the importance of the tripodal supporting ligand in tuning the spin-state energetics of pseudotetrahedral transition metal imido complexes. In particular, we have focused on Co(III)-imido complexes, where our best estimate (OLYP) of the singlet-triplet splitting varies from 0.75 eV for a trisphosphine complex (1) and 0.3 eV for a tris(N-heteroyclic-carbene) complex (2) to essentially 0.0 eV for a hydrotris(pyrazolyl)borate (3) complex. The experimentally studied analogues of 1, 2, and 3 all exhibit S = 0 ground states; however, the experimental analogue of 3 exhibits spin-crossover behavior due to a low-lying S = 1 state. Interestingly, whereas all the pure functionals examined successfully predict nearly equienergetic singlet end triplet states for 3, the hybrid functionals B3LYP and O3LYP exhibit a clear (and incorrect) preference for the S = 2 state. In addition, we have also carried out an exploratory survey of Cr(III), Mn(III), and Fe(III) imido complexes with trisphosphine and hydrotris(pyrazolyl)borate (Tp) supporting ligands. Among the more interesting predictions of this study is that an FeIII(Tp)(imido) species should exhibit a high-spin S = 5/2 ground state, which would be unique for an iron-imido complex. PMID- 17713904 TI - Investigations on a novel silyl transfer reaction in heterodimetallic chemistry. AB - Heterodinuclear silyl complexes of the type [(OC)3(R3Si)[Fe(mu PPh2)Pt](CO)(PPh3)], which contain a [Fe(mu-P)Pt] triangular core, were previously reported to undergo an unprecedented dyotropic-type rearrangement involving migration of the silyl group from iron to platinum with concomitant 1,2 migration of CO from Pt to Fe. In the resulting complexes of formula [(OC)4[Fe(mu PPh2)Pt](SiR3)(PPh3)], the Si atom occupies a cis position at the planar Pt center with respect to the phosphido bridge. DFT calculations were employed to elucidate the mechanism of this intramolecular silyl migration reaction. When the Fe-Pt precursor complex is [(OC)3(R3Si)[Fe(mu-PPh2)Pt](PPh3)2], the reaction sequence involves (i) the substitution of PPh3 by CO at Pt, (ii) the concerted migration of CO and SiR3, and (iii) the cis-trans isomerization at Pt. The calculations support the exergonic character of the overall process. An explanation for the experimental observation of only one product isomer being formed is possible via frontier molecular orbital analysis. Consistent with the experimental findings, the transition states of the migration (a species with a triply bridged intermetallic bond) and isomerization steps were found to be energetically within reach at room temperature. Additional support for the suggested mechanism also comes from the fact that relative silyl migration activities could be rationalized by the means of quantum chemistry. PMID- 17713905 TI - Making amines strong bases: thermodynamic stabilization of protonated guests in a highly-charged supramolecular host1. AB - A highly charged, cavity-containing supramolecular assembly formed by metal ligand interactions acts as a host to dramatically shift the effective basicity of encapsulated protonated amine guests. The scope of encapsulated protonated amine and phosphine guests shows size selectivity consistent with a constrained binding environment. Protonation of the encapsulated guests is confirmed by (31)P NMR studies, mass spectrometry studies, and the pH dependence of guest encapsulation. Rates of guest self-exchange were measured using the selective inversion recovery method and were found to correlate with the size rather than with the basicity of the guests. The activation parameters for guest self exchange are consistent with the established mechanism for guest exchange. The binding constants of the protonated amines are then used to calculate the effective basicity of the encapsulated amines. Depending on the nature of the guest, shifts in the effective basicities of the encapsulated amines of up to 4.5 pK(a) units are observed, signifying a substantial stabilization of the protonated form of the guest molecule and effectively making phosphines and amines strong bases. PMID- 17713906 TI - Photophysical and structural properties of cyanoruthenate complexes of hexaazatriphenylene. AB - The tritopic bridging ligand hexaazatriphenylene (HAT) has been used to prepare the mono-, di-, and trinuclear cyanoruthenate complexes [Ru(CN)(4)(HAT)](2-) ([1](2-)), [{Ru(CN)(4)}(2)(mu(2)-HAT)](4-) ([2](4-)), and [{Ru(CN)(4)}(3)(mu(3) HAT)](6-) ([3](6-)). These complexes are of interest both for their photophysical properties and ability to act as sensitizers, associated with strong MLCT absorptions; and their structural properties, with up to 12 externally directed cyanide ligands at a single "node" for preparation of coordination networks. The complexes are strongly solvatochromic, with broad and intense MLCT absorption manifolds arising from the presence of low-lying pi* orbitals on the HAT ligand, as confirmed by DFT calculations; in aprotic solvents [3](6-) is a panchromatic absorber of visible light. Although nonluminescent in fluid solution, the lowest MLCT excited states have lifetimes in D(2)O of tens of nanoseconds and could be detected by time-resolved IR spectrosocopy. For dinuclear [2](4-) and trinuclear [3](6-) the TRIR spectra are indicative of asymmetric MLCT excited states containing distinct Ru(III) and Ru(II) centers on the IR time scale. The complexes show red (3)MLCT luminescence as solids and in EtOH/MeOH glass at 77 K. Ln(III) salts of [1](2-), [2](4-), and [3](6-) form infinite coordination networks based on Ru-CN-Ln bridges with a range of one-, two-, and three dimensional polymeric structures. In the Yb(III) and Nd(III) salts of [3](6- )the complex anion forms an 8-connected node. Whereas all of the Gd(III) salts show strong (3)MLCT luminescence in the solid state, the Ru-based emission in the Nd(III) and Yb(III) analogues is substantially quenched by Ru --> Ln photoinduced energy transfer, which results in sensitized near-infrared luminescence from Yb(III) and Nd(III). PMID- 17713907 TI - Ligand-directed dynamics of adenine riboswitch conformers. PMID- 17713908 TI - Molecular dynamics computational study of the 199Hg-199Hg NMR spin-spin coupling constants of [Hg-Hg-Hg]2+ in SO2 solution. AB - The isotropic one-bond and two-bond 199Hg-199Hg nuclear magnetic spin-spin coupling constants (J-couplings) of [Hg-Hg-Hg]2+ were calculated using density functional theory, the zeroth-order regular approximation (ZORA) to treat relativistic effects, and Born-Oppenheimer molecular dynamics (BOMD) including SO2 molecules explicitly for the description of solvent effects. The final BOMD average of 150 kHz for 1J (199Hg-199Hg) agrees well with the experimental spin spin coupling of 140 kHz measured in liquid SO2, while computations not considering explicit solvation at the quantum-mechanical level yielded one-bond coupling constants between 230 and 260 kHz. The two-bond coupling is similarly strongly affected by solvent effects. An analysis of the BOMD data shows that the effect is mainly due to close contacts between the terminal Hg atoms of [Hg-Hg Hg]2+ and the solvent's oxygen atoms. The results highlight the importance of solvent effects for the NMR parameter of heavy metals and demonstrate the usefulness of treating such solvent effects with the help of molecular dynamics based averaging. PMID- 17713910 TI - Tetrahedral zinc complexes with liquid crystalline and luminescent properties: interplay between nonconventional molecular shapes and supramolecular mesomorphic order. AB - Novel metallomesogens with luminescent properties and liquid crystalline behavior at room temperature have been achieved by the preparation of zinc complexes with polycatenar pyrazole and bis(pyrazolyl)methane ligands. Their molecular structures do not have a conventional shape in that they are far from the typical rod-like and flat disc-like geometries of common liquid crystals. They consist of a nonplanar nucleus due to the methylene spacer and/or the coordination to the tetrahedral center, as confirmed by single crystal analysis of the cores. The different numbers and positions of side chains in the pyrazole ligand enabled us to access lamellar and columnar mesophases and, of particular interest, to obtain columnar arrangements at room temperature. Supramolecular models for the organization of the molecules in the mesophases are proposed on the basis of the small-angle XRD diffractograms. The zinc complexes display luminescence in the near UV-blue region with large Stokes shifts. An interplay between non conventional molecular shapes (due to the tetrahedral core) and the supramolecular mesomorphic order (due to the ligand design) led to materials that interestingly embody two rather opposite properties, a columnar self organizational ability and luminescence with weak intermolecular interactions. PMID- 17713909 TI - Water-soluble phosphinothiols for traceless staudinger ligation and integration with expressed protein ligation. AB - The traceless Staudinger ligation is an effective means to synthesize an amide bond between two groups of otherwise orthogonal reactivity: a phosphinothioester and an azide. An important application of the Staudinger ligation is in the ligation of peptides at a variety of residues. Here, we demonstrate that the traceless Staudinger ligation can be achieved in water with a water-soluble reagent. Those reagents that provide a high yield of amide product discourage protonation of the nitrogen in the key iminophosphorane intermediate. The most efficacious reagent, bis(p-dimethylaminoethyl)phosphinomethanethiol, mediates the rapid ligation of equimolar substrates in water. This reagent is also able to perform a transthioesterification reaction with the thioester intermediate formed during intein-mediated protein splicing. Hence, the traceless Staudinger ligation can be integrated with expressed protein ligation, extending the reach of modern protein chemistry. PMID- 17713911 TI - Peripheral fabrications of a bis-gold(III) complex of [26]hexaphyrin(1.1.1.1.1.1) and aromatic versus antiaromatic effect on two-photon absorption cross section. PMID- 17713912 TI - Ultrasensitive detection of enzymatic activity with nanowire electrodes. PMID- 17713913 TI - One-pot separation of tea components through selective adsorption on pore engineered nanocarbon, carbon nanocage. PMID- 17713916 TI - More than a protective group: synthesis and applications of a new chiral silane. AB - Enantiomerically pure (-)-(R)- and (+)-(S)-(1-methoxy-2,2,2 triphenylethyl)dimethylsilanes (MOTES-H) were synthesized from triphenylacetaldehyde in five synthetic steps and with 60% overall yield. MOTES protected alpha- and beta-hydroxycarbonyl compounds were used in Grignard and Diels-Alder reactions in the presence of MgBr2 to afford addition products with 87-98% yield and selectivities of up to >120:1 dr. With this method, the pine beetle pheromone (-)-frontalin (67%, 98.5% ee) and naturally occurring (-)-(R) octane-1,3-diol (90%, >99% ee) were synthesized. PMID- 17713917 TI - Metal-catalyzed silylene transfer to imines: synthesis and reactivity of silaaziridines. AB - Metal-catalyzed silylene transfer to imines provides an efficient synthesis of silaaziridines. These strained cyclic silanes undergo selective bond-forming reactions, permitting the synthesis of nitrogen-containing compounds after protodesilylation of the resulting vinyl silane. PMID- 17713918 TI - An efficient, inexpensive, and shelf-stable diazotransfer reagent: imidazole-1 sulfonyl azide hydrochloride. AB - The design and synthesis of a new diazotransfer reagent, imidazole-1-sulfonyl azide hydrochloride, are reported. This reagent has proven to equal triflyl azide in its ability to act as a "diazo donor" in the conversion of both primary amines into azides and activated methylene substrates into diazo compounds. Crucially, this reagent can be prepared in a one-pot reaction on a large scale from inexpensive materials, is shelf-stable, and is conveniently crystalline. PMID- 17713919 TI - Skeletal diversity through radical cyclization of tetrahydropyridine scaffolds. AB - Suitably functionalized tetrahydropyridines (methyl pipecolates) have been used as conformationally biased templates for radical cyclizations to access benzoisoquinuclidines and linearly fused indenopiperidines. Variation of skeletal types is determined by location of a radical-initiating element. PMID- 17713920 TI - Total synthesis of (+/-)-frondosin B. AB - An expeditious reaction sequence featuring a microwave-assisted tandem 5-exo cyclization-Claisen rearrangement process was used to assemble the A/B ring system of frondosin B. Completion of the target natural product was achieved in 38.2% yield over an eight-step linear sequence. PMID- 17713921 TI - Protein and lipid oxidation during frozen storage of rainbow trout (Oncorhynchus mykiss). AB - This study aimed at investigating protein and lipid oxidation during frozen storage of rainbow trout. Rainbow trout fillets were stored for 13 months at -20, -30, or -80 degrees C, and samples were analyzed at regular intervals for lipid and protein oxidation markers. Lipid oxidation was followed by measuring lipid hydroperoxides (PV), as well as secondary oxidation products (volatiles) using dynamic headspace GC-MS. Free fatty acids (FFA) were measured as an estimation of lipolysis. Protein oxidation was followed using the spectrophotometric determination of protein carbonyls and immunoblotting. Significant oxidation was observed in samples stored at -20 degrees C, and at this temperature lipid and protein oxidation seemed to develop simultaneously. FFA, PV, and carbonyls increased significantly for the fish stored at -20 degrees C, whereas the fish stored at -30 and -80 degrees C did not show any increase in oxidation during the entire storage period when these methods were used. In contrast, the more sensitive GC-MS method used for measurement of the volatiles showed that the fish stored at -30 degrees C oxidized more quickly than those stored at -80 degrees C. Detection of protein oxidation using immunoblotting revealed that high molecular weight proteins were oxidized already at t = 0 and that no new protein oxidized during storage irrespective of the storage time and temperature. The results emphasize the need for the development of more sensitive and reliable methods to study protein oxidation in order to gain more explicit knowledge about the significance of protein oxidation for food quality and, especially, to correlate protein oxidation with physical and functional properties of foods. PMID- 17713922 TI - Quantitative sandwich ELISA for the determination of tropomyosin from crustaceans in foods. AB - The ubiquitous muscle protein tropomyosin has been identified as the major shrimp allergen and is suggested to be a cross-reacting allergen. Previously, only a few methods for the detection of tropomyosin in food have been published. A quantitative sandwich enzyme-linked immunosorbent assay (ELISA) for the detection of tropomyosin from crustaceans in foods has been developed and validated. A polyclonal rabbit antitropomyosin capture antibody and the biotinylated conjugate of the same antibody for detection were the basis for the ELISA, which was specific for crustaceans. The ELISA was able to quantitate tropomyosin in various food matrixes, had a detection limit of 1 microg/g, and cross-reacted to some extent with cockroach. Recoveries ranged from 63 to 120%, and the intra and interassay coefficients of variation were <6 and <14%, respectively. PMID- 17713923 TI - Calcium occupancy of N-terminal sites within calmodulin induces inhibition of the ryanodine receptor calcium release channel. AB - Calmodulin (CaM) regulates calcium release from intracellular stores in skeletal muscle through its association with the ryanodine receptor (RyR1) calcium release channel, where CaM association enhances channel opening at resting calcium levels and its closing at micromolar calcium levels associated with muscle contraction. A high-affinity CaM-binding sequence (RyRp) has been identified in RyR1, which corresponds to a 30-residue sequence (i.e., K3614-N3643) located within the central portion of the primary sequence. However, it is presently unclear whether the identified CaM-binding sequence in association with CaM (a) senses calcium over the physiological range of calcium concentrations associated with RyR1 regulation or alternatively, (b) plays a structural role unrelated to the calcium dependent modulation of RyR1 function. Therefore, we have measured the calcium dependent activation of the individual domains of CaM in association with RyRp and their relationship to the CaM-dependent regulation of RyR1. These measurements utilize an engineered CaM, permitting the site-specific incorporation of N-(1-pyrene)maleimide at either T34C (PyN-CaM) or T110C (PyC CaM) in the N- and C-domains, respectively. Consistent with prior measurements, we observe a high-affinity association of both apo-CaM and calcium-activated CaM with RyRp. Upon association with RyRp, fluorescence changes in PyN-CaM or PyC-CaM permit the measurement of the calcium-dependent activation of these individual domains. Fluorescence changes upon calcium activation of PyC-CaM in association with RyRp are indicative of high-affinity calcium-dependent activation of the C terminal domain of CaM at resting calcium levels; at calcium levels associated with muscle contraction, activation of the N-terminal domain occurs with concomitant increases in the fluorescence intensity of PyC-CaM that is associated with structural changes within the CaM-binding sequence of RyR1. Occupancy of calcium-binding sites in the N-domain of CaM mirrors the calcium dependence of RyR1 inhibition observed at activating calcium levels, where [Ca]1/2 = 4.3 +/- 0.4 microM, suggesting a direct regulation of RyR1 function upon the calcium dependent activation of CaM. These results indicate that occupancy of the N terminal domain calcium binding sites in CaM bound to the identified CaM-binding sequence K3614-N3643 induces conformational rearrangements within the complex between CaM and RyR1 responsible for the CaM-dependent modulation of the RyR1 calcium release channel. PMID- 17713924 TI - Inactivation of Escherichia coli L-aspartate aminotransferase by (S)-4-amino-4,5 dihydro-2-thiophenecarboxylic acid reveals "a tale of two mechanisms". AB - As a mechanism-based inactivator of PLP-enzymes, (S)-4-amino-4,5-dihydro-2 thiophenecarboxylic acid (SADTA) was cocrystallized with Escherichia coli aspartate aminotransferase (l-AspAT) at a series of pH values ranging from 6 to 8. Five structural models with high resolution (1.4-1.85 A) were obtained for l AspAT-SADTA complexes at pH 6.0, 6.5, 7.0, 7.5, and 8.0. Electron densities of the models showed that two different adducts had formed in the active sites. One adduct was formed from SADTA covalently linked to pyridoxal 5'-phosphate (PLP) while the other adduct was formed with the inhibitor covalently linked to Lysine246,1 the active site lysine. Moreover, there is a strong indication based on the electron densities that the occurrence of the two adducts is pH dependent. We conclude that SADTA inactivates l-AspAT via two different mechanisms based on the binding direction of the inactivator. Additionally, the structural models also show pH dependence of the protein structure itself, which provided detailed mechanistic implications for l-AspAT. PMID- 17713925 TI - Initiation and propagation of spectrin heterodimer assembly involves distinct energetic processes. AB - Red cell spectrin alpha and beta subunits consist primarily of many tandem homologous motifs with very similar three- helix-bundle structures and similar dimer interfaces. Although misassembled homodimers can form under some conditions, correctly aligned heterodimers consistently assemble provided a small "dimer initiation" site near the actin binding domain is present. The dimer initiation site has been characterized to some extent, but little is known about the subsequent, low-affinity lateral interactions of the remaining motifs along the length of this ropelike molecule or the forces involved in these two steps of the dimerization process. In this study, we used isothermal titration calorimetry to deduce the mechanism and energetics of the two heterodimer assembly phases. The high-affinity initiation of dimerization is primarily enthalpically driven, which is consistent with initial alignment and docking of specific complementary alpha and beta motifs in the dimer initiation site driven by long-range electrostatic interactions followed by tight binding stabilized by hydrogen bonds and other hydrophilic interactions. In contrast, the subsequent weak lateral associations of additional motifs are primarily entropically driven, suggesting binding primarily involves weak hydrophobic interactions. Although initial docking is largely electrostatic, the only lateral interaction within the first four pairs of motifs that involves a net change in protons is the interaction of the alpha18 and beta4 repeats. This substoichiometric uptake of protons could be due to a pKa shift of a histidine in the alpha18 motif located near the dimer interface in a proposed homology-based model. On the basis of this analysis of heterodimer thermodynamics, a detailed model of spectrin dimer assembly is proposed. PMID- 17713926 TI - Solution structure of the hDlg/SAP97 PDZ2 domain and its mechanism of interaction with HPV-18 papillomavirus E6 protein. AB - The E6 protein from high-risk types of human papillomavirus (HPV) binds PDZ domain containing proteins and targets them for degradation. We used isothermal titration calorimetry to measure the interaction of a peptide from the C-terminus of HPV-18 E6 to the second PDZ domain (PDZ2) from the human homologue of the Drosophila discs large tumor suppressor protein (hDlg). Isothermal titration calorimetry experiments with a series of peptides showed that HPV-18 E6 bound hDlg PDZ2 about 5-fold stronger than HPV-16 E6, that the contribution of Arg154 to binding was about 1 kcal/mol, and that the binding was disabled by phosphorylation at Thr156. We then used NMR to determine the solution structure of the complex of PDZ2 bound to the HPV-18 E6 peptide. The resultant structures were of high quality and had backbone root-mean-square deviations of less than 0.5 A. The structure shows a novel mode of interaction in which six residues of the HPV-18 E6 peptide are contacted by the PDZ2 domain, in contrast to the typical four residues used by class I PDZ domains. Molecular dynamics simulations supported a model in which the C- and N-terminal ends of the peptide had different mobilities within the complex. Comparison of the NMR complex structure to previously determined X-ray structures of PDZ2 by itself and bound to different peptides allows a description of conformational changes required for PDZ2 to bind to HPV-18 E6. PMID- 17713927 TI - The activation and inhibition of cyclin-dependent kinase-5 by phosphorylation. AB - Despite the very similar 3-dimensional structures as reflected by the more than 60% identity in amino acid sequences, CDK2 and CDK5 have very different functions and characteristics. Phosphorylation on a conserved Thr14 can inhibit activities of both the kinases, but phosphorylating another conserved Tyr15, however, can lead to totally opposite inhibition and stimulation consequences in CDK2 and CDK5. Our molecular dynamics (MD) simulations suggest a similar inhibition mechanism of phosphorylation on the Thr14 as in the CDK2 system. In both the systems, the kinase activities are inhibited by the phosphorylation because it causes ATP phosphate moiety misalignment and changes in the Mg2+ ion coordination sphere, which have been proven to be critical for the phosphate group of the ATP transferring to the hydroxyl group on the serine in the substrate peptide. The calculations indicate that ATP adopts a more favorable conformation and location in the phosphorylated Tyr15 complex to facilitate the interactions with the substrate and the Mg2+ is wrapped more strongly by the phosphate group than in the unphosphorylated system, which might be favored by the transfer reaction. PMID- 17713928 TI - Structure of 2-amino-3,7-dideoxy-D-threo-hept-6-ulosonic acid synthase, a catalyst in the archaeal pathway for the biosynthesis of aromatic amino acids. AB - Genes responsible for the generation of 3-dehydroquinate (DHQ), an early metabolite in the established shikimic pathway of aromatic amino acid biosynthesis, are absent in most euryarchaeotes. Alternative gene products, Mj0400 and Mj1249, have been identified in Methanocaldococcus jannaschii as the enzymes involved in the synthesis of DHQ. 2-Amino-3,7-dideoxy-d-threo-hept-6 ulosonic acid (ADH) synthase, the product of the Mj0400 gene, catalyzes a transaldol reaction between 6-deoxy-5-ketofructose 1-phosphate and l-aspartate semialdehyde to yield ADH. Dehydroquinate synthase II, the product of the Mj1249 gene, then catalyzes deamination and cyclization of ADH, resulting in DHQ, which is fed into the canonical pathway. Three crystal structures of ADH synthase were determined in this work: a complex with a substrate analogue, fructose 1,6 bisphosphate, a complex with dihydroxyacetone phosphate (DHAP), thought to be a product of fructose 1-phosphate cleavage, and a native structure containing copurified ligands, modeled as DHAP and glycerol. On the basis of the structural analysis and comparison of the enzyme with related aldolases, ADH synthase is classified as a new member of the class I aldolase superfamily. The description of the active site allows for the identification and characterization of possible catalytic residues, Lys184, which is responsible for formation of the Schiff base intermediate, and Asp33 and Tyr153, which are candidates for the general acid/base catalysis. PMID- 17713929 TI - Alkaline conformational transition and gated electron transfer with a Lys 79 --> his variant of iso-1-cytochrome c. AB - To probe the mechanism of the alkaline conformational transition and its effect on the dynamics of gated electron transfer (ET) reactions, a Lys 79 --> His (K79H) variant of iso-1-cytochrome c has been prepared. Guanidine hydrochloride denaturation monitored by circular dichroism and absorbance at 695 nm indicates that this variant unfolds from a partially unfolded state. The conformation of the wild type (WT) and K79H proteins was monitored at 695 nm from pH 2 to 11. These data indicate that acid unfolding is multi-state for both K79H and WT proteins and that the His 79-heme alkaline conformer is more stable than a previously reported His 73-heme alkaline conformer. Fast and slow phases are observed in the kinetics of the alkaline transition of the K79H variant. The pH dependence of the fast phase kinetic data shows that ionizable groups with pKa values near 6.8 and 9 modulate the formation of the His 79-heme alkaline conformer. The slow phase kinetic data are consistent with a single ionizable group with a pKa near 9.5 promoting the Lys 73-heme alkaline transition. In the broader context of data on the alkaline transition, ionization of the ligand replacing Met 80 appears to play a primary role in promoting the formation of the alkaline conformer, with other ionizable groups acting as secondary modulators. Intermolecular ET with hexaammineruthenium(II) chloride shows conformational gating due to both His 79-heme and Lys 73-heme alkaline conformers. Both the position and the nature of the alkaline state ligand modulate the dynamics of ET gating. PMID- 17713932 TI - Electrochemical surface plasmon resonance investigation of dodecyl sulfate adsorption to electroactive self-assembled monolayers via ion-pairing interactions. AB - The redox-induced assembly of amphiphilic molecules and macromolecules at electrode surfaces is a potentially attractive means of electrochemically modulating the organization of materials and nanostructures on solid substrates via ion-pairing interactions or charge-transfer complexation. In this regard, we have investigated the potential-induced adsorption and aggregation of dodecyl sulfate, a common anionic surfactant, at a ferrocenylundecanethiolate (FcC11SAu) self-assembled monolayer (SAM)/aqueous solution interface by electrochemical surface plasmon resonance (ESPR) spectroscopy. The surfactant anions adsorb onto the electroactive SAM by specific ion-pairing interactions with the oxidized ferricinium species. The ferricinium charge density (QFc+) obtained by cyclic voltammetry and surface coverage measured by SPR indicate that the dodecyl sulfate forms an interdigitated monolayer, where half of the surfactant molecules have their sulfate headgroups paired to the surface and half have their headgroups exposed to the aqueous solution. The surface coverage of dodecyl sulfate was found to depend on both the ferricinium surface concentration and the surfactant aggregation state in solution. A maximum coverage of dodecyl sulfate on the ferricinium surface is obtained below the critical micelle concentration (cmc), in contrast to dodecyl sulfate adsorption to SAM surfaces of static positive charge. This marked difference in adsorption behavior is attributed to the dynamic generation of ferricinium by potential cycling and the specific nature of the ion-pairing interactions versus pure electrostatic ones. The results presented point to a new way of organizing molecules via electrical stimulus. PMID- 17713931 TI - Colloidal dispersions of tannins in water-ethanol solutions. AB - The molecular interactions of grape-seed tannins dissolved in water-ethanol solutions have been studied through small angle neutron scattering, light scattering, and physical separation techniques. Through selective precipitation in different solvent mixtures, three populations of tannin macromolecules have been identified: T1 (2% of the total tannin), which forms colloidal particles when the ethanol content of the solvent is brought below phiA = 0.6; T2a (33% of the tannin), which phase-separates below phiA = 0.08 in ionic conditions that are typical of wine; and T2b (65% of the tannin), which remains in solution regardless of ethanol content. Each population remains molecularly dissolved (i.e., it does not form any association structures such as stacks or micelles) until the threshold where dense colloidal particles are formed through nucleation and growth. The colloidal dispersions are metastable, due to the adsorption of organic acids on the particle surfaces; increasing ionic strength and reducing ethanol content cause the loss of this metastability and the aggregation of the particles. PMID- 17713930 TI - Secretory carrier membrane protein SCAMP2 and phosphatidylinositol 4,5 bisphosphate interactions in the regulation of dense core vesicle exocytosis. AB - Secretory carrier membrane protein 2 (SCAMP2) functions in late steps of membrane fusion in calcium-dependent granule exocytosis. A basic/hydrophobic peptide segment within SCAMP2 (SCAMP2 E: CWYRPIYKAFR) has been implicated in this function and shown to bind and sequester phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2 or PIP2] within membranes through an electrostatic mechanism. We now show that alanine substitution of tryptophan W2 within SCAMP2 E substantially weakens peptide binding to negatively charged liposomes; other substitutions for arginine R4 and lysine K8 have only limited effects on binding. Electron paramagnetic resonance analysis of liposomes containing spin-labeled PIP2 shows that R4 but not K8 is critical for SCAMP E binding to PIP2. The interfacial locations of SCAMP E and its structural variants within lipid bicelles measured by oxygen enhancement of nuclear relaxation are all similar. Corresponding point mutations within full-length SCAMP2 (SC2-R204A, SC2-K208A, and SC2-W202A) have been analyzed for biological effects on dense core vesicle exocytosis in neuroendocrine PC12 cells. With the same level of overexpression, SC2-R204A but not SC2-K208A inhibited secretion of cotransfected human growth hormone and of noradrenalin. Inhibition by SC2-R204A was the same as or greater than previously observed for SC2-W202A. Analysis of noradrenalin secretion by amperometry showed that inhibitory mutants of SCAMP2 decrease the probability of fusion pore opening and the stability of initially opened but not yet expanded fusion pores. The strong correlation between SCAMP2 E interactions with PIP2 and inhibition of exocytosis, particularly by SC2-R204A, led us to propose that SCAMP2 interaction with PIP2 within the membrane interface regulates fusion pore formation during exocytosis. PMID- 17713933 TI - Effect of temperature and surfactant type on the stability and aggregation behavior of styrene-acrylate copolymer colloids. AB - The colloidal stability, aggregation kinetics, and cluster structure of two styrene-acrylate copolymer latexes, stabilized with an aliphatic sulfonate and an aliphatic carboxylate surfactant, respectively, have been investigated experimentally in the temperature range between 283 and 323 K. The main objective of this study is to investigate the role of temperature and surfactant type on the aggregation kinetics and cluster structure. For this, the values of the Fuchs stability ratio and the time evolutions of the average radius of gyration, hydrodynamic radius, and structure factor of the clusters have been determined using static and dynamic light scattering techniques at different temperatures. It is found that although the two latexes exhibit a somewhat different dependence of the colloidal stability on temperature, all of the values of the average radius of gyration (or hydrodynamic radius) measured at different temperatures and surfactant types, which are plotted as a function of a properly defined dimensionless time, collapse to form a single master curve. Similarly, all of the measured average structure factors also collapse to form a single master curve when they are plotted as a function of the wavevector normalized using the average radius of gyration. These results indicate that, at least for the conditions investigated in this work, the aggregation mechanism and cluster structure are independent of temperature and surfactant type. PMID- 17713934 TI - Formation of protein-metal oxide nanostructures by the sonochemical method: observation of nanofibers and nanoneedles. AB - The sonochemical reaction of iron pentacarbonyl is explored in water and in water with the protein BSA (bovine serum albumen). In water, the reaction is found to produce spherical nanoparticles of magnetite (Fe3O4) with a particle size distribution of <10 to approximately 60 nm. In water with BSA, the reaction produces either nanofibers or nanoneedles, depending on the concentration of BSA. The nanofiber and nanoneedle samples are found to be mixtures of goethite, lepidocrocite, and hematite (alpha-FeOOH, gamma-FeOOH, and alpha-Fe2O3, respectively). The sonochemical reaction of iron pentacarbonyl with BSA in water is thought to proceed through the thermal decomposition mechanism for iron pentacarbonyl with BSA acting as a templating agent. PMID- 17713935 TI - Interactions of L-alanine with alumina as studied by vibrational spectroscopy. AB - The interactions of L-alanine with gamma- and alpha-alumina have been investigated by diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). L-alanine/alumina samples were dried from aqueous suspensions, at 36.5 degrees C, with two amino acid concentrations (0.4 and 0.8 mmol g-1) and at different pH values (1, 6, and 13). The vibrational spectra proved that the nature of L-alanine interactions with both aluminas is the same (hydrogen bonding), although the groups involved depend on the L-alanine form and on alumina surface groups, both controlled by the pH. For samples prepared at pH 1, cationic L-alanine [CH3CH(NH3+)COOH] displaces physisorbed water from alumina, and strong hydrogen bonds are established between the carbonyl groups of alanine, as electron donors, and the surface Al-OH2+ groups of alumina. This occurs at the expense of alanine dimer dissociation and breaking of intramolecular bonds. When samples are prepared at pH 6, the interacting groups are Al-OH2+ and the carboxylate groups of zwitterionic L-alanine [CH3CH(NH3+)COO-]. The affinity of L alanine toward alumina decreases, as the strong NH3+...-OOC intermolecular hydrogen bonds prevail over the interactions with alumina. Thus, for a load of 0.8 mmol g-1, phase segregation is observed. On alpha-alumina, crystal deposition is even observed for a load of 0.4 mmol g-1. At pH 13, the carboxylate groups of anionic L-alanine [CH3CH(NH2)COO-] are not affected by alumina. Instead, hydrogen bond interactions occur between NH2 and the Al-OH surface groups of the substrate. Complementary N2 adsorption-desorption isotherms showed that adsorption of L-alanine occurs onto the alumina pore network for samples prepared at pH 1 and 13, whereas at pH 6 the amino acid/alumina interactions are not strong enough to promote adsorption. The mesoporous structure and the high specific surface area of gamma-alumina make it a more efficient substrate for adsorption of L-alanine. For each alumina, however, it is the nature of the specific interactions and not the porosity of the substrate that determines the adsorption process. PMID- 17713936 TI - Structural evolution of gold nanorods during controlled secondary growth. AB - Single-crystalline gold nanorods synthesized by the Ag(I)-mediated seeded-growth method (see: El-Sayed, M. A.; Nikoobakht, B. Chem. Mater. 2003, 15, 1957) were used as seeds for the preferential overgrowth of gold on particular crystallographic facets by systematic variation of the conditions during overgrowth. The results support previous reports about the relevance of the cationic surfactant cetyltrimethylammonium bromide (CTAB) and Ag(I) in stabilizing anisotropic particle shapes and demonstrate that the regulation of the amount of ascorbic acid facilitates the preferential overgrowth of {111} crystal facets to form Xi-type particle shapes. Interestingly, secondary overgrowth is found to inevitably result in a loss of particle shape anisotropy. A mechanism based on surface reconstruction is proposed to rationalize the "shape reversal" that is generally observed in the nanorod growth process, that is, the initial increase and subsequent decrease of particle anisotropy with increasing reaction time. High-resolution electron microscopy analysis of gold nanorods reveals clear evidence for (1 x 2) missing row surface reconstruction of high energetic {110} facets that form during the initial phase during particle growth. PMID- 17713938 TI - Performance evaluation of third-order thermodynamic perturbation theory and comparison with existing liquid state theories. AB - To evaluate the performance of a recently proposed third-order thermodynamic perturbation theory (TPT), we employ the third TPT for calculation of thermodynamic properties such as compressibility factor, internal energy, excess chemical potential, gas-liquid coexistence curve, and critical properties of several fluids. By comparing the third-order TPT results with corresponding simulation data available in literature and supplied in the present report and theoretical results from several other theoretical approaches, one concludes that the third-order TPT is, in general, more accurate than other approaches such as Barker-Henderson second-order TPT using a macroscopic compressibility approximation (MCA-TPT), self-consistent Ornstein-Zernike approach, Monte Carlo perturbation theory, and a specially devised equation of state. Specifically, the third-order TPT can predict quantitatively a double critical phenomena of gas liquid transition and a low-density liquid (LDL)-high-density liquid (HDL) transition associated with a soft core (SC) potential fluid very satisfactorily, but the predictions for the LDL-HDL transition based on the second-order MCA-TPT are quantitatively very bad or qualitatively incorrect. The failure of the second order MCA-TPT for the SC fluid can be ascribed to the facts that for the SC potential the second-order and third-order terms of the perturbation expansion are not small quantities and that the second-order term is underestimated by the MCA. It is concluded that the present third-order version of the TPT is reliable for varying model fluids. PMID- 17713937 TI - Potential of mean force of hydrophobic association: dependence on solute size. AB - The potentials of mean force (PMFs) were determined for systems involving formation of nonpolar dimers composed of methane, ethane, propane, isobutane, and neopentane, respectively, in water, using the TIP3P water model, and in vacuo. A series of umbrella-sampling molecular dynamics simulations with the AMBER force field was carried out for each pair in either water or in vacuo. The PMFs were calculated by using the weighted histogram analysis method (WHAM). The shape of the PMFs for dimers of all five nonpolar molecules is characteristic of hydrophobic interactions with contact and solvent-separated minima and desolvation maxima. The positions of all these minima and maxima change with the size of the nonpolar molecule, that is, for larger molecules they shift toward larger distances. The PMF of the neopentane dimer is similar to those of other small nonpolar molecules studied in this work, and hence the neopentane dimer is too small to be treated as a nanoscale hydrophobic object. The solvent contribution to the PMF was also computed by subtracting the PMF determined in vacuo from the PMF in explicit solvent. The molecular surface area model correctly describes the solvent contribution to the PMF together with the changes of the height and positions of the desolvation barrier for all dimers investigated. The water molecules in the first solvation sphere of the dimer are more ordered compared to bulk water, with their dipole moments pointing away from the surface of the dimer. The average number of hydrogen bonds per water molecule in this first hydration shell is smaller compared to that in bulk water, which can be explained by coordination of water molecules to the hydrocarbon surface. In the second hydration shell, the average number of hydrogen bonds is greater compared to bulk water, which can be explained by increased ordering of water from the first hydration shell; the net effect is more efficient hydrogen bonding between the water molecules in the first and second hydration shells. PMID- 17713939 TI - Ab initio calculation of solid-state NMR spectra for different triazine and heptazine based structure proposals of g-C3N4. AB - We present a comprehensive theoretical study of the structure and NMR parameters of a large number of triazine and heptazine based structure proposals for g-C3N4 in different condensation states. This approach includes a detailed investigation of cyclic melon which tends toward the formation of densely packed hydrogen bonded meshes. In all of the investigated systems, we found planar layers to represent saddlepoints on the energy surface, whereas corrugated species were identified as minima. The corrugation source was linked to the repulsion of nitrogen lone pairs in close NN contacts. A linear dependency of the corrugation energy from the number of NN interactions in the investigated clusters was found. Heptazine based systems gain about twice as much energy per NN close contact in comparison to triazine structures which could be understood in terms of the distortion mechanism in the investigated structures. Furthermore, a full study of the 15N and 13C chemical shift tensors was performed for the different C/N layers. The description of the NMR parameters required dividing the investigated systems into subclusters for which the NMR tensors were calculated with density functional theory (DFT) methods. A statistical analysis of these entities allowed for the investigation of the change in the chemical shift upon corrugation and, in the case of the cyclic melon system, hydrogen bonding. With the here presented study, the most prominent structure models for g-C3N4 are characterized in terms of the 15N and 13C NMR parameters which now can directly be compared to experimental spectra. PMID- 17713940 TI - Optical absorption of a green fluorescent protein variant: environment effects in a density functional study. AB - We present an ab initio study of the optical absorption properties of a particularly interesting fluorescent protein (E2GFP), whose complex photophysics still escapes elucidation. In particular, we focus on the role of the protein environment, showing that the effects of both nearby residues and the external field due to residues not accounted for explicitly are needed to properly reproduce the experimental data. The spectra calculated taking such contributions into account provide for the first time a robust identification of the states relevant for the photophysics of this system. PMID- 17713941 TI - Theoretical study of the scalar coupling constants across the noncovalent contacts in RNA base pairs: the cis- and trans-watson-crick/sugar edge base pair family. AB - The structure and function of RNA molecules are substantially affected by non Watson-Crick base pairs actively utilizing the 2'-hydroxyl group of ribose. Here we correlate scalar coupling constants across the noncovalent contacts calculated for the cis- and trans-WC/SE (Watson-Crick/sugar edge) RNA base pairs with the geometry of base to base and sugar to base hydrogen bond(s). 23 RNA base pairs from the 32 investigated were found in RNA crystal structures, and the calculated scalar couplings are therefore experimentally relevant with regard to the binding patterns occurring in this class of RNA base pairs. The intermolecular scalar couplings 1hJ(N,H), 2hJ(N,N), 2hJ(C,H), and 3hJ(C,N) were calculated for the N H...N and N-H...O=C base to base contacts and various noncovalent links between the sugar hydroxyl and RNA base. Also, the intramolecular 1J(N,H) and 2J(C,H) couplings were calculated for the amino or imino group of RNA base and the ribose 2'-hydroxyl group involved in the noncovalent interactions. The calculated scalar couplings have implications for validation of local geometry, show specificity for the amino and imino groups of RNA base involved in the linkage, and can be used for discrimination between the cis- and trans-WC/SE base pairs. The RNA base pairs within an isosteric subclass of the WC/SE binding patterns can be further sorted according to the scalar couplings calculated across different local noncovalent contacts. The effect of explicit water inserted in the RNA base pairs on the magnitude of the scalar couplings was calculated, and the data for discrimination between the water-inserted and direct RNA base pairs are presented. The calculated NMR data are significant for structural interpretation of the scalar couplings in the noncanonical RNA base pairs. PMID- 17713942 TI - Rigidity and/or flexibility of calixarenes. effect of the p sulfonatocalix[n]arenes (n = 4, 6, and 8) on the electron transfer process [Ru(NH3)5pz]2+ + Co(C2O4)3(3-). AB - The reaction [Ru(NH3)5pz]2+ + Co(C2O4)33- has been studied in aqueous solutions of p-sulfonatocalix[n]arene (n = 4, 6, and 8). The results are interpreted by using the pseudophase model. Results show that the rigidity and/or flexibility of the assembled rings have a great effect on the thermodynamics of inclusion of the guest into the host and, therefore, on the kinetics of the electron transfer processes that take place in these media. The obtained results are discussed from the viewpoint of two types of interactions: electrostatic and nonelectrostatic. From surface potential measurements, the guest-host interactions have been demonstrated to be mainly due to nonelectrostatic interactions, although the species are charged. So, the nonelectrostatic contribution to the equilibrium constant in all the calixarenes studied is 1 order of magnitude higher than the electrostatic one (Knel = 144 and 884 mol-1 dm3 for p-sulfonatocalix[n]arene (n = 4 and 6, respectively) and Kel approximately 10 mol-1 dm3). Electrostatic interactions also affect the kinetic results. PMID- 17713943 TI - Transferable potentials for phase equilibria. 9. Explicit hydrogen description of benzene and five-membered and six-membered heterocyclic aromatic compounds. AB - The explicit hydrogen version of the transferable potentials for phase equilibria (TraPPE-EH) force field is extended to benzene, pyridine, pyrimidine, pyrazine, pyridazine, thiophene, furan, pyrrole, thiazole, oxazole, isoxazole, imidazole, and pyrazole. While the Lennard-Jones parameters for carbon, hydrogen (two types), nitrogen (two types), oxygen, and sulfur are transferable for all 13 compounds, the partial charges are specific for each compound. The benzene dimer energies for sandwich, T-shape, and parallel-displaced configurations obtained for the TraPPE-EH force field compare favorably with high-level electronic structure calculations. Gibbs ensemble Monte Carlo simulations were carried out to compute the single-component vapor-liquid equilibria for benzene, pyridine, three diazenes, and eight five-membered heterocycles. The agreement with experimental data is excellent with the liquid densities and vapor pressures reproduced within 1 and 5%, respectively. The critical temperatures and normal boiling points are predicted with mean deviations of 0.8 and 1.6%, respectively. PMID- 17713944 TI - Can marcus theory be applied to redox processes in ionic liquids? A comparative simulation study of dimethylimidazolium liquids and acetonitrile. AB - Simulations of a model system of charged spherical ions in the ionic liquids dimethylimidazolium chloride, [dmim][Cl], dimethylimidazolium hexafluorophosphate, [dmim][PF6], and the polar liquid acetonitrile, MeCN, are used to investigate the applicability of Marcus theory to electrochemical half cell redox processes in these liquids. The free energy curves for solvent fluctuations are found to be approximately parabolic and the Marcus solvent reorganization free energies and activation free energies are determined for six possible redox processes in each solvent. The similarities between the different types of solvent are striking and are attributed to the essentially long-range nature of the relevant interactions and the effectiveness of the screening of the ion potential. Nevertheless, molecular effects are seen in the variation of solvent screening potential with distances up to 2 nm. PMID- 17713945 TI - Identification and localization of cyanophycin in bacteria cells via imaging of the nitrogen distribution using energy-filtering transmission electron microscopy. AB - In this study the technique of energy-filtering transmission electron microscopy was applied to localize cyanophycin (CGP) in recombinant strains of Ralstonia eutropha. Since CGP is a polymer consisting of the amino acids aspartate and arginine, which functions as a temporary nitrogen reserve that is deposited as insoluble inclusions in the cytoplasm of the cell, its nitrogen content is significantly higher than that of the other cell matter. In this study, we recorded nitrogen distribution maps, which represent the location of CGP in ultrathin sections of resin-embedded cells of recombinant strains of R. eutropha expressing the cyanophycin synthetase of Anabaena sp. strain PCC 7120. Furthermore, the existence of nitrogen in CGP granules was additionally proven by recording electron energy-loss spectra. The samples of R. eutropha H16 (pBBR1MCS 2::cphA1(7120)) revealed a second type of granule, which does not show nitrogen in the corresponding maps and which can be identified as an inclusion containing poly(3-hydroxybutyric acid). The methods applied in this study are suitable to identify storage compounds with elevated nitrogen contents and to reveal their location in the bacterial cell. The methods are also very helpful to distinguish between inclusions of different chemical compositions that occur both at the same time in the cells but cannot or only hardly be distinguished by other methods. PMID- 17713946 TI - Synthesis and characterization of novel organic/inorganic hybrid material with short peptide brushes generated on the surface. AB - A novel route to synthesize an organic/inorganic hybrid material containing short peptide chains attached on the surface (e.g., oligo(S-benzyl-L-cysteine)) was developed. Poly[N-(beta-aminoethylene)acrylamide] (PAEA) adsorbed onto silica particles surface (main diameter between 15 and 40 microm) was irreversibly fixed by the reaction between the accessible primary amino groups of the PAEA and 3,3',4,4'-benzophenone tetracarboxylic dianhydride (BTCDA). After the deposition of PAEA from a salt-free aqueous solution onto microporous silica particles and stabilization by a cross-linking reaction with BTCDA, five repeated coupling reactions of boc-S-benzyl-L-cysteine were performed. Changes in surface charges during the polyelectrolyte adsorption were studied by electrokinetic measurements. The cross-linking degree was a tool to control the surface charge of the PAEA/silica hybrid particles. X-ray photoelectron spectroscopy (XPS) was employed to obtain information about the amount of the adsorbed polyelectrolyte as well as the amount of the amino acid S-benzyl-L-cysteine that was covalently bound to the hybrid particle surface and polycondensed there. In the XPS spectra, the sulfur peaks (S 2p3/2, S 2p1/2, and S 2s) qualitatively and quantitatively indicated the presence of the amino acid on the hybrid material surface. After each step of coupling, the intensity of the S 2s peak was increased by a constant value. This indicates the oligopeptide growth. The novel hybrid material offers possibilities for subsequent derivatization reactions such as coupling other amino acids, peptides, obtaining hybrid ion exchange resins, and so forth. PMID- 17713947 TI - Modular one-pot synthesis of tetrasubstituted pyrroles from alpha (alkylideneamino)nitriles. AB - 2,3,4,5-Tetrasubstituted pyrroles have been prepared with high regioselectivity by a formal cycloaddition of alpha-(alkylideneamino)nitriles and nitroolefins followed by elimination of HCN and HNO2. The reaction allows the convergent construction of the pyrrole ring in four steps from a nitroalkane and three aldehydes. PMID- 17713948 TI - Enantioselective benzoylation of alpha-amino esters using (S)-1-benzoyl-2- (alpha acetoxyethyl)benzimidazole, a chiral benzimidazolide. AB - A new chiral benzimidazolide is developed as a nonenzymatic acylating agent for enantioselective benzoylation of racemic alpha-amino esters. The process is highly efficient, which exhibits uniformly high enantioselectivity for alpha amino esters with or without aryl substituents under mild reaction conditions. The chiral benzimidazolide is inexpensive and is easily accessible. PMID- 17713949 TI - Synthesis and application of P-stereogenic phosphines as superior reagents in the asymmetric aza-Wittig reaction. AB - A wide variety of P-stereogenic aryldialkylphosphines were prepared in enantioenriched form by a systematic diversification of the (-)-sparteine mediated dynamic kinetic resolution of racemic lithiophosphine-boranes reported by Livinghouse. Excellent asymmetric induction was observed provided that the intermediate lithiophosphine/sparteine complex precipitated from solution; more soluble derivatives returned poor ee's or racemic material. The resulting phosphine-boranes were deprotected and used as reagents in the desymmetrizing asymmetric aza-Wittig reaction of 2-alkyl-2-(3-azidopropyl)cyclohexane-1,3 diones, delivering the highest ee's yet observed in this process (up to 84% ee). Phosphines bearing bulky substituents required heating for the aza-Wittig reaction to proceed to completion, which 31P NMR studies showed to be due to interception of the reaction by the formation of unreactive (E)-phosphazides. This was circumvented by use of methyltrioxorhenium to catalyze the formation of iminophosphoranes from the azide and phosphine, allowing reactions to take place at ambient temperature, although the ee's of the asymmetric reactions were reduced in these examples. PMID- 17713950 TI - Spongolactams, farnesyl transferase inhibitors from a marine sponge: isolation through an LC/MS-guided assay, structures, and semisyntheses. AB - Novel nitrogenous diterpenoids, spongolactams A-C (1-3), were isolated as trace components of an Okinawan marine sponge, Spongia sp., by an LC/MS-guided assay for farnesyl transferase (FTase) inhibitors. Their structures were elucidated by spectroscopic analyses. To evaluate their structures and biological activity, the metabolites were semisynthesized from the known furanoditerpene 5, obtained from the same sponge. Three related compounds 4, 13, and 16 were also semisynthesized. The IC50 values against FTase for 1-3 were 23, 130, and >260 microM, respectively, while the IC50 values against a human tumor cell line were 2.0, 3.5, and 20 microM, respectively. The structure-activity relationships within the six compounds suggest some positive correlation between FTase inhibitory and cytotoxic activities. PMID- 17713951 TI - New preparation of 1,2,4,5,7,8-hexaoxonanes. AB - A new versatile procedure was developed for the synthesis of 1,2,4,5,7,8 hexaoxonanes based on the Lewis acid catalyzed reaction of acetals with 1,1' dihydroperoxydicycloalkyl peroxides. The procedure substantially extends the structural diversity of these compounds and, in most cases, allows the synthesis of these compounds in higher yields (to 96%) and with higher selectivity. Complexation of hexaoxonane with chloroform was documented for the first time. The structures of several triperoxides were established by X-ray diffraction. PMID- 17713952 TI - Selective templated complexation of a cylindrical macrotricyclic host with neutral guests: three cation-controlled switchable processes. AB - A novel triptycene-based cylindrical macrotricyclic host 1 containing an anthracene unit and two dibenzo [24]crown-8 moieties was synthesized, and its cation binding properties were studied. It was found that the host could not only form complex with the paraquat derivative 4, but also show selective templated complexation with pyromellitic diimide 2 and anthraquinone 3 in the presence of lithium and potassium ions, respectively. Consequently, two novel cascade complexes with neutral molecules as bridging species were formed in solution and in the solid state, which were structurally studied by NMR, MS spectra, and X-ray methods. Moreover, we also found that the association and dissociation of the complexes could be easily achieved by the addition and removal of lithium or potassium ions, which resulted in three cation-controlled switchable processes. PMID- 17713953 TI - Attempted synthesis of spongidines by a radical cascade terminating onto a pyridine ring. AB - Mn(III)-based oxidative free-radical cyclization of an unsaturated beta-keto ester containing a pyridine ring as radical trap has been studied. This intramolecular reaction of nucleophilic carbon-centered radicals with the pyridine ring leads to the stereospecific construction of a tetracyclic compound in which five chiral centers are created in one pot. This synthetic approach represents the first attempt to prepare the anti-inflammatory pyridinium alkaloids spongidine A, B, and D. PMID- 17713954 TI - Computational methods in organic thermochemistry. 2. Enthalpies and free energies of formation for functional derivatives of organic hydrocarbons. AB - Standard state enthalpies and free energies of formation for nitrogen-, oxygen-, sulfur-, fluorine-, chlorine-, and silicon-containing compounds can be computed with reasonable accuracy (usually within four and often two kJ/mol) using the G3 and G3MP2 model chemistries. In several of the families, compounds with as many as 10 carbon atoms have been computed. Larger errors are found in the free energies of these longer chain molecules which can be reduced by compensating for the presence of multiple conformers having a significant population at 298.15 K. In some instances, those substances showing large deviations are found to have experimental energies that may be erroneous. PMID- 17713955 TI - EDA study of pi-conjugation in tunable Bis(gem-diethynylethene) fluorophores. AB - The strength of pi-conjugation in a family of bis(gem-diethynylethene) fluorophores is estimated within the density functional theory framework using the energy decomposition analysis (EDA) method. The observed very good linear correlations between the calculated pi-conjugation and the experimental values for the UV absorption and fluorescence emission for this series of compounds suggest that the values given by the EDA are useful for the interpretation and prediction of photochemical properties of the molecules. The calculated data predict that adequate modifications in the core moiety of the molecule such as pi donor substituents in the aromatic ring or in the periphery of the bis-enedyine unit like pi-acceptor groups placed in the para position of the aryl substituent increase the total pi-conjugation in the systems and thus provoke significant changes in both the absorption and emission spectra leading to large Stokes shifts. The effect of such substituents is quantitatively predicted by the EDA data. PMID- 17713956 TI - A concise synthesis of (S)-N-ethoxycarbonyl-alpha-methylvaline. AB - A practical and efficient protocol for the three-step synthesis of (S)-N ethoxycarbonyl-alpha-methylvaline 3 is described which utilizes readily available commercial starting materials. The key transformations involve resolution crystallization of tartrate salt 6 followed by a one-pot procedure for the preparation of 3 which is isolated as the dicyclohexylamine salt in 45% overall yield and in 91-95% ee. PMID- 17713957 TI - Lipase-catalyzed kinetic resolution of cyclic trans-1,2-diols bearing a diester moiety: synthetic application to chiral seven-membered-ring alpha,alpha disubstituted alpha-amino acid. AB - Chiral cycloalkane-trans-1,2-diols (+/-)-3 and (+/-)-8 having a diester moiety have been prepared from dimethyl dialkenylmalonate using olefin metathesis by Grubbs catalyst, followed by epoxidation and acidic hydrolysis. Kinetic resolution of racemic cyclopentane-trans-1,2-diol (+/-)-3 by lipase-catalyzed transesterification afforded an optically active monoacetate (-)-5 of 95% ee in 46% yield and the recovered diol (-)-3 of 92% ee in 51% yield, and that of cycloheptane-trans-1,2-diol (+/-)-8 gave a monoacetate (+)-10 of 95% ee in 51% yield and the diol (-)-8 of >99% ee in 43% yield, respectively. The enantiomer selectivity of racemic cyclic trans-1,2-diols bearing a diester moiety by lipases (Amano PS and Amano AK) was opposite to that of the reported simple racemic cycloalkane-trans-1,2-diols. To explain the lipase-catalyzed enantiomer selectivity, computer modeling of lipase-substrate complexes was performed. Furthermore, the optically active diester (-)-8 could be efficiently converted into an optically active seven-membered-ring alpha,alpha-disubstituted amino acid (4R,5R)-(-)-15. PMID- 17713958 TI - Alpha-hydroxyallylation reaction of carbonyl compounds. PMID- 17713959 TI - Rayleigh imaging of graphene and graphene layers. AB - We investigate graphene and graphene layers on different substrates by monochromatic and white-light confocal Rayleigh scattering microscopy. The image contrast depends sensitively on the dielectric properties of the sample as well as the substrate geometry and can be described quantitatively using the complex refractive index of bulk graphite. For a few layers (<6), the monochromatic contrast increases linearly with thickness. The data can be adequately understood by considering the samples behaving as a superposition of single sheets that act as independent two-dimensional electron gases. Thus, Rayleigh imaging is a general, simple, and quick tool to identify graphene layers, which is readily combined with Raman scattering, that provides structural identification. PMID- 17713960 TI - Dipolar structures in colloidal dispersions of PbSe and CdSe quantum dots. AB - We show by cryogenic transmission electron microscopy that PbSe and CdSe nanocrystals of various shapes in a liquid colloidal dispersion self-assemble into equilibrium structures that have a pronounced dipolar character, to an extent that depends on particle concentration and size. Analyzing the cluster size distributions with a one-dimensional (1D) aggregation model yields a dipolar pair attraction of 8-10 kBT at room temperature. This accounts for the long-range alignment of the crystal planes of individual nanocrystals in self-assembled superstructures and for anisotropic nanostructures grown via oriented attachment. PMID- 17713961 TI - Structural evidence of the similarity of Sb(OH)3 and As(OH)3 with glycerol: implications for their uptake. AB - Recent experimental results suggest that As(III) and Sb(III) transport in prokaryotes and eukaryotes might be facilitated by aquaglyceroporins. GlpF, the glycerol facilitator in Escherichia coli was the first to be identified as a trivalent metalloid transporter. Quantum calculations have been performed to study the possible existence of common structural properties between As(OH) 3 and Sb(OH) 3 and glycerol. Because the mechanism of substrate migration is primarily related to the successive formation of hydrogen bonds between the substrate and the hydrophilic part of the channel wall, this study has focused on the structural, thermodynamic, and electrostatic comparison of the main As(III) and Sb(III) compounds present in aqueous solution at physiological pH values, As(OH) 3 and Sb(OH) 3, with the glycerol conformation closest to the structures of these As- and Sb-containing compounds. This particular glycerol conformation has then been compared to three known experimental conformations of glycerol present in the protein channel. Besides their stoichiometry and electroneutral condition, As(OH) 3 and Sb(OH) 3 show very strong similarities to both each other and the studied conformation of the glycerol molecule: Namely, they show a similar charge distribution and a slightly smaller volume than glycerol. Their smaller size can be an additional advantage for the transit through the narrowest region of the GlpF channel. However, the metalloid hydroxyl groups lack the flexibility of glycerol, which probably helps this molecule to adapt its conformation to the topology of the GlpF channel. PMID- 17713962 TI - TIMES-SS--a mechanistic evaluation of an external validation study using reaction chemistry principles. AB - The TImes MEtabolism Simulator platform used for predicting skin sensitization (TIMES-SS) is a hybrid expert system that was developed at Bourgas University using funding and data from a consortium comprised of industry and regulators. TIMES-SS encodes structure-toxicity and structure-skin metabolism relationships through a number of transformations, some of which are underpinned by mechanistic three-dimensional quantitative structure-activity relationships. Here, we describe an external validation exercise that was recently carried out. As part of this exercise, data were generated for 40 new chemicals in the murine local lymph node assay (LLNA) and then compared with predictions made by TIMES-SS. The results were promising with an overall good concordance (83%) between experimental and predicted values. The LLNA results were evaluated with respect to reaction chemistry principles for sensitization. Additional testing on a further four chemicals was carried out to explore some of the specific reaction chemistry findings in more detail. Improvements for TIMES-SS, where appropriate, were put forward together with proposals for further research work. TIMES-SS is a promising tool to aid in the evaluation of skin sensitization potential under legislative programs such as REACH. PMID- 17713963 TI - Cinchona-modified platinum catalysts: from ligand acceleration to technical processes. AB - This Account records work carried out in our laboratories during the last 2 decades in the field of enantioselective heterogeneous hydrogenation. Of particular interest was Orito's catalytic system, platinum catalysts modified with cinchona alkaloids for the hydrogenation of activated ketones. Described are the development of the optimal platinum catalyst and modifier and the expansion of the scope of the catalyst. Kinetic studies aimed at understanding the mode of action of the catalyst revealed that the cinchona modifier not only renders the catalyst enantioselective but strongly accelerates the hydrogenation. This was the first case of ligand acceleration with a heterogeneous catalytic system. Finally, a number of industrial processes are summarized with the enantioselective hydrogenation of various alpha-keto esters as a key step. PMID- 17713964 TI - Visual methods for interpreting optical nonlinearity at the molecular level. AB - The emergence of nonlinear optical (NLO) measurement approaches has provided new windows into molecular and macromolecular structure within thin films and materials. The greatest barriers in mining this structural information increasingly appear in meaningfully relating these macroscopic results back to molecular-level descriptions, driven largely by the increasing complexity of the molecular systems and interfacial architectures under interrogation. As NLO methods continue their expansion into increasingly diverse disciplines, so grows the need for tools to guide this evolution without sacrificing the mathematical rigor of more traditional tensor representations. Recent developments reviewed in this Account are designed to facilitate interpretation of complex assemblies using relatively simple but still quantitatively accurate visual representations of the polarization-dependent optical nonlinearity, both for individual chromophores and for polymeric assemblies of coupled chromophores. Although the primary focus of this Account is on second-order nonlinear optical effects, including second harmonic generation and sum frequency generation, many of these same concepts also directly apply to higher-order phenomena. PMID- 17713966 TI - Peptide fragment intensity statistical modeling. AB - We present new statistical models of peptide fragment peak intensities that achieve unprecedented accuracy, and we discuss their application to the problem of scoring in database searching or peptide de novo sequencing. The models, made available via open-source computer programs, are very general and can potentially improve any intensity-based scoring. PMID- 17713965 TI - Method for screening and MALDI-TOF MS sequencing of encoded combinatorial libraries. AB - We describe a new method for encoded synthesis, efficient on-resin screening, and rapid unambiguous sequencing of combinatorial peptide libraries. An improved binary tag system for encoding peptide libraries during synthesis was designed to facilitate unequivocal assignment of isobaric residues by MALDI-TOF MS analysis. The improved method for encoded library synthesis was combined with a new versatile on-resin screening strategy that permitted multiple stages and types of screening to be employed successively on one library under mild conditions. The new method facilitated a combinatorial study of transglutaminase (TGase) enzyme substrate peptides, revealing new details of the effect of amino acid composition on TGase substrates. The approach was first demonstrated for an encoded library (130,321 compounds) of lysine pentapeptide substrates of TGase, synthesized using the "split-mix" method. The library was reacted on-resin with TGase enzyme and a soluble desthiobiotin labeled glutamine substrate. Initial screening was performed by adsorbing streptavidin-coated magnetic microparticles onto library beads, followed by magnetic separation. The differential binding affinities of desthiobiotin and biotin for streptavidin were exploited to release the magnetic microparticles and regenerate the desthiobiotin-labeled resin beads for further screening by flow-cytometry-based automated bead sorting, resulting in 345 beads that were sequenced by MALDI-TOF MS analysis. A second library consisted of encoded glutamine hexapeptide substrates, which was reacted on-resin with TGase enzyme and a soluble desthiobiotin-labeled cadaverine. Two-stage screening identified 267 glutamine peptides as TGase-reactive, of which 21 were further analyzed by solution-phase enzyme kinetics. Kinetic results indicated that the peptide PQQQYV from the library has a 68-fold greater substrate specificity than the best known glutamine substrate QQIV. The new encoding and screening strategies described here are expected to be broadly applicable to synthesis and screening of combinatorial peptide libraries in the future. PMID- 17713967 TI - Nafion-tris(2-2'-bipyridyl)ruthenium(II) Ultrathin Langmuir-Schaefer films: redox catalysis and electrochemiluminescent properties. AB - A simple procedure to incorporate tris(2-2'-bipyridyl)ruthenium(II), [Ru(bpy)3]2+, into Nafion Langmuir-Schaefer (LS) films is described. Nafion LS films (tens of nanometers thick) were formed on quartz glass and indium tin oxide (ITO) directly from Nafion-[Ru(bpy)3]2+ Langmuir films assembled at the water-air interface. This procedure allowed the direct incorporation of [Ru(bpy)3]2+ into Nafion films without the need for subsequent loading. UV-vis spectroscopy confirmed the successful incorporation of [Ru(bpy)3]2+ within the LS films and showed that the amount of [Ru(bpy)3]2+ immobilized in this way scaled with film thickness. Voltammetric studies on ITO-modified electrodes confirmed the successful incorporation of [Ru(bpy)3]2+ and demonstrated that [Ru(bpy)3]2+ was retained within the ultrathin films over a long time scale. These electrodes were tested for the electrocatalytic reduction of tripropylamine. Significant catalysis was observed due to the rapid turnover of [Ru(bpy)3]2+/3+ between the electrode surface and outer boundary of the film, as a direct consequence of the ultrathin film dimensions. Concomitant electrochemiluminescence (ECL) was demonstrated highlighting the potential of this material for sensing applications. PMID- 17713968 TI - Channel and substrate zone two-dimensional resolution for chemiluminescent multiplex immunoassay. AB - A two-dimensional resolution system of channels and substrate zones was proposed for multiplex immunoassay performed with a designed multichannel chemiluminescent (CL) detection device coupled with a single photomultiplier. Using carcinoma antigen 125 (CA 125), carcinoma antigen 153 (CA 153), carcinoma antigen 199 (CA 199), and carcinoembryonic antigen (CEA) as two couples of model analytes, two couples of capture antibodies were immobilized in two channels, respectively. With a sandwich format, the CL substrates for alkaline phosphatase and horseradish peroxidase were delivered into the channels sequentially to perform a multiplex immunoassay after the sample and tracer antibodies were introduced into the channels for on-line incubation. CA 125, CA 153, CA 199, and CEA could be assayed in the ranges of 0.50-80, 2.0-100, and 5.0-150 U/mL and 1.0-70 ng/mL with limits of detection of 0.15, 0.80, and 2.0 U/mL and 0.65 ng/mL at 3sigma, respectively. The whole assay process including regeneration of the device could be completed in 37 min. The proposed system showed acceptable detection and fabrication reproducibility, and the results obtained were in acceptable agreement with those from parallel single-analyte test of practical clinical sera. This technique provides a new strategy for a simple, automated, and near simultaneous multianalyte immunoassay. PMID- 17713969 TI - The optimization of magnetosandwich assays for the sensitive and specific detection of proteins in serum. AB - Over the past decade, the use of magnetic particles (MPs) as labels in magnetic biosensors has attracted increasing interest because it provides a highly sensitive platform that can meet the diagnostic needs that are currently not met by existing technologies. However, preparing magnetic biosensors for a specific diagnostic application is a challenging task, and the (bio)chemical aspects are often neglected. Hence, one of the major remaining bottlenecks in the development of magnetic biosensors is the lack of an optimized magnetosandwich assay for the highly sensitive and specific detection of proteins in complex sample matrices. Therefore, in this article, we report on the impact of several different aspects of magnetosandwich assay development, that is, surface chemistry, MP size, rinsing procedure, sample matrix, and blocking procedure on the total-assay performance using quartz crystal microbalance and optical microscopy analysis. The optimization focused on the diagnostically relevant protein S100betabeta, a marker for stroke and minor head injury. It was observed that small MPs in combination with a strong rinsing and a BSA/Tween-20 blocking allows for the most specific and sensitive detection of S100betabeta in serum over a wide concentration range. PMID- 17713970 TI - Substituted NDP-MSH peptides paired with mutant melanocortin-4 receptors demonstrate the role of transmembrane 6 in receptor activation. AB - The melanocortin-4 receptor (MC4R) is involved in regulating energy homeostasis and is a potential therapeutic target for obesity and cachexia. Molecular interactions between peptide ligands and MC4R have been studied in detail. Less is known regarding the role of these interactions in the mechanism of MC4R activation. The aim of this study was to investigate the molecular mechanism of human MC4R activation by [Nle4, d-Phe7]alpha-melanocyte-stimulating hormone (NDP MSH), by first defining the role of the His6-d-Phe7-Arg8-Trp9 residues in receptor activation (Emax for stimulation of cAMP accumulation) using modified peptides, then understanding how their interaction with the receptor modulates activation using site-directed mutagenesis and a molecular model of NDP-MSH bound to the active state of the receptor. Alanine substitution indicated that the d Phe7, Arg8, and Trp9 side chains contribute binding energy but are not essential for the receptor activation event. Conversely, His6 to Ala6 substitution reduced receptor activation but did not affect affinity. Chlorine substitutions on the d Phe7 side chain also inhibited receptor activation. F261(6.51)A and F284(7.35)A receptor mutations acted as gain-of-function mutations, restoring efficacy to the His6 and d-Phe7 substituted peptides that had lost efficacy at the wild-type receptor. Based on a model of NDP-MSH and MC4R interaction, the antagonist behavior of these peptides is consistent with the prevention of transmembrane 6 (TM6) rotation. This data supports the hypothesis that increasing the size of d Phe7 directly interferes with TM6 rotation, preventing receptor activation. We further propose that removing the interaction with the His6 side chain reorients the peptide within the binding pocket, indirectly impeding TM6 rotation by strengthening peptide interaction with F261(6.51) and F284(7.35). These findings refine the molecular basis for the mechanism of ligand-stimulated hMC4R activation and will be useful for the development of hMC4R agonists and antagonists. PMID- 17713972 TI - Clinical pharmacokinetics of darunavir. AB - Darunavir (TMC114) is a newly developed HIV-1 protease inhibitor with potent antiviral activity against both wild-type and multidrug resistant HIV-1 strains. The drug is currently approved by the US FDA for antiretroviral treatment experienced patients with limited therapeutic options. The approved dosage of darunavir is 600 mg in combination with ritonavir 100mg twice daily. Darunavir is rapidly absorbed after oral administration, reaching peak plasma concentrations after 2.5-4 hours. Absorption is followed by a fast distribution/elimination phase and a subsequent slower elimination phase with a terminal elimination half life of 15 hours in the presence of low-dose ritonavir. Darunavir is approximately 95% plasma protein bound, mainly to alpha(1)-acid glycoprotein. Systemic exposure is increased by 30% when darunavir is taken with a meal. Darunavir is extensively and almost exclusively metabolised by cytochrome P450 (CYP) 3A4. Coadministration with small doses of the strong CYP3A4 inhibitor ritonavir results in an increase in darunavir bioavailability from 37% to 82%. Darunavir and its metabolites are mainly excreted in faeces (79.5%) and, to a lesser extent, in urine (13.9%). With regard to the necessary coadministration with low-dose ritonavir as a potent CYP3A4 inhibitor, coadministration of other substrates of CYP3A4 with darunavir/ritonavir requires caution or is even contraindicated. Guidance is derived from drug-drug interaction trials and experience from comparable ritonavir-boosted protease inhibitor regimens. PMID- 17713973 TI - Phase I evaluation of the safety, pharmacokinetics and pharmacodynamics of CP 481,715. AB - BACKGROUND AND OBJECTIVES: The chemokine receptor CCR1 is believed to play a role in several inflammatory diseases, primarily by promoting the migration of leukocytes through the endothelial barrier. Thus, a possible strategy for treating inflammatory diseases is inhibition of leukocyte infiltration by antagonising CCR1. Recently, CP-481,715 has been described as a potent and specific antagonist of CCR1. The aims of this study were to assess the safety, pharmacokinetics and pharmacodynamics of CP-481,715 along with drug interactions with ciclosporin. SUBJECTS AND METHODS: This was a phase I randomised, double blind, placebo-controlled study with CP-481,715 in 78 healthy male volunteers. Subjects were administered escalating CP-481,715 doses of up to 3000 mg with food and after fasting in the single-dose study. In the drug interaction study, which was a single-dose, two-way crossover study, 12 subjects received a 300 mg dose of CP-481,715 as a suspension of polymorph A under fasted conditions, both with and without prior administration of ciclosporin. RESULTS AND CONCLUSIONS: All doses of CP-481,715 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of CP-481,715 was detected ex vivo by demonstrating a dose-related and linear increase in the amount of macrophage inflammatory protein-1alpha, CCL3, required to induce CD11b upregulation. Analysis of vital signs indicated no consistent clinical effects, and statistical analysis of ECG characteristics demonstrated no significant prolongation of the corrected QT interval. A drug-drug interaction study with ciclosporin demonstrated that CP-481,715 clearance was decreased by ciclosporin, consistent with its ability to compete with P-glycoprotein. Phase II studies may be warranted to see if CP-481,715 exhibits efficacy in treating inflammatory diseases such as rheumatoid arthritis, multiple sclerosis or transplant rejection. PMID- 17713974 TI - Pharmacokinetics and tolerability of duloxetine following oral administration to healthy Chinese subjects. AB - OBJECTIVES: The objectives of the study were to characterise the pharmacokinetics and assess the tolerability of duloxetine in healthy Chinese subjects after single and multiple oral 60 mg dosing. METHODS: This was a single-centre, double blind, randomised, placebo-controlled, single-period study in healthy native Chinese subjects. A total of 32 subjects, 19 men (14 on duloxetine, 5 on placebo) and 13 women (10 on duloxetine, 3 on placebo) between the ages of 20 and 39 years, participated in the study. Duloxetine 60 mg (enteric-coated pellets in a capsule) was given orally once on day 1 and once daily on days 4 to 9. Sequential blood samples were collected over 72 hours after the dose on days 1 and 9, and a predose sample was obtained on days 7 and 8. Duloxetine concentrations in plasma were determined by a validated liquid chromatography-tandem mass spectrometry method. The tolerability evaluation included a physical examination, vital signs, adverse event monitoring and clinical laboratory evaluations. RESULTS: Duloxetine disposition on oral administration is characterised by a one-compartment pharmacokinetic model. Duloxetine is well absorbed, with a median time of maximum plasma concentration at 6 and 4 hours following single and multiple dosing, respectively. At steady state, the mean apparent oral clearance (CL(ss)/F), mean apparent volume of distribution (V(ss)/F) and mean terminal elimination half-life (t((1/2))) were 86.8 L/h, 1570L and 11 hours, respectively. CL/F and V(ss)/F on single dosing were not statistically significantly different (p > 0.05) compared with multiple dosing. The linearity index, calculated as the ratio of the area under the plasma concentration-time curve (AUC) during the dosing interval tau at steady state (AUC(tau)(,ss)) to the AUC from time zero to infinity after single dosing (AUC(infinity,single dose)) was 1.15 (coefficient of variation 35.7%). The accumulation in duloxetine exposure was estimated to be 50% on multiple dosing compared with single dosing, consistent with the t((1/2)) and dosing interval (24 hours). The pharmacokinetic parameters of duloxetine in Chinese subjects were not statistically significantly different from those reported previously in Caucasian and Japanese subjects. There were no clinically significant adverse events, abnormal safety laboratory data or vital sign changes reported. CONCLUSION: Duloxetine pharmacokinetics in healthy Chinese subjects given a 60 mg once-daily dosing regimen were well characterised and consistent with known duloxetine pharmacokinetics in healthy Caucasian and Japanese subjects. Both single dosing and multiple once-daily dosing of duloxetine 60 mg were well tolerated by healthy Chinese subjects in this study. PMID- 17713971 TI - Integrated pharmacokinetics and pharmacodynamics in drug development. AB - Drug development is a complex, lengthy and expensive process. Pharmaceutical companies and regulatory authorities have recognised that the drug development process needs optimisation for efficiency in view of the return on investments. Pharmacokinetics and pharmacodynamics are the two main principles determining the relationship between dose and response. This article provides an update on integrated approaches towards drug development by linking pharmacokinetics, pharmacodynamics and disease aspects into mathematical models. Gradually, a transition is taking place from a rather empirical approach towards a modelling- and simulation-based approach to drug development. The main learning phases should be phases 0, I and II, whereas phase III studies should merely have a confirmatory purpose. In model-based drug development, mechanism-based mathematical models, which are iteratively refined along the path of development, incorporate the accumulating knowledge of the investigational drug, the disease and their mutual interference in different subsets of the target population. These models facilitate the design of the next study and improve the probability of achieving the projected efficacy and safety endpoints. In this article, several theoretical and practical aspects of an integrated approach towards drug development are discussed, together with some case studies from different therapeutic areas illustrating the application of pharmacokinetic/pharmacodynamic disease models at different stages of drug development. PMID- 17713975 TI - Increased absorption of digoxin from the human jejunum due to inhibition of intestinal transporter-mediated efflux. AB - BACKGROUND AND OBJECTIVES: The contribution of transport in the small intestine by the apically located efflux pump P-glycoprotein to variable drug absorption in humans is still poorly understood. We therefore investigated whether inhibition of intestinal P-glycoprotein-mediated efflux by quinidine leads to increased absorption of the P-glycoprotein substrate digoxin. METHODS: Using a multilumen perfusion catheter, we investigated the impact of P-glycoprotein inhibition on absorption of two compounds: the P-glycoprotein substrate digoxin and the marker for passive transcellular absorption antipyrine. Two 20cm adjacent jejunal segments were isolated with the multilumen perfusion catheter in seven healthy subjects. Unlabelled and deuterated digoxin and antipyrine, respectively, were simultaneously infused into either of the intestinal segments. One of the segments was additionally perfused with the P-glycoprotein inhibitor quinidine. Intestinal perfusates were collected for 3 hours, and drug concentrations were determined in the intestinal perfusates, plasma and urine. RESULTS: Quinidine did not affect the disposition of antipyrine. In contrast, coadministration of quinidine into one jejunal segment caused a considerable increase in the amount of digoxin absorbed from this segment compared with the absorption from the other quinidine-free segment (22.3 +/- 8.9% vs 55.8 +/- 21.2% of the dose; p < 0.05). Accordingly, the area under the plasma concentration-time curve and the maximum plasma concentration of digoxin were considerably higher when luminal quinidine was coadministered (p < 0.05 and p < 0.001, respectively). Differences in digoxin absorption from the two intestinal segments were also reflected by pronounced differences in urinary digoxin elimination (5.5 +/- 3.3% vs 19.2 +/- 8.1% of the dose; p < 0.01). CONCLUSIONS: P-glycoprotein inhibition in enterocytes increases systemic exposure of orally administered drugs that are P-glycoprotein substrates. These data highlight the importance of the small intestine as an active barrier against xenobiotics. PMID- 17713977 TI - Thiopurine treatment in inflammatory bowel disease. PMID- 17713976 TI - The absolute oral bioavailability and population-based pharmacokinetic modelling of a novel dipeptidylpeptidase-IV inhibitor, vildagliptin, in healthy volunteers. AB - BACKGROUND AND OBJECTIVE: Vildagliptin is a potent, selective, orally active inhibitor of dipeptidylpeptidase-IV being developed for the treatment of type 2 diabetes mellitus. The objective of this study was to assess the absolute oral bioavailability of vildagliptin by comparing the systemic exposure after oral and intravenous administration in healthy volunteers. METHODS: This was an open label, randomised, two-period, two-treatment, crossover study in 11 healthy volunteers. Subjects received vildagliptin 50mg orally or 25mg as a 30-minute intravenous infusion on two occasions separated by a 72-hour washout period. Vildagliptin concentrations were determined by a specific assay in urine (lower limit of quantification [LLQ] = 5 ng/mL) and serial plasma samples (LLQ = 2 ng/mL) obtained up to 24 hours after dosing. Noncompartmental analysis and population pharmacokinetic modelling were performed. RESULTS: Both noncompartmental analysis and population pharmacokinetic modelling estimated the absolute oral bioavailability of vildagliptin to be 85%. Renal elimination of unchanged vildagliptin accounted for 33% and 21% of the administered dose 24 hours after intravenous and oral administration, respectively. Renal clearance (13 L/h) was approximately one-third of the total systemic clearance (41 L/h). Two peaks were observed in plasma concentrations at 1 and 3 hours after oral administration in nine of 11 subjects. Modelling based on the population approach identified two absorption sites with lag-times of 0.225 and 2.46 hours. Both absorption rate constants were slower than the elimination rate constant, indicating 'flip-flop' kinetics after oral administration. Bodyweight was identified as a factor with an impact on the volume of distribution of the peripheral compartment. Clearance was 24% greater in males (44.6 L/h) than in females (36.1 L/h). CONCLUSIONS: Vildagliptin is rapidly and well absorbed with an estimated absolute bioavailability of 85%. Two possible sites of absorption were identified, and the absorption rates were slower than the elimination rate, indicating a flip-flop phenomenon after oral dosing. PMID- 17713979 TI - Making performance-based funding work for health. PMID- 17713980 TI - Defining childhood severe falciparum malaria for intervention studies. AB - BACKGROUND: Clinical trials of interventions designed to prevent severe falciparum malaria in children require a clear endpoint. The internationally accepted definition of severe malaria is sensitive, and appropriate for clinical purposes. However, this definition includes individuals with severe nonmalarial disease and coincident parasitaemia, so may lack specificity in vaccine trials. Although there is no "gold standard" individual test for severe malaria, malaria attributable fractions (MAFs) can be estimated among groups of children using a logistic model, which we use to test the suitability of various case definitions as trial endpoints. METHODS AND FINDINGS: A total of 4,583 blood samples were taken from well children in cross-sectional surveys and from 1,361 children admitted to a Kenyan District hospital with severe disease. Among children under 2 y old with severe disease and over 2,500 parasites per microliter of blood, the MAFs were above 85% in moderate- and low-transmission areas, but only 61% in a high-transmission area. HIV and malnutrition were not associated with reduced MAFs, but gastroenteritis with severe dehydration (defined by reduced skin turgor), lower respiratory tract infection (clinician's final diagnosis), meningitis (on cerebrospinal fluid [CSF] examination), and bacteraemia were associated with reduced MAFs. The overall MAF was 85% (95% confidence interval [CI] 83.8%-86.1%) without excluding these conditions, 89% (95% CI 88.4%-90.2%) after exclusions, and 95% (95% CI 94.0%-95.5%) when a threshold of 2,500 parasites/mul was also applied. Applying a threshold and exclusion criteria reduced sensitivity to 80% (95% CI 77%-83%). CONCLUSIONS: The specificity of a case definition for severe malaria is improved by applying a parasite density threshold and by excluding children with meningitis, lower respiratory tract infection (clinician's diagnosis), bacteraemia, and gastroenteritis with severe dehydration, but not by excluding children with HIV or malnutrition. PMID- 17713981 TI - Increasing coverage and decreasing inequity in insecticide-treated bed net use among rural Kenyan children. AB - BACKGROUND: Inexpensive and efficacious interventions that avert childhood deaths in sub-Saharan Africa have failed to reach effective coverage, especially among the poorest rural sectors. One particular example is insecticide-treated bed nets (ITNs). In this study, we present repeat observations of ITN coverage among rural Kenyan homesteads exposed at different times to a range of delivery models, and assess changes in coverage across socioeconomic groups. METHODS AND FINDINGS: We undertook a study of annual changes in ITN coverage among a cohort of 3,700 children aged 0-4 y in four districts of Kenya (Bondo, Greater Kisii, Kwale, and Makueni) annually between 2004 and 2006. Cross-sectional surveys of ITN coverage were undertaken coincidentally with the incremental availability of commercial sector nets (2004), the introduction of heavily subsidized nets through clinics (2005), and the introduction of free mass distributed ITNs (2006). The changing prevalence of ITN coverage was examined with special reference to the degree of equity in each delivery approach. ITN coverage was only 7.1% in 2004 when the predominant source of nets was the commercial retail sector. By the end of 2005, following the expansion of heavily subsidized clinic distribution system, ITN coverage rose to 23.5%. In 2006 a large-scale mass distribution of ITNs was mounted providing nets free of charge to children, resulting in a dramatic increase in ITN coverage to 67.3%. With each subsequent survey socioeconomic inequity in net coverage sequentially decreased: 2004 (most poor [2.9%] versus least poor [15.6%]; concentration index 0.281); 2005 (most poor [17.5%] versus least poor [37.9%]; concentration index 0.131), and 2006 with near-perfect equality (most poor [66.3%] versus least poor [66.6%]; concentration index 0.000). The free mass distribution method achieved highest coverage among the poorest children, the highly subsidised clinic nets programme was marginally in favour of the least poor, and the commercial social marketing favoured the least poor. CONCLUSIONS: Rapid scaling up of ITN coverage among Africa's poorest rural children can be achieved through mass distribution campaigns. These efforts must form an important adjunct to regular, routine access to ITNs through clinics, and each complimentary approach should aim to make this intervention free to clients to ensure equitable access among those least able to afford even the cost of a heavily subsidized net. PMID- 17713982 TI - HIV denial in the Internet era. PMID- 17713984 TI - Improving case definitions for severe malaria. PMID- 17713983 TI - Antiretroviral treatment and prevention of peripartum and postnatal HIV transmission in West Africa: evaluation of a two-tiered approach. AB - BACKGROUND: Highly active antiretroviral treatment (HAART) has only been recently recommended for HIV-infected pregnant women requiring treatment for their own health in resource-limited settings. However, there are few documented experiences from African countries. We evaluated the short-term (4 wk) and long term (12 mo) effectiveness of a two-tiered strategy of prevention of mother-to child transmission of HIV (PMTCT) in Africa: women meeting the eligibility criteria of the World Health Organization (WHO) received HAART, and women with less advanced HIV disease received short-course antiretroviral (scARV) PMTCT regimens. METHODS AND FINDINGS: The MTCT-Plus Initiative is a multi-country, family-centred HIV care and treatment program for pregnant and postpartum women and their families. Pregnant women enrolled in Abidjan, Cote d'Ivoire received either HAART for their own health or short-course antiretroviral (scARV) PMTCT regimens according to their clinical and immunological status. Plasma HIV-RNA viral load (VL) was measured to diagnose peripartum infection when infants were 4 wk of age, and HIV final status was documented either by rapid antibody testing when infants were aged > or = 12 mo or by plasma VL earlier. The Kaplan-Meier method was used to estimate the rate of HIV transmission and HIV-free survival. Between August 2003 and June 2005, 107 women began HAART at a median of 30 wk of gestation, 102 of them with zidovudine (ZDV), lamivudine (3TC), and nevirapine (NVP) and they continued treatment postpartum; 143 other women received scARV for PMTCT, 103 of them with sc(ZDV+3TC) with single-dose NVP during labour. Most (75%) of the infants were breast-fed for a median of 5 mo. Overall, the rate of peripartum HIV transmission was 2.2% (95% confidence interval [CI] 0.3%-4.2%) and the cumulative rate at 12 mo was 5.7% (95% CI 2.5%-9.0%). The overall probability of infant death or infection with HIV was 4.3% (95% CI 1.7%-7.0%) at age week 4 wk and 11.7% (95% CI 7.5%-15.9%) at 12 mo. CONCLUSIONS: This two-tiered strategy appears to be safe and highly effective for short- and long-term PMTCT in resource-constrained settings. These results indicate a further benefit of access to HAART for pregnant women who need treatment for their own health. PMID- 17713985 TI - Conserving biodiversity efficiently: what to do, where, and when. AB - Conservation priority-setting schemes have not yet combined geographic priorities with a framework that can guide the allocation of funds among alternate conservation actions that address specific threats. We develop such a framework, and apply it to 17 of the world's 39 Mediterranean ecoregions. This framework offers an improvement over approaches that only focus on land purchase or species richness and do not account for threats. We discover that one could protect many more plant and vertebrate species by investing in a sequence of conservation actions targeted towards specific threats, such as invasive species control, land acquisition, and off-reserve management, than by relying solely on acquiring land for protected areas. Applying this new framework will ensure investment in actions that provide the most cost-effective outcomes for biodiversity conservation. This will help to minimise the misallocation of scarce conservation resources. PMID- 17713986 TI - Recombination speeds adaptation by reducing competition between beneficial mutations in populations of Escherichia coli. AB - Identification of the selective forces contributing to the origin and maintenance of sex is a fundamental problem in biology. The Fisher-Muller model proposes that sex is advantageous because it allows beneficial mutations that arise in different lineages to recombine, thereby reducing clonal interference and speeding adaptation. I used the F plasmid to mediate recombination in the bacterium Escherichia coli and measured its effect on adaptation at high and low mutation rates. Recombination increased the rate of adaptation approximately 3 fold more in the high mutation rate treatment, where beneficial mutations had to compete for fixation. Sequencing of candidate loci revealed the presence of a beneficial mutation in six high mutation rate lines. In the absence of recombination, this mutation took longer to fix and, over the course of its substitution, conferred a reduced competitive advantage, indicating interference between competing beneficial mutations. Together, these results provide experimental support for the Fisher-Muller model and demonstrate that plasmid mediated gene transfer can accelerate bacterial adaptation. PMID- 17713990 TI - Epidemiology, disease progression, and economic burden of colorectal cancer. AB - BACKGROUND: Every 3.5 minutes, someone is diagnosed with colorectal cancer (CRC); every 9 minutes, someone dies from CRC; and every 5 seconds, someone who should be screened for CRC is not. The 5-year mortality for people diagnosed with CRC is approximately 40%; however, survival improves substantially if the cancer is diagnosed while still localized. OBJECTIVE: To track and review the rapid progress researchers have made in CRC. SUMMARY: among patients who have CRC, approximately 50% will eventually develop liver metastases. The oncology field's significant advances in the last few years, especially in CRC, challenge clinicians and patients. Multiple facets of care intersect in CRC: medical management, pharmacy management, symptom management, case management, and patient advocacy. CRC develops over many years as environmental and genetic factors interact. The american Cancer Society recommends screening all men and women older than 50 years and those at high risk at an earlier age. In the past, patients presenting with the same stage of CRC were considered similar. The staging criteria of the american joint Committee on Cancer recognizes that subsets of patients with varying survival statistics can be identified and that each patient requires a strategic approach. The U.S. Food and drug administration approval of irinotecan in 1996 and oxaliplatin in 2002 changed the landscape, and ultimately, the oral agent capecitabine and the biologics bevacizumab and cetuximab also significantly expanded treatment options. CONCLUSION: Clinicians must consider all available treatment options and regimen sequences across multiple lines of therapy, creating an early plan for each patient to extend survival while minimizing side effects. PMID- 17713988 TI - Quantitative characteristics of gene regulation by small RNA. AB - An increasing number of small RNAs (sRNAs) have been shown to regulate critical pathways in prokaryotes and eukaryotes. In bacteria, regulation by trans-encoded sRNAs is predominantly found in the coordination of intricate stress responses. The mechanisms by which sRNAs modulate expression of its targets are diverse. In common to most is the possibility that interference with the translation of mRNA targets may also alter the abundance of functional sRNAs. Aiming to understand the unique role played by sRNAs in gene regulation, we studied examples from two distinct classes of bacterial sRNAs in Escherichia coli using a quantitative approach combining experiment and theory. Our results demonstrate that sRNA provides a novel mode of gene regulation, with characteristics distinct from those of protein-mediated gene regulation. These include a threshold-linear response with a tunable threshold, a robust noise resistance characteristic, and a built-in capability for hierarchical cross-talk. Knowledge of these special features of sRNA-mediated regulation may be crucial toward understanding the subtle functions that sRNAs can play in coordinating various stress-relief pathways. Our results may also help guide the design of synthetic genetic circuits that have properties difficult to attain with protein regulators alone. PMID- 17713991 TI - Medicare challenges and solutions--reimbursement issues in treating the patient with colorectal cancer. AB - BACKGROUND: Medicare covers costs far more than 50% of all cancer patients, and most private payers follow Medicare's lead on coverage and benefits for cancer care. Medicare and private payers are legally required by federal statute to cover anticancer chemotherapeutic products based on U.S. Food and drug administration-approved labeling and indicate how off-label uses are covered. OBJECTIVE: To review reimbursement issues unique to Medicare with regard to oncology drugs. SUMMARY: Currently, the Centers for Medicare & Medicaid Services (CMS) recognizes 2 compendia for purposes of evaluating off-label uses of drugs. Coverage determinations can be pursued nationally, locally, and case by case. Because of the impact and scope of colorectal cancer on the national budget, CMS initiated a process to establish national coverage determinations. This and other such Medicare reforms will have significant repercussions for clinicians who work with oncology patients. Major administrative and access challenges for both health care providers and beneficiaries include a diverse array of plan choices. In terms of Medicare Part d, the 25% of patients who are chronically ill and prescribed expensive therapies (including antineoplastics and supportive care agents) may find the coverage gap ("donut hole") challenging and even prohibitive in their access to appropriate care. Lack of coverage could potentially affect therapy compliance, and managed care must pursue additional payment or coverage support mechanisms. Evaluating formularies will be critical for cancer patients and those who use specialty drugs as they select their Part d plans in the future. CONCLUSION: Oncologists and their patients are left with difficult choices regarding not only the clinical efficacy of a treatment but also the financial considerations of the treatment. PMID- 17713987 TI - The scent of the waggle dance. AB - The waggle dance of honey bee (Apis mellifera L.) foragers communicates to nest mates the location of a profitable food source. We used solid-phase microextraction and gas chromatography coupled with mass spectrometry to show that waggle-dancing bees produce and release two alkanes, tricosane and pentacosane, and two alkenes, Z-(9)-tricosene and Z-(9)-pentacosene, onto their abdomens and into the air. Nondancing foragers returning from the same food source produce these substances in only minute quantities. Injection of the scent significantly affects worker behavior by increasing the number of bees that exit the hive. The results of this study suggest that these compounds are semiochemicals involved in worker recruitment. By showing that honey bee waggle dancers produce and release behaviorally active chemicals, this study reveals a new dimension in the organization of honey bee foraging. PMID- 17713992 TI - Colorectal cancer: complexities and challenges in managed care. AB - BACKGROUND: Managed care weighs advances and associated costs to determine whether the combination of longer life at sometimes significantly increased cost represents value. The price of treatment is only 1 factor. OBJECTIVE: To review treatment decision processes for oncologic agents in managed care environments. SUMMARY: Price can be exceptionally high for individuals. But if the population size is low, the per-member-per-month (PMPM) impact can be almost negligible, unlike treatments that have moderate costs but are used ubiquitously. Cancer therapies have, for the most part, escaped managed care's notice. For 2007, the national Cancer Institute projects that antineoplastic agents will consume almost a quarter of the overall drug spend. The Medicare population is a unique concern with regard to cancer. Traditionally, Medicare reimbursement of chemotherapeutic agents was based on average wholesale price (AWP) discounting, not the oncologist's purchasing cost. This allowed oncologists to use reimbursement for infusions to support their medical practices. The proposed plan of the Center for Medicare & Medicaid Services (CMS) to use average sales price (ASP) plus 6% to reimburse for drugs used in the office setting leads to significant problems. Pharmacy and therapeutics committees will also face challenges: fewer data are available for some agents because they have become available through the U.S. Food and drug administration's Fast Track, Priority review, or accelerated approval processes. CONCLUSION: Oncology disease management programs must reach out to patients and not necessarily deal with oncology issues directly, but address tangential issues that impact care, especially depression and pain management. PMID- 17713993 TI - Asthma management guidelines: updates, advances, and new options. AB - BACKGROUND: Asthma still poses a substantial and unacceptable health and economic burden. The National Asthma Education and Prevention Program (NAEPP) guidelines for the management of asthma continue to evolve based on emerging clinical data, improving the understanding of asthma and approaches to its management. OBJECTIVE: To examine the clinical implications of current NAEPP guidelines for the diagnosis and treatment of asthma and the potential impact of the proposed 2007 guidelines update on asthma management. To examine the role of managed care organizations in fostering evidence-based asthma management. SUMMARY: Current NAEPP guidelines recognize symptom control as the chief therapeutic target in the management of asthma. The proposed update to NAEPP guidelines places greater emphasis on symptom control by expanding its definition to not only include measures of impairment but also the risk for deteriorating pulmonary function, asthma exacerbations, and controller medication side effects. Although inhaled corticosteroids remain central to achieving long-term asthma control in both current and proposed guidelines, the latter offers greater treatment flexibility and recognizes combination therapy as a preferred choice for achieving control in many patients with moderate persistent asthma. Managed care organizations, primarily using disease management programs, provide impetus for the widespread adoption of evidence-based asthma treatment guidelines. CONCLUSION: Widespread adoption of evidence-based asthma management programs offers the opportunity for achieving and maintaining asthma control. PMID- 17713994 TI - Assisted living: where are we now and where are we going? AB - Assisted living is a rapidly changing environment. An increase in the numbers of elderly assisted living residents, who have more medical and care needs, has prompted many facilities to adopt a higher standard of care. Increasingly, pharmacists are being called on to help assisted living residents manage their medications--even in states where this service is not mandated--and they are finding that serving assisted living facilities often requires a unique approach. PMID- 17713995 TI - Patient diaries: charting the course. AB - Clinical diaries are a way for patients to assess their own health status without clinician bias or interpretation. Diaries are especially useful in understanding symptoms' temporal dynamics, including triggers that exacerbate symptoms; they also help individuals to evaluate the impact of their treatment. Diary format should be patient-specific, with thoughtful consideration given to rating scales, symptom descriptors, number of daily entries required, and the duration of diary recording. While compliance, recall biases, and diary fatigue affect data quality, a diary's potential for individualizing treatment strategies is tremendous. PMID- 17713997 TI - Vitamins: the wise choice for women with cardiovascular disease. AB - OBJECTIVE: Enhance the pharmacist's ability to recognize and make treatment recommendations for the safe use of vitamins and supplements for an ambulatory, postmenopausal woman with cardiovascular disease. DATA SOURCES: Literature listed in MEDLINE, IDIS, and PubMED, with emphasis on material published since 2002, were reviewed. An online search of government and proprietary nutrition Web sites as well were reviewed. STUDY SELECTION: Literature reports were selected for their clinical relevance with emphasis on randomized, controlled trials, meta analyses, cohort studies, and information from the American Heart Association and the Food and Nutritional Board of the Institute of Medicine. DATA EXTRACTION: An outline was developed and literature reports were separated into the categories of vitamins, minerals, and supplements. DATA SYNTHESIS: The primary literature provided information for the use of vitamins, minerals, and supplements, which are popular with older women with chronic disease states. The results included current guidelines that have been established to assist in maintaining good health and to prevent disease in a specific population, those 51 years of age or older. CONCLUSION: When dietary intake is inadequate, a combination of a vitamin preparation, calcium, and an omega-3 preparation can help maintain good health in older women with cardiovascular disease. PMID- 17713996 TI - Assessment of psychotropic and psychoactive drug loads and falls in nursing facility residents. AB - OBJECTIVE: To determine if there were any differences in fall risk and actual falls between those who were prescribed and those who were not prescribed psychotropic and psychoactive medications in a skilled nursing facility. DESIGN: An observational, retrospective cohort study of prospective patient data in a skilled nursing facility. SETTING: A public skilled nursing facility of more than 100 beds. PATIENTS: Patient charts and consultant pharmacists' drug regimen review monthly report records for 177 patients who were residents for 30 or more days over a 19-month period during 1996-1997 were tabulated. INTERVENTIONS: A fall risk using an assessment method that incorporated patient fall history, conditions, diseases, and medications associated with falls was performed on each resident. MAIN OUTCOME MEASURES: Patient demographics, medication usage, fall risk, and fall occurrences. RESULTS: Falls occurred in 107 of 177 (60.5%) residents over the study period. There were 428 documented falls. Fall rates appeared to be directly related to the number of psychotropic drugs, but not other psychoactive medications, until two or more were used concurrently. CONCLUSIONS: Preliminary evidence suggests multiple psychotropic and psychoactive drugs may increase the risk of falls in a skilled nursing facility in proportion to the total load of these agents. Minimization of inappropriate prescribing of psychotropic and psychoactive medications in elderly nursing facility residents, as mandated by current federal guidelines, may affect the risk of falls in nursing facility patients. PMID- 17713999 TI - Jumpstarting your QI program: Quick Kills, Constant Readiness, and Fast Failures. PMID- 17713998 TI - Deja vu all over again: the "J-curve" phenomenon. PMID- 17714000 TI - Medication errors in long-term care: part 1. AB - The consultant pharmacist has a vital role in the management of medications in the long-term care setting, but this activity is retrospective, and it may uncover medication errors that have already occurred. However, this process does not prevent medication errors from occurring. This first part of a two-part series will look at the underlying causes that lead to medication errors and provide recommendations for consultant pharmacists to address the potential for error. PMID- 17714001 TI - Fatigue: implications for the elderly. AB - Sporadic and chronic fatigue are common, but an underlying etiology is identified in only up to 10% of cases. Under-reporting makes fatigue's prevalence unknown. Some estimate up to 50% of elders suffer from mild fatigue. Causes vary, but prevailing theory links most fatigue as a secondary consequence to illness and medication. Fatigue is prominently linked to sleep disorders, depression, heart disease, Parkinson's disease, anemia, and cancer. Fatigue and its consequences should be assessed routinely. Empiric treatment is the norm, focusing on managing fatigue, and, when possible, selecting agents with fewer side effects. Exercise, diet, and promoting good sleep hygiene have beneficial effects in symptom management. PMID- 17714002 TI - Measuring clinical outcomes of animal-assisted therapy: impact on resident medication usage. AB - OBJECTIVE: To measure changes in medication usage of as-needed, psychoactive medications and other select as-needed medication usage as a result of a therapy dog residing in the rehabilitation facility. Additional measures are participants' thoughts and feelings on quality-of-life factors. DESIGN: One group, pretest, post-test. SETTING: Residential rehabilitation facility. PARTICIPANTS: Convenience sample, N = 58 residents living at the facility. INTERVENTION: A certified, trained therapy dog. MAIN OUTCOME MEASURE(S): Changes in as-needed medication usage for the following categories: analgesics, psychoactive medications, and laxatives, as well as changes in vital sign measurements of blood pressure, pulse, respiration rate, and body weight. Additionally, changes in the residents' perception of quality-of-life factors. RESULTS: One of the three monitored drug classes, analgesia, revealed a decrease in medication usage (mean = 2.6, standard deviation [SD] +/- 6.90, P = 0.017), and one of four monitored vital signs, pulse, showed a decrease (mean = 5.8, SD +/-7.39, P = 0.000) in study participants exposed to the therapy dog. Positive changes were reported in study participants' quality of life. CONCLUSION: The benefits to human welfare as a result of the presence of a therapy dog have the potential to decrease medication usage for certain conditions in long-term care patients as well as decrease costs. Pharmacist involvement in animal-assisted therapy has the potential to make unique and measurable improvements to best patient care. PMID- 17714003 TI - Adverse drug reactions and current state of drug regimen review in nursing facilities: need for a change? AB - OBJECTIVE: To review the salient issue of adverse drug reactions in nursing facilities. SETTING: Nursing facilities across the United States. PRACTICE DESCRIPTION: Federally mandated, retrospective drug regimen reviews (DRRs) performed by consultant pharmacists are discussed as the impetus for change. PRACTICE INNOVATION: A prospective process of medication therapy management that involves pharmacists interacting with the interdisciplinary care team is described as a way to deliver high-quality, medication-related health care at the point of care. The paper presents the Fleetwood model as an exemplar of the proposed care model and--as well as the recent revisions to the interpretive guidelines for the State Operations Manual (SOM)--as a means of changing the way medication therapy management is deployed in nursing facilities. MAIN OUTCOME MEASURES: Change in nursing facility pharmacy practice. RESULTS: In settings where the Fleetwood model has been implemented, researchers have observed numerous changes, including increased clinical involvement by dispensing and consultant pharmacists, reduced time spent on traditional DRR, increased time spent on pharmaceutical care planning, improved communication among the interdisciplinary team, and more efficient processes within the nursing facility pharmacy. Changes in the Pharmacy Services Tags (F425, F428, F431) and Unnecessary Medications Tag (F329) in the interpretive guidelines for the SOM, released by the Centers for Medicare and Medicaid Services, have significant implications for the way consultant pharmacists practice. CONCLUSIONS: Application of prospective medication therapy management, such as that contained in the Fleetwood model, and changes to the interpretive guidelines support greater pharmacist involvement at the point of care, which has potential to dramatically decrease adverse drug reactions in nursing facilities. PMID- 17714004 TI - Postherpetic neuralgia in an elderly patient. AB - A 67-year-old patient presented to the community pharmacy with poorly controlled postherpetic neuralgia (PHN) pain following an episode of herpes zoster. The clinical pharmacist did a medication review and found that, although the patient was receiving medications proven effective in the treatment of PHN, she was not receiving optimal therapy. Additionally, the patient was experiencing intolerable side effects. The pharmacist provided recommendations to the patient's primary care physician that ultimately improved the patient's pain control. Managing PHN pain requires practitioners to be vigilant in titrating pain regimens and trying various combinations of therapies with different mechanisms of action. Such an approach is one that tailors medication therapy to each individual patient, provides the most relief, and restores a patient's quality of life. PMID- 17714005 TI - Discourse, syntax, and prosody: the brain reveals an immediate interaction. AB - Speech is structured into parts by syntactic and prosodic breaks. In locally syntactic ambiguous sentences, the detection of a syntactic break necessarily follows detection of a corresponding prosodic break, making an investigation of the immediate interplay of syntactic and prosodic information impossible when studying sentences in isolation. This problem can be solved, however, by embedding sentences in a discourse context that induces the expectation of either the presence or the absence of a syntactic break right at a prosodic break. Event related potentials (ERPs) were compared to acoustically identical sentences in these different contexts. We found in two experiments that the closure positive shift, an ERP component known to be elicited by prosodic breaks, was reduced in size when a prosodic break was aligned with a syntactic break. These results establish that the brain matches prosodic information against syntactic information immediately. PMID- 17714007 TI - Musicians detect pitch violation in a foreign language better than nonmusicians: behavioral and electrophysiological evidence. AB - The aim of this study was to determine whether musical expertise influences the detection of pitch variations in a foreign language that participants did not understand. To this end, French adults, musicians and nonmusicians, were presented with sentences spoken in Portuguese. The final words of the sentences were prosodically congruous (spoken at normal pitch height) or incongruous (pitch was increased by 35% or 120%). Results showed that when the pitch deviations were small and difficult to detect (35%: weak prosodic incongruities), the level of performance was higher for musicians than for nonmusicians. Moreover, analysis of the time course of pitch processing, as revealed by the event-related brain potentials to the prosodically congruous and incongruous sentence-final words, showed that musicians were, on average, 300 msec faster than nonmusicians to categorize prosodically congruous and incongruous endings. These results are in line with previous ones showing that musical expertise, by increasing discrimination of pitch--a basic acoustic parameter equally important for music and speech prosody--does facilitate the processing of pitch variations not only in music but also in language. Finally, comparison with previous results [Schon, D., Magne, C., & Besson, M. The music of speech: Music training facilitates pitch processing in both music and language. Psychophysiology, 41, 341-349, 2004] points to the influence of semantics on the perception of acoustic prosodic cues. PMID- 17714008 TI - Differentiating morphology, form, and meaning: neural correlates of morphological complexity. AB - The role of morphological structure in word recognition raises issues about the nature and structure of the language system. One major issue is whether morphological factors provide an independent principle for lexical organization and processing, or whether morphological effects can be reduced to the joint contribution of form and meaning. The independence of form, meaning, and morphological structure can be directly investigated using derivationally complex words, because derived words can share form but need not share meaning (e.g., archer-arch). We used an event-related functional magnetic resonance imaging paradigm to investigate priming between pairs of words that potentially shared a stem, where this link was either semantically transparent (e.g., bravely-brave) or opaque (e.g., archer-arch). These morphologically related pairs were contrasted with identity priming (e.g., mist-mist) and priming for pairs of words that shared only form (e.g., scandal-scan) or meaning (e.g., accuse-blame). Morphologically related words produced significantly reduced activation in left frontal regions, whether the pairs were semantically transparent or opaque. The effect was not found for any of the control conditions (identity, form, or meaning). Morphological effects were observed separately from processing form and meaning and we propose that they reflect segmentation of complex derived words, a process triggered by surface morphological structure of complex words. PMID- 17714006 TI - Role of features and second-order spatial relations in face discrimination, face recognition, and individual face skills: behavioral and functional magnetic resonance imaging data. AB - We compared the contribution of featural information and second-order spatial relations (spacing between features) in face processing. A fully factorial design has the same or different "features" (eyes, mouth, and nose) across two successive displays, whereas, orthogonally, the second-order spatial relations between those features were the same or different. The range of such changes matched the possibilities within the population of natural face images. Behaviorally, we found that judging whether two successive faces depicted the same person was dominated by features, although second-order spatial relations also contributed. This influence of spatial relations correlated, for individual subjects, with their skill at recognition of faces (as famous, or as previously exposed) in separate behavioral tests. Using the same repetition design in functional magnetic resonance imaging, we found feature-dependent effects in the lateral occipital and right fusiform regions. In addition, there were spatial relation effects in the bilateral inferior occipital gyrus and right fusiform that correlated with individual differences in (separately measured) behavioral sensitivity to those changes. The results suggest that featural and second-order spatial relation aspects of faces make distinct contributions to behavioral discrimination and recognition, with features contributing most to face discrimination and second-order spatial relational aspects correlating best with recognition skills. Distinct neural responses to these aspects were found with functional magnetic resonance imaging, particularly when individual skills were taken into account for the impact of second-order spatial relations. PMID- 17714009 TI - Linear coding of voice onset time. AB - Voice onset time (VOT) provides an important auditory cue for recognizing spoken consonant-vowel syllables. Although changes in the neuromagnetic response to consonant-vowel syllables with different VOT have been examined, such experiments have only manipulated VOT with respect to voicing. We utilized the characteristics of a previously developed asymmetric VOT continuum [Liederman, J., Frye, R. E., McGraw Fisher, J., Greenwood, K., & Alexander, R. A temporally dynamic contextual effect that disrupts voice onset time discrimination of rapidly successive stimuli. Psychonomic Bulletin and Review, 12, 380-386, 2005] to determine if changes in the prominent M100 neuromagnetic response were linearly modulated by VOT. Eight right-handed, English-speaking, normally developing participants performed a VOT discrimination task during a whole-head neuromagnetic recording. The M100 was identified in the gradiometers overlying the right and left temporal cortices and single dipoles were fit to each M100 waveform. A repeated measures analysis of variance with post hoc contrast test for linear trend was used to determine whether characteristics of the M100 were linearly modulated by VOT. The morphology of the M100 gradiometer waveform and the peak latency of the dipole waveform were linearly modulated by VOT. This modulation was much greater in the left, as compared to the right, hemisphere. The M100 dipole moved in a linear fashion as VOT increased in both hemispheres, but along different axes in each hemisphere. This study suggests that VOT may linearly modulate characteristics of the M100, predominately in the left hemisphere, and suggests that the VOT of consonant-vowel syllables, instead of, or in addition to, voicing, should be examined in future experiments. PMID- 17714010 TI - Masking disrupts reentrant processing in human visual cortex. AB - In masking, a stimulus is rendered invisible through the presentation of a second stimulus shortly after the first. Over the years, authors have typically explained masking by postulating some early disruption process. In these feedforward-type explanations, the mask somehow "catches up" with the target stimulus, disrupting its processing either through lateral or interchannel inhibition. However, studies from recent years indicate that visual perception- and most notably visual awareness itself--may depend strongly on cortico-cortical feedback connections from higher to lower visual areas. This has led some researchers to propose that masking derives its effectiveness from selectively interrupting these reentrant processes. In this experiment, we used electroencephalogram measurements to determine what happens in the human visual cortex during detection of a texture-defined square under nonmasked (seen) and masked (unseen) conditions. Electro-encephalogram derivatives that are typically associated with reentrant processing turn out to be absent in the masked condition. Moreover, extrastriate visual areas are still activated early on by both seen and unseen stimuli, as shown by scalp surface Laplacian current source density maps. This conclusively shows that feedforward processing is preserved, even when subject performance is at chance as determined by objective measures. From these results, we conclude that masking derives its effectiveness, at least partly, from disrupting reentrant processing, thereby interfering with the neural mechanisms of figure-ground segmentation and visual awareness itself. PMID- 17714011 TI - Open Access Series of Imaging Studies (OASIS): cross-sectional MRI data in young, middle aged, nondemented, and demented older adults. AB - The Open Access Series of Imaging Studies is a series of magnetic resonance imaging data sets that is publicly available for study and analysis. The initial data set consists of a cross-sectional collection of 416 subjects aged 18 to 96 years. One hundred of the included subjects older than 60 years have been clinically diagnosed with very mild to moderate Alzheimer's disease. The subjects are all right-handed and include both men and women. For each subject, three or four individual T1-weighted magnetic resonance imaging scans obtained in single imaging sessions are included. Multiple within-session acquisitions provide extremely high contrast-to-noise ratio, making the data amenable to a wide range of analytic approaches including automated computational analysis. Additionally, a reliability data set is included containing 20 subjects without dementia imaged on a subsequent visit within 90 days of their initial session. Automated calculation of whole-brain volume and estimated total intracranial volume are presented to demonstrate use of the data for measuring differences associated with normal aging and Alzheimer's disease. PMID- 17714012 TI - Implicit trustworthiness decisions: automatic coding of face properties in the human amygdala. AB - Deciding whether an unfamiliar person is trustworthy is one of the most important decisions in social environments. We used functional magnetic resonance imaging to show that the amygdala is involved in implicit evaluations of trustworthiness of faces, consistent with prior findings. The amygdala response increased as perceived trustworthiness decreased in a task that did not demand person evaluation. More importantly, we tested whether this response is due to an individual's idiosyncratic perception or to face properties that are perceived as untrustworthy across individuals. The amygdala response was better predicted by consensus ratings of trustworthiness than by an individual's own judgments. Individual judgments accounted for little residual variance in the amygdala after controlling for the shared variance with consensus ratings. These findings suggest that the amygdala automatically categorizes faces according to face properties commonly perceived to signal untrustworthiness. PMID- 17714013 TI - Common and unique neural activations in autobiographical, episodic, and semantic retrieval. AB - This study sought to explore the neural correlates that underlie autobiographical, episodic, and semantic memory. Autobiographical memory was defined as the conscious recollection of personally relevant events, episodic memory as the recall of stimuli presented in the laboratory, and semantic memory as the retrieval of factual information and general knowledge about the world. Our objective was to delineate common neural activations, reflecting a functional overlap, and unique neural activations, reflecting functional dissociation of these memory processes. We conducted an event-related functional magnetic resonance imaging study in which we utilized the same pictorial stimuli but manipulated retrieval demands to extract autobiographical, episodic, or semantic memories. The results show a functional overlap of the three types of memory retrieval in the inferior frontal gyrus, the middle frontal gyrus, the caudate nucleus, the thalamus, and the lingual gyrus. All memory conditions yielded activation of the left medial-temporal lobe; however, we found a functional dissociation within this region. The anterior and superior areas were active in episodic and semantic retrieval, whereas more posterior and inferior areas were active in autobiographical retrieval. Unique activations for each memory type were also delineated, including medial frontal increases for autobiographical, right middle frontal increases for episodic, and right inferior temporal increases for semantic retrieval. These findings suggest a common neural network underlying all declarative memory retrieval, as well as unique neural contributions reflecting the specific properties of retrieved memories. PMID- 17714015 TI - The functional neuroanatomy of thematic role and locative relational knowledge. AB - Lexical-semantic investigations in cognitive neuroscience have focused on conceptual knowledge of concrete objects. By contrast, relational concepts have been largely ignored. We examined thematic role and locative knowledge in 14 left hemisphere-damage patients. Relational concepts shift cognitive focus away from the object to the relationship between objects, calling into question the relevance of traditional sensory-functional accounts of semantics. If extraction of a relational structure is the critical cognitive process common to both thematic and locative knowledge, then damage to neural structures involved in such an extraction would impair both kinds of knowledge. If the nature of the relationship itself is critical, then functional neuroanatomical dissociations should occur. Using a new lesion analysis method, we found that damage to the lateral temporal cortex produced deficits in thematic role knowledge and damage to inferior fronto-parietal regions produced deficits in locative knowledge. In addition, we found that conceptual knowledge of thematic roles dissociates from its mapping onto language. These relational knowledge deficits were not accounted for by deficits in processing nouns or verbs or by a general deficit in making inferences. Our results are consistent with the hypothesis that manners of visual motion serve as a point of entry for thematic role knowledge and networks dedicated to eye gaze, whereas reaching and grasping serve as a point of entry for locative knowledge. Intermediary convergence zones that are topographically guided by these sensory-motor points of entry play a critical role in the semantics of relational concepts. PMID- 17714014 TI - Proprioception contributes to the sense of agency during visual observation of hand movements: evidence from temporal judgments of action. AB - The ability to recognize visually one's own movement is important for motor control and, through attribution of agency, for social interactions. Agency of actions may be decided by comparisons of visual feedback, efferent signals, and proprioceptive inputs. Because the ability to identify one's own visual feedback from passive movements is decreased relative to active movements, or in some cases is even absent, the role of proprioception in self-recognition has been questioned. Proprioception during passive and active movements may, however, differ, and so to address any role for proprioception in the sense of agency, the active movement condition must be examined. Here we tested a chronically deafferented man (I.W.) and an age-matched group of six healthy controls in a task requiring judgement of the timing of action. Subjects performed finger movements and watched a visual cursor that moved either synchronously or asynchronously with a random delay, and reported whether or not they felt they controlled the cursor. Movement accuracy was matched between groups. In the absence of proprioception, I.W. was less able than the control group to discriminate self- from computer-produced cursor movement based on the timing of movement. In a control visual discrimination task with concurrent similar finger movements but no agency detection, I.W. was unimpaired, suggesting that this effect was task specific. We conclude that proprioception does contribute to the visual identification of ownership during active movements and, thus, to the sense of agency. PMID- 17714016 TI - Modifying the cortical processing for motor preparation by repetitive transcranial magnetic stimulation. AB - To investigate the effects of repetitive transcranial magnetic stimulation (rTMS) on the central processing of motor preparation, we had subjects perform a precued choice reaction time (RT) task. They had to press one of two buttons as quickly as possible after a go signal specifying both the hand to be used and the button to press. A precue preceding this signal conveyed full, partial, or no advance information (hand and/or button), such that RT shortened with increasing amount of information. We applied 1200 to 2400 pulses of 1-Hz rTMS over various cortical areas and compared the subjects' performances at various times before and after this intervention. rTMS delayed RT at two distinct phases after stimulation, one within 10 min and another with a peak at 20 to 30 min and lasting for 60 to 90 min, with no significant effects on error rates or movement time. The effect was significantly larger on left- than on right-hand responses. RT was prominently delayed over the premotor and motor cortices with similar effects across different conditions of advance information, suggesting that preparatory processes relatively close to the formation of motor output were influenced by rTMS. In contrast, the effect of rTMS over the supplementary motor area and the anterior parietal cortex varied with the amount of advance information, indicating specific roles played by these areas in integrating target and effector information. The primary motor area, especially of the left hemisphere, may take over this processing, implementing motor output based on the information processed in other areas. PMID- 17714018 TI - Where are we with the treatment of metastatic bladder cancer? AB - Although bladder cancer is a chemosensitive tumor, metastatic disease is related with poor prognosis and short-term survival. For two decades, the treatment of choice for metastatic bladder cancer has been cisplatin-based chemotherapy. Nowadays, non-platinum regimes have been tested such as taxanes and gemcitabine, which is considered as an attractive alternative. In parallel, double and triplet combination chemotherapy have been assessed in clinical trials. Furthermore, individualized treatments through the identification of molecular prognostic factors and application of targeted therapy have gained considerable interest. PMID- 17714017 TI - Social regulation of affective experience of humor. AB - The element of surprise, a necessary condition for the experience of humor, often derives from the fact that the alternative interpretation/resolution offered by the punch line of a joke is physically or socially forbidden. Children's humor typifies violation of physical norms, whereas adult humor typically pushes the boundaries of social norms. Excess norm violation, to the point of offending, can attenuate the experience of humor/mirth. To examine the neural basis of regulation of affective experience of humor by social norms, we scanned 16 normal subjects while they viewed a series of cartoons that varied in funniness and social acceptability. Behavioral results indicated two separate groups of subjects, those who found the cartoons less offensive and those who found them more offensive. In the group that found the jokes more offensive, there was a negative correlation between funniness and social inappropriateness. In this group, the corresponding Humor by Social inappropriateness interaction during functional magnetic resonance imaging revealed enhanced activation in the right hippocampus along with relative deactivation in the ventral medial prefrontal cortex (VMPFC). By contrast, the Funniness by Social appropriateness interaction resulted in activation in the VMPFC and relative deactivation in the right hippocampus. These results suggest that the regulation of humor by social norms involves reciprocal response patterns between VMPFC and hippocampus regions implicated in contextual regulation of behavior and memory, respectively. PMID- 17714019 TI - Discontinued drugs in 2006: cardiovascular drugs translational medicine perspective. AB - This perspective on discontinued cardiovascular drugs is the first in a series of papers on drugs dropped from clinical development in 2006. The compounds described in this perspective have been removed from development in various stages and for different reasons. This paper hereby provides a translational medicine perspective on these compounds based on information available through the Pharmaprojects pipeline database. In particular, potential gaps in the pipeline, due to a lack of biomarkers and translational medicine perspectives are emphasized. PMID- 17714020 TI - Discontinued drugs in 2006: pulmonary-allergy, dermatological, gastrointestinal and arthritis drugs. AB - This perspective is the second in a series discussing drugs dropped from development in 2006, with a focus on pulmonary-allergy, dermatological, gastrointestinal and arthritis drugs. A survey of discontinued drugs from 2006 is provided, based on data from the Pharmaprojects database, along with an analysis of biology, mechanisms of action and economic considerations in developing new drugs. PMID- 17714021 TI - Cyclophilin inhibitors in hepatitis C viral infection. AB - Cyclophilins (Cyps) are proteins that are ubiquitously present with peptidyl prolyl cis-trans isomerase activity and play an important role in de novo protein folding and in isomerization of native proteins in several cellular systems. There is growing evidence that indicates CypB is a positive modulator of the HCV RNA-dependent RNA polymerase in the replication complex. Early in vitro and animal data with selective Cyp inhibitors show a potent anti-HCV effect. This anti-HCV effect was confirmed in the first patient study with the selective Cyp inhibitor Debio-025. Preclinical data suggest that Cyp inhibitors may present a higher barrier to the selection of resistance than protease and polymerase inhibitors and that a combination of Cyp inhibitors with either of these drugs or interferon results in additive or synergistic anti-HCV activity. By interfering at the level of host-viral interaction, Cyp inhibition may open the way for a novel approach to anti-HCV treatment that could be complementary, not only to interferon-based treatment, but also to future treatments that directly target HCV replication enzymes such as protease and polymerase inhibitors. PMID- 17714022 TI - The use of herbal medicines in early drug development for the treatment of HIV infections and AIDS. AB - This review systematically assesses the beneficial and harmful effects of herbal medicines in people with HIV infection and AIDS. Based on a Cochrane review and updated searches, the author identifies the available evidence on herbal medicines compared with placebo or antiretroviral drugs in patients with HIV infection, HIV-related disease or AIDS. There are ten randomised controlled trials, involving 571 individuals with HIV infection or AIDS, that met the inclusion criteria. Some herbal medicines, such as IGM-1 seem to be effective in symptom improvement, but generally no significant effect on antiviral or immunity enhancement among reviewed herbs was seen. Combined treatment of Chinese herbal medicine, SH and antiretroviral agents showed increased antiviral benefit compared with antiretrovirals alone. These findings suggest beneficial effects from some of the tested herbs but more evidence from larger studies are needed to support this evidence in the future. PMID- 17714023 TI - Triple uptake inhibitors: therapeutic potential in depression and beyond. AB - Drugs that interfere with the uptake and/or metabolism of biogenic amines have been used to treat depression for > 4 decades. Early medications such as tricyclic antidepressants and monoamine oxidase inhibitors are effective but possess many side effects that limit their usefulness. Selective serotonin reuptake inhibitors (SSRIs) or selective noradrenaline reuptake inhibitors (SNRIs) are the results of rational design to find drugs that are as effective as the tricyclic antidepressants, but with more selectivity towards a single monoamine transporter. The SSRI class of drugs, which includes fluoxetine, paroxetine and sertraline, were previously viewed as the agents of choice for treating major depression. Recently, inhibitors of both serotonin and noradrenaline uptake ('dual uptake inhibitors'; SSRI/SNRI such as venlafaxine, duloxetine and milnacipran) have gained acceptance in the market. However, neither the SSRIs nor the SSRI/SNRI are fully satisfactory due to a delayed onset of action, low rate of response and side effect that can affect compliance. An important recent development has been the emergence of the triple uptake inhibitors (SSRI/SNRI/selective dopamine reuptake inhibitor), which inhibit the uptake of all three neurotransmitters that are most closely linked to depression: serotonin, noradrenaline and dopamine. Preclinical studies and clinical trials indicate that a drug inhibiting the uptake of all three of these neurotransmitters could produce a more rapid onset of action and possess greater efficacy than traditional antidepressants. This review discusses the evolution of biogenic amine-based therapies, the emerging strategies involved in the design and synthesis of novel triple uptake inhibitors as antidepressants and the therapeutic potential of triple uptake inhibitors. PMID- 17714024 TI - Combined treatments for major depression. AB - Major depression is a chronic disorder with a high morbidity and mortality. Approved treatment for major depression at present includes monotherapy with antidepressants of different pharmacologic classes. There is increasingly widespread use of two other options: augmentation, the addition to an antidepressant of a second compound that is not an antidepressant when used alone; and combination, which is the use of two antidepressants concurrently to enhance or accelerate response. This review focuses on the data available to support these various augmentation and combination treatments. PMID- 17714025 TI - Early experience with novel immunomodulators for cancer treatment. AB - Immunotherapy involves the treatment of cancer by modification of the host-tumour relationship. It is now known that this relationship is quite complex and only some of the interactions have been elucidated. Early attempts at immunotherapy, such as Coley's toxins, were undertaken without an understanding of the processes mediating the effects. With a better understanding of the immunology of this anticancer response, recent trials have focussed on certain aspects of the process to stimulate an antitumour response. In this review, the authors discuss a number of novel biological response modifiers that work as general stimulants of the immune system, through varied mechanisms including induction of stimulatory cytokines (such as IFN-alpha, TNF-alpha and IL-12) and activation of T cells and the antigen-presenting dendritic cells. These compounds include Toll like receptor agonists, several of which are in clinical trials at present. In addition to immunomodulatory activity, some compounds such as 5,6 dimethylxanthenone-4-acetic acid (DMXAA) and thalidomide and its analogues also target existing or developing tumour vasculature. Some of these compounds have single-agent activity in clinical trials, while others such as DMXAA have shown promise in combination with chemotherapy without increasing toxicity. Lactoferrin is another compound that has shown clinical activity with low toxicity. At present, accepted indications for immunotherapy are limited to a few cancers such as renal cell carcinoma and melanoma. This paper looks at some of the reasons for the limited impact of immunotherapy so far and suggest possible avenues for further research with a greater likelihood of success. PMID- 17714026 TI - HU-331: a cannabinoid quinone, with uncommon cytotoxic properties and low toxicity. AB - The oxidation of cannabis constituents has given rise to their corresponding quinones, which have been identified as cytotoxic agents. Out of these molecules the quinone of cannabidiol--the most abundant non-psychoactive cannabinoid in Cannabis sativa--has shown the highest cytotoxicity. This compound was named HU 331 and it exerts antiangiogenic properties, induces apoptosis to endothelial cells and inhibits topoisomerase II in nanomolar concentrations. Unlike other quinones, it is not cardiotoxic and does not induce the formation of free radicals. A comparative in vivo study in mice has shown HU-331 to be less toxic and more effective than the commonly used doxorubicin. This review summarises the properties of HU-331 and compares it with doxorubicin and other topoisomerase II inhibitors. PMID- 17714027 TI - IPdR: a novel oral radiosensitizer. AB - IPdR (5-iodo-2-pyrimidinone-2'-deoxyribose) is a novel orally available, halogenated thymidine (TdR) analog and is a potential radiosensitizer for use in human tumors, such as rectal, pancreas, sarcoma and glioma tumors. IPdR is a prodrug that is efficiently converted to IUdR (5-iodo-2'-deoxyuridine), an intravenous radiosensitizer by a hepatic aldehyde oxidase, resulting in high IPdR and IUdR plasma levels in mice for > or = 1 h after oral IPdR. Athymic mice tolerated oral IPdR to doses up to 1500 mg/kg/day t.i.d. for 6 - 14 days without significant systemic toxicities. A number of in vivo preclinical studies have demonstrated that IPdR is a superior radiosensitizer compared with IUdR given as a continuous infusion in terms of safety and efficacy with a significantly lower toxicity profile, including gastrointestinal and hematologic side effects. A preclinical study has shown that IPdR is effective in inducing human colon cancer xenograft radiosensitization in drug-resistant DNA mismatch repair-proficient and -deficient tumor models, as well as in human globlastoma xenograft. In anticipation of performing a clinical Phase I trial in humans, investigators also studied the drug pharmacokinetics and host toxicities in two non-rodent, animal species during a 14-day treatment course. Dose-limiting systemic toxicities (diarrhea, emesis, weight loss and decreased motor activity) were observed in ferrets receiving IPdR at 1500 mg/kg/day on a 14-day schedule that were not found previously in athymic mice. Recently, a once-daily IPdR dosing up to 2000/mg/kg for 28 days in Fischer-344 rats showed reversible mild-to-moderate systemic toxicities without any severe or life-threatening toxicities. However, in all preclinical toxicity studies so far, no significant hematologic, biochemical or histopathologic changes have been found. Hepatic aldehyde oxidase activity was reduced in a dose-dependent fashion in the ferret liver, suggesting partial enzyme inactivation by this IPdwR schedule, but that is not found in Fischer-344 rats. The plasma pharmacokinetic profile in Rhesus monkeys showing biexponential clearance are similar to previously published data in athymic mice. In this paper, the authors review the development, mechanism of action, preclinical data and rationale for clinical studies. PMID- 17714028 TI - Advances in the development of hormonal modulators for the treatment of benign prostatic hyperplasia. AB - Benign prostatic hyperplasia (BPH) is a leading disorder of the ageing male population and is characterized by a progressive enlargement of the prostate, resulting in the obstruction of the proximal urethra and hence the disturbance in normal urinary flow and further quality of life of the patients. Therefore, there is an imperative need to develop a therapeutic modality to combat the overgrowth of the prostate with improvements in both the urinary flow rate and the quality of life of the patients. At present, alpha-blockers, which act on the dynamic component of the disease to regulate the increased adrenergic tone of the lower urinary tract smooth muscles, and 5-alpha-reductase inhibitors, which control the overgrowth of the prostate and hence static component by regulating the levels of androgens, are the mainstay of therapies for the treatment of BPH and associated lower urinary tract symptoms. However, each target class has its own limitations in terms of compromised efficacy or tolerability. Therefore, it is pertinent to have an effective and safe therapeutic modality for the further improvement of life of the geriatric male population. Hormone modulators, which regulate the overgrowth of the prostate, represent one of the important categories that have been explored and that is still undergoing certain investigations towards the development of a therapeutic entity for the treatment of BPH. The key lies in achieving the differentiation in terms of improved tolerability with comparable or better efficacy over the existing class of drugs. Gonadotropin receptor modulators and vitamin D receptor agonists may represent promising druggable targets in this therapeutic area, due to the availability of proof of principles and concepts in preclinical animal models and human subjects. PMID- 17714029 TI - Iclaprim. AB - Iclaprim is a novel diaminopyrimidine, and an inhibitor of dihydrofolate reductase, which has shown potent, extended-spectrum in vitro activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate and vancomycin-resistant S. aureus and macrolide-, quinolone- and trimethoprim-resistant strains. In addition, iclaprim has demonstrated activity against Streptococcus pneumoniae including penicillin-, erythromycin-, levofloxacin- and trimethoprim/sulfamethoxazole-resistant strains. Furthermore, in vitro activity has also been observed against Gram-negative bacteria and atypical bacteria. The pharmaco-kinetic profile of this agent reveals that iclaprim is available for intravenous and oral use, with good oral bioavailability. Phase II clinical trials have shown promise in its use for complicated skin and skin structure infections that are caused by methicillin resistant S. aureus and two Phase III clinical trials have been recently completed for the same indication. Phase II trials evaluating the efficacy in respiratory infections are expected to start in 2007. At this early point in clinical development, the available reported data indicate potential for iclaprim as a new antibiotic for parenteral and oral treatment of complicated skin and skin structure infections. PMID- 17714030 TI - New therapeutic perspectives with clevidipine: an ultra-short-acting intravenous Ca2+ channel blocker. AB - Intravenous antihypertensive agents are used in clinical situations in which the immediate, precise control of blood pressure is a clinical necessity. Clevidipine is a new, vascular-selective, dihyrdopyridine Ca(2+) channel blocker, which exerts its hemodynamic effects through selective arterial vasodilation without effects on the venous circulation. Because it is a potent coronary vasodilator, reduction in mean arterial pressure does not impair coronary perfusion. The unique properties of clevidipine include an ultra-short pharmacodynamic duration of action and a half-life after intravenous administration of approximately 2 min, resulting in very rapid onset and offset of antihypertensive effects. In clinical trials performed in patients undergoing cardiac surgery, clevidipine proved superior to nitroprusside and nitroglycerin in maintaining blood pressure within predetermined ranges during the perioperative period. Its safety profile is comparable to nicardipine and nitroglycerin and, in one study, was associated with reduced 30-day mortality compared with nitroprusside. Clevidipine constitutes a useful addition to available intravenous agents and could prove particularly valuable in circumstances that require the ability to rapidly terminate the blood pressure-lowering effects of administered agents. PMID- 17714031 TI - Talabostat. AB - Talabostat mesilate is an orally active, specific inhibitor of dipeptidyl peptidases, including tumor-associated fibroblast activation protein. However, by an independent mechanism, talabostat also stimulates the upregulation of cytokines and chemokines to engender a tumor-specific host immune response, thus giving it a unique dual mechanism of action. In clinical trials, talabostat has demonstrated significant activity, including achieving complete responses in patients with non-small-cell lung cancer and malignant melanoma. PMID- 17714032 TI - Melphalan: old and new uses of a still master drug for multiple myeloma. AB - The treatment of multiple myeloma has seen significant changes from the initial use of melphalan to the introduction of stem cell transplantation and, most recently, to the era of novel targeted agents. Melphalan still remains as a reference drug for combination regimens, including emerging newer therapeutic options, either used at a standard dose for initial or salvage treatments in patients who are not eligible for more intensive therapies, or in conjunction with new molecules within high-dose chemotherapy programs. In this review, the authors analyze old and novel regimens, including melphalan for the treatment of newly diagnosed or relapsed/resistant patients with multiple myeloma in the clinical settings of standard chemotherapy, as well as autologous or allogeneic stem cell transplantation. PMID- 17714033 TI - Phosphodiesterase 4 inhibitors and inflammatory bowel disease: emerging therapies in inflammatory bowel disease. AB - Crohn's disease and ulcerative colitis (UC) are common, chronic inflammatory bowel diseases (IBDs) characterized by episodes of life-altering symptoms such as diarrhea, bleeding, fecal urgency and incontinence, abdominal pain and cramps, and fever lasting weeks to months at a time. Existing treatments are 5 aminosalicyclates or immunosuppressants, but long-term control of IBD is a major problem for a large number of patients. Phosphodiesterase 4 (PDE4) is a key enzyme in cell homeostasis and inflammation and its inhibition has been useful in diseases such as asthma and chronic obstructive pulmonary disease, rheumatoid arthritis and multiple sclerosis. This review focuses on the role of oxidative stress in IBD and the PDE4 inhibitor OPC-6535 (tetomilast), an investigational agent for the treatment of UC. The authors detail the clinical development of the compound and report and provide insight into some of the unpublished data from the recently completed multicenter Phase III trials in UC. PMID- 17714034 TI - A novel MR-imaging technique using arterial spin labeling for thyroid gland perfusion in thyrotoxicosis. PMID- 17714035 TI - Nitric oxide/cGMP signaling inhibits TSH-stimulated iodide uptake and expression of thyroid peroxidase and thyroglobulin mRNA in FRTL-5 thyroid cells. AB - OBJECTIVE: Nitric oxide (NO) induces morphological and functional alterations in primary cultured thyroid cells. The aim of this paper was to analyze the direct influence of a long-term exposition to NO on parameters of thyroid hormone biosynthesis in FRTL-5 cells. DESIGN: Cells were treated with the NO donor sodium nitroprusside (SNP) for 24-72 h. MAIN OUTCOME: SNP (50-500 micromol/L) reduced iodide uptake in a concentration-dependent manner. The inhibition of iodide uptake increased progressively with time and matched nitrite accumulation. SNP inhibited thyroperoxidase (TPO) and thyroglobulin (TG) mRNA expression in a concentration-dependent manner. SNP enhanced 3',5'-cyclic guanosine monophosphate (cGMP) production. 3',5'-cyclic adenosine phosphate (cAMP) generation was reduced by a high SNP concentration after 48 h. 8-Bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP), a cGMP analog, inhibited iodide uptake as well as TPO and TG mRNA expression. The cGMP-dependent protein kinase (cGK) inhibitor KT-5823 reversed SNP or 8-Br-cGMP-inhibited iodide uptake. Thyroid-stimulating hormone pretreatment for 24-48 h prevented SNP-reduced iodide uptake although nitrite levels remained unaffected. CONCLUSION: These findings favor a long-term inhibitory role of the NO/cGMP pathway on parameters of thyroid hormone biosynthesis. A novel property of NO to inhibit TPO and TG mRNA expression is supported. The NO action on iodide uptake could involve cGK mediation. The long term inhibition of steps of thyroid hormonogenesis by NO could be of interest in thyroid pathophysiology. PMID- 17714037 TI - Sunitinib (sutent)-induced thyrotoxicosis due to destructive thyroiditis: a case report. AB - Numerous drugs have been associated with destructive thyroiditis (subacute thyroiditis). Sunitinib, a tyrosine kinase inhibitor employed in renal cell carcinoma and gastrointestinal stromal tumors, has recently been linked to destructive thyroiditis with resultant hypothyroidism. We report a patient with transient overt thyrotoxicosis followed by hypothyroidism, apparently related to sunitinib therapy. PMID- 17714036 TI - HLA-DQ haplotypes in Spanish and German families with Graves' disease: contribution to DQA1*0501-DQB1*0301 mediated genetic susceptibility from fathers. AB - Genetic and environmental factors are involved in the pathogenesis of Graves' disease. The human leukocyte antigen (HLA) locus is considered to be one risk factor for Graves' disease but parent of origin effects have not been studied. Therefore, we investigated the transmission of HLA risk haplotypes DQA1*0501, DQA1*0501-DQB1*0201 (DQ2), and DQA1*0501-DQB1*0301 (DQ7) in two Graves' disease family-cohorts from Spain and Germany. Altogether 208 trio-families (109 from Spain and 99 from Germany; n = 624 individuals) with Graves' disease were genotyped for HLA-DQ alleles DQA1*0501 and the haplotypes DQA1*0501-DQB1*0201 (DQ2) and DQA1*0501-DQB1*0301 (DQ7). Since both family groups-German and Spanish showed the same pattern of HLA transmission and nontransmission, they were analyzed together. HLA DQA1*0501 and DQA1*0501-DQB1*0201 (DQ2) were significantly overtransmitted from the parents to the affected offspring (204 vs. 131, p = 0.0057, pc = 0.0228 and 109 vs. 55, p = 0.0036, pc = 0.0144, respectively). These haplotypes were preferentially transmitted from fathers and DQA1*0501-DQB1*0301 (DQ7) was also more prevalent in fathers (24.0% vs. 17.1%, p = 0.0162, pc = 0.0648). We conclude, that HLA DQA1*0501 and DQA1*0501-DQB1*0201 (DQ2) are strongly associated with Graves' disease in both populations. A parent of origin effect of risk haplotypes can not be excluded at present, warranting further family studies. PMID- 17714039 TI - Global and local alignments in HIV/AIDS prevention trainings: a case study from Burkina Faso. AB - This article presents a linguistic analysis of data from an ongoing research project exploring HIV/AIDS education in West African Burkina Faso. I argue that we can identify different, sometimes even competing, discourses about the disease in prevention interactions. Thus, communication about HIV/AIDS in Burkina Faso- and probably in most of the Sub-Saharan countries--might be characterized by what I will call, with reference to Bakhtin, discursive heteroglossia. There is clear evidence of such discursive heteroglossia, that is, the participants' alignment to local and global HIV discourses, deployed in the communication of health workers. In my analysis of peer educators training sessions, I draw on theoretical and methodological principles from discourse analysis and interactional linguistics. I focus on the linguistic devices and conversational strategies the participants use to indicate the relevance of the local or the global discourses. Three particular devices--namely, metaphors, epistemic and evidential markers, and word explanations--will be examined in a more detailed way. I will also show how the local and the global interweave at different levels of prevention discourse. PMID- 17714040 TI - 'Screwed for life': examining identification and division in addiction narratives. AB - In this study, we investigate the use of narrative in online conversations among persons suffering from chronic opiate addiction and evaluate both its positive and negative uses. Illness narratives, as argued by sociologist Arthur Frank and psychiatrist/medical anthropologist Arthur Kleinman, enable patients to give order to life experiences and receive support from others. We wished to explore under what circumstances online support coalesces and breaks apart. The narratives we examined exemplify two topics frequently discussed on the message board: the recovery process and what it means to be 'clean'. To better understand these narratives from a theoretically based approach, we used the work of rhetorical theorist Kenneth Burke. Burke's description of two human motives, suffering and perfection, led us to an understanding of how unification and division happened within the online community. We found that the recovery narrative primarily embodied the author's suffering and, consequently, received support from other members of the message board. The second narrative centered on what it means to be 'clean' through a discussion of the author's desire to court temptation, revealing what Burke calls the rotten nature of perfection. As a result, the author of the narrative provoked disagreements and did not receive support. PMID- 17714041 TI - 'Don't get caught out': pragmatic and discourse features of informational and promotional texts in international healthcare insurance. AB - This paper examines the pragmatic and discourse features of a number of multimodal international healthcare insurance texts. The texts contain specialized language related to the provision and treatment of healthcare and to insurance coverage and are aimed at a fairly well-defined target readership, many of them actual or potential expatriates. They thus serve a useful function, that of providing the readership with an informed and comprehensible guide to the services and products available. Some of them have a more strictly promotional aspect, that of advertising specific insurance policies. In particular, the paper focuses on the language choices favored by these texts and the strategies they serve, noting that the distinction between their informative and promotional dimensions is not always clear-cut. It further suggests that the writers of these texts make a specific use of discourse features and languaging strategies in order to achieve their rhetorical purposes. PMID- 17714042 TI - Who gets to talk? An alternative framework evaluating companion effects in geriatric triads. AB - Most studies evaluating companion effects on medical triadic interaction focus on the doctors' part, e.g., how the companion's presence diverts doctors' attention away from the patient. In contrast to this mainstream approach, the current research proposes an alternative framework by focusing on the patient parties- especially on how companion participation reshapes the discourse sequences where patient parties provide information, and how it affects patient full turns and priority in providing complete first-hand information to doctors. By examining fifteen geriatric triadic conversations collected in a teaching hospital in southern Taiwan, this proposed framework concludes that in the companion's presence, the information providing sequences are restructured into eight patterns, among which sole information provider is preferred to joint providers. Furthermore, the more companions participate in providing information, the less patients by themselves volunteer information or respond to doctors' questions prior to companions' verbal involvement. A more striking companion effect shows that even in the triads with a low-participation companion, whenever the companion does participate, the patient rarely has a full turn or priority to complete an information unit. The patient's turns are either taken, are simultaneous with, or cut-off by the companion's participation. PMID- 17714044 TI - The construction of identity during group therapy among adults with traumatic brain injury. AB - This investigation examined how the interpretive practices of a speech-language pathologist (SLP) contributed to the construction of identity among adults with traumatic brain injury (TBI) during group therapy in a hospital setting. Six group therapy sessions were video-recorded and transcribed (yielding a total of 8,056 utterances). Attention was paid to patient expressions of identity and ability, the communicative functions of these expressions, and the manner in which these expressions were evaluated by the SLP. The SLP was also interviewed regarding the nature of therapy practice. Analysis revealed that the interpretive voice of the SLP dominated in ascribing a patient identity of self as damaged goods. Implications are discussed in terms of how the institutional setting, the perceived nature of TBI, the agenda of the SLP, and the interactional substrate combined to motivate such interpretive practices on the part of the SLP. PMID- 17714045 TI - The fashioned survivor: institutionalized representations of women with breast cancer. AB - This paper explores some institutionalized visual representations of women with breast cancer and examines the rhetoric of the images in the American Cancer Society product catalogue (2000) and the Look Good ... Feel Better pamphlet. I show that these cultural discourses promote notions of appearance that are 'acceptable', 'desirable', and 'beautiful' even when a person is sick. Suggestions and models offered for women when there is a 'problem' with their bodies through the frame of 'helping' them to cope with the effects of cancer--by managing their appearance--provide models for renewed femininity during/after cancer treatment and function to maintain the existing definitions of beauty, femininity, and gendered appearances even in times of crisis. With an emphasis on the 'normalization' of one's changed 'problematic' appearance, the images function to narrow down women's meanings and choices about their bodies and the ways in which they can manage their bodily appearance. Furthermore, this paper points to possible alternative discourses for further exploration. This study aims to enrich our understandings of cultural meanings of illness by making visual materials a significant part of our research. PMID- 17714046 TI - Adapting to conversation as a language-impaired speaker: changes in aphasic turn construction over time. AB - Using the methodology and findings of conversation analysis, we analyze changes in the talk of a man with aphasia (a language disorder acquired following brain damage) at two points in his spontaneous recovery period in the first months post stroke. We note that in the earlier conversation (15 weeks post-stroke) two of the turn constructional methods he particularly makes use of are replacement (a form of repair) and extension. By the time of the latter conversation (30 weeks poststroke) these methods are less prevalent, while another repair operation, insertion, is now used in a particular way not seen in the earlier conversation. We suggest that these methods are means by which the aphasic speaker adapts his limited linguistic resources to the demands of constructing a turn-at-talk in conversation in order to lessen the extent of repair and delay with the turn and thus lessen the exposure of his linguistic noncompetence and his identity as 'different', 'disabled', or 'language impaired'. These turn constructional methods are dynamic and change as the speaker recovers. We suggest that communication disorders such as aphasia can be problematic not only because of difficulties they can cause in conveying information or producing other social actions, but also because they can create difficulties in the presentation of self in everyday life. PMID- 17714047 TI - No less a man: reconstructing identity after prostate cancer. AB - Few diagnoses present as great a challenge to one's life as cancer. Many men each year are confronted with a diagnosis of early stage prostate cancer and find themselves making decisions about treatment in the face of side effects that present often devastating effects, including problems controlling one's urine and an inability to perform sexually. In this paper, we explore the narratives of men who, having chosen and undergone treatment for early stage prostate cancer, are living with the consequences. Faced with what Charmaz calls an 'identity dilemma', how do these men linguistically construct their identities in the face of challenges to their bodily, personal, and social integrity? Drawing upon theories of social languages and Discourses, we examine how men linguistically resolve the identity dilemmas they encounter and in turn construct an identity in response to a question about the quality of their lives in the face of the adverse event of prostate cancer. We present an analysis of the interview narratives of two men and show how they 're-collage' an identity in the face of fundamental changes in their functioning as men. We argue that these men draw upon alternative discourses to construct themselves as whole, competent, and 'no less a man'. PMID- 17714048 TI - Commentary. Six basic principles in the communication of social identities: the special case of discourses and illness. PMID- 17714049 TI - Commentary 1. 'Quality of life to the end'. PMID- 17714050 TI - Commentary 2. 'Quality of life to the end'. PMID- 17714051 TI - Commentary 3. 'Quality of life to the end'. PMID- 17714054 TI - Preventing cardiovascular and renal complications in the management of hypertension and metabolic syndrome. AB - This editorial discusses the history, definition and prevelance of the metabolic syndrome. Pathophysiological factors, such as girth, blood pressure, glucose, triglycerides, HDL-cholesterol, obesity, raised levels of plasma insulin and insulin resistance are outlined as being components of the syndrome. The paper examines the relationship of cardiovascular and all-cause mortality to the metabolic syndrome, and discusses the risk of cardiovascular disease associated with the metabolic syndrome. In addition, the article explores the link between metabolic syndrome, kidney function, insulin resistance and chronic kidney disease. Finally, the article discusses the issue of managing metabolic syndrome. PMID- 17714055 TI - Effect of buccal dwell time on the pharmacokinetic profile of fentanyl buccal tablet. AB - BACKGROUND: The time fentanyl buccal tablet (FBT) takes to completely dissolve after placement on the buccal mucosa (i.e., 'dwell time') could exceed the time to onset of analgesia. OBJECTIVE: To examine the relationship between FBT dwell time and fentanyl pharmacokinetic parameters. RESEARCH DESIGN AND METHODS: This was a post hoc exploratory analysis of data from two randomized, open-label, crossover, pharmaco-kinetic studies that were designed to assess dose proportionality within the anticipated therapeutic dose range. Healthy adults received single FBT doses of 200-1080 microg in Study 1 (n = 28) and 270-1300 microg in Study 2 (n = 42). MAIN OUTCOME MEASURES: Assessments included buccal dwell time, defined as the duration of FBT presence in the oral cavity, and the following pharmacokinetic measures: maximum serum concentration (C(max)), time to C(max) (T(max)) and area under the concentration-time curve (AUC; exposure) from 0 minutes to median T(max) adjusted for the dose (T(max')) (AUC(0 T(max'))). Spontaneously reported adverse events were recorded. RESULTS: Mean buccal dwell time for FBT across the dose range varied from 14 to 25 minutes (range 3 - 62 minutes). There was no evidence of an association between FBT dwell time and values for T(max) (medians 45 - 60 minutes), dose-normalized C(max) (means 0.42 0.66 pg/ml/200 microg) or dose-normalized AUC(0 T(max')) (means 0.24-0.38 pg x h/ml/200 microg) over the range of FBT doses delivered. All adverse events reported were mild to moderate; none were unexpected or serious. CONCLUSION: The pharmacokinetic parameters of FBT did not appear to be related to its buccal dwell time. PMID- 17714056 TI - Immediate removal of femoral-sheath following protamine administration in patients undergoing intracoronary paclitaxel-eluting-stent implantation. AB - BACKGROUND: Immediate sheath-removal using post-procedural reversal of heparin with protamine reduces groin complications, shortens bed rest and hospital stay after percutaneous coronary intervention (PCI) with bare-metal stents. No data are available with newer and possibly more thrombogenic paclitaxel-eluting stents (PES). AIM: We assessed the safety and efficacy of post-procedural protamine administration after successful coronary PES implantation in elective PCI and in patients with acute coronary syndromes (ACS). METHODS: A consecutive series of 291 patients received 0.5 mg of protamine per 100 units of heparin whenever the post-procedural ACT was > 180 seconds, followed by immediate removal of the sheath (protamine group). Outcomes were compared to a historic control group comprising 291 consecutive patients, who also underwent PCI with PES, but without reversal of anticoagulation by protamine (non protamine group). The incidence of post-procedural vascular complications and bleeding complications, as well as hospital stay, were compared; as were the incidence of major cardiac events at 24 h, 30 days and 6 months. RESULTS: The post-procedural bleeding complications were significantly higher in the non-protamine group. Vascular complications were also more frequent in patients who were not treated with protamine. Hospitalisation length was significantly lower in the protamine group than in the non-protamine group (13.6 +/- 7 h versus 20.41 +/- 3.9 h; p < 0.001). The protamine-group patients also had a significantly reduced bed rest (10.3 h +/- 5.6 h versus 18 h +/- 3.5 h; p < 0.001). During hospitalisation, after PES implantation, no deaths or acute stent thrombosis were observed in either group. The overall incidence of thrombosis and major adverse cardiac events at follow-up were similar in the two groups. CONCLUSIONS: Immediate heparin neutralisation by protamine after successful PES implantation appears to be safe and feasible, also in patients with ACS. Use of protamine and early sheath removal after PCI confers early deambulation and may significantly limit healthcare cost, reduce vascular complications, bedrest, delayed discharge and patient discomfort. PMID- 17714057 TI - The prevalence of pantoprozole associated thrombocytopenia in a community hospital. AB - OBJECTIVE: Proton pump inhibitors (PPIs) are widely used in the treatment of gastritis, gastroesophageal reflux disease and peptic ulcer disease. Thrombocytopenia is not listed as one of the main side effects of PPI therapy. However, there have been documented cases of thrombocytopenia with the use of PPIs in the literature. Our objective was to determine whether exposure to PPIs leads to an increased incidence of thrombocytopenia in hospitalized patients. METHODS: This retrospective cohort study examined the platelet counts of 468 hospitalized patients who were 18 - 80 years of age, were prescribed pantoprazole for a minimum of 3 days and were matched to 468 non-medicated controls. The primary outcome was defined as either a drop in the platelet count by >/= 50% relative to baseline, or a drop to < 150,000/ml. Exclusion criteria were baseline thrombocytopenia and hospitalization for < 3 days. RESULTS: No difference was found in the occurrence of thrombocytopenia between the two groups (6.2%; 95% CI = 4.1 - 8.7%) in the study group versus (6.6%; 95% CI = 4.5 - 9.2%) in the control group (p = 0.90). Post-hoc analysis revealed a higher incidence of > 20% drop in platelet count in the study group compared with the controls (23%; 95% CI = 19 - 27% versus 11%; 95% CI = 8 - 14%, respectively; p < 0.001). CONCLUSION: This study failed to demonstrate an increased incidence of thrombocytopenia for patients treated with pantoprazole. Our study adds support to the favorable safety profile of PPI therapy in hospitalized patients. Further investigation is needed to evaluate the effects of PPI use in the outpatient setting. PMID- 17714058 TI - Eating disorders: an overview of treatment responses and the potential impact of vulnerability genes and endophenotypes. AB - Anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED) are the three main eating disorders. Antidepressants, antipsychotics, anticonvulsants, prokinetic agents, opiate antagonists, appetite suppressants, tetrahydrocannabinol, cyproheptadine, zinc and ondansetron have been tested, and are frequently associated with psychological treatment. Selective serotonin reuptake inhibitors have a proven efficacy in BN and binge eating disorder. Other treatments, such as atypical antipsychotics in AN, anticonvulsants in BN and BED, and naltrexone and ondansetron in BN, may be promising, but lack the appropriate trials. The development of genetic researches in eating disorders may help the clinician to choose the most appropriate treatment in forthcoming years, using genetic polymorphisms of vulnerability genes, those linked to endophenotypes, or genes implicated in the metabolism of the drug treatment. PMID- 17714059 TI - Pharmacogenetics as a tool for optimising drug therapy in solid-organ transplantation. AB - Existing immunosuppressive therapies used for solid-organ transplantation have narrow therapeutic indices, whereby underdosing is associated with acute immunological rejection of the transplanted organ and overdosing is associated with infections and malignancy, as well as organ-specific toxicities. There is significant inter-individual variation in the pharmacokinetics and pharmacodynamics of these drugs, an issue that has been addressed, in part, by therapeutic drug monitoring. Genetic polymorphisms in drug metabolising enzymes, drug efflux pumps and drug targets which may underly this heterogeneity have been identified and may provide a tool to guide prescribing. There are a number of associations between genotype and pharmacology, but as of now, only thiopurine-S methyltransferase and cytochrome P450 3A5 have a sufficiently large influence to have potential in guiding therapy. Recent studies have also identified that donor genotype may play a significant role in immunosuppressive drug pharmacokinetics and pharmacodynamics. PMID- 17714060 TI - Metabolic syndrome management. AB - Overweight, obesity and the metabolic syndrome occur in genetically susceptible individuals with environmental influences, and may be further compounded by other disorders of metabolism or pharmacological therapy that increase insulin resistance or promotes weight gain. Treatment of the metabolic syndrome should focus on treatment on [corrected] each individual component, but first, lifestyle modification, including diet and exercise with weight reduction, should be [corrected] the foundation of any successful treatment regimen for the metabolic syndrome. Pharmacological therapy should be individualized and targeted to normalize blood pressure, HDL cholesterol, triglycerides and glucose values. If successful, comprehensive management of the metabolic syndrome promises to delay or prevent the development of coronary heart disease and Type 2 diabetes mellitus. PMID- 17714061 TI - Non-corticosteroid therapy for the long-term control of asthma. AB - The non-corticosteroids approved for the maintenance therapy of persistent asthma include the long-acting inhaled beta(2) agonists (LABAs), leukotriene modifiers, chromones, theophylline and omalizumab. This review assesses the benefits and risks of each in relation to the inhaled corticosteroids and each other. Neither the LABAs nor omalizumab should be used as monotherapy for persistent asthma. There is no evidence of clinically significant differences in efficacy between the chromones, theophylline and leukotriene modifiers as monotherapy in mild moderate persistent asthma; thus the choice of one therapy over the other is a clinical decision based upon differences in safety, acceptability to the patient and ease of use. Although there is significant variability in response to various therapies, non response to one therapy is not predictive of response to another. Neither studies of phenotypes nor genotypes have provided acceptable determinants of response as yet. As adjunctive therapy to the inhaled corticosteroids for moderate-severe persistent asthma, the LABAs provide superior improvement in lung function and reduction in exacerbations relative to higher doses of inhaled corticosteroids and the other noncorticosteroids used as adjunctive therapy. Thus, LABAs remain the adjunctive therapy of choice in patients not adequately controlled on low-medium dose inhaled corticosteroids. Omalizumab has not been compared with the other adjunctive therapies, so its relative efficacy is unknown. However, it is the only adjunctive therapy added to the combination of an inhaled corticosteroid plus LABA to demonstrate further improvement in a controlled clinical trial. PMID- 17714062 TI - The use of TNF-alpha blocking agents in rheumatoid arthritis: an update. AB - TNF-alpha has been found to play a pivotal role in the pathogenic mechanisms of rheumatoid arthritis (RA). Drugs targeting TNF-alpha have been developed to neutralise the deleterious effects of this inflammatory cytokine. There are, at present, three drugs available for the treatment of RA patients with active disease who are refractory to conventional treatments including methotrexate: 2 monoclonal antibodies, infliximab and adalimumab, and a fusion protein with p75 receptors, etanercept. These three agents have proved to be effective and safe in large placebo-controlled trials enrolling patients with established or early disease and showed effectiveness in controlling signs and symptoms of the disease, improving quality of life and in slowing and even arresting the progression of radiographic damage. With the long-term surveillance of these drugs were described serious adverse events, particularly infections such as tuberculosis, especially with infliximab. The risk for malignancies under TNF alpha antagonists, especially lymphoma, remains controversial. Specific recommendations are given by international experts for selecting and monitoring RA patients with TNF-alpha antagonists. Other drugs targeting TNF-alpha such as PEGylated molecules (CDP870 or certolizumab) are in development. These new biological therapies blocking TNF-alpha undoubtedly constitute a considerable advancement in the management of RA, but careful evaluation at the initiation of the treatment and long-term surveillance of the patients receiving such drugs remains necessary. PMID- 17714063 TI - Targeting polyamine metabolism: a viable therapeutic/preventative solution for cancer? AB - The polyamine pathway has been identified as a target for the design of new antiproliferative drugs, due to the strong positive relationship between intracellular polyamine content and cell, particularly cancer cell growth. A number of single enzyme inhibitors have been synthesised against the two key biosynthetic enzymes, ornithine decarboxylase and S-adenosylmethionine decarboxylase, but their success in the clinic has been limited due to incomplete polyamine depletion and induction of compensatory mechanisms that counteract the effects of enzyme inhibition. Overall, clinical trials of these agents as chemotherapeutic drugs have proved disappointing, with either little clinical efficacy or unacceptable toxicity. The polyamine analogues provide an alternative strategy that shows promise, particularly against diseases other than cancer. Combination of the polyamine inhibitors with classic cytotoxic agents may be an alternative strategy that is showing some promise, at least in vitro. An avenue that is, however, presently more promising is the use of polyamine inhibitors or analogues as chemopreventative agents against a range of human cancers. It seems likely that the future use of these drugs will be in disease prevention rather than treatment. With regard to the newer agents with restricted conformation that are now undergoing clinical trials, it is too early to say whether they will be chemotherapeutic and/or chemopreventative. This article focuses on the clinical use and responses to inhibitors of polyamine metabolism. PMID- 17714064 TI - Venous thromboembolism prevention in cancer patients: the search for common antecedents. AB - Venous thromboembolism (VTE) is a well-recognized concomitant of cancer. Although treatment with warfarin is often difficult and tedious, the heparins, and particularly the low molecular weight heparins, have afforded improved care of the patient with cancer-associated VTE, but with increased cost and the need for self-injection. Development by the pharmaceutical industry of inhibitors of specific activated coagulation factors and P-selectin holds promise for improved control of thrombosis with reduced toxicity. Increasing understanding of the interplay between the coagulation mechanism and neoplasia has yielded clues to the upstream origins of both, which may lead to experimental intervention potentially capable of preventing both. PMID- 17714065 TI - Stimulant therapy in the management of ADHD: mixed amphetamine salts (extended release). AB - The efficacy of amphetamines in the management of attention-deficit/hyperactivity disorder (ADHD) is well established. However, their value in improving the symptoms of ADHD has been compromised by concerns about compliance, abuse potential and adverse events. An extended-release formulation of mixed amphetamine salts (MAS XR) provided the first long-acting amphetamine formulation, and thus, filled an important gap in available treatments for ADHD. MAS XR has been shown to improve ADHD symptoms in children, adolescents and adults in both short- and long-term studies. The drug is generally well tolerated in clinical trials. Although its safety profile in patients with concomitant cardiovascular conditions in a real-world setting has yet to be fully evaluated, a tolerability study of mixed amphetamine salts in adults with ADHD who were being treated for primary essential hypertension showed that these patients can be safely treated with MAS XR. PMID- 17714066 TI - Combined use of ultra-short acting beta-blocker esmolol and intravenous phosphodiesterase 3 inhibitor enoximone. AB - In patients with impaired myocardial contractility associated with downregulation of the beta-receptors, compounds inhibiting phosphodiesterase (PDE) 3 may be useful to increase contractility. The PDE3 inhibitor enoximone has been shown to improve pump-function independent from the beta-receptor pathway. A simultaneous decrease in ventricular preload and afterload by vasodilation has led to the term 'inodilator'. Esmolol is the only available ultra-short acting intravenous beta blocking agent. Due to its half-life of approximately 9 min, beta-blockade, and thus, heart rate, can easily be titrated. Esmolol appears to be a helpful tool to avoid myocardial ischemia (e.g., in the perioperative setting). As with all other beta-blockers, it has dose-dependent negative inotropic effects, and this limits its use in patients with severe heart failure showing low cardiac output. It seems reasonable that an intravenous combination of both approaches, enoximone induced positive inotropy and esmolol-associated protection from myocardial ischemia, might offer advantages by producing beneficial hemodynamic effects and by compensating each other's limitations in a complementary way. In spite of some promising results, the place of a combination of enoximone and esmolol in the process of treating patients with (acute) heart failure showing low output is still not entirely clear, and needs further confirmation. PMID- 17714067 TI - Ranolazine in patients with coronary artery disease. AB - Traditional anti-anginal agents such as beta-blockers and nitrates improve symptoms of cardiac ischemia by affecting either blood pressure or heart rates. Despite aggressive therapy, many patients suffer persistent angina, and optimal therapy is limited by intolerance to traditional agents. Ranolazine, a novel anti anginal agent that is approved for use in the US, is felt to improve ischemic symptoms by reducing myocardial cellular sodium and calcium overload via inhibition of the late sodium current (I(Na)) of the cardiac action potential. Several Phase-III trials in patients with chronic angina have demonstrated that ranolazine improves exercise tolerance and reduces ischemic symptoms as compared with placebo. In the largest evaluation of ranolazine, the MERLIN-TIMI 36 trial (Metabolic Efficiency with Ranolazine for Less Ischemia in non ST elevation acute coronary syndrome), ranolazine did not reduce the risk of death or recurrent myocardial infarction in patients with non-ST-elevation acute coronary syndromes, but it did improve ischemic symptoms over the subsequent year of therapy. Thus, ranolazine offers clinicians a new therapy in the long-term treatment of patients with chronic angina. PMID- 17714068 TI - Simvastatin: present and future perspectives. AB - Simvastatin is lipophilic statin with a short half-life that is primarily metabolized by CYP450 3A4. At doses of 5 - 80 mg, simvastatin lowers LDL cholesterol by 25 - 50%. Simvastatin has been shown to reduce the risk of cardiovascular disease by 35% and overall mortality by up to 30% over 5 years. The recommended starting dose of simvastatin 40 mg is approved as a lipid lowering agent and for all high-risk patients, including those with cardiovascular disease and diabetes, regardless of the baseline LDL level. Simvastatin dose should be adjusted in those receiving CYP3A4 inhibitors, gemfibrozil, or ciclosporin, amiodarone, or in those with severe renal insufficiency. Coformulation of simvastatin with ezetimibe is now available, and coformulation with extended release niacin is under development. PMID- 17714069 TI - Update on montelukast and its role in the treatment of asthma, allergic rhinitis and exercise-induced bronchoconstriction. AB - Montelukast sodium (Singulair, Merck and Co., Inc., Whitehouse Station, NJ) is a selective and orally-active leukotriene receptor antagonist with demonstrated effectiveness for treating allergic asthma and allergic rhinitis in adults and children as young as 12 months of age for allergic asthma and 6 months of age for allergic rhinitis. It was recently approved in the US for prevention of exercise induced bronchoconstriction in patients who are > or = 15 years of age. This paper updates a prior review of the data on the clinical efficacy of montelukast published in this journal. PMID- 17714070 TI - Lapatinib: a tyrosine kinase inhibitor with a clinical role in breast cancer. AB - Lapatinib is a dual (ErbB-1 and ErB-2) receptor tyrosine kinase inhibitor (TKI) that was recently approved by the FDA for the treatment of advanced breast cancer. It shows synergy with trastuzumab, and has demonstrated clinical activity in trastuzumab-resistant tumour. This paper reviews the drug development of lapatinib from preclinical studies to the pivotal Phase III trial and ongoing clinical studies. Areas of interest include the advantages of small molecule TKIs versus antibodies in targeting HER receptors and the efficacy of lapatinib in the treatment of cerebral metastases. The surprisingly high response rate in inflammatory breast cancer raises the possibility of other novel predictive biomarkers. The potential for combination and sequencing with other biological and cytotoxic agents is both exciting and challenging. PMID- 17714071 TI - A purification method for improving the process yield and quality of recombinant human granulocyte colony-stimulating factor expressed in Escherichia coli and its characterization. AB - A purification method employing a process-control strategy was developed for improving the yield of rhG-CSF (recombinant human granulocyte colony-stimulating factor). A purity of >/=99% with an overall yield of 2.18 g/l was achieved in the present study. Analysis of the product during purification indicated that detergents removed 72% of LPS (lipopolysaccharides) and 98% of HCPs (host cell proteins) without removing nucleic acid. Cysteine concentration was a key parameter in protein refolding. The bed height and HETP (height equivalent theoretical plates) value in the SEC (size-exclusion chromatography) column was evaluated and its impact on the resolution was studied. Formulation during SEC was found to be crucial for increasing the product yields with saving of time and process costs. The yield obtained in the present study is nearly four times higher than that reported in the literature. The product obtained was found to be acceptable for toxicological studies. PMID- 17714072 TI - High-fat diets: healthy or unhealthy? AB - In the current dietary recommendations for the treatment and prevention of Type 2 diabetes and its related complications, there is flexibility in the proportion of energy derived from monounsaturated fat and carbohydrate as a replacement for saturated fat. Over the last few years, several population studies have shown that subjects eating a lot of refined grains and processed foods have a much larger increase in waist circumference than those following a diet higher in monounsaturated fat, protein and carbohydrates rich in fibre and whole grain. In the present issue of Clinical Science, Sinitskaya and co-workers have demonstrated that, in normal-weight rodents categorized into groups of high-fat and medium-carbohydrate [53%/30% of energy as fat/carbohydrate; 19.66 kJ/g (4.7 kcal/g)], high-fat and low-carbohydrate [67%/9% of energy as fat/carbohydrate; 21.76 kJ/g (5.2 kcal/g)] and high-fat and carbohydrate-free [75%/0% of energy as fat/carbohydrate; 24.69 kJ/g (5.9 kcal/g)] diets, the high-fat diets containing carbohydrates were both obesogenic and diabetogenic, whereas the very-high-fat and carbohydrate-free diet was not obesogenic but led to insulin resistance and higher risk of cardiovascular disease. This finding may indicate that high-fat diets could easily give rise to an unhealthy diet when combined with carbohydrates, highlighting the significance of macronutrient composition, rather than caloric content, in high-fat diets. PMID- 17714073 TI - The C-terminus of connexin43 adopts different conformations in the Golgi and gap junction as detected with structure-specific antibodies. AB - The C-terminus of the most abundant and best-studied gap-junction protein, connexin43, contains multiple phosphorylation sites and protein-binding domains that are involved in regulation of connexin trafficking and channel gating. It is well-documented that SDS/PAGE of NRK (normal rat kidney) cell lysates reveals at least three connexin43-specific bands (P0, P1 and P2). P1 and P2 are phosphorylated on multiple, unidentified serine residues and are found primarily in gap-junction plaques. In the present study we prepared monoclonal antibodies against a peptide representing the last 23 residues at the C-terminus of connexin43. Immunofluorescence studies showed that one antibody (designated CT1) bound primarily to connexin43 present in the Golgi apparatus, whereas the other antibody (designated IF1) labelled predominately connexin43 present in gap junctions. CT1 immunoprecipitates predominantly the P0 form whereas IF1 recognized all three bands. Peptide mapping, mutational analysis and protein protein interaction experiments revealed that unphosphorylated Ser364 and/or Ser365 are critical for CT1 binding. The IF1 paratope binds to residues Pro375 Asp379 and requires Pro375 and Pro377. These proline residues are also necessary for ZO-1 interaction. These studies indicate that the conformation of Ser364/Ser365 is important for intracellular localization, whereas the tertiary structure of Pro375-Asp379 is essential in targeting and regulation of gap junctional connexin43. PMID- 17714074 TI - Molecules incorporating a benzothiazole core scaffold inhibit the N myristoyltransferase of Plasmodium falciparum. AB - Recombinant N-myristoyltransferase of Plasmodium falciparum (termed PfNMT) has been used in the development of a SPA (scintillation proximity assay) suitable for automation and high-throughput screening of inhibitors against this enzyme. The ability to use the SPA has been facilitated by development of an expression and purification system which yields considerably improved quantities of soluble active recombinant PfNMT compared with previous studies. Specifically, yields of pure protein have been increased from 12 microg x l(-1) to >400 microg x l(-1) by use of a synthetic gene with codon usage optimized for expression in an Escherichia coli host. Preliminary small-scale 'piggyback' inhibitor studies using the SPA have identified a family of related molecules containing a core benzothiazole scaffold with IC50 values <50 microM, which demonstrate selectivity over human NMT1. Two of these compounds, when tested against cultured parasites in vitro, reduced parasitaemia by >80% at a concentration of 10 microM. PMID- 17714075 TI - Tuning the formation of a covalent haem-protein link by selection of reductive or oxidative conditions as exemplified by ascorbate peroxidase. AB - Previous work [Metcalfe, Ott, Patel, Singh, Mistry, Goff and Raven (2004) J. Am. Chem. Soc. 126, 16242-16248] has shown that the introduction of a methionine residue (S160M variant) close to the 2-vinyl group of the haem in ascorbate peroxidase leads to the formation of a covalent haem-methionine linkage under oxidative conditions (i.e. on reaction with H2O2). In the present study, spectroscopic, HPLC and mass spectrometric evidence is presented to show that covalent attachment of the haem to an engineered cysteine residue can also occur in the S160C variant, but, in this case, under reducing conditions analogous to those used in the formation of covalent links in cytochrome c. The data add an extra dimension to our understanding of haem to protein covalent bond formation because they show that different types of covalent attachment (one requiring an oxidative mechanism, the other a reductive pathway) are both accessible within same protein architecture. PMID- 17714076 TI - Proteasomal dysfunction activates the transcription factor SKN-1 and produces a selective oxidative-stress response in Caenorhabditis elegans. AB - SKN-1 in the nematode worm Caenorhabditis elegans is functionally orthologous to mammalian NRF2 [NF-E2 (nuclear factor-E2)-related factor 2], a protein regulating response to oxidative stress. We have examined both the expression and activity of SKN-1 in response to a variety of oxidative stressors and to down-regulation of specific gene targets by RNAi (RNA interference). We used an SKN-1-GFP (green fluorescent protein) translational fusion to record changes in both skn-1 expression and SKN-1 nuclear localization, and a gst-4-GFP transcriptional fusion to measure SKN-1 transcriptional activity. GST-4 (glutathione transferase-4) is involved in the Phase II oxidative stress response and its expression is lost in an skn-1(zu67) mutant. In the present study, we show that the regulation of skn-1 is tied to the protein-degradation machinery of the cell. RNAi-targeted removal of most proteasome subunits in C. elegans caused nuclear localization of SKN-1 and, in some cases, induced transcription of gst-4. Most intriguingly, RNAi knockdown of proteasome core subunits caused nuclear localization of SKN-1 and induced gst-4, whereas RNAi knockdown of proteasome regulatory subunits resulted in nuclear localization of SKN-1 but did not induce gst-4. RNAi knockdown of ubiquitin-specific hydrolases and chaperonin components also caused nuclear localization of SKN-1 and, in some cases, also induced gst-4 transcription. skn-1 activation by proteasome dysfunction could be occurring by one or several mechanisms: (i) the reduced processivity of dysfunctional proteasomes may allow oxidatively damaged by-products to build up, which, in turn, activate the skn-1 stress response; (ii) dysfunctional proteasomes may activate the skn-1 stress response by blocking the constitutive turnover of SKN-1; and (iii) dysfunctional proteasomes may activate an unidentified signalling pathway that feeds back to control the skn-1 stress response. PMID- 17714077 TI - Structure-based design of small peptide inhibitors of protein kinase CK2 subunit interaction. AB - X-ray crystallography studies, as well as live-cell fluorescent imaging, have recently challenged the traditional view of protein kinase CK2. Unbalanced expression of catalytic and regulatory CK2 subunits has been observed in a variety of tissues and tumours. Thus the potential intersubunit flexibility suggested by these studies raises the likely prospect that the CK2 holoenzyme complex is subject to disassembly and reassembly. In the present paper, we show evidence for the reversible multimeric organization of the CK2 holoenzyme complex in vitro. We used a combination of site-directed mutagenesis, binding experiments and functional assays to show that, both in vitro and in vivo, only a small set of primary hydrophobic residues of CK2beta which contacts at the centre of the CK2alpha/CK2beta interface dominates affinity. The results indicate that a double mutation in CK2beta of amino acids Tyr188 and Phe190, which are complementary and fill up a hydrophobic pocket of CK2alpha, is the most disruptive to CK2alpha binding both in vitro and in living cells. Further characterization of hotspots in a cluster of hydrophobic amino acids centred around Tyr188-Phe190 led us to the structure-based design of small-peptide inhibitors. One conformationally constrained 11-mer peptide (Pc) represents a unique CK2beta-based small molecule that was particularly efficient (i) to antagonize the interaction between the CK2 subunits, (ii) to inhibit the assembly of the CK2 holoenzyme complex, and (iii) to strongly affect its substrate preference. PMID- 17714078 TI - A CBS domain-containing pyrophosphatase of Moorella thermoacetica is regulated by adenine nucleotides. AB - CBS (cystathionine beta-synthase) domains are found in proteins from all kingdoms of life, and point mutations in these domains are responsible for a variety of hereditary diseases in humans; however, the functions of CBS domains are not well understood. In the present study, we cloned, expressed in Escherichia coli, and characterized a family II PPase (inorganic pyrophosphatase) from Moorella thermoacetica (mtCBS-PPase) that has a pair of tandem 60-amino-acid CBS domains within its N-terminal domain. Because mtCBS-PPase is a dimer and requires transition metal ions (Co2+ or Mn2+) for activity, it resembles common family II PPases, which lack CBS domains. The mtCBS-PPase, however, has lower activity than common family II PPases, is potently inhibited by ADP and AMP, and is activated up to 1.6-fold by ATP. Inhibition by AMP is competitive, whereas inhibition by ADP and activation by ATP are both of mixed types. The nucleotides are effective at nanomolar (ADP) or micromolar concentrations (AMP and ATP) and appear to compete for the same site on the enzyme. The nucleotide-binding affinities are thus 100-10000-fold higher than for other CBS-domain-containing proteins. Interestingly, genes encoding CBS-PPase occur most frequently in bacteria that have a membrane-bound H+-translocating PPase with a comparable PP(i)-hydrolysing activity. Our results suggest that soluble nucleotide-regulated PPases act as amplifiers of metabolism in bacteria by enhancing or suppressing ATP production and biosynthetic reactions at high and low [ATP]/([AMP]+[ADP]) ratios respectively. PMID- 17714079 TI - Sensory neural targets for the treatment of cough. AB - 1. Cough is a primary defensive reflex that protects the airways from potentially harmful stimuli. 2. During many respiratory diseases, the cough reflex threshold is lowered and coughing becomes excessive. 3. Currently available therapeutics are mostly ineffective at suppressing excessive coughing. 4. In the present review, we describe the sensory neural pathways involved in cough, how these pathways may become dysfunctional in airway disease and the most recent advances that have been made in identifying future targets for cough suppression. PMID- 17714080 TI - What makes a CGRP2 receptor? AB - 1. Heterogeneity in the receptors for the neuropeptide calcitonin gene-related peptide (CGRP) has been apparent for nearly 20 years. This is most clearly manifested in the observation of CGRP(8-37)-sensitive and -insensitive populations of CGRP-activated receptors. The pA(2) values for CGRP(8-37) in excess of 7 are widely considered to be the result of antagonism of CGRP(1) receptors, whereas those below 7 are believed to be the consequence of antagonism of a second population of receptors, namely CGRP(2) receptors. 2. However, a multitude of pA(2) values exist for CGRP(8-37), spanning several log units, and as such no obvious clusters of values are apparent. Understanding the molecular nature of the receptors that underlie this phenomenon is likely to aid the development of selective pharmacological tools to progress our understanding of the physiology of CGRP and related peptides. Because there is active development of CGRP agonists and antagonists as therapeutics, such information would also further this pursuit. 3. The CGRP(1) receptor is pharmacologically and molecularly well defined as a heterodimer of the calcitonin receptor-like receptor (CL) and receptor activity modifying protein (RAMP) 1. The CL/RAMP1 complex is highly sensitive to CGRP(8-37). Conversely, the constituents of the CGRP(2) receptor have not been identified. In fact, there is little evidence for a distinct molecular entity that represents the CGRP(2) receptor. 4. Recent pharmacological characterization of receptors related to CGRP(1) has revealed that some of these receptors may explain CGRP(2) receptor pharmacology. Specifically, AMY(1(a)) (calcitonin receptor/RAMP1) and AM(2) (CL/RAMP3) receptors can be activated by CGRP but are relatively insensitive to CGRP(8-37). 5. This, along with other supporting data, suggests that the 'CGRP(2) receptor' that has been extensively reported in the literature may, in fact, be an amalgamation of contributions from a variety of CGRP-activated receptors. The use of appropriate combinations of agonists and antagonists, along with receptor expression studies, could allow such receptors to be separated. PMID- 17714081 TI - 17Beta-oestradiol partially attenuates the inhibition of nitric oxide synthase-3 by advanced glycation end-products in human platelets. AB - 1. Diabetes mellitus predisposes to and female sex protects against arterial thrombosis. The aim of the present study was to determine whether advanced glycation end-products (AGE), which accumulate in diabetes, impair platelet function through effects on platelet nitric oxide (NO) generation and whether this can be prevented by 17beta-oestradiol. 2. Aggregation responses of human platelet-rich plasma to ADP were determined in the absence or presence of 200 mg/L AGE-modified albumin (AGE-albumin), 10(-5) mol/L 17beta-oestradiol and 10( 5) mol/L ICI 182 780 (the pure oestrogen receptor antagonist). 3. Intraplatelet cGMP, an index of bioactive NO, was measured by radioimmunoassay and expression of nitric oxide synthase (NOS)-3, phosphoserine-1177-NOS-3 and O-glycosylated NOS 3 was quantified by western blotting in response to these same treatments. 4. Advanced glycation end-products-albumin increased platelet aggregatory responses to ADP. This increase was largely prevented by 17beta-oestradiol. Advanced glycation end-products-albumin decreased and 17beta-oestradiol increased intraplatelet NO-attributable cGMP and 17beta-oestradiol attenuated the AGE albumin-induced decrease in NO-attributable cGMP. Despite no effect on NOS-3 expression, AGE-albumin decreased and 17beta-oestradiol increased phosphoserine 1177-NOS-3 and 17beta-oestradiol largely prevented the decrease in phosphoserine 1177-NOS-3 induced by AGE-albumin. Alone, AGE-albumin increased O-glycosylation of NOS-3 by N-acetylglucosamine, an effect largely inhibited by 17beta oestradiol. 5. In conclusion, AGE-albumin inhibits platelet NO biosynthesis through effects on serine phosphorylation and O-glycosylation of platelet NOS-3 and this may explain, at least in part, the increase in platelet aggregability induced by AGE-albumin. These effects of AGE-albumin are largely prevented by 17beta-oestradiol. These actions may contribute to the effects of diabetes and sex on arterial thrombosis in vivo. PMID- 17714082 TI - Vasodilatation induced by sinomenine lowers blood pressure in spontaneously hypertensive rats. AB - 1. Sinomenine is an alkaloid with a wide range of pharmacological actions. In the present study, we investigated the effect of sinomenine on blood pressure and its possible mechanisms of action. 2. Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were given intraperitoneal injections of sinomenine. At 30 min, 2.5-10 mg/kg sinomenine decreased systolic blood pressure (SBP) in a dose-dependent manner in SHR, but had no effect on the SBP in WKY rats. 3. The vascular effect of sinomenine was then examined in aortic rings isolated from Wistar rats. Sinomenine (0.1-10 micromol/L) produced concentration dependent relaxation in aortic rings precontracted with phenylephrine (10 nmol/L) or KCl (40 mmol/L). Glibenclamide (1-100 micromol/L), a specific inhibitor of ATP sensitive K(+) channels attenuated the sinomenine-induced relaxation, but this effect was not observed when inhibitors of other types of K(+) channels were used. 4. We further investigated the effects of sinomenine on changes in intracellular Ca(2+) concentrations ([Ca(2+)](i)) in cultured aortic smooth muscle (A7r5) cells by using the Ca(2+)-sensitive dye fura-2 as an indicator. Sinomenine, over the concentration range 0.1-10 micromol/L, decreased the increases in [Ca(2+)](i) elicited by phenylephrine (1 micromol/L) or KCl (40 mmol/L) in a concentration-dependent manner. Glibenclamide (1-100 micromol/L) abolished the effects of sinomenine. 5. In conclusion, sinomenine causes vascular relaxation by opening ATP-sensitive K(+) channels, thus decreasing [Ca(2+)](i). PMID- 17714083 TI - Effect of angiotensin AT1 receptor antagonist on D-galactosamine-induced acute liver injury. AB - 1. Acute liver injury is a severe disease in which metabolic homeostasis is affected. The presence of liver cell death triggers a cascade of inflammatory responses leading to various degrees of liver damage. The pathophysiology of liver injury is complex, involving an interplay between parenchymal and non parenchymal cells. 2. There is increasing evidence for a role of the local renin angiotensin system (RAS) in liver cell death, inflammatory response and liver regeneration. It has been shown that the local RAS plays an important regulatory role in a variety of tissues. In experimental hepatic fibrogenesis, the angiotensin AT(1) receptor (AT(1)R) blocker losartan has been shown to be able to attenuate transforming growth factor-b1 activity and collagen gene expression. 3. In the present study, using a D-galactosamine (GalN)-induced liver failure rat, AT(1)R were localized around the centrilobular region, which was not evident in normal liver. Blood tests showed an elevation of total bilirubin and alanine aminotransferase. Furthermore, there was an increase in tissue-specific inhibitor of metalloproteinase (TIMP)-1 protein in the liver. Losartan treatment was able to reduce all these parameters. Levels of TIMP-1 protein were reduced by 1.5- and 1.56-fold on Days 1 and 3, respectively (both P < 0.05), in the losartan-treated group relative to the GalN-treated group. The survival rate of the losartan treated group was significantly higher than that of the GalN-treated group (5 day survival 85 vs 42.5%, respectively; P < 0.05). 4. In conclusion, the AT(1)R blocker losartan suppresses GalN-induced liver injury. This may indicate that AT(1)R blockers may have therapeutic potential in the treatment of acute liver injury. PMID- 17714084 TI - Simultaneous genotyping of CYP2D6*3, *4, *5 and *6 polymorphisms in a Spanish population through multiplex long polymerase chain reaction and minisequencing multiplex single base extension analysis. AB - 1. The aim of the present study was to perform a descriptive study of the prevalence of the four major CYP2D6 poor metaboliser (PM) alleles (*3, *4, *5 and *6) in a Spanish population (n = 290) using a method based on a new combination of multiplex long polymerase chain reaction (PCR) and minisequencing through multiplex single base extension (SBE) analysis. 2. The method was validated using different strategies, such as allelic discrimination assay and PCR-restriction fragment length polymorphism (RFLP). 3. The allele frequencies were similar to those described for other Spanish populations, namely 0.9% (95% confidence interval (CI) 0.5-1.3), 16.4% (95% CI 14.9-18.0), 2.7% (95% CI 2.0-3.4) and 0.7% (95% CI 0.3-1.0) for the *3, *4, *5 and *6 alleles, respectively. The results were satisfactory and left little doubt as to the genotypes, which were confirmed either by allelic discrimination assay (*4 and *6) or PCR-RFLP (*3) with 100% concordance. 4. The present study corroborates the low prevalence of the most frequent polymorphism (CYP2D6*4) that leads to null CYP2D6 activity in Spain and the allelic geographical gradient between Caucasian populations in the north and south. The present study reports a technique for the detection of four polymorphisms that account for 98% of the CYP2D6 defect alleles. This multiplex long PCR-SBE technique is a combination of several known methods to genotype CYP2D6 alleles (*3, *4, *5 and*6). Given the importance of CYP2D6 in drug metabolism and the need to genotype a large number of samples, we believe that this method will find broad application. PMID- 17714085 TI - 17Beta-oestradiol regulates the expression of Na+/K+-ATPase beta1-subunit, sarcoplasmic reticulum Ca2+-ATPase and carbonic anhydrase iv in H9C2 cells. AB - 1. It is necessary to improve our understanding of the effect of 17beta oestradiol (E2) on the heart at a molecular and cellular level. In the present study, the effects of E2 on Na(+)/K(+)-ATPase, sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA) and carbonic anhydrase IV (CAIV) in H9C2 cells were investigated. To identify the mechanism of action of E2 on these proteins, the oestrogen receptor (ER) antagonist tamoxifen was used. 2. The results indicated that 1 and 100 nmol/L E2 can enhance the activity of Na(+)/K(+)-ATPase and SERCA and upregulate the expression of the Na(+)/K(+)-ATPase beta1-subunit, SERCA2a and CAIV at both the mRNA and protein level compared with 0 and 0.01 nmol/L E2. 17beta-Oestradiol had the greatest effect at 100 nmol/L; 1 micromol/L E2 did not further protein expression compared with 100 nmol/L E2. 3. Tamoxifen (10 nmol/L) significantly decreased the activity of SERCA, as well as the expression of the Na(+)/K(+)-ATPase beta1-subunit and SERCA at the mRNA and protein level, in H9C2 cells cultured with 1 nmol/L E2. Tamoxifen alone had no significant effect on these proteins in H9C2 cells. 4. It may be hypothesized that a suitable E2 concentration has a protective effect on the heart and that the actual dose of E2 used in hormone-replacement therapy is important in menopausal women. PMID- 17714086 TI - Indices of vascular stiffness and wave reflection in relation to body mass index or body fat in healthy subjects. AB - 1. Obesity appears to influence vascular stiffness, an important cardiovascular risk factor. An accurate picture of arterial stiffness may be obtained when a combination of various techniques is used. 2. The purpose of the present study was to assess whether the body mass index (BMI) and body fat content obtained by bioimpedance were of equal value in estimating the influence of body fatness on various indices of vascular stiffness and wave reflection. 3. A total of 175 healthy subjects was studied. Anthropometric measurements and total body bio impedance analysis were performed to assess fat mass as a proportion of total body composition. Arterial stiffness and wave reflection were assessed using digital volume pulse analysis and tonometric measurement of the wave reflection indices and central haemodynamics. 4. Significant differences in the stiffness index (SI(DVP); P < 0.0001), peripheral augmentation index (pAI(x); P < 0.0001), central augmentation index (cAI(x); P < 0.0001), peripheral pulse pressure (pPP; P = 0.026) and central pulse pressure (cPP; P < 0.0001) were found when the population examined was divided accordingly to tertile of body fat content. However, subdividing various indices of arterial stiffness according to the tertile of BMI did not reveal any significant differences between groups, except for pPP and cPP. 5. Body fat content was significantly correlated with SI(DVP), pAI(x), cAI(x), pPP and cPP. The BMI correlated weakly with SI(DVP), pPP and cPP. 6. In conclusion, the BMI is not very useful in predicting changes in arterial stiffness and wave reflection due to obesity. However, stiffness and wave reflection indices derived from digital volume pulse analysis, the characteristics of radial and aortic pressure waveforms and peripheral and aortic pulse pressure are all related to body fat content, as estimated by bioimpedance. PMID- 17714087 TI - Anticonvulsant, but not antiepileptic, action of valproate on audiogenic seizures in metaphit-treated rats. AB - 1. The blocking effects of valproate (2-propylpentanoic acid), a standard anti epileptic drug, on metaphit (1-[1-(3-isothiocyanatophenyl)-cyclohexyl] piperidine)-induced audiogenic seizures as a model of generalized, reflex audiogenic epilepsy in adult Wistar male rats were studied. 2. Rats were stimulated using an electric bell (100 +/- 3 dB, 5-8 kHz, 60 s) 60 min after i.p. metaphit (10 mg/kg) injection and afterwards at hourly intervals. For power spectra and electroencephalograph (EEG) recordings, three gold-plated screws were implanted into the skull. Different doses of valproate (50, 75 and 100 mg/kg) were injected i.p. into rats with fully developed metaphit seizures after the eighth audiogenic testing. 3. In metaphit-treated animals, the EEG appeared as polyspikes, spike-wave complexes and sleep-like patterns, whereas the power spectra were increased compared with the corresponding controls. 4. Valproate reduced the incidence and intensity of convulsions and prolonged the duration of the latency period in a dose-dependent manner 4 h after administration. 5. The ED(50) of valproate in the first hour after injection was 63.19 mg/kg (95% confidence interval 51.37-77.71 mg/kg). 6. None of the doses of valproate applied eliminated the EEG signs of metaphit-provoked epileptiform activity. 7. Taken together, these results suggest that all doses of valproate examined acted to suppresse behavioural but not epileptic EEG spiking activity in metaphit-induced seizures. PMID- 17714088 TI - Role of macrophages in complications of type 2 diabetes. AB - 1. Macrophage accumulation is a feature of Type 2 diabetes and is associated with the development of diabetic complications (nephropathy, atherosclerosis, neuropathy and retinopathy). The present article reviews the current evidence that macrophages contribute to the complications of Type 2 diabetes. 2. Macrophage-depletion studies in rodent models have demonstrated a causal role for macrophages in the development of diabetic complications. 3. Components of the diabetic milieu (high glucose, advanced glycation end-products and oxidized low density lipoprotein) promote macrophage accumulation (via induction of chemokines and adhesion molecules) and macrophage activation within diabetic tissues. 4. Macrophages mediate diabetic injury through a variety of mechanisms, including production of reactive oxygen species, cytokines and proteases, which result in tissue damage leading to sclerosis. 5. A number of existing and experimental therapies can indirectly reduce macrophage-mediated injury in diabetic complications. The present article discusses the use of these therapies, given alone and in combination, in suppressing macrophage accumulation and activity. 6. In conclusion, current evidence supports a critical role for macrophages in the evolution of diabetic complications. Present therapies are limited in slowing the progression of macrophage-mediated injury. Novel strategies that are more specific at targeting macrophages may provide better protection against the development of Type 2 diabetic complications. PMID- 17714089 TI - Human heart beta-adrenoceptors: beta1-adrenoceptor diversification through 'affinity states' and polymorphism. AB - 1. In atrium and ventricle from failing and non-failing human hearts, activation of beta(1)- or beta(2)-adrenoceptors causes increases in contractile force, hastening of relaxation, protein kinase A-catalysed phosphorylation of proteins implicated in the hastening of relaxation, phospholamban, troponin I and C protein, consistent with coupling of both beta(1)- and beta(2)-adrenoceptors to stimulatory G(salpha)-protein but not inhibitory G(ialpha)-protein. 2. Two 'affinity states', namely beta(1H) and beta(1L), of the beta(1)-adrenoceptor exist. In human heart, noradrenaline elicits powerful increases in contractile force and hastening of relaxation. These effects are blocked with high affinity by beta-adenoceptor antagonists, including propranolol, (-)-pindolol, (-)-CGP 12177 and carvedilol. Some beta-blockers, typified by (-)-pindolol and (-)-CGP 12177, not only block the receptor, but also activate it, albeit at much higher concentrations (approximately 2 log units) than those required to antagonize the effects of catecholamines. In human heart, both (-)-CGP 12177 and (-)-pindolol increase contractile force and hasten relaxation. However, the involvement of the beta(1)-adrenoceptor was not immediately obvious because (-)-pindolol- and (-) CGP 12177-evoked responses were relatively resistant to blockade by (-) propranolol. Abrogation of cardiostimulant effects of (-)-CGP 12177 in beta(1) /beta(2)-adrenoceptor double-knockout mice, but not beta(2)-adrenoceptor-knockout mice, revealed an obligatory role of the beta(1)-adrenoceptor. On the basis of these results, two 'affinity states' have been designated, the beta(1H)- and beta(1L)-adrenoceptor, where the beta(1H)-adrenoceptor is activated by noradrenaline and blocked with high affinity by beta-blockers and the beta(1L) adrenoceptor is activated by drugs such as (-)-CGP 12177 and (-)-pindolol and blocked with low affinity by beta-blockers such as (-)-propranolol. The beta(1H)- and beta(1L)-adrenoceptor states are consistent with high- and low-affinity binding sites for (-)-[(3)H]-CGP 12177 radioligand binding found in cardiac muscle and recombinant beta(1)-adrenoceptors. 3. There are two common polymorphic locations of the beta(1)-adrenoceptor, at amino acids 49 (Ser/Gly) and 389 (Arg/Gly). Their existence has raised several questions, including their role in determining the effectiveness of heart failure treatment with beta-blockers. We have investigated the effect of long-term maximally tolerated carvedilol administration (> 1 year) on left ventricular ejection fraction (LVEF) in patients with non-ischaemic cardiomyopathy (mean left ventricular ejection fraction 23 +/- 7%; n = 135 patients). The administration of carvedilol improved LVEF to 37 +/- 13% (P < 0.005); however, the improvement was variable, with 32% of patients showing pound 5% improvement. Upon segregation of patients into Arg389Gly-beta(1)-adrenoceptors, it was found that carvedilol caused a greater increase in left ventricular ejection faction in patients carrying the Arg389 allele with Arg389Arg > Arg389Gly > Gly389Gly. PMID- 17714090 TI - Beta2-adrenoceptor polymorphisms and obstructive airway diseases: important issues of study design. AB - 1. Asthma and chronic obstructive pulmonary disease (COPD) are chronic airway diseases characterized by airflow obstruction. The beta(2)-adrenoceptor mediates bronchodilatation in response to exogenous and endogenous beta-adrenoceptor agonists. 2. Single nucleotide polymorphisms in the beta(2)-adrenoceptor gene (ADRB2) cause amino acid changes (e.g. Arg16Gly, Gln27Glu) that potentially alter receptor function. Recently, a large cohort study found no association between asthma susceptibility and beta(2)-adrenoceptor polymorphisms. In contrast, asthma phenotypes, such as asthma severity and bronchial hyperresponsiveness, have been associated with beta(2)-adrenoceptor polymorphisms. Of importance to asthma management, coding region polymorphisms may alter the response to short-acting and long-acting beta-adrenoceptor agonists, which are commonly prescribed asthma treatments. 3. Optimizing study design would enhance the robustness of genetic association studies of ADRB2 polymorphisms in airway diseases. Characteristics of high-quality studies include suitable study design and subject selection, optimal study of polymorphisms and haplotypes, disease outcomes of relevance, adequate sample size, adjustment for confounding factors, supportive functional data and appropriate analysis, interpretation and replication. Enhancing these study design factors will provide high-quality evidence regarding the biological and clinical importance of beta(2)-adrenoceptor pharmacogenomics in asthma and COPD. PMID- 17714091 TI - Effect of gender and sex hormones on vascular oxidative stress. AB - 1. It is well documented that the incidence and severity of several vascular diseases, such as hypertension, atherosclerosis and stroke, are lower in premenopausal women than men of similar age and post-menopausal women. The mechanisms responsible for gender differences in the incidence and severity of vascular disease are not well understood. However, emerging evidence suggests that sex hormone-dependent differences in vascular oxidative stress may play an important role. The aim of the present brief review is to provide an insight into the effect of gender and sex hormones on vascular oxidative stress. 2. When production of reactive oxygen species (ROS) is enhanced and/or their metabolism by anti-oxidant enzymes is impaired, a condition known as 'oxidative stress' can develop. Oxidative stress is believed to play an important role in both the initiation and progression of a variety of vascular diseases, including hypertension and atherosclerosis. NADPH oxidases are believed to be the major source of vascular ROS. Moreover, excessive production of ROS by NADPH oxidases has been linked to the development of vascular oxidative stress. 3. Increasing evidence suggests that levels of vascular ROS may be lower in women than men during health and disease. Indeed, the activity and expression of vascular NADPH oxidase is lower in female versus male animals under healthy, hypertensive and atherosclerotic conditions. 4. Gonadal sex hormones may play an important role in the regulation of vascular oxidative stress. For example, oestrogens, which are present in highest levels in premenopausal women, have been reported to lower vascular oxidative stress by modulating the expression and function of NADPH oxidases, as well as anti-oxidant enzymes. 5. Further studies are needed to clarify whether lower vascular oxidative stress in women in fact protects against the initiation and development of vascular disease and to further define the roles of gonadal sex hormones in such an effect. Knowledge gained from these studies may potentially lead to advances in the clinical diagnosis and treatment of vascular disease in both genders. PMID- 17714092 TI - Combustion-derived nanoparticles: mechanisms of pulmonary toxicity. AB - 1. The general term 'nanoparticle' (NP) is used to define any particle less than 100 nm in at least one dimension and NPs are generally classified as natural, anthropogenic or engineered in origin. Anthropogenic, also referred to as 'ultrafine' particles (UFPs), are predominately combustion derived and are characterized by having an equivalent spherical diameter less than 100 nm. 2. These particles, considered to be 'combustion-derived nanoparticles' (CDNPs), are of toxicological interest given their nanosized dimensions, with properties not displayed by their macroscopic counterparts. 3. The pulmonary deposition efficiency of inhaled UFPs, along with their large surface areas and bound transition metals, is considered important in driving the emerging health effects linked to respiratory toxicity. 4. The toxicology of CDNPs is currently used to predict the health outcomes in humans following exposure to manufactured NPs. Their similar physicochemistry would suggest similar adverse health effects (i.e. pulmonary (and perhaps cardiac) toxicity). As such, it is essential to fully understand CDNP nanotoxicology in order to minimize occupational and environmental exposure. PMID- 17714093 TI - Potentiation of 3,4-methylenedioxymethamphetamine-induced 5-HT release in the rat substantia nigra by clorgyline, a monoamine oxidase A inhibitor. AB - 1. It is well established that the commonly used recreational drugs 3,4 methylenedioxymethamphetamine (MDMA, 'ecstasy') and para-methoxyamphetamine (PMA) facilitate the release and prevent the reuptake of 5-hydroxytryptamine (5-HT, serotonin). Although these drugs have similar potencies for their abilities to increase the release and inhibit the re-uptake of 5-HT, PMA has greater potency as an inhibitor of monoamine oxidase (MAO)-A. 2. The present study compared the abilities of PMA and MDMA to increase extracellular 5-HT concentrations in animals with functional MAO-A and when MAO-A activity was inhibited by clorgyline. 3. Samples of extracellular fluid from rat substantia nigra were collected using microdialysis and then analysed for 5-HT and 5-hydroxyindol acetic acid (5-HIAA) by high-performance liquid chromatography coupled with electrochemical detection. The 5-HT-mediated effects on body temperature and behaviour were also recorded. Rats were pretreated with saline or 10 mg/kg, i.p., clorgyline and, 24 h later, injected with 10 mg/kg MDMA, PMA or saline. 4. Both MDMA and PMA produced significant increases in extracellular 5-HT concentrations (482 +/- 83 and 726 +/- 287%, respectively; P < 0.05). Rats treated with PMA and MDMA displayed significantly increased 5-HT-related behavours (P < 0.05). Furthermore, only MDMA was capable of producing additional significant increases in 5-HT concentrations (1033 +/- 131%; P < 0.01) when coadministered with clorgyline. 5. The results of the present study suggest that PMA and MDMA are similar in their abilities to increase extracellular 5-HT levels in animals with functional MAO-A activity. However, coadministration of these substituted amphetamines with an MAO-A inhibitor causes significant potentiation in the ability to increase extracellular levels of 5-HT for MDMA, but not PMA. PMID- 17714094 TI - Glutamate receptor plasticity at excitatory synapses in the brain. AB - 1. Synapse plasticity, defined as an activity dependent change in the strength of synapses, was first described in 1973 and, since those seminal experiments were reported, the field of synapse plasticity has expanded into one of the most widely studied areas in neuroscience. 2. Significant effort has been focused on determining the expression mechanisms of the changes in synapse strength. The present review will focus on the changes in the post-synaptic expression of glutamate receptors that have been shown to occur during the expression of synapse plasticity. 3. Biochemical studies of excitatory synapses in the central nervous system have revealed a high density of proteins concentrated at dendritic spines. These proteins appear to play critical roles in synaptic structure, plasticity and in trafficking receptors to synapses. 4. There is growing evidence that synapse plasticity could be the cellular basis of certain forms of learning and memory. Determining the behavioural correlates of this fundamental synaptic process will continue to be addressed in current and future research. PMID- 17714095 TI - Inhibitory interneurons in the piriform cortex. AB - 1. The piriform cortex (PC) is the largest subdivision of the olfactory cortex and the first cortical destination of olfactory information. Despite the relatively simple anatomy of the PC and its obvious appeal as a model system for the study of cortical sensory processing, there are many outstanding questions about its basic cell physiology. In the present article, we review what is known about GABAergic inhibitory interneurons in the PC. 2. The GABA-containing neurons in the PC are morphologically diverse, ranging from small neurogliaform cells to large multipolar forms. Some of these classes are distributed across all three main layers of the PC, whereas others have a more restricted laminar expression. 3. Distinct and overlapping populations of GABAergic basket cells in Layers II and III of the PC express different combinations of calcium-binding proteins and neuropeptides. Few Layer I interneurons express any of the molecular markers so far examined. 4. The intrinsic firing properties of one or two types of putative PC interneurons have been measured and inhibitory post-synaptic responses have been recorded in PC pyramidal cells following extracellular stimulation. However, little is known about the physiology of the subtypes of interneurons identified. 5. In view of the likely importance of PC interneurons in olfactory learning, olfactory coding and epileptogenesis, further investigation of their properties is likely to be highly informative. PMID- 17714096 TI - Does spike timing-dependent synaptic plasticity underlie memory formation? AB - 1. Synaptic plasticity is thought to underlie learning and memory formation in the brain. However, how synaptic plasticity is induced during these processes remains controversial. An attractive candidate mechanism for learning at the neuronal level is spike timing-dependent synaptic plasticity (STDP), which depends on the precise (msec) timing of the synaptic input and the post-synaptic action potential. This temporal relationship resembles typical features of associative learning. Here, we review recent evidence suggesting that STDP is likely to underlie certain forms of learning. 2. First, we discuss the cellular mechanisms of STDP elucidated by in vitro experiments. A special focus is put onto aspects known to differ between in vitro preparations and the in vivo situation. 3. Second, we review the experimental induction of STDP in vivo, in various systems ranging from Xenopus tectum to human motor cortex. 4. The last part of the review addresses the question whether STDP can be induced by activity patterns occurring during normal behaviour. 5. We conclude that STDP is a robust phenomenon in vivo and a likely mechanism underlying sensory map plasticity in the neocortex. Further experimental evidence is required to determine whether STDP also has a role in more complex forms of learning. PMID- 17714097 TI - Functions of SK channels in central neurons. AB - 1. SK channels are small-conductance calcium-activated potassium channels that are widely expressed in neurons. The traditional view of the functional role of SK channels is in mediating one component of the after-hyperpolarization that follows action potentials. Calcium influx via voltage-gated calcium channels active during action potentials opens SK channels and the resultant hyperpolarization lowers the firing frequency of action potentials in many neurons. 2. Recent advances have shown that, in addition to controlling action potential firing frequency, SK channels are also important in regulating dendritic excitability, synaptic transmission and synaptic plasticity. 3. In accordance with their role in modulating synaptic plasticity, SK channels are also important in regulating several learning and memory tasks and may also play a role in a number of neurological disorders. 4. The present review discusses recent findings on the role of SK channels in central neurons. PMID- 17714098 TI - Intracellular calcium in the fertilization and development of mammalian eggs. AB - 1. Mammalian eggs are arrested at metaphase of their second meiotic division when ovulated and remain arrested until fertilized. The sperm delivers into the egg phospholipase C (PLC) zeta, which triggers a series of Ca(2+) spikes lasting several hours. The Ca(2+) spikes provide the necessary and sufficient trigger for all the events of fertilization, including exit from metaphase II arrest and extrusion of cortical granules that block the entry of other sperm. 2. The oscillatory Ca(2+) signal switches on calmodulin-dependent protein kinase II (CaMKII), which phosphorylates the egg-specific protein Emi2, earmarking it for degradation. To remain metaphase II arrested, eggs must maintain high levels of maturation-promoting factor (MPF) activity, a heterodimer of CDK1 and cyclin B1. Emi2 prevents loss of MPF by blocking cyclin B1 degradation, a process that is achieved by inhibiting the activity of the anaphase-promoting complex/cyclosome. However, CaMKII is not the primary initiator in the extrusion of cortical granules. 3. Ca(2+) spiking is also observed in mitosis of one-cell embryos, probably because PLCzeta contains a nuclear localization signal and so is released into the cytoplasm following nuclear envelope breakdown. The function of these mitotic Ca(2+) spikes remains obscure, although they are not absolutely required for passage through mitosis. 4. Intriguingly, the pattern of Ca(2+) spikes observed at fertilization has an effect on both pre- and postimplantation development in a manner that is independent of their ability to activate eggs. This suggests that the Ca(2+) spikes set in train at fertilization are having effects on processes initiated in the newly fertilized egg but whose influences are only observed several cell divisions later. The nature of the signals remains little explored, but their importance is clear and so warrants further investigation. PMID- 17714099 TI - Evidence-based medicine: our responsibility to our patients. PMID- 17714100 TI - Clinical research in interventional pain management techniques: the clinician's point of view. AB - Interventional pain management techniques are considered for patients whose pain proves refractory to conventional treatment. According to the evidence-based medicine (EBM) guidelines, the highest level of evidence for efficacy and safety of a treatment is generated in high-quality randomized controlled trials and systematic reviews. A randomized controlled trial is defined as an experiment that determines the influence of an intervention on the natural history of the disease, which means that the comparative group should receive placebo, which is a sham intervention in case of the interventional pain management techniques. The systematic review summarizes in a structured way the results of the available information. When randomized controlled trials are available, observational studies will often be discarded. As new information on a treatment becomes available the perceived value may change, thus determining the survival time of clinical evidence. This survival time is not different when based on randomized or nonrandomized studies. The inclusion criteria are an important component of the randomized controlled trial and are designed to test a treatment in a homogeneous patient population. As interventional pain management techniques are mainly used for the management of spinal pain, it needs to be stressed that there is no gold standard for the diagnosis. This lack of validated standard diagnostic procedures is at the origin of different patient selection criteria, which makes the interpretation of the different randomized controlled trials and the meta analyses very difficult. Moreover, the extrapolation of randomized controlled trials with carefully selected patient populations to daily practice is a major problem. Randomized controlled trials in interventional pain management techniques often prove to be underpowered, which can be attributed to the difficulty in motivating patients and the referring physicians to participate in a trial where there is 50% chance of receiving a placebo/sham for intractable pain. Furthermore, the validity of sham intervention as a reflection of the natural course of the disease is questioned. It is stated that any new technique should prove to be at least equally effective as the best available treatment option, which offers the possibility of comparing two groups, both receiving active treatment. The reference treatment may be pharmacological or a rehabilitation program (cognitive behavioral) in which case blinding becomes a problem. It has been demonstrated that large observational studies with a cohort or case-control design do not systematically overestimate the magnitude of the associations between exposure and outcome as compared with the results of randomized controlled trials. There is an urgent need for guidelines on performing prospective cohort trials that should be designed to confirm or refute the anecdotal findings from retrospective studies. PMID- 17714101 TI - Diagram of reliability and net gain: a new method for summarizing and displaying the results of controlled trials. AB - BACKGROUND: Sound evidence-based clinical and policy therapy recommendations depend on a process of acquiring literature, appraising it for study design and quality, and assessing its results in terms of relative benefits and harms. In this article we describe two summary metrics that have been developed to assist guideline developers to assess the importance of the quality/size of trials and the relative benefit and harm of treatments, and a related graphical method for displaying them together. METHODS: To illustrate this graphic approach, we have used the evidence base for drug therapies for neuropathic pain. "Reliability" is calculated from the sample size and quality of trials, while the second metric, "Net Gain," is calculated from the relative benefit and harm of each trial. RESULTS: The graphical method differentiated the evidence for neuropathic pain drugs. CONCLUSIONS: This graphical output provides a simple and relatively easy way to understand summary of information on large amounts of trial data across a number of therapies, which may present an impression of the evidence at a glance even for a non-expert. The usefulness of this graphical approach needs to be tested in the development of future clinical guidelines. PMID- 17714102 TI - Self-efficacy beliefs predict sustained long-term sick absenteeism in individuals with chronic musculoskeletal pain. AB - Recovery beliefs are assumed to predict rehabilitation outcomes and return-to work in various clinical conditions but are less frequently assessed in musculoskeletal disorders. We tested the hypothesis that recovery beliefs constitute a risk factor for sustained long-term sick absenteeism in men and women suffering from nonspecific chronic musculoskeletal disorders. A total of 233 subjects with a recent or ongoing experience of long-term sick leave were included in a prospective design. Subjects answered a postal baseline questionnaire and were followed up via register data for 1 year. Multivariate logistic regression analyses indicated that subjects with negative recovery beliefs (OR: 2.41; CI: 1.22-4.77), low sense of mastery (OR: 2.08; CI: 1.27 3.40), perceived high mental demands at work (OR: 1.77; CI: 1.05-2.99), and prior experiences of long-term sick absenteeism (OR: 1.86; CI: 1.02-3.37) had an increased probability of receiving sickness benefits at follow-up. We conclude that prolonged sickness absence contributes strongly to increase patients' sense of helplessness, lower self-efficacy, and hinder future work return. To improve work return, patients' maladaptive beliefs should be clarified and challenged early in the rehabilitation process. PMID- 17714103 TI - Cognitive dysfunction and depression may decrease activities in daily life more strongly than pain in community-dwelling elderly adults living with persistent pain. AB - BACKGROUND AND OBJECTIVES: Chronic pain, dementia, and depression may reduce activities of daily life in elderly people. We evaluated the correlation between pain intensity and daily activities, cognitive state, and depression, as well as their interrelationships in home-dwelling elderly people with chronic pain. METHODS: Forty-one elderly home-dwelling people who suffered from long-lasting pain, and who participated in a rehabilitation program, were enrolled. Severity of pain at rest and after pain-provoked motion was assessed on a visual analog scale (VAS, 0 to 100) and a 5-point verbal rating scale (VRS). Cognitive status was assessed with the mini-mental state examination (MMSE, 0 to 30), depression on the geriatric depression scale (GDS, 0 to 15), and functional ability in daily life was assessed with the Barthel Index (0 to 100). RESULTS: VAS and VRS scores correlated positively with each other. Rating pain at rest on the VRS (mean 1.0, median 1) correlated with severity of depression (GDS mean 5.4) (r = 0.3997, P < 0.01), while scores on the VAS did not. Pain ratings at rest did not correlate with the Barthel Index (mean 87.7), but the latter correlated positively with motion-evoked VRS pain scores (mean 2.8, median 3) (r = 0.42829, P < 0.01). The MMSE (mean 25.3) did not correlate with any pain parameter, but it correlated positively with the Barthel Index (r = 0.3660, P < 0.05). The Barthel Index correlated negatively with the GDS (r = -0.39969, P < 0.01). CONCLUSION: In home dwelling elderly people, chronic pain states do not seem to reduce daily activities as much as cognitive dysfunction and depression. The seemingly controversial finding of a positive correlation between daily activities and pain in motion, and lack of correlation with pain at rest, may be explained by a relatively low intensity of pain in our study people. PMID- 17714104 TI - Prospective, randomized, single-blind, sham treatment-controlled study of the safety and efficacy of an electromagnetic field device for the treatment of chronic low back pain: a pilot study. AB - OBJECTIVES: To evaluate the efficacy and safety of therapeutic electromagnetic fields (TEMF) on chronic low back pain. Secondary objectives included the investigation of the effects of TEMF on psychometric measures. SETTING: Pain Research center in an Urban Academic Rehabilitation Facility. DESIGN: Prospective, randomized, single-blind, placebo (sham) treatment-controlled design in which participants were evaluated over a 6-week period. A total of 40 subjects were randomly assigned: 20 subjects to 15 milliTESLA (mT) treatment using a prototype electromagnetic field device and 20 to sham treatment. INTERVENTIONS: After a 2-week baseline period, eligible individuals were randomized to one of the treatment groups (sham or 15 mT) for six 30-minute treatments over 2 weeks, then a 2-week follow-up period. OUTCOME MEASURES: The primary outcome measure was the self-report of pain severity using a 100 mm visual analog scale collected using a twice daily McGill Pain Questionnaire-Short Form. Several secondary measures were assessed. RESULTS: Both groups (15 mT and sham) improved over time (P < 0.05). Although groups were similar during the treatment period, treated subjects (TEMF of 15 mT) improved significantly over sham treatment during the 2 week follow-up period (20.5% reduction in pain; F(1,34) = 10.62, P = 0.003). There were no reported serious adverse events. CONCLUSIONS: This study demonstrates that TEMF may be an effective and safe modality for the treatment of chronic low back pain disorders. More studies are needed to test this hypothesis. PMID- 17714105 TI - The short-term effects of acupuncture on myofascial pain patients after clenching. AB - AIM: Short-term pain reduction from acupuncture in chronic myofascial pain subjects was evaluated using an 11-point (0 to 10) numeric rating scale, visual analog scale (VAS), and pain rating of mechanical pressure on the masseter muscle. METHODS: A single-blind, randomized, controlled, clinical trial with an independent observer was performed. Fifteen chronic myofascial pain subjects over the age of 18 were randomly assigned into groups: nine subjects received real acupuncture; six subjects received sham acupuncture. Each subject clenched his/her teeth for 2 minutes. Acupuncture or sham acupuncture was administered at the Hegu Large Intestine 4 acupoint. Sham acupuncture was conducted by lightly pricking the skin with a shortened, blunted acupuncture needle through a foam pad, without penetrating the skin. The foam pad visually conceals the needle's point of the entry, so that the subject cannot discern which technique is being used. The subjects rated their general pain on a numeric rating scale. A mechanical pain stimulus was applied with an algometer and the subject rated his/her pain on a VAS. Statistical analysis was performed using the repeated measures anova, paired t-tests, and Fisher's exact test as appropriate. RESULTS: There was a statistically significant difference in pain tolerance with acupuncture (P = 0.027). There was statistically significant reduction in face pain (P = 0.003), neck pain (P = 0.011), and headache (P = 0.015) with perception of real acupuncture. CONCLUSION: Pain tolerance in the masticatory muscles increased significantly more with acupuncture than sham acupuncture. PMID- 17714106 TI - Nonmalignant chronic pain evaluation in the Turkish population as measured by the McGill Pain Questionnaire. AB - BACKGROUND: The purpose of this study was to explore how Turkish nonmalignant pain patients described their pain and how the language of pain used by Turkish patients compares to the language found in common pain assessment tools. OBJECTIVE: Pain is influenced by a combination of ethnic, cultural, psychological, and social variants. In the Turkish language, six words are central to pain-like experiences: agri (pain), aci (suffering), sizi (aching), sanci (colic), istirap (agony), and dert (torture). We assessed discriminant characteristics of the Turkish translation of the McGill Pain Questionnaire (MPQ). METHODS: Chronic clinical nonmalignant pain patients (n = 319, 35.7% males, 64.3% females) were questioned with the Turkish translation of the MPQ. Pain symptoms were categorized as headache (33.5%), musculoskeletal pain (33.2%), visceral pain (18.8%), and low back pain (14.5%). RESULTS: The visceral pain group had the highest mean value in the evaluative subscale (2.6 +/- 1.9). Descriptions used for sensory subscale included throbbing, sharp, aching, and tingling, while affective subscale words included tiring, suffocating, sickening, cruel, and wretched. In all pain groups, frequently chosen words for the miscellaneous subscale were nagging and penetrating. CONCLUSION: Pain descriptors were identified for each type of pain. This is, to our knowledge, the first assessment of the Turkish translation of the MPQ in nonmalignant pain patients. PMID- 17714107 TI - An integrative approach for treating postherpetic neuralgia--a case report. AB - This report describes the successful treatment of a patient with postherpetic neuralgia using traditional pharmacology in combination with acupuncture. CASE REPORT: A 13-year-old girl developed postherpetic neuralgia following a severe attack of varicella zoster. Despite a 1-week course of intravenous acyclovir initiated at the onset of symptoms, the patient developed persistent left facial pain and constant nausea after lesions were healed. A comprehensive pain treatment regimen, consisting of a stellate ganglia block, medications, transcutaneous electrical nerve stimulation and hypnosis, was administered, but the patient did not gain any incremental pain relief. The acupuncture service was consulted to provide assistance with this patient's pain management. A combination of body and auricular acupuncture as well as related techniques, including acupressure and transcutaneous acupoint electrical stimulation, was added to the pain treatment regimen. After 10 complementary acupuncture treatments over a 2-month period, the patient's nausea disappeared. Her left facial pain continued to decline from a maximum of 10 to 0 as assessed by a visual analog scale over a period of 4 months following self-administered treatments of acupressure and transcutaneous acupoint electrical stimulation. The patient was then gradually weaned off all her medications and the complementary acupuncture treatment. She was discharged from the pediatric pain clinic after 5 months of the combined therapy. CONCLUSIONS: Acupuncture and its related techniques may be an effective adjunctive treatment for symptoms associated with postherpetic neuralgia and deserve further study. PMID- 17714108 TI - Introduction of infection control measures to reduce infection associated with implantable pain therapy devices. AB - INTRODUCTION: Implantable pain therapy devices for chronic pain include spinal cord stimulators (SCS) and intrathecal drug delivery systems (IDDS). A number of different complications can occur after implantation of these devices, but among the most serious is infection. Based on Centers for Disease Control and Prevention guidelines for prevention of surgical site infection, published literature on infection risk with implantable pain therapy devices, and recommendations from groups within our own our institution, we introduced infection control measures for all patients receiving either SCS or IDDS. METHODS: After approval from the Institutional Review Board, we performed a retrospective review of patients undergoing primary implantation of SCS or IDDS before and after introduction at our institution of safety measures designed to reduce device-related infection. We compared infection incidence and compliance to infection precautions before and after introduction of these measures. RESULTS: Thirty-four SCS or IDDS were implanted before implementation of the infection control measures and 58 were placed after. Five device-related infections occurred. Adherence to most infection precautions improved during the study period, but 100% compliance was seen only with venue used for implantation. Infection incidence declined after introduction of the safety measures, but the reduction was not statistically significant. CONCLUSIONS: Introduction of infection control measures for implantable pain therapy devices improved adherence to most infection precautions in our practice. Lack of specific documentation could have hindered practice surveillance within our group. A tool to document performance of infection control measures would be useful not only as a marker of compliance but could also serve as a reminder to perform certain safety measures. PMID- 17714109 TI - Intradiscal intravasation of contrast during a transforaminal epidural injection. PMID- 17714110 TI - Open breast biopsy under local anesthesia: a well-tolerated method. PMID- 17714112 TI - Duloxetine status. PMID- 17714113 TI - Diabetic peripheral neuropathic pain: recognition and management. AB - The occurrence of diabetic peripheral neuropathy (DPN) is linked to poor glycemic control over time. While most people never develop diabetic peripheral neuropathic pain (DPNP) as a consequence of DPN, enough of them do that we must have effective options for the management of this disabling condition. Two years ago there were no formally approved medications for the treatment of DPNP, and now there are two medications with Food and Drug Administration approval for DPNP. One of these medications, duloxetine has been established to significantly improve pain and to address depression by its reuptake inhibition of norepinephrine and serotonin. This article examines the epidemiology of DPNP, its underlying pathogenesis, necessary evaluation methods, and treatment options available with a focus on the role of duloxetine. PMID- 17714114 TI - Assessing the impact of pharmacologic intervention on the quality of life in diabetic peripheral neuropathic pain and fibromyalgia. AB - Chronic, neuropathic pain may be secondary to myriad etiologies including diabetic peripheral neuropathy and fibromyalgia. It is a debilitating condition that imposes a significant burden on individuals and society alike. This article will review various instruments designed to assess quality of life (QoL) and key data assessing QoL of patients suffering from these diseases as well as currently available pharmacologic agents for symptomatic management. As basic and clinical science progress over the next few years, along with the introduction of novel pharmacologic agents, we anticipate greater potential for pain intervention and improvement in the quality of life of our patients. PMID- 17714115 TI - Safety profile of treatment in diabetic peripheral neuropathic pain. AB - New treatment options for diabetic peripheral neuropathic pain (DPNP) have recently been developed, including two Food and Drug Administration (FDA) approved agents, duloxetine and pregabalin. As clinicians face a broader spectrum of efficacious treatments, side-effect profiles play an increasingly important role in the development of a pain management regimen. In this article we review the safety profile of agents commonly used in the treatment of DPNP. PMID- 17714116 TI - Epidemiology, public health burden, and treatment of diabetic peripheral neuropathic pain: a review. AB - OBJECTIVE: The literature examining the epidemiology, quality of life burden, cost, and treatment of diabetic peripheral neuropathy pain (DPNP) in U.S. adults was reviewed. DESIGN: A comprehensive computerized literature review of DPNP was conducted using MEDLINE and other databases, which were searched from 1995 through August 2004 using the Medical Subject Headings diabetic neuropathies and pain combined with relevant terms. A supplementary MEDLINE search of clinical trials of pharmacological treatments for DPNP was conducted through July 2005. RESULTS: The search resulted in 321 articles. Several epidemiological studies assessed diabetic peripheral neuropathy among patients with diabetes and reported prevalence rates of 26-47%. No estimates of DPNP prevalence were reported, although one study (N = 2,405) reported that 26.8% of participants with diabetes experienced either pain or tingling. Randomized clinical trials have been conducted of several medications and classes of medication in patients with DPNP, and the U.S. Food and Drug Administration has approved two drugs for DPNP. Several published studies reported that DPNP impairs quality of life. Estimates of the costs of DPNP in the United States were limited. One study estimated average annual pain medication costs of $1,004 per DPNP patient. CONCLUSIONS: This review of DPNP identifies gaps in the literature and highlights the need for further study. The establishment of a consistent definition and diagnostic code for DPNP would improve ability to collect data and understand the impact of DPNP on patients and the health care system. Well-designed, prospective studies are needed to better define the epidemiology and public health burden of DPNP. PMID- 17714117 TI - Duloxetine and other antidepressants in the treatment of patients with fibromyalgia. AB - OBJECTIVE: To review the use of duloxetine, a new selective serotonin and norepinephrine reuptake inhibitor (SNRI), and other antidepressants in the treatment of patients with fibromyalgia. DESIGN: Two randomized, placebo controlled, double-blind, parallel-group, 12-week trials of duloxetine in the treatment of fibromyalgia were reviewed. Other published, randomized, placebo controlled, double-blind trials, and meta-analyses of antidepressant treatment of fibromyalgia were identified by a PubMed search that was augmented by reference cross-check. RESULTS: Duloxetine has been shown to be an effective and safe treatment for many of the symptoms associated with fibromyalgia, particularly for women. Other selective SNRIs also show promise in the treatment of fibromyalgia. Until recently, tricyclic agents that have serotonin and norepinephrine reuptake inhibitory activity had been the most commonly studied group of antidepressants, and they are effective in treating pain and other symptoms associated with fibromyalgia, although their use may be limited by safety and tolerability concerns. There are few randomized, controlled studies of selective serotonin reuptake inhibitors in fibromyalgia, and the results have been mixed. CONCLUSIONS: Antidepressants play an important role in the treatment of patients with fibromyalgia. Agents with dual effects on serotonin and norepinephrine appear to have more consistent benefits than selective serotonin antidepressants for the treatment of persistent pain associated with fibromyalgia. PMID- 17714118 TI - Painful physical symptoms in depression: a clinical challenge. AB - Painful physical symptoms are common elements within mood disorders and provide a therapeutic challenge when such patients attribute their pain to causes other than the mood disorder. These somatic presentations may lead to under-diagnosis and inappropriate treatment of patients with mood disorders. Antidepressant agents that inhibit both serotonin and norepinephrine reuptake effectively remit mood disorders, thereby providing relief of painful physical symptoms often associated with these disorders. They may also provide analgesia for neuropathic pain, such as that caused by diabetic neuropathy, which are associated with mood disorders. Newer generation dual acting antidepressants such as duloxetine and venlafaxine offer a well-tolerated and safe alternative to tricyclics. Concurrent with medication and management, the physician must educate the patient about the nature of both depressed mood and painful physical states that are augmented by and inherent in the depressive disorders. This mini review addresses the problems inherent to the treatment of painful physical symptoms in depression. PMID- 17714119 TI - Effective treatment for dermatophytoses of the foot: effect on restoration of depressed cell-mediated immunity. AB - Superficial infections caused by dermatophyte fungi are highly prevalent throughout the world. Modern antimycotic agents like the azole itraconazole or the synthetic allylamine terbinafine greatly improved treatment outcomes in comparison with former therapeutic options with griseofulvin or older azole preparations like ketoconazole or fluconazole. In randomized trials involving patients with dermotophytoses, a great effectiveness has been shown especially for terbinafine. Oral terbinafine in general is well tolerated, has a low potential for drug interactions and, therefore, may be the most often used therapeutic agent for dermatophyte onychomycosis. However, there is a group of patients suffering from chronic dermatophytoses or early reinfections after antifungal therapy. For these patients, a depression of the delayed-type hypersensitivity reactivity was postulated. Just recently, effective antimycotic treatment, in particular with terbinafine, was shown to enhance and restore cell mediated immunity, which potentially improves the therapeutic outcome even for this group of patients. PMID- 17714120 TI - Practical aspects of management of recurrent aphthous stomatitis. AB - Treatment of recurrent aphthous stomatitis (RAS) remains, to date, empirical and non-specific. The main goals of therapy are to minimize pain and functional disabilities as well as decrease inflammatory reactions and frequency of recurrences. Locally, symptomatically acting modalities are the standard treatment in simple cases of RAS. Examples include topical anaesthetics and analgesics, antiseptic and anti-phlogistic preparations, topical steroids as cream, paste or lotions, antacids like sucralfate, chemically stable tetracycline suspension, medicated toothpaste containing the enzymes amyloglucosidase and glucoseoxidase in addition to the well-known silver nitrate application. Dietary management supports the treatment. In more severe cases, topical therapies are again very useful in decreasing the healing time but fail to decrease the interval between attacks. Systemic immunomodulatory agents, like colchicine, pentoxifylline, prednisolone, dapsone, levamisol, thalidomide, azathioprine, methotrexate, cyclosporin A, interferon alpha and tumour necrosis factor (TNF) antagonists, are helpful in resistant cases of major RAS or aphthosis with systemic involvement. PMID- 17714121 TI - A pragmatic randomized controlled trial on the effectiveness of low concentrated saline spa water baths followed by ultraviolet B (UVB) compared to UVB only in moderate to severe psoriasis. AB - OBJECTIVE: To evaluate whether low concentrated saline spa water baths followed by ultraviolet B (LC-SSW-UVB) are superior to UVB alone in moderate to severe psoriasis. BACKGROUND: There is a lack of sufficiently large randomized controlled clinical trial evaluating the additional benefit of saltwater baths followed by UVB compared to UVB only in psoriasis. STUDY DESIGN: Partly evaluator blind, multicentre, pragmatic, randomized controlled trial. SETTING: Five German spa centres. SUBJECTS: One hundred and forty-three adults with stable psoriasis during the last month and a Psoriasis Area and Severity Index (PASI) of > 10 and/or an affected body surface area of > 15%. INTERVENTIONS: LC-SSW-UVB or UVB thrice a week until remission (PASI < 5) or for a maximum of 6 weeks. Sodium chloride concentrations of natural springs varied between 4.5% and 12%. Conventional UVB (broadband UVB or selective UVB phototherapy) was used as irradiation source. MAIN OUTCOME: Reduction of PASI and/or affected body surface area of 50% at the end of the intervention period (PASI-50). Only participants receiving at least one intervention were included in the primary analysis. RESULTS: Patients allocated to LC-SSP-UVB attained a statistically significantly higher rate of PASI-50 at the end of the intervention period than patients allocated to UVB [58/79 (73%) vs. 32/64 (50%); P = 0.01; NNT, 4.3, 95% CI, 2.4 18.1]. Benefit persisted until 3 months only for one of two secondary outcomes considered. CONCLUSIONS: In routine clinical practice balneophototherapy using conventional UVB is superior to conventional UVB only at the end of a 6-week treatment course. PMID- 17714122 TI - Oral R115866 in the treatment of moderate to severe plaque-type psoriasis. AB - BACKGROUND: R115866 (Rambazole) is a new generation all-trans retinoic acid metabolism blocking agent, highly specific against the retinoic acid 4 hydroxylase. The drug alleviates hyperproliferation and normalizes differentiation of the epidermis in animal models of psoriasis. OBJECTIVE: To explore the efficacy, safety and tolerability of systemic R115866 in patients with moderate to severe plaque-type psoriasis. PATIENTS AND METHODS: In this open label, single-arm trial, patients were treated with R115866, 1 mg/day for 8 weeks, followed by a 2-week treatment-free follow-up period. Patients were monitored for efficacy and safety. RESULTS: Nineteen patients (intent-to-treat population) were treated and 14 completed the entire study. Two patients discontinued due to lack of efficacy and three due to adverse events. At the end of the treatment, 26% of the patients showed at least 50% reduction in Psoriasis Area Severity Index (PASI) compared to baseline. Further improvement was observed at the end of the 2-week follow-up period where 47% of the patients showed a 50% or greater reduction in PASI. Kinetic data showed no evidence of accumulation of either R115866 or retinoic acid in plasma. The most common adverse events were pruritus, xerosis, cheilitis and an increase in blood triglycerides. The majority of adverse events were mild to moderate. No deaths or serious adverse events were reported. CONCLUSION: Eight-week daily treatment with 1 mg R115866 resulted in a significant reduction in PASI from baseline to end of therapy. Additional improvement was seen after the 2-week follow-up period. The drug was well tolerated. R115866 merits further evaluation to optimize its clinical efficacy and safety profile in moderate to severe plaque-type psoriasis. PMID- 17714123 TI - High serum levels of antibodies against the recombinant 70 kDa ribonucleoprotein are useful for diagnosing mixed connective tissue disease. AB - BACKGROUND: Anti-Sm antibodies and anti-RNP antibodies are considered to be diagnostic markers of systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). However, cross-reactivity between the antibodies diminishes their discriminating specificity between these diagnoses. OBJECTIVE: We examined whether we could achieve better differentiation between these two disease entities using recombinant antigens to RNP70 and SmD and quantitative immunoassays. PATIENTS/METHODS: Sera from 51 patients with SLE and 10 patients with MCTD and from a control group of 59 patients were used in a cross-sectional setting. Semiquantitative ELISAs for the detection of antibodies to RNP-70, RNP A, RNP-C, SmBB' and SmD were used and the results were compared to conventional ELISA tests using U(1)-snRNP and a mixture of SmBB' and SmD as antigenic substrates. RESULTS: Sera from MCTD patients showed higher levels of anti-RNP-70 antibodies than sera from SLE patients. Levels of anti-SmBB' or anti-SmD antibodies were not significantly different between SLE and MCTD sera. However, the presence of antibodies directed against SmD was more frequent in SLE. CONCLUSIONS: Our results suggest that the use of RNP-70 and SmD antigens may increase the practical value of immunoassays used to confirm a diagnosis of SLE or MCTD in patients with connective tissue disease. PMID- 17714124 TI - Human papillomavirus (HPV) viral load and HPV type in the clinical outcome of HIV positive patients treated with imiquimod for anogenital warts and anal intraepithelial neoplasia. AB - OBJECTIVE: To evaluate the efficacy of 5% imiquimod in HIV-positive male patients with anogenital warts or anal intraepithelial neoplasia (AIN), and to elucidate whether human papillomavirus (HPV) type and viral load were important for clinical outcome and recurrences. METHODS: Thirty-seven patients with histologically proven anogenital warts or AIN were enrolled. Topical 5% imiquimod was applied three times per week for more than 8 h overnight for 16 weeks, although patients were allowed to continue therapy for 4 more weeks if they did not have complete clearance of lesions. RESULTS: Mean age was 34 years. The perianal area was the main lesion location. Thirty-three patients had CD4 counts of < 500 cells/mm(3). Eighteen patients had a histopathological diagnosis of AIN 1. Main HPV types detected corresponded to low-risk HPV types. At 20 weeks of therapy, 46% patients achieved total clearance whereas 14 patients had > 50% clearance. Recurrence was observed in 5 of 17 patients who cleared. Clearance was not influenced by patients' CD4 counts, wart location, HIV viral load or HPV viral load. CONCLUSIONS: The assumption that visible perianal warts are benign lesions in HIV-positive patients has to be reevaluated since an important number of such lesions could correspond to low-grade anal disease, which in turn could progress to high-grade anal disease or cancer. In addition, our results in this preliminary study indicate that imiquimod appears to be effective in treating AIN in HIV-positive patients. Further studies are needed to document its utility to prevent high-grade dysplasia and/or anal cancer. PMID- 17714125 TI - Screening for asymptomatic carriage of Trichophyton tonsurans in household contacts of patients with tinea capitis: results of 209 patients from South London. AB - BACKGROUND: There is currently an epidemic of tinea capitis in urban areas of developed countries caused by Trichophyton tonsurans. Recurrence or re-infection with dermatophyte is not uncommon after adequate oral treatment. Asymptomatic carriers who are household contacts may partly explain this observation by forming a reservoir for infection. PATIENTS/METHODS: Two-hundred and nine household contacts of patients with tinea capitis were examined and screened for asymptomatic carriage of dermatophyte. RESULTS: Only 7.2% had clinically evident disease yet 44.5% had silent fungal carriage on the scalp. Children under 16 years were much more likely to be carriers than adults (P < 0.001) and males were less likely than females to be affected (P < 0.01). CONCLUSION: This evidence poses questions about factors relevant in transmission of dermatophytes. The authors propose that all household contacts of patients with tinea capitis should be offered screening to eradicate a potential reservoir of infection. PMID- 17714126 TI - Cheilitis granulomatosa and Melkersson-Rosenthal syndrome: evaluation of gastrointestinal involvement and therapeutic regimens in a series of 14 patients. AB - BACKGROUND: Cheilitis granulomatosa and Melkersson-Rosenthal syndrome are both rare and benign diseases. Because of their granulomatous character, a relationship to Crohn's disease has been suggested. Furthermore, because of their unknown aetiology, treatment is difficult, and evaluation of response is hampered by the natural tendency to spontaneous resolution and recurrence. OBJECTIVES AND METHODS: To evaluate gastrointestinal involvement by clinical history, conventional endoscopy, and capsule endoscopy as well as to compare efficacy of treatment modalities on a series of 14 patients, one of the biggest collectives reported. RESULTS: Four patients (4 of 14) were previously, simultaneously, or subsequently diagnosed with Crohn's disease. In six patients (6 of 14) with minor gastrointestinal symptoms as flatulence, occasional constipation, diarrhoea, or admixture of mucus with the stool, we could not detect any signs of inflammatory bowel disease by capsule endoscopy. Nine patients received clofazimine, and eight patients responded to treatment (four complete responses, four partial responses). Two patients were successfully treated with infliximab. Systemic methylprednisone was not successful in two patients. CONCLUSION: Close to 30% of patients showed an association of cheilitis granulomatosa and Crohn's disease. Forty-three per cent of patients reported minor gastrointestinal irregularities without any detectable changes of Crohn's disease. Clofazimine seems to be an effective treatment, although long-term application is necessary with frequent aggravation in the beginning. Infliximab, an effective drug in Crohn's disease, could be a promising treatment option for severe cases. PMID- 17714127 TI - Reliability testing of a sun exposure questionnaire for the Northern Ireland population. AB - BACKGROUND: Sunbathing and other types of exposure to ultraviolet radiation are the major preventable risk factors for skin cancer. Due to the continued increase in incidence of melanoma in Northern Ireland, we have conducted a questionnaire survey in an attempt to gather information about sunbathing habits and other forms of ultraviolet light exposure amongst the Northern Ireland population. AIM: The aim of this study was to examine the test-retest reliability of a questionnaire used in a large-scale cross-sectional population survey pertaining to sunbathing habits, use of sun screen, skin types, and frequencies of sunburn and to assess the responses given by the subjects to determine the nature of their sun-related behaviour. METHODS: Thirty control subjects were randomly selected from a population control sample participating in a large case-control study investigating melanoma in the Northern Ireland population. All participants completed the interview questionnaire on two occasions, with a median of 15 days (range, 12-42 days) between interviews. We randomly chose control subjects who had been visited by the same research nurse, thus ruling out interobserver bias in the analyses. We used the test-retest method. Kappa statistics were used to calculate the association between test and retest scores of all the individual items. If the items contained within the questionnaire are reliable, then repeated measurement after a fairly short period of time should result in high within-subject repeatability. RESULTS: Questions pertaining to hours spent in the sun and sun bed usage showed high reliability (kappa > 0.7). Questions about sunscreen usage showed moderately high reliability (kappa > 0.6) in all but one of the 10-year age bands and complete agreement (kappa = 1) in one age category (>50 years). CONCLUSION: This questionnaire is a reliable method of assessing sun associated behaviour identifying high-risk sun-related behaviour and misconceptions about tanning, which can be targeted for improvement in public health. PMID- 17714128 TI - Factors associated with thorough skin self-examination for the early detection of melanoma. AB - BACKGROUND: Regular thorough skin self-examination (TSSE) has potential for detecting melanoma early and reducing melanoma mortality. OBJECTIVES: We sought to model factors associated with skin self-examination (SSE) and test whether efficacy and attitudes about SSE mediated these relationships. PATIENTS/METHODS: The Check-It-Out project is a randomized trial of an intervention to encourage TSSE; 2126 participants were recruited from the practices of primary care physicians. Correlates predicting baseline TSSE included demographic variables, skin cancer risk, physician advice to examine skin, and appropriate conditions for conducting SSE (availability of partner to assist with self-examination, availability of a wall mirror, and use of contact lenses/glasses). RESULTS: Those who were given physician advice, had a wall mirror, and had a partner available were more likely to perform TSSE. LIMITATIONS: We identified the factors associated with concurrent TSSE practices. Further research is needed to determine if these same factors predict future behaviour. Our findings may not be applicable in geographical areas other than our recruitment area. CONCLUSIONS: Primary care providers can recommend SSE and provide materials to increase ability to recognize skin problems. Providing instructions and aids for conducting TSSE may increase self-efficacy. PMID- 17714129 TI - Natural history of extensive Mongolian spots in mucopolysaccharidosis type II (Hunter syndrome): a survey among 52 Japanese patients. AB - BACKGROUND: Recent reports have shown a correlation between extensive Mongolian spots and mucopolysaccharidosis type II (Hunter syndrome). However, a statistical survey of the incidence and natural history of extensive Mongolian spots among the patients with Hunter syndrome is lacking. OBJECTIVES: To determine the prevalence of extensive Mongolian spots, to determine the natural course of the spots according to age in Japanese patients with Hunter syndrome, and to compare them with the results obtained from the patients' brothers who did not have Hunter syndrome. PATIENTS/METHODS: Fifty-two males with Hunter syndrome aged 3 to 40 years were studied. Twenty-five patients were examined in two clinics to determine the existence and characteristics of the spots. We interviewed their families about the spots in their neonates and the natural course of the spots according to their ages. The same survey was done among another 27 patients using a mailed questionnaire to their families. As control, we investigated 21 brothers of the patients by a mailed questionnaire to their families. RESULTS: The extensive Mongolian spots are identified in almost all the infants with Hunter syndrome and disappear extremely later in their life. The lesions had a high incidence of deep-blue hyperpigmentation. Regardless of age, the overall incidence was 78%. All of the brothers who did not have Hunter syndrome had common-type Mongolian spots in neonates, which regressed during their childhood. CONCLUSION: Our results confirm a strong correlation between extensive Mongolian spots and Hunter syndrome for the Japanese population. The presence of extensive Mongolian blue spots should alert the physician to the possibility of Hunter syndrome. PMID- 17714130 TI - Dermoscopy is a suitable method for the observation of the pregnancy-related changes in melanocytic nevi. AB - BACKGROUND: It is a common opinion that expansion and darkening in melanocytic nevi may occur during pregnancy. The main problem is that whether it is a usual finding, or it is a condition that requires suspicion about melanoma. OBJECTIVES: It was aimed to find the changes that might occur in the sizes and structures of melanocytic nevi during pregnancy. METHODS: Ninety-seven nevi of the 56 pregnant women in the first trimester were evaluated in the study. The localization and size of the nevi were recorded on a standard body diagram. After clinical examination, dermoscopic analyses were applied. Pattern analyses were done, and total dermoscopy scores (TDS) were calculated by applying ABCD scoring system. All subjects were seen again during the third trimester. RESULTS: There was a statistically significant difference between the mean diameters of nevi in the first and third trimester (P = 0.001). Of nevi whose diameters increased, 10 (50.00%) were localized on the front of body, 6 (30.00%) on the face and neck, 3 (15.00%) on the legs, and 1 (5.00%) on the back. The enlargement in diameters was more significant on the front of the body, but there was no statistically significant difference. Compared according to the pattern analysis, new dot formation was observed only on the structure of six nevi during the last trimester. Four of them were localized on the front of the body. There was statistically significant increase in mean TDS in comparison between the first and third trimesters (P = 0008). CONCLUSIONS: During the pregnancy, widening in diameters and structure changes of nevi may be seen especially on the front of the body. We also think that these findings might be connected with expansion of the skin during pregnancy. Dermoscopic controls are the first choice of method to analyse the nevi since the patient may not recognize these changes. PMID- 17714131 TI - The 'EpiEnlist' project: a dermo-epidemiologic study on a representative sample of young Italian males. Prevalence of selected pigmentary lesions. AB - BACKGROUND: Few studies on the prevalence and incidence of many skin conditions in the general population are available because it is difficult to submit to dermatologic examination large samples of seemingly healthy population. OBJECTIVE: The aim of this study was to estimate the prevalence of several skin conditions among a sample that is deemed to be representative of the general population of young men living in southern Italy. PATIENTS/METHODS: Potential conscripts resident in the coastal regions of southern Italy and called at the age of 18 to the Draft's Council Medical Unit in Taranto underwent a clinical and instrumental examination to evaluate their psycho-physical fitness to compulsory service in Italian Navy. From January 1998 to April 2004 a dermo-epidemiologic project named EpiEnlist (EPIdemiology in ENLISTed Men) project was carried out by the Department of Dermatology of the Italian Navy Hospital in Taranto under the auspices of the Italian Group for Epidemiological Research in Dermatology. All the subjects showing skin lesions evocative of neurofibromatosis (NF), congenital melanocytic nevus (CMN), Becker nevus (BN), and vitiligo were referred to the Department of Dermatology of the Italian Navy Hospital for confirming the diagnosis. The confirmed cases were recorded in a predefined patient's card, containing the main anamnestic, clinical, instrumental, and laboratory data. RESULTS: Because the recording of the various conditions started and ended in different times, the total number of examined subjects varied. NF type 1 was diagnosed in 6 of 34 740 subjects [prevalence 1:5735 or 0.017%; 95% confidence interval (95% CI), 0.0008-0.0037], CMN in 157 of 23 354 (prevalence 1:148 or 0.67%; 95% CI, 0.57-0.79). BN was observed in 70 of 27 954 young men (prevalence 1:399 or 0.25%; 95% CI, 0.15-0.35), and its mean age of appearance was 11.9 years (minimum 5-maximum 17). In 41 subjects (58.6%), the age of appearance was over 10 years. Vitiligo was recorded in 60 of 34 740 persons (prevalence 1:579 or 0.17%; 95% CI, 0.13-0.22). In 40 subjects with vitiligo, the blood test was done: in 40% of these circulating autoantibodies, mainly anti-thyroid (25.6%) and anti-smooth muscle (17.3%) autoantibodies were detected, but only in 5% of cases, a thyroid disease was diagnosed, and no other sign of autoimmune diseases was observed. CONCLUSIONS: The epidemiological data of the skin conditions considered in the present study can be considered roughly in agreement with those reported in the available surveys. Because they were obtained in a large sample of Italian young males from the general population, they can be useful for therapeutic and preventive interventions by the public health organizations. PMID- 17714132 TI - Attitudes and perceptions regarding skin cancer and sun protection behaviour in an Irish population. AB - BACKGROUND: Although people seem to be well educated on the harmful effects of the sun, they continue to intentionally expose themselves without adequate protection. AIMS: To ascertain baseline knowledge regarding skin cancer and review the sun protection behaviours in an Irish population and the effect of doctor-based education on these behaviours. METHODS: Two hundred participants were recruited for a questionnaire-based study on their perceptions regarding skin cancer and their sun protection behaviour. They were divided into two groups, with one group receiving doctor-based education following the initial survey, and a follow-up questionnaire was carried out within 3 months. RESULTS: Ninety per cent of participants knew that sun exposure was the major risk factor for skin cancer, and 95% knew that sun beds were not a safe way to tan. Despite this, < 20% used regular sunscreen, and 30% had used or were currently using sun beds in order to tan. CONCLUSION: Our study indicated that although the participants' knowledge of skin cancer and risk of sun exposure is high, their sun-protective attitudes were not influenced by education in the clinical setting. PMID- 17714133 TI - Eosinophilic, polymorphic and pruritic eruption associated with radiotherapy (EPPER) in two patients with breast tumour. AB - Eosinophilic polymorphic and pruritic eruption associated with radiotherapy (EPPER) is a rare entity that appears in oncological patients after radiotherapy. We describe two patients with breast tumour who presented with EPPER in a different area from the one that had been irradiated. One of them needed different types of treatment, topical and systemic corticosteroids, antihistamines and narrowband ultraviolet B. The other one responded to the application of topical corticosteroids. We suggested that this eruption could be more frequent than has been reported. PMID- 17714134 TI - Acute generalized skin eruption due to adalimumab: report of two cases. PMID- 17714135 TI - Angiolymphoid hyperplasia: a case of a rare arterial involvement and successful recurrence treatment with laser therapy. PMID- 17714137 TI - Study of nanomechanical properties of human hair shaft in a case of pili annulati by atomic force microscopy. PMID- 17714136 TI - Lifetime prevalence distribution of chronic discoid lupus erythematosus. PMID- 17714138 TI - Malassezia and psoriasis: Koebner's phenomenon or direct causation? PMID- 17714139 TI - Postzoster cutaneous pseudolymphoma in a patient with B-cell chronic lymphocytic leukaemia. PMID- 17714140 TI - Generalized granuloma annulare and eruptive folliculitis in an HIV-positive man: resolution after antiretroviral therapy. PMID- 17714141 TI - Congenital dermal melanocytosis confined to the palm. PMID- 17714142 TI - Interstitial granuloma annulare and borreliosis: a new case. PMID- 17714144 TI - Silicon in hair loss: a preliminary SEM microanalysis study. PMID- 17714143 TI - Linking allergy to mercury to HLA and burning mouth syndrome. PMID- 17714145 TI - Successful treatment of follicular cutaneous T-cell lymphoma without mucinosis with narrow-band UVB irradiation. PMID- 17714146 TI - Eosinophilic pustular folliculitis associated with pulmonary eosinophilia. PMID- 17714147 TI - Laminaria ochroleuca extract reduces skin inflammation. PMID- 17714148 TI - Localized sclerosis of the scalp (alopecia porphyrinica) as predominant presentation of porphyria cutanea tarda. PMID- 17714149 TI - Subcutaneous dermatofibrosarcoma protuberans masquerading as a cyst. PMID- 17714150 TI - The occurrence of eccrine poroma on a burn site. PMID- 17714151 TI - Generalized tinea corporis due to Trichophyton rubrum in ichthyosis vulgaris. PMID- 17714152 TI - Sclerodermiform aspect of arm lymphoedema after treatment with docetaxel for breast cancer. PMID- 17714154 TI - Polymastia or type 1 accessory mammary tissue. PMID- 17714153 TI - Photoprotective properties of chloroquine phosphate. PMID- 17714155 TI - Pancytopenia induced by low-dose methotrexate in a haemodialysis patient treated for bullous pemphigoid. PMID- 17714156 TI - Eccrine squamous syringometaplasia associated with sunitinib therapy. PMID- 17714157 TI - Tacrolimus ointment in onychodystrophy associated with eczema. PMID- 17714158 TI - Highly active antiretroviral therapy: a treatment for cutaneous polyarteritis nodosa-like syndrome in a HIV positive patient? PMID- 17714160 TI - Fatal Pseudomona pneumonia following rituximab therapy in a patient with epidermolysis bullosa acquisita. PMID- 17714159 TI - Magnetic resonance (MR) imaging-induced deep second-degree burns of lower extremities by conducting loop. PMID- 17714161 TI - Generalized nevus anaemicus in an adult. PMID- 17714162 TI - Pityriasis lichenoides chronica in a patient affected by multiple myeloma. PMID- 17714163 TI - Clinicopathological spectrum of chemotherapy induced Grover's disease. PMID- 17714164 TI - Remote sensing-based neural network mapping of tsunami damage in Aceh, Indonesia. AB - In addition to the loss of human life, the tsunami event of 26 December 2004 caused extensive damage to coastal areas. The scale of the disaster was such that remote sensing may be the only way to determine its effects on the landscape. This paper presents the results of a neural network-based mapping of part of the region of Aceh, Sumatra. Before-and-after satellite imagery, combined with a novel neural network methodology, enabled a characterisation of landscape change. The neural network technique used a threshold of acceptance for identification, in combination with a bootstrapped identification method for identifying problem pixels. Map analysis allowed identification of urban areas that were inaccessible by road, and which aid agencies could therefore only reach by air or sea. The methods used provide a rapid and effective mapping ability and would be a useful tool for aid agencies, insurance underwriters and environmental monitoring. PMID- 17714165 TI - The significance of a small, level-3 'semi evacuation' hospital in a terrorist attack in a nearby town. AB - Terrorist attacks can occur in remote areas causing mass-casualty incidents MCIs far away from level-1 trauma centres. This study draws lessons from an MCI pertaining to the management of primary and secondary evacuation and the operational mode practiced. Data was collected from formal debriefings during and after the event, and the medical response, interactions and main outcomes analysed using Disastrous Incidents Systematic Analysis through Components, Interactions and Results (DISAST-CIR) methodology. A total of 112 people were evacuated from the scene-66 to the nearby level 3 Laniado hospital, including the eight critically and severely injured patients. Laniado hospital was instructed to act as an evacuation hospital but the flow of patients ended rapidly and it was decided to admit moderately injured victims. We introduce a novel concept of a 'semi-evacuation hospital'. This mode of operation should be selected for small scale events in which the evacuation hospital has hospitalization capacity and is not geographically isolated. We suggest that level-3 hospitals in remote areas should be prepared and drilled to work in semi-evacuation mode during MCIs. PMID- 17714166 TI - Realising a resilient and sustainable built environment: towards a strategic agenda for the United Kingdom. AB - Recent natural and human-induced emergencies have highlighted the vulnerability of the built environment. Although most emergency events are not entirely unexpected, and the effects can be mitigated, emergency managers in the United Kingdom have not played a sufficiently proactive role in the mitigation of such events. If a resilient and sustainable built environment is to be achieved, emergency management should be more proactive and receive greater input from the stakeholders responsible for the planning, design, construction and operation of the built environment. This paper highlights the need for emergency management to take a more systematic approach to hazard mitigation by integrating more with professions from the construction sector. In particular, design changes may have to be considered, critical infrastructures must be protected, planning policies should be reviewed, and resilient and sustainable agendas adopted by all stakeholders. PMID- 17714167 TI - The application of seismic risk-benefit analysis to land use planning in Taipei City. AB - In the developing countries of Asia local authorities rarely use risk analysis instruments as a decision-making support mechanism during planning and development procedures. The main purpose of this paper is to provide a methodology to enable planners to undertake such analyses. We illustrate a case study of seismic risk-benefit analysis for the city of Taipei, Taiwan, using available land use maps and surveys as well as a new tool developed by the National Science Council in Taiwan--the HAZ-Taiwan earthquake loss estimation system. We use three hypothetical earthquakes to estimate casualties and total and annualised direct economic losses, and to show their spatial distribution. We also characterise the distribution of vulnerability over the study area using cluster analysis. A risk-benefit ratio is calculated to express the levels of seismic risk attached to alternative land use plans. This paper suggests ways to perform earthquake risk evaluations and the authors intend to assist city planners to evaluate the appropriateness of their planning decisions. PMID- 17714168 TI - Operation Child-ID: reunifying children with their legal guardians after Hurricane Katrina. AB - Children constitute a vulnerable population and special considerations are necessary in order to provide proper care for them during disasters. After disasters such as Hurricane Katrina, the rapid identification and protection of separated children and their reunification with legal guardians is necessary in order to minimise secondary injuries (i.e. physical and sexual abuse, neglect and abduction). At Camp Gruber, an Oklahoma shelter for Louisianans displaced by Hurricane Katrina, a survey tool was used to identify children separated from their guardians. Of the 254 children at the camp, 36 (14.2 per cent) were separated from their legal guardians. Answering 'no' to the question of whether the accompanying adult was the guardian of the child prior to Hurricane Katrina was a strong predictor (27.8 per cent versus 3.2 per cent) of being listed as 'missing' by the National Center for Missing and Exploited Children (NCMEC). All the children at Camp Gruber who were listed as 'missing' by the NCMEC were subsequently reunited with their guardians. PMID- 17714169 TI - Hurricane Katrina disaster diplomacy. AB - Hurricane Katrina struck the United States at the end of August 2005. The consequent devastation appeared to be beyond the US government's ability to cope with and aid was offered by several states in varying degrees of conflict with the US. Hurricane Katrina therefore became a potential case study for 'disaster diplomacy', which examines how disaster-related activities do and do not yield diplomatic gains. A review of past disaster diplomacy work is provided. The literature's case studies are then categorised using a new typology: propinquity, aid relationship, level and purpose. Hurricane Katrina and its aftermath are then placed in the context of the US government's foreign policy, the international response to the disaster and the US government's reaction to these responses. The evidence presented is used to discuss the potential implications of Hurricane Katrina disaster diplomacy, indicating that factors other than disaster-related activities generally dominate diplomatic relations and foreign policy. PMID- 17714170 TI - The role of reflection in the library and information sector: a systematic review. AB - OBJECTIVES: To systematically review published literature on the role of reflection in the library and information science sector. To identify examples of good practice and to investigate the reported contribution, if any, of reflection by library and information workers as part of their professional practice. METHODS: Free text searches (reflective or reflection* or reflexion*) were conducted for English language papers on the Library and Information Science Abstracts (lisa) bibliographic database in two phases; in March 2004 for literature dating from 1969 to 2003 and between 2004 and 2006 in January 2006. Thirteen papers met the inclusion criteria and were coded and analysed using thematic analysis. RESULTS: Two categories of reflection exist: analytical and non-analytical. These focus on events in the recent and distant past. Non analytical reflective accounts generally adopt a retrospective tone in reporting on multiple events over a number of decades. In contrast, analytical accounts of reflection focused on single events and attempt to understand the relationship between past experiences and how this might impact on future practice. CONCLUSION: From the examples of reflective practice identified, greatest personal and professional benefit is reported when time is given to considering the implications of past events on future practice, that is, analytical reflection. PMID- 17714171 TI - The education and training needs of health librarians - the generalist versus specialist dilemma. AB - AIMS AND OBJECTIVES: The aims of the study were to examine whether and how librarians with a generalist background can transfer to roles demanding more expert knowledge in the health sector. The objectives were (i) to compare the education and training needs of health librarians with science degrees with the education and training needs of health librarians with arts and humanities degrees; (ii) to compare the education and training needs of librarians working in the National Health Service (NHS) sector with the education and training needs of librarians working for the health sector but within higher education. METHODS: Face-to-face interviews with 16 librarians, a convenience sample of librarians working in the Thames Valley NHS region. RESULTS: The main findings confirmed that structured continuing professional development (CPD) is required to meet the rapidly changing needs in the health sector. The emphasis ought to be on teaching skills, outreach work, marketing and promotion, research skills and methods, subject knowledge and terminology, and management skills. Library school curricula do not appear to meet the demands of medical library posts. A first degree in scientific subjects is advantageous in the early stages of a career but diminishes with continuing training and experience. There is no evidence of a significant difference in training needs and provision between the librarians in NHS posts as opposed to those in higher education (HE) posts. CONCLUSIONS: The conclusions suggest that library schools need to update their programmes to include teaching skills, advanced search skills, project management skills, research methods, with more practical exercises. Particular attention should be given to librarians with a first degree in non-scientific subjects in terms of time allocated for CPD, quality of training and access to reliable mentorship. PMID- 17714172 TI - Community outreach library services in the UK: a case study of Wirral Hospital NHS Trust (WHNT). AB - AIMS AND OBJECTIVES: The study evaluates the Community Outreach Library Service at Wirral Hospital National Health Service Trust (WHNT). It considers the information seeking behaviour and information needs of primary care staff, and service effectiveness in meeting those needs. METHODS: A literature review established the current context and areas of best practice. The investigative case study used postal questionnaires to 250 primary care staff and an interview with the Community Outreach Librarian. FINDINGS: Themes emerged from the literature regarding information seeking behaviour, information needs, and meeting user needs through effective service delivery. Outreach services have value in terms of improving information skills and providing services at point of need. Time is a major constraint for both users and service providers. CONCLUSIONS: Investment is needed from appropriate funding sources to support the provision and marketing of outreach library services. Librarians benefit from sharing best practice. The continued evaluation of outreach library services is recommended. PMID- 17714173 TI - Do published search filters to identify diagnostic test accuracy studies perform adequately? AB - OBJECTIVES: To assess the performance of published search filters in finding diagnostic test accuracy studies. METHODS: Diagnostic test accuracy search filters were identified by searching medline, our own files and by requesting unpublished filters from colleagues. We applied the filters to a case study review of diagnostic test accuracy studies for urinary tract infections (UTI) in young children. The included studies with records in medline formed the gold standard. The performance of the filters in finding those gold standard records was assessed. RESULTS: We identified twenty-three diagnostic test accuracy search filters for use with medline. The case study systematic review of UTI included 179 studies of diagnostic test accuracy, of which 160 were available in medline. The filters showed a wide range of sensitivities (range: 20.6% to 86.9%) and precision (range: 1% to 9.4%). CONCLUSIONS: Our results broadly support those reported in two other studies. The search filters tested do not offer an adequate trade-off between sensitivity and precision to be used to identify studies for systematic reviews. However, there are methods available to explore whether search filters are viable based on an objective statistical analysis of the text and indexing used in records. PMID- 17714174 TI - Journal usage in NHS hospitals: a comparison report of total usage at an acute NHS Trust and a specialist NHS Trust in the North West of England. AB - BACKGROUND: Health care libraries spend a large amount of their non-pay budgets on the purchase of scientific, technical and medical journals. In a typical hospital library in the National Health Service (NHS) North West Strategic Health Authority (SHA), this can represent between 80 and 90% of the collection development budget. METHODS AND RESULTS: Data were collected from 1 December 2005 to 30 November 2006 using COUNTER-generated usage statistics obtained from publishers' administration tools. Between the two trusts included in the study, 93 376 full-text article downloads were recorded; of these, 15 952 or 17.1% articles were downloaded from national core content journals via Proquest. Photocopies made by users for their own use were recorded whenever this data were available. CONCLUSIONS: NHS staff at the sites included in this study recorded a high volume of journal usage. There was a marked difference in usage patterns between the acute and specialist trusts in the study. The journals provided by national core content represented a much higher proportion of total usage at the acute trust (29.9%) compared with the specialist cancer trust (4.5%). This study supports the view that the local purchasing of journal titles is an important component of the overall journal-based information provision to NHS staff. PMID- 17714175 TI - Searching a biomedical bibliographic database from Bulgaria: the ABS database. AB - BACKGROUND: The University of Sofia, Bulgaria, disseminates local biomedical literature (1994 to present) through a free online database, ABS. OBJECTIVES: Our objectives were to systematically search ABS, identify citations to controlled trials and discover what proportion of these studies are to be found on medline. METHODS: We searched using Bulgarian and English phrases; manually selected citations of controlled trials and sought these citations on medline. RESULTS: Using the two languages, we found a total of 628 unique citations, 47 of which seem to be relevant controlled trials (precision 7.48%, 13% of ABS citations were found on medline). The trials in ABS commonly focused on evaluation of care for people with cardiovascular or urological problems. DISCUSSION: ABS is another source of easily accessed trials not readily available elsewhere. PMID- 17714176 TI - Gender and online health information: a partitioned technology assessment. AB - OBJECTIVE: To examine the extent to which health information seeking behaviors vary across genders or are differentially associated with access to computers, the Internet, and online health information. RESEARCH DESIGN: Stratified survey, data analysis. METHODS: Using binary logistic regression we examine information seeking differences between demographic groups. Questions addressed include: 1) Are any identified groups significantly underserved regarding access to computers, access to the Internet, and preferences for seeking online health information, and 2) have differences between gender groups in access to computers, Internet services and online health information narrowed, remained constant, or widened over recent years, following recent national initiatives to narrow the technology gap for underserved populations? OUTCOMES: Information seeking variation across gender groups and between technologies was at times significant. There was little difference in the access to computer between females and males. In 2002, 75.4% and 73.1% of female and male participants reported that they occasionally use computers, respectively. In 2000, the respective figures were 72.4% and 72.7%. The rates of use of Internet services among computer users, however, were quite different between female and male (P(at 2002)= 0.0002 and P(at 2000)= 0.0082) and the disparity in 2000 (OR = 0.7366 [0.5870, 0.9243]) increased in 2002 (OR = 0.5675 [0.4222, 0.7627]). The odds ratios (OR) indicate that females were 0.7366 and 0.5675 times less likely to use computers than male counterparts in 2000 and 2002, respectively. CONCLUSION: Recent technology initiatives in the US aimed at reducing disparities in access to online resources appear to have had little effect in facilitating equal access to web-based health information. PMID- 17714177 TI - Retractions, press releases and newspaper coverage. AB - OBJECTIVES: To explore how often newspapers cover the retraction of a medical journal article and whether newspaper coverage corresponds with the appearance of a press release about the retraction. METHODS: Fifty citations were identified in PubMed that had been indexed with the Medical Subject Heading 'Retracted Publication'. Next, the archives of LexisNexis's 'Major Newspapers' and EurekAlert's press releases were searched to find references to those retracted publications. RESULTS: Newspaper articles addressed exactly three of the 50 retracted publications, and press releases, exactly four of the 50 retracted publications. All three retracted publications that received newspaper coverage also had a press release. In other words, newspapers only covered a retraction that had been introduced by a press release. CONCLUSION: One would expect that newspaper coverage would increase after a press release, but the suggested relationships among a medical journal article retraction, a press release and newspaper coverage should be further investigated. If the linkage suggested by the data of this study holds, and if newspaper coverage stimulates library patron interest, then a medical library might prepare itself for information requests following a press release. PMID- 17714178 TI - Unique lessons from the Cuban National Health Care Network and Portal - INFOMED. PMID- 17714180 TI - Evidence in 'real time': the story of an international workshop. PMID- 17714179 TI - Where the action is. PMID- 17714181 TI - Protective effect of acetyl-L-carnitine on the apoptotic pathway of peripheral neuropathy. AB - Peripheral neuropathies are widespread disorders induced by autoimmune diseases, drug or toxin exposure, infections, metabolic insults or trauma. Nerve damage may cause muscle weakness, altered functionalities and sensitivity, and a chronic pain syndrome characterized by allodynia and hyperalgesia. Pathophysiological mechanisms related to neuropathic disease are associated with mitochondrial dysfunctions that lead to the activation of the apoptotic cascade. In a model of peripheral neuropathy, obtained by the loose ligation of the rat sciatic nerve (CCI), we describe a nerve apoptotic state that encompasses the release of cytochrome C in the cytosol, the activation of caspase 3, and the fragmentation of the genome. Animal treatment with acetyl-L-carnitine (ALCAR), but not with L carnitine (L-Carn) or Gabapentin, prevents apoptosis induction. ALCAR reduces cytosolic cytochrome C and caspase 3 active fragments expression in a significant manner with respect to saline treatment. Accordingly, ALCAR treatment impairs caspase 3 protease activity, as demonstrated by reduced levels of cleaved PARP. Finally, ALCAR decreases the number of piknotic nuclei. This protection correlates with the induction of X-linked inhibitor apoptosis protein (XIAP). Taken together these results show that CCI is a valuable model to investigate neuropathies-related apoptosis phenomena and that ALCAR is able to prevent regulated cell death in the damaged sciatic nerve. PMID- 17714182 TI - PI3K/akt, JAK/STAT and MEK/ERK pathway inhibition protects retinal ganglion cells via different mechanisms after optic nerve injury. AB - Recently we unexpectedly found that PI3K/akt, JAK/STAT and MEK/ERK pathway inhibitors enhanced retinal ganglion cell (RGC) survival after optic nerve (ON) axotomy in adult rat, a phenomenon contradictory to conventional belief that these pathways are pro-survival. In this study we showed that: (i) the RGC protection was pathway inhibition-dependent; (ii) inhibition of PI3K/akt and JAK/STAT, but not MEK/ERK, activated macrophages in the eye, (iii) macrophage removal from the eye using clodronate liposomes significantly impeded PI3K/akt and JAK/STAT inhibition-induced RGC survival and axon regeneration whereas it only slightly affected MEK/ERK inhibition-dependent protection; (iv) in the absence of recruited macrophages in the eye, inhibition of PI3K/akt or JAK/STAT did not influence RGC survival; and (v) strong PI3K/akt, JAK/STAT and MEK/ERK pathway activities were located in RGCs but not macrophages after ON injury. In retinal explants, in which supply of blood-derived macrophages is absent, MEK/ERK inhibition promoted RGC survival whereas PI3K/akt or JAK/STAT inhibition had no effect on RGC viability. However, MEK/ERK inhibition exerted opposite effects on the viability of purified adult RGCs at different concentrations in vitro, suggesting that this pathway may be bifunctional depending on the level of pathway activity. Our data thus demonstrate that inhibition of the PI3K/akt or JAK/STAT pathway activated macrophages to facilitate RGC protection after ON injury whereas the two pathways per se did not modulate RGC viability under the injury conditions (in the absence of the pathway activators). In contrast, the MEK/ERK pathway inhibition protected RGCs via macrophage-independent mechanism(s). PMID- 17714183 TI - Oxidative stress-induced phosphorylation, degradation and aggregation of alpha synuclein are linked to upregulated CK2 and cathepsin D. AB - Intracellular accumulation of alpha-synuclein (alpha-Syn) as filamentous aggregates is a pathological feature shared by Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, referred to as synucleinopathies. To understand the mechanisms underlying alpha-Syn aggregation, we established a tetracycline-off inducible transfectant (3D5) of neuronal lineage overexpressing human wild-type alpha-Syn. Alpha-Syn aggregation was initiated by exposure of 3D5 cells to FeCl2. The exposure led to formation of alpha-Syn inclusions and oligomers of 34, 54, 68 kDa and higher molecular weights. The oligomers displayed immunoreactivity with antibodies to the amino-, but not to the carboxyl (C)-, terminus of alpha-Syn, indicating that C-terminally truncated alpha-Syn is a major component of oligomers. FeCl2 exposure also promoted accumulation of S129 phosphorylated monomeric alpha-Syn (P alpha-Syn) and casein kinase 2 (CK2); however, G-protein-coupled receptor kinase 2 was reduced. Treatment of FeCl2 exposed cells with CK2 inhibitors (DRB or TBB) led to decreased formation of alpha-Syn inclusions, oligomers and P alpha-Syn. FeCl2 exposure also enhanced the activity/level of cathepsin D. Treatment of the FeCl2-exposed cells with pepstatin A or NH4Cl led to reduced formation of oligomers/inclusions as well as of approximately 10 and 12 kDa truncated alpha-Syn. Our results indicate that alpha-Syn phosphorylation caused by FeCl2 is due to CK2 upregulation, and that lysosomal proteases may have a role in producing truncated alpha-Syn for oligomer assembly. PMID- 17714184 TI - Docosahexaenoic acid stimulates non-amyloidogenic APP processing resulting in reduced Abeta levels in cellular models of Alzheimer's disease. AB - Epidemiological studies suggest that a high intake of polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), is associated with a reduced risk of Alzheimer's disease. Here, we examined the effects of DHA on amyloid precursor protein (APP) processing in cellular models of Alzheimer's disease by analysing levels of different APP fragments, including amyloid-beta (Abeta). DHA administration stimulated non-amyloidogenic APP processing and reduced levels of Abeta, providing a mechanism for the reported beneficial effects of DHA in vivo. However, an increased level of APP intracellular domain was also observed, highlighting the need to increase our knowledge about the relevance of this fragment in Alzheimer's disease pathogenesis. In conclusion, our results suggest that the proposed protective role of DHA in Alzheimer's disease pathogenesis might be mediated by altered APP processing and Abeta production. PMID- 17714185 TI - Requirement of the tumour suppressor APC for the clustering of PSD-95 and AMPA receptors in hippocampal neurons. AB - Mutations in the adenomatous polyposis coli (APC) gene are associated with familial adenomatous polyposis and sporadic colorectal tumours. The APC gene is expressed ubiquitously in various tissues, especially throughout the large intestine and central nervous system (CNS). In the CNS, the expression of the APC protein is highest during embryonic and early postnatal development. APC associates through its C-terminal region with postsynaptic density (PSD)-95, a neuronal protein that participates in synapse development. Here, we examined the involvement of APC in synaptogenesis. In cultured hippocampal neurons, both overexpression of a dominant-negative construct that disrupts the APC-PSD-95 interaction and knockdown of APC expression using small interfering RNA (siRNA) inhibited the clustering of PSD-95 and a glutamate receptor subunit, and reduced alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA)-induced activity of AMPA receptors; however, the clustering of an N-methyl-D-aspartate (NMDA) receptor subunit was unaffected. These results are suggestive of APC involvement in the development of glutamatergic synapses. PMID- 17714186 TI - Misfolded transthyretin causes behavioral changes in a Drosophila model for transthyretin-associated amyloidosis. AB - Familial amyloidotic polyneuropathy is an autosomal dominant neurodegenerative disorder caused by accumulation of mutated transthyretin (TTR) amyloid fibrils in different organs and prevalently around peripheral nerves. We have constructed transgenic flies, expressing the clinical amyloidogenic variant TTRL55P and the engineered variant TTR-A (TTRV14N/V16E) as well as the wild-type protein, all in secreted form. Within a few weeks, both mutants but not the wild-type TTR demonstrated a time-dependent aggregation of misfolded molecules. This was associated with neurodegeneration, change in wing posture, attenuation of locomotor activity including compromised flying ability and shortened life span. In contrast, expression of wild-type TTR had no discernible effect on either longevity or behavior. These results suggest that Drosophila can be used as a disease-model to study TTR amyloid formation, and to screen for pharmacological agents and modifying genes. PMID- 17714187 TI - Sensory nerves have altered function contralateral to a monoarthritis and may contribute to the symmetrical spread of inflammation. AB - Rheumatoid arthritis (RA) and rat models of RA exhibit symmetrical mirror-image spread. Many studies have sought to understand the underlying mechanisms and have reported contralateral effects that are manifested in many different forms. It is now well accepted that neurogenic mechanisms contribute to the symmetrical spread of inflammation. However, very few investigators have directly assessed changes in contralateral nerve function and there is a paucity of data. In the present study our aim was to investigate whether there are changes, in particular in the nervous system but also in the vascular system contralateral to an inflamed rat knee joint, that might precede overt inflammation and symmetrical spread. Three to five days following Complete Freund's Adjuvant (CFA) injection we found spontaneous antidromic (away from the CNS) activity in the homologous sensory nerve contralateral to the inflamed joint. Antidromic activity of this nature is known to result in the peripheral release of pro-inflammatory and vasoactive neuropeptides. Importantly, this activity was modulated by systemic analgesic treatment. Furthermore, levels of Evans blue dye extravasation were significantly increased in the joint contralateral to inflammation, indicating altered vascular function. These data suggest that contralateral increases in sensory neural activity and vascular function may account for the symmetrical spread of RA, and that early analgesic treatment may prevent or delay the spread of this debilitating disease. PMID- 17714188 TI - Laminar organization of spinal dorsal horn neurones activated by C- vs. A-heat nociceptors and their descending control from the periaqueductal grey in the rat. AB - The periaqueductal grey can differentially control A- vs. C-nociceptor-evoked spinal reflexes and deep spinal dorsal horn neuronal responses. However, little is known about the control of A- vs. C-fibre inputs to lamina I and the lateral spinal nucleus, and how this correlates with the control of deeper laminae. To address this, the laminar distributions of neurones expressing Fos-like immunoreactivity were determined following preferential activation of A- or C heat nociceptors, using fast or slow rates of skin heating, respectively, in the absence or presence of descending control evoked from the periaqueductal grey. In lamina I, numbers of Fos-positive neurones following both fast and slow rates of skin heating were reduced significantly following activation in the ventrolateral and dorsolateral/lateral periaqueductal grey. In contrast, in the deep dorsal horn (laminae III-VI), activation in both the ventrolateral and dorsolateral/lateral periaqueductal grey significantly reduced the numbers of Fos positive neurones evoked by C- but not A-nociceptor stimulation. C- but not A heat nociceptor activation evoked Fos bilaterally in the lateral spinal nucleus. Stimulation in the ventrolateral but not the dorsolateral/lateral periaqueductal grey significantly increased the numbers of Fos-positive neurones evoked by A- and C-nociceptor stimulation bilaterally in the lateral spinal nucleus. These data have demonstrated differences in the descending control of the superficial vs. the deep dorsal horn and lateral spinal nucleus with respect to the processing of A- and C-fibre-evoked events. The data are discussed in relation to the roles of A- and C-nociceptors in acute and chronic pain. PMID- 17714189 TI - Isolation, purification and expansion of myelination-competent, neonatal mouse Schwann cells. AB - Most studies of peripheral nerve myelination using culture models are performed with dorsal root ganglion neurons and Schwann cells pre-purified from the rat. The potential of this model is severely compromised by the lack of rat myelin mutants and the published protocols work poorly with mouse cells, for which numerous myelin mutants are available. This is partly due to difficulties in obtaining sufficient quantities of myelination-competent mouse Schwann cells. Here, we describe the isolation, purification and expansion of wild-type, myelination-competent Schwann cells from the sciatic nerves of 4-day-old mouse pups. The method consistently yields 1.9-3.3 x 10(6) of approximately 95% pure Schwann cells from the sciatic nerves of 12-15 4-day-old mouse pups, within 14-20 days. The Schwann cell proliferation rate ranges from 2.7- to 4.30-fold growth/week. Proliferation ceases within 4 weeks, when the cells become quiescent. Growth is reinduced by the presence of neurons; neuregulin is not sufficient for this effect. The Schwann cells isolated by this protocol are able to form compact myelin in culture, as judged by the segregated expression patterns of early (myelin-associated glycoprotein) and late (myelin basic protein) myelination markers in a three-dimensional neuron/Schwann cell coculture model. The Schwann cell batch yields are sufficient to perform 100-150 individual myelinating coculture assays. Employing mixed phenotype/genotype mouse neuron/Schwann cell cocultures, it will be possible to analyse the cell specificity of a mutation, and the cumulative effects of different mutations, without having to cross-breed the animals. PMID- 17714190 TI - The mental retardation gene CC2D1A/Freud-1 encodes a long isoform that binds conserved DNA elements to repress gene transcription. AB - The CC2D1A/Freud-1 gene has recently been linked to non-syndromic mental retardation and a short isoform of mouse Five prime REpressor Under Dual repression binding protein 1 (Freud-1) can repress the serotonin-1A (5-HT1A) receptor gene in rodent cells. In this study, we addressed the expression, localization and regulation of the human 5-HT1A receptor gene by a long isoform of human Freud-1 protein (Freud-1L). We show that human CC2D1A/Freud-1 RNA is expressed in brain and peripheral tissues and encodes short and long isoforms, which differ by an upstream in-frame translational start site. Whereas previous studies identified the short isoform of Freud-1 as the predominant isoform in rodent cells, we demonstrate that the long isoform is more abundant in human cells, especially in the nuclear fraction. The nuclear localization of Freud-1L was enriched upon inhibition of chromosome region maintenance 1/exportin 1 dependent nuclear export, indicating a dynamic regulation of Freud-1 nuclear localization. Consistent with a functional role in the nucleus, human Freud-1L bound specifically to its dual repressor element in the 5-HT1A receptor gene in vitro and repressed transcription from these sites. Importantly, chromatin immunoprecipitation using antibodies specific for human Freud-1L demonstrated that it is bound to the dual repressor element in chromatin, indicating a functional role in regulating the basal expression of the 5-HT1A receptor gene. Taken together, these results indicate that both the short and long isoforms of Freud-1 are expressed, although Freud-1L is the major isoform that regulates the human 5-HT1A receptor gene. Disruption of transcriptional regulation by mutation of Freud-1 may play a role in abnormal brain function leading to mental retardation. PMID- 17714191 TI - The impact of chronic network hyperexcitability on developing glutamatergic synapses. AB - The effects recurring seizures have on the developing brain are an important area of debate because many forms of human epilepsy arise in early life when the central nervous system is undergoing dramatic developmental changes. To examine effects on glutamatergic synaptogenesis, epileptiform activity was induced by chronic treatment with GABAa receptor antagonists in slice cultures made from infant rat hippocampus. Experiments in control cultures showed that molecular markers for glutamatergic and GABAergic synapses recapitulated developmental milestones reported previously in vivo. Following a 1-week treatment with bicuculline, the intensity of epileptiform activity that could be induced in cultures was greatly diminished, suggesting induction of an adaptive response. In keeping with this notion, immunoblotting revealed the expression of NMDA and AMPA receptor subunits was dramatically reduced along with the scaffolding proteins, PSD95 and Homer. These effects could not be attributed to neuronal cell death, were reversible, and were not observed in slices taken from older animals. Co treating slices with APV or TTX abolished the effects of bicuculline suggesting that effects were dependent on NMDA receptors and neuronal activity. Neurophysiological recordings supported the biochemical findings and demonstrated decreases in both the amplitude and frequency of NMDA and AMPA receptor-mediated miniature EPSCs (mEPSCs). Taken together these results suggest that neuronal network hyperexcitability interferes with the normal maturation of glutamatergic synapses, which could have implications for cognitive deficits commonly associated with the severe epilepsies of early childhood. PMID- 17714192 TI - Spatial receptive field properties of lateral geniculate cells in the owl monkey (Aotus azarae) at different contrasts: a comparative study. AB - Several physiological properties of owl monkey lateral geniculate nucleus (LGN) cells were studied to verify whether its nocturnal habit has an influence on the organization of its subcortical visual system. Receptive field (RF) dimensions were measured using drifting gratings and bipartite field stimuli. We found that owl monkey cells LGN have larger RFs and were on average more non-linear than those of diurnal monkeys. But, as in other anthropoids, there is an increase in RF centre size with increasing eccentricity, and there is a limited correlation between these centre sizes and retinal ganglion cell dendritic tree sizes. The influence of contrast on sizes and peak sensitivities of RF centres and surrounds and on the response phases was studied. Both the sizes and peak sensitivities of the RF centres and surrounds decrease as contrast increases. As a result, the responses to low spatial frequency stimuli saturate with increasing contrast. Estimates of contrasts at half-maximal responses confirm the presence of saturation. It was found that the magnocellular cells saturate more strongly than parvocellular cells. The response phase increases with increasing contrast. These data resemble those obtained in the common marmoset, indicating that these are basic features of the primate visual system. We conclude that during evolution and as an adaptation to a nocturnal lifestyle, cells in the owl monkey LGN display an increased spatial integration in comparison with diurnal primate species, without a change in the basic organization common to the primate subcortical visual system. PMID- 17714193 TI - Suppression of vibrotactile discrimination by transcranial magnetic stimulation of primary somatosensory cortex. AB - A number of human and animal studies have reported a differential representation of the frequency of vibrotactile stimuli in the somatosensory cortices: neurons in the primary somatosensory cortex (SI) are predominantly responsive to lower frequencies of tactile vibration, and those in the secondary somatosensory cortex (SII) are predominantly responsive to higher frequencies. We employed transcranial magnetic stimulation (TMS) over SI in human subjects to investigate the extent to which the inactivation of SI disrupted the discrimination of vibrotactile stimulation at frequencies that give rise to the tactile sensations of flutter (30 Hz) and vibration (200 Hz). Frequency discrimination around the 30 Hz standard following application of TMS to SI was reduced in seven of the eight subjects, and around the 200-Hz standard was reduced in all eight subjects. The average change in discrimination following TMS was about 20% for both low and high frequencies of vibrotactile stimulation. These data suggest that disruption of SI: (1) has a direct effect on the discrimination of both low and high frequencies of vibrotactile stimuli, consistent with a serial model of processing, or (2) has a direct effect on low-frequency vibrotactile stimuli and an indirect effect on the processing of high-frequency vibrotactile stimuli by SII via cortico-cortical connections between the two regions. PMID- 17714195 TI - Spatio-temporal prediction and inference by V1 neurons. AB - In normal vision, visual scenes are predictable, as they are both spatially and temporally redundant. Evidence suggests that the visual system may use the spatio temporal regularities of the external world, available in the retinal signal, to extract information from the visual environment and better reconstruct current and future stimuli. We studied this by recording neuronal responses of primary visual cortex (area V1) in anaesthetized and paralysed macaques during the presentation of dynamic sequences of bars, in which spatio-temporal regularities and local information were independently manipulated. Most V1 neurons were significantly modulated by events prior to and distant from stimulation of their classical receptive fields (CRFs); many were more strongly tuned to prior and distant events than they were to CRFs bars; and several showed tuning to prior information without any CRF stimulation. Hence, V1 neurons do not simply analyse local contours, but impute local features to the visual world, on the basis of prior knowledge of a visual world in which useful information can be distributed widely in space and time. PMID- 17714196 TI - Distinct movement parameters are represented by different neurons in the motor cortex. AB - Recent studies suggested that a single motor cortical neuron typically encodes multiple movement parameters, but parameters often display strong temporal interdependencies. To address this issue, we recorded single-unit activity while macaque monkeys made continuous movements and employed an analysis that explicitly considered temporal correlations between several kinematic parameters; hand position, velocity, and acceleration. We found that while the activity of almost all motor cortical neurons was modulated during movement, most neurons were related only to a single dominant parameter. The activity of different neurons covaried with different parameters with similar strength, but neurons related to velocity were far more common than neurons related to any other parameter. These results were obtained for neurons recorded in the primary motor (M1) and dorsal premotor (PMd) cortices. Although neural activity tended to precede movement and PMd activity tended to precede M1 activity, time lags were widely dispersed. Shoulder and elbow muscles had the same properties as neurons, but their activity strictly preceded movement. These results demonstrate single neuron specificity and heterogeneity within a population of neurons with respect to movement parameters and time lags. Our results suggest that distinct subsets of motor cortical neurons are involved in computations related to distinct movement parameters. PMID- 17714194 TI - Activation of afferents to the ventral tegmental area in response to acute amphetamine: a double-labelling study. AB - The ventral tegmental area (VTA), primary source of the mesocorticolimbic dopaminergic system, is regarded as a critical site for initiation of behavioural sensitization to psychostimulants. The present study was undertaken to identify the neural pathways converging on the VTA that are potentially implicated in this process. Rats were sensitized by a single exposure to amphetamine (5 mg/kg, s.c.). The distribution of VTA-projecting neurons activated by amphetamine was examined by combining retrograde transport of the cholera toxin beta subunit (CTb), injected into the VTA, with immunodetection of Fos. The quantitative analysis of CTb-Fos double labelling demonstrates that amphetamine induced a rapid activation of Fos in a large number of brain areas projecting to the VTA. More than half of the CTb-Fos double-labelled neurons were located in the prefrontal cortex, lateral preoptic area-lateral hypothalamus, pontomesencephalic tegmentum, dorsal raphe nucleus, ventral pallidum and nucleus accumbens. In addition, scattered CTb-Fos double-labelled cells were observed in many other VTA afferent structures, such as claustrum, lateral septum, diagonal band magnocellular preoptic nucleus, deep mesencephalic nucleus, oral part of pontine reticular nucleus and dorsomedial tegmental area. This suggests that systemic amphetamine activates a wide population of neurons projecting to the VTA that may be important for the modulation of neurobehavioural plasticity produced by this psychostimulant. PMID- 17714197 TI - Enhanced affective brain representations of chocolate in cravers vs. non-cravers. AB - To examine the neural circuitry involved in food craving, in making food particularly appetitive and thus in driving wanting and eating, we used fMRI to measure the response to the flavour of chocolate, the sight of chocolate and their combination in cravers vs. non-cravers. Statistical parametric mapping (SPM) analyses showed that the sight of chocolate produced more activation in chocolate cravers than non-cravers in the medial orbitofrontal cortex and ventral striatum. For cravers vs. non-cravers, a combination of a picture of chocolate with chocolate in the mouth produced a greater effect than the sum of the components (i.e. supralinearity) in the medial orbitofrontal cortex and pregenual cingulate cortex. Furthermore, the pleasantness ratings of the chocolate and chocolate-related stimuli had higher positive correlations with the fMRI blood oxygenation level-dependent signals in the pregenual cingulate cortex and medial orbitofrontal cortex in the cravers than in the non-cravers. To our knowledge, this is the first study to show that there are differences between cravers and non-cravers in their responses to the sensory components of a craved food in the orbitofrontal cortex, ventral striatum and pregenual cingulate cortex, and that in some of these regions the differences are related to the subjective pleasantness of the craved foods. Understanding individual differences in brain responses to very pleasant foods helps in the understanding of the mechanisms that drive the liking for specific foods and thus intake of those foods. PMID- 17714200 TI - Database research in Australia: time to dredge up some action. PMID- 17714201 TI - Palliative care in haematology. PMID- 17714202 TI - Assessment of clinical performance: gathering evidence. AB - The focus of assessment of clinical performance has moved from over-reliance on individual tools to constructing a coherent assessment programme. The purpose of such an assessment programme is to gather high-quality evidence to make well informed decisions. This requires clarity on the decisions to be made and an ability to gather a sufficient amount of high-quality data. The assessment programme should be aligned to doing the job well so that a successful assessment result reflects what is valued. A variety of assessments over a variety of times, matched against the areas of interest and value, enhances both reliability and validity. Workplace-based assessment tools can complement centralized assessment tools. Multiple snapshots, even if some are not totally in focus, give a better picture than one poorly aimed photograph. PMID- 17714203 TI - Two steps forward, one step back: advance care planning, Australian regulatory frameworks and the Australian Medical Association. AB - The Australian Medical Association has recently adopted a policy position concerning advance care planning, which is generally supportive of extending patient self-determination beyond the loss of decision-making capacity. It calls for uniform national legislation for legally enforceable advance health directives (AHD), and statutory protection for practitioners who comply with valid AHD, or who do not comply on several grounds. Analysis of the grounds for non-compliance indicate that they undermine patient autonomy, and aspects of the policy are inconsistent with current common law and statutory regimes that allow an adult to complete a legally binding AHD. The policy therefore threatens the patient self-determination, which it endorses, and places doctors who participate in advance care planning at legal risk. PMID- 17714204 TI - Q fever cases at a North Queensland centre during 1994-2006. AB - This study reviewed the epidemiological features, management and outcomes of patients with Q fever treated at a tertiary facility in North Queensland during the period from July 1994 to January 2006. Twenty-seven patients were identified. Our findings were consistent with the observations about Q fever that have been made in other regions of Australia. A diagnosis of Q fever should be considered in patients with a non-specific febrile illness. PMID- 17714205 TI - Failure to weigh patients in hospital: a medication safety risk. AB - Often patients are not weighed in hospital. Failure to weigh patients prescribed renally excreted drugs may correlate to adverse drug events. We carried out a cross-sectional study of patients prescribed common renally excreted drugs (heparin, enoxaparin and gentamicin), admitted to two wards at Royal North Shore Hospital, Sydney over 3 months. Of all patients surveyed, 28% (22/78) in the orthopaedic ward and 22% (27/124) in the medical ward were weighed. Among those prescribed therapeutic doses of the study drugs, 25% (3/12) in the orthopaedic ward and 27% (7/26) in the medical ward were weighed. Patients prescribed therapeutic anticoagulation who were not weighed experienced more haemorrhagic complications than patients who were weighed (P = 0.03). Patients prescribed renally excreted drugs in hospital are frequently not weighed. This is associated with reduced medication safety. PMID- 17714206 TI - Angioedema, lymphoproliferative disorder and angiotensin-converting enzyme inhibitors: masking of diagnosis by corticosteroids. AB - Angioedema is a relatively common clinical disorder. Although most cases are idiopathic, the use of angiotensin-converting enzyme inhibitors is a well recognized cause of angioedema and a further rare but important diagnostic consideration is acquired C1 inhibitor deficiency. We discuss the diagnosis of C1 inhibitor deficiency in angioedema, with reference to a case in which the diagnosis was initially masked by the use of corticosteroids, which normalized the C1 inhibitor level. PMID- 17714207 TI - Chronic disease management: time for consultant physicians to take more leadership in system redesign. AB - There is a need for system redesign to meet the needs of individuals with chronic disease. New models of chronic disease care include team-based paradigms that focus on continuous and patient-centred care. In such models the roles of providers and patients must change. In this article we focus on new roles for consultant physicians, as well as barriers and incentives to these roles. PMID- 17714208 TI - Air embolism in the right ventricle. PMID- 17714209 TI - Spontaneous intramural intestinal haematoma. PMID- 17714210 TI - Wheat flour immunotherapy in baker's asthma. PMID- 17714211 TI - Cyclical Cushing's syndrome due to an ectopic adrenocorticotropic hormone producing adenoma. PMID- 17714212 TI - Direct-to-consumer advertising policy in Australia: realism in whose interests? PMID- 17714214 TI - In vitro spermatogenesis as a method to bypass pre-meiotic or post-meiotic barriers blocking the spermatogenetic process: genetic and epigenetic implications in assisted reproductive technology. AB - Pregnancies achieved by assisted reproduction technologies and particularly by ooplasmic injections of either in vivo or in vitro generated immature male germ cells are susceptible to genetic risks inherent to the male population treated with assisted reproduction and additional risks inherent to these innovative procedures. The documented, as well as the theoretical risks, are discussed in this review. These risks represent mainly the consequences of genetic abnormalities underlying male infertility and may become stimulators for the development of novel approaches and applications in the treatment of infertility. Recent data suggest that techniques employed for in vitro spermatogenesis, male somatic cell haploidization, stem cell differentiation in vitro and assisted reproductive technology may also affect the epigenetic characteristics of the male gamete, the female gamete, or may have an impact on early embryogenesis. They may be also associated with an increased risk for genomic imprinting abnormalities. Production of haploid male gametes in vitro may not allow the male gamete to undergo all the genetic and epigenetic alterations that the male gamete normally undergoes during in vivo spermatogenesis. PMID- 17714215 TI - Serum leptin correlates in infertile oligozoospermic males. AB - Leptin is an adipocyte-secreted protein that participates in the regulation of energy homeostasis. Eighty men were investigated; fertile normozoospermia as a control (n = 30) and infertile oligozoospermia (n = 50). The patients underwent estimation of body weight (kg), height (cm), calculation of body mass index (BMI), semen analysis, serum leptin and testosterone hormones. Mean body weight was significantly higher in infertile oligozoospermia compared with controls. Mean height, BMI and serum testosterone levels showed nonsignificant differences between the two groups. Infertile oligozoospermia had significantly higher mean serum leptin level than controls (mean +/- SD; 6.88 +/- 8.65, 16.3 +/- 13.98 ng ml(-1), P < 0.01). Serum leptin demonstrated significant positive correlation with age, body weight, BMI and significant inverse correlation with serum testosterone. It had nonsignificant correlation with the height and sperm concentration. These results are suggestive of a link between the adipocyte derived hormone, leptin and male reproduction. PMID- 17714216 TI - Plasma levels of dihydrotestosterone remain in the normal range in men treated with long-acting parenteral testosterone undecanoate. AB - The major goal of androgen therapy is to achieve testosterone levels as close to physiological concentrations as possible. For some androgen-dependent functions, testosterone is a pro-hormone, peripherally converted to 5 alpha dihydrotestosterone (DHT) and 17beta-oestradiol of which the levels preferably should also be within their normal physiological ranges. In this study, the resulting plasma DHT levels in 122 hypogonadal men treated with a novel testosterone treatment modality: parenteral long-acting testosterone undecanoate (Nebido), were investigated. Following the treatment, there were no abnormally high/low plasma DHT levels; levels varied between 86 and 511 ng l(-1) (normal range: 40-575 ng l(-1)). In conclusion, treatment with testosterone undecanoate generates physiological levels of DHT. Prostate safety parameters did not undergo changes. PMID- 17714217 TI - Mast cells in testicular biopsies of azoospermic men. AB - This work aimed at identifying mast cells in testicular biopsies from 10 normal fertile controls, 20 patients with obstructive azoospermia and 70 patients with nonobstructive azoospermia. The biopsies were stained with haematoxylin and eosin stain for tubular-modified Johnson score and with toluidine blue stain for mast cells. Two populations of mast cells, peritubular and interstitial, were demonstrated in all sections with varied counts. Testicular sections with Sertoli cell only and spermatogenic arrest patterns demonstrated a significant increase in both peritubular and interstitial mast cells compared with other groups, whereas obstructive azoospermia demonstrated a nonsignificant increase compared with the controls. Mast cell count was significantly correlated negatively with Johnson score for both peritubular (P = 0.001) and interstitial (P = 0.001) populations. Whether these results could be a cause or an effect, a special role might be assigned to mast cells in the pathogenesis of disturbed spermatogenesis. PMID- 17714218 TI - Mutation analysis of the X-chromosome linked, testis-specific TAF7L gene in spermatogenic failure. AB - The precise temporal and spatial expressions of specific transcription regulation factors (TRF) have long been considered essential for spermatogenesis. Recently, it has been speculated that mammals have evolved more specialised TRF genes. In the human, the TAF7L gene may be essential for maintenance of spermatogenesis. In this study, we investigated the possible role of the TAF7L gene located on the X chromosome in testicular function and spermatogenic failure. In a case-controlled retrospective study, we recruited 16 infertile males with consistent, nonobstructive azoospermia and with normal serum follicle-stimulating hormone (FSH) levels. Twenty age-matched men with normal spermatogenesis with the same ethnic background (Caucasian) were recruited as controls. Their genomic DNA was screened for sequence changes in the coding regions and part of the flanking introns of the TAF7L gene by direct sequencing. Amino acid sequence was compared with the NCBI standard sequence (BC043391). Semen analysis and hormone evaluation were performed. We observed six sequence variations in four patients, consisting of two point mutations, one each in exon 9 and 13 and one six-basepair deletion in exon 13 with concomitant changes in amino acid. One additional nucleotide exchange was observed in intron 8. Most of these changes were also found in eight controls with the exception of changes in exon 13. A meta-analysis including the present study and literature data suggests a possible association of the point mutation in exon 13 with infertility. There was no association or relationship with reproductive hormones. In conclusion, the sequence variants in the cDNA sequence observed are common polymorphisms. The changes in intron 8 appear novel. We report for the first time that most of the alterations are not associated with gonadal dysfunction, while the sequence variant in exon 13 may represent a risk factor for spermatogenic failure. PMID- 17714219 TI - Male infertility as a component of Carney complex. AB - Carney complex (CNC) is a multiple neoplasia syndrome characterised by endocrine tumours, spotty skin pigmentation, cardiac and other myxomas, psamommatous and pigmented schwannomas, large cell calcifying Sertoli cell tumours, and mammary ductal adenomas and other more rare lesions. CNC is inherited in an autosomal dominant manner and has been mapped to at least two chromosomal loci. Patients who map to the CNC1 locus located on chromosome 17 carry inactivating mutations of the PRKAR1A gene that encodes the cAMP-dependent protein kinase regulatory subunit type 1-alpha (Kirschner et al., 2000). One gene responsible for type 2 (CNC2) is located on chromosome 2p16. Infertility in CNC can be caused by a number of factors; there is evidence that prkar1a deficiency in mice leads directly to infertility (Burton et al., 2006), but patients with CNC also have Sertoli cell tumours and a number of other reasons to affect fertility. We report on an infertile male with CNC and present evidence that male infertility should be considered as part of the phenotype of CNC. PMID- 17714220 TI - Azoospermia in a renal transplant recipient during sirolimus (rapamycin) treatment. AB - Sirolimus is used as a powerful immunosuppressant drug in patients after organ transplantation. It was shown to block spermatogenesis by interrupting the stem cell factor/c-kit system. Oligozoospermia was shown in single patients. In addition, a decrease of testosterone and an increase of gonadotropin levels were observed. We report on a young patient who showed azoospermia during the treatment with sirolimus after renal transplantation. After changing the immunosuppression to tacrolimus, spermatogenesis of the patient recovered. Five months after cessation of the treatment with sirolimus, a sperm concentration of 8 x 10(6) ml(-1) was found. Depression of spermatogenesis is an important side effect in younger men who aspire paternity, so that waiving of sirolimus is advisable in these patients. PMID- 17714223 TI - Verbal and physical abuse and neglect as manifestations of HIV/AIDS stigma in five African countries. AB - OBJECTIVE: To explore the experience of HIV/AIDS-related stigma for people living with HIV/AIDS (PLWA) in Lesotho, Malawi, South Africa, Swaziland, and Tanzania. DESIGN AND SAMPLE: Descriptive study using 43 focus groups (n=251 participants), which included male and female PLWA from both rural and urban areas and nurses working with PLWA. METHODS: Participants were asked to relate incidents of HIV/AIDS-related stigma that they had experienced or observed. Focus group discussions were taped, and data were content analyzed to identify examples of abuse (verbal and physical abuse and neglect) related to HIV/AIDS stigma. Data analysis also explored targets of abuse, abusers, and consequences of abuse. RESULTS: Participant reports documented extensive verbal and physical abuse and neglect or negating (disallowing of access to services and opportunities) experienced by PLWA and observed by nurses caring for them, and identified negative consequences experienced by PLWA whose HIV-positive status was disclosed to family, friends, or community members. CONCLUSIONS: Health care workers who encourage PLWA to disclose their HIV status must carefully consider the implications of encouraging disclosure in an environment with high levels of stigma, and must recognize the real possibility that PLWA may experience serious verbal and physical abuse as a consequence of disclosure. PMID- 17714224 TI - Talk-story: perspectives of children, parents, and community leaders on community violence in rural Hawaii. AB - PURPOSE: To enhance our understanding of what community violence means to a multiethnic school community in rural Hawaii and obtain people's perspectives of how to deal with and prevent violence-related behaviors among children. DESIGN AND SAMPLE: An exploratory design was used to collect qualitative data from a purposive sample of 150 key stakeholder participants, including 84 school children aged 5-10 years and 66 adults. MEASUREMENT: Focus group methodology via Hawaiian island-style (culturally adapted techniques) of "talk-story" and a metaphor of introduction were used to elicit contextual data on the experiences, meanings, and perceptions of youth violence. Qualitative narrative analyses were used to analyze the data. RESULTS: Five higher order themes were found, including the need to: build a common understanding of what violence looks like; develop school-based identification, management, and prevention efforts; develop comprehensive school health services; develop state-level school health policies; and conduct outreach to make violence prevention a community affair. CONCLUSION: The findings will inform the development of a school-based culturally adapted violence-prevention program led by teachers, in partnership with parents, students, and community-cultural leaders. PMID- 17714225 TI - Legacies of advantage and disadvantage: the case of teen mothers. AB - OBJECTIVES: The life trajectories of teen mothers and their children were examined with data from a larger longitudinal study. DESIGN: All 5 waves of the study were designed from the hermeneutic tradition. SAMPLE: Sixteen families began the study in 1988-1989 (Time 1) and were invited to participate in subsequent studies (1993, 1997, 2001, and 2005). Twenty-eight informants participated in the fifth wave of the study (Time 5). MEASUREMENT: This analysis capitalized on the diversity of teen mothers' family backgrounds to examine the life chances of mothers and their first-born children as mothers entered their 30s. Three domains are addressed: teen mothers' educational attainment, their social class status, and their oldest child's school progress and sexual activity. RESULTS: Teen mothers' life trajectories reflected legacies of unequal life chances that began in childhood and persisted into their 30s. Mothers with childhood advantages fared better over time than impoverished mothers, and a legacy of advantage contributed to a cushion of safety and opportunity for their teenaged children. CONCLUSION: The powerful legacy of social class and racial divisions on teen mothers' long-term outcomes challenges the view that teen mothering leads to a downward spiral with negative repercussions for mothers and children. PMID- 17714226 TI - Public health perspectives on the rising incidence of pertussis. AB - OBJECTIVES: Pertussis is one of the few vaccine-preventable diseases on the rise in the United States, particularly among adolescents. We analyzed the epidemiology of pertussis, focusing on disease burden in public health, and examined methods for controlling pertussis and reducing its incidence. DESIGN, SAMPLE, AND MEASUREMENTS: We evaluated current knowledge about pertussis, reported cases of pertussis in the United States, and the changing recognition, diagnosis, and management of the disease. The development of a pertussis vaccine, now licensed and recommended for use in adolescents and adults, was reviewed. RESULTS: Of reported cases in 2004, 38% occurred in adolescents. The increased incidence of pertussis may be the result of better diagnosis, better reporting, and increased awareness of the disease. The burden of adolescent and adult pertussis is significant and includes medical visits, laboratory tests, treatment for cases and contacts, time lost from school and work, disruption of schools experiencing outbreaks, and public health and media turmoil. At current disease rates, the financial cost of adolescent pertussis in this decade is projected at $3.2 billion. CONCLUSIONS: Efforts are needed to increase health care providers' knowledge of pertussis disease and vaccines, improve on-time infant immunization rates, promote immunization registries and public health surveillance, and ensure adequate compensation for vaccine purchase and administration. Universal recommendations for and widespread use of acellular pertussis vaccines in adolescents are the most effective measures in controlling the disease. PMID- 17714228 TI - Credentialing for public health nurses: personally valued ... But not well recognized. AB - OBJECTIVE: This study examined the extent to which public health nurses (PHNs) see value in credentialing and perceive specific barriers related to a community/public health nursing (C/PHN) credential. DESIGN: A cross-sectional exploratory survey was used to examine the perceived value of credentialing for PHNs and the perceived barriers to obtaining or maintaining the C/PHN credential as the primary variables of interest. SAMPLE: Data were collected from 655 PHN members of national public health nursing organizations who participated in an online survey. MEASUREMENT: Responses related to the perceived value of credentialing were analyzed using factor analysis and descriptive statistics. Data regarding perceived barriers to the C/PHN credential were analyzed through descriptive statistics and through the Borda Count Method for analysis of ranked data (Tannenbaum, 1995). RESULTS: Similar to nurses in other specialties, study participants perceived that credentialing has a high personal value for PHNs, but that certification provides less value in terms of extrinsic recognition. Respondents identified issues related to the lack of external recognition as particular barriers to the C/PHN credential. CONCLUSIONS: These findings provide guidance to public health nursing leaders and inform discussions regarding the development of credentialing systems within the field of public health. PMID- 17714227 TI - Concerns in workforce development: linking certification and credentialing to outcomes. AB - Investments in public health workforce development are based on the assumption that capacity and competencies are linked with the effectiveness and efficiency of providing essential public health services. However, evidence of the effects of workforce quantity or quality on the performance of core public health functions is limited. A review of public health, health care, and teacher education literature was conducted to determine the state of research in the field and to identify promising approaches and study designs for application to public health workforce training. A total of 861 articles and abstracts were reviewed from the health literature and 470 from teacher education literature. Sixty-five reports in the public health or health care literature and 68 in the education literature met the inclusion criteria. Eleven studies in public health or health literature reported positive correlations and 3 determined no substantial correlation to credentials. In the education literature, 10 studies reported a positive link, whereas 9 studies reported mixed or nonsignificant results. We conclude that a paucity of quality research or compelling evidence exists linking certification or credentialing to any related outcome. Until further research is conducted, discussions on the need for public health workforce certification and credentialing will be based on good-faith expectations for improving individual and organizational performance. PMID- 17714229 TI - Factors associated with the professional competencies of public health nurses employed by local government agencies in Japan. AB - OBJECTIVE: This paper aims to clarify some of the factors associated with the professional competencies of public health nurses (PHNs) employed by local government agencies in Japan. DESIGN: A cross-sectional study. SAMPLE: PHNs (N=1,614) working in local government agencies in Japan. MEASUREMENTS: Based on self-reported questionnaires, the nurses were grouped according to experience. Statistical differences between the groups were analyzed using analysis of variance. Multiple regression analyses were used to determine associated factors. RESULTS: Variables contributing to high self-evaluation of interpersonal health support competencies were length of experience as a PHN, an awareness of the role expectations of community health support and administration, marital status, and participation in off-the-job training programs. The same variables contributed to high self-evaluation of community health support and administration competencies. In addition, experience of job transfer or rotation was found to be a variable. CONCLUSIONS: These results show the importance of off-the-job training programs designed to foster exposure to a wide variety of personal and professional experiences. They also illustrate the importance of planned on-the-job training programs that promote an understanding of the nature of the field, as well as developing planning and administrative competency in career development. PMID- 17714230 TI - Clinical specialist in community health nursing: advanced practice fit or misfit? AB - The purpose of this paper is to address several questions and issues about the clinical specialist role in community health nursing. A brief history of the development of the clinical specialist role sets the background for a discussion of how the community health nurse specialist fits within advanced practice nursing. The rationale for including the community health nurse clinical specialist role with other specialist roles is presented. The purpose and importance of certification at the advanced practice level in community health nursing are presented. Continued discussion about these and other issues of importance for the specialty is encouraged. PMID- 17714231 TI - Recommendations from the Exploring Accreditation for State and Local Health Departments: do we have the political will? AB - Acting upon several years of related work from a variety of public health practice arenas, 4 leading public health organizations received funding to conduct a study of the desirability and feasibility of establishing a national voluntary public health accreditation system. The study was conducted by a 25 member Steering Committee, with representatives from public health organizations at the local, state, and federal levels. The study was advised by input from additional numbers of public health experts participating in workgroups, as consultants, or in public comment groups. Public health nursing was represented by 3 members of the Steering Committee, including the chair, and by 7 other nurses who served on work groups or as staff to the process. The report of the study committee, released in the fall of 2006, contained answers to 2 questions related to the desirability and feasibility of such a program. Additionally, the report contained recommendations regarding the program's initial implementation. This article summarizes those recommendations and discusses the policy implications for their implementation, with a special emphasis on the role of the public health nursing community in the establishment of a national voluntary public health accreditation system. PMID- 17714232 TI - Logic model use in developing a survey instrument for program evaluation: emergency preparedness summits for schools of nursing in Georgia. AB - The objective of this paper is to describe a method for using a logic model to guide program evaluation by detailing the steps used, providing diagrams that visually depict the process, and giving an example based on the evaluation of emergency preparedness nursing summits in Georgia. Developing a logic model is an ideal way to visually depict the inputs, activities, outputs, and outcomes of a program, thus providing a clear framework of the workings and functions of the program. In planning a comprehensive evaluation, being able to view all the elements in a program and how they interrelate makes it easier to determine the areas that should be addressed. When a survey is part of a program evaluation, determining that the goals, objectives, research questions, logic model, and survey questions maintain consistency in the way they relate and lead to each other can help document the completeness and symmetry of the assessment. By showing these linkages, the utility of the logic model is maximized and the stakeholders in the assessment of the program have clear evidence that their expectations and needs have been met for a valuable, useful evaluation product. PMID- 17714233 TI - Public health nursing competencies 1953-1966: effective and efficient. AB - The Quad Council of Public Health Nursing Organizations developed public health nursing competencies in 2003. They are guides for determining skills at two levels, and they identify public health nurses as providing care to individuals and families or to populations and systems with the nurse having proficiency, awareness, or knowledge. The primary purpose of this paper is to discuss historical nursing roles and qualifications as judged by the 2003 competencies, including educational preparation and experience for the administrative and staff nurse. The historical exemplar for the nursing roles is a combination public/private nursing association, referred to as the partnership, that took place in 1953-1966. Primary sources include archived material from the Instructive Visiting Nurse Association, Richmond, VA. Administrative responsibilities were divided between the chief nurse and the nursing supervisors. Staff nurse responsibilities included clinic activities, home visitation, and referral coordination between health care organizations. The delineation of nursing roles demonstrates nurses' meeting the 2003 competencies. Based on the Quad Council's 2003 public health nursing competencies, the partnership nurses were competent. PMID- 17714235 TI - A dialogue on the future of nursing practice. AB - PURPOSE: The challenges of health care; its safety, effectiveness, and efficiency; the quality of care; and the outcomes patients experience are issues central to nursing practice. This centrality needs to be affirmed as the profession shapes its practice over the next 50 years. The purpose of this article is to initiate a dialogue on the future of nursing practice. METHODS: The methods used are observation, reflection, dialogue, and proposed actions. FINDINGS: The results of this process are preliminary. They suggest that the establishment of nursing hospitals is a distinct possibility. CONCLUSIONS: This article concludes with a series of arguments for and against this position along with an invitation for your participation in this dialogue. NURSING IMPLICATIONS: The major implications of this article are not "nursing" implications per se but client and patient implications and the future contribution of nursing to improved health and patient care. PMID- 17714236 TI - The expert nurse profile and diagnostic content validity of Sedentary Lifestyle: the Spanish validation. AB - PURPOSE: To identify the diagnostic content validity of Sedentary Lifestyle and to identify the expert nurse profile in validating this nursing diagnosis in the Spanish cultural context. METHODS: Fehring's Diagnostic Content Validity (DCV), the factorial validity of the defining characteristics, the analysis of convergent validity, and the expert profile were assessed. FINDINGS: The DCV index for experts was .70. The factorial validity showed two different factors: the expression of laziness and the performance of activities of daily living. On the expert profile related factors analysis, two factors, experience and education, were identified. CONCLUSIONS: The DCV for Sedentary Lifestyle was high among the expert nurses. A nurse was considered to be an expert who was able to accurately answer the four labels identified as nursing diagnoses, had read at least one nursing process article in the past year, and was able to list three nursing process reference books. IMPLICATIONS FOR PRACTICE: Clarifying the manifestations of sedentary lifestyle will assist clinical nurses in determining this diagnosis, and the expert profiles will assist in the selection of participants for content validity studies. PMID- 17714238 TI - Application of Orem's self-care deficit theory and standardized nursing languages in a case study of a woman with diabetes. AB - PURPOSE: This paper aims to illustrate the process of theory-based nursing practice by presenting a case study of a clinical nurse specialist's assessment and care of a woman with type 2 diabetes. DESIGN: Orem's self-care deficit theory and standardized nursing language, NANDA, NIC (Nursing Interventions Classification), and NOC (Nursing Outcomes Classification), guided assessment and the identification of outcomes and interventions related to the client's management of diabetes. FINDINGS: Theory-based nursing care and standardized nursing language enhanced the client's ability to self-manage the chronic illness: diabetes. CONCLUSION: Nursing theory and standardized nursing language enhance communication among nurses and support a client's ability to self-manage a chronic illness. PMID- 17714237 TI - Measuring diagnostic competency and the analysis of factors influencing competency using written case studies. AB - PURPOSES: To measure nurses' diagnostic competencies by using written case studies and to analyze factors influencing these competencies. METHODS: A descriptive study was conducted using survey methods and a mailed questionnaire with a convenience sample of 376 nurses. Two written case studies were used to measure the diagnostic competencies of the subjects. Possible factors influencing nurses' judgments in making nursing diagnoses that were measured were clinical experience, decision-making responsibility, knowledge of nursing diagnosis, and attitude toward the use of nursing diagnosis. FINDINGS: Subjects who demonstrated all three competencies were 35% (n = 131) for case study 1, and 53% (n = 200) for case study 2. Subjects who demonstrated diagnostic competency in defining diagnostic labels had the longest length of clinical experience. Subjects who were primary nurses with the usual responsibility of identifying nursing diagnoses showed the highest percentage of competency rates for defining characteristics, related factors, and risk factors. CONCLUSIONS: Many of these Japanese nurses did not perform at satisfactory levels of diagnostic competency with these two written case studies. Factors that influenced diagnostic competency were length of clinical experience, decision-making responsibility, and frequency of studying nursing diagnosis. PMID- 17714246 TI - Genome justice: genetics and group rights. PMID- 17714247 TI - Population genomics and research ethics with socially identifable groups. AB - In this paper, the author questions whether the research ethics guidelines and procedures are robust enough to protect groups when conducting genetics research with socially identifiable populations, particularly with Native American groups. The author argues for a change in the federal guidelines in substance and procedures of conducting genetic research with socially identifiable groups. PMID- 17714248 TI - Genes and spleens: property, contract, or privacy rights in the human body? AB - This article compares three frameworks for legal regulation of the human body. Property law systematically favors those who use the body to create commercial products. Yet contract and privacy rights cannot compete with the property paradigm, which alone affords a complete bundle of rights enforceable against the whole world. In the face of researchers' property rights, the theoretical freedom to contract and the meager interest in privacy leave those who supply body parts vulnerable to exploitation. PMID- 17714250 TI - Cultural challenges to biotechnology: Native American genetic resources and the concept of cultural harm. AB - This article examines the intercultural context of issues related to genetic research on Native peoples. In particular, the article probes the disconnect between Western and indigenous concepts of property, ownership, and privacy, and examines the harms to Native peoples that may arise from unauthorized uses of blood and tissue samples or the information derived from such samples. The article concludes that existing legal and ethical frameworks are inadequate to address Native peoples' rights to their genetic resources and suggests an intercultural framework for accommodation based on theories of intergroup equality and fundamental human rights. PMID- 17714249 TI - Human genetics studies: the case for group rights. AB - In this essay, the author focuses on an underlying theoretical issue which she believes seriously affects our collective response to the idea of group rights in the genetic-control context. That issue is to what extent are our responses to claims of group rights hampered by our bringing to the table (consciously or unconsciously) a model which is structured to acknowledge only individual concerns? Put another way, to what extent are our objections to group rights in this context a product of our inability (or refusal) to imagine the idea of group rights, rather than the product of truly substantive concerns? PMID- 17714251 TI - Narratives of race and indigeneity in the Genographic Project. AB - In its quest to sample 100,000 "indigenous and traditional peoples," the Genographic Project deploys five problematic narratives: (1) that "we are all African"; (2) that "genetic science can end racism"; (3) that "indigenous peoples are vanishing"; (4) that "we are all related"; and (5) that Genographic "collaborates" with indigenous peoples. In so doing, Genographic perpetuates much critiqued, yet longstanding notions of race and colonial scientific practice. PMID- 17714252 TI - The human genome as common heritage: common sense or legal nonsense? AB - This essay identifies two legal lineages underlying the common heritage concept, and applies each to the human genome. The essay notes some advantages and disadvantages of each approach, and argues that patenting of human genes would be allowable under either approach. PMID- 17714253 TI - Partnership in U.K. Biobank: a third way for genomic property? AB - A property analysis of the U.K. Biobank reveals a new imagination of the genomic biobank as a national common-pool resource. U.K. Biobank's treatment of property and governance exhibit both strengths and weaknesses that may be instructive to genome project planners around the world. PMID- 17714254 TI - Individuality and human beginnings: a reply to David DeGrazia. AB - The author argues that individuality does not require indivisibility and that twinning can be explained as the reprogramming of blastomeres that already have begun to differentiate in accordance with the needs of the unified organism that originates at conception. PMID- 17714255 TI - Discontinuity and disaster: gaps and the negotiation of culpability in medication delivery. AB - This paper shows how discontinuities in the process of drug delivery enable but also underdetermine the isolation of a culprit in adverse medication events. A case example illustrates how we are forced to abandon conceptualizations of blame that assume a dichotomy (either culpable or not), and shift instead to a more nuanced version that estimates the degree to which an actor desired, generated, or could have foreseen the harmful outcome, and the extent to which constraints external to the actor altered the event. The paper concludes that meaningful safety interventions in a system as diverse, socially embedded and complex as health care delivery cannot just build on "good science" (e.g., good methods) to generate "root" causes. Rather, they need to somehow be sensitive to how and which narratives of success and failure are created, as these constrain which countermeasures are likely to be encouraged, funded, and accepted. PMID- 17714256 TI - Off the grid: vaccinations among homeschooled children. AB - To protect public health, states require that parents have their children immunized before they are permitted to attend public or private school. But for homeschooled children, the rules vary. With the spectacular growth in the number of homeschooled students, it is becoming more difficult to reach these youth to ensure that they are immunized at all. These children are frequently unvaccinated, leaving them open to infection with diseases that are all but stamped out in the United States with immunization requirements. States should encourage parents to get their homeschooled students vaccinated through enacting the same laws as those used for public school students. This could be done by enforcing current laws through neglect petitions or by requiring that children be immunized before participating in school sponsored programs. As most states require some filing to allow parents to homeschool their children, it would be easy to enact laws requiring that homeschooled children be immunized or exempted before completing registration. PMID- 17714257 TI - Informed consent: physician inexperience is a material risk for patients. AB - This paper examines the case for an expanded interpretation of the concept of "material risk" such that it necessitates voluntary disclosure of physician inexperience with a specific medical procedure. Informed consent law in the United States, Canada, and most commonwealth jurisdictions has become a driver of standards of risk disclosure by physicians during the informed consent process. The legal standard of risk disclosure expected of a physician hinges on the interpretation of the entity called "material risk." Any impairment of the physician related to drug usage, disease, or alcohol which compounds the risk of a procedure is very likely to be considered material by a patient. This paper argues that physician inexperience is a factor that a reasonable patient would attach significance to and that it should therefore be viewed as a "material risk" requiring disclosure. PMID- 17714258 TI - Libertarianism and universal health care: it's not what you think it is. PMID- 17714259 TI - The Professor's viewpoint: should we say what we think in the classroom? PMID- 17714260 TI - Mandatory cervical cancer vaccinations. PMID- 17714261 TI - State-dependent risk-taking by green sea turtles mediates top-down effects of tiger shark intimidation in a marine ecosystem. AB - 1. A predictive framework of community and ecosystem dynamics that applies across systems has remained elusive, in part because non-consumptive predator effects are often ignored. Further, it is unclear how much individual-level detail community models must include. 2. Previous studies of short-lived species suggest that state-dependent decisions add little to our understanding of community dynamics. Body condition-dependent decisions made by long-lived herbivores under risk of predation, however, might have greater community-level effects. This possibility remains largely unexplored, especially in marine environments. 3. In the relatively pristine seagrass community of Shark Bay, Australia, we found that herbivorous green sea turtles (Chelonia mydas Linnaeus, 1758) threatened by tiger sharks (Galeocerdo cuvier Peron and LeSueur, 1822) select microhabitats in a condition-dependent manner. Turtles in poor body condition selected profitable, high-risk microhabitats, while turtles in good body condition, which are more abundant, selected safer, less profitable microhabitats. When predation risk was low, however, turtles in good condition moved into more profitable microhabitats. 4. Condition-dependent use of space by turtles shows that tiger sharks modify the spatio-temporal pattern of turtle grazing and their impacts on ecosystem dynamics (a trait-mediated indirect interaction). Therefore, state-dependent decisions by individuals can have important implications for community dynamics in some situations. 5. Our study suggests that declines in large-bodied sharks may affect ecosystems more substantially than assumed when non-lethal effects of these top predators on mesoconsumers are not considered explicitly. PMID- 17714262 TI - Time allocation of a parasitoid foraging in heterogeneous vegetation: implications for host-parasitoid interactions. AB - 1. Changing plant composition in a community can have profound consequences for herbivore and parasitoid population dynamics. To understand such effects, studies are needed that unravel the underlying behavioural decisions determining the responses of parasitoids to complex habitats. 2. The searching behaviour of the parasitoid Diadegma semiclausum was followed in environments with different plant species composition. In the middle of these environments, two Brassica oleracea plants infested by the host Plutella xylostella were placed. The control set-up contained B. oleracea plants only. In the more complex set-ups, B. oleracea plants were interspersed by either Sinapis alba or Hordeum vulgare. 3. Parasitoids did not find the first host-infested plant with the same speed in the different environments. Sinapis alba plants were preferentially searched by parasitoids, resulting in fewer initial host encounters, possibly creating a dynamic enemy-free space for the host on adjacent B. oleracea plants. In set-ups with H. vulgare, also, fewer initial host encounters were found, but in this case plant structure was more likely than infochemicals to interfere with the searching behaviour of parasitoids. 4. On discovering a host-infested plant, parasitoids located the second host-infested plant with equal speed, demonstrating the effect of experience on time allocation. Further encounters with host-infested plants that had already been visited decreased residence times and increased the tendency to leave the environment. 5. Due to the intensive search of S. alba plants, hosts were encountered at lower rates here than in the other set-ups. However, because parasitoids left the set-up with S. alba last, the same number of hosts were encountered as in the other treatments. 6. Plant composition of a community influences the distribution of parasitoid attacks via its effects on arrival and leaving tendencies. Foraging experiences can reduce or increase the importance of enemy-free space for hosts on less attractive plants. PMID- 17714263 TI - Resource selection by female moths in a heterogeneous environment: what is a poor girl to do? AB - 1. According to the preference-performance hypothesis, female insects select resources that maximize offspring performance. To achieve high fitness, leaf miner females should then adjust their oviposition behaviour in response to leaf attributes signalling high host quality. 2. Here we investigate resource selection in Tischeria ekebladella, a leaf-mining moth of the pedunculate oak (Quercus robur), in relation to two alternative hypotheses: (1) females select their resources with respect to their future quality for developing larvae; or (2) temporal changes in resource quality prevent females from selecting the best larval resources. 3. Specifically, we test whether females show the strongest selection at the levels at which quality varies the most (shoots and leaves); whether they respond to specific leaf attributes (leaf size, phenolic content and conspecific eggs); and whether female preference is reflected in offspring performance. 4. Female choice of leaves was found to be non-random. Within trees, the females preferred certain shoots, but when the shoots were on different trees the degree of discrimination was about four times larger than when they were on the same trees. 5. While females typically lay more eggs on large leaves, this is not a result of active selection of large leaves, but rather a result of females moving at random and ovipositing at regular intervals. 6. The females in our study did not adjust their oviposition behaviour in response to leaf phenolic contents (as measured by the time of larval feeding). Neither did they avoid leaves with conspecific eggs. 7. Female choice of oviposition sites did not match patterns of offspring performance: there was no positive association between offspring survival and counts of eggs. 8. We propose that temporal variation in resource quality may prevent female moths from evaluating resource quality reliably. To compensate for this, females may adopt a risk-spreading strategy when selecting their resources. PMID- 17714264 TI - The effects of latitude and day length on fattening strategies of wintering coal tits Periparus ater (L.): a field study and aviary experiment. AB - 1. Cyclic daily fattening routines are very common in wintering small wild birds, and are thought to be the consequence of a trade-off between different environmental and state-dependent factors. According to theory, these trajectories should range from accelerated (i.e. mass increases exponentially towards dusk) when mass-dependent predation costs are the most important cause of mortality risk, to decelerated (i.e. the rate of mass gain is highest at dawn and decreases afterward) when starvation is the greater risk. 2. We examine if geographically separate populations of coal tits, wintering in Scotland and central Spain under contrasting photoperiods, show differences in their strategies of daily mass regulation. We describe population differences in wild birds under natural conditions, and experimentally search for interpopulation variation in diurnal body mass increase under common, manipulated, photoperiod conditions (LD 9 : 15 h vs. 7 : 17 h), controlling for temperature, food availability, predator pressure and foraging arena. 3. Winter diurnal mass gain of wild coal tits was more delayed towards the latter part of the daylight period in central Spain (i.e. the locality with longer winter days) than in Scotland. In both localities, the pattern was linked to the average mass at dawn, with mass increasing more rapidly in lighter birds. However, under the controlled photoperiod situation the pattern of daily mass gain was similar in both populations. Diurnal body mass gain was more accelerated at the end of the day, and the increase in body mass in the first hour of the day was considerably lower under the long (9 h) than under the short (7 h) photoperiod in both populations. 4. Wintering coal tits show patterns of mass gain through the day that are compatible with current theories of the costs and benefits of fat storage, with birds at lower latitudes (with longer winter days) having a greater tendency to delay mass gain until late in the day. The experimental study revealed that these patterns are plastic, with birds responding directly to the photoperiod that they experience, suggesting that they are continually making fine-scale adjustments to energy reserves on the basis of both inherent (e.g. state-dependent) and extrinsic cues. PMID- 17714266 TI - Why do female lizards lay their eggs in communal nests? AB - 1. In many reptile species, females oviposit communally (i.e. many clutches are laid within the same nest). This behaviour might result from constraint (scarcity of nest-sites offering suitable incubation conditions) or adaptation (direct fitness benefits accruing from the proximity of other eggs). 2. To test between these alternatives, we gathered field and laboratory data on montane scincid lizards Bassiana duperreyi from south-eastern Australia. Our data support the adaptationist hypothesis. 3. In the field, communal vs. solitary clutches were laid in similar sites, and the relative frequency of communal nesting was not predictable from nest-site availability. Thermal regimes for incubation did not differ between communal vs. solitary nests, nor between eggs at the core vs. periphery of a communal nest. In the laboratory, females selectively oviposited beside existing eggs rather than in otherwise identical potential nesting sites. 4. From cycling-temperature incubation in the laboratory, eggs incubated within a cluster of other eggs took up less water, but produced hatchlings that were larger and faster-running than were hatchlings from eggs incubated alone. 5. Hydric modifications of incubation conditions within a cluster of tightly packed eggs thus may provide a direct fitness benefit to communal oviposition. PMID- 17714265 TI - Prolonging the arctic pulse: long-term exploitation of cached eggs by arctic foxes when lemmings are scarce. AB - 1. Many ecosystems are characterized by pulses of dramatically higher than normal levels of foods (pulsed resources) to which animals often respond by caching foods for future use. However, the extent to which animals use cached foods and how this varies in relation to fluctuations in other foods is poorly understood in most animals. 2. Arctic foxes Alopex lagopus (L.) cache thousands of eggs annually at large goose colonies where eggs are often superabundant during the nesting period by geese. We estimated the contribution of cached eggs to arctic fox diets in spring and autumn, when geese were not present in the study area, by comparing stable isotope ratios (delta(13)C and delta(15)N) of fox tissues with those of their foods using a multisource mixing model in Program IsoSource. 3. The contribution of cached eggs to arctic fox diets was inversely related to collared lemming Dicrostonyx groenlandicus (Traill) abundance; the contribution of cached eggs to overall fox diets increased from < 28% in years when collared lemmings were abundant to 30-74% in years when collared lemmings were scarce. 4. Further, arctic foxes used cached eggs well into the following spring (almost 1 year after eggs were acquired) - a pattern that differs from that of carnivores generally storing foods for only a few days before consumption. 5. This study showed that long-term use of eggs that were cached when geese were superabundant at the colony in summer varied with fluctuations in collared lemming abundance (a key component in arctic fox diets throughout most of their range) and suggests that cached eggs functioned as a buffer when collared lemmings were scarce. PMID- 17714267 TI - Migration of the painted lady butterfly, Vanessa cardui, to north-eastern Spain is aided by African wind currents. AB - 1. Thousands of records of migratory butterfly species such as Vanessa cardui flying just above ground-level on fixed compass bearings have led to the common belief that these insects migrate within the so-called 'flight-boundary layer', where movements are relatively independent of the wind. 2. Given the selective advantages of windborne migration and the existence of a number of observations of flights of V. cardui from the upper levels of the atmosphere, we tested the hypothesis that migration from North Africa to southern Europe in this species is influenced by synoptic-scale wind currents. 3. Even with modern technology, it is extremely difficult to observe high-altitude flights directly, so we rely on an indirect approach that examines whether or not arrival peaks in north-eastern Spain are associated with winds blowing from Africa. 4. Arrivals of V. cardui were determined for the spring period (1 March-27 June, 1997-2006) at 79 sites in the Catalan Butterfly Monitoring Scheme. Wind patterns were described on the basis of synoptic-scale maps, transport models and back-trajectories calculated for each day of the spring period. 5. We found a strong association between migration and winds from North Africa, both for the whole data set (1997-2006; chi(2) = 4.7, P = 0.03) and for a restricted data set that excludes years in which the species was very scarce (chi(2) = 7.26, P = 0.007). 6. Episodes of massive northward migration within the species' flight-boundary layer also coincided with spells of winds from North Africa, suggesting a connection between low-altitude (observational) and high-altitude flights (inferred from wind patterns). 7. Finally, on the assumption that migration in V. cardui is windborne, a source-receptor transport model applied to spring abundance data in north-eastern Spain enables us to identify the most probable population source areas in North Africa. PMID- 17714268 TI - Demographic analysis of a declining pika Ochotona collaris population: linking survival to broad-scale climate patterns via spring snowmelt patterns. AB - 1. Demographic analysis is essential in order to determine which factors, such as survival, fertility and other life-history characteristics, have the greatest influence on a population's rate of growth (lambda). 2. We used life-table response experiments (LTREs) to assess the relative importance of survival and fertility rates for an alpine lagomorph, the collared pika Ochotona collaris, using 12 years (1995-2006) of census data. The LTRE analysis was repeated for each of three subpopulations within the main study site that were defined by aspect (east, west and south). 3. Across the entire study site, the survival and fertility of adults contributed 35.6 and 43.5%, respectively, to the variance observed in the projected population growth rate, V(lambda), whereas juvenile survival contributed 20.9%. Adult survival and fertility contributed approximately equal amounts for each subpopulation when considered separately, although their rank order varied spatially. 4. Adult survival across the entire site was positively correlated to the Pacific Decadal Oscillation (PDO) with a time lag of 1 year, and was uncorrelated to adult density. The PDO was negatively correlated to the timing of spring snowmelt at our site, implicating the importance of earlier spring conditions and plant phenology on the subsequent winter survival of adults and therefore, population growth. 5. When subpopulations were analysed separately, survivals and fertilities were variously correlated to lagged PDO and adult densities, but the patterns varied spatially. Therefore, the mechanisms underlying V(lambda) can vary substantially over relatively short distances. PMID- 17714269 TI - Family effects on early survival and variance in long-term reproductive success of female cheetahs. AB - 1. While it is generally accepted that the survival of offspring within families may be correlated, the extent of correlation has been largely untested. Furthermore, the impact of such correlation on the estimated variance in females' reproductive success has rarely been quantified. 2. Here we use an exceptional data set from a long-term study of individually recognized cheetahs from the Serengeti National Park in Tanzania to formally quantify family effects in carnivores. 3. We show (i) that cubs from the same litter exhibit more similar fates than unrelated cubs when it comes to first-year survival; and (ii) that the observed variance of the long-term reproductive success of females is twice the variance expected under the assumption of complete independence of fates between cubs. 4. We suggest that family effects are likely to be widespread in vertebrates with average litter sizes > 1, and could have important consequences for population dynamics and population viability analyses. PMID- 17714270 TI - Age-related change in breeding performance in early life is associated with an increase in competence in the migratory barn swallow Hirundo rustica. AB - 1. We investigated age-related changes in two reproductive traits (laying date and annual fecundity) in barn swallows Hirundo rustica L. using a mixed model approach to di-stinguish among between- and within-individual changes in breeding performance with age. 2. We tested predictions of age-related improvements of competence (i.e. constraint hypothesis) and age-related progressive disappearance of poor-quality breeders (i.e. selection hypothesis) to explain age-related increase in breeding performance in early life. 3. Reproductive success increased in early life, reaching a plateau at middle age (e.g. at 3 years of age) and decreasing at older age (> 4 years). Age-related changes in breeding success were due mainly to an effect of female age. 4. Age of both female and male affected timing of reproduction. Final linear mixed effect models (LME) for laying date included main and quadratic terms for female and male age, suggesting a deterioration in reproductive performance at older age for both males and females. 5. We found evidence supporting the constraints hypothesis that increases in competence within individuals, with ageing being the most probable cause of the observed increase in breeding performance with age in early life. Two mechanisms were implicated: (1) advance in male arrival date with age provided middle-aged males with better access to mates. Yearling males arrived later to the breeding grounds and therefore had limited access to high-quality mates. (2) Breeding pairs maintaining bonds for 2 consecutive years (experienced pairs) had higher fecundity than newly formed inexperienced breeding pairs. 6. There was no support for the selection hypothesis because breeding performance was not correlated with life span. 7. We found a within-individual deterioration in breeding and migratory performance (arrival date) in the oldest age-classes consistent with senescence in these reproductive and migratory traits. PMID- 17714271 TI - The impact of disease on the survival and population growth rate of the Tasmanian devil. AB - 1. We investigated the impact of a recently emerged disease, Devil Facial Tumour Disease (DFTD), on the survival and population growth rate of a population of Tasmanian devils, Sarcophilus harrisii, on the Freycinet Peninsula in eastern Tasmania. 2. Cormack-Jolly-Seber and multistate mark-recapture models were employed to investigate the impact of DFTD on age- and sex-specific apparent survival and transition rates. Disease impact on population growth rate was investigated using reverse-time mark-recapture models. 3. The arrival of DFTD triggered an immediate and steady decline in apparent survival rates of adults and subadults, the rate of which was predicted well by the increase in disease prevalence in the population over time. 4. Transitions from healthy to diseased state increased with disease prevalence suggesting that the force of infection in the population is increasing and that the epidemic is not subsiding. 5. The arrival of DFTD coincided with a marked, ongoing decline in the population growth rate of the previously stable population, which to date has not been offset by population compensatory responses. PMID- 17714272 TI - Effects of maternal care on the lifetime reproductive success of females in a neotropical harvestman. AB - 1. Few studies have experimentally quantified the costs and benefits of female egg-guarding behaviour in arthropods under field conditions. Moreover, there is also a lack of studies assessing separately the survival and fecundity costs associated with this behavioural trait. 2. Here we employ field experimental manipulations and capture-mark-recapture methods to identify and quantify the costs and benefits of egg-guarding behaviour for females of the harvestman Acutisoma proximum Mello-Leitao, a maternal species from south-eastern Brazil. 3. In a female removal experiment that lasted 14 days, eggs left unattended under natural conditions survived 75.6% less than guarded eggs, revealing the importance of female presence preventing egg predation. 4. By monitoring females' reproductive success for 2 years, we show that females experimentally prevented from guarding their eggs produced new clutches more frequently and had mean lifetime fecundity 18% higher than that of control guarding females. 5. Regarding survival, our capture-mark-recapture study does not show any difference between the survival rates of females prevented from caring and that of control guarding females. 6. We found that experimentally females prevented from guarding their eggs have a greater probability to produce another clutch (0.41) than females that cared for the offspring (0.34), regardless of their probability of surviving long enough to do that. 7. Our approach isolates the ecological costs of egg guarding that would affect survival, such as increased risk of predation, and suggests that maternal egg-guarding also constrains fecundity through physiological costs of egg production. 8. Weighting costs and benefits of egg guarding we demonstrate that the female's decision to desert would imply an average reduction of 73.3% in their lifetime fitness. Despite the verified fecundity costs of egg-guarding, this behaviour increases female fitness due to the crucial importance of female presence aimed to prevent egg predation. PMID- 17714273 TI - Understanding contributions of cohort effects to growth rates of fluctuating populations. AB - 1. Understanding contributions of cohort effects to variation in population growth of fluctuating populations is of great interest in evolutionary biology and may be critical in contributing towards wildlife and conservation management. Cohort-specific contributions to population growth can be evaluated using age specific matrix models and associated elasticity analyses. 2. We developed age specific matrix models for naturally fluctuating populations of stoats Mustela erminea in New Zealand beech forests. Dynamics and productivity of stoat populations in this environment are related to the 3-5 year masting cycle of beech trees and consequent effects on the abundance of rodents. 3. The finite rate of increase (lambda) of stoat populations in New Zealand beech forests varied substantially, from 1.98 during seedfall years to 0.58 during post seedfall years. Predicted mean growth rates for stoat populations in continuous 3 , 4- or 5-year cycles are 0.85, 1.00 and 1.13. The variation in population growth was a consequence of high reproductive success of females during seedfall years combined with low survival and fertility of females of the post-seedfall cohort. 4. Variation in population growth was consistently more sensitive to changes in survival rates both when each matrix was evaluated in isolation and when matrices were linked into cycles. Relative contributions to variation in population growth from survival and fertility, especially in 0-1-year-old stoats, also depend on the year of the cycle and the number of transitional years before a new cycle is initiated. 5. Consequently, management strategies aimed at reducing stoat populations that may be best during one phase of the beech seedfall cycle may not be the most efficient during other phases of the cycle. We suggest that management strategies based on elasticities of vital rates need to consider how population growth rates vary so as to meet appropriate economic and conservation targets. PMID- 17714274 TI - A critical look at some widely used estimators in mark-resighting experiments. AB - 1. For many species and circumstances, mark-resighting procedures constitute valid alternatives to capture-recapture methods. Indeed, resightings are generally cheaper to acquire than physically recapturing and rehandling the animals, especially when radiotelemetry or other tracking devices are available. 2. In order to estimate population abundance, the joint hypergeometric maximum likelihood estimator, the Minta-Mangel estimator and the Bowden estimator are implemented in noremark, software which has become very popular with biologists in the past decade. 3. In this paper, the basic assumptions regarding these widely applied procedures are delineated and discussed. A simulation study is performed in order to investigate the robustness of the estimators under failure of the assumptions. 4. Theoretical considerations and simulation results motivate the use of the Bowden estimator which, when marks are distributed quite evenly among groups, constitutes the sole reliable method, offering computational simplicity and robustness. On the other hand, if the marks are distributed unevenly, no mark-resighting procedure seems reliable. An application to a case study is considered. PMID- 17714275 TI - Positive effects of helpers on reproductive success in the brown treecreeper and the general importance of future benefits. AB - 1. Numerous studies of cooperatively breeding species have tested for effects of helpers on reproductive success to evaluate hypotheses for the evolution of cooperation, but relatively few have used experimental or statistical approaches that control for the confounding effects of breeder and territory quality. 2. In the brown treecreeper Climacteris picumnus, most helpers are male offspring of the breeding pair that have delayed dispersal. We analysed 5 years of data (97 territory-years) using hierarchical linear modelling to test for effects of helpers on reproductive success while controlling for confounding factors. 3. The number of helpers was related positively to reproductive success even after controlling for differences between territories and breeders. A threshold effect was observed, with success increasing most with the presence of a second helper (i.e. at group size of four). 4. Feeding at the nest was one mechanism responsible for this effect, as larger groups had higher total feeding rates at all nesting stages. Higher total feeding rates, as well as higher feeding rates by helpers, were correlated in turn with greater reproductive success. 5. An analysis of the effects of helper feeding rate on reproductive success in groups with just one helper produced only weak support for a positive effect of helpers. Controlled comparisons of this kind utilize only a small fraction of the total data available and thus have limited statistical power compared to hierarchical or mixed-modelling. 6. A number of hypotheses to explain the evolution and maintenance of helping behaviour are consistent with our results for brown treecreepers including kin selection and hypotheses based on future direct benefits. 7. A previous synthesis of studies of helper effects that controlled for confounding factors suggested a pattern in which male helpers rarely have positive effects on reproductive success. However, revising that synthesis to include recent hierarchical or mixed-modelling studies suggests that helpers of both sexes usually have positive effects, and that the relative importance of future direct benefits may have been underestimated. PMID- 17714276 TI - Low functional diversity and no redundancy in British avian assemblages. AB - 1. Spatial and temporal patterns in functional diversity can reveal the patterns and processes behind community assembly and whether ecological redundancy exists. Here, we analyse functional diversity in British avian assemblages over a period of about 20 years. 2. Functional diversity is generally lower than expected by chance, indicating that assemblages contain species with relatively similar functional traits. One potential explanation is filtering for traits suitable to particular habitats, though other explanations exist. 3. There was no evidence of ecological redundancy over the 20 years. In fact, changes in functional diversity were almost exactly proportional to changes in species richness. 4. The absence of functional redundancy results from little redundancy intrinsic to the species' functional relationships and also because compositional change was nonrandom. Observed extinction and colonization events caused greater changes in functional diversity than if these events were random. 5. Our findings suggest that community assembly is influenced by the traits of species and that observed changes in functional diversity provide no reason to believe that the functioning of natural systems is buffered against change by ecological redundancy. PMID- 17714277 TI - Interactions of components of habitats alter composition and variability of assemblages. AB - 1. The nature and resources supplied by different components of habitats influence species, creating variability from place to place within a habitat. 2. Experiments were done to investigate the effects of altering components of habitats on the variability of assemblages of numerous species of intertidal gastropods. 3. Artificial habitats with three levels of structure, combining different types of turf (i.e. different densities and height of fronds) were sampled 8 weeks after deployment in the intertidal. They were rapidly colonized by up to 66 species of gastropods. 4. Independently of the types of turf combined to form different habitats, there were differences in assemblages where there was more than one type of component present. Multivariate dissimilarities among units making up each habitat were also greater where there were more than one type of unit, but there was no such difference in the variance of numbers of species per unit. 5. Altering the relative abundances of different types of components made little change to the assemblages, nor their multivariate variability among units of habitat and the variance in number of species per unit in each habitat. 6. Differences in assemblages due to the different structure of habitat are complex to interpret and simple characterizations of structure of habitat are inadequate. Comparing different habitats requires appropriate experimentation to ensure that variability within habitats is also investigated. PMID- 17714278 TI - The role of prey size and abundance in the geographical distribution of spider sociality. AB - 1. Social species in the spider genus Anelosimus predominate in lowland tropical rainforests, while congeneric subsocial species occur at higher elevations or higher latitudes. 2. We conducted a comparative study to determine whether differences in total biomass, insect size or both have been responsible for this pattern. 3. We found that larger average insect size, rather than greater overall biomass per se, is a key characteristic of lowland tropical habitats correlating with greater sociality. 4. Social species occupied environments with insects several times larger than the spiders, while subsocial species nearing dispersal occupied environments with smaller insects in either high or low overall biomass. 5. Similarly, in subsocial spider colonies, individuals lived communally at a time when they were younger and therefore smaller than the average insect landing on their webs. 6. We thus suggest that the availability of large insects may be a critical factor restricting social species to their lowland tropical habitats. PMID- 17714279 TI - Food limitation and insect outbreaks: complex dynamics in plant-herbivore models. AB - 1. The population dynamics of many herbivorous insects are characterized by rapid outbreaks, during which the insects severely defoliate their host plants. These outbreaks are separated by periods of low insect density and little defoliation. In many cases, the underlying cause of these outbreaks is unknown. 2. Mechanistic models are an important tool for understanding population outbreaks, but existing consumer-resource models predict that severe defoliation should happen much more often than is seen in nature. 3. We develop new models to describe the population dynamics of plants and insect herbivores. Our models show that outbreaking insects may be resource-limited without inflicting unrealistic levels of defoliation. 4. We tested our models against two different types of field data. The models successfully predict many major features of natural outbreaks. Our results demonstrate that insect outbreaks can be explained by a combination of food limitation in the herbivore and defoliation and intraspecific competition in the host plant. PMID- 17714280 TI - Interaction diversity within quantified insect food webs in restored and adjacent intensively managed meadows. AB - 1. We studied the community and food-web structure of trap-nesting insects in restored meadows and at increasing distances within intensively managed grassland at 13 sites in Switzerland to test if declining species diversity correlates with declining interaction diversity and changes in food-web structure. 2. We analysed 49 quantitative food webs consisting of a total of 1382 trophic interactions involving 39 host/prey insect species and 14 parasitoid/predator insect species. Species richness and abundance of three functional groups, bees and wasps as the lower trophic level and natural enemies as the higher trophic level, were significantly higher in restored than in adjacent intensively managed meadows. Diversity and abundance of specific trophic interactions also declined from restored to intensively managed meadows. 3. The proportion of attacked brood cells and the mortality of bees and wasps due to natural enemies were significantly higher in restored than in intensively managed meadows. Bee abundance and the rate of attacked brood cells of bees declined with increasing distance from restored meadows. These findings indicate that interaction diversity declines more rapidly than species diversity in our study system. 4. Quantitative measures of food-web structure (linkage density, interaction diversity, interaction evenness and compartment diversity) were higher in restored than in intensively managed meadows. This was reflected in a higher mean number of host/prey species per consumer species (degree of generalism) in restored than in intensively managed meadows. 5. The higher insect species and interaction diversity was related to higher plant species richness in restored than in intensively managed meadows. In particular, bees and natural enemies reacted positively to increased plant diversity. 6. Our findings provide empirical evidence for the theoretical prediction that decreasing species richness at lower trophic levels should reduce species richness at higher trophic levels, and in addition lead to even stronger reductions in interaction diversity at these higher levels. Species at higher trophic levels may thus benefit relatively more than species at lower trophic levels from habitat restoration in the grassland ecosystems studied. We also demonstrate enhanced compartment diversity and lower interaction evenness in restored than in intensively managed meadows, both of which are theoretically positively associated with increased ecosystem stability in restored meadows. PMID- 17714281 TI - Non-equivalence of growth arrest induced by predation risk or food limitation: context-dependent compensatory growth in anuran tadpoles. AB - 1. To gain insight into the evolution of compensatory growth, we studied the growth patterns of anuran (Rana temporaria) larvae following either a period of exogenous growth depression (food restriction) or a period of endogenous depression (exposure to predators). We also investigated the potential deferred costs that larval compensatory growth could impose on post-metamorphic individuals. 2. Food-deprived larvae exhibited full compensatory growth in response to reduced growth rates caused by food limitation, and the growth trajectories of low- and high-rations tadpoles converged before the onset of metamorphosis. 3. According to our predictions, individuals exposed to larval predators did not show growth compensation following predator removal despite undergoing a significant reduction in growth rate associated with low activity levels. 4. Jumping ability of individuals exposed to predators during only 20 days from the commencement of the larval phase was equivalent to that of non exposed animals, and greater than the jumping capacity of those maintained with predators until the time of metamorphosis. This pattern was consistent with the pattern observed for variation in relative leg length. 5. These results support the suggestion that submaximum and compensatory growth could have evolved to minimize the overall growth/mortality costs in environments with high spatiotemporal variation in predation intensity. PMID- 17714282 TI - Evolutionary biology of starvation resistance: what we have learned from Drosophila. AB - Most animals face periods of food shortage and are thus expected to evolve adaptations enhancing starvation resistance (SR). Most of our knowledge of the genetic and physiological bases of those adaptations, their evolutionary correlates and trade-offs, and patterns of within- and among-population variation, comes from studies on Drosophila. In this review, we attempt to synthesize the various facets of evolutionary biology of SR emerging from those studies. Heritable variation for SR is ubiquitous in Drosophila populations, allowing for large responses to experimental selection. Individual flies can also inducibly increase their SR in response to mild nutritional stress (dietary restriction). Both the evolutionary change and the physiological plasticity involve increased accumulation of lipids, changes in carbohydrate and lipid metabolism and reduction in reproduction. They are also typically associated with greater resistance to desiccation and oxidative stress, and with prolonged development and lifespan. These responses are increasingly seen as facets of a shift of the physiology towards a 'survival mode', which helps the animal to survive hard times. The last decade has seen a great progress in revealing the molecular bases of induced responses to starvation, and the first genes contributing to genetic variation in SR have been identified. In contrast, little progress has been made in understanding the ecological significance of SR in Drosophila; in particular it remains unclear to what extent geographical variation in SR reflect differences in natural selection acting on this trait rather than correlated responses to selection on other traits. Drosophila offers a unique opportunity for an integrated study of the manifold aspects of adaptation to nutritional stress. Given that at least some major molecular mechanisms of response to nutritional stress seem common to animals, the insights from Drosophila are likely to apply more generally than just to dipterans or insects. PMID- 17714283 TI - Detecting local adaptation in a natural plant-pathogen metapopulation: a laboratory vs. field transplant approach. AB - Antagonistic coevolution between hosts and parasites in spatially structured populations can result in local adaptation of parasites. Traditionally parasite local adaptation has been investigated in field transplant experiments or in the laboratory under a constant environment. Despite the conceptual importance of local adaptation in studies of (co)evolution, to date no study has provided a comparative analysis of these two methods. Here, using information on pathogen population dynamics, I tested local adaptation of the specialist phytopathogen, Podosphaera plantaginis, to its host, Plantago lanceolata at three different spatial scales: sympatric host population, sympatric host metapopulation and allopatric host metapopulations. The experiment was carried out as a field transplant experiment with greenhouse-reared host plants from these three different origins introduced into four pathogen populations. In contrast to results of an earlier study performed with these same host and parasite populations under laboratory conditions, I did not find any evidence for parasite local adaptation. For interactions governed by strain-specific resistance, field studies may not be sensitive enough to detect mean parasite population virulence. Given that parasite transmission potential may be mediated by the abiotic environment and genotype-by-environment interactions, I suggest that relevant environmental variation should be incorporated into laboratory studies of parasite local adaptation. PMID- 17714285 TI - Short-term rates of parasite evolution predict the evolution of host diversity. AB - Coevolution with parasites has been implicated as an important factor driving the evolution of host diversity. Studies to date have focussed on gross effects of parasites: how host diversity differs in the presence vs. absence of parasites. But parasite-imposed selection is likely to show rapid variation through time. It is unclear whether short-term fluctuations in the strength of parasite-imposed selection tend to affect host diversity, because increases in host diversity are likely to be constrained by both the supply of genetic variation and ecological processes. We followed replicate populations of coevolving, initially isogenic, bacteria and phages through time, measuring host diversity (with respect to bacterial colony morphologies), host density and rates of parasite evolution. Both host density and time-lagged rates of parasite evolution were good independent predictors of the magnitude of bacterial within- and between population diversities. Rapid parasite evolution and low host density decreased host within-population diversity, but increased between-population diversity. This study demonstrates that short-term changes in the rate of parasite evolution can predictably drive patterns of host diversity. PMID- 17714284 TI - Predictable males and unpredictable females: sex difference in repeatability of parental care in a wild bird population. AB - Repeatability of parental care, let alone heritability of care, has been rarely measured, although there has been much research linking sexual selection to male parental care and also examining biparental care in relation to game theory models. We investigated within- and between-year repeatabilities of incubation and nestling provisioning and how these two types of parental care were related in a sexually dimorphic species, the house sparrow, Passer domesticus. We found that between- and within-year repeatabilities of feeding rate were high in males and low to moderate in females, but that between- and within-year repeatabilities of incubation time were low to moderate in both sexes. Interestingly, the amount of time during which neither sex incubated significantly predicted the subsequent male feeding rate but not the female feeding rate. Our results suggest a need for a new theoretical framework that encompasses variation in the predictability and plasticity of parental investment by individuals. PMID- 17714286 TI - Sex-specific plasticity of growth and maturation size in a spider: implications for sexual size dimorphism. AB - Sex-specific plasticity in body size has been recently proposed to cause intraspecific patterns of variation in sexual size dimorphism (SSD). We reared juvenile male and female Mediterranean tarantulas (Lycosa tarantula) under two feeding regimes and monitored their growth until maturation. Selection gradients calculated across studies show how maturation size is under net stabilizing selection in females and under directional selection in males. This pattern was used to predict that body size should be more canalized in females than in males. As expected, feeding affected male but not female maturation size. The sex specific response of maturation size was related to a dramatic divergence between subadult male and female growth pathways. These results demonstrate the existence of sex-specific canalization and resource allocation to maturation size in this species, which causes variation in SSD depending on developmental conditions consistent with the differential-plasticity hypothesis explaining Rensch's Rule. PMID- 17714287 TI - Precision in sex allocation is influenced by mate choice in Drosophila melanogaster. AB - Theory predicts that a 1 : 1 sex ratio is favoured in the absence of countervailing selection pressures. In an experiment with Drosophila melanogaster, we found significantly greater variation in the offspring sex ratios of freely mated flies than would be expected by the binomial distribution. In a surprise result, control flies given no mate choice exhibited significant under-dispersal in their sex ratio variation, possibly from sperm limitation. Both treatments, however, produced populations with a 1 : 1 sex ratio. This supports the hypothesis that sexually antagonistic selection for reproductive success in sons, and fecundity in daughters, may overcome selection for an equal sex ratio. Such precision in sex allocation may allow for the maintenance of genetic variation underlying trade-offs between male and female reproductive success. PMID- 17714288 TI - Adaptive divergence within and between ecotypes of the terrestrial garter snake, Thamnophis elegans, assessed with F(ST)-Q(ST) comparisons. AB - Populations of the terrestrial garter snake (Thamnophis elegans) around Eagle Lake in California exhibit dramatic ecotypic differentiation in life history, colouration and morphology across distances as small as a few kilometres. We assayed the role of selection in ecotypic differentiation in T. elegans using F(ST)-Q(ST) analysis and identified selective agents using direct and indirect observations. We extended the conventional implementation of the F(ST)-Q(ST) approach by using three-level analyses of genetic and phenotypic variance to assess the role of selection in differentiating populations both within and between ecotypes. These results suggest that selection has driven differentiation between as well as within ecotypes, and in the presence of moderate to high gene flow. Our findings are discussed in the context of previous correlational selection analyses which revealed stabilizing and correlational selection for some of the traits examined. PMID- 17714289 TI - Sympatric host races of the European corn borer: adaptation to host plants and hybrid performance. AB - The European corn borer (ECB), Ostrinia nubilalis, is a major pest of maize crops. In Europe, two sympatric host races are found: one feeds on maize (Zea mays) and the other mainly on mugwort (Artemisia vulgaris). The two host races are genetically differentiated, seldom crossing in the laboratory or in the field, and females preferentially lay eggs on their native host species. We conducted two independent experiments, in field and greenhouse conditions, to determine whether the two host races are locally adapted to their host species. The effect of larval density and the performance of hybrids were also investigated. Despite some differences in overall larval feeding performance, both experiments revealed consistent patterns of local adaptation for survival and for larval weight in males. In females the same trend was observed but with weaker statistical support. F1 hybrids did not seem to be disadvantaged compared with the two parental races. Overall, our results showed that both host races are physiologically adapted to their native host. The fitness trade-off between the two host plants provides a potential driving force for ecological speciation in this species. PMID- 17714290 TI - Phylogenetic analysis of floral integration in Schizanthus (Solanaceae): does pollination truly integrate corolla traits? AB - To assess whether floral integration patterns result from the action of pollinator selection on functionally related traits, we compared corolla integration patterns in eight Schizanthus species differing in pollination systems and in their degree of pollinator dependence across a molecular phylogeny. Integration patterns differed among species and these differences were not related to their phylogenetic relatedness. When the putative original function of some corolla traits was lost in pollinator-dependent species, the integration among nonfunctional characters and the rest of the corolla traits was disrupted. This pattern was not presented in species adapted for late autonomous selfing, which exhibited higher corolla integration than their pollinator dependent relatives. These results suggest that corolla integration in pollinator dependent species was shaped by pollinator-mediated selection. Decoupling of nonfunctional traits in these species may result from a relaxation of correlational selection or from selection acting against a default covariation provided by genetic and developmental connections. PMID- 17714291 TI - Sexual conflict over care: antagonistic effects of clutch desertion on reproductive success of male and female penduline tits. AB - A fundamental tenet of sexual conflict theory is that one sex may increase its reproductive success (RS) even if this harms the other sex. Several studies supported this principle by showing that males benefit from reduced paternal care whereas females suffer from it. By investigating penduline tits Remiz pendulinus in nature, we show that parental conflict may be symmetric between sexes. In this small passerine a single female (or male) cares for the offspring, whereas about 30% of clutches are deserted by both parents. Deserting parents enhance their RS by obtaining multiple mates, and they reduce the RS of their mates due to increased nest failure. Unlike most other species, however, the antagonistic interests are symmetric in penduline tits, because both sexes enhance their own RS by deserting, whilst harming the RS of their mates. We argue that the strong antagonistic interests of sexes explain the high frequency of biparental desertion. PMID- 17714292 TI - Male choice generates stabilizing sexual selection on a female fecundity correlate. AB - We know very little about male mating preferences and how they influence the evolution of female traits. Theory predicts that males may benefit from choosing females on the basis of traits that indicate their fecundity. Here, we explore sexual selection generated by male choice on two components of female body size (wing length and body mass) in Drosophila serrata. Using a dietary manipulation to alter female size and 828 male mate choice trials, we analysed linear and nonlinear sexual selection gradients on female mass and wing length. In contrast to theoretical expectations and prevailing empirical data, males exerted stabilizing rather than directional sexual selection on female body mass, a correlate of fecundity. Sexual selection was detected only among females with access to standard resource levels as an adult, with no evidence for sexual selection among resource-depleted females. Thus the mating success of females with the same body mass differed depending upon their access to resources as an adult. This suggests that males in this species may rely on signal traits to assess body mass rather than assessing it directly. Stabilizing rather than directional sexual selection on body mass together with recent evidence for stabilizing sexual selection on candidate signal traits in this species suggests that females may trade-off resources allocated to reproduction and sexual signalling. PMID- 17714293 TI - Evolutionary diversification of clades of squamate reptiles. AB - We analysed the diversification of squamate reptiles (7488 species) based on a new molecular phylogeny, and compared the results to similar estimates for passerine birds (5712 species). The number of species in each of 36 squamate lineages showed no evidence of phylogenetic conservatism. Compared with a random speciation-extinction process with parameters estimated from the size distribution of clades, the alethinophidian snakes (2600 species) were larger than expected and 13 clades, each having fewer than 20 species, were smaller than expected, indicating rate heterogeneity. From a lineage-through-time plot, we estimated that a provisional rate of lineage extinction (0.66 per Myr) was 94% of the rate of lineage splitting (0.70 per Myr). Diversification in squamate lineages was independent of their stem age, but strongly related to the area of the region within which they occur. Tropical vs. temperate latitude exerted a marginally significant influence on species richness. In comparison with passerine birds, squamates share several clade features, including: (1) independence of species richness and age; (2) lack of phylogenetic signal with respect to clade size; (3) general absence of exceptionally large clades; (4) over-representation of small clades; (5) influence of region size on clade size; and (6) similar rates of speciation and extinction. The evidence for both groups suggests that clade size has achieved long-term equilibrium, suggesting negative feedback of species richness on the rate of diversification. PMID- 17714294 TI - Sexual conflict does not drive reproductive isolation in experimental populations of Drosophila pseudoobscura. AB - Sexual conflict has been predicted to drive reproductive isolation by generating arbitrary but rapid coevolutionary changes in reproductive traits among allopatric populations. A testable prediction of this proposal is that allopatric populations experiencing different levels of sexual conflict should exhibit different levels of reproductive isolation. We tested this prediction using experimentally evolved populations of the promiscuous Drosophila pseudoobscura. We manipulated sexual conflict by enforcing either monogamy, maintaining natural levels of promiscuity, or elevating promiscuity. Within each treatment, we carried out sympatric and allopatric crosses using replicated populations and examined pre-zygotic (number of mating pairs, mating speed and copulation duration) and post-zygotic (hybrid inviability and sterility) indicators of reproductive isolation. After 50 generations of selection, none of the measures conformed to predictions of sexual conflict driving reproductive isolation. Our results cannot be explained by lack of genetic variation or weak selection and suggest that sexual conflict may not be a widespread engine of speciation. PMID- 17714295 TI - The costs and benefits of resource sharing: reciprocity requires resource heterogeneity. AB - The evolution of resource sharing requires that the fitness benefits to the recipients be much higher than the costs to the giver, which requires heterogeneity among individuals in the fitness value of acquiring additional resources. We develop four models of the evolution of resource sharing by either direct or indirect reciprocity, with equal or unequal partners. Evolution of resource sharing by reciprocity requires differences between interacting individuals in the fitness value of the resource, and these differences must reverse although previous acts of giving are remembered and both participants survive. Moreover, inequality in the expected reproductive value of the interacting individuals makes reciprocity more difficult to evolve, but may still allow evolution of sharing by kin selection. These constraints suggest that resource sharing should evolve much more frequently by kin selection than by reciprocity, a prediction that is well supported by observations in the natural world. PMID- 17714296 TI - Habitat-dependent geographical variation in ontogenetic allometry of the shiner perch Cymatogaster aggregata Gibbons (Teleostei: Embiotocidae). AB - Studies of intraspecific morphological variation in fishes have traditionally focused on freshwater rather than marine species. In addition, such studies typically focus on adults, although causes and intensities of selective pressures most likely vary through an individual's lifetime. In this study, body and head shape of a marine species, shiner perch Cymatogaster aggregata Gibbons were compared among localities along the Pacific Northwest coast of North America. Evidence was found for intraspecific variation in ontogenetic allometry, and for a closer correlation of body shape with environment rather than geographical proximity. This correlation with environment was more evident in younger fish, thereby demonstrating the importance of analysing multiple life stages. A common garden experiment suggests both environmental and genetic bases for the observed differences. Recognizing intraspecific ecomorphological complexity and its specificity to habitat and/or life stage can have important consequences for understanding the role of local adaptation and population dynamics in macroecology. PMID- 17714297 TI - Molecular evidence of Pleistocene bidirectional faunal exchange between Europe and the Near East: the case of the bicoloured shrew (Crocidura leucodon, Soricidae). AB - We sequenced 1077 bp of the mitochondrial cytochrome b gene and 511 bp of the nuclear Apolipoprotein B gene in bicoloured shrew (Crocidura leucodon, Soricidae) populations ranging from France to Georgia. The aims of the study were to identify the main genetic clades within this species and the influence of Pleistocene climatic variations on the respective clades. The mitochondrial analyses revealed a European clade distributed from France eastwards to north western Turkey and a Near East clade distributed from Georgia to Romania; the two clades separated during the Middle Pleistocene. We clearly identified a population expansion after a bottleneck for the European clade based on mitochondrial and nuclear sequencing data; this expansion was not observed for the eastern clade. We hypothesize that the western population was confined to a small Italo-Balkanic refugium, whereas the eastern population subsisted in several refugia along the southern coast of the Black Sea. PMID- 17714298 TI - Game theory and the evolution of fearfulness in wild birds. AB - When animals in a group live under predation threat, the fate of each individual depends on the way it reacts to danger, but also on the behaviour of its companions. Game theory should then help to understand the evolution of fearful behaviour in gregarious animals. To illustrate this approach, a model determines evolutionarily stable levels of fearfulness in bird flocks, assuming that flocks are the object of both predatory attacks and nonlethal disturbance. In the model, high levels of flightiness limit the risk of being killed by predators, but increase the amount of energy lost in flights during the season. The predicted levels of fearfulness are extremely variable. They depend on the respective frequencies of predatory attacks and simple disturbing events, and on the capacity of birds to detect and escape predators. These results may help to explain the variability of flightiness reported in birds. PMID- 17714299 TI - Basal metabolic rate: heritability and genetic correlations with morphological traits in the zebra finch. AB - Studies of genetic variation in metabolic traits have so far not focused on birds. In our study population of captive zebra finches we found evidence for a significant heritable genetic component in basal metabolic rate (BMR). Heritability of all morphological traits investigated (body mass, head length, tars length and wing length) was significantly larger than zero. All traits were positively phenotypically correlated. Eight of 10 genetic correlations presented in this study differed significantly from zero, all being positive, suggesting the possibility of correlated responses to any selection acting on the traits. When conditioned on the genetic variance in body mass, the heritability of BMR was reduced from 25% to 4%. Hence, our results indicate that genetic changes in BMR through directional selection are possible, but the potential for adaptation independent of body mass may be limited. PMID- 17714300 TI - Strong artificial selection in the wild results in predicted small evolutionary change. AB - Estimates of genetic variation and selection allow for quantitative predictions of evolutionary change, at least in controlled laboratory experiments. Natural populations are, however, different in many ways, and natural selection on heritable traits does not always result in phenotypic change. To test whether we were able to predict the evolutionary dynamics of a complex trait measured in a natural, heterogeneous environment, we performed, over an 8-year period, a two way selection experiment on clutch size in a subdivided island population of great tits (Parus major). Despite strong artificial selection, there was no clear evidence for evolutionary change at the phenotypic level. Environmentally induced differences in clutch size among years are, however, large and can mask evolutionary changes. Indeed, genetic changes in clutch size, inferred from a statistical model, did not deviate systematically from those predicted. Although this shows that estimates of genetic variation and selection can indeed provide quantitative predictions of evolutionary change, also in the wild, it also emphasizes that demonstrating evolution in wild populations is difficult, and that the interpretation of phenotypic trends requires great care. PMID- 17714301 TI - Evolutionary acceleration in the most endangered mammal of Canada: speciation and divergence in the Vancouver Island marmot (Rodentia, Sciuridae). AB - The Vancouver Island marmot is the most endangered mammal of Canada. Factors which have brought this population to the verge of extinction have not yet been fully elucidated, but the effects of deforestation and habitat fragmentation on survival rates, as well as those of variation in rainfall, temperature, snowpack depth and snowmelt strongly suggest that marmots on the island are struggling to keep pace with environmental changes. Genetic analyses, however, seem to indicate that the Vancouver Island marmot may merely represent a melanistic population of its parental species on the mainland. Were it not for its black pelage colour, it is unlikely that it would have attracted much attention as a conservation priority. Our study uses three-dimensional coordinates of cranial landmarks to further assess phenotypic differentiation of the Vancouver Island marmot. A pattern of strong interspecific divergence and low intraspecific variation was found which is consistent with aspects of drift-driven models of speciation. However, the magnitude of shape differences relative to the putatively neutral substitutions in synonymous sites of cytochrome b is too large for being compatible with a simple neutral model. A combination of bottlenecks and selective pressures due to natural and human-induced changes in the environment may offer a parsimonious explanation for the large phenotypic differentiation observed in the species. Our study exemplifies the usefulness of a multidisciplinary approach to the study of biological diversity for a better understanding of evolutionary models and to discover aspects of diversity that may be undetected by using only a few genetic markers to characterize population divergence and uniqueness. PMID- 17714302 TI - Variable visual habitats may influence the spread of colourful plumage across an avian hybrid zone. AB - Several studies have shown that hybridization can be a creative process by acting as a conduit for the spread of adaptive traits between species, but few provide the mechanism that favours this spread. In the hybrid zone between the golden- (Manacus vitellinus) and white-collared (Manacus candei) manakins, sexual selection drives the introgression of golden/yellow plumage into the white species; however, the mechanism for the yellow male's mating advantage and the reasons why yellow plumage has not swept further into the white species remain mostly speculative. We quantified the colour properties of male plumage, the background and the ambient light at the hybrid zone, and allopatric golden and white populations. As measured by the perceived difference in colour between plumage and background, we found that yellow plumage appears more conspicuous than white plumage in the hybrid zone and allopatric golden-collar habitats, whereas white plumage appears more conspicuous than yellow plumage in the allopatric white-collared habitat. These results suggest a mechanism for the unidirectional spread of yellow plumage across the hybrid zone but slowed movement beyond it. PMID- 17714303 TI - Influence of genetic dissimilarity in the reproductive success and mate choice of brown trout - females fishing for optimal MHC dissimilarity. AB - We examined the reproductive success of 48 adult brown trout (Salmo trutta L.) which were allowed to reproduce in a stream that was controlled for the absence of other trout. Parentage analyses based on 11 microsatellites permitted us to infer reproductive success and mate choice preferences in situ. We found that pairs with intermediate major histocompatibility complex (MHC) dissimilarity mated more often than expected by chance. It appears that female choice was the driving force behind this observation because, compared with other individuals, males with intermediate MHC dissimilarity produced a larger proportion of offspring, whereas female reproductive output did not show this pattern. Hence, rather than seeking mates with maximal MHC dissimilarity, as found in several species, brown trout seemed to prefer mates of intermediate MHC difference, thus supporting an optimality-based model for MHC-dependent mate choice. PMID- 17714304 TI - Postglacial intra-lacustrine divergence of Icelandic threespine stickleback morphs in three neovolcanic lakes. AB - The geographical context of divergence and local adaptation of lacustrine fish is controversial. Despite recent theoretical support for sympatric and parapatric divergence, empirical studies providing unequivocal support for this remain scant. An important component of such a case would be where multiple lakes have different morphs and a range of markers, both mitochondrial and nuclear, show monophyly within lakes. Here we describe such a situation for threespine sticklebacks in three lakes in Iceland. By analysing the variation at nuclear and mitochondrial markers in several freshwater and marine populations as well as three pairs of intra-lacustrine morphs we infer their phylogenetic relationships and colonization pattern. There were high levels of microsatellite variation in all populations and no evidence was found for either repeated colonization of marine fish or colonization from distinct glacial refugia. Intra-lacustrine threespine stickleback morphs in all three lakes show significant genetic divergence probably indicating restricted gene flow. PMID- 17714305 TI - Constraints on microbial metabolism drive evolutionary diversification in homogeneous environments. AB - Understanding the evolution of microbial diversity is an important and current problem in evolutionary ecology. In this paper, we investigated the role of two established biochemical trade-offs in microbial diversification using a model that connects ecological and evolutionary processes with fundamental aspects of biochemistry. The trade-offs that we investigated are as follows:(1) a trade-off between the rate and affinity of substrate transport; and (2) a trade-off between the rate and yield of ATP production. Our model shows that these biochemical trade-offs can drive evolutionary diversification under the simplest possible ecological conditions: a homogeneous environment containing a single limiting resource. We argue that the results of a number of microbial selection experiments are consistent with the predictions of our model. PMID- 17714306 TI - How to separate genetic and environmental causes of similarity between relatives. AB - Related individuals often have similar phenotypes, but this similarity may be due to the effects of shared environments as much as to the effects of shared genes. We consider here alternative approaches to separating the relative contributions of these two sources to phenotypic covariances, comparing experimental approaches such as cross-fostering, traditional statistical techniques and more complex statistical models, specifically the 'animal model'. Using both simulation studies and empirical data from wild populations, we demonstrate the ability of the animal model to reduce bias due to shared environment effects such as maternal or brood effects, especially where pedigrees contain multiple generations and immigration rates are low. However, where common environment effects are strong, a combination of both cross-fostering and an animal model provides the best way to avoid bias. We illustrate ways of partitioning phenotypic variance into components of additive genetic, maternal genetic, maternal environment, common environment, permanent environment and temporal effects, but also show how substantial confounding between these different effects may occur. Whilst the flexibility of the mixed model approach is extremely useful for incorporating the spatial, temporal and social heterogeneity typical of natural populations, the advantages will inevitably be restricted by the quality of pedigree information and care needs to be taken in specifying models that are appropriate to the data. PMID- 17714307 TI - Phylogenetic analysis of interspecific variation in nectar of hummingbird-visited plants. AB - We tested whether phylogeny, flower size and/or altitude were significant predictors of interspecific variation in nectar production of hummingbird-visited plants in an assembled database (289 species, in 22 orders, 56 families and 131 genera). Although the study is focused on hummingbird-pollinated plants (241 plant species), plants with different pollinator syndromes (48 species) are also included in the analyses. Nectar volume secreted in a given time period (usually 24 h) by a given flower, its sugar concentration and corolla length were compiled mainly from the literature. Altitude was also obtained from the original references. Sugar production was computed basically as the product of nectar secretion and sugar concentration, and expressed on a per 24-h basis. All nectar traits and corolla length (all log transformed), as well as altitude, showed statistically significant phylogenetic signal. Both nonphylogenetic and phylogenetically informed (independent contrasts) analyses indicated a highly significant positive correlation between corolla length and both nectar volume and sugar production. In addition, altitude (which is partially a surrogate for temperature) was significantly negatively correlated with both sugar concentration and production. Possible reasons for coadaptation of nectar production and sugar production with corolla length are discussed. PMID- 17714308 TI - Partial host fidelity in nest selection by the shiny cowbird (Molothrus bonariensis), a highly generalist avian brood parasite. AB - Obligate avian brood parasites can be host specialists or host generalists. In turn, individual females within generalist brood parasites may themselves be host specialists or generalists. The shiny cowbird Molothrus bonariensis is an extreme generalist, but little is known about individual female host fidelity. We examined variation in mitochondrial control region sequences from cowbird chicks found in nests of four common Argentinean hosts. Haplotype frequency distributions differed among cowbird chicks from nests of these hosts, primarily because eggs laid in nests of house wrens Troglodytes aedon differed genetically from those laid in nests of the other three hosts (chalk-browed mockingbird Mimus saturninus, brown-and-yellow marshbird Pseudoleistes virescens, and rufous collared sparrow Zonotrichia capensis). These differences in a maternally inherited marker indicate the presence of a nonrandom laying behaviour in the females of this otherwise generalist brood parasite, which may be guided by choice for nest type, as house wrens nest in cavities whereas the other three species are open cup nesters. PMID- 17714309 TI - The role of marker traits in the assortative mating within red crossbills, Loxia curvirostra complex. AB - We conducted mate choice experiments to determine whether differences in calls or bill morphology might influence assortative mating between call types of red crossbills (Loxia curvirostra complex) that have diverged in bill structure to specialize on different species of conifers. Females preferred males that gave calls that matched their own type, but did not prefer males that more closely approximated the average or optimal bill size of the female's call type. These results were consistent with our breeding simulations, which showed that females gained an indirect fitness benefit by choosing a male of her own call type because this reduced the production of offspring with morphologies that fell between adaptive peaks. However, choice based on bill morphology within a call type provided no further benefit. Calls, which crossbills learn from their parents, likely act as a marker trait indicative of the morphological adaptations of the group, allow for easy assessment of potential mates and facilitate rapid divergence under ecological selection. PMID- 17714310 TI - The spread of apomixis and its effect on resident genetic variation. AB - In a simulation model we investigated how much of the initial genetic variation that is retained in a population after a dominant mutation has brought apomixis to fixation in it. A marker allele associated with the apomixis mutation is generally retained after the fixation of apomixis, particularly if the two alleles are closely linked. The spread of asexuality, however, normally leads to almost no loss of genetic variation, neither with respect to cytotypes nor with respect to genotypes. This holds for large populations and apomixis mutants with strong pollen production. In smaller populations, and with apomicts with reduced pollen production, the outcome is more variable, ranging from no genetic variation retained to only weakly reduced variability compared with the initial state. These results help explain the high genetic variability in many apomicts. They also imply that natural selection will have many genotypes to act on even after the spread of apomixis. PMID- 17714311 TI - Sexual selection maintains whole-body chiral dimorphism in snails. AB - Although the vast majority of higher animals are fixed for one chiral morph or another, the cause for this directionality is known in only a few cases. In snails, for example, rare individuals of the opposite coil are unable to mate with individuals of normal coil, so directionality is maintained by frequency dependent selection. The snail subgenus Amphidromus presents an unexplained exception, because dextral (D) and sinistral (S) individuals occur sympatrically in roughly equal proportions (so-called 'antisymmetry') in most species. Here we show that in Amphidromus there is sexual selection for dimorphism, rather than selection for monomorphism. We found that matings between D and S individuals occur more frequently than expected by chance. Anatomical investigations showed that the chirality of the spermatophore and the female reproductive tract probably allow a greater fecundity in such inter-chiral matings. Computer simulation confirms that under these circumstances, sustained dimorphism is the expected outcome. PMID- 17714312 TI - Does foraging mode mould morphology in lacertid lizards? AB - Evolutionary changes in foraging style are often believed to require concurrent changes in a complex suite of morphological, physiological, behavioural and life history traits. In lizards, species from families with a predominantly sit-and wait foraging style tend to be more stocky and robust, with larger heads and mouths than species belonging to actively foraging families. Here, we test whether morphology and foraging behaviour show similar patterns of association within the family Lacertidae. We also examine the association of bite force abilities with morphology and foraging behaviour. Lacertid lizards exhibit considerable interspecific variation in foraging indices, and we found some evidence for a covariation between foraging style and body shape. However, the observed relationships are not always in line with the predictions. Also, the significance of the relationships varies with the evolutionary model used. Our results challenge the idea that foraging style is evolutionarily conservative and invariably associated with particular morphologies. It appears that the flexibility of foraging mode and its morphological correlates varies among lizard taxa. PMID- 17714313 TI - Speciation in killifish and the role of salt tolerance. AB - Species pairs whose distributions are tied to environmental conditions provide intriguing candidates for the study of ecological speciation. Here, we examine the role that adaptation to salinity has played in the divergence between two closely related species, Lucania goodei and Lucania parva, whose distributions reflect salinity (L. goodei- fresh water, L. parva- euryhaline). We first tested whether these two species display local adaptation and, subsequently, tested for ecological, genic and behavioural isolation by performing crosses within and between L. goodei and L. parva and raising offspring under various salinities. We found strong evidence for differential adaptation to salinity and also for behavioural isolation where animals preferentially mated with conspecifics over heterospecifics. However, we found no evidence for F1 hybrid inviability. We discuss the general lack of evidence for genic isolation in teleost fish and whether this is a real phenomenon or simply a reflection of experimental design. PMID- 17714314 TI - Modelling the genetics and demography of step cline formation: gastropod populations preyed on by experimentally introduced crabs. AB - Whether a prey population goes extinct or adapts in response to an invading predator may depend on the number of contiguous populations that experience increased predation. We created invaded snail populations by building shelters for predatory shore crabs on a rocky intertidal bench. The crabs preyed selectively on thin-shelled snails tethered next to the shelters but did not prey on those more than 2 m away. This caused strong directional selection for increased shell thickness in populations close to the shelters but did not change selection in those farther away. The field experiment was used to parameterize a new individual-based quantitative genetic model that included demography. In the model a detectable step cline in shell thickness evolved rapidly even though the region of increased predation was shorter than Slatkin's characteristic length. The cline's step size in the model was similar to that measured in the field 10 years after the experiment began. PMID- 17714315 TI - Insight into post-mating interactions between the sexes: relatedness suppresses productivity of singly mated female Drosophila melanogaster. AB - Post-mating, prefertilization inbreeding avoidance (PPIA) is well established in plants but not in animals. Support for animal PPIA comes from sperm competition studies showing success of a male's gametes declining with his relatedness to the multiply mated female; however, such studies confound female-male and male-male interaction. To avoid this problem, we investigated offspring productivity of singly mated Drosophila melanogaster females using flies from four different genetic backgrounds. Our experiments established that intrapopulation crosses using highly related parents (within-strain) were significantly less productive than intrapopulation crosses using unrelated individuals from the same population (between-strain). Furthermore, we showed that these effects were not due to inbreeding depression. The average decrease in offspring productivity of within strain crosses relative to between-strain crosses was 18.3% [nonlaboratory populations: Zimbabwe 20.3%, Riverside 11.4%, neither of which showed inbreeding depression; and temperature-adapted laboratory populations, uncorrected (corrected) for nonsignificant inbreeding depression: 18 degrees C, 26.5% (24.2%) and 29 degrees C, 20.1% (9.5%)]. The significant reduction of within-cross productivity demonstrates PPIA in the absence of multiple mating. PMID- 17714316 TI - Adaptive switch from infanticide to parental care: how do beetles time their behaviour? AB - In species where parents may commit infanticide, temporal kin recognition can help ensure parents kill unrelated young but care for their own offspring. This is not true recognition, but rather depends on accurate timing of the arrival of young and a behavioural switch from killing to caring for offspring. Mistakes have clear fitness consequences; how do species that use temporal kin recognition ensure accurate timing? We manipulated photic cues and show that the switch from infanticide to parental care in the burying beetle Nicrophorus vespilloides depends on day-length inputs. Extending the light period after carcass discovery influenced timing of both oviposition and the cessation of infanticide. Manipulation of the light : dark cycle after oviposition also influenced timing of the switch to parental care. The timing mechanism is therefore sensitive to photic cues and access to a carcass and is not triggered by oviposition. The behavioural switch is directly related to the timing mechanism rather than changes in reproductive physiology. Given the conserved nature and extensive homology of genetic influences on biological timing, we speculate that the molecular mechanisms regulating circadian behaviour may have been co-opted to allow beetles to determine how much time has passed after carcass discovery even though this is over 50 h. PMID- 17714317 TI - Individual MHC class I and MHC class IIB diversities are associated with male and female reproductive traits in the three-spined stickleback. AB - Genes of the major histocompatibility complex (MHC) are indispensable for pathogen defence in vertebrates. With wild-caught three-spined sticklebacks (Gasterosteus aculeatus) we conducted the first study to relate individual reproductive parameters to both MHC class I and II diversities. An optimal MHC class IIB diversity was found for male nest quality. However, male breeding colouration was most intense at a maximal MHC class I diversity. One MHC class I allele was associated with male redness. Similarly, one MHC class IIB allele was associated with continuous rather than early female reproduction, possibly extending the reproductive period. Both alleles occurred more frequently with increasing individual allele diversity. We suggest that if an allele is currently not part of the optimum, it had not been propagated by choosy females. The parasite against which this allele provides resistance is therefore unlikely to have been predominant the previous year - a step to negative frequency-dependent selection. PMID- 17714318 TI - Adaptation in a spider mite population after long-term evolution on a single host plant. AB - Evolution in a single environment is expected to erode genetic variability, thereby precluding adaptation to novel environments. To test this, a large population of spider mites kept on cucumber for approximately 300 generations was used to establish populations on novel host plants (tomato or pepper), and changes in traits associated to adaptation were measured after 15 generations. Using a half-sib design, we investigated whether trait changes were related to genetic variation in the base population. Juvenile survival and fecundity exhibited genetic variation and increased in experimental populations on novel hosts. Conversely, no variation was detected for host choice and developmental time and these traits did not evolve. Longevity remained unchanged on novel hosts despite the presence of genetic variation, suggesting weak selection for this trait. Hence, patterns of evolutionary changes generally matched those of genetic variation, and changes in some traits were not hindered by long-term evolution in a constant environment. PMID- 17714319 TI - Moult speed constrains the expression of a carotenoid-based sexual ornament. AB - We investigated the effect of moult speed on the expression of a sexually selected, carotenoid-based feather ornament in the rock sparrow (Petronia petronia). We experimentally accelerated the moult speed of a group of birds by exposing them to a rapidly decreasing photoperiod and compared the area and the spectral characteristics of their ornaments with those of control birds. Birds with accelerated moulting rate showed a smaller yellow patch with lower yellow reflectance compared to their slow-moulting counterparts. Considering that the time available for moulting is usually constrained between the end of the breeding season and migration or wintering, carotenoid feather ornaments, whose expression is mediated by moult speed, may convey long term information about an individual's condition, potentially encompassing the previous breeding season. Furthermore, the observed trade-off between moult speed and ornament expression may represent a previously unrecognized selective advantage for early breeding birds. PMID- 17714320 TI - Historic and contemporary levels of genetic variation in two New Zealand passerines with different histories of decline. AB - We compared historic and contemporary genetic variation in two threatened New Zealand birds (saddlebacks and robins) with disparate bottleneck histories. Saddlebacks showed massive loss of genetic variation when extirpated from the mainland, but no significant loss of variation following a severe bottleneck in the 1960s when the last population was reduced from approximately 1000 to 36 birds. Low genetic variation was probably characteristic of this isolated island population: considerably more genetic variation would exist in saddlebacks today if a mainland population had survived. In contrast to saddlebacks, contemporary robin populations showed only a small decrease in genetic variation compared with historical populations. Genetic variation in robins was probably maintained because of their superior ability to disperse and coexist with introduced predators. These results demonstrate that contemporary genetic variation may depend more greatly on the nature of the source population and its genetic past than it does on recent bottlenecks. PMID- 17714321 TI - Sex and differentiation: population genetic divergence and sexual dimorphism in Mexican goodeid fish. AB - Genetic differentiation arises due to the interaction between natural and sexual selection, migration and genetic drift. A potential role of sexual selection in speciation has received much interest, although comparative studies are inconsistent in finding supporting evidence. A poorly tested prediction is that species subject to a higher intensity of sexual selection should show greater genetic differentiation amongst populations because females from these populations should be more choosy in mate choice. The Goodeinae is a group of endemic Mexican fishes in which female choice has driven some species to be morphologically sexually dimorphic, whereas others are relatively monomorphic. Here, we measured population divergence, using microsatellite loci, within four goodeid species which show contrasting levels of sexual dimorphism. We found higher levels of differentiation between populations of the more dimorphic species, implying less gene flow between populations. We also found evidence of higher levels of genetic differences between the sexes within populations of the dimorphic species, consistent with greater dispersal in males. Adjusted for geographic distance, the mean F(ST) for the dimorphic species is 0.25 compared with 0.16 for the less dimorphic species. We conclude that population differentiation is accelerated in more sexually dimorphic species, and that comparative phylogeography may provide a more powerful approach to detecting processes, such as an influence of sexual selection on differentiation, than broad-scale comparative studies. PMID- 17714322 TI - Abundant, diverse, and consequential P elements segregate in promoters of small heat-shock genes in Drosophila populations. AB - The present study extends evidence that Drosophila heat-shock genes are distinctively evolvable because of insertion of transposable elements by examining the genotypic diversity and phenotypic consequences of naturally occurring P element insertions in the proximal promoter regions of two small heat shock genes. Detailed scrutiny of two populations revealed 16 distinctive P transposable elements collectively segregating in proximal promoters of two small heat-shock genes, Hsp26 and Hsp27. These elements vary in size, orientation and insertion site. Frequencies of P element-containing alleles varied from 5% to 100% in these populations. Two Hsp26 elements chosen for detailed study, R(s)P(26) and D(2)P(m), reduced or abolished Hsp26 expression respectively. The R(s)P(26) element increased or did not affect inducible tolerance of high temperature, increased fecundity, but decreased developmental rate. On the other hand, the D(2)P(m) element decreased thermotolerance and fecundity. In lines subjected to experimental evolution, the allelic frequency of the R(s)P(26)P element varied considerably, and was at lower frequencies in lines selected for increased longevity and for accelerated development than in controls. Transposable element insertions into small Hsp genes in Drosophila populations can have dramatic fitness consequences, and therefore create variation on which selection can act. PMID- 17714323 TI - Body size evolution in South American Liolaemus lizards of the boulengeri clade: a contrasting reassessment. AB - Bergmann's rule predicts larger body sizes in species living in higher latitudes and altitudes. This rule appears to be valid for endotherms, but its relevance to ectotherm vertebrates has largely been debated. In squamate reptiles (lizards and snakes), only one study, based on Liolaemus species of the boulengeri clade, has provided phylogenetic evidence in favour of Bergmann's clines. We reassessed this model in the same lizard clade, using a more representative measure of species body size and including a larger number of taxa in the sample. We found no evidence to support Bergmann's rule in this lineage. However, these non significant results appear to be explained only by the inclusion of further species rather than by a different estimation of body size. Analyses conducted on the 16 species included in the previous study always revealed significant relationships between body size and latitude-altitude, whereas, the enlarged sample always rejected the pattern predicted by Bergmann's rule. PMID- 17714324 TI - No direct selection to increase offspring number of bet-hedging strategies in large populations: Simons' model revisited. AB - In mixed or 'bet-hedging' strategies, offspring phenotypes are taken randomly from a distribution determined by the genotype and shaped by evolution. Offspring of a single parent represent a finite sample from this distribution, and therefore are subject to variability because of sampling. Contrary to a recent article by A.M. Simons (2007; J. Evol. Biol.20: 813-817), I show that selection does not favour the production of many offspring just to reduce sampling variability when such mixed strategies are used in large populations. PMID- 17714325 TI - Oxygen metabolism changes in patients with idiopathic normal pressure hydrocephalus before and after shunting operation. AB - OBJECTIVE: The present study revealed the changes in cerebral oxygen metabolism before and after ventriculo-peritoneal shunt (VPS) using (15)O positron emission tomography ((15)O-PET). METHODS: Eight patients with idiopathic normal pressure hydrocephalus (i-NPH) underwent VPS. A (15)O-PET study was undertaken before and approximately 3 months after VPS. In five patients, the symptoms improved based on the classification by Krauss et al. [Neurosurgery 1996;39:292] (good responders) after VPS. In three patients, the symptoms improved subjectively following VPS (poor responders). The changes in oxygen metabolism before and after VPS were analyzed. RESULTS: The postoperative regional cerebral metabolic rate of oxygen (rCMRO(2)) of the good responders increased significantly. The postoperative regional oxygen extraction fraction (rOEF) is reduced in the poor responders. CONCLUSION: The improvement of rCMRO(2) correlated with the response to VPS. Significant changes in rOEF might predict poor response to VPS. PMID- 17714326 TI - Elevated levels of anti-Chlamydia pneumoniae IgA and IgG antibodies in young adults with ischemic stroke. AB - INTRODUCTION: Data on the role of Chlamydia pneumoniae in patients with ischemic stroke are inconsistent. We investigated the presence of anti-C. pneumoniae antibodies in young adults with ischemic stroke. METHODS: 94 patients (<55 years) with ischemic stroke and 103 controls were enrolled. Indices of anti-C. pneumoniae IgA and IgG were assessed with an ELISA. We determined OR and 95% CI for the IgA and IgG seropositivity in stroke cases. RESULTS: Mean IgA and IgG indices were higher in stroke patients vs controls (IgA: 1.40 vs 0.56; P < 0.001; IgG: 0.85 vs. 0.78; P < 0.003). The IgA seropositivity was associated with stroke risk (11.92; 5.94-23.92; P < 0.001) as well as IgG seropositivity was (2.31; 1.15 4.61; P < 0.016). Seropositivity assessed with combined IgA and IgG indices was associated with increased stroke risk (OR 9.35; 95% CI 4.78-18.29; P < 0.0001). After controlling for age and sex, the IgA seropositivity yielded a significantly adjusted OR for stroke (8.95; 4.44-18.07; P < 0.002), while IgG seropositivity did not (0.85; 0.53-1.63). CONCLUSIONS: We find an increased risk of stroke in young patients seropositive to C. pneumoniae in the IgA antibody class. Further studies to explore this finding are warranted. PMID- 17714327 TI - Long-term mortality among young ischemic stroke patients in western Norway. AB - OBJECTIVES: To obtain data on long-term mortality among young ischemic stroke patients compared with controls in this population-based study. MATERIAL AND METHODS: We used Kaplan-Meier survival analysis to compare 232 patients aged 15 49 years with first-ever cerebral infarction in 1988-1997 and 453 controls followed from inclusion to death or 1 August 2005 for 2515 and 5558 person-years respectively. In a subanalysis of 192 patients, we compared risk factor variables using the Kaplan-Meier method and log-rank testing. We applied a Cox proportional hazards model to adjust for multiple risk factors. RESULTS: Forty-five patients and nine controls died during follow-up (P < 0.0005). Independent risk factors for mortality were active tumor disease (P < 0.0005), high consumption of alcohol (P < 0.0005), coronary atherosclerosis (P < 0.001), living alone (P < 0.02), seizures (P < 0.04) and smoking (P = 0.08). CONCLUSIONS: Long-term mortality was significantly increased among young stroke patients, mainly due to such lifestyle factors as high consumption of alcohol and tobacco. PMID- 17714328 TI - Neglect assessment as an application of virtual reality. AB - OBJECTIVE: In this study a cancellation task in a virtual environment was applied to describe the pattern of search and the kinematics of hand movements in eight patients with right hemisphere stroke. METHODS: Four of these patients had visual neglect and four had recovered clinically from initial symptoms of neglect. The performance of the patients was compared with that of a control group consisting of eight subjects with no history of neurological deficits. RESULTS: Patients with neglect as well as patients clinically recovered from neglect showed aberrant search performance in the virtual reality (VR) task, such as mixed search pattern, repeated target pressures and deviating hand movements. The results indicate that in patients with a right hemispheric stroke, this VR application can provide an additional tool for assessment that can identify small variations otherwise not detectable with standard paper-and-pencil tests. CONCLUSION: VR technology seems to be well suited for the assessment of visually guided manual exploration in space. PMID- 17714329 TI - Migration of T-cell subsets in multiple sclerosis and the effect of interferon beta1a. AB - OBJECTIVES: Migration of inflammatory cells across the blood-brain barrier is a central event in the formation of multiple sclerosis (MS) lesions and is known to be enhanced in MS patients. This study investigates the migration of CD4+ and CD8+ T-cell subsets and the effects of interferon-beta1a (IFN-beta1a) treatment on migration and matrix metalloproteinase-9 (MMP-9) production of these T-cell subsets. MATERIALS AND METHODS: An ex vivo transwell system was established to compare the migratory behaviour of lymphocytes isolated from normal controls and untreated MS patients. In addition, MS patients were investigated longitudinally after initiation of IFN-beta1a treatment. RESULTS: Migration of CD4+ T cells (P < 0.05), but not of CD8+ T cells, was enhanced in untreated MS patients compared with controls and was normalized by treatment with IFN-beta1a. In addition, IFN beta1a treatment reduced MMP-9 production of CD4+ but not CD8+ T cells. CONCLUSION: Our results indicate that CD4+ T cells, but not CD8+ T cells, contribute to the enhanced ex vivo migration observed in MS. PMID- 17714330 TI - Neuropathological postmortem evaluation of BNCT for GBM. AB - BACKGROUND: Thirty patients with glioblastoma multiforme (GBM) were treated by boron neutron capture therapy (BNCT) at the Studsvik facility in Sweden, in a clinical trial exploring a procedure in which 900 mg p-boronophenylalanine (BPA) per kilo body weight was infused in 6 h. OBJECTIVE: The present study was designed to assess tumor efficacy and radiation damage to the brain for the seven patients in the Studsvik trial that were available for postmortem neuropathological examination. METHOD: Whole brain slices containing the initial tumor site and other regions showing pathological changes were chosen for microscopy and selected areas were studied by immunological methods. RESULTS: Local control of GBM was observed in all cases. Conclusive evidence for radiation induced brain damage was not found. CONCLUSION: Using a novel procedure for BPA infusion, BNCT achieves local control of GBM for minimum tumor doses as low as 15 wGy, allowing treatment with very low concomitant doses to surrounding healthy tissues. PMID- 17714331 TI - Dementia in Parkinson's disease: diffusion tensor imaging. AB - OBJECTIVE: Dementia occurs frequently in patients with Parkinson's disease (PD). However, the nature of the dementing process remains controversial. We evaluated various cognitive functions in patients with PD, compared fractional anisotropy (FA) values between PD patients with and without dementia. METHODS: Thirty-seven consecutive patients with Hoehn-Yahr stage III or IV PD participated in this study. Patients were divided into two groups: (i) PD with dementia group (PDD) and (ii) PD without dementia group (PDND). There were 11 PDD and 26 PDND cases. Ten controls were also studied. RESULTS: The PDD group showed significant FA reduction in the bilateral posterior cingulate bundles compared with PDND. FA values in the left posterior cingulate bundle showed significant correlations with many cognitive parameters. INTERPRETATION: Our results showed that the posterior cingulate areas play some important roles in the dementing process in PDD. However, as the pathological processes responsible for dementia in PD patients may be multifaceted, further studies are necessary. PMID- 17714332 TI - Global Mobility Task: index for evaluating motor impairment and motor rehabilitation programs in Parkinson's disease patients. AB - OBJECTIVE: In this study, the validity of a motor task, i.e., the Global Mobility Task (GMT), was assessed in a group of Parkinson's disease (PD) patients. PATIENTS AND METHODS: Fifty-eight PD patients (mean age: 68.7 years) and 18 healthy subjects (mean age: 65.8 years) were enrolled in the study. The GMT measures the ability of an adult to roll over on the floor and stand up in five steps using two parameters: 'Time' and 'Score', i.e., the time needed and the ability to perform each step of the task. As the GMT has never been evaluated before, internal consistency and concurrent and discriminative validity were considered in assessing its characteristics in a group of PD patients at the beginning and at the end of a motor rehabilitation program. To determine whether the GMT could also quantify the extrapyramidal impairment, we compared data collected using this task with data obtained using clinical scales such as the Unified Parkinson's Disease Rating Scale III (UPDRS part III) and Hoehn & Yahr's score. RESULTS: Results showed that the GMT had good consistency and inter-rater reproducibility, was closely related to clinical scales and was able to detect the amelioration of extrapyramidal symptoms at the end of the motor rehabilitation program. CONCLUSION: we propose the GMT as a tool for measuring impaired mobility in PD patients and for evaluating the objective effects of motor rehabilitation programs. PMID- 17714333 TI - Clinical evaluation of Parkinson's disease dementia: association with aging and visual hallucination. AB - OBJECTIVES: In order to explore factors associated with the development of dementia in Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), we systematically investigated the clinical evaluation of PD and DLB patients hospitalized in the Department of Neurology at Tottori University Hospital, Japan. RESULTS: There were 208 patients diagnosed as having PD and 39 patients diagnosed with DLB in this study. Of the patients with PD, 67 (32%) developed dementia and only five PD+ patients were considered to have cognitive impairment attributable to Alzheimer's disease (AD) or vascular dementia (VaD). Fifty-four (81%) PDD patients had visual hallucinations (VH) with or without cognitive fluctuation. The onset age of parkinsonian motor symptoms of patients with PD dementia (PDD) did not differ from that of PD patients without dementia. There was a significant inverse correlation between the onset age of motor symptoms in PD and the onset of their dementia in PDD. Seventy-five (36%) patients with PD had experienced VH and most of the PDD patients had experienced VH within 1 year before or after diagnosis of PDD. CONCLUSIONS: These results indicate that aging and VH are important factors associated with dementia in PD. PMID- 17714334 TI - Sustained attention in cranial dystonia patients treated with botulinum toxin. AB - BACKGROUND: Primary cranial dystonia (PCD) is related to a functional disorder in basal ganglia usually accompanied by impaired executive function. AIM: To investigate symptom relief and neurocognitive change in response to treatment with botulinum toxin (BTX) in a group of patients with PCD. METHODS: We assessed nine patients with PCD and nine age- and educationally matched healthy individuals using tests of memory, sustained attention, span of auditory attention, and perceptual flexibility. RESULTS: Despite well-preserved intellectual skills relative to controls, we identified a sustained attention deficit in patients with PCD. After BTX treatment, there was an increase in the scores of the concentration endurance test (sustained attention) and the values did not differ significantly from control group patients' scores. CONCLUSION: The results support the view that executive dysfunction in PCD is secondary to the disrupting effects of the symptoms. Treatment with BTX alleviates the symptoms and, consequently, improves sustained attention. PMID- 17714335 TI - Women drug users in North Cumbria: what influences initiation into heroin in this non-urban setting? AB - This paper reports on a qualitative study which has investigated female problem drug use in North Cumbria, a relatively isolated area of the UK. Cumbria is the second most sparsely populated county in England with some of the most beautiful countryside juxtaposed with areas of disadvantage, particularly in towns along the west coast. Previous research has focused on female city dwellers and less is known about the social and cultural context of drug use in non-urban settings. The reasons for women's drug use remain controversial but gender differences appear to emerge. One frequent explanation is the influence of male oppression but some studies describe women as active players in their initiation. Findings from North Cumbria challenge the conventional view of women being coerced into illicit drug use and present greater complexity. The data derived from semi structured interviews account for the impact of curiosity and trust, motives often tempered by a range of complex personal circumstances. A known individual, usually male, was often present at initiation and this relationship appears pivotal. I discuss these factors and will call for prevention initiatives to recognise the gender-specific determinants of initiation into problem drug use. PMID- 17714336 TI - Watch out for the aunties! Young British Asians' accounts of identity and substance use. AB - This paper considers how young people able to trace their origins from Pakistan or India (henceforth 'Asians'), discuss their use of, or abstention from, alcohol and tobacco in terms of religious and cultural tradition. The role of religion, ethnicity, gender and generation in the uptake or avoidance of alcohol and tobacco was explored in 19 qualitative group and individual interviews with 47 Asians aged 16-26 years and analysed in terms of pioneering and conservative forms of tradition. Religious proscriptions on alcohol and tobacco were reported to be formally gender blind, but concerns about reputation and future marriage chances, sanctioned by gossip, meant that women's behaviour was consistently more constrained than men's. Muslims' abstinence from alcohol was tightly linked with an Islamic identity in that drinking jeopardised one's claim to being a Muslim, whereas cigarette smoking was tolerated among young men. Sikhs' and Hindus' avoidance of tobacco was strongly sanctioned, but smoking did not strongly jeopardise a religious identity. Sikh men's abstention indicated manly strength central to a devout identity. Some experimentation was possible out of view of the older generation, especially the aunties, but the risk of gossip damaging young women's reputations was keenly felt. While damage to women's reputations was hard to undo, men's reputations tarnished by substance use, could be compensated for by their parents' honourable status. Discussion of tradition as innovation was rare and met with resistance. Tradition was largely experienced as a constraint to be circumvented. PMID- 17714337 TI - Migrating identities: the relational constitution of drug use and addiction. AB - This paper aims to develop a properly social conceptualisation of addiction through drawing on analyses of rich, in-depth data from ex/users of heroin. Practices of addiction are considered as in and of themselves constitutive of particular identities, ways of being, and ways of being with and for others. The discussion seeks to demonstrate how heroin use is predicated upon, and productive of, purposeful drug-using relationships in which users produce and reproduce the conditions for continued use (e.g. scoring, grafting, using). Accordingly, the concept of 'dependence' is here reconfigured to encompass both dependence on the provision (and ingestion) of drugs and, simultaneously, dependence upon diverse configurations of users, clinicians, support workers, and so on. The paper makes a critical departure from existing debates in which addiction, even if conceived as a social practice, is nonetheless understood at the level of 'the individual'. It is argued that this tendency towards ontological individualism leads towards conceiving the problem of addiction as residing predominantly in the individual negotiation and, ultimately, resolution of identity narratives. The analyses presented here explore how the migration from addict to non-addict involves more than identity work. Theorisations of the level of 'field' or 'configuration' are developed, and considered as both a level of analysis and a conceptual lens for understanding changes in the ongoing, relational, practices involved in such identity migration. Finally, the consequences of intersecting, relational, dimensions of time horizons, place and space in the talk of ex/users are considered for strategies for successful recovery, identified during the research. PMID- 17714338 TI - The (ir)relevance of genetics: engendering parallel worlds of procreation and reproduction. AB - Informing offspring of the nature of their conception when conceived via donated gametes such as donor sperm, is increasingly considered by professionals and policy makers to be desirable for many reasons. The aim of this research is to explore and understand processes within families that either facilitate or hinder the telling of children about their conception. This exploration includes analysing the complexity of sociocultural processes surrounding parents' attempts to make sense of, and construct meanings of 'family'. We analyse the stories of a group of New Zealand parents, representing 41 families, who have formed their families with the assistance of donor insemination. The analysis takes its point of departure from current sociological and anthropological debates in the field of kinship, or family studies. We argue that parents generate a parallel construct whereby genetic inheritance is seen to be simultaneously irrelevant (to the constitution of the family), and yet at the same time relevant (in highly bounded domains, for example related to medically specified conditions). We analyse the ambiguities of interpreting this construct as one reflecting a separation of procreation from the process of reproduction, and reflect on the implications for information-sharing. PMID- 17714340 TI - Explaining chronic obstructive pulmonary disease (COPD): perceptions of the role played by smoking. AB - There are few studies that investigate how people personally affected by a chronic disease associated with cigarette smoking account for their illness. Chronic obstructive pulmonary disease (COPD) is a respiratory condition largely caused by cigarette smoking. In order to better understand how people diagnosed with COPD view the relationship between cigarette smoking and their illness we conducted semi-structured interviews with 19 participants. We found a widespread scepticism among our respondents about medical attempts to link their illness with cigarette smoking, and doubts about whether their illness was in fact COPD at all. Only four participants described smoking as the principal reason why they had developed breathing problems. Most participants gave multi-causal accounts that emphasised explanatory factors such as a familial tendency to respiratory illness or workplace exposure to pollution. Our findings have relevance for the development of smoking cessation interventions for people with COPD. PMID- 17714339 TI - 'Good luck to them if they can get it': exploring working class men's understandings and experiences of income inequality and material standards. AB - This paper seeks to contribute to the recent debate within the field of inequalities in health that has focused on the relationship between income distribution and health. This has contested the extent to which the main effects of income on health are not directly related to material standards but operate through psychosocial mechanisms, linked to how people experience and perceive their relative position. However, whilst this has focused attention on the qualitative dimensions of income inequality as a potential determinant of health inequality, very little empirical work has directly examined lay perspectives. In this study I attempted to address this gap by exploring how two groups of working class men living in contrasting socio-economic areas understood and experienced differences in income and material circumstances and how these were perceived to impact on their health. This study shows that the anger and resentment felt by these men had their roots largely in the perceptions of others and the way others treated them, rather than in income differentials per se. There was little evidence of feelings of shame or inferiority. For men at the bottom of the social ladder, financial hardship was additionally perceived as having the greatest impact on their health and well-being. PMID- 17714341 TI - The fuzzy buzz word: conceptualisations of disability in disability research classics. AB - The article analyses five classical texts from the field of disability research/studies. The focus of the analysis is on how disability is defined both on a theoretical level and on an empirical or applied level. The findings suggest that definitional clarity can be questioned. First, a 'traditional' problem of validity occurs in some of the texts. Secondly, lack of clearly expressed and explicit definitions makes it difficult for the reader to understand what the author means with the term disability. Thirdly, some authors alter the definition of disability through their texts, without any explanations, making it arduous for the reader to follow the use and meaning of the term. It is suggested that these problems stem from the lack of proper theorising within the field of disability research. Disability researchers have been focusing on defining separate concepts, without any ambitions to relate them to each other in a theoretical frame. This means that the field of disability research consists of free-floating concepts, poorly related to each other. PMID- 17714342 TI - Learning disability and the limits of liberal citizenship: interactional impediments to political empowerment. AB - Recent policy initiatives have moved decisively toward empowering learning disabled citizens, recognising ability over disability, and promoting people's political empowerment and voice in the design of public services. While laudable and encouraging, these initiatives raise an important question: to what extent can a group of service users, whose very entitlement to state-sponsored assistance is justified by putative intellectual impairment, be empowered according to an exclusively liberal model of citizenship that presumes and requires, as its very defining features, intellectual ability and independence? In this paper we consider this question by means of an ethnographic analysis of an innovative advocacy group: the Parliament for People with Learning Disabilities (PPLD). We first document both an institutional and an interactional preference for clients to speak actively for themselves. We then describe three types of interactional trouble that emerged in the PPLD as obstacles to realising this preference in practice and the strikingly similar remedies that were generated to overcome these troubles. We conclude by discussing the limits of an approach to empowering learning disabled individuals that is cast too exclusively in terms drawn from liberal models of citizenship that prioritise voice over care, security, and wellbeing. PMID- 17714346 TI - Probiotics: contributions to oral health. AB - Probiotics have been extensively studied for their health-promoting effects. The main field of research has been in the gastrointestinal tract. However, in the past few years probiotics have also been investigated in the oral health perspective, which is the topic of the present review. We discuss the mechanisms of bacterial adhesion, potential of probiotics in oral cavity colonization, interspecies interactions, and possible effects on immunomodulation, and means of probiotic administration. We suggest that probiotic treatment of diseases other than dental caries and periodontal disease should also be systematically investigated. In general, hardly any randomized controlled trials have been conducted in this area and the studies on probiotics vs oral health are still in their cradle. Hence, much more investigations are called for before any evidence based conclusions can be drawn: if or not probiotic therapy can be recommended for oral health purposes. PMID- 17714347 TI - Regenerative approaches in the craniofacial region: manipulating cellular progenitors for oro-facial repair. AB - This review aims to highlight the potential for regeneration that resides within the bony tissues of the craniofacial region. We examine the five main cues which determine osteogenic differentiation: heritage of the cell, mechanical cues, the influence of the matrix, growth factor stimulation and cell-to-cell contact. We review how successful clinical procedures, such as guided tissue regeneration and distraction osteogenesis exploit this resident ability. We explore the developmental origins of the flat bones of the skull to see how such programmes of differentiation may inform new therapies or regenerative techniques. Finally we compare and contrast existing approaches of hard tissue reconstruction with future approaches inspired by the regenerative medicine philosophy, with particular emphasis on the potential for using chondrocyte-inspired factors and replaceable scaffolds. PMID- 17714348 TI - Immunohistochemical detection of phosphorylated Akt, PI3K, and PTEN in ameloblastic tumors. AB - OBJECTIVE: To evaluate roles of the Akt signaling pathway in oncogenesis and cytodifferentiation of odontogenic tumors, expression of phosphorylated Akt (pAkt), PI3K, and PTEN was analyzed in ameloblastic tumors as well as in tooth germs. METHODS: 11 tooth germs, 40 ameloblastomas, and 5 malignant ameloblastic tumors were examined immunohistochemically with antibodies against pAkt, PI3K, and PTEN. RESULTS: Immunoreactivity for pAkt, PI3K, and PTEN was detected predominantly in odontogenic epithelial cells near the basement membrane in tooth germs and ameloblastic tumors. The levels of immunoreactivity for pAkt and PI3K were slightly higher in ameloblastic tumors than in tooth germs. Plexiform ameloblastomas showed significantly higher expression of PI3K than follicular ameloblastomas, and PI3K immunoreactivity in ameloblastomas without cellular variation was significantly higher than that in acanthomatous ameloblastomas. The level of PTEN immunoreactivity was significantly lower in ameloblastomas than in tooth germs. CONCLUSION: Expression of pAkt, PI3K, and PTEN in tooth germs and ameloblastic tumors suggests that these signaling molecules regulate cell survival and growth in normal and neoplastic odontogenic tissues by mediating growth factor signals. Increased expression of pAkt and PI3K and decreased expression of PTEN in ameloblastic tumors may participate in oncogenesis of odontogenic epithelium by activating the Akt signaling pathway. PMID- 17714349 TI - Low-frequency noise effects on the parotid gland of the Wistar rat. AB - BACKGROUND: Long-term low-frequency noise (LFN) (or=5 mm, attachment loss >or=3 mm), and 30 healthy volunteers. Neutrophil response followed by metalloproteinase-9 (MMP-9) and interleukin-8 (IL-8) secretion was assayed by zymography and enzyme-linked immunosorbent assay, respectively, on both whole blood and purified neutrophils. In addition to periodontal pathogen extracts, known stimulating agents were tested, such as Escherichia coli-lipopolysaccharide (LPS), phytohemagglutinin, and zymosan A. RESULTS: Neutrophil response, expressed as a secretion ratio under stimulated and non-stimulated conditions, measured in whole blood, showed no differences between periodontitis and healthy controls. Instead, in purified neutrophils from patients, MMP-9 exhibited a significantly higher secretion ratio with LPS and Pg (1.5- to 2-fold), whereas IL-8 showed a larger increase in secretion ratio (3- to 7-fold) in the presence of Pg, Aa, LPS, and zymosan A. CONCLUSION: Peripheral neutrophils of periodontitis-affected patients are more reactive as suggested by their significantly higher response toward periodontal pathogen extracts and other stimulating agents. PMID- 17714351 TI - Dentin structure in familial hypophosphatemic rickets: benefits of vitamin D and phosphate treatment. AB - OBJECTIVE: To evaluate the outcome of 1-(OH) vitamin D and oral phosphate treatment on dentin structure in patients with familial hypophosphatemic rickets, and expression of SIBLINGs (a family of non-collagenous proteins involved in dentinogenesis) and osteocalcin. PATIENTS AND METHODS: Seven patients with familial hypophosphatemic rickets (age 3-16 years) were studied before or during treatment. Deciduous and permanent teeth were prepared for scanning electron microscopy (SEM) analysis and immunohistochemistry. RESULTS: Untreated or inadequately treated patients had necrotic teeth with impaired dentin mineralization including unmerged calcospherites and accumulation of non collagenous proteins in wide interglobular spaces. Most of the primary incisors analyzed displayed fissures linking enamel subsurface to pulp horn. These elements may explain the bacterial penetration and dental abscesses despite the absence of carious lesions. Well-treated patients had healthy teeth with good dentin mineralization and little evidence of calcospherites. CONCLUSION: Treatment of hypophosphatemic children with 1-(OH) vitamin D and oral phosphate insures good dentin development and mineralization, and prevents clinical anomalies such as the dental necrosis classically associated with the disease. Starting treatment during early childhood and good adherence to the therapy are mandatory to observe these beneficial effects. PMID- 17714353 TI - An MTT-based method for quantification of periodontal ligament cell viability. AB - OBJECTIVE: Survival of periodontal ligament cells is crucial issue after tooth replantation. To understand this matter, we introduced MTT assay, which can be used as a tool for measuring the viability of periodontal ligament cells from extracted rat molars. MATERIALS AND METHODS: The maxillary molars of 4-week-old Sprague-Dawley white female rats were used. Ten teeth of each immediate, 1 h Viaspan and 1 h dry were processed for MTT evaluation. Another 10 teeth from each group were treated in the same manner as above, but were replanted into their original socket. After 2 weeks, the animals were killed and the prevalence of resorption pits was evaluated. RESULTS: In vivo MTT assay corresponded with the histological results of the resorption pits (P or = 15 to differentiate ASDs from children with nonspectrum disorders (NS). METHODS: Diagnostic discrimination of the SCQ was evaluated alone and in combination with the ADOS (Autism Diagnostic Observation Schedule) in a clinical and research-referred sample of 590 children and adolescents (2 to 16 years), with best estimate consensus diagnoses of autism, pervasive developmental disorder, not otherwise specified (PDD-NOS) and non-ASD disorders. The SCQ was completed before the evaluation in most cases. Performance of the SCQ was also compared with the Autism Diagnostic Interview - Revised (ADI R). RESULTS: Absolute scores and sensitivity in the younger children and specificity for all groups were lower than reported in the original study. Using receiver operating curves (ROC) to examine the area under the curve (AUC), the SCQ was more similar to the ADI-R total score in differentiating ASD from NS disorders in the older (8-10, >11) than younger age groups (<5, 5-7). Lowering the cutoff score in the 2 younger groups improved sensitivity, with specificity remaining relatively low in all groups. Using the SCQ in combination with the ADOS resulted in improved specificity. Diagnostic discrimination was best using the ADI-R and ADOS in combination. CONCLUSIONS: Those interested in using the SCQ should consider adjusting cutoff scores according to age and purpose, and using it in combination with another measure. Sensitivity or specificity may be prioritized for research or screening depending on goals. PMID- 17714379 TI - Family context and young children's responses to earthquake. AB - BACKGROUND: Family context can affect children's vulnerability to various stresses, but little is known regarding the role of family variables on children's reactions to natural disaster. This prospective study examined the influence of predisaster observed parenting behaviors and postdisaster parental stress on young children's distress following an earthquake. METHODS: Participants were 117 two-parent families with a child age 4-5 at the initial assessment. The families experienced different degrees of impact from the earthquake. Pre-earthquake family context comprised observations of parents' positive and negative behaviors during a parent-child play task. Eight months after the earthquake, mothers reported symptoms of parental stress and children's distress. RESULTS: Earthquake impact and children's distress symptoms were moderately correlated (r = .44), but certain pre-earthquake parental behaviors moderated the relationship. The dose-response association between earthquake impact and children's symptoms did not hold for families in which fathers showed high levels of negative behaviors with daughters, or mothers showed low levels of positive behaviors with sons. In addition, results consistent with full mediation for boys (and partial mediation for girls) indicated that 86% of the total effect of earthquake impact on boys' distress (and 29% on girls' distress) occurred through the mediator of reported parental stress. CONCLUSIONS: These findings demonstrate that young children's responses to an abrupt, negative environmental event, such as an earthquake, are influenced in part by the nature of the parent child relationship prior to the event as well as by the responses parents exhibit following the event. PMID- 17714380 TI - Prevalence and correlates of psychopathology in a sample of deaf adolescents. AB - AIMS: To examine prevalence and correlates of psychopathology in deaf adolescents using a multi-method multi-informant approach. METHODS: Data for the study came from checklist assessments by parents (Child Behavior Checklist (CBCL)) and teachers (Teacher's Report Form (TRF)) of 70 deaf adolescents aged 13 to 21 years, from semi-structured clinical interviews of the adolescents (Semi structured Clinical Interview for Children and Adolescents (SCICA)), and from expert ratings of dossier data. RESULTS: The percentages of Total Problems scores in the borderline clinical range in this population as found with the CBCL, TRF and SCICA are 28%, 32% and 49-63% respectively. Expert dossier ratings identified psychiatric caseness in 49% and DSM-classifications in 46% of the adolescents (primary classifications: emotional disorder 27%, behavioral disorder 11%, other disorder 7%). Cross-informant agreement between single ratings and expert dossier ratings was better than agreement between single ratings. Logistic regression analyses revealed that low IQ, a signing mode of communication and a history of three or more physical disorders were associated with psychiatric caseness. CONCLUSIONS: Findings suggest a high prevalence of psychopathology in the population studied and argue for a special focus on the early detection of significant emotional and behavioral problems as well as a multi-informant approach to the assessment of disorder in deaf children and adolescents. The correlational findings support the view that it is not deafness per se that contributes to psychiatric problems. PMID- 17714383 TI - Isolation of Laribacter hongkongensis, a novel bacterium associated with gastroenteritis, from drinking water reservoirs in Hong Kong. AB - AIMS: Freshwater fish has been found to be the reservoir of Laribacter hongkongensis, a recently discovered bacterium associated with community-acquired gastroenteritis. However, little is known about the ecology of this bacterium in the aquatic environment. We carried out a surveillance study to investigate the presence of L. hongkongensis in water and freshwater fish from 10 drinking water reservoirs in Hong Kong. METHODS AND RESULTS: Using membrane filtration, L. hongkongensis was isolated from the waters of six reservoirs, with numbers ranging from 1 to 12 CFU l(-1). Higher recovery rates were observed in summer and during days of higher water and ambient temperatures. Of 27 freshwater fish collected from the reservoirs, L. hongkongensis was recovered from the intestines of two fish, a Goldfish and a Nile tilapia. Overall, 35 different pulsed-field gel electrophoresis patterns are found among the 59 isolates recovered from water and the two isolates from freshwater fish. CONCLUSIONS: The present report represents the first to demonstrate the presence of L. hongkongensis in natural water environments. SIGNIFICANCE AND IMPACT OF THE STUDY: Although it is unlikely that treated, drinking water is an important source of L. hongkongensis associated gastroenteritis, one should be aware of the possibility of other contaminated water as a source of human infection. PMID- 17714384 TI - Hydrolysis and microbial community analyses in two-stage anaerobic digestion of energy crops. AB - AIMS: The roles of the diverse populations of micro-organisms responsible for biodegradation of organic matter to form methane and carbon dioxide are rudimentarily understood. To expand the knowledge on links between microbial communities and the rate limiting, hydrolytic stage of two-stage biogas production from energy crops, this study was performed. METHODS AND RESULTS: The process performance and microbial communities (as determined by fluorescence in situ hybridization) in two separate two-stage batch digestions of sugar beets and grass/clover were studied. The microbial populations developed in the hydrolytic stage of anaerobic digestion of beets and grass/clover showed very few similarities, despite that the hydrolysis dynamics were similar. In both substrates, the solubilization of organic material was rapid for the first 10 days and accompanied by a build-up of volatile fatty acids (VFAs) and lactate. Between days 10 and 15, VFA and lactate concentrations decreased, as did the solubilization rates. For both substrates, Archaea started to appear in the hydrolytic stage between days 10 and 15, and the fraction of Bacteria decreased. The major bacterial group detected in the leachate fraction for beets was Alphaproteobacteria, whereas for grass/clover it was Firmicutes. The number of cells that bound to probes specifically targeting bacteria with cellulolytic activity was higher in the digestion of grass than in the digestion of beet. CONCLUSIONS: This study allowed the identification of the general bacterial groups involved, and the identification of a clear shift in the microbial population when hydrolysis rate became limiting for each of the substrates investigated. SIGNIFICANCE AND IMPACT OF THE STUDY: The findings from this study could be considered as a first step towards the development of strategies to stimulate hydrolysis further and ultimately increasing the methane production rates and yields from reactor-based digestion of these substrates. PMID- 17714385 TI - Predictive models for reduction of Salmonella Hadar on chicken skin during single and double sequential spraying treatments with acetic acid. AB - AIMS: The response surface methodology was used to evaluate the effect of acetic acid concentration, spraying time and temperature on the reduction of Salmonella Hadar on poultry skin in a laboratory spraying process, and to identify the best conditions required to develop this operation. METHODS AND RESULTS: A comparative analysis was carried out to ascertain the effects of the application of single (SS) and double sequential decontamination (DSS) treatments on skin samples inoculated with Salm. Hadar. While on the SS treatment, the linear and quadratic acid concentration terms and the interaction of the temperature and time term of the model are statistically significant at P < or = 0.001, P < or = 0.01 and P < or = 0.05, respectively, the other terms do not significantly affect (P > 0.05) the reduction of Salm. Hadar. On the DSS model the acid concentration and time linear terms significantly affected (P < or = 0.001 and P < or = 0.01) the Salm. Hadar reduction within the experimental range assayed. CONCLUSION: Any of the models could be used as an approach to optimize spray washing during chicken processing. SIGNIFICANCE AND IMPACT OF THE STUDY: Neither the SS or the DSS treatment has the capability of eliminating Salm. Hadar from carcasses. However, reductions of approx. 99% initial load could be attained if DSS treatment were put into practice. PMID- 17714386 TI - Modelling the behaviour of Listeria monocytogenes in ground pork as a function of pH, water activity, nature and concentration of organic acid salts. AB - AIMS: to study and model the effect of sodium acetate, sodium lactate, potassium sorbate and combination of acid salts on the behaviour of Listeria monocytogenes in ground pork. METHODS AND RESULTS: Water activity (a(w)), pH and concentration of acid salt of the meat were adjusted. The behaviour of inoculated L. monocytogenes was studied and modelled according to physicochemical parameters values. Whatever the acid salt concentration used, we observed an inhibition of the growth of L. monocytogenes at pH 5.6 and a(w) 0.95. At pH 6.2 and a(w) 0.97, addition of 402 mmol l(-1) of sodium lactate or 60 mmol l(-1) of potassium sorbate was required to observe a slower growth. CONCLUSIONS: The inhibitory effect of acid salts was a function of pH, a(w), as well as of the nature and concentration of acid salts added. When one acid salt was added, the Augustin's model (Augustin et al. 2005) yielded generally correct predictions of either the survival or growth of L. monocytogenes. SIGNIFICANCE AND IMPACT OF THE STUDY: The suggested model can be used for risk assessment concerning L. monocytogenes in pork products. PMID- 17714387 TI - Biohydrogenation of linoleic acid by rumen fungi compared with rumen bacteria. AB - AIMS: To investigate biohydrogenation of linoleic acid by rumen fungi compared with rumen bacteria, and to identify the fungus with the fastest biohydrogenation rate. METHODS AND RESULTS: Biohydrogenation of linoleic acid by mixed rumen fungi and mixed rumen bacteria were compared in vitro. With mixed rumen bacteria, all biohydrogenation reactions were finished within 100 min of incubation and the end product of biohydrogenation was stearic acid. With mixed rumen fungi, biohydrogenation proceeded more slowly over a 24-h period. Conjugated linoleic acid (CLA; cis-9, trans-11 C18 : 2) was an intermediate product, and vaccenic acid (VA; trans-11 C18 : 1) was the end product of biohydrogenation. Fourteen pure fungal isolates were tested for biohydrogenation rate. DNA sequencing showed that the isolate with the fastest rate belonged to the Orpinomyces genus. CONCLUSIONS: It is concluded that rumen fungi have the ability to biohydrogenate linoleic acid, but biohydrogenation is slower in rumen fungi than in rumen bacteria. The end product of fungal biohydrogenation is VA, as for group A rumen bacteria. Orpinomyces is the most active biohydrogenating fungus. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study to demonstrate that rumen fungi can biohydrogenate fatty acids. Fungi could influence CLA content of ruminant products. PMID- 17714388 TI - The effect of lactating rabbit does on the development of the caecal microbial community in the pups they nurture. AB - AIMS: To study the effect of microbial community of the rabbit does as influenced by dietary factors, on the development of the gut microbiota of their litters. METHODS AND RESULTS: Twenty-four lactating does were given a diet unsupplemented (NAB) or with 100 ppm of bacitracin (BAC) or tiamulin (TIA) to modify their digestive microbiota. Litters were adjusted to six pups. In Trial 1, four does per diet milked their own six pups. In Trial 2, two does per diet nursed three of their pups and three fostered from the doe given the same diet. In Trial 3, two does on each diet nursed three of their pups and three fostered from another doe fed on another diet. Denaturing gradient gel electrophoresis (DGGE) analyses of the litter microbiota showed that the effect of the milking mother was greater than the influence of the biological mother. TIA had a strong effect on the bacterial profile even prevailing over that of the milking mother, in contrast to BAC. CONCLUSIONS: Nursing mother microbiota plays an important role over that of the litter. Caecal colonization that occurs during the lactation process prevailed over that during the partum. SIGNIFICANCE AND IMPACT OF THE STUDY: Manipulation of the mother's microbiota may help for adaptation of the litter microbial community against pathologic digestive processes. PMID- 17714389 TI - Multiple-locus variable-number tandem repeat analysis of Salmonella enterica subsp. enterica serovar Typhimurium: comparison of isolates from pigs, poultry and cases of human gastroenteritis. AB - AIMS: Pulsed-field gel electrophoresis (PFGE) and variable number tandem repeat (VNTR) profiles of 195 epidemiologically unrelated Salmonella Typhimurium strains isolated in 1997-2004 from pigs were analysed and the results compared to establish the discriminatory ability of each method. In order to investigate the epidemiology of S. Typhimurium from different populations, the VNTR profiles from pigs were compared with those obtained from 190 S. Typhimurium strains isolated from poultry and 186 strains isolated from human cases of gastroenteritis. METHODS AND RESULTS: A total of 195 strains of S. Typhimurium were tested by PFGE and VNTR. For PFGE, the restriction enzyme XbaI was used, and for VNTR, the number of repeats at five loci (STTR 9, 5, 6, 10pl and 3) were counted and assigned an allele number based on an established VNTR scheme. The results obtained showed improved discrimination of VNTR when compared with PFGE with 34 PFGE profiles identified compared with 96 different VNTR profiles for the pig isolates and 56 different VNTR types within the most common PFGE type. Within the three different populations, VNTR showed distinct subpopulations of VNTR type related not only to source, but also demonstrated common VNTR types within samples obtained from humans, poultry and pigs, especially in strains of phage type DT104. CONCLUSIONS: VNTR has taken the discrimination to a further level than that obtained through PFGE, and demonstrated an overlap in the genetic diversity of isolates tested across the three different populations, confirming previous suggestions that animals have an involvement in the dissemination of S. Typhimurium through the food chain. SIGNIFICANCE AND IMPACT OF THE STUDY: Salmonella Typhimurium remains an important concern as a food-borne zoonotic agent. The VNTR strategy described provides an accurate method of tracing strain dissemination, and adds a further level of discrimination to the PFGE type, providing potential benefits to epidemiological studies and the possibility of deciphering source attribution of cases. PMID- 17714390 TI - Survival of Campylobacter jejuni and Escherichia coli in groundwater during prolonged starvation at low temperatures. AB - AIMS: To evaluate the survival of Campylobacter jejuni relative to that of Escherichia coli in groundwater microcosms varying in nutrient composition. METHODS AND RESULTS: Studies were conducted in groundwater and deionized water incubated for up to 470 days at 4 degrees C. Samples were taken for culturable and total cell counts, nutrient and molecular analysis. Die-off in groundwater microcosms was between 2.5 and 13 times faster for C. jejuni than for E. coli. Campylobacter jejuni had the lowest decay rate and longest culturability in microcosms with higher dissolved organic carbon (4 mg l(-1)). Escherichia coli survival was the greatest when the total dissolved nitrogen (12.0 mg l(-1)) was high. The transition of C. jejuni to the coccoid stage was independent of culturability. CONCLUSION: The differences in the duration of survival and response to water nutrient composition between the two organisms suggest that E. coli may be present in the waters much longer and respond to water composition much differently than C. jejuni. SIGNIFICANCE AND IMPACT OF THE STUDY: The data from these studies would aid in the evaluation of the utility of E. coli as an indicator of C. jejuni. This study also provided new information about the effect of nutrient composition on C. jejuni viability. PMID- 17714391 TI - Isolation, taxonomic identification and hydrogen peroxide production by Lactobacillus delbrueckii subsp. lactis T31, isolated from Mongolian yoghurt: inhibitory activity on food-borne pathogens. AB - AIMS: The aim of this work was to isolate lactic acid bacteria (LAB) strains from Mongolian tarag (a traditionally homemade yoghurt) displaying antimicrobial activities against food-borne pathogens, identify inhibitory substances and study the kinetics of their production. METHODS AND RESULTS: Inhibitory substance producing bacterial strains were isolated from tarag. From 300 bacterial clones, 31 were able to inhibit the growth of the indicator strain Lactobacillus bulgaricus 340. One of the most active strains was identified as Lactobacillus delbrueckii subsp. lactis strain T31 by using cluster analysis of amplified fragment length polymorphism (AFLP) DNA fingerprints. The antimicrobial substance was inactivated by catalase, demonstrating the production of hydrogen peroxide (H(2)O(2)). Production of H(2)O(2) was studied under aerated and nonaerated culture conditions. The amount of H(2)O(2) in the culture supernatant increased during bacterial growth and reached a maximum (5.12 mmol l(-1)) at the early stationary phase under aerated conditions (agitated cultures). H(2)O(2) was not detected in the culture performed without agitation. In mixed cultures performed in milk with either Lact. delbrueckii subsp. lactis T31 in the presence of Escherichia coli, or Lact. delbrueckii subsp. lactis T31 in the presence of Listeria innocua under aerated and nonaerated conditions, a significant decrease in pathogen count was observed in aerated cultures. SIGNIFICANCE AND IMPACT OF THE STUDY: The significant decrease in Listeria viability observed in aerated mixed cultures of Lact. delbrueckii subsp. lactis T31 is mainly because of H(2)O(2) production. Lactobacillus delbrueckii subsp. lactis T31 could be used as a protective culture in food industries or as a probiotic to prevent intestinal and urogenital infections. PMID- 17714392 TI - Modelling of Campylobacter survival in frozen chicken meat. AB - AIMS: To model the survival kinetics of Campylobacter jejuni on frozen chicken meat. METHODS AND RESULTS: Three different types of chicken meat surface (skin, skinned muscle and cut muscle) were inoculated with stationary phase cells of C. jejuni (8 log(10) CFU cm(-2)) and frozen for 5 weeks at -20 degrees C. Bacterial numbers were determined weekly using two different methods of enumeration to quantify uninjured and injured cells. Analysis of variance of the results showed that the type of chicken surface and the method used to enumerate surviving cells were the most significant sources of variations in the numbers recovered (P < 0.0001), much more than the freezing time. To identify an appropriate model for the description of effects of freezing on survival over time, several models were fitted to the count data. Decay was found to be nonlinear. In general, survival was least on skin, better on skinned muscle and best on cut muscle. After 2 weeks, additional inactivation by freezing appeared to be negligible. CONCLUSION: Because of the variability of survival it was not possible to fit and select a general model useful for all the different surfaces types. SIGNIFICANCE AND IMPACT OF THE STUDY: The injured state of the cells leads to variability and the underestimation of bacterial survival. This is an essential factor for the assessment of Campylobacter-associated risk. PMID- 17714393 TI - A comparison of changes in the transformation of isoflavones in soymilk using varying concentrations of exogenous and probiotic-derived endogenous beta glucosidases. AB - AIMS: To compare endogenous and exogenous beta-glucosidases for the hydrolysis of the predominant isoflavone glucosides in soymilk in order to improve the biological activity. METHODS AND RESULTS: beta-glucosidase activity of probiotic organisms, including Bifidobacterium animalis ssp. lactis Bb12, Lactobacillus acidophilus ATCC 4461 and Lactobacillus casei 2607 in soymilk, was evaluated and was related to the increase in the concentration of isoflavone aglycones during fermentation. The concentrations of isoflavone compounds in soymilk were monitored using a Varian model HPLC with an Amperometric electrochemical detector. The aglycone composition, also known as aglycone equivalent ratio, has been considered to be important for the delivery of health benefits of isoflavones, and was monitored during the fermentation of soymilk. Comparison of the hydrolytic effectiveness of both exogenous and endogenous enzyme during 4-h incubation in soymilk was conducted using the Otieno-Shah (O-S) index. Results showed that exogenous enzyme exhibited faster rate of isoflavone glucoside hydrolysis than that by endogenous enzyme. Highest O-S indices were obtained after 4, 3 and 2 h of incubation with enzyme solution having beta-glucosidase activity of 0.288 U ml(-1), 0.359 U ml(-1) and 0.575 U ml(-1), resulting into aglycone concentration increments of 5.87-, 6.07- and 5.94-fold, respectively. Conversely, aglycone concentration in the soymilk with B. animalis ssp. lactis Bb12, L. casei 2607 and L. acidophilus 4461 increased by 3.43-, 2.72- and 3.03 fold, respectively, after 4 h of fermentation at 37 degrees C. In addition, the O S index of endogenous enzyme was much lower than that of the exogenous enzyme over the same 4-h incubation period. Optimum aglycone equivalent ratios coincided with highest O-S indices and highest aglycone concentrations in soymilk hydrolysed with exogenous enzyme. The same correlation of O-S indices and highest aglycone concentrations occurred for endogenous enzyme during the 24 h of fermentation. CONCLUSIONS: Obtaining highest aglycone concentration and optimum aglycone equivalent ratio could provide a critical beginning point in clinical trials for the realization of unique health benefits of soy isoflavones. SIGNIFICANCE AND IMPACT OF THE STUDY: Screening for beta-glucosidase activities of probiotics in soymilk and comparing their hydrolytic potentials with that of exogenous beta-glucosidase could find wide applications in the development of different aglycone-rich functional soy beverages. PMID- 17714394 TI - Constitutive expression of the nifA gene activates associative nitrogen fixation of Enterobacter gergoviae 57-7, an opportunistic endophytic diazotroph. AB - AIMS: This study was undertaken to investigate whether a nitrogen-fixing bacterium Enterobacter gergoviae 57-7, which was isolated from surface-sterilized maize (Zea mays L.) roots, can colonize in roots and whether constitutive expression of the nifA gene encoding the transcriptional activator of nitrogenase genes can activate nif gene expression in planta. METHODS AND RESULTS: Maize seedlings grown in an agar medium were inoculated with Ent. gergoviae strains containing the green fluorescent protein reporter gene. Root colonization and expression of the dinitrogenase reductase gene (nifH) by Ent. gergoviae were observed by confocal laser scanning microscopy. gfp-tagged Ent. gergoviae was observed to colonize predominantly in cortical aerenchyma of primary and lateral roots and in stellar parenchyma cells and xylem vessels of primary roots. In planta nifH :: gfp expression was not detected but after a constitutively expressed nifA gene was introduced into Ent. gergoviae. CONCLUSIONS: Enterobacter gergoviae 57-7 is an opportunistic endophyte because it can live in soil and colonize in maize roots in the gnotobiotic agar culture. In agreement with previous (15)N-dilution evidence that Ent. gergoviae 57-7 did not fix N(2) in association with maize in pots whereas a derivative E7 containing a constitutively expressed nifA gene promoted plant growth partly through associative nitrogen fixation, constitutive expression of the nifA gene can activate bacterial nif gene expression in planta. SIGNIFICANCE AND IMPACT OF THE STUDY: This study and our previous studies suggest that manipulation of the promoter of the nifA gene in a nitrogen-fixing bacterium having a high colonization competence is a practical and promising approach to achieve a stable associative nitrogen fixation for cereals. PMID- 17714395 TI - Destruction of planktonic, adherent and biofilm cells of Staphylococcus epidermidis using a gliding discharge in humid air. AB - AIMS: To determine the efficiency of an electric discharge of the gliding arc type for the destruction of Staphylococcus epidermidis planktonic, adherent and biofilm cells. METHODS AND RESULTS: Bacterial cells were treated in humid air and at atmospheric pressure by a nonthermal quenched plasma of the glidarc type. The kinetics of destruction (followed by plating) were modelled by an Add-inn for Microsoft Excel, GInaFiT. For planktonic cells, log-linear destruction was obtained, whereas biphasic kinetics were observed for sessile cells. An increased resistance of biofilm cells was observed: the reduction of 6 logarithm units of the population was obtained in 15, 30 and 70 min for planktonic, adherent and biofilm cells, respectively. The experiments also show that the cells destruction did not depend on the adhesion surface but was governed by the gap between the target and the plasma source. CONCLUSION: The complete destruction of planktonic, adherent and more resistant biofilm cells of Staph. epidermidis is achieved by a glidarc air plasma at atmospheric pressure. SIGNIFICANCE AND IMPACT OF THE STUDY: The glidarc plasma technology is a promising candidate among the emerging nonthermal techniques for decontamination, as it can destroy even biofilms that are known as particularly resistant to various antimicrobials. PMID- 17714396 TI - Probiotic properties of Lactococcus lactis ssp. lactis HV219, isolated from human vaginal secretions. AB - AIMS: To determine the resistance of Lactococcus lactis ssp. lactis HV219 to acids, bile, antibiotics, inflammatory drugs and spermicides, compare adsorption of the strain to bacteria and Caco-2 cells under stress, and evaluate the antimicrobial activity of bacteriocin HV219. METHODS AND RESULTS: Bacteriocin HV219 activity against Gram-positive and Gram-negative bacteria was confirmed by leakage of DNA and beta-galactosidase, and atomic force microscopy. Adsorption of bacteriocin HV219 to bacteria is influenced by pH, temperature, surfactants and salts. Initially, only 3% of HV219 cells adhered to Caco-2 cells. However, after 2 h, adherence increased to 7%. Strain HV219 and Listeria monocytogenes ScottA did not compete for colonization. Strain HV219 is sensitive to most antibiotics tested, but resistant to amikacin, ceftazidime, nalidixic acid, metronidazole, neomycin, oxacillin, streptomycin, sulphafurazole, sulphamethoxazole, sulphonamides, tetracycline and tobramycin. Ibuprofen, ciprofloxacin, diklofenak and nonoxylol-9 inhibited the growth of strain HV219. CONCLUSION: Strain HV219 is resistant to hostile conditions in the intestinal tract, including therapeutic levels of specific antibiotics and binds to Caco-2 cells, but not in competition with L. monocytogenes. SIGNIFICANCE AND IMPACT OF THE STUDY: Strain HV219 will only be effective as probiotic if taken with specific antibiotics and not with anti-inflammatory drugs and spermicides. PMID- 17714397 TI - Correlations between Campylobacter spp. prevalence in the environment and broiler flocks. AB - AIMS: To investigate (i) possible correlations between the presence of Campylobacter spp. in the surroundings of broiler farms and their incidence in flocks, and (ii) possible associations between weather conditions and the occurrence of Campylobacter spp. METHODS AND RESULTS: Farms were selected according to previous results from the Swedish Campylobacter programme. Samples were collected in and around broiler houses during the rearing period from 131 flocks on 31 farms, including sock samples from the ground outside, from the floor in the broiler houses and anterooms, and samples from insects, water, feed and ventilation shafts. CONCLUSIONS: As expected, there was a difference in Campylobacter isolation rates for different categories of farms regarding samples taken in the houses. However, there were no differences regarding the presence of Campylobacter spp. in the environment between producers that often deliver Campylobacter-positive slaughter batches and those that rarely deliver positive batches. Campylobacter spp. were more frequently found in the surroundings on rainy days when compared with sunny days. SIGNIFICANCE AND IMPACT OF THE STUDY: Physical barriers between outside and inside the houses appeared to be important for preventing Campylobacter spp. in the environment to be transferred into the broiler houses. PMID- 17714398 TI - Growth inhibitory factors in bovine faeces impairs detection of Salmonella Dublin by conventional culture procedure. AB - AIMS: To analyse the relative importance of different biological and technical factors on the analytical sensitivity of conventional culture methods for detection of Salmonella Dublin in cattle faeces. METHODS AND RESULTS: Faeces samples collected from six adult bovines from different salmonella-negative herds were split into subpools and spiked with three strains of S. Dublin at a concentration level of c. 10 CFU g(-1) faeces. Each of the 18 strain-pools was divided into two sets of triplicates of four volumes of faecal matter (1, 5, 10 and 25 g). The two sets were pre-enriched with and without novobiocin, followed by combinations of culture media (three types) and selective media (two types). The sensitivity of each combination and sources of variation in detection were determined by a generalized linear mixed model using a split-plot design. CONCLUSIONS: Biological factors, such as faecal origin and S. Dublin strain influenced the sensitivity more than technical factors. Overall, the modified semi-solid Rappaport Vassiliadis (MSRV)-culture medium had the most reliable detection capability, whereas detection with selenite cystine broth and Mueller Kauffman tetrathionate broth combinations varied more in sensitivity and rarely reached the same level of detection as MSRV in this experiment. SIGNIFICANCE AND IMPACT OF THE STUDY: The study showed that for MSRV-culture medium and xylose lysine decarboxylase agar as the indicative medium, the sensitivity of the faecal culture method may be improved by focusing on the strain variations and the ecology of the faecal sample. Detailed investigation of the faecal flora (pathogens and normal flora) and the interaction with chemical factors may result in developing an improved method for detection of S. Dublin. PMID- 17714399 TI - The Lactobacillus plantarum strain ACA-DC287 isolated from a Greek cheese demonstrates antagonistic activity in vitro and in vivo against Salmonella enterica serovar Typhimurium. AB - AIMS: The purpose of this study was to investigate the antibacterial activity of the Xynotyri cheese isolate Lactobacillus plantarum ACA-DC287 using a set of in vitro and in vivo assays. METHODS AND RESULTS: The co-culture of L. plantarum strain ACA-DC287 and Salmonella enterica serovar Typhimurium strain SL1344 results in the killing of the pathogen. The killing activity was produced mainly by non-lactic acid molecule(s) that were present in the cell-free culture supernatant of the L. plantarum strain ACA-DC287. The culture of the L. plantarum strain ACA-DC287 inhibited the penetration of S. typhimurium SL1344 into cultured human enterocyte-like Caco-2/TC7 cells. In conventional mice infected with S. typhimurium SL1344, the intake of L. plantarum strain ACA-DC287 results in a decrease in the levels of Salmonella associated with intestinal tissues or those present in the intestinal contents. In germ-free mice, the L. plantarum strain ACA-DC287 colonized the gastrointestinal tract. CONCLUSIONS: The L. plantarum strain ACA-DC287 strain exerts anti-Salmonella activity similar that of the established probiotic strains Lactobacillus rhamnosus GG, Lactobacillus casei Shirota YIT9029 and Lactobacillus johnsonii La1. SIGNIFICANCE AND IMPACT OF THE STUDY: The observation that a selected cheese Lactobacillus strain exerted antibacterial activity that was similar to those of probiotic Lactobacillus strains, is of interest for the use of this strain as an adjunct strain for the production of health-giving cheeses. PMID- 17714400 TI - Identification and characterization of starter lactic acid bacteria and probiotics from Columbian dairy products. AB - AIMS: Considering the significant rise in the probiotic market in Columbia, and given the lack of reports concerning the microbial population and strain performance in products from different producers, this study aims at determining the number of viable starter bacteria and probiotics in bio-yoghurts available at the Columbian market, identifying the species and analysing the performance of the isolated strains in bile acid resistance, antagonistic activity against pathogens, and adherence capacity to human intestinal epithelial cells. METHODS AND RESULTS: Seven bio-yoghurts were analysed for the bacterial species present. Species identification was carried out using 16S rRNA gene targeted PCR. The cultured bacteria were tested for bile acid resistance, adherence to a human intestinal epithelial cell line, and antagonism against the pathogen Salmonella enterica serovar Typhimurium. A total of 17 different strains were identified. Based on plate counting, all bio-yoghurts have at least total viable cells of approximately 10(7) CFU ml(-1). Streptococcus thermophilus and Lactobacillus delbrueckii ssp. bulgaricus were the most frequently isolated bacteria. Viable Bifidobacterium was only recovered from one product. However, after PCR analysis, DNA of this genus was confirmed in five out of seven products. Major differences were found for S. typhimurium antagonism. The adherence capacity to Caco-2 cells was observed in 10 of the isolated strains. In general, low survival to simulated gastric juice was observed. CONCLUSIONS: Some of the isolated strains have probiotic potential, although not all of them were present in the advised amount to exert beneficial health effects. However, the full correct scientific name of the isolated bacteria and their viable counts were not included on the product label. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report describing the identification and functionality of starter bacteria and probiotics present in dairy products on the Columbian market. PMID- 17714401 TI - Phylogenetic analysis of intestinal bacteria in the Chinese mitten crab (Eriocheir sinensis). AB - AIMS: To identify the dominant intestinal bacteria in the Chinese mitten crab, and to investigate the differences in the intestinal bacteria between pond-raised and wild crabs. METHODS AND RESULTS: The diversity of intestinal bacteria in the Chinese mitten crabs was investigated by denaturing gradient gel electrophoresis (DGGE) fingerprinting, 16S rRNA gene clone library analysis and real-time quantitative PCR. The principal component analysis of DGGE profiles indicated that substantial intersubject variations existed in intestinal bacteria in pond raised crab. The sequencing of 16S rRNA genes revealed that 90-95% of the phylotypes in the clone libraries were affiliated with Proteobacteria and Bacteroidetes. Some genera were identified as unique in wild crabs and in pond raised crabs, whereas Bacteroidetes was found to be common in all sampled crab groups. Real-time quantitative PCR indicated that the abundance of Bacteroides and the total bacterial load were approximately four-to-10 times higher in pond raised crabs than in wild crabs. A significant portion of the phylotypes shared low similarity with previously sequenced organisms, indicating that the bacteria in the gut of Chinese mitten crabs are yet to be described. CONCLUSIONS: The intestinal bacteria of pond-raised crabs showed higher intersubject variation, total diversity and abundance than that observed in wild crabs. The high proportion of the clones of Proteobacteria and Bacteroidetes in the clone library is an indication that these bacteria may be the dominant population in the gut of the Chinese mitten crab. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrated obvious differences in the intestinal bacterial composition of pond raised crabs and wild crabs. This knowledge will increase our understanding of the effects of aquaculture operations on bacterial community composition in the crab gut and provide necessary data for the development of probiotic products for crab cultivation. PMID- 17714402 TI - Improvement of Cupressus atlantica Gaussen growth by inoculation with native arbuscular mycorrhizal fungi. AB - AIMS: The study aimed to determine whether inoculation with native arbuscular mycorrhizal (AM) fungi could improve survival and growth of seedlings in degraded soils of Morocco. METHODS AND RESULTS: Soil samples were collected from the rhizosphere of Cupressus atlantica trees in the N'Fis valley (Haut Atlas, Morocco). AM spores were extracted from the soil, identified and this mixture of native AM fungi was propagated on maize for 12 weeks on a sterilized soil to enrich the fungal inoculum. Then C. atlantica seedlings were inoculated with and without (control) mycorrhizal maize roots, cultured in glasshouse conditions and further, transplanted into the field. The experiment was a randomized block design with one factor and three replication blocks. The results showed that a high AM fungal diversity was associated with C. atlantica; native AM fungi inoculation was very effective on the growth of C. atlantica seedlings in glasshouse conditions and this plant growth stimulation was maintained for 1 year after outplanting. CONCLUSIONS: Inoculation of C. atlantica with AM fungi increased growth and survival in greenhouse and field. SIGNIFICANCE AND IMPACT OF THE STUDY: The data indicate that use of native species of AM fungi may accelerate reforestation of degraded soils. Further studies have to be performed to determine the persistence of these mycorrhizae for a longer period of plantation and to measure the effects of this microbial inoculation on soil biofunctioning. PMID- 17714403 TI - Comparison of the properties of Bacillus subtilis spores made in liquid or on agar plates. AB - AIMS: To compare the properties of the spores of Bacillus subtilis prepared in liquid and on plates. METHODS AND RESULTS: The spores of B. subtilis were prepared at 37 degrees C using a nutrient exhaustion medium either in liquid or on agar plates. The levels of core water, dipicolinic acid (DPA) and small, acid soluble spore proteins (SASP) were essentially identical in spores made in liquid or on plates. Spores prepared in liquid were killed approximately threefold more rapidly at 90 degrees C in water than the spores prepared on plates, and the spores prepared in liquid were more sensitive to nitrous acid and a diluted stable superoxidized water. Spores prepared in liquid also germinated more rapidly with several agents than those prepared on plates. Pellets of spores prepared on plates were darker than spores prepared in liquid, and spores prepared in liquid had more readily extracted coat protein. However, there were no major differences in the relative levels of individual coat proteins or the cross-linking of the coat protein GerQ in the two types of spores, although the inner membrane of spores prepared on plates had a higher ratio of anteiso- to iso fatty acids. CONCLUSIONS: The preparation in liquid yielded spores with some different properties than those made on agar plates. Spores made in liquid had lower resistance to heat and several chemicals, and germinated more readily with several agents. There were also differences in the composition of the inner membrane of spores prepared under these two conditions. However, there were no major differences in the levels of DPA, core water, SASP and individual coat proteins or the cross-linking of a coat protein in spores made in liquid and on plates. SIGNIFICANCE AND IMPACT OF THE STUDY: This work demonstrates that the preparation method can affect the resistance and germination properties of bacterial spores, even if an identical medium and temperature are used. Evidence was also obtained consistent with the role of the inner membrane in spore resistance and germination, and that some factor in addition to core water, DPA and SASP content plays a role in spore resistance to wet heat. PMID- 17714404 TI - High throughput, real-time detection of Naegleria lovaniensis in natural river water using LED-illuminated Fountain Flow Cytometry. AB - AIMS: To test Fountain Flow Cytometry (FFC) for the rapid and sensitive detection of Naegleria lovaniensis amoebae (an analogue for Naegleria fowleri) in natural river waters. METHODS AND RESULTS: Samples were incubated with one of two fluorescent labels to facilitate detection: ChemChrome V6, a viability indicator, and an R-phycoerytherin (RPE) immunolabel to detect N. lovaniensis specifically. The resulting aqueous sample was passed as a stream in front of a light-emitting diode, which excited the fluorescent labels. The fluorescence was detected with a digital camera as the sample flowed toward the imager. Detections of N. lovaniensis were made in inoculated samples of natural water from eight rivers in France and the United States. FFC enumeration yielded results that are consistent with other counting methods: solid-phase cytometry, flow cytometry, and hemocytometry, down to concentrations of 0.06 amoebae ml(-1), using a flow rate of 15 ml min(-1). CONCLUSIONS: This study supports the efficacy of using FFC for the detection of viable protozoa in natural waters and indicates that use of RPE illuminated at 530 nm and detected at 585 nm provides a satisfactory means of attenuating background. SIGNIFICANCE AND IMPACT OF THE STUDY: Because of the severe global public health issues with drinking water and sanitation, there is an urgent need to develop a technique for the real-time detection of viable pathogens in environmental samples at low concentrations. FFC addresses this need. PMID- 17714405 TI - Diversity of Shewanella population in fish Sparus aurata harvested in the Aegean Sea. AB - AIMS: To study the diversity of Shewanella population in Sparus aurata fish harvested in the Aegean Sea, as well as to elucidate the influence of fish storage conditions on the selection in Shewanella strains. METHODS AND RESULTS: A total of 108 strains of Shewanella spp. were isolated from Sparus aurata during storage under various conditions. Conventional phenotypic analysis along with sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of whole cell proteins and 16S rRNA sequence analysis were used for the characterization of the strains. Numerical analysis of whole cell protein profiles showed that the isolates were separated into two distinct clusters A and B with 47% similarity. Cluster B was further subdivided into two subclusters B1 and B2 with 70% similarity. One strain could not be assigned to any of these groups. The different ability of isolates to utilize deoxycholate, D-saccharate, D glucuronate, N-acetyl-glycosamine, D-maltose, gluconate and citrate, as well as the different type of metabolism on the Hugh and Leifson medium distinguished the different Shewanella biogroups, as these were defined by the SDS-PAGE analysis. Representative strains from the three biogroups were further investigated by 16S rRNA sequence analysis and showed more than 99.4% similarity. CONCLUSIONS: Significant similarities between the isolates and the type strains of S. baltica, S. putrefaciens and S. oneidensis at both phenotypic and molecular level signalize that the new isolates are closely related with the above Shewanella species, but do not provide a clear evidence to which of these species they belong. SIGNIFICANCE AND IMPACT OF THE STUDY: The lack of information about the diversity of Shewanella population in Sparus aurata fish originated from Mediterranean Sea could be confronted using conventional phenotypic techniques, SDS-PAGE analysis of whole cell proteins and 16S rRNA sequencing. PMID- 17714406 TI - Use of phage battery to investigate the actinofloral layers of termite gut microflora. AB - AIMS: The termite gut microbiota can include a variety of micro-organisms from the three domains: Bacteria, Archaea and Eucarya. The bacterial groups from the gut systems are mainly affiliated to the proteobacteria, the Gram-positive groups Bacterioiodes/Flavobacterium branch and the spirochetes, Firmicutes and Actinobacteria. However, culture independent molecular studies have revealed that the majority of these microbial gut symbionts have not yet been cultured, including actinobacterial clusters associated with termite guts. Accordingly, the aim of this study was to selectively isolate the actinofloral layers of gut associated microflora of the Coptotermes lacteus (Froggatt) species located at the Sunshine Coast Region of Queensland, Australia to increase our knowledge on the diversity of actinobacterial taxa present in the termite guts. METHODS AND RESULTS: Actinofloral layers associated with the guts of the wood-eating subterranean termite C. lacteus were investigated by exploiting the phage susceptibility of different gut associated bacteria which impede the growth of actinomycetes on isolation plates. These unwanted microbial taxa were removed by exposing the gut contents to polyvalent bacteriophages specifically targeting different background bacterial taxa and after their removal from the isolation plates previously undetected and novel actinomycetes were successfully cultured from the gut samples. CONCLUSIONS: Use of bacteriophages as a means of selective pressure successfully revealed the presence of novel actinomycete species within the guts of C. lacteus. SIGNIFICANCE AND IMPACT OF THE STUDY: Molecular ecology has undoubtedly revealed the fascinating diversity of micro-organisms, which cannot be cultured. However, these advances in the field still have not provided the ability to detect and isolate micro-organisms effectively from their ecological niches. Accordingly, studies like the one described here have importance in increasing the chances of uncultured taxa to be isolated to complement molecular microbial ecological efforts towards the establishment of an understanding on the diversity of termite gut microflora. PMID- 17714407 TI - Wine colour adsorption phenotype: an inheritable quantitative trait loci of yeasts. AB - AIMS: In this work, a population of 88 descendants derived from three wine strains of Saccharomyces cerevisiae was tested for the enological trait 'wine colour adsorption' (WCA) to evaluate its inheritability. METHODS AND RESULTS: The WCA phenotype was tested on plate agar medium specifically formulated for the purpose. After 10 days of anaerobic incubation at 28 degrees C, a computer assisted assessment of WCA aptitude of the yeasts was carried out. The biomass colour -- ranging from white to dark brown -- reflects the adsorption of grape pigments: white and dark brown biomass colour corresponds to low and high adsorption, respectively. In order to confirm biomass colour results, microvinification trials using red must were performed, and the obtained wines were analysed. CONCLUSIONS: The analysis of the progeny demonstrated that the enological trait WCA is inheritable and polygenic. SIGNIFICANCE AND IMPACT OF THE STUDY: A way to describe the polygenic effect of the WCA trait has been found, also showing that this trait is inheritable. The impact of the work revolves more around the large-scale screening method, which could then assist in breeding wine yeast, and can also be used as a scientific tool to investigate WCA trait. PMID- 17714408 TI - Interactions between strains of Staphylococcus xylosus and Kocuria varians isolated from fermented meats. AB - AIMS: To evaluate the interactions of Staphylococcus xylosus on Kocuria varians strains isolated from fermented meat products. METHODS AND RESULTS: Interactions were assessed in vitro by agar spot test, agar well diffusion assay and spectrophotometric assay. The growth of K. varians (five strains) alone was compared with that in the presence of growing cells of S. xylosus (50 strains) or in the presence of heat-treated or untreated supernatants of S. xylosus. Sixteen strains stimulated the growth of K. varians K4, while four strains inhibited the K4 strain. Heated cell-free supernatants of S. xylosus did not have any effect on K. varians. The proteolytic activity of single strains or their combinations was assessed in vitro and in vivo by sodiumdodecylsulfate-polyacrylamide gel electrophoresis of sarcoplasmic protein extracts. Combinations of stimulatory strains of S. xylosus and K. varians showed a higher proteolytic activity compared with that of S. xylosus or K. varians alone. CONCLUSIONS: The interactions between strains may influence both the growth of the co-cultured strains and proteolysis, technologically relevant characteristics. SIGNIFICANCE AND IMPACT OF THE STUDY: The study of interactions between coagulase-negative cocci may guide the formulation of mixed strain starters for the production of fermented sausages. PMID- 17714411 TI - Abstracts of the Society for Psychophysiological Research 47th annual meeting, October 16-21, 2007, Savannah, Georgia, USA. PMID- 17714410 TI - Fracture strength of bovine incisors after intra-radicular treatment with MTA in an experimental immature tooth model. AB - AIM: To evaluate, using an experimental immature tooth model, the fracture resistance of bovine incisors submitted to different reinforcement treatments with mineral trioxide aggregate (MTA). METHODOLOGY: An immature tooth model was created by sectioning the coronal and apical portions of 40 bovine incisors 8 mm above and 12 mm below the cementoenamel junction. The root canals were irrigated with 1.0% sodium hypochlorite. They were enlarged both coronally and apically using number 703 carbide burs (ISO: 500-104-168-007-021) and their internal diameter was standardized to 2.1 mm. The specimens were assigned to four groups (n = 10): GI-control (without filling); GII-apical MTA plug + filling with gutta percha and endodontic sealer; GIII-filling with MTA; GIV-apical MTA plug + filling with MTA + metallic post (Reforpost I). A polyether impression material was used to simulate the periodontal ligament. The specimens were submitted to a compressive load at a crosshead speed of 0.5 mm min(-1) in a servo-hydraulic universal testing machine (MTS 810) applied at 45 degrees to the long axis of the tooth until failure. Data were submitted to statistical analysis by the Kruskal Wallis test at 5% significance level. RESULTS: GIV presented the highest fracture resistance (32.7N) and differed significantly from the other groups (P < 0.05). No statistically difference was found between GII (16.6N) and GIII (23.4N) (P > 0.05). GIII had a significantly higher fracture resistance than GI (P < 0.05). CONCLUSIONS: The use of MTA + metallic post as an intra-radicular reinforcement treatment increased the resistance to fracture of weakened bovine teeth in an experimental immature tooth model. PMID- 17714412 TI - Quality and stability of red cells derived from gravity-separated placental blood with a hollow-fiber system. AB - BACKGROUND: Several studies show that donor red blood cells (RBCs) can be processed by gravity separation with a hollow-fiber filtration system. This study investigated whether fetal blood could be filtered in the same way. STUDY DESIGN AND METHODS: Twelve newborns born after healthy pregnancies were included in the study. Placental blood was sampled with standard procedures. The sampled blood was separated with a specially designed hollow-fiber filtration system (Sangofer neonatal, Heim Group). The RBC bag contained 10 mL of saline, adenine, glucose mannitol (SAG-M) for stabilization. After processing, the resulting RBC volume was estimated. Quality variables (blood counts, hemolysis rate) were measured before and after 35 days of storage at +4 degrees C. RESULTS: The 12 processed RBC units had a mean volume of 62.3 +/- 13.5 mL and a mean hematocrit level of 0.56 +/- 0.06. No white blood cell contamination could be detected in any of the RBC units tested. After 35 days of storage, the hemolysis was 0.1 +/- 0.07 and the amount of free hemoglobin was 0.28 +/- 0.017 mmol per L. CONCLUSIONS: This study shows that it is possible to process placental blood to RBCs by gravity separation with a hollow-fiber system. The quality of the RBCs thus processed was suitable for 35 days storage. The use of placental blood in the treatment of children with anemia (e.g., malaria) in the underresourced world is widely discussed. Because the separation device used here needs no additional equipment or electrical devices, it is considered to be an ideal method for use in these countries. PMID- 17714413 TI - Translation of glycoprotein IIIa in stored blood platelets. AB - BACKGROUND: Platelet (PLT) products have a short shelf life (5 days) owing in part to the deterioration of the quality of PLTs stored at 22 degrees C. This creates significant inventory challenges, and blood banks may suffer shortages and high wastage as a result. The precise biochemical pathways involved in the PLT storage lesion are unknown and must be understood before storage time can be extended. STUDY DESIGN AND METHODS: Informed by previous proteomics analysis, specific PLT glycoprotein (GP) concentration and surface expression were examined by Western blot and flow cytometry. mRNA concentration was determined by Northern blot and real-time polymerase chain reaction. Protein synthesis was confirmed by [(35)S]methionine labeling. RESULTS: Western blots of GPIIIa revealed a twofold increase in concentration on Day 7 of storage and a fourfold increase on Day 10. By flow cytometry, surface expression of the GPIIb/IIIa increased by 13.4 percent on Day 7 and 41.9 percent on Day 10. Full-length GPIIIa mRNA was present throughout this storage period and was shown to have a half-life of approximately 2.9 days. Translation of GPIIb and IIIa during storage was confirmed by [(35)S]methionine labeling. CONCLUSION: This article confirms that PLTs are capable of synthesizing biologically relevant proteins ex vivo throughout a 10 day storage period with particularly long-lived mRNA and provides a framework through which the biochemical mechanisms involved in the translational regulation of proteins thought to be involved in the initiation or exacerbation of the PLT storage lesion can be investigated. PMID- 17714414 TI - Chemical treatment of anti-D results in improved efficacy for the inhibition of Fcgamma receptor-mediated phagocytosis. AB - BACKGROUND: This study investigated whether treatment of immunoglobulins anti-D or intravenous immune globulin (IVIG) with chemicals previously shown to inhibit phagocytosis could result in an enhancement of Fcgamma receptor (FcgammaR) blockade in vitro. If successful, this approach may provide the possibility of targeting these chemicals to monocyte-macrophages for increased efficacy of immunoglobulin-based therapies in vivo. STUDY DESIGN AND METHODS: For proof-of concept, the chemical thimerosal, a prototype FcgammaR inhibitor, was combined with RhIG or IVIG. Residual chemical was removed by extensive dialysis. With a monocyte monolayer assay (MMA) and a concentration of immunoglobulin alone that results in 50 percent inhibition of MMA phagocytosis of antibody-coated red blood cells, the effect of thimerosal treatment on the ability of the immunoglobulin to show a significant enhancement of efficacy was determined. RESULTS: It is shown that combining thimerosal with anti-D, either slide and rapid tube or commercially available (WinRho SDF, Cangene), results in a highly significant increase in efficacy over anti-D alone to inhibit phagocytosis in vitro. This effect was not due to residual unbound compound or to cellular toxicity of the chemically treated immunoglobulins. Treatment of IVIG with thimerosal had no significant effect on its ability to inhibit in vitro phagocytosis. CONCLUSION: Our results indicate that it is possible to modify an immunoglobulin by chemical treatment such that the treated immunoglobulin demonstrates significantly enhanced ability to inhibit FcgammaR-mediated phagocytosis. It is also demonstrated that IVIG and anti-D appear to respond differently after chemical treatment. Further examination of this strategy is warranted and has the potential to reduce the dose, cost, and possibly, adverse effects of immunoglobulin-based therapies. PMID- 17714415 TI - Altered processing of thawed red cells to improve the in vitro quality during postthaw storage at 4 degrees C. AB - BACKGROUND: The use of a functionally closed system (ACP215, Haemonetics) for the glycerolization and deglycerolization of red blood cell (RBC) units allows for prolonged postthaw storage. In this study, the postthaw quality of previously frozen, deglycerolized RBCs resuspended in saline-adenine-glucose-mannitol (SAGM) or additive solution AS-3 was investigated. STUDY DESIGN AND METHODS: Leukoreduced RBC units were frozen with 40 percent glycerol and stored at -80 degrees C for at least 14 days. The thawed units were deglycerolized with the ACP215, resuspended in SAGM or AS-3, and stored at 2 to 6 degrees C for up to 21 days. RESULTS: The mean +/- standard deviation in vitro freeze-thaw-wash recovery was 81 +/- 5 percent. During storage, hemolysis of deglycerolized cells remained below 0.8 percent for 2 days in SAGM and for 14 days in AS-3. This difference was explained by the protective effect of citrate, which is present in AS-3. Cells stored in AS-3 showed a lower glycolytic activity and a faster decline in adenosine 5'-triphosphate (ATP) than cells in SAGM. Increasing the internal pH of cells before storage in AS-3 by use of phosphate-buffered saline (PBS) in the deglycerolization procedure resulted in elevated lactate production and better maintenance of intracellular ATP content. After 3 weeks of storage, the ATP content of PBS-washed cells amounted to 2.5 +/- 0.5 micromol per g of hemoglobin (Hb), whereas for saline/glucose-washed cells this value was decreased to 1.0 +/- 0.3 micromol per g of Hb. CONCLUSIONS: Leukoreduced, deglycerolized RBCs can be stored for 48 hours in SAGM. Improved ATP levels during refrigerated storage can be observed with thawed cells, resuspended in AS-3, when PBS is used as a washing solution. PMID- 17714416 TI - Leukoreduction filtration of whole-blood units from sickle trait donors: effects of a metered citrate anticoagulant system. AB - BACKGROUND: Polymerization of hemoglobin (Hb) S is exacerbated by acidic and hyperosmotic citrate anticoagulant solutions and often results in occlusion of leukoreduction filters by red blood cells (RBCs) from sickle cell trait (Hb AS) donors. This study evaluates a blood collection instrument that adds citrate anticoagulant in a metered fashion, thus mitigating adverse citrate effects. STUDY DESIGN AND METHODS: Collection of whole blood by a metered anticoagulant system was compared to traditional phlebotomy in 12 Hb AS and 12 non-sickle trait (Hb AA) donors. Each donated twice; on one occasion, units were filtered after 4 hour storage at 20 to 24 degrees C, and on the other, units were stored at 1 to 6 degrees C for 24 hours before filtration. RESULTS: Filtration times, RBC recoveries, and residual white blood cell (WBC) counts met defined criteria more often in Hb AS units collected by a metered anticoagulant system (9 of 12, 8 of 12, and 4 of 12, respectively) compared to traditional phlebotomy (1 of 12, 2 of 12, and 0 of 12, respectively). Overall, Hb AS units filtered better after storage at 1 to 6 degrees C for 24 hours, with units collected by a metered anticoagulant system undergoing filtration most effectively (5 of 6 had >85% RBC recovery, 3 of 6 had <5 x 10(6) residual WBC). Units exhibited similar changes in RBC storage parameters. CONCLUSION: Use of a metered anticoagulation instrument demonstrates potential for successful leukoreduction and acceptable storage of Hb AS units; however, the system needs further modifications and improvements before it can be utilized to collect and leukoreduce Hb AS blood. PMID- 17714418 TI - The alloimmune response to the human platelet antigen-1a is not related to maternal-fetal killer immunoglobulinlike receptor/HLA-Cw combinations. AB - BACKGROUND: Human platelet antigen (HPA)-1a fetomaternal alloimmune thrombocytopenia, responsible in the most severe cases for fetal or neonatal intracranial hemorrhages leading to death or survival with neurologic sequelae, was shown to be restricted to the human leukocyte antigen (HLA) Class II DRB3*0101-encoded molecule. Whereas more than 90 percent of alloimmunized mothers display the DRB3*0101 allele, the positive predictive value of the presence of DRB3*0101 is only 35 percent. Additional genetic risk factors may exist of which elucidation could improve the undertaking of incompatible pregnancies in at-risk families, encouraging an antenatal screening. Interactions of killer immunoglobulinlike receptors (KIRs) on maternal decidual NK cells with HLA-Cw molecules on fetal trophoblasts were reported as one of the mechanisms involved in the fetomaternal tolerance during pregnancy. STUDY DESIGN AND METHODS: Genotyping was performed of 16 KIR genes in HPA-1a-negative/DRB3*0101-positive alloimmunized mothers and in HPA-1a-negative/DRB3*0101-positive nonimmunized mothers as well as HLA-Cw genotyping in thrombocytopenic children and their nonaffected siblings. RESULTS: No particular KIR genes or KIR genotypes were observed in the alloimmunized or nonimmunized mothers. Distribution of HLA-Cw genes in affected infants and nonaffected siblings did not reveal any HLA-Cw specificity associated with triggering or modulation of the HPA-1a alloimmunization. No maternal KIR/fetal HLA-Cw combinations were demonstrated in association with a detrimental or a protective effect on the HPA-1a alloimmunization. CONCLUSION: Maternal KIR/fetal HLA-Cw gene combinations that are involved in the fetomaternal tolerance do not appear to play a role in the HPA-1a alloimmunization. PMID- 17714417 TI - Divergent expression of cellular prion protein on blood cells of human and nonhuman primates. AB - BACKGROUND: Four recent transmissions of variant Creutzfeldt-Jakob disease infection by transfusion highlight the need for detailed understanding of blood related prion pathogenesis. Nonhuman primates are the most relevant models of human prion diseases. STUDY DESIGN AND METHODS: Quantitative flow cytometry with monoclonal antibodies FH11, 3F4, and 6H4 against different parts of the normal cellular form of the prion protein (PrP(C)) was used to evaluate its expression on blood cells of humans, chimpanzees, cynomolgus macaques, rhesus macaques, squirrel monkeys, and microcebe lemurs. RESULTS: Chimpanzees, rhesus macaques, and squirrel monkeys displayed a much higher quantity of total blood cell membrane PrP(C) than humans, due to a markedly higher expression of PrP(C) on their red blood cells (RBCs). In contrast, cynomolgus macaques and lemurs demonstrated substantially lower levels of membrane PrP(C) due to the lack of significant PrP(C) expression on RBCs and platelets (PLTs). All species displayed PrP(C) on white blood cells (WBCs), with the highest levels found on human cells. Only humans, chimpanzees, and to a lesser degree rhesus macaques expressed PrP(C) on PLTs. CONCLUSION: If PrP(C) contributes to the propagation or transport of prion infectivity in blood, the differences reported here need to be considered when extrapolating results of transmission studies in primate models to blood and blood components in humans. PMID- 17714419 TI - Dismantling applied tension: mechanisms of a treatment to reduce blood donation related symptoms. AB - BACKGROUND: Blood donation-related symptoms such as dizziness, nausea, and fainting are unpleasant for the donor and a significant disincentive for repeat donation. The muscle tensing technique of applied tension (AT) reduced symptoms in several studies. STUDY DESIGN AND METHODS: This study was a randomized controlled trial of different components of AT. A total of 1209 donors were randomly assigned to one of six conditions involving tension of different muscle groups or donation as usual. Dependent measures included a symptom questionnaire and whether or not the donor's chair was reclined to treat a reaction. RESULTS: Replicating previous findings, donors who practiced the "full" AT procedure reported significantly fewer symptoms, were less likely to require chair reclining, and rated their chances of giving blood again as greater than those in the donation-as-usual group. Of the component groups, donors who tensed only their lower body were most similar to the full-AT group. Upper-body tension in and of itself did not reduce symptoms though another condition involving upper body tension, which directed attention away from the arm with the needle in it had several significant effects. CONCLUSION: The positive effects of AT on blood donation outcome appear to be mediated primarily by lower-body tension though distraction also probably contributes to its impact. PMID- 17714420 TI - Peripheral blood hematopoietic stem cell mobilization and collection efficacy is not an independent prognostic factor for autologous stem cell transplantation. AB - BACKGROUND: The successful mobilization and collection of hematopoietic stem cells are dependent on a number of clinical factors such as previous chemotherapy and disease stage. The aim of this retrospective study was to determine whether the effectiveness of mobilization and collection is an independent prognostic factor for autologous stem cell transplantation outcome. STUDY DESIGN AND METHODS: A total of 358 patients who received transplants from January 2003 to December 2004 (201 male and 157 female patients, ages from 2.7 to 77.3 years with median of 53 years of age) underwent autologous hematopoietic stem cell collection after mobilization with granulocyte-colony-stimulating factor (G-CSF) or G-CSF plus chemotherapy priming. This retrospective study included patients with diagnoses of acute myelogenous leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, and solid tumors. All patients underwent stem cell collection until a target or a minimum CD34+ cell dose was reached. Correlations were performed between stem cell mobilization and/or collection efficacy and transplantation outcomes. RESULTS: In general, both larger reinfused CD34+ cell dose and shorter number of days for the stem cell count to reach the minimum of 2 x 10(6) per kg CD34+ cells do not foster quicker engraftment. Reinfused CD34+ cell dose of less than 12 x 10(6) and number of days stem cell collection to reach this minimum CD34+ cell dose did not independently affect the overall survival (OS) or disease-free survival (DFS). CONCLUSION: The effectiveness of hematopoietic stem cell mobilization and collection as defined as number of days to reach a CD34+ cell dose of 2 x 10(6) per kg should not be used independently to forecast posttransplantation prognosis, engraftment, DFS, and OS. PMID- 17714421 TI - Peripheral blood progenitor uncontrolled-rate freezing: a single pediatric center experience. AB - BACKGROUND: Controlled-rate freezing (CRF) followed by storage in liquid nitrogen is employed by most centers as the standard procedure for peripheral blood progenitor cell (PBPC) cryopreservation. Uncontrolled-rate freezing (URF) at -80 degrees C is more simple, time-saving, less expensive, and, possibly, as effective as CRF. The aim of this retrospective analysis was to compare CRF and URF in childhood transplantation. STUDY DESIGN AND METHODS: A total of 54 PBPC transplants performed in 39 children aged 3 to 16 years (median, 9.5 years) were analyzed: 23 transplants in 16 children with CRF versus 31 transplants performed in 23 children with -80 degrees C URF. All grafts contained at least 2 x 10(6) per kg unselected CD34+ cells, enumerated before freezing. Nucleated cells infused ranged from 1.32 x 10(8) to 4.3 x 10(8) per mL with a median of 3.1 x 10(8) per mL. Cryoprotectant solution consisted of a final dimethyl sulfoxide (DMSO) concentration of 10 percent DMSO with autologous plasma. RESULTS: The two study groups did not differ in terms of timing of neutrophil and platelet recovery or transfusion requirements. Adverse events related to graft infusion, severe complications, and transplant-related mortality were not significantly different between CRF and URF groups. In both groups only mild adverse events were observed during graft administration. URF procedures, however, were simpler and less expensive. At a median follow-up of 72 months, no secondary myelodysplasia was observed in either group. CONCLUSION: Our analysis suggests that URF is safe and effective in the pediatric population. PMID- 17714422 TI - Detection of anti-D in D- recipients transfused with D+ red blood cells. AB - BACKGROUND: The D antigen is highly immunogenic, requiring only a small quantity of transfused red blood cells (RBCs) to cause alloimmunization in D- immunocompetent recipients. The relatively low sensitization rate in oncology patients transfused with D+ platelets is well documented. A study of the alloimmunization rate of primarily nononcology D- recipients transfused with D+ RBCs was undertaken. STUDY DESIGN AND METHODS: Transfusion service records were examined to identify D- recipients who were not alloimmunized to the D antigen and who had a follow-up antibody screen performed at least 10 days after the initial D+ RBC transfusion(s). The age and sex of the recipients, date and number of D+ RBC transfusion(s) and their leukoreduction status, all subsequent serologic investigations, and the hospital ward where the units were issued were recorded. RESULTS: There were 98 study-eligible recipients identified who received a total of 445 D+ RBC units. The mean follow-up length was 182 days. Most recipients (87%) had antibody screens performed more than 21 days after the initial D+ RBC transfusion. In total, 24 recipients made 44 new alloantibodies: 22 anti-D (22%), 11 anti-E, 5 anti-C, 2 anti-K, and 1 each of anti-Kp(a), anti Jk(a), anti-Bg, and anti-Fy(b). The rate of anti-D alloimmunization among recipients of entirely leukoreduced D+ units was 13 percent (1/8). Reexposure to D+ RBCs after the initial bleeding episode did not increase the rate of alloimmunization. CONCLUSIONS: The 22 percent rate of anti-D alloimmunization in patients requiring urgent RBC transfusion was intermediate between the rates previously reported for D- oncology patients transfused with D+ RBCs and that in immunocompetent volunteer recipients. PMID- 17714423 TI - Treatment allocation in clinical trials. PMID- 17714424 TI - Dramatic tissue response after a single granulocyte transfusion. PMID- 17714425 TI - Blood donor screening for parvovirus B19 in Germany and Austria. AB - BACKGROUND: Although the main transmission pathway of parvovirus B19 (B19) is typically via the respiratory route, several transfusion-transmitted infections have been reported. To increase blood safety, all blood donations to our blood donor service have been screened by a B19 minipool real-time nucleic acid testing (NAT) since April 2000. Additional customers have been screened since the summer of 2003. STUDY DESIGN AND METHODS: In total, 2.8 million donations from Germany and Austria were screened for B19 by real-time minipool NAT. A subgroup of 50 B19 DNA-positive donors was screened for B19 immunoglobulin G (IgG) and IgM antibodies and B19 DNA over a 6-month period. Results were compared to those of 100 B19 DNA-negative donors. RESULTS: Data accumulated over the past 6 years indicate a high incidence period from May 2004 to January 2006. In total, the incidence was 12.7 and 261.5 per 100,000 donations with high virus loads equal to or above 10(5) and below 10(5) IU per mL, respectively. Median virus concentration in the case group was 4.85 x 10(7) IU per mL at Time Point T0 and was reduced to 4 x 10(2) IU per mL at the time of the next donation (3 months later). Neutralizing antibodies (VP2) were detected in all donations if virus load was reduced to less than 10(5) IU per mL. CONCLUSION: The release of B19 DNA positive blood products with a concentration of less than 105 IU per mL is thought to be safe due to the high level of neutralizing VP2 antibodies and is currently examined in a donor recipient infectivity study. In contrast, blood products with a high B19 DNA concentration (> or =10(5) IU/mL), some of which did not contain neutralizing antibodies, were discarded to protect at risk individuals. PMID- 17714426 TI - Homodimerization antagonizes nuclear export of survivin. AB - Survivin plays separate roles during different phases of the cell cycle. In mitosis, Survivin is a key regulator of cell division, while in interphase, Survivin is able to protect cells from apoptosis. Survivin shuttles between nucleus and cytoplasm under the influence of one or more nuclear export signals (NESs). Paradoxically, our data show that Survivin poorly binds CRM1 in vitro because hydrophobic residues of the NES are occupied in homodimer contacts. We show that NES-preserving dimerization mutants behave as monomers in solution, show dramatically increased CRM1 binding and are more efficiently exported in vivo than wild-type Survivin. These data indicate that Survivin contains a monomer-specific NES and that dimerization modulates cytoplasmic access of the protein. Our findings have implications for both the mitotic and interphase roles of survivin. PMID- 17714427 TI - rAAV6-microdystrophin rescues aberrant Golgi complex organization in mdx skeletal muscles. AB - Muscular dystrophies are a diverse group of severe degenerative muscle diseases. Recent interest in the role of the Golgi complex (GC) in muscle disease has been piqued by findings that several dystrophies result from mutations in putative Golgi-resident glycosyltransferases. Given this new role of the Golgi in sarcolemmal stability, we hypothesized that abnormal Golgi distribution, regulation and/or function may constitute part of the pathology of other dystrophies, where the primary defect is independent of Golgi function. Thus, we investigated GC organization in the dystrophin-deficient muscles of mdx mice, a mouse model for Duchenne muscular dystrophy. We report aberrant organization of the synaptic and extrasynaptic GC in skeletal muscles of mdx mice. The GC is mislocalized and improperly concentrated at the surface and core of mdx myofibers. Golgi complex localization is disrupted after the onset of necrosis and normal redistribution is impaired during regeneration of mdx muscle fibers. Disruption of the microtubule cytoskeleton may account in part for aberrant GC localization in mdx myofibers. Golgi complex distribution is restored to wild type and microtubule cytoskeleton organization is significantly improved by recombinant adeno-associated virus 6-mediated expression of DeltaR4-R23/DeltaCT microdystrophin showing a novel mode of microdystrophin functionality. In summary, GC distribution abnormalities are a novel component of mdx skeletal muscle pathology rescued by microdystrophin expression. PMID- 17714428 TI - Arabidopsis GCP2 and GCP3 are part of a soluble gamma-tubulin complex and have nuclear envelope targeting domains. AB - In higher plants, microtubules (MTs) are assembled in distinctive arrays in the absence of a defined organizing center. Three MT nucleation sites have been described: the nuclear surface, the cell cortex and cortical MT branch points. The Arabidopsis thaliana (At) genome contains putative orthologues encoding all the components of characterized mammalian nucleation complexes: gamma-tubulin and gamma-tubulin complex proteins GCP2 to GCP6. We have cloned the cDNA encoding AtGCP2, and show that gamma-tubulin, AtGCP2 and AtGCP3 are part of the same tandem affinity-purified complex and are present in a large membrane-associated complex. In addition, small soluble gamma-tubulin complexes of the size expected for a gamma-tubulin core complex are recruited to isolated nuclei. Using immunogold labelling, AtGCP3 is localized to both the nuclear envelope (NE) and the plasma membrane. To identify domains that could play a role in targeting complexes to these nucleation sites, truncated AtGCP2- and AtGCP3-green fluorescent protein fusion proteins were expressed in BY-2 cells. Several domains from AtGCP2 and AtGCP3 are capable of targeting fusions to the NE. We propose that regulated recruitment of soluble gamma-tubulin-containing complexes is responsible for nucleation at dispersed sites in plant cells and contributes to the formation and organization of the various MT arrays. PMID- 17714429 TI - The E3 ligase AtCHIP ubiquitylates FtsH1, a component of the chloroplast FtsH protease, and affects protein degradation in chloroplasts. AB - The Arabidopsis E3 ligase AtCHIP was found to interact with FtsH1, a subunit of the chloroplast FtsH protease complex. FtsH1 can be ubiquitylated by AtCHIP in vitro, and the steady-state level of FtsH1 is reduced in AtCHIP-over-expressing plants under high-intensity light conditions, suggesting that the ubiquitylation of FtsH1 by AtCHIP might lead to the degradation of FtsH1 in vivo. Furthermore, the steady-state level of another subunit of the chloroplast FtsH protease complex, FtsH2, is also reduced in AtCHIP-over-expressing plants under high intensity light conditions, and FtsH2 interacts physically with AtCHIP in vivo, suggesting the possibility that FtsH2 is also a substrate protein for AtCHIP in plant cells. A substrate of FtsH protease in vivo, the photosystem II reaction center protein D1, is not efficiently removed by FtsH in AtCHIP-over-expressing plants under high-intensity light conditions, supporting the assumption that FtsH subunits are substrates of AtCHIP in vivo, and that AtCHIP over-expression may lead to a reduced level of FtsH in chloroplasts. AtCHIP interacts with cytosolic Hsp70 and the precursors of FtsH1 and FtsH2 in the cytoplasm, and Hsp70 also interacts with FtsH1, and these protein-protein interactions appear to be increased under high-intensity light conditions, suggesting that Hsp70 might be partly responsible for the increased degradation of the substrates of Hsp70, such as FtsH1 and FtsH2, in AtCHIP-over-expressing plants under high-intensity light conditions. Therefore, AtCHIP, together with Hsp70, may play an important role in protein quality control in chloroplasts. PMID- 17714430 TI - Molecular cloning and function analysis of the stay green gene in rice. AB - Chloroplasts undergo drastic morphological and physiological changes during senescence with a visible symptom of chlorophyll (Chl) degradation. A stay green mutant was identified and then isolated from the japonica rice (Oryza sativa) cv. Huazhiwu by gamma-ray irradiation. The stay green mutant was characterized by Chl retention, stable Chl-protein complexes, and stable thylakoid membrane structures, but lost its photosynthetic competence during senescence. The gene, designated Stay Green Rice (SGR), was cloned by a positional cloning strategy encoding an ancient protein containing a putative chloroplast transit peptide. SGR protein was found in both soluble and thylakoid membranes in rice. SGR, like the gene for pheophorbide a oxygenase (PaO), was constitutively expressed, but was upregulated by dark-induced senescence in rice leaves. Senescence-induced expression of SGR and PaO was enhanced by ABA, but inhibited by cytokinin. Overexpression of SGR reduced the number of lamellae in the grana thylakoids and reduced the Chl content of normally growing leaves. This indicates that upregulation of SGR increases Chl breakdown during senescence in rice. A small quantity of chlorophyllide a accumulated in sgr leaves, but this also accumulated in wild-type rice leaves during senescence. Some pheophorbide a was detected in sgr leaves in the dark. According to these observations, we propose that SGR may be involved in regulating or taking part in the activity of PaO, and then may influence Chl breakdown and degradation of pigment-protein complex. PMID- 17714431 TI - Preserving breastfeeding practice through the HIV pandemic. AB - Breastfeeding, particularly for the first 6 months of life, is unquestionably the ideal way to feed most infants. However, the human immunodeficiency virus (HIV) pandemic has caused debate and confusion about the best way for HIV-positive mothers to feed their children. This review provides recent key findings and opinions around making breastfeeding safer for HIV-positive women, and argues for preservation of breastfeeding, as opposed to complete avoidance of breastfeeding for all HIV-positive women. PMID- 17714432 TI - Short communication: first record of Aedes albopictus in Gabon, Central Africa. AB - The Asian tiger mosquito Aedes albopictus is an important arbovirus vector. Originating in East Asia, the species has been introduced to the Americas, the Indo-Pacific and Australasian regions as well as Europe and Africa, mostly during the past 30 years and probably by transportation in used tires. We report Ae. albopictus for the first time from Gabon (Libreville). In addition, the yellow fever mosquito Ae. aegypti ssp. formosus and 16 other culicid species were detected throughout the city, four of which are also new records for Gabon. PMID- 17714433 TI - A serological study of Cryptosporidium transmission in a periurban area of a Brazilian Northeastern city. AB - OBJECTIVES: To study the prevalence of Cryptosporidium infection by measuring the levels of anti-Cryptosporidium IgG antibodies among people inhabiting three neighbourhoods of a periurban area of Salvador, Northeast of Brazil; and to investigate the effects of environmental sanitation measures, hygienic habits and household water supply, storage and handling on the frequency of these antibodies in sera of the studied population. METHODS: Cryptosporidium inter-household transmission was studied by comparing the frequency of anti-Cryptosporidium IgG antibodies among people inhabiting areas with or without different environmental sanitation measures and intra-household transmission by comparing the presence of these antibodies in families with or without cases of diarrhoea, associated with the presence of Cryptosporidium oocysts in their stools. Children or family members with diarrhoeal episodes were evaluated parasitologically for Cryptosporidium infection by testing stool specimens with the Ritchie-modified formol-ether concentration and the acid-fast staining methods. All groups were serologically evaluated for parasite exposure by an indirect enzyme-linked immunosorbent assay. RESULTS: A statistically significant difference was detected in the prevalence of Cryptosporidium infection between area 1 which had no environmental sanitation measures and area 3 which had improved environmental sanitation measures (P = 0.044). Most of the hygienic habits investigated did not correlate with the presence of anti-Cryptosporidium antibody in sera of the population studied. However, positive associations were found between both poor household water supply (OD = 0.17; 90% CI = 0.09-0.32; P = 0.0001) and drinking unboiled/unfiltered water (OD = 0.40; 90% CI = 0.24-0.67; P = 0.0002) with high levels of anti-Cryptosporidium antibodies in sera. CONCLUSIONS: These data suggest that although uncorrected household water supply, storage and handling play an important role on Cryptosporidium transmission in periurban areas of developing country cities, like Salvador, Brazil, inadequate environmental conditions may also contribute to the spread of this parasite. PMID- 17714434 TI - Vps22/EAP30 in ESCRT-II mediates endosomal sorting of growth factor and chemokine receptors destined for lysosomal degradation. AB - The ubiquitin-binding protein Hrs and endosomal sorting complex required for transport (ESCRT)-I and ESCRT-III are involved in sorting endocytosed and ubiquitinated receptors to lysosomes for degradation and efficient termination of signaling. In this study, we have investigated the role of the ESCRT-II subunit Vps22/EAP30 in degradative protein sorting of ubiquitinated receptors. Vps22 transiently expressed in HeLa cells was detected in endosomes containing endocytosed epidermal growth factor receptors (EGFRs) as well as Hrs and ESCRT-I and ESCRT-III. Depletion of Vps22 by small interfering RNA, which was accompanied by decreased levels of other ESCRT-II subunits, greatly reduced degradation of EGFR and its ligand EGF as well as the chemokine receptor CXCR4. EGFR accumulated on the limiting membranes of early endosomes and aberrantly small multivesicular bodies in Vps22-depleted cells. Phosphorylation and nuclear translocation of extracellular-signal-regulated kinase1/2 downstream of the EGF-activated receptor were sustained by depletion of Hrs or the ESCRT-I subunit Tsg101. In contrast, this was not the case when Vps22 was depleted. These results indicate an important role for Vps22 in ligand-induced EGFR and CXCR4 turnover and suggest that termination of EGF signaling occurs prior to ESCRT-II engagement. PMID- 17714435 TI - In vitro fusion catalyzed by the sporulation-specific t-SNARE light-chain Spo20p is stimulated by phosphatidic acid. AB - Sec9p and Spo20p are two SNAP25 family SNARE proteins specialized for different developmental stages in yeast. Sec9p interacts with Sso1/2p and Snc1/2p to mediate intracellular trafficking between post-Golgi vesicles and the plasma membrane during vegetative growth. Spo20p replaces Sec9p in the generation of prospore membranes during sporulation. The function of Spo20p requires enzymatically active Spo14p, which is a phosphatidylcholine (PC)-specific phospholipase D that hydrolyzes PC to generate phosphatidic acid (PA). Phosphatidic acid is required to localize Spo20p properly during sporulation; however, it seems to have additional roles that are not fully understood. Here we compared the fusion mediated by all combinations of the Sec9p or Spo20p C terminal domains with Sso1p/Sso2p and Snc1p/Snc2p. Our results show that Spo20p forms a less efficient SNARE complex than Sec9p. The combination of Sso2p/Spo20c is the least fusogenic t-SNARE complex. Incorporation of PA in the lipid bilayer stimulates SNARE-mediated membrane fusion by all t-SNARE complexes, likely by decreasing the energetic barrier during membrane merger. This effect may allow the weak SNARE complex containing Spo20p to function during sporulation. In addition, PA can directly interact with the juxtamembrane region of Sso1p, which contributes to the stimulatory effects of PA on membrane fusion. Our results suggest that the fusion strength of SNAREs, the composition of organelle lipids and lipid-SNARE interactions may be coordinately regulated to control the rate and specificity of membrane fusion. PMID- 17714437 TI - Intracellular trafficking of Pseudomonas ExoS, a type III cytotoxin. AB - Pseudomonas aeruginosa ExoS is a bifunctional type III cytotoxin that disrupts Ras- and Rho-signaling pathways in mammalian cells. A hydrophobic region (residues 51-77, termed the membrane localization domain) targets ExoS to the plasma membrane (PM) and late endosomes of host cells. In the current study, metabolic inhibitors and dominant-negative proteins that disrupt known vesicle trafficking pathways were used to define the intracellular trafficking of ExoS. Release of ExoS from PM was independent of dynamin and ADP ribosylation factor 6 but inhibited by methyl-beta-cyclodextrin, a cholesterol-depleting reagent, and perinuclear localization of ExoS was disrupted by nocodazole. p50 dynamitin, a dynein inhibitor partially disrupted perinuclear localization of ExoS. Methyl beta-cyclodextrin and nocodazole inhibited the ability of type-III-delivered ExoS to ADP-ribosylated Golgi/endoplasmic reticulum-resident Ras. Methyl-beta cyclodextrin also relocated ExoS from the perinuclear region to the PM, indicating that ExoS can cycle through anterograde as well as through retrograde trafficking pathways. These findings show that ExoS endocytosis is cholesterol dependent, and it utilizes host microtubules, for intracellular trafficking. Understanding how type III cytotoxins enter and traffic within mammalian cells may identify new targets for therapeutic intervention of gram-negative bacterial pathogens. PMID- 17714436 TI - Trafficking of siderophore transporters in Saccharomyces cerevisiae and intracellular fate of ferrioxamine B conjugates. AB - We have studied the intracellular trafficking of Sit1 [ferrioxamine B (FOB) transporter] and Enb1 (enterobactin transporter) in Saccharomyces cerevisiae using green fluorescent protein (GFP) fusion proteins. Enb1 was constitutively targeted to the plasma membrane. Sit1 was essentially targeted to the vacuolar degradation pathway when synthesized in the absence of substrate. Massive plasma membrane sorting of Sit1 was induced by various siderophore substrates of Sit1, and by coprogen, which is not a substrate of Sit1. Thus, different siderophore transporters use different regulated trafficking processes. We also studied the fate of Sit1-mediated internalized siderophores. Ferrioxamine B was recovered in isolated vacuolar fractions, where it could be detected spectrophotometrically. Ferrioxamine B coupled to an inhibitor of mitochondrial protoporphyrinogen oxidase (acifluorfen) could not reach its target unless the cells were disrupted, confirming the tight compartmentalization of siderophores within cells. Ferrioxamine B coupled to a fluorescent moiety, FOB-nitrobenz-2-oxa-1,3-diazole, used as a Sit1-dependent iron source, accumulated in the vacuolar lumen even in mutants displaying a steady-state accumulation of Sit1 at the plasma membrane or in endosomal compartments. Thus, the fates of siderophore transporters and siderophores diverge early in the trafficking process. PMID- 17714438 TI - Rhodococcus equi lung infection in an allogeneic hematopoietic stem cell transplant recipient. AB - In this report, we describe a case of Rhodococcus equi lung infection diagnosed in an allogeneic hematopoietic stem cell transplant with oral graft-versus-host disease 3 months after stem cell infusion. The lung lesion persisted despite an approximate 3 months of vancomycin therapy, but then responded favorably to a combination of intravenous ertapenem at 1 g daily and oral rifampin at 600 mg daily for 1 month. An overview of Rhodococcus infection in transplant recipients is presented. This case and the discussed literature suggest that combination antibiotic therapy is warranted in patients with decreased humoral and cellular immunity. PMID- 17714439 TI - Development of transgenic rice seed accumulating a major Japanese cedar pollen allergen (Cry j 1) structurally disrupted for oral immunotherapy. AB - Rice seed-based edible vaccines expressing T-cell epitope peptides derived from Japanese cedar major pollen allergens have been used to successfully suppress allergen-specific Th2-mediated immunoglobulin E (IgE) responses in mouse experiments. In order to further expand the application of seed-based allergen specific immunotherapy for controlling Japanese cedar pollinosis, we generated transgenic rice plants that specifically express recombinant Cry j 1 allergens in seeds. Cry j 1 allergens give low specific IgE-binding activity but contain all of the T-cell epitopes. The allergens were expressed directly or as a protein fusion with the major rice storage protein glutelin. Fusion proteins expressed under the control of the strong rice endosperm-specific GluB-1 promoter accumulated in rice endosperm tissue up to 15% of total seed protein. The fusion proteins aggregated with cysteine-rich prolamin and were deposited in endoplasmic reticulum-derived protein body I. The production of transgenic rice expressing structurally disrupted Cry j 1 peptides with low IgE binding activity but spanning the entire Cry j1 region can be used as a universal, safe and effective tolerogen for rice seed-based oral immunotherapy for cedar pollen allergy in humans and other mammals. PMID- 17714440 TI - Up-regulation of an N-terminal truncated 3-hydroxy-3-methylglutaryl CoA reductase enhances production of essential oils and sterols in transgenic Lavandula latifolia. AB - Spike lavender (Lavandula latifolia) essential oil is widely used in the perfume, cosmetic, flavouring and pharmaceutical industries. Thus, modifications of yield and composition of this essential oil by genetic engineering should have important scientific and commercial applications. We generated transgenic spike lavender plants expressing the Arabidopsis thaliana HMG1 cDNA, encoding the catalytic domain of 3-hydroxy-3-methylglutaryl CoA reductase (HMGR1S), a key enzyme of the mevalonic acid (MVA) pathway. Transgenic T0 plants accumulated significantly more essential oil constituents as compared to controls (up to 2.1- and 1.8-fold in leaves and flowers, respectively). Enhanced expression of HMGR1S also increased the amount of the end-product sterols, beta-sitosterol and stigmasterol (average differences of 1.8- and 1.9-fold, respectively), but did not affect the accumulation of carotenoids or chlorophylls. We also analysed T1 plants derived from self-pollinated seeds of T0 lines that flowered after growing for 2 years in the greenhouse. The increased levels of essential oil and sterols observed in the transgenic T0 plants were maintained in the progeny that inherited the HMG1 transgene. Our results demonstrate that genetic manipulation of the MVA pathway increases essential oil yield in spike lavender, suggesting a contribution for this cytosolic pathway to monoterpene and sesquiterpene biosynthesis in leaves and flowers of the species. PMID- 17714442 TI - The role of VlsE antigenic variation in the Lyme disease spirochete: persistence through a mechanism that differs from other pathogens. AB - The linear plasmid, lp28-1, is required for persistent infection by the Lyme disease spirochete, Borrelia burgdorferi. This plasmid contains the vls antigenic variation locus, which has long been thought to be important for immune evasion. However, the role of the vls locus as a virulence factor during mammalian infection has not been clearly defined. We report the successful removal of the vls locus through telomere resolvase-mediated targeted deletion, and demonstrate the absolute requirement of this lp28-1 component for persistence in the mouse host. Moreover, successful infection of C3H/HeN mice with an lp28-1 plasmid in which the left portion was deleted excludes participation of other lp28-1 non-vls genes in spirochete virulence, persistence and the process of recombinational switching at vlsE. Data are also presented that cast doubt on an immune evasion mechanism whereby VlsE directly masks other surface antigens similar to what has been observed for several other pathogens that undergo recombinational antigenic variation. PMID- 17714441 TI - Spore cortex formation in Bacillus subtilis is regulated by accumulation of peptidoglycan precursors under the control of sigma K. AB - The bacterial endospore cortex peptidoglycan is synthesized between the double membranes of the developing forespore and is required for attainment of spore dehydration and dormancy. The Bacillus subtilis spoVB, spoVD and spoVE gene products are expressed in the mother cell compartment early during sporulation and play roles in cortex synthesis. Here we show that mutations in these genes block synthesis of cortex peptidoglycan and cause accumulation of peptidoglycan precursors, indicating a defect at the earliest steps of peptidoglycan polymerization. Loss of spoIV gene products involved in activation of later, sigma(K)-dependent mother cell gene expression results in decreased synthesis of cortex peptidoglycan, even in the presence of the SpoV proteins that were synthesized earlier, apparently due to decreased precursor production. Data show that activation of sigma(K) is required for increased synthesis of the soluble peptidoglycan precursors, and Western blot analyses show that increases in the precursor synthesis enzymes MurAA, MurB, MurC and MurF are dependent on sigma(K) activation. Overall, our results indicate that a decrease in peptidoglycan precursor synthesis during early sporulation, followed by renewed precursor synthesis upon sigma(K) activation, serves as a regulatory mechanism for the timing of spore cortex synthesis. PMID- 17714443 TI - 6S RNA: a regulator of transcription. AB - The past decade has seen an explosion in discovery of small, non-coding RNAs in all organisms. As functions for many of the small RNAs have been identified, it has become increasingly clear that they are important components in regulating gene expression. A multitude of RNAs target mRNAs for regulation at the level of translation or stability, including the microRNAs in higher eukaryotes and the Hfq binding RNAs in bacteria. Other RNAs regulate transcription, such as murine B2 RNA, mammalian 7SK RNA and the bacterial 6S RNA, which will be the focus of this review. Details of 6S RNA interactions with RNA polymerase, how 6S RNA regulates transcription, and how 6S RNA function contributes to cellular survival are discussed. PMID- 17714445 TI - CWH43 is required for the introduction of ceramides into GPI anchors in Saccharomyces cerevisiae. AB - After glycosylphosphatidylinositols (GPIs) are added to GPI proteins of Saccharomyces cerevisiae, the fatty acid in sn-2 of the diacylglycerol moiety can be replaced by a C26:0 fatty acid by a deacylation-reacylation cycle catalysed by Per1p and Gup1p. Furthermore the diacylglycerol moiety of the yeast GPI anchor can also be replaced by ceramides. CWH43 of yeast is homologous to PGAP2, a gene that recently was implicated in a similar deacylation reacylation cycle of GPI proteins in mammalian cells, where PGAP2 is required for the reacylation of monoradylglycerol-type GPI anchors. Here we show that mutants lacking CWH43 are unable to synthesize ceramide-containing GPI anchors, while the replacement of C18 by C26 fatty acids on the primary diacylglycerol anchor by Per1p and Gup1p is still intact. CWH43 contains the COG3568 metal hydrolase motif, which is found in many eukaryotic and prokaryotic enzymes. The conserved His 802 residue of this motif was identified as being essential for ceramide remodelling. Ceramide remodelling is not required for the normal integration of GPI proteins into the cell wall. All remodelling reactions are dependent on prior removal of the inositol-linked fatty acid by Bst1p. PMID- 17714446 TI - Plasmid partition and incompatibility--the focus shifts. AB - The mitotic apparatus that a plasmid uses to ensure its stable inheritance responds to the appearance of an additional copy of the plasmid's centromere by segregating it from the pre-existing copies: if the new copy arises by replication of the plasmid the result is partition, if it arrives on a different plasmid the result is incompatibility. Incompatibility thus serves as a probe of the partition mechanism. Coupling of distinct plasmids via their shared centromeres to form mixed pairs has been the favoured explanation for centromere based incompatibility, because it supports a long-standing assumption that pairing of plasmid replicas is a prerequisite for their partition into daughter cells. Recent results from molecular genetic and fluorescence microscopy studies challenge this mixed pairing model. Partition incompatibility is seen to result from various processes, including titration, randomized positioning and a form of mixed pairing that is based on co-activation of the same partition event rather than direct contact between partition complexes. The perspectives thus opened onto the partition mechanism confirm the continuing utility of incompatibility as an approach to understanding bacterial mitosis. The results considered are compatible with the view that direct pairing of plasmids is not essential to plasmid partition. PMID- 17714444 TI - Identification of an alpha(1-->6) mannopyranosyltransferase (MptA), involved in Corynebacterium glutamicum lipomanann biosynthesis, and identification of its orthologue in Mycobacterium tuberculosis. AB - Corynebacterium glutamicum and Mycobacterium tuberculosis share a similar cell wall architecture, and the availability of their genome sequences has enabled the utilization of C. glutamicum as a model for the identification and study of, otherwise essential, mycobacterial genes involved in lipomannan (LM) and lipoarabinomannan (LAM) biosynthesis. We selected the putative glycosyltransferase-Rv2174 from M. tuberculosis and deleted its orthologue NCgl2093 from C. glutamicum. This resulted in the formation of a novel truncated lipomannan (Cg-t-LM) and a complete ablation of LM/LAM biosynthesis. Purification and characterization of Cg-t-LM revealed an overall decrease in molecular mass, a reduction of alpha(1-->6) and alpha(1-->2) glycosidic linkages illustrating a reduced degree of branching compared with wild-type LM. The deletion mutant's biochemical phenotype was fully complemented by either NCgl2093 or Rv2174. Furthermore, the use of a synthetic neoglycolipid acceptor in an in vitro cell free assay utilizing the sugar donor beta-D-mannopyranosyl-1-monophosphoryl decaprenol together with the neoglycolipid acceptor alpha-D-Manp-(1-->6)-alpha-D Manp-O-C8 as a substrate, confirmed NCgl2093 and Rv2174 as an alpha(1-->6) mannopyranosyltransferase (MptA), involved in the latter stages of the biosynthesis of the alpha(1-->6) mannan core of LM. Altogether, these studies have identified a new mannosyltransferase, MptA, and they shed further light on the biosynthesis of LM/LAM in Corynebacterianeae. PMID- 17714447 TI - Phase variable type III restriction-modification systems of host-adapted bacterial pathogens. AB - Phase variation, the high-frequency on/off switching of gene expression, is a common feature of host-adapted bacterial pathogens. Restriction-modification (R M) systems, which are ubiquitous among bacteria, are classically assigned the role of cellular defence against invasion of foreign DNA. These enzymes are not obvious candidates for phase variable expression, a characteristic usually associated with surface-expressed molecules subject to host immune selection. Despite this, numerous type III R-M systems in bacterial pathogens contain repetitive DNA motifs that suggest the potential for phase variation. Several roles have been proposed for phase variable R-M systems based on DNA restriction function. However, there is now evidence in several important human pathogens, including Haemophilus influenzae, Neisseria meningitidis and Neisseria gonorrhoeae, that these systems are 'phasevarions' (phase variable regulons) controlling expression of multiple genes via a novel epigenetic mechanism. PMID- 17714449 TI - A proposed structural basis for picrotoxinin and picrotin binding in the glycine receptor pore. AB - Picrotoxin, an antagonist of structurally-rated GABA(A) receptors (GABA(A)Rs) and glycine receptors (GlyRs), is an equimolar mixture of picrotoxinin (PTXININ) and picrotin (PTN). These compounds share a common structure except that PTN contains a slightly larger dimethylmethanol in place of the PTXININ isopropenyl group. Although the homomeric alpha1 GlyR is equally sensitive to both compounds, we show here that homomeric alpha2 and alpha3 GlyRs, like most GABA(A)Rs, are selectively inhibited by PTXININ. As conservative mutations to pore-lining 6' threonines equally affect the sensitivity of the alpha1 GlyR to both compounds, we conclude that PTXININ and PTN bind to 6' threonines by hydrogen bonding with exocyclic oxygens common to both molecules. In contrast, substitution of the 2' pore-lining glycine by serine selectively reduces PTN sensitivity, whereas the introduction of 2' alanines selectively increases PTXININ sensitivity. These results define the orientation of PTXININ and PTN binding in the alpha1 GlyR pore and allow us to conclude that the relatively reduced sensitivity of PTN at GABA(A)Rs and alpha2 and alpha3 GlyRs is due predominantly to its larger size and reduced ability to form hydrophobic interactions with 2' alanines. PMID- 17714450 TI - A role for polyamines in retinal ganglion cell excitotoxic death. AB - Neuronal death due to excessive activation of N-methyl-d-aspartate (NMDA) receptors is a hallmark of neurodegenerative diseases. The polyamines: putrescine, spermine, and spermidine, bind to specific sites on the NMDA receptor and promote its activation, but their role in NMDA-induced neuronal death is ill defined. In this study, we characterized the role of polyamines in excitotoxic death of retinal ganglion cells (RGCs), a population of central neurons susceptible to NMDA-induced damage. Our data show that endogenous arginase I, the rate limiting enzyme for polyamine biosynthesis, is expressed in the intact, adult retina. Intraocular injection of NMDA visibly increased arginase I expression in Muller cells, the predominant glial cell-type in the mammalian retina. Inhibition of polyamine synthesis using di-fluoro-methyl-ornithine (DFMO) was markedly neuroprotective, while injection of exogenous polyamines in conjunction with NMDA exacerbated RGC death. Blockade of the polyamine binding sites on NMDA receptors using the non-competitive antagonist ifenprodil was neuroprotective, suggesting that polyamines contribute to excitotoxic death, at least partly, by binding to NMDA receptors. Importantly, we also demonstrate that NMDA leads to activation of both the Erk1/2 and PI3 K/Akt pathways, but only the PI3 K/Akt kinase was required for di-fluoro-methyl-ornithine-induced RGC survival. In summary, our study reveals that polyamines modulate neuronal death in the retina via different mechanisms that potentiate NMDA-triggered excitotoxicity. PMID- 17714448 TI - Subtype selective antagonism of substantia nigra pars compacta Group I metabotropic glutamate receptors protects the nigrostriatal system against 6 hydroxydopamine toxicity in vivo. AB - Evidence suggests that increased glutamatergic input to the substantia nigra pars compacta as a result of hyperactivity of subthalalmic nucleus output pathways may contribute to the progressive degeneration of nigral dopaminergic neurones in Parkinson's disease (PD), a debilitating neurodegenerative disorder which affects approximately 1% of people aged over 65. Substantial electrophysiological evidence suggests that the excitation of nigral dopaminergic neurones is regulated by the activation of Group I metabotropic glutamate receptors (mGluR), comprising mGluR1 and mGluR5 subtypes. As activation of these receptors by endogenous glutamate may promote multiple cascades leading to excitotoxic neuronal death, it may be hypothesised that functional antagonism of Group I mGluR should be neuroprotective and could form the basis of a novel neuroprotective treatment for PD. To investigate this hypothesis, the neuroprotective potential of the selective competitive mGlu1 antagonist (+)-2 methyl-4-carboxyphenylglycine ((S)-(+)-alpha-amino-4-carboxy-2 methlybenzeneacetic acid; LY367385) and the selective allosteric mGlu5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) was tested in a rodent 6 hydroxydopamine (6-OHDA) model of PD in vivo. Both acute and subchronic intranigral administration of either LY367385 or MPEP resulted in significant neuroprotection of nigral tyrosine hydroxylase immunoreactive cell bodies, which correlated closely with prevention of striatal monoamine depletion following 6 OHDA lesioning. This neuroprotective action of LY367385 and MPEP displayed a clear concentration-dependent effect, suggesting a receptor-mediated mechanism of action. LY367385 produced robust neuroprotection at all concentrations tested (40, 200 and 1000 nmol in 4 microL), whilst MPEP displayed a bell-shaped neuroprotective profile with significant neuroprotection at low concentrations (2 and 10 nmol in 4 microL) but not at higher concentrations (50 nmol). Importantly, subchronic intranigral administration of MPEP and LY367385 appeared to slow the degeneration of remaining nigral dopaminergic neurones and prevented further striatal dopamine depletion in animals with established 6-OHDA induced nigrostriatal lesions, suggesting that these compounds may significantly influence disease progression in this model. PMID- 17714451 TI - bFGF promotes photoreceptor cell survival in vitro by PKA-mediated inactivation of glycogen synthase kinase 3beta and CREB-dependent Bcl-2 up-regulation. AB - Although there is substantial evidence supporting the neuroprotective efficacy of basic fibroblast growth factor (bFGF) in the rodent retina there is no consensus to date as to the protective mechanism involved. We hypothesise that bFGF can assert its neuroprotective effects directly on mouse photoreceptors transduced via the activation of specific intracellular signalling pathways. In mouse photoreceptor-derived 661W cells, bFGF promoted a rapid inactivation of glycogen synthase kinase 3beta (GSK3beta) by phosphorylation at Ser9. The effects of bFGF on GSK3beta were dependent on protein kinase A (PKA) activation, as inhibition of this pathway blocked inactivation. Furthermore, bFGF protection against oxidative stress was dependent on PKA inactivation of GSK3beta as PKA inhibition attenuated bFGF-induced protection. Furthermore, transfection of cells with mutant dominant negative GSK3betaS9A that cannot be phosphorylated on Ser9 also abrogated neuroprotection. Activation of the transcription factor cAMP-response element binding protein (CREB) and subsequent up-regulation of Bcl-2 in response to bFGF was also dependent on PKA as inhibition with H-89 attenuated increased pCREB levels and Bcl-2 expression. These results indicate that the protective efficacy of bFGF in mouse photoreceptors involves PKA-dependent inactivation of GSK3beta and subsequent up-regulation of Bcl-2 via CREB activation. PMID- 17714452 TI - Three gene products govern (p)ppGpp production by Streptococcus mutans. AB - The current dogma implicating RelA as the sole enzyme controlling (p)ppGpp production and degradation in Gram-positive bacteria does not apply to Streptococcus mutans. We have now identified and characterized two genes, designated as relP and relQ, encoding novel enzymes that are directly involved in (p)ppGpp synthesis. Additionally, relP is co-transcribed with a two-component signal transduction system (TCS). Analysis of the (p)ppGpp synthetic capacity of various mutants and the behaviour of strains lacking combinations of the synthetase enzymes have revealed a complex regulon and fundamental differences in the way S. mutans manages alarmone production compared with bacterial paradigms. The functionality of the RelP and RelQ enzymes was further confirmed by demonstrating that expression of relP and relQ restored growth of a (p)ppGpp(0) Escherichia coli strain in minimal medium, SMG and on medium containing 3-amino 1,2,4-triazole, and by demonstrating (p)ppGpp production in various complemented mutant strains of E. coli and S. mutans. Notably, RelQ, and RelP and the associated TCS, are harboured in some, but not all, pathogenic streptococci and related Gram-positive organisms, opening a new avenue to explore the variety of strategies employed by human and animal pathogens to survive in adverse conditions that are peculiar to environments in their hosts. PMID- 17714453 TI - TRPV1 expression-dependent initiation and regulation of filopodia. AB - Transient receptor potential vanilloid subtype 1 (TRPV1), a non-selective cation channel, is present endogenously in dorsal root ganglia (DRG) neurons. It is involved in the recognition of various pain producing physical and chemical stimuli. In this work, we demonstrate that expression of TRPV1 induces neurite like structures and filopodia and that the expressed protein is localized at the filopodial tips. Exogenous expression of TRPV1 induces filopodia both in DRG neuron-derived F11 cells and in non-neuronal cells, such as HeLa and human embryonic kidney (HEK) cells. We find that some of the TRPV1 expression-induced filopodia contain microtubules and microtubule-associated components, and establish cell-to-cell extensions. Using live cell microscopy, we demonstrate that the filopodia are responsive to TRPV1-specific ligands. But both, initiation and subsequent cell-to-cell extension formation, is independent of TRPV1 channel activity. The N-terminal intracellular domain of TRPV1 is sufficient for filopodial structure initiation while the C-terminal cytoplasmic domain is involved in the stabilization of microtubules within these structures. In addition, exogenous expression of TRPV1 results in altered cellular distribution and in enhanced endogenous expression of non-conventional myosin motors, namely myosin IIA and myosin IIIA. These data indicate a novel role of TRPV1 in the regulation of cellular morphology and cellular contact formation. PMID- 17714454 TI - Trafficking and potential assembly patterns of epsilon-containing GABAA receptors. AB - Incorporation of the epsilon subunit into the GABAA receptor has been suggested to confer unusual, but variable, biophysical and pharmacological characteristics to both recombinant and native receptors. Due to their structural similarity with the gamma subunits, epsilon subunits have been assumed to substitute at the single position of the gamma subunit in assembled receptors. However, prior work suggests that functional variability in epsilon-containing receptors may reflect alternative sites of incorporation and of not just one, but possibly multiple epsilon subunits in the pentameric receptor complex. Here we present data indicating that increased expression of epsilon, in conjunction with alpha2 and beta3 subunits, results in expression of GABAA receptors with correspondingly altered rectification, deactivation and levels of spontaneous openings, but not increased total current density. We also provide data that the epsilon subunit, like the beta3 subunit, can self-export and data from chimeric receptors suggesting that similarities between the assembly domains of the beta3 and the epsilon subunits may allow the epsilon subunit to replace the beta, as well as the gamma, subunit. The substitution of an epsilon for a beta, as well as the gamma subunit and formation of receptors with alternative patterns of assembly with respect to epsilon incorporation may underlie the observed variability in both biophysical and pharmacological properties noted not only in recombinant, but also in native receptors. PMID- 17714455 TI - GABA(A) receptors in aging and Alzheimer's disease. AB - In this article we present a comprehensive review of relevant research and reports on the GABA(A) receptor in the aged and Alzheimer's disease (AD) brain. In comparison to glutamatergic and cholinergic systems, the GABAergic system is relatively spared in AD, but the precise mechanisms underlying differential vulnerability are not well understood. Using several methods, investigations demonstrate that despite resistance of the GABAergic system to neurodegeneration, particular subunits of the GABA(A) receptor are altered with age and AD, which can induce compensatory increases in GABA(A) receptor subunits within surrounding cells. We conclude that although aging- and disease-related changes in GABA(A) receptor subunits may be modest, the mechanisms that compensate for these changes may alter the pharmacokinetic and physiological properties of the receptor. It is therefore crucial to understand the subunit composition of individual GABA(A) receptors in the diseased brain when developing therapeutics that act at these receptors. PMID- 17714456 TI - Breaking bad news: consultants' experience, previous education and views on educational format and timing. AB - CONTEXT: Breaking bad news is a difficult task for health professionals. Senior hospital doctors acknowledge the importance of breaking bad news well, but previous surveys have found them to be sceptical of formal training and disinclined to seek courses in this area. We sought to ascertain if this view was still held. METHODS: A postal questionnaire was sent to 285 consultants across 3 acute hospital trusts in the Midlands, UK. Questions included items on the frequency and types of breaking bad news situations encountered, and the timing and modality of previous training. Open comment on what forms of education would be useful, and when, was requested. RESULTS: Eleven consultants were no longer in post. Of the remainder, 173/274 (63%) replied; 153 (56%) returned questionnaires of which 150 (55%) were useable. Respondents represented 32/33 (97%) of the surveyed specialties. The majority reported breaking bad news frequently (> 1-2 times weekly); however, almost half (49%) had received no formal training in this specific area, although 53% described having received experiential training in either clinical, training or management contexts. Of 118 respondents who commented, only 5 believed no form of training was useful, whereas 47 specifically recommended some form of role play. Regarding timing, 72 thought it desirable at postgraduate level or at all stages of training, with 44 explicitly stating at consultant level. CONCLUSIONS: Consultants in clinical specialties break bad news frequently. Although many have not received formal training, the majority believe it is useful and are increasingly willing to undertake experiential approaches. This augurs well for future training programmes. PMID- 17714457 TI - Collaborative clinical quality improvement for pressure ulcers in nursing homes. AB - The National Nursing Home Improvement Collaborative aimed to reduce pressure ulcer (PU) incidence and prevalence. Guided by subject matter and process experts, 29 quality improvement organizations and six multistate long-term care corporations recruited 52 nursing homes in 39 states to implement recommended practices using quality improvement methods. Facilities monitored monthly PU incidence and prevalence, healing, and adoption of key care processes. In residents at 35 regularly reporting facilities, the total number of new nosocomial Stage III to IV PUs declined 69%. The facility median incidence of Stage III to IV lesions declined from 0.3 per 100 occupied beds per month to 0.0 (P<.001) and the incidence of Stage II to IV lesions declined from 3.2 to 2.3 per 100 occupied beds per month (P=.03). Prevalence of Stage III to IV lesions trended down (from 1.3 to 1.1 residents affected per 100 occupied beds (P=.12). The incidence and prevalence of Stage II lesions and the healing time of Stage II to IV lesions remained unchanged. Improvement teams reported that Stage II lesions usually healed quickly and that new PUs corresponded with hospital transfer, admission, scars, obesity, and immobility and with noncompliant, younger, or newly declining residents. The publicly reported quality measure, prevalence of Stage I to IV lesions, did not improve. Participants documented disseminating methods and tools to more than 5,359 contacts in other facilities. Results suggest that facilities can reduce incidence of Stage III to IV lesions, that the incidence of Stage II lesions may not correlate with the incidence of Stage III to IV lesions, and that the publicly reported quality measure is insensitive to substantial improvement. The project demonstrated multiple opportunities in collaborative quality improvement, including improving the measurement of quality and identifying research priorities, as well as improving care. PMID- 17714458 TI - Psychiatric comorbidity and greater hospitalization risk, longer length of stay, and higher hospitalization costs in older adults with heart failure. AB - OBJECTIVES: To explore associations between psychiatric comorbidity and rehospitalization risk, length of hospitalization, and costs. DESIGN: Cross sectional study of 1-year hospital administrative data. SETTING: Claims-based study of older adults hospitalized in the United States. PARTICIPANTS: Twenty-one thousand four hundred twenty-nine patients from a 5% national random sample of U.S. Medicare beneficiaries aged 65 and older, with at least one acute care hospitalization in 1999 with a Diagnostic-Related Group of congestive heart failure. MEASUREMENTS: The number of hospitalizations, mean length of hospital stay, and total hospitalization costs in calendar year 1999. RESULTS: Overall, 15.8% of patients hospitalized for heart failure (HF) had a coded psychiatric comorbidity; the most commonly coded comorbid psychiatric disorder was depression (8.5% of the sample). Most forms of psychiatric comorbidity were associated with greater inpatient utilization, including risk of additional hospitalizations, days of stay, and hospitalization charges. Additional hospitalization costs associated with psychiatric comorbidity ranged up to $7,763, and additional days length of stay ranged up to 1.4 days. CONCLUSION: Psychiatric comorbidity appears in a significant minority of patients hospitalized for HF and may affect their clinical and economic outcomes. The associations between psychiatric comorbidity and use of inpatient care are likely to be an underestimate, because psychiatric illness is known to be underdetected in older adults and in hospitalized medical patients. PMID- 17714459 TI - High-intensity environmental light in dementia: effect on sleep and activity. AB - OBJECTIVES: To determine whether high-intensity ambient light in public areas of long-term care facilities will improve sleeping patterns and circadian rhythms of persons with dementia. DESIGN: A cluster-unit crossover intervention trial involving four conditions: morning bright light, evening bright light, all-day bright light, and minimum standard light. SETTING: The common areas of two geriatric units in a psychiatric hospital and a dementia-specific residential care facility. PARTICIPANTS: Sixty-six older adults with dementia. INTERVENTION: Ambient bright light of approximately 2,500 lux, delivered through a low-glare lighting system installed in the dining and activity areas. Participant exposure averaged 2.5 to 3.0 hours for the morning and evening interventions and 8.4 hours for the all-day intervention. MEASUREMENTS: Nighttime sleep using wrist actigraphy and daytime activity using nonobtrusive daytime observations. RESULTS: Night-time sleep increased significantly in participants exposed to morning and all-day light, with the increase most prominent in participants with severe or very severe dementia (mean increase 16 minutes (P=.008) for morning, and 14 minutes (P=.01) for all-day). Morning light produced a mean phase advance of 29 minutes (P=.02) and evening light a mean phase delay of 15 minutes (P=.06). Effects on daytime sleepiness were inconsistent, and the number of sleep bouts, mesor, amplitude, intradaily variability, and interdaily stability were not significantly different, indicating that the overall strength of day and night activity rhythms did not change significantly under any treatment condition. CONCLUSION: Bright light appears to have a modest but measurable effect on sleep in this population, and ambient light may be preferable to stationary devices such as light boxes. PMID- 17714460 TI - Improving quality of care for urban older people with diabetes mellitus and cardiovascular disease. AB - The management of older patients with chronic medical conditions dominates medical practice. Cardiovascular disease (CVD) and diabetes mellitus type 2 (DM) in patients aged 65 and older have reached epidemic proportions. Using elements of the Chronic Care Model (CCM), a quality improvement project was undertaken to restructure the Geriatric Ambulatory Practice at Boston Medical Center, Boston's safety net hospital, to improve the quality of care for CVD and diabetes mellitus. Two hundred eighty-three eligible patients who had CVD, DM, or both were identified. The 39-month project period was divided into a 12-month baseline period and three follow-up periods. The multifaceted intervention consisted of development of a disease registry that centralized clinical information, implementation of an electronic medical record, patient education, physician education regarding evidence-based guidelines, feedback of provider-specific and practice data to physicians, and implementation of a foot examination protocol. Clinical measures included glycosylated hemoglobin, a diabetic foot examination, lipid profile, and blood pressure measurement. These were collected at baseline and at each patient visit for the entire project period. The average age of all patients was 76; 64% were female, 64% were African American, 72% had Medicare, and 22% had state subsidized medical insurance. Patients in all disease groups showed significant improvement in all clinical measures over time, independent of the frequency of visits. Using the CCM as a quality improvement framework can improve clinical measures for older urban minority populations with CVD and DM. PMID- 17714461 TI - Empirical assessment of a research advance directive for persons with dementia and their proxies. AB - OBJECTIVES: To evaluate a research advance directive for persons with established dementia diagnoses and their family caregivers or proxies. DESIGN: Prospective randomized, controlled trial. SETTING: Three clinics, one each in Ohio, Kentucky, and Illinois. PARTICIPANTS: At the end of separate interviews about enrollment choices in five types of hypothetical research projects, 149 persons with established dementia diagnoses and their family proxies were randomized to jointly complete the Planning Ahead Together (PAT) document, a research advance directive (n=69) or to remain in the control group (n=80). INTERVENTION: The directive was assessed at two points: immediately after sample members received naturally occurring invitations to participate in other studies and again 2 years after initial enrollment. MEASUREMENTS: Personal enrollment rates, reported ease of enrollment decision for patients and proxies, and proxy comfort were compared between the experimental and control groups. RESULTS: Forty-one dyads were reinterviewed immediately after consent discussions for other trials. Forty-seven patients and 106 proxies were interviewed at 2-year follow-up. There was no evidence immediately after a trial enrollment opportunity or in the follow-up interview that the research advance directive (PAT) assisted patients or proxies. Enrollment rates, decision ease, and proxy comfort and certainty were similar in the PAT and control groups. CONCLUSION: Patient and proxy experience making hypothetical decisions in the interview may have affected enrollment decisions by the PAT and control groups. Although the low number of recruitment attempts and the natural attrition of the geriatric population limit conclusions about effectiveness that may be drawn from this unique data set, the feasibility of a research advance directive is clearly demonstrated. PMID- 17714463 TI - Cross-species transferability of microsatellite markers from six aphid (Hemiptera: Aphididae) species and their use for evaluating biotypic diversity in two cereal aphids. AB - The abundance and distribution of microsatellites, or simple sequence repeats (SSRs) were explored in the expressed sequence tag (EST) and genomic sequences of the pea aphid, Acyrthosiphon pisum (Harris), and the green peach aphid, Myzus persicae (Sulzer). A total of 108 newly developed, together with 40 published, SSR markers were investigated for their cross-species transferability among six aphid species. Genetic diversity among six greenbug, Schizaphis graminum (Rondani) and two Russian wheat aphid, Diuraphis noxia (Kurdjumov) biotypes was further examined with 67 transferable SSRs. It was found that the pea aphid genome is abundant in SSRs with a unique frequency and distribution of SSR motifs. Cross-species transferability of EST-derived SSRs is dependent on phylogenetic closeness between SSR donor and target species, but is higher than that of genomic SSRs. Neighbor-joining analysis of SSR data revealed host-adapted genetic divergence as well as regional differentiation of greenbug biotypes. The two Russian wheat aphid biotypes are genetically as diverse as the greenbug ones although it was introduced into the USA only 20 years ago. This is the first report of large-scale development of SSR markers in aphids, which are expected to have wide applications in aphid genetic, ecological and evolutionary studies. PMID- 17714462 TI - Regulation of Junonia coenia densovirus P9 promoter expression. AB - Transcriptional activity of the Junonia coenia densovirus (JcDNV) P9 promoter depends on a 557-bp sequence located within the overlapping 3' sequences for viral capsid and nonstructural genes. Utilizing a somatic transformation assay to assess JcDNV promoter activity in Drosophila melanogaster and Plodia interpunctella, viral sequences were subjected to deletional analysis. Removal of a 685-bp fragment reduced P9-driven expression to background levels. Inclusion of a second expression cassette demonstrated vector persistence and confirmed somatic transformation. P9 promoter-driven expression was restored by insertion of a 557-bp JcDNV fragment or by inclusion of a heterologous baculovirus hr5 enhancer. Consensus polycomb transcriptional factor binding sites were identified within the 557-bp fragment, which suggests a potential role in regulating densoviral transcription. PMID- 17714464 TI - Highly similar piggyBac transposase-like sequences from various Bactrocera (Diptera, Tephritidae) species. AB - The piggyBac transposable element is currently the vector of choice for transgenesis, enhancer trapping, gene discovery and gene function determination in both insects and mammals. However, the recent discovery of sequences with similarity to piggyBac in a wide diversity of organisms suggests that piggyBac may be horizontally transferred to distantly related species. This has raised concern on the wide-range application of piggyBac-based transformation vectors and their stability. In this paper, the presence of sequences homologous to the piggyBac transposase was investigated in 17 species belonging to six genera within the Tephritidae family, including many pest species for which transformation has already been achieved. piggyBac-like sequences, with a high degree of similarity to the original Trichoplusia ni transposase sequence were identified only in six species of the Bactrocera genus. PMID- 17714465 TI - The sealing ability of GuttaFlow in oval-shaped canals: an ex vivo study using a polymicrobial leakage model. AB - AIM: To compare systematically the sealing ability provided by four endodontic cements: AH Plus, Pulp Canal Sealer EWT, RoekoSeal and GuttaFlow. METHODOLOGY: A sample of 100 human mandibular incisors with oval-shaped canals was selected from an initial sampling of two hundred teeth. The root canals in 80 teeth were prepared and filled by the same operator using the cold lateral compaction technique with one of the following four cements (n = 20): G1: AH Plus; G2: Pulp Canal Sealer EWT; G3: RoekoSeal and G4: GuttaFlow. Ten teeth with intact crowns served as negative controls and 10 teeth that were not root filled served as positive controls. All teeth were mounted in a two chamber apparatus and then exposed to human saliva. The number of days over a 9-weeks-period was recorded for the appearance of turbidity in the BHI broth. A Log-rank test was used to analyse the leakage data. RESULTS: Overall, 30% of the samples of the AH Plus group (G1) and 35% of the Pulp Canal Sealer EWT group (G2) were fully contaminated after 9 weeks, whereas 15% of RoekoSeal (G3) and GuttaFlow (G4) groups were fully contaminated. There was a significant difference between (G1/G2) and (G3/G4) (P < 0.05). There was no significant difference between G1 and G2 or between G3 and G4 (P > 0.05). CONCLUSION: The silicone-based sealers revealed the best results throughout the experimental period. Leakage patterns of AH plus and Pulp Canal Sealer were statistically similar. PMID- 17714466 TI - Salvaging a tooth with a deep palatogingival groove: an endo-perio treatment--a case report. AB - AIM: To describe the diagnosis and management of tooth 22 with a necrotic pulp and severe periodontal destruction associated with a deep palatogingival groove extending to the root apex. SUMMARY: Palatogingival grooves are uncommon in maxillary lateral incisors, but when present may contribute to the pathogenesis of periodontal and endodontic lesions. In the present case, the prognosis was considered poor, as the patient presented with a deep probing defect, advanced bone loss and grade III mobility of tooth 22. Root canal treatment was performed, followed by periodontal surgery, during which the groove was conditioned and sealed with conventional glass-ionomer cement and the osseous defect filled with indigenously prepared hydroxyapatite. The 18 month post-operative follow up showed substantial resolution of the osseous defect with gain in attachment and decreased tooth mobility. KEY LEARNING POINTS: Teeth with deep palatogingival grooves may be significantly compromised with severe periodontal and periapical bone loss. Following thorough evaluation, the careful application of endodontic and periodontal surgical procedures may restore satisfactory function. PMID- 17714468 TI - Root and canal morphology of permanent mandibular molars in a Sudanese population. AB - AIM: To investigate variations in the root canal systems of first and second permanent mandibular molar teeth in a Sudanese population using a clearing technique. METHODOLOGY: Two hundred extracted first and second permanent mandibular molars from three cities in the state of Khartoum were studied. Access cavities were prepared and pulp tissue was removed by immersion in 5% sodium hypochlorite under ultrasonication; Indian ink was then injected into the root canal systems assisted by a vacuum applied apically. The teeth were rendered clear by demineralization and immersion in methyl salicylate before evaluation. The following observations were made (i) number of roots and their morphology; (ii) number of root canals per tooth; (iii) number of root canals per root and (iv) root canal configuration. RESULTS: Overall 59% of mandibular first molars had four canals with 3% having a third distolingual root. Seventy-eight per cent of second mandibular molars had two separate flat roots, whilst 10% were C shaped. The most common canal system configurations were type IV (73%) and type II (14%). Inter-canal communications were more common in the mesial roots. The prevalence of inter-canal communications was 65% in first molars and 49% in second molars. CONCLUSIONS: In this sample of Sudanese teeth, 59% of the mandibular first permanent molars had four root canals whilst 10% of the mandibular second molars had C-shaped roots/canals. PMID- 17714467 TI - Evaluation of formocresol versus ferric sulphate primary molar pulpotomy: a systematic review and meta-analysis. AB - AIM: To present a systematic review of the effects of formocresol and ferric sulphate when used as medicaments in pulpotomized primary molar teeth. METHODOLOGY: The study list was obtained by using MEDLINE, the Cochrane Library, EMBASE and SCI search. Only those papers which met the inclusion criteria were accepted. The quality of studies used for meta-analysis was assessed by a series of validity criteria according to Jadad's scale. A systematic review and meta analysis were performed. RESULTS: Eleven clinical studies comprising four randomized-clinical trials (RCTs), four controlled clinical trials (CCTs) and three retrospective studies were included. The results of the meta-analysis of six prospective clinical trials suggested that the two popular pulpotomy medicaments were not significantly different in terms of clinical outcomes, radiographic findings, prevalence of apical and furcal destruction, internal root resorption or pulp canal obliteration. The relative risk (RR) value and 95% CI for those parameters were 0.72 (0.43-1.23), 0.87 (0.59-1.30), 0.67 (0.27-1.66), 1.77 (0.56-5.58) and 1.41 (0.63-3.15), respectively. The overall clinical and radiographic success rates based on the data of treatments with ferric sulphate from the 11 studies included ranged from 78% to 100% (mean 91.6 +/- 8.15%) and from 42% to 97% (mean 73.5 +/- 18.40%), respectively. CONCLUSIONS: In primary molar teeth with exposure of vital pulps by caries or trauma, pulpotomies performed with either formocresol or ferric sulphate have similar clinical and radiographic success. Ferric sulphate may be recommended as a suitable replacement for formocresol. PMID- 17714469 TI - Histological evaluation of MTA as a root-end filling material. AB - AIM: To assess the histological response associated with grey mineral trioxide aggregate (GMTA) and zinc oxide eugenol (ZOE) as root-end filling materials in teeth where the root canals were not filled and the coronal access cavities were not restored. METHODOLOGY: Periapical lesions were developed in 24 premolar teeth in three dogs. The root canals were prepared and half of them were dried, filled and the coronal access restored (closed). The remaining teeth were not root filled and no coronal restoration was placed (open). Apical root-end resections were performed 3 mm from the apex, and root-end cavities were prepared with ultrasonic tips. These were randomly filled with either ZOE or GMTA in the same number of specimens using MAPSYSTEM device. After 180 days the animals were killed and blocks of tissues removed and processed for histological examination. Periradicular tissue reaction was evaluated, including severity of inflammation and cementum formation. Statistical analysis was performed using anova analysis and Tukey's test. RESULTS: A significant difference was found between the levels of inflammation in the periradicular tissues of the GMTA/closed group, compared with the ZOE/open and ZOE/closed groups (P < 0.05) but not between GMTA/closed and GMTA/open groups. Cementum formation was not found over any ZOE specimens but over MTA in all specimens. No microorganisms were found in the interface between the material and the dentinal walls. CONCLUSIONS: GMTA was associated with less periapical inflammation and tissue response when used as a root-end filling material, even when no root filling or coronal restoration was present. PMID- 17714470 TI - Class III beta-tubulin, a marker of resistance to paclitaxel, is overexpressed in pancreatic ductal adenocarcinoma and intraepithelial neoplasia. AB - AIMS: Class III beta-tubulin (TUBB3) reduces microtubule stability and confers resistance to microtubule-stabilizing taxanes, including paclitaxel and docetaxel. Pancreatic ductal adenocarcinomas show limited responsiveness to taxanes, but little is known of the underlying mechanisms. The aim of this study was to examine TUBB3 expression in pancreatic cancer cell lines, invasive pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia (PanIN). METHODS AND RESULTS: Reverse transcriptase-polymerase chain reaction and Western blot were used to study TUBB3 expression in pancreatic cancer cell lines. Immunohistochemistry was employed to assess TUBB3 in pancreatic cancer specimens, including 75 invasive adenocarcinomas and 41 PanIN precursor lesions. TUBB3 was undetectable in non-neoplastic ducts of the pancreas. In contrast, the vast majority (78-93%) of pancreatic ductal adenocarcinomas demonstrated either diffuse or focal TUBB3 expression. TUBB3 was found to increase progressively in PanIN lesions from 3/16 of PanIN-1 (19%), 5/17 of PanIN-2 (29%) to 5/8 of PanIN-3 lesions (63%). CONCLUSIONS: TUBB3 is expressed in most pancreatic ductal adenocarcinomas, possibly accounting for the suboptimal response of these tumours to microtubule-stabilizing agents. Up-regulation of TUBB3 in PanIN lesions suggests that microtubule dysfunction is an early feature of this disease. TUBB3 immunohistochemistry could potentially help identify pancreatic cancer patients lacking TUBB3 expression who might benefit from taxane therapy. PMID- 17714471 TI - Candidate genes responsible for human hepatocellular carcinoma identified from differentially expressed genes in hepatocarcinogenesis of the tree shrew (Tupaia belangeri chinesis). AB - AIM: To explore gene expression profiles during hepatocarcinogenesis of the tree shrew, and to find the genes responsible for human hepatocellular carcinoma (HCC). METHODS: Tree shrews were used as an animal model for HCC induction employing aflatoxin B(1) (AFB(1)) alone or AFB(1) plus hepatitis B virus (HBV) as etiological factors. Gene expression profiles from the tissues of HCC, HCC surrounding liver tissues (para-HCC) and the corresponding biopsies taken from the same animals before HCC had developed (pre-HCC) were analyzed by cDNA microarray assay to identify differentially expressed genes. Two genes, CuZn superoxide dismutase (SOD1) and glutathione S-transferase A1 (GSTA1), were further investigated by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemical (IHC) assays were done on tree shrew and human HCC samples. RESULTS: RESULTS from the cDNA microarray analysis indicated that the gene expression profiles of HCC between AFB(1)and AFB(1) + HBV treatment groups were markedly different. A total of 11 genes, including SOD1 and GSTA1, were found changing in expression levels in all detected samples from both groups. RESULTS from RT-PCR and IHC assays indicated that mRNA and protein levels of SOD1 and GSTA1 were markedly downregulated in both tree shrew and human HCC, and downregulation of SOD1 and GSTA1 proteins in human HCC samples was closely correlated with the histopathological grading (P < 0.05). CONCLUSION: The differentially expressed genes found in all HCC cases induced by different etiological factors among different species should be considered as good candidate genes responsible for HCC. Downregulation of SOD1 and GSTA1 might play an important role in hepatocarcinogenesis. PMID- 17714472 TI - Hepatocyte growth factor promotes remodeling of murine liver fibrosis, accelerating recruitment of bone marrow-derived cells into the liver. AB - AIM: Hepatocyte growth factor (HGF) ameliorates liver fibrosis/cirrhosis in animal models, while the participation of bone marrow-derived cells (BMC) in the repair process of injured organs has recently been reported. In this study we investigated the roles of HGF and BMC in a remodeling process of liver fibrosis. METHODS: C57BL/6 J mice were treated with carbon tetrachloride (CCl(4)) for 10 weeks. At week six, the mice underwent whole body irradiation and transplantation with bone marrow cells from syngenic LacZ-transgenic mice. After the transplantation, gene transfer of HGF into skeletal muscles was performed once a week for four weeks. In the control group, sterile saline was injected. RESULTS: HGF gene transfer ameliorated the CCl(4)-induced liver fibrosis, accelerating recruitment of LacZ-expressing cells into the liver. This phenomenon was accompanied byincreased gelatinase activity in the liver. A large number of the LacZ-positive cells expressed markers of vascular endothelial cells, while some of them had a marker of macrophages. Expression of stromal cell-derived factor (SDF)-1 in the liver was upregulated around the central veins, especially in the HGF gene-transferred animals, recruiting chemokine (C-X-C motif) receptor (CXCR) 4-positive cells in this area. CONCLUSION: Transplanted BMC participate in the HGF-induced remodeling process of liver fibrosis. The roles of HGF in this process include the recruitment of BMC, possibly through increased expression of SDF-1 in part, as well as anti-apoptotic, mitogenic and antifibrotic activities on liver cells. PMID- 17714473 TI - Early decline of hemoglobin can predict progression of hemolytic anemia during pegylated interferon and ribavirin combination therapy in patients with chronic hepatitis C. AB - AIM: Ribavirin, used to treat chronic hepatitis C, can induce hemolytic anemia, forcing the discontinuance of treatment. To establish a predictive measure to help circumvent this, we evaluated the relationship of hemoglobin (Hb) decline with the discontinuance of treatment during the progression of ribavirin-induced anemia. METHODS: One hundred and sixteen patients (71% male) with genotype 1 chronic hepatitis C were treated with pegylated interferon (PegIFN) alpha-2b and ribavirin. The mean age was 50.6 years and 55% were IFN naive. A decline of Hb concentration by 2 g/dL at two weeks from the start of the treatment ("2 by 2" standard) was adopted as the predictive factor for the progression of anemia. RESULTS: By applying the "2 by 2" standard, with DeltaHb >/= 2 g/dL (34%, n = 39), treatment was discontinued in 12 cases (31%), three of which (8%) because of severe anemia. ForDeltaHb < 2 g/dL (64%, n = 76), treatment was discontinued in 11 (14%) cases; none due to severe anemia. Ten percent (4/39) of patients showed the minimum Hb /= 2 g/dL group, with none in the DeltaHb < 2 g/dL group (P = 0.001). Furthermore, the patients with minimum Hb 70 years) human volunteers. No significant differences between aged and young donors were observed on (1) cell surface TLR2, TLR6 and TLR4 expression on lymphocytes, monocytes and granulocytes, (2) production of cytokines [IL-8, IL-1beta, IL-6, IL-10, tumour necrosis factor (TNF)-alpha and IL-12p70] and prostaglandin E(2) (PGE(2)) by whole human blood in response to C. albicans and (3) fungicidal activity of whole blood. A statistically significant higher titre of natural anti-C. albicans antibodies was found in plasma of volunteers between 80 and 95 years old when compared with other age groups, probably as a consequence of the increased levels of serum Ig that has been described in elderly subjects. Therefore, the results indicate that the increased susceptibility to C. albicans infections in the elderly is not a consequence of defects in TLRs expression or signalling, nor of an impaired fungicidal activity of blood. PMID- 17714491 TI - Aggregative adherence of uropathogenic Proteus mirabilis to cultured epithelial cells. AB - Proteus mirabilis is an important cause of urinary tract infection (UTI) in patients with complicated urinary tracts. Thirty-five strains of P. mirabilis isolated from UTI were examined for the adherence capacity to epithelial cells. All isolates displayed the aggregative adherence (AA) to HEp-2 cells, a phenotype similarly presented in LLC-MK(2) cells. Biofilm formation on polystyrene was also observed in all strains. The mannose-resistant Proteus-like fimbriae (MR/P), Type I fimbriae and AAF/I, II and III fimbriae of enteroaggregative Escherichia coli were searched by the presence of their respective adhesin-encoding genes. Only the MR/P fimbrial subunits encoding genes mrpA and mrpH were detected in all isolates, as well as MR/P expression. A mutation in mrpA demonstrated that MR/P is involved in aggregative adherence to HEp-2 cells, as well as in biofilm formation. However, these phenotypes are multifactorial, because the mrpA mutation reduced but did not abolish both phenotypes. The present results reinforce the importance of MR/P as a virulence factor in P. mirabilis due to its association with AA and biofilm formation, which is an important step for the establishment of UTI in catheterized patients. PMID- 17714492 TI - Facilitation can increase the phylogenetic diversity of plant communities. AB - With the advent of molecular phylogenies the assessment of community assembly processes has become a central topic in community ecology. These processes have focused almost exclusively on habitat filtering and competitive exclusion. Recent evidence, however, indicates that facilitation has been important in preserving biodiversity over evolutionary time, with recent lineages conserving the regeneration niches of older, distant lineages. Here we test whether, if facilitation among distant-related species has preserved the regeneration niche of plant lineages, this has increased the phylogenetic diversity of communities. By analyzing a large worldwide database of species, we showed that the regeneration niches were strongly conserved across evolutionary history. Likewise, a phylogenetic supertree of all species of three communities driven by facilitation showed that nurse species facilitated distantly related species and increased phylogenetic diversity. PMID- 17714493 TI - Nitric oxide regulates growth cone filopodial dynamics via ryanodine receptor mediated calcium release. AB - Nitric oxide (NO) is a gaseous intercellular messenger involved in numerous processes during development, including wiring of the nervous system. Neuronal growth cones are responsible for establishing the correct connectivity in the nervous system, but how NO might affect neuronal pathfinding is not fully understood. We have demonstrated in a previous study that local application of a NO donor, NOC-7, via micropipette onto individual growth cones from Helisoma trivolvis B5 neurons results in an increase in filopodial length, a decrease in filopodial number and an increase in the intracellular calcium concentration ([Ca(2+)](i)). Moreover, these NO-induced effects were demonstrated to be mediated via an intracellular cascade involving soluble guanylyl cyclase, protein kinase G (PKG) and cyclic adenosine diphosphate ribose (cADPR). We now demonstrate that the increase in the [Ca(2+)](i) that results from local NO application is mediated via release from ryanodine receptor (RyR)-sensitive intracellular stores. We also show that PKG and RyRs are localized within growth cones and microinjection of cADPR mimics the effects of NO, providing further support that the NO-induced effects are mediated via cADPR. Lastly, we provide evidence that calcium influx across the plasma membrane is a necessary component of the NO-induced calcium increase; however, this calcium influx is secondary to the RyR-induced calcium release from intracellular stores. This study details a signalling pathway by which NO can cause changes in growth cone morphology and thus provides a mechanism by which NO could affect neuronal wiring by acting locally on individual growth cones during the pathfinding process. PMID- 17714494 TI - Tripchlorolide protects against MPTP-induced neurotoxicity in C57BL/6 mice. AB - Many current studies of Parkinson's disease (PD) suggest that inflammation is involved in the neurodegenerative process. Tripchlorolide (TW397), a traditional Chinese herbal compound with anti-inflammatory and immunosuppressive properties, has been shown to protect dopaminergic neurons against, and restore their function after, the neurotoxicity induced by 1-methyl-4-phenylpyridinium ions in vitro. This study was designed to investigate the effect of TW397 in vivo in the PD model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned C57BL/6 mice. In the animals that received vehicle-only (i.e., no TW397) treatment with MPTP i.p. injection, the survival ratios of tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the substantia nigra pars compacta and TH-IR fibres in the striatum were only 59 and 13%, respectively, compared with the normal controls. Intriguingly, in conjunction with MPTP, treatment with TW397, 1 microg/kg for 16 days, once per day, dramatically improved the survival rate of the TH-IR neurons and TH-IR fibres to 80 and 43% of the control. The treatment with TW397 also significantly improved the level of dopamine in the substantia nigra and striatum to 157 and 191%, respectively, of the MPTP- plus vehicle-treated group. In addition, in MPTP-treated animals the rota-rod performances of those treated with 0.5 or 1 microg/kg TW397 were significantly improved, by approximately 2- and 3 fold, respectively, relative to vehicle-treated animals. The neuroprotective effect of TW397 was coincident with an attenuated astroglial response within the striatum. These data demonstrate a neuroprotective action of TW397 in vivo against MPTP toxicity, with important implications for the treatment of PD. PMID- 17714495 TI - 4-Chloro-m-cresol, an activator of ryanodine receptors, inhibits voltage-gated K(+) channels at the rat calyx of Held. AB - 4-Chloro-m-cresol (4-CmC) is thought to be a specific activator of ryanodine receptors (RyRs). Using this compound, we examined whether the RyR-mediated Ca(2+) release is involved in transmitter release at the rat calyx of Held synapse in brainstem slices. Bath application of 4-CmC caused a dramatic increase in the amplitude of excitatory postsynaptic currents (TIFCs) with the half maximal effective concentration of 0.12 mm. By making direct patch-clamp whole cell recordings from presynaptic terminals, we investigated the mechanism by which 4-CmC facilitates transmitter release. 4-CmC markedly prolonged the duration of action potentials, with little effect on their rise time kinetics. In voltage-clamp recordings, 4-CmC inhibited voltage-gated presynaptic K(+) currents (I(pK)) by 53% (at +20 mV) but had no effect on voltage-gated presynaptic Ca(2+) currents (I(pCa)). In simultaneous pre- and postsynaptic recordings, 4-CmC had no effect on the TIFC evoked by I(pCa). Although immunocytochemical study of the calyceal terminals showed immunoreactivity to type 3 RyRs, ryanodine (0.02 mm) had no effect on the 4-CmC-induced TIFC potentiation. We conclude that the facilitatory effect of 4-CmC on nerve-evoked transmitter release is mediated by its inhibitory effect on I(pK). PMID- 17714496 TI - Recovery of two independent sweet taste systems during regeneration of the mouse chorda tympani nerve after nerve crush. AB - In rodents, section of the taste nerve results in degeneration of the taste buds. Following regeneration of the cut taste nerve, however, the taste buds reappear. This phenomenon can be used to study the functional reformation of the peripheral neural system responsible for sweet taste. In this study we examined the recovery of sweet responses by the chorda tympani (CT) nerve after nerve crush as well as inhibition of these responses by gurmarin (Gur), a sweet response inhibitor. After about 2 weeks of CT nerve regeneration, no significant response to any taste stimuli could be observed. At 3 weeks, responses to sweet stimuli reappeared but were not significantly inhibited by Gur. At 4 weeks, Gur inhibition of sweet responses reached statistically significant levels. Thus, the Gur-sensitive (GS) component of the sweet response reappeared about 1 week later than the Gur-insensitive (GI) component. Moreover, single CT fibers responsive to sucrose could be classified into distinct GS and GI groups at 4 weeks. After 5 weeks or more, responses to sweet compounds before and after treatment with Gur became indistinguishable from responses in the intact group. During regeneration, the GS and GI components of the sucrose response could be distinguished based on their concentration-dependent responses to sucrose. These results suggest that mice have two different sweet-reception systems, distinguishable by their sensitivity to Gur (the GS and GI systems). These two sweet-reception systems may be reconstituted independently during regeneration of the mouse CT nerve. PMID- 17714497 TI - Regulation of the norepinephrine transporter by alpha-synuclein-mediated interactions with microtubules. AB - alpha-Synuclein (alpha-Syn) regulates catecholaminergic neurotransmission. We demonstrate that alpha-Syn regulates the activity and surface expression of the norepinephrine transporter (NET), depending on its expression levels. In cells co transfected with NET and low amounts of alpha-Syn, NET activity and cell surface expression were increased and protein interactions with alpha-Syn decreased, compared with cells transfected with NET alone. Converse effects were observed at higher levels of alpha-Syn expression. Treatment with nocodazole and other microtubule (MT) destabilizers abolished the expression-dependent bimodal regulation of NET by alpha-Syn. At low alpha-Syn levels, nocodazole had no effect on NET surface expression or protein interactions, while inducing increases in these measures at higher levels. Cells that were transfected with NET alone displayed no sensitivity to nocodazole, indicating that alpha-Syn expression was necessary for the MT-dependent changes in NET activity. MT destabilizers also caused a significant increase in [(3)H]-NE uptake in brainstem primary neurons and synaptosomes from the frontal cortex, but not striatal synaptosomes. These findings suggest that the surface localization and activity of NET is modulated by alpha-Syn in a manner that is both dependent on interactions with the MT cytoskeleton and varies across brain regions. PMID- 17714498 TI - Arbuscular mycorrhizal symbiosis can counterbalance the negative influence of the exotic tree species Eucalyptus camaldulensis on the structure and functioning of soil microbial communities in a sahelian soil. AB - The hypothesis of the present study was that bacterial communities would differentiate under Eucalyptus camaldulensis and that an enhancement of arbuscular mycorrhizal (AM) density would minimize this exotic plant species effect. Treatments consisted of control plants, preplanting fertilizer application and AM inoculation. After 4 months of culture in autoclaved soil, E. camaldulensis seedlings were either harvested for growth measurement or transferred into containers filled with the same soil but not sterilized. Other containers were kept without E. camaldulensis seedlings. After 12 months, effects of fertilizer amendment and AM inoculation were measured on the growth of Eucalyptus seedlings and on soil microbial communities. The results clearly show that this plant species significantly modified the soil bacterial community. Both community structure (assessed by denaturing gradient gel electrophoresis profiles) and function (assessed by substrate-induced respiration responses including soil catabolic evenness) were significantly affected. Such changes in the bacterial structure and function were accompanied by disturbances in the composition of the herbaceous plant species layer. These results highlight the role of AM symbiosis in the processes involved in soil bio-functioning and plant coexistence and in afforestation programmes with exotic tree species that target preservation of native plant diversity. PMID- 17714499 TI - Geographic variation in avian incubation periods and parental influences on embryonic temperature. AB - Theory predicts shorter embryonic periods in species with greater embryo mortality risk and smaller body size. Field studies of 80 passerine species on three continents yielded data that largely conflicted with theory; incubation (embryonic) periods were longer rather than shorter in smaller species, and egg (embryo) mortality risk explained some variation within regions, but did not explain larger differences in incubation periods among geographic regions. Incubation behavior of parents seems to explain these discrepancies. Bird embryos are effectively ectothermic and depend on warmth provided by parents sitting on the eggs to attain proper temperatures for development. Parents of smaller species, plus tropical and southern hemisphere species, commonly exhibited lower nest attentiveness (percent of time spent on the nest incubating) than larger and northern hemisphere species. Lower nest attentiveness produced cooler minimum and average embryonic temperatures that were correlated with longer incubation periods independent of nest predation risk or body size. We experimentally tested this correlation by swapping eggs of species with cool incubation temperatures with eggs of species with warm incubation temperatures and similar egg mass. Incubation periods changed (shortened or lengthened) as expected and verified the importance of egg temperature on development rate. Slower development resulting from cooler temperatures may simply be a cost imposed on embryos by parents and may not enhance offspring quality. At the same time, incubation periods of transferred eggs did not match host species and reflect intrinsic differences among species that may result from nest predation and other selection pressures. Thus, geographic variation in embryonic development may reflect more complex interactions than previously recognized. PMID- 17714500 TI - The Baldwin effect and genetic assimilation: revisiting two mechanisms of evolutionary change mediated by phenotypic plasticity. AB - Two different, but related, evolutionary theories pertaining to phenotypic plasticity were proposed by James Mark Baldwin and Conrad Hal Waddington. Unfortunately, these theories are often confused with one another. Baldwin's notion of organic selection posits that plasticity influences whether an individual will survive in a new environment, thus dictating the course of future evolution. Heritable variations can then be selected upon to direct phenotypic evolution (i.e., "orthoplasy"). The combination of these two processes (organic selection and orthoplasy) is now commonly referred to as the "Baldwin effect." Alternately, Waddington's genetic assimilation is a process whereby an environmentally induced phenotype, or "acquired character," becomes canalized through selection acting upon the developmental system. Genetic accommodation is a modern term used to describe the process of heritable changes that occur in response to a novel induction. Genetic accommodation is a key component of the Baldwin effect, and genetic assimilation is a type of genetic accommodation. I here define both the Baldwin effect and genetic assimilation in terms of genetic accommodation, describe cases in which either should occur in nature, and propose that each could play a role in evolutionary diversification. PMID- 17714501 TI - The evolution of dispersal in a Levins' type metapopulation model. AB - We study the evolution of the dispersal rate in a metapopulation model with extinction and colonization dynamics, akin to the model as originally described by Levins. To do so we extend the metapopulation model with a description of the within patch dynamics. By means of a separation of time scales we analytically derive a fitness expression from first principles for this model. The fitness function can be written as an inclusive fitness equation (Hamilton's rule). By recasting this equation in a form that emphasizes the effects of competition we show the effect of the local competition and the local population size on the evolution of dispersal. We find that the evolution of dispersal cannot be easily interpreted in terms of avoidance of kin competition, but rather that increased dispersal reduces the competitive ability. Our model also yields a testable prediction in term of relatedness and life-history parameters. PMID- 17714502 TI - Introgression versus immigration in hybridizing high-dispersal echinoderms. AB - Phylogeographic studies designed to estimate rates and patterns of genetic differentiation within species often reveal unexpected and graphically striking cases of allele or haplotype sharing between species (introgression) via hybridization and backcrossing. Does introgression between species significantly influence population genetic structure relative to more conventional sources of differentiation (drift) and similarity (dispersal) among populations within species? Here we use mtDNA sequences from four species in two genera of sea urchins and sea stars to quantify the relative magnitude of gene flow across oceans and across species boundaries in the context of the trans-Arctic interchange of marine organisms between the Pacific and Atlantic oceans. In spite of the much smaller distances between sympatric congeners, rates of gene flow between sympatric species via heterospecific gamete interactions were small and significantly lower than gene flow across oceans via dispersal of planktonic larvae. We conclude that, in these cases at least, larvae are more effective than gametes as vectors of gene flow. PMID- 17714503 TI - Sex allocation in a simultaneously hermaphroditic marine shrimp. AB - Two fundamental questions dealing with simultaneous hermaphrodites are how resources are optimally allocated to the male and female function and what conditions determine shifts in optimal sex allocation with age or size. In this study, I explored multiple factors that theoretically affect fitness gain curves (that depict the relationship between sex-specific investment and fitness gains) to predict and test the overall and size-dependent sex allocation in a simultaneously hermaphroditic brooding shrimp with an early male phase. In Lysmata wurdemanni, sperm competition is absent as hermaphrodites reproducing in the female role invariably mated only once with a single other shrimp. Shrimps acting as females preferred small over large shrimps as male mating partners, male mating ability was greater for small compared to large hermaphrodites, and adolescent males were predominant in the population during the breeding season. In addition, brooding constraints were not severe and varied linearly with body size whereas the ability to acquire resources increased markedly with body size. Using sex allocation theory as a framework, the findings above permitted to infer the shape of the male and female fitness gain curves for the hermaphrodites. The absence of sperm competition and the almost unconstrained brooding capacity imply that both curves saturate, however the male curve levels off much more quickly than the female curve with increasing level of investment. In turn, the predominance of adolescent males in the population implies that the absolute gain of the female curve is greater than that of the male curve. Last, the size dependent female preference and male mating ability of hermaphrodites determines that the absolute gain of the male curve is greater for small than for large hermaphrodites. Taking into consideration the inferred shape of the fitness gain curves, two predictions with respect to the optimal sex allocation were formulated. First, overall sex allocation should be female biased; it permits hermaphrodites to profit from the female function that provides a greater fitness return than the male function. Second, sex allocation should be size-dependent with smaller hermaphrodites allocating more than proportionally resources to male reproduction than larger ones. This size-dependent sex allocation permits hermaphrodites to profit from male mating opportunities that are the greatest at small body sizes. Size-dependent sex allocation is also expected because the male fitness gain curve decelerates more quickly than the female gain curve and experiments indicated that resources are greater for large than small hermaphrodites. These two predictions were tested when determining the sex allocation of hermaphrodites by dissecting their gonad and quantifying ovaries versus testes mass. Supporting the predictions above, hermaphrodites allocated, on average, 118 times more to the female than to the male gonad and the proportion of resources devoted to male function was higher in small than in large hermaphrodites. A trade-off between male and female allocation is assumed by theory but no negative correlation between male and female reproductive investment was observed. In L. wurdemanni, the relationship between sex-specific investment and fitness changes during ontogeny in a way that is consistent with an adjustment of sex allocation to improve size-specific reproductive success. PMID- 17714504 TI - Beta-thalassemic trait cannot be safely differentiated from iron deficiency anemia by red blood cell indices. PMID- 17714505 TI - Typing of the immunological system in human embryos by coelocentesis. AB - Coelocentesis offers a new opportunity for gaining access to the human embryos from 28 d postfertilization. However, while some studies about its biochemical composition have been reported, our knowledge about immunological pattern of this compartment is still limited. For this reason, we studied the human coelomic fluids sampled from 6.6 to 10 wk of gestation. The majority of cellular population consisted in mesenchymal/epithelial cells. In fluids sampled before 10 wk we found only a preT Cell Receptor expression and an absence or a very low frequency of B lymphocytes, T lymphocytes and NK (natural killer) antigens. These preliminary data suggest that the immunological system in human embryos could be in the ideal conditions to start a process of tolerance induction. PMID- 17714506 TI - In vitro activity of daptomycin and tigecycline against coagulase-negative staphylococcus blood isolates from bone marrow transplant recipients. AB - BACKGROUND AND OBJECTIVE: Multi-resistant coagulase-negative staphylococci (CNS) may cause systemic infections in patients undergoing bone marrow transplantation. Daptomycin, a new lipopeptide, and tigecycline, a new glycylcycline, have excellent activity against Gram-positive bacteria including methicillin-resistant staphylococci. This study presents the in vitro activity of daptomycin and tigecycline compared to vancomycin and fosfomycin against 105 CNS isolated from 76 bone marrow transplant patients with symptomatic bacteremia. MATERIAL AND METHODS: Blood stream isolates of Staphylococcus epidermidis (n = 102) and Staphylococcus haemolyticus (n = 3) from bone marrow transplant patients were collected from 2000 to 2006. The susceptibility of all isolates was tested using methods of the Clinical Laboratory Standards Institute. RESULTS: The minimal inhibitory concentrations MIC(50) and MIC(90) were 0.125 microg/mL and 0.25 microg/mL for daptomycin, 0.25 and 0.5 microg/mL for tigecycline, 1 microg/mL and 2 microg/mL for vancomycin, and 8 microg/mL and >256 microg/mL for fosfomycin, respectively. MIC values of tested agents were similar for both methicillin sensitive and methicillin-resistant S. epidermidis strains. CONCLUSIONS: All CNS isolates were susceptible to the new antistaphylococcal agents daptomycin and tigecycline. Although vancomycin had been used over the past 30 yr at our bone marrow transplant unit all CNS were still susceptible to vancomycin. PMID- 17714507 TI - Using directed evolution to improve the solubility of the C-terminal domain of Escherichia coli aminopeptidase P. Implications for metal binding and protein stability. AB - There have been many approaches to solving problems associated with protein solubility. This article describes the application of directed evolution to improving the solubility of the C-terminal metal-binding domain of aminopeptidase P from Escherichia coli. During the course of experiments, the domain boundary and sequence were allowed to vary. It was found that extending the domain boundary resulted in aggregation with little improvement in solubility, whereas two changes to the sequence of the domain resulted in dramatic improvements in solubility. These latter changes occurred in the active site and abolished the ability of the protein to bind metals and hence catalyze its physiological reaction. The evidence presented here has led to the proposal that metals bind to the intact protein after it has folded and that the N-terminal domain is necessary to stabilize the structure of the protein so that it is capable of binding metals. The acid residues responsible for binding metals tend to repel one another - in the absence of the N-terminal domain, the C-terminal domain does not fold properly and forms inclusion bodies. Evolution of the C-terminal domain has removed the destabilizing effects of the metal ligands, but in so doing it has reduced the capacity of the domain to bind metals. In this case, directed evolution has identified active site residues that destabilize the domain structure. PMID- 17714508 TI - Mapping of the active site of glutamate carboxypeptidase II by site-directed mutagenesis. AB - Human glutamate carboxypeptidase II [GCPII (EC 3.4.17.21)] is recognized as a promising pharmacological target for the treatment and imaging of various pathologies, including neurological disorders and prostate cancer. Recently reported crystal structures of GCPII provide structural insight into the organization of the substrate binding cavity and highlight residues implicated in substrate/inhibitor binding in the S1' site of the enzyme. To complement and extend the structural studies, we constructed a model of GCPII in complex with its substrate, N-acetyl-l-aspartyl-l-glutamate, which enabled us to predict additional amino acid residues interacting with the bound substrate, and used site-directed mutagenesis to assess the contribution of individual residues for substrate/inhibitor binding and enzymatic activity of GCPII. We prepared and characterized 12 GCPII mutants targeting the amino acids in the vicinity of substrate/inhibitor binding pockets. The experimental results, together with the molecular modeling, suggest that the amino acid residues delineating the S1' pocket of the enzyme (namely Arg210) contribute primarily to the high affinity binding of GCPII substrates/inhibitors, whereas the residues forming the S1 pocket might be more important for the 'fine-tuning' of GCPII substrate specificity. PMID- 17714510 TI - Regulated expression by PPARalpha and unique localization of 17beta hydroxysteroid dehydrogenase type 11 protein in mouse intestine and liver. AB - 17beta-Hydroxysteroid dehydrogenase type 11 (17beta-HSD11) is a member of the short-chain dehydrogenase/reductase family involved in the activation and inactivation of sex steroid hormones. We recently identified 17beta-HSD11 as a gene that is efficiently regulated by peroxisome proliferator-activated receptor alpha PPARalpha in the intestine and the liver [Motojima K (2004) Eur J Biochem271, 4141-4146]. In this study, we characterized 17beta-HSD11 at the protein level to obtain information about its physiologic role in the intestine and liver. For this purpose, specific antibodies against 17beta-HSD11 were obtained. Western blotting analysis showed that administration of a peroxisome proliferator-activated receptor-alpha agonist induced 17beta-HSD11 protein in the jejunum but not in the colon, and to a much higher extent than in the liver of mice. A subcellular localization study using Chinese hamster ovary cells and green fluorescent protein-tagged 17beta-HSD11 showed that it was mostly localized in the endoplasmic reticulum under normal conditions, whereas it was concentrated on lipid droplets when they were induced. A pulse-chase experiment suggested that 17beta-HSD11 was redistributed to the lipid droplets via the endoplasmic reticulum. Immunohistochemical analysis using tissue sections showed that 17beta HSD11 was induced mostly in intestinal epithelia and hepatocytes, with heterogeneous localization both in the cytoplasm and in vesicular structures. A subcellular fractionation study of liver homogenates confirmed that 17beta-HSD11 was localized mostly in the endoplasmic reticulum when mice were fed a normal diet, but was distributed in both the endoplasmic reticulum and the lipid droplets of which formation was induced by feeding a diet containing a proliferator-activated receptor-alpha agonist. Taken together, these data indicate that 17beta-HSD11 localizes both in the endoplasmic reticulum and in lipid droplets, depending on physiologic conditions, and that lipid droplet 17beta-HSD11 is not merely an endoplasmic reticulum contaminant or a nonphysiologically associated protein in the cultured cells, but a bona fide protein component of the membranes of both intracellular compartments. PMID- 17714509 TI - Comprehensive interaction of dicalcin with annexins in frog olfactory and respiratory cilia. AB - Dicalcin (renamed from p26olf) is a dimer form of S100 proteins found in frog olfactory epithelium. S100 proteins form a group of EF-hand Ca(2+)-binding proteins, and are known to interact with many kinds of target protein to modify their activities. To determine the role of dicalcin in the olfactory epithelium, we identified its binding proteins. Several proteins in frog olfactory epithelium were found to bind to dicalcin in a Ca(2+)-dependent manner. Among them, 38 kDa and 35 kDa proteins were most abundant. Our analysis showed that these were a mixture of annexin A1, annexin A2 and annexin A5. Immunohistochemical analysis showed that dicalcin and all of these three subtypes of annexin colocalize in the olfactory cilia. Dicalcin was found to be present in a quantity almost sufficient to bind all of these annexins. Colocalization of dicalcin and the three subtypes of annexin was also observed in the frog respiratory cilia. Dicalcin facilitated Ca(2+)-dependent liposome aggregation caused by annexin A1 or annexin A2, and this facilitation was additive when both annexin A1 and annexin A2 were present. In this facilitation effect, the effective Ca(2+) concentrations were different between annexin A1 and annexin A2, and therefore the dicalcin-annexin system in frog olfactory and respiratory cilia can cover a wide range of Ca(2+) concentrations. These results suggested that this system is associated with abnormal increases in the Ca(2+) concentration in the olfactory and other motile cilia. PMID- 17714511 TI - Novel repressor of the human FMR1 gene - identification of p56 human (GCC)(n) binding protein as a Kruppel-like transcription factor ZF5. AB - A series of relatively short (GCC)(n) triplet repeats (n = 3-30) located within regulatory regions of many mammalian genes may be considered as putative cis acting transcriptional elements (GCC-elements). Fragile X-mental retardation syndrome is caused by an expansion of (GCC)(n) triplet repeats within the 5' untranslated region of the human fragile X-mental retardation 1 (FMR1) gene. The present study aimed to characterize a novel human (GCC)(n)-binding protein and investigate its possible role in the regulation of the FMR1 gene. A novel human (GCC)(n)-binding protein, p56, was isolated and identified as a Kruppel-like transcription factor, ZF5, by MALDI-TOF analysis. The capacity of ZF5 to specifically interact with (GCC)(n) triplet repeats was confirmed by the electrophoretic mobility shift assay with purified recombinant ZF5 protein. In cotransfection experiments, ZF5 overexpression repressed activity of the GCC element containing mouse ribosomal protein L32 gene promoter. Moreover, RNA interference assay results showed that endogenous ZF5 acts as a repressor of the human FMR1 gene. Thus, these data identify a new class of ZF5 targets, a subset of genes containing GCC-elements in their regulatory regions, and raise the question of whether transcription factor ZF5 is implicated in the pathogenesis of fragile X syndrome. PMID- 17714512 TI - Construction and biological activity of a full-length molecular clone of human Torque teno virus (TTV) genotype 6. AB - Torque teno virus (TTV) is a non-enveloped human virus with a circular negative sense (approximately 3800 nucleotides) ssDNA genome. TTV resembles in genome organization the chicken anemia virus, the animal pathogen of the Circoviridae family, and is currently classified as a member of a new, floating genus, Anellovirus. Molecular and cell biological research on TTV has been restricted by the lack of permissive cell lines and functional, replication-competent plasmid clones. In order to examine the key biological activities (i.e. RNA transcription and DNA replication) of this still poorly characterized ssDNA virus, we cloned the full-length genome of TTV genotype 6 and transfected it into cells of several types. TTV mRNA transcription was detected by RT-PCR in all the cell types: KU812Ep6, Cos-1, 293, 293T, Chang liver, Huh7 and UT7/Epo-S1. Replicating TTV DNA was detected in the latter five cell types by a DpnI-based restriction enzyme method coupled with Southern analysis, a novel approach to assess TTV DNA replication. The replicating full-length clone, the cell lines found to support TTV replication, and the methods presented here will facilitate the elucidation of the molecular biology and the life cycle of this recently identified human virus. PMID- 17714513 TI - Lipopolyamine treatment increases the efficacy of intoxication with saporin and an anticancer saporin conjugate. AB - Saporin is a type I ribosome-inactivating protein that is often appended with a cell-binding domain to specifically target and kill cancer cells. Urokinase plasminogen activator (uPA)-saporin, for example, is an anticancer toxin that consists of a chemical conjugate between the human uPA and native saporin. Both saporin and uPA-saporin enter the target cell by endocytosis and must then escape the endomembrane system to reach the cytosolic ribosomes. The latter process may represent a rate-limiting step for intoxication and would therefore directly affect toxin potency. In the present study, we document two treatments (shock with dimethylsulfoxide and lipopolyamine coadministration) that generate substantial cellular sensitization to saporin/uPA-saporin. With the use of lysosome-endosome X (LEX)1 and LEX2 mutant cell lines, an endosomal trafficking step preceding cargo delivery to the late endosomes was identified as a major site for the dimethylsulfoxide-facilitated entry of saporin into the cytosol. Dimethylsulfoxide and lipopolyamines are known to disrupt the integrity of endosome membranes, so these reagents could facilitate the rapid movement of toxin from permeabilized endosomes to the cytosol. However, the same pattern of toxin sensitization was not observed for dimethylsulfoxide- or lipopolyamine treated cells exposed to diphtheria toxin, ricin, or the catalytic A chain of ricin. The sensitization effects were thus specific for saporin, suggesting a novel mechanism of saporin translocation by endosome disruption. Lipopolyamines have been developed as in vivo gene therapy vectors; thus, lipopolyamine coadministration with uPA-saporin or other saporin conjugates could represent a new approach for anticancer toxin treatments. PMID- 17714514 TI - Pyroptosis and host cell death responses during Salmonella infection. AB - Salmonella enterica are facultatively intracellular pathogens causing diseases with markedly visible signs of inflammation. During infection, Salmonella interacts with various host cell types, often resulting in death of those cells. Salmonella induces intestinal epithelial cell death via apoptosis, a cell death programme with a notably non-inflammatory outcome. In contrast, macrophage infection triggers caspase-1-dependent proinflammatory programmed cell death, a recently recognized process termed pyroptosis, which is distinguished from other forms of cellular demise by its unique mechanism, features and inflammatory outcome. Rapid macrophage pyroptosis depends on the Salmonella pathogenicity island-1 type III secretion system (T3SS) and flagella. Salmonella dynamically modulates induction of macrophage pyroptosis, and regulation of T3SS systems permits bacterial replication in specialized intracellular niches within macrophages. However, these infected macrophages later undergo a delayed form of caspase-1-dependent pyroptosis. Caspase-1-deficient mice are more susceptible to a number of bacterial infections, including salmonellosis, and pyroptosis is therefore considered a generalized protective host response to infection. Thus, Salmonella-induced pyroptosis serves as a model to understand a broadly important pathway of proinflammatory programmed host cell death: examining this system affords insight into mechanisms of both beneficial and pathological cell death and strategies employed by pathogens to modulate host responses. PMID- 17714515 TI - Regulation of cell death during infection by the severe acute respiratory syndrome coronavirus and other coronaviruses. AB - Both apoptosis and necrosis have been observed in cells infected by various coronaviruses, suggesting that the regulation of cell death is important for viral replication and/or pathogenesis. Expeditious research on the severe acute respiratory syndrome (SARS) coronavirus, one of the latest discovered coronaviruses that infect humans, has provided valuable insights into the molecular aspects of cell-death regulation during infection. Apoptosis was observed in vitro, while both apoptosis and necrosis were observed in tissues obtained from SARS patients. Viral proteins that can regulate apoptosis have been identified, and many of these also have the abilities to interfere with cellular functions. Occurrence of cell death in host cells during infection by other coronaviruses, such as the mouse hepatitis virus and transmissible porcine gastroenteritis virus, has also being extensively studied. The diverse cellular responses to infection revealed the complex manner by which coronaviruses affect cellular homeostasis and modulate cell death. As a result of the complex interplay between virus and host, infection of different cell types by the same virus does not necessarily activate the same cell-death pathway. Continuing research will lead to a better understanding of the regulation of cell death during viral infection and the identification of novel antiviral targets. PMID- 17714516 TI - Mast cells initiate early anti-Listeria host defences. AB - The Gram-positive bacterium Listeria monocytogenes (L. m.) is the aetiological agent of listeriosis. The early phase listeriosis is characterized by strong innate host responses that play a major role in bacterial clearance. This is emphasized by the fact that mice deficient in T and B cells have a remarkable ability to control infection. Mast cells, among the principal effectors of innate immunity, have largely been studied in the context of hyper-reactive conditions such as allergy and autoimmune diseases. In the present study, we evaluated the significance of mast cells during the early phase of listeriosis. Compared with controls, mice depleted of mast cells showed hundred-fold higher bacterial burden in spleen and liver and were significantly impaired in neutrophil mobilization. Although L. m. interacts with and triggers mast cell degranulation, bacteria were hardly found within such cells. Mainly neutrophils and macrophages phagozytosed L. m. Thus, mast cells control infection not via direct bacterial uptake, but by initiating neutrophils influx to the site of infection. We show that this is initiated by pre-synthesized TNF-alpha, rapidly secreted by mast cell upon activation by L. m. We also show that upon recruitment, neutrophils also become activated and additionally secrete TNF-alpha thus amplifying the anti-L. m. inflammatory response. PMID- 17714517 TI - Lysosomal ubiquitin and the demise of Mycobacterium tuberculosis. AB - The antimicrobial activity of macrophages is mediated by both oxidative and non oxidative mechanisms. Oxidative mechanisms include the action of reactive oxygen and nitrogen intermediates on bacteria. Non-oxidative mechanisms include the maturation of the phagosome into an acidified, hydrolytically active compartment as well as the action of antimicrobial peptides. Mycobacterium tuberculosis parasitizes the host macrophage by arresting the normal maturation of its phagosome and resides in a compartment that fails to fuse with lysosomes. When bacteria are unable to regulate phagosome maturation, such as in activated macrophages, they are delivered to lysosomal compartments, where they are killed. Recent data indicate that the antimycobacterial mechanism of the lysosome is due in part to the action of ubiquitin-derived peptides. PMID- 17714518 TI - The grateful dead: calcium and cell death in plant innate immunity. AB - Plant cells sensing pathogenic microorganisms evoke defence systems that can confer resistance to infection. This innate immune reaction can include triggering of basal defence responses as well as programmed cell death, or hypersensitive response (HR). In both cases (basal defence and HR), pathogen perception is translated into elevated cytosolic Ca(2+) (mediated by plasma membrane and intracellular channels) as an early step in a signalling cascade. Cyclic nucleotide-gated channels contribute to this influx of Ca(2+) into the cell. The molecular nature of other transport proteins contributing to the Ca(2+) elevation is unclear. Pathogen recognition occurs at two levels: the perception of pathogen-associated molecular pattern (PAMP) molecules widely present in microorganisms, and an interaction between pathogen avirulence gene products (if present) and corresponding plant R (resistance) gene products. The Ca(2+) elevation occurring in response to PAMP perception or R gene interactions could occur due to phosphorylation events, G-protein signalling and/or an increase in cyclic nucleotides. Downstream from the initial Ca(2+) rise, the signalling cascade includes: activation of calmodulin and protein kinases, and nitric oxide and reactive oxygen species generation. Some of these downstream events amplify the Ca(2+) signal by further activation of Ca(2+) transporters. PMID- 17714519 TI - Role of BK(Ca) channels in cephalic vasodilation induced by CGRP, NO and transcranial electrical stimulation in the rat. AB - Both calcitonin gene-related peptide (CGRP) and nitric oxide (NO) are potent vasodilators that have been shown to induce headache in migraine patients. Their antagonists are effective in the treatment of migraine attacks. In the present study, we hypothesize that vasodilation induced by the NO donor glyceryltrinitrate (GTN) or by CGRP is partially mediated via large conductance calcium-activated potassium (BK(Ca)) channels. The effects of the BK(Ca) channel selective inhibitor iberiotoxin on dural and pial vasodilation induced by CGRP, GTN and endogenously released CGRP by transcranial electrical stimulation (TES) were examined. Iberiotoxin significantly attenuated GTN-induced dural and pial artery dilation in vivo and in vitro, but had no effect on vasodilation induced by CGRP and TES. Our results show that GTN- but not CGRP-induced dural and pial vasodilation involves opening of BK(Ca) channels in rat. PMID- 17714520 TI - Association of the C677T polymorphism in the MTHFR gene with migraine: a meta analysis. AB - There are conflicting data concerning the association between migraine and C677T polymorphism of the MTHFR gene. The C677T polymorphism reduces enzymatic capability by 50% and causes hyperhomocysteinaemia. We performed a meta-analysis of all published studies investigating the association between the MTHFR gene and migraine. Pooled odds ratios (OR) were estimated using random (RE) and fixed effects (FE) models. Among the overall 2961 migraineurs there was no significant difference compared with controls. Only in migraine with aura was the TT genotype associated with a higher risk of disease compared with the CC genotype [FE OR 1.30, 95% confidence interval (CI) 1.06, 1.58; RE OR 1.66, 95% CI 1.06, 2.59]. In the same subgroup a significant difference was observed in the comparison between TT and CT + CC genotypes (FE OR 1.32, 95% CI 1.10, 1.59; RE OR 1.63, 95% CI 1.10, 2.43). This study provides evidence for an association of the MTHFR gene only in migraine with aura. PMID- 17714521 TI - Pharmacokinetic and pharmacodynamic variability as possible causes for different drug responses in migraine. A comment. AB - The pharmacokinetics of antimigraine drugs zolmitriptan and sumatriptan varied considerably with a fourfold to 10-fold variation in plasma levels. In addition, the pharmacodynamics of triptans as investigated in vitro also varied considerably. In theory, there should probably be a 10-fold variation in doses available, but in clinical practice a fourfold difference in doses will probably cover the needs of most patients. PMID- 17714522 TI - Development of 16S rRNA-based probes for the identification of Gram-positive anaerobic cocci isolated from human clinical specimens. AB - Fluorescent probes targeted at 16S rRNA were designed for Peptostreptococcus anaerobius and Peptostreptococcus stomatis (Pana134), Parvimonas micra (Pamic1435), Finegoldia magna (Fmag1250), Peptoniphilus asaccharolyticus (Pnasa1254), Peptoniphilus ivorii (Pnivo731), Peptoniphilus harei (Pnhar1466), Anaerococcus vaginalis (Avag1280) and Anaerococcus lactolyticus (Alac1438), based on the 16S rRNA sequences of reference strains and 88 randomly chosen clinical isolates. These strains were also used for validation of the probes. Application of the probes to an additional group of 100 clinical isolates revealed that 87% of Gram-positive anaerobic cocci (GPAC) could be identified with this set of probes. The 16S rRNAs of 13 clinical isolates that could not be identified were sequenced. Most of these isolates were GPAC that were not targeted by the probes. No clinical isolates of Pn. asaccharolyticus were encountered. Near full-length sequences were obtained from 71 of 101 (n = 88 + 13) sequenced clinical isolates. Of these, 25 showed <98% similarity with the homologues of the closest established species. The Fmag1250, Pamic1435, Pnhar1466, Pana134, Pnasa1254 and Pnivo731 probes allowed reliable identification and hybridised with all corresponding isolates. The Avag1280 and Alac1438 probes failed to hybridise with two isolates and one isolate, respectively, because of intra-species variation. However, overall, the set of probes yielded fast and reliable identification for the majority of clinical isolates. PMID- 17714523 TI - Detection of diarrhoea-causing protozoa in general practice patients in The Netherlands by multiplex real-time PCR. AB - The diagnostic value of a multiplex real-time PCR for the detection of Entamoeba histolytica, Giardia lamblia and Cryptosporidium parvum/Cryptosporidium hominis was evaluated by comparing the PCR results obtained with those of routinely performed microscopy of faecal samples from patients consulting their general practitioner (GP) because of gastrointestinal complaints. Analysis of 722 faecal DNA samples revealed that the prevalence of G. lamblia was 9.3% according to PCR, as compared to 5.7% by microscopy. The number of infections detected was more than double in children of school age. Furthermore, G. lamblia infection was detected in 15 (6.6%) of 228 faecal samples submitted to the laboratory for bacterial culture only. C. parvum/C. hominis infections were not diagnosed by routine procedures, but DNA from these organisms was detected in 4.3% of 950 DNA samples. A strong association with age was noted, with Cryptosporidium being detected in 21.8% of 110 children aged <5 years. C. hominis was the most prevalent species. E. histolytica was not detected in this study population. Analysis of microscopy data revealed that the number of additional parasites missed by PCR was small. Overall, the study demonstrated that a multiplex real time PCR approach is a feasible diagnostic alternative in the clinical laboratory for the detection of parasitic infections in patients consulting GPs because of gastrointestinal symptoms. PMID- 17714524 TI - Mumps vaccine failure or vaccination scheme failure? PMID- 17714525 TI - Oral infections and systemic disease--an emerging problem in medicine. AB - The relationship between oral and general health has been increasingly recognised during the past two decades. Several epidemiological studies have linked poor oral health with cardiovascular disease, poor glycaemic control in diabetics, low birth-weight pre-term babies, and a number of other conditions, including rheumatoid arthritis and osteoporosis. Oral infections are also recognised as a problem for individuals suffering from a range of chronic conditions, including cancer and infection with human immunodeficiency virus, as well as patients with ventilator-associated pneumonia. This review considers the systemic consequences of odontogenic infections and the possible mechanisms by which oral infection and inflammation can contribute to cardiovascular disease, as well as the oral conditions associated with medically compromised patients. A large number of clinical studies have established the clinical efficacy of topical antimicrobial agents, e.g., chlorhexidine and triclosan, in the prevention and control of oral disease, especially gingivitis and dental plaque. The possible risks of antimicrobial resistance are a concern, and the benefits of long-term use of triclosan require further evaluation. Oral infections have become an increasingly common risk-factor for systemic disease, which clinicians should take into account. Clinicians should increase their knowledge of oral diseases, and dentists must strengthen their understanding of general medicine, in order to avoid unnecessary risks for infection that originate in the mouth. PMID- 17714526 TI - Clarithromycin suspension-associated toxic epidermal necrolysis in a 2-year-old girl. PMID- 17714527 TI - A case of Ferguson-Smith type multiple keratoacanthomas associated with keratoacanthoma centrifugum marginatum: response to oral acitretin. AB - Keratoacanthoma centrifugum marginatum (KCM) is a rare entity, usually classified as solitary keratoacanthoma (KA). The Ferguson-Smith type is the most common form of multiple KAs. Because development of multiple KAs and KCM in a single patient has rarely been reported, this association presents a therapeutic challenge. We report a 46-year-old man with Ferguson-Smith multiple KAs and KCM, who was successfully treated with acitretin. PMID- 17714528 TI - Oral isotretinoin, neuropathy and hypovitaminosis A. PMID- 17714529 TI - Staphylococcal scalded skin syndrome as a complication of septic arthritis. PMID- 17714530 TI - Epidermal interleukin-8 and its receptor CXCR2 in drug-induced toxic epidermal necrolysis. AB - BACKGROUND: In drug-induced toxic epidermal necrolysis (TEN), the epidermal destruction is associated with a slight to moderate lymphomonocytic cell infiltrate. Interleukin (IL)-8, which is a keratinocyte-derived pro-inflammatory cytokine, might be involved in this process. The IL-8 receptor CXCR2 has also been shown to be overexpressed in some epidermal disorders. METHODS: IL-8 concentration was measured by ELISA in both serum and blister fluid from 10 patients with TEN. Data were compared with similar dosages performed in 15 cases of second-degree burn and 7 cases of bullous pemphigoid (BP). CXCR2 expression on keratinocytes was studied using immunohistochemistry on skin biopsies performed in TEN bullous lesions and clinically uninvolved skin of the same patients. RESULTS: IL-8 was significantly overexpressed in TEN blister fluid compared with TEN serum (P = 0.0015). However, no difference was found in IL-8 concentrations present in blister fluid of TEN, second-degree burn and BP. CXCR2 was moderately expressed in the epidermis of some TEN blisters, but was never expressed in clinically uninvolved skin. CXCR2 expression was not found in the follicular epidermal root sheaths of patients with TEN. CONCLUSIONS: These results indicate that abundant IL-8 appears to be locally produced in TEN epidermis, but this overexpression is not disease-specific. Because of the paucity of the inflammatory infiltrate in TEN, it is unlikely that IL-8 induces epidermal destruction through its chemotactic activity. Moreover, the complete absence of neutrophils in TEN lesions indicates that the major chemotactic effect of IL-8 on neutrophils is not operative in TEN skin. This implies that IL-8 activates different functions according to the local environment. CXCR2 expression on TEN keratinocytes is expressed on some necrotic keratinocytes, consistent with a discrete IL-8 proapoptotic activity. The lack of CXCR2 expression in the follicular root sheaths argues against a role for IL-8 in TEN epidermal repair. PMID- 17714531 TI - Sporotrichoid cutaneous tuberculosis. AB - Three patients with sporotrichoid cutaneous tuberculosis have been described. Two were children of either sex with lesions of lupus vulgaris along the lower limb and one woman had scrofuloderma along the left arm. Culture for Mycobacteria being negative, the diagnosis was based on the clinical picture, positive tuberculin test, granulomatous dermatitis on histopathology and regression with anti-tubercular DOTS therapy. Sporotrichoid presentation of scrofuloderma appeared to simulate sporotrichosis more than sporotrichoid lupus vulgaris. As seen from other reports and the present one, children and those just past adolescence have often been affected. Since sporotrichoid pattern is known to be usually associated with the less pathogenic atypical or non-tuberculous mycobacteria, it is speculated that the good lymphatic drainage and proneness to trauma that go with the high physical activity in these age groups may rarely result in this clinical presentation of cutaneous tuberculosis. PMID- 17714532 TI - In vitro antifungal susceptibility patterns of dermatophyte strains causing tinea unguium. AB - BACKGROUND: Dermatophytes are the major responsible organisms in onychomycosis. Although recent antifungal agents have high success rates in treating this condition, lack of clinical response may occur in 20%. Antifungal drug resistance may be one of the causes of treatment failure. The need for in vitro antifungal drug resistance in daily practice is still under discussion. OBJECTIVE: We aimed to determine the in vitro susceptibility patterns of dermatophytes causing onychomycosis, against the traditionally available systemic antifungal agents terbinafine, itraconazole and fluconazole. METHODS: In total, 100 otherwise healthy patients with suspected onychomycosis were included. Nail clippings were cultured on Sabouraud dexrose agar, mycobiotic agar and dermatophyte test medium. Antifungal susceptibility tests were carried out, mainly following The National Committee for Clinical and Laboratory Standards (M38-P) protocol standard for filamentous fungi. Different concentrations of terbinafine (0.008-8 microg/mL), itraconazole (0.015-16 microg/mL) and fluconazole (0.06-64 microg/mL) were tested. Minimum inhibitory concentration end-point determination was chosen as 100% growth inhibition for terbinafine and 80% for azoles. RESULTS: Of the 100 nail samples, 43% grew dermatophytes. The main causative organism was Trichophyton rubrum (91%) followed by Trichophyton mentagrophytes (9%). Terbinafine had the lowest minimum inhibitory concentration (0.008 microg/mL) followed by itraconazole. Fluconazole showed the greatest variation in minimum inhibitory concentration (0.03-2 microg/mL) and had different susceptibility patterns for the two species. CONCLUSIONS: Of the three antifungals tested, terbinafine had the most potent in vitro antifungal activity against dermatophytes. Antifungal susceptibility tests would be useful to screen antifungal-resistant dermatophyte strains. PMID- 17714533 TI - Laparoscopic emergency and elective surgery for ulcerative colitis. AB - OBJECTIVE: To analyse surgical outcomes of fulminate and medically resistant ulcerative colitis (UC) carried out laparoscopically. METHOD: A prospective database identified 69 consecutive patients who underwent surgery for UC under the senior author over a 5-year period to April 2006. RESULTS: Thirty-two patients (18 male patients), median BMI 26, underwent laparoscopic subtotal colectomy (LSTC): 22 acute emergencies, 10 refractory to medical therapy and unfit for restorative proctocolectomy. All were receiving iv steroids; azathioprine (7), cyclosporin (5). The median operation time was 135 min (65 280). There was one conversion. Twenty-nine patients have subsequently undergone completion proctectomy and W-pouch formation [24 patients were performed laparoscopically - laparoscopic completion proctectomy (LCP)]; widespread adhesions precluded in five patients. Twenty-six patients underwent restorative laparoscopic proctocolectomy (LRP) - one conversion. Twenty patients underwent W pouch reconstruction via a Pfannenstiel incision. Six J-pouches were constructed and returned via the ileostomy site. Three underwent a laparoscopic pan proctocolectomy (LPPC); one conversion. Eight patients underwent open STC. The median time to normal diet was 48 h (1-7 days) for LSTC/LCP and 36 h (1-5 days) for LRP. There were two major complications following LRP, two following LSTC, one following LCP, one following LPPC and five following open surgery. Median hospital stay was 8 days (6-72) for LSTC, 7 days (6-9) for LCP and 5 days (3-45) for LRP. There were six 30-day readmissions following laparoscopic surgery (DVT, reactive depression, ileostomy hold up (2), abdominal pain and high output ileostomy). CONCLUSION: Laparoscopic subtotal and restorative proctocolectomies in fulminate and medically resistant UC are feasible, safe and largely predictable operations that allow for early hospital discharge. Laparoscopic colectomy facilitates subsequent proctectomy and pouch construction. PMID- 17714534 TI - Beneficial effects of suplatast tosilate (IPD-1151T) in a rat cystitis model induced by intravesical hydrochloric acid. AB - OBJECTIVE: To examine the effects of suplatast tosilate (IPD-1151T), a Th2 cytokine inhibitor recently recognized to improve the symptoms in patients with interstitial cystitis (IC), in a rat model of HCl-induced chronic cystitis, to elucidate the possible mechanisms by which the drug improves the symptoms of IC. MATERIALS AND METHODS: Chronic cystitis was induced by intravesical instillation of 0.2 mL of 0.4 m HCl in female adult rats. After a once-daily oral administration of IPD-1151T (0.1-100 mg/kg) or prednisolone (5 mg/kg) for 7 days, cystometry was performed under urethane anaesthesia. The bladder from HCl-induced cystitis rats was also assessed histopathologically. RESULTS: On cystometrography there was frequent voiding in cystitis rats. Administration of IPD-1151T for 7 days after intravesical HCl instillation dose-dependently increased the micturition volume and intercontraction intervals. Treatment with prednisolone had similar therapeutic effects. Histological analyses in the bladder from cystitis rats revealed oedema and infiltration of inflammatory cells such as mast cells and eosinophils in the lamina propria and the transitional epithelial thickening. These histological changes and the number of mast cells and eosinophils were reduced by administration of IPD-1151T or prednisolone. CONCLUSION: The present results indicate that IPD-1151T improves bladder function and pathological changes in HCl-induced cystitis rats, as previously observed in patients with IC. The rat cystitis model induced by HCl could provide useful information for studying proposed therapies for IC which might involve T cell dependent inflammatory responses as one of its potential pathophysiologies. PMID- 17714535 TI - The 'follicular trochanter': an epithelial compartment of the human hair follicle bulge region in need of further characterization. AB - Recent articles on hair follicle stem cells have summarized the current state of knowledge of what has been termed the hair follicle 'bulge'. During the course of immunohistological studies aimed at characterizing the expression of selected extracellular matrix proteins in the - as yet insufficiently characterized - niche of human bulge hair follicle stem cells, we have recently come across a largely forgotten, peculiar epithelial protrusion of the outer root sheath, which was visible in only a minority of all examined hair follicles. The morphology and immunoreactivity patterns of this structure, the 'follicular trochanter', are described herein. PMID- 17714536 TI - Physician end-of-life decision-making in newborns in a less developed health care setting: insight in considerations and implementation. AB - BACKGROUND: A substantial proportion of the decisions to withhold or withdraw life-prolonging treatment are based on the newborn's predicted poor quality of life. All previous studies on end-of-life decisions were done in countries with adequate support for disabled neonatal intensive care units (NICU) survivors. Data on quality-of-life considerations in countries with developing health care are not available yet. AIM: The aim of the study was to examine the considerations of physicians taking end-of-life decisions in sick newborns and how those decisions are carried out in practice in a less developed health care setting. METHOD: Thirty-two deaths over 18 months in a neonatal unit were retrospectively analyzed. RESULTS: Twenty-four deaths (75%) were attributable to withholding or withdrawing of treatment. In 7 of these cases (29%), the decisions were based on quality-of-life considerations, mostly predicted suffering and expected hospital dependency. For the majority of paediatricians, end-of-life decision making was not influenced by legal or economic considerations or by considerations regarding availability of supportive care after discharge. CONCLUSION: Our study suggests that physician end-of-life decision making in this unit in a less developed health care setting is found to be similar to that in developed health care settings and is independent of availability of supportive care after discharge for infants with disabilities. PMID- 17714537 TI - Time course of faecal calprotectin in preterm newborns during the first month of life. PMID- 17714538 TI - Antibiotic prescribing patterns as empirical therapy among hospitalized patients in a Bolivian paediatric teaching hospital. PMID- 17714539 TI - Brain haemodynamic effects of nasal continuous airway pressure in preterm infants of less than 30 weeks' gestation. AB - AIM: To evaluate the hypothesis that increasing levels of nasal continuous positive airway pressure (NCPAP) may decrease cerebral blood volume (CBV) and cerebral oxygenation in infants with gestational age (GA) less than 30 weeks. METHODS: We prospectively studied a cohort of preterm infants treated with NCPAP using near-infrared spectroscopy (NIRS). The pressure limit of NCPAP was set at 2, 4, 6 and again 2 cm H(2)O for 30 min. RESULTS: Changes of pressure levels were not followed by significant changes of oxygenated haemoglobin (O(2)Hb), deoxygenated haemoglobin (HHb), cerebral intravascular oxygenation (HbD), oxidized-reduced cytochrome aa3 (CtOx), tissue oxygenation index (TOI), tissue haemoglobin index (THI) and cerebral blood volume (DeltaCBV). CONCLUSION: NCPAP at 2-6 cm H(2)O pressure levels did not affect cerebral oxygenation and CBV. These findings are reassuring and confirm the safety of NCPAP in preterm infants with GA less than 30 weeks. PMID- 17714540 TI - Nobel Prizes for discovering the cause of malaria and the means of bringing the disease under control: hopes and disappointments. PMID- 17714542 TI - Stimulation of sucking and swallowing to promote oral feeding in premature infants. AB - AIM: To study the effect of stimulation of sucking and swallowing on weaning from nasogastric (NG) feeding and length of hospital stay in premature infants. METHOD: Randomized controlled trial with blinded evaluation. Premature infants on NG feeds and post-menstrual age (PMA) less than 36 weeks who had poor ability to suck were randomized to receive one daily session of stimulation according to Vojta or no intervention other than standard nursing care. RESULTS: Of 36 infants, 18 received stimulation and 18 were observed without intervention. Mean gestational age at birth was 32.2 weeks (SD 2.4) versus 31.4 (2.3) weeks, p = 0.27, and PMA at study entry 35.1 weeks (0.8) versus 34.4 (0.9) weeks, p = 0.01, respectively. NG feeding was discontinued at 36.8 weeks (0.9) versus 36.3 (0.9) weeks' PMA, p = 0.25, and they were discharged at 37.8 weeks (0.9) versus 37.7 (1.3) weeks, p = 0.81. CONCLUSION: The stimulation programme did not result in earlier weaning from NG feeding or earlier discharge. However, such studies may need to be large to limit the possibility of type II errors. PMID- 17714541 TI - Pasteurization of mother's own milk reduces fat absorption and growth in preterm infants. AB - AIM: A randomized study was conducted to evaluate whether pasteurized milk (Holder pasteurization 62.5 degrees C, 30 min) reduces fat absorption and growth in preterm infants. METHODS: Preterm infants (825-1325 g) born with gestational age < or =30 weeks were randomized into two groups, of which one started with pasteurized own mother's milk for 1 week and continued with raw milk the following week, and a second group was fed in reverse order. By using this design the infants served as their own controls. At the end of each week, a 72-h fat balance was performed and growth was monitored. RESULTS: We found, on an average, 17% higher fat absorption with raw as compared to pasteurized milk. Infants gained more weight and linear growth assessed as knee-heel length was also greater during the week they were fed raw milk as compared to the week they were fed pasteurized milk. CONCLUSION: Feeding preterm infants pasteurized as compared to raw own mother's milk reduced fat absorption. When the infants were fed raw milk, they gained more in knee-heel length compared to when they were fed pasteurized milk. PMID- 17714543 TI - Aetiologic and clinical characteristics of syncope in Chinese children. AB - AIM: This study aimed to improve diagnostic efficacy of syncope in children by analyzing the aetiology and clinical characteristics of syncope in Chinese children. METHODS: We retrospectively analyzed the causes of syncope and diagnostic workup in 154 consecutive children seen in the Department of Pediatrics, Peking University First Hospital, China, because of a syncope-related event. RESULTS: In all patients with transient loss of consciousness (TLOC), there were 136 (88.31%) patients attributing to syncope, and 18 (11.69%) belonging to nonsyncopal cases. Neurally mediated syncope (NMS) was the most common cause of syncope (99 cases; 64.3%), with cardiac causes ranking second (10 cases; 6.5%). Other nonsyncopal causes included psychiatric problems and neurological and metabolic disorders. In 25 cases (16.2%), the cause was uncertain. Cases of NMS often had clear inducement of syncope and prodromes. Children with cardiac syncope often had a history of cardiac disease, were often younger than those with NMS, and showed exercise-related syncope, syncope spells in any body position or at an early age, or sudden death in family members but no prodromes. Neurological disorder was suspected in cases of TLOC with seizures, TLOC spells in any position, postictal phase of disorientation or abnormal neurological signs. A metabolic cause is suspected with a history of metabolic disease, prolonged anger, or violent vomiting and diarrhoea. Children with psychiatric disorders were adolescent girls, with prolonged TLOC spells, who had more frequent TLOC. Although many tests were used in diagnosis, most were not goal directed. Now, electrocardiography is recommended in almost all children with syncope. Neurological testing, including electroencephalography and computed tomography were rarely helpful unless with evidence of neurological signs and symptoms. Head-up tilt test (HUTT) was most useful in children with recurrent syncope in whom heart disease was not suspected. CONCLUSION: NMS was the most common cause of syncope. We recommended HUTT as the important basis of the TLOC workup. PMID- 17714545 TI - Vaginal delivery and threshold retinopathy of prematurity. PMID- 17714544 TI - Effect of pacifier use on mandibular position in preterm infants. AB - AIM: It has been hypothesized that the association of pacifier use with reduced risk of sudden infant death is mediated by forward movement of the mandible and tongue that helps open the upper airway. Our aim was to examine whether the mandible is moved forward when an infant is sucking on a pacifier, and if so, whether the mandible remains advanced after the pacifier is removed. METHODS: In sixty clinically stable premature infants (corrected gestation age 36.5 +/- 0.3 weeks, mean +/- SEM) the distance from each ear where the pinna met the cheek to the most prominent point of the chin was measured bilaterally, and the average was used as an index of mandibular position. Mandibular position was determined before and after allowing the infants to suck on a pacifier for 10-15 min, and after removing the pacifier. RESULTS: There was a significant forward movement of the mandible when the infants were sucking on the pacifier (59.5 +/- 0.7 vs. 58.6 +/- 0.7 mm, p = 0.001), with no significant change after the pacifier was removed. CONCLUSIONS: Pacifier use in preterm infants was associated with a small significant forward displacement of the jaw. These data suggest that pacifier use may help protect the upper airway. PMID- 17714546 TI - Anaesthetic neurotoxicity in rodents: is the ketamine controversy real? PMID- 17714548 TI - Down with trends. PMID- 17714549 TI - Hepatic mesenchymal hamartoma in a preterm newborn: demonstration by low-dose multidetector CT. AB - Primary liver tumours are very rare in the neonatal period. Differential diagnoses include haemangioendothelioma, malignant hepatoblastoma and mesenchymal hamartoma. Due to non-specific clinical symptoms and indecisive imaging findings, correct diagnosis may be difficult to establish. We report a female preterm newborn who was delivered at 33 weeks of gestation and in whom ultrasonography (US) revealed a large cystic intraabdominal tumour of unknown origin. For further evaluation, contrast-enhanced multidetector computed tomography (CT) was performed on the 4th day of life using a low-dose protocol (80 kVp, 50 mAs, collimation 0.75 mm, total effective dose 3.6 mSv). Based on CT findings, diagnosis of an intrahepatic mesenchymal hamartoma was made and confirmed by tumour resection and histopathological examination. In conclusion, multidetector CT (MDCT) using a low-dose protocol can be exceptionally used to establish diagnosis of a mesenchymal hamartoma in a preterm newborn. PMID- 17714547 TI - Bed-sharing in the first four months of life: a risk factor for sudden infant death. AB - AIM: To investigate the risk of sudden infant death in the Netherlands during bed sharing in the first half year of life and the protective effect of breastfeeding on it. METHODS: During a 10-year period between September 1996 and September 2006 nationwide, 213 cot deaths were investigated. RESULTS AND DISCUSSION: Of 138 cot deaths of less than 6 months of age, 36 (26%) bed-shared. In a reference group of 1628 babies from infant welfare centres only 9.4% were bed-sharing in the night prior to the interview. After correction for smoking of one or both parents the odds ratio for cot death during bed-sharing with parents decreased with age from 9.1 (CI 4.2-19.4) at 1 month, to 4.0 (CI 2.3-6.7) at 2 months, to 1.7 (CI 0.9 3.4) at 3 months and to 1.3 (CI 1.0-1.6) at 4 through 5 months of age. The excess risk (OR > 1) associated with bed-sharing is itself not significantly influenced by the presence or absence of breastfeeding. CONCLUSION: Bed-sharing is a serious risk factor for sudden infant death for all babies of less than 4 months of age. From 4 months onwards bed-sharing did not contribute significantly to the risk of cot death anymore in our study. PMID- 17714550 TI - No consumption of IgE antibody in serum during allergic drug anaphylaxis. AB - BACKGROUND: The general understanding is that a blood sample for analysis of immunoglobulin (Ig) E antibodies to an allergen suspected to cause an anaphylaxis cannot be drawn until several weeks after the reaction. As this is most unpractical, the changes in IgE antibody levels during anaphylaxis were studied to evaluate the possibility of using samples drawn at the time of the reaction. METHODS: Immunoglobulin E antibodies to suxamethonium were quantitated with ImmunoCAP before, during and after an anaphylactic reaction occurring during anaesthesia using neuromuscular blocking agents. RESULTS: Serum IgE antibody concentrations against suxamethonium in blood samples collected up to 6 h after the reaction were not different from those in samples drawn before or days and weeks after the anaphylaxis. CONCLUSIONS: A serum sample intended to trace the drug involved in an IgE-mediated anaphylactic reaction can be drawn in direct relation to the reaction. PMID- 17714551 TI - Effect of grass pollen immunotherapy with Alutard SQ on quality of life in seasonal allergic rhinoconjunctivitis. AB - BACKGROUND: Treatment of allergic rhinitis with subcutaneous allergen immunotherapy is effective in terms of reductions in symptoms and seasonal use of reliever medication. Its effect on quality of life (QoL), reflecting the impact of symptoms on work/school performance and leisure activities is, however, important and often overlooked. AIMS OF THE STUDY: To assess effect on QoL of specific immunotherapy with two doses of Alutard SQ Phleum pratense in patients with moderately to severe seasonal allergic rhinoconjunctivitis inadequately controlled by standard drug therapy. METHODS: Double-blind, randomized, placebo controlled study of 410 patients with seasonal allergic rhinoconjunctivitis. Participants were randomized (2 : 1 : 1) to receive Alutard SQ P. pratense (ALK Abello) at maintenance doses of 100,000 SQ-U (203 subjects), 10,000 SQ-U (104 subjects) or placebo (103 subjects) given by subcutaneous injections. The groups were well matched for demographics and baseline symptoms. Quality of life was assessed using the Rhinoconjunctivitis Quality of Life Questionnaire which covers seven domains of health before and in the peak of the pollen season. RESULTS: While all domain scores were significantly improved when comparing 100,000 SQ-U with placebo, two domain scores were significantly improved when comparing 10,000 SQ-U with placebo. When comparing 100,000 SQ-U with 10,000 SQ-U, four domain scores were significantly improved. CONCLUSION: Treatment with Alutard SQ significantly improved the seasonal QoL of patients suffering from allergic rhinoconjunctivitis. The improvement was more pronounced and wider ranging in patients who received the higher 100,000 SQ-U maintenance dose. PMID- 17714553 TI - Acidity surrounding the squamocolumnar junction in GERD patients: "acid pocket" versus "acid film". AB - AIM: This study aimed to localize the gastric-to-esophageal pH transition point relative to the squamocolumnar junction (SCJ) and esophagogastric junction (EGJ) high-pressure zone in controls and GERD patients. METHODS: Ten controls and 10 GERD patients were studied. Subjects had an endoclip placed at the SCJ prior to a pH catheter pull-through (upright and supine) during concurrent fluoroscopy before and after consuming a standardized meal. Six controls and 6 GERD patients also underwent concurrent manometry. The relative positions of the SCJ, EGJ high pressure zone, and pH transition points were analyzed. RESULTS: Most controls and GERD patients exhibited an unbuffered acidified segment in the proximal stomach postprandially. The proximal pH transition point was confined distal to the SCJ in control subjects, regardless of posture or meal state. GERD patients exhibited a more proximal pH transition point, extending above the SCJ and EGJ high pressure zone in the supine position, especially postprandially. However, the high-pressure zone was intact. CONCLUSION: A short segment of unbuffered acidity of unknown volume exists after meals in the proximal stomach. In controls, the unbuffered acidic segment is contained distal to the SCJ while in the GERD patients it extended into and even across the EGJ high-pressure zone. However, this extension through the EGJ in GERD patients occurred in the context of an intact sphincter suggesting that this is best conceptualized as an acid "film" rather than a "pocket." This observation may help explain the propensity of the distal esophageal mucosa to lesions of reflux disease. PMID- 17714552 TI - A novel antagonist of CRTH2 blocks eosinophil release from bone marrow, chemotaxis and respiratory burst. AB - BACKGROUND: Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) has been revealed to be a novel receptor for prostaglandin (PG) D(2), which is a major mast cell product released during the allergic response. The aim of this study was to analyze the effects of a newly developed small molecule antagonist of CRTH2, Cay10471, on eosinophil function with respect to recruitment, respiratory burst and degranulation. METHODS: Chemotaxis of guinea pig bone marrow eosinophils and human peripheral blood eosinophils were determined using microBoyden chambers. Eosinophil release from bone marrow was investigated in the in situ perfused guinea pig hind limb preparation. Respiratory burst and degranulation were measured by flow cytometry. RESULTS: Cay10471 bound with high affinity to recombinant human and guinea pig CRTH2, but not DP, receptors. The antagonist prevented the PGD(2)-induced release of eosinophils from guinea pig bone marrow, and inhibited the chemotaxis of guinea pig bone marrow eosinophils and human peripheral blood eosinophils. Pretreatment with PGD(2) primed eosinophils for chemotaxis towards eotaxin, and this effect was prevented by Cay10471. In contrast, PGD(2) inhibited the C5a-induced up regulation of CD63, a cellular marker of degranulation, in a Cay10471-sensitive manner. Finally, Cay10471 abolished the respiratory burst of eosinophils upon stimulation by PGD(2). CONCLUSION: These data further emphasize the importance of CRTH2 in eosinophil function and show that Cay10471 is a highly potent and selective antagonist of PGD(2)-induced eosinophil responses. Cay10471 might hence be a useful compound for the treatment of allergic diseases. PMID- 17714554 TI - Strong protective effect of DR3 against ulcerative colitis in the Spanish population. AB - OBJECTIVES: Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colon. Major histocompatibility complex (MHC) on the short arm of human chromosome 6 has been thoroughly studied as a susceptibility locus. However, one of the strongest MHC associations found, that of HLA-DR3 with UC protection, has not been observed in all populations. Our aim in the present study was to evaluate this negative association in a large cohort of Spanish UC patients and controls, and to try to elucidate which, if any, of the diverse DR3 haplotypes (identified by TNFa and b microsatellites, located in the MHC class III region) is most tightly associated (negatively) with the disease. METHODS: A total of 537 UC patients and 748 healthy controls from Spain were included in the present study. Low-resolution DR genotyping was performed by PCR and hybridization with allele-specific oligonucleotide probes. TNFa and b microsatellites were studied in a subset of samples (279 UC patients and 503 healthy controls) by PCR followed by capillary electrophoresis. DR-TNFa-TNFb haplotypes were estimated by the expectation-maximization algorithm and comparisons were performed by a chi2 test. RESULTS: After a stepwise procedure, the only DR alleles significantly associated with the disease were DR3 (very strongly, protection) and DR4 (weakly, protection). The strong protective effect of DR3 was evenly distributed among the haplotypes DR3-TNFa1b5, DR3-TNFa2b3, and DR3-TNFother. CONCLUSIONS: Our results confirm the strong protective effect of DR3 in our population, and suggest that the relevant protective gene is located centromeric to TNFa and TNFb markers in the MHC region. PMID- 17714555 TI - The impact of colon cleanliness assessment on endoscopists' recommendations for follow-up colonoscopy. AB - OBJECTIVE: Repeat colonoscopy is advocated for low-quality preparations. However, there are few data on how endoscopists assess the quality of bowel preparation. We aimed to investigate, in a visually reproducible manner, endoscopists' assessment of colon cleanliness, as reflected by their subsequent recommendations for follow-up. METHODS: Gastroenterologists attending the Israeli Gastroenterology Association meeting were presented with photographs depicting varying degrees of colon cleanliness at a hypothetical screening colonoscopy. Endoscopists were requested to denote their recommendation for the timing of a follow-up procedure for each of the different preparations, both when no polyps were detected and when two small adenomas were found. RESULTS: Seventy-eight gastroenterologists were included. There was considerable interobserver variability in endoscopists' assessment of preparation adequacy, and recommended follow-up timing ranged from more than 5 yr to immediate repeat colonoscopy for identical preparations. Interestingly, even when repeat colonoscopy was not considered necessary, most endoscopists recommended progressively shorter follow up intervals in line with reduced preparation quality (mean interval dropping from 9.2+/-1.7 to 6.3+/-2.8 to 2.5+/-2 yr, P<0.001 for trend). Similar findings were observed when two adenomas were hypothetically found on the index procedure, although follow-up intervals were shorter. No correlation was found between endoscopists' clinical experience or acquaintance with clinical guidelines and their actual recommendation. CONCLUSIONS: Clinical decisions derived from colon cleanliness assessment vary considerably among endoscopists, and there is little agreement on what constitutes a disqualifying preparation. Moreover, when confronted with an intermediate-quality preparation, most gastroenterologists recommend a shorter follow-up interval, rather than repeating the procedure. Further studies are required to validate this management approach and to standardize the assessment of preparation quality. PMID- 17714556 TI - Association between model for end-stage liver disease and spontaneous bacterial peritonitis. AB - OBJECTIVE: To determine whether a greater Model for End-Stage Liver Disease (MELD) score is associated with a greater risk of spontaneous bacterial peritonitis (SBP). METHODS: Our retrospective case-control study enrolled 271 consecutive patients with cirrhosis and ascites who underwent diagnostic paracentesis upon hospital admission (2002-2005). After excluding immunosuppressed patients, those recently exposed to antibiotics, those with a potential confounding etiology for ascites, and those with a prior history of SBP, 111 were included in the study. SBP was defined as a paracentesis yielding>or=250 neutrophils/mL ascites fluid. Multivariable logistic regression was performed to determine the odds ratio for the development of SBP associated with MELD score and grouped MELD score (or=25). Potential confounders assessed included age, diabetes mellitus, gender, race, alcohol use, serum sodium, and etiology of liver disease. RESULTS: Twenty-nine of 111 hospitalized patients with cirrhosis were found to have SBP. Patient characteristics were similar between groups with and without SBP. The mean MELD score for patients with SBP was 24 and for those without 18 (P=0.0003). The odds ratio for developing SBP by each MELD point was 1.11 (1.05-1.19, P=0.001). Patients with MELD>or=25 had an odds ratio of 9.67 (2.35-39.82, P=0.002) for SBP, compared to subjects with MELD/=5 mmHg) in 47% of the recording time. There was a highly significant relationship between the levels of the mean ICP wave amplitude and the levels of glutamate, glycerol and lactate/pyruvate ratio. The levels of metabolites were increased when the mean ICP wave amplitude was >/=5 mmHg as compared with mean ICP wave amplitude levels <5 mmHg. We tentatively suggest that increased mean ICP wave amplitudes indicative of reduced intracranial compliance can be associated with brain ischaemia. PMID- 17714573 TI - Pulse pressure variation as a tool to detect hypovolaemia during pneumoperitoneum. AB - BACKGROUND: Pulse pressure variation (DeltaPP) and systolic pressure variation (SPV) induced by mechanical ventilation have been proposed to detect hypovolaemia and guide fluid therapy. During laparoscopic surgery, chest compliance is decreased by pneumoperitoneum. This may affect the value of SPV and DeltaPP as indicators of intravascular volume status. Thereby, we investigated the effects of pneumoperitoneum and hypovolaemia on SPV and DeltaPP. METHODS: We measured DeltaPP, SPV and the inspiratory (Deltaup) and expiratory (Deltadown) components of SPV, at baseline, during pneumoperitoneum, during pneumoperitoneum and hypovolaemia and after the return to baseline conditions, in 11 mechanically ventilated rabbits. Pneumoperitoneum was induced by inflating the abdomen with carbon dioxide, and hypovolaemia was induced by controlled haemorrhage. RESULTS: Pneumoperitoneum induced an increase in SPV from 8.5 +/- 1.6 to 13.3 +/- 2.6 mmHg (+56%, P < 0.05) as a result of an increase in Deltaup from 2.0 +/- 1.0 to 6.7 +/ 2.1 mmHg (+236%, P < 0.05), but no significant change in Deltadown, nor in DeltaPP. Haemorrhage induced a significant (P < 0.05) increase in SPV from 13.3 +/- 2.6 to 19.9 +/- 3.7 mmHg (+50%), in Deltadown from 6.6 +/- 3.3 to 14.0 +/- 4.9 mmHg (+112%) and in DeltaPP from 11.1 +/- 4.8 to 24.9 +/- 9.8% (+124%) but no change in Deltaup. All parameters returned to baseline values after blood re infusion and abdominal deflation. CONCLUSIONS: SPV is modified by haemorrhage but it is also influenced by pneumoperitoneum. In contrast, DeltaPP is modified by haemorrhage but not by pneumoperitoneum. These findings suggest that DeltaPP should be used preferentially instead of SPV to detect hypovolaemia and guide fluid therapy during laparoscopic surgery. PMID- 17714574 TI - Use of non-invasive-stimulated muscle force assessment in long-term critically ill patients: a future standard in the intensive care unit? AB - BACKGROUND: This study's main purpose was to test the feasibility of employing a non-invasive-stimulated muscle force assessment approach in long-term critically ill patients. METHODS: A case series was performed over a 4-year period in the intensive care unit (ICU). Of the 25 patients initially recruited, eight patients required long-time mechanical ventilation for a median of 3.8 weeks (range 2-10 weeks) and were immobilized for 5 weeks (range 2-10 weeks). With a previously tested non-invasive measuring device, we weekly assessed peak torques and rates of force development and relaxation of patients' ankle dorsiflexor contractile responses, induced via peroneal nerve stimulation. Subsequently, we derived each patient's time course of observed progressive weakness and/or recovery. RESULTS: During their critical illnesses, seven out of eight patients elicited significant decreases in measured peak torques. In survivors (n = 6) during their recovery periods, torques gradually recovered. In the two patients who died, their strengths decreased continuously until death. The rate of force development data elicited similar trends as peak torque responses, whereas relative relaxation rates differed more widely between individuals. CONCLUSION: This approach of non invasive-stimulated muscle force assessment can be used in long-term critically ill patients and may eventually become a standard in the intensive care unit, e.g. for assessing recovery. This method is easy to employ, reproducible, provides important phenotypic quantification of skeletal muscle contractile function, and can be used for long-term outcomes assessment. PMID- 17714575 TI - Limitations of arterial pulse pressure variation and left ventricular stroke volume variation in estimating cardiac pre-load during open heart surgery. AB - BACKGROUND: In addition to their well-known ability to predict fluid responsiveness, functional pre-load parameters, such as the left ventricular stroke volume variation (SVV) and pulse pressure variation (PPV), have been proposed to allow real-time monitoring of cardiac pre-load. SVV and PPV result from complex heart-lung interactions during mechanical ventilation. It was hypothesized that, under open-chest conditions, when cyclic changes in pleural pressures during positive-pressure ventilation are less pronounced, functional pre-load indicators may be deceptive in the estimation of ventricular pre-load. METHODS: Forty-five patients undergoing coronary artery bypass grafting participated in this prospective, observational study. PPV and SVV were assessed by pulse contour analysis. The thermodilution technique was used to measure the stroke volume index and global and right ventricular end-diastolic volume index. Trans-oesophageal echocardiography was used to determine the left ventricular end diastolic area index. All parameters were assessed before and after sternotomy, and, in addition, after weaning from cardiopulmonary bypass before and after chest closure (pericardium left open). Patients were ventilated with constant tidal volumes (8 +/- 2 ml/kg) throughout the study period using pressure control. RESULTS: SVV and PPV decreased after sternotomy and increased after chest closure. However, these changes could not be related to concomitant changes in the ventricular pre-load. The stroke volume index was correlated with SVV and PPV in closed-chest conditions only, whereas volumetric indices reflected cardiac pre load in both closed- and open-chest conditions. SVV and PPV were correlated with left and right ventricular pre-load in closed-chest-closed-pericardium conditions only (with the best correlation found for the right ventricular end-diastolic volume index). CONCLUSIONS: SVV and PPV may be misleading when estimating cardiac pre-load during open heart surgery. PMID- 17714576 TI - The comparative effects of sevoflurane vs. isoflurane on cerebrovascular carbon dioxide reactivity in patients with hypertension. AB - BACKGROUND: Sevoflurane has been shown to have different effects on cerebrovascular CO(2) reactivity in comparison with isoflurane. In this study, the comparative effects of sevoflurane vs. isoflurane on cerebrovascular CO(2) reactivity were examined in patients with hypertension. METHODS: Fifty patients, 30 hypertensive and 20 normotensive, were included in this study. The 30 hypertensive patients were divided into two groups: sevoflurane and isoflurane. Patients with controlled hypertension (n= 9 in each of the two groups) were those with normal blood pressure levels (systolic blood pressure below 139 mmHg). Patients with uncontrolled hypertension (n= 6 in each of the two groups) were those with high blood pressure levels despite medication (systolic blood pressure above 160 mmHg). Anesthesia was maintained with either 1.0 minimum alveolar concentration (MAC) of sevoflurane or 1.0 MAC of isoflurane in 33% oxygen and 67% nitrous oxide. A 2.5-MHz pulsed transcranial Doppler probe was attached to the patient's head at the right temporal window for continuous measurement of the mean blood flow velocity in the middle cerebral artery (V(mca)). After establishing baseline values of V(mca) and cardiovascular hemodynamics, the end tidal CO(2) was increased by decreasing the ventilatory frequency by 2-5 breaths per minute. RESULTS: Values of the absolute and relative CO(2) reactivity in the sevoflurane groups were lower than those in the isoflurane groups. There were no significant intra-group differences in the absolute and relative CO(2) reactivity within the sevoflurane and isoflurane groups. CONCLUSIONS: Our findings suggest that, in hypertensive patients, the control of cerebral blood flow by altering the pressure of arterial CO(2) (P(a)co(2)) can be more effectively achieved during isoflurane rather than sevoflurane anesthesia. PMID- 17714577 TI - The successful use of recombinant factor VIIa in a patient with vascular-type Ehlers-Danlos syndrome. AB - Vascular-type Ehlers-Danlos syndrome is an inherited connective tissue disorder resulting in an increased risk of serious peri-operative bleeding during surgery for spontaneous organ or vessel rupture. The excessive bleeding may result in coagulopathy, and thus compound the difficulty in securing surgical haemostasis. With the advent of recombinant factor VIIa, a new therapy has become available for the management of intractable surgical bleeding. PMID- 17714578 TI - Methylprednisolone and ketorolac rapidly reduce hyperalgesia around a skin burn injury and increase pressure pain thresholds. AB - BACKGROUND: Glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) decrease acute postoperative pain and hyperalgesia. The objectives of this study were to investigate the effects of methylprednisolone and ketorolac on hyperalgesia around a skin burn injury and on pressure pain thresholds. METHODS: In a double-blind, placebo-controlled, randomized trial with cross-over design, methylprednisolone 125 mg, ketorolac 60 mg or placebo was administered intravenously in 12 male volunteers on three separate days at least 4 days apart. Primary and secondary hyperalgesia were produced by a first-degree burn injury on abdominal skin 45 min before injection of the test medicines. The area of secondary mechanical hyperalgesia outside the site of injury was measured. Pressure pain stimuli were applied on the base of a fingernail, increasing until the pressure pain detection threshold (PPDT) and pressure pain tolerance threshold (PPTT) were reached. RESULTS: Compared with placebo, the active drugs reduced the area of secondary hyperalgesia (methylprednisolone, P < 0.001; ketorolac, P < 0.01). Ketorolac but not methylprednisolone increased PPDT compared with placebo (P < 0.05). Both active drugs increased PPTT compared with placebo (methylprednisolone, P < 0.01; ketorolac, P < 0.001). Ketorolac increased PPTT more than methylprednisolone (P < 0.05). CONCLUSIONS: Methylprednisolone and ketorolac increased PPTT attenuated secondary hyperalgesia around a skin burn injury. PPTT increased after both methylprednisolone and ketorolac. The present study demonstrates analgesic and anti-hyperalgesic properties of a glucocorticoid and a non-selective NSAID that have not been demonstrated previously in human subjects. PMID- 17714579 TI - Overtriage in trauma - what are the causes? AB - BACKGROUND: Different criteria are employed to activate trauma teams. Because of a growing concern about overtriage, the objective of this study was to investigate the performance of our trauma team's activation protocol. METHODS: Injured patients with trauma team activation (TTA), admission to an intensive care unit or surgical intermediate care unit with a trauma diagnosis, or trauma related death in the emergency department were investigated retrospectively from 1 January 2004 to 31 December 2005. Different TTA criteria were analysed with respect to sensitivity, positive predictive value (PPV) and overtriage (1 - PPV). RESULTS: Eight hundred and nine patients were included, 185 (23%) of whom had an Injury Severity Score (ISS) of more than 15. The performance of our protocol showed a sensitivity of 87%, PPV of 22% and overtriage of 78%. The mechanism of injury as a TTA criterion had a sensitivity of 14%, PPV of 7% and overtriage of 93%. Physiological/anatomical criteria and interfacility transfer showed higher PPV and less overtriage. Undertriage (no TTA despite ISS > 15) was identified in 23 patients (13%), 18 of whom were hospital transfers. CONCLUSION: A TTA protocol based on physiological, anatomical and interfacility transfer criteria seems to yield a higher precision than, in particular, that based on mechanism of injury criteria. Because of substantial overtriage in our hospital, the TTA protocol needs to be re-evaluated. PMID- 17714580 TI - Mechanism of the ropivacaine-induced increase in intracellular Ca2+ concentration in rat aortic smooth muscle. AB - BACKGROUND: Ropivacaine is a long-acting local anesthetic with low cardiac toxicity that induces vasoconstriction in vitro and in vivo. Vascular smooth muscle tone is regulated by changes in both intracellular Ca(2+) concentration ([Ca(2+)](i)) and myofilament Ca(2+) sensitivity. Therefore, the aim of this study was to examine the mechanism underlying the increase in [Ca(2+)](i) in ropivacaine-induced vascular contraction. METHODS: Ropivacaine-induced contractile responses and changes in [Ca(2+)](i) were examined using an isometric force transducer and a fluorometer, respectively. RESULTS: Ropivacaine induced a biphasic, concentration-dependent change in [Ca(2+)](i) and contractile response in rat aortic smooth muscles: an increase in [Ca(2+)](i) occurred at lower ropivacaine concentrations (3 x 10(-5) to 3 x 10(-4) M) and a decrease was observed at higher concentrations (10(-3) to 3 x 10(-3) M). Contraction and the [Ca(2+)](i) increase induced by ropivacaine were attenuated significantly by a voltage-dependent Ca(2+) channel antagonist, an inositol 1,4,5-triphosphate receptor antagonist and Ca(2+)-free solution (P < 0.01, n = 6). CONCLUSION: Ropivacaine-induced contraction of rat aortic smooth muscle is, in part, regulated by Ca(2+) influx from the extracellular space and Ca(2+) release from the sarcoplasmic reticulum. PMID- 17714581 TI - Low density lipoprotein from patients with Type 2 diabetes increases expression of monocyte matrix metalloproteinase and ADAM metalloproteinase genes. AB - AIMS: Type 2 diabetes is characterised by increased plasma concentrations of pro inflammatory cytokines [such as tumour necrosis factor - alpha; TNF-alpha] and soluble forms of adhesion molecules involved in leukocyte - endothelial interactions. These molecules are synthesised as transmembrane proteins and the plasma soluble forms are generated by ectodomain cleavage from the cell surface by members of the ADAM [adisintegrin and metalloproteinase] proteinase family. We hypothesised that plasma low density lipoprotein [LDL] from subjects with Type 2 diabetes would influence in vitro monocytic ADAM and matrix metalloproteinase [MMP] gene expression differently compared to control LDL. METHODS: We examined relative mRNA expression by real time PCR in a monocytic cell line [THP-1] cultured for 4, 8 and 24 hrs with human plasma LDL derived from subjects with [n = 5] or without [n = 4] Type 2 diabetes. Gene expression for MMP-1 and 9, and ADAM - 8, 15, 17 and 28 was studied. RESULTS: Type 2 diabetes LDL significantly increased gene expression of MMP - 1 [p < 0.01] MMP - 9 [p < 0.001], and ADAM 17 [p < 0.05], - 28 [p < 0.01] and - 15 [p < 0.01] compared to control LDL. Type 2 diabetes LDL had disparate effects on inhibitors of MMP. CONCLUSION: These data suggest that Type 2 diabetes LDL could lead to increased adhesion molecule and TNF alpha cell surface shedding, and vascular plaque instability, by promoting increased expression of ADAM and MMP genes. PMID- 17714582 TI - Complete DNA sequences of the plastid genomes of two parasitic flowering plant species, Cuscuta reflexa and Cuscuta gronovii. AB - BACKGROUND: The holoparasitic plant genus Cuscuta comprises species with photosynthetic capacity and functional chloroplasts as well as achlorophyllous and intermediate forms with restricted photosynthetic activity and degenerated chloroplasts. Previous data indicated significant differences with respect to the plastid genome coding capacity in different Cuscuta species that could correlate with their photosynthetic activity. In order to shed light on the molecular changes accompanying the parasitic lifestyle, we sequenced the plastid chromosomes of the two species Cuscuta reflexa and Cuscuta gronovii. Both species are capable of performing photosynthesis, albeit with varying efficiencies. Together with the plastid genome of Epifagus virginiana, an achlorophyllous parasitic plant whose plastid genome has been sequenced, these species represent a series of progression towards total dependency on the host plant, ranging from reduced levels of photosynthesis in C. reflexa to a restricted photosynthetic activity and degenerated chloroplasts in C. gronovii to an achlorophyllous state in E. virginiana. RESULTS: The newly sequenced plastid genomes of C. reflexa and C. gronovii reveal that the chromosome structures are generally very similar to that of non-parasitic plants, although a number of species-specific insertions, deletions (indels) and sequence inversions were identified. However, we observed a gradual adaptation of the plastid genome to the different degrees of parasitism. The changes are particularly evident in C. gronovii and include (a) the parallel losses of genes for the subunits of the plastid-encoded RNA polymerase and the corresponding promoters from the plastid genome, (b) the first documented loss of the gene for a putative splicing factor, MatK, from the plastid genome and (c) a significant reduction of RNA editing. CONCLUSION: Overall, the comparative genomic analysis of plastid DNA from parasitic plants indicates a bias towards a simplification of the plastid gene expression machinery as a consequence of an increasing dependency on the host plant. A tentative assignment of the successive events in the adaptation of the plastid genomes to parasitism can be inferred from the current data set. This includes (1) a loss of non-coding regions in photosynthetic Cuscuta species that has resulted in a condensation of the plastid genome, (2) the simplification of plastid gene expression in species with largely impaired photosynthetic capacity and (3) the deletion of a significant part of the genetic information, including the information for the photosynthetic apparatus, in non-photosynthetic parasitic plants. PMID- 17714583 TI - Convergent algorithms for protein structural alignment. AB - BACKGROUND: Many algorithms exist for protein structural alignment, based on internal protein coordinates or on explicit superposition of the structures. These methods are usually successful for detecting structural similarities. However, current practical methods are seldom supported by convergence theories. In particular, although the goal of each algorithm is to maximize some scoring function, there is no practical method that theoretically guarantees score maximization. A practical algorithm with solid convergence properties would be useful for the refinement of protein folding maps, and for the development of new scores designed to be correlated with functional similarity. RESULTS: In this work, the maximization of scoring functions in protein alignment is interpreted as a Low Order Value Optimization (LOVO) problem. The new interpretation provides a framework for the development of algorithms based on well established methods of continuous optimization. The resulting algorithms are convergent and increase the scoring functions at every iteration. The solutions obtained are critical points of the scoring functions. Two algorithms are introduced: One is based on the maximization of the scoring function with Dynamic Programming followed by the continuous maximization of the same score, with respect to the protein position, using a smooth Newtonian method. The second algorithm replaces the Dynamic Programming step by a fast procedure for computing the correspondence between C alpha atoms. The algorithms are shown to be very effective for the maximization of the STRUCTAL score. CONCLUSION: The interpretation of protein alignment as a LOVO problem provides a new theoretical framework for the development of convergent protein alignment algorithms. These algorithms are shown to be very reliable for the maximization of the STRUCTAL score, and other distance-dependent scores may be optimized with same strategy. The improved score optimization provided by these algorithms provide means for the refinement of protein fold maps and also for the development of scores designed to match biological function. The LOVO strategy may be also used for more general structural superposition problems such as flexible or non-sequential alignments. The package is available on-line at http://www.ime.unicamp.br/~martinez/lovoalign. PMID- 17714584 TI - Improve protective efficacy of a TB DNA-HSP65 vaccine by BCG priming. AB - Vaccines are considered by many to be one of the most successful medical interventions against infectious diseases. But many significant obstacles remain, such as optimizing DNA vaccines for use in humans or large animals. The amount of doses, route and easiness of administration are also important points to consider in the design of new DNA vaccines. Heterologous prime-boost regimens probably represent the best hope for an improved DNA vaccine strategy. In this study, we have shown that heterologous prime-boost vaccination against tuberculosis (TB) using intranasal BCG priming/DNA-HSP65 boosting (BCGin/DNA) provided significantly greater protection than that afforded by a single subcutaneous or intranasal dose of BCG. In addition, BCGin/DNA immunization was also more efficient in controlling bacterial loads than were the other prime-boost schedules evaluated or three doses of DNA-HSP65 as a naked DNA. The single dose of DNA-HSP65 booster enhanced the immunogenicity of a single subcutaneous BCG vaccination, as evidenced by the significantly higher serum levels of anti-Hsp65 IgG2a Th1-induced antibodies, as well as by the significantly greater production of IFN-gamma by antigen-specific spleen cells. The BCG prime/DNA-HSP65 booster was also associated with better preservation of lung parenchyma. The improvement of the protective effect of BCG vaccine mediated by a DNA-HSP65 booster suggests that our strategy may hold promise as a safe and effective vaccine against TB. PMID- 17714585 TI - Vena cava inferior thrombosis detected by venous hum: a case report. AB - We describe a patient in which a venous hum, heard during abdominal auscultation, lead to the diagnosis of a vena cava inferior thrombosis. PMID- 17714586 TI - Dentin dysplasia type I: a challenge for treatment with dental implants. AB - BACKGROUND: Dentin dysplasia type I is characterized by a defect of dentin development with clinical normal appearance of the permanent teeth but no or only rudimentary root formation. Early loss of all teeth and concomitant underdevelopment of the jaws are challenging for successful treatment with dental implants. METHODS: A combination of sinus lifting and onlay bone augmentation based on treatment planning using stereolithographic templates was used in a patient with dentin dysplasia type I to rehabilitate the masticatory function. RESULTS: (i) a predisposition for an increased and accelerated bone resorption was observed in our patient, (ii) bone augmentation was successful using a mixture of allogenic graft material with autogenous bone preventing fast bone resorption, (iii) surgical planning, based on stereolithographic models and surgical templates, facilitated the accurate placement of dental implants. CONCLUSION: Bony augmentation and elaborate treatment planning is helpful for oral rehabilitation of patients with dentin dysplasia type I. PMID- 17714587 TI - Early activation of quorum sensing in Pseudomonas aeruginosa reveals the architecture of a complex regulon. AB - BACKGROUND: Quorum-sensing regulation of gene expression in Pseudomonas aeruginosa is complex. Two interconnected acyl-homoserine lactone (acyl-HSL) signal-receptor pairs, 3-oxo-dodecanoyl-HSL-LasR and butanoyl-HSL-RhlR, regulate more than 300 genes. The induction of most of the genes is delayed during growth of P. aeruginosa in complex medium, cannot be advanced by addition of exogenous signal, and requires additional regulatory components. Many of these late genes can be induced by addition of signals early by using specific media conditions. While several factors super-regulate the quorum receptors, others may co-regulate target promoters or may affect expression posttranscriptionally. RESULTS: To better understand the contributions of super-regulation and co-regulation to quorum-sensing gene expression, and to better understand the general structure of the quorum sensing network, we ectopically expressed the two receptors (in the presence of their cognate signals) and another component that affects quorum sensing, the stationary phase sigma factor RpoS, early in growth. We determined the effect on target gene expression by microarray and real-time PCR analysis. Our results show that many target genes (e.g. lasB and hcnABC) are directly responsive to receptor protein levels. Most genes (e.g. lasA, lecA, and phnAB), however, are not significantly affected, although at least some of these genes are directly regulated by quorum sensing. The majority of promoters advanced by RhlR appeared to be regulated directly, which allowed us to build a RhlR consensus sequence. CONCLUSION: The direct responsiveness of many quorum sensing target genes to receptor protein levels early in growth confirms the role of super-regulation in quorum sensing gene expression. The observation that the induction of most target genes is not affected by signal or receptor protein levels indicates that either target promoters are co-regulated by other transcription factors, or that expression is controlled posttranscriptionally. This architecture permits the integration of multiple signaling pathways resulting in quorum responses that require a "quorum" but are otherwise highly adaptable and receptive to environmental conditions. PMID- 17714588 TI - A rapid genome-wide response to Drosophila melanogaster social interactions. AB - BACKGROUND: The actions and reactions integral to mate recognition and reproduction are examples of multifaceted behaviors for which we are only beginning to comprehend the underlying genetic and molecular complexity. I hypothesized that social interactions, such as those involved in reproductive behaviors, would lead to immediate and assayable changes in gene expression. Such changes may have important effects on individual reproductive success and fitness through alterations in physiology or via short-term or long-term changes in nervous system function. RESULTS: I used Affymetrix Drosophila Genome arrays to identify genes whose expression profiles would change rapidly due to the social interactions occurring during Drosophila melanogaster courtship. I identified 43 loci with significant expression profile changes during a 5-min exposure period. These results indicate that social interactions can lead to extremely rapid changes in mRNA abundance. CONCLUSION: The known functions of the up-regulated genes identified in this study include nervous system signaling and spermatogenesis, while the majority of down-regulated loci are implicated in immune signaling. Expression of two of the up-regulated genes, Odorant-binding protein 99b (Obp99b) and female-specific independent of transformer (fit), is controlled by the Drosophila sex-determination gene hierarchy, which regulates male and female mating behaviors and somatic differentiation. Therefore, additional identified loci may represent other long-elusive targets of Drosophila sex-determination genes. PMID- 17714590 TI - Children's unique experience of depression: using a developmental approach to predict variation in symptomatology. AB - BACKGROUND: Current clinical knowledge suggests that children can have different types of depressive symptoms (irritability and aggression), but presents no theoretical basis for these differences. Using a developmental approach, the present study sought to test the relationship between developmental level (mental age) and expression of depressive symptoms. The primary hypothesis was that as children's mental age increased, so would the number of internalizing symptoms present. METHODS: Participants were 252 psychiatric inpatients aged 4 to 16 with a diagnosed depressive disorder. All children were diagnosed by trained clinicians using DSM criteria. Patients were predominantly male (61%) with varied ethnic backgrounds (Caucasian 54%; African American 22%; Hispanic 19%; Other 5%). Children were given an IQ test (KBIT or WISC) while within the hospital. Mental age was calculated by using the child's IQ score and chronological age. Four trained raters reviewed children's records for depressive symptoms as defined by the DSM-IV TR. Additionally, a ratio score was calculated to indicate the number of internalizing symptoms to total symptoms. RESULTS: Mental age positively correlated (r = .51) with an internalizing total symptom ratio score and delineated between several individual symptoms. Mental age also predicted comorbidity with anxiety and conduct disorders. Children of a low mental age were more likely to be comorbid with conduct disorders, whereas children with a higher mental age presented more often with anxiety disorders. Gender was independently related to depressive symptoms, but minority status interacted with mental age. CONCLUSION: The results of this study indicate that a developmental approach is useful in understanding children's depressive symptoms and has implications for both diagnosis and treatment of depression. If children experience depression differently, it follows that treatment options may also differ from that which is effective in adults. PMID- 17714589 TI - p21 is decreased in polycystic kidney disease and leads to increased epithelial cell cycle progression: roscovitine augments p21 levels. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease with few treatment options other than renal replacement therapy. p21, a cyclin kinase inhibitor which has pleiotropic effects on the cell cycle, in many cases acts to suppress cell cycle progression and to prevent apoptosis. Because defects in cell cycle arrest and apoptosis of renal tubular epithelial cells occur in PKD, and in light of earlier reports that polycystin-1 upregulates p21 and that the cyclin-dependent kinase inhibitor roscovitine arrests progression in a mouse model, we asked whether (1) p21 deficiency might underlie ADPKD and (2) the mechanism of the salutary roscovitine effect on PKD involves p21. METHODS: p21 levels in human and animal tissue samples as well as cell lines were examined by immunoblotting and/or immunohistochemisty. Apoptosis was assessed by PARP cleavage. p21 expression was attenuated in a renal tubular epithelial cell line by antisense methods, and proliferation in response to p21 attenuation and to roscovitine was assessed by the MTT assay. RESULTS: We show that p21 is decreased in human as well as a non-transgenic rat model of ADPKD. In addition, hepatocyte growth factor, which induces transition from a cystic to a tubular phenotype, increases p21 levels. Furthermore, attenuation of p21 results in augmentation of cell cycle transit in vitro. Thus, levels of p21 are inversely correlated with renal tubular epithelial cell proliferation. Roscovitine, which has been shown to arrest progression in a murine model of PKD, increases p21 levels and decreases renal tubular epithelial cell proliferation, with no affect on apoptosis. CONCLUSION: The novelty of our study is the demonstration in vivo in humans and rat models of a decrement of p21 in cystic kidneys as compared to non-cystic kidneys. Validation of a potential pathogenetic model of increased cyst formation due to enhanced epithelial proliferation and apoptosis mediated by p21 suggests a mechanism for the salutary effect of roscovitine in ADPKD and supports further investigation of p21 as a target for future therapy. PMID- 17714591 TI - Improvement of chronic facial pain and facial dyskinesia with the help of botulinum toxin application. AB - BACKGROUND: Facial pain syndromes can be very heterogeneous and need individual diagnosis and treatment. This report describes an interesting case of facial pain associated with eczema and an isolated dyskinesia of the lower facial muscles following dental surgery. Different aspects of the pain, spasms and the eczema will be discussed. CASE PRESENTATION: In this patient, persistent intense pain arose in the lower part of her face following a dental operation. The patient also exhibited dyskinesia of her caudal mimic musculature that was triggered by specific movements. Several attempts at therapy had been unsuccessful. We performed local injections of botulinum toxin type A (BTX-A) into the affected region of the patient's face. Pain relief was immediate following each set of botulinum toxin injections. The follow up time amounts 62 weeks. CONCLUSION: Botulinum toxin type A (BTX-A) can be a safe and effective therapy for certain forms of facial pain syndromes. PMID- 17714593 TI - A new implicit review instrument for measuring quality of care delivered to pediatric patients in the emergency department. AB - BACKGROUND: There are few outcomes experienced by children receiving care in the Emergency Department (ED) that are amenable to measuring for the purposes of assessing of quality of care. The purpose of this study was to develop, test, and validate a new implicit review instrument that measures quality of care delivered to children in EDs. METHODS: We developed a 7-point structured implicit review instrument that encompasses four aspects of care, including the physician's initial data gathering, integration of information and development of appropriate diagnoses; initial treatment plan and orders; and plan for disposition and follow up. Two pediatric emergency medicine physicians applied the 5-item instrument to children presenting in the highest triage category to four rural EDs, and we assessed the reliability of the average summary scores (possible range of 5-35) across the two reviewers using standard measures. We also validated the instrument by comparing this mean summary score between those with and without medication errors (ascertained independently by two pharmacists) using a two sample t-test. RESULTS: We reviewed the medical records of 178 pediatric patients for the study. The mean and median summary score for this cohort of patients were 27.4 and 28.5, respectively. Internal consistency was high (Cronbach's alpha of 0.92 and 0.89). All items showed a significant (p < 0.005) positive correlation between reviewers using the Spearman rank correlation (range 0.24 to 0.39). Exact agreement on individual items between reviewers ranged from 70.2% to 85.4%. The Intra-class Correlation Coefficient for the mean of the total summary score across the two reviewers was 0.65. The validity of the instrument was supported by the finding of a higher score for children without medication errors compared to those with medication errors which trended toward significance (mean score = 28.5 vs. 26.0, p = 0.076). CONCLUSION: The instrument we developed to measure quality of care provided to children in the ED has high internal consistency, fair to good inter-rater reliability and inter-rater correlation, and high content validity. The validity of the instrument is supported by the fact that the instrument's average summary score was lower in the presence of medication errors, which trended towards statistical significance. PMID- 17714592 TI - Multilocus dataset reveals demographic histories of two peat mosses in Europe. AB - BACKGROUND: Revealing the past and present demographic history of populations is of high importance to evaluate the conservation status of species. Demographic data can be obtained by direct monitoring or by analysing data of historical and recent collections. Although these methods provide the most detailed information they are very time consuming. Another alternative way is to make use of the information accumulated in the species' DNA over its history. Recent development of the coalescent theory makes it possible to reconstruct the demographic history of species using nucleotide polymorphism data. To separate the effect of natural selection and demography, multilocus analysis is needed because these two forces can produce similar patterns of polymorphisms. In this study we investigated the amount and pattern of sequence variability of a Europe wide sample set of two peat moss species (Sphagnum fimbriatum and S. squarrosum) with similar distributions and mating systems but presumably contrasting historical demographies using 3 regions of the nuclear genome (appr. 3000 bps). We aimed to draw inferences concerning demographic, and phylogeographic histories of the species. RESULTS: All three nuclear regions supported the presence of an Atlantic and Non-Atlantic clade of S. fimbriatum suggesting glacial survival of the species along the Atlantic coast of Europe. Contrarily, S. squarrosum haplotypes showed three clades but no geographic structure at all. Maximum likelihood, mismatch and Bayesian analyses supported a severe historical bottleneck and a relatively recent demographic expansion of the Non-Atlantic clade of S. fimbriatum, whereas size of S. squarrosum populations has probably decreased in the past. Species wide molecular diversity of the two species was nearly the same with an excess of replacement mutations in S. fimbriatum. Similar levels of molecular diversity, contrasting phylogeographic patterns and excess of replacement mutations in S. fimbriatum compared to S. squarrosum mirror unexpected differences in the demography and population history of the species. CONCLUSION: This study represents the first detailed European wide phylodemographic investigation on bryophytes and shows how pattern of nucleotide polymorphism can reveal unexpected differences in the population history of haploid plants with seemingly similar characteristics. PMID- 17714594 TI - Involvement of Akt and endothelial nitric oxide synthase in ventilation-induced neutrophil infiltration: a prospective, controlled animal experiment. AB - INTRODUCTION: Positive pressure ventilation with large tidal volumes has been shown to cause release of cytokines, including macrophage inflammatory protein-2 (MIP-2), a functional equivalent of human IL-8, and neutrophil infiltration. Hyperoxia has been shown to increase ventilator-induced lung injury, but the mechanisms regulating interaction between a large tidal volume and hyperoxia are unclear. We hypothesized that large tidal volume ventilation using hyperoxia would increase MIP-2 production and neutrophil infiltration via the serine/threonine kinase/protein kinase B (Akt) pathway and the endothelial nitric oxide synthase (eNOS) pathway. METHODS: C57BL/6 mice were exposed to large tidal volume (30 ml/kg) mechanical ventilation with room air or hyperoxia for 1-5 hours. RESULTS: Large tidal volume ventilation using hyperoxia induced neutrophil migration into the lung, MIP-2 production, and Akt and eNOS activation in a time dependent manner. Both the large tidal volume ventilation of Akt mutant mice and the pharmacological inhibition of Akt with LY294002 attenuated neutrophil sequestration, MIP-2 protein production, and Akt and eNOS activation. CONCLUSION: We conclude that hyperoxia increased large tidal volume-induced MIP-2 production and neutrophil influx through activation of the Akt and eNOS pathways. PMID- 17714595 TI - Western Australian Food Security Project. AB - BACKGROUND: The aim of the Western Australian (WA) Food Security Project was to conduct a preliminary investigation into issues relating to food security in one region within the Perth metropolitan area in Western Australia. The first phase of the project involved a food audit in one lower income area that was typical of the region, to identify the range, variety and availability of foods in the region. METHODS: A comprehensive food audit survey was provided to all food outlet owners/operators in one lower socio-economic region within the City of Mandurah (n = 132 outlets). The purpose of the survey was to investigate the range, variety and availability of foods in the Mandurah region as well as examining specific in-store characteristics such as the types of clientele and in store promotions offered. Surveys were competed for 99 outlets (response rate = 75%). RESULTS: The range of foods available were predominantly pre-prepared with more than half of the outlets pre-preparing the majority of their food. Sandwiches and rolls were the most popular items sold in the outlets surveyed (n = 51 outlets) followed by pastries such as pies, sausage rolls and pasties (n = 33 outlets). Outlets considered their healthiest food options were sandwiches or rolls (n = 51 outlets), salads (n- = 50 outlets), fruit and vegetables (n = 40 outlets), seafood (n = 27 outlets), meats such as chicken (n = 26 outlets and hot foods such as curries, soups or quiches (n = 23 outlets). The majority of outlets surveyed considered pre-prepared food including sandwiches, rolls and salads, as healthy food options regardless of the content of the filling or dressings used. Few outlets (n = 28%) offered a choice of bread type other than white or wholemeal. High fat pastries and dressings were popular client choices (n = 77%) as were carbonated drinks (n = 88%) and flavoured milks (n = 46%). CONCLUSION: These findings clearly indicate the need for further investigation of the impact of access to quality, healthy foods at reasonable cost (food security) on public health, particularly in lower socio-economic areas. PMID- 17714596 TI - Site-directed in vitro immunization leads to a complete human monoclonal IgG4 lambda that binds specifically to the CDR2 region of CTLA-4 (CD152) without interfering the engagement of natural ligands. AB - BACKGROUND: The ability to acquire fully human monoclonal antibodies (mAbs) with pre-defined specificities is critical to the development of molecular tags for the analysis of receptor function in addition to promising immunotherapeutics. Yet most of the arriving affinity maturated and complete human immunoglobulin G (IgG) molecules, which are actually derived from single human B cells, have not widely been used to study the conserved self antigens (Ags) such as CD152 (cytotoxic T lymphocyte antigen-4, CTLA-4) because proper hosts are lacking. RESULTS: Here we developed an optimized protocol for site-directed in vitro immunizing peripheral blood mononuclear cells (PBMC) by using a selected epitope of human CD152, an essential receptor involved in down-regulation of T cell activation. The resultant stable trioma cell lines constantly produce anti-CD152 mAb (gamma4lambdahuCD152), which contains variable (V) regions of the heavy chain and the light chain derived from the VH3 and V lambda human germline genes, respectively, and yet displays an unusual IgG4 isotype. Interestingly, gamma4lambdahuCD152 has a basic pI not commonly found in myeloid monoclonal IgG4 lambdas as revealed by the isoelectric focusing (IEF) analysis. Furthermore, gamma4lambdahuCD152 binds specifically, with nanomolar affinity, to an extracellular constituency encompassing the putative second complementarity determining region (CDR2) of CD152, whereby it can react to activated CD3+ cells. CONCLUSION: In a context of specific cell depletion and conditioned medium,in vitro induction of human Abs against a conserved self Ag was successfully acquired and a relatively basic mAb, gamma4lambdahuCD152, with high affinity to CDR2 of CD152 was thus obtained. Application of such a human IgG4 lambda mAb with designated CDR2 specificity may impact upon and prefer for CD152 labeling both in situ and ex situ, as it does not affect the binding of endogenous B7 ligands and can localize into the confined immunological synapse which may otherwise prevent the access of whole IgG1 molecules. PMID- 17714597 TI - A predictive Bayesian approach to risk analysis in health care. AB - BACKGROUND: The Bayesian approach is now widely recognised as a proper framework for analysing risk in health care. However, the traditional text-book Bayesian approach is in many cases difficult to implement, as it is based on abstract concepts and modelling. METHODS: The essential points of the risk analyses conducted according to the predictive Bayesian approach are identification of observable quantities, prediction and uncertainty assessments of these quantities, using all the relevant information. The risk analysis summarizes the knowledge and lack of knowledge concerning critical operations and other activities, and give in this way a basis for making rational decisions. RESULTS: It is shown that Bayesian risk analysis can be significantly simplified and made more accessible compared to the traditional text-book Bayesian approach by focusing on predictions of observable quantities and performing uncertainty assessments of these quantities using subjective probabilities. CONCLUSION: The predictive Bayesian approach provides a framework for ensuring quality of risk analysis. The approach acknowledges that risk cannot be adequately described and evaluated simply by reference to summarising probabilities. Risk is defined by the combination of possible consequences and associated uncertainties. PMID- 17714598 TI - Parameter and model uncertainty in a life-table model for fine particles (PM2.5): a statistical modeling study. AB - BACKGROUND: The estimation of health impacts involves often uncertain input variables and assumptions which have to be incorporated into the model structure. These uncertainties may have significant effects on the results obtained with model, and, thus, on decision making. Fine particles (PM2.5) are believed to cause major health impacts, and, consequently, uncertainties in their health impact assessment have clear relevance to policy-making. We studied the effects of various uncertain input variables by building a life-table model for fine particles. METHODS: Life-expectancy of the Helsinki metropolitan area population and the change in life-expectancy due to fine particle exposures were predicted using a life-table model. A number of parameter and model uncertainties were estimated. Sensitivity analysis for input variables was performed by calculating rank-order correlations between input and output variables. The studied model uncertainties were (i) plausibility of mortality outcomes and (ii) lag, and parameter uncertainties (iii) exposure-response coefficients for different mortality outcomes, and (iv) exposure estimates for different age groups. The monetary value of the years-of-life-lost and the relative importance of the uncertainties related to monetary valuation were predicted to compare the relative importance of the monetary valuation on the health effect uncertainties. RESULTS: The magnitude of the health effects costs depended mostly on discount rate, exposure-response coefficient, and plausibility of the cardiopulmonary mortality. Other mortality outcomes (lung cancer, other non-accidental and infant mortality) and lag had only minor impact on the output. The results highlight the importance of the uncertainties associated with cardiopulmonary mortality in the fine particle impact assessment when compared with other uncertainties. CONCLUSION: When estimating life-expectancy, the estimates used for cardiopulmonary exposure-response coefficient, discount rate, and plausibility require careful assessment, while complicated lag estimates can be omitted without this having any major effect on the results. PMID- 17714599 TI - GntR family of regulators in Mycobacterium smegmatis: a sequence and structure based characterization. AB - BACKGROUND: Mycobacterium smegmatis is fast growing non-pathogenic mycobacteria. This organism has been widely used as a model organism to study the biology of other virulent and extremely slow growing species like Mycobacterium tuberculosis. Based on the homology of the N-terminal DNA binding domain, the recently sequenced genome of M. smegmatis has been shown to possess several putative GntR regulators. A striking characteristic feature of this family of regulators is that they possess a conserved N-terminal DNA binding domain and a diverse C-terminal domain involved in the effector binding and/or oligomerization. Since the physiological role of these regulators is critically dependent upon effector binding and operator sites, we have analysed and classified these regulators into their specific subfamilies and identified their potential binding sites. RESULTS: The sequence analysis of M. smegmatis putative GntRs has revealed that FadR, HutC, MocR and the YtrA-like regulators are encoded by 45, 8, 8 and 1 genes respectively. Further out of 45 FadR-like regulators, 19 were classified into the FadR group and 26 into the VanR group. All these proteins showed similar secondary structural elements specific to their respective subfamilies except MSMEG_3959, which showed additional secondary structural elements. Using the reciprocal BLAST searches, we further identified the orthologs of these regulators in Bacillus subtilis and other mycobacteria. Since the expression of many regulators is auto-regulatory, we have identified potential operator sites for a number of these GntR regulators by analyzing the upstream sequences. CONCLUSION: This study helps in extending the annotation of M. smegmatis GntR proteins. It identifies the GntR regulators of M. smegmatis that could serve as a model for studying orthologous regulators from virulent as well as other saprophytic mycobacteria. This study also sheds some light on the nucleotide preferences in the target-motifs of GntRs thus providing important leads for initiating the experimental characterization of these proteins, construction of the gene regulatory network for these regulators and an understanding of the influence of these proteins on the physiology of the mycobacteria. PMID- 17714600 TI - The epidemiology of melioidosis in the Balimo region of Papua New Guinea. AB - The distribution of Burkholderia pseudomallei was determined in soil collected from a rural district in Papua New Guinea (PNG) where melioidosis had recently been described, predominately affecting children. In 274 samples, 2.6% tested culture-positive for B. pseudomallei. Pulsed-field gel electrophoresis using SpeI digests and rapid polymorphic DNA PCR with five primers demonstrated a single clone amongst clinical isolates and isolates cultured from the environment that was commonly used by children from whom the clinical isolates were derived. We concluded that individuals in this region most probably acquired the organism through close contact with the environment at these sites. Burkholderia thailandensis, a closely related Burkholderia sp. was isolated from 5.5% of samples tested, an observation similar to that of melioidosis-endemic areas in Thailand. This is the first report of an environmental reservoir for melioidosis in PNG and confirms the Balimo district in PNG as melioidosis endemic. PMID- 17714601 TI - Proteins of the malaria parasite sexual stages: expression, function and potential for transmission blocking strategies. AB - The sexual phase of the malaria pathogen, Plasmodium falciparum, culminates in fertilization within the midgut of the mosquito and represents a crucial step in the completion of the parasite's life-cycle and transmission of the disease. Two decades ago, the first sexual stage-specific surface proteins were identified, among them Pfs230, Pfs48/45, and Pfs25, which were of scientific interest as candidates for the development of transmission blocking vaccines. A decade later, gene information gained from the sequencing of the P. falciparum genome led to the identification of numerous additional sexual-stage proteins with antigenic properties and novel enzymes that putatively possess regulatory functions during sexual-stage development. This review aims to summarize the sexual-stage proteins identified to date, to compare their stage specificities and expression patterns and to highlight novel regulative mechanisms of sexual differentiation. The prospective candidacy of select sexual-stage proteins as targets for transmission blocking strategies will be discussed. PMID- 17714602 TI - Cloning and characterization of an orphan seven transmembrane receptor from Schistosoma mansoni. AB - A partial cDNA sequence was obtained from the human blood fluke, Schistosoma mansoni using a signal sequence trap approach. The full-length cDNA was cloned and termed Sm-7TM. The corresponding open reading frame had 7 membrane spanning domains and shared identity with a small, novel group of seven transmembrane (7TM) receptors from vertebrates and invertebrates, including the human ee3 receptor - a heptahelical protein implicated in neuronal signalling. Phylogenetic analysis of this novel family showed that the Sm-7TM ORF formed a clade with exclusively invertebrate sequences. Based on topology modelling with ee3, Sm-7TM was predicted to possess an intracellular C-terminal tail, which was expressed as a soluble thioredoxin fusion protein (Sm-7TMC) in Escherichia coli and purified using metal ion-affinity chromatography. A polyclonal antiserum against this domain was used to detect Sm-7TM in detergent-soluble parasite extracts and to immunolocalize the receptor to the tegument of adult S. mansoni. PMID- 17714603 TI - Statistical approach to measure the efficacy of anthelmintic treatment on horse farms. AB - Resistance to anthelmintics in gastrointestinal nematodes of livestock is a serious problem and appropriate methods are required to identify and quantify resistance. However, quantification and assessment of resistance depend on an accurate measure of treatment efficacy, and current methodologies fail to properly address the issue. The fecal egg count reduction test (FECRT) is the practical gold standard for measuring anthelmintic efficacy on farms, but these types of data are fraught with high variability that greatly impacts the accuracy of inference on efficacy. This paper develops a statistical model to measure, assess, and evaluate the efficacy of the anthelmintic treatment on horse farms as determined by FECRT. Novel robust bootstrap methods are developed to analyse the data and are compared to other suggested methods in the literature in terms of Type I error and power. The results demonstrate that the bootstrap methods have an optimal Type I error rate and high power to detect differences between the presumed and true efficacy without the need to know the true distribution of pre treatment egg counts. Finally, data from multiple farms are studied and statistical models developed that take into account between-farm variability. Our analysis establishes that if inter-farm variability is not taken into account, misleading conclusions about resistance can be made. PMID- 17714604 TI - Evaluation of immunoglobulin G4 subclass antibody in a peptide-based enzyme linked immunosorbent assay for the serodiagnosis of human fascioliasis. AB - SUMMARYTo improve the diagnosis of human fascioliasis caused by Fasciola gigantica, we developed a peptide-based enzyme-linked immunosorbent assay (peptide-based ELISA) based on the detection of specific IgG4 subclass antibody. Two identified B-cell epitopes of F. gigantica cathepsin L1 were synthesized as single synthetic peptides, acetyl-DKIDWRESGYVTELKDQGNC-carboxamide (peptide L) and acetyl-DKIDWRESGYVTEVKDQGNC-carboxamide (peptide V), and their diagnostic potential was evaluated. The sera of 25 patients infected with F. gigantica, 212 patients with other parasitic infections, 32 cholangiocarcinoma patients and 57 healthy controls were analysed. The sensitivity, specificity, accuracy, and positive and negative predictive values of this assay were the same with both peptides at 100%, 99.7%, 99.7%, 96.2% and 100%, respectively. These highly sensitive and specific peptide-based ELISAs for the detection of specific IgG4 antibody could be useful for laboratory diagnosis of human fascioliasis in future large-scale surveys throughout Southeast Asia where this disease is prevalent. PMID- 17714605 TI - Biotic and abiotic predictors of tick (Dermacentor variabilis) abundance and engorgement on free-ranging raccoons (Procyon lotor). AB - We examined the relative importance of abiotic and biotic factors on the ability of adult Dermacentor variabilis ticks to attach and engorge with blood across 10 populations of free-ranging raccoons (Procyon lotor). We developed a priori models that represented explicit hypotheses based on the literature and tested the ability of these models to explain non-replete and replete (fully engorged with blood) tick infestation using generalized linear models and Akaike's Information Criterion. Abiotic models that included month and site of collection clearly provided a better fit for non-replete tick abundance data, while biotic models with host age and sex covariates best fit the replete tick data. Abiotic models of non-replete abundance were superior to biotic models because of large seasonal and site fluctuations in non-replete abundance that masked differences due to host characteristics. Conversely, best-fitting models of replete tick abundance included only age and sex and suggest that once a tick has reached a host, host-parasite interactions are the primary determinant of engorgement by female ticks. Host population structure may have a large influence on potential cohort size of ticks by reducing or increasing the total number and proportion that can become engorged and moult or lay eggs. PMID- 17714606 TI - Systematic review of trials of the effect of continued use of oral non-selective NSAIDs on blood pressure and hypertension. AB - OBJECTIVE: To investigate the effects of continued use of non-selective NSAIDs (nsNSAIDs) on blood pressure and hypertension. RESEARCH DESIGN AND METHODS: This was a systematic review of randomized clinical trials of oral nsNSAIDs used for at least a 4-week duration. Searches were conducted of PubMed and the Cochrane Database of Systematic Reviews, using key terms for nsNSAIDs and blood pressure or hypertension, to identify articles published in the English language peer reviewed literature through March 2007. MAIN OUTCOME MEASURES: Change from baseline to end of study in systolic blood pressure (SBP) and diastolic blood pressure (DBP), and the incidence of hypertension. Pooled statistics were computed using fixed and random-effects analyses. RESULTS: Thirty-two articles were included. The mean change (95% confidence interval [CI]) in blood pressure (in mmHg) from baseline to end of study for five trials of ibuprofen was 3.54 (2.70, 4.39) for SBP and 1.16 (0.68, 1.64) for DBP (p < 0.001 for both changes). Results of four trials of indomethacin were similar to those for ibuprofen: 2.90 (-0.28, 6.08) for SBP (p = 0.07) and 1.58 (0.29, 2.87) for DBP (p = 0.02). Mean changes from baseline for two trials of diclofenac were -0.46 (-1.48, 0.56) for SBP (p = 0.38) and -0.56 (-1.19, 0.07) for DBP (p = 0.08) and were similar to those for placebo. Changes from baseline in SBP were positive but not statistically significant for naproxen, sulindac, and nabumetone. Compared with placebo, the risk ratio (95% CI) for hypertension was 2.85 (1.44, 5.65; p = 0.003) in two ibuprofen trials. CONCLUSIONS: Continued use of ibuprofen increases blood pressure and raises the incidence of hypertension. There appears to be heterogeneity in such effects with continued use of other nsNSAIDs but, due to limitations in the data, results for naproxen, sulindac, and nabumetone are inconclusive. PMID- 17714607 TI - Comparison of a step-down dose of once-daily ciclesonide with a continued dose of twice-daily fluticasone propionate in maintaining control of asthma. AB - OBJECTIVE: To compare a step-down approach in well-controlled asthma patients, as recommended by treatment guidelines, from fluticasone propionate 250 microg twice daily (FP250 BID), or equivalent, to ciclesonide 160 microg once daily (CIC160 OD) with continued FP250 BID treatment. RESEARCH DESIGN AND METHODS: Patients with well-controlled asthma prior to study entry were included in two identical, randomized, double-blind, double-dummy, parallel-group studies. After a 2-week run-in period with FP250 BID, patients were randomized to CIC160 OD (n = 58) or FP250 BID (n = 53) for 12 weeks. Primary endpoints were percentage of days with asthma control, asthma symptom-free days, rescue medication-free days and nocturnal awakening-free days. Secondary endpoints included lung function variables, asthma symptom scores, rescue medication use and asthma exacerbations. Safety variables were also recorded. RESULTS: Patients had >or= 97% of days with asthma control, 98% asthma symptom-free days and 100% of days free from rescue medication use and nocturnal awakenings in both treatment groups (median values). There were no significant between-treatment differences for any of the primary or secondary efficacy variables. Overall, 42 treatment-emergent adverse events (TEAEs) were reported in the CIC160 OD group and 49 TEAEs were reported in the FP250 BID group. There were no clinically relevant changes from baseline in the safety variables in either treatment group. CONCLUSIONS: Patients well controlled on FP250 BID, or equivalent, who were stepped down to CIC160 OD, maintained similar asthma control compared with patients who received continued treatment standardized to FP250 BID. PMID- 17714612 TI - A 15-year-old Chinese IUD. PMID- 17714613 TI - Clomiphene citrate: an old favourite lives on. PMID- 17714614 TI - Influenza-attributed hospitalization rates among pregnant women in Canada 1994 2000. AB - BACKGROUND: Although it is recommended that pregnant women at risk for influenza complications receive influenza vaccine, it is not clear if healthy pregnant women are at increased risk for adverse outcomes. We aimed to estimate the rate of hospitalization attributable to influenza for healthy pregnant women and for those with known co-morbidities. METHODS: Hospital admission records of women admitted from 1994 to 2000 with a respiratory condition during pregnancy were extracted from the hospitalization database (Canadian Institute of Health Information). Admissions for childbirth were excluded. Weekly admissions, stratified by the presence of co-morbid conditions, were modelled as a function of viral activity, seasonality, trend, and holiday effects using Poisson regression with proxies for influenza and other viral activity developed previously for similar age-specific models of influenza-attributed hospital admissions. RESULTS: Approximately 300 hospitalizations of pregnant women per year were attributed to influenza, of which 140 were in women with co morbidities. This hospitalization rate corresponds to 150 (95% CI 140-170) hospitalizations per 100,000 pregnant women per year. An estimated 1 in 1000 healthy pregnant women were hospitalized due to influenza per year. Asthma was the most important risk factor, accounting for an estimated 450 (95% CI 300-600) admissions per 100,000 pregnant women. Admission rates in pregnant women were relatively constant across multiple influenza seasons of varying severity among older adults. During the four weeks of peak influenza activity, 60% of respiratory-related admissions of otherwise healthy pregnant women could be attributed to influenza. CONCLUSION: Healthy pregnant Canadian women have consistently higher rates of hospital admission attributable to influenza infection than their non-pregnant peers. The admission rate for healthy pregnant women corresponds to the rate for men and women aged 65 to 69 years, which suggests that this population may benefit from annual influenza immunization. PMID- 17714615 TI - Awareness and use of maternal serum screening among women from the St. John's region of Newfoundland and Labrador. AB - OBJECTIVES: To examine the awareness and use of maternal serum screening (MSS) among women from the St. John's region of Newfoundland and Labrador. METHOD: We surveyed 300 women who had recently given birth. Our main outcomes were whether the woman had heard of MSS (prior to the study) and whether she had MSS during her pregnancy. RESULTS: Among the 200 respondents (response rate 66.7%), 139 (69.5%) had heard of MSS and 53 (26.5%) had MSS (38.1% of those who had heard of it). A larger proportion of women over 35 years (59.0%) had heard of MSS than younger women (31.5%) (P = 0.001). Among those who had heard of MSS, a larger proportion of women who had MSS (96.2%) than those who did not have MSS (72.1%) discussed the test with their physician (P 0.001); 54.9% of the women who discussed MSS with their physicians decided not to have MSS. Most discussions regarding MSS (82.6%) lasted 10 minutes or less; discussion length was not related to use of MSS. CONCLUSION: Almost two thirds of women surveyed were aware of MSS, and roughly one quarter had MSS. These findings confirm that most physicians offer MSS to their patients and suggest that patient preference accounts for the low use of MSS in the province. Understanding why women do not have MSS may lead to strategies to improve screening rates. PMID- 17714616 TI - Prosthetic heart valves and arrhythmias in pregnancy. AB - The majority of women with bioprosthetic valves do not require anticoagulation during pregnancy. In women with mechanical valves, a detailed discussion of the advantages and disadvantages of the three anticoagulant options (warfarin, unfractionated heparin and low molecular weight heparin) is indicated. The majority of women with arrhythmias during pregnancy have a benign increased rate of atrial or ventricular premature beats. Those women who are hemodynamically stable can be reassured and do not usually require treatment. Women with more ominous arrhythmias should be managed in collaboration with a cardiologist, usually using the same agents that would be chosen in the non-pregnant patient, including electrical cardioversion when necessary. This is the fifth and final article in a series reviewing in detail the assessment and management of specific cardiac disorders in pregnancy. PMID- 17714617 TI - Far from home? A pilot study tracking women's journeys to a Canadian abortion clinic. AB - OBJECTIVE: Abortion has been recognized internationally as an essential health service. The geographical distance to an abortion provider is acknowledged as a major barrier to access. This pilot study tracks women's journeys to the Toronto Morgentaler Clinic for abortion services. METHODS: A questionnaire was developed specifically for this study and was administered over a four-month period to women using abortion services at the clinic. Questions asked for demographic information and details of the costs, distances, and women's experiences of their journeys to the clinic. RESULTS: A total of 1022 of 1256 surveys were completed for an overall response rate of 81%. The majority of women in the sample (54%) were 21 to 30 years old, had a partner (55.8%), were employed full time (50.5%), and had an income of less than $30 000 per year (68.2%). Most women had travelled an hour or more to the clinic (73.5%), and the remainder had travelled for less than half an hour. Women reporting incomes of less than 30,000 dollars were more likely than wealthier women to have travelled from 200 km to more than 1000 km (OR 1.74; 95% CI 1.16-2.71). Women who were under the age of 30 were more likely to rate their journey as difficult or very difficult (OR 1.68; 95% CI 0.98-2.88). CONCLUSION: More research is needed to determine how far women must travel for abortion services in Canada and to determine the wider health, political, and legal implications of these journeys. PMID- 17714618 TI - A randomized trial of oral misoprostol in premenopausal women before hysteroscopy. AB - OBJECTIVE: To determine if the use of oral misoprostol in premenopausal women undergoing diagnostic hysteroscopy produces a clinically important difference in pre-procedural cervical dilatation. METHODS: At a tertiary care hospital, premenopausal women undergoing diagnostic hysteroscopy were randomized to receive either 400 microg of misoprostol or a vitamin B6 placebo orally 12 hours before the procedure. Patients were stratified on the basis of parity. The primary outcome was the pre-procedural dilatation of the cervix. Secondary outcomes included the need to further dilate the cervix, the time required to further dilate the cervix, and side effects. RESULTS: Sixty-four women (11 nulliparous and 53 parous) undergoing diagnostic hysteroscopy consented to participate in the study. Thirty-three women received misoprostol and 31 received placebo. Baseline demographics showed no difference in age and parity between the two groups. There were no significant differences in pre-procedural dilatation (5.0 mm vs. 4.7 mm, P = 0.52), need to further dilate the cervix (56.7% vs. 63.0%, P = 0.63), and time required to further dilate the cervix (12.7 seconds vs. 25.7 seconds, P = 0.27). Significantly more women in the misoprostol group experienced menstrual like cramping (24.2% vs. 3.3%, P = 0.03) and vaginal spotting (21.2% vs. 3.3%, P = 0.05). CONCLUSION: In premenopausal women, there is no improvement in pre procedural cervical dilatation with administration of oral misoprostol 12 hours before diagnostic hysteroscopy. Further research is required in both nulliparous and parous premenopausal women to determine whether oral misoprostol improves cervical dilatation and, if so, the ideal dose, route and timing. PMID- 17714619 TI - Epithelial ovarian cancer surgical staging by Ontario gynaecologic surgeons: is there a gap between current practice and the Canadian clinical practice guidelines? AB - OBJECTIVES: By determining, through self-report, Ontario gynaecologic surgeons' practices regarding surgical staging for epithelial ovarian cancer, this study aimed to quantify the gap between current practice and the ideal practice of surgical staging for ovarian cancer, as defined by the corresponding Canadian clinical practice guidelines. METHODS: All 711 active Ontario gynaecologic surgeons identified from the website of the College of Physicians and Surgeons of Ontario were confidentially surveyed by mail, using a structured questionnaire to explore individuals' surgical management of an adnexal mass suspicious for epithelial ovarian cancer, using a clinical case simulation. Specifically, gynaecologic surgeons' adherence to the CPGs was determined by self-report, and various physician characteristics were explored for potential associations with adherence to the CPGs in the clinical case simulation using the Fisher exact test. RESULTS: The survey response rate was 69.8%. Only 44.3% of Ontario gynaecologic surgeons adhered to the CPGs in their responses to the clinical case simulation. Gynaecologic oncologists were more likely than non-oncologists to self-report surgical staging according to the CPGs during the clinical case simulation (P = 0.0004). Adherence was also significantly associated with practice at a university centre (P = 0.013) and practice at a centre with a gynaecologic oncologist (P = 0.001) but was not associated with surgical volume. CONCLUSION: This study has confirmed that a significant gap exists between current practice and the ideal practice of surgical staging for epithelial ovarian cancer in Ontario, as defined by the corresponding Canadian CPGs. Further investigation will explore potential barriers to optimal practice to facilitate the development of a knowledge translation strategy to improve surgical staging for ovarian cancer in Ontario. PMID- 17714620 TI - Assessment of patient satisfaction with postoperative pain management after ambulatory gynaecologic laparoscopy. AB - OBJECTIVE: To determine patient satisfaction with postoperative pain control after ambulatory gynaecologic laparoscopic surgery. METHODS: A prospective cohort study in a major tertiary care centre was performed to assess patient satisfaction with postoperative analgesia on the day of surgery and on postoperative days one and two. Data were collected either by telephone or mail in questionnaire on each postoperative day. Each patient rated her level of satisfaction according to a 5-point scale at the end of each postoperative day as an average for that day. The final outcome was recorded as either satisfied, with all days classified as "very satisfied" or "perfectly satisfied," or unsatisfied, if any single day was rated as "not satisfied at all," "only slightly satisfied," or "somewhat or partly satisfied." RESULTS: Forty-nine patients completed the questionnaire. Surgical procedures included tubal ligation with cautery (20), ovarian cystectomy (5), oophorectomy (2), diagnostic laparoscopy (14), and Burch procedure (8). Sixty percent of patients (30/49) were classified as satisfied with their level of postoperative analgesia. CONCLUSION: Only 60% of patients undergoing gynaecologic laparoscopy as day surgery were satisfied with postoperative pain control. This is suboptimal, particularly in light of the ongoing trend towards more complex procedures being performed as day surgery via minimally invasive techniques. PMID- 17714621 TI - Fetal safety of letrozole and clomiphene citrate for ovulation induction. PMID- 17714622 TI - A tribute to Kieran O'Driscoll (1920-2007). PMID- 17714623 TI - Influenza vaccine programs and pregnancy: new Canadian evidence for immunization. AB - Among healthy pregnant women, excess deaths due to influenza were documented during pandemics, but the impact of influenza on pregnant women in non-pandemic years is not clear. In Canada, influenza immunization is recommended for pregnant women only if they have comorbidities known to place them at increased risk of complications or if they deliver during influenza season, therefore becoming a contact of a high-risk infant. The National Advisory Committee on Immunization has indicated that additional evidence, relevant to healthy pregnant Canadian women, is needed to support a recommendation for influenza immunization for all pregnant women. In this commentary we summarize new Canadian data supporting universal influenza immunization for pregnant women and discuss ways in which the Society of Obstetricians and Gynaecologists of Canada might take a leadership role in making influenza vaccination in pregnancy a priority to decrease influenza morbidity in pregnant Canadian women. PMID- 17714624 TI - A perspective on the role of emerging technologies for the propagation of companion animals, non-domestic and endangered species. AB - Assisted reproductive technologies (ART) have been used successfully in humans, domestic and laboratory species for many years. In contrast, our limited knowledge of basic reproductive physiology has restricted the application of ART in companion animal, non-domestic and endangered species (CANDES). Although there are numerous benefits, and in some cases a necessity, for applying ART for the reproductive and genetic management of CANDES, the challenges encountered with even the most basic procedures have limited the rate of progress. In this foreword we discuss the status of conventional ART, such as artificial insemination and in vitro fertilisation, as well as their benefits and inherent difficulties when applied to CANDES. It is upon these techniques, and ultimately our knowledge of basic reproductive physiology, that the success of emerging technologies, such as those described in this special issue, are dependent for success. PMID- 17714625 TI - Applications and interpretation of computer-assisted sperm analyses and sperm sorting methods in assisted breeding and comparative research. AB - Theoretical and practical knowledge of sperm function is an essential requirement in almost every aspect of modern reproductive technology, if the overarching objective is the eventual production of live offspring. Artificial insemination (AI) techniques depend on the availability of high quality semen, whether fresh, diluted and stored, or frozen. Assessing such semen for quality and the likelihood of fertility is therefore also important, as much time, resources and effort can easily be wasted by using poor samples. Some semen technologies are aimed not at quality assessment, but at attempting to skew the breeding outcomes. Sex preselection by separating the male- and female-bearing spermatozoa using flow cytometry is now practised routinely in the agricultural industry, but speculatively it may eventually be possible to use other genetic markers besides the sex chromosomes. A moment's reflection shows that although sex-biasing flow cytometry technology is well developed and generally fulfils its purpose if presorting of sperm quality is adequate, other technologies aimed specifically at semen assessment are also sophisticated but provide inadequate data that say little about fertility. This is especially true of instrumentation for objective sperm motility assessment. Here we aim to examine this technological paradox and suggest that although the sperm assessment equipment might be sophisticated, the shortcomings probably lie largely with inappropriate objectives and data interpretation. We also aim to review the potential value and use of sperm sexing technology for non-domestic species, arguing in this case that the limitations also lie less with the technology itself than with the applications envisaged. Finally, the potential application of a sorting method directed at motility rather than sperm DNA content is discussed. PMID- 17714627 TI - Germ cell transplantation for the propagation of companion animals, non-domestic and endangered species. AB - The transplantation of spermatogonial stem cells between males results in a recipient animal producing spermatozoa carrying a donor's haplotype. First pioneered in rodents, this technique has now been used in several animal species. Importantly, germ cell transplantation was successful between unrelated, immuno competent large animals, whereas efficient donor-derived spermatogenesis in rodents requires syngeneic or immuno-compromised recipients. Transplantation requires four steps: recipient preparation, donor cell isolation, transplantation and identifying donor-derived spermatozoa. There are two main applications for this technology. First, genetic manipulation of isolated germ line stem cells and subsequent transplantation will result in production of transgenic spermatozoa. Transgenesis through the male germ line has tremendous potential in species in which embryonic stem cells are not available and somatic cell nuclear transfer and reprogramming pose several problems. Second, spermatogonial stem cell transplantation within or between species offers a means of preserving the reproductive potential of genetically valuable individuals. This might have significance in the captive propagation of non-domestic animals of high conservation value. Transplantation of germ cells is a uniquely valuable approach for the study, preservation and manipulation of male fertility in mammalian species. PMID- 17714626 TI - Novel gamete storage. AB - The aim of this review is to outline recent advances in gamete storage that are beneficial for rescuing endangered species or for the breeding of companion animals. Much more information is available on the technical resolutions and practical applications of sperm cryopreservation in various species than of female gametes, reproductive tissues or organs. Mammalian sperm cryopreservation often works relatively efficiently; however, the ability of female gametes to be cryopreserved and still be viable for fertilisation is also essential for rescuing endangered species. For a proper evaluation of gamete cryopreservation possibilities in a given species, it is essential to understand the basic mechanism affecting the survival of cryopreserved cells, the technical and physical limitations, the available techniques and the new avenues to resolve the specific problems in that species. This paper is aimed to provide some help for this process. The limited length of this paper resulted in the omission of information on many important areas, including most data on teleosts, amphibian and insect cryopreservation. PMID- 17714628 TI - Embryonic stem cells in companion animals (horses, dogs and cats): present status and future prospects. AB - Reproductive technologies have made impressive advances since the 1950s owing to the development of new and innovative technologies. Most of these advances were driven largely by commercial opportunities and the potential improvement of farm livestock production and human health. Companion animals live long and healthy lives and the greatest expense for pet owners are services related to veterinary care and healthcare products. The recent development of embryonic stem cell and nuclear transfer technology in primates and mice has enabled the production of individual specific embryonic stem cell lines in a number of species for potential cell-replacement therapy. Stem cell technology is a fast-developing area in companion animals because many of the diseases and musculoskeletal injuries of cats, dogs and horses are similar to those in humans. Nuclear transfer-derived stem cells may also be selected and directed into differentiation pathways leading to the production of specific cell types, tissues and, eventually, even organs for research and transplantaton. Furthermore, investigations into the treatment of inherited or acquired pathologies have been performed mainly in mice. However, mouse models do not always faithfully represent the human disease. Naturally occurring diseases in companion animals can be more ideal as disease models of human genetic and acquired diseases and could help to define the potential therapeutic efficiency and safety of stem cell therapies. In the present review, we focus on the economic implications of companion animals in society, as well as recent biotechnological progress that has been made in horse, dog and cat embryonic stem cell derivation. PMID- 17714629 TI - Cloning in companion animal, non-domestic and endangered species: can the technology become a practical reality? AB - Somatic cell nuclear transfer (SCNT) can provide a unique alternative for the preservation of valuable individuals, breeds and species. However, with the exception of a handful of domestic animal species, successful production of healthy cloned offspring has been challenging. Progress in species that have little commercial or research interest, including many companion animal, non domestic and endangered species (CANDES), has lagged behind. In this review, we discuss the current and future status of SCNT in CANDES and the problems that must be overcome to improve pre- and post-implantation embryo survival in order for this technology to be considered a viable tool for assisted reproduction in these species. PMID- 17714630 TI - Transgenic farm animals: an update. AB - The first transgenic livestock species were reported in 1985. Since then microinjection of foreign DNA into pronuclei of zygotes has been the method of choice. It is now being replaced by more efficient protocols based on somatic nuclear transfer that also permit targeted genetic modifications. Lentiviral vectors and small interfering ribonucleic acid (siRNA) technology are also becoming important tools for transgenesis. In 2006 the European Medicines Agency (EMEA) gave green light for the commercialistion of the first recombinant protein produced in the milk of transgenic animals. Recombinant antithrombin III will be launched as ATryn for prophylactic treatment of patients with congenital antithrombin deficiency. This important milestone will boost the research activities in farm animal transgenesis. Recent developments in transgenic techniques of farm animals are discussed in this review. PMID- 17714631 TI - Ovarian and testicular tissue xenografting: its potential for germline preservation of companion animals, non-domestic and endangered species. AB - In the present paper we aim to review the development of both ovarian and testicular xenografting with specific emphasis on its usage for companion animals, non-domestic and endangered species. Ovarian and testicular tissue xenografting has been used successfully across a variety of species for the harvesting of mature gametes and subsequent fertilisation. It has become a novel and promising tool to explore various aspects of testicular development and function and was useful for determination of gonadotoxic treatments on xenografted gonads. In rodent animal models live births have been reported using gametes from xenografted gonadal tissue. Live births were also reported after grafting of human ovarian tissue. We envisage that it will not be long before the first live births across other species, including companion animals, non-domestic and endangered species, will be achieved. PMID- 17714632 TI - Endovascular repair of thoracic aortic disease: overview of current devices and clinical results. AB - Endovascular repair of thoracic aortic aneurysm has become an important treatment modality in patients who are at increased risk for open surgical repair. Since the US Food and Drug Administration (FDA) approved the clinical application of this technology in the thoracic aorta in 2005, there has been a rapid growth in this treatment modality as numerous endovascular devices have been introduced in the application of thoracic aortic pathology. Although thoracic aortic aneurysm is the only FDA-approved treatment indication for endovascular repair, this technology may lead to a broader clinical applicability in other thoracic pathologies. This article reviews the current endovascular devices designed for the treatment of thoracic aortic pathology. These devices are described, and the current clinical results are discussed. PMID- 17714633 TI - Ruptured abdominal aortic aneurysm: endovascular repair does not confer any long term survival advantage over open repair. AB - Recent studies have suggested that endovascular aneurysm repair (EVAR) may reduce the perioperative mortality of ruptured abdominal aortic aneurysm (AAA). Whether EVAR confers any long-term survival advantage over published results for open repair of ruptured AAA has not been established. We conducted a single-center retrospective study over a 10-year period (1994-2004) examining the long-term outcome of patients who have undergone endovascular repair of ruptured AAA. Fifty four patients underwent endovascular repair of a ruptured AAA. The median age was 75 years (interquartile range 69.5-79.5 years); 42 (78%) patients were male. The perioperative mortality rate was 37%. During a median follow-up of 32 months (range 14-48 months), there were 5 aneurysm-related and 13 non-aneurysm-related deaths. Overall, the 3- and 5-year survival rates were 36% and 26%, respectively. EVAR does not appear to confer any overall survival advantage in the mid- to long term compared with the published results for open repair. The reasons for this remain unclear. Further, larger studies are required to confirm these results. PMID- 17714634 TI - Hypotensive hemostatis (permissive hypotension) for ruptured abdominal aortic aneurysm: are we really in control? AB - The purpose of this study was to investigate whether a protocol for permissive hypotension was feasible for patients admitted with a ruptured abdominal aortic aneurysm (RAAA). It was aimed to limit prehospital intravenous fluid administration to 500 mL and to maintain systolic blood pressure at a range of 50 to 100 mm Hg following admission, using nitrates when indicated. The diagnosis of RAAA was confirmed with sonography, and all patients with uncontrolled hypovolemic shock immediately underwent open aneurysm repair (OAR). In all other cases, computed tomographic (CT) angiography was performed to determine the eligibility for endovascular aneurysm repair (EVAR). From January 1, 2004, to December 31, 2006, 95 patients with a suspected RAAA were admitted. In 77 patients, the diagnosis of RAAA was confirmed. Twenty-eight cases (36%) underwent OAR for uncontrolled hemodynamic instability. Following CT-angiographic evaluation, 25 of the remaining 49 cases were considered unsuitable for EVAR and subsequently underwent OAR. In 24 of 77 cases (31%), the RAAA was treated with EVAR. Preoperative systolic blood pressure recordings in EVAR patients showed median values (+/- SD) of 98 (+/- 34.7) mm Hg in the emergency department and 114 (+/- 26.2) mm Hg in the operating theater. The desired systolic blood pressure range of 50 to 100 mm Hg was reached in 11 of 24 cases (46%). In 13 of 24 cases (54%), a systolic blood pressure higher than 100 mm Hg was recorded for a period longer than 60 minutes. The 30-day mortality was 32 of 77 (42%), with 6 of 24 (25%) in the EVAR group and 26 of 53 (49%) in the OAR group. This is the first published series of RAAA in which a protocol of permissive hypotension has been adopted. The concept appeared to be feasible in the majority of cases. Protocol violations were sparse (n = 5). Uncontrolled hypotension occurred in 36% (28 of 77) of all patients, and the desired systolic blood pressure range was achieved in 46% (11 of 24) of the EVAR patients. PMID- 17714635 TI - Open surgical treatment of aneurysmal sac expansion following endovascular abdominal aneurysm repair: solution for an unresolved clinical dilemma. AB - The advantages of endovascular aneurysm repair (EVAR) are probably related to the avoidance of the three major physiological insults associated with open abdominal aortic aneurysm (AAA) repair: laparotomy, aortic cross-clamping and ischemia reperfusion injury. Continuing aneurysm expansion indicates a failure to exclude the AAA from the circulation. We describe our experience with open surgery of post-EVAR sac expansion. A consecutive series of 68 EVAR patients was followed up. Endovascular and minimally invasive procedures were the initial treatment option. Failure of these attempts to curtail AAA sac expansion or type 2 large endoleaks (EL) resulted in opening of the aneurysm sac. The procedure includes positioning of a deflated occlusion balloon proximal to the stent graft (SG). Laparotomy with opening of the eneurysm sac was then performed. The thrombus was removed and backbleeding vessels oversewn. The aneurysm sac was then plicated over the SG. Four patients (5.9%) were diagnosed as having either persistent large type 2 EL or sac enlargement. In all patients the procedure was accomplished successfully. One patient died from acute myocardial infarction perioperatively. Three patients recovered uneventfully and follow-up computed tomography confirmed the absence of endoleak and a disappearance of the AAA. We believe that whenever EVAR fails to exclude the aneurysm from the circulation, open exploration without graft replacement should be considered. PMID- 17714636 TI - Temporal trends in eversion carotid endarterectomy for carotid atherosclerosis: single-center experience with 5,034 patients. AB - The aim of this article is to review our experience in surgical treatment of carotid atherosclerosis using eversion carotid endarterectomy (ECEA) in 5,034 patients, with particular attention to temporal changes in patients' characteristics, diagnostic approach, surgical technique, medical therapy, and outcome in the early (group A, 1991-1997) versus late (group B 1998-2004) period of ECEA. From January 1991 to December 2004, 5,034 primary ECEAs were performed for high-grade carotid stenosis. Patients treated for restenosis after previous carotid surgery were excluded from the analysis. Group A consisted of 1,714 patients who underwent surgery between 1991 and 1997, and group B consisted of 3,320 patients who underwent surgery between 1998 and 2004. Follow-up included routine clinical evaluation and noninvasive surveillance, with duplex scanning at 1 month after surgery, after 6 months, and annually afterward. Only 3% of patients in group A and 0.6% in group B were asymptomatic, with 23% and 47% of them having preoperative stroke, respectively. In group A, angiography was used for the final diagnosis in 78% of patients. In group B, duplex scanning was performed in 82% of patients and angiography in only 18% (p < .001). Clamping time was shorter in the latter group (12.4 +/- 3.1 vs 14.5 +/- 4.1 min, p < .01). Introperative shunting and regional anesthesia were rarely performed in both groups (1.4% vs. 0.4%, p < .01, and 2% vs 0.3%, p < .001). Total and neurologic morbidity was significantly higher in group A than in group B (6.41% +/- 0.47% vs 4.81% +/- 0.53%, p < .001, and 2.14% +/- 0.31% vs 1.23% +/- 0.29%, p < .001, respectively). Total mortality was also higher in group A than in group B (1.92% +/- 0.24% vs 1.36% +/- 0.50%, p < .05), but although there was a trend toward lower neurologic mortality, it did not reach statistical significance (1.04% +/- 0.5% vs 0.57% +/- 0.25%, p = .074). There was a lower rate of nonsignificant restenosis (< 50%) in group B (2% vs 5%, p < .01), but the incidence of restenosis > or = 50% was identical between the groups (5.5% for both). Our data show that ECEA is a reliable surgical technique for the treatment of atherosclerotic carotid disease. Temporal trends in our patients demonstrated a decline in periopertive mortality and morbidity, despite a higher incidence of preoperative stroke. PMID- 17714637 TI - Kissing stents in the common femoral artery bifurcation for critical limb ischemia: technical description and report of three cases. AB - The purpose of this article is to describe three cases of kissing stent placement in the common femoral artery bifurcation in patients unsuitable for open endarterectomy and patch plasty. In three patients with critical limb ischemia, caused by primary atherosclerotic disease or dissection-related injury when performing a lower extremity intervention, a technique of kissing stents was used to treat the flow-obstructing lesion in the common femoral artery bifurcation. Technical success was uniform, and during follow-up (4.5-8 months), all patients showed improved symptoms, wound healing, and duplex ultrasonography-verified patency of the stents. Kissing stents in the common femoral artery bifurcation are a feasible treatment option in patients with limited mobililty or contraindications to open repair. The short-term results seem promising, but longer follow-up and an increased number of patients will be needed to assess the durability of the reconstruction. PMID- 17714638 TI - Mycotic aneurysm of the internal carotid artery presenting with multiple cerebral septic emboli. AB - Mycotic aneurysms of the extracranial carotid artery are uncommon and always warrant surgical treatment to prevent eventual rupture and death. Septic embolization to the brain is an even rarer complication of these aneurysms. We present a case of a 79-year-old male with an extracranial internal carotid artery mycotic aneurysm during Staphylococcus aureus bacteremia. He presented with hemiparesis owing to brain embolism from multiple septic emboli originating from the aneurysm. Multidetector computed tomographic angiography contributed to the diagnosis. Resection of the aneurysm and restoration of arterial supply to the brain by vein graft interpositioning was the therapeutic procedure along with long-term antibiotic treatment. A high index of suspicion is required for the diagnosis of a mycotic carotid aneurysm and aggressive treatment is always needed to prevent lethal complications. PMID- 17714639 TI - Thoracic endograft positioning and carotid-subclavian bypass grafting in a patient with a saccular aneurysm at the aortic arch. AB - A 75-year-old man was referred to our hospital because of sudden thoracic pain. A saccular aneurysm of the aortic arch extending on the anterior surface of the aortic arch was found on computed tomographic arteriography. The patient was hemodynamically stable and he was programmed for a staged surgical and endovascular approach (hybrid approach). As a first stage and in order to prevent major cardiac complications due to the overstenting of the left subclavian artery (LSA) with the occlusion of the aortocoronary bypass, the patient underwent a polytetrafluoroethylene bypass graft (GORE-TEX, W.L. Gore & Associates, Flagstaff, AZ) between the LSA and the left carotid artery. Intraoperative arteriography revealed a good patency of the left carotid-subclavian bypass and of the left internal mammary bypass on the left anterior descending artery. As a second stage the endovascular procedure was accomplished 5 days later in the operating room. A Gore TAG stent graft (W.L. Gore & Associates) was deployed in the aortic arch 20 mm proximally to the aneurysmatic segment covering the ostium of the LSA. The postoperative course was uneventful and the patient was discharged on the fifth postoperative day in good general conditions. Hybrid procedures for treatment of aneurysms of the aortic arch or of the descending thoracic aorta are a promising alternative to open surgery especially in high risk patients, with lower early morbidity and mortality rates. Long-term effectiveness remains to be fully elucidated. PMID- 17714640 TI - Modified distal revascularization with interval ligation procedure for steal syndrome after arteriovenous fistula creation for hemodialysis access. AB - Patients diagnosed with steal syndrome after hemodialysis access surgery have a few options for symptom relief while maintaining vascular access. These include fistula lengthening, banding, distal revascularization with interval ligation (DRIL), revision using distal inflow (RUDI) or proximalization of the arterial inflow (PAI). Two cases are described in which a modified DRIL procedure without interval ligation was used to relieve steal syndrome, leaving the arterial supply of an ischemic hand not entirely dependent upon a bypass. Furthermore, a review of the literature is presented in order to elucidate this relatively new treatment option as a viable means to improve hand perfusion while maintaining a functional fistula. PMID- 17714641 TI - Successful surgical management of a ruptured true pancreaticoduodenal artery aneurysm following failed transcatheter embolization. AB - A ruptured splanchnic artery aneurysm is a rare clinical entity. Its diagnosis requires a high index of clinical suspicion, and management usually requires a multidisciplinary approach. We present a case of ruptured true pancreaticoduodenal artery aneurysm in an 83-year-old woman who was initially treated with transcatheter embolization, but it failed to arrest the bleeding, and she subsequently required laparotomy and surgical ligation. The clinical course and management are discussed with a review of the literature. PMID- 17714642 TI - Recurrent aortoenteric fistula: two different bridge solutions. AB - A "recurrent" aortoenteric fistula (AEF) is very rare and in literature anecdotic. Currently, graft excision and extra-anatomic bypass are considered the treatments of choice, but are associated with significant mortality and morbidity. Herein, we describe the case of a "recurrent" AEF treated before definitive extra-anatomic bypass, by two different, staged bridge solutions: allograft in situ replacement and endovascular grafting. At 1, 3 and 6-month follow-up, the patient was asymptomatic and normally active. PMID- 17714643 TI - Transperitoneal laparoscopic left gonadal vein ligation can be the right treatment option for pelvic congestion symptoms secondary to nutcracker syndrome. AB - The nutcracker phenomenon refers to compression of the left renal vein at the origin of the superior mesenteric artery and is often underdiagnosed. This can cause symptoms of pelvic venous congestion with retrograde venous flow and a dilated gonadal vein. Here we describe a case in a 39-year-old female, who following imaging investigations to confirm the diagnosis, underwent transperitoneal laparoscopic ligation of the left gonadal vein. Laparoscopic sterilization was also performed with the aid of the gynecologists. Multiparous women, who are more likely to develop pelvic congestion symptoms, more commonly request sterilization and thus we propose that a dual laparoscopic procedure in these cases could be the treatment of choice. PMID- 17714644 TI - Stepping of the forelegs over obstacles establishes long-lasting memories in cats. PMID- 17714645 TI - Biological components of sex differences in color preference. PMID- 17714647 TI - Language acquisition: when does the learning begin? AB - Language acquisition is quite sophisticated by four months of age. Two cues that babies use to discriminate their language from another are the stress patterns of words and visual cues inherent in language production. PMID- 17714646 TI - Transcriptional rewiring: the proof is in the eating. AB - Transcriptional rewiring is an emerging evolutionary principle. Analysis of the galactose genetic pathway in Candida albicans and comparison with the classical pathway in Saccharomyces cerevisiae have revealed remarkable differences in its regulation in the two yeasts. PMID- 17714648 TI - Replication licensing: oops! ... I did it again. AB - All eukaryotes use multiple controls to restrict DNA replication to once per cell cycle. Nevertheless, inactivation of a single gene, cul-4, causes massive re replication in Caenorhabditis elegans. A novel study explains this dramatic phenotype by demonstrating that the CUL-4 E3 ligase simultaneously controls two critical licensing factors: CDT-1 and CDC-6. PMID- 17714649 TI - Comparative biomechanics: the jellyfish paradox resolved. AB - Studying the mechanics of swirling water has solved a mystery about the evolution of body shape and size in jellyfish. PMID- 17714650 TI - Bacterial cytoskeleton: not your run-of-the-mill tubulin. AB - Large plasmids of some Bacillus species encode a distinct tubulin homolog, TubZ, implicated in maintenance of the host plasmid. A recent study has shown that TubZ polymers exhibit treadmilling behavior in vivo, suggesting that they are involved in mitotic activity. PMID- 17714651 TI - Circadian clock: time for a phase shift of ideas? AB - A recent study shows that cycling of cryptochrome proteins is dispensable for circadian clock function in mammalian cells. Is it time for a paradigm shift in how we think about the circadian clock mechanism? PMID- 17714652 TI - Asymmetric cell division: a CAB driver for spindle movements. AB - To divide asymmetrically, a cell must position the mitotic spindle relative to localized cell fate determinants. Recent work in the early ascidian embryo reveals the function of a single factor that coordinates this act to control cleavage pattern and cell fate determination. PMID- 17714653 TI - Social cognition: overturning stereotypes of and with autism. AB - New data suggest that even children with autism are subject to race and gender stereotypes. This result constrains theories of stereotype acquisition and social cognition in autism. PMID- 17714654 TI - Mitosis: ran scales the alps of spindle formation. AB - Alp7/TACC has been identified as an important target for Ran GTPase in spindle formation in fission yeast. This discovery underlines a general role for Ran in orchestrating mitosis in all eukaryotes. PMID- 17714655 TI - Respiratory biology: why insects evolved discontinuous gas exchange. AB - Many, but not all, insects breathe in a discontinuous gas-exchange cycle. A recent study has evaluated rival hypotheses for the evolution of this trait, concluding that the most likely is the one invoking minimization of respiratory water loss. PMID- 17714656 TI - All of life is social. PMID- 17714657 TI - Social spiders. PMID- 17714658 TI - The social life of corvids. PMID- 17714659 TI - Hyena societies. PMID- 17714660 TI - Evolutionary explanations for cooperation. AB - Natural selection favours genes that increase an organism's ability to survive and reproduce. This would appear to lead to a world dominated by selfish behaviour. However, cooperation can be found at all levels of biological organisation: genes cooperate in genomes, organelles cooperate to form eukaryotic cells, cells cooperate to make multicellular organisms, bacterial parasites cooperate to overcome host defences, animals breed cooperatively, and humans and insects cooperate to build societies. Over the last 40 years, biologists have developed a theoretical framework that can explain cooperation at all these levels. Here, we summarise this theory, illustrate how it may be applied to real organisms and discuss future directions. PMID- 17714661 TI - Kin selection versus sexual selection: why the ends do not meet. AB - I redevelop the hypothesis that lifetime monogamy is a fundamental condition for the evolution of eusocial lineages with permanent non-reproductive castes, and that later elaborations--such as multiply-mated queens and multi-queen colonies- arose without the re-mating promiscuity that characterizes non-social and cooperative breeding. Sexually selected traits in eusocial lineages are therefore peculiar, and their evolution constrained. Indirect (inclusive) fitness benefits in cooperatively breeding vertebrates appear to be negatively correlated with promiscuity, corroborating that kin selection and sexual selection tend to generally exclude each other. The monogamy window required for transitions from solitary and cooperative breeding towards eusociality implies that the relatedness and benefit-cost variables of Hamilton's rule do not vary at random, but occur in distinct and only partly overlapping combinations in cooperative, eusocial, and derived eusocial breeding systems. PMID- 17714662 TI - The cold war of the social amoebae. AB - When confronted with starvation, the amoebae of Dictyostelium discoideum initiate a developmental process that begins with cell aggregation and ends with a ball of spores supported on a stalk. Spores live and stalk cells die. Because the multicellular organism is produced by cell aggregation and not by growth and division of a single cell, genetically diverse amoebae may enter an aggregate and, if one lineage has a capacity to avoid the stalk cell fate, it may have a selective advantage. Such cheater mutants have been found among wild isolates and created in laboratory strains. The mutants raise a number of questions--how did such a cooperative system evolve in the face of cheating? What is the basis of self recognition? What genes are involved? How is cheating constrained? This review summarizes the results of studies on the social behavior of Dictyostelium and its relatives, including the familiar asexual developmental cycle and the lesser known, but puzzling, sexual cycle. PMID- 17714663 TI - Social immunity. AB - Social insect colonies have evolved collective immune defences against parasites. These 'social immune systems' result from the cooperation of the individual group members to combat the increased risk of disease transmission that arises from sociality and group living. In this review we illustrate the pathways that parasites can take to infect a social insect colony and use these pathways as a framework to predict colony defence mechanisms and present the existing evidence. We find that the collective defences can be both prophylactic and activated on demand and consist of behavioural, physiological and organisational adaptations of the colony that prevent parasite entrance, establishment and spread. We discuss the regulation of collective immunity, which requires complex integration of information about both the parasites and the internal status of the insect colony. Our review concludes with an examination of the evolution of social immunity, which is based on the consequences of selection at both the individual and the colony level. PMID- 17714664 TI - Social learning in insects--from miniature brains to consensus building. AB - Communication and learning from each other are part of the success of insect societies. Here, we review a spectrum of social information usage in insects- from inadvertently provided cues to signals shaped by selection specifically for information transfer. We pinpoint the sensory modalities involved and, in some cases, quantify the adaptive benefits. Well substantiated cases of social learning among the insects include learning about predation threat and floral rewards, the transfer of route information using a symbolic 'language' (the honeybee dance) and the rapid spread of chemosensory preferences through honeybee colonies via classical conditioning procedures. More controversial examples include the acquisition of motor memories by observation, teaching in ants and behavioural traditions in honeybees. In many cases, simple mechanistic explanations can de identified for such complex behaviour patterns. PMID- 17714665 TI - Sociality, evolution and cognition. AB - Variations in brain size and proportions can be linked to the cognitive capacities of different animal species, and correlations with ecology may give clues to the evolutionary origins of these specializations. Much recent evidence has implicated the social domain as a major challenge driving increases in problem-solving abilities of mammals. However, the methods of measurement available to researchers are often indirect and sometimes appear to give conflicting answers, and other intellectual challenges may also have been influential in cognitive evolution. While the cause of an evolutionary increase in intelligence may be domain-specific (sociality, for example), and the brain specialization that results may largely implicate a single perceptual system, such as vision, the intelligence shown in consequence can be very 'general purpose' (as in primates and some avian taxa). Future research needs to get beyond vague ascription of 'greater intelligence' or 'faster learning' towards a precise account of the cognitive mechanisms that underlie particular mental skills in different species; that will allow theory-testing against data from complex, natural situations as well as from the laboratory, on a common metric. PMID- 17714666 TI - Social cognition in humans. AB - We review a diversity of studies of human social interaction and highlight the importance of social signals. We also discuss recent findings from social cognitive neuroscience that explore the brain basis of the capacity for processing social signals. These signals enable us to learn about the world from others, to learn about other people, and to create a shared social world. Social signals can be processed automatically by the receiver and may be unconsciously emitted by the sender. These signals are non-verbal and are responsible for social learning in the first year of life. Social signals can also be processed consciously and this allows automatic processing to be modulated and overruled. Evidence for this higher-level social processing is abundant from about 18 months of age in humans, while evidence is sparse for non-human animals. We suggest that deliberate social signalling requires reflective awareness of ourselves and awareness of the effect of the signals on others. Similarly, the appropriate reception of such signals depends on the ability to take another person's point of view. This ability is critical to reputation management, as this depends on monitoring how our own actions are perceived by others. We speculate that the development of these high level social signalling systems goes hand in hand with the development of consciousness. PMID- 17714667 TI - Ensuring food safety in a globalised economy. PMID- 17714668 TI - HIV control efforts should directly address incarceration. PMID- 17714669 TI - Capsule switching and capsule replacement in vaccine-preventable bacterial diseases. PMID- 17714671 TI - It's not easy being green. PMID- 17714672 TI - Cutaneous leishmaniasis. AB - Cutaneous leishmaniasis is endemic in the tropics and neotropics. It is often referred to as a group of diseases because of the varied spectrum of clinical manifestations, which range from small cutaneous nodules to gross mucosal tissue destruction. Cutaneous leishmaniasis can be caused by several Leishmania spp and is transmitted to human beings and animals by sandflies. Despite its increasing worldwide incidence, but because it is rarely fatal, cutaneous leishmaniasis has become one of the so-called neglected diseases, with little interest by financial donors, public-health authorities, and professionals to implement activities to research, prevent, or control the disease. In endemic countries, diagnosis is often made clinically and, if possible, by microscopic examination of lesion biopsy smears to visually confirm leishmania parasites as the cause. The use of more sophisticated diagnostic techniques that allow for species identification is usually restricted to research or clinical settings in non-endemic countries. The mainstays of cutaneous leishmaniasis treatment are pentavalent antimonials, with new oral and topical treatment alternatives only becoming available within the past few years; a vaccine currently does not exist. Disease prevention and control are difficult because of the complexity of cutaneous leishmaniasis epizoology, and the few options available for effective vector control. PMID- 17714673 TI - Combined schedules of pneumococcal conjugate and polysaccharide vaccines: is hyporesponsiveness an issue? AB - Streptococcus pneumoniae is a major cause of morbidity and mortality in children less than 5 years of age. Prevention of pneumococcal disease and death in children in the developing world through vaccination with recently developed, highly efficacious pneumococcal conjugate vaccines (PCVs) is now possible. Schedules combining PCV with 23-valent pneumococcal polysaccharide vaccine (PPV23) have been studied and proposed as a means to expand disease protection against serotypes not included in the PCVs. Studies of group A and C meningococcal polysaccharide vaccine and repeated doses of PPV23 in adults and children have shown that a state of immune tolerance, or hyporesponsiveness, can develop to repeated polysaccharide vaccine antigen exposures. In this Review, we describe the evidence for and against this hyporesponsiveness and explore the possible mechanisms for such an occurrence. PMID- 17714674 TI - Mycobacterium avium subspecies paratuberculosis and Crohn's disease: a systematic review and meta-analysis. AB - This systematic review assesses the evidence for an association between Mycobacterium avium subspecies paratuberculosis (MAP) and Crohn's disease. We analysed 28 case-control studies comparing MAP in patients with Crohn's disease with individuals free of inflammatory bowel disease (IBD) or patients with ulcerative colitis. Compared with individuals free of IBD, the pooled odds ratio (OR) from studies using PCR in tissue samples was 7.01 (95% CI 3.95-12.4) and was 1.72 (1.02-2.90) in studies using ELISA in serum. ORs were similar for comparisons with ulcerative colitis patients (PCR, 4.13 [1.57-10.9]; ELISA, 1.88 [1.26-2.81]). The association of MAP with Crohn's disease seems to be specific, but its role in the aetiology of Crohn's disease remains to be defined. PMID- 17714675 TI - The untapped potential of virtual game worlds to shed light on real world epidemics. AB - Simulation models are of increasing importance within the field of applied epidemiology. However, very little can be done to validate such models or to tailor their use to incorporate important human behaviours. In a recent incident in the virtual world of online gaming, the accidental inclusion of a disease-like phenomenon provided an excellent example of the potential of such systems to alleviate these modelling constraints. We discuss this incident and how appropriate exploitation of these gaming systems could greatly advance the capabilities of applied simulation modelling in infectious disease research. PMID- 17714676 TI - Intracranial abscess from embolic Serratia marcescens endocarditis. PMID- 17714677 TI - Women at risk for sexually transmitted diseases: correlates of intercourse without barrier contraception. AB - OBJECTIVE: The purpose of this study was to evaluate the correlates of vaginal intercourse without barrier contraception (unprotected intercourse). STUDY DESIGN: Baseline data from a randomized trial were analyzed to evaluate factors that are associated with intercourse without barrier method use among women < 35 years old. Logistic regression models provided estimates of the association of demographic, reproductive, and sexual history variables with unprotected intercourse. RESULTS: Intercourse without barrier contraception was common; 65% of participants had > or = 2 episodes of intercourse without barrier contraception use in the past month. Factors that were associated with increased odds of unprotected intercourse included the number of coital episodes, a male partner's unwillingness to use condoms (adjusted odds ratio, 4.1; 95% CI, 2.3 6.9), and, among women < 20 years old, low condom use self-efficacy score (adjusted odds ratio, 1.6; 95% CI, 1.0-2.9). CONCLUSION: Risk factors for unprotected intercourse included coital frequency and the male partner's unwillingness to use condoms. Self-efficacy for condom use was especially important for women < 20 years old. PMID- 17714678 TI - High-risk cervical epithelial neoplasia grade 1 treated by loop electrosurgical excision: follow-up and value of HPV testing. AB - OBJECTIVE: This study was undertaken to evaluate the value of high-risk human papillomavirus (HPV) testing in the follow-up of cervical intraepithelial neoplasia grade 1/low-grade squamous intraepithelial lesion treated by loop electrosurgical excision procedure because of the risk criteria established by the American Society for Colposcopy and Cervical Pathology (ie, unsatisfactory colposcopy or positive endocervical curettage, persistence of cervical intraepithelial neoplasia grade 1/low-grade squamous intraepithelial lesion, or high-risk HPV infection for longer than 2 years and older than 40 years). STUDY DESIGN: Seventy-seven women with cervical intraepithelial neoplasia grade 1/low grade squamous intraepithelial lesion treated by loop electrosurgical excision procedure and followed-up with colposcopy, cytology, and high-risk HPV detection using Hybrid Capture II. RESULTS: More than 67% (67.6%) of women had cervical intraepithelial neoplasia grade 1 in the specimen; 22% a cervical intraepithelial neoplasia grade 2-3; and 10.4% had no lesion. Pretreatment HPV testing was positive in 100% of cervical intraepithelial neoplasia grade 2-3, in 93.5% of cervical intraepithelial neoplasia 1, and in 14.3% of cases with no lesion (P < .01). Pretreatment high-risk HPV testing was positive in all cases eventually developing residual/recurrent disease. Fifty percent of women with pretreatment viral load more than 100 relative light units had residual/recurrent disease develop. Posttreatment high-risk HPV testing during the follow-up reached a sensitivity and negative predictive value of 100% for detecting residual/recurrent disease. CONCLUSION: Patients with low-grade squamous intraepithelial lesion/cervical intraepithelial neoplasia grade 1 and risk factors have a significant risk of harboring a cervical intraepithelial neoplasia grade 2-3 lesion. A conservative approach should be considered when basal high risk HPV test is negative. High pretreatment high-risk HPV loads should be considered a risk factor for developing residual/recurrent disease. Posttreatment Hybrid Capture II has an extremely high sensitivity for detecting recurrences. PMID- 17714679 TI - Prepregnancy body mass index, hypertensive disorders of pregnancy, and long-term maternal mortality. AB - OBJECTIVE: Recent studies have shown increased maternal mortality rates after hypertensive disorders of pregnancy (HDP), but the reasons for this increase remain unclear. This study examines the relationship between elevated prepregnancy body mass index (BMI), HDP, and postpregnancy mortality. STUDY DESIGN: Data came from a 1975-1976 subset (n = 13,722 women) of a population based cohort. Multiple logistic regression was used to examine the risk of HDP by BMI; age-adjusted Cox proportional hazards models were used to examine survival rates. RESULTS: Overweight (BMI, 25-29.9 kg/m2) and obesity (BMI, > or = 30 kg/m2) were associated with increased HDP (odds ratio [OR], 2.82; 95% confidence interval [CI], 2.40-3.31 and OR, 5.51; 95% CI, 4.15-7.31]) and decreased survival (hazard ratio [HR], 1.42; 95% CI, 1.10-1.83 and HR, 2.43; 95% CI, 1.61-3.68), compared with normal weight (BMI, 18.5-24.9 kg/m2). HDP was significantly associated with increased mortality rates for women who survived > 15 years (HR, 1.94; 95% CI, 1.42-2.67]; HR adjusted for BMI, 1.65; 95% CI, 1.19-2.79]). A greater increase in risk of death after HDP was seen in the overweight women (HR, 1.86; 95% CI, 1.07-3.20) and obese women (HR, 2.90; 95% CI, 1.28-6.58), compared with normal weight women (HR, 1.26; 95% CI, 0.74-2.14). CONCLUSION: Elevated prepregnancy BMI is associated with increased risk of HDP, which are in turn is associated with increased long-term maternal mortality rates. This association between HDP and mortality rates increases with elevated prepregnancy BMI. PMID- 17714680 TI - Symptoms of anal incontinence and difficult defecation among women with prolapse and a matched control cohort. AB - OBJECTIVE: The purpose of this study was to quantify the risk for anal incontinence and difficult defecation among women with prolapse by comparing them with women without prolapse of similar age, body mass index, race, and hysterectomy status, and to determine whether there are characteristics or findings in women with prolapse that are associated with greater symptom severity. STUDY DESIGN: Women with primary pelvic organ prolapse (n = 151) were compared with women without prolapse (n = 135). All subjects underwent pelvic examination and completed symptom questionnaires regarding how frequently anal incontinence and difficult defecation were experienced. Incontinence of flatus was considered to be present if it occurred on "most" or "every" day; difficult defecation was considered to be present if it was experienced with "most" or "every" bowel movement. Symptoms that occurred "on occasion" or "never" were considered to be absent. RESULTS: Incontinence of flatus was reported by 23.1% of cases vs 8.3% of control subjects (P = .006). Incontinence of liquid or solid stool was present in 4.7% and 3.5%, respectively, and was not reported by control subjects (P < .001 and .009, respectively). Difficult defecation, which was characterized by pushing on the vaginal walls to complete defecation, was present in 19.7% vs 4.4% of control subjects (P = .001). Cases that reported symptoms were compared with those that did not report symptoms. Among those reporting difficult defecation, the length of the perineal body length was greater when straining (4.0 vs 3.4 cm; P = .020). Among those reporting incontinence of flatus, mean parity was higher (3.3 vs 2.5; P = .012), and a positive standing cough stress test was more likely (39.3% vs 18.5%; P = .025). Symptoms of anal incontinence and/or difficult defecation were present in 35.3% of subjects (52/147). CONCLUSION: Women with prolapse are more likely than control subjects to have symptoms of anal incontinence or difficult defecation; approximately one third of these women will have symptoms. PMID- 17714681 TI - Among pregnant women with bacterial vaginosis, the hydrolytic enzymes sialidase and prolidase are positively associated with interleukin-1beta. AB - OBJECTIVE: The objective of the study was to explore the mechanisms of local innate immunity induction and modulation in pregnant women with bacterial vaginosis (BV). STUDY DESIGN: A total of 200 singleton pregnant women in early gestation (12 +/- 4 weeks) with BV (Nugent 7-10) without concurrent vaginal infections with Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, syphilis, and yeast. Concentrations of vaginal interleukin (IL) 1beta and IL-8, the number of neutrophils, and the levels of sialidase and prolidase hydrolytic enzymes were determined in vaginal fluid. RESULTS: Concentrations of vaginal IL-1beta had a strong positive correlation with levels of sialidase (P < .001) and prolidase (P < .001). Conversely, such enzymes were negatively correlated with the ratio of IL-8/IL-1beta (both P < .001) and were not significantly associated with concentrations of IL-8. Notably, the number of vaginal neutrophils had a negative correlation with sialidase (P = .007). CONCLUSION: The strong induction of IL-1beta in BV-positive women appears to be associated with the production of the hydrolytic enzymes sialidase and prolidase by BV-associated bacteria. However, these 2 enzymes may inhibit the expected amplification of the proinflammatory IL-1beta cascade as evaluated by the down regulation of the IL-8/IL-1beta ratio. A blunted response to IL-1beta signals may cause the poor rise of neutrophils, which is peculiar to BV. This impairment of local defense may contribute to increased susceptibility to adverse outcomes in BV-positive pregnant women. PMID- 17714682 TI - A comparative analysis of lichen sclerosus of the vulva and lichen sclerosus that evolves to vulvar squamous cell carcinoma. AB - OBJECTIVE: The aim of this study was to determine whether the premalignant change in lichen sclerosus (LS) could be identified with immunohistochemical analyses. STUDY DESIGN: Eight cases of histologically diagnosed vulvar LS, which showed, after a period of 10 months-9 years, an evolution to carcinoma of the vulva that was histologically documented, were compared with 8 cases of vulvar LS, for which follow-up information was available for at least 9 years. The proliferative index and the expression of tumor suppressors p16 and p53 were analyzed. RESULTS: The difference of MIB1 labeling index of evolving or unchanged LS cases was significant (P = .005). The difference in the p53 of evolving or unchanged LS cases shows a trend towards association (P = .08). Both LS cases (evolving or unchanged) did not show p16 positive staining. CONCLUSION: The evaluation of MIB1 and p53 may identify those vulvar LS cases with a high likelihood of evolving into squamous cell carcinoma, which would need careful periodic checks or adjunctive biopsies. The study must be confirmed by a larger number of cases to substantiate this observation. PMID- 17714683 TI - Does a maximum dose of oxytocin affect risk for uterine rupture in candidates for vaginal birth after cesarean delivery? AB - OBJECTIVE: The purpose of this study was to determine whether the maximum dose of oxytocin impacts the risk of uterine rupture in women who attempt vaginal birth after cesarean delivery (VBAC). STUDY DESIGN: We conducted a retrospective, multicenter cohort study of women with a history of cesarean delivery. We compared uterine rupture rates between VBAC candidates that did and did not receive oxytocin, analyzing the association between maximum dose of oxytocin and uterine rupture. Bivariate and multivariate analyses were performed. RESULTS: Of the 13,523 patients who elected a VBAC trial, 128 women experienced a uterine rupture; 80 of these ruptures were in women who received oxytocin (62.5%). There was evidence of "dose response" for maximum oxytocin amount and uterine rupture, with a uterine rupture rate of 2.07% (adjusted odds ratio, 2.98; 95% CI 1.51 5.90) at the highest dosages. CONCLUSION: In VBAC attempts, a dose-response relationship of maximum oxytocin and uterine rupture exists. These results provide evidence for vigilance when higher doses of oxytocin are given to patients who attempt VBAC. PMID- 17714684 TI - Effect of a lipid-enriched diet on body composition and some regulatory hormones of food intake in growing rats. AB - OBJECTIVE: The aim of the present study was to investigate the effects of a lipid enriched diet on body composition and on main regulatory hormones of food intake (insulin, adiponectin, leptin, ghrelin). METHOD: Two groups of 16 rats, 35 days old, weighing 80+/-6 g, were constituted. One group (S) was given a standard diet during 10 weeks and served as control. The second group (L) was given a lipidic enriched diet (containing: G: 41.5, L: 38.5, P: 20% calorie). Food and water were given "ad libitum". RESULTS: Total food intake, body weight, skeletal area and lean body mass of rats eating lipid-enriched diet were lowered (6694+/-178 vs. 8160+/-184 kcal, P=0.01; 431+/-38 vs. 468+/-25 g, P=0.003; 72.19+/-0.96 vs. 76.07+/-1.31 cm2, P=0.03; 369+/-18 vs. 409+/-23 g, P=0.0006), fat mass difference was not statistically significant (82.5+/-17 vs. 80+/-17 g, P=0.7). Blood ghrelin, adiponectin levels were lowered (1517+/-224 vs. 1915+/-579 pg/ml, P=0.03; 10+/-3 vs. 19+/-3 microg/ml, P=0.003) whereas insulin and leptin were unchanged (1.8+/-1.5 vs. 2.6+/-1.4 ng/ml, P=0.1; 16+/-11 vs. 13+/-10 ng/ml, P=0.4). CONCLUSION: A period of high fat diet in growing rats leads to a hypophagia, resulting in a lower lean body mass development. Some regulatory hormones of food intake did not change, while others significantly decreased, notably ghrelin being possible causal factor of the observed hypophagia linked to high fat diet. PMID- 17714685 TI - Permeation of a beta-heptapeptide derivative across phospholipid bilayers. AB - Based on a number of experiments it is concluded that the fluorescein labeled beta-heptapeptide fluoresceinyl-NH-CS-(S)-beta(3)hAla-(S)-beta(3)hArg-(R) beta(3)hLeu-(S)-beta(3)hPhe-(S)-beta(3)hAla-(S)-beta(3)hAla-(S)-beta(3)hLys-OH translocates across lipid vesicle bilayers formed from DOPC (1,2-dioleoyl-sn glycero-3-phosphocholine). The conclusion is based on the following observations: (i) addition of the peptide to the vicinity of micrometer-sized giant vesicles leads to an accumulation of the peptide inside the vesicles; (ii) if the peptide is injected inside individual giant vesicles, it is released from the vesicles in a time dependent manner; (iii) if the peptide is encapsulated within sub micrometer-sized large unilamellar vesicles, it is released from the vesicles as a function of time; (iv) if the peptide is submitted to immobilized liposome chromatography, the peptide is retained by the immobilized DOPC vesicles. Furthermore, the addition of the peptide to calcein-containing DOPC vesicles does not lead to significant calcein leakage and vesicle fusion is not observed. The finding that derivatives of the beta-heptapeptide (S)-beta(3)hAla-(S)-beta(3)hArg (R)-beta(3)hLeu-(S)-beta(3)hPhe-(S)-beta(3)hAla-(S)-beta(3)hAla-(S)-beta(3)hLys OH can translocate across phospholipid bilayers is supported by independent measurements using Tb(3+)-containing large unilamellar vesicles prepared from egg phosphatidylcholine and wheat germ phosphatidylinositol (molar ratio of 9:1) and a corresponding peptide that is labeled with dipicolinic acid instead of fluorescein. The experiments show that this dipicolinic acid labeled beta heptapeptide derivative also permeates across phospholipid bilayers. The possible mechanism of the translocation of the particular beta-heptapeptide derivatives across the membrane of phospholipid vesicles is discussed within the frame of the current understanding of the permeation of certain oligopeptides across simple phospholipid bilayers. PMID- 17714686 TI - Two distinct mechanisms of vesicle-to-micelle and micelle-to-vesicle transition are mediated by the packing parameter of phospholipid-detergent systems. AB - The detergent solubilization and reformation of phospholipid vesicles was studied for various detergents. Two distinct mechanisms of vesicle-to-micelle and micelle to-vesicle transition were observed by turbidimetry and cryo-electron microscopy. The first mechanism involves fast solubilization of phospholipids and occurs via open vesicular intermediates. The reverse process, micelle-to-vesicle transition, mimics the vesicle-to-micelle transition. In the second mechanism the solubilization is a slow process that proceeds via micelles that pinch off from closed vesicles. During vesicle reformation, the micelle-to-vesicle transition, a large number of densely packed multilamellar vesicles are formed. The route used, for solubilization and reformation, by a given detergent-phospholipid combination is critically dependent on the overall packing parameter of the detergent saturated phospholipid membranes. By a change of the overall packing parameter the solubilization and or reformation mechanism could be changed. All five detergents tested fit within the proposed model. With two detergents the mechanism could be changed by changing the phospholipid composition or the medium conditions. PMID- 17714687 TI - miRNomics-The bioinformatics of microRNA genes. AB - MicroRNAs (miRNAs) are tiny genetic rheostats in plants, animals, and viruses, regulating the expression of messenger RNAs by targeting transcripts for cleavage or translational repression. Their regulatory impact is even more pervasive as a potential therapeutic tool. Since inception, computational methods have been an invaluable tool complementing experimental approaches. Here, we outline miRNA bioinformatics highlighting the biological and therapeutic repertoire of miRNAs, in silico prediction of miRNA genes and their targets, along with a glimpse of the bioinformatic challenges that lie ahead. PMID- 17714688 TI - Heteromeric complex formation of ASK2 and ASK1 regulates stress-induced signaling. AB - Apoptosis signal-regulating kinase 2 (ASK2) is an interaction partner of the highly related ASK1. Here, we describe a regulatory function of ASK2 in stress signaling-induced cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). Increased cleavage of caspase-3 and PARP was demonstrated by overexpression as well as knockdown of ASK2 after stress-induction by serum-starvation. We show that ectopically expressed ASK2 homo-oligomerized while endogenous ASK2 and ASK1 formed hetero-oligomers, which decreased upon serum-starvation. Co-expression of ASK2 and ASK1 stabilized these two proteins and reduced starvation-induced caspase-3 activation and degradation of PARP. Analysis of the intracellular localization of ASK2 exhibited a similar localization compared with ASK1 in the nucleus, cytoplasm, and in mitochondria. We propose that ASK2 regulates stress induced caspase-3 and PARP cleavage in a dose-dependent manner by heteromeric complex formation with ASK1. PMID- 17714689 TI - An ADAM metalloprotease is a Cry3Aa Bacillus thuringiensis toxin receptor. AB - Bacillus thuringiensis insecticidal proteins toxic action relies on the interaction with receptor molecules on insect midgut target cells. Here, we describe an ADAM metalloprotease as a novel type of B. thuringiensis toxin receptor on the basis of the following data: (i) by ligand blot and N-terminal analysis, we detected a Colorado potato beetle Cry3Aa toxin binding molecule that shares homology with an ADAM10 metalloprotease; (ii) Colorado potato beetle brush border membrane vesicles display ADAM activity since it cleaves an ADAM fluorogenic substrate; (iii) Cry3Aa acts as a competitor of the cleavage of the ADAM fluorogenic substrate; (iv) Cry3Aa sequence contains the recognition motif R(345)FQPGYYGND(354) present in ADAM10 substrates. Accordingly, a peptide representative of the recognition motif localized within loop 1 of Cry3Aa domain II (Ac-F(341)HTRFQPGYYGNDSFN(358)-NH(2)) effectively prevented Cry3Aa proteolytic processing and nearly abolished pore formation, evidencing the functional significance of the Cry3Aa-ADAM interaction in relation to this toxin mode of action. PMID- 17714690 TI - Osteoclastic activity induces osteomodulin expression in osteoblasts. AB - Bone resorption by osteoclasts stimulates bone formation by osteoblasts. To isolate osteoblastic factors coupled with osteoclast activity, we performed microarray and cluster analysis of 8 tissues including bone, and found that among 10,490 genes, osteomodulin (OMD), an extracellular matrix keratan sulfate proteoglycan, was simultaneously induced with osteoclast-specific markers such as MMP9 and Acp5. OMD expression was detected in osteoblasts and upregulated during osteoblast maturation. OMD expression in osteoblasts was also detected immunohistochemically using a specific antibody against OMD. The immunoreactivity against OMD decreased in op/op mice, which lack functional macrophage colony stimulating factor (M-CSF) and are therefore defective in osteoclast formation, when compared to wild-type littermates. OMD expression in op/op mice was upregulated by M-CSF treatment. Since the M-CSF receptor c-Fms was not expressed in osteoblasts, it is likely that OMD is an osteoblast maturation marker that is induced by osteoclast activity. PMID- 17714691 TI - Nicotinic interactions with antipsychotic drugs, models of schizophrenia and impacts on cognitive function. AB - People with schizophrenia often have substantial cognitive impairments, which may be related to nicotinic receptor deficits, (alpha7 and alpha4beta2), documented in the brains of people with schizophrenia. The large majority of people with schizophrenia smoke cigarettes. Thus, nicotinic interactions with antipsychotic drugs are widespread. Complementary co-therapies of novel nicotinic ligands are being developed to add to antipsychotic therapy to treat the cognitive impairment of schizophrenia. Thus, it is critical to understand the interaction between nicotinic treatments and antipsychotic drugs. Nicotinic interactions with antipsychotic drugs, are complex since both nicotine and antipsychotics have complex actions. Nicotine stimulates and desensitizes nicotinic receptors of various subtypes and potentiates the release of different neurotransmitters. Antipsychotics also act on a verity of receptor systems. For example, clozapine acts as an antagonist at a variety of neurotransmitter receptors such as those for dopamine, serotonin, norepinepherine and histamine. In a series of studies, we have found that in normally functioning rats, moderate doses of clozapine impair working memory and that clozapine blocks nicotine-induced memory and attentional improvement. Clozapine and nicotine can attenuate each other's beneficial effects in reversing the memory impairment caused by the psychototmimetic drug dizocilpine. A key to the clozapine-induced attenuation of nicotine-induced cognitive improvement appears to be its 5HT(2) antagonist properties. The selective 5HT(2) antagonist ketanserin has a similar action of blocking nicotine-induced memory and attentional improvements. It is important to consider the interactions between nicotinic and antipsychotic drugs to develop the most efficacious treatment for cognitive improvement in people with schizophrenia. PMID- 17714693 TI - Identification of novel bradykinin-potentiating peptides (BPPs) in the venom gland of a rattlesnake allowed the evaluation of the structure-function relationship of BPPs. AB - Aiming to extend the knowledge about the diversity of bradykinin-potentiating peptides (BPPs) and their precursor proteins, a venom gland cDNA library from the South American rattlesnake (Crotalus dursissus terrificus, Cdt) was screened. Two novel homologous cDNAs encoding the BPPs precursor protein were cloned. Their sequence contain only one single longer BPP sequence with the typical IPP tripeptide, and two short potential BPP-like molecules, revealing a unique structural organization. Several peptide sequences structurally similar to the BPPs identified in the precursor protein from Cdt and also from others snakes, were chemically synthesized and were bioassayed both in vitro and in vivo, by means of isolated smooth muscle preparations and by measurements of blood pressure in anaesthetized rats, respectively. We demonstrate here that a pyroglutamyl residue at the N-terminus with a high content of proline residues, even with the presence of a IPP moiety characteristic of typical BPPs, are not enough to determine a bradykinin-potentiating activity to these peptides. Taken together, our results indicate that the characterization of the BPPs precursor proteins and identification of characteristic glutamine residues followed by proline-rich peptide sequences are not enough to predict if these peptides, even with a pyroglutamyl residue at the N-terminus, will present the typical pharmacological activities described for the BPPs. PMID- 17714694 TI - Modulation of glyceraldehyde 3 phosphate dehydrogenase activity and tyr phosphorylation of Band 3 in human erythrocytes treated with ferriprotoporphyrin IX. AB - Erythrocyte glyceraldehyde-3-phosphate dehydrogenase (G3PD), is a glycolytic enzyme normally inhibited upon binding to the anion transporter Band 3 and activated when free in the cytosol. We have previously reported that ferric protoporphyrin IX (FP) enhances G3PD activity in human erythrocytes (RBC). This could be due to two mechanisms considered in this work: Band 3 tyrosine phosphorylation or oxidative damage of specific G3PD binding sites in the membrane. In both cases binding of G3PD to the membrane would be prevented, leading to the enhancement of G3PD activity. Here, we show that FP induces a dose and time-dependent phosphorylation of tyrosine 8 and 21 of Band 3, as confirmed by the recruitment of SHP2 phosphatase to the membrane. It appears that Band 3 phosphorylation is due to the oxidation of critical sulfydryl groups of a membrane phosphatase (PTP). Data on membrane localization, Mg2+ dependence, sensitivity to thiol oxidizing agents and protection by N-acetylcysteine (NAC) and DTT strongly suggest the involvement of PTP1B, the major PTP of human RBC associated to and acting on Band 3. However, FP activates G3PD even when Band 3 phosphorylation is inhibited, therefore phosphorylation is not the mechanism underlying G3PD activation by FP. The capacity of NAC of counteracting the stimulatory activity of FP, supports the hypothesis that FP might induce the oxidative damage of specific G3PD binding sites in the membrane, causing the displacement of the enzyme into the cytosol and/or the release from its binding site and therefore its activation. PMID- 17714692 TI - Treating schizophrenia symptoms with an alpha7 nicotinic agonist, from mice to men. AB - Current antipsychotic treatments fail to fully address the range of symptoms of schizophrenia, particularly with respect to social and occupational dysfunctions. Recent work has highlighted the role of nicotinie in both cognitive and attentional deficits as well as deficient processing of repetitive sensory information. The predilection for schizophrenia patients to be extremely heavy cigarette smokers may be related to their attempt to compensate for a reduction in hippocampal alpha7 nicotinic cholinergic receptors by delivering exogenous ligand to the remaining receptors. Studies in rodent models of both learning and memory deficits and deficits in sensory inhibition have confirmed a role for the alpha7 subtype of the nicotinic cholinergic receptor in these processes. Rodent studies also demonstrated the efficacy of a selective partial alpha7 nicotinic agonist, DMXBA, to improve these deficits. Subsequent human clinical trials demonstrated improved sensory inhibition in 12 schizophrenia patients and showed improvement in several subtests of the RBANS learning and memory assessment instrument. These data suggest that therapeutic agents selected for alpha7 nicotinic activity may have utility in treating certain symptoms of schizophrenia. PMID- 17714695 TI - Effects of anti-inflammatory drugs on proliferation, cytotoxicity and osteogenesis in bone marrow mesenchymal stem cells. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) were found to suppress proliferation and induce cell death in cultured osteoblasts, and steroids were found to decrease the osteogenesis potential of mesenchymal stem cells. In this study, we further tested the effects of anti-inflammatory drugs (AIDs) on the functions of bone marrow mesenchymal stem cells (BMSCs). The BMSCs from mice (D1 cells) and humans (hBMSCs) were treated with dexamethasone (10(-7) to 10(-6) M), cyclooxygenase-2 (COX-2) selective NSAIDs (10(-6) to 10(-5) M) and non-selective NSAIDs (10(-5) to 10(-4) M). Drug effects on proliferation, cell cycle kinetics, cytotoxicity and mRNA and protein expressions of cell cycle regulators were tested. The osteogenesis potential of D1-cells were evaluated by testing mRNA expressions of type Ialpha collagen and osteocalcin 2-8 days after treatments, and testing mineralization 1-3 weeks after treatments. The results showed that all the tested drugs suppressed proliferation and arrested cell cycle of D1 cells, but no significant cytotoxic effects was found. Prostaglandin E1, E2 and F2alpha couldn't rescue the effects of AIDs on proliferation. The p27kip1 expression was up-regulated by indomethacin, celecoxib and dexamethasone in both D1-cells and hBMSCs. Higher concentrations of indomethacin and dexamethasone also up-regulated p21Cip1/Waf1 expression in hBMSCs, and so did celecoxib on D1-cells. Expressions of cyclin E1 and E2 were down-regulated by these AIDs in D-cells, while only cyclin E2 was down-regulated by dexamethasone in hBMSCs. All the tested NSAIDs revealed no obvious detrimental effects on osteogenic differentiation of D1-cells. These results suggest that the proliferation suppression of AIDs on BMSCs may act via affecting expressions of cell cycle regulators, but not prostaglandin-related mechanisms. PMID- 17714696 TI - Differential regulation on human skin fibroblast by alpha1 adrenergic receptor subtypes. AB - Alpha 1 adrenoceptor (alpha1-AR) regulation of DNA synthesis was studied in human neonatal foreskin fibroblast. Saturation assay with a specific radioligand for alpha1 adrenergic [3H]-prazosin revealed two saturated and specific binding sites with high or low affinity. Competitive binding assay with different antagonist subtypes, defined pharmacologically three major types of alpha1-AR. The alpha1-AR agonists (from 1x10(-10) to 1x10(-4) M) triggered a biphasic action on DNA synthesis reaching maximal stimulation at 1x10(-9) M and maximal inhibition at 1x10(-6) M. Prazosin, abolished the stimulatory (pA2: 9.24) and inhibitory (pA2: 8.80) actions of alpha1-AR agonists. The alpha1-AR stimulation resulted in the activation of phosphoinositide turnover (InsP) via phospholipase C (PLC) involving calcium/calmodulin (CaM) and nitric oxide synthase (NOS) that correlates with the DNA synthesis increment; whereas the inhibition resulted in a decrease of cyclic AMP (cAMP) accumulation via adenylate cyclase inhibition. The potency displayed by the specific antagonists tested in binding, DNA synthesis, InsP and NOS at low agonist concentration suggests that they can be elicited by the activation of the same receptor (alpha1B-AR subtype); while the decrement in DNA synthesis and cAMP at high concentration account by the activation of alpha1D AR coupled to Gi protein. Non-functional alpha1A-AR in neonatal human foreskin fibroblast was observed. Results suggest that the expression of alpha1-AR subtypes on human skin fibroblast may differentially activate signaling pathways that modulate physiological response of the cells. PMID- 17714697 TI - Preparation and characterization of dialkylphosphoryl-obidoxime conjugates, potent anticholinesterase derivatives that are quickly hydrolyzed by human paraoxonase (PON1192Q). AB - The potential of the most active pyridinium-4-aldoximes, such as obidoxime and trimedoxime, to reactivate phosphorylated acetylcholinesterase is not fully exploited because of inevitable formation of phosphoryloximes (POXs) with extremely high anticholinesterase activity. Hence, a topochemical equilibrium is expected at the active site, with the freshly reactivated enzyme being rapidly re inhibited by POX produced during reactivation. In the present study, dimethylphosphoryl-, diethylphosphoryl-, and diisopropyl-obidoxime conjugates were generated and isolated in substance. Their inhibition rate of acetylcholinesterase from human red cell membranes was by a factor of 2250, 480 and 600 higher than that observed with paraoxon-methyl, paraoxon-ethyl, and diisopropyl phosphorofluoridate, respectively. All three POXs were hydrolyzed by human paraoxonase (PON1), with the alloenzyme PON1192Q being about 50-fold more active than PON1192R. The rate of hydrolysis, yielding obidoxime, was 1:6:0.03 for the three POXs, respectively. The rate of non-enzymic degradation, yielding obidoxime mononitrile, was similar with the three POXs and showed a high dependency on the reaction temperature (activation energy 83 kJ/mol), while enzymic hydrolysis required less energy (16 kJ/mol). To determine POX-hydrolase activity, we preferred a reaction temperature of 20 degrees C to reduce the noise of spontaneous degradation. A plot of POX-hydrolase versus salt-stimulated paraoxonase activity showed a highly discriminating power towards the PON1Q192R alloenzymes, which may be based on repulsive forces of the quaternary nitrogen atoms of the protonated arginine subtype and the bisquaternary POXs. It is concluded that the pharmacogenetic PON1Q192R polymorphism may be another contributor to the large variability of susceptible subjects seen in obidoxime treated patients. PMID- 17714698 TI - Enriched environment and the effect of age on ischemic brain damage. AB - Stroke affects all age groups from the newborn to the elderly. Previous work from our laboratory has shown that despite a greater susceptibility to brain damage, the immature brain recovers more rapidly and to a greater extent than does the more mature nervous system. In the current study, we examined the influence of environmental enrichment on the effects of age on the brain damaging effects of stroke. Rats aged 10, 63, and 180 days received ischemic insults following stereotactic intra-cerebral injection of endothelin-1, and resulting in injury to the right middle cerebral artery territory. Rats were then housed in either environmentally enriched cages, or standard cages for 60 days, after which they were sacrificed, and brain volumes determined for the extent of neurologic injury. Rats receiving the insult at 10 days of age showed a reduction of pathologic injury when housed in the enriched cages compared to standard. Conversely, rats receiving the insult at 180 days and housed environmentally enriched cages actually showed an increased volume of brain damage compared to controls. Our findings clearly indicate the dramatic influence of age on the extent of stroke and the influence of rehabilitative therapies. Behavioral correlation to morphologic alterations is required. Attempts at therapeutic interventions clearly need to be age-specific. PMID- 17714700 TI - Hoxd and Gli3 interactions modulate digit number in the amniote limb. AB - During limb development, Sonic hedgehog (SHH) and HOX proteins are considered among the most important factors regulating digit number and identity. SHH signaling prevents the processing of GLI3 into a short form that functions as a strong transcriptional repressor. Gli3 mutant limbs are characterized by a severe polydactyly and associated ectopic anterior expression of 5'Hoxd genes. To genetically determine the involvement of 5'Hoxd genes in the polydactyly of Gli3 mutants, we have generated a compound mutant that simultaneously removes the three most 5'-located Hoxd genes and Gli3. Remarkably, the limbs that form in the absence of all four of these genes show the most severe polydactyly so far reported in the mouse. The analysis of gene expression performed in compound mutants allows us to propose that the increase in the number of digits is mediated by the gain in function of Hoxd10 and Hoxd9. Our results also support the notion that an adequate balance between positive and negative effects of different Hoxd genes is required for pentadactyly. PMID- 17714699 TI - Identification of transcriptional targets of the dual-function transcription factor/phosphatase eyes absent. AB - Drosophila eye specification and development relies on a collection of transcription factors termed the retinal determination gene network (RDGN). Two members of this network, Eyes absent (EYA) and Sine oculis (SO), form a transcriptional complex in which EYA provides the transactivation function while SO provides the DNA binding activity. EYA also functions as a protein tyrosine phosphatase, raising the question of whether transcriptional output is dependent or independent of phosphatase activity. To explore this, we used microarrays together with binding site analysis, quantitative real-time PCR, chromatin immunoprecipitation, genetics and in vivo expression analysis to identify new EYA SO targets. In parallel, we examined the expression profiles of tissue expressing phosphatase mutant eya and found that reducing phosphatase activity did not globally impair transcriptional output. Among the targets identified by our analysis was the cell cycle regulatory gene, string (stg), suggesting that EYA and SO may influence cell proliferation through transcriptional regulation of stg. Future investigation into the regulation of stg and other EYA-SO targets identified in this study will help elucidate the transcriptional circuitries whereby output from the RDGN integrates with other signaling inputs to coordinate retinal development. PMID- 17714701 TI - The Drosophila nerfin-1 mRNA requires multiple microRNAs to regulate its spatial and temporal translation dynamics in the developing nervous system. AB - The mRNA encoding the Drosophila Zn-finger transcription factor Nerfin-1, required for CNS axon pathfinding events, is subject to post-transcriptional silencing. Although nerfin-1 mRNA is expressed in many neural precursor cells including all early delaminating CNS neuroblasts, the encoded Nerfin-1 protein is detected only in the nuclei of neural precursors that divide just once to generate neurons and then only transiently in nascent neurons. Using a nerfin-1 promoter-controlled reporter transgene, replacement of the nerfin-1 3' UTR with the viral SV-40 3' UTR releases the neuroblast translational block and prolongs reporter protein expression in neurons. Comparative genomics analysis reveals that the nerfin-1 mRNA 3' UTR contains multiple highly conserved sequence blocks that either harbor and/or overlap 21 predicted binding sites for 18 different microRNAs. To determine the functional significance of these microRNA-binding sites and less conserved microRNA target sites, we have studied their ability to block or limit the expression of reporter protein in nerfin-1-expressing cells during embryonic development. Our results indicate that no single microRNA is sufficient to fully inhibit protein expression but rather multiple microRNAs that target different binding sites are required to block ectopic protein expression in neural precursor cells and temporally restrict expression in neurons. Taken together, these results suggest that multiple microRNAs play a cooperative role in the post-transcriptional regulation of nerfin-1 mRNA, and the high degree of microRNA-binding site evolutionary conservation indicates that all members of the Drosophila genus employ a similar strategy to regulate the onset and extinction dynamics of Nerfin-1 expression. PMID- 17714702 TI - Tanshinone congeners improve memory impairments induced by scopolamine on passive avoidance tasks in mice. AB - Tanshinones are a group of diterpenoids found in the roots of Salvia miltiorrhiza Bunge which has been used to treat cardiac disease. In the present study, we investigated the effect of the tanshinone congeners, tanshinone I, tanshinone IIA, cryptotanshinone, and 15, 16-dihydrotanshinone I, on learning and memory impairments induced by scopolamine (1 mg/kg, i.p.), a muscarinic antagonist, using passive avoidance tasks in mice. Tacrine was used as a positive control. Tanshinone I (2 or 4 mg/kg, p.o.), tanshinone IIA (10 or 20 mg/kg, p.o.), cryptotanshinone (10 mg/kg, p.o.), and 15, 16-dihydrotanshinone I (2 or 4 mg/kg, p.o.) significantly reversed scopolamine-induced cognitive impairments (P<0.05). Tanshinone I (2 mg/kg, p.o.) and tanshinone IIA (10 or 20 mg/kg, p.o.) were also reversed diazepam-induced cognitive dysfunctions (P<0.05). In addition, cryptotanshinone and 15, 16-dihydrotanshinone I were found to have an inhibitory effect on acetylcholinesterase in vitro with IC(50) values 82 and 25 microM, respectively. Furthermore, cryptotanshinone inhibited acetylcholinesterase activity for 3 h and 15, 16-dihydrotanshinone I for 6 h in an ex-vivo study. These results suggest that tanshinone congeners may be useful for the treatment of cognitive impairment and that their beneficial effects are mediated, in part, by cholinergic signaling enhancement. PMID- 17714703 TI - Reorganization of the actin cytoskeleton via transcriptional regulation of cytoskeletal/focal adhesion genes by myocardin-related transcription factors (MRTFs/MAL/MKLs). AB - RhoA is a crucial regulator of stress fiber and focal adhesion formation through the activation of actin nucleation and polymerization. It also regulates the nuclear translocation of myocardin-related transcription factor-A and -B (MRTF A/B, MAL or MKL 1/2), which are co-activators of serum response factor (SRF). In dominant-negative MRTF-A (DN-MRTF-A)-expressing NIH 3T3 cell lines, the expressions of several cytoskeletal/focal adhesion genes were down-regulated, and the formation of stress fiber and focal adhesion was severely diminished. MRTF A/B-knockdown cells also exhibited such cytoskeletal defects. In reporter assays, both RhoA and MRTF-A enhanced promoter activities of these genes in a CArG-box dependent manner, and DN-MRTF-A inhibited the RhoA-mediated activation of these promoters. In dominant-negative RhoA (RhoA-N19)-expressing NIH 3T3 cell lines, the nuclear translocation of MRTF-A/B was predominantly prevented, resulting in the reduced expression of cytoskeletal/focal adhesion proteins. Further, constitutive-active MRTF-A/B increased the expression of endogenous cytoskeletal/focal adhesion proteins, and thereby rescued the defective phenotype of stress fibers and focal adhesions in RhoA-N19 expressing cells. These results indicate that MRTF-A/B act as pivotal mediators of stress fiber and focal adhesion formation via the transcriptional regulation of a subset of cytoskeletal/focal adhesion genes. PMID- 17714704 TI - Ranibizumab inhibits multiple forms of biologically active vascular endothelial growth factor in vitro and in vivo. AB - Neovascular age-related macular degeneration (AMD) is the leading cause of blindness in older adults in the Western world. Ranibizumab (Lucentis), a humanized antibody fragment directed against vascular endothelial growth factor (VEGF-A), was recently approved by the US Food and Drug Administration (FDA) for the treatment of neovascular AMD. The objective of this study was to characterize the binding affinity and pharmacological activity of ranibizumab for 3 biologically active forms of VEGF-A: VEGF165, VEGF121, and VEGF110. The apparent equilibrium binding affinity of ranibizumab for VEGF-A molecules was determined by Biacore analysis; the biological activity of VEGF-A was demonstrated in a human umbilical vein endothelial cell (HUVEC) proliferation-inhibition assay. Inhibition of VEGF-A-induced vascular permeability by ranibizumab was assessed in vivo using hairless guinea pigs and a modified Miles assay. Ranibizumab was capable of binding to recombinant human VEGF165, VEGF121, and VEGF110 (KD < or = 192 pM), inhibiting VEGF-A-induced HUVEC proliferation in a concentration dependent manner. Ranibizumab also exerted potent dose-dependent inhibition (IC(50) of 0.4-1.2 nM) of the vascular permeability-enhancing activity of VEGF165, VEGF121, and VEGF110 in the Miles assay. In conclusion, these results show that ranibizumab is capable of binding to and specifically inhibiting the activities of 3 biologically active forms of VEGF-A. As VEGF-A plays a pivotal role in the pathogenesis of neovascular AMD, ranibizumab activity, as demonstrated in this study, supports its clinical utility in the treatment of this disease. PMID- 17714705 TI - Behavioral alterations in the pilocarpine model of temporal lobe epilepsy in mice. AB - Psychiatric disorders frequently occur in patients with epilepsy, but the relationship between epilepsy and psychopathology is poorly understood. Frequent comorbidities in epilepsy patients comprise major depression, anxiety disorders, psychosis and cognitive dysfunction. Animal models of epilepsy, such as the pilocarpine model of acquired epilepsy, are useful to study the relationship between epilepsy and behavioral dysfunctions. However, despite the advantages of mice in studying the genetic underpinning of behavioral alterations in epilepsy, mice have only rarely been used to characterize behavioral correlates of epilepsy. This prompted us to study the behavioral and cognitive alterations developing in NMRI mice in the pilocarpine model of epilepsy, using an anxiety test battery as well as tests for depression, drug-induced psychosis, spatial memory, and motor functions. In order to ensure the occurrence of status epilepticus (SE) and decrease mortality, individual dosing of pilocarpine was performed by ramping up the dose until onset of SE. This protocol was used for studying the consequences of SE, i.e. hippocampal damage, incidence of epilepsy with spontaneous recurrent seizures, and behavioral alterations. SE was terminated by diazepam after either 60, 90 or 120 min. All mice that survived SE developed epilepsy, but the severity of hippocampal damage varied depending on SE length. In all anxiety tests, except the elevated plus maze test, epileptic mice exhibited significant increases of anxiety-related behavior. Surprisingly, a decrease in depression-like behavior was observed in the forced swimming and tail suspension tests. Furthermore, epileptic mice were less sensitive than controls to most of the behavioral effects induced by MK-801 (dizocilpine). Learning and memory were impaired in epileptic mice irrespective of SE duration. Thus, the pilocarpine-treated mice seem to reflect several of the behavioral and cognitive disturbances that are associated with epilepsy in humans. This makes these animals an ideal model to study the neurobiological mechanisms underlying the association between epilepsy and psychopathology. PMID- 17714706 TI - Cortical cholinergic deficiency enhances amphetamine-induced dopamine release in the accumbens but not striatum. AB - Cholinergic dysfunction has been implicated as a putative contributing factor in the pathogenesis of schizophrenia. Recently, we showed that cholinergic denervation of the neocortex in adult rats leads to a marked increase in the behavioral response to amphetamine. The main objective of this study was to investigate if the enhanced locomotor response to amphetamine seen after cortical cholinergic denervation was paralleled by an increased amphetamine-induced release of dopamine in the nucleus accumbens and/or striatum. The corticopetal cholinergic projections were lesioned by intraparenchymal infusion of 192 IgG saporin into the nucleus basalis magnocellularis of adult rats. Amphetamine induced dopamine release in the nucleus accumbens or striatum was monitored by in vivo microdialysis 2 to 3 weeks after lesioning. We found that cholinergic denervation of the rat neocortex leads to a significantly increased amphetamine induced dopamine release in the nucleus accumbens. Interestingly, the cholinergic lesion did not affect amphetamine-induced release of dopamine in the striatum. The enhanced amphetamine-induced dopamine release in the nucleus accumbens in the cholinergically denervated rats could be reversed by administration of the muscarinic agonist oxotremorine, but not nicotine, prior to the amphetamine challenge, suggesting that loss of muscarinic receptor stimulation is likely to have caused the observed effect. The results suggest that abnormal responsiveness of dopamine neurons can be secondary to cortical cholinergic deficiency. This, in turn, might be of relevance for the pathophysiology of schizophrenia and provides a possible link between cholinergic disturbances and alteration of dopamine transmission. PMID- 17714708 TI - Cardiac mitochondrial ATP-sensitive potassium channel is activated by nitric oxide in vitro. AB - Previous observations on the activation of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) by nitric oxide (NO) in myocardial preconditioning were based on indirect evidence. In this study, we have investigated the direct effect of NO on the rat cardiac mitoK(ATP) after reconstitution of the inner mitochondrial membranes into lipid bilayers. We found that the mitoK(ATP) was activated by exogenous NO donor S-nitroso-N-acetyl penicillamine or PAPA NONOate. This activation was inhibited by mitoK(ATP) blockers 5-hydroxydecanoate or glibenclamide. Our observations confirm that NO can directly activate the cardiac mitoK(ATP), which may underlie its contribution to myocardial preconditioning. PMID- 17714709 TI - A novel mutation c.118delA in exon 1 of the androgen receptor gene resulting in complete androgen insensitivity syndrome within a large family. AB - OBJECTIVE: To confirm the clinical diagnosis of complete androgen insensitivity syndrome (CAIS) by molecular genetic testing and to offer carriership testing in female relatives should a disease-causing mutation be found. DESIGN: Case report. SETTING: University hospital. PATIENT(S): Caucasian family in which two sisters were clinically diagnosed with CAIS during childhood. INTERVENTION(S): Molecular genetic testing of the androgen receptor (AR) gene. MAIN OUTCOME MEASURE(S): Genetic counseling in affected and unaffected female family members. RESULT(S): Identification of a novel mutation in exon 1 of the AR gene, c.118delA. This frameshift mutation (p.R40fs174ter) is located in the N-terminal transactivation domain and leads to a predicted truncated protein of 173 amino acids with loss of the major part of the N-terminal transactivation domain, and the DNA-binding and ligand-binding domain. Segregation analysis showed carriership of this mutation in the mother and two sisters. CONCLUSION(S): In agreement with functional studies of other AR gene mutations located in the N-terminal transactivation domain, this novel mutation c.118delA is presumed to result in a complete loss of AR function and to be associated with CAIS. Our study extends the spectrum of exon 1 mutations in the AR gene leading to CAIS. Molecular genetic testing of CAIS is recommended not only for diagnostic purposes in affected individuals but also for carriership testing and genetic counseling in unaffected female family members. PMID- 17714707 TI - Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia. AB - Cerebrovascular inflammation contributes to secondary brain injury following ischemia. Recent in vitro studies of cell migration and molecular guidance mechanisms have indicated that the Slit family of secreted proteins can exert repellant effects on leukocyte recruitment in response to chemoattractants. Utilizing intravital microscopy, we addressed the role of Slit in modulating leukocyte dynamics in the mouse cortical venular microcirculation in vivo following TNFalpha application or global cerebral ischemia. We also studied whether Slit affected neuronal survival in the mouse global ischemia model as well as in mixed neuronal-glial cultures subjected to oxygen-glucose deprivation. We found that systemically administered Slit significantly attenuated cerebral microvessel leukocyte-endothelial adherence occurring 4 h after TNFalpha and 24 h after global cerebral ischemia. Administration of RoboN, the soluble receptor for Slit, exacerbated the acute chemotactic response to TNFalpha. These findings are indicative of a tonic repellant effect of endogenous Slit in brain under acute proinflammatory conditions. Three days of continuous systemic administration of Slit following global ischemia significantly attenuated the delayed neuronal death of hippocampal CA1 pyramidal cells. Moreover, Slit abrogated neuronal death in mixed neuronal-glial cultures exposed to oxygen-glucose deprivation. The ability of Slit to reduce the recruitment of immune cells to ischemic brain and to provide cytoprotective effects suggests that this protein may serve as a novel anti-inflammatory and neuroprotective target for stroke therapy. PMID- 17714710 TI - Conservative management of a near-term cervico-isthmic pregnancy, followed by a successful subsequent pregnancy: a case report. AB - OBJECTIVE: To describe a rare case of a cervico-isthmic pregnancy with anterior placenta percreta that was treated at 34 weeks of gestation by removing the placenta and the attached uterine wall in one piece. DESIGN: Case report. SETTING: Tertiary university hospital. PATIENT(S): A 32-year-old woman was diagnosed with a cervico-isthmic pregnancy and an anterior placenta percreta at 34 weeks' gestation at delivery by a cesarean section. INTERVENTION(S): Delivery of the neonate was performed by a uterine incision beyond the limits of the placenta. Thereafter, the placenta and the attached uterine wall were removed step by step by ligature section. MAIN OUTCOME MEASURE(S): Intraprocedural or postprocedural complications and fertility preservation. RESULT(S): The delivery was successfully performed without intraprocedural or postprocedural complications and with preservation of the patient's fertility. A successful pregnancy was conducted 1 year later. CONCLUSION(S): In case of cervico-isthmic pregnancy with anterior placenta percreta, resection in one block of the placenta and the attached uterine wall may be an option for preserving fertility. PMID- 17714711 TI - Prognosis for clinical pregnancy and delivery after total fertilization failure during conventional in vitro fertilization or intracytoplasmic sperm injection. AB - OBJECTIVE: To determine the prognosis for clinical pregnancy and delivery after total fertilization failure. DESIGN: Retrospective analysis of patient treatment cycles. SETTING: Private fertility clinic. PATIENT(S): 555 couples who had total fertilization failure during a cycle of conventional in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Delivery rates, peak estradiol level, number of mature follicles, number of oocytes retrieved, number of mature oocytes, sperm concentration, and sperm motility. RESULT(S): Delivery rates for IVF patients who elected to continue treatment after fertilization failure were 44% per patient, 25% per embryo transfer (ET), and 22% per cycle. Delivery rates for ICSI patients were 36% per patient, 23% per ET, and 18% per cycle. The number of mature oocytes was always statistically significantly lower in the total fertilization failure cycle when compared with fertilization cycles that occurred either before or after, whether ICSI or conventional IVF was involved. CONCLUSION(S): The prognosis for pregnancy is encouraging in subsequent cycles after total fertilization failure. Fertilization failure was a result of suboptimal response to ovarian stimulation. PMID- 17714712 TI - Prolactin receptor, growth hormone receptor, and putative somatolactin receptor in Mozambique tilapia: tissue specific expression and differential regulation by salinity and fasting. AB - In fish, pituitary growth hormone family peptide hormones (growth hormone, GH; prolactin, PRL; somatolactin, SL) regulate essential physiological functions including osmoregulation, growth, and metabolism. Teleost GH family hormones have both differential and overlapping effects, which are mediated by plasma membrane receptors. A PRL receptor (PRLR) and two putative GH receptors (GHR1 and GHR2) have been identified in several teleost species. Recent phylogenetic analyses and binding studies suggest that GHR1 is a receptor for SL. However, no studies have compared the tissue distribution and physiological regulation of all three receptors. We sequenced GHR2 from the liver of the Mozambique tilapia (Oreochromis mossambicus), developed quantitative real-time PCR assays for the three receptors, and assessed their tissue distribution and regulation by salinity and fasting. PRLR was highly expressed in the gill, kidney, and intestine, consistent with the osmoregulatory functions of PRL. PRLR expression was very low in the liver. GHR2 was most highly expressed in the muscle, followed by heart, testis, and liver, consistent with this being a GH receptor with functions in growth and metabolism. GHR1 was most highly expressed in fat, liver, and muscle, suggesting a metabolic function. GHR1 expression was also high in skin, consistent with a function of SL in chromatophore regulation. These findings support the hypothesis that GHR1 is a receptor for SL. In a comparison of freshwater (FW)- and seawater (SW)-adapted tilapia, plasma PRL was strongly elevated in FW, whereas plasma GH was slightly elevated in SW. PRLR expression was reduced in the gill in SW, consistent with PRL's function in freshwater adaptation. GHR2 was elevated in the kidney in FW, and correlated negatively with plasma GH, whereas GHR1 was elevated in the gill in SW. Plasma IGF-I, but not GH, was reduced by 4 weeks of fasting. Transcript levels of GHR1 and GHR2 were elevated by fasting in the muscle. However, liver levels of GHR1 and GHR2 transcripts, and liver and muscle levels of IGF-I transcripts were unaffected by fasting. These results clearly indicate tissue specific expression and differential physiological regulation of GH family receptors in the tilapia. PMID- 17714714 TI - Circadian behavioral and melatonin rhythms in the European starling under light dark cycles with steadily changing periods: evidence for close mutual coupling? AB - In European starlings exposed to constant conditions, circadian rhythms in locomotion and feeding can occasionally exhibit complete dissociation from each other. Whether such occasional dissociation between two behavioral rhythms reflects on the strength of the mutual coupling of their internal oscillators has not been investigated. To examine this, as well as to elucidate the role of melatonin in this system, we simultaneously measured the rhythms of locomotion, feeding and melatonin secretion in starlings exposed to light-dark (LD) cycles of low intensity with steadily changing periods (T). In birds initially entrained to T 24 LD cycles (12L:12D, 10:0.2 lx), beginning on day 15, T was either lengthened to 26.5 h (experiment 1) or shortened to T 21.5 h (experiment 2) by changing the daily dark period 4 min each day. After 18 and 19 cycles of T 26.5 and T 21.5, respectively, birds were released into constant dim light conditions (LL(dim); 0.2 lx) for about 2 weeks. Locomotor and feeding rhythms were continuously recorded. Plasma melatonin levels were measured at three times: in T 24, when T equaled 26 or 22 h and at the end of T 26.5 or T 21.5 exposure. The results show that, contrary to our expectations, the three rhythms were not dissociated. Rather they remained synchronized and changed their phase angle difference with the light zeitgeber concomitantly and at the same rate. The melatonin rhythm stayed in synchrony with the behavioral rhythms and as a consequence, peaked either during day or at night, depending on the phase relationship between the activity rhythm and the zeitgeber cycle. PMID- 17714713 TI - Effects of reproductive activity and sex hormones on apoptosis in the epigonal organ of the skate (Leucoraja erinacea). AB - In elasmobranchs, a unique association exists between an immune tissue, the epigonal organ, and the gonads. The intimate morphological relationship between these tissues suggests functional interactions. In this study, we used apoptosis to assess differences between epigonal tissues of reproductively active (RA) and non-reproductively active (NRA) skates (Leucoraja erinacea). Plasma steroid levels were significantly higher in RA than in NRA animals, and TUNEL analysis showed that epigonal tissue of RA skates had greater DNA fragmentation than NRA skates. Addition of steroids to epigonal leukocytes in vitro demonstrated that progesterone, testosterone, and dexamethasone, but not estrogen, induced apoptosis of epigonal leukocytes as evidenced by DNA laddering and caspase-3 antibody labeling. This study supports recent evidence that cellular homeostasis of epigonal lymphomyeloid tissue may be influenced by gonadal activity and reproductive steroids in a representative of the most basal gnathastome group. PMID- 17714715 TI - Two simple and novel SISO controllers for induction motors based on adaptive passivity. AB - The design of two single-input single-output (SISO) controllers for induction motors based on adaptive passivity is presented in this paper. The two controllers work together with a field orientation block. Because of the adaptive nature of the proposed controllers, the knowledge of the set motor-load parameters is not needed and robustness under variations of such parameters is guaranteed. Simple proportional controllers for the torque, rotor flux and stator current control loops are used, due to the control simplification given by the use of feedback passive equivalence. A new principle called the "Torque-Flux Control Principle" is also stated in this article, which considerably simplifies the controller design, diminishing the control efforts and avoiding also rotor flux estimation. PMID- 17714716 TI - Positive association of adiponectin with soluble vascular cell adhesion molecule sVCAM-1 levels in patients with vascular disease or dyslipidemia. AB - The aim of our study was to evaluate the relationship of adiponectin to soluble forms of vascular cell adhesion molecule-1 (sVCAM-1) and intercellular cell adhesion molecule-1 (sICAM-1) in patients with cardiovascular disease or dyslipidemia. Two hundred and sixty-four patients (134 men/130 women, mean age 43.8+/-14.8/46.0+/-14.9 years) of Lipid Center, University Hospital Olomouc, off hypolipidemic therapy for at least 6 weeks, participated in the study. In multiple regression analysis, adiponectin was independently positively associated with serum HDL-cholesterol (p<0.0001) and sVCAM-1 (p<0.0001), female gender (p<0.0001) and negatively with hs-CRP (p=0.014). Serum concentration of adiponectin and sICAM-1 did not correlate but sICAM-1 was independently, positively associated with sVCAM-1 (p<0.0001) and negatively with markers of insulin resistance and inflammation, namely atherogenic index log[triglycerides/HDL-cholesterol] (p<0.0001), hs-CRP (p<0.001) and HOMA (p<0.05). Positive association of adiponectin with HDL-C and negative association with hs-CRP indicate anti-atherogenic properties of adiponectin. The finding of the positive association of adiponectin with sVCAM-1 in patients at risk is unexpected. We hypothesize that adiponectin may be involved (directly or indirectly) in shedding of ectodomains of VCAM-1 from endothelial surface and in this way down-regulates their effects. This process may be protective in the initial stages of atherosclerosis. PMID- 17714718 TI - C-reactive protein is related to extent and progression of coronary and extra coronary atherosclerosis; results from the Rotterdam study. AB - AIMS: Although prospective studies have unequivocally shown that C-reactive protein (CRP) is an independent predictor of future cardiovascular events, studies on the association between CRP and atherosclerosis have provided inconsistent results. We investigated the association of CRP with extent and progression of atherosclerosis in multiple vessel beds in a large, population based cohort study. METHODS: In the Rotterdam Study, standardized measurements of coronary and extra-coronary atherosclerosis were performed in 1962 persons and 6582 persons, respectively. Progression of extra-coronary atherosclerosis during a mean follow-up period of 6.4 years was assessed in 3757 persons. RESULTS: Independent and graded associations were found of CRP with the number of carotid plaques and carotid plaque progression ((OR 1.72; 95% CI 1.14-2.59) for severe progression in participants with CRP>3mg/dl versus participants with CRP<1mg/dl). Similarly, CRP was independently and graded related to ankle-brachial-index (ABI) and worsening ABI over the years ((OR 1.99; 95% CI 1.37-2.88) for severe progression in participants with CRP>3mg/dl versus participants with CRP<1mg/dl). Although CRP was independently related to the highest level of carotid intima media thickness (IMT), the association with change in IMT was not significant. Furthermore, there was an independent, graded relation between CRP and aortic calcification, but no independent association was observed with progression of aortic calcification, nor with the amount of coronary calcification. CONCLUSION: In this population-based study, independent and graded associations were present of CRP with extent and progression of carotid plaques and ABI, while associations with carotid IMT and aortic and coronary calcification were less pronounced. PMID- 17714719 TI - Effect of fatigue on the intra-cycle acceleration in front crawl swimming: a time frequency analysis. AB - The present study analyzes the changes in acceleration produced by swimmers before and after fatiguing effort. The subjects (n = 15) performed a 25-m crawl series at maximum speed without fatigue, and a second series with fatigue. The data were registered with a synchronized system that consisted of a position transducer (1 kHz) and a video photogrametry (50 Hz). The acceleration (ms(-2)) was obtained by the derivative analysis of the variation of the position with time. The amplitude in the time domain was calculated with the root mean square (RMS); while the peak power (PP), the peak power frequency (PPF) and the spectrum area (SA) were calculated in the frequency domain with Fourier analysis. On the one hand, the results of the temporal domain show that the RMS change percentage between series was 67.5% (p < 0.001). On the other hand, PP, PPF, and SA show significant changes (p < 0.001). PP and SA were reduced by 63.1% and 59.5%, respectively. Our results show that the acceleration analysis of the swimmer with Fourier analysis permits a more precise understanding of which propulsive forces contribute to the swimmer performance before and after fatigue appears. PMID- 17714717 TI - Association between brachial artery reactivity and cardiovascular disease status in an elderly cohort: the cardiovascular health study. AB - BACKGROUND AND OBJECTIVES: The association of brachial flow-mediated dilation (FMD) and cardiovascular disease (CVD) status is unclear especially in older adults whose FMD is greatly diminished. We assessed the association of FMD and the presence or absence of subclinical and clinical CVD in a population based cohort of older adults. METHODS AND RESULTS: FMD was measured in 2971 adults aged 72-98 years (mean age 78.6 years) who participated in the Cardiovascular Health Study. Multiple linear regression analysis was used to examine the association between FMD and CVD status (clinical, subclinical and free of CVD). Out of 2791 with complete data, 82.7% were Caucasians and 59% females. Seven hundred and forty-three were classified as having clinical CVD, 607 as subclinical CVD and 1441 as neither clinical CVD nor subclinical CVD (CVD free). FMD was higher in the CVD free group compared with either the clinical (3.13+/-0.05% vs 2.93+/ 0.07%, p=0.025) or the subclinical CVD group (3.13+/-0.05% vs 2.95+/-0.08%, p=0.05) after adjusting for covariates. There was no significant difference between the FMD of subjects with clinical and subclinical CVD (2.93+/-0.07% vs 2.95+/-0.08%, p=0.84). Similar but inverted associations were observed between height adjusted brachial artery diameter (BAD) and CVD status. However, FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD. CONCLUSION: Among older adults, those with either clinical or subclinical CVD have lower FMD than CVD free subjects. BAD showed similar but inverted associations with CVD status in this cohort. FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD. PMID- 17714720 TI - Development of a titanium dioxide nanoparticle pipette-tip for the selective enrichment of phosphorylated peptides. AB - The selective enrichment of specific proteins or peptides on micropipette tips prior to mass spectrometry analysis, which can minimize non-specific interferences as well as sample loss, has been an important issue in current proteomics field. In this paper, we have developed an easy-to-use phosphopeptide selective pipette tip in which titanium dioxide nanoparticles were embedded in monolithic structure photopolymerized from ethylene glycol dimethacrylate. The simple and convenient fabrication was feasible in a commercial polypropylene pipette tip. Phosphorylated peptides were isolated from non-phosphopeptides by TiO(2) nanoparticle and eluted by 100 mM ammonium phosphate (pH 8.5), which was compatible with 2,5-dihydroxybenzoic acid (DHB)/1% phosphoric acid matrix and allowed for direct analysis of the elution fraction by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) without the necessity of desalting pretreatment. Tryptic digested alpha-casein and beta-casein spiked into bovine serum albumin (BSA) nonphosphorylated peptides (molar ratio 1:1:10) were used to assess the selectivity of TiO(2) tips. The effect of 50 mM ammonium hydrogencarbonate, pH 8 in 50% acetonitrile used as a wash buffer in reduction of nonspecific bound peptide to TiO(2) tip was dramatic. Almost all non phosphopeptides were not detected by MALDI-MS analysis. The lowest detectable amount of phosphopeptide was estimated at low femtomole level. The easy-to-use TiO(2)-embeded tips operated in combination with the modified wash and elution conditions enable an efficient phosphopeptide enrichment for mass spectrometric analysis. PMID- 17714721 TI - Optimization of the matrix solid-phase dispersion sample preparation procedure for analysis of polycyclic aromatic hydrocarbons in soils: comparison with microwave-assisted extraction. AB - A fast and simple preparation procedure based on the matrix solid-phase dispersion (MSPD) technique is proposed for the first time for the isolation of 16 polycyclic aromatic hydrocarbons (PAHs) from soil samples. Naphthalene, acenaphthene, fluorene, phenanthrene, anthracene, fluoranthene, pyrene, benz[a]anthracene, chrysene, benzo[e]pyrene, benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[a]pyrene, dibenzo[a,h]anthracene, benzo[g,h,i]perylene, and indeno[1,2,3-c,d]pyrene were considered in the study. Extraction and clean-up of samples were carried out in a single step. The main parameters that affect extraction yield, such as dispersant, type and amount of additives, clean-up co-sorbent and extractive solvent were evaluated and optimized. The addition of an alkali solution in MSPD was required to provide quantitative recoveries. Analytical determinations were carried out by high performance liquid chromatography (HPLC) with fluorescence detection. Quantification limits (between 0.01 and 0.6 ng g(-1) dry mass) were well below the regulatory limits for all the compounds considered. The extraction yields for the different compounds obtained by MSPD were compared with the yields obtained by microwave-assisted extraction (MAE). To test the accuracy of the MSPD technique, the optimized methodology was applied to the analysis of standard reference material BCR-524 (contaminated industrial soil), with excellent results. PMID- 17714723 TI - Wetting behavior of a SiO(2)-polystyrene nanocomposite surface. AB - A SiO(2)-polystyrene (PS) nanocomposite surface was prepared with a simple method. The wetting behavior of the as-prepared surface was investigated. It was found that the as-prepared surface could be varied from superhydrophilicity to superhydrophobicity just by controlling the drying temperature and the content of SiO(2) nanoparticles in the system. In addition, a transition from the Wenzel regime to the Cassie regime was observed. PMID- 17714722 TI - Surface speciation of Cd(II) and Pb(II) on kaolinite by XAFS spectroscopy. AB - Little spectroscopic evidence exists in the literature describing the surface complexation of cadmium (Cd) and lead (Pb) on kaolinite, the dominant clay mineral present in highly weathered soils of tropical and humid climates. X-ray absorption fine structure (XAFS) spectroscopy data at the Cd K and Pb L(III) edges were collected on Cd- and Pb-sorbed kaolinite samples and compared to a suite of reference materials including Pb and Cd sorbed on amorphous (am )gibbsite. Cadmium formed dominantly (>75%) outer sphere complexes on kaolinite and a small fraction of CdOHCl complexes. In contrast Cd adsorbed as an inner sphere complex on gibbsite, suggesting that the Si tetrahedral sheet hindered Cd sorption to the Al octahedral sheet on kaolinite. Lead formed polymeric complexes, which bonded to kaolinite via edge sharing with surface Al octahedra. Two distinct Pb-Al edge-sharing distances on am-gibbsite, as opposed to one on kaolinite, suggested a similar steric hindrance effect for the surface complexation of polymeric Pb complexes on kaolinite. The results of this study show that the Si tetrahedral sheet limited the surface complexation of Cd and Pb on kaolinite, elevating kaolinite's permanent negative charge properties in retaining these heavy metals at its surface. PMID- 17714724 TI - Counterion and composition effects on discotic nematic lyotropic liquid crystals II. Ion exchange and molecular dynamics. AB - The static fluorescence quenching of pyrene by bromide, at the interface of mixed TTAC/TTAB discotic nematic lyotropic liquid crystals, allowed an estimation of the equilibrium constant for the exchange of chloride by bromide. The affinity of the interface for bromide is much higher than for chloride (K(Br-/Cl-) = 13.2). For a molecular level understanding of the experimental results of this and the preceding paper, 20 ns molecular dynamics (MD) simulations were calculated for samples with TTAB/TTAC molar percent ratios 100/0 (A), 50/50 (B) and 0/100 (C). The increment in the concentration of chloride induces a wider distribution of ammonium headgroups along the axis normal to the bilayer surface, increasing the width of the interface. The charge density profile of simulation B shows that the concentration of bromide is higher than the concentration of chloride in the vicinity the ammonium headgroups. The short range contribution to the electrostatic energy from the ammonium-ammonium repulsion is 291.7 kJ/mol for TTAC and 195.6 kJ/mol for TTAB, and the short range ammonium-halide interaction is -6166 kJ/mol for TTAC and -6607 kJ/mol for TTAB, from simulations A and C, respectively. These results are in agreement with a more neutralized TTAB interface. Consistently, the electric dipole moments of water are significantly more aligned with the larger electric field of the TTAB interface. PMID- 17714725 TI - Interfacial tension studies of crown ethers at air/water and hexane/water interfaces. AB - The adsorption of phase transfer catalysts, 18-crown-6 and dicyclohexano-18-crown 6, at the air/water and the hexane/water interfaces were investigated. Interfacial tension sigma decreased by increasing concentrations of these compounds and therefore both of these crown ethers are accumulated at interfaces. The variation of sigma with concentration for both compounds follows the Szyszkowski equation very well, from which the values of saturated surface densities and interaction parameters have been evaluated. On the basis of occupied surface area of each molecule, the orientation of each of molecules at the air/water and the hexane/water interfaces have been proposed. The present results show that dicyclohexano-18-crown-6 has the higher tendency not only to dissolve into the hexane phase but also to adsorb at the hexane/water interface than 18-crown-6 and that the Starks extraction mechanism was suggested for the present phase transfer catalysis systems. PMID- 17714726 TI - Solution synthesis of magnesium hydroxide sulfate hydrate nanobelts using sparingly soluble carbonate salts as supersaturation control agents. AB - Magnesium hydroxide sulfate hydrate (MHSH, 5Mg(OH)(2)MgSO(4)3H(2)O) nanobelts were synthesized under the conditions of ambient pressure and boiling temperature (approximately 101 degrees C). Several sparingly soluble carbonate salts were selected based on the hypothesis that the sparingly soluble carbonate salts in aqueous solution can provide OH(-) ion in a slow and continual manner, which is important to maintain a low supersaturation environment for one-dimensional MHSH nanobelt growth. The results indicated that the concentration of the reaction ions in the solution is one of the critical parameters for nanobelt growth. Scanning electron microscopy (SEM) showed that the nanobelts are about 50 nanometers in thickness, 200-500 nanometers in width and tens to hundreds of micrometers in length. The higher the solubility product constant of the sparingly soluble salt, the faster the reaction occurred. The effect of temperature on the reaction rate was investigated. The chemistry of the reaction was studied and the mechanism of nanobelt growth was proposed. PMID- 17714727 TI - Temporal evolution of composition and crystal structure of cobalt hexacyanoferrate nano-polymers synthesized in reversed micelles. AB - Nanometer-size metal coordination polymers are fascinating to explore, since their unique properties are controlled by a large ratio of surface atoms, which is an entirely different effect from that in a bulk crystal. In this report, we have demonstrated the reaction time-induced structural conversion of nanometer sized metal coordination nano-polymers (MCNPs). The MCNP selected here was a Prussian blue analogue, cobalt hexacyanoferrate (Fe-CN-Co) with ca. 3 nm. When Fe CN-Co MCNPs were synthesized in reverse micelles of cationic surfactants, cetyltrimethylammonium halides [CTAX, X=B (bromide), C (chloride)], their color dramatically changed from red to green with increasing the reaction time. We investigated the mechanism of this characteristic color change using XRD, FT-IR, UV-vis spectra, CHN elemental analyses, ICP, and TGA, which indicated that the coordination geometry of Co(II) ions was changed from a 6-coordinate octahedral (Oh) to a 4-coordinate tetrahedral (Td) with clear crystal distortion. The magnetic behavior of the prepared Fe-CN-Co MCNPs was also reaction-time dependent, as illustrated by SQUID and 57Fe Mossbauer spectra. PMID- 17714728 TI - Co- and counter-current spontaneous imbibition into groups of capillary tubes with lateral connections permitting cross-flow. AB - A model for co- and counter-current imbibition through independent capillaries has already been developed and experiments conducted to verify the theory [E. Unsal, G. Mason, N.R. Morrow, D.W. Ruth, J. Colloid Interface Sci. 306 (2007) 105]. In this paper, the work is extended to capillaries which are connected laterally and in which cross-flow can take place. The fundamental pore geometry is a rod in an angled round-bottomed slot with a gap between the rod and a capping glass plate. The surfaces of the slot, rod and plate form capillaries and interconnecting passages which have non-axisymmetric cross-sections. Depending on the gap size either (i) a large single meniscus, (ii) two menisci one on each side of the rod, or (iii) three menisci, one between the rod and the glass additional to the ones on each side can be formed. A viscous refined oil was applied to one end of the capillaries and co-current and counter-current spontaneous imbibition experiments were performed. The opposite end was left open to the atmosphere for co-current experiments. When the gap between the rod and the plate was large, the imbibing oil advanced into the tubes with the meniscus in the largest capillary always lagging behind the two menisci in the other two smaller capillaries. For counter-current imbibition experiments the open end was sealed and connected to a sensitive pressure transducer. In some experiments, the oil imbibed into the smaller capillaries and expelled air as a series of bubbles from the end of the largest capillary. In other experiments, the oil was allowed to imbibe part way into the tubes before counter-current imbibition was started. The meniscus curvatures of the capillaries have been calculated using the Mayer and Stowe-Princen method for different cell slot angles and gap sizes using a value of zero for the contact angle. These values have been compared with actual values by measuring the capillary rise in the tubes; agreement was very close. A model for co-current and counter-current imbibition has also been developed. The significance of this model is that some hydraulic/capillary properties are common for both co-current and counter-current imbibition. The experiments give an illustration of behavior expected in a real porous material and verify the importance of the 'perfect cross-flow' modification to the 'bundle of parallel tubes' model. PMID- 17714729 TI - Cerium modified MCM-41 nanocomposite materials via a nonhydrothermal direct method at room temperature. AB - Ce-containing MCM-41 materials were prepared via a direct, nonhydrothermal method at room temperature from tetra-ethoxysilane, n-hexadecyl trimethyl ammonium bromide, ammonia solution, and cerium(IV) ammonium nitrate precursors. Composite materials containing the nominated ratios of 5 and 10% (w/w) CeO2/MCM-41 were targeted. The obtained materials were investigated by TGA, DSC, FTIR, diffuse reflectance UV-vis, XRD, N2 adsorption/desorption isotherms, and SEM. Results indicated the insertion of cerium ions in tetrahedral environment in the framework of MCM-41. BET surface area amounting to 824 and 726 m2/g; total pore volume amounting to 0.427 and 0.515 cm3/g; and narrow pore size distribution maximizing at 22.5 and 23.7 A, respectively were obtained for the 5 and 10% CeO2/MCM-41 calcined composites. SEM showed a spherical type morphology for the composites which is rather similar to their blank MCM-41, and no clear ceria aggregates were observed on the external surfaces of composites spherical particles. Thus, the adopted method allows the persistence of MCM-41 texture with cerium inserts in the framework of MCM-41 and/or forms finely divided ceria nanoparticles on the wall of MCM-41 materials. Moreover, stabilization of any formed ceria nanoparticles was attributed to the short nonintersecting porous nature of MCM-41 matrix, which hinders their aggregation upon calcinations. PMID- 17714730 TI - Do illustrations enhance preschoolers' memories for stories? Age-related change in the picture facilitation effect. AB - This study investigated whether illustrations facilitate story recall in preschoolers (N=58) 46 to 63 months of age. Each child was exposed to either a verbal story narrative with illustrations (Verbal and Picture condition), the narrative alone (Verbal Only condition), the narrative with uninformative illustrations (Verbal and Irrelevant Picture condition), or the illustrations alone (Picture Only condition). Children recalled the story immediately and after a 1-week delay. With increasing age, the Verbal and Picture group increasingly outperformed the other verbal groups, particularly when recalling central details conveyed by both narrative and illustrations. Performance did not vary among the three verbal groups at lower values of age, whereas the Verbal and Picture group recalled more than the other verbal groups at the older ages. Regardless of age, all verbal groups outperformed the Picture Only group, suggesting that preschoolers are unlikely to spontaneously generate a narrative from pictures alone. PMID- 17714731 TI - Contrasting glycosylation profiles between Fab and Fc of a human IgG protein studied by electrospray ionization mass spectrometry. AB - A conserved structural feature of human IgG molecules is the presence of an oligosaccharide moiety within the Fc region at Asn297. In addition, 15-20% of normal polyclonal IgG molecules bear N-linked oligosaccharides in the variable (V) regions of the light (L) and/or heavy (H) chains. Electrospray ionization mass spectrometry (ESI-MS) has been applied to the glycan analysis of two IgG1 myeloma proteins (Wid and Cri) after mild reduction and acidification. Heterogeneous ion peaks were observed for both the H and L chains of Wid in contrast to Cri whose L chain peak was homogeneous. Site-specific deglycosylation of the H and L chains of IgG Wid was achieved under native conditions with peptide-N-glycosidase F and endoglycosidase F2, respectively. The Fc glycoforms differed between the two proteins in that Cri-Fc bears diantennary complex-type glycans that are fully core-fucosylated and partially sialylated while Wid-Fc glycans are non-fucosylated, partially galactosylated and non-sialylated. In contrast to the Fc glycans, the L chain glycans of Wid were shown to be fucosylated, fully galactosylated and sialylated, indicating that the glycosylation machinery of the Wid-producing myeloma cells is intact. Thus, combination of the two endoglycosidases can provide a simple means of glycan analysis of both Fab and Fc by ESI-MS, which may contribute to the development of therapeutic IgG with customized glycan profiles. PMID- 17714732 TI - Sympathetic hyperactivity and cardiac dysfunction post-MI: different impact of specific CNS versus general AT1 receptor blockade. AB - In rats, blockade of the brain renin-angiotensin-aldosterone system prevents sympathetic hyperactivity and markedly attenuates LV dysfunction post-MI. We evaluated whether peripheral administration of an AT(1) receptor blocker has similar effects. In the first experiment, Wistar rats were injected subcutaneously (sc) daily with losartan at a regular or high dose (15 or 100 mg/kg/day) starting 2 days post-MI. At 4 weeks, sympathetic reactivity to air stress was enhanced, baroreflex function was impaired and cardiac function clearly decreased. Increased AT(1) receptor binding densities post-MI were decreased by losartan towards (regular dose) or well below (high dose) levels of sham rats. Losartan at the high dose prevented sympathetic hyperactivity and baroreflex impairment, and lowered LVEDP but further decreased LVPSP and dP/dt(max). In the second experiment, as of 2 days post-MI, losartan (1 mg/kg/day), spironolactone (10 microg/kg/day) or vehicle was infused intracerebroventricularly (i.c.v), or losartan (100 mg/kg/day) was injected sc for 4 weeks. LV dysfunction and increased fibrosis and cardiomyocyte diameter were clearly present at 4 weeks. Icv losartan or spironolactone improved or normalized LV diastolic and systolic function, LV dimensions, fibrosis and myocyte diameter. In contrast, although sc losartan similarly improved fibrosis and LVEDP, again it did not improve LV systolic function. These data indicate that specific central and general AT(1) receptor blockade can similarly improve sympathetic hyperactivity, cardiac fibrosis and LVEDP, but only central blockade improves LV systolic function, possibly due to differences in the extent of blockade of AT(1) receptors in cardiac myocytes and/or peripheral sympathetic nerves. PMID- 17714733 TI - Hypertension induces compensatory arterial remodeling following arteriotomy. AB - BACKGROUND: Hypertension has been traditionally considered a risk factor for restenosis following carotid arteriotomy. Genetic and morphological response to carotid arteriotomy in normotensive Wystar-Kyoto (WKY), spontaneously hypertensive (SHR), and Milan hypertensive (MHS) rats were analyzed. MATERIAL AND METHODS: C-myc, angiotensin II receptor-1 (AT1), angiotensin II receptor-2 (AT2), endothelin-1 receptor A (ET(A)), endothelin-1 receptor B (ET(B)), Bcl-2 family members (Bcl-2/Bax, Bcl-X(L/S)) were analyzed in surgically injured as well as uninjured carotids of WKY and hypertensive strains (HS). Thirty-day histology and morphometry were accomplished on injured and uninjured carotids. RESULTS: C-myc mRNA is activated earlier and/or to a greater extent in hypertensive strains than in WKY. AT1 mRNA increases in WKY after injury, while it decreases in SHR and MHS. AT2 shows the opposite, decreasing in WKY and increasing in hypertensive strains. ET(A) mRNA decreases in all strains although with different timing and levels, associated with a replacement by ET(B) mRNA. Bcl-2/Bax ratio gradually decreases in WKY, while it shows only a transient decrease in SHR and MHS 4 h after the injury. Negative remodeling is observed in all injured carotids, although neointima was detected in WKY only. Thirty days following arteriotomy, morphometry demonstrated a significant decrease of luminal area, with consistent gain in the medial area in WKY, whereas hypertensive strains showed significant increase of the luminal area, consistent with a contemporary decrease of the medial area. CONCLUSIONS: Vaso-relaxant AT2 and ET(B) induced limited vasoconstriction in HS. Less apoptosis in hypertensive rats reduced cell proliferation, contrasting c-myc. These responses favorably modulated media/lumen area ratio following arteriotomy in HS. PMID- 17714735 TI - Three-person game facilitates indirect reciprocity under image scoring. AB - Reputation building plays an important role in the evolution of reciprocal altruism when the same individuals do not interact repeatedly because, by referring to reputation, a reciprocator can know which partners are cooperative and can reciprocate with a cooperator. This reciprocity based on reputation is called indirect reciprocity. Previous studies of indirect reciprocity have focused only on two-person games in which only two individuals participate in a single interaction, and have claimed that indirectly reciprocal cooperation cannot be established under image scoring reputation criterion where the reputation of an individual who has cooperated (defected) becomes good (bad). In this study, we specifically examine three-person games, and reveal that indirectly reciprocal cooperation can be formed and maintained stably, even under image scoring, by a nucleus shield mechanism. In the nucleus shield, reciprocators are a shield that keeps out unconditional defectors, whereas unconditional cooperators are the backbone of cooperation that retains a good reputation among the population. PMID- 17714734 TI - Effects of the proteasome inhibitor bortezomib on gene expression profiles of pancreatic cancer cells. AB - BACKGROUND: Pancreatic cancer remains a highly chemoresistant malignancy. Gemcitabine is a widely used clinical chemotherapeutic agent against locally advanced and metastatic pancreatic cancer. Proteasome inhibitor bortezomib has been shown to result in enhanced cytotoxicity and apoptosis when used alone or in combination with gemcitabine in pancreatic cancer cell lines. MATERIALS AND METHODS: To determine the effect of bortezomib on gene expression profile of pancreatic adenocarcinoma cells with different sensitivity to gemcitabine, we used Affymetrix HG U133A 2.0 GeneChip (Santa Clara, CA) and measured changes induced by bortezomib in pancreatic cancer cell lines with high (BxPC-3) and low (PANC-1) sensitivity to gemcitabine, at time points 24 h. Selected genes were subsequently validated by quantitative real-time polymerase chain reaction. RESULTS: Forty-four common genes in both PANC-1 and BxPC-3 cells were identified as up-regulated (>3-fold) induced by bortezomib analyzed by microarray, which are associated with multiple cytotoxic and cytoprotective effects. Bcl-2 was repressed by bortezomib in both PANC-1 and BxPC-3 cells, while no changes induced in either cell by bortezomib were disclosed in all five members of nuclear factor kappa B family. Other interesting genes related to apoptosis or drug metabolism, such as TP53 and ABCB1 (mdr1), were not found differentially expressed in common. CONCLUSIONS: Bortezomib exhibits antitumor effects toward pancreatic cancer in vitro and in vivo. Genes with divergent apoptotic effects are induced by bortezomib, which may become promising targets for pancreatic cancer treatment. PMID- 17714736 TI - The regulatory effect of endogenous hydrogen sulfide on pulmonary vascular structure and gasotransmitters in rats with high pulmonary blood flow. AB - The study aimed to explore the regulatory effect of endogenous hydrogen sulfide (H(2)S), a novel gasotransmitter, on pulmonary vascular structure and gasotransmitters in rats with high pulmonary blood flow. Thirty-two Sprague Dawley rats were randomly divided into a sham group, shunt group, sham+PPG (propargylglycine, an inhibitor of cystathionine-gamma-lyase) group and shunt+PPG group. Rats in the shunt and shunt+PPG groups underwent abdominal aorta-inferior vena cava shunting. Rats in the shunt+PPG and sham+PPG groups were intraperitoneally injected with PPG. After 4 weeks of shunting, mean pulmonary artery pressure (MPAP) and pulmonary vascular structural remodeling (PVSR) were evaluated. H(2)S, nitric oxide (NO) and carbon monoxide (CO) contents were measured in lung tissues. Meanwhile, nitric oxide synthase (eNOS), heme oxygenase (HO-1) and proliferative cell nuclear antigen (PCNA) protein expressions and ERK activation were evaluated. After 4 weeks of shunting, rats showed PVSR with increased lung tissue H(2)S and NO content but decreased CO content. After the PPG treatment, MPAP further increased and PVSR was aggravated. Meanwhile, PCNA expression and ERK activation were augmented with decreased lung tissue CO and HO 1 protein production but increased lung tissue NO production and eNOS expression. H(2)S exerted a protective effect on PVSR, and the inhibition of the NO/NOS pathway and the augmentation of the CO/HO pathway might be involved in the mechanisms by which H(2)S regulates PVSR in rats with high pulmonary flow. PMID- 17714737 TI - Kinin B1 receptor participates in the control of cardiac function in mice. AB - The kinins have an important role in control of the cardiovascular system. They have been associated with protective effects in the heart tissue. Kinins act through stimulation of two 7-transmembrane G protein-coupled receptors, denoted B(1) and B(2) receptors. However, the physiological relevance of B(1) receptor in the heart has not been clearly established. Using B(1) kinin receptor gene knock out mice we tested the hypothesis that the B(1) receptor plays an important role in the control of baseline cardiac function. We examined the functional aspects of the intact heart and also in the isolated cardiomyocytes to study intracellular Ca(2+) cycling by using confocal microscopy and whole-cell voltage clamp techniques. We measured heart rate, diastolic and systolic tension, contraction and relaxation rates and, coronary perfusion pressure. Whole-cell voltage clamp was performed to measure L-type Ca(2+) current (I(Ca,L)). The hearts from B(1)(-/-) mice showed smaller systolic tension. The average values for WT and B(1)(-/-) mice were 2.6+/-0.04 g vs. 1.6+/-0.08 g, respectively. This result can be explained, at least in part, by the decrease in the Ca(2+) transient (3.1+/-0.06 vs. 3.4+/-0.09 for B(1)(-/-) and WT, respectively). There was an increase in I(Ca,L) at depolarized membrane potentials. Interestingly, the inactivation kinetics of I(Ca,L) was statistically different between the groups. The coronary perfusion pressure was higher in the hearts from B(1)(-/-) mice indicating an increase in coronary resistance. This result can be explained by the significant reduction of eNOS (NOS-3) expression in the aorta of B(1)(-/-) mice. Collectively, our results demonstrate that B(1) receptor exerts a fundamental role in the mammalian cardiac function. PMID- 17714738 TI - Adenovirus-mediated delivery of human IFNgamma gene inhibits prostate cancer growth. AB - Interferon gamma (IFNgamma) is regarded as a potent antitumor agent, but therapy with IFNgamma is hampered by its short half-life and significant side effects. We developed a replication defective adenovirus carrying the human IFNgamma gene and evaluated the effects of adenovirus-mediated IFNgamma (Ad-IFNgamma) gene transfer on human prostate cancer cell lines in vitro and on xenografts in vivo. Our results showed infection of prostate cancer cells with Ad-IFNgamma led to production of an active cytokine and resulted in an antiproliferative effect on the prostate cancer cells. Intratumoral injection of Ad-IFNgamma significantly inhibited the growth of DU-145 cell xenografts in vivo, while no significant toxicity effect was observed. RT-PCR analysis indicated transgene expression mainly enriched in tumors in vivo, and slightly distributed in livers. These findings suggest adenovirus-mediated IFNgamma gene transfer is a promising approach in the treatment of advanced prostate cancer. PMID- 17714739 TI - The spectra of large second-step mutations are similar for two different mouse autosomes. AB - Loss of tumor suppressor gene expression via mutations plays a critical role in cancer development, particularly when occurring in heterozygous cells. These so called "second-step" mutational events are often large in size and arise most often from chromosome loss, mitotic recombination, or interstitial deletion. An open question in cancer research is whether different chromosomes are equally susceptible to formation of large mutations, or alternatively if the unique sequence of each chromosome will lead to chromosome-specific mutational spectra. To address this question, the spectra of second-step mutations were determined for chromosomes 8 and 11 in Aprt and Tk mutants, respectively, isolated from primary kidney clones heterozygous for both loci. The results showed that the spectra of large mutational events were essentially the same. This observation suggests that internal and external cellular environments provide the driving force for large autosomal mutational events, and that chromosome structure per se is the substrate upon which these forces act. PMID- 17714740 TI - GSTM1 genotype influences the susceptibility of men to sperm DNA damage associated with exposure to air pollution. AB - Previous studies have provided evidence for an association between exposure to high levels of air pollution and increased DNA damage in human sperm. In these studies DNA damage was measured using the sperm chromatin structure assay (SCSA) wherein the percentage of sperm with abnormal chromatin/fragmented DNA is determined and expressed as % DNA fragmentation index (%DFI). Here we extend these observations to address the following hypothesis: men who are homozygous null for glutathione-S-transferase M1 (GSTM1-) are less able to detoxify reactive metabolites of carcinogenic polycyclic aromatic hydrocarbons (c-PAHs) found in air pollution. Consequently they are more susceptible to the effects of air pollution on sperm chromatin. Using a longitudinal study design in which men provided semen samples during periods of both low (baseline) and episodically high air pollution, this study revealed a statistically significant association between GSTM1 null genotype and increased SCSA-defined %DFI (beta=0.309; 95% CI: 0.129, 0.489). Furthermore, GSTM1 null men also showed higher %DFI in response to exposure to intermittent air pollution (beta=0.487; 95% CI: 0.243, 0.731). This study thus provides novel evidence for a gene-environment interaction between GSTM1 and air pollution (presumably c-PAHs). The significance of the findings in this study with respect to fertility status is unknown. However, it is biologically plausible that increases in %DFI induced by such exposures could impact the risk of male sub/infertility, especially in men who naturally exhibit high levels of %DFI. PMID- 17714741 TI - [Pseudotumoral presentation of multiple sclerosis]. AB - INTRODUCTION: Multiple sclerosis is one of the most common diseases of the central nervous system with a variety of clinical and radiological presentations. Several cases have been reported of demyelinating processes mimicking a tumour of the central nervous system. OBSERVATION: A 45-year-old man was admitted with acute right hemiparesis associated with intracranial hypertension syndrome. Initial CT scan and magnetic resonance imaging of the brain revealed a mass lesion in the left hemisphere. Combined, careful history taking, assessment of the clinical course and magnetic resonance imaging findings led to the final diagnosis of multiple sclerosis. COMMENTARY AND CONCLUSION: This case report illustrates the wide variety of multiple sclerosis presentation. Recognition of the demyelinating tumor like lesions is essential; the diagnosis of multiple sclerosis should be considered in young adults with similar presentations. PMID- 17714742 TI - Cross-sensitization and cross-tolerance between exogenous cannabinoid antinociception and endocannabinoid-mediated stress-induced analgesia. AB - Footshock stress induces both endocannabinoid mobilization and antinociception. The present studies investigated behavioral plasticity in cannabinoid antinociceptive mechanisms following repeated activation using the tail-flick test. A secondary objective was to ascertain whether blockade of stress antinociception by the CB(1) antagonist rimonabant could be attributed to changes in locomotor activity. The cannabinoid agonist WIN55,212-2 induced hypoactivity in the open field relative to vehicle-treated controls. By contrast, rimonabant, administered at a dose that virtually eliminated endocannabinoid-mediated stress antinociception, failed to alter locomotor behavior (i.e. time resting, ambulatory counts, distance traveled) in rats subjected to the same stressor. Rats exposed acutely to footshock were hypersensitive to the antinociceptive effects of WIN55,212-2 and Delta(9)-tetrahydrocannabinol (Delta(9)-THC). The converse was also true; acute Delta(9)-THC and WIN55,212-2 administration potentiated stress antinociception, suggesting a bidirectional sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception. Stress antinociception was also attenuated following chronic relative to acute treatment with WIN55,212-2 or Delta(9)-THC. Repeated exposure to footshock (3 min/day for 15 days), however, failed to attenuate antinociception induced by either footshock stress or WIN55,212-2. Our results demonstrate that endocannabinoid-mediated stress antinociception cannot be attributed to motor suppression. Our results further identify a functional plasticity of the cannabinoid system in response to repeated activation. The existence of cross-sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception suggests that these phenomena are mediated by a common mechanism. The observation of stress-induced hypersensitivity to effects of exogenous cannabinoids may have clinical implications for understanding marijuana abuse liability in humans. PMID- 17714743 TI - Pharmacological comparison of anticonvulsant drugs in animal models of persistent pain and anxiety. AB - Signs and symptoms of persistent pain are associated with neuronal hyperexcitability within nociceptive pathways. This manifests behaviourally as a decrease in the nociceptive threshold to sensory stimulation, and is closely correlated with altered affective pain processing and increased expression of anxiety-like symptoms. Anticonvulsant drugs can have marked analgesic actions in animals and humans, and some have also been reported to possess anxiolytic-like properties in animals. In the current study, we have compared the antinociceptive actions of diazepam (allosteric GABA(A) receptor modulator), gabapentin (binds to alpha(2)delta Ca(2+) channel subunit), lamotrigine, riluzole and phenytoin (Na(+) channel blockers), levetiracetam (unknown mechanism), sodium valproate (potentiates GABA-mediated inhibition), ethosuximide (T-type Ca(2+) channel blocker) and retigabine (K(v)7 channel opener) in the rat formalin test, with their anxiolytic actions in the rat conditioned emotional response (CER) model of anxiety. Lamotrigine, gabapentin, riluzole, retigabine and ethosuximide attenuated second phase nociceptive responses in the formalin test. Lamotrigine, gabapentin and riluzole also displayed an anxiolytic-like profile in the CER model. Notably, the minimum doses of these drugs required to attenuate anxiety behaviour were similar to, or considerably lower than those needed to reverse pain-like behaviours. Diazepam was anxiolytic but only attenuated pain-like behaviours at sedative doses. The other drugs tested were inactive in both models. Our data suggests: (i) an antiepileptic mechanism of action per se is not necessarily sufficient for a compound to display antinociceptive and/or anxiolytic actions; and (ii) the combined antinociceptive and anxiolytic-like profiles of lamotrigine, gabapentin and riluzole suggests that these compounds likely modulate both sensory and affective dimensions of pain. PMID- 17714744 TI - CB1 receptor-dependent and -independent inhibition of excitatory postsynaptic currents in the hippocampus by WIN 55,212-2. AB - We investigated the effect of a synthetic cannabinoid, WIN 55,212-2 on excitatory postsynaptic currents (EPSCs) evoked by stimulation of Schaffer collaterals in CA1 pyramidal cells. Bath application of WIN 55,212-2 reduced the amplitude of EPSCs in dose-dependent manner tested between 0.01 nM and 30 microM. In rats and mice, this cannabinoid ligand inhibited excitatory synapses in two steps at the nM and muM concentrations. When the function of CB(1) cannabinoid receptors (CB(1)R) was impaired, either by the application of a CB(1)R antagonist AM251, or by using CB(1)R knockout mice, WIN 55,212-2 in microM concentrations could still significantly reduced the amplitude of EPSCs. WIN 55,212-2 likely affected the efficacy of excitatory transmission only at presynaptic sites, since both at low and high doses the paired pulse ratio of EPSC amplitude was significantly increased. The inactive enantiomer, WIN 55,212-3, mimicked the effect of WIN 55,212-2 applied in high doses. In further experiments we found that the CB(1)R independent effect of 10 microM WIN 55,212-2 at glutamatergic synapses was fully abolished, when slices were pre-treated with omega-conotoxin GVIA, but not with omega-agatoxin IVA. These data suggest that, in the hippocampus, WIN 55,212-2 reduces glutamate release from Schaffer collaterals solely via CB(1)Rs in the nM concentration range, whereas in microM concentrations, WIN 55,212-2 suppresses excitatory transmission, in addition to activation of CB(1)Rs, by directly blocking N-type voltage-gated Ca(2+) channels independent of CB(1)Rs. PMID- 17714745 TI - Type-1 cannabinoid receptors colocalize with caveolin-1 in neuronal cells. AB - Type-1 (CB1) and type-2 (CB2) cannabinoid receptors belong to the rhodopsin family of G protein-coupled receptors, and are activated by endogenous lipids termed "endocannabinoids". Recent reports have demonstrated that CB1R, unlike CB2R and other receptors and metabolic enzymes of endocannabinoids, functions in the context of lipid rafts, i.e. plasma membrane microdomains which may be important in modulating signal transduction. Here, we present novel data based on cell subfractionation, immunoprecipitation and confocal microscopy studies, that show that in C6 cells CB1R co-localizes almost entirely with caveolin-1. We also show that trafficking of CB1R in response to the raft disruptor methyl-beta cyclodextrin (MCD) is superimposable on that of caveolin-1, and that MCD treatment increases the accessibility of CB1R to its specific antibodies. These findings may be relevant for the manifold CB1R-dependent activities of endocannabinoids, like the regulation of apoptosis and of neurodegenerative diseases. PMID- 17714746 TI - Cannabidiol arrests onset of autoimmune diabetes in NOD mice. AB - We have previously reported that cannabidiol (CBD) lowers the incidence of diabetes in young non-obese diabetes-prone (NOD) female mice. In the present study we show that administration of CBD to 11-14 week old female NOD mice, which are either in a latent diabetes stage or with initial symptoms of diabetes, ameliorates the manifestations of the disease. Diabetes was diagnosed in only 32% of the mice in the CBD-treated group, compared to 86% and 100% in the emulsifier treated and untreated groups, respectively. In addition, the level of the proinflammatory cytokine IL-12 produced by splenocytes was significantly reduced, whereas the level of the anti-inflammatory IL-10 was significantly elevated following CBD-treatment. Histological examination of the pancreata of CBD-treated mice revealed more intact islets than in the controls. Our data strengthen our previous assumption that CBD, known to be safe in man, can possibly be used as a therapeutic agent for treatment of type 1 diabetes. PMID- 17714747 TI - Cytotoxic ent-abietane diterpenes from Gelonium aequoreum. AB - Seventeen ent-abietane diterpenes, including gelomulides K-X (1-14), and three known compounds, were isolated from a dichloromethane-soluble extract of Gelonium aequoreum through bioassay-guided fractionation. Their structures were identified by spectroscopic methods, and stereochemistry was confirmed by X-ray crystallographic analysis, CD spectral data, and Mosher's method. The isolates were evaluated for in vitro cytotoxic activity, and compounds 1 and 3 showed moderate cytotoxicity against lung (A549), breast (MDA-MB-231 and MCF7), and liver (HepG2) cancer cell lines. PMID- 17714748 TI - Mature Amaranthus hypochondriacus seeds contain non-processed 11S precursors. AB - Amaranth is a dicotyledonous plant whose major seed storage proteins are globulins and glutelins. An unique feature of amaranth seeds is the presence of a fraction named albumin-2, that is extractable with water only after an exhaustive extraction of globulins and albumin-1. In this work, we tested the hypothesis that albumin-2 fraction could be constituted by a non-processed 11S globulin (proglobulin). To this end, the gene encoding the amaranth 11S subunit was cloned and expressed in Escherichia coli. Subsequently, the recombinant proglobulin and albumin-2 purified from seeds were treated with a sunflower vacuolar processing enzyme (VPE). A 55 kDa component of albumin-2 was specifically cleaved into 38 and 17-15 kDa polypeptides, as a consequence of this endoproteolytic cleavage a change of the oligomeric state from trimeric to hexameric was observed. Amaranth 11S globulin fraction was not modified under these proteolysis conditions. Using VPE-specific antibodies, it was shown that amaranth expresses a 57 kDa VPE, and that both developing and mature amaranth seeds have VPE activity, although the increase of this activity during amaranth seed development is higher than that observed for sunflower seeds. These results confirm the presence of unprocessed 11S precursors in mature amaranth seeds; this phenomenon cannot, however, be attributed to low VPE activity during developing of amaranth seeds. PMID- 17714749 TI - Elucidation of the opening of the epoxidic ring of the 3beta-acetoxy 14alpha,15alpha-epoxy-5alpha-cholest-8-en-7-one by methanol, using NMR techniques assisted by a conformational study through theoretical calculations. AB - This paper demonstrates that the crystallization of 3beta-acetoxy-14alpha,15alpha epoxy-5alpha-cholest-8-en-7-one from methanol affords the 3beta-acetoxy-9alpha methoxy-15alpha-hydroxycholest-8(14)-en-7-one. The structure of this steroid, which shows an apparently anomalous UV absorption maximum, is determined by high field NMR experiments, supporting the coupling constant values assignments and the NOE contacts by a conformational study through theoretical calculations at the B3LYP/6-31G* level. The computational study also justifies the observed UV absorption of the steroid, thus demonstrating the usefulness of computer chemistry in providing support for the identification of unknown compounds. PMID- 17714750 TI - Cholesterol biosynthesis from birth to adulthood in a mouse model for 7 dehydrosterol reductase deficiency (Smith-Lemli-Opitz syndrome). AB - Smith-Lemli-Opitz syndrome (SLOS) is caused by deficiency in the terminal step of cholesterol biosynthesis, which is catalyzed by 7-dehydrocholesterol reductase (DHCR7). The disorder exhibits several phenotypic traits including dysmorphia and mental retardation with a broad range of severity. Pathogenesis of SLOS is complex due to multiple roles of cholesterol and may be further complicated by unknown effects of aberrant metabolites that arise when 7-dehydrocholesterol (7 DHC), the substrate for DHCR7, accumulates. A viable mouse model for SLOS has recently been developed, and here we characterize cholesterol metabolism in this model with emphasis on changes during the first few weeks of postnatal development. Cholesterol and 7-DHC were measured in "SLOS" mice and compared with measurements in normal mice. SLOS mice had measurable levels of 7-DHC at all ages tested (up to 1 year), while 7-DHC was below the threshold for detection in normal mice. In perinatal to weaning age SLOS mice, cholesterol and 7-DHC levels changed dramatically. Changes in brain and liver were independent; in brain cholesterol increased several fold while 7-DHC remained relatively constant, but in liver cholesterol first increased then decreased again while 7-DHC first decreased then increased. In older SLOS animals the ratio of 7-DHC/cholesterol, which is an index of biochemical severity, tended to approach, but not reach, normal. While these mice provide the best available genetic animal model for the study of SLOS pathogenesis and treatment, they probably will be most useful at early ages when the metabolic effects of the mutations are most dramatic. To correlate any experimental treatment with improved sterol metabolism will require age-matched controls. Finally, determining the mechanism by which these "SLOS" mice tend to normalize may provide insight into the future development of therapy. PMID- 17714752 TI - The mechanism of cytotoxicity by Naja naja atra cardiotoxin 3 is physically distant from its membrane-damaging effect. AB - In order to dissect out whether multiple activities of cardiotoxins (CTXs) are connected, to some extent, with each other, studies on reduced and S carboxyamidomethylated (Rcam) Naja naja atra CTX3 were carried out in the present study. Although both CTX3 and Rcam-CTX3 induced apoptotic death of PC-3 cells as evidenced by propodium iodide/annexin V double staining, degradation of procaspases and DNA fragmentation, the cytotoxicity of Rcam-CTX3 was mostly 100 fold lower than that noted with native toxin. However, Rcam-CTX3 retained approximately 38% of the membrane-damaging activity of native toxin as revealed by the decrease in calcein self-quenching from phospholipid vesicles. These results are likely to reflect that the mechanism of cytotoxicity by CTX3 is not heavily dependent on its membrane-perturbing effect, and suggest that the structural elements within CTX3 responsible for the two activities are probably separated. PMID- 17714753 TI - Productive entry of type C foot-and-mouth disease virus into susceptible cultured cells requires clathrin and is dependent on the presence of plasma membrane cholesterol. AB - We have characterized the entry leading to productive infection of a type C FMDV in two cell lines widely used for virus growth, BHK-21 and IBRS-2. Inhibition of clathrin-mediated endocytosis by sucrose treatment decreased both cell entry and virus multiplication. Evidence of a direct requirement of clathrin for productive viral entry was obtained using BHK21-tTA/anti-CHC cells, which showed a significant reduction of viral entry and infection when the synthesis and functionality of clathrin heavy chain was inhibited (Tet- cells). This was also observed for vesicular stomatitis virus (VSV) productive entry. The effect of NH(4)Cl and concanamycin A on FMDV entry and infection was consistent with the requirement of acidic compartments for decapsidation and virus replication. As expected from its higher stability at acidic pH, this requirement was higher for VSV. Since BHK-21 and IBRS-2 cells expressed caveolin-1, we explored the effect on productive virus entry of drugs that interfere with caveolae-mediated endocytosis. Treatment with nystatin did not reduce entry and infection of FMDV or VSV, while cholesterol depletion with MbetaCD significantly inhibited both steps of the FMDV cycle, indicating that plasma membrane cholesterol is required for virus productive entry. PMID- 17714754 TI - Iron(3) oxide-based nanoparticles as catalysts in advanced organic aqueous oxidation. AB - Water contaminated with dissolved organic matter is an important issue to resolve for all-purpose uses. The catalytic behavior of iron-based nanocatalysts was investigated for the treatment of contaminated water in the advanced chemical oxidation process. In this study, typical organic contaminants, such as ethylene glycol and phenol, were chosen to simulate common contaminants. It was shown that the two substances are efficiently destroyed by the Fenton-like reaction using iron(3) oxide-based nanocatalysts in the presence of hydrogen peroxide without the need for UV or visible radiation sources at room temperature. A strong effect of nanocatalyst concentration on reaction rate was shown. The kinetic reaction was found and the reaction rate coefficient k was calculated. PMID- 17714755 TI - Development of a black carbon-inclusive multi-media model: application for PAHs in Stockholm. AB - A multi-media model was developed for predicting the fate of organic chemicals in the Greater Stockholm Area, Sweden, and applied to selected polycyclic aromatic hydrocarbons (PAHs). Although urban models have been previously developed, this model is novel in that it includes sorption to pyrogenically-derived particles, commonly termed "black carbon" (BC), within the model structure. To examine the influence of BC sorption on environmental fate of PAHs, two versions of the model were generated and run: one in which sorption to BC was included and one in which BC sorption was excluded. The inclusion of BC sorption did not cause any significant variations to air levels, but it did cause an average 20-30% increase in sediment concentrations related to increased sediment solids partitioning. The model also predicted reduced advective losses out of the model domain, as well as chemical potential to diffuse from sediments, whilst total chemical inventory increased. In all cases, the lighter PAHs were more affected by BC inclusion than their heavier counterparts. We advocate the addition of sorption to BC in future multi-media fate and exposure models, which as well as influencing fate will also alter (lower) chemical availability and, thus, wildlife exposure to hydrophobic chemicals. A quantification of the latter was derived with the help of the soot inclusive model version, which estimated a lowering of dissolved water concentrations between five and >200 times for the different PAHs of this study. PMID- 17714751 TI - Delayed and persistent ERK1/2 activation is required for 4-hydroxytamoxifen induced cell death. AB - Tamoxifen (Tam), and its active metabolite, 4-hydroxytamoxifen (OHT), compete with estrogens for binding to the estrogen receptor (ER). Tam and OHT can also induce ER-dependent apoptosis of cancer cells. 10-100nM OHT induces ER-dependent apoptosis in approximately 3 days. Using HeLaER6 cells, we examined the role of OHT activation of signal transduction pathways in OHT-ER-mediated apoptosis. OHT ER activated the p38, JNK and ERK1/2 pathways. Inhibition of p38 activation with SB203580, or RNAi-knockdown of p38alpha, moderately reduced OHT-ER mediated cell death. A JNK inhibitor partly reduced cell death. Surprisingly, the MEK1/2 inhibitor, PD98059, completely blocked OHT-ER induced apoptosis. EGF, an ERK1/2 activator, enhanced OHT-induced apoptosis. OHT induced a delayed and persistent phosphorylation of ERK1/2 that persisted for >80h. Addition of PD98059 as late as 24h after OHT largely blocked OHT-ER mediated apoptosis. The antagonist, ICI 182,780, blocked both the long-term OHT-mediated phosphorylation of ERK1/2 and OHT-induced apoptosis. Our data suggests that the p38 and JNK pathways, which often play a central role in apoptosis, have only a limited role in OHT-ER mediated cell death. Although rapid activation of the ERK1/2 pathway is often associated with cell growth, persistent activation of the ERK1/2 pathway is essential for OHT-ER induced cell death. PMID- 17714756 TI - Effect of mean cell residence time on the performance and microbial diversity of pre-denitrification submerged membrane bioreactors. AB - The effect of mean cell residence time (MCRT) (5, 8.3, 16.7, and 33.3d) on domestic wastewater treatment performance had been investigated using four bench scale pre-denitrification submerged membrane bioreactors (MBR) operated in parallel. The 33.3-d MCRT MBR had the lowest microbial activities in terms of specific oxygen uptake rate, specific denitrification rate and observed sludge yield. Excellent COD removal efficiency (more than 95%) and nitrification (more than 97%) were observed in all the four MBRs investigated. Even though high nitrification can be achieved in all the MBRs, total nitrogen (TN) removal efficiency was found to be affected by MCRT with a maximum of 77% at 33.3-d MCRT. Better TN removal efficiency achieved in the 33.3-d MCRT MBR was due to the combined effect of high mixed liquor concentration and lower dissolved oxygen concentration in the recycled mixed liquor. A comparison of terminal-restriction fragment length polymorphisms (T-RFLP) fingerprints based on 16S rRNA and nirS gene revealed that the microbial communities of 5- and 8.3-d MCRT are grouped under the same branch while 16.7- and 33.3-d MCRT are grouped in another branch. T-RFLP based on amoA gene shows that members from the Nitrosomonas genus were more dominant under shorter MCRT operating environment. Clustering analysis did not show any correlation with the organic and nitrogen removal performance obtained in this study. PMID- 17714758 TI - Helicobacter pylori in the palatine tonsils of patients with IgA nephropathy compared with those of patients with recurrent pharyngotonsillitis. AB - Helicobacter pylori infection is acquired by oral ingestion. However, the morphology and microscopic localization of H pylori in the human oral cavity and pharynx are unknown. In the present study, we performed immunohistochemistry, immunoelectron microscopy, in situ hybridization, and polymerase chain reaction to identify H pylori in the palatine tonsils of 32 patients with immunoglobulin A nephropathy (IgAN) and 141 patients with recurrent pharyngotonsillitis (RPT). H pylori in coccoid form was present in bacterial colonies and horny layers of the stratified squamous epithelium in tonsillar crypts. We described for the first time the morphology of H pylori in palatine tonsils. Most bacterial colonies were sulfur granules with Actinomyces israelii (A israelii), and A israelii showed significant coexistence with H pylori (P=.011). The prevalence of H pylori in palatine tonsils of the RPT group increased steeply with age, but one fourth of the patients were found not to have tonsillar H pylori in adulthood. All patients with IgAN had H pylori in palatine tonsils. The prevalence of H pylori was greater in the IgAN group than in the RPT group, and the difference was statistically significant (P<.001). In contrast, A israelii was unrelated to age and clinical diagnosis (P=.722). In conclusion, our results demonstrate that H pylori in coccoid form is present in palatine tonsils and may indicate that H pylori in palatine tonsils is among the antigens causative of IgAN. PMID- 17714757 TI - Assessment of bone marrow plasma cell infiltrates in multiple myeloma: the added value of CD138 immunohistochemistry. AB - Assessment of bone marrow involvement by malignant plasma cells is an important element in the diagnosis and follow-up of patients with multiple myeloma and other plasma cell dyscrasias. Microscope-based differential counts of bone marrow aspirates are used as the primary method to evaluate bone marrow plasma cell percentages. However, multiple myeloma is often a focal process, a fact that impacts the accuracy and reliability of the results of bone marrow plasma cell percentages obtained by differential counts of bone marrow aspirate smears. Moreover, the interobserver and intraobserver reproducibility of counting bone marrow plasma cells microscopically has not been adequately tested. CD138 allows excellent assessment of plasma cell numbers and distribution in bone marrow biopsies. We compared estimates of plasma cell percentages in bone marrow aspirates and in hematoxylin-eosin- and CD138-stained bone marrow biopsy sections (CD138 sections) in 79 bone marrows from patients with multiple myeloma. There was a notable discrepancy in bone marrow plasma cell percentages using the different methods of observation. In particular, there was a relatively poor concordance of plasma cell percentage estimation between aspirate smears and CD138 sections. Estimates of plasma cell percentage using CD138 sections demonstrated the highest interobserver concordance. This observation was supported by computer-assisted image analysis. In addition, CD138 expression highlighted patterns of plasma cell infiltration indicative of neoplasia even in the absence of plasmacytosis. We conclude that examination of CD138 sections should be considered for routine use in the estimation of plasma cell load in the bone marrow. PMID- 17714759 TI - The impact of large sections on the study of in situ and invasive duct carcinoma of the breast. AB - Large histologic sections (LHSs) are increasingly used in the study of normal and neoplastic breast tissue. LHSs allow the direct visualization of a large part of the breast glandular tree. Accordingly, LHSs have shown that in situ and invasive lobular carcinoma is a multilobar (and hence multifocal) neoplastic lesion in more than 50% of the cases, and that poorly differentiated duct carcinoma in situ (DCIS grade 3) is frequently unifocal, whereas it is often multifocal when the in situ lesion is a well-differentiated type (DCIS grade 1). Forty-five mastectomies were studied with large sections. Mastectomies were performed when quadrantectomy did not guarantee radical excision of the tumor with adequate cosmesis because of the large size of the lesion or because the neoplastic lesion was located below the nipple. Excluded were cases of lobular neoplasia or invasive lobular carcinoma, because they were reported separately, and cases of mastectomies performed for sarcoma or recurrent phyllodes tumor. All cases had undergone a preoperative diagnostic procedure (fine needle aspiration), and the relative positive material was reviewed. All 45 cases showed in situ duct carcinoma and 37 showed evidence of invasive duct carcinoma. Forty-two cases of DCIS were multifocal, whereas only 4 invasive duct carcinoma were shown as multifocal. When DCIS lesions were subdivided into 3 grades, no statistical significance was seen among the 3 groups of DCIS in regard to multifocality. Nevertheless, DCIS grade 1 was a widespread condition involving more than one lobe and quadrant, whereas DCIS grades 2 and 3 appeared more localized. DCIS grade 1 was more similar to that previously observed in lobular in situ neoplasia/lobular in situ carcinoma. In 66.6% of the cases, DCIS foci were found within the invasive areas, indicating a more than fortuitous occurrence (2-sided P=.0357). PMID- 17714760 TI - Expression of epidermal growth factor receptor, but not K-RAS mutations, is present in congenital cystic airway malformation/congenital pulmonary airway malformation. AB - Congenital cystic airway malformation/congenital pulmonary airway malformation (CCAM/CPAM) of the lung is a rare but well-described malformative lesion of pulmonary parenchyma characterized by the abnormal maturation of airways along with an increase in terminal respiratory structures, resulting in cysts of variable sizes. Five types have been classified based on morphological analysis. Although the etiology of the lesion is still unclear, recent data suggest that bronchial atresia is a predisposing/associated anomaly. A described association between type 1 CCAM/CPAM and bronchioloalveolar carcinoma suggests that type 1 CCAM/CPAM may predispose to malignant transformation by as yet unidentified tumorigenic mechanisms. Here we studied epidermal growth factor receptor (EGFR) and K-RAS oncogene, 2 biological markers closely associated with tumorigenesis and altered in many types of tumors, including lung carcinomas. For this purpose, we used immunohistochemistry and gene sequencing in paraffin-embedded tissue. Our results demonstrate expression of EGFR in types 1 and 3 CCAM/CPAM, with a distinctive distribution and intensity, compared with that of type 2. Of special interest, mucinous areas in 2 cases of type 1 CCAM/CPAM lacked EGFR expression, whereas adjacent epithelial cystic linings were strongly positive. This supports the hypothesis that mucinous differentiation in CCAM/CPAM, always present in cases with malignant transformation, could be related to other molecular pathways. The K-RAS gene was screened for mutations usually found in lung carcinomas; however, no mutations were present in any of the studied samples. These findings support the notion that EGFR may play an important role in the pathogenesis and phenotype of CCAM/CPAM. PMID- 17714761 TI - Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response. AB - We retrospectively reviewed the clinicopathological features of a series of 68 renal AA amyloidosis observations collected between 1990 and 2005. The amyloidogenic disease was a chronic infection (40.8%), a chronic inflammation (38%), a tumor (9.9%), a hereditary disease (9.9%), or was undetermined in 1.4% of cases. Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of patients, respectively. The distribution pattern of glomerular amyloid deposits was mesangial segmental (14.7%), mesangial nodular (26.5%), mesangiocapillary (32.3%), and hilar (26.5%). Glomerular form was observed in 80.9% of cases and vascular form in 19.1%. AA amyloidosis-related inflammation was noted in 30 patients (44.1%) and appeared as a multinucleated giant cell reaction (27.9%) or a glomerular inflammatory infiltrate (25%), including glomerular crescents (17.6%). At the end of follow-up, 26 patients (38.2%) showed end-stage renal disease. The clinical presentation of glomerular and vascular forms was distinct with a clear predominance of proteinuria in glomerular form. Inflammatory reaction was preferentially observed in biopsies with a codeposition of immunoglobulin chains and/or complement factors in AA amyloid deposits. The distribution pattern of glomerular amyloid deposits and glomerular inflammatory reaction were independent factors influencing proteinuria level. Tubular atrophy, abundance, and distribution pattern of glomerular amyloid deposits at the time of biopsy were independent predictors of renal outcome. In conclusion, the glomerular involvement appeared as the determining histological factor for clinical manifestations and outcome of renal AA amyloidosis. AA amyloidosis related inflammation could partly result from an immune response directed against AA fibrils and could induce amyloid resolution and crescents. PMID- 17714762 TI - Enhanced B-Raf protein expression is independent of V600E mutant status in thyroid carcinomas. AB - BRAF (7q24) encodes a serine/threonine protein kinase, and its expression level varies in different tissues. Although a high prevalence of BRAF mutation has been suggested as an important event in thyroid tumorigenesis, little is known about the expression pattern of B-Raf in the thyroid. Thus, we examined the expression of B-Raf in various neoplastic and nonneoplastic thyroid tissues and compared it with BRAF mutational status. Normal and hyperplastic thyroid tissues showed focal and faint immunoreactivity for B-Raf, especially in cuboidal follicular cells of small follicles. In contrast, diffuse expression of B-Raf was observed in follicular adenomas and well-differentiated carcinomas. The missense point mutation BRAF(V600E) was identified in 42% (13/31 cases) of papillary carcinomas and 33% (5/15 cases) of undifferentiated carcinomas but not in normal thyroid tissues, nodular hyperplasia, follicular adenomas, or follicular carcinomas. The immunohistochemical expression of B-Raf did not correlate with BRAF mutational status. Moreover, Western blotting revealed that B-Raf expression in thyroid carcinoma cell lines was also independent of BRAF mutation. Serum or fibroblast growth factor-1 stimulation further activates ERK1/2 in heterozygous BRAF(V600E) positive carcinoma cells as well as BRAF(V600E) mutation-negative carcinoma cells. In conclusion, heterogeneous focal expression of wild-type B-Raf in nonneoplastic tissues may play a role in the growth or functional activity of thyroid follicular cells. In contrast, diffuse expression of wild-type and/or mutant B-Raf may be involved in the tumorigenic process resulting in activation of the mitogen-activated protein kinase signaling pathway in cooperation with other genetic abnormalities and activation of ligand-receptor signaling pathways. PMID- 17714763 TI - High innate production capacity of tumor necrosis factor-alpha and decline of handgrip strength in old age. AB - Increased signaling of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) elicits apoptosis of skeletal muscle cells in various animal models. Within a population-based prospective follow up study of elderly people aged 85 years we show that a high innate production capacity of TNF-alpha precedes a steeper decline in muscle strength over time. PMID- 17714765 TI - Trace element pattern in patients with fibromyalgia. AB - An imbalance of the trace element status in human tissues and body fluids has been suggested as a contributing factor for the development of fibromyalgia (FM). The study comprised 38 females with defined fibromyalgia (FM) according to generally accepted criteria from the American College of Rheumatology (ACR). They were compared with 41 females matched for age and geographic location. The concentrations of about 30 trace element and ions were determined in whole blood, urine and drinking water of all participants by inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma optical emission spectroscopy (ICP-OES). Significantly higher concentrations in whole blood of Cd, Co, Cu, Fe, Se, Sn and Zn (p< or =0.046) were observed in the FM-cases in comparison with the referents. A different pattern was noted in urine with increased urinary excretion of Ag (p=0.003) among the FM-patients. The urinary excretion of the other elements were of the same magnitude or slightly lower in FM-cases as compared to referents. As nearly all of the concentrations of the studied elements in blood and urine were within reported reference intervals in non-occupationally exposed populations, the clinical significance of the differences observed seems to be limited. The element concentrations of the studied elements in drinking water were within present national and international guideline values (EU, WHO) and the concentrations of potentially toxic metals such as e.g. Cd, Hg and Pb were low. In conclusion, the present investigation could not demonstrate abnormal levels of trace elements in blood or urine of FM patients and, thus, does not support the hypothesis that trace element abnormalities play a significant role in the development of FM. PMID- 17714764 TI - Age-related transcription levels of KU70, MGST1 and BIK in CD34+ hematopoietic stem and progenitor cells. AB - Despite the known longevity of human hematopoietic stem and progenitor cells (HSC), numerous functional impairments of these cells can be observed in an age dependent manner. However, the molecular alterations associated with aging of HSC are largely unknown. Therefore, we scrutinized gene expression patterns of HSC from newborn, young and old healthy donors. CD34+ HSC were isolated via immuno magnetic separation and evaluated by FACS analysis. We performed cDNA macroarray analyses on a first set of CD34+ samples (n=13). We found the genes encoding KU antigen 70 kD (KU70), microsomal glutathione S-transferase 1 (MGST1) and BCL2 interacting killer (BIK) to possess age-related mRNA expression levels. KU70 is a DNA repair gene and part of the DNA-dependent protein kinase (DNA-PK) complex. Its expression was negatively correlated with donor age showing highest expression levels in newborn, 2.6-fold lower levels in young and 6.3-fold lower levels in old donors. The transcription levels of MGST1, a gene protecting against oxidative stress, progressively increased with age. Expression was lowest in newborn, 2.6-fold higher in young and 4.3-fold higher in old donors. BIK is a proapoptotic gene and its expression was positively correlated with donor age: lowest in newborn, 1.8-fold higher in young and 4.1-fold higher in old donors. These findings were confirmed with an independent, second set of CD34+ samples (n=16) by means of quantitative real-time RT-PCR. Elucidation of age-dependent molecular alterations in healthy HSC facilitate a better understanding of functional impairments in hematopoiesis and may become valuable for anti-aging drug development and the emerging field of regenerative medicine. PMID- 17714766 TI - Primary Sjogren's syndrome: current and prospective therapies. AB - OBJECTIVE: To summarize data on existing and experimental therapies for primary Sjogren's syndrome (pSS), referring both to sicca syndrome and to other systemic disease manifestations. METHODS: Relevant English and non-English articles acquired through Medline were reviewed. RESULTS: pSS usually has a benign clinical course, centered on sicca features and general musculoskeletal manifestations, and is managed symptomatically. However, a subset of patients develops more severe extraglandular disease that warrants close monitoring and aggressive treatment. For dry eyes and mouth, nonpharmacologic measures to preserve secretions, and tear and saliva substitutes, offer some symptomatic relief. Muscarinic agonists and topical cyclosporine yield well-documented improvement in ocular sicca features. Although traditional antirheumatic drugs are used empirically for polyarthritis and other Sjogren's symptoms, their efficacy in pSS overall and as disease-modifying agents is limited. For the potential severe, nonexocrine manifestations complicating pSS, standard high-dose immunosuppression is used. Among the biologic agents already examined in pSS, those targeting tumor necrosis factor (TNF)-alpha failed to demonstrate significant benefit. Nonetheless, rituximab and other B-cell-depleting therapies appear promising. CONCLUSIONS: Treatment of pSS patients with severe extraglandular disease should differ from that of patients with predominantly sicca features and/or general muscoloskeletal manifestations. pSS treatment is mainly symptomatic, primarily directed against sicca complaints. The traditional anti-rheumatic agents show limited efficacy in the systemic process and use of systemic TNF-alpha inhibitors has been very disappointing. B cell depleting treatments and other newer biologic therapies appear more promising. PMID- 17714767 TI - New candidate chromosomal regions for chordoma development. AB - BACKGROUND: Chordomas are rare, slow growing, infiltrative tumors thought to arise from vestigial or ectopic notochord. Chordoma can occur along the axial skeleton, predominantly in the sphenooccipital, vertebral, and sacrococcygeal regions. Although most chordomas are sporadic, familial cases have also been reported. The most common molecular cytogenetic abnormalities in these tumors are monosomy of chromosome 1 and gain of chromosome 7. In addition, a variety of other chromosomal changes, which are associated with losses and gains of different chromosomes, have also been described in chordomas, such as 1q, 2p, 3p, 5q, 9p, 10, 12q, 13q, 17, and 20q. METHODS: In this study, using molecular cytogenetics (iFISH), we have studied 1p36, 1q25, 3p13-p14, 7q33, 17p13.1 (p53 gene locus), 2p13 (TGF-alpha locus), 6p12 (VEGF locus), and 4q26-q27 (bFGF/FGF2 locus) loci in chordoma tissues from seven patients with 7 primary tumors and 11 recurrences. RESULTS: We found that chromosomes 1p36, 1q25, 2p13, and 7q33 are affected in primary chordomas, and these aberrations persist in recurrences. However, the chromosome 6p12 aberration was seen only in primary chordomas, but not in recurrences, indicating that this locus may be associated with chordoma genesis. CONCLUSIONS: Our descriptive data from interphase FISH analyses suggest that future studies should incorporate a larger number of patients and should focus on identifying the candidate genes in chordoma pathogenesis. Such studies may use a whole-genomic approach, in addition to the regions identified in this study and others. PMID- 17714768 TI - Extramedullary hematopoeisis within a convexity meningioma. AB - BACKGROUND: Hematopoiesis outside the bone marrow is known to occur in patients with severe anemia, leukemia, polycythemia, or myelofibrosis, and in patients affected by chronic poisoning by marrow-toxic substances. CASE DESCRIPTION: A 66 year-old right-handed man complained of 4 days of terrible right-sided, sharp, and shooting headache for which he saw his primary care provider. Routine laboratory examination showed a WBC count of 30800/microL. Neuroimaging showed a large, right frontotemporal, extra-axial, heterogeneously enhancing, dural based mass with associated recent intramural hemorrhage with evidence of midline shift and uncal herniation. The mass was resected using a right-sided extended craniotomy with anterior fossa and middle fossa approach. A hematoxylin-eosin stained biopsy specimen showed whorls of tumor cells, diagnostic of a meningioma. Interspersed within the tumor bulk were nucleated RBCs, representing areas of extramedullary erythropoiesis within a meningioma. Flow cytometric evaluation confirmed the clinical suspicion of an underlying chronic lymphocytic leukemia. CONCLUSION: Occurrence of extramedullary hematopoiesis within a meningioma is extremely rare. Various theories may explain the occurrence of extramedullary hematopoiesis occurring within a meningioma in our patient, such as hematopoietic differentiation of multipotent mesenchymal tumor cells; direct extension of hematopoietic activity from the neighboring marrow cavity; displacement from bone marrow of stem cells that settle and develop in tissues where capillaries and blood vessels proliferate, such as a meningioma; or congenital heterotopia of totipotent connective tissue cells, which, under certain circumstances, may transform into hematopoietic tissue. PMID- 17714769 TI - Matrix metalloproteinases and tissue inhibitors of metalloproteinases expression in human cerebral ruptured and unruptured aneurysm. AB - BACKGROUND: [corrected] Matrix metalloproteinases and TIMPs are potent elastases and collagenases, which regulate the remodeling of vascular and play an important role in the development of cerebral aneurysm. Until now, little quantitative data regarding MMPs and TIMPs exist. METHODS: Tissue samples of cerebral aneurysm were obtained from 30 patients who underwent cerebral aneurysm clipping operation. We used real-time RT-PCR method to quantitatively measure mRNA levels in small tissue samples and determined gene expression levels of MMPs and TIMPs relative to that of GAPDH in each sample. The ELISA method has been used to measure the serum level of MMP-2 and MMP-9 in patients with cerebral ruptured aneurysm and patients with unruptured aneurysm. RESULT: Matrix metalloproteinase-2 and MMP-9 were overexpressed in cerebral ruptured aneurysm compared with unruptured aneurysm (4.28 +/- 2.01 vs 0.16 +/- 0.12 [P < .01] and 5.21 +/- 0.87 vs 1.69 +/- 1.00 [P < .05], respectively). The expression levels of MMP-2 to TIMP-1, MMP-2 to TIMP-2, MMP-2 to TIMP-3, and MMP-9 to TIMP-2 were higher in cerebral ruptured aneurysms than in unruptured aneurysms (1.22 +/- 0.53 vs 0.18 +/- 0.05, 4.23 +/- 1.32 vs 0.53 +/- 0.12, 1.69 +/- 0.49 vs 0.18 +/- 0.02, and 7.61 +/- 1.61 vs 2.76 +/- 0.76, respectively; P < .05). Patients with cerebral ruptured aneurysm (n = 15) had higher serum MMP-2 and MMP-9 levels than those with unruptured aneurysm detectable by angiography (n = 15) (1047 +/- 33 vs 110 +/- 26 ng/mL and 1066 +/- 43 vs 120 +/- 27 ng/mL, respectively; P < .02). CONCLUSION: The disproportional expression of among MMP-2, MMP-9, and TIMP contribute to the evolution of cerebral aneurysm. Real-time RT-PCR method is suitable for the determination of mRNA levels in small samples of vascular tissue. PMID- 17714771 TI - Relationships among multiple behaviors for childhood and adolescent obesity prevention. AB - BACKGROUND: Curbing the epidemic of childhood and adolescent obesity requires impacting multiple behaviors. This article examines the interrelationships of physical activity, fruit and vegetable consumption, and limiting television time among elementary, middle, and high school students. METHODS: Nationwide samples of students in grades 4 through 12 (n=4091) completed self-administered questionnaires assessing Transtheoretical Model constructs and behavioral indicators for physical activity, fruit and vegetable consumption, and limiting television time. Analyses were conducted to compare the prevalence of students at risk for the target behaviors across the age groups and to examine the interrelationships of the target behavior risks. RESULTS: Across the three age groups, physical activity and fruit and vegetable consumption declined, while limiting TV time increased. In addition, high school students had the greater number of behavioral risks. Across all three samples, being at-risk for one behavior almost always significantly increased the odds of being at-risk for another behavior. CONCLUSION: The findings of this study provide further evidence for the need for early promotion of healthy lifestyle behaviors. The relationships among the target behaviors in three samples strongly support a multiple behavior approach for obesity prevention. Transtheoretical Model-based tailored interventions are currently being used to change multiple behaviors without overwhelming students. PMID- 17714772 TI - Induced immotility during long-term storage at +5 degrees C does not prolong survival of dog spermatozoa. AB - This study investigated whether the immotility induced by the CLONE chilled semen extender prolongs the lifespan of dog spermatozoa stored at 5 degrees C, compared with a Tris-egg yolk-glucose (TG) extender, which maintains motility. Pooled semen was split in four aliquots, centrifuged, and the four sperm pellets mixed with TG extender; with the CLONE chilled semen (CL) extender; with TG extender mixed with an activator (TG+A(TG)); or with the CLONE extender mixed with the CLONE activator (CL+A(CL)). Samples were stored at 5 degrees C for 23 days and examined 12 times for sperm motility, plasma membrane and acrosome integrity, glucose consumption, and DNA fragmentation index (DFI). The experiment was performed in triplicate. Glucose consumption was not significantly different between extenders until the period 15-23 days, when it was higher in CL and CL+A(CL) than in TG (P=0.0055) and TG+A(TG) (P=0.0010). No breakdown of DNA chromatin (P>0.05) occurred until day 14. Spermatozoa preserved in TG or TG+A(TG) showed better values for all the different parameters throughout the experiment compared with sperm subjected to CL or CL+A(CL). In conclusion, the immotility induced by the CLONE chilled semen extender during long-term cold storage at 5 degrees C did not prolong the lifespan of spermatozoa compared with the lifespan following storage in Tris-egg yolk-glucose. In addition, our results indicate that good quality dog semen may possibly be stored for up to 14 days in TG extender at 5 degrees C, with retained fertilizing capacity. In vivo studies should, however, be performed to further support this conclusion. PMID- 17714770 TI - Agmatine reduces balance deficits in a rat model of third trimester binge-like ethanol exposure. AB - This study examined the effects of binge-like ethanol (ETOH) exposure in neonatal rats on a cerebellar-mediated balance task, and the ability of agmatine, an n methyl-d-aspartate receptor (NMDAR) modulator, to reverse such effects. Five neonatal treatments groups were used, including ETOH (6.0 g/kg/day), AG (20 mg/kg), ETOH plus AG (6.0 g/kg/day and 20 mg/kg), a maltose control, and a non treated control. Ethanol was administered via oral intubation twice daily for eight days, (AG was administered with the last ETOH intubation only). Two exposure periods were used; PND 1-8 or PND 8-15. On PND 31-33, balance performance on a single dowel was tested. Treatment with AG during withdrawal in ETOH exposed animals improved performance relative to ETOH alone among the PND 1 8 exposure period. ETOH exposure during the 2nd postnatal week did not impair balance. These findings provide further support that exposure to ETOH during critical developmental periods can impair performance on a cerebellar-dependent balance task. Of perhaps greater significance, co-administration of agmatine reduced these deficits suggesting that NMDA modulation via polyamine blockade may provide a novel approach to attenuating damage associated with binge-like ETOH consumption. PMID- 17714773 TI - Recovery rate, morphological quality and nuclear maturity of canine cumulus oocyte complexes collected from anestrous or diestrous bitches of different ages. AB - Canine cumulus-oocyte complexes (COC) were recovered from ovaries of post pubertal animals (1-3, 4-6 and 7-10 years old) at different ovarian estrous phases (anestrus and diestrus). The number of COCs, and the number and nuclear maturity of high-quality (grade-1) oocytes were assessed. For all animals, no significant differences were found between the two reproductive phases relatively to the total number of COCs and grade-1 oocytes recovered. However, significant higher numbers of COCs were recovered from young than from elderly animals, and the proportion of grade-1 oocytes was also significantly higher in the younger group than in the other two age-groups. Of 226 grade-1 oocytes, 73% were at the germinal vesicle stage (GV), 10% had resumed meiosis (9% at germinal vesicle breakdown; 1% at metaphase-I) and 17% were degenerated. A significant effect of the reproductive phase on oocyte nuclear maturity was found only for adult animals, with a higher number of GV oocytes being found at anestrous (79%) due to higher rates of meiosis resumption (34%) at diestrous. The high number of grade-1 oocytes with meiosis resumption and fragmented or unidentified nuclear contents, indicates that current criteria for the selection of viable canine COCs are not optimized and need a new definition. PMID- 17714774 TI - Effects of ovarian stimulation, with and without human chorionic gonadotrophin, on oocyte meiotic and developmental competence in the marmoset monkey (Callithrix jacchus). AB - A reliable ovarian stimulation protocol for marmosets is needed to enhance their use as a model for studying human and non-human primate oocyte biology. In this species, a standard dose of hCG did not effectively induce oocyte maturation in vivo. The objectives of this study were to characterize ovarian response to an FSH priming regimen in marmosets, given without or with a high dose of hCG, and to determine the meiotic and developmental competence of the oocytes isolated. Ovaries were removed from synchronized marmosets treated with FSH alone (50 IU/d for 6 d) or the same FSH treatment combined with a single injection of hCG (500 IU). Cumulus-oocyte complexes (COCs) were isolated from large (>1.5mm) and small (0.7-1.5mm) antral follicles. In vivo-matured oocytes were subsequently activated parthenogenetically or fertilized in vitro. Immature oocytes were subjected to in vitro maturation and then activated parthenogenetically. Treatment with FSH and hCG combined increased the number of expanded COCs from large antral follicles compared with FSH alone (23.5 +/- 9.3 versus 6.4 +/- 2.7, mean +/- S.E.M.). Approximately 90% of oocytes surrounded by expanded cumulus cells at the time of isolation were meiotically mature. A blastocyst formation rate of 47% was achieved following fertilization of in vivo-matured oocytes, whereas parthenogenetic activation failed to induce development to the blastocyst stage. The capacity of oocytes to complete meiosis in vitro and cleave was positively correlated with follicle diameter. A dramatic effect of follicle size on spindle formation was observed in oocytes that failed to complete meiosis in vitro. Using the combined FSH and hCG regimen described in this study, large numbers of in vivo matured marmoset oocytes could be reliably collected in a single cycle, making the marmoset a valuable model for studying oocyte maturation in human and non-human primates. PMID- 17714775 TI - Atmospheric nitrogen deposition to the Mullica River-Great Bay Estuary. AB - Measurements of nitrate and ammonium in precipitation and associated with aerosols were conducted at Rutgers University Marine Field Station in Tuckerton, New Jersey from March 2004 to March 2005 to characterize atmospheric nitrogen deposition to the Mullica River-Great Bay Estuary. The arithmetic means of nitrate and ammonium concentrations for precipitation samples were 2.3mgL(-1) and 0.42mgL(-1), respectively. Nitrate and ammonium concentrations in aerosol samples averaged 3.7microgm(-3) and 1.6microgm(-3), respectively. Wet deposition rates appeared to vary with season; the highest rate of inorganic nitrogen deposition (nitrate+ammonium) occurred in the spring with an average value of 1.33kg-Nha( 2)month(-1). On an annual basis, the total (wet and dry) direct atmospheric deposition fluxes into the Mullica River-Great Bay Estuary were 7.08kg-Nha( 2)year(-1) for nitrate and 4.44kg-Nha(-2)year(-1) for ammonium. The total atmospheric inorganic nitrogen directly deposited to the Mullica River-Great Bay Estuary was estimated to be 4.79x10(4)kg-Nyear(-1), and the total atmospheric inorganic nitrogen deposited to the Mullica River watershed was estimated to be 1.69x10(6)kg-Nyear(-1). Only a fraction of the nitrogen deposited on the watershed will actually reach the estuary; most of the nitrogen will be retained in the watershed due to utilization and denitrification during transport. The amount of N reaching the Mullica River-Great Bay Estuary indirectly is estimated to be 5.07x10(4)kg-Nyear(-1), approximately 97% is retained within the watershed. This atmospheric nitrogen deposition may stimulate phytoplankton productivity in the Mullica River-Great Bay ecosystem. PMID- 17714776 TI - Identification of estrogen-like alkylphenols in produced water from offshore oil installations. AB - Produced water released into the sea from oil installations contains a vast number of organic compounds. This work focuses on the analysis and identification of phenols in produced water, in particular long-chain para-substituted alkylphenols, which act as endocrine disruptors for marine biota. Some alkylphenol standards, unavailable commercially, have been synthesised and some compounds of interest identified. However, a complete identification is not possible since conventional GC techniques cannot achieve the desired degree of separation. An overview of the levels of the 52 known alkylphenols in produced water from nine oil installations in the North and Norwegian Seas has been made. The previously unidentified alkylphenols in produced water have been characterised by means of alkylphenol retention indices (APRI) and mass spectrometry, and their total amounts estimated for the same nine locations. Our results confirm the presence of naphthols and other as yet unidentified compounds in produced water, while thiophenols were not detected by the used technique. PMID- 17714777 TI - Sulfated chitooligosaccharides as prolyl endopeptidase inhibitor. AB - Prolyl endopeptidase (PEP, EC 3.4.21.26) is a proline-specific endopeptidase with a serine-type mechanism, which digests small peptide-like hormones, neuroactive peptides, and various cellular factors. PEP has been involved in neurodegenerative disorders, therefore, the discovery of PEP inhibitors can revert memory loss caused by amnesic compounds. In this study, we prepared hetero chitooligosaccharides (COSs) with different molecular sizes using ultrafiltration (UF) membrane reactor system from hetero-chitosan with different degrees of deacetylation (DD; 90%, 75% and 50% deacetylation), and synthesized sulfated COSs (SCOSs). PEP inhibitory activities of SCOSs were evaluated and the results showed that 50% deacetylated SCOSs (50-SCOSs) exhibited higher inhibitory activities than those of 90% and 75% deacetylated SCOSs (90-SCOSs and 75-SCOSs). Among the 50-SCOSs (50-SCOS I, 5000-10,000Da; 50-SCOS II, 1000-5000Da; 50-SCOS III, below 1000Da), 50-SCOS II possessed the highest inhibitory activity and IC(50) value was 0.38mg/ml. Kinetics studies with 50-SCOS II indicated a competitive enzyme inhibition with a K(i) value of 0.78mg/ml. It was concluded that the 50-SCOS II may be useful for PEP inhibitor and for developing a new type PEP inhibitor from carbohydrate based materials. PMID- 17714778 TI - Stress-corrosion crack growth of Si-Na-K-Mg-Ca-P-O bioactive glasses in simulated human physiological environment. AB - This paper describes research on the stress-corrosion crack growth (SCCG) behavior of a new series of bioactive glasses designed to fabricate coatings on Ti and Co-Cr-based implant alloys. These glasses should provide improved implant fixation between implant and exhibit good mechanical stability in vivo. It is then important to develop an understanding of the mechanisms that control environmentally assisted crack growth in this new family of glasses and its effect on their reliability. Several compositions have been tested in both static and cyclic loading in simulated body fluid. These show only small dependences of SCCG behavior on the composition. Traditional SCCG mechanisms for silicate glasses appear to be operative for the new bioactive glasses studied here. At higher velocities, hydrodynamic effects reduce growth rates under conditions that would rarely pertain for small natural flaws in devices. PMID- 17714779 TI - Immunosuppression by placental indoleamine 2,3-dioxygenase: a role for mesenchymal stem cells. AB - BACKGROUND/OBJECTIVES: Mesenchymal stem cells (MSC) can be isolated from human placenta and have the potential to contribute to the immunosuppressive properties of placental tissue. The objectives of this study were to investigate the phenotype and differentiation characteristics of MSC derived from human placenta and evaluate the role of the tryptophan degrading enzyme, indoleamine 2,3 dioxygenase (IDO), in mediating their immunosuppressive affect. METHODS: MSC obtained from placental tissue (pMSC) were characterised using flow cytometry and tested for multipotency by determining differentiation into all mesenchymal lineages. The immunosuppressive properties of pMSC were tested in allogeneic mixed lymphocyte reactions and IDO expression and activity were measured by semi quantitative real-time PCR and HPLC respectively. RESULTS: Multipotent stem cells were isolated from placenta and displayed chondrogenic, osteogenic and limited adipogenic differentiation. Cell surface antigen expression of pMSC was similar to bone marrow MSC (bMSC) with lack of the haematopoietic and common leukocyte markers (CD34, CD45), and expression of adhesion (CD29, CD166, CD44) and stem cell (CD 90, CD105, CD73) markers. Placental MSC were suppressive of allogeneic T cell proliferation, an effect which was intensified following IDO induction by IFN-gamma. Replenishment of tryptophan or treatment with the IDO-blocker, 1 methyl-tryptophan (1-MT), attenuated the immunosuppressive action of pMSC. CONCLUSIONS: These results suggest that placental tissue contains MSC, which are phenotypically and functionally similar to bMSC, and that IDO is a key mediator of their immunosuppressive effect. Further investigation is needed to determine if pMSC function effects pregnancy outcome. PMID- 17714781 TI - Flowcytometry in myelodysplastic syndromes: towards a new paradigm in diagnosis and prognostication? PMID- 17714780 TI - Expression and function of the calcitonin receptor by myeloma cells in their osteoclast-like activity in vitro. AB - Malignant plasma cells exert osteoclast-like activity in vitro. We investigated the function of the calcitonin (CT) receptor (R) on myeloma cells from patients and in myeloma cell lines. Primary myeloma cells expressed high CTR levels whereas the cell lines uniformly exposed the CTR-2 variant expressed by osteoclasts. Treatment of myeloma cell lines with CT modified the intracellular Ca(2+) and cAMP levels, suggesting the activation of both PKC and PKA pathways, and abrogated their bone resorptive property as erosive pits on osteologic substrates. Thus, the expression, sensitivity and function of CTR-2 in myeloma cells emphasize their osteoclast-like behavior in vitro. PMID- 17714782 TI - High incidence of tuberculosis after alemtuzumab treatment in Hong Kong Chinese patients. AB - Twenty-seven patients received the anti-CD52 monoclonal antibody alemtuzumab for hematologic malignancies and autoimmune cytopenias in a tuberculosis-endemic area. Seven patients developed mycobacterium tuberculosis (TB) infections (median: 4, 1-24, months from alemtuzumab). The actuarial 1- and 2-year incidence of TB was 31% and 45%. All patients had severe depression of lymphocyte counts subsequent to alemtuzumab treatment, and tuberculosis was extra-pulmonary in three cases. All seven patients had received prior chemotherapy/immunosuppression and tuberculosis had not occurred until alemtuzumab was administered. Patients receiving alemtuzumab in areas endemic for tuberculosis should have careful initial evaluation of TB exposure, so that prophylactic antibiotics might be administered. Tuberculosis reactivation should be considered for unexplained fever and symptoms after alemtuzumab treatment. PMID- 17714783 TI - Relationships between physicochemical parameters and the toxicity of leachates from a municipal solid waste landfill. AB - Landfills are used to dispose municipal solid wastes, and although on-site recycling in these places is an extensive practice in Latin America, diverse pollutants are incorporated into the leachates. The objective of this work was to establish relationships between composition and toxicity of leachates from the landfill of the city of Cartagena, Colombia. Leachates were characterized measuring Cd, Ni, Hg, Mn, Cu, and Pb concentrations, and physicochemical parameters including pH, conductivity, chemical oxygen demand (COD), and hardness. Bioassays were conducted diluting with synthetic sea water, recording toxicity against Artemia franciscana as median lethal concentrations (LC50 values) after 24 and 48 h exposure. Average LC(50) values oscillated between 3.20% and 39.33% (v/v). Multivariate analysis showed that toxicity was dependent on Cd and COD. The slope of the concentration-response curve correlated with Ni concentration independently from toxicity. Results suggest toxicity of these leachates depends on Cd concentrations associated with organic matter, this effect being modulated by Ni. PMID- 17714784 TI - An unusual intraventricular lesion: tuberculoma. PMID- 17714785 TI - The inhibitory CD200R is differentially expressed on human and mouse T and B lymphocytes. AB - To ensure an adequate response against pathogens and prevent unwanted self reactivity, immune cells need to functionally express both activating and inhibitory receptors. CD200R is an inhibitory receptor mainly expressed on myeloid cells that down-modulates cellular activation both in vivo and in vitro. Although previously mainly studied as a regulator of myeloid function, we now show that CD200R is differentially expressed on human and mouse T-cell subsets. In both species, CD4+ T cells express higher amounts of CD200R than CD8+ T cells, and memory cells express higher amounts of CD200R than naive or effector cells. CD200R expression is up-regulated on both CD4+ and CD8+ T cells after stimulation in vitro. Furthermore, we show CD200R expression on human and mouse B cells. In human tonsils, CD200R is differentially expressed on B cells, with high expression on memory cells and plasmablasts. Mice lacking the ligand for CD200R, CD200-/- mice, do not show abnormal composition of the lymphocyte compartment and have normal B cell responses to antigenic challenge. Although the functional implications remain to be elucidated, the expression of CD200R on lymphocytes suggests a much broader role for CD200R-mediated immune regulation than previously anticipated. PMID- 17714786 TI - Changes in HIV prevalence and sexual behavior among men who have sex with men in a northern Chinese city: 2002-2006. AB - OBJECTIVE: To examine HIV prevalence and sexual behavior changes among MSM in Harbin. METHODS: Three community-based cross-sectional surveys among MSM were conducted based on the same protocol and methodology in 2002, 2004 and 2006 in Harbin, China. Men who were eligible were interviewed with a standard questionnaire. Urine samples were collected to screen their HIV status. RESULTS: Among the MSM in Harbin, an increased trend was observed towards more self identifying as homosexual (from 58% to 80%) and more living with a male partner (from 12% to 41%) over the study period. Although there was a trend towards a reduction in the rate of never using a condom and an increase in the rate of always using condoms during anal sex in the past six months, the prevalence of unprotected anal intercourse (UAI) was still at a high level (from 90% in 2002 to 72% in 2006). The HIV prevalence in 2006 (2.2%, 15/674) was higher than that in other study years, but no statistically significant change was detected. CONCLUSIONS: Although an increase in condom use and a decline in drug use, STD infection and commercial sex have been monitored under current HIV prevention strategies, the MSM in Harbin is still highly vulnerable to HIV transmission given a high level of UAI and an increasing number of male sexual partners over the study period. PMID- 17714787 TI - Weather variables and Japanese encephalitis in the metropolitan area of Jinan city, China. AB - OBJECTIVE: To identify weather-related risk factors and their roles in Japanese encephalitis transmission and to provide policy implications for local health authorities and communities. METHODS: Data on notified cases of Japanese encephalitis and weather variables over the period 1959-1979 were collected from Jinan city, a temperate city in China. Due to seasonality of the disease, the data analysis was restricted to five months from June to October each year. Spearman correlation analysis and time-series adjusted Poisson regression analysis were performed to quantify the relationship between weather and the number of cases. The Hockey Stick model was used to detect potential threshold temperatures. RESULTS: Monthly mean maximum and minimum temperatures, monthly total rainfall and monthly mean relative humidity were positively correlated to monthly notification of Japanese encephalitis, while monthly mean air pressure was inversely correlated. Lag times varied from one to two months. All these weather variables were significant in the adjusted Poisson regression model. Thresholds of 25.2 degrees C for maximum temperature and 21.0 degrees C for minimum temperature were also detected. CONCLUSIONS: Weather variables could have affected the transmission of Japanese encephalitis in this urban area of China. Public health interventions should be developed at this stage to reduce future risks related to climate change. PMID- 17714788 TI - Incidence and risk factors of major opportunistic infections after initiation of antiretroviral therapy among advanced HIV-infected patients in a resource-limited setting. AB - OBJECTIVE: To study incidence, risk factors, and impact of major opportunistic infections (OIs) after initiation of antiretroviral therapy (ART). METHODS: A retrospective cohort study was conducted among naive HIV-infected patients who were initiated ART during January 2003-December 2004. All patients were followed until 15 months after ART. RESULTS: There were 793 patients with mean+/-SD age of 35.2+/-7.4 years and 56.3% male. Median (IQR) CD4 was 26 (9-78) cells/mm3. Of 793 patients, 61 (8%) patients developed 81 episodes of OIs after ART. These included tuberculosis (48.1%), CMV retinitis (19.8%), MAC infection (14.8%), PCP (9.9%), cryptococcosis (6.2%) and penicilliosis (1.2%). Overall incidence of new episode of OIs after ART was 8.0% during the first year of ART. Probabilities of OIs at 1, 2, 3, 6, and 12 months after ART were 2.6%, 4.0%, 5.3%, 6.9% and 8.0%, respectively. Baseline CD4 < or = 50 cells/mm3, male gender, and low body weight were associated with higher incidence of OIs after ART (P<0.05). CONCLUSIONS: Most of new episodes of major OIs develop within the first three months after ART. Tuberculosis is the most frequent OIs in this situation. The substantial increase of new episode of OIs after ART was observed among HIV-infected patients with CD4 cell counts < or = 50 cells/mm3 at ART initiation. PMID- 17714789 TI - Tuberculosis in adult patients with sickle cell disease. AB - OBJECTIVE: Although infection, in particular pulmonary infection, is a common complication of sickle cell disease (SCD) and although SCD is frequent in populations where the prevalence of tuberculosis is high, the relationship between the two diseases has never been studied. We conducted a study to assess the epidemiological and clinical pattern of tuberculosis in adult patients with SCD. METHODS: We retrospectively reviewed the cases of tuberculosis reported within our cohort of 457 SCD patients from January 1998 to April 2006 in the adult sickle cell center of Hopital Tenon, Paris, France. RESULTS: We identified 12 cases of tuberculosis, 8 men and 4 women. There were 7 lymph node lesions, 3 pulmonary lesions and 2 vertebral lesions. The incidence of pulmonary and extrapulmonary tuberculosis was respectively of 82 and 246 cases per 100,000, to compare with an expected incidence of 184 cases, and 65 cases per 100,000. Three of the patients with lymph node tuberculosis were asymptomatic. No case of multi organ involvement was seen. No other cause of immunodepression than the functional asplenia was found. All the patients showed clinical improvement under treatment. CONCLUSIONS: In SCD patients, lymph node tuberculosis appears to have a higher incidence than that in an epidemiologically comparable population, and has a rather indolent presentation and a favourable outcome. Pulmonary tuberculosis seems to be less frequent than expected. PMID- 17714790 TI - Maternal depression and infant temperament characteristics. AB - One hundred-thirty-nine women participated in this longitudinal study from the third trimester of pregnancy through 8-months postpartum. Women completed depression scales at several time points and rated their infant's characteristics and childcare stress at 2- and 6-months postpartum. Mothers' reports of infant temperament were significantly different for depressed and non-depressed mothers, with depressed mothers reporting more difficult infants at both measurement points. These differences remained after controlling for histories of maternal abuse or prenatal anxiety, which occurred more often in the depressed mothers. There were no significant differences in childcare stress or perceived support between the groups. Infant temperament and childcare stress did not change over time. Recommendations for practice include consistent ongoing evaluations of the "goodness of fit" within the dyad and exploring interventions for depressed mothers that provide guidance about interactions with their infants and the appropriateness of the infant behaviors. PMID- 17714791 TI - Matching native electrical stimulation by graded chemical stimulation in isolated mouse adrenal chromaffin cells. AB - Adrenal chromaffin cells release multiple transmitters in response to sympathetic stimulation. Modest cell firing, matching sympathetic tone, releases small freely soluble catecholamines. Elevated electrical firing rates matching input under sympathetic stress results in release of catecholamines as well as semi-soluble vaso- and neuro-active peptides packaged within the dense core of the secretory granule. This activity-dependent differential transmitter release has been shown to rely on a mechanistic shift in the mode of exocytosis through the regulated dilation of the secretory fusion pore between granule and cell surface membranes. However, biochemical description of the mechanism regulating fusion pore dilation remains elusive. In the experimental setting, electrical stimulation designed to mimic sympathetic input, is achieved through single-cell voltage-clamp. While precise, this approach is incompatible with biochemical and proteomic analysis, both of which require large sample sizes. We address this limitation in the current study. We describe a bulk chemical stimulation paradigm calibrated to match defined electrical activity. We utilize calcium and single-cell amperometric measurements to match extracellular potassium concentrations to physiological electrical stimulation under sympathetic tone as well as acute stress conditions. This approach provides larger samples of uniformly stimulated cells for determining molecular players in activity-dependent differential transmitter release from adrenal chromaffin cells. PMID- 17714792 TI - Cytokine expression in naive and previously infected lambs after challenge with Teladorsagia circumcincta. AB - Infection of sheep with Teladorsagia circumcincta triggers an immune response with predominantly type-2 (Th2) characteristics, including local eosinophila, mastocytosis and increased mucus production. In order to better understand the protective immune responses elicited, we used RT-PCR assays to define the changes in expression levels of a range of cytokine transcripts in lymph nodes draining the ovine abomasum following a challenge infection with T. circumcincta. This study compared the changes in cytokine expression in the abomasal lymph node following challenge with T. circumcincta in naive sheep (Group 2) and sheep immunised by a previous trickle infection (Group 3), in comparison to unchallenged naive sheep (Group 1). There was a significant up-regulation of interleukin-4 (IL-4), IL-5 and IL-13 in both the challenged groups compared to naive individuals. There was also an up-regulation of IL-1beta, IL-6, IL-10, IL 18, transforming growth factor-beta1 (TGFbeta1) and tumour necrosis factor-alpha (TNFalpha) by day 5 after infection. IL-12p40 was found to be increased in the previously infected Group 3 animals by day 5 following challenge. By contrast, transcription of this cytokine was found to be reduced by day 10 following infection of Group 2 animals. Expression of IL-2 and Interferon-gamma (IFNgamma) did not significantly differ between the three groups. PMID- 17714793 TI - Disease resistance and immunity. PMID- 17714794 TI - Location, location, timing: analysis of cytomegalovirus epitopes for neutralizing antibodies. AB - Attempts to produce a vaccine to human cytomegalovirus (HCMV) have failed. The principal target of the humoral immune response to HCMV is the viral envelope glycoprotein gB, which contains several immunodominant epitopes. Here we discuss human antibodies reacting with gB and offer an explanation as to why most humans make antibodies to an epitope that does not always elicit neutralizing antibodies. We suggest modifications to gB for an improved HCMV vaccine design. PMID- 17714795 TI - Beneficial effects of r-h-CLU on disease severity in different animal models of peripheral neuropathies. AB - Clusterin is a protein involved in multiple biological events, including neuronal cytoprotection, membrane recycling and regulation of complement-mediated membrane attack after injury. We investigated the effect of recombinant human clusterin in preclinical models of peripheral neuropathies. Daily treatment with clusterin accelerated the recovery of nerve motor evoked potential parameters after sciatic nerve injury. Prophylactic or therapeutic treatment of experimental autoimmune neuritis rats with clusterin also accelerated the rate of recovery from the disease, associated with remyelination of demyelinated nerve fibers. These data demonstrate that clusterin is capable of ameliorating clinical, neurophysiological and pathological signs in models of peripheral neuropathies. PMID- 17714796 TI - Use of complementary and alternative medicine in pediatric otolaryngology patients attending a tertiary hospital in the UK. AB - OBJECTIVE: Little data is available on complementary and alternative medicine (CAM) use in children attending otolaryngology services. We investigated the prevalence and pattern of CAM use among children attending the pediatric otolaryngology department in a tertiary pediatric teaching hospital in Scotland. DESIGN: A cross-sectional survey conducted by administering an anonymous questionnaire to the parents accompanying patients attending the pediatric otolaryngology department. Elective admissions and clinic attendees were included over a 3-month period in 2005/2006. SETTING: Academic tertiary care referral centre in North-East Scotland. PATIENTS: Five hundred and fifty-four consecutive patients aged less than 16 years were eligible. The response rate was 59% (n=327). MAIN OUTCOME MEASURES: Prevalence of CAM use in children. Secondary measures include types of CAM used, indications for use and communication with family physicians. RESULTS: Based on 327 responses, 93 patients (29%) had ever used CAM, 20% within the last year. Commonly used CAM preparations were cod-liver oil, echinacea, aloe vera, cranberry, primrose oil and herbal vitamin supplements. The popular non-herbal CAM included homeopathy, massage, aromatherapy, chiropractic, yoga and reiki. Nineteen percent used CAM for their admission illness. Sixty-one percent of parents thought that CAM was effective and 65% would recommend it to others. Fifty-one percent of parents stated that the family physician was unaware of CAM use by the child. CONCLUSIONS: Despite concerns regarding the efficacy, safety and cost effectiveness of complementary and alternative medicine, its use among the pediatric otolaryngology population is more common than many providers may realize. This has implications for all healthcare workers involved in their care. PMID- 17714797 TI - Long-term storage at tropical temperature of dried-blood filter papers for detection and genotyping of RNA and DNA viruses by direct PCR. AB - In tropical countries the diagnosis of viral infections of humans or animals is often hampered by the lack of suitable clinical material and the necessity to maintain a cold chain for sample preservation up to the laboratory. This study describes the use of filter papers for rapid sample collection, and the molecular detection and genotyping of viruses when stored over long periods at elevated temperatures. Infected blood was collected on filter papers, dried and stored at different temperatures (22, 32 and 37 degrees C) for various periods (up to 9 months). Two animal viruses, African swine fever, a large double-stranded DNA virus and Peste des Petits Ruminants, a negative single-stranded RNA virus, were used to validate the method. Filter papers with dried blood containing virus or control plasmid DNA were cut in small 5mm(2) pieces and added directly to the PCR tube for conventional PCR. Nucleic acid from both viruses could still be detected after 3 months at 32 degrees C. Moreover, the DNA virus could be detected at least 9 months after conservation at 37 degrees C. PCR products obtained from the filter papers were sequenced and phylogenetic analysis carried out. The results were consistent with published sequences, demonstrating that this method can be used for virus genotyping. PMID- 17714799 TI - Cerebral processing of gustatory stimuli in patients with taste loss. AB - Aim was to investigate differences in the central-nervous processing of gustatory stimuli between normogeusic subjects and patients with taste disorders. Twelve subjects with normal gustatory function and eight patients suffering from hypo- to ageusia underwent one fMRI run each in a 1.5 T scanner where they received liquid gustatory stimuli. fMRI analyses were performed by means of SPM2. Across all participants clusters of activated voxels were mainly found in orbitofrontal and insular regions of interest. Even those patients who did not perceive any stimuli showed some activation of gustatory centers. Group comparisons revealed higher activation of the insular and orbitofrontal cortices in patients compared to the group of healthy subjects. While further studies are needed, this finding may be interpreted in terms of enhanced neuronal recruitment due to functional impairment in patients with gustatory loss. It may ultimately prove useful in terms of the prognostic evaluation of individual patients. PMID- 17714798 TI - GABAA and GABAB agonist microinjections into medial accumbens shell increase feeding and induce anxiolysis in an animal model of anxiety. AB - This study investigated the effect of GABAA (muscimol, MUSC) and GABAB (baclofen, BACL) agonist receptors microinjected into medial accumbens shell on feeding and the level of fear in free-feeding rats submitted to the elevated plus-maze (EPM), an animal model of anxiety. Bilateral microinjections of either MUSC (128 pmol/0.2 microl/side) or BACL (128 and 256 pmol/0.2 microl/side) induced an anxiolytic-like effect since they decreased the occurrence of risk assessment, a defensive behaviour positively correlated with the animal anxiety level. Bilateral BACL microinjection (128 pmol), but not MUSC, also increased the head dipping frequency over the open arms of the EPM, another representative behaviour of anxiety, but negatively correlated with it. In addition to anxiolysis, the present study also showed that the microinjection of MUSC and BACL agonists into rostral sites of the medial Acb shell (AP, +1.2 to +1.6) increased food intake significantly whereas drinking behaviour kept unchanged. Both doses of MUSC and BACL also decreased feeding latency. BACL but not MUSC dose-dependently increased food length. The data indicated a putative role of GABA receptors (especially GABAB) in the medial Acb shell for anxiety modulation in rats. PMID- 17714800 TI - Serial reversal learning and acute tryptophan depletion. AB - Cognitive flexibility (i.e. the ability to adapt goal-directed behaviour in response to changed environmental demands) has repeatedly been shown to depend on the prefrontal cortex (PFC). Recent data from primate studies moreover show that depletion of prefrontal 5-HT impairs reversal learning of visual stimuli [Clarke HF, Walker SC, Crofts HS, Dalley JW, Robbins TW, Roberts AC. Prefrontal serotonin depletion affects reversal learning but not attentional set shifting. J Neurosci 2005;25:532-8; Clarke HF, Walker SC, Dalley JW, Robbins TW, Roberts AC. Cognitive inflexibility after prefrontal serotonin depletion is behaviorally and neurochemically specific. Cereb Cortex 2007;17:18-27]. It is not clear however if 5-HT serves a general role in reversal learning or if it is involved only in specific reversal problems. A first aim of these experiments was to study the role of 5-HT in serial reversal learning of a spatial discrimination. Literature has, moreover, repeatedly shown that the PFC is involved in the initial acquisition of a reversal problem but hardly when the task is well practiced. A second aim concerns the role of 5-HT in early versus late reversal learning. With the current experiment, we aim to clarify whether 5-HT is differentially involved in early versus late reversal learning. To this end, we tested rats on a serial two-lever reversal task and induced a temporary reduction of 5-HT availability in these rats by restricting dietary intake of the 5-HT precursor tryptophan at an early and a late reversal. Our results indicate that acute tryptophan depletion (ATD) did not affect either early or late reversal learning, nor extinction and suggest that spatial reversal learning, in contrast to visual reversal learning, might not be dependent on 5-HT. The data furthermore provide insight in the behavioural strategies employed in serial reversal learning and suggests the formation of a learning-set. PMID- 17714801 TI - Are rats predisposed to learn 22 kHz calls as danger-predicting signals? AB - Alarm calls are widely used in mammals. Their biological function is to deter predators and warn relatives of danger. Despite this important function of alarm calls, the development of alarm call recognition is poorly understood. Using laboratory rats, the present study investigated in a first experiment whether alarm calls are recognized innately. In experimentally naive animals, we found significantly increased freezing if stimuli in the 22 kHz range were presented but this response was not specific to conspecific 22 kHz calls. Therefore, a second experiment addressed the hypothesis whether recognition of conspecific 22 kHz calls can be learned and whether this learning is facilitated by a preparedness to acquire defensive responses to alarm calls. Our data show that rats learned quickly to associate the 22 kHz calls with aversive stimuli. Interestingly, the animals were more reluctant to extinguish this memory, and this information retained longer in memory than in the case of other types of calls and ultrasonic stimuli. We, therefore, conclude that rats are predisposed to acquire adaptive defensive behaviour in response to alarm calls. In particular, our data indicate that better encoding of such learning in rats leads to a stable memory which better resists extinction. PMID- 17714802 TI - The effects of copper on the morphological and functional development of zebrafish embryos. AB - Waterborne copper exposure can exert a variety of physiological effects in fish, including the disruption of sensory system function, which has wide-reaching implications for fish behaviour. In developing fish larvae, copper is known to affect key parameters, such as survival and growth and more recently has been shown to interfere with the octavolateral system. The present study aimed to take a combined view of morphological (e.g. length, yolk sac area) and functional (e.g. heart beat, behaviour) processes to understand the complex effect of copper on fish development. In the first of two experiments, zebrafish embryos were exposed to a range of copper concentrations (11-1000 microg l(-1)) from fertilisation for a 72 h period. The greatest mortality was seen between 5 and 24h post-fertilisation (hpf) and was more pronounced at the higher copper concentrations. Copper also had an inhibitory effect on hatching. Length and yolk sac area of individuals were recorded across treatments at 72 hpf and elevated copper was found to slow development. Individuals from the higher copper treatments had the fastest heart rates at 28 hpf suggesting that stress responses were induced in the embryos during copper exposure. In the second experiment, embryos were exposed in a similar manner to two copper concentrations, based on those from Experiment 1 that resulted in <50% mortality. At 120 hpf, embryos exposed to both copper concentrations possessed significantly fewer functional neuromasts, an effect which was associated with a reduced ability to orientate in a current. Therefore, although mortality at these copper concentrations was low initially, and then almost non-existent after 24 hpf, the inability of copper exposed larvae to orientate in a water current as a result of lateral line dysfunction is likely to seriously compromise survival. PMID- 17714803 TI - Histone modifications in Trypanosoma brucei. AB - Several biological processes in Trypanosoma brucei are affected by chromatin structure, including gene expression, cell cycle regulation, and life-cycle stage differentiation. In Saccharomyces cerevisiae and other organisms, chromatin structure is dependent upon posttranslational modifications of histones, which have been mapped in detail. The tails of the four core histones of T. brucei are highly diverged from those of mammals and yeasts, so sites of potential modification cannot be reliably inferred, and no cross-species antibodies are available to map the modifications. We therefore undertook an extensive survey to identify posttranslational modifications by Edman degradation and mass spectrometry. Edman analysis showed that the N-terminal alanine of H2A, H2B, and H4 could be monomethylated. We found that the histone H4 N-terminus is heavily modified, while, in contrast to other organisms, the histone H2A and H2B N termini have relatively few modifications. Histone H3 appears to have a number of modifications at the N-terminus, but we were unable to assign many of these to a specific amino acid. Therefore, we focused our efforts on uncovering modification states of H4. We discuss the potential relevance of these modifications. PMID- 17714804 TI - Comparative molecular analysis of two asparaginyl endopeptidases and encoding genes from Fasciola gigantica. AB - In this study we describe the first cysteine proteinases of the MEROPS Clan CD family C13 in Fasciola gigantica. Family C13 contains asparaginyl endopeptidases and glycosylphosphatidylinositol-anchor transamidases and is also called the legumain family due to the discovery of the first asparaginyl endopeptidase in a legume. The cDNAs encoding two asparaginyl endopeptidases, FgLGMN-1 and FgLGMN-2, were cloned and used for the analysis of nucleic acid and protein properties. The deduced amino acid sequences showed 47.4% identity to each other and from 42.2 to 51.1% identity to homologs of other trematode species. The catalytic site residues histidine, cysteine and preceding hydrophobic residues, characteristic for the cysteine proteinase families C11, C13, C14, and C25, were found conserved. Northern and reverse transcription PCR analyses demonstrated that the transcriptional products are present in metacercariae, juveniles and adults. RNA in situ hybridization and immunohistochemistry revealed that RNA and protein products of the two genes are specifically expressed in the intestinal epithelium of juveniles and adults. Immune sera of mice infected with F. gigantica reacted with immunoblotted, bacterially expressed recombinant proteins starting 4 weeks after infection. Polyclonal antisera raised against the recombinant proteins detected 40 and 30 kDa antigens, respectively in crude worm protein extracts but not in the excretion-secretion products of adult parasites. Likewise, legumain specific activity was found in crude worm protein extracts but not in excretion secretion products. This study elucidates the molecular characteristics of these proteins in F. gigantica and demonstrates differences in the biology between Fasciola and Schistosoma which may prove useful for the development of vaccines against fasciolosis in domestic livestock. PMID- 17714805 TI - Exposure of Plasmodium sporozoites to the intracellular concentration of potassium enhances infectivity and reduces cell passage activity. AB - Malaria sporozoites migrate through several cells prior to a productive invasion that involves the formation of a parasitophorous vacuole (PV) where sporozoites undergo transformation into Exo-erythorcytic forms (EEFs). The precise mechanism leading to sporozoite activation for invasion is unknown, but prior traversal of host cells is required. During cell migration sporozoites are exposed to large shifts in K(+) concentration. We report here that incubation of sporozoites to the intracellular K(+) concentration enhances 8-10 times the infectivity of Plasmodium berghei and 4-5 times the infectivity of Plasmodium yoelli sporozoites for a hepatocyte cell line, while simultaneously decreasing cell passage activity. The K(+) enhancing effect was time and concentration dependent, and was significantly decreased by K(+) channel inhibitors. Potassium-treated P. berghei sporozoites also showed enhanced numbers of EEFs in non-permissive cell lines. Treated sporozoites had reduced infectivity for mice, but infectivity was enhanced upon Kupffer cell depletion. Transcriptional analysis of K(+) treated and control sporozoites revealed a high degree of correlation in their levels of gene expression, indicating that the observed phenotypic changes are not due to radical changes in gene transcription. Only seven genes were upregulated by more than two-fold in K(+) treated sporozoites. The highest level was noted in PP2C, a phosphatase known to dephosphorylate the AKT potassium channel in plants. PMID- 17714806 TI - Identification and functional analysis of Relish homologs in the silkworm, Bombyx mori. AB - Two cDNAs designated BmRelish1 and 2, that encode Relish homologs, were cloned from the silkworm, Bombyx mori. BmRelish1 had an IkappaB-like domain with 5 ankyrin repeats in addition to Rel homology domain (RHD), nuclear localization signal (NLS), and acidic and hydrophobic amino acids (AHAA) rich regions. On the other hand, BmRelish2 lacked the AHAA and ankyrin repeats (ANK). Knockdown of the BmRelish gene in transgenic silkworms resulted in failure of the activation of antimicrobial peptide genes by Escherichia coli, suggesting that BmRelish plays an important role in antimicrobial peptide gene expression. Functional analysis of BmRelish1 and 2 in mbn-2 cells showed that both Relish homologs do not activate promoters of B. mori antimicrobial peptide genes encoding cecropin B1, attacin, lebocin 3 and lebocin 4. However, a gene construct BmRelish1-d2 lacking the ANK strongly activated promoters of these genes. Another gene construct lacking AHAA and ANK failed to activate these genes, suggesting that BmRelish becomes active by removal of the ANK and that the AHAA-rich region is a transactivation domain. BmRelish2 was shown to repress activation of Cecropin B1 gene expression by BmRelish1-d2, suggesting that BmRelish2 plays a role as a dominant negative factor against the BmRelish1 active form. Necessity of kappaB sites of Cecropin B1, Attacin and Lebocin 4 genes for the full activation of these genes by BmRelish1-d2 was confirmed. The requirement of the mandatory kappaB sites for Lebocin 4 gene expression was different between BmRelish1 active form and BmRelA, suggesting differential roles for kappaB sites in antimicrobial peptide gene activation by different transcription factors. The binding of the RHD portion of BmRelish1 fusion protein to the kappaB sites of Cecropin B1 and Attacin genes was also confirmed. PMID- 17714807 TI - Identifying right ventricular dysfunction with tissue Doppler imaging in pulmonary hypertension. AB - BACKGROUND: Standard echocardiographic assessment of right ventricular (RV) function is problematic due to the complex RV geometry. We used tissue Doppler imaging to identify RV dysfunction in patients with pulmonary hypertension (PH). METHODS: Study population consisted of 44 patients (mean age 52+/-11; 30 females) with PH who underwent color tissue Doppler imaging of the RV and right heart catheterization within 2 days of each other. Peak systolic velocity and strain were measured at the RV free wall and correlated with invasive measures of PH and RV function. Myocardial velocity and strain was also measured in 20 healthy volunteers who served as normal controls (mean age 47+/-13; 13 females). RESULTS: PH patients had significantly reduced RV free wall velocity (6.4+/-2.1 cm/s vs. 8.2+/-2.1 cm/s; p<0.05) and RV strain (-18+/-7% vs. -28+/-6%; p<0.001) versus controls. RV peak strain demonstrated excellent correlation with transpulmonary gradient (r=0.72; p<0.001), pulmonary vascular resistance (r=0.73; p<0.001), and significant inverse correlation with cardiac index (r=-0.69; p<0.001). RV velocity had a significant, but weaker, correlation with cardiac index (r=0.33; p<0.05) and no association with transpulmonary gradient or pulmonary vascular resistance. In a multivariate model, RV strain but not RV velocity was independently associated with cardiac index. CONCLUSIONS: RV myocardial strain demonstrated excellent correlation with hemodynamic variables indicative of RV performance in PH patients. PMID- 17714808 TI - QT interval prolongation and ventricular fibrillation in childhood end-stage renal disease. AB - Ventricular arrhythmia is a major cause of death in end-stage renal disease (ESRD). Corrected QT (QTc) interval prolongation, which is one of the predictors of ventricular arrhythmia, may be associated with ESRD. We report an 11-year-old boy who had ESRD with marked QTc interval prolongation and developed torsade de pointes with subsequent ventricular fibrillation during the induction of anesthesia. QTc interval was normalized completely after renal transplantation. PMID- 17714809 TI - Predictors of ventricular dysfunction and coronary artery disease in Iranian patients with left bundle branch block. AB - Patients with coronary artery disease (CAD) and concomitant left bundle branch block (LBBB) have increased cardiovascular mortality rates in comparison with those with CAD but without LBBB. In patients with LBBB, therefore, the delineation of the presence and severity of CAD may be helpful in providing prognostic information. In this cross-sectional study 219 patients with LBBB and suspected CAD that underwent coronary angiography, assessed for having CAD and left ventricular (LV) dysfunction. CAD was present in 124 (56.3%) patients and left ventricular ejection fraction <50% was seen in 147 (67.1%) patients. Advanced age (p=0.001), male gender (p=0.027, OR=1.94), history of chest pain (p=0.015, OR=2.08) and LVEF <50% (p=0.026, OR=3.04) were predictors of CAD and older age (p=0.004), male gender (p=0.017, OR=2.11), history of diabetes mellitus (p=0.043, OR=1.45) and angiographically documented CAD (p=0.001, OR=3.41) were predictors of LV dysfunction. PMID- 17714810 TI - Relationship between slightly elevated NT-proBNP and alterations in diastolic function detected by echocardiography in patients without structural heart disease. PMID- 17714811 TI - Lipomatous hypertrophy of the interatrial septum. AB - Lipomatous hypertrophy of the interatrial septum (LHIS) is a rare benign disorder that is characterized by accumulation and deposition of fat in the interatrial septum. Its etiology is still unknown, despite the theories that have been suggested. It usually occurs in older, obese people with a higher incidence in women. In most cases its diagnosis is made incidentally. Cardiac arrhythmias including atrial fibrillation, atrial premature contractions and atrioventricular block may occur as a consequence of involvement of the atrial wall and atrioventricular conduction pathways. We present a case of LHIS in an 87-year-old Italian woman. PMID- 17714812 TI - Effect of bone morphogenetic protein-4 on cardiac differentiation from mouse embryonic stem cells in serum-free and low-serum media. AB - In spite of previous reports, the precise role of bone morphogenetic proteins (BMPs) on cardiomyocyte differentiation, especially in the absence or presence of minimum amount of serum in culture medium is still unclear. So, the aim of the present study was to investigate the effect of BMP-4 on mouse embryonic stem cells (ESCs)-derived cardiomyocyte differentiation in serum-free and low-serum media. The mouse ESCs differentiation to cardiomyocytes was induced by embryoid bodies' (EBs') development through hanging drop, suspension and plating stages. Different models of differentiation were designed according to addition of fetal bovine serum (FBS) or knockout serum replacement (KoSR) to the medium of three stages. 10 ng/ml BMP-4 was added throughout the suspension period. Up to 30 days after plating, contraction and beating frequency were monitored and evaluated daily. The growth characteristics of cardiomyocytes were assessed by cardioactive drugs, immunocytochemistry, transmission electron microscopy (TEM) and reverse transcription-polymerase chain reaction (RT-PCR). In the complete absence of serum, neither control nor BMP-4 treated groups resulted in cardiac differentiation. Addition of FBS to hanging drop stage resulted in the appearance of beating cardiac clusters in some BMP-4 treated EBs. In the best designed differentiation model in which only hanging drop and the first 24 h of plating stage was carried out at the presence of FBS, the BMP-4 treatment resulted in cardiac differentiation in EBs characterized by positive immunostaining for the applied antibodies, chronotropic response to the cardioactive drugs and cardiac specific genes expression at different developmental stages. These cardiomyocytes showed immature myofibrils and numerous intercellular junctions. In conclusion, BMP-4 is unable to induce cardiomyocyte differentiation from mouse ESCs in serum free models, and at least small amount of FBS in hanging drop stage is necessary. Furthermore, serum factors are not strictly necessary after the initial activation, but they do favor a better differentiation of cardiomyocytes. PMID- 17714813 TI - Utility of lipid biomarkers in support of bioremediation efforts at army sites. AB - Lipid biomarker analysis has proven valuable in testing the hypothesis that attributes of the extant microbiota can directly reflect the occurrence of contaminant biodegradation. Two past research efforts have demonstrated this utility and are described here. A 4.5 m vertical core was obtained from a diesel fuel oil contamination plume. Core material was assayed for total petroleum hydrocarbons (TPH) and bacterial membrane phospholipids (PLFA) via a single solvent extraction. Microbial viable biomass and the relative abundance of Gram negative bacterial PLFA biomarkers were found to be significantly correlated with TPH concentration. The core TPH profile also revealed two distinct areas where the average TPH level of 3,000 microg g(-1) fell to near detection limits. Both areas were characterized by a three-fold decrease in the hexadecane/pristane ratio, indicating alkane biodegradation, and a distinct PLFA profile that showed a close similarity to the uncontaminated surface soil. Low-order, incomplete detonations can deposit hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) into training range surface soils. Since surface soils are exposed to temporal and diurnal moisture cycles, we investigated the effect two very different soil moisture tensions had on the in situ microbiota and RDX biodegradation. Saturated soils were characterized by rapid RDX biodegradation, 4 day half-life, a decrease in number of species detected and increase in PLFA biomarkers for Gram-negative proteobacteria (n16:1omega7c, n18:1omega9c, and n18:1omega7c) and Gram-positive firmicutes (i15:0 and a15:0). Terminal restriction fragment length polymorphism (T-RFLP) profiles of endpoint microbial communities indicated a shift from 18 to 36% firmicutes, the loss of gamma-proteobacteria and the emergence of alpha proteobacteria. These two past research efforts demonstrated the utility of the lipid biomarker analysis in identifying microbial community characteristics that were associated with two very different soil contaminants. Lipid biomarkers defined areas of TPH biodegradation and identified community shifts as a result of soil conditions that affected explosives fate. Information like this can be used to enhance the predictive power of ecological models such as the Army Training and Testing Area Carrying Capacity for munitions model [ATTACC]. PMID- 17714814 TI - The radioprotector O-phospho-tyrosine stimulates DNA-repair via epidermal growth factor receptor- and DNA-dependent kinase phosphorylation. AB - BACKGROUND AND PURPOSE: Purpose of the study was to elucidate the underlying molecular mechanism of the radioprotector O-phospho-tyrosine (P-Tyr). METHODS: Molecular effects of P-Tyr at the level of EGFR responses were investigated in vitro with bronchial carcinoma cell line A549. Nuclear EGFR transport and DNA-PK activation were quantified after Western blotting. Residual DNA-damages were quantified by help of gammaH(2)AX focus assay. RESULTS: As determined by dose response curves, treatment of cells with P-Tyr for 16h before irradiation results in radioprotection. Simultaneous treatment with EGFR blocking antibody Cetuximab abolished P-Tyr associated radioprotection. At the molecular level P-Tyr mediated a general phosphorylation of EGFR and a pronounced phosphorylation of nuclear EGFR at residue Thr No. 654, also observed after treatment with ionizing radiation. This phosphorylation was associated with nuclear EGFR accumulation. Moreover, P-Tyr-triggered EGFR nuclear accumulation was associated with phosphorylation of DNA-PK at Thr 2609. This activated form of DNA-PK was not DNA associated, but after radiation, DNA binding increased, particularly after P-Tyr pre-treatment. These molecular effects of P-Tyr resulted in a reduction of residual DNA-damage after irradiation. CONCLUSIONS: Radioprotection by P-Tyr is mediated through its stimulation of nuclear EGFR transport and concurrent, but DNA-damage independent, activation of DNA-PK. Thus, subsequent irradiation results in increased binding of DNA-PK to DNA, improved DNA-repair and increased cell survival. PMID- 17714815 TI - Dysphagia disorders in patients with cancer of the oropharynx are significantly affected by the radiation therapy dose to the superior and middle constrictor muscle: a dose-effect relationship. AB - PURPOSE/OBJECTIVE: To assess the relationship between the radiation therapy (RT) dose received by the muscular components of the swallowing (sw) apparatus and - dysphagia related - quality of life (QoL) in oropharyngeal cancer. MATERIALS/METHODS: Between 2000 and 2005, 81 patients with SCC of the oropharynx were treated by 3DCRT or IMRT, with or without concomitant chemotherapy (CHT); 43 out of these 81 patients were boosted by brachytherapy (BT). Charts of 81 patients were reviewed with regard to late dysphagia complaints; 23% experienced severe dysphagia. Seventeen patients expired. Fifty-six out of 64 (88%) responded to quality of life (QoL) questionnaires; that is, the Performance Status Scales of List, EORTC H&N35, and the M.D. Anderson Dysphagia Inventory. The superior (scm), middle (mcm), and inferior constrictor muscle (icm), the cricopharyngeus muscle and the inlet of the esophagus, are considered of paramount importance for swallowing. The mean dose was calculated in the muscular structures. Univariate analysis and multivariate analysis were performed using the proportional odds model. RESULTS: Mean follow-up was 18 months (range 2-34) for IMRT, and 46 months for 3DCRT (range 2-72). At 3-years, a LRC of 84%, DFS of 78% and OS of 77% were observed. A significant correlation was observed between the mean dose in the scm and mcm, and severe dysphagia complaints (univariate analysis). A steep dose effect relationship, with an increase of the probability of dysphagia of 19% with every additional 10 Gy, was established. In the multivariate analysis, BT (dose) was the only significant factor. CONCLUSION: A dose-effect relationship between dose and swallowing complaints was observed. One way to improve the QoL is to constrain the dose to be received by the swallowing muscles. PMID- 17714816 TI - High definition three-dimensional ultrasound to localise the tumour bed: a breast radiotherapy planning study. AB - BACKGROUND AND PURPOSE: Complex radiation techniques, such as conformal radiotherapy for partial breast irradiation, require accurate localisation of the tumour bed. This study investigated high definition 3D ultrasound for breast tumour bed localisation. Study aims were: firstly, to determine how easily a tumour cavity could be visualised with 3D ultrasound; secondly, to determine the accuracy of computed tomography (CT) and 3D ultrasound co-registration; thirdly, to compare 3D ultrasound with other methods of localisation. MATERIALS AND METHODS: 3D ultrasound examinations were carried out in 40 women attending for breast radiotherapy. 3D position data were co-registered with the radiotherapy planning CT. 2D ultrasound and CT, surgical clips and CT, and CT alone were also used to localise the tumour bed in 32/40, 14/40 and 5/40 patients, respectively. Tumour bed volume and centre of gravity measurements for all methods of localisation were compared. RESULTS: Mean surgery to imaging interval was 44 days (range 23-86 days). The post-operative cavity was seen in all cases using the 3D ultrasound, and was graded as highly visible, visible and subtle in 21/40 (53%), 12/40 (30%) and 7/40 (17%) cases, respectively. There was a statistically significant improvement in the ability of 3D ultrasound to localise the tumour bed compared with 2D ultrasound. CT-ultrasound registration was achieved in all cases. Two-dimensional and 3D ultrasound showed smaller tumour bed volumes than clips. CONCLUSIONS: Three-dimensional ultrasound localisation of the tumour bed appears superior to 2D ultrasound. It can also be co-registered with a planning CT, thus allowing additional information on the size and location of the tumour bed to be integrated into complex radiotherapy planning. PMID- 17714817 TI - Localization of calcium-binding protein (calretinin, 29 kD) in the brain and pituitary gland of teleost fish: an immunohistochemical study. AB - Immunocytochemical techniques were used to investigate the distribution of calretinin in the brain and pituitary gland of the hardhead catfish Arius felis. Calretinin immunoreactive neurons were found in the telencephalon (lateral nucleus of ventral telencephalic area), diencephalon (around the medial forebrain bundle, lateral tuberal nucleus, central pretectal nucleus, posterior periventricular hypothalamic nucleus, medial preglomerular nucleus, diffuse nucleus of the inferior lobe), mesencephalon (nucleus of the medial longitudinal fascicle, ventral nucleus of the semicircular torus), cerebellum (valvula cerebelli, eurydendroid cells) and rhombencephalon (secondary gustatory nucleus, isthmic nucleus, trigeminal motor nucleus, medial auditory nucleus of the medulla, medial and inferior reticular formation, anterior, descending, posterior and tangential octaval nuclei). Calretinin-labeled fibers were observed in the optic nerve and at the levels of the central pretectal nucleus, the nucleus of the medial longitudinal fascicle, the ventral nucleus of the semicircular torus, the secondary gustatory nucleus, the trigeminal motor nucleus, the eurydendroid cells, the medial auditory nucleus of the medulla and the octaval nucleus. For the first time, we are reporting on calretinin-positive cells in the rostral and proximal pars distalis of the adenohypophysis. Although, it seems speculatory, calretinin-expressing cells in the pituitary gland may be involved in hormonal regulation and hence, calretinin might play a significant role in governing hypophysial functions in fishes. Our results suggest that calretinin shows species-specific variations also among the teleost fish, similar to mammals. PMID- 17714818 TI - The thermodynamic principles of ligand binding in chromatography and biology. AB - In chromatography, macromolecules do not adsorb in the traditional sense of the word but bind to ligands that are covalently bonded to the surface of the porous bead. Therefore, the adsorption must be modelled as a process where protein molecules bind to the immobilised ligands. The paper discusses the general thermodynamic principles of ligand binding. Models of the multi-component adsorption in ion-exchange and hydrophobic chromatography, HIC and RPLC, are developed. The parameters in the models have a well-defined physical significance. The models are compared to the Langmuir model. In the traditional adsorption models, the standard state Gibbs energy change of adsorption does not depend level of occupancy, but when it depends on the level of occupancy it gives rise to an adsorptive behaviour known as cooperativity. The binding of oxygen to haemoglobin is a well-known example from biology but it is also observed in chromatography due to protein-protein interactions. Retention measurements on beta-lactoglobulin A demonstrate this. A discussion of salt effects on hydrophobic interactions in precipitation and chromatography of proteins concludes the paper. PMID- 17714820 TI - Attachment of infectious influenza A viruses of various subtypes to live mammalian and avian cells as measured by flow cytometry. AB - At present there is much interest in the cell tropism and host range of influenza viruses, especially those of the H5N1 subtype. We wished to develop a method that would enable investigation of attachment of infectious virus through the interaction of the hemagglutinin molecule and live mammalian and avian cells and the subsequent infection of these cells. To this end, influenza viruses of various HA subtypes were constructed that either carry the green fluorescent protein (GFP) instead of the neuraminidase protein, or that express GFP in the cytoplasm of infected cells. The HA genes were derived from influenza viruses A/PR/8/34 (H1N1), A/Netherlands/178/95 (H3N2) and A/Vietnam/1194/04 (H5N1). Using these pairs of viruses, attachment and post-attachment events in the virus replication cycle can be distinguished. In general, the expression of NeuAc(alpha2-3)Gal or NeuAc(alpha2-6)Gal receptors on the cells tested corresponded with the attachment of the viruses that were studied with respect to predicted receptor specificity. Virus attachment was not always predictive for efficient infection of the cells. PMID- 17714819 TI - Collagen biomaterial doped with colominic acid for cell culture applications with regard to peripheral nerve repair. AB - Colominic acid (CA) is a homopolymer of sialic acid residues and is solely composed of polymerised units of alpha-2,8-linked N-acetylneuraminic acid. CA is a specific derivative of polysialic acid (PSA), produced as the capsular polysaccharide of Escherichia coli K1 derived molecule of PSA. PSA in vivo plays a significant role in synaptic plasticity and neural development. The use of collagen materials doped with defined CA is presented for the cultivation of various cell lines relevant for possible applications in Tissue Engineering. First, the release behaviour under culture conditions of the collagen-based (C CA) materials was investigated by thiobarbituric acid assay. Additionally, the established cell lines, PC-12 and immortalised Schwann cells (ISC), used for neurobiological and neurochemical studies and the model liver cell line Hep-G2 as indicator for biocompatibility testing, were cultured on the C-CA matrix. Cell proliferation (MTT-test) and cell adhesion (DAPI-staining) of the cell lines on the matrices were observed. Likewise, gene expression of the marker genes thyrosine hydroxylase for the PC-12 cells, and albumin, transferrin and CYP3A4 for the Hep-G2 cells was evaluated via RT-PCR. The results indicate that CA integration in established biomaterial constructs enhances cell proliferation and offers promising features as conduits additive in regarding peripheral nerve regeneration. PMID- 17714821 TI - The NS5A protein of hepatitis C virus represses gene expression of hRPB10alpha, a common subunit of host RNA polymerases, through interferon regulatory factor-1 binding site. AB - The nonstructural (NS) 5A protein of hepatitis C virus (HCV) plays important roles in both viral RNA replication and modulation of the physiology of the host cell. Here we report that NS5A repressed gene expression of hRPB10alpha, a common subunit of host RNA polymerases (Pol), in hepatoma cell lines and Huh-7 cells harboring HCV replicon. Analysis of the hRPB10alpha promoter region revealed that interferon regulatory factor-1 binding element (IRF-E) was essential for its transcription. The IRF-E was responsible for the NS5A-mediated repression of the hRPB10alpha transcription and its induction by IRF-1 that is known to be induced by interferon-alpha. Electrophoretic mobility shift assay showed that IRF-1 bound to the IRF-E and the binding reduced when NS5A was expressed. NS5A appeared to negatively regulate IRF-1 expression, which might be partly responsible for the decrease of hRPB10alpha expression. NS5A expression moderately decreased promoter independent Pol activity in vitro. Transcription of adenoviral genes that are dependent on Pol II or III and propagation of adenoviral genome were impaired in HeLa cells with stable NS5A expression. The results suggest that NS5A may partly modulate host cell transcription by the down-regulation of hRPB10alpha. PMID- 17714822 TI - Molecular epidemiology of astrovirus type 1 in Belem, Brazil, as an agent of infantile gastroenteritis, over a period of 18 years (1982-2000): identification of two possible new lineages. AB - Human astroviruses (HAstV) are worldwide recognized as important viral enteropathogens during childhood. This study aims to determine the incidence, genetic diversity and intertype variability of HAstV-1 in children less than 5 years of age enrolled in several studies conducted in Belem/Para, and Sao Luis/Maranhao, Brazil, from December 1982 to May 2000. Using EIA and RT-PCR, an overall positivity of 6.1% (155/2.534) was achieved, of these, 140 were positive by RT-PCR. The analysis of a 348bp ORF2 fragment revealed that HAstV-1 was the predominant genotype (85/140, 60.7%) throughout the 18 years of study. Phylogenetic analysis was performed for 81 of these strains, and 76 (93.8%) were genetically classified as HAstV-1a. The remainder of strains (n=5) were assigned to possible new lineages, 1e and 1f. Four of these five strains were detected in 1983 and 1984, and the lineage 1a circulated during 10 consecutive years (1990/2000). Genome sequence variation was found among the HAstV-1 strains involving all lineages, but only five nucleotide changes translated into aminoacid changes over this period, suggesting that HAstV-1 was very stable. The data obtained in this study should be useful for further studies at molecular level, including improvement of disease surveillance based on molecular diagnostic tools, and vaccine development. PMID- 17714823 TI - Type of antidepressant therapy and risk of type 2 diabetes in people with depression. AB - OBJECTIVE: The objective of this study was to evaluate the differential risk of diabetes among people with depression taking antidepressant therapy. METHODS: A nested case control design was used to investigate the study objective. Data from the Canadian province of Saskatchewan was available from January 1, 1991 to December 31, 2001; the average length of follow-up was 4.07 years. Type 2 diabetes was identified based on ICD-9 diagnostic codes and antidiabetic medication prescriptions; prior depression was ascertained based on ICD-9 diagnostic codes and antidepressant prescriptions. RESULTS: Multivariate logistic regression analysis was used to estimate the odds ratio (OR) and 95% confidence intervals (CI). We identified 2391 individuals with incident depression treated with antidepressant therapy. The mean age was 53.6 (S.D.: 16.4) and 68% were female. After multivariate adjustment, the concurrent use of selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCA) was associated with a significantly increased risk of type 2 diabetes (adjusted OR: 1.89; 95% CI: 1.35-2.65). CONCLUSIONS: Concurrent use of TCA and SSRI was associated with an increased risk of developing type 2 diabetes compared to using TCA alone. Individuals taking combination TCA and SSRI therapy should be closely monitored for development of type 2 diabetes. PMID- 17714825 TI - Hepatitis C impairs survival following liver transplantation irrespective of concomitant hepatocellular carcinoma. AB - BACKGROUND/AIMS: Liver transplantation (LTX) is the only curative treatment for end-stage liver disease caused by hepatitis C (HCV). Hepatocellular carcinoma (HCC) is common in patients with HCV cirrhosis. METHODS: Two hundred and eighty two HCV patients listed for LTX in the Nordic countries in a 17-year period were included. For comparison a group of patients with non-viral chronic liver disease (n=1552) was used. RESULTS: Two hundred and fifty-three (90%) patients received a first liver allograft. HCC was found in 38% of the explanted livers. Survival at 1, 3 and 5years was 82%, 69% and 61% vs. 85%, 80% and 76% for the comparison group (p<0.0001), this survival difference was also evident when excluding patients with HCC (p=0.007). HCV patients with HCC had 1, 3 and 5year survival of 73%, 52% and 46% compared with 88%, 80% and 71% for the HCV patients without HCC (p=0.0005). In an intention-to-treat analysis (from time of acceptance to the waiting list) HCV was also associated with an impaired survival. CONCLUSIONS: HCV cirrhosis, which is now also an important indication for LTX in the Nordic countries, and significantly impairs survival following LTX. Concomitant HCC and donor age are the two most important factors contributing to an impaired survival. PMID- 17714824 TI - Safety and efficacy of repaglinide in combination with metformin and bedtime NPH insulin as an insulin treatment regimen in type 2 diabetes. AB - OBJECTIVE: To evaluate the efficacy and safety of the association of repaglinide, metformin and bedtime NPH insulin compared to two classic regimens: metformin plus NPH and two doses of NPH in patients with poorly controlled type 2 diabetes despite two or more oral antidiabetic drugs (OADs). PATIENTS AND METHODS: Random, parallel and open study of 24 weeks with 37 patients randomized into three therapeutic groups: group A (n=12) (repaglinide/metformin/NPH), group B (n=12) (metformin/NPH) and group C (n=13) (NPH/NPH). The insulin was adjusted in the visits to obtain a basal blood glucose <110 mg/dl. The endpoint criteria included HbA1c, blood glucose profile, hypoglycemias and body weight. RESULTS: At the end of the study, group A presented HbA1c (mean+/-standard deviation) 7.2+/-0.7%, which was significantly less than B (8.8+/-0.1%) and C (8.4+/-1.2%). In terms of absolute reduction, there were only differences (p=0.01) between group A (-2.4+/ 1.1%) and B (-0.7+/-1.2%). Group A presented lower postprandial blood glucose values (p<0.01). Nor were there any significant differences in weight gain and incidence of hypoglycemia. CONCLUSIONS: The combination of repaglinide, metformin and bedtime NPH is safe and effective and it provides better postprandial blood glucose control. The association of metformin and a dose of NPH does not obtain suitable control in patients with a long evolution who have already received two or more OADs. PMID- 17714826 TI - Low expression of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) indicates a shorter survival after resection in patients with adenocarcinoma of the lung. AB - It has been reported that an endogenous matrix metalloproteinase (MMP) inhibitor, reversion-inducing cysteine-rich protein with Kazal motifs (RECK), is able to inhibit tumour angiogenesis, invasion, and metastasis through inhibition of MMP 2, MMP-9, and membrane type-1 (MT1)-MMP (MMP-14) secretion and activity. In this study, using quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR), we have analysed RECK expression levels in resected non-small cell lung cancer (NSCLC) tissue and compared these data with the clinicopathological features of these patients to investigate the role of RECK in NSCLC. We have also analysed the expression of MMP-2, MMP-9, and MMP-14 and compared the data with those for RECK expression. Tissue samples of primary lung cancers were obtained from a total of 83 patients [46 with adenocarcinomas (ADC) and 37 with squamous cell carcinomas (SCC)] who underwent curative resection. The samples were taken from 83 tumours and 20 matched normal lung tissue samples as controls. Expressions of RECK in ADC and SCC were significantly lower than in the control. In ADC tissue, the expression of RECK was higher in stage IA than in stage IB-IIIA. There was no such a correlation in SCC. In ADC, univariate analysis for relapse-free survival using Cox regression analysis identified low RECK expression (p=0.036), low MMP-14 expression (p=0.038), and tumour T2 (p=0.034) as significant negative prognostic predictors. However, in SCC, none of the clinicopathological factors assessed, including RECK expression, had prognostic value. In conclusion, our study suggests that suppression of RECK expression is involved in the progression of ADC of the lung and that RECK expression in resected ADC of the lung is a favorable predictor of patients' prognosis. PMID- 17714827 TI - Optimization of submerged keratinocyte cultures for the synthesis of barrier ceramides. AB - Epidermal differentiation results in the formation of the extracellular lipid barrier in the stratum corneum, which mainly consists of ceramides, free fatty acids, and cholesterol. Differentiating keratinocytes of the stratum granulosum synthesize a series of complex long-chain ceramides and glucosylceramides with different chain lengths and hydroxylation patterns at intracellular membranes of the secretory pathway. Formation of complex extracellular ceramides parallels the transition of keratinocytes from the stratum granulosum to the stratum corneum, where their precursors, complex glucosylceramides and sphingomyelin, are secreted and exposed to extracellular lysosomal lipid hydrolases. Submerged cultures used so far showed a reduced ceramide content compared to the native epidermis or the air-exposed, organotypic culture system. In order to investigate the sphingolipid metabolism during keratinocyte differentiation, we optimized a simple cell culture system to generate the major barrier sphingolipids. This optimized model is based on the chemically well-defined serum-free MCDB medium. At low calcium ion concentrations (0.1mM), keratinocytes proliferate and synthesize mainly Cer(NS) and a small amount of Cer(NP). Supplementation of the MCDB cell culture medium with calcium ions (1.1mM) and 10 microM linoleic acid triggered differentiation of keratinocytes and synthesis of a complex pattern of free and covalently bound ceramides as found in native epidermis or air-exposed organotypic cultures, though at a reduced level. The mRNA levels of the differentiation markers keratin 10 and profilaggrin increased, as well as those of ceramide glucosyltransferase and glucosylceramide-beta-glucosidase. The described culture system was thus suitable for biochemical studies of the sphingolipid metabolism during keratinocyte differentiation. The addition of serum or vitamin A to the medium resulted in a decrease in ceramide and glucosylceramide content. Lowering the medium pH to 6, while maintained cell viability, led to an increase in the processing of probarrier lipids glucosylceramide and sphingomyelin to free ceramides and protein-bound ceramide Cer(OS). PMID- 17714828 TI - A high-glycemic meal pattern elicited increased subjective appetite sensations in overweight and obese women. AB - We examined the effects of variations in postprandial glycemia and insulinemia on subjective satiety in overweight and obese women. We altered the ingestion rate of a glucose beverage to model the postprandial effects of high- and low-glycemic meals. Fourteen women were tested in a within-subjects' design with two conditions: (1) Rapid, with a large glucose beverage consumed with breakfast and lunch and (2) Slow, with the same volume of glucose beverage consumed in eight portions (one with each meal, and the remaining seven at 20-min intervals after each meal). Meals were identical in the two conditions. Subjective appetitive sensations were measured with visual analog scales before and after meals, and hourly after each meal until 5 pm. Serum glucose and insulin were measured at similar time points. Subjects reported higher ratings of hunger and prospective consumption in the Rapid versus Slow condition at 4h after breakfast and several hours after lunch. Serum glucose was more strongly correlated with the appetitive ratings in the Rapid than the Slow condition, and explained more of the variance (20-31%) than insulin (2-4%). The results of this study support the glucostatic theory linking dynamic changes in blood glucose with appetitive sensations. PMID- 17714829 TI - PACAP-related peptide (PRP)--molecular evolution and potential functions. AB - PACAP-related peptide (PRP) and PACAP are structurally related peptides that are encoded in the same transcripts. In the past, it was believed that the mammalian PRPs are evolved from GHRHs in non-mammals. With the recent discovery of authentic GHRH and receptor genes in frog and fish, this review aims to (1) coin the name of all GHRH-like peptides in previous literature as PRPs and (2) provide the background for new research direction for PRP in vertebrates. As a goldfish receptor highly specific for PRP with distinct tissue distribution has previously been characterized, it is highly possible that PRP plays a physiological role in non-mammalian vertebrates and the function of PRP has somehow been lost in mammals as a consequence of the loss of its receptor in the genome. This information may provide clues to elucidate functions of PRP in the future. PMID- 17714830 TI - Extrasynaptic GABAA receptors in the crosshairs of hormones and ethanol. AB - Gamma-aminobutyric acid (GABA) is the main chemical inhibitory neurotransmitter in the brain. In the central nervous system (CNS) it acts on two distinct types of receptor: an ion channel, i.e., an "ionotropic" receptor permeable to Cl- and HCO3- (GABAA receptors) and a G-protein coupled "metabotropic" receptor that is linked to various effector mechanisms (GABAB receptors). This review will summarize novel developments in the physiology and pharmacology of GABAA receptors (GABAARs), specifically those found outside synapses. The focus will be on a particular combination of GABAAR subunits sensitive to ovarian and adrenal cortical steroid hormone metabolites that are synthesized in the brain (neurosteroids) and to sobriety impairing concentrations of ethanol. These receptors may be the final common pathway for interactions between ethanol and ovarian and stress-related neurosteroids. PMID- 17714831 TI - VDR gene variants associate with cognitive function and depressive symptoms in old age. AB - Vitamin D has been recently implicated in brain function. Our objective was to test whether genetic variance in the vitamin D receptor (VDR) gene is associated with cognitive functioning and depressive symptoms in old age. The study was carried out in the prospective population-based Leiden 85-plus Study. All 563 participants of the study were genotyped for Cdx-2, FokI, BsmI, ApaI and TaqI polymorphisms in the VDR gene. Our data revealed an overall worse performance on tests measuring cognitive functioning for carriers of BsmI (p=0.013) and TaqI (p=0.004) polymorphisms, and of haplotype 2 (BAt) (p=0.004). In contrast, carriers of ApaI variant-allele and of haplotype 1 (baT) had better cognitive functioning together with less depressive symptoms. These associations could not be explained by differences in calcium levels, and by selective survival, since no associations between the VDR gene variants and calcium levels and mortality were observed. In conclusion, our results show that genetic variance in the VDR gene influences the susceptibility to age-related changes in cognitive functioning and in depressive symptoms. PMID- 17714833 TI - Exploration of physicochemical properties and molecular modelling studies of 2 sulfonyl-phenyl-3-phenyl-indole analogs as cyclooxygenase-2 inhibitors. AB - In the present work, modelling study has been performed to explore the physicochemical requirements of 2-sulfonyl-phenyl-3-phenyl-indole analogs as COX 2 enzyme inhibitors. The multivariant regression expressions were developed using sequential multiple linear regression (SEQ-MLR) technique, considering adjustable correlation coefficient (r(adj)(2)). The statistical quality of SEQ-MLR equations was evaluated considering parameters like correlation coefficient (r), standard error of estimation (SEE), and variance ratio (F) at explicit degree of freedom (df). Orthogonality of the descriptors in SEQ-MLR was established through variance inflation factor (VIF). Developed equations have been internally validated using leave-one-out technique and further validated with test set, considering predictive squared correlation coefficient (r(pred)(2)). The orientation of the most potent and selective COX-2 inhibitor of training set, 2 (4-phenyl sulfonamide)-3-phenyl-5-methylindole, in the COX-2 active site was explored by docking. The phenyl sulfonamide moiety positioned in secondary pocket of enzyme which consists of amino acid residues Phe(518), Gln(192), Arg(513), Leu(352), Ser(353) and Val(523) is responsible for the selectivity. The unsubstituted phenyl ring positions in a hydrophobic cavity are lined by Tyr(385), Trp(387), Tyr(348), Leu(384) and Met(522). Interestingly, the indole C 5 CH(3)-substituent is located in a hydrophobic region formed by Ile(345), Val(349), Ala(527), Leu(531) and Leu(534). The hydrophobic interactions of methyl group might be crucial for the potency of 2-sulfonyl-phenyl-3-phenyl-indole analogs. Study has revealed that atomic van der Waals volume and atomic masses explain COX-2 inhibitory activity of 2-sulfonyl-phenyl-3-phenyl-indole analogs significantly. PMID- 17714832 TI - Antimycobacterial activity of diphenylpyraline derivatives. AB - 2-Substituted derivatives of diphenylpyraline and their 1-phenyl and 1-phenethyl analogues have been prepared in several steps from dihydropyridine-2(1H)-thiones. The structures of all new compounds have been confirmed by NMR spectroscopy. Their activity against Mycobacterium tuberculosis H(37)Rv as well as their cytotoxicity against human cells (HEK-293) have been determined via in vitro assays. The antimycobacterial potency was in general increased by substitution in ring position 2. The most promising modifications were a 2-isopropyl derivative and a 1,2-diphenyl analogue. PMID- 17714834 TI - Facilitating research students in formulating qualitative research questions. AB - One of the initial and challenging processes that research students and students undertaking research modules encounter is the formation or appraisal of the research question. Research questions acquire significance as the rigor and validity of the research project rests on the extent to which the conclusions of the study have answered the research question. For qualitative studies the research question acquires even greater significance since the notions of audit trail, which commences from the research question is considered as an indication of a valid or not research. Hence, the formation of a qualitative research question requires to be based on a framework as to have specific content, coherence and structure. The content takes the form of a declarative statement that provides focus on a specific issue, but at the same time allows enough flexibility as for variables to emerge from the data. The coherence should smoothly bridge the philosophical/theoretical propositions of the qualitative paradigms with the practical execution of the study and this is achieved by the use of specific verbs, nouns and phrases. Lastly, the structure needs to adequately answer to the who, when, where, what, how and why of the study. PMID- 17714835 TI - Thinking narratively: artificial persons in nursing and healthcare. AB - Positioned within my research program that explores nurses' experience and construction of their daily praxis, I think narratively about how to stay in my work as a nurse-teacher, how students enter the profession and how registered nurses stay in nursing practice. I present co-participants' stories (all names are pseudonyms except for the author's "I") that reveal how a nurse is often in between autobiographically informed actions and the certainty of institutional roles that shape us into artificial persons. I explore the nature of the relationship between nurses, their professional roles and a primary accountability to people who happen to be patients - or students. This paper has implications for retention of nurses in practice and in education within the context of a global shortage of nurses. Further inquiry is invited in relation to our ability to shape social situations towards health. When narrative inquiry is working, people are drawn into their own experience and can discern new plotlines for relationships and possibilities for action within their social environments. PMID- 17714836 TI - Hepatitis B immunity in children vaccinated with recombinant hepatitis B vaccine beginning at birth: a follow-up study at 15 years. AB - BACKGROUND: The duration of protection after hepatitis B vaccination of infants is unknown. We determined antibody to hepatitis B surface antigen (anti-HBs) and response to a booster dose 15 years after vaccination among Alaskan children born to hepatitis B surface antigen-negative mothers. These children had protective anti-HBs concentrations when tested after receiving a three-dose series of 2.5 microg recombinant hepatitis B vaccine starting at birth. METHODS: Participants received 5 microg of recombinant hepatitis B vaccine. Sera were collected at baseline, 10-14 days and 1 month after vaccination, and tested for antibody to hepatitis B core antigen (anti-HBc) and anti-HBs. An anamnestic response was defined as an anti-HBs increase within 15 days, from either undetectable to >/=10 mIU/mL, or, if the baseline concentration was detectable, a 4-fold increase. RESULTS: None of 37 participants (mean age 14.6 years) were anti-HBc positive. An anamnestic response (GMC=254 mIU/mL, range 16-2767 mIU/mL) was observed in 18 (51%) of 35 participants who had sera collected within 15 days after the booster. CONCLUSIONS: In this small study, half of children who had received hepatitis B vaccine starting at birth did not have evidence of immune memory as measured by development of anamnestic responses to booster vaccination. Additional studies are needed to assess whether this indicates susceptibility to infection and whether persons vaccinated starting at birth may benefit from a hepatitis B vaccine booster to maintain long-term protection. PMID- 17714837 TI - Pediatric hospitalization for pneumococcal diseases preventable by 7-valent pneumococcal conjugate vaccine in Hong Kong. AB - In a population-based study, we use ICD-9-CM codes to estimate the hospitalization rates for pneumococcal disease among young children in Hong Kong, 2000-2005 and the preventable burden using several outcome indicators. For children aged or =18 years who were not knowingly HIV-positive and reported having unprotected sex with > or =1 client in the prior 2 months underwent interviews and testing for HIV, syphilis, gonorrhea and Chlamydia. Logistic regression identified factors associated with injecting drugs within the last month. RESULTS: Of 924 FSWs, 18.0% had ever injected drugs. Among FSW-IDUs (N=114), prevalence of HIV, syphilis titers > or =1:8, gonorrhea and Chlamydia was significantly higher at 12.3%, 22.7%, 15.2% and 21.2% compared to 4.8%, 13.1%, 5.2% and 11.9% among other FSWs (N=810). FSW-IDUs also had more clients in the past 6 months (median: 300 versus 240, p=0.02). Factors independently associated with injecting drugs in the past month included living in Tijuana, being younger, being married/common-law, longer duration in the sex trade, speaking English, earning less for sex without condoms, often using drugs before sex, and knowing other FSWs who injected drugs. CONCLUSIONS: FSW-IDUs had higher STI levels, engaged in riskier behaviors and were more vulnerable to having unsafe sex with clients compared to other FSWs, indicating that this subgroup is an important bridge population requiring focused prevention. PMID- 17714889 TI - Identification and functional characterization of pfm, a novel gene involved in swimming motility of Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa, an important opportunistic pathogen, has a single polar flagellum which is an important virulence and colonization factor by providing swimming motility. This paper describes the functional characterization of a novel gene pfm (PA2950) of P. aeruginosa. The pfm encodes a protein that is similar to a number of short-chain alcohol dehydrogenases of other bacterial species. Mutation of this gene results in a defect in swimming motility which can be completed back to that of wild type by a plasmid containing the pfm. Interestingly, the pfm mutant possesses an intact flagellum which does not rotate, thus giving rise to a non-motile phenotype. The pfm gene is encoded on an operon together with two upstream genes which code for electron transfer flavoprotein (ETF). Yeast two-hybrid tests indicated that the PFM interacts with the ETF, suggesting that the putative dehydrogenase (PFM) is involved in energy metabolism that is critical for the rotation of flagellum in P. aeruginosa. PMID- 17714890 TI - Extensive mitochondrial DNA transfer in a rapidly evolving rodent has been mediated by independent insertion events and by duplications. AB - Mitochondrial DNA translocations to the nucleus (numt pseudogenes) are pervasive among eukaryotes, but copy number within the nuclear genome varies widely among taxa. As an increasing number of genomes are sequenced in their entirety, the origins, transfer mechanisms and insertion sites of numts are slowly being characterized. We investigated mitochondrial transfers within a genetically diverse rodent lineage and here report 15 numts totaling 21.8 kb that are harbored within the nuclear genome of the vole Microtus rossiaemeridionalis. The 15 numts total 21.8 kb and range from 0.39 to over 3.0 kb in length. Phylogenetic analyses revealed that these numts resulted from three independent insertions to the nucleus, two of which were followed by subsequent nuclear duplication events. The dates of the two translocations that led to subsequent duplications were estimated at 1.97 and 1.19 MYA, which coincide with the origin and radiation of the genus Microtus. Numt sequence data from five Microtus species were used to estimate an average rate of nucleotide substitution as 2.6x10(-8) subs/site/yr. This substitution rate is higher than in many other mammals, but is concordant with the elevated rate of mtDNA substitution in this lineage. Our data suggest that numt translocation in Microtus is more extensive than in either Mus or in Rattus, consistent with the elevated rate of speciation, karyotypic rearrangement, and mitochondrial DNA evolution in Microtus. PMID- 17714891 TI - Long-term effect of vaccination against gonadotropin-releasing hormone, using Improvac, on hormonal profile and behaviour of male pigs. AB - The objective of this study was to evaluate the long-term effect of a gonadotropin-releasing hormone (GnRH) vaccine, Improvac (Pfizer Ltd.), on the levels of GnRH antibodies, testosterone, estrone sulphate (E1S) and androstenone, as well as skatole and indole in male pigs. Additionally, the long-term effect of immunocastration on social and sexual behaviour was studied. Male pigs were assigned to two treatment groups: a treatment group given two doses of Improvac (n=12) and a control group of entire male pigs (n=12). The pigs were kept either 16 or 22 weeks after vaccination. Blood samples were collected five or six times; prior to both first and second vaccination, then three or four times during the 16 or 22 week period after second vaccination. Immunocastration significantly reduced levels of testosterone and E1S in plasma, and levels of androstenone in fat (P<0.001 for all). Skatole and indole levels in plasma and fat were also lower in immunocastrated pigs than in entire male pigs. These effects lasted up to 22 weeks after the second vaccination. Testis weight and bulbourethral gland length were lower in immunocastrated pigs at slaughter and these pigs showed less social, manipulating and aggressive behaviour than entire male pigs. The immunocastrated pigs remained sexually inactive throughout the study. Our study represents a further step in the evaluation of the effectiveness of Improvac as an alternative to surgical castration of entire male pigs. It shows that Improvac may have an extended effect compared with that currently implied by the directions for use. PMID- 17714893 TI - Application of molecular modelling to determine the surface energy of mannitol. AB - In this paper, molecular modelling was used to investigate the nature of probe/surface interactions during the analysis of Dbeta-mannitol using inverse gas chromatography (IGC). IGC was used to experimentally measure the dispersive components of surface free energy (gamma(S)(D)) and the specific components of free energy of adsorption (-DeltaGA(SP)) of Dbeta-mannitol by calculating the retention time of non-polar (n-alkanes) and polar (tetrahydrofuran and chloroform) probes, respectively. The results showed that Dbeta-mannitol surface is acidic in nature because the basic probe had more interaction with the surface as compared to acidic probe. Cerius(2) software package was used to model the two morphologically important surfaces, which showed the presence of surface hydroxyl groups. Molecular dynamics simulations were performed in Cerius(2) to model the adsorption of the same probes (n-alkanes, tetrahydrofuran and chloroform) on the Dbeta-mannitol surfaces. The adsorption energies calculated from the simulation showed a close match to those determined experimentally. The calculated values are slightly higher for all probes except chloroform, but as a single perfect crystal was modelled without considering the effect of impurities, solvent and other physical factors this is not unexpected. PMID- 17714892 TI - Gastrointestinal distribution and absorption behavior of Eudragit-coated chitosan prednisolone conjugate microspheres in rats with TNBS-induced colitis. AB - Conjugate of chitosan and succinyl-prednisolone, termed Ch-SP, was synthesized, and Ch-SP microspheres (Ch-SP-MS) and Eudragit L100-coated Ch-SP-MS (Ch-SP MS/EuL) were prepared using Ch-SP. Ch-SP-MS and Ch-SP-MS/EuL had a mean size of 1.5 and 26.6microm, respectively, and a drug content of 4.6 and 3% (w/w), respectively. Prednisolone (PD) was released very slow in JP 14 first fluid (pH 1.2), and gradually in JP 14 second fluid (pH 6.8). The addition of cecal or colonic content did not accelerate the release. Rats with 2,4,6 trinitrobenzenesulfonic acid (TNBS)-induced colitis were used in animal studies. Gastrointestinal distribution and plasma concentration were investigated by oral administration of PD alone and Ch-SP-MS/EuL. For PD alone, PD was distributed at the stomach and small intestine, and disappeared from the gastrointestinal tracts within 8h. When administering Ch-SP-MS/EuL, the drug was distributed mainly in the lower intestine between 3 and 24h. Plasma concentration was much lower in Ch SP-MS/EuL than in PD alone, suggesting lower toxic side effects of Ch-SP-MS/EuL. Thus, Ch-SP-MS/EuL delivered PD specifically near the diseased site and PD was released gradually, with much less plasma concentration of PD. Ch-SP-MS/EuL are suggested as a useful delivery system to the site of inflammatory bowel disease. PMID- 17714894 TI - Evaluation of chitosan salts as non-viral gene vectors in CHO-K1 cells. AB - The aim of this study was to investigate chitosan/DNA complexes formulated with various chitosan salts (CS) including chitosan hydrochloride (CHy), chitosan lactate (CLa), chitosan acetate (CAc), chitosan aspartate (CAs) and chitosan glutamate (CGl). They were assesed for their DNA complexing ability, transfection efficiency in CHO-K1 (Chinese hamster ovary) cells and their effect on cell viability. CHy, CLa, CAc, CAs and CGl, MW 45kDa formed a complex with pcDNA3-CMV Luc at various N/P ratios. CGl/DNA complexes were formulated with various chitosan molecular weights (20, 45, 200 and 460kDa). The CS/DNA complexes were characterized by agarose gel electrophoresis and investigated for their transfection efficiency in CHO-K1 cells. The cytotoxicity of the complexes was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in CHO-K1 cells. Gel electrophoresis illustrated that complete complexes formed at N/P ratios above 2 in all CS of MW 45kDa. The transfection efficiency of CS/DNA complexes was dependent on the salt form and MW of chitosan, and the N/P ratio of CS/DNA complexes. Of different CS, the maximum transfection efficiency was found in different N/P ratios. CHy/DNA, CLa/DNA, CAc/DNA, CAs/DNA and CGl/DNA complexes showed maximum transfection efficiencies at N/P ratios of 12, 12, 8, 6 and 6, respectively. Cytotoxicity results showed that all CS/DNA complexes had low cytotoxicity. This study suggests CS have the potential to be used as safe gene delivery vectors. PMID- 17714895 TI - Evaluation of the deformation behavior of binary systems of methacrylic acid copolymers and hydroxypropyl methylcellulose using a compaction simulator. AB - Methacrylic acid copolymers have been shown to enhance release of weakly basic drugs from rate controlling polymer matrices through the mechanism of microenvironmental pH modulation. Since these matrices are typically formed through a compaction process, an understanding of the deformation behavior of these polymers in there neat form and in combination with rate controlling polymers such as HPMC is critical to their successful formulation. Binary mixes of two methacrylic acid copolymers, Eudragit L100 and L100-55 in combination with HPMC K4M were subjected to compaction studies on a compaction simulator. The deformation behavior of the powder mixes was analyzed based on pressure-porosity relationships, strain rate sensitivity (SRS), residual die wall force data and work of compaction. Methacrylic acid copolymers, L100-55 and L-100 and the hydrophilic polymer, HPMC K4M exhibited Heckel plots representative of plastic deformation although L-100 exhibited significantly greater resistance to densification as evident from the high yield pressure values ( approximately 120MPa). The yield pressures for the binary mixes were linearly related to the weight fractions of the components. All powder mixes exhibited significant speed sensitivity with SRS values ranging from 21.7% to 42.4%. The residual die-wall pressures indicated that at slow speeds (1mm/s) and at lower pressures (<150MPa), HPMC possesses significant elastic behavior. However, the good compacts formed at this punch speed indicate significant plastic deformation and bond formation which is able to predominate over the elastic recovery component. The apparent mean yield pressure values, the residual die-wall forces and the net work of compaction exhibited a linear relationship with mixture composition, thereby indicating predictability of these parameters based on the behavior of the neat materials. PMID- 17714896 TI - Cellular uptake of solid lipid nanoparticles and cytotoxicity of encapsulated paclitaxel in A549 cancer cells. AB - The aim of this study was to investigate the cellular uptake of solid lipid nanoparticles (SLN) and cytotoxicity of its paclitaxel delivery system. The conjugate of octadecylamine-fluorescein isothiocyanate (ODA-FITC) was synthesized, and used as a marker to prepare fluorescent SLN. The cellular uptakes of fluorescent SLN with different lipid material were evaluated by fluorescence microscopy and the measurement of fluorescence intensity. The order of cellular uptake ability was glycerol tristearate SLN>monostearin SLN>stearic acid SLN>Compritol 888 ATO SLN (ATO888 SLN). The cellular cytotoxicities of paclitaxel were highly enhanced by the encapsulation of lipid matrix. Due to the lower drug entrapment efficiency of glycerol tristearate SLN, monostearin SLN was considered as the best lipid material to improve the cytotoxicity of drug. The polyethylene glycol monostearate (PEG-SA) and the synthesized conjugate of folic acid-stearic acid (FA-SA) were further introduced into monostearin SLN, respectively. The PEG and folate modified SLN could enhance the cellular uptake of SLN and the cellular cytotoxicity of drug by the membrane disturb ability of PEG chains on the SLN surface and the improved endocytosis mediated by folate receptor. PMID- 17714897 TI - Lippia sidoides and Myracrodruon urundeuva gel prevents alveolar bone resorption in experimental periodontitis in rats. AB - In Brazilian folk medicine, Lippia sidoides (Ls) and Myracrodruon urundeuva (Mu) have gained popularity and reputation as effective antimicrobial and anti inflammatory agents. This work aimed to evaluate the effect of topical herbal gel from Ls 0.5% (v/w) and Mu 5% (w/w) in experimental periodontal disease (EPD) in rats. Wistar rats were subjected to ligature placement around the second upper left molars. Animals were treated topically with Ls and/or Mu-based gel, immediately after EPD induction and three times/day for 11 days until the rats were sacrificed (11th day). Saline-based gel was utilized as control for all experiments and doxycycline based gel 10% (w/w) was utilized as reference substance. Animals were weighed daily. Alveolar bone loss was measured as the difference (in millimeters) between the cusp tip and the alveolar bone. The periodontum and the surrounding gingivae were examined at histopathology, as well as the neutrophil influx into the gingivae was assayed using myeloperoxidase activity and cytokine production mainly tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels by ELISA method. The local bacterial flora was assessed through culture of the gingival tissue in standard aerobic and anaerobic media. Alveolar bone loss was significantly inhibited by Ls and Mu combined treatment compared to the saline control group. Ls and Mu combined treatment reduced tissue lesion at histopathology, with partial preservation of the periodontum, coupled to decreased myeloperoxidase activity as well as significantly inhibited TNF-alpha and IL-1beta production in gingival tissue compared to the saline control group. Ls and Mu combined treatment also prevented the growth of oral microorganisms and the weight loss. Ls and Mu combined based gel treatment preserved alveolar bone resorption and demonstrated anti inflammatory and antibacterial activities in experimental periodontitis. PMID- 17714898 TI - Traditional uses of medicinal plants among the rural communities of Churu district in the Thar Desert, India. AB - The traditional uses of medicinal plants in healthcare practices are providing clues to new areas of research; hence its importance is now well recognized. However, information on the uses of indigenous plants for medicine is not well documented from many rural areas of Rajasthan including Churu district. The study aimed to look into the diversity of plant resources that are used by local people for curing various ailments. Questionnaire surveys, participatory observations and field visits were planned to elicit information on the uses of various plants. It was found that 68 plant species are commonly used by the local people for curing various diseases. In most of the cases (31%) leaves were used. The interviewees mentioned 188 plant usages. Those most frequently reported had therapeutic value for treating fever, rheumatism, diarrhea, asthma and piles. The knowledge about the total number of medicinal plants available in that area and used by the interviewees was positively correlated with people's age, indicating that this ancient knowledge tends to disappear in the younger generation. PMID- 17714899 TI - Further remarks on: "Paternity analysis in special fatherless cases without direct testing of alleged father" [FSI 146S (2004) S159-S161] and remarks on it [FSI 163 (2006) 158-160]. PMID- 17714900 TI - Gasoline on hands: preliminary study on collection and persistence. AB - The identification of an arsonist remains one of the most difficult challenges a fire investigation has to face. Seeking and detection of traces of gasoline could provide a valuable information to link a suspect with an arson scene where gasoline was used to set-up the fire. In this perspective, a first study was undertaken to evaluate a simple, fast and efficient method for collecting gasoline from hands, and to assess its persistence over time. Four collection means were tested: PVC, PE and Latex gloves, as well as humidified filter paper. A statistical assessment of the results indicates that Latex and PVC gloves worn for about 20 min, as well as paper filter rubbed on hands, allow an efficient collection of gasoline applied to hands. Due to ease of manipulation and to a reduced amount of volatile compounds detected from the matrix, PVC gloves were selected for the second set of experiments. The evaluation of the persistence of gasoline on hands was then carried out using two initial quantities (500 and 1000 microl). Collection was made with PVC gloves after 0, 30 min, 1, 2 and 4h, on different volunteers. The results show a common tendency of massive evaporation of gasoline during the first 30 min: a continued but non-linear decrease was observed along different time intervals. The results of this preliminary study are in agreement with other previous researches conducted on the detection of flammable liquid residues on clothes, shoes and skin. PMID- 17714901 TI - Cerebrospinal fluid pterins and neurotransmitters in early severe epileptic encephalopathies. AB - Early-onset epileptic encephalopathies are devastating conditions. Little is known about pathophysiology and biological markers. We aimed to identify a relationship between the type and prognosis of epileptic encephalopathies starting in infancy and the cerebrospinal fluid profile of pterins and neurotransmitters. Cerebrospinal fluid samples of 23 infants with epileptic encephalopathies were analysed for biogenic amine metabolites (homovanillic and 5 hydroxyindoleacetic acids), and pterins (neopterin and biopterin). West syndrome, early-infantile epileptic encephalopathy with suppression-bursts or Ohtahara syndrome, severe epilepsy with multiple independent spike foci and partial epilepsy with multiple independent spike foci were the four types of epileptic encephalopathy studied. We report clinical, electroencephalographic, neuroimaging and follow-up data. Among the 23 patients studied, 7 had high neopterin levels. Four of them had partial epilepsy with multiple independent spike foci. High neopterin values were associated with mortality (chi square = 7.304, p = 0.007). 5-Hydroxyindoleacetic acid levels were above reference values in three patients, two with partial epilepsy with multiple independent spike foci and one with West syndrome. Homovanillic acid was normal in almost all infants studied. In conclusion, high neopterin levels suggest a cellular immune activation in the central nervous system of these infants, with apparent prognosis implications. PMID- 17714902 TI - [Microbiological and pharmacological data useful for the treatment of Lyme disease. Treatment and follow up of early Lyme disease (erythema migrans)]. AB - The aim of this review was first to analyze the microbiological and pharmacological criteria used to choose a treatment for Lyme disease. The determination of Borrelia burgdorferi sensu lato susceptibility to antibiotics is difficult, especially because of the lack of standardization in the methods used. In vitro data is helpful to determine Lyme treatment but discrepancies between in vitro and in vivo results highlight the need to confirm this data by clinical trials. The second part is an analysis of the literature made to evaluate the current strategies of treatment and follow up of early Lyme disease characterized by erythema migrans (EM). beta-lactams (penicillin G and V, amoxicillin, cefuroxime axetil, ceftriaxone), tetracyclines (doxycycline), and macrolides (mainly azithromycin) are the drugs most frequently used during clinical trials. The comparison between treatments is difficult because of the lack of reliable clinical and biological criteria to identify complete recovery. However the prognosis of treated EM is good in most trials. If a clinical follow-up remains necessary after the treatment of an EM, prolonged antibody production among asymptomatic patients reduces the interest of a serological follow-up. PMID- 17714903 TI - Analysis of HLA-DRB1, DQA1, DQB1 haplotypes in Sardinian centenarians. AB - Some genetic determinants of longevity might reside in those polymorphisms for the immune system genes that regulate immune responses. Many longevity association studies focused their attention on HLA (the human MHC) polymorphisms, but discordant results have been obtained. Sardinians are a relatively isolate population and represent a suitable population for association studies. Some HLA DR and DQ alleles form very stable haplotypes with a strong linkage disequilibrium. In a previous study on Sardinian centenarians we have suggested that HLA-DRB1 *15 allele might be marginally associated to longevity. HLA-DR,DQ haplotypes are in strong linkage disequilibrium and well conserved playing a role in the association to diseases. Hence, we have evaluated, by amplification refractory mutation system/polymerase chain reaction (ARMS-PCR) the HLADQA1 and HLA-DQB1 allele frequencies in 123 centenarians and 92 controls from Sardinia to assess whether the association to HLA-DRB1 *15 allele may be due to the other genes involved in the HLA-DR,DQ haplotypes. The frequencies of HLA-DQA1, DQB1 haplotypes were not significantly modified in centenarians. Nevertheless by evaluating the frequency of DRB1 *15 linked haplotypes, we observed a not significant increase in centenarians of HLA-DQA1 *01, DQB1 *05 and HLA-DQA1 *01,DQB1 *06 haplotypes. These data suggest that these haplotypes might have a role in determining life span expectancy and longevity. PMID- 17714904 TI - Added diagnostic value of T2-weighted MR imaging to gadolinium-enhanced three dimensional dynamic MR imaging for the detection of small hepatocellular carcinomas. AB - PURPOSE: To assess the added value of T2-weighted MRI to gadolinium-enhanced dynamic MRI for detection of HCCs. MATERIALS AND METHODS: Two readers retrospectively analyzed MRIs of 115 patients with 131 HCCs (size; 0.6-2.0 cm) that had been diagnosed by histology (n=41) or imaging findings (n=90). Two separate blind image analyses of the gadolinium set and the combined T2-weighted imaging and gadolinium sets were performed. Diagnostic accuracy was evaluated using the alternative-free response receiver operating characteristic method with four-point scale. Sensitivity and positive predictive value were also calculated. RESULTS: For both observers, the Az values and sensitivities with the combined T2 weighed imaging and gadolinium set (mean Az 0.806, sensitivity 84.7) were significantly higher than those with the gadolinium set (mean Az 0.660, sensitivity 59.9) (p<0.05). The addition of T2-weighted imaging led to a change in diagnosis for 27 lesions by both observers, which at gadolinium set were assigned a confidence level of 1 or 2 but at additional reading of T2-weighted imaging were assigned a confidence level of 3 or 4. For the positive predictive values, each image set showed a similar value for each observer. CONCLUSION: The addition of T2-weighted imaging to gadolinium-enhanced 3D dynamic imaging could be helpful in the detection of HCC by increasing reader confidence for HCCs with equivocal findings on gadolinium-enhanced MRIs. PMID- 17714905 TI - The value of gamma camera and computed tomography data set coregistration to assess Lewis Y antigen targeting in small cell lung cancer by (111)Indium-labeled humanized monoclonal antibody 3S193. AB - AIM: To assess the value of data set coregistration of gamma camera and computed tomography (CT) in the assessment of targeting of humanized monoclonal antibody 3S193 labeled with indium-111 ((111)In-hu3S193) to small cell lung cancer (SCLC). METHODS AND MATERIALS: Ten patients (6 male and 4 female; mean age+/-S.D., 60+/-4 years), from an overall population of 20 patients with SCLCs expressing Lewis Y antigen at immunohistochemical analysis, completed a four weekly injections of (111)In-hu3S193 and underwent gamma camera imaging. All had had, as part of their baseline evaluation, Fluorine18 fluoro-2-deoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT). Two readers in consensus retrospectively coregistered the gamma camera images with the CT component of the FDG PET/CT by automatic or manual alignment. The resulting image sets were visually examined and SCLC lesions targeting at coregistered gamma camera and CT was correlated side-by-side with the (18)F-FDG uptake. RESULTS: A total number of 31 lesions from SCLC with a thoracic (n=13) or extrathoracic location (n=18) were all positive on FDG PET/CT. Coregistration of the gamma camera to the CT demonstrated targeting of antibody to all lesions >2 cm (n=20) and in a few lesions < or =2 cm (n=2), with no visualization of most lesions < or = 2 cm (n=9). No (111)In hu3S193 uptake in normal tissues was observed. CONCLUSION: Coregistration of antibody gamma camera imaging to FDG PET/CT is feasible and allows valuable assessment of (111)In-hu3S193 antibody targeting to SCLC lesions >2cm, while lesions < or =2 cm reveal a limited targeting. PMID- 17714906 TI - Analysis of exogenous nandrolone metabolite in horse urine by gas chromatography/combustion/carbon isotope ratio mass spectrometry. AB - Nandrolone (17beta-hydroxy-4-estren-3-one, NAD) is an endogenous steroid hormone; thus, the detection of its metabolites is not conclusive of NAD doping in racehorses. NAD doping control in male horses is based on the threshold, namely, the concentration ratio of 5alpha-estran-3beta,17alpha-diol (ETA) to 5(10)-estren 3beta,17alpha-diol (ETE). The ETA/ETE ratio of 1/1 was determined based on statistical data of authentic horses in International Federation of Horseracing Authorities. To individuals with complex metabolic disorders, however, such a threshold might not be applicable. The aim of this study was to establish an analytical method that discriminates endogenous steroids from exogenous ones in horse urine after NAD administration using gas chromatography/combustion/carbon isotope ratio mass spectrometry (GC/C/IRMS). Urine was sampled from NAD administered and authentic horses. Ten millilitres of urine was hydrolyzed and subjected to liquid-liquid extraction and solid phase extraction. The residue of the extracts purified by HPLC was derivatized by acetylation. As a result of measurement of the (13)C/(12)C ratio (delta(13)C) by GC/C/IRMS, the delta(13)C values of ETA for NAD-administered and authentic horses were -32.20+/-0.35 per thousand and -27.85+/-0.75 per thousand (n=60), respectively. The detection limit of ETA in this GC/C/IRMS analysis was approximately 25 ng/ml. This study indicates that the measurement of delta(13)C by GC/C/IRMS enables us to discriminate exogenous ETA derived from NAD administration from endogenous ETA, proving that GC/C/IRMS is a useful technique to complement the ETA/ETE ratio. PMID- 17714907 TI - Evidence based management of acute bronchitis; sustained competence of enhanced communication skills acquisition in general practice. AB - OBJECTIVE: To determine if a communication skills training program for general practitioners involving context-rich learning experiences and 'peer review' of consultation transcripts results in communication skills acquisition and maintenance, while preserving time-efficiency in consultations. METHODS: A pre test-post-test evaluation of training 20 general practitioners (GPs) in enhanced communication skills. Audio taped consultations with simulated patients in routine practice conducted before, within 2 weeks and again 6 months after communication skills training were analysed and consultation length measured. Transcripts were scored for specific skills to determine differences in short and longer-term competence of GPs for the communication skills. RESULTS: There was good evidence that GPs acquired key communication skills after training and that these were maintained over 6 months. Consultations remained within normal consultation length in primary care. CONCLUSION: Specific communication skills for acute bronchitis can be successfully acquired by GPs through context-rich communication training with peer review of transcripts with simulated patients, without making consultation length unfeasible. PRACTICE IMPLICATIONS: This approach to skill acquisition is useful for enhancing communication skills competence in general medical practice. PMID- 17714908 TI - Performing the first pelvic examination: female medical students' transition to examiners. AB - OBJECTIVE: To gain a deeper understanding of how female medical students perceive and experience performing their first pelvic examination (PE). METHODS: A qualitative study. In-depth interviews after the students' involvement in a learning session about the PE, with professional patients (PPs) as instructors and a gynaecologist as supervisor. The interviews were analysed according to the constant comparative method to acquire a deeper understanding of the students' experiences and the ongoing social processes. RESULTS: "Transcending unspoken boundaries and taboos, a prerequisite for learning" was the essence of the entire material and was identified from two categories: "A didactic design facilitates the transition to examiner" and "Interactive support enables creative learning of interpersonal and palpation skills". CONCLUSION: Through interactive guidance from the PPs, the students overcame affective obstacles and achieved the aim of becoming an examiner. The favourable learning experience heightened their awareness of their own bodies and promoted a deeper interest in PEs, both as examiners and as patients. PRACTICE IMPLICATIONS: Engaging voluntary, healthy and knowledgeable women as instructors in the PE situation creates a safe learning environment and promotes interaction with students. Immediate feedback teaches students to integrate communicative and behavioural skills in a professional manner and to palpate the uterus. PMID- 17714909 TI - In vitro models of oxidative stress in rat erythrocytes: effect of antioxidant supplements. AB - The present study was designed to induce oxidative stress in lipid and aqueous phases through azo bis(2-amidinopropane)dihydrochloride (AAPH), 2,2'-azobis 2,4 dimethylvaleronitrile (ADVN) and hydrogen peroxide (H(2)O(2)) either alone or in combination with vitamin C or vitamin El and to assess the vulnerability of rat erythrocytes to oxidative stress. While AAPH acted equally on cell membrane and cytosol, ADVN increased OS in the membrane. The extent of hemolysis and increased membrane fragility caused was more in the case of azo compounds than of H(2)O(2). While vitamin E (2mM) reduced oxidative stress in the membrane, vitamin C (60mM) was more effective in the lysates. The concentration of malondialdehyde and advanced oxidation protein products was lowered by antioxidants. The level of lipofuscin, a product of lipid peroxidation was also increased by ADVN and H(2)O(2). Antioxidants, did, however, reduce the accumulation of protein carbonyl content in cells exposed to azo compounds although they were ineffective in inhibiting oxidation of membrane band 3 protein and sulphydryl content. Taken together, our study demonstrated the antioxidative property of vitamin E and vitamin C in reducing oxidative stress in aqueous as well as lipid phases of erythrocytes and further suggested the feasibility of in vitro models in evaluating the mechanisms of oxidative injury. PMID- 17714910 TI - Identification of six putative human transporters with structural similarity to the drug transporter SLC22 family. AB - The solute carrier family 22 (SLC22) is a large family of organic cation and anion transporters. These are transmembrane proteins expressed predominantly in kidneys and liver and mediate the uptake and excretion of environmental toxins, endogenous substances, and drugs from the body. Through a comprehensive database search we identified six human proteins not yet cloned or annotated in the reference sequence databases. Five of these belong to the SLC22 family, SLC22A20, SLC22A23, SLC22A24, SLC22A25, and SPNS3, and the sixth gene, SVOPL, is a paralog to the synaptic vesicle protein SVOP. We identified the orthologs for these genes in mouse and rat and additional homologous proteins and performed the first phylogenetic analysis on the entire SLC22 family in human, mouse, and rat. In addition, we performed a phylogenetic analysis which showed that SVOP and SV2A-C are, in a comparison with all vertebrate proteins, most similar to the SLC22 family. Finally, we performed a tissue localization study on 15 genes on a panel of 30 rat tissues using quantitative real-time polymerase chain reaction. PMID- 17714911 TI - Direct identification of chlamydiae from clinical samples using a DNA microarray assay: a validation study. AB - While DNA microarrays have become a widely accepted tool for mRNA expression monitoring, their use in rapid diagnosis of bacterial and viral pathogens is only emerging. So far, insufficient sensitivity and high costs have been the major limiting factors preventing more widespread use of microarray platforms in direct testing of clinical samples. In the present study, a total of 339 samples, among them 293 clinical specimens from animals and humans, were examined by the ArrayTube (AT) DNA microarray assay to detect chlamydial DNA and identify the species of Chlamydia and Chlamydophila involved. Samples included nasal and conjunctival swabs, formalin-fixed, paraffin-embedded and fresh organ tissue, milk, feces and cell culture. Notably, the AT test was shown to detect mixed infections in clinical samples. The calculated median sensitivity of 0.81 over the entire panel of clinical samples was comparable to conventional 16S PCR, but slightly lower than real-time PCR and other PCR assays. However, when a panel of long-time stored swab samples was excluded from the calculation, the sensitivity was clearly higher (0.87) and equivalent to that of real-time PCR. Altogether, the data demonstrate the suitability of this DNA microarray assay for routine diagnosis. PMID- 17714912 TI - Modeling of gene regulatory networks with hybrid differential evolution and particle swarm optimization. AB - In the last decade, recurrent neural networks (RNNs) have attracted more efforts in inferring genetic regulatory networks (GRNs), using time series gene expression data from microarray experiments. This is critically important for revealing fundamental cellular processes, investigating gene functions, and understanding their relations. However, RNNs are well known for training difficulty. Traditional gradient descent-based methods are easily stuck in local minima and the computation of the derivatives is also not always possible. Here, the performance of three evolutionary-swarm computation technology-based methods, known as differential evolution (DE), particle swarm optimization (PSO), and the hybrid of DE and PSO (DEPSO), in training RNNs is investigated. Furthermore, the gene networks are reconstructed via the identification of the gene interactions, which are explained through corresponding connection weight matrices. The experimental results on two data sets studied in this paper demonstrate that the DEPSO algorithm performs better in RNN training. Also, the RNN-based model can provide meaningful insight in capturing the nonlinear dynamics of genetic networks and revealing genetic regulatory interactions. PMID- 17714913 TI - Interpolating vectors for robust pattern recognition. AB - This paper proposes a powerful algorithm for pattern recognition, which uses interpolating vectors for classifying patterns. Labeled reference vectors in a multi-dimensional feature space are first produced by a kind of competitive learning. We then assume a situation where virtual vectors, called interpolating vectors, are densely placed along line segments connecting all pairs of reference vectors of the same label. From these interpolating vectors, we choose the one that has the largest similarity to the test vector. Its label shows the result of pattern recognition. In practice, we can get the same result with a simpler process. We applied this method to the neocognitron for handwritten digit recognition and reduced the error rate from 1.52% to 1.02% for a blind test set of 5000 digits. PMID- 17714914 TI - Robust stability of stochastic delayed additive neural networks with Markovian switching. AB - This paper is concerned with the problem of robust stability for stochastic interval delayed additive neural networks (SIDANN) with Markovian switching. The time delay is assumed to be time-varying. In such neural networks, the features of stochastic systems, interval systems, time-varying delay systems and Markovian switching are taken into account. The mathematical model of this kind of neural networks is first proposed. Secondly, the global exponential stability in the mean square is studied for the SIDANN with Markovian switching. Based on the Lyapunov method, several stability conditions are presented, which can be expressed in terms of linear matrix inequalities. As a subsequent result, the stochastic interval additive neural networks with time-varying delay are also discussed. A sufficient condition is given to determine its stability. Finally, two simulation examples are provided to illustrate the effectiveness of the results developed. PMID- 17714915 TI - A kernel-based approach to categorizing laryngeal images. AB - This paper is concerned with an approach to automated analysis of vocal fold images aiming to categorize laryngeal diseases. Colour, texture, and geometrical features are used to extract relevant information. A committee of support vector machines is then employed for performing the categorization of vocal fold images into healthy, diffuse, and nodular classes. The discrimination power of both, the original and the space obtained based on the kernel principal component analysis is investigated. A correct classification rate of over 92% was obtained when testing the system on 785 vocal fold images. Bearing in mind the high similarity of the decision classes, the correct classification rate obtained is rather encouraging. PMID- 17714916 TI - Holistic polar map for integrated evaluation of cardiac imaging results. AB - Polar map display (PM) is a comprehensive interpretation of the left ventricle. This is a non-rigid registration of the left ventricle originally for the visual and quantitative analysis of tomographic myocardial perfusion scintigrams. In this scheme the maximal-count circumferential profiles of well-defined short- and long-axis planes are plotted to a map showing the distribution of the perfusion tracer onto a two-dimensional polar representation. The usual coronary artery distribution is often indicated on the PMs of SPECT studies by referring to the regions of the three main coronary branches, nevertheless, the individual variations may differ extensively. We set out to develop an Access (Microsoft) based computer program that permits an integrated evaluation of the imaging results (coronary angiography, echocardiography and SPECT) on patients with coronary artery disease. This semi-quantitative registration of the coronary tree to a PM focused on the relation between the supplying coronary branches and the myocardial regions of the 16-segment left ventricular evaluating model. All the recorded anatomical and functional data were related to these 16 left ventricular segments, which allowed the direct comparison and holistic synthesis of the results. Two projections were taken into consideration for generation of the coronary PM: from the right anterior oblique projections, the left anterior descendent (LAD)/right coronary artery (RCA) border was assessed through the comparison of the left and right coronary angiograms. The terminations of the visually detected end-arteries showed the separation of the myocardial beds supplied by the two branches. The border of the myocardial beds on the polar map was determined on the "vertical axis" of the local coordinate system. The RCA/ left circumflex (LCx) separation can be determined from the left anterior oblique view. In this projection, the left ventricular septal edge was delineated by the LAD, while the LCx indicated the lateral epicardial surface. The individual coronary artery circulation was typified from among 12 variations in the Holistic Coronary Care program. With this determination of the individual coronary circulation, the lesion-associated segments are generated automatically by the software. The lesion-associated regions are defined as the myocardial bed of a diseased artery distal to the lesion. The PMs generated from the coronary angiographic results were compared with those of 99Tc-labelled MIBI single photon emission computed tomography (SPECT) in order to test the accuracy of the localizing method. The overlap between the segments associated with the coronary lesion and the stress perfusion defects (<80% relative MIBI activity during stress tests) was analyzed in 10 patients with (sub)total coronary occlusion after myocardial infarction. The distributions of the segments with stress perfusion defects on MIBI SPECT gave positive and negative predictive values of coronary occlusion of 0.94 and 0.8, respectively. According to the 16-segment wall motion analysis by echocardiography, the positive and negative predictive values of coronary occlusion for wall motion abnormality were 0.82 and 0.76, respectively. While the distal part of the subtended region usually demonstrated a higher degree perfusion abnormality than the proximal part, the high positive predictive value proved that, during the stress condition, the perfusion defect could be detected in practically all the subtended regions. The low negative predictive value of the coronary lesion for the wall motion abnormality was associated with the remodeling of the entire left ventricle. PMID- 17714917 TI - Transcriptomal profiling of site-specific Ras signals. AB - Ras proteins are distributed in distinct plasma-membrane microdomains and endomembranes. The biochemical signals generated by Ras therein differ qualitatively and quantitatively, but the extent to which this spatial variability impacts on the genetic program switched-on by Ras is unknown. We have used microarray technology to identify the transcriptional targets of localization-specific Ras subsignals in NIH3T3 cells expressing H-RasV12 selectively tethered to distinct cellular microenvironments. We report that the transcriptomes resulting from site-specific Ras activation show a significant overlap. However, distinct genetic signatures can also be found for each of the Ras subsignals. Our analyses unveil 121 genes uniquely regulated by Ras signals emanating from plasma-membrane microdomains. Interestingly, not a single gene is specifically controlled by lipid raft-anchored Ras. Furthermore, only 9 genes are exclusive for Ras signals from endomembranes. Also, we have identified 31 genes common to the site-specific Ras subsignals capable of inducing cellular transformation. Among these are the genes coding for Vitamin D receptor and for p120-GAP and we have assessed their impact in Ras-induced transformation. Overall, this report reveals the complexity and variability of the different genetic programs orchestrated by Ras from its main sublocalizations. PMID- 17714918 TI - Cardiovascular risk factors and homocysteine in epilepsy. AB - Epidemiological studies have found the risk for heart disease and stroke are increased in persons with epilepsy. Anti-epileptic drugs (AEDs) have varying effects on serum lipids and homocysteine-an independent risk factor for coronary disease. The prevalence of cardiovascular risk factors (high cholesterol, hypertension, diabetes, obesity and smoking) and homocysteine were investigated in a multiethnic epilepsy population. Data included demographics, clinical factors, lab assessments and supplementation patterns. Mean age was 45 years (71 males and 94 females)-75 were African American, 27 Latino and 60 Caucasian. Fifty two percent of participants had two or more cardiovascular risk factors when compared with rates for the general population of 28%. The Framingham risk score (FRS) assessment was also used to compare risk levels. Twenty-nine percent of men and 1% of women had a FRS indicating >5% level of risk, only 7% had a FRS>10%. Cardiovascular screening and primary preventative recommendations based on the American Heart Association and supplementation should be suggested for the adult epilepsy population when appropriate. PMID- 17714919 TI - Associations of IL-2 and IL-4 gene polymorphisms with psoriasis in the Korean population. AB - BACKGROUND: Psoriasis is association with an overexpression of T-helper cell type 1(Th1) cytokines and relative underexpression of Th2 cytokines. The cytokine production is under genetic control, and certain allelic variants of cytokine genes are associated with higher or lower cytokine production in vitro and in vivo. OBJECTIVES: We aimed to evaluate association of cytokine genes polymorphisms with psoriasis in the Korean population. METHODS: We investigated the polymorphisms of IL-2 -330, IL-4 -590, IL-4 receptor +1902, IL-10 -1082 and 819, and IFN-gamma intron 1 in 114 psoriasis patients and 281 healthy normal controls in Korean. RESULTS: IL-2 -330*G and IL-4 -590*C alleles significantly increased in psoriasis patients, especially late-onset group, compared to the control. The combined effect of IL-2 -330*G and IL-4 -590*C showed that the positive combination of IL-2 -330*G and IL-4 -590*C alleles were more significantly associated with the late-onset group of psoriasis patients than the controls. CONCLUSIONS: These results suggest that the genetic polymorphisms of IL 2 and IL-4 genes can be susceptible to psoriasis in Korean, especially late-onset psoriasis group. PMID- 17714920 TI - Dehydroepiandrosterone and monoamines in the limbic system of a genetic animal model of childhood depression. AB - Monoamines and dehydroepiandrosterone (DHEA) levels were measured in a genetic animal model for childhood depression in four subcortical structures: nucleus accumbens (Nac), ventral tegmental area (VTA), amygdala and hypothalamus. The "depressive-like" strain was the Flinders Sensitive Line (FSL), compared to their controls, Sprague-Dawley (SD) rats. Prepubertal FSL rats showed abnormal levels of only a few monoamines and their metabolites in these brain regions. This is in contrast to former studies, in which adult FSL rats exhibited significantly higher levels of all the monoamines and their metabolites measured. These different abnormal monoamine patterns between the "depressed" prepubertal rats and their adults, may help to explain why depressed children and adolescents fail to respond to antidepressant treatment as well as adults do. On the other hand, FSL prepubertal rats exhibited the same pattern of abnormal DHEA basal levels as was found in adults in previous experiments. The results from the current study may imply that treatment with DHEA could be a promising novel therapeutic option for depressed children and adolescents that fail to respond to common (monoaminergic) antidepressant treatments. PMID- 17714921 TI - Development and validation of in silico models for estimating drug preformulation risk in PEG400/water and Tween80/water systems. AB - Solubility is one of the most important properties of drug candidates for achieving the targeted plasma concentrations following oral dosing. Furthermore, the formulations adopted in the in vivo preclinical studies, for both oral and intravenous administrations, are usually solutions. To formulate compounds sparingly soluble in water, pharmaceutically acceptable cosolvents or surfactants are typically employed to increase solubility. Compounds poorly soluble also in these systems will likely show severe formulation issues. In such cases, relatively high amount of compounds, rarely available in the early preclinical phases, are needed to identify the most appropriate dosing vehicles. Hence, the purpose of this study was to build two computational models which, on the basis of the molecular structure, are able to predict the compound solubility in two vehicle systems (40% PEG400/water and 10% Tween80/water) used in our company as screening tools for anticipating potential formulation issues. The two models were developed using the solubility data obtained from the analysis of approximately 2000 chemically diverse compounds. The structural diversity and the drug-like space covered by these molecules were investigated using the ChemGPS methodology. The compounds were classified (high/low preformulation risk) based on the experimental solubility value range. A combination of descriptors (i.e. logD at two different pH, E-state indices and other 2D structural descriptors) was correlated to these classes using partial least squares discriminant (PLSD) analysis. The overall accuracy of each PLSD model applied to independent sets of compounds was approximately 78%. The accuracy reached when the models were used in combination to identify molecules with low preformulation risk in both systems was 83%. The models appeared a valuable tool for predicting the preformulation risk of drug candidates and consequently for identifying the most appropriate dosing vehicles to be further investigated before the first in vivo preclinical studies. Since only a small number of 2D descriptors is need to evaluate the preformulation risk classes, the models resulted easy to use and characterized by high throughput. PMID- 17714922 TI - Simultaneous determination of two active components in compound aspirin tablets using principal component artificial neural networks (PC-ANNs) on NIR spectroscopy. AB - A method for simultaneous, non-destructive analysis of aspirin and phenacetin in compound aspirin tablets with different concentrations has been developed by principal component artificial neural networks (PC-ANNs) on near-infrared (NIR) spectroscopy. In PC-ANNs models, the spectra data were first analyzed by principal component analysis (PCA). Then the scores of the principal compounds (PCs) were chosen as input nodes for input layer instead of the spectra data. The artificial neural networks (ANNs) models using the spectra data as input nodes were also established, which were compared with the PC-ANNs models. Four different preprocessing methods (first-derivation, second-derivation, standard normal variate (SNV) and multiplicative scatter correction (MSC)) were applied to NIR conventional spectra. The result shows the first-derivative model of PC-ANNs multivariate calibration has the lowest training errors and predicting errors. The concept of the degree of approximation was introduced and performed as the selective criterion of the optimum network parameters. PMID- 17714924 TI - Multi-scaled morphological features for the characterization of mammographic masses using statistical classification schemes. AB - OBJECTIVE: A comprehensive signal analysis approach on the mammographic mass boundary morphology is presented in this article. The purpose of this study is to identify efficient sets of simple yet effective shape features, employed in the original and multi-scaled spectral representations of the boundary, for the characterization of the mammographic mass. These new methods of mass boundary representation and processing in more than one domain greatly improve the information content of the base data that is used for pattern classification purposes, introducing comprehensive spectral and multi-scale wavelet versions of the original boundary signals. The evaluation is conducted against morphological and diagnostic characterization of the mass, using statistical methods, fractal dimension analysis and a wide range of classifier architectures. METHODS AND MATERIALS: This study consists of (a) the investigation of the original radial distance measurements under the complete spectrum of signal analysis, (b) the application of curve feature extractors of morphological characteristics and the evaluation of the discriminative power of each one of them, by means of statistical significance analysis and dataset fractal dimension, and (c) the application of a wide range of classifier architectures on these morphological datasets, in order to conduct a comparative evaluation of the efficiency and effectiveness of all architectures, for mammographic mass characterization. Radial distance signal was exploited using the discrete Fourier transform (DFT) and the discrete wavelet transform (DWT) as additional carrier signals. Seven uniresolution feature functions were applied over these carrier signals and multiple shape descriptors were created. Classification was conducted against mass shape type and clinical diagnosis, using a wide range of linear and non linear classifiers, including linear discriminant analysis (LDA), least-squares minimum distance (LSMD), k-nearest neighbor (k-NN), radial basis function (RBF) and multi-layered perceptron (MLP) neural networks (NN), and support vector machines (SVM). Fractal analysis was employed as a dataset analysis tool in the feature selection phase. The discriminative power of the features produced by this composite analysis is subsequently analyzed by means of multivariate analysis of variance (MANOVA) and tested against two distinct classification targets, namely (a) the morphological shape type of the mass and (b) the histologically verified clinical diagnosis for each mammogram. RESULTS: Statistical analysis and classification results have shown that the discrimination value of the features extracted from the DWT components and especially the DFT spectrum, are of great importance. Furthermore, much of the information content of the curve features in the case of DFT and DWT datasets is directly related to the texture and fine-scale details of the corresponding envelope signal of the spectral components. Neural classifiers outperformed all other methods (SVM not used because they are mainly two-class classifiers) with overall success rate of 72.3% for shape type identification, while SVM achieved the overall highest 91.54% for clinical diagnosis. Receiver operating characteristic (ROC) analysis has been employed to present the sensitivity and specificity of the results of this study. PMID- 17714925 TI - High dose rate endorectal brachytherapy as a neoadjuvant treatment for patients with resectable rectal cancer. AB - In the era of total mesorectal surgery, the issue of radiation toxicity is raised. A novel endocavitary brachytherapy technique was tested as a neoadjuvant treatment for patients with resectable rectal cancer. The objectives of the study were to evaluate the treatment-related toxicity and effects on local recurrence. A dose of 26 Gy was prescribed to the gross tumour volume and intramesorectal deposits seen on magnetic resonance imaging and given over four daily treatments, using the high dose rate delivery system followed by surgery 6-8 weeks later. The study included 93 T3, four T4 and three T2 tumours. Acute proctitis of grade 2 was observed in all patients, but one required transfusion. At a median follow-up time of 60 months, the 5-year actual local recurrence rate was 5%, disease-free survival was 65%, and overall survival was 70%. High dose rate endorectal brachytherapy seems to prevent local recurrence and has a favourable toxicity pattern compared with external beam radiotherapy. PMID- 17714927 TI - Diagnostic utility of inflammatory biomarkers in asthma: exhaled nitric oxide and induced sputum eosinophil count. AB - BACKGROUND: Even though an inflammatory process is known to be the underlying cause of asthma, diagnosis is based on clinical history, reversible airway obstruction and bronchial hyperresponsiveness according to international guidelines. The fraction of exhaled nitric oxide (FE(NO)) and induced sputum eosinophil count (Eos%) have been used as non-invasive inflammatory biomarkers. OBJECTIVES: The aim of this study was to compare the sensitivity and specificity of FE(NO), Eos% and spirometry and to assess whether their combined use in clinical practice would improve diagnostic yield. METHODS: In 50 patients with asthma symptoms we performed spirometry, a methacholine challenge test, FE(NO) measurement and assessment of Eos% in induced sputum. The standard diagnosis of asthma followed the guidelines of the Global Initiative for Asthma. RESULTS: Twenty-two of the 50 patients were diagnosed with asthma. The sensitivity and diagnostic accuracy were higher for FE(NO) measurement (77%; area under the receiver operating curve [AUC], 0.8) than for spirometry (22%; AUC, 0.63). The sensitivity and specificity of Eos% in induced sputum were 40% and 82%, respectively, and the diagnostic accuracy of Eos% was lower (AUC, 0.58). When both inflammatory biomarkers were used together specificity increased to 76%. CONCLUSIONS: The diagnostic accuracy of FE(NO) measurement was superior to that of the standard diagnostic spirometry in patients with symptoms suggestive of asthma. The use of FE(NO) measurement and induced sputum Eos% together to diagnose asthma in clinical practice is more accurate than spirometry or FE(NO) assessment alone and easier to perform. PMID- 17714926 TI - Response to: Scottish Intercollegiate Guidelines Network (SIGN) 84 -- National Clinical Guideline for the Management of Breast Cancer in Women (Reed, Clin Oncol 2007;19:588-590). PMID- 17714928 TI - Towards zero waste in emerging countries - a South African experience. AB - The aim of this paper is to describe the optimisation of Waste Minimisation/Zero Waste strategies into an already established integrated waste management system and to present a Zero Waste model for post-consumer waste for urban communities in South Africa. The research was undertaken towards the fulfilment of the goals of the Polokwane Declaration on Waste Management [DEAT, 2001. Department of Environmental Affairs and Tourism, Government of South Africa. Polokwane Declaration. Drafted by Government, Civil Society and the Business Community. National Waste Summit, Polokwane, 26-28 September 2001], which has set as its target the reduction of waste generation and disposal by 50% and 25%, respectively, by 2012 and the development of a plan for Zero Waste by 2022. Two communities, adjacent to the Mariannhill Landfill site in Durban, were selected as a case study for a comparative analysis of formal and informal settlements. Since the waste generated from these two communities is disposed of at the Mariannhill landfill, the impact of Zero Waste on landfill volumes could be readily assessed. A Zero Waste scheme, based on costs and landfill airspace savings, was proposed for the area. The case study demonstrates that waste minimisation schemes can be introduced into urban areas, in emerging countries, with differing levels of service and that Zero Waste models are appropriate to urban areas in South Africa. PMID- 17714929 TI - Recovery of nickel, cobalt and some salts from spent Ni-MH batteries. AB - This work provides a method to help recover nickel, cobalt metals and some of their salts having market value from spent nickel-metal hydride batteries (SNiB). The methodology used benefits the solubility of the battery electrode materials in sulfuric or hydrochloric acids. The results obtained showed that sulfuric acid was slightly less powerful in leaching SNiB compared to HCl acid. Despite that, sulfuric acid was extremely applied on economic basis. The highest level of solubility attained 93.5% using 3N sulfuric acid at 90 degrees C for 3h. The addition of hydrogen peroxide to the reacting acid solution improved the level of solubility and enhanced the process in a shorter time. The maximum recovery of nickel and cobalt metals was 99.9% and 99.4%, respectively. Results were explained in the light of a model assuming that solubility was a first order reaction. It involved a multi-step sequence, the first step of which was the rate determining step of the overall solubility. Nickel salts such as hydroxide, chloride, hexamminenickel chloride, hexamminenickel nitrate, oxalate and nickel oleate were prepared. With cobalt, basic carbonate, chloride, nitrate, citrate, oleate and acetate salts were prepared from cobalt hydroxide Cost estimates showed that the prices of the end products were nearly 30% lower compared to the prices of the same chemicals prepared from primary resources. PMID- 17714930 TI - An engineering approach to solid waste collection system: Ibadan North as case study. AB - This research centered on finding and perfecting methods of collection and disposal of refuse in Ibadan North Local Government Areas. The methodology used included questionnaire administration, personal interviews, field reconnaissance, and biochemical tests of water samples, all aimed at providing useful data for the design of effective methods of collecting and disposing refuse. The local government area was divided into three classes based on resident income: a high income area (Bodija Avenue, etc.), a medium-income area (Sanngo, Oluyole, etc.), and a low-income area (Beere, Adeoyo, etc.). The research outcomes revealed that the waste generation rate for the local government ranged from 0.2 to 0.33 kg/cap/day and waste density ranged from 172.41 to 217.61 kg/m3. Water analyses showed that the chloride, manganese, lead, and cadmium levels in water from low income areas were above the WHO standard. The refuse generated in high and medium income areas was collected and transported to the disposal site properly while only 54.5% of wastes were handled properly in low-income areas. Also, in order to make low-income areas free from wastes daily, an additional 15 metal skips and 9 refuse vehicles would be needed. PMID- 17714932 TI - Learning to hear: plasticity of auditory cortical processing. AB - Sensory experience and auditory cortex plasticity are intimately related. This relationship is most striking during infancy when changes in sensory input can have profound effects on the functional organization of the developing cortex. But a considerable degree of plasticity is retained throughout life, as demonstrated by the cortical reorganization that follows damage to the sensory periphery or by the more controversial changes in response properties that are thought to accompany perceptual learning. Recent studies in the auditory system have revealed the remarkably adaptive nature of sensory processing and provided important insights into the way in which cortical circuits are shaped by experience and learning. PMID- 17714931 TI - Shh and Gremlin1 chromosomal landscapes in development and disease. AB - Two regulatory signals play major roles in digit patterning during vertebrate limb development, the SHH morphogen and the BMP antagonist Gremlin1. Their dynamic expression in limb buds is controlled by distant cis-regulatory elements embedded in unrelated neighboring genes, which has confused identification of the primary cause of different types of congenital limb malformations affecting mice and humans. Comparative and functional genomics have uncovered the large and complex chromosomal landscapes that control Shh and Gremlin1 expression, identified the molecular cause of the congenital malformations and provided insights into limb evolution. While most of the transacting factors remain unknown, Hoxd proteins have been shown to bind to the far upstream Shh cis regulatory elements and activate their expression in limb buds. PMID- 17714933 TI - Auditory attention--focusing the searchlight on sound. AB - Some fifty years after the first physiological studies of auditory attention, the field is now ripening, with exciting recent insights into the psychophysics, psychology, and neural basis of auditory attention. Current research seeks to unravel the complex interactions of pre-attentive and attentive processing of the acoustic scene, the role of auditory attention in mediating receptive-field plasticity in both auditory spatial and auditory feature processing, the contrasts and parallels between auditory and visual attention pathways and mechanisms, the interplay of bottom-up and top-down attentional mechanisms, the influential role of attention, goals, and expectations in shaping auditory processing, and the orchestration of diverse attentional effects at multiple levels from the cochlea to the cortex. PMID- 17714935 TI - Analysis of X-ray and neutron scattering from biomacromolecular solutions. AB - New developments in small-angle X-ray and neutron scattering studies of biological macromolecules in solution are presented. Small-angle scattering is rapidly becoming a streamline tool in structural molecular biology providing unique information about overall structure and conformational changes of native individual proteins, functional complexes, flexible macromolecules and assembly processes. PMID- 17714934 TI - Sensory adaptation. AB - Adaptation occurs in a variety of forms in all sensory systems, motivating the question: what is its purpose? A productive approach has been to hypothesize that adaptation helps neural systems to efficiently encode stimuli whose statistics vary in time. To encode efficiently, a neural system must change its coding strategy, or computation, as the distribution of stimuli changes. Information theoretic methods allow this efficient coding hypothesis to be tested quantitatively. Empirically, adaptive processes occur over a wide range of timescales. On short timescales, underlying mechanisms include the contribution of intrinsic nonlinearities. Over longer timescales, adaptation is often power law-like, implying the coexistence of multiple timescales in a single adaptive process. Models demonstrate that this can result from mechanisms within a single neuron. PMID- 17714937 TI - Should radiotherapy be avoided or delivered differently in elderly patients with rectal cancer? AB - Purpose is to give an overview of treatment possibilities of rectal cancer over time, but also of the real management of rectal cancer especially in relation to age. From literature search representative randomised studies on patients with resectable rectal cancer, comparing only surgery, post- and preoperative radiotherapy with or without chemotherapy, are reviewed. We also reviewed the literature regarding radiotherapy for rectal cancer described in population-based studies. The overview of the trials showed that preoperative radiotherapy improves local control in relation to no or postoperative radiotherapy. Adding chemotherapy did not significantly improve survival. No relations were seen between age and complications. All population-based studies showed that increasing age is associated with less (neo)adjuvant treatment. To avoid local recurrence, the best possible treatment, being preoperative RT, should be given to all patients with resectable rectal cancer, irrespective of age. PMID- 17714936 TI - Structural principles of intramembrane proteases. AB - Intramembrane proteases are present in most organisms, and are used by cells to send signal across membranes, to activate growth factors, and to accomplish many other tasks that are beyond the capability of their soluble cousins. These enzymes specialize in cleaving peptide bonds that are normally embedded in cell membranes. They contain multiple membrane-spanning segments, and their catalytic residues are often found within these hydrophobic domains. In the past year, a number of important papers have been published that began to address the structural features of these membrane proteins by X-ray crystallography, electron microscopy, and biochemical methods, including the first report of an intramembrane protease crystal structure, that of Escherichia coli GlpG. Taken together, these studies started to reveal patterns of how intramembrane proteases are constructed, how waters are supplied to the membrane-embedded active site, and how membrane protein substrates interact with them. PMID- 17714938 TI - Poly(ADP-ribose) polymerase (PARP) inhibition or PARP-1 gene deletion reduces angiogenesis. AB - Poly(ADP-ribose) polymerase (PARP)-1 has recently been shown to promote tumour progression. Since angiogenesis is an essential requirement for tumour growth, we examined whether PARP inhibition/deletion might affect endothelial cell functions. To this end, the influence of PARP inhibitors on endothelial cell proliferation, migration, tube formation and angiogenesis in PARP-1 knock-out mice, using an in vivo matrigel plug assay, was investigated. The results indicated that the PARP inhibitor GPI 15427 (IC50 on endothelial PARP: 237 +/- 27 nM), at concentrations devoid of cytotoxic effects (0.5-1 microM), abrogated migration in response to vascular endothelial growth factor or placenta growth factor, hampered formation of tubule-like networks and impaired angiogenesis in vivo. The anti-angiogenic effect of the PARP inhibitor was confirmed in PARP-1 knock-out mice that displayed a defect of angiogenesis induced by growth factors. These results provide evidence for targeting PARP for anti-angiogenesis, adding novel therapeutic implications to the use of PARP inhibitors in cancer treatment. PMID- 17714939 TI - Tumors of the liver in children. AB - In this review we examine the diagnosis and treatment of pediatric liver tumors- both malignant and benign. The two most common malignant tumors are hepatoblastoma and hepatocellular carcinoma. Hepatoblastoma is seen in younger children, hepatocellular carcinoma in older children. Other malignant liver tumors are quite rare and include biliary rhabdomyosarcoma, angiosarcoma, rhabdoid tumor, and undifferentiated sarcoma. The commonly seen benign liver tumors in children are infantile hemangioma, mesenchymal hamartoma, and focal nodular hyperplasia. Rare benign tumors are hepatic adenoma, which is occasionally seen in teenage girls, and teratoma which is a very rare liver tumor in infants. PMID- 17714940 TI - Treatment of hydroponic wastewater by denitrification filters using plant prunings as the organic carbon source. AB - This study investigated the feasibility of using pre-treated plant liquors as organic carbon sources for the treatment of hydroponic wastewater containing high nitrate-N (>300 mg N/L). The waste plant material was pre-treated to extract organic carbon-rich liquors. When this plant liquor was used as an organic carbon source in denitrification filters at the organic carbon:nitrogen dose rate of 3C:N, nitrate removal efficiencies were >95% and final effluent nitrate concentrations were consistently <20mg N/L. However, at this dose rate, relatively high concentrations (>140 mg/L) of organic carbon (fBOD5) remained in the final effluents. Therefore, a 'compromise' organic carbon:nitrogen dose rate (2C:N) was trialled, at which nitrate removal efficiencies were maintained at >85%, final effluent nitrate concentrations were consistently below 45 mg N/L, and effluent fBOD5 concentrations were <25mg/L. This study has demonstrated that waste plant material is a suitable carbon source for the removal of nitrate from hydroponic wastewater in a denitrification filter. PMID- 17714941 TI - Effect of effluent recycling and shock loading on the biodegradation of complex phenolic mixture in hybrid UASB reactors. AB - This study describes the feasibility of anaerobic treatment of synthetic coal wastewater using four identical 13.5L (effective volume) bench scale hybrid up flow anaerobic sludge blanket (HUASB) reactors (R1, R2, R3 and R4) under mesophilic (27+/-5 degrees C) conditions. Synthetic coal wastewater with an average chemical oxygen demand (COD) of 2240 mg/L and phenolics concentration of 752 mg/L was used as substrate. Effluent recirculation was employed at four different effluent to feed recirculation ratios (R/F) of 0.5, 1.0, 1.5 and 2.0 for 100 days to study the effect of recirculation on the performance of the reactors. Phenolics and COD removal was found to improve with increase in effluent recirculation. An effluent to feed recycle ratio of 1.0 resulted in maximum removal of phenolics and COD. Phenolics and COD removal improved from 88% and 92% to 95% each, respectively. The concentration of volatile fatty acids in the effluent was lower than the influent when effluent to feed recirculation was employed. Effect of shock loading on the reactors revealed that phenolics shock load up to 2.5 times increase in the normal input phenolics concentration in the form of continuous shock load for 4days did not affect the reactors performance irreversibly. PMID- 17714942 TI - Behavior of natural estrogens in semicontinuous activated sludge biodegradation reactors. AB - Biological degradation of natural estrogens was investigated by separately spiking 17 beta-estradiol (E2) and estrone (E1) into activated sludge reactors operated in a semi-continuous flow mode under aerobic conditions. By conducting runs for simultaneous addition of glucose over the designated initial concentrations of 0, 10, 30, 50 and 100 mg l(-1), respectively, the likely effect of the easily biodegradable organic constituent on the degradation rate of the natural estrogens was also studied. The spiked E2 disappeared in a manner much faster than E1; and its disappearance occurred through elimination of its metabolic byproduct of E1. The apparent first-order disappearance rate of E2 and E1 fell in the ranges of 0.84-4.31h(-1) and 0.15-0.84 h(-1), respectively when spiked separately into respective reactors. A general trend of decreases in the disappearance rate with increases of the initial glucose concentration was revealed. The presence of glucose was also found capable of lowering the conversion ratio from E2 to E1. PMID- 17714943 TI - Packed bed dynamics during microbial treatment of wastewater: modelling and simulation. AB - A mathematical model consisting of mass balance equations and accounting for bioreaction and mass transfer is presented to describe both unsteady and steady state degradation of phenol in a biofilter. The model has been validated for the steady-state situation with literature work. The model has been able to predict the dynamics of the biofiltration process with variations in system and operating conditions as inlet substrate concentration, liquid phase mass transfer coefficients, particle size, Henry's constant, inlet velocity, growth and half saturation constants and bed void fraction. The results show that inlet substrate concentration, inlet velocity, growth and half saturation constants and liquid phase mass transfer coefficients significantly control the operational dynamics. It is also shown that inhibition effects can be neglected for low concentrations (<0.5 kg m(-3)) of phenol. Thus, the model can be used as a design tool for a biofilter. PMID- 17714945 TI - Post-mastectomy radiation therapy: translating local benefits into improved survival. AB - Several randomized trials and the most recent meta-analysis from the Oxford Overview have confirmed the efficacy of post-mastectomy radiation therapy (PMRT) in improving local control and long-term survival. The survival advantage of PMRT has been established in patients with a 10% risk of local regional recurrence. Patients with four or more positive lymph nodes fall in this category, even with effective systemic therapy. However, it remains difficult to identify the subset of patients with 1-3 positive lymph nodes at highest risk of local recurrence, who would most likely demonstrate a survival benefit with PMRT. When PMRT is used, careful treatment planning, particularly with regard to cardiac dose, is critical to minimizing serious late effects of treatment. Further developments in pathologic stratification of these patients, guided by expression profiles or novel biologic markers, are required to enable individualized assessment of long term therapeutic risks and benefits. PMID- 17714944 TI - Biosorption of Pb(II) and Cr(III) from aqueous solution by lichen (Parmelina tiliaceae) biomass. AB - The biosorption characteristics of Pb(II) and Cr(III) ions from aqueous solution using the lichen (Parmelina tiliaceae) biomass were investigated. Optimum biosorption conditions were determined as a function of pH, biomass dosage, contact time, and temperature. Langmuir, Freundlich and Dubinin-Radushkevich (D R) models were applied to describe the biosorption isotherm of the metal ions by P. tiliaceae biomass. Langmuir model fitted the equilibrium data better than the Freundlich isotherm. The monolayer biosorption capacity of P. tiliaceae biomass for Pb(II) and Cr(III) ions was found to be 75.8 mg/g and 52.1mg/g, respectively. From the D-R isotherm model, the mean free energy was calculated as 12.7 kJ/mol for Pb(II) biosorption and 10.5 kJ/mol for Cr(III) biosorption, indicating that the biosorption of both metal ions was taken place by chemical ion-exchange. The calculated thermodynamic parameters (delta G degrees , delta H degrees and delta S degrees ) showed that the biosorption of Pb(II) and Cr(III) ions onto P. tiliaceae biomass was feasible, spontaneous and exothermic under examined conditions. Experimental data were also tested in terms of biosorption kinetics using pseudo-first-order and pseudo-second-order kinetic models. The results showed that the biosorption processes of both metal ions followed well pseudo second-order kinetics. PMID- 17714946 TI - Pathological definitions of invasion, metastatic potential and responsiveness to targeted therapies. AB - The tailored treatment of patients with primary breast carcinoma relies mainly on the assessment of invasion, metastatic potential and responsiveness to targeted therapies. Accordingly, the role of the pathologist is to ensure the most accurate evaluation of the prognostic and predictive parameters, which will have a major impact in the planning of the adjuvant interventions. Every effort has to be made to improve the accuracy and the inter-laboratory reproducibility of the histopathological and biological characterization of breast carcinomas, taking advantage of the newly developed molecular assays. This review article will focus mainly on some controversial issues, like intracystic papillary carcinomas, whose invasive or non-invasive nature is still debated; the suitability of sophisticated molecular assays to assess the metastatic potential of primary breast carcinomas better than what is currently done; and the need for modifying the scoring criteria of the assays to assess tumor responsiveness to anti-HER2 treatments. PMID- 17714947 TI - The prevalence of intrinsic subtypes and prognosis in breast cancer patients of different races. AB - A recent report indicated that a high prevalence of basal-like breast tumors (estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, human epidermal growth factor receptor [HER] 2-negative, and cytokeratin 5/6-positive and/or HER1-positive) could contribute to a poor prognosis in African American women with breast cancer. It has been reported that Japanese women with breast cancer have a significantly better survival rate than other races in the USA. These findings suggest that breast cancers in Japanese women have favorable biological characteristics. To clarify this hypothesis, we conducted a cohort study to investigate the prevalence of intrinsic subtypes and prognosis for each subtype in 793 Japanese patients. This study revealed a very low prevalence (only 8%) of basal-like breast tumors with aggressive biological characteristics in Japanese patients. Survival analysis showed a significantly poorer prognosis in patients with basal-like tumors than in those with luminal A tumors (ER- and/or PR-positive, and HER2-negative) with favorable biological characteristics. These findings support the hypothesis that breast cancers in Japanese women have more favorable biological characteristics and a better prognosis than those in other races. In conclusion, the prevalence of basal-like breast tumors could influence the prognosis of breast cancer patients of different races. The prevalence of intrinsic subtypes should be taken into account when analyzing survival data in a multi-racial/international clinical study. PMID- 17714948 TI - Breast cancer and pregnancy. AB - The frequency with which breast cancer is diagnosed in pregnant women is low (in the region of 1 in 1000 pregnancies), but the management of these women presents a considerable challenge to those involved in their care. Women frequently present with tumours displaying adverse pathological prognostic features. Initial investigation may be carried out as for non-pregnant women, but with particular attention paid to the risks of exposure to the foetus of ionizing radiation. Surgery can be carried out with seemingly little increased risk to the mother or foetus, but radiotherapy is usually avoided. In terms of short-term complications chemotherapy may be given relatively safely when administered outside of the first trimester and not around the time of delivery. However, the principle concern with all of these interventions is what the long-term implications for the newborn might be. PMID- 17714949 TI - The dilemma of DCIS. AB - The increasingly frequent diagnosis of ductal carcinoma in situ (DCIS) presents a major clinical dilemma. Our inability to predict which DCIS will progress to invasive cancer or the time interval in which recurrent DCIS or invasive cancer will occur has resulted in treatments ranging from mastectomy to excision and observation being offered to patients. Four randomized trials have demonstrated that the use of radiation reduces the risk of local recurrence by about 50% in women with DCIS. Prospective attempts to duplicate retrospective findings that wide excision results in high rates of local control have been unsuccessful. Patient attitudes towards risks and benefits of treatment are an important component of treatment choice in the absence of predictors of biologic behavior. PMID- 17714950 TI - The karyotype and sex chromosomes of Praomys tullbergi (Muridae, Rodentia): a detailed characterization. AB - Here we present the first detailed characterization of Praomys tullbergi karyotype, enlightening several chromosome features such as constitutive heterochromatin, telomeric and LINE-1 sequences. The combination of these approaches provided some interesting insights about the genome organization of this African species, which is one of the tullbergi complex elements, a group of species belonging to Murinae (Rodentia, Muridae). Evolutionary considerations on Praomys chromosomes were also achieved, namely, the autosomal complement and the X chromosome from P. tullbergi seem to be derivative chromosomes, most probably resulting from extensive reshufflings during the course of evolution. This conclusion came from the fact that the majority of the chromosomes telomeric sequences are located interstitially, seeming footprints of evolutionary chromosome rearrangements. The detailed analysis of Praomys tullbergi X chromosome suggests that chromosome rearrangements and/or centromere transpositions and addition/elimination of heterochromatin must have been the main evolutionary events that shaped this chromosome. PMID- 17714951 TI - Benchtop phase-contrast X-ray imaging. AB - Clinical radiography has traditionally been based on contrast obtained from absorption when X-rays pass through the body. The contrast obtained from traditional radiography can be rather poor, particularly when it comes to soft tissue. A wide range of media of interest in materials science, biology and medicine exhibit very weak absorption contrast, but they nevertheless produce significant phase shifts with X-rays. The use of phase information for imaging purposes is therefore an attractive prospect. Some of the X-ray phase-contrast imaging methods require highly monochromatic plane wave radiation and sophisticated X-ray optics. However, the propagation-based phase-contrast imaging method adapted in this paper is a relatively simple method to implement, essentially requiring only a microfocal X-ray tube and electronic detection. In this paper, we present imaging results obtained from two different benchtop X-ray sources employing the free space propagation method. X-ray phase-contrast imaging provides higher contrast in many samples, including biological tissues that have negligible absorption contrast. PMID- 17714953 TI - Antidiabetic effect of Phlomis anisodonta: effects on hepatic cells lipid peroxidation and antioxidant enzymes in experimental diabetes. AB - The present study investigated the effects of aerial parts of Phlomis anisodonta methanolic extract (PAE) on streptozotocin (STZ)-induced diabetic rats by measuring fasting blood glucose, serum insulin, change in body weight, ferric reducing antioxidant power (FRAP), lipid peroxidation (LPO), and liver antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). Male Wistar rats were randomly divided into six groups of six animals. Treatment of diabetic rats with oral administration of PAE at doses of 100, 200 and 400 mg kg(-1) for 10 days resulted in a significant reduction in fasting blood glucose, and an increase in serum insulin levels in comparison with diabetic control group. PAE also protected rats from STZ-induced loss in body weight. Hepatic FRAP increased and LPO in diabetic rats decreased after treatment by PAE at doses of 200 and 400 mg kg(-1). PAE-treated diabetic rats at three doses indicated a significant increase in hepatic SOD, CAT, and GPx activities. These results suggest that PAE is beneficial in the control of diabetes by reduction of blood glucose and increasing insulin levels and combating oxidative stress by activation of hepatic antioxidant enzymes. PMID- 17714952 TI - Abnormal glutamate homeostasis and impaired synaptic plasticity and learning in a mouse model of tuberous sclerosis complex. AB - Mice with inactivation of the Tuberous sclerosis complex-1 (Tsc1) gene in glia (Tsc1 GFAP CKO mice) have deficient astrocyte glutamate transporters and develop seizures, suggesting that abnormal glutamate homeostasis contributes to neurological abnormalities in these mice. We examined the hypothesis that Tsc1 GFAP CKO mice have elevated extracellular brain glutamate levels that may cause neuronal death, abnormal glutamatergic synaptic function, and associated impairments in behavioral learning. In vivo microdialysis documented elevated glutamate levels in hippocampi of Tsc1 GFAP CKO mice and several cell death assays demonstrated neuronal death in hippocampus and neocortex. Impairment of long-term potentiation (LTP) with tetanic stimulation was observed in hippocampal slices from Tsc1 GFAP CKO mice and was reversed by low concentrations of NMDA antagonist, indicating that excessive synaptic glutamate directly inhibited LTP. Finally, Tsc1 GFAP CKO mice exhibited deficits in two hippocampal-dependent learning paradigms. These results suggest that abnormal glutamate homeostasis predisposes to excitotoxic cell death, impaired synaptic plasticity and learning deficits in Tsc1 GFAP CKO mice. PMID- 17714954 TI - The fine transformation between the oxidized and reduced forms of interleukin-1 receptor antagonist. AB - The active and pure recombinant forms of human interleukin-1 receptor antagonist (rHIL-1ra) were obtained from inclusion body expressed in Escherichia coli BL21 (DE3). However, the final purified protein was found to be in an unstable reduced form and easily converted to the other forms. Which form of the protein was involved and precisely how this occurred remained obscure. Therefore, we changed oxidizing and reducing conditions to delineate the subtle change between the reduced and oxidized states of rHIL-1ra based on high-pressure liquid chromatography (HPLC). The fine transformation between the two states was further verified through matrix-assisted laser desorption-ionization time of flight (MALDI-TOF) mass spectroscopy. Meanwhile, which form might be beneficial to the protein was also investigated by testing its full bioactivity based upon methyl thiazolyl tetrazolium (MTT) method. PMID- 17714955 TI - Neural correlates of object indeterminacy in art compositions. AB - Indeterminate art invokes a perceptual dilemma in which apparently detailed and vivid images resist identification. We used event-related fMRI to study visual perception of representational, indeterminate and abstract paintings. We hypothesized increased activation along a gradient of posterior-to-anterior ventral visual areas with increased object resolution, and postulated that object resolution would be associated with visual imagery. Behaviorally, subjects were faster to recognize familiar objects in representational than in both indeterminate and abstract paintings. We found activation within a distributed cortical network that includes visual, parietal, limbic and prefrontal regions. Representational paintings, which depict scenes cluttered with familiar objects, evoked stronger activation than indeterminate and abstract paintings in higher tier visual areas. Perception of scrambled paintings was associated with imagery related activation in the precuneus and prefrontal cortex. Finally, representational paintings evoked stronger activation than indeterminate paintings in the temporoparietal junction. Our results suggest that perception of familiar content in art works is mediated by object recognition, memory recall and mental imagery, cognitive processes that evoke activation within a distributed cortical network. PMID- 17714956 TI - Divergence times in the termite genus Macrotermes (Isoptera: Termitidae). AB - The evolution of fungus-growing termites is supposed to have started in the African rain forests with multiple invasions of semi-arid habitats as well as multiple invasions of the Oriental region. We used sequences of the mitochondrial COII gene and Bayesian dating to investigate the time frame of the evolution of Macrotermes, an important genus of fungus-growing termites. We found that the genus Macrotermes consists of at least 6 distantly related clades. Furthermore, the COII sequences suggested some cryptic diversity within the analysed African Macrotermes species. The dates calculated with the COII data using a fossilized termite mound to calibrate the clock were in good agreement with dates calculated with COI sequences using the split between Locusta and Chortippus as calibration point which supports the consistency of the calibration points. The clades from the Oriental region dated back to the early Tertiary. These estimates of divergence times suggested that Macrotermes invaded Asia during periods with humid climates. For Africa, many speciation events predated the Pleistocene and fall in range of 6-23 million years ago. These estimates suggest that savannah adapted African clades radiated with the spread of the semi-arid ecosystems during the Miocene. Apparently, events during the Pleistocene were of little importance for speciation within the genus Macrotermes. However, further investigations are necessary to increase the number of taxa for phylogenetic analysis. PMID- 17714957 TI - Contribution of collagen network features to functional properties of engineered cartilage. AB - BACKGROUND: Damage to articular cartilage is one of the features of osteoarthritis (OA). Cartilage damage is characterised by a net loss of collagen and proteoglycans. The collagen network is considered highly important for cartilage function but little is known about processes that control composition and function of the cartilage collagen network in cartilage tissue engineering. Therefore, our aim was to study the contribution of collagen amount and number of crosslinks on the functionality of newly formed matrix during cartilage repair. METHODS: Bovine articular chondrocytes were cultured in alginate beads. Collagen network formation was modulated using the crosslink inhibitor beta aminopropionitrile (BAPN; 0.25mM). Constructs were cultured for 10 weeks with/without BAPN or for 5 weeks with BAPN followed by 5 weeks without. Collagen deposition, number of crosslinks and susceptibility to degradation by matrix metalloproteinase-1 (MMP-1) were examined. Mechanical properties of the constructs were determined by unconfined compression. RESULTS: BAPN for 5 weeks increased collagen deposition accompanied by increased construct stiffness, despite the absence of crosslinks. BAPN for 10 weeks further increased collagen amounts. Absence of collagen crosslinks did not affect stiffness but ability to hold water was lower and susceptibility to MMP-mediated degradation was increased. Removal of BAPN after 5 weeks increased collagen amounts, allowed crosslink formation and increased stiffness. DISCUSSION: This study demonstrates that both collagen amounts and its proper crosslinking are important for a functional cartilage matrix. Even in conditions with elevated collagen deposition, crosslinks are needed to provide matrix stiffness. Crosslinks also contribute to the ability to hold water and to the resistance against degradation by MMP-1. PMID- 17714958 TI - Origin of diplochromosomal polyploidy in near-senescent fibroblast cultures: heterochromatin, telomeres and chromosomal instability (CIN). AB - The near-senescence associated phenomena of increases in cells with chromosomal damage (CIN) and in endopolyploid mitotic cells were analyzed for possible inter relationships by cytogenetics. Gross chromosomal abnormalities in all phases of mitosis were analyzed in situ. Hetrochromatization of telomeres, centromeres and interstitial chromatin regions (i.e., chromocenters/SAHF) were shown to be specific occurrences in the near-senescent phase. Stickiness between such chromatin regions caused breakage/fragmentation by anaphase-pulls on clumped chromosomes. Gluey heterochromatin is therefore, seen as a cause of CIN in near senescence. Detrimental effects on chromosomes from heterochromatin have been observed for decades, and can be explained from chromatin remodeling in epigenetics. A consequence of genomic damage was re-replication to polyploidy of arrest-escaped cells with G2/M-DNA content. This second synthetic period produced diplochromosomal cells that cycled by bi-polar division into genome reduced cells. This sequence from h-chromatization to CIN and further to cycling endopolyploidy is believed to be a basic mechanism for the production of genetic variability in neoplasia. PMID- 17714959 TI - BRS-3 activation transforms the effect of human bronchial epithelial cells from PGE2 mediated inhibition to TGF-beta1 dependent promotion on proliferation and collagen synthesis of lung fibroblasts. AB - Airway re-modelling in asthma usually results in an irreversible weakness of pulmonary ventilation, however, its initiating or controlling mechanism remains unclear. In this study, we hypothesize that signal communication between airway epithelial cells and sub-mucosal fibroblast cells may play an important role in the maintenance of structure homeostasis in a physiologic condition and in initiation of airway remodelling in a stressed condition. To test the hypothesis, a co-cultured system of human bronchial epithelial cells (BEC) and human lung fibroblasts (HLF) were designed to observe the effects of BEC, in the normal state or in a BRS-3 activated state, on the proliferation and collagen synthesis of HLF. The results showed that the proliferation activities of both BEC and HLF inhibited each other under the normal state. BRS-3-activated BEC can transform the reciprocal inhibition into promoting effects. The secretion of TGF-beta1 increased and the synthesis of PGE2 decreased from BRS-3-activated BEC, which were correlated with the proliferation and collagen synthesis of HLF. The proliferation activities of HLF were weakened by co-culture with TGF-beta1 antisense oligonucleotides (ASO) treated BEC. It was concluded that, in the normal state, BEC inhibits the activities of fibroblasts through release of PGE2 to maintain the airway homeostasis; however when stressed, for example by BRS-3 activation, BEC promote the activities of fibroblasts mediated by TGF-beta1, thereby facilitating the airway re-modelling. PMID- 17714961 TI - Aortic paraprosthetic-colonic fistulae: a review of the literature. AB - BACKGROUND: Aortic graft-colonic fistulae are a rare complication of aortic reconstructive surgery. METHODS AND FINDINGS: A comprehensive review of this entity was performed based on the available literature from 1950 until 2006. Available reports were analyzed with respect to demographics, prior surgical intervention and its indication, prosthetic material used during the initial intervention, clinical presentation, the time interval in between the initial operation and symptoms, the method of treatment of the aortic graft-colonic fistula and its outcome. PMID- 17714960 TI - Enhanced cognitive activity--over and above social or physical activity--is required to protect Alzheimer's mice against cognitive impairment, reduce Abeta deposition, and increase synaptic immunoreactivity. AB - Although social, physical, and cognitive activities have each been suggested to reduce the risk of Alzheimer's disease (AD), epidemiologic studies cannot determine which activity or combination of activities is most important. To address this question, mutant APP transgenic AD mice were reared long-term in one of four housing conditions (impoverished, social, social+physical, or complete enrichment) from 1(1/2) through 9 months of age. Thus, a stepwise layering of social, physical, and enhanced cognitive activity was created. Behavioral evaluation in a full battery of sensorimotor, anxiety, and cognitive tasks was carried out during the final 5 weeks of housing. Only AD mice raised in complete enrichment (i.e., enhanced cognitive activity) showed: (1) protection against cognitive impairment, (2) decreased brain beta-amyloid deposition, and (3) increased hippocampal synaptic immunoreactivity. The protection provided by enhanced cognitive activity spanned multiple cognitive domains (working memory, reference learning, and recognition/identification). Cognitive and neurohistologic benefits of complete enrichment occurred without any changes in blood cytokine or corticosterone levels, suggesting that enrichment-dependent mechanisms do not involve changes in the inflammatory response or stress levels, respectively. These results indicate that the enhanced cognitive activity of complete enrichment is required for cognitive and neurologic benefit to AD mice physical and/or social activity are insufficient. Thus, our data suggest that humans who emphasize a high lifelong level of cognitive activity (over and above social and physical activities) will attain the maximal environmental protection against AD. PMID- 17714963 TI - Ischaemic rest pain of the head: a case report. AB - A 54-year-old man presented with a 3-year history of rest pain of an ischaemic scalp ulcer. Angiography demonstrated that the only blood supply to his head was the left internal carotid artery. Stenting the left subclavian artery and subsequently allowing flow into his left vertebral artery alleviated his symptoms. PMID- 17714964 TI - Fracture resistance of roots obturated with three different materials. AB - OBJECTIVE: The aim of this study was to compare the fracture resistance of roots obturated with different materials. STUDY DESIGN: Sixty root canals were instrumented and divided into 4 equal groups (n = 15 each). The root canals in group 1 were filled with AH26 sealer and gutta-percha, in group 2 with Resilon and Epiphany, and in group 3 with Ketac-Endo Aplicap and gutta-percha. Fifteen root canals had no obturation. The force required to fracture was recorded. The data was analyzed with analysis of variance and Duncan test. RESULTS: The mean force of fracture for group 1 was significantly higher than for the other 3 groups (P < .05). There was significant difference between group 2 and group 3 (P < .05). Group 2 and group 3 were not significantly different from the control group (P > .05). CONCLUSION: The use of AH26 + gutta-percha increased the fracture resistance of instrumented root canals compared with Resilon + Epiphany and Ketac-Endo Aplicap + gutta-percha. PMID- 17714965 TI - Nitrogen-14 nuclear quadrupole resonance (NQR): dramatic sensitivity enhancement by large and fast temperature lowering. AB - We have observed that, when going rapidly from ambient temperature down to liquid nitrogen temperature, the nitrogen-14 NQR signal (for transitions involving the m=0 spin state, nitrogen-14 being a quadrupolar nucleus of spin I=1) is increased by a factor of ca. 10(2). While Boltzmann statistics cannot explain this enhancement, the strong temperature dependence of the quadrupolar interaction is very likely to be at the origin of this phenomenon. Indeed, the quadrupolar Hamiltonian becomes time dependent and is prone to induce transitions toward the spin state associated with m=0. Its binding and slow relaxing properties result in a durable increased population and consequently in an increased intensity of NQR lines originating from the state m=0. PMID- 17714966 TI - Use of serum insulin-like growth factor-I levels to predict psychiatric non response to donepezil in patients with Alzheimer's disease. AB - OBJECTIVE: Insulin-like growth factor-I (IGF-I) deficiency may be involved in cognitive deficits seen with aging and in neurodegenerative diseases such as Alzheimer's disease (AD). This study was aimed at investigating whether non responder to donepezil could be predicted using decreased serum levels of IGF-I in AD patients. DESIGN: This study involved 106 elderly subjects: 50 patients with AD and 56 age-matched controls without dementia. In patients with AD, donepezil was given orally 3 mg/day for 4 weeks and 5 mg/day for another 12 weeks. AD patients were divided into responders and non-responders based on the changes in mini-mental state examination (MMSE) scores before and 16 weeks after treatment with donepezil. Serum levels of IGF-I and atherogenic biomarkers were determined. RESULTS: Before treatment with donepezil, there was a significant positive correlation between serum IGF-I levels and the MMSE scores in all subjects. Serum IGF-I levels and the MMSE scores were significantly lower in AD patients than in non-demented controls and were the lowest in non-responders to donepezil. Atherogenic biomarkers (LDL cholesterol, triglycerides, lipoprotein(a), lipid peroxide, apolipoprotein E, and glucose levels) did not differ significantly among these groups. On multiple logistic regression, non responders to donepezil showed decreased serum IGF-I levels <110 ng/ml and MMSE scores <15 points before treatment. CONCLUSIONS: These findings suggest that decreased levels of serum IGF-I combined with MMSE scores before treatment could predict non-responders to donepezil among AD patients, which may be a simple and practical method for selecting patients expected to show a response to treatment. PMID- 17714967 TI - Relationship between GH-induced metabolic changes and changes in body composition: a dose and time course study in GH-deficient adults. AB - OBJECTIVE: Although growth hormone (GH)-induced changes in fat and protein metabolism are likely to underlie changes in body composition, the relationship has not been clearly defined. The aim was to study the effects of dose and time course on substrate metabolism and relate to body compositional changes during GH treatment. DESIGN: In an open randomised-controlled study, 16 GH-deficient adults were randomised to treatment with GH 3 microg/kg/d (low dose, n=6) or 6 microg/kg/d (higher dose, n=10) for 12 weeks. Changes in whole body protein metabolism, estimated using the leucine turnover technique, and resting energy expenditure (REE) were assessed after short-term GH (two weeks) and longer-term GH (12 weeks). Changes in lean body mass (LBM) and fat mass (FM) over 12 weeks were assessed by DXA. RESULTS: The maximal changes in leucine oxidation (Lox) ( 3.9+/-1.1 versus +0.8+/-1.8 micromol/min, p=0.03) and REE (+132+/-36 versus -28+/ 41 kcal/d, p=0.01) were significantly greater in the higher, than the low dose group. FM fell (-1.4+/-0.4 kg, p=0.005) and LBM increased (+2.2+/-0.7 kg, p=0.01) significantly in the higher dose group only. The acute reduction in Lox at two weeks in the higher dose group was no longer significant after 12 weeks. The change in Lox after two (r=-0.53, p=0.035), but not 12, weeks was significantly correlated with the change in LBM. CONCLUSIONS: GH-induced changes in protein metabolism were influenced by the dose and duration of GH treatment. Suppression of protein oxidation occurred soon after initiation of GH in the higher dose group and predicted a later gain in LBM. Early assessment of whole body protein metabolism may allow prediction of the anabolic potential of GH. PMID- 17714968 TI - Clinical investigation of the transient evoked otoacoustic emission test in Crimean-Congo hemorrhagic fever. AB - OBJECTIVE: The aim of this study was to investigate cochlear damage in Crimean Congo hemorrhagic fever (CCHF) infection. METHODS: Thirty-two CCHF patients (study group) and 13 healthy people (controls) were included in the study. CCHF patients were also grouped for the presence of fever. CCHF was diagnosed with the presence of CCHF virus-specific IgM antibody or CCHF virus (CCHFV) antigen by ELISA. Cochlear damage was determined by a 'fail' in the transient evoked otoacoustic emission (TEOAE) test. RESULTS: The proportion of TEOAE test 'fail' results in the CCHF patients was significantly higher than in the control group (p<0.05). We found no increase in the proportion of TEOAE test 'fail' results related to fever in the study group. CONCLUSIONS: CCHF disease damages cochlear function regardless of fever. PMID- 17714969 TI - Tungiasis: consequences of delayed presentation/diagnosis. PMID- 17714970 TI - Maxillofacial Rosai-Dorfman disease in a newly diagnosed HIV-infected patient. PMID- 17714971 TI - [Extramedullary haematopoiesis: report of two cases]. AB - Extramedullary haematopoiesis is a physiologic response to chronic anaemia, commonly observed in various haematological disorders. This phenomenon is habitually asymptomatic but it may induce compression of adjacent organs such as the spinal cord. We present the cases of two patients suffering from chronic anaemia, who developed foci of ectopic hematopoiesis, and we discuss through a review of literature, the presentation and the management of this disease, with focus on the role of decompressive radiotherapy. PMID- 17714973 TI - [Pathogenesis of endometriosis]. AB - Endometriosis, defined by the development of endometrial tissue outside the uterus, is a benign disease responsible for infertility and pelvic pain. The diagnosis based on a detailed gynecological history and a careful clinical examination should be done as early as possible in order to treat patients correctly. Medical treatment is not appropriate in all cases and surgical treatment should be proposed but morbidity is related to the severity of the lesion. Ectopic implantation of endometrial cells needs complex interactions between host tissue and epithelial endometrial cells. The conditions for the development of endometriosis are estrogeno-dependent growth of endometrial cells, induction of angiogenesis and lymphangiogenesis. Principal cellular and molecular factors of angiogenesis, lymphangiogenesis and fibrosis should be identified in order to develop new therapeutic strategies of endometriosis. PMID- 17714972 TI - The inflammasome, autoinflammatory diseases, and gout. AB - IL-1beta is a cytokine with major roles in inflammation and innate immune responses. IL-1beta is produced as an inactive proform that must be cleaved within the cell to generate biologically active IL-1beta. The enzyme caspase-1 catalyzes the reaction. Recent work showed that caspase-1 must be activated by a complex known as the inflammasome. The inflammasome comprises NALP, which is an intracellular receptor involved in innate immunity, and an ASC adapter that ensures caspase-1 recruitment to the receptor. The most extensively described inflammasome to date is formed by the NALP3 receptor within monocytes. Mutations involving the NALP3 gene cause hereditary periodic fever syndromes in humans. Increased inflammasome activity responsible for uncontrolled IL-1beta production occurs in these syndromes. Inhibition of the IL-1beta pathway by IL-1 receptor antagonist (anakinra) is a highly effective treatment for inherited periodic fever syndromes. A major role for inflammasome activity in the development of gout attacks was established recently. Urate monosodium crystals are specifically detected via the NALP3 inflammasome, which results in marked IL-1beta overproduction and initiation of an inflammatory response. This finding opens up new possibilities for the management of gouty attacks. PMID- 17714975 TI - Computational representation and hemodynamic characterization of in vivo acquired severe stenotic renal artery geometries using turbulence modeling. AB - The present study reports on computational fluid dynamics in the case of severe renal artery stenosis (RAS). An anatomically realistic model of a renal artery was reconstructed from CT scans, and used to conduct CFD simulations of blood flow across RAS. The recently developed shear stress transport (SST) turbulence model was pivotally applied in the simulation of blood flow in the region of interest. Blood flow was studied in vivo under the presence of RAS and subsequently in simulated cases before the development of RAS, and after endovascular stent implantation. The pressure gradients in the RAS case were many orders of magnitude larger than in the healthy case. The presence of RAS increased flow resistance, which led to considerably lower blood flow rates. A simulated stent in place of the RAS decreased the flow resistance at levels proportional to, and even lower than, the simulated healthy case without the RAS. The wall shear stresses, differential pressure profiles, and net forces exerted on the surface of the atherosclerotic plaque at peak pulse were shown to be of relevant high distinctiveness, so as to be considered potential indicators of hemodynamically significant RAS. PMID- 17714974 TI - Adaptive computation of approximate entropy and its application in integrative analysis of irregularity of heart rate variability and intracranial pressure signals. AB - The present study introduces an adaptive calculation of approximate entropy (ApEn) by exploiting sample-by-sample construction and update of nearest neighborhoods in an n-dimensional space. The algorithm is first validated with a standard numerical test set. It is then applied to electrocardiogram R wave interval (RR) and beat-to-beat intracranial pressure signals recorded from 12 patients undergoing normal pressure hydrocephalus diagnosis. The ApEn time series are further processed using the causal coherence analysis to study the interaction between ICP and RR interval. Numerical validation demonstrates that the proposed algorithm reproduces the known time-varying patterns in the test set and better tracks abrupt signal changes. It is also demonstrated that occurrences of large-amplitude ICP oscillation are associated with decreased ICP ApEn and RR ApEn for all 12 patients. The causal coherence analysis of ApEn time series shows that coherence between RR ApEn and ICP ApEn, after mathematically decoupling RR effect on ICP, is enhanced for the oscillatory ICP state and so is the amplitude of transfer function between ICP and RR interval. However, no enhanced coherence is observed after mathematically decoupling ICP effect on RR interval. In conclusion, the adaptive ApEn algorithm can be used to track nonstationary signal characteristics. Furthermore, interactions between dynamic systems could be studied by using ApEn time series of the direct observations of systems. PMID- 17714977 TI - Good clinical practice in orthokeratology. AB - Overnight orthokeratology is becoming more and more popular especially in the Asia-Pacific region where the treatment is primarily used for myopic control in young children. Risk of complications in contact lens wear increases during overnight wear and may further increase when the treatment is used on children. The aim of this paper is to provide a comprehensive guideline for practitioners to improve their orthokeratology practice and minimize unnecessary or preventable complications. The fundamental requirement for starting an orthokeratology practice is to have proper education in the area and to equip the practice appropriately. Overnight trial fitting is recommended to confirm the physiological response prior to commencement of the treatment. Practitioners should provide adequate information, both oral and written, to patients before and after the commencement of treatment to avoid any legal dilemmas and to improve patients' compliance. Costs for the treatment should be transparent and provision of an emergency contact number is a must. Patients should be regularly recalled for aftercare visits and all communication with patients should be properly documented. In this paper, patient selection and the clinical procedures were discussed and a standard of practice in orthokeratology proposed. We believe that the key to providing a safe orthokeratology practice is to continually update knowledge in the field, and to practice to the highest professional standards. PMID- 17714976 TI - Iron metabolism at the host pathogen interface: lipocalin 2 and the pathogen associated iroA gene cluster. AB - The host innate immune defense protein lipocalin 2 binds bacterial enterobactin siderophores to limit bacterial iron acquisition. To counteract this host defense mechanism bacteria have acquired the iroA gene cluster, which encodes enzymatic machinery and transporters that revitalize enterobactin in the form of salmochelin. The iroB enzyme introduces glucosyl residues at the C5 site on 2,3 dihydroxybenzoylserine moieties of enterobactin and thereby prevents lipocalin 2 binding. Additional strategies to evade lipocalin 2 have evolved in other bacteria, such as Mycobacteria tuberculosis and Bacillus anthracis. Targeting these specialized bacterial evasion strategy may provide a mechanism to reinvigorate lipocalin 2 in defense against specific pathogens. PMID- 17714978 TI - Comment on "the flow cytometric analysis of premalignant and malignant lesions in head and neck squamous cell carcinoma" [Kamal-Eldin Ahmed Abou-Elhamd and Tito Naeem Habib. Oral Oncol 2007;43(4):366-72]. PMID- 17714980 TI - Virus-host interactions in salt lakes. AB - Natural hypersaline waters are widely distributed around the globe, as both continental surface waters and sea floor lakes, the latter being maintained by the large density difference between the hypersaline and overlying marine water. Owing to the extreme salt concentrations, close to or at saturation (approximately 35%, w/v), such waters might be expected to be devoid of life but, in fact, maintain dense populations of microbes. The majority of these microorganisms are halophilic prokaryotes belonging to the Domain Archaea, 'haloarchaea'. Viruses infecting haloarchaea are a vital part of hypersaline ecosystems, in many circumstances outnumbering cells by 10-100-fold. However, few of these 'haloviruses' have been isolated and even fewer have been characterised in molecular detail. In this review, we explore the methods used by haloviruses to replicate within their hosts and consider the implications of haloviral haloarchaeal interactions for salt lake ecology. PMID- 17714981 TI - Competitive cesium-133 NMR spectroscopic study of complexation of different metal ions with dibenzo-21-crown-7 in acetonitrile-dimethylsulfoxide and nitromethane dimethylsulfoxide mixtures. AB - (133)Cs NMR spectroscopy was used to determine the stoichiometry and stability of the Cs(+) ion complex with dibenzo-21-crown-7 (DB21C7) in acetonitrile dimethylsulfoxide (96.5:3.5, w/w) and nitromethane-dimethylsulfoxide (96.5:3.5, w/w) mixtures. A competitive (133)Cs NMR technique was also employed to probe the complexation of Na(+), K(+), Rb(+), Ag(+), Tl(+), NH(4)(+), Mg(2+), Ba(2+), Hg(2+), Pb(2+) and UO(2)(2+) ions with DB21C7 in the same solvent systems. All the resulting 1:1 complexes in nitromethane-dimethylsulfoxide were more stable than those in acetonitrile-dimethylsulfoxide solution. In both solvent systems, the stability of the resulting complexes was found to vary in the order Rb(+)>K(+) approximately Ba(2+)>Tl(+)>Cs(+)>NH(4)(+) approximately Pb(2+)>Ag(+)>UO(2)(2+)>Hg(2+)>Mg(2+)>Na(+). PMID- 17714979 TI - Is phage DNA 'injected' into cells--biologists and physicists can agree. AB - The double-stranded DNA inside bacteriophages is packaged at a density of approximately 500 mg/ml and exerts an osmotic pressure of tens of atmospheres. This pressure is commonly assumed to cause genome ejection during infection. Indeed, by the addition of their natural receptors, some phages can be induced in vitro to completely expel their genome from the virion. However, the osmotic pressure of the bacterial cytoplasm exerts an opposing force, making it impossible for the pressure of packaged DNA to cause complete genome ejection in vivo. Various processes for complete genome ejection are discussed, but we focus on a novel proposal suggesting that the osmotic gradient between the extracellular environment and the cytoplasm results in fluid flow through the phage virion at the initiation of infection. The phage genome is thereby sucked into the cell by hydrodynamic drag. PMID- 17714982 TI - Solvent effects on the absorption and fluorescence spectra of some laser dyes: estimation of ground and excited-state dipole moments. AB - The absorption and fluorescence spectra of three extensively used laser dyes namely 1,1,4,4-tetraphenyl-1,3-butadiene (TPB), 2-(4'-t-butylphenyl)-5-(4'' biphenylyl)-1-oxa-3,4-diazole (BPBD), 1,4-bis[2-(2-methylphenyl)ethenyl]-benzene (Bis-MSB) have been recorded at room temperature (300K) in solvents of different polarities. The effects of the solvents upon the spectral properties are discussed. The ground-state dipole moments (mu(g)) were determined experimentally by Guggenheim and Higasi method separately and were compared with theoretical values obtained using quantum chemical method. The ground-state dipole moments obtained by using Guggenheim method were then used in the estimation of excited state dipole moments (mu(e)) by using Lippert's, Bakhshiev's and Kawski-Chamma Viallet's equations. In all the above three equations the variation of the Stokes shift with the solvent dielectric constant and refractive index was made use of. It was observed that dipole moments of excited state were higher than those of the ground state for all the dyes. PMID- 17714983 TI - The risk of using the Internet as reference resource: a comparative study. AB - OBJECTIVE: We sought to examine the frequency and the specific problems encountered in accessing Internet references in two leading medical journals during the last 3 years. METHODS: Two investigators independently reviewed all publications in the issues of the New England Journal of Medicine and The Lancet during October 2005 to March 2006, November 2004 to January 2005, and November 2003 to January 2004. We calculated the total number of references and the subset referred to an Internet source of each article. Then, we visited the electronic sources to identify the Internet references and noted the problems of accessibility, if any. When we failed to directly access the reference in the electronic address provided by the authors, we visited the referred website; if this was also inadequate, we performed Google searches to retrieve the missing reference(s). RESULTS: 465/18,850 (2.5%) and 952/24,630 (3.9%) of the reviewed references in the New England Journal of Medicine and The Lancet, respectively, referred to Internet sources; from these we could not access 68/465 (14.6%) and 170/952 (17.9%) in the two journals, respectively. There were increasing proportions of lost Internet references as they age. Searching into the website referred by the authors of the reviewed articles could not provide the missing information in a considerable proportion (62.2%). However, the use of an Internet search engine (Google) helped us to identify references in other websites, reducing the proportion of missing Internet references to 17/465 (3.7%) and 17/952 (1.8%) for the two journals, respectively. CONCLUSIONS: The response "page not found" was commonly encountered when we tried to access Internet references in publications of leading medical journals during the last 3 years. A considerable proportion of missing references was identified with the use of Google search engine. Authors of scientific articles should be aware of the problem of missing Internet references and until well-established Internet archiving solutions are in use, they should choose carefully their Internet references from reliable websites whenever it is impossible to avoid using them. PMID- 17714984 TI - Development and evaluation of real-time PCR assays for the detection of the newly identified KI and WU polyomaviruses. AB - BACKGROUND: Recently, novel human polyomaviruses, KI (KIV) and WU (WUV) were described. Their role in human disease has not yet been determined. OBJECTIVES: The aim of this study was to develop sensitive and specific assays for the detection of KIV and WUV. STUDY: Two KIV (KI-A and KI-B) and three WUV (WU-A, WU B and WU-C) real-time polymerase chain reaction (rtPCR) assays were developed and evaluated. Clinical sensitivities and specificities were determined by testing 200 respiratory specimens and the results compared to those for previously described conventional PCR assays. Limits of detection were determined, and the analytical specificities of the assays were investigated. RESULTS: No cross reactivity was observed between the rtPCR methods and unrelated organisms. All five rtPCR assays could reliably detect 10 copies of genomic DNA equivalents per reaction, which was more sensitive than conventional methods. Compared to the conventional PCR assays, the sensitivity of the KI-A, KI-B, WU-A, WU-B and WU-C assays was 100%, 86.7% 95.5%, 100% and 100%, respectively. Specificity was 94.6%, 97.3%, 96.6%, 97.7% and 97.2%, respectively. CONCLUSIONS: The KI-A, WU-B and WU-C assays provide the most sensitive detection of KIV and WUV in clinical specimens and may be used for further research into these viruses. PMID- 17714985 TI - N1 and P2 components of auditory event-related potentials in children with and without reading disabilities. AB - OBJECTIVE: The effects of within stimulus presentation rate and rise time on basic auditory processing were investigated in children with reading disabilities and typically reading children. METHODS: Children with reading disabilities (RD; N=19) and control children (N=20) were studied using event-related potentials (ERPs). Paired stimuli were used with two different within-pair-intervals (WPI; 10 and 255 ms) and two different rise times (10 and 130 ms). Each stimulus was presented with equal probability and long between-pair inter-stimulus intervals (1-5s). The study focused on N1 and P2 components. RESULTS: The P2 responses to the first tone in the pair showed differences between children with RD and control children. Also, children with RD had larger N1 response than control children to stimuli with short WPI and long rise time. CONCLUSIONS: These results provide evidence for basic auditory processing abnormalities in children with RD. This processing difference could be related to extraction of stimulus features from sounds or to attentional mechanisms. SIGNIFICANCE: Our results show support for behavioral findings that children with RD and control children process rise times differently. More than half of children with RD showed atypical auditory processing. PMID- 17714986 TI - Effect of pinching-evoked pain on jaw-stretch reflexes and exteroceptive suppression periods in healthy subjects. AB - OBJECTIVE: To investigate the influence of conditioning cutaneous nociceptive inputs by a new "pinch" model on the jaw-stretch reflex and the exteroceptive suppression periods (ES1 and ES2) in jaw muscles. METHODS: The jaw-stretch reflex was evoked with the use of a custom-made muscle stretcher and electrical stimuli were used to evoke an early and late exteroceptive suppression period (ES1 and ES2) in the jaw-closing muscles. Electromyographic (EMG) activity was recorded bilaterally from the masseter and temporalis muscles. These brainstem reflexes were recorded in 19 healthy men (28.8+/-1.1 years) during three different conditions: one painful clip applied to the earlobe; one painful clip applied to the nostril, and four painful clips applied simultaneously to the earlobe, nostril, eyebrow, and lower lip. Pain intensity induced by the application of the clips was scored continuously by the subjects on a 100mm visual analogue scale (VAS). RESULTS: The highest VAS pain scores were evoked by placement of four clips (79+/-0.5mm). There was no significant modulation of the jaw-stretch reflex (ANOVAs: P=0.929), the ES1 (P=0.298) or ES2 (P=0.082) in any of the three painful conditions. CONCLUSIONS: Intense and tonic cutaneous pain could be elicited by this new "pinch" pain model; however, there was no significant modulation on either excitatory or inhibitory brainstem reflex responses. SIGNIFICANCE: The novel observation that high-intensity pinch stimuli applied to the craniofacial region fail to modulate two different brainstem reflexes is in contrast to other experimental pain studies documented facilitation of the jaw-stretch reflexes or inhibition of exteroceptive suppression periods. The clinical implication of the present findings is that only some craniofacial pain conditions could be expected to show perturbation of the brainstem reflex responses. PMID- 17714988 TI - Helicobacter pylori vaccine development: optimisation of strategies and importance of challenging strain and animal model. AB - Gastric infection with the gram-negative bacterial pathogen Helicobacter pylori is widespread (approximately 50% of the human population is affected) and is associated with the induction of specific gastroduodenal disease. Although extensive studies in the H. pylori mouse model have demonstrated the feasibility of both therapeutic and prophylactic immunisations, the mechanism of vaccine induced protection is still poorly understood. We report here on novel strategies to optimise the generation of H. pylori ghosts as vaccine candidates and highlight the need to concentrate on alternative animal models and the use of fully virulent H. pylori type I strains for vaccination. An effective vaccine strategy against H. pylori has the potential to significantly improve population health worldwide. PMID- 17714987 TI - An open study of repetitive transcranial magnetic stimulation in treatment resistant depression with Parkinson's disease. AB - OBJECTIVE: Major depression is a common concomitant of chronic central nervous system disorders, notably Parkinson's disease (PD). Repetitive transcranial magnetic stimulation (rTMS) has been investigated as a potential treatment for depression in PD and for the movement disorder of PD, but comprehensive testing in multiple areas of performance has seldom been carried out within a single study. We studied the effect of left dorsolateral prefrontal rTMS on several different functional domains. METHODS: Fourteen PD patients with treatment resistant depression entered an open, 10-day inpatient study of 10-Hz rTMS, undergoing extensive psychiatric, neuropsychological, and motor testing from baseline to 6 weeks after treatment. Motor testing included a defined "off" state. RESULTS: rTMS was well tolerated. Highly significant improvement in depression scores was seen 3 days and 3-6 weeks after treatment. Improvement was also found in anxiety, movement scores (especially in the off state), and some neuropsychological measures. We found no evidence of increased risk from rTMS in this population. CONCLUSIONS: Further controlled trials of rTMS in PD appear worthwhile, and should include a defined "off" state. SIGNIFICANCE: TMS may be beneficial for depressed PD patients in multiple functional domains. PMID- 17714989 TI - Physiological demands of basketball refereeing during international competition. AB - To date, the physiological effects of elite competition on basketball players have been reported while very little information exists concerning the effects of elite competition on referees. Therefore, the aim of this study was to examine the physiological demands of basketball refereeing during international competition. Seven elite basketball referees volunteered for this study during a pre-Olympic women's basketball tournament. During each of the eight tournament matches, heart rate (HR), relative exercise intensity as a percentage of age predicted maximum HR (HR(max)), proportion of match time within the ACSM-defined exercise intensity categories were recorded for each referee during each quarter of and the entire match. Comparisons between quarters for each variable were conducted using one-way ANOVAs. There were no significant differences between quarters for any variable. Referees, using a two-referee per match format, worked at an average HR of 150bpm (range 110-181bpm) for each quarter of the match, equating to a relative intensity of >70% HR(max) for the majority ( approximately 76%) of each quarter. Basketball refereeing during international competition results in significant physiological exertion at relatively high exercise intensities for Australian referees. Further studies will assist in the development of appropriate training programs for elite basketball referees to maintain and/or maximise performance. PMID- 17714990 TI - The acute effect of vibration exercise on concentric muscular characteristics. AB - This study was designed to compare the acute effect of vibration exercise with a concentric-only activity (arm cranking) on concentric-only muscle action using an upper body isoinertial exercise. Twelve healthy, physically active men, 30.0y+/ 6.1 (mean+/-S.D.); height 1.81m+/-0.06; and weight 83.4kg+/-9.7, performed four maximal prone bench pull (PBP) efforts before and after a 5-min period of three different interventions: (1) acute vibration exercise (VBX); (2) arm cranking (AC); and (3) control (no exercise) (NVBX). Electromyography (EMG) activity was assessed from the middle trapezius muscle during PBP. Acute VBX was induced with an electric-powered dumbbell (DB) (frequency 26Hz, amplitude 3mm), with 30-s exposures at five different shoulder positions. NVXB was performed with the participants holding the DB with the machine turned off, and AC was performed at 25W. There was a significant (intervention x pre-post) interaction such that acute VBX and AC enhanced peak power by 4.8% (p<0.001) and 3.0% (p<0.001), respectively, compared to NVBX (-2.7%). However, there was no effect of any treatments on EMG activity compared to the control. In conclusion, acute VBX provides an acute ergogenic effect which potentiates concentric-only muscle performance, though not to a significantly greater extent than concentric (arm cranking) exercise. PMID- 17714991 TI - Survival for eight major cancers and all cancers combined for European adults diagnosed in 1995-99: results of the EUROCARE-4 study. AB - BACKGROUND: EUROCARE is the largest population-based cooperative study on survival of patients with cancer. The EUROCARE project aims to regularly monitor, analyse, and explain survival trends and between-country differences in survival. This report (EUROCARE-4) presents survival data for eight selected cancer sites and for all cancers combined, diagnosed in adult (aged >/=15 years) Europeans in 1995-99 and followed up until the end of 2003. METHODS: We analysed data from 83 cancer registries in 23 European countries on 2 699 086 adult cancer cases that were diagnosed in 1995-99 and followed up to December, 2003. We calculated country-specific and mean-weighted age-adjusted 5-year relative survival for eight major cancers. Additionally, case-mix-adjusted 5-year survival for all cancers combined was calculated by countries ranked by total national expenditure on health (TNEH). Changes to survival were analysed relative to cases diagnosed in 1990-94. FINDINGS: Mean age-adjusted 5-year relative survival for colorectal (53.8% [95% CI 53.3-54.1]), lung (12.3% [12.1-12.5]), breast (78.9% [78.6-79.2]), prostate (75.7% [75.2-76.2]), and ovarian (36.3% [35.7-37.0]) cancer was highest in Nordic countries (except Denmark) and central Europe, intermediate in southern Europe, lower in the UK and Ireland, and worst in eastern Europe. Survival for melanoma (81.6% [81.0-82.3]), cancer of the testis (94.2% [93.4-95.0]), and Hodgkin's disease (80.0% [79.0-81.0]) varied little with geography. All-cancer survival correlated with TNEH for most countries. Denmark and UK had lower all cancer survival than countries with similar TNEH; Finland had high all-cancer survival, but moderate TNEH. Survival increased and intercountry survival differences narrowed between the data for 1990-94 and 1995-99 for, notably, Hodgkin's disease (range 66.1-82.9 [IQR 72.2-78.6] vs 74.0-83.9 [78.6-81.9]), colorectal (29.4-56.7 [45.8-54.1] vs 38.8-59.7 [50.7-57.5]), and breast (61.7 82.7 [72.3-78.3] vs 69.3-87.6 [76.6-82.7]) sites. INTERPRETATION: Increases in survival and decreases in geographic differences over time, which are mainly due to improvements in health-care services in countries with poor survival, might indicate better cancer care. Wealthy countries with high TNEH generally had good cancer outcomes, but those with conspicuously worse outcomes than those with similar TNEH might not be allocating health resources efficiently. PMID- 17714992 TI - EUROCARE-4 studies bring new data on cancer survival. PMID- 17714993 TI - Recent cancer survival in Europe: a 2000-02 period analysis of EUROCARE-4 data. AB - BACKGROUND: Traditional cancer-survival analyses provide data on cancer management at the beginning of a study period, and are often not relevant to current practice because they refer to survival of patients treated with older regimens that might no longer be used. Therefore, shortening the delay in providing survival estimates is desirable. Period analysis can estimate cancer survival by the use of recent data. We aimed to apply the period-analysis method to data that were collected by European cancer registries to estimate recent survival by country and cancer site, and to assess survival changes in Europe. We also compared our findings with data on cancer survival in the USA from the US SEER (Surveillance, Epidemiology, and End Results) programme. METHODS: We analysed survival data for patients diagnosed with cancer in 2000-02, collected from 47 of the European cancer registries participating in the EUROCARE-4 study. 5-year period relative survival for patients diagnosed in 2000-02 was estimated as the product of interval-specific relative survival values of cohorts with different lengths of follow-up. 5-year survival profiles for patients diagnosed in 2000-02 were estimated for the European mean and for five European regions, and findings were compared with US SEER registry data for patients diagnosed in 2000-02. A 5-year survival profile for patients diagnosed in 1991-2002 and a 10 year survival profile for patients diagnosed in 1997-2002 were also estimated by the period method for all malignancies, by geographical area, and by cancer site. FINDINGS: For all cancers, age-adjusted 5-year period survival improved for patients diagnosed in 2000-02, especially for patients with colorectal, breast, prostate, and thyroid cancer, Hodgkin's disease, and non-Hodgkin lymphoma. The European mean age-adjusted 5-year survival calculated by the period method for 2000-02 was high for testicular cancer (97.3% [95% CI 96.4-98.2]), melanoma (86.1% [84.3-88.0]), thyroid cancer (83.2% [80.9-85.6]), Hodgkin's disease (81.4% [78.9-84.1]), female breast cancer (79.0% [78.1-80.0]), corpus uteri (78.0% [76.2 79.9]), and prostate cancer (77.5% [76.5-78.6]); and low for stomach cancer (24.9% [23.7-26.2]), chronic myeloid leukaemia (32.2% [29.0-35.7]), acute myeloid leukaemia (14.8% [13.4-16.4]), and lung cancer (10.9% [10.5-11.4]). Survival for patients diagnosed in 2000-02 was generally highest for those in northern European countries and lowest for those in eastern European countries, although, patients in eastern European had the highest improvement in survival for major cancer sites during 1991-2002 (colorectal cancer from 30.3% [28.3-32.5] to 44.7% [42.8-46.7]; breast cancer from 60% [57.2-63.0] to 73.9% [71.7-76.2]; for prostate cancer from 39.5% [35.0-44.6] to 68.0% [64.2-72.1]). For all solid tumours, with the exception of stomach, testicular, and soft-tissue cancers, survival for patients diagnosed in 2000-02 was higher in the US SEER registries than for the European mean. For haematological malignancies, data from US SEER registries and the European mean were comparable in 2000-02, except for non Hodgkin lymphoma. INTERPRETATION: Cancer-service infrastructure, prevention and screening programmes, access to diagnostic and treatment facilities, tumour-site specific protocols, multidisciplinary management, application of evidence-based clinical guidelines, and recruitment to clinical trials probably account for most of the differences that we noted in outcomes. PMID- 17714994 TI - Does the UK really have an effective cancer plan? PMID- 17714995 TI - Staff development in the Australian context: engaging with clinical contexts for successful knowledge transfer and utilisation. AB - The relationship of nursing education and research with the development of quality patient outcomes is clearly acknowledged in contemporary health care. While education and research positions within nursing structures aim to facilitate the dissemination and integration of knowledge into clinical interventions, there are still many limitations with the translation of knowledge into care work and also, useful projects to inform clinical practice. By providing multifaceted initiatives that target the individual and the organisation a central Nursing Practice Development Unit can be a strategic resource to improve clinical outcomes. A modus operandi that moves away from classroom based education of clinical knowledge and research methods, to the establishment of cross organisational structures and processes that facilitate their integration is powerful in effecting clinical practice that makes a difference. This contrasts with education and research activities targeted at individuals that fall short of their anticipated outcomes because of external influence. PMID- 17714996 TI - Will BEACOPP be the standard for high risk Hodgkin lymphoma patients in advanced stages? AB - Hodgkin Lymphoma (HL) has become one of the most curable cancers, even in adulthood, through continuous improvement of therapeutic options and their verification by large multicenter trials. Today more than 95% of patients with HL in early stages and in advanced stages 85-90% can be cured. Nevertheless, these good results are threatened by treatment associated toxicities such as infertility, cardiopulmonary toxicity and secondary malignancies. It is therefore the aim of future trial generations both to maintain the excellent treatment results and to minimize late effects. In 1964 for the first time deVita et al. described the MOPP polychempotherapy for patients with advanced HL which led to cure rates in more than 50%. Around ten years later Bonadonna et al. established the non cross resistant alternative regime to MOPP, ABVD which nowadays is accepted as "gold standard" for the treatment of advanced HL. MOPP and/or ABVD and furthermore the alternating MOPP/ABVD or the MOPP/ABV hybrid with and without the help of consolidative radiation resulted in around 70% long term survival rates, 30-40% of patients experienced tumor progression or relapses within 5 years. This led the German Hodgkin Study Group (GHSG) [Diehl V, Franklin J, Pfreundschuh M, Lathan B, Paulus U, Hasenclever D, et al. Standard and increased dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med 2003; 348: 2386-95] to improve the efficacy of COPP/ABVD by time- and dose-intensification, omission of Velban and Dacarbazin and adding Etoposide resulting in the BEACOPP principle. From the initial pilot studies in 1992 three trial generations, HD9, HD12, HD15, have now established this principle as one of the most effective chemotherapy regimen in advanced HL. We certainly hope that it will not last another 20 years to establish the BEACOPP regimen as an attractive curative treatment option for at least the high risk cohorts of HL. PMID- 17714998 TI - Dynamic mild subaortic left ventricular obstruction caused by an accessory mitral valve attached to the anterior mitral valve in a young pregnant woman. AB - Accessory mitral valve tissue is an extremely rare congenital cardiac anomaly of embryologic development of the endocardial cushion. This anomaly is often associated with left ventricular outflow tract obstruction (LVOTO). A 26-year-old pregnant female was referred to our Department of Cardiology with exertional shortness of breath and tachycardia. Transthoracic and transesophageal echocardiography revealed a flexible circular (1.3 x 1.4 cm), mobile structure attached to the ventricular side of anterior mitral valve leaflet, with chordal attachments structure from anterior papillary muscle. This picture is compatible with a parachute-like accessory mitral valve tissue. We performed an echocardiographic exercise test that shows a systolic flow turbulence starting immediately proximal to this structure, resulting in a small increase in left ventricular outflow tract (LVOT) gradient (30 mmHg). Therefore we started low dose of beta-blocker therapy in order to decrease heart frequency and reduce the future risk of a worsening of an LVOT dynamic obstruction. Transthoracic and transesophageal echocardiography is critical for the differential diagnosis of LVOT and in the management of accessory mitral valve tissue. In patients without rest and only an exertional mild LVOTO and no other cardiac malformations, prophylactic removal of mitral accessory tissue excision is not required; antibiotic prophylaxis for endocarditis can be indicated and a regular follow-up is recommended to identify any progression in LVOTO entity. PMID- 17714997 TI - Fetal surgery for neural tube defects. AB - Open spina bifida remains a major source of disability despite an overall decrease in incidence. It is frequently diagnosed prenatally and can thus - potentially - be treated by fetal surgery. Animal studies and preliminary human studies strongly suggest that at least a portion of the neurological abnormalities seen in these patients are secondary, and occur in mid-gestation. It is estimated that approximately 400 fetal operations have now been performed for myelomeningocele world wide. Despite this large experience, the technique remains of unproven benefit. Preliminary results suggest that fetal surgery results in reversal of hindbrain herniation (the Chiari II malformation), a decrease in shunt-dependent hydrocephalus, and possibly improvement in leg function, but these findings might be explained by selection bias and changing management indications. A randomized prospective trial (the MOMS trial) is currently being conducted by three centers in the United States, and is estimated to be completed in 2009. PMID- 17714999 TI - Real-time three-dimensional echocardiography of congenital heart disease using a high frequency paediatric matrix transducer. AB - New matrix transducers are now available for three-dimensional echocardiography which have a higher frequency and smaller footprint than previous matrix probes. This has resulted in better image resolution in infants and children. Current applications include assessment of cardiac morphology and function. Intraoperative epicardial techniques may be used in addition to a conventional transthoracic approach. PMID- 17715000 TI - Full or pressure limited reperfusion of an acute myocardial infarct results in a different wall thickness and deformation of the distal myocardium--implications for clinical reperfusion strategies. AB - AIM: The study aim was to determine the sequence of changes in both wall thickness and function in 'at risk' myocardium (using M-mode and radial strain/strain-rate imaging) induced by reperfusion of an acute transmural infarction, and to relate these changes to the presence or absence of a pressure limiting stenosis in the infarct related epicardial vessel. METHODS: Eighteen closed-chest pigs were randomized into two groups (each with nine animals). In Group I, 4 weeks prior to induction of an acute transmural infarct, a copper coated stent was implanted in the proximal circumflex artery (Cx) to create a coronary artery stenosis of between 30 and 95% lumen diameter. At 4 weeks, the stenotic Cx vessel was occluded for 90 min by inflation of a PTCA balloon placed proximal to the stenosis to produce an acute transmural infarction. In Group II (the control group), 90 min Cx occlusion was performed in a normal vessel. In both groups the resulting acute transmural infarction was reperfused after 90 min by removing the PTCA balloon. For both groups, cardiac ultrasound data, including strain/strain-rate imaging, were collected at all stages of the investigation for subsequent offline analysis. RESULTS: In both groups, acute reperfusion (TIMI flow 3 or 2), immediately increased infarct zone end-diastolic wall thickness due to the development of oedema. The acute increase in wall thickness was significantly higher in the non-stenotic animals as compared to the ones with a residual stenosis. Neither of the groups showed any tendency to normalize deformation (strain) during the reperfusion period. CONCLUSION: In this experimental study, the measurement of end-diastolic wall thickness was a simple and non-invasive tool to monitor acute infarct reperfusion. It also provided information on the presence of a flow limiting stenosis in the infarct related artery after restoration of the flow. The deformation of the myocardium remained impaired during early reperfusion, whether reflow was at full pressure or low pressure due to a residual stenosis in the infarct related artery. PMID- 17715001 TI - Memory consolidation and accelerated forgetting in children with idiopathic generalized epilepsy. AB - Whether children with idiopathic generalized epilepsy exhibit accelerated forgetting of verbal and nonverbal information in comparison to healthy controls matched for age and IQ was explored. Twenty-one children with IGE were compared with 21 healthy controls on measures of verbal and visuospatial memory at delays of 30 minutes and 1 week by use of a minimum-learning criterion controlled for initial learning. For the auditory-verbal memory test, group performance was comparable at 30 minutes, but children with IGE recalled significantly less than controls at 1 week. When the number of learning trials to criterion was controlled, the main effects of group and delay became nonsignificant. No group differences were found with respect to recognition performance. Comparisons for the visuospatial task were nonsignificant. Overall, poor initial learning efficiency led to retrieval difficulties, specifically at the longer delay, and was more common in the IGE group. These results, although preliminary, have implications for education planning in childhood IGE. PMID- 17715003 TI - Comprehensive screening method for the qualitative detection of narcotics and stimulants using single step derivatisation. AB - A selective and sensitive screening method for the detection of prohibited narcotic and stimulating agents in doping control is described and validated. This method is suitable for the detection of all narcotic agents mentioned on the World Anti-Doping Agency (WADA) doping list in addition to numerous stimulants. The analytes are extracted from urine by a combined extraction procedure using CH(2)Cl(2)/MeOH (9/1, v/v) and t-butylmethyl ether as extraction solvents at pH 9.5 and 14, respectively. Prior to GC-MS analysis the obtained residues are combined and derivatised with MSTFA. The mass spectrometer is operated in the full scan mode in the range between m/z 40 and 550. The obtained limits of detection (LOD) for all components included in this extensive screening method are in the range 20-500 ng/ml, which is in compliance with the requirements set by WADA. Besides narcotic and stimulating agents, this method is also capable of detecting several agents with anti-estrogenic activity and some beta-agonists. As an example, a positive identification of hydroxyl-methoxy-tamoxyfen is shown. PMID- 17715002 TI - Mutator alleles of yeast DNA polymerase zeta. AB - The yeast REV3 gene encodes the catalytic subunit of DNA polymerase zeta (pol zeta), a B family polymerase that performs mutagenic DNA synthesis in cells. To probe pol zeta mutagenic functions, we generated six mutator alleles of REV3 with amino acid replacements for Leu979, a highly conserved residue inferred to be at the pol zeta active site. Replacing Leu979 with Gly, Val, Asn, Lys, Met or Phe resulted in yeast strains with elevated UV-induced mutant frequencies. While four of these strains had reduced survival following UV irradiation, the rev3-L979F and rev3-L979M strains had normal survival, suggesting retention of pol zeta catalytic activity. UV mutagenesis in the rev3-L979F background was increased when photoproduct bypass by pol eta was eliminated by deletion of RAD30. The rev3 L979F mutation had little to no effect on mutagenesis in an ogg1Delta background, which cannot repair 8-oxo-guanine in DNA. UV-induced can1 mutants from rev3-L979F and rad30Deltarev3-L979F strains primarily contained base substitutions and complex mutations, suggesting error-prone bypass of UV photoproducts by L979F pol zeta. Spontaneous mutation rates in rev3-L979F and rev3-L979M strains are elevated by about two-fold overall and by two- to eight-fold for C to G transversions and complex mutations, both of which are known to be generated by wild-type pol zetain vitro. These results indicate that Rev3p-Leu979 replacements reduce the fidelity of DNA synthesis by yeast pol zetain vivo. In conjunction with earlier studies, the data establish that the conserved amino acid at the active site location occupied by Leu979 is critical for the fidelity of all four yeast B family polymerases. Reduced fidelity with retention of robust polymerase activity suggests that the homologous rev3-L979F allele may be useful for analyzing pol zeta functions in mammals, where REV3 deletion is lethal. PMID- 17715004 TI - A rapid and sensitive method for the quantitation of montelukast in sheep plasma using liquid chromatography/tandem mass spectrometry. AB - A rapid LC-MS/MS method was developed and partially validated for the quantitation of montelukast in spiked sheep plasma. A total run time of 1.5 min was achieved using a short monolithic column and employing a rapid gradient. Sample preparation involved protein precipitation with twofold acetonitrile by volume during which a deuterated internal standard (montelukast D-6) was incorporated. The MRM transitions for montelukast and the deuterated internal standard were 586/422 and 592/427, respectively. A linear dynamic range of 0.25 500 ng/mL with a correlation coefficient of 0.9999 was achieved. Precision was below 5% at all levels except at the LOQ (0.36 ng/mL) which demonstrated an overall of R.S.D. of 8%. Post-column infusion experiments were performed with precipitated plasma matrix and showed minimal interference with the peaks of interest. PMID- 17715005 TI - Odontogenic keratocyst in a 5-year-old child: a rare cause of maxillary swelling in children. AB - Odontogenic keratocysts in children are uncommon. They are cysts of the jaws that have a tendency for recurrence and are usually seen in adults. We report an exceptionally rare case in a young child and discuss its management. PMID- 17715006 TI - A seventy percent overestimation of the burden of hip fractures in women aged 85 and over. AB - BACKGROUND: Hip fractures are the most devastating result of osteoporosis and are common worldwide. Based on an exponential increase in incidence with age, many studies in the 1990s forecasted an epidemic of hip fracture in women in the next 15 years which is not currently being observed. Despite the ageing of the populations, accurate description of hip fracture incidence in women aged 85 or older are scarce. METHODS: All women aged 60 to 95, living in the Rhone-Alpes area of France, who were admitted to hospitals during 2001-2004 for treatment of hip fracture were selected from the French claims databases. An exponential model was tested to describe the increase in hip fracture incidence in women aged 60-84 and 60-95. The first model was used to predict annual hip fracture incidence in women aged 85-95 in the Rhone-Alpes area, in France and in Europe. RESULTS: An exponential model was adequate to describe the increase in incidence in women aged 60-84. Assuming an exponential increase in incidence in women aged 85-95, the predicted number of cases was overestimated by 70% in the Rhone-Alpes. In France and in Europe, the excess number of incident cases is believed to be respectively 16,000 and 85,965 a year. INTERPRETATION: The age-specific incidence estimates an average risk although the individual risks are heterogeneous throughout the population. The slower increase in incidence after age 85 might not be related to a decreasing individual risk with age but rather might indicate that women at higher risk have already experienced hip fracture or have died. After age 85, women who are still at risk may represent a population with a lower risk of hip fracture. Models adapted to the elderly population should be developed to improve the accuracy of predictions and optimise the health care system. PMID- 17715007 TI - [Computer-aided molecular modeling and activity estimation for ligand screening with specific phage clone as the target]. AB - OBJECTIVE: To investigate the interaction between tumor necrosis factor alpha (TNF alpha) mimotopes and TNF alpha-binding peptides screened from random phage display peptide library with TNF alpha mimotopes displayed on phage clone as the target, the computational docking program AutoDock (with confirmation calculations using Discover) was used to predict and analyze the binding modes of LLT-18 (TNF alpha binding peptide, sequence EHMALTYPFRPP) with TNF alpha, after which LCS-7 (TNF alpha mimic phage clone, displayed positive sequence c-RRPAQSG c) was docked to LLT-18 manually. The binding between LLT-18 and TNF alpha or LCS 7 was stabilized predominantly through electrostatic interaction and H-bond formation. The Arg residues in TNF alpha or LCS-7 were important for their interaction with LLT-18. For LLT-18, the key amino acid residues were Glu1, His2, Met3 and Tyr7. These results suggest the feasibility of screening ligand to single epitope with specific phage clone as the target, and of predicting the interaction between small peptides by computer-aided molecular modeling. PMID- 17715008 TI - [Effect of p53 gene knockout on cell migration]. AB - OBJECTIVE: To investigate the role of p53 gene in serum-induced cell migration. METHODS: The effects of p53 knockout on serum-induced formation of lamellipodia and cell migration were observed using Transwell cell migration system. RESULTS: p53(+/+) cells developed lamellipodia upon serum stimulation and showed enhanced activity of cell migration, but these effects were not observed in p53 knockout cells after serum stimulation. CONCLUSION: p53 plays a role in serum-induced cell migration. PMID- 17715010 TI - [Identification and tissue localization of intermediate filament protein in Angiostrongylus cantonensis]. AB - OBJECTIVE: To identify the type of the intermediate filament (IF) protein of Angiostrongylus cantonensis and analyze its tissue localization. METHODS: Recombinant pET-IF of antigen IF was expressed in E.coli with IPTG induction, and the expression products were purified by His.Bind column and identified for determining the type of the IF protein by Western blotting. Anti-IF antibody was prepared by multi-spot subcutaneous injection into mouse and used to detect the tissue slices of A. cantonensis by immunohistochemical analysis. RESULTS: The antigen IF were correctly expressed and purified, and identified as a keratin located in the intestine wall and cytoplusma. CONCLUSION: The antigen IF is distributed in the intestine wall of A. cantonensis. PMID- 17715009 TI - [Biodistribution of (99m)Tc-labeled anti-VEGF mAb 5-FU loaded polylactic acid nanoparticles in human gastric carcinoma xenografts]. AB - OBJECTIVE: To prepare (99m)Tc-labeled Anti-VEGF mAb 5-FU loaded polylactic acid nanoparticles ((99m)Tc-Ab-5-FU-NPs) and investigate its biodistribution in human gastric carcinoma xenografts. METHODS: (99m)Tc-Ab-5-FU-NPs were prepared by labeling Ab-5-FU-NPs with (99m)Tc using improved Schwarz method. After isolation of (99m)Tc-Ab-5-FU-NPs using SephadexG250 column, the labeling ratio and radiochemical purity were determined using chromatography. The immunocompetence of (99m)Tc- Ab-5-FU-NPs was detected by ELISA and immunohistochemistry. (99m)Tc Ab-5-FU-NPs were then injected via the tail vein into SCID mice bearing human gastric carcinoma, and (99m)Tc labeled mice-derived monoclonal IgG loaded polylactic acid nanoparticles were used as the control, followed by radioimmunoscintigraphic imaging at 2 and 6 h. The radioactive count and radioactive ratio of the tumor and non-tumor tissue (T/NT) in the animal models were calculated using ROI technique. After imaging at 24 h, SCID mice were sacrificed and the radioactive distribution, the %ID/g, as well as the T/NT radioactive ratio were examined, respectively. The concentrations of 5-FU in the tumor and blood were also detected using HPLC method. RESULTS: The labeling ratio of (99m)Tc-Ab-5-FU-NPs was 90%-95%. (99m)Tc-Ab-5-FU-NPs were detected in the tumor tissues by radioimmunoimaging 2 h after the injection. ID%/g in the tumor tissues at 2 and 6 h were both significantly higher than that of the control group. Both the ID%/g in tumor tissues and radioactive ratio of tumor and blood at 6 h were higher than those at 2 h, and the concentration of 5-FU in experimental group increased continuously with time and was significantly higher than that in control group. CONCLUSIONS: (99m)Tc-Ab-5-FU-NPs prepared in this study can meet the demands of radioimmunoimaging, and the anti-VEGF monoclonal antibody possesses reliable immune targeting ability. Six hours after injection, (99m)Tc-Ab-5-FU-NPs can specifically accumulate in the tumor tissues in human gastric carcinoma xenografts at high concentration. PMID- 17715012 TI - [Time course of calpain activity changes in rat neurons following fluid percussion injury and the interventional effect of mild hypothermia]. AB - OBJECTIVE: To investigate the time course of calpain activity changes in rat neurons following fluid percussion injury (FPI) under normothermia (37 degrees celsius;) and mild hypothermia (32-/+0.5) degrees celsius;. METHODS: In vitro cultured rat neurons were subjected to FPI followed by application of mild hypothermia for intervention at different time points, and the changes in intraneuronal calpain activity following FPI and the interventional effect of mild hypothermia on calpain activity were evaluated by UV-spectrophotometry at different time points. RESULTS: Remarkable changes occurred in calpain activity in the neurons following FPI at 37 degrees celsius;, and mild hypothermia produced obvious interventional effect on calpain activity in close relation to the timing of intervention initiation. CONCLUSION: Intraneuronal calpain activity changes following FPI are involved in the pathological process of cellular injury, and mild hypothermia might offer protection against traumatic brain injury to some extent by regulating calpain activity. The interventional effect of mild hypothermia is associated with the timing of the intervention initiation. PMID- 17715011 TI - [Cloning, screening and sequence analysis of the major allergens of Psilgramma menephorn]. AB - OBJECTIVE: To identify and isolate the genes encoding the allergens of Psilgramma menephorn by screening the cDNA expression library. METHODS: The cDNA expression library of Psilgramma menephorn was constructed in lambdaZAPIIphage, and the library was screened using the sera from the patients allergic to Psilgramma menephorn and those from the rabbits immunized with Psilgramma menephorn extracts. The positive clones were subcloned into pBluescript plas, and the cDNA in the positive clones were amplified with PCR and sequenced. RESULTS AND CONCLUSION: Five positive clones were obtained by immunological screening of 5 x 10(4) recombinants. Sequence analysis showed that the positive clones contained the new genes of Psilgramma menephorn allergens. This success in isolating these genes may facilitate the development of specific immunotherapy against Psilgramma menephorn allergy and further research of allergic diseases. PMID- 17715013 TI - [Preliminary effect of VEGF promoter-driven recombinant adenovirus containing double suicide genes on apoptosis of human gastric carcinoma cells]. AB - OBJECTIVE: To study the effect of the adenovirus containing CD/TK fusion gene controlled by the human vascular endothelial growth factor (VEGF) promoter on apoptosis of human gastric carcinoma cells SGC-7901. METHODS: VEGF-expressing SGC 7901 cells were infected by the recombinant adenovirus Ad-VEGFP-CD/TK, and the infection efficiencies were observed with fluorescence microscopy. The toxic effect and intracellular calcium concentration induced by 5-fluorocytosine (5-FC) and ganciclovic (GCV) were determined by light microscopy, electron microscopy and flow cytometry. RESULTS: The transfection efficiency of the recombinant adenovirus in SGC-7901 cells increased with the viral titer. At the multiplicity of infection (MOI) of 100, 5-FC and GCV could induce apoptosis of SGC-7901 cells within a given dose range in a dose- and time-dependent manner, and apoptotic changes of the cells were observed with electron microscopy. Apoptotic peak was also detected by flow cytometry. Cell cycle analysis revealed increased cell percentage in G(0)-G(1) phase and decreased percentage of cells in G(2)-M and S phases in response to treatment with the pro-drugs, which also induced marked elevation of intracellular calcium concentration in the infected cells. CONCLUSIONS: CD/TK fusion gene system driven by VECF promoter selectively induces apoptosis of VEGF-expressing SGC-7901 cells, the action of which is probably mediated by intracellular calcium variation. PMID- 17715014 TI - [Identification of differentially expressed genes in primary cultured nasopharyngeal carcinoma cells by cDNA microarray]. AB - OBJECTIVE: To analyze the global gene expression profile of primary cultured nasopharyngeal carcinoma (NPC) cells using cDNA microarray techniques to screen new candidate genes related to the occurrence and progression of NPC. METHODS: A NPC cell line C666 and primary cultured NPC cells from biopsy specimens in 5 cases were analyzed with microarray techniques in comparison with 3 normal nasopharyngeal epithelial (NPE) biopsy specimens. Several differentially expressed genes identified from the microarray results were verified by fluorescence real-time PCR (FQ-PCR) and immunohistochemistry (IHC). RESULTS: Primary cultured cells of both NPC and NPE were verified by cytokeratin IHC, EBER1 in situ hybridization and EBV-DNA real-time PCR. Compared with NPE cells, a total of 493 genes in at least 4/6 of the samples were identified to be differentially expressed in the primary cultured NPC cells, including 264 up regulated and 229 down-regulated ones. Several differentially expressed genes according to the microarray results were confirmed by real-time PCR and IHC. CONCLUSION: cDNA microarray technique provides an effective and accurate means for global gene expression profiling of primary cultured NPC cells to screen the differentially expressed genes, which may serve as an important basis for studying the mechanism, classification and diagnosis of NPC at the molecular level. PMID- 17715015 TI - [Establishment of a whole-body visualization model of orthotopically implanted colorectal carcinoma and metastasis model in nude mice]. AB - OBJECTIVE: To establish an animal model visualizing orthotopic growth and metastasis of colorectal cancer. METHODS: pEGFP-N1 plasmid was transfected into human colorectal carcinoma cell line SW480 so that the resultant SW480/EGFP cells emitted fluorescence that could be detected externally by fluorescence stereo microscope. SW480/EGFP cells were inoculated subcutaneously in nude mice, and the orthotopic tumor growth was evaluated in real time. Whole-body visualization models of orthotopically implanted colorectal carcinoma was established surgically, and the tumor growth and metastasis are evaluated by conventional pathological methods. RESULTS: SW480/EGFP cells stably expressed high-levels of enhanced green fluorescent protein. Subcutaneous injection of SW480/EGFP cells resulted in tumor growth in nude mice, and the emitted fluorescence could be quantitatively detected and imaged with fluorescence stereo microscope to visualize real-time tumor growth. Visualization animal model was established successfully with surgical orthotopic implantation (SOI) of the tumor, and all mice survived. After two weeks, all the mice developed colorectal carcinoma without metastasis, but 4 weeks later, 75%percnt; of the mice developed peritoneal tumor metastasis and 50% had liver metastasis. The whole-body visualization animal model was successfully validated by pathological detection. CONCLUSION: Whole-body visualization model of orthotopic and metastatic tumor growths provides a reliable means for observing the behavior of human colorectal carcinoma and can be helpful to study the growth and metastasis patterns of the cancer. PMID- 17715016 TI - [Anatomical variation of the donor hepatic arteries: analysis of 843 cases]. AB - OBJECTIVE: To investigate the anatomical variations of donor hepatic artery and explore the measures that can be taken to avoid accidental hepatic artery injury during graft procurement and reconstruction. METHODS: The data of totally 843 consecutive patients undergoing orthotopic liver transplantation (OLT) during the period from April 2001 to July 2006 was reviewed in relation to anatomical variation of the donor hepatic arteries. The variations of the hepatic artery, the relationship between the anomalous hepatic artery and accidental injury of the hepatic artery were analyzed. RESULTS: In the 843 cases of OLT, the total anatomical variation rate of the donor hepatic arteries was 20.4% (172/843). The common variations included replaced or accessory right hepatic arteries originated from superior mesenteric artery (6.67%, 57/843), replaced or accessory left hepatic arteries originated from the left gastric artery (6.41%, 54/843) or from the celiac trunk and gastro-duodenal artery (1.66%, 14/843), replaced or accessory right hepatic arteries originated from the celiac trunk, common hepatic artery and gastro-duodenal artery (1.54%,13/843), replaced or accessory right hepatic arteries and left hepatic arteries coexistence (0.83%, 7/843), variation of the common hepatic artery from the superior mesenteric artery (1.54%, 13/843) or from the abdominal aorta (0.95%, 8/843). CONCLUSION: During graft procurement and reconstruction, accidental injury of the hepatic artery is more likely in the presence of hepatic arterial variation, which can be a common clinical entity. Acquaintance with hepatic arterial variation and maintenance of the integrity of the superior mesenteric artery and celiac trunk are key to reducing potential hepatic artery injuries. PMID- 17715017 TI - [Changes in tight junction of intestinal mucosa in patients with irritable bowel syndrome: a study with tracing electron microscope]. AB - OBJECTIVE: To investigate the presence of tight junction (TJ) changes of the intestinal mucosa, and elucidate the possible mechanism for changes in bowel evacuation in patients with irritable bowel syndrome (IBS). METHODS: In 10 normal control subjects, 10 patients with constipation predominant IBS (C-IBS) and 10 with diarrhea predominant IBS (D-IBS), biopsies were taken from the terminal ileum and ascending colon. Lanthanum nitrate tracing electron microscope and cytochemical technique were employed to observe TJ changes in the intestinal mucosa. RESULTS: Like the control subjects, C-IBS patients had normal TJ structure in the intestinal mucosa, whereas D-IBS patients exhibited some abnormalities in TJ structure either in their terminal ileum (7 in 10) or ascending colon (8 in 10), revealed by TJ gap widening with lanthanum nitrate extravasation into the surrounding tissue. Such changes were also observed in 3 of the 4 patients with a history of acute infectious diarrhea. CONCLUSION: The changes in the intestinal mucosal TJ structure and function might contribute to altered bowel evacuation in patients with irritable bowel syndrome. PMID- 17715018 TI - [Protective effects of orientin on myocardial ischemia and hypoxia in animal models]. AB - OBJECTIVE: To study the protective effects of orientin against myocardial ischemia and hypoxia in rats. METHODS: The protective effect of orientin against myocardial ischemia and hypoxia was observed in mice by recording their survival time under closed normobaric hypoxia and time of cardiac electric disappearance due to trachea clamping, in rabbits by evaluating arachidonic acid (AA)-induced blood platelet aggregation, in guinea pigs by measuring the coronal flow in the isolated heart and in SD rats with myocardial ischemia induced by pituitrin injection. RESULTS: Orientin (1, 2, 4 mg/kg) significantly prolonged the survival time of mice under closed normobaric hypoxia and the gasping duration induced by decapitation. Orientin at concentrations of 3, 10, and 30 micromol/L also inhibited AA-induced blood platelet aggregation in rabbits and increased coronal flow in the isolated heart of guinea pigs. At 0.75, 1.5, and 3.0 mg/kg, orientin significantly antagonized pituitrin-induced ECG changes. CONCLUSION: Orientin may offer protection against myocardial ischemia and hypoxia in animal models in dose dependent fashions. PMID- 17715019 TI - [Clinical application of a method for evaluating von Willebrand factor cleaving protease activity]. AB - OBJECTIVE: To establish a method for evaluating the activity of von Willebrand factor cleaving protease (vWF-cp) and evaluate its clinical application. METHODS: Purified von Willebrand factor polymer was isolated by gel filtration from human fresh-frozen plasma as the enzyme substrate. SDS-PAGE, Western blotting, and luminographic detection were used to evaluate vWF-cp activity of 60 healthy adults, 28 patients with cerebral infarction (CI) and 7 with thrombotic thrombocytopenic purpura (TTP). RESULTS: In the subjects involved, the method for evaluating vWF-cp activity had intra- and inter-batch coefficient of variation(CV) of 4.81% (n=8) and 8.63% (n=6), respectively. According to this method, the plasma vWF-cp activity in the 60 healthy adults was significantly higher than that in the CI patients [(86.53-/+17.49)% vs (77.15-/+16.72)%, P<0.05]. In TTP patients before plasma replacement, the vWF-cp activity was (9.06 /+7.17)% and increased significantly to (47.00-/+6.27)% 24 h after plasma replacement, respectively, but still significantly lower than that of healthy adults (P<0.01), whereas in the convalescent stage, the activity approached the normal level [(83.18-/+8.83)%, P>0.05]. CONCLUSIONS: According to the described method, which allows accurate vWF-cp activity measurement with good sensitivity, specificity and reproducibility, vWF-cp activity is lower in CI patients and even more so in TTP patients than that of healthy adults. Plasma replacement can effectively increase the vWF-cp activity in TTP patients. PMID- 17715020 TI - [Analgesic effect of interleukin-2 in mouse models of spared nerve injury]. AB - OBJECTIVE: To investigate the analgesic effect of interleukin-2 (IL-2) in mice with spared nerve injury (SNI). METHOD: IL-2 was intraperitoneally injected in mice with induced SNI, and von Frey Filaments test and cold plate test were carried out to accesses the analgesic effects of IL-2 and the effect of naloxone in antagonizing the effects of IL-2. RESULTS: IL-2 produced analgesic effects against hyperalgesia and allodynia in mouse models of SNI, and the effect of IL-2 lasted for more than 24 h, showing a double-peak pattern in its action with the two peaks occurring at 30 and 105 min, respectively. The effect of IL-2 could be significantly antagonized by naloxone. CONCLUSIONS: IL-2 has long-lasting analgesic effects in mouse models of SNI model, showing a double-peak pattern of its action. The analgesic effect of IL-2 is probably mediated by opiate receptor. PMID- 17715021 TI - [Effect of irradiation-induced pcDNA3.1-Egr.1p-p16 on cell apoptosis and cell cycle of JF305 cells]. AB - OBJECTIVE: To observe the effect of pcDNA3.1-Egr.1p-p16 plasmid on apoptosis and cell cycle of pancreatic carcinoma JF305 cell line. METHODS: JF305 cells were cultured and transfected with pcDNA3.1-Egr.1p-p16 plasmid via Lipofectamine(TM) 2000, followed by irradiation by 6MV-X at 4 Gy (dose rate 2.50 Gy/min). The cell cycle and cell apoptosis changes were analyzed by flow cytometry. RESULTS: In cells infected with pcDNA3.1-Egr.1p-p16 plasmid and those with pcDNA3.1-Egr.1p p16 plasmid infection before 4 Gy irradiation, the percentages of viable apoptotic cells were 6.4% and 10.4%, and those of advanced stage apoptotic or dead cells were 16.8% and 33.8%, significantly higher than those in the control group (P<0.05). JF305 cell apoptosis in 4 Gy irradiation group was obviously increased in comparison with non-irradiated plasmid-infected cells (P<0.05). Irradiation resulted in a predominant G(2) arrest of the plasmid-infected JF305 cells. Both pcDNA3.1-p16 plasmid and pcDNA3.1-Egr.1p-p16 plasmid infections could induce G1 arrest of JF-305 cells, and irradiation did not produce significant changes in G(1)-arrested cells in the two plasmid infection groups, but cells arresting at G(2) phase increased. CONCLUSION: pcDNA3.1-Egr.1p-p16 can induce JF 305 cells apoptosis, which is enhanced by irradiation. pcDNA3.1-Egr.1p-p16 tranfection may result in G(1) arrest of the cells, and when combined with irradiation, the cells arrested at G(2) phase can increase. PMID- 17715022 TI - [Effect of interleukin-6 on the chondrocytes in the cartilage endplate of rabbits in vitro]. AB - OBJECTIVE: To evaluate the effect of interleukin-6 (IL-6) on the biological behaviors of the chondrocytes in the cartilage endplate of rabbits. METHODS: Chondrocytes isolated from the cartilage endplate of New Zealand rabbits, verified for their biological characteristics by such means as toluidine blue staining for type II collagen, were treated with IL-6 at different concentrations. The proliferation of the chondrocytes was evaluated by MTT assay at different time points following the treatment, the cell cycle changes were determined by flow cytometry and the changes of aggrecan and type II collagen mRNAs detected by RT-PCR. RESULTS: At the concentrations of 10, 50 and 100 ng/ml, IL-6 did not obviously affect the rate of chondrocyte proliferation. IL-6 at 50 ng/ml resulted in no obvious changes of the cell cycle of the chondrocytes, but significantly decreased the expression of collagen IIa mRNA. CONCLUSION: IL-6 has no effect on the proliferation and cell cycle of the chondrocytes, but at higher concentrations, it inhibits matrix synthesis of the chondrocytes to promote intervertebral disc degeneration. PMID- 17715023 TI - [Clinicopathological implications of positive CK7 expression in colorectal carcinoma]. AB - OBJECTIVE: To investigate the clinicopathological significance of positive CK7 expression in human colorectal carcinoma (HCC). METHODS: Immunohistochemistry was used to detect CK7 and CK20 protein expressions in 68 cases of HCC, 20 cases of canalicular adenoma (CA), 5 cases of serrated adenoma (SA) and 20 cases of hyperplastic polyps (HP). RESULTS: The positivity rate of CK20 expression was 89.7% in HCC, and 100% in CA, SA and HP. In HCC, the expression rate of CK7 (39.7%) was not correlated with Dukes' classification, differentiation and tumor location. CK7 positivity rate in colon cancer was 35.7% (15/52) and 42.3% (11/26) in rectal cancer. CK7 expression was negative in CA. CK7 positivity rate in SA was 49% and 30% in HP. CONCLUSION: CK7 is a possible marker for colorectal carcinogenesis from HP to SA, and ultimately to HCC, and examination of the colorectal polypoid lesions for CK7 expression can be significant for estimating the colorectal polypous cancerization. PMID- 17715024 TI - [Combined modality therapy for primary choriocarcinoma in the pineal region: report of two cases]. AB - OBJECTIVE: We report two rare cases of primary choriocarcinoma in the pineal region verified histologically. In both cases, the pre-operative serum level of human chorionic gonadotropin (HCG) was significantly elevated to 128-/+935.7 and 9 -/+088.9 mIU/ml, respectively, and serum alpha-fetoprotein (AFP) was negative. The tumors were microsurgically removed, and postoperative hydrocephalus were treated by endoscopic third ventriculostomy. Both patients underwent chemotherapy and radiotherapy. After adjunctive treatment, the serum HCG decreased within normal range. During the two-year-long follow-up, no radiological (MRI) evidence was found to suggest recurrence in MR imaging, and the serum HCG was normal in one patient, but mildly elevated in the other. HCG measurement can be crucial to the diagnosis and post-treatment monitoring of choriocarcinoma, and radical surgical tumor removal and combined modality therapy including chemotherapy and radiotherapy may ensure good results. PMID- 17715025 TI - [Measurement of the vertebral pedicle in children]. AB - OBJECTIVE: To obtain the spinal anatomic data of children for the development of implants used for scoliosis correction in children. METHODS: Twelve children cadaver spines (C(3)-L(5)) were separated into single vertebrae after CT scanning of the specimens. The transverse and sagittal pedicle length, transverse and sagittal pedicle angle, pedicle length versus spinal level were measured with either electronic vernier caliper or on reconstructed 3D model of the spine. RESULTS: The transverse pedicle length, sagittal pedicle length, transverse pedicle angle, sagittal pedicle angle and pedicle length were significantly different among cervical, thoracic and lumbar groups, and these data suggest significant differences of children's pedicle from the documented adult spine data. CONCLUSION: The measurement can provide basic anatomic data for the development of the implant for scoliosis correction in children. PMID- 17715026 TI - [Effect of phosphorylated c-Jun expression on COX-2 expression in the substantia nigra of MPTP mouse model of subacute Parkinson disease]. AB - OBJECTIVE: To investigate the effect of phophorylated c-Jun (p-c-Jun) expression on the expression of COX-2 in the substantia nigra (SN) of the MPTP mouse model of subacute Parkinson disease (PD) and explore the possible mechanism of the dopaminergic (DA) neuron death in PD. METHODS: C57BL/6N mice were treated with MPTP to establish subacute PD model. The changes of TH-, COX-2- and p-c-Jun positive cells, and the expression levels of TH, COX-2 and p-c-Jun in the SN in the midbrain were observed with inmmunohistochemistry and Western blotting before and after administration of SP600125, a specific JNK inhibitor. RESULTS: Compared with the mice in control group, the PD mice exhibited typical symptoms of PD. The number of TH-positive neurons and expression level of TH in the model group were significantly reduced in the substantia nigra by about 65% and 75% (P<0.001) 7 days after the fifth injection of MPTP. The number of COX-2-immunoreactive cells and the expression level of COX-2 were significantly increased. P-c-Jun was specifically expressed in the nuclei of neurons and p-c-Jun expression level was significantly increased in the SN 6 h after the third injection of MPTP. Double labeling immunofluorescence assay showed coexpression of COX-2 and p-c-Jun in TH positive neurons in the SN. In mice treated with JNK inhibitor, the number of TH positive neurons and TH expression level in the SN was only decreased by 15% and 20% as compared with the control group (P<0.001) 7 days after the fifth injection of MPTP, COX-2-positive cell number and COX-2 expression level were obviously reduced as compared with the model group (P<0.001), and p-c-Jun was expressed mainly in the cytoplasm of the neurons whose expression level in SN were significantly decreased 6 h after the third injection of MPTP. The PD mice treated with SP600125 showed slight behavioral symptoms. CONCLUSION: P-c-Jun expression may play an important role in mediating COX-2 expression in the SN in the MPTP model of subacute PD, and inhibiting p-c-Jun activity may provide neuroprotection to the mouse model. PMID- 17715027 TI - [Influence of stapedectomy on the hearing of guinea pigs]. AB - OBJECTIVE: To compare the influences of stapedectomy and small fenestra stapedotomy on the hearing of guinea pigs. METHODS: Twenty-four (48 ears) guinea pigs were randomized equally into two groups, and the left ears were subjected to stapedectomy and total stapes replacement with a prosthesis, or sham operation (12 ears) to expose the footplate of the stapes and the round window. Each guinea pig was tested by ABR perioperatively. Four guinea pigs were chosen randomly from each group and decapitated for morphological examination by light microscopy and scanning electron microscopy after ABR test. RESULTS: In the sham operation group, the post-operative latencies of each wave, the intervals and the hearing threshold exhibited no significant changes other than prolonged latency of wave I. In stapedectomy group, the hearing threshold increased to 23.75-/+3.77 dBSPL 1 h after operation with significantly prolonged post-operative latencies of all the waves and intervals but for III-IV interval, which was shortened. The latencies of each wave (especially waves I and III) in the stapedectomy group were increased by a greater magnitude than those in the sham operation group, but the intervals were comparable between the two groups. No significant difference was noted in the parameters of ABR either 1 h or 1 day after the operation between the two groups, in which the architecture of cochleas remained intact with similar number of spiral ganglion cells. The stereocilia of the outer hearing cells (OHC) were normal in the sham operation group while in stapedectomy group, slight stereocilia disorder occurred but became normal 1 day after operation. No obvious changes were found in the stereocilia of the inner hearing cell (IHC) in either groups. CONCLUSION: Stapedectomy can induce mild hearing loss without seriously damaging the function of the cochlea in guinea pigs. PMID- 17715028 TI - [Sweat function evaluation for early diagnosis of diabetic peripheral neuropathy]. AB - OBJECTIVE: To evaluate the clinical value of sweat function examination in early diagnosis of diabetic peripheral neuropathy (DPN). METHODS: Ninety-eight hospitalized type 2 diabetic patients with or without DPN (DN and DC groups) according to Michigan Diabetic Neruopathy Score (DNS) and 40 healthy volunteers (NC group) were evaluated for their sweat function of the feet in relation to the peripheral autonomic nerve with sweat printing method using Neuropad. The Neuropad color-changing time was recorded to assess the sensitivity and specificity of sweat printing methods relative to DNS for DNP evaluation, and the correlation of the Neuropad color-changing time to DNS score was analyzed. RESULTS: The average Neuropad color-changing time was 4.0-/+0.6, 4.3-/+1.2 and 23.0-/+6.1 min in NC, DC, and DN groups, respectively, showing significant differences between the 3 groups (P<0.05). The morbidity rate detected by sweat printing method was 62.2%, similar to that detected by DNS (57.1%, P>0.05). The sensitivity of the sweat printing method for DPN diagnosis was 92.8%, with specificity of 78.5%, positive predictive value of 93.2%, and negative predictive value of 78.6%. DNS showed significant positive correlation with the Neuropad color-changing time (r=0.46, P<0.05). CONCLUSION: Sweat printing method provides an objective, simple and reliable method for sweat function evaluation of the feet of type 2 diabetic patients to help in early DPN diagnosis, and quantification of the results of sweat printing method can be indicative of the DPN severity. PMID- 17715029 TI - [Analysis of acute cerebral arterial thrombosis with multiple organ dysfunction syndrome]. AB - OBJECTIVE: To investigate the incidence, case fatality and risk factors of acute cerebral arterial thrombosis complicated by multiple organ dysfunction syndrome (MODS). METHODS: A retrospective study was conducted in 830 patients with acute cerebral arterial thrombosis, among whom 89 also developed MODS. RESULTS: The incidence of MODS in these patients was 10.7% with case fatality of 58.4%. The presence of concurrent infection and increased number of organ involved both resulted in higher case fatality. The preceding health status, number of failing organs and score of neurologic impairment were the main fetal factors according to logistic regression analysis. CONCLUSION: MODS usually occurs in two weeks after the onset of acute cerebral arterial thrombosis. Prevention of MODS involves rigorous treatment of the compromised organs and comprehensive systemic therapy in addition to the management of the primary diseases. PMID- 17715030 TI - [Changes of Substance P in the substantia gelatinosa of the dorsal horn field after liquid nitrogen freezing of severed nerve for prevention of terminal neuroma]. AB - OBJECTIVE: To determine the changes of Substance P in the substantia gelatinosa of the dorsal horn field after transient liquid nitrogen freezing of severed rat sciatic nerve for prevention of terminal neuroma. METHODS: The bilateral sciatic nerves of 20 SD rats were severed, and the left sciatic nerves was subjected to transient liquid nitrogen freezing with the right sciatic nerve as control. After 20 and 28 weeks, the nerve ends were resected and prepared for microscopic examination, and Substance P in the substantia gelatinosa of the dorsal horn field was determined by immunohistochemistry. RESULTS: Typical neuromas occurred in the severed ends of the right sciatic nerves but not in the left sciatic nerves. The distribution and optical density of Substance P in the substantia gelatinosa of the dorsal horn field was significantly smaller in the left than in the right nerves (P<0.05). CONCLUSION: Liquid nitrogen freezing of the severed sciatic nerve results in decreased release of Substance P in the substantia gelatinosa of the dorsal horn field, suggesting that noxious stimulation may increase Substance P release in the substantia gelatinosa of the dorsal horn field. PMID- 17715031 TI - [Effect of esmolol on propofol dose requirement for anesthesia in thyroidectomy]. AB - OBJECTIVE: To observe the effect of esmolol application before and during operation on propofol dose required for anesthesia induction and maintenance. METHODS: Forty patients (ASA physical status I or II) undergoing general anesthesia for thyroidectomy were randomized equally into esmolol and control groups. Patients in esmolol group received a loading dose of esmolol at 0.5 mg/kg in 30 ml normal saline over a period of 5 min followed by an intravenous infusion of esmolol at 50 microg.kg(-1).min(-1) until the end of surgery, while patients in the control group were given normal saline in the same manner, in addition to anesthesia with protofol. Perioperative hemodynamic parameters and BIS were measured, and the duration of anesthesia, operation and recovery time from anesthesia were recorded. RESULTS: There were significant differences between the two groups in propofol dose required for anesthesia induction and recovery time from anesthesia, but not in maintenance propofol dose. Patients in esmolol group had significantly lower HR and BIS during tracheal intubation than those in the control group , and no significant differences were found in HR, BP and BIS during operation between the two groups. The hemodynamic parameters during extubation showed less fluctuation in esmolol group. CONCLUSION: Perioperative esmolol administration during anesthesia reduces propofol dose required for anesthesia induction and recovery time from anesthesia, and decreases HR and BIS variation during tracheal intubation and hemodynamic response during extubation without affecting the maintenance propofol dose. PMID- 17715032 TI - [Reduced irradiation target volume of mediastinal lymph node drainage in conformal radiotherapy for patients with non-small cell lung cancer after thoracic surgery]. AB - OBJECTIVE: To decrease lung and esophageal radiation injuries by reducing irradiation target volume of mediastinal lymph mode drainage in conformal radiotherapy (CRT) for patients with non-small cell lung cancer (NSCLC) after thoracic surgery. METHODS: Fifty-three patients with NSCLC were randomized into groups A and B to receive 3D-CRT after thoracic surgery. Patients in group A, according to conventional therapy, received preventive nodal irradiation (PNI) of the mediastinal lymph node drainage, and those in group B, according to pathological nodal staging after operation, did not have PNI of the metastasis free area to reduce the clinical target volume (CTV). Patients in both groups were treated with conventional fractionated radiotherapy (CFRT) at 2 Gy in each fraction, and 5 fractions each week. All patients were followed up for two years to record their 2-year survival rate, local relapse of lymph node drainage and lung and esophageal radiation injuries. RESULTS: The total 2-year survival rate was 58.5%in these patients and comparable between the two groups. The rates of local regional relapse and recurrence out of the CTV were 13.8% and 3.4% in group A and 16.7% and 8.3% in group B, respectively (P=1 and P=0.571). The incidence of radiation pneumonia and lung fibrosis were 6.9% and 62.1% in group A and 0% and 58.3% in group B (P=0.459 and P=0.782), and that of radiation esogphagitis and esophagus stricture rates were 27.6% and 6.9% in group A and 12.5% and 4.2% in group B, respectively (P=0.039 and P=1). CONCLUSION: Reduced CTV does not warrant decrease in the local control but may lower the incidence of acute esophageal radiation injury in postoperative patients with NSCLC. PMID- 17715033 TI - [Changes in the sonographic appearance of the endometrium after different premenopausal tamoxifen therapies]. AB - OBJECTIVE: To assess the effect of different schemes of premenopausal tamoxifen therapy on the endometrium. METHODS: Totally 109 normal premenopausal women positive for high-risk factors of breast cancer were divided into two groups, namely periodic and consecutive tamoxifen treatment groups. Endometrial thickness as examined by vaginal sonography was assessed in relation to duration of tamoxifen use and time from discontinuation of the drug. RESULTS: After one year of tamoxifen use, the mean endometrial thickness in periodic treatment group was 6.5-/+1.4 mm, and 10.2-/+2.0 mm in consecutive treatment group. Endometrial thickness increased with the duration of tamoxifen use at the rate of 0.51 mm/year in the periodic treatment group, and 0.73 mm/year in consecutive treatment group. After discontinuation of tamoxifen, the endometrial thickness in the former group decreased by 1.29 mm/year, and by 1.33 mm/year in the latter. CONCLUSIONS: Endometrial hyperplasia is obviously milder in premenopausal women receiving periodic tamoxifen treatment who are at risk for breast cancer than that in women with consecutive treatment. After discontinuation of the drug, the endometrial thickness decreases at a roughly equal slow rate in the two groups. PMID- 17715034 TI - [CT manifestation in comparison with histopathological findings of radiation induced liver disease in pigs: a pilot study]. AB - OBJECTIVE: To study the pathological basis of radiological reaction types of radiation-induced liver disease on multiphasic CT scans. METHODS: Three pigs (tagged with A, B, and C) were subjected to single-dose radiation of 40, 40 and 30 Gy on the right or left lobe of the liver, respectively. At 42, 56, 133, and 168 days after irradiation, all pigs were examined with non-enhanced scan and contrast-enhanced scans at different time points after contrast injection. Hounsfield units (HU) were measured in each CT study to evaluate the density of irradiated and non-irradiated liver tissue to determine the reaction type. Liver tissues in the irradiation area obtained by needle biopsy with CT guidance were examined with electron microscopy, and specimens of the tissue corresponding to the region of interest on CT were obtained from necropsies for pathological examination. RESULTS: Radiologically, the 3 pig models presented with 3 reaction types on the multiphasic CT scans on days 133, 56, and 168 after radiation, respectively. Type 1 presented constant low-density change in all phases, the pathological basis of which was radiation hepatitis; type 2 showed pre-contrast phase isodense, arterial phase hyperdense, portal phase isodense and later phase hyperdense changes; type 3 was characterized by pre-contrast phase isodense, arterial phase hyperdense, portal phase hypodense and later phase hyperdense changes. The pathological basis of the last two radiological reaction types was radiation cirrhosis (postnecrotic cirrhosis). CONCLUSIONS: Different radiological reaction types of radiation liver injury on multiphase CT have different pathological basis, and multiphase contrast-enhanced CT may help distinguish the radiation reactions from tumor recurrence. PMID- 17715035 TI - [A multivariate analysis of prevalence and risk factors of retinopathy of prematurity]. AB - OBJECTIVE: To investigate the prevalence and risk factors of retinopathy of prematurity (ROP). METHODS: This investigation involved 125 premature infants admitted in the neonate intensive unit between July 1st, 2006 and Feb 1st, 2007, who were less than 37 weeks of postconceptional age, or more than 37 weeks but with birth weight <2500 g. At the fourth postnatal week or the corrected gestational age of 32 to 34 weeks, the infants underwent ROP examination of both eyes using RetCam digital retinal camera. Diagnosis and staging of ROP were established according to the international guidelines, with another 20 full-term infants as the control group. RESULTS: All the 125 infants completed the follow up. The prevalence of ROP in the premature group was 6.4%, while no ROP was found in the control group. Of the premature infants, the prevalence of ROP in infants with birth weight 0.05). The killing effects were positively correlated with the concentration of HpD and the dosage of laser irradiation. Exposure to 20 J/cm(2) resulted in an IC(50) of LoVo and CoLo205 cells of 0.4 and 0.6 microg/ml respectively, which were not significantly different (P>0.05). The cellular HpD fluorescence intensities were also similar between the two cells. CONCLUSION: HpD PDT may effectively kill LoVo and CoLo205 cells cultured in vitro. PMID- 17715040 TI - [Change of renal graft dendritic cells in the early stage following transplantation: a dynamic observation in rats]. AB - OBJECTIVE: To observe the dynamic changes of dendritic cells (DCs) in the renal graft of rats within 72 h after renal transplantation. METHODS: Using SD rats as the donors and Wistar rats as the recipients, renal transplantation was performed in 30 pairs of rats, with another 5 donor kidneys that were not transplanted serving as the sham operation group. The transplanted kidneys were harvested at 1, 6, 12, 24, 48 and 72 h after recovery of blood circulation, paraffin-embedded and sectioned ,followed by HE staining and immunohistochemical staining for S-100 protein for DC identification. The pathological changes and the DC density per glomerulus in the renal graft were observed with optical microscope. RESULTS: No signs of acute rejection were found in these sections. Few DCs were observed in the sham operation group and in the renal graft 1 h after transplantation. The number of DCs in the renal graft increased with time and reached the maximum 24 h after transplantation followed by gradual decrease. CONCLUSIONS: Within 72 h after renal transplantation, the number of DCs in the graft varies following a curve with a single peak. Increased DC density in the graft may result from recipient DC migration into the graft, and accordingly, decreased recipient DC migration results in decrease of DC density in the graft. The pattern of DC number variation in the graft can be helpful to further improve the therapy against graft rejection. PMID- 17715041 TI - [Changes of work of breathing in patients with acute exacerbation of chronic obstructive pulmonary disease during non-invasive positive pressure ventilation]. AB - OBJECTIVE: To investigate the effect of non-invasive positive pressure ventilation (NIPPV) on the work of breathing (WOB) in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD). METHODS: Eleven patients with acute exacerbation of COPD received pressure support ventilation (PSV) at different levels during NIPPV. The changes of inspiratory muscle effort and breathing pattern of the patients were observed. RESULTS: The average minute ventilation (VE, P<0.01) and tidal volume (VT, P<0.05) of the patients were significantly higher during routine PSV and high pressure support (H-PS) than those during spontaneous breathing (SB), and the breathing pattern of the patients did not undergo significant changes during high positive end expiratory pressure (H-PEEP). The WOB of the inspiratory muscles was reduced significantly during PSV as compared with that measured in SB (P<0.01), while the WOB of exspiratory muscle increased significantly (P<0.01). CONCLUSION: NIPPV can relieve the load of the inspiratory muscles in patients with acute exacerbation of COPD, and the WOB of the inspiratory muscles can be reduced by PSV, H-PEEP and H-PS (by 75%, 71% and 76%, respectively), but higher PSV during NIPPV can cause higher WOB of the exspiratory muscles. PMID- 17715042 TI - [Relative bioavailability and bioequivalence of azithromycin tablets in healthy volunteers]. AB - OBJECTIVE: To evaluate the bioavailability and bioequivalence of azithromycin tablets in healthy volunteers. METHODS: A single dose (500 mg) of azithromycin tablet (from 3 pharmaceutical companies) was given to 18 healthy volunteers according to a randomized cross-over design. The plasma concentrations of azithromycin were determined by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). RESULTS AND CONCLUSION: The T(max) of azithromycin products of the 3 pharmaceutical companies were 2.3-/+1.1, 3.0-/+1.1 and 2.9 /+0.8 h, C(max) were 319.2-/+176.7, 303.10-/+144.60 and 313.70-/+165.00 ng/ml, AUC(0-144) were 5073.60-/+2933.00, 4296.80-/+1896.20 and 4797.80-/+3234.00 ng.h/ml, AUC(0-max) were 5461.60-/+3236.00, 4804.40-/+2162.90 and 5163.20 /+3497.50 ng.h/ml, respectively. Statistical analysis of the above main pharmacokinetic parameters of azithromycin tablets suggests the bioequivalence of the three formulations. PMID- 17715043 TI - [Relationship between hepatitis B virus YMDD mutation and serum viral DNA loadings]. AB - OBJECTIVE: To investigate the relationship between lamivudine-resistant mutants of hepatitis B virus (HBV) and serum HBV DNA loading before antiviral therapy. METHODS: This study involved 106 patients with hepatitis B receiving lamivudine treatment for an average of 32 months (rang 12-48 months). Serum HBV DNA loadings were measured with PCR before and every 4 to 6 months during lamivudine therapy. HBV YMDD mutants were detected using mismatched PCR-restriction fragment length polymorphism (PCR-RFLP) during lamivudine treatment. RESULTS: HBV DNA loading was significantly higher in patients infected with HBV YMDD mutants during lamivudine therapy than those infected with HBV without YMDD mutation. CONCLUSION: High viral loading in hepatitis B patients before treatment is associated with high likeliness of HBV YMDD mutation during lamivudine treatment. HBV DNA loading may be indicative for the occurrence of YMDD mutation during lamivudine therapy. PMID- 17715044 TI - [Factors related to chronic hepatitis B relapse after interferon-alpha treatment: a follow-up study]. AB - OBJECTIVE: To investigate the related to relapse of chronic hepatitis B (CHB) after recombinant interferon-alpha (rIFN-alpha) treatment. METHODS: This investigation involved 523 pathologically confirmed CHB patients including 403 HBeAg-positive and 120 HBeAg-negative patients, who were treated with 5 MU rIFN alpha subcutaneously thrice a week for 6-25 months. For each patient, serum alanine aminotransferase (ALT) was measured biochemically, serum HBV DNA level detected with quantitative fluorescent PCR, and HBeAg level with enzyme immuoassay every 1-3 months during therapy and every 3-6 months during the follow up period. RESULTS: Early response to rIFN-alpha treatment was observed in 302 (57.7%) patients at the end of treatment, among whom 39.4% (119/302) suffered relapse during the follow-up for 39.2-/+21.5 months. Age, HBeAg status before treatment, and follow-up duration were the predictive factors for post-treatment relapse. The mean age of patients with CHB relapse was significantly higher than that of the sustained responders (P<0.001), and the relapse rates in HBeAg negative group (55.8%, 43/77) were significantly higher than that in HBeAg positive group (33.8%, 76/225) at the end of follow up (P<0.001). The relapse rate and accumulative relapse rates at each year during the follow-up (for 5 years as the longest) differed significantly (P<0.001, P=0.000), but the accumulative relapse rates differed little between the years after the initial 2 of the follow-up (P=0.670). The relapse was not related to the patient's gender, pretreatment serum ALT, HBV DNA, grade of liver inflammation, stage of liver fibrosis, or duration of treatment. In HBeAg-positive patients, however, the mean HBV DNA was significantly higher in relapse group than in sustained response group (P=0.017). CONCLUSION: Age, pretreatment HBeAg status, and follow-up duration are independent predictive factors for post-treatment CHB relapse. In HBeAg positive patients, pretreatment serum HBV DNA is also one of the risk factors for relapse. PMID- 17715045 TI - [Expression of heparanase and nuclear factor kappa B in pancreatic adenocarcinoma]. AB - OBJECTIVE: To detect the expressions of heparanase and nuclear factor kappa B p65 (NF-kappaB p65) in pancreatic adenocarcinomas and analyze their relation to patients' prognosis and the regulatory mechanism of NF-kappaB on heparanase expression. METHODS: Heparanase and NF-kappaB p65 proteins in the tumor and adjacent tissues were detected by immunohistochemistry in 48 patients with pancreatic adenocarcinoma and analyzed for their clinicopathological significance. RESULTS: Heparanase and NF-kappaB p65 proteins were found in 30 (62.5%) and 22 (45.9%) tumor specimens, respectively, a rate significantly higher than that in the adjacent tissues. High heparanase expression was closely related to advanced TNM stage (P=0.031), lymph node metastasis (P=0.003) and decreased 3 year postoperative survival (20.0% vs 0%, P=0.001). NF-kappaB p65 expression was associated with lymph node metastasis (P=0.017) and distant metastasis (P=0.031), but had a higher positive rate in heparanase-positive cases than in heparanase negative cases (P=0.018). Multivariate analysis showed that neither heparanase nor NF-kappaB p65 was the independent prognostic factors. CONCLUSION: Heparanase is overexpressed in pancreatic adenocarcinomas in association with decreased postoperative survival. NF-kappaB may up-regulate heparanase expression and promote heparanase-dependent tumor invasion and metastasis. PMID- 17715046 TI - [Assessment of early-stage physiological response to acute lung injury in canine models using balloon catheter system for measuring esophageal and gastric pressure]. AB - OBJECTIVE: To explore feasible and reliable methods for estnbolishment and of acute lung injury model in animal models. METHODS: Twenty-four healthy adult mongrel dogs with oleic acid-induced acute lung injury were evaluated for early stage physiological response to acute lung injury using a balloon catheter system for measuring esophageal and gastric pressure. RESULTS: In canine models of early stage oleic acid-induced acute lung injury that sustained spontaneous breathing, in terms of respiratory mechanics, some parameters obviously increased including the respiratory rate (RR), minute ventilation (VE), peak inspiratory volume (Vinsp, peak), mean inspiratory volume (VT/Ti), inspiratory airway resistance (Raw, insp) (P<0.001 for all the parameters), with also significantly increased peak transdiaphragmatic pressure (Pdi, peak, P=0.0185). The tidal volume (VT) and dynamic lung compliance (CL,dyn), however, were significantly decreased (P<0.001), and significant variation occurred in the ratio of inspiratory time to duration of one breath (Ti/Ttot, P=0.163). In terms of gas exchange, the pH, PaO(2), SaO(2), PaO(2)/FiO(2), and end tidal partial pressure of carbon dioxide (PETCO(2)) all evidently declined (P<0.001), but PaCO(2) and ratio of alveolar dead space to tidal volume [VD(alv)/VT] increased significantly (P<0.001). CONCLUSION: Application of balloon catheter system for measuring esophageal and gastric pressures allows objective evaluation of the various physiological responses in early stage of acute lung injury. PMID- 17715047 TI - [Role of platelet-derived growth factor in the pathogenesis of preeclampsia]. AB - OBJECTIVE: To study the role of platelet-derived growth factor (PDGF) in the pathogenesis of preeclampsia (PRE). METHODS: Thirteen normal and 20 PRE late pregnancy women were enrolled in this study. The serum PDGF-BB levels were measured with enzyme-linked immunosorbent assay, and the expression of PDGF-B mRNA in the decidual blood vessel was determined using in situ hybridization. RESULTS: PDGF-BB levels in PRE group was significantly higher than that in normal pregnant women (83.54 -/+34.52 vs 39.61-/+18.20, P<0.001), and the expression of PDGF-B mRNA in decidual blood vessel was also significantly higher in PRE group (P<0.001), showing a positive correlation between serum PDGF and PDGF-B mRNA expression (r=0.603, P<0.001). CONCLUSION: PDGF is associated with the pathology of decidual blood vessel. Elevated serum PDGF levels and PDGF-B mRNA expression in the decidual blood vessel may play an important role in the pathogenesis of PRE. PMID- 17715048 TI - [Diagnostic value of serum anti-cyclic citrullinated peptide antibodies in patients with rheumatoid arthritis]. AB - OBJECTIVE: To explore the diagnostic value of serum anti-cyclic citrullinated peptide (Anti-CCP) antibodies in patients with rheumatoid arthritis (RA). METHODS: Anti-CCP antibodies were detected in the serum samples of 120 RA patients, 71 non-RA patients with various rheumatic diseases, and 50 normal controls by enzyme-linked immunosorbent assay (ELISA) using domestic and imported commercial detection kits. Rheumatoid factors (RF) were assayed by immune nephelometry. The correlation between Anti-CCP and RF in RA diagnosis was analyzed by calculating the area under curve of the receiver operating characteristic (ROC) curve. RESULTS: The positive rates for Anti-CCP, detected using both domestic and imported kits, were 61.7% (74/120) and 69.2% (83/120) in RA group, significantly higher than those in the non-RA group (9.9%, 7/71 and 7.0%, 5/71) and normal control group (both 0, P<0.001). The sensitivities for Anti-CCP and RF were 69.2% and 64.2%, and the specificities were 92.9% and 67.6%, respectively. The positive predictive value was 94.3% for Anti-CCP and 77.0% for RF, whereas the negative predictive value was 64.1% for Anti-CCP and 52.7% for RF. The likelihood ratio (LR) was 9.82 for anti-CCP and 1.98 for RF. The area under curve of ROC for Anti-CCP was 0.829 and 0.740 for RF. Anti-CCP antibodies had greater diagnostic value than RF in RA diagnosis, and Anti-CCP showed significant correlation with RF (r=0.29, P=0.001). CONCLUSION: Anti-CCP antibodies are an excellent serological marker for RA, which shows high diagnostic specificity at early stage, and can increase its diagnostic value when combined with RF detection, but the role of Anti-CCP in the occurrence and prognosis of RA remains to be further investigated. PMID- 17715049 TI - [Comparison of target controlled propofol infusion and sevoflurane inhalational anesthesia in laparoscopic cholecystectomy]. AB - OBJECTIVE: To compare the effects of propofol target controlled infusion (TCI) and sevoflurane inhalational anesthesia on the hemodynamics and postoperative recovery in patients undergoing laparoscopic cholecystectomy. METHODS: Sixty ASA IorII patients scheduled for laparoscopic cholecystectomy were randomized into propofol TCI group (group P) and sevoflurane inhalational anesthesia group (group S). In group P, TCI propofol was maintained after intubation until incision closure with the target concentration at 3 microg/ml. In group S, sevoflurane (end-tidal concentration of 2%) was maintained with oxygen flow rate of 2 L/min until incision closure. Fentanyl and vecuronium were intravenously infused according to the depth of anesthesia during the operation. MAP and HR were measured before anesthesia (T(1)), immediately after intubation (T(2)), at skin incision (T(3)), 10 min after pneumoperitoneum (T(4)) and immediately after completion of the operation (T(5)) respectively. Awake time, postoperative nausea and vomiting of the patients were observed after operation. RESULTS: There was significant difference in MAP and HR at T(4) between the two groups (P<0.05), but not at T(1), T(2), T(3) and T(5) (P>0.05). No significant difference was also found in the awake time between the two groups (P>0.05). The incidence of PONV, however, was significantly lower in group P than in group S (P<0.05). CONCLUSION: Propofol TCI and sevoflurane inhalational anesthesia are all effective in inducing good anesthetic effect, maintaining hemodynamic stability and ensuring rapid recovery, but propofol TCI causes lower incidence of PONV in operations such as laparoscopic cholecystectomy. PMID- 17715050 TI - [Magnetic resonance imaging of bone and joint transfixed with stainless steel lag screws]. AB - OBJECTIVE: To explore the method of displaying the bone and joint structures transfixed with stainless steel lag screws using magnetic resonance imaging (MRI), 2 patients whose knee joints (and ankle joint in one case) were transfixed with stainless steel underwent MRI with FSE-XL pulse sequence. The images clearly displayed the bones, ligaments and articular cartilage around the stainless steel materials, demonstrating the efficacy of FSE-XL pulse sequence in evaluation of the anatomical features of the bones and joints transfixed with stainless steel materials. PMID- 17715051 TI - [Efficient and rapid non-test tube cloning of Jatropha curcas]. AB - OBJECTIVE: To develop a new technique for efficient and rapid non-test tube cloning of the medicinal and energy- producing plant Jatropha curcas. METHODS: Using the mini-stem fragment (2-3 cm) of Jatropha curcas with merely one axillary bud as the explant, the effect of an auxin IBA concentration on the plantlet regeneration was studied. RESULTS AND CONCLUSION: When treated with 1 mg/LIBA for 1h, the explants showed the most rapid propagation. The mini-stem fragments high root regeneration ratio (96.7%), short root regeneration period (18.2-/+2.0 d), large number of new roots per explant (6.3-/+1.8), and long total root length (6.8-/+3.5 cm), demonstrating that this technique can be a simple and efficient method for rapid non-test tube cloning of Jatropha curcas of potential industrial value. PMID- 17715052 TI - On the use of cellular telephony for audio interaction with animals. AB - Playback is an important method of surveying animals, assessing habitats and studying animal communication. However, conventional playback methods require on site observers and therefore become labour-intensive when covering large areas. Such limitations could be circumvented by the use of cellular telephony, a ubiquitous technology with increasing biological applications. In addressing concerns about the low audio quality of cellular telephones, this paper presents experimental data to show that owls of two species (Strix varia and Megascops asio) respond similarly to calls played through cellular telephones as to calls played through conventional playback technology. In addition, the telephone audio recordings are of sufficient quality to detect most of the two owl species' responses. These findings are a first important step towards large-scale applications where networks of cellular phones conduct real-time monitoring tasks. PMID- 17715053 TI - Marker-assisted selection: an approach for precision plant breeding in the twenty first century. AB - DNA markers have enormous potential to improve the efficiency and precision of conventional plant breeding via marker-assisted selection (MAS). The large number of quantitative trait loci (QTLs) mapping studies for diverse crops species have provided an abundance of DNA marker-trait associations. In this review, we present an overview of the advantages of MAS and its most widely used applications in plant breeding, providing examples from cereal crops. We also consider reasons why MAS has had only a small impact on plant breeding so far and suggest ways in which the potential of MAS can be realized. Finally, we discuss reasons why the greater adoption of MAS in the future is inevitable, although the extent of its use will depend on available resources, especially for orphan crops, and may be delayed in less-developed countries. Achieving a substantial impact on crop improvement by MAS represents the great challenge for agricultural scientists in the next few decades. PMID- 17715054 TI - Genetic modulation of cognitive flexibility and socioemotional behavior in rhesus monkeys. AB - In human and nonhuman primates, structural variants of the gene encoding the serotonin transporter [5-hydroxytryptamine transporter (5-HTT)] affect the transcription and functional efficacy of 5-HTT. Prior work has shown that structural variants differentially affect function of the amygdala and ventromedial prefrontal cortex (VMPFC), regions important for the regulation and expression of emotion. However, relatively little is known about the impact of 5 HTT allelic variants on cognition. To address this question, we tested rhesus monkeys carrying orthologous structural variants of 5-HTT on a battery of tasks that assess cognitive flexibility, reward processing, and emotion. Here we show that rhesus monkeys carrying two copies of the short allele (SS) of the rhesus 5 HTT gene-linked polymorphic region (rh5-HTTLPR) show significantly reduced cognitive flexibility as measured by two tasks in the battery: object discrimination reversal learning and instrumental extinction. Monkeys with the SS genotype also displayed alterations in socioemotional behavior. Genotype variation was not related to visual perceptual abilities, valuation of food rewards, or the ability to express a wide range of defensive responses. Although emotional alterations associated with 5-HTT variation have been described as the primary phenotype, the present study reports differences in at least one type of cognitive flexibility, which has not been described previously. Because behaviors modulated by the 5-HTTLPR are a subset of those dependent on the VMPFC, analysis of structural and functional correlates of gene variation in this region may inform the nature of the genetic modulation of cognition. PMID- 17715055 TI - Microfluidic system for on-chip high-throughput whole-animal sorting and screening at subcellular resolution. AB - We report a suite of key microfluidic devices for complex high-throughput whole animal genetic and drug screens. We demonstrate a high-speed microfluidic sorter that can isolate and immobilize Caenorhabditis elegans in a well defined geometry for screening phenotypic features at subcellular resolution in physiologically active animals. We show an integrated chip containing individually addressable screening-chamber devices for incubation and exposure of individual animals to biochemical compounds and high-resolution time-lapse imaging of many animals on a single chip without the need for anesthesia. We describe a design for delivery of compound libraries in standard multiwell plates to microfluidic devices and also for rapid dispensing of screened animals into multiwell plates. When used in various combinations, these devices will facilitate a variety of high-throughput assays using whole animals, including mutagenesis and RNAi and drug screens at subcellular resolution, as well as high-throughput high-precision manipulations such as femtosecond laser microsurgery for large-scale in vivo neural degeneration and regeneration studies. PMID- 17715056 TI - Crystal structure of the incretin-bound extracellular domain of a G protein coupled receptor. AB - Incretins, endogenous polypeptide hormones released in response to food intake, potentiate insulin secretion from pancreatic beta cells after oral glucose ingestion (the incretin effect). This response is signaled by the two peptide hormones glucose-dependent insulinotropic polypeptide (GIP) (also known as gastric inhibitory polypeptide) and glucagon-like peptide 1 through binding and activation of their cognate class 2 G protein-coupled receptors (GPCRs). Because the incretin effect is lost or significantly reduced in patients with type 2 diabetes mellitus, glucagon-like peptide 1 and GIP have attracted considerable attention for their potential in antidiabetic therapy. A paucity of structural information precludes a detailed understanding of the processes of hormone binding and receptor activation, hampering efforts to develop novel pharmaceuticals. Here we report the crystal structure of the complex of human GIP receptor extracellular domain (ECD) with its agonist, the incretin GIP(1-42). The hormone binds in an alpha-helical conformation in a surface groove of the ECD largely through hydrophobic interactions. The N-terminal ligand residues would remain free to interact with other parts of the receptor. Thermodynamic data suggest that binding is concomitant with structural organization of the hormone, resulting in a complex mode of receptor-ligand recognition. The presentation of a well structured, alpha-helical ligand by the ECD is expected to be conserved among other hormone receptors of this class. PMID- 17715058 TI - Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease. AB - Defects in the mitochondrial cytochrome c oxidase (COX) have been associated with Alzheimer's Disease, in which the age-dependent accumulation of beta-amyloid plays an important role in synaptic dysfunction and neurodegeneration. To test the possibility that age-dependent decline in the mitochondrial respiratory function, especially COX activity, may participate in the formation and accumulation of beta-amyloid, we generated mice expressing mutant amyloid precursor protein and mutant presenilin 1 in a neuron-specific COX-deficient background. A neuron-specific COX-deficient mouse was generated by the Cre-loxP system, in which the COX10 gene was deleted by a CamKIIalpha promoter-driven Cre recombinase. COX10 is a farnesyltransferase involved in the biosynthesis of heme a, required for COX assembly and function. These KO mice showed an age-dependent COX deficiency in the cerebral cortex and hippocampus. Surprisingly, COX10 KO mice exhibited significantly fewer amyloid plaques in their brains compared with the COX-competent transgenic mice. This reduction in amyloid plaques in the KO mouse was accompanied by a reduction in Abeta42 level, beta-secretase activity, and oxidative damage. Likewise, production of reactive oxygen species from cells with partial COX activity was not elevated. Collectively, our results suggest that, contrary to previous models, a defect in neuronal COX does not increase oxidative damage nor predispose for the formation of amyloidgenic amyloid precursor protein fragments. PMID- 17715059 TI - Protection against telomeric position effects by the chicken cHS4 beta-globin insulator. AB - Epigenetic silencing of genes relocated near telomeres, termed telomeric position effect, has been extensively studied in yeast and more recently in vertebrates. However, protection of a transgene against telomeric position effects by chromatin insulators has not yet been addressed. In this work we investigated the capacity of the chicken beta-globin insulator cHS4 to shield a transgene against silencing by telomeric heterochromatin. Using telomeric repeats, we targeted transgene integration into telomeres of the chicken cell line HD3. When the chicken cHS4 insulator is incorporated to the transgene, we observe a sustained gene expression of single-copy integrants that can be maintained for >100 days of continuous culture. However, uninsulated single-copy clones showed an accelerated gene expression extinction profile. Unexpectedly, telomeric silencing was not reversed with trichostatin A or nicotidamine. In contrast, significant reactivation was obtained with 5-aza-2'-deoxycytidine, consistent with the subtelomeric DNA methylation status. Strikingly, insulated transgenes integrated into telomeric regions were enriched in histone methylation, such as H3K4me2 and H3K79me2, but not in histone acetylation. Furthermore, the cHS4 insulator counteracts telomeric position effects in an upstream stimulatory factor independent manner. Our results suggest that this insulator has the capacity to adapt to different chromatin propagation signals in distinct insertional epigenome environments. PMID- 17715057 TI - Searching for species in haloarchaea. AB - Prokaryotic (bacterial and archaeal) species definitions and the biological concepts that underpin them entail clustering (cohesion) among individuals, in terms of genome content and gene sequence similarity. Homologous recombination can maintain gene sequence similarity within, while permitting divergence between, clusters and is thus the basis for recent efforts to apply the Biological Species Concept in prokaryote systematics and ecology. In this study, we examine isolates of the haloarchaeal genus Halorubrum from two adjacent ponds of different salinities at a Spanish saltern and a natural saline lake in Algeria by using multilocus sequence analysis. We show that, although clusters can be defined by concatenation of multiple marker sequences, barriers to exchange between them are leaky. We suggest that no nonarbitrary way to circumscribe "species" is likely to emerge for this group, or by extension, to apply generally across prokaryotes. Arbitrary criteria might have limited practical use, but still must be agreed upon by the community. PMID- 17715060 TI - Resolving vesicle fusion from lysis to monitor calcium-triggered lysosomal exocytosis in astrocytes. AB - Optical imaging of individual vesicle exocytosis is providing new insights into the mechanism and regulation of secretion by cells. To study calcium-triggered secretion from astrocytes, we used acridine orange (AO) to label vesicles. Although AO is often used for imaging exocytosis, we found that imaging vesicles labeled with AO can result in their photolysis. Here, we define experimental and analytical approaches that permit us to distinguish unambiguously between fusion, leakage, and lysis of individual vesicles. We have used this approach to demonstrate that lysosomes undergo calcium-triggered exocytosis in astrocytes. PMID- 17715063 TI - Cortical dysplasia and skull defects in mice with a Foxc1 allele reveal the role of meningeal differentiation in regulating cortical development. AB - We report the identification of a hypomorphic mouse allele for Foxc1 (Foxc1(hith)) that survives into adulthood revealing previously unknown roles for Foxc1 in development of the skull and cerebral cortex. This line of mice was recovered in a forward genetic screen using ENU mutagenesis to identify mutants with cortical defects. In the hith allele a missense mutation substitutes a Leu for a conserved Phe at amino acid 107, leading to destabilization of the protein without substantially altering transcriptional activity. Embryonic and postnatal histological analyses indicate that diminished Foxc1 protein expression in all three layers of meningeal cells in Foxc1(hith/hith) mice contributes to the cortical and skull defects in mutant mice and that the prominent phenotypes appear as the meninges differentiate into pia, arachnoid, and dura. Careful analysis of the cortical phenotypes shows that Foxc1(hith/hith) mice display detachment of radial glial endfeet, marginal zone heterotopias, and cortical dyslamination. These abnormalities have some features resembling defects in type 2 (cobblestone) lissencephaly or congenital muscular dystrophies but appear later in corticogenesis because of the delay in breakdown of the basement membrane. Our data reveal that the meninges regulate the development of the skull and cerebral cortex by controlling aspects of the formation of these neighboring structures. Furthermore, we provide evidence that defects in meningeal differentiation can lead to severe cortical dysplasia. PMID- 17715062 TI - Ionotropic glutamate-like receptor delta2 binds D-serine and glycine. AB - The orphan glutamate-like receptor GluRdelta2 is predominantly expressed in Purkinje cells of the central nervous system. The classification of GluRdelta2 to the ionotropic glutamate receptor family is based on sequence similarities, because GluRdelta2 does not form functional homomeric glutamate-gated ion channels in transfected cells. Studies in GluRdelta2(-/-) knockout mice as well as in mice with naturally occurring mutations in the GluRdelta2 gene have demonstrated an essential role of GluRdelta2 in cerebellar long-term depression, motor learning, motor coordination, and synaptogenesis. However, the lack of a known agonist has hampered investigations on the function of GluRdelta2. In this study, the ligand-binding core of GluRdelta2 (GluRdelta2-S1S2) was found to bind neutral amino acids such as D-serine and glycine, as demonstrated by isothermal titration calorimetry. Direct evidence for binding of D-serine and structural rearrangements in the binding cleft of GluRdelta2-S1S2 is provided by x-ray structures of GluRdelta2-S1S2 in its apo form and in complex with D-serine. Functionally, D-serine and glycine were shown to inactivate spontaneous ion channel conductance in GluRdelta2 containing the lurcher mutation (EC(50) values, 182 and 507 microM, respectively). These data demonstrate that the GluRdelta2 ligand-binding core is capable of binding ligands and that cleft closure of the ligand-binding core can induce conformational changes that alter ion permeation. PMID- 17715064 TI - Vertebrate heart growth is regulated by functional antagonism between Gridlock and Gata5. AB - Embryonic organs attain their final dimensions through the generation of proper cell number and size, but the control mechanisms remain obscure. Here, we establish Gridlock (Grl), a Hairy-related basic helix-loop-helix (bHLH) transcription factor, as a negative regulator of cardiomyocyte proliferative growth in zebrafish embryos. Mutations in grl cause an increase in expression of a group of immediate-early growth genes, myocardial genes, and development of hyperplastic hearts. Conversely, cardiomyocytes with augmented Grl activity have diminished cell volume and fail to divide, resulting in a marked reduction in heart size. Both bHLH domain and carboxyl region are required for Grl negative control of myocardial proliferative growth. These Grl-induced cardiac effects are counterbalanced by the transcriptional activator Gata5 but not Gata4, which promotes cardiomyocyte expansion in the embryo. Biochemical analyses show that Grl forms a complex with Gata5 through the carboxyl region and can repress Gata5 mediated transcription via the bHLH domain. Hence, our studies suggest that Grl regulates embryonic heart growth via opposing Gata5, at least in part through their protein interactions in modulating gene expression. PMID- 17715065 TI - Intravenous immunoglobulin (IVIG) protects the brain against experimental stroke by preventing complement-mediated neuronal cell death. AB - Stroke is among the three leading causes of death worldwide and the most frequent cause of permanent disability. Brain ischemia induces an inflammatory response involving activated complement fragments. Here we show that i.v. Ig (IVIG) treatment, which scavenges complement fragments, protects brain cells against the deleterious effects of experimental ischemia and reperfusion (I/R) and prevents I/R-induced mortality in mice. Animals administered IVIG either 30 min before ischemia or after 3 h of reperfusion exhibited a 50-60% reduction of brain infarct size and a 2- to 3-fold improvement of the functional outcome. Even a single low dose of IVIG given after stroke was effective. IVIG was protective in the nonreperfusion model of murine stroke as well and did not exert any peripheral effects. Human IgG as well as intrinsic murine C3 levels were significantly higher in the infarcted brain region compared with the noninjured side, and their physical association was demonstrated by immuno-coprecipitation. C5-deficient mice were significantly protected from I/R injury compared with their wild-type littermates. Exposure of cultured neurons to oxygen/glucose deprivation resulted in increased levels of C3 associated with activation of caspase 3, a marker of apoptosis; both signals were attenuated with IVIG treatment. Our data suggest a major role for complement-mediated cell death in ischemic brain injury and the prospect of using IVIG in relatively low doses as an interventional therapy for stroke. PMID- 17715067 TI - Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells. AB - The maintenance of immune tolerance to apoptotic cells (AC) within an inflammatory milieu is vital to prevent autoimmunity. To investigate this, we administered syngeneic AC i.v. into mice carrying a cohort of ovalbumin (OVA) specific transgenic T cells (DO11.10) along with OVA peptide and complete Freund's adjuvant, observing a dramatic increase in OVA-specific IL-10 secretion. Activated splenic B cells responded directly to AC, increasing secretion of IL 10, and this programming by AC was key to inducing T cell-derived IL-10. We went on to ask whether AC are able to modulate the course of autoimmune-mediated, chronic inflammation. AC given up to 1 month before the clinical onset of collagen-induced arthritis protected mice from severe joint inflammation and bone destruction. Antigen-specific CD4(+) T cells again secreted significantly more IL 10, associated with a reduced titer of pathogenic anti-collagen II antibodies. Inhibition of IL-10 in vivo reversed the beneficial effects of AC. Passive transfer of B cells from AC-treated mice provided significant protection from arthritis. These data demonstrate that AC exert a profound influence on an adaptive immune response through the generation of CD19(+) regulatory B cells, which in turn are able to influence the cytokine profile of antigen-specific effector T cells. PMID- 17715066 TI - Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models. AB - Mutants of superoxide dismutase-1 (SOD1) cause ALS by an unidentified cytotoxic mechanism. We have previously shown that the stable SOD1 mutants D90A and G93A are abundant and show the highest levels in liver and kidney in transgenic murine ALS models, whereas the unstable G85R and G127X mutants are scarce but enriched in the CNS. These data indicated that minute amounts of misfolded SOD1 enriched in the motor areas might exert the ALS-causing cytotoxicity. A hydrophobic interaction chromatography (HIC) protocol was developed with the aim to determine the abundance of soluble misfolded SOD1 in tissues in vivo. Most G85R and G127X mutant SOD1s bound in the assay, but only minute subfractions of the D90A and G93A mutants. The absolute levels of HIC-binding SOD1 were, however, similar and broadly inversely related to lifespans in the models. They were generally enriched in the susceptible spinal cord. The HIC-binding SOD1 was composed of disulfide-reduced subunits lacking metal ions and also subunits that apparently carried nonnative intrasubunit disulfide bonds. The levels were high from birth until death and were comparable to the amounts of SOD1 that become sequestered in aggregates in the terminal stage. The HIC-binding SOD1 species ranged from monomeric to trimeric in size. These species form a least common denominator amongst SOD1 mutants with widely different molecular characteristics and might be involved in the cytotoxicity that causes ALS. PMID- 17715068 TI - The circadian clock stops ticking during deep hibernation in the European hamster. AB - Hibernation is a fascinating, yet enigmatic, physiological phenomenon during which body temperature and metabolism are reduced to save energy. During the harsh season, this strategy allows substantial energy saving by reducing body temperature and metabolism. Accordingly, biological processes are considerably slowed down and reduced to a minimum. However, the persistence of a temperature compensated, functional biological clock in hibernating mammals has long been debated. Here, we show that the master circadian clock no longer displays 24-h molecular oscillations in hibernating European hamsters. The clock genes Per1, Per2, and Bmal1 and the clock-controlled gene arginine vasopressin were constantly expressed in the suprachiasmatic nucleus during deep torpor, as assessed by radioactive in situ hybridization. Finally, the melatonin rhythm generating enzyme, arylalkylamine N-acetyltransferase, whose rhythmic expression in the pineal gland is controlled by the master circadian clock, no longer exhibits day/night changes of expression but constantly elevated mRNA levels over 24 h. Overall, these data provide strong evidence that in the European hamster the molecular circadian clock is arrested during hibernation and stops delivering rhythmic output signals. PMID- 17715069 TI - AJR Teaching File: infertility in a young woman. PMID- 17715070 TI - AJR Teaching File: intermittent claudication of the lower extremity in a young patient. PMID- 17715071 TI - AJR Teaching File: weight lifter with swelling in the upper arm. PMID- 17715072 TI - AJR Teaching File: chest pain in a woman with an inferior vena cava filter. PMID- 17715073 TI - AJR Teaching File: dyspnea following surgical repair of partial anomalous venous return. PMID- 17715061 TI - Patterns of damage in genomic DNA sequences from a Neandertal. AB - High-throughput direct sequencing techniques have recently opened the possibility to sequence genomes from Pleistocene organisms. Here we analyze DNA sequences determined from a Neandertal, a mammoth, and a cave bear. We show that purines are overrepresented at positions adjacent to the breaks in the ancient DNA, suggesting that depurination has contributed to its degradation. We furthermore show that substitutions resulting from miscoding cytosine residues are vastly overrepresented in the DNA sequences and drastically clustered in the ends of the molecules, whereas other substitutions are rare. We present a model where the observed substitution patterns are used to estimate the rate of deamination of cytosine residues in single- and double-stranded portions of the DNA, the length of single-stranded ends, and the frequency of nicks. The results suggest that reliable genome sequences can be obtained from Pleistocene organisms. PMID- 17715074 TI - AJR Teaching File: child with chronic constipation. PMID- 17715075 TI - AJR Teaching File: multiple symmetric abnormalities in a radionuclide bone scan. PMID- 17715076 TI - Sonographic training program at a district hospital in a developing country: work in progress. AB - OBJECTIVE: The purposes of this study were to assess the feasibility of a sonographic training program at a district hospital in a developing country and to evaluate the effect of the program on public health care services. SUBJECTS AND METHODS: A sonographic training program is being conducted on Pemba Island, Tanzania. A maximum of 10 trainees participate in the program. Courses in sonography conducted by European physicians are scheduled every 4 months for 2 consecutive weeks each time. The sonographic training program lasts 5 years and is divided into three stages in which basic, advanced, and specialized courses are organized. At the end of every course, the trainees take a multiple-choice test (score, 1-10) and a practical test with patients (score, 1-5). To advance to the next stage, a trainee needs a score of at least 7 on the theory test and at least 3 on the practical. RESULTS: Three courses have been completed. The total mean scores on the multiple-choice test were 7.4 (range, 6.5-9) at the end of the first course, 7.3 (range, 6.5-8.5) at the end of the second course, and 6.2 (range, 4.0-9.5) at the end of the third course. A shortage of electricity hindered the practical test after the first and second courses. At the end of the third course, the total mean score on the practical was 3.5 (range, 1.5-5.0). Seven of 10 trainees were admitted to the second year of the sonographic training program. The mean monthly hospital earnings during the three-course period were 673,200 Tanzanian shillings. CONCLUSION: Sonography is an affordable technology for developing countries. Training in sonography should be included in the planning of long-term projects in which multiple access and feedback are provided in the same area. PMID- 17715078 TI - Sonographically guided percutaneous needle lavage in calcific tendinitis of the shoulder: short- and long-term results. AB - OBJECTIVE: The purpose of our study was to evaluate the short- and long-term effectiveness of sonographically guided percutaneous needle aspiration and lavage in calcific tendinitis of the shoulder and to study the progress of calcifications and symptoms in the first year after treatment. MATERIALS AND METHODS: Symptoms and radiologic findings after percutaneous aspiration of calcific tendinitis were prospectively evaluated in the short and the long term using a shoulder pain and disability index, evaluation of shoulder motion, and a survey of the self-perception by the patients regarding the progress of their disease. RESULTS: Sixty-seven consecutive shoulders were treated. A significant improvement was seen in shoulder motion, pain, and disability in the short term and in the long term (p < 0.0001). One year after treatment, 91% of shoulders had substantially or completely improved, 64% had perfect motion, and calcifications on radiography had resolved completely or nearly completely in 89%. A transitory recurrence was observed approximately 15 weeks after treatment in 44.3% of shoulders that improved. CONCLUSION: Percutaneous needle aspiration and lavage is effective in the short term and in the long term in calcific tendinitis of the shoulder, with results similar to or better than those published for other techniques, and it is only slightly invasive and painful. Progress after treatment may include a transitory period of recurrence of the pain. PMID- 17715077 TI - Selective atrophy of the abductor digiti quinti: an MRI study. AB - OBJECTIVE: Entrapment of the first branch of the lateral plantar nerve is a well recognized but diagnostically elusive cause of heel pain. The MR finding of selective atrophy of the abductor digiti quinti (ADQ) muscle has been reported as a marker of such entrapment. We performed a prospective study of consecutive patients undergoing foot and ankle MRI to determine the prevalence of ADQ atrophy and to examine the clinical symptoms of patients found to have ADQ atrophy. SUBJECTS AND METHODS: A prospective study of all patients referred for ankle and foot MRI examinations was performed. Six hundred two patients were included in the study: 387 females and 215 males. All images were evaluated for the presence of selective fatty atrophy of the ADQ muscle. The clinical notes on all patients with findings of ADQ atrophy were analyzed for descriptions of symptoms leading to the MR examination, the presence of symptoms that might be related to nerve entrapment, and the influence on clinical management related to the MR finding of ADQ atrophy. RESULTS: Thirty-eight of the 602 patients had selective fatty atrophy of the ADQ, 29 females and nine males. Only one patient had a clinical diagnosis of possible nerve entrapment before MR examination. MRI findings of ADQ atrophy altered clinical management in only one patient. CONCLUSION: Selective fatty atrophy of the ADQ is not a rare finding on MR examination of the foot and ankle, being seen in 6.3% of all studies and in 7.5% of all studies in females. The clinical relevance of selective ADQ atrophy seen on MRI is uncertain. PMID- 17715079 TI - Pulmonary hemorrhage in a patient with acute coronary syndrome. PMID- 17715081 TI - Treatment of hypertension from renal artery entrapment by percutaneous CT-guided botulinum toxin injection into diaphragmatic crus as alternative to surgery and stenting. AB - OBJECTIVE: Our objective was to describe the technique and outcome of CT-guided injection of botulinum toxin into the diaphragmatic crus in a patient with hypertension caused by left diaphragmatic crus compression of the left renal artery. CONCLUSION: After the procedure, the patient's hypertension disappeared. We propose this technique, which directly targets inhibition of overactivity of the diaphragmatic crus, for treatment of hypertension caused by diaphragmatic compression of the renal artery as an alternative to surgery and renal artery stenting. PMID- 17715080 TI - Sonographically guided percutaneous catheter drainage versus needle aspiration in the management of pyogenic liver abscess. AB - OBJECTIVE: The purpose of this study was to determine the effectiveness of percutaneous catheter drainage (PCD) and to compare PCD with percutaneous needle aspiration in the management of liver abscess. SUBJECTS AND METHODS: Sixty patients with pyogenic liver abscess were randomly assigned to two groups in a prospective study. Antibiotics were administered for 10 days, starting the day of the beginning of percutaneous treatment. One group was treated with sonographically guided PCD and the other group with repeated percutaneous needle aspiration. Percutaneous needle aspiration was attempted a maximum of three times. Lack of response to the third aspiration was considered failure of treatment; these patients were treated with PCD but were not included in the PCD group for analysis. Patient demographics, duration of hospital stay, treatment outcome, and complications were analyzed. RESULTS: Percutaneous needle aspiration was successful in 20 (67%) of the 30 patients after one (n = 12), two (n = 7), or three (n = 1) aspirations. PCD was curative in all 30 patients after one (n = 24) or two (n = 6) procedures. All abscesses 50 mm or less in longest diameter were successfully managed, 10 by percutaneous needle aspiration and 12 by PCD. None of patients in the percutaneous needle aspiration group with multiloculated abscesses (n = 5) was successfully treated. Hospital stay did not differ significantly between the groups. There were no complications related to the procedure. CONCLUSION: PCD is more effective than percutaneous needle aspiration in the management of liver abscess. Percutaneous needle aspiration can be used as a valid alternative for simple abscesses 50 mm in diameter or smaller. PMID- 17715082 TI - Multiple-electrode radiofrequency ablation of symptomatic hepatic cavernous hemangioma. PMID- 17715083 TI - Congenital absence of the portal vein in a patient with urolithiasis. PMID- 17715085 TI - Three-phase dynamic CT of pelioid hepatocellular carcinoma. PMID- 17715084 TI - Liver volume variation in patients with virus-induced cirrhosis: findings on MDCT. AB - OBJECTIVE: The objective of our study was to establish a standard liver volume formula and explore the correlation between hepatic lobe variations in patients with virus-induced cirrhosis and the severity of disease by measuring the volume of the whole liver, the left lateral segment, and the caudate lobe using 16-MDCT. MATERIALS AND METHODS: The volume and per-body surface area (BSA) volume of the whole liver, the left lateral segment, and the caudate lobe were calculated in 113 patients with normal livers and 101 patients with virus-induced cirrhosis who underwent volume CT. The proportion of the left lateral segment volume and the proportion of the caudate lobe volume to the total liver volume, the volume index, and the volume change ratio were also calculated, and these data were grouped by Child-Pugh classification and compared. The standard liver volume formula was constructed from body weight and body height or from BSA. RESULTS: There was a positive correlation between liver volume (LV) and body height, body weight (BW) [LV (cm3) = 12.90 x BW (kg) + 437.91], and BSA [LV (cm3) = 882.08 x BSA (m2) - 308.12]. The total mean +/- standard error (SE) liver volume of the control group was 1,222.76 +/- 216.96 cm3. The mean volumes of the whole liver and of the left lateral segment were 798.01 +/- 203.64 and 213.04 +/- 74.84 cm3, respectively, for Child-Pugh class C patients, which was significantly smaller than those values for Child-Pugh class A and B patients (p < 0.05). The mean volume of the caudate lobe was 36.83 +/- 22.11 cm3 for Child-Pugh class A patients, which is significantly larger than those values for Child-Pugh class B and C patients (p < 0.05). CONCLUSION: CT-measured liver volume and standard liver volume formulas were helpful in evaluating liver volume variations. Enlargement of the left lateral segment was absolute in Child-Pugh class A and B patients, but was relative in Child-Pugh class C patients; enlargement of the caudate lobe was absolute in Child-Pugh class A patients, but was relative in Child-Pugh class B and C patients. PMID- 17715086 TI - Fat-fluid levels in renal caliceal cavities: a CT sign of lipolysis due to urine extravasation after kidney rupture. PMID- 17715087 TI - Preclinical medical student education in radiology. PMID- 17715088 TI - Renal mass core biopsy. PMID- 17715089 TI - Will dialysis prevent the development of nephrogenic systemic fibrosis after gadolinium-based contrast administration? PMID- 17715091 TI - MRI of Marjolin's ulcer. PMID- 17715090 TI - Real-time elastography in the assessment of liver fibrosis. PMID- 17715093 TI - The beginning of the end of self-referral? PMID- 17715094 TI - Radiologic errors and malpractice: a blurry distinction. PMID- 17715095 TI - Preliminary radiology resident interpretations versus final attending radiologist interpretations and the impact on patient care in a community hospital. AB - OBJECTIVE: At academic institutions, overnight emergency radiology examinations are interpreted by the on-call radiology resident and are reviewed by an attending radiologist in the morning. The objective of our study was to determine the rate of discrepancies between the two interpretations and the possible effect, if any, on patient care. MATERIALS AND METHODS: The preliminary reports for 11,908 emergency diagnostic imaging examinations interpreted after hours by residents over a 3-year period (January 2002-January 2005) were reviewed retrospectively for any discrepancy with the attending radiologist's final interpretation. A discrepancy was noted if verbal notification of the ordering physician was required. The medical charts of the cases for which there was a major discrepancy between the two interpretations were reviewed. The discrepancies were categorized as to the effect on patient morbidity. The resident discrepancy rates were also compared with RADPEER data from our institution. RESULTS: The overall major discrepancy rate was 2.6%. This rate is comparable to RADPEER data, which found a misinterpretation rate of 2.1%. The technique most commonly involved in cases with discrepant interpretations was contrast-enhanced CT of the abdomen and pelvis, with the most common diagnosis related to acute appendicitis (total of 21 cases). The rate of discrepancy was highest for residents who were in their third year of training. The indications for these examinations varied; however, the effect on patient management was no significant effect in 92.8%, some negative effect in 6.9%, and significant negative effect in 0.3%. CONCLUSION: The results of this investigation highlight the minimal discrepancy rate that occurs with overnight resident coverage. Thus, there is no detrimental effect on the quality of patient care from relying on preliminary interpretations made by radiology residents. PMID- 17715096 TI - Volume CT: state-of-the-art reporting. AB - OBJECTIVE: CT has undergone generational change that has led to true volume imaging. Interpretation of volume images requires interaction between the radiologist and the volume data sets. The aim of this review is to examine postprocessing options and the evidence in the literature for changing the process of reporting to digital volume reporting. CONCLUSION: Diagnostic confidence and the accuracy of interpretation of volume CT images have increased with improvements in postprocessing techniques. PMID- 17715097 TI - JPEG 2000 compression of abdominal CT: difference in tolerance between thin- and thick-section images. AB - OBJECTIVE: The purpose of our study was to compare the tolerance of Joint Photographic Experts Group (JPEG) 2000 compression between thin- and thick section abdominal CT images. MATERIALS AND METHODS: One hundred 0.67-mm-thick and corresponding 5-mm-thick images were compressed to four different levels: reversible and irreversible 6:1, 10:1, and 15:1. Five radiologists determined if the compressed images were distinguishable from the originals. The percentage of distinguishable pairs and peak signal-to-noise ratio (PSNR) were compared between the thin and thick sections. The visually lossless threshold was estimated by comparing the percentages of the distinguishable pairs between each irreversible compression and the reversible compression. Paired Student's t tests and exact tests for paired proportions were used. RESULTS: Thin sections had smaller PSNRs at each compression level (p < 0.001). According to the pooled responses, the percentages of distinguishable pairs for the thin and thick sections, respectively, were 0% (0/100) and 0% at reversible compression, 27% and 0% at 6:1 (p < 0.001), 100% and 80% at 10:1 (p < 0.001), and 100% and 100% at 15:1. Artifacts increased significantly (p < 0.001) at 6:1 or more for the thin sections and at 10:1 and 15:1 for the thick sections, indicating that the visually lossless thresholds were below 6:1 and between 6:1 and 10:1, respectively. CONCLUSION: Thin-section abdominal CT images are less tolerant of compression, and a lower compression level should be used for the visually lossless threshold. PMID- 17715098 TI - Assessment of musculoskeletal infection in rats to determine usefulness of SPIO enhanced MRI. AB - OBJECTIVE: The objective of our study was to evaluate the usefulness of superparamagnetic iron oxide (SPIO)-enhanced MRI in experimental models of infectious disease and to analyze the intracellular uptake of SPIO. MATERIALS AND METHODS: Nine rats with infectious arthritis of the knee or soft-tissue infection were imaged on an MRI unit on days 4-6 after i.v. injection of a bacterial suspension. All animals were imaged on a T2-weighted fast spin-echo sequence before and 24 hours after administration of SPIO. The nine rats were classified into two groups according to the dose of SPIO. We calculated the relative signal to-noise ratio (SNR) change and compared the relative SNR change with the histologic findings. We analyzed iron-loaded cells and the intracellular uptake of iron particles according to the dose of SPIO. RESULTS: The SNR value decreased in proportion to the increase in the number of iron-laden macrophages or fibroblasts in the wall of the soft-tissue abscess (p < 0.01). The intracellular uptake of iron particles was shown in fibroblasts as well as in macrophages, and their uptake in the fibroblasts was greater than that in the macrophages (p < 0.05). There was no statistically significant difference in the intracellular uptake of iron particles according to the dose of SPIO (p > 0.1). CONCLUSION: SPIO-enhanced MRI can be useful in evaluating infectious disease of the joint or soft tissue and is influenced by the uptake of iron particles in fibroblasts as well as macrophages. PMID- 17715099 TI - MRI of the distal biceps femoris muscle: normal anatomy, variants, and association with common peroneal entrapment neuropathy. AB - OBJECTIVE: The objectives of our study were to describe the previously unreported normal MR anatomy of the distal biceps femoris muscle and its relationship with the common peroneal nerve and to present a case in which previously unreported MR evidence of an anatomic variation in the distal biceps femoris muscle was associated with common peroneal entrapment neuropathy. MATERIALS AND METHODS: One hundred consecutive 1.5-T knee MR studies of 97 asymptomatic patients were retrospectively reviewed by two observers in consensus for, first, normal anatomy of the distal biceps femoris muscle; second, anatomic variations of the muscle; and, third, the relationship of the muscle to the common peroneal nerve. Measurements of the distal and posterior extents of the short and long heads of the biceps femoris were performed. An MR study of a symptomatic patient with clinical evidence of common peroneal neuropathy associated with a surgically proven anatomic variation of the distal biceps femoris was reviewed. RESULTS: Two MR anatomic patterns were seen in the asymptomatic patient group: First, in 77 knees (77%), the common peroneal nerve was located within abundant fat posterolateral to the biceps femoris; and, second, in 23 cases (23%), the common peroneal nerve traversed within a narrow fatty tunnel between the biceps femoris and lateral head of the gastrocnemius muscles. There was a positive correlation between the distal and posterior extents of the short head of the biceps femoris muscle and the presence of the tunnel. CONCLUSION: Variations in the posterior and distal extents of the biceps femoris muscle can produce a tunnel in which the common peroneal nerve travels. We also described a case of common peroneal neuropathy secondary to tunnel formation. PMID- 17715100 TI - MRI follow-up of posttraumatic bone bruises of the knee in general practice. AB - OBJECTIVE: Our purpose was to study the natural course of bone bruises in posttraumatic knees and to describe possible determinants of this course. SUBJECTS AND METHODS: Prospective MRI follow-up data were gathered for patients with bone bruises after sustained knee trauma. Follow-up ceased when the bone bruise could no longer be discerned or after 1 year of follow-up. For each patient we studied the relationships between time to healing of all bone bruises and the explanatory variables age, sex, obesity, workload, sports load, number of bone bruises, osteoarthritis, and concomitant knee lesions using survival analyses. We also investigated the relationships between resolution of individual bone bruises and lesion type, size and location, and the explanatory variables at 6 months and at 12 months separately, using logistic regression analyses for repeated measurements and generalized estimating equations. RESULTS: In 80 patients, 157 bone bruises were found. The estimated median healing time was 42.1 weeks. Healing was prolonged in patients having a higher number of bone bruises and in the presence of osteoarthritis. Resolution of individual bone bruises was prolonged in the presence of osteoarthritis and greater age. Reticular lesions were less likely to be present after 6 months than other bone bruise types. None of the remaining tested variables had prognostic value. CONCLUSION: Median healing time of bone bruises is 42.1 weeks. Prognosis is particularly influenced by the presence of osteoarthritis. Age, type of bone bruise, and number of bruises also have prognostic value. PMID- 17715101 TI - A cervical nerve block approach to improve safety. AB - OBJECTIVE: The objective of this report is to describe a previously unreported technique of selective cervical nerve block, performed from January 1, 2004, to May 19, 2006, in 560 injections, that was designed to allow continual monitoring of injectate passage and verification of needle tip position. We also illustrate faulty needle placement in a cadaveric neck. CONCLUSION: Using a short connecting tube, contrast material mixed with the final injectate, and fluoroscopy when performing a selective cervical nerve block allows continual monitoring of injectate including where washout of the original testing contrast material actually flows. A true lateral view shows a more dangerous anterior needle tip placement. In addition, performing a test with anesthetic and contrast material, waiting 1.5 minutes before administering the final injectate, and using a water soluble steroid may provide further safety with selective cervical nerve block. PMID- 17715102 TI - Dual-source CT coronary angiography: image quality, mean heart rate, and heart rate variability. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of mean heart rate and heart rate variability on the image quality of dual-source CT coronary angiography. SUBJECTS AND METHODS: Eighty patients underwent dual-source CT coronary angiography. Thirteen data sets were reconstructed in 5% steps from 20 80% of the R-R interval. Heart rate variability was calculated as SD of mean heart rate. Two independent blinded reviewers assessed the image quality of each segment. RESULTS: Mean heart rate was 65.3 +/- 13.9 (SD) beats per minute (bpm) (range, 35-99 bpm) with a variability of 3.4 +/- 4.1 bpm (range, 0.4-17.5 bpm). Image quality was sufficient for diagnosis for 97.8% (1,043/1,066) of arterial segments. No significant correlation was found between mean heart rate and image quality in any segment or any coronary artery. No significant correlation was found between heart rate variability and image quality in any segment, the right coronary artery, or the left anterior descending artery, but there was a significant (p < 0.05) correlation in the left circumflex artery. A significant correlation (p < 0.05) between overall image quality was found for mean and variability of heart rate as shared predictors, the latter having a greater contribution. CONCLUSION: The overall image quality of dual-source CT coronary angiography is sufficient for diagnosis within a wide range of mean heart rates and variability of heart rates. Only heart rates that are both high and variable significantly deteriorate image quality, but the quality remains adequate for diagnosis. PMID- 17715103 TI - Diagnostic performance of 64-slice computed tomography in evaluation of coronary artery bypass grafts. AB - OBJECTIVE: The purpose of this study was to compare the diagnostic accuracy of 64 slice CT with that of invasive angiography in the detection of greater than 50% graft stenosis within 2 weeks of coronary artery bypass grafting and to investigate the clinical value of 64-slice CT. SUBJECTS AND METHODS: Forty-one patients (70 grafts, 46 arterial and 24 venous) underwent 64-slice CT a mean of 2.6 years after minimally invasive or conventional coronary artery bypass surgery. RESULTS: All 70 grafts were assessable, and none of the grafts was excluded from analysis. For the detection of 50-90% graft stenosis, the sensitivity of CT was 75%, the specificity was 95%, the positive predictive value was 67%, and the negative predictive value was 97% (true disease prevalence, 8/70 grafts; 11%). Greater than 50% graft stenosis and occlusion pooled together (prevalence, 14/70; 20%) were detected with a sensitivity of 85%, specificity of 95%, positive predictive value of 80%, and negative predictive value of 96%. Vein graft disease was found in eight (42%) of 19 patent vein grafts (graft age, 15.6 +/- 2.3 years). The disease was nonobstructive in three (16%) of the 19 grafts. The course of the left internal mammary artery was median retrosternal (< 1 cm deep) in 33.3% of conventionally sutured grafts. CONCLUSION: Sixty-four-slice CT angiography can be used for accurate exclusion of greater than 50% graft stenosis, but detection of distal anastomotic stenosis is limited, and the degree of stenosis can be overestimated. The advantages of CT, however, are that it is noninvasive, vein graft disease can be diagnosed at an early stage, and complementary evaluation of extracardiac anatomic features provides useful information before coronary artery bypass grafting is redone. PMID- 17715104 TI - Artifacts in ECG-synchronized MDCT coronary angiography. AB - OBJECTIVE: In MDCT coronary angiography, image artifacts are the major cause of false-positive and false-negative interpretations regarding the presence of coronary artery stenoses. Hence, it is important that observers reporting these investigations are aware of the potential presence of image artifacts and that these artifacts are recognized. CONCLUSION: The article explores the technical causes for various artifacts in MDCT coronary angiography imaging and clinical examples are given. PMID- 17715105 TI - Right heart dilatation in adults: congenital causes. AB - OBJECTIVE: The purpose of this article is to illustrate the common congenital cardiac lesions that are characterized by right-sided heart enlargement that may be seen on routine thoracic or cardiac imaging. CONCLUSION: A systematic approach to the evaluation of the right heart and an understanding of the congenital abnormalities causing right chamber enlargement will allow the radiologist to diagnose unsuspected cardiac abnormalities on routine clinical thoracic and cardiac imaging as well as accurately identify these defects on dedicated cardiac CT or MRI examinations. PMID- 17715106 TI - Indeterminate CT angiography in blunt thoracic trauma: is CT angiography enough? AB - OBJECTIVE: The primary objective of our study was to determine whether catheter angiography is needed to exclude aortic and intrathoracic great vessel injury when CT angiography (CTA) findings are indeterminate (mediastinal hematoma without direct evidence of aortic or intrathoracic great vessel injury). The secondary objective was to devise a classification scheme for mediastinal hematomas. MATERIALS AND METHODS: This study is a retrospective analysis of patients presenting with blunt trauma over 4.5 years at a level 1 trauma center. Indeterminate CTA findings in patients with blunt injury were identified through a database search of imaging reports. CTA findings and final outcomes, including catheter angiography and clinicopathologic records, were reviewed independently by blinded observers. RESULTS: One hundred seven patients (age range, 11-88 years) met the inclusion criteria. Seventy-two (age range, 15-88 years) had a reference standard of subsequent catheter angiography, and 35 subjects (age range, 11-87 years) did not undergo catheter angiography and therefore had a reference standard of clinicopathologic review. No subjects with isolated mediastinal hematoma on CTA had aortic or intrathoracic great vessel injury, for a positive predictive value of 0% (95% CI, 0-0.028). Using our proposed classification scheme, we found a direct correlation between the percentage of cases that underwent catheter angiography and hematoma severity. CONCLUSION: When CTA is indeterminate in blunt thoracic trauma, conventional angiography is unlikely to show an aortic or intrathoracic great vessel injury and may be unnecessary. A grading system for mediastinal hematomas could help triage patients to conventional angiography when further imaging is desired. PMID- 17715107 TI - Breast imaging: current utilization, trends, and implications. PMID- 17715108 TI - Tomosynthesis: potential clinical role in breast imaging. PMID- 17715110 TI - Issues in imaging-guided tumor ablation in children versus adults. AB - OBJECTIVE: Despite the growing use of percutaneous imaging-guided tumor ablation in adults, few reports describe its use in children except for osteoid osteoma. Our objective is to describe how tumor ablation in children and adults may differ, both to facilitate dialogue on pediatric tumor ablation and to increase awareness and use of this valuable technique. CONCLUSION: There are numerous indications for which various ablative techniques may be safe and effective for treatment of pediatric tumors. Nonetheless, important differences between the pediatric and adult populations warrant consideration. PMID- 17715109 TI - Digital breast tomosynthesis: initial experience in 98 women with abnormal digital screening mammography. AB - OBJECTIVE: The purpose of our study was to compare the image quality of tomosynthesis with that of conventional mammography and to estimate the recall rate of screening when tomosynthesis is used in addition to mammography. MATERIALS AND METHODS: Women with an abnormal screening mammography were recruited sequentially. Consenting women underwent tomosynthesis of the affected breast corresponding to the views obtained with diagnostic mammography. The study radiologist compared the image quality, including lesion conspicuity and feature analysis, of tomosynthesis with diagnostic film-screen mammography and assessed the need for recall when tomosynthesis was added to digital screening mammography. Screening recalls were considered unnecessary when tomosynthesis did not show a corresponding abnormality or allowed definitely benign lesion characterization. Fisher's exact test was used to determine the association of equivalence and recall status with mammographic finding type. RESULTS: There were 99 digital screening recalls in 98 women. The image quality of tomosynthesis was equivalent (n = 51) or superior (n = 37) to diagnostic mammography in 89% (88/99). Finding type was significantly (p < 0.001) associated with equivalence. Approximately half--52/99 (52%)--of the findings would not have been recalled when digital screening mammography was supplemented with tomosynthesis. When adjusting for confounding conditions, the recall reduction was 40% (37/92). The likelihood of recall was also dependent on finding type (p = 0.004). CONCLUSION: Subjectively, tomosynthesis has comparable or superior image quality to that of film-screen mammography in the diagnostic setting, and it has the potential to decrease the recall rate when used adjunctively with digital screening mammography. PMID- 17715111 TI - MRI and biologic behavior of desmoid tumors in children. AB - OBJECTIVE: The outcome of desmoid tumor in children cannot be reliably predicted on the basis of histologic findings. We sought to determine whether the postoperative presence of residual or recurrent tumor can be predicted on the basis of demographic variables and baseline MRI features of the tumor. We also aimed to determine how imaging features change during adjuvant treatment and how the imaging features relate to the histologic features. MATERIALS AND METHODS: Two radiologists retrospectively reviewed images from 281 MRI examinations performed at baseline and during postoperative therapy for desmoid tumor. The examinations had been performed on 17 children treated between September 1991 and March 2003. Tumor volume; distinctness of margins; involvement of bone and neurovascular bundle; and T1-weighted, T2-weighted, and STIR signal intensity and contrast enhancement pattern were recorded. Baseline imaging and demographic features were correlated with the postoperative presence of residual or recurrent tumor. Imaging changes during follow-up were compared with treatment response and outcome. The imaging features of eight tumors were compared with percentage cellularity and collagen deposition in biopsy samples obtained within 30 days of imaging. RESULTS: Baseline involvement of the neurovascular bundle approached significance as a predictor of the presence of residual or recurrent tumor (p = 0.08). Other baseline imaging and demographic features were not predictive (p > or = 0.4). Changes in imaging features were variable during follow-up. T2 weighted and STIR signal intensity may be correlated with percentage cellularity and collagen deposition. CONCLUSION: MRI has limited value in prediction of the postoperative presence of residual or recurrent desmoid tumor in children. It is useful, however, for detecting disease and monitoring postoperative adjuvant therapy. PMID- 17715112 TI - MDCT and 3D CT angiography of splanchnic artery aneurysms. AB - OBJECTIVE: The purpose of this article is to review our experience with the use of MDCT and 3D imaging in the detection and management of patients with both symptomatic and asymptomatic splanchnic artery aneurysms. CONCLUSION: Although splanchnic artery aneurysms are relatively rare, they are being diagnosed with increased frequency given the widespread availability of MDCT and 3D imaging capabilities. It is important that these aneurysms be diagnosed accurately because they can carry a high morbidity and mortality, even in asymptomatic patients. PMID- 17715113 TI - Characterization of cystic pancreatic masses: relative accuracy of CT and MRI. AB - OBJECTIVE: The objective of our study was to determine the role and relative accuracy of CT and MRI in the characterization of cystic pancreatic masses. MATERIALS AND METHODS: We retrospectively identified 58 patients with histopathologically proven cystic pancreatic masses at our institution who underwent preoperative CT (n = 40), MRI (n = 6), or both (n = 12). Two radiologists independently recorded their leading diagnoses with levels of diagnostic certainty (0-100%), their estimates of overall likelihood of malignancy (0-100%), and the morphologic characteristics of the tumors. Data were analyzed to determine relative accuracy in the diagnosis of malignancy, relationship between diagnostic certainty and accuracy, and frequency of malignancy in unilocular thin-walled cysts smaller than 4 cm. RESULTS: Twenty-one (36%) of 58 masses were malignant. CT and MRI were equally accurate in establishing the diagnosis of malignancy (area under the receiver operating characteristic curve [A(z)] = 0.91 and 0.85 for reviewers 1 and 2 at MRI vs 0.82 and 0.76 at CT, respectively; p > 0.05). The leading diagnosis given by reviewers 1 and 2 was correct in 46% (32/70) and 43% (30/70) of the studies, respectively. When reviewer diagnostic certainty was 90% or more, the corresponding values were not significantly (p > 0.05) improved at 55% (12/22) and 48% (10/21), respectively. Two (15%) of 13 unilocular thin-walled cysts smaller than 4 cm were frankly malignant. CONCLUSION: CT and MRI are reasonably and similarly accurate in the characterization of cystic pancreatic masses as benign or malignant; limitations include a substantial rate of misdiagnosis even when reviewer certainty is high and a moderate frequency of malignancy in small morphologically benign-appearing cysts. PMID- 17715114 TI - Relative accuracy of CT and MRI for characterization of cystic pancreatic masses. PMID- 17715115 TI - Gadolinium-enhanced MRI for tumor surveillance before liver transplantation: center-based experience. AB - OBJECTIVE: The purpose of this study was to evaluate prospectively acquired institutional results to determine the accuracy of gadolinium-enhanced MRI in liver tumor surveillance before transplantation. SUBJECTS AND METHODS: One hundred fifteen patients underwent MRI of the abdomen within 90 days before liver transplantation. Images were acquired with gadolinium-enhanced 3D gradient-echo sequences in the arterial, venous, and delayed phases. Detection of hepatocellular carcinoma (HCC) was based on the imaging criteria arterial phase enhancement, delayed phase hypointensity, and development of an enhancing outer margin capsule. Imaging findings were compared with findings at histopathologic evaluation of the explanted liver. RESULTS: Thirty-six HCCs in 27 patients were detected at histopathologic evaluation. Patient-based analysis showed the sensitivity of MRI was 88.9% (24/27); specificity, 97.7% (false-positive findings in two patients); and accuracy, 95.7%. MRI depicted 28 of 36 HCCs, resulting in a lesion-based sensitivity of 77.8%. Although all 18 HCCs 2 cm or larger were depicted with MRI, only 10 of 18 HCCs smaller than 2 cm were correctly diagnosed. However, two HCCs measuring smaller than 2 cm at pathologic examination were rated as dysplastic nodules on MRI. CONCLUSION: Contrast-enhanced MRI can be used as a primary diagnostic method for accurate detection and characterization of HCC 2 cm or larger as required by the criteria of the Model for End-Stage Liver Disease used by the United Network for Organ Sharing. MRI can be considered a standard tool for surveillance before liver transplantation. Reduction in cost and risk may be derived from the diminished need for other diagnostic imaging studies and biopsy and the avoidance of use of iodinated contrast agents in imaging of patients with cirrhosis, many of whom have impaired renal function. PMID- 17715116 TI - Effect of slice thickness and primary 2D versus 3D virtual dissection on colorectal lesion detection at CT colonography in 452 asymptomatic adults. AB - OBJECTIVE: The objective of our study was to compare the performance of primary 3D search using 360 degree virtual dissection with primary 2D search using a 2.5- versus a 1.25-mm slice thickness. SUBJECTS AND METHODS: Four hundred fifty-two asymptomatic patients underwent CT colonography (CTC) and colonoscopy. Examinations were reconstructed to 1.25- and 2.5-mm slice thicknesses and interpreted using primary 3D search (360 degree virtual dissection) and primary 2D search. Two of three experienced reviewers were randomly assigned to each case; 1,808 interpretations were performed. RESULTS: There were 64 adenomas > or = 6 mm, 26 of which were large adenomas > or = 1 cm. For adenomas 6-9 mm in diameter, the area under the receiver operating characteristic curve (AUC) using 2.5-mm data sets was 0.66, 0.62, 0.90 and 0.78, 0.69, 0.67 for reviewers 1, 2, and 3, respectively, using primary 3D versus 2D search (p = not significant [NS]). For neoplasms > or = 10 mm, the AUC using 2.5-mm data sets was 0.74, 0.85, 0.89 and 0.66, 0.86, 0.92 for reviewers 1, 2, and 3 using primary 3D versus 2D search (p = NS). There was no significant difference using 1.25-mm collimation. Double review using both primary 3D and 2D search yielded sensitivities of 84% (16/19) and 95% (18/19) for large neoplasms (> or = 1 cm) using 2.5- and 1.25-mm data sets, respectively. Five of five (100%) adenocarcinomas were identified. The sensitivity of colonoscopy for large neoplasms was 77% (20/26) (20% [1/5] for adenocarcinoma). CONCLUSION: No advantage exists for 1.25- or 2.5-mm slice thickness or for primary 3D versus 2D search at CTC. Double review using primary 3D (virtual dissection) and 2D search reduces interobserver variability and competes with colonoscopy for the detection of large lesions. PMID- 17715117 TI - Competitive speed eating: truth and consequences. AB - OBJECTIVE: The purpose of our investigation was to assess the stomachs of a world class speed-eating champion and of a control subject during a speed-eating test in our gastrointestinal fluoroscopy suite to determine how competitive speed eaters are able to eat so much so fast. CONCLUSION: Our observations suggest that successful speed eaters expand the stomach to form an enormous flaccid sac capable of accommodating huge amounts of food. We speculate that professional speed eaters eventually may develop morbid obesity, profound gastroparesis, intractable nausea and vomiting, and even the need for a gastrectomy. Despite its growing popularity, competitive speed eating is a potentially self-destructive form of behavior. PMID- 17715118 TI - I.v. N-acetylcysteine and emergency CT: use of serum creatinine and cystatin C as markers of radiocontrast nephrotoxicity. AB - OBJECTIVE: The purpose of this study was to assess the effect of i.v. administration of N-acetylcysteine (NAC) on serum levels of creatinine and cystatin C, two markers of renal function, in patients with renal insufficiency who undergo emergency contrast-enhanced CT. SUBJECTS AND METHODS: Eighty-seven adult patients with renal insufficiency who underwent emergency CT were randomized to two groups. In the first group, in addition to hydration, patients received a 900-mg injection of NAC 1 hour before and another immediately after injection of iodine contrast medium. Patients in the second group received hydration only. Serum levels of creatinine and cystatin C were measured at admission and on days 2 and 4 after CT. Nephrotoxicity was defined as a 25% or greater increase in serum creatinine or cystatin C concentration from baseline value. RESULTS: A 25% or greater increase in serum creatinine concentration was found in nine (21%) of 43 patients in the control group and in two (5%) of 44 patients in the NAC group (p = 0.026). A 25% or greater increase in serum cystatin C concentration was found in nine (22%) of 40 patients in the control group and in seven (17%) of 41 patients in the NAC group (p = 0.59). CONCLUSION: On the basis of serum creatinine concentration only, i.v. administration of NAC appears protective against the nephrotoxicity of contrast medium. No effect is found when serum cystatin C concentration is used to assess renal function. The effect of NAC on serum creatinine level remains unclear and may not be related to a renoprotective action. PMID- 17715119 TI - Incidental findings on renal MR angiography. AB - OBJECTIVE: The purpose of this article is to assess the incidence of incidental vascular and nonvascular findings in patients undergoing renal MR angiography and to determine the extent to which these findings alter patient management. MATERIALS AND METHODS: Reports from 380 consecutive renal MR angiography examinations performed at a single institution over a 12-month interval were examined. The presence of incidental vascular (i.e., nonrenal artery) and nonvascular findings was noted. Clinical records of patients with significant incidental findings were examined to determine whether additional imaging, biopsy, or surgery was performed. RESULTS: Overall, 151 (40%) of 380 patients had one or more additional vascular findings not related to the renal arteries, and 221 (58%) of 380 patients had one or more additional nonvascular findings. Vascular findings included mesenteric artery stenosis or occlusion in 33% of patients, moderate to severe aortic atherosclerosis in 17%, aortic aneurysms in 7%, and aortic dissection in 2%. Incidental malignancies were detected in 10 patients (3%), and indeterminate lesions requiring follow-up imaging, biopsy, or surgery were noted in 18 patients (5%). Overall, management in 5% of patients was significantly altered (i.e., required biopsy, surgery, or other intervention) by incidental findings detected on renal MR angiography. Benign lesions not requiring additional imaging or follow-up occurred in 54% of patients and consisted predominantly of renal cysts. CONCLUSION: Incidental findings on renal MR angiography are common. Most incidental lesions can be adequately detected and characterized with the addition of a few pulse sequences to the standard renal MR angiography protocol at a minimal cost in imaging time. The high incidence of incidental findings emphasizes the importance of performance and interpretation of these examinations by physicians with training in abdominal cross-sectional imaging. PMID- 17715120 TI - 16-MDCT angiography of aortoiliac and lower extremity arteries: comparison with digital subtraction angiography. AB - OBJECTIVE: The objective of our study was to prospectively compare CT angiography (CTA) performed on a 16-MDCT scanner and digital subtraction angiography (DSA) in patients with peripheral arterial disease. SUBJECTS AND METHODS: CTA and DSA were compared in 50 patients. CTA was independently evaluated by two blinded observers. DSA was evaluated by two additional blinded observers in consensus. Consensus DSA served as the reference standard for comparisons with CTA in terms of diagnostic quality, grading of stenoocclusive lesions, visualization of collaterals, impact on patient management, and time required for analysis. RESULTS: No significant differences in diagnostic quality were observed between CTA and DSA above the ankle; both CTA observers noted significantly better visualization of pedal arteries (70 and 72 segments, respectively) than on DSA (57 segments). Of 958 stenoocclusive lesions on DSA, CTA observers 1 and 2 detected 933 and 929 lesions, respectively. Sensitivity and specificity for the detection of hemodynamically relevant (> 50%) lesions was 93.3% and 96.5% for observer 1 and 90.1% and 95.6% for observer 2. Collaterals were seen at 150 arterial levels on DSA compared with 97 and 92 levels on CTA (p < 0.05, both observers). Patient management decisions based on CTA were equivalent to those based on DSA in 49 of the 50 patients. CONCLUSION: CTA is an effective noninvasive alternative to DSA for the evaluation of peripheral arterial disease. PMID- 17715121 TI - Vascular Ehlers-Danlos syndrome: imaging findings. AB - OBJECTIVE: Vascular Ehlers-Danlos syndrome (EDS), formerly known as EDS type IV, is an autosomal dominant disorder characterized by fragility of medium and large arteries due to type III procollagen deficiency. Our purpose was to review the imaging findings in a cohort of patients with a diagnosis of vascular EDS. MATERIALS AND METHODS: The radiologic, surgical, and genetic databases at a single multispecialty medical practice were reviewed for a 35-year period between 1971 and 2006. Thirty-three patients with a clinical diagnosis of vascular EDS were identified. Imaging studies were available for 28 patients, 13 men and 15 women, with a mean age of 39.8 +/- 16 years at the time of diagnosis. A vascular radiologist reviewed a total of 189 imaging examinations: 87 CT, 27 MRI, 59 sonography, and 16 angiography. RESULTS: Vascular abnormalities were present in 22 (78%) of 28 patients. Arterial abnormalities included 41 aneurysms, 19 dissections, 12 ectasias, and 10 occlusions. There was one splenic vein aneurysm and one carotid cavernous fistula. Six patients had a total of 10 parenchymal infarcts involving the brain (n = 5), kidney (n = 3), and spleen (n = 2). Nine patients had 10 hemorrhagic events, five related to spontaneous vascular rupture and five associated with interventional or surgical procedures. Six patients had 13 nonvascular findings. CONCLUSION: The most common findings were arterial aneurysms and dissections, followed by arterial ectasias and occlusions. Life threatening complications included hemorrhage and infarcts. PMID- 17715122 TI - MRI of cerebral microhemorrhages. AB - OBJECTIVE: The purpose of this pictorial essay is to discuss the differential diagnosis of cerebral microhemorrhages on T2*-weighted gradient-echo MRI. CONCLUSION: Cerebral amyloid angiopathy and chronic systemic hypertension are the two most common causes of cerebral microhemorrhages. Less common causes include diffuse axonal injury, cerebral embolism, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, multiple cavernous malformations, vasculitis, hemorrhagic micrometastasis, radiation vasculopathy, and Parry-Romberg syndrome. PMID- 17715123 TI - Gene expression profiles, histologic analysis, and imaging of squamous cell carcinoma model treated with focused ultrasound beams. AB - OBJECTIVE: The purpose of our study was to evaluate the effect of short-pulse high-intensity focused ultrasound (HIFU) on inducing cell death in a head and neck cancer model (SCCVII [squamous cell carcinoma]) compared with continuous HIFU to get a better understanding of the biologic changes caused by HIFU therapy. MATERIALS AND METHODS: HIFU was applied to 12 SCCVII tumors in C3H/Km mice using a dual sonography system (imaging, 6 MHz; therapeutic, 1 MHz). A continuous HIFU mode (total time, 20 seconds; intensity, 6,730.6 W/cm2) and a short-pulse HIFU mode (frequency, 0.5 Hz; pulse duration, 50 milliseconds; total time, 16.5 minutes; intensity, 134.4 W/cm2) was applied. Three hours later, MR images were obtained on a 1.5-T scanner. After imaging, the treated and untreated control tumor tissue samples were taken out for histology and oligonucleotide microarray analysis. RESULTS: Prominent changes were observed in the MR images in the continuous HIFU mode, whereas the short-pulse HIFU mode showed no discernible changes. Histology (H and E, TUNEL [terminal deoxynucleotidyl transferase mediated dUTP {deoxyuridine triphosphate} nick-end labeling], and immunohistochemistry) of the tumors treated with the continuous HIFU mode revealed areas of significant necrosis. In the short-pulse HIFU mode, the H and E staining showed multifocal areas of coagulation necrosis. TUNEL staining showed a high apoptotic index in both modes. Gene expression analysis revealed profound differences. In the continuous HIFU mode, 23 genes were up-regulated (> twofold change) and five genes were down-regulated (< twofold change), and in the short pulse HIFU mode, 32 different genes were up-regulated and 16 genes were down regulated. CONCLUSION: Genomic analysis might be included when investigating tissue changes after interventional therapy because it offers the potential to find molecular targets for imaging and therapeutic applications. PMID- 17715124 TI - Trends of prevalence of primary HIV drug resistance in Germany. AB - BACKGROUND: Primary HIV drug resistance (PDR) is associated with poor treatment outcome of first-line highly active antiretroviral therapy (HAART). The aim of the study was to observe the trend of prevalence of PDR between 2001 and 2005. METHODS: In a prospective multicentre study in the state of Nordrhein-Westfalen, Germany, 831 treatment-naive chronically HIV-infected patients underwent genotypic resistance testing. RESULTS: Six hundred and forty (77%) of them were male. Two-thirds of the patients (558, 67%) were infected with HIV subtype B. PDR was found in 75 of 831 [9%; 95% confidence interval (CI) 7.1-10.9] cases entering the study between January 2001 and December 2005. An increasing trend of PDR was found from 2001 (4.8%; CI 2.1-9.4) to 2005 (9.0%; CI 5.4-12.6; P = 0.08). A significant tendency to higher PDR was observed for ethnicity other than Caucasian (P = 0.04), HIV subtypes other than B (P = 0.02) and transmission routes other than homosexual (P = 0.03). CONCLUSIONS: A non-significant increase in prevalence of PDR was observed from 2001 to 2005. A significant trend to higher PDR rate was detected in non-Caucasian patients, patients infected with non-B subtypes, and in patients with risk factors for acquisition of HIV other than homosexual transmission. Based on the fact that there is a trend to higher PDR rate, resistance testing in untreated HIV-infected patients starting HAART becomes more important in clinical routine. The identification of patient subgroups with a remarkable risk of PDR makes continuous monitoring of PDR mandatory. PMID- 17715125 TI - Sex issues in HIV-1-infected persons during highly active antiretroviral therapy: a systematic review. AB - BACKGROUND: Since the introduction of highly active antiretroviral therapy (HAART), morbidity and mortality rates have sharply decreased among HIV-infected patients. Studies of possible differences between men and women in the course of HIV infection give conflicting results. The objective of this study was to assess sex differences during HAART. METHODS: A literature search by using the MEDLINE database between March 2002 and February 2007 was performed to identify all published studies on the sex-specific differences on the impact of HAART. All articles with measures of effect (preferably adjusted odds ratio, relative risk or hazard ratio with 95% CI) of sex on viroimmunological and clinical parameters during HAART were included. Five different topics of interest in our research were selected: time of initiation of HAART, adherence, viroimmunological response, clinical response and adverse reactions during HAART. RESULTS: US data report an initiation of HAART at an earlier disease stage in men compared with women. After initiation of HAART, most authors do not report any viroimmunological difference, although a few clinical studies showed a significantly better virological response in women compared with men. Nevertheless, women were more likely to be less adherent to antiretrovirals and to have non-structured treatment interruptions than men. This is likely to be related to the higher number of adverse reactions they experience during HAART. Finally, discordant opinions with regard to clinical benefits during HAART exist, but recent clinical and observational trials suggest a better clinical outcome for women. CONCLUSIONS: We found little evidence of sex differences during antiretroviral treatment. Nevertheless, most of these studies were underpowered to detect sex differences and had limited follow-up at 6 or 12 months. Design of new gender-sensitive clinical trials with both prolonged follow-up and sample size representative of the current HIV prevalence among women are strongly needed to detect the likely sex differences of antiretroviral agents during HIV infection. PMID- 17715126 TI - In vivo studies on the antileishmanial activity of buparvaquone and its prodrugs. AB - OBJECTIVES: The efficacy of different formulations of the naphthoquinone buparvaquone and two phosphate prodrugs in in vivo models of both visceral and cutaneous leishmaniasis is described. METHODS: Several topical formulations of buparvaquone containing acceptable excipients were tested in vivo against Leishmania major cutaneous lesions in BALB/c mice. In vivo studies against Leishmania donovani investigated whether the prodrugs had improved efficacy when compared with buparvaquone. RESULTS: Both a hydrous gel and water-in-oil emulsion of buparvaquone significantly reduced cutaneous parasite burden (P < 0.05, 22 days post-infection) and lesion size, compared with the untreated control (P < 0.0001, 16 days post-infection). The prodrug 3-phosphonooxymethyl-buparvaquone was formulated into an anhydrous gel and this also significantly reduced parasite burden and lesion size (P < 0.0001, 16 days post-infection). Histology confirmed this efficacy. In the visceral model, both prodrugs were significantly more effective at reducing liver parasite burden than the parent drug, buparvaquone. Buparvaquone-3-phosphate was shown to be the most effective antileishmanial (P = 0.0003, 50 mg buparvaquone molar equivalent/kg/day five times), reducing the liver parasite burden by approximately 34% when compared with the untreated control. CONCLUSIONS: The introduction of a topical formulation, such as buparvaquone (or its prodrug), would be a significant advance for the treatment of simple cutaneous lesions. In particular, the avoidance of the parenteral antimonials would greatly increase patient compliance and reduce treatment costs. PMID- 17715127 TI - Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. AB - Sirtuins are homologues of the yeast transcriptional repressor Sir2p and are conserved from bacteria to humans. We report that human SIRT4 is localized to the mitochondria. SIRT4 is a matrix protein and becomes cleaved at amino acid 28 after import into mitochondria. Mass spectrometry analysis of proteins that coimmunoprecipitate with SIRT4 identified insulindegrading enzyme and the ADP/ATP carrier proteins, ANT2 and ANT3. SIRT4 exhibits no histone deacetylase activity but functions as an efficient ADP-ribosyltransferase on histones and bovine serum albumin. SIRT4 is expressed in islets of Langerhans and colocalizes with insulin expressing beta cells. Depletion of SIRT4 from insulin-producing INS-1E cells results in increased insulin secretion in response to glucose. These observations define a new role for mitochondrial SIRT4 in the regulation of insulin secretion. PMID- 17715128 TI - Allosteric transinhibition by specific antagonists in CCR2/CXCR4 heterodimers. AB - Chemokine receptors are presently used as targets for candidate drugs in the frame of inflammatory diseases and human immunodeficiency virus infection. They were shown to dimerize, but the functional relevance of dimerization in terms of drug action remains poorly understood. We reported previously the existence of negative binding cooperativity between the subunits of CCR2/CCR5 heterodimers. In the present study, we extend these observations to heterodimers formed by CCR2 and CXCR4, which are more distantly related. We also show that specific antagonists of one receptor inhibit the binding of chemokines to the other receptor as a consequence of their heterodimerization, both in recombinant cell lines and primary leukocytes. This resulted in a significant functional cross inhibition in terms of calcium mobilization and chemotaxis. These data demonstrate that chemokine receptor antagonists regulate allosterically the functional properties of receptors on which they do not bind directly, with important implications on the effects of these potential therapeutic agents. PMID- 17715129 TI - A novel N-terminal isoform of the neuron-specific K-Cl cotransporter KCC2. AB - The neuronal K-Cl cotransporter KCC2 maintains the low intracellular chloride concentration required for the hyperpolarizing actions of inhibitory neurotransmitters gamma-aminobutyric acid and glycine in the central nervous system. This study shows that the mammalian KCC2 gene (alias Slc12a5) generates two neuron-specific isoforms by using alternative promoters and first exons. The novel KCC2a isoform differs from the only previously known KCC2 isoform (now termed KCC2b) by 40 unique N-terminal amino acid residues, including a putative Ste20-related proline alanine-rich kinase-binding site. Ribonuclease protection and quantitative PCR assays indicated that KCC2a contributes 20-50% of total KCC2 mRNA expression in the neonatal mouse brain stem and spinal cord. In contrast to the marked increase in KCC2b mRNA levels in the cortex during postnatal development, the overall expression of KCC2a remains relatively constant and makes up only 5-10% of total KCC2 mRNA in the mature cortex. A rubidium uptake assay in human embryonic kidney 293 cells showed that the KCC2a isoform mediates furosemide-sensitive ion transport activity comparable with that of KCC2b. Mice that lack both KCC2 isoforms die at birth due to severe motor defects, including disrupted respiratory rhythm, whereas mice with a targeted disruption of the first exon of KCC2b survive for up to 2 weeks but eventually die due to spontaneous seizures. We show that these mice lack KCC2b but retain KCC2a mRNA. Thus, distinct populations of neurons show a differential dependence on the expression of the two isoforms: KCC2a expression in the absence of KCC2b is presumably sufficient to support vital neuronal functions in the brain stem and spinal cord but not in the cortex. PMID- 17715130 TI - Caveolin-1 regulates the delivery and endocytosis of the glutamate transporter, excitatory amino acid carrier 1. AB - The sodium-dependent glutamate transporter, excitatory amino acid carrier 1 (EAAC1), has been implicated in the regulation of excitatory signaling and prevention of cell death in the nervous system. There is evidence that EAAC1 constitutively cycles on and off the plasma membrane and that under steady state conditions up to 80% of the transporter is intracellular. As is observed with other neurotransmitter transporters, the activity of EAAC1 is regulated by a variety of molecules, and some of these effects are associated with redistribution of EAAC1 on and off the plasma membrane. In the present study we tested the hypothesis that a structural component of lipid rafts, caveolin-1 (Cav 1), may participate in EAAC1 trafficking. Using C6 glioma cells as a model system, co-expression of Cav-1 S80E (a dominant-negative variant) or small interfering RNA-mediated knock-down of caveolin-1 reduced cell surface expression of myc epitope-tagged EAAC1 or endogenous EAAC1, respectively. Cav-1 S80E slowed the constitutive delivery and endocytosis of myc-EAAC1. In primary cultures derived from caveolin-1 knock-out mice, a similar reduction in delivery and internalization of endogenous EAAC1 was observed. We also found that caveolin-1, caveolin-2, or Cav-1 S80E formed immunoprecipitable complexes with EAAC1 in C6 glioma and/or transfected HEK cells. Together, these data provide strong evidence that caveolin-1 contributes to the trafficking of EAAC1 on and off the plasma membrane and that these effects are associated with formation of EAAC1-caveolin complexes. PMID- 17715132 TI - Pannexin1 channels contain a glycosylation site that targets the hexamer to the plasma membrane. AB - Pannexins are newly discovered channel proteins expressed in many different tissues and abundantly in the vertebrate central nervous system. Based on membrane topology, folding and secondary structure prediction, pannexins are proposed to form gap junction-like structures. We show here that Pannexin1 forms a hexameric channel and reaches the cell surface but, unlike connexins, is N glycosylated. Using site-directed mutagenesis we analyzed three putative N-linked glycosylation sites and examined the effects of each mutation on channel expression. We show for the first time that Pannexin1 is glycosylated at Asn-254 and that this residue is important for plasma membrane targeting. The glycosylation of Pannexin1 at its extracellular surface makes it unlikely that two oligomers could dock to form an intercellular channel. Ultrastructural analysis by electron microscopy confirmed that Pannexin1 junctional areas do not appear as canonical gap junctions. Rather, Pannexin1 channels are distributed throughout the plasma membrane. We propose that N-glycosylation of Pannexin1 could be a significant mechanism for regulating the trafficking of these membrane proteins to the cell surface in different tissues. PMID- 17715131 TI - Functional characterization of premnaspirodiene oxygenase, a cytochrome P450 catalyzing regio- and stereo-specific hydroxylations of diverse sesquiterpene substrates. AB - Solavetivone, a potent antifungal phytoalexin, is derived from a vetispirane-type sesquiterpene, premnaspirodiene, by a putative regio- and stereo-specific hydroxylation, followed by a second oxidation to yield the alpha,beta-unsaturated ketone. Mechanistically, these reactions could occur via a single, multifunctional cytochrome P450 or some combination of cytochrome P450s and a dehydrogenase. We report here the characterization of a single cytochrome P450 enzyme, Hyoscyamus muticus premnaspirodiene oxygenase (HPO), that catalyzes these successive reactions at carbon 2 (C-2) of the spirane substrate. HPO also catalyzes the equivalent regio-specific (C-2) hydroxylation of several eremophilane-type (decalin ring system) sesquiterpenes, such as with 5-epi aristolochene. Moreover, HPO displays interesting comparisons to other sesquiterpene hydroxylases. 5-Epi-aristolochene di-hydroxylase (EAH) differs catalytically from HPO by introducing hydroxyl groups first at C-1, then C-3 of 5 epi-aristolochene. HPO and EAH also differ from one another by 91-amino acid differences, with four of these differences mapping to putative substrate recognition regions 5 and 6. These four positions were mutagenized alone and in various combinations in both HPO and EAH and the mutant enzymes were characterized for changes in substrate selectivity, reaction product specificity, and kinetic properties. These mutations did not alter the regio- or stereo specificity of either HPO or EAH, but specific combinations of the mutations did improve the catalytic efficiencies 10-15-fold. Molecular models and comparisons between HPO and EAH provide insights into the catalytic properties of these enzymes of specialized metabolism in plants. PMID- 17715134 TI - The Mre11/Rad50/Nbs1 complex plays an important role in the prevention of DNA rereplication in mammalian cells. AB - The Mre11/Nbs1/Rad50 complex (MRN) plays multiple roles in the maintenance of genome stability, including repair of double-stranded breaks (DSBs) and activation of the S-phase checkpoint. Here we demonstrate that MRN is required for the prevention of DNA rereplication in mammalian cells. DNA replication is strictly regulated by licensing control so that the genome is replicated once and only once per cell cycle. Inactivation of Nbs1 or Mre11 leads to a substantial increase of DNA rereplication induced by overexpression of the licensing factor Cdt1. Our studies reveal that multiple mechanisms are likely involved in the MRN mediated suppression of rereplication. First, both Mre11 and Nbs1 are required for facilitating ATR activation when Cdt1 is overexpressed, which in turn suppresses rereplication. Second, Cdt1 overexpression induces ATR-mediated phosphorylation of Nbs1 at Ser343 and this phosphorylation depends on the FHA and BRCT domains of Nbs1. Mutations at Ser343 or in the FHA and BRCT domains lead to more severe rereplication when Cdt1 is overexpressed. Third, the interaction of the Mre11 complex with RPA is important for the suppression of rereplication. This suggests that modulating RPA activity via a direct interaction of MRN is likely one of the effector mechanisms to suppress rereplication. Moreover, we demonstrate that MRN is also required for preventing the accumulation of DSBs when rereplication is induced. Therefore, our studies suggest new roles of MRN in the maintenance of genome stability through preventing rereplication and rereplication-associated DSBs when licensing control is compromised. PMID- 17715133 TI - NMR solution structure of lipocalin-type prostaglandin D synthase: evidence for partial overlapping of catalytic pocket and retinoic acid-binding pocket within the central cavity. AB - Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) catalyzes the isomerization of PGH(2), a common precursor of various prostanoids, to produce PGD(2), an endogenous somnogen and nociceptive modulator, in the brain. L-PGDS is a member of the lipocalin superfamily and binds lipophilic substances, such as retinoids and bile pigments, suggesting that L-PGDS is a dual functional protein acting as a PGD(2)-synthesizing enzyme and a transporter for lipophilic ligands. In this study we determined by NMR the three-dimensional structure of recombinant mouse L PGDS with the catalytic residue Cys-65. The structure of L-PGDS exhibited the typical lipocalin fold, consisting of an eight-stranded, antiparallel beta-barrel and a long alpha-helix associated with the outer surface of the barrel. The interior of the barrel formed a hydrophobic cavity opening to the upper end of the barrel, the size of which was larger than those of other lipocalins, and the cavity contained two pockets. Molecular docking studies, based on the result of NMR titration experiments with retinoic acid and PGH(2) analog, revealed that PGH(2) almost fully occupied the hydrophilic pocket 1, in which Cys-65 was located and all-trans-retinoic acid occupied the hydrophobic pocket 2, in which amino acid residues important for retinoid binding in other lipocalins were well conserved. Mutational and kinetic studies provide the direct evidence for the PGH(2) binding mode. These results indicated that the two binding sites for PGH(2) and retinoic acid in the large cavity of L-PGDS were responsible for the broad ligand specificity of L-PGDS and the non-competitive inhibition of L-PGDS activity by retinoic acid. PMID- 17715135 TI - Evidence for a dinuclear active site in the metallo-beta-lactamase BcII with substoichiometric Co(II). A new model for metal uptake. AB - Metallo-beta-lactamases are zinc-dependent enzymes that constitute one of the main resistance mechanisms to beta-lactam antibiotics. Metallo-beta-lactamases have been characterized both in mono- and dimetallic forms. Despite many studies, the role of each metal binding site in substrate binding and catalysis is still unclear. This is mostly due to the difficulties in assessing the metal content and site occupancy in solution. For this reason, Co(II) has been utilized as a useful probe of the active site structure. We have employed UV-visible, EPR, and NMR spectroscopy to study Co(II) binding to the metallo-beta-lactamase BcII from Bacillus cereus. The spectroscopic features were attributed to the two canonical metal binding sites, the 3H (His(116), His(118), and His(196)) and DCH (Asp(120), Cys(221), and His(263)) sites. These data clearly reveal the coexistence of mononuclear and dinuclear Co(II)-loaded forms at Co(II)/enzyme ratios as low as 0.6. This picture is consistent with the macroscopic dissociation constants here determined from competition binding experiments. A spectral feature previously assigned to the DCH site in the dinuclear species corresponds to a third, weakly bound Co(II) site. The present work emphasizes the importance of using different spectroscopic techniques to follow the metal content and localization during metallo-beta-lactamase turnover. PMID- 17715136 TI - Akt mediates the effect of insulin on epithelial sodium channels by inhibiting Nedd4-2. AB - The epithelial sodium channel (ENaC) plays an important role in transepithelial Na(+) absorption; hence its function is essential for maintaining Na(+) and fluid homeostasis and regulating blood pressure. Insulin is one of the hormones that regulates activity of ENaC. In this study, we investigated the contribution of two related protein kinases, Akt (also known as protein kinase B) and the serum- and glucocorticoid-dependent kinase (Sgk), on insulin-induced ENaC activity in Fisher rat thyroid cells expressing ENaC. Overexpression of Akt1 or Sgk1 significantly increased ENaC activity, whereas expression of a dominant-negative construct of Akt1, Akt1(K179M), decreased basal activity of ENaC. Inhibition of the endogenous expression of Akt1 and Sgk1 by short interfering RNA not only inhibited ENaC but also disrupted the stimulatory effect on ENaC of insulin and of the downstream effectors of insulin, phosphatidylinositol 3-kinase and PDK1. Conversely, overexpression of Akt1 or Sgk1 increased expression of ENaC at the cell membrane and overcame the inhibitory effect of Nedd4-2 on ENaC. Furthermore, mutation of consensus phosphorylation sites on Nedd4-2 for Akt1 and Sgk1, Ser(342) and Ser(428), completely abolished the inhibitory effect of Sgk1 and Akt1 on Nedd4-2 action. Together these data suggest that both Akt and Sgk are components of an insulin signaling pathway that increases Na(+) absorption by up regulating membrane expression of ENaC via a regulatory system that involves inhibition of Nedd4-2. PMID- 17715137 TI - Changes to the HIV long terminal repeat and to HIV integrase differentially impact HIV integrase assembly, activity, and the binding of strand transfer inhibitors. AB - Human immunodeficiency virus (HIV) integrase enzyme is required for the integration of viral DNA into the host cell chromosome. Integrase complex assembly and subsequent strand transfer catalysis are mediated by specific interactions between integrase and bases at the end of the viral long terminal repeat (LTR). The strand transfer reaction can be blocked by the action of small molecule inhibitors, thought to bind in the vicinity of the viral LTR termini. This study examines the contributions of the terminal four bases of the nonprocessed strand (G(2)T(1)C(-1)A(-2)) of the HIV LTR on complex assembly, specific strand transfer activity, and inhibitor binding. Base substitutions and abasic replacements at the LTR terminus provided a means to probe the importance of each nucleotide on the different functions. An approach is described wherein the specific strand transfer activity for each integrase/LTR variant is derived by normalizing strand transfer activity to the concentration of active sites. The key findings of this study are as follows. 1) The G(2):C(2) base pair is necessary for efficient assembly of the complex and for maintenance of an active site architecture, which has high affinity for strand transfer inhibitors. 2) Inhibitor-resistant enzymes exhibit greatly increased sensitivity to LTR changes. 3) The strand transfer and inhibitor binding defects of a Q148R mutant are due to a decreased affinity of the complex for magnesium. 4) Gln(148) interacts with G(2), T(1), and C(-1) at the 5' end of the viral LTR, with these four determinants playing important and overlapping roles in assembly, strand transfer catalysis and high affinity inhibitor binding. PMID- 17715138 TI - Stability of checkpoint kinase 2 is regulated via phosphorylation at serine 456. AB - Checkpoint kinase 2 (Chk2), a DNA damage-activated protein kinase, is phosphorylated at Thr-68 by ataxia telangiectasia mutated leading to its activation by phosphorylation at several additional sites. Using mass spectrometry we identified a new Chk2 phosphorylation site at Ser-456. We show that phosphorylation of Ser-456 plays a role in the regulation of Chk2 stability particularly after DNA damage. Mutation of Ser-456 to alanine results in hyperubiquitination of Chk2 and dramatically reduced Chk2 stability. Furthermore, cells expressing S456A Chk2 show a reduction in the apoptotic response to DNA damage. These findings suggest a mechanism for stabilization of Chk2 in response to DNA damage via phosphorylation at Ser-456 and proteasome-dependent turnover of Chk2 protein via dephosphorylation of the same residue. PMID- 17715139 TI - Randomized, double-blind study comparing the efficacy of moderate-dose metoclopramide and ondansetron for the prophylactic control of postoperative vomiting in children after tonsillectomy. AB - BACKGROUND: Postoperative vomiting (POV) is a major cause of morbidity after tonsillectomy in children. It has been well established that anti-serotinergic agents are effective for the prophylactic control of POV in this patient group. It has been suggested that at moderate doses (0.5 mg kg(-1)), metoclopramide is also an effective agent. No study has been performed comparing the efficacy of an anti-serotinergic agent and moderate-dose metoclopramide. METHODS: A total of 557 children undergoing tonsillectomy with or without adenoidectomy were randomly allocated to receive either ondansetron 0.1 mg kg(-1) or metoclopramide 0.5 mg kg(-1). All received a standardized muscle-relaxant anaesthetic and dexamethasone 0.1 mg kg(-1). The primary outcome was any vomit in the immediate postoperative period. Comparisons were made of the proportion in each group reaching the primary outcome and the time until their first vomit. The study was designed to detect equivalence. RESULTS: The incidence of vomiting in the group receiving ondansetron (25.3%) was 12% lower (95% CI 4.4-19.7) than those in metoclopramide (37.3%). The time until first vomit was significantly longer in the group receiving ondansetron (hazard ratio 0.61, 95% CI 0.45-0.82). CONCLUSIONS: Although the incidence of vomiting was similar, when these results are compared with a pre-specified zone of equivalence of 0-15%, it cannot be concluded that the effect of metoclopramide is equivalent to ondansetron. Survival analysis indicated that those in the metoclopramide group vomited substantially earlier. It is concluded, therefore, that ondansetron 0.1 mg kg(-1) is a superior drug to metoclopramide 0.5 mg kg(-1) for the prophylactic control of POV in children undergoing tonsillectomy. PMID- 17715140 TI - Detection of oesophageal intubations using cuff pressures in a pig trachea oesophagus model. AB - BACKGROUND: The cuff pressures may be different in oesophageal and tracheal intubations. We conducted a study to evaluate if cuff pressures of endotracheal tubes (ETTs) could provide information to distinguish tracheal or oesophageal intubations in a pig trachea-oesophagus model. METHODS: In each preparation of pig trachea-oesophagus model, the trachea and the oesophagus were intubated separately with a cuffed ETT, and the cuff pressures were measured after each 1 ml increment of air (1-10 ml) during inflation. The cuff pressures and the pressure-volume relationships in both intubations were compared. RESULTS: The cuff pressures of oesophageal intubations were significantly higher than those of tracheal intubations in all comparisons from 1 to 10 ml of cuff volumes (P < 0.05). The cuff pressure-volume curve was steeper in the oesophageal intubation group, and the difference between the two curves was the largest when the cuff volume was 4-5 ml. CONCLUSIONS: We conclude that the cuff pressures may be useful in detecting oesophageal intubations. This method is faster than other confirmation measures as it can detect inadvertent oesophageal intubations at the time of inflating the cuffs. PMID- 17715141 TI - Progesterone for the treatment of experimental brain injury; a systematic review. AB - Steroid sex hormones are potential neuroprotective candidates following CNS injury. All clinical trials to date have examined the effects of oestrogen alone or oestrogen-progestin combination therapy. Experimental studies have suggested that progesterone, in its own right, is a potential neuroprotective agent following acute cerebral injury. We performed a systematic review of controlled animal studies that administered progesterone before, or after, acute cerebral injury and measured lesion volume. Relevant studies were found from searching PubMed, Embase and Web of Science. From 119 identified publications, data from 18 studies using 480 experimental subjects met specific criteria and were analysed using the Cochrane Review Manager software. Following cerebral ischaemia, a significant benefit of progesterone was observed regardless of the assigned study quality score (P = 0.0002) whereas, following traumatic brain injury (TBI) a significant benefit of progesterone was only observed in studies that obtained the highest quality score of 5 (P = 0.02). Progesterone reduced lesion volume in a dose-dependent manner following either cerebral ischaemia (P < 0.001) or TBI (P = 0.03) with the most effective progesterone dose varying according to experimental injury model used. Progesterone treatment was only effective at reducing lesion volume when administered immediately following (i.e. 0-2 h) cerebral ischaemia (P = 0.0008). No studies using models of cerebral ischaemia or TBI assessed efficacy when progesterone was administered at later than 6 h following the onset of cerebral injury. Limited data were available for different groups of animals according to age/hormonal status and the full dose-response relationship was not available in all experimental groups. Although this systematic review provides some supporting evidence for a neuroprotective role of progesterone following either cerebral ischaemia or TBI importantly it highlights areas which need further pre-clinical investigation. PMID- 17715142 TI - Direct immobilization of DNA oligomers onto the amine-functionalized glass surface for DNA microarray fabrication through the activation-free reaction of oxanine. AB - Oxanine having an O-acylisourea structure was explored to see if its reactivity with amino group is useful in DNA microarray fabrication. By the chemical synthesis, a nucleotide unit of oxanine (Oxa-N) was incorporated into the 5'-end of probe DNA with or without the -(CH2)n- spacers (n = 3 and 12) and found to immobilize the probe DNA covalently onto the NH2-functionalized glass slide by one-pot reaction, producing the high efficiency of the target hybridization. The methylene spacer, particularly the longer one, generated higher efficiency of the target recognition although there was little effect on the amount of the immobilized DNA oligomers. The post-spotting treatment was also carried out under the mild conditions (at 25 or 42 degrees C) and the efficiencies of the immobilization and the target recognition were evaluated similarly, and analogous trends were obtained. It has also been determined under the mild conditions that the humidity and time of the post-spotting treatment, pH of the spotting solution and the synergistic effects with UV-irradiation largely contribute to the desired immobilization and resulting target recognition. Immobilization of DNA oligomer by use of Oxa-N on the NH2-functionalized surface without any activation step would be employed as one of the advanced methods for generating DNA-conjugated solid surface. PMID- 17715143 TI - Design of extended short hairpin RNAs for HIV-1 inhibition. AB - RNA interference (RNAi) targeted towards viral mRNAs is widely used to block virus replication in mammalian cells. The specific antiviral RNAi response can be induced via transfection of synthetic small interfering RNAs (siRNAs) or via intracellular expression of short hairpin RNAs (shRNAs). For HIV-1, both approaches resulted in profound inhibition of virus replication. However, the therapeutic use of a single siRNA/shRNA appears limited due to the rapid emergence of RNAi-resistant escape viruses. These variants contain deletions or point mutations within the target sequence that abolish the antiviral effect. To avoid escape from RNAi, the virus should be simultaneously targeted with multiple shRNAs. Alternatively, long hairpin RNAs can be used from which multiple effective siRNAs may be produced. In this study, we constructed extended shRNAs (e-shRNAs) that encode two effective siRNAs against conserved HIV-1 sequences. Activity assays and RNA processing analyses indicate that the positioning of the two siRNAs within the hairpin stem is critical for the generation of two functional siRNAs. E-shRNAs that are efficiently processed into two effective siRNAs showed better inhibition of virus production than the poorly processed e shRNAs, without inducing the interferon response. These results provide building principles for the design of multi-siRNA hairpin constructs. PMID- 17715144 TI - Psoralen-induced DNA adducts are substrates for the base excision repair pathway in human cells. AB - Interstrand cross-link (ICL) is a covalent modification of both strands of DNA, which prevents DNA strand separation during transcription and replication. Upon photoactivation 8-methoxypsoralen (8-MOP+UVA) alkylates both strands of DNA duplex at the 5,6-double bond of thymidines, generating monoadducts (MAs) and ICLs. It was thought that bulky DNA lesions such as MAs are eliminated only in the nucleotide excision repair pathway. Instead, non-bulky DNA lesions are substrates for DNA glycosylases and AP endonucleases which initiate the base excision repair (BER) pathway. Here we examined whether BER might be involved in the removal of psoralen-DNA photoadducts. The results show that in human cells DNA glycosylase NEIL1 excises the MAs in duplex DNA, subsequently the apurinic/apyrimidinic endonuclease 1, APE1, removes the 3'-phosphate residue at single-strand break generated by NEIL1. The apparent kinetic parameters suggest that NEIL1 excises MAs with high efficiency. Consistent with these results HeLa cells lacking APE1 and/or NEIL1 become hypersensitive to 8-MOP+UVA exposure. Furthermore, we demonstrate that bacterial homologues of NEIL1, the Fpg and Nei proteins, also excise MAs. New substrate specificity of the Fpg/Nei protein family provides an alternative repair pathway for ICLs and bulky DNA damage. PMID- 17715145 TI - The RAGNYA fold: a novel fold with multiple topological variants found in functionally diverse nucleic acid, nucleotide and peptide-binding proteins. AB - Using sensitive structure similarity searches, we identify a shared alpha+beta fold, RAGNYA, principally involved in nucleic acid, nucleotide or peptide interactions in a diverse group of proteins. These include the Ribosomal proteins L3 and L1, ATP-grasp modules, the GYF domain, DNA-recombination proteins of the NinB family from caudate bacteriophages, the C-terminal DNA-interacting domain of the Y-family DNA polymerases, the uncharacterized enzyme AMMECR1, the siRNA silencing repressor of tombusviruses, tRNA Wybutosine biosynthesis enzyme Tyw3p, DNA/RNA ligases and related nucleotidyltransferases and the Enhancer of rudimentary proteins. This fold exhibits three distinct circularly permuted versions and is composed of an internal repeat of a unit with two-strands and a helix. We show that despite considerable structural diversity in the fold, its representatives show a common mode of nucleic acid or nucleotide interaction via the exposed face of the sheet. Using this information and sensitive profile-based sequence searches: (1) we predict the active site, and mode of substrate interaction of the Wybutosine biosynthesis enzyme, Tyw3p, and a potential catalytic role for AMMECR1. (2) We provide insights regarding the mode of nucleic acid interaction of the NinB proteins, and the evolution of the active site of classical ATP-grasp enzymes and DNA/RNA ligases. (3) We also present evidence for a bacterial origin of the GYF domain and propose how this version of the fold might have been utilized in peptide interactions in the context of nucleoprotein complexes. PMID- 17715147 TI - Novel high-resolution characterization of ancient DNA reveals C > U-type base modification events as the sole cause of post mortem miscoding lesions. AB - Ancient DNA (aDNA) research has long depended on the power of PCR to amplify trace amounts of surviving genetic material from preserved specimens. While PCR permits specific loci to be targeted and amplified, in many ways it can be intrinsically unsuited to damaged and degraded aDNA templates. PCR amplification of aDNA can produce highly-skewed distributions with significant contributions from miscoding lesion damage and non-authentic sequence artefacts. As traditional PCR-based approaches have been unable to fully resolve the molecular nature of aDNA damage over many years, we have developed a novel single primer extension (SPEX)-based approach to generate more accurate sequence information. SPEX targets selected template strands at defined loci and can generate a quantifiable redundancy of coverage; providing new insights into the molecular nature of aDNA damage and fragmentation. SPEX sequence data reveals inherent limitations in both traditional and metagenomic PCR-based approaches to aDNA, which can make current damage analyses and correct genotyping of ancient specimens problematic. In contrast to previous aDNA studies, SPEX provides strong quantitative evidence that C > U-type base modifications are the sole cause of authentic endogenous damage-derived miscoding lesions. This new approach could allow ancient specimens to be genotyped with unprecedented accuracy. PMID- 17715146 TI - Physical and functional interactions between Werner syndrome helicase and mismatch-repair initiation factors. AB - Werner syndrome (WS) is a severe recessive disorder characterized by premature aging, cancer predisposition and genomic instability. The gene mutated in WS encodes a bi-functional enzyme called WRN that acts as a RecQ-type DNA helicase and a 3'-5' exonuclease, but its exact role in DNA metabolism is poorly understood. Here we show that WRN physically interacts with the MSH2/MSH6 (MutSalpha), MSH2/MSH3 (MutSbeta) and MLH1/PMS2 (MutLalpha) heterodimers that are involved in the initiation of mismatch repair (MMR) and the rejection of homeologous recombination. MutSalpha and MutSbeta can strongly stimulate the helicase activity of WRN specifically on forked DNA structures with a 3'-single stranded arm. The stimulatory effect of MutSalpha on WRN-mediated unwinding is enhanced by a G/T mismatch in the DNA duplex ahead of the fork. The MutLalpha protein known to bind to the MutS alpha-heteroduplex complexes has no effect on WRN-mediated DNA unwinding stimulated by MutSalpha, nor does it affect DNA unwinding by WRN alone. Our data are consistent with results of genetic experiments in yeast suggesting that MMR factors act in conjunction with a RecQ type helicase to reject recombination between divergent sequences. PMID- 17715149 TI - Cyanobacteriochrome TePixJ of Thermosynechococcus elongatus harbors phycoviolobilin as a chromophore. AB - Cyanobacteria have several putative photoreceptors (designated cyanobacteriochromes) that are related to but distinct from the established phytochromes. The GAF domain of the phototaxis regulator, PixJ, from a thermophilic cyanobacterium Thermosynechococcus elongatus BP-1 (TePixJ_GAF) is a cyanobacteriochrome which exhibits reversible photoconversion between a blue light-absorbing form (max = 433 nm) and a green light-absorbing form (max = 531 nm). To study the chromophore, we prepared TePixJ_GAF chromoprotein from heterologously expressed Synechocystis and performed spectral analysis after denaturation by comparing it with the cyanobacterial phytochrome Cph1 which harbors phycocyanobilin (PCB) as a chromophore. The results indicated that the chromophore of TePixJ is not PCB, but its isomer, phycoviolobilin (PVB). It is suggested that the GAF domain of TePixJ has auto-lyase and auto-isomerase activities. PMID- 17715148 TI - Brief report: Taiwanese infants' mental and motor development--6-24 months. AB - OBJECTIVES: To establish the normative data of the Bayley Scales of Infant Development-Second Edition (BSID-II) on Taiwanese infants from age 6 to 24 months and to explore the factors that relate to their mental and motor development. METHODS: Five hundred and seven Taiwanese full-term infants were prospectively examined with the BSID-II at 6, 12, 18, and 24 months of age. RESULTS: Taiwanese infants' Bayley mental and motor raw scores were lower than the United States norms from age 6 to 24 months, however, the discrepancy gradually declined with increasing age. Gender, intrauterine growth status, birth order, region of residence, maternal education, and paternal occupation were shown to have longitudinal associations with their mental and/or motor scores. CONCLUSIONS: Differences existed in the mental and motor development among Taiwanese and American infants. Our preliminary norms of the BSID-II may be more appropriate than the United States norms for Taiwanese children. PMID- 17715151 TI - BioManager: the use of a bioinformatics web application as a teaching tool in undergraduate bioinformatics training. AB - The completion of the human genome project, and other genome sequencing projects, has spearheaded the emergence of the field of bioinformatics. Using computer programs to analyse DNA and protein information has become an important area of life science research and development. While it is not necessary for most life science researchers to develop specialist bioinformatic skills (including software development), basic skills in the application of common bioinformatics software and the effective interpretation of results are increasingly required by all life science researchers. Training in bioinformatics is increasingly occurring within the university system as part of existing undergraduate science and specialist degrees. One difficulty in bioinformatics education is the sheer number of software programs required in order to provide a thorough grounding in the subject to the student. Teaching requires either a well-maintained internal server with all the required software, properly interfacing with student terminals, and with sufficient capacity to handle multiple simultaneous requests, or it requires the individual installation and maintenance of every piece of software on each computer. In both cases, there are difficult issues regarding site maintenance and accessibility. In this article, we discuss the use of BioManager, a web-based bioinformatics application integrating a variety of common bioinformatics tools, for teaching, including its role as the main bioinformatics training tool in some Australian and international universities. We discuss some of the issues with using a bioinformatics resource primarily created for research in an undergraduate teaching environment. PMID- 17715150 TI - The fiber specificity of the cotton FSltp4 gene promoter is regulated by an AT rich promoter region and the AT-hook transcription factor GhAT1. AB - Fiber-specific genes are expressed preferentially or exclusively in cotton (Gossypium spp.) fiber and are thought to have important functions in fiber development. The promoters of these genes are of interest because they control transcription in the fiber cell and may be used in the genetic manipulation of fiber quality. The promoter of a cotton lipid transfer protein gene, FSltp4, was isolated and shown to direct fiber-specific transcription of an abundant mRNA in cotton. In transgenic tobacco, this promoter was strongly active in leaf trichomes. Deletion analysis of the promoter identified an AT-rich 84 bp fiber specificity region (FSR) necessary for activity exclusively in the fiber cells. Cotton fiber proteins that bind the FSR were isolated using a yeast one-hybrid assay. One of these was a putative AT-hook transcription factor (GhAT1) containing two AT-hook motifs. GhAT1 was shown to be nuclear localized, and GhAT1 transcripts were found to be preferentially expressed in ovules and non-fiber tissues. Overexpression of GhAT1 strongly repressed the activity of the FSltp4 promoter in the trichomes of transgenic tobacco. These results suggest that GhAT1 assists in the specification of fiber cells by repressing FSltp4 in the non-fiber tissues of the cotton plant. PMID- 17715152 TI - Editing the JPH. PMID- 17715153 TI - Communicable disease and health protection quarterly review: January to March 2007. From the Health Protection Agency, Centre for Infections. PMID- 17715154 TI - Evolution of the eukaryotic membrane-trafficking system: origin, tempo and mode. AB - The emergence of an endomembrane system was a crucial stage in the prokaryote-to eukaryote evolutionary transition. Recent genomic and molecular evolutionary analyses have provided insight into how this critical system arrived at its modern configuration. The apparent relative absence of prokaryotic antecedents for the endomembrane machinery contrasts with the situation for mitochondria, plastids and the nucleus. Overall, the evidence suggests an autogenous origin for the eukaryotic membrane-trafficking machinery. The emerging picture is that early eukaryotic ancestors had a complex endomembrane system, which implies that this cellular system evolved relatively rapidly after the proto-eukaryote diverged away from the other prokaryotic lines. Many of the components of the trafficking system are the result of gene duplications that have produced proteins that have similar functions but differ in their subcellular location. A proto-eukaryote possessing a very simple trafficking system could thus have evolved to near modern complexity in the last common eukaryotic ancestor (LCEA) via paralogous gene family expansion of the proteins encoding organelle identity. The descendents of this common ancestor have undergone further modification of the trafficking machinery; unicellular simplicity and multicellular complexity are the prevailing trend, but there are some remarkable counter-examples. PMID- 17715155 TI - Aurora-A: the maker and breaker of spindle poles. AB - The gene encoding the Aurora-A protein kinase is located in the 20q13 breast cancer amplicon and is also overexpressed in colorectal, pancreatic and gastric tumours. Although Aurora-A may not be a bona fide oncoprotein in humans, it is a promising drug target in cancer therapy. Thus, it is surprising that so little is known of its role in normal cells. The primary function of Aurora-A is to promote bipolar spindle assembly, but the molecular details of this process remained obscure until recently. The discovery of several novel Aurora-A-binding proteins and substrates has implicated Aurora-A in centrosome maturation and separation, acentrosomal and centrosomal spindle assembly, kinetochore function, cytokinesis and in cell fate determination. Here we discuss recent advances in determining the early mitotic role of Aurora-A, with a strong emphasis on its function at the mitotic spindle poles. PMID- 17715156 TI - The muscle-specific microRNAs miR-1 and miR-133 produce opposing effects on apoptosis by targeting HSP60, HSP70 and caspase-9 in cardiomyocytes. AB - The microRNAs miR-1 and miR-133 are preferentially expressed in cardiac and skeletal muscles and have been shown to regulate differentiation and proliferation of these cells. We report here a novel aspect of cellular function of miR-1 and miR-133 regulation of cardiomyocyte apoptosis. miR-1 and miR-133 produced opposing effects on apoptosis, induced by oxidative stress in H9c2 rat ventricular cells, with miR-1 being pro-apoptotic and miR-133 being anti apoptotic. miR-1 level was significantly increased in response to oxidative stress. We identified single target sites for miR-1 only, in the 3'-untranslated regions of the HSP60 and HSP70 genes, and multiple putative target sites for miR 133 throughout the sequence of the caspase-9 gene. miR-1 reduced the levels of HSP60 and HSP70 proteins without changing their transcript levels, whereas miR 133 did not affect HSP60 and HSP70 expression at all. By contrast, miR-133 repressed caspase-9 expression at both the protein and mRNA levels. The post transcriptional repression of HSP60 and HSP70 and caspase-9 was further confirmed by luciferase reporter experiments. Our results indicate that miR-1 and miR-133 are involved in regulating cell fate with increased miR-1 and/or decreased miR 133 levels favoring apoptosis and decreased miR-1 and/or miR-133 levels favoring survival. Post-transcriptional repression of HSP60 and HSP70 by miR-1 and of caspase-9 by miR-133 contributes significantly to their opposing actions. PMID- 17715157 TI - Prescription of paracetamol-containing medications as indicator of quality of prescribing. PMID- 17715158 TI - No evidence of the Chlamydia trachomatis variant in the UK. AB - OBJECTIVES: The discovery of a variant strain of Chlamydia trachomatis (Ct) in Sweden has raised awareness of its possible undetected spread in the UK. The assays that fail to detect this variant are widely used in this country. This study aimed to determine if this variant is circulating in the UK. METHOD: 1,680 genital specimens tested negative by the Roche assays were retested by Aptima Combo2. Discordant results were sequenced to check for the deletion variant. RESULTS: Of 1,680 specimens tested, 29 were candidates for sequencing: 16 were negative for the variant, 11 failed to amplify, and 2 were lost. DISCUSSION: No Ct deletion variants were found in the UK. If it is circulating, then the prevalence is low (0-0.77%), but even a low level cannot be ignored. The system we describe is simple and suitable for rapid response and phasing of surveillance to match an unknown level of threat if other variants emerge. PMID- 17715159 TI - Mendelian randomization as an instrumental variable approach to causal inference. AB - In epidemiological research, the causal effect of a modifiable phenotype or exposure on a disease is often of public health interest. Randomized controlled trials to investigate this effect are not always possible and inferences based on observational data can be confounded. However, if we know of a gene closely linked to the phenotype without direct effect on the disease, it can often be reasonably assumed that the gene is not itself associated with any confounding factors - a phenomenon called Mendelian randomization. These properties define an instrumental variable and allow estimation of the causal effect, despite the confounding, under certain model restrictions. In this paper, we present a formal framework for causal inference based on Mendelian randomization and suggest using directed acyclic graphs to check model assumptions by visual inspection. This framework allows us to address limitations of the Mendelian randomization technique that have often been overlooked in the medical literature. PMID- 17715160 TI - Applying artificial neural networks to the diagnosis of organic dyspepsia. AB - BACKGROUND: Dyspepsia diagnoses and treatment decisions are made in situations in which multiple factors must be taken into account. Evolving from neuro-biological insights, artificial neural networks (ANNs) can employ multiple factors in resolving medical prediction, classification, pattern recognition, and pattern completion. The objective of this study was to compare predictive results classifying people with organic dyspepsia with Helicobacter pylori testing (rapid urease test), a scoring system based on patients' symptoms (derived using logistic regression), classification and regression trees (CART) and the most common ANN approach used in medicine: a feed-forward multilayer perceptron (MLP) trained by back-propagation. METHODS: A scoring system, CART algorithm, and MLP model were constructed. Predictive accuracy was calculated for them and for Helicobacter pylori testing. RESULTS: MLP model had a sensitivity of 0.91 (0.81 for all data) and a specificity of 0.74 (0.79 for all data) for test data. That compares favorably with Helicobacter pylori testing (sensitivity = 0.80, specificity = 0.43), the scoring system (sensitivity = 0.85, specificity = 0.60), and the CART model (sensitivity = 0.88, specificity = 0.53). Diagnostic accuracy, the area under the curve, was 0.82 using the MLP model, 0.61 using Helicobacter pylori testing, 0.78 using the scoring system, and 0.72 for the test set using CART. CONCLUSIONS: The results of the analysis showed that the ANN model derived has better predictive accuracy than Helicobacter pylori testing, than a scoring system based on patients' symptoms and than a decision tree algorithm (CART). ANN model could be used as a predictive tool for organic dyspepsia and would be useful in the process of referral of dyspeptic patients from primary care to endoscopy units. PMID- 17715161 TI - Markov transition models for binary repeated measures with ignorable and nonignorable missing values. AB - Motivated by problems encountered in studying treatments for drug dependence, where repeated binary outcomes arise from monitoring biomarkers for recent drug use, this article discusses a statistical strategy using Markov transition model for analyzing incomplete binary longitudinal data. When the mechanism giving rise to missing data can be assumed to be ;ignorable', standard Markov transition models can be applied to observed data to draw likelihood-based inference on transition probabilities between outcome events. Illustration of this approach is provided using binary results from urine drug screening in a clinical trial of baclofen for cocaine dependence. When longitudinal data have ;nonignorable' missingness mechanisms, random-effects Markov transition models can be used to model the joint distribution of the binary data matrix and the matrix of missingness indicators. Categorizing missingness patterns into those for occasional or ;intermittent' missingness and those for monotonic missingness or ;missingness due to dropout', the random-effects Markov transition model was applied to a data set containing repeated breath samples analyzed for expired carbon monoxide levels among opioid-dependent, methadone-maintained cigarette smokers in a smoking cessation trial. Markov transition models provide a novel reconceptualization of treatment outcomes, offering both intuitive statistical values and relevant clinical insights. PMID- 17715162 TI - Segmental modeling of changing viral load to assess drug resistance in HIV infection. AB - Studies of viral dynamics are important to our understanding of the pathogenesis of HIV-1 infection and in assessment of the potency of antiretroviral therapies. Although many different viral dynamic models and methods for estimating viral dynamic parameters have been proposed and used in various studies, none has been entirely satisfactory. We propose here a segmental model to describe the viral load, and estimate the dynamic parameters by using a mixed-effects model. We address the relation between the baseline viral load and the decay rate of the first phase of viral load decay, and divide patients into three categories on the basis of their changing viral load patterns. PMID- 17715163 TI - Impact on patients' health status following early identification of a COPD exacerbation. AB - The current study aimed to assess the impact on patient health status during an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). A total of 421 COPD patients were enrolled in a multicentre, single-arm study with a 6-month observational follow-up period. Patients received two inhalations of Symbicort 200 Turbuhaler(R) twice a day. Patients were assessed before the run-in period, at baseline and at 1, 3 and 6 months. Patients were instructed to report a change in respiratory symptoms lasting >24 h. This defined an AECOPD. In addition to the initial call, the St George's Respiratory Questionnaire (SGRQ), COPD Control Questionnaire (CCQ), Medical Research Council (MRC) dyspnoea scale and activities of daily living (ADL) were completed at 5-7 and 12-14 days. A group of 176 patients reported at least one AECOPD. Exacerbations were associated with statistically significant mean changes (worsening) in the SGRQ activity and impact domains at onset (mean +/- sd 12.1 +/- 18.1 and 14.0 +/- 15.2), during the first (9.8 +/- 19.0 and 9.4 +/- 16.6) and second weeks (3.1 +/- 15.5 and 3.3 +/- 14.7). Clinically significant deterioration in SGRQ impact scores was shown in 71% of patients following early identification, with 55 and 37% during the first and second weeks of an AECOPD, respectively. Acute exacerbation severely impacts on health status. The current study provides valuable information on the change in health status during an acute exacerbation of chronic obstructive pulmonary disease that can be utilised for future trials that evaluate therapeutic intervention. PMID- 17715164 TI - Anti-inflammatory effects of inhaled carbon monoxide in patients with COPD: a pilot study. AB - In vitro and in vivo studies have shown that carbon monoxide (CO) has both anti inflammatory and anti-oxidant capacities. Since chronic obstructive pulmonary disease (COPD) is characterised by inflammation and oxidative stress, low-dose CO could be of therapeutic use. The aim of the present study was to investigate the feasibility and anti-inflammatory effects of 100-125 ppm CO inhalation in patients with stable COPD. In total, 20 ex-smoking COPD patients with post bronchodilator forced expiratory volume in one second (FEV(1)) >1.20 L and FEV(1)/forced vital capacity <70% were enrolled in a randomised, placebo controlled, crossover study. Effects on inflammation were measured in induced sputum and blood. CO inhalation was feasible and patients' vital signs were unaffected; 2 h.day(-1) inhalation of low-dose CO on 4 consecutive days led to a maximal individual carboxyhaemoglobin level of 4.5%. Two exacerbations occurred in the CO period. CO inhalation led to trends in reduced sputum eosinophils (median reduction 0.25% point) and improved responsiveness to methacholine (median provocative concentration causing a 20% fall in FEV(1) 0.85 versus 0.63 mg.mL(-1)). Inhalation of 100-125 ppm carbon monoxide by patients with chronic obstructive pulmonary disease in a stable phase was feasible and led to trends in reduction of sputum eosinophils and improvement of responsiveness to methacholine. Further studies need to confirm the safety and efficacy in inflammatory lung diseases. PMID- 17715165 TI - Use of a T-cell interferon-gamma release assay for the diagnosis of tuberculous pleurisy. AB - The diagnosis of pleural tuberculosis (plTB) by the analysis of pleural effusions (PEs) with standard diagnostic tools is difficult. In routine clinical practice, the present authors evaluated the performance of a commercially available Mycobacterium tuberculosis (MTB)-specific enzyme-linked immunospot assay on peripheral blood mononuclear cells (PBMCs) and pleural effusion mononuclear cells (PEMCs) in patients with suspect plTB. The T-SPOT.TB test (Oxford Immunotec Ltd, Abingdon, UK) was performed on PBMCs and PEMCs in 20 patients with a clinical and radiological suspect of plTB and in 21 control subjects with a diagnosis of PE of nontuberculous origin at four centres participating in the European Tuberculosis Network. In total, 18 (90%) out of 20 patients with plTB tested T-SPOT.TB positive on PBMCs and 19 (95%) out of 20 on PEMCs. Among controls, T-SPOT.TB was positive in seven out of 21 (33%) patients when performed on PBMCs (these patients were assumed to be latently infected with MTB) and five (23%) out of 21 when performed on PEMCs. Sensitivity and specificity of T-SPOT.TB for the diagnosis of active plTB when performed on PEMCs were 95 and 76%, respectively. Enumerating Mycobacterium tuberculosis-specific T-cells in pleural effusion mononuclear cells by ELISPOT is feasible in routine clinical practice and may be useful for a rapid and accurate diagnosis of pleural tuberculosis. PMID- 17715166 TI - Magnetic resonance-compatible-spirometry: principle, technical evaluation and application. AB - The aim of this study was to assess the feasibility and accuracy of a novel magnetic resonance-compatible (MRc)-spirometer. The influence of body posture, magnetic resonance (MR)-setting and image acquisition on lung function was evaluated. Dynamic MR imaging (dMRI) was compared with simultaneously measured lung function. The development of the MRc-spirometer was based on a commercial spirometer and evaluated by flow-generator measurements and forced expiratory manoeuvres in 34 healthy nonsmokers (17 females and 17 males, mean age 32.9 yrs). Mean differences between forced expiratory volume in one second (FEV(1)) and forced vital capacity (FVC) were calculated and a sample paired t-test and Bland Altman plots were generated. A total of 11 subjects underwent different subsequent MRc-spirometric measurements to assess the influence of the components of the MR system on lung function. The mean (95% confidence interval) difference of FEV(1) and FVC between the two systems was 0.004 (-0.04-0.04) L and 0.018 ( 0.05-0.09) L, respectively. In the subgroup analysis, an influence of the MR system on FEV(1) was found. FEV(1) correlated well with the dMRI measurement of the apico-diaphragmatic distance-change after the first second of forced expiration (r = 0.72). In conclusion, magnetic resonance-compatible-spirometry is feasible, reliable and safe. The magnetic resonance-setting only has a small influence on simultaneously measured forced expiratory volume in one second. Dynamic magnetic resonance imaging measurements correlate well with simultaneously acquired lung function parameters. PMID- 17715167 TI - Influenza- and respiratory syncytial virus-associated mortality and hospitalisations. AB - The aim of the current study was to estimate influenza- and respiratory syncytial virus (RSV)-associated mortality and hospitalisations, especially the influenza associated burden among low-risk individuals < or =65 yrs old, not yet recommended for influenza vaccination in many European countries. Retrospectively during 1997-2003, Dutch national all-cause mortality and hospital discharge figures and virus surveillance data were used to estimate annual average influenza- and RSV-associated excess mortality and hospitalisation using rate difference methods. Influenza virus active periods were significantly associated with excess mortality among 50-64-yr-olds and the elderly, but not in younger age categories. Influenza-associated hospitalisation was highest and about equal for 0-1-yr-olds and the elderly, and also significant for low-risk adults. Hospitalisation among children was mostly due to respiratory conditions, and among adults cardiovascular complications were frequent. RSV-active periods were associated with excess mortality and hospitalisation among the elderly. The highest RSV-related excess hospitalisation was found in 0-1-yr-olds. Influenza associated mortality was demonstrated in 50-64-yr-olds. Among low-risk individuals < or =65 yrs of age, influenza-associated hospitalisation rates were highest for 0-4-yr-olds, but also significant for 5-64-yr-olds. These data may further support extension of recommendations for influenza vaccination to include younger low-risk persons. The respiratory syncytial virus-associated burden was highest for young children but also substantial for the elderly. PMID- 17715168 TI - Outcome and prognostic factors of lung cancer patients admitted to the medical intensive care unit. AB - The aim of the present study was to assess the outcome of lung cancer patients who were admitted to a medical intensive care unit (MICU) and to identify the measurable predictors of their MICU outcome. The retrospective study took place at the MICUs of a university-affiliated medical centre and involved adult lung cancer patients admitted to the MICU between January 1998 and October 2005. A total of 139 lung cancer patients were included during the study period. The mean age+/-sd at MICU admission was 64.2+/-10.2 yrs (48% males, 52% females). In total, 96 (69%) patients had nonsmall cell lung cancer, 18 (13%) patients had small cell lung cancer, and one patient had mesothelioma. The MICU mortality was 22% (31 patients), while the in-hospital mortality was 40% (56 patients). Sixty eight (49%) patients required mechanical ventilation (MV), with MICU mortality of 38% and in-hospital mortality of 53%. The independent predictors of poor MICU outcome were: the need for MV; Acute Physiology And Chronic Health Evaluation III and Simplified Acute Physiology Score III scores; the use of vasopressors; positive blood cultures; high serum lactate; two or more organ system failures; and the need for adult cardiac life support. On multivariate analysis, only the need for vasopressors and the presence of two or more organ system failures predicted poor MICU outcome. The present study shows that the medical intensive care unit outcome of lung cancer patients is better than previously reported. Intensive care and mechanical ventilation should not be considered futile care in this patient population. While there were no absolute predictors of mortality, the need for vasopressors and the presence of two or more organ system failures predicted poor medical intensive care unit care. PMID- 17715169 TI - Diagnosis of pulmonary embolism in hospitalised patients: retrospective survey of an institutional standard. AB - The aim of the present study was to assess the safety and implementation of a diagnostic strategy in hospitalised patients with suspected acute pulmonary embolism (PE). A diagnostic strategy was established and implemented in a general hospital. A retrospective cohort study, including 400 consecutive in-patients, was performed in order to assess the appropriateness of the diagnostic management and the incidence of symptomatic venous thromboembolic events (VTE) during follow up. PE was confirmed in 116 (29%) patients. The incremental value of adding compression ultrasonography (CUS) to multidetector-row computed tomography (MDCT) for the diagnosis of PE was 8.6%. PE was appropriately excluded in 169 (42%) patients due to a normal lung scan (n = 34), a negative MDCT providing an alternative diagnosis (n = 94), and a negative MDCT and CUS (n = 41). During follow-up, VTE occurred in 3.5% patients. The almost unique cause of inappropriate management was the absence of further work-up after a MDCT-negative result for PE providing no alternative diagnosis (n = 115). Inappropriate management was associated with a nonsignificant increased risk of VTE (7.2%). A frontline diagnostic work-up based on pulmonary multidetector-row computed tomography associated with a compression ultrasonography of the leg veins is effective and more sensitive than pulmonary multidetector-row computed tomography alone in ruling out pulmonary embolism. PMID- 17715170 TI - Clinical determinants of exacerbations in severe, early-onset COPD. AB - Chronic obstructive pulmonary disease (COPD) exacerbations impair health. The present authors analysed participants in the Boston Early-Onset COPD Study for familial aggregation and propensity for COPD exacerbations. In the present study, two exacerbation outcomes, episodes of cough and phlegm, and frequent exacerbations were analysed with multivariable modelling and generalised estimating equations. In early-onset COPD probands, passive tobacco smoke exposure within the home was strongly associated with episodes of cough and phlegm. Chronic phlegm production was associated with both exacerbation phenotypes in probands. In first-degree relatives of early-onset COPD probands, chronic bronchitis, episodic wheezing, pneumonia and active smoking were associated with the episodes of cough and phlegm phenotype. In relatives, identical characteristics plus exertional dyspnoea were associated with frequent exacerbations. Exacerbation risk increased with declining lung function. Familial aggregation for episodes of cough and phlegm was observed in relatives with severe obstruction. In conclusion, passive smoke exposure increases morbidity in severe early-onset chronic obstructive pulmonary disease probands, and chronic obstructive pulmonary disease exacerbations correlate with chronic sputum production in probands and relatives. The familial aggregation of exacerbations suggests a genetic basis for susceptibility to chronic obstructive pulmonary disease exacerbations. PMID- 17715171 TI - Asymptomatic Brugada syndrome: a cardiac ticking time-bomb? PMID- 17715172 TI - Cytokines in arthritis--the 'big numbers' move centre stage. AB - More than 20 yrs ago, T-helper lymphocytes were divided into Th1 and Th2 subsets on the basis of their cytokine production. The pro-inflammatory Th1 subset was considered predominant in inflammatory arthritis, but evidence for this notion was incomplete, and some called into question the role of helper T cells. The identification of a novel T cell subset, Th17 cells, which appears to be critical for several forms of autoimmune inflammation, including arthritis, requires a reconsideration of arthritis pathogenesis and the role of T cells. This review deals with several of the newly described ('big number') cytokines which are involved in the differentiation and action of Th17 cells, and pays particular attention to the pathogenesis of spondyloarthritis because of the implication of the same cytokine networks in psoriasis and inflammatory bowel disease. The role of dendritic cells as coordinators of T cell differentiation in response to pathogen-derived signals in also emphasized. PMID- 17715173 TI - Patient education on cardiovascular aspects of rheumatoid disease: an unmet need. PMID- 17715175 TI - Rab11 maintains connections between germline stem cells and niche cells in the Drosophila ovary. AB - All stem cells have the ability to balance their production of self-renewing and differentiating daughter cells. The germline stem cells (GSCs) of the Drosophila ovary maintain such balance through physical attachment to anterior niche cap cells and stereotypic cell division, whereby only one daughter remains attached to the niche. GSCs are attached to cap cells via adherens junctions, which also appear to orient GSC division through capture of the fusome, a germline-specific organizer of mitotic spindles. Here we show that the Rab11 GTPase is required in the ovary to maintain GSC-cap cell junctions and to anchor the fusome to the anterior cortex of the GSC. Thus, rab11-null GSCs detach from niche cap cells, contain displaced fusomes and undergo abnormal cell division, leading to an early arrest of GSC differentiation. Such defects are likely to reflect a role for Rab11 in E-cadherin trafficking as E-cadherin accumulates in Rab11-positive recycling endosomes (REs) and E-cadherin and Armadillo (beta-catenin) are both found in reduced amounts on the surface of rab11-null GSCs. The Rab11-positive REs through which E-cadherin transits are tightly associated with the fusome. We propose that this association polarizes the trafficking by Rab11 of E-cadherin and other cargoes toward the anterior cortex of the GSC, thus simultaneously fortifying GSC-niche junctions, fusome localization and asymmetric cell division. These studies bring into focus the important role of membrane trafficking in stem cell biology. PMID- 17715174 TI - How should gestational weight gain be assessed? A comparison of existing methods and a novel method, area under the weight gain curve. AB - BACKGROUND: Gestational weight gain is important to assess for epidemiological and public health purposes: it is correlated with infant growth and may be related to maternal outcomes such as reproductive health and chronic disease risk. Methods commonly used to assess weight gain incorporate assumptions that are usually not borne out, such as a linear weight gain, or do not account for differential length of gestation. METHODS: We introduce a novel method to assess gestational weight gain, the area under the weight gain curve. This is easily interpretable as the additional pound-days carried due to pregnancy and avoids many flaws in alternative assessments. We compare the performance of the simple difference, weekly gain, Institute of Medicine categories and the area under the weight gain curve in predicting birthweight and maternal weight retention at 6, 12, 24 and 36 months postpartum. The analytic sample comprises 2016 participants in Project Viva, an observational prospective cohort study of pregnant women in Massachusetts. RESULTS: For birthweight outcomes, none of the weight gain measures is a meaningfully superior predictor. For 6-month postpartum weight retention the simple difference is superior, while for 12-, 24- and 36-month weight retention the area under the weight gain curve is superior. CONCLUSIONS: These findings are plausible biologically: the same amount of weight gained early vs later in the pregnancy may reflect increased maternal fat stores. The timing of weight gain is reflected best in the area under the weight gain curve. Different methods of measuring gestational weight gain may be appropriate depending on the context. PMID- 17715176 TI - Cell tracing reveals a dorsoventral lineage restriction plane in the mouse limb bud mesenchyme. AB - Regionalization of embryonic fields into independent units of growth and patterning is a widespread strategy during metazoan development. Compartments represent a particular instance of this regionalization, in which unit coherence is maintained by cell lineage restriction between adjacent regions. Lineage compartments have been described during insect and vertebrate development. Two common characteristics of the compartments described so far are their occurrence in epithelial structures and the presence of signaling regions at compartment borders. Whereas Drosophila compartmental organization represents a background subdivision of embryonic fields that is not necessarily related to anatomical structures, vertebrate compartment borders described thus far coincide with, or anticipate, anatomical or cell-type discontinuities. Here, we describe a general method for clonal analysis in the mouse and use it to determine the topology of clone distribution along the three limb axes. We identify a lineage restriction boundary at the limb mesenchyme dorsoventral border that is unrelated to any anatomical discontinuity, and whose lineage restriction border is not obviously associated with any signaling center. This restriction is the first example in vertebrates of a mechanism of primordium subdivision unrelated to anatomical boundaries. Furthermore, this is the first lineage compartment described within a mesenchymal structure in any organism, suggesting that lineage restrictions are fundamental not only for epithelial structures, but also for mesenchymal field patterning. No lineage compartmentalization was found along the proximodistal or anteroposterior axes, indicating that patterning along these axes does not involve restriction of cell dispersion at specific axial positions. PMID- 17715177 TI - Retinoic acid, meiosis and germ cell fate in mammals. AB - Although mammalian sex is determined genetically, the sex-specific development of germ cells as sperm or oocytes is initiated by cues provided by the gonadal environment. During embryogenesis, germ cells in an ovary enter meiosis, thereby committing to oogenesis. By contrast, germ cells in a testicular environment do not enter meiosis until puberty. Recent findings indicate that the key to this sex-specific timing of meiosis entry is the presence or absence of the signaling molecule retinoic acid. Although this knowledge clarifies a long-standing mystery in reproductive biology, it also poses many new questions, which we discuss in this review. PMID- 17715178 TI - Involvement of splanchnic vascular bed in anaphylactic hypotension in anesthetized BALB/c mice. AB - Using in vivo and isolated perfused liver preparations of BALB/c mice, we determined the roles of the liver and splanchnic vascular bed in anaphylactic hypotension. Intravenous injection of ovalbumin antigen into intact-sensitized mice decreased systemic arterial pressure (P(sa)) from 92 +/- 2 to 39 +/- 3 (SE) mmHg but only slightly increased portal venous pressure (P(pv)) from 6.4 +/- 0.1 cmH(2)O to the peak of 9.9 +/- 0.5 cmH(2)O at 3.5 min after antigen. Elimination of the splanchnic vascular beds by ligation of the celiac and mesenteric arteries, combined with total hepatectomy, attenuated anaphylactic hypotension. Ligation of these arteries alone, but not partial hepatectomy (70%), similarly attenuated anaphylactic hypotension. In contrast, isolated sensitized mouse liver perfused portally at constant flow did not show anaphylactic venoconstriction but, rather, substantial constriction in response to the anaphylaxis-associated platelet-activating factor, indicating that venoconstriction in mice in vivo may be induced by mediators released from extrahepatic tissues. These results suggest that splanchnic vascular beds are involved in BALB/c mouse anaphylactic hypotension. They presumably act as sources of chemical mediators to cause the anaphylaxis-induced portal hypertension, which induced splanchnic congestion, resulting in a decrease in circulating blood volume and, thus, systemic arterial hypotension. Mouse hepatic anaphylactic venoconstriction may be induced by factors outside the liver, but not by anaphylactic reaction within the liver. PMID- 17715179 TI - Effects of disinhibition of neurons in the dorsomedial hypothalamus on central respiratory drive. AB - Neurons within the dorsomedial hypothalamus (DMH) play a critical role in subserving the cardiovascular and neuroendocrine response to psychological stress. An increase in respiratory activity is also a characteristic feature of the physiological response to psychological stress, but there have been few studies of the role of DMH neurons in regulating respiratory activity. In this study we determined the effects of activation of DMH neurons on respiratory activity (assessed by measuring phrenic nerve activity, PNA) and the relationship between evoked changes in respiratory activity and changes in sympathetic vasomotor activity in spontaneously breathing urethane-anesthetized rats. Microinjections of bicuculline (4-40 pmol in 20 nl) into the DMH evoked dose dependent increases in PNA burst frequency and amplitude. These were accompanied by dose-dependent decreases in mean tracheal CO(2) levels, indicative of hyperventilation. In control experiments, microinjections of bicuculline into sites adjacent to the DMH evoked much smaller or no changes in PNA. In experiments where renal sympathetic nerve activity (RSNA) was also measured, cycle-triggered averaging revealed that RSNA under resting conditions was partly correlated with the PNA, but in response to DMH disinhibition there was no consistent change in the amplitude of the respiratory-related variations in RSNA. The results indicate that DMH neurons can exert a powerful stimulatory effect on respiratory activity, causing hyperventilation. This is not associated with an increase in the degree of coupling between PNA and RSNA, indicating that the DMH evoked increase in RSNA is not a consequence of increased central respiratory drive. PMID- 17715180 TI - Inspiratory muscle work in acute hypoxia influences locomotor muscle fatigue and exercise performance of healthy humans. AB - Our aim was to isolate the independent effects of 1) inspiratory muscle work (W(b)) and 2) arterial hypoxemia during heavy-intensity exercise in acute hypoxia on locomotor muscle fatigue. Eight cyclists exercised to exhaustion in hypoxia [inspired O(2) fraction (Fi(O(2))) = 0.15, arterial hemoglobin saturation (Sa(O(2))) = 81 +/- 1%; 8.6 +/- 0.5 min, 273 +/- 6 W; Hypoxia-control (Ctrl)] and at the same work rate and duration in normoxia (Sa(O(2)) = 95 +/- 1%; Normoxia Ctrl). These trials were repeated, but with a 35-80% reduction in W(b) achieved via proportional assist ventilation (PAV). Quadriceps twitch force was assessed via magnetic femoral nerve stimulation before and 2 min after exercise. The isolated effects of W(b) in hypoxia on quadriceps fatigue, independent of reductions in Sa(O(2)), were revealed by comparing Hypoxia-Ctrl and Hypoxia-PAV at equal levels of Sa(O(2)) (P = 0.10). Immediately after hypoxic exercise potentiated twitch force of the quadriceps (Q(tw,pot)) decreased by 30 +/- 3% below preexercise baseline, and this reduction was attenuated by about one-third after PAV exercise (21 +/- 4%; P = 0.0007). This effect of W(b) on quadriceps fatigue occurred at exercise work rates during which, in normoxia, reducing W(b) had no significant effect on fatigue. The isolated effects of reduced Sa(O(2)) on quadriceps fatigue, independent of changes in W(b), were revealed by comparing Hypoxia-PAV and Normoxia-PAV at equal levels of W(b). Q(tw,pot) decreased by 15 +/- 2% below preexercise baseline after Normoxia-PAV, and this reduction was exacerbated by about one-third after Hypoxia-PAV (-22 +/- 3%; P = 0.034). We conclude that both arterial hypoxemia and W(b) contribute significantly to the rate of development of locomotor muscle fatigue during exercise in acute hypoxia; this occurs at work rates during which, in normoxia, W(b) has no effect on peripheral fatigue. PMID- 17715181 TI - Autonomic nervous nonlinear interactions lead to frequency modulation between low and high-frequency bands of the heart rate variability spectrum. AB - Cardiac sympathetic and parasympathetic neural activities have been found to interact with each other to efficiently regulate the heart rate and maintain homeostasis. Quantitative and noninvasive methods used to detect the presence of interactions have been lacking, however. This may be because interactions among autonomic nervous systems are nonlinear and nonstationary. The goal of this work was to identify nonlinear interactions between the sympathetic and parasympathetic nervous systems in the form of frequency and amplitude modulations in human heart rate data. To this end, wavelet analysis was performed, followed by frequency analysis of the resultant wavelet decomposed signals in several frequency brackets defined as very low frequency (f < 0.04 Hz), low frequency (LF; 0.04-0.15 Hz), and high frequency (HF; 0.15-0.4 Hz). Our analysis suggests that the HF band is significantly modulated by the LF band in the heart rate data obtained in both supine and upright body positions. The strength of modulations is stronger in the upright than supine position, which is consistent with elevated sympathetic nervous activities in the upright position. Furthermore, significantly stronger frequency modulation than in the control condition was also observed with the cold pressor test. The results with the cold pressor test, as well as the body position experiments, further demonstrate that the frequency modulation between LF and HF is most likely due to sympathetic and parasympathetic nervous interactions during sympathetic activations. The modulation phenomenon suggests that the parasympathetic nervous system is frequency modulated by the sympathetic nervous system. In this study, there was no evidence of amplitude modulation among these frequencies. PMID- 17715182 TI - Right ventricular TNF resistance during endotoxemia: the differential effects on ventricular function. AB - Right and left ventricular myocytes originate from different cellular progenitors; however, it is unknown whether these cells differ in their response to endotoxemia. We hypothesized that 1) the percentage of endotoxemic functional depression within the right ventricle (RV) would be smaller than that of the left ventricle; and 2) that better RV function would correlate with lower levels of right ventricular TNF production. Adult Sprague-Dawley rats were divided into right and left control and endotoxin groups. Controls received vehicle, while endotoxin groups received LPS at 20 mg/kg ip. Hearts were excised either 2 or 6 h after injection. Hearts excised at 2 h were assayed for TNF, IL-6, TNF receptor 1 (TNFR1), TNFR2, and via ELISA, while hearts excised at 6 h were assayed via the Langendorff model. The percentage of cardiac functional depression, exhibited as developed pressure, contractility, and rate of relaxation (expressed as a percentage of control) was significantly smaller in right ventricles compared with left ventricles following endotoxin exposure. Tissue levels of TNF were significantly elevated in both right and left ventricles 2 h after endotoxin exposure, and right ventricular endotoxin groups expressed higher levels of TNF compared with their left ventricular counterparts. No significant differences in IL-6, TNFR1, or TNFR2 levels were noted between endotoxin-exposed ventricles. This is the first study to demonstrate that right and left ventricular function differs after endotoxin exposure. PMID- 17715183 TI - Molecular expression of SLC4-derived Na+-dependent anion transporters in selected human tissues. AB - NaHCO(3) transporters are involved in maintenance of intracellular pH and transepithelial HCO(3)(-) movement in many rodent tissues. To establish the human relevance of the many investigations on rodents, this study aimed to map these transporters and a related polypeptide, NaBC1 [solute carrier 4 (SLC4)A11], to several human tissues by using PCR on reverse transcribed human mRNA and immunoperoxidase histochemistry. The mRNA encoding the electroneutral Na(+):HCO(3)(-) cotransporter (NBCe1; SLC4A4), was expressed in renal cortex, renal medulla, stomach, duodenum, jejunum, ileum, colon, pancreas, choroid plexus, cerebellum, cerebrum, and hippocampus. NBCe2 (SLC4A5) and NBCn1 (SLC4A7) mRNAs were mainly found in kidney and brain tissues, as was mRNA encoding the Na(+)-dependent anion exchangers NCBE (SLC4A10) and NDCBE1 (SLC4A8). In addition to previous findings, NBCn1 protein was localized to human renal medullary thick ascending limbs and duodenal epithelial villus cells and NBCe2 protein to renal collecting ducts. Finally, the message encoding NaBC1 was found in kidney, stomach, duodenum, pancreas, and brain, and the corresponding protein in the anterior and posterior corneal epithelia, renal corpuscules, proximal tubules, collecting ducts, pancreatic ducts, and the choroid plexus epithelium. In conclusion, the selected human tissues display distinct expression patterns of HCO(3)(-) transporters, which closely resemble that of rodent tissues. PMID- 17715184 TI - Effects of temperature on ventilatory response to hypercapnia in newborn mice heterozygous for transcription factor Phox2b. AB - Congenital central hypoventilation syndrome (CCHS) is a rare disease with variable severity, generally present from birth and chiefly characterized by impaired chemosensitivity to hypercapnia. The main cause of CCHS is a mutation in the PHOX2B gene, which encodes a transcription factor involved in the development of autonomic medullary reflex pathways. Temperature regulation is abnormal in many patients with CCHS. Here, we examined whether ambient temperature influenced CO(2) sensitivity in a mouse model of CCHS. A weak response to CO(2) at thermoneutrality (32 degrees C) was noted previously in 2-day-old mice with an invalidated Phox2b allele (Phox2b+/-), compared with wild-type littermates. We exposed Phox2b+/- pups to 8% CO(2) at three ambient temperatures (TAs): 29 degrees C, 32 degrees C, and 35 degrees C. We measured breathing variables and heart rate (HR) noninvasively using a novel whole body flow plethysmograph equipped with contact electrodes. Body temperature and baseline breathing increased similarly with TA in mutant and wild-type pups. The hypercapnic ventilatory response increased linearly with TA in both groups, while remaining smaller in mutant than in wild-type pups at all TAs. The differences between the absolute increases in ventilation in mutant and wild-type pups become more pronounced as temperature increased above 29 degrees C. The ventilatory abnormalities in mutant pups were not associated with significant impairments of heart rate control. In both mutant and wild-type pups, baseline HR increased with TA. In conclusion, TA strongly influenced the hypercapnic ventilatory response in Phox2b+/- mutant mice. These findings suggest that abnormal temperature regulation may contribute to the severity of respiratory impairments in CCHS patients. PMID- 17715185 TI - Effect of mesenteric vascular congestion on reflex control of renal blood flow. AB - Portal hypertension initiates a splenorenal reflex, whereby increases in splenic afferent nerve activity and renal sympathetic nerve activity cause a decrease in renal blood flow (RBF). We postulated that mesenteric vascular congestion similarly compromises renal function through an intestinal-renal reflex. The portal vein was partially occluded in anesthetized rats, either rostral or caudal to the junction with the splenic vein. Portal venous pressure increased (6.5 +/- 0.1 to 13.2 +/- 0.1 mmHg; n = 78) and mesenteric venous outflow was equally obstructed in both cases. However, only rostral occlusion increased splenic venous pressure. Rostral occlusion caused a fall in RBF (-1.2 +/- 0.2 ml/min; n = 9) that was attenuated by renal denervation (-0.5 +/- 0.1 ml/min; n = 6), splenic denervation (-0.2 +/- 0.1 ml/min; n = 11), celiac ganglionectomy (-0.3 +/- 0.1 ml/min; n = 9), and splenectomy (-0.5 +/- 0.1 ml/min; n = 6). Caudal occlusion induced a significantly smaller fall in RBF (-0.5 +/- 0.1 ml/min; n = 9), which was not influenced by renal denervation (-0.2 +/- 0.2 ml/min; n = 6), splenic denervation (-0.1 +/- 0.1 ml/min; n = 7), celiac ganglionectomy (-0.1 +/- 0.3 ml/min; n = 8), or splenectomy (-0.3 +/- 0.1 ml/min; n = 7). Renal arterial conductance fell only in intact animals subjected to rostral occlusion (-0.007 +/ 0.002 ml.min(-1).mmHg(-1)). This was accompanied by increases in splenic afferent nerve activity (15.0 +/- 3.5 to 32.6 +/- 6.2 spikes/s; n = 7) and renal efferent nerve activity (32.7 +/- 5.2 to 39.3 +/- 6.0 spikes/s; n = 10). In animals subjected to caudal occlusion, there were no such changes in renal arterial conductance or splenic afferent/renal sympathetic nerve activity. We conclude that the portal hypertension-induced fall in RBF is initiated by increased splenic, but not mesenteric, venous pressure, i.e., we did not find evidence for intestinal-renal reflex control of the kidneys. PMID- 17715186 TI - Oxygen availability and PCr recovery rate in untrained human calf muscle: evidence of metabolic limitation in normoxia. AB - In contrast to their exercise-trained counterparts, the maximal oxidative rate of skeletal muscle in sedentary humans appears not to benefit from supplemental O(2) availability but is impacted by severe hypoxia, suggesting a metabolic limitation either at or below ambient O(2) levels. However, the critical level of O(2) availability at which maximal metabolic rate is reduced in sedentary humans is unknown. Using (31)P magnetic resonance spectroscopy and arterial oximetry, phosphocreatine (PCr) recovery kinetics and arterial oxygenation were assessed in six sedentary subjects performing 5-min bouts of plantar flexion exercise followed by 6 min of recovery. Each trial was repeated while breathing one of four different fractions of inspired O(2) (FI(O(2))) (0.10, 0.12, 0.15, and 0.21). The PCr recovery rate constant (a marker of oxidative capacity) was unaffected by reductions in FI(O(2)), remaining at a value of 1.5 +/- 0.2 min(-1) until arterial O(2) saturation (Sa(O(2))) fell to less than approximately 92%, the average value reached breathing an FI(O(2)) of 0.15. Below this Sa(O(2)), the PCr rate constant fell significantly by 13 and 31% to 1.3 +/- 0.2 and 1.0 +/- 0.2 min(-1) (P < 0.05) as Sa(O(2)) was reduced to 82 +/- 3 and 77 +/- 2%, respectively. In conclusion, this study has revealed that O(2) availability does not impact maximal oxidative rate in sedentary humans until the O(2) level falls well below that of ambient air, indicating a metabolic limitation in normoxia. PMID- 17715187 TI - Analysis of rhythmic patterns produced by spinal neural networks. AB - A network of spinal neurons known as central pattern generator (CPG) produces the rhythmic motor patterns required for coordinated swimming, walking, and running in mammals. Because the output of this network varies with time, its analysis cannot be performed by statistical methods that assume data stationarity. The present work uses short-time Fourier (STFT) and wavelet-transform (WT) algorithms to analyze the nonstationary rhythmic signals produced in isolated spinal cords of neonatal rats during activation of the CPGs. The STFT algorithm divides the time series into consecutive overlapping or nonoverlapping windows and repeatedly applies the Fourier transform across the signal. The WT algorithm decomposes the signal using a family of wavelets varying in scale, resulting in a set of wavelet coefficients presented onto a continuous frequency range over time. Our studies revealed that a Morlet WT algorithm was the tool of choice for analyzing the CPG output. Cross-WT and wavelet coherence were used to determine interrelations between pairs of time series in time and frequency domain, while determining the critical values for statistical significance of the coherence spectra using Monte Carlo simulations of white-noise series. The ability of the cross-Morlet WT and cross-WT coherence algorithms to efficiently extract the rhythmic parameters of complex nonstationary output of spinal pattern generators over a wide range of frequencies with time is demonstrated in this work under different experimental conditions. This ability can be exploited to create a quantitative dynamic portrait of experimental and clinical data under various physiological and pathological conditions. PMID- 17715188 TI - Patch-clamp analysis of gene-targeted vomeronasal neurons expressing a defined V1r or V2r receptor: ionic mechanisms underlying persistent firing. AB - Sensory neurons in the mouse vomeronasal organ consist of two major groups, apical and basal, that project to different brain regions, express unique sets of receptors, and serve distinct functions. Electrical properties of these two subpopulations, however, have not been systematically characterized. V1rb2-tau GFP and V2r1b-tau-GFP tagged vomeronasal sensory neurons (VSNs) were selected as prototypical apical or basal VSNs, respectively, and their biophysical properties were analyzed in acute slices that minimized cell damage. Basal V2r1b-expressing VSNs had voltage-gated conductances, and especially Na(+) (Nav) and Ca(2+) (Cav) currents, that were substantially larger than those observed in apical V1rb2 VSNs, although the resting membrane potential, input resistance, and membrane capacitance were similar in both cell types. Of several types of Cav currents, T type and L-type Cav currents contributed to action potential firing, and both currents alone were capable of generating oscillatory Ca(2+) spikes. The L-type Cav current was uniquely coupled to a BK large-conductance K(+) current, and interplay between these channels played a critical role in repolarizing spikes and maintaining persistent firing in VSNs. Larger Nav and Cav conductances, along with a more positive inactivation voltage of the Nav current in the V2r1b VSNs, contributed to the larger spike amplitude and higher spike frequency induced by depolarizing current in these cells compared with V1rb2 VSNs. Basal GFP-negative VSNs and V2r1b VSNs responded to prolonged depolarization with persistent, but adapting discharge that could be relevant in sensory adaptation. Collectively, these results suggest a novel mechanism for regulating and encoding neuronal activity in the accessory olfactory system. PMID- 17715189 TI - Coordination of smooth pursuit and saccade target selection in monkeys. AB - The coordination of saccadic and smooth pursuit eye movements in macaque monkeys was investigated using a target selection paradigm with two moving targets crossing at a center fixation point. A task in which monkeys selected a target based on its color was used to test the hypothesis that common neural signals underlie target selection for pursuit and saccades, as well as testing whether target selection signals are available to the saccade and pursuit systems simultaneously or sequentially. Several combinations of target color, speed, and direction were used. In all cases, smooth pursuit was highly selective for the rewarded target before any saccade occurred. On >80% of the trials, the saccade was directed toward the same target as both pre- and postsaccadic pursuit. The results favor a model in which a shared target selection signal is simultaneously available to both the saccade and pursuit systems, rather than a sequential model. PMID- 17715190 TI - Proactive and reactive mechanisms play a role in stepping on inverting surfaces during gait. AB - Ankle inversions have been studied extensively during standing conditions. However, inversion traumas occur during more dynamic conditions, like walking. Therefore in this study sudden ankle inversions were elicited in 12 healthy subjects who stepped on a trap door while walking on a treadmill. First, 10 control trials (0 degrees of rotation) were presented. Then, 20 stimulus (25 degrees of rotation) and control trials were presented randomly. EMG recordings were made of six lower leg muscles. All muscles showed a short-latency response (SLR) of about 40 ms and a late-latency response (LLR) of about 90 ms. The peroneal muscles showed the largest amplitudes in both responses. The functionally more important, larger, and more consistent LLR response was too late to resist the induced stretch during the inversion. The functional relevance of this response must lie after the inversion. During the first trial a widespread "startle-like" coactivation of the LLR was observed. The last trials showed only a recruitment of the peroneal muscles and, to a lesser extent, the gastrocnemius lateralis, which is seen as a switch from reactive control to more proactive adaptive strategies. These proactive strategies were investigated separately by comparing trials in which inversion was expected (but did not occur) with those in which subjects knew that no inversion would occur. Anticipation of a possible inversion was expressed in decreased tibialis anterior activity before initial contact, consistent with a more cautious and stable foot placement. Furthermore, immediately after landing, the peroneal muscles were activated to counteract the upcoming stretch. PMID- 17715192 TI - Characterization of lobula giant neurons responsive to visual stimuli that elicit escape behaviors in the crab Chasmagnathus. AB - In the grapsid crab Chasmagnathus, a visual danger stimulus elicits a strong escape response that diminishes rapidly on stimulus repetition. This behavioral modification can persist for several days as a result of the formation of an associative memory. We have previously shown that a generic group of large motion sensitive neurons from the lobula of the crab respond to visual stimuli and accurately reflect the escape performance. Additional evidence indicates that these neurons play a key role in visual memory and in the decision to initiate an escape. Although early studies recognized that the group of lobula giant (LG) neurons consisted of different classes of motion-sensitive cells, a distinction between these classes has been lacking. Here, we recorded in vivo the responses of individual LG neurons to a wide range of visual stimuli presented in different segments of the animal's visual field. Physiological characterizations were followed by intracellular dye injections, which permitted comparison of the functional and morphological features of each cell. All LG neurons consisted of large tangential arborizations in the lobula with axons projecting toward the midbrain. Functionally, these cells proved to be more sensitive to single objects than to flow field motion. Despite these commonalities, clear differences in morphology and physiology allowed us to identify four distinct classes of LG neurons. These results will permit analysis of the role of each neuronal type for visually guided behaviors and will allow us to address specific questions on the neuronal plasticity of LGs that underlie the well-recognized memory model of the crab. PMID- 17715193 TI - Crossed commissural pathways in the spinal hindlimb enlargement are not necessary for right left hindlimb alternation during turtle swimming. AB - We examined the coordination between right and left hindlimbs during voluntary forward swimming in adult red-eared turtles, before and after midsagittal section of the spinal cord hindlimb enlargement (segments D8-S2) or the enlargement plus the first preenlargement segment (D7-S2). Our purpose was to assess the role of crossed commissural axons in these segments for right-left hindlimb alternation during voluntary locomotion. Midsagittal splitting severed commissural fibers and separated the right and left halves of the posterior spinal cord. Adult turtles (n = 9) were held by a band clamp around the shell in a water-filled tank while digital video of forward swimming was recorded from below and computer analyzed with motion analysis software. In a subset of these animals (n = 5), we also recorded electromyograms from hip extensor and/or hip flexor muscles on both sides. Surprisingly, splitting spinal segments D8-S2 or D7-S2 did not affect the strength of out-of-phase coordination between right and left hindlimbs, although hindlimb movement amplitudes were reduced compared with presurgical controls. These results show that commissural axons in the hindlimb enlargement and preenlargement cord are not necessary for right-left hindlimb alternation during voluntary swimming. We suggest that alternating propriospinal drive from the right and left sides of the forelimb enlargement maintains the out-of-phase coordination of right and left hindlimbs in the bisected-cord preparation. Our data support the hypothesis that descending propriospinal (forelimb-hindlimb) and crossed commissural (hindlimb-hindlimb) spinal cord pathways function together as redundant mechanisms to sustain right-left hindlimb alternation during turtle locomotion. PMID- 17715191 TI - Serotonergic raphe magnus cell discharge reflects ongoing autonomic and respiratory activities. AB - Serotonergic cells are located in a restricted number of brain stem nuclei, send projections to virtually all parts of the CNS, and are critical to normal brain function. They discharge tonically at a rate modulated by the sleep-wake cycle and, in the case of medullary serotonergic cells in raphe magnus and the adjacent reticular formation (RM), are excited by cold challenge. Yet, beyond behavioral state and cold, endogenous factors that influence serotonergic cell discharge remain largely mysterious. The present study in the anesthetized rat investigated predictors of serotonergic RM cell discharge by testing whether cell discharge correlated to three rhythms observed in blood pressure recordings that averaged >30 min in length. A very slow frequency rhythm with a period of minutes, a respiratory rhythm, and a cardiac rhythm were derived from the blood pressure recording. Cross-correlations between each of the derived rhythms and cell activity revealed that the discharge of 38 of the 40 serotonergic cells studied was significantly correlated to the very slow and/or respiratory rhythms. Very few serotonergic cells discharged in relation to the cardiac cycle and those that did, did so weakly. The correlations between serotonergic cell discharge and the slow and respiratory rhythms cannot arise from baroreceptive input. Instead we hypothesize that they are by-products of ongoing adjustments to homeostatic functions that happen to alter blood pressure. Thus serotonergic RM cells integrate information about multiple homeostatic activities and challenges and can consequently modulate spinal processes according to the most pressing need of the organism. PMID- 17715194 TI - Bursting in substantia nigra pars reticulata neurons in vitro: possible relevance for Parkinson disease. AB - Projection neurons of the substantia nigra reticulata (SNr) convey basal ganglia (BG) processing to thalamocortical and brain stem circuits responsible for movement. Two models try to explain pathological BG performance during Parkinson disease (PD): the rate model, which posits an overexcitation of SNr neurons due to hyperactivity in the indirect pathway and hypoactivity of the direct pathway, and the oscillatory model, which explains PD as the product of pathological pattern generators disclosed by dopamine reduction. These models are, apparently, incompatible. We tested the predictions of the rate model by increasing the excitatory drive and reducing the inhibition on SNr neurons in vitro. This was done pharmacologically with bath application of glutamate agonist N-methyl-d aspartate and GABA(A) receptor blockers, respectively. Both maneuvers induced bursting behavior in SNr neurons. Therefore synaptic changes forecasted by the rate model induce the electrical behavior predicted by the oscillatory model. In addition, we found evidence that Ca(V)3.2 Ca(2+) channels are a critical step in generating the bursting firing pattern in SNr neurons. Other ion channels involved are: hyperpolarization-activated cation channels, high-voltage-activated Ca(2+) channels, and Ca(2+)-activated K(+) channels. However, although these channels shape the temporal structure of bursting, only Ca(V)3.2 Ca(2+) channels are indispensable for the initiation of the bursting pattern. PMID- 17715196 TI - Spatial and cross-modal attention alter responses to unattended sensory information in early visual and auditory human cortex. AB - Attending to a visual or auditory stimulus often requires irrelevant information to be filtered out, both within the modality attended and in other modalities. For example, attentively listening to a phone conversation can diminish our ability to detect visual events. We used functional magnetic resonance imaging (fMRI) to examine brain responses to visual and auditory stimuli while subjects attended visual or auditory information. Although early cortical areas are traditionally considered unimodal, we found that brain responses to the same ignored information depended on the modality attended. In early visual area V1, responses to ignored visual stimuli were weaker when attending to another visual stimulus, compared with attending to an auditory stimulus. The opposite was true in more central visual area MT+, where responses to ignored visual stimuli were weaker when attending to an auditory stimulus. Furthermore, fMRI responses to the same ignored visual information depended on the location of the auditory stimulus, with stronger responses when the attended auditory stimulus shared the same side of space as the ignored visual stimulus. In early auditory cortex, responses to ignored auditory stimuli were weaker when attending a visual stimulus. A simple parameterization of our data can describe the effects of redirecting attention across space within the same modality (spatial attention) or across modalities (cross-modal attention), and the influence of spatial attention across modalities (cross-modal spatial attention). Our results suggest that the representation of unattended information depends on whether attention is directed to another stimulus in the same modality or the same region of space. PMID- 17715195 TI - Calcium-dependent fast depolarizing afterpotentials in vasopressin neurons in the rat supraoptic nucleus. AB - Oxytocin (OT) and vasopressin (VP) synthesizing magnocellular cells (MNCs) in the supraoptic nucleus (SON) display distinct firing patterns during the physiological demands for these hormones. Depolarizing afterpotentials (DAPs) in these neurons are involved in controlling phasic bursting in VP neurons. Our whole cell recordings demonstrated a Cs(+)-resistant fast DAP (fDAP; decay tau = approximately 200 ms), which has not been previously reported, in addition to the well-known Cs(+)-sensitive slower DAP (sDAP; decay tau = approximately 2 s). Immunoidentification of recorded neurons revealed that all VP neurons, but only 20% of OT neurons, expressed the fDAP. The activation of the fDAP required influx of Ca(2+) through voltage-gated Ca(2+) channels as it was strongly suppressed in Ca(2+)-free extracellular solution or by bath application of Cd(2+). Additionally, the current underlying the fDAP (I(fDAP)) is a Ca(2+)-activated current rather than a Ca(2+) current per se as it was abolished by strongly buffering intracellular Ca(2+) with BAPTA. The I-V relationship of the I(fDAP) was linear at potentials less than -60 mV but showed pronounced outward rectification near -50 mV. I(fDAP) is sensitive to changes in extracellular Na(+) and K(+) but not Cl(-). A blocker of Ca(2+)-activated nonselective cation (CAN) currents, flufenamic acid, blocked the fDAP, suggesting the involvement of a CAN current in the generation of fDAP in VP neurons. We speculate that the two DAPs have different roles in generating after burst discharges and could play important roles in determining the distinct firing properties of VP neurons in the SON neurons. PMID- 17715197 TI - Alpha5GABAA receptors regulate the intrinsic excitability of mouse hippocampal pyramidal neurons. AB - GABA(A) receptors generate both phasic and tonic forms of inhibition. In hippocampal pyramidal neurons, GABA(A) receptors that contain the alpha5 subunit generate a tonic inhibitory conductance. The physiological role of this tonic inhibition is uncertain, although alpha5GABA(A) receptors are known to influence hippocampal-dependent learning and memory processes. Here we provide evidence that alpha5GABA(A) receptors regulate the strength of the depolarizing stimulus that is required to generate an action potential in pyramidal neurons. Neurons from alpha5 knock-out (alpha5-/-) and wild-type (WT) mice were studied in brain slices and cell cultures using whole cell and perforated-patch-clamp techniques. Membrane resistance was 1.6-fold greater in alpha5-/- than in WT neurons, but the resting membrane potential and chloride equilibrium potential were similar. Membrane hyperpolarization evoked by an application of exogenous GABA was greater in WT neurons. Inhibiting the function of alpha5GABA(A) receptor with nonselective (picrotoxin) or alpha5 subunit-selective (L-655,708) compounds depolarized WT neurons by approximately 3 mV, whereas no change was detected in alpha5-/- neurons. The depolarizing current required to generate an action potential was twofold greater in WT than in alpha5-/- neurons, whereas the slope of the input-output relationship for action potential firing was similar. We conclude that shunting inhibition mediated by alpha5GABA(A) receptors regulates the firing of action potentials and may synchronize network activity that underlies hippocampal-dependent behavior. PMID- 17715198 TI - Itch induced by a novel method leads to limbic deactivations a functional MRI study. AB - Functional brain imaging studies on itch usually use histamine as a stimulus and, in consequence, have to cope with the highly variable time course of this particular itch sensation. In this study, we describe a novel method of histamine application. To provoke itch, a mixture of histamine and codeine was applied through intradermally positioned microdialysis fiber. The itch was terminated by lidocaine application through the same fiber. During one fMRI session, this procedure was repeated four times in four different microdialysis fibers, including one placebo control. Itch ratings of the subjects were correlated with blood-oxygen-level-dependent (BOLD) effects. In a subsequent experiment performed in the same fMRI session, heat pain was provoked in the right forearm with a Peltier thermode. During both experiments, activation clusters were found in brain areas that have been described previously to be frequently activated in response to painful stimuli. This includes prefrontal areas, supplementary motor areas (SMA), premotor cortex, anterior insula, anterior midcingulate cortex, S1, S2, thalamus, basal ganglia, and cerebellum. In general, itch stimulation entailed more activation clusters, in particular on the contralateral brain side. Only on itch, but not on heat pain, negative BOLD signals were found in the subgenual anterior cingulate cortex and the amygdala. The latter results may be associated with the itch induced urge to scratch. Amygdala deactivation may be related to the preparation of scratching by aiming to dissolve the otherwise aversive effects of the noxious scratch stimuli. These negative BOLD effects may also be attributed to the stressful character of itch stimulation. PMID- 17715199 TI - Heterogeneous electrotonic coupling and synchronization of rhythmic bursting activity in mouse Hb9 interneurons. AB - The neurons and mechanisms involved in mammalian spinal cord networks that produce rhythmic locomotor activity remain largely undefined. Hb9 interneurons, a small population of discretely localized interneurons in the mouse spinal cord, are conditionally bursting neurons. Here we applied potassium channel blockers with the aim of increasing neuronal excitability and observed that under these conditions, postnatal Hb9 interneurons exhibited bursts of action potentials with underlying voltage-independent spikelets. The bursts were insensitive to antagonists to fast chemical synaptic transmission, and the bursting and spikelets were blocked by tetrodotoxin. Calcium imaging studies using 2-photon excitation in spinal cord slices revealed that clustered Hb9 interneurons exhibited synchronous and occasional asynchronous, calcium transients that were also insensitive to fast synaptic transmission blockade. All transients were blocked by the gap junction blocker carbenoxolone. Paired whole cell patch-clamp recordings of Hb9 interneurons in the late postnatal mouse revealed common chemical synaptic inputs but no evidence of current transfer (i.e., electrotonic coupling) between the neurons. However, Hb9 and a previously defined population of non-Hb9 interneurons were electrotonically coupled. In the absence of fast chemical transmission in the whole spinal cord preparation, 2-photon excitation calcium imaging revealed bursting activity of Hb9 interneurons synchronous with rhythmic ventral root output. Thus Hb9 interneurons are both endogenous bursters and rhythmically active within a heterogeneous electrotonically coupled network. A network with these properties could produce the wide range of stable rhythms necessary for locomotor activity. PMID- 17715200 TI - Regional specification of threshold sensitivity and response time in CBA/CaJ mouse spiral ganglion neurons. AB - Previous studies of spiral ganglion neuron electrophysiology have shown that specific parameters differ according to cochlear location, with apical neurons being distinctly different from basal neurons. To align these features more precisely along the tonotopic axis of the cochlea, we developed a novel spiral ganglion culture system in which positional information is retained. Patch-clamp recordings made from neurons of known gangliotopic location revealed two basic firing pattern distributions. Membrane characteristics related to spike timing, such as accommodation, latency and onset tau, were distinctly heterogeneous, yet when averaged, they were distributed in a graded manner along the length of the cochlea. Action potential threshold levels also displayed a wide range, the averages of which were distributed nonmonotonically such that neurons with the greatest sensitivity were localized to the mid-regions of the ganglion. These studies shed new light on the complexity and sophistication of the intrinsic firing features of spiral ganglion neurons. Because timing-related elements are organized in an overall tonotopic manner, it is hypothesized that they contribute to aspects of frequency-dependent acoustic processing. On the other hand, the different distribution of threshold levels, with the greatest sensitivity in the middle region of the tonotopic map, suggests that this neuronal parameter is regulated differently and thus may contribute a distinct realm of auditory sensory processing. PMID- 17715201 TI - Inhibition and synchronization of basal amygdala principal neuron spiking by parvalbumin-positive interneurons. AB - Using mice that express enhance green fluorescent protein (EGFP) under the control of the parvalbumin promoter, we made paired recordings from interneurons and principal neurons in the basal amygdala. In synaptically connected pairs, we show that single action potentials in a parvalbumin expressing interneuron can inhibit spiking in the synaptically connected principal neuron. When principal neurons were provided with suprathreshold oscillatory drive via a somatic patch pipette, action potentials in the interneuron inhibited spiking in principal neurons only when the interneuron spike occurred shortly before excitation reached threshold in the principal neuron. Moreover, after this spike inhibition, there was a rebound excitation in the principal neurons that was seen as an increased probability of firing on the cycle after inhibition. These results illustrate the major role of local inhibition in the basal amygdala. We propose that these interneurons in the basal amygdala provide a potent inhibition that acts to inhibit firing of principal neurons during cortically driven oscillations. PMID- 17715202 TI - Different contributions of the corpus callosum and cerebellum to motor coordination in monkey. AB - We investigated the different contribution of the corpus callosum (CC) and cerebellum to motor control in two macaque monkeys trained to perform a precision grip task with one or both hands. Recordings were made from antidromically identified CC cells and nearby unidentified neurons (UIDs) in the hand representation of the supplementary motor area (SMA) and compared with cells from the deep cerebellar nuclei (DCN). All cells showed their greatest modulation in activity (rate change locked to particular task event) during the movement epochs of the task (CC, 21.3 +/- 22.2; UIDs, 36.2 +/- 30.1 spike/s for contralateral trials; DCN, 63 +/- 56.4 for ipsilateral trials; mean +/- SD). Surprisingly, CC cells fired at very low basal rates compared with UIDs (3.9 +/- 4.9 vs. 10 +/- 9.1 spike/s) or DCN neurons (50.8 +/- 23.8 spike/s). However, SMA cells had the greatest rate modulation to baseline ratio (CC: 12.1 +/- 13.7; UID: 5.3 +/- 5.4; DCN: 1.7 +/- 2.0). This would allow them to code the timing of a behavioral event with better fidelity than DCN cells. A multivariate regression analysis between cell firing and EMG measured cells' representation of moment-by-moment modulations in muscle activity. CC neurons coded these real-time behavioral parameters significantly less well than the other cells types, using both linear and nonlinear models. Basal firing rate substantially constrains cell function. CC cells with low basal rates have restricted dynamic range for coding continuous parameters, but efficiently code the time of discrete behavioral events. DCN neurons with higher basal rates are better suited to control continuously variable parameters of movement. PMID- 17715203 TI - Coronary artery disease risk factors in patients with schizophrenia: effects of short term antipsychotic treatment. AB - The aim of the present study was to investigate serum paraoxonase/arylesterase activities and oxidation/oxidizability of apolipoprotein B-containing lipoproteins and several coronary artery disease risk factors, including homocysteine, high sensitive C-reactive protein, tumour necrosis factor-alpha, leptin and adiponectin in patients with schizophrenia. Oxidation of lipoproteins plays an important role in atherogenesis, and the enzyme paraoxonase has been shown to prevent lipoprotein oxidation. Furthermore, low paraoxonase activity has been suggested to predict coronary artery disease. Forty patients who fully met the fourth Diagnostic and Statistical Manual of Mental Disorders criteria for schizophrenia and 35 healthy control subjects were included in the study. Serum paraoxonase/arylesterase activities were determined spectrophotometrically. Malondialdehyde levels of apolipoprotein B-containing lipoproteins were determined before and after incubation with copper-sulphate, which yielded basal- and Delta-malondialdehyde values, respectively. Homocysteine and highly sensitive C-reactive protein levels were determined using a fluorescence-polarization immunoassay and immunonephelometry, respectively. Leptin and adiponectin levels were measured with radioimmunoassay and tumour necrosis factor-alpha was determined by enzyme linked immunosorbent assay. Serum paraoxonase and arylesterase activities were significantly lower and Delta-malondialdehyde levels were significantly higher in the schizophrenia group compared with the control group. However, there were not any significant differences in other parameters of the study between the study groups. There was a significant increase in body mass index and serum triglyceride and very low density lipoprotein cholesterol levels in the schizophrenic group after 6 weeks of treatment. These parameters were significantly increased in patients treated with atypical antipsychotics but not in patients treated with typic or long acting antipsychotics. The results of the present study suggest that patients with schizophrenia might have increased risk for coronary artery disease related to reduced serum paraoxonase activity and increased oxidizability of apolipoprotein B-containing lipoproteins. PMID- 17715205 TI - Chronic citalopram treatment does not sensitize the adrenal gland to ACTH (1-24) in rats. AB - We have previously reported that rats exposed chronically to citalopram are able to elicit a corticosterone but not adrenocorticotropic hormone (ACTH) response to restraint stress. Thus we proposed the hypothesis that the corticosterone response to restraint in citalopram-treated rats was maintained due to increased adrenal sensitivity to lower ACTH levels. To test this hypothesis, we intravenously injected ACTH (1-24) to rats (dose 3 ng/rat) exposed to citalopram through minipump infusion for 14 days and to control rats (no citalopram). ACTH significantly increased plasma corticosterone levels in both control and citalopram treated rats over a period of 120 min. There was no significant difference in plasma corticosterone between citalopram treated rats and control rats at any time point. Therefore we conclude that, under these experimental conditions, citalopram does not appear to sensitize the rodent adrenal gland to ACTH, and that other mechanisms may be responsible for the ACTH/corticosterone disconnection. PMID- 17715204 TI - Statins are effective in treating dyslipidemia among psychiatric patients using second-generation antipsychotic agents. AB - Statins are widely used in the treatment of patients having high levels of serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). However, there is little documentation on the ability of statins to treat dyslipidemia induced by second-generation antipsychotics (SGAs) and if so, to what extent. A goal of the present study was to evaluate these aspects among psychotic inpatients who were prescribed SGAs in a typical clinical setting. The study sample consisted of 28 psychotic male forensic psychiatric inpatients (mean age 44 years). All had sGA medication for their psychotic symptoms. secondary causes of dyslipidemia were excluded and statin therapy was initiated, according to the established guidelines. The change in TC, LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) levels were evaluated retrospectively and analysed by the Wilcoxon signed Ranks test. The lowering effectivity of statin treatment was 36% for TC, 49% for LDL-C and 29% for TG. Most of the patients (84%) achieved a target value for LDL-C of <3.0 mmol/L, and 54% achieved target value of <2.6 mmol/L, while HDL-C remained unchanged. These results were achieved with a low or moderate dose of statin during a period of 1 month. The effect of statins in lowering of TC, LDL-C and TG among dyslipidemic psychiatric patients that were treated with sGA was similar to the effectiveness of statin therapy in other clinical trial settings, and should be used when they are indicated. PMID- 17715206 TI - Serum prolactin levels, plasma risperidone levels, polymorphism of cytochrome P450 2D6 and clinical response in patients with schizophrenia. AB - The object of this study is to assess 1) the relationship between plasma antipsychotic drug concentration, serum prolactin levels and the clinical efficacy of risperidone, 2) the relationship between the CYP2D6 polymorphisms and metabolizing of risperidone and 3) the role of 9-hydroxyrisperidone in elevating prolactin levels. One-hundred and eighteen Chinese schizophrenia patients (40 males, 78 females, age 15-60 years) were given risperidone at dosages ranging from 2-8 mg/day for 8 weeks. Clinical efficacy was determined using the Brief Psychiatric Rating Scores (BPRS). Serum prolactin levels were assayed before and after the 8 week treatment and plasma risperidone and 9-hydroxyrisperidone levels were also measured at the end of the 8-week treatment. The results showed there was no significant correlation between the concentration of active moiety and clinical response. Risperidone treatment significantly increased serum prolactin levels. Furthermore, changes of prolactin levels were not correlated with the clinical response. For the risperidone/ 9-hydroxyrisperidone ratio, there was a statistically significant difference among the CYP2D6*1/*1, *1/*10, *10/*10 genotypes (Kruskal-Wallis test, p = 0.012). No significant differences were found in the concentration of 9-hydroxyrisperidone and active moiety among the genotypes. In addition, the concentration of 9-hydroxyrisperidone was not significantly correlated with the increase of serum prolactin. In conclusion, our study has, for the first time, produced evidence that in Chinese schizophrenic patients, the metabolism of risperidone is dependent on CYP2D6. Neither changes in serum prolactin levels nor plasma concentration of active moiety were significantly correlated with clinical efficacy of risperidone. 9 hydroxyrisperidone may not play a predominant role in elevating serum prolactin level. PMID- 17715207 TI - Recurrent priapism during treatment with clozapine, quetiapine and haloperidol. AB - The following is a letter to the editor that represents a case of recurrent priapism. The patient received clozapine, quetiapine and haloperidol and had the adverse reaction of priapism, one episode of which required surgical intervention. This case highlights the need for physicians to be aware of the potential for this serious adverse effect and to be especially mindful to carefully monitor those patients who have already had one episode of priapism as they may be at risk for recurrence. PMID- 17715208 TI - Repeated cortisol administration attenuates the EEG response to buspirone in healthy volunteers: evidence for desensitization of the 5-HT1A autoreceptor. AB - It has previously been postulated that the therapeutic effect of antidepressants, particularly selective serotonin re-uptake inhibitors (SSRIs), is mediated by a down-regulation of somatodendritic (presynaptic) 5-HT(1A) autoreceptors with chronic treatment. Animal studies have revealed that repeated administration of corticosteroids similarly down-regulate this receptor. However, it has previously been difficult to explore if this receptor is similarly modulated in man in vivo. The objective of this study was to explore the effect of repeated administration of cortisol to healthy volunteers utilising a novel putative index of somatodendritic 5-HT(1A) autoreceptor function. This method involves the administration of the 5-HT(1A) agonist buspirone and observing the subsequent negative shift in the frequency spectrum of the electroencephalogram (EEG). Healthy male volunteers were treated with cortisol 20 mg, or placebo, orally twice daily for 7 days in a double-blind random-order crossover study. After each treatment period volunteers were administered buspirone 30 mg orally prior to EEG recordings. Following a week's treatment with placebo, buspirone led to a negative shift in the EEG frequency spectrum as previously reported. However, following treatment with cortisol, the effect of buspirone was significantly attenuated. This is consistent with corticosteroids having a similar effect on somatodendritic 5-HT(1A) autoreceptors in man as seen in rodents. PMID- 17715209 TI - Effects of acute tyrosine depletion on subjective craving and selective processing of smoking-related cues in abstinent cigarette smokers. AB - We investigated the impact of the administration of a tyrosine-depleting amino acid mixture compared to a balanced mixture on measures of mood, craving and selective processing of smoking-related cues in healthy cigarette smokers instructed to abstain from smoking for 12 h prior to, and during, the experiment. A modified stroop task was used to index selective processing of smoking-related cues. We observed evidence for an increase in subjective craving among males, and an attenuation of the selective processing of smoking-related cues compared to control cues among females, in the tyrosine-depleting condition compared to the balanced condition. No effects of mixture were observed on measures of subjective mood. These results tentatively support for the role of dopaminergic neurotransmission in mediating the response of cigarette smokers to smoking related cues. In addition, these results also provide further evidence for sex differences in the factors that maintain cigarette smoking, in particular with respect to conditioned reinforcement of smoking behaviour, and suggest that the relationship between subjective craving and selective processing of smoking related cues may differ in males and females. PMID- 17715210 TI - Chronic heroin and cocaine abuse is associated with decreased serum concentrations of the nerve growth factor and brain-derived neurotrophic factor. AB - Chronic cocaine and heroin users display a variety of central nervous system (CNS) dysfunctions including impaired attention, learning, memory, reaction time, cognitive flexibility, impulse control and selective processing. These findings suggest that these drugs may alter normal brain functions and possibly cause neurotoxicity. Neurotrophins are a class of proteins that serve as survival factors for CNS neurons. In particular, nerve growth factor (NGF) plays an important role in the survival and function of cholinergic neurons while brain derived neurotrophic factor (BDNF) is involved in synaptic plasticity and in the maintenance of midbrain dopaminergic and cholinergic neurons. In the present study, we measured by enzyme-linked immunosorbent assay (ELISA) the NGF and BDNF levels in serum of three groups of subjects: heroin-dependent patients, cocaine dependent patients and healthy volunteers. Our goal was to identify possible change in serum neurotrophins in heroin and cocaine users. BDNF was decreased in heroin users whereas NGF was decreased in both heroin and cocaine users. These findings indicate that NGF and BDNF may play a role in the neurotoxicity and addiction induced by these drugs. In view of the neurotrophin hypothesis of schizophrenia the data also suggest that reduced level of neurotrophins may increase the risk of developing psychosis in drug users. PMID- 17715211 TI - Selective serotonin re-uptake inhibitor treatment-emergent sexual dysfunction: randomized double-blind placebo-controlled parallel-group fixed-dose study of a potential adjuvant compound, VML-670. AB - Sexual dysfunction is common during acute and continuation treatment of depressed patients with selective serotonin (5-hydroxytryptamine, 5-HT) re-uptake inhibitors (ssRIs), but there is no consensus on clinical management. Compounds with 5-HT(1A) agonist properties have been proposed as adjuvant agents in patients continuing with ssRIs. Randomized double-blind placebo-controlled parallel-group fixed-dose 4-week treatment study. Previously depressed male or female patients in symptomatic remission receiving stable doses of fluoxetine or paroxetine but experiencing treatment-emergent sexual dysfunction were randomised to double-blind treatment with placebo or VML-670 (a 5-HT(1A) and 5-HT(1D) agonist). sexual dysfunction was assessed by the Arizona sexual Experiences scale (ASEX). Two-hundred and eighty-eight patients (204 women, 84 men; mean age 44.2 years) received VML-670 (n = 149; 107 women, 42 men) or placebo (n = 139; 97 women, 42 men). In the intention-to-treat, last-observation carried forward analysis (n = 282), proportionately more patients became free of sexual dysfunction with VML-670 (34.3% versus 27.9% with placebo) but this difference was not statistically significant. Male patients treated with VML-670 showed a significantly greater (p =0.01) improvement in ability to achieve and maintain penile erection (a secondary outcome measure). A similar proportion of patients reported on-treatment, treatment-emergent adverse events with VML-670 (71.1%) and placebo (68.3%), and a similar proportion experienced at least one treatment related adverse event (36.9% versus 35.3%). Double-blind treatment with VML-670 offered no significant advantage over placebo on the primary outcome measure in the overall sample. Further studies may be warranted in larger groups of male patients with sexual dysfunction. PMID- 17715212 TI - Effects of acute tiagabine administration on aggressive responses of adult male parolees. AB - Experimental and clinical studies have supported a relationship between gamma aminobutyric acid (GABA) and aggressive behavior in non-humans and humans. Tiagabine is a GABA uptake inhibitor that has been shown to produce acute behavioral effects in animals. In addition, tiagabine has been shown to decrease aggression in agitated patients when administered chronically. The present study was designed to investigate the effects of acute administration of tiagabine on aggressive responding on a laboratory task in adult humans. Ten adult males participated in experimental sessions on the Point Subtraction Aggression Paradigm (PSAP), which provided subjects with aggressive, escape, and monetary reinforced response options. All subjects received four acute oral doses of Tiagabine (4, 8, 12 and 16 mg) separated by placebo sessions. Tiagabine decreased aggression at doses that either did not affect, or affected to a lesser extent, monetary-reinforced responding. The results are consistent with some prior research using the PSAP showing a possible unique role for GABA in the regulation of human aggression. A possible behavioral mechanism for the rate-decreasing effects on aggressive responding produced in the present study is that tiagabine may modify aggressive responding by suppressing reactions to aversive stimuli. PMID- 17715213 TI - Polyomaviruses of birds: etiologic agents of inflammatory diseases in a tumor virus family. PMID- 17715214 TI - Activation of phosphatidylinositol 3-kinase signaling by the nonstructural NS1 protein is not conserved among type A and B influenza viruses. AB - Recently it has been shown by several laboratories that the influenza A virus nonstructural protein 1 (A/NS1) binds and activates phosphatidylinositol 3-kinase (PI3K). This function of the protein is likely to prevent premature apoptosis induction during viral propagation. Here we show that the B/NS1 protein completely lacks the capacity to induce PI3K signaling. Thus, PI3K activation is another unique function of A/NS1 that is different from the action of its influenza B virus counterpart. PMID- 17715215 TI - Capsid protein-mediated recruitment of host DnaJ-like proteins is required for Potato virus Y infection in tobacco plants. AB - The capsid protein (CP) of potyviruses is required for various steps during plant infection, such as virion assembly, cell-to-cell movement, and long-distance transport. This suggests a series of compatible interactions with putative host factors which, however, are largely unknown. By using the yeast two-hybrid system the CP from Potato virus Y (PVY) was found to interact with a novel subset of DnaJ-like proteins from tobacco, designated NtCPIPs. Mutational analysis identified the CP core region, previously shown to be essential for virion formation and plasmodesmal trafficking, as the interacting domain. The ability of NtCPIP1 and NtCPIP2a to associate with PVY CP could be confirmed in vitro and was additionally verified in planta by bimolecular fluorescence complementation. The biological significance of the interaction was assayed by PVY infection of agroinfiltrated leaves and transgenic tobacco plants that expressed either full length or J-domain-deficient variants of NtCPIPs. Transient expression of truncated dominant-interfering NtCPIP2a but not of the functional protein resulted in strongly reduced accumulation of PVY in the inoculated leaf. Consistently, stable overexpression of J-domain-deficient variants of NtCPIP1 and NtCPIP2a dramatically increased the virus resistance of various transgenic lines, indicating a critical role of functional NtCPIPs during PVY infection. The negative effect of impaired NtCPIP function on viral pathogenicity seemed to be the consequence of delayed cell-to-cell movement, as visualized by microprojectile bombardment with green fluorescent protein-tagged PVY. Therefore, we propose that NtCPIPs act as important susceptibility factors during PVY infection, possibly by recruiting heat shock protein 70 chaperones for viral assembly and/or cellular spread. PMID- 17715216 TI - Analysis of human cell heterokaryons demonstrates that target cell restriction of cyclosporine-resistant human immunodeficiency virus type 1 mutants is genetically dominant. AB - The host cell protein cyclophilin A (CypA) binds to CA of human immunodeficiency virus type 1 (HIV-1) and promotes HIV-1 infection of target cells. Disruption of the CypA-CA interaction, either by mutation of the CA residue at G89 or P90 or with the immunosuppressive drug cyclosporine (CsA), reduces HIV-1 infection. Two CA mutants, A92E and G94D, previously were identified by selection for growth of wild-type HIV-1 in cultures of CD4(+) HeLa cell cultures containing CsA. Interestingly, infection of some cell lines by these mutants is enhanced in the presence of CsA, while in other cell lines these mutants are minimally affected by the drug. Little is known about this cell-dependent phenotype of the A92E and G94D mutants, except that it is not dependent on expression of the host factor TRIM5alpha. Here, we show that infection by the A92E and G94D mutants is restricted at an early post-entry stage of the HIV-1 life cycle. Analysis of heterokaryons between CsA-dependent HeLa-P4 cells and CsA-independent 293T cells indicated that the CsA-dependent infection by A92E and G94D mutants is due to a dominant cellular restriction. We also show that addition of CsA to target cells inhibits infection by wild-type HIV-1 prior to reverse transcription. Collectively, these results support the existence of a cell-specific human cellular factor capable of restricting HIV-1 at an early post-entry step by a CypA-dependent mechanism. PMID- 17715217 TI - A human lung carcinoma cell line supports efficient measles virus growth and syncytium formation via a SLAM- and CD46-independent mechanism. AB - Measles virus (MV) propagates mainly in lymphoid organs throughout the body and produces syncytia by using signaling lymphocyte activation molecule (SLAM) as a receptor. MV also spreads in SLAM-negative epithelial tissues by unknown mechanisms. Ubiquitously expressed CD46 functions as another receptor for vaccine strains of MV but not for wild-type strains. We here show that MV grows and produces syncytia efficiently in a human lung adenocarcinoma cell line via a SLAM and CD46-independent mechanism using a novel receptor-binding site on the hemagglutinin protein. This infection model could advance our understanding of MV infection of SLAM-negative epithelial cells and tissues. PMID- 17715218 TI - The capsid and tegument of the alphaherpesviruses are linked by an interaction between the UL25 and VP1/2 proteins. AB - How alphaherpesvirus capsids acquire tegument proteins remains a key question in viral assembly. Using pseudorabies virus (PRV), we have previously shown that the 62 carboxy-terminal amino acids of the VP1/2 large tegument protein are essential for viral propagation and when transiently expressed as a fusion to green fluorescent protein relocalize to nuclear capsid assemblons following viral infection. Here, we show that localization of the VP1/2 capsid-binding domain (VP1/2cbd) into assemblons is conserved in herpes simplex virus type 1 (HSV-1) and that this recruitment is specifically on capsids. Using a mutant virus screen, we find that the protein product of the UL25 gene is essential for VP1/2cbd association with capsids. An interaction between UL25 and VP1/2 was corroborated by coimmunoprecipitation from cells transiently expressing either HSV-1 or PRV proteins. Taken together, these findings suggest that the essential function of the VP1/2 carboxy terminus is to anchor the VP1/2 tegument protein to capsids. Furthermore, UL25 encodes a multifunctional capsid protein involved in not only encapsidation, as previously described, but also tegumentation. PMID- 17715219 TI - Herpes simplex virus mutants with multiple substitutions affecting DNA binding of UL42 are impaired for viral replication and DNA synthesis. AB - Herpes simplex virus mutants with single substitutions that decrease DNA binding by the DNA polymerase processivity subunit UL42 are only modestly impaired for viral replication. In this study, recombinant viruses harboring two or four of these mutations were constructed. The more substitutions, the more severe the defects in viral replication and DNA synthesis, suggesting that DNA binding by UL42 is important for these processes. PMID- 17715220 TI - White spot syndrome virus proteins and differentially expressed host proteins identified in shrimp epithelium by shotgun proteomics and cleavable isotope-coded affinity tag. AB - Shrimp subcuticular epithelial cells are the initial and major targets of white spot syndrome virus (WSSV) infection. Proteomic studies of WSSV-infected subcuticular epithelium of Penaeus monodon were performed through two approaches, namely, subcellular fractionation coupled with shotgun proteomics to identify viral and host proteins and a quantitative time course proteomic analysis using cleavable isotope-coded affinity tags (cICATs) to identify differentially expressed cellular proteins. Peptides were analyzed by offline coupling of two dimensional liquid chromatography with matrix-assisted laser desorption ionization-tandem time of flight mass spectrometry. We identified 27, 20, and 4 WSSV proteins from cytosolic, nuclear, and membrane fractions, respectively. Twenty-eight unique WSSV proteins with high confidence (total ion confidence interval percentage [CI%], >95%) were observed, 11 of which are reported here for the first time, and 3 of these novel proteins were shown to be viral nonstructural proteins by Western blotting analysis. A first shrimp protein data set containing 1,999 peptides (ion score, > or =20) and 429 proteins (total ion score CI%, >95%) was constructed via shotgun proteomics. We also identified 10 down-regulated proteins and 2 up-regulated proteins from the shrimp epithelial lysate via cICAT analysis. This is the first comprehensive study of WSSV-infected epithelia by proteomics. The 11 novel viral proteins represent the latest addition to our knowledge of the WSSV proteome. Three proteomic data sets consisting of WSSV proteins, epithelial cellular proteins, and differentially expressed cellular proteins generated in the course of WSSV infection provide a new resource for further study of WSSV-shrimp interactions. PMID- 17715221 TI - The transcription profile of the bocavirus bovine parvovirus is unlike those of previously characterized parvoviruses. AB - The Bocavirus bovine parvovirus generated a single pre-mRNA from a promoter at its left-hand end; however, the pattern of its alternative polyadenylation and splicing was different from that of other parvoviruses. A large left-hand-end open reading frame (ORF) encoded a nonstructural protein of approximately 95 kDa. An abundant, spliced, internally polyadenylated transcript encoded the viral NP1 protein from an ORF in the center of the genome. Transcripts encoding the capsid proteins were polyadenylated in the right-hand terminal palindrome. This is the first published transcription map of a member of the Bocavirus genus of the Parvovirinae. PMID- 17715222 TI - Differential virus replication, cytokine production, and antigen-presenting function by microglia from susceptible and resistant mice infected with Theiler's virus. AB - Infection with Theiler's murine encephalomyelitis virus (TMEV) in the central nervous system (CNS) causes an immune system-mediated demyelinating disease similar to human multiple sclerosis in susceptible but not resistant strains of mice. To understand the underlying mechanisms of differential susceptibility, we analyzed viral replication, cytokine production, and costimulatory molecule expression levels in microglia and macrophages in the CNS of virus-infected resistant C57BL/6 (B6) and susceptible SJL/J (SJL) mice. Our results indicated that message levels of TMEV, tumor necrosis factor alpha, beta interferon, and interleukin-6 were consistently higher in microglia from virus-infected SJL mice than in those from B6 mice. However, the levels of costimulatory molecule expression, as well as the ability to stimulate allogeneic T cells, were significantly lower in TMEV-infected SJL mice than in B6 mice. In addition, microglia from uninfected naive mice displayed differential viral replication, T cell stimulation, and cytokine production, similar to those of microglia from infected mice. These results strongly suggest that different levels of intrinsic susceptibility to TMEV infection, cytokine production, and T-cell activation ability by microglia contribute to the levels of viral persistence and antiviral T-cell responses in the CNS, which are critical for the differential susceptibility to TMEV-induced demyelinating disease between SJL and B6 mice. PMID- 17715223 TI - Cooperation of NF-kappaB2/p100 activation and the PDZ domain binding motif signal in human T-cell leukemia virus type 1 (HTLV-1) Tax1 but not HTLV-2 Tax2 is crucial for interleukin-2-independent growth transformation of a T-cell line. AB - Human T-cell leukemia virus type 1 (HTLV-1) but not HTLV-2 is associated with adult T-cell leukemia, and the distinct pathogenicity of these two closely related viruses is thought to stem from the distinct biological functions of the respective transforming proteins, HTLV-1 Tax1 and HTLV-2 Tax2. In this study, we demonstrate that Tax1 but not Tax2 interacts with NF-kappaB2/p100 and activates it by inducing the cleavage of p100 into the active transcription factor p52. Using RNA interference methods, we further show that NF-kappaB2/p100 is required for the transformation induced by Tax1, as determined by the ability to convert a T-cell line (CTLL-2) from interleukin-2 (IL-2)-dependent to -independent growth. While Tax2 shows a reduced transforming activity relative to Tax1, Tax2 fused with a PDZ domain binding motif (PBM) present only in Tax1 shows transforming activity equivalent to that of Tax1 in CTLL-2 cells expressing an inducer of p52 processing. These results reveal that the activation of NF-kappaB2/p100 plays a crucial role in the Tax1-mediated transformation of T cells and that NF kappaB2/p100 activation and PBM function are both responsible for the augmented transforming activity of Tax1 relative to Tax2, thus suggesting that these Tax1 specific functions play crucial roles in HTLV-1 leukemogenesis. PMID- 17715224 TI - A heterologous DNA prime-Venezuelan equine encephalitis virus replicon particle boost dengue vaccine regimen affords complete protection from virus challenge in cynomolgus macaques. AB - A candidate vaccine (D1ME-VRP) expressing dengue virus type 1 premembrane and envelope proteins in a Venezuelan equine encephalitis (VEE) virus replicon particle (VRP) system was constructed and tested in conjunction with a plasmid DNA vaccine (D1ME-DNA) expressing identical dengue virus sequences. Cynomolgus macaques were vaccinated with three doses of DNA (DDD), three doses of VRP (VVV group), or a heterologous DNA prime-VRP boost regimen (DDV) using two doses of DNA vaccine and a third dose of VRP vaccine. Four weeks after the final immunization, the DDV group produced the highest dengue virus type 1-specific immunoglobulin G antibody responses and virus-neutralizing antibody titers. Moderate T-cell responses were demonstrated only in DDD- and DDV-vaccinated animals. When vaccinated animals were challenged with live virus, all vaccination regimens showed significant protection from viremia. DDV-immunized animals were completely protected from viremia (mean time of viremia = 0 days), whereas DDD- and VVV-vaccinated animals had mean times of viremia of 0.66 and 0.75 day, respectively, compared to 6.33 days for the control group of animals. PMID- 17715225 TI - Severe acute respiratory syndrome coronavirus evades antiviral signaling: role of nsp1 and rational design of an attenuated strain. AB - The severe acute respiratory syndrome (SARS) epidemic was caused by the spread of a previously unrecognized infectious agent, the SARS-associated coronavirus (SARS CoV). Here we show that SARS-CoV could inhibit both virus- and interferon (IFN) dependent signaling, two key steps of the antiviral response. We mapped a strong inhibitory activity to SARS-CoV nonstructural protein 1 (nsp1) and show that expression of nsp1 significantly inhibited the activation of all three virus dependent signaling pathways. We show that expression of nsp1 significantly inhibited IFN-dependent signaling by decreasing the phosphorylation levels of STAT1 while having little effect on those of STAT2, JAK1, and TYK2. We engineered an attenuated mutant of nsp1 in SARS-CoV through reverse genetics, and the resulting mutant virus was viable and replicated as efficiently as wild-type virus in cells with a defective IFN response. However, mutant virus replication was strongly attenuated in cells with an intact IFN response. Thus, nsp1 is likely a virulence factor that contributes to pathogenicity by favoring SARS-CoV replication. PMID- 17715227 TI - Production of pseudoinfectious yellow fever virus with a two-component genome. AB - Application of genetically modified, deficient-in-replication flaviviruses that are incapable of developing productive, spreading infection is a promising means of designing safe and effective vaccines. Here we describe a two-component genome yellow fever virus (YFV) replication system in which each of the genomes encodes complete sets of nonstructural proteins that form the replication complex but expresses either only capsid or prM/E instead of the entire structural polyprotein. Upon delivery to the same cell, these genomes produce together all of the viral structural proteins, and cells release a combination of virions with both types of genomes packaged into separate particles. In tissue culture, this modified YFV can be further passaged at an escalating scale by using a high multiplicity of infection (MOI). However, at a low MOI, only one of the genomes is delivered into the cells, and infection cannot spread. The replicating prM/E encoding genome produces extracellular E protein in the form of secreted subviral particles that are known to be an effective immunogen. The presented strategy of developing viruses defective in replication might be applied to other flaviviruses, and these two-component genome viruses can be useful for diagnostic or vaccine applications, including the delivery and expression of heterologous genes. In addition, the achieved separation of the capsid-coding sequence and the cyclization signal in the YFV genome provides a new means for studying the mechanism of the flavivirus packaging process. PMID- 17715226 TI - Functional genomic and serological analysis of the protective immune response resulting from vaccination of macaques with an NS1-truncated influenza virus. AB - We are still inadequately prepared for an influenza pandemic due to the lack of a vaccine effective for subtypes to which the majority of the human population has no prior immunity and which could be produced rapidly in sufficient quantities. There is therefore an urgent need to investigate novel vaccination approaches. Using a combination of genomic and traditional tools, this study compares the protective efficacy in macaques of an intrarespiratory live influenza virus vaccine produced by truncating NS1 in the human influenza A/Texas/36/91 (H1N1) virus with that of a conventional vaccine based on formalin-killed whole virus. After homologous challenge, animals in the live-vaccine group had greatly reduced viral replication and pathology in lungs and reduced upper respiratory inflammation. They also had lesser induction of innate immune pathways in lungs and of interferon-sensitive genes in bronchial epithelium. This postchallenge response contrasted with that shortly after vaccination, when more expression of interferon-sensitive genes was observed in bronchial cells from the live-vaccine group. This suggested induction of a strong innate immune response shortly after vaccination with the NS1-truncated virus, followed by greater maturity of the postchallenge immune response, as demonstrated with robust influenza virus specific CD4+ T-cell proliferation, immunoglobulin G production, and transcriptional induction of T- and B-cell pathways in lung tissue. In conclusion, a single respiratory tract inoculation with an NS1-truncated influenza virus was effective in protecting nonhuman primates from homologous challenge. This protection was achieved in the absence of significant or long lasting adverse effects and through induction of a robust adaptive immune response. PMID- 17715228 TI - Identification of novel small-molecule inhibitors of West Nile virus infection. AB - West Nile virus (WNV) has spread throughout the United States and Canada and now annually causes a clinical spectrum of human disease ranging from a self-limiting acute febrile illness to acute flaccid paralysis and lethal encephalitis. No therapy or vaccine is currently approved for use in humans. Using high-throughput screening assays that included a luciferase expressing WNV subgenomic replicon and an NS1 capture enzyme-linked immunosorbent assay, we evaluated a chemical library of over 80,000 compounds for their capacity to inhibit WNV replication. We identified 10 compounds with strong inhibitory activity against genetically diverse WNV and Kunjin virus isolates. Many of the inhibitory compounds belonged to a chemical family of secondary sulfonamides and have not been described previously to inhibit WNV or other related or unrelated viruses. Several of these compounds inhibited WNV infection in the submicromolar range, had selectivity indices of greater than 10, and inhibited replication of other flaviviruses, including dengue and yellow fever viruses. One of the most promising compounds, AP30451, specifically blocked translation of a yellow fever virus replicon but not a Sindbis virus replicon or an internal ribosome entry site containing mRNA. Overall, these compounds comprise a novel class of promising inhibitors for therapy against WNV and other flavivirus infections in humans. PMID- 17715229 TI - Differential effects of mutations in NS4B on West Nile virus replication and inhibition of interferon signaling. AB - West Nile virus (WNV) is a human pathogen that can cause symptomatic infections associated with meningitis and encephalitis. Previously, we demonstrated that replication of WNV inhibits the interferon (IFN) signal transduction pathway by preventing the accumulation of phosphorylated Janus kinase 1 (JAK1) and tyrosine kinase 2 (Tyk2) (J. T. Guo et al., J. Virol. 79:1343-1350, 2005). Through a genetic analysis, we have now identified a determinant on the nonstructural protein 4B (NS4B) that controls IFN resistance in HeLa cells expressing subgenomic WNV replicons lacking the structural genes. However, in the context of infectious genomes, the same determinant did not influence IFN signaling. Thus, our results indicate that NS4B may be sufficient to inhibit the IFN response in replicon cells and suggest a role for structural genes, or as yet unknown interactions, in the inhibition of the IFN signaling pathway during WNV infections. PMID- 17715230 TI - Protection of rabbits against challenge with rabbit papillomaviruses by immunization with the N terminus of human papillomavirus type 16 minor capsid antigen L2. AB - Current L1 virus-like particle (VLP) vaccines provide type-restricted protection against a small subset of the human papillomavirus (HPV) genotypes associated with cervical cancer, necessitating continued cytologic screening of vaccinees. Cervical cancer is most problematic in countries that lack the resources for screening or highly multivalent HPV VLP vaccines, suggesting the need for a low cost, broadly protective vaccinogen. Here, N-terminal L2 polypeptides comprising residues 1 to 88 or 11 to 200 derived from HPV16, bovine papillomavirus type 1 (BPV1), or cottontail rabbit papillomavirus (CRPV) were produced in bacteria. Rabbits were immunized with these N-terminal L2 polypeptides and concurrently challenged with CRPV and rabbit oral papillomavirus (ROPV). Vaccination with either N-terminal L2 polypeptides of CRPV effectively protected rabbits from CRPV challenge but not from papillomas induced by cutaneous challenge with CRPV genomic DNA. Furthermore, papillomas induced by CRPV genomic DNA deficient for L2 expression grew at the same rate as those induced by wild-type CRPV genomic DNA, further suggesting that the L2 polypeptide vaccines lack therapeutic activity. Neutralizing serum antibody titers of >15 correlated with protection (P < 0.001), a finding consistent with neutralizing antibody-mediated protection. Surprisingly, a remarkable degree of protection against heterologous papillomavirus types was observed after vaccination with N-terminal L2 polypeptides. Notably, vaccination with HPV16 L2 11-200 protected against cutaneous and mucosal challenge with CRPV and ROPV, respectively, papillomaviruses that are evolutionarily divergent from HPV16. Further, vaccination with HPV16 L2 11-200 generates broadly cross-neutralizing serum antibody, suggesting the potential of L2 as a second-generation preventive HPV vaccine antigen. PMID- 17715231 TI - Regulatory T-cell markers, indoleamine 2,3-dioxygenase, and virus levels in spleen and gut during progressive simian immunodeficiency virus infection. AB - High levels of viral replication occur in gut-associated lymphoid tissue (GALT) and other lymphoid tissues (LT) since the early phase of human/simian immunodeficiency virus (HIV/SIV) infection. Regulatory T cells (T(reg)), a subset of immunosuppressive T cells expressing CTLA-4 and the FoxP3 transcription factor, accumulate in LT during HIV/SIV infection. Here we show that FoxP3 and CTLA-4 mRNA are increased in leukocytes from the spleens, lymph nodes (LN), and mucosal sites of chronically SIV-infected macaques with high viremia (SIV(HI)) compared to animals with low viremia (SIV(LO)). FoxP3 and CTLA-4 correlated with SIV RNA levels in tissues; SIV virus levels in the spleen, inguinal LN, mesenteric LN, colon, and jejunum directly correlated with the plasma virus level. Importantly, CTLA-4 and FoxP3 mRNA were predominantly increased in the CD25(-) subpopulation of leukocytes from SIV(HI), further challenging the classical definition of T(reg) as CD4(+) CD25(+) T cells. Similar to CTLA-4 and FoxP3, expression of indoleamine 2,3-dioxygenase (IDO), an immunosuppressive enzyme induced by T(reg) in antigen-presenting cells, was increased in the spleens, mesenteric LN, colons, and jejuna from SIV(HI) compared to SIV(LO) and directly correlated to SIV RNA in the same tissues. Accordingly, plasma kynurenine/tryptophan, a marker for IDO enzymatic activity, was significantly higher in SIV(HI) compared to SIV(LO) and correlated with plasma viral levels. Increased T(reg) and IDO in LT of SIV-infected macaques may be the consequence of increased tissue inflammation and/or may favor virus replication during the chronic phase of SIV infection. PMID- 17715232 TI - The p122 subunit of Tobacco Mosaic Virus replicase is a potent silencing suppressor and compromises both small interfering RNA- and microRNA-mediated pathways. AB - One of the functions of RNA silencing in plants is to defend against molecular parasites, such as viruses, retrotransposons, and transgenes. Plant viruses are inducers, as well as targets, of RNA silencing-based antiviral defense. Replication intermediates or folded viral RNAs activate RNA silencing, generating small interfering RNAs (siRNAs), which are the key players in the antiviral response. Viruses are able to counteract RNA silencing by expressing silencing suppressor proteins. It has been shown that many of the identified silencing suppressor proteins bind long double-stranded RNA or siRNAs and thereby prevent assembly of the silencing effector complexes. In this study, we show that the 122 kDa replicase subunit (p122) of crucifer-infecting Tobacco mosaic virus (cr-TMV) is a potent silencing-suppressor protein. We found that the p122 protein preferentially binds to double-stranded 21-nucleotide (nt) siRNA and microRNA (miRNA) intermediates with 2-nt 3' overhangs inhibiting the incorporation of siRNA and miRNA into silencing-related complexes (e.g., RNA-induced silencing complex [RISC]) both in vitro and in planta but cannot interfere with previously programmed RISCs. In addition, our results also suggest that the virus infection and/or sequestration of the siRNA and miRNA molecules by p122 enhances miRNA accumulation despite preventing its methylation. However, the p122 silencing suppressor does not prevent the methylation of certain miRNAs in hst-15 mutants, in which the nuclear export of miRNAs is compromised. PMID- 17715234 TI - Adeno-associated viruses can induce phosphorylation of eIF2alpha via PKR activation, which can be overcome by helper adenovirus type 5 virus-associated RNA. AB - Mutants of adenovirus type 5 (Ad5) virus-associated RNA I deficient in inhibiting the activation and subsequent phosphorylation of protein kinase R (PKR) could neither function as helpers for adeno-associated virus type 5 (AAV5) replication nor enhance AAV5 protein accumulation in either the presence or absence of Ad5 E4Orf6 and E2a. Furthermore, a short region of the AAV5 capsid gene RNA leader sequence surrounding the AUG of VP1 could induce the phosphorylation of eIF2alpha. Both short interfering RNA directed against PKR and the addition of the herpes simplex virus ICP34.5 protein enhanced the accumulation of AAV5 capsid protein in the presence of the AAV5 capsid gene PKR-inducing element, suggesting that VA RNA acted to overcome direct AAV5-induced activation of PKR that led to the phosphorylation of eIF2alpha. The expression of both the closely related goat derived AAV and the prototype AAV2 capsid gene transcription units also induced the phosphorylation of eIF2alpha, suggesting that the induction of the PKR/eIF2alpha cellular response may be a previously unrecognized general feature of at least the Dependovirus genus of the Parvovirinae. PMID- 17715233 TI - Experimental transmission of pospiviroid populations to weed species characteristic of potato and hop fields. AB - Weed plants characteristic for potato and hop fields have not been considered in the past as potential hosts that could transmit and lead to spreading of potato spindle tuber (PSTVd) and hop stunt (HSVd) viroids, respectively. To gain insight into this problem, we biolistically inoculated these weed plants with viroid populations either as RNA or as cDNA. New potential viroid host species, collected in central Europe, were discovered. From 12 weed species characteristic for potato fields, high viroid levels, detectable by molecular hybridization, were maintained after both RNA and DNA transfers in Chamomilla reculita and Anthemis arvensis. Low viroid levels, detectable by reverse transcription-PCR (RT PCR) only, were maintained after plant inoculations with cDNA in Veronica argensis and Amaranthus retroflexus. In these two species PSTVd concentrations were 10(5) and 10(3) times, respectively, lower than in tomato as estimated by real-time PCR. From 14 weeds characteristic for hop fields, high HSVd levels were detected in Galinsoga ciliata after both RNA and DNA transfers. HSVd was found, however, not to be transmissible by seeds of this weed species. Traces of HSVd were detectable by RT-PCR in HSVd-cDNA-inoculated Amaranthus retroflexus. Characteristic monomeric (+)-circular and linear viroid RNAs were present in extracts from weed species propagating viroids to high levels, indicating regular replication, processing, and circularization of viroid RNA in these weed species. Sequence analyses of PSTVd progenies propagated in C. reculita and A. arvensis showed a wide spectrum of variants related to various strains, from mild to lethal variants; the sequence variants isolated from A. retroflexus and V. argensis exhibited similarity or identity to the superlethal AS1 viroid variant. All HSVd clones from G. ciliata corresponded to a HSVdg variant, which is strongly pathogenic for European hops. PMID- 17715235 TI - Nuclear export of the human cytomegalovirus tegument protein pp65 requires cyclin dependent kinase activity and the Crm1 exporter. AB - We have previously shown that treatment of human cytomegalovirus-infected cells with the cyclin-dependent kinase (cdk) inhibitor roscovitine has significant effects on several stages of the virus life cycle depending on the time of addition (V. Sanchez, A. K. McElroy, J. Yen, S. Tamrakar, C. L. Clark, R. A. Schwartz, and D. H. Spector, J. Virol. 78:11219-11232, 2004; V. Sanchez and D. Spector, J. Virol. 80:5886-5896, 2006). In this report, we add to these findings by demonstrating alterations in the phosphorylation and localization of pp65 (UL83) in cells treated with roscovitine. We observed that inhibition of cdk activity causes the retention of pp65 within the nucleus at late times postinfection. At the same time, we observed a change in the phosphorylation pattern of the protein. Interestingly, mutation of potential cdk phosphorylation sites did not affect the ability of pp65 to localize to the nucleus or to relocalize to the cytoplasm late in infection. However, we found that the cytoplasmic accumulation of pp65 late in infection was sensitive to the Crm1 inhibitor leptomycin B. PMID- 17715236 TI - Induction of epitope-specific neutralizing antibodies against West Nile virus. AB - Previous studies have established that an epitope on the lateral ridge of domain III (DIII-lr) of West Nile virus (WNV) envelope (E) protein is recognized by strongly neutralizing type-specific antibodies. In contrast, an epitope against the fusion loop in domain II (DII-fl) is recognized by flavivirus cross-reactive antibodies with less neutralizing potential. Using gain- and loss-of-function E proteins and wild-type and variant WNV reporter virus particles, we evaluated the expression pattern and activity of antibodies against the DIII-lr and DII-fl epitopes in mouse and human serum after WNV infection. In mice, immunoglobulin M (IgM) antibodies to the DIII-lr epitope were detected at low levels at day 6 after infection. However, compared to IgG responses against other epitopes in DI and DII, which were readily detected at day 8, the development of IgG against DIII-lr epitope was delayed and did not appear consistently until day 15. This late time point is notable since almost all death after WNV infection in mice occurs by day 12. Nonetheless, at later time points, DIII-lr antibodies accumulated and comprised a significant fraction of the DIII-specific IgG response. In sera from infected humans, DIII-lr antibodies were detected at low levels and did not correlate with clinical outcome. In contrast, antibodies to the DII-fl were detected in all human serum samples and encompassed a significant percentage of the anti-E protein response. Our experiments suggest that the highly neutralizing DIII-lr IgG antibodies have little significant role in primary infection and that the antibody response of humans may be skewed toward the induction of cross-reactive, less-neutralizing antibodies. PMID- 17715237 TI - Neuroinvasion of fluorescein-positive monocytes in acute simian immunodeficiency virus infection. AB - Monocytes and macrophages play a central role in the pathogenesis of human immunodeficiency virus (HIV)-associated dementia. They represent prominent targets for HIV infection and are thought to facilitate viral neuroinvasion and neuroinflammatory processes. However, many aspects regarding monocyte brain recruitment in HIV infection remain undefined. The nonhuman primate model of AIDS is uniquely suited for examination of the role of monocytes in the pathogenesis of AIDS-associated encephalitis. Nevertheless, an approach to monitor cell migration from peripheral blood into the central nervous system (CNS) in primates had been lacking. Here, upon autologous transfer of fluorescein dye-labeled leukocytes, we demonstrate the trafficking of dye-positive monocytes into the choroid plexus stromata and perivascular spaces in the cerebra of rhesus macaques acutely infected with simian immunodeficiency virus between days 12 and 14 postinfection (p.i.). Dye-positive cells that had migrated expressed the monocyte activation marker CD16 and the macrophage marker CD68. Monocyte neuroinvasion coincided with the presence of the virus in brain tissue and cerebrospinal fluid and with the induction of the proinflammatory mediators CXCL9/MIG and CCL2/MCP-1 in the CNS. Prior to neuroinfiltration, plasma viral load levels peaked on day 11 p.i. Furthermore, the numbers of peripheral blood monocytes rapidly increased between days 4 and 8 p.i., and circulating monocytes exhibited increased functional capacity to produce CCL2/MCP-1. Our findings demonstrate acute monocyte brain infiltration in an animal model of AIDS. Such studies facilitate future examinations of the migratory profile of CNS-homing monocytes, the role of monocytes in virus import into the brain, and the disruption of blood cerebrospinal fluid and blood-brain barrier functions in primates. PMID- 17715239 TI - Three-dimensional structure of the human cytomegalovirus cytoplasmic virion assembly complex includes a reoriented secretory apparatus. AB - Human cytomegalovirus (HCMV) induces profound changes in infected cell morphology, including a large cytoplasmic inclusion that corresponds to the virion assembly complex (AC). In electron micrographs, the AC is a highly vacuolated part of the cytoplasm. Markers of cellular secretory organelles have been visualized at the outer edge of the AC, and we recently showed that a marker for early endosomes (i.e., early endosome antigen 1) localizes to the center of the AC. Here, we examined the relationship between the AC and components of the secretory apparatus, studied temporal aspects of the dramatic infection-induced cytoplasmic remodeling, examined the three-dimensional structure of the AC, and considered the implications of our observations for models of HCMV virion maturation and egress. We made three major observations. First, in addition to being relocated, the expression levels of some organelle markers change markedly during the period while the AC is developing. Second, based on three-dimensional reconstructions from z-series confocal microscopic images, the observed concentric rings of vesicles derived from the several compartments (Golgi bodies, the trans-Golgi network [TGN], and early endosomes) are arranged as nested cylinders of organelle-specific vesicles. Third, the membrane protein biosynthetic and exocytic pathways from the endoplasmic reticulum to the Golgi bodies, TGN, and early endosomes are in an unusual arrangement that nonetheless allows for a conventional order of biosynthesis and transport. Our model of AC structure suggests a mechanism by which the virus can regulate the order of tegument assembly. PMID- 17715238 TI - Specific asparagine-linked glycosylation sites are critical for DC-SIGN- and L SIGN-mediated severe acute respiratory syndrome coronavirus entry. AB - Severe acute respiratory syndrome (SARS) is caused by a newly emerged coronavirus (CoV) designated SARS-CoV. The virus utilizes angiotensin-converting enzyme 2 (ACE2) as the primary receptor. Although the idea is less clear and somewhat controversial, SARS-CoV is thought to use C-type lectins DC-SIGN and/or L-SIGN (collectively referred to as DC/L-SIGN) as alternative receptors or as enhancer factors that facilitate ACE2-mediated virus infection. In this study, the function of DC/L-SIGN in SARS-CoV infection was examined in detail. The results of our study clearly demonstrate that both proteins serve as receptors independently of ACE2 and that there is a minimal level of synergy between DC/L SIGN and ACE2. As expected, glycans on spike (S) glycoprotein are important for DC/L-SIGN-mediated virus infection. Site-directed mutagenesis analyses have identified seven glycosylation sites on the S protein critical for DC/L-SIGN mediated virus entry. They include asparagine residues at amino acid positions 109, 118, 119, 158, 227, 589, and 699, which are distinct from residues of the ACE2-binding domain (amino acids 318 to 510). Amino acid sequence analyses of S proteins encoded by viruses isolated from animals and humans suggest that glycosylation sites N227 and N699 have facilitated zoonotic transmission. PMID- 17715240 TI - Vaccines based on novel adeno-associated virus vectors elicit aberrant CD8+ T cell responses in mice. AB - We recently discovered an expanded family of adeno-associated viruses (AAVs) that show promise as improved gene therapy vectors. In this study we evaluated the potential of vectors based on several of these novel AAVs as vaccine carriers for human immunodeficiency virus type 1 Gag. Studies with mice indicated that vectors based on AAV type 7 (AAV7), AAV8, and AAV9 demonstrate improved immunogenicity in terms of Gag CD8(+) T-cell and Gag antibody responses. The quality of these antigen-specific responses was evaluated in detail for AAV2/8 vectors and compared to results with an adenovirus vector expressing Gag (AdC7). AAV2/8 produced a vibrant CD8(+) T-cell effector response characterized by coexpression of gamma interferon and tumor necrosis factor alpha as well as in vivo cytolytic activity. No CD8(+) T-cell response generated by any of the AAVs was effectively boosted with AdC7, a result consistent with the finding of a relative lack of cells expressing interleukin-2 (IL-2) or a central memory phenotype at 3 months after the prime. The primary response to an AdC7 vaccine differed from that generated by AAVs in that the peak effector response evolved into populations of Gag-specific T cells expressing high levels of cytokines, including IL-2, and with effector memory and central memory phenotypes. A number of mechanisms could be considered to explain the aberrant activation of CD8(+) T cells by AAV, including insufficient inflammatory responses, CD4 help, and/or chronic antigen expression and T-cell exhaustion. Interestingly, the B-cell response to AAV encoded Gag was quite vibrant and easily boosted with AdC7. PMID- 17715241 TI - Functional modulation of the geminivirus AL2 transcription factor and silencing suppressor by self-interaction. AB - The DNA genomes of geminiviruses have a limited coding capacity that is compensated for by the production of small multifunctional proteins. The AL2 protein encoded by members of the genus Begomovirus (e.g., Tomato golden mosaic virus) is a transcriptional activator, a silencing suppressor, and a suppressor of a basal defense. The related L2 protein of Beet curly top virus (genus Curtovirus) shares the pathogenicity functions of AL2 but lacks transcriptional activation activity. It is known that AL2 and L2 can suppress local silencing by interacting with adenosine kinase (ADK) and can suppress basal defense by interacting with SNF1 kinase. However, how the activities of these viral proteins are regulated remains an unanswered question. Here, we provide some answers by demonstrating that AL2, but not L2, interacts with itself. The zinc finger-like motif (CCHC) is required but is not sufficient for AL2 self-interaction. Alanine substitutions for the invariant cysteine residues that comprise the motif abolish self-interaction or cause aberrant subnuclear localization but do not abolish interaction with ADK and SNF1. Using bimolecular fluorescence complementation, we show that AL2:AL2 complexes accumulate primarily in the nucleus, whereas AL2:ADK and L2:ADK complexes accumulate mainly in the cytoplasm. Further, the cysteine residue mutations impair the ability of AL2 to activate the coat protein promoter but do not affect local silencing suppression. Thus, AL2 self-interaction correlates with nuclear localization and efficient activation of transcription, whereas AL2 and L2 monomers can suppress local silencing by interacting with ADK in the cytoplasm. PMID- 17715242 TI - Reactivation of expression from quiescent herpes simplex virus type 1 genomes in the absence of immediate-early protein ICP0. AB - Model systems have previously been developed in which herpes simplex virus (HSV) is retained in human fibroblasts in a nonreplicating state known as quiescence. The HSV type 1 (HSV-1) immediate-early (IE) protein ICP0, an important activator of gene expression, reactivates the quiescent genome and promotes the resumption of virus replication. Previous studies reported that infection with ICP0-null HSV 1 mutants fails to reactivate quiescent HSV, even when the mutant itself undergoes productive replication, leading to the hypothesis that quiescent genomes exist in a silent configuration in which they are shielded from trans acting factors. I reinvestigated these findings, using HSV-1 mutants with lesions in the transcription activators VP16, ICP0, and ICP4 to establish quiescent infection at high efficiency. Superinfection with ICP0-null HSV-1 mutants at a low multiplicity of infection (MOI), so that individual plaques were formed, reactivated expression from the quiescent genome, demonstrating that the requirement for ICP0 is not absolute. The previously reported failure to observe reactivation by ICP0-null mutants was shown to be a consequence of either a low initial MOI or a high superinfecting MOI. Competition between viral genomes at the level of gene expression and virus replication, especially when ICP0 was absent, was demonstrated during reactivation and also during normal infection of human fibroblasts. The results show that the multiplicity-dependent phenotype of ICP0-null mutants limits the efficiency of reactivation at low MOIs and that competition between genomes occurs at high MOIs. The conclusion that quiescent HSV genomes are extensively silenced and intrinsically insensitive to trans acting factors must be reevaluated. PMID- 17715243 TI - Immunization of primates with a Newcastle disease virus-vectored vaccine via the respiratory tract induces a high titer of serum neutralizing antibodies against highly pathogenic avian influenza virus. AB - The ongoing outbreak of highly pathogenic avian influenza virus (HPAIV) in birds, the incidence of transmission to humans with a resulting high mortality rate, and the possibility of a human pandemic warrant the development of effective human vaccines against HPAIV. We developed an experimental live-attenuated vaccine for direct inoculation of the respiratory tract based on recombinant avian Newcastle disease virus (NDV) expressing the hemagglutinin (HA) glycoprotein of H5N1 HPAIV (NDV-HA). Expression of the HPAIV HA gene slightly reduced NDV virulence, as evidenced by the increased mean embryo death time and reduced replication in chickens. NDV-HA was administered to African green monkeys in two doses of 2 x 10(7) infectious units each with a 28-day interval to evaluate the systemic and local antibody responses specific to H5N1 HPAIV. The virus was shed only at low titers from the monkeys, indicative of safety. Two doses of NDV-HA induced a high titer of H5N1 HPAIV-neutralizing serum antibodies in all of the immunized monkeys. Moreover, a substantial mucosal immunoglobulin A response was induced in the respiratory tract after one and two doses. The titers of neutralizing antibodies achieved in this study suggest that the vaccine would be likely to prevent mortality and reduce morbidity caused by the H5N1 HPAIV. In addition, induction of a local immune response in the respiratory tract is an important advantage that is likely to reduce or prevent transmission of the virus during an outbreak or a pandemic. This vaccine is a candidate for clinical evaluation in humans. PMID- 17715244 TI - Canada's doctors assail pharmacist prescribing. PMID- 17715245 TI - Rashomon revisited: two views of monitoring the Women's Health Initiative trials. PMID- 17715246 TI - Monitoring and reporting of the Women's Health Initiative randomized hormone therapy trials. AB - BACKGROUND: The Women's Health Initiative (WHI) randomized trial of estrogen plus progestin (E + P) was terminated early based on an assessment of harms exceeding benefits for disease prevention. The results contravened prevailing wisdom and a large body of literature regarding benefits of menopausal hormone therapy. The results and their interpretation have been the subject of considerable debate. PURPOSE/METHODS: To describe the process of developing a trial monitoring plan, the key interim and final data, and to explain the choice of statistical methods used in trial monitoring and reporting. RESULTS: A formalized monitoring plan was developed using statistical methods that acknowledged protocol-defined design and analysis plans, input of monitoring board members especially regarding the role of various study outcomes, and multiple comparisons. Major early departures from design assumptions concerning treatment effects indicated a need for additional flexibility in safety monitoring. When the trials were stopped early, questions arose as to how closely the statistical methods in published reports should correspond to those defined by protocol or used in monitoring. METHODS: were selected to provide a simple and transparent summary of the primary results, with a cautious interpretation promoted by acknowledgement of multiple testing. CONCLUSIONS: Developing a formal trial monitoring plan with a view towards influencing clinical practice is useful for creating consensus among DSMB members regarding the evidence that would justify stopping a trial and the framework to be used to address statistical complexities. Departures from design assumptions typically occur. These reinforce the role of the DSMB in exercising their judgment, and the judicious adaptation of these statistical guidelines in monitoring and reporting trials. In communicating the results in such circumstances, priority should be given to presenting as fair, accurate and transparent a view of the data and findings as current methods and technology allow. PMID- 17715247 TI - Monitoring the randomized trials of the Women's Health Initiative: the experience of the Data and Safety Monitoring Board. AB - Data Safety Monitoring Committees (DSMB) for large, long-term randomized trials of agents in common use face challenging problems especially when the emerging data indicate unanticipated effects. The DSMB for the Women's Health Initiative Clinical Trials, on observing early indication of a surprising adverse cardiovascular effect of post-menopausal hormones, spent several years deliberating what recommendations it should make. This paper describes the dilemmas faced by the DSMB and the considerations it made over the course of its existence. The paper concludes with some recommendations for other DSMBs. PMID- 17715248 TI - Dose-finding in phase I clinical trials based on toxicity probability intervals. AB - BACKGROUND: Most phase I clinical trials conducted at the M. D. Anderson Cancer Center use the algorithmic 3 + 3 design, despite the availability of more advanced model-based designs such as the continual reassessment method. PURPOSE: Through simple statistical modeling and computing, we develop a dose-finding design that can be easily understood and implemented by non-statisticians. METHODS: We propose a beta/binomial Bayesian model and a probabilistic up-and down rule that allow all possible dose-assignment actions to be tabulated in a spreadsheet. We have developed an Excel macro (available at http://odin.mdacc. tmc.edu/~yuanj) that generates trial monitoring tables, which contain the dose assignment actions corresponding to various toxicity outcomes. RESULTS: The new design outperforms the 3 + 3 design and performs comparably to other model-based methods in the literature. LIMITATIONS: The proposed method assumes that the observed toxicity is a binary variable and that toxicity increases with dose level. CONCLUSION: The new dose-finding design enables physicians to readily determine dose assignments for new patients by referencing a trial monitoring table. PMID- 17715249 TI - An exploratory test for an excess of significant findings. AB - BACKGROUND: The published clinical research literature may be distorted by the pursuit of statistically significant results. PURPOSE: We aimed to develop a test to explore biases stemming from the pursuit of nominal statistical significance. METHODS: The exploratory test evaluates whether there is a relative excess of formally significant findings in the published literature due to any reason (e.g., publication bias, selective analyses and outcome reporting, or fabricated data). The number of expected studies with statistically significant results is estimated and compared against the number of observed significant studies. The main application uses alpha = 0.05, but a range of alpha thresholds is also examined. Different values or prior distributions of the effect size are assumed. Given the typically low power (few studies per research question), the test may be best applied across domains of many meta-analyses that share common characteristics (interventions, outcomes, study populations, research environment). RESULTS: We evaluated illustratively eight meta-analyses of clinical trials with >50 studies each and 10 meta-analyses of clinical efficacy for neuroleptic agents in schizophrenia; the 10 meta-analyses were also examined as a composite domain. Different results were obtained against commonly used tests of publication bias. We demonstrated a clear or possible excess of significant studies in 6 of 8 large meta-analyses and in the wide domain of neuroleptic treatments. LIMITATIONS: The proposed test is exploratory, may depend on prior assumptions, and should be applied cautiously. CONCLUSIONS: An excess of significant findings may be documented in some clinical research fields. PMID- 17715250 TI - Comments on 'An exploratory test for an excess of significant findings' by JPA loannidis and TA Trikalinos. PMID- 17715252 TI - Who refuses enrollment in cardiac clinical trials? AB - OBJECTIVE: To evaluate the factors associated with refusal to participate in acute cardiac clinical trials. BACKGROUND: Cardiac clinical trials in the acute setting pose a set of unique challenges to enrollment, such as the ability to obtain meaningful informed consent. In addition, it is unclear whether enrollment is associated with the sociodemographic characteristics (such as age, race and gender) of those being recruited. While policies have been instituted to enhance the representation of women and minorities in research, limited data exist on current enrollment patterns and reasons for refusal to participate in cardiac clinical trials. METHODS: 184 patients approached to participate in one of 25 cardiac clinical trials at Duke University Medical Center from 11/01 to 05/04 were surveyed regarding reasons for or against participation in clinical trials to identify predictors of non-enrollment. RESULTS: The mean age of the respondents was 61.6 years (SD 12.2), with 36% female and 32% non-white patients. There were no differences in refusal rates by age, gender or ethnicity. Higher acuity trials had higher refusal rates OR 3.6 (1.68-7.75) as well as not reading the informed consent form OR 2.99 (1.37-6.54). The main reasons people refused enrollment were due to inconvenience and not wanting to be experimented upon. LIMITATIONS: This study was cross-sectional and conducted at a single institution that conducts a high-volume of clinical research. In addition, a majority of the patients in the procedure/device studies were enrolled in one relatively low-risk cardiac catheterization laboratory trial with a low refusal rate. These attributes may limit the generalizability of the findings reported here. CONCLUSION: Older persons, women and minorities are equally likely to agree to enroll in cardiac clinical trials as younger persons, men and non-minorities. Future efforts to increase the efficiency of recruitment should focus on improving convenience for participants in this acute setting and improving basic understanding of clinical trials. PMID- 17715253 TI - Applying justice in clinical trials for diverse populations. AB - BACKGROUND: Considerable attention has focused on increasing clinical trial participation for members of "underrepresented groups". However, doing so involves clarifying how to meet the demands of justice, or fairness, which provides the ethical mandate to enhance broad trial representation. PURPOSE: To examine the ethical principle of justice as it applies to recruiting diverse populations to clinical trials representation. METHODS: In this paper, we analyse the conceptual and practical challenges in applying the principle of justice to clinical trials representation. RESULTS: Different facets of justice include demands for both fair outcomes and fair processes. Including both of these facets in clinical trials policy should not only promote access to trials, but also help to provide a framework to improve fairness in representation in clinical trials. Efforts to evaluate recruitment of representation should include outcome and process measures. LIMITATIONS: The suggestions offered based on this conceptual analysis need to be tested empirically. CONCLUSIONS: Those involved in the design, conduct and oversight of clinical trials should consider all of the facets of justice when assessing representation in clinical trials and attempt to balance fair access to trials with a fair process that may require protection from being unduly pressured to participate. PMID- 17715254 TI - Comments on 'Applying justice in clinical trials for diverse population' by J Tilburt et al. PMID- 17715256 TI - Perspectives of clinical research coordinators on disclosing financial conflicts of interest to potential research participants. AB - BACKGROUND: Disclosing financial interests to potential research participants during the informed consent process is one strategy for managing conflicts of interest. Given that clinical research coordinators are typically charged with administering the informed consent process, it is critical to understand their experiences, attitudes and beliefs regarding the disclosure of financial interests in research. PURPOSE: To understand the role of clinical research coordinators in disclosing financial interests in research, and potential barriers to such disclosures. METHODS: We developed a survey designed to measure clinical research coordinators' awareness of financial interests in clinical research, previous experience with disclosing financial interests, comfort with answering questions about financial interests and barriers to disclosing financial interests to potential research participants. Next we conducted cognitive interviews with 10 clinical research coordinators to assess understandability and content validity and to further refine the survey. We then administered the survey to clinical research coordinators attending the 2006 Global Conference of the Association of Clinical Research Professionals. RESULTS: Among 300 clinical research coordinators who completed the survey, there was a general awareness of financial interests in research. Forty-one percent reported disclosing such financial interests to potential research participants, and 28% reported being asked about them. Greater comfort in responding to questions about financial interests was associated with previous experience with disclosure, previous experience answering questions about financial interests, and greater length of time obtaining informed consent. Respondents indicated that there were barriers to disclosure, including lack of information (76%) and that participants would not understand disclosures (26%). LIMITATIONS: Possible sample bias due to using a convenience sample. CONCLUSIONS: Making information about financial interests in research readily available to clinical research coordinators, as well as providing education and training, should facilitate the disclosure of financial interests in research to potential research participants during the informed consent process. PMID- 17715257 TI - Clinical decision making and the expected value of information. AB - BACKGROUND: The results of the HOPE study, a randomized clinical trial, provide strong evidence that 1) ramipril prevents the composite outcome of cardiovascular death, myocardial infarction or stroke in patients who are at high risk of a cardiovascular event and 2) ramipril is cost-effective at a threshold willingness to-pay of $10,000 to prevent an event of the composite outcome. In this report the concept of the expected value of information is used to determine if the information provided by the HOPE study is sufficient for decision making in the US and Canada. METHODS: and results Using the cost-effectiveness data from a clinical trial, or from a meta-analysis of several trials, one can determine, based on the number of future patients that would benefit from the health technology under investigation, the expected value of sample information (EVSI) of a future trial as a function of proposed sample size. If the EVSI exceeds the cost for any particular sample size then the current information is insufficient for decision making and a future trial is indicated. If, on the other hand, there is no sample size for which the EVSI exceeds the cost, then there is sufficient information for decision making and no future trial is required. Using the data from the HOPE study these concepts are applied for various assumptions regarding the fixed and variable cost of a future trial and the number of patients who would benefit from ramipril. CONCLUSIONS: Expected value of information methods provide a decision-analytic alternative to the standard likelihood methods for assessing the evidence provided by cost-effectiveness data from randomized clinical trials. PMID- 17715258 TI - The role of intention to treat in analysis of noninferiority studies. AB - In analysing clinical trials designed to show superiority of one treatment compared to another, it is standard to use an intention to treat analytic approach. In active-controlled noninferiority studies, this is not standard, due to concerns that such an analysis will inflate the chance of falsely rejecting the null hypothesis, accepting therapeutic noninferiority when it is not justified. The reasons for using intention to treat (ITT) approaches in superiority studies include a desire to capture all information on study subjects, a need to prevent bias, and assurance that comparative groups are, on average, equivalent in prognostic factors. In this commentary, we argue that these same justifications carry over to noninferiority studies, and that for those and other reasons it should be the preferred analytic approach. We review regulatory guidelines, and propose a number of approaches to minimizing the potential disadvantages of the ITT approach in the noninferiority setting. PMID- 17715259 TI - Elevated phosphorus modulates vitamin D receptor-mediated gene expression in human vascular smooth muscle cells. AB - Clinical observations show that an increase in serum inorganic phosphorus (Pi) is linked to higher cardiovascular (CV) mortality, while vitamin D receptor (VDR) agonist therapy is associated with survival benefit in stage 5 chronic kidney disease. Smooth muscle cells (SMCs) play an important role in CV pathophysiology, but the interaction between Pi and the VDR signaling pathway in SMCs is not known. Real-time RT-PCR studies revealed that elevated Pi (2.06 mM) modulated VDR mediated regulation of a panel of genes including thrombomodulin and osteopontin in SMCs. DNA microarray results demonstrated that increasing Pi from 0.9 to 2.06 mM exerted a widespread modulating effect on VDR-mediated gene expression. A total of 325 target genes were affected by paricalcitol at 0.9 mM Pi, with 195 up and 130 downregulated. The number of target genes affected by paricalcitol at 2.06 mM Pi decreased to 86, with 55 up- and 31 downregulated. VDR-mediated gene expression in As4.1 cells (a juxtaglomerular cell-like cell line derived from kidney tumors in SV40 T-antigen transgenic mice) and peroxisome proliferator activated receptor (PPAR)gamma-mediated gene expression in SMCs were also altered by elevated Pi, suggesting that the observation is not unique to VDR in SMCs. Mechanism analysis showed that elevated Pi had no significant effect on VDR or PPARgamma protein level but altered the cytosolic vs. nuclear distribution of NF kappaB or nuclear receptor corepressor 1 (NCoR1). Our results demonstrate for the first time that elevated Pi affects VDR-mediated gene expression in human coronary artery SMCs and the effect is not limited to VDR in SMCs. PMID- 17715260 TI - The effect of oral contraceptives on the nitric oxide system and renal function. AB - We have demonstrated that oral contraceptive (OC) users exhibit elevated angiotensin II levels and angiotensin II type 1 receptor expression, indicative of renin-angiotensin system (RAS) activation, yet the renal and systemic consequences are minimal, suggesting that there is increased vasodilatory activity, counteracting the effect of RAS activation. We hypothesized that the nitric oxide (NO) system would be upregulated in OC users and that this would be reflected by a blunted hemodynamic response to l-arginine infusion. All subjects were studied after a 7-day controlled sodium and protein diet. Inulin and para aminohippurate clearance techniques were used to assess renal function. l Arginine was infused at 100, 250, and 500 mg/kg, each over 30 min. Skin endothelial NO synthase mRNA expression was assessed by real-time PCR. While OC nonusers exhibited significant increases in effective renal plasma flow (670.8 +/ 35.6 to 816.2 +/- 59.7 ml.min(-1).1.73 m(-2)) and glomerular filtration rate (133.4 +/- 4.3 to 151.0 +/- 5.7 ml.min(-1).1.73 m(-2), P = 0.04) and declines in renal vascular resistance (81.1 +/- 6.1 to 63.5 +/- 6.2 mmHg.ml(-1).min, P = 0.001) at the lower l-arginine infusion rates, the responses in OC users were blunted. While l-arginine reduced mean arterial pressure at the 250 and 500 mg/kg doses in OC nonusers, OC users only exhibited a decrease in mean arterial pressure at the highest infusion rate. In contrast, tissue endothelial NO synthase mRNA levels were higher in the OC users (P = 0.04). In summary, these findings suggest that the NO system is upregulated by OC use in young, healthy women. Increased activity of the NO pathway may modulate the hemodynamic effects of RAS activation in OC users. PMID- 17715261 TI - Changes in urinary bladder smooth muscle function in response to colonic inflammation. AB - Visceral organ "cross talk" is suspected to contribute to multiorgan symptomatology found in conditions such as irritable bowel syndrome and interstitial cystitis. The goal of the present study was to investigate the short and long-term effects of acute colitis on bladder detrusor muscle contractility. We hypothesized that inflammation of the colon leads to changes in bladder function via direct changes in detrusor smooth muscle contractility. In this study, colonic inflammation was induced in male rats via an enema of trinitrobenzenesulfonic acid (TNBS) (50 mg/kg, 0.5 ml, 25% ethanol). Colitis was confirmed using gross morphology, histology, and measurements of myeloperoxidase activity. Saline enema-treated rats served as controls. Three, 15, and 30 days postenema treatment, bladder detrusor muscle contractility was investigated in response to electrical field stimulation (EFS), cholinergic agonism with carbachol (CCh), and KCl. During active colonic inflammation (day 3 post-TNBS enema), the bladder detrusor muscle appeared normal and showed no significant inflammation. However, abnormalities in bladder detrusor muscle contractility occurred in response to EFS and CCh but not KCl. During and after recovery from colonic inflammation (days 15 and 30 post-TNBS enema), changes in bladder detrusor muscle contractility in response to EFS and CCh returned to control levels. We found that a transient colonic inflammatory insult significantly attenuates the amplitude of bladder detrusor muscle contractions in vitro, at least in part, through changes in cholinergic innervation, which are reversible after recovery from the colitis. PMID- 17715262 TI - Polycystic kidney disease and renal injury repair: common pathways, fluid flow, and the function of polycystin-1. AB - The root cause for most cases of autosomal-dominant polycystic kidney disease (ADPKD) is mutations in the polycystin-1 (PC1) gene. While PC1 has been implicated in a perplexing variety of protein interactions and signaling pathways, what its normal function is and why its disruption leads to the proliferation of renal epithelial cells are unknown. Recent results suggest that PC1 is involved in mechanotransduction by primary cilia measuring the degree of luminal fluid flow. PC1 has also recently been shown to regulate the mTOR and signal transducers and activators of transcription (STAT) 6 pathways. These two pathways are normally dormant in the healthy kidney but are activated in response to injury and appear to drive a proliferative repair response. This review develops the idea that a critical function of PC1 and primary cilia in the adult kidney may be to sense renal injury by detecting changes in luminal fluid flow and to trigger proliferation. Constitutive activation of these pathways in ADPKD would lead to the futile attempt to repair a nonexisting injury, resulting in cyst growth. The existence of many known cellular and molecular similarities between renal repair and ADPKD supports this model. PMID- 17715264 TI - Glomerular filtration into the subpodocyte space is highly restricted under physiological perfusion conditions. AB - Production of urine is initiated by fluid and solute flux across the glomerular filtration barrier. Recent ultrastructural studies have shown that under extreme conditions of no filtration, or very high filtration, a restriction to flow is predicted in a space underneath the podocyte cell body or its processes, the subpodocyte space (SPS). The SPS covered up to two-thirds of the glomerular filtration barrier (GFB) surface. The magnitude of this restriction to flow suggested that it might be unlikely that filtration into and flow through the SPS would contribute significantly to total flow across the entire GFB under these conditions. To determine whether the SPS has similar properties under normal physiological conditions, we have carried out further three-dimensional reconstruction of rat glomeruli perfused at physiologically normal hydrostatic and colloid osmotic pressures. These reconstructions show that the sub-podocyte space is even more restricted under these conditions, with a mean height of the SPS of 0.34 microm, mean pathlength of 6.7 +/- 1.4 mum, a mean width of the SPS exit pore of 0.15 +/- 0.05 microm, and length of 0.25 +/- 0.05 microm. Mathematical modeling of this SPS based on a circular flow model predicts that the resistance of these dimensions is 2.47 times that of the glomerular filtration barrier and exquisitely sensitive to changes in the dimensions of the SPS exit pore (SEP), indicating that the SEP could be the principal regulator of the extravascular pressure in the SPS. This suggests a physiological role of the podocyte in the regulation of glomerular fluid flux across most of the GFB. PMID- 17715263 TI - Lead, at low levels, accelerates arteriolopathy and tubulointerstitial injury in chronic kidney disease. AB - Chronic lead exposure has been epidemiologically linked with hypertension and renal disease. Clinical studies suggest that low lead levels may contribute to renal progression. However, experimental studies have not examined whether low levels of lead accelerate progression in experimental chronic renal disease. Sprague-Dawley rats were administered lead (L; 150 ppm in drinking water, n = 16) for 4 wk, followed by remnant kidney (RK) surgery with continuation of lead for an additional 12 wk; control rats (n = 9) were treated similarly but did not receive lead. Lead treatment was well tolerated and resulted in modest elevations in whole blood lead levels (26.4 +/- 4.5 vs. 1 +/- 0 mug/dl, week 16, P < 0.001). Lead treatment was associated with higher systolic blood pressure (P < 0.05) and worse renal function (creatinine clearance 1.4 +/- 0.4 vs. 1.8 +/- 0.5 ml/min, RK+L vs. RK, P < 0.05), and with a tendency for greater proteinuria (6.6 +/- 6.1 vs. 3.6 +/- 1.5 mg protein/mg creatinine, RK+L vs. RK, P = 0.08). While glomerulosclerosis tended to be worse in lead-treated rats (37.6 +/- 11 vs. 28.8 +/- 2.3%, RK+L vs. RK, P = 0.06), the most striking finding was the development of worse arteriolar disease (P < 0.05), peritubular capillary loss (P < 0.05), tubulointerstitial damage, and macrophage infiltration (P < 0.05) in association with significantly increased renal expression of monocyte chemoattractant protein 1 mRNA. In conclusion, lead accelerates chronic renal disease, primarily by raising blood pressure and accelerating microvascular and tubulointerstitial injury. PMID- 17715265 TI - Aldosterone receptor antagonism alleviates proteinuria, but not malignant hypertension, in Cyp1a1-Ren2 transgenic rats. AB - The contribution of elevated aldosterone to the pathogenesis of malignant, ANG II dependent hypertension remains uncertain. Therefore, we examined whether chronic mineralocorticoid receptor blockade attenuates the development of malignant hypertension in transgenic rats (TGRs) with inducible expression of the Ren2 gene [TGR(Cyp1a1Ren2)]. Systolic blood pressure (SBP) was measured by radiotelemetry in male TGRs in three groups: 1) control (n = 9), 2) hypertensives (HT; n = 8), and 3) hypertensives + spironolactone (11 mg.kg(-1).day(-1) sc; HTS; n = 8). Malignant hypertension was induced with dietary indole-3-carbinol (0.3%) for 10 days. Metabolic measurements were taken at the beginning of the study and at days 2 and 9. HT exhibited elevated SBP (125 +/- 3 vs. 187 +/- 5 mmHg), plasma renin activity (5 +/- 1 vs. 29 +/- 10 ng ANG I.ml(-1).h(-1)), plasma ANG II (175 +/- 39 vs. 611 +/- 74 fmol/ml), and plasma aldosterone (0.31 +/- 0.04 vs. 5.42 +/- 1.02 nmol/l). Urinary aldosterone excretion increased 5.5-fold by day 2 and an additional 90% by day 9. HT was associated with a 1.8-fold increase in proteinuria by day 9 that was alleviated by treatment with spironolactone (25 +/- 5 vs. 13 +/- 3 mg/day), suggesting that aldosterone contributes to the renal damage observed in malignant hypertension. Urinary Na+ excretion was decreased 76% on day 2, despite a sixfold increase in urinary aldosterone excretion. Decrease in urinary Na+ excretion on day 2 in HT suggests that Na+ reabsorption was increased in response to the increase in aldosterone; however, the lack of a change in SBP between HT and HTS suggests that mechanisms independent of aldosterone stimulation make a greater contribution to the maintenance of elevated arterial pressure in malignant hypertension in Cyp1a1-Ren2 transgenic rats. PMID- 17715267 TI - Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years. AB - OBJECTIVE: To assess risk factors for liver-related death, we re-evaluated, after a median follow-up of 25 years, a cohort of 70 Caucasian patients with hepatitis B e antigen (HBeAg) positive chronic hepatitis (CH) at presentation. METHODS: Follow-up studies included clinical and ultrasound examinations, biochemical and virological tests, and cause of death. RESULTS: Sixty-one (87%) patients underwent spontaneous HBeAg seroconversion. During a median period of 22.8 years after HBeAg seroclearance, 40 (66%) patients became inactive carriers, whereas the remaining 21 (34%) showed alanine aminotransferase elevation: one (1%) had HBeAg reversion, nine (15%) detectable serum HBV DNA but were negative for HBeAg, eight (13%) concurrent virus(es) infection and three (5%) concurrent non alcoholic fatty liver disease. Liver-related death occurred in 11 (15.7%) patients, caused by hepatocellular carcinoma in five and liver failure in six. The 25-year survival probability was 40% in patients persistently HBeAg positive, 50% in patients with HBeAg negative CH or HBeAg reversion and 95% in inactive carriers. Older age, male sex, cirrhosis at entry and absence of sustained remission predicted liver-related death independently. The adjusted hazard ratios (95% CI) for liver related death were 33 (3.01-363) for persistently HBeAg positive patients and 38.73 (4.65-322) for those with HBeAg negative CH or HBeAg reversion relative to inactive carriers. CONCLUSION: Most patients with HBeAg seroconversion became inactive carriers with very good prognosis. The risk of liver-related mortality in Caucasian adults with CH is strongly related with sustained disease activity and ongoing high level of HBV replication independently of HBeAg status. PMID- 17715266 TI - Characterization of a putative intrarenal serotonergic system. AB - Serotonin [5-hydroxytryptamine (5HT)] acts through multiple G protein-coupled 5 HT receptors, and its activity is also regulated by the 5-HT transporter. The current studies report the expression and localization of the 5-HT receptors and transporter in the kidney. In addition, the enzymatic pathway mediating 5-HT synthesis is present in renal cortex, especially in the proximal tubules and glomerular epithelial cells and mesangial cells. Expression of the 5-HT receptors and 5-HT transporter was detected by RT-PCR in cell lines of these cell types. In cultured proximal tubule cells and podocytes, 5-HT activated ERK1/2 and increased the expression of connective tissue growth factor and transforming growth factor beta, two key mediators of extracellular matrix accumulation. Immunohistochemistry and real-time RT-PCR studies also indicated that 5-HT stimulated expression of vascular endothelial growth factor in podocytes in vitro and in vivo. Therefore, these results indicate the presence of an integrated intrarenal serotonergic system and suggest a possible role for 5-HT as a mediator of renal fibrosis in the kidney. PMID- 17715269 TI - Electromyography (EMG) accuracy compared to muscle biopsy in childhood. AB - Reports show wide variability of electromyography (EMG) in detecting pediatric neuromuscular disorders. The study's aim was to determine EMG/nerve conduction study accuracy compared to muscle biopsy and final clinical diagnosis, and sensitivity for myopathic motor unit potential detection in childhood. Of 550 EMG/nerve conduction studies performed by the same examiner from a pediatric neuromuscular service, 27 children (ages 6 days to 16 years [10 boys; M:F, 1:1.7]) with muscle biopsies and final clinical diagnoses were compared retrospectively. Final clinical diagnoses were congenital myopathies (5 of 27,18%), nonspecific myopathies (biopsy myopathic, final diagnosis uncertain; 6 of 27, 22%), congenital myasthenic syndrome (3 of 27, 11%), juvenile myasthenia gravis (1 of 27, 4%), arthrogryposis multiplex congenita (2 of 27, 7%), hereditary motor and sensory neuropathy (1 of 27, 4%), bilateral peroneal neuropathies (1 of 27, 4%), and normal (8 of 27, 30%). There were no muscular dystrophy or spinal muscular atrophy patients. EMG/nerve conduction studies had a 74% agreement with final clinical diagnoses and 100% agreement in neurogenic, neuromuscular junction, and normal categories. Muscle biopsies concurred with final diagnoses in 87%, and 100% in myopathic and normal categories. In congenital myasthenic syndrome, muscle biopsies showed mild variation in fiber size in 2 of 3 children and were normal in 1 of 3. EMG sensitivity for detecting myopathic motor unit potentials in myopathies was 4 of 11 (36%), greater over 2 years of age (3 of 4, 75%), compared to infants less than 2 years (1 of 7, 14%), not statistically significant (P = .0879). EMGs false-negative for myopathy in infants < 2 years of age were frequently neurogenic (3 of 6, 50%). In congenital myopathies EMG detected myopathic motor unit potentials in 40%, with false negative results neurogenic (20%) or normal (40%). Because our study has no additional tests for active myopathies, for example Duchenne muscular dystrophy genetic testing, our sensitivity for myopathies is lower than if we used a more global view. In conclusion, EMG detection rate of myopathic motor unit potentials at a young age was low, improving in children over 2 years of age. In neurogenic and neuromuscular junction disorders, the EMG has a very high detection rate. In children with mild to moderate neurogenic EMG findings and normal nerve conduction, a myopathy should always be considered. PMID- 17715268 TI - Absence epilepsy in childhood: electroencephalography (EEG) does not predict outcome. AB - Absence epilepsy is a form of generalized epilepsy commonly seen in children. The clinician is often presented with a patient whose electroencephalogram does not fit the typical absence pattern. The purpose of this study is to more closely examine both typical and atypical absence variants and their outcome. A retrospective chart review was performed on children diagnosed with absence epilepsy over the past 5 years at the University of Alberta. A total of 119 patients were reviewed. Patients were classified with typical or atypical absence seizures following International League Against Epilepsy criteria and electroencephalography (EEG) characteristics. Clinical seizure characteristics, magnetic resonance imaging (MRI), initial response to treatment, and outcome were examined. Seizure characteristics were similar in both the typical and atypical absence groups. Aura, complex automatisms, changes in tone, and incontinence were seen in both groups, although status epilepticus was found only in the atypical group. Associated comorbid conditions such as attention-deficit hyperactivity disorder (ADHD), learning disorders, and enuresis were found equally in both groups. Developmental delay was found more often in the atypical group. Of the typical group, 83% responded to an initial antiepileptic drug (either valproic acid or ethosuximide), whereas only 51% of the atypical group came under control. Remission at 2 years however, was similar between groups, with 76% of the typical group and 71% of the atypical group completely seizure free. Absence seizures in childhood, both typical and atypical, share similar clinical and electroencephalographic features and appear to be part of a continuum. Associated comorbid features such as ADHD, learning disorders, and developmental delay are also seen in both groups. The outcome for both types is excellent, although the atypical variants may be initially more difficult to control. PMID- 17715270 TI - Spectral Doppler imaging of vessels in the optic nerve of children. AB - Elevation and blur of the optic disc margin with hyperemia and flame hemorrhages are classic features of papilledema that may not be present with mild elevations of the cerebral spinal fluid pressure. In children, the disc can be dramatically elevated with indistinct margins in pseudopapilledema. Children with equivocal disc features are sedated for neuroimaging and lumbar puncture to measure opening intracranial pressure. PMID- 17715271 TI - Methylphenidate-induced changes in cerebral hemodynamics measured by functional near-infrared spectroscopy. AB - The aim of the present preliminary study was to evaluate the feasibility of measuring cerebral hemodynamic effects of a clinical dose of methylphenidate by near-infrared spectroscopy in 10 boys (median age, 10.7 years; range, 8.6-11.8 years) with developmental attention-deficit/hyperactivity disorder (ADHD). Using a Trail Making Test known to activate the left dorsolateral prefrontal cortex, cerebral hemodynamic changes show a lower increase of cerebral blood volume in the right prefrontal cortex (P = .033) and a lower increase of the tissue oxygenation index in the left prefrontal cortex (P = .015) in the condition after intake of methylphenidate compared with a drug-naive situation. A lower increase of the tissue oxygenation index indicates a changing regional oxygen metabolism and consumption induced by methylphenidate. Near-infrared spectroscopy is a sensitive tool for measuring pharmacological effects of methylphenidate on the cerebral hemodynamics. PMID- 17715272 TI - Neonatal arterial ischemic stroke and sinovenous thrombosis associated with meningitis. AB - This series describes 5 neonates with meningitis associated with arterial ischemic stroke or cerebral sinovenous thrombosis identified from a tertiary children's hospital perinatal stroke database. A retrospective chart review was performed to collect data on clinical presentations, type of meningitis, radiographic and electroencephalographic findings, neonatal intensive care unit course and complications, additional risk factors associated with stroke, and outcomes. The proportion of arterial ischemic stroke and sinovenous thrombosis in the database associated with meningitis was calculated. Neonates came to medical attention because of seizures (2), hydrocephalus (1), and behavior changes (2). The median age of presentation was birth (range, 0-18 days). Meningitis was bacterial in 4 and viral in 1. The median time from symptom onset to identification of the causative organisms of meningitis was 16.8 days (range, 13 23 days) and from symptom onset to diagnosis of stroke was 11 days (range, 4-18 days). One child had arterial ischemic stroke. Four had cerebral sinovenous thrombosis. One child died in the neonatal intensive care unit. Outcome data were available for 3 of the 4 surviving children; all had some degree of neurological deficit. All 5 of the neonates described had risk factors for perinatal thrombosis or embolization in addition to meningitis. Meningitis is associated with 1.6% (1/63) of cases of arterial ischemic stroke and 7.7% (4/52) of cases of cerebral sinovenous thrombosis in our perinatal stroke database. Further work is needed to clarify when infarction occurs during meningitis and which children are at highest risk. PMID- 17715273 TI - Epilepsy in children in Navarre, Spain: epileptic seizure types and epileptic syndromes. AB - Data for children 1 month to 15 years of age at the time of diagnosis of epilepsy were recorded from the children's hospital "Virgen del Camino" in Pamplona (Spain) from January to December 2005. International League Against Epilepsy criteria were used for diagnoses. A total of 365 children were recruited into the study. Mean age at diagnosis was 5.97 years, and time of follow-up was 4.6 years. Etiology was idiopathic in 166 (45.5%), cryptogenic in 106 (29.0%), and symptomatic in 93 (25.5%). Focal seizures were seen in 52.9% of the patients, generalized epilepsy in 43.5%, and 3.6% were not determined. In infants, West syndrome (34.1%) and focal symptomatic seizures (24.4%) were the most prevalent syndromes. In early childhood, the main syndromes were cryptogenic focal epilepsies (17.7%) and Doose syndrome (12.8%). In school-aged children, benign epilepsies (27.3%) and absences (24.5%) were prevalent. In adolescents, cryptogenic focal epilepsies (26.6%) and benign epilepsies (23.4%). PMID- 17715274 TI - Topiramate in the prophylaxis of pediatric migraine: a double-blind placebo controlled trial. AB - Several large, randomized controlled trials have demonstrated the efficacy of topiramate in migraine prophylaxis in adults. However, there are limited data about the use of topiramate in migraine prophylaxis in children. We conducted this single-center, double-blind, placebo-controlled trial to evaluate the efficacy and safety of topiramate in the prophylaxis of migraine in children. A total of 44 children with migraine were randomized using random number tables to receive topiramate (n = 22) or placebo (n = 22). The total duration of treatment was 4 months, including a baseline period of 1 month during which topiramate was titrated weekly in 25-mg increments to 100 mg/d in 2 divided doses or to the maximum tolerated dose. The titration was followed by a 12-week maintenance phase during which topiramate was given in 2 divided doses. The primary outcome measures were the reduction in the mean migraine frequency and severity of headache. Secondary outcome measures included the number of times analgesics were required for a month for acute attacks and functional disability. Functional disability was measured by comparing school absenteeism and Pediatric Migraine Disability Assessment Scale (PedMIDAS). The decrease in mean (+/-SD) monthly migraine frequency from 16.14 (+/-9.35) at baseline to 4.27 (+/-1.95) at the end of the study in the topiramate group was significantly greater as compared with a decrease from 13.38 (+/-7.78) to 7.48 (+/-5.94) at the end of the study in the placebo group (P = .025). The difference in number of rescue medications used for topiramate and placebo was not statistically significant (P = .059). There was a statistically significant decrease in the PedMIDAS score from 50.66 (+/-32.1) to 10.42 (+/-6.39) at the end of the study in the topiramate group compared with a decrease from 42.66 (+/-27.5) to 23.7 (+/-19.1) at the end of 4 months in the placebo group (P = .003). The decrease in school absenteeism was significant with topiramate compared with placebo (P = .002). Weight loss, decreased concentration in school, sedation, and parasthesias were important side effects with topiramate. Most of these side effects were mild to moderate and were not significant enough to cause dropout from the study. PMID- 17715275 TI - Temporal lobe epilepsy in childhood: comprehensive neuropsychological assessment. AB - The neuropsychological features of children with temporal lobe epilepsy are not yet well defined. The aim of this study was to identify the neuropsychological deficits in children with temporal lobe epilepsy. We evaluated 25 patients and compared them with 25 normal children. All children underwent a comprehensive neuropsychological assessment. We found a significant difference in favor of the control group in the following measures: IQ; forward digit; Trail Making Test for Children B; Wisconsin Card Sorting Test; block design; Boston naming test, verbal fluency; and Wide Range Assessment of Memory and Learning verbal learning, visual learning, verbal memory, visual memory, delayed recall of verbal learning, delayed recall of stories, and recognition of stories. Our findings show that children with temporal lobe epilepsy present with several neuropsychological deficits, despite normal IQ. These findings point to a dysfunction of cerebral areas other than temporal lobe, particularly the frontal lobes. PMID- 17715276 TI - Brain structure in prenatal stroke: quantitative magnetic resonance imaging (MRI) analysis. AB - Neonatal stroke outcome studies demonstrate variable findings of either relatively spared intellectual function or persistent impairments. Volumetric measurement of the brain can provide more precise data on lesion-cognition outcomes. We studied 7 children with unilateral focal lesions from prenatal stroke. Whole-brain magnetic resonance imaging scans were analyzed to produce volumes of cortical gray matter, total white matter, cerebrospinal fluid, lesion, and lesion constricted fluid, and we ascertained the relationship of morphometric variables to intellectual and clinical outcome. Children with cystic encephalomalacia plus atrophy had poorer outcomes than children with atrophy or gliosis alone. These children also demonstrated the largest lesion size, smallest gray matter volume, and greatest proportion of hyperintense white matter in the affected hemisphere. Findings suggest that the type and size of the lesion, in addition to the integrity of white matter and residual cortex, may be better predictors of intellectual functioning than either of these indices alone. PMID- 17715277 TI - Long-term neuromotor speech deficits in survivors of childhood posterior fossa tumors: effects of tumor type, radiation, age at diagnosis, and survival years. AB - The cerebellum is important for the coordination of fluent speech. The authors studied how childhood cerebellar tumors affect long-term neuromotor speech outcomes, including the relation between outcome and tumor type, radiation, age at diagnosis, and survival years. Videotaped speech samples of child and adult long-term survivors of childhood cerebellar astrocytoma (nonradiated) and medulloblastoma (radiated) tumors and healthy controls were analyzed by 2 speech pathologists for ataxic dysarthria, dysfluency, and speech rate. Ataxia varied with tumor type/radiation. Medulloblastoma survivors had significantly more ataxic dysarthric features than either survivors of astrocytomas or controls, who did not differ from each other. Dysfluency varied with a history of a posterior fossa tumor. Medulloblastoma and astrocytoma survivors were each significantly more dysfluent than controls but did not differ from each other. Speech rate varied with age and tumor type. Adult controls were significantly faster than child controls, although adult tumor survivors were comparable to their child counterparts. Adult controls had significantly faster speech rates than adult survivors of medulloblastoma tumors. Ataxic dysarthric speech characteristics are more frequent in radiated survivors of medulloblastoma tumors than nonradiated survivors of astrocytoma tumors. Dysfluent and slow speech occur in cerebellar tumor survivors, regardless of tumor type and radiation history. Cerebellar tumors in childhood limit speech rate in adulthood. PMID- 17715278 TI - Hashimoto encephalopathy responding to risperidone. AB - This report describes a case of Hashimoto encephalopathy in an 11-year-old girl. She presented with features typical of this disorder including encephalopathy, seizures, and neuropsychiatric symptoms. Diagnosis was supported by an elevated thyroid-stimulating hormone level, a low levo-thyroxine level, and positive results for antithyroperoxidase antibody. Her response to typical treatment with levo-thyroxine was incomplete, requiring additional therapy with valproic acid and methylprednisone. Her course was further complicated by the development of acute psychosis. Treatment with risperidone was correlated with resolution of her psychosis and improvement in neuropsychiatric symptoms. Response to antipsychotic therapy has not previously been described in the pediatric population with Hashimoto encephalopathy. This case highlights the need for guidelines for the management of this rare disorder. PMID- 17715279 TI - Mitochondrial encephalomyopathy due to a novel mutation in the tRNAGlu of mitochondrial DNA. AB - A 14-year-old boy had exercise intolerance, weakness, ataxia, and lactic acidosis. Because his muscle biopsy showed a mosaic pattern of fibers staining intensely with the succinate dehydrogenase reaction but not at all with the cytochrome c oxidase reaction, we sequenced his mitochondrial DNA and found a novel mutation (C14680A) in the gene for tRNAGlu. The mutation was present in accessible tissues from the asymptomatic mother but not from a brother with Asperger syndrome. These data expand the clinical heterogeneity of mutations in this mitochondrial gene. PMID- 17715280 TI - A neurologic presentation of familial hemophagocytic lymphohistiocytosis which mimicked septic emboli to the brain. AB - Familial hemophagocytic lymphohistiocytosis is an inherited deficiency of natural killer cell function and excessive cytokine activity, which predominantly presents in early childhood. The initial symptoms of familial hemophagocytic lymphohistiocytosis are often nonspecific but may be predominantly neurologic. The case presented here describes an 18-month-old boy who initially presented with fever, encephalopathy, and hemiparesis. He had innumerable brain lesions visualized on magnetic resonance imaging scans. An infectious etiology was excluded, and brain, liver, and bone marrow biopsies were nonspecific but consistent with hemophagocytic lymphohistiocytosis. Cells were sent for flow cytometry perforin analysis, which demonstrated defective natural killer cell function. A diagnosis of familial hemophagocytic lymphohistiocytosis was confirmed by mutation analysis and decreased expression of the perforin gene, in the patient and immediate family members. These results showed the patient to be a compound heterozygote for perforin mutations. His case illustrates the potential for a fulminant neurological presentation of familial hemophagocytic lymphohistiocytosis with widespread lesions in the brain. PMID- 17715281 TI - Mosaic trisomy r(14) associated with epilepsy and mental retardation. AB - We report a patient with moderate mental retardation, benign clinical course of epilepsy, and type 2 diabetes mellitus. The patient has a mosaic karyotype with 2 cell lines: 1 with a ring chromosome 14 [r(14)], and 1 with an apparently duplicated r(14) chromosome. PMID- 17715282 TI - Congenital cervical spinal cord lesions: pathogenesis, management, and outcome. AB - Three patients (2 boys) presented with nontraumatic congenital lesions of the spinal cord resulting in paralysis and contractures of their upper limbs from birth. Limited improvement occurred in all. Two survived. One patient required ventilation support after birth; his upper limbs had lower motor neuron flaccid paralysis, and his lower limbs evolved to pyramidal tract impairment. He died at 9 months of age with an intercurrent chest infection. The other 2 patients had lower motor neuron pathology in their upper limbs and normal lower limb function. One of these patients attained ambulation. All 3 patients retained normal higher mental function. Neuroimaging of the spinal cord from the most affected patient demonstrated atrophy of the cervical and high thoracic regions (C4-T3). Spinal neuroimaging results from the less affected patient were normal. Multidisciplinary management assisted these children to reach their full potential in a resource-poor setting. The etiology of focal pathology to the cervical region in these infants with congenital nontraumatic insults remains undefined, similar to the few cases in the literature. The diverse pathogeneses are hypothesized and the literature reviewed. PMID- 17715283 TI - Exercise capacity in a child with McArdle disease. AB - We report the exercise capacity of an 8-year-old boy with clinical, histological, biochemical, and genetic evidence of McArdle disease. The patient presented with severe myalgia, proteinuria, hematuria, pyrexia, and elevated creatine kinase after swimming. After pre-exercise ingestion of sucrose, he performed treadmill exercise to symptom limitation. His peak oxygen uptake (18.8 mL/kg/min) and ventilatory threshold (16.0 mL/kg/min) were reduced by 40% and 20% compared with healthy age-matched and gender-matched controls. The results suggest that exercise capacity is reduced early in life in patients with McArdle disease and suggest the need for prophylactic exercise training (following pre-exercise feeding to prevent rhabdomyolysis) to minimize deconditioning. PMID- 17715284 TI - Craniodigital syndrome of Scott: clinical and neuroradiological features of a new case. AB - We report on a girl presenting with mental retardation, craniofacial dysmorphisms, and syndactyly. The child's mother and maternal grandfather presented bilateral syndactyly of toes 2 and 3. These manifestations, falling within the ambit of what has been termed the craniodigital syndromes, were first reported by Scott et al (1971) in 3 brothers. PMID- 17715285 TI - Benign afebrile seizures in acute gastroenteritis: is rotavirus the culprit? AB - Three patients, a 2-year-old girl, a 14-month-old girl, and a 15-month-old boy, were admitted with multiple episodes of benign afebrile seizures. Electroencephalograms recorded 1 or 2 days after the last seizure revealed epileptiform discharges. All 3 patients developed a fulminant Rotazyme-positive diarrhea toward the end of their respective hospital stay. The prospects of immunological detection in diagnosis and treatment are discussed. PMID- 17715286 TI - Spinocerebellar ataxia type 2 in a Turkish family. AB - Autosomal dominant spinocerebellar ataxias are neurodegenerative disorders that generally present in adulthood. Due to extreme expansion of the repeat size during spermatogenesis, they can also be observed in childhood. The diagnosis in childhood is very difficult in the absence of family history. Here we describe an 8-year-old girl with spinocerebellar ataxia type 2 who presented with progressive ataxia, cognitive deficits, and dysarthria. A detailed family history exhibited similarly affected cases on the paternal side. Molecular testing for spinocerebellar ataxia type 2 revealed abnormal "cytosineadenine-guanosine" expansion in all affected family members. The number of cytosine-adenine guanosine repeats in the index case was 70. The mean size of expansion in the relatives of the patient was 42 (39-46). This finding explains the early onset of symptoms in the index case. PMID- 17715287 TI - Clinical and inheritance profiles of hyperekplexia in Jordan. AB - Hyperekplexia is a rare nonepileptic disorder characterized by excessive startle response to acoustic, visual, or other stimuli. Patients with hyperekplexia are often misdiagnosed as having epilepsy. The presentation modalities, phenotypes, and the modes of inheritance among patients with hyperekplexia from 9 Jordanian families are described. All families were referred with the preliminary diagnosis of uncontrolled seizures with onset of the disease in the neonatal period and with variable and atypical presenting features. The inheritance profile in 4 families was compatible with autosomal recessive and in 1 family with autosomal dominant inheritance. Four families showed sporadic cases of hyperekplexia. This is the first report of a series of patients with hyperekplexia from Jordan. The clinical manifestations show atypical features that have not been previously reported, pointing to the probable broader clinical spectrum of this entity. Recognition of the syndrome allows for prompt proper management and provision of genetic counseling. PMID- 17715288 TI - Novel mutation in splicing donor of dystrophin gene first exon in a patient with dilated cardiomyopathy but no clinical signs of skeletal myopathy. AB - One cause of X-linked dilated cardiomyopathies is mutation of the dystrophin gene. We report the case of a young boy who suffered from dilated cardiomyopathy caused only by dystrophin-deficient cardiac muscle, but who did not present with any clinical signs of skeletal myopathy. Sequence analysis of the patient's dystrophin gene revealed the presence of a novel single point mutation at the first exon-intron boundary, inactivating the 5' splice site consensus sequence of the first intron. The lack of muscle weakness observed clinically can be explained by expression of the brain and Purkinje dystrophin isoforms in skeletal muscle. PMID- 17715289 TI - Lack of evidence for association between D2S124 and D2S111 polymorphisms of the SCN2A gene and idiopathic generalized epilepsy with generalized tonic clonic seizures. AB - Idiopathic generalized epilepsy syndromes are generally considered as brain channelopathies due to alteration of several genes. The aim of our study was to compare the distribution of D2S124 and D2S111 genetic polymorphisms of the SCN2A gene between cases with a specific idiopathic generalized epilepsy subtype (with generalized tonic-clonic seizures) and healthy controls. Allele frequencies of both the D2S111 and the D2S124 polymorphisms were not significantly different between cases and control. Further studies are needed to investigate if possible polymorphic variants of SCN2A gene may influence seizures susceptibility of idiopathic generalized epilepsy with tonic-clonic seizures. PMID- 17715290 TI - Intermediate maple syrup urine disease: neuroimaging observations in 3 patients from South India. AB - Maple syrup urine disease is a disorder of branched-chain keto acid metabolism. Three children were diagnosed with the intermediate form of maple syrup urine disease during routine evaluation of mental retardation. Clinical features were characterized by mental retardation, seizures, autistic features, and movement disorder in the form of dystonia. High-performance liquid chromatography of the urine and serum revealed elevated levels of branched-chain amino acids, suggesting a diagnosis of maple syrup urine disease. Magnetic resonance imaging showed diffuse hyperintense signals in the white matter along with involvement of the thalami and globus pallidus. Magnetic resonance imaging in the intermediate form showed myelination in the posterior limb of the internal capsule, in contrast to the classic form of the disease. Knowledge about the neuroimaging findings of this rare disease will help to narrow down the differential diagnosis when evaluating children with unexplained mental retardation and seizures. PMID- 17715291 TI - Metabolic engineering of a genetic selection system with tunable stringency. AB - The biosynthesis of small molecules can be fine-tuned by (re)engineering metabolic flux within cells. We have adapted this approach to optimize an in vivo selection system for the conversion of prephenate to phenylpyruvate, a key step in the production of the essential aromatic amino acid phenylalanine. Careful control of prephenate concentration in a bacterial host lacking prephenate dehydratase, achieved through provision of a regulable enzyme that diverts it down a parallel biosynthetic pathway, provides the means to systematically increase selection pressure on replacements of the missing catalyst. Successful differentiation of dehydratases whose activities vary over a >50,000-fold range and the isolation of mechanistically informative prephenate dehydratase variants from large protein libraries illustrate the potential of the engineered selection strain for characterizing and evolving enzymes. Our approach complements other common methods for adjusting selection pressure and should be generally applicable to any selection system that is based on the conversion of an endogenous metabolite. PMID- 17715292 TI - Disruption of CXCR4 enhances osteoclastogenesis and tumor growth in bone. AB - CXCR4 regulates hematopoietic and tumor cell homing to bone, but its role during osteoclast (OC) development is unknown. We investigated the role of CXCR4 in osteoclastogenesis and in a model of bone metastasis. Compared with controls, mice reconstituted with CXCR4 null hematopoietic cells exhibited elevated markers of bone resorption, increased OC perimeter along bone, and increased bone loss. CXCR4-/- OCs demonstrated accelerated differentiation and enhanced bone resorption in vitro. Furthermore, tumor growth specifically in bone was significantly increased in mice reconstituted with CXCR4-/- hematopoietic cells. Finally, enhancement of bone tumor growth in the absence of CXCR4 was abrogated with the OC inhibitor, zoledronic acid. These data demonstrate that disruption of CXCR4 enhances osteoclastogenesis and suggest that inhibition of CXCR4 may enhance established skeletal tumor burden by increasing OC activity. PMID- 17715294 TI - A Drosophila gustatory receptor required for the responses to sucrose, glucose, and maltose identified by mRNA tagging. AB - In Drosophila, detection of tastants is thought to be mediated by members of a family of 68 gustatory receptors (Grs). However, only one receptor, Gr5a, has been associated with a sugar, and it appears to be activated specifically by trehalose. It is unclear whether other sugar receptors are activated by single or multiple sugars. Currently, no Grs are known to colocalize with Gr5a. Such Grs would be candidate sugar receptors because Gr5a-expressing cells function in the responses to attractive tastants. Here we use an "mRNA tagging" approach to identify Gr RNAs that are coexpressed with Gr5a. We found that all seven Grs most related to Gr5a (Gr64a-f and Gr61a) were expressed in Gr5a-expressing cells, whereas none of the other Grs examined were enriched in these Gr neurons (GRNs). We characterized the role of one Gr5a-related receptor, Gr64a, and found that it was required for the behavioral responses to glucose, sucrose, and maltose. Gr64a was required for GRN function because action potentials induced by these sugars were dependent on expression of Gr64a in GRNs. These data demonstrate that multiple Grs are coexpressed with Gr5a and that Drosophila Gr64a is required for the responses to multiple sugars. PMID- 17715293 TI - Identification and characterization of a selenoprotein family containing a diselenide bond in a redox motif. AB - Selenocysteine (Sec, U) insertion into proteins is directed by translational recoding of specific UGA codons located upstream of a stem-loop structure known as Sec insertion sequence (SECIS) element. Selenoproteins with known functions are oxidoreductases containing a single redox-active Sec in their active sites. In this work, we identified a family of selenoproteins, designated SelL, containing two Sec separated by two other residues to form a UxxU motif. SelL proteins show an unusual occurrence, being present in diverse aquatic organisms, including fish, invertebrates, and marine bacteria. Both eukaryotic and bacterial SelL genes use single SECIS elements for insertion of two Sec. In eukaryotes, the SECIS is located in the 3' UTR, whereas the bacterial SelL SECIS is within a coding region and positioned at a distance that supports the insertion of either of the two Sec or both of these residues. SelL proteins possess a thioredoxin like fold wherein the UxxU motif corresponds to the catalytic CxxC motif in thioredoxins, suggesting a redox function of SelL proteins. Distantly related SelL-like proteins were also identified in a variety of organisms that had either one or both Sec replaced with Cys. Danio rerio SelL, transiently expressed in mammalian cells, incorporated two Sec and localized to the cytosol. In these cells, it occurred in an oxidized form and was not reducible by DTT. In a bacterial expression system, we directly demonstrated the formation of a diselenide bond between the two Sec, establishing it as the first diselenide bond found in a natural protein. PMID- 17715295 TI - Thermodynamically reengineering the listerial invasion complex InlA/E-cadherin. AB - Biological processes essentially all depend on the specific recognition between macromolecules and their interaction partners. Although many such interactions have been characterized both structurally and biophysically, the thermodynamic effects of small atomic changes remain poorly understood. Based on the crystal structure of the bacterial invasion protein internalin (InlA) of Listeria monocytogenes in complex with its human receptor E-cadherin (hEC1), we analyzed the interface to identify single amino acid substitutions in InlA that would potentially improve the overall quality of interaction and hence increase the weak binding affinity of the complex. Dissociation constants of InlA-variant/hEC1 complexes, as well as enthalpy and entropy of binding, were quantified by isothermal titration calorimetry. All single substitutions indeed significantly increase binding affinity. Structural changes were verified crystallographically at < or =2.0-A resolution, allowing thermodynamic characteristics of single substitutions to be rationalized structurally and providing unique insights into atomic contributions to binding enthalpy and entropy. Structural and thermodynamic data of all combinations of individual substitutions result in a thermodynamic network, allowing the source of cooperativity between distant recognition sites to be identified. One such pair of single substitutions improves affinity 5,000-fold. We thus demonstrate that rational reengineering of protein complexes is possible by making use of physically distant hot spots of recognition. PMID- 17715296 TI - Collagen-binding proteoglycan fibromodulin can determine stroma matrix structure and fluid balance in experimental carcinoma. AB - Research on the biology of the tumor stroma has the potential to lead to development of more effective treatment regimes enhancing the efficacy of drug based treatment of solid malignancies. Tumor stroma is characterized by distorted blood vessels and activated connective tissue cells producing a collagen-rich matrix, which is accompanied by elevated interstitial fluid pressure (IFP), indicating a transport barrier between tumor tissue and blood. Here, we show that the collagen-binding proteoglycan fibromodulin controls stroma structure and fluid balance in experimental carcinoma. Gene ablation or inhibition of expression by anti-inflammatory agents showed that fibromodulin promoted the formation of a dense stroma and an elevated IFP. Fibromodulin-deficiency did not affect vasculature but increased the extracellular fluid volume and lowered IFP. Our data suggest that fibromodulin controls stroma matrix structure that in turn modulates fluid convection inside and out of the stroma. This finding is particularly important in relation to the demonstration that targeted modulations of the fluid balance in carcinoma can increase the response to cancer therapeutic agents. PMID- 17715298 TI - Transgenic animal bioreactors: a new line of defense against chemical weapons? PMID- 17715297 TI - pak2a mutations cause cerebral hemorrhage in redhead zebrafish. AB - The zebrafish is a powerful model for studying vascular development, demonstrating remarkable conservation of this process with mammals. Here, we identify a zebrafish mutant, redhead (rhd(mi149)), that exhibits embryonic CNS hemorrhage with intact gross development of the vasculature and normal hemostatic function. We show that the rhd phenotype is caused by a hypomorphic mutation in p21-activated kinase 2a (pak2a). PAK2 is a kinase that acts downstream of the Rho family GTPases CDC42 and RAC and has been implicated in angiogenesis, regulation of cytoskeletal structure, and endothelial cell migration and contractility among other functions. Correction of the Pak2a-deficient phenotype by Pak2a overexpression depends on kinase activity, implicating Pak2 signaling in the maintenance of vascular integrity. Rescue by an endothelial-specific transgene further suggests that the hemorrhage seen in Pak2a deficiency is the result of an autonomous endothelial cell defect. Reduced expression of another PAK2 ortholog, pak2b, in Pak2a-deficient embryos results in a more severe hemorrhagic phenotype, consistent with partially overlapping functions for these two orthologs. These data provide in vivo evidence for a critical function of Pak2 in vascular integrity and demonstrate a severe disease phenotype resulting from loss of Pak2 function. PMID- 17715299 TI - Cultural mosaics and mental models of nature. AB - For much of their history, the relationship between anthropology and psychology has been well captured by Robert Frost's poem, "Mending Wall," which ends with the ironic line, "good fences make good neighbors." The congenial fence was that anthropology studied what people think and psychology studied how people think. Recent research, however, shows that content and process cannot be neatly segregated, because cultural differences in what people think affect how people think. To achieve a deeper understanding of the relation between process and content, research must integrate the methodological insights from both anthropology and psychology. We review previous research and describe new studies in the domain of folk biology which examine the cognitive consequences of different conceptualizations of nature and the place of humans within it. The focus is on cultural differences in framework theories (epistemological orientations) among Native Americans (Menominee) and European American children and adults living in close proximity in rural Wisconsin. Our results show that epistemological orientations affect memory organization, ecological reasoning, and the perceived role of humans in nature. This research also demonstrates that cultural differences in framework theories have implications for understanding intergroup conflict over natural resources and are relevant to efforts to improve science learning, especially among Native American children. PMID- 17715300 TI - An 11-amino acid beta-hairpin loop in the cytoplasmic domain of band 3 is responsible for ankyrin binding in mouse erythrocytes. AB - The best-studied cytoskeletal system is the inner surface of the erythrocyte membrane, which provides an erythrocyte with the structural support needed to be stable yet flexible as it passes through the circulation. Current structural models predict that the spectrin-actin-based cytoskeletal network is attached to the plasma membrane through interactions of the protein ankyrin, which binds to both spectrin and the cytoplasmic domain of the transmembrane protein band 3. The crystal structure of the cytoplasmic domain of band 3 predicted that the ankyrin binding site was located on a beta-hairpin loop in the cytoplasmic domain. In vitro, deletion of this loop eliminated ankyrin affinity for band 3 without affecting any other protein-band 3 interaction. To evaluate the importance of the ankyrin-band 3 linkage to membrane properties in vivo, we generated mice with the nucleotides encoding the 11-aa beta-hairpin loop in the mouse Slc4a1 gene replaced with sequence encoding a diglycine bridge. Mice homozygous for the loop deletion were viable with mildly spherocytic and osmotically fragile erythrocytes. In vitro, homozygous ld/ld erythrocytes were incapable of binding ankyrin, but contrary to all previous predictions, abolishing the ankyrin-band 3 linkage destabilized the erythrocyte membrane to a lesser degree than complete deficiencies of either band 3 or ankyrin. Our data indicate that as yet uncharacterized interactions between other membrane proteins must significantly contribute to linkage of the spectrin-actin-based membrane cytoskeleton to the plasma membrane. PMID- 17715302 TI - Spatial reduction algorithm for atmospheric chemical transport models. AB - Numerical modeling of global atmospheric chemical dynamics presents an enormous challenge, associated with simulating hundreds of chemical species with time scales varying from milliseconds to years. Here we present an algorithm that provides a significant reduction in computational cost. Because most of the fast reactants and their quickly decomposing reaction products are localized near emission sources, we use a series of reduced chemical models of decreasing complexity with increasing distance from the source. The algorithm diagnoses the chemical dynamics on-the-run, locally and separately for every species according to its characteristic reaction time. Unlike conventional time-scale separation methods, the spatial reduction algorithm speeds up not only the chemical solver but also advection-diffusion integration. Through several examples we demonstrate that the algorithm can reduce computational cost by at least an order of magnitude for typical atmospheric chemical kinetic mechanisms. PMID- 17715301 TI - Oxidation of the sugar moiety of DNA by ionizing radiation or bleomycin could induce the formation of a cluster DNA lesion. AB - Bleomycin, a radiomimetic drug currently used in human cancer therapy, is a well known carcinogen. Its toxicity is mostly attributed to its potentiality to induce DNA double strand breaks likely arising from the formation of two vicinal DNA strand breaks, initiated by C4-hydrogen abstraction on the 2-deoxyribose moiety. In this work we demonstrate that such a hydrogen abstraction reaction is able to induce the formation of a clustered DNA lesion, involving a 3' strand break together with a modified sugar residue exhibiting a reactive alpha,beta unsaturated aldehyde that further reacts with a proximate cytosine base. The lesion thus produced was detected as a mixture of four isomers by HPLC coupled to tandem mass spectrometry subsequent to DNA extraction and enzymatic digestion. The modified nucleosides that constitute new types of cytosine adducts were identified as the likely two pairs of diastereomers of 6-(2-deoxy-beta-D-erythro pentofuranosyl)-2-hydroxy-3(3-hydroxy-2-oxopropyl)-2,6-dihydroimidazo[1,2-c] pyrimidin-5(3H)-one as inferred from mass spectrometry and NMR analyses of the chemically synthesized nucleosides. We demonstrate that bleomycin, and to a minor extent ionizing radiation, are able to induce significant amounts of the cytosine damage in cellular DNA. In addition, the repair kinetic of the lesion in a human lymphocyte cell line is rather slow, with a half-life of 10 h. The 2' deoxycytidine adducts thus characterized that represent the first example of complex DNA lesions isolated and identified in cellular DNA upon one radical hit are likely to play an important role in the toxicity of bleomycin. PMID- 17715304 TI - Rhythms and alternating patterns in plants as emergent properties of a model of interaction between development and functioning. AB - BACKGROUND AND AIMS: To model plasticity of plants in their environment, a new version of the functional-structural model GREENLAB has been developed with full interactions between architecture and functioning. Emergent properties of this model were revealed by simulations, in particular the automatic generation of rhythms in plant development. Such behaviour can be observed in natural phenomena such as the appearance of fruit (cucumber or capsicum plants, for example) or branch formation in trees. METHODS: In the model, a single variable, the source sink ratio controls different events in plant architecture. In particular, the number of fruits and branch formation are determined as increasing functions of this ratio. For some sets of well-chosen parameters of the model, the dynamical evolution of the ratio during plant growth generates rhythms. KEY RESULTS AND CONCLUSIONS: Cyclic patterns in branch formation or fruit appearance emerge without being forced by the model. The model is based on the theory of discrete dynamical systems. The mathematical formalism helps us to explain rhythm generation and to control the behaviour of the system. Rhythms can appear during both the exponential and stabilized phases of growth, but the causes are different as shown by an analytical study of the system. Simulated plant behaviours are very close to those observed on real plants. With a small number of parameters, the model gives very interesting results from a qualitative point of view. It will soon be subjected to experimental data to estimate the model parameters. PMID- 17715303 TI - Protection of telomeres by a conserved Stn1-Ten1 complex. AB - Telomeres are specialized chromatin structures that protect chromosome ends. Critical among telomere proteins are those that bind the telomeric single-strand DNA (ssDNA) overhangs. These proteins are thought to differ among eukaryotes. Three interacting proteins (Cdc13, Stn1, and Ten1) associate with the telomeric overhang in budding yeast, a single protein known as Pot1 (protection of telomeres-1) performs this function in fission yeast, and a two-subunit complex consisting of POT1 and TPP1 associates with telomeric ssDNA in humans. Cdc13 and Pot1 have related oligonucleotide/oligosaccharide-binding fold (OB-fold) domains that bind the telomeric ssDNA overhang. Here we show that Schizosaccharomyces pombe has Stn1- and Ten1-like proteins that are essential for chromosome end protection. Stn1 orthologs exist in all species that have Pot1, whereas Ten1-like proteins can be found in all fungi. Fission yeast Stn1 and Ten1 localize at telomeres in a manner that correlates with the length of the ssDNA overhang, suggesting that they specifically associate with the telomeric ssDNA. Unlike in budding yeast, in which Cdc13, Stn1, and Ten1 all interact, fission yeast Stn1 and Ten1 associate with each other, but not with Pot1. Our findings suggest that two separate protein complexes are required for chromosome end protection in fission yeast. Structural profiling studies detect OB-fold domains in Stn1 and Ten1 orthologs, indicating that protection of telomeres by multiple proteins with OB-fold domains is conserved in eukaryotic evolution. PMID- 17715305 TI - Differentiation of malignant from benign distal ureteral obstructions: assessment using transrectal and color Doppler ultrasonography. AB - OBJECTIVE: The purpose of this study was to evaluate the feasibility of transrectal ultrasonography (TRUS) and color Doppler ultrasonography (CDUS) in differentiating malignant from benign distal ureteral obstructions. METHODS: Our study group consisted of 16 malignant distal ureteral obstructions and 12 benign distal ureteral obstructions. The 16 malignant distal ureteral obstructions were transitional cell carcinomas involving the distal ureter. The 12 benign distal ureteral obstructions consisted of benign strictures (n = 4), ureteral edema after stone passage (n = 3), tuberculosis (n = 2), a fibroepithelial polyp (n = 1), amyloidosis (n = 1), and a hematoma (n = 1). Findings from gray scale transabdominal ultrasonography, gray scale TRUS, CDUS, and duplex Doppler imaging were retrospectively evaluated. RESULTS: Gray scale transabdominal ultrasonography and TRUS showed no specific difference between malignant and benign distal ureteral obstructions. On CDUS, malignant distal ureteral obstructions showed dotlike blood flow in 5, moderately increased blood flow in 9, and markedly increased blood flow in 2; and benign distal ureteral obstructions showed absence of blood flow in 5 and dotlike blood flow in 7. Flow spectra could be obtained in 12 malignant distal ureteral obstructions, and they showed arterial waveforms. Duplex Doppler imaging was not tried in 4 malignant distal ureteral obstructions. In 7 benign distal ureteral obstructions with dotlike blood flow, flow spectra could not be obtained. CONCLUSIONS: Moderately or markedly increased blood flow within a ureteral mass on CDUS and an arterial waveform within a ureteral mass on duplex Doppler imaging may be helpful in differentiating malignant from benign distal ureteral obstructions. PMID- 17715306 TI - A new parameter for staging bladder carcinoma: ultrasonographic contact length and height-to-length ratio. AB - OBJECTIVE: The purpose of this study was to investigate the value of tumor bladder wall contact length (CL), tumor height (H), and height-to-length ratio (H/CL) for preoperative staging of bladder carcinoma. METHODS: Fifty-seven patients with bladder tumors underwent suprapubic ultrasonography preoperatively, and the CL of the tumor with the bladder wall and H in the bladder lumen were measured. The CL, H, and H/CL values were correlated with the wall invasion determined by histopathologic analysis of the cystectomy material. Invasion was staged according to the TNM classification system. RESULTS: Statistically significant differences were found for CL (P < .001) and H/CL (P = .001) between the superficial and invasive tumor groups. These parameters were also effective for differentiating superficial or deep muscle invasion. A CL of greater than 41.5 mm and an H/CL of less than 0.605 were calculated as cutoff values for differentiating superficial and invasive tumors. Height had no value for determining invasion. CONCLUSIONS: The ultrasonographic measurements of CL of the tumor with the bladder wall and H/CL may be useful for staging bladder carcinoma by verification of these findings in larger groups of patients. PMID- 17715307 TI - Prospective use of ultrasound imaging to detect bony hand injuries in adults. AB - OBJECTIVE: We hypothesized that high-resolution linear ultrasound imaging performed by emergency sonologists would be accurate in the diagnosis of bony injuries of the hand. METHODS: This was a prospective observational study of adult patients with injuries of the hand at an urban emergency department with trained emergency sonologists. After informed consent, high-frequency linear ultrasound was used to evaluate the bony structures below the area of injury or tenderness of the hand. The presence of a fracture or dislocation was recorded. A standard radiograph was taken subsequently and read by a blinded radiologist. Standard descriptive statistics with confidence intervals were calculated. RESULTS: A total of 78 patients were enrolled in the study. The incidence of deformity was 28%; swelling, 90%; and erythema, 20%. Thirty patients had a total of 31 fractures: 21 metacarpal and 10 phalangeal. Ultrasound imaging identified 28 of 31 fractures found on standard radiographs, except for 1 patient's fractures, which were confirmed at surgery. One dislocation was found on ultrasound imaging and confirmed by radiographs. Ultrasound imaging showed the following accuracy for fracture: sensitivity, 90%; specificity, 98%; likelihood ratio (LR)(+), 42.5; and LR(-), 0.1. In comparison, individual physical examination findings of deformity, swelling, and erythema had a maximal LR(+) of 5.15 and minimum LR(-) of 0.51. One metacarpal fracture at the base of the first metacarpal, 1 spiral nondisplaced mid-third metacarpal fracture, and 1 distal tuft phalangeal fracture were missed by ultrasound imaging. There was 1 false positive ultrasound finding. CONCLUSIONS: Ultrasound imaging performed by emergency sonologists showed excellent sensitivity and specificity in the diagnosis of hand fractures. PMID- 17715308 TI - The utility of focused assessment with sonography for trauma as a triage tool in multiple-casualty incidents during the second Lebanon war. AB - OBJECTIVE: The purpose of this study was to evaluate the role of focused assessment with sonography for trauma (FAST) as a triage tool in multiple casualty incidents (MCIs) for a single international conflict. METHODS: The charts of 849 casualties that arrived at our level 1 trauma referral center were reviewed. Casualties were initially triaged according to the Injury Severity Score at the emergency department gate. Two-hundred eighty-one physically injured patients, 215 soldiers (76.5%) and 66 civilians (23.5%), were admitted. Focused assessment with sonography for trauma was performed in 102 casualties suspected to have an abdominal injury. Sixty-eight underwent computed tomography (CT); 12 underwent laparotomy; and 28 were kept under clinical observation alone. We compared FAST results against CT, laparotomy, and clinical observation records. RESULTS: Focused assessment with sonography for trauma results were positive in 17 casualties and negative in 85. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of FAST were 75%, 97.6%, 88.2%, 94.1%, and 93.1%, respectively. A strong correlation between FAST and CT results, laparotomy, and clinical observation was obtained (P < .05). CONCLUSIONS: In a setting of a war conflict-related MCI, FAST enabled immediate triage of casualties to laparotomy, CT, or clinical observation. Because of its moderate sensitivity, a negative FAST result with strong clinical suspicion demands further evaluation, especially in an MCI. PMID- 17715310 TI - Fetal transcerebellar diameter measurement for prediction of gestational age at the extremes of fetal growth. AB - OBJECTIVE: The purpose of this study was to determine the accuracy of our previously published and prospectively validated transcerebellar diameter (TCD) nomogram in the prediction of gestational age (GA) in intrauterine growth restricted (IUGR) and large fetuses. METHODS: We established a cross-sectional nomogram of TCD in 24,026 well-dated singleton fetuses and prospectively validated the nomogram using 2597 fetuses from a separate population. This nomogram was validated in both IUGR (n = 55) and large (n = 16) fetuses (estimated fetal weight, <10th and >90th percentiles, respectively). The actual GA was subtracted from the TCD-predicted GA in IUGR and large fetuses, and the concordance between the actual and predicted GAs was assessed using the Pearson correlation coefficient. RESULTS: Concordance between the actual and predicted GA based on our previously published singleton TCD nomogram was high for both IUGR and large fetuses (Pearson correlation, r = 0.98 and 0.95, respectively; P < .001). The means (SDs) of actual and predicted GA based on TCD in IUGR fetuses were 24.9 (6.5) and 25.1 (6.3) weeks, respectively. The predicted GA based on TCD in IUGR fetuses was within 3 days in 97.5% in the second trimester and 93.3% in the third trimester. In large fetuses, the difference between the actual and predicted GA based on TCD within 3 days was 100% in both the second and third trimesters. CONCLUSIONS: This study shows that our institution-specific TCD nomogram is reliable and accurate in predicting GA even at extremes of fetal growth. PMID- 17715311 TI - Is fetal anatomic assessment on follow-up antepartum sonograms clinically useful? AB - OBJECTIVE: The purpose of this study was to evaluate the clinical usefulness of a fetal anatomic survey on follow-up antepartum sonograms. METHODS: A retrospective follow-up study was conducted at a low-risk maternity clinic from July 1, 2005, to June 30, 2006. Eligible women had at least 1 prior sonographic examination beyond 18 weeks' gestation with a complete and normal fetal anatomic assessment and at least 1 follow-up sonogram. Full fetal anatomic surveys were performed on all follow-up sonograms regardless of the indication. Neonatal charts were reviewed for those patients whose follow-up sonograms revealed unanticipated fetal anomalies. Neonatal intervention was defined as surgical or medical therapy or arranged subspecialty follow-up specifically for the suspected fetal anomaly. RESULTS: Of a total of 4269 sonographic examinations performed, 437 (10.2%) were follow-up studies. Of these, 101 (23.1%) were excluded because the initial sonogram revealed a suspected fetal anomaly, and 42 (9.8%) were excluded for other reasons. Of the remaining 294 women, 21 (7.1%) had an unanticipated fetal anomaly, most often renal pyelectasis. Compared with follow-up sonography for other reasons, repeated sonography for fetal growth evaluation yielded a higher incidence of unexpected fetal anomalies: 15 (12.3%) of 122 versus 6 (3.5%) of 172 (P = .01). When compared with the neonates in the nongrowth indications group, those neonates whose mothers had sonographic examinations for fetal growth had a higher rate of neonatal interventions: 6 (40.0%) of 15 versus 0 (0%) of 6 (P = .04). CONCLUSIONS: A fetal anatomic survey on follow-up sonograms may identify unanticipated fetal anomalies, especially when the indication is for fetal growth. PMID- 17715309 TI - Carotid artery distensibility: a reliability study. AB - OBJECTIVE: Carotid distensibility (CD) is a measure of carotid artery elasticity that has been introduced as a risk factor for cardiovascular disease. Information regarding reproducibility of sonographic CD measures is limited. The objective of this study was to evaluate the inter-reader reliability of sonographic measurements of common carotid artery (CCA) diameters and derived metrics of CD. METHODS: Two independent readers (R1 and R2) measured the systolic diameter (SD) and diastolic diameter (DD) for the right CCA from the B/M-mode sonographic registrations among 118 subjects. The derived CD metrics (strain, elastic modulus [E], stiffness [beta], and CD) were calculated. The inter-reader type 3 intraclass correlation coefficients (ICC3,1) for carotid diameters were calculated. RESULTS: The mean SDs +/- standard deviation were 7.15 +/- 1.43 mm for R1 and 7.24 +/- 1.43 mm for R2. The mean DDs were 6.71 +/- 1.36 mm for R1 and 6.68 +/- 1.41 mm for R2. The mean differences of SD and DD between R1 and R2 were 0.08 +/- 0.40 mm (paired t test, P = .04) and 0.03 +/- 0.43 mm (paired t test, P = .46), respectively. Inter-reader type 3 intraclass correlation coefficients were 0.96 for SD and 0.95 for DD. We observed a significant association of demographics with carotid diameters but not with derived CD metrics or risk factors. CONCLUSIONS: Our results suggest good reproducibility of CCA diameters measured with B/M-mode sonography. However, very small changes in linear measurements of carotid diameters can have big effects on estimates of arterial mechanical properties such as strain and Young's modulus. The standard boundary identification methods may not be precise and reproducible enough for use in a clinical setting. PMID- 17715313 TI - Elastographic evaluation of the temporal formation of ethanol-induced hepatic lesions: preliminary in vitro results. AB - OBJECTIVE: The purpose of this study was to evaluate the temporal formation of ethanol-induced hepatic lesions using ultrasound elastography. METHODS: An in vitro porcine liver was used as the specimen, and 4 lesions were created by injection of 2 mL of ethanol. After the ethanol injection, freehand elastography of the lesion from an identical scan plane was obtained during a time series (with an interval of approximately 30 seconds in the first 2 minutes and 1 minute afterward) using a real-time ultrasound scanner. The area of the lesion in the elastographic sequences was calculated to depict the temporal formation of the lesion. RESULTS: The ethanol-induced lesion on elastography appeared as a low strain region whose boundary was clear and irregular. The elastographic sequences obtained after the ethanol injection showed that the lesion formed quickly in the first 2 minutes and then changed little in shape. The area of the lesion grew notably in the first 2 minutes after ethanol injection, and then it reached a plateau of about 0.7 cm(2). CONCLUSIONS: Ultrasound elastography is capable of monitoring the temporal formation of ethanol-induced lesions and is a potential imaging modality to evaluate the response of percutaneous ethanol injection therapy. PMID- 17715314 TI - Diagnosing cysts with correlation coefficient images from 2-dimensional freehand elastography. AB - OBJECTIVE: We compared the diagnostic potential of using correlation coefficient images versus elastograms from 2-dimensional (2D) freehand elastography to characterize breast cysts. METHODS: In this preliminary study, which was approved by the Institutional Review Board and compliant with the Health Insurance Portability and Accountability Act, we imaged 4 consecutive human subjects (4 cysts, 1 biopsy-verified benign breast parenchyma) with freehand 2D elastography. Data were processed offline with conventional 2D phase-sensitive speckle-tracking algorithms. The correlation coefficient in the cyst and surrounding tissue was calculated, and appearances of the cysts in the correlation coefficient images and elastograms were compared. RESULTS: The correlation coefficient in the cysts was considerably lower (14%-37%) than in the surrounding tissue because of the lack of sufficient speckle in the cysts, as well as the prominence of random noise, reverberations, and clutter, which decorrelated quickly. Thus, the cysts were visible in all correlation coefficient images. In contrast, the elastograms associated with these cysts each had different elastographic patterns. The solid mass in this study did not have the same high decorrelation rate as the cysts, having a correlation coefficient only 2.1% lower than that of surrounding tissue. CONCLUSIONS: Correlation coefficient images may produce a more direct, reliable, and consistent method for characterizing cysts than elastograms. PMID- 17715312 TI - The role of the sagittal view of the ductal arch in identification of fetuses with conotruncal anomalies using 4-dimensional ultrasonography. AB - OBJECTIVE: Conotruncal anomalies represent one fifth of all congenital heart defects (CHDs) detected in the fetus. However, the spatial relationship of the great vessels is incorrectly defined in about 20% of these cases. The sagittal view of the ductal arch is considered a standard ultrasonographic view in fetal echocardiography and can be easily visualized using 4-dimensional (4D) ultrasonography. This study was designed to determine the role of this ultrasonographic plane for the prenatal diagnosis of conotruncal anomalies. METHODS: We reviewed 4D volume data sets, acquired with the spatiotemporal image correlation technique, from fetuses with and without confirmed conotruncal anomalies. The visualization rate of the sagittal view of the ductal arch was compared among groups using standardized multiplanar views. RESULTS: This study included 183 volume data sets from fetuses in the following groups: (1) normal echocardiographic findings (n = 130); (2) conotruncal anomalies (n = 18); and (3) other CHDs (n = 35). Volumes of poor image quality were excluded from analysis (8.2% [15/183]). The visualization rate of the sagittal view of the ductal arch was significantly lower in fetuses with conotruncal anomalies (5.6% [1/18]) than that in fetuses without abnormalities (93.1% [108/116]) and that in fetuses with other CHDs (79.4% [27/34]; P < .01). Absence of visualization of the sagittal view of the ductal arch was associated with a likelihood ratio of 9.44 (95% confidence interval, 5.8-15.5) to have conotruncal anomalies. CONCLUSIONS: The sagittal view of the ductal arch may play an important role in the screening and prenatal diagnosis of conotruncal anomalies in 4D ultrasonography. PMID- 17715316 TI - Three-dimensional power Doppler sonography in the prenatal diagnosis of a true knot of the umbilical cord: value and limitations. AB - OBJECTIVE: The purpose of this study was to examine the value of 3-dimensional power Doppler sonography in the prenatal diagnosis of a true knot of the umbilical cord. METHODS: Cases in which the diagnosis of a true knot of the umbilical cord was suspected by prenatal 2-dimensional sonography were reviewed. The presumably affected segment of the cord was examined with 3-dimensional power Doppler sonography for further characterization. Confirmation of the prenatal diagnosis was sought by reviewing the delivery records and contacting the referring obstetrician and the patients themselves. RESULTS: Eight consecutive cases were studied. Three-dimensional power Doppler sonography displayed a vascular spatial configuration pattern consistent with a true knot of the umbilical cord in all of them. However, the prenatal diagnosis was confirmed at delivery in only 5 cases (62.5%). Although there were no cases of a false knot mimicking a true knot of the umbilical cord, all incorrect diagnoses in this series were associated with multiple loops of the umbilical cord in the third trimester. CONCLUSIONS: Three-dimensional power Doppler sonography seems to be helpful in determining the presence of a true knot of the umbilical cord in utero, especially in the second trimester. However, this should not be considered a definitive method for the diagnosis because multiple loops of the umbilical cord lying close to each other can generate a sonographic image that can be undistinguishable from a true knot of the umbilical cord prenatally, especially when located in a small pocket of amniotic fluid. Therefore, the presumable diagnosis of a true knot of the umbilical cord in utero should be taken with caution. PMID- 17715315 TI - Sonographic detection of trisomy 13 in the first and second trimesters of pregnancy. AB - OBJECTIVE: The purpose of this study was to examine sonographic findings in fetuses with trisomy 13. METHODS: A retrospective review of the cytogenetic laboratory databases at 6 tertiary referral centers identified all cases of trisomy 13. The prenatal sonographic studies in fetuses of less than 22 weeks' gestation, done before invasive testing for karyotype, were reviewed for anatomic and biometric findings. We defined abnormal fetal biometric findings as a biometric measurement (biparietal diameter, abdominal circumference, or femur length) below the fifth percentile in the second trimester. RESULTS: There were 8 cases of trisomy 13 found in the first trimester and 54 cases found in the second trimester, a total of 62 in all. In the first trimester, 6 of 8 had an anomaly identified (4 with cystic hygroma). In the second trimester, 49 of 54 were identified by sonography; 45 had an anomaly, and 4 had an abnormal fetal biometric measurement without an anomaly. The 5 missed diagnoses had early gestational age (<17 weeks; n = 3) or an inadequate survey secondary to poor visualization. Overall, 22 of 54 fetuses with trisomy 13 had an abnormal biometric measurement. The most common anomalies detected in the second trimester were heart defects (n = 34), central nervous system anomalies (n = 30), facial clefts (n = 19), abnormal hands (n = 13), and genitourinary anomalies (n = 9). CONCLUSIONS: Targeted sonography identified abnormal fetal anatomy or abnormal biometric measurements in 95% of fetuses with trisomy 13 in the second trimester after 17 weeks' gestation. A biometric measurement below the fifth percentile was noted in nearly half of cases in the second trimester. PMID- 17715317 TI - Increased detection of early vascular abnormalities after renal biopsies by color Doppler sonography. AB - OBJECTIVE: The purpose of this study was to assess the frequency of abnormal vascular findings after renal biopsies as detected by color and pulsed Doppler sonography. METHODS: With both color and pulsed Doppler sonography, we examined 77 patients who underwent a renal biopsy of a native kidney. The examination was carried out before and immediately after the biopsy. A follow-up sonographic assessment was performed 24 hours later. If abnormal vascular findings were detected, the patients were reexamined after 2 weeks or even for a longer period. RESULTS: Tissue samples suitable for histologic diagnosis were obtained in 94% of the biopsies. In 17 of 77 patients, changes were observed in the color and pulsed Doppler examination immediately after the biopsy. A small localized flow disturbance was diagnosed in 10 kidneys, and a color tract was seen in 7. In 1 case, this tract was associated with a small localized flow disturbance. In 2 other patients, a localized flow disturbance was detected only in the examination performed 24 hours after the biopsy. Eight of the 10 flow disturbances diagnosed immediately after the biopsy and all tracts were not visible at the 24-hour follow-up examination. All these vascular findings were undetectable on sonographic examination without color and pulsed Doppler imaging. CONCLUSIONS: The results indicate that vascular lesions, detectable with color and pulsed Doppler sonography, are not rare findings early after renal biopsies. These vascular findings show a high rate of spontaneous resolution within the first 24 hours. PMID- 17715318 TI - Inflammatory myofibroblastic tumor of the paratestis: sonographic appearance with pathologic correlation. PMID- 17715319 TI - Sclerosing lipogranuloma of the scrotum: sonographic findings and pathologic correlation. PMID- 17715320 TI - Percutaneous intrauterine laser ablation of the abnormal vessel in pulmonary sequestration with hydrops at 29 weeks' gestation. PMID- 17715321 TI - Prenatal diagnosis of isolated laryngeal atresia: case report and literature review. PMID- 17715322 TI - Segmental dilatation of the ileum: diagnostic clarification by prenatal and postnatal imaging. PMID- 17715323 TI - Prenatal sonographic diagnosis of a hiatal hernia in a fetus with asplenia syndrome. PMID- 17715324 TI - Sonographic diagnosis of an inverted Meckel diverticulum: distinct criteria enable the correct diagnosis. PMID- 17715325 TI - Pneumobilia caused by a clostridial liver abscess: rapid diagnosis by bedside sonography in the intensive care unit. PMID- 17715326 TI - Molecular characterization of clinical isolates of Mycobacterium tuberculosis and their association with phenotypic virulence in human macrophages. AB - Among 125 clinical isolates of Mycobacterium tuberculosis collected in Hong Kong and Shanghai, China, between 2002 and 2004, IS6110 typing revealed that 71 strains (57%) belonged to the Beijing family. The intracellular growth of the strains in human peripheral blood monocyte-derived macrophages was measured ex vivo on days 0, 3, 6, and 10. Among all tested strains, three hypervirulent strains showed significant increases in intracellular growth after 10 days of incubation. With an initial bacterial load of 10(4) CFU, most of the clinical isolates and H37Ra (an avirulent strain) exhibited no intracellular survival on day 10, while the three hypervirulent strains together with H37Rv (a virulent strain) showed on average a two- to fourfold rise in CFU count. These three hypervirulent strains belonging to a non-Beijing family were isolated from patients suffering from tuberculosis meningitis. Cytokines secreted by gamma interferon-activated macrophages were measured daily after challenge with selected strains of M. tuberculosis. The levels of tumor necrosis factor alpha were elevated after 24 h of infection among all strains, but the levels were significantly lower among the three hypervirulent strains, whereas interleukin 10 (IL-10) and IL-12 were not detected. Results were concordant with the differential expression of the corresponding cytokine genes in activated macrophages, as monitored by real-time PCR. Our findings highlighted that these three hypervirulent strains may possess an innate mechanism for escaping host immunity, which accounts for their characteristic virulence in patients presenting with a more severe form of disease. PMID- 17715327 TI - Improved efficacy of a licensed acellular pertussis vaccine, reformulated in an adjuvant emulsion of liposomes in oil, in a murine model. AB - The immunogenicities and efficacies of a licensed diphtheria, tetanus, acellular pertussis, and inactivated poliovirus vaccine and the same vaccine formulated in a liposome/oil emulsion adjuvant were compared in a mouse model of pertussis respiratory infection. A single dose of the liposome/oil emulsion-adjuvanted vaccine produced significantly higher antibody levels than one dose of the licensed vaccine and protected mice from Bordetella pertussis infection with an efficacy equivalent to that of three doses of the licensed vaccine. PMID- 17715328 TI - Synthetic Toll-like receptor 4 agonist enhances vaccine efficacy in an experimental model of toxic shock syndrome. AB - The development of new protein subunit vaccines has stimulated the search for improved adjuvants to replace traditional aluminum-containing products. We investigated the adjuvant effects of a synthetic Toll-like receptor 4 (TLR4) agonist on vaccine efficacy in an experimental model of toxic shock syndrome. The TLR4 agonist E6020 has a simplified structure consisting of a hexa-acylated acyclic backbone. The vaccine examined is a recombinantly attenuated form of staphylococcal enterotoxin B (STEBVax). Using cells stably transfected with TLRs, E6020 transduced signals only through TLR4, suggesting monospecificity, while Escherichia coli 055:B5 lipopolysaccharide activated both the TLR2/6 heterodimer and TLR4. Coadministration of E6020 with STEBVax, by the intramuscular or intranasal route, induced significant levels of immunoglobulin G (IgG) in BALB/c mice. Further, increased IgG production resulted from the combination of E6020 with aluminum hydroxide adjuvant (AH). The antibody response to the vaccine coadministered with E6020 was a mixed Th1/Th2 response, as opposed to the Th2 biased response obtained with AH. Mice vaccinated with STEBVax coadministered with AH, TLR4 agonists, or a combination of both adjuvants were protected from toxic shock. Our data demonstrate the effectiveness of the synthetic TLR4 agonist E6020 as an alternative adjuvant for protein subunit vaccines that may also be used in combination with traditional aluminum-containing adjuvants. PMID- 17715329 TI - Monkeypox-induced immunity and failure of childhood smallpox vaccination to provide complete protection. AB - Following the U.S. monkeypox outbreak of 2003, blood specimens and clinical and epidemiologic data were collected from cases, defined by standard definition, and household contacts of cases to evaluate the role of preexisting (smallpox vaccine derived) and acquired immunity in susceptibility to monkeypox disease and clinical outcomes. Orthopoxvirus-specific immunoglobulin G (IgG), IgM, CD4, CD8, and B-cell responses were measured at approximately 7 to 14 weeks and 1 year postexposure. Associations between immune responses, smallpox vaccination, and epidemiologic and clinical data were assessed. Participants were categorized into four groups: (i) vaccinated cases, (ii) unvaccinated cases, (iii) vaccinated contacts, and (iv) unvaccinated contacts. Cases, regardless of vaccination status, were positive for orthopoxvirus-specific IgM, IgG, CD4, CD8, and B-cell responses. Antiorthopoxvirus immune responses consistent with infection were observed in some contacts who did not develop monkeypox. Vaccinated contacts maintained low levels of antiorthopoxvirus IgG, CD4, and B-cell responses, with most lacking IgM or CD8 responses. Preexisting immunity, assessed by high antiorthopoxvirus IgG levels and childhood smallpox vaccination, was associated (in a nonsignificant manner) with mild disease. Vaccination failed to provide complete protection against human monkeypox. Previously vaccinated monkeypox cases manifested antiorthopoxvirus IgM and changes in antiorthopoxvirus IgG, CD4, CD8, or B-cell responses as markers of recent infection. Antiorthopoxvirus IgM and CD8 responses occurred most frequently in monkeypox cases (vaccinated and unvaccinated), with IgG, CD4, and memory B-cell responses indicative of vaccine derived immunity. Immune markers provided evidence of asymptomatic infections in some vaccinated, as well as unvaccinated, individuals. PMID- 17715330 TI - Prospective study to determine accuracy of rapid serological assays for diagnosis of acute dengue virus infection in Laos. AB - There is an urgent need for accurate and simple dengue virus infection diagnostic assays in limited-resource settings of dengue endemicity, to assist patient management. Using a panel of reference samples (S. D. Blacksell, P. N. Newton, D. Bell, J. Kelley, M. P. Mammen, D. W. Vaughn, V. Wuthiekanun, A. Sungkakum, A. Nisalak, and N. P. Day, Clin. Infect. Dis. 42:1127-1134, 2006), we recently evaluated eihgt commercially available immunochromatographic rapid diagnostic tests (RDTs) designed to detect dengue virus-specific immunoglobulin M (IgM) and/or IgG. We found that 6/8 RDTs had sensitivities of less than 50% (range, 6 to 65%), but specificities were generally high. Here, in conjuction with dengue virus serotyping by reverse transcriptase PCR and in the limited-resource setting of Laos, where dengue virus is endemic, we evaluated the same eight RDTs against a previously validated dengue IgM/IgG enzyme-linked immunosorbent assay for diagnosis of acute dengue virus infection. Paired serum samples were collected from 87 patients, of whom 38 had confirmed dengue virus infections (4 had primary infections, 33 had secondary infections, and 1 had an infection of indeterminate status). RDT sensitivity was low, with 7/8 RDTs having admission sample sensitivities of less than 20% (range, 4 to 26%). The majority (6/8) of the RDTs, demonstrated high specificity (>95%). Kappa statistic values ranged from 6 to 54% for the RDTs, demonstrating poor to moderate variation between three operators. No RDT adequately differentiated between primary and secondary dengue virus infections. The findings of this study suggest that currently available RDTs based on the detection of IgM antibodies for the diagnosis of acute dengue virus infections are unlikely to be useful for patient management. PMID- 17715332 TI - Partial protection against Brucella infection in mice by immunization with nonpathogenic alphaproteobacteria. AB - Previous findings indicate that Brucella antigens and those from nonpathogenic alphaproteobacteria (NPAP) are cross-recognized by the immune system. We hypothesized that immunization with NPAP would protect mice from Brucella infection. Mice were immunized subcutaneously with heat-killed Ochrobactrum anthropi, Sinorhizobium meliloti, Mesorhizobium loti, Agrobacterium tumefaciens, or Brucella melitensis H38 (standard positive control) before intravenous challenge with Brucella abortus 2308. Cross-reacting serum antibodies against Brucella antigens were detected at the moment of challenge in all NPAP-immunized mice. Thirty days after B. abortus challenge, splenic CFU counts were significantly lower in mice immunized with O. anthropi, M. loti, and B. melitensis H38 than in the phosphate-buffered saline controls (protection levels were 0.80, 0.66, and 1.99 log units, respectively). In mice immunized intraperitoneally with cytosoluble extracts from NPAP or Brucella abortus, protection levels were 1.58 for the latter, 0.63 for O. anthropi, and 0.40 for M. loti. To test whether the use of live NPAP would increase protection further, mice were both immunized and challenged by the oral route. Immunization with NPAP induced a significant increase in serum immunoglobulin G (IgG), but not serum or fecal IgA, against Brucella antigens. After challenge, anti-Brucella IgA increased significantly in the sera and feces of mice orally immunized with O. anthropi. For all NPAP, protection levels were higher than those obtained with systemic immunizations but were lower than those obtained by oral immunization with heat-killed B. abortus. These results show that immunization with NPAP, especially O. anthropi, confers partial protection against Brucella challenge. However, such protection is lower than that conferred by immunization with whole Brucella or its cytosoluble fraction. PMID- 17715331 TI - Monoclonal antibody to fungal glucosylceramide protects mice against lethal Cryptococcus neoformans infection. AB - Glucosylceramides (GlcCer) are involved in the regulation of Cryptococcus neoformans virulence. In the present study, we demonstrate that passive immunization with a monoclonal antibody to GlcCer significantly reduces host inflammation and prolongs the survival of mice lethally infected with C. neoformans, revealing a potential therapeutic strategy to control cryptococcosis. PMID- 17715333 TI - European multicenter evaluation of commercial enzyme immunoassays for detecting norovirus antigen in fecal samples. AB - A total of 2,254 fecal samples were tested in a European multicenter evaluation of commercially available norovirus antigen detection assays. Two commercial enzyme immunoassays, IDEIA Norovirus (Oxoid; Thermo Fisher Scientific, Ely, United Kingdom) and RIDASCREEN Norovirus (R-Biopharm, Darmstadt, Germany), were included in the evaluation, and their performance was compared with the results of reverse transcription-PCR (RT-PCR). Included in the evaluation were samples collected in sporadic cases of gastroenteritis, samples from outbreaks in which two or more samples were collected, well-characterized samples representing genotypes currently cocirculating within Europe, and samples collected from patients with gastroenteritis caused by a pathogen other than norovirus. The sensitivities and specificities of the IDEIA Norovirus and RIDASCREEN Norovirus assays were 58.93 and 43.81% and 93.91 and 96.37%, respectively, compared with RT PCR. The sensitivities of both assays for outbreak investigations improved when six or more samples from an outbreak were examined. The IDEIA Norovirus assay exhibited reactivity to a broader range of norovirus genotypes than the RIDASCREEN Norovirus assay, which showed genotype-dependent sensitivities. The results indicate that, if used, these assays should serve as screening assays and the results should be confirmed by RT-PCR. PMID- 17715334 TI - Selective pressures of HLA genotypes and antiviral therapy on human immunodeficiency virus type 1 sequence mutation at a population level. AB - The objective of this study was a comprehensive analysis of the immune-driven evolution of viruses of human immunodeficiency virus type 1 (HIV-1) clade B in a large patient cohort treated at a single hospital in Germany and its implications for antiretroviral therapy. We examined the association of the HLA-A, HLA-B, and HLA-DRB1 alleles with the emergence of mutations in the complete protease gene and the first 330 codons of the reverse transcriptase (RT) gene of HIV-1, studying their distribution and persistence and their impact on antiviral drug therapy. The clinical data for 179 HIV-infected patients, the results of HLA genotyping, and virus sequences were analyzed using a variety of statistical approaches. We describe new HLA-associated mutations in both viral protease and RT, several of which are associated with HLA-DRB1. The mutations reported are remarkably persistent within our cohort, developing more slowly in a minority of patients. Interestingly, several HLA-associated mutations occur at the same positions as drug resistance mutations in patient viruses, where the viral sequence was acquired before exposure to these drugs. The influence of HLA on thymidine analogue mutation pathways was not observed. We were able to confirm immune-driven selection pressure by major histocompatibility complex (MHC) class I and II alleles through the identification of HLA-associated mutations. HLA-B alleles were involved in more associations (68%) than either HLA-A (23%) or HLA DRB1 (9%). As several of the HLA-associated mutations lie at positions associated with drug resistance, our results indicate possible negative effects of HLA genotypes on the development of HIV-1 drug resistance. PMID- 17715337 TI - Dendritic spikes in apical dendrites of neocortical layer 2/3 pyramidal neurons. AB - Layer 2/3 (L2/3) pyramidal neurons are the most abundant cells of the neocortex. Despite their key position in the cortical microcircuit, synaptic integration in dendrites of L2/3 neurons is far less understood than in L5 pyramidal cell dendrites, mainly because of the difficulties in obtaining electrical recordings from thin dendrites. Here we directly measured passive and active properties of the apical dendrites of L2/3 neurons in rat brain slices using dual dendritic somatic patch-clamp recordings and calcium imaging. Unlike L5 cells, L2/3 dendrites displayed little sag in response to long current pulses, which suggests a low density of I(h) in the dendrites and soma. This was also consistent with a slight increase in input resistance with distance from the soma. Brief current injections into the apical dendrite evoked relatively short (half-width 2-4 ms) dendritic spikes that were isolated from the soma for near-threshold currents at sites beyond the middle of the apical dendrite. Regenerative dendritic potentials and large concomitant calcium transients were also elicited by trains of somatic action potentials (APs) above a critical frequency (130 Hz), which was slightly higher than in L5 neurons. Initiation of dendritic spikes was facilitated by backpropagating somatic APs and could cause an additional AP at the soma. As in L5 neurons, we found that distal dendritic calcium transients are sensitive to a long-lasting block by GABAergic inhibition. We conclude that L2/3 pyramidal neurons can generate dendritic spikes, sharing with L5 pyramidal neurons fundamental properties of dendritic excitability and control by inhibition. PMID- 17715335 TI - Functional organization of presynaptic metabotropic glutamate receptors in vagal brainstem circuits. AB - We demonstrated previously that, by suppressing cAMP levels, metabotropic glutamate receptors (mGluRs) play a crucial role in opioid receptor trafficking on GABAergic nerve terminals within gastric brainstem vagal circuits. Using whole cell patch-clamp recordings, we aimed to correlate the influence of sensory vagal afferent fibers with the functional organization of mGluRs on the synaptic connections between the nucleus tractus solitarius and dorsal motor nucleus of the vagus. Group II mGluRs were identified on both excitatory and inhibitory synapses; the receptor-selective agonist APDC [(2R,4R)-4-aminopyrrolidine-2,4 dicarboxylate] induced a concentration-dependent decrease in glutamatergic and GABAergic synaptic transmission (EC50, approximately 20 microM for both). The group II mGluRs were activated tonically on GABAergic, but not glutamatergic synapses, as the receptor-selective antagonist (2S)-alpha-ethylglutamic acid (EGLU; 200 microM) modulated GABA currents only. After selective vagal deafferentation, EGLU was without effect, suggesting that vagal afferent (sensory) fibers are the source of this tonic input. Conversely, group III mGluRs, although not activated tonically, were present on excitatory, but not inhibitory, synapses; in fact, the receptor-selective agonist L-AP-4 [L-(+)-2 amino-4-phosphonbutyric acid] induced a concentration-dependent decrease in glutamatergic synaptic transmission (EC50, approximately 2 microM) but had no effect on GABAergic synaptic transmission. Together with our previous results on receptor trafficking, these data suggest that visceral information plays a fundamental role in shaping the response of homeostatic brainstem circuits that receive inputs from higher integrative neuronal centers. PMID- 17715336 TI - Longitudinal evaluation of the Hdh(CAG)150 knock-in murine model of Huntington's disease. AB - Several murine genetic models of Huntington's disease (HD) have been developed. Murine genetic models are crucial for identifying mechanisms of neurodegeneration in HD and for preclinical evaluation of possible therapies for HD. Longitudinal analysis of mutant phenotypes is necessary to validate models and to identify appropriate periods for analysis of early events in the pathogenesis of neurodegeneration. Here we report longitudinal characterization of the murine Hdh(CAG)150 knock-in model of HD. A series of behavioral tests at five different time points (20, 40, 50, 70, and 100 weeks) demonstrates an age-dependent, late onset behavioral phenotype with significant motor abnormalities at 70 and 100 weeks of age. Pathological analysis demonstrated loss of striatal dopamine D1 and D2 receptor binding sites at 70 and 100 weeks of age, and stereological analysis showed significant loss of striatal neuron number at 100 weeks. Late-onset behavioral abnormalities, decrease in striatal dopamine receptors, and diminished striatal neuron number observed in this mouse model recapitulate key features of HD. The Hdh(CAG)150 knock-in mouse is a valid model to evaluate early events in the pathogenesis of neurodegeneration in HD. PMID- 17715338 TI - Sulfatide storage in neurons causes hyperexcitability and axonal degeneration in a mouse model of metachromatic leukodystrophy. AB - Metachromatic leukodystrophy is a lysosomal storage disorder caused by deficiency in the sulfolipid degrading enzyme arylsulfatase A (ASA). In the absence of a functional ASA gene, 3-O-sulfogalactosylceramide (sulfatide; SGalCer) and other sulfolipids accumulate. The storage is associated with progressive demyelination and various finally lethal neurological symptoms. Lipid storage, however, is not restricted to myelin-producing cells but also occurs in neurons. It is unclear whether neuronal storage contributes to symptoms of the patients. Therefore, we have generated transgenic ASA-deficient [ASA(-/-)] mice overexpressing the sulfatide synthesizing enzymes UDP-galactose:ceramide galactosyltransferase (CGT) and cerebroside sulfotransferase (CST) in neurons to provoke neuronal lipid storage. CGT-transgenic ASA(-/-) [CGT/ASA(-/-)] mice showed an accumulation of C18:0 fatty acid-containing SGalCer in the brain. Histochemically, an increase in sulfolipid storage could be detected in central and peripheral neurons of both CGT/ASA(-/-) and CST/ASA(-/-) mice compared with ASA(-/-) mice. CGT/ASA(-/-) mice developed severe neuromotor coordination deficits and weakness of hindlimbs and forelimbs. Light and electron microscopic analyses demonstrated nerve fiber degeneration in the spinal cord of CGT/ASA(-/-) mice. CGT/ASA(-/-) and, to a lesser extent, young ASA(-/-) mice exhibited cortical hyperexcitability, with recurrent spontaneous cortical EEG discharges lasting 5-15 s. These observations suggest that SGalCer accumulation in neurons contributes to disease phenotype. PMID- 17715339 TI - Activation of presynaptic GABA(A) receptors induces glutamate release from parallel fiber synapses. AB - The parallel fibers relay information coming into the cerebellar cortex from the mossy fibers, and they form synapses with molecular layer interneurons (MLIs) and Purkinje cells. Here we show that activation of ionotropic GABA receptors (GABA(A)Rs) induces glutamate release from parallel fibers onto both MLIs and Purkinje cells. These GABA-induced EPSCs have kinetics and amplitudes identical to random spontaneous currents (sEPSCs), but, unlike sEPSCs, they occur in bursts of between one and five successive events. The variation in amplitude of events within bursts is significantly less than the variation of all sEPSC amplitudes, suggesting that the bursts result from repetitive activation of single presynaptic fibers. Electron microscopy of immunogold-labeled alpha-1 subunits revealed GABA(A)Rs on parallel fiber terminals. We suggest that the activation of these receptors underlies the increased amplitude of parallel fiber-evoked Purkinje cell EPSCs seen with application of exogenous GABA or after the release of GABA from local interneurons. These results occur only when molecular layer GABA(A)Rs are activated, and the effects are abolished when the receptors are blocked by the GABA(A)R antagonist gabazine (5 microM). From these data, we conclude that GABA(A)Rs located on parallel fibers depolarize parallel fiber terminals beyond the threshold for Na+ channel activation and thereby induce glutamate release onto MLIs and Purkinje cells. PMID- 17715341 TI - Dark rearing rescues P23H rhodopsin-induced retinal degeneration in a transgenic Xenopus laevis model of retinitis pigmentosa: a chromophore-dependent mechanism characterized by production of N-terminally truncated mutant rhodopsin. AB - To elucidate the molecular mechanisms underlying the light-sensitive retinal degeneration caused by the rhodopsin mutation P23H, which causes retinitis pigmentosa (RP) in humans, we expressed Xenopus laevis, bovine, human, and murine forms of P23H rhodopsin in transgenic X. laevis rod photoreceptors. All P23H rhodopsins caused aggressive retinal degeneration associated with low expression levels and retention of P23H rhodopsin in the endoplasmic reticulum (ER), suggesting involvement of protein misfolding and ER stress. However, light sensitivity varied dramatically between these RP models, with complete or partial rescue by dark rearing in the case of bovine and human P23H rhodopsin, and no rescue for X. laevis P23H rhodopsin. Rescue by dark rearing required an intact 11 cis-retinal chromophore binding site within the mutant protein and was associated with truncation of the P23H rhodopsin N terminus. This yielded an abundant nontoxic approximately 27 kDa form that escaped the ER and was transported to the rod outer segment. The truncated protein was produced in the greatest quantities in dark-reared retinas expressing bovine P23H rhodopsin and was not observed with X. laevis P23H rhodopsin. These results are consistent with a mechanism involving enhanced protein folding in the presence of 11-cis-retinal chromophore, with ER exit assisted by proteolytic truncation of the N terminus. This study provides a molecular mechanism for light sensitivity observed in other transgenic models of RP and for phenotypic variation among RP patients. PMID- 17715340 TI - Angiotensin II controls occludin function and is required for blood brain barrier maintenance: relevance to multiple sclerosis. AB - The blood-brain barrier (BBB) restricts molecular and cellular trafficking between the blood and the CNS. Although astrocytes are known to control BBB permeability, the molecular determinants of this effect remain unknown. We show that angiotensinogen (AGT) produced and secreted by astrocytes is cleaved into angiotensin II (AngII) and acts on type 1 angiotensin receptors (AT1) expressed by BBB endothelial cells (ECs). Activation of AT1 restricts the passage of molecular tracers across human BBB-derived ECs through threonine-phosphorylation of the tight junction protein occludin and its mobilization to lipid raft membrane microdomains. We also show that AGT knock-out animals have disorganized occludin strands at the level of the BBB and a diffuse accumulation of the endogenous serum protein plasminogen in the CNS, compared with wild-type animals. Finally, we demonstrate a reduction in the number of AGT-immunopositive perivascular astrocytes in multiple sclerosis (MS) lesions, which correlates with a reduced expression of occludin similarly seen in the CNS of AGT knock-out animals. Such a reduction in astrocyte-expressed AGT and AngII is dependent, in vitro, on the proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma. Our study defines a novel physiological role for AngII in the CNS and suggests that inflammation-induced downregulation of AngII production by astrocytes is involved in BBB dysfunction in MS lesions. PMID- 17715342 TI - Actin polymerization and ERK phosphorylation are required for Arc/Arg3.1 mRNA targeting to activated synaptic sites on dendrites. AB - The mRNA for the immediate early gene Arc/Arg3.1 is induced by strong synaptic activation and is rapidly transported into dendrites, where it localizes at active synaptic sites. NMDA receptor activation is critical for mRNA localization at active synapses, but downstream events that mediate localization are not known. The patterns of synaptic activity that induce mRNA localization also trigger a dramatic polymerization of actin in the activated dendritic lamina and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) throughout the postsynaptic cytoplasm. The local polymerization of actin in the activated dendritic lamina is of particular interest because it occurs in the same dendritic domains in which newly synthesized Arc/Arg3.1 mRNA localizes. Here, we explore the role of activity-induced alterations in the actin network and mitogen activated protein (MAP) kinase activation in Arc/Arg3.1 mRNA localization. We show that actin polymerization induced by high-frequency stimulation is blocked by local inhibition of Rho kinase, and Arc/Arg3.1 mRNA localization is abrogated in the region of Rho kinase blockade. Local application of latrunculin B, which binds to actin monomers and inhibits actin polymerization, also blocked the targeting of Arc/Arg3.1 mRNA to activated synaptic sites. Local application of the MAP kinase kinase inhibitor U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-amino phenylthio]butadiene) blocked ERK phosphorylation, and also blocked Arc/Arg3.1 mRNA localization. Our results indicate that the reorganization of the actin cytoskeletal network in conjunction with MAP kinase activation is required for targeting newly synthesized Arc/Arg3.1 mRNA to activated synaptic sites. PMID- 17715343 TI - Astroglial glutamate-glutamine shuttle is involved in central sensitization of nociceptive neurons in rat medullary dorsal horn. AB - Growing evidence suggests that astroglia are involved in pain states, but no studies have tested their possible involvement in modulating the activity of nociceptive neurons per se. This study has demonstrated that the central sensitization induced in functionally identified nociceptive neurons in trigeminal subnucleus caudalis (the medullary dorsal horn) by application of an inflammatory irritant to the rat's tooth pulp can be significantly attenuated by continuous intrathecal superfusion of methionine sulfoximine (MSO; 0.1 mM), an inhibitor of the astroglial enzyme glutamine synthetase that is involved in the glutamate-glutamine shuttle. Simultaneous superfusion of MSO and glutamine (0.25 mM) restored the irritant-induced central sensitization. In control experiments, superfusion of either MSO or glutamine alone, or vehicle, did not produce any significant changes in neuronal properties. These findings suggest that the astroglial glutamate-glutamine shuttle is essential for the initiation of inflammation-induced central sensitization but that inhibition of astroglial function may not affect normal nociceptive processing. PMID- 17715344 TI - Metabotropic glutamate 2/3 receptors in the ventral tegmental area and the nucleus accumbens shell are involved in behaviors relating to nicotine dependence. AB - The motivation to maintain nicotine self-administration and dependence may involve alterations in glutamatergic neurotransmission. Metabotropic glutamate (mGlu) 2/3 receptors regulate glutamate and dopamine release in the ventral tegmental area (VTA) and the nucleus accumbens (NAc) shell, two brain areas critically involved in reward and motivational processes. We found that acute systemic, as well as intra-VTA or intra-NAc, administration of the mGlu2/3 receptor agonist LY379268 [(-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6 dicarboxylate] decreased nicotine, but not food, self-administration in rats. In addition, nicotine self-administration downregulated mGlu2/3 receptor function in corticolimbic rat brain sites including the VTA and the NAc, demonstrated by decreased coupling of mGlu2/3 receptors to G-proteins in the [35S]GTPgammaS binding assay. Furthermore, repeated treatment with LY379268 reduced nicotine self-administration at the beginning of a 14 d treatment period; however, the number of nicotine infusions earned gradually returned to baseline levels, indicating tolerance to the effects of repeated LY379268 treatment. Finally, LY379268 administration decreased both cue-induced reinstatement of nicotine- and food-seeking behavior. Together, these findings indicate an important role for mGlu2/3 receptors in the posterior VTA and the NAc shell in the mediation of the rewarding effects of nicotine and potentially in cue-induced nicotine-seeking behavior. PMID- 17715345 TI - Ca2+/calmodulin regulates trafficking of Ca(V)1.2 Ca2+ channels in cultured hippocampal neurons. AB - As the Ca2+-sensor for Ca2+-dependent inactivation, calmodulin (CaM) has been proposed, but never definitively demonstrated, to be a constitutive Ca(V)1.2 Ca2+ channel subunit. Here we show that CaM is associated with the Ca(V)1.2 pore forming alpha1C subunit in brain in a Ca2+-independent manner. Within its CaM binding pocket, alpha1C has been proposed to contain a membrane targeting domain. Because ion channel subunits assemble early during channel biosynthesis, we postulated that this association with CaM could afford the opportunity for Ca2+ dependent regulation of membrane targeting. We showed that the isolated domain functioned as a Ca2+/CaM regulated trafficking determinant for CD8 (a model transmembrane protein) using fluorescent-activated cell sorting analysis and, using green fluorescent protein-tagged alpha1C subunits expressed in cultured hippocampal neurons, that Ca2+/CaM interaction with this domain accelerated trafficking of Ca(V)1.2 channels to distal regions of the dendritic arbor. Furthermore, this Ca2+/CaM-accelerated trafficking was activity dependent. Thus, CaM imparts Ca2+-dependent regulation not only to mature Ca(V)1.2 channels at the cell surface but also to steps during channel biosynthesis. PMID- 17715346 TI - Requirement for Slit-1 and Robo-2 in zonal segregation of olfactory sensory neuron axons in the main olfactory bulb. AB - The formation of precise stereotypic connections in sensory systems is critical for the ability to detect and process signals from the environment. In the olfactory system, olfactory sensory neurons (OSNs) project axons to spatially defined glomeruli within the olfactory bulb (OB). A spatial relationship exists between the location of OSNs within the olfactory epithelium (OE) and their glomerular targets along the dorsoventral axis in the OB. The molecular mechanisms underlying the zonal segregation of OSN axons along the dorsoventral axis of the OB are poorly understood. Using robo-2(-/-) (roundabout) and slit-1( /-) mice, we examined the role of the Slit family of axon guidance cues in the targeting of OSN axons during development. We show that a subset of OSN axons that normally project to the dorsal region of the OB mistarget and form glomeruli in the ventral region in robo-2(-/-) and slit-1(-/-) mice. In addition, we show that the Slit receptor, Robo-2, is expressed in OSNs in a high dorsomedial to low ventrolateral gradient across the OE and that Slit-1 and Slit-3 are expressed in the ventral region of the OB. These results indicate that the dorsal-to-ventral segregation of OSN axons are not solely defined by the location of OSNs within the OE but also relies on axon guidance cues. PMID- 17715347 TI - Odorant category profile selectivity of olfactory cortex neurons. AB - The olfactory cortex receives converging axonal inputs from many mitral and tufted cells in the olfactory bulb. Recent studies indicate that single cortical neurons integrate signals from diverse odorants. However, there remains a basic question, namely, the signals from which kinds of odorants are integrated by the individual cortical neurons? The present study examined the possibility that some cortical neurons integrate signals from distinct component odorants of natural foods because individual foods produce a fixed combination of odorants. Previous psychophysical studies of core odorants emitted by fruits and vegetables suggest that the olfactory images of individual natural foods are basically characterized by the profile of structural and perceptual categories of food-born odorants. The single-unit spike responses of neurons in the dorsoposterior part of rat anterior piriform cortex to a panel of eight food-related categories of odorants were herein examined. The results showed that many cortical neurons in this region are tuned selectively to either a single category or a specific combination of distinct categories. The cortical neurons showed mixture facilitation and mixture inhibition when stimulated with mixtures of distinct categories, thus suggesting that olfactory circuits may play a role in enhancing the category-profile selectivity of individual neurons. These results indicate that signals from distinct categories of food-born odorants are integrated in these cortical neurons. This suggests that these cortical neurons detect the odorant-category profile of foods to distinguish distinct food odors. PMID- 17715348 TI - Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. AB - Immunotherapies for various neurodegenerative diseases have recently emerged as a promising approach for clearing pathological protein conformers in these disorders. This type of treatment has not been assessed in models that develop neuronal tau aggregates as observed in frontotemporal dementia and Alzheimer's disease. Here, we present that active immunization with a phosphorylated tau epitope, in P301L tangle model mice, reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. Females had more tau pathology than males but were also more receptive to the immunotherapy. The tau antibodies generated in these animals recognized pathological tau on brain sections. Performance on behavioral assays that require extensive motor coordination correlated with tau pathology in corresponding brain areas, and antibody levels against the immunogen correlated inversely with tau pathology. Interestingly, age-dependent autoantibodies that recognized recombinant tau protein but not the immunogen were detected in the P301L mice. To confirm that anti-tau antibodies could enter the brain and bind to pathological tau, FITC tagged antibodies purified from a P301L mouse, with a high antibody titer against the immunogen, were injected into the carotid artery of P301L mice. These antibodies were subsequently detected within the brain and colocalized with PHF1 and MC1 antibodies that recognize pathological tau. Currently, no treatment is available for clearing tau aggregates. Our present findings may lead to a novel therapy targeting one of the major hallmarks of Alzheimer's disease and frontotemporal dementia. PMID- 17715350 TI - To do or not to do: the neural signature of self-control. AB - Voluntary action is fundamental to human existence. Recent research suggests that volition involves a specific network of brain activity, centered on the fronto median cortex. An important but neglected aspect of intentional action involves the decision whether to act or not. This decision process is crucial in daily life because it allows us to form intentions without necessarily implementing them. In the present study, we investigate the neural correlates of intentionally inhibiting actions using functional magnetic resonance imaging. Our data show that a specific area of the fronto-median cortex is more strongly activated when people prepare manual actions but then intentionally cancel them, compared with when they prepare and then complete the same actions. Our results suggest that the human brain network for intentional action includes a control structure for self-initiated inhibition or withholding of intended actions. The mental control of action has an enduring scientific interest, linked to the philosophical concept of "free will." Our results identify a candidate brain area that reflects the crucial decision to do or not to do. PMID- 17715351 TI - The inhibition site on myelin-associated glycoprotein is within Ig-domain 5 and is distinct from the sialic acid binding site. AB - Myelin-associated glycoprotein (MAG) is a potent inhibitor of axonal regeneration. It contains five Ig-like domains and is a sialic binding protein. Previously, we showed that the sialic acid binding site on MAG maps to arginine 118 in Ig domain 1 (Kelm et al., 1994). However, sialic acid binding was neither necessary nor sufficient for MAG to bring about inhibition of neurite outgrowth. Consistent with this, we now map a distinct inhibition site on MAG to Ig domain 5 (Ig-5). We show that when a truncated form of MAG missing Ig domains 1 and 2 is expressed by Chinese hamster ovary (CHO) cells, it does not bind sialic acid, but still inhibits neurite outgrowth almost as effectively as full-length MAG. To determine whether the inhibition site mapped to Ig-3, Ig-4, or Ig-5, we made chimeric molecules of various combinations of these three MAG Ig domains fused to Ig domains from another Ig family member, sialoadhesin (Sn), which also binds to sialic acid in the same linkage as MAG. The MAG-Sn molecules were expressed in CHO cells and all contained five Ig domains and were able to bind sialic acid. However, only the chimeric molecules containing MAG Ig-5 inhibited neurite outgrowth. Furthermore, peptides corresponding to sequences in MAG Ig-5, but not Ig-4 or Sn Ig-5, are able to block inhibition of neurite outgrowth by both wild type MAG and CNS myelin. We conclude that the inhibition site on MAG is carried by Ig domain 5 and that this site is distinct from the sialic-acid binding site. PMID- 17715349 TI - GABA(A) receptor-mediated signaling alters the structure of spontaneous activity in the developing retina. AB - Ambient GABA modulates firing patterns in adult neural circuits by tonically activating extrasynaptic GABA(A) receptors. Here, we demonstrate that during a developmental period when activation of GABA(A) receptors causes membrane depolarization, tonic activation of GABA(A) receptors blocks all spontaneous activity recorded in retinal ganglion cells (RGCs) and starburst amacrine cells (SACs). Bath application of the GABA(A) receptor agonist muscimol blocked spontaneous correlated increases in intracellular calcium concentration and compound postsynaptic currents in RGCs associated with retinal waves. In addition, GABA(A) receptor agonists activated a tonic current in RGCs that significantly reduced their excitability. Using a transgenic mouse in which green fluorescent protein is expressed under the metabotropic glutamate receptor subtype 2 promoter to target recordings from SACs, we found that GABA(A) receptor agonists blocked compound postsynaptic currents and also activated a tonic current. GABA(A) receptor antagonists reduced the holding current in SACs but not RGCs, indicating that ambient levels of GABA tonically activate GABA(A) receptors in SACs. GABA(A) receptor antagonists did not block retinal waves but did alter the frequency and correlation structure of spontaneous RGC firing. Interestingly, the drug aminophylline, a general adenosine receptor antagonist used to block retinal waves, induced a tonic GABA(A) receptor antagonist-sensitive current in outside-out patches excised from RGCs, indicating that aminophylline exerts its action on retinal waves by direct activation of GABA(A) receptors. These findings have implications for how various neuroactive drugs and neurohormones known to modulate extrasynaptic GABA(A) receptors may influence spontaneous firing patterns that are critical for the establishment of adult neural circuits. PMID- 17715352 TI - The tau N279K exon 10 splicing mutation recapitulates frontotemporal dementia and parkinsonism linked to chromosome 17 tauopathy in a mouse model. AB - Intracellular tau deposits are characteristic of several neurodegenerative disorders called tauopathies. The tau protein regulates the stability and assembly of microtubules by binding to microtubules through three or four microtubule-binding repeats (3R and 4R). The number of microtubule-binding repeats is determined by the inclusion or exclusion of the second microtubule binding repeat encoded by exon 10 of the TAU gene. TAU gene mutations that alter the inclusion of exon 10, and hence the 4R:3R ratio, are causal in the tauopathy frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). A mutation located in exon 10 has been identified in several FTDP-17 families that present with increased exon 10 inclusion in both mRNA and protein, parkinsonism, movement disorders, and dementia. We have engineered a human tau minigene construct that was designed to allow alternative splicing of the tau exon 10. Here we demonstrate that transgenic mice expressing human tau protein with this mutation develop neurodegeneration as result of aberrant splicing. The mice recapitulate many of the disease hallmarks that are seen in patients with this mutation, including increased tau exon 10 inclusion in both mRNA and protein, motor and behavioral deficits, and tau protein accumulation in neurons and tufted astrocytes. Furthermore, these mice present with degeneration of the nigrostriatal dopaminergic pathway, suggesting a possible mechanism for parkinsonism in FTDP-17. Additionally, activated caspase-3 immunoreactivity in both neurons and astrocytes implicates the involvement of the apoptotic pathway in the pathology of these mice. PMID- 17715353 TI - Disorganized microtubules underlie the formation of retraction bulbs and the failure of axonal regeneration. AB - Axons in the CNS do not regrow after injury, whereas lesioned axons in the peripheral nervous system (PNS) regenerate. Lesioned CNS axons form characteristic swellings at their tips known as retraction bulbs, which are the nongrowing counterparts of growth cones. Although much progress has been made in identifying intracellular and molecular mechanisms that regulate growth cone locomotion and axonal elongation, a comprehensive understanding of how retraction bulbs form and why they are unable to grow is still elusive. Here we report the analysis of the morphological and intracellular responses of injured axons in the CNS compared with those in the PNS. We show that retraction bulbs of injured CNS axons increase in size over time, whereas growth cones of injured PNS axons remain constant. Retraction bulbs contain a disorganized microtubule network, whereas growth cones possess the typical bundling of microtubules. Using in vivo imaging, we find that pharmacological disruption of microtubules in growth cones transforms them into retraction bulb-like structures whose growth is inhibited. Correspondingly, microtubule destabilization of sensory neurons in cell culture induces retraction bulb formation. Conversely, microtubule stabilization prevents the formation of retraction bulbs and decreases axonal degeneration in vivo. Finally, microtubule stabilization enhances the growth capacity of CNS neurons cultured on myelin. Thus, the stability and organization of microtubules define the fate of lesioned axonal stumps to become either advancing growth cones or nongrowing retraction bulbs. Our data pinpoint microtubules as a key regulatory target for axonal regeneration. PMID- 17715354 TI - High-resolution maps of real and illusory tactile activation in primary somatosensory cortex in individual monkeys with functional magnetic resonance imaging and optical imaging. AB - Although blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has been widely used to explore human brain function, questions remain regarding the ultimate spatial resolution of positive BOLD fMRI, and indeed the extent to which functional maps revealed by positive BOLD correlate spatially with maps obtained with other high-spatial-resolution mapping techniques commonly used in animals, such as optical imaging of intrinsic signal (OIS) and single-unit electrophysiology. Here, we demonstrate that the positive BOLD signal at 9.4T can reveal the fine topography of individual fingerpads in single-condition activation maps in nonhuman primates. These digit maps are similar to maps obtained from the same animal using intrinsic optical imaging. Furthermore, BOLD fMRI reliably resolved submillimeter spatial shifts in activation in area 3b previously identified with OIS (Chen et al., 2003) as neural correlates of the "funneling illusion." These data demonstrate that at high field, high-spatial-resolution topographic maps can be achieved using the positive BOLD signal, weakening previous notions regarding the spatial specificity of the positive BOLD signal. PMID- 17715355 TI - Excitatory synaptic transmission persists independently of the glutamate glutamine cycle. AB - The glutamate-glutamine cycle is thought to be integral in continuously replenishing the neurotransmitter pool of glutamate. Inhibiting glial transfer of glutamine to neurons leads to rapid impairment in physiological and behavioral function; however, the degree to which excitatory synaptic transmission relies on the normal operation of this cycle is unknown. In slices and cultured neurons from rat hippocampus, we enhanced the transfer of glutamine to neurons, a fundamental step in this cycle, by adding exogenous glutamine. Although raising glutamine augments synaptic transmission by increasing vesicular glutamate, access to this synthetic pathway by exogenously applied glutamine to neurons is delayed and slow, challenging mechanisms linking the rapid effects of pharmacological inhibitors to decreased vesicular glutamate. We find that pharmacological inhibitors of glutamine synthetase or system A transporters cause an acute depression of basal synaptic transmission that is rapidly reversible, which is unlikely to be attributable to the rapid loss of vesicular glutamate. Furthermore, release of vesicular glutamate remains robust even during the prolonged removal of glutamine from pure neuronal cultures. We conclude that neurons have the capacity to store or produce glutamate for long periods of time, independently of glia and the glutamate-glutamine cycle. PMID- 17715356 TI - Microarray analysis of the cellular pathways involved in the adaptation to and progression of motor neuron injury in the SOD1 G93A mouse model of familial ALS. AB - The cellular pathways of motor neuronal injury have been investigated in the SOD1 G93A murine model of familial amyotrophic lateral sclerosis (ALS) using laser capture microdissection and microarray analysis. The advantages of this study include the following: analysis of changes specifically in motor neurons (MNs), while still detecting effects of interactions with neighboring cells; the ability to profile changes during disease progression, an approach not possible in human ALS; and the use of transgenic mice bred on a homogeneous genetic background, eliminating the confounding effects arising from a mixed genetic background. By using this rigorous approach, novel changes in key cellular pathways have been detected at both the presymptomatic and late stages, which have been validated by quantitative reverse transcription-PCR. At the presymptomatic stage (60 d), MNs extracted from SOD1 G93A mice show a significant increase in expression of genes subserving both transcriptional and translational functions, as well as lipid and carbohydrate metabolism, mitochondrial preprotein translocation, and respiratory chain function, suggesting activation of a strong cellular adaptive response. Mice 90 d old still show upregulation of genes involved in carbohydrate metabolism, whereas transcription and mRNA processing genes begin to show downregulation. Late in the disease course (120 d), important findings include the following: marked transcriptional repression, with downregulation of multiple transcripts involved in transcriptional and metabolic functions; upregulation of complement system components; and increased expression of key cyclins involved in cell-cycle regulation. The changes described in the motor neuron transcriptome evolving during the disease course highlight potential novel targets for neuroprotective therapeutic intervention. PMID- 17715357 TI - Different species of alpha-synuclein oligomers induce calcium influx and seeding. AB - Aggregation of alpha-synuclein (alpha-syn) has been linked to the pathogenesis of Parkinson's disease (PD) and other neurodegenerative diseases. Increasing evidence suggests that prefibrillar oligomers and protofibrils, rather than mature fibrils of alpha-syn, are the pathogenic species in PD. Despite extensive effort on studying oligomerization of alpha-syn, no studies have compared different oligomer species directly on a single-particle level and investigated their biological effects on cells. In this study, we applied a novel highly sensitive single molecule detection system that allowed a direct comparison of different oligomer types. Furthermore, we studied biological effects of different oligomer types on cells. For this purpose, we developed new oligomerization protocols, that enabled the use of these different oligomers in cell culture. We found that all of our three aggregation protocols resulted in heterogeneous populations of oligomers. Some types of oligomers induced cell death via disruption of cellular ion homeostasis by a presumably pore-forming mechanism. Other oligomer types could directly enter the cell resulting in increased alpha syn aggregation. Based on our results, we propose that under various physiological conditions, heterogeneous populations of oligomeric forms will coexist in an equilibrium. These different oligomer types lead directly or indirectly to cell damage. Our data indicate that inhibition of early alpha-syn aggregation events would consequently prevent all alpha-syn oligomer related toxicities. This has important implications for the development of disease modifying drugs for the treatment of PD and other synucleinopathies. PMID- 17715358 TI - Human 5-HT transporter availability predicts amygdala reactivity in vivo. AB - The amygdala plays a central role in fear conditioning, emotional processing, and memory modulation. A postulated key component of the neurochemical regulation of amygdala function is the neurotransmitter 5-hydroxytryptamine (5-HT), and synaptic levels of 5-HT in the amygdala and elsewhere are critically regulated by the 5-HT transporter (5-HTT). The aim of this study was to directly examine the relationship between 5-HTT availability and amygdala activity using multimodal [positron emission tomography (PET) and functional magnetic resonance imaging (fMRI)] imaging measures in the same individuals. Healthy male volunteers who had previously undergone an [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl) benzonitrile ([11C]-DASB) PET scan to determine 5-HTT availability completed an fMRI emotion recognition task. [11C]-DASB binding potential values were calculated for the amygdala using arterial input function and linear graphical (Logan) analysis. fMRI was performed on a 3T Philips Intera scanner, and data were analyzed using SPM2 (Wellcome Department Imaging Neuroscience, University College London). Percentage signal change during the task was extracted from the amygdala using MarsBaR (Brett et al., 2002). fMRI analysis revealed significant amygdala activation during the emotion recognition task. Region of interest analyses demonstrated a significant negative correlation between fMRI signal change in the left amygdala and 5-HTT availability in the left amygdala, with 5 HTT availability accounting for approximately 42% of the variability in left amygdala activity. Our novel in vivo data highlight the central importance of the serotonergic system in the responsiveness of the human amygdala during emotional processing. PMID- 17715359 TI - Amplitude modulation patterns of local field potentials reveal asynchronous neuronal populations. AB - Neural oscillations, which appear in several areas of the nervous system and cover a wide frequency range, are a prominent issue in current neuroscience. Extracellularly recorded oscillations are generally thought to be a manifestation of a neural population with synchronized electrical activity resulting from coupling mechanisms. The vertebrate olfactory neuroepithelium exhibits beta-band oscillations, termed peripheral waves (PWs), in their population response to odor stimulation. Here, we examine PWs in the channel catfish and propose that their properties could be explained as the superposition of asynchronous oscillators. Our model shows that the intriguing random pattern of amplitude-modulated PWs could be explained by Rayleigh fading, an interference phenomenon well known in physics and recognizable using statistical methods and signal analysis. We are proposing a mathematical fingerprint to characterize neural signals generated by the addition of random phase oscillators. Our interpretation of PWs as arising from asynchronous oscillators could be generalized to other neuronal populations, because it suggests that neural oscillations, detected in local field potential recordings within a narrow frequency band, do not necessarily originate from synchronization events. PMID- 17715360 TI - Annexin A2 is a soluble mediator of macrophage activation. AB - On the surface of the macrophage, annexin A2 tetramer (A2t) serves as a docking protein or recognition element for bacterial and viral pathogens. Plasma levels of free A2t have been reported to increase following infection, although the mechanistic significance of this observation is unclear. Although annexin A2 had generally been thought to play an anti-inflammatory role, soluble A2t stimulates MAP kinase activity in bone marrow stromal cells downstream of a recently cloned receptor. This raises the question of whether A2t activates human macrophages via MAP kinases and whether it might be capable of acting as an inflammatory mediator. To this end, human monocyte-derived macrophages were treated with soluble A2t and MAP kinase phosphorylation, p65 NF-kappaB activation, and inflammatory mRNA and protein levels were measured. It was found that A2t caused rapid phosphorylation of several MAP kinases, as well as translocation of p65 NF kappaB to the nucleus. A2t stimulated the production of TNF-alpha, IL-1beta, and IL-6, as well as several members of the chemokine family within 24 h, which are capable of recruitment and/or activation of a broad range of leukocyte classes. Furthermore, A2t-activated macrophages demonstrated enhanced phagocytic ability for the ingestion of GFP-expressing Escherichia coli. These data are the first to suggest the participation of an annexin in microbial clearance, as well as the establishment of inflammation and the immune response, including the recruitment and activation of immune cells to the site of infection. PMID- 17715361 TI - Roles of Candida albicans Sfl1 in hyphal development. AB - The ability to switch between different morphological forms is an important feature of Candida albicans and is relevant to its pathogenesis. Many conserved positive and negative transcription factors are involved in morphogenetic regulation of the two dimorphic fungi Candida albicans and Saccharomyces cerevisiae. In S. cerevisiae, the transcriptional repressor Sfl1 and the activator Flo8 function antagonistically in invasive and filamentous growth. We have previously reported that Candida albicans Flo8 is a transcription factor essential for hyphal development and virulence in C. albicans. To determine whether a similar negative factor exists in C. albicans, we identified Candida albicans Sfl1 as a functional homolog of the S. cerevisiae sfl1 mutant. Sfl1 is a negative regulator of hyphal development in C. albicans. Deletion of C. albicans SFL1 enhanced filamentous growth and hypha-specific gene expression in several media and at several growth temperatures. Overexpression of the SFL1 led to a significant reduction of filament formation. Both deletion and overexpression of the SFL1 attenuated virulence of C. albicans in a mouse model. Deleting FLO8 in an sfl1/sfl1 mutant completely blocked hyphal development in various growth conditions examined, suggesting that C. albicans Sfl1 may act as a negative regulator of filamentous growth by antagonizing Flo8 functions. We suggest that, similar to the case for S. cerevisiae, a combination of dual control by activation and repression of Flo8 and Sfl1 may contribute to the fine regulatory network in C. albicans morphogenesis responding to different environmental cues. PMID- 17715362 TI - Two trypanosome-specific proteins are essential factors for 5S rRNA abundance and ribosomal assembly in Trypanosoma brucei. AB - We have previously identified and characterized two novel nuclear RNA binding proteins, p34 and p37, which have been shown to bind 5S rRNA in Trypanosoma brucei. These two proteins are nearly identical, with one major difference, an 18 amino-acid insert in the N-terminal region of p37, as well as three minor single amino-acid differences. Homologues to p34 and p37 have been found only in other trypanosomatids, suggesting that these proteins are unique to this ancient family. We have employed RNA interference (RNAi) studies in order to gain further insight into the interaction between p34 and p37 with 5S rRNA in T. brucei. In our p34/p37 RNAi cells, decreased expression of the p34 and p37 proteins led to morphological alterations, including loss of cell shape and vacuolation, as well as to growth arrest and ultimately to cell death. Disruption of a higher molecular-weight complex containing 5S rRNA occurs as well as a dramatic decrease in 5S rRNA levels, suggesting that p34 and p37 serve to stabilize 5S rRNA. In addition, an accumulation of 60S ribosomal subunits was observed, accompanied by a significant decrease in overall protein synthesis within p34/p37 RNAi cells. Thus, the loss of the trypanosomatid-specific proteins p34 and p37 correlates with a diminution in 5S rRNA levels as well as a decrease in ribosome activity and an alteration in ribosome biogenesis. PMID- 17715363 TI - Mitogen-activated protein kinase pathways and fungal pathogenesis. PMID- 17715364 TI - Class I histone deacetylase Thd1p promotes global chromatin condensation in Tetrahymena thermophila. AB - Class I histone deacetylases (HDACs) regulate DNA-templated processes such as transcription. They act both at specific loci and more generally across global chromatin, contributing to acetylation patterns that may underlie large-scale chromatin dynamics. Although hypoacetylation is correlated with highly condensed chromatin, little is known about the contribution of individual HDACs to chromatin condensation mechanisms. Using the ciliated protozoan Tetrahymena thermophila, we investigated the role of a specific class I HDAC, Tauhd1p, in the reversible condensation of global chromatin. In this system, the normal physiological response to cell starvation includes the widespread condensation of the macronuclear chromatin and general repression of gene transcription. We show that the chromatin in Thd1p-deficient cells failed to condense during starvation. The condensation failure correlated with aberrant hyperphosphorylation of histone H1 and the overexpression of CDC2, encoding the major histone H1 kinase. Changes in the rate of acetate turnover on core histones and in the distribution of acetylated lysines 9 and 23/27 on histone H3 isoforms that were found to correlate with normal chromatin condensation were absent from Thd1p mutant cells. These results point to a role for a class I HDAC in the formation of reversible higher-order chromatin structures and global genome compaction through mechanisms involving the regulation of H1 phosphorylation and core histone acetylation/deacetylation kinetics. PMID- 17715366 TI - Tudor nuclease genes and programmed DNA rearrangements in Tetrahymena thermophila. AB - Proteins containing a Tudor domain and domains homologous to staphylococcal nucleases are found in a number of eukaryotes. These "Tudor nucleases" have been found to be associated with the RNA-induced silencing complex (A. A. Caudy, R. F. Ketting, S. M. Hammond, A. M. Denli, A. M. Bathoorn, B. B. Tops, J. M. Silva, M. M. Myers, G. J. Hannon, and R. H. Plasterk, Nature 425:411-414, 2003). We have identified two Tudor nuclease gene homologs, TTN1 and TTN2, in the ciliate Tetrahymena thermophila, which has two distinct small-RNA pathways. Characterization of single and double KOs of TTN1 and TTN2 shows that neither of these genes is essential for growth or sexual reproduction. Progeny of TTN2 KOs and double knockouts occasionally show minor defects in the small-RNA-guided process of DNA deletion but appear to be normal in hairpin RNA-induced gene silencing, suggesting that Tudor nucleases play only a minor role in RNA interference in Tetrahymena. Previous studies of Tetrahymena have shown that inserted copies of the neo gene from Escherichia coli are often deleted from the developing macronucleus during sexual reproduction (Y. Liu, X. Song, M. A. Gorovsky, and K. M. Karrer, Eukaryot. Cell 4:421-431, 2005; M. C. Yao, P. Fuller, and X. Xi, Science 300:1581-1584, 2003). This transgene deletion phenomenon is hypothesized to be a form of genome defense. Analysis of the Tudor nuclease mutants revealed exceptionally high rates of deletion of the neo transgene at the TTN2 locus but no deletion at the TTN1 locus. When present in the same genome, however, the neo gene is deleted at high rates even at the TTN1 locus, further supporting a role for trans-acting RNA in this process. This deletion is not affected by the presence of the same sequence in the macronucleus, thus providing a counterargument for the role of the macronuclear genome in specifying all sequences for deletion. PMID- 17715365 TI - Make it or take it: fatty acid metabolism of apicomplexan parasites. PMID- 17715367 TI - Characterization of metacaspases with trypsin-like activity and their putative role in programmed cell death in the protozoan parasite Leishmania. AB - In this report, we have characterized two metacaspases of Leishmania donovani, L. donovani metacaspase-1 (LdMC1) and LdMC2. These two proteins show 98% homology with each other, and both contain a characteristic C-terminal proline-rich domain. Both genes are transcribed in promastigotes and axenic amastigotes of L. donovani; however, LdMC1 shows increased mRNA levels in axenic amastigotes. An anti-LdMC antibody was obtained and showed reactivity with a single approximately 42-kDa protein band in both promastigote and axenic amastigote parasite whole cell lysates by Western blotting. Pulse-chase experiments suggest that LdMCs are not synthesized as proenzymes, and immunofluorescence studies show that LdMCs are associated with the acidocalcisome compartments of L. donovani. Enzymatic assays of immunoprecipitated LdMCs show that native LdMCs efficiently cleave trypsin substrates and are unable to cleave caspase-specific substrates. Consistently, LdMC activity is insensitive to caspase inhibitors and is efficiently inhibited by trypsin inhibitors, such as leupeptin, antipain, and N(alpha)-tosyl-L-lysine chloromethyl ketone (TLCK). In addition, our results show that LdMC activity was induced in parasites treated with hydrogen peroxide, a known trigger of programmed cell death (PCD) in Leishmania and that parasites overexpressing metacaspases are more sensitive to hydrogen peroxide-induced PCD. These findings suggest that Leishmania metacaspases are not responsible for the caspase-like activities reported in this organism and suggest a possible role for LdMCs as effector molecules in Leishmania PCD. PMID- 17715368 TI - Role of actin cytoskeletal dynamics in activation of the cyclic AMP pathway and HWP1 gene expression in Candida albicans. AB - Changes in gene expression during reversible bud-hypha transitions of the opportunistic fungal pathogen Candida albicans permit adaptation to environmental conditions that are critical for proliferation in host tissues. Our previous work has shown that the hypha-specific adhesin gene HWP1 is up-regulated by the cyclic AMP (cAMP) signaling pathway. However, little is known about the potential influences of determinants of cell morphology on HWP1 gene expression. We found that blocking hypha formation with cytochalasin A, which destabilizes actin filaments, and with latrunculin A, which sequesters actin monomers, led to a loss of HWP1 gene expression. In contrast, high levels of HWP1 gene expression were observed when the F-actin stabilizer jasplakinolide was used to block hypha formation, suggesting that HWP1 expression could be regulated by actin structures. Mutants defective in formin-mediated nucleation of F-actin were reduced in HWP1 gene expression, providing genetic support for the importance of actin structures. Kinetic experiments with wild-type and actin-deficient cells revealed two distinct phases of HWP1 gene expression, with a slow, actin independent phase preceding a fast, actin-dependent phase. Low levels of HWP1 gene expression that appeared to be independent of stabilized actin and cAMP signaling were detected using indirect immunofluorescence. A connection between actin structures and the cAMP signaling pathway was shown using hyper- and hypomorphic cAMP mutants, providing a possible mechanism for up-regulation of HWP1 gene expression by stabilized actin. The results reveal a new role for F actin as a regulatory agent of hypha-specific gene expression at the bud-hypha transition. PMID- 17715369 TI - Histatin 5 initiates osmotic stress response in Candida albicans via activation of the Hog1 mitogen-activated protein kinase pathway. AB - Histatin 5 (Hst 5) is a salivary cationic peptide that has toxicity for Candida albicans by inducing rapid cellular ion imbalance and cell volume loss. Microarray analyses of peptide-treated cells were used to evaluate global gene responses elicited by Hst 5. The major transcriptional response of C. albicans to Hst 5 was expression of genes involved in adaptation to osmotic stress, including production of glycerol (RHR2, SKO1, and PDC11) and the general stress response (CTA1 and HSP70). The oxidative-stress genes AHP1, TRX1, and GPX1 were mildly induced by Hst 5. Cell defense against Hst 5 was dependent on the Hog1 mitogen activated protein kinase (MAPK) pathway, since C. albicans hog1/hog1 mutants were significantly hypersensitive to Hst 5 but not to Mkc1 MAPK or Cek1 MAPK mutants. Activation of the high-osmolarity glycerol (HOG) pathway was demonstrated by phosphorylation of Hog1 MAPK as well as by glycerol production following Hst 5 treatment in a dose-dependent manner. C. albicans cells prestressed with sorbitol were less sensitive to subsequent Hst 5 treatment; however, cells treated concurrently with osmotic stress and Hst 5 were hypersensitive to Hst 5. In contrast, cells subjected to oxidative stress had no difference in sensitivity to Hst 5. These results suggest a common underlying cellular response to osmotic stress and Hst 5. The HOG stress response pathway likely represents a significant and effective challenge to physiological levels of Hst 5 and other toxic peptides in fungal cells. PMID- 17715371 TI - Human immunodeficiency virus type 1 (HIV-1) plasma load discrepancies between the Roche COBAS AMPLICOR HIV-1 MONITOR Version 1.5 and the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 assays. AB - We compared plasma viral load values obtained with COBAS AMPLICOR human immunodeficiency virus type 1 (HIV-1) MONITOR version 1.5 and with COBAS TaqMan HIV-1 assays. Mean values were 4.2 and 2.9 log(10) copies/ml, respectively, showing the lack of agreement between the two assays. PMID- 17715372 TI - Reevaluating the serotype II capsular locus of Streptococcus agalactiae. AB - We report a novel sequence of the serotype II capsular locus of group B streptococcus that resolves inconsistencies among the results of various groups and the sequence in GenBank. This locus was found in diverse lineages and presents genes consistent with the complete synthesis of the type II polysaccharide. PMID- 17715370 TI - Down-regulation of the trypanosomatid signal recognition particle affects the biogenesis of polytopic membrane proteins but not of signal peptide-containing proteins. AB - Protein translocation across the endoplasmic reticulum is mediated by the signal recognition particle (SRP). In this study, the SRP pathway in trypanosomatids was down-regulated by two approaches: RNA interference (RNAi) silencing of genes encoding SRP proteins in Trypanosoma brucei and overexpression of dominant negative mutants of 7SL RNA in Leptomonas collosoma. The biogenesis of both signal peptide-containing proteins and polytopic membrane proteins was examined using endogenous and green fluorescent protein-fused proteins. RNAi silencing of SRP54 or SRP68 in T. brucei resulted in reduced levels of polytopic membrane proteins, but no effect on the level of signal peptide-containing proteins was observed. When SRP deficiency was achieved in L. collosoma by overexpression of dominant-negative mutated 7SL RNA, a major effect was observed on polytopic membrane proteins but not on signal peptide-containing proteins. This study included two trypanosomatid species, tested various protein substrates, and induced depletion of the SRP pathway by affecting either the levels of SRP binding proteins or that of SRP RNA. Our results demonstrate that, as in bacteria but in contrast to mammalian cells, the trypanosome SRP is mostly essential for the biogenesis of membrane proteins. PMID- 17715373 TI - DNA microarray-based detection and identification of fungal pathogens in clinical samples from neutropenic patients. AB - The increasing incidence of invasive fungal infections (IFI) in immunocompromised patients emphasizes the need to improve diagnostic tools. We established a DNA microarray to detect and identify DNA from 14 fungal pathogens (Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Candida albicans, Candida dubliniensis, Candida glabrata, Candida lusitaniae, Candida tropicalis, Fusarium oxysporum, Fusarium solani, Mucor racemosus, Rhizopus microsporus, Scedosporium prolificans, and Trichosporon asahii) in blood, bronchoalveolar lavage, and tissue samples from high-risk patients. The assay combines multiplex PCR and consecutive DNA microarray hybridization. PCR primers and capture probes were derived from unique sequences of the 18S, 5.8S, and internal transcribed spacer 1 regions of the fungal rRNA genes. Hybridization with genomic DNA of fungal species resulted in species-specific hybridization patterns. By testing clinical samples from 46 neutropenic patients with proven, probable, or possible IFI or without IFI, we detected A. flavus, A. fumigatus, C. albicans, C. dubliniensis, C. glabrata, F. oxysporum, F. solani, R. microsporus, S. prolificans, and T. asahii. For 22 of 22 patients (5 without IFI and 17 with possible IFI), negative diagnostic results corresponded with negative microarray data. For 11 patients with proven (n = 4), probable (n = 2), and possible IFI (n = 5), data for results positive by microarray were validated by other diagnostic findings. For 11 of 11 patients with possible IFI, the microarray results provided additional information. For two patients with proven and probable invasive aspergillosis, respectively, microarray results were negative. The assay detected genomic DNA from 14 fungal pathogens from the clinical samples, pointing to a high significance for improving the diagnosis of IFI. PMID- 17715374 TI - Comparison of single- and multilocus sequence typing and toxin gene profiling for characterization of methicillin-resistant Staphylococcus aureus. AB - We compared three novel methicillin-resistant Staphylococcus aureus (MRSA) genotyping methods with multilocus sequence typing (MLST) and spa typing to assess their utility for routine strain typing. The new methods were femA and nuc sequence typing and toxin gene profiling (TGP), using a multiplex-PCR-based reverse line blot assay to detect 13 pyrogenic superantigen and exfoliative toxin genes. Forty-two well-characterized MRSA strains, representing 15 MLSTs or 9 clonal clusters (CCs), were genotyped by all methods. Twenty-two spa, nine femA, and seven nuc sequence types were identified. The femA sequence types correlated exactly with CCs; nuc sequences types were less discriminatory but generally correlated well with femA types and CCs. Ten isolates contained none of 13 toxin genes; TGPs of the remainder comprised 1 to 5 toxin genes. The combination of spa typing and TGPs identified 26 genotypes among the 42 strains studied. A combination of two or three rapid, inexpensive genotyping methods could potentially provide rapid MRSA strain typing as well as useful information about clonal origin and virulence. PMID- 17715375 TI - Differentiation of West Nile and St. Louis encephalitis virus infections by use of noninfectious virus-like particles with reduced cross-reactivity. AB - Differential diagnosis of St. Louis encephalitis virus (SLEV) and West Nile virus (WNV) infections can be complicated due to the high degree of cross-reactivity observed in most serodiagnostic assays. In an effort to provide a more specific diagnostic test, we developed virus-like particle (VLP) antigens with reduced cross-reactivity for both SLEV and WNV by identifying and mutating envelope protein amino acids within the cross-reactive epitopes of VLP expression plasmids. To determine the serodiagnostic discriminatory ability of the antigens with reduced cross-reactivity, a panel of 134 human serum samples collected predominately from North American patients with SLEV or WNV infections was used to evaluate the performance of these novel antigens in imunoglobulin M antibody capture enzyme-linked immunosorbent assays. Positive/negative ratios and the resulting diagnostic classifications were compared between the mutant and the wild-type (WT) VLPs. The mutant VLP antigens were more specific, with higher positive predictive values and higher likelihood ratios than the WT VLP antigens. Both the SLEV and WNV mutant VLPs greatly reduced the observed cross-reactivity, significantly increasing the specificity and sensitivity of the assay. The use of these novel VLP antigens with reduced cross-reactivity in these serodiagnostic assays and others should lead to more accurate diagnoses of current infections, thereby reducing the need for time-consuming and cumbersome confirmatory plaque reduction neutralization tests to differentiate between SLEV and WNV infections in North America. PMID- 17715376 TI - Antimicrobial resistance among Gram-negative bacilli causing infections in intensive care unit patients in the United States between 1993 and 2004. AB - During the 12-year period from 1993 to 2004, antimicrobial susceptibility profiles of 74,394 gram-negative bacillus isolates recovered from intensive care unit (ICU) patients in United States hospitals were determined by participating hospitals and collected in a central location. MICs for 12 different agents were determined using a standardized broth microdilution method. The 11 organisms most frequently isolated were Pseudomonas aeruginosa (22.2%), Escherichia coli (18.8%), Klebsiella pneumoniae (14.2%), Enterobacter cloacae (9.1%), Acinetobacter spp. (6.2%), Serratia marcescens (5.5%), Enterobacter aerogenes (4.4%), Stenotrophomonas maltophilia (4.3%), Proteus mirabilis (4.0%), Klebsiella oxytoca (2.7%), and Citrobacter freundii (2.0%). Specimen sources included the lower respiratory tract (52.1%), urine (17.3%), and blood (14.2%). Rates of resistance to many of the antibiotics tested remained stable during the 12-year study period. Carbapenems were the most active drugs tested against most of the bacterial species. E. coli and P. mirabilis remained susceptible to most of the drugs tested. Mean rates of resistance to 9 of the 12 drugs tested increased with Acinetobacter spp. Rates of resistance to ciprofloxacin increased over the study period for most species. Ceftazidime was the only agent to which a number of species (Acinetobacter spp., C. freundii, E. aerogenes, K. pneumoniae, P. aeruginosa, and S. marcescens) became more susceptible. The prevalence of multidrug resistance, defined as resistance to at least one extended-spectrum cephalosporin, one aminoglycoside, and ciprofloxacin, increased substantially among ICU isolates of Acinetobacter spp., P. aeruginosa, K. pneumoniae, and E. cloacae. PMID- 17715377 TI - Distinguishing acute from chronic and resolved hepatitis C virus (HCV) infections by measurement of anti-HCV immunoglobulin G avidity index. AB - An assay to measure avidity index (AI) was developed to diagnose incident hepatitis C virus (HCV) infections. The assay demonstrated an AI value statistically significantly lower in primary HCV infections than in chronic infections. When the assay was applied to past resolved infections, the difference in AI values was not as significant as the difference between incident and chronic infections. Lower AI values obtained in past resolved infections may be directly related to lower levels of immunoglobulin G anti-HCV in past resolved infections than in either new infections or chronic infections. PMID- 17715378 TI - Activation of nonsteroidal anti-inflammatory drug-activated gene-1 via extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase revealed a isochaihulactone-triggered apoptotic pathway in human lung cancer A549 cells. AB - The novel lignan isochaihulactone inhibits cell proliferation and is an effective inducer of apoptosis in a variety of carcinoma cell lines. To determine the mechanisms underlying these effects, we examined isochaihulactone-induced changes in gene expression using oligodeoxynucleotide-based microarray screening of a human lung carcinoma cell line, A549. Isochaihulactone-inducible genes included the early growth response gene-1 (EGR-1) and nonsteroidal anti-inflammatory drug activated gene (NAG-1). Isochaihulactone increased EGR-1 and then NAG-1 mRNA and protein expression. Pure isochaihulactone induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Isochaihulactone-induced increases in EGR-1 and NAG-1 expression were reduced by the mitogen-activated protein kinase kinase 1/2 inhibitor 2'-amino-3'-methoxyflavone (PD98059), and this effect was not blocked by the phosphatidylinositol 3-kinase/protein kinase B pathway inhibitor 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002). Inhibition of isochaihulactone-induced NAG-1 expression by EGR-1 small interfering RNA blocked isochaihulactone-induced apoptosis in A549 cells, suggesting that induction of EGR-1 expression decreases survival of A549 cells. RNA interference using double-stranded RNA specific for NAG-1 also inhibited isochaihulactone-induced apoptosis, and cells transfected to increased NAG-1 expression had a greater apoptotic response to isochaihulactone and reduced colony formation efficiency. In addition, treatment of nude mice with isochaihulactone increased the in vivo NAG-1 expression as examined by immunohistochemistry from tumor biopsy. Isochaihulactone treatment increased the luciferase activity of NAG-1 in A549 cells transfected with the NAG-1 promoter construct. This induction increased expression of NAG-1 that was p53-independent and Sp1-dependent. Our findings suggest that NAG-1 expression is up-regulated by isochaihulactone through an ERK-dependent pathway involving the activation of EGR 1. PMID- 17715379 TI - Airway inflammation in COPD: friend or foe? PMID- 17715380 TI - Indoor air, passive smoking, and COPD. PMID- 17715381 TI - Occupational bronchiolitis obliterans masquerading as COPD. PMID- 17715382 TI - Notes from the NHLBI Director: National Heart, Lung, and Blood Institute core values and shaping the 2007 budget. PMID- 17715383 TI - Optimizing medications for poorly controlled asthma. PMID- 17715384 TI - Lung hyperinflation despite lung-protective ventilation. PMID- 17715385 TI - On the correct statistical analysis of exacerbation rates in clinical trials. PMID- 17715386 TI - Functional characterization of testis-specific rodent multidrug and toxic compound extrusion 2, a class III MATE-type polyspecific H+/organic cation exporter. AB - Mammalian multidrug and toxic compound extrusion (MATE) proteins are classified into three subfamilies: classes I, II, and III. We previously showed that two of these families act as polyspecific H(+)-coupled transporters of organic cations (OCs) at final excretion steps in liver and kidney (Otsuka et al. Proc Natl Acad Sci USA 102: 17923-17928, 2005; Omote et al. Trends Pharmacol Sci 27: 587-593, 2006). Rodent MATE2 proteins are class III MATE transporters, the molecular nature, as well as transport properties, of which remain to be characterized. In the present study, we investigated the transport properties and localization of mouse MATE2 (mMATE2). On expression in human embryonic kidney (HEK)-293 cells, mMATE2 localized to the intracellular organelles and plasma membrane. mMATE2 mediated pH-dependent TEA transport with substrate specificity similar to, but distinct from, that of mMATE1, which prefers N-methylnicotinamide and guanidine as substrates. mMATE2 expressed in insect cells was solubilized and reconstituted with bacterial H(+)-ATPase into liposomes. The resultant proteoliposomes exhibited ATP-dependent uptake of TEA that was sensitive to carbonyl cyanide 3 chlorophenylhydrazone but unaffected by valinomycin in the presence of K(+). Immunologic techniques using specific antibodies revealed that mMATE2 was specifically expressed in testicular Leydig cells. Thus mMATE2 appears to act as a polyspecific H(+)/OC exporter in Leydig cells. It is concluded that all classes of mammalian MATE proteins act as polyspecific and electroneutral transporters of organic cations. PMID- 17715387 TI - P2Y receptor regulation of sodium transport in human mammary epithelial cells. AB - Primary human mammary epithelial (HME) cells were immortalized by stable, constitutive expression of the catalytic subunit of human telomerase. Purinergic receptors were identified by RT-PCR and quantitative RT-PCR from mRNA isolated from primary and immortalized cells grown to confluence on membrane filters. Several subtypes of P2Y receptor mRNA were identified including P2Y(1), P2Y(2), P2Y(4), and P2Y(6) receptors. RT-PCR experiments also revealed expression of A(2b) adenosine receptor mRNA in primary and immortalized cells. Confluent monolayers of HME cells exhibited a basal short-circuit current (I(sc)) that was abolished by amiloride and benzamil. When monolayers were cultured in the presence of hydrocortisone, mRNA expression of Na(+) channel (ENaC) alpha-, beta , and gamma-subunits increased approximately threefold compared with that in cells grown without hydrocortisone. In addition, basal benzamil-sensitive Na(+) transport was nearly twofold greater in hydrocortisone-treated monolayers. Stimulation with UTP, UDP, or adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS) produced increases in intracellular calcium concentration that were significantly reduced following pretreatment with the calcium-chelating agent BAPTA-AM. Concentration-response relationships indicated that the rank order of potency for these agonists was UTP > UDP > ATPgammaS. Basolateral stimulation with UTP produced a rapid but transient increase in I(sc) that was significantly reduced if cells were pretreated with BAPTA-AM or benzamil. Moreover, basolateral treatment with either charybdotoxin or clotrimazole significantly inhibited the initial UTP-dependent increase in I(sc) and eliminated the sustained current response. These results indicate that human mammary epithelial cells express multiple P2 receptor subtypes and that Ca(2+) mobilization evoked by P2Y receptor agonists stimulates Na(+) absorption by increasing the activity of Ca(2+) activated K(+) channels located in the basolateral membrane. PMID- 17715388 TI - Delays in maturation among adolescents with hemophilia and a history of inhibitors. AB - Inhibitory antibodies to factors VIII or IX have the potential to affect a broad range of outcomes among people with hemophilia; however, their possible effect on growth and maturation has not been explored. We evaluated skeletal maturation (bone age), pubertal progression, serum testosterone levels, height velocity, and stature in the multicenter Hemophilia Growth and Development Study. A total of 333 children and adolescents (mean age, 12.4 years) were enrolled from 1989 to 1990 and followed for 7 years. Of these, 18% (n = 60) had a history of inhibitors. Bone age among HIV(-) adolescents with a history of inhibitors lagged 9 or more months behind those without inhibitors at every age from 12 to 15 years. Those with a history of inhibitors were older at every Tanner stage transition, attained a lower maximum growth velocity, and their serum testosterone levels were significantly lower compared with those without inhibitors. Delays were greater among HIV(+) patients with a history of inhibitors compared with those without inhibitors; however, the differences were generally small and not statistically significant. The results of this investigation underscore the importance of monitoring the growth and maturation of children and adolescents with hemophilia, particularly those with inhibitors. PMID- 17715389 TI - Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. AB - Nilotinib, an orally bioavailable, selective Bcr-Abl tyrosine kinase inhibitor, is 30-fold more potent than imatinib in pre-clinical models, and overcomes most imatinib resistant BCR-ABL mutations. In this phase 2 open-label study, 400 mg nilotinib was administered orally twice daily to 280 patients with Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia in chronic phase (CML-CP) after imatinib failure or intolerance. Patients had at least 6 months of follow up and were evaluated for hematologic and cytogenetic responses, as well as for safety and overall survival. At 6 months, the rate of major cytogenetic response (Ph < or = 35%) was 48%: complete (Ph = 0%) in 31%, and partial (Ph = 1%-35%) in 16%. The estimated survival at 12 months was 95%. Nilotinib was effective in patients harboring BCR-ABL mutations associated with imatinib resistance (except T315I), and also in patients with a resistance mechanism independent of BCR-ABL mutations. Adverse events were mostly mild to moderate, and there was minimal cross-intolerance with imatinib. Grades 3 to 4 neutropenia and thrombocytopenia were observed in 29% of patients; pleural or pericardial effusions were observed in 1% (none were severe). In summary, nilotinib is highly active and safe in patients with CML-CP after imatinib failure or intolerance. This clinical trial is registered at http://clinicaltrials.gov as ID no. NCT00109707. PMID- 17715390 TI - Tissue-specific histone modification and transcription factor binding in alpha globin gene expression. AB - To address the mechanism by which the human globin genes are activated during erythropoiesis, we have used a tiled microarray to analyze the pattern of transcription factor binding and associated histone modifications across the telomeric region of human chromosome 16 in primary erythroid and nonerythroid cells. This 220-kb region includes the alpha globin genes and 9 widely expressed genes flanking the alpha globin locus. This un-biased, comprehensive analysis of transcription factor binding and histone modifications (acetylation and methylation) described here not only identified all known cis-acting regulatory elements in the human alpha globin cluster but also demonstrated that there are no additional erythroid-specific regulatory elements in the 220-kb region tested. In addition, the pattern of histone modification distinguished promoter elements from potential enhancer elements across this region. Finally, comparison of the human and mouse orthologous regions in a unique mouse model, with both regions coexpressed in the same animal, showed significant differences that may explain how these 2 clusters are regulated differently in vivo. PMID- 17715391 TI - MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts. AB - The interaction between osteoclasts (OCs) and multiple myeloma (MM) cells plays a key role in the pathogenesis of MM-related osteolytic bone disease (OBD). MM cells promote OC formation and, in turn, OCs enhance MM cell proliferation. Chemokines are mediators of MM effects on bone and vice versa; in particular, CCL3 enhances OC formation and promotes MM cell migration and survival. Here, we characterize the effects of MLN3897, a novel specific antagonist of the chemokine receptor CCR1, on both OC formation and OC-MM cell interactions. MLN3897 demonstrates significant impairment of OC formation (by 40%) and function (by 70%), associated with decreased precursor cell multinucleation and down regulation of c-fos signaling. OCs secrete high levels of CCL3, which triggers MM cell migration; conversely, MLN3897 abrogates its effects by inhibiting Akt signaling. Moreover, MM cell-to-OC adhesion was abrogated by MLN3897, thereby inhibiting MM cell survival and proliferation. Our results therefore show novel biologic sequelae of CCL3 and its inhibition in both osteoclastogenesis and MM cell growth, providing the preclinical rationale for clinical trials of MLN3897 to treat OBD in MM. PMID- 17715392 TI - Novel role for EKLF in megakaryocyte lineage commitment. AB - Megakaryocytes and erythroid cells are thought to derive from a common progenitor during hematopoietic differentiation. Although a number of transcriptional regulators are important for this process, they do not explain the bipotential result. We now show by gain- and loss-of-function studies that erythroid Kruppel like factor (EKLF), a transcription factor whose role in erythroid gene regulation is well established, plays an unexpected directive role in the megakaryocyte lineage. EKLF inhibits the formation of megakaryocytes while at the same time stimulating erythroid differentiation. Quantitative examination of expression during hematopoiesis shows that, unlike genes whose presence is required for establishment of both lineages, EKLF is uniquely down-regulated in megakaryocytes after formation of the megakaryocyte-erythroid progenitor. Expression profiling and molecular analyses support these observations and suggest that megakaryocytic inhibition is achieved, at least in part, by EKLF repression of Fli-1 message levels. PMID- 17715394 TI - Rational engineering of human cytochrome P450 2B6 for enhanced expression and stability: importance of a Leu264->Phe substitution. AB - Despite the emerging importance of human P450 2B6 in xenobiotic metabolism, thorough biochemical and biophysical characterization has been impeded as a result of low expression in Escherichia coli. Comparison with similar N-terminal truncated and C-terminal His-tagged constructs (rat P450 2B1dH, rabbit 2B4dH, and dog 2B11dH) revealed that P450 2B6dH showed the lowest thermal stability, catalytic tolerance to temperature, and chemical stability against guanidinium chloride-induced denaturation. Eleven P450 2B6dH mutants were rationally engineered based on sequence comparison with the three other P450 2B enzymes and the solvent accessibility of residues in the ligand-free crystal structure of P450 2B4dH. L198M, L264F, and L390P showed approximately 3-fold higher expression than P450 2B6dH. L264F alone showed enhanced stability against thermal and chemical denaturation compared with P450 2B6dH and was characterized further functionally. L264F showed similar preferential inhibition by pyridine over imidazole derivatives as P450 2B6dH. The Leu(264)-->Phe substitution did not alter the K(s) for inhibitors or the substrate benzphetamine, the K(m) for 7 ethoxy-4-(trifluoromethyl)coumarin, or the benzphetamine metabolite profiles. The enhanced stability and monodisperse nature of L264F made it suitable for isothermal titration calorimetry studies. Interaction of 1-benzylimidazole with L264F yielded a clear binding isotherm with a distinctly different thermodynamic signature from P450 2B4dH. The inhibitor docked differently in the binding pocket of a P450 2B6 homology model than in 2B4, highlighting the different chemistry of the active site of these two enzymes. Thus, L264F is a good candidate to further explore the unique structure-function relationships of P450 2B6 using X-ray crystallography and solution thermodynamics. PMID- 17715393 TI - Regulated Fox-2 isoform expression mediates protein 4.1R splicing during erythroid differentiation. AB - A regulated splicing event in protein 4.1R pre-mRNA-the inclusion of exon 16 encoding peptides for spectrin-actin binding-occurs in late erythroid differentiation. We defined the functional significance of an intronic splicing enhancer, UGCAUG, and its cognate splicing factor, mFox2A, on exon 16 splicing during differentiation. UGCAUG displays cell-type-specific splicing regulation in a test neutral reporter and has a dose-dependent enhancing effect. Erythroid cells express 2 UGCAUG-binding mFox-2 isoforms, an erythroid differentiation inducible mFox-2A and a commonly expressed mFox-2F. When overexpressed, both enhanced internal exon splicing in an UGCAUG-dependent manner, with mFox-2A exerting a much stronger effect than mFox-2F. A significant reciprocal increase in mFox-2A and decrease in mFox-2F occurred during erythroid differentiation and correlated with exon 16 inclusion. Furthermore, isoform-specific expression reduction reversed mFox-2A-enhancing activity, but not that of mFox-2F on exon 16 inclusion. Our results suggest that an erythroid differentiation-inducible mFox 2A isoform is a critical regulator of the differentiation-specific exon 16 splicing switch, and that its up-regulation in late erythroid differentiation is vital for exon 16 splicing. PMID- 17715395 TI - Monitoring interactions between receptor tyrosine kinases and their downstream effector proteins in living cells using bioluminescence resonance energy transfer. AB - A limited number of whole-cell assays allow monitoring of receptor tyrosine kinase (RTK) activity in a signaling pathway-specific manner. We present the general use of the bioluminescence resonance energy transfer (BRET) technology to quantitatively study the pharmacology and signaling properties of the receptor tyrosine kinase (RTK) superfamily. RTK BRET-2 assays monitor, in living cells, the specific interaction between RTKs and their effector proteins, which control the activation of specific downstream signaling pathways. A total of 22 BRET assays have been established for nine RTKs derived from four subfamilies [erythroblastic leukemia viral (v-erb-b) oncogene homolog (ErbB), platelet derived growth factor (PDGF), neurotrophic tyrosine kinase receptor (TRK), vascular endothelial growth factor (VEGF)] monitoring the interactions with five effectors (Grb2, p85, Stat5a, Shc46, PLCgamma1). These interactions are dependent on the RTK kinase activity and autophosphorylation of specific tyrosine residues in the carboxyl terminus. RTK BRET assays are highly sensitive for quantifying ligand-independent (constitutive), agonist-induced, or antagonist-inhibited RTK activity levels. We studied the signaling properties of the PDGF receptor, alpha polypeptide (PDGFRA) isoforms (V561D; D842V and delta842-845) carrying activating mutations identified in gastrointestinal stromal tumors (GIST). All three PDGFRA isoforms are fully constitutively activated, insensitive to the growth factor PDGF-BB, but show differential sensitivity of their constitutive activity to be inhibited by the inhibitor imatinib (Gleevec). Epidermal growth factor receptor (EGFR) BRET structure-function studies identify the tyrosine residues 1068, 1114, and 1148 as the main residues mediating the interaction of EGFR with the adapter protein Grb2. The BRET technology provides an assay platform to study signaling pathway-specific RTK structure-function and will facilitate drug discovery efforts for the identification of novel RTK modulators. PMID- 17715396 TI - Gbetagamma interferes with Ca2+-dependent binding of synaptotagmin to the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. AB - Presynaptic inhibitory G protein-coupled receptors (GPCRs) can decrease neurotransmission by inducing interaction of Gbetagamma with the soluble N ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. We have shown that this action of Gbetagamma requires the carboxyl terminus of the 25-kDa synaptosome-associated protein (SNAP25) and is downstream of the well known inhibition of Ca2+ entry through voltage-gated calcium channels. We propose a mechanism in which Gbetagamma and synaptotagmin compete for binding to the SNARE complex. Here, we characterized the Gbetagamma interaction sites on syntaxin1A and SNAP25 and demonstrated an overlap of the Gbetagamma- and synaptotagmin I -binding regions on each member of the SNARE complex. Synaptotagmin competes in a Ca2+-sensitive manner with binding of Gbetagamma to SNAP25, syntaxin1A, and the assembled SNARE complex. We predict, based on these findings, that at high intracellular Ca2+ concentrations, Ca2+-synaptotagmin I can displace Gbetagamma binding and the Gbetagamma-dependent inhibition of exocytosis can be blocked. We tested this hypothesis in giant synapses of the lamprey spinal cord, where 5-HT works via Gbetagamma to inhibit neurotransmission (Blackmer et al., 2001). We showed that increased presynaptic Ca2+ suppresses the 5-HT- and Gbetagamma-dependent inhibition of exocytosis. We suggest that this effect may be due to Ca2+-dependent competition between Gbetagamma and synaptotagmin I for SNARE binding. This type of dynamic regulation may represent a novel mechanism for modifying transmitter release in a graded manner based on the history of action potentials that increase intracellular Ca2+ concentrations and of inhibitory signals through G(i)-coupled GPCRs. PMID- 17715398 TI - Assessment of the roles of serines 5.43(239) and 5.46(242) for binding and potency of agonist ligands at the human serotonin 5-HT2A receptor. AB - We assessed the relative importance of two serine residues located near the top of transmembrane helix 5 of the human 5-HT(2A) receptor, comparing the wild type with S5.43(239)A or S5.46(242)A mutations. Using the ergoline lysergic acid diethylamide (LSD), and a series of substituted tryptamine and phenethylamine 5 HT(2A) receptor agonists, we found that Ser5.43(239) is more critical for agonist binding and function than Ser5.46(242). Ser5.43(239) seems to engage oxygen substituents at either the 4- or 5-position of tryptamine ligands and the 5 position of phenylalkylamine ligands. Even when a direct binding interaction cannot occur, our data suggest that Ser5.43(239) is still important for receptor activation. Polar ring-substituted tryptamine ligands also seem to engage Ser5.46(242), but tryptamines lacking such a substituent may adopt an alternate binding orientation that does not engage this residue. Our results are consistent with the role of Ser5.43(239) as a hydrogen bond donor, whereas Ser5.46(242) seems to serve as a hydrogen bond acceptor. These results are consistent with the functional topography and utility of our in silico-activated homology model of the h5-HT(2A) receptor. In addition, being more distal from the absolutely conserved Pro5.50, a strong interaction with Ser5.43(239) may be more effective in straightening the kink in helix 5, a feature that is possibly common to all type A GPCRs that have polar residues at position 5.43. PMID- 17715397 TI - Disruption of clock gene expression alters responses of the aryl hydrocarbon receptor signaling pathway in the mouse mammary gland. AB - The biological effects of many environmental toxins are mediated by genes containing Per-Arnt-Sim (PAS) domains, the aryl hydrocarbon receptor (AhR), and AhR nuclear translocator. Because these transcription factors interact with other PAS genes that form the circadian clockworks in mammals, we determined whether targeted disruption of the clock genes, Per1 and/or Per2, alters toxin-induced expression of known biological markers in the AhR signaling pathway. 2,3,7,8 Tetrachlorodibenzo-p-dioxin (TCDD), a prototypical Ahr agonist, had an inductive effect on mammary gland expression of cytochrome P450, subfamily I, polypeptide 1 (Cyp1A1) mRNA regardless of genotype. However, TCDD-mediated Cyp1A1 induction in the mammary glands of Per1(ldc) and Per1(ldc)/Per2(ldc) mice was significantly (17.9- and 5.9-fold) greater than that in wild-type (WT) animals. In addition, TCDD-induced Cyp1B1 expression in Per1(ldc) and Per1(ldc)/Per2(ldc) mammary glands was significantly increased relative to that in WT mice. Similar to in vivo observations, experiments using primary cultures of mammary gland tissue demonstrated that TCDD-induced Cyp1A1 and Cyp1B1 expression in Per1(ldc) and Per1(ldc)/Per2(ldc) mutant cells was significantly greater than that in WT cultures. AhR mRNA levels were distinctively elevated in cells derived from all mutant genotypes, but they were commonly decreased in WT and mutant cultures after TCDD treatment. In WT mice, an interesting corollary is that the inductive effects of TCDD on mammary gland expression of Cyp1A1 and Cyp1B1 vary over time and are significantly greater during the night. These findings suggest that clock genes, especially Per1, may be involved in TCDD activation of AhR signaling pathways. PMID- 17715400 TI - Dimerization region of soluble guanylate cyclase characterized by bimolecular fluorescence complementation in vivo. AB - The ubiquitously expressed nitric oxide (NO) receptor soluble guanylate cyclase (sGC) plays a key role in signal transduction. Binding of NO to the N-terminal prosthetic heme moiety of sGC results in approximately 200-fold activation of the enzyme and an increased conversion of GTP into the second messenger cGMP. sGC exists as a heterodimer the dimerization of which is mediated mainly by the central region of the enzyme. In the present work, we constructed deletion mutants within the predicted dimerization region of the sGC alpha(1)- and beta(1) subunit to precisely map the sequence segments crucial for subunit dimerization. To track mutation-induced alterations of sGC dimerization, we used a bimolecular fluorescence complementation approach that allows visualizing sGC heterodimerization in a noninvasive manner in living cells. Our study suggests that segments spanning amino acids alpha(1)363-372, alpha(1)403-422, alpha(1)440 459, beta(1)212-222, beta(1)304-333, beta(1)344-363, and beta(1)381-400 within the predicted dimerization region are involved in the process of heterodimerization and therefore in the expression of functional sGC. PMID- 17715399 TI - Association of nucleophosmin negatively regulates CXCR4-mediated G protein activation and chemotaxis. AB - CXCR4, the primary receptor for CXCL12, plays a critical role in the development of hematopoietic, vascular, central nervous, and immune systems by mediating directional migration of precursor cells. This mechanism promotes homing of tumor cells to metastatic sites that secrete CXCL12, and CXCR4 expression is a negative prognostic factor in acute myelogenous leukemia (AML). To elucidate mechanisms that regulate CXCR4 signaling, we used a proteomic approach to identify proteins physically associated with CXCR4. Analysis of CXCR4 immune complexes identified nucleophosmin (NPM), which was confirmed by reciprocal coimmunoprecipitation for NPM. Constitutively active CXCR4 variants bound higher levels of NPM than the wild-type receptor, which was reversed by T140, an inverse agonist. NPM binding to CXCR4 localized interactions to the C terminus and cytoplasmic loop (CL)-3, but not CL-1 or CL-2. Alanine scanning mutagenesis demonstrated that positively charged amino acids in CL-3 were critical for NPM binding. Recombinant NPM decreased GTP binding in membrane fractions after activation of CXCR4 by CXCL12. Suppression of NPM expression enhanced chemotactic responses to CXCL12, and, conversely, overexpression of a cytosolic NPM mutant reduced chemotaxis induced by CXCL12. This study provides evidence for a novel role for NPM as a negative regulator of CXCR4 signaling induced by CXCL12 that may be relevant to the biology of AML. PMID- 17715401 TI - Inhibition of the Na+/dicarboxylate cotransporter by anthranilic acid derivatives. AB - The Na(+)/dicarboxylate cotransporter NaDC1 absorbs citric acid cycle intermediates from the lumen of the small intestine and kidney proximal tubule. No effective inhibitor has been identified yet, although previous studies showed that the nonsteroidal anti-inflammatory drug, flufenamate, inhibits the human (h) NaDC1 with an IC(50) value of 2 mM. In the present study, we have tested compounds related in structure to flufenamate, all anthranilic acid derivatives, as potential inhibitors of hNaDC1. We found that N-(p-amylcinnamoyl) anthranilic acid (ACA) and 2-(p-amylcinnamoyl) amino-4-chloro benzoic acid (ONO-RS-082) are the most potent inhibitors with IC(50) values lower than 15 microM, followed by N (9-fluorenylmethoxycarbonyl)-anthranilic acid (Fmoc-anthranilic acid) with an IC(50) value of approximately 80 microM. The effects of ACA on NaDC1 are not mediated through a change in transporter protein abundance on the plasma membrane and seem to be independent of its effect on phospholipase A(2) activity. ACA acts as a slow inhibitor of NaDC1, with slow onset and slow reversibility. Both uptake activity and efflux are inhibited by ACA. Other Na(+)/dicarboxylate transporters from the SLC13 family, including hNaDC3 and rbNaDC1, were also inhibited by ACA, ONO-RS-082, and Fmoc-anthranilic acid, whereas the Na(+)/citrate transporter (hNaCT) is much less sensitive to these compounds. The endogenous sodium dependent succinate transport in Caco-2 cells is also inhibited by ACA. In conclusion, ACA and ONO-RS-082 represent promising lead compounds for the development of specific inhibitors of the Na(+)/dicarboxylate cotransporters. PMID- 17715402 TI - The neurosteroids dehydroepiandrosterone sulfate and pregnenolone sulfate inhibit the UNC-49 GABA receptor through a common set of residues. AB - Neurosteroids are endogenous neuromodulators that bind and allosterically regulate GABA(A) receptors. Residues were recently identified in the first transmembrane domain (M1) of GABA(A) receptor subunits that are important for neurosteroid modulation. We are studying the inhibition of GABA(A) receptors by sulfated neurosteroids. One of these neurosteroid, pregnenolone sulfate (PS), depends on six identified M1 residues to inhibit the UNC-49 GABA receptor, a homomeric GABA receptor from Caenorhabditis elegans that is homologous to the mammalian GABA(A) receptor. Here, we investigate the inhibition of the UNC-49 GABA receptor by another sulfated neurosteroid, dehydroepiandrosterone sulfate (DHEAS). DHEAS is identical to PS except that it contains a carbonyl oxygen instead of an acetyl group at C17 on the steroid D ring. UNC-49 mutations that affect PS inhibition had broadly parallel effects on DHEAS, suggesting the two neurosteroids act through similar mechanisms. However, certain M1 mutations affected DHEAS differently than PS. Considering that first, the D ring contains the only structural difference between PS and DHEAS, and second, the strongest chemical and steric effects of a mutation are likely to be felt in the local environment of the altered residues, this result implies that the steroid D ring may contact M1 near the mutated residues. This possibility is interesting because current models of neurosteroid interactions with GABA(A) receptors, based on pregnane steroids, suggest that the steroid A ring binds M1, whereas the D ring binds M4. Our findings suggest that there may be considerable diversity in the way different classes of neurosteroids interact with GABA(A) receptors. PMID- 17715404 TI - Differential regulation of homocysteine transport in vascular endothelial and smooth muscle cells. AB - OBJECTIVE: We previously reported that homocysteine (Hcy) inhibits endothelial cell (EC) growth and promotes vascular smooth muscle cell (VSMC) proliferation. This study characterized and directly compared Hcy transport in cultured human aortic ECs (HAECs) and smooth muscle cells (HASMCs). METHODS AND RESULTS: Hcy (10 micromol/L) was transported into both cell types in a time-dependent fashion but was approximately 4-fold greater in HASMCs, and is nonstereoenantiomer specific. Hcy transport in HAECs had a Michaelis-Menten constant (Km) of 39 micromol/L and a maximal transport velocity (Vmax) of 873 pmol/mg protein/min. In contrast, Hcy transport in HASMCs had a lower affinity (Km = 106 micromol/L) but a higher transport capacity (Vmax = 4192 pmol/mg protein/min). Competition studies revealed that the small neutral amino acids tyrosine, cysteine, glycine, serine, alanine, methionine, and leucine inhibited Hcy uptake in both cell types, but the inhibition was greater for tyrosine, serine, glycine, and alanine in HAECs. Sodium-depletion reduced Hcy transport to 16% in HAECs and 56% in HASMCs. Increases in pH from 6.5 to 8.2 or lysosomal inhibitors blocked Hcy uptake only in HAECs. In addition, Hcy shares carrier systems with cysteine, in a preferable order of alanine-serine-cysteine (ASC) > aspartate and glutamate (X(AG)) = large branched-chain neutral amino acids (L) transporter systems in HAECs and ASC > L > X(AG) in HASMCs. The sodium-dependent system ASC plays a predominant role for Hcy transport in vascular cells. CONCLUSIONS: Transport system ASC predominantly mediates Hcy transport in EC and is lysosomal dependent. PMID- 17715405 TI - Images in clinical medicine. Peutz-Jeghers syndrome. PMID- 17715406 TI - Healing our Sicko health care system. PMID- 17715407 TI - Election 2008 - campaign contributions, lobbying, and the U.S. Health Sector. PMID- 17715408 TI - Effects of bariatric surgery on mortality in Swedish obese subjects. AB - BACKGROUND: Obesity is associated with increased mortality. Weight loss improves cardiovascular risk factors, but no prospective interventional studies have reported whether weight loss decreases overall mortality. In fact, many observational studies suggest that weight reduction is associated with increased mortality. METHODS: The prospective, controlled Swedish Obese Subjects study involved 4047 obese subjects. Of these subjects, 2010 underwent bariatric surgery (surgery group) and 2037 received conventional treatment (matched control group). We report on overall mortality during an average of 10.9 years of follow-up. At the time of the analysis (November 1, 2005), vital status was known for all but three subjects (follow-up rate, 99.9%). RESULTS: The average weight change in control subjects was less than +/-2% during the period of up to 15 years during which weights were recorded. Maximum weight losses in the surgical subgroups were observed after 1 to 2 years: gastric bypass, 32%; vertical-banded gastroplasty, 25%; and banding, 20%. After 10 years, the weight losses from baseline were stabilized at 25%, 16%, and 14%, respectively. There were 129 deaths in the control group and 101 deaths in the surgery group. The unadjusted overall hazard ratio was 0.76 in the surgery group (P=0.04), as compared with the control group, and the hazard ratio adjusted for sex, age, and risk factors was 0.71 (P=0.01). The most common causes of death were myocardial infarction (control group, 25 subjects; surgery group, 13 subjects) and cancer (control group, 47; surgery group, 29). CONCLUSIONS: Bariatric surgery for severe obesity is associated with long-term weight loss and decreased overall mortality. PMID- 17715409 TI - Long-term mortality after gastric bypass surgery. AB - BACKGROUND: Although gastric bypass surgery accounts for 80% of bariatric surgery in the United States, only limited long-term data are available on mortality among patients who have undergone this procedure as compared with severely obese persons from a general population. METHODS: In this retrospective cohort study, we determined the long-term mortality (from 1984 to 2002) among 9949 patients who had undergone gastric bypass surgery and 9628 severely obese persons who applied for driver's licenses. From these subjects, 7925 surgical patients and 7925 severely obese control subjects were matched for age, sex, and body-mass index. We determined the rates of death from any cause and from specific causes with the use of the National Death Index. RESULTS: During a mean follow-up of 7.1 years, adjusted long-term mortality from any cause in the surgery group decreased by 40%, as compared with that in the control group (37.6 vs. 57.1 deaths per 10,000 person-years, P<0.001); cause-specific mortality in the surgery group decreased by 56% for coronary artery disease (2.6 vs. 5.9 per 10,000 person-years, P=0.006), by 92% for diabetes (0.4 vs. 3.4 per 10,000 person-years, P=0.005), and by 60% for cancer (5.5 vs. 13.3 per 10,000 person-years, P<0.001). However, rates of death not caused by disease, such as accidents and suicide, were 58% higher in the surgery group than in the control group (11.1 vs. 6.4 per 10,000 person years, P=0.04). CONCLUSIONS: Long-term total mortality after gastric bypass surgery was significantly reduced, particularly deaths from diabetes, heart disease, and cancer. However, the rate of death from causes other than disease was higher in the surgery group than in the control group. PMID- 17715410 TI - A study of sexuality and health among older adults in the United States. AB - BACKGROUND: Despite the aging of the population, little is known about the sexual behaviors and sexual function of older people. METHODS: We report the prevalence of sexual activity, behaviors, and problems in a national probability sample of 3005 U.S. adults (1550 women and 1455 men) 57 to 85 years of age, and we describe the association of these variables with age and health status. RESULTS: The unweighted survey response rate for this probability sample was 74.8%, and the weighted response rate was 75.5%. The prevalence of sexual activity declined with age (73% among respondents who were 57 to 64 years of age, 53% among respondents who were 65 to 74 years of age, and 26% among respondents who were 75 to 85 years of age); women were significantly less likely than men at all ages to report sexual activity. Among respondents who were sexually active, about half of both men and women reported at least one bothersome sexual problem. The most prevalent sexual problems among women were low desire (43%), difficulty with vaginal lubrication (39%), and inability to climax (34%). Among men, the most prevalent sexual problems were erectile difficulties (37%). Fourteen percent of all men reported using medication or supplements to improve sexual function. Men and women who rated their health as being poor were less likely to be sexually active and, among respondents who were sexually active, were more likely to report sexual problems. A total of 38% of men and 22% of women reported having discussed sex with a physician since the age of 50 years. CONCLUSIONS: Many older adults are sexually active. Women are less likely than men to have a spousal or other intimate relationship and to be sexually active. Sexual problems are frequent among older adults, but these problems are infrequently discussed with physicians. PMID- 17715411 TI - Clinical practice. Isolated systolic hypertension in the elderly. PMID- 17715412 TI - Normotensive ischemic acute renal failure. PMID- 17715413 TI - Images in clinical medicine. "Maltese crosses" in the nephrotic syndrome. PMID- 17715414 TI - Case records of the Massachusetts General Hospital. Case 26-2007 - a 61-year-old man with recurrent fevers. PMID- 17715415 TI - The missing link - lose weight, live longer. PMID- 17715416 TI - Sex and aging. PMID- 17715417 TI - Aspirin, COX-2, and the risk of colorectal cancer. PMID- 17715418 TI - Correction of cryptorchidism and testicular cancer. PMID- 17715419 TI - Mechanisms of hypertension. PMID- 17715420 TI - Prognosis in heart failure with a normal ejection fraction. PMID- 17715421 TI - Tympanic-membrane perforation as a marker of concussive brain injury in Iraq. PMID- 17715422 TI - Pharmacokinetics and absolute bioavailability of selegiline following treatment of healthy subjects with the selegiline transdermal system (6 mg/24 h): a comparison with oral selegiline capsules. AB - The selegiline transdermal system is a monoamine oxidase inhibitor that was recently approved by the US Food and Drug Administration for the treatment of major depressive disorder. The current study was conducted during the selegiline transdermal system development program to characterize the single-dose pharmacokinetics and absolute bioavailability of selegiline administered by the 6 mg/24-h selegiline transdermal system in healthy volunteers. Selegiline transdermal system results were compared with those obtained after a single 10-mg oral dose of selegiline HCl. The selegiline pharmacokinetics differed greatly between the 2 routes of administration. Transdermal selegiline administration reduced metabolism and produced a high, sustained plasma selegiline concentration over the dosing period, with an absolute bioavailability of 73%. By contrast, oral dosing produced a sharp plasma selegiline peak that occurred within 1 hour and declined rapidly, with an absolute bioavailability of 4%. The data provide the basis for therapeutic advantages of the selegiline transdermal system in administering antidepressant doses of selegiline. PMID- 17715423 TI - A polymorphism in the gene encoding procolipase produces a colipase, Arg92Cys, with decreased function against long-chain triglycerides. AB - Type 2 diabetes mellitus is a multifactorial and polygenic disorder with increasing prevalence. Recently, a polymorphism in the gene encoding procolipase, a cysteine for arginine substitution at position 92, was associated with type 2 diabetes in two human populations. Because procolipase plays a critical role in dietary fat metabolism, polymorphisms that affect the function of procolipase could influence the development of type 2 diabetes. We hypothesized that the Arg92Cys polymorphism has functional consequences. To test our hypothesis, we expressed recombinant cysteine 92 (Cys92) procolipase in a yeast expression system and compared the function and stability of purified Cys92 with that of the more common arginine 92 (Arg92) procolipase. Cys92 fully restored the activity of bile-salt inhibited lipase with short- and medium-chain triglycerides but only had 50% of Arg92 function with long-chain triglycerides. After storage at 4 degrees C, Cys92 lost the ability to restore pancreatic triglyceride lipase activity with medium- and long-chain triglycerides. The loss of function correlated with the inability of Cys92 to anchor lipase on an emulsion surface and oxidation of the cysteine. No detectable degradation or intramolecular disulfide formation occurred in Cys92 after storage. Our findings demonstrate that the Arg92Cys polymorphism decreases the function of Cys92 colipase. This change may contribute to the development of type 2 diabetes. PMID- 17715424 TI - Dietary n-3 PUFA deprivation for 15 weeks upregulates elongase and desaturase expression in rat liver but not brain. AB - Fifteen weeks of dietary n-3 PUFA deprivation increases coefficients of conversion of circulating alpha-linolenic acid (alpha-LNA; 18:3n-3) to docosahexaenoic acid (DHA; 22:6n-3) in rat liver but not brain. To determine whether these increases reflect organ differences in enzymatic activities, we examined brain and liver expression of converting enzymes and of two of their transcription factors, peroxisome proliferator-activated receptor alpha (PPARalpha) and sterol-regulatory element binding protein-1 (SREBP-1), in rats fed an n-3 PUFA "adequate" (4.6% alpha-LNA of total fatty acid, no DHA) or "deficient" (0.2% alpha-LNA, no DHA) diet for 15 weeks after weaning. In rats fed the deficient compared with the adequate diet, mRNA and activity levels of Delta5 and Delta6 desaturases and elongases 2 and 5 were upregulated in liver but not brain, but liver PPARalpha and SREBP-1 mRNA levels were unchanged. In rats fed the adequate diet, enzyme activities generally were higher in liver than brain. Thus, differences in conversion enzyme expression explain why the liver has a greater capacity to synthesize DHA from circulating alpha-LNA than does the brain in animals on an adequate n-3 PUFA diet and why liver synthesis capacity is increased by dietary deprivation. These data suggest that liver n-3 PUFA metabolism determines DHA availability to the brain when DHA is absent from the diet. PMID- 17715425 TI - Quantitative measurement of stressful trunk postures in nursing professions. AB - INTRODUCTION: The evaluation of stress to the spinal column in the provision of care has mostly concentrated on the handling of loads. However, awkward body postures alone, without load transfer, can also be stressful for the spinal column. Therefore in this study all the body postures and movements of nurses were quantitatively measured within a working shift. METHODS: The body postures were recorded with the CUELA measurement system (computer-assisted recording and long-term analysis of musculoskeletal loads), coupled to the individual, and this detected all movements of the trunk and the legs. These measurements were supported by video recordings, so that exact allocation of the measured data to the tasks performed was possible. In all, 24 shift measurements were carried out in 8 wards. Extent, frequency and duration of trunk postures were measured in three planes and assessed on the basis of several standards (DIN EN 1005-1, DIN EN 1005-4, ISO 11226). RESULTS: A mean of 1131 (+/-377) trunk inclinations of >20 degrees were performed in each shift. This corresponds to a frequency of 3.5 min( 1). A total of 237 of these inclinations lasted for >4 s. A total of 72 (+/-35) min was spent bending forward with an inclination of >20 degrees . However, the mean time spent in transferring patients (counting only the lifting process) and heavy materials was only 2 min per shift. Postures with trunk inclination of >60 degrees were adopted for a mean of 175 (+/-133) times. The main tasks responsible for this were 'bed making' (21%), 'basic care' (16%) and 'clearing up/cleaning' (16%). CONCLUSIONS: It could be shown that many stressful trunk postures are assumed in nursing work during a shift. Future preventive measures should therefore consider not only load handling but also tasks with awkward postures. PMID- 17715426 TI - Vapours and aerosols of bitumen: exposure data obtained by the German Bitumen Forum. PMID- 17715429 TI - Annexins are candidate oviductal receptors for bovine sperm surface proteins and thus may serve to hold bovine sperm in the oviductal reservoir. AB - The sperm of eutherian mammals are held in a storage reservoir in the caudal segment of the oviduct by binding to the mucosal epithelium. The reservoir serves to maintain the fertility of sperm during storage and to reduce the incidence of polyspermic fertilization. Bovine sperm bind to the epithelium via seminal vesicle secretory proteins in the bovine seminal plasma protein (BSP) family, namely, PDC109 (BSPA1/A2), BSPA3, and BSP30K, which coat the sperm head. Our objective was to identify the receptors for bull sperm on the oviductal epithelium. Proteins extracted from apical plasma membrane preparations of bovine oviductal epithelium were subjected to affinity purification using purified BSPs bound to corresponding antibodies conjugated to Protein A agarose beads. Oviductal protein bands of approximately 34 and 36 kDa were eluted by EGTA from the beads and identified by tandem mass spectrometry as annexins (ANXAs) 1, 2, 4, and 5. Subsequently, antibodies to each of the ANXAs were found to inhibit sperm binding to explants of oviductal epithelium. Anti-ANXA antibodies labeled the apical surfaces and cilia of the mucosal epithelium in sections of bovine oviduct. Western blots confirmed the presence of ANXAs in apical plasma membranes. Because fucose had been determined to be a critical component of the oviductal receptor, the ANXAs were immunoprecipitated from solubilized apical plasma membranes and were probed with Lotus tetragonolobus lectin to verify the presence of fucose. Thus, these ANXAs are strong candidates for the sperm receptors on bovine oviductal epithelium. PMID- 17715428 TI - Patterns of expression of messenger RNAs encoding GDF9, BMP15, TGFBR1, BMPR1B, and BMPR2 during follicular development and characterization of ovarian follicular populations in ewes carrying the Woodlands FecX2W mutation. AB - Woodlands sheep have a putative genetic mutation (FecX2(W)) that increases ovulation rate. At present, the identity of FecX2(W) is unknown. The trait does not appear to be due to the previously described mutations in bone morphogenetic protein 15 (BMP15), growth differentiation factor 9 (GDF9), or bone morphogenetic protein receptor type 1B (BMPR1B) that affect ovulation rate in sheep. Potentially, FecX2(W) could be an unidentified genetic mutation in BMP15 or in the closely related GDF9, which interacts with BMP15 to control ovarian function. Alternatively, FecX2(W) may affect ovulation rate by changing the expression patterns in the molecular pathways activated by genes known to regulate ovulation rate. The objectives of these experiments were to sequence the complete coding region of the BMP15 and GDF9 genes, determine the patterns of expression of mRNAs encoding GDF9, BMP15, TGFBR1, BMPR1B, and BMPR2 during follicular development, and characterize the follicular populations in ewes heterozygous for the Woodlands mutation and their wild-type contemporaries. No differences in the coding sequences of BMP15 or GDF9 genes were identified that were associated with enhanced ovulation rate. The expression patterns of GDF9 and BMPR2 mRNAs were not different between genotypes. However, expression of BMP15 mRNA was less in oocytes of FecX2(W) ewes in large preantral and antral follicles. Expression of ALK5 mRNA was significantly higher in the oocytes of FecX2(W) ewes, whereas expression of BMPR1B was decreased in both oocytes and granulosa cells of FecX2(W) ewes. FecX2(W) ewes also had increased numbers of antral follicles <1 mm in diameter. These follicles were smaller in average diameter, with the oocytes also being of a smaller mean diameter. Given that a mutation in BMP15 or BMPR1B results in increased ovulation rates in sheep, the differences in expression levels of BMP15 and BMPR1B may play a role in the increase in ovulation rate observed in Woodlands ewes with the FecX2(W) mutation. PMID- 17715430 TI - Uterine stretch regulates temporal and spatial expression of fibronectin protein and its alpha 5 integrin receptor in myometrium of unilaterally pregnant rats. AB - The adaptive growth of the uterus during pregnancy is a critical event that involves increased synthesis of extracellular matrix (ECM) proteins and dynamic remodeling of smooth muscle cell (SMC)-ECM interactions. We have previously found a dramatic increase in the expression of the mRNAs that encode fibronectin (FN) and its alpha5-integrin receptor (ITGA5) in pregnant rat myometrium near to term. Since the myometrium at term is exposed to considerable mechanical stretching of the uterine wall by the growing fetus(es), the objective of the present study was to examine its role in the regulation of FN and ITGA5 expression at late gestation and during labor. Using myometrial tissues from unilaterally pregnant rats, we investigated the temporal changes in Itga5 gene expression in gravid and empty uterine horns by Northern blotting and real-time PCR, in combination with immunoblotting and immunofluorescence analyses of the temporal/spatial distributions of the FN and ITGA5 proteins. In addition, we studied the effects of early progesterone (P4) withdrawal on Itga5 mRNA levels and ITGA5 protein detection. At all time-points examined, the Itga5 mRNA levels were increased in the gravid uterine horn, compared to the empty horn (P < 0.05). Immunoblot analysis confirmed higher ITGA5 and FN protein levels in the myometrium, associated with gravidity (P < 0.05). Immunodetection of ITGA5 was consistently high in the longitudinal muscle layer, increased with gestational age in the circular muscle layer of the gravid horn, and remained low in the empty horn. ITGA5 and FN immunostaining in the gravid horn exhibited a continuous layer of variable thickness associated directly with the surfaces of individual SMCs. In contrast to the effects of stretch, P4 does not appear to regulate ITGA5 expression. We speculate that the reinforcement of the FN-ITGA5 interaction: 1) contributes to myometrial hypertrophy and remodeling during late pregnancy; and 2) facilitates force transduction during the contractions of labor by anchoring hypertrophied SMCs to the uterine ECM. PMID- 17715431 TI - Bovine luteal cells stimulate proliferation of major histocompatibility nonrestricted gamma delta T cells. AB - Luteal cells are potent activators of T cell proliferation in vitro. The purpose of this study was to determine which subset of T cells is stimulated by luteal cells and whether luteal cell-induced T cell activation elicits a proinflammatory or anti-inflammatory T cell response. The first objective was to determine if luteal cell-stimulated T cell proliferation was mediated by class I or II major histocompatibility complex (MHC) molecules. T cell proliferation was inhibited by anti-MHC class I but not anti-MHC class II antibodies. The second objective was to determine which T cell subtype proliferates when cultured with luteal cells. The proportions of CD4(+) and CD8(+) cells were unchanged, but the number of gamma delta T cells was increased by coculture with luteal cells. Immunohistochemistry confirmed the presence of gamma delta T cells in midcycle and regressing corpus luteum. The final objective was to characterize T cell cytokine production stimulated by luteal cells. The concentrations of interferon gamma (IFNG) and interleukin 10 (IL10) were increased in luteal cell-T cell cocultures, whereas IL4 was undetectable, and IL12 was barely detectable in culture medium. It was concluded that coculture of luteal cells and T cells resulted in activation of a somewhat unique T cell subset, gamma delta T cells, as well as production of both pro- and anti-inflammatory cytokines. To our knowledge, this is the first report of gamma delta T cell activation by luteal parenchymal cells of any species, raising the possibility that tissue-resident gamma delta T cells are involved in regulating the balance between tissue homeostasis and luteolysis. PMID- 17715432 TI - Effects of CDB-4022 on Leydig cell function in adult male rats. AB - CDB-4022, an indenopryridine, suppresses spermatogenesis and decreases inhibin secretion in adult male rats. In the present study, we investigated the effects of CDB-4022 on Leydig cell function. A single oral dose of CDB-4022 (2.5 mg/kg) resulted in a 2-fold decrease in serum testosterone levels after 7 days that was paralleled by a decrease in Cyp17a1 mRNA and protein levels and 17alpha hydroxylase enzymatic activity compared with vehicle-treated rats. Consistent with the lower serum testosterone levels, pituitary Lhb and Fshb mRNA levels were increased 3.2- and 2.3-fold, respectively, by CDB-4022 treatment. Ultrastructural analysis of pituitary gonadotrophs showed distended endoplasmic reticulum (ER) and fewer secretory granules in CDB-4022-treated rats, characteristic of enhanced secretory activity. Conversely, CDB-4022 increased serum progesterone levels, testicular Star mRNA and protein expression, and the number of Leydig cells per testis. Serum inhibin B levels were undetectable in CDB-4022-treated rats, while serum activin A levels were similar to controls, indicating that the CDB-4022 treated rats have an elevated activin A:inhibin B ratio. In the presence of hCG stimulation, activin A directly suppressed testosterone secretion but enhanced progesterone secretion from rat Leydig cell primary cultures. Likewise, treatment of MA-10 cells with activin A was found to enhance cAMP-stimulated progesterone secretion and STAR expression. Together, our data indicate that CDB-4022 treatment inhibits CYP17A1 and stimulates STAR expression, thereby decreasing testosterone but increasing progesterone production. We propose that unopposed actions of activin A most likely contribute to the steroid profile in rats after CDB-4022 treatment. Our findings establish CDB-4022 as a new model to examine intratesticular control mechanisms that modulate Leydig cell gene expression and function. PMID- 17715434 TI - Vitamin D in pregnancy: an old problem still to be solved? PMID- 17715433 TI - Mother-child vitamin D deficiency: an international perspective. PMID- 17715435 TI - The British Paediatric Surveillance Unit: the first 20 years. PMID- 17715436 TI - Dilemmas in the medical treatment of patients facing inevitable death. PMID- 17715437 TI - Images in paediatrics: Sinovenous thrombosis due to mastoiditis. PMID- 17715439 TI - Images in paediatrics: Ironing board impalement. PMID- 17715438 TI - High prevalence of vitamin D deficiency in newborn infants of high-risk mothers. AB - OBJECTIVE: To determine the prevalence of vitamin D deficiency in newborn infants of mothers at risk of vitamin D deficiency because of dark skin or the wearing of concealing clothes (such as a veil) compared with a group presumed not to be at risk. A second aim was to correlate these newborn infants' vitamin D concentrations with biochemical parameters of vitamin D metabolism and bone turnover at birth. DESIGN: A prospective study conducted between April 2004 and February 2006 including women delivering during this period and their newborn infants. SETTING: The outpatient clinic of the obstetrics department, Sint Franciscus Gasthuis, Rotterdam, the Netherlands. PATIENTS: Eighty seven newborn infants of healthy mothers with either dark skin and/or concealing clothing (risk group) or light skin (control group). RESULTS: We found a significant difference in the prevalence of vitamin D deficiency (25-hydroxyvitamin D(3) <25 nmol/l) between newborn infants of mothers at risk and those of mothers in the control group (63.3% vs 15.8%; p<0.001). Mean alkaline phosphatase concentrations were significantly higher in the at risk group. CONCLUSIONS: Newborn infants of mothers with dark skin or wearing concealing clothes are at great risk of vitamin D deficiency at birth. The clinical implications are unknown. Further research is necessary to determine the long-term consequences of maternal and neonatal vitamin D deficiency so that guidelines on vitamin D supplementation during pregnancy can be issued. PMID- 17715441 TI - Very prematurely born infants wheezing at follow-up: lung function and risk factors. AB - OBJECTIVES: To determine whether abnormalities of lung volume and/or airway function were associated with wheeze at follow-up in infants born very prematurely and to identify risk factors for wheeze. DESIGN: Lung function data obtained at 1 year of age were collated from two cohorts of infants recruited into the UKOS and an RSV study, respectively. SETTING: Infant pulmonary function laboratory. PATIENTS: 111 infants (mean gestational age 26.3 (SD 1.6) weeks). INTERVENTIONS: Lung function measurements at 1 year of age corrected for gestational age at birth. Diary cards and respiratory questionnaires were completed to document wheeze. MAIN OUTCOME MEASURES: Functional residual capacity (FRC(pleth) and FRC(He)), airways resistance (R(aw)), FRC(He):FRC(pleth) and tidal breathing parameters (T(PTEF):T(E)). RESULTS: The 60 infants who wheezed at follow-up had significantly lower mean FRC(He), FRC(He):FRC(pleth) and T(PTEF):T(E), but higher mean R(aw) than the 51 without wheeze. Regression analysis demonstrated that gestational age, length at assessment, family history of atopy and a low FRC(He):FRC(pleth) were significantly associated with wheeze. CONCLUSIONS: Wheeze at follow-up in very prematurely born infants is associated with gas trapping, suggesting abnormalities of the small airways. PMID- 17715443 TI - Transition of care from paediatric to adult services in haematology. AB - The need for adequate preparation for transition for young people with health care needs who require long term follow-up in the adult sector has long been recognised and is a required part of the national service framework for children. The Royal College of Paediatrics and Child Health and the Royal College of Nursing have endorsed this need for improvement in services for adolescents. In 2006 the Department of Health launched guidelines with a wealth of recommendations. Despite these initiatives only slow progress has been made (usually by enthusiasts) and much work is needed to develop good programmes in many specialties, including non-malignant haematology. PMID- 17715445 TI - The EU's new paediatric medicines legislation: serving children's needs? AB - In new legislation for paediatric medicines which came into effect on 26 January 2007, the European Union (EU) has attempted to address several unresolved issues relating to children's needs for medicines in Europe. This article reviews the legislation's main proposals and makes some comparisons with equivalent legislation in the USA. We argue that the legislation suffers from several gaps and uncertainties in relation to the specific proposals and their intended aims. As the establishment of new legislation in this area offered the EU an opportunity to set some clear guidelines and objectives, and had the potential to go beyond the equivalent American rules, we thus see the proposals as something of a disappointment. PMID- 17715444 TI - Transition of care from paediatric to adult rheumatology. AB - The origin of paediatric rheumatology in the UK mainly lies in adult rheumatology and this has proved invaluable in terms of transition provision, education and training, and collaborative research. The last 5 years have seen adolescent rheumatology gather momentum with the creation of an objective evidence base, a sound foundation for future work addressing the many unanswered questions and hypotheses in the area of transitional care. The aim of this paper is to review the evidence supporting the recent developments in transitional care within rheumatology. Acknowledging the non-categorical nature of transition, the author will also refer to evidence from other chronic illnesses which has informed these developments. PMID- 17715446 TI - Understanding chronic heart failure. AB - The key principles of chronic heart failure and the development of clinical management strategies are described. The physiological changes in chronic heart failure and the clinical management of children with heart failure are considered, but the treatment of heart failure related to congenital heart disease or the intensive care management of heart failure are not mentioned as both topics require consideration in their own right. A greater understanding of the maladaptive responses to chronic heart failure has enabled targeted therapy to be introduced with consequent improvement in symptoms, reduction in hospitalisation and lower mortality. PMID- 17715447 TI - Towards evidence-based medicine for paediatricians. PMID- 17715448 TI - Is wet combing effective in children with pediculosis capitis infestation? PMID- 17715449 TI - Leukocytosis as a predictor for progression to haemolytic uraemic syndrome in Escherichia coli O157:H7 infection. PMID- 17715450 TI - Is a once daily dose of gentamicin safe and effective in the treatment of uti in infants and children? PMID- 17715451 TI - Avidity of Haemophilus influenzae type b antibody in UK infants. PMID- 17715452 TI - Indication for tracheal intubation in meningococcal disease and septic shock. PMID- 17715453 TI - Introduction of a paediatric pain management protocol improves assessment and management of pain in children in the emergency department. PMID- 17715454 TI - Survey of early identification systems to identify inpatient children at risk of physiological deterioration. PMID- 17715456 TI - Performing saccadic eye movements or blinking improves postural control. AB - To determine the relationship between eye movement and postural control on an undisturbed upright stance maintenance protocol, 15 young, healthy individuals were tested in various conditions. These conditions included imposed blinking patterns and horizontal and vertical saccadic eye movements. The directions taken by the center of pressure (CP) were recorded via a force platform on which the participants remained in an upright position. The CP trajectories were used to estimate, via a low-pass filter, the vertically projected movements of the center of gravity (CGv) and consequently the difference CP-CGv. An analysis of the frequency shows that regular bilateral blinking does not produce a significant change in postural control. In contrast, performing saccadic eye movements induces some reduced amplitude for both basic CGv and CP-CGv movements principally along the antero-posterior axis. The present result supports the theory that some ocular movements may modify postural control in the maintenance of the upright standing position in human participants. PMID- 17715457 TI - Postural control in down syndrome: the use of somatosensory and visual information to attenuate body sway. AB - The purpose of this study was to examine the effects of visual and somatosensory information on body sway in individuals with Down syndrome (DS). Nine adults with DS (19-29 years old) and nine control subjects (CS) (19-29 years old) stood in the upright stance in four experimental conditions: no vision and no touch; vision and no touch; no vision and touch; and vision and touch. In the vision condition, participants looked at a target placed in front of them; in the no vision condition, participants wore a black cotton mask. In the touch condition, participants touched a stationary surface with their right index finger; in the no touch condition, participants kept their arms hanging alongside their bodies. A force plate was used to estimate center of pressure excursion for both anterior posterior and medial-lateral directions. MANOVA revealed that both the individuals with DS and the control subjects used vision and touch to reduce overall body sway, although individuals with DS still oscillated more than did the CS. These results indicate that adults with DS are able to use sensory information to reduce body sway, and they demonstrate that there is no difference in sensory integration between the individuals with DS and the CS. PMID- 17715458 TI - Joint-action coordination of redundant force contributions in a virtual lifting task. AB - In this study we investigated redundancy control in joint action. Ten participantpairs (dyads) performed a virtual lifting task in which isometric forces needed to be generated with two or four hands. The participants were not allowed to communicate but received continuous visual feedback of their performance. When the task had to be performed with four hands, participants were confronted with a redundant situation and between-hand force synergies could, in principle, be formed. Performance timing, success rates, cross-correlations, and relative phase analyses of the force-time functions were scrutinized to analyze such task-dependent synergies. The results show that even though the dyads performed the task slower and less synchronized in the joint than in the solo conditions, the success rates in these conditions were identical. Moreover, correlation and relative phase analyses demonstrated that, as expected, the dyads formed between-participant synergies that were indicative of force sharing in redundant task conditions. PMID- 17715459 TI - Analyzing variance in multi-degree-of-freedom movements: uncovering structure versus extracting correlations. AB - An important aspect of the study of multi-degree-of-freedom motor control is the analysis of high-dimensional variance data. Through the "uncontrolled manifold" (UCM) approach the structure in such data can be discovered and interpreted. The covariation by randomization (CR) approach provides nonlinear and potentially multi-dimensional measures of covariance. We critically examine these two approaches and compare them relative to the three fundamental issues of choice of variables, choice of model, and adoption of either a geometrical or a correlational view of variance. The UCM approach is a geometrical approach that seeks to discover the structure of variance in multi-degree-of-freedom task spaces in which all degrees of freedom have a common metric. The structure of variance in that space is interpreted in terms of its meaning for task variables. The CR approach seeks to uncover correlations between interpretable elemental variables. It requires a defined and common metric in the space of task variables, but not the elemental variables. Although the CR approach is better suited for systems with strong nonlinearities, variance structure that is not caused by correlation but by different amounts of variance in the different elemental variables is undetected by this approach. PMID- 17715460 TI - Toward a new theory of motor synergies. AB - Driven by recent empirical studies, we offer a new understanding of the degrees of freedom problem, and propose a refined concept of synergy as a neural organization that ensures a one-to-many mapping of variables providing for both stability of important performance variables and flexibility of motor patterns to deal with possible perturbations and/or secondary tasks. Empirical evidence is reviewed, including a discussion of the operationalization of stability/flexibility through the method of the uncontrolled manifold. We show how this concept establishes links between the various accounts for how movement is organized in redundant effector systems. PMID- 17715461 TI - Solvent-stable Pseudomonas aeruginosa PseA protease gene: identification, molecular characterization, phylogenetic and bioinformatic analysis to study reasons for solvent stability. AB - We have previously isolated a solvent-stable protease from a novel solvent tolerant strain of Pseudomonas aeruginosa (PseA). Here we report cloning and characterization of the gene coding for this solvent-tolerant protease. A homology search of the N-terminal amino acid sequence of the purified PseA protease revealed an exact match to a P. aeruginosa PST-01 protease gene, lasB. The c-DNA sequence of the PST-01 protease was used to design primers for the amplification of a 1,494-bp open reading frame encoding a 53.6-kDa, 498-amino acid PseA LasB polypeptide. The deduced PseA LasB protein contained a 23-residue signal peptide (2.6 kDa) followed by a propeptide of 174 residues and a 33-kDa mature product of 301 residues. A phylogenetic analysis placed PseA lasB closest to the known zinc metalloproteases from P. aeruginosa. This gene was also found to contain a conserved HEXXH zinc-binding motif, characteristic of all zinc metallopeptidases. The 3D structure analysis of PseA protease revealed the presence of 7 alpha-helices (36% of the sequence). The molecule was found to have two disulfide bonds (between Cys-227 and Cys-255 and between Cys-467 and Cys-494) and had a number of hydrophobic clusters at the protein surface. These hydrophobic patches (21% of the sequence) and disulfide bonds may possibly be responsible for the solvent-stable nature of the enzyme. PMID- 17715462 TI - Leukemia inhibitory factor-expressing human embryonic lung fibroblasts as feeder cells for human embryonic germ cells. AB - A robust culture system is critical for maintaining both proliferation and the developmental potential of human embryonic germ (hEG) cells. Here, we use human embryonic lung fibroblasts (hELF) overexpressing leukemia inhibitory factor (LIF) as feeder cells to support the self-renewal of hEG cells. We examine the morphology, gene expression, and developmental potential of hEG cells grown on a feeder layer of LIF-expressing hELF (hELF/lif) cells. hEG cells were positive for alkaline phosphatase (AP), stage-specific embryonic antigen (SSEA)-1, SSEA-4, tumor rejection antigen (TRA)-1-60, and TRA-1-81. In addition, hEG cells maintained on hELF/lif expressed higher levels of pluripotency genes such as Oct4 and Nanog. In addition, hEG cells maintained on hELF/lif cells gave rise to differentiated tissues when grown as embryoid bodies, consistent with the broad developmental potential of the starting population. Our results suggest that a hELF/lif feeder layer can support the proliferation of hEG cells, and that LIF signaling plays an essential role in this process. This human-derived culture system provides an attractive alternative to more commonly used mouse-derived feeder layers for use in clinical applications. PMID- 17715463 TI - Facioscapulohumeral muscular dystrophy: a multicenter study on hearing function. AB - Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant progressive myopathy, characteristically associated with a 4q35 deletion. In the unusual infantile-onset form of this degenerative disease, sensorineural hearing loss is a frequent clinical manifestation, whereas in patients with typical late onset FSHD, investigations regarding hearing impairment yielded controversial results. We describe the findings of a multicenter investigation on possible auditory impairment in a series of 73 FSHD patients with a genetically confirmed diagnosis. Among them, 49 cases with no risk factors for deafness, aside from the disease, were identified by a clinical questionnaire and otoscopic examination (mean age 37.8 years, 31 males and 18 females). These subjects were evaluated by pure-tone audiometry. None were aware of hearing loss, while 4 had raised unilateral or bilateral pure-tone audiometric thresholds at 4000 and 8000 Hz, when evaluated by standardized tables. However, the mean raw pure-tone audiometric threshold values for these 49 cases were not significantly different from those of 55 controls (mean age 37.1 years, 32 males and 23 females). Moreover, by statistical analysis, age of onset, degree of muscular weakness and 4q35 EcoRI fragment size made no significant difference to auditory thresholds in our FSHD patients. Overall, the results of our multicenter study suggest that hearing loss in typical FSHD is not more prevalent than in the normal population. PMID- 17715464 TI - The effects of electrode montage on the amplitude of wave V in the auditory brainstem response to maximum length sequence stimuli. AB - The use of maximum length sequence (MLS) stimuli to elicit an auditory brainstem response (ABR) has been limited, in part, by the observation that these stimuli reduce ABR wave amplitudes. This study recorded ABR waveforms from 14 normally hearing adults using MLS click stimuli (maximum stimulus rate = 250 clicks per second) at stimulus levels of 70, 60, 50, 40, 30 and 20 dB nHL, with a vertical and then an ipsilateral electrode montage. The vertical electrode montage produced significantly larger (p < 0.05) wave V amplitudes, with no change in wave V latencies (p > 0.05), at all stimulus levels. This result suggests a vertical electrode montage could be used to counter some of the loss in wave V amplitude observed when using MLS stimuli. PMID- 17715465 TI - Effects of ambient acoustic noise on the auditory steady-state response thresholds in normally hearing adults. AB - The effect of noise on auditory steady-state response (ASSR) has not been systematically studied, despite the fact that ASSR thresholds are sometimes measured in noisy environments. This study examined the effects of noise (speech babble) on the ASSR thresholds obtained from 31 normal hearing adults aged from 17 to 36 years (mean = 25 years). The ASSR thresholds at 0.5, 1, 2 and 4 kHz were measured in the right ear only using the Biologic MASTER system twice in quiet and in the presence of 55 dB A and 75 dB A of speech babble. The results showed no change in mean ASSR thresholds across the test-retest conditions in quiet. The mean ASSR thresholds obtained in the quiet conditions were 23.8, 22.5, 18.2 and 20.4 dB HL at 0.5, 1, 2 and 4 kHz, respectively. No significant shift in ASSR thresholds across all test frequencies was found when 55 dB A of speech babble was presented. However, when 75 dB A of noise was applied, the mean ASSR thresholds were significantly shifted by 9.5, 3.8, 4.2 and 5.8 dB at 0.5, 1, 2 and 4 kHz, respectively. PMID- 17715466 TI - Vestibular rehabilitation in individuals with inner-ear dysfunction: a pilot study. AB - A randomised control prospective study was carried out examining patient outcomes after performing a 10-week vestibular home exercise programme. Thirty-two adults with vestibular dysfunction who reported vestibular symptoms negatively affecting daily life were enrolled. Test subjects were provided with an individualised vestibular rehabilitation programme designed by a physiotherapist. Control subjects received a set of strength and endurance exercises only. All subjects performed their exercises 3 times a day for 10 weeks. Subjective and objective patient measures were collected at 0, 6, 10 and 26 weeks. Results showed that both groups improved after beginning exercise, and that test subjects significantly benefited compared to the controls. These benefits were long term and measurable 6 months later. This study provides evidence that individualised vestibular exercises promote better outcomes for patients with vestibular dysfunction. PMID- 17715468 TI - The discovery of salicylate ototoxicity. AB - Although the name of the discoverer of salicylate ototoxicity is still debated, most authors have quoted Muller and his 1877 report. To the best of our knowledge, the true discoverer of the transient ototoxicity of salicylate was the Italian chemist Cesare Bertagnini who reported this evidence in 1855 in the journal Il Nuovo Cimento. PMID- 17715467 TI - Effects of sex, age and hearing asymmetry on the interaural differences of auditory brainstem responses. AB - Healthy patients with asymmetric sensorineural hearing loss who had received examination of auditory brainstem responses (ABR) were gathered for retrospective analysis. The effects of sex, age and hearing asymmetry on the interaural differences of ipsilateral ABR were determined by multivariant linear regression. Our results showed that the interaural differences of ABR wave III and wave V latencies were significantly affected by hearing asymmetry but not by sex or age. However, in female subjects younger than 50 years, differences of III-V intervals could be negatively correlated with hearing asymmetry. We suggest that plasticity in the auditory brainstem in younger females might account for asymmetrical peripheral hearing in this group. PMID- 17715469 TI - Outer- and middle-ear contributions to presbycusis in the Brown Norway rat. AB - This paper examines the contribution of the outer and middle ears to the hearing loss associated with presbycusis in Brown Norway rats. Animals were formed into two groups; young adults (2-3 months old) and aged animals (approximately 34 months old). Auditory brainstem response (ABR) thresholds were obtained with the outer ear intact or surgically removed. Tympanic membrane (TM) velocity transfer functions were measured from the umbo with the outer ear removed. The length of the auditory meatus, TM surface area, and TM thickness were quantified. The ABR thresholds were 17-26 dB less sensitive in the aged animals between 8.0 and 40.0 kHz when the outer ear was intact. A significant and reliable reduction in the aged rat velocity transfer function of 5-8 dB occurred between 10.0 and 32.0 kHz, while the low frequency velocity response was only a few decibels greater in the younger animals. The ABR threshold differences between young adult and aged ears were compensated by removing the outer/middle ear effects of aging to reveal a purely sensorineural component of presbycusis. The outer and middle ear effects were calculated directly when the ABR and TM velocity data were obtained with the outer ear removed. The outer ear intact condition was modeled in order to compare the ABR data obtained with the outer ear intact with the TM velocity data obtained with the outer removed. With either procedure, removal of the age related contributions of the outer and middle ear to the ABR threshold resulted in similar age-related ABR threshold shifts between the two age groups. The pure sensorineural threshold shift component of the ABR response was restricted to frequencies between 5.0 and 20.0 kHz and reached a maximum of approximately 15 dB. These results support the conclusion that there is an outer- and middle-ear contribution to the threshold loss defining presbycusis. PMID- 17715470 TI - NOTES: a new way of performing surgery using natural body orifices. PMID- 17715471 TI - Mental health and the city. PMID- 17715472 TI - Debate over pollution. PMID- 17715473 TI - Traffic safety. PMID- 17715474 TI - ["Selection is not free of moral values"]. PMID- 17715476 TI - Breast metastasis in a male patient with nonsmall cell lung carcinoma. PMID- 17715475 TI - [Diabetic patient with weight loss and sleep disorders. Why is blood glucose level suddenly out of control?]. PMID- 17715477 TI - Life-threatening, multiple hypersensitivity reactions induced by rifampicin in one patient with pulmonary tuberculosis. PMID- 17715478 TI - Fifty-six-month sentence for unprotected sex with two girlfriends. PMID- 17715479 TI - Court rejects appeal where man disclosed HIV status to police, claimed he didn't know HIV endangered life. PMID- 17715480 TI - Federal Court rejects "irreparable harm" argument of HIV-positive failed refugee claimant seeking to stop deportation. PMID- 17715481 TI - UK: man sentenced to nine years for reckless transmission of HIV and HCV. PMID- 17715482 TI - Australia: HIV-positive man facing criminal charges fails attempt to have his identity suppressed. PMID- 17715483 TI - India: Supreme Court suspends manufacture of ayurvedic medicine being sold as a "cure" for AIDS. PMID- 17715484 TI - I have skin cancer. Should I consider Mohs' surgery? PMID- 17715485 TI - Are canned fruits and vegetables a healthy alternative to fresh produce? PMID- 17715486 TI - Diagnostic quiz. Case No. 2: central ossifying fibroma. PMID- 17715488 TI - Diagnostic quiz. Case No. 2: zygomycotic sinusitis. PMID- 17715487 TI - Erratum to "changes in cutaneous sensory nerve fibers induced by skin-scratching in mice". AB - BACKGROUND: Skin-scratching behavior, a common response observed in patients with pruritus, is supposed to promote the sprouting of cutaneous sensory nerve fibers. Thus, it sometimes exacerbates the original lesions. However, the precise changes that develop in cutaneous sensory nerve fibers after skin-scratching have not yet been elucidated. OBJECTIVE: To investigate how and what kinds of cutaneous sensory nerve fibers increase and how nerve growth factor (NGF) and its receptors change after skin-scratching. METHODS: After scratching the dorsal skin of anesthetized ICR mice, change in cutaneous nerve fibers was detected by immunofluorescence for protein gene product 9.5 (PGP9.5), substance P (SP) and/or calcitonin gene-related peptide (CGRP). To investigate the involvement of NGF signaling, the production of NGF and the expression of its receptors were examined using ELISA and/or immunofluorescence, respectively. RESULTS: Skin scratching dramatically induced the sprouting of cutaneous nerve fibers. Both dermal and epidermal nerve fibers began to increase and reached a peak at days 3 7. At the same time, nerve fibers containing SP or CGRP increased significantly. NGF in the scratched skin increased immediately and reached a peak at days 1-3. The expression of NGF receptors, such as phosphorylated trk A and p75, on nerve fibers was remarkably upregulated within 2 days. CONCLUSIONS: Skin-scratching induced the sprouting of cutaneous sensory nerve fibers in the skin within several days, thus possibly leading to enhanced neurogenic inflammation. Analysis of the expression of NGF and its receptors suggest that NGF signaling may be, at least in part, involved in these changes. PMID- 17715490 TI - Heat waves and heat-related illness: preparing for the increasing influence of climate on health in temperate areas. PMID- 17715489 TI - Diagnostic quiz. Case No. 2: erythema migrans. PMID- 17715491 TI - Ability of prenylflavanones present in hops to induce apoptosis in a human Burkitt lymphoma cell line. AB - The identification of effective cancer preventive compounds from hops has become an important issue in public health-related research. We compared the antiproliferative and apoptosis-inducing effects of side chain variants of prenylflavanones, e. g., 8-prenylnaringenin (7) and 8-geranylnaringenin (10), which have been identified in hops (Humulus lupulus), and their synthetic variations 8-furanmethylnaringenin (8) and 8-cinnamylnaringenin (9). These were accessible by a Mitsunobu reaction and Claisen rearrangement. Flavanones 9 and 10 showed cytotoxic and apoptotic activities. Apoptosis was induced in a mitochondrial dependent manner. 8-Cinnamylnaringenin (9) displayed noticeably improved apoptotic effects when compared to 8-prenylnaringenin. The potential of 8-prenylnaringenin (7) is shown in an ex vivo experiment on a multi-drug resistant leukaemia blast. PMID- 17715492 TI - Exploring the information in p-values for the analysis and planning of multiple test experiments. AB - A new methodology is proposed for estimating the proportion of true null hypotheses in a large collection of tests. Each test concerns a single parameter delta whose value is specified by the null hypothesis. We combine a parametric model for the conditional cumulative distribution function (CDF) of the p-value given delta with a nonparametric spline model for the density g(delta) of delta under the alternative hypothesis. The proportion of true null hypotheses and the coefficients in the spline model are estimated by penalized least squares subject to constraints that guarantee that the spline is a density. The estimator is computed efficiently using quadratic programming. Our methodology produces an estimate g(delta) of the density of delta when the null is false and can address such questions as "when the null is false, is the parameter usually close to the null or far away?" This leads us to define a falsely interesting discovery rate (FIDR), a generalization of the false discovery rate. We contrast the FIDR approach to Efron's (2004, Journal of the American Statistical Association 99, 96 104) empirical null hypothesis technique. We discuss the use of g in sample size calculations based on the expected discovery rate (EDR). Our recommended estimator of the proportion of true nulls has less bias compared to estimators based upon the marginal density of the p-values at 1. In a simulation study, we compare our estimators to the convex, decreasing estimator of Langaas, Lindqvist, and Ferkingstad (2005, Journal of the Royal Statistical Society, Series B 67, 555 572). The most biased of our estimators is very similar in performance to the convex, decreasing estimator. As an illustration, we analyze differences in gene expression between resistant and susceptible strains of barley. PMID- 17715494 TI - Biofuels and the environment. PMID- 17715493 TI - Urinary metabolic fingerprinting for thioacetamide-induced rat acute hepatic injury using fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS), with reference to detection of potential biomarkers for hepatotoxicity. AB - In this study, we performed urinary metabolic fingerprinting using Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS) in the thioacetamide (TAA)-induced rat model of acute hepatic injury to search for useful biomarkers involved in the acute hepatic toxicity. TAA was intraperitonealy administered a single dose of 300 mg/kg, and urine sample and livers were collected on predose, and days 1, 3, 5, and 7 postdose (Days 1, 3, 5, and 7). Histopathologically, infiltration of macrophages occurred in the TAA induced centrilobular injured area on Days 1 and 3, and the injured liver recovered on Days 5 and 7. On the scores plot of principal component analysis (PCA), the ion profiles of Days 1 and 3 were different from those of the predose, Days 5 and 7. The loading plot revealed that the metabolites causing PCA results were m/z 266.05390, 401.20737, and 429.23882. The ion at m/z 266.05390 was identified as a potassium ion adduct of deoxycytidine (dCyt). Because the appearance of urinary dCyt was corresponding to macrophage infiltration in the rat-injured liver, it was considered that the urinary dCyt might be released from infiltrated macrophages. dCty might be a biomarker for the acute hepatotoxicity in rats. PMID- 17715495 TI - Common goals. PMID- 17715496 TI - Diabetes drugs under scrutiny in a post-Vioxx world. PMID- 17715497 TI - 'Back to the future' for Chinese herbal medicines. PMID- 17715498 TI - An audience with... Joseph DiMasi. PMID- 17715499 TI - Tapping the potential of fixed-dose combinations. PMID- 17715501 TI - [Treatment of bleeding gastroduodenal ulcers]. PMID- 17715500 TI - Eculizumab. PMID- 17715502 TI - [Spontaneous rupture of thoracic esophagus complicated with purulent mediastinitis, two-sided hydropneumothorax, pleural empyema and bronchial fistula]. PMID- 17715503 TI - [Hemangioma of small intestine complicated with profuse hemorrhage]. PMID- 17715504 TI - [Methods of treatment of chronic thromboembolic pulmonary hypertension]. PMID- 17715505 TI - [Reflux-esophagitis: current state of problem]. PMID- 17715506 TI - [To 150th birthday anniversary of Prof. V.I. Razumovsky]. PMID- 17715507 TI - [Main stages of formation and development of esophagus surgery at Russia in XIX XX century]. PMID- 17715508 TI - Rapid, low-cost DNA testing. PMID- 17715509 TI - An error in the code: what can a rare disorder tell us about human behavior? PMID- 17715510 TI - Slippery business: the trade in adulterated olive oil. PMID- 17715511 TI - Proceedings of the 4th International Conference on Oxidation Technologies for Water and Wastewater Treatment, Goslar, Germany, 15-17 May 2006. PMID- 17715512 TI - Falling: Can you parachute twenty-five miles and survive? PMID- 17715513 TI - Findings of misconduct in science. PMID- 17715514 TI - Health care braces for boomers; one in six will have multiple chronic illnesses by 2030. PMID- 17715515 TI - Self-inflicted gunshot wound mimicking assault: a rare variant of factitious disorder. AB - This paper presents the case of 52-year-old man who died in an attempt to prove factitious allegations of persecution. To the best of our knowledge, there are no other reported cases of a self-inflicted, long-distance gunshot injury causing death. We discuss other cases of crime-scene "staging" and review the literature on factitious disorders and malingering in our search for motive, and stress again the importance of crime scene analysis and investigation of circumstances in determining the manner of death. PMID- 17715516 TI - Endogenous androgens and cardiovascular risk. PMID- 17715518 TI - Engendering bold leadership against HIV/AIDS. AB - The importance of leadership, especially human rights-driven leadership, in the fight against HIV/AIDS is widely recognized. However, argues Michael Pates in this commentary, the type of bold leadership required to really make a difference has been lacking. Pates calls for the development of an AIDS Leadership Initiative and describes how it might happen. PMID- 17715517 TI - Male circumcision and HIV prevention: a human rights and public health challenge. AB - Three recent randomized clinical trials from Africa concluded that male circumcision can lead to a significant reduction in HIV risk for men. As a result, an exponential scale-up of services required to circumcise men is already figuring in the thinking of AIDS policy-makers at many levels. At this writing, the World Health Organization (WHO) is reviewing the three studies and other evidence, and is developing policy recommendations for making this HIV prevention intervention widely available. WHO says that this policy exercise"will need to take into account cultural and human rights considerations associated with promoting circumcision,"among other factors. In this article, Joanne Csete identifies some of the most important human rights questions that should be taken into account in the development of guidelines for national governments. The author argues that a scale-up of services to provide male circumcision provides an excellent opportunity to address issues concerning the subordination of women. PMID- 17715519 TI - Subcommittee fails to recommend legal reforms needed to promote human rights of sex workers. AB - In December 2006, the House of Commons Subcommittee on Solicitation Laws released its longawaited report on the criminal laws related to prostitution in Canada, entitled The Challenge of Change: A Study of Canada's Criminal Prostitution Laws. The Subcommittee's report fails to call for amendments to the Criminal Code provisions which have been demonstrated to increase the health and safety threats faced by sex workers. The Canadian HIV/AIDS Legal Network and two sex worker organizations, Stella and Maggie's, jointly published an analysis of the report. PMID- 17715520 TI - Conservative government ends funding for research on Insite. AB - The federal government has stopped providing funding for for the ongoing evaluation of Insite, North America's only supervised injection facility (SIF), even as the latest studies continue to demonstrate the positive impact of the facility. PMID- 17715521 TI - Draft evaluation suggests pilot safer tattooing program had potential to reduce disease transmission. AB - As reported in the last issue of the Review, effective 30 September 2006 the Canadian federal government terminated the pilot safer tattooing initiative which had been operating in six prisons.1 A draft of the evaluation report, obtained under access to information laws, detailed positive outcomes, constraints and enhancements to address implementation issues and cost-effectiveness of the initiative. PMID- 17715522 TI - Public health agency says prison needle exchanges reduce risk, do not threaten safety or security. AB - In April 2006, the Public Health Agency of Canada (PHAC) provided a report to the Correctional Service of Canada (CSC) regarding the potential risks and benefits of introducing needle exchange programs in Canadian federal prisons (PNEPs). The PHAC report concludes that while definitive data concerning the impact of PNEPs on the transmission of blood-borne pathogens among prisoners does not exist, such programs have resulted in a decrease in behaviours which risk transmission and have not threatened prison safety or security. PMID- 17715523 TI - Ontario passes new mandatory blood testing law: a preliminary review. AB - In December 2006, the Mandatory Blood Testing Act, 2006 passed third reading in the Legislative Assembly of Ontario. When this new Act comes into force, it will replace the existing administrative system for forced blood testing, currently operating under Ontario's public health law. Responsibility for forced blood testing will shift from the Minister of Health and Long-Term Care to the Minister of Community Safety and Corrections. PMID- 17715524 TI - Bill eliminating conditional sentences amended to exclude drug offences. AB - Opposition parties in the House of Commons have forced changes to legislation introduced by the minority Conservative government designed to eliminate conditional sentencing for certain offences. The legislation no longer applies to drug offences. PMID- 17715525 TI - Vancouver: Mayor proposes new treatment plan for stimulant-drug users. AB - Vancouver Mayor Sam Sullivan is pushing for the establishment of a drug substitution treatment program for the city's cocaine and crystal-meth users. The program would take the form of a clinical trial for up to 700 users. PMID- 17715526 TI - Funding announcements from federal government, Gates Foundation. AB - In two separate announcements, in December 2006 and February 2007, the federal government allocated new funding for HIV/AIDS. The latter announcement was accompanied by a pledge from the Gates Foundation. PMID- 17715527 TI - Progress report on national pharmaceuticals strategy released. PMID- 17715528 TI - Auditor-General critical of Health Canada regulatory performance. PMID- 17715529 TI - Thailand: government issues compulsory licences for HIV/AIDS drugs. AB - In January 2007, the government of Thailand issued compulsory licences for two medicines in an effort to lower prices on drugs for treatment of heart disease and HIV/AIDS. The drugs in question are Plavix, a blood thinner for heart disease, and the HIV/AIDS drug Kaletra. A compulsory licence had previously been issued for Efavirenz, another HIV/AIDS drug, in November 2006. PMID- 17715530 TI - U.S.: proposed federal legislation to allow condom distribution and HIV testing in prison. AB - Representative Barbara Lee (D-CA) is reintroducing legislation in the U.S. House of Representatives that would require federal correctional facilities to allow community organizations to distribute condoms and provide voluntary counselling and testing for HIV and STDs for inmates. The bill has been referred to the House Judiciary Committee's Subcommittee on Crime, Terrorism, and Homeland Security. PMID- 17715531 TI - Russian Federation: governments threaten freedom of association and assembly for LGBT organizations. AB - Moscow Mayor Yuri Luzhkov has insisted that he will not allow the Moscow's Gay Pride parade,scheduled for 27 May 2007, to go ahead, calling it a "satanic" event. Luzhkov banned the first planned Gay Pride parade which was scheduled to take place on the same date in 2006. On that occasion, the authorities stated that permission for the event was denied because of impossibility to provide adequate security for the participants. Two court decisions later affirmed the ban. PMID- 17715532 TI - Russian Federation: inhumane conditions in drug treatment facilities lead to tragedy. AB - On 9 December 2006, a fire in a Moscow drug treatment hospital caused the death of 44 HIV-positive women undergoing treatment for drug dependence, and two hospital staff. An additional 11 people were severely burnt in the fire. PMID- 17715533 TI - U.K.: new publications on HIV transmission and exposure and the criminal justice system. AB - Two important new medico-legal publications aimed at individuals who work within- or are in contact with--the criminal justice system have recently been published by two U.K.-based organisations,NAM (a community-based provider of HIV information) and the National AIDS Trust (NAT).Although both publications are U.K.-focused, much of the information is relevant to other settings. PMID- 17715534 TI - India: multi-national pharmaceutical company challenges patent law. PMID- 17715535 TI - UNHCR: new strategy for provision of antiretroviral therapy to refugees. PMID- 17715536 TI - Africa: new report on how HIV/AIDS programming is failing LGBT people. PMID- 17715537 TI - Federal Court of Appeal examines for first time refugee protection on the basis inadequate health care. AB - On 10 November 2006, in a precedent-setting case, the Federal Court of Appeal dismissed an application by a Mexican national to remain in Canada as a "person in need of protection" under the Immigration and Refugee Protection Act (IRPA). The principal issue before the Court was whether the IRPA excludes from protection people who face a risk to life if returned to their home country, where the risk arises from the fact the government does not provide affordable medical treatment. PMID- 17715538 TI - Criminal law and HIV transmission or exposure: new cases and developments. PMID- 17715540 TI - Smoking worsens degenerative knee arthritis. PMID- 17715539 TI - Health tips. Sources of soluble fiber. PMID- 17715541 TI - The power of 3. Omega-3 fatty acids. PMID- 17715542 TI - Age-related hearing loss. Know the signs. PMID- 17715543 TI - Are electric toothbrushes better than regular toothbrushes? PMID- 17715544 TI - Rethinking posttraumatic stress disorder. What is a traumatic event, and how does it produce symptoms? PMID- 17715545 TI - Antipsychotic drugs in dementia. PMID- 17715546 TI - Treatment for bipolar depression: new studies. PMID- 17715547 TI - Torture by any other name. PMID- 17715548 TI - The Clock gene and bipolar disorder. Commentary. PMID- 17715549 TI - Travel by sea: health considerations. PMID- 17715550 TI - Lecturers' and students' perceptions of current teaching methods about schizophrenia. PMID- 17715551 TI - Re: the democratization of psychiatry. PMID- 17715553 TI - Building a Vertical Advisory system: how to succeed as an educator and mentor without going insane. AB - Creating and using a Vertical Advisory system allows students and residents to obtain rapid and effective responses to questions or requests for advice. It also encourages this group to become active advisors, teachers, and mentors to those behind them, in the hopes of nurturing strong future academic role models and mentors. PMID- 17715552 TI - What is unique about your role in patient education? PMID- 17715554 TI - The order behind reverse logic: adverse effects in a controversial environment. PMID- 17715555 TI - [Pius Brinzeu (1911-2002)]. PMID- 17715557 TI - Abstracts of the XXXVIII Annual Meeting of the Argentine Society of Experimental Pharmacology, November 1-3, 2006, Cordoba, Argentina. PMID- 17715556 TI - The Hellenic Journal of Cardiology and the Internet. PMID- 17715558 TI - Abstracts of the VIII Congress, XXVI Annual Meeting of the Rosario Biology Society, December 5-7, 2006, Rosario, Argentina. PMID- 17715560 TI - AARC clinical practice guideline. Long-term invasive mechanical ventilation in the home--2007 revision & update. PMID- 17715561 TI - AARC clinical practice guideline. Oxygen therapy in the home or alternate site health care facility--2007 revision & update. PMID- 17715562 TI - Check Program. PMID- 17715559 TI - Abstracts of the Cuyo Biology Society XXIV Annual Meeting and the Argentine Microscopy Society IV Annual Meeting, December 1-2, 2006, Potrero de los Funes, Argentina. PMID- 17715563 TI - Biomedical models. PMID- 17715564 TI - Pharmacology of adult ADHD with stimulants. PMID- 17715566 TI - Protective effect of Cyclea peltata Lam on cisplatin-induced nephrotoxicity and oxidative damage. AB - The aim of the present investigation was to evaluate the protective effect of a 70% methanolic leaf extract of Cyclea peltata Lam on cisplatin-induced renal toxicity. The concentration of creatinine, urea, sodium, and potassium in serum and levels of malonyldyaldehyde (MDA), glutathione (GSH), as well as gluathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) activities were determined in kidney tissue. The marked cisplatin-induced renal damage, characterized by a significant increase in creatinine and urea levels, decreased in extract-treated group, whereas sodium and potassium levels did not change significantly. C. peltata Lam extract significantly changed the increased MDA level and decreased GSH levels found in rats treated with cisplatin alone. The reduced activities of GSH-Px, SOD, and CAT in groups treated with cisplatin alone were significantly increased by the extract. The protective effect was greater in the post-treated than in the pre-treated group of animals. The results indicate that the post-treatment of C. peltata Lam extract might effectively ameliorate the oxidative stress parameters observed in cisplatin induced renal toxicity and could be used as a natural antioxidant against cisplatin-induced oxidative stress. PMID- 17715565 TI - Occupational lead exposure in battery manufacturing workers, silver jewelry workers, and spray painters in western Maharashtra (India): effect on liver and kidney function. AB - We studied liver and kidney function tests of occupational lead exposed Battery Manufacturing Workers (BMW) (n = 30), Silver Jewelry Workers (SJW) (n = 30), and Spray Painters (SP) (n = 35) and normal healthy subjects (n = 35), all 20 to 40 years of age, in Western Maharashtra (India). Venous blood and random urine samples were collected from all groups. The blood lead (Pb-B) and urinary lead (Pb-U) levels were significantly increased in all experimental groups, except urinary lead excretion in SJW as compared with the controls. Liver functions tests parameters (serum transaminase enzymes SGOT, AST, SGPT, ALT) activities were significantly increased only in SP; no alteration was noticed in BMW and SJW as compared with the control group. Serum total protein levels were significantly decreased in all three experimental groups as compared with control subjects. Serum albumin concentrations were significantly decreased in SJW, SP, and increased in BMW. The serum globulin levels, however, were significantly decreased, and the albumin/globulin (A/G) ratio was increased in BMW and SJW as compared with the control. The bilirubin level was significantly increased only in BMW. Blood urea was significantly increased only in BMW, and blood urea and serum uric acid were decreased in SJW. The serum creatinine level was not significantly altered in any experimental groups. Increased Pb-B values in all experimental groups indicate the greater rate of lead absorption and impairment of liver and kidney functions in all three types of occupational lead-exposed workers of Western Maharashtra (India). PMID- 17715567 TI - Glucocorticoids and oxidative stress. AB - Glucocorticoids (GC) are used widely for the treatment of patients with various disorders, including autoimmune diseases, allergies, and lymphoproliferative disorders. Glucocorticoid therapy is often limited by several adverse reactions associated with GC excess. Excess GC can elicit a variety of symptoms and signs, including growth retardation in children; immunosuppression; cardiovascular disorders like hypertension and atherosclerosis; osteoporosis; myopathy; and diabetes mellitus. Currently, attention is focused on oxidative stress as one of the major determinants of endothelial dysfunction and cardiovascular senescence. The main reason for all unwanted effects of GC is that dexamethasone induces the overproduction of reactive oxygen species, causing dysregulation of physiological processes. Humans and animals with GC-induced hypertension exhibit reduced nitric oxide levels; patients with excess GC levels also suffer from depression as a consequence of low levels of serotonin and melatonin. The common cofactor for the production of these vasoactive molecules is tetrahydrobiopterin (BH4), which is required for nitric oxide synthesis. PMID- 17715568 TI - Does metformin prevent short-term oxidant-induced dna damage? In vitro study on lymphocytes from aged subjects. AB - Metformin(1-(diaminomethylidene)-3,3-dimethyl-guanidine), an anti-hyperglycemic agent, also has antioxidant effects. Although the origin is not clearly understood, the antioxidant activity of metformin might result from a direct effect on reactive oxygen species (ROS) or could have an indirect action on the superoxide anions produced by hyperglycemia. The ability of metformin to modulate DNA damage produced by oxidative stress is not known. For this reason, we examined the short term effect of metformin (50 microM, 2 h) on the DNA damage of cumene hydroperoxide (CumOOH)-induced lymphocytes from aged and young control groups (n = 10 each). In this study, DNA damage elicited by CumOOH (1 mM) was detected with the Comet Assay and the ELISA technique. Our results showed a significant increase in apoptotic DNA fragmentation and DNA strand breaks (Comet assay tail factor %) that was detected before and after CumOOH induction in lymphocytes of healthy elderly subjects when compared with healthy young control. Metformin significantly decreased CumOOH-induced apoptotic DNA fragmentation and DNA strand breaks in lymphocytes from aged subjects, although it did not produce a long-term effect. The in vitro results indicate that the short-term effect of metformin can protect against prooxidant stimulus-induced DNA damage in lymphocytes from elderly subjects. PMID- 17715569 TI - Dose-related anxiogenic effect of glycine in the elevated plus maze and in electrodermal activity. AB - We investigated effect of glycine on anxiety at different doses using electrodermal activity and an elevated-plus maze. A single dose of glycine was injected intraperitoneally into three different groups of mice at 250 mg/kg, 750 mg/kg, and 1250 mg/kg. The anxiety scores with the elevated-plus maze, consisting of two open arms and two enclosed arms, were measured 30 minutes after injection. Then skin conductance level was measured. Glycine significantly decreased the times spent on the open arms in middle-dose and high-dose groups compared with the control group. The skin conductance level was statistically lower in high dose group than control groups. Conclusion; glycine at a dose of 750 mg/kg induced a nearly maximal anxiogenic effect because a higher dose was not more effective. PMID- 17715570 TI - Monthly number of preterm births and environmental physical activity. AB - Recent studies have reported links between external physical factors and human homeostasis. OBJECTIVE: to determine whether the monthly values of specific physical environmental factors are associated with the monthly number of preterm births in a major medical center in Israel. METHODS: The sample included 1006 infants weighing less than 1500g born live to 774 mothers during 96 consecutive months (1995-2002) at a tertiary medical center in Israel. Monthly values of indices of solar, cosmic ray, and geomagnetic activity for the same period were obtained from national data monitoring facilities in the United States of America, Russia, and Finland. The findings were statistically correlated with the monthly number of preterm births. RESULTS: The number of preterm births correlated with the month of the year (1-12), with a progressive rise in the number of infants born as the year progressed (p = .02). The monthly number of preterm births showed a significant and direct correlation with solar activity indices (r = .32, p = .0016), and a significant and inverse correlation with cosmic ray activity indices (r = -0.3, p = .008). The relation was significant only for singelton births and for the whole group of preterm newborns, but not for multiple pregnancies. CONCLUSION: Our findings suggest that solar and cosmic ray activity may play a role in the timing of premature labor, however in multiple pregnancies additional factors are dominant. PMID- 17715571 TI - Influence of panel reactive antibodies (PRA) on perioperative course in patients undergoing elective cardiac surgery procedures, and impact of these procedures on PRA occurrence. AB - BACKGROUND: Cardiac surgery is supposed to be a risk factor of PRA formation, however the role of PRA presence in non-transplant subjects is not known. Aim of the study was to assess PRA occurrence in patients undergoing elective cardiosurgery procedures and to evaluate its influence on the perioperative course. MATERIAL AND METHODS: Blood samples were obtained before operation in 44 subjects (36M/8F; 55.9 +/- 8.1 y/o) undergoing primary elective cardiosurgery procedures--CABG (n = 30), CABG + valve (n = 2) or valve procedure (n = 12). PRA results were obtained after the discharge, and patients were retrospectively divided into: Group A (n = 18) with PRA > 1%, and Group B (n = 26) with PRA. < or = 1%. PRA screening was repeated 3 months after the procedure in 41 subjects. They were divided into Group I (n = 13) with PRA > 1%, and Group II (n = 28) with PRA < or = 1%. Comparison was performed of Groups A vs. B, and I vs. II. RESULTS: Differences in pre-operative characteristics and procedure type distribution were insignificant. Post-operative complications were more frequent in Groups A and I (pulmonary hypertension in Group I vs. II: 38 vs. 4%; p = 0.01). Duration of post operative ICU stay was longer in Group I vs. 11 (2.9 vs. 1.9d.; p = 0.01). Overall hospital stay was longer in Group A vs. B (10.1 vs. 7.8d.; p = 0.054). Increase of PRA titers was observed in 10 subjects (3 pts. /17% from Group A, and 7 pts. /27% from Group B), exceeding 10% in 2 females after valve replacement. 6 months after procedure, detectable PRA was still observed in 7 patients. CONCLUSIONS: Cardiac surgery is not a strong causative factor of PRA formation. The presence of perceptible PRA level may be associated with increased incidence of complications and consequently prolonged in-hospital stay. Influence of PRA on peri-operative course is not dependent on the source of its increased level. PMID- 17715572 TI - Pancreas retransplantation in patient with previous simultaneous pancreas kidney transplantation (SKP)--first case in Poland. AB - Pancreatic transplantation is a generally accepted treatment modality for patients with type I diabetes mellitus to control metabolism of glucose and prevent complications of diabetes. Graft thrombosis, chronic rejection, surgical complications are the leading cause of pancreatic graft loss among diabetic patients who undergo pancreas transplantation. Pancreas retransplantation is an important option for patients, who lost their primary pancreatic grafts. The 1 year graft survival rates for pancreas retransplantations are comparable to a primary pancreas transplantation. We report a case of pancreas retransplantation in 51-year-old male with a history of type I diabetes mellitus of a 40-year duration, after SKP 20 month before and graft pancreatectomy because of thrombosis 2 weeks after SKP. Pancreatic graft was placed on the right side of the pelvis and enteric drainage was used. Immunosuppressive regimen included daclizumab and thymoglobulin for induction, and mycophenolate mofetil, tacrolimus and short-term steroids for the maintenance of treatment. Four reexplorations were performed due to donor duodenum perforation caused by the stricture of the intestine situated in the area of previous anastomosis or/and after the transplant pancreatectomy. Enteroplasty was performed. Three months after surgery the patient remains normoglycemic, insulin-independent with good kidney function. PMID- 17715573 TI - DNA transfer in bacteria and animals (humans). AB - Transplanted vascularized organs shed passenger cells, normal constituents of whole organs, that migrate to recipient lymphoid tissues and produce microchimerism. These cells lysed by recipient cytotoxic cells release cellular organelles into the recipient circulation. In addition, warm and cold ischemia as well as immune rejection of the transplanted organ or tissue bring about destructive changes in the graft parenchymatous cells. Fragments of disintegrated cellular organelles are phagocytized by recipient scavenger cells located in lymph nodes, spleen and liver and digested. Some fragments are incorporated into dendritic cells (DC) and processed. Donor DNA is present in the ingested cellular debris. The allografting with immunosppression is accompanied by microbial infections and host reaction. A large volume of bacterial and viral DNA is shed in the recipient circulation. The fate of the shed DNA remains largely unknown. Does it undergo total disintegration or may be reutilized? What reaction may the non-methylated bacterial DNA evoke in the graft and what is the response of allogeneic recipient to donor DNA remain the unanswered questions. PMID- 17715574 TI - Innate and adaptive processes in the spleen. AB - The spleen is a lymphatic organ interposed in the blood stream. It remains a largely neglected aggregate of lymphoid tissue. The spleen immune system is responsible for protecting the body from invading pathogens and detecting senescent, mechanically damaged, displaced and aberrant cells that could lead to tumor formation. Recent studies prove its dominant role in a simultaneous dual reaction to bacterial and allogeneic antigens. Spleen is the site of innate and adaptive immune processes. Microbial penetration of tissues evokes an immediate reaction of the innate system, whereas the adaptive immune response involves the interaction of cells that recognize a particular antigen in context with MHC molecules presented by antigen-presenting cells. This review gives some insight into the immune events in the spleen and its neglected systemic role in the allogeneic reaction. PMID- 17715575 TI - Endogeneous sources of infection in transplant recipients. AB - The mammal organisms carry on their surfaces and in their tissues cohorts of microorganisms of various nature. There is a balance of interests and profits between the host and microbial inhabitants. The bacteria and fungi behave like comensals, colonizers, dormants, however, under certain, mostly unknown, conditions may evoke reaction of the host. This process is damaging both for the host and microbes. Large surgical trauma and allograft itself, as well as, immunosuppression create favorable conditions for imbalance between inhabiting microorganism and the recipient. The host flora and that transplanted with the organ graft become activated. Active combating of the proliferating bacteria with antibiotics becomes necessary. Our knowledge of the bacterial flora of the so called "sterile" tissues remains rudimentary. There is still a great deal of prejudice on the sterility of deep tissues e.g. muscles, fat tissue, etc. This review cumulates pertinent literature data on the microorganisms-host interactions. Our own findings on colonization of arteries and adjacent tissues are discussed in the context of atherosclerosis and grafting. PMID- 17715576 TI - Memory response in allografting and bacterial infections in lymphoid and non lymphoid tissues. AB - Allografting with immunosuppression is accompanied by chronic rejection and continuing response of the host to infections. Upon first encounter with allogeneic and bacterial antigens the naive T and B cells react within days. Simultaneously cohorts of memory cells are created characterized by rapid response to the second antigenic stimulus. A number of unanswered questions remains as to whether where are the memory cells located, do they persist in the region of the first encounter with antigens or are they mobilized from the bone marrow and spleen, do they react differently to allogeneic and bacterial antigens, are they sensitive to the immunosuppressive drugs? This review cumulates recent data on the subject. Scanty information points to the necessity of more intensive studies on memory cells to allogeneic, bacterial and self antigens after transplantation in the environment saturated with immunosuppressive drugs. PMID- 17715577 TI - Dermal keratinocytes--protective mechanical, biochemical and immune functions related to grafting. AB - Clinical transplantation of skin remains an unsolved problem. The rejection process is a rapid one and high doses of immunosuppressive drugs are needed to mitigate it, bringing about systemic complications in the recipient. The strong response of skin cells to alloantigens is dictated by their evolutionarily developed innate reaction to the penetrating microorganisms. The details of this mechanism are still unclear. The understanding of immune processes in a transplanted skin requires more knowledge of the physiological functional relationship between the keratinocytes, Langerhans cells, macrophages, fibroblasts and endothelial cells and their receptors and humoral products. Transplanted skin is a site of host-versus-graft and graft-versus-host reaction. PMID- 17715578 TI - The Trauma Act of 2007 and the future of surgical emergency care. PMID- 17715579 TI - 21 years of reinvention: Dennis O'Leary, MD, discusses the past and future of the Joint Commission. Interview by Diane S. Schneidman. PMID- 17715580 TI - Civilian hospital response to mass casualty events: basic principles. PMID- 17715582 TI - The singing surgeon. PMID- 17715581 TI - The American College of Surgeons Bariatric Surgery Center Network: establishing standards. PMID- 17715583 TI - The house of pain. PMID- 17715584 TI - Neuronal nicotinic acetylcholine receptors: involvement in Alzheimer's disease and schizophrenia. AB - Nicotinic acetylcholine receptors (nAChRs) play a role in a variety of diseases of the central nervous system including Alzheimer's disease (AD) and schizophrenia. There is great interest in evaluating disease-related nA ChR changes, and pharmacological treatment of nAChR deficits is a promising therapy. In AD, 7 nAChRs remain relatively stable, contrasting to 4 2 nAChRs that are lost in substantial numbers. -amyloid, a major neuropathology in AD, blocks 4 2 and 7 nAChRs. Agonists selective to 7nAChRs are neuroprotective against--amyloid. Paradoxically, 7nAChRs may function as receptors for -amyloid. These results indicate 7 nAChR antagonists may be appropriate therapy in AD. In schizophrenia, 7 nAChRs are significantly reduced in hippocampus and neocortex. The exceptionally high rate of smoking in schizophrenics is likely a form of self medication. Therapy with 7 nAChR agonists relieves some schizophrenic symptoms. Despite disparities in etiology and symptomatology, AD and schizophrenia share a target for therapeutic intervention--7 nAChRs. PMID- 17715585 TI - Recognizing emotion from facial expressions: psychological and neurological mechanisms. AB - Recognizing emotion from facial expressions draws on diverse psychological processes implemented in a large array of neural structures. Studies using evoked potentials, lesions, and functional imaging have begun to elucidate some of the mechanisms. Early perceptual processing of faces draws on cortices in occipital and temporal lobes that construct detailed representations from the configuration of facial features. Subsequent recognition requires a set of structures, including amygdala and orbitofrontal cortex, that links perceptual representations of the face to the generation of knowledge about the emotion signaled, a complex set of mechanisms using multiple strategies. Although recent studies have provided a wealth of detail regarding these mechanisms in the adult human brain, investigations are also being extended to nonhuman primates, to infants, and to patients with psychiatric disorders. PMID- 17715586 TI - How does the brain process upright and inverted faces? AB - The face inversion effect (FIE) is defined as the larger decrease in recognition performance for faces than for other mono-oriented objects when they are presented upside down. Behavioral studies suggest the FIE takes place at the perceptual encoding stage and is mainly due to the decrease in ability to extract relational information when discriminating individual faces. Recently, functional magnetic resonance imaging and scalp event-related potentials studies found that turning faces upside down slightly but significantly decreases the response of face-selective brain regions, including the so-called fusiform face area (FFA), and increases activity of other areas selective for nonface objects. Face inversion leads to a significantly delayed (sometimes larger) N170 component, an occipito-temporal scalp potential associated with the perceptual encoding of faces and objects. These modulations are in agreement with the perceptual locus of the FIE and reinforce the view that the FFA and N170 are sensitive to individual face discrimination. PMID- 17715587 TI - Neural systems for perceptual skill learning. AB - Recent studies have begun to use functional neuroimaging techniques to examine the changes in brain activity that occur as humans learn new skills. This review outlines results from a number of imaging studies examining visual perceptual skill learning. Although the regions engaged during skill learning differ across tasks, a common finding has been increasing activation in the inferior temporal and fusiform gyri as skill is acquired and activation of the caudate nucleus in association with learning. Neuroimaging has great promise for the understanding of learning at the level of large neural populations, but further work is necessary to understand the specificity of learning-related changes and their relation to underlying neurophysiological plasticity. PMID- 17715588 TI - Unsolved mysteries: the hippocampus. AB - The continuing explosion of scientific interest in the hippocampus began in the 1950s, initiated in large part by the recognition of the importance of the observations of hippocampectomized monkeys made by Kluver and Bucy and the remarkable memory loss of patient H. M. following temporal lobe surgery. Subsequent to these studies, research and theories about the hippocampus grew exponentially in number and diversity. As yet, no theory of hippocampal function explains all of the phenomena discovered in the clinic or laboratory. In this article, experimental results that have been forgotten or ignored in most theories are presented. Adequate theories of hippocampal function must account for known, reliable postsurgical behavioral observations and consider the conditions under which anomalies are noted. Comprehensive theories will require new approaches in which the interactions of the hippocampus with the central nervous system are understood. PMID- 17715589 TI - Insights into seeing and grasping: distinguishing the neural correlates of perception and action. AB - Vision contributes to both perception and visuomotor control, and it has been suggested that many higher brain structures specialize in one or the other function. An alternative view, presented here, is that most higher brain areas participate in both visuomotor and perceptual functions. In the anterior frontal cortex, for example, the activity of one population of neurons reflects perceptual reports about a visual stimulus, whereas the activity of an intermingled population reflects movements aimed at the same stimulus. Similarly, posterior parietal and inferior temporal areas appear to function in both visual perception and visuomotor control. Visuomotor signals in higher order cortical areas could contribute to the perception of one's own action. They also might reflect the existence of two systems for visual information processing: one stressing accuracy for the control of movement and the other generating hypotheses about the world. PMID- 17715590 TI - Memory in neuroscience: rhetoric versus reality. AB - The central point of this article is that the concept of memory as information storage in the brain is inadequate for and irrelevant to understanding the nervous system. Beginning from the sensorimotor hypothesis that underlies neuroscience--that the entire function of the nervous system is to connect experience to appropriate behavior--the paper defines memories as sequences of events that connect remote experience to present behavior. Their essential components are (a) persistent events that bridge the time from remote experience to present behavior and (b) junctional events in which connections from remote experience and recent experience merge to produce behavior. The sequences comprising even the simplest memories are complex. This is both necessary--to preserve previously learned behaviors--and inevitable--due to secondary activity driven plasticity. This complexity further highlights the inadequacy of the information storage concept and the importance of extreme simplicity in models used to study memory. PMID- 17715591 TI - A neurobehavioral examination of individuals with high-functioning autism and Asperger's disorder using a fronto-striatal model of dysfunction. AB - The repetitive, stereotyped, and obsessive behaviors that characterize autism may in part be attributable to disruption of the region of the fronto-striatal system, which mediates executive abilities. Neuropsychological testing has shown that children with autism exhibit set-shifting deficiencies on tests such as the Wisconsin Card Sorting task but show normal inhibitory ability on variants of the Stroop color-word test. According to Minshew and Goldstein's multiple primary deficit theory, the complexity of the executive functioning task is important in determining the performance of individuals with autism. This study employed a visual-spatial task (with a Stroop-type component) to examine the integrity of executive functioning, in particular inhibition, in autism (n = 12) and Asperger's disorder (n = 12) under increasing levels of cognitive complexity. Whereas the Asperger's disorder group performed similarly to age- and IQ-matched control participants, even at the higher levels of cognitive complexity, the high functioning autism group displayed inhibitory deficits specifically associated with increasing cognitive load. PMID- 17715593 TI - Semantic retrieval, mnemonic control, and prefrontal cortex. AB - Accessing stored knowledge is a fundamental function of the cognitive and neural architectures of memory. Here, the authors review evidence from cognitive behavioral paradigms, neuropsychological studies of patients with focal neural insult, and functional brain imaging concerning the mechanisms underlying retrieval of semantic knowledge and their association with prefrontal cortex. First, the authors examine behavioral and neuropsychological evidence distinguishing between controlled and automatic semantic retrieval. Then the authors review the subregions of prefrontal cortex that functional neuroimaging has associated with semantic retrieval across a range of memory demanding tasks. Finally, two hypotheses concerning the nature of processing in these brain regions--the controlled semantic retrieval and selection hypotheses--are critically examined, and a possible synthesis is proposed. PMID- 17715592 TI - Motivation, working memory, and decision making: a cognitive-motivational theory of personality vulnerability to alcoholism. AB - This article presents a cognitive-motivational theory (CMT) of the mechanisms associated with three basic dimensions of personality vulnerability to alcoholism, impulsivity/novelty seeking, harm avoidance, and excitement seeking. CMT describes the interrelationships between activity in basic motivational systems and attentional, decision-making and working memory processes as the mechanisms associated with variation in each personality trait. Impulsivity/novelty seeking reflects activity in both appetitive and inhibitory motivational systems, greater attention to reward cues, and increased emotional reactivity to reward and frustration. Harm avoidance reflects individual differences in fearfulness and activity in specific inhibitory systems. Excitement seeking reflects the need to engage in appetitive behaviors in less predictable environments to experience positive affect. CMT also describes the impact of working memory and the specific motivational processes underlying each trait dimension on the dynamics of decision making from the perspective of decision field theory. PMID- 17715594 TI - Cortical region interactions and the functional role of apical dendrites. AB - The basal and distal apical dendrites of pyramidal cells occupy distinct cortical layers and are targeted by axons originating in different cortical regions. Hence, apical and basal dendrites receive information from distinct sources. Physiological evidence suggests that this anatomically observed segregation of input sources may have functional significance. This possibility has been explored in various connectionist models that employ neurons with functionally distinct apical and basal compartments. A neuron in which separate sets of inputs can be integrated independently has the potential to operate in a variety of ways not possible for the conventional neuron model, in which all inputs are treated equally. This article thus considers how functionally distinct apical and basal dendrites can contribute to the information-processing capacities of single neurons and, in particular, how information from different cortical regions could have disparate effects on neural activity and learning. PMID- 17715595 TI - Psychological functions of the cerebellum. AB - For most of the 20th century, the brain science community held the view that the cerebellum was exclusively involved in motor control functions. Over the past 20 years, this has largely been replaced by the idea that the cerebellum participates in a variety of motor and nonmotor functions and, importantly, may contain neurons that display long- and short-term plasticity, encoding behavioral and cognitive functions. The authors present evidence for the involvement of the cerebellun in motor and nonmotor functions and further suggest that the cerebellum's internal neural architecture and connectivity patterns with other areas of the brain determine the range of functions that the cerebellum participates in. To stress the interactive nature of the structure, the authors suggest that the phenomena that the cerebellum encodes may be best described generally as the psychological functions of the cerebellum instead of attempting to categorize all functions as either motor or nonmotor. PMID- 17715596 TI - Stages of memory in the nematode Caenorhabditis elegans. AB - Studies on the cellular basis of learning and memory have revealed several distinct phases of memory that can be distinguished by their time course. In addition to the traditional short-term and long-term memory distinction, several other phases of memory have been identified: forms of intermediate-term memory, at least two seperable forms of long-term memory, and possibly several forms of short-term memory. This article presents the contributions made by research on phases of memory for habituation in the nematode Caenorhabditis elegans. Through behavioral, neural circuit and genetic analyses of habituation, research using this simple organism has provided insights into different memory phases. Studying experience-dependent plasticity of this behavior has not only provided corroborating evidence for the existence of short-, intermediate-, and long-term forms of memory, as have been demonstrated in both Aplysia and Drosophila, but also has revealed the possible existence of multiple forms of short-term memory. PMID- 17715598 TI - How does the cerebral cortex work? Development, learning, attention, and 3-D vision by laminar circuits of visual cortex. AB - A key goal of behavioral and cognitive neuroscience is to link brain mechanisms to behavioral functions. The present article describes recent progress toward explaining how the visual cortex sees. Visual cortex, like many parts of perceptual and cognitive neocortex, is organized into six main layers of cells, as well as characteristic sublamina. Here it is proposed how these layered circuits help to realize processes of development, learning, perceptual grouping, attention, and 3-D vision through a combination of bottom-up, horizontal, and top down interactions. A main theme is that the mechanisms which enable development and learning to occur in a stable way imply properties of adult behavior. These results thus begin to unify three fields: infant cortical development, adult cortical neurophysiology and anatomy, and adult visual perception. The identified cortical mechanisms promise to generalize to explain how other perceptual and cognitive processes work. PMID- 17715597 TI - Psychological and neural perspectives on the role of motion in face recognition. AB - In the real world, faces are in constant motion. Recently, researchers have begun to consider how facial motion affects memory for faces. The authors offer a theoretical framework that synthesizes psychological findings on memory for moving faces. Three hypotheses about the possible roles of facial motion in memory are evaluated. In general, although facial motion is helpful for recognizing familiar/famous faces, its benefits are less certain with unfamiliar faces. Importantly, the implicit social signals provided by a moving face (e.g., gaze changes, expression, and facial speech) may mediate the effects of facial motion on recognition. Insights from the developmental literature, which highlight the significance of attention in the processing of social information from faces, are also discussed. Finally, a neural systems framework that considers both the processing of socially relevant motion information and static feature-based information is presented. This neural systems model provides a useful framework for understanding the divergent psychological findings. PMID- 17715599 TI - [Sharing knowledge for a better care]. PMID- 17715600 TI - [Tetralogy of fallot: evolution of medical-surgical management (part 1)]. AB - Despite Tetralogy of Fallot is a well-known cardiac congenital disease, still an important cardiovascular surgery and intensive care challenge. The following is a selective account of medical and surgical concepts and procedures; the emphasis is on therapeutic developments during the last 50 years. This review is divided into two parts: the first of which traces the evolution of medical and palliative techniques; the second part approaches the surgical corrections and try to explain the reinterventional causes and the residual defects responsible of cardiac failure. PMID- 17715601 TI - Protocols to manage postoperative pain in neonates and children hospitalized in a surgical ward. Methodological issues and cultural background. AB - The authors describe the cultural background and methods they adopted to construct protocols for analgesia in newborns and children hospitalized in a surgical ward. Drugs and dosages are reported in the Appendix, whereas scales for pain measurement and cut off ratings for rescue doses (or otherwise relevant) are described respectively in Tables 2 and 3. Genetics and cognitive structures play a crucial role in pain and analgesia. Protocols have a critical role, however their application must be tailored to the single child. PMID- 17715602 TI - [Ultrasound bone densitometry in children and adolescents; Italian refence curves with multi-site device (Omnisense)]. AB - The values of bone density represent one of the best parameters for the prediction of the risk of fracture in the adult. Since the peak of bone mass depends over that on genetic factors also on modifiable environmental factors, the evaluation of the state of bone health in paediatric populations has assumed great importance; the ultrasound techniques seem to represent a potential alternative to DXA and QTC. Using Omnisense device (Omnisense, Sunlight Ultrasound Technologies) we have evaluated the bone strength in a champion of 652 children and teen-agers aged 6-18 (328 females, 324 males). The measurements have been made at the distal third of the radius and midshaft tibia. The purpose has been to record the values of SOS in a healthy paediatric population, building a normal database and to find a correlation between the SOS values and anthropometric data, dietary factors and physical activity. The comparison with an analogous study conducted by other Authors prompted us to conclude that in the paediatric population the construction of proper curves of reference, with which to compare the data of the patients, is essential to avoid errors in the evaluation of bone density, in agreement with how much already underlined in literature. Besides a correct interpretation of the data obtained with ultrasounds systems asks for a change of the thresholds values established by the OMS for the diagnosis of osteopenia/osteoporosis with the DXA. As already happened for the adult population in children also it will be therefore necessary to compare a great number of pathological subjects with the normal database, establishing so the new values of Z-Score and giving a clinical meaning to the effected measurements. PMID- 17715603 TI - [Umbilical acid-base status of term infants: correlation with delivery mode]. AB - OBJECTIVE: To determine possible relations between Apgar score, umbilical artery haemogasanalysis and delivery mode. METHODS: 948 babies were considered; preterm infants and charts with incomplete data were excluded. 762 newborns and their respective umbilical artery blood gas parameters at delivery were evaluated. The collected Data were related to mode of delivery: vaginal with and without analgesia, elective caesarean section (CS), CS after labour, emergency CS for non reassuring trace. RESULTS: Mean pH (+/- DS) was 7.26 (+/- 0.08). The comparison vaginal delivery vs. CS was statistically significant (p < 0.0001). Analyzing the CS only, the babies born by emergency CS for non reassuring trace had pH statistically lower (ANOVA p < 0.004) and, in the latter group, there was a statistically difference between Italian newborns and those from other ethnicities (p < 0.02). No difference were found on Apgar score, excluding babies by vaginal delivery with analgesia that showed lower scores both at 1 (p < 0.02) and 5 (p < 0.002) minutes versus newborns without analgesia. CONCLUSIONS: Normal labour causes frequently a mild degree of acidosis, but it is not always related to neonatal asphyxia. The differences found between different delivery modes are, probably, the expression of causes related to the obstetric choice. That is also remarked by the statistically difference found in emergency CS for non reassuring trace in Italian population and in other ethnicities, showing a probably different cultural level, mainly about the "obstetric emergency" poorly understood by the pregnant. In vaginal deliveries the analgesia does not modify the neonatal metabolism, but can be a reason of delayed adaptation of extrauterine life. PMID- 17715604 TI - [Early infantile and late infantile form of Krabbe disease: CT and MRI findings]. AB - The Authors present the CT and MR findings in three patients with Krabbe disease: early infantile, late infantile and juvenile. Three children, 5 and 9 months old respectively with Krabbe disease, were studied with CT and MR. the children presented with spasticity and signs of peripheral neuropathy, blindness and no interaction with the environment. In all patient CT revealed nonenhancing discrete dense lesions, simmetrically distribuited in the posterior limb of the internal capsule and posterior thalami and focal hypodensities of the midcerebellar peduncles and dentate nuclei, with mild cerebral atrophy. In one patients CT demonstrated bilateral calcifications of paraventricular white matter. Mr, in all, showed a generalized increase in T2 values of the periventricular white matter. The thalami and adjacents regions had markedly shortened T1 and slightly shortenede T2. The cerebellum and the brainstem appeared mottled with scattered areas of increased T2. MR confirmed the cerebral atrophy. In conclusion CT and MR findings in Krabbe disease (early infantile and late infantile) are usually not specific. However when they are both performed at the onset of neurological symptoms they can alert clinicians to the possibility of Krabbe disease. PMID- 17715605 TI - [Video-assisted treatment for biliary atresia]. AB - BACKGROUND: The surgical treatment of biliary atresia is still a great challenge for pediatric surgeons. Kasai's operation usually needs a wide, painful, muscle cutting laparotomies that quite often are followed by pain and peritoneal adhesion. These possible complications may disturb the post-operative course and humper liver transplantation. Advancements in minimally invasive surgery have allowed even the most complex procedures to be approached using these techniques. METHODS: The authors present a case of successful Roux-en-Y laparoscopic portoenterostomy for the treatment of biliary atresia. We report a case of a 3 month-old patient with biliary atresia who weighted Kg 5,300 at the operation. The patient was placed in supine position. The procedure was performed with 4 trocars of 3 mm and 1 of 10 mm. The umbilical site was used for extracorporeal Roux-en-Y enteroenterostomy. CO2 was insufflated at a pressure of 8 mmHg and a flow of 0.5 L/min. A drain was placed through the lower trocar site with the tip near the anastomosis. RESULTS: The procedure was free of neither intraoperative nor post-operative complications. Feeding by nasogastric tube was started after 2 days. Total oral feeding was possible after 8 days. CONCLUSION: Laparoscopic approach to perform Kasai's operation is technically feasible and thanks to a magnified vision, it allows to abtain a good visualization of the portal structures with an adequate retraction of the liver. This procedure can avoid or decrease the post-operative complications such as pain, breathing difficulty, adhesions and resulting in very small scars. Anyway laparoscopic Kasaiportoenterostomy should be done by a surgeon with a good experience in laparoscopic hand-suturing and neonatal experience and with the support of an experienced in neonatal and infantile videosurgery anaesthesiologist. PMID- 17715606 TI - Toxic epidermal necrolysis in a child. A case report and review of the literature. AB - A 7-year-old boy with toxic epidermal necrolysis (TEN) is reported. The patient was treated with intravenous fluids, antibiotics, steroids, and immunoglobulins. Moreover, total parenteral nutrition was required for 4 days. He gradually improved and was discharged in a good clinical condition. Appropriate treatment for TEN is still controversial. Larger study are required to address this issue. PMID- 17715607 TI - [Neuroimaging in the early diagnosis of Krabbe leukodystrophy types 1 and 2]. PMID- 17715608 TI - Erectile dysfunction: a marker of early coronary heart disease. PMID- 17715609 TI - Clinical experience from 1000 consecutive cardiovascular MRI cases at a tertiary referral medical center. AB - We present our experience from the first 1000 clinical cardiovascular magnetic resonance imaging cases performed at our institution. The case load included pediatric and adult patients with a male predominance (two thirds of the patient population). The spectrum of diseases was very broad, and included myopathic, atherosclerotic, vascular, valvular, pericardial, neoplasmatic and congenital heart disease. Our experience demonstrates the areas where cardiovascular magnetic resonance imaging has established value and suggests areas of future development. PMID- 17715610 TI - Cardiovascular disease and drowning: autopsy and laboratory findings. AB - INTRODUCTION: The purpose of this report is to describe the main autopsy and laboratory findings from a large number of drowning victims in Greece. METHODS: A retrospective analysis was carried out of the consecutive cases of drowning victims autopsied in our department during the period 1997-2004. RESULTS: A total of 197 submersion cases were referred to the Department. In 168 cases drowning was considered as the cause of death. In 82 cases (49%) significant histopathological findings from the cardiovascular system were present. Alcohol was found in 21 cases (13%) and psychoactive substances in 4 cases (2%). Food was found in the stomach of 45 drowning victims (27%). Men (65%) and elderly people (60 years and older, 74%) made up the majority of drowning victims. In 29 submersion cases the cause of death was other than drowning; in 25 of these cases death was attributed to cardiovascular disease (complication of coronary artery disease, 23 cases; dissecting aortic aneurysm, 1 case; cerebral stroke, 1 case). CONCLUSIONS: The great majority of drowning victims are the elderly and men. Moreover, in a considerable number of submersion cases cardiovascular disease was related to the death, either as a contributing factor, or as the cause of death. PMID- 17715611 TI - Characterisation of a rat model of pulmonary arterial hypertension. AB - INTRODUCTION: Pulmonary hypertension portends an adverse outcome. Animal models have improved current understanding of the complex pathophysiology of the disease, but may be technically demanding. Moreover, plexiform vascular lesions are rarely observed, limiting the extrapolation to human pathophysiology. The aim of the present study was first, to assess the feasibility of closed-chest pressure recordings, and mainly, to further characterise a new model of endothelin receptor-B deficient rats. METHODS: Jugular venous catheterisation was assessed in 15 Wistar rats. Pressure recordings via a left lateral thoracotomy and histological findings were compared in three rat groups (age 20 +/- 1 weeks, weight 200-250 g): (a) wild type (n = 10, group A); (b) wild type after monocrotaline injection (n=10, group B); and (c) endothelin receptor-B deficient rats (n = 10, group C) after monocrotaline injection. RESULTS: Pressure recordings via the jugular approach were feasible in only 3 (20%) rats. Compared to group A, there was a trend (H = 4.6, p = 0.0962) towards increased mortality in groups B and C, due to respiratory arrest during intubation attempts. Pulmonary artery systolic pressure in group C was 24.7 +/- 1.3 mmHg, higher than in group B (21.5 +/- 1.2, p = 0.036) or group A (11.8 +/- 0.5, p < 0.0001). Adverse pulmonary vascular remodelling was more prominent in group C than in group B. CONCLUSIONS: Endothelin receptor-B deficient rats constitute a useful model of pulmonary artery hypertension after monocrotaline injection. The ease of pressure recordings via a left lateral thoracotomy may aid in the more widespread use of this model. PMID- 17715613 TI - Coronary revascularisation in patients with chronic renal disease. PMID- 17715612 TI - Clinical usefulness of attenuation and scatter correction in Tl-201 SPECT studies using coronary angiography as a reference. AB - INTRODUCTION: The aim of this investigation was to evaluate the clinical usefulness of both attenuation and scatter correction in 201Tl SPECT studies. METHODS: We studied 102 patients (76 males, 26 females, mean age 54 years) who underwent coronary angiography prior to or after a scintigraphic examination. A 201Tl one-day protocol was used. Simultaneous transmission-emission images were obtained by a gamma-camera equipped with an attenuation and scatter correction system based on two moving collimated 153Gd rod sources. Stress and delay reconstructed images, uncorrected for attenuation and scatter, were diagnosed. One month later, stress and delay reconstructed images corrected for attenuation and scatter were diagnosed by the same readers. The results were compared using the coronary angiography findings as reference. A stenosis 50% or larger was considered significant. RESULTS: Attenuation and scatter corrected images demonstrated a significant increase in specificity for findings in the right coronary artery territory, i.e. 89% vs. 41% for uncorrected images (p < 0.05), with a non-significant loss in sensitivity from 96% to 89%. When we split the population on a gender basis, statistically significant differences in specificity between corrected and non-corrected images were observed in the left anterior descending territory for the females (100% vs. 42%) and in the right coronary artery territory for males (87% vs. 26%). CONCLUSION: Attenuation and scatter correction in 201Tl SPECT studies may significantly decrease false positive lesions in the inferior wall as well as in the anterior in females. PMID- 17715614 TI - Hypertrophic cardiomyopathy in children, teenagers and young adults. PMID- 17715615 TI - Carcinoid heart disease in a patient with primary ovarian carcinoid tumour. PMID- 17715617 TI - Acute myocardial infarction following the combined use of cocaine and alcohol. AB - We describe the case of a 37-year-old man who presented with inferior wall myocardial infarction shortly after the concomitant use of cocaine and ethanol. The patient showed prompt ST resolution after thrombolytic therapy. Within two hours from his arrival at the hospital the patient had an episode of ventricular fibrillation, which was successfully treated with electrical cardioversion. Coronary angiography showed normal coronary arteries. The number of patients with acute myocardial infarction after the use of cocaine alone, or in combination with ethanol, is increasing in the USA and other countries; most are young adults. In Greece such cases are still rare, because of the lesser extent of cocaine abuse in the general population and the low sensitivity in recognising cocaine users who present with chest pain in the emergency department. PMID- 17715618 TI - Percutaneous coil embolisation of a false aortic aneurysm following coronary surgery and mediastinitis. AB - A 71-year-old male patient was admitted with methicillin-resistant staphylococcus aureus mediastinitis two months after coronary artery bypass grafting. Treatment with immediate surgical debridement, removal of sternal wires and use of vacuum assisted closure device was started. Spiral computerised tomography and aortography revealed a false aortic aneurysm at the cannulation site. Active mediastinitis and the patient's objection to further surgery led us to perform percutaneous coil embolisation. No postoperative complication was observed and one year later the patient is in excellent condition. PMID- 17715620 TI - The ant, the grasshopper, and meritocracy: where has Aesop's fable gone wrong? PMID- 17715619 TI - Anaemia in chronic heart failure: is there a rationale to treat? PMID- 17715616 TI - Surgical treatment of coronary subclavian steal syndrome. AB - The internal mammary artery is the conduit of choice for cardiac revascularization. Atherosclerotic disease of the coronary arteries may simultaneously involve the subclavian artery. Proximal stenosis in the left subclavian artery may result in recurrent myocardial ischemia in patients with a patent left internal mammary artery (LIMA), due to coronary steal syndrome through the LIMA. PMID- 17715621 TI - [Cardiovascular disease. First cause of death in adults in Mexico and worldwide]. PMID- 17715622 TI - [Associated factors to increased sensitivity in the transthoracic echocardiogram for the diagnosis of infective endocarditis]. AB - INTRODUCTION AND OBJECTIVES: Echocardiography is considered a basic tool in the diagnosis and management of infective endocarditis. Transesophageal echocardiography is more sensitive than transthoracic echocardiography. Our aim was to describe which factors are related to the ability of transthoracic echocardiography to establish the diagnosis of infective endocarditis. The presence of this factors in a patient with a normal transthoracic echocardiography would make unnecessary to perform a transesophageal echocardiography and would suggest to seek for other diagnostic possibilities. METHODS: 127 consecutive patients admitted to our hospital with the diagnosis of infective endocarditis and a complete transthoracic echocardiography and transesophageal echocardiography comprised our study group. Predisposing factors and clinical, echocardiographic and microbiological variables were studied. RESULTS: The presence of a cardiac murmur, the presence of an optimal acoustic window, degenerative valvular disease as the predisposing factor for infective endocarditis and positive blood cultures were related to the ability of transthoracic echocardiography to diagnose the existence of signs of infective endocarditis on its own. Nevertheless, only the presence of a cardiac murmur (RR 2.724; 95% CI 1.071-6.926; p 0,035) and the presence of an optimal acoustic window (RR 5.538; 95% IC 2.75-11.15; p < 0.001) were found as independent factors to detect those patients in which transthoracic echocardiography is able to diagnose signs of infective endocarditis on its own. CONCLUSIONS: The diagnostic accuracy of transthoracic echocardiography to detect echocardiographic signs of infective endocarditis is high in those patients with cardiac murmur and optimal acoustic window. In those patients with these characteristics, without prosthetic heart valves and a negative transthoracic echocardiography for infective endocarditis other diagnostic possibilities should be ruled out before performing of a transesophageal echocardiography. PMID- 17715623 TI - [Long-term results of percutaneous mitral valvuloplasty in patients over 50 years old]. AB - Advanced age has been identified as a predictor factor for complications and poor outcome at Percutaneous Mitral Valvulotomy (PMV) with balloon, nevertheless this has been associated to the inadequate valvular anatomy, whereby the contribution of each factor needs to be determinate. OBJECTIVE: Describe the immediate and final outcome of PMV with Inoue balloon in patients over 50 years old and associate complications with age and Wilkins score. MATERIAL AND METHODS: A retrospective and analytic study was performed with a data base of 430 patients. We included all the patients proceeding from the Centro Medico Nacional Siglo XXI Cardiology Hospital. From January 1996 to December 2005. RESULTS: We selected 137 patients with rheumatic mitral stenosis. We found a Mitral Valvular Area (MVA) before the PMV proceeding of 1.01 cm2 +/- 0.18 and 1.99 cm2 +/- 0.30 post PMV (P < 0.001), with pre procedure transmitral gradient of 14.3 +/- 3.18 mm Hg and of 4.3 +/- 2.6 mm Hg post (P < 0.001). In 128 (93%) the immediate proceeding was considered successful. The Wilkins score was 8.41 +/- 1.31. The observed complications were present in 19 (13.8%), stroke in 3 (2.2%), tamponade in 3 (2.2%), conduction disorder in 5 (3.7%), severe mitral insufficiency in 7 (5.1%), residual interatrial communication in 1 (0.7%). A clinical and echocardiographic follow-up was performed in 113 (83%) MVA was > 1.5 cm2 in 113 at 70 [IBM1] months average, 1.1 to 1.49 cm2 in 14 (10.2%) and < 1 cm2 in 9 (7%). CONCLUSIONS: PMV with Inoue balloon in patients over 50 years old is a procedure with an immediate high successful index and of acceptable risk. We found a restenosis index of 27 (19%) after long follow-up 70 months average. PMID- 17715624 TI - [Clinical restenosis in diabetic patients treated with drug eluting stents for de novo lesions]. AB - We evaluated immediate and mid-term clinical and angiographic results in diabetic patients with percutaneous coronary intervention with deployment of drug eluting stents. METHODS: Between November of 2004 and June of 2005 percutaneous coronary interventions were performed 860 with the deployment of 112 drug eluting stents to 42 diabetic patients. The mean of stents was 2.6 per patient, and the type of drug eluting stent was paclitaxel in 60% and sirolimus in 40%. The average of age was 51.2 +/- 9.6 years old. The gender was male in 25 (60%) of patients and female in 17 (40%). The indication of coronary angiography was unstable angina in 15 (35%) patients and stable angina in 27 (65%). There was history of anterior myocardial infarction in 20 (47%), inferior myocardial infarction in 8 (20%) and multiple vessel disease in 16 (38%). The stenosis severity of the lesion was 85.9% +/- 12.2% and the left ventricular function was (55 +/- 10). The hospital stay was 7 +/- 5.4 days. RESULTS: Both clinical and angiographic immediate success was 100%. The average follow was 7.6 +/- 3.3 months in 34 patients (80.9%). The target lesion revascularization (TLR) was 7.1%. (3 patients). Death, myocardial infarction or reinfarction (0%). COMPLICATIONS: One patient (2.3%) developed contrast induced nephropathy. CONCLUSIONS: These results suggest that the use of drug eluting stents (paclitaxel or sirolimus) in diabetic patients has a high rate of success with good angiographic and clinical results and with a low rate of complications or restenosis in this high risk group of patients. PMID- 17715625 TI - [Non invasive quantification of the parietal systolic stress of the left ventricle in patients with heart failure and its clinical application]. AB - The purpose of this study is to calculate non invasivelly left ventricular systolic wall stress by echocardiography in patients with primary heart failure, and compare the results with those obtained in parients with overloaded heart failure, diastolic dysfunction by Inapropiatte hypertrophy, with normal ejection fraction and people with normal heart, there stablish the value of the results in clinical settings. We studied 33 patients with heart failure by dilated cardiomyopathy. There was no significant association between the systolic wall stress and the ejection fraction, fractional shortening, dp/dt or left ventricular mass in this group of study. There was a significant association between systolic h/r ratio and the systolic wall stress. This study shows that in primary heart failure the afterload increases and has inverse relationship with ejection fraction (r = 0.86); but, when heart failure obey to an excessive overload exists an exquisite inverse relationship between systolic wall stress and ejection fraction (r = 0.93). The excessive hypertrophy (Inappropriate) reduces the systolic wall stress but causes diastolic dysfunction. The increase of systolic wall stress in Aortic regurgitation with normal ventricular performance is responsible of adequate left ventricular hypertrophy, by other means, in mitral insufficiency the presence of low or normal systolic wall The purpose of this study is to calculate non invasivelly left ventricular systolic wall stress by echocardiography in patients with primary heart failure, and compare the results with those obtained in parients with overloaded heart failure, diastolic dysfunction by Inapropiatte hypertrophy, with normal ejection fraction and people with normal heart, there stablish the value of the results in clinical settings. We studied 33 patients with heart failure by dilated cardiomyopathy. There was no significant association between the systolic wall stress and the ejection fraction, fractional shortening, dp/dt or left ventricular mass in this group of study. There was a significant association between systolic h/r ratio and the systolic wall stress. This study shows that in primary heart failure the afterload increases and has inverse relationship with ejection fraction (r = 0.86); but, when heart failure obey to an excessive overload exists an exquisite inverse relationship between systolic wall stress and ejection fraction (r = 0.93). The excessive hypertrophy (Inappropriate) reduces the systolic wall stress but causes diastolic dysfunction. The increase of systolic wall stress in Aortic regurgitation with normal ventricular performance is responsible of adequate left ventricular hypertrophy, by other means, in mitral insufficiency the presence of low or normal systolic wall stress does not induce left ventricular hypertrophy, then diameter increases and the hypertrophy is inadequate, despite this, left ventricular function is normal. PMID- 17715626 TI - [Right ventricular thrombous and pulmonary artery aneurysms in Behcet's disease. Report of one case]. AB - Behcet's disease uncommon in the pediatric population. Intracardiac thrombus and bilateral pulmonary artery aneurysms are uncommon manifestations. We are reporting one case. A 14 years old patient was admitted, with high fever, dyspnea and hemoptysis since 4 months ago. Two years ago, fever, oral ulcers, aphthae (gingival, palate, tonsils), nose ulceration in and arthralgias-arthritis were noted. Chest radiograph showed round mass in the right lower lung field. The chest tomographic computed scan and pulmonary centellography were done to investigate malformations arterial. An Intracardiac thrombus of 27 x 12 mm was identified in the right ventricle by transthoracic echocardiography. Catheterization and pulmonary angiography showed an aneurism located in the right and left lobares arteries. Medical management with immunosuppressive and anticoagulation therapy resulted in complete remission of the clinical manifestations. Due to heamodynamic compromise surgical removal of the intracardiac thrombus was done. IN SUMMARY: The Behcet's disease is rare disease in children. Intracardiac thrombus and bilateral pulmonary artery aneurysms are rare complications. Medical treatment (immunosupressive and anticoagulation) is the first line therapy with resolution of the mucous, skin, cardiac and pulmonary manifestations. PMID- 17715627 TI - [Computer multidetector tomography of coronary arteries. State-of-the-art. Part 1. Technical aspects]. AB - The study of atherosclerotic disease in coronary arteries is fundamental since it is the first cause of death in the Western hemisphere. The gold standard for its diagnosis is invasive angiography, but it contributes to an increase in costs for this group of patients. Nowadays fourth generation computed tomography (CT) equipments can construct acquisition data of up to 256 images in only 400 milliseconds (ms), which is 900 to 1000 times faster than first generation apparatus. CT multidetector (CTMD) is the noninvasive choice diagnosis method for a vascular evaluation of the thorax. Its role in the study of the heart was limited, but today it is possible to obtain three-dimensional heart and whole body images in only seconds. CTMD is a fast, low-cost, noninvasive method that generates cardiac and extra cardiac images without adjacent structure interference. The higher temporal resolution due to an increase of the gantry's rotation and new reconstruction algorithms, as well as its higher spatial resolution and elevated time acquisition due to the presence of more detectors, have permitted CTMD to give significantly better and precise diagnosis of coronary arteries. PMID- 17715628 TI - [On the diagnostic value of indirect electrocadiographic signs of left posterolateral basal infarction]. AB - The left basal posterolateral infarct does not give pathological Q waves nor ventricular QS complexes in the low lateral leads V5 and V6. For that, the increased voltage of R waves in the lead V2 and or transitional leads V3 and V4, constitutes only an indirect sign of the presence of dead myocardium in the left posterolateral basal regions. Naturally, in these cases, a differential diagnosis with left ventricular or biventricular hypertrophy is mandatory. Therefore it is suitable to register left posterior thoracic leads V7-V9 or, preferably, a complete thoracic circle. We present here three examples: two experimental and another clinical, in which the electrocardiographic findings corresponded to anatomical data of a left posterolateral basal infarction. This fact speaks for a no absolute but relative diagnostic value of the indirect electrocardiographic signs of altered ventricular depolarization and repolarization in the left posterolateral basal regions of the left ventricle. PMID- 17715629 TI - Immunogenicity of infliximab: how to handle the problem? AB - BACKGROUND: The introduction of infliximab has greatly advanced the therapeutic armamentarium of the inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis. Although the benefit/risk ratio for infliximab is positive, of particular concern has been the problem of immunogenicity ascribed to the chimeric properties of the drug. Antibody formation is associated with allergic reactions and loss of response. AIMS AND METHODS: A literature search was undertaken on the magnitude of the problem of immunogenicity and on the clinical consequences. A survey was conducted about the clinical practice and management of acute and delayed allergic reactions to infliximab in different centres in Belgium. For this, a questionnaire was sent to all members of the Belgian IBD research group (n = 38 belonging to 29 centers). RESULTS AND CONCLUSION: Infusion reactions are important immunologic events induced by the presence of a substantial concentration of antibodies against infliximab (ATI) in the serum. Concomitant immunosuppressive treatment may optimize response to infliximab by preventing the formation of antibodies. Steroid administration prior to an infliximab infusion can further reduce the immunogenicity. Probably the most effective strategy to optimize treatment and avoid immunogenicity is maintenance therapy. If infliximab therapy can be discontinued is yet unclear but when treatment goals have been reached, we feel this should be attempted. In the case of relapse, infliximab should be restarted as maintenance long term. Practical guidelines on how to handle the problem of immunogenicity to infliximab are important for clinicians treating patients with IBD. PMID- 17715630 TI - Appropriate management of symptomatic GORD in primary care: has expert opinion changed between 2001 and 2005? AB - OBJECTIVE: To determine current opinions of clinical experts on the appropriate management of symptomatic GORD in primary care, and to compare these opinions with those from a similar study conducted in 2001. METHODS: In 2001, a panel of 6 Belgian general practitioners and 6 gastroenterologists assessed the appropriateness of referral versus short-term anti-secretory medication for 768 different patient profiles, using the RAND/UCLA method. Applying a similar methodology, the same panel repeated these assessments in 2005. In addition, panellists were asked to indicate the preferred type of medication for all patient profiles. RESULTS: Agreement between the results of 2001 and 2005 was high. Appropriateness ratings on referral versus medication were similar in 79% of patient profiles (weighted kappa value 0.77). Higher age and use of NSAIDs remained the dominant factors in favour of referral. Medication preference (not measured in 2001) showed marked differences between general practitioners and gastroenterologists. Gastroenterologists showed a higher preference for PPI high dose, whereas general practitioners more frequently chose for PPI low dose. H2 receptor antagonists were preferred in only few cases. CONCLUSIONS: This study showed that expert opinion on the appropriateness of referral for endoscopy in patients with symptomatic GORD has only slightly changed over the past few years. Preferences for low and high dose PPIs varied between the two groups of physicians, which is most likely to be ascribed to the different patient populations seen in either primary or specialised care. PMID- 17715632 TI - Percutaneous and surgical radiofrequency ablation of liver malignancies: a single institutional experience. AB - BACKGROUND: the purpose of this study was to report a single academic institution's experience with radiofrequency ablation (RFA) of liver malignancies METHODS: Sixty-five patients underwent RFA technique through a percutaneous (Group I: 33 patients) or a surgical approach (Group II: 32 patients). The two groups were different according to type of disease selection (more hepatocellular carcinoma in Group I and liver metastases in Group II) and tumour features (smaller size but greater number of lesions in Group II). In Group II, RFA was associated to liver resection in 23 patients (72%). RESULTS: The 2-month postoperative mortality and complication rates were low in both groups. The postoperative hospital stay was longer in Group II. During a median follow-up of 24 months in Group I and 21 months in Group II, the local "in-situ" recurrence rate was 41.4% and 9.1%, respectively. For RFA-treated tumours < 30 mm in size, the local "in-situ" recurrence rate was 40.5% in Group I and 0% in Group II. Multivariate statistical analysis demonstrated that larger tumour and a percutaneous approach for RFA were independent predictive factors of local "in situ" liver tumour recurrence. CONCLUSIONS: RFA appears to be a safe technique for treating liver malignancies by both approaches. Tumour size and type of RFA approach are predictive factors of in-situ liver tumour recurrence. PMID- 17715631 TI - A health economic model to assess the cost-effectiveness of pegylated interferon alpha-2a and ribavirin in patients with moderate chronic hepatitis C and persistently normal alanine aminotransferase levels. AB - BACKGROUND AND STUDY AIMS: The treatment of patients with moderate chronic hepatitis C and persistently normal alanine aminotransferase levels is still under discussion and the cost-effectiveness of such strategy is unknown. The objective of this study was to estimate the cost-effectiveness of their treatment in comparison with no treatment. PATIENTS AND METHODS: The assessed treatment is composed of pegylated interferon alpha-2a and ribavirin, which is the current standard treatment. Two groups were studied: patients with genotype 1 and patients with genotypes 2-3. At the beginning of the study, patients were aged of 45. Long-term economic and clinical outcomes over a 30 year period were predicted using a Markov simulation model. A health care payer perspective was chosen. Data were obtained from published literature. Variations of uncertainty parameters were assessed through a sensitivity analysis. RESULTS: The incremental cost effectiveness ratios (ICERs) were Euro 5,338/QALY for genotype 1 and Euro 1,080/QALY for genotypes 2-3. In the sensitivity analysis, ratios remained lower than Euro 20,000. A Monte Carlo simulation with 1,000 iterations gives a 95% confidence interval for the ICER of Euro 3,199 to Euro 8,972 for genotype 1 and Euro 56 to Euro 1,981 for genotypes 2-3. CONCLUSION: Even though the treatment of these patients generates a cost, it has the advantage that in comparison with no treatment, a great number of people are cured, complications are less frequent and patients gain more quality-adjusted life-year (QALY), which involves an ICER considered as acceptable for the European society (< Euro 20,000). PMID- 17715633 TI - Endoscopic sphincterotomy for acute relapsing pancreatitis associated with periampullary diverticula: a long-term follow-up. AB - BACKGROUND AND STUDY AIMS: Periampullary diverticula (PAD) are extraluminal outpouchings of the duodenum arising within a radius of 2-3 cm from the ampulla of Vater. Data concerning the association of PAD with biliopancreatic disease are inconsistent, but an association between acute pancreatitis and PAD has been reported. The aim of this retrospective study was to evaluate the outcome of endoscopic sphincterotomy (ES) in a Greek cohort of patients with acute relapsing pancreatitis associated with PAD. PATIENTS AND METHODS: A total of 344 patients who had undergone ERCP between 1994 and 2005 for investigation of acute pancreatitis were retrospectively entered into a database. Of these patients, 11 (3.19% ; median age: 69 years; range: 58-78; 3 men, 8 women) were found to have acute relapsing pancreatitis associated with PAD. All patients underwent ES and were followed for new episodes of acute pancreatitis or other complications. RESULTS: No further episodes of acute pancreatitis occurred after ES, during a long-term follow-up (median: 4.3 years, range: 1.9-10.4). Two patients (18.2%) presented post-procedure mild pancreatitis and one patient (9.1%) post-ES stenosis with two small common bile duct stones and was treated with ES and extraction of stones. CONCLUSION: ES is the treatment of choice for patients with acute relapsing pancreatitis associated with PAD. PMID- 17715634 TI - Endoscopic retrogade cholangiopancreatography is safe and effective method for diagnosis and treatment of biliary and pancreatic disorders in octogenarians. AB - BACKGROUND AND AIM: Diagnosis and treatment of pancreatic and biliary diseases represents a special problem in old patients who often suffer from one or more concomitant diseases. The aim of this study was to evaluate the safety and efficacy of ERCP in very old patients (octogenarians). PATIENTS AND METHODS: Patients 80 years or older who underwent ERCP from October 2001 to December 2005 were studied retrospectively. RESULTS: A total of 209 patients (121 women, 88 men), with a mean age 86 +/- 4.4 years old (80-102) underwent 251 ERCPs. All but three patients tolerated the procedure well. Three procedures were not completed due to patients' discomfort (1.4%). Two of these patients underwent percutaneous transhepatic cholangiography and the other one was treated conservatively. A cholangiogram was obtained in 193 cases (92.3%), although in 7 patients an additional attempt was required. The main endoscopic findings were common bile duct stones in 51.8% (100/193) and cancer in 28% (54/193) of patients. Based on the diagnostic findings, a therapeutic intervention was indicated in 189 patients (90.4%) and was achieved in 181 of them (95.8%). Complications were observed in 9.6% of ERCPs (24/251). Post - ERCP mild pancreatitis was the more frequent complication in 11 procedures (4.4%). No severe pancreatitis was observed. Six procedures were complicated by cholangitis (2.4%) and two by cholecystitis (0.8%). Early surgical intervention was required in 2 cases because of oesophageal perforation and retroperitoneal perforation respectively. Two patients died (0.8%); one patient with pancreatic cancer died due to septic shock after inadequate biliary drainage and the other one died after operation for retroperitoneal perforation. CONCLUSIONS: In conclusion, ERCP is safe and effective method for diagnosis and treatment of biliary and pancreatic disorders in octogenarians despite the high comorbidity in this group of patients. PMID- 17715636 TI - Acute liver failure--practical management. AB - The three most important components of the management of Acute Liver Failure are: 1) Identification of causes requiring specific treatment including hepatic lymphoma, the Budd-Chiari syndrome, ischaemic hepatic necrosis, fulminating septicaemia, Wilson's disease and reactivation of HBV in chronic carriers. 2) Institution of early monitoring and optimal intensive care for multi-organ involvement to improve chances of spontaneous recovery or of transplantation. Deteriorating encephalopathy with cerebral oedema is related to a systemic inflammatory response and infections need to be treated aggressively. 3) Assessment of the need for transplantation based on strong positive predictive values provided by the King's or Clichy criteria. A significant percentage of those not fulfilling criteria also progress. The MARS liver support device has corrective effects on the disturbed pathophysiology of ALF and may be used to enhance spontaneous recovery or as a bridge to transplant, although the latter is not yet proven by controlled clinical trial. PMID- 17715635 TI - Hepatopulmonary syndrome and portopulmonary hypertension: what's new? AB - Hepatopulmonary syndrome (HPS) is found in 4-47% of patients with cirrhosis and is characterized by intrapulmonary vascular dilatations especially in the basal parts of the lung. Liver injury and/or portal hypertension trigger the release of endothelin-l, TNF-alpha, cytokines and mediate vascular shear stress and release of nitric oxide and carbon monoxide, all contributing to intrapulmonary vasodilation. Severe HPS increases mortality (30%) after liver transplantation, especially if Pa O2 is below 50 mmHg. The diagnosis is made by calculating the alveolar-arterial oxygen gradient and by performing a contrast echocardiography. Medical therapy fails and the only long-term treatment available is liver transplantation. More than 85% experience significant improvement or complete resolution in hypoxaemia, but this may take more than 1 year. Portopulmonary hypertension (PPHT) occurs in 2-8% of the patients with cirrhosis. Imbalance between vasodilating (decreased pulmonary expression of eNOS and prostacyclin I2) and vasoconstrictive agents (increased expression of ET-1 and angiotensin 1) may be responsible for misguided angiogenesis and pulmonary hypertension. The diagnosis is made by performing an echocardiography and a right heart catheterisation when systolic pulmonary artery pressure is higher than 30 mmHg on echocardiography. Although prostacyclin analogues are efficacious, adverse effects in terms of safety, tolerability and drug delivery occur. Bosentan is probably the therapy of choice for patients with PPHT because it decreases pulmonary but can also diminish portal hypertension. Sildenafil, a phosphodiesterase-5 inhibitor is used for idiopathic pulmonary hypertension, however, it should be used cautiously in patients with portal hypertension as it may increase portal hypertension by splanchnic vasodilation. PMID- 17715637 TI - Hypoxic hepatitis: the point of view of the clinician. AB - Hypoxic hepatitis better known under the terms of ischemic hepatitis or shock liver is the clinical manifestation of an acute liver cell necrosis consecutive to liver hypoxia. The clinical syndrome is defined as a massive but rapidly resolutive increase in serum aminotransferase activities (AT) occurring in a clinical setting of hemodynamic failure. Actually, when confronted to a case of massive increase in serum AT in the setting of cardiac or respiratory failure, the diagnosis of HH may be assumed without liver biopsy if another cause of hepatocyte necrosis such as viral hepatitis or drug induced hepatitis may be excluded. To our opinion, in these patients often aged and in poor general condition, it is particularly important to exclude herpes simplex virus infection and paracetamol intoxication. In case of doubt, a mere ultrasonography of the liver will be helpful. Indeed the majority of these patients will have a dilation of hepatic veins due to passive congestion of the liver. There is no specific liver therapy and the prognosis is poor depending on the severity of the underlying condition. In this point of view, we report what could be of interest for the hospital clinician. PMID- 17715638 TI - Treatment of cirrhotic ascites. AB - Cirrhosis is the most common cause of ascites and accounts for almost 85% of all cases. It is the most common complication of cirrhosis, after development of ascites only 50% of patients will survive for 2 to 5 years. Successful treatment is dependent on accurate diagnosis of the cause of ascites. Because sodium and water retention is the basic abnormality leading to ascites formation, restriction of sodium intake and enhancing sodium excretion is the mainstay of the treatment of ascites. Patients with cirrhosis and ascites must limit sodium intake to 2 gram per day. Enhancement of sodium excretion can be accomplished by usage of oral diuretics. The recommended initial dose is spironolactone 100-200 mg/d and furosemide 20-40 mg/d. usual maximum doses are 400 mg/d of spironolactone and 160 mg/d of furosemide. The recommended weight loss in patients without peripheral edema is 300 to 500 g/d. There is no limit to the daily weight loss of patients who have edema. About 90% of patients respond well to medical therapy for ascites. Refractory ascites is defined as fluid overload that is unresponsive to sodium restricted diet and high dose diuretic treatment (diuretic resistant) or when there is an inability to reach maximal dose of diuretics because of adverse effects (diuretic-intractable). It has a poor prognosis. Treatment options for patients with refractory ascites are serial therapeutic paracentesis, transjugular intrahepatic stent-shunt (TIPS) or peritoneovenous shunt and liver transplantation. TIPS should be considered in patients who repeatedly fail large-volume paracentesis and have relatively preserved liver functions. Liver transplantation is the only modality that is associated with improved survival. PMID- 17715639 TI - Chronic oesophagitis dissecans: a case report. AB - Chronic oesophagitis dissecans is an often unrecognised cause of chronic dysphagia. It usually occurs in otherwise healthy patients and was first described as We report the case of a patient with chronic dysphagia due to chronic oesophagitis dissecans. PMID- 17715640 TI - Acute motor sensory polyneuropathy (AMSAN) complicating active ulcerative colitis with a patchy distribution. AB - We report a case of acute motor and sensory neuropathy during a flare of ulcerative colitis. A 28-year-old male presented with a flare of distal ulcerative colitis despite treatment with mesalamine enemas and suppositories simultaneously with rapidly deteriorating weakness and needle sensation in both legs. Neurological assessment showed axonal sensorimotor polyneuropathy affecting mainly the lower limbs and to a lesser extent the upper limbs. Colonoscopy revealed moderately to severe active ulcerative colitis with a patchy distribution involving the rectum and the right colon. Vitamin and folic acid levels were normal. Virological, immunological and other laboratory tests were negative except for positive anti-ganglioside antibodies (anti-GM1). Ulcerative colitis and polyneuropathy improved when patient was treated with immunosuppressive therapy (corticosteroids, immunoglobulin and azathioprine). Peripheral polyneuropathy is a rare extraintestinal manifestation of ulcerative colitis and it is probably associated with an autoimmune pathogenetic mechanism. PMID- 17715641 TI - A case of early gastric cancer with bone metastases: are bone marrow micrometastases significant? AB - Gastric adenocarcinoma is currently the 14th cause of death worldwide. Early gastric cancer, defined as cancer not penetrating deeper than the submucosa, is considered to carry an excellent prognosis with 5-year survival rates reaching more than 90%. Cases of bone metastases due to intramucosal gastric cancer are very rarely described. A case of a 70-year old male presenting with confirmed bone metastases 7 years after a curative resection for a mucosal gastric carcinoma is discussed. The patient was investigated with bone marrow biopsy and bone scan and showed no other signs of disease. The clinicopathologic features included poor differentiation, signet ring cells presence, no lymph node involvement and a negative second laparotomy two years after the initial surgery. Studies concerning the presence of residual disease in the form of bone marrow micrometastases are briefly reviewed emphasizing that intramucosal gastric cancer still carries the p sibility for metastasis, many years after a curative resection, mandating long term alertness from the attending physician. PMID- 17715642 TI - Clear cell adenocarcinoma of colorectum: a case report and review of the literature. AB - Primary clear cell adenocarcinoma of the colorectum is a rare neoplasm, which differs from ordinary carcinomas of the colorectum in morphological features, but shares some traits of clear cell carcinoma of other organs. The tumor is usually composed of polygonal or oval cells with abundant granular and clear cytoplasm. The nuclei are often in hyperchromatic shapes with vesicular nucleoli. We report the first case of clear cell adenocarcinoma of the colorectum in China and review the related published cases. The tumor was located in descending colon of a 37 year-old man, and was rich in glycogen but poor in mucin. By immunoperoxidase and histochemical staining, we clarified the clinicopathological characteristics, diagnosis and differential diagnoses, and pursued its potential pathogenesis. In our case, necrosis, high mitotic activity and lymph node metastasis may suggest a highly malignant tumor and an advanced pathological stage. Nevertheless, the patient has survived for one year with the help of operation and postoperative adjuvant chemotherapy. Regardless of the stage and differentiation, surgical therapy and proper adjuvant chemotherapy are effective means to treat the clear cell adenocarcinoma of the colorectum. PMID- 17715643 TI - Thoracoabdominal wall tumour seeding after percutaneous radiofrequency ablation for recurrent colorectal liver metastatic lesion: a case report with a brief literature review. AB - Radiofrequency is a safe and effective minimally invasive procedure in the treatment of liver and other organs neoplastic lesions. Percutaneous access of neoplastic liver tissue is the most common access and electrodes are placed with imaging guidance into the tumour to be ablated. Complications during and after radiofrequency ablation (RFA) are of major or minor severity. Tumour dissemination related to the percutaneous access seems to be very unusual. Herein, we present a rare case of thoracoabdominal tumour wall dissemination after RFA of a recurrent hepatic colorectal metastasis previously removed by surgery. A 64-year-old man with a recurrent hepatic metastatic lesion was treated with internally cooled radiofrequency (RF) for ablation of a 3x3 cm in size tumour mass. Two sessions of RFA in one-month period were performed. Computed tomography (CT) of the upper abdomen and carcinoembryonic (CEA) antigen were used for estimation of the disease progression in the patient's follow-up. Ten months after RFA the patient presented abdominal pain and a mass appeared on the right thoracoabdominal area with simultaneous lung metastases. In conclusion, a large size, bulky and superficial mass on the liver parenchyma adjacent to the thoracoabdominal wall as well as multiple RFA sessions, seem to represent risk factors for tumour dissemination through the needle electrode used during the RFA procedure in hepatic metastases of colorectal cancer. PMID- 17715644 TI - Hypocalcaemic seizures: sign of intestinal disease? AB - We describe a baby admitted with convulsions, fever, low protein level and coagulation abnormalities where congenital intestinal lymphangiectasia was confirmed by endoscopy and histology. Treatment with a low fat diet, supplemented with medium chain triglycerides (MCT), resulted in a disappearance of the symptoms and normal growth. When confronted with seizure-like attacks, electrolyte disturbances and hypo-albuminemia one should consider the possibility of protein losing enteropathy. PMID- 17715645 TI - Does your child have pica? PMID- 17715646 TI - Idiosyncratic toxic hepatitis secondary to single dose of naproxen. PMID- 17715647 TI - The robustness of hearing aid microphone preferences in everyday listening environments. AB - Automatic directionality algorithms currently implemented in hearing aids assume that hearing-impaired persons with similar hearing losses will prefer the same microphone processing mode in a specific everyday listening environment. The purpose of this study was to evaluate the robustness of microphone preferences in everyday listening. Two hearing-impaired persons made microphone preference judgments (omnidirectional preferred, directional preferred, no preference) in a variety of everyday listening situations. Simultaneously, these acoustic environments were recorded through the omnidirectional and directional microphone processing modes. The acoustic recordings were later presented in a laboratory setting for microphone preferences to the original two listeners and other listeners who differed in hearing ability and experience with directional microphone processing. The original two listeners were able to replicate their live microphone preferences in the laboratory with a high degree of accuracy. This suggests that the basis of the original live microphone preferences were largely represented in the acoustic recordings. Other hearing-impaired and normal hearing participants who listened to the environmental recordings also accurately replicated the original live omnidirectional preferences; however, directional preferences were not as robust across the listeners. When the laboratory rating did not replicate the live directional microphone preference, listeners almost always expressed no preference for either microphone mode. Hence, a preference for omnidirectional processing was rarely expressed by any of the participants to recorded sites where directional processing had been preferred as a live judgment and vice versa. These results are interpreted to provide little basis for customizing automatic directionality algorithms for individual patients. The implications of these findings for hearing aid design are discussed. PMID- 17715648 TI - Cortical auditory evoked potentials in the assessment of auditory neuropathy: two case studies. AB - Infants with auditory neuropathy and possible hearing impairment are being identified at very young ages through the implementation of hearing screening programs. The diagnosis is commonly based on evidence of normal cochlear function but abnormal brainstem function. This lack of normal brainstem function is highly problematic when prescribing amplification in young infants because prescriptive formulae require the input of hearing thresholds that are normally estimated from auditory brainstem responses to tonal stimuli. Without this information, there is great uncertainty surrounding the final fitting. Cortical auditory evoked potentials may, however, still be evident and reliably recorded to speech stimuli presented at conversational levels. The case studies of two infants are presented that demonstrate how these higher order electrophysiological responses may be utilized in the audiological management of some infants with auditory neuropathy. PMID- 17715649 TI - Tympanometric and acoustic stapedius reflex measures in older adults: the Blue Mountains Hearing Study. AB - Tympanometric peak pressure, peak compensated static acoustic admittance (peak Ytm) and acoustic stapedius reflex (ASR) thresholds were obtained for a representative sample of 1565 older Australians who were participants in the Blue Mountains Hearing Study (BMHS). No significant age or gender effects were found for tympanometric peak pressure. Peak Ytm measures, however, decreased with age in the left ear only across all age groups and were consistently higher for men than for women. After allowing for hearing loss, the effect of age on ASR thresholds was inconsistent. An increase in ASR thresholds with age was observed at selected frequencies but only when measured contralaterally, and these changes were not clinically significant. Overall, our findings suggest that current normative data for peak Ytm is too restricted for application in the older population, but there is insufficient evidence to warrant alternative normative data for the ASR threshold range in this same population. PMID- 17715650 TI - The effect of digital phase cancellation feedback reduction systems on amplified sound quality. AB - The effect of feedback reduction (FBR) systems on sound quality recorded from two commercially available hearing aids was evaluated using paired comparison judgments by 16 participants with mild to severe sloping hearing loss. These comparisons were made with the FBR systems on and off without audible feedback and while attempting to control for differences in gain and clinical fitting factors. Wilcoxon signed rank test analyses showed that the participants were unable to differentiate between signals that had been recorded with the FBR systems on and off within the same hearing aid. However, significant between instrument differences in sound quality were identified. The results support the activation of the FFT-phase cancellation FBR systems evaluated herein without concern for a noticeable degradation of sound quality. PMID- 17715651 TI - Influence of music and music preference on acceptable noise levels in listeners with normal hearing. AB - Acceptable noise level (ANL) is defined as the maximum level of background noise that an individual is willing to accept while listening to speech. The type of background noise does not affect ANL results with the possible exception of music. The purpose of this study was to determine if ANL for music was different from ANL for twelve-talker babble and investigate if there was a correlation between ANL for music samples and preference for those music samples. Results demonstrated that ANL for music tended to be better than ANL for twelve-talker babble, indicating listeners were more willing to accept music as a background noise than speech babble. The results further demonstrated that ANL for the music samples were not correlated with preference for the music samples, indicating that ANL for music was not related to music preference. Therefore, music appeared to be processed differently as a background noise than twelve-talker babble. PMID- 17715652 TI - An update on professional education and clinical practices in central auditory processing. AB - Results of an online questionnaire probing audiologists' professional education and clinical practices in central auditory processing and its disorders are reported. Respondents demonstrated scant knowledge of the efficiency of central auditory tests and procedures; however, they were rather consistent in reporting more frequent use of tests and procedures they rated as more efficient. Many of the tests and procedures (including electrophysiologic measures) reported as most frequently used are among those cited in the literature as having good sensitivity and specificity. Respondents recognized the audiologist's treatment responsibilities in the areas of environmental accommodations and assistive listening devices; however, less than half of the respondents judged auditory training to fall within the audiologist's purview. Comparison with a similar study published in 1998 revealed an increase in respondents' academic preparation in (C)APD, with little change in clinical preparation, and use of a more efficient central auditory test battery. PMID- 17715653 TI - Tetracycline-family antibiotics and pseudotumor cerebri. PMID- 17715654 TI - [Nodules in the navel. From time to time comes bloody secretion]. PMID- 17715655 TI - [Only a projection? Sought: the good physician]. PMID- 17715656 TI - [An alternative to creams? Sunscreens to swallow]. PMID- 17715657 TI - [What can surgery do in the service of beauty. Construction-place face]. PMID- 17715658 TI - [Proctological diseases have to be carefully ascertained. No diagnosis through the trousers]. PMID- 17715659 TI - [Burnout--alcohol problems--risk of suicide. Role reversal: the doctor as patient]. PMID- 17715660 TI - [Burnout in doctors]. AB - According to the international ICD classification, burnout is not a defined disease. Signs of burnout are frequently associated with psychiatric symptoms. Many doctors experience a reality shock at the beginning of their professional careers due to the great discrepancy between expectations and reality. Frustration and overwork eventually develop into exhaustion, often substance misuse and resignation. Especially doctors usually resort to medical help only in the final stage of burnout when clear psychiatric symptoms are recognizable. Hence, it is all the more important to heed the early warning signs and to counteract increasing stress. PMID- 17715661 TI - [Addicted physicians--intervention programme of the General Medical Council of Hamburg]. PMID- 17715663 TI - [High blood pressure and changes in the ocular fundus]. PMID- 17715664 TI - [Hyperkeratoses]. PMID- 17715665 TI - [Loss of libido in women]. PMID- 17715662 TI - [Suicide and suicide prevention for female and male physicians]. AB - The medical profession represents one of the groups of people who are not reached by the present help system for suicidal behaviour. The suicide rate of male physicians is slightly higher than that of the general population, while that of their female colleagues is clearly higher. This tendency is most pronounced in female psychiatrists and anaesthetists. In addition to the usual preventive measures such as the treatment of depression and addiction, the necessity of a qualified, professional treatment especially for doctors must be recognized because there is often a penchant for ineffective self-treatment. The symptoms are played down and even in acute crisis situations the urgently needed help is not enlisted. PMID- 17715666 TI - [Chicken egg independent production of influenza vaccine substance]. PMID- 17715667 TI - [Opinion of the experts--possible general and individual uses. High purity- additional safety aspect]. PMID- 17715668 TI - [Hessen AOK will boost the use of discounted drugs. 20 Euro bonus for family physicians who "accordingly" prescribe]. PMID- 17715669 TI - [Calculation of case point numbers. Small and rural practices in the East profit from the acknowledgment of fixed operating expenditures]. PMID- 17715670 TI - [Collision with the competition law? Family physicians as seller monopoly]. PMID- 17715671 TI - Predicting kidney function from renal biopsy. Semiquantitative versus quantitative approach. AB - The term glomerulonephritis encompass a heterogeneous group of diseases; these are a important cause of end stage renal disease. Although several evidence exist, that the main prognostic factors are extraglomerular lesions, no quantitative assessment is usually done. In nephropathological practice a semiquantitative approach is preferred. However, most of work on extraglomerular lesions significance was done with quantitative methods. The aim of the study was to compare the effects of quantitative and semiquantitative assessment of extraglomerular lesions in glomerulonephritis. The material consisted of 120 renal biopsies. On inspection, percentage of sclerosed glomeruli, degree of interstitial fibrosis, degree of interstitial infiltration, degree of tubular atrophy were and degree of mesangial matrix expansion assessed. For quantitative measurements AnalySIS 3.0 pro image analysis system was used. Relative interstitial volume, volume of interstitial infiltrate, with their variability- ross sectional areas of proximal and distal tubules were assessed by point counting method. Relative interstitial volume was significantly correlated to percentage of sclerosed glomeruli (R = 0.33 p < 0.001), degree of tubular atrophy (gamma = 0.57 p < 0.00001), degree interstitial fibrosis (gamma = 0.31 p < 0.0002) and mesangial matrix expansion (gamma = 0.24 p < 0.001). Semiquantitative and quantitative assessment of interstitial infiltrate was significantly correlated as well (gamma = 0.81 p < 0.001). Semiquantitatively assessed degree of tubular atrophy showed significant relation to total proximal tubular area (gamma = -0.30 p = 0,004). Percentage of sclerosed glomeruli was significantly correlated to creatinine level (R = 0.24 p = 0.03), but not to urea level (R = 0.09, NS). Semiquantitatively assessed degree of interstitial fibrosis showed only marginal correlation to creatinine level (gamma = 0.18 NS), however degree of interstitial infiltration was significantly correlated to creatinine (gamma = 0.34 p = 0.002) and urea level (gamma = 0.22 p = 0.06). Degree of tubular atrophy was significantly correlated to creatinine (gamma = 0.43 p < 0.001) and urea level (gamma = 0.28 p = 0.015). Relative interstitial volume was the very most important correlate of creatinine (R = 0.47 p < 0.0001) and urea level (R = 0.30 p < 0.01). In conclusion, it was confirmed, that the strongest correlate of renal function is relative interstitial volume. Some, but not all of semiquantitative parameters are also significantly correlated to kidney function. PMID- 17715672 TI - Interstitial, tubular and vascular factors in progression of primary glomerulonephritis. AB - Glomerulonephritis is one of the diseases leading to chronic renal failure and need of renal replacement therapy. Changes in extraglomerular compartments, especially in the interstitium, are thought to play a major role in progression. However, the exact relationships between renal interstitium, tubules and vessels and their prognostic impact are less well understood. The material consisted of 111 biopsies with primary glomerulonephritis. Normal renal tissue from surgically removed kidneys served as controls. Relative interstitial volume (RIV), its variability, volume of interstitial infiltrate, cross-sectional tubular area were measured with the point-counting method. A number of vascular parameters were also measured. The assessed interstitial and tubular parameters were strongly correlated to creatinine level. The strongest correlation was seen for RIV, also on multiple regression. In patients with renal failure, increased RIV, more pronounced vascular lesions and interstitial infiltrates were seen. Survival analysis showed that interstitial expansion is the most important factor leading to renal failure. Tubulointerstitial and vascular factors are interrelated and linked to renal function. RIV has strongest impact on renal function and survival, even taking into account other factors. PMID- 17715673 TI - The infrequent simultaneous genetic alterations in glioblastoma multiforme (LOH 10, 17, 19q, TP53 mutation and EGFR amplification) with short clinical course. AB - We described the case of an unusual, complex genetic alteration in 57 year-old male patient with glioblastoma multiforme (GBM) with short survival (6 and half months). Alterations consisted of p53 mutation, LOH 10, LOH 17, LOH 19q and EGFR amplification. LOH1p, LOH 9 and LOH 13 were negative. Immunohistochemical study did not correlate with molecular results. The overexpression of TP53 protein and RB protein was detected only in small percentage of cells and interestingly the overexpression of EGFR was present only focally. Immnunostainings for PTEN, P16, PI3-K were negative. Additionally, we observed an overexpression of IGFB2 protein. This case indicates the accumulation of molecular changes in glioblastoma multiforme in patient with short survival. PMID- 17715674 TI - Current position of electron microscopy in the diagnosis of glomerular diseases. AB - To establish the role of electron microscopy in the diagnosis of glomerular diseases we reviewed retrospectively 113 renal biopsies. The biopsies were included in this study if tissue was received for light microscopy, immunofluorescence and electron microscopy. The biopsy was assigned to one of the three following categories on the contribution of the ultrastructural findings to the primary diagnosis: essential, important, and not required. Our study revealed that electron microscopy was essential to establish the primary diagnosis in 35 cases (31.0%), was important, but did not alter the preliminary diagnosis in 15 cases (13.3%) and in 63 cases (55.7%) the ultrastructural examination was not needed to confirm the diagnosis. Electron microscopy was essential to create diagnosis in a total of two cases of thin basement membrane disease, in nephropathy in Alport syndrome, in nephropathy in Fabry disease, and was necessary for establishing final diagnosis in 12 cases (85.7%) of minimal lesion. On the basis of electron microscopy it was also possible to establish the precise diagnosis of subtypes in mesangiocapillary glomerulonephritides, describe the stage of membranous glomerulopathy, and find thickening of glomerular basement membrane in the pre-diabetic state. Moreover, ultrastructural examination was helpful to differentiate membranous and mesangiocapillary glomerulonephritis, minimal change nephropathy and early membranous lesions, and distinguish membranous lupus nephritis from idiopathic membranous nephropathy The electron microscopy findings were not of any help in establishing the diagnosis and did not obtain any valuable information in all cases of amyloid nephropathy and IgA nephropathy, as well as in the majority of focal segmental glomerulosclerosis, extracapillary glomerulonephritides, and mesangial proliferative glomerulopathies. In conclusion, the results showed that in 44.3% of glomerulopathies the ultrastructural study provides fundamental or important diagnostic information, and therefore electron microscopy still remains a useful tool in the diagnosis of glomerular diseases. PMID- 17715675 TI - Immunophenotype of isolated tumour cells in the blood, bone marrow and lymph nodes of patients with gastric cancer. AB - Immunophenotype of isolated (disseminated or circulating) tumour cells (ITC) in the blood, bone marrow and lymph nodes were studied in patients with gastric cancer. Coexpression of metalloproteinases inducer (EMMPRIN), chemokine receptors (CCR6, CXCR4) and adhesion molecules (Ep-CAM, CD44) was determined on cytokeratin positive (CK+) cells in CD45- cell population sorted out from the blood and/or bone marrow. Eight cytospin samples of blood and 69 samples of bone marrow containing CK+ cells from patients with gastric cancer were included into study. Expression of EMMPRIN and CCR6 were noted in a half of CK+ samples (of blood/bone marrow) whereas the expression of CXCR4 and Ep-CAM was much lower. Analysis of paired data of these determinants expression on CK+ cells showed no association between them. Expression of EMMPRIN, Ep-CAM, CCR6, CCR7, CXCR1, and CXCR4 on ITC in lymph nodes was determined by flow cytometry. In 18 lymph nodes (out of 36 assayed) CK+ cells were found. The expression of CCR6 and Ep-CAM on CK+ cells was observed in almost all studied lymph nodes, CXCR1--in half of them. The expression of EMMPRIN and CCR7 cells was lower. These results suggest that ITC of gastric cancer express variably several molecules that may be involved in metastasis formation. PMID- 17715676 TI - The pathomorphology of Bartholin's gland. Analysis of surgical data. AB - Medline data did not reveal any statistical approach to Bartholin's gland pathomorphological lesions, especially when the social aspect was considered. Objectives. To complete knowledge and data according to this subject on the basis of own surgical material analysis. Microscopic examinations of histopathological 5 microm thick specimens stained with hematoxylin-eosin and in selected cases with histochemical and immunohistochemical methods on 104 Bartholin's glands taken from 103 female patients in age of 39.4 +/- 9.6. Retention cysts, suppurating lesions (abscesses), extrauterine endometriosis and neoplasms were separated from obtained samples. Localization of lesions, the patients' age and education status were determined. P < 0.05 was considered as statistically significant. Retention cysts were observed in 84.6% of cases, abscesses in 10.6%, extrauterine endometriosis in 2% and neoplasms in nearly 3% of patients. In 54.1% of cases the lesion was localized on the left side, in 45.9% on the right. 17.2% of female patients presented with university education, 29.9% with elementary education, while 52.9% with secondary education. The average age of operated patients amounted to 33 +/- 9.8 years in case of university education, being significantly lower as compared to the average age of secondary (40.5 +/- 7 years) and elementary (42.4 +/- 12 years) education (p < 0.01 and p < 0.02 respectively). 47.7% of retention cysts demonstrated various degrees of inflammatory infiltration. However, the anatomical variability of the ductal and glandular epithelium was higher in cases of non-inflammatory cysts. Considering three Bartholin's gland neoplasms, two were diagnosed as adenocarcinomas and one as a fibromyoma. All of them were observed in female patients with a rare blood type (twice Rh-minus and once AB Rh-plus). There was no significant relationship between the type of pathomorfological lesions and age of operated patients, in spite of the fact that the lowest mean age was observed in woman with endometriosis while the highest in those with neoplasms. The pathology of Bartholin's gland mostly concerns female patients with secondary education. However, early diagnosis is associated with patients with university education. Thus, further investigations considering the statistical analysis of Bartholin's gland neoplasms in order to determine the possible relationship between blood type antigens and neoplasm development are required. PMID- 17715677 TI - Extrapulmonary lymphangioleiomyomatosis presented as the asymptomatic retroperitoneal tumours--two cases report. PMID- 17715678 TI - Locking plating: a revolution in orthopaedic fracture treatment. PMID- 17715680 TI - The hospitalist. PMID- 17715679 TI - Data linkage of inpatient hospitalization and workers' claims data sets to characterize occupational falls. AB - PROBLEM: The identification of industry, occupation, and associated injury costs for worker falls in Kentucky have not been fully examined. The purpose of this study was to determine the associations between industry and occupation and 1) hospitalization length of stay; 2) hospitalization charges; and 3) workers' claims costs in workers suffering falls, using linked inpatient hospitalization discharge and workers' claims data sets. METHODS: Hospitalization cases were selected with ICD-9-CM external cause of injury codes for falls and payer code of workers' claims for years 2000-2004. Selection criteria for workers'claims cases were International Association of Industrial Accident Boards and Commissions Electronic Data Interchange Nature (IAIABCEDIN) injuries coded as falls and/or slips. Common data variables between the two data sets such as date of birth, gender, date of injury, and hospital admission date were used to perform probabilistic data linkage using LinkSolv software. Statistical analysis was performed with non-parametric tests. RESULTS: Construction falls were the most prevalent for male workers and incurred the highest hospitalization and workers' compensation costs, whereas most female worker falls occurred in the services industry. The largest percentage of male worker falls was from one level to another, while the largest percentage of females experienced a fall, slip, or trip (not otherwise classified). When male construction worker falls were further analyzed, laborers and helpers had longer hospital stays as well as higher total charges when the worker fell from one level to another. CONCLUSIONS: Data linkage of hospitalization and workers' claims falls data provides additional information on industry, occupation, and costs that are not available when examining either data set alone. PMID- 17715681 TI - [Effects of colforsin daropate hydrochloride on myocardium, smooth muscle and renal function]. AB - In the failing heart, numerous changes occur in cardiac adrenergic receptors (ARs) and intracellular signal transduction pathways. The most striking of these alterations appears at beta1 ARs, and the desensitization is the most prominent. Since malfunctions of beta1 ARs prevent intracellular signal transduction, the desensitization plays an important role in the onset and progression of the heart failure. Currently, several lines of evidence show the efficacy of inotropic agents, such as adenylate cyclase activator, that depend not on the ARs. Thus, it is essential to understand the pathway for the etiologic/pathologic evaluation for appropriate usage of these drugs for an adequate period. A novel water soluble forskolin derivative, colforsin daropate hydrochloride (CDH) is a positive inotropic agent for treatment of the heart failure, especially in the severe stage with the beta1 AR desensitization. CDH potentiates cAMP activity via its direct action on adenylate cyclase, resulting in cardiotonic action. On the other hand, CDH relaxes vascular smooth muscle, while it antagonizes antidiuretic effects of angiotensin II and noradrenaline, involved in renal protection. In addition, CDH attenuates the mesangial cell proliferation and the inflammatory reaction, related with antiproliferative property of adrenomedullin and ketamine. To gain insights into the CDH action, we should take into account that intracellular signal transduction pathways in myocardium, smooth muscle and mesangial cell are controlled in a distinct manner. PMID- 17715682 TI - [Effects of intravenous anesthetics on acidosis induced apoptosis in primary brain cell culture]. AB - BACKGROUND: We have reported protective effects of intravenous anesthetics on the brain cell. This study examined the effects of extracellular Ca2+ on acidosis induced apoptosis and the protective effects of intravenous anesthetics on such appearance of apoptosis. METHODS: Using the primary culture of rat cerebellular granule cells, extracellular acidosis was produced at pH 6.7 and pH 6.3 and the extracellular Ca2+ free condition was produced by 1 mM EGTA instead of 1.2 mM CaCl2. The cell death was determined by the calcein method and the measurement of apoptosis was done using the screening kit for apoptosis with TUNEL method. Bcl-2 mRNA was detected using quantified RT-PCR method. Midazolam, pentobarbital and propofol were used as typical intravenous anesthetics. RESULTS: Under extracellular acidosis, the significant cell death was detected 6 hr after exposure to acidosis. Moreover, in case of extracellular Ca2+ free/acidosis condition, there was a greater incidence of cell death. Such cell death was much enhanced 20 hr after exposure to acidosis. Furthermore, in case of extracellular acidosis and Ca2+ free condition, there were a significant increase of apoptosis and significant changes of bcl-2. By treatment with intravenous anesthetics, the significant inhibition of cell death and appearance of apoptosis were observed. In these protections by intravenous anesthetics, midazolam and pentobarbital significantly increased the bcl-2 levels. CONCLUSIONS: We demonstrated that intracellular Ca2+ modulates the appearance of apoptosis under acidosis. Moreover it seems that the inhibitory effects of midazolam and pentobarbital on acidosis induced apoptosis are different from that of propofol. PMID- 17715683 TI - [Propofol does not induce retrograde amnesia at the hypnotic dose]. AB - BACKGROUND: We evaluated retrograde amnesic effects of propofol at the hypnotic dose on 28 healthy medical personnel volunteers (17 men, 11 women). METHODS: Explicit memory function was measured after the emergence from bolus infusion of propofol 2 mg x kg(-1); how one could answer the correct number and symbol of 5 playing cards which he had picked up randomly and intentionally memorized before induction? As control, one also took the same test during working hour without any drugs. RESULTS: After infusion of propofol, the rate of correct answers was 96.4 +/- 9.1% and in control, it was 92.1 +/- 18.3% (P = 0.297142). There was no significant difference among two situations. CONCLUSIONS: These results suggest that propofol dose not induce retrograde amnesia at hypnotic dose. PMID- 17715684 TI - [Use of ultrasound for thoracic paravertebral block]. AB - Thoracic paravertebral block is the technique of injecting local anesthetic adjacent to the intervertebral foramina, resulting in unilateral somatic and sympathetic nerve blockade. Previous studies have reported its effectiveness for thoracic surgery including breast surgery and relief of postoperative and chronic pain of unilateral origin from the chest and abdomen. The technique is relatively easy to learn and safer than thoracic epidural. Its clinical advantages include the inhibition of stress and pressor responses to surgical stimuli, maintenance of hemodynamic stability, low incidence of complication, long duration of analgesia, and few contraindications. Recent advances in ultrasound technology can further increase the effectiveness and the safety of thoracic paravertebral block, although identification of the nerve and needle is not still possible. PMID- 17715685 TI - [Causes of postoperative delirium after abdominal surgery in elderly patients]. AB - BACKGROUND: There are many causes for postoperative delirium in elderly patients. Hypotension is considered as one of the causes. In our retrospective study, hypotension during operation was not taken care of strictly. Slight hypotension was observed every so often. We recognized that the drop of cerebral blood flow due to hypotension and duration of hypotension were risk factors of postoperative delirium. METHODS: We did a retrospective study, covering the period between April 1, 2005 and March 31, 2006, in 30 elderly patients for elective laparotomy. We compared postoperative delirium group (D group) with no delirium group (ND group). RESULTS: There were great differences in transfusion, fluid infusion, anesthesia time, operation time, blood loss, extreme hypotension and the duration of hypotension between the two groups. CONCLUSIONS: Our results indicate that permissive hypotension induced the drop of cerebral blood flow and it can be a risk factor of postoperative delirium in elderly patients. To prevent extreme hypotension, to decrease duration of hypotension, and to raise the blood pressure quickly are very important to decrease postoperative delirium in elderly patients. PMID- 17715686 TI - [Anesthetic management for wake-up test during reconstruction surgery of the anterior crucial ligament]. AB - BACKGROUND: Seven patients were subjected to intraoperative wake-up tests during reconstruction surgery of the anterior crucial ligament (ACL) to measure the tension of the reconstructed ligament. METHODS: The patients were of 18 to 28 of age with ASA physical status 1. Anesthesia was maintained with nitrous oxide sevoflurane-fentanyl or propofol-fentanyl under orotracheal intubation. RESULTS: Patients anesthetized with nitrous oxide-sevoflurane-fentanyl did not perform smoothly in the wake-up test because of restless or delayed emergence from anesthesia, and two of them experienced intraoperative awareness. On the other hand, all patients anesthetized with propofol-fentanyl performed smoothly, and no patient experienced intraoperative awareness. CONCLUSIONS: Propofol-fentanyl is better than nitrous oxide-sevoflurane-fentanyl as the method of anesthesia for wake-up tests of ACL reconstruction surgery. PMID- 17715687 TI - [Experience in postoperative sedation with dexmedetomidine for mandibular osteotomy]. AB - BACKGROUND: Dexmedetomidine may be suitable for postoperative sedation of patients with mandibular osteotomy. METHODS: Twenty patients were sedated with dexmedetomidine (group D) employing loading infusion at 1.0 microg x kg(-) x hr( 1) and then continuous infusion at 0.7 mg x kg(-1) x hr(-1). Other twenty patients were sedated with midazolam 0.1 mg x kg(-1) (group C). Ramsay score was recorded at 3 hours and 12 hours after infusing sedative drugs. Then, we questioned patients, nurses and doctors. RESULTS: Ramsay score in the group D was higher than that in the group C (P < 0.01). Hypotension and respiratory depression did not occur. But bradycardia occurred in two cases. By adding propofol, group D showed more effective sedation. CONCLUSIONS: This study shows that sedation with dexmedetomidine is more suitable than that with midazolam. PMID- 17715688 TI - [Neurological deficit following lumbar epidural anesthesia with ropivacaine]. AB - A 38-year-old woman with placenta previa was scheduled for cesarean section. She had no abnormal medical history including neurological deficit before the operation. Prior to general anesthesia, an epidural catheter was inserted in the L2-3 interspace for postoperative analgesia. There was no difficulty in threading the catheter. No pain, paresthesia or bleeding was elicited at any time. After a test dose of 1% lidocaine 1 ml, a bolus of 0.75% ropivacaine 12 ml was injected through the epidural catheter. At the end of the operation, a continuous epidural infusion of 0.2% ropivacaine (the pump speed of 6 ml x h(-1)) was started. On the second postoperative day, sudden sensory loss level to L2 (right lower extremity), L3 (left one) and flaccid paralysis of bilateral lower extremities occurred. MRI and myelogram showed no abnormality of the spinal cord. Her neurological deficit showed slight improvement but her sensory and motor paralysis still remained. Neurotoxicity of ropivacaine may be the cause of this neurological deficit. PMID- 17715689 TI - [Unsuccessful anesthetic management for cesarean section in a patient with primary pulmonary hypertension]. AB - A 31-year-old woman with primary pulmonary hypertension presented for an elective cesarean section at the 34-week gestation. After monitoring pulmonary artery, systemic artery blood pressures and an electrocardiogram, continuous lumbar epidural anesthesia was performed. Uneventful delivery was followed by a sudden decrease in systemic pressure and loss of consciousness. Her trachea was intubated and administration of epinephrine was started. Nitroprusside and milrinone were infused to decrease pulmonary artery pressure and to maintain systemic arterial pressure. However, she died after 16 hours due to an impairment of right ventricular function. Although the patient with PPH had been managed successfully using continuous epidural analgesia until delivery, sudden hemodynamic alterations following delivery could not be controlled by pharmacological interventions. PMID- 17715690 TI - [Epidural blood patch for intracranial hypotension with closed system in a Jehovah's Witness]. AB - We report a case of treating intracranial hypotension with an epidural blood patch using closed system that allows blood collection and epidural injection without loss of continuity. The patient was a 34-year-old woman with severe headache for several months. The headache failed to respond to conservative management. By radioisotope cisternography, it was diagnosed as intracranial hypotension. Epidural blood patch was planned for intracranial hypotension. We used the method of epidural blood patch in a closed venous blood transfusion system to the epidural space, because she is a member of the Jehovah's Witness. Twenty five ml of blood was drawn into the syringe and injected into the epidural space with closed system. The patient was discharged home after 3 days with dramatically reduced symptons. Epidural blood patching with closed system is a safe, and effective procedure that is acceptable to a Jehovah's Witness. PMID- 17715691 TI - [Laryngeal edema and vocal cord paralysis due to lithium battery ingestion; a case report]. AB - We report a case of an 8-year-old boy with laryngeal edema and vocal cord paralysis due to lithium battery ingestion. He had ingested a lithium battery of a television remote controller, and was admitted to our hospital. He was suffering from wheezing and retractive respiration with crying. The foreign body was removed under general anesthesia about two hours after the ingestion. It was a 3 volt lithium battery of 20 millimeters in diameter. Endoscopy showed chemical burn of the postcricoid area and severe edema of the laryngeal arytenoids. Twelve days later we confirmed healing of edema and extubated the tracheal tube, but endoscopy showed bilateral vocal fold paralysis. He had no difficulty in breathing and eating but the vocal cord paralysis remained. Lithium batteries ingestion may cause severe airway injury in a short period because of their large size and high voltage. Immediate removal and careful management are required. PMID- 17715692 TI - [Transient hyperglycemia following intra-peritoneal irrigation with 5% glucose in a patient with pseudomyxoma peritonei]. AB - Pseudomyxoma peritonei is a condition characterized by the production of a large amount of mucopolysaccharide by a neoplastic epithelium. Although surgical removal of the mucinous ascites may be attempted, complete removal of the material is difficult. Thus, intra-peritoneal lavage with the liquid containing glucose or dextrose has been advocated to prevent reaccumulation of the mucus and complications such as bowel obstruction requiring repeated surgery. We report a case showing transient hyperglycemia following intra-peritoneal irrigation with 5% glucose in a patient with psudomyxoma peritonei. The patient was a 72-year-old woman. Preoperatively, she had hypertension and angina pectoris; but no history of glucose intolerance. Serum glucose was 92 mg x dl(-1). General anesthesia was induced with propofol (100 mg), vecuronium (6 mg), and fentanyl, and maintained with oxygen (33%), nitrous oxide and sevoflurane (1-2%). A mucinous tumor was found with a great deal of mucinous ascites. To remove the mucus and prevent subsequent re-accumulation, intra-peritoneal irrigation with 5% glucose in water was performed. Shortly after this procedure, the patient was found to be hyperglycemic (serum glucose 266 mg x dl(-1)) with normal oxygenation and hemodynamic data. The patient recovered uneventfully and could be extubated soon after surgery. Serum glucose level returned to 154 mg x dl(-1) one hour after surgery. Therefore, we think that this acute hyperglycemic condition, presumable due to intra-peritoneal irrigation, was transient. It is important to be aware of this dangerous complication associated with intra-peritoneal glucose instillation. Glucose monitoring during and after irrigation with glucose or dextrose is recommended. PMID- 17715693 TI - [Nasal endotracheal intubation using GlideScope]. AB - We describe the performance of GlideScope in 34 consecutive patients who required nasal endotracheal intubation for surgical convenience. In the 34 patients, nasal endotracheal intubation was achieved in 52 +/- 22 (mean +/- SD) sec by unexperienced clinicians, and in 50 +/- 17 sec by anesthetists in the department. Margill forceps were not needed for any patient during nasotracheal intubation. The improved coordination afforded by an image on a video monitor seen by both the assistant providing laryngeal manipulation and the anesthetist handling the laryngoscope resulted in a significant advantage over the conventional laryngoscope technique. GlideScope seems to be a novel useful device for nasal endotracheal intubation. PMID- 17715694 TI - [Cerebrovascular accidents developing in the operating theater: a JSA survey for the year 2004]. AB - BACKGROUND: The incidence of cerebrovascular accidents (CVA) developing in the operating theater has not been investigated on a large scale. In 2004, the Japanese Society of Anesthesiologists (JSA) started to survey neurological as well as life-threatening events in the operating theater. The incidence of CVA developing in the operating theater was examined using data obtained by the 2004 survey. METHODS: JSA has conducted annual surveys of life-threatening and neurological events in the operating theater by sending and collecting confidential questionnaires to all JSA certified training hospitals. The recovery rate was 91% (874/960 hospitals) in 2004. Seven hundred fourteen hospitals sent valid responses, and 1,218,371 anesthesias were registered. Among these cases, 123 patients were reported to have developed CVA in the operating theater. Incidences according to age class, ASA PS and surgical sites, causes, and their outcome were investigated. The patients with ASA PS 1 or 2 were classified as having good physical status, and those with ASA PS 3-5 were classified as having poor physical status. The causes of events were classified as follows: totally attributable to anesthetic management (AM), mainly to intraoperative pathological events (IP), to preoperative co-morbidity (PC), and to surgical management (SM). RESULTS: Overall incidence of CVA was 1.01/10,000 anesthesias. The incidence in patients aged 66 years or above was 2.00/10,000 anesthesias, which was 3.83-(95% confidential interval 2.57-5.71) fold higher than that in patients aged between 19 and 65 years. The incidences in elective and emergency patients with poor physical status were 3.27 and 7.91/10,000 anesthesias, respectively, which was 7.04- (4.56-10.87) and 17.06-(10.90-26.69) fold higher than that in elective patients with good physical status, respectively. The incidences in patients undergoing thoracotomy combined with laparotomy, craniotomy, or cardiovascular surgery were 2.76, 5.96 and 11.65/10,000 anesthesias, respectively, which were 7.22- (1.64-31.76), 15.59- (8.14-29.86), and 30.52- (16.80-55.44) fold higher than that in patients undergoing laparotomy alone. Among cardiovascular surgery, thoracic aortic surgery showed the highest number of incidents (57.98/10,000 anesthesias), followed by on-pump coronary artery bypass (11.07/10,000 anesthesias). Only one patient undergoing off-pump coronary artery bypass developed CVA, resulting in an 8.14- (1.00-66.18) fold lower incidence of CVA compared to that of on-pump coronary artery bypass. AM, IP, PC and SM were responsible for 4.1%, 24.4%, 27.6% and 35.0% of CVA. The incidence of CVA caused by AM or IP was calculated to be 0.29/ 10,000 anesthesias. If patients undergoing cardiovascular surgery or craniotomy were excluded, the incidence of CVA caused by AM or IP was calculated to be 0.13/ 10,000 anesthesias (15/ 1,134,398 anesthesias). The overall outcome of CVA was as follows: uneventful recovery 9.8%, death within 30 post-operative days 26.0%, vegetative state 6.5%, and sequelae involving deficits in the central nervous system 52.0%. The outcome of CVA caused by AM or IP was as follows: uneventful recovery 20.0%, death within 30 post-operative days 22.9%, vegetative state 8.6%, or sequelae involving deficits in central nervous system 45.7%. Twenty-seven point six percent of reported CVA were considered to have been preventable. CONCLUSIONS: The overall incidence of CVA developing in the operating theater in Japan was reported to be 123 among 1.2 million anesthesias. The incidence was high in elderly patients, in patients with poor physical status, and in patients undergoing cardiovascular surgery. Because the prognosis of CVA developing in the operating theater was poor, clinical strategies for prevention, early detection, prompt diagnosis, and appropriate treatment of CVA should be established. PMID- 17715695 TI - Does resection of an intact breast primary improve survival in metastatic breast cancer? AB - The recommended primary treatment approach for women with metastatic breast cancer and an intact primary tumor is the use of systemic therapy. Local therapy of the primary tumor is recommended only for palliation of symptoms. However, a series of retrospective studies examining practice patterns for this problem show that about half the women presenting with de novo metastatic disease undergo resection of the primary tumor, and suggest that women so treated survive longer than those who do not undergo resection of the intact primary. In analyses that adjust for tumor burden (number of metastatic sites), types of metastases (visceral, nonvisceral), and the use of systemic therapy, the hazard ratio for death is reduced by 40% to 50% in women receiving surgical treatment of the primary tumor. The benefit of surgical treatment appears to be confined to women whose tumors were resected with free margins. However, these results may simply reflect a selection bias (ie, younger, healthier women with a smaller tumor burden are more likely to receive surgical treatment). In addition, the role of other locoregional therapy such as axillary dissection and radiotherapy is not addressed in these studies. In view of these data, the role of local therapy in women with stage IV breast cancer needs to be reevaluated, and local therapy plus systemic therapy should be compared to systemic therapy alone in a randomized trial. PMID- 17715696 TI - Chemotherapy-induced nausea and vomiting: which antiemetic for which therapy? AB - Chemotherapy-induced nausea and vomiting (CINV) remains an important and common toxicity of cancer treatment. Recent guideline revisions have classified chemotherapeutic agents into four categories of emesis risk without the use of preventive agents: high (> 90%), moderate (30%--90%), low (10%-30%), and minimal (< 10%). Currently available antiemetic agents, including corticosteroids, 5 hydroxytryptamine (HT)3 receptor antagonists, and neurokinin (NK)-1 antagonists are used alone or in combination depending on the level of emetogenic potential as prophylaxis against the development of CINVduring the acute period (up to 24 hours after chemotherapy) and the delayed period (up to 5 days after treatment). Newer agents, including the second-generation 5-HT3 receptor antagonist palonosetron (Aloxi) and the NK-1 antagonist aprepitant (Emend), offer additional clinical benefit in highly and moderately emetogenic therapy. However, delayed nausea and vomiting continue to occur frequently in many patients and have an impact on quality of life. Other classes of agents including the benzodiazepines and cannabinoids offer the potential for additional protective benefit. Continued research with new drugs and combinations is necessary to meet this significant unmet need of cancer patients. PMID- 17715697 TI - Clinical use of monoclonal antibodies to the epidermal growth factor receptor in colorectal cancer. AB - Monoclonal antibodies to the epidermal growth factor receptor (EGFR) are among the promising novel targeted therapies being explored in colorectal cancer. Two such agents that inhibit EGFR signaling by interfering with ligand-binding are cetuximab (Erbitux) and panitumumab (Vectibix). This review will address the use of cetuximab and panitumumab in chemotherapy-refractory colorectal cancer as well as in front-line therapy for the disease, consider predictors of response and resistance, and outline comparisons between these agents. PMID- 17715698 TI - Hodgkin's lymphoma in the elderly: a different disease in patients over 60. AB - With improved prognosis for patients with Hodgkin's lymphoma (HL), interest has increasingly focused on high-risk groups such as elderly patients. Advanced age at presentation is still one of the strongest negative risk factors. Many different factors influence the prognosis in elderly patients. These include biologic differences such as more aggressive histology, different distribution of disease, more frequent diagnosis of advanced stage, and shorter history of disease. In addition, however, aging itself and associated factors such as comorbidity, reduced tolerability of conventional therapy, more severe toxicity and treatment-related deaths, failure to maintain dose intensity, shorter survival after relapse, and death due to other causes contribute to the poorer outcome in elderly patients. Besides the evaluation of specific causes and risk factors, this review highlights recent and ongoing studies for elderly patients with HL as well as international approaches and recommendations for this age group. PMID- 17715699 TI - Reviving the acid phosphatase test for prostate cancer. AB - Prostatic acid phosphatase (PAP) emerged as the world's first clinically useful tumor marker in the 1940s and 1950s. With the introduction of the prostate specific antigen (PSA) test in the 1980s, which performed significantly better than PAP in terms of screening and monitoring response to treatment, PAP fell into disfavor. An increasing number of recent studies have identified PAP as a significant prognostic factor for patients with intermediate- and high-risk prostate cancer. PAP appears to be particularly valuable in predicting distant failure in higher-risk patients for whom high levels of local control are achieved with aggressive initial local treatment. As prostate cancer care becomes increasingly focused on identifying the minority of patients who would benefit from aggressive systemic therapy, a reevaluation of the potential contribution of the prostatic acid phosphatase test seems timely. PMID- 17715700 TI - One moment in research. PMID- 17715701 TI - Breaking the cycle of fear. AB - Two approaches to eradicating pervasive and chronic fear include viewing mistakes and errors as informative rather than cause for personal evaluation, and improving people's skills for confronting and resolving these crucial conversations. PMID- 17715702 TI - Creating & sustaining a blame-free culture: a foundation for process improvement. AB - Discover steps that physician leaders can take to end the blame game and begin working as a much more functional and focused team. PMID- 17715703 TI - Seeing systems in health care organizations. AB - "Systems" in health care organizations are difficult to visualize and understand by people across the organization. Systems exist as behaviors that have reasons and consequences rather than strict, linear cause and effect relationships. Learn how to sketch and see the systems at work in health care, and how to change them to help end the blame game. PMID- 17715704 TI - East meets West: internist also practices acupuncture. AB - Meet Col. Arnyce Pock, a Western-trained internist who made several trips to China to study the ancient art of acupuncture. PMID- 17715705 TI - A marketing plan: like it or not, you already have one. AB - A physician executive dives into the world of marketing and discovers that just coming up with a marketing plan for a group practice can be very pricey. PMID- 17715706 TI - How to keep good staff from leaving. AB - There are many moves you can make to maintain staff morale, provide staff with challenges and keep them content. PMID- 17715707 TI - The push for health care value spurs greater physician scrutiny. AB - Health plans are profiling physicians on efficiency measures-producing new clinical, operational and strategic challenges for practices. PMID- 17715708 TI - Negotiation: the CMO's indispensable skill. AB - Negotiation is the most important tool that a chief medical officer, or any physician leader, can possess. Here are some tips and insights on ways to improve your negotiation skills. PMID- 17715709 TI - My third year as chief of staff. AB - Passing a Joint Commission survey, dealing with a sexual harassment complaint and writing a performance pay plan are just a few of the issues that a chief of staff in the VA wrestled with during his third year on the job. PMID- 17715710 TI - How to make innovation happen--part 3. AB - In the last installment of this 3-part series, learn the framework needed to support an innovation team that can make change happen. PMID- 17715711 TI - Why pre-set pricing could work. PMID- 17715712 TI - Time for 'coopetition' is now. PMID- 17715713 TI - Is God happy with the ethics committee? PMID- 17715714 TI - Communication skills predict success. PMID- 17715715 TI - Why do process redesigns fail? PMID- 17715716 TI - Recent health care employment cases lead to push for new federal laws. PMID- 17715717 TI - Multicentric giant cell tumour of bone. AB - Although giant cell tumour (GCT) is seen quite frequently, multicentric giant cell tumour (MCGCT) is a rare entity occurring in less than 1% of patients with GCT. The pathogenesis of MCGCT is debated; various mechanisms have been postulated, including contiguous spread, iatrogenic tumour cell seeding, benign metastasis, malignant transformation and de novo formation. A literature review revealed 101 cases of MCGCT reported worldwide, of which we could trace and review 83 cases. We noted that MCGCT, unlike the solitary GCT, more frequently involves the short bones of the hand and feet and is commoner in the meta diaphyseal region of long bones. The present literature review noted a higher incidence in females and skeletally immature patients (21%). Individual lesions in a patient with MCGCT are radiologically and histologically indistinguishable from the solitary GCT. In our review we noted 42 recurrences in 157 lesions (26%), thus negating the commonly held point of view that MCGCT was clinically more aggressive. Four lung metastases and two histologically malignant lesions were found. The literature does not define the exact time period beyond which a lesion can be classified as metachronous; however a significant number of the subsequent lesions occur within 2-3 years of the index lesion. We recommend from our review, that with the present state of knowledge, special care should be taken in cases with primary meta-diaphyseal lesions, GCTs seen at atypical locations, and in females of younger age group, to ensure that multicentricity is picked up earlier. PMID- 17715718 TI - Primary hyperparathyroidism and pathological fractures: a review. AB - Primary hyperparathyroidism is due most often to a parathyroid adenoma secreting parathyroid hormone. Elevated PTH levels cause bone resorption, the formation of polyostotic lesions and a reduction in bone mineral density, predisposing to pathological fractures. The final stage of this disease is osteitis fibrosa cystica. The authors review the literature about osteitis fibrosa cystica and the treatment options when a pathologic fracture occurs. PMID- 17715719 TI - Hemiarthroplasty for three- and four- part displaced fractures of the proximal humerus in patients over 65 years of age. AB - This is a prospective case series, in which the outcome of shoulder hemiarthroplasty in recent three- and four-part fractures of the proximal humerus was evaluated in patients over 65 years of age. From February 1993 to October 2002, 51 patients with 3- or 4-part fractures of the proximal humerus were entered into the study. The criteria for inclusion were age over 65 years and 3- or 4- part displaced fracture. The mean age of the patients was 73 years (range: 65 to 84). The mean follow-up was 5.5 years (range: 2 to 12). According to the Constant-Murley scale, the results were satisfactory or very satisfactory for 74% of the patients. Thirty nine patients (78%) experienced mild or no pain, 50% achieved active anterior elevation greater than 120 degrees, while 40% had active lateral elevation of more than 120 degrees. None of the patients experienced complete recovery of strength and full range of motion. Thirty four patients were able to resume all their daily activities. There were complications in 26% of the patients. Assessment following the Constant-Murley scale demonstrated that two thirds of the patients were pain free and regained a wide range of shoulder movement, while one third resumed their pre-fracture activities to a great extent. The majority of the patients did not recover normal strength. PMID- 17715720 TI - Kiloh-Nevin syndrome: a compression neuropathy or brachial plexus neuritis? AB - Kiloh-Nevin syndrome was first described in 1948 by Parsonage and Turner and further defined in 1952 by Kiloh and Nevin. The aetiology is highly debated. Two common causes of Kiloh-Nevin syndrome are compression neuropathy and brachial plexus neuritis. In this study the results in six patients who were treated operatively and were evaluated after a mean follow-up of 42 months (range: 24 to 60), are presented. Retrospectively, two subgroups could be identified based on initial clinical presentation and EMG: one subgroup of patients presented with a compression neuropathy and the other subgroup presented with brachial plexus neuritis. An important difference in outcome was seen between the two subgroups. There were excellent results after surgical decompression in the patients with a compression neuropathy, whereas the results after surgical decompression in the subgroup presenting with brachial plexus neuritis were less predictable. The data presented here and the data found in the literature, suggest that if the clinical image and the EMG suggest a compression neuropathy, surgical decompression, after two months of conservative treatment, will give excellent results. If the clinical image and EMG suggest brachial plexus neuritis, a conservative treatment may be more appropriate. PMID- 17715721 TI - Interposition arthroplasty using an acellular dermal matrix scaffold. AB - We have used arthroscopic debridement and interposition arthroplasty with an acellular dermal matrix allograft in treatment of first carpometacarpal joint arthritis successfully in a limited number of patients. The purpose of this investigation was to study the use of an acellular dermal matrix graft in a rabbit model of interposition arthroplasty. Eleven rabbits underwent excision of the lunate bone and interposition of extensor tendon (control) or dermal matrix graft (experimental). Radiographic analysis and either histological or vascular studies were performed. No adverse immunological response was noted. Increasing fibroblast like cells were noted over time in both groups with greater infiltration in control specimens. Vascular infusion showed infiltration in both arthroplasty groups. Both groups maintained the resection space and promoted cellular ingrowth without adverse immune response. Vascular infiltration occurred in both arthroplasty groups. These results support use of this graft in interposition arthroplasty. PMID- 17715722 TI - Contralateral slip prediction in slipped capital femoral epiphysis: is bone age the answer? AB - Prophylactic pinning of an asymptomatic hip in Slipped Capital Femoral Epiphysis (SCFE) is controversial. Bone age has been used as a predictor of future contralateral slip risk and also in the decision making for prophylactic intervention. The efficacy of bone age at predicting a contralateral slip was tested in this study. Eighteen Caucasian children prospectively had bone age assessment using wrist and hand radiographs when presenting with a unilateral SCFE. After in situ fixation of the affected side prospective monitoring was performed at regular intervals in the outpatient department. Surgical intervention was undertaken if the contralateral hip was symptomatic. Three children (2 boys and 1 girl) went on to develop a contralateral slip at a mean of 20 months from initial presentation. Six children were deemed at risk of contralateral slip due to a bone age of > or = 12.5 years for boys and > or = 10.5 years for girls. Only one from this group developed a contralateral slip. The relative risk of proceeding to a contralateral slip when the bone age is below the designated values was 1 (95% confidence interval of 0.1118 to 8.95). The sensitivity and specificity were 33% and 66% respectively. The positive predictive value was 15% and the diagnostic efficiency was 61%. Although this is a small study, it would appear that delayed bone age by itself is not a good predictor of future contralateral slip. Routine prophylactic pinning is not justified based on bone age alone, with the risks of surgical fixation it carries. A prospective long term longitudinal study is required. PMID- 17715723 TI - Impaction allografting revision for B3 periprosthetic femoral fractures using a Mennen plate to contain the graft: a technical report. AB - We prospectively evaluated the long-term results of a technique using the Mennen plate to contain impacted allograft and support cemented Exeter stem revision fixation for the treatment of three B3 periprosthetic femoral fractures (PFFs). Three patients with a median age of 77 years were followed-up for a median of 84 months. In all cases the stem bypassed the distal fracture line by a median length of 85 mm (median ratio over femoral diameter = 2.13). The median postoperative Charnley-Merle d'Aubigne-Postel score for pain, function and range of movement was 5, 3 and 6 respectively. Impaction allografting revision could be used for B3 PFFs when the stem bypasses the most distal fracture line by at least two ipsilateral femoral diameters. The Mennen plate can aid to contain the impacted allograft and to maintain fracture reduction and short term stability thereafter, but the long stem is necessary for long-term stability and healing. PMID- 17715724 TI - Patients poorly estimate the overall costs of a total knee arthroplasty and strongly overestimate the surgeon's fee. AB - In an attempt to reduce health care expenses, regulated competition between health care providers has been introduced in The Netherlands. As for total hip and knee arthroplasties, health care providers have to publish their prices to make them available for the insurance companies and the public. Eventually, competition between health care providers should result in optimal care for lower prices. The purpose of this study was to define the patients' consciousness of the overall costs and specialist's fee for a total knee arthroplasty. Thirty-nine patients with a recent total knee arthroplasty were asked to estimate the total costs and the surgeon's fee of this procedure. The average overall cost of a total knee arthroplasty in our hospital was Euro 11.500. The orthopaedic surgeon's fee represents a non-negotiable 5% of these total costs. The mean estimate of the overall costs of a total knee arthroplasty by the patients was Euro 10.000 (range: Euro 600 to Euro 55.000). Only 26% of the patients (n = 10) gave an estimate within the accepted "correct" range of Euro 8.500 to Euro 14.500. The surgeon's fee was estimated at 32% (range: 5% to 75%) of the total costs and a majority reckoned the actual fraction of 5% was low. Patients have a poor notion of the overall costs of a total knee arthroplasty and strongly overestimate the specialist's fee. Whether the introduction of budget competition in health care may actually result in a decrease in health care costs remains to be seen. PMID- 17715726 TI - Reconstruction of distal tibial defects following resection of malignant tumours by pedicled vascularised fibular grafts. AB - The aim of this study was to evaluate the oncologic and functional outcome after wide resection of malignant tumours of the distal tibia and reconstruction of the defect by ipsilateral pedicled vascularised fibular graft and ankle arthrodesis. Thirteen patients (9 males and 4 females) with primary malignant tumours of the distal tibia were treated by wide resection. The mean age of the patients at the time of surgery was 15 years. The fibula was mobilised to fill the defect, pedicled on the peroneal vessels. The average size of the defects reconstructed was 10 cms. Patients were evaluated functionally using the Musculoskeletal Tumor Society evaluation system. The mean duration of follow-up was 27 months. Chest metastases developed in 4 patients and local recurrence in one. The mean functional score was 80% at the time of last follow-up. The average time to union of the graft both proximally and distally was 6 months. Complications were minimal and did not affect the functional outcome. Reconstruction of distal tibial defects with an ipsilateral pedicled vascularised fibular graft is a technically easy reconstructive option which offers a predictable long standing functional outcome. PMID- 17715725 TI - The effect of proximal tibial fractures on the limb axis in children. AB - Between 1985 and 2002 we treated 38 children with 39 fractures of the proximal tibia. Fractures affecting the proximal tibial physis were excluded from this study. Mean age at the time of injury was 7.1 years (range: 2.5 to 14). Conservative treatment was followed in 34 cases and four patients underwent surgery. We examined 31 children with 32 fractures followed up for an average of 4.8 years (range: 16 months to 15 years). Twenty eight (90.3%) patients developed post-traumatic tibia valga. Deformities were observed at an average 5.3 months after injury. All the cases with fractures of the medial cortex developed valgus angulation. The mean valgus angular deformity was 5.5 degrees. There was also an average of 5.31 mm limb lengthening in 27 patients. Eleven patients with an angulation >5 degrees were reevaluated at an average of 7.4 years from the initial injury. Partial remodelling was observed in 6 patients (54.5%) and total remodelling in 3 (25%). We recommend that children with proximal metaphyseal tibial fractures should be initially treated conservatively and followed up during skeletal development, because valgus deformity tends to remodel with age. PMID- 17715727 TI - Immediate unprotected weight-bearing of operatively treated ankle fractures. AB - The objective of this study was to determine whether immediate mobilisation and unprotected weight-bearing of rigidly internally fixed fractured ankles had a significant effect on ankle function or whether it predisposed the ankle to loss of reduction or hardware failure. Twenty five patients with operated Weber A/B/C fractures were allowed immediate full weight-bearing without a plaster and were compared with matched historical controls treated in a non-weight-bearing plaster cast. Matched-pair analysis revealed no differences for hospital stay and functional outcome on Olerud and Molander scoring system but significant difference in time until return to work (mean: 91.3 +/- 20.2 vs. 54.6 +/- 15.5 days). In the cast group four patients had postoperative complications; one patient had loss of internal fixation and one had non-union while four patients in the non cast group had mainly wound-healing related problems. Patients in the non cast group tolerated earlier full weight-bearing compared with patients in the cast group, and there were no disadvantages concerning hospital stay, pain intensities, and functional scores. Treating patients without plaster may result in faster rehabilitation. PMID- 17715728 TI - Congenital convex pes valgus (congenital vertical talus). The condition and its treatment: a review of the literature. AB - Much discussion exists about the best operative technique to treat congenital convex pes valgus. In this article a table of surgical approaches and an algorithm, based upon literature review, are presented. In our opinion the technique of choice in a child younger than 2 years of age is extensive release with lengthening of tendons and fixation procedures. In a child over 2 years of age, extensive release with tendon transfer is the preferred procedure. When this procedure has failed, naviculectomy with extensive release and tendon transfer, or subtalar / triple arthrodesis must be considered. PMID- 17715729 TI - Flexor tendon lengthening for hammer toes and curly toes in paediatric patients. AB - The purpose of this retrospective study was to evaluate the outcome of flexor tendon lengthening performed for hammer toes or curly toes in children, after a mean follow up of 31 months. Specific attention was given to postoperative active flexion of the toe. The deformity improved in all patients, but less in the fourth and fifth toe. Active flexion returned and strength was recovered in all patients. We think that open flexor tendon lengthening for hammer and curly toes is a safe and reliable procedure. We recommend a transverse skin incision, Z lengthening of the flexor digitorum longus in hammer toes and an associated tenotomy of the flexor digitorum brevis in curly toes. PMID- 17715730 TI - Comparison of autologous transfusion drains versus no drain in total knee arthroplasty. AB - Primary total knee arthroplasty is associated with blood loss both during surgery and in the immediate postoperative period, that may require allogenic blood transfusion. In view of the risks and financial implications of using allogenic blood, an accepted solution has been to utilise autotransfusion drains in the postoperative period thus allowing re-infusion of a patient's own blood. A number of studies have compared retransfusion techniques with standard drain use, but few report comparison with no drain use at all. We analysed data from patients undergoing primary total knee arthroplasty within our unit over an 18-month period. A total of 121 patients were included in the study: 53 received retransfusion drains whilst the remaining 68 received no drain at all. The mean postoperative haemoglobin drop was not significantly different between the two groups (p > 0.05). In the retransfusion group only one patient (2%) required allogenic blood transfusion postoperatively, whilst 4 of the 68 (6%) did so in the control group. This difference was not statistically significant either. This study showed a low rate of allogenic blood use postoperatively (< 5%) where either a retransfusion drain or no drain was used at all. However because there was no measurable difference between the two, we conclude that using a retransfusion technique does not appear to be of significant financial or clinical benefit with regards to allogenic blood transfusions compared with using no drain. PMID- 17715731 TI - Patient acceptance of a foot pump device used for thromboprophylaxis. AB - Our study aimed to find out patients' opinion on a foot pump device used for thromboprophylaxis, as compared to subcutaneous low molecular weight heparin injections. A survey of 43 consecutive patients undergoing hip and knee joint replacement was carried out at our hospital. Patients were assessed for pain and a questionnaire was used to gauge patients' attitudes towards the two thromboprophylactic measures. There was no statistically significant difference in the level of discomfort as assessed on the visual analogue score, between two methods. An equal percentage of patients (74.4%) disagreed that either the foot pump or injection was painful (p = 1). Though a larger percentage of patients (footpumps: 44.2%, injections: 27.9%; p = 0.12) would rather not use the foot pump, still 69.8% would be willing to keep on using these foot pumps at home for 4 weeks after discharge from the hospital. Eighty one percent were agreeable to foot pump use if they have another joint replacement later. Overall, the foot pump was at least as well tolerated as subcutaneous low molecular weight heparin in the group studied. Its use as post discharge prophylaxis is also acceptable to the majority of our patients. PMID- 17715732 TI - Kirschner wire migration causing spinal cord injury one year after internal fixation of a clavicle fracture. AB - K-wire migration after internal fixation of the clavicle has rarely been reported to cause spinal cord injuries. A 30-year-old man presented with progressive paraparesis, hypaesthesia under a Th4 level and electric pain in the neck and arms. CT of the spine revealed a migrated K-wire from a one-year-old clavicle osteosynthesis, penetrating the spinal canal through the Th2 nerve root foramen, and perforating the spinal cord with a transversal trajectory. Surgical removal of the K-wire was performed after exposing both ends. Laminectomy allowed visual control of the entry point and correction of cerebrospinal fluid leakage. The pain disappeared and the patient recovered a normal gait after 6 weeks. The use of two incisions is advocated in such cases: one lateral to allow wire removal, and one medial for dural repair and early intradural bleeding control. Regular follow ups, K-wire removal after fracture healing as well as bending the wire end in a walking stick shape should minimise the risk of migration. PMID- 17715733 TI - Occult Monteggia fracture in an adult: a case report. AB - Injuries with the Monteggia fracture-dislocation pattern necessitate operative fixation of the ulna fracture in an adult. It is important to identify this by taking radiographs of the elbow and wrist joints in all cases of ulna fracture. We present a case of an occult Monteggia fracture-dislocation in an adult, which was not apparent on the initial radiographs. A thorough clinical examination along with an examination under anaesthesia in view of the high index of suspicion helped us to achieve the diagnosis. PMID- 17715735 TI - Lipoblastoma--a rare paediatric foot tumour. AB - Lipoblastoma, a rare benign tumour arising from embryonic fat, is usually found in areas of abundant adipose tissue. Various reports describe a predilection of lipoblastoma for sites with primitive adipose tissue such as axilla, neck, retroperitoneum and prevertebral soft tissue. The plantar aspect of the foot is an extremely rare site due to scarcity of fatty tissue. Differential diagnosis includes lipomas, fibromyxolipomas and liposarcomas. Age of presentation, chromosomal markers and histopathological examination help in arriving at final diagnosis. Radical surgeries are not advocated; however, complete excision is necessary to avoid recurrence. PMID- 17715734 TI - Post-traumatic bone loss of the femur treated with segmental bone allograft and bone morphogenetic protein: a case report. AB - Reconstruction of a major bone loss remains a challenge for the orthopaedic surgeon. Most of the bone defects result from a bone tumour resection whereas a post-traumatic bone loss is more rare due to the numerous options available for bone fixation. However in high-energy trauma, the injury to bone may be so extensive as to justify removal of fragmented bone. A 57-year-old man presented with a severe injury at the thigh after a hunting accident, including a comminuted fracture of the femoral shaft. After thorough debridement, he was left with a large diaphyseal bone defect which was subsequently treated with a structural bone allograft, autogenous graft and rhBMP-7. Bone healing was achieved after several months. PMID- 17715736 TI - Type 1 neurofibromatosis and adult extremity sarcoma. A report of two cases. AB - We report two cases of malignant soft-tissue tumours--one myxoid malignant fibrous histiocytoma and one pleomorphic rhabdomyosarcoma--which were diagnosed in two young adult patients with type 1 neurofibromatosis (NF 1). The patients were evaluated with criteria for Neurofibromatosis 1 and NF 1 gene analysis was performed. Four of seven criteria were found in both patients. The tumours were stage II and III respectively. Both patients were treated with radiotherapy or chemotherapy and surgical intervention. Diagnoses of myxoid malignant fibrous histiocytoma and pleomorphic rhabdomyosarcoma in adult NF 1 patients are exceedingly rare. Thus detection of subtypes of rhabdomyosarcoma and malignant fibrous histiocytoma with immunohistochemistry may be helpful for the management of these tumours among other pleomorphic sarcomas that may occur in type 1 Neurofibromatosis. PMID- 17715737 TI - The healing potential in cauda equina syndrome secondary to traumatic posterior L5-S1 dislocation. A case report with 16 years follow-up. AB - Cauda equina syndrome is the result of any lesion that compresses or paralyzes cauda equina roots which are both motor and sensory. It is an uncommon syndrome, which features low back pain, sciatica, variable lower extremity motor and sensory loss with possible bladder and bowel dysfunction. It is an emergency situation as it may cause significant morbidity such as permanent paralysis, impaired bladder and/or bowel control or loss of sexual sensation. We present the case of a patient who was admitted to the emergency department with a traumatic posterior L5-S1 dislocation, low back pain and bladder dysfunction 8 days following an initial trauma. Open L5-S1 reduction and posterior stabilization was performed and the dural sac was decompressed. Most of the patient's neurological deficits resolved over several years, following the initial surgery. PMID- 17715738 TI - Solitary eosinophilic granuloma of the radius. An unusual differential diagnosis. AB - A case of an 11-year-old patient with a lesion in the proximal metaphyseo diaphyseal region of the right radius is presented. The clinico-radiological suspicion was either infection or tumour of the proximal radius. Subsequently, a biopsy proved the lesion to be an eosinophilic granuloma of bone. Following curettage and after a follow-up of two years, there was complete resolution of the lesion with restitution of the cortex. PMID- 17715740 TI - Forum 'fiasco' sparks call for change. PMID- 17715739 TI - Paradoxical fat embolism after uncemented total hip arthroplasty: a case report. AB - The authors report a paradoxical presentation of fat embolism after uncemented total hip arthroplasty. The patient presented vertigo and diplopia after surgery. Cerebral fat embolism was diagnosed by MRI. A patent foramen ovale was responsible for the venous to arterial circulation shunt. Treatment was conservative. Spontaneous and complete recovery occurred. PMID- 17715741 TI - 'Is there no difference between looking at an image and being a paedophile'? PMID- 17715742 TI - Intensive care for vulnerable families. PMID- 17715743 TI - The struggle to nurse in Malawi. PMID- 17715744 TI - Recognising and responding to acute illness in hospital. PMID- 17715745 TI - Respiratory procedures. Part 1--use of a non-rebreathing oxygen mask. PMID- 17715746 TI - Understanding diabetic foot ulcers 2: diagnosis and care. AB - The second part of this two-part unit on diabetic foot ulcers examines the principles of diagnosis. It also looks at prevention and treatment. Part 1 outlined the pathophysiology, risk factors and signs and symptoms. PMID- 17715747 TI - An epiphany--requisite for all physicians. PMID- 17715748 TI - Christina's world. American icon and medical enigma. PMID- 17715749 TI - Doctors and disease in Jamestown colony. Looking back 400 years. PMID- 17715750 TI - Invaders from Mars, with commentary from Robbie Burns. PMID- 17715751 TI - In the wake of Katrina. An update on the Louisiana State University School of Medicine in New Orleans. PMID- 17715752 TI - Mentoring. Nurturing clinician and physician scientists in an academic career. PMID- 17715753 TI - Unintentional fraud. An oxymoron? PMID- 17715754 TI - Maimonides's primer for treating bipolar illness. PMID- 17715755 TI - The faculty dining room. PMID- 17715757 TI - Re "The tradition of the gold-headed cane". PMID- 17715756 TI - A surgeon in the Yom Kippur War. October 1973. PMID- 17715758 TI - Re: Intelligent design. PMID- 17715759 TI - Resident duty hours--second thoughts. PMID- 17715760 TI - [Walking in the sun: heat stroke and heat exhaustion during the Four-Day March in Nijmegen, in 2006]. AB - The annual Four-Day March in Nijmegen, The Netherlands, in July 2006 was cancelled after the first day because two participants had died, men aged 65 and 57 years, and many had become unwell while walking in unusually high ambient temperatures. However, the cause of death of the two who died turned out to be cardiovascular and not heat-related. The case of two of the people that became unwell, men aged 58 and 59 years, respectively, shows that heat stroke and heat exhaustion were important causative conditions. Heat-related illnesses are relatively uncommon in the Netherlands due to its temperate climate. Heat stroke is the most severe of these and associated with a high mortality rate if not recognised and treated promptly. The primary cause is accumulation of heat due either to diminished loss or increased endogenous heat production, such as by physical exertion. Heat exhaustion is caused by salt or water depletion. PMID- 17715761 TI - [Chronic low back pain: the failure of organic medicine]. AB - In this issue of the journal, a series of 67 patients is presented with persistent or recurrent chronic low back pain and leg pain after insertion of a lumbar-disc prosthesis in a private hospital in Germany. A relationship between degenerative changes in the vertebral column and chronic low back pain is often assumed but lacks a scientific basis. Psychosocial factors are much more important than biomechanical factors in determining the outcome, but the interaction between these determinants is far more complicated than just 'having problems'. Accordingly, a multidisciplinary approach is the most successful mode of treatment, while local measures aimed at the vertebral column are generally ineffective or of unproven value. Patients will continue to seek magic cures from 'quacks with a knife' as long as medical specialists are insufficiently trained to deal with unexplained somatic symptoms. PMID- 17715762 TI - [Comments on screening spirometry for detection of COPD]. AB - World COPD day is an annual event intended to increase awareness of chronic obstructive pulmonary disease. During this day, in November 2006, free spirometry testing was offered to the public in approximately 100 places including hospitals, pharmacies, offices of GPs and tents on main squares throughout the Netherlands. The objective of this action is laudable. However, screening for COPD is generally considered ineffective. Furthermore, the application of a fixed ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) (FEV1/FVC < 0.70) as recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) to detect airflow limitation, required for a diagnosis of COPD, may lead to underdiagnosis of COPD in the young and to overdiagnosis in the elderly. In addition, spirometry was generally performed without bronchodilation, thus further increasing the likelihood of a false positive diagnosis ofCOPD. Smoking cessation is important in halting the progression of COPD. Therefore, identifying smokers at risk for developing COPD seems a logical reason for screening or case finding for COPD. However, it has not been clearly demonstrated that early detection of COPD may contribute to improved smoking cessation rates. Also, smokers with normal spirometry may be led to believe that smoking has no adverse effects on their health. Therefore, a different strategy should be adopted to increase awareness of COPD on the next World COPD day. PMID- 17715763 TI - [Pregabalin in the treatment of neuropathic pain]. AB - Pregabalin is increasingly being used for the treatment ofneuropathic pain, often as the first-line choice. The question is, however, whether this choice is based on evidence. Seven trials have been published on the effect ofpregabalin in patients with postherpetic neuralgia and painful diabetic neuropathy. These trials more frequently report a 50% reduction in pain in pregabalin treated patients than in patients treated with placebo (number needed to treat 4.3). Dizziness and somnolence are the most frequent adverse events of pregabalin. The number needed to harm for adverse events leading to discontinuation of treatment varies from 3.7 to 113.1 in these studies. Pregabalin has not been compared head to-head with other drugs commonly used for neuropathic pain. Indirect comparison reveals the effectiveness of pregabalin is comparable with that of carbamazepin, tramadol, and gabapentin; pregabalin is possibly less effective than amitriptylin. However, taking into account its price and the lack of clinical experience and evidence, using pregabalin as first-line choice is not recommended. PMID- 17715764 TI - [Guideline on polyneuropathy]. AB - In the Netherlands, approximately 100,000-400,000 people suffer from polyneuropathy. Polyneuropathy has many different causes, diabetes mellitus being the most frequent one. The practice guideline 'Polyneuropathy' describes the diagnostic procedure in patients with signs or symptoms of polyneuropathy that need to be followed in order to identify the cause of the condition. After history taking and neurological examination, the diagnosis ofpolyneuropathy can be made with a high degree of accuracy. Electrophysiological investigation may be of help, especially in classifying an axonal or demyelinating form of polyneuropathy. This subclassification is important because it helps to identify possibly treatable forms ofpolyneuropathy. Most polyneuropathies follow a slowly progressive course. If the course of the polyneuropathy deviates from what is to be expected, neurological consultation and additional diagnostic tests should be performed. A diagnostic flowchart has been designed to serve as a practical guide to an effective and rapid procedure to diagnose the cause of a polyneuropathy. Amitryptiline and carbamazepine have been proven to be effective and are the drugs of first-choice, except in HIV-related polyneuropathy, in which case only lamotrigine has been proven effective. PMID- 17715765 TI - [Antibiotic prophylaxis indicated in dental procedures in patients with a joint prosthesis]. AB - Randomised controlled trials concerning antibiotic prophylaxis are lacking and reported incidence of late infections after dental procedures is probably underestimated by the high rate of antibiotic prescription in the past and the difficulty in establishing the origin of late infection. Bacteraemia after dental procedures has been proven, especially in infected areas and, given the serious morbidity of late prosthetic joint infections, antibiotic prophylaxis is advised, particularly for patients with risk factors such as rheumatoid arthritis and haemophilia. PMID- 17715766 TI - [Antibiotic prophylaxis not indicated in dental procedures in patients with a joint prosthesis]. AB - Antibiotic prophylaxis is suggested for high-risk patients undergoing dental procedures to prevent haematogenous infection of the artificial joint. However, randomised placebo-controlled trials are lacking. Case reports are difficult to interpret, because bacteraemias are very common after chewing and tooth brushing anyway. Widespread use of antibiotics has serious downsides. Therefore, more convincing data are needed to support the use of antibiotic prophylaxis for high risk patients. PMID- 17715767 TI - [Diagnostic image (332). A young woman with amenorrhoea]. AB - A 16-year-old girl presented with amenorrhoea and a tense abdomen, due to a mature cystic teratoma with the characteristics ofa dermoid cyst. PMID- 17715768 TI - [Findings in 67 patients with recurrent or persistent symptoms after implantation of a disc prosthesis for low back pain]. AB - OBJECTIVE: To determine the symptoms in patients who presented with persistent or recurrent backache or leg pain after implantation of an artificial disc prosthesis. DESIGN: Descriptive. METHOD: During the past II years in the Maastricht University Hospital (n=65) and the Utrecht University Medical Centre (n=2), 67 patients were seen with persistent or recurrent backache or leg pain in whom, an average of 53 months previously, one or more SB Charite-III lumbar-disc prostheses had been implanted elsewhere. The results were evaluated. RESULTS: The most prominent findings were: migration of the prosthesis (n=6); subsidence into the vertebra (n=35); disc degeneration at one or more neighbouring levels (n=34) and arthrosis of facet joints (n=24). In 9 cases, rupture of the metal wire around the polyethylene core was observed and in 5 cases there were radiological signs of polyethylene wear. Re-operation (spondylodesis) was generally unsatisfactory if the prosthesis was left in place. In 21 patients, the prosthesis was removed; all specimens showed polyethylene wear or rupture. CONCLUSION: Published results are mostly case series and suffer from observer bias; moreover, the benefits are moderate. Given the uncertain role ofdisc degeneration in patients with chronic backache, the real risk of complications and the uncertain advantages, the implantation ofa disc prosthesis is difficult to defend. PMID- 17715769 TI - [Persistent pulmonary hypertension in a neonate caused by blood aspiration following vaginal blood loss]. AB - A preterm neonate, with a gestational age of 30 1/7 weeks, was born after a period of prolonged rupture of the membranes and a retroplacental haematoma causing vaginal bleeding. During admission to the neonatal intensive-care unit, mechanical ventilation was indicated because of acute respiratory failure following blood aspiration, which was causing oxygenation and ventilation problems. Endotracheal surfactant was administered and, because of persistent pulmonary hypertension of the newborn (PPHN), NO-inhalation therapy was started. A quick recovery was seen and two days post partum the patient could be extubated. Blood aspiration may cause acute respiratory problems and PPHN, with quick recovery after effective mechanical ventilation, surfactant and NO inhalation therapy. PMID- 17715770 TI - [A colo-colic invagination on the basis of MutYH-associated polyposis in a boy aged 14]. AB - A 14-year-old boy presented with acute abdominal pain, vomiting and diarrhoea. Colo-colic intussusception was diagnosed by means of a colonic contrast X-ray. The intussusception was successfully reduced during this procedure. Hundreds of polyps were seen throughout the entire colon. Genetic research showed a mutation of the MutYH gene. Proctocolectomy with ileoanal pouch anastomosis was carried out. The pathology specimen showed an intramucosal carcinoma and multiple adenomas. MutYH-associated polyposis coli is an autosomal recessive disease that occurs as a result of a mutation in the MutYH gene. This will lead to polyposis coli. An intussusception is a rarely seen symptom. Patients need preventive surgical treatment because of the high risk developing a colorectal carcinoma. PMID- 17715771 TI - [The consequences of postponing pregnancy]. AB - The postponement of childbearing is determined by societal factors and is related to the fact that it is often difficult for women to combine an education, a job or a career with having children and taking care of a family. Especially gynaecologists are increasingly confronted with women who undergo the medical consequences of such postponement. Postponing the first pregnancy is accompanied by an increased risk of unwanted infertility. If women do succeed in becoming pregnant later in life, there is an increased risk of complications during pregnancy and delivery. The child runs a greater risk of chromosomal aberrations and of mental and physical handicaps related to increased numbers of premature births and fertility treatments. All these problems begin to increase after age 30, but especially after age 35. Finally, the risk of breast cancer is also increased if a woman delays the birth of her first child or remains childless. PMID- 17715773 TI - [Post-academic dental specialties 12. Post-graduate specialization in 'dealing with fear of the dentist']. AB - As a result of the recognized need for dentists with a special expertise in the field of managing and treating patients who are difficult to treat especially because they are fearful, a post-graduate programme was established, in 2001, in 'dealing with fear of dentists.' This 3-year programme of study makes it possible for dentists, both working within and outside of departments of special dental care, to develop knowledge and experience in this field. The intention behind this initiative is to contribute to the quality of care provided to patients who avoid treatment out of fear. A brief summary of the programme's target group and academic goals, as well as its organization and contents are provided. PMID- 17715772 TI - [Diagnosing and treatment of dental foci in Dutch medical centres]. AB - Although not scientifically proven, dental foci are believed to result in severe local or systemic disease. Eradicating dental foci in order to prevent possible interference with a medical treatment may be important in specific patient groups. To gain insight in the number of dental focus examinations, the medical evidence, the number of potential foci determined, as well as the treatment eradicating the focus, all dental focus examinations in 16 Dutch hospitals were registered during 3 months. A total number of 470 examinations were performed. Scheduled heart(valve)surgery and radiotherapy of the head and neck were the main reasons for a dental focus examination. Dental foci were found and treated in more than 50% of the patients examined. There was a significant difference between dentate and edentulous patients in the percentage of patients diagnosed and treated for a dental focus. More than 80% of dentate and less than 20% of edentulous patients were treated. PMID- 17715774 TI - [Post-academic dental specialties 13. What are anxious dental patients most afraid of?]. AB - What are the dental stimuli and situations that are experienced as more or less fear provoking by anxious dental patients?To investigate this question, 81 highly anxious patients, who were referred to a centre of special dental care were presented with a list of 76 potentially fear provoking objects and situations. The results showed that invasive dental procedures are considered as most terrifying by anxious patients, and that stimuli related to the dental office (dental chair), the dental team (dentist) and their equipment (protecting clothes) are considered as least fear provoking. Root canal treatments were rated as most fear provoking. The results emphasize the importance of assessing the whole range of potentially terrifying stimuli for each anxious patient. Only in this way an approach focused on the extinction of patients' dental fear can be successful. PMID- 17715775 TI - [Arteriovenous malformation in the mandibula]. AB - A 15-year-old autistic boy of subnormal intelligence appeared at the office of his dental practitioner complaining about pain in the third quadrant. Investigation revealed that the second molar could be intruded easily. No other irregularities, such as caries or periodontal disease were apparent. Due to the severe pain it was decided that the tooth should be extracted. Extraction of the tooth induced massive bleeding. Hemostasis was achieved by repositioning the molar in its alveolus, according to the principle of putting a cork in a bottle. Radiographic investigation showed the presence of an intraosseous arteriovenous malformation. These malformations are potentially life-threatening lesions. Treatment of choice is a combination of transarterial embolization and surgical removal of the malformation. PMID- 17715777 TI - 40 per cent of nurses harassed or assaulted while working alone. PMID- 17715776 TI - [Multiple mandibular radiolucencies in an asymptomatic girl]. AB - Routine dental radiographic examination in a 16-year-old girl revealed the presence of 3 well-defined radiolucent cystlike structures in the mandible. After clinical and radiological examination, a multiple traumatic bone cyst was diagnosed. Surgical exploration confirmed the diagnosis. Curettage of the lesions was performed. Fifteen months later, a panoramic radiograph showed almost complete ossification. PMID- 17715778 TI - Eviction of elderly is 'lawful' despite the Human Rights Act. PMID- 17715779 TI - When care breaks down. AB - Four years ago, Amanda Steane's husband committed suicide. She maintains he would still be alive today if he had been given enough water to drink in hospital. PMID- 17715780 TI - 'Our patients feel safe'. AB - A commitment to excellent patient care and staff development has resulted in high retention rates in one haematology unit. PMID- 17715781 TI - Malawi and me. AB - RCN Scotland has forged links with nurses in Malawi. The partnership is growing and benefiting both countries. PMID- 17715782 TI - Think of the children. PMID- 17715783 TI - Like a rat in a trap. PMID- 17715784 TI - Running a nurse-led Chlamydia testing service. AB - Healthy Respect is a Scottish Executive funded National Health Demonstration Project, which addresses young people's sexual health. One of the 19 projects in phase 1 (2001 to 2004) was to introduce Chlamydia trachomatis testing in non medical settings. This involved the development, implementation and evaluation of an initiative in a sexual health service which aimed to encourage young people under the age of 25 years in Lothian to be tested for Chlamydia. This article discusses why it is important to test for Chlamydia and details an initiative that was set up to provide this service. PMID- 17715785 TI - Neurovascular assessment. AB - The ability to carry out a neurovascular assessment on a patient's limb is an important skill for all registered nurses. All nurses, whether working in primary or acute care environments, are exposed to patients who have sustained injury or trauma to a limb or have a cast or restrictive bandages in place. The ability to detect a compromised limb through careful observation enables prompt referral and subsequent treatment, which may otherwise result in a permanent deficit. This article discusses the importance of undertaking neurovascular observations providing a step-by-step guide for the reader. PMID- 17715786 TI - Promoting patient dignity in healthcare settings. AB - Dignity is important to every individual, irrespective of the situation in which they find themselves, including healthcare settings. This article aims to heighten awareness of patient dignity, encourage readers to reflect on the concept and apply it to practice. Self-awareness of knowledge, skills and attitude is a prerequisite for supporting patient dignity. Using personal and professional knowledge, readers will reflect on practice to identify factors that influence the maintenance of patient dignity and develop strategies to promote and support it in clinical practice. PMID- 17715787 TI - Urinary tract infection. PMID- 17715788 TI - Development of a tool to examine the effect of venous ulcers on patients' quality of life. AB - AIM: Nurses should be able to demonstrate the effectiveness of their practice. One method of measuring the effectiveness of nursing is to determine how nurses improve a patient's quality of life. The aim of this study is to develop a quality of life questionnaire that can be used to measure quality of life and outcome in patients with venous leg ulcers. METHODS: The project consists of three stages. The first used semi-structured interviews and focus groups to talk to patients and clinical staff about how venous ulcers affect patients. The second stage uses the data from the interviews and focus groups to design the questionnaire. The third stage involves validating the questionnaire. RESULTS: The project started in October 2005 and is due to finish in October 2008. The first stage of the project has been completed and used qualitative techniques to identify items to be included in the questionnaire. The questionnaire is now being developed. CONCLUSION: This project will result in the production of a quality of life questionnaire that can be used to measure quality of life and outcome in patients with venous leg ulcers. PMID- 17715789 TI - Evidence for skeletal pin site care. AB - This article explores the management of skeletal pin sites focusing on the research that underpins current practice. The effectiveness of pin site care depends on assessment and delivery of appropriate care. Because pin site management varies greatly between clinical areas, it is important that clinicians are aware of the evidence base on which their current practice is founded. PMID- 17715790 TI - What makes a good nurse? PMID- 17715791 TI - Power of effective communication. PMID- 17715792 TI - History of memory. PMID- 17715793 TI - Georg Elias Muller (1850-1934): a founder of experimental memory research in psychology. PMID- 17715794 TI - A review of cognitive impairments in dementia with Lewy bodies relative to Alzheimer's disease and Parkinson's disease with dementia. AB - Dementia with Lewy bodies (DLB) has recently been identified as a separate disease but diagnosis can be difficult, in particular the differentiation from related dementias of Alzheimer's disease (AD) and Parkinson's disease with dementia (PDD). Careful cognitive assessment may aid differential diagnosis between these different types of dementia and can provide theoretical insight into the nature of the underlying impairments. Recent reviews on DLB have primarily dealt with medical issues of clinical diagnostic criteria, pathology, epidemiology and treatment (Ballard, 2004; Barber et al., 2001; Cercy and Bylsma, 1997; Cummings, 2004; Kaufer, 2004; McKeith, 2002; McKeith et al., 2004a; Rampello et al., 2004) and only a few papers have reviewed cognitive impairments in DLB (Collerton et al., 2003; Lambon-Ralph et al., 2001; Simard et al., 2000). The present paper is more specifically targeted to a neuropsychological audience. It provides an up-to-date, detailed and comprehensive review of the available evidence regarding visual and olfactory perception, attention, cognitive fluctuation, frontal-executive functions, working memory, episodic memory, and semantic memory in DLB relative to AD and PDD. In addition, an attempt is made to relate available data to current theoretical frameworks of cognition. Implications for future research and clinical issues such as the problem of differential diagnosis, and the relation between cognitive impairments and clinical features of visual hallucinations and cognitive fluctuation will be discussed. PMID- 17715795 TI - Is the paced auditory serial addition test (PASAT) a valid means of assessing executive function in Parkinson's disease? AB - Parkinson's disease (PD) is usually associated with a dysexecutive syndrome. However, many executive function tasks require visuo-spatial abilities which themselves are known to be impaired in PD. The use of a non-visual procedure may thus represent a means of avoiding this type of methodological difficulty. The aim of the present study was to determine whether the paced auditory serial addition test (PASAT) might constitute a useful procedure for assessing executive functions in PD. Twenty-seven non-demented PD patients early in the course of the disease participated in the study, together with 15 healthy control (HC) subjects. All participants performed the PASAT and a set of clinical tasks assessing information processing speed, working memory and executive functions. Compared with HCs, the PD patients were significantly impaired in their performance of the PASAT. Significant impairment (compared with controls) was also evidenced by only one of the clinical tasks - the symbol coding task, which assesses information processing speed. Our results demonstrate the high sensitivity of the PASAT to cognitive impairment. However, correlation analyses showed that the main factor explaining the PD patients' PASAT impairment was cognitive slowing. PMID- 17715796 TI - A temporal lobe factor in verb fluency. AB - Verb fluency requires self-sustained verb retrieval. The brain correlates of this task are virtually unknown. We investigated the relations between verb and noun (semantic) fluency and regional brain perfusion in subjects with varying degrees of cognitive decline, ranging from very mild subjective impairment to Alzheimer's disease (AD). Data consisted of single-photon emission computed tomography (SPECT) data and temporally resolved verb and noun fluency scores from 93 participants. Impaired verb fluency was predicted by a temporal lobe hypoperfusion factor and low education, whereas high age and low perfusion in the parietotemporal-occipital region predicted impaired noun fluency. Analysis of perfusion within the temporal region indicated primary involvement of the temporal pole and medial temporal lobe in AD. This might reflect pathology of the anterior parahippocampal region, which appears early in neurodegenerative disease. Although temporal lobe structures have not usually been implicated in verb processing, early temporal pathology thus appears to contribute to impaired verb fluency in cognitive decline. PMID- 17715797 TI - Forgetting due to retroactive interference: a fusion of Muller and Pilzecker's (1900) early insights into everyday forgetting and recent research on anterograde amnesia. AB - Ebbinghaus' seminal work suggested that forgetting occurred as a function of time. However, it raised a number of fundamental theoretical issues that still have not been resolved in the literature. Muller and Pilzecker (1900) addressed some of these issues in a remarkable manner but their observations have been mostly ignored in recent years. Muller and Pilzecker (1900) showed that the materials and the task that intervene between presentation and recall may interfere with the to-be-remembered items, and they named this phenomenon "retroactive interference" (RI). They further asked whether there is a type of RI that is based only on distraction, and not on the similarity between the memoranda and the interfering stimuli. Their findings, and our follow up research in healthy volunteers and amnesiacs, confirm that forgetting can be induced by any subsequent mentally effortful interpolated task, irrespective of its content; the interpolated "interfering" material does not have to be similar to the to-be remembered stimuli. PMID- 17715798 TI - Measures of short-term memory: a historical review. AB - Following Ebbinghaus (1885/1964), a number of procedures have been devised to measure short-term memory using immediate serial recall: digit span, Knox's (1913) cube imitation test and Corsi's (1972) blocks task. Understanding the cognitive processes involved in these tasks was obstructed initially by the lack of a coherent concept of short-term memory and later by the mistaken assumption that short-term and long-term memory reflected distinct processes as well as different kinds of experimental task. Despite its apparent conceptual simplicity, a variety of cognitive mechanisms are responsible for short-term memory, and contemporary theories of working memory have helped to clarify these. Contrary to the earliest writings on the subject, measures of short-term memory do not provide a simple measure of mental capacity, but they do provide a way of understanding some of the key mechanisms underlying human cognition. PMID- 17715799 TI - Memory, imagination and language in eighteenth-century French sensualism. AB - Most eighteenth-century philosophers tended to attach memory to imagination, thinking that memory basically consists in the reproduction of previously received sensations, which have perhaps only lost some of their vividness. In his Essai sur l'origine des connoissances humaines (1746) Condillac, however, insists on separating memory and imagination. This is surprising in so far as one would expect him, as a sensualist, to reduce memory to the faculty of reproducing sensations in the manner of Locke and other empiricists. But in fact, Condillac emphasizes that one can well remember perceptions without being able to reproduce them. He claims that the capacity to remember requires the ability to use conventional signs, that is, language. Instead of picturing memory as the reproduction of sensations or of ideas, he sees it consisting in the capacity to form connections between ideas, insisting at the same time on their organization as well as on the role of this organization in voluntary search and recall. Attaching the capacity to direct attention to the use of conventional signs, Condillac contrasts the voluntary nature of memory processes with the passivity of imagination. Condillac's view of memory as an active and complex process of conceptual organization involving language appears in many respect advanced in comparison to the simplifications of many of his contemporaries and, in fact, also compared to many of his followers, who continued the tradition which sees memory merely in terms of passive recording and reproduction of sensations or of images. PMID- 17715800 TI - Bilingualism and memory: early 19th century ideas about the significance of polyglot aphasia. AB - In the second half of the 19th century, there was very little attention given to bilingual speakers within the growing clinical literature on aphasia. The first major publication on this topic (Pitres, 1895), appeared three decades after Broca's seminal work. Previously, Ribot (1881) had discussed the phenomenon of bilingual aphasia in the context of diseases of memory. Although interest in the neurological basis of the language faculty was in fact present throughout the century, the theoretical implications of the knowledge of more than one language did not appear to be linked to this issue. A number of British authors writing in the first half of the 19th century have been identified who did consider the significance of these cases. Importantly, these writers speculated on the implication of bilingual aphasia specifically with regard to ideas about memory rather than language. Consideration of these writings helps to illuminate the history of ideas about the organization of language in the brain. PMID- 17715801 TI - Post Katrina: the story of the LSUHSC School of Nursing. PMID- 17715802 TI - Implementing a new faculty workload formula. AB - The severe shortage of nursing faculty in recent years has led to changes in faculty mix, with nursing programs relying on increased numbers of faculty members prepared at the master's level for coverage of nursing courses. To address the impact of these changes on faculty workload, one nursing program established a Workload Task Force to develop a workload formula that would recognize teaching, scholarship, and service contributions of all faculty members and help ensure equity in workload assignments. Details of the workload formula are offered, along with recommendations for gaining the support of faculty and ensuring transparency in implementation. PMID- 17715803 TI - Learning Skills Profiles of master's students in nursing administration: assessing the impact of problem-based learning. AB - Attempts to compare graduate student performances before and after introducing new curricula are rare; yet faculties need outcome measures to justify program costs and demonstrate effectiveness. Boyatzis and Kolb's Learning Skills Profile is used to assess the outcomes of a problem-based learning MSN program. Increases were demonstrated among all 12 learning skills; statistically significant increases were found in eight of the personal learning skills and six of the job skill demands. Comparisons are made between scores of students in the MSN program and scores of master's students in business administration. PMID- 17715804 TI - Ethics education in advanced practice nursing: respect for human dignity. AB - Ethics education is an essential component of academic programs that prepare nurses for advanced practice; the concept of respect for human dignity is integral to this education. Sixty-three graduate students enrolled in their first course of a nurse practitioner program completed a researcher-developed Ethics Questionnaire that was designed to elicit their baseline ethics-related knowledge, including their understanding of the concept "respect for human dignity". Qualitative analysis of data yielded findings that validate the importance of using the American Nurses Association Code of Ethics for Nurses with Interpretive Statements as an essential foundation for ethics content and as a framework for understanding the meaning of human dignity in advanced practice nursing. Assessment and learning strategies are recommended. PMID- 17715805 TI - Engaging students through collaboration: how Project FUN works. AB - Students from three disciplines designed, developed, and implemented exercise and nutrition interventions, online modules and videos, to benefit low-income middle school students. The process used to incorporate the scholarship of teaching ito a collaborative college-level application of learning is described. PMID- 17715806 TI - Revitalizing the humanistic imperative in nursing education. AB - This article describes a teaching strategy that focuses students' attention on the humanistic imperative in nursing practice. The Humanistic Teaching Method provides a framework for adapting nursing courses to accommodate person-to person, human-centered nursing care alongside scientific and technological competencies. Through this approach, students integrate concepts such as humanism, existentialism, and phenomenology into patient interactions. In addition to producing a favorable effect on patients and colleagues, this approach contributes to personal gratification in making a difference in the lives of others. Pedagogical strategies currently in use may need to be modified to accommodate the humanistic conceptual framework. PMID- 17715807 TI - Nursing education 2.0: Poke me. Where's your face in space? PMID- 17715808 TI - Compensation for nurse educators: findings from the NLN/Carnegie National Survey with implications for recruitment and retention. PMID- 17715809 TI - [Questions and answers about MRSA in farm animals]. PMID- 17715810 TI - [Prevalence of allergies in the dog in the animal clinic]. PMID- 17715811 TI - [Part 4. viruses, bacteria and fungi]. PMID- 17715812 TI - [Not much wiser from the East]. PMID- 17715813 TI - [Footvax causes problems--part 2]. PMID- 17715814 TI - ["Actions should be based on evidence"]. PMID- 17715816 TI - [Satisfaction.nl also for you! First experiences with new client satisfaction research]. PMID- 17715815 TI - [Practice management: taking the lead and giving the lead. The person as a critical success factor]. PMID- 17715818 TI - Food-borne zoonotic infections: environmental-vehicle-human interface. PMID- 17715819 TI - Application of Campylobacter molecular classification and typing techniques in veterinary medicine: old-established methods and new perspectives. AB - In this review the application and usefulness of Campylobacter genotypical classification and typing in veterinary medicine will be discussed.While there is a large area of overlapping applications between the veterinary and the medical field, several differences exist, as the spectrum of veterinary pathogens is different from the human and contaminated food of healthy animal origin may cause disease in man. In general, genotyping in the veterinary field can be applied in three different areas: (a) purely diagnostic purposes for classification of Campylobacter species and subspecies, (b) typing methods useful for monitoring or surveillance of animals as well as food products of animal origin, and (c) typing methods that can be applied during outbreaks and for source tracing. In addition, typing methods applied in areas (b) and (c) should be distinguished in regard to local short-term and global long-term epidemiology, respectively. While a whole plethora of discriminative typing methods are available, classification tools of certain species and subspecies are still missing. Perspectively, as the genomes of many relevant Campylobacter species have now been sequenced, this will help to identify several species specific loci, the products of which should be available to develop easy and fast applicable diagnostic tools. Global cooperation, sharing of strains and databases should close the currently existing gaps in Campylobacter identification tools. PMID- 17715820 TI - Enterohaemorrhagic Escherichia coli O26:H11/H-: a human pathogen in emergence. AB - Enterohaemorrhagic Escherichia coli (EHEC) O26:H11 have emerged as the most important non-O157:H7 EHEC, with respect to their ability to cause diarrhoea and the haemolytic uraemic syndrome (HUS). HUS is a leading cause of acute renal failure in children, and is mainly caused by EHEC expressing Shiga toxins (Stx) 1 and/or 2. Since 1996, EHEC O26, which produce Stx2 only and appear to have enhanced virulence, have been increasingly isolated from HUS patients in Germany. In contrast, EHEC O26 found in cattle predominantly produce Stx1 as the sole Stx. Additional potential virulence factors of EHEC O26 include cytolysins (EHEC hemolysin), serine proteases (EspP), lymphotoxins (Efal) and adhesins (intimin). The genes encoding the virulence factors are located within pathogenicity islands (eae, efa1), bacteriophages (stx) or plasmids (EHEC-hlyA, espP). In addition, EHEC O26 possess, in contrast to other EHEC, the "high pathogenicity island" (HPI), which is also present in pathogenic Yersiniae. This island contains genes involved in the biosynthesis, regulation and transport of the siderophore yersiniabactin. Comparative genomic analyses between EHEC O26 and non-pathogenic E. coli, as well as investigations of mechanisms involved in the transfer of virulence genes, provide a deeper insight into the evolution of EHEC O26. These studies demonstrate how horizontal transfer of virulence genes, even from distantly related organisms, can lead in brief intervals to the rise of a highly virulent clone within a particular E. coli serotype.The classical bacteriological methods are no longer sufficient to determine the risk posed by EHEC O26. However, knowledge of the complete virulence profiles of these pathogens and understanding their stepwise evolution form a foundation for developing new strategies to prevent human infections and new methods for their laboratory diagnosis. PMID- 17715821 TI - Shiga toxin-producing Escherichia coli and their bacteriophages as a model for the analysis of virulence and stress response of a food-borne pathogen. AB - Enterohemorrhagic Escherichia coli (EHEC) are a subgroup of Shiga toxin-producing Escherichia coli (STEC) that are able to cause serious food-borne intestinal diseases which can be followed in 5 to 15% by extraintestinal sequelae such as the hemolytic-uremic syndrome (HUS). One of the major pathogenicity factors of EHEC is the production of one or more Shiga toxins (Stx), which act as inhibitors of protein biosynthesis and have profound effects on the signal transduction and immunological response in eukaryotic cells. The stx genes are located in the genome of heterogeneous, lambdoid, functional or cryptic bacteriophages and are expressed during the phage life cycle. Due to the linkage between the phage life cycle and stx expression, STEC and their bacteriophages are useful as a model for the analysis of stress response and virulence of this food-borne pathogen. PMID- 17715822 TI - Longitudinal prevalence study of diarrheagenic Escherichia coli in dairy calves. AB - A longitudinal study (cohort study) elaborating 1,224 rectal swabs from 221 calves aging between 1 and 12 weeks was conducted on 11 dairy farms (i) to ascertain associations between diarrhea and shedding of diarrheagenic E. coli and (ii) to facilitate the zoonotic potential assessment of E. coli strains shed by young calves. Calves were screened weekly by PCR of swab cultures for shedding of enterotoxigenic E coli [ETEC; by detection of heat stable (est) and heat labile enterotoxin genes (elt)], diffusely adhering E. coli [DAEC; diffuse adhesion (daa)], typical enteropathogenic E. coli [EPEC; bundle-forming pili (bfpA) and intimin (eae)] as well as enterohemorrhagic E. coli [EHEC, intimin (eae) and Shiga toxin (stx)]. In addition, EHEC-hemolysin- (Hly(EHEC)) and alpha-hemolysin- (alpha-Hly) producing E. coli were detected by inoculation of blood agar plates. Within the 221 calves, prevalences were 69.7% (25.2% of the 1,224 samples) for Hly(EHEC)-producing E. coli, 55.3% (19.3%) for eae, and 18.2% (4.5%) for stx. E. coli strains exhibiting an alpha-Hly phenotype were detected in 66.5% of the calves and 21.9% of fecal samples. The est gene was detectable in 31.7% of the calves from only 9 of 11 herds and in 7.8% of the samples. Calves shedding DAEC or typical EPEC were not identified. The detection frequency of virulence traits significantly depended on the calves' age and shedding dynamics differed between the traits. A significant correlation between calf diarrhea and shedding of EHEC virulence traits was determined for several postnatal periods (1 week: Hly(EHEC); 1st & 10th week: eae; 4th week stx). Shedding of ETEC (est) was associated with diarrhea in newborn calves (1st week) only. Hly(EHEC)- and alpha-Hly-producing E. coli were shed significantly more frequently by diarrheic calves in 1st and 8th week of life, respectively. The knowledge gained in this study highlights the high prevalence of zoonotic E. coli already in calves. The age-dependent shedding dynamic of the various E. coli pathovars has to be considered regarding prophylaxis as well as planning intervention studies, both for calves and humans. PMID- 17715823 TI - Virulence and fitness gene patterns of Shiga toxin-encoding Escherichia coli isolated from pigs with edema disease or diarrhea in Germany. AB - Fecal Escherichia coli isolates (n = 3,218) from piglets with edema disease or diarrhea were screened for the genes of Stx2 and Stx2 variants. A total of 283 E. coli isolates (8.8%) proved exclusively positive for Stx2e and most of these (85.1%) harbored genes for F18 fimbria. No recognized adhesins were detectable in 14.5% of the isolates. Genes for heat-stable or heat-labile E. coli enterotoxins were found in F18+ as well as F18 isolates (51.9% and 33.3%, respectively). Five isolates also harbored fyuA and irp2 genes which are indicative of a high pathogenicity island in E. coli. All Stx2e+ isolates lacked genes for intimin, EHEC hemolysin, STEC autoagglutinating adhesin, subtilase cytotoxin, serine protease Espl. The majority of Stx2e+ isolates belonged to phylogenetic groups A (59.3%) and D (38.9%) and only few isolates were classified as B1 and B2 (1.8%). The results suggest that Stx2e-producing E. coli strains are highly prevalent in diseased pigs in Germany. Despite their significant diversity, most strains possess all typical features (Stx2e, F18) of porcine edema disease E. coli. However, a considerable portion of porcine strains resembles published human Stx2e+ strains in that they lack any recognized pig-associated adhesin. Thus, a zoonotic potential cannot be excluded for these strains. PMID- 17715824 TI - Salmonella pathogenicity islands in host specificity, host pathogen-interactions and antibiotics resistance of Salmonella enterica. AB - Salmonella enterica is a pathogen highly successful in causing a variety of gastrointestinal and systemic diseases in animals and humans. While some serovars of S. enterica are able to infect a broad range of host organisms, other serovars are highly restricted to specific host species. The colonization of hosts by S. enterica depends on the function of a large number of virulence determinants. The molecular analyses of virulence genes demonstrated that most of these loci are clustered within Salmonella Pathogenicity Islands (SPI). SPI1 and SPI2 each encode type III secretion systems (T355) that confer main virulence traits of S. enterica, i.e. invasion, enteropathogenesis and intracellular survival and proliferation. Further SPI encode factors that contribute to intracellular survival, different types of adhesins, or effector proteins of the SPI1-T3SS or SPI2-T3SS. The availability of genome sequences of several serovars of S. enterica also revealed serovar-specific SPI. In this review, the main characteristics of the currently known SPI are summarized with focus on their roles in various animal hosts and putative functions in human infections. PMID- 17715825 TI - Salmonella in poultry flocks and humans--S. enterica subspecies enterica serovar Enteritidis in the past. AB - After importing of breeder lines for laying flocks from Canada into the former GDR in 1966 the egg industry in this country was completely isolated from that in Western Germany or other Western European countries until opening the border in Germany in 1989. Because of this isolation from other countries, an analysis of the clonal diversity of Salmonella (S.) Enteritidis isolates originated from humans, chickens and food in the former GDR during the 1980s would provide a unique opportunity to obtain new insight into factors that may have triggered the S. Enteritidis epidemic. While isolates had previously been typed by the phage typing scheme of Lalko and Laszlo we applied for the first time the extended phage typing scheme by Ward for the retrospective analysis of the S. Enteritidis strains. Furthermore, isolates of phage type (PT) 4/6 (Ward / Lalko and Laszlo) from different livestocks were investigated by ribotyping. Although in total the PT4/6 dominated between 1986 and 1989 in poultry, other phage types have prevailed in the early 1980s and represented a considerable fraction of isolates until 1989. For instance, PT8/7 was isolated from one large layer farm (district Halle) from 1988 until 1989. During that time in another farm (district Cottbus) only PT8/7 was detected too. PT4/6 was isolated from neither of these two laying hen farms. The strains of PT4/6 could be distinguished by ribotyping in 19 different subtypes. The strains from the northern farms were distinct from those isolated in the southern regions. As farms which were harbouring either PT4/6 or PT8/7 had obtained laying hens from the same sources (breeder lines in Deersheim and Spreenhagen) it is highly probable that S. Enteritidis infection was acquired from the environment at each individual farm. This conclusion is also supported by the presence of different PT4/6 ribotypes in different farms. The presence of different phage types or PT4/6 ribotypes at different farms of laying hens suggests that in each case the S. Enteritidis strains present in the environment were able to enter chicken flocks. PMID- 17715826 TI - [Ring-trial results for the cultural detection of Salmonella in poultry faeces]. AB - The Directive 2003/99/EG of the European Parliament and of the Council on the monitoring of zoonoses and zoonotic agents demands a quality management (QM) system for the execution of its monitoring programmes. Consequently the National Salmonella Reference Laboratory of Germany performed two ring-trials in 2005 and 2006 on the microbiological detection of Salmonella from poultry feces among all participating laboratories in the Federal States. Salmonella detection was performed according to the EN ISO 6579:2002 standard method which was modified according to the recommendations of the Community Reference Laboratory for Salmonella in Bilthoven, The Netherlands. This method uses modified-semisolid Rappaport-Vassiliadis Agar as the only selective enrichment. In 2005 twenty-four and in 2006 twenty-two laboratories participated. They received eight identical samples of the contamination levels L0 (no Salmonella), L1 (11 and 16 cfu per 10 g faeces respectively) and L2 (292 and 418 cfu per 10 g faeces respectively). For both years the data of 20 laboratories could statistically be evaluated. The relative accuracy of the respected results increased from 88.8% in 2005 to 98% in 2006. This is as well reflected in the improved COR- and Kappa-Indices. Taken all together the data show, that the modified-semisolid Rappaport-Vassiliadis protocol is a sensitive, established method for the detection of Salmonella from poultry faeces. PMID- 17715827 TI - Pork and pork products as a source for human salmonellosis in Germany. AB - Pork and pork products are increasingly recognized as an important source of human salmonellosis. In the present study, we describe the characteristics of recent German salmonellosis outbreaks related to pork, and discuss legal efforts for Salmonella control. From 2001 to 2005,five large salmonellosis outbreaks were reported in Germany for which pork was the probable vehicle of infection. Evidence came from epidemiologic studies, microbiologic testing, and trace back investigations. All outbreaks showed disperse spatial distribution, affecting multiple federal states. A full trace back of implicated food items was not possible in three of these outbreaks. In two outbreaks, international trade in pigs appears to have played a role. To prevent further human disease from contaminated pork and pork products, an integrated programme for the reduction of Salmonella on all steps of the production chain is warranted. In addition, close collaboration between epidemiologists and microbiologists from both the human and the veterinary side should be further strengthened. PMID- 17715828 TI - The porcine immune system--differences compared to man and mouse and possible consequences for infections by Salmonella serovars. AB - The porcine immune system differs in many aspects from that of humans and mice. Morphological differences in the lymphatic system (e.g. lymph nodes, Peyer's patches), and phenotypic differences in immune cells have been observed as well as functional differences in immune cell populations. Indeed, even the prenatal development of the embryonic piglet proceeds in a principally different way. However, it remains unclear to what extent these differences might contribute to the predisposition to and outcomes of bacterial infections, in particular those with zoonotic potential. In the following article we will review some of the peculiarities of the porcine immune system and consider possible implications for the course of infections in swine, with an emphasis on Salmonella serovars. PMID- 17715829 TI - Thailand diabetes registry project: type of diabetes, glycemic control and prevalence of microvascular complications in children and adolescents with diabetes. AB - OBJECTIVE: To determine the etiology, glycemic control and prevalence of microvascular complications in Thai diabetic patients who were diagnosed at the age of less than 18 years and who attended diabetes clinics in university or tertiary care hospitals. MATERIAL AND METHOD: A cross-sectional, multi-center, hospital-based diabetes registry was carried out from diabetes clinics of 11 tertiary centers. Demographic data including laboratory results and microvascular complications were recorded. RESULTS: Two-hundred-and-fifty out of the 9419 (2.66%) diabetic patients were diagnosed before the age of 18 years, 78% had Type 1 diabetes (T1DM), 18.4% had Type2 diabetes (T2DM) and 3.6% had other types of diabetes. Mean +/- SD HbAlc of T1DM was 9.3 +/- 2.5, T2DM was 9.7 +/- 2.6 and other types of diabetes were 8.6 +/- 4%. The majority of patients had poor glycemic control according to ADA and WHO guidelines. The percentage of patients who had diabetes for more than 5 years but had not been screened for nephropathy and retinopathy were 57.7% and 16% in T1DM and were 46.4% and 14.2% in T2DM respectively. A significant correlation between microvacular complications (nephropathy and retinopathy) and duration of disease was found in T1DM (p < 0.001). CONCLUSION: The majority of Thai children and adolescents with diabetes had TIDM and unsatisfactory glycemic control. Screening for microvascular complications was under international standard. The national strategic plan for management of this disease especially in this age group should be urgently implemented. PMID- 17715830 TI - Thailand diabetes registry project: prevalence of diabetic retinopathy and associated factors in type 1 diabetes mellitus. AB - OBJECTIVE: To determine the prevalence and factors associated with Diabetic Retinopathy (DR) of type 1 diabetes mellitus in Thailand. MATERIAL AND METHOD: A cross-sectional, multicenter hospital-based study was carried out from April to December 2003. Diabetic patients in diabetic clinics of 11 tertiary centers were registered. Retinopathy was evaluated by the ophthalmologists. RESULTS: Seven thousand one hundred and ni neteen diabetic patients received retinal examination. The number of patients with type 1 diabetes was 347. The prevalence of DR in type 1 diabetes was 21.6% (75). This consisted of Non-Proliferative DR (NPDR) 10.9% (38) and Proliferative DR (PDR) 10.7%. Patients with DR were significantly older, predominantly female, longer duration ofdiabetes, had higher BMI, systolic Blood Pressure (BP), diastolic BP serum creatinine, and TriGlycerides (TG) levels than those without DR. Both groups ofpatients were not different in term ofplasma glucose and glycosylated hemoglobin levels. Although the patients with DR had a higher percentage of overt proteinuria than those without DR, there was no difference in percentage of patients with positive microalbuminuria in both groups. This may be explained by limitation of data (only 16% had results of microalbuminuria and 19% had results of proteinuria). After adjusted for duration of diabetes, serum creatinine and smoking status, factors (adjusted odds ratio [95% confidence interval]) associated with DR were duration of diabetes 5-9.9 years (4.0 [1.49-10.91]), 10-14.9 years (6.86 [2.45 19.20]), 15-19.9 years (21.13 [7.22-61.78]), > or =20 years (22.15 [7.32-66.99]) when compared with duration of diabetes less than 5 years, serum creatinine >2 mg/dl (6.0 [2.09-17.22]) when compared with creatinine less than 2 mg/dl. From the presented model, age, gender, systolic BP >140 mmHg, diastolic BP >90 mmHg, serum TG and smoking status were not factors associated with DR. CONCLUSION: Diabetic retinopathy affects about one fifth of type 1 diabetic patients in our study. The authors found the factors associated with DR in type 1 DM were duration of diabetes and serum creatinine. Regular screening for DR and more aggressive management of metabolic factors should be done to reduce the prevalence ofDR. PMID- 17715831 TI - Thailand diabetes registry project: prevalence of diabetic retinopathy and associated factors in type 2 diabetes mellitus. AB - OBJECTIVE: To determine the prevalence of and factors associated with Diabetic Retinopathy (DR) in type 2 diabetes in Thailand. MATERIAL AND METHOD: A cross sectional, multicenter; hospital-based study was carried out between April and December 2003. Diabetic patients in diabetic clinics of 11 tertiary centers in Thailand were registered. Retinal examination of the participants was performed by ophthalmologists. RESULTS: 7119 of 9419 (75.6%) diabetic patients received retinal examination using direct ophthalmoscopy after full dilatation of pupils. 6707 cases were type 2 diabetic patients. The prevalence of DR was 31.4% (N=2105) which consisted of Non-Proliferative DR (NPDR) 22% (N=1475), Proliferative DR (PDR) 9.4% (N= 630). Patients with DR were significantly older; had longer duration ofdiabetes, and higher Fasting Plasma Glucose (FPG), HbA1c, serum LDL, serum Tri Glyceride (TG) and systolic Blood Pressure (BP) levels than those without DR. Nephropathy (which consisted of positive microalbuminuria, proteinuria or renal insufficiency). Thepatients with DR presented in a significantly higher number of than those without DR. A. The factors associated with DR (adjusted Odds Ratio (OR) [95% CI]) were (1) duration of diabetes 1.4 [1.04-1.82]for duration of 5-9.9 years, 1.9 [1.47-2.58] for duration of 10-14.9 years, 2.9 [2.11-3.95] for duration of 15-19.9 years, 3.5 [2.58-4.79]for duration of > or =20 years when compared with duration of diabetes of less than 5 years, (2) latest HbA1c > 7% (1.5 [1.24-1.88]) when compared with HbAlc < or = 7%, (3) systolic BP > 140 mmHg (1.4 [1.18-1.71]) when compared with systolic BP < or =140 mmHg, (4) nephropathy status i.e. positive microalbuminuria (1.5 [1.21-1.93]), positive proteinuria (1.9 [1.45-2.35]) and renal insufficiency (3.3 [2.29-4.70]) when compared with no nephropathy. CONCLUSION: Diabetic retinopathy was present in about one third of type 2 diabetic patients in Thailand. The authors found the factors associated with DR were duration of diabetes, latest HbA1c level, systolic BP and diabetic nephropathy. Regular screening for DR and more aggressive management of associated factors should be done to reduce the prevalence ofDR. PMID- 17715833 TI - Thailand diabetes registry project: prevalence and risk factors associated with lower extremity amputation in Thai diabetics. AB - OBJECTIVE: To determine the prevalence and risk factors associated with lower extremity amputation (LEA) in Thai diabetics. MATERIAL AND METHOD: A cross sectional, multicenter hospital-based diabetes registry was carried out from April to December 2003. Baseline characteristics and risk factors were analysed from 9419 diabetic patients. peripheral vascular disease (PVD) was defined as absent or diminished dorsalis pedis (DP) and posterior tibialis (PT) pulses to palpation in the same limb. LEA was defined as surgical removal of part of a lower extremity. RESULTS: The prevalence of LEA was 1.5% (142). Mean diabetes duration was 10 years (SD = 7.6). Out of 556 patients with a history of foot ulcer 123 (22.1%) underwent amputation. PVD was present in 370 patients. Most ofLEAs were toe amputations (64.1%). Multiple logistic regression analysis of risk factors (adjusted OR, [95% confidence interval], p value) revealed a high risk of LEA in patients with a history of ulcer (59.2, [32.8-106.8], p < 0.001), peripheral vascular disease (5.3, [3.1-9.2], p < 0.001), diabetic retinopathy (2.2, [1.3-3.8], p = 0.004), and insulin injection (1.9, [1.1-3.2], p < 0.023). CONCLUSION: Patients at risk for LEA were those with a history of foot ulcer, absence of peripheral pulse, diabetic retinopathy and insulin injection. Preventive strategies should be considered in these groups of patients. Data should be interpreted with caution as the number of patients with amputation was few and information on neuropathy was not available. PMID- 17715832 TI - Thailand diabetes registry project: prevalence, characteristics and treatment of patients with diabetic nephropathy. AB - OBJECTIVES: To identify the prevalence and characteristics of patients with Diabetic Nephropathy (DN) and to evaluate adequacy of glycemic and blood pressure control of these patients in the authors' registry. MATERIAL AND METHOD: A cross sectional, multicenter, hospital-based diabetic registry was carried out in diabetes clinics of 11 tertiary centers in Thailand. DN was defined as the presence of at least two out of three of these symptoms; positive microalbuminuria, positive dipstick proteinuria or creatinine levels equal to or greater than 2 mg/dl. One center that did not perform urine microalbumin measurement was excludedfrom the analysis. Overt nephropathy was defined as the presence of gross proteinuria or renal insufficiency. RESULTS: The study included 4875 patients (females 63.8%) with a mean (SD) duration ofdiabetes of 12.8 (8.2) years. The prevalence of DN was 42.9% (microalbuminuria 19.7% and overt nephropathy 23.2%). There were 373 (7.7%) patients with renal insufficiency and 24 (0.47%) with end-stage renal disease. By multivariate analysis, factors associated with DN were age, duration of diabetes, male sex, smoking, blood pressure, HbA1c, dyslipidemia and presence of diabetic retinopathy. Prevalence of ischemic heart disease and cerebrovascular disease in patients with DN was 11.5% and 6.6% respectively. Mean (SD) HbA1c in patients with nephropathy was 8.2 (2.6)%. Only 25% of subject had HbA1c of less than 7%, 46% had blood pressure ofmore than 140/90 mmHg and 84% received at least one antihypertensive drug. However, the target blood pressure of less than 130/80 mmHg could be achieved in only 18% of these patients. The mean (SD) number of antihypertensive drugs was 1.7 (1.1). Nearly 60% of patients received either ACE inhibitors or ARBs. CONCLUSION: DN was very common. The overall picture of DN in the present survey suggests the seriousness of the problem and prompts more aggressive intervention. PMID- 17715834 TI - Thailand diabetes registry project: prevalence and risk factors of stroke in thai diabetic patients. AB - OBJECTIVE: To determine the prevalence of stroke and its risk factors in Thai diabetic patients who attended the diabetes clinics of university and tertiary care hospitals. MATERIAL AND METHOD: A cross-sectional, multi-center hospital based diabetes registry was carried out at diabetes clinics of 11 university and tertiary-care hospitals. Demographic data, clinical characteristics, common drugs used and laboratory parameters were analyzed for prevalence and risk factors associated with stroke. RESULTS: The prevalence of stroke in the patients studied was 3.5%. Most of the patients were type 2 diabetes and had ischemic stroke. One of the risk factors associated with stroke was age greater than 60 years, and the risk appeared to be highest if the patients' age was greater than 70 years (adjust OR = 3.29, p = 0.012). Other risk factors included male sex, systolic blood pressure of > or =140 mmHg, use of oral hypoglycemic agents, lipid lowering agents and aspirin. There was no association between stroke and duration of diabetes, occupation, educational level, BMI, smoking, alcohol drinking, diastolic blood pressure, use of antihypertensive drugs or insulin, glycemic control, lipid profiles and kidney function. CONCLUSION: Ischemic stroke was common among Thai patients with diabetes especially in the elderly. The present result emphasizes the relationship between level of systolic blood pressure and the occurrence of stroke. Optimal blood pressure control should be underscored in caring for diabetic patients. PMID- 17715835 TI - Thailand diabetes registry project: current status of dyslipidemia in Thai diabetic patients. AB - OBJECTIVE: To determine the prevalence of dyslipidemia in adult Thai type 2 diabetes who attended diabetes clinics in university and tertiary-care hospitals. MATERIAL AND METHOD: A cross-sectional, multi-center, hospital-based diabetes registry was conducted in 11 diabetic clinics in tertiary medical centers in Bangkok and major provinces between April and December 2003. A group of 9419 diabetic patients were registered. Individual Demographic data including education and socioeconomic status were collected. The results of the physical examination for complications, history screening and laboratory results were recorded. The prevalence of the various complications of diabetes was analyzed and the percentage achievement of metabolic control calculated. RESULTS: Of the 9419 diabetic patients registered 8769 had complete demographic and plasma lipid data. Mean age was 59.5 +/- 13.3 years. The percentage of male patients was 33.9%. In the present study, there were 8464 type 2 diabetes and 383 type I diabetes. History of coronary artery disease and cerebrovascular disease were present in 8.1 and 4.2 percent ofthepatients, respectively. More than 80% of the patients had dyslipidemia. The patients with CVD had higher proportion of achieving the LDL target (< 100 mg/dl, 43 vs. 34%). More than half of the patients (55%) were taking lipid lowering medications, but one-third (30%) did not despite havingfulfilled indications. The patients covered by government supported health plan were less likely to received lipid-lowering medication than the patients covered by private health plans (OR 0.65, 95% CI 0.57-0.75). The two most commonly used lipid-lowering agents were HMG CoA reductase inhibitors (76%) and fibrates (19%), both agents were used in combination in 5% ofthe patients. Only 40.1% ofthe patients on lipid-lowering medications reached the target LDL goal (<100 mg/dl). CONCLUSION: Elevated LDL cholesterol was the most common lipid abnormality in the present study. Although 55% of the patients were taking lipid lowering agents, another 42% of the patients needed the medication. More than half of the patients treated needed more intensive lipid lowering in order to achieve the LDL goal. If the authors wish to follow the current (2005) American Diabetes Association recommendations, we would have to treat up to 97% of diabetic patients with lipid lowering PMID- 17715836 TI - Thailand diabetes registry project: glycemic control in Thai type 2 diabetes and its relation to hypoglycemic agent usage. AB - OBJECTIVE: To determine the pattern of hyperglycemic agent usage in Thai type 2 diabetics (T2 DM) who attended the diabetes clinic in university and tertiary care hospitals. The achievement oftarget glycemic control by various modalities of treatment was also analyzed. MATERIAL AND METHOD: A cross-sectional, hospital based diabetes registry of 8913 type 2 diabetic patients in 11 tertiary care hospitals and medical schools was carried out from April to December 2003. Demographic data, usage of hypoglycemic agents and level of glycemic control were collected to determine the pattern ofuse, associated factors, and achievement of glycemic control. RESULTS: Overall, 2342 (26.3%) of T2 DM achieved HbA1C less than 7%. The percentage of patients treated with metformin was 70.8%, sulfonylureas (SU) was 68.7% and insulin was 25.3%. Only 7.0% of patients received alpha-Glucosidase Inhibitor (AGI), 5.7% received ThaiZoliDinediones (TZD), 1.1% received repaglinide, and 3.2% was on diet control alone. Target glycemic control was achieved in 57.6%, 37.1%, 52%, 16.7%, 62.5%, 52% and 16.9% of patients who were on diet control only, monotherapy with SQU, metformin, TZD, AGI, repaglinide and insulin,respectively. Sulfonylureas were the most commonly used drug for monotherapy. Metformin with sulfonylurea was the most common combination therapy and was used in 39.5% of patients. More than 60% of the patients treated with metformin monotherapy had body mass index (BMI) of more than 25 kg/m2, as compare to less than half of patient treated with other monotherapy agent. Mean +/- SD duration of diabetes in thepatients treated with metformin alone was 5.9 +/- 5.5 years, less than that in the SU-treated patients (8.3 +/- 7.1 years) and also in the insulin-treated patients (14.8 +/- 9.0 years). TDZ were commonly prescribed in combination with sulfonylureas and metformin in subjects with relatively longer duration of diabetes. CONCLUSION: Better treatment strategies for glucose control ofdiabetic patients on medical treatments should be encouraged to improve glycemic control and reduce long term complications. PMID- 17715837 TI - Thailand diabetes registry project: prevalence of hypertension, treatment and control of blood pressure in hypertensive adults with type 2 diabetes. AB - OBJECTIVE: To determine the prevalence of hypertension, patterns of antihypertensive treatment and level of blood pressure control in adult Thai type 2 diabetic patients who attended diabetes clinics in university and tertiary-care hospitals. MATERIAL AND METHOD: A cross-sectional, multi-center, hospital-based diabetes registry of 8884 adults 18 years old and older was carried out from diabetes clinics of 11 tertiary centers. Demographic data, including use of antihypertensive drugs and blood samples were collected and analyzed for prevalence, associated factors, patterns of antihypertensive therapy and level of blood pressure control. RESULTS: The prevalence of hypertension in adult Thai type 2 diabetic patients was 78.4 (6965)%. Antihypertensive drugs were prescribed in 84.4 (5878)% of all hypertensive patients. The achievement of blood pressure control (less than 130/80 mmHg) w as 13.85%. Thepercentage of patients receiving 1, 2, 3, 4, and 5 drugs were 45 (2645)%, 33.4 (1963)%, 16.8 (987)%, 4.4 (259)%, and 0.4 (24)% respectively. Angiotensin-converting enzyme inhibitors were the most commonly prescribed antihypertensive agents (54.6%), followed by diuretics (43.8%), and calcium channel blockers (34.6%). CONCLUSION: Blood pressure control in hypertensive adults with type 2 diabetes was suboptimal. Strategies to improve awareness and adequacy of blood pressure control in these subjects should be seriously considered. PMID- 17715838 TI - Efficacy of bisphosphonates for the control of alveolar bone loss in periodontitis. AB - Periodontal disease is characterized by periodontal bone loss. For this reason, we conducted a study to test the effect of alendronate (ALN), an inhibitor of bone resorption, on alveolar bone mass. A total of 335 patients with periodontal disease (men = 162, women = 173), aged 30 to 79, were randomized to either placebo or ALN 70 mg once weekly. All patients received prophylaxis at baseline, and at 6, 12, and 18 months. Smokers accounted for 62% of patients, and 71% of the patients had severe periodontal disease. The primary efficacy endpoint was the change in alveolar bone loss (ABL). When all subjects were analyzed, 2 years of treatment with alendronate 70 mg once weekly did not significantly change either ABL or alveolar bone density (ABD) relative to placebo. However, in the subgroup of patients with low mandibular bone mineral density (BMD) at baseline, alendronate significantly reduced bone loss relative to placebo (p < 0.01). No such effect was seen in patients with normal baseline mandibular BMD. The overall and upper gastrointestinal safety and tolerability profile of alendronate after 2 years of treatment was very favorable compared to placebo. No cases of osteonecrosis of the jaw were observed. In summary, in patients with periodontal disease receiving prophylaxis, alendronate 70 mg once weekly was well tolerated, but did not have a detectable effect on alveolar bone loss, except in those patients with low mandibular BMD at baseline. PMID- 17715839 TI - The effect of osteoporosis on periodontal status, alveolar bone and orthodontic tooth movement. A literature review. AB - Osteoporosis, an age-related condition, is defined as a systemic skeletal disease characterized by low bone mass and micro-architectural deterioration with a consequent increase in bone fragility and susceptibility to fracture. It is considered the most common bone metabolic disease and it constitutes a major public health problem. Several studies indicate that osteoporosis may be related to decreased oral bone density and alveolar bone loss. In osteoporotic patients, uncoupling of bone resorption and bone formation has taken place. Both bone resorption and bone formation are accelerated, and excessive bone resorption usually leads to loss of attachment. Osteoporosis could also affect the rate of tooth movement through the involvement of alveolar bone. In healthy individuals, bone is constantly being remodeled in the coupled sequence of bone resorption and formation. When a force is applied to a tooth, alveolar bone formation and resorption occur predominantly on the tension and pressure sides of the root, respectively, and the tooth moves with increased alveolar bone remodeling. Experimental studies suggest that systemic-osteoporotic hormone imbalance increases bone turnover and accelerates tooth movement while under orthodontic treatment. Based on these observations it can be concluded that deviations in bone turnover and consequent periodontal problems influence the response to orthodontic forces, and this should be taken into consideration when planning orthodontic treatment in adult patients with metabolic bone disease, especially postmenopausal females or those on chronic medication affecting bone metabolism. PMID- 17715840 TI - Root trunk height as a risk factor for periodontal furcation involvement in maxillary first molars: an in vitro study. AB - The aim of this study was to correlate the root trunk height from the furcation openings on the buccal, mesial and distal surfaces to the cemento-enamel junction in upper first permanent molars in human beings with risk for periodontal disease progression. One hundred extracted maxillary first molars were used. Reference points and demarcations were determined from the entrance of the buccal (F1), mesial (F2) and distal (F3) furcations to the cemento-enamel junction in millimeters. The mean distances found were 3.50 mm, 4.44 mm and 4.26 mm for the buccal, mesial and distal furcations, respectively, in relation to the cemento enamel junction. The statistical analyses were Student's t-test and Chi-square (X2). With periodontal disease progression, the buccal furcation presents a greater compromising risk due to its proximity to the cemento-enamel junction, while the mesial furcation is the most distant, comprising a lesser risk. PMID- 17715842 TI - Retail clinics: if you can't beat 'em, join 'em. PMID- 17715841 TI - The coronally advanced flap for the treatment of multiple recession defects: a modified surgical approach for the upper anterior teeth. AB - OBJECTIVE: The aim of the study was to evaluate the clinical efficacy of a modification of the flap-design of the coronally advanced flap for the treatment of multiple gingival recessions affecting the anterior teeth in patients with aesthetic demands. METHODS: Six systemically and periodontally healthy subjects with multiple recession-type defects affecting the upper incisors and canines (recession depth < or = 2 mm) were enrolled in the study. All recessions fell into Miller class I or II. In each patient all present recessions were treated at the same surgical time with a modification of the coronally advanced flap technique. The clinical re-evaluation was made one year after the surgery. RESULTS: A total of 25 recessions (mean recession depth 2.84 +/- 1.0 mm) were treated. The mean number of gingival recessions treated in each subject was 4.1 (range 3 - 5). At the one-year examination, on average, 97% of the root surface was covered with soft tissue and 89% of the defects showed complete root coverage. Complete root coverage in all recessions was achieved in four out of the six (67%) treated patients. A statistically significant increase of keratinized tissue height (0.64 +/- 0.6 mm) was observed after one year. CONCLUSIONS: The frontal approach of the coronally advanced flap was effective for the treatment of multiple gingival recessions affecting the anterior teeth in patients with aesthetic demands, and these results were successful both in terms of root coverage and increase in keratinized tissue height. PMID- 17715843 TI - Giving patients the alternative. Hospitals find success integrating holistic medicine into service lines. PMID- 17715845 TI - More tips to help build a successful, supportive diversity program. PMID- 17715846 TI - Prices to rise; healthcare industry expects employment boost, increase in capital expenditure spend. PMID- 17715844 TI - Is 'relationship' an overworked term? PMID- 17715847 TI - Follow these six suggestions to ensure obese patients do not jeopardize safety, leave you unprepared. PMID- 17715848 TI - Cephalosporin continues decline in first quarter. PMID- 17715850 TI - The use of splints for managing TMD and bruxism. PMID- 17715849 TI - Overcome three more common materials challenges. PMID- 17715851 TI - TMD: pain for patients and dentists. PMID- 17715852 TI - Treating patients with sleep apnea. Is it within the scope of dental practice? PMID- 17715853 TI - An interview with Val J. Halamandaris: Looking back and looking forward. Interview by Patty M Graham. PMID- 17715854 TI - Delivering on the promise...a home care & hospice public policy timeline. PMID- 17715855 TI - The incredible future of home care and hospice. PMID- 17715857 TI - A defining moment in home care. PMID- 17715856 TI - The changing face of home care: agency business models adapt to evolving circumstances. PMID- 17715859 TI - Electronic health records: the future for home health. PMID- 17715858 TI - Reflections on home care, hospice, and NAHC: members share their memories and hopes for the future. PMID- 17715860 TI - Your brand is your promise. PMID- 17715861 TI - Getting past the gatekeeper. AB - Favorite home care and hospice sales topics involve overcoming "gatekeeper" barriers. But concerns of getting to the referral decision maker in a physician office addresses only one end of a spectrum. The micro-economic dimension of understanding and exploiting medical office policy is counterpoint to the more significant macro-economic government policy that likewise must be understood and exploited to assure growth. The "micro" gatekeeper is the front desk personnel while the "macro" gatekeeper is Congress. Addressing the needs of both gatekeepers is critical and, coincidentally, utilizes similar strategies. PMID- 17715862 TI - Crafting your uniqueness. PMID- 17715863 TI - Pillow angel. PMID- 17715864 TI - Looking back--looking forward. PMID- 17715865 TI - The nursing standards in Texas states that if you believe a fellow nurse is practicing impaired, you must notify the board. PMID- 17715867 TI - The nursing standards in Texas states that if you believe a fellow nurse is practicing impaired, you must notify the board. PMID- 17715866 TI - When the going gets tough... PMID- 17715868 TI - Promoting communication and documentation of advance care planning in long-term care facilities. AB - This paper describes the findings of Phase I of an advance care planning (ACP) demonstration project, undertaken collaboratively between the Texas Partnership on End-of-Life Care and the North Texas Alliance of Nursing Homes. The goal of the project, designed as a continuous quality improvement program for the nine volunteer nursing facilities (NFs), was to increase the systematic implementation of ACP Phase I consisted of baseline data collection of ACP documentation from the nine NFs. This was followed by a pre-intervention train-the-trainer educational program for facility coordinators and other interested staff who subsequently would implement the procedures in their NFs, to increase the use of advance directives (ADs). Following the Phase II implementation, a model will be developed for replication in other Texas facilities. Reported here are the pre intervention baseline chart review findings documenting ACP and various AD documents. Based on the experience of this chart review, recommendations are outlined for improving the quality of ACP communication and documentation. PMID- 17715869 TI - Healthcare ergonomics--it takes two to tango. AB - Transfers and mobilization can be the occasion of a very positive experience for both the caregiver and the resident if certain principles are applied: a feeling connection between the caregiver and resident, taking a small amount of extra time to insure that the resident is invited to move and signals their intention to work with the caregiver to accomplish the move, and being aware and working with "normal movements." Obviously, there are some residents who will be able to participate very little, if at all, in mobility and transfers and there are some that will be very resistant. For those individuals, the transfer/mobility task may not need to be done at all, or it may need to done as carefully as possible, mechanically, without the resident's cooperation. However, it is a mistake to make assumptions about the residents' lack of ability to connect and communicate with the caregiver in the transfer/mobility process. Applying the principles outlined above to improve the experience of transfers and and mobility means that the caregiver must think of themselves and the resident as "one unit" much as the tango dancers are one unit when dancing their beautiful dance. PMID- 17715870 TI - Treatment strategies for the management of GERD in older adults. PMID- 17715872 TI - A guide to fall prevention: understanding a Fall Prevention Program. PMID- 17715871 TI - The QUEST process--an innovative approach to improving patient care. PMID- 17715873 TI - Integrative care--can ginkgo improve cognitive function? PMID- 17715874 TI - Facing down hurricanes and whirlwind surveys. PMID- 17715875 TI - Healthcare system-owned collection agencies. PMID- 17715876 TI - Financial intelligence creates financial clearance. PMID- 17715877 TI - Changes are coming to the IPPS. PMID- 17715878 TI - Lasers in dental implantology: innovation improves patient care. PMID- 17715879 TI - CMS unveils proposed list of 'no-payment' conditions. AB - CMS identifies 13 different conditions that may eventually be included. Quality managers take on even greater importance in light of new proposal. Accurate, timely documentation will be a key to optimizing reimbursement. PMID- 17715880 TI - Study casts new doubt on effectiveness of P4P. AB - CMS participants also targeted measures that were not financially rewarded. Both groups showed improved outcomes--at similar rates. Higher incentives might make P4P even more attractive. PMID- 17715881 TI - Health systems form 'Safest Hospital Alliance'. AB - 172 safety measures to be implemented, with 80% improvement sought in two years. Safety threats will be "called out" immediately, and root cause analyses conducted. Sponsors hope template will be transferable to any health system. PMID- 17715882 TI - Telehealth helps hospital cut readmissions by 75%. AB - Most hospitals lose money for every heart failure admission, so issue is critically important. Program teaches patients how to effectively self-manage their condition. Reach expanded from 40 patients to 100 after initial success. PMID- 17715883 TI - Mass General makes its survey findings public. AB - Hospital takes two-pronged approach, dealing with transparency while pursuing performance improvement. In addition to a copy of The Joint Commission survey, facility answers key questions and provides regular updates on web site. Policy of openness helps generate staff buy-in for PI initiatives. PMID- 17715885 TI - Varietal differences in the bioaccessibility of beta-carotene from mango (Mangifera indica) and papaya (Carica papaya) fruits. AB - Mango and papaya, which are rich sources of beta-carotene, are widely consumed in India. In this study, beta-carotene content and its bioaccessibility were determined in six locally available varieties of mango, namely, Badami, Raspuri, Mallika, Malgoa, Totapuri, and Neelam, and two varieties of papaya, namely, Honey Dew and Surya. Varietal differences were evident in both beta-carotene content and its bioaccessibility in the case of mango. beta-Carotene content in ripe mango ranged from 0.55 +/- 0.03 mg/100 g in the Malgoa variety to 3.21 +/- 0.25 mg/100 g in the Badami variety. Similarly, in the Honey Dew and Surya varieties of papaya, beta-carotene contents were 0.70 +/- 0.10 and 0.74 +/- 0.12 mg/100 g, respectively. Bioaccessibility of beta-carotene ranged from 24.5% in Badami to 39.1% in Raspuri varieties of mango. Considering both the percent bioaccessibility and the inherent beta-carotene content, the amount of bioaccessible beta-carotene was highest in the Mallika variety (0.89 mg/100 g), followed by Badami (0.79 mg/100 g). Because mango and papaya are also consumed as a blend with milk, the influence of the presence of milk on the bioaccessibility of beta-carotene from these fruits was also examined. Addition of milk generally brought about a significant increase in the bioaccessibility of beta-carotene from mango, the increase ranging from 12 to 56%. Bioaccessibility of beta carotene from the two varieties of papaya examined was similar (31.4-34.3%). Addition of milk increased this bioaccessibility by 19 and 38% in these two varieties. Considering the beta-carotene content of mango and papaya, the latter has to be consumed in amounts roughly 3 times that of mango to derive the same amount of beta-carotene. Thus, this study has indicated that varietal differences exist in the content and bioaccessibility of beta-carotene in mango and that the addition of milk is advantageous in deriving this provitamin A from the fruit pulp of mango and papaya. PMID- 17715886 TI - Characterization of protein changes associated with sugar beet (Beta vulgaris) resistance and susceptibility to Fusarium oxysporum. AB - Fusarium oxysporum (F-19) is a serious threat to sugar beet. Resistance exists, but the basis for resistance and disease is unknown. Protein extracts from sugar beet genotypes C1200.XH024 (resistant, R) and Fus7 (susceptible, S) were analyzed by multidimensional liquid chromatography at 2 and 5 days postinoculation (dpi) and compared to mock-inoculated controls. One hundred twenty-one (R) and 73 (S) protein peaks were induced/repressed by F-19, approximately 12 (R) and 8% (S) of the total proteome detected. Temporal protein regulation occurred within and between each genotype, indicating that the timing of expression may be important for resistance. Thirty-one (R) and 48 (S) of the differentially expressed peaks were identified using matrix-assisted laser desorption-ionization with tandem time-of-flight mass spectrometry; others were below detection level. Comparison between the two genotypes uncovered R- and S-specific proteins with potential roles in resistance and disease development, respectively. Use of these proteins to select for new sources of resistance and to develop novel disease control strategies is discussed. PMID- 17715884 TI - Expression of cancer-testis (CT) antigens in placenta. AB - Besides their variable presence in fetal and adult germ cells, CT antigens have occasionally been detected in placental tissue. However, these data are scarce and solely based on mRNA analyses; nothing is known about their presence at the protein level. Here, we analyzed the expression of various CT antigens in placental tissues from gestational age week 5 to week 42 using monoclonal antibodies to various antigens of the MAGE-A and -C families, NY-ESO-1, as well as GAGE. We show that CT antigen expression in placenta varies widely for the various antigens, ranging from completely negative to abundant. Since little is known about the function and biology of CT antigens, interpretation of this highly variable expression pattern is purely speculative. However, our data indicate that the various CT antigens have different functions during placental development. PMID- 17715887 TI - Preparation of specific monoclonal antibodies (MAbs) against heavy metals: MAbs that recognize chelated cadmium ions. AB - Monoclonal antibodies (MAbs) were produced against chelated Cd (2+). Since Cd (2+) ions are too small to elicit an immune response, the metal was coupled to protein carrier (keyhole limpet hemocyanin, KLH) using a bifunctional chelator 1 (4-isothiocyanobenzyl)ethylenediamine N, N, N', N'-tetraacetic acid (ITCBE). Several mice were immunized with this Cd (2+)-ITCBE-KLH immunoconjugate. Spleen cells of two immunized mice were fused with myeloma cells, and the resulting hybridomas were screened using protein conjugates with covalently bound metal free ITCBE (ethylenediamine tetraacetic acid) or Cd (2+)-ITCBE. Four hybridoma cell lines that produced MAbs with high selectivity and sensitivity (Aa4, Aa6, Ac4, and Ba2) were expanded for further study. Cross-reactivities with other metals were below 1% except for Hg (2+), which showed a slight cross-reactivity in competitive ELISA. These antibodies were used to construct competitive ELISAs for ionic cadmium; the IC 50 of the four antibodies (Aa4, Aa6, Ac4, and Ba2) were 10.59, 4.19, 29.45, and 6.63 microg/L, respectively. The detection range and the lowest detection limit for cadmium, using the Aa6 antibody, were 2.19-86.38 microg/L and 0.313 microg/L, respectively. Spike-recovery studies in tap and stream water showed that the most sensitive antibody can be used for cadmium detection in drinking water. PMID- 17715889 TI - Mycotoxins in corn-based food products consumed in Brazil: an exposure assessment for fumonisins. AB - Samples from 10 different corn-based food products commercially sold in the Federal District of Brazil were analyzed for fumonisins (FB1 and FB2) using HPLC/fluorescence following naphthalene-2,3 dicarboxaldehyde (NDA) derivatization (limit of quantification (LOQ) = 0.020 mg/kg). Samples were also analyzed for aflatoxins (B1, B2, G1, and G2) on a thin-layer chromatrography (TLC) plate under UV light (LOQ of 2 microg/kg). From the 208 samples analyzed, 80.7 and 71.6% had quantifiable levels of FB1 and FB2, respectively. Mean levels of total fumonisins (FB1 + FB2) ranged from 0.127 mg/kg for corn flakes to 2.04 mg/kg for cornmeal ( creme de milho). No FBs were detected in any of the fresh, sweet corn on the cob samples analyzed. Aflatoxins were not detected in any of the 101 samples analyzed. The daily intakes of fumonisins through the consumption of corn-based food products was estimated using consumption data estimated from the 2002/2003 Brazilian Household Budget Survey and the level of fumonisins found in this and other studies conducted in Brazil. In the Federal District, the calculated total daily intake for the total and the consumers-only populations represented, respectively, 9.0 and 159% of the provisional maximum total daily intake (PMTDI) of 2 microg/kg body weight per day. At the national level, the intakes were calculated based on the fumonisin levels found in the Federal District and on published data from studies conducted elsewhere in the country. They represented 24.1 and 355% PMTDI for the total and the consumers-only populations, respectively. The high incidence of fumonisins in some corn-based products and the exposure levels found for specific subpopulations in the present study indicate the need for setting safe regulatory levels for fumonisins in food in Brazil. PMID- 17715888 TI - Dietary combination of fucoxanthin and fish oil attenuates the weight gain of white adipose tissue and decreases blood glucose in obese/diabetic KK-Ay mice. AB - Fucoxanthin is a marine carotenoid found in edible brown seaweeds. We previously reported that dietary fucoxanthin attenuates the weight gain of white adipose tissue (WAT) of diabetic/obese KK- A(y) mice. In this study, to evaluate the antiobesity and antidiabetic effects of fucoxanthin and fish oil, we investigated the effect on the WAT weight, blood glucose, and insulin levels of KK- A(y) mice. Furthermore, the expression level of uncoupling protein 1 (UCP1) and adipokine mRNA in WAT were measured. After 4 weeks of feeding, 0.2% fucoxanthin in the diet markedly attenuated the gain of WAT weight in KK- A(y) mice with increasing UCP1 expression compared with the control mice. The WAT weight of the mice fed 0.1% fucoxanthin and 6.9% fish oil was also significantly lower than that of the mice fed fucoxanthin alone. In addition, 0.2% fucoxanthin markedly decreased the blood glucose and plasma insulin concentrations in KK- A(y) mice. The mice fed with the combination diet of 0.1% fucoxanthin and fish oil also showed improvements similar to that of 0.2% fucoxanthin. Leptin and tumor necrosis factor (TNFalpha) mRNA expression in WAT were significantly down-regulated by 0.2% fucoxanthin. These results suggest that dietary fucoxanthin decreases the blood glucose and plasma insulin concentration of KK- A(y) along with down-regulating TNFalpha mRNA. In addition, the combination of fucoxanthin and fish oil is more effective for attenuating the weight gain of WAT than feeding with fucoxanthin alone. PMID- 17715890 TI - Near-infrared reflectance spectroscopy-based methods for phytase registration in feed industry. AB - The application of biotechnological products in the feed industry has undergone explosive growth in recent years, and phytase from microorganism accounts for one third of the entire feed enzyme market. In this study, some differences in the composition of protein and denaturation temperature between two commercial phytases were determined by HPLC and differential scanning calorimetry, which were derived from the same origin of E. coli. At the same time, we found that it was advantageous for near-infrared reflectance spectroscopy (NIRS) to display the protein differences in the commercial phytase, which is most important for ensuring the traceability of biotechnological products in feed and food safety control. Furthermore, NIRS could track the changes in phytase during the spray drying process and the change of enzyme activity during storage of phytase. Our experiments proved that the information from NIRS could describe well the individual characteristics of the commercial phytase, which indicated that near infrared reflectance spectra could be exploited to use in the registration system of commercial phytase. PMID- 17715891 TI - Identification of allyl esters in garlic cheese. AB - This study describes the identification of six allyl esters in a garlic cheese preparation and in a commercial cream cheese. The extracts were prepared by liquid/liquid extraction and concentrated by the SAFE process. The identification of the allyl esters of acetic, butyric, hexanoic, heptanoic, octanoic, and decanoic acids is based on the correlation of their mass spectrometric data and chromatographic retention time data obtained from the extracts with those of authentic standards. In addition to the gas chromatography (GC)/mass spectrometry analysis, the flavor ingredients were characterized by GC sniffing by a trained flavorist. Some of the esters were isolated by preparative GC. PMID- 17715892 TI - Induction of glucokinase mRNA by dietary phenolic compounds in rat liver cells in vitro. AB - Diabetes and its complications, including oxidative stress, are major reasons for medical intervention and one of the most frequent causes of death in developed countries. Several lines of data suggest that the use of certain dietary polyphenolic compounds may alter glucose metabolism, thus decreasing the risk for type 2 diabetes. In this paper, we present the effect of phenolic acids (caffeic, chlorogenic, rosmarinic, and ferulic) and extracts from Smallanthus sonchifolius and Prunella vulgaris on glucose production in rat hepatocytes and on glucokinase, glucose-6-phosphatase, and phosphoenol-pyruvate carboxykinase mRNA expression in rat hepatoma Fao cells. The phenolics at 500 microM and after 1 h incubation lowered glucose production via both gluconeogenesis (10 mM alanine or dihydroxyacetone as precursors) and glycogenolysis compared with metformin. Most of the phenolics increased the level of glucokinase mRNA after 24 h in the same way as insulin (10(-7) M). PMID- 17715894 TI - Accumulation of bioactive compounds during growth and development of mango ginger (Curcuma amada Roxb.) rhizomes. AB - Accumulation of bioactive compounds and storage components during developmental stages of mango ginger ( Curcuma amada Roxb.) rhizome was investigated from 60 to 240 days, as a function of physiological maturity. Four distinct developmental phases were defined, namely, vegetative phase (up to 60 days from planting), initiation and development phase (60-150 days), maturation phase (150-180 days), and senescence phase (180 days). Difurocumenonol, a bioactive terpenoid compound and phenolics were identified as biomarkers, to determine the optimum physiological maturity to harvest mango ginger rhizome. Accumulation of phenolics was observed in newly initiated rhizomes (after 60 days from planting). The phenolic content was high in mango ginger pulp compared to its juice. Newly initiated rhizome contained no difurocumenonol, and it was observed after 120 days after planting. Peak accumulation of phenolics, difurocumenonol, and total protein were noticed in 180 day old rhizome. Accordingly, the abundance of these components on 180 days was set as an optimum maturity standard for harvest of mango ginger rhizome, compared with a conventional harvest period that ranges from 200 to 240 days. PMID- 17715893 TI - Herbicidal potential of stagonolide, a new phytotoxic nonenolide from Stagonospora cirsii. AB - Stagonospora cirsii is a pathogen of Cirsium arvense, causing necrotic lesions on leaves of this noxious weed. The fungus produced toxic metabolites when grown in liquid culture. A new phytotoxin, named stagonolide, was isolated and characterized as (8R,9R)-8-hydroxy-7-oxo-9-propyl-5-nonen-9-olide by spectroscopic methods. Stagonolide was shown to be a nonhost-specific but selective phytotoxin. Leaves of C. arvense were most sensitive and leaves of tomato and pepper (both Solanaceae) were less sensitive to stagonolide, which was assayed at 5 x 10(-3) M, than other plants. Stagonolide assayed at 5 x 10(-6) M was demonstrated to be a strong inhibitor of root growth in seedlings of C. arvense and some other Asteraceae species. Seedlings growth in wheat and radish was much less affected by the toxin, and seedlings of cucumber were insensitive to it. PMID- 17715895 TI - Identification of bitter off-taste compounds in the stored cold pressed linseed oil. AB - Whereas freshly pressed linseed oil provides a delicate nutty flavor, a lingering bitter off-taste is developing upon storage at room temperature. Using a sensory guided fractionation approach, the key bitter compound was identified in stored linseed oil, and its structure was determined as the methionine sulfoxide containing, cyclic octapeptide cyclo(PLFIM OLVF) by means of FTIR, LC-MS, NMR spectroscopy, and amino acid analysis. Although this peptide is known in the literature as cyclolinopeptide E, the bitter taste activity of this compound has not previously been described. Sensory evaluation revealed a recognition threshold concentration of 12.3 micromol/L water. PMID- 17715896 TI - Amla (Emblica officinalis Gaertn.) attenuates age-related renal dysfunction by oxidative stress. AB - To investigate the effects of amla on renal dysfunction involved in oxidative stress during the aging process, we employed young (2 months old) and aged (13 months old) male rats and administered SunAmla (Taiyo Kagaku Co., Ltd., Japan) or an ethyl acetate (EtOAc) extract of amla, a polyphenol-rich fraction, at a dose of 40 or 10 mg/kg body weight/day for 100 days. The administration of SunAmla or EtOAc extract of amla reduced the elevated levels of serum creatinine and urea nitrogen in the aged rats. In addition, the tail arterial blood pressure was markedly elevated in aged control rats as compared with young rats, while the systolic blood pressure was significantly decreased by the administration of SunAmla or EtOAc extract of amla. Furthermore, the oral administration of SunAmla or EtOAc extract of amla significantly reduced thiobarbituric acid-reactive substance levels of serum, renal homogenate, and mitochondria in aged rats, suggesting that amla would ameliorate oxidative stress under aging. The increases of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expression in the aorta of aging rats were also significantly suppressed by SunAmla extract or EtOAc extract of amla, respectively. Moreover, the elevated expression level of bax, a proapoptotic protein, was significantly decreased after oral administration of SunAmla or EtOAc extract of amla. However, the level of bcl-2, an antiapoptotic protein, did not show any difference among the groups. The expressions of renal nuclear factor-kappaB (NF-kappaB), inhibitory kappaB in cytoplasm, iNOS, and COX-2 protein levels were also increased with aging. However, SunAmla or EtOAc extract of amla reduced the iNOS and COX-2 expression levels by inhibiting NF-kappaB activation in the aged rats. These results indicate that amla would be a very useful antioxidant for the prevention of age related renal disease. PMID- 17715897 TI - Purification of antifreeze protein from wheat bran (Triticum aestivum L.) based on its hydrophilicity and ice-binding capacity. AB - Wheat-bran ( Triticum aestivum L.) antifreeze protein ( TaAFP) was purified 323 fold to electrophoretic homogeneity with an overall yield of 1.64% from wheat bran protein by a specific three-step procedure. The three-step procedure was quicker, cheaper, and more effective than the five-step procedure we used earlier. First, TaAFP was concentrated by a phosphate buffer, on the basis of its strong hydrophilicity that was validated by thermal gravimetric analyses and a surface hydrophobicity analysis. Second, TaAFP was trapped in ice crystals for its specific ice-binding capacity, which was proved by ice-binding protocols. Remarkably, the ice-binding step was the most effective step, and the purification factor of this step was up to 270-fold. Finally, TaAFP was purified by HPLC purification, a complementary step for the specific ice-binding protocol, to electrophoretic homogeneity. Our protocols provide peers a novel and effective way for the search and purification of potential AFPs. PMID- 17715898 TI - Lipid oxidation in milk, yoghurt, and salad dressing enriched with neat fish oil or pre-emulsified fish oil. AB - This study compared the oxidative stabilities of fish-oil-enriched milk, yoghurt, and salad dressing and investigated the effects on oxidation of adding either neat fish oil or a fish-oil-in-water emulsion to these products. Milk emulsions had higher levels of a fishy off-flavor and oxidized faster, as determined by the peroxide value and volatile oxidation products, than fish-oil-enriched yoghurt and dressing, despite the fact that dressings had a higher fish oil content and were stored at room temperature. Additionally, fish-oil-enriched yoghurt generally had higher oxidative stability than fish-oil-enriched dressings, irrespective of the mode of fish oil addition. Yoghurt thus seemed to be a good delivery system of lipids containing n-3 polyunsaturated fatty acids. Different effects of adding fish oil either as neat fish oil or as a fish-oil-in-water emulsion were observed for milk, yoghurt, and dressing. Yoghurt and dressing enriched with neat fish oil were more stable than those enriched with a fish-oil in-water emulsion, whereas milk enriched with neat fish oil was less stable than milk enriched with the fish-oil-in-water emulsion. Overall, it seemed that application of neat fish oil was a good option for preserving the final quality in yoghurt and dressings, but a pre-emulsion may still be considered for the fish oil enrichment of certain food products, for example, milk. PMID- 17715899 TI - Process development of continuous glycerolysis in an immobilized enzyme-packed reactor for industrial monoacylglycerol production. AB - Continuous and easily operated glycerolysis was studied in different lipase packed columns to evaluate the most potential process set-ups for industrial monoacylglycerol (MAG) production. Practical design-related issues such as enzyme filling degree, required reaction time, mass transfer investigations, and capacity and stability of the enzyme were evaluated. A commercially available immobilized Candida antarctica lipase B was used to catalyze the glycerolysis reaction between glycerol and sunflower oil dissolved in a binary tert-butanol: tert-pentanol medium. Considering easy handling of the enzyme and measured expansion when wetted with a reaction mixture, a filling degree of 52 vol % dry enzymes particles per column volume seemed appropriate. Twenty minutes was required to reach equilibrium conditions with a MAG content of 50-55 wt %. Only insignificant indications of mass transfer limitations were observed. Hence, the commercial lipase seemed adequate to use in its available particle size distribution ranging from 300 to 900 microm. A column length-to-diameter ratio of less than 25 did not interfere with the transfer of the fluid mixture through the column. Under the tested conditions, the enzyme could be active for approximately 92 days before enzyme renewal was needed. This corresponds to a very high enzyme capacity with approximately 2000 L pure MAG produced per kg enzyme. PMID- 17715900 TI - Oligomeric proanthocyanidins from mangosteen pericarps. AB - Oligomeric proanthocyanidins were extracted from mangosteen pericarps and fractionated by a Sephadex LH-20 column to give 0.66% yield (dry matter). (13)C and (1)H NMR signals showed the presence of predominantly procyanidins together with a few prodelphinidin units along with small amounts of stereoisomers of afzelechin/epiafzelechin, catechin/epicatechin, and gallocatechin/epigallocatechin. Depolymerization with benzylmercaptan resulted in epicatechin thioether as the major product, and the mean degree of polymerization was determined to be 6.6. The electron spray ionization-mass spectrometry and matrix-assisted laser desorption/ionization time-of-flight mass spectra revealed the dominant B type oligomers with mainly epicatechin units and with a small amount of A type oligomers. The isolated proanthocyanidins are potent peroxyl radical scavengers as evidenced by the high oxygen radical scavenging capacity at 1.7 x 10 (4) micromol TE/g, much higher than that of pine bark and grape seed extracts. PMID- 17715901 TI - Multiphilic descriptor for chemical reactivity and selectivity. AB - In line with the local philicity concept proposed by Chattaraj et al. (Chattaraj, P. K.; Maiti, B.; Sarkar, U. J. Phys. Chem. A. 2003, 107, 4973) and a dual descriptor derived by Morell, Grand and Toro-Labbe, (J. Phys. Chem. A 2005, 109, 205), we propose a multiphilic descriptor. It is defined as the difference between nucleophilic (omega(k)+) and electrophilic (omega(k)-) condensed philicity functions. This descriptor is capable of simultaneously explaining the nucleophilicity and electrophilicity of the given atomic sites in the molecule. Variation of these quantities along the path of a soft reaction is also analyzed. Predictive ability of this descriptor has been successfully tested on the selected systems and reactions. Corresponding force profiles are also analyzed in some representative cases. Also, to study the intra- and intermolecular reactivities another related descriptor, namely, the nucleophilicity excess (Deltaomega(g)-/+) for a nucleophile over the electrophilicity in it, has been defined and tested on all-metal aromatic compounds. PMID- 17715902 TI - Analysis of the substituent effect on the reactivity modulation during self protonation processes in 2-nitrophenols. AB - A voltammetric and spectroelectrochemical ESR study of the reduction processes of five substituted 4-R-2-nitrophenols (R = -H, -OCH(3), -CH(3), -CN, -CF(3)) in acetonitrile was performed. In the potential range considered here (-0.2 to -2.5 V vs Fc+/Fc), two reduction signals (Ic and IIc) were detected; the first one was associated with the formation of the corresponding hydroxylamine via a self protonation pathway. The voltammetric analysis at the first reduction signal showed that there are differences in the reduction pathway for each substituted 4 R-2-nitrophenol, being the E1/2 values determined by the inductive effect of the substituent in the meta position with respect to the nitro group, while the electron-transfer kinetics was determined by the protonation rate (k(1)+ ) of the anion radical electrogenerated. However, at potential values near the first reduction peak, no ESR signal was recorded from stable radical species, indicating the instability of the radical species in solution. Nevertheless, an intense ESR spectrum generated at the second reduction peak was detected for all compounds, indicating the monoelectronic reduction of the corresponding deprotonated 4-R-2-nitrophenols. The spin-coupling hyperfine structures revealed differences in the chemical nature of the electrogenerated radical; meanwhile, the -CF(3) and -CN substituents induced the formation of a dianion radical structure, and the -H, -CH(3), and -OCH(3) substituents provoked the formation of an anion radical structure due to protonation by acetonitrile molecules of the initially electrogenerated dianion radical. This behavior was confirmed by analyzing the ESR spectra in deuterated acetonitrile and by performing quantum chemical calculations of the spin densities at each site of the electrogenerated anionic radicals. PMID- 17715903 TI - White-light-induced fragmentation of methane. AB - We experimentally probe molecular ionization and dissociation of methane molecules in the gas phase upon their irradiation by intense pulses of white light that spans the wavelength range 500-850 nm. White light pulses are generated upon irradiation of BK7 glass by 36-fs-long pulses of intense 820 nm laser light. Comparison is made of the molecular fragmentation patterns obtained using white light that is depolarized with those obtained using single-color (820 nm) light that is highly chirped. On the basis of such comparison, we make hitherto-unavailable estimates of the in situ intensity of white light pulses. Results obtained using white light also indicate that resonances apparently do not play any role in the ionization dynamics that ensue upon irradiation by intense, broadband light; neither are the dynamics affected by the polarization properties of the 820 nm light that is used to generate the white light. PMID- 17715904 TI - Femtosecond spectroscopy of the primary charge separation in reaction centers of Chloroflexus aurantiacus with selective excitation in the QY and Soret bands. AB - The primary charge separation and electron-transfer processes of photosynthesis occur in the reaction center (RC). Isolated RCs of the green filamentous anoxygenic phototrophic bacterium Chloroflexus aurantiacus were studied at room temperature by using femtosecond transient absorption spectroscopy with selective excitation. Upon excitation in the Q(Y) absorbance band of the bacteriochlorophyll (BChl) dimer (P) at 865 nm, a 7.0 +/- 0.5 ps kinetic component was observed in the 538 nm region (Q(X) band of the bacteriopheophytin (BPheo)), 750 nm region (Q(Y) band of the BPheo), and 920 nm region (stimulated emission of the excited-state of P), indicating that this lifetime represents electron transfer from P to BPheo. The same time constant was also observed upon 740 nm or 800 nm excitation. A longer lifetime (300 +/- 30 ps), which was assigned to the time of reduction of the primary quinone, Q(A), was also observed. The transient absorption spectra and kinetics all indicate that only one electron-transfer branch is involved in primary charge separation under these excitation conditions. However, the transient absorption changes upon excitation in the Soret band at 390 nm reveal a more complex set of energy and electron transfer processes. By comparison to studies on the RCs of the purple bacterium Rhodobacter sphaeroides, we discuss the possible mechanism of electron-transfer pathway dependence on excitation energy and propose a model of the Cf. aurantiacus RC that better explains the observed results. PMID- 17715905 TI - Free-radical-induced oxidative and reductive degradation of sulfa drugs in water: absolute kinetics and efficiencies of hydroxyl radical and hydrated electron reactions. AB - Absolute rate constants and degradation efficiencies for hydroxyl radical and hydrated electron reactions with four different sulfa drugs in water have been evaluated using a combination of electron pulse radiolysis/absorption spectroscopy and steady-state radiolysis/high-performance liquid chromatography measurements. For sulfamethazine, sulfamethizole, sulfamethoxazole, and sulfamerazine, absolute rate constants for hydroxyl radical oxidation were determined as (8.3 +/- 0.8) x 10(9), (7.9 +/- 0.4) x 10(9), (8.5 +/- 0.3) x 10(9), and (7.8 +/- 0.3) x 10(9) M(-1) s(-1), respectively, with corresponding degradation efficiencies of 36% +/- 6%, 46% +/- 8%, 53% +/- 8%, and 35% +/- 5%. The reduction of these four compounds by their reaction with the hydrated electron occurred with rate constants of (2.4 +/- 0.1) x 10(10), (2.0 +/- 0.1) x 10(10), (1.0 +/- 0.03) x 10(10), and (2.0 +/- 0.1) x 10(10) M(-1) s(-1), respectively, with efficiencies of 0.5% +/- 4%, 61% +/- 9%, 71% +/- 10%, and 19% +/- 5%. We propose that hydroxyl radical adds predominantly to the sulfanilic acid ring of the different sulfa drugs based on similar hydroxyl radical rate constants and transient absorption spectra. In contrast, the variation in the rate constants for hydrated electrons with the sulfa drugs suggests the reaction occurs at different reaction sites, likely the different heterocyclic rings. The results of this study provide fundamental mechanistic parameters, hydroxyl radical and hydrated electron rate constants, and degradation efficiencies that are critical for the evaluation and implementation of advanced oxidation processes (AOPs). PMID- 17715906 TI - Density functional theory analysis of molybdenum isotope fractionation. AB - Analytical studies have found an enrichment of the lighter Mo isotopes in oxic marine sediments compared to seawater, with isotope fractionation factors of -1.7 to -2.0 per thousand for Delta97/95Mosediment-seawater. These data place constraints on the possible identities of dissolved and adsorbed species because the equilibrium isotope fractionation depends on the energy differences between the isotopomers of the adsorbed species, minor dissolved species, and the dominant solution species, MoO42-. Adsorption likely involves molybdic acid, whose structure is indicated by previous studies to be MoO3(H2O)3. Here we used DFT calculations of vibrational frequencies to determine the isotope fractionation factors versus MoO42-. The results indicate that isotope equilibration of MoO42- with MoO3(H2O)3, yielding Delta97/95Momolybdic acid molybdate=-1.33 per thousand, is most likely responsible for the isotope fractionation of Mo between oxic sediments and seawater. The difference between the calculated value of Delta97/95Momolybdic acid-molybdate for MoO3(H2O)3 and the value observed in natural sediments and experiments is probably due to effects of solvation and adsorption onto the manganese oxyhydroxide surface. PMID- 17715907 TI - Vacuum ultraviolet (VUV) photoionization of small water clusters. AB - Tunable vacuum ultraviolet (VUV) photoionization studies of water clusters are performed using 10-14 eV synchrotron radiation and analyzed by reflectron time-of flight (TOF) mass spectrometry. Photoionization efficiency (PIE) curves for protonated water clusters (H2O)(n)H+ are measured with 50 meV energy resolution. The appearance energies of a series of protonated water clusters are determined from the photoionization threshold for clusters composed of up to 79 molecules. These appearance energies represent an upper limit of the adiabatic ionization energy of the corresponding parent neutral water cluster in the supersonic molecular beam. The experimental results show a sharp drop in the appearance energy for the small neutral water clusters (from 12.62 +/- 0.05 to 10.94 +/- 0.06 eV, for H2O and (H2O)4, respectively), followed by a gradual decrease for clusters up to (H2O)23 converging to a value of 10.6 eV (+/-0.2 eV). The dissociation energy to remove a water molecule from the corresponding neutral water cluster is derived through thermodynamic cycles utilizing the dissociation energies of protonated water clusters reported previously in the literature. The experimental results show a gradual decrease of the dissociation energy for removal of one water molecule for small neutral water clusters (3 (p-tosyl)CH(2)NC > (alkyl)NC in LAuCl, a trend that is also commensurate with the relative long-term photosensitivity of the corresponding solids and solutions. A new method for preparing stable small gold nanoparticles is described based on the fundamental findings above. Thus, photolysis of different concentrations of LAuX in solutions containing a primary amine-terminated dendrimer leads to clear solutions exhibiting tunable visible plasmon absorptions of gold nanoparticles; these solutions maintain their colors and stability indefinitely. TEM measurements for representative samples prepared by photolysis of (p-tosyl)CH(2)NCAuCl solutions give rise to spherical nanoparticles as small as 5 nm. PMID- 17715917 TI - Electronic structures of tris(dioxolene)chromium and tris(dithiolene)chromium complexes of the electron-transfer series [Cr(dioxolene)(3)](z) and [Cr(dithiolene)(3)](z) (z = 0, 1-, 2-, 3-). A combined experimental and density functional theoretical study. AB - From the reaction mixture of 3,6-di-tert-butylcatechol, H2[3,6L(cat)], [CrCl3(thf)3], and NEt3 in CH3CN in the presence of air, the neutral complex [CrIII(3,6L*(sq))3] (S = 0) (1) was isolated. Reduction of 1 with [Co(Cp)2] in CH2Cl2 yielded microcrystals of [Co(Cp)2][CrIII(3,6L*(sq))2(3,6L(cat))] (S = 1/2) (2) where (3,6L*(sq)(1-) is the pi-radical monoanionic o-semiquinonate of the catecholate dianion (3,6Lcat)(2-). Electrochemistry demonstrated that both species are members of the electron-transfer series [Cr(3,6LO,O)]z (z = 0, 1-, 2 , 3-). The corresponding tris(benzo-1,2-dithiolato)chromium complex [N(n Bu)4][CrIII(3,5L*S,S)2(3,5LS,S)] (S = 1/2) (3) has also been isolated; (3,5LS,S)(2-) represents the closed-shell dianion 3,5-di-tert-butylbenzene-1,2 dithiolate(2-), and (3,5L*S,S)(1-) is its monoanionic pi radical. Complex 3 is a member of the electron-transfer series [Cr(3,5L(S,S))3]z (z = 0, 1-, 2-, 3-). It is shown by Cr K-edge and S K-edge X-ray absorption, UV-vis, and EPR spectroscopies, as well as X-ray crystallography, of 1 and 3 that the oxidation state of the central Cr ion in each member of both electron-transfer series remains the same (+III) and that all redox processes are ligand-based. These experimental results have been corroborated by broken symmetry density functional theoretical calculations by using the B3LYP functional. PMID- 17715920 TI - Superconducting MgB2 nanohelices grown on various substrates. PMID- 17715919 TI - Characterization of protein conformational states by normal-mode frequencies. AB - Conformational change in polymers including proteins is central to many molecular processes. Defining conformational states, however, remains a difficult and increasingly common problem, with many existing methods based on arbitrary or potentially unrepresentative measures. Furthermore, the expanding length of molecular dynamics simulations and direct observation of transitions between different energy basins suggest that this issue will only become evermore important. Methods commonly used to characterize conformational states include principal component analysis, root-mean-square deviation-based clustering, and geometric measurements such as hinge angles and distances. Here we present a method where the eigenvector frequencies derived from a Gaussian network model (Bahar, I.; Atilgan, A. R.; Erman, B. Folding Des. 1997, 2, 173-181) of a trajectory of structures from a molecular dynamics simulation are used to describe the state of the protein at each time point. We apply the method to three proteins that share the same fold as the type II periplasmic binding proteins: The lysine-arginine-ornithine-binding protein, the glutamine-binding protein, and the ligand-binding domain from the NR1 N-methyl-D-aspartate receptor. We find that the method can distinguish different states in good agreement with a variety of previous analyses and additionally provides information on the dynamic properties of that system at a given time point. PMID- 17715921 TI - Trapping of a dopaquinone intermediate in the TPQ cofactor biogenesis in a copper containing amine oxidase from Arthrobacter globiformis. AB - The biogenesis of the topaquinone (TPQ) cofactor of copper amine oxidase (CAO) is self-catalyzed and requires copper and molecular oxygen. A dopaquinone intermediate has been proposed to undergo 1,4-addition of a copper-associated water molecule to form the reduced form of TPQ (TPQ(red)), followed by facile oxidation by O(2) to yield the mature TPQ (TPQ(ox)). In this study, we have incorporated a lysine residue in the active site of Arthrobacter globiformis CAO (AGAO) by site-directed mutagenesis to produce D298K-AGAO. The X-ray crystal structure of D298K-AGAO at 1.7-A resolution revealed that a covalent linkage formed between the epsilon-amino side chain of Lys298 and the C2 position of a dopaquinone derived from Tyr382, a precursor to TPQ(ox). We assigned the species as an iminoquinone tautomer (LTI) of lysine tyrosylquinone (LTQ), the organic cofactor of lysyl oxidase (LOX). The time course of the formation of LTI at pH 6.8 was followed by UV/vis and resonance Raman spectroscopies. In the early phase of the reaction, an LTQ-like intermediate was observed. This intermediate then slowly converted to LTI in an isosbestic manner. Not only is the presence of a dopaquinone intermediate in the TPQ biogenesis confirmed, but it also provides strong support for the proposed intermediacy of a dopaquinone in the biogenesis of LTQ in LOX. Further, this study indicates that the dopaquinone intermediate in AGAO is mobile and can swing from the copper site into the active-site wedge to react with Lys298. PMID- 17715923 TI - Origin of magic stability of thiolated gold clusters: a case study on Au25(SC6H13)18. PMID- 17715922 TI - Synthetic analogues of glycosylphosphatidylinositol-anchored proteins and their behavior in supported lipid bilayers. AB - Positioned at the C-terminus of many eukaryotic proteins, the glycosylphosphatidylinositol (GPI) anchor is a posttranslational modification that anchors the modified proteins in the outer leaflet of the plasma membrane. GPI-anchored proteins play vital roles in signal transduction, the vertebrate immune response, and the pathobiology of trypanosomal parasites. While many GPI anchored proteins have been characterized, the biological functions of the GPI anchor have yet to be elucidated at a molecular level. We synthesized a series of GPI-protein analogues bearing modified anchor structures that were designed to dissect the contribution of various glycan components to the GPI-protein's membrane behavior. These anchor analogues were similar in length to native GPI anchors and included mimics of the native structure's three domains. A combination of expressed protein ligation and native chemical ligation was used to attach these analogues to the green fluorescent protein (GFP). These modified GFPs were incorporated in supported lipid bilayers, and their mobilities were analyzed using fluorescence correlation spectroscopy. The data from these experiments suggest that the GPI anchor is more than a simple membrane-anchoring device; it also may prevent transient interactions between the attached protein and the underlying lipid bilayer, thereby permitting rapid diffusion in the bilayer. The ability to generate chemically defined analogues of GPI-anchored proteins is an important step toward elucidating the molecular functions of this interesting post-translational modification. PMID- 17715924 TI - Rapid three-step cleavage of RNA and DNA model systems promoted by a dinuclear Cu(II) complex in methanol. energetic origins of the catalytic efficacy. AB - A dinuclear Cu(II) complex of 1,3-bis-N(1)-(1,5,9-triazacyclododecyl)propane with an associated methoxide (2-Cu(II)(2):(-OCH(3))) was prepared, and its kinetics of reaction with an RNA model (2-hydroxypropyl-p-nitrophenyl phosphate (1, HPNPP)) and two DNA models (methyl p-nitrophenyl phosphate (3) and iso-butyl p chlorophenyl phosphate (4)) were studied in methanol solution at (s)(s)pH 7.2 +/- 0.2. X-ray diffraction structures of 2-Cu(II)(2):(-OH)(H(2)O)(CF(3)SO(3) )(3):0.5CH(3)CH(2)OCH(2)CH(3) and 2-Cu(II)(2):(-OH)((C(6)H(5)CH(2)O)(2)PO(2) )(CF(3)SO(3)-)2 show the mode of coordination of the bridging -OH and H(2)O between the two Cu(II) ions in the first complex and bridging -OH and phosphate groups in the second. The kinetic studies with 1 and 3 reveal some common preliminary steps prior to the chemical one of the catalyzed formation of p nitrophenol. With 3, and also with the far less reactive substrate (4), two relatively fast events are cleanly observed via stopped-flow kinetics. The first of these is interpreted as a binding step which is linearly dependent on [catalyst] while the second is a unimolecular step independent of [catalyst] proposed to be a rearrangement that forms a doubly Cu(II)-coordinated phosphate. The catalysis of the cleavage of 1 and 3 is very strong, the first-order rate constants for formation of p-nitrophenol from the complex being approximately 0.7 s(-1) and 2.4 x 10(-3) s(-1), respectively. With substrate 3, 2-Cu(II)(2):( OCH(3)) exhibits Michaelis-Mentin kinetics with a k(cat)/K(M) value of 30 M(-1) s(-1) which is 3.8 x 10(7)-fold greater than the methoxide promoted reaction of 3 (7.9 x 10(-7) M(-1) s(-1)). A free energy calculation indicates that the binding of 2-Cu(II)(2):(-OCH(3)) to the transition states for 1 and 3 cleavage stabilizes them by -21 and -24 kcal/mol, respectively, relative to that of the methoxide promoted reactions. The results are compared with a literature example where the cleavage of 1 in water is promoted by a dinuclear Zn(II) catalyst, and the energetic origins of the exalted catalysis of the 2-Cu(II)(2) and 2-Zn(II)(2) methanol systems are discussed. PMID- 17715925 TI - Rh-mediated polymerization of carbenes: mechanism and stereoregulation. AB - Ligand variation, kinetic investigations, and computational studies have been used to elucidate the mechanism of rhodium-catalyzed diazoalkane polymerization. Variations in the "N,O" donor part of the catalyst precursors (diene)Rh(I)(N,O) result in different activities but virtually identical molecular weights, indicating that this part of the precursor is lost on forming the active species. In contrast, variation of the diene has a major effect on the nature of the polymer produced, indicating that the diene remains bound during polymerization. Kinetic studies indicate that only a small fraction of the Rh (1-5%) is involved in polymerization catalysis; the linear relation between polymer yield and M(w) suggests that the chains terminate slowly and chain transfer is not observed (near living character). Oligomers and fumarate/maleate byproducts are most likely formed from other "active" species. Calculations support a chain propagation mechanism involving diazoalkane coordination at the carbon atom, N(2) elimination to form a carbene complex, and carbene migratory insertion into the growing alkyl chain. N(2) elimination is calculated to be the rate-limiting step. On the basis of a comparison of NMR data with those of known oligomer fragments, the stereochemistry of the new polymer is tentatively assigned as syndiotactic. The observed syndiospecificity is attributed to chain-end control on the rate of N(2) elimination from diastereomeric diazoalkane complexes and/or on the migratory insertion step itself. PMID- 17715927 TI - Reactions of hydrido(hydrosilylene)tungsten complexes with alpha,beta-unsaturated carbonyl compounds: selective formation of (eta3-siloxyallyl)tungsten complexes. PMID- 17715926 TI - Direct spectroscopic evidence for a high-spin Fe(IV) intermediate in tyrosine hydroxylase. PMID- 17715928 TI - Chiral counteranions in asymmetric transition-metal catalysis: highly enantioselective Pd/Bronsted acid-catalyzed direct alpha-allylation of aldehydes. PMID- 17715929 TI - Highly efficient and reusable supported pd catalysts for Suzuki-Miyaura reactions of aryl chlorides. AB - Syntheses of air- and moisture-stable heterogeneous (tert butylarylphosphino)polystyrene-supported Pd catalysts and their use for versatile Suzuki-Miyaura reactions of aryl chlorides and arylboronic acids under non anhydrous conditions are reported. The catalysts are easily recovered by filtration. They can be used many times (more than seven) without showing any loss of activity, and the amount of Pd leached is extremely low (<0.1%). PMID- 17715930 TI - First enantioselective organocatalytic conjugate addition of aldehydes to vinyl phosphonates. AB - Chiral amines catalyze the enantioselective conjugate addition of aldehydes to vinyl phosphonates in high yields and with enantioselectivities up to 97% ee. This novel process provides synthetically useful chiral gamma-geminal phosphonate aldehydes which can be easily converted in a few steps into chiral beta substituted vinyl phosphonates with conservation of the optical purity. PMID- 17715931 TI - Synthesis and ring expansions of functionalized spirocyclobutanones. AB - The first condensations between bis(trimethylsilyloxy)cyclobutene derivatives and functionalized orthoesters are reported. The resulting adducts are readily converted into spirocycloethers, which undergo a variety of -CH2- and -O- insertions with excellent regioselectivity. PMID- 17715932 TI - Synthesis of pentafluorosulfanylpyrazole and pentafluorosulfanyl-1,2,3-triazole and their derivatives as energetic materials by click chemistry. AB - 1-Pentafluorosulfanyl acetylene and its derivatives react with azide or diazomethane giving rise to an SF5-substituted 1,2,3-triazole or pyrazole. The SF5 group increases density remarkably and as a result enhances the detonation performance of the energetic materials relative to the CF3 group. PMID- 17715933 TI - Hydroxyl-directed nitrile oxide cycloaddition reactions with cyclic allylic alcohols. AB - Diastereoselective cycloaddition reactions between a nitrile oxide and cyclic allylic alcohols are reported. The products isolated are densely functionalized building blocks that are not otherwise easily accessed with existing methods and concepts previously established for the construction of acyclic polyketides. PMID- 17715934 TI - Palladium-catalyzed [3+2] cycloaddition of carbon dioxide and trimethylenemethane under mild conditions. AB - Carbon dioxide undergoes a Pd-catalyzed [3+2] cycloaddition with trimethylenemethane (TMM) under mild conditions (1 atm, 75 degrees C, 30 min) to produce a gamma-butyrolactone product in 63% yield, when the Pd-TMM complex is generated from 2-(acetoxymethyl)-3-(trimethylsilyl)propene. The reaction reported here is more rapid than the all-carbon [3+2] cycloaddition, and only the gamma butyrolactone is produced in a competition experiment. With substituted substrates, the reaction is completely regioselective, producing the product derived from the kinetic Pd-TMM complex. PMID- 17715935 TI - Analyzing sulfur amino acids in selected feedstuffs using least-squares nonlinear regression. AB - Five feedstuffs were oxidized using performic acid, and these, along with their unoxidized counterparts, were acid hydrolyzed for multiple times (0-144 h) in degassed and vacuum-sealed glass tubes. The methionine sulfone, cysteic acid, methionine, and cysteine contents were determined for each hydrolysis time. Least squares nonlinear regression of the sulfur amino acid contents and hydrolysis time was used to predict the actual sulfur amino acid content as well as the hydrolysis and loss rates. Least-squares nonlinear regression estimates for methionine content compared well with those of methionine sulfone for most of the feedstuffs tested. In contrast, the estimates for cysteine agreed poorly with cysteic acid. The loss rates during acid hydrolysis for methionine, methionine sulfone, and cysteic acid were low. Overall, acid hydrolysis in an evacuated sealed tube for 24 h without prior oxidation is suitable for methionine, but not cysteine, quantitation in some complex feedstuffs. PMID- 17715936 TI - Optimal fed batch experiment design for estimation of monod kinetics of Azospirillum brasilense: from theory to practice. AB - In this paper the problem of reliable and accurate parameter estimation for unstructured models is considered. It is illustrated how a theoretically optimal design can be successfully translated into a practically feasible, robust, and informative experiment. The well-known parameter estimation problem of Monod kinetic parameters is used as a vehicle to illustrate our approach. As known for a long time, noisy batch measurements do not allow for unique and accurate estimation of the kinetic parameters of the Monod model. Techniques of optimal experiment design are, therefore, exploited to design informative experiments and to improve the parameter estimation accuracy. During the design process, practical feasibility has to be kept in mind. The designed experiments are easy to implement in practice and do not require additional monitoring equipment. Both design and experimental validation of informative fed batch experiments are illustrated with a case study, namely, the growth of the nitrogen-fixing bacteria Azospirillum brasilense. PMID- 17715937 TI - Determining antibody stability: creation of solid-liquid interfacial effects within a high shear environment. AB - The purpose of this study was to assess the stability of protein formulations using a device designed to generate defined, quantifiable levels of shear in the presence of a solid-liquid interface. The device, based on a rotating disk, produced shear strain rates of up to 3.4 x 10(4) s(-1) (at 250 rps) and was designed to exclude air-liquid interfaces and enable temperature to be controlled. Computational fluid dynamics (CFD) was used to study the fluid flow patterns within the device and to determine the shear strain rate (s(-1)) at a range of disk speeds. The device was then used to study the effect on a monoclonal IgG4 of high levels of shear at the solid-liquid interface. Monomeric antibody concentration and aggregation of the protein in solution were monitored by gel permeation HPLC and turbidity at 350 nm. High shear strain rates were found to cause significant levels of protein aggregation and precipitation with reduction of protein monomer following first-order kinetics. Monomer reduction rate was determined for a range of disk speeds and found to have a nonlinear relationship with shear strain rate, indicating the importance of identifying and minimizing such environments during processing. PMID- 17715938 TI - A simple visualization technique to understand the system dynamics in bioreactors. AB - In this article, we present a graph theoretic method to visualize and analyze the system behavior under different operating conditions. The system attributes (or variables) are the nodes in the graphs, and partial correlation between a pair of attributes defines the distance between corresponding nodes, resulting in a fully connected graph. Then, the redundant links are reduced using Pathfinder Network Scaling technique to uncover the latent network structure. We use a simulated biological reactor dataset in normal and faulty operation to validate our method. The method is general and can be used to analyze several different systems. PMID- 17715939 TI - Characterization of an ethanol-inducible promoter system in Catharanthus roseus hairy roots. AB - Efforts to engineer Catharanthus roseus hairy roots to produce commercially significant amounts of valuable compounds, such as the terpenoid indole alkaloids vinblastine and vincristine, require the development of tools to study the effects of overexpressing key metabolic and regulatory genes. The use of inducible promoters allows researchers to control the timing and level of expression of genes of interest. In addition, use of inducible promoters allows researchers to use a single transgenic line as both the control and experimental line, minimizing the problems associated with clonal variation. We have previously characterized the use of a glucocorticoid-inducible promoter system to study the effects of gene overexpression within the terpenoid indole alkaloid pathway on metabolite production. Here the feasibility of using an ethanol inducible promoter within C. roseus hairy roots is reported. This ethanol inducible promoter is highly sensitive to ethanol concentration with a concentration of 0.005% ethanol causing a 6-fold increase in CAT reporter activity after 24 h of induction. The ethanol-inducible CAT activity increased 24 fold over a 72-h induction period with 0.5% ethanol. PMID- 17715940 TI - Use of a derivative of Escherichia coli BL21(DE3) for efficient production of three different recombinant proteins. AB - Plasmid instability and growth inhibition of plasmid-bearing cells after induction were encountered when E. coli BL21(DE3) was used as host for the production of antihuman ovarian carcinoma x antihuman CD3 single-chain bispecific antibody (AhOC x AhCD3), human soluble B lymphocyte stimulator fused with thioredoxin (Trx-hsBLyS) and human parathyroid hormone fused with thioredoxin (Trx-hPTH). A derivative of BL21(DE3), namely, BLRM(DE3), isolated and showing superiority in AhOC x AhCD3 production in our previous work, was further used here for more efficient production of these three different recombinant proteins. By using BLRM(DE3) as host, the simplified one-stage fermentation process was developed, which was more labor-saving and yielded AhOC x AhCD3, comparable to that of the traditional two-stage fermentation process. Also, the plasmid stabilities and production yields of Trx-hsBLyS and Trx-hPTH were dramatically improved by the application of BLRM(DE3) instead of BL21(DE3). A high Trx-hsBLyS yield (about 3.5 g/L) was obtained, which was more than twice as much as that of the recombinant BL21(DE3) strain. The Trx-hPTH yield was improved from about 700 mg/L to 1 g/L. These results further showed the superiority of BLRM(DE3) to BL21(DE3) and suggested its effectiveness for other BL21(DE3)/pET heterologous protein expression systems, which encounter similar problems. PMID- 17715941 TI - Scaleable production of adenoviral vectors by transfection of adherent PER.C6 cells. AB - Recombinant adenoviruses are efficient gene delivery vectors that are being evaluated in many gene therapy and vaccine applications. Methods for rapid production of ca. 10(12)-10(13) virus particles (VPs) are desired to enable rapid initial evaluation of such vectors. For this purpose, a scalable transfection procedure was developed for production of an adenovirus type 5 vector expressing HIV-1 gag gene (MRKAd5gag). Adherent PER.C6 cells were transfected by calcium phosphate coprecipitation of the linearized, 36 kb adenovirus plasmid in disposable culture vessels. Various process variables including precipitate formation time, DNA concentration, and harvest time were investigated to rapidly achieve desired virus yields using an adenovirus plasmid encoding the green fluorescent protein (pAd5gfp). Using an optimized procedure, consistent production of >5 x 10(10) VPs per 1-tray Nunc cell factory (NCF) with a ratio of infectious units to virus particles of >1:10 was obtained for the MRKAd5gag vector. This scaleable process can be used to produce adenoviral vectors using several 1-tray NCFs or a single multiple-tray NCF within 1 month from the time of plasmid construction. PMID- 17715942 TI - Comparison of different strategies to reduce acetate formation in Escherichia coli. AB - E. coli cells produce acetate as an extracellular coproduct of aerobic cultures. Acetate is undesirable because it retards growth and inhibits protein formation. Most process designs or genetic modifications to minimize acetate formation aim at balancing growth rate and oxygen consumption. In this research, three genetic approaches to reduce acetate formation were investigated: (1) direct reduction of the carbon flow to acetate (ackA-pta, poxB knock-out); (2) anticipation on the underlying metabolic and regulatory mechanisms that lead to acetate (constitutive ppc expression mutant); and (3) both (1) and (2). Initially, these mutants were compared to the wild-type E. coli via batch cultures under aerobic conditions. Subsequently, these mutants were further characterized using metabolic flux analysis on continuous cultures. It is concluded that a combination of directly reducing the carbon flow to acetate and anticipating on the underlying metabolic and regulatory mechanism that lead to acetate, is the most promising approach to overcome acetate formation and improve recombinant protein production. These genetic modifications have no significant influence on the metabolism when growing the micro-organisms under steady state at relatively low dilution rates (less than 0.4 h(-1)). PMID- 17715943 TI - Interaction of beta2-glycoprotein 1 with phosphatidylserine-containing membranes: ligand-dependent conformational alterations initiate bivalent binding. AB - Beta2-glycoprotein 1 (beta2GP1), a 50 kDa serum glycoprotein that binds anionic phospholipid-containing membranes, plays a regulatory role in physiology and pathology. The protein is a member of the short consensus repeat (SCR) superfamily containing four typical repeating domains and an aberrant fifth domain constructed into an SCR-like core at the C-terminus. To investigate the contribution of the individual domains to the binding of beta2GP1, a series of sequential domain-deleted recombinant protein fragments were generated and assessed for their interaction with PS-containing vesicles. Spectral analyses of lipid binding-dependent alterations in tryptophan emission spectra revealed that the (single) tryptophan residues of the individual domains underwent binding dependent conformational alterations. Depending on the ionic strength, some domains moved from polar to nonpolar environments, while others moved from less polar to more polar environments. Analysis of a series of acrylamide quenching and resonance energy transfer experiments indicated that the binding of N terminal domain 1 to PS membranes exists in two, ionic strength-dependent, conformations. At low ionic strengths, domain 1 bound to the vesicles and induced their precipitation and/or aggregation. At physiologic ionic strengths, domain 1 detached from the membrane surface while the remaining domains maintained their association with the membrane. Under these conditions, membrane-bound conformationally altered domain 1 projects away from the membrane surface, enabling it to interact with other proteins and/or cell surface ligands or receptors. PMID- 17715944 TI - Amyloid protofibril is highly voluminous and compressible. AB - We report here results of the first direct measurement of partial volume and compressibility changes of a protein as it forms an amyloid protofibril. We use a high precision density meter and an ultrasonic velocity meter on a solution of intrinsically denatured, disulfide-deficient variant of hen lysozyme, and follow the time-dependent changes in volume and compressibility, as the protein spontaneously forms a protofibril. We have found a large increase in partial specific volume with time from 0.684 to 0.724 mL x g-1 (Deltanu = 0.040 mL x g-1 corresponding to 570 mL x (mol monomer)-1) and in partial specific adiabatic compressibility coefficient from -7.48 x 10(-12) to +1.35 x 10(-12) cm2 x dyn-1 (Deltabetas = 8.83 x 10(-12) x cm2 x dyn-1) as the monomer transforms into a protofibril. The results demonstrate that the protofibril is a highly voluminous and compressible entity, disclosing a cavity-rich, fluctuating nature for the amyloid protofibril. The volume and compressibility changes occur in two phases, the faster one preceding the major development of the beta-structure in the protofibril as monitored by CD. PMID- 17715945 TI - A monomeric, biologically active, full-length human apolipoprotein E. AB - Apolipoprotein E (apoE) is an exchangeable apolipoprotein that plays an important role in lipid/lipoprotein metabolism and cardiovascular diseases. Recent evidence indicates that apoE is also critical in several other important biological processes, including Alzheimer's disease, cognitive function, immunoregulation, cell signaling, and infectious diseases. Although the X-ray crystal structure of the apoE N-terminal domain was solved in 1991, the structural study of full length apoE is hindered by apoE's oligomerization property. Using protein engineering techniques, we generated a monomeric, biologically active, full length apoE. Cross-linking experiments indicate that this mutant is nearly 95 100% monomeric even at 20 mg/mL. CD spectroscopy and guanidine hydrochloride denaturation demonstrate that the structure and stability of the monomeric mutant are identical to wild-type apoE. Monomeric and wild-type apoE display similar lipid-binding activities in dimyristoylphosphatidylcholine clearance assays and formation of reconstituted high-density lipoproteins. Furthermore, the monomeric and wild-type apoE proteins display an identical LDL receptor binding activity. Availability of this monomeric, biologically active, full-length apoE allows us to collect high quality NMR data for structural determination. Our initial NMR data of lipid-free apoE demonstrates that the N-terminal domain in the full length apoE adopts a nearly identical structure as the isolated N-terminal domain, whereas the C-terminal domain appears to become more structured than the isolated C-terminal domain fragment, suggesting a weak domain-domain interaction. This interaction is confirmed by NMR examination of a segmental labeled apoE, in which the N-terminal domain is deuterated and the C-terminal domain is double labeled. NMR titration experiments further suggest that the hinge region (residues 192-215) that connects apoE's N- and C-terminal domains may play an important role in mediating this domain-domain interaction. PMID- 17715946 TI - Structural basis for the role of Asp-120 in metallo-beta-lactamases. AB - Metallo-beta-lactamases (mbetals) are zinc-dependent enzymes that hydrolyze a wide range of beta-lactam antibiotics. The mbetal active site features an invariant Asp-120 that ligates one of the two metal ions (Zn2) and a metal bridging water/hydroxide (Wat1). Previous studies show that substitutions at Asp 120 dramatically affect mbetal activity, but no consensus exists as to its role in beta-lactam turnover. Here we present crystal structures of the Asn and Cys mutants of Asp-120 of the L1 mbetal from Stenotrophomonas maltophilia. Both mutants retain a dinuclear zinc center with Wat1 present. In the essentially inactive Cys enzyme Zn2 is displaced to a more buried position relative to that in the wild-type enzyme. In the catalytically impaired Asn enzyme the coordination of Zn2 is altered, neither it nor Wat1 is coordinated by Asn-120, and the N-terminal 19 amino acids, important to cooperative interactions between subunits in the wild-type enzyme, are disordered. Comparison with the structure of L1 complexed with the hydrolyzed oxacephem moxalactam suggests that in the Cys mutant Zn2 can no longer make stabilizing interactions with anionic nitrogen species formed in the hydrolytic reaction. The diminished activity of the Asn mutant arises from a combination of loss of intersubunit interactions and impaired proton transfer to, and reduced interaction of Zn2 with, the substrate amide nitrogen. We conclude that, while interactions of Asp-120 with active site water molecules are important to proton transfer and possibly nucleophilic attack by Wat1, its primary role is to optimally position Zn2 for catalytically important interactions with the charged amide nitrogen of substrate. PMID- 17715947 TI - The N-terminal module of HPV16 E7 is an intrinsically disordered domain that confers conformational and recognition plasticity to the oncoprotein. AB - The HPV16 E7 oncoprotein is an extended dimer, with a stable and cooperative fold, but that displays properties of "natively unfolded" proteins. Two regions of conserved sequence are found in E7 proteins, where the N-terminus (1-40) includes the retinoblastoma tumor suppressor binding and casein kinase II phosphorylation sites. A fragment containing the highly acidic N-terminal half shows an apparently disordered conformation by far-UV-circular dichroism (CD) at neutral pH, and its hydrodynamic radius is much larger than a neutral peptide of the same length. Trifluoroethanol and micellar concentrations of sodium dodecyl sulfate stabilize a much more helical structure at pH 4.0 than at pH 7.5, while submicellar concentrations of the detergent yield a beta-strand. The shape, pH, and temperature dependence of the CD spectrum at pH 7.5 are indicative of a poly proline type II structure. This structure is stabilized by phosphorylation, which would translate into increased transforming activity in the cell. Thus, the intrinsically disordered properties of the N-terminal module of E7 are responsible for the structural plasticity of the oncoprotein. Although the domain is not a compact and cooperatively folded unit, it is a bona fide functional domain, evolved to maintain a dynamic but extended structure in the cell. These properties allow adaptation to a variety of protein targets and expose the PEST degradation sequence that regulates its turnover in the cell, a modification of which leads to the accumulation of E7 species with consequences in the transformation process. PMID- 17715948 TI - Elucidation of the chemistry of enzyme-bound thiamin diphosphate prior to substrate binding: defining internal equilibria among tautomeric and ionization states. AB - Both solution and crystallographic studies suggest that the 4'-aminopyrimidine ring of the thiamin diphosphate coenzyme participates in catalysis, likely as an intramolecular general acid-base catalyst via the unusual 1',4'-iminopyrimidine tautomer. It is indeed uncommon for a coenzyme to be identified in its rare tautomeric form on its reaction pathways, yet this has been possible with thiamin diphosphate, in some cases even in the absence of substrate [Nemeria, N., Chakraborty, S., Baykal, A., Korotchkina, L., Patel, M. S., and Jordan, F. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 78-82.]. The ability to detect both the aminopyrimidine and iminopyrimidine tautomeric forms of thiamin diphosphate on enzymes has enabled us to assign the predominant tautomeric form present in individual intermediates on the pathway. Herein, we report the pH dependence of these tautomeric forms providing the first data for the internal thermodynamic equilibria on thiamin diphosphate enzymes for the various ionization and tautomeric forms of this coenzyme on four enzymes: benzaldehyde lyase, benzoylformate decarboxylase, pyruvate oxidase, and the E1 component of the human pyruvate dehydrogenase multienzyme complex. Evidence is provided for an important function of the enzyme environment in altering both the ionization and tautomeric equilibria on the coenzyme even prior to addition of substrate. The pKa for the 4'-aminopyrimidinium moiety coincides with the pH for optimum activity thereby ensuring that all ionization states and tautomeric states are accessible during the catalytic cycle. The dramatic influence of the protein on the internal equilibria also points to conditions under which the long-elusive ylide intermediate could be stabilized. PMID- 17715949 TI - Preparation and thermally promoted ripening of water-soluble gold nanoparticles stabilized by weakly physisorbed ligands. AB - Here, we report on a facile method for the preparation of an aqueous dispersion of 3.6 nm gold nanoparticles electrostatically stabilized by a weakly physisorbed ligand, namely, 4-(dimethylamino)pyridine (DMAP). The nature and extent of the interaction of this ligand with the surface of a gold nanoparticle has been examined. We also report on the thermally promoted ripening of these nanoparticles under mild conditions to yield a dispersion of 11.3 nm gold nanoparticles. The role of the weakly physisorbed DMAP ligand in facilitating thermally promoted ripening under mild conditions has also been examined. PMID- 17715950 TI - The effect of local defects on water adsorption in silicalite-1 zeolite: a joint experimental and molecular simulation study. AB - We report a joint experimental and molecular simulation study of water condensation in silicalite-1 zeolite. A sample was synthesized using the fluoride route and was found to contain essentially no defects. A second sample synthesized using the hydroxide route was found to contain a small amount of silanol groups. The thermodynamics of water condensation was studied in these two samples, as well as in a commercial sample, in order to understand the effect of local defects on water adsorption. The molecular simulation study enabled us to qualitatively reproduce the experimentally observed condensation thermodynamics features. A shift and a rounding of the condensation transition was observed with an increasing hydrophilicity of the local defect, but the condensation transition was still observed above the water saturation vapor pressure P0. Both experiments and simulations agree on the fact that a small water uptake can be observed at very low pressure, but that the bulk liquid does not form from the gas phase below P0. The picture that emerges from the observed water condensation mechanism is the existence of a heterogeneous internal surface that is overall hydrophobic, despite the existence of hydrophilic "patches". This heterogeneous surface configuration is thermodynamically stable in a wide range of reduced pressures (from P/P0 = 0.2 to a few thousands), until the condensation transition takes place. PMID- 17715951 TI - Dense passivating poly(ethylene glycol) films on indium tin oxide substrates. AB - We describe the formation and characterization of surface-passivating poly(ethylene glycol) (PEG) films on indium tin oxide (ITO) glass substrates. PEG chains with a molecular weight of 2000 and 5000 D were covalently attached to the substrates in a systematic approach using different coupling schemes. The coupling strategies included the direct grafting with PEG-silane, PEG methacrylate, and PEG-bis(amine), as well as the two-step functionalization with aldehyde-bearing silane films and subsequent coupling with PEG-bis(amine). Elemental analysis by X-ray photoelectron spectroscopy (XPS) confirmed the successful surface modification, and XPS and ellipsometry provided values for film thicknesses. XPS and ellipsometry thickness values were almost identical for PEG-silane films but differed by up to 400% for the other PEG layers, suggesting a homogeneous layer for PEG-silane but an inhomogeneous distribution for other PEG coatings on the molecularly rough ITO substrates. Atomic force microscopy (AFM) and water contact angle goniometry confirmed the different degrees of surface homogeneity of the polymer films, with PEG-silane reducing the AFM rms surface roughness by 50% and the water contact angle hysteresis by 75% compared to uncoated ITO. The ability of the PEG layers to passivate the substrate against the nonspecific adsorption of biopolymers was tested using fluorescence-labeled immunoglobulin G and DNA oligonucleotides in combination with fluorescence microscopy. The results indicate a positive relationship between film density and homogeneity on one hand and the ability to passivate against biopolymer adhesion on the other hand. The most homogeneous layers prepared with PEG-silane reduced the nonspecific adsorption of fluorescence-labeled DNA by a factor of 300 compared to uncoated ITO. In addition, the study finds that the ratio of film thicknesses derived by ellipsometry and XPS is a useful parameter to quantify the structural integrity of PEG layers on molecularly rough ITO surfaces. The findings may be applied to characterize PEG or other polymeric films on similarly coarse substrates. PMID- 17715952 TI - Factors affecting the synthesis of polymeric nanostructures from template assisted admicellar polymerization. AB - Template assisted admicellar polymerization (TAAP) utilizes a surfactant layer adsorbed on a surface to localize a monomer to the surface prior to polymerization of the monomer. Nanostructures are formed by restricting adsorption to the uncovered sites of an already-templated surface, in this case, to the interstitial sites between adsorbed latex spheres. This work studies the factors affecting the synthesis of polymeric nanostructures from TAAP for three different monomers, aniline, pyrrole, and methyl methacrylate, and three different surfaces, highly ordered pyrolytic graphite (HOPG), gold, and SiO2. Among the parameters discussed are the effects of monomer and surfactant concentration, surfactant chain length, polymerization time and temperature, and solution ionic strength. Control of the aforementioned parameters allows some control over the nanostructure morphology. Polymer nanopillars, nanorings, honeycombs, and "honeytubes" have been synthesized. Important conclusions regarding the conditions favoring admicellar polymerization relative to polymerization in solution are drawn from the experimental results as well. Sample characterization includes scanning electron microscopy (SEM), Raman spectroscopy, and alternating current (ac) impedance measurements. PMID- 17715954 TI - Aggregate formation in aqueous solutions of carboxymethylcellulose and cationic surfactants. AB - The addition of cationic surfactants to an aqueous solution of an anionic polymer, carboxymethylcellulose (carboxyMC), causes the spontaneous formation of aggregates in a certain range of concentrations. Here we studied two surfactants, dodecyl and hexadecyl trimethylammonium bromide (DTAB and CTAB, respectively). Using different techniques (light scattering, potentiometry, viscosimetry, and zetametry), we found that a simple lengthening of the surfactant tail length by four CH2 groups drastically changes the aggregate morphology, size, and charge. We explored in detail how the surfactant and polymer concentrations act on these systems. PMID- 17715953 TI - Phase separation and fractal domain formation in phospholipid/diacetylene supported lipid bilayers. AB - Phase separation in lipid bilayers is a phenomenon dependent on many environmental parameters such as pH, temperature, ionic strength, and pressure. Its importance in biological systems is reflected by the fact that it has been implicated in the spatial reorganization of plasma membranes, which leads to signaling and stimulation. Here, we present the study of phase separation, domain formation, and domain morphology of supported lipid bilayers composed of mixtures of diacetylene lipids and phospholipids. We have used high-resolution fluorescence and atomic force microscopy to characterize the phase separation between these lipids, and have found that at temperatures below 40 degrees C diacetylene molecules form fractal-like domains. These molecules aggregate in tetralayer stacks with an average monolayer thickness of 3 nm. Boundary and area fractal dimensions were calculated to quantify the domain growth and morphology. A transition from dendritic to dense branching growth was observed as the relative diacetylene concentration was increased. The ability to tailor the growth pattern by changing the relative amount of diacetylene molecules makes this a useful model system for the study of nonequilibrium growth phenomena. In addition, we have explored the possibility of promoting diacetylene domain nucleation through the use of nanostructured surfaces. We found that nanoscale perturbations acted as nucleation sites and modified the growth pattern of diacetylene domains. Phase separation induced by nanometer-scale perturbations could prove useful in selectively positioning lipid patches with specific compositions. PMID- 17715955 TI - Physical vapor deposition of one-dimensional nanoparticle arrays on graphite: seeding the electrodeposition of gold nanowires. AB - One-dimensional (1D) ensembles of 2-15 nm diameter gold nanoparticles were prepared using physical vapor deposition (PVD) on highly oriented pyrolytic graphite (HOPG) basal plane surfaces. These 1D Au nanoparticle ensembles (NPEs) were prepared by depositing gold (0.2-0.6 nm/s) at an equivalent thickness of 3-4 nm onto HOPG surfaces at 670-690 K. Under these conditions, vapor-deposited gold nucleated selectively at the linear step edge defects present on these HOPG surfaces with virtually no nucleation of gold particles on terraces. The number density of 2-15 nm diameter gold particles at step edges was 30-40 microm-1. These 1D NPEs were up to a millimeter in length and organized into parallel arrays on the HOPG surface, following the organization of step edges. Surprisingly, the deposition of more gold by PVD did not lead to the formation of continuous gold nanowires at step edges under the range of sample temperature or deposition flux we have investigated. Instead, these 1D Au NPEs were used as nucleation templates for the preparation by electrodeposition of gold nanowires. The electrodeposition of gold occurred selectively on PVD gold nanoparticles over the potential range from 700-640 mV vs SCE, and after optimization of the electrodeposition parameters continuous gold nanowires as small as 80-90 nm in diameter and several micrometers in length were obtained. PMID- 17715956 TI - Multiple mechanical relaxations in ethylcyclohexane above the glass transition temperature. AB - The mechanical response of ethylcyclohexane has been investigated at ultrasonic frequencies in a large temperature range from 300 K down to the glass transition region. The results indicate the existence of a secondary relaxation not yet reported for this system. The comparison with literature data leads to a rather complex dynamic behavior. In fact, this molecular liquid exhibits three different mechanical relaxations above the glass transition temperature: a main structural process and two additional processes, both having a possible intramolecular origin. PMID- 17715957 TI - Gas-phase formation of radical cations of monomers and dimers of guanosine by collision-induced dissociation of Cu(II)-guanosine complexes. AB - An electrosprayed water/methanol solution of guanosine and Cu(NO3)2 was observed to give rise to gas-phase copper complexed ions of [CuLn]*2+, [CuL(MeOH)n]*2+, and [CuG n(NO3)]*+, as well as the ions [L]*+, [L+H]+, [G]*+, and [G+H]+ (L=guanosine, G=guanine). The Collision-Induced Dissociation (CID) of [CuL3]*2+ and [CuL(MeOH)n]*2+ (n=2, 3) generates guanosine radical cations [L]*+, while dimeric guanosine radical cations [L2]*+ are generated in the dissociation of [CuL4]*2+. Protonated guanosine [L+H]+ is one of the main products in the primary dissociation of [CuL2]*2+, while the dissociation of the higher-order [CuG2]*2+ produces the [G]*+ radical cation. The guanosine dimer radical cation, [L2]*+ presumably arises from the interaction of two guanosine molecules via proton and hydrogen bonding and is observed to dissociate into [L+H]+ and [L-H]* at low energies. We propose that the first two ligands bind strongly with Cu(II) through N7 and O6 to form a [CuL2]*2+ complex with a four-coordinated planar structure and that a third ligand binds loosely with copper to form [CuL3]*2+. Additional ligation observed in the formation of [CuLn]*2+ (n1 microm) that have not invoked suitable cellular responses to promote adequate osteointegration to enable these devices to be successful for long periods. By contrast, owing to their ability to mimic the dimensions of constituent components of natural bone (e.g., proteins and hydroxyapatite), nanophase materials may be an exciting successful alternative orthopedic implant material. In this article, the ability of novel nanomaterials that promote osteointegration is discussed. Potential pitfalls or undesirable side effects associated with the use of nanomaterials in orthopedic applications are also reviewed. PMID- 17716107 TI - Biomimetic nanocomposites for bone graft applications. AB - Allograft bone, dematerialized bone matrix and calcium-based synthetic materials have long been used as bone graft substitutes. First-generation bone graft substitutes as stand-alone graft substitutes have not developed as hoped. It remains a great challenge to design an ideal bone graft that emulates nature's own structures or functions. To further improve the performance of such bone graft substitutes, scientists are investigating biomimetic processes to incorporate the desirable nano-features into the next generation of biomaterials. In this regard, nanostructured biomaterials less than 100 nm in at least one dimension, in particular nanocomposites, are perceived to be beneficial and potentially ideal for bone applications, owing to their nanoscale functional characteristics that facilitate bone cell growth and subsequent tissue formation. In fact, bone itself is a nanocomposite system with a complex hierarchical structure. This review reports the impact of biomimetically derived nanocomposite biomaterials for use in bone applications and provides possible suggestions for future research and development. PMID- 17716108 TI - Biomimetic self-assembling peptides as injectable scaffolds for hard tissue engineering. AB - The production of bone-, dentine- and enamel-like biomaterials for the engineering of mineralized (hard) tissues is a high-priority in regenerative medicine and dentistry. An emerging treatment approach involves the use of short biomimetic peptides that self-assemble to form micrometer-long nanofibrils with well defined surface chemistry and periodicity that display specific arrays of functional groups capable of mineral nucleation. The fibrils also give rise to dynamically stable 3D scaffold gels for the potential control of crystal disposition and growth. Peptides can also be injected in their monomeric fluid state, with subsequent self-assembly and gelation in situ triggered by physiological conditions. In this way, they can infiltrate and self-assemble within irregular or microscopic cavities, for restorative treatment of bone defects, dentinal hypersensitivity or dental decay. Cell adhesion and proliferation is also supported by these scaffolds, offering further advantages for applications in hard tissue engineering. These self-assembling matrices also provide well defined model systems that can contribute greatly to the elucidation of the biological mechanisms of protein-mediated biomineralization. PMID- 17716109 TI - Biomedical applications of plasmon resonant metal nanoparticles. AB - The strong optical absorption and scattering of noble metal nanoparticles is due to an effect called localized surface plasmon resonance, which enables the development of novel biomedical applications. The resonant extinction, which can be tuned to the near-infrared, allows the nanoparticles to act as molecular contrast agents in a spectral region where tissue is relatively transparent. The localized heating due to resonant absorption, also tunable into the near infrared, enables new thermal ablation therapies and drug delivery mechanisms. The sensitivity of these resonances to their environment leads to simple affinity sensors for the detection of low-level molecular analytes. Coupled with their general lack of toxicity, these applications suggest that noble metal nanoparticles are a highly promising class of nanomaterials for new biomedical applications. PMID- 17716110 TI - Quantum dots and multifunctional nanoparticles: new contrast agents for tumor imaging. AB - Nanometer-sized particles, such as semiconductor quantum dots and iron oxide nanocrystals, have novel optical, electronic, magnetic or structural properties that are not available from either molecules or bulk solids. When linked with tumor-targeting ligands, such as monoclonal antibodies, peptide fragments of tumor-specific proteins or small molecules, these nanoparticles can be used to target tumor antigens (biomarkers) and tumor vasculatures with high affinity and specificity. In the mesoscopic size range of 5-100 nm diameter, quantum dots and related nanoparticles have large surface areas and functional groups that can be linked to multiple diagnostic (e.g., optical, radioisotopic or magnetic) and therapeutic (e.g., anticancer) agents. In this review, recent advances in the development and applications of bioconjugated quantum dots and multifunctional nanoparticles for in vivo tumor imaging and targeting are discussed. PMID- 17716111 TI - Localized surface plasmon resonance biosensors. AB - In this review, the most recent progress in the development of noble metal nano optical sensors based on localized surface plasmon resonance (LSPR) spectroscopy is summarized. The sensing principle relies on the LSPR spectral shifts caused by the surrounding dielectric environmental change in a binding event. Nanosphere lithography, an inexpensive and simple nanofabrication technique, has been used to fabricate the nanoparticles as the LSPR sensing platforms. As an example of the biosensing applications, the LSPR detection for a biomarker of Alzheimer's disease, amyloid-derived diffusable ligands, in human brain extract and cerebrospinal fluid samples is highlighted. Furthermore, the LSPR sensing method can be modified easily and used in a variety of applications. More specifically, a LSPR chip capable of multiplex sensing, a combined electrochemical and LSPR protocol and a fabrication method of solution-phase nanotriangles are presented here. PMID- 17716112 TI - Resolving the nanoparticles paradox. AB - There is a paradox in that some types of nanoparticles (a generic term for particles less than approximately 100 nm in diameter) are used in nanomedicine for imaging and therapy, whereas other types of nanoparticles produced by combustion are thought by many scientists to be responsible for the adverse health effects of air pollution. In addition, the nanotechnology industry is in the process of producing new nanoparticles whose hazard and potential for human exposure are not yet determined. Medicinal nanoparticles are being designed and tested on a case-by-case basis using testing procedures derived from biomaterials and drug safety and with due regard to risk-benefit. There are considerable differences in physical and chemical properties between medicinal nanoparticles and the industrial and combustion-derived nanoparticles studied by particle toxicologists, a recognized branch of toxicology that studies particles. Medical nanoparticles tend to be composed of materials that are similar to biological molecules and they are generally biodegradable. By contrast, combustion-derived nanoparticles are carbon-centered and contaminated with metals and organics, with a biopersistent core. To fully address the paradox that nanoparticles can be both beneficial and harmful, there is a need, over the next 10 years, to advance our understanding of the characteristics that determine acute and chronic toxicity, translocation, biodegradation and elimination of all types of nanoparticles likely to gain access to the human body. PMID- 17716113 TI - Nanoparticles in drug delivery and environmental exposure: same size, same risks? AB - Engineered nanoparticles are an important tool for future nanomedicines to deliver and target drugs or bring imaging agents to the targets where they are required. Since the original application of liposomes in the 1970s, a wealth of carrier and imaging systems has been developed, including magnetoliposomes, dendrimers, fullerenes and polymer carriers. However, to make use of this potential, toxicological issues must be addressed, in particular because of findings on combustion-derived nanoparticles in environmentally exposed populations, which show effects in those with respiratory or cardiovascular diseases. These effects are mediated by oxidative stress, lung and systemic inflammation and different mechanisms of internalization and translocation. Many effects found with combustion-derived nanoparticles have now tested positive with engineered nanoparticles, such as single-wall nanotubes. This article aims to identify common concepts in the action of nanoparticles in order to enable future cross-talk and mutual use of concepts. PMID- 17716114 TI - Medipol: the guardian angel of biologics. AB - Medipol Ltd is a solution provider to the pharma, medtech and biotech industry. It helps these companies to improve their management of the lifecycle of biotechnological drugs and maintain market leadership through the protection and delivery of biologics in medical applications. The company was incorporated in May 2003 in Lausanne, Switzerland. Medipol's management and researchers are credited with decades of experience in the application of biopolymers and are authors of more than 30 patents in the field. Medipol's current focus is rheumatoid arthritis and the delivery of biopharmaceuticals. The company has been rewarded for its pioneering technology by the Foundation for Innovation and Technology, the IMD business school, the Swiss Commission for Innovation and Technology and Venture Leaders 2006. PMID- 17716115 TI - Strategies for developing and commercializing nanobio drugs, diagnostics and devices. PMID- 17716116 TI - Regulatory issues surrounding nanomedicines: setting the scene for the next generation of nanopharmaceuticals. PMID- 17716117 TI - Fighting cancer: the potential of quantum dots and rods. PMID- 17716118 TI - Targeted delivery of multifunctional magnetic nanoparticles. AB - Magnetic nanoparticles and their magnetofluorescent analogues have become important tools for in vivo imaging using magnetic resonance imaging and fluorescent optical methods. A number of monodisperse magnetic nanoparticle preparations have been developed over the last decade for angiogenesis imaging, cancer staging, tracking of immune cells (monocyte/macrophage, T cells) and for molecular and cellular targeting. Phage display and data mining have enabled the procurement of novel tissue- or receptor-specific peptides, while high-throughput screening of diversity-oriented synthesis libraries has identified small molecules that permit or prevent uptake by specific cell types. Next-generation magnetic nanoparticles are expected to be truly multifunctional, incorporating therapeutic functionalities and further enhancing an already diverse repertoire of capabilities. PMID- 17716119 TI - Synthetic delivery systems for intravenous administration of nucleic acids. AB - At present, there are no intravenously administered nucleic acid-based therapeutics that have been approved for human use. This reflects the difficulties in applying nucleic acid-based drugs: they are nuclease sensitive and have difficulties in reaching their site of action. Important challenges for intravenously administered nucleic acid formulations are the requirements that they can transport the nucleic acids efficiently in the circulation, have the ability to direct nucleic acids to the desired cell type and are able to steer their intracellular processing. Here, we evaluate nanotechnological strategies that improve the pharmacokinetics and colloidal stability of nucleic acids in the bloodstream, focus biodistribution towards the target tissue and facilitate interactions with and trafficking within the desired cell type. PMID- 17716120 TI - Oral administration of peptides and proteins: nanoparticles and cyclodextrins as biocompatible delivery systems. AB - This review discusses drawbacks to peptide and protein oral formulations related to these drugs' chemical and physical instability. Means used to overcome such limitations are mentioned and discussed in parallel with manufacturing considerations, metabolism, absorption mechanisms and the efflux systems that peptides and proteins experience as they travel through the gastrointestinal tract. Special focus is given to the use of delivery systems based on nanoparticles and cyclodextrins. Advantages of these systems relate to the protection from degradation, enhancement of absorption, targeting and controlling the release of the drug. Biodistribution and safety issues are discussed once material from the delivery system is expected to be absorbed by the body and thus interact with biological components. Operating parameters regarding nanoparticle manufacture and composition are also overviewed since nanoparticle physicochemical characteristics influence the ability to successfully entrap the intended drug as well as interaction with body. PMID- 17716121 TI - Supramolecular organization of elastin and elastin-related nanostructured biopolymers. AB - The ultrastructure of elastin has been extensively analyzed by different methodologies. Starting from the first descriptions, where elastin was depicted as an amorphous structure, more complex and, in some cases, varied morphologies were revealed. The supramolecular structures found for elastin have been compared with those found for other elastin-related polypeptides, such as alpha-elastin and tropoelastin, and very similar features emerged. This review will deal with the supramolecular organization exhibited by many elastin-related compounds, starting from elastin, going through polypeptides constituted by different domains of tropoelastin, up to polymers containing repetitive sequences of elastin. In particular, recent developments on biopolymers of general type poly(Val-Pro-Gly-Xaa-Gly) and poly(Xaa-Gly-Gly-Zaa-Gly) (Xaa, Zaa = Val, Leu, Lys, Glu, Orn) obtained either by chemical synthesis or recombinant DNA techniques will be discussed in detail. The general aim is to describe the supramolecular features useful for the identification of elastin-inspired nanostructured biopolymers for developing highly functional and biocompatible vascular grafts as well as scaffolds for tissue regeneration. PMID- 17716122 TI - Doxorubicin-loaded PLGA nanoparticles by nanoprecipitation: preparation, characterization and in vitro evaluation. AB - AIMS: The lack of specificity of chemotherapeutic agents to cancer tissue commonly leads to dose-limiting side effects and poor therapeutic results. Drug delivery systems promise to improve the deficiencies of chemotherapeutic treatment by modifying the biodistribution and pharmacokinetics of the drug in vivo. Here, we report the preparation, characterization and in vitro evaluation of a carrier for the chemotherapeutic drug doxorubicin based on acid-capped poly(lactic-co-glycolic acid) nanoparticles. METHODS: Doxorubicin-loaded nanoparticles were prepared by nanoprecipitation with bovine serum albumin as the stabilizer. Nanoparticles were characterized and their interaction with MDA-MB 231 breast cancer cells was examined with confocal microscopy and a toxicological assay. RESULTS: Spherical particles with an average diameter of 230 nm, a zeta potential of -45 mV and a maximum drug loading of 5 wt% were prepared. Doxorubicin was found to be quickly released at endolysosomal pH of 4.0 but was released at a slower rate at pH 7.4. Nanoparticles were found to deliver the drug into cells quickly and in higher quantity than when presented in solution and were found to result in a therapeutic efficacy comparable to the free drug. DISCUSSION: Nanoprecipitation was found to be a promising method for the preparation of nanoparticles with relatively high doxorubicin loading. The pH dependent release behavior is discussed to possibly be a result of accelerated degradation of the polymer and decreasing ionic interaction between the drug and the polymer at acidic pH. Additional studies are needed to determine why increased nuclear localization of the drug when delivered in the form of nanoparticles did not result in increased therapeutic efficacy in vitro. CONCLUSION: Nanoparticles formulated by nanoprecipitation of acid-ended poly(lactic-co-glycolic acid) were found to be able to control the release of doxorubicin in a pH-dependent manner and to effectively deliver high payloads of the drug in an active form to MDA-MB-231 breast cancer cells. PMID- 17716123 TI - Preparation and characterization of nanoparticles containing an atypical antipsychotic agent. AB - AIM: The aim of this work was to prepare poly(epsilon-caprolactone) nanoparticles of risperidone and to characterize them. METHODS: Risperidone-loaded poly(epsilon caprolactone) nanoparticles were prepared by the nanoprecipitation method using poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock polymeric stabilizer (PluronicF-68). The particles were characterized for particle size by photon correlation spectroscopy and transmission electron microscopy. The free dissolved drug in the nanosuspension was determined by the bulk equilibrium reverse dialysis bag technique. In vitro release studies were carried out using the dialysis bag diffusion technique. RESULTS: The particle size of the prepared nanoparticles ranged from 90 to 300 nm. Nanoparticles of risperidone were obtained with high encapsulation efficiency (70-80%). The drug release from the risperidone nanoparticles was sustained in some batches for more than 24 h with 80% drug release, whereas release from risperidone in polyethylene glycol 400 solution showed release within 2 h. CONCLUSION: These studies suggest the feasibility of formulating risperidone-loaded poly(epsilon-caprolactone) nanoparticles for the treatment of psychotic disorders. PMID- 17716124 TI - Clusterization of nanoparticles during their interaction with living cells. AB - AIMS: Clusters of nanoparticles may significantly improve the sensitivity of diagnostics and the safety and efficacy of therapeutic nanotechnologies in medicine. We report methods for the formation of nanoparticle clusters and for monitoring their accumulation in cancer cells. METHODS: The accumulation of gold nanoparticles in tumor cells was studied using flow cytometry, optical scattering and fluorescent, atomic force, photothermal and scanning electron microscopy. RESULTS: Incubation of cells at 37 degrees C for 30 min or more with 10-30-nm nanoparticles resulted in the formation of clusters of nanoparticles as large as 20 nanoparticles or more. CONCLUSIONS: Specific targeting using a monoclonal antibody as a vector increases the concentration of nanoparticles on the surface of target cells compared with nonspecific nanoparticle accumulation. In turn, an increased concentration of nanoparticles on the target surface yields larger nanoparticle clusters inside the cells due to endocytosis. Photothermal and scattering microscopy were found to be the most sensitive methods for imaging nanoparticle clusters in living cells. PMID- 17716125 TI - Nanotechnology: the next wave of commercial development for health and medical devices--an Australian story. AB - For the past two decades, nanotechnology has been the realm of the physicist and the surface chemist. Medicine has largely ignored nanotechnology as a specific field because medical research teams had worked with nanoscale structures for many years. However, over the last 5 years, a body of work has emerged in which materials scientists have become the drivers of a new group of medical technologies and products. These developments require an integration of disciplines that has rarely been achieved before and that has been problematic for many university-based research providers. When managed successfully, this integration provides the opportunity for significant benefits. PMID- 17716126 TI - Nanomedicine: how it could reshape clinical practice. PMID- 17716127 TI - Potential uses of carbon nanotubes in the medical field: how worried should patients be? PMID- 17716129 TI - Nanoparticle albumin-bound paclitaxel: a novel Cremphor-EL-free formulation of paclitaxel. AB - Standard formulation paclitaxel requires the use of solvents, such as Cremphor EL, which contribute to some of the toxicities commonly associated with paclitaxel-based therapy. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel solvent-free formulation of paclitaxel. The formulation is prepared by high-pressure homogenization of paclitaxel in the presence of serum albumin into a nanoparticle colloidal suspension. The human albumin-stabilized paclitaxel particles have an average size of 130 nm. Nab-paclitaxel has several practical advantages over Cremphor-EL-paclitaxel, including a shorter infusion time (30 min) and no need for premedications for hypersensitivity reactions. The nab paclitaxel formulation eliminates the impact of Cremphor-EL on paclitaxel pharmacokinetics and utilizes the endogenous albumin transport mechanisms to concentrate nab-paclitaxel within the tumor. A recent Phase III trial compared nab- and Cremphor-EL-paclitaxel in patients with metastatic breast cancer. Patients treated with nab-paclitaxel experienced a higher response, longer time to tumor progression and, in patients receiving second-line or greater therapy, a longer median survival. Patients treated with nab-paclitaxel had a significantly lower rate of severe neutropenia and a higher rate of sensory neuropathy. The preclinical and clinical data indicate that the nab-paclitaxel formulation has significant advantages over Cremphor-EL-paclitaxel. PMID- 17716130 TI - Rise of the nanomachine: the evolution of a revolution in medicine. AB - Although the current array of nanomachines mostly comprises simple devices (at least from a mechanical viewpoint), the underlying physical and chemical interactions that play key roles in the 'assembly' of these machines have required decades of research to ascertain a fundamental understanding of how such processes can be manipulated at the nanoscale. In this review, we wish to convey a realistic picture of the current developments in the design and implementation of nanomachines, with an emphasis on how these developments are leading to practical applications in medicine, including a sense of how such simple devices are rapidly becoming the building blocks for assembling the nanorobots of tomorrow. PMID- 17716131 TI - Electrospun matrices made of poly(alpha-hydroxy acids) for medical use. AB - Biomaterials are widely used in diverse applications as substances, materials or important elements of biomedical devices. Biodegradable polymers, both natural and synthetic, have been utilized in applications in which they act as temporary substitutes. Poly(alpha-hydroxy acids), especially lactic acids and glycolic acid and their copolymers with epsilon-caprolactone, are the most widely known and used among all biodegradable polymers. They degrade in vivo into safe end products mainly by hydrolysis in a few weeks to several months, depending on several factors, including molecular structure/morphology, average molecular weight, size and shape. They are processed into tailor-made materials for diverse applications, although mainly for soft and hard tissue repair. Electrospinning is a method of producing nanofibers and nonwoven matrices from their solutions and melts. Several factors affect fiber diameter and resulting nonwoven structures/morphologies. Recently, electrospun matrices made of lactic acids, glycolic acid and epsilon-caprolactone homo- and co-polymers have been attracting increasing attention for fabrication of novel materials for medical use. This review briefly describes poly(alpha-hydroxy acids) and the elecrospinning process, and gives some selected recent applications of electrospun matrices made from these polymers. PMID- 17716132 TI - Nanopore-based single-molecule DNA analysis. AB - Nanopore-based DNA analysis is a single-molecule technique with revolutionary potential. It promises to carry out a range of analyses, orders of magnitude faster than current methods, including length measurement, specific sequence detection, single-molecule dynamics and even de novo sequencing. The concept involves using an applied voltage to drive DNA molecules through a narrow pore that separates chambers of electrolyte solution. This voltage also drives a flow of electrolyte ions through the pore, measured as an electric current. When molecules pass through the pore, they block the flow of ions and, thus, their structure and length can be determined based on the degree and duration of the resulting current reductions. In this review, I explain the nanopore-based DNA analysis concept and briefly explore its historical foundations, before discussing and summarizing all experimental results reported to date. I conclude with a summary of the obstacles that must be overcome for it to realize its promised potential. PMID- 17716133 TI - Use of degradable and nondegradable nanomaterials for controlled release. AB - Drug-delivery devices are fundamentally important in improving the pharmacological profiles of therapeutic molecules. Nanocontrolled-release systems are attracting a lot of attention currently owing to their large surface area and their ability to target delivery to specific sites in the human body. In addition, they can penetrate the cell membrane for gene, nucleic acid and bioactive peptide/protein delivery. Representative applications of nanodrug delivery systems include controlled-release wound dressings, controlled-release scaffolds for tissue regeneration and implantable biodegradable nanomaterial based medical devices integrated with drug-delivery functions. We review the present status and future perspectives of various types of nanocontrolled-release systems. Although many of the well-established degradable and nondegradable controlled-release vehicles are being investigated for their processing into nanocarriers, several new emerging nanomaterials are being studied for their controlled-release properties. The release of multiple bioactive agents, each with its own kinetic profile, is becoming possible. In addition, integration of the nanocontrolled-release systems with other desirable functions to create new, cross-discipline applications can also be realized. PMID- 17716135 TI - Optically switchable nanoparticles for biological imaging. AB - Optical imaging in live cells has provided a wealth of information regarding the various biological mechanisms, including using genetically coded green fluorescent protein-conjugated organic dye molecules and, more recently, highly luminescent quantum dots as optical tags for the target biomolecules. Cells are inherently complex, grow constantly and have autofluorescence covering the entire visible spectrum ranging from green to red. At the single quantum-emitter level, it is often difficult to distinguish optical probes from fortuitous fluorophores inside living cells owing to complexity and constant evolvement. We have developed photoswitchable nanoparticles-optical nanoprobes that can be highlighted in either red or green during fluorescence imaging. Such optically addressable nanoprobes offer unambiguous detection of sites of biological interactions, and successfully implementing such optically switchable nanoprobes should greatly reduce the occurrence of false-positives in biomedical imaging and unambiguous detections. PMID- 17716134 TI - Upstream ethics in nanomedicine: a call for research. AB - Insufficient attention has been given to ethical and social issues integral to nanomedicine. Part of this deficiency arises from some mistaken assumptions about ethics. I consider five of these: that ethics is only important when a technology is mature (reactionary ethics); that there are no new ethical issues in nanomedicine; that ethics involves a kind of risk assessment that is already being conducted; that ethics is a hindrance to science; and that ethics is a luxury for an ideal world. After critically assessing these assumptions, I consider two types of nanomedicine and the kinds of ethical issues they raise. Type 1 nanomedicine is of an incremental kind, and proper ethical assessment of the issues must involve a fine grained study of the specific application. Type 2 nanomedicine is of a more foundational, programmatic kind. Ethical issues raised by these more programmatic developments include challenges integral to formation of interdisciplinary teams; issues related to intellectual property, authorship and publication; development of informed consent and confidentiality protections associated with new data sets; future challenges to the clinician-patient relation and personalized medicine. Ethical analysis should also consider some of the reductionistic implications of engineering models and metaphors integral to nanomedicine, as well as uses of nanomedicine for non-medical purposes, such as human enhancement. Many of these challenges concern rate-limiting steps in nanomedical research, and they should be prominently featured in developing nanomedicine initiatives. PMID- 17716137 TI - Additive-free albumin nanoparticles of alendronate for attenuating inflammation through monocyte inhibition. AB - AIMS: Particulated dosage forms of bisphosphonates, such as polymeric nanoparticles and liposomes, deplete circulating monocytes and attenuate inflammation. The aim of this work was to develop a novel formulation of albumin nanoparticles with no crosslinkers that encapsulate the bisphosphonate, alendronate and, further, to examine its bioactivity in vitro and in vivo. RESULTS: The novel formulation was prepared by desolvation of human serum albumin in acidic pH induced by alendronate, which enables an electrostatic interaction between albumin and the acidic drug. The mean particle size of the negatively charged nanoparticle was 250-300 nm and drug-entrapment efficiency was 49%. The formulation can be filter sterilized and lyophilized for increased stability. Alendronate nanoparticles exhibited significant inhibitory effects on RAW264 macrophage growth and a significant attenuation of stenosis in rats. CONCLUSION: It is concluded that bioactive nanoparticles of human albumin can be formulated without crosslinkers and potentially toxic additives. PMID- 17716136 TI - Fibrin-targeted perfluorocarbon nanoparticles for targeted thrombolysis. AB - BACKGROUND: Reperfusion of the ischemic brain is the most effective therapy for acute stroke, restoring blood flow to threatened tissues. Thrombolytics, such as recombinant tissue plasminogen activator, administered within 3 h of symptom onset can improve neurologic outcome, although the potential for adverse hemorrhagic events limits its use to less than 3% of acute ischemic stroke patients. Targeting of clot-dissolving therapeutics has the potential to decrease the frequency of complications while simultaneously increasing treatment effectiveness, by concentrating the available drug at the desired site and permitting a lower systemic dose. OBJECTIVES: We aimed to develop a fibrin specific, liquid perfluorocarbon nanoparticle that is surface modified to deliver the plasminogen activator streptokinase. We also aimed to evaluate its effectiveness for targeted thrombolysis in vitro using quantitative acoustic microscopy. METHODS: Human plasma clots were formed in vitro and targeted with streptokinase-loaded nanoparticles, control nanoparticles or a mixture of both. Depending on the treatment group, clots were then exposed to either phosphate buffered saline (PBS), PBS with plasminogen or PBS with plasminogen and free streptokinase. Spatially registered ultrasound scans were performed at 15-min intervals for 1 h to quantify changes in clot morphology and backscatter. RESULTS: Nanoparticles bound to the clot significantly increased the acoustic contrast of the targeted clot surface, permitting volumetric estimates. Profile plots of detected clot surfaces demonstrated that streptokinase-loaded, fibrin targeted perfluoro-octylbromide nanoparticles in the presence of plasminogen induced rapid fibrinolysis (<60 min) without concurrent microbubble production and cavitation. Streptokinase-loaded or fibrin-targeted control nanoparticles insonified in PBS did not induce clot lysis. Morphologic changes in the treated group were accompanied by temporal and spatial changes in backscatter. Ultrasound exposure had no effect on the digestion process. Effective concentrations of targeted streptokinase were orders of magnitude lower than equivalently efficacious levels of free drug. Moreover, increasing competitive inhibition of fibrin-bound streptokinase nanoparticles reduced clot lysis in a monotonic fashion. As little as 1% surface targeting of streptokinase nanoparticles produced significant decreases in clot volumes (approximately 30%) in 1 h. CONCLUSION: This new nanoparticle-based thrombolytic agent provides specific and rapid fibrinolysis in vitro and may have a clinical role in early reperfusion during acute ischemic stroke. PMID- 17716139 TI - Tumor-targeting nanosystems for the delivery of siRNA. PMID- 17716138 TI - Cell electrospinning highly concentrated cellular suspensions containing primary living organisms into cell-bearing threads and scaffolds. AB - AIMS: We recently pioneered the cell electrospinning of living cells as viable biological threads and scaffolds. In that study, we demonstrated the process with an immortalized human brain astrocytoma (1321N1, European Collection of Cell Cultures) cell line at a cell concentration of 10(6) cells/ml. The next stage was to demonstrate the ability to cell electrospin primary living cells at cell concentrations of 10(7) cells/ml (the highest-ever cell concentration threaded by any threading methodology). Furthermore, the post-threaded cells needed their viability assessed over a long period of time by way of flow cytometry, which accurately assesses the viable cell populations. MATERIALS & METHODS: In this work, we employ primary porcine vascular and rabbit aorta smooth-muscle cells prepared as cellular suspensions at cell concentrations of 10(7) cells/ml. The cell electrospinning device employs a coaxial needle arrangement that enables the flow of either highly concentrated cellular suspension in the inner needle while the outer needle accommodates the flow of a viscoelasticity medical-grade polydimethylsiloxane medium. Cell viability was assessed over a long timeframe by way of flow cytometry in comparison with controls. RESULTS & DISCUSSION: The work reported here demonstrates the ability to cell electrospin primary living organisms as highly concentrated cellular suspensions. The viable population of cells post-cell electrospinning are significant and remain viable over both the short and long term, as assessed by flow cytometry. CONCLUSION: Our work elucidates the ability to cell electrospin primary cells as highly concentrated cellular suspensions. The post-cell electrospun organisms are viable over long periods of time, demonstrating a significant active cell population when compared with controls. PMID- 17716140 TI - Challenges and optimism for nanoengineering. PMID- 17716142 TI - Launch of the London Centre for Nanotechnology. AB - Is nanomedicine an area with the promise that its proponents claim? Professors Gabriel Aeppli and Quentin Pankhurst explore the issues in light of the new London Centre for Nanotechnology (LCN)--a joint enterprise between Imperial College and University College London--opened on November 7, 2006. The center is a multidisciplinary research initiative that aims to bridge the physical, engineering and biomedical sciences. In this interview, Professor Gabriel Aeppli, LCN co-Director, and Deputy Director Professor Quentin Pankhurst discuss the advent and future role of the LCN with Nanomedicine's Morag Robertson. Professor Aeppli was formerly with NEC, Bell Laboratories and MIT and has more than 15 years' experience in the computer and telecommunications industry. Professor Pankhurst is a physicist with more than 20 years' experience of working with magnetic materials and nanoparticles, who now works closely with clinicians and medics on innovative healthcare applications. He also recently formed the new start-up company Endomagnetics Inc. PMID- 17716143 TI - Radical nanomedicine. AB - Nanotechnology has made significant advances in the reduction of free radical damage in the field of materials science. Cross-disciplinary interactions and the application of this technology to biological systems has led to the elucidation of novel nanoparticle antioxidants, which are the subject of this review. Recent reports suggest that cerium oxide and other nanoparticles are potent, and probably regenerative, free radical scavengers in vitro and in vivo. The neuroprotective, longevity-enhancing and anti-inflammatory properties of nanoparticles are summarized and hypotheses regarding their unique mechanism of action are presented. The chemical and physical properties of antioxidant nanoparticles are discussed in an interdisciplinary manner, with emphasis on biological properties and biomedical applications. Additionally, the need for alterations in traditional pharmacological parameters of dose and absorption, distribution, metabolism, and excretion are discussed and future directions necessary for bringing nanoparticle antioxidants into the realm of clinical reality are presented. PMID- 17716144 TI - Nanoparticles for multiplex diagnostics and imaging. AB - The drive to understand biology and medicine at the molecular level with accurate quantitation demands much of current high-throughput analysis systems. Nanomaterials and nanotechnology combined with modern instrumentation have the potential to address this emerging challenge. Using a variety of nanomaterials for multiplex diagnostics and imaging applications will offer sensitive, rapid and cost-effective solutions for the modern clinical laboratory. New nanomaterials have been developed with optical-encoding capabilities for selective tagging of a wide range of medically important targets, including bacteria, cancer cells and individual molecules, such as proteins and DNA, in a single assay. We envision further development in this field will provide numerous advanced tools with increased sensitivity and improved multiplexing capability, for unique applications in molecular biology, genomics and drug discovery. PMID- 17716145 TI - Nucleoprotein assemblies at the nanoscale: medical implications. AB - Bionanotechnology is exploiting the rich structural knowledge now available on DNA and DNA-protein interactions to construct nucleoprotein-based devices that have the potential not only to contribute to our understanding of the structure and function of the proteins and nucleic acids involved but also to new approaches to problems in medicine. Assemblies under development currently are poised to contribute to diagnosis and therapy. Here, I discuss recent work in this emerging field. PMID- 17716146 TI - Molecularly imprinted polymer particles: synthetic receptors for future medicine. AB - Molecular imprinting is a relatively new and rapidly evolving technique used to create synthetic receptors; it also possesses great potential in a number of applications in the life sciences. Traditionally, molecularly imprinted polymers are prepared by bulk polymerization, followed by crushing and sieving to obtain polymer beads. However, several methods can be used to synthesize polymer micro- and nano-particles directly, thereby avoiding the time- and labor-consuming process of crush sieving. Possible applications are foreseen in enhanced drug loading, controlled drug delivery and drug targeting. This review describes the different methods of synthesis of molecularly imprinted micro- and nano-particles and discusses how these methods challenge the outstanding issues that molecular imprinting is facing today, thereby facilitating biomedical applications in the future. PMID- 17716147 TI - Biomedical interfaces: titanium surface technology for implants and cell carriers. AB - Titanium and its alloys have become key materials for biomedical applications, mainly owing to their compatibility with human tissues and their mechanical strength. Effects of surface topography on cell and tissue response have been investigated extensively in the past, while (bio)chemical surface modification and its combination with designed topographies have remained largely unexplored. The following report describes some of the strategies used or intended to modify titanium surfaces, based on biological principles, with a focus on ultrathin biomimetic adlayers. One of the visions behind such approaches is to achieve improved healing and integration responses after implantation for patients, especially for those suffering from deficiencies, for example, diabetes or osteoporosis, two diseases that have increased drastically in our society during the last century. PMID- 17716148 TI - Aligned core-shell nanofibers delivering bioactive proteins. AB - AIMS: Continuous nanostructures embedded with proteins may synergistically present topographical and biochemical signals to cells for tissue engineering applications. This study presents the co-axial electrospinning of aligned poly(epsilon-caprolactone) nanofibers encapsulated with bovine serum albumin and platelet-derived growth factor-bb for demonstration of controlled release and bioactivity retention, respectively. MATERIALS & METHODS: Controllable release kinetics is achieved by incorporation of poly(ethylene glycol) as a porogen in the shell of the nanofibers. RESULTS & DISCUSSION: Poly(ethylene glycol) leaches out in a concentration- and molecular weight-dependent fashion, leading to bovine serum albumin release half-lives that range from 1 to 20 days. Optimized platelet derived growth factor-bb-encapsulated nanofibers can completely release the protein with near zero-order kinetics and preserved bioactivity. CONCLUSION: Co axial electrospinning is shown to be a versatile technique in achieving the delivery of biochemical signals in a controlled manner for regenerative medicine applications. PMID- 17716150 TI - Nanocarriers for overcoming multidrug resistance in cancers. PMID- 17716149 TI - Laser-induced explosion of gold nanoparticles: potential role for nanophotothermolysis of cancer. AB - AIMS: This article explores the laser-induced explosion of absorbing nanoparticles in selective nanophotothermolysis of cancer. METHODS: This is realized through fast overheating of a strongly absorbing target during the time of a short laser pulse when the influence of heat diffusion is minimal. RESULTS: On the basis of simple energy balance, it is found that the threshold laser fluence for thermal explosion of different gold nanoparticles is in the range of 25-40 mJ/cm(2). CONCLUSION: Explosion of nanoparticles may be accompanied by optical plasma, generation of shock waves with supersonic expansion and particle fragmentation with fragments of high kinetic energy, all of which can contribute to the killing of cancer cells. PMID- 17716155 TI - Cenamps: adding value to the North East region. AB - Cenamps' highly talented and commercially experienced team work closely with business leaders to stimulate and manage market-led innovation, enabling businesses to develop new products and services as well as strengthen the regional economic foundation, R&D capabilities and performance. Cenamps achieves this by establishing new state-of-the-art R&D facilities and applied research projects for developing new technologies that will yield significant societal, economic and commercial benefits. PMID- 17716156 TI - Establishing nanomedicine. PMID- 17716157 TI - Acid-sensitive nanoparticles filled with tumor-destroying drugs promise new method to target and kill ovarian cancer cells. PMID- 17716158 TI - Nanobiotechnological approach to engineered biomaterial design: the example of elastin-like polymers. AB - Today, the development of advanced biomaterials is still lacking an appropriate tailored engineering approach. Most of the biomaterials currently used have their origin in materials developed for other technological applications. This lack of adequate biomaterial design is probably due to the peculiar environment where those materials must operate. On the one hand, this environment is dominated by the immune rejection system. On the other hand, the functionality of natural biomolecules is based on complex topological physical-chemical function distributions at the nanometer level. This review presents arguments concerning the role of biotechnology and nanotechnology in the future development of new advanced biomaterials and the potential of these biomaterials as a way to achieve highly biofunctional and truly biocompatible biomaterials for hot areas, such as regenerative medicine and controlled release. Recombinant protein-polymers will be presented as an example of candidates for this new paradigm in biomaterial design and production. PMID- 17716159 TI - 3D polymer scaffolds for tissue engineering. AB - This review discusses some of the most common polymer scaffold fabrication techniques used for tissue engineering applications. Although the field of scaffold fabrication is now well established and advancing at a fast rate, more progress remains to be made, especially in engineering small diameter blood vessels and providing scaffolds that can support deep tissue structures. With this in mind, we introduce two new lithographic methods that we expect to go some way to addressing this problem. PMID- 17716160 TI - New-concept chemotherapy by nanoparticles of biodegradable polymers: where are we now? AB - No substantial progress has really been observed during the past 50 years in fighting cancer, and the way we currently detect and treat cancer is similar to 30 years ago. Cancer nanotechnology will change the situation radically. Progress in developing nanoparticles of biodegradable polymers for new-concept chemotherapy is reviewed here by using the in vitro and in vivo experimental results obtained in my laboratory as a proof-of-concept demonstration. The prospects of using multifunctional nanoparticles for targeting, diagnosing, therapy delivery and result-reporting as a possible solution for cancer detection and treatment are also described. I believe that cancer will become curable using targeted and sustained chemotherapy by such nanoparticles at the earliest stage of disease. High efficacy and low side effects can be achieved, since high drug concentrations can be delivered selectively to the cancer cells, leaving healthy cells untouched. Thus, the required amount of the drug can be minimized. PMID- 17716161 TI - Sol-gel production of bioactive nanocoatings for medical applications. Part 1: an introduction. AB - Coatings offer the possibility of modifying the surface properties of surgical grade materials to achieve improvements in performance, reliability and biocompatibility. Sol-gel-derived coatings demonstrate promise owing to their relative ease of production, ability to form a physically and chemically pure and uniform coating over complex geometric shapes and potential to deliver exceptional mechanical properties owing to their nanocrystalline structure. Other advantages unique to sol-gel include the production of a homogeneous material, since mixing takes place on the atomic scale, and its relatively low processing temperature avoids decomposition of the coating materials and limits the damage to metallic substrate materials as a result of exposure to elevated temperatures. A range of materials can be adapted easily for a number of biomedical and engineering applications. PMID- 17716162 TI - Nanomedicine opportunities for cardiovascular disease with perfluorocarbon nanoparticles. AB - Nanomedicine promises to enhance the ability of clinicians to address some of the serious challenges responsible for cardiovascular mortality, morbidity and numerous societal consequences. Targeted imaging and therapy applications with perfluorocarbon nanoparticles are relevant to a broad spectrum of cardiovascular diseases, ranging from asymptomatic atherosclerotic disease to acute myocardial infarction or stroke. As illustrated in this article, perfluorocarbon nanoparticles offer new tools to recognize and characterize pathology, to identify and segment high-risk patients and to treat chronic and acute disease. PMID- 17716163 TI - Videovisualization of dynamic cell responses and its molecular analysis for nanomedicine. AB - This report proposes and reviews a new approach that provides a more straightforward methodology for visualizing and determining molecular mechanisms as they occur within cells. A direct observation of the dynamic behavior of cells using a video microscope shows unexpected but very rational behavior that challenges us to elucidate its molecular mechanism. Since mass spectrometry is a rapid and sensitive tool for molecular analysis, single-cell matrix-assisted laser desorption-ionization time of flight mass spectrometry is useful and a morphological and molecular analysis combined method called video-mass-scope is also proposed. For analysis of the function of new molecules, single molecular imaging should be straightforward and the dynamic image of molecular movement or transport, called nanokinetics, is also necessary for the application to nanomedicine. Various research examples, based mainly on biological self-defense or secretion processes, are reviewed. The combination of these analytical techniques will enable us to understand the dynamic molecular mechanisms of cells and this knowledge could be applied to nanomedicine in the future. PMID- 17716164 TI - Nanokinetics of drug molecule transport into a single cell. AB - AIMS: To analyze drug transport at a single cell level, a mast cell line, RBL 2H3, was treated with cell-permeable fluorescent compounds, such as quinacrine, and was monitored by a fluorescence video microscope. METHODS: Small areas in the video that corresponded to granules and part of the cytosol in a cell were chosen and the signal intensity in these areas was monitored sequentially. RESULTS: The initial rate of quinacrine uptake through the cell membrane calculated from the fluorescent signal was correlated with quinacrine concentration, and it decreased at a lower temperature, showing that the transport was an energy-requiring process, such as active transport. The kinetics of the transport through the microgranular membrane did not depend on the temperature but the pH in the cytosol, therefore this process should be passive transport by pH gradient. CONCLUSION: These data indicate that the observation of video microscope-mediated drug transport using fluorescent dye is useful in kinetic analysis at the nanometer scale. PMID- 17716165 TI - Designing orthopedic implant surfaces: harmonization of nanotopographical and chemical aspects. PMID- 17716166 TI - Hope for the short-term use of nanorough metallic implant formulations in the clinical arena. PMID- 17716168 TI - Micro/nano 3D structures made by thin film rolling. PMID- 17716169 TI - Biologically inspired energy: harnessing molecular functionality towards nanosystemic design. PMID- 17716167 TI - Temporal targeting in cancer: combined chemotherapy and antiangiogenic therapy. PMID- 17716170 TI - Insulin: a model system for nanomedicine? AB - One of the predominant aims of insulin therapy for diabetes is to appropriately mimic physiological insulin secretion levels and their correlation with glucose concentration in healthy individuals. This report outlines current methods and their limitations in glycemic control and their possible relationship to insufficient knowledge about the structure and dynamics of the insulin hormone itself. Based on recent experimental and computational work, a possible approach to less-invasive insulin administration is sketched. PMID- 17716172 TI - Don't bury your head in the nanostuff. PMID- 17716173 TI - Smelling out a protein? 'Nano nose' sniffs around. PMID- 17716174 TI - Mitochondria-specific nanotechnology. AB - Mitochondrial research has made an enormous leap since mitochondrial DNA mutations were identified as a primary cause for human diseases in 1988 and the organelle's crucial role in apoptosis was identified during the 1990s. Considerable progress has been made in identifying the molecular components of the mitochondrial machinery responsible for life and cell death; however, effective therapies for diseases caused by mitochondrial dysfunction remain elusive. An impediment to manipulating, probing and assessing the functional components of mammalian mitochondria within living cells is their limited accessibility to direct physical, biochemical and pharmacological manipulation. Recent advances in nanotechnology hold the promise of helping to overcome these obstacles. New tools will undoubtedly emerge, creating new avenues for the diagnosis and therapy of mitochondrial disorders. This review briefly discusses current efforts to merge nanobiotechnology with mitochondrial medicine. PMID- 17716176 TI - Magnetic and fluorescent nanoparticles for multimodality imaging. AB - The development of nanoparticulate contrast agents is providing an increasing contribution to the field of diagnostic and molecular imaging. Such agents provide several advantages over traditional compounds. First, they may contain a high payload of the contrast-generating material, which greatly improves their detectability. Second, multiple properties may be easily integrated within one nanoparticle to allow its detection with several imaging techniques or to include therapeutic qualities. Finally, the surface of such nanoparticles may be modified to improve circulation half-lives or to attach targeting groups. Magnetic resonance imaging and optical techniques are highly complementary imaging methods. Combining these techniques would therefore have significant advantages and may be realized through the use of nanoparticulate contrast agents. This review gives a survey of the different types of fluorescent and magnetic nanoparticles that have been employed for both magnetic resonance and optical imaging studies. PMID- 17716175 TI - Peptides and metallic nanoparticles for biomedical applications. AB - In this review, we describe the contribution of peptides to the biomedical applications of metallic nanoparticles. We also discuss strategies for the preparation of peptide-nanoparticle conjugates and the synthesis of the peptides and metallic nanoparticles. An overview of the techniques used for the characterization of the conjugates is also provided. Mainly for biomedical purposes, metallic nanoparticles conjugated to peptides have been prepared from Au and iron oxide (magnetic nanoparticles). Peptides with the capacity to penetrate the plasma membrane are used to deliver nanoparticles to the cell. In addition, peptides that recognize specific cell receptors are used for targeting nanoparticles. The potential application of peptide-nanoparticle conjugates in cancer and Alzheimer's disease therapy is discussed. Several peptide-nanoparticle conjugates show biocompatibility and present a low degree of cytotoxicity. Furthermore, several peptide-metallic nanoparticle conjugates are used for in vitro diagnosis. PMID- 17716177 TI - Novel synthesis of cerium oxide nanoparticles for free radical scavenging. AB - AIMS: The aim of this article is to present a novel synthetic route to form CeO(2) nanoparticles that protects against the detrimental influence of oxidative stress in mammalian cells. METHODS: The noncytotoxic surfactant lecithin was used to synthesize CeO(2) nanoparticles and the products were colloidally stabilized in a biocompatible tri-sodium citrate buffer. These nanoparticles were delivered into murine insulinoma betaTC-tet cells, and intracellular free radical concentrations responding to exposure to hydroquinone were measured in a variety of extracellular CeO(2) concentrations. RESULTS: Well-dispersed, highly crystallized CeO(2) nanoparticles of 3.7 nm in size were achieved that are chemically and colloidally stable in Dulbecco's modified Eagle's medium for extended periods of time. Treating betaTC-tet cells with these nanoparticles alleviated detrimental intracellular free radical levels down to the primary level. CONCLUSION: CeO(2) nanoparticles synthesized from this route are demonstrated to be effective free radical scavengers within betaTC-tet cells. Furthermore, it is shown that CeO(2) nanoparticles provide an effective means to improve cellular survival in settings wherein cell loss due to oxidative stress limits native function. PMID- 17716178 TI - Vitamin E TPGS-emulsified poly(lactic-co-glycolic acid) nanoparticles for cardiovascular restenosis treatment. AB - AIMS: Paclitaxel is one of the most effective antiproliferative agents and it has been applied in the development of drug-eluting stents. There are difficulties, however, in using paclitaxel in clinical applications owing to its poor solubility and side effects. We have synthesized nanoparticles of biodegradable polymers for the effective and sustainable delivery of paclitaxel and other antiproliferative agents for restenosis treatment. METHODS & RESULTS: Paclitaxel loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles were prepared by a modified solvent extraction/evaporation method with D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) or polyvinyl alcohol (PVA) as an emulsifier. Drug-loaded nanoparticles were characterized for size and size distribution, surface morphology, surface charge, drug-encapsulation efficiency and in vitro drug-release kinetics. Cellular uptake of fluorescent nanoparticles was investigated in vitro in coronary artery smooth muscle cells and in vivo in the carotid arteries of rabbits. The antiproliferative effects of the nanoparticle formulations were assessed in vitro in close comparison with Taxol((R)). Both the PVA- and TPGS-emulsified nanoparticles have similar size and size distribution, surface morphology and dispersion stability and showed great advantages over paclitaxel in in vitro cellular uptake and cytotoxicity than Taxol. The TPGS-emulsified nanoparticle formulation has higher drug-encapsulation efficiency, cellular uptake and cytotoxicity than the PVA-emulsified nanoparticle formulation. IC(50) in 24-h culture with coronary artery smooth muscle cells is 748 ng/ml for paclitaxel, 708 ng/ml for PVA-emulsified nanoparticles and 474 ng/ml for TPGS-emulsified nanoparticles, respectively. CONCLUSION: TPGS emulsified PLGA nanoparticles have great potential for the effective and sustainable delivery of antiproliferative agents and for the development of nanoparticle-coated stents, which may become the third generation of cardiovascular stents. PMID- 17716179 TI - Ethics in nanomedicine. AB - As the science and technology of nanomedicine speed ahead, ethics, policy and the law are struggling to keep up. It is important to proactively address the ethical, social and regulatory aspects of nanomedicine in order to minimize its adverse impacts on the environment and public health and also to avoid a public backlash. At present, the most significant concerns involve risk assessment, risk management of engineered nanomaterials and risk communication. Although in vivo animal experiments and ex vivo laboratory analyses can increase our understanding of the interaction of engineered nanomaterials in biological systems, they cannot eliminate all of the uncertainty surrounding the exposure of a human subject to nanomedicine products in clinical trials. Significant risks can still materialize after a product has cleared the Phase I hurdle and is in Phase II or III clinical trials. Furthermore, as the use of engineered nanomaterials in nanomedicine increases, questions of social justice, access to healthcare and the use of nanotechnology for physical enhancement become increasingly important. PMID- 17716180 TI - Patents and nanomedicine. AB - Big pharma's business model, which relies on a few blockbusters to generate profits, is clearly broken. Patent expiration on numerous blockbusters in recent years is already altering the drug landscape. Drug companies are also facing other challenges that necessitate development and implementation of novel R&D strategies, including those that focus on nanotechnology and miniaturization. Clearly, there is enormous excitement and expectation regarding nanomedicine's potential impact. However, securing valid and defensible patent protection will be critical. Although early forecasts for nanomedicine commercialization are encouraging, there are numerous bottlenecks as well. One of the major hurdles is an emerging thicket of patent claims, resulting primarily from patent proliferation as well as continued issuance of surprisingly broad patents by the US Patent and Trademark Office (PTO). Adding to this confusion is the fact that the US National Nanotechnology Initiative's widely cited definition of nanotechnology is inaccurate and irrelevant from a nanomedicine perspective. It is also the cause of the inadequate patent classification system that was recently unveiled by the PTO. All of this is creating a chaotic, tangled patent landscape in various sectors of nanomedicine where the competing players are unsure of the validity and enforceability of numerous issued patents. If this trend continues, it could stifle competition and limit access to some inventions. Therefore, reforms are urgently needed at the PTO to address problems ranging from poor patent quality and questionable examination practices to inadequate search capabilities, rising attrition, poor employee morale and a skyrocketing patent application backlog. Only a robust patent system will stimulate the development of commercially viable nanomedicine products that can drastically improve a patient's quality of life and reduce healthcare costs. PMID- 17716181 TI - Mimicking nature's nanocarrier: synthetic low-density lipoprotein-like nanoparticles for cancer-drug delivery. PMID- 17716182 TI - Particulate nanomedicine in the footsteps of platelet homing. PMID- 17716183 TI - Controlled release of recombinant human bone morphogenetic protein-7 in nanoscaffolds. PMID- 17716184 TI - BioForce Nanosciences, Inc. AB - BioForce Nanosciences, Inc. (BFNH.OB) develops and commercializes nanotechnology tools and applications for the life sciences. The company is based in Ames, Iowa, and has two divisions--instruments and applications. The instrument division includes the Nano eNabler system and associated consumables (SPT print cartridges and Sindex substrates) and a surface decontamination device known as the ProCleaner. The applications division develops Nano eNabler-based applications for a variety of purposes. The current application pipeline includes the patented ViriChip pathogen detection and identification system, the Chip-On-A-Tip ultraminiaturized cancer biomarker detection system and a proprietary method for high-throughput molecular interaction screening known as FAST. The unique capabilities of the Nano eNabler system allow the creation of novel applications that take advantage of vastly reduced spatial scales and sample volumes. Popular applications of the Nano eNabler system include: functionalizing biosensors, including micro-electromechanical systems/nano-electromechanical systems devices; patterning surfaces with molecules to study cell growth, behavior and differentiation; performing ultrasensitive bioassays; and printing arrays in confined spaces in microfluidic devices. PMID- 17716185 TI - Nanotechnology in clinical proteomics. PMID- 17716186 TI - Run, rabbit, run: animal study with nanotubes provides promising results. PMID- 17716187 TI - Ocular drug delivery: nanomedicine applications. AB - Nanocarriers, such as nanoparticles, liposomes and dendrimers, are used to enhance ocular drug delivery. Easily administered as eye drops, these systems provide a prolonged residence time at the ocular surface after instillation, thus avoiding the clearance mechanisms of the eye. In combination with a controlled drug delivery, it should be possible to develop ocular formulations that provide therapeutic concentrations for a long period of time at the site of action, thereby reducing the dose administered as well as the instillation frequency. In intraocular drug delivery, the same systems can be used to protect and release the drug in a controlled way, reducing the number of injections required. Another potential advantage is the targeting of the drug to the site of action, leading to a decrease in the dose required and a decrease in side effects. PMID- 17716188 TI - Recent advances on surface engineering of magnetic iron oxide nanoparticles and their biomedical applications. AB - Magnetic nanoparticles with appropriate surface coatings are increasingly being used clinically for various biomedical applications, such as magnetic resonance imaging, hyperthermia, drug delivery, tissue repair, cell and tissue targeting and transfection. This is because of the nontoxicity and biocompatibility demand that mainly iron oxide-based materials are predominantly used, despite some attempts to develop 'more magnetic nanomaterials' based on cobalt, nickel, gadolinium and other compounds. For all these applications, the material used for surface coating of the magnetic particles must not only be nontoxic and biocompatible but also allow a targetable delivery with particle localization in a specific area. Magnetic nanoparticles can bind to drugs and an external magnetic field can be applied to trap them in the target site. By attaching the targeting molecules, such as proteins or antibodies, at particles surfaces, the latter may be directed to any cell, tissue or tumor in the body. In this review, different polymers/molecules that can be used for nanoparticle coating to stabilize the suspensions of magnetic nanoparticles under in vitro and in vivo situations are discussed. Some selected proteins/targeting ligands that could be used for derivatizing magnetic nanoparticles are also explored. We have reviewed the various biomedical applications with some of the most recent uses of magnetic nanoparticles for early detection of cancer, diabetes and atherosclerosis. PMID- 17716189 TI - Thiomers: forms, functions and applications to nanomedicine. AB - Thiolated polymers or designated thiomers are gained by immobilization of sulhydryl-bearing ligands on the polymeric backbone of well established polymers, such as chitosan and poly(acrylates). This functionalization leads to significantly improved properties compared with the corresponding unmodified polymers. Mucoadhesive properties are strongly improved by the formation of disulfide bonds between thiol groups of the thiomer and cysteine-rich glycoproteins of the mucus gel layer. Moreover, enzyme- and efflux-pump inhibiting, as well as significantly improved permeation-enhancing properties, are advantages of polymer thiolization. Thiomer micro- and nano-particlulate delivery systems can be generated via different techniques, such as in situ gelation and subsequent covalent crosslinking, radical emulsion polymerization, emulsification/solvent evaporation or air jet milling. As thiomer micro- and nano particles were shown to exhibit the same features as thiolated polymers per se, they might be useful tools for the delivery of various types of challenging drugs. PMID- 17716190 TI - Sol-gel production of bioactive nanocoatings for medical applications. Part II: current research and development. AB - Over the years, the use of hydroxyapatite as coatings for medical devices and drug-delivery systems has gone through a revolution - from being a rarity to being an absolute necessity. Without these coatings, many medical implants and devices would never reach their true potential in their intended applications, such as in the dental and orthopedic fields. Coatings of hydroxyapatite are often applied to metallic implants to alter their surface properties. The aim of this article is to present an evaluation of the published work regarding current research and applications and to review the methods used for the production of hydroxyapatite nanocoatings. PMID- 17716191 TI - Visualization and dynamic size evaluation of nanoparticles in solution by single optical fiber-illuminated video microscope analysis. AB - AIM: It is hoped that nanoparticles will become ever more useful in the development of nanomedicine. To evaluate the behavior of nanoparticles in solution, we aimed to establish a single optical fiber-illumination method that is easy to integrate with a conventional microscope at low cost. METHODS: Solutions of gold nanoparticles and carbon nanotubes were analyzed in a single optical fiber-illuminated video microscope and the tracks of Brownian motion of these nanoparticles were traced using video images. Their diffusion coefficient was measured by the mean square displacement of the movement. Using the diffusion coefficient in the Stokes-Einstein equation, the hydrodynamic diameter of the nanoparticles in solution was evaluated. RESULTS: The visualization of gold nanoparticles clearly in a high signal-to-noise ratio was achieved. The evaluated particle sizes of gold nanoparticles were similar to those obtained by a transmission electron microscope and the aggregation process of the carbon nanotubes following incubation was also observed and similar size estimation of the aggregates was performed. CONCLUSION: The single fiber-illumination method was applicable to visualize nanoparticle movement clearly and to estimate their sizes in solution. This simple method is suitable for the in situ observation of the nanoparticle-binding process to target cells. PMID- 17716192 TI - Quantum dot-based sensor for improved detection of apoptotic cells. AB - The development of new imaging probes to noninvasively detect, diagnose and guide therapy for a large variety of diseases is needed. Quantum dots are highly fluorescent and photostable nanoparticles that are finding increasing applications as imaging probes. We have conjugated quantum dots to annexin A5, in order to develop a sensor for detecting apoptotic cells. The sensor specifically recognizes phosphatidylserine on the extracellular leaflet of the plasma membrane through the annexin A5. This quantum dot-based sensor allows increased sensitivity of detection and continuous monitoring of apoptotic cells over time periods that are longer than previously possible. PMID- 17716193 TI - A platform for ultrasensitive and selective multiplexed marker protein assay toward early-stage cancer diagnosis. AB - Multiplexed marker protein assay is critical in the diagnosis of complex diseases that cannot be diagnosed by detection of a single marker protein. Gold nanoparticle (Au NP) probes barcoded with reporter DNAs and magnetic microparticles functionalized with a capture antibody were developed for the multiplexed detection of three cancer marker proteins. Three types of Au NP probes were used and each Au NP probe was cofunctionalized with reporter (barcode) DNAs and a specific antibody for each corresponding target protein. Target proteins (antigens) were exposed to magnetic microparticles to form complexes and Au NP probes bound to the resulting target-magnetic microparticle complex through antigen-antibody interaction in a different region of the target protein. After magnetic separation of the complexes, barcode DNAs were released, hybridized with capture DNAs printed on a chip and then identified using a scanometric assay that involved silver amplification. Using this method, Mirkin and colleagues successfully demonstrated, for the first time, a highly selective and sensitive multiplexed protein assay against three cancer marker proteins at low picomolar concentration in a buffer of serum media. PMID- 17716195 TI - Liposome-nanoparticle hybrids for multimodal diagnostic and therapeutic applications. AB - Liposomes have a decade-long clinical presence as nanoscale delivery systems of encapsulated anthracycline molecules. However, their use as delivery systems of nanoparticles is still in the preclinical development stages. Liposome nanoparticle hybrid constructs present great opportunities in terms of nanoscale delivery system engineering for combinatory therapeutic-imaging modalities. Moreover, many novel materials are being developed in nanotechnology laboratories that often require methodologies to enhance their compatibility with the biological milieu in vitro and in vivo. Liposomes are structurally suitable to make nanoparticles biocompatible and offer a clinically proven, versatile platform for the further enhancement of pharmacological efficacy. Small iron oxide nanoparticles, quantum dots, liposomes, silica and polystyrene nanoparticles have been incorporated into liposomes for a variety of different applications. In this review, all such liposome-nanoparticle hybrid systems are described, both in terms of their structural characteristics and the potential they offer as diagnostic and therapeutic multimodality agents. PMID- 17716196 TI - Mesoporous silica nanomaterial-based biotechnological and biomedical delivery systems. AB - This review details the recent advancements in the design of mesoporous silica nanomaterials for controlled release drug, gene and neurotransmitter delivery applications. The high surface area (>900 m2/g), tunable pore diameter (2-20 nm) and uniform mesoporous structure (hexagonal channels or cubic pores) of the mesoporous silicas offer a unique advantage for loading and releasing large quantities of biomedical agents. Recent breakthroughs in controlling the particle size and shape of these materials have greatly improved the biocompatibility and the cellular uptake efficiency. The strategy of using various removable capping moieties, such as photo- or redox-responsive organic groups, inorganic nanoparticles, dendrimers and polymers, to encapsulate guest biomolecules inside the porous matrices further enables the utilization of these surface functionalized mesoporous silica nanomaterials for stimuli-responsive controlled release in vitro and in vivo. In addition to the reviewed studies, many new and exciting applications of these novel materials will soon be realized. PMID- 17716197 TI - Functionalized gold nanoparticles for drug delivery. AB - Functionalized gold nanoparticles represent highly attractive and promising candidates in the applications of drug delivery owing to their unique dimensions, tunable functionalities on the surface and controllable drug release. This review illustrates the recent advances in the field of drug delivery using gold nanoparticles as carriers for therapeutic agents. PMID- 17716198 TI - Hyperthermic effects of gold nanorods on tumor cells. AB - Plasmon-resonant gold nanorods, which have large absorption cross sections at near-infrared frequencies, are excellent candidates as multifunctional agents for image-guided therapies based on localized hyperthermia. The controlled modification of the surface chemistry of the nanorods is of critical importance, as issues of cell-specific targeting and nonspecific uptake must be addressed prior to clinical evaluation. Nanorods coated with cetyltrimethylammonium bromide (a cationic surfactant used in nanorod synthesis) are internalized within hours into KB cells by a nonspecific uptake pathway, whereas the careful removal of cetyltrimethylammonium bromide from nanorods functionalized with folate results in their accumulation on the cell surface over the same time interval. In either case, the nanorods render the tumor cells highly susceptible to photothermal damage when irradiated at the nanorods' longitudinal plasmon resonance, generating extensive blebbing of the cell membrane at laser fluences as low as 30 J/cm2. PMID- 17716200 TI - The emergence of nanomedicine: a field in the making. PMID- 17716203 TI - Role of nanotechnology in developing new therapies for diseases of the nervous system. PMID- 17716205 TI - Nanotechnology for antiangiogenic cancer therapy. AB - Nanotechnology has advanced greatly in recent years and antiangiogenic therapy is becoming a promising approach for cancer treatment. Therefore, a combination of nanotechnology with antiangiogenic therapy should significantly enhance our ability to treat this deadly disease. alpha(v)beta(3)-integrin has often been used to target 'angiogenically active' tumor endothelium and many nanoparticles have been developed by combining this molecule with other agents for imaging and/or therapy. Development of improved and multifunctional nanoparticles is in progress for the enhancement of imaging, targeting, delivery and other processes. Modification for clinical use has been challenging. Concerns remain regarding safety, stability and tissue targeting of the particles, yet significant progress has been made. In this review, studies targeting 'angiogenically active' tumor endothelium using nanoparticles are discussed. The number of studies using multifunctional nanotechnology in tumor angiogenesis is still limited; however, significant advancement in this area is expected to come in the near future. PMID- 17716206 TI - Optical molecular imaging agents for cancer diagnostics and therapeutics. AB - The National Cancer Institute has set the goal of eliminating suffering and death due to cancer by 2015. A key strategy to achieve this goal is to improve early detection and prevention using novel molecularly targeted cancer diagnostics and therapeutics. As we begin to better understand the cellular and molecular pathways of carcinogenesis, it is possible to identify and treat precursors to cancer before changes are detected at anatomical levels. Developing imaging techniques with the ability to detect molecular signatures will not only target these abnormalities for therapy at the earliest possible stages but will also prove useful in further unraveling the molecular origins of cancer. The ability to image noninvasively in real-time makes optical imaging well suited to early detection. Molecular characterization in combination with optical imaging provides a sensitive and specific method to detect and prevent the progression of precancerous lesions. PMID- 17716207 TI - Magnetic micro- and nano-particle-based targeting for drug and gene delivery. AB - The use of magnetic micro- and nano-particles as carriers for in vivo targeting of therapeutic compounds was first proposed over 25 years ago. Since then, a variety of animal studies have demonstrated the efficacy of the technique, however, only a handful of Phase I/II clinical trials have taken place. While the theoretical underpinnings have been lacking, recent advances in mathematical modeling of magnetic targeting, as well as the development of novel magnetic nanoparticle carriers and implantable magnets, show promise in progressing this technology from the laboratory to the clinic. PMID- 17716208 TI - Template synthesized nanotubes for biomedical delivery applications. AB - This review details the advances made in alumina template-synthesized nanotubes and nano test tubes as delivery vehicles for biomedical applications. Most current research has focused on spherical nanoparticles because they are easier to make; however, cylindrical particles or nanotubes offer many advantages over spherical particles. One advantage is that the template is tunable, which means the pore diameter and template thickness can be controlled, resulting in larger payload capacities for nanotubes. Another advantage is that template synthesized nanotubes can be differentially functionalized on their inner and outer surfaces. Inner and outer surface nanotube modification for use in drug extraction, antibody-antigen interactions and magnetization is discussed. Recent advances made in covalent capping ('corking') nanotubes to prevent premature payload leakage are also covered. Although many applications for nanotubes have already been discovered, many new and exciting paths await exploration. PMID- 17716209 TI - Nanowire sensors for medicine and the life sciences. AB - The interface between nanosystems and biosystems is emerging as one of the broadest and most dynamic areas of science and technology, bringing together biology, chemistry, physics and many areas of engineering, biotechnology and medicine. The combination of these diverse areas of research promises to yield revolutionary advances in healthcare, medicine and the life sciences through, for example, the creation of new and powerful tools that enable direct, sensitive and rapid analysis of biological and chemical species, ranging from the diagnosis and treatment of disease to the discovery and screening of new drug molecules. Devices based on nanowires are emerging as a powerful and general platform for ultrasensitive, direct electrical detection of biological and chemical species. Here, representative examples where these new sensors have been used for detection of a wide-range of biological and chemical species, from proteins and DNA to drug molecules and viruses, down to the ultimate level of a single molecule, are discussed. Moreover, how advances in the integration of nanoelectronic devices enable multiplexed detection and thereby provide a clear pathway for nanotechnology, enabling diverse and exciting applications in medicine and life sciences, are highlighted. PMID- 17716210 TI - Cell signaling arising from nanotopography: implications for nanomedical devices. AB - This review discusses the roles in signaling to cells by nanochemical, nanostructural (nanotopography) and mechanical means, as well as recent work and trends in nanobioscience that are relevant to therapeutic applications. It is suggested that the mechanical results may often integrate the other two types of signal. Although the field is still in an almost embryonic but rapidly developing state, it is possible to envisage potential medical devices. Nanoparticle-based therapies are recognized as having some appreciable hazards, while those based on extended nanofeatured surfaces probably have fewer risks. PMID- 17716211 TI - Novel surface patterning approaches for tissue engineering and their effect on cell behavior. AB - Methods for the creation of specially designed surfaces for use in the preparation of tailor-made tissue constructs with the ultimate aim of tissue engineering are reviewed here. Fundamental aspects of cell adhesion, proliferation and differentiation and the parameters involved in these processes are discussed. A survey of recent micro- and nano-technological methods for creating physical and chemical cues on tissue engineering carriers is presented. This overview is supported with data from the literature on various applications of different cells on materials with widely differing chemistries and physical properties. Interactions between different cell types and micro- and nano fabricated substrates are summarized. PMID- 17716212 TI - Bioceramics as nanomaterials. AB - Nanostructured materials possess unique capabilities for specific interactions with biological entities. This article reviews several types of nanostructured ceramics, cements and coatings that are being considered for use in medical applications. The processing methods for obtaining ceramics are presented and related to the properties (such as wettability, topography and charge) that directly affect interactions with biological entities (ions, biomacromolecules and cells). The literature reviewed demonstrates that these interactions are directly affected by the nanostructure of the ceramic surfaces. Thus, the understanding and control of the interactions between nanoceramics and biological entities may play one of the leading roles in the development of nanomedicine. PMID- 17716213 TI - Potential biomedical applications of the scanned nanopipette. AB - One grand challenge in current biology is to understand how individual cellular molecules interact together to form a functioning living cell. This requires new methods to image a live cell on the nanoscale. The scanned nanopipette can be used to obtain high resolution noncontact images of the surface of live cells under physiological conditions and has been used to develop a family of related methods that allow mapping of cell function on the nanoscale, and hence allow the relationship between cell structure and function to be probed. This is a powerful method to bridge the current gap between high resolution structures of individual molecular complexes and low resolution imaging of live cell structure and function. PMID- 17716214 TI - Nanostructure-mediated thermal therapy--the path from bench to clinic. PMID- 17716215 TI - Quantum-dots-FRET nanosensors for detecting unamplified nucleic acids by single molecule detection. PMID- 17716216 TI - Pushing miRNA quantification to the limits: high-throughput miRNA gene expression analysis using single-molecule detection. PMID- 17716219 TI - Zyvex Corporation. AB - Founded in 1997, Zyvex is the first molecular nanotechnology company. The company's vision is to become the worldwide supplier of tools, products and services that enable adaptable, affordable and molecularly precise manufacturing. Zyvex technology is being used in biomaterials and subcellular characterization, nanomaterial composites for biomedical implants and 3D microsystems for miniature instrumentation. Nanotechnology is pervasive within biological systems, from membranes (tens of nanometers thick) that facilitate molecular trafficking into and within cells, to proteins (just a few nanometers in size) that perform most structural and functional duties of living organisms. It therefore stands to reason that tools to enable exploration and characterization of biological nanosystems and materials to enhance and repair these systems will be required to realize the full potential of nanomedicine. PMID- 17716221 TI - Genetic variation that contributes to nicotine dependence. PMID- 17716223 TI - RNAi extravaganza: from biochemistry to drugs and therapeutics. PMID- 17716224 TI - Glutathione S-transferases pi 1, alpha 1 and M3 genetic polymorphisms and the risk of hepatocellular carcinoma in humans. AB - INTRODUCTION: Glutathione S-transferases pi1, alpha1 and micro3 are members of an enzymatic superfamily involved in the conjugation and detoxification of carcinogens. Polymorphisms affecting the genes encoding these enzymes may modify their ability to neutralize carcinogens. Our aim was to investigate whether these polymorphisms affect the risk of developing hepatocellular carcinoma in humans. METHODS: A total of 184 white Spanish patients diagnosed with hepatocellular carcinoma and 248 healthy control subjects from the same ethnic origin were included. GSTA1*B promoter allele, GSTM3*B 3-bp-deleted allele and GSTP1 Ile105Val SNP were identified. RESULTS: No differences were found between the distribution of the studied polymorphisms, or in the allele frequencies for variant alleles in patients and controls: 0.411 and 0.371 for GSTA1, 0.116 and 0.131 for GSTM3, and 0.285 and 0.309 for GSTP1, respectively. Among patients the GSTP1 mutated allele was more frequent in those drinking more than 50 g ethanol/day (odds ratio: 2.00; 95% confidence intervals: 1.06-3.78). Age at diagnosis, gender, tobacco use and hepatitis B and C viral status did not influence these results. CONCLUSION: We conclude that the studied polymorphisms affecting GSTP1, GSTA1 and GSTM3 genes are probably not related to the risk of developing hepatocellular carcinoma in the studied population. PMID- 17716225 TI - Association between paraoxonase-1 Q192R polymorphism and lung function among Saskatchewan grain handlers. AB - INTRODUCTION: Paraoxonase-1 (PON1) is a high-density, lipoprotein-associated, multifunctional antioxidant enzyme that is detected in nonciliated bronchiolar epithelial cells, although its role in the lung has not yet been clarified. We therefore investigated the association between the PON1 Q192R polymorphism and lung function. PATIENTS & METHODS: A total of 216 male Saskatchewan grain handlers provided demographic, occupational and respiratory-symptom information by means of questionnaires, and thereafter underwent PON1 Q192R genotyping and lung-function testing. RESULTS: Mean lung-function values did not differ among the Q192R genotypes. However, current smokers with the Q/Q genotype had a higher mean percent predicted forced expiratory volume in the first second (FEV(1)), and absolute and percent predicted FEV(1) per forced vital capacity (FVC) compared with current smokers with at least one 192R allele (100.9 +/- 11.2% vs 92.0 +/- 15.1%, p = 0.01; 78.0 +/- 5.9% vs 74.1 +/- 6.8%, p = 0.03; and 96.8 +/- 7.1% vs 92.1 +/- 8.3%, p = 0.03; respectively). The incidence of subjects with FEV(1)/FVC less than 70% was significantly higher in current smokers with at least one 192R allele than in nonsmokers with the Q/Q genotype (odds ratio: 5.0; 95% confidence interval: 1.5-17.4). The protective effect of the Q/Q genotype was not found in nonsmokers. The FVC was not influenced by either PON1 genotype or smoking status. CONCLUSION: The results obtained from grain handlers suggest that PON1 may play some role in the protection of the airways against the toxicity of cigarette smoke, and the 192R allele may be a novel genetic risk factor for airway injury. PMID- 17716226 TI - Role of MED12 in transcription and human behavior. AB - The Mediator complex is a fluid assemblage of approximately 25 proteins that is essential for eukaryotic transcriptional regulation. Mediator of RNA polymerase II transcription (MED)12 (HOPA) is a 25-kb Xq13 member of the Mediator complex that plays a key role in the complex and directly moderates receptor tyrosine kinase, nuclear receptor and Wnt pathway signaling. Sequence variation in two MED12 protein domains has been linked to neuropsychiatric illness. First, variants in the Leu-Ser domain have been linked to Opitz-Kaveggia and Lujan syndromes, which are forms of X-linked mental retardation. Second, a balanced polymorphism in the C terminus opposite-paired domain, a key motif in the MED12 mediated transcriptional repression of Wnt signaling, has been associated with increased risk for psychosis. We conclude that variation of MED12 is associated with a wide variety of clinical presentations whose severity is dependent on the location and nature of the variation, and that a thorough understanding of MED12's role in transcriptional regulation could have significant benefits for human healthcare. PMID- 17716227 TI - Pharmacogenetics of thiazolidinedione therapy. AB - The thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor gamma agonists and have glucose-lowering, insulin-sensitizing and anti inflammatory effects. TZDs are approved for the treatment of Type 2 diabetes, and have been studied as a diabetes-prevention strategy. Despite widespread use of TZDs, a large number of patients fail to achieve a substantial reduction in glucose, or an improvement in insulin sensitivity, following treatment. Available data suggest that polymorphisms in genes encoding TZD drug targets, effector proteins and metabolizing enzymes contribute to the observed interindividual variability in TZD response and disposition. The purpose of this review is to highlight recent developments in the field of TZD pharmacogenetics, specifically focusing on clinical studies that have investigated genetic determinants of TZD response (i.e., reduction in glycemia and improvement in insulin sensitivity), disposition (i.e., pharmacokinetics), and side effects in patients with Type 2 diabetes and patients at risk for Type 2 diabetes. PMID- 17716228 TI - Pharmacogenetics of the response to beta 2 agonist drugs: a systematic overview of the field. AB - The response to beta2-agonist treatment shows large repeatability within individuals and may thus be determined by genetic influences. Here we present a systematic overview of the available genetic association and linkage data for beta2-agonist treatment response. Systematic searches identified 66 eligible articles, as of March 2007, pertaining either to B2AR gene polymorphisms and short-acting or long-acting beta2-agonists or to another 29 different genes. We systematize these study results according to gene, agent and type of outcomes addressed. The systematic review highlights major challenges in the field, including extreme multiplicity of analyses; lack of consensus for main phenotypes of interest; typically small sample sizes; and poor replicability of the proposed genetic variants. Future studies will benefit from standardization of analyses and outcomes, hypothesis-free genome-wide association testing platforms, potentially additional fine mapping around new discovered variants, and large scale collaborative studies with prospective plans for replication among several teams, with transparent public recording of all data. PMID- 17716230 TI - miRNAs: from neurogeneration to neurodegeneration. AB - miRNAs are reported to sequence-specifically control the translation of target mRNAs by binding to 3 UTRs. The abundant expression of miRNAs in the brain highlights their biological significance in neurodevelopment. Many studies have shown that miRNAs are involved in a variety of functions, including developmental transitions and neuronal patterning, apoptosis, fat metabolism and regulation of hematopoietic lineage differentiation in different organisms. miRNAs act as regulatory switches in the determination of developmental fate through their distinct patterns of expression. The tissue-specific expression of miRNAs during brain development could possibly direct the development of cells in different subtypes. Several miRNAs are localized to neuronal subtypes and exhibit a more diverse or specific expression pattern within various neuronal cell types such as glial cells and neuronal progenitor cells. Perturbations in the expression pattern of miRNAs could lead to defects in human brain development and neurological disorders. The bioinformatic prediction tools suggest that some genes involved in synaptic formations and mental retardation are putative targets for miRNAs. miRNAs have been shown to specify cell fates in the nervous system of worms and brain morphogenesis in fish, and their distinct expression patterns during mammalian brain development. This suggests a potential role of miRNAs in neurodevelopment of mammals and other organisms. In this review, I have focused on the role of miRNAs in brain development and possible neurological disorders. PMID- 17716229 TI - Apolipoprotein E and neurological disease: therapeutic potential and pharmacogenomic interactions. AB - The apolipoprotein E (apoE) polymorphism is emerging as a uniquely important genetic modifier that affects functional outcome from both acute and chronic neurological injuries. Recent attention has focused on common denominator mechanisms by which apoE might affect brain injury and/or brain repair responses in clinically diverse diseases. Although endogenous apoE likely serves several adaptive functions in the injured CNS, there is growing evidence that its effect on modifying brain inflammatory responses and providing protection from excitotoxic injury may be central to its protective properties. A more complete understanding of the role that apoE plays in the injured brain has led to novel therapeutic strategies for both acute and chronic neurological disease. PMID- 17716231 TI - Gene therapy for erectile dysfunction. AB - Erectile dysfunction is a disease that affects half of American men aged over 50 years. Many men respond to oral phosphodiesterase inhibitors but many do not. For this reason, many researchers are focusing their efforts on developing novel gene therapies for the treatment of erectile dysfunction. Aided by the meticulous characterization of the molecular cascades involved in the physiology of erection, several groups around the world are studying gene therapies in animal models, and one in a human clinical trial. Here we provide a review of the pathophysiology of erectile dysfunction and how it relates to the molecular targets of novel gene therapeutics. The field of gene therapy for the treatment of erectile dysfunction is continually growing, and this decade will likely see exciting results as the expansion from animal models to human clinical trials continues. PMID- 17716232 TI - G>C SNP of thymidylate synthase with respect to colorectal cancer. AB - Several studies indicate that low thymidylate synthase (TS) protein levels in tumor and normal tissues of colorectal cancer patients are associated with better clinical response to fluorouracil-based chemotherapy and higher risk of toxicity. However, no correlation or even reverse correlation has also been reported. These conflicting results may be partly due to the methodological limitations of the immunohistochemical techniques generally used to quantify thymidylate synthase expression. In this sense, a genetic approach aiming at determining the influence of the TS gene polymorphisms on clinical outcome seems more appealing. So far three polymorphisms have been identified and studied in the TYMS gene: the variable number of 28-bp tandem repeats (2R or 3R) in the 5 UTR; the G>C substitution at the 12th nucleotide in the second repeat of the 3R allele (3RG>3RC) and the 6-bp deletion in the 3 UTR (+6bp/-6bp 3 UTR). In vitro studies indicate that each of these polymorphisms can influence thymidylate synthase expression. In particular, the G>C SNP, which alters the E-box sequence binding an upstream stimulatory factor (USF-1), seems more important than the variable number of tandem repeats in determining TS gene expression in that the 3RC allele has a reduced translational activity compared with the 3RG allele, while showing the same activity as the 2R allele. In contrast with the in vitro findings, the clinical studies in colorectal patients failed to find a consistent relationship between the G>C polymorphism and clinical outcome measures (response, survival or toxicity). This discrepancy may be due to methodological heterogeneities amongst the studies, including genotyping in normal or tumor tissues, loss of heterozygosity in tumor cells not evaluated, variable doses and schedules of fluorouracil-based therapy, and variable tumor stage. The complexity of TYMS gene regulation, and the possibility that other polymorphisms may contribute to fluorouracil response, call for further studies before TYMS genotyping can be used in clinical practice to select colorectal cancer patients who are most likely to benefit from chemotherapy. PMID- 17716233 TI - Genetic diversity of hepatocellular carcinomas and its potential impact on targeted therapies. AB - Hepatocellular carcinoma (HCC) is one of the most frequent solid tumors worldwide and represents the third cause of mortality among deaths from cancer. It has been extensively studied in terms of genetic alteration in the last 10 years and our knowledge has dramatically increased in this field, leading to the definition of different altered pathways in hepatocarcinogenesis. Recently, a comprehensive study of genetic and transcriptomic alterations in a large series of HCC tumors enabled the identification of a six-group molecular-based classification of HCC, defined by a simple 16-gene signature. This classification is closely related to specific alteration of WNT and AKT oncogenic pathways. Together with the analysis of defined oncogenic proteins, such global classifications could be useful in the prediction of future-targeted therapy efficiency. PMID- 17716234 TI - Protein kinases as targets for cancer treatment. AB - In various types of malignancies, conventional forms of therapy (surgery, radiation and chemotherapy) are often ineffective, as well as harmful. In the last few years, a convergence of scientific advances has enabled the identification of molecular targets and signaling pathways specific to cancer cells, resulting in therapies with enhanced selectivity and efficacy and reduced toxicity. Compound validation has relied on target validation first, although some of the most successful drugs often have effects outside of their postulated mechanism. Protein kinases represent such molecular targets; considerable research effort has been devoted to the development of targeted drugs that inhibit the action of pathogenic kinases, and clinical studies performed so far have validated the positive effects of kinase inhibitors for cancer treatment. In this review, the specificity, mechanism of action and antitumor activity of several new small-molecule inhibitors of tyrosine and serine/threonine kinases are discussed. PMID- 17716236 TI - Increasing the robustness and validity of RNAi screens. AB - RNAi screening in mammalian cells has become a valuable method to identify and describe genetic relationships in both basic biology and disease mechanisms. Multiple efforts are underway to standardize how RNAi screening data are reported, including establishing experimental criteria for defining a validated hit from a screen, and the extent to which the primary screening data themselves are reported. These discussions have identified several key areas that require consistency, or at least understanding, before RNAi screening data can be used generally. Successfully addressing these targeted areas would broaden the use of RNAi screening data beyond advancing one or a few hits into validation experiments, to enable verification of primary screening data, and to facilitate comparisons between sample groups based on screening profiles. Areas for improving RNAi screening include general guidelines for validating hits from screens, the creation of standardized reporting structures for RNAi screening data, such as Minimum Information About an RNAi Experiment (MIARE), statistical methods for analyzing screening data that explicitly account for differences between screening RNAi reagents versus small molecules, and technical improvements to RNAi screening that improve the analysis of gene knockdowns, including multiparametric approaches, such as high-content screening. This review will discuss how these approaches can improve RNAi screening data at the community level and for an individual researcher trying to manage an RNAi screen. PMID- 17716235 TI - Toxicogenomics of A375 human malignant melanoma cells. AB - Toxicogenomics applications are increasingly applied to the evaluation of preclinical drug safety, and to explain toxicities associated with compounds at the mechanism level. In this review, we aim to describe the application of toxicogenomics tools for studying the genotoxic effect of active compounds on the gene-expression profile of A375 human malignant melanoma cells, through the other molecular functions of target genes, regulatory pathways and mechanisms of malignant melanomas. It also includes the current systems biology approaches, which are very useful for analyzing the biological system and understanding the entire mechanisms of malignant melanomas. We believe that this review would be very potent and useful for studying the toxicogenomics of A375 melanoma cells, and for further diagnostic and therapeutic applications. PMID- 17716237 TI - Evidence-based management of nutrigenomics expectations and ELSIs. AB - Nutrigenomics is a new application context for genomics technologies that focuses on the bidirectional study of genetic factors influencing host (individuals' or populations') response to diet and the effects of bioactive constituents in food on host genome and gene expression. Nutrigenomics is considered the next wave after pharmacogenomics for individualization of health interventions. However, relatively little attention has been given to the specific ethical-legal-social issues (ELSIs) and sociotechnical expectations raised by nutrigenomics research. Some of the ELSIs, such as ensuring privacy of genetic information and implications of genetic testing for health insurance and employment, may be shared across the continuum of genomic technology applications in human disease genetics, pharmacogenomics and nutrigenomics. However, there are certain aspects of nutrigenomics research that may result in unique or unprecedented ELSIs. For example, nutrigenomics has a strong focus on public health and the prevention/modification of 'predisease phenotypes' in apparently healthy individuals. Thus, in contrast to previous applications of genomics technologies, where the goal is to distinguish existing disease from absence of disease, the aim of nutrigenomics is the discernment of nuanced differences in predisease states. Moreover, there is evidence to suggest that ELSIs may be different in biomarker discovery, translational research and clinical testing stages of nutrigenomics. Ideally, ELSI research and nutrigenomics bioscience should progress in parallel and in a commensurate manner. We suggest that qualitative research methods, using a hypothesis-free approach, can be employed to gain deeper insights on complex bioethics issues that do not ordinarily lend themselves to formal hypothesis testing with the quantitative methods used in biomedical sciences. PMID- 17716238 TI - Characterization of the drugged human genome. AB - Human drug targets are a part of our genome of special relevance to human disease. However, the number and nature of drug target genes has not yet been conclusively assessed. We analyzed involvement in biochemical functions, biological processes and pathways, with chromosome, cellular and tissue distribution of the 392 human drug targets collected in DrugBank. Comparison with the whole human genome reveals their scarcely diverse characteristics, largely dominated by rhodopsin-like 7 transmembrane receptors involved in the neuroactive ligand-receptor interaction pathway and located in the plasma membrane. Drug target genes are frequently expressed in multiple tissues, suggesting drug application in distinct disease classes. Intersections with other clinically relevant gene sets, such as the Mendelian disorder-linked genes and various molecular cancer signatures, are discussed. PMID- 17716239 TI - Silent SNPs: impact on gene function and phenotype. AB - Evaluation of: Kimchi-Sarfaty C, Oh JM, Kim IW et al.: A 'silent' polymorphism in the MDR1 gene changes substrate specificity. Science 315, 525-528 (2007) [1] . Individuals carrying silent SNPs in the MDR1 gene encoding P-glycoprotein sometimes reveal altered P-glycoprotein pharmacokinetics. There is no rational explanation for why silent SNPs might have such effects, especially when no change in P-glycoprotein mRNA and protein expression levels has been observed. The purpose of this study was to perform careful ex vivo (in cells) analysis of the effects of the three polymorphisms (C1236T, G2677T C3435T) on P-glycoprotein expression and activity. As a result, it has been shown that silent polymorphisms (in particular, C3435T) in MDR1 can alter P-glycoprotein conformation and protein activity/substrate specificity. This study is of immense importance as it demonstrates for the first time that naturally occurring silent SNPs can lead to the synthesis of protein product with the same amino acid sequence but different structural and functional properties. Thus, silent SNPs should no longer be neglected in determining the likelihood of development of various diseases, and should be taken into account in personalized drug treatment and development programs. PMID- 17716240 TI - SimuGen Ltd: reliable, early prediction of drug toxicity with toxicogenomics, human cell culture and computational models. AB - Toxicogenomics is, arguably, the most exciting endeavor to better understand and/or predict the toxicity of drugs during their development, using technologies such as gene-expression microarrays. Through much of its (sometimes overzealous) build-up, toxicogenomics has found a natural niche as a bioinformatics and/or pattern-recognition tool, aiming to improve the mechanistic understanding of toxicity and animal-to-human extrapolation. The problem is that current approaches still need maturing and are expensive, slow, highly variable, often qualitative and do not easily yield information useful to decide whether to progress a drug candidate or not. Most crucially, they fail to address the main problem that industry faces--to be able to predict toxicity earlier in the discovery/development process. Rather than providing a conventional animal toxicogenomics service, SimuGen Ltd is launching a product that models gene expression in human cell culture, using an entirely novel approach to predict a remarkable spectrum of human in vivo (clinical) toxic end points, and to predict dose-toxicity relationships and molecular structure-toxicity relationships. PMID- 17716241 TI - Na+/Ca2+ exchangers: three mammalian gene families control Ca2+ transport. AB - Mammalian Na+/Ca2+ exchangers are members of three branches of a much larger family of transport proteins [the CaCA (Ca2+/cation antiporter) superfamily] whose main role is to provide control of Ca2+ flux across the plasma membranes or intracellular compartments. Since cytosolic levels of Ca2+ are much lower than those found extracellularly or in sequestered stores, the major function of Na+/Ca2+ exchangers is to extrude Ca2+ from the cytoplasm. The exchangers are, however, fully reversible and thus, under special conditions of subcellular localization and compartmentalized ion gradients, Na+/Ca2+ exchangers may allow Ca2+ entry and may play more specialized roles in Ca2+ movement between compartments. The NCX (Na+/Ca2+ exchanger) [SLC (solute carrier) 8] branch of Na+/Ca2+ exchangers comprises three members: NCX1 has been most extensively studied, and is broadly expressed with particular abundance in heart, brain and kidney, NCX2 is expressed in brain, and NCX3 is expressed in brain and skeletal muscle. The NCX proteins subserve a variety of roles, depending upon the site of expression. These include cardiac excitation-contraction coupling, neuronal signalling and Ca2+ reabsorption in the kidney. The NCKX (Na2+/Ca2+-K+ exchanger) (SLC24) branch of Na+/Ca2+ exchangers transport K+ and Ca2+ in exchange for Na+, and comprises five members: NCKX1 is expressed in retinal rod photoreceptors, NCKX2 is expressed in cone photoreceptors and in neurons throughout the brain, NCKX3 and NCKX4 are abundant in brain, but have a broader tissue distribution, and NCKX5 is expressed in skin, retinal epithelium and brain. The NCKX proteins probably play a particularly prominent role in regulating Ca2+ flux in environments which experience wide and frequent fluctuations in Na+ concentration. Until recently, the range of functions that NCKX proteins play was generally underappreciated. This situation is now changing rapidly as evidence emerges for roles including photoreceptor adaptation, synaptic plasticity and skin pigmentation. The CCX (Ca2+/cation exchanger) branch has only one mammalian member, NCKX6 or NCLX (Na+/Ca2+-Li+ exchanger), whose physiological function remains unclear, despite a broad pattern of expression. PMID- 17716242 TI - Retaining the professionalism of cosmetic dermatology. PMID- 17716243 TI - Paradoxical effects of hair removal systems: a review. AB - Although a variety of lasers have proven to be clinically effective for long-term hair removal, the use of these lasers has also been associated with undesirable side effects, such as hyper- and hypopigmentation, crusting, erythema, and edema. One notable side effect that seems to be underreported in the literature is the growth of fine dark hair in untreated areas close to the treated ones. This contradictory hypertrichosis is known as the paradoxical effect. In this paper, we review the published reports of the paradoxical effect and offer some possible explanations for this effect. The paradoxical effect has been documented most commonly after the use of induced pulse light and alexandrite lasers. One possible explanation is the activation of dormant hair follicles by suboptimal fluences. Another mechanism may be the synchronization of hair growth cycles by direct light stimulation. PMID- 17716244 TI - The third dimension in facial rejuvenation: a review. AB - BACKGROUND: Facial rejuvenation has long been dominated by surgical techniques that act on only two dimensions of the face, ignoring the third dimension (facial volume); therefore, a truly youthful look remains elusive. OBJECTIVES: This paper aims to define the various surgical procedures employed by cosmetic surgeons that can be combined with alloplastic implants or injectable devices in order to restore lost facial volume. METHODS AND MATERIALS: A search of the literature was performed. RESULTS: Alloplastic augmentation and implants provide permanent restoration of facial volume, but require invasive surgery. Soft-tissue fillers include autologous fat, calcium hydroxylapatite, and a variety of polymers. Devices based on collagen and hyaluronic acids provide correction of superficial lines and folds, but cannot offer long-lasting restoration of facial volume. The only fillers that have been proven to augment facial volume are autologous fat, calcium hydroxylapatite, poly-L-lactic acid, polyacrylamide, poly-alkyl-imide, and methylpolysiloxane. CONCLUSIONS: For optimal facial rejuvenation, the accepted surgical techniques of skin lifting and tightening could be combined with volumizing devices, thereby addressing ptosis, lines, folds, and volume loss. PMID- 17716245 TI - Treatment of cellulite with a bipolar radiofrequency, infrared heat, and pulsatile suction device: a pilot study. AB - BACKGROUND: Very few therapeutic options have proven effective in the treatment of cellulite. AIMS: To evaluate the effectiveness and adverse effects of a bipolar radiofrequency (RF), infrared (IR) heat and pulsatile suction device for the treatment of cellulite. METHODS: Twelve subjects were treated with the RF light-based device. All subjects were treated twice weekly for a total number of eight to nine treatments. Subjects were evaluated using standardized photographs, and measurements of body weight and circumference of treatment sites at baseline, immediately after the last treatment, and four weeks and one year after the last treatment. Clinical improvement scores of comparable photographs using a quartile grading scale (0 = <25%, 1 = 25-50%, 2 = 51-75%, 3 = >75% improvement) were judged independently by two non-treating dermatologists after the series of treatment. RESULTS: The average body weights at baseline, immediately after the last treatment, and four weeks and one year after the complete treatment were 56.30, 56.05, 56.23, and 56.53 kg, respectively. The average circumferential reductions of the abdomen and thigh at the last treatment visit were 5.17 +/- 1.04 cm (6.32%+/- 1.82%) and 3.50 +/- 2.16 cm (6.23 +/- 3.58%), respectively. At four weeks after the last treatment, the average circumferential reductions of the abdomen and thigh were sustained at 3.17 +/- 2.75 cm (4.04%+/- 3.69%) and 3.50 +/- 2.04 cm (6.26%+/- 3.52%), respectively. At one year follow-up visit, the average circumferential reductions of the abdomen and thigh were maintained at 3.83 +/- 0.76 cm (4.64%+/- 1.15%) and 3.13 +/- 3.54 (5.50%+/- 6.12%), respectively. Average clinical improvement scores of the abdomen and thigh after the series of treatments were 0.75 (corresponding to approximately 25% improvement), and 1.75 (corresponding to approximately 50% improvement), respectively. CONCLUSIONS: A bipolar RF, IR heat and pulsatile suction device provides a beneficial effect on reduction of abdomen and thigh circumference, and smoothening of the cellulite. PMID- 17716246 TI - Transfer of the experimental methodology described in the FDA guidance for corticosteroid bioequivalence testing to pharmacodynamic effects caused by nicotinates. AB - BACKGROUND: The measurement of the pharmacodynamic response allows the noninvasive quantification of cutaneous drug penetration. AIMS: The objective of this study was to investigate whether the experimental methods described in the US Food and Drug Administration Guidance for Industry "Topical Dermatologic Corticosteroids: In vivo Bioequivalence" may be transferred to other response parameters such as skin redness and surface temperature. METHODS: Drug penetration experiments with methyl nicotinate in two different lipophilic vehicles were performed according to the FDA guidance for corticosteroid bioequivalence testing measuring the cutaneous erythema and skin temperature response. RESULTS: The guidance methodology was transferred to the response parameters redness and temperature. Bioequivalence testing was feasible with these response parameters. CONCLUSIONS: An open one-compartment model could only be confirmed for skin redness data by a compartmental analysis of response vs. time profiles. The obtained temperature data can neither be described by an open one-compartment nor by a two-compartment model. A correlation between skin color and skin surface temperature could not be found. PMID- 17716247 TI - Topical atropine sulfate for the treatment of axillary hyperhidrosis. AB - BACKGROUND: Axillary hyperhidrosis does not have a low-cost, free of secondary effects, satisfactory treatment. Eccrine hidrocystomas have been successfully treated with topical atropine solution. Hypothesis Axillary hyperhidrosis could respond to the topical application of atropine solution. METHODS: Ten patients were selected. Eight with mild pure primary axillary hyperhidrosis and two with compensatory sweating after sympathectomy. One milliliter of a water solution of atropine sulfate at 1% was applied twice a day over the affected area and massaged for 30 s. Treatment was maintained for 15 days. The results were rated using a scale from 1 to 10 of satisfaction. RESULTS: Only 2 of the 10 treated patients responded partially to the topical application of atropine sulfate. No local or systemic secondary effects were observed. CONCLUSIONS: The results of the study demonstrated that focal hyperhidrosis does not improve after the local application of anticholinergic drugs such as atropine sulfate. PMID- 17716248 TI - Cosmetic camouflage. AB - Although many skin conditions are amenable to treatment, on certain occasions dermatology and plastic surgery have not much to offer and patients are left with disfigurements. Cosmetic camouflage is a therapy that has been developed to alleviate the suffering of those who have been disfigured by a congenital or an acquired lesion and who have no other choice than living with their deformity. PMID- 17716249 TI - Injectable lipolysis: speculation vs. science. PMID- 17716250 TI - Established treatments of skin hypermelanoses. AB - Cutaneous hypermelanoses are frequently encountered conditions that can have severe adverse psychosocial and emotional effects on affected patients. Melasma, postinflammatory hyperpigmentation, drug-induced pigmentation, and erythema dischromicum perstans are among the most common cutaneous disorders leading to acquired skin hyperpigmentation. The treatment of these disorders is often challenging and requires a great deal of patience from the patient and a wealth of experience and knowledge from the dermatologist. Current treatments include depigmenting agents, chemical peels, and lasers. The ideal bleaching agent has to fulfill certain pharmacologic criteria. It should have a potent bleaching effect with a rapid time of onset, carry no side effects, and lead to a permanent removal of undesired pigment. We review the established treatment approaches of cutaneous hyperpigmentation based on literature review and our personal experience. PMID- 17716251 TI - Glucosamine: an ingredient with skin and other benefits. AB - Both glucosamine and its derivative N-acetyl glucosamine are amino monosaccharides that serve key biochemical functions on their own and as substrate precursors for the biosynthesis of polymers such as glycosaminoglycans (e.g., hyaluronic acid) and for the production of proteoglycans. Glucosamine has an excellent safety profile and has been shown to provide benefits in several clinical disorders. Glucosamine compounds have been reported to have several beneficial effects on the skin or skin cells. Because of its stimulation of hyaluronic acid synthesis, glucosamine has been shown to accelerate wound healing, improve skin hydration, and decrease wrinkles. In addition, as an inhibitor of tyrosinase activation, it inhibits melanin production and is useful in treatment of disorders of hyperpigmentation. Mechanistically, glucosamine also has both anti-inflammatory and chondroprotective effects. Clinical trials have shown benefit in using oral glucosamine supplementation to improve symptoms and slow the progression of osteoarthritis in humans. Glucosamine has also been used to prevent and treat osteoarthritis in animals. Based on other observations, glucosamine has been suggested for additional clinical uses, including treatment of inflammatory bowel disease, migraine headaches, and viral infections. The current clinical uses for topical and oral glucosamine compounds and the mechanistic rationale for these uses are reviewed here. PMID- 17716254 TI - Photoprotection: where do we stand? AB - Ultraviolet sun radiation can cause several deleterious effects on the skin, including photoaging and carcinogenesis. Physical protection and sunscreens are currently the two main types of photoprotection. Overall, people seem informed about the dangers of sun exposure, but sometimes they are not willing to implement the right sun-protection measures. Sunscreens are reported to be the most frequently used method worldwide, but they cannot substitute physical protection and a proportion of people do not apply them correctly. Public campaigns, together with fashion and the right role models, can still offer a lot in persuading people to change their habits towards a more sun-protected life. PMID- 17716255 TI - The staggered installation of dental implants and its effect on bone stresses. AB - PURPOSE: The aim of this study was to investigate the effect of offsetting the middle or peripheral implant on the compressive stress values in the crestal bone around the neck of the dental implant. MATERIALS AND METHODS: Three finite element models describing three titanium implants installed in quadrilateral pieces of bone was executed. A 2-mm nickel chromium superstructure representing a bridge was modeled over the implant abutments. In model 1, implants were installed along a straight line. Model 2 had the middle implant installed outside the line connecting the two peripheral implants buccally. Model 3 had the mesial implant installed out of alignment. Six 100-N loads were modeled on top of the mesial and middle implants of the three models individually. Loads 1 and 2 were directed vertically on the mesial and middle implants, while loads 3 and 4 represented the horizontal loads in the buccal direction. Loads 5 and 6 were directed mesially on the mesial and central implants. Maximal compressive stress levels in the crestal bone of the three models were then investigated. RESULTS: The results demonstrated that offset implant installation revealed slightly lower bone stresses under buccally or lingually directed horizontal forces. Slightly higher bone stresses under vertical loads were observed. Horizontal mesial or distal loads resulted in slightly higher bone stresses than those caused by buccal or lingual loading. CONCLUSIONS: The in-line implant alignment clearly had the safest compressive stress outcome on the surrounding structure under vertical loads. Under buccolingual loads, implant alignment with peripheral offset would have, relatively, the safest compressive stress outcome on bone. PMID- 17716256 TI - Internal sinus manipulation (ISM) procedure: a technical report. AB - BACKGROUND: The sinus augmentation procedure has facilitated dental implant treatment in the posterior maxilla where there is insufficient bone for implant placement. A modified Caldwell-Luc, lateral window technique can be applied in most cases needing sinus augmentation in order to create a larger bone volume. However, treatment morbidity can be a concern, especially in the form of postoperative swelling due to surgical trauma. Vertical augmentation using osteotomes has also been selected as a choice of treatment due to less invasive surgery and less postoperative trauma. Although the osteotome technique enables the surgeon to raise the sinus membrane internally through an implant osteotomy site, the quantity and predictability of bone augmentation can be limiting due to the elasticity of the Schneiderian sinus membrane, difficulty of the membrane to separate from the floor as well as the inability to have direct tactile access to "peel" the membrane off of the floor. PURPOSE: The objective of this report is to present a new, minimally invasive sinus augmentation technique, called the Internal Sinus Manipulation (ISM) procedure, which has been developed to facilitate sinus floor augmentation while reducing treatment morbidity and yet have direct tactile access to raise the membrane off of the sinus floor. SURGICAL TECHNIQUE: Access to the Schneiderian sinus membrane is achieved without perforation of the membrane through a conventional osteotomy drilling procedure alone or combined with osteotome technique, followed by reflection of the membrane utilizing special ISM instrumentation and bone graft procedure laterally and vertically through the osteotomy site. A planned implant is then placed. CONCLUSION: The Internal Sinus Manipulation procedure can be used as an alternative treatment modality for sinus augmentation as compared to the external lateral window technique while reducing postoperative morbidity for the patients who need implant treatment in posterior maxillary areas. PMID- 17716257 TI - Immediate loading of two implants supporting a ball attachment-retained mandibular overdenture: a prospective clinical study. AB - BACKGROUND: A prospective clinical study was conducted to evaluate clinically and radiographically the performance of two implants immediately loaded supporting a ball attachment-retained mandibular overdenture. MATERIALS AND METHODS: Seventeen completely edentulous patients were included in the study. Each patient received two implants inserted after a minimal flap reflection and no vestibular extension in order to reduce the postoperative swelling and facilitate immediate prosthesis connection. After implant placement, a mandibular complete denture was connected to the implants using ball attachments of appropriate height according to the depth of the peri-implant tissue. Patients were asked not to remove the denture for 1 week. No limitations to chewing function were given. At implant placement, the maximum value of insertion torque was recorded. Patients were examined at 1, 2, 4, 12, and 52 weeks postsurgery. At postoperative visit, occlusion was checked and the need for any prosthesis maintenance was recorded. The radiographic bone level (RBL) change was measured on periapical radiographs at baseline and 12 months after loading. RESULTS: After 12 months of loading, no implant failure was reported and the survival rate was 100%. Average RBL change was 0.7 mm +/- 0.5 mm. Of the 17 cases, two had major prosthetic complications and five patients required minor extra maintenance appointments. CONCLUSIONS: The immediate loading of two implants by means of ball attachment-retained mandibular complete denture may be a predictable treatment option. This clinical approach offers increased stability and comfort, while keeping a high implant success rate. PMID- 17716258 TI - Evaluation of factors influencing resonance frequency analysis values, at insertion surgery, of implants placed in sinus-augmented and nongrafted sites. AB - BACKGROUND: The immediate loading technique requires a high primary stability. Resonance frequency analysis (RFA) has been proposed to assess this stability with a quantitative method. PURPOSE: The aim of the present study was to evaluate if a good primary stability could be achieved in sites that had undergone a sinus augmentation procedure and also to evaluate the importance of different clinical factors in the determination of resonance frequency values at implant insertion. MATERIALS AND METHODS: In 14 patients, 80 implants were inserted. Sixty-three implants were inserted in a site previously treated with a sinus augmentation procedure, while 17 implants were inserted in healed or postextraction sites. For each implant, diameter, length, bone density, insertion torque, RFA value, and percentage of implant fixed to a nongrafted bone were recorded. RESULTS: Grafted sites showed high RFA values. A statistically significant positive correlation was found between resonance frequency values and implant diameter (p=0.007), implant length (p=0.02), diameter of the last bur used (p=0.01). No statistically significant correlation between RFA values and all the other variables considered was found. CONCLUSIONS: Sites treated with sinus augmentation procedures can offer good primary stability after 6 months of healing. The length and diameter of the implants, together with the geometry of the implant used, are important to obtain high RFA values. PMID- 17716259 TI - Maxillary sinus augmentation using sinus membrane elevation and peripheral venous blood for implant-supported rehabilitation of the atrophic posterior maxilla: case series. AB - BACKGROUND: Dental implants need appropriate bone volume for adequate stability in the rehabilitation after tooth loss. In the severely atrophic posterior maxilla, the clinical success of implant treatment sometimes requires a vertical ridge augmentation in the maxillary sinus floor. PURPOSE: The purpose of this investigation was to evaluate a maxillary sinus floor augmentation technique using a replaceable bone window, elevation of the membrane, placement of implants, and injection of the patient's own venous blood to fill the voids. MATERIALS AND METHODS: Six patients with need of maxillary sinus floor augmentation participated in the study. After preparation of a replaceable bone window in the lateral aspect of the sinus and careful elevation of the Schneiderian membrane, a total of 14 Branemark implants (TiUnite, MK III, Nobel Biocare AB, Goteborg, Sweden) were installed in the residual bone penetrating into the sinus cavity. The sinus cavity was then filled with peripheral venous blood and the bone window replaced and stabilized with a medical tissue glue (Aron Alpha A, Sankyo, Inc., Tokyo, Japan) to prevent blood leakage from the created compartment in the maxillary sinus. RESULTS: After a healing period of a minimum of 6 months, new bone was successfully generated in all 14 implant sites as judged from radiographs. One of the 14 implants failed, corresponding to a survival rate of 92.9% after a follow-up period ranging 12 to 34 months. CONCLUSIONS: The present case series demonstrate that the creation of a secluded space in the maxillary sinus and filling with venous blood results in bone formation at simultaneously installed dental implants over a 6-month period. PMID- 17716260 TI - Topography, microhardness, and precision of fit on ready-made zirconia abutment before/after sintering process. AB - BACKGROUND: Sintering porcelain on a ceramic abutment may change the microstructure and result in aging processes that influence the mechanical properties, internal strain, and the three-dimensional form of the abutment, thus causing a possible misfit between the abutment and the fixture. PURPOSE: The aim was to investigate topography, microhardness, and precision of fit on yttrium stabilized zirconia (Y-TZP) abutments before/after the sintering process. MATERIALS AND METHODS: Ten Y-TZP abutment samples were ground to a shape used in the clinical situation and divided at random into two groups: before/after sintering. After the surface roughness was measured on all abutments, the abutments were connected to fixture replicas, embedded in resin, and cut in the longitudinal axis. Both sides of the cut samples were measured with respect to microhardness and minimum distance between fixture and abutment surface. t-Test, one-way analysis of variance, and Bonferroni multiple comparisons were used to investigate statistical significant differences. RESULTS: The surface roughness (S(a) and S(dr)) after sintering was significantly higher than before sintering. The total average values of microhardness after sintering were statistically lower than before sintering with a difference of 2%. The total distance between abutment/fixture before/after sintering demonstrated no statistically significant difference. Contact between abutment/fixture was most common at the top area of the fixture. CONCLUSION: A slight decrease of microhardness and contamination of porcelain particles immediately below the veneered part were found on the Y-TZP abutment after sintering. The sintering process did not affect the precision of fit. PMID- 17716261 TI - A literature review on biomaterials in sinus augmentation procedures. AB - BACKGROUND: Sinus augmentation is a common procedure to increase bone volume and allow for proper implant placement in the atrophic posterior maxilla. Although the patient's own bone is considered the best grafting material, various synthetic or bovine-derived alternatives are used to simplify the grafting procedure. PURPOSE: The overall objective of this review was to assess the efficacy of different graft materials used in sinus augmentation procedures as demonstrated in animal studies. MATERIALS AND METHODS: A specific and sensitive database was initially created via PUBMED, focusing on studies published in English peer-reviewed journals between 1995 and 2004 and kept updated until 2006. RESULTS: Twenty-six articles were available for comparison and discussion; none concerned the use of alloplastic materials; 24 were comparative histomorphometric; and two were biomechanical studies. Because of a great variability in study designs, different implant types, great range in follow-up, and lack of specific integration or loading period, a comparison of the studies and the biomaterials used was difficult. CONCLUSIONS: In general, autogenous bone is the most predictable material of choice for augmentation procedures, despite a 40% resorption, because it is highly osteoconductive and less dependent on sinus floor endosteal bone migration. The addition of bovine bone mineral to autogenous bone can be beneficial for graft success because it acts as a slowly resorbing space maintainer. Porous hydroxyapatite is suitable when mixed with autogenous bone because it enhances bone formation and bone-to-implant contact in augmented sinuses. Histological evaluation showed that demineralized freeze-dried bone is inferior to other materials. Within the limitation of the animal studies examined in this review and only based on histological examination, the initial osseointegration of implants seems independent of the biomaterial used in grafting procedures. PMID- 17716262 TI - Review of clinical EMG studies related to muscle and occlusal factors in healthy and TMD subjects. AB - Several electronic instruments have been developed as adjuncts to objectively record the dysfunctional features of temporomandibular disorders and to study the effectiveness of various treatment interventions. The aim of this review was to assess the value and contribution of clinical electromyographic research in the understanding of asymptomatic and dysfunctional muscle function and the therapeutic effects of interocclusal appliances. For this purpose MedLine and PubMed searches were conducted with the following main keywords alone and in various combinations: electromyography, muscles of mastication, masseter, temporalis, temporomandibular, TMD, utility, validity, repeatability, rest, postural, vertical dimension, occlusal, splint, treatment. The review includes critical evaluation, discussion and conclusions regarding electromyographic studies in asymptomatic and dysfunctional muscles, rest position, occlusal parameters and interocclusal appliances, as well as a critical summary and proposals for further research. Much of earlier critique of many electromyographic studies still applies regarding comparative sample selections, research designs, analyses and conclusions. The areas not well-understood include normal biological variation, capacity for adaptation, fluctuations regarding the clinical course and multidimensional features of temporomandibular disorders and long-term follow-up data, especially in studies that evaluate the effectiveness of therapeutic measures. Considering the required improvements in technical and research designs features and critical appraisal electromyographic research could have value as an adjunct research tool to study features of craniofacial muscle related dysfunction. Until electromyographic measures are correlated with other multidimensional, especially subjective and pain-related methods, the clinical use of this method for diagnostic purposes of temporomandibular disorders remains in doubt, and is not at present recommended. PMID- 17716263 TI - Influence of playing wind instruments on activity of masticatory muscles. AB - The aim of this study was to elucidate the influence of change in sound tone of playing wind instruments on activity of jaw-closing muscles and the effect of sustained playing for a long time on fatigue of jaw-closing muscles. Electromyograms (EMG) of 19 brass instrument players and 14 woodwind instrument players were measured while playing instruments in tuning tone and high tone and under other conditions. Nine brass instrument players and nine woodwind instrument players played instruments for 90 min. Before and after the exercise, power spectral analyses of EMG from masseter muscles at 50% of maximum voluntary clenching level were performed and mean power frequency (MPF) were calculated. Root mean square (RMS) of EMG in masseter and temporal muscles while playing were slightly larger than those at rest but extremely small in comparison with those during maximum clenching. Root mean square in orbicularis oris and digastric muscles were relatively large when playing instruments. In the brass instrument group, RMS in high tone was significantly higher than that in tuning tone in all muscles examined. In the woodwind instrument group, RMS in high tone was not significantly higher than that in tuning tone in those muscles. Mean power frequency was not decreased after sustained playing in both instrument groups. These findings indicate that contractive load to jaw-closing muscles when playing a wind instrument in both medium and high tone is very small and playing an instrument for a long time does not obviously induce fatigue of jaw-closing muscles. PMID- 17716264 TI - Relation between cervical posture on lateral skull radiographs and electromyographic activity of masticatory muscles in caucasian adult women: a cross-sectional study. AB - The aim of this study was to evaluate the association between cervical posture on lateral skull radiographs and surface electromyographic recordings (sEMG) of head and neck muscles. The sample comprised 40 Caucasian adult females, average age 26.8 (20-48); lateral skull radiographs were obtained in natural head position (mirror position). sEMG activity was bilaterally investigated for the following muscles: masseter, anterior temporalis, digastric, posterior cervical, sternocleidomastoid and upper and lower trapezius. All muscles were monitored at rest and during maximal voluntary clenching (MVC). A Pearson's correlation coefficient revealed significant correlations (P < 0.01) between cranio-cervical angulations and sEMG activity of masseter, digastric, lower trapezius, during MVC and anterior temporalis at rest. Significant correlations (P < 0.01) were also found between cervical lordosis angle and sEMG activity of masseter (during MVC) and lower trapezius (at rest). In view of transversal method, no conclusion was possible about the mechanism concerning these results. Future longitudinal studies should be directed to understand the extent of environmental and genotype influences by masticatory muscle activity on cervical posture. PMID- 17716265 TI - Head posture and dental wear evaluation of bruxist children with primary teeth. AB - The aim of the present study was to compare the head position and dental wear of bruxist and non-bruxist children with primary dentition. METHODS: All the subjects had complete primary dentition, dental and skeletal class I occlusion and were classified as bruxist or non-bruxist according to their anxiety level, bruxism described by their parents and signs of temporomandibular disorders. The dental wear was drawn in dental casts and processed in digital format. Physiotherapeutic evaluation and a cephalometric radiograph with natural head position were also performed for each child to evaluate the cranio-cervical position for the bruxist group (n = 33) and the control group (n = 20). The variables of the two groups were compared, using the Student t-test and Mann Whitney U-test. RESULTS: A more anterior and downward head tilt was found in the bruxist group, with statistically significant differences compared with the controls. More significant dental wear was observed in the bruxist children. CONCLUSIONS: Bruxism seems to be related to altered natural head posture and more intense dental wear. Further studies are necessary to explore bruxism mechanisms. PMID- 17716266 TI - A two-colour chewing gum test for masticatory efficiency: development of different assessment methods. AB - OBJECTIVE: The aim of this study was to investigate different assessment methods of a two-colour chewing gum test for masticatory efficiency to determine its validity for research and clinical purposes. MATERIALS AND METHODS: Twenty adult volunteers, eleven women and nine men (mean age of 27.5 years), participated in this study. All participants perceived their masticatory efficiency as normal. The task was to chew five samples of a two-colour chewing gum for 5, 10, 20, 30 and 50 cycles respectively. Maximum bite force was measured. All samples were assessed twice by two independent operators both, as 'bolus' and after flattening to 1 mm thick 'wafers'. The latter were scanned and the unmixed pixels counted using Adobe Photoshop Elements to calculate the ratio of unmixed colour to the total surface. RESULTS: Digital image processing confirmed a significant correlation between colour mixing and chewing duration (P < 0.001). Subjective assessment proved less accurate with fair to substantial intra-examiner agreement for 'bolus' (0.20 < kappa < 0.63) and substantial to almost perfect agreement for 'wafer' (0.60 < kappa < 0.88). Inter-examiner agreement was consistently moderate or substantial only for specimen chewed 20 cycles or longer. No significant correlation was found between the colour mixture and the maximum bite force. CONCLUSION: Digital image processing of the two-colour chewing gum test specimen provides reliable quantitative data for chewing efficiency. Visual assessments were less reliable but might still be useful in screening for chewing deficiencies in a clinical setting. In this context, the test should be performed with a flattened specimen chewed, probably for 20 cycles. PMID- 17716267 TI - Influence of altered occlusal guidance on masticatory muscle activity during clenching. AB - This study investigated the influence of experimentally altered occlusal guidance on masticatory muscle activity. Twenty healthy human subjects (15 males and five females with an average age of 26.5 years) volunteered to participate in this study. Metallic occlusal overlays were fabricated for the lower working side canine and overlaid on the second molar and the non-working side second molar to simulate a canine-protected occlusion, group function occlusion and bilateral balanced occlusion. Electromyography (EMG) activities in the bilateral masseter, anterior and posterior temporalis were recorded during maximal clenching. The experimental occlusal pattern revealed to have statistically significant effects on EMG activity. As the most characteristic change, EMG activity in the anterior temporalis significantly increased in the simulated group function occlusion and the simulated bilateral balanced occlusion compared with the simulated cuspid protected occlusion. The increased teeth contacts to the posterior region altered the unilateral pattern of the anterior temporalis activity to the bilateral pattern, while that of masseter activity remained unchanged. PMID- 17716268 TI - The role of Candida in inflammatory papillary hyperplasia of the palate. AB - The objective of this study was to investigate the expression by immunohistochemistry of the major basement membrane (BM) components (laminin, collagen type IV, fibronectin) in specimens from the palatal mucosa lesions of patients with complete dentures and diagnosis of inflammatory papillary hyperplasia of the palate (IPHP). Furthermore to evaluate the potential role of candidal infection in patients with IPHP. Biopsies of palatal mucosa were obtained from patients with IPHP, generally healthy/orally healthy patients with dentures, and healthy subjects. Immunohistochemical studies performed with specific antibodies to BM proteins. Scrapings and swaps of oral lesions from all patients and control groups were taken from the palate, and Candida species colonization was assessed with mycology tests. Immunohistochemical expression of BM components revealed thin linear staining in the BM of healthy palatal mucosa. In IPHP discontinuities or disruptions in BM were observed at the interface between epithelium and the underlying connective tissue in the areas of severe inflammatory response. Our findings suggest an interaction between the expression of BM components and Candida involvement in the development of IPHP, a disorder involving inflammatory reaction and modification of soft tissues. PMID- 17716269 TI - Temperature change, dentinal fluid flow and cuspal displacement during resin composite restoration. AB - Dentin-bonding agents and resin composite materials typically require light activation for polymerization. Light curing generates heat, which may influence dentinal fluid flow (DFF) and cuspal displacement. This study investigated the relationship among temperature increase, DFF and cuspal displacement in extracted human maxillary premolars with a mesial occlusal distal (MOD) cavity preparation. Two types of curing light were compared. Temperature changes were measured using thermocouples located on the occlusal cavity floor and at the pulp-dentine junction, during polymerization of bonding agent and resin composite material. DFF and cuspal displacement were measured simultaneously using automated flow measurement apparatus and direct current differential transformers respectively. Temperature increases of up to 15 degrees C were recorded during the restoration procedures. A quartz tungsten halogen (QTH) unit produced a significantly greater temperature increase than a light-emitting diode unit and curing of the bonding agent generated less temperature increase than curing of the resin composite. Heating due to exothermic reaction during polymerization of bonding agent and resin was not significantly different between light sources or between bonding and curing (P > 0.05). The QTH unit produced both greater inward fluid flow and cuspal displacement during the irradiation of bonding agent and resin composite than the light-emitting diode unit. There was not a simple relationship between temperature increase, fluid movement and cuspal displacement. From a clinical point of view, the light-emitting diode unit can be considered preferable to the QTH light, because it caused significantly smaller temperature increase, fluid shift and cuspal displacement. PMID- 17716270 TI - Fracture strength of four-unit Y-TZP FPD cores designed with varying connector diameter. An in-vitro study. AB - Reported clinical success rates of all-ceramic fixed partial dentures (FPDs) made of high-strength oxide ceramics range between 82.5% and 100%. The main cause of all-ceramic FPD failure is fracture in the connector area. There is, however, no consensus on what connector dimensions are adequate. The aim of this in-vitro study was, therefore, to compare the fracture strength of four-unit Y-TZP FPD cores designed with different connector diameters. A total of 40 four-unit FPD cores supported by end abutments and having two pontics were manufactured in Procera Zirconia. Five groups of FPD cores with connector dimensions of 2.0, 2.5, 3.0, 3.5 and 4.0 mm were produced. All FPD cores underwent a firing programme according to the manufacturer's recommendations for the veneering porcelain, a cyclic preload, thermocycling and finally, load until fracture. Fracture strength was significantly higher for each increase in connector diameter except for the 2.0-mm and 2.5-mm diameters where all fractures occurred during preload. All FPD cores fractured in the connector area. Within the limitations of this in-vitro study, a minimum diameter of 4.0 mm is recommended for all-ceramic zirconia-based FPDs with long spans or replacing molars. Clinical studies are, however, needed to determine adequate connector dimensions. PMID- 17716271 TI - Mood changes after sleep deprivation in morningness-eveningness chronotypes in healthy individuals. AB - Inconsistent results have been found in the studies evaluating the effect of both total and partial sleep deprivation (SD) on mood in healthy subjects and a few variables have been analyzed as possible predictors. In the present study, we examined whether circadian preference modifies the effect of SD on mood changes in healthy subjects. Sample consisted of 60 healthy volunteers (including 30 morningness and 30 eveningness subjects). Then, the two groups were again divided into two groups for two SD procedures. Fifteen morningness and 15 eveningness chronotypes were total sleep deprived and 15 morningness and 15 eveningness subjects were partial sleep deprived. The mood changes were evaluated before and after SD using Profile of Mood States. Two main results were obtained from our study: a significant increase in depression subscale in morningness chronotypes and a significant decrease in depression subscale score after total SD (TSD) in eveningness chronotypes. The changes in depression-dejection scores of eveningness chronotypes after total (P < 0.01) and partial SD (P < 0.01) were significantly different from changes in morningness chronotypes after TSD. Our results suggest that the effect of SD on mood in normal subjects is related to their circadian preferences. The morningness or eveningness characteristics of the shift workers have significant impact on their mood states. Therefore, adjusting the work schedule with the morningness and eveningness characteristics of the workers may improve their mood alterations. PMID- 17716272 TI - The effects of one night of sleep deprivation on known-risk and ambiguous-risk decisions. AB - Sleep deprivation has been shown to alter decision-making abilities. The majority of research has utilized fairly complex tasks with the goal of emulating 'real life' scenarios. Here, we use a Lottery Choice Task (LCT) which assesses risk and ambiguity preference for both decisions involving potential gains and those involving potential losses. We hypothesized that one night of sleep deprivation would make subjects more risk seeking in both gains and losses. Both a control group and an experimental group took the LCT on two consecutive days, with an intervening night of either sleep or sleep deprivation. The control group demonstrated that there was no effect of repeated administration of the LCT. For the experimental group, results showed significant interactions of night (normal sleep versus total sleep deprivation, TSD) by frame (gains versus losses), which demonstrate that following as little as 23 h of TSD, the prototypical response to decisions involving risk is altered. Following TSD, subjects were willing to take more risk than they ordinarily would when they were considering a gain, but less risk than they ordinarily would when they were considering a loss. For ambiguity preferences, there seems to be no direct effect of TSD. These findings suggest that, overall, risk preference is moderated by TSD, but whether an individual is willing to take more or less risk than when well-rested depends on whether the decision is framed in terms of gains or losses. PMID- 17716273 TI - Pulsed radio-frequency electromagnetic fields: dose-dependent effects on sleep, the sleep EEG and cognitive performance. AB - To establish a dose-response relationship between the strength of electromagnetic fields (EMF) and previously reported effects on the brain, we investigated the influence of EMF exposure by varying the signal intensity in three experimental sessions. The head of 15 healthy male subjects was unilaterally exposed for 30 min prior to sleep to a pulse-modulated EMF (GSM handset like signal) with a 10 g averaged peak spatial specific absorption rate of (1) 0.2 W kg(-1), (2) 5 W kg( 1), or (3) sham exposed in a double-blind, crossover design. During exposure, subjects performed two series of three computerized cognitive tasks, each presented in a fixed order [simple reaction time task, two-choice reaction time task (CRT), 1-, 2-, 3-back task]. Immediately after exposure, night-time sleep was polysomnographically recorded for 8 h. Sleep architecture was not affected by EMF exposure. Analysis of the sleep electroencephalogram (EEG) revealed a dose dependent increase of power in the spindle frequency range in non-REM sleep. Reaction speed decelerated with increasing field intensity in the 1-back task, while accuracy in the CRT and N-back task were not affected in a dose-dependent manner. In summary, this study reveals first indications of a dose-response relationship between EMF field intensity and its effects on brain physiology as demonstrated by changes in the sleep EEG and in cognitive performance. PMID- 17716274 TI - Posturographic sleepiness monitoring. AB - Although reduced sleep often underlies traffic and occupational accidents, convenient sleepiness testing is lacking. We show that posturographic balance testing addresses this issue, because balance testing predicts hours of wakefulness, which could facilitate sleepiness testing. Here, we equate balance scores from separate trials, blinded to the experimenter, with those recorded as a function of known and increasing time awake (i.e. during sustained wakefulness); we show, that the time awake in separate trials is posturographically measurable: positive predictive value 69%, sensitivity 56%, and specificity 96%. These results encourage further work developing posturographic sleepiness monitoring. PMID- 17716275 TI - Nocturnal sleep, daytime sleepiness, and napping among women with significant emotional/behavioral premenstrual symptoms. AB - The objective of this study is to examine daytime sleepiness and alertness and nap characteristics among women with significant emotional/behavioral premenstrual symptoms, and to determine their relationship with nocturnal sleep. Participants spent one night during the follicular phase and two nights during the late-luteal phase, one of which occurred after a 40 min opportunity to nap, sleeping in the laboratory. Subjective measures of sleepiness and alertness were completed during the afternoon of each recording. Setting took place at the sleep laboratory at the University of Ottawa. A total number of participants were 10 women with significant and nine women with minimal emotional/behavioral premenstrual symptoms (mean age 26 years). The results were compared with the follicular phase, both groups of women had less slow wave sleep and more stage 2 sleep at night, as well as a higher daytime and nocturnal mean and maximum temperature during the late-luteal phase. Women with significant symptoms were sleepier and less alert during the late-luteal phase and had a higher overall mean nocturnal temperature compared with women with minimal symptoms. No significant differences were found between the two groups on nap characteristics and nocturnal sleep characteristics. Results show that women with more severe premenstrual symptoms are sleepier during the late-luteal phase than women with minimal symptoms. The increased daytime sleepiness seems to be unrelated to nocturnal sleep or nap characteristics. PMID- 17716276 TI - Improving actigraphic sleep estimates in insomnia and dementia: how many nights? AB - In order to investigate how the duration of actigraphic recordings affects the reliability of actigraphic estimates of sleep and 24-h activity rhythm variables, two to 3 weeks of actigraphy were recorded, from which pairs of variables derived from two periods of increasing length (1-10 days) were compared. Two groups were studied: (1) 10 subjects suffering from primary insomnia; and (2) 12 demented elderly subjects living semi-independently in group care facilities of homes for the elderly. Actigraphic estimates of primary measures of sleep (duration and efficiency) and of the 24-h activity pattern (interdaily stability, intradaily variability and amplitude) were calculated on variable lengths of the actigraphic recordings. The average absolute difference of two estimates decreased - and reliability increased - strongly with an increasing number of days analysed. An acceptable reliability of the interdaily stability estimate required more than 7 days of recording. It can be concluded that a valuable improvement in the reliability of actigraphic sleep estimates can be obtained by simply increasing the number of recording nights. The results support the importance of day-to-day variability in insomnia and dementia that has already been previously noted by others, and even suggest the presence of 'week-to-week' variability. This variability may have been involved in the equivocal results of treatment studies in insomnia and dementia where outcome measures were based on a limited number of nights. Such studies could profit from extension of the recording duration to, e.g. 2 weeks, and from the inclusion of variability measures as measures of clinical interest. PMID- 17716277 TI - Intensive Sleep Retraining treatment for chronic primary insomnia: a preliminary investigation. AB - The aim of this study was to assess the effectiveness of Intensive Sleep Retraining, a novel, short duration behavioural therapy in treating chronic primary insomnia. Seventeen consecutive volunteers from the general public (mean age = 39.1 years), meeting selection criteria for chronic primary insomnia participated in the treatment study. The study was performed as a case replication series. Assessment involved sleep diary, actigraph and questionnaire measures of sleep and daytime functioning for a period of 2 weeks prior to, immediately after, and 6 weeks following the treatment. Treatment involved a single night of sleep deprivation, facilitating short sleep latencies (mean: 6.9 min) to a series of 50 brief nap opportunities. Following treatment, Sleep Onset Latency significantly decreased by a mean of 30.5 min (SD = 28.3), Wake Time after Sleep Onset significantly decreased by a mean of 28 min (SD = 34.0), and Total Sleep Time significantly increased by 64.6 min (SD = 45.5). Significant improvements were also seen in the daytime functioning and psychological measures of fatigue and vigour, cognitive sleep anticipatory anxiety and self-efficacy for sleep. This brief therapy was effective in improving sleep and some daytime functioning and psychological questionnaire measures. These improvements were maintained up to 2 months following the treatment weekend. Further exploration of this brief therapy is needed, with larger, randomized, placebo-controlled trials over longer follow-up periods, and in comparison to other traditional therapies for insomnia. PMID- 17716278 TI - Adverse childhood experiences associated with sleep in primary insomnia. AB - The objectives were to explore the association between self-reported adverse childhood experiences (ACE) and sleep in adults suffering from primary insomnia and to examine the impact of presleep stress on this relationship. Fifty-nine patients with primary insomnia, aged 21-55 years, were administered the Childhood Trauma Questionnaire (CTQ) and then divided into two groups according to the achieved scores: with moderate/severe or low/no reports of ACE. The participants spent three consecutive nights in the sleep laboratory in order to record polysomnographic and actigraphic sleep parameters. A stress induction technique was administered by activating negative autobiographical memories immediately before sleep in the second or third night. Results show that 46% of the insomniac patients reported moderate to severe ACE. This group exhibited a significantly greater number of awakenings and more movement arousals compared to patients with low or no reports of ACE. Actigraphic data also indicated more disturbed sleep and increased nocturnal activity for the high-ACE group. On the other hand, no specific group differences were found with regard to stress condition. The results support the assumption that it is possible to identify a subgroup among patients with primary insomnia who has experienced severe maltreatment in childhood and adolescence. This subgroup appears to differ in several sleep parameters, indicating a more disturbed sleep compared to primary insomniacs with low or no reports of ACE. With regard to sleep-disturbing nightly patterns of arousal, parallels between individuals with high ACE and trauma victims as well as post-traumatic stress disorder-patients suggest themselves. PMID- 17716279 TI - Depression: relationships to sleep paralysis and other sleep disturbances in a community sample. AB - Sleep disturbances are important correlates of depression, with epidemiologic research heretofore focused on insomnia and sleepiness. This epidemiologic study's aim was to investigate, in a community sample, depression's relationships to other sleep disturbances: sleep paralysis (SP), hypnagogic/hypnopompic hallucinations (HH), cataplexy - considered rapid eye movement-related disturbances - and automatic behavior (AB). Although typical of narcolepsy, these disturbances are prevalent, albeit under-studied, in the population. Cross sectional analyses (1998-2002), based on Wisconsin Sleep Cohort Study population based data from 866 participants (mean age 54, 53% male), examined: depression (Zung Self-Rating Depression Scale), trait anxiety (Spielberger State-Trait Anxiety Inventory, STAI-T >or= 75th percentile), and self-reported sleep disturbances. Descriptive sleep data were obtained by overnight polysomnography. Adjusted logistic regression models estimated depression's associations with each (>few times ever) outcome - SP, HH, AB, and cataplexy. Depression's associations with self-reported SP and cataplexy were not explained by anxiety. After anxiety adjustment, severe depression (Zung >or=55), vis-a-vis Zung <50, increased SP odds approximately 500% (P = 0.0008). Depression (Zung >or=50), after stratification by anxiety given an interaction (P = 0.02), increased self reported cataplexy odds in non-anxious (OR 8.9, P = 0.0008) but not anxious (OR 1.1, P = 0.82) participants. Insomnia and sleepiness seemed only partial mediators or confounders for depression's associations with self-reported cataplexy and SP. Anxiety (OR 1.9, P = 0.04) partially explained depression's (Zung >or=55) association with HH (OR 2.2, P = 0.08). Anxiety (OR 1.6, P = 0.02) was also more related than depression to AB. Recognizing depression's relationships to oft-neglected sleep disturbances, most notably SP, might assist in better characterizing depression and the full range of its associated sleep problems in the population. Longitudinal studies are warranted to elucidate mediators and causality. PMID- 17716280 TI - Prevalence of papilloedema in patients with sleep apnoea syndrome: a prospective study. AB - The association of papilloedema (PO) with respiratory diseases and especially obstructive sleep apnoea (OSA) syndrome has been emphasised in many reports. The pathophysiology could rely on the episodic increase of intracranial pressure related to apnoeic episodes during night sleep. Nevertheless, prevalence of papilloedema in patient with OSA syndrome remains unknown. As this information could improve diagnosis and therapeutic strategies, the aim of the present study was to investigate the prevalence of PO in an OSA syndrome population. From 95 successive, recently diagnosed OSA patients, 35 answered a questionnaire about visual symptoms and underwent fundoscopic examination. Visual symptoms suggestive of PO were present in 40% of the patients, but none had PO. As a conclusion, PO does not seem to be frequently associated with OSA syndrome and systematic screening of PO in these patients does not seem to be warranted. Nevertheless, patients with visual complaints evocative of papilloedema should have their eye fundus checked since the association between OSA and PO exists. Further studies, including more patients, might be useful to establish which patients are at particular risk for this complication. PMID- 17716281 TI - The relationship between craniofacial anatomy and obstructive sleep apnoea: a case-controlled study. AB - The aim of the study was to identify craniofacial and pharyngeal anatomical factors directly related to obstructive sleep apnoea (OSA). The design and setting was a hospital-based, case-controlled study. Ninety-nine subjects (78 males and 21 females) with a confirmed diagnosis of OSA, who were referred to the Dental Hospital for construction of a mandibular advancement splint were recruited. A similar number of control subjects, matched for age and sex, were recruited after completing snoring and Epworth Sleepiness Scale questionnaires to exclude habitual snoring and daytime sleepiness. An upright cephalogram was obtained and skeletal and soft tissue landmarks were traced and digitized. In OSA subjects the anteroposterior skeletal measurements, including maxillary and mandibular length were reduced (P < 0.001). The intermaxillary space was found to be 3.1 mm shorter in OSA subjects (P = 0.001). The nasopharyngeal airway in OSA subjects was narrower (P < 0.001) but pharyngeal length showed no difference. The tongue size was increased (P = 0.021), soft plate length, thickness and area were all greater (P < 0.001) and the hyoid bone was more inferiorly positioned in OSA subjects (P < 0.001). This study identifies a significant number of craniofacial and pharyngeal anatomical factors directly related to OSA. PMID- 17716282 TI - Daytime sympathetic hyperactivity in OSAS is related to excessive daytime sleepiness. AB - The aim of this study was to investigate the relationships among sympathetic hyperactivity, excessive daytime sleepiness (EDS) and hypertension in obstructive sleep apnoea syndrome (OSAS). Ten newly diagnosed OSAS patients with untreated EDS and daytime hypertension underwent polysomnography (PSG) and daytime measurements of plasma noradrenaline (NA), ambulatory blood pressure (BP), muscle sympathetic nerve activity (MSNA) by microneurography and objective assessment of EDS before and during 6 months of compliance-monitored continuous positive airway pressure (CPAP) treatment. One month after the start of CPAP, BP, MSNA and NA were significantly lowered, remaining lower than baseline also after 3 and 6 months of treatment. CPAP use caused a significant improvement of sleep structures, and reduced EDS. A statistical correlation analysis demonstrated that EDS was not correlated with sleep measures obtained from baseline PSG (% sleep stages, apnoea and arousal index, mean oxygen saturation value), whereas daytime sleepiness was significantly correlated with MSNA. Furthermore, MSNA and BP showed no correlation. Our data obtained from selected patients suggest that the mechanisms inducing EDS in OSAS are related to the degree of daytime sympathetic hyperactivity. Additionally, resting MSNA was unrelated to BP suggesting that factors other than adrenergic neural tone make a major contribution to OSAS related hypertension. The results obtained in this pilot study need, however, to be confirmed in a larger study involving more patients. PMID- 17716284 TI - Dry skin in dermatology: a complex physiopathology. AB - Dry skin (xerosis) is a common dermatosis affecting people of varying skin types and ages and various areas of the body. It is associated with both skin thickening and skin thinning and is triggered by both exogenous (e.g. climate, environment, lifestyle) and endogenous (e.g. medication, hormone fluctuations, organ diseases) factors. Skin requires a water content of 10-15% to remain supple and intact. This water is either 'static' (i.e. bound) or 'dynamic'. The predominance of hydrophobic substances in intercellular constituents is a means of regulating the humidity of the skin. Emollients, highly effective treatment adjuncts in the management of all dry skin disorders, help to restore damaged intercorneocyte lipid structures and increase the water content of the skin, helping to reduce scaling and improving its barrier function. PMID- 17716283 TI - Periodic leg movements during sleep and wakefulness in narcolepsy. AB - The objectives of the study were to measure the prevalence of periodic leg movements during NREM and REM sleep (PLMS) and while awake (PLMW) and to assess the impact of PLMS on nocturnal sleep and daytime functioning in patients with narcolepsy. One hundred and sixty-nine patients with narcolepsy and 116 normal controls matched for age and gender were included. Narcoleptics with high and low PLMS indices were compared to assess the impact of PLMS on sleep and Multiple Sleep Latency Test (MSLT) variables. More narcoleptics than controls had a PLMS index greater than 5 per hour of sleep (67% versus 37%) and an index greater than 10 (53% versus 21%). PLMS indices were higher both in NREM and REM sleep in narcoleptic patients, but the between-group difference was greater for REM sleep. A significant increase of PLMS index was also found with aging in both narcoleptic patients and controls. PLMW indices were also significantly higher in narcoleptic patients. Patients with an elevated index of PLMS had a higher percentage of stage 1 sleep, a lower percentage of REM sleep, a lower REM efficiency and a shorter MSLT latency. The present study demonstrates a high frequency of PLMS and PLMW in narcolepsy, an association between the presence of PLMS and measures of REM sleep and daytime functioning disruption. These results suggest that PLMS represent an intrinsic feature of narcolepsy. PMID- 17716285 TI - How the skin reacts to environmental factors. AB - The skin is one of the main points of contact with the environment. Usually, interactions between skin and environmental factors are harmonious. But sometimes, the skin barrier is modified (dry or greasy skin) or skin inflammation can occur (irritated, reactive, allergic or atopic skin). PMID- 17716286 TI - Contact dermatitis: epidemiology and frequent sensitizers to cosmetics. AB - Contact dermatitis is defined as a pattern of inflammatory response that may occur as a result of contact with external factors. The two most common causes are irritants and allergens. Very few reliable data on prevalence and incidence of contact dermatitis exist, and data from the few studies that have been carried out cannot be compared because of differences in methodology. Occupational contact dermatitis constitutes up to 30% of all occupational diseases for which compensation is payable and affects sufferers' home and social lives as well as their working lives. Patients can be advised about the use of personal protective equipment and creams and emollients to avoid or ameliorate their condition, but there is little epidemiological evidence for their efficacy. Patch testing, using the European Standard Series of Allergens, is necessary to determine which agent is responsible for the condition. Fragrances and preservatives used in cosmetics are among the most common allergens in contact allergic dermatitis, although the frequency of contact allergy in the general population is small. It is to be hoped that the European Dermato-Epidemiology Network Fragrance Study will go some way to addressing the need for a large population-based epidemiological study in order that public health organizations can give reliable advice about avoiding and treating contact dermatitis. PMID- 17716287 TI - Is there room for improvement in the emollients for adjuvant therapy? AB - Emollients play an important part in the management of patients with dry skin disorders, such as atopy, allergy, eczema, psoriasis or dryness following chemotherapy or radiotherapy. Their use in the treatment of diseased and sensitive skin requires not only an efficient hydrating and lipid-replenishing effect on the skin, but minimal risk for skin irritation or sensitization. This will be influenced by their formulation and number and type of ingredients and, due to the nature of their application, requires clinical testing to ensure their appropriateness for dermatological rather than cosmetic use. A new generation of emollients has been developed for the care of dry, or very dry, and sensitive skin. Among these, Dardia Lipo Line (Intendis GmbH, Berlin, Germany) has been formulated specifically for use in post-therapy preventive skin care. The current clinical evidence for this line of emollients is reviewed here. PMID- 17716288 TI - Evaluation of the effect of Dardia Lipo Line on skin inflammation induced by surfactants using the repeated open-application test. AB - BACKGROUND: Medical skin care products are topical preparations with mainly moisturizing properties. A new line of medical skin products with an excellent tolerability profile and improved hydration for dry skin has been developed, but beneficial effects have not yet been investigated on damaged skin. AIM: To investigate if these products maintain barrier function and hydration status, improve subjective symptoms due to irritant contact dermatitis and to prove their tolerability on damaged skin. DESIGN AND METHODS: Single-centre, blinded, randomized, controlled study in 20 healthy Caucasian women. 5% sodium lauryl sulphate solution was used to induce skin irritation. Two sites on the inside surface of both forearms of each subject were treated daily for 5 days (irritation period). Lipo Cream, Lipo Milk (water-in-oil emulsions) and Lipo Ointment (water-free formulation) were applied twice daily to three of the four test sites on days 1-5. The fourth site was used as a control. Visual readings, subjective symptom assessments, transepidermal water loss (TEWL) and colorimetric measurements, corneometry and skin microrelief macrophotographies were done on days 1-6. RESULTS: On day 6, TEWL was increased vs baseline on all sites; however, TEWL with Lipo Cream or Lipo Ointment was significantly lower than control. At day 6, skin capacitance was 94%, 100% and 85% of baseline value for the cream, milk and ointment, respectively, versus 72% for control. All test products were well tolerated. CONCLUSIONS: Lipo Line products showed both protective properties against epidermal dysfunction and significant hydrating effect. PMID- 17716291 TI - The interface between oral and systemic health: the need for more collaboration. AB - The focus of this review is to highlight the need for improved communication between medical and dental professionals in order to deliver more effective care to patients. The need for communication is increasingly required to capitalise on recent advances in the biological sciences and in medicine for the management of patients with chronic diseases. Improvements in longevity have resulted in populations with increasing special oral-care needs, including those who have cancer of the head and neck, those who are immunocompromised due to HIV/AIDS, advanced age, residence in long-term care facilities or the presence of life-long conditions, and those who are receiving long-term prescription medications for chronic conditions (e.g., anti-hypertensives, anticoagulants, immunosuppressants, antidepressants). These medications can cause adverse reactions in the oral cavity, such as xerostomia and ulceration. Patients with xerostomia are at increased risk of tooth decay, periodontal disease and infection. The ideal management of such individuals should involve the collaborative efforts of physicians, nurses, dentists and dental hygienists, thus optimising treatment and minimising secondary complications deriving from the oral cavity. PMID- 17716290 TI - Relationship between periodontal infections and systemic disease. AB - Oral conditions such as gingivitis and chronic periodontitis are found worldwide and are among the most prevalent microbial diseases of mankind. The cause of these common inflammatory conditions is the complex microbiota found as dental plaque, a complex microbial biofilm. Despite 3000 years of history demonstrating the influence of oral status on general health, it is only in recent decades that the association between periodontal diseases and systemic conditions such as coronary heart disease and stroke, and a higher risk of preterm low birth-weight babies, has been realised. Similarly, recognition of the threats posed by periodontal diseases to individuals with chronic diseases such as diabetes, respiratory diseases and osteoporosis is relatively recent. Despite these epidemiological associations, the mechanisms for the various relationships remain unknown. Nevertheless, a number of hypotheses have been postulated, including common susceptibility, systemic inflammation with increased circulating cytokines and mediators, direct infection and cross-reactivity or molecular mimicry between bacterial antigens and self-antigens. With respect to the latter, cross-reactive antibodies and T-cells between self heat-shock proteins (HSPs) and Porphyromonas gingivalis GroEL have been demonstrated in the peripheral blood of patients with atherosclerosis as well as in the atherosclerotic plaques themselves. In addition, P. gingivalis infection has been shown to enhance the development and progression of atherosclerosis in apoE-deficient mice. From these data, it is clear that oral infection may represent a significant risk-factor for systemic diseases, and hence the control of oral disease is essential in the prevention and management of these systemic conditions. PMID- 17716292 TI - Common therapeutic approaches for the control of oral biofilms: microbiological safety and efficacy. AB - Triclosan is widely employed in many consumer and healthcare products. The increasing employment of triclosan in a range of consumer products where there is no proven benefit for hygiene has been severely criticised. Laboratory studies demonstrate theoretical risks that the wide-scale use of triclosan might compromise its efficacy as well as the activity of third-party antibiotics. The precautionary principle would dictate against the use of triclosan, at least in those products where there was no demonstrable health benefit. The theoretical risks, however, are not supported by either field or clinical studies, or by laboratory studies using bacterial microcosms. Numerous clinical studies, as well as historical data, demonstrate the clinical benefits of hygiene adjuncts such as triclosan and triclosan/copolymer in oral care products where these compensate for deficiencies in mechanical hygiene (brushing and flossing). The balance of risk and benefit is firmly in favour of the continued use of dentifrices (toothpastes) and mouthwashes containing active agents such as triclosan. PMID- 17716293 TI - The clinical efficacy of triclosan/copolymer and other common therapeutic approaches to periodontal health. AB - The maintenance of an effective level of oral hygiene is the cornerstone of all attempts to prevent and control periodontal disease, and yet the widespread prevalence of the disease indicates the inability of most people to maintain a level of plaque control commensurate with periodontal health. The inclusion of antibacterial agents, such as chlorhexidine and triclosan, in oral care products has provided a means to improve oral health. Randomised, controlled clinical trials have demonstrated that the unsupervised use of a dentifrice (toothpaste) containing triclosan/copolymer significantly improves gingival health, prevents the onset of periodontitis and reduces further progression of tissue destruction. The delivery of such benefits has positive implications for the oral health of individuals and populations. PMID- 17716294 TI - Guidelines for the validation and application of typing methods for use in bacterial epidemiology. AB - For bacterial typing to be useful, the development, validation and appropriate application of typing methods must follow unified criteria. Over a decade ago, ESGEM, the ESCMID (Europen Society for Clinical Microbiology and Infectious Diseases) Study Group on Epidemiological Markers, produced guidelines for optimal use and quality assessment of the then most frequently used typing procedures. We present here an update of these guidelines, taking into account the spectacular increase in the number and quality of typing methods made available over the past decade. Newer and older, phenotypic and genotypic methods for typing of all clinically relevant bacterial species are described according to their principles, advantages and disadvantages. Criteria for their evaluation and application and the interpretation of their results are proposed. Finally, the issues of reporting, standardisation, quality assessment and international networks are discussed. It must be emphasised that typing results can never stand alone and need to be interpreted in the context of all available epidemiological, clinical and demographical data relating to the infectious disease under investigation. A strategic effort on the part of all workers in the field is thus mandatory to combat emerging infectious diseases, as is financial support from national and international granting bodies and health authorities. PMID- 17716295 TI - The role of glitazones in management of type 2 diabetes. A dream or a nightmare? AB - Glitazones have been introduced as second-step medication for type 2 diabetics, and today rosiglitazone and pioglitazone are blockbuster drugs. However, glitazones may have important adverse effects that outweight their beneficial effect on insulin resistance and glycemia. The larger trials have shown that glitazones produce a weight gain of 4-5 kg over 3-4 years of treatment, and the weight gain cannot be explained by fluid retention. Moreover, the risk of myocardial infarction is increased by 43% by rosiglitazone, and there are clear indications of increased risk of heart failure. Furthermore, there are studies to suggest that glitazones also increase the risk of fractures, whereas an increased cancer risk is not supported. In conclusion, given the increased cardiovascular risk, and that a weight gain of few kg can increase risks of cancer of the breast, colon, prostate and endometrium, the use of glitazones should be questioned. There is a need for more safe and weight neutral drugs to treat type 2 diabetes. PMID- 17716296 TI - Maternal obesity and risk of cesarean delivery: a meta-analysis. AB - Despite numerous studies reporting an increased risk of cesarean delivery among overweight or obese compared with normal weight women, the magnitude of the association remains uncertain. Therefore, we conducted a meta-analysis of the current literature to provide a quantitative estimate of this association. We identified studies from three sources: (i) a PubMed search of relevant articles published between January 1980 and September 2005; (ii) reference lists of publications selected from the search; and (iii) reference lists of review articles published between 2000 and 2005. We included cohort designed studies that reported obesity measures reflecting pregnancy body mass, had a normal weight comparison group, and presented data allowing a quantitative measurement of risk. We used a Bayesian random effects model to perform the meta-analysis and meta-regression. Thirty-three studies were included. The unadjusted odd ratios of a cesarean delivery were 1.46 [95% confidence interval (CI): 1.34-1.60], 2.05 (95% CI: 1.86-2.27) and 2.89 (95% CI: 2.28-3.79) among overweight, obese and severely obese women, respectively, compared with normal weight pregnant women. The meta-regression found no evidence that these estimates were affected by selected study characteristics. Our findings provide a quantitative estimate of the risk of cesarean delivery associated with high maternal body mass. PMID- 17716297 TI - Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer. AB - Upper body obesity and the related metabolic disorder type 2 diabetes have been identified as risk factors for breast cancer, and associated with late-stage disease and a poor prognosis. Components of the metabolic syndrome, including visceral adiposity, insulin resistance, hyperglycemia and hyperinsulinemia, with or without clinically manifest diabetes mellitus, low serum high-density lipoprotein cholesterol and hypertension have all been related to increased breast cancer risk. The biochemical mechanisms include extraglandular oestrogen production, reduced sex hormone-binding globulin with consequent elevation of the bioactive plasma free oestradiol and increased insulin biosynthesis, all of which exert mitogenic effects on both untransformed and neoplastic breast epithelial cells. Obesity, type 2 diabetes and the metabolic syndrome also have in common an increased production of leptin and a decreased production of adiponectin by adipose tissue, with consequent elevations and reductions, respectively, in the circulating levels of these two adipokines. These changes in plasma leptin and adiponectin, acting through endocrine and paracrine mechanisms, have been associated in several studies with an increase in breast cancer risk and, perhaps, to more aggressive tumours; studies in vitro showed that leptin stimulates, and adiponectin inhibits, tumour cell proliferation and the microvessel angiogenesis which is essential for breast cancer development and progression. PMID- 17716298 TI - Cognitive dysfunction associated with metabolic syndrome. AB - Metabolic syndrome which includes visceral obesity, elevated triglycerides, elevated fasting blood sugar, high blood pressure and a decrease in high-density lipoprotein cholesterol levels comprises the most common chronic physical illnesses in modern society. Components of the metabolic syndrome play a role in the pathogenesis of a plethora of medical illnesses. Evidence has emerged highlighting the detrimental effects of metabolic syndrome and its constituent features on the cognitive aspects of neurological function. The precise mechanisms underlying this association are not known but a combination of neuroanatomical changes and neuroendocrine consequences of somatic dysregulation may be relevant. As the population ages and the prevalence of metabolic syndrome increases, it is important that this clinically relevant association be recognized. PMID- 17716299 TI - Polymorphisms in adiponectin receptor genes ADIPOR1 and ADIPOR2 and insulin resistance. AB - Adiponectin plays an important role in insulin sensitivity via adiponectin receptor 1 and 2 signalling. To date, six genetic association studies have examined the role of polymorphisms in the adiponectin receptor 1 and 2 genes (ADIPOR1 and ADIPOR2) in insulin resistance and type 2 diabetes. These studies are summarized in this review along with unpublished data from the authors. In addition, these polymorphism studies are used to illustrate some of the potential pitfalls and reasons for poor reproducibility of findings in genetic association studies. PMID- 17716301 TI - Behavioural interventions for preventing and treating obesity in adults. AB - The purpose of this study was to review existing behavioural interventions for preventing and treating obesity in adult population that were published between 2000 and September 2006. A total of 23 interventions were found. Most of these interventions targeted both physical activity and nutrition behaviours. Majority of the interventions were not based on any explicit behavioural theory. In terms of duration, the interventions ranged from 3 weeks to 9 years. Approximately half of the interventions were less than 6 months in duration. Most of the interventions were implemented by the researchers themselves. However, some interventions were implemented by nurse educators, nutritionists, trained public health nurses, dietitians, healthcare providers, fitness workers and certified diabetic educators. Most of the interventions used group sessions as the predominant method to deliver the programme. Three of the interventions used media. Majority of the interventions were implemented in patient care settings with some in community settings. The most common determinant for measuring impact of the interventions has been body mass index. Fifteen interventions showed positive change in adiposity indices while six showed no change in adiposity indices. Recommendations for enhancing the effectiveness of behavioural interventions for prevention of obesity are presented. PMID- 17716300 TI - Potential environmental determinants of physical activity in adults: a systematic review. AB - The objective of this systematic review of observational studies was to gain insight into potential determinants of various types and intensities of physical activity among adult men and women. Studies were retrieved from Medline, PsycInfo, Embase and Social scisearch. The ANGELO framework was used to classify environmental factors. In total, 47 publications were identified. Social support and having a companion for physical activity were found to be convincingly associated with different types of physical activity [(neighbourhood) walking, bicycling, vigorous physical activity/sports, active commuting, leisure-time physical activity in general, sedentary lifestyle, moderately intense physical activity and a combination of moderately intense and vigorous activity]. Availability of physical activity equipment was convincingly associated with vigorous physical activity/sports and connectivity of trails with active commuting. Other possible, but less consistent correlates of physical activity were availability, accessibility and convenience of recreational facilities. No evidence was found for differences between men and women. In conclusion, supportive evidence was found for only very few presumed environmental determinants. However, most studies used cross-sectional designs and non validated measures of environments and/or behaviour. Therefore, no strong conclusions can be drawn and more research of better quality is clearly needed. PMID- 17716302 TI - Battle of the bulge: an analysis of the obesity prevention campaigns in the United States and Germany. AB - Obesity is not a problem exclusive to the United States. The European Union Commission for Health and Consumer Protection admits that obesity is the major emerging threat to public health in Europe. As a recent survey suggested that the prevalence of obese men and women has approximately doubled in both countries within the last 20 years, this study compares the message elements and linguistic tactics used in either campaign of those two countries to highlight differences and similarities. The current US obesity prevention campaign is based on sound research and preparation and disseminates memorable and inspiring messages. The educational, help-for-self-help focus on the individual disseminated through mass media is a trademark of this campaign. The German campaign attempts to interact extensively with the public, local government and the professions, and focuses on public participation in healthy behaviors, generally emphasizing call-to-action activities over educational media messages. This study maintains that obesity communication research should find ways to analyse and evaluate the effectiveness and success rate of efforts taking place in other areas and other countries. In addition, in order to facilitate active thought about health messages in the absence of a perceived need, introduced guidelines relating to presentation of content and linguistic variables that motivate cognitive effort should be considered. PMID- 17716303 TI - The impact of Internet use for weight loss. AB - With rising rates of obesity and obesity-related health problems, finding additional means to help reduce obesity is critical. This review examined the impact of the Internet as a medium to deliver weight loss programs. Specifically, the review examined the public's interest, the availability and the known efficacy of Internet-based weight loss programs. Findings showed that the general public is turning to the Internet for diet and fitness information and has reported that information they found online has impacted their behaviour. Little is known about who is interested in using the Internet for weight loss and what their experiences have been. The programs most readily available to the general consumer tend to vary widely in quality, with few efficacy studies. However, researchers have shown that efficacious programs have been delivered via the Internet. Successful online programs included a structured approach to modifying energy balance, the use of cognitive-behavioural strategies such as self monitoring, and individualized feedback and support. Implications include developing strategies to increase distribution of programs with known efficacy, determining the applicability of effective programs for diverse audiences, conducting media literacy education for the general public, and continued research into understanding who may be best served by online weight loss programming. PMID- 17716304 TI - The burden of overweight and obesity-related ill health in the UK. AB - This paper reviews previous cost studies of overweight and obesity in the UK. It proposes a method for estimating the economic and health costs of overweight and obesity in the UK which could also be used in other countries. Costs of obesity studies were identified via a systematic search of electronic databases. Information from the WHO Burden of Disease Project was used to calculate the mortality and morbidity cost of overweight and obesity. Population attributable fractions for diseases attributable to overweight and obesity were applied to National Health Service (NHS) cost data to estimate direct financial costs. We estimate the direct cost of overweight and obesity to the NHS at pound 3.2 billion. Other estimates of the cost of obesity range between pound 480 million in 1998 and pound 1.1 billion in 2004 [Correction added after online publication 11 June 2007: 'of the cost of obesity' added after 'Other estimates']. There is wide variation in methods and estimates for the cost of overweight and obesity to the health systems of developed countries. The method presented here could be used to calculate the costs of overweight and obesity in other countries. Public health initiatives are required to address the increasing prevalence of overweight and obesity and reduce associated healthcare costs. PMID- 17716305 TI - Cloning of a novel protease required for the molting of Locusta migratoria manilensis. AB - Molting is required for progression between larval stages in the life cycle of an insect. The essence of insect molting is the laying down of new cuticle followed by shedding of the old cuticle. Degradation and recycling of old cuticle are brought about by enzymes present in the molting fluid, which fills the space between the old and new cuticle. Here, we describe the cloning of a novel protease gene from Locusta migratoria manilensis, designated as Lm-TSP. The cDNA and its deduced protein sequences were deposited in GenBank (accession numbers EF081255 and ABN13876, respectively). Sequence analysis indicated that Lm-TSP belongs to the trypsin-like serine protease family. We show, by RNA interference (RNAi), that silencing of Lm-TSP leads to dramatic reductions in protease and cuticle-degrading activity of a molting fluid, which leads to molting defects from fourth-instar larvae (L4) to fifth-instar larvae (L5), and between L5 and adult stages. These observations suggest that Lm-TSP plays a critical role in L. migratoria manilensis ecdysis. PMID- 17716306 TI - Drosophila NAT1, a homolog of the vertebrate translational regulator NAT1/DAP5/p97, is required for embryonic germband extension and metamorphosis. AB - Translational regulation has been to shown to play major roles in the patterning of the early Drosophila embryo. The eIF4G family member NAT1/p97/DAP5 has been identified as a novel translational repressor. To genetically dissect the in vivo function of this unconventional eIF4G-related translational regulator, Drosophila NAT1 (dNAT1) mutants were isolated using a reverse-genetics approach. Four transposon insertion mutants and a deletion mutant affecting the dNAT1 locus were analyzed. Genetic complementation tests and germline rescue using a 12 kb dNAT1 genomic DNA fragment revealed these to be loss-of-function mutants. One P-element insertion line, dNAT1(GS1.), shows severe embryonic lethality and abnormal germband extension. Abnormalities at metamorphosis were also found, including defective head eversion and salivary gland degeneration in the hypomorphic allele dNAT(ex1). A phenotypic analysis of dNAT1 mutants suggests that dNAT protein plays a specific rather than general role in translational regulation. PMID- 17716307 TI - A new era in the prevention of hepatocellular carcinoma. PMID- 17716308 TI - MMP-13 and TIMP-1 determinations in progressive chronic periodontitis. AB - Matrix metalloproteinase (MMP)-13 is a collagenase involved in extracellular matrix degradation either by its direct degradative effects or by processing bioactive substrates. The aim of this study was to determine the levels of MMP-13 and tissue inhibitor of metalloproteinase (TIMP)-1 in gingival crevicular fluid (GCF) and gingival biopsies obtained from active and inactive sites during chronic periodontitis progression. MATERIALS AND METHODS: This was a longitudinal study in which chronic periodontitis patients with moderate to severe disease were included and followed until they developed progression determined by the tolerance method. GCF samples were obtained from periodontitis, active, inactive and healthy sites and additional gingival biopsies were taken from active and inactive sites. MMP-13 and TIMP-1 determinations were carried out by immunodot blots and immunowestern blots. RESULTS: In progressive periodontitis, MMP-13 and TIMP-1 remained unchanged between active and inactive sites, but as the TIMP-1 relative levels increased together with MMP-13 elevation in inactive samples, an inverse correlation was observed in active sites. Besides, MMP-13 was undetectable in healthy controls. CONCLUSION: Chronic periodontitis is characterized by increased MMP-13 expression. During disease progression, active sites tended to decrease TIMP-1 levels in association with MMP-13 elevation. PMID- 17716310 TI - Intra- and extra-oral halitosis: finding of a new form of extra-oral blood-borne halitosis caused by dimethyl sulphide. AB - AIM: The aim of this study was to unravel the origen and cause of intra-oral and extra-oral halitosis. MATERIAL AND METHODS: We studied 58 patients complaining of halitosis, using gas chromatography of volatile sulphur compounds (VSCs) in mouth and nose breath, organoleptic scoring of mouth and nose breath, Halimeter readings of mouth air and tongue-coating inspection. Subjects had no precence or history of periodontitis. RESULT: Of 58 patients, 47 patients had halitosis of oral origin, six had halitosis of extra-oral origin and five had no halitosis (halitophobia). A strong correlation was found between the degree of intra-oral halitosis as measured by organoleptic scoring of mouth breath and the concentration of the VSCs hydrogen sulphide (H(2)S) and methyl mercaptan (CH(3)SH) in mouth breath. Taking into account the much larger odour index of CH(3)SH, it was concluded that CH(3)SH is the main contributor to intra-oral halitosis. In all six cases of extra-oral halitosis, halitosis was caused by the presence of elevated levels of dimethyl sulphide (CH(3)SCH(3)) in mouth and nose breath. CONCLUSION: Our study provides evidence that the VSC, CH(3)SH and to a lesser extent H(2)S are the main contributors to intra-oral halitosis and that CH(3)SCH(3) is the main contributor to extra-oral or blood-borne halitosis, due to a hitherto unknown metabolic disorder. PMID- 17716309 TI - Periodontal therapy alters gene expression of peripheral blood monocytes. AB - AIMS: We investigated the effects of periodontal therapy on gene expression of peripheral blood monocytes. METHODS: Fifteen patients with periodontitis gave blood samples at four time points: 1 week before periodontal treatment (#1), at treatment initiation (baseline, #2), 6-week (#3) and 10-week post-baseline (#4). At baseline and 10 weeks, periodontal status was recorded and subgingival plaque samples were obtained. Periodontal therapy (periodontal surgery and extractions without adjunctive antibiotics) was completed within 6 weeks. At each time point, serum concentrations of 19 biomarkers were determined. Peripheral blood monocytes were purified, RNA was extracted, reverse-transcribed, labelled and hybridized with AffymetrixU133Plus2.0 chips. Expression profiles were analysed using linear random-effects models. Further analysis of gene ontology terms summarized the expression patterns into biologically relevant categories. Differential expression of selected genes was confirmed by real-time reverse transcriptase polymerase chain reaction in a subset of patients. RESULTS: Treatment resulted in a substantial improvement in clinical periodontal status and reduction in the levels of several periodontal pathogens. Expression profiling over time revealed more than 11,000 probe sets differentially expressed at a false discovery rate of <0.05. Approximately 1/3 of the patients showed substantial changes in expression in genes relevant to innate immunity, apoptosis and cell signalling. CONCLUSIONS: The data suggest that periodontal therapy may alter monocytic gene expression in a manner consistent with a systemic anti-inflammatory effect. PMID- 17716311 TI - Reported methodological quality of split-mouth studies. AB - BACKGROUND/AIM: Hujoel & Moulton previously questioned the reported quality of split-mouth studies. Since then, there has been little enquiry into the methodology of this study design. The aim was to conduct a systematic review of the reported methodology of clinical studies using a split-mouth design published in dental journals over a 1-year period (2004). MATERIAL AND METHODS: An extension of the CONSORT guidelines for cluster-randomized designs was used to evaluate quality. We evaluated the methods used and quality of reporting split mouth studies. RESULTS: Thirty-four studies were eligible for this review. The results showed that many papers lack essential qualities of good reporting, e.g. five of 34 papers gave the rationale for choosing a split-mouth design, 19 of 34 (56%) used appropriate analytical statistical methods and only one of 34 presented an appropriate sample size calculation. Of the five studies that used survival analysis, none of them used a paired approach. CONCLUSIONS: Despite some progress in statistical analysis, if the reporting of studies represents the actual methodology of the trial, this review has identified important aspects of split-mouth study design and analysis that would benefit from development. PMID- 17716312 TI - Efficacy of sub-antimicrobial dose doxycycline in post-menopausal women: clinical outcomes. AB - AIMS: To determine the clinical efficacy of a 2-year continuous sub-antimicrobial dose doxycycline (SDD; 20 mg bid) in post-menopausal, osteopenic, oestrogen deficient women on periodontal maintenance. MATERIALS AND METHODS: One-hundred and twenty-eight subjects were randomized to SDD (n=64) or placebo (n=64). Clinical measurements were performed at posterior interproximal sites at baseline and every 6 months during this 2-year randomized, double-blind, placebo controlled clinical trial with adjunctive, no-cost 3-4-month periodontal maintenance. Statistical analyses of secondary outcomes from this clinical trial used Generalized Estimating Equations in primarily intent-to-treat analyses. RESULTS: For the placebo group, 3.4% of the sites showed improvement in clinical attachment levels (CAL) and 2.7% had progressive loss in CAL; for the SDD group, 5.0% of the sites showed an improvement in CAL and 2.2% had progressive loss in CAL. This difference (2.1% of sites) was more favourable in the SDD group than in the placebo [odds ratio (OR)=0.81 [corrected] 95% confidence interval (CI): 0.67 0.97, p=0.03] in these well-maintained patients, whereas probing depths, bleeding on probing and supragingival plaque did not differ significantly between groups (p>0.2). However, in exploratory subgroup analysis of non-smokers, SDD showed reduced bleeding versus placebo (27%versus 33%; p=0.05). In protocol-adherent subjects, the odds of bleeding were 34% lower for SDD (p=0.05). CONCLUSIONS: Analyses of secondary outcomes of this clinical trial indicated that SDD may be of benefit in reducing progressive attachment loss in post-menopausal females; additional research is needed to confirm these findings. Protocol registered at (ClinicalTrials.gov). Identifier:NCT00066027. PMID- 17716314 TI - Immediate post-operative effects of different periodontal treatment modalities on oral health-related quality of life: a randomized clinical trial. AB - AIM: Oral health-related quality of life (OHQoL) characterizes a person's perception of how oral health influences an individual's life quality. The aim of this study is to investigate how the treatment modalities may affect the immediate post-operative quality of life of patients with periodontitis. MATERIALS AND METHODS: Sixty psychologically and socio-demographically matched periodontitis patients were randomly divided into three groups [20 non-surgical (NS), 20 surgical (SG), 20 surgical plus enamel matrix protein derivative (S+EMD)]. The OHQoL was assessed with two patient-centred outcome measures [Oral Health Impact Profile-14 (OHIP-14) and General Oral Health Assessment Index (GOHAI)] in the post-operative period of 1 week. RESULTS: Whereas there were no differences of OHQoL at the baseline, the patients treated by surgery had reported that they had experienced a worse OHQoL compared with the NS and S+EMD groups both in the OHIP-14 and GOHA indexes (p=0.001). CONCLUSIONS: The results of this study clearly indicated that patient perceptions on the immediate post operative period were significantly better in the NS and S+EMD groups when compared with the SG group. These findings need to be confirmed in further studies with larger populations. PMID- 17716313 TI - Subantimicrobial dose doxycycline effects on alveolar bone loss in post menopausal women. AB - AIM: Determine the efficacy of 2-year continuous subantimicrobial dose doxycycline (SDD; 20 mg bid) on alveolar bone in post-menopausal osteopenic, oestrogen-deficient women undergoing periodontal maintenance in a 2-year double blind, placebo-controlled, randomized clinical trial. MATERIAL AND METHODS: One hundred and twenty-eight subjects randomized to SDD or placebo (n=64 each). Posterior vertical bite wings taken at baseline, 1 and 2 years for alveolar bone density (ABD), using radiographic absorptiometry (RA) and computer-assisted densitometric image analysis (CADIA), and alveolar bone height (ABH). Statistical analyses utilized generalized estimating equations; primary analyses were intent to treat (ITT). Results are presented as SDD versus placebo. RESULTS: Under ITT, there was no statistically significant effect of SDD on ABD loss (RA: p=0.8; CADIA: p=0.2) or ABH loss (p=0.2). Most sites (81-95%) were inactive. For subgroup analyses, mean CADIA was higher with SDD for non-smokers (p=0.05) and baseline probing depths > or =5 mm (p=0.003). SDD was associated with 29% lower odds of more progressive ABH loss in women >5 years post-menopausal (p=0.05) and 36% lower among protocol-adherent subjects (p=0.03). CONCLUSIONS: In post menopausal osteopenic women with periodontitis, SDD did not differ overall from placebo. Based on exploratory subgroup analyses, additional research is needed to determine the usefulness of SDD in non-smokers, subjects >5 years post-menopausal and in deeper pockets. Protocol registered at (ClinicalTrials.gov). Identifier: NCT00066027. PMID- 17716315 TI - Inflammatory mediator release following bone grafting in humans: a pilot study. AB - AIM: The aim of this pilot study was to track markers of periodontal inflammation and bone resorption associated with decalcified freeze-dried bone allografts. MATERIAL AND METHODS: Eleven subjects completed standardized treatment of intrabony defects > or =3 mm with allografts. Gingival crevicular fluid was collected from the defect site and an adjacent interproximal site within the surgical field at baseline, 2, 4, and 8 weeks post-operatively, and analysed for biochemical markers of inflammation/bone resorption. Probing depth, recession, bleeding on probing, plaque, and 6-month radiographic bone height change were measured. RESULTS: Both prostaglandin E(2) (p=0.007) and bone-specific type 1 collagen (p=0.01) increased in crevicular fluid after 2 weeks in the bone graft sites. Matrix metalloproteinase-9 levels remained constant over time. There were positive correlations between prostaglandin levels during the first 8 weeks and bone height change over 6 months. CONCLUSIONS: Periodontal bone grafts stimulate an inflammatory response during the first 2 weeks post-operatively, and the potential negative effects of inhibiting prostaglandins post-operatively should be investigated further. PMID- 17716316 TI - Impact of supportive periodontal therapy and implant surface roughness on implant outcome in patients with a history of periodontitis. AB - OBJECTIVE: This review searched for a relationship between susceptibility to periodontitis and peri-implantitis, with implant outcome as the primary outcome variable and supportive periodontal therapy (SPT) and implant surface roughness as confounding factors. MATERIAL AND METHODS: It is based on a MEDLINE search up to June 2006. Only 16 fulfilled the selection criteria. The heterogeneity of the studies (e.g. periodontal status, SPT, prosthetic design, ...) rendered a meta analysis impossible. The impact of a history of periodontitis on early implant loss was negligible. Only five papers reported sub-data for patients with different degrees of periodontitis. Four out of five papers indicate a higher incidence of late implant loss and/or marginal bone loss in patients with a history of periodontitis. This difference was most obvious for very rough implants (three papers), and/or when SPT was not organized (one paper). Other confounding factors were often neglected. Another 10 papers only reported the outcome of implants in patients with a history of periodontitis. In case of SPT and when avoiding roughened surfaces, late implant loss remained below 3%, and marginal bone loss remained low. CONCLUSIONS: These results seem to indicate that periodontally compromised patients can be successfully treated with minimally/moderately rough implants, in the presence of SPT. PMID- 17716318 TI - Selective, tailored, biopsychosocial pain treatment: our past is our future. PMID- 17716317 TI - Accuracy of implant placement based on pre-surgical planning of three-dimensional cone-beam images: a pilot study. AB - AIM: To evaluate the precision of transfer of a computer-based three-dimensional (3D) planning, using re-formatted cone-beam images, for oral implant placement in partially edentulous jaws. MATERIAL AND METHODS: Four formalin-fixed cadaver jaws were imaged in a 3D Accuitomo FPD cone-beam computed tomography (CT). Data were used to produce an accurate implant planning with a transfer to surgery by means of stereolithographic drill guides. Pre-operative cone-beam CT images were subsequently matched with post-operative ones to calculate the deviation between planned and installed implants. RESULTS: Placed implants (length: 10-15 mm) showed an average angular deviation of 2 degrees (SD: 0.8, range: 0.7-4.0 degrees ) as compared with the planning, while the mean linear deviation was 1.1 mm (SD: 0.7 mm, range 0.3-2.3 mm) at the hex and 2.0 mm (SD: 0.7 mm, range 0.7-2.4 mm) at the tip. CONCLUSIONS: Cone-beam images could be used for implant planning, taking into account a maximal 4 degrees angular and 2.4 mm linear deviation at the apical tip. PMID- 17716320 TI - What do experimental pain models tell us about aging and clinical pain? PMID- 17716321 TI - A double-blind, randomized, placebo-controlled comparison of botulinum toxin type a injection sites and doses in the prevention of episodic migraine. AB - BACKGROUND: Several randomized, controlled studies have reported benefits of botulinum toxin type A (BoNTA; Allergan Inc., Irvine, CA, USA) over placebo in the treatment of migraine. Some studies reported significant benefits at dosages as low as 16 U, while other studies reported safety, tolerability, and efficacy at dosages up to 260 U. However, the optimal treatment paradigm and patient population have yet to be defined. OBJECTIVE: To compare different injection sites and doses of BoNTA in the prevention of episodic migraine. DESIGN AND METHODS: This was a randomized, double-blind, placebo-controlled study of 232 patients with a history of four to eight moderate to severe migraines per month, with or without aura. Patients were randomized to placebo or one of four BoNTA groups that received injections into different muscle regions: frontal (10 U), temporal (6 U), glabellar (9 U), or all three areas (total dose 25 U). For 3 months following a single treatment, patients recorded migraine-related variables in a daily diary. RESULTS: BoNTA and placebo produced comparable decreases from baseline in the frequency of migraines (P > or = 0.411). In general, no statistically significant differences were observed for any efficacy variable. The overall rates of adverse events (any type) or treatment-related adverse events were similar among the groups. CONCLUSIONS: In this exploratory study of episodic migraine patients, low-dose injections of BoNTA into the frontal, temporal, and/or glabellar muscle regions were not more effective than placebo. BoNTA was safe and well tolerated. Future studies may examine higher BoNTA doses, flexible injection sites, multiple treatments, and disallow concomitant prophylactic medications. PMID- 17716322 TI - The role of tooth-grinding in the maintenance of myofascial face pain: a test of alternate models. AB - OBJECTIVE: While mechanisms of myofascial face pain are poorly understood, bruxism has been implicated in the maintenance of this painful disorder. This study evaluates whether evidence of one aspect of bruxism, tooth-grinding, is positively associated with pain severity, as predicted by a psychophysiological model, or negatively associated, as predicted by an adaptation model of face pain. PATIENTS: Participants were 51 women who met Research Diagnostic Criteria for the myofascial subtype of temporomandibular disorder. OUTCOME MEASURES: Tooth grinding was quantified by changes in microwear features of the molar teeth over 2 weeks. Palpated pain severity was quantified on an 11-point scale in response to palpation of the skin overlying the masseter and temporalis muscles bilaterally. Other measures included validated scales of spontaneous pain severity, stress, distress, and psychological symptoms. Association was quantified as Pearson correlation coefficients. RESULTS: Data showed an inverse correlation (r = -0.37, P < 0.05) between palpated pain severity and the index of tooth wear, supporting the adaptation model. This correlation provided a weighted average of a strong effect (r = -0.80, P < 0.01) seen in those women reporting pain only the right side of their face with an effect that approximated zero in those reporting bilateral pain. Tooth wear measures were negatively associated with ratings of pain severity only over the right masseter. DISCUSSION: While these data do not address the role of clenching, they cast serious doubt on the theory that myofascial face pain is maintained by tooth-grinding. PMID- 17716323 TI - Use of the Synera patch for local anesthesia before vascular access procedures: a randomized, double-blind, placebo-controlled study. AB - OBJECTIVE: This randomized, double-blind, placebo-controlled, paired study compared the Synera patch, a drug delivery device comprised of an eutectic mixture of lidocaine (70 mg) and tetracaine (70 mg) whose onset is accelerated by a controlled heating device, with placebo. The objective of the study was to evaluate the efficacy of Synera in inducing local anesthesia before a vascular access procedure. DESIGN: Before the vascular access procedures, adult volunteers randomly received a concurrent application of Synera and placebo to the right and left antecubital surfaces. Forty subjects received 20-minute treatments. After each vascular access procedure, efficacy evaluations were completed by the subject, investigator, and an independent observer. Median subject-reported pain intensity, using the visual analog scale scores (VAS, 0-100 mm scale) were significantly lower for Synera than placebo (5 mm vs 28 mm, P < 0.001). RESULTS: Compared with placebo, more subjects reported adequate anesthesia following Synera (73% vs 31%, P = 0.002), and more subjects indicated they would use Synera again (70% vs 33%, P = 0.006). Investigators rated more subjects having no pain with Synera compared with placebo (63% vs 33%, P = 0.021), and more subjects having adequate anesthesia with Synera (60% vs 23%, P = 0.004). Independent observers rated 68% of subjects having no pain with Synera compared with 38% with placebo (P = 0.015). Side-effects were limited to localized pruritus and erythema. Erythema was more common with Synera than placebo (62% vs 42%, P = 0.018). CONCLUSIONS: A 20-minute application of Synera consistently provided clinically useful anesthesia for vascular access procedures, and appears to be well suited for topical dermal anesthesia due to its reduced time required to produce adequate anesthesia and high subject and investigator acceptance. PMID- 17716324 TI - An open-label 52-week clinical extension comparing duloxetine with routine care in patients with diabetic peripheral neuropathic pain. AB - OBJECTIVE: To assess the safety of duloxetine at a fixed-dose of 60 mg twice daily (BID) for up to 52 weeks, and compare duloxetine with routine care in the management of patients with diabetic peripheral neuropathic pain (DPNP). DESIGN AND INTERVENTIONS: Patients who completed a 13-week, randomized, double-blind, placebo-controlled acute therapy period were randomly reassigned in a 2:1 ratio to therapy with duloxetine 60 mg BID (N = 197) or routine care (N = 96) for an additional 52 weeks. PATIENTS: The trial included outpatients > or =18 years of age diagnosed with moderate to severe DPNP caused by type 1 or type 2 diabetes. RESULTS: Fourteen patients discontinued due to adverse events or death (11 [5.6%] duloxetine- and 3 [3.1%] routine care-treated patients). There were no significant therapy-group differences observed for patients with >/=1 serious adverse event. In total, 110 (55.8%) duloxetine- and 47 (49%) routine care treated patients had > or =1 treatment-emergent adverse event (TEAE). The TEAE with a significant therapy-group difference, with patients in the duloxetine therapy group experiencing a higher percentage of events, was asthenia (11 [5.6%] duloxetine- vs no routine care-treated patients). Duloxetine did not appear to adversely affect lipid profiles, or nerve or eye function. There were no significant therapy-group differences observed in mean change in systolic blood pressure, weight, or electrocardiogram parameters. Significant therapy-group differences were observed in favor of duloxetine in the SF-36 physical component summary score, and subscale scores of physical functioning, bodily pain, mental health, and vitality. CONCLUSIONS: The results of this study provide support for the use of duloxetine in the long-term management of DPNP. PMID- 17716325 TI - Age interacts with stimulus frequency in the temporal summation of pain. AB - OBJECTIVE: There is growing interest in the impact of aging on the plasticity of pain responses. Up-regulation characterizes pain responses in clinical situations, and consequently aging effects on the development and resolution of increased sensitivity have important implications for the experience of pain in those older age groups who are more likely to suffer from chronic conditions. This study examined temporal summation of pain at different stimulus frequencies to gain further insights into the effect of age on pain plasticity. DESIGN: In a group of younger and a group of older subjects, trains of five brief electrical stimuli were applied to the skin over the sural nerve at frequencies ranging between 0.2 and 2.0 Hz. Nociceptive reflexes were recorded throughout the application of stimuli. Single pulses and the fifth pulse of each series were rated for pain intensity with a visual analog scale. RESULTS: The younger subjects demonstrated temporal summation at frequencies of stimulation that were consistent with previous reports, namely 0.33 to 2.0 Hz. The older group had a greater mean rating of the fifth pulse relative to a single pulse at all frequencies of stimulation. The behavior of the nociceptive reflex to repeated stimuli was equivalent for the two age groups, only summating at a frequency of 2.0 Hz. CONCLUSIONS: The temporal summation of low-frequency stimuli in the older subjects suggests that aging impacts on the capacity of the nociceptive system to down-regulate subsequent to sensitization. PMID- 17716326 TI - Placement of an implantable drug delivery system under the breast. AB - OBJECTIVE: Our case will demonstrate a safe and practical alternative location for an implantable drug delivery system (IDDS) pump. Traditionally, these pumps have been placed subcutaneously in the lower abdomen. We will describe the technique used for under the breast placement. PATIENT: The patient was a 52-year old female with metastatic colon cancer and chronic flank pain. RESULTS: The pump was placed in the retromammary location with no complications or problems with patient discomfort. Adequate pain control was achieved. CONCLUSION: The retromammary location for the IDDS pump is a safe and aesthetically pleasing option for some patients. This location is a useful alternative for female cachectic patients, or patients with abdominal ostomies. PMID- 17716327 TI - Open-label exploration of an intravenous nalbuphine and naloxone mixture as an analgesic agent following gynecologic surgery. AB - OBJECTIVE: The purpose of this series was to explore a 12.5:1 fixed-dose ratio of an intravenous nalbuphine and naloxone mixture (NNM) for use in patients following gynecologic surgery. DESIGN AND PATIENTS: Open-label, nonrandomized case series. The first series was a dose-ranging investigation for 12 patients following elective total abdominal hysterectomy or myomectomy. In this series, fentanyl was used for intraoperative analgesia, and patients were assigned to a lower NNM (2.5 mg/0.2 mg) or to a higher NNM (5 mg/0.4 mg) dose group. The second series evaluated the fixed dose of 5 mg nalbuphine/0.4 mg naloxone for four patients undergoing ambulatory gynecologic procedures. In the second series, no opioid agents were administered intraoperatively to eliminate the possibility of mu-opioid reversal by naloxone postoperatively. OUTCOME MEASURES: Pain control was assessed using a Verbal Pain Scale (0-10). Vital signs, side effects, and adverse events were recorded to determine drug safety. RESULTS: In the first series, there were no adverse events; however, each patient required rescue medication (either morphine or fentanyl). In the second series, two of the four patients reported a reduction in pain following drug administration and did not require any further analgesic agents in the 3-hour postoperative period. One patient had an asymptomatic lowering of heart rate after receiving the drug. CONCLUSION: Additional research of the unique combination therapy of nalbuphine and naloxone is warranted to further determine its potential clinical efficacy and safety. PMID- 17716328 TI - Use of topiramate for glossodynia. AB - INTRODUCTION: Glossodynia is a multifunctional disorder characterized by painful sensations in the mouth and throat and especially on the tongue. It is commonly cured by long-term therapy with systemic regimens of anxiolytics, antidepressants, and anticonvulsants. CASE: We report here the case of a 65-year old woman with a 4-month history of glossodynia. Clinical and laboratory evaluations performed the diagnosis of idiopathic glossodynia, and several treatments with carbamazepine and then with gabapentin induced the development of serious adverse reaction. Only treatment with topiramate has been able to induce a complete improvement of symptoms. DISCUSSION: The pathogenesis of idiopathic glossodynia remains unclear, since it recently has been suggested as a possible neuropathic basis of burning mouth syndrome, demonstrating an altered excitability in the trigeminal nociceptive pathway at peripheral and/or central nervous system level. The various mechanisms of topiramate, which act at different neural transmission levels, blocking sodium and calcium channels, enhancing GABA concentration, and decreasing glutamate function at postsynaptic site, may explain the effects of topiramate in our patient. CONCLUSION: Therefore, we suggest that topiramate could represent a useful therapeutic option in the treatment of glossodynia. PMID- 17716330 TI - Treating nonacute pain in the cancer population. PMID- 17716329 TI - Meningitis after percutaneous radiofrequency trigeminal ganglion lesion. Case report and review of literature. AB - CASE REPORT: A 79-year-old man with severe trigeminal neuralgia presented to the pain clinic, and was offered a radiofrequency trigeminal ganglion lesion. He had only partial response to the first procedure, so a second was undertaken. The following day he presented with signs of meningitis and the diagnosis was confirmed on lumbar puncture. He was treated with appropriate antibiotics, and recovered well. LITERATURE REVIEW: The current literature on reports of meningitis after percutaneous trigeminal ganglion lesioning reveals an overall mean incidence of meningitis of 0.15% (confidence interval 0.10-0.21). The Scottish Intercollegiate Guidelines Network guide the decision on the routine use of antimicrobial prophylaxis, and although the risk of infection can be estimated from the literature and the severity of infection is high, the effectiveness and consequences of prophylaxis cannot be established. CONCLUSION: If breach of the oral mucosa has occurred, then antibiotic prophylaxis should be administered. PMID- 17716332 TI - Should we tolerate tolerability as an objective in early drug development? PMID- 17716336 TI - Abstracts of the 43rd Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology, 8-12 September 2007, Broadbeach, Australia. PMID- 17716335 TI - Thyroid hormone levels in children with Prader-Willi syndrome before and during growth hormone treatment. AB - BACKGROUND: Prader-Willi syndrome (PWS) is a neurogenetic disorder characterized by muscular hypotonia, psychomotor delay, obesity and short stature. Several endocrine abnormalities have been described, including GH deficiency and hypogonadotrophic hypogonadism. Published data on thyroid hormone levels in PWS children are very limited. OBJECTIVE: To evaluate thyroid function in children with PWS, before and during GH treatment. DESIGN/PATIENTS: At baseline, serum levels of T4, free T4 (fT4), T3, reverse T3 (rT3) and TSH were assessed in 75 PWS children. After 1 year, assessments were repeated in 57 of the them. These children participated in a randomized study with two groups: group A (n = 34) treated with 1 mg GH/m(2)/day and group B (n = 23) as controls. RESULTS: Median age (interquartile range, IQR) of the total group at baseline was 4.7 (2.7-7.6) years. Median (IQR) TSH level was -0.1 SDS (-0.5 to 0.5), T4 level -0.6 SDS (-1.7 to 0.0) and fT4 level -0.8 SDS (-1.3 to -0.3), the latter two being significantly lower than 0 SDS. T3 level, at 0.3 SDS (-0.3 to 0.9), was significantly higher than 0 SDS. After 1 year of GH treatment, fT4 decreased significantly from -0.8 SDS (-1.5 to -0.2) to -1.4 SDS (-1.6 to -0.7), compared to no change in untreated PWS children. However, T3 did not change, at 0.3 SDS (-0.1 to 0.8). CONCLUSIONS: We found normal fT4 levels in most PWS children. During GH treatment, fT4 decreased significantly to low-normal levels. TSH levels remained normal. T3 levels were relatively high or normal, both before and during GH treatment, indicating that PWS children have increased T4 to T3 conversion. PMID- 17716337 TI - Medicine, Ageing & Nutrition 2007, Conjoint Scientific Meeting of the Australian & New Zealand Society for Geriatric Medicine, Internal Medicine Society of Australia & New Zealand in association with International Academy of Nutrition & Aging, 5-8 September 2007, Adelaide Australia. Abstracts. PMID- 17716338 TI - Not all models of fatty liver are created equal: understanding mechanisms of steatosis development is important. PMID- 17716339 TI - Measurement of advanced glycation end products may change NASH management. PMID- 17716340 TI - Admission risk markers for upper gastrointestinal bleeding: can urgent endoscopy be avoided? PMID- 17716341 TI - Applicability of cost-effectiveness analysis to management of chronic hepatitis B. PMID- 17716342 TI - Outcomes after medical and surgical treatment of diverticulitis: a systematic review of the available evidence. AB - There is still controversy regarding the appropriate management of diverticulitis of the colon in cases when both surgical and conservative treatment may be an option. We performed a systematic review of the available evidence regarding the outcomes after medical and surgical treatment of diverticulitis from studies published after 1980 and indexed in the PubMed database. We included original studies that reported comparative data for at least one outcome in medically- and surgically-treated patients with transverse or left colon diverticulitis. The main outcomes of interest were mortality, morbidity, and recurrence of diverticulitis after medical or surgical treatment. There were 21 studies fulfilling our inclusion criteria out of 1360 initially identified as possibly relevant. More patients were treated conservatively in the included studies compared to emergency surgery (24 862 vs 6504). Emergency surgery was the main option for patients with severe complications of diverticular disease, including peritonitis. In most studies, in-hospital mortality for patients treated surgically was generally higher than that of patients treated medically, whereas there were insufficient comparative data regarding mortality during follow up. However, readmission to the hospital due to diverticular disease during follow up was more common in the group of patients treated conservatively compared to those treated surgically (4358/23 446 [18.6%]vs 22/359 [6.1%]). Conservatively-treated patients, with a first or second episode of diverticulitis, required surgery for recurrent disease during follow up in a maximum of 45% of cases, with larger studies reporting percentages lower than 11%. It should be emphasized that medical and surgical treatments have not ever been compared in a randomized controlled trial in patients with diverticulitis (without generalized peritonitis that is a surgical emergency). Although medical treatment results in more readmissions due to recurrence, it may be reasonable to avoid surgical therapy in the vast majority of patients with acute diverticulitis. It is unclear what the best treatment option is for younger patients (<50 years), namely whether elective surgery should be considered with the first episode of diverticulitis. PMID- 17716343 TI - Comparative cost-effectiveness of antiviral therapies in patients with chronic hepatitis B: a systematic review of economic evidence. AB - BACKGROUND AND AIM: Economic efficiency of the alternative antiviral therapies for chronic hepatitis B has not been systematically investigated and their quality remains unknown. The aim of the present study was to systematically overview economic evidence of antiviral therapies for chronic hepatitis B. METHODS: We searched six databases and eight major journals supplemented with screening references of eligible studies. Full economic evaluations comparing alternative antiviral therapies in patients with chronic hepatitis B virus infection were included. Two investigators assessed the study quality and transferability, independently. Data were analyzed qualitatively with adjustment when appropriate. RESULTS: Fourteen studies (six modeling vs eight trials and database analyses) were included. Quality was high in five studies, moderate in one US and five Chinese studies, and low in three Chinese studies. The major problems of quality are costing methods and analysis and the presentation of results. In Australia and Poland, lamivudine-preferred strategies dominated interferon (IFN)-alpha and its related strategy from the health-care sector perspective. In the US, adefovir salvage produced US$8446 per additional quality adjusted life years (QALY) compared with IFN-alpha. In Spain, the cost of adefovir was US$34,840 for additional virological response. In Taiwan, the use of pegylated IFN-alpha (pegIFN-alpha) produced US$11,711.4 per additional QALY, compared with lamivudine. In China, the incremental cost-effectiveness ratios of combination therapy lamivudine ranged from US$2860 to US$22,160 per additional loss of hepatitis B e antigen (HBeAg), and IFN-alpha versus lamivudine ranged from US$2490 to US$8890 per additional loss of HBeAg. CONCLUSION: The cost effectiveness frontiers of treatment alternatives vary and are influenced by the comparators and socioeconomic conditions of countries. Lamivudine-containing therapy is cost-effective when newer antiviral agents (e.g. adefovir/pegIFN alpha) were not available. Economic methods should be further improved in studies, particularly in China. PMID- 17716344 TI - Treatment of irritable bowel syndrome with osteopathy: results of a randomized controlled pilot study. AB - BACKGROUND AND AIM: Effective treatment for irritable bowel syndrome (IBS) is not yet available. Osteopathy is a manual treatment which relies on mobilizing and manipulating procedures in order to relieve complaints. In the present study, a randomized controlled trial was carried out to evaluate the effects of osteopathic treatment for IBS. METHODS: Eligible IBS patients were randomized between osteopathy and standard care. Follow-up was 6 months and validated means of follow-up were used. After 1, 3 and 6 months an overall assessment of symptoms was noted and a symptom score was obtained on a 5-point Likert scale. Quality of life (QOL) was scored with the standardized IBSQOL 2000 questionnaire and the Functional Bowel Disorder Severity Index was used. RESULTS: Twenty patients were randomized into the osteopathy group (OG) and 19 patients were included in the standard care group (SCG). Sixty-eight percent of patients in the OG noted definite overall improvement in symptoms and 27% showed slight improvement. One patient (5%) was free of symptoms at the end of the study. In the SCG, 18% noted definite improvement, 59% showed slight improvement, and in 17% worsening of symptoms was present. The difference in change in overall symptomatic improvement was statistically significant in favor of the osteopathic treatment (P < 0.006). Mean Functional Bowel Disorder Severity Index (FBDSI) score in the OG decreased from 174 to 74 at 6 months (P < 0.0001). Also, a significant decrease was noted in the SCG from 171 to 119 (P < 0.0001). However, the decrease in the OG was significantly higher compared with the standard treatment (P = 0.02). Mean symptom score in the OG decreased from 9.1 to 6.8 but this did not reach statistical significance. In the SCG, no change in symptom score occurred (8.7 vs 10). At 6 months, the score in the OG was significantly lower (6.8 vs 10; P = 0.02). The QOL score increased in the OG at 111 versus 129 (P < 0.009). In the SCG an increase was also noted, but this was not statistically significant (109 vs 121). CONCLUSION: Osteopathic therapy is a promising alternative in the treatment of patients with IBS. Patients treated with osteopathy overall did better, with respect to symptom score and QOL. PMID- 17716345 TI - Blatchford scoring system is a useful scoring system for detecting patients with upper gastrointestinal bleeding who do not need endoscopic intervention. AB - BACKGROUND AND AIM: Several scoring systems have been devised to identify patients with upper gastrointestinal (UGI) bleeding who are at a high risk of adverse outcomes. We retrospectively evaluated the accuracy of the Blatchford scoring system for assessing the need for clinical intervention in cases of UGI bleeding admitted to the emergency department (ED). METHODS: This was a retrospective study conducted on patients who underwent emergency GI endoscopy at the ED of our hospital. Those who needed blood transfusion, operative or endoscopic interventions to control the hemorrhage were classified into the 'high risk' group. RESULTS: Of the 93 enrolled patients, 70 (75.3%) were classified into the high risk group. The Blatchford score was significantly higher in the high risk group than in the low risk group. When a cut-off value of 2 was used, the sensitivity and specificity of the Blatchford scoring system were determined to be 100% and 13%, respectively. Thus, the Blatchford scoring system was deemed to be useful for distinguishing between the high risk group and the low risk group of patients with GI hemorrhage admitted to the ED. CONCLUSION: The Blatchford scoring system is accurate for identifying definitively low-risk patients of GI hemorrhage, even prior to the performance of emergency UGI endoscopy at the ED. PMID- 17716346 TI - Epidemiology of gastroesophageal reflux disease in Tehran, Iran. AB - BACKGROUND AND AIM: Epidemiological studies have indicated an increase in the prevalence of gastroesophageal reflux disease in Western countries; however, there is a lack of information about its prevalence in Iran. The aim of this study was to measure gastroesophageal reflux disease prevalence in a representative sample of the Tehran population in 1999. METHODS: In a cross sectional study, 700 people, with a male : female ratio of 1:1, were selected by stratified randomization based on the probability of 20% prevalence of gastroesophageal reflux disease and 3% error. They were divided equally into seven age groups. Heartburn and acid regurgitation were considered as the most common symptoms of gastroesophageal reflux disease. The severity and frequency of heartburn and the role of personal habits in the appearance of this symptom were determined. The prevalence of gastroesophageal reflux disease in samples was measured, and its actual prevalence in society was estimated. RESULTS: Of 700 people, 350 were male and 350 were female. The major symptoms of gastroesophageal reflux disease were observed in 278 (39.7%) people. The prevalence of gastroesophageal reflux disease of smokers was twice that of non-smokers. CONCLUSIONS: Gastroesophageal reflux disease is a serious and unresolved problem in Western countries, and its increasing prevalence correlates with an increasing prevalence of adenocarcinoma of distal esophagus. The prevalence of gastroesophageal reflux disease appears to be increasing in Iran also; therefore, it is recommended that major attention be paid to this disease. PMID- 17716347 TI - Post-infectious gastroparesis: clinical and electerogastrographic aspects. AB - AIMS: Post-infectious gastroparesis (PIGP) is a subgroup of idiopathic gastroparesis. The aim of this study was to identify post-viral gastroparesis and to characterize clinical and electrogastrographic aspects of the disease and their usefulness as a diagnostic tool. METHODS: Patients diagnosed with gastroparesis were defined as PIGP if they had a clear history of an acute viral illness prior to the development of their symptoms. All patients underwent evaluation of gastric emptying and electrogastrography (EGG). RESULTS: Seven patients met the criteria for diagnosis of PIGP. Patients' age ranged from 3 months to 47 years. A specific virus was identified in two patients (one cytomegalovirus [CMV] and one Epstein-Barr virus [EBV]). EGG was pathological in six out of seven patients. In four out of seven patients, symptoms resolved spontaneously within 4 weeks to 12 months, three patients had improved but were still symptomatic at the time of the writing of this work. CONCLUSION: We conclude that post-infectious gastroparesis is an uncommon and often over looked condition. It is self-limiting in most cases. EGG is pathological in most patients. PMID- 17716348 TI - Effects of interleukin-10 gene polymorphism on the development of gastric cancer and peptic ulcer in Japanese subjects. AB - BACKGROUND: Anti-inflammatory cytokines play an important role in downregulation of inflammation and the prevention of neoplastic disorders. Genetic variations of anti-inflammatory cytokines are assumed to influence such responses. The aim of the present study was to clarify the association between the IL-10 polymorphism, one of the representative anti-inflammatory cytokines, and susceptibility to gastric cancer and peptic ulcer in Japan. METHODS: The IL-10-1082 (A/G)/-819 (T/C)/-592 (A/C) polymorphisms were assessed in Helicobacter pylori-positive patients with gastritis only (n = 162), gastric ulcers (n = 110), duodenal ulcers (n = 94), or gastric cancers (n = 105), and H. pylori-negative controls (n = 168) by allele specific primer-polymerase chain reaction methods. RESULTS: The carriage of IL-10-592 C (age and sex-adjusted odds ratio [OR]: 1.851, 95% confidence interval [CI]: 1.018-3.380) and IL-10-819 C (adjusted OR: 1.868, 95%CI: 1.023-3.411) allele were associated with an increased risk for gastric cancer development, not gastric ulcer and duodenal ulcer. The IL-10-1082 polymorphism had no association with development of gastric cancer and peptic ulcers. The presence of the ATA/GCC haplotype of IL-10-1082/-819/-592 polymorphism significantly increased the risk of gastric cancer development (adjusted OR: 2.805, 95%CI: 1.258-6.254) compared with presence of the ATA/ATA haplotype. CONCLUSIONS: The IL-10-1082/-819/-592 genotype status and haplotype were associated with an increased risk for gastric cancer development, not peptic ulcer, in Japan. The genotyping test of this anti-inflammatory cytokine would be useful for the detection of individuals with higher risk of gastric cancer development. PMID- 17716349 TI - Ulcerative colitis in China: retrospective analysis of 3100 hospitalized patients. AB - BACKGROUND AND AIMS: This retrospective study analyzed the clinical characteristics of hospitalized patients with ulcerative colitis (UC) in China. METHODS: A total of 3100 hospitalized patients with UC admitted to 23 hospitals in China from 1990 to 2003 were retrospectively investigated and their clinical characteristics were analyzed. RESULTS: A male/female ratio of 1.34/1.00 was found in the 3100 patients, who had an average age of 44 +/- 15.1 years at diagnosis. Of the patients, 2972 (95.9%) had active UC. Active UC was mild in 35.4% of the 2972 patients, moderate in 42.9% and severe in 21.7%. Of the 2726 patients with a description of their lesion extent, 14.8% had proctitis, 26.4% had proctosigmoiditis, 25.0% had left-sided colitis, 6.3% had extensive colitis, 25.8% had pancolitis and 1.7% had regional colitis. The predominant complaints of the patients with UC were bloody diarrhea (48.2%), abdominal pain (67.3%) and mucus stools (58.4%). Among these patients, 13.6% had extraintestinal manifestations and 9.6% had related complications. A differential diagnosis was difficult to make, as there were 19 varieties of the disease; infectious enterocolitis had a misdiagnosis rate of 22.9% before admission. The main medications for UC in China were aminosalicylates (66.8%) and steroids (42.8%). Only 94 (3%) of the patients required colectomy and only 19 (0.6%) died of UC. CONCLUSIONS: Compared with UC in Western countries, ulcerative colitis in China has some differences in clinical characteristics. Therefore, a further population based epidemiological study is required to determine the prevalence and incidence rates of UC in China. PMID- 17716350 TI - Effects of washout following indomethacin administration on electrical field stimulation-induced isolated rat gastric fundus strip contractions. AB - BACKGROUND AND AIM: Although gastric hypermotility is one of the mechanisms proposed to explain the ulcerogenic action of indomethacin, the drug has shown relaxatory effects on isolated longitudinal and transverse rat gastric fundus. To explain the above discrepancy, the aim of this study was to investigate the effects of washout following indomethacin administration on the contractile response of isolated rat gastric strips to electrical field stimulation. METHODS: Transverse and longitudinal strips of stomach were suspended in organ baths containing oxygenated Krebs solution. Contractile responses to electrical field stimulation were recorded on a physiograph before and after administration of a single concentration of indomethacin. Recordings were also taken 15 min after the washout of the drug. To study the part played by K(ATP) channels on post-washout response, the effects of diazoxide as a channel opener and glybenclamide as a channel blocker were also studied. RESULTS: The amplitude of the contractions was not changed following indomethacin administration but was significantly increased 15 min after washout of the drug. Diazoxide pretreatment inhibited the stimulatory post-washout response of both strips. Glybenclamide pretreatment showed different results depending on the type of strip. In the transverse strips the drug showed no effect while in the longitudinal strips it decreased the post washout response. CONCLUSIONS: The present data suggest that indomethacin has a delayed stimulatory effect on gastric smooth muscle, which will appear after the exposure of the strip to the drug followed by its washout. This effect seems to be under the influence of K(ATP) channel modulators. PMID- 17716351 TI - Therapeutic effect of nimesulide on colorectal carcinogenesis in experimental murine ulcerative colitis. AB - BACKGROUND: Patients with ulcerative colitis (UC) exhibit an increased risk for the development of cancer of the colon and rectum. Cyclooxygenase (COX)-2 inhibitors are known to suppress sporadic colorectal cancer, but it is unknown whether selective COX-2 inhibitors exhibit a preventive effect in UC-associated neoplasia. This study investigated the preventive effect of nimesulide, a selective COX-2 inhibitor, on colorectal carcinogenesis in an experimental model of murine UC. METHODS: Chronic colitis was induced in mice by administration of four cycles of dextran sulfate sodium (DSS) (each cycle: 5% DSS for 7 days and then distilled water for 14 days). The mice were killed 120 days after the completion of the fourth cycle. The mice were divided into the following five groups: group A served as a disease control; group B received a diet mixed with 400 p.p.m. of nimesulide during the whole period; group C received nimesulide during the four cycles of DSS administration (active phase); group D received nimesulide for 120 days from the end of the fourth cycle (remission phase); group E received no agents including DSS and served as a normal control. RESULTS: The incidence of dysplasia and/or cancer was 28%, 15%, 11.8%, 6.7% and 0% in groups A E, respectively. In group D, nimesulide significantly suppressed the occurrence of dysplasia and/or cancer (P < 0.05). Strong COX-2 expression was detected by immunohistochemistry in cancer and dysplastic lesions while diffusely weak COX-2 expression was also found in the residual colon (i.e. lesion-free colon). The mucosal concentration of prostaglandin E(2) was significantly lower in groups B and D than in group A. CONCLUSIONS: The administration of the selective COX-2 inhibitor nimesulide (especially during the remission phase) exerts a suppressive effect on the development of dysplasia and/or cancer in a murine model of DSS induced colitis. These findings may have relevance to long-standing UC in humans. PMID- 17716352 TI - Prevalence and etiology of elevated serum alanine aminotransferase level in an adult population in Taiwan. AB - BACKGROUND: The prevalence and etiologies of elevated alanine aminotransferase (ALT) have geographic variations and they are rarely reported in Taiwan. Through a population-based screening study, the prevalence and etiologies of elevated ALT in an adult population of Taiwan were assessed. METHODS: A cross-sectional community study in a rural village of Taiwan was conducted in 3260 Chinese adults (age >or=18 years) undergoing ultrasonography (US), blood tests, and interviews with a structured questionnaire. The diagnostic criteria of non-alcoholic fatty liver disease (NAFLD) included alcohol intake <20 g/week for women or <30 g/week for men, negative hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, no known etiologies of liver disease, and US consistent with fatty liver. RESULTS: The prevalence of elevated ALT was 11.4% (372/3260). The probable cause of this elevation was excess alcohol consumption in 0.8%, HBV in 28.5%, HCV in 13.2%, both HBV and HCV in 2.2%, NAFLD in 33.6%, and unexplained cause in 21.8%. The etiologic distribution of elevated ALT was similar in both genders, although elevation was more common in men compared to women (17.3%vs 6.1%, P < 0.05). The prevalence of elevated ALT in NAFLD was 18.1% (125/691), and the positive predictive value was 33.6% (125/372). The development of NAFLD was related to increasing age (age between 40 years and 64 years, odds ratio [OR] 1.59, 95% confidence interval [CI]: 1.25-2.01; age >or= 65 years, OR 1.46, 95%CI: 1.08 1.96), fasting plasma glucose (FPG) >or= 126 mg/dL (OR 1.54, 95%CI: 1.11-2.14), body mass index (BMI) >or= 25 kg/m(2) (OR 5.01, 95%CI: 4.13-6.26), triglyceridemia >or= 150 mg/dL (OR 1.96, 95%CI: 1.58-2.42), and hyperuricemia (OR 1.50, 95%CI: 1.22-1.84). Elevated ALT was related to male gender, BMI >or= 25 kg/m(2), and triglyceridemia >or= 150 mg/dL in subjects without known etiologies of liver disease (all P < 0.05). CONCLUSIONS: Non-alcoholic fatty liver disease appears to be the commonest cause of elevated ALT and presumed liver injury in Taiwan. The development of NAFLD is closely associated with many metabolic disorders. Metabolic disorders are also related to elevated ALT in subjects without known etiologies of liver disease. PMID- 17716354 TI - Hepatitis C virus (HCV) viremia in HIV-infected patients without HCV antibodies detectable by third-generation enzyme immunoassay. AB - BACKGROUND: The detection of hepatitis C virus antibody (anti-HCV) by enzyme immunoassay to screen HCV infection in HIV-1-infected individuals may yield false negative results, especially in patients with advanced immunosuppression. In such cases, a diagnosis would be possible only by use of a viral RNA detection technique. Third-generation anti-HCV enzyme immunoassays seem to have superior performance compared to second-generation immunoassays in this context. METHODS: A cross-sectional study was conducted to ascertain the presence of HCV by polymerase chain reaction (PCR) in 61 HIV-1-infected patients with CD(4)(+) cell counts <200 cells/mm(3), and no detectable HCV antibodies by a third-generation enzyme immunoassay. RESULTS: Six (10%) of 61 patients tested HCV-RNA positive by PCR assay. There was one patient who seroconverted during observation. Hence, there were five patients with HCV viremia without detectable antibodies to HCV throughout the study, which represents 8.2% (95% confidence interval: 2.8-18.4) of 61 HIV-1-infected patients. All five carriers of HCV viremia had CD4 counts <100 cells/mm(3) and were diagnosed with an opportunistic disease at some stage. CONCLUSIONS: The HCV viremia and no detectable HCV antibodies by third-generation immunoassay were found only in individuals with a CD(4) count of <100 cells/mm(3). Molecular assays to detect HCV-RNA should be considered as an important tool to diagnose hepatitis C in HIV-1-infected patients with advanced immunosuppression. PMID- 17716353 TI - Cost-effectiveness of peginterferon alpha-2a compared to lamivudine treatment in patients with hepatitis B e antigen positive chronic hepatitis B in Taiwan. AB - BACKGROUND: Peginterferon alpha-2a (40KD), a new treatment option for patients with chronic hepatitis B (CHB), offers improved efficacy with a defined treatment duration compared with lamivudine, but at a higher cost. We undertook an economic evaluation of peginterferon alpha-2a from the perspective of the Taiwan Bureau of National Health Insurance to assess the clinical outcomes and costs of 48 weeks of peginterferon alpha-2a for the treatment of patients with hepatitis B e antigen (HBeAg)-positive CHB, compared to lamivudine treatment for 48 weeks. METHODS: We performed a cost-effectiveness analysis using a state-transition Markov model simulating the natural history of HBeAg-positive CHB. Efficacy data were obtained from a randomized clinical trial of 820 patients (87% were Asian) comparing peginterferon alpha-2a to lamivudine. We modeled a hypothetical cohort of 32-year-old patients with HBeAg-positive CHB. Life expectancy, quality adjusted life expectancy, lifetime costs ($NTD) and incremental cost effectiveness ratios (ICER) were estimated. One-way sensitivity analyses were performed on all parameters in the model to evaluate uncertainty. RESULTS: Treatment with peginterferon alpha-2a compared to lamivudine resulted in higher total costs, but longer quality-adjusted life expectancy, yielding an ICER of $NTD 381 000 ($US 12,000) per quality-adjusted life year (QALY) gained. Although there is uncertainty associated with the prognosis of HBeAg-positive CHB, the ICER did not exceed $NTD 485,000 ($US 15,000) per QALY gained despite variation in the parameters used in the analysis. CONCLUSIONS: Our analysis suggests that 48-week treatment with peginterferon alpha-2a compared to 48-week treatment with lamivudine in HBeAg-positive patients offers life expectancy and quality of life benefits at a favorable cost-effectiveness ratio. PMID- 17716356 TI - Education and imaging. Hepatobiliary and pancreatic: hepatic arteriovenous malformations in hereditary hemorrhagic telangiectasia. PMID- 17716355 TI - Essential pathogenic and metabolic differences in steatosis induced by choline or methione-choline deficient diets in a rat model. AB - BACKGROUND AND AIM: Choline deficient (CD) and methione-choline deficient (MCD) diets are rodent models for steatosis, with potentially dissimilar biochemical backgrounds. The aim of this study was to assess the metabolic and pathological derangements in rats fed CD and MCD diets. METHODS: Male Wistar rats received CD or MCD diet up to 7 weeks. Nutritional status, liver histopathology, Kupffer cell mediated inflammation and injury, oxidative stress via thiobarbituric reactive species (TBARS), hepatic and plasma glutathione (GSH) and insulin homeostasis were assessed. RESULTS: In CD-fed rats, mainly microvesicular steatosis developed with occasional inflammatory cells. In MCD-fed rats, macrovesicular steatosis progressed to steatohepatitis (collagen deposition, activated stellate cells). Hepatic TBARS was increased and GSH decreased in the MCD-fed rats compared to no changes in the CD-fed rats. The CD-fed rats developed obesity, dyslipidemia and insulin resistance, in contrast to undetectable plasma lipids, unaffected insulin homeostasis and loss of body weight in the MCD-fed rats. CONCLUSIONS: The CD diet induced uncomplicated steatosis as compared to progressive inflammation and fibrinogenesis in the MCD diet. CD and MCD diets represent two pathogenically different models of steatosis. Although equivalence for the outcome of both diets can be found in clinical steatosis, the results of models using these diets should be compared with caution. PMID- 17716357 TI - Education and imaging. Gastrointestinal: glycogenic acanthosis. PMID- 17716358 TI - Education and imaging. Gastrointestinal: natural history of squamous cell carcinoma of the esophagus. PMID- 17716359 TI - Education and imaging. Hepatobiliary and pancreatic: torsion of the gallbladder. PMID- 17716360 TI - Education and imaging. Gastrointestinal: tubular duplication of the descending colon. PMID- 17716361 TI - Aeromonas hydrophilia colitis mimicking ischaemic colitis in an elderly woman. PMID- 17716363 TI - Diagnostic outcome of two different CT-guided fine needle biopsy procedures. AB - BACKGROUND: CT-guided fine needle bioptic procedures (CTFNP) are characterised by low invasiveness, precise sample collection, a high diagnostic efficiency and support a rapid diagnostic process. A number of different fine needles and bioptic procedures are mainly used for tumour diagnostics today.The aim of the present study was to characterise the most important technical issues of fine needle bioptic procedures. In addition, we directly compared the diagnostic outcome and reliability of the most commonly used Rotex Screw Needle--(RSN) and Yale Needle--(YN) bioptic procedure. METHODS: In an experimental part of the study, using pig spleen, we measured the maximum number of sampled cells using different needles and aspiration volumes.For the clinical questions we analysed all consecutive 340 patients in which CTFNP were performed between 1/97-12/05 in the hospital Grosshansdorf. We evaluated the number of adverse events based on all clinical available information and compared the cytological findings with the respective final diagnosis (confirmed: clinically n = 192, histologically n = 148). RESULTS: Using the YN with at least some negative pressure we found a proportional increase of cell and tissue recovery with increasing number of needle movements. A sensitivity of 78% and a specificity 98% indicate a high diagnostic outcome of CTFNP. We found no statistical significant difference in terms of sensitivity (80 vs. 68%) as well as complication rates (5.9 vs. 4.4%) between RSN or YN. CONCLUSION: As fine needle basically works like a cutting instrument, it is possible to raise the cell/tissue recovery. Keeping this in mind we found a high diagnostic outcome of CTFNP, which was largely independent of needle type and bioptic technique, and comparable with other conventional bioptic procedures. PMID- 17716364 TI - Rationale, design and conduct of a randomised controlled trial evaluating a primary care-based complex intervention to improve the quality of life of heart failure patients: HICMan (Heidelberg Integrated Case Management). AB - BACKGROUND: Chronic congestive heart failure (CHF) is a complex disease with rising prevalence, compromised quality of life (QoL), unplanned hospital admissions, high mortality and therefore high burden of illness. The delivery of care for these patients has been criticized and new strategies addressing crucial domains of care have been shown to be effective on patients' health outcomes, although these trials were conducted in secondary care or in highly organised Health Maintenance Organisations. It remains unclear whether a comprehensive primary care-based case management for the treating general practitioner (GP) can improve patients' QoL. METHODS/DESIGN: HICMan is a randomised controlled trial with patients as the unit of randomisation. Aim is to evaluate a structured, standardized and comprehensive complex intervention for patients with CHF in a 12 months follow-up trial. Patients from intervention group receive specific patient leaflets and documentation booklets as well as regular monitoring and screening by a prior trained practice nurse, who gives feedback to the GP upon urgency. Monitoring and screening address aspects of disease-specific self-management, (non)pharmacological adherence and psychosomatic and geriatric comorbidity. GPs are invited to provide a tailored structured counselling 4 times during the trial and receive an additional feedback on pharmacotherapy relevant to prognosis (data of baseline documentation). Patients from control group receive usual care by their GPs, who were introduced to guideline-oriented management and a tailored health counselling concept. Main outcome measurement for patients' QoL is the scale physical functioning of the SF-36 health questionnaire in a 12-month follow up. Secondary outcomes are the disease specific QoL measured by the Kansas City Cardiomyopathy questionnaire (KCCQ), depression and anxiety disorders (PHQ-9, GAD 7), adherence (EHFScBS and SANA), quality of care measured by an adapted version of the Patient Chronic Illness Assessment of Care questionnaire (PACIC) and NT proBNP. In addition, comprehensive clinical data are collected about health status, comorbidity, medication and health care utilisation. DISCUSSION: As the targeted patient group is mostly cared for and treated by GPs, a comprehensive primary care-based guideline implementation including somatic, psychosomatic and organisational aspects of the delivery of care (HICMAn) is a promising intervention applying proven strategies for optimal care. PMID- 17716365 TI - Social inequalities in injury occurrence and in disability retirement attributable to injuries: a 5 year follow-up study of a 2.1 million gainfully employed people. AB - BACKGROUND: Inequalities in injury related disability retirement may be due to differences in injury risk and or differences in retirement given injury. The aim of the present study was to measure social inequalities in injury occurrence and injury related disability retirement. METHODS: All people in the Danish labour force aged 20-59 years 1 January 1997 were followed for injury related hospital contacts during 1997 and all people in the Danish labour force aged 21-54 years 1 January 1998 were followed for injury related hospital contacts during 1997 and for disability retirements during 1998-2002. As inequality indices we used excess fractions (EF) i.e. the proportions of the cases that would not have occurred if the risks in each social group had been as low as they were in the occupational group with the highest skill requirements. RESULTS: With regard to the risk that an injury will occur, the EF was 36% among men and 10% among women. With regard to the risk that an injury will lead to disability retirement, the EF was 43% among men and 47% among women. The combined effect of the two types of inequalities rendered an EF for injury related disability retirement of 64% among men and 53% among women. The correlation between the case disability rate ratios among men and those among women was low (r = -0.110, P = 0.795). CONCLUSION: The social inequality in injury related disability retirement lies only to some degree in the differences in the injury risk. More important are differences in the consequences of an injury. This was especially pronounced among the women. PMID- 17716367 TI - The low and declining risk of malaria in travellers to Latin America: is there still an indication for chemoprophylaxis? AB - A comparison was made between local malaria transmission and malaria imported by travellers to identify the utility of national and regional annual parasite index (API) in predicting malaria risk and its value in generating recommendations on malaria prophylaxis for travellers. Regional malaria transmission data was correlated with malaria acquired in Latin America and imported into the USA and nine European countries. Between 2000 and 2004, most countries reported declining malaria transmission. Highest API's in 2003/4 were in Surinam (287.4) Guyana (209.2) and French Guiana (147.4). The major source of travel associated malaria was Honduras, French Guiana, Guatemala, Mexico and Ecuador. During 2004 there were 6.3 million visits from the ten study countries and in 2005, 209 cases of malaria of which 22 (11%) were Plasmodium falciparum. The risk of adverse events are high and the benefit of avoided benign vivax malaria is very low under current policy, which may be causing more harm than benefit. PMID- 17716366 TI - Burn size determines the inflammatory and hypermetabolic response. AB - BACKGROUND: Increased burn size leads to increased mortality of burned patients. Whether mortality is due to inflammation, hypermetabolism or other pathophysiologic contributing factors is not entirely determined. The purpose of the present study was to determine in a large prospective clinical trial whether different burn sizes are associated with differences in inflammation, body composition, protein synthesis, or organ function. METHODS: Pediatric burned patients were divided into four burn size groups: <40% total body surface area (TBSA) burn, 40-59% TBSA burn, 60-79% TBSA burn, and >80% TBSA burn. Demographic and clinical data, hypermetabolism, the inflammatory response, body composition, the muscle protein net balance, serum and urine hormones and proteins, and cardiac function and changes in liver size were determined. RESULTS: One hundred and eighty-nine pediatric patients of similar age and gender distribution were included in the study (<40% TBSA burn, n = 43; 40-59% TBSA burn, n = 79; 60-79% TBSA burn, n = 46; >80% TBSA burn, n = 21). Patients with larger burns had more operations, a greater incidence of infections and sepsis, and higher mortality rates compared with the other groups (P < 0.05). The percentage predicted resting energy expenditure was highest in the >80% TBSA group, followed by the 60-79% TBSA burn group (P < 0.05). Children with >80% burns lost the most body weight, lean body mass, muscle protein and bone mineral content (P < 0.05). The urine cortisol concentration was highest in the 80-99% and 60-79% TBSA burn groups, associated with significant myocardial depression and increased change in liver size (P < 0.05). The cytokine profile showed distinct differences in expression of IL-8, TNF, IL-6, IL-12p70, monocyte chemoattractant protein-1 and granulocyte macrophage colony-stimulating factor (P < 0.05). CONCLUSION: Morbidity and mortality in burned patients is burn size dependent, starts at a 60% TBSA burn and is due to an increased hypermetabolic and inflammatory reaction, along with impaired cardiac function. PMID- 17716368 TI - HIV-1 sequence evolution in vivo after superinfection with three viral strains. AB - With millions of people infected worldwide, the evolution of HIV-1 in vivo has been the subject of much research. Although recombinant viruses were detected early in the epidemic, evidence that HIV-1 dual infections really occurred came much later. Dual infected patients, consisting of coinfected (second infection before seroconversion) and superinfected (second infection after seroconversion) individuals, opened up a new area of HIV-1 evolution studies. Here, we describe the in-depth analysis of HIV-1 over time in a patient twice superinfected with HIV-1, first with a subtype B (B2) strain and then with CRF01_AE after initial infection with a subtype B (B1) strain. The nucleotide evolution of gag and env V3 of the three strains followed a similar pattern: a very low substitution rate in the first 2-3 years of infection, with an increase in synonymous substitutions thereafter. Convergent evolution at the protein level was rare: only a single amino acid in a gag p24 epitope showed convergence in the subtype B strains. Reversal of CTL-epitope mutations were also rare, and did not converge. Recombinant viruses were observed between the two subtype B strains. Luciferase assays suggested that the CRF01_AE long terminal repeat (LTR) constituted the strongest promoter, but this was not reflected in the plasma viral load. Specific real-time PCR assays based upon the env gene showed that strain B2 and CRF01_AE RNA was present in equal amounts, while levels of strain B1 were 100-fold lower. All three strains were detected in seminal plasma, suggesting that simultaneous transmission is possible. PMID- 17716369 TI - Predicting the response of localised oesophageal cancer to neo-adjuvant chemoradiation. AB - BACKGROUND: A complete pathological response to neo-adjuvant chemo-radiation for oesophageal cancer is associated with favourable survival. However, such a benefit is seen in the minority. If one could identify, at diagnosis, those patients who were unlikely to respond unnecessary toxicity could be avoided and alternative treatment can be considered. The aim of this review was to highlight predictive markers currently assessed and evaluate their clinical utility. METHODS: A systematic search of Pubmed and Google Scholar was performed using the following keywords; "neo-adjuvant", "oesophageal", "trimodality", "chemotherapy", "radiotherapy", "chemoradiation" and "predict". The original manuscripts were sourced for further articles of relevance. RESULTS: Conventional indices including tumour stage and grade seem unable to predict histological response. Immuno-histochemical markers have been extensively studied, but none has made its way into routine clinical practice. Global gene expression from fresh pre treatment tissue using cDNA microarray has only recently been assessed, but shows considerable promise. Molecular imaging using FDG-PET seems to be able to predict response after neo-adjuvant chemoradiation has finished, but there is a paucity of data when such imaging is performed earlier. CONCLUSION: Currently there are no clinically useful predictors of response based on standard pathological assessment and immunohistochemistry. Genomics, proteomics and molecular imaging may hold promise. PMID- 17716370 TI - Evolutionary optimization of classifiers and features for single-trial EEG discrimination. AB - BACKGROUND: State-of-the-art signal processing methods are known to detect information in single-trial event-related EEG data, a crucial aspect in development of real-time applications such as brain computer interfaces. This paper investigates one such novel approach, evaluating how individual classifier and feature subset tailoring affects classification of single-trial EEG finger movements. The discrete wavelet transform was used to extract signal features that were classified using linear regression and non-linear neural network models, which were trained and architecturally optimized with evolutionary algorithms. The input feature subsets were also allowed to evolve, thus performing feature selection in a wrapper fashion. Filter approaches were implemented as well by limiting the degree of optimization. RESULTS: Using only 10 features and 100 patterns, the non-linear wrapper approach achieved the highest validation classification accuracy (subject mean 75%), closely followed by the linear wrapper method (73.5%). The optimal features differed much between subjects, yet some physiologically plausible patterns were observed. CONCLUSION: High degrees of classifier parameter, structure and feature subset tailoring on individual levels substantially increase single-trial EEG classification rates, an important consideration in areas where highly accurate detection rates are essential. Also, the presented method provides insight into the spatial characteristics of finger movement EEG patterns. PMID- 17716371 TI - mRNA/microRNA gene expression profile in microsatellite unstable colorectal cancer. AB - BACKGROUND: Colorectal cancer develops through two main genetic instability pathways characterized by distinct pathologic features and clinical outcome. RESULTS: We investigated colon cancer samples (23 characterized by microsatellite stability, MSS, and 16 by high microsatellite instability, MSI-H) for genome-wide expression of microRNA (miRNA) and mRNA. Based on combined miRNA and mRNA gene expression, a molecular signature consisting of twenty seven differentially expressed genes, inclusive of 8 miRNAs, could correctly distinguish MSI-H versus MSS colon cancer samples. Among the differentially expressed miRNAs, various members of the oncogenic miR-17-92 family were significantly up-regulated in MSS cancers. The majority of protein coding genes were also up-regulated in MSS cancers. Their functional classification revealed that they were most frequently associated with cell cycle, DNA replication, recombination, repair, gastrointestinal disease and immune response. CONCLUSION: This is the first report that indicates the existence of differences in miRNA expression between MSS versus MSI-H colorectal cancers. In addition, the work suggests that the combination of mRNA/miRNA expression signatures may represent a general approach for improving bio-molecular classification of human cancer. PMID- 17716372 TI - Variance in multiplex suspension array assays: microsphere size variation impact. AB - BACKGROUND: Luminex suspension microarray assays are in widespread use. There are issues of variability of assay readings using this technology. METHODS AND RESULTS: Size variation is demonstrated by transmission electron microscopy. Size variations of microspheres are shown to occur in stepwise increments. A strong correspondence between microsphere size distribution and distribution of fluorescent events from assays is shown. An estimate is made of contribution of microsphere size variation to assay variance. CONCLUSION: A probable significant cause of variance in suspended microsphere assay results is variation in microsphere diameter. This can potentially be addressed by changes in the manufacturing process. Provision to users of mean size, median size, skew, the number of standard deviations that half the size range represents (sigma multiple), and standard deviation is recommended. Establishing a higher sigma multiple for microsphere production is likely to deliver a significant improvement in precision of raw instrument readings. Further research is recommended on the molecular architecture of microsphere coatings. PMID- 17716373 TI - Disentangling manual muscle testing and Applied Kinesiology: critique and reinterpretation of a literature review. AB - Cuthbert and Goodheart recently published a narrative review on the reliability and validity of manual muscle testing (MMT) in the Journal. The authors should be recognized for their effort to synthesize this vast body of literature. However, the review contains critical errors in the search methods, inclusion criteria, quality assessment, validity definitions, study interpretation, literature synthesis, generalizability of study findings, and conclusion formulation that merit a reconsideration of the authors' findings. Most importantly, a misunderstanding of the review could easily arise because the authors did not distinguish the general use of muscle strength testing from the specific applications that distinguish the Applied Kinesiology (AK) chiropractic technique. The article makes the fundamental error of implying that the reliability and validity of manual muscle testing lends some degree of credibility to the unique diagnostic procedures of AK. The purpose of this commentary is to provide a critical appraisal of the review, suggest conclusions consistent with the literature both reviewed and omitted, and extricate conclusions that can be made about AK in particular from those that can be made about MMT. When AK is disentangled from standard orthopedic muscle testing, the few studies evaluating unique AK procedures either refute or cannot support the validity of AK procedures as diagnostic tests. The evidence to date does not support the use of MMT for the diagnosis of organic disease or pre/subclinical conditions. PMID- 17716374 TI - Prevalence and associated factors of suicidal ideation among school-going adolescents in Guyana: results from a cross sectional study. AB - BACKGROUND: Adolescent suicidal behaviour is a neglected public health issue especially in middle- and low-income countries. Informed policy decision-making on suicidal behaviour will need reliable information on the prevalence and correlates of suicidal ideation which is a determinant of suicidal behaviour. METHODS: We estimated the prevalence and associated factors of suicidal ideation among school-going adolescents using data from the Global School-Based Health Survey conducted in 2004 in Guyana. RESULTS: Of the 1197 respondents, 18.4% (14.9% males and 21.6% females)reported having seriously considered committing suicide in the last12 months. Males were less likely to seriously consider committingsuicide than females (OR = 0.45; 95% CI [0.30, 0.67]). Subjects whoreported having been bullied were more than twice as likely tocontemplate committing suicide as those who had not been bullied (OR = 2.46 [1.71, 3.54]). History of depression was positivelyassociated with suicidal ideation (OR = 2.67; 95% [1.87, 3.81] whilehaving close friends and understanding parents were negativelyassociated with suicide ideation (OR = 0.51; 95% CI [0.28, 0.94] and OR = 0.51; 95% CI [0.35, 0.76] respectively). CONCLUSION: Suicidal ideation is a significant public health issue among in-school adolescents in Guyana that requires attention. The design, implementation and evaluation of suicidal behaviour interventions should incorporate our knowledge of these associated factors. PMID- 17716375 TI - Divergent calcium signaling in RBCs from Tropidurus torquatus (Squamata- Tropiduridae) strengthen classification in lizard evolution. AB - BACKGROUND: We have previously reported that a Teiid lizard red blood cells (RBCs) such as Ameiva ameiva and Tupinambis merianae controls intracellular calcium levels by displaying multiple mechanisms. In these cells, calcium stores could be discharged not only by: thapsigargin, but also by the Na+/H+ ionophore monensin, K+/H+ ionophore nigericin and the H+ pump inhibitor bafilomycin as well as ionomycin. Moreover, these lizards possess a P2Y-type purinoceptors that mobilize Ca2+ from intracellular stores upon ATP addition. RESULTS: Here we report, that RBCs from the tropidurid lizard Tropidurus torquatus store Ca2+ in endoplasmic reticulum (ER) pool but unlike in the referred Teiidae, these cells do not store calcium in monensin-nigericin sensitive pools. Moreover, mitochondria from T. torquatus RBCs accumulate Ca2+. Addition of ATP to a calcium free medium does not increase the [Ca2+]c levels, however in a calcium medium we observe an increase in cytosolic calcium. This is an indication that purinergic receptors in these cells are P2X-like. CONCLUSION: T. torquatus RBCs present different mechanisms from Teiid lizard red blood cells (RBCs), for controlling its intracellular calcium levels. At T. torquatus the ion is only stored at endoplasmic reticulum and mitochondria. Moreover activation of purinergic receptor, P2X type, was able to induce an influx of calcium from extracellular medium. These studies contribute to the understanding of the evolution of calcium homeostasis and signaling in nucleated RBCs. PMID- 17716376 TI - Effects of a community-based healthy heart program on increasing healthy women's physical activity: a randomized controlled trial guided by Community-based Participatory Research (CBPR). AB - BACKGROUND: Cardiovascular disease remains the leading killer of women in most developed areas of the world. Rates of physical inactivity and poor nutrition, which are two of the most important modifiable risk factors for cardiovascular disease in women, are substantial. This study sought to examine the effectiveness of a community-based lifestyle-modification program on increasing women's physical activity in a randomized trial guided by community-based participatory research (CBPR) methods. METHODS: A total of 335 healthy, 25-64 years old women who had been selected by a multiple-stage stratified cluster random sampling method in Bushehr Port/I.R. Iran, were randomized into control and intervention groups. The intervention group completed an 8-week lifestyle modification program for increasing their physical activity, based on a revised form of Choose to Move program; an American Heart Association Physical Activity Program for Women. Audio taped activity instructions with music and practical usage of the educational package were given to the intervention group in weekly home-visits by 53 volunteers from local non-governmental and community-based organizations. RESULTS: Among the participants, the percentage who reported being active (at lease 30 minutes of moderate intensity physical activity for at least 5 days a week, or at least 20 minutes of vigorous physical activity for at least three days a week) increased from 3% and 2.7% at baseline to 13.4% and 3% (p < 0.0001) at the ending of the program in the intervention and control groups, respectively. The participants in the intervention group reported more minutes of physical activity per week (mean = 139.81, SE = 23.35) than women in the control group (mean = 40.14, SE = 12.65) at week 8 (p < 0.0001). The intervention group subjects exhibited a significantly greater decrease in systolic blood pressure ( 10.0 mmHg) than the control group women (+2.0. mmHg). The mean ranks for posttest healthy heart knowledge in the intervention and control groups were 198.91 and 135.77, respectively (P < 0.0001). CONCLUSION: An intervention based on CBPR methods can be effective for the short-term adoption of physical activity behavior among women. The development of participatory process to support the adequate delivery of lifestyle-modification programs is feasible and an effective healthcare delivery strategy for cardiovascular community health promotion. TRIAL REGISTRATION: ACTRNO12606000521527. PMID- 17716377 TI - Protein structural similarity search by Ramachandran codes. AB - BACKGROUND: Protein structural data has increased exponentially, such that fast and accurate tools are necessary to access structure similarity search. To improve the search speed, several methods have been designed to reduce three dimensional protein structures to one-dimensional text strings that are then analyzed by traditional sequence alignment methods; however, the accuracy is usually sacrificed and the speed is still unable to match sequence similarity search tools. Here, we aimed to improve the linear encoding methodology and develop efficient search tools that can rapidly retrieve structural homologs from large protein databases. RESULTS: We propose a new linear encoding method, SARST (Structural similarity search Aided by Ramachandran Sequential Transformation). SARST transforms protein structures into text strings through a Ramachandran map organized by nearest-neighbor clustering and uses a regenerative approach to produce substitution matrices. Then, classical sequence similarity search methods can be applied to the structural similarity search. Its accuracy is similar to Combinatorial Extension (CE) and works over 243,000 times faster, searching 34,000 proteins in 0.34 sec with a 3.2-GHz CPU. SARST provides statistically meaningful expectation values to assess the retrieved information. It has been implemented into a web service and a stand-alone Java program that is able to run on many different platforms. CONCLUSION: As a database search method, SARST can rapidly distinguish high from low similarities and efficiently retrieve homologous structures. It demonstrates that the easily accessible linear encoding methodology has the potential to serve as a foundation for efficient protein structural similarity search tools. These search tools are supposed applicable to automated and high-throughput functional annotations or predictions for the ever increasing number of published protein structures in this post-genomic era. PMID- 17716378 TI - Validation of a screening questionnaire for hip and knee osteoarthritis in old people. AB - BACKGROUND: To develop a sensitive and specific screening tool for knee and hip osteoarthritis in the general population of elderly people. METHODS: The Knee and Hip OsteoArthritis Screening Questionnaire (KHOA-SQ) was developed based on previous studies and observed data and sent to 11,002 people aged 60 to 90 years, stratified by age and gender, who were selected by random sampling. Algorithms of the KHOA-SQ were created. Respondents positive for knee or hip OA on the KHOA-SQ were invited to be evaluated by an orthopedic surgeon. A sample of 300 individuals negative for knee or hip OA on the KHOA-SQ were also invited for evaluation. Sensitivity and specificity were determined for the KHOA-SQ, as well as for KHOA-SQ questions. Classification and Regression Tree analysis was used to find alternative screening algorithms from the questionnaire. RESULTS: Of 11,002 individuals contacted, 7,577 completed the KHOA-SQ. Of 1,115 positive for knee OA, on the KHOA-SQ, 710 (63.6%) were diagnosed with it. For hip OA, 339 of the 772 who screened positive (43.9%) were diagnosed it. Sensitivity for the hip algorithm was 87.4% and specificity 59.8%; for the knee, sensitivity was 94.5% and specificity 43.8%. Two alternative algorithms provided lower specificity. CONCLUSION: The KHOA-SQ offers high sensitivity and moderate specificity. Although this tool correctly identifies individuals with knee or hip OA, the high false positive rate could pose problems. Based on our questions, no better algorithm was found. PMID- 17716382 TI - Physiology of airway mucus secretion and pathophysiology of hypersecretion. AB - Mucus secretion is the first-line defense against the barrage of irritants that inhalation of approximately 500 L of air an hour brings into the lungs. The inhaled soot, dust, microbes, and gases can all damage the airway epithelium. Consequently, mucus secretion is extremely rapid, occurring in tens of milliseconds. In addition, mucus is held in cytoplasmic granules in a highly condensed state in which high concentrations of Ca(2+) nullify the repulsive forces of the highly polyanionic mucin molecules. Upon initiation of secretion and dilution of the Ca(2+), the repulsion forces of the mucin molecules cause many-hundred-fold swelling of the secreted mucus, to cover and protect the epithelium. Secretion is a highly regulated process, with coordination by several molecules, including soluble N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) proteins, myristoylated alanine-rich C kinase substrate (MARCKS), and Munc proteins, to dock the mucin granules to the secretory cell membrane prior to exocytosis. Because mucus secretion appears to be such a fundamental airway homeostatic process, virtually all regulatory and inflammatory mediators and interventions that have been investigated increase secretion acutely. When given longer-term, many of these same mediators also increase mucin gene expression and mucin synthesis, and induce goblet cell hyperplasia. These responses induce (in contrast to the protective effects of acute secretion) long term, chronic hypersecretion of airway mucus, which contributes to respiratory disease. In this case the homeostatic, protective function of airway mucus secretion is lost, and, instead, mucus hypersecretion contributes to pathophysiology of a number of severe respiratory conditions, including asthma, chronic obstructive pulmonary disease, and cystic fibrosis. PMID- 17716379 TI - Genomic and proteomic profiling I: leiomyomas in African Americans and Caucasians. AB - BACKGROUND: Clinical observations indicate that leiomyomas occur more frequently in African Americans compared to other ethnic groups with unknown etiology. To identify the molecular basis for the difference we compared leiomyomas form A. Americans with Caucasians using genomic and proteomic strategies. METHODS: Microarray, realtime PCR, 2D-PAGE, mass spectrometry, Western blotting and immunohistochemistry. RESULTS: Using Affymetrix U133A array and analysis based on P ranking (P < 0.01) 1470 genes were identified as differentially expressed in leiomyomas compared to myometrium regardless of ethnicity. Of these, 268 genes were either over-expressed (177 genes) or under-expressed (91 genes) based on P < 0.01 followed by 2-fold cutoff selection in leiomyomas of A. Americans as compared to Caucasians. Among them, the expression E2F1, RUNX3, EGR3, TBPIP, ECM2, ESM1, THBS1, GAS1, ADAM17, CST6, CST7, FBLN5, ICAM2, EDN1 and COL18 was validated using realtime PCR low-density arrays. 2D PAGE coupled with image analysis identified 332 protein spots of which the density/volume of 31 varied by greater than or equal to 1.5 fold in leiomyomas as compared to myometrium. The density/volume of 34 protein-spots varied by greater than or equal to 1.5 fold (26 increased and 8 decreased) in leiomyomas of A. Americans as compared to Caucasians. Tandem mass spectrometric analysis of 15 protein spots identified several proteins whose transcripts were also identified by microarray, including 14-3-3 beta and mimecan, whose expression was confirmed using western blotting and immunohistochemistry. CONCLUSION: These findings imply that the level rather than the ethnic-specific expression of a number of genes and proteins may account for the difference between leiomyomas and possibly myometrium, in A. Americans and Caucasians. Further study using larger sample size is required to confirm these findings. PMID- 17716383 TI - Bronchial mucus transport. AB - Effective clearance of inhaled particles requires mucus production and continuous mucus transport from the lower airways to the oropharynx. Mucus production takes place mainly in the peripheral airways. Mucus transport is achieved by the action of the ciliated cells that cover the inner surface of the airways (mucociliary transport) and by expiratory airflow. The capacity for mucociliary transport is highest in the peripheral airways, whereas the capacity for airflow transport is highest in the central airways. In patients with airways disease, mucociliary transport may be impaired and airflow transport may become the most important mucus transport mechanism. PMID- 17716380 TI - In search of induction and latency periods: space-time interaction accounting for residential mobility, risk factors and covariates. AB - BACKGROUND: Space-time interaction arises when nearby cases occur at about the same time, and may be attributable to an infectious etiology or from exposures that cause a geographically localized increase in risk. But available techniques for detecting interaction do not account for residential mobility, nor do they evaluate sensitivity to induction and latency periods. This is an important problem for cancer, where latencies of a decade or more occur. METHODS: New case only clustering techniques are developed that account for residential mobility, latency and induction periods, relevant covariates (such as age) and risk factors (such as smoking). The statistical behavior of the methods is evaluated using simulated data to assess type I error (false positives) and statistical power. These methods are applied to 374 cases from an ongoing study of bladder cancer in 11 counties in southeastern Michigan, and the ability of the methods to localize space-time interaction at the individual-level is demonstrated. RESULTS: Significant interaction is found for induction periods of approximately 5 years and latency approximately 19.5 years. Data are still being collected and the observed clusters may be attributable to differential sampling in the study area. CONCLUSION: Residential histories are increasingly available, raising the possibility of routine surveillance in a manner that accounts for individual mobility and that incorporates models of cancer latency and induction. These new techniques provide a mechanism for identifying those geographic locations and times associated with increases in cancer risk above and beyond that expected given covariates and risk factors in geographically mobile populations. PMID- 17716384 TI - Inhaled adrenergics and anticholinergics in obstructive lung disease: do they enhance mucociliary clearance? AB - Pulmonary mucociliary clearance is an essential defense mechanism against bacteria and particulate matter. Mucociliary dysfunction is an important feature of obstructive lung diseases such as chronic obstructive pulmonary disease, asthma, cystic fibrosis, and bronchiectasis. This dysfunction in airway clearance is associated with accelerated loss of lung function in patients with obstructive lung disease. The involvement of the cholinergic and adrenergic neural pathways in the pathophysiology of mucus hypersecretion suggests the potential therapeutic role of bronchodilators as mucoactive agents. Although anticholinergics and adrenergic agonist bronchodilators have been routinely used, alone or in combination, to enhance mucociliary clearance in patients with obstructive lung disease, the existing evidence does not consistently show clinical effectiveness. PMID- 17716385 TI - Mucoactive agents for airway mucus hypersecretory diseases. AB - Airway mucus hypersecretion is a feature of a number of severe respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). However, each disease has a different airway inflammatory response, with consequent, and presumably linked, mucus hypersecretory phenotype. Thus, it is possible that optimal treatment of the mucus hypersecretory element of each disease should be disease-specific. Nevertheless, mucoactive drugs are a longstanding and popular therapeutic option, and numerous compounds (eg, N acetylcysteine, erdosteine, and ambroxol) are available for clinical use worldwide. However, rational recommendation of these drugs in guidelines for management of asthma, COPD, or CF has been hampered by lack of information from well-designed clinical trials. In addition, the mechanism of action of most of these drugs is unknown. Consequently, although it is possible to categorize them according to putative mechanisms of action, as expectorants (aid and/or induce cough), mucolytics (thin mucus), mucokinetics (facilitate cough transportability), and mucoregulators (suppress mechanisms underlying chronic mucus hypersecretion, such as glucocorticosteroids), it is likely that any beneficial effects are due to activities other than, or in addition to, effects on mucus. It is also noteworthy that the mucus factors that favor mucociliary transport (eg, thin mucus gel layer, "ideal" sol depth, and elasticity greater than viscosity) are opposite to those that favor cough effectiveness (thick mucus layer, excessive sol height, and viscosity greater than elasticity), which indicates that different mucoactive drugs would be required for treatment of mucus obstruction in proximal versus distal airways, or in patients with an impaired cough reflex. With the exception of mucoregulatory agents, whose primary action is unlikely to be directed against mucus, well-designed clinical trials are required to unequivocally determine the effectiveness, or otherwise, of expectorant, mucolytic, and mucokinetic agents in airway diseases in which mucus hypersecretion is a pathophysiological and clinical issue. It is noteworthy that, of the more complex molecules in development, it is simple inhaled hypertonic saline that is currently receiving the greatest attention as a mucus therapy, primarily in CF. PMID- 17716386 TI - Conventional chest physical therapy for obstructive lung disease. AB - Chest physical therapy (CPT) is a widely used intervention for patients with airway diseases. The main goal is to facilitate secretion transport and thereby decrease secretion retention in the airways. Historically, conventional CPT has consisted of a combination of forced expirations (directed cough or huff), postural drainage, percussion, and/or shaking. CPT improves mucus transport, but it is not entirely clear which groups of patients benefit from which CPT modalities. In general, the patients who benefit most from CPT are those with airways disease and objective signs of secretion retention (eg, persistent rhonchi or decreased breath sounds) or subjective signs of difficulty expectorating sputum, and with progression of disease that might be due to secretion retention (eg, recurrent exacerbations, infections, or a fast decline in pulmonary function). The most effective and important part of conventional CPT is directed cough. The other components of conventional CPT add little if any benefit and should not be used routinely. Alternative airway clearance modalities (eg, high-frequency chest wall compression, vibratory positive expiratory pressure, and exercise) are not proven to be more effective than conventional CPT and usually add little benefit to conventional CPT. Only if cough and huff are insufficiently effective should other CPT modalities be considered. The choice between the CPT alternatives mainly depends on patient preference and the individual patient's response to treatment. PMID- 17716387 TI - Forced expiratory technique, directed cough, and autogenic drainage. AB - In health, secretions produced in the respiratory tract are cleared by mucociliary transport, cephalad airflow bias, and cough. In disease, increased secretion viscosity and volume, dyskinesia of the cilia, and ineffective cough combine to reduce secretion clearance, leading to increased risk of infection. In obstructive lung disease these conditions are further complicated by early collapse of airways, due to airway compression, which traps both gas and secretions. Techniques have been developed to optimize expiratory flow and promote airway clearance. Directed cough, forced expiratory technique, active cycle of breathing, and autogenic drainage are all more effective than placebo and comparable in therapeutic effects to postural drainage; they require no special equipment or care-provider assistance for routine use. Researchers have suggested that standard chest physical therapy with active cycle of breathing and forced expiratory technique is more effective than chest physical therapy alone. Evidence-based reviews have suggested that, though successful adoption of techniques such as autogenic drainage may require greater control and training, patients with long-term secretion management problems should be taught as many of these techniques as they can master for adoption in their therapeutic routines. PMID- 17716388 TI - High-frequency assisted airway clearance. AB - High-frequency airway clearance assist devices generate either positive or negative transrespiratory pressure excursions to produce high-frequency, small volume oscillations in the airways. Intrapulmonary percussive ventilation creates a positive transrespiratory pressure by injecting short, rapid inspiratory flow pulses into the airway opening and relies on chest wall elastic recoil for passive exhalation. High-frequency chest wall compression generates a negative transrespiratory pressure by compressing the chest externally to cause short, rapid expiratory flow pulses, and relies on chest wall elastic recoil to return the lungs to functional residual capacity. High-frequency chest wall oscillation uses a chest cuirass to generate biphasic changes in transrespiratory pressure. In any case (positive or negative pressure pulses or both), the general idea is get air behind secretions and move them toward the larger airways, where they can be coughed up and expectorated. These techniques have become ubiquitous enough to constitute a standard of care. Yet, despite over 20 years of research, clinical evidence of efficacy for them is still lacking. Indeed, there is insufficient evidence to support the use of any single airway clearance technique, let alone judge any one of them superior. Aside from patient preference and capability, cost-effectiveness studies based on existing clinical data are necessary to determine when a given technique is most practical. PMID- 17716389 TI - Cerebral oxygen metabolism in idiopathic-normal pressure hydrocephalus. AB - OBJECTIVE: To distinguish idiopathic-normal pressure hydrocephalus (i-NPH) from the elder with brain atrophy is difficult. This investigation was undertaken to determine the cerebral oxygen metabolism and the cerebral blood flow using positron emission tomography (PET) in patients with i-NPH. Comparison of the variables between i-NPH patients and the age-comparable control with asymptomatic ventricular dilatation were performed. METHODS: Nineteen patients were studied. Nine i-NPH patients with a mean age of 74.8 +/- 1.8 years (mean +/- SD) were examined using PET. The subjects who underwent a ventriculoperitoneal shunt (VPS) had the triad of NPH and ventricular dilatation on computed tomography (CT) and/or magnetic resonance imaging (MRI). The results of the PET study were compared with those for ten age-comparable controls (74.8 +/- 5.5 years) with asymptomatic ventricular dilatation and no severe cerebrovascular disease on MRI and magnetic resonance angiography (MRA). The PET study included analyses of regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), regional oxygen extraction fraction (rOEF) and regional cerebral metabolic rate of oxygen (rCMRO(2)). RESULTS: In i-NPH, rCBF tended to decrease in the frontal lobe and the basal ganglia. rCMRO(2) in the frontal lobe of i-NPH was significantly higher than that in the controls (p<0.05 by Student's t-test), although rCMRO(2) in the basal ganglia of i-NPH was reduced. rCBV and rOEF showed no significant differences. CONCLUSION: Reduction of oxygen metabolism in the basal ganglia might be one of the factors causing symptoms in i-NPH. Particular pattern of cerebral oxygen metabolism in i-NPH was not obvious in the present study. PMID- 17716390 TI - Catalpol protects rat pheochromocytoma cells against oxygen and glucose deprivation-induced injury. AB - OBJECTIVES: Catalpol has been identified to have neuroprotective effect on gerbils subjected to transient global cerebral ischemia. However, the mechanism that catalpol prevents ischemia is still unclear. In the present study, PC12 cells, exposed to oxygen and glucose deprivation (OGD) followed by reperfusion, were used as an in vitro model of ischemia. The protective effects of catalpol were investigated in ischemic-induced apoptosis in PC12 cells. METHODS: After OGD for 3 hours and reoxygenation for 18 hours, cell survival was quantified by the reduction of 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were determined using commercially available kits. Caspase-3 assay was performed using caspase-3 assay kit. Microplate reader was used to detect the intensities of rhodamine123 (Rh123) and reactive oxygen species (ROS). The level of Bcl-2 protein was measured by flow cytometry. RESULTS: Catalpol attenuated ischemia induced apoptotic death via preventing the decrease in the level of Bcl-2 protein and the activities of SOD and GSH-PX, inhibiting the reduction of mitochondrial membrane potential and suppressing activation of caspase-3. DISCUSSION: The results suggest that the catalpol has the potential to prevent ischemic-induced apoptosis. PMID- 17716391 TI - The effect of 2-methoxyestradiol, a HIF-1 alpha inhibitor, in global cerebral ischemia in rats. AB - Global cerebral ischemia is an important clinical problem with few effective treatments. The hippocampus, which is important for memory, is especially vulnerable during global ischemia. Brain-specific knockout of hypoxia inducible factor-1 alpha (HIF-1 alpha) has been shown to be protective in focal ischemia in vivo. 2-methoxyestradiol (2ME2) is a natural metabolite of estrogen that is known to inhibit HIF-1 alpha. We tested 2ME2 in a rat model of global cerebral ischemia. Global ischemia was induced with the two-vessel occlusion model (2VO) which entailed hemorrhagic hypotension to a mean arterial pressure of 38-42 mmHg with simultaneous bilateral common carotid artery occlusion for 8 minutes. Sprague-Dawley rats (male, 280-350 g) were randomly assigned to three groups: global ischemia (GI, n=17), global ischemia with 2ME2 treatment (GI + 2ME2, n=17) and sham surgery (sham, n=12). 2ME2 treatment (15 mg/kg in 1% DMSO) was rendered 10 minutes after reperfusion. Rats in the GI and sham groups received similar doses of the DMSO solvent. Rats were killed 24 hours, 72 hours and 7 days after reperfusion. Quantitative CA1 hippocampal cell counts demonstrated significantly lower cell survival in the GI + 2ME2 group compared to either the GI or sham groups, in spite of a statistically significant reduction in HIF-1 alpha by Western blotting analysis of the GI + 2ME2 group. We conclude that 2ME2 worsens outcomes after global ischemia in rats. PMID- 17716392 TI - Down-regulation of Stat3 induces apoptosis of human glioma cell: a potential method to treat brain cancer. AB - OBJECTIVES: Glioma is the most common brain tumor in central nervous system. Traditional therapies are not effective to cure this disease. Stat3 is a member of the signal transducer and activator of transcription family, and it has the potential to mediate cell survival, growth and differentiation. METHODS: In this study, we testified that Stat3 was constitutively expressed in glioma cell line SHG44 and then investigated the role of a low level of Stat3 expression in glioma cells by constructing an interfering RNA expression plasmid. RESULTS: The results showed that glioma cells underwent morphologic and biochemical changes after the RNAi treatment. DISCUSSION: We hypothesized that a low level of Stat3 expression could induce apoptosis of glioma cell, which further proved that Stat3 played an important role in growth, survival and proliferation of glioma cells. This study provides a new alternative to gene therapy for glioma treatment. PMID- 17716398 TI - An in vivo confocal Raman study of the delivery of trans retinol to the skin. AB - The purpose of this study is to monitor in vivo the delivery of trans-retinol into human skin. Delivery to real systems, such as skin, can be extremely difficult to execute and is problematic to confirm and measure. So far, methods for studying the delivery of compounds through the skin are mostly ex vivo and so inherently influence the skin and may not translate directly to the in vivo situation. Raman spectroscopy is uniquely placed to be able to measure biological processes in vivo, and this paper shows that the trans-retinol penetration into the skin can successfully be measured in vivo using this technique. This study measured the volar forearm of volunteers treated with 0.3% trans-retinol in propylene glycol (PG)/ethanol and 0.3% trans-retinol in caprylic/capric acid triglyceride (MYRITOL318), an oil found in skin creams. Solutions were applied and then confocal Raman depth profiles were obtained of the stratum corneum (SC) and into the viable epidermis (VE) up to 10 hours after treatment. Remarkable differences between a penetrating and a nonpenetrating solution can clearly be observed. Treating with trans-retinol in PG/ethanol results in trans-retinol penetrating through the SC and into the VE. Its penetration was also observed to be highly correlated with the depth of penetration of the PG, which is well known as an efficient penetration enhancer. In contrast, while treating with trans retinol in MYRITOL318, trans-retinol hardly penetrates at all. For the first time, the penetration of trans-retinol has been monitored directly after application of solutions, in vivo without skin excision. Here, the effect of two different solutions on the delivery of trans-retinol into the skin was measured very effectively in vivo by Raman spectroscopy. PMID- 17716397 TI - Contrast enhancement for in vivo visible reflectance imaging of tissue oxygenation. AB - Results are presented illustrating a straightforward algorithm to be used for real-time monitoring of oxygenation levels in blood cells and tissue based on the visible spectrum of hemoglobin. Absorbance images obtained from the visible reflection of white light through separate red and blue bandpass filters recorded by monochrome charge-coupled devices (CCDs) are combined to create enhanced images that suggest a quantitative correlation between the degree of oxygenated and deoxygenated hemoglobin in red blood cells. The filter bandpass regions are chosen specifically to mimic the color response of commercial 3-CCD cameras, representative of detectors with which the operating room laparoscopic tower systems are equipped. Adaptation of this filter approach is demonstrated for laparoscopic donor nephrectomies in which images are analyzed in terms of real time in vivo monitoring of tissue oxygenation. PMID- 17716400 TI - Potential of surface-enhanced Raman spectroscopy for the rapid identification of Escherichia coli and Listeria monocytogenes cultures on silver colloidal nanoparticles. AB - Surface-enhanced Raman (SERS) spectra of various batches of bacteria adsorbed on silver colloidal nanoparticles were collected to explore the potential of the SERS technique for rapid and routine identification of E. coli and L. monocytogenes cultures. Relative standard deviation (RSD) of SERS spectra from silver colloidal suspensions and ratios of SERS peaks from small molecules (K(3)PO(4)) were used to evaluate the reproducibility, stability, and binding effectiveness of citrate-reduced silver colloids over batch and storage processes. The results suggested consistent reproducibility of silver colloids over batch process and also stability and consistent binding effectiveness over an eight-week storage period. A variety of mixtures of E. coli/L. monocytogenes cultures with different colloidal batches revealed that, despite large variations in relative intensities and positions of SERS active bands, characteristic and unique bands at 712 and 390 cm(-1) were consistently observed and were the strongest in E. coli and L. monocytogenes cultures, respectively. Two specific bands were used to develop simple algorithms in the evaluation of binding effectiveness of silver colloids over storage and further to identify E. coli and L. monocytogenes cultures with a 100% success. A single spectrum acquisition took 5 approximately 6 min, and a minimum of 25 microL silver colloid was directly mixed with 25 microL volume of incubated bacterial culture. The short acquisition time and small volume of incubated bacterial culture make silver colloidal nanoparticle based SERS spectroscopy ideal for potential use in the routine and rapid screening of E. coli and L. monocytogenes cultures on large scales. This is the first report of the development of simple and universal algorithms for bacterial identification from the respective exclusive SERS peaks. PMID- 17716399 TI - Raman spectroscopic discrimination of cell response to chemical and physical inactivation. AB - Raman spectroscopy was applied to study Escherichia coli and Staphylococcus epidermidis cells that were inactivated by different chemicals and stress conditions including starvation and high temperature. E. coli cells exposed to starvation conditions over several days lost viability at the same rate that spectral bands assigned to DNA and RNA bases decreased in intensity. Band intensities correlate with standard plate counts with R(2) = 0.99 and R(2) = 0.97, respectively. Principal components analysis and discriminant analysis multivariate statistical techniques were used to evaluate the spectral data collected. Significant changes were observed in the spectra of treated cells in comparison with their respective controls (samples without treatment). As a result, there was a significant differentiation between viable and non-viable cells (treated and non-treated cells) in the first and second principal component plots for all the treatments. Discriminant analysis was used along with PCA to estimate a classification rate based on viability status of the cells. Non-viable cells were differentiated from viable cells with classification rates that ranged between 60 and 90% for specific treatments (i.e., EDTA-treated cells versus control cells). The classification rate obtained considering all the treatments (non-viable cells) and controls (viable cells) at the same time for each of the species studied was 86%. The classification rate based on species differentiation when all the spectra (viable and non-viable) were used was 87%. These results suggest that Raman spectroscopy is a powerful tool that can be used to evaluate viability and to study metabolic changes in microorganisms. It is a robust method for bacterial identification even when high spectral variations are introduced. PMID- 17716402 TI - Shift-excitation Raman difference spectroscopy-difference deconvolution method for the luminescence background rejection from Raman spectra of solid samples. AB - The feasibility of the shift-excitation Raman difference spectroscopy-difference deconvolution (SERDS-DDM) method for fluorescence suppression from Raman spectra of solid samples is discussed. For SERDS measurements a tunable diode laser source with an emission band centered at 684 nm is coupled to a conventional micro-Raman apparatus and a monochromator device is used for checking the excitation frequency stability. The shifted Raman spectra are then mathematically treated and a deconvolution procedure is used to reconstruct the Raman spectrum devoid of fluorescence. Two different cases are presented. In the first one, fluorescence is intrinsic to the sample and the Raman spectrum of cinnabar pigment is finally reconstructed. In the second, the presence of an external luminescence background in the spectrum of a pure sulfur crystal is considered. The SERDS-DDM reconstructed spectra are compared with spectra obtained via multi point baseline subtraction and a significant improvement in the detection of weak bands is demonstrated. Practical insights for the application of this method are presented as well. PMID- 17716401 TI - Single nanoparticle based optical pH probe. AB - This paper describes the development of a nanoscale optical pH probe based upon the surface-enhanced Raman scattering (SERS) properties of silica-gold core-shell nanoparticles. In this approach, a thin layer of gold is deposited onto a core of silica to form a metallic nanoshell with surface plasmon modes in the red-to-near infrared spectral region. The surface of the nanoshell is functionalized with a pH-sensitive SERS reporter molecule, 4-mercaptopyridine (4-MPy). The SERS spectra of 4-MPy is shown to be sensitive to the pH of the surrounding media within the range of 3 to 7. In addition, it is shown that individual silica-gold core-shell nanoparticles yield more reliable SERS spectra than aggregates of core-shell nanoparticles. PMID- 17716403 TI - Raman signal enhancement in deep spectroscopy of turbid media. AB - A new, passive method for enhancing spontaneous Raman signals for the spectroscopic investigation of turbid media is presented. The main areas to benefit are transmission Raman and spatially offset Raman spectroscopy approaches for deep probing of turbid media. The enhancement, which is typically several fold, is achieved using a multilayer dielectric optical element, such as a bandpass filter, placed within the laser beam over the sample. This element prevents loss of the photons that re-emerge from the medium at the critical point where the laser beam enters the sample, the point where major photon loss occurs. This leads to a substantial increase of the coupling of laser radiation into the sample and consequently an enhanced laser photon-medium interaction process. The method utilizes the angular dependence of dielectric optical elements on impacting photon direction with its transmission spectral profile shifting to the blue with increase in the deviation of photons away from normal incidence. This feature enables it to act as a unidirectional mirror passing a semi-collimated laser beam through unhindered from one side, and at the other side, reflecting photons emerging from the sample at random directions back into it with no restrictions to the detected Raman signal. With substantial restrictions to the spectral range, the concept can also be applied to conventional backscattering Raman spectroscopy. The use of additional reflective elements around the sample to enhance the Raman signal further is also discussed. The increased signal strength yields higher signal quality, a feature important in many applications. Potential uses include sensitive noninvasive disease diagnosis in vivo, security screening, and quality control of pharmaceutical products. The concept is also applicable in an analogous manner to other types of analytical methods such as fluorescence or near-infrared (NIR) absorption spectroscopy of turbid media or it can be used to enhance the effectiveness of the coupling of laser radiation into tissue in applications such as photodynamic therapy for cancer treatment. PMID- 17716404 TI - Phonon confinement in SiC nanocrystals: comparison of the size determination using transmission electron microscopy and Raman spectroscopy. AB - Silicon carbide fibers of different generation/processing routes (NLM-Nicalon and Tyranno SA3) were thermally treated to trigger the growth of nanocrystals, which were analyzed using Raman spectroscopy and transmission electron microscopy (TEM). The nanocrystals were also aged in molten sodium nitrate to investigate their reactivity. The spatial correlation model has been used to model the Raman spectra and extract accurate and statistical information on the nanocrystallites' structure and dimension. For the NLM fibers, an average size of 2.5 to 7.0 nm was calculated, which was in good agreement with TEM observations. For the Tyranno SA3 fiber, despite the heavily faulted stacking sequence, the Raman peaks remained sharp, indicating that the crystallite dimension calculated from the Raman spectra is only dependent on the actual size of the nanocrystals and is not affected by the sequence of the stacking faults. PMID- 17716405 TI - Investigation of the Christiansen effect in the mid-infrared region for airborne particles. AB - During measurements of open-path Fourier transform infrared spectra, airborne dust may be present in the infrared beam. We have investigated the feasibility of identifying and quantifying the airborne particulate matter from spectra measured in this way. Although the results showed that analysis of the particulate matter was not able to be performed from these spectra, insight into the size and wavelength dependence of the Christiansen effect at wavelengths where the particles absorb strongly was obtained. Airborne particles larger than or equal to the wavelength of the incident radiation give rise to asymmetrical features in the spectrum caused by the Christiansen effect. However, the transmittance at wavelengths where the refractive index of the particles equals that of the atmosphere never reaches 1.0 because of absorption by the particles. As the particle size becomes much smaller than the wavelength of the incident radiation, the Christiansen effect becomes less pronounced and eventually is not exhibited. PMID- 17716406 TI - Phase angle description of perturbation correlation analysis and its application to time-resolved infrared spectra. AB - A method of spectral analysis, phase angle description of perturbation correlation analysis, is proposed. This method is based on global phase angle description of generalized two-dimensional (2D) correlation spectroscopy, proposed by Shin-ichi Morita et al., and perturbation-correlation moving-window 2D (PCMW2D) correlation spectroscopy, proposed by Shigeaki Morita et al. For a spectral data set collected under an external perturbation, such as time-resolved infrared spectra, this method provides only one phase angle spectrum. A phase angle of the Fourier frequency domain correlation between a spectral intensity (e.g., absorbance) variation and a perturbation variation (e.g., scores of the first principle component) as a function of spectral variable (e.g., wavenumber) is plotted. Therefore, a degree of time lag of each band variation with respect to the perturbation variation is directly visualized in the phase angle spectrum. This method is applied to time-resolved infrared spectra in the O-H stretching region of the water sorption process into a poly(2-methoxyethyl acrylate) (PMEA) film. The time-resolved infrared (IR) spectra show three broad and overlapping bands in the region. Each band increases toward saturated water sorption with different relaxation times. In comparison to conventional methods of generalized 2D correlation spectroscopy and global phase angle mapping, the method proposed in the present study enables the easier visualization of the sequence as a degree of phase angle in the spectrum. PMID- 17716407 TI - Two-dimensional correlation analysis of polyimide films using attenuated total reflection-based dynamic compression modulation step-scan Fourier transform infrared spectroscopy. AB - Attenuated total reflection (ATR)-based dynamic compression modulation two dimensional (2D) correlation study of poly(p-phenylene biphenyltetracarboximide) film is carried out in combination with spectral simulation analysis by density functional theory (DFT). The dynamic 2D infrared (IR) correlation spectra in the region of imide I (C=O stretching mode) show three distinct correlation peaks located around 1777, 1725, and 1708 cm(-1). The band at 1708 cm(-1) is the lower wavenumber shift component of 1777 or 1735 cm(-1) peaks and is attributed to the results from intermolecular interactions, according to the DFT analysis. The 1708 cm(-1) band also shows the largest dynamic response, suggesting that these intermolecular interactions may enhance the dynamic response. The dynamic 2D IR correlation spectra in the region of imide II (C-N-C axial stretching mode) vibrations also show three correlation peaks located around 1335, 1355, and 1370 cm(-1), although the imide II band is shown to consist substantially of one component by the DFT analysis. These multiple peaks may be attributed to the compression-induced wavenumber shift of the band in the backbone structures. The sequential analysis of 2D correlation data show that, upon applying the dynamic compression, the response of the backbone regions (imide II) occurs first, followed by that of the side-chain regions (imide I, C=O). PMID- 17716408 TI - Estimation of wood stiffness and strength properties of hybrid larch by near infrared spectroscopy. AB - This work was undertaken to investigate the feasibility of near-infrared (NIR) spectroscopy for estimating wood mechanical properties, i.e., modulus of elasticity (MOE) and modulus of rupture (MOR) in bending tests. Two sample sets having large and limited density variation were prepared to examine the effects of wood density on estimation of MOE and MOR by the NIR technique. Partial least squares (PLS) analysis was employed and it was found that the relationships between laboratory-measured and NIR-predicted values were good in the case of sample sets having large density variation. MOE could be estimated even when density variation in the sample set was limited. It was concluded that absorption bands due to the OH group in the semi-crystalline or crystalline regions of cellulose strongly influenced the calibrations for bending stiffness of hybrid larch. This was also suggested from the result that both alpha-cellulose content and cellulose crystallinity showed moderate positive correlation to wood stiffness. PMID- 17716410 TI - Vacuum ultraviolet photoionization mass spectra and cross-sections for volatile organic compounds at 10.5 eV. AB - Vacuum ultraviolet single-photon ionization time-of-flight mass spectrometry (VUV SPI-TOFMS) has been applied to the detection of volatile organic compounds (VOCs), including aromatic, chlorinated, and oxygenated compounds. Photoionization mass spectra of 23 VOCs were measured using SPI-TOFMS at 10.5 eV (118 nm). The limits of detection of VOCs using SPI-TOFMS at 10.5 eV were estimated to be a few ppbv. The mass spectra of 20 VOCs exhibit only the parent ion and its isotopes' signals. The ionization processes of the VOCs were discussed on the basis of the reaction enthalpies predicted by the quantum chemical calculations. Absolute photoionization cross-sections for 23 VOCs, including 12 newly measured VOCs, at 10.5 eV were determined in comparison to the reported absolute photoionization cross-section of NO. PMID- 17716409 TI - Analysis of composite structure and primordial wood remains in petrified wood. AB - Among all the fossils, petrified wood belongs to the most impressive and most common of materials. Still, its study has not exceeded the purely phenomenological level. The recognition of the conserved structure of petrified wood seems to be of meaning for understanding the geological past, the complete carbon cycle inside the Earth, and the structure of potential new materials. The first ever published spatial distributions of the remains of the primordial organic material (lignin, cellulose, pectins) in the cells of permineralized wood, from Dunarobba (Central Italy), are presented here. They were collected using micro-Raman spectrometry. The composite nature of the petrified material (calcite located in the lumena of cells and goethite located in the cell walls) was confirmed by electron, proton, and X-ray microprobes. The structure of the cell walls was well preserved. The mineralization process was induced by the tracheidal water flow and was stopped after formation of pipe-like goethite shielding of the cell walls on the cellulose scaffolds. The chemical (Eh and pH ranges) and probable microbial conditions for such a pattern of mineralization were determined. We estimate that substantial amounts of the primordial organic matter were preserved in bodies of petrified wood on a global scale. The wood petrifaction process, if well understood, can be a basis for the production of "everlasting" organic-inorganic composite compounds. PMID- 17716411 TI - Fluorescence spectrum of 2-trifluoromethyl-1,1,1,2,4,4,5,5,5-nonafluoro-3 pentanone. AB - A perfluorinated ketone, 2-trifluoromethyl-1,1,1,2,4,4,5,5,5-nonafluoro-3 pentanone, has been investigated to determine several physical and spectroscopic properties. It was found to exhibit fluorescence similar to that of acetone, emitting over the 360-550 nm range with a peak near 420 nm when excited at 355 nm. This compound's emission is nearly unaffected over a wide range of temperature and pressure in an argon bath gas. Its fluorescence efficiency was found to be three times higher than that of acetone. Combined with low reactivity and thermal stability up to 500 degrees C, this makes the material an excellent tracer for spectroscopic measurement techniques. PMID- 17716412 TI - Why don't clinicians engage with quality improvement? PMID- 17716413 TI - Slow slow, quick quick slow: the health technology guidance tango. PMID- 17716415 TI - Are the best available clinical effectiveness data used in economic evaluations of drug therapies? AB - OBJECTIVES: Use of evidence on clinical effectiveness that is of poor quality or is biased in favour of the therapy under study is a concern in economic evaluations and may contribute to a mistrust of pharmacoeconomic studies. This study aimed to determine whether the authors of economic evaluations use the best available evidence for clinical effectiveness. METHODS: One hundred economic evaluations of drug therapies (published in 2001-2003) were sampled randomly from the National Health Service Economic Evaluation Database, and the source of clinical evidence was identified. For each therapy, alternative, high quality sources of clinical effectiveness data were sought by searching the Database of Abstracts of Reviews of Effects and Health Technology Assessment databases. The magnitude and direction of the effect size in the different sources of evidence were compared. RESULTS: Relevant systematic reviews were found for only 32 of the 100 economic evaluations in the sample. In three cases these reviews had been identified by the authors of the economic evaluations and two of these cases were used in the evaluation. Comparisons were possible in 21 cases. The clinical effects reported in all 21 comparisons were similar in direction but differed in magnitude. Compared to the systematic reviews, the authors of economic evaluations used evidence that was more favourable in five cases, less favourable in four cases, and similar in 12 cases. Six of the economic evaluations and corresponding systematic reviews did not present measures of effectiveness in a manner that allowed comparison. CONCLUSIONS: Authors of economic evaluations have not made sufficient use of the evidence available from systematic reviews of clinical effectiveness. The central role of economic evaluations in health policy makes it essential that improvements in economic methods are accompanied by a structured search for the highest quality information on clinical effectiveness. PMID- 17716414 TI - Do patients value continuity of care in general practice? An investigation using stated preference discrete choice experiments. AB - OBJECTIVES: To estimate the relative importance to patients of continuity of care compared with other aspects of a primary care consultation. METHODS: We carried out a discrete choice experiment in Leicestershire and London on a stratified random sample of 646 community dwelling adults taken from general practitioner (GP) registers, plus 20 interviews with Punjabi, Urdu and Gujarati speakers. The attributes examined were: the type of professional consulted, relational continuity, informational continuity and access. RESULTS: Individuals' values changed according to their reason for making a primary care consultation. If consulting for minor familiar symptoms, individuals would be prepared to trade off one extra day's wait to see a GP rather than a nurse, 0.9 days for relational continuity, and 1.6 days for informational continuity. If consulting for a new condition they were uncertain about, they would be prepared to trade off an additional wait of 3.5 days to see a GP rather than a nurse, 2.4 days for relational continuity and 3.9 days for informational continuity. For a routine check-up, an individual would be prepared to trade off an additional wait of 3.5 days to see a GP rather than a nurse, 4.2 days for relational continuity and 7.8 days for informational continuity. CONCLUSIONS: Respondents stated their preference to wait longer to see a familar medical practitioner who was well informed about their case when they had a problem causing uncertainty or needed a routine check-up. They preferred quick access for likely minor 'low impact' symptoms. Appointment systems in general practice should be sufficiently flexible to meet these different preferences. PMID- 17716416 TI - Health technology appraisal of interventional procedures: comparison of rapid and slow methods. AB - OBJECTIVE: To describe a method for the rapid appraisal of new interventional procedures and to compare its conclusions with those derived from a slower, more thorough method. METHODS: Explanation of an algorithm, pragmatically developed over a decade at the British United Provident Association (BUPA), to classify requests for funding for new interventional procedures as 'Fund routinely'; 'Fund as a one-off'; 'Fund in trial only'; 'Do not fund currently' within about 48 hours. Comparison of the resulting categorizations of 39 interventional procedures against the subsequent work of the English National Institute for Health and Clinical Excellence (NICE) Interventional Procedures team. The first two BUPA categories were equated with NICE's 'evidence adequate' and the second two with 'evidence inadequate'. RESULTS: The algorithm is fit for purpose. It facilitated 114 requests for funding, received before June 2005, being successfully allocated: fund routinely, 33 (28.9%); fund as a one-off, 20 (17.5%); fund in trial only, 37 (32.5%); do not fund, 24 (21.1%). NICE subsequently categorized 18 being 'evidence adequate' and 21 'evidence inadequate'. There was concordance between BUPA and NICE on 35/39 (90%) of the topics. The four discrepancies are discussed. CONCLUSION: Rapid appraisal of new interventional procedures using the BUPA algorithm is feasible and in most instances its output is similar to that obtained from a slower more thorough method. PMID- 17716417 TI - Impact of managed care on physicians' decisions to manipulate reimbursement rules: an explanatory model. AB - OBJECTIVE: To develop and test an explanatory model of the impact of managed care on physicians' decisions to manipulate reimbursement rules for patients. METHODS: A self-administered mailed questionnaire of a national random sample of 1124 practicing physicians in the USA. Structural equation modelling was used. The main outcome measure assessed whether or not physicians had manipulated reimbursement rules (such as exaggerated the severity of patients conditions, changed billing diagnoses, or reported signs or symptoms that the patients did not have) to help patients secure coverage for needed treatment or services. RESULTS: The response rate was 64% (n = 720). Physicians' decisions to manipulate reimbursement rules for patients are directly driven not only by ethical beliefs about gaming the system but also by requests from patients, the perception of insufficient time to deliver care, and the proportion of Medicaid patients. Covert advocacy is also the indirect result of utilization review hassles, primary care specialty, and practice environment. CONCLUSIONS: Managed care is not just a set of rules that physicians choose to follow or disobey, but an environment of competing pressures from patients, purchasers, and high workload. Reimbursement manipulation is a response to that environment, rather than simply a reflection of individual physicians' values. PMID- 17716418 TI - Impact of patients' socioeconomic status on the distance travelled for hospital admission in the English National Health Service. AB - OBJECTIVES: To compare the distances travelled for inpatient treatment in England between electoral wards prior to the introduction of a policy to extend patient choice and to consider the impact of patients' socio-economic status. METHODS: Using Hospital Episode Statistics for 2003-04, the distance from a patient's residence to a National Health Service hospital was calculated for each admission. Distances were summed to electoral ward level to give the distribution of distances travelled at ward level. These were analysed to show the distance travelled for different admission types, ages of patient, rural/urban location, and the socioeconomic deprivation of the population of the ward. RESULTS: There is considerable variation in the distances travelled for hospital admission between electoral wards. Some of this is explained by geographical location: individuals living in more rural areas travel further for elective (median 27.2 versus 15.0 km), emergency (25.3 versus 13.9 km) and maternity (25.0 versus 13.9 km) admissions. But individuals located in highly deprived wards travel less far, and this shorter distance is not explained simply by the closer location of hospitals to these wards. CONCLUSIONS: Before the introduction of more patient choice, there were considerable differences between individuals in the distances they travelled for hospital care. An increase in patient choice may disproportionately benefit people from less deprived areas. PMID- 17716419 TI - Reallocating resources: how should the National Institute for Health and Clinical Excellence guide disinvestment efforts in the National Health Service? AB - The recent acute budgetary pressures within the English National Health Service (NHS) have accentuated calls for targeted disinvestment thereby eliminating ineffective or low-value services to provide resources that can be reallocated toward more cost-effective purposes. This challenge extends beyond allocating new resources wisely, a goal that has been, since its inception, the primary focus of the National Institute for Health and Clinical Excellence (NICE). But on 6 September 2006, the Department of Health announced a new mandate for NICE to help the NHS identify interventions that are not effective. This paper discusses current NICE efforts to support value in the NHS and then explores the policy options available to the Institute as it prepares to launch a programme to meet the NHS request for guidance on disinvestment. All of the possible options present challenges. NICE will need to collaborate in new ways with partners inside, and perhaps outside, the NHS. However, the Institute has an established reputation for rigour, transparency and political durability that makes it well qualified to sustain public support in the face of difficult decisions. Disinvestment will provide a stern test of these qualities. PMID- 17716420 TI - Toward a general theory of indifference to research-based evidence. AB - Evidence-based medicine (EBM) and evidence-based decision-making (EBDM) were intended to revolutionize health care and health policy. Thus far they have not. A great deal of research has demonstrated the persistent ubiquity of error in health care, wide and unjustifiable variations in practice and the minimal impact of decision aids such as clinical practice guidelines. This paper attempts to explain why EBM and EBDM have remained largely unrealized ambitions. It advances 10 propositions that together constitute a general theory of indifference to research-based evidence. Some of these propositions are conceptual (e.g. the epistemic resistance to the randomized trial), some are empirical (e.g. the impact of the corruption of science by industry), some are cognitive (e.g. human problems are holistic while science is typically fragmented and narrative free) and some are normative (e.g. the primary goal is not adherence to methods, but to make better decisions with better outcomes, irrespective of their origins). EBM and EBDM over-reached, and their failure was, as a consequence, inevitable. However, with corrective action on a number of fronts, research-based evidence can and should be more influential. The first step is to reconceive EBM and EBDM as habits of mind rather than a toolbox and to recognize that the sociology of knowledge is as important as its technical content. PMID- 17716421 TI - Inter-rater reliability of case-note audit: a systematic review. AB - OBJECTIVE: The quality of clinical care is often assessed by retrospective examination of case-notes (charts, medical records). Our objective was to determine the inter-rater reliability of case-note audit. METHODS: We conducted a systematic review of the inter-rater reliability of case-note audit. Analysis was restricted to 26 papers reporting comparisons of two or three raters making independent judgements about the quality of care. RESULTS: Sixty-six separate comparisons were possible, since some papers reported more than one measurement of reliability. Mean kappa values ranged from 0.32 to 0.70. These may be inflated due to publication bias. Measured reliabilities were found to be higher for case note reviews based on explicit, as opposed to implicit, criteria and for reviews that focused on outcome (including adverse effects) rather than process errors. We found an association between kappa and the prevalence of errors (poor quality care), suggesting alternatives such as tetrachoric and polychoric correlation coefficients be considered to assess inter-rater reliability. CONCLUSIONS: Comparative studies should take into account the relationship between kappa and the prevalence of the events being measured. PMID- 17716422 TI - Transforming doctor-patient relationships. PMID- 17716423 TI - What motivates health professionals? Opportunities to gain greater insight from theory. AB - Health care policy-makers and researchers need to pay more attention to understanding the influence of motivation on professional behaviour. Goal setting theory, including two hypotheses - the business case and the pride case - dominates current attempts to motivate professionals. However, the predominance of goal setting theory stifles other approaches to conceptualizing professional motivation. These approaches include other cognitive theories of motivation, such as self-determination theory (concerned with how to use extrinsic rewards that enhance intrinsic motivation), as well as content, psychoanalytic and environmental theories. A valuable opportunity exists to develop and test such theories in addition to possible hybrids, for example, by elaborating goal setting theory in health care. The results can be expected to inform health policy and motivate individual professionals, groups, organizations and workforces to improve and deliver high quality care. PMID- 17716424 TI - Myth: We can improve quality one doctor at a time. PMID- 17716427 TI - Searching for a threshold - Not so NICE... PMID- 17716429 TI - Risk factors for human schistosomiasis in the Upper Benue valley, in northern Cameroon. AB - The Upper Benue valley is inhabited by human populations of mixed background and socio-economic status. The area is an old and intense focus of both urinary schistosomiasis (caused by Schistosoma haematobium) and intestinal schistosomiasis (caused by S. mansoni). Most of the local villages have stand pipes that provide clean drinking water but bathing, laundry, dishwashing and swimming are largely confined to nearby, snail-infested rivers, streams, irrigation canals and pools. The results of interviews and a multivariate analysis indicated that, in this region of Cameroon, a subject's age, knowledge of schistosomiasis, ethnic group and intensity of water contact (with rivers, streams and pools) were all significantly associated with schistosome infection. Curiously, a high level of knowledge about schistosomiasis was positively associated with infection. PMID- 17716430 TI - Community acceptability of the use of low-dose niclosamide (Bayluscide), as a molluscicide in the control of human schistosomiasis in Sahelian Cameroon. AB - Although field trials of the application of molluscicides for the control of human schistosomiasis have been conducted in several settings, the acceptability of molluscide use at the community level has been poorly documented. The death and putrefaction of aquatic organisms in water treated with niclosamide (Bayluscide), for example, and the yellowish colouration of such water, may decrease the molluscide's acceptability. It may be possible, however, to use doses of a molluscicide that are only just high enough to kill the target snails but not high enough to kill non-target fish and frogs, thereby reducing the application's impact on water quality and colour and improving its acceptability to local communities. In a study in northern Cameroon, Bayluscide WP70 was applied to ponds at concentrations of 0, 0.25, 0.5 or 1 g/m(3). Changes in human contact with the water in the ponds were explored both by direct observation and by in-depth interviews with key informants from the local community. Although all applications of niclosamide greatly decreased human use of the treated ponds for a few days, most informants (99%) were in favour of niclosamide application and only 6% of the interviewees gave change in water colour or bad smell as a reason for not using a particular water body. Over the few days post-application, use of ponds treated with 0.25 or 0.5 g Bayluscide WP70/m(3) was higher than that of the ponds treated with 1 g/m(3), indicating that relatively low-dose applications, if effective in controlling snails, may be more acceptable to local communities than applications at higher doses. PMID- 17716431 TI - Efficacy of a limb-care regime in preventing acute adenolymphangitis in patients with lymphoedema caused by bancroftian filariasis, in Colombo, Sri Lanka. AB - The efficacy of a programme of community home-based care (CHBC) for lymphoedematous limbs was evaluated among 163 lymphoedema patients attending two filariasis clinics in Colombo. Each patient was interviewed and examined and his or her lymphoedema was graded during a baseline assessment, before the CHBC programme, and again, during a post-intervention assessment, after the patient had been in the programme for 1 year. The number of patients having entry lesions was 24% lower at the post-intervention assessment than at the baseline (P<0.001), with a reduction in the frequency of each type of entry lesion investigated. In the year the patients were in the CHBC programme, 30% fewer of them experienced at least one attack of adenolymphangitis (ADL; P<0.001), the mean number of ADL attacks/patient was lower (P<0.001), and the mean duration of each ADL attack suffered was slightly shorter (5.70 v. 5.84 days; P>0.05) than in the year before the baseline assessment. The reduction in the incidence of ADL attacks was greatest in the patients with the higher grades of lymphoedema. Approximately 66% of the patients perceived an improvement in their swollen limb post-intervention. Eleven patients had grade-II lymphoedema at baseline but only grade-I lymphoedema after being on the CHBC programme for a year (P=0.012). The programme appeared to increase the frequencies with which patients followed each of the limb-care measures considered and most of the measures for the home management of ADL attacks that were investigated. It is recommended that the CHBC programme be implemented as a national programme in Sri Lanka. PMID- 17716433 TI - Spatial modelling and the prediction of Loa loa risk: decision making under uncertainty. AB - Health decision-makers working in Africa often need to act for millions of people over large geographical areas on little and uncertain information. Spatial statistical modelling and Bayesian inference have now been used to quantify the uncertainty in the predictions of a regional, environmental risk map for Loa loa (a map that is currently being used as an essential decision tool by the African Programme for Onchocerciasis Control). The methodology allows the expression of the probability that, given the data, a particular location does or does not exceed a predefined high-risk threshold for which a change in strategy for the delivery of the antihelmintic ivermectin is required. PMID- 17716434 TI - First detection and sequence analysis of the bla-CTX-M-15 gene in Lebanese isolates of extended-spectrum-beta-lactamase-producing Shigella sonnei. AB - The emergence in Shigella species of extended-spectrum beta-lactamases (ESBL) that impart resistance to third-generation cephalosporins is a growing concern world-wide. So far, however, ESBL-producing Shigella have only been reported seven times, albeit from seven different countries. In Lebanon, three ESBL producing clinical isolates of S. sonnei were recovered from 30 cases of shigellosis diagnosed between July 2004 and October 2005. All three were found to be resistant to amoxycillin, cefotaxime, ceftazidime, aztreonam, trimethoprim/sulphamethoxazole, gentamicin, and kanamycin. Each harboured the bla CTX-M gene, and the results of sequence analysis indicated this to be of the bla CTX-M-15 type and encoded on a 70-kb plasmid, flanked by an insertion element (ISEcp1). The bla-TEM-1 gene was also detected on the chromosomes of two of the ESBL-producing isolates. Class-2 integrons containing dhfr1, aadA1 and sat1 genes were detected on the chromosomes of all three isolates but not on the plasmids. Fluoroquinolone-modifying factors [QnrA, QnrB, QnrS or AAC(6')-Ib-cr] were not detected. The results of RAPD analysis, combined with data on antimicrobial susceptibility, indicated that each isolate was unique. In conclusion, the emergence of ESBL-producing isolates of S. sonnei has been demonstrated for the first time in Lebanon. The resistance of these isolates to third-generation cephalosporins was mediated by the CTX-M-15 enzyme, which was plasmid-encoded. PMID- 17716435 TI - A randomized and controlled comparison of the wash-resistances and insecticidal efficacies of four types of deltamethrin-treated nets, over a 6-month period of domestic use with washing every 2 weeks, in a rural area of Iran. AB - In a randomized, prospective, 6-month-long field study in a rural area of Iran, the wash resistances of 200 nets (40 PermaNet, 40 Yorkool and 40 A-Z nets), that their manufacturers claimed be long-lasting insecticidal nets (LLIN), were compared with those of 40 nets conventionally treated with deltamethrin (using K O Tab tablets). All the nets were kept in routine domestic use and subjected to standardized hand-washing at 2-week intervals. Wild-caught or laboratory-reared Anopheles stephensi were used for the bio-assays of insecticidal activity. The regular washing and domestic use led to reductions in the insecticidal activities of all the treated nets after 6 months. Although the PermaNet nets showed the smallest reduction, they were not significantly better than the conventionally treated nets, which still showed acceptable insecticidal activity after 6 months. The PermaNet and A-Z nets both performed significantly better than the Yorkool nets, which were slightly but not significantly worse than the conventionally treated nets. In questionnaire-based interviews, the local householders were found to wash their own (non-study) nets at median and mean frequencies of every 2 and 2.1 weeks, respectively. In conclusion, the PermaNet nets showed better wash resistance than any of the other commercial nets, and were the only commercial nets tested that truly appeared to be LLIN. There still appears to be scope, however, for the impregnation, and thus the wash-resistance, of even the PermaNet nets to be improved. PMID- 17716436 TI - First report of an unclassified Demodex mite causing demodicosis in a Venezuelan dog. AB - For the first time in Venezuela, a case of canine demodicosis apparently caused by a simultaneous infection with an unclassified Demodex and Demodex canis has been observed. The most severely affected area of the dog involved, a 3-month-old male Doberman Pinscher, was the head, particularly the peri-orbital skin. Skin samples of the affected areas were taken and evaluated by both light and scanning electron microscopy. The mites of the unclassified Demodex were smaller than those of D. canis and appeared relatively stout. In the skin scrapings, D. canis outnumbered the unclassified Demodex by a ratio of 30:1, making it unclear if the unclassified Demodex is pathogenic to dogs. A combination of superficial and deep skin scrapings, from a suspected case of demodicosis, may help to reveal other infestations of the unclassified Demodex that would otherwise be masked by concurrent infections with D. canis. PMID- 17716437 TI - Epidemiology of amoebic liver abscess in Mexico: the case of Sonora. PMID- 17716438 TI - Cryptosporidium in patients with diarrhoea, on Tenerife, Canary Islands, Spain. PMID- 17716440 TI - Solitary hydatid cyst in the tibia. PMID- 17716439 TI - Intestinal microsporidial infections among Orang Asli (aborigine) children from Malaysia. PMID- 17716441 TI - Is the El Nino-Southern Oscillation likely to increase the risk of Fasciola transmission? PMID- 17716442 TI - Oral treatment with a potential probiotic (Enterococcus faecalis CECT 7121) appears to reduce the parasite burden of mice infected with Toxocara canis. PMID- 17716443 TI - Introduction of rotavirus vaccines in developing countries: remaining challenges. AB - Rotavirus is the principal agent of severe, dehydrating gastro-enteritis in infants and young children worldwide. The main public health tool that can prevent hospitalisation and death from rotavirus is vaccination. One of two current rotavirus vaccines is now licensed in more than 80 countries and is incorporated into childhood immunisation schedules across several countries in the Americas and Europe. However, since the majority of childhood deaths from rotavirus occur in the developing countries of Africa and Asia, widespread use of vaccine in these two continents will be necessary before a major impact on global diarrhoea mortality is seen. Challenges in these latter settings which primarily relate to vaccine efficacy, safety and financing will be addressed within the next 3-5 years, and thus perhaps finally allow introduction of rotavirus vaccine into the populations in greatest need. PMID- 17716444 TI - Clinical, laboratory and echocardiographic profile of acute rheumatic fever in Nepali children. AB - BACKGROUND: Acute rheumatic fever (RF) is a common, preventable health problem in developing countries. Sporadic outbreaks and the prevalence in some indigenous populations have renewed interest in RF in developed countries also. AIMS: To describe the clinical, laboratory and echocardiographic features, outcome and value of echocardiography in detecting valvular disease in RF. METHODS: A prospective, cross-sectional study was conducted over 2 years. Patients under 14 years admitted to the cardiology unit of Kanti Children's Hospital, Kathmandu with RF using the Jones criteria were recruited consecutively. RESULTS: The median age (range) of the 51 patients was 11 (5-14) years, the male:female ratio was 1.6:1 and 39% had a history of a sore throat. Clinical and laboratory features detected were as follows: carditis 92%, arthritis 33%, chorea 8%, subcutaneous nodules 4%, fever 51%, arthralgia 37%, elevated antistreptolysin O titre 94%, elevated CRP 78%, prolonged PR interval 45%, pericardial effusion 22% and cardiac failure 28%. In total, 36 patients (71%) complained of joint pains. A murmur on auscultation was significantly associated with underlying diseased valves confirmed by echocardiography (p=0.001). A murmur was audible in 78.4% and diseased valves were confirmed by echocardiography in 88.2%. The mitral valve was the most commonly involved valve (82%) and mitral regurgitation the commonest lesion (24%). A thickened mitral valve predicted carditis (p=0.007). Five (10%) patients died. CONCLUSION: Inclusion of echocardiographic evidence of carditis and possibly arthralgia as major criteria would improve case detection. PMID- 17716445 TI - The role of vascular endothelial growth factor leading to vascular leakage in children with dengue virus infection. AB - Increased vascular permeability is the main aetiology for hypovolaemic shock and circulatory failure in dengue haemorrhagic fever (DHF). AIM: To investigate the role of vascular endothelial growth factor (VEGF) in the pathogenesis of DHF. METHODS: Serum samples from 41 patients [15 dengue fever (DF), 26 DHF] with serologically confirmed dengue virus infection during the febrile, toxic, convalescent stages and at follow-up were analysed for VEGF. Plasma samples from an additional 27 children (16 DF and 11 DHF) during the febrile, toxic stages and at 4-week follow-up and from eight healthy controls were analysed for VEGF. RESULTS: Serum and plasma VEGF levels were not elevated during the febrile or toxic stages of dengue virus infection and did not differ between patients with DF and DHF. CONCLUSION: Plasma leakage in patients with DHF cannot be explained by elevation of VEGF during the toxic stage of the illness. PMID- 17716446 TI - Clinical and radiographic improvement of rickets in Bangladeshi children as a result of nutritional advice. AB - BACKGROUND: Calcium-deficiency rickets is common in south-east Bangladesh and responds to calcium supplementation. AIM: To evaluate the healing effect on active rickets of a five-component nutritional advice programme aimed at doubling dietary calcium intakes. METHODS: Forty-nine children aged <10 years with mild lower limb deformities and active rickets were followed over a period of 12 months. All were provided with a five-component nutritional advice programme advocating (i) the routine addition of 1 g limestone/kg rice, (ii) consuming small fish (including bones) instead of large ones, and (iii) daily consumption of 5 g ground sesame seeds, (iv) 100 g leafy vegetables and, if possible, (v) 100 ml of milk. RESULTS: Radiographic scores improved in 90% of children. The response was positively associated with age (r=0.34, n=48, p=0.01) and severity of radiographic score at baseline (r=0.85, n=49, p<0.0001). CONCLUSIONS: Despite the lack of a statistically significant association between radiographic improvement and compliance with nutritional advice, in mild calcium-deficiency active rickets, nutritional advice may be a cost-effective treatment and possibly a valuable long-term solution to the problem. PMID- 17716447 TI - Acute chest syndrome in Omani children with sickle cell disease: epidemiology and clinical profile. AB - AIMS: To describe the epidemiology and clinical profile of acute chest syndrome (ACS) in Omani Arab children. METHODS: Prospective, clinical study of consecutive episodes of ACS in patients with sickle cell disease (SCD) seen at Nizwa Regional Referral Hospital, Oman between June 2001 and May 2006. RESULTS: Of 240 patients registered with SCD, 52 (22%) developed 55 episodes of ACS. There were 31 (59.6%) males and ages ranged between 14 months and 12 years [median (SD) 6.5 (2.49) years]; ACS occurred fairly evenly in those aged between 2 and 10 years. Ten (18%) episodes were mild, 51% moderate and 31% severe. In general, there was no relationship between severity of SCD and the incidence of ACS, but in 71% of cases a vaso-occlusive crisis (VOC) preceded the episodes. Other probable precipitating factors were acute upper respiratory tract infections (in 29% of cases) and use of morphine (26%). The distribution of ACS during the year was bimodal, peaking in May and September and at its lowest in June and December/January. Fever, cough, chest pain, tachypnoea, reduced breath sounds, crackles and chest radiograph opacities were the main manifestations. However, respiratory physical signs were absent in 36% of episodes. CONCLUSIONS: ACS is common in SCD. Irrespective of SCD severity, all patients appeared to be at risk of the syndrome, but the risk is increased by VOCs. Prevention of VOCs, prompt and effective treatment of respiratory infections and caution in the use of morphine during a VOC should reduce the incidence of ACS. PMID- 17716448 TI - Effect of breastfeeding during venepuncture in neonates. AB - BACKGROUND: Evidence suggests that infants feel pain, and painful experiences may lead to subsequent increased pain sensitivity. Owing to concerns regarding the potential adverse effects of pharmacological interventions in newborns, effective alternatives for pain control are being sought. AIM: The Neonatal Infant Pain Scale (NIPS) was used to determine the analgesic effect of breastfeeding during venepuncture. METHODS: The study was of cross-over design where each neonate served as his/her own control. Median pain scores during venepuncture when neonates were being breastfed (BF) were compared with those when neonates were not being breastfed (NBF). The site of venepuncture and number of previous venepunctures were noted. Pain was assessed using NIPS. RESULTS: In all, 38 term neonates (25 male, 13 female) were recruited. Mean (SD) age and weight were 8.42 (8.74) days and 2.89 (0.67) kg, respectively. The median pain score (interquartile range) of the neonates when breastfed was 1.50 (1-2), and 4.00 (2 6) when not breastfed (p=0.0001). The Kruskal-Wallis H-test did not show statistically significant differences between the BF and NBF groups when the number of previous punctures (p=0.57, p=0.27) and site of venepuncture (p=0.71, p=0.77) were considered. CONCLUSION: Using NIPS, it has been demonstrated that breastfeeding is analgesic in neonates during venepuncture and previous venepuncture/s and site of venepuncture do not seem to affect pain scores. Breastfeeding should be the first-choice analgesic during painful procedures in neonates. PMID- 17716449 TI - Digitally recycled incubators: better economic alternatives to modern systems in low-income countries. AB - The need to maintain a neutral thermal environment is critical to newborn care. AIM: To investigate reasons for the insufficiency of functional incubators and develop a cost-effective technique for using electronic digital components to recycle obsolete incubators in Nigeria. METHODS: Following interview of 84 clinicians and administrators in Nigerian hospitals, it was identified that inadequate funding was the main reason for lack of functional incubators. Two groups of incubator units were then created and their performance compared. Sixteen units of modern (group A) and 19 units of obsolete (group B) incubators were obtained from six hospitals. An assembly design applying independent generic components for recycling systems was specified and produced. These were sourced through the internet at competitive cost and fitted into the reconstructed panels of the obsolete systems. The functional performance of each recycled system was rigorously monitored for 6 months and graded using ten performance indices. The same indices were used to quantify group A systems. RESULTS: The performance of the recycled incubators (group B) was found to be similar to those of modern incubators. Group B's cost index was found to be 25% of that of group A's. CONCLUSION: Appropriate incubator recycling is a cost-effective method of re equipping hospitals in low-income countries. PMID- 17716450 TI - Behavioural disorders in 6-11-year-old, HIV-infected Indian children. AB - BACKGROUND: HIV-infected children are at risk of behaviour problems. The transition of HIV from an acute, lethal disease to survival with sub-acute, chronic disease has enormous implications for the psychosocial development and requirement for support of affected children and families. AIM: To study the behavioural patterns and factors responsible for psychiatric disorders among HIV infected and uninfected children in the age group 6-11 years. METHODS: A prospective, random-sampling study was undertaken to examine the unique and combined influences of HIV and socio-demographic characteristics on the behaviour of 140 infected and 301 age- and income-matched controls. Controls were normal children recruited from government schools. The Child Behaviour Check List was used to assess behaviour patterns. RESULTS: Multivariate analyses comparing HIV infected children with their uninfected peers from similar backgrounds showed more subjective distress in the HIV-infected group. Behaviour problems in HIV infected children were reported by 80.7% of primary caregivers compared with 18.3% for controls. Psychiatric behaviour in HIV-infected children as a risk factor for HIV was also identified in a significant proportion (p<0.0001). CONCLUSIONS: By analysing behaviour, a psycho-medical team can examine the extent to which psychosocial and demographic factors are involved in causing and exacerbating behaviour problems in HIV-infected children. PMID- 17716451 TI - Community perception of child drowning in South India: a qualitative study. AB - BACKGROUND: World-wide, drowning is one of the leading causes of death in children between 1 and 12 years of age, especially in low- and middle-income countries. AIM: To assess the community's perceptions of the common causes of death in children, the level of awareness of drowning as a major cause and the reasons for the high rate of drowning, and to discuss preventive measures. METHOD: Five focus group discussions were conducted with representatives from five different categories of people in the community. The groups included health aides, extension workers and part-time community health workers in the peripheral health care team of the Department of Community Health, Christian Medical College, Vellore and land owners/village leaders. The data were analysed using content analysis to detect themes and trends. RESULTS: Drowning was not perceived as a major cause of childhood death. Unprotected bodies of water was acknowledged as a reason for the high rate of drowning. The groups suggested some preventive measures including intensive education on the causes of drowning, the introduction of more balwadis (day nurseries) in the villages, and the identification of resources to protect open bodies of water. CONCLUSIONS: There is an urgent need among rural communities to create awareness of the high rate of drowning in children and to motivate and facilitate individuals, communities, organisations and government agencies to make the communities safer for children. PMID- 17716452 TI - Familial haemophagocytic lymphohistiocytosis in two newborn siblings: a good mimicker of newborn sepsis. AB - Familial haemophagocytic lymphohistiocytosis (FHL) is a rare, autosomal recessive disorder. We report two newborn siblings diagnosed as FHL. PMID- 17716453 TI - Glomerulocystic disease: a severe form in a monozygous twin. AB - One of monozygous twins presented with anuria from birth and was diagnosed on renal biopsy with glomerulocystic kidney disease. There was no associated congenital or hereditary disorder. The other twin was normal and ultrasonography of the renal tracts of both infants was normal. He was managed by peritoneal dialysis. As renal transplantation was not available, the parents discharged him without further treatment. PMID- 17716454 TI - Serious and life-threatening bleeding in late vitamin K deficiency. PMID- 17716455 TI - Development, survival, and reproduction of the predatory mite Kampimodromus aberrans (Acari: Phytoseiidae) at different constant temperatures. AB - Development, survival, and reproduction of the predatory mite Kampimodromus aberrans Oudemans were studied at constant temperatures in the range from 15 to 35 degrees C under laboratory conditions. Larval developmental rate for both males and females increased gradually from 15 to 35 degrees C and decreased at higher temperatures. Lactin's nonlinear model described with adequate accuracy the relationship between developmental rate and temperature. The model predicted that lower and upper threshold temperatures for preimaginal development ranged from 9.8 to 11.8 degrees C and from 37.2 to 39.8 degrees C, respectively. The intrinsic rate of population increase (rm) at the different temperatures ranged from 0.0442 to 0.1575, with the highest value recorded at 25 degrees C. At 33 degrees C a negative rm value was estimated. The rm values determined at different temperatures were fitted to Lactin's nonlinear model, and the lower and upper threshold and the optimal temperatures for population increase were 10.5, 32.4, and 27.6 degrees C, respectively. These data indicate that K. aberrans may be better adapted to intermediate temperatures around 27 degrees C and, therefore, could be a useful biocontrol agent of spider mites during spring and early summer when such temperatures are prevalent in northern Greece. The results could also be useful in developing a population model for K. aberrans under field conditions. PMID- 17716456 TI - Influence of constant temperatures on life history parameters of the cotton aphid, Aphis gossypii, infesting cotton. AB - Laboratory clip-cage studies were conducted to quantify the temperature-dependent development, survivorship, and reproduction and to generate life history characteristics and population growth parameters of the cotton aphid, Aphis gossypii Glover, on phenologically standardized greenhouse-grown cottons at 10, 15, 20, 25, 30, and 35 degrees C. The developmental thresholds were estimated to be 6.3, 6.7, 5.9, 5.9, and 6.3 degrees C for first to fourth instars and for total nymphal development, respectively. The maximum rate of development were estimated to occur at 32.2, 30.8, 30.4, 30.0, and 30.2 degrees C for first to fourth instars and for total nymphal development, respectively. Increased temperature resulted in more rapid decline in survivorship, which was particularly sharp at 35 degrees C, dropping from 94 to 17% in 5 d. Number of days elapsed until first deposition of progeny increased progressively and sharply at temperatures 10 (26 d) to 15 (15 d) to 20 degrees C (8 d) and stabilized at 5 d for 25, 30, and 35 degrees C. Average lifetime fecundity of females rose from a low of 9.76 progeny at 10 degrees C to a peak of 58.9 progeny at 30 degrees C and declined sharply to 17.3 at 35 degrees C. Finite rate of population growth was highest at 25 degrees C and lowest at 10 degrees C. Although stage-specific developmental maxima occurred between 30 and 32 degrees C, a nonlinear regression model estimated 28.6 degrees C to be the optimum temperature for overall cotton aphid development, reproduction, and population increase. PMID- 17716457 TI - Influence of body size and environmental temperature on carbon dioxide production by forest centipedes from southwestern North America. AB - We conducted a laboratory study to evaluate the mass and temperature dependence of carbon dioxide production by three dominant centipede species--Arctogeophilus umbraticus McNeill, Gonibius glyptocephalus Chamberlin, and Oabius sp.--from a montane forest in southwestern North America. We found that CO2 production (Q, microl/h) of resting, nonfasted individuals was related to body mass (M, mg live) and environmental temperature (T, K) as Q=e18.32M0.82e-0.49/kT, where e is the base of the natural logarithm and k is Boltzmann's constant (8.62x10(-5) eV/K). Our results indicated that the mass and temperature dependence of centipede metabolism is comparable with that of other arthropods. They also supported previous claims that centipede metabolic rate, for a given mass and temperature, is relatively low compared with other arthropods. Suggestions are given for using resulting metabolic rate equations in conjunction with data on abundance, body size, and environmental temperature to assess energy flux by centipede populations. PMID- 17716458 TI - Temperature thresholds and thermal requirements for development of Nasonovia ribisnigri (Hemiptera: Aphididae). AB - Early detection of Nasonovia ribisnigri (Mosley) (Hemiptera: Aphididae) on lettuce is of primary importance for its effective control. Temperature thresholds for development of this pest were estimated using developmental rates [r(T)] at different constant temperatures (8, 12, 16, 20, 24, 26, and 28 degrees C). Observed developmental rates data and temperature were fitted to two linear (Campbell and Muniz and Gil) and a nonlinear (Lactin) models. Lower temperature threshold estimated by the Campbell model was 3.6 degrees C for apterous, 4.1 degrees C for alates, and 3.1 degrees C for both aphid adult morphs together. Similar values of the lower temperature threshold were obtained with the Muniz and Gil model, for apterous (4.0 degrees C), alates (4.2 degrees C), and both adult morphs together (3.7 degrees C) of N. ribisnigri. Thermal requirements of N. ribisnigri to complete development were estimated by Campbell and Muniz and Gil models for apterous in 125 and 129 DD and for both adult morphs together in 143 and 139 DD, respectively. For complete development from birth to adulthood, the alate morph needed 15-18 DD more than the apterous morph. The lower temperature threshold determined by the Lactin model was 5.3 degrees C for alates, 2.3 degrees C for apterous, and 1.9 degrees C for both adult morphs together. The optimal and upper temperature thresholds were 25.2 and 33.6 degrees C, respectively, for the alate morph, 27 and 35.9 degrees C, respectively, for the apterous morph, and 26.1 and 35.3 degrees C, respectively, for the two adult morphs together. The Campbell model provided the best fit to the observed developmental rates data of N. ribisnigri. This information could be incorporated in forecasting models of this pest. PMID- 17716459 TI - Individual and population effects of eugregarine, Gregarina niphandrodes (Eugregarinida: Gregarinidae), on Tenebrio molitor (Coleoptera: Tenebrionidae). AB - Gregarines are single-celled parasites in the phylum Apicomplexa that infect invertebrates. They are highly abundant on three levels: among a large diversity of invertebrates, in the proportion of population of organisms they infect, and within individually infected organisms. Because of their remarkable prevalence, we hypothesize that they play an important role in support of their hosts. However, studies done to date on the impact of gregarines on their host are conflicting. Therefore, we studied the impact of gregarines on their host using a model Gregarina niphandrodes infection in Tenebrio molitor. The impact of infection was measured by comparing beetles with no or low infection to those with artificially induced high infection. The numbers of individuals in each of the three easily visible developmental stages of the T. molitor (larva, pupa, and adult) were censused weekly. From these observations, fertilities and probabilities of survival with transition between stages were estimated. These estimated vital rates were used to construct a stage-classified projection matrix model. We also measured the longevity of individual beetles with low and high infection that were grown in isolation. The results indicate that there is no significant difference in the population dynamics of beetles with low and high infection. However, the longevity was significantly different between beetles with low infection than the deliberately highly infected group. PMID- 17716460 TI - Assessment of herbivore performance on host plants. AB - Two models for assessing the performance of herbivores on a variety of host plants are developed by combining knowledge of population genetics and population ecology, especially that of the fixation probability of mutant genes. The absolute host performance model precisely assesses host performance for one herbivore population based on parameters of fecundity, larval survivorship, and selection pressure. The relative host performance model compares host performance for one population among different host plant species and for several populations on the same host species. Two herbivore populations, Bemisia tabaci (Gennadius) and Tetranychus truncates Ehara, were used to validate the absolute and relative host performance models. Results indicated that the assessment systems of host performance were reasonable and reliable. These models could be applied to a wide range of herbivore species for assessing their performance on host plants. PMID- 17716461 TI - Density and structure of Saissetia oleae (Hemiptera: Coccidae) populations on citrus and olives: relative importance of the two annual generations. AB - Saissetia oleae (Olivier) (Hemiptera: Coccidae) populations were studied and compared in citrus (Citrus spp.) and olive (Olea europaea L.) groves to determine the number of generations, crawler emergence periods and changes in population density during the year. Ten citrus and four olive groves were sampled regularly between March 2003 and December 2005 in eastern Spain, covering an area of 10,000 km2. Each sample consisted of 16 branches and 64 leaves. Saissetia oleae populations presented a similar trend in both crops during the three years of study. Populations peaked in July, when crawlers emerged after the egg-laying period, and decreased during several months due to mortality of first instars in summer. A second crawler emergence period, with lower numbers and more variability from year to year, occurred between October and March. Populations did not increase during this period, probably because most eggs and crawlers perished during the winter and also because females that gave rise to this fall winter generation were half as big and fecund as spring females. No differences were found between the size of mature females that had developed on citrus and on olives during the spring. Considering this population pattern, the best seasonal period to apply pesticides to control S. oleae would be at the end of July, when populations are synchronous, all crawlers have already emerged, and first instars predominate. PMID- 17716462 TI - Developmental polymorphism in a Newfoundland population of the hemlock looper, Lambdina fiscellaria (Lepidoptera: Geometridae). AB - The hemlock looper [Lambdina fiscellaria (Guenee)], a widespread and highly polyphagous Geometridae, is considered one of the most economically important defoliators of North American coniferous forests. Variations in the number of larval instars between geographic populations of this species have been previously reported in the literature. However, whether such developmental polymorphism occurs within a given population is unknown. In this study, we report the presence of both four and five larval instar individuals within a population of hemlock looper in Newfoundland when reared on balsam fir. For both sexes, the majority of individuals reared on balsam fir shoots went through four larval instars, but more than one third of the females (35.3%) went through five larval instars. Females with four larval instars developed faster and had smaller pupal weight than females with five larval instars. However, a growth-related index (weight gain per unit of time) was similar for the two ecotypes (four or five larval instars). No significant difference was observed between the two ecotypes in terms of reproductive capacity (fecundity and egg size). We also found significant differences in life history traits between males and females. Results indicate that developmental polymorphism, in this case, the variation in the number of larval instars, might provide some adaptive attributes that allowed exploitation of a broader ecological niche. PMID- 17716463 TI - Host plants of the tarnished plant bug (Heteroptera: Miridae) in Central Texas. AB - The tarnished plant bug, Lygus lineolaris (Palisot de Beauvois), has taken on added importance as a pest of cotton in the Cotton Belt after successful eradication efforts for the boll weevil (Anthonomus grandis grandis Boheman). Because the Southern Blacklands region of Central Texas is in advanced stages of boll weevil eradication, blooming weeds and selected row crops were sampled during a 3-yr study to determine lygus species composition and associated temporal host plants. L. lineolaris was the sole lygus species in the region. Thirteen previously unreported host plants were identified for L. lineolaris, of which 69% supported reproduction. Rapistrum rugosum L. Allioni and Ratibida columnifera (Nuttall) Wooton and Standley were primary weed hosts during the early season (17 March to 31 May). Conyza canadensis L. Cronquist variety canadensis and Ambrosia trifida L. were primary weed hosts during the midseason (1 June to 14 August) and late-season (15 August to 30 November), respectively. Sisymbrium irio L. and Lamium amplexicaule L. sustained L. lineolaris populations during the overwintering period (1 December to 16 March). The proportion of females and numbers of nymphs found in R. rugosum, C. canadensis, A. trifida, and S. irio suggests these weeds supported reproductive adults during the early, mid , and late season and overwintering period, respectively. Medicago sativa L. was the leading crop host for L. lineolaris; Glycine max L. Merrill did not yield L. lineolaris. Few L. lineolaris were collected in Gossypium hirsutum L. These results provide a more comprehensive assessment of host plants contributing to L. lineolaris populations in central Texas. PMID- 17716464 TI - Associations of fire ant phorids and microhabitats. AB - We examined flight activity patterns for a guild of fire ant parasitoids in western Argentina in relationship to their host's location (mound/foraging trail) and light condition (full sun/partial sun/full shade) at different scales, from the individually sampled mound to the full day's summation for each species. We asked first whether taxa showed preferences among these conditions, and second, whether certain species and sexes might be found together more frequently than expected to by chance. All species, except the P. obtusus species complex, were significantly more likely to be found attacking ants at disturbed mounds than at paired foraging trails. The P. nocens complex and P. litoralis were more likely to be in the shade when temperatures were above the overall mean of the study (28.3 degrees C), whereas others, such as the P. obtusus complex and P. tricuspis, were more likely to be in full sun under these same conditions. Our analyses indicated that a limited set of species, particularly P. nocens with P. litoralis, and males with female P. obtusus and P. tricuspis, were more likely to be found together than expected. We also found decreasing proportions of males with increasing time of analysis. We discuss the implications of host location, metereological conditions, and sex ratios in relationship to ongoing classical biological control efforts using species of these phorids. PMID- 17716465 TI - Quantitative association of bark beetles with pitch canker fungus and effects of verbenone on their semiochemical communication in Monterey pine forests in Northern Spain. AB - The association between 11 species of bark beetles (Coleoptera: Scolytinae) and one weevil (Coleoptera: Entiminae) with the pitch canker fungus, Fusarium circinatum Nirenberg and O'Donnell, was determined by crushing beetles on selective medium and histone H3 gene sequencing. Pityophthorus pubescens (Marsham) (25.00%), Hylurgops palliatus (Gyllenhal) (11.96%), Ips sexdentatus (Borner) (8.57%), Hypothenemus eruditus Westwood (7.89%), Hylastes attenuatus Erichson (7.40%), and Orthotomicus erosus (Wollaston) (2.73%) were found to carry the inoculum. In addition, the root weevil Brachyderes incanus L. (14.28%) had the second highest frequency of occurrence of the fungus. The responses of the insects to a range of verbenone doses were tested in field bioassays using funnel traps. Catches of P. pubescens, a species colonizing branch tips of live trees, were significantly reduced in a log-linear dose-dependent relationship. Catches of I. sexdentatus, an opportunistic species normally attacking fresh dead host material, were also gradually reduced with increasing verbenone dose. Catches of Tomicus piniperda L., O. erosus, Dryocoetes autographus (Ratzeburg), H. eruditus, Xyleborus dryographus (Ratzeburg), Hylastes ater (Paykull), Hylurgus ligniperda (F.), H. attenuatus, and B. incanus were not significantly affected by verbenone. The effects of verbenone were consistent with differences in host-age preference. Semiochemical disruption by verbenone in P. pubescens and I. sexdentatus could represent an integrated pest management strategy for the prevention of the spread of pitch canker disease between different stands. However, several species associated with F. circinatum were unaffected by verbenone, not supporting this compound for prevention of the establishment of potential vectors in Northern Spain. PMID- 17716466 TI - Attractiveness of Michigan native plants to arthropod natural enemies and herbivores. AB - The use of plants to provide nectar and pollen resources to natural enemies through habitat management is a growing focus of conservation biological control. Current guidelines frequently recommend use of annual plants exotic to the management area, but native perennial plants are likely to provide similar resources and may have several advantages over exotics. We compared a set of 43 native Michigan perennial plants and 5 frequently recommended exotic annual plants for their attractiveness to natural enemies and herbivores for 2 yr. Plant species differed significantly in their attractiveness to natural enemies. In year 1, the exotic annual plants outperformed many of the newly established native perennial plants. In year 2, however, many native perennial plants attracted higher numbers of natural enemies than exotic plants. In year 2, we compared each flowering plant against the background vegetation (grass) for their attractiveness to natural enemies and herbivores. Screening individual plant species allowed rapid assessment of attractiveness to natural enemies. We identified 24 native perennial plants that attracted high numbers of natural enemies with promise for habitat management. Among the most attractive are Eupatorium perfoliatum L., Monarda punctata L., Silphium perfoliatum L., Potentilla fruticosa auct. non L., Coreopsis lanceolata L., Spiraea alba Duroi, Agastache nepetoides (L.) Kuntze, Anemone canadensis L., and Angelica atropurpurea L. Subsets of these plants can now be tested to develop a community of native plant species that attracts diverse natural enemy taxa and provides nectar and pollen throughout the growing season. PMID- 17716467 TI - Rapid inventory of the ant assemblage in a temperate hardwood forest: species composition and assessment of sampling methods. AB - Ants are key indicators of ecological change, but few studies have investigated how ant assemblages respond to dramatic changes in vegetation structure in temperate forests. Pests and pathogens are causing widespread loss of dominant canopy tree species; ant species composition and abundance may be very sensitive to such losses. Before the experimental removal of red oak trees to simulate effects of sudden oak death and examine the long-term impact of oak loss at the Black Rock Forest (Cornwall, NY), we carried out a rapid assessment of the ant assemblage in a 10-ha experimental area. We also determined the efficacy in a northern temperate forest of five different collecting methods--pitfall traps, litter samples, tuna fish and cookie baits, and hand collection--routinely used to sample ants in tropical systems. A total of 33 species in 14 genera were collected and identified; the myrmecines, Aphaenogaster rudis and Myrmica punctiventris, and the formicine Formica neogagates were the most common and abundant species encountered. Ninety-four percent (31 of 33) of the species were collected by litter sampling and structured hand sampling together, and we conclude that, in combination, these two methods are sufficient to assess species richness and composition of ant assemblages in northern temperate forests. Using new, unbiased estimators, we project that 38-58 ant species are likely to occur at Black Rock Forest. Loss of oak from these forests may favor Camponotus species that nest in decomposing wood and open habitat specialists in the genus Lasius. PMID- 17716468 TI - Multiple sources of isotopic variation in a terrestrial arthropod community: challenges for disentangling food webs. AB - Documenting trophic links in a food web has traditionally required complex exclusion experiments coupled with extraordinarily labor-intensive direct observations of predator foraging. Newer techniques such as stable isotope analysis (SIA) may facilitate relatively quick and accurate assessments of consumer feeding behavior. Ratios of N and C isotopes are thought to be useful for determining species' trophic position (e.g., 1 degrees consumer, 2 degrees consumer, or omnivore) and their original carbon source (e.g., C3 or C4 plants; terrestrial or marine nutrients). Thus far, however, applications of stable isotopes to terrestrial arthropod food webs have suggested that high taxon specific variation may undermine the effectiveness of this method. We applied stable isotope analysis to a pear orchard food web, in which biological control of a dominant pest, pear psylla (Cacopsylla pyricola), involves primarily generalist arthropod predators with a high frequency of omnivory. We found multiple sources of isotopic variation in this food web, including differences among plant tissues; time, stage, and taxon-specific differences among herbivores (despite similar feeding modes); and high taxon-specific variation among predators (with no clear evidence of omnivory). Collectively, these multiple sources of isotopic variation blur our view of the structure of this food web. Idiosyncrasies in consumer trophic shifts make ad hoc application of SIA to even moderately complex food webs intractable. SIA may not be a generally applicable "quick and dirty" method for delineating terrestrial food web structure-not without calibration of specific consumer food trophic shifts. PMID- 17716469 TI - Interactions among three trophic levels and diversity of parasitoids: a case of top-down processes in Mexican tropical dry forest. AB - The objective of this study was to analyze the relationship between plant hosts, galling insects, and their parasitoids in a tropical dry forest at Chamela Cuixmala Biosphere Reserve in western Mexico. In 120 transects of 30 by 5 m (60 in deciduous forest and 60 in riparian habitats), 29 galling insects species were found and represented in the following order: Diptera (Cecidomyiidae, which induced the greatest abundance of galls with 22 species; 76%), Homoptera (Psylloidea, 6.9%; Psyllidae, 6.9%; Triozidae, 3.4%), Hymenoptera (Tanaostigmatidae, 3.4%; which were rare), and one unidentified morphospecies (3.4%). In all cases, there was a great specificity between galling insect species and their host plant species; one galling insect species was associated with one specific plant species. In contrast, there was no specificity between parasitoid species and their host galling insect species. Only 11 species of parasitoids were associated with 29 galling insect species represented in the following families: Torymidae (18.2%), Eurytomidae (18.2%), Eulophidae (18.2%), Eupelmidae (9.1%), Pteromalidae (9.1%), family Braconidae (9.1%), Platygastridae (9.1%), and one unidentified (9.1%). Most parasitoid species parasitized several gall species (Torymus sp.: 51.1%, Eurytoma sp.: 49.7%, Torymoides sp.: 46.9%). Therefore, the effects of variation in plant defenses do not extend to the third trophic level, because a few species of parasitoids can determine the community structure and composition of galling insect species in tropical plants, and instead, top-down processes seem to be regulating trophic interactions of galling insect species in tropical gall communities. PMID- 17716470 TI - Small-scale spatial pattern of web-building spiders (Araneae) in alfalfa: relationship to disturbance from cutting, prey availability, and intraguild interactions. AB - Understanding the development of spatial patterns in generalist predators will improve our ability to incorporate them into biological control programs. We studied the small-scale spatial patterns of spider webs in alfalfa by analyzing the relationship between web locations over distances ranging from 4 to 66 cm. Using a coordinate-based spatial statistic (O-ring) and assuming a heterogeneous distribution of suitable web sites, we analyzed the impact of cutting and changes in spider abundance on web distribution. We analyzed the influence of small-scale variation in prey availability by comparing web distributions to the pattern of sticky-trap captures of Aphididae and Diptera described by a count-based spatial statistic (SADIE). Cutting of alfalfa reduced the overall density of web-building spiders but had no immediate impact on the spatial distribution of their webs. Availability of aphids was highest before the alfalfa was cut and was clumped at a scale of 66 cm. Spider webs, however, were not clumped at any scale or date. In contrast, webs were regularly distributed at smaller distances (<20 cm) immediately before and after cutting. Because cursorial and web-building spiders were most active during this period, we hypothesize that the development of small scale regularity in web locations was driven by intraguild interactions. Our results suggest that intraguild interactions contribute to the development of small-scale spatial patterns of spider webs in alfalfa. Variation in prey availability may have more of an influence on web distribution in crops with a different vegetation structure or if patterns are studied at larger spatial scales. PMID- 17716472 TI - Effects of volcanic ash on the forest canopy insects of Montserrat, West Indies. AB - The impact of ash deposition levels on canopy arthropods was studied on the West Indian island of Montserrat, the site of an ongoing volcanic eruption since 1995. Many of the island's natural habitats have been buried by volcanic debris, and remaining forests regularly receive volcanic ash deposition. To test the effect of ash on canopy arthropods, four study sites were sampled over a 15-mo period. Arthropod samples were obtained using canopy fogging, and ash samples were taken from leaf surfaces. Volcanic ash has had a significant negative impact on canopy arthropod populations, but the decline is not shared equally by all taxa present, and total population variation is within the variance attributed to other aboitic and biotic factors. The affected populations do not differ greatly from those of the neighboring island of St. Kitts, which has not been subject to recent volcanic activity. This indicates that observed effects on Montserrat's arthropod fauna have a short-term acute response to recent ash deposition rather than a chronic depression caused by repeated exposure to ash over the last decade. PMID- 17716471 TI - Effects of the insecticide phosmet on solitary bee foraging and nesting in orchards of Capitol Reef National Park, Utah. AB - Capitol Reef National Park, in southcentral Utah, contains 22 small orchards planted with antique fruit varieties by Mormon pioneers beginning over a century ago. The orchards continue to be managed in a pick-and-pay program, which includes spraying with phosmet to suppress codling moth (Cydia pomonella L.). The park is also home to a rich diversity of flowering plants, many of which are rare, bee-pollinated, and have populations within 1 km of the orchards. Over 3 yr, we studied the short-term effects of phosmet spraying on bee populations: (1) foraging on plants within the orchard understory and adjacent to it; and (2) nesting in, and at several distances from, the orchards. We recorded a rich bee fauna (47 taxa) in the orchards and on plants nearby. In 2 yr (2002 and 2004), we found no difference in the number of native bee visits to several species of plants flowering in and near to orchards immediately before and 1 d after spraying. Conversely, our nesting studies using the semidomesticated alfalfa leafcutting bee, Megachile rotundata (F.), showed strong significant declines in the number of adult males, nesting females, and progeny production subsequent to spraying at distances up to 160 m from sprayed orchards where the bees were presumably foraging. We showed that M. rotundata is negatively affected by phosmet spraying and suggest that caution should be exercised in its use in areas where bees are apt to forage. PMID- 17716473 TI - Field parasitism of nontarget weevil species (Coleoptera: Curculionidae) by the introduced biological control agent Microctonus aethiopoides Loan (Hymenoptera: Braconidae) over an altitude gradient. AB - The parasitoid, Microctonus aethiopoides Loan (Hymenoptera: Braconidae) was introduced into New Zealand in 1982 to control the alfalfa pest, Sitona discoideus Gyllenhal (Coleoptera: Curculionidae). Studies have shown that a number of nontarget weevil species are attacked in the field by this parasitoid. A field study was carried out to investigate nontarget parasitism by M. aethiopoides over an altitudinal sequence from the target host habitat (alfalfa) into native grassland. Three locations were selected for the study, and at each, the alfalfa growing in the valley floor was sampled annually for parasitism of the target pest that ranged between 17 and 78%. At progressively higher altitudes, three further grassland sites at each location were sampled monthly during spring to autumn for up to 6 yr. Weevil densities were estimated, species identified, and dissections carried out to determine reproductive status and parasitism. Almost 12,000 weevils were collected during the study, which were identified as 36 species in total from the three locations. Eight weevil species were found to be parasitized, including S. discoideus, the target host that was found at all sites. Parasitism of nontarget species was approximately 2% overall but varied with location, site, and season. Substantial nontarget parasitism was found at only one of the locations, with up to 24% parasitism of a native weevil, Nicaeana fraudator Broun (Coleoptera: Curculionidae), recorded. Another species, Irenimus egens (Broun) (Coleoptera: Curculionidae), was also found at this location at similar population densities but was attacked far less by M. aethiopoides. Results are discussed in relation to weevil phenology. PMID- 17716474 TI - Population dynamics of Aphis glycines (Homoptera: Aphididae) and impact of natural enemies in northern China. AB - Field surveys of soybean aphid, Aphis glycines Matsumura, and its natural enemies, as well as natural enemy exclosure experiments, were conducted during 2003 and 2004 in soybean fields near Langfang, China. In 2003, aphid density increased six-fold during 12 d in July from 66+/-12 per 10 plants to a seasonal peak of 401+/-79 per 10 plants. Aphid density remained high for another 10 d and declined during late July and early August. In 2004, aphid density increased 29 fold during 13 d in July from 14+/-2 per 10 plants to a seasonal peak of 375+/-30 per 10 plants. Unlike 2003, aphid density remained relatively high during late July and August, peaking again at 296+/-31 per 10 plants on 24 August. In both years, aphid density remained below economic injury level and seemed to be limited by natural enemies. Exclosure of natural enemies led to increases in A. glycines density in 2003 and 2004. In 2003, peak aphid densities in large- and medium-mesh cages were three- and seven-fold higher, respectively, than densities on uncaged plants. In 2004, peak aphid densities in large- and medium-mesh cages were 2-fold and 30-fold higher, respectively, than densities on uncaged plants in one experiment. In another experiment, peak aphid densities in large-, medium-, and small-mesh cages were 8-fold, 28-fold, and 68-fold higher, respectively, than densities on uncaged plants. Both predators and parasitoids were important in limiting aphid density. We compare our results with those from North America and discuss implications for biological control. PMID- 17716475 TI - Laboratory and realized host ranges of Chaetorellia succinea (Diptera: Tephritidae), an unintentionally introduced natural enemy of yellow starthistle. AB - In 1999, we reported our discovery, in California and Oregon, of Chaetorellia succinea (Costa) (Diptera: Tephritidae) destroying the seeds of yellow starthistle, Centaurea solstitialis L., one of the worst weeds in the western United States. This fly, an unintentional introduction from Greece, dispersed rapidly throughout California and the northwest, and there is interest in using this adventive fly as a classical biological control agent for this weed. Because the host range of Ch. succinea has not been studied, this fly might pose a risk to other members of the thistle tribe Cardueae, especially the many thistle species native to California and other parts of the western United States. We determined the physiological host range of this fly in the laboratory by exposing it under no-choice conditions to 14 potential Cardueae hosts. Two introduced weed species and the native American basketflower (Centaurea americana Nuttall) were laboratory hosts. Under less restrictive choice test conditions, yellow starthistle was highly preferred, but there was a small amount of oviposition, and a few adult Ch. succinea emerged from all three of these plant species. Because Ch. succinea is now widespread throughout California, we collected flower heads from 24 potential host plant species at 111 sites to determine the realized host range in the field. These collections did not include American basketflower, which does not occur naturally in California. Ch. succinea emerged only from the other two known hosts: Ce. melitensis and Ce. sulfurea. Our results suggest that American basketflower growing in the southwestern United States may be at risk if Ch. succinea expands its range into that region. PMID- 17716476 TI - Effect of summer drought relief on the impact of the root weevil Cyphocleonus achates on spotted knapweed. AB - A recent decline in spotted knapweed, Centaurea stoebe L. subsp. micranthos (Asteraceae), has been observed in parts of western Montana. The release of the biological control agent Cyphocleonus achates (Fahraeus) is thought to contribute to the decline, but persistent drought since at least 1999 may be an additional factor. We conducted outdoor plot experiments to test the relative impacts of C. achates weevils and summer drought relief on spotted knapweed survival and growth. Groups of spotted knapweed transplants were assigned to one of four weekly water addition treatments (no added water, and 0.25, 0.5 or full recovery of plant water deficit, where "deficit" refers to potential evapotranspiration minus rainfall) in May to August 2004 and June to August 2005 and to either exposure to or protection from C. achates. In June of each subsequent year (2005 and 2006), plants were harvested and growth attributes that reflect plant vigor were measured. Drought indices showed that throughout the time of the study until January 2006, western Montana was in drought alert or severe drought. Summer drought relief had no effect on aboveground biomass and plant height of knapweed plants in subsequent years, but feeding by C. achates larvae reduced these two measures of plant vigor. Knapweed plants resuming growth after the drought ended in spring 2006 were significantly larger than those resuming growth under drought conditions in spring 2005. Spring drought may reduce knapweed growth, but C. achates reduced knapweed growth regardless of drought conditions. PMID- 17716477 TI - Mate location and recognition in Glenea cantor (Fabr.) (Coleoptera: Cerambycidae: Lamiinae): roles of host plant health, female sex pheromone, and vision. AB - Glenea cantor (Fabricius) is an important pest of kapok trees [Bombax ceiba L.=Gossampinus malabaricus (DC.) Merr.] in southern China and Vietnam, and its adults are diurnally active. We carried out both field and laboratory experiments to examine the mechanisms that brought G. cantor sexes together from a long distance and facilitated mate location and recognition in a close range. Long range sex pheromones are not involved in mate location. Mutual attraction of sexes to weakened kapok trees where adult feeding, mating, and oviposition occur plays the key role in mate location from a long distance. In a close range, vision and a female sex pheromone that operates over a short distance (3-3.5 cm) and/or by contact are major cues males use for mate location and recognition. Males seem to use combined chemical and visual cues to achieve mating. Male antennae, particularly the terminal five segments, are critical for males to detect and recognize females. Removal of male palpi has no significant effect on mate location and recognition by males. PMID- 17716478 TI - Locomotion ability variation among instars of the bean bug, Riptortus pedestris (Fabricius) (Heteroptera: Alydidae) nymphs. AB - The nymphal locomotion ability (walking distance) of the stenophagous bean bug Riptortus pedestris (Fabricius) was studied in each instar. We measured the walking distance using two systems. The walking distance in photophase was measured for 6 h using a tracking system with a charge coupled device (CCD) camera and computer software. The daily activity of nymphs was measured by an actograph system counting the number of infrared beam intercepts. The actograph data were converted to distance using a linear regression against the data of the tracking system. The longevity of nymphs without food was also studied to estimate the potential walking distance. Using both the tracking and actograph systems, it was determined that first instars walked less than the other instars (only 10.7 m within 6 h). The second to fifth instars could move 20-25 m within 6 h, and this distance did not differ among instar. This indicates that first instars seldom move after hatching in the field. The walking distance for 24 h varied and was greatest for the third instars (80.8 m). The potential longevity of nymphs was found to increase with instar age. Potential locomotion ability (walking distance for 24 hxpotential longevity) was high in the third to fifth instars (approximately 340 m). The potential locomotion ability for the second instars was relatively low compared with the elder instars (approximately 180 m). From these results, nymphs of R. pedestris seem to adapt by identifying feeding site locations after hatching and elder instars may be able to find a novel feeding site after the degradation of previous habitat. PMID- 17716479 TI - Plant characteristics associated with natural enemy abundance at Michigan native plants. AB - Habitat management is a type of conservation biological control that focuses on increasing natural enemy populations by providing them with plant resources such as pollen and nectar. Insects are known to respond to a variety of plant characteristics in their search for plant-provided resources. A better understanding of the specific characteristics used by natural enemy insects in selecting these resources could greatly improve efficiency in screening plants for habitat management. We examined 5 previously tested and widely recommended resource plants and 43 candidate plants to test whether the number and type of natural enemies and herbivores at each plant were predicted by plant characteristics including: period of peak bloom, floral area, maximum flower height, hue, chroma, and corolla size. Natural enemy abundance increased with week of peak bloom and greater floral area across all plants tested. Ordination of plant characteristics indicated that increasing floral area, period of peak bloom, maximum flower height, and decreasing corolla width grouped together into a single principal component. Both natural enemy and herbivore abundance increased significantly with the principal component for this set of characteristics, but the relationship with herbivore abundance was weaker. These results indicate that, for a given time of the season, selection of plants with the largest floral area has potential to increase natural enemy abundance in habitat management plantings and streamline plant selection for habitat management. PMID- 17716480 TI - Parasitism of Tuta absoluta (Lepidoptera, Gelechiidae) by Pseudapanteles dignus (Hymenoptera, Braconidae) under laboratory conditions. AB - Laboratory studies were conducted to measure selected life history traits and the functional response of the parasitoid Pseudapanteles dignus (Muesebeck), a major enemy of Tuta absoluta (Meyrick) in tomato crops in South America. Newly mated P. dignus females were individually exposed to 10 host larvae in mines for 24 h. We determined developmental time from egg to pupal formation and pupal stage duration, female adult life span, fecundity, reproductive period, daily parasitism rate, and sex ratio of offspring. For the functional response experiment, treatments consisted of six host densities: 3, 5, 7, 10, 15, 20, or 30 larvae. The number and proportion of parasitized hosts were calculated for each density. The shape of the functional response curve was analyzed by logistic regression. P. dignus females attacked hosts daily, exhibiting modest lifetime fecundity (approximately 32 parasitized hosts per female) and a female-biased offspring sex ratio. Female adult life span was 36 d. P. dignus showed a type I functional response within the range of host densities tested. We observed that females detect and parasitize the host within a wide range of densities, including low densities. The functional response curve reached an asymptote at a mean density of six hosts per day and seemed not to be egg-limited. Percent parasitism was approximately 30%. The ecological implications of the results in relation to the potential of P. dignus for the biological control of T. absoluta in tomato are discussed. PMID- 17716481 TI - First report of an attractant for a tumbling flower beetle (Coleoptera: Mordellidae). AB - In 2004 and 2005, large numbers of the tumbling flower beetle, Falsomordellistena bihamata (Melsheimer), were found on traps baited with sweet birch oil, whereas significantly fewer individuals were found on control traps. In both years, peak captures were at 680 DD10 degrees C. Trapping was conducted in Naugatuck State Forest in Naugatuck, CT. Little is known about the ecology and biology of the tumbling flower beetles (Coleoptera: Mordellidae), and the larval food plant for this species is not known. Thus, we cannot say why the beetle is attracted to sweet birch oil. Sweet birch oil is approximately 99.8% methyl salicylate (MeSA). MeSA is found constitutively in large quantities in some plants, but it is also an important signal in, and product of, plant stress-response pathways. MeSA has been found to attract both herbivores that need stressed plants as food and natural enemies of herbivores in stressed plants. To our knowledge, this is the first report of mass trapping of a tumbling flower beetle. Fuller understanding of the phenomenon awaits further study. PMID- 17716482 TI - Divergent host acceptance behavior suggests host specialization in populations of the polyphagous mite Abacarus hystrix (Acari: Prostigmata: Eriophyidae). AB - For phytophagous arthropods, host acceptance behavior is a key character responsible for host plant specialization. The grain rust mite, Abacarus hystrix (Nalepa), is an obligately phytophagous, polyphagous eriophyid mite recorded from at least 70 grass species. In this study, the hypothesis that two host populations of this mite (one collected from quackgrass and the other from ryegrass) are highly host-specific was tested using behavioral data. For this purpose, female behavior when exposed to familiar and novel host plants was observed in no-choice cross experiments. Altogether, 13 variables were used to describe mite behavior. Data were subjected to principal component analysis, and host acceptance behavior was subsequently tested with generalized estimating equations (GEE). Distinct variation in female behavior between familiar and novel hosts was observed. Females from neither population accepted novel hosts. This was recorded as significant differences in the occupation of and overall activity on particular plant parts. On their familiar host, females were not active and showed little tendency to move. On novel hosts females were more active and mobile, spending more time walking, running, and climbing on the whole plant surface and showing a tendency to disperse. Other differences in behavior between studied populations were also observed. Thus, the results suggest that mites of these two studied populations (1) differ in their behaviors during plant exploitation and (2) can quickly distinguish between their familiar host and an unfamiliar host used by a conspecific. These findings support the hypothesis of narrow host specialization of ryegrass and quackgrass populations of this highly polyphagous species. PMID- 17716483 TI - Effects of maternal age and environment on offspring vital rates in the oleander aphid (Hemiptera: Aphididae). AB - Maternal effects have the potential to affect population dynamics and evolution. To affect population dynamics, maternal effects must influence offspring vital rates (birth, death, or movement). Here, we explore the magnitude of nongenetic maternal influence on the vital rates of an insect herbivore and explore predictability of maternal effects with reference to published studies. We experimentally studied the effects of maternal age, host plant species (two Asclepias spp.), and density on offspring vital rates in Aphis nerii, the oleander aphid. Older mothers produced offspring that lived shorter lives, consistent with the "Lansing Effect." Older mothers also produced offspring that matured at a younger age. As maternal age increased, offspring mass at maturity decreased when mothers were on Asclepias syriaca. However, offspring mass was highest from intermediate aged mothers on A. viridis. The absence of maternal density effects seems to exclude maternal density as a potential source of delayed density dependence in A. nerii. Our results indicate that maternal effects have some influence on A. nerii vital rates. However, references to published studies suggest that only the Lansing Effect is a predictable response to maternal age in insects. Moreover, the magnitude of observed effects was generally low. PMID- 17716485 TI - Behavioral responses of Homalodisca vitripennis (Hemiptera: Auchenorrhyncha: Cicadellidae) on four Vitis genotypes. AB - Pierce's disease is a major threat to the California grape industry. The disease causing bacterium Xylella fastidiosa is vectored by a number of leafhoppers including Homalodisca vitripennis (Germar) (Hemiptera: Cicadellidae). Experiments were conducted to study H. vitripennis preference, feeding, and survivorship in response to four Vitis genotypes. Plants of V. vinifera ('Chardonnay'), V. girdiana, V. candicans, and a V. rupestris x V. arizonica/candicans hybrid (D8909 17) were grown in pots in the greenhouse and transferred to laboratory conditions for experiments with field-collected H. vitripennis. A choice test without prior insect acclimation on grapes revealed that H. vitripennis selected Chardonnay over V. candicans throughout the duration of the experiment, whereas a shift in preference between D8909-17 and V. girdiana was observed over time. In a second set of choice tests, which were preceded by an acclimation on one of the four grape genotypes, significant genotype, time, and acclimation x genotype effects were observed. Chardonnay was preferred over V. candicans independent of acclimation genotype. Although H. vitripennis confined on D8909-17 excreted 1.8 fold (dry-weight corrected) the amount of insects feeding on V. candicans, differences in the rate of excreta production per insect or insect dry weight were not significant among grape genotypes. Adult mortality was greatest on V. candicans when H. vitripennis were confined in parafilm sachets for excreta collection as well as in a no-choice test. Grape genotype affected the behavior of adult H. vitripennis under controlled conditions, which may influence Pierce's disease epidemiology under field conditions. PMID- 17716486 TI - Role of oviposition preference in an invasive crambid impacting two graminaceous host crops. AB - Oviposition preference studies of the Mexican rice borer, Eoreuma loftini (Dyar), on sugarcane, Saccharum spp., and rice, Oryza sativa L., showed that drought stressed sugarcane was 1.8-fold more attractive based on egg masses/plant than well watered sugarcane. The E. loftini susceptible sugarcane cultivar LCP 85-384 was 1.6-fold more attractive than HoCP 85-845 based on numbers of eggs per egg mass. Egg masses were 9.2-fold more abundant and 2.3-fold larger on sugarcane than on rice. Rice, however, was preferred to sugarcane on a plant biomass basis. Oviposition on sugarcane occurred exclusively on dry leaf material, which increased under drought stress. Egg masses per plant increased on drought stressed sugarcane and were correlated with several foliar free amino acids essential for insect growth and development. The more resistant (based on injury) but more attractive (based on oviposition) rice cultivar XL8 had higher levels of several free amino acids than the susceptible cultivar Cocodrie. The association of host plant characteristics to oviposition preference is discussed. Projected oviposition patterns relative to sugarcane and rice production areas were estimated for Texas and Louisiana based on the availability of each host in different regions of each state. These results suggest that, where sugarcane and rice co-occur, the majority of eggs would be found on sugarcane early in the season, because of this crop's substantially greater biomass compared with rice. Abundance later in the season would also favor sugarcane; however, the abundance on rice would be greater than expected solely based on host availability, largely because of the greater preference per gram of rice plant dry weight. PMID- 17716484 TI - Antagonistic effects of soybean viruses on soybean aphid performance. AB - Although there is long-standing recognition that pest complexes require different management approaches than individual pests, relatively little research has explored how pests interact. In particular, little is known of how herbivorous insects and plant pathogens interact when sharing the same host plant. The soybean aphid, Aphis glycines Mastumura, a recently introduced pest of soybean in the upper midwestern United States, and a complex of plant viruses vectored to soybean by insects have become a major concern for growers in the region. Given the abundance of soybean aphid and the increase in virus incidence in recent years, soybean aphids often use soybean infected by plant viral pathogens. We tested the hypothesis that soybean aphid performance is affected by virus infection of soybean plants. We conducted a series of field and laboratory experiments that examined how infection of soybeans with the common plant viruses, alfalfa mosaic, soybean mosaic, and bean pod mottle viruses, influenced soybean aphid performance. Soybean plants (in the field and laboratory) were hand inoculated with individual viruses, and aphids were allowed to colonize plants naturally in field experiments or added to the plants in clip-cages or within mesh bags in laboratory assays. In the field, aphid density on uninfected control soybean plants was nearly double that on infected plants. In laboratory assays, aphid population growth rates were on average 20% lower for aphids on virus infected compared with uninfected plants. Life table analyses showed that increased mortality on virus-infected plants likely explain differences in aphid population growth. Although there was some heterogeneity in the significance of treatment effects among different experiments, when independent experiments are taken together, there is on average an overall negative effect of these viruses on soybean aphids. PMID- 17716487 TI - Evidence from molecular markers and population genetic analyses suggests recent invasions of the Western North Pacific region by biotypes B and Q of Bemisia tabaci (Gennadius). AB - Invasive events by Bemisia tabaci (Gennadius) biotypes in various parts of the world are of continuing interest. The most famous is biotype B that has caused great economic losses globally. In addition, biotype Q has also recently been reported to be a new invasive pest. These two biotypes have been monitored for some time in the Western North Pacific region, but the invasive events and population genetic structures of these two biotypes are still not clear in this region. In this study, the mitochondrial cytochrome oxidase I (COI) gene was used to reconstruct a phylogenetic tree for identifying biotypes B and Q and to study the relationships between invasive events and ornamental plants. Population genetic analyses of mtCOI sequences were also used to study the genetic relationships within and between populations. A combination of a phylogenetic tree and haplotype analysis suggested the recent invasion of biotype Q in this region is related to the international ornamental trade from the Mediterranean region. Low levels of haplotype diversity and nucleotide diversity indicate that the presence of biotypes B and Q in the Western North Pacific region are caused by multiple invasions. Hierarchical analysis of molecular variance supports the hypothesis of multiple invasions. In addition, high sequence identities and low genetic distances within and between populations of the two biotypes revealed that these invasive events occurred recently. The low levels of genetic differentiation revealed by pairwise F (ST) values between populations also suggests the invasions were recent. Therefore, results of this study suggested that biotypes B and Q entered this region through multiple recent invasions. A quarantine of agricultural crops may be necessary to prevent further invasions. PMID- 17716488 TI - Mitochondrial haplotypic diversity of pine cone beetles (Scolytinae: Conophthorus) collected on food sources. AB - Conophthorus Hopkins attack, oviposit, and feed in immature cones of many pine (Pinus) species. They are a serious pest of pine seed orchards and can destroy up to 100% of the cone crop. Beetles can plague orchards over many years because emerging beetles tend to attack cones of the same or a nearby tree. However, fluctuating pine cone production suggests that beetles may disperse from their natal tree stand to find second-year cones for oviposition. These dispersal behaviors may influence population level genetic diversity, that is, populations may exhibit low or high diversity. In this study, we assess the mitochondrial haplotypic diversity among 10 populations of Conophthorus representing four species. Furthermore, the haplotypic diversities are compared with published haplotypic diversities of other scolytine species to assess the influence of fluctuating food resources on Conophthorus haplotype diversity. Conophthorus haplotypic diversity ranged between 13 and 70%, which was similar to population level haplotypic diversities of other scolytines. The tendency of the emerging brood to reinfest the same tree has little influence on haplotype composition of populations and haplotype diversity is likely more influenced by beetles in search of pine cones. PMID- 17716489 TI - Effects of cultivation of genetically modified Bt maize on epigeic arthropods (Araneae; Carabidae). AB - A field study was conducted in Germany to determine the possible effects of transgenic maize cultivation on nontarget epigeic predator organisms. During the growing period of 2001-2003, the activity abundances of spiders and carabid beetles were recorded and compared in three treatments: (1) Bt-maize (Mon 810) expressing the Cry1ab protein from Bacillus thuringiensis (Berliner), (2) an isogenic variety, and (3) the isogenic variety treated with insecticide. All three treatments were replicated in eight plots. The results were evaluated using three different methods. The activity abundances of single species were statistically analyzed by confidence interval methods. In addition, the phenological behaviors of the spider and carabid beetle species were determined, and multivariate statistical evaluation of the community by principal component analysis was conducted. Significantly different activity abundances in Bt plots compared with isogenic control plots were observed both for spiders and carabid beetles during 2001. However, in 2002 and 2003, no changes in community structure were detectable in any of the treatments. The change in the first year may have been caused by the influence of a massive cornborer infestation and accompanying large changes in microclimatic factors. PMID- 17716490 TI - Development of tier-I toxicity assays for Orius insidiosus (Heteroptera: Anthocoridae) for assessing the risk of plant-incorporated protectants to nontarget heteropterans. AB - A 13-d continuous dietary exposure bioassay using nymphs of the insidious flower bug, Orius insidiosus (Say) (Heteroptera: Anthocoridae), was developed to assess the potential dietary effects of insecticidal substances that have little or no contact toxicity. The nymphs were fed a bee pollen diet treated with different concentrations of an inorganic stomach poison, potassium arsenate, and a cysteine protease inhibitor, E-64. The results showed that the test system was capable of detecting the dietary effects of both substances on the survival and development of O. insidiosus from the nymph to the adult stage in a dose-dependent manner. For the potassium arsenate treatments, approximately 25% of the nymphs survived and developed to the adult stage by 13 d of dietary exposure at 3.8 microg/g of diet, whereas no test nymphs survived to adulthood at or above 15 microg/g of diet. The assay time required for a 75% mortality response ranged from approximately 7 d at 30 microg/g of diet to 13 d at 3.8 microg/g of diet. For the E-64 treatments, no test insects survived to adulthood at any of the concentration tested (75-600 microg/g of diet) by 13 d of dietary exposure, and the assay time required for a 75% mortality response ranged from 5 to 11 d at dietary rates of 600 and 75 microg/g, respectively. The research presented here describes a robust test system that is useful for evaluating potential adverse effects (or toxicity) of plant-incorporated protectants on nontarget heteropteran predators such as O. insidiosus. PMID- 17716492 TI - A review of neonatal morbidity and mortality in Aminu Kano Teaching Hospital, northern Nigeria. AB - Neonatal morbidity and mortality still poses a serious challenge in developing countries. Low level of obstetric care, unsupervised home deliveries and late referrals lead to poor outcome even in special care baby units (SCBU). To identify the common causes of neonatal morbidity and mortality among babies admitted to the SCBU in Aminu Kano Teaching Hospital (AKTH) the case-notes of all admitted neonates from January 1998 to December 2004 were retrospectively reviewed. A total of 2963 (98.3%) babies had complete records. There were 1455 (49.1%) in-born (delivered in AKTH) and 1508 (50.9%) out-born (delivered elsewhere) babies. The sex ratio was 1.25:1 in favour of males. A total of 1868 (63.0%) were of normal birth weight, while 951 (32.1%) and 134 (4.5%) were low birth weight and macrocosmic, respectively. The leading diagnoses were birth asphyxia (27%) (severe birth asphyxia 18.1%, moderate asphyxia 8.9%), neonatal sepsis (25.3%) and prematurity (16.0%). Out of the 2963 babies, 501 (16.9%) died. The risk of dying was significantly higher (20.5%) among out-born babies compared with those delivered in AKTH (6.4%) (odds ratio = 1.71, 95% confidence interval = 1.4-2.1). In conclusion, the causes of neonatal morbidity and mortality at this centre are similar to those reported from other units. They could be prevented through effective antenatal care, supervised delivery and appropriate care and early referral of sick neonates. PMID- 17716493 TI - Evaluating the use and acceptability of a needle-remover device in India. AB - The objective of this study was to assess the effect of the use of a manually operated needle remover on sharps-waste management practices in clinical settings in India - specifically, evaluating its acceptability and performance. Thirty-one Balcan Mini-Destructor needle removers were introduced into seven health facilities in two cities in India - Delhi and Jaipur. One hundred and nineteen health workers, including auxiliary nurse midwives, nurses, and laboratory staff, used the device. Data were prospectively collected by observation and interview on device usage, malfunction and acceptability over a 23-week period. Focus group discussions on current practices were conducted prior to study initiation and, after completion, on device acceptability and performance. The manual needle remover was well accepted. Devices were seen as easy to use and durable. In total, 88,719 needles were removed. In conclusion, the needle-remover device was considered an acceptable method of preventing needle reuse and isolating infectious sharps waste in clinical settings. PMID- 17716495 TI - Esmarch tourniquet in orthopaedic surgery. AB - A bloodless field is important in many orthopaedic operations necessitating the use of a pneumatic tourniquet or Esmarch bandage. The outcome of the use of an Esmarch bandage for exsanguination and as a tourniquet in 112 consecutive patients who had elective orthopaedic operations on 131 limbs was evaluated. The setting was at Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria, from March 2003 to February 2005. The mean age of the patients was 25.7 + standard deviation years (range 1-70 years). The duration of tourniquet application ranged from 20 min to 2 h 35 min. Four limbs (3.1%) developed acute compartment syndrome; four (3.1%) had tourniquet paralysis with ulnar nerve involvement in three limbs. All limbs regained full neurological function following physiotherapy. There was wound infection in two limbs (1.5%). In spite of its drawbacks, the Esmarch bandage is still useful for exsanguination and as a tourniquet in orthopaedic surgery where there is no pneumatic tourniquet. PMID- 17716494 TI - Lymphatic filariasis in the coastal areas of Digha, West Bengal, India. AB - The state of West Bengal, India, has a long coastline with the Bay of Bengal. No information exists regarding filarial epidemiology and its vector in these coastal areas. The present study was designed to assess the epidemiology of lymphatic filariasis and the role of available mosquitoes as its vector in eight coastal villages around Digha, West Bengal. Night blood samples of 4016 individuals were collected and each of them was examined clinically for any manifestations of the disease. Overall, microfilaria rate, mean microfilarial density and disease rate were 9.06%, 8.63% and 7.72%, respectively. The causative parasite was identified as Wuchereria bancrofti and Culex quinquefasciatus was incriminated as the vector responsible. Vector infection and infectivity rates were assessed to be 12.5% and 0.73%, respectively. The human blood index of human house-frequenting vector population was 70%. Vector density, vector infection, infectivity rates and human blood index were higher in the rainy season in the study area. Overall, the filarial situation was bad and, as a measure, single dose diethylcarbamazine citrate (6 mg/kg body weight) treatment was given to all the microfilariaemic patients. Night blood samples of the treated individuals were tested for microfilariae on days 10 and 365, which revealed interesting results. PMID- 17716496 TI - Hypertension in Delhi: prevalence, awareness, treatment and control. AB - Two cross-sectional, population-based studies were conducted to assess the prevalence, awareness, treatment and control of hypertension, among people aged 20-59 years and those over 60 years in Delhi. Study 1 (20-59 years): in total,1213 subjects from 120 clusters spread across Delhi were studied. The prevalence of hypertension was 27.5%. Of the hypertensives, 53.3% were aware of their diagnosis; 42.8% were taking treatment and only 10.5% had controlled blood pressure. About 9.0% of the hypertensives had coexisting diabetes mellitus and 8.4% were suffering from coronary disease. The prevalence of hypertension was significantly higher in urban areas, but there was no significant difference in levels of awareness, treatment and control between urban and slum areas. The prevalence of hypertension was comparable in both sexes. Women, however, were more likely to be aware of their condition. Study 2 (> or =60 years): in total,1105 subjects from 110 clusters were studied. Prevalence of hypertension was 63.8%. Isolated systolic hypertension (ISH) was found in 15.3% of the subjects. About 54% of the hypertensives were aware of their diagnosis; 43.4% were taking treatment and only 8.5% had controlled blood pressure. Prevalence of hypertension and ISH were comparable among sexes. Women were more aware and better treated. About 21.3% hypertensives had coexisting diabetes mellitus, and 14.3% were suffering from coronary disease. There was no significant difference between sexes. Urban and slum areas were also found to be comparable. Over 3% of the elderly were controlling their raised blood pressure by non-pharmacological measures. They belonged to the 'aware' category yet could not be labelled as 'hypertensives', highlighting an operational fault in the Joint National Committee definition. PMID- 17716497 TI - Raising parents' awareness of the benefits of immunization by using a visual aid tool. AB - A visual aid tool was used in two communities of Chad to raise parents' awareness of the benefits of immunization. In one community, the tool was administered by social workers two weeks before national immunization days (NIDs) and in the other community by vaccinators during NIDs. Parents' awareness significantly rose in both communities but was more significant in the community where the tool was administered by social workers. A significant association was found between parents' unawareness and children who missed immunization in both communities. PMID- 17716498 TI - 'Superglue': a novel approach in the management of faecal fistulae. PMID- 17716499 TI - Echocardiographic, chest X-ray and electrocardiogram findings in children presenting with heart failure to a Ugandan paediatric ward. AB - The aim of this study was to describe the aetiology of congestive cardiac failure (CCF) in children with suspected structural abnormalities presenting to a regional hospital in southwestern Uganda. The method used was a prospective descriptive study of successive admissions of children with persistent cardiac signs after routine treatment of CCF. Children with severe anaemia (haemoglobin [Hb]<7 g/dL), pneumonia, sepsis or severe malnutrition were excluded. Chest X ray, electrocardiogram and echocardiography data were validated by a paediatric cardiologist and radiologist at the Bristol Royal Hospital for Children, UK. A cohort of 58 patients was identified. The aetiology of heart failure in this cohort (n = 58) was due to congenital heart disease (35%), renal hypertensive disease (26%), rheumatic heart disease (17%), cardiomyopathies (12%), endomyocardial fibrosis (7%) and tamponade (3%). In conclusion, this study confirmed the ongoing prevalence of congenital heart disease, rheumatic heart disease and endomyocardial fibrosis in this area. The cardiac effect of renal hypertension was a new and significant finding. PMID- 17716500 TI - Impact of HIV-1infection on survival in patients with haematological malignancies in Yaoundee, Cameroon. AB - The impact of HIV-1 infection on the survival of patients with haematological cancers in Yaoundee, Cameroon, was examined. The prevalence of HIV-1 was 26.2% among 172 patients, predominantly lymphoid malignancies. At the time of analysis, 75% of patients had died giving an incidence rate of 0.05 deaths per year and a median of survival of 15 (6-27) months. However, the hazard ratio for HIV infected patients to die was not statistically different from that of uninfected patients (1.3, 95% confidence interval: 0.9-2.0). PMID- 17716501 TI - Burden of diabetic illness in an urban hospital in Nigeria. AB - This is a retrospective study that set out to determine the mortality patterns and case fatality rates of people with diabetes mellitus (DM) in a Nigerian hospital. The sources of data were the medical records, ward admissions, deaths register and death certificates. Of a total of 13,797 medical admissions made over a period of 11 years (1990-2000),1423 (10.3%) were DM related and the documented case fatality rate of DM was 22.6%. PMID- 17716502 TI - Amodiaquine in future combination treatment of malaria in Ghana. AB - A total of 198 patients were treated with amodiaquine for uncomplicated malaria. Parasite clearance at day 14 was 85.4 and 48% at day 28. PMID- 17716504 TI - Diagnostic accuracy of the haemoglobin colour scale in neonates and young infants in resource-poor countries. AB - Due to the insidious nature of infant anaemia, this disorder frequently remains undetected and untreated by health-care workers in resource-poor settings. We assessed the accuracy of a low-cost and simple diagnostic tool, the haemoglobin colour scale (HCS), in estimating haemoglobin (Hb) values in infants between zero and four months of age. In a rural hospital in Zambia, blood samples were analysed for Hb concentration by HCS and HemoCue method. Bland-Altman plots were used to express agreement between the two methods. The mean difference between HCS and HemoCue at birth (n = 94), two months (n = 87) and four months (n = 69) was 0.39, 0.20 and -0.11 g/dL, respectively. Limits of agreement were -2.39 to 1.51, -1.80 to 2.20 and -1.98 to 1.75 g/dL, respectively. Disagreement with HemoCue measurements of more than 2 g/dL was noted in only 4% of all blood samples. We conclude that the HCS provides Hb estimations in infants aged 0-4 months that are sufficiently accurate to improve timely recognition of anaemia in settings where there is no laboratory. PMID- 17716503 TI - Proteinuria and onchocerciasis in an endemic area in Cameroon under community based treatment with ivermectin. AB - The present study was aimed at determining the prevalence of onchocerciasis and proteinuria as well as the association between manifestations of heavy chronic onchocerciasis (HCO) and proteinuria among patients in Cameroon. Of the 482 (277: 57.5% females and 205: 42.5% males) subjects recruited from an area with an ivermectin treatment coverage rate of 77.8%, the average prevalence of microfilaridermia by skin snip (mf/ss) was 31.9%, the community microfilaria load was 9.3 mf/ss and the overall prevalence of proteinuria was 4.4%. There was no statistically significant difference in the prevalence of symptoms of HCO when subjects were matched in the presence and absence of proteinuria with regard to positive ss (P = 0.0860), presence of nodules (P = 0.5000), depigmentation (P = 0.1459), visual impairment (P = 0.5000) and recent ingestion of ivermectin (P = 0.6366). Fourteen (66.6%) of the 21 subjects with protein to creatinine ratios (P/CR) > or = 0.2 had HCO, while 15 (71.4%) of the 21 subjects with P/CR < 0.2 had HCO. This gives an odd ratio of 0.8 and a P value of 0.62. However, there is need to carry out studies with a larger sample size before firm conclusions can be drawn about the association between onchocerciasis and proteinuria. PMID- 17716505 TI - Mortality due to dapsone hypersensitivity syndrome complicating multi-drug therapy for leprosy in Nepal. AB - Dapsone is a component of multi-drug therapy (MDT) for the treatment of all types of leprosy. It is known that dapsone hypersensitivity syndrome (DHS) complicates the treatment in a proportion of patients. We performed a retrospective study of patients commenced on MDT between 1990 and 2006; 2% developed DHS and 0.25% died due to DHS. PMID- 17716506 TI - Intestinal parasites and the growth status of internally displaced children in Sri Lanka. AB - The growth status and intestinal parasitic infections among a group of children displaced by war in Sri Lanka was investigated. There was a high prevalence of growth retardation (wasting, stunting and underweight being 41%, 28% and 69.9%, respectively) and intestinal parasitic infections (40.2%) among the study population. Provision of adequate food, purified drinking water, sanitation and broad-spectrum anthelmintics is recommended. PMID- 17716507 TI - Neonatal tetanus at the close of the 20th century in Nigeria. AB - The year 2000 marked another failed World Health Organization deadline for neonatal tetanus (NNT) eradication. Existing preventive strategies can be enhanced by exploring factors involved in the persistence of the scourge. Thus, records of neonates admitted between 1996 and 2000 into the Wesley Guild Hospital, Ilesa, were analysed. Of 3051 total neonatal admissions,162 (5.3%) had NNT. Eighty-nine (54.9%) mothers had clinic-based antenatal care (ANC), but only 59 (36.4%) had tetanus toxoid (TT) vaccines. The majority (66.7%) of them delivered at home or churches and others at either private clinics or primary health centres. Overall, the case fatality rate was 43.8%, though it was significantly higher among babies whose mothers had neither clinic-based ANC (odds ratio [OR] = 2.62; 95% confidence interval [CI] = 1.33-5.18) nor antenatal TT vaccination (OR = 2.41; 95% CI = 1.17-5.03). Thus, improvement on ANC, anti tetanus immunization and ensuring hygienic deliveries are crucial for eliminating NNT in the 21st century. PMID- 17716508 TI - Assessment of nutritional status of HIV-infected patients at a tertiary centre in North India. AB - Infection with HIV has an adverse effect on nutritional status, and can result in progressive involuntary weight loss. We assessed the nutritional status of our patients with HIV infection and found that HIV-infected patients had significantly low nutrient intake and body mass index as compared with controls. Involuntary weight loss, altered body composition and reduced nutritional status were present throughout the stages of HIV infection. PMID- 17716509 TI - A 12-year review of cases of adult tetanus managed at the University College Hospital, Ibadan, Nigeria. AB - In this review, hospital case records of 202 adult tetanus managed between January 1990 and December 2001 in a tertiary institution in Southwestern Nigeria were reviewed. The mean age of the patients was 36.1+/-17.8 years with male:female ratio of 2.2:1 and an overall mortality rate of 64%. Patients with unfavourable outcomes spent 4.5+/-0.41 days compared with 16.6+/-1.2 days by those who survived. Factors associated with poor prognosis are age >60 years (P=0.029), incubation period <7 days (P=0.007), period of onset <48 h (P=0.0001), tachycardia with pulse rate >120/min (P=0.001) and spasm (P=0.002). Gender (P=0.11), post-injury vaccination (P=0.48) and types of antibiotics administered (P=0.49) were not significantly associated with increased mortality. The three most common complications were aspiration pneumonitis, sepsis and urinary bladder obstruction while complications with highest mortality (100%) were sepsis and cardiac arrest. PMID- 17716510 TI - An unusual presentation of post-kala-azar dermal leishmaniasis. AB - An atypical presentation of post-kala-azar dermal leishmaniasis is reported to highlight the importance of suspecting dermatosis in patients from areas endemic for kala-azar. PMID- 17716511 TI - A series of 32 prostatectomies in the Democratic Republic of Congo. AB - Abdominal prostatectomy is viewed with some trepidation in Africa due to the possible postoperative complications. A plea is made in this paper to remove the prostate under direct vision by a retropubic route rather than by attempting a blind suprapubic (transvesical) procedure. A series of 32 retropubic prostatectomies is reviewed. PMID- 17716513 TI - Breast tuberculosis mimicking other diseases. AB - Breast tuberculosis can confuse the clinician by its close resemblance to carcinoma or non-specific abscess, with obvious negative therapeutical implications. We present two cases, one mimicking a breast malignancy and the other being confused with non-specific abscess, to illustrate the misdiagnosis risks and diagnostic challenges. PMID- 17716512 TI - Prevalence of filariasis in symptomatic patients in Moyen Chari district, south of Chad. AB - Filarial parasites infect an estimated 140 million people worldwide. Wuchereria bancrofti, Onchocerca volvulus, Loa loa and Mansonella perstans are responsible for most filarial infections in sub-Saharan Africa. We describe the prevalence and the clinical characteristics of filariasis in symptomatic patients in Goundi Sanitary district:167 patients were enrolled (99 men, 68 women). M. perstans microfilariae were isolated in peripheral blood in 164 cases, while Loa loa and Wuchereria bancrofti filariasis were diagnosed in only six and three cases, respectively. The most frequent filariasis observed in our study were due to M. perstans and L. loa, while the few cases of W. bancrofti filariasis seem to have been acquired abroad. No cases of O. volvulus were observed. Microfilarial burden was not related to symptoms, but a correlation between eosinophilia and pruritus was evident. No relationship was observed between eosinophils and symptoms. The prevalence observed in symptomatic patients could reflect the real prevalence of filariasis. PMID- 17716514 TI - Endoscopic variceal sclerotherapy in patients with Symmers periportal fibroses. AB - This is a prospective study, carried out in patients with portal hypertension and bleeding oesophageal varices secondary to Symmers (Schistosomal) periportal fibroses, to determine the efficacy of sclerotherapy, the number of sessions needed to achieve full sclerosis, the complications associated with sclerotherapy and the incidence and risk factors for rebleeding. In total, 85 patients were studied with a mean age of 38 years, 76.5% were males. All underwent upper gastrointestinal endoscopy, had different grades of oesophageal varices and underwent intravariceal injection with 5% ethanolamine oleate until they achieved full sclerosis or were referred to surgery. Complications of sclerotherapy included oesophageal strictures, deep oesophageal ulcers, pleural effusion and ascites. Following obliteration of oesophageal varices, 3.5% and 20% developed new gastric varices and portal gastropathy, respectively. Rebleeding occurred in 32% - the only significant predictive risk factor for which was patients with GIII varices following the first sclerotherapy session. Varices recurred in 6% of patients after a mean follow-up period of one year. In total, 93% of our patients achieved full sclerosis after an average of four sessions, and 3.5% were referred for surgery. Three patients (3.5%) died, all from massive rebleeding. In conclusion, sclerotherapy is a safe effective method for treating patients with oesophageal varices due to periportal fibroses. PMID- 17716515 TI - Drug susceptibility pattern of Mycobacterium tuberculosis in adult patients with miliary tuberculosis. AB - Miliary tuberculosis (TB) is a fatal form of TB. Although drug resistance in TB patients has increased worldwide, there is limited information on drug resistance in miliary TB. This study from Pakistan evaluated drug susceptibility pattern among miliary TB patients of a high TB-burden country. All adult patients with miliary TB, admitted between 1994 and 2001, were identified using a computerized database. Culture-positive isolates were evaluated for drug susceptibility using middle brook 7H10 agar according to National Committee for Clinical Laboratories Standard criteria. Of 110 patients diagnosed with miliary TB, 32 (30%) were culture positive (yielding 35 culture isolates). The sources of positive cultures were sputum (37%), cerebrospinal fluid (18%), lymph nodes (12%), bone marrow (9%), bronchial wash (9%), urine (6%), lungs (6%) and liver (3%). Isoniazid resistance was found in three (9%) isolates. All the isolates were sensitive to rifampicin, ethambutol, pyrazinamide and streptomycin. Despite a worldwide increase in TB drug resistance, patients with miliary TB have infection with drug sensitive mycobacterium. First-line anti-TB drugs should be used as initial therapy in miliary TB patients. PMID- 17716516 TI - Ethnic variations in health-seeking behaviours and attitudes between Fulani herders and Oruba farmers in southwestern Nigeria. AB - Rural Yoruba and Fulani residents of two local governments in Oyo State, Nigeria, were surveyed to determine differences in health-seeking behaviour. Fulani residents were more likely to use private facilities during a recent illness, while Yoruba residents more commonly used government facilities: a fact reflected in the overall attitudes of those surveyed. The need for greater outreach and involvement of minority populations is recommended to enhance public service utilization. PMID- 17716517 TI - Overdiagnosis of malaria in hospitalized patients in Namibia. PMID- 17716518 TI - Stroke mortality in a teaching hospital in South Western Nigeria. AB - Stroke, a major cause of morbidity and mortality, is on the increase and with increasing mortality. Our retrospective review of all stroke admissions from 1990 2000 show that cerebrovascular disease accounted for 3.6% (293/8144) of all medical admissions; it has a case fatality rate of 45% with the majority (61%) occurring in the first week; the mean age of stroke deaths was 62 years (standard deviation+/-13); and severe as well as uncontrolled hypertension is the most important risk factor. Community-based programmes aimed at early detection and treatment of hypertension, in addition to screening for those with high risk factors, should be put in place. PMID- 17716519 TI - Outbreak of Coxsackie B4 arthritis among newborns and staff of a neonatal unit. AB - We investigated an outbreak of Coxsackie B4 arthritis in a neonatal unit involving 20 neonates and 12 staff members, over an eight-month period. Laboratory investigations, serology tests, indicate that the outbreak was caused by Coxsackie B4 virus. Contamination of one of the overhead water reservoirs, supplying the nursery, was responsible. After the water tanks were cleaned out, no new cases were reported over five years. PMID- 17716520 TI - Penetrating abdominal injuries in a developing country. PMID- 17716522 TI - The popularity of insecticide-treated bed-nets as a preventative method of malaria control among residents of Calabar Municipality, Cross River State, Nigeria. AB - The popularity of insecticide-treated bednets (ITNs) was assessed among 612 residents of Calabar Municipality between June and September 2004. A questionnaire was administered to the respondents, majority of whom (88.9% [544:612]) claimed that they were aware of the use of ITNs for preventing mosquito bites. Only 13.2% of the respondents (72:544) owned ITNs at the time of filling the questionnaire. PMID- 17716521 TI - The partograph: a life-saving tool for African midwives. PMID- 17716524 TI - Malaria and dengue infection after Tsunami in Southern Thailand. PMID- 17716523 TI - Children's surgery cancelled due to malaria and anaemia. AB - At our hospital 461 children were admitted for elective orthopaedic and reconstructivesurgery between January and December 2003; 90 of these (19.5%) were positive for malaria, and 37 (8%) had haemoglobin levels below 8 g/dL. The mean delay between admission and operation was five days for patients without anaemia or malaria, 7.17 days for patients with malaria,11.05 days for patients with anaemia and 13 days for patients with both anaemia and malaria. PMID- 17716525 TI - Binocular interaction: contrast matching and contrast discrimination are predicted by the same model. AB - How do signals from the 2 eyes combine and interact? Our recent work has challenged earlier schemes in which monocular contrast signals are subject to square-law transduction followed by summation across eyes and binocular gain control. Much more successful was a new 'two-stage' model in which the initial transducer was almost linear and contrast gain control occurred both pre- and post-binocular summation. Here we extend that work by: (i) exploring the two dimensional stimulus space (defined by left- and right-eye contrasts) more thoroughly, and (ii) performing contrast discrimination and contrast matching tasks for the same stimuli. Twenty-five base-stimuli made from 1 c/deg patches of horizontal grating, were defined by the factorial combination of 5 contrasts for the left eye (0.3-32%) with five contrasts for the right eye (0.3-32%). Other than in contrast, the gratings in the two eyes were identical. In a 2IFC discrimination task, the base-stimuli were masks (pedestals), where the contrast increment was presented to one eye only. In a matching task, the base-stimuli were standards to which observers matched the contrast of either a monocular or binocular test grating. In the model, discrimination depends on the local gradient of the observer's internal contrast-response function, while matching equates the magnitude (rather than gradient) of response to the test and standard. With all model parameters fixed by previous work, the two-stage model successfully predicted both the discrimination and the matching data and was much more successful than linear or quadratic binocular summation models. These results show that performance measures and perception (contrast discrimination and contrast matching) can be understood in the same theoretical framework for binocular contrast vision. PMID- 17716526 TI - Modelling the spatial tuning of the Hermann grid illusion. AB - PURPOSE: Does a physiologically plausible model of the retinal ganglion cell (RGC) receptive field (RF) predict the spatial tuning properties of the Hermann Grid Illusion (HGI)? METHODS: The spatial tuning of a single intersection HGI was measured psychophysically in normal observers using a nulling technique at different vertical grid line luminances. We used a model based upon a standard RGC RF, balanced to produce zero response under uniform illumination, to predict the response of the model cell to the equivalent range of stimulus conditions when placed in either the 'street' or the 'intersection' of a single element of a Hermann grid. We determined the equivalent of the nulling luminance required to balance these responses and minimise the HGI. RESULTS: The model and the psychophysical data demonstrated broad spatial tuning with similarly shaped tuning profiles and similar strengths of illusion. The line width at the peak of the model tuning function was around twice the model RGC RF centre size. Modelling the psychophysical functions gave RF centre sizes smaller than expected from human anatomical evidence but similar to that suggested by primate physiological evidence. In the model and psychophysically the strength of the illusion varied with the luminance of the vertical grid line when HGI strength was expressed as a Michelson nulling contrast, but this effect was smaller when HGI strength was expressed as a nulling luminance. CONCLUSIONS: The shape, width, height and position of the spatial tuning function of the HGI can be well modelled by a RGC RF based model. The broad tuning of these functions does not appear to require a broad range of different cell sizes either in the retina or later in the visual pathway. PMID- 17716527 TI - Assessment of fused videos using scanpaths: a comparison of data analysis methods. AB - The increased interest in image fusion (combining images of two or more modalities such as infrared and visible light radiation) has led to a need for accurate and reliable image assessment methods. Previous work has often relied upon subjective quality ratings combined with some form of computational metric analysis. However, we have shown in previous work that such methods do not correlate well with how people perform in actual tasks utilising fused images. The current study presents the novel use of an eye-tracking paradigm to record how accurately participants could track an individual in various fused video displays. Participants were asked to track a man in camouflage outfit in various input videos (visible and infrared originals, a fused average of the inputs; and two different wavelet-based fused videos) whilst also carrying out a secondary button-press task. The results were analysed in two ways, once calculating accuracy across the whole video, and by dividing the video into three time sections based on video content. Although the pattern of results depends on the analysis, the accuracy for the inputs was generally found to be significantly worse than that for the fused displays. In conclusion, both approaches have good potential as new fused video assessment methods, depending on what task is carried out. PMID- 17716528 TI - Complex backgrounds delay low-load visual search. AB - Past research has shown, separately, that endogenous location cues and high perceptual load search tasks increase the specificity of attentional deployment to task-relevant regions of the visual field, while complex task-irrelevant backgrounds greatly resembling task-relevant stimuli reduce it. Here, we investigated in the same study whether the perceptual load created by an endogenously cued set of task-relevant stimuli determines whether a surrounding complex background of similar task-irrelevant stimuli would interfere with search. Our results show that high perceptual load protects against interference from a complex background of similar but task-irrelevant stimuli, situated just beyond the boundaries of the task-relevant set. Furthermore, our findings demonstrate that search characteristics do not change when the relevant set is restricted attentionally to a smaller delineated area, even in the presence of a background. Finally, we found that the efficacy of endogenous location cueing is not dependent on the type of search task that occurs in the cued area. Our findings also reveal that alternative attention-directing strategies, such as guided search and signal detection, may be employed in such tasks in the absence of endogenous location cueing. PMID- 17716529 TI - Stereoscopic acuity, observation distance and fixation disparity: a commentary on 'Stereoscopic acuity and observation distance' by Bradshaw and Glennerster (2006). PMID- 17716534 TI - Lung hyperinflation, perception of bronchoconstriction and airway hyperresponsiveness. AB - PURPOSE: To compare the influence of underlying airway inflammation and lung hyperinflation on dyspnea during induced bronchoconstriction in subjects with mild asthma (or asymptomatic airway hyperresponsiveness (AAHR). METHODS: Fourteen mild asthmatic and 14 AAHR subjects had methacholine and 5'-adenosine monophosphate (AMP) challenges, and induced sputum analysis. Changes in inspiratory capacity (IC) and respiratory symptom scores were measured after challenges. Perception of respiratory symptoms was recorded on a modified Borg scale. RESULTS: The mean baseline FEV1, IC, mean provocative concentration of methacholine inducing a 20% decrease in FEV1 (PC20), the mean PC20 AMP and median inflammatory cell counts were similar in both groups. After methacholine, mean (+/-SD) reductions in FEV1 were 24.7+/-10.3% in mild asthma and 35.6+/-19.1% in AAHR (P>0.05); reductions in IC were, respectively, 10+/-12% and 24+/-20% (P>0.05); mean breathlessness scores at PC20 were 1.1 in mild asthma and 0 in AAHR P=0.003), and mean chest tightness scores were 1.2 in mild asthma and 0.8 in AAHR (P>0.05). Maximum chest tightness scores following MC correlated with the maximum decrease in IC in mild asthma (rs=0.75,P=0.009) and with the maximum decrease in FEV1 in AAHR (rs=0.60,P=0.04). After AMP, symptom scores were not significantly correlated with decreases in FEV1 or IC. The number of inflammatory cells was not correlated with decreases in IC after methacholine, AMP or with their PC20s, although inflammation was minimal in both groups. CONCLUSION: Lower breathlessness scores in AAHR compared to mild asthma were not explained by differences in lung hyperinflation nor in airway inflammation. PMID- 17716535 TI - Biochemical measurement of muscle injury created by lumbar surgery. AB - PURPOSES: 1. To determine whether lumbar disc surgery (LS) provides a sufficiently detectable rise in serum creatine kinase (CK) concentration to serve as a model to study biochemical measurement of muscle injury, and 2. To use the model to examine the consistency of the time course of CK concentration changes. METHOD: The study used a repeated measures design. Six women and six men scheduled for LS were recruited. Blood samples were taken in the pre-operative waiting areas, immediately after surgery, at 6 hour intervals until discharge, and at 2, 4, and 6 to 7 days following surgery. Total serum CK was quantified using the Roche Modular to detect enzyme concentration. RESULTS: Following LS, mean Total CK increased from a baseline 50 U/L (SD = 53) to a peak 114 U/L (SD = 32) in women (P < 0.001) and from 183 U/L (SD = 69) to a peak 454 U/L (SD = 173) in men (P < 0.05). Baseline to peak changes in CK exceeded subjects' own baseline fluctuations in all 6 women and all 6 men, and amounted to a mean 6 fold (SD = 4) increase in women and 16 fold (SD = 31) increase in men. While CK concentrations returned to baseline over the observation period in all subjects, time to peak ranged between 9 to 47 hours. CONCLUSIONS: The LS model produced a consistently detectable CK response in both genders. Time to peak is variable indicating a need for multiple serial measures to capture this biochemical injury response. PMID- 17716536 TI - Homocysteine (Hcy) follow-up study. AB - BACKGROUND: Hyperhomocysteinemia confers an increased risk of coronary artery disease, stroke, and deep vein thrombosis, and is a strong predictor of mortality among patients with ischemic heart disease. PURPOSE: To determine the long term clinical outcome of patients with risk factors to atherosclerosis with high concentrations of homocysteine (Hcy). METHODS: 89 patients with one or more risk factors for atherosclerosis, whose plasma total Hcy concentrations were measured, were followed for 5 years. Patients were interviewed and underwent a clinical examination in the outpatient clinic. Their medical records were reviewed in the last 5 years including smoking habits, medications, other diseases (hypertension, diabetes mellitus, hyperlipidemia) and their management. SPSS was used to describe and explore possible relationships between Hcy concentration, other diseases, medications and the clinical long term outcome. RESULTS: All men with normal Hcy concentrations (10.76+/-1.71 micromol/L) survived during the 5 years' follow up, while 5 of the men with high Hcy concentrations (21.27+/-5.37 micromol/L), died (17%) (P< 0.05). In women Hcy concentration did not affect survival. No association was found between diabetes mellitus, hypercholesterolemia, hypertension and Hcy. Long term treatment with Beta Blockers, ACE inhibitors, Calcium Channel blockers, and especially with Aspirin prevented death and changed the natural history of patients with high Hcy concentrations (P < 0.05). CONCLUSIONS: Hyperhomocysteinemia may have an effect on survival in men. Long term treatment with Beta Blockers, ACE inhibitors, Calcium Channel Blockers, and especially with Aspirin--prevented death and changed the natural history of patients with high Hcy concentrations. PMID- 17716537 TI - Characteristics and conviction rates of injured alcohol-impaired drivers admitted to a tertiary care Canadian Trauma Centre. AB - PURPOSE: Alcohol intoxication is an important factor in motor vehicle crash (MVC) related morbidity and mortality. Despite greater societal attention, medical admission after MVC results in avoidance of legal consequences. We sought to determine characteristics of, and consequences to, injured alcohol-impaired drivers (IAIDs). METHODS: All injured adults [Injury Severity Score (ISS) >12, age>18] entered in a Trauma Centre registry between April 1 1995 to March 31 2003 were reviewed. Legally intoxicated patients who had been drivers involved in a MVC and who had a blood alcohol content (BAC) > or =80 mg/dl were cross referenced to municipal and federal databases to identify investigations, charges, and legal outcomes. RESULTS: Of BACs obtained from 1933 (41%) of 4727 patients; 39% (757) were legally intoxicated (BAC > or =80 mg/dl); 185 (24%) were IAIDs. The IAIDs were generally very intoxicated (mean BAC 190 mg/dl); seriously injured (median ISS 22); often in ICU (47%), and had 8% mortality. Charges were laid against 69 (37%) of IAIDs, only 58 (31%) suffered legal consequences; 27 (15%) of impaired driving, and 31 (17%) of other convictions. All IAIDs who caused a fatal injury to another were convicted. A lower severity of injury of the IAIDs, non-fatal injury to another, and occurrence in the more recent years of the study were independently associated with a conviction in multivariable analysis. CONCLUSION: Despite increasing convictions over time and among most of those charged, the majority of injured drivers escape legal consequences. Increased BAC testing and reporting of this phenomenon could address this. PMID- 17716538 TI - The CAGE questionnaire for alcohol misuse: a review of reliability and validity studies. AB - PURPOSE: To review the reliability and validity of the CAGE questionnaire across different patient populations and discuss its role in the detection of alcohol related problems. METHODS: The Cochrane Database for Systematic Reviews, Medline, Embase, and Psychinfo were searched. No systematic reviews were found on the Cochrane Database. Search of the other databases yielded one systematic review and one meta-analysis, on different aspects of CAGE. Three articles on reliability and 16 on validity of CAGE were found and used. Studies generally yielded Level II evidence. RESULTS: CAGE has demonstrated high test-retest reliability (0.80-0.95), and adequate correlations (0.48-0.70) with other screening instruments. The questionnaire is a valid tool for detecting alcohol abuse and dependence in medical and surgical inpatients, ambulatory medical patients, and psychiatric inpatients (average sensitivity 0.71, specificity 0.90). Its performance in primary care patients has been varied, while it has not performed well in white women, prenatal women, and college students. Furthermore, it is not an appropriate screening test for less severe forms of drinking. CONCLUSIONS: CAGE is short, feasible to use, and easily applied in clinical practice. However, users should be aware of its limitations when interpreting the results. A positive screen should be followed by a proper diagnostic evaluation using standard clinical criteria. PMID- 17716539 TI - Impact of physician income source on productivity. AB - Based on data from the 2004 National Physician Survey, physicians whose primary payment method was fee-for-service saw more patients per week than physicians remunerated by other methods, including salary or blended payments. This result did not change when examined according to specialty or specialty grouping (Table 1), physician age (Table 2) Family physicians versus specialists, type of practice (office-based versus hospital-based; data not shown), or practice setting (urban versus rural; data not shown). Overall, fee-for-service (FFS) physicians saw approximately twice the number of patients per week as salaried physicians. These data provide convincing evidence that FFS physicians see substantially more patients. PMID- 17716540 TI - The relationship between stress and hair cortisol in healthy pregnant women. AB - PURPOSE: Stress has been shown to cause a large range of adverse fetal effects. This pilot study is the first attempt to examine cortisol level in the hair of pregnant women and assess its potential as a biomarker of gestational stress. PATIENTS AND METHODS: Twenty-five healthy pregnant women, in whom hair cortisol levels and the Perceived Stress Scale (PSS) were measured and correlated. RESULTS: Maternal hair cortisol levels, ranging between 0.06 and 0.23 nmol/g of hair correlated positively and significantly with measures of perceived stress (ranging between 2-22); (Rs=0.47) (P < 0.05). CONCLUSIONS: Our findings corroborate recent primate studies with induced stress, and suggest that hair cortisol is a potential biomarker of chronic stress in pregnancy. This new long term biological marker may have important implications in research and clinical practice. PMID- 17716541 TI - Human newborn polymorphonuclear neutrophils exhibit decreased levels of MyD88 and attenuated p38 phosphorylation in response to lipopolysaccharide. AB - PURPOSE: Human newborn infants have increased susceptibility to gram-negative bacterial infection. Since lipopolysaccharide (LPS) primes polymorphonuclear neutrophils (PMN) to enhance host defense functions, we investigated its effect on adult and newborn PMN in vitro. METHODS: PMN were isolated from blood of healthy adults and umbilical cords of full term newborns using dextran and Ficoll Paque gradient sedimentation. Gel electrophoresis and Western blotting of membranes were used to probe for Mitogen-Activated Protein (MAP) kinase p38 phosphorylation, Toll-like Receptor-4 (TLR-4) and Myeloid Differentiation Factor 88 (MyD88) on isolated PMN membranes using specific antibodies. LPS induced degranulation was assessed using CD66 expression on PMN measured by flow cytometry. RESULTS: We show that p38 phosphorylation in newborn PMN is attenuated in response to LPS stimulation even though adult and newborn PMN have similar amounts of p38 protein. The degree of attenuation in newborn PMN is dependent on the osmolarity of the medium. In addition, LPS-induced degranulation, a process that is p38 dependent, was also absent in newborn PMN. Although the LPS receptor TLR-4 is present at similar levels on newborn and adult PMN, its downstream adaptor protein MyD88 was significantly diminished in newborn PMN compared to adult cells. CONCLUSIONS: Although the mechanism of PMN priming by LPS is not fully understood, our results suggest that MyD88 and p38 phosphorylation are important pathways in the process and contribute to attenuated response of newborn PMN to LPS in vitro. PMID- 17716542 TI - Comprehensive rehabilitation in chronic heart failure--better psycho-emotional status related to quality of life, brain natriuretic peptide concentrations, and clinical severity of disease. AB - PURPOSE: To evaluate the effects of a comprehensive outpatient rehabilitation program in chronic heart failure (CHF) on quality of life (QoL) in relation to emotional status and clinical severity of disease. PATIENTS AND METHODS: 25 patients with CHF were included in the 12-week comprehensive rehabilitation program. Initially, and at the end of the program, patients underwent graded cardio-pulmonary exercise testing, echocardiography, and determination of brain natriuretic peptide (BNP) concentration. In addition, they were assessed using: The Minnesota Living with Health Failure Questionnaire [MLHFQ]) for disease Specific QoL, the Hospital Anxiety and Depression Scale [HADS], and the State Trait Anger Expression Inventory [STAXI]). RESULTS: After 12 weeks of rehabilitation improvements in NYHA class, left ventricular ejection fraction (LVEF), and peak oxygen consumption were found, while mean BNP concentrations did not change. Disease specific QoL demonstrated improvements in physical component and the total score. Relative improvement of psycho-emotional scores correlated positively with relative improvement of disease specific QoL. In patients with LVEF > or =30% at baseline, changes in BNP concentration were positively associated with both anxiety and state anger, and with the emotional component score of MLHFQ. CONCLUSION: Improvements in disease-specific QoL were closely associated to improvements of psycho-emotional status and clinical severity of CHF. PMID- 17716544 TI - Tomato-rich (Mediterranean) diet does not modify inflammatory markers. AB - BACKGROUND: The Mediterranean diet is rich in lycopene and has been reported to reduce cardiovascular events. The mechanism of prevention of cardiovascular events has not been clearly established. Our aim was to study the effects of a tomatoes-rich diet on markers of vascular inflammation. METHODS: Plasma concentrations of E-selectin, intercellular adhesion molecule 1 (ICAM-1), and high sensitivity C-reactive protein (hs-CRP) were determined by ELISA in 103 apparently healthy volunteers. Volunteers were randomly assigned to two groups: 50 participants ate 300 g tomatoes daily for 1 month, and 53 participants ate their usual diet with tomatoes prohibited during that period. Markers of inflammation were measured before enrollment and 1 month after their assigned diet. RESULTS: The two diet groups had similar baseline clinical characteristics and similar baseline levels of inflammatory markers. After 30 days of assigned diet concentrations of hs-CRP, E-selectin and ICAM-1 were unchanged compared with baseline in the tomato-rich diet. However, ICAM-1 concentration was increased in the regular diet group from 247.55+/-55 ng/ml to 264.71+/-60.42 ng/ml (P=0.01). CONCLUSIONS: The mechanisms of benefit of the tomato-rich diet are not directly related to inhibition of markers of vascular inflammation. PMID- 17716543 TI - Exploring patient demographic and clinical characteristics associated with lipid lowering pharmacotherapy use in primary care. AB - BACKGROUND: Lipid-lowering therapeutics, particularly HMG Co-A reductase inhibitors, can be beneficial in primary and secondary cardiovascular prevention. The Canadian population frequently uses these medications but the manner in which they are used in community-based practice is unknown. OBJECTIVES: To assess the patient characteristics associated with lipid lowering drug use in community based clinical practice across four geographic regions in Canada. To assess amongst lipid-lowering drugs users the proportion of patients that would meet accepted dyslipidemia management guidelines. To assess the community-based effectiveness of anti-hyperlipidemic drugs. METHODS: Patients filling a prescription for any anti-hyperlipidemia therapy in selected pharmacies in Ontario (ON), Quebec (PQ), British Columbia (BC) and Nova Scotia (NS). All eligible patients were interviewed over the telephone. Physicians who were providing healthcare to the participating patients were requested to provide information from the patient's medical record. RESULTS: The mean patient age was > 60 yr in all four provinces. There were some differences amongst the four provinces pertaining to patient characteristics, prescription patterns and therapeutic indicators, but not to outcomes. Anti-hyperlipidemia therapy was associated with a 1.81 mmol/L decrease in LDL-Cholesterol (P < 0.001); however only 73% of patients achieved target LDL-Cholesterol concentrations. A lag time of 1.96 yr (P < 0.0001) was observed from the diagnosis of dyslipidemia until the drug treatment was initiated. Patients had an average of 2.8 cardiovascular (CV) risk factors and 86% of patients had at two or more CV risk factors. Thirty-nine percent (95% CI, 36% - 42%) of the patients were being treated for secondary prevention. Thirteen percent (11-16%) of patients who were being treated for primary prevention had diabetes. Metabolic syndrome was observed in 32% (29-35%) of patients. CONCLUSION: Almost all patients fulfilled guideline requirements for the use of anti-hyperlipidemic therapy. Although the use of pharmacotherapy was associated with a lowering of LDL cholesterol more aggressive management is required to attain target LDL cholesterol concentrations. PMID- 17716545 TI - Serial procalcitonin responses in infection of children with secondary immunodeficiency. AB - PURPOSE: Procalcitonin has proven to be a sensitive inflammatory marker in non neutropenic patients. The aim of this study was to determine and compare Procalcitonin with other inflammatory markers in the serum of immunosuppressed children with haematological malignancies; and to assess the predictive value of these mediators in distinguishing between bacterial and non-bacterial infection. METHODS & RESULTS: The study included 37 children with acute lymphoblastic leukaemia undergoing intensive chemotherapy. They were divided into 3 groups, A, B and C. Group A consisted of 29 neutropenic children with 94 febrile episodes, group B of 20 neutropenic children with 56 afebrile episodes and group C of 13 non-neutropenic children with 58 afebrile episodes. Serial serum levels of PCT, C Reactive Protein, Neopterin, Interleukin-6 and NO2/NO3 were all determined on a day-to-day basis for 7 consecutive days. In serum the concentrations of CRP was determined by nephelometry, of PCT by immunoluminescence and of Neopterin, IL-6 and NO2/NO3 by ELISA method. CONCLUSIONS: According to our results the Procalcitonin concentration increased rapidly in patients with microbial infection; the response was detectable within 24 hs of the onset of fever due to microbial infections. Procalcitonin is a specific and sensitive marker of microbial infection in patients with neutropenic fever. The markers, C-Reactive Protein, Interleukin-6 and NO2/NO3 may not help to identify infections and distinguish the etiology of infection in neutropenic febrile children with acute lymphoblastic leukaemia. PMID- 17716546 TI - Lack of association polymorphisms of the IL1RN, IL1A, and IL1B genes with knee osteoarthritis in Turkish patients. AB - PURPOSE: To examine whether polymorphisms of the interleukin 1 receptor antagonist (IL1RN), interleukin 1 alpha (IL1A) and interleukin 1 beta (IL1B) genes are markers of genetic susceptibility to knee osteoarthritis in Turkish patients. METHODS: One hundred and seven patients with knee osteoarthritis and 67 controls were studied. Three polymorphisms of IL1A, IL1B, and IL1RN genes were typed from genomic DNA. Allelic frequencies were compared between patients and control subjects. RESULTS: No significant differences were observed in genotype and allele frequencies of the IL1RN VNTR, IL1A+4845, IL1B+3953 genes polymorphisms between patients and controls. Furthermore, we did not detect any association genotypes of the polymorphisms with the clinical, radiological, and laboratory profiles of patients. CONCLUSIONS: The present study suggest that the IL1RN VNTR, IL1A+4845, IL1B+3953 genes polymorphisms are not genetic markers of susceptibility to knee osteoarthritis in Turkish patients, and are unrelated to the clinical, radiological, and laboratory characteristics of knee osteoarthritis. PMID- 17716547 TI - Bleeding during critical illness: a prospective cohort study using a new measurement tool. AB - PURPOSE: To estimate the incidence, severity, duration and consequences of bleeding during critical illness, and to test the performance characteristics of a new bleeding assessment tool. METHODS: Clinical bleeding assessments were performed prospectively on 100 consecutive patients admitted to a medical surgical intensive care unit (ICU) using a novel bleeding measurement tool called HEmorrhage MEasurement (HEME). Bleeding assessments were done daily in duplicate and independently by blinded, trained assessors. Inter-rater agreement and construct validity of the HEME tool were calculated using phi. Risk factors for major bleeding were identified using a multivariable Cox proportional hazards model. RESULTS: Overall, 90% of patients experienced a total of 480 bleeds of which 94.8% were minor and 5.2% were major. Inter-rater reliability of the HEME tool was excellent (phi = 0.98, 95% CI: 0.96 to 0.99). A decrease in platelet count and a prolongation of partial thromboplastin time were independent risk factors for major bleeding but neither were renal failure nor prophylactic anticoagulation. Patients with major bleeding received more blood transfusions and had longer ICU stays compared to patients with minor or no bleeding. CONCLUSIONS: Bleeding, although primarily minor, occurred in the majority of ICU patients. One of five patients experienced a major bleed which was associated with abnormal coagulation tests but not with prophylactic anticoagulants. These baseline bleeding rates can inform the design of future clinical trials in critical care that use bleeding as an outcome and HEME is a useful tool to measure bleeding in critically ill patients. PMID- 17716548 TI - Achieving the daily step goal of 10,000 steps: the experience of a Canadian family attached to pedometers. AB - BACKGROUND: Health experts recommend daily step goals of 10,000 steps for adults and 12,000 steps for youths to achieve a healthy active living. This article reports the findings of a Canadian family project to investigate whether the recommended daily step goals are achievable in a real life setting, and suggests ways to increase the daily steps to meet the goal. The family project also provides an example to encourage more Canadians to conduct family projects on healthy living. METHODS: This is a pilot feasibility study. A Canadian family was recruited for the study, with 4 volunteers (father, mother, son and daughter). Each volunteer was asked to wear a pedometer and to record daily steps for three time periods of each day during a 2-month period. Both minimal routine steps, and additional steps from special non-routine activities, were recorded at work, school and home. RESULTS: The mean number of daily steps from routine minimal daily activities for the family was 6685 steps in a day (16 hr, approx 400 steps/hr). There was thus a mean deficit of 4315 steps per day, or approximately 30,000 steps per week, from the goal (10,000 steps for adults; 12,000 steps for youths). Special activities that were found to effectively increase the steps above the routine level include: walking at brisk pace, grocery shopping, window shopping in a mall, going to an entertainment centre, and attending parties (such as to celebrate the holiday season and birthdays). DISCUSSION: To increase our daily steps to meet the daily step goal, a new culture is recommended: "get off the chair". By definition, sitting on a chair precludes the opportunity to walk. We encourage people to get off the chair, to go shopping, and to go partying, as a practical and fun way to increase the daily steps. This paper is a call for increased physical activity to meet the daily step goal. PMID- 17716549 TI - Periodontal care may improve systemic inflammation. AB - BACKGROUND: Periodontitis is an infectious chronic insidious disease of the tooth supporting structures that causes a general inflammatory response. The aims of the study were to determine whether periodontitis is associated with markers of general inflammation high-sensitivity (hs) C-reactive protein (CRP) leading to cardiovascular disease, and whether proper management of the periodontal disease would improve inflammation and thus, may prevent cardiovascular disease in the future. METHODS: This was a prospective case-controlled pilot study. Nine patients (3 women, 6 men; 40+/-5 yr) took part. All had severe periodontitis, without systemic disorders, and were all treated conservatively without surgical intervention. All had a 2nd visit after 3 months of treatment at the Outpatient Dental Clinic of the Hospital. Periodontal status and hs-CRP were evaluated on entry to the study and 3 months after treatment. Nine age and sex-matched healthy volunteers without periodontal disease served as the control group. RESULTS: Periodontal clinical parameters were improved after 3 months' treatment: probing depth (PD) (mean) at baseline was 4.3 and after 3 months' treatment improved to 3.2 (P=0.001), clinical attachment level (CAL) (mean) was 4.6 and changed to 3.7 (P=0.01), bleeding on probing (BOP %) changed from 64% to 33% (P=0.001), and Plaque index (Pi) changed from 49% to 25% (P=0.001). hs-CRP level was different between the patients'group (pre treatment) and the healthy volunteers: 2.97+/ 0.58 mg/L vs. 0.25+/-0.14 mg/L (P=0.00002). After completing 3 months' treatment, hs-CRP levels were decreased from 2.97+/-0.58 mg/L to 2.3+/-0.7 mg/L (P=0.009). CONCLUSIONS: Periodontitis is an infectious condition that may be an insidious cause of chronic inflammation and may be a risk factor for future cardiovascular disease. Treating periodontitis improved inflammation, and might be used as an important prevention tool for cardiovascular disease. PMID- 17716550 TI - The oral glucose tolerance test induces myocardial ischemia in healthy older adults. AB - PURPOSE: Postprandial myocardial ischemia has been observed in frail older adults with postprandial hypotension and in patients with severe coronary artery disease, especially after high doses of carbohydrates. The impact of oral glucose on myocardial oxygen supply and demand in healthy older adults without postprandial hypotension or postprandial angina remains unexamined. We hypothesized that oral glucose would result in decreased myocardial oxygen supply relative to demand in a healthy older subject pool free of postprandial hypotension, reversible coronary risk factors and postprandial angina. METHODS: 19 older adults (mean age 71.9+/-1.1 yr) were screened for reversible coronary risk factors. Subjects were given a standardized oral glucose load (75 g) or a sham isovolumetric unsweetened drink during two separate sessions. Indirect measures of oxygen supply (Diastolic Pressure Time Index, DPTI) and demand (Rate Pressure Product, RPP; Systolic Pressure Time Index, SPTI) were obtained from aortic arterial blood pressure waveforms. The Subendocardial Viability Ratio (SEVR, DPTI/SPTI) and DPTI/RPP were also calculated. RESULTS: Oral glucose resulted in decreases in both SEVR (P=0.016) and DPTI/RPP (P=0.028) in the glucose session, indicating a decrease in the relative myocardial oxygen supply to demand. This was due solely to a decrease in myocardial oxygen supply while measures of myocardial oxygen demand did not change significantly. CONCLUSIONS: Oral glucose decreases myocardial oxygen supply in older adults free of severe coronary artery disease and without postprandial hypotension. This represents a previously unrecognized complication of oral glucose tolerance tests in healthy older adults. PMID- 17716551 TI - A time for transformative leadership in academic health sciences. AB - Academic medicine, in its broadest sense, has made major contributions to human health in the past quarter century. This has been achieved in large part because it has attracted an outstanding cadre of--largely altruistic--professionals. These pioneering efforts have served as the life-blood of the discipline. Their journeys of discovery, often complemented by collaboration with the pharmaceutical, biotechnological and device industry have yielded remarkable insights into the diagnosis, treatment and prevention of disease and been celebrated by a stunning array of Nobel laureates in medicine and related arenas of endeavour.1 The translation of discovery to the bedside, clinic and the community coupled, most recently, with insights into the gap between potential effectiveness and what ultimately occurs as part of health care delivery, have been monumental in scope. This progress has unquestionably been the province of the university based clinician scientist. Within Canada, the emergence of the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, and the Canada Research Chairs has been pivotal in launching the careers of a new generation of clinician scientists. The excitement of discovery, gratification associated with direct patient care, and satisfaction of inspiring learning while engaging the next generation of emerging health professionals is rewarded by a career in academic medicine characterized by extraordinary challenge, fulfillment and meaning. As remarkable as these advances in quantity and quality of life have been (in large part attributable to health care research and its implementation) the promises of molecular medicine and abundant new technologies portend an exciting future whereby academic medicine can build upon its noble and traditional contributions to human health. PMID- 17716552 TI - Coronary microvascular reperfusion injury and no-reflow in acute myocardial infarction. AB - PURPOSE: To review (1) the mechanisms of coronary microvascular reperfusion injury, particularly in the relationships between microvascular endothelium dysfunction, microstructure damage, microemboli and no-reflow phenomena; (2) the no-reflow presentation and management at ischemia-reperfusion to suggest future direction for no-reflow therapy in acute myocardial infarction. SOURCES: Original articles and reviews published between 1997 and 2007 and focusing on the no reflow phenomenon in MEDLINE and PubMed. The search terms used were "no-reflow", "microvascular injury", "acute myocardial infarction" and "reperfusion injury". All papers identified were English-language, full text papers. In addition, the reference lists of identified relevant articles were also searched. CONCLUSIONS: The no-reflow phenomenon is characterised by damage to microvascular function and microstructure at ischaemia-reperfusion. Microemboli contribute to no-reflow. Clinical myocardial contrast echocardiography (MCE), scintigraphic and magnetic resonance imaging (MRI) have shown evidence of microvascular damage, eg, perfusion defects are closely related to lack of contractile recovery and irreversible myocyte damage. Clinical agents and devices targeting microvascular injury (especially protection of endothelium and reduction of microemboli) after acute myocardial infarction may be key points to improve no-reflow. PMID- 17716553 TI - Daily step goal of 10,000 steps: a literature review. AB - BACKGROUND: This review looks at ways to increase physical activity, by walking and other sports and home activities, to reach the daily 10,000 steps goal. It also looks at a number of issues associated with achieving the daily step goal, such as considerations in walking, step counting and physical activity. METHODS: The review is based on MEDLINE (1982-2006) and Google searches using keywords "pedometer", "daily step goal", "physical activity", "exercise". RESULTS: Research has suggested a daily 10,000 step goal for maintaining a desirable level of physical activity for health. However, this is not normally achievable through routine daily activities. For many, there is a daily deficit of approximately 4000 steps (most from 3000 to 6000 steps), which must be gained from other more rigorous activities. This paper provides information based on the Compendium of Physical Activities, to help people to choose their physical activities to supplement their daily steps, through both sports activities and home activities. It thus helps people to better achieve the goals of Canada's Physical Activity Guide. There are issues to consider in counting steps. A pedometer is not an exact method to measure energy expenditure. Focusing on counting steps may lead to an obsessive attitude toward exercise. Excessive walking and physical activity may lead to certain health problems. DISCUSSION: Walking is a practical and fun way to change our sedentary life style and to improve the health of the nation. When there is a deficit in daily steps, both sports and home activities can be used to supplement the daily steps to reach the daily step goal. The user friendly table provided in this paper helps people to identify the sports and home activities, and estimate the durations needed, to meet the daily step goal. PMID- 17716593 TI - Clinical research lags behind biomedical, population-based health, and health services research at multiple levels. AB - PURPOSE: Concerns regarding a decline in clinical research have been raised internationally. In this study, research initiatives and competitiveness of investigators seeking funding for clinical research were compared with those for three other health research themes in Canada, namely, biomedical, population based, and health services research. METHODS: A retrospective, multi-level descriptive study was conducted using administrative data from the Canadian Institutes for Health Research (CIHR) research grants program. Annual growth rates in numbers of proposals submitted since year 2000 (level I of comparison), success rates of submissions (level II), and growth rates in funding received since fiscal-year 1999-00 (level III) were compared across themes. RESULTS: Proposal submission (Level I): The average annual rate of growth in proposal submissions for biomedical, clinical, population-based and health services research was 11.8%, 6.3%, 105.0% and 43.2%, respectively. Success rate (Level II) was lower in clinical research (24%; P-value < 0.001) compared with biomedical (34%), population-based (29%), and health services (28%) research. Funding (Level III) grew at an average rate of 16.1% per year for biomedical, 28.2% for clinical, 65.9% for population-based, and 86.2% for health services research. However, the median amount funded for clinical projects (CAD $154,535) was less (P-value < 0.0001) than that for biomedical projects ($225,346). CONCLUSION: The overall growth of research activities in clinical theme was slower than with research in other themes-fewer proposals were submitted and lower proportion of submissions was successful. Smaller amounts of funding were received for clinical projects compared with biomedical projects, but a handful of large-scale clinical projects influenced the growth rate in funding for all clinical research. This report underscores the concern that multi-level problems plague clinical research. PMID- 17716595 TI - Dream disorders and treatment. AB - Consensus does not exist regarding what should constitute a "dream disorder." Conditions with disordered dreaming may be thought of as primary (ie, arising from changes in dreaming per se) or secondary to extrinsic disorders that impinge on structures involved in dreaming. The major primary disorder of dreaming, nightmare disorder, is covered in depth in this article. Definition of nightmare, diagnostic criteria for nightmare disorder, and differential diagnosis are discussed. The value of a sleep-disorders perspective on nightmares, and the possible exacerbating effects of sleep disorders that cause arousals, are indicated. The importance of a perspective that appreciates nightmares as richly and personally meaningful, with links to complex psychological factors present and past, is emphasized. Two types of treatment approaches are discussed: approaches that target the symptom of nightmares in relative isolation, and approaches that aim at working out psychological issues viewed as causing nightmares and a variety of other interconnected symptoms and problems. The former type of treatment includes the cognitive-behavioral approach "imagery rehearsal therapy," and the medication prazosin. The latter approach entails exploratory or psychodynamic psychotherapies. The approaches are seen as so different in scope, aim, and conceptual framework as to defy ready comparison. I think that a thorough psychological/psychiatric evaluation is essential for informed consideration in conjunction with the patient's choice of treatment approach. Sleep terrors are discussed as a non-rapid eye movement sleep arousal disorder that at times may be linked to broader psychological issues warranting consideration of psychotherapy. Brief summaries are provided of dream disorders secondary to other sleep disorders, drug and alcohol effects, medical disorders, and organic brain damage. PMID- 17716594 TI - Investigation of sources of potential bias in laboratory surveillance for anti microbial resistance. AB - PURPOSE: There are a number of biases that may influence the validity of laboratory-based surveillance for antimicrobial resistance. Our objective was to evaluate the potential magnitude of bias in reporting of etiologic agents and their resistance rates associated with inclusion of multiple patient samples and non-random timing and location of sampling. METHODS: All urine cultures submitted to a regional laboratory in the Calgary Health Region during 2004 and 2005 were studied. Comparisons were then made using either the overall cohort or different subgroups compared with the "reference" or gold standard population where only the first isolate per patient per year per species was included. RESULTS: Overall 56,897 organisms were cultured at > or =104 cfu/mL from 53,548 samples from 35,890 patients; 39,835 organisms were included in the reference cohort. Escherichia coli was reported in 37,246 (65.5%) of overall cohort and 28,257 (70.9%) of the reference cohort. Therefore, the overall cohort resulted in a relative underestimation of the importance of E. coli as the principal cause of urinary tract infections by 8%. Similarly, reported rates of resistance to antimicrobial agents most notably ciprofloxacin [6,480/52,544 (12.3%) vs. 2,647/37,086 (7.1%)], gentamicin [2,991/48,070 (6.2%) vs. 1,567/34,608 (4.5%)], and ceftriaxone [1,737/44,922 (3.9%) vs. 889/32,745 (2.7%)] were higher in the overall than in the reference cohorts. There were large differences in both the distribution of organisms and rates of resistance associated with sampling during different times of the day, week, and year as well as from acute care hospitals and outpatient clinics (P< or =0.001). CONCLUSIONS: Reports from laboratory-based surveillance studies may be biased depending on the population studied and method of sampling employed. Care must be taken in interpreting results of surveillance studies that do not protect from these major sources of bias. PMID- 17716596 TI - Sleep in rheumatic diseases and other painful conditions. AB - Insufficient sleep is an under-recognized public health problem that is projected to increase in the next decade as the US population ages. Chronic insomnia alone impacts 10% to 15% of adults. Epidemiologic data indicate that pain, fatigue, and mood disturbance are common correlates of persistent insomnia. Rates of most sleep disorders are substantially elevated in rheumatologic diseases, with chronic insomnia impacting at least 50% of patients. Clinicians treating patients with rheumatologic disorders should screen for sleep disorders and possess a basic knowledge of sleep physiology and empirically based intervention approaches. Sleep disturbances occurring within the context of chronic medical illnesses, including rheumatologic diseases, do not typically respond to primary disease and/or pain management interventions. Identification of co-occurring sleep disorders followed by aggressive treatment is recommended and has the potential to improve quality of life, ameliorate pain, and improve psychosocial adaptation to the primary illness. In this report, we briefly highlight that sleep disturbance increases risk for both comorbidities and symptoms associated with rheumatologic diseases, we identify specific sleep disorders commonly encountered in rheumatologic populations, and we discuss pharmacologic and behavioral treatment approaches for the most common sleep disorder observed in rheumatologic conditions, chronic insomnia. PMID- 17716598 TI - Sleep and breathing in multiple system atrophy. AB - Sleep disorders are common manifestations in multiple system atrophy (MSA) and include reduced and fragmented sleep, excessive daytime sleepiness, rapid eye movement (REM) sleep behavior disorder (RBD), stridor, and sleep-disordered breathing. RBD and nocturnal stridor are considered red flags and may be the first symptoms of the disease. RBD occurs in 90% to 100% of the patients, indicating severe and widespread pathologic impairment in the brain structures that regulate REM sleep. In 50% of the patients, RBD precedes the onset of waking motor symptoms and autonomic failure by several years. Sleep-disordered breathing manifests as 1) central hypoventilation that reflects impaired automatic control of ventilation secondary to degeneration of the pontomedullary respiratory centers; and, more commonly, as 2) stridor and obstructive sleep apnea due to larynx narrowing secondary to combined vocal cord abductor paralysis and excessive adductor activation during inspiration. Nocturnal stridor is a life threatening condition in MSA associated with respiratory failure and sudden death during sleep. Long-term treatment with continuous positive airway pressure (CPAP) eliminates nocturnal stridor. Tracheostomy is advised when CPAP is not tolerated and stridor occurs during wakefulness. PMID- 17716597 TI - Sleep dysfunction in patients with cancer. AB - Sleep complaints are common in cancer patients. Insomnia is particularly a concern in this population. Although pharmacotherapy is the most prescribed treatment for sleep disturbances, there is evidence that cognitive-behavioral therapy (CBT) is an effective treatment for insomnia in all patients, including those with cancer. CBT for insomnia is a flexible treatment, tailored to the needs of a specific patient, and focusing on behavioral and psychologic skills that foster better sleep and lower anxiety. Many cancer patients with insomnia may be hesitant to use drugs for their sleep treatment because they are already overwhelmed by the chemical and pharmacologic treatments they are prescribed for the cancer; thus, CBT may become the treatment of choice for insomnia in these patients. PMID- 17716599 TI - How schizophrenia and depression disrupt reward circuitry. AB - Altered reward behavior in Parkinson's disease (PD) is supported by observations of a placebo effect, prevalence of addiction to dopamine agonists, incidence of compulsive reward-seeking behaviors, and disturbed affective symptoms in PD patients. However, it is not clear how dopamine neuron loss causes or supports these aberrant reward behaviors and alterations in affect. For example, striatal dopamine transporter loss has a small, significant relationship with depression and anxiety in mild/moderate PD, but not in severe PD. Also, dopamine loss itself does not appear to predict depression or anhedonia, the diminished capacity to experience pleasure. Other neuropsychiatric disorders such as schizophrenia and depression may provide models of disturbed reward biology that may prove useful when thinking about altered reward circuitry and behavior in PD and other neurological disorders. PMID- 17716600 TI - Apathy and its treatment. AB - Apathy is a common problem observed in numerous neurologic, psychiatric, and other medical conditions. It is independent from other symptoms and has been associated with a variety of negative outcomes. However, little empirical research has been conducted on potential psychologic or pharmacologic treatments for apathy. The impact of several different medications has been investigated, but very few reports have used well-controlled study designs. At present, agents that potentiate dopamine release and/or delay dopamine reuptake in the central nervous system appear promising for use in apathy. Among these, atypical antipsychotics and methylphenidate have received the greatest attention, and both have been demonstrated to reduce apathy in several patient populations. These findings appear consistent with evidence supporting a role for frontal subcortical circuitry abnormality in the etiology of apathy. Another class of medication that has been the subject of a larger number of investigations is the acetylcholinesterase inhibitors. These have been reported to reduce apathy in patients with dementia and individuals with traumatic brain injury. Several psychologic interventions have been assessed, largely in geriatric populations, but most have been the subject of only one or a very small number of studies. With this caveat, interventions that have shown promise include participation in discussion groups and cognitive stimulation. Despite some promising findings, further large-scale, well-controlled clinical trials of potentially helpful pharmacologic and psychologic interventions for apathy are essential before any firm recommendations can be made. In the interim, careful evaluation of possible psychosocial and biological contributors to apathy in any given patient is suggested, with treatment planning based accordingly. PMID- 17716601 TI - Treatment of pathologic laughing and crying. AB - Pathologic laughing and crying (PLC) denotes paroxysms of involuntary and uncontrollable crying and/or laughing resulting from neurologic illnesses. These paroxysms of affect are often provoked by nonsentimental stimuli; even when the inciting stimulus is sentimentally meaningful, the intensity of the affective response is excessive. The crying and/or laughing of PLC are variably accompanied by episode-congruent subjective emotional feelings. In unusual cases, episode related feelings are of a valence contradictory to the expressed affect (ie, feeling happy while crying, or vice versa). PLC does not bear a predictable relationship to the prevailing mood of the patient, and the occurrence of such episodes does not produce a sustained mood disturbance. Therefore, patients with PLC must not be misunderstood as "depressed" or "manic" solely on the basis of their frequent episodic crying or laughing. In rare circumstances, PLC or PLC like symptoms may be the presenting symptom of a neurologic illness. In such circumstances, a prompt and thorough diagnostic evaluation for that neurologic illness should be undertaken before initiating treatment for PLC. Selective serotonin reuptake inhibitors (SSRIs) are efficacious, safe, and well-tolerated treatments for PLC and are recommended as first-line treatments for this condition. Tricyclic antidepressants, dextromethorphan/quinidine, or dopaminergic agents may be useful alternative treatments in patients in whom SSRIs are ineffective or poorly tolerated. Education and supportive therapy may help patients and families mitigate the social isolation and embarrassment that PLC episodes frequently produce. PMID- 17716602 TI - The psychiatric management of patients with alcohol dependence. AB - Alcohol dependence is a chronic, relapsing biobehavioral disease mediated by various parts of the brain, including reward systems, memory circuits, and the prefrontal cortex. It is characterized by loss of the ability to drink alcohol in moderation and continued drinking despite negative consequences. The alcohol withdrawal syndrome is a common but not universal diagnostic feature of alcohol dependence. Benzodiazepine detoxification of the alcohol withdrawal syndrome prevents the development of withdrawal seizures and delirium tremens, and makes patients more comfortable, which promotes engagement in treatment. Symptom triggered dosing, based on a withdrawal rating scale such as the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised, is optimal for minimizing the total benzodiazepine dosage. Use of a long-acting benzodiazepine (eg, chlordiazepoxide) is preferred in uncomplicated patients. Thiamine should be administered routinely before the administration of intravenous fluids to prevent the development of Wernicke's encephalopathy and Wernicke-Korsakoff syndrome. In combination with psychosocial treatment, disulfiram, naltrexone, and acamprosate can reduce the frequency of relapse. Naltrexone may be more effective for reduction of loss of control with the first drink and cue-related craving, and acamprosate may be more effective for stabilizing the physiology of post-acute withdrawal. Disulfiram, an aversive deterrent, can be useful if administration can be monitored and tied to meaningful contingencies or when used prophylactically for situations anticipated to carry high risk of relapse. Psychiatric comorbidity, especially depression, is common and is best addressed concurrently, although definitive diagnosis may have to await a period of prolonged sobriety. Prescription of addictive substances, including benzodiazepines beyond the period of acute detoxification, should be avoided, and if necessary should be closely monitored (eg, by frequent visits with small prescriptions, clinic-administered disulfiram, and/or urine or breath alcohol screenings). Abstinence from alcohol is recommended for persons with alcohol dependence. Psychosocial treatment and participation in Alcoholics Anonymous can help patients achieve and maintain abstinence. PMID- 17716603 TI - Early detection of life-threatening intracranial haemorrhage using a portable near-infrared spectroscopy device. AB - OBJECTIVE: To determine whether infrared spectroscopy allows early recognition of epidural and subdural haematomas among trauma patients. METHODS: Injured people admitted to two trauma units were enrolled in a prospective multicentre observational study, and infrared spectroscopy was performed before computed tomography of the head as a part of their initial evaluation. Subsequent CT findings suggestive of epidural or subdural haematoma served as controls. RESULTS: Over 12 months, 110 patients were enrolled; 64 (58.1%) were men and 46 (41.9%) were women. Mean age was 56.2 years, and mean Glasgow Coma Scale on admission was 12.6. Infrared spectroscopy was 90.5% sensitive and 95.5% specific for epidural and subdural haematoma. Positive and negative predictive values were 82.6% and 97.7%, respectively. CONCLUSIONS: Infrared spectroscopy allows early recognition of epidural and subdural haematomas in trauma cases. Further studies are needed to evaluate whether immediate confirmation or exclusion of epidural and subdural haematomas with portable near-infrared spectroscopy devices improves the decision-making process in the treatment of severely injured people. PMID- 17716605 TI - Perspectives of third-year medical students toward their surgical clerkship and a surgical career. AB - INTRODUCTION: A deficit of surgeons currently exists in the health care workforce. We have designed a study that identifies predictors of students choosing a career in surgery. First, we conducted two feasibility studies, and on the basis of these data, designed a third study for addressing our specific aims. The design and one-year results for the new study are provided here. METHODS: For the feasibility studies, students participating in the third-year surgery clerkship at our institution were asked to complete surveys using two different study designs. For the new study, which began in June 2005, students complete surveys covering domains of interest at the beginning of the clerkship and at weekly intervals throughout the clerkship, and will be providing match results. RESULTS: The feasibility studies offered insight into ways to improve our study design. In the first year of this multi-year study, 93 students participated (response rate = 77%). Forty-five students were women (48%), and the average age was 26.09 (sd 2.85). Proportion of students rating general surgery or a surgery subspecialty in their top three choices for a career increased over the course of the clerkship by 24.7% (n = 32, 34.4% at baseline; n = 55, 59.1% at end of clerkship). Seventy-one students (76.3%) reported having a meaningful experience on the clerkship, and 30 (32.3%) received honors grades. CONCLUSION: Our study design benefitted from the knowledge we gained from our feasibility studies. We look forward to achieving the necessary sample size in the next several years to report the final results of this study. PMID- 17716606 TI - High dosage of simvastatin reduces TNF-alpha-induced apoptosis of endothelial progenitor cells but fails to prevent apoptosis induced by IL-1beta in vitro. AB - Endothelial progenitor cells (EPC) could provide a possible source for the improvement of neovascularization in injured tissues following multiple trauma. Recently, it became obvious that at least two types of EPC can be cultured from peripheral blood mononuclear cells. In this work we focused on the fraction of the easily accessible early EPC, which can be generated in clinically relevant amounts within 5 days. Periods of hyper-inflammation, systemic or local, often occur during a multiple trauma. Thus, this study was conducted to elucidate the influence of the prototypical proinflammatory cytokines interleukin (IL)-1beta and tumor necrosis factor-alpha (TNF-alpha) on the survival of early EPC. In the past years it was observed that HMG-CoA reductase inhibitors (statins) exert protective effects during inflammatory processes. Therefore, the effect of a preconditioning of early EPC with simvastatin on the survival of EPC under proinflammatory conditions was tested as well. Incubation with 50 mu/mL TNF-alpha [0.45 ng/mL] or IL-1beta [0.25 ng/mL] resulted in a 3-fold (18.4 +/- 2.9%), respectively, 4-fold (25.5 +/- 3.4%) increase of apoptotic EPC in comparison to the untreated control (6.1 +/- 1.6%). In accordance, 24 h after the cytokines had been added, the EPC number per high power field decreased significantly. A preconditioning with simvastatin [25 microM] resulted in significant inhibition of the TNF-alpha-induced apoptosis, whereas the IL-1beta-mediated apoptosis was only slightly reduced. In conclusion, this study shows clearly that TNF-alpha and IL-1beta are harmful to early EPC and that the HMG-CoA reductase inhibitor simvastatin protects EPC from TNF-alpha- and eventually from IL-1beta-mediated apoptosis. These results suggest that simvastatin has protective effects on EPC survival and differentiation in a hyperinflammatory situation. PMID- 17716607 TI - Evidence of genetic locus heterogeneity for familial bicuspid aortic valve. AB - OBJECTIVE: We sought to determine if the gene responsible for bicuspid aortic valve (BAV) in an extended family corresponds to previously reported loci for inherited forms of the disorder. BACKGROUND: Loci at 15q25.1-26 and 9q34 have been reported to be associated with cardiovascular abnormalities involving BAV. METHODS: Linkage analysis was performed on DNA collected from a large multigenerational family in which BAV disease segregates in an autosomal dominant manner, using microsatellite markers from the regions previously reported to segregate with the phenotype. RESULTS: Lod scores were determined for genetic markers near the NOTCH1 gene and for a locus on chromosome 15q25.1-26 previously reported as being linked to BAV. The lod scores were negative or less than 1.0 for all markers tested. CONCLUSIONS: There is no evidence of linkage of BAV in our pedigree to either the NOTCH1 gene or to the chromosome 15 locus. The disorder in this family appears to be caused by a gene at a novel locus. PMID- 17716608 TI - Hemofiltration and immune response in severe sepsis. AB - BACKGROUND: Levels of pro- and anti-inflammatory cytokines have been determined in numerous investigations. However, measurements of isolated cytokines do not allow conclusions on the resulting immune state. The purpose of this study was to determine resulting immune functions in patients' plasma. Additionally, similar measurements were performed with ultrafiltrate gained from continuous venovenous hemofiltration (CVVH). MATERIALS AND METHODS: Nine septic patients and six critically ill patients with renal dysfunction in a surgical intensive care unit were observed. Two immune functions were chosen for detailed investigation over a time period of 72 h. The ability of patients' plasma to induce or suppress beta(2)-integrin expression on neutrophils of healthy controls served as marker for leukocyte activation. Interleukin (IL)-6 production or inhibition in washed whole blood cells induced through patients' plasma was used as a marker of cytokine secretion. RESULTS: Plasma from septic patients led to a constantly increased expression of beta(2)-integrins on isolated, unstimulated neutrophils. At the same time, septic plasma permanently suppressed the production of IL-6 and IL-10 in stimulated whole blood. Ultrafiltrate from CVVH mirrors the equivalent immune response patterns found for plasma. We did not find significant differences pre- and postfilter or over the next 72 h in the potential to cause IL-6 and IL-10 production or beta(2)-integrin expression. CONCLUSIONS: Plasma from septic patients triggers an increased expression of adhesion molecules and inhibited secretion of IL-6 and IL-10 in stimulated whole blood cells compared with nonseptic critically ill patients. Moreover, CVVH withdraws triggering mediators from plasma in equally bioactive proportions. PMID- 17716609 TI - Developing an interstitial ultrasound applicator for thermal ablation in liver: results of animal experiments. AB - BACKGROUND: In this project, an interstitial ultrasound applicator was developed for the treatment of primary and secondary cancers of the liver. Experiments on animals were used to check the destructive capabilities of this probe within the hepatic parenchyma of the pig in vivo, with a study of the physical parameters of the ultrasound treatment. In parallel, the possibility of visualizing the lesions induced by means of ultrasound imaging was also studied. MATERIALS AND METHODS: Thirteen pigs were used in this project, which had received the prior approval of the ethics committee of Lyon Veterinary School. Ultrasound lesions were performed by varying the physical parameters of the treatment (acoustic intensity and shot time) with the aim of obtaining larger and larger areas of destruction. An operative device was developed to ensure precision in treatments. Two types of lesions were performed: elementary lesions corresponding to single shots at 40 degrees to 50 degrees rotation intervals, and cylindrical lesions obtained by a continuous rotary deployment of the probe. The effect of hepatic pedicle clamping on the size of ultrasound lesions was studied. The aspect and dimension of the lesions were analyzed by means of operative ultrasound imaging and macroscopic examination. Histological analysis showed the impact of the treatment on the hepatic parenchyma. RESULTS: This work made it possible to study the elementary ultrasound lesions produced by our probe. Seventy elementary ultrasound lesions were analyzed. Treatments could be performed on all pigs without any difficulty. There were no operative incidents. The ultrasound-induced elementary lesions showed complete necrosis, with lesion length of up to 37 mm obtained without resort to pedicle clamping; this must be considered as a radius of the final lesion obtained over a complete rotary deployment (360 degrees ), then a diameter of 7 cm of thermal ablation can theoretically be obtained. The effect of pedicle clamping was studied and showed improvement of the lesion length. Results of continuous rotary deployment of the probe were encouraging. Operative ultrasound imaging proved to be a simple tool for directing and positioning the applicator in the target zone on the one hand and which, on the other hand, enabled accurate, real-time visualization of the ultrasound lesions. On histological analysis, the ultrasound-induced necrosis was complete and well defined. CONCLUSION: This work shows that it is feasible to treat cancers of the liver using interstitial ultrasound probe. Thermal damage obtained on the hepatic parenchyma of pigs in vivo is complete and can be monitored using simple diagnostic ultrasound. The ultrasound parameters can be adapted to obtain destruction of variable size. PMID- 17716611 TI - Adolescent sexual health. PMID- 17716613 TI - A spectrophotometric biochemical oxygen demand determination method using 2,6 dichlorophenolindophenol as the redox color indicator and the eukaryote Saccharomyces cerevisiae. AB - A method to determine the spectrophotometric biochemical oxygen demand (BOD(sp)) was studied with high sensitivity and reproducibility by employing 2,6 dichlorophenolindophenol (DCIP) as a redox color indicator, the yeast Saccharomyces cerevisiae, and a temperature-controlling system providing a three consecutive-stir unit. The absorbance of DCIP decreased due to the metabolism of organic substances in aqueous samples by S. cerevisiae. Under optimum conditions, a calibration curve for glucose glutamic acid concentration between 1.1 and 22mg O(2) L(-1) (r=0.988, six points, n=3) was obtained when the incubation mixture was incubated for 10min at 30 degrees C. The reproducibility of the optical responses in the calibration curve was 1.77% (average of relative standard deviations; RSD(av)). Subsequently, the characterization of this method was studied. The optical responses to pure organic substances and the influence of chloride ions, artificial seawater, and heavy metal ions on the sensor response were investigated before use with real samples. Measurements of real samples using river water were performed and compared with those obtained using the BOD(5) method. Finally, stable responses were obtained for 36 days when the yeast cell suspension was stored at 4 degrees C (response reduction, 89%; RSD(av) value for 9 testing days, 8.4%). PMID- 17716614 TI - ABAP: antibody-based assay for peptidylarginine deiminase activity. AB - Members of the family of peptidylarginine deiminases (PADs, EC 3.5.3.15) catalyze the posttranslational modification of peptidylarginine into peptidylcitrulline. Citrulline-containing epitopes have been shown to be major and specific targets of autoantibodies produced by rheumatoid arthritis patients. Recently, the citrullination of histone proteins by PAD enzyme was reported to influence gene expression levels. These findings greatly increase the interest in the PAD enzymes and their activities. A few procedures to monitor PAD activity in biological samples have been described previously. However, these assays either have low sensitivity or are rather laborious. Here we describe a reliable and reproducible method for the determination of PAD activity in both purified and crude samples. The method is based on the quantification of PAD-dependent citrullination of peptides, immobilized in microtiter plates, using antibodies that are exclusively reactive with the reaction product(s). Our results demonstrate that this antibody-based assay for PAD activity, called ABAP, is very sensitive and can be applied to monitor PAD activity in biological samples. PMID- 17716615 TI - Efficient electrocatalysis of L-cysteine oxidation at carbon ionic liquid electrode. AB - The electrochemistry of L-cysteine (CySH) in neutral aqueous media was investigated using carbon ionic liquid electrode (CILE). Comparative experiments were carried out using glassy carbon electrodes. At CILE, highly reproducible and well-defined cyclic voltammograms were obtained for l-cysteine with a peak potential of 0.49V vs Ag/AgCl, showing that CILE manifests a good electrocatalytic activity toward oxidation of l-cysteine. A linear dynamic range of 2-210microM with an experimental detection limit of 2microM was obtained. The method was successfully applied to the determination of l-cysteine in a sample of soya milk. Cysteine oxidation at CILE does not result in deactivation of the electrode surface. Mechanistic studies showed that, at CILE, the overall CySH oxidation is controlled by the oxidation of the CyS(-) electroactive species. PMID- 17716616 TI - Limitation of the Ellman method: cholinesterase activity measurement in the presence of oximes. AB - The Ellman method for assaying thiols is widely used for cholinesterase activity measurement. Cholinesterase activity is measured indirectly by quantifying the concentration of 5-thio-2-nitrobenzoic acid (TNB) ion formed in the reaction between the thiol reagent 5,5'-dithiobis-2-nitrobenzoic acid (DTNB) and thiocholine, a product of substrate (i.e., acetylthiocholine [ATCh]) hydrolysis by the cholinesterase. Oximes, reactivators of inhibited cholinesterase, are nucleophiles that also react with ATCh (oximolysis), producing thiocholine and (indirectly) TNB ion. The aim of this study was to characterize ATCh oximolysis. Therefore, we measured the oximolysis between oximes (K027 and HI-6) and ATCh in the presence of DTNB at different pH values, taking into account the final concentration of a product that is thiocholine. To confirm oximate ion involvement in the nucleophilic attack, we also determined the reaction rate between the oximes and ATCh, without DTNB, at different pH values by measuring the decrease in oximate ion absorption over time. The oximate ion of K027 reacted 14 times faster with ATCh (306M(-1)min(-1)) than the oximate ion of HI-6 (22M( 1)min(-1)). However, the rate constants obtained with the Ellman method were 84M( 1)min(-1) for K027 and 22M(-1)min(-1) for HI-6. Our results confirmed that the rate obtained with K027 using the Ellman method is actually the rate of the Ellman reaction itself. This suggests that the Ellman method cannot be used uncritically to evaluate oxime reaction with choline esters, in particular when oximolysis is faster than the Ellman reaction itself at a given pH. PMID- 17716617 TI - Separation of a disulfide-linked phosphoprotein by diagonal SDS-PAGE with optimized gel crosslinking. PMID- 17716618 TI - Automated sample preparation facilitated by PhyNexus MEA purification system for oligosaccharide mapping of glycoproteins. AB - A reproducible high-throughput sample cleanup method for fluorescent oligosaccharide mapping of glycoproteins is described. Oligosaccharides are released from glycoproteins using PNGase F and labeled with 2-aminobenzoic acid (anthranilic acid, AA). A PhyNexus MEA system was adapted for automated isolation of the fluorescently labeled oligosaccharides from the reaction mixture prior to mapping by HPLC. The oligosaccharide purification uses a normal-phase polyamide resin (DPA-6S) in custom-made pipette tips. The resin volume, wash, and elution steps involved were optimized to obtain high recovery of oligosaccharides with the least amount of contaminating free fluorescent dye in the shortest amount of time. The automated protocol for sample cleanup eliminated all manual manipulations with a recycle time of 23 min. We have reduced the amount of excess AA by 150-fold, allowing quantitative oligosaccharide mapping from as little as 500 ng digested recombinant immunoglobulin G (rIgG). This low sample requirement allows early selection of a cell line with desired characteristics (e.g., oligosaccharide profile and high specific productivity) for the production of glycoprotein drugs. In addition, the use of Tecan or another robotic platform in conjunction with this method should allow the cleanup of 96 samples in 23 min, a significant decrease in the amount of time currently required to process such a large number of samples. PMID- 17716619 TI - Ca(2+) -independent effects of BAPTA and EGTA on single-channel Cl(-) currents in brown adipocytes. AB - The Cl(-) channels of brown adipocytes electrophysiologically resemble outwardly rectifying Cl(-) channels (ORCC). To study tentative Ca(2+) regulation of these channels, we attempted to control Ca(2+) levels at the cytoplasmic side of the inside-out membrane patches with Ca(2+)-chelating agents. However, we found that the commonly used Ca(2+)-chelators EGTA and BAPTA by themselves influenced the Cl(-) channel currents, unrelated to their calcium chelating effects. Consequently, in this report we delineate effects of Ca(2+)-chelators (acting from the cytoplasmic side) on the single Cl(-) channel currents in patch-clamp experiments. Using fixed (1-2 mM) concentrations of chelators, two types of Cl(-) channels were identified, as discriminated by their reaction to the Ca(2+) chelators and by their conductance: true-blockage channels (31 pS) and quasi blockage channels (52 pS). In true-blockage channels, EGTA and BAPTA inhibited channel activity in a classical flickery type manner. In quasi-blockage channels, chelators significantly shortened the duration of individual openings, as in a flickering block, but the overall channel activity tended to increase. This dual effect of mean open time decrease accompanied by a tendency of open probability to increase we termed a quasi-blockage. Despite the complications due to the chelators as such, we could detect a moderate inhibitory effect of Ca(2+). The anionic classical Cl(-) channel blockers DIDS and SITS could mimic the true/quasi blockage of EGTA and BAPTA. It was concluded that at least in this experimental system, standard techniques for Ca(2+) level control in themselves could fundamentally affect the behaviour of Cl(-) channels. PMID- 17716620 TI - Inhibition of the formation of the neurotoxin 5-S-cysteinyl-dopamine by polyphenols. AB - The death of nigral neurons in Parkinson's disease is thought to involve the formation of the endogenous neurotoxin, 5-S-cysteinyl-dopamine. In the present study, we show that the polyphenols, (+)-catechin and caffeic acid, which contain a catechol moiety, inhibit tyrosinase-induced formation of 5-S-cysteinyl-dopamine via their capacity to undergo tyrosinase-induced oxidation to yield cysteinyl polyphenol adducts. In contrast, the inhibition afforded by the flavanone, hesperetin, was not accompanied by the formation of cysteinyl-hesperetin adducts, indicating that it may inhibit via direct interaction with tyrosinase. Whilst the stilbene resveratrol also inhibited 5-S-cysteinyl-dopamine formation, this was accompanied by the formation of dihydrobenzothiazine, a strong neurotoxin. Our data indicate that the inhibitory effects of polyphenols against 5-S-cysteinyl dopamine formation are structure-dependent and shed further light on the mechanisms by which polyphenols exert protection against neuronal injury relevant to neurodegenerative diseases. PMID- 17716621 TI - Structural analysis of obscurin gene in hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is a cardiac disease characterized by left ventricular hypertrophy with diastolic dysfunction. Molecular genetic studies have revealed that HCM is caused by mutations in genes for sarcomere/Z-band components including titin/connectin and its associate proteins. However, disease causing mutations can be found in about half of the patients, suggesting that other disease-causing genes remain to be identified. To explore a novel disease gene, we searched for obscurin gene (OBSCN) mutations in HCM patients, because obscurin interacts with titin/connectin. Two linked variants, Arg4344Gln and Ala4484Thr, were identified in a patient and functional analyses demonstrated that Arg4344Gln affected binding of obscurin to Z9-Z10 domains of titin/connectin, whereas Ala4484Thr did not. Myc-tagged obscurin showed that Arg4344Gln impaired obscurin localization to Z-band. These observations suggest that the obscurin abnormality may be involved in the pathogenesis of HCM. PMID- 17716622 TI - The effect of RanBPM on the regulation of the hypothalamic-pituitary axis by thyroid hormone receptors is isoform-specific. AB - Although crucial for TH homeostasis, the molecular mechanisms responsible of thyroid hormone receptors (TRs)-mediated regulation of the hypothalamic-pituitary thyroid axis (HPT) axis remain unclear. We examined the role played by TR isoforms in combination with RanBPM, a novel coactivator of TRs. In transient transfections studies with the human TRH and TSH-alpha subunit promoters, we found that the overexpression of RanBPM increases the transcriptional activity of all TR-isoforms by a magnitude of 1.7- to 3-fold. The addition of RanBPM, in the absence of THs, increased the ligand-independent activation (LIA) of TRalpha1 and TRbeta1 on both promoters tested by 300% and 200%, respectively, whereas, the LIA of TRbeta2 was not significantly modified. This data reinforces the concept of isoform-specific regulation of genes of the HPT axis and demonstrates that RanBPM may be an important factor to achieve adequate regulation of nTREs in the presence of low TH levels. PMID- 17716623 TI - Over-expression of the Arabidopsis DRE/CRT-binding transcription factor DREB2C enhances thermotolerance. AB - The dehydration responsive element binding protein 2 (DREB2) subgroup belongs to the plant-specific APETALA2/ethylene-responsive element binding factor (AP2/ERF) family of transcription factors. We have characterized cDNA encoding Arabidopsis thaliana DREB2C, which is induced by mild heat stress. Both an electrophoretic mobility shift assay (EMSA) and a yeast one-hybrid assay revealed that DREB2C(145 528) was able to form a complex with the dehydration responsive element/C-repeat (DRE/CRT; A/GCCGAC) motif. A trans-activating ability test in yeast demonstrated that DREB2C could effectively function as a trans-activator. Constitutive expression of DREB2C under the control of the cauliflower mosaic virus (CaMV) 35S promoter led to enhanced thermotolerance in transgenic lines of Arabidopsis. Microarray and RT-PCR analyses of transgenic plants revealed that DREB2C regulates expression of several heat stress-inducible genes that contain DRE/CRT elements in their promoters. From these data, we deduced that DREB2C is a regulator of heat stress tolerance in Arabidopsis. PMID- 17716624 TI - Refolding of human beta-1-2 GlcNAc transferase (GnT1) and the role of its unpaired Cys 121. AB - Human beta1-2N-acetylglucosaminyltransferase (hGnT1) lacking the first 103 amino acids was expressed as a maltose binding protein (MBP) fusion protein in inclusion bodies (IBs) in Escherichia coli and refolded using an oxido-shuffling method. GnT1 mutants were prepared by replacing a predicted unpaired cysteine (C121) with alanine (C121A), serine (C121S), threonine (C121T) or aspartic acid (C121D). A double mutant R120A/C121H, was generated to mimic Gly14, the Caenorhabditis elegans GnT1 counterpart to hGNT1. Each mutant hGnT1 was constructed as an MBP fusion protein and resultant IBs were isolated and refolded. Wild type hGnT1 and mutants C121A, C121S and R120A/C121H transferred UDP-GlcNAc to the glycoprotein acceptor Man(5)-RNAse B, whereas mutants C121T and C121D were inactive. These findings indicated that cysteine 121 has a structural role in maintaining active site geometry of hGnT1, rather than a catalytic role, and illustrates for the first time the potential utility of E. coli as an expression system for hGnT1. PMID- 17716625 TI - Molecular dynamics simulations of thioredoxin with S-glutathiolated cysteine-73. AB - Thioredoxin-1 (Trx) becomes inactive when cysteine-73 forms a mixed disulfide with glutathione. This reversible S-glutathiolation may serve as a regulatory mechanism. However, molecular basis for the glutathiolation-induced inhibition has not been established due to the lack of its structure. Molecular dynamics (MD) simulations were performed with Gromacs to obtain structural information on glutathiolated Trx. Glutathiolation did not cause a large change in overall shape of Trx although small local changes in the secondary structures were evident. The glutathione moiety was much more flexible than the peptide and spanned a large conformational space. It remained very close to the active site for a large part of the simulation time. Therefore inhibition of Trx by glutathiolation appears to be due to steric hindrance imposed by the covalently attached glutathione. PMID- 17716626 TI - Marked change in microRNA expression during neuronal differentiation of human teratocarcinoma NTera2D1 and mouse embryonal carcinoma P19 cells. AB - MicroRNAs (miRNAs) are small noncoding RNAs, with a length of 19-23 nucleotides, which appear to be involved in the regulation of gene expression by inhibiting the translation of messenger RNAs carrying partially or nearly complementary sequences to the miRNAs in their 3' untranslated regions. Expression analysis of miRNAs is necessary to understand their complex role in the regulation of gene expression during the development, differentiation and proliferation of cells. Here we report on the expression profile analysis of miRNAs in human teratocarcinoma NTere2D1, mouse embryonic carcinoma P19, mouse neuroblastoma Neuro2a and rat pheochromocytoma PC12D cells, which can be induced into differentiated cells with long neuritic processes, i.e., after cell differentiation, such that the resultant cells look similar to neuronal cells. The data presented here indicate marked changes in the expression of miRNAs, as well as genes related to neuronal development, occurred in the differentiation of NTera2D1 and P19 cells. Significant changes in miRNA expression were not observed in Neuro2a and PC12D cells, although they showed apparent morphologic change between undifferentiated and differentiated cells. Of the miRNAs investigated, the expression of miRNAs belonging to the miR-302 cluster, which is known to be specifically expressed in embryonic stem cells, and of miR-124a specific to the brain, appeared to be markedly changed. The miR-302 cluster was potently expressed in undifferentiated NTera2D1 and P19 cells, but hardly in differentiated cells, such that miR-124a showed an opposite expression pattern to the miR-302 cluster. Based on these observations, it is suggested that the miR 302 cluster and miR-124a may be useful molecular indicators in the assessment of degree of undifferentiation and/or differentiation in the course of neuronal differentiation. PMID- 17716628 TI - Neuroprotective function of thymosin-beta and its derivative peptides on the programmed cell death of chick and rat neurons. AB - Thymosin-betas (Tbetas) are small polypeptides with various biological functions, including cytoskeletal remodeling, angiogenesis, cellular migration, wound healing, and regulation of apoptosis. Recently, we found that Tbeta is involved in the control of programmed cell death (PCD) of motoneurons (MNs) in chick embryo, and that the anti-apoptotic action of Tbeta is independent of its actin sequestering activity. In this study, we observed that a synthetic peptide derived from Tbeta suppressed staurosporine-induced neuronal apoptosis in vitro, and PCD of chick or rat MNs in vivo. Furthermore, inhibition of Tbeta4 in chick embryo by antibody significantly augmented the PCD of MNs, suggesting that secreted form of Tbeta is physiological regulator of PCD. Based on these findings, we propose that extracellularly secreted Tbeta is involved in the control of PCD of neurons during development, and Tbeta-derived peptides could be useful for the anti-apoptotic therapy of neuropathologies related to neuronal apoptosis. PMID- 17716627 TI - Regulation of repp86 stability by human Siah2. AB - Human repp86 is a nuclear protein that is expressed in a tightly limited period of time during the cell cycle and plays an essential role in its progression. Manipulation of repp86 expression by reduction of endogenous repp86 or overexpression of exogenous repp86 results in cell cycle arrest. We found that repp86 interacts with human Siah2, which is a known mediator for proteasomal degradation. Siah2 failed to interact with repp86 lacking the first 67 N-terminal amino acids. Overexpression of Siah2 reduced endogenous and exogenous repp86 at the protein level without affecting its mRNA, as shown by cotransfection and RT PCR experiments. Furthermore, MG-132--a specific inhibitor of the proteasome- blocked the degradation of repp86 in Siah2 overexpressing cells. Moreover, transiently transfected Siah2 abrogated the mitotic arrest in repp86 overexpressing cells. Our data show that Siah2 is an important mediator of repp86 protein degradation. PMID- 17716629 TI - High resolution X-ray molecular structure of the nitrile hydratase from Rhodococcus erythropolis AJ270 reveals posttranslational oxidation of two cysteines into sulfinic acids and a novel biocatalytic nitrile hydration mechanism. AB - The crystal structure of Fe-type nitrile hydratase from Rhodococcus erythropolis AJ270 was determined at 1.3A resolution. The two cysteine residues (alphaCys(112) and alphaCys(114)) equatorially coordinated to the ferric ion were post translationally modified to cysteine sulfinic acids. A glutamine residue (alphaGln(90)) in the active center gave double conformations. Based on the interactions among the enzyme, substrate and water molecules, a new mechanism of biocatalysis of nitrile hydratase was proposed, in which the water molecule activated by the glutamine residue performed as the nucleophile to attack on the nitrile which was simultaneously interacted by another water molecule coordinated to the ferric ion. PMID- 17716630 TI - CRF1 not glucocorticoid receptors mediate prepulse inhibition deficits in mice overexpressing CRF. AB - BACKGROUND: Both corticotropin-releasing factor (CRF) and glucocorticoid receptors (GR) are implicated in the psychotic symptoms of psychiatric disorders. Correspondingly, it is of interest to determine their respective involvement in the sensorimotor gating deficits displayed by transgenic mice overexpressing CRF. These mice reveal lifelong elevations of CRF and corticosterone levels. METHODS: Effects of the GR antagonists ORG34517 (5-45 mg/kg by mouth [PO]) and mifepristone (5-45 mg/kg PO) and the CRF(1) receptor antagonists CP154,526 (20-80 mg/kg intraperitoneally [IP]) and DMP695 (2.5-40.0 mg/kg IP) on prepulse inhibition (PPI) of the acoustic startle response were studied in mice overexpressing CRF and in their wild-type littermates. In addition, PPI was measured in both genotypes 2 weeks after adrenalectomy with or without exogenous corticosterone administration via subcutaneous pellet implant (20 mg corticosterone). RESULTS: ORG34517 and mifepristone did not influence perturbation of PPI in mice overexpressing CRF; reducing corticosterone levels by adrenalectomy likewise did not improve PPI. Further, elevation in corticosterone levels by pellet implantation did not disrupt PPI in wild-type mice. Conversely, both CRF(1) receptor antagonists, CP154,526 (40-80 mg/kg IP) and DMP695 (40 mg/kg IP), significantly restored PPI in CRF-overexpressing mice. CONCLUSIONS: Sustained overactivation of CRF(1) receptors rather than excessive GR receptor stimulation underlies impaired sensorimotor gating in CRF-overexpressing mice. CRF(1) receptors thus may play a role in the expression of psychotic features in stress-related psychiatric disorders. PMID- 17716631 TI - Sex specific associations between common glucocorticoid receptor gene variants and hypothalamus-pituitary-adrenal axis responses to psychosocial stress. AB - BACKGROUND: Alterations in glucocorticoid (GC) signaling have been associated with a number of psychiatric disorders. Genetic variation of the glucocorticoid receptor (GR) might be one of the factors underlying susceptibility to stress related disease. METHODS: We investigated 206 healthy subjects and assessed associations between four common GR gene (NR3C1) polymorphisms (ER22/23EK, N363S, BclI, 9beta) and hypothalamic-pituitary-adrenal (HPA) axis responses to psychosocial stress (Trier Social Stress Test, TSST) and glucocorticoid sensitivity measured by a dexamethasone suppression test (DST). RESULTS: Male 9beta AG carriers displayed the highest adrenocorticotropic hormone (ACTH) and total cortisol TSST responses (for ACTH: main effect genotype p = .02) whereas male BclI GG carriers showed diminished responses. Remarkably, the BclI GG genotype in women (all using oral contraceptives) was associated with the highest total cortisol TSST responses, resulting in a significant sex by genotype interaction (p = .03). Following the DST, male 9beta AG carriers had elevated ACTH levels (sex by genotype interaction p = .03). CONCLUSIONS: We observed significant sex specific associations between GR gene polymorphisms and HPA axis responses to psychosocial stress as well as GC sensitivity. These findings support the relevance of GR gene polymorphisms in HPA axis regulation. Genetic variations of the GR might constitute a risk factor in development of HPA axis related disorders. PMID- 17716633 TI - Implanted embryonic sensory neurons project axons toward adult auditory brainstem neurons in roller drum and Stoppini co-cultures. AB - Previously we have shown in vivo the survival, migration and integration of embryonic dorsal root ganglion (DRG) neurons that were grafted into the inner ear and peripheral auditory nervous system. In order to evaluate relevant factors determining integration of sensory neurons further into the central auditory nervous system, complementary in vitro techniques are necessary. The advantages of in vitro systems are that a large number of factors including various grafts and different conditions can be efficiently examined for. Hence, we co-cultured 300 microm thick postnatal rat brainstem slices containing the cochlear nucleus including the central part of the 8th cranial nerve with mouse embryonic DRG neurons. The organotypic co-cultures were either grown on coverslips using the roller drum method described by Gahwiler or on membranes according to the interface method described by Stoppini. Neurons in the cochlear nucleus were labeled with DiI. The results demonstrate that (1) brainstem slices survive for up to 5 weeks in culture, and that (2) co-cultures of embryonic sensory neurons and brainstem show a high degree of neuronal survival, and that (3) survival and axonal outgrowth from the implanted embryonic neurons are dependent on the presence of the brainstem slice rather than on exogenous NGF and that (4) implanted embryonic neurons send axons toward neurons in the cochlear nucleus. PMID- 17716632 TI - Generalizing the dynamic field theory of spatial cognition across real and developmental time scales. AB - Within cognitive neuroscience, computational models are designed to provide insights into the organization of behavior while adhering to neural principles. These models should provide sufficient specificity to generate novel predictions while maintaining the generality needed to capture behavior across tasks and/or time scales. This paper presents one such model, the dynamic field theory (DFT) of spatial cognition, showing new simulations that provide a demonstration proof that the theory generalizes across developmental changes in performance in four tasks-the Piagetian A-not-B task, a sandbox version of the A-not-B task, a canonical spatial recall task, and a position discrimination task. Model simulations demonstrate that the DFT can accomplish both specificity-generating novel, testable predictions-and generality-spanning multiple tasks across development with a relatively simple developmental hypothesis. Critically, the DFT achieves generality across tasks and time scales with no modification to its basic structure and with a strong commitment to neural principles. The only change necessary to capture development in the model was an increase in the precision of the tuning of receptive fields as well as an increase in the precision of local excitatory interactions among neurons in the model. These small quantitative changes were sufficient to move the model through a set of quantitative and qualitative behavioral changes that span the age range from 8 months to 6 years and into adulthood. We conclude by considering how the DFT is positioned in the literature, the challenges on the horizon for our framework, and how a dynamic field approach can yield new insights into development from a computational cognitive neuroscience perspective. PMID- 17716634 TI - Light deprivation delays morphological differentiation of bipolar cells in the rabbit retina. AB - Bipolar cells are responsible for transmitting light signals from the photoreceptors to the ganglion cells in the vertebrate retina. Their maturation process is not only important for establishing normal visual function, but may also underlie the dendritic remodeling of ganglion cells during development. It is known that light deprivation affects the synaptic connections of ganglion cells in the mammalian retina, but little is known about impact of visual experience on bipolar cell development. We used dye injection and gene gun labeling to identify bipolar cells, and characterized their morphological differentiation in normal-reared and dark-reared rabbits. Our results show that immature bipolar cells can be found as early as P1-3, and most characteristic bipolar cells can be identified during P4-6. More importantly, we found that light deprivation causes a delay rather than a permanent arrest of bipolar cell maturation in the rabbit retina. By eye opening at P10-11, both normal-reared and dark-reared rabbits possessed adult-like bipolar cells. This suggests that visual experience has a facilitating effect on the morphological differentiation of bipolar cells. PMID- 17716636 TI - Mass synthesis of single-crystal gold nanosheets based on chitosan. AB - Single-crystal Au nanosheets with {111} planes as basal surfaces have been synthesized on the basis of the polysaccharide chitosan. The preferential adsorption of polar groups in chitosan molecules on {111} planes of Au nuclei may account for the formation of anisotropic nanosheets. Appropriate precursor (HAuCl(4)) concentrations are vital for the formation of Au nanosheets. The Au nanostructures thus prepared exhibit interesting shape-dependent optical properties. This convenient, environmentally friendly and low-cost route may be amenable to mass production. PMID- 17716637 TI - Overlapping paclitaxel-eluting stents: long-term effects in a porcine coronary artery model. AB - OBJECTIVE: At 4-year follow-up, paclitaxel-eluting stents (PES, TAXUS) have demonstrated clinical effectiveness in reducing restenosis without increasing death or myocardial infarction. Concerns remain with all drug-eluting stents, however, regarding potential interference with long-term healing, particularly in zones with adjacent stent overlap due to theoretical doubling in both drug release and tissue contact with coating polymer. Therefore, we evaluated long term healing of overlapped TAXUS stents in an accepted animal model. METHODS: Seventy-one non-injured swine underwent coronary artery placement of 138 overlapping stent-pairs (91 PES TAXUS Liberte 1 microg/mm(2) slow release formulation, 3.0 or 3.5 mm diameter pairs and 47 control bare metal Liberte pairs) deployed at a 1.1:1 to 1.2:1 target stent-to-artery diameter ratio. Pathological analysis was performed at 30 (9 bare, 10 paclitaxel), 90 (9 bare, 10 paclitaxel), 180 (10 bare, 16 paclitaxel), 360 (10 bare, 21 paclitaxel), and 580 (9 bare, 22 paclitaxel) days. RESULTS: At all time intervals overlapped TAXUS stents were consistently endothelialized and free of luminal thrombus or vascular dilatation. Full healing, however, was delayed compared to control, with macrophage processed para-strut fibrin and cellular debris still present, but reduced and sequestered from blood flow by an endothelialized neointima at 360 and 580 days. While neointimal thickness in TAXUS overlap zones was significantly less than control at 30 days, greater neointima formation was observed with TAXUS at > or =90 days, but was stable and did not progress further from 90 to 580 days. CONCLUSION: In this porcine model TAXUS stents demonstrated safety and acceptable healing with prolonged time to resolution of para-strut deposits, and did not produce the sustained neointimal suppression seen clinically. PMID- 17716635 TI - Cortical pyramidal cells as non-linear oscillators: experiment and spike generation theory. AB - Cortical neurons are capable of generating trains of action potentials in response to current injections. These discharges can take different forms, e.g., repetitive firing that adapts during the period of current injection or bursting behaviors. We have used a combined experimental and computational approach to characterize the dynamics leading to action potential responses in single neurons. Specifically we investigated the origin of complex firing patterns in response to sinusoidal current injections. Using a reduced model, the theta neuron, alongside recordings from cortical pyramidal cells we show that both real and simulated neurons show phase-locking to sine wave stimuli up to a critical frequency, above which period skipping and 1-to-x phase-locking occurs. The locking behavior follows a complex "devil's staircase" phenomena, where locked modes are interleaved with irregular firing. We further show that the critical frequency depends on the time scale of spike generation and on the level of spike frequency adaptation. These results suggest that phase-locking of neuronal responses to complex input patterns can be explained by basic properties of the spike-generating machinery. PMID- 17716638 TI - Functional, structural and molecular aspects of diastolic heart failure in the diabetic (mRen-2)27 rat. AB - OBJECTIVE: Diabetic cardiomyopathy is an increasingly recognized cause of cardiac failure despite preserved left ventricular systolic function. Given the over expression of angiotensin II in human diabetic cardiomyopathy, we hypothesized that combining hyperglycaemia with an enhanced tissue renin-angiotensin system would lead to the development of diastolic dysfunction with adverse remodeling in a rodent model. METHODS: Homozygous (mRen-2)27 rats and non-transgenic Sprague Dawley (SD) rats were randomized to receive streptozotocin (diabetic) or vehicle (non-diabetic) and followed for 6 weeks. Prior to tissue collection, animals underwent pressure-volume loop acquisition. RESULTS: Diabetic Ren-2 rats developed impairment of both active and passive phases of diastole, accompanied by reductions in SERCA-2a ATPase and phospholamban along with activation of the fetal gene program. Structural features of diabetic cardiomyopathy in the Ren-2 rat included interstitial fibrosis, cardiac myocyte hypertrophy and apoptosis in conjunction with increased activity of transforming growth factor-beta (p<0.01 compared with non-diabetic Ren-2 rats for all parameters). No significant functional or structural derangements were observed in non-transgenic, SD diabetic rats. CONCLUSION: These findings indicate that the combination of enhanced tissue renin-angiotensin system and hyperglycaemia lead to the development of diabetic cardiomyopathy. Fibrosis, and myocyte hypertrophy, a prominent feature of this model, may be a consequence of activation of the pro sclerotic cytokine, transforming growth factor-beta, by the diabetic state. PMID- 17716639 TI - Immunogenicity of mitochondrial DNA modified by hydroxyl radical. AB - Mitochondria consume about 90 percent of oxygen used by the body, and are a particularly rich source of reactive oxygen species (ROS). In this research communication mitochondrial DNA (mtDNA) was isolated from fresh goat liver and modified in vitro by hydroxyl radical generated from UV irradiation (254 nm) of hydrogen peroxide. As a consequence of hydroxyl radical modification, mtDNA showed hyperchromicity and sensitivity to nuclease S1 digestion as compared to control mtDNA. Animals immunized with mtDNA and ROS-modified mtDNA induced antibodies as detected by direct binding and competition ELISA. The data suggest that immunogenicity of mtDNA got augmented after treatment with hydroxyl radical. IgG isolated from immune sera showed specificity for respective immunogen and cross-reaction with other nucleic acids. Binding of induced antibodies with array of antigens clearly indicates their polyspecific nature. Moreover, the polyspecificity exhibited by induced antibodies is unique in view of similar multiple antigen binding properties of naturally occurring anti-DNA antibodies derived from SLE patients. PMID- 17716641 TI - Screening and diagnosis of congenital disorders of glycosylation. AB - The aim of this paper is to review the diagnostics of congenital disorders of glycosylation (CDG), an ever expanding group of diseases. Development delay, neurological, and other clinical abnormalities as well as various non-specific laboratory changes can lead to the first suspicion of the disease. Still common screening test for most CDG types, including CDG Ia, is isoelectric focusing/polyacrylamide gel electrophoresis (IEF). IEF demonstrates the hypoglycosylation of various glycoproteins, usually serum transferrin. Other methods, such as agarose electrophoresis, capillary electrophoresis, high performance liquid chromatography, micro-column separation combined with turbidimetry, enzyme-(EIA) and radioimmunoassay (RIA) have also been used for screening. However, these methods do not recognize all CDG defects, so other approaches including analysis of membrane-linked markers and urine oligosaccharides should be taken. Confirmation of diagnosis and detailed CDG subtyping starts with thorough structure analysis of the affected lipid-linked oligosaccharide or protein-(peptide)-linked-glycan using metabolic labeling and various (possibly mass-spectrometry combined) techniques. Decreased enzyme activity in peripheral leukocytes/cultured fibroblasts or analysis of affected transporters and other functional proteins combined with identification of specific gene mutations confirm the diagnosis. Prenatal diagnosis, based on enzyme assay or mutation analysis, is also available. Peri-/post-mortem investigations of fatal cases are important for genetic counseling. Evaluation of various analytical approaches and proposed algorithms for investigation complete the review. PMID- 17716640 TI - Amelogenin test: From forensics to quality control in clinical and biochemical genomics. AB - BACKGROUND: The increasing number of samples from the biomedical genetic studies and the number of centers participating in the same involves increasing risk of mistakes in the different sample handling stages. We have evaluated the usefulness of the amelogenin test for quality control in sample identification. METHODS: Amelogenin test (frequently used in forensics) was undertaken on 1224 individuals participating in a biomedical study. Concordance between referred sex in the database and amelogenin test was estimated. Additional sex-error genetic detecting systems were developed. RESULTS: The overall concordance rate was 99.84% (1222/1224). Two samples showed a female amelogenin test outcome, being codified as males in the database. The first, after checking sex-specific biochemical and clinical profile data was found to be due to a codification error in the database. In the second, after checking the database, no apparent error was discovered because a correct male profile was found. False negatives in amelogenin male sex determination were discarded by additional tests, and feminine sex was confirmed. A sample labeling error was revealed after a new DNA extraction. CONCLUSION: The amelogenin test is a useful quality control tool for detecting sex-identification errors in large genomic studies, and can contribute to increase its validity. PMID- 17716642 TI - Design of a DSP-based instrument for real-time classification of pulmonary sounds. AB - Auscultation of pulmonary sounds provides valuable clinical information but has been regarded as a tool of low diagnostic value due to the inherent subjectivity in the evaluation of these sounds. In this work, a Digital Signal Processor is used to design an instrument capable of acquiring, parameterizing and subsequently classifying lung sounds into two classes with an aim to evaluate them objectively in real time. The instrument operates on sound signal from a chest microphone and flow signal from a pneumotachograph. The classification is carried out separately on the 12 reference libraries (pathological and healthy) of six sub-phases of a full respiration cycle and the results are combined to arrive at a final decision. The k-nearest neighbour and minimum distance classifiers with different distance metrics have been implemented in the instrument. The instrument was tested in the clinical environment, attaining 96% accuracy in real-time classification. PMID- 17716644 TI - Early development and axis specification in the sea anemone Nematostella vectensis. AB - We investigated the early development of the sea anemone Nematostella vectensis, an emerging model system of the Cnidaria. Early cleavage stages are characterized by substantial variability from embryo to embryo, yet invariably lead to the formation of a coeloblastula. The coeloblastula undergoes a series of unusual broad invaginations-evaginations which can be blocked by cell cycle inhibitors suggesting a causal link of the invagination cycles to the synchronized cell divisions. Blastula invagination cycles stop as cell divisions become asynchronous. Marking experiments show a clear correspondence of the animal vegetal axis of the egg to the oral-aboral axis of the embryo. The animal pole gives rise to the concave side of the blastula and later to the blastopore of the gastrula, and hence the oral pole of the future polyp. Asymmetric distribution of granules in the unfertilized egg suggest an animal-vegetal asymmetry in the egg in addition to the localized position of the pronucleus. To determine whether this asymmetry reflects asymmetrically distributed determinants along the animal vegetal axis, we carried out blastomere isolations and embryonic divisions at various stages. Our data strongly indicate that normal primary polyps develop only if cellular material from the animal hemisphere is included, whereas the vegetal hemisphere alone is incapable to differentiate an oral pole. Molecular marker analysis suggests that also the correct patterning of the aboral pole depends on signals from the oral half. This suggests that in Nematostella embryos the animal hemisphere contains organizing activity to form a normal polyp. PMID- 17716643 TI - C. elegans seu-1 encodes novel nuclear proteins that regulate responses to UNC 6/netrin guidance cues. AB - In C. elegans, ectopic expression of the UNC-5 netrin receptor is sufficient to cause repulsion of growth cones and cells away from ventral sources of the UNC 6/netrin guidance cue. A genetic suppressor screen identified the seu-1 gene as required for repulsion of touch neuron growth cones ectopically expressing unc-5. We report here that seu-1 mutations also enhance the frequency of distal tip cell migrations of unc-5 or unc-40 mutants. The seu-1 gene encodes two novel proteins (SEU-1A and SEU-1B) containing a charged central domain and several regions of low amino acid complexity. Transgenic rescue experiments indicate that seu-1 can act cell autonomously in the touch neurons and distal tip cells and that SEU-1 function requires both the SEU-1A and SEU-1B isoforms. A GFP fusion construct was expressed in a dynamic pattern throughout development and localized in the nuclei of neuronal and non-neuronal cells, including gonadal leader cells. These results implicate nuclear SEU-1 in the interpretation of UNC-6/netrin directional information by migrating growth cones and cells. PMID- 17716645 TI - Asymmetric developmental potential along the animal-vegetal axis in the anthozoan cnidarian, Nematostella vectensis, is mediated by Dishevelled. AB - The relationship between egg polarity and the adult body plan is well understood in many bilaterians. However, the evolutionary origins of embryonic polarity are not known. Insight into the evolution of polarity will come from understanding the ontogeny of polarity in non-bilaterian forms, such as cnidarians. We examined how the axial properties of the starlet sea anemone, Nematostella vectensis (Anthozoa, Cnidaria), are established during embryogenesis. Egg-cutting experiments and sperm localization show that Nematostella eggs are only fertilized at the animal pole. Vital marking experiments demonstrate that the egg animal pole corresponds to the sites of first cleavage and gastrulation, and the oral pole of the adult. Embryo separation experiments demonstrate an asymmetric segregation of developmental potential along the animal-vegetal axis prior to the 8-cell stage. We demonstrate that Dishevelled (Dsh) plays an important role in mediating this asymmetric segregation of developmental fate. Although NvDsh mRNA is ubiquitously expressed during embryogenesis, the protein is associated with the female pronucleus at the animal pole in the unfertilized egg, becomes associated with the unipolar first cleavage furrow, and remains enriched in animal pole blastomeres. Our results suggest that at least one mechanism for Dsh enrichment at the animal pole is through its degradation at the vegetal pole. Functional studies reveal that NvDsh is required for specifying embryonic polarity and endoderm by stabilizing beta-catenin in the canonical Wnt signaling pathway. The localization of Dsh to the animal pole in Nematostella and two other anthozoan cnidarians (scleractinian corals) provides a possible explanation for how the site of gastrulation has changed in bilaterian evolution while other axial components of development have remained the same and demonstrates that modifications of the Wnt signaling pathway have been used to pattern a wide variety of metazoan embryos. PMID- 17716646 TI - Concentrations of vehicle-related air pollutants in an urban parking garage. AB - There is growing evidence that traffic-related air pollution poses a public health threat, yet the dynamics of human exposure are not well understood. The urban parking garage is a microenvironment that is of concern but has not been characterized. Using time-resolved measurement methods, we evaluated air toxics levels within an urban parking garage and assessed the influence of vehicle activity and type on their levels. Carbon monoxide (CO) and particle-bound polycyclic aromatic hydrocarbons (pPAH) were measured with direct-reading instruments. Volatile organic compounds (VOCs) were measured in 30 min intervals using a sorbent tube loaded sequential sampler. Vehicle volume and type were evaluated by video recording. Sampling was conducted from June 24 to July 17, 2002. We observed garage traffic median volumes of 71 counts/h on weekdays and 6 counts/h on weekends. The 12-fold reduction in traffic volume from weekday to weekend corresponded with a decrease in median air pollution that varied from a minimum 2- (CO) to a maximum 7 (pPAH)-fold. The actual 30-min median weekday and weekend values were: CO--2.6/1.2 ppm; pPAH--19/2.6 ng/m(3); 1,3-butadiene-0.5/0.2 microg/m(3), MTBE-7.4/0.4 microg/m(3); and benzene-2.7/0.3 microg/m(3). The influence of traffic was quantified using longitudinal models. The pollutant coefficients provide an indication of the average air pollution vehicle source contribution and ranged from 0.31 (CO) to 1.08 (pPAH) percent increase/vehicle count. For some pollutants, a slightly higher (0.5-0.6%) coefficient was observed for light-trucks relative to cars. This study has public health relevance in providing a unique assessment of air pollution levels and source contribution for the urban parking garage. PMID- 17716647 TI - Angiotensin-converting enzyme (ACE) inhibitors have different selectivity for bradykinin binding sites of human somatic ACE. AB - The angiotensin-converting enzyme (ACE) has two natural substrates and two catalytic domains: one cleaving angiotensin I and one inactivating bradykinin. The aim of this study was to investigate the comparative binding affinity of ACE inhibitors for the two binding sites of human endothelial ACE. In vitro binding assays were performed to test the ability of bradykinin, angiotensin I, or various ACE inhibitors (enalaprilat, perindoprilat, quinaprilat, ramiprilat, and trandolaprilat) to displace a saturating concentration of [(125)I]351A, a radiolabeled lisinopril analogue, from ACE binding sites. The calculated IC(50) values for the ACE inhibitors were in the nanomolar range, while those for the natural substrates were in the micromolar range. The bradykinin/angiotensin I selectivity ratios calculated from double displacement experiments were: perindoprilat, 1.44; ramiprilat, 1.16; quinaprilat, 1.09; trandolaprilat, 1.08; enalaprilat, 1.00. The ACE inhibitors generally had higher affinity for the bradykinin than the angiotensin I binding sites, supporting the idea that these agents are primarily inhibitors of bradykinin degradation, and secondarily inhibitors of angiotensin II production. Perindoprilat had the highest selectivity for bradykinin versus angiotensin I binding sites, and enalaprilat has the lowest. These results indicate that there are differences in the affinity of ACE inhibitors toward sites for bradykinin degradation, which could lead to differences in efficacy in cardiovascular disease. PMID- 17716648 TI - A comparison of the effect of anticancer drugs, idarubicin and adriamycin, on soluble chromatin. AB - The biological activity of an anticancer agent is related to its physicochemical interaction with biological receptors. In the present study we have investigated and compared the affinity and mode of action of two potent anticancer drugs, adriamycin and idarubicin on soluble chromatin using ultraviolet/visible and fluorescence spectroscopy, hydroxyapatite (HAP) chromatography and gel electrophoresis techniques. The results show that addition of various concentrations of drugs to chromatin solution individually, reduced both absorbance and fluorescence emission intensity of chromatin and precipitated it in a dose dependent manner, however, the extent of reduction was different for two drugs used. This effect was also observed on the histone gel patterns of the drug treated samples revealing that the chromatin is less affected by idarubicin compared to adriamycin implying higher aggregation of chromatin with the former. As hydroxyapatite chromatograms show, histone H1 represented the highest drug binding activity. The results suggest that although adriamycin and idarubicin are both grouped anthracycline antibiotic anticancer drugs, they differ considerably on their binding affinity to cellular chromatin. PMID- 17716649 TI - Secretion of antiretroviral chemokines by human cells cultured with acyclic nucleoside phosphonates. AB - Acyclic nucleoside phosphonates are novel class of clinically broadly used antivirotics effective against replication of both DNA viruses and retroviruses including human immunodeficiency virus (HIV). We have investigated their in vitro effects on immune defence mechanisms in human peripheral blood mononuclear cells, with the main emphasis on expression of cytokines which are able to suppress the entry of HIV in cells. Included in the study were prototype acyclic nucleoside phosphonates, i.e. 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; adefovir), 9-[2 (phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP), (R)-and (S)-enantiomers of 9 [2-(phosphonomethoxy)propyl]adenine [(R)-PMPA; tenofovir] and [(S)-PMPA], and of 9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine [(R)-PMPDAP] and [(S)-PMPDAP], and their N(6)-substituted derivatives. Some of the compounds were found to substantially enhance secretion of chemokines such as macrophage inflammatory protein-1alpha (MIP-alpha/CCL3), and "regulated on activation of normal T cell expressed and secreted" (RANTES/CCL5). Secretion of MIP-1beta/CCL4 was only marginally increased, whereas production of interleukin-16 (IL-16) and interferon gamma (IFN-gamma) remained uninfluenced. The most effective proved to be the N(6) cyclooctyl-PMEDAP, N(6)-isobutyl-PMEDAP, N(6)-pyrrolidino-PMEDAP, N(6) cyclopropyl-(R)-PMPDAP, and N(6)-cyclopentyl-(R)-PMPDAP derivatives. Remarkably enhanced secretion of chemokines was reached within 2-4 h of the cell culture, and was observed at concentration of 2-5 microM. It may be suggested that acyclic nucleoside phosphonates represent a new generation of antivirotics with combined antimetabolic and therapeutically prospective immunostimulatory properties. PMID- 17716651 TI - p38 and JNK MAPK, but not ERK1/2 MAPK, play important role in colchicine-induced cortical neurons apoptosis. AB - Colchicine is a microtubule interfering agent and is able to induce neural apoptosis. However, the intracellular pathway involved in its neurotoxicity is still unclear. In the present study, three of mitogen-activated protein kinases (MAPKs): p38, c-Jun N-terminal kinase (JNK) and extracellular-regulated kinase 1/2 (ERK1/2) were investigated in colchicine-induced apoptosis on cortical neurons for the first time. Our results showed that 1 microM colchicine administration in primarily cultured cortical neurons led to typical neuronal apoptosis, and the apoptosis was attenuated by taxol, a microtubule stabilizer. Moreover, activation of p38 MAPK was found for the first time, as well as that of JNK MAPK, but not of ERK1/2 MAPK, after colchicine exposure. Apoptosis was inhibited by p38 MAPK inhibitors, SB203580 (4-(4-fluorophenyl)-2-(4 methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole), SB239063 (trans-1-(4 hydroxycyclohexyl)-4-(fluorophenyl)-5-(2-methoxypyrimidin-4-yl) imidazole), and JNK MAPK pathway inhibitors, CEP11004 (9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1' kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid, 2,3,9,10,11,12-hexahydro 10-hydroxy-9-methyl-5,16-bis[[(1-methylethyl)thio]methyl]-1-oxo-, methyl ester, (9S,10R,12R)-), SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one). However, PD98059 (2 (2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one) and U0126 (1,4-diamino-2,3 dicyano-1, 4-bis[2-aminophenylthio]butadiene), ERK1/2 MAPK inhibitors, did not work. Furthermore, better neuronal protective effects were achieved by using JNK and the p38 MAPK inhibitors together as compared to that by using either alone. The results suggested that p38 MAPK, JNK MAPK, but not ERK1/2 MAPK may play pivotal role in colchicine's neurotoxicity in primarily cultured cortical neurons, and the protective effects of the inhibition of p38 or JNK MPAK on cortical neurons were synergistically. PMID- 17716650 TI - Mathematical analysis of involvement ratio between central and peripheral COX-2 in rat pain models with two types of COX-2 inhibitors with different distribution, celecoxib and CIAA. AB - The purpose of this study is to clarify involvement ratios between central and peripheral cyclooxygenase (COX)-2 in rat inflammatory pain models, by evaluating celecoxib and [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid (CIAA) on carrageenan-induced mechanical and thermal hyperalgesia. Celecoxib and CIAA exhibited ID(30) values with 1.5 and 7.7 mg/kg on mechanical hyperalgesia, respectively, and ID(25) values with 0.54 and 36 mg/kg on thermal hyperalgesia, respectively. By solving quadratic functional analysis with prostaglandin E(2) (PGE(2)) inhibitory activities, it was calculated that involvement ratios between central and peripheral COX-2 involvement were 0.47 and 0.53 on mechanical hyperalgesia, and 0.97 and 0.03 on thermal hyperalgesia, respectively. These data suggest that central and peripheral COX-2 are equally involved in mechanical hyperalgesia, while central COX-2 is predominantly involved in thermal hyperalgesia. PMID- 17716652 TI - Reduction of CD4 positive T cells and improvement of pathological changes of collagen-induced arthritis by FTY720. AB - FTY720 belongs to a new class of immunosuppressants. Little is known about its influence on T cell subtypes and pathological changes in arthritis. Here we illustrated the effect of FTY720 on peripheral T cell subsets and joint damage of collagen-induced arthritis rats. Rats were administered FTY720 or prednisone daily from day 0 to day 28. Body weight, hind paw swelling and arthritis index were measured. Bone destruction was determined by micro-computed tomography and histopathology, and T cell subsets were analyzed by flow cytometry and immunohistochemistry. The results showed that FTY720 inhibited the development of arthritis. Radiological analysis revealed that FTY720 treated collagen-induced arthritic rats had much less joint damage in comparison to untreated collagen induced arthritic rats. Histological study showed that collagen-induced arthritic rats suffered from inflammatory cell infiltration and synovial hyperplasia in their joints, and FTY720 treatment clearly reduced these pathological changes. Immunohistochemical analysis showed that FTY720 treatment significantly decreased the number of CD4(+) T cells in the synovium of collagen-induced arthritic rats. Collagen-induced arthritic rats appeared to have more CD4(+), but not CD8(+) T cells in their peripheral blood than normal control rats. Following FTY720 treatment, peripheral blood CD3(+) and CD4(+) T cells in collagen-induced arthritic rats were significantly decreased. In conclusion, FTY720 is an effective compound in the treatment of collagen-induced arthritic rats and in reducing CD4(+) T cells in collagen-induced arthritic rats. PMID- 17716653 TI - Degranulation of mast cells and histamine release involved in rat pain-related behaviors and edema induced by scorpion Buthus martensi Karch venom. AB - In the present study, it was investigated whether the degranulation of mast cells and histamine release were involved in rat pain-related behaviors and edema induced by the venom of scorpion Buthus martensi Karch (BmK) or not. It was found that the obvious degranulation of mast cells could be triggered in rat hindpaw skin by BmK venom. The chronic degranulation of mast cells using compound 48/80 relieved the spontaneous nociceptive responses, the primary thermal and bilateral mechanical hyperalgesia and the rat paw edema, as well as partially reduced c-Fos expression in superficial layers (laminae I-II) of bilateral spinal cord induced by BmK venom. In addition, individual peripheral co-administration of either 100 nmol chlorpheniramine or 100 nmol pyrilamine (histamine H(1) receptor antagonist) or 500 nmol cimetidine (histamine H(2) receptor antagonist) and BmK venom suppressed the spontaneous nociceptive responses, partially the primary thermal and bilateral mechanical hyperalgesia and rat paw edema induced by BmK venom. Thus, these results suggest that the peripheral cellular incidents of mast cells degranulation and histamine release are involved in BmK venom-induced pain related behaviors and inflammation. PMID- 17716654 TI - Chemotherapeutic potential of the volatile oils from Zanthoxylum rhoifolium Lam leaves. AB - In this work, the anti-tumor properties of the volatile oil from Zanthoxylum rhoifolium Lam leaves and some terpenes (alpha-humulene, beta-caryophyllene, alpha-pinene and beta-pinene) were investigated in vitro and in vivo using the Ehrlich ascites tumor model. Treatment of Ehrlich ascites tumor-bearing mice with 20 mg/kg of the volatile oil and beta-caryophyllene for 4 days has significantly increased survival, whereas administration of alpha-humulene, alpha-pinene and beta-pinene were ineffective in affording protection. Volatile oil and beta caryophyllene exhibited little direct activity against Ehrlich tumor cells in vitro, while alpha-humulene, alpha-pinene and beta-pinene did not such activity. Investigation of the effects of the volatile oil (and terpenes) treatment on total natural killer cells (NK cell) activity from tumor-bearing mice as a possible mechanism of these compounds in vivo revealed that volatile oil and beta caryophyllene significantly improved NK cell cytotoxicity against YAC-1, a Moloney virus-induced mouse T-cell lymphoma of A/SN origin and Ehrlich ascites cells. As expected, tumor growth in non-treated mice markedly suppressed NK cell cytolysis while the volatile oil and beta-caryophyllene reversed this effect when mice were treated with 20-mg/kg dosages of these compounds for 4 days. Summing up, volatile oil exhibits anti-tumor efficacy and significative immunomodulatory action in vivo, which may be related to beta-caryophyllene associated to the synergism of other natural compounds presented in volatile oil from Z. rhoifolium Lam leaves. PMID- 17716655 TI - In vivo adenosine A(2B) receptor desensitization in guinea-pig airway smooth muscle: implications for asthma. AB - This study was aimed at characterizing the role of adenosine receptor subtypes in the contractility modulation of guinea-pig airway smooth muscle in normal and pathological settings. In vitro and in vivo experiments were performed by testing selective agonists and antagonists on isolated tracheal smooth muscle preparations and pulmonary inflation pressure, respectively, under normal conditions or following ovalbumin-induced allergic sensitization. In normal and sensitized animals, the adenosine A(2A)/A(2B) receptor agonist, NECA, evoked relaxing responses of isolated tracheal preparations precontracted with histamine, and such an effect was reversed by the adenosine A(2B) antagonist, MRS 1706, in the presence or in the absence of epithelium. The expression of mRNA coding for adenosine A(2B) receptors was demonstrated in tracheal specimens. In vitro desensitization with 100 microM NECA markedly reduced the relaxing effect of the agonist. In vivo NECA or adenosine administration to normal animals inhibited histamine-mediated bronchoconstriction, while these inhibitory effects no longer occurred in sensitized guinea-pigs. Adenosine plasma levels were significantly higher in sensitized than normal animals. In conclusion, our data demonstrate that: (i) adenosine A(2B) receptors are responsible for the relaxing effects of adenosine on guinea-pig airways; (ii) these receptors can undergo rapid adaptive changes that may affect airway smooth muscle responsiveness to adenosine; (iii) ovalbumin-induced sensitization promotes a reversible inactivation of adenosine A(2B) receptors which can be ascribed to homologous desensitization. These findings can be relevant to better understand adenosine functions in airways as well as mechanisms of action of asthma therapies targeting the adenosine system. PMID- 17716656 TI - Frizzled-7 turnover at the plasma membrane is regulated by cell density and the Ca(2+) -dependent protease calpain-1. AB - Frizzled are seven-transmembrane domain G-protein coupled receptors involved in cell polarity and Wnt signaling. The mechanisms regulating their turnover at the plasma membrane remain unclear. We have identified a regulated C-terminus cleavage of Frizzled-7 in endothelial cells using ectopic expression of N- and C termini-tagged Frizzled-7 proteins. This specific cleavage produced a 10 kDa C terminus fragment that remained associated with intracellular vesicles and was localized within the 3rd intracytoplasmic loop using N-terminal sequencing and targeted mutagenesis. Frizzled-7 mutated forms displaying reduced C-terminus cleavage were also defective for dvl2 translocation at the plasma membrane. PMA, an activator of PKC and endocytosis, but not Wnt13A and Wnt5A, increased the appearance of Frizzled-7 C-terminus-containing vesicles and Frizzled-7 cleavage. Concanavalin-A, an inhibitor of receptor internalization decreased both constitutive and PMA-induced Frizzled-7 cleavage, while inhibition of the endocytic pathway with Delta95-295-Eps15 dominant-negative prevented only PMA induced Frizzled-7 cleavage. Frizzled-7 C-terminus cleavage was increased with cell density and by the Ca(2+) ionophore ionomycin and was decreased by specific calpain inhibitors, by the expression of DN-calpain-1 and the down-regulation of calpain-1 levels by siRNAs. Altogether, our findings pinpoint calpain-1 as a regulator of Frizzled-7 turnover at the plasma membrane and reveal a link between Frizzled-7 cleavage and its activity. PMID- 17716658 TI - A role for the urokinase-type plasminogen activator system in amyotrophic lateral sclerosis. AB - There is substantial evidence, implicating extracellular matrix (ECM) regulating enzymes in the pathogenesis of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The most important ECM-degrading proteases are serine proteases (plasminogen activators, PA) and matrix metalloproteinases (MMPs). Since the role of MMPs in ALS has been addressed recently, we investigated the expression of the serine protease urokinase-type plasminogen activator (uPA) and its receptor in ALS. Employing rtPCR, zymography and immunohistochemistry we analyzed the expression of uPA and its receptor uPAR in spinal cord tissue of ALS cases and in the G93A SOD1 transgenic mouse. In the ventral horn of the spinal cord of ALS cases we found increased uPAR staining of motor neurons. In G93A mice, the expression profile of uPA and uPAR mRNA was significantly increased starting at the age of 90 days as compared to non-transgenic littermates. The uPA-dependent plasminogen activation in G93A mice at endstage increased markedly compared with controls and immunostaining of the spinal cord from G93A mice revealed increased uPAR immunostaining in neurons. To determine the functional role of uPA, we investigated the effect of intraperitoneal (i.p.) administration of the uPA inhibitor WX-340 (10 mg/kg), starting at the age of 30 days (n=18). Treatment with WX-340 prolonged (p<0.05) survival of the animals (135+/-2 vs. 126+/-3) as well as improving rotarod performance. Our experiments demonstrate that uPA and its receptor are expressed in ALS patients and in an animal model of ALS. Early inhibition with a synthetic uPA inhibitor prolonged the life of the transgenic animals. These findings indicate that the urokinase-type plasminogen activator system may play a role in the complex pathogenesis of ALS. PMID- 17716657 TI - Microtubule regulation of corneal fibroblast morphology and mechanical activity in 3-D culture. AB - The purpose of this study was to investigate the role of microtubules in regulating corneal fibroblast structure and mechanical behavior using static (3 D) and dynamic (4-D) imaging of both cells and their surrounding matrix. Human corneal fibroblasts transfected to express GFP-zyxin (to label focal adhesions) or GFP-tubulin (to label microtubules) were plated at low density inside 100 microm thick type I collagen matrices. After 24h, the effects of nocodazole (to depolymerize microtubules), cytochalasin D (to disrupt f-actin), and/or Y-27632 (to block Rho-kinase) were evaluated using 3-D and 4-D imaging of both cells and ECM. After 24h of incubation, cells had well organized microtubules and prominent focal adhesions, and significant cell-induced matrix compaction was observed. Addition of nocodazole induced rapid microtubule disruption which resulted in Rho activation and additional cellular contraction. The matrix was pulled inward by retracting pseudopodial processes, and focal adhesions appeared to mediate this process. Following 24h exposure to nocodazole, there was an even greater increase in both the number of stress fibers and the amount of matrix compaction and alignment at the ends of cells. When Rho-kinase was inhibited, disruption of microtubules resulted in retraction of dendritic cell processes, and rapid formation and extension of lamellipodial processes at random locations along the cell body, eventually leading to a convoluted, disorganized cell shape. These data suggest that microtubules modulate both cellular contractility and local collagen matrix reorganization via regulation of Rho/Rho-kinase activity. In addition, microtubules appear to play a central role in dynamic regulation of cell spreading mechanics, morphology and polarity in 3-D culture. PMID- 17716660 TI - Role of ChREBP in hepatic steatosis and insulin resistance. AB - Non-alcoholic fatty liver disease is tightly associated with insulin resistance, type 2 diabetes and obesity, but the molecular links between hepatic fat accumulation and insulin resistance are not fully identified. Excessive accumulation of triglycerides (TG) is one the main characteristics of non alcoholic fatty liver disease and fatty acids utilized for the synthesis of TG in liver are available from the plasma non-esterified fatty acid pool but also from fatty acids newly synthesized through hepatic de novo lipogenesis. Recently, the transcription factor ChREBP (carbohydrate responsive element binding protein) has emerged as a central determinant of lipid synthesis in liver through its transcriptional control of key genes of the lipogenic pathway, including fatty acid synthase and acetyl CoA carboxylase. In this mini-review, we will focus on the importance of ChREBP in the physiopathology of hepatic steatosis and insulin resistance by discussing the physiological and metabolic consequences of ChREBP knockdown in liver of ob/ob mice. PMID- 17716659 TI - Lentiviral RNAi-induced downregulation of adenosine kinase in human mesenchymal stem cell grafts: a novel perspective for seizure control. AB - Cell therapies based on focal delivery of the inhibitory neuromodulator adenosine were previously shown to provide potent seizure suppression in animal models of epilepsy. However, hitherto used therapeutic cells were derived from rodents and thus not suitable for clinical applications. Autologous patient-derived adenosine releasing cell implants would constitute a major therapeutic advance to avoid both xenotransplantation and immunosuppression. Here we describe a novel approach based on lentiviral RNAi mediated downregulation of adenosine kinase (ADK), the major adenosine-removing enzyme, in human mesenchymal stem cells (hMSCs), which would be compatible with autologous cell grafting in patients. Following lentiviral transduction of hMSCs with anti-ADK miRNA expression cassettes we demonstrate up to 80% downregulation of ADK and a concentration of 8.5 ng adenosine per ml of medium after incubating 10(5) cells for 8 h. hMSCs with a knockdown of ADK or cells expressing a scrambled control sequence were transplanted into hippocampi of mice 1 week prior to the intraamygdaloid injection of kainic acid (KA). While mice with control implants expressing a scrambled miRNA sequence or sham treated control animals were characterized by KA induced status epilepticus and subsequent CA3 neuronal cell loss, animals with therapeutic ADK knockdown implants displayed a 35% reduction in seizure duration and 65% reduction in CA3 neuronal cell loss, when analyzed 24 h after KA injection. We conclude that lentiviral expression of anti-ADK miRNA constitutes a versatile tool to generate therapeutically effective adenosine releasing hMSCs, thus representing a model system to generate patient identical autologous adult stem cell grafts. PMID- 17716661 TI - Differential sialylation regulates the apoptotic activity of glycodelin A. AB - Glycodelin A (GdA), a dimeric lipocalin, expressed by the uterine endometrium, is an immunomodulatory agent and induces apoptosis in T-cells. In this study we demonstrate that two populations of GdA with subtle differences in their net ionic charge are present in the amniotic fluid and that, apoptotic activity is exhibited only by the population with more sialic acid residues. Significantly, removal of sialic acid residues from the active populations of GdA abrogates the activity of the molecule, suggesting that the extent of sialylation might be a factor regulating the activity of GdA. PMID- 17716662 TI - Human oncogene tissue-specific expression level significantly correlates with sequence compositional features. AB - To explore whether there exist correlations between human gene expressions and corresponding sequence features, the expression levels for 81 oncogenes in 24 human tissues were collected and correlated with 159 sequence features. It was found that there do exist significant correlations between them, some of which are of significance to understanding translational selection on sequence features of human genes and some have important implications for diagnosing cancers. PMID- 17716664 TI - Cholesterol is more susceptible to oxidation than linoleates in cultured cells under oxidative stress induced by selenium deficiency and free radicals. AB - Polyunsaturated fatty acids and their esters are known to be susceptible to free radical mediated oxidation, while cholesterol is more resistant to oxidation. The present study focused on the relative susceptibilities of linoleates and cholesterol in Jurkat cells under oxidative stress induced by selenium deficiency and free radical insult, as assessed by total hydroxyoctadecadienoic acids (tHODE) and total 7-hydroxycholesterol (t7-OHCh) measured after reduction and saponification. It was observed that the levels of tHODE and t7-OHCh significantly increased by both oxidative insults. The increased amounts of t7 OHCh were higher than those of tHODE in both selenium-deficient and free radical treated cells. These results suggest that, in contrast to plasma oxidation where cholesterol is much more resistant to oxidation than linoleates, cellular cholesterol is more susceptible to oxidation than cellular linoleates. PMID- 17716663 TI - Absence of 4-1BB increases cell influx into the peritoneal cavity in response to LPS stimulation by decreasing macrophage IL-10 levels. AB - Peritoneal injection of lipopolysaccharide (LPS) increased the influx of polymorphonuclear leukocytes and macrophages into the peritoneal cavity (PEC), with significantly higher cell numbers in the 4-1BB-deficient (KO) mice than in wild-type (WT) mice. The peritoneal macrophages of KO mice contained less IL-10 transcripts and protein than those of WT after LPS treatment, and immobilization of 4-1BB-Fc increased the level of IL-10. Injection of IL-10 resulted in lower cell numbers into the PEC of KO mice, suggesting that lower level of IL-10 is responsible for stimulated cell influx in KO mice due to lack of 4-1BB and 4-1BBL interaction. PMID- 17716665 TI - Single exposure of human fibroblasts (WI-38) to a sub-cytotoxic dose of UVB induces premature senescence. AB - In this work, we present a new model of stress-induced premature senescence obtained by exposing human fibroblasts (WI-38) at early passages (passages 2-4) to a single sub-cytotoxic dose of UVB (200 mJ/cm(2)). We show that this treatment leads to the appearance of several biomarkers of senescence such as enlarged and flattened cell morphology, the presence of nuclear heterochromatic foci and beta galactosidase activity. Furthermore, we demonstrate that a mild ROS production and p53 activation are upstream events required for the induction of premature senescence. Our method represents an alternative in vitro model in photoaging research and could be used to test potential anti-photoaging compounds. PMID- 17716666 TI - Cytokinesis is not controlled by calmodulin or myosin light chain kinase in the Caenorhabditis elegans early embryo. AB - Furrow ingression in animal cell cytokinesis is controlled by phosphorylation of myosin II regulatory light chain (mRLC). In Caenorhabditis elegans embryos, Rho dependent Kinase (RhoK) is involved in, but not absolutely required for, this phosphorylation. The calmodulin effector myosin light chain kinase (MLCK) can also phosphorylate mRLC and is widely regarded as a candidate for redundant function with RhoK. However, our results show that RNA mediated interference against C. elegans calmodulin and candidate MLCKs had no effect on cytokinesis in wild-type or RhoK mutant embryos, ruling out the calmodulin/MLCK pathway as the missing regulator of cytokinesis in the C. elegans early embryo. PMID- 17716667 TI - Recombinant Tol2 transposase with activity in Xenopus embryos. AB - The Tol2 transposon system is a useful gene transduction technique, but the injection of mRNA is not sufficiently effective in Xenopus embryos to express Tol2 transposase (Tol2TP). To overcome this, we bacterially synthesized recombinant Tol2TP (rTol2TP) protein and showed that rTol2TP efficiently excised the Tol2 element from an injected donor plasmid in Xenopus embryos. Furthermore, injected embryos exhibited uniform and ubiquitous expression of an EGFP reporter gene placed within the Tol2 element. Importantly, size-exclusion chromatography suggests that rTol2TP forms a tetramer, which differs from the reported hexamer formed by Hermes transposase, although both belong to the same hAT family. The use of rTol2TP may facilitate efficient gene transduction in Xenopus, and the biochemical characterization of Tol2TP. PMID- 17716668 TI - The double-strand RNA-dependent protein kinase PKR plays a significant role in a sustained ER stress-induced apoptosis. AB - Sustained ER stress leads to apoptosis. However, the exact mechanism still remains to be elucidated. Here, we demonstrate that the double strand RNA dependent protein kinase (PKR) is involved in the ER stress-mediated signaling pathway. ER stress rapidly activated PKR, inducing the phosphorylation of eIF2alpha, followed by the activation of the ATF4/CHOP pathway. ER-stress mediated eIF2alpha/ATF4/CHOP signaling and associated cell death was markedly reduced by PKR knockdown. We also found that PKR activation was mediated by PACT, the expression of which was elevated by ER-stress. These results indicate that the ER-stress-mediated eIF2alpha/ATF4/CHOP/cell death pathway is, to some degree, dependent on PACT-mediated PKR activation apart from the PERK pathway. PMID- 17716669 TI - A mechanism of Munc18b-syntaxin 3-SNAP25 complex assembly in regulated epithelial secretion. AB - Syntaxin and Munc18 are essential for regulated exocytosis in all eukaryotes. It was shown that Munc18 inhibition of neuronal syntaxin 1 can be overcome by CDK5 phosphorylation, indicating that structural change disrupts the syntaxin-Munc18 interaction. Here, we show that this phosphorylation promotes the assembly of Munc18b-syntaxin 3-SNAP25 tripartite complex and membrane fusion machinery SNARE. Using siRNAs to screen for genes required for regulated epithelial secretion, we identified the requirements of CDK5 and Munc18b in cAMP-dependent gastric acid secretion. Biochemical characterization revealed that Munc18b bears a syntaxin 3 selective binding site located at its most C-terminal 53 amino acids. Significantly, the phosphorylation of Thr572 by CDK5 attenuates Munc18b-syntaxin 3 interaction and promotes formation of Munc18b-syntaxin 3-SNAP25 tripartite complex, leading to an assembly of functional Munc18b-syntaxin 3-SNAP25-VAMP2 membrane fusion machinery. Thus, our studies suggest a novel regulatory mechanism in which phosphorylation of Munc18b operates vesicle docking and fusion in regulated exocytosis. PMID- 17716671 TI - Conditioned medium obtained from in vitro differentiated adipocytes and resistin induce insulin resistance in human hepatocytes. AB - Adipocyte-derived factors might play a role in the development of hepatic insulin resistance. Resistin was identified as an adipokine linking obesity and insulin resistance. Resistin is secreted from adipocytes in rodents but in humans it was proposed to originate from macrophages and its impact for insulin resistance has remained elusive. To analyze the role of adipokines in general and resistin as a special adipokine, we cultured the human liver cell line HepG2 with adipocyte conditioned medium (CM) containing various adipokines such as IL-6 and MCP-1, and resistin. CM and resistin both induce insulin resistance with a robust decrease in insulin-stimulated phosphorylation of Akt and GSK3. Insulin resistance could be prevented by co-treatment with troglitazone but not by co-stimulation with adiponectin. As human adipocytes do not secrete resistin, HepG2 cells were also treated with resistin added into CM. CM with resistin addition induced stronger insulin resistance than CM alone pointing to a specific role of resistin in the initiation of hepatic insulin resistance in humans. PMID- 17716670 TI - The RhoA transcriptional program in pre-T cells. AB - The GTPase RhoA is essential for the development of pre-T cells in the thymus. To investigate the mechanisms used by RhoA to control thymocyte development we have used Affymetrix gene profiling to identify RhoA regulated genes in T cell progenitors. The data show that RhoA plays a specific and essential role in pre-T cells because it is required for the expression of transcription factors of the Egr-1 and AP-1 families that have critical functions in thymocyte development. Loss of RhoA function in T cell progenitors causes a developmental block that pheno-copies the consequence of losing pre-TCR expression in Recombinase gene 2 (Rag2) null mice. Transcriptional profiling reveals both common and unique gene targets for RhoA and the pre-TCR indicating that RhoA participates in the pre-TCR induced transcriptional program but also mediates pre-TCR independent gene transcription. PMID- 17716672 TI - Bim mediates mitochondria-regulated particulate matter-induced apoptosis in alveolar epithelial cells. AB - We studied the role of Bim, a pro-apoptotic BCL-2 family member in Airborne particulate matter (PM 2.5 microm)-induced apoptosis in alveolar epithelial cells (AEC). PM induced AEC apoptosis by causing significant reduction of mitochondrial membrane potential and increase in caspase-9, caspase-3 and PARP-1 activation. PM upregulated pro-apoptotic protein Bim and enhanced translocation of Bim to the mitochondria. ShRNABim blocked PM-induced apoptosis by preventing activation of the mitochondrial death pathway suggesting a role of Bim in the regulation of mitochondrial pathway in AEC. Accordingly, we provide the evidence that Bim mediates PM-induced apoptosis via mitochondrial pathway. PMID- 17716673 TI - Downstream intronic splicing enhancers. AB - Alternative splicing leads to multiple proteins from individual genes and the most common deviation from the norm is precise exon omission. Mutations that cause this can be found deep in introns, especially downstream of the cassette exon. This review summarises what is known about these intronic splicing enhancers and their RNA-binding proteins that cause spliceosome assembly on the upstream exon. PMID- 17716674 TI - Ecdysteroids, juvenile hormone and insect neuropeptides: Recent successes and remaining major challenges. AB - In the recent decade, tremendous progress has been realized in insect endocrinology as the result of the application of a variety of advanced methods in neuropeptidome- and receptor research. Hormones of which the existence had been shown by bioassays four decades ago, e.g. bursicon (a member of the glycoprotein hormone family) and pupariation factor (Neb-pyrokinin 2, a myotropin), could be identified, along with their respective receptors. In control of diurnal rhythms, clock genes got company from the neuropeptide Pigment Dispersing Factor (PDF), of which the receptor could also be identified. The discovery of Inka cells and their function in metamorphosis was a true hallmark. Analysis of the genomes of Caenorhabditis elegans, Drosophila melanogaster and Apis mellifera yielded about 75, 100 and 200 genes coding for putative signaling peptides, respectively, corresponding to approximately 57, 100 and 100 peptides of which the expression could already be proven by means of mass spectrometry. The comparative approach invertebrates-vertebrates recently yielded indications for the existence of counterparts in insects for prolactin, atrial natriuretic hormone and Growth Hormone Releasing Hormone (GRH). Substantial progress has been realized in identifying the Halloween genes, a membrane receptor(s) for ecdysteroids, a nuclear receptor for methylfarnesoate, and dozens of GPCRs for insect neuropeptides. The major remaining challenges concern the making match numerous orphan GPCRs with orphan peptidic ligands, and elucidating their functions. Furthermore, the endocrine control of growth, feeding-digestion, and of sexual differentiation, in particular of males, is still poorly understood. The finding that the prothoracic glands produce an autocrine factor with growth factor-like properties and secrete proteins necessitates a reevaluation of their role in development. PMID- 17716675 TI - Hormonal correlates of human paternal interactions: a hospital-based investigation in urban Jamaica. AB - To expand our understanding of the neuroendocrine mechanisms underlying human fatherhood, including its cross-cultural expression, we investigated the hormonal correlates of fatherhood in the greater Kingston, Jamaica area. We recruited 43 men, aged 18-38, to participate: 15 single men; 16 "coresidential" fathers (men who live with their adult female partner and youngest child); and 12 "visiting" fathers (men who live apart from their adult female partner and youngest child). The research protocol entailed biological sampling before and after a 20-min behavioral session during which single men sat alone and fathers interacted with their partner and youngest child. Hormone measures relied upon minimally invasive techniques (salivary testosterone and cortisol, finger prick blood spot prolactin, urinary oxytocin and vasopressin). Results revealed significant group differences in average male testosterone levels (p=0.006), with post hoc contrasts indicating that visiting fathers had significantly (p<0.05) lower testosterone levels than single men. Prolactin profiles also differed significantly across groups (p=0.010) whereby post hoc contrasts showed that prolactin levels of single men declined significantly compared with the flat levels of visiting fathers (p<0.05). No group differences in cortisol, oxytocin or vasopressin levels were observed. However, among fathers, vasopressin levels were significantly and negatively (r=-.431, p=0.022) correlated with the age of a man's youngest child. These results thus implicate lower testosterone levels as well as prolactin and vasopressin in human fatherhood. These findings also highlight the importance of sociocultural context in human fatherhood while exhibiting parallels with existing data on the non-human vertebrate hormonal bases of paternal care. PMID- 17716677 TI - Simultaneous separation of anionic and cationic proteins by capillary electrophoresis using high concentration of poly(diallyldimethylammonium chloride) as an additive. AB - The simultaneous separation of anionic and cationic proteins has been achieved by addition of high concentration of poly(diallyldimethylammonium chloride) (PDDAC) in capillary electrophoresis. A capillary was filled with PDDAC so that it would act as ion-pair reagents in the separation of anionic proteins. On the other hand, the PDDAC can also be used as coating additives for the analysis of cationic proteins. Increasing the concentration of PDDAC in the separation buffer had the ability to improve the separation efficiency, change the electrophoretic mobility, and alter the separation selectivity; however, this was not true in the case of analyzing proteins by using the PDDAC larger than 1.6%. By both using a buffer containing 1.6% PDDAC and applying pH-stepwise techniques, 13 proteins with a wide range of pI (4.7-11.1) and molecular masses (6.5-198.0 kDa) could be separated within 30 min in a single run. In addition to this separation, we observed not only more peaks from alpha-chymotrypsinogen A and aprotinin but also the bovine serum albumin (BSA) dimer and trimer. With the 50 nL protein injection sample, the limits of detections at signal-to-noise of 3 for proteins are in the range of 0.07-0.79 microM. Except for BSA, the relative standard derivation values of migration time and peak height for all proteins were <1.3 and <6.9%, respectively. We suggested that this proposed method is a promising approach for clinical diagnosis and proteomics applications. PMID- 17716676 TI - In vivo micro-CT scanning of a rabbit distal femur: repeatability and reproducibility. AB - Before in vivo micro-CT scanning can be used to investigate femoral trabecular microarchitecture over time in rabbits, its repeatability and reproducibility must be demonstrated. To accomplish this, both distal femurs of two 6-month-old New Zealand white rabbits were scanned five times each in 1 day under different conditions (repeatability). Scanning was done at 28 microm isotropic voxel size to produce five image stacks of each femur. Three operators then followed a standard image processing protocol (reproducibility) to isolate two separate cubes from each anterior femoral condyle [total n = (8 cube sites)(5 scans)(3 operators) = 120]. Bone volume fraction (BV/TV) of the eight different cube sites (sample) ranged from 0.408 to 0.501 (mean: 0.453); trabecular thickness (Tb.Th) ranged from 158.1 to 185.5 microm (mean: 168.6 microm); and trabecular separation (Tb.Sp) ranged from 179.4 to 233.1 microm (mean: 204.7 microm). Using ANOVA and the variance component method, the total process variation was +/- 14.1% of the mean BV/TV of 0.453. The sample variation was +/- 13.9% (p < 0.001), the repeatability was +/- 2.1% (p < 0.001), and the reproducibility was +/- 0.1% (p > 0.05). Results were similar for Tb.Th and Tb.Sp. Though the contribution due to repeatability was statistically significant for each of the three indices, the natural sample differences were far greater than differences caused by repeated scanning under different conditions or by different operators processing the images. These findings suggest that in vivo micro-CT scanning of rabbit distal femurs was repeatable and reproducible and can be used with confidence to measure differences in trabecular bone microarchitecture at a single location in a longitudinal study design. PMID- 17716678 TI - From simple amphiphilic to surfactant behavior: analysis of (1)H NMR chemical shift variations. AB - Analysis of the (1)H NMR chemical shift variations for the methyl protons of sodium decanoate and decanoic acid in D(2)O solutions using reduced variables is consonant with a narrow distribution of sizes about the mean aggregation number for decanoate ion micelles, in contrast with decanoic acid polydisperse aggregates which increase their size with concentration, until phase separation is reached. At defined temperatures between 10 and 50 degrees C, the chemical shift coefficients for the methyl group protons exhibit a negative temperature slope (shielding) for decanoate ion micelles and a positive temperature slope (deshielding) for decanoic acid aggregates. These results suggest that an increase of temperature improves the mobility of the decanoate ion chains in the micelles, thus inducing the methyl groups of the decanoate ion micelles to spend more time near the micelle-water interfaces. In turn, the size of polydisperse decanoic acid aggregates increases with temperature. PMID- 17716679 TI - Water in oil emulsion droplet size characterization using a pulsed field gradient with diffusion editing (PFG-DE) NMR technique. AB - This paper describes a proton nuclear magnetic resonance (NMR) technique, pulsed field gradient with diffusion editing (PFG-DE), to quantify drop size distributions of brine/crude oil emulsions. The drop size distributions obtained from this technique were compared to results from the traditional pulsed field gradient (PFG) technique. The PFG-DE technique provides both transverse relaxation (T2) and drop size distributions simultaneously. In addition, the PFG DE technique does not assume a form of the drop size distribution. An algorithm for the selection of the optimal parameters to use in a PFG-DE measurement is described in this paper. The PFG-DE technique is shown to have the ability to resolve drop size distributions when the T2 distribution of the emulsified brine overlaps either the crude oil or the bulk brine T2 distribution. Finally, the PFG DE technique is shown to have the ability to resolve a bimodal drop size distribution. PMID- 17716680 TI - Detection and quantitation of eosinophils in the murine respiratory tract by flow cytometry. AB - Traditionally, the identification and quantification of eosinophils in inflammatory tissues and exudates has been primarily based upon morphologic criteria and manual counting. In this study, we describe a new flow cytometry based assay to enumerate eosinophils present in murine bronchoalveolar lavage fluid (BAL) and lung parenchyma obtained from the normal/non-inflamed respiratory tract, following experimentally-induced allergic pulmonary inflammation, and during experimental infection with respiratory syncytial virus (RSV). By using a murine Siglec-F-specific antibody in combination with antibodies directed to CD45 and CD11c, we demonstrate that eosinophils can be distinguished from other cell types in the BAL fluid and lung parenchyma based upon their distinct CD45(+) Siglec-F(+) and CD11c(low/-) staining profile. In the BAL fluid, this flow cytometry-based method of eosinophil identification/quantitation yields results comparable to the standard morphology-based method without the potential observer bias or staining artifacts inherent in morphology-based quantitation. Furthermore, this flow cytometry-based method can be directly adapted to enumerate eosinophils infiltrating the inflamed lung parenchyma, thereby obviating the need for quantitative morphometry of tissue sections. PMID- 17716681 TI - Large scale expansion of gamma 9 delta 2 T lymphocytes: Innacell gamma delta cell therapy product. AB - gamma9delta2 T lymphocytes are non-conventional lymphocytes presenting a direct cytotoxic effect against a broad range of tumour targets. These cells also secrete inflammatory cytokines that can boost the other components of the immune system. In contrast to conventional CD8(+) T cells, the cytotoxic effect of gamma9delta2 T lymphocytes does not depend on the expression of major histocompatibility complex molecules by target tumour cells. INNACELL gammadeltatrade mark is a cell therapy product obtained by ex vivo amplification of mononuclear cells. The stimulation is achieved by a specific synthetic agonist of gamma9delta2 T lymphocytes, bromohydrin pyrophosphate (BrHPP). After a single stimulation with BrHPP, gamma9delta2 T lymphocytes are expanded for 2 weeks in a closed system in culture medium with interleukin-2 (IL-2). On day 15, cells are washed and harvested in 4% human serum albumin. In this manufacturing process, the total cell population is expanded by approximately 10-fold and gamma9delta2 T lymphocytes undergo a specific 1000-fold expansion, corresponding to a gamma9delta2 T lymphocyte enrichment of more than 70% at the end of the culture. This manufacturing process is much simpler than most current cellular therapy approaches using conventional CD8(+) T-cell lines or clones: there is no final or initial separation, no purification step and no use of feeder cells; the specific T-cell receptor-mediated signal provided by BrHPP is sufficient to trigger the IL 2-dependent expansion of the gamma9delta2 subset, which then becomes predominant in the cell culture in large amounts. PMID- 17716682 TI - An Affinity Capture Elution (ACE) assay for detection of anti-drug antibody to monoclonal antibody therapeutics in the presence of high levels of drug. AB - Monoclonal antibody therapeutics typically have relatively long half-lives and can be dosed at high levels. Although formation of anti-drug antibodies (ADA) is relatively rare, detection of these antibodies can be very difficult in the presence of high circulating levels of drug. Typically these ADA are detected by bridging ELISAs which can be very sensitive to even low levels of drug. We describe an ELISA method based on affinity capture of ADA on solid-phase drug followed by removal of excess free drug, release and transfer of bound ADA and subsequent detection using biotinylated drug. The assay is both sensitive and highly tolerant to free drug with detection of 500 ng/ml of ADA readily achieved in the presence of 500 mug/ml of drug. PMID- 17716683 TI - Autologous CD4/CD8 co-culture assay: a physiologically-relevant composite measure of CD8+ T lymphocyte function in HIV-infected persons. AB - During HIV-1 infection, the CD8(+) T lymphocyte response is critical to controlling the virus; indeed, the development of AIDS results, in large part, from the eventual failure of this response. The ability to measure the composite CD8(+) T lymphocyte anti-viral activity is, therefore, an essential requirement in the evaluation of immune based therapies and potential vaccines. We report here the details of a reproducible assay that measures the ability of CD8(+) T lymphocytes to suppress viral production by infected autologous CD4(+) T lymphocytes. The assay is not limited to persons with any specific HLA type, and the use of bi-specific antibodies for cell expansion makes the assay feasible in situations where cell numbers may be limiting. The measurement of viral production over time provides a global readout of the CD8(+) T lymphocyte overall function against HIV-1, which can be used for longitudinal assessment of individual HIV-infected persons in order to evaluate therapy, immune reconstitution, and new vaccines. PMID- 17716684 TI - Validation of RNA-based molecular clonotype analysis for virus-specific CD8+ T cells in formaldehyde-fixed specimens isolated from peripheral blood. AB - Recent advances in the field of molecular clonotype analysis have enabled detailed repertoire characterization of viably isolated antigen-specific T cell populations directly ex vivo. However, in the absence of a biologically contained FACS facility, peripheral blood mononuclear cell (PBMC) preparations derived from patients infected with agents such as HIV must be formaldehyde fixed to inactivate the pathogen; this procedure adversely affects nucleic acid template quality. Here, we developed and validated a method to amplify and sequence mRNA species derived from formaldehyde fixed PBMC specimens. Antigen-specific CD8+ cytotoxic T-lymphocyte populations were identified with standard fluorochrome conjugated peptide-major histocompatibility complex class I tetramers refolded around synthetic peptides representing immunodominant epitopes from HIV p24 Gag (KRWII[M/L]GLNK/HLA B*2705) and CMV pp65 (NLVPMVATV/HLA A*0201 and TPRVTGGGAM/HLA B*0702), and acquired in separate laboratories with or without fixation. In the presence of proteinase K pre-treatment, the observed antigen-specific CD8+ T-cell repertoire determined by molecular clonotype analysis was statistically no different whether derived from fixed or unfixed PBMC. However, oligo-dT recovery methods were not suitable for use with fixed tissue as significant skewing of clonotypic representation was observed. Thus, we have developed a reliable RNA based method for molecular clonotype analysis that is compatible with formaldehyde fixation and therefore suitable for use with primary human samples isolated by FACS outside the context of a biological safety level 3 containment facility. PMID- 17716685 TI - Cell death and regeneration in the midgut of the mosquito, Culex quinquefasciatus. AB - Haematophagy, the utilization of blood as food, has evolved independently among insects such as mosquitoes, bedbugs, fleas, and others. Accordingly, several distinct biological adaptations have occurred in order to facilitate the finding, ingestion and digestion of blood from vertebrate sources. Although blood meals are essential for survival and reproduction of these insects, mechanical and chemical stresses are caused by the ingestion of a sizable meal (frequently twice or more times the weight of the insect) containing large amounts of cytotoxic molecules such as haem. Here we present data showing that the stresses caused by a blood meal induce cell death in the midgut epithelium of Culex quinquefasciatus mosquitoes. The process involves apoptosis, ejection of dead cells to the midgut lumen and differentiation of basal regenerative cells to replace the lost digestive cells. The basal cell differentiation in blood-fed mosquito midguts represents an additional mechanism by which insects cope with the stresses caused by blood meals. C. quinquefasciatus adult females are unable to replace lost cells following a third or fourth blood meal, which may have a significant impact on mosquito longevity, reproduction and vectorial capacity. PMID- 17716686 TI - Perceptual differences in trail-following leaf-cutting ants relate to body size. AB - Leaf-cutting ants of the genus Atta have highly size-polymorphic workers, and size is related to division of labor. We studied trail-following behavior of different-sized workers in a laboratory colony of Atta vollenweideri. For small and large workers, we measured responsiveness and preference to artificial conspecific and heterospecific pheromone trails made from poison gland extracts of A. vollenweideri and A. sexdens. Responsiveness was measured as the probability of trail-following, and preference was measured by testing the discrimination between one conspecific and one heterospecific trail. Minute amounts of the releaser component methyl-4-methylpyrrole-2-carboxylate (0.4pg/1m), present in both, conspecific and heterospecific trails, suffice to elicit trail-following behavior. Workers followed heterospecific trails, and these trails (after normalizing their concentration) were as effective as conspecific trails. Small workers were less likely to follow a trail of a given concentration than large workers. In the discrimination test, small workers preferred the conspecific trail over the heterospecific trail, whereas large workers showed no significant preference. It is suggested that large workers primarily respond to the releaser component present in both trails, whereas small workers focus more on the conspecific traits provided by the blend of components contained in the trail pheromone. PMID- 17716687 TI - Characterization and identification of virulent Klebsiella oxytoca isolated from abalone (Haliotis diversicolor supertexta) postlarvae with mass mortality in Fujian, China. AB - An epidemic of mass mortality of abalone (Haliotis diversicolor supertexta) postlarvae aged 40 days or less has existed across south coast of China since the second half of 2002. Among 20 bacterial strains isolated from diseased abalone postlarvae on 2216E marine agar plates during an outbreak of postlarval disease in August 2005, a predominant strain (designated strain 20) was demonstrated to be virulent to postlarvae with an LD(50) value of 1.0x10(5) colony forming units (CFUml(-1)) on day 4, while the other 19 strains were either avirulent (16 strains) or weakly virulent (3 strains). The same bacterium could be re-isolated from postlarvae after bacterial challenge using 2216E marine agar plates. Preliminary toxicity tests of ECPs of strain 20 revealed that at 2.77mgproteinml( 1), crude ECPs completely liquefied postlarvae within 24h, leaving only shells. API 20E analysis identified strain 20 as Klebsiella oxytoca. 16S and ITS rDNA sequencing and phylogenetic analyses further confirmed this identification. Antibiotic susceptibility tests showed that strain 20 exhibited 94% of susceptibility to 16 various antibiotics tested and only showed resistance to streptomycin. Results of this work demonstrated that K. oxytoca is also linked to this epidemic in Fujian, China. This is considered to be the first report regarding K. oxytoca involved in the mass mortality of postlarval abalone in south China and the world. PMID- 17716688 TI - Do stem cells in the heart truly differentiate into cardiomyocytes? AB - Chronic congestive heart failure (CHF) is a common consequence of heart muscle or valve damage and remains a major cause of morbidity and mortality worldwide. There are increasing interests to treat cardiac failure by stem cell-based therapy. Many types of stem cells or progenitor cells have been suggested for cellular therapy of heart failure. While stem cell-based therapy was initially thought to be achieved by transdifferentiation of stem cells into myocardial cells including cardiomyocytes it has become clear that this may be rather an infrequent event. Instead cardiac regeneration may result from vascular differentiation of stem cells or even from stem cell-mediated reverse remodelling. Thus the term stem cell-mediated cardiac regeneration covers the spectrum from stem cell transdifferentiation into cardiomyocytes to cell-mediated pharmacotherapy. In this review we revise stem cell-based cardiac regeneration both in experimental models and in clinical application. We have limited our discussion on some selected types of stem cells, with particular emphasis on their differentiation potential, current status and perspectives on their future applications. PMID- 17716689 TI - Structure of the Wilms tumor suppressor protein zinc finger domain bound to DNA. AB - The zinc finger domain of the Wilms tumor suppressor protein (WT1) contains four canonical Cys(2)His(2) zinc fingers. WT1 binds preferentially to DNA sequences that are closely related to the EGR-1 consensus site. We report the structure determination by both X-ray crystallography and NMR spectroscopy of the WT1 zinc finger domain in complex with DNA. The X-ray structure was determined for the complex with a cognate 14 base-pair oligonucleotide, and composite X-ray/NMR structures were determined for complexes with both the 14 base-pair and an extended 17 base-pair DNA. This combined approach allowed unambiguous determination of the position of the first zinc finger, which is influenced by lattice contacts in the crystal structure. The crystal structure shows the second, third and fourth zinc finger domains inserted deep into the major groove of the DNA where they make base-specific interactions. The DNA duplex is distorted in the vicinity of the first zinc finger, with a cytidine twisted and tilted out of the base stack to pack against finger 1 and the tip of finger 2. By contrast, the composite X-ray/NMR structures show that finger 1 continues to follow the major groove in the solution complexes. However, the orientation of the helix is non-canonical, and the fingertip and the N terminus of the helix project out of the major groove; as a consequence, the zinc finger side-chains that are commonly involved in base recognition make no contact with the DNA. We conclude that finger 1 helps to anchor WT1 to the DNA by amplifying the binding affinity although it does not contribute significantly to binding specificity. The structures provide molecular level insights into the potential consequences of mutations in zinc fingers 2 and 3 that are associated with Denys-Drash syndrome and nephritic syndrome. The mutations are of two types, and either destabilize the zinc finger structure or replace key base contact residues. PMID- 17716690 TI - Novel SACS mutation in a Belgian family with sacsin-related ataxia. AB - The authors describe the four patients in the first known Belgian family with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). A novel homozygous missense mutation, NM_014363.3: c.3491T>A in exon 9, of the SACS gene was identified in the present family, which results in an original amino acid of methionine to lysine substitution at amino acid residue 1164 (p.M1164K). Although the cardinal clinical features, i.e., spastic ataxia with peripheral neuropathy, in our patients were similar to those in Quebec patients, our patients exhibited some atypical clinical features, e.g., teenage-onset and absence of retinal hypermyelination. The present family is from Wallonia, and there could be shared ethnicity with the families of Charlevoix-Saguenay. PMID- 17716691 TI - Mechanokinetic model of cell membrane: theoretical analysis of plasmalemma homeostasis, growth and division. AB - A theoretical model dealing with endocytosis, exocytosis and caveolae invagination, describing plasmalemma homeostasis during cell growth and division, is proposed. It considers transmembrane pressure, membrane tension and mechanosensitivity of membrane processes. Membrane hydraulic conductivity and the flux of transmembrane nonvesicular transport are taken into account. The developed mathematical analysis operates with a formulated set of constitutive equations describing the mechanical state and kinetics of changes in an open dynamic membrane system. The standard version of a model with adjusted parameters was implemented, and predictions including a discussion on the effect of possible parameter modifications were presented. Computer simulations indicate big changes in the magnitude of membrane tension and elasticity, and in the number of membrane buddings in young cells and during mitosis. They also show the extent of cell growth inhibition resulting from a decrease in transmembrane transport or an increase in the exerted difference in osmotic pressure. Moreover, the simulations reveal that exocytosis regulated during mitosis may not be as important for cell growth, as sometimes presumed. Finally, practical application and possible extension of the model are discussed. PMID- 17716692 TI - Introduction of Trojan sex chromosomes to boost population growth. AB - Conservation programs that deal with small or declining populations often aim at a rapid increase of population size to above-critical levels in order to avoid the negative effects of demographic stochasticity and genetic problems like inbreeding depression, fixation of deleterious alleles, or a general loss of genetic variability and hence of evolutionary potential. In some situations, population growth is determined by the number of females available for reproduction, and manipulation of family sex ratios towards more daughters has beneficial effects. If sex determination is predominantly genetic but environmentally reversible, as is the case in many amphibia, reptiles, and fish, Trojan sex chromosomes could be introduced into populations in order to change sex ratios towards more females. We analyse the possible consequences for the introduction of XX-males (XX individuals that have been changed to phenotypic males in a XY/XX sex determination system) and ZW males, WW males, or WW females (in a ZZ/ZW sex determination system). We find that the introduction of WW individuals can be most effective for an increase of population growth, especially if the induced sex change has little or no effect on viability. PMID- 17716693 TI - Do blood capillaries exhibit optimal bumpiness? PMID- 17716694 TI - Energetic heavy ions accelerate differentiation in the descendants of irradiated normal human diploid fibroblasts. AB - Ionizing radiation-induced genomic instability has been demonstrated in a variety of endpoints such as delayed reproductive death, chromosome instability and mutations, which occurs in the progeny of survivors many generations after the initial insult. Dependence of these effects on the linear energy transfer (LET) of the radiation is incompletely characterized; however, our previous work has shown that delayed reductions in clonogenicity can be most pronounced at LET of 108 keV/microm. To gain insight into potential cellular mechanisms involved in LET-dependent delayed loss of clonogenicity, we investigated morphological changes in colonies arising from normal human diploid fibroblasts exposed to gamma-rays or energetic carbon ions (108 keV/microm). Exposure of confluent cultures to carbon ions was 4-fold more effective at inactivating cellular clonogenic potential and produced more abortive colonies containing reduced number of cells per colony than gamma-rays. Second, colonies were assessed for clonal morphotypic heterogeneity. The yield of differentiated cells was elevated in a dose- and LET-dependent fashion in clonogenic colonies, whereas differentiated cells predominated to a comparable extent irrespective of radiation type or dose in abortive colonies. The incidence of giant or multinucleated cells was also increased but much less frequent than that of differentiated cells. Collectively, our results indicate that carbon ions facilitate differentiation more effectively than gamma-rays as a major response in the progeny of irradiated fibroblasts. Accelerated differentiation may account, at least in part, for dose- and LET-dependent delayed loss of clonogenicity in normal human diploid cells, and could be a defensive mechanism that minimizes further expansion of aberrant cells. PMID- 17716695 TI - Visual half-field experiments are a good measure of cerebral language dominance if used properly: evidence from fMRI. AB - Traditional neuropsychology employs visual half-field (VHF) experiments to assess cerebral language dominance. This approach is based on the assumption that left cerebral dominance for language leads to faster and more accurate recognition of words in the right visual half-field (RVF) than in the left visual half-field (LVF) during tachistoscopic presentation. Information in the RVF is directly projected to the left hemisphere, whereas information presented in the LVF needs interhemispheric transfer to reach the left half of the brain. This interpretation of the RVF superiority for word recognition lacks direct evidence however, and a multitude of studies have lead to contradictory findings. To investigate this matter further we try to establish the ideal parameters for VHF experiments to measure language dominance, and subsequently compare laterality indices (LIs) obtained from RT patterns in bilateral VHF tasks to those LIs acquired in the same individuals during a mental word generation task in the fMRI scanner. Our results reveal a direct link between VHF advantages and individual language lateralization. Differences in behavioral performance between left hemisphere dominant and right-hemisphere dominant individuals suggest that carefully designed VHF tests can be used as a reliable predictor of cerebral language dominance. PMID- 17716696 TI - Effects of aging on true and false memory formation: an fMRI study. AB - Compared to young, older adults are more likely to forget events that occurred in the past as well as remember events that never happened. Previous studies examining false memories and aging have shown that these memories are more likely to occur when new items share perceptual or semantic similarities with those presented during encoding. It is theorized that decreased item-specific encoding and increased gist encoding contribute to these age differences in memory performance. The current study used a modified version of the Deese-Roediger McDermott (DRM) paradigm to investigate the neural correlates of true and false memory encoding. Results indicated that, compared to young, older adults showed reduced activity in medial temporal lobes (MTL), left ventrolateral prefrontal cortex (VLPFC), and visual cortices associated with subsequent true memories. Despite these decreases older adults showed increased activity in right VLPFC and left superior temporal gyrus (STG) for subsequent true memories. Age-related increases in STG were also associated with subsequent false memories. Results support the theory that older adults engage in less item-specific encoding and greater gist encoding, and that these increases in gist encoding support both subsequent true and false memories. Furthermore, results extend findings of reduced frontal asymmetry in aging, often found in block designs, to the subsequent memory paradigm. Results suggest that greater bilateral frontal activity during encoding in aging are not just task-related, but may be associated with subsequent successful memory performance. PMID- 17716698 TI - Maternal care affects male and female offspring working memory and stress reactivity. AB - Variations in maternal care affect the development of individual differences in learning and memory and neuroendocrine responses to stress in adult male offspring, but it is not known how variations in maternal care affect adult female offspring. The present study investigated the performance of adult Sprague Dawley male and female offspring exposed to either low or high levels of maternal licking/grooming on a spatial memory task (Experiment 1) and the effects of acute stress on corticosterone levels and spatial memory performance (Experiment 2). In Experiment 1 rats were trained for 24 days on the spatial working/reference memory version of the radial arm maze (RAM). In Experiment 2, rats were trained on the same RAM task, exposed to an acute stress, and the effect of stress on corticosterone levels and subsequent spatial memory was examined. In Experiment 1, adult female offspring of low licking/grooming dams had enhanced working memory compared to all other groups. In Experiment 2, all groups of male and female offspring had enhanced working memory 24 h after exposure to acute 2 h restraint stress while reference memory was enhanced after stress in male and female offspring of low licking/grooming dams. Furthermore, female offspring of low licking/grooming dams showed the largest corticosterone response to the acute restraint stress compared to all other groups. Male offspring of low licking/grooming dams showed a flattened corticosterone response to stress. Thus variations in maternal care differentially affect working memory and stress reactivity in male and female offspring. PMID- 17716699 TI - Assessment of the IgG index in dogs by indirect immunoenzimatic assays as diagnostic tool for inflammatory diseases of central nervous system. AB - The IgG index measures the intrathecal immunoglobulin production and it is a useful tool for diagnosis of inflammatory diseases involving the central nervous system. This index is based on the precise quantification of albumin and IgG in canine cerebrospinal fluid and serum. Here, we report the development of an indirect competitive ELISAs for the detection of both antigens. Thirty-two dogs were included in this study, divided into three experimental groups. Group A was composed of 22 healthy animals, as determined by standard clinical examination. In group B, six animals, presented neurological pathologies associated with endogenous IgG production and, in group C four animals presented neurological diseases or symptoms not associated with intrathecal IgG production. Cerebrospinal fluid and serum samples were obtained from these animals. As expected, by using the indirect ELISAs proposed here, the IgG indexes obtained in healthy animals (A) were 0.371+/-0.252 (SD). In B and C, the values (3.002+/ 1.897; 0.36+/-0.306, respectively), were in agreement with the pathologic conditions of the individuals in each group. Thus, the immunometric competition ELISA methods proposed here allow the discrimination of abnormal intrathecal IgG production, in a variety of inflammatory pathologic conditions of the central nervous system. PMID- 17716700 TI - Highly sensitive determination of estrone and estradiol in human serum by liquid chromatography-electrospray ionization tandem mass spectrometry. AB - A highly sensitive and specific quantification method of estrone and estradiol in human serum was described based upon the use of picolinoyl derivatization and liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) in a positive mode. Estrogens were treated with picolinoyl chloride hydrochloride or picolinic acid and 2-methyl-6-nitrobenzoic anhydride followed by a solid-phase extraction with ODS cartridge. Picolinoyl derivatization proceeded quantitatively even in a microscale, and the picolinoyl esters provided simple positive ESI-mass spectra showing [M+H](+) as base peaks for these estrogens. The picolinoyl derivatives of these estrogens showed 100-fold higher detection response compared to underivatized intact molecules by LC-ESI-MS (selected reaction monitoring). Using this derivatization, estrogens spiked in the charcoal treated human serum samples were analyzed with limit of quantification (LOQ), intra-day accuracy and precision of 1.0pg/ml, 96.0% and 9.9% for estrone, and 0.5pg/ml, 84.4% and 12.8% for estradiol, respectively. Estrone and estradiol added to the crude serum samples were recovered with comparable LOQ and accuracy obtained for the charcoal treated serum samples as well. PMID- 17716697 TI - Effects of anabolic androgenic steroids on the development and expression of running wheel activity and circadian rhythms in male rats. AB - In humans, anabolic androgenic steroid (AAS) use has been associated with hyperactivity and disruption of circadian rhythmicity. We used an animal model to determine the impact of AAS on the development and expression of circadian function. Beginning on day 68 gonadally intact male rats received testosterone, nandrolone, or stanozolol via constant release pellets for 60 days; gonadally intact controls received vehicle pellets. Wheel running was recorded in a 12:12 LD cycle and constant dim red light (RR) before and after AAS implants. Post-AAS implant, circadian activity phase, period and mean level of wheel running wheel activity were compared to baseline measures. Post-AAS phase response to a light pulse at circadian time 15 h was also tested. To determine if AAS differentially affects steroid receptor coactivator (SRC) expression we measured SRC-1 and SRC-2 protein in brain. Running wheel activity was significantly elevated by testosterone, significantly depressed by nandrolone, and unaffected by stanozolol. None of the AAS altered measures of circadian rhythmicity or phase response. While SRC-1 was unaffected by AAS exposure, SRC-2 was decreased by testosterone in the hypothalamus. Activity levels, phase of peak activity and circadian period all changed over the course of development from puberty to adulthood. Development of activity was clearly modified by AAS exposure as testosterone significantly elevated activity levels and nandrolone significantly suppressed activity relative to controls. Thus, AAS exposure differentially affects both the magnitude and direction of developmental changes in activity levels depending in part on the chemical composition of the AAS. PMID- 17716701 TI - The identification and simultaneous quantification of neuroactive androstane steroids and their polar conjugates in the serum of adult men, using gas chromatography-mass spectrometry. AB - Certain androstane steroids (AS) modulate ionotropic receptors, as do the pregnane steroids. Whereas women produce significant amounts of neuroactive progesterone metabolites, the steroid neuromodulators in men originate mainly from the 3-oxo-4-ene C(19)-steroids, which are converted to their 3alpha- and 3beta-hydroxy-5alpha/5beta-reduced metabolites. The neuromodulating effects of AS prompted us to monitor circulating levels of the steroids to estimate metabolic pathways in the periphery that may influence brain concentrations of AS. Hence, the serum levels of 20 steroids and 16 steroid polar conjugates including 17-oxo- and 17beta-hydroxy-derivatives of 5alpha/beta-androstane-3alpha/beta-hydroxy androstane steroids were quantified in 15 men (16-62 years of age) using GC-MS. The conjugated AS for the most part reached micromolar concentrations, these being two or three orders of magnitude higher than those of the free steroids. The ratios of conjugates to free steroids were one to two orders of magnitude higher than the values for the corresponding pregnane steroids. This data suggested that conjugation may considerably restrain the transport of free AS from the periphery into the central nervous system. PMID- 17716702 TI - The degradation pathway for the HBV envelope proteins involves proteolysis prior to degradation via the cytosolic proteasome. AB - To study the pathway of degradation of the hepatitis B virus (HBV) middle envelope protein (M), human hepatoblastoma cells were transfected with a plasmid that specifies production of M in the absence of other viral proteins. When expressed in HepG2 cells, 90% of M protein was secreted into the culture media within a 24-h period. However, quite surprisingly, 10% of this protein remained cell associated and was only slowly degraded over a 24-48-h period. Treatment with inhibitors of the cytosolic proteasome complex resulted in the accumulation of full-length HBV M protein and M derived HBV-specific polypeptides of 20 and 17 kDa. Treatment with the endoglycosidases PNGase F and Endo H, confirmed that the two species were derived from a similar polypeptide with a N-linked glycan modification. Evidence that this peptide was derived from a proteolytic processing event was determined through the detection of the C-terminal fragment using a C-terminal tagged HA tagged construct. The hypothesis that the 20 and 17 kDa polypeptide species are intermediates of M degradation was reinforced by their detection in cells transfected with vectors specifying M secretion defective mutants that accumulate intracellular M. Moreover, deletion of a putative cleavage sites prevented the detection of the 20 and 17 kDa species, consistent with the notion that they are generated by the action of a cellular protease prior to proteasomal degradation. Thus, these results highlight an important way in which large protein aggregates, such as the HBsAg can be processed for efficient degradation via the proteasomes and allow for proper antigen presentation via the MHC I pathway. PMID- 17716704 TI - Biomonitoring of nine elements by the lichen Xanthoria parietina in Adriatic Italy: a retrospective study over a 7-year time span. AB - The results of long-term biomonitoring of nine elements (Cd, Cr, Ni, Pb, V, Cu, Zn, Fe and Al) with the epiphytic lichen Xanthoria parietina over a seven year time span are reported. A total of 51 sampling stations were monitored in two surveys, obtaining information about heavy metal concentrations in a large area characterized by a high impact of industrial and urban sources of air pollution. The results showed that the approach adopted is indeed a reliable tool to assess environmental alteration, pinpointing not only the trends of the nine elements analysed but also their reciprocal correlations. As a consequence it was possible to characterize changes in air pollution composition and the common origin and behavior of several groups of elements. PMID- 17716705 TI - The sedimentary fluxes of polycyclic aromatic hydrocarbons in the Yangtze River Estuary coastal sea for the past century. AB - Polycyclic aromatic hydrocarbons (PAHs) in two (210)Pb dated sediment cores from the coastal East China Sea, strongly influenced by the discharge from the Yangtze River, were determined to help to reconstruct the economic development over the past century in East China. The variations in PAH concentrations and fluxes in the sediment cores were primarily due to energy structure change, severe floods and dam construction activities. The impact on PAHs by the river discharge overwhelmed the atmospheric depositions. The profiles of PAH fluxes and concentrations as well as compositions in the cores revealed the transformation from an agricultural economy to an industrial one especially after the 1990s' in the region. PAHs in the study area were dominated by pyrolytic sources. PMID- 17716703 TI - Human cytomegalovirus and human immunodeficiency virus type-1 co-infection in human cervical tissue. AB - Human cytomegalovirus (HCMV) and human immunodeficiency virus type-1 (HIV-1) infect the female genital tract. A human cervical explant model was developed to study single and dual infection by these viruses in the genital compartment. An HCMV strain expressing green fluorescent protein, and two clinical HCMV strains produced peak viral DNA copies at 14 to 21 days post-infection. Peak levels of HIV-1(Ba-L) p24 antigen occurred at 7 days post-infection. HIV-1(Ba-L) appeared to enhance HCMV in co-infected tissues. Singly and dually infected explants produced increased levels of cytokines IL-6, IL-8, and GRO-alpha in culture supernatants. Immunohistochemical and flow cytometric analysis showed HCMV infection of leukocytes with the phenotype CD45+/CD1a+/CD14+/HLA-DR+ but not stromal or endothelial cells. Cells expressing both GFP and HIV-1 p24 antigen were detected in co-infected tissues. The cervical explants provide an ex vivo human model for examining mechanisms of virus-virus interaction and pathogenesis in clinically relevant tissue. PMID- 17716706 TI - Modeling of trihalomethane (THM) formation via chlorination of the water from Dongjiang River (source water for Hong Kong's drinking water). AB - The Dongjiang River is the major source of drinking water supply for Hong Kong. The deterioration of the water quality of the Dongjiang River and excessive trihalomethanes (THMs) in the tap water of some districts in Hong Kong have become causes for public concern. The main objective of the present study is to investigate and model THM formation due to the chlorination of the Dongjiang River water under different chlorination conditions. The results showed that the total THM formation ranged between 11.7 and 91.8 mg L(-1) and that control of the levels was primarily due to the reaction time and the Br(-) level in the water. Bromide concentration was a key factor in determining bromine-containing THM formation and consequently the speciation of THMs. Higher concentrations of bromide shifted THM species to more-bromine-containing ones, while the kinetics reflected the competing halogenation reactions. As the two mixed-halogen THMs had high cancer potency, the cancer risk of total THMs appeared to reach a peak at a bromide concentration ranging between 218 and 262 mg L(-1) (with a bromide to dissolved organic carbon molar ratio (Br(-)/DOC) ranging between 15 and 18 mM/mM). PMID- 17716708 TI - Factors influencing particle number concentrations, size distributions and modal parameters at a roof-level and roadside site in Leicester, UK. AB - Measurements of urban particle number concentrations and size distributions in the range 5-1000 nm were taken at elevated (roof-level) and roadside sampling sites on Narborough Road in Leicester, UK, along with simultaneous measurements of traffic, NO(x), CO and 1,3-butadiene concentrations and meteorological parameters. A fitting program was used to determine the characteristics of up to five modal groups present in the particle size distributions. All particle modal concentrations peaked during the morning and evening rush hours. Additional events associated with the smallest mode, that were not observed to be connected to primary emissions, were also present suggesting that this mode consisted of newly formed secondary particles. These events included peaks in concentration which coincided with peaks in solar radiation, and lower concentrations of the larger modes. Investigation into the relationships between traffic flow and occupancy indicated three flow regimes; free-flow, unstable and congested. During free-flow conditions, positive linear relationships existed between traffic flow and particle modal number concentrations. However, during unstable and congested periods, this relationship was shown to break-down. Similar trends were observed for concentrations of the gas phase pollutants NO(x), CO and 1,3-butadiene. Strong linear relationships existed between NO(x), CO, 1,3-butadiene concentrations, nucleation and Aitken mode concentrations at both sampling locations, indicating a local traffic related emission source. At the roadside, both nucleation and Aitken mode are best represented by a decreasing exponential function with wind speed, whereas at the roof-level this relationship only occurred for Aitken mode particles. The differing relationships at the two sampling locations are most likely due to a combination of meteorological factors and distance from the local emission source. PMID- 17716707 TI - Glutathione-S-transferase polymorphism, metallothionein expression, and mercury levels among students in Austria. AB - BACKGROUND: Detoxification is an essential process in all living organisms. Humans accumulate heavy metals primarily as a result of lifestyle and environmental contamination. However, not all humans experience the estimated individual exposure. This suggests the presence of genetic regulatory mechanisms. OBJECTIVE: In order to identify genetic factors underlying the inter-individual variance in detoxification capacity for the heavy metal mercury, 192 students were investigated. We focused on the relationship between polymorphisms in glutathione-S-transferase (GST) genes and mercury concentrations in blood, urine, and hair. The correlation between blood mercury levels, GSTT1 and GSTM1 polymorphism, and gene expression of certain metallothionein subgroups (MT1, MT3) was evaluated in a further group of students (N=30). METHODS: Mercury levels in acid digested samples were measured by cold vapor AAS. Genotyping of the GSTT1 and GSTM1-gene deletion polymorphism was performed by means of PCR. Gene expression of several MT genes was analyzed in lymphocytes from fresh peripheral blood by semiquantitative RT-PCR. RESULTS: The following was noted: a) hair mercury concentrations are significantly increased in persons with the double deleted genotype (GSTT1-/- and GSTM1-/-) as compared to persons with the intact genotype, and b) MT1X expression is higher in persons with the intact genotype (GSTT1+/+ and GSTM1+/+). CONCLUSIONS: We conclude that the epistatic effect of the GSTT1 and the GSTM1 deletion polymorphism is a risk factor for increased susceptibility to mercury exposure. The relationship between MT gene expression and GST gene polymorphisms needs further investigation. If MT expression depends on GST polymorphisms it would have important implications on the overall metal detoxification capability of the human organism. PMID- 17716709 TI - Source apportionment of PM(2.5) and selected hazardous air pollutants in Seattle. AB - The potential benefits of combining the speciated PM(2.5) and VOCs data in source apportionment analysis for identification of additional sources remain unclear. We analyzed the speciated PM(2.5) and VOCs data collected at the Beacon Hill in Seattle, WA between 2000 and 2004 with the Multilinear Engine (ME-2) to quantify source contributions to the mixture of hazardous air pollutants (HAPs). We used the 'missing mass', defined as the concentration of the measured total particle mass minus the sum of all analyzed species, as an additional variable and implemented an auxiliary equation to constrain the sum of all species mass fractions to be 100%. Regardless of whether the above constraint was implemented and/or the additional VOCs data were included with the PM(2.5) data, the models identified that wood burning (24%-31%), secondary sulfate (20%-24%) and secondary nitrate (15%-20%) were the main contributors to PM(2.5). Using only PM(2.5) data, the model distinguished two diesel features with the 100% constraint, but identified only one diesel feature without the constraint. When both PM(2.5) and VOCs data were used, one additional feature was identified as the major contributor (26%) to total VOC mass. Adding VOCs data to the speciated PM(2.5) data in source apportionment modeling resulted in more accurate source contribution estimates for combustion related sources as evidenced by the less 'missing mass' percentage in PM(2.5). Using the source contribution estimates, we evaluated the validity of using black carbon (BC) as a surrogate for diesel exhaust. We found that BC measured with an aethalometer at 370 nm and 880 nm had reasonable correlations with the estimated concentrations of diesel particulate matters (r>0.7), as well as with the estimated concentrations of wood burning particles during the heating seasons (r=0.56-0.66). This indicates that the BC is not a unique tracer for either source. The difference in BC between 370 and 880 nm, however, correlated well exclusively with the estimated wood smoke source (r=0.59) and may be used to separate wood smoke from diesel exhaust. Thus, when multiple BC related sources exist in the same monitoring environment, additional data processing or modeling of the BC measurements is needed before these measurements could be used to represent the diesel exhaust. PMID- 17716710 TI - Correlation between cardiac biomarkers and right ventricular enlargement on chest CT in non massive pulmonary embolism. AB - BACKGROUND: Troponin I (cTnI), myoglobin, heart-type fatty acid binding protein (H-FABP), and natriuretic peptides (BNP, NTproBNP) were all reported to be elevated in patients with pulmonary embolism (PE). METHODS: To assess the correlation between the aforementioned markers and helical computed tomography (hCT) right ventricular dysfunction (RVD) in non massive PE, we performed this prospective pilot study on 50 patients. RESULTS: Patients with RVD had significant higher natriuretic peptides prevalence than cardiomyocytes damage related markers (48% vs 20%, P=0.006). Significant prevalence differences were observed only for natriuretic peptides when patients with RVD and those without were compared (74% vs 33% for NT-pro BNP, P=0.005 and 65% vs 22% for BNP, P=0.003). Patients with RVD had significant higher biomarkers median plasmatic values than those without (BNP: 170 vs 36 pg/ml, P=0.0027; NT-proBNP: 1369 vs 170.7 pg/ml, P=0.0024; cTnI: 0.032 vs 0 ng/ml, P=0.0034; H-FABP: 4.32 vs 2.23 ng/ml, P=0.0032; myoglobin: 36.7 vs 28.2 ng/ml, P=0.03). Significant correlations were only obtained between RV/LV index and plasmatic natriuretic peptides (NT proBNP: r=0.36, P=0.009; BNP r=0.28; P=0.047). CONCLUSIONS: Natriuretic peptides prevalence elevation and median values are significantly higher when RVD is present and significantly correlate with hCT RVD. PMID- 17716711 TI - The effects of heparin and low molecular weight heparins on bone. AB - Recent clinical trials have shown that the risk of developing osteoporosis is substantially lower when low molecular weight heparins (LMWHs) are used in place of unfractionated heparin. While the reason(s) for this difference has not been fully elucidated, studies with animals have suggested that heparin causes bone loss by both decreasing bone formation and increasing bone resorption. In contrast, LMWHs appear to cause less bone loss because they only decrease bone formation. Whether all LMWHs decrease bone formation and therefore cause bone loss is unknown. For example, preliminary in vitro studies with the synthetic pentasaccaride, Fondaparinux, have suggested that it may not decrease bone formation and thus, may have no deleterious effects on bone. Further studies are required in order to determine if all LMWHs cause bone loss equally. PMID- 17716712 TI - CA-125 level preoperative assessment in early and advanced ovarian carcinoma. PMID- 17716713 TI - S1P and LPA have an attachment-dependent regulatory effect on invasion of epithelial ovarian cancer cells. AB - OBJECTIVES: We previously demonstrated the regulation of epithelial ovarian cancer (EOC) cell invasiveness by the bioactive phospholipid sphingosine 1 phosphate (S1P). Low-dose S1P stimulated invasion like lysophosphatidic acid (LPA), while high-dose S1P inhibited invasion. Here we investigate how cell attachment status affects response to S1P and examine the effects of S1P and LPA on cell-cell and cell-extracellular matrix (ECM) adhesion. METHODS: EOC Dov13 cell invasion, ECM attachment and cell adhesion were tested through in vitro assays of Matrigel invasion and attachment to Matrigel, collagen or cell monolayer. Fractionated membrane and cytoplasmic proteins and biotin-labeled surface proteins were analyzed by western analysis. Actin cytoskeleton and FAK were visualized by immunofluorescence. RESULTS: S1P (20 muM) inhibited invasion of sustained, attached cells but enhanced that of invading cells. Membrane N cadherin was depleted upon reattachment to ECM. S1P pretreatment (20 muM) accelerated N-cadherin recovery, while 40 muM LPA or 0.5 muM S1P delayed recovery. Cell-cell adhesion and stress fibers were decreased by LPA and by 0.5 muM S1P but increased by 20 muM S1P. While S1P increased cellular attachment to Matrigel and collagen-I, LPA inhibited attachment to Matrigel. Surface N cadherin, gamma- and beta-catenins, FAK and integrinbeta1 were altered by both reattachment and treatment with S1P or LPA. CONCLUSIONS: S1P inversely affects invasion of attached and invading cells, switching from inhibition to stimulation. This switch is associated with depletion of N-cadherin and membrane FAK. The recovery of membrane N-cadherin, change in cell-cell adhesion and actin stress fibers intensity in response to LPA and S1P inversely correlate with their effects on cellular invasiveness. PMID- 17716715 TI - Central nervous system activity of acute administration of isopulegol in mice. AB - Isopulegol is a monoterpene alcohol intermediate in the preparation of (-) menthol and it is present in the essential oils of various plants. This work presents behavioral effects of isopulegol in animal models of open field, elevated plus maze (EPM), rota rod, hole board, barbiturate-induced sleeping time, tail suspension and forced swimming tests in mice. Isopulegol was administered intraperitoneally to male mice at single doses of 25 and 50 mg/kg, while diazepam 1 or 2 mg/kg and imipramine 10 or 30 mg/kg were used as standard drugs. The results showed that, similar to diazepam (1 mg/kg), both doses of isopulegol significantly modified all the observed parameters in the EPM test, without alter the general motor activity in the open field test. In the same way, both doses of isopulegol increased the number of head dips in the hole-board test. Forced swimming and tail suspension tests showed that isopulegol (25 and 50 mg/kg) was able to induce a significant increase in the immobility time, in opposite to imipramine, a recognized antidepressant drug. There was a decrease in the sleep latency time and prolongation of the pentobarbital-induced sleeping time with both doses of Isopulegol. Different from diazepam (2 mg/kg), isopulegol (25 e 50 mg/kg) had no effect on the motor coordination of animals in the rota rod test. These results showed that isopulegol presented depressant- and anxiolytic-like effects. PMID- 17716714 TI - Continuous intracerebroventricular infusion of the competitive NMDA receptor antagonist, LY235959, facilitates escalation of cocaine self-administration and increases break point for cocaine in Sprague-Dawley rats. AB - Although escalation of consumption is an important characteristic of cocaine dependence, the neurobiological mechanisms that mediate this phenomenon have not been fully described. In this study, we used male, Sprague-Dawley rats to measure the effects of acute and continuous intracerebroventricular (ICV) administration of the competitive NMDA receptor antagonist, LY235959, on cocaine self administration behavior under various schedules of reinforcement and access conditions. Single ICV infusions of LY235959 (0.03-0.3 microg/5 microl) produced dose-dependent and statistically significant decreases in the number of cocaine infusions earned under a progressive ratio schedule of reinforcement. In a second experiment, vehicle or LY235959 (0.2-0.3 microg/day) was continuously administered ICV to rats via surgically-implanted subcutaneous osmotic minipump/intracranial cannula assemblies. Both vehicle- and LY235959-treated rats significantly escalated cocaine self-administration over the 10 long access sessions; however, rats treated with LY235959 escalated cocaine self administration faster and to a greater degree than vehicle-treated rats. There was a statistically significant increase in cocaine infusions earned under the PR schedule in LY235959-treated rats, but not vehicle-treated rats, after 10 long access cocaine self-administration sessions. These data support the hypothesis that escalation of cocaine consumption is mediated by hypo-glutamatergic tone in the central nervous system and this facilitation of escalation is associated with an increase in motivation to respond for cocaine. PMID- 17716716 TI - An economic analysis of aspirin desensitization in aspirin-exacerbated respiratory disease. AB - BACKGROUND: Aspirin desensitization is an effective therapy for moderate-to severe aspirin-exacerbated respiratory disease (AERD). Desensitization also allows the use of aspirin for secondary cardiovascular prevention. OBJECTIVE: We sought to investigate the cost-effectiveness of aspirin desensitization with subsequent aspirin therapy in patients with AERD. METHODS: The Healthcare Cost and Utilization Project was used, together with average reimbursements from a large Midwestern health care plan, to model the costs of aspirin desensitization for therapeutic and prophylactic use in patients with AERD. Event probabilities were based on the published literature. RESULTS: Ambulatory desensitization for AERD cost $6768 per quality-adjusted life year (QALY) saved ($18.54 per additional symptom-free day). Aspirin desensitization for AERD remained cost effective (<$50,000 per QALY saved) across a wide range of assumptions. When secondary cardiovascular prophylaxis was considered, ambulatory aspirin desensitization was less expensive than an alternative antiplatelet agent, clopidogrel. Clopidogrel cost $106,453 per incremental QALY saved when compared with desensitization. CONCLUSIONS: Aspirin desensitization is a cost-effective therapeutic intervention in patients with moderate-to-severe AERD. Although the incremental cost-effectiveness of clopidogrel in individuals with aspirin allergy is marginal, if available, ambulatory desensitization remains a less-expensive option for secondary cardiovascular prophylaxis. PMID- 17716717 TI - Mosquitoes as sources of inhalant allergens: clinicoimmunologic and biochemical studies. PMID- 17716718 TI - Infant frequent wheezing correlated to Clara cell protein 10 (CC10) polymorphism and concentration, but not allergy sensitization, in a perinatal cohort study. AB - BACKGROUND: Wheezing episodes are common in young infants. However, the molecular mechanism of wheezing is unclear, and very few therapeutic regimens are effective. OBJECTIVE: This study investigated the genetic and environmental factors predisposing to infant wheezing in a birth cohort study. METHODS: A cohort of 1211 pregnant women was recruited for this study. Infant wheezing episodes during the first 18 months of life were correlated to parental atopic history, parental smoking, prematurity, CB IgE levels, and the sequence variant (G+38A) of the Clara cell protein 10 (CC10) gene encoding a secretary anti inflammatory CC10 protein. RESULTS: Nine hundred eighty-three infants completed umbilical cord blood collection, and 813 infants completed the 18-month postnatal follow-up. Twenty-two percent of the infants experienced at least 1 wheezing episode, and 6.6% of the infants experienced frequent wheezing (> or =3 episodes). Multivariate logistic regression showed that male sex and the CC10 G+38A polymorphism, but not prematurity, CB IgE level, passive smoking, or parental atopy, were predictors of frequent wheezing. Further studies found that infant frequent wheezing was significantly associated with the CC10 +38AA genotype and lower plasma CC10 levels at 18 months of age (P = .046), and infants with acute wheezing episodes had significantly lower CC10 levels than those without (P = .023). No association of wheezing episodes with allergic sensitization was observed in this cohort population. CONCLUSION: Infant frequent wheezing is associated with the CC10 G+38A polymorphism and lower CC10 levels but not infant atopy. CLINICAL IMPLICATIONS: Lower CC10 expression, but not allergy sensitization, is involved in the pathogenesis of infant frequent wheezing. PMID- 17716720 TI - Wheat lipid transfer protein is a major allergen associated with baker's asthma. AB - BACKGROUND: Baker's asthma is a frequent occupational allergic disorder mainly caused by inhalation of cereal flours. Lipid transfer proteins (LTPs) constitute a family of plant food panallergens, but their role as inhalant and wheat allergens is still unclear. OBJECTIVE: We sought to explore the involvement of wheat LTPs in baker's asthma caused by wheat flour sensitization. METHODS: Forty patients with occupational asthma caused by wheat flour inhalation were studied. Wheat LTP, Tri a 14, was purified by using a 2-step chromatographic protocol and characterized by N-terminal amino acid sequencing and 3-dimensional modeling. Its reactivity was confirmed by means of IgE immunodetection, ELISA and ELISA inhibition assays, and skin prick tests. RESULTS: Specific IgE to Tri a 14 was found in 60% of 40 individual sera from patients with baker's asthma, and the purified allergen elicited positive skin prick test reactions in 62% of 24 of these patients. Tri a 14 and peach LTP, Pru p 3, showed a sequence identity of 45%, but the low cross-reactivity between both allergens detected in several individual sera reflected great differences in their 3-dimensional IgE-binding regions. CONCLUSIONS: Wheat LTP is a major inhalant allergen associated with baker's asthma caused by wheat flour sensitization. Poor cross-reactivity with its peach homolog was found in some patients. CLINICAL IMPLICATIONS: LTPs can be considered relevant inhalant allergens linked to respiratory disorders. LTP from wheat (Tri a 14) can be used as a helpful tool for the diagnosis of baker's asthma. PMID- 17716721 TI - Neuroimmune crosstalk in asthma: dual role of the neurotrophin receptor p75NTR. AB - BACKGROUND: Neurotrophins have been implicated in the pathogenesis of asthma because of their ability to induce airway inflammation and to promote hyperreactivity of sensory neurons, which reflects an important mechanism in the pathogenesis of airway hyperreactivity. Neurotrophins use a dual-receptor system consisting of Trk-receptor tyrosine kinases and the structurally unrelated p75NTR. Previous studies revealed an important role of p75NTR in the pathogenesis of allergic asthma. OBJECTIVES: The aim of the study was to investigate the precise mechanisms of neurotrophins in neuroimmune interaction, which can lead to both airway inflammation and sensory nerve hyperreactivity in vivo. METHODS: Mice selectively expressing p75NTR in immune cells or nerves, respectively, were generated. After sensitization and allergen provocation, hyperreactivity of sensory nerves was tested in response to capsaicin. Airway inflammation was analyzed on the basis of differential cell counts and cytokine levels in bronchoalveolar lavage fluids. RESULTS: Allergic mice selectively expressing p75NTR in immune cells showed normal inflammation but no sensory nerve hyperreactivity, whereas mice selectively expressing p75NTR in nerve cells had a diminished inflammation and a distinct sensory nerve hyperreactivity. CONCLUSION: Our data indicate that p75NTR plays a dual role by promoting hyperreactivity of sensory nerves and airway inflammation. Additionally, our study provides experimental evidence that development of sensory nerve hyperreactivity depends on an established airway inflammation in asthma. In contrast, development of airway inflammation seems to be independent from sensory nerve hyperreactivity. CLINICAL IMPLICATIONS: Because of its dual function, antagonization of p75NTR mediated signals might be a novel approach in asthma therapy. PMID- 17716722 TI - Exhaled nitric oxide in children with asthma at high altitude. PMID- 17716723 TI - Severe serum sickness-like syndrome after omalizumab therapy for asthma. PMID- 17716724 TI - Efficacy of hCG and GnRH for inducing ovulation in the jenny. AB - Knowledge about management of ovulation in the donkey is limited compared to that in the horse. This experiment was designed to evaluate the efficacy of injecting single doses of lecirelin (a GnRH-analogue) or of hCG to induce ovulation in the jenny and to determine whether effects are dependent upon follicular diameter at time of injection. Ovarian activity and follicular growth were monitored by rectal ultrasonography. Jennies were randomly allotted to the following groups: Group GnRH, treated with 100 microg lecirelin; Group hCG, treated with 2500 IU hCG; Group C, untreated and monitored for spontaneous ovulation. Animals were also categorized into subgroups depending upon follicular diameter: 30-35 mm (GnRH-1, hCG-1 and C-1) or 36-40 mm (GnRH-2, hCG-2 and C-2). Jennies in the two hormone treatment groups did not differ significantly for time from treatment to ovulation, but there was a significant reduction in time to ovulation as follicle size at treatment increased. Jennies treated with either lecirelin or hCG had significantly smaller follicle size at ovulation than jennies in the Control groups that underwent spontaneous ovulation. Treatment groups did not differ significantly in the proportion of jennies that ovulated within 48 h of injection or between 25 and 48 h following injection. These results highlight the usefulness of lecirelin for induction and synchronization of ovulation in the jenny, particularly since it would avoid the risk of reduced hCG response in reproductive management programs in which that hormone was repeatedly used. PMID- 17716725 TI - Design of targeted lipid nanocapsules by conjugation of whole antibodies and antibody Fab' fragments. AB - Immunonanocapsules were synthesized by conjugation to lipid nanocapsules (LNC) of whole OX26 monoclonal antibodies (OX26 MAb) directed against the transferrin receptor (TfR). The TfR is overexpressed on the cerebral endothelium and mediates the transcytosis mechanism. Fab' fragments, known for their reduced interaction with the reticuloendothelial system, were also conjugated to LNC. This coupling was facilitated by the incorporation of lipid PEG(2000) functionalized with reactive-sulfhydryl maleimide groups (DSPE-PEG(2000)-maleimide) into LNC shells by a post-insertion procedure, developed initially for liposome pegylation. An interfacial model using the dynamic rising drop technique helped determine the parameters influencing the DSPE-PEG(2000)-maleimide insertion and the quality of the anchorage. Heat was essential to promote both an important and stable adsorption of DSPE-PEG(2000)-maleimide onto LNC. OX26 MAb were thiolated to react with maleimide functions whereas thiol residues on Fab' fragments were used directly. The number of ligands per nanocapsule was adjusted according to their initial quantity in the coupling reaction mixture, with densities from 16 to183 whole antibodies and between 42 and 173 Fab' fragments per LNC. The specific association of immunonanocapsules to cells overexpressing TfR was thus demonstrated, suggesting their ability to deliver drugs to the brain. PMID- 17716726 TI - Active targeting of brain tumors using nanocarriers. AB - The delivery of drugs to brain tumors is limited by the presence of the blood brain barrier (BBB) separating the blood from the cerebral parenchyma. An understanding of the specific mechanisms of the brain capillary endothelium has led to the development of various strategies to enhance the penetration of drugs into the brain tissue. Active targeting is a non-invasive approach, which consists in transporting drugs to target organs using site-specific ligands. Drug loaded nanocarriers capable of recognizing brain capillary endothelial cells and cerebral tumoral cells have shown promising potential in oncology. Endogenous and chimeric ligands binding to carriers or receptors of the BBB have been directly or indirectly conjugated to nanocarriers. This review indexes the main targeted colloidal systems used for drug delivery to the brain. Their pharmacological behavior and their therapeutic effect are discussed. PMID- 17716727 TI - Multi-dimensional resolution of elementary Ca2+ signals by simultaneous multi focal imaging. AB - Elementary events such as puffs and sparks are cytosolic microdomains of Ca2+ from which cellular Ca2+ signals are constructed. Because of the tight localization and fast kinetics of elementary events, imaging studies have been hindered by instrumental limitations of confocal and deconvolution fluorescence microscopy which necessitate compromises between spatial and temporal resolution. Here, we describe a novel, yet simple 'multi-focal' fluorescence microscopy system that employs three high-speed cameras focused at different axial depths to enable 4-dimensional imaging with millisecond resolution. We demonstrate the utility of this system for studies of puffs in Xenopus oocytes by mapping the axial distribution of puff sites, by obtaining measurements of puff amplitudes undistorted by focus error, and by deriving deblurred images that reveal novel sub-micron jumps of Ca2+ release sites. PMID- 17716728 TI - Roles of mitochondria and temperature in the control of intracellular calcium in adult rat sensory neurons. AB - We recorded Ca2+ current and intracellular Ca2+ ([Ca2+](i)) in isolated adult rat dorsal root ganglion (DRG) neurons at 20 and 30 degrees C. In neurons bathed in tetraethylammonium and dialyzed with cesium, warming reduced resting [Ca2+](i) from 87 to 49 nM and the time constant of the decay of [Ca2+](i) transients (tau(r)) from 1.3 to 0.99s (Q(10)=1.4). The Buffer Index, the ratio between Ca2+ influx and Delta[Ca2+](i) (f I(ca)d(t)/Delta[Ca2+]i) , increased two- to threefold with warming. Neither inhibition of the plasma membrane Ca2+ -ATPase by intracellular sodium orthovanadate nor inhibition of Ca2+ uptake by the endoplasmic reticulum by thapsigargin plus ryanodine were necessary for the effects of warming on these parameters. In contrast, inhibition of the mitochondrial Ca2+ uniporter by intracellular ruthenium red largely reversed the effects of warming. Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP, 500 nM) increased resting [Ca2+](i) at 30 degrees C. Ten millimolar intracellular sodium prolonged the recovery of [Ca2+](i) transients to 10-40s. This effect was reversed by an inhibitor of mitochondrial Na(+)/Ca2+ -exchange (CGP 37157, 10 microM). Thus, mitochondrial Ca2+ uptake is necessary for the temperature dependent increase in Ca2+ buffering and mitochondrial Ca2+ fluxes contribute to the control of [Ca2+](i) between 50 and 150 nM at 30 degrees C. PMID- 17716730 TI - Polybrominated diphenyl ethers (PBDEs) in sediment by salinity and land-use type from Australia. AB - Brominated flame retardants, including polybrominated diphenyl ethers (PBDEs) have been incorporated in numerous products to reduce flammability. Depending on their bromination, PBDEs are relatively persistent in the environment and have the potential to bioaccumulate through the food web. The present study was initiated to provide a better understanding on the levels and possible origin of PBDEs in the aquatic environment of Australia. PBDEs were detected at 35 out of 46 sites and concentrations were relatively low in the majority of samples analysed. Mean+/-standard deviation and median SigmaPBDE concentrations across all sites were 4707+/-12,580 and 305 pg g(-1) dw, respectively, excluding the limit of detection. At 83% of sites, concentrations were below 1000 pg g(-1) dw, whereas elevated levels were found at sites downstream of STP outfalls and in areas dominated by industrial and urban land-use types. Concentrations of PBDEs differed significantly (p=0.007) among sites according to predominant type of land-use. Significantly (p=0.02) higher SigmaPBDE concentrations were also present in estuarine compared to freshwater environments, while PBDEs were below the limit of detection at the marine site. At most sites, BDE-209 contributed the highest proportion to the SigmaPBDE concentrations. The exception was one site with an elevated concentration of BDE-183. Sampling and analytical variability were investigated as part of this study. Results showed generally satisfactory results for repeat analysis at a different laboratory and low variability among samples collected within 1000 m at low contaminated sites. However, at sites with elevated PBDE levels, sampling variability was high, with several fold to magnitudes of higher concentrations present among replicate sites. Corresponding to findings from elsewhere, these results demonstrate that urban and industrial activities provide the key input sources of PBDEs to the aquatic environment and provide a baseline for further investigation into the specific origin of contamination, as well as information on the background status of aquatic sediment contamination with PBDEs. PMID- 17716729 TI - Diversity in penaeidin antimicrobial peptide form and function. AB - Penaeidins are a diverse family of two-domain antimicrobial peptides expressed in shrimp. Variation in penaeidin sequence results in functional diversity, which was discovered using synthetic reproductions of native penaeidins. An isoform of penaeidin class 3 from Litopenaeus setiferus (Litset Pen3-4) was synthesized using native ligation and compared directly with the synthetic penaeidin class 4 known to be expressed in the same organism. New antimicrobial activity data are included in this review that emphasize differences in effectiveness that are apparent from a direct comparison of two classes. A novel approach to intact penaeidin analysis is presented in the form of Fourier Transform Ion-Cyclotron Resonance Mass Spectrometry, which has implications for the identification of individual penaeidin isoforms without chemical modification or enzymatic cleavage. The new information included in this review helps gather the perspective on relevance of penaeidin diversity to antimicrobial function, the use of synthetic peptides as tools to evaluate specific immune functions and the application of high mass resolution, top-down sequencing methods to the intact analysis of individual penaeidin isoforms. PMID- 17716731 TI - Paradoxical ozone associations could be due to methyl nitrite from combustion of methyl ethers or esters in engine fuels. AB - We review studies of the effects of low ambient ozone concentrations on morbidity that found a negative coefficient for ozone concentration. We call this a Paradoxical Ozone Association (POA). All studies were in regions with methyl ether in gasoline. All but one study carefully controlled for the effects of other criterion pollutants, so the phenomenon cannot be attributed to them. One was in southern California in mid-summer when ozone levels are highest. Because ozone is created by sunlight, the most plausible explanation for a POA would be an ambient pollutant that is rapidly destroyed by sunlight, such as methyl nitrite (MN). A previously published model of engine exhaust chemistry suggested methyl ether in the fuel will create MN in the exhaust. MN is known to be highly toxic, and closely related alkyl nitrites are known to induce respiratory sensitivity in humans. Support for the interpretation comes from many studies, including three linking asthma symptoms to methyl tertiary butyl ether (MTBE) and the observation that a POA has not been seen in regions without ether in gasoline. We also note that studies in southern California show a historical trend from more significant to less significant ozone-health associations. The timing of those changes is consistent with the known timing of the introduction of gasoline oxygenated with MTBE in that region. PMID- 17716732 TI - Health risk assessment of indoor air pollution in Finnish ice arenas. AB - Poor indoor air quality and epidemic carbon monoxide (CO) and nitrogen dioxide (NO(2)) poisonings due to exhaust emissions from ice resurfacers have been continuously reported from enclosed ice arenas for over 30 years. The health risks in users of Finnish ice arenas were analysed in three ways: (1) evaluation of four cases of epidemic CO poisonings, (2) modelling the association between NO(2) exposure and respiratory symptoms among junior ice hockey players, and (3) estimation of the number of arena users at risk of breathing poor quality air due to non-compliance of ice arenas with recommended abatement measures. The common causes for the CO poisonings involving over 300 subjects were large emissions from propane-fuelled ice resurfacer, small arena volume, negligible ventilation, and very recent opening of the arena. Rhinitis (prevalence 18.3%) and cough (13.7%) during or after training or game were significantly associated with the estimated personal NO(2) exposure of young hockey players (n=793) to average concentrations ranging from 21 to 1176 microg/m(3) in their home arena. During a 6-year follow-up of an intensive information campaign the portion of electric resurfacers increased from 9% to 27%, and that of emission control technology on propane-fuelled resurfacers increased from 13% to 84%. The portion of inadequately ventilated arenas decreased from 34% to 25%. However, 48% of the investigated Finnish ice arenas (n=125) did not fully comply with the non regulatory recommendations. Consequently, 20000 daily users of ice arenas were estimated to remain in 2001 at risk of breathing poor quality air. Modern small and inadequately ventilated ice arenas pose their users (mostly children and young adults) at risk of breathing poor quality air and suffering from acute adverse health effects. Governmental regulations are needed worldwide to ensure safe sports in enclosed ice arenas. PMID- 17716733 TI - Visual field changes after transient elevation of intraocular pressure in eyes with and without glaucoma. AB - PURPOSE: To evaluate visual field (VF) changes in glaucomatous and nonglaucomatous eyes after transient elevation of intraocular pressure (IOP). DESIGN: Prospective experimental study. PARTICIPANTS: One hundred subjects (38 with glaucoma, 62 glaucoma suspects and controls). METHODS: Intraocular pressure elevation was induced in the right eye of all subjects with a modified LASIK suction ring. Intraocular pressure was elevated to an average of 64 mmHg for <30 seconds. Humphrey Matrix perimetry 24-2 threshold tests were performed before and after the procedure. A cohort of patients who demonstrated significant deterioration in postprocedural perimetry was recalled for further testing. MAIN OUTCOME MEASURES: Mean deviation (MD) and pattern standard deviation (PSD) from Humphrey Matrix perimetry. RESULTS: A significant decline in MD of the right eye could be observed on immediate postprocedural perimetry amongst glaucoma and control patients, whereas no significant changes in PSD were seen in either group. Forty-five of 47 patients, whose immediate postprocedural perimetry showed a loss of MD > 2 decibels, attended for repeat perimetric testing with a median follow-up of 6 days. Both eyes among 28 control patients and the left eye among 17 glaucoma patients showed statistically significant improvement in MD. Similar improvement was seen in the right eye of glaucoma patients, but this failed to reach statistical significance. Six patients from the glaucoma group demonstrated deterioration in MD upon recall, compared with 3 in the control group (P = 0.046). These 6 patients were significantly younger than the rest of the group, but no other defining characteristics were identified. CONCLUSIONS: Transient elevation of IOP in adult eyes with and without glaucomatous optic neuropathy did not lead to functional optic nerve change, as measured by Matrix perimetry, in the short term for the majority of patients. It is possible that a small cohort of patients with preexisting glaucomatous optic neuropathy may be more susceptible to transient increase in IOP, although the result is inconclusive. Prominent learning effects may have masked subtle worsening of visual function in our subjects; corresponding structural analyses of the optic nerve and longer term follow-up may provide further information. PMID- 17716736 TI - Health care charges for patients with ocular hypertension or primary open-angle glaucoma. AB - OBJECTIVES: To determine the total and condition-related direct health care charges of patients with ocular hypertension (OH) or primary open-angle glaucoma (POAG) and identify factors that affect these charges. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with OH (n = 36 767) and POAG (n = 72 412) with > or =1 year of continuous enrollment during calendar years 1998 through 2005 in a nationally representative, multimanaged health plan database (PharMetrics). METHODS: First year total health care and condition-related charges were calculated. Subsequently multivariate linear regression models determined the impact of ophthalmic condition (OH or POAG), age, index year, gender, geographic region, payer mix, product type, treatment with glaucoma medication, ocular comorbidities, and systemic comorbidities on these charges. MAIN OUTCOME MEASURES: Per-person per year first-year total health care and ocular condition-related charges in United States dollars, adjusted for multiple covariates. RESULTS: Patients with POAG had significantly higher adjusted total and condition-related health care charges during the first year of follow-up than patients with OH in multivariable analysis ($2070 vs. $1990, P<0.0001 and $556 vs. $322 P<0.0001, respectively). Females and older patients had higher total health care charges compared with males and younger patients ($586 or 28.3% more; P<0.0001 and $27 per year or 0.8% per year more; P<0.0001, respectively). However, neither gender nor age were strong determinants of condition-related charges (P = 0.13 and P = 0.052, respectively). Index year, region, payer, and product types significantly dictated both total and disease-related charges. Patients with ocular comorbid conditions, including cataracts, cataract surgery, diabetic retinopathy, and blindness, had significantly higher total and condition related health care charges than patients without these conditions (P<0.0001). CONCLUSION: Total and condition-related health care charges are considerable for patients with OH and POAG. These data identify several factors that dictate these charges. PMID- 17716734 TI - Type 2 diabetes mellitus and the risk of open-angle glaucoma the Los Angeles Latino Eye Study. AB - PURPOSE: To examine the relationship between type 2 diabetes mellitus (T2DM) and the risk of having open-angle glaucoma (OAG) in an adult Latino population. DESIGN: Population-based cross-sectional study. PARTICIPANTS: Latinos 40 years and older (n = 5894) from 6 census tracts in Los Angeles, California. METHODS: Participants from the Los Angeles Latino Eye Study (LALES), a large population based study of self-identified adult Latinos, answered an interviewer administered questionnaire and underwent a clinical and complete ocular examination, including visual field (VF) testing and stereo fundus photography. A participant was defined as having diabetes mellitus (DM) if she or he had a history of being treated for DM, the participant's glycosylated hemoglobin was measured at 7.0% or higher, or the participant had random blood glucose of 200 mg% or higher. Type 2 DM was defined if the participant was 30 years or older when diagnosed with DM. Open-angle glaucoma was defined as the presence of an open angle and a glaucomatous VF abnormality and/or evidence of glaucomatous optic disc damage in at least one eye. Logistic regression analysis was used to identify the risk of having OAG in persons with T2DM. MAIN OUTCOME MEASURE: Prevalence of OAG. RESULTS: Of the 5894 participants with complete data, 1157 (19.6%) had T2DM and 288 (4.9%) had OAG. The prevalence of OAG was 40% higher in participants with T2DM than in those without T2DM (age/gender/intraocular pressure-adjusted odds ratio, 1.4; 95% confidence interval, 1.03-1.8; P = 0.03). Trend analysis revealed that a longer duration of T2DM (stratified into 5-year increments) was associated with a higher prevalence of OAG (P<0.0001). CONCLUSION: The presence of T2DM and a longer duration of T2DM were independently associated with a higher risk of having OAG in the LALES cohort. The high prevalences of T2DM and OAG and their association in this fastest growing segment of the United States population have significant implications for designing screening programs targeting Latinos. PMID- 17716737 TI - Use of a standardized patient satisfaction questionnaire to assess the quality of care provided by ophthalmology residents. AB - PURPOSE: To develop and use a standardized patient satisfaction questionnaire (PSQ) to address two study questions: (1) What is the overall level of satisfaction with resident care? (2) Can the study questionnaire be used to detect differences in the level of satisfaction patients have with care delivered by individual residents? DESIGN: Cross-sectional study comprising a survey administration to an ophthalmology resident clinic population of an existing PSQ, namely, the Duke Clinics Patient Satisfaction Questionnaire-adapted for use in ophthalmology ambulatory clinic settings. The questionnaire subscales roughly correlate to 3 Accreditation Council for Graduate Medical Education (ACGME) general competencies: interpersonal and communication skills, professionalism, and technical quality of care. PARTICIPANTS: The survey was completed by 167 qualified patients of the Durham, North Carolina Veterans Administration Hospital Eye Clinic, a clinic staffed by residents of Duke Eye Center. METHODS: Patients were administered a standardized PSQ assessing 4 areas of care: interpersonal manner, communication, technical quality, and professionalism. Overall levels of satisfaction with care were assessed; bivariate analyses were used to assess scores by resident. Primary outcomes were measured as levels of satisfaction on a 5-point scale (1 = lowest satisfaction, 5 = greatest). Outcomes were calculated separately for the 4 satisfaction subscales. MAIN OUTCOME MEASURE: Patient satisfaction using a standardized PSQ. RESULTS: Mean scores were 4.46 for interpersonal manner, 4.46 for communication, 4.27 for technical quality, and 4.63 for professionalism. Analysis by resident yielded statistically significant (P<0.05) differences in scores between residents on the interpersonal manner (P = 0.02) and communication (P = 0.03) subscales. CONCLUSIONS: The ACGME has established 6 areas of patient care "general competencies" in which all residency programs are mandated to train and evaluate residents, creating a need for the development of new measurement tools. Using a modified version of an established PSQ to measure 3 general competencies, we found that patients were generally satisfied with resident care, and that differences in patient satisfaction with the interpersonal and communication skills of individual residents can be identified using our PSQ. The PSQ described here may be a useful assessment tool for ACGME-mandated resident core competency in interpersonal and communication skills. PMID- 17716735 TI - Carotenoids and antioxidants in age-related maculopathy italian study: multifocal electroretinogram modifications after 1 year. AB - OBJECTIVE: To evaluate the influence of short-term carotenoid and antioxidant supplementation on retinal function in nonadvanced age-related macular degeneration (AMD). DESIGN: Randomized controlled trial. PARTICIPANTS: Twenty seven patients with nonadvanced AMD and visual acuity > or =0.2 logarithm of the minimum angle of resolution were enrolled and randomly divided into 2 age-similar groups: 15 patients had oral supplementation of vitamin C (180 mg), vitamin E (30 mg), zinc (22.5 mg), copper (1 mg), lutein (10 mg), zeaxanthin (1 mg), and astaxanthin (4 mg) (AZYR SIFI, Catania, Italy) daily for 12 months (treated AMD [T-AMD] group; mean age, 69.4+/-4.31 years; 15 eyes); 12 patients had no dietary supplementation during the same period (nontreated AMD [NT-AMD] group; mean age, 69.7+/-6.23 years; 12 eyes). At baseline, they were compared with 15 age-similar healthy controls. METHODS: Multifocal electroretinograms in response to 61 M stimuli presented to the central 20 degrees of the visual field were assessed in pretreatment (baseline) conditions and, in nonadvanced AMD patients, after 6 and 12 months. MAIN OUTCOME MEASURES: Multifocal electroretinogram response amplitude densities (RAD, nanovolt/deg(2)) of the N1-P1 component of first-order binary kernels measured from 5 retinal eccentricity areas between the fovea and midperiphery: 0 degrees to 2.5 degrees (R1), 2.5 degrees to 5 degrees (R2), 5 degrees to 10 degrees (R3), 10 degrees to 15 degrees (R4), and 15 degrees to 20 degrees (R5). RESULTS: At baseline, we observed highly significant reductions of N1-P1 RADs of R1 and R2 in T-AMD and NT-AMD patients when compared with healthy controls (1-way analysis of variance P<0.01). N1-P1 RADs of R3-R5 observed in T AMD and NT-AMD were not significantly different (P>0.05) from controls. No significant differences (P>0.05) were observed in N1-P1 RADs of R1-R5 between T AMD and NT-AMD at baseline. After 6 and 12 months of treatment, T-AMD eyes showed highly significant increases in N1-P1 RADs of R1 and R2 (P<0.01), whereas no significant (P>0.05) change was observed in N1-P1 RADs of R3-R5. No significant (P>0.05) changes were found in N1-P1 RADs of R1-R5 in NT-AMD eyes. CONCLUSIONS: In nonadvanced AMD eyes, a selective dysfunction in the central retina (0 degrees -5 degrees ) can be improved by the supplementation with carotenoids and antioxidants. No functional changes are present in the more peripheral (5 degrees -20 degrees ) retinal areas. PMID- 17716739 TI - Cortisol reactivity, maternal sensitivity, and learning in 3-month-old infants. AB - This study investigated the effects of adrenocortical functioning on infant learning during an emotionally challenging event (brief separation from mother). We also explored possible relationships between maternal sensitivity and both infant and maternal cortisol reactivity during the learning/maternal separation episode. Sixty-three 3-month-olds and their mothers were videotaped for a 10 min normal interaction period, and mother-infant behavioral synchrony was measured using Isabella and Belsky's [Isabella, R. A., & Belsky, J. (1991). Interactional synchrony and the origins of infant-mother attachment: A replication study. Child Development, 62, 373-384] coding scheme. The percentage of synchronous behaviors served as a measure of maternal sensitivity. Learning and short-term memory involved relating the infant's mother's voice with a moving colored block in a preferential looking paradigm. Infants whose cortisol increased during the session showed no learning or memory, infants whose cortisol declined appeared to learn and remember the association, while infants whose cortisol did not change evidenced learning, but not memory for the voice/object correspondence. Sensitivity and cortisol reactivity were correlated for mothers, but not for infants. Infant and maternal cortisol values for the first sampling period were highly correlated, but their cortisol reactivity values were uncorrelated, supporting the notion that infants and mothers have coordinated adrenocortical functioning systems when physically together, but become uncoordinated during a separation/learning event. PMID- 17716740 TI - The role of amyloid beta peptide 42 in Alzheimer's disease. AB - During the last 20 years, an expanding body of research has elucidated the central role of amyloid precursor protein (APP) processing and amyloid beta peptide (Abeta) production in the risk, onset, and progression of the neurodegenerative disorder Alzheimer's disease (AD), the most common form of dementia. Ongoing research is establishing a greater level of detail for our understanding of the normal functions of APP, its proteolysis products, and the mechanisms by which this processing occurs. The importance of this processing machinery in normal cellular function, such as Notch processing, has revealed specific concerns about targeting APP processing for therapeutic purposes. Aspects of AD that are now well studied include direct and indirect genetic and other risk factors for AD, APP processing, and Abeta production. Emerging from these studies is the particular importance of the long form of Abeta, Abeta42. Elevated Abeta42 levels, as well as particularly the elevation of the ratio of Abeta42 to the shorter major form Abeta40, has been identified as important in early events in the pathogenesis of AD. The specific pathological importance of Abeta42 has drawn attention to seeking drugs that will selectively lower the levels of this peptide through reduced production or increased clearance while allowing normal protein processing to remain substantially intact. An increasing variety of compounds that modulate APP processing to reduce Abeta levels are being identified, some with Abeta42 selectivity. Such compounds are now reaching clinical evaluation to determine how they may be of benefit in the treatment of AD. PMID- 17716738 TI - Nickel and the carbon cycle. AB - This article, dedicated to Edward Stiefel, reviews three nickel enzymes that play important roles in the carbon cycle: CO dehydrogenase, acetyl-CoA synthase, and methyl-coenzyme M reductase. After a short discussion of the carbon cycle, the structures of the active centers of the proteins and their proposed mechanisms are discussed. A brief description of future research areas is presented for each enzyme system. A short perspective on future research on nickel enzymes ends this contribution. PMID- 17716742 TI - Fetal programming of hypothalamic-pituitary-adrenal (HPA) axis function and behavior by synthetic glucocorticoids. AB - Reduced fetal growth has been closely associated with an increased risk for the development of chronic disease in later life. Accumulating evidence indicates that fetal exposure to excess glucocorticoids represents a critical mechanism underlying this association. Approximately 7% of pregnant women are at risk of preterm delivery and these women are routinely treated with synthetic glucocorticoids (sGC) between 24 and 34 of weeks gestation to improve neonatal outcome. Animal studies have demonstrated that maternally administered sGC crosses the placenta, affecting fetal hypothalamic-pituitary-adrenal (HPA) development, resulting in changes in HPA axis function that persist throughout life. These changes appear to be modulated at the level of glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) in the brain and pituitary. As the HPA axis interacts with many other physiological pathways, the changes in endocrine function are also sex-specific and age-dependent. Alterations in behavior, particularly locomotion, in animals exposed to sGC in utero have also been demonstrated. Consistent with the finding in animal models, emerging human data are indicating attention deficit-hyperactivity disorder (ADHD)-like symptoms in children exposed to repeated courses of sGC in utero. This behavioral phenotype is likely linked to alterations in dopamine (DA) signaling, suggesting that sGC are able to permanently modify or 'program' this system. Finally, it is emerging that changes in HPA axis function and behavior following antenatal exposure to sGC are transgenerational and likely involve epigenetic mechanisms. A comprehensive understanding of the acute and long-term impact of sGC exposure in utero is necessary to begin to develop recommendations and treatment options for pregnant women at risk of preterm delivery. PMID- 17716741 TI - The spinobulbar system in lamprey. AB - Locomotor networks in the spinal cord are controlled by descending systems which in turn receive feedback signals from ascending systems about the state of the locomotor networks. In lamprey, the ascending system consists of spinobulbar neurons which convey spinal network signals to the two descending systems, the reticulospinal and vestibulospinal neurons. Previous studies showed that spinobulbar neurons consist of both ipsilaterally and contralaterally projecting cells distributed at all rostrocaudal levels of the spinal cord, though most numerous near the obex. The axons of spinobulbar neurons ascend in the ventrolateral spinal cord and brainstem to the caudal mesencephalon and within the dendritic arbors of reticulospinal and vestibulospinal neurons. Compared to mammals, the ascending system in lampreys is more direct, consisting of excitatory and inhibitory monosynaptic inputs from spinobulbar neurons to reticulospinal neurons. The spinobulbar neurons are rhythmically active during fictive locomotion, representing a wide range of timing relationships with nearby ventral root bursts including those in phase, out of phase, and active during burst transitions between opposite ventral roots. The spinobulbar neurons are not simply relay cells because they can have mutual synaptic interactions with their reticulospinal neuron targets and they can have synaptic outputs to other spinal neurons. Spinobulbar neurons not only receive locomotor inputs but also receive direct inputs from primary mechanosensory neurons. Due to the relative simplicity of the lamprey nervous system and motor control system, the spinobulbar neurons and their interactions with reticulospinal neurons may be advantageous for investigating the general organization of ascending systems in the vertebrate. PMID- 17716745 TI - The effectiveness of group cognitive behaviour therapy for unipolar depressive disorders. AB - This paper evaluates the effectiveness of group cognitive behaviour therapy (GCBT) as an intervention for unipolar depressive disorders. PsychINFO and PubMed databases were selected to generate the 34 papers used for this review. Our results showed that effect sizes for GCBT over the control conditions range from small (0.1) to large (2.87) with the mean effect size of 1.10. The pre-post treatment effect sizes for GCBT range from 0.30 to 3.72 with a mean of 1.30. Convergent evidence was demonstrated across different outcome measures of GCBT. Our findings indicated that GCBT yielded outcomes better than no-treatment controls and was comparable with other treatments (including both bona fide and non-bona fide comparison treatments). It was concluded that GCBT was effective for the treatment of Unipolar depression and thus can be used with confidence. There is now an urgent need to develop and evaluate a coherent GCBT theory, in particular the roles of group processes in GCBT, before further major advancement in this area can be made. PMID- 17716744 TI - Measurement of contractile force of skeletal and extraocular muscles: effects of blood supply, muscle size and in situ or in vitro preparation. AB - Contractile forces can be measured in situ and in vitro. To maintain metabolic viability with sufficient diffusion of oxygen, established guidelines for in vitro skeletal muscle preparations recommend use of relatively thin muscles (< or =1.25 mm thick). Nevertheless, forces of thin extraocular muscles vary substantially between studies. Here, we examined parameters that affect force measurements of in situ and in vitro preparations, including blood supply, nerve stimulation, direct muscle stimulation, muscle size, oxygenated or non-oxygenated buffer solutions and the time after interruption of vascular circulation. We found that the absolute forces of extraocular muscle are substantially lower when examined in vitro. In vitro preparation of 0.58 mm thick extraocular muscle from 3-week-old birds underestimated contractile function, but not of thinner (0.33 mm) muscle from 2-day-old birds. Our study shows that the effective criteria for functional viability, tested in vitro, differ between extraocular and other skeletal muscle. We conclude that contractile force of extraocular muscles will be underestimated by between 10 and 80%, when measurements are made after cessation of blood supply (at 5-40 min). The mechanisms responsible for the declining values for force measurements are discussed, and we make specific recommendations for obtaining valid measurements of contractile force. PMID- 17716746 TI - Inflammatory markers in late-life depression: results from a population-based study. AB - BACKGROUND: Previous studies have reported conflicting results concerning the association between several inflammatory markers and depression. The association between inflammation and depression may depend on the presence of specific chronic diseases or be relevant in specific sub-groups of depressed patients only. OBJECTIVE: To assess associations between inflammatory markers and depression in older people, taking account of confounding and effect-modifying factors. METHOD: Population-based study of 1285 participants of the Longitudinal Aging Study Amsterdam, aged 65 and over. Plasma concentrations of Interleukin-6 (IL-6) and C-reactive protein (CRP) were measured. Major depression (first- or recurrent episode) and sub-threshold depression were assessed. Associations were adjusted for confounding variables. Associations with inflammatory markers were further studied with regard to severity and duration of depression, and with regard to specific depressive symptoms. RESULTS: High levels of IL-6 (above 5 pg/mL) were associated with major depression (odds ratio 2.49 (1.07-5.80), both in recurrent and first episodes. No significant effect of either one of the markers on specific symptom dimensions of depression was found. Mildly elevated plasma levels of CRP (above 3.2 mg/L) were associated with higher CES-D scores, but not after correction for the confounding effect of age and chronic diseases. LIMITATIONS: The cross-sectional design limits conclusions regarding causality. CONCLUSIONS: A high plasma level of IL-6, but not CRP, is associated with an increased prevalence of major depression in older people, independent of age, chronic diseases, cognitive functioning and anti-depressants. Present results suggest new directions for clinical research into the prevention of physical consequences of depression. PMID- 17716743 TI - Mechanisms involved in the cerebrovascular dilator effects of N-methyl-d aspartate in cerebral cortex. AB - Glutamate and its synthetic analogues N-methyl-d-aspartate (NMDA), kainate, and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) are potent dilator agents in the cerebral circulation. The close linkage between neural activity based release and actions of glutamate on neurons and the related decrease in cerebral vascular resistance is a classic example in support of the concept of tight coupling between increased neural activity and cerebral blood flow. However, mechanisms involved in promoting cerebral vasodilator responses to glutamatergic agents are controversial. Here we review the development and current status of this important field of research especially in respect to cerebrovascular responses to NMDA receptor activation. PMID- 17716747 TI - Verbal fluency dysfunction in euthymic bipolar patients: a controlled study. AB - OBJECTIVE: To study the executive functioning in euthymic bipolar patients in comparison to healthy controls and to examine the relationship between neuropsychological deficits and clinical variables. METHODS: Twenty-five euthymic bipolar patients and 31 controls underwent a battery of executive tasks including mental flexibility, inhibitory control and verbal fluency tests. RESULTS: There were no significant differences between bipolar patients and controls in relation to mental flexibility and inhibitory control. However, patients performed worse than controls on verbal fluency tests. Poor performances on the Stroop Test and the Hayling and Brixton Tests--part A were associated to lifetime occurrence of psychotic symptoms, prior number of episodes, and previous hospitalizations. CONCLUSIONS: In our study, only verbal fluency tests differentiated bipolar euthymic patients from healthy controls. Patients who showed deficits in information processing speed and inhibitory control had more episodes and hospitalizations and lifetime occurrence of psychotic symptoms. PMID- 17716748 TI - The effects of viscero-somatic interactions on thalamic mast cell recruitment in cystitic rats. AB - Mast cells accessing the brain parenchyma through the blood-brain barrier in healthy animals are limited to pre-cortical sensory relays - the olfactory bulb and the thalamus. We have demonstrated that unilateral repetitive stimulation of the abdominal wall generates asymmetry in midline thalamic mast cell (TMC) distribution in cyclophosphamide-injected rats, consisting of contralateral side prevalence with respect to the abdominal wall stimulation. TMC asymmetry 1) was generated in strict relation with cystitis, and was absent in disease-free and mesna-treated animals, 2) was restricted to the anterior portion of the paraventricular pars anterior and reuniens nuclei subregion, i.e., the rostralmost part of the paraventricular thalamic nucleus, the only thalamic area associated with viscero-vagal and somatic inputs, via the nucleus of the solitary tract, and via the medial contingent of the spinothalamic tract, respectively, and 3) originated from somatic tissues, i.e., the abdominal wall where bladder inflammation generates secondary somatic hyperesthesia leading to referred pain in humans. Present data suggest that TMCs may be involved in thalamic sensory processes, including some aspects of visceral pain and abnormal visceral/somatic interactions. PMID- 17716749 TI - Corrosive esophageal injuries in children. A shortlived experience in Sierra Leone. AB - OBJECTIVE: Children with caustic ingestions in developing countries are often treated at home, sometimes by traditional healers, or are referred, frequently late, to tertiary hospitals, which only seldom offer adequate endoscopic and dilatation facilities. Therefore, when dilatations are performed, the stricture is often already well established, making dilatation more difficult. The aim of this paper is to report our experience in the management of corrosive injuries in a group of children of Sierra Leone, all complaining accidental ingestion of caustic soda, many of them treated months after the ingestion. METHOD: We considered all children admitted after corrosive ingestion, from November 2001 to November 2005, to the "Emergency" Surgical Center in Goderich-Freetown, Sierra Leone. In December 2005 the hospital was supplied with endoscopes and dilatation devices. The children still followed up clinically were recalled to submit them to an endoscopic follow-up and to a dilatation, if needed. RESULTS: Forty children were admitted (mean age: 4.5 years): 16 (group A) after an esophageal perforation during dilatation performed elsewhere (death rate: 56%). Twenty-four children (group B) were observed after ingestion, 58% being submitted to a surgical gastrostomy. Death rate after ingestion was nil. The mean interval between ingestion and endoscopy was 8.8 months. Fifty-three dilatations were carried out in 17 children over a 3 months period. We report three perforations (17.6%) and a death rate of 5.8% (1/17). Two patients were lost to follow-up. Three patients (17.6%) did not show any improvement. Four children complained recurrent dysphagia after the first dilatation cycle. Overall, 10 children (58.8%) showed a clear-cut improvement at 6 months. CONCLUSIONS: The majority of treated strictures were late, therefore difficult to dilate and at higher risk of perforation. Dilatation with Savary bougies seems safer than with balloon catheters. Recurrent strictures and a long-term dilatation treatment should be expected. Retrograde dilatations through gastrostomies should be the preferred method of treatment and surgical gastrostomies should be performed without hesitation. Esophageal replacement is unlikely in these countries, except in very few referral centres. Therefore, any effort should be made to treat caustic strictures by timely dilatation programs. PMID- 17716750 TI - Otologic findings in children with gastroesophageal reflux. AB - BACKGROUND: Nearly 90-95% of children with drool have physiologic gastroesophageal reflux (GER) that usually resolves by 12-15 months of age; however, 5-10% of children with drool have pathologic GER. Of these children, most recover clinically by 18 months of age without therapy, yet 10% develop chronic, recurrent gastroesophageal reflux disease (GERD) with sequelae. The respiratory symptoms associated with GER consist mainly of bronchial asthma and laryngospasm, but often include a persistent cough of unknown aetiology, obstructive apnoea, and an obstructive respiratory syndrome confined to the nasopharynx. Gastric acid reflux, enters the adenoids, causes oedema of the tubal orifices, and later leads to relapsing diseases of the middle ear in children. AIM AND SCOPE: To evaluate the incidence of otologic manifestations in children with GER and the efficacy of treatment, comparing two different groups of children (i.e., treated versus untreated). SUBJECTS AND METHODS: From January 2005 to November 2006, audiologic screening of newborns and suckling children (0 24 months of age) at risk for auditory illnesses was held at the University Department of Otolaryngology in Catania. Seventy-three children (average age, 13 months) were selected after failing acoustic otoemissions for chronic bilateral catarrhal pathology involving the middle ear (tympanometry type B) and were positive for at least one of the different signs of GER at the time of history taking. The children were randomised and subdivided into two groups: (1) a group of 40 children (27 females and 13 males; average age, 12 months) who received treatment; and (2) a group of 29 children (16 males and 13 females; average age, 14 months) who did not receive treatment. Four children were lost to follow-up after completing the study. All children enrolled in the study underwent a rhinopharynxlaryngeal fibroscopy with flexible optics, a gastric ultrasound scan after clinical observation, and a multi-channel pH-metry for 18-24h. RESULTS: Findings obtained by rhinopharynxlaryngeal fibroscopy showed that 82% of cases had diffuse hyperaemia involving the entire rhinopharyngeal mucosa and 13% of the cases had arytenoidal hyperaemia. Resolution and improvement of the reflux occurred in 52.5 and 40% of the cases in the treated group, respectively, versus complete resolution and an improvement in symptoms of 45 and 30% of cases, respectively, in the control group. CONCLUSIONS: The hypothesis of a correlation between reflux and chronic middle otitis of the serous-mucous type was confirmed in the present study. Adopting a preventive treatment strategy may be useful in reducing the possibility of ear involvement. PMID- 17716751 TI - Re-prediction of protein-coding genes in the genome of Amsacta moorei entomopoxvirus. AB - Using the Z curve method, the protein-coding genes in AmEPV genome are re predicted. On the basis of the parameters trained on the experimentally validated genes, all of the 30 experimentally validated genes and 67 putative genes are predicted correctly as coding genes. The sensitivities of the present method for self-test and cross-validation are all 100% based on these test sets. Thirty eight annotated conserved and hypothetical genes are predicted as non-coding ORFs. The number of re-predicted protein-coding genes in AmEPV is 256. It is significantly less than the number 294 reported in the original annotation. After extending the present method trained in AeEPV genome to the other entomopoxvirus genome, it is found that 116 of the 123 known and putative genes are predicted correctly as coding. Six of the seven falsely missed genes are less than 300bp. The present method could be extended to other poxvirus genomes with or without adaptation of training sets. PMID- 17716752 TI - Effects of chronic and acute stressors and CRF on depression-like behavior in mice. AB - The effects of chronic footshock (CFS) on behavioral responses of CD1 mice to acute footshock and restraint were studied in tests commonly used to assess antidepressant treatments. Adult male mice were subjected to 20 min of footshock daily for 14-16 days, and then tested in the tail suspension test (TST) and the forced swim test (FST). CFS treatment did not alter immobility in the TST when mice were tested before the footshock on that day. However, when the TST was performed after the footshock, immobility decreased in both control and CFS mice. In the FST, chronic footshock significantly increased the time spent floating when mice were tested before footshock on that day. However, when the FST was performed immediately after the footshock, floating decreased in the CFS mice, but not in previously unshocked mice. Restraint, shortly before the FST, decreased floating in both CFS and unshocked mice. Thus, CFS induced depression like activity in the FST, but not in the TST, whereas acute footshock or restraint immediately before testing induced antidepressant-like effects in both the TST and the FST. In unshocked mice, intracerebroventricular corticotropin releasing factor (CRF) consistently decreased immobility in the TST and the FST, with significant effects at the 100ng dose. The same dose of CRF depressed activity in the open field, so that these changes in immobility are unlikely to reflect a change in overall activity. CRF thus mimicked the effects of the acute stressors in the TST and the FST. Responses to icv CRF were attenuated by chronic footshock suggesting that CFS desensitizes the brain to CRF. CFS treatment did not alter basal concentrations of ACTH and corticosterone in blood plasma. Acute footshock increased the plasma concentrations of the hormones but in CFS mice these responses were attenuated, significantly for plasma ACTH. Acute footshock activated brain dopamine, norepinephrine and serotonin metabolism, and increased tryptophan concentrations in the brain. In CFS mice, these responses were attenuated, significantly for hypothalamic NE. PMID- 17716754 TI - Percutaneous drug-eluting stent implantation in a patient with dextrocardia and situs inversus. PMID- 17716755 TI - Malabsorption causing failure of pharmacological therapy in the treatment of atrial fibrillation. AB - We report a case of atrial fibrillation (AF) refractory to medical management. The patient had previously undergone extensive gastric and small bowel surgery. Subsequently we demonstrated malabsorption of administered anti-arrhythmics as the cause of her refractory AF. Malabsorption, even to lesser degrees and from other causes should be considered in cases of unexplained therapeutic refractoriness. PMID- 17716753 TI - Value of right ventricular dysfunction for prognosis in pulmonary embolism. AB - BACKGROUND: Acute pulmonary embolism (APE) patients with right ventricular dysfunction (RVD) have a worse prognosis. We assessed RVD, deciding the indexes correlating best with prognosis. METHODS: The prospective multi-center study included 520 consecutive APE patients from 41 collaborating hospitals in China, between June 2002 and November 2004. RVD was diagnosed in the presence of at least 2 of the following: right ventricular (RV) dilatation, loss of inspiratory collapse of inferior vena cava (IVC), right ventricular hypokinesis, tricuspid regurgitant jet velocity >2.8 m/s. RESULTS: Mean age was 57.4+/-14.1 years and 323 patients (62.1%) were male. The 14-day mortality in normotensive patients with RVD was higher (2.0% vs 0.4%, p<0.01) than without RVD. RVD was associated with adverse 14-day outcomes (OR 5.23, 95% CI, 2.44-11.23) and the combination of RV dilation and IVC broadening was more valuable than the combination of RV dilation and RV hypokinesis (p<0.01). A multiple logistic regression model implied that RVD, right/left ventricular end-diastolic diameter ratio (RVED/LVED) and systolic pulmonary artery pressure (SPAP) be independent predictors of adverse 14-day clinical outcomes (p<0.01). ROC curve showed that the best cut-off values of RVED/LVED and SPAP were 0.67 and 60 mm Hg, respectively. Hemodynamic instability, 14-day clinical outcome, and SPAP were independent harbingers for 3 month outcomes (p<0.01). CONCLUSIONS: RVD was a discriminator for a poor prognosis in normotensive patients. Early detection of RVD (especially combination of RV dilation and IVC broadening, RVED/LVED>0.67 and/or SPAP>60 mm Hg) was beneficial for identifying high-risk patients. Hemodynamic instability, 14-day clinical outcomes, and SPAP independently predicted 3-month clinical outcomes. PMID- 17716756 TI - Iodide mumps. AB - Acute sialadenitis following contrast administration is characterized by rapid, painless, bilateral enlargement of salivary glands, and is due to a rare adverse reaction to the administration of iodine containing contrast material. It is usually a benign, self-limiting condition and may recur with further exposure to iodinated contrast. PMID- 17716757 TI - Large pericardial effusion due to peritoneopericardial fistula. AB - A 50 years old male with previous history of dilated cardiomyopathy was admitted to cardio-intensive unit with dyspnea, cough, ascites and lower limb edema ascending to the inguinal region. 2D-Ecocardiogram revealed large pericardial effusion, without signs of diastolic restriction. The patient underwent pericardial drainage, which rapidly recollected in the following day. Abdominal ultrasound showed fibrotic and reduced size liver and subsequent radionuclide scan demonstrated direct communication between peritoneal and pericardial spaces. With the resolution of ascites, pericardial effusion did not recur. Embryologic explanation of this rare condition is still elusive, but incomplete closure of diaphragmatic muscle and thoracic-abdominal communication may represent the model of this anatomic functional anomaly. PMID- 17716758 TI - Description of empirical movement data from Canadian swine herds with an application to a disease spread simulation model. AB - We report the methods and findings of a survey of Canadian swine producers summarizing farm-types at-risk of foreign animal disease (FAD) and the routine movement of animals, semen and workers among swine farms, as observed during a 42 day period. Of the 311 producers who returned completed questionnaires, 17% represented swine-herds with no swine or semen movement on or off the farm during the 42 days, 57% were sow herds or farrow-to-finish herds with limited movement onto the farm but movement off the farm, and 26% were swine-herds with movements on and off the farm. A substantial number of premises (>50% in some provinces) with swine also kept other animal species on the same premises. We applied the empirical movement data from the survey in a stochastic simulation model to estimate the number of herds infected and the basic regional distribution of infection that could be expected to occur if the FAD was not detected and routine movements were permitted to occur up to 42 days after infection with a FAD of a single randomly selected herd. Forty-five percent of the simulations did not involve spread beyond the index farm, whereas 34.8% involved spread among five or more farms after 42 days of routine movement. PMID- 17716759 TI - Evaluation of respiratory-induced target motion for esophageal tumors at the gastroesophageal junction. AB - PURPOSE: To quantify the internal motion margin requirements for radiotherapy of tumors near the gastroesophageal junction (GEJ). METHODS AND MATERIALS: Four dimensional computed tomography (4DCT) scans were obtained for 25 patients with primary tumors located near the GEJ. The gross tumor volume (GTV) was manually contoured on the exhale-phase image from the 4DCT image set. A deformable image registration method was used to automatically propagate the contours to other phases of the 4DCT images. To quantify target motion, we measured the displacement of the GTV centroid and the variations in the target boundary and volume. Internal margins were calculated in the lateral (RL), anterior-posterior (AP), and superior-inferior (SI) directions. RESULTS: The mean+/-standard deviation peak-to-peak GTV centroid motion was 0.39+/-0.27cm (range, 0.04-1.09cm) in the RL, 0.38+/-0.23cm (range, 0.10-0.94cm) in the AP, and 0.87+/-0.47cm (range, 0.43-2.63cm) in the SI directions, respectively. On average, the internal target volume was 72% (range, 9-172%) larger than the GTV defined on a single phase CT image. Variations in tumor boundaries due to tissue motion and deformation suggested asymmetric margins: 1.0cm left [toward the stomach], 0.8cm right, 1.1cm anterior, 0.6cm posterior, 1.0cm superior (toward the distal esophagus), and 1.6cm inferior (toward the stomach). CONCLUSION: Because tumors near the GEJ are subject to a marked but asymmetric amount of respiratory-induced intrafractional tumor motion, the use of asymmetric internal margins may be beneficial. PMID- 17716760 TI - Conformal radiation therapy for portal vein tumor thrombosis of hepatocellular carcinoma. AB - BACKGROUND AND PURPOSE: The prognosis of patients with portal vein tumor thrombosis (PVTT) from hepatocellular carcinoma (HCC) is poor; without treatment, their survival is less than 3months. We retrospectively evaluated the treatment outcomes of conformal radiation therapy (CRT) in patients with HCC-PVTT. MATERIALS AND METHODS: Thirty-eight HCC patients with PVTT in whom other treatment modalities were not indicated underwent CRT. The total dose was translated into a biologic effective dose (BED) of 23.4-59.5Gy(10) (median 50.7Gy(10)) as the alpha/beta ratio=10. Predictive factors including the age, performance status, Child-Pugh classification, PVTT size, and BED were evaluated for tumor response and survival. RESULTS: Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) were observed in 6 (15.8%), 11 (28.9%), 17 (44.7%), and 4 (10.5%) patients, respectively. The response rate (CR+PR) was 44.7%. The PVTT size (<30 vs. 30mm) and BED (<58 vs. 58Gy(10)) were significant factors for tumor response. The median survival and 1 year survival rate were 9.6months and 39.4%. The Child-Pugh classification (A vs. B) and BED were significant factors for survival. CONCLUSIONS: CRT is effective not only for tumor response but also for survival in HCC-PVTT patients in whom other treatment modalities are not indicated. PMID- 17716761 TI - Epidemiology of Fusarium head blight on small-grain cereals. AB - Fusarium head blight (FHB) is one of the most serious diseases affecting wheat and barley worldwide. It is caused by Fusarium graminearum along with F. culmorum, F. avenaceum and other related fungi. These fungi also produce several mycotoxins. Though the disease results in reduced seed quality and yield, the toxins which may accompany the disease are often a more serious problem. Pathogen inoculum is usually very abundant, however production and dispersal of inoculum are weather-sensitive processes. An abundance of colonized substrate (i.e. maize or cereal debris) in a region contributes to airborne inoculum throughout the area. Local residues beneath the cereal crop (i.e. from previous crop) may have a less obvious effect, particularly in regions where long-distance dispersal is likely due to wind conditions. The host is most susceptible to infection at anthesis and shortly thereafter. A warm, moist environment characterized by frequent precipitation or heavy dew is highly favorable to fungal growth, infection and development of disease in head tissues. As the fungus grows, it produces mycotoxins which are water-soluble and may be translocated between tissues or leeched from source tissues. Important epidemiological issues have arisen recently and include an apparent shift in prevalence of Fusarium species on infected heads in Europe toward F. graminearum; and the presence of multiple chemotypes and aggressiveness variants within a species in a region. PMID- 17716762 TI - A new technique to prevent the main post harvest diseases in berries during storage: inclusion complexes beta-cyclodextrin-hexanal. AB - Natural occurring volatiles such as hexanal have a well know antifungal capacity but limited post harvest use due to their volatility. Taking this into consideration, hexanal was inserted into beta-cyclodextrins (beta-CD) to develop a controlled release mechanism and then evaluated in vitro against Colletotrichum acutatum, Alternaria alternata and Botrytis cinerea, the three main causes of post harvest diseases in berries. Different concentrations of both pure volatile hexanal and its inclusion complexes (IC) were analyzed for their fungistatic and fungicidal effects for 7 days at 23 degrees C. Hexanal has fungistatic effect on all fungi tested, however, fungicidal activity was only observed on C. acutatum. Results showed that hexanal's effectiveness was greater against C. acutatum than A. alternata and B. cinerea. Concentrations of 1.1, 2.3 and 1.3 microL hexanal/L air respectively were necessary to prevent C. acutatum, A. alternata and B. cinerea growth. Lower concentrations reduced fungal growth depending on the included amount and type of fungus. Same amount of hexanal released from beta cyclodextrin had a lower antifungal effect on C. acutatum. Thus, ICs beta cyclodextrin-hexanal can be used to reduce or avoid post harvest berry diseases because of their capacity to provide an antifungal volatile during storage, distribution, and consumer purchasing. PMID- 17716763 TI - Antimicrobial resistance of 114 porcine isolates of Campylobacter coli. AB - Campylobacter species were isolated from 24 pig farms in 10 different regions of Korea, and were assayed with regard to their susceptibility to eight antimicrobial agents. A total of 114 Campylobacter isolates from 572 intestinal samples were all identified as C. coli via both classical methods and molecular methods, including 16S rDNA sequence analysis and polymerase chain reactions (PCR) using specific primer sets for the hippuricase gene and the aspartokinase gene, designed to differentiate C. coli from C. jejuni. Minimal inhibitory concentrations of seven antimicrobial agents were determined via agar dilution: the MIC(90)s were 64 microg/ml for ampicillin, 8 microg/ml for chloramphenicol, 64 microg/ml for ciprofloxacin, 16 microg/ml for enrofloxacin, >or=128 microg/ml for erythromycin, >or=128 microg/ml for gentamicin, and >or=128 microg/ml for tetracycline. The proportion of isolates resistant to each antimicrobial agent was as follows: 28.9% for ampicillin, 2.6% for chloramphenicol, 84.2% for ciprofloxacin, 83.3% for enrofloxacin, 46.5% for erythromycin, 20.2% for gentamicin, and 56.1% for tetracycline. All 114 isolates were found to be resistant to at least one antimicrobial agent, and 61 isolates (53.5%) were found to be multi-drug resistant (resistant to more than three antimicrobial agents in different classes). PMID- 17716764 TI - An overview of ochratoxin A in beer and wine. AB - Ochratoxin A (OTA) is a mycotoxin produced mainly by several fungal species of the genera Aspergillus and Penicillium. This mycotoxin has been shown to be nephrotoxic, hepatotoxic, teratogenic and carcinogenic to animals and has been classified as a possible carcinogen to humans. OTA occurs in a variety of foods, including beer and wine. Reports on OTA occurrence in beer indicate that this is a worldwide problem due to the widespread consumption of this beverage. At present, the European Union (EU) has not set a maximum allowable limit (MAL) for this mycotoxin in beer, although there is a limit in barley and malt. Studies carried out in different countries agree in the high proportion of samples contaminated with OTA although levels are, usually, below 0.2 ng/ml. OTA occurrence has been related to the contamination of malt barley with ochratoxigenic species, particularly Penicillium verrucosum. OTA produced in grains is carried to wort and, although fermentation decreases the concentration, the toxin is not eliminated. Reducing the fungal contamination of malt barley is the most promising strategy for reducing OTA in beer. With regard to wine, surveys on the presence of OTA have been conducted worldwide. The proportion of wines in which OTA is detected is very high (above 50%) in some countries (especially in the Mediterranean basin) although only a few wines contained concentrations exceeding the MAL laid down by the EU (2.0 ng/ml). A gradient of concentration is usually recognized; OTA levels decrease in the order red, rose, and white wine but also with increasing latitude of the producing countries. OTA presence in wines is due to the black aspergilli, mainly A. carbonarius, which can grow on grapes in the vineyards and produce the toxin. At grape crushing, the juice can be contaminated with the toxin which is carried over into wine, where it persists due to its stability. Pre- and post-harvest treatments are being investigated to diminish contamination of wines as much as possible. PMID- 17716765 TI - Screening of lactic acid bacteria isolates from dairy and cereal products for exopolysaccharide production and genes involved. AB - A total of 174 lactic acid bacteria (LAB) strains isolated from dairy and cereal products were screened for the production of exopolysaccharides (EPS). Therefore, a rapid screening method was developed based on ultrafiltration and gel permeation chromatography. Furthermore, a screening through the polymerase chain reaction (PCR) was performed with primer pairs targeting different genes involved in EPS production. Nine isolates produced a homopolysaccharide of the glucan type, whereas only one strain produced a heteropolysaccharide. The production of a glucan by a strain of Lactococcus lactis and the production of a heteropolysaccharide by a strain of Lactobacillus curvatus are reported for the first time. The PCR screening revealed many positive strains. For three of the ten EPS-producing strains, no corresponding genes could be detected. Furthermore, a lot of strains possessed one or more eps genes but did not produce an EPS. Therefore, a screening on the molecular level should always be accompanied by another screening method that is able to distinguish true EPS producer strains from non-producing ones. Statistical analysis did not reveal any relationship between the type and origin of the strains, the presence or absence of a capsular polysaccharide or EPS, and the presence or absence of eps genes. PMID- 17716766 TI - Marker-assisted selection for Fusarium head blight resistance in wheat. AB - The cultivation of wheat varieties resistant to Fusarium head blight (FHB) is recognized as one of the most important components to diminish losses due to this disease. Although there is no known immunity to this disease in wheat germplasm, considerable improvements in genetic resistance have been achieved by concentrated breeding efforts that have relied primarily upon repeated field and greenhouse-based screening. DNA markers are a relatively new technology that can be used to increase breeding progress, especially for traits such as FHB that are difficult to select for under field conditions and that are controlled by multiple genes. Marker-assisted selection (MAS) uses markers to select for particular DNA segments that are genetically linked to genes that provide incremental resistance to FHB. One particular gene, designated Fhb1, provides a 20-25% average reduction in FHB symptoms. This gene and its associated markers have been validated in numerous breeding programs and is widely used to more precisely breed for resistance. About a dozen other genes affecting FHB reaction have been identified, but they have smaller and more inconsistent effects compared with Fhb1. Nevertheless, breeders are discovering which of these markers can be combined with Fhb1 in their genetic backgrounds to enhance resistance. The establishment of the USDA-ARS Regional Small Grains Genotyping Centers and similar facilities around the world have increased the capacity for wheat breeders to utilize this powerful technology. More efficient DNA extraction technologies and marker platforms will allow breeders to more fully implement MAS in the future. PMID- 17716767 TI - Strategies for managing Fusarium head blight and deoxynivalenol accumulation in wheat. AB - Many mycotoxigenic fungi infect plant hosts and cause disease in the field. Therefore, control of field infection by these fungi is a critical step in managing mycotoxin accumulation in the harvested product. Fusarium graminearum, also known as Gibberella zeae, is the causal agent of Fusarium head blight (FHB), or scab, in cereals and is also the primary agent responsible for contamination of grain with deoxynivalenol (DON). Research efforts worldwide are devoted to the development of strategies to control field infection of wheat and barley by this pathogen. Strategies include the use of fungicides and biological control agents to protect flowering heads from infection. There is extensive effort in breeding for host resistance to infection and spread of the pathogen within the heads. Scientists are also seeking exogenous traits to introduce into cereals to enhance resistance. Cultural practices are also being examined, primarily as measures to reduce pathogen survival and inoculum production in crop residues. The successes and limitations of these strategies in the management of Fusarium head blight and deoxynivalenol are discussed. PMID- 17716768 TI - Rapid detection of Listeria monocytogenes by nanoparticle-based immunomagnetic separation and real-time PCR. AB - The objective of this study was to develop a method combining nanoparticle-based immunomagnetic separation (IMS) with real-time PCR for a rapid and quantitative detection of Listeria monocytogenes. Carboxyl modified magnetic nanoparticles were covalently bound with rabbit anti-L. monocytogenes via the amine groups. Several factors, such as the amount of immunomagnetic nanoparticles (IMNPs), reaction and collection times, and washing step, were optimized, and the nanoparticle-based IMS in combination with real-time PCR was further evaluated for detecting L. monocytogenes from artificially contaminated milk. The cell numbers calculated from the means of threshold cycles (CT) of PCR amplification curves were compared to those from plate counts in order to determine the correspondence degree of quantitative data. The capture efficiency (CE) by plating from IMNP-based IMS was 1.4 to 26 times higher than those of Dynabeads based IMS depending on the initial cell concentrations inoculated into milk samples. When combined with real-time PCR, L. monocytogenes DNA was detected in milk samples with L. monocytogenes >or=10(2) CFU/0.5 ml. In the range of 10(3) to 10(7)L. monocytogenes CFU/0.5 ml, cell numbers calculated from CT values were 1.5 to 7 times higher than those derived from plate counts. Our results demonstrated that both the use of nanoparticles and the choice of anti-L. monocytogenes in our IMNP-based IMS in combination with real-time PCR has improved the sensitivity of L. monocytogenes detection from both nutrient broth and milk samples. PMID- 17716769 TI - Chemical-specific continuous biomonitoring using a recombinant bioluminescent bacterium DNT5 (nagR-nagAa::luxCDABE). AB - The recombinant bioluminescent bacterium, DNT5, containing a nagR-nagAa::luxCDABE fusion, was tested in a multi-channel continuous monitoring system to evaluate its ability to detect benzoic acid derivatives. Seven chemicals, benzoic acid, salicylic acid, 2,5-dihydroxy benzoic acid, 3,5-dihydroxy benzoic acid, benzene, naphthalene and phenol, were used to characterize the responses of DNT5. This strain responded uniquely to each chemical, and these responses were then evaluated based upon the structures of each chemical. The greatest bioluminescent responses were to salicylic acid and benzoic acid, followed by 2,5-dihydroxy benzoic acid and 3,5-dihydroxy benzoic acid, but DNT5 was unresponsive when exposed to benzene, phenol and naphthalene, suggesting it has a strong preference for benzoic acid derivatives with few or no ring-substituted groups. PMID- 17716770 TI - Process stability and microbial community structure in anaerobic hydrogen producing microflora from food waste containing kimchi. AB - Hydrogen production by the dark fermentation of food wastes is an economic and environmentally friendly technology to produce the clean energy source as well as to treat the problematic wastes. However, the long-term operations of the continuous anaerobic reactor for fermentative hydrogen production were frequently unstable. In this study, the structure of microbial community within the anaerobic reactor during unstable hydrogen production was examined by denaturing gradient gel electrophoresis (DGGE) and terminal restriction fragment length polymorphism (T-RFLP) techniques. The changes in microbial community from H(2) producing Clostridium spp. to lactic acid-producing Lactobacillus spp. were well coincident with the unexpected process failures and the changes of metabolites concentrations in the effluent of the anaerobic reactor. As the rate of hydrogen production decreased, effluent lactic acid concentration increased. Low rate of hydrogen production and changes in microbial community were related to the 'kimchi' content and storage temperature of food waste feed solution. After low temperature control of the storage tank of the feed solution, any significant change in microbial community within the anaerobic reactor did not occur and the hydrogen production was very stably maintained for a long time. PMID- 17716771 TI - Cationic lipids and polymers mediated vectors for delivery of siRNA. AB - RNA interference (RNAi) is one of the most importantly protective phenomena forming from the process combating against virus. Since its high efficiency for silencing the expression of proteins at the posttranscriptional level, RNAi shows great prospect in therapeutics for diseases. However, the delivery of siRNA into cells, tissues or organs remains to be a big obstacle for its applications. Many vectors for siRNA delivery have been developed including viral vectors and non viral vectors, among them non-viral vectors have the advantages of low toxicity, ease of synthesis and low immune response over viral ones. Cationic liposomes and polymer particles, major varieties of non-viral vectors, used for gene delivery, have shown to be suitable for the delivery of siRNA. Based on the concise introduction of RNAi, this article reviews the non-viral delivery systems of siRNA, hoping to provide helpful information for the development of delivery systems of siRNA, and to summarize literatures about siRNA delivery published in recent years. PMID- 17716772 TI - What are determining factors for stable drug incorporation into polymeric micelle carriers? Consideration on physical and chemical characters of the micelle inner core. AB - Partially benzyl-esterified poly(ethylene glycol)-b-poly(aspartic acid) (PEG P(Asp(Bzl))) having different hydrophobic inner-core structure were synthesized and analyzed. We obtained two types of the block copolymers for formation of polymeric micelle drug carriers; one had an amide-bond ratio of 1:3 (alpha/beta) in the poly(aspartic acid) residues through alkaline hydrolysis, and the other one had 100% of the alpha-amide through acid hydrolysis. Subsequently, we prepared partially benzyl-esterified block copolymers with an esterification degree of 40 to 100% in the aspartic acid residue. Regarding camptothecin (CPT) incorporation into polymeric micelles, we evaluated effects that block copolymers' inner hydrophobic block structures have on CPT behavior. Regarding CPT-incorporation stability, PEG-P(alpha,beta-Asp(Bzl) block copolymers with the alpha and beta-amides were found to exhibit higher CPT-incorporation stability. Using fluorescent probes, we evaluated the properties of inner-core blocks such as hydrophobicity and mobility/rigidity, and the findings implied that stable CPT incorporation could be obtained by an adequate balance between the micelle inner core's hydrophobicity and the micelle inner core's rigidity or between the micelle inner core's hydrophobicity and steric configuration of the hydrophobic block chain. PMID- 17716773 TI - Relationship between plasma levels of soluble CD40L and insulin sensitivity and insulin secretion status in non-diabetic dyslipidemic patients. AB - OBJECTIVE: We have measured circulating plasma sCD40L as well as the platelet surface of CD40L and its receptor in a sample of non-diabetic dyslipidemic patients and then evaluated its relationship with the insulin resistance (IR) and insulin secretion (IS) status. DESIGN AND METHODS: Anthropometric measurements, fasting glucose, insulin, lipids, and IR and IS [estimated by the homeostasis model assessment (HOMA)] were assessed in 86 dyslipidemic subjects. Circulating sCD40L were determined by ELISA. By flow cytometry, CD40L, CD40 and P-selectin were evaluated in the platelet-surface. RESULTS: Non-diabetic dyslipidemic IR patients (HOMA-IR>or=3.8) showed higher plasma sCD40L concentrations and a more unfavorable cardiovascular risk profile (higher BMI, waist, fasting insulin and mean triglyceride levels) than dyslipidemic patients with low IS (HOMA beta cell<98). In a multivariable model, only measures of insulin sensitivity and higher waist remained significantly associated with increased plasma levels of sCD40L. Surface expression of CD40L on platelets decreased significantly and CD40 increased in IR patients, compared with patients with low IS. CONCLUSIONS: IR dyslipidemic patients show increased plasma sCD40L and decreased platelet membrane CD40L expression compared to dyslipidemic patients with low IS. PMID- 17716774 TI - Avoidance of ACE inhibitors or angiotensin receptor blockers among women of childbearing potential with diabetes. PMID- 17716775 TI - The role of vascular endothelial growth factor, tumor necrosis factor alpha and interleukin-6 in pathogenesis of diabetic retinopathy. AB - The aim of the study was to analyze the relation between early diabetic retinopathy and the pro-inflammatory cytokines tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF) in children with diabetes mellitus type 1. Two hundred and two children with diabetes mellitus type 1 aged 13.2+/-3.83 years and 85 healthy controls were analyzed. Patients were divided into two subgroups: children with retinopathy (Group 1, n=39) and children without retinopathy (Group 2, n=163). All the children had 24h urine albumin secretion rate, glycosylated hemoglobin HbA1c level, and C-reactive protein level measured, underwent 24h blood pressure monitoring and had ophthalmologic examination performed. Additionally, all the children had serum TNF-alpha, IL-6 and VEGF level measured using an ELISA test (Quantikine High Sensitivity Human). Statistically significant higher blood serum levels of HbA1c, VEGF, TNF-alpha and IL-6 were found in the Group 1 in comparison with the Group 2. Additionally, the children of the Group 1 showed statistically significant correlation between serum VEGF and serum TNF-alpha (R=0.35, p=0.000), CRP level (R=0.23, p=0.006), 24h albumin urine secretion rate (R=0.45, p=0.000) and duration of the disease (R=0.26, p=0.002). The results of the current study suggest that there is a relationship between VEGF, TNF-alpha, IL-6 and the development of the diabetic retinopathy in children with diabetes mellitus type 1. PMID- 17716776 TI - Acute thrombocytopenia after liver transplant: role of platelet activation, thrombopoietin deficiency and response to high dose intravenous IgG treatment. AB - BACKGROUND/AIMS: Thrombocytopenia is common after liver transplantation due to platelet sequestration secondary to hypersplenism. The aim of this study was to further investigate the causes of this condition, as well as the response of thrombocytopenia to high dose intravenous immunoglobulins. METHODS: We retrospectively studied 73 patients who underwent liver transplantation. Out of these 73 patients, 27 had severe thrombocytopenia and were treated with high dose intravenous immunoglobulin. Additionally, we retrospectively studied 8 patients undergoing liver transplantation. RESULTS: Our data suggest that splenomegaly is not the only factor responsible for thrombocytopenia after liver transplantion and two additional phenomena, namely, reduced platelet production due to reduced thrombopoietin levels and sustained platelets activation take part in the pathogenesis of this condition. The infusion of high dose immunoglobulins induced a safe, prompt, complete and persistent resolution of severe thrombocytopenia in more than 70% of patients. CONCLUSIONS: Based on these findings, treatment with high dose intravenous immunoglobulins should be considered in the management of severe thrombocytopenia after liver transplant, although additional randomized trials are warranted. PMID- 17716777 TI - Rhythmic pattern in pain and their chronotherapy. AB - Pain control is one of the most important therapeutic priorities; nonetheless, inadequate pain relief remains a significant health care issue. Thus, it is important to determine whether the analgesic effect can be improved by using the chronopharmacological approach. This paper reviews the data on the rhythmic patterns in pain level and their chronotherapy. It underlines the major issues and problems related to the development of chronotherapeutic strategies, and it examines emerging aspects of new drug-delivery systems for achieving such. PMID- 17716778 TI - Pneumonectomy: post-operative quality of life and lung function. AB - BACKGROUND: Pneumonectomy is associated with high morbidity and mortality. After pneumonectomy, data on health-related quality of life (HRQoL) or its correlation with dyspnea and lung function are scarce. Our main aim was to evaluate long-term HRQoL after pneumonectomy. METHODS: In a retrospective one-center cross-sectional study, we investigated 31 of 98 patients who underwent pneumonectomy between January 1997 and October 2003 due to primary lung cancer. Pre- or postoperative chemotherapy or radiotherapy was applied according to hospital protocol. In June 2004, all patients alive received the generic HRQoL instrument (15D), as well as the Baseline Dyspnea Index (BDI). Results of the 15D were compared with those for an age- and gender-standardized general population. In April 2005, 20 patients participated in follow-up spirometric pulmonary function tests. RESULTS: The 15D total score and its various dimensions were significantly lower after pneumonectomy than in the general population. Females both in 15D score and in the BDI had more dyspnea (p<0.05). No difference appeared between right and left pneumonectomy patients, except for more prominent dyspnea in women with right sided pneumonectomy. CONCLUSIONS: Pneumonectomy had a negative impact on patients' HRQoL. The use of a broad HRQoL instrument like the 15D, which covers multiple dimensions of HRQoL, yields a more accurate evaluation than did a single dimension HRQoL instrument. Possibilities for sleeve-resection should be considered thoroughly before any pneumonectomy. SUMMARY: Quality of life (QoL) after pneumonectomy, as measured with a generic QoL instrument, the 15D, was compared in an age- and gender-standardized population. QoL after pneumonectomy was significantly lower, especially in women after right-sided pneumonectomy. PMID- 17716779 TI - Randomized phase II trial of three intrapleural therapy regimens for the management of malignant pleural effusion in previously untreated non-small cell lung cancer: JCOG 9515. AB - To evaluate the efficacy and toxicity of three intrapleural therapy regimens consisting of bleomycin (BLM), OK-432 (a pulverized product of heat-killed Streptococcus pyogenes) or cisplatin plus etoposide (PE) for the management of malignant pleural effusion (MPE) in previously untreated non-small cell lung cancer. Eligible patients were randomized to the BLM arm: BLM 1mg/kg (maximum 60mg/body), the OK-432 arm: OK-432 0.2 Klinische Einheit units (KE)/kg (maximum 10KE/body), or the PE arm: cisplatin (80mg/m(2)) and etoposide (80mg/m(2)). Pleural response was evaluated every 4 weeks according to the study-specific criteria. All responders received systemic chemotherapy consisting of PE every 3 4 weeks for two or more courses. Pleural progression-free survival (PPFS) was defined as the time from randomization to the first observation of pleural progression or death due to any cause. The primary endpoint was the 4-week PPFS rate. Of 105 patients enrolled, 102 were assessed for response. The 4-week PPFS rate for the BLM arm was 68.6%, 75.8% for the OK-432 arm, and 70.6% for PE arm. Median survival time (MST) for the BLM arm was 32.1 weeks, 48.1 weeks for the OK 432 arm, and 45.7 weeks for the PE arm. However, the outcomes did not differ significantly between groups. Toxicity was tolerable in all arms except for one treatment-related death due to interstitial pneumonia induced by BLM. We will select intrapleural treatment using OK-432 in the management of MPE in NSCLC for further investigation because it had the highest 4-week PPFS rate. PMID- 17716780 TI - In vitro differentiation of murine embryonic stem cells into keratinocyte-like cells. AB - Embryonic stem (ES) cells are omnipotent; they can differentiate into every cell type of the body. The development of culture conditions that allow their differentiation has made it conceivable to produce large numbers of cells with lineage-specific characteristics in vitro. Here, we describe a method by which murine ES cells can be differentiated into cells with characteristics of epidermal keratinocytes. Keratinocyte-like cells were isolated from embryoid bodies and grown in culture. Potential applications of this method are the in vitro differentiation of cells of interest from ES cells of mice with lethal phenotypes during embryonic development and the production of genetically modified epidermal keratinocytes that could be used as temporary wound dressing or as carriers of genes of interest in gene therapeutic treatments. PMID- 17716781 TI - Engaging with healthy eating discourse(s): ways of knowing about food and health in three ethnocultural groups in Canada. AB - The aim of this study was to increase our understanding of how people make sense of healthy eating discourses by exploring the 'ways of knowing' about healthy eating among members of three different ethnocultural groups in Canada: African Nova Scotians, Punjabi British Columbians and Canadian-born European Nova Scotians and British Columbians. Data for this paper come from in-depth, individual interviews with 105 adults where they described their experiences, interpretations, and reasoning used in learning and deciding what to believe and/or reject about healthy eating. Between and within ethnocultural group differences in how people come to know and use practices about healthy eating were examined as they were represented through three broad healthy eating discourses: cultural/traditional, mainstream and complementary/ethical. The discourses represented different ways to interpret the food-health relationship and make sense of the evidence about healthy eating in the everyday experience. Engagement with different discourses led participants to undertake different practices upon themselves in the name of healthy eating. We suggest that each of the discourses has a significant contribution to make in a dialogue about how healthy eating, as part of health and well-being, should be conceptualized by a society. PMID- 17716782 TI - The role of PACAP in the control of circadian expression of clock genes in the chicken pineal gland. AB - Several features of the molecular circadian oscillator of the chicken pineal gland show homology with those in the mammalian SCN. Studies have shown the effects of PACAP on the mammalian SCN, but its effects on the expression of clock genes in the avian pineal gland have not yet been demonstrated. Clock and Cry1 expression was analyzed in pineal glands of chicken embryos after exposure to PACAP-38 in vitro. PACAP reduced expression of both clock genes within 2h. Ten hours after exposure, mRNA contents exceeded that of the controls. Our results support the hypothesis that the molecular clock machinery in the chicken pineal gland is also sensitive to PACAP. PMID- 17716784 TI - Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being. AB - The neuroendocrine system affects the immune system through the neuroendocrine humoral outflow via the pituitary, and through direct neuronal influences via the sympathetic, parasympathetic (cholinergic) and peptidergic/sensory innervation of peripheral tissues. Circulating hormones or locally released neurotransmitters and neuropeptides regulate major immune functions, such as antigen presentation, antibody production, lymphocyte activity, proliferation and traffic, and the secretion of cytokines including the selection of T helper (Th)1 or Th2 cytokine responses. During inflammation, the activation of the stress system, through induction of a Th2 shift protects the organism from systemic "overshooting" with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones, substance P, ATP and the activation of the corticotropin-releasing hormone/substance P-histamine axis may actually facilitate inflammation, through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor (TNF) alpha and CRP production. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression and atherosclerosis. Better understanding of the neuroendocrine control of inflammation may provide critical insights into mechanisms underlying a variety of common human immune-related diseases. PMID- 17716783 TI - Characterization of interactions between phencyclidine and amphetamine in rodent prefrontal cortex and striatum: implications in NMDA/glycine-site-mediated dopaminergic dysregulation and dopamine transporter function. AB - N-Methyl-D-aspartate (NMDA) antagonists induced behavioral and neurochemical changes in rodents that serve as animal models of schizophrenia. Chronic phencyclidine (PCP, 15 mg/(kg day) for 3 weeks via Alzet osmotic pump) administration enhances the amphetamine (AMPH)-induced dopamine (DA) efflux in prefrontal cortex (PFC), similar to that observed in schizophrenia. NMDA/glycine site agonists, such as glycine (GLY), administered via dietary supplementation, reverse the enhanced effect. The present study investigated mechanisms of glycine induced reversal of PCP-induced stimulation of AMPH-induced DA release, using simultaneous measurement of DA and AMPH in brain microdialysate, as well as peripheral and tissue AMPH levels. PCP treatment, by itself, increased peripheral and central AMPH levels, presumably via interaction with hepatic enzymes (e.g. cytochrome P450 CYP2C11). GLY (16% diet) had no effect on peripheral AMPH levels in the presence of PCP. Nevertheless, GLY significantly reduced extracellular/tissue AMPH ratios in both PFC and striatum (STR), especially following PCP administration, suggesting a feedback mediated effect on the dopamine transporter. GLY also inhibited acute AMPH (5 mg/kg)-induced DA release in PFC, but not STR. These findings suggest that GLY may modulate DA release in brain by producing feedback regulation of dopamine transporter function, possibly via potentiation of NMDA-stimulated GABA release and presynaptic GABAB receptor activation. The present studies also demonstrate pharmacokinetic interaction between AMPH and PCP, which may be of both clinical and research relevance. PMID- 17716785 TI - Different oxidative profile and nicotinic receptor interaction of amphetamine and 3,4-methylenedioxy-methamphetamine. AB - d-Amphetamine (AMPH) and MDMA increased intracellular production of reactive oxygen species (ROS) in isolated mouse striatal synaptosomes. MDMA showed a maximal oxidative effect at 50-100 microM. However, for AMPH a double maximum was obtained, the first between 0.1 and 1 microM and the second at 1mM. No oxidative effect was present in synaptosomes from reserpinized mice. Cocaine and l-deprenyl inhibited MDMA and AMPH (0.1 microM) ROS production but not that of AMPH at a higher concentration (1mM). When this high concentration was used, its oxidative effect was abolished by a phospholipase A(2) inhibitor. Delta(9) Tetrahydrocannabinol fully prevented the oxidative effect of AMPH and MDMA, by a CB(1) receptor-independent mechanism, as did it NPC 15437 and genistein. The pro oxidative effect induced by AMPH and MDMA showed a strong dependence on calcium (extracellular and from internal stores) and also was inhibited by nicotinic receptor (nAChR) antagonists dihydro-beta-erythroidine, methyllycaconitine (MLA) and alpha-bungarotoxin. MDMA displaced [(3)H]epibatidine and [(3)H]MLA binding with higher affinity than AMPH. Both amphetamines competitively displaced [(3)H]epibatidine from heteromeric receptors but results obtained from [(3)H]MLA binding demonstrated a non-competitive profile. Preincubation of PC12 cells with AMPH or MDMA reduced [(3)H]dopamine uptake. For MDMA, this effect was prevented by MLA. To summarize, comparing AMPH and MDMA we have demonstrated that these drugs induce an oxidative effect dependent on drug concentration and also reduce dopamine uptake. Processes that are known to affect dopamine transporter functionality also seem to modulate amphetamine derivatives-induced ROS production. For MDMA, acute effects tested are blocked by nAChR antagonists, which points to the possibility that these antagonists could be used to treat some of the adverse effects described in MDMA abusers. Conversely, no implication of nicotinic receptors has been proved for AMPH-induced effects at concentrations achievable in CNS after its administration. PMID- 17716786 TI - CSF cortisol in Alzheimer's disease and mild cognitive impairment. AB - Hypercortisolaemia occurs in Alzheimer's disease (AD) and may be involved in the AD related neurodegenerative process. In order to determine whether brain structures are exposed to high cortisol concentrations early in AD, we measured cerebrospinal fluid (CSF) cortisol in 66 subjects with AD, 33 subjects with mild cognitive impairment (MCI) and 34 control subjects. CSF cortisol concentrations were higher in AD subjects compared to controls (p<0.001) and to MCI subjects (p=0.002). There was no significant increase of cortisol in MCI subjects compared with controls suggesting that the increase of CSF cortisol is not an early event in the course of AD. PMID- 17716787 TI - A creative-bonding intervention and a friendly visit approach to promote nursing students' self-transcendence and positive attitudes toward elders: a pilot study. AB - Nursing students' disinterest in caring for elders presents health care challenges. As the aged population increases, nursing faculty are challenged to improve students' attitudes toward elder care. Reed's self-transcendence theory guided this pilot study with nursing students (n=22) who implemented either a Creative-Bonding Intervention (CBI) or a Friendly Visit (FV) at senior citizen centers to test the effect of creative approaches on student self-transcendence and attitudes toward elders. Demographic data, a revised Kogan's Attitudes toward Old People statements, and Reed's Self-transcendence Scale were analyzed with descriptive, paired t test, ANCOVA, and Pearson correlation statistics. Results demonstrated significant differences in attitudes in the FV and changes in the expected directions in the CBI group. Self-transcendence had no significant changes. Valuable information was provided by students' comments about the interventions. Reed's belief that self-transcendence is present regardless of age was supported. Future studies are suggested with an increased sample size, a combined CBI/FV intervention, and supportive help during students' intervention delivery. PMID- 17716788 TI - Adjuvant effects of plasmid-generated hairpin RNA molecules on DNA vaccination. AB - Cellular recognition of double-stranded RNA and subsequent antiviral molecular events are important components of host defense, which are responsible for initiating innate immune responses to infection. Here we showed that hairpin RNA molecules with various stem lengths, which were transcribed from antigen-encoding plasmids had profound effects on the host cell apoptosis, foreign gene expression as well as the antigen-specific immune responses elicited by DNA vaccination. The plasmid generating the short-stem (40bp) RNA molecule showed slight effects on cell apoptosis and reporter gene expression level but stimulated significantly enhanced antigen-specific cellular immune responses. Although the DNA construct encoding the long-stem (750bp) RNA induced vigrous cell apoptosis, no significant improvement in cell-medicated immune responses was observed when mice were immunized with DNA vaccines encoding the long-stem RNA. In addition, our data also showed that none of DNA vaccine constructs carrying hairpin RNA cassettes enhanced antigen-specific humoral immune responses. This study introduced a novel approach for improving plasmid vector design and showed that the DNA vectors generating hairpin RNA in vivo have a great potential in vaccination and immunotherapy against infectious and malignant diseases. . PMID- 17716791 TI - Epignathus: two cases. AB - Epignathus is a rare congenital nasopharyngeal tumour that is derived from the upper jaw, palate, and sphenoid bone. It usually protrudes through the mouth, leading to an appreciable risk of obstruction of the upper airway and death soon after birth. We report two cases of unusual presentations that illustrated some uncommon and similar characteristics. Although these tumours are not consistent in origin, number, and differentiation of tissues, both contained structures that were derived from all three layers of germ cells, including different anomalous tissues internally (dental bud, fat and muscular tissues, mucosal epithelium). Externally, they contained normal epidermis (skin with fine hairs). Imaging studies and operative findings showed that both tumours originated from the anterior portion of the sphenoid bone causing a sphenoidal sinus cleft without intracranial communication. PMID- 17716790 TI - Long- and short-time immunological memory in different strains of mice given nasally an adjuvant-combined nasal influenza vaccine. AB - Immunological memory induced by nasal immunization with adjuvant-combined influenza vaccine was analyzed in different ages and strains of mice. The memory activities were assessed by secondary nasal-wash IgA and serum IgG antibody (Ab) responses and protection against challenge infection with a lethal dose of influenza virus. Mice were primed with 0.1 microg of vaccine and boosted with 0.1 or 1.0 microg vaccine 1 (short-term memory)- or 17 (long-term memory)-months later. Influenza-specific short-term memory responses in young adult BALB/c mice (2-month-old) were significantly higher than those of long-term memory activities in mice boosted at 19 months of age. However, those influenza-specific long-term memory responses provided protective immunity against influenza virus challenge and were higher than short-term memory in aged mice primed at 18-month-old and boosted 1 month later. These results show that the age at which initial nasal immunization is given is critically important in order to induce protective immunity in aged mice. Similar findings were noted in the C3H mouse strain; however, C57BL/6 mice failed to induce influenza-specific immune responses in both young adult and aged mice. These results indicate that low doses of cholera toxin B subunit (supplemented with 0.2% of hole toxin) combined nasal vaccine may required further improvement in order to provide protective immunity in human use. PMID- 17716792 TI - Heavy metal accumulation in Littoraria scabra along polluted and pristine mangrove areas of Tanzania. AB - The periwinkle Littoraria scabra was collected at polluted and pristine mangrove sites along the Tanzanian coastline, including Msimbazi, Mbweni (i.e. Dar es Salaam) and Kisakasaka, Nyamanzi and Maruhubi (i.e. Zanzibar). Periwinkles were morphologically characterized, sexed and their heavy metal content was determined using ICP-MS. Analysis revealed that L. scabra from polluted areas contained higher soft tissue heavy metal levels, were significantly smaller and weighed less compared to their conspecifics from the unpolluted mangroves. The current morphological observations may be explained in terms of growth and/or mortality rate differences between the polluted and non-polluted sites. Although a variety of stressors may account for these adverse morphological patterns, our data suggest a close relationship with the soft tissue heavy metal content. Compared to soft tissue heavy metal levels that were measured in L. scabra along the same area in 1998, most metals, except for arsenic, chromium and iron have decreased dramatically. PMID- 17716794 TI - The passing dilemma in socially invisible diseases: narratives on chronic headache. AB - This contribution concerns the experience of chronic diseases and how it disrupts the trajectory of a person's biography, undermining his/her identity, self reliance and social relationships. The study focuses particular attention on those diseases which have not yet been fully acknowledged and can, therefore, be considered a socially invisible disease: chronic headache is one of these. Thirty one life stories were collected from patients attending a specialized headache centre in Northern Italy, and selected in order to include all common varieties of chronic headache. Following the principles of grounded theory, interviews began by adopting a minimal theoretical framework which consisted of asking people how they became aware of the objective (disease), subjective (illness) and social (sickness) aspects of their condition. The analysis highlighted particular points in the patients' life trajectories: first, the biographical disruption that takes place because of the disease; second, how people succeed or fail in identity negotiation, which is vital for developing an acceptable social representation of the disease. Results show that patient's choices follow a vicious circle, where a partial social representation of the disease is produced. People who suffer from chronic headache face a dilemma in social relationships: should they conceal their disease, or make it evident? If they conceal, any possible social representation of the disease is denied, which could lead to carrying the burden of the disease alone, with no social support. On the other hand, making chronic headache visible could result in stigma. PMID- 17716793 TI - Explaining medically unexplained symptoms-models and mechanisms. AB - We summarize the psychological mechanisms that have been linked to the development and maintenance of medically unexplained symptoms (MUS). Many models postulate that patients with MUS misinterpret physical sensations and show other cognitive abnormalities (e.g., an over-exclusive concept of health) that play a major role in symptom development. While there is strong evidence for the role of cognitive aspects, there is less evidence for their interaction with perceptual features (e.g., perceptual sensitivity, lowered perceptual threshold). Modern neuroimaging techniques show that the expectation of symptoms leads to the activation of brain areas corresponding to symptom perception, while distraction from symptoms reduces brain activity in perception areas. The frequently postulated monocausal organic attribution for physical sensations by patients with MUS needs to be modified, as many patients report multiple symptom attributions, including psychological. Symptom attributions and causal models depend on memorized concepts, and so memory processes need to be investigated in more detail. Aberrations in memory processes not only offer a link to understanding perceptual processes, but are also involved in doctor-patient interaction. This encounter is characterized by unsuccessful medical reassurance, which again involves memory processes. We conclude that psychological mechanisms such as expectation, distraction, and memory processes need to be integrated with biological models to aid understanding of MUS. PMID- 17716795 TI - Schizophrenia with auditory hallucinations: a voxel-based morphometry study. AB - Many studies have shown widespread but subtle pathological changes in gray matter in patients with schizophrenia. Some of these studies have related specific alterations to the genesis of auditory hallucinations, particularly in the left superior temporal gyrus, but none has analysed the relationship between morphometric data and a specific scale for auditory hallucinations. The present study aims to define the presence and characteristics of structural abnormalities in relation with the intensity and phenomenology of auditory hallucinations by means of magnetic resonance voxel-based morphometry (MR-VBM) method applied on a highly homogeneous group of 18 persistent hallucinatory patients meeting DSM-IV criteria for schizophrenia compared to 19 healthy matched controls. Patients were evaluated using the PSYRATS scale for auditory hallucinations. Reductions of gray matter concentration in patients to controls were observed in bilateral insula, bilateral superior temporal gyri and left amygdala. In addition, specific relationships between left inferior frontal and right postcentral gyri reductions and the severity of auditory hallucinations were observed. All these areas might be implicated in the genesis and/or persistence of auditory hallucinations through specific mechanisms. Precise morphological abnormalities may help to define reliable MR-VBM biomarkers for the genesis and persistence of auditory hallucinations. PMID- 17716796 TI - The effect of atypical antipsychotics, perospirone, ziprasidone and quetiapine on microglial activation induced by interferon-gamma. AB - An accumulating body of evidences point to the significance of neuroinflammation and immunogenetics in schizophrenia, characterized by increased serum concentration of several pro-inflammatory cytokines. In the central nervous system (CNS), the microglial cells are the major immunocompetent cells which release pro-inflammatory cytokines, nitric oxide (NO) and reactive oxygen species to mediate the inflammatory process. In the present study, we investigated whether or not atypical antipsychotics, namely perospirone, quetiapine and ziprasidone, would have anti-inflammatory effects on the activated microglia which may potentiate neuroprotection. All three atypical antipsychotics significantly inhibited NO generation from activated microglia while perospirone and quetiapine significantly inhibited the TNF-alpha release from activated microglia. Antipsychotics, especially perospirone and quetiapine may have an anti inflammatory effect via the inhibition of microglial activation, which is not only directly toxic to neurons but also has an inhibitory effect on neurogenesis and oligodendrogenesis, both of which have been reported to play a crucial role in the pathology of schizophrenia. PMID- 17716797 TI - Distinct behavioral and neurochemical alterations induced by intermittent hypoxia or paradoxical sleep deprivation in rats. AB - The current study investigated the effects of paradoxical sleep deprivation and intermittent hypoxia by examining whether a combination of the two would induce anxiety-like alterations in behavior. The neurochemical effects of these manipulations were investigated by measuring cortical, striatal and hippocampal monoamine concentrations. Wistar Hannover rats were submitted to subchronic (3 days) intermittent hypoxia exposure (alternating cycles of 2 min room air-2 min 10% O2 from 0700-1900 h) and paradoxical sleep deprivation using the single platform method. Rats were randomly assigned to four different protocols: 1) control, 2) intermittent hypoxia during the light period (12 h/day), 3) paradoxical sleep deprivation (24 h/day), and 4) intermittent hypoxia combined with paradoxical sleep deprivation. Rats subjected to intermittent hypoxia showed no modification in the behavioral or neurochemical parameters assessed. Although paradoxical sleep deprivation did not produce alterations in anxiety-like behavior, the rats did increase exploratory activity in the elevated plus-maze. Moreover, a significant increase in striatal epinephrine and hippocampal homovanilic acid (HVA) concentrations was found in the paradoxical sleep deprivation groups, but not in the intermittent hypoxia/paradoxical sleep deprivation group. Of note, both paradoxical sleep deprivation and intermittent hypoxia/paradoxical sleep deprivation groups showed an increase in plasma corticosterone concentration. These results suggest that paradoxical sleep deprivation induces behavioral alterations, and these abnormalities may reflect altered neurotransmission in the brain. When paradoxical sleep deprivation was combined with intermittent oxygen depletion, the behavioral and biochemical parameters were comparable to those of control rats. PMID- 17716798 TI - The effects of orally administered crude alcohol and aqueous extracts of African potato (Hypoxis hemerocallidea) corm on the morphometry of viscera of suckling rats. AB - The litter from six Sprague-Dawley rats was used to study the short-term effects of African potato (AP) corm extracts in suckling rats. Ten days after birth, the pups in each litter were assigned to treatment groups and received alcohol (AL) or aqueous (AQ) extracts of AP (50 mg kg(-1) b.w. in 0.9% saline, 10 ml kg(-1) b.w., and a high dose 200 mg kg(-1) b.w. in 0.9% saline, 10 ml kg(-1) b.w.) via a stomach tube, for 5 consecutive days. A fifth group (control) received 0.9% saline (10 ml kg(-1) b.w.). Between gavage, the pups were kept with their dams. The pups were then killed and the viscera removed for gross and microscopic morphometric measurements. The low dose of AQ and AL extracts of AP significantly increased (P<0.01, ANOVA) the mean weight gain. The high dose of AQ significantly increased (P<0.05, ANOVA) the weight of the caeca whilst the low dose of the AL extract reduced pancreas weight compared to the control and low dose AQ groups. All other morphometric parameters of the viscera measured did not differ significantly between the groups. The small intestinal villi and crypts did not reveal any signs of pathology. PMID- 17716799 TI - Sulfur dioxide derivatives increase a hyperpolarization-activated inward current in dorsal root ganglion neurons. AB - The effect of derivatives of sulfur dioxide (SO(2)), a common air pollutant, which exists in vivo at equilibrium between bisulfate and sulfite, was studied on hyperpolarization-activated cation current (I(h)) in cultured post-natal dorsal root ganglion (DRG) neurons using the whole cell configuration of patch-clamp technique. SO(2) derivatives increased I(h) current in a dose and voltage dependent manner. The EC(50) value was 25 microM and the Hill coefficient was 1.44. 50 microM SO(2) derivatives significantly shifted the activation curve of I(h) in the hyperpolarizing direction by 5.5 mV. The reversal potential of I(h) was shifted to 5.2 mV in positive direction by 10 microM SO(2) derivatives. According to the functional role of I(h), the increase of I(h) should result in an enhanced neuronal excitability, which was possibly the basis for neuropathic pain. PMID- 17716800 TI - Up to 17-year controlled clinical study on post-and-cores and covering crowns. AB - OBJECTIVE: The aim of this long-term follow-up was to collect up to 17-year survival data of different metal post-and-core restorations with a covering crown. METHODS: At initiation of the study, a controlled clinical trial, single tooth was provided with an artificial covering crown, by 18 operators. Restorations under investigation were the post-and-core restorations: cast post and-core restorations, prefabricated metal post and resin composite core restorations, and post-free all-composite core restorations. Before treatment allocation, the recipient tooth was categorized according to the expected dentin height after tooth preparation. A tooth was assessed to have "substantial dentin height" (Trial 1) or "minimal dentin height" (Trial 2). The study sample consisted of 257 patients that received 307 core restorations. The performance of the restorations was based on data collected from the files of the current dentists monitoring the oral health of the patients. The survival probability was analyzed at different levels: on the restoration level (S(R)), and on the level of the tooth carrying the restoration (S(T)). Kaplan Meier analyses were used to compare survival probabilities. RESULTS: "Type of post-and-core restoration" showed no influence on the survival probability (at both levels) in both trials (P-value>0.05). The 17-year survival rates at restoration level varied from 71% to 80%, and at tooth level from 83% to 92%. CONCLUSIONS: The results of this study showed no difference in survival probabilities among different core restorations under a covering crown of endodontically treated teeth. The preservation of substantial remaining coronal tooth structure seems to be critical to the long-term survival of endodontically treated crowned teeth. PMID- 17716801 TI - Myristic acid increases the activity of dihydroceramide Delta4-desaturase 1 through its N-terminal myristoylation. AB - Dihydroceramide Delta4-desaturase (DES) catalyzes the desaturation of dihydroceramide into ceramide. In mammals, two gene isoforms named DES1 and DES2 have recently been identified. The regulation of these enzymes is still poorly understood. This study was designed to examine the possible N-myristoylation of DES1 and DES2 and the effect of this co-translational modification on dihydroceramide Delta4-desaturase activity. N-MyristoylTransferases (NMT) catalyze indeed the formation of a covalent linkage between myristoyl-CoA and the N-terminal glycine of candidate proteins, as found in the sequence of DES proteins. The expression of both rat DES in COS-7 cells evidenced first that DES1 but not DES2 was associated with an increased dihydroceramide Delta4-desaturase activity. Then, we showed that recombinant DES1 was myristoylated in vivo when expressed in COS-7 cells. In addition, in vitro myristoylation assay with a peptide substrate corresponding to the N-terminal sequence of the protein confirmed that NMT1 has a high affinity for DES1 myristoylation motif (apparent K(m)=3.92 microM). Compared to an unmyristoylable mutant form of DES1 (Gly replaced by an Ala), the dihydroceramide Delta4-desaturase activity of the myristoylable DES1-Gly was reproducibly and significantly higher. Finally, the activity of wild-type DES1 was also linearly increased in the presence of increased concentrations of myristic acid incubated with the cells. These results demonstrate that DES1 is a newly discovered myristoylated protein. This N terminal modification has a great impact on dihydroceramide Delta4-desaturase activity. These results suggest therefore that myristic acid may play an important role in the biosynthesis of ceramide and in sphingolipid metabolism. PMID- 17716802 TI - The structural and compositional changes of glycosaminoglycans are closely associated with tissue type in human laryngeal cancer. AB - Hyaluronan and sulfated glycosaminoglycans, as intrinsic components of proteoglycans, are playing important roles in cancer biology. In the present study, we investigated in detail the glycosaminoglycans on both fine chemical and structural levels in laryngeal cartilaginous and non-cartilaginous tissues at different stages of laryngeal cancer. The results indicated that in cartilaginous tissues the amounts of chondroitin sulfate, keratan sulfate, dermatan sulfate and hyaluronan presented a dramatic decrease in contrast to the non-cartilaginous tissues, which showed a significant increase of these glycosaminoglycans compared to their normal counterparts. On fine chemical structure, the molar ratios of 4 sulfated to 6-sulfated and non-sulfated to sulfated disaccharides from both cartilaginous and non-cartilaginous cancerous tissues showed a significant increase. On molecular-size level, in laryngeal cancer, the chromatographic behaviour of the sulfated glycosaminoglycan chains from both tissue-types revealed their lower M(r) with a more polydisperse and heterogeneous distribution compared to the normal ones. In addition, in both tissues, a significant decrease of high molecular-size hyaluronan was observed. Of particular interest was the great increase of hyaluronan of low molecular mass in the laryngeal non cartilaginous tissues, which ranged from 330 to 890 kDa. The kind and the extent of these alterations, which presented an intense stage-related behaviour, depended on the tissue origin and could be associated with the malignant phenotype of human laryngeal cancer. PMID- 17716804 TI - Amiodarone--avoid the danger of torsade de pointes. AB - We present two patients who had life-threatening arrhythmias, which are highly likely to be secondary to amiodarone. This class III anti-arrhythmic is commonly prescribed for the acute presentation of supra-ventricular and ventricular arrhythmias. However, occasionally its use can transform arrhythmias from benign to dangerous. These cases highlight the need for careful attention to the indications, cautions and contra-indications of amiodarone as well as the need for vigilance following initiation of anti-arrhythmic therapy. PMID- 17716805 TI - Prehospital ultrasound detects pericardial tamponade in a pregnant victim of stabbing assault. AB - The development of handheld, portable ultrasound devices has enabled the use of this diagnostic tool also in the out-of-hospital environment. We report on a pregnant teenager who was found haemodynamically unstable after a stab assault. When she suffered cardiac arrest shortly thereafter, diagnosis of cardiac tamponade was made by portable ultrasound, and immediate pericardiocentesis was performed by the emergency physician. While her baby died after emergency Caesarean section, the teenager survived after thoracotomy and prolonged resuscitation without neurological sequelae. PMID- 17716803 TI - Prospects and challenges of building a cancer vaccine targeting telomerase. AB - Despite their origin from self-tissue, tumor cells can be immunogenic and trigger immune responses that can profoundly influence tumor growth and development. Clinically, it may be possible to amplify or induce anti-tumor immune responses to achieve tumor rejection in patients. Increasing data over the last 8 years suggest that the human telomerase reverse transcriptase hTERT is immunogenic both in vitro and in vivo and may be a suitable target for novel cancer immunotherapy. Peptides derived from hTERT are naturally processed by tumors and presented on MHC molecules and trigger effector functions of specific T lymphocytes. Vaccination of cancer patients against hTERT epitopes induces anti-tumor T cells without clinical toxicity. If second-generation vaccines and other strategies are able to generate optimal cellular immunity against hTERT without toxicity in humans, the possibility of broad-spectrum immunotherapy or even immunoprevention therapy of cancer may be possible. PMID- 17716807 TI - Carbon dioxide flux as affected by tillage and irrigation in soil converted from perennial forages to annual crops. AB - Among greenhouse gases, carbon dioxide (CO(2)) is one of the most significant contributors to regional and global warming as well as climatic change. A field study was conducted to (i) determine the effect of soil characteristics resulting from changes in soil management practices on CO(2) flux from the soil surface to the atmosphere in transitional land from perennial forages to annual crops, and (ii) develop empirical relationships that predict CO(2) flux from soil temperature and soil water content. The CO(2) flux, soil temperature (T(s)), volumetric soil water content (theta(v)) were measured every 1-2 weeks in no-till (NT) and conventional till (CT) malt barley and undisturbed soil grass-alfalfa (UGA) systems in a Lihen sandy loam soil (sandy, mixed, frigid Entic Haplustoll) under irrigated and non-irrigated conditions in western North Dakota. Soil air filled porosity (epsilon) was calculated from total soil porosity and theta(v) measurements. Significant differences in CO(2) fluxes between land management practices (irrigation and tillage) were observed on some measurement dates. Higher CO(2) fluxes were detected in CT plots than in NT and UGA treatments immediately after rainfall or irrigation. Soil CO(2) fluxes increased with increasing soil moisture (R(2)=0.15, P<0.01) while an exponential relationship was found between CO(2) emission and T(s) (R(2)=0.59). Using a stepwise regression analysis procedure, a significant multiple regression equation was developed between CO(2) flux and theta(v), T(s) (CO(2) flux = e( 3.477+0.123T(s)+6.381theta)(v); R(2)=0.68, P or =98%) in the lung, and at steady state, daily urine NE excretion reflects approximately 90% of the retained nicotine dose from cigarette smoking. PMID- 17716839 TI - From the "climacteric disease" to the "male climacteric" The historical origins of a modern concept. AB - The historical origins of the modern concept of a "male climacteric" have hitherto been traced to the late 19th and early 20th centuries. Based on a careful scrutiny of early modern and 19th-century sources, this paper shows that the concept goes back much further, however. It evolved from the ancient notion of critical "climacterical years" which recurred every 7th year throughout human life and from the concept of a predominantly male "climacteric disease" which Henry Halford put forward in 1813. In the course of the 19th century, this concept of a "climacteric disease" was gradually reframed under the influence of contemporary interest in the female "menopause" and eventually both largely merged into the single notion of a "climacteric" in both sexes. By 1900, the "climacteric" had become so strongly associated with the female sex that the observation of a "male climacteric" could be presented as a new finding, although the symptoms associated with it were, in retrospect, largely taken from the older notions of the "climacteric disease" and the female "menopause". PMID- 17716840 TI - Thiolated chitosan: development and in vitro evaluation of an oral delivery system for acyclovir. AB - The aim of the study was to develop a novel oral delivery system for the efflux pump substrate acyclovir (ACY) utilizing thiolated chitosan as excipient which is capable of inhibiting P-glycoprotein (P-gp). Three chitosan-4-thiobutylamidine (Chito-TBA) conjugates with increasing molecular mass (Chito-9.4kDa-TBA, Chito 150kDa-TBA and Chito-600kDa-TBA) were synthesized and permeation studies on rat intestinal mucosa and Caco-2 monolayers were performed. Additionally, tablets comprising the conjugates and ACY were tested towards their drug release behaviour. The efflux ratio (secretory P(app)/absorptive P(app)) of ACY across Caco-2 monolayers was determined to be 2.5 and in presence of 100microM verapamil 1.1 which indicates ACY as P-gp substrate. In comparison to buffer only, the transport of ACY in presence of 0.5% (m/v) unmodified chitosan, 0.5% (m/v) Chito 150kDa-TBA and 0.5% (m/v) Chito-150kDa-TBA with 0.5% (m/v) reduced glutathione (GSH), was 1.3-, 1.6- and 2.1-fold improved, respectively. Transport studies across Caco-2 monolayers showed that P-gp inhibition is dependent on the average molecular mass of thiolated chitosan showing following rank order: 0.5% (m/v) Chito-150kDa-TBA/GSH>0.5% (m/v) Chito-9.4kDa-TBA/GSH>0.5% (m/v) Chito-600kDa TBA/GSH. The higher the molecular mass of Chito-TBA was, the more sustained was the release of ACY. Chito-150kDa-TBA/GSH might be an appropriate sustained release drug delivery system for ACY, which is able to enhance ACY transport due to efflux pump inhibition. PMID- 17716841 TI - Imprinted polymers as drug delivery vehicles for metal-based anti-inflammatory drug. AB - A drug delivery system based on metal-chelate imprinting is described for the first time for a metal-based drug, copper salicylate. Metal-chelate embedded polymer (MCEP) material was prepared by adding 2 equiv. of 4-vinyl pyridine, 8 equiv. of 2-hydroxyethyl methacrylate, 32 equiv. of ethyleneglycoldimethacrylate to 1 equiv. of copper salicylate in 10 ml of 2-methoxyethanol and then polymerizing thermally in the presence of 2,2'-azobisisobutyronitrile as initiator. The removal of the embedded copper salicylate from MCEP to prepare metal-chelate imprinted polymer (MCIP) was assessed by X-ray photoelectron spectroscopy (XPS), flame atomic absorption spectroscopy (FAAS) and high performance liquid chromatography (HPLC) techniques. Conventional or non imprinted polymer material was prepared in a similar manner to MCEP, but without the addition of copper salicylate to the synthesis recipe. The drug release behaviour was examined in vitro with polymer materials having different template to monomer ratio, different crosslinker density and with polymer material loaded with copper salicylate to different extent. Detailed drug release studies with the drug loaded to MCIP and NIP materials unequivocally establish the higher and sustained release of the therapeutic agent over several days in addition to higher drug loading capacity with the former material. PMID- 17716842 TI - Dirhenium decacarbonyl-loaded PLLA nanoparticles: influence of neutron irradiation and preliminary in vivo administration by the TMT technique. AB - In a previous study, we have described the elaboration of PLLA-based nanoparticles loaded with non radioactive dirhenium decacarbonyl [Re(2)(CO)(10)], a novel neutron-activatable radiopharmaceutical dosage form for intra-tumoral radiotherapy. These nanoparticles are designed for a neutron irradiation which can be carried out in a nuclear reactor facility. This new paper describes the neutron irradiation influence on these Re(2)(CO)(10)-loaded PLLA nanoparticles. The loaded nanoparticles with 23% (w/w) of metallic rhenium have shown to remain stable and separated and to keep out their sphericity at the lower neutron flux (1x10(11)n/cm(2)/s for 0.5h) which was used for rhenium content determination (neutron activation analysis, NAA). However, when loaded nanoparticles were irradiated at the higher neutron flux (1.45x10(13)n/cm(2)/s, 1h), they have shown to be partially coagglomerated and some pores appeared at their surface. Furthermore, DSC results showed a decrease in the PLLA melting point and melting enthalpy in both blank and loaded nanoparticles indicating a decrease in polymer crystallinity. In addition, the polymer molecular weights (M(n), M(w)) decreased after irradiation but without largely affecting the polymer polydispersity index (P.I.) which indicated that an irradiation-induced PLLA chain scission had occurred in a random way. The XRD patterns of irradiated PLLA provided another proof of polymer loss of crystallinity. FTIR spectra results have shown that irradiated nanoparticles retained the chemical identity of the used Re(2)(CO)(10) and PLLA despite the reduction in polymer crystallinity and molecular weight. Nanoparticles suspending after irradiation became also more difficult, but it was properly achievable by adding PVA (1%) and ethanol (10%) into the dispersing medium. Moreover, after 24h incubation of different irradiated nanoparticles in two different culture mediums, visual examination did not show bacterial growth indicating that applied neutron irradiation, yielding an absorbed dose of 450kGy, can be a terminal method for nanoparticles sterilisation. Thereafter, in a preliminary in vivo experiment, superparamagnetic non radioactive nanoparticles loaded with Re(2)(CO)(10) and oleic-acid coated magnetite have been successfully injected into a mice animal model via targeted multi therapy (TMT) technique which would be our selected administration method for future in vivo studies. In conclusion, although some induced neutron irradiation damage to nanoparticles occurs, dirhenium decacarbonyl-loaded PLLA nanoparticles retain their chemical identity and remain almost as re-dispersible and injectable nanoparticles by the TMT technique. These nanoparticles represent a novel interesting candidate for local intra-tumoral radiotherapy. PMID- 17716844 TI - Transmission of infrasonic pressure waves from cerebrospinal to intralabyrinthine fluids through the human cochlear aqueduct: Non-invasive measurements with otoacoustic emissions. AB - The cochlear aqueduct connecting intralabyrinthine and cerebrospinal fluids (CSF) acts as a low-pass filter that should be able to transmit infrasonic pressure waves from CSF to cochlea. Recent experiments have shown that otoacoustic emissions generated at 1kHz respond to pressure-related stapes impedance changes with a change in phase relative to the generator tones, and provide a non invasive means of assessing intracochlear pressure changes. In order to characterize the transmission to the cochlea of CSF pressure waves due to respiration, the distortion-product otoacoustic emissions (DPOAE) of 12 subjects were continuously monitored around 1kHz at a rate of 6.25epochs/s, and their phase relative to the stimulus tones was extracted. The subjects breathed normally, in different postures, while thoracic movements were recorded so as to monitor respiration. A correlate of respiration was found in the time variation of DPOAE phase, with an estimated mean amplitude of 10 degrees , i.e. 60mm water, suggesting little attenuation across the aqueduct. Its phase lag relative to thoracic movements varied between 0 degrees and -270 degrees . When fed into a two-compartment model of CSF and labyrinthine spaces, these results suggest that respiration rate at rest is just above the resonance frequency of the CSF compartment, and just below the corner frequency of the cochlear-aqueduct low pass filter, in line with previous estimates from temporal bone and intracranial measurements. The fact that infrasonic CSF waves can be monitored through the cochlea opens diagnostic possibilities in neurology. PMID- 17716846 TI - Acute and subacute toxicity evaluation of ethanolic extract from fruits of Schinus molle in rats. AB - Ethanolic and hexanic extracts from fruits and leaves of Schinus molle showed ability to control several insect pests. Potential vertebrate toxicity associated with insecticidal plants requires investigation before institutional promotion. The aim of the present study was to evaluate the acute and subacute toxicity of ethanolic extracts from fruits of Schinus molle in rats. The plant extract was added to the diet at 2g/kg body weight/day during 1 day to evaluate acute toxicity and at 1g/kg body weight/day during 14 days to evaluate subacute toxicity. At the end of the exposure and after 7 days, behavioral and functional parameters in a functional observational battery and motor activity in an open field were assessed. Finally, histopathological examinations were conducted on several organs. In both exposures, an increase in the arousal level was observed in experimental groups. Also, the landing foot splay parameter increased in the experimental group after acute exposure. Only the subacute exposure produced a significant increase in the motor activity in the open field. All these changes disappeared after 7 days. None of the exposures affected the different organs evaluated. Our results suggest that ethanolic extracts from fruits and leaves of Schinus molle should be relatively safe to use as insecticide. PMID- 17716845 TI - Screening of indigenous Palestinian medicinal plants for potential anti inflammatory and cytotoxic activity. AB - Organic extracts of 24 selected plant species, used by Palestinian traditional healers to treat different illnesses and diseases, were tested for their anti inflammatory and anti-tumoral activities. The plant selection was based on existing ethnobotanic information and interviews with local healers. The extracts of the plants under investigation were tested for their potential anti-tumor (cytotoxic) effect on the murine fibrosarcoma L929sA cells, and on the human breast cancer cells MDA-MB231 and MCF7. Cytotoxicity screening models provide important preliminary data to select plant extracts with potential antineoplastic properties. MTT (Tetrazolium blue) colorimetric assay was used to evaluate the reduction of viability of cell cultures in the presence or absence of the extracts. The extract from Withania somnifera, L. Dunal (Solanaceae) presented an IC(50) value at 24h of 150 and 60 microg/ml, on L929sA and MCF7 cells, respectively, while the extract from Psidium guajava L. (Myrtaceae) presented an IC(50) value at 24h of 55 microg/ml on MCF7 cells. Other extracts examined, like Laurus nobilis L. (Lauraceae) and Salvia fruticosa M. (Labiatae), also displayed a remarkable activity. Additionally, as the nuclear transcription factor NFkappaB regulates the expression of various genes that play critical roles in apoptosis and immunomodulation, we further investigated the effect of nine promising plant extracts, withheld from the first cell viability screening on NFkappaB activation. The extracts showed variable degrees of NFkappaB-inhibitory activity. Whereas Withania somnifera extract demonstrated the strongest NFkappaB-inhibitory activity, other extracts derived from Laurus nobilis, Psidium guajava and Foeniculum vulgare M. (Umbiliferrae) also revealed immunomodulatory NFkappaB activities. These species are good candidates for further activity-monitored fractionation to identify active constituents. PMID- 17716843 TI - Closure of supporting cell scar formations requires dynamic actin mechanisms. AB - In many vertebrate inner ear sensory epithelia, dying sensory hair cells are extruded, and the apices of surrounding supporting cells converge to re-seal the epithelial barrier between the electrochemically-distinct endolymph and perilymph. These cellular mechanisms remain poorly understood. Dynamic microtubular mechanisms have been proposed for hair cell extrusion; while contractile actomyosin-based mechanisms are required for cellular extrusion and closure in epithelial monolayers. The hypothesis that cytoskeletal mechanisms are required for hair cell extrusion and supporting cell scar formation was tested using bullfrog saccules incubated with gentamicin (6h), and allowed to recover (18h). Explants were then fixed, labeled for actin and cytokeratins, and viewed with confocal microscopy. To block dynamic cytoskeletal processes, disruption agents for microtubules (colchicine, paclitaxel) myosin (Y-27632, ML-9) or actin (cytochalasin D, latrunculin A) were added during treatment and recovery. Microtubule disruption agents had no effect on hair cell extrusion or supporting cell scar formation. Myosin disruption agents appeared to slow down scar formation but not hair cell extrusion. Actin disruption agents blocked scar formation, and largely prevented hair cell extrusion. These data suggest that actin-based cytoskeletal processes are required for hair cell extrusion and supporting cell scar formation in bullfrog saccules. PMID- 17716847 TI - Harmonization of strategies for the validation of quantitative analytical procedures. A SFSTP proposal--part III. AB - In the first two documents [Ph. Hubert, J.J. Nguyen-Huu, B. Boulanger, E. Chapuzet, P. Chiap, N. Cohen, P.A. Compagnon, W. Dewe, M. Feinberg, M. Lallier, M. Laurentie, N. Mercier, G. Muzard, C. Nivet, L. Valat, J. Pharm. Biomed. Anal. 36 (2004) 579-586; Ph. Hubert, J.J. Nguyen-Huu, B. Boulanger, E. Chapuzet, P. Chiap, N. Cohen, P.A. Compagnon, W. Dewe, M. Feinberg, M. Lallier, M. Laurentie, N. Mercier, G. Muzard, C. Nivet, L. Valat, E. Rozet, J. Pharm. Biomed. Anal., in press], a recent SFSTP Commission on the validation of analytical procedure has introduced a harmonized approach for the validation of analytical procedures. In order to complete this guide, the statistical methodology allowing to correctly conclude about the validity of a procedure is proposed in this third part of the guide. Indeed all the steps to obtain the decision tool namely the accuracy profile are described and illustrated step by step by a numerical example. This tool, based on the concept of total error (bias+standard deviation) build with a beta-expectation tolerance interval, allows to easily take the right decision and simultaneously minimizing the risk of the future use of the analytical procedure. PMID- 17716848 TI - The many ways to cleave hyaluronan. AB - Hyaluronan is being used increasingly as a component of artificial matrices and in bioengineering for tissue scaffolding. The length of hyaluronan polymer chains is now recognized as informational, involving a wide variety of size-specific functions. Inadvertent scission of hyaluronan can occur during the process of preparation. On the other hand, certain size-specific hyaluronan fragments may be desirable, endowing the finished bioengineered product with specific properties. In this review, the vast arrays of reactions that cause scission of hyaluronan polymers is presented, including those on an enzymatic, free radical, and chemical basis. PMID- 17716849 TI - Biodesulfurization of refractory organic sulfur compounds in fossil fuels. AB - The stringent new regulations to lower sulfur content in fossil fuels require new economic and efficient methods for desulfurization of recalcitrant organic sulfur. Hydrodesulfurization of such compounds is very costly and requires high operating temperature and pressure. Biodesulfurization is a non-invasive approach that can specifically remove sulfur from refractory hydrocarbons under mild conditions and it can be potentially used in industrial desulfurization. Intensive research has been conducted in microbiology and molecular biology of the competent strains to increase their desulfurization activity; however, even the highest activity obtained is still insufficient to fulfill the industrial requirements. To improve the biodesulfurization efficiency, more work is needed in areas such as increasing specific desulfurization activity, hydrocarbon phase tolerance, sulfur removal at higher temperature, and isolating new strains for desulfurizing a broader range of sulfur compounds. This article comprehensively reviews and discusses key issues, advances and challenges for a competitive biodesulfurization process. PMID- 17716850 TI - Referral bias in thyroid cancer surgery: direction and magnitude. AB - AIM: This study was conducted to clarify the impact of referral bias in thyroid cancer surgery. METHODS: Analysis of 1419 consecutive patients with papillary (n=653), follicular (n=248), and medullary thyroid cancer (n=518) referred to a specialist center for initial surgery or reoperation. RESULTS: With increasing travel distance (successive postal code areas), mean age decreased among patients referred for initial surgery (from 53 to 35 years for papillary cancer, 65 to 49 years for sporadic medullary cancer, and 40 to 23 years for hereditary medullary cancer, all p< or =0.001; and from 65 to 54 years for follicular cancer, p=0.26). The significant decline in mean age continued among patients reoperated on for papillary cancer (from 53 to 43 years, p<0.001), but was lost among patients reoperated on for medullary cancers. For patients with differentiated, but not medullary cancers, greater travel distance was associated with higher frequencies of extrathyroidal extension at initial surgery (from 17% to 63% for follicular cancer, p=0.003) and reoperation (from 18% to 47% for papillary, and 5% to 44% for follicular cancer, all p<0.001), and higher frequencies of lymph node metastasis at initial surgery (from 23% to 58% for papillary, and 17% to 50% for follicular cancer, p< or =0.008) and reoperation (from 27% to 77% for papillary, and 0% to 35% for follicular cancer, all p<0.001). CONCLUSION: Referral bias in thyroid cancer surgery can include two components working in opposite directions: age and extent of disease. Controlling for these components should reduce the impact of referral bias on thyroid cancer research. PMID- 17716851 TI - 3D-Histological evaluation of surgery in dermatofibrosarcoma protuberans and malignant fibrous histiocytoma: differences in growth patterns and outcome. AB - AIMS: To evaluate the microscopic growth pattern of dermatofibrosarcoma protuberans (DFSP) and malignant fibrous histiocytoma (MFH) and the long-term outcome using 3D-histologic surgery with paraffin sections to cover complete margins and to detect subclinical spreads very sensitively. METHODS: One hundred and one patients have been included comprising 70 DFSP, 31 MFH. Data from 87 patients treated since 1992 were collected prospectively. RESULTS: Mean clinical tumor-size was 45 mm, mean histological tumor size 65 mm. A mean excision margin of 19 mm achieved negative margins. The histological infiltration shows an asymmetrical pattern with horizontal or vertical extension either cord-, sector- or multiple-like up to 70 mm in length, detectable by 3D-histology. Age and localization differed significantly between DFSP and MFH lesions. MFH tumors had a significantly deeper infiltration than DFSP. The mean follow up was 60 months. In 70 patients with DFSP one local recurrence after 62 months occurred, but no metastasis. 31 patients with MFH developed 8 local recurrences, and 4 metastases (lymph nodes and/ or lungs); 3 of them died of the disease, all 3 had a postoperative status of R1 (p=0.001). CONCLUSIONS: There are significant differences in growth pattern and clinical outcome between DFSP and MFH. DFSP can be cured by surgery following 3D-histology with paraffin sections. MFH is significantly more malignant. After local R0-resection proofed by 3D-histology higher cure rates can be achieved. PMID- 17716852 TI - [Annual scientific meetings at Claude Bernard Hospital]. PMID- 17716853 TI - Palliative medicine and intensive care medicine--two sides of the same coin? PMID- 17716854 TI - How well are we supporting hospice staff? Initial results of the Survey of Team Attitudes and Relationships (STAR) validation study. AB - Despite the emotional and interpersonal challenges that hospice staff face in providing care to patients near the end of life, no systematic effort has been made to evaluate the work environment that hospices provide to their staff. The aim of this project was to develop a job satisfaction survey that could be used to evaluate the hospice work environment and, ultimately, to guide interventions to improve the work experience for hospice staff. A first draft of the Survey of Team Attitudes and Relationships (STAR) was developed through semi-structured interviews with an interdisciplinary sample of staff from nine hospices, and then refined with input from additional interviews and from an expert panel. The draft was tested on larger samples of staff (n=160) from six hospices and revised with input from the expert panel. The final survey was tested with 599 staff from 10 hospices. The final survey contains 45 items in six domains: individual work rewards, teamwork, management support, organizational support, workload issues, and global assessment of job satisfaction. Items had excellent psychometric characteristics, with acceptable floor and ceiling effects. The overall STAR had a Cronbach's alpha of 0.93, indicating good homogeneity, and each domain had alpha values that are appropriate for between-group comparisons (range 0.74 0.84). These results suggest that the STAR offers a unique instrument to measure the work environment hospices provide to their staff. PMID- 17716855 TI - Phase II enzyme levels in HepG2 cells and cryopreserved primary human hepatocytes and their induction in HepG2 cells. AB - The HepG2 cell line is a valuable tool for screening for cytotoxicity in the early phase of pharmaceutical development. Some compounds which produce reactive and toxic metabolites, are classified as being toxic in HepG2 cells. In contrast, other compounds, which are toxic in primary human hepatocytes, are not toxic in HepG2 cells. A difference in metabolism between HepG2 cells and primary human hepatocytes might be the reason. To investigate this, cytochrome P450 and Phase II enzyme levels were characterized. In the present study the focus is on Phase II enzyme metabolism. Transcript levels of UDP-glucuronosyl transferases (UGTs), sulfotransferases (SULTs), glutathione S-transferases (GSTs), N-acetyltransferase 1 (NAT1) and epoxide hydrolase (EPHX1) were measured with quantitative PCR in HepG2 cells and cryopreserved primary human hepatocytes. Levels of SULT1A1, 1A2, 1E1, 1A2, and 2A1, microsomal GST 1, GST mu1, NAT1, and EPHX1 in HepG2 cells were almost similar to levels in primary human hepatocytes. In contrast, levels of UGT1A1 and 1A6 transcripts were between 10- and more than 1000-fold higher in the primary hepatocytes. The regulatory processes of Phase II enzymes by the aryl hydrocarbon receptor, pregnane X receptor and constitutive androstane receptor were studied in HepG2 cells and appeared quite similar to those in primary human hepatocytes. Due to the involvement of Phase II enzymes in the toxication of some compounds, HepG2 cells can be a valuable cellular system to predict toxicity for these compounds. On the other hand, the normal expression of most Phase II enzymes in combination with the lower expression of cytochrome P450 enzymes in HepG2 cells might result in an underestimation of toxicity for several compounds. Compared to primary human hepatocytes, HepG2 cells are a relatively easy-to handle tool to study the up-regulation of Phase II enzymes. PMID- 17716856 TI - Oxidative metabolism of lung macrophages exposed to sodium arsenite. AB - Arsenic pollution has become increasingly severe. It occurs as the result of geological processes and different human activities. Arsenic toxicity at the respiratory level occurs mainly by inhalation of products of coal combustion. The aim of this study was to evaluate sodium arsenite (As(3+)) toxicity in murine alveolar macrophages (AMs) in vitro and its association with the alterations in cell metabolism. No changes in viability, apoptosis or cell area were detected in AMs treated with As(3+) concentrations up to 2 microM for 24-96 h. A marked decrease in these end-points was observed for As(3+) concentrations ranging from 2.5 microM to 10 microM. Regarding the dynamics of the endo-exocytic process triggered by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell incorporation, no variations were detected for As(3+) concentrations lower than 2 microM while higher concentrations markedly modified this response. MTT specific activity, as a measure of cell metabolic activity, was not modified irrespective of the As(3+) concentration assayed. However, nitroblue tetrazolium (NBT) specific activity, as a measure of superoxide anion generation, is responsive but only to low As(3+) doses. Although this study focuses on lung macrophages, the effects of As(3+) described herein may also apply to the response of macrophages residing in other organs. Arsenite modifies the metabolic and the oxidative status of AMs in vitro. When macrophages are in an As(3+) rich medium, they exhibit a reduction in respiratory burst levels and lose their intrinsic capacity to respond to toxicants. PMID- 17716857 TI - Obesity, depression, and chronic low-grade inflammation in women with polycystic ovary syndrome. AB - BACKGROUND AND OBJECTIVE: Women with polycystic ovary syndrome (PCOS) present with multiple risk factors for cardiovascular diseases at a young age, including obesity and chronic low-grade inflammation. Since depression is common in PCOS, this study aimed to address whether depression correlates with indices of chronic low-grade inflammation beyond the association with obesity. METHODS: Serum concentrations of IL-6, the stimulated production of IFN-gamma, TNF-alpha, IL-2, IL-4, IL-5, and IL-10, leukocyte numbers, and hsCRP were analyzed in 57 PCOS patients and 28 healthy women, together with clinical parameters, including body mass index (BMI), testosterone, and insulin resistance (HOMA-IR), and psychological parameters, including Beck Depression Inventory (BDI) and health related quality-of-life (SF-36) scores. RESULTS: PCOS patients demonstrated significantly increased hsCRP, IL-6, and leukocyte numbers. Group differences in IL-6 and leukocyte numbers, but not hsCRP, disappeared after controlling for BMI. The stimulated production of IFN-gamma, TNF-alpha, IL-2, IL-4, and IL-5 was significantly decreased, irrespective of BMI. In PCOS, hsCRP, IL-6, and leukocyte numbers were correlated with BMI, HDL, diastolic blood pressure, and with insulin resistance. On the other hand, no correlations were found with depression scores or with PCOS-specific endocrine abnormalities. In regression models, BMI was a significant predictor of the key immune markers, and explained a large amount of variance, whereas BDI was not included in either model. CONCLUSIONS: These data confirm that obesity plays a pivotal role in inflammatory processes relevant to cardiovascular risk in women with PCOS. However, even lean PCOS patients may display subtle alterations in specific aspects of immunity. Our findings did not support a correlation of depression with chronic low-grade inflammation in PCOS. PMID- 17716858 TI - Sympathetic nervous modulation of the skin innate and adaptive immune response to peptidoglycan but not lipopolysaccharide: involvement of beta-adrenoceptors and relevance in inflammatory diseases. AB - Disorders of the skin immune activity are implicated in the pathogenesis of acquired inflammatory skin disorders. Inflammatory diseases including psoriasis, atopic dermatitis, lichen planus and vitiligo have also been associated with local alterations of adrenergic mechanisms and emotional stress. Here we show that the beta-adrenergic receptors antagonist propranolol along with peptidoglycan, but not LPS, combined with intradermal injection of a soluble protein, shifted the recall memory response to the Th1 type. The specific beta2 AR antagonist ICI 118,551 did not reproduce this effect suggesting that inhibition of both beta1- and beta2-AR caused the Th1 polarization. The underlying mechanism included enhanced local expression of IFN-gamma, IL-12 and IL-23 as well as of IFN-beta and CXCR3 ligands during the innate phase of the response which resulted in an increase of antigen-positive plasmacytoid dendritic cells (pDCs) in the draining lymph node. In particular, modulation of inflammatory cytokines, and IFN-beta inducible genes expression appeared to involve also the beta1-AR. Plasmacytoid dendritic cells and IL-23 were recently reported to play a central role in the pathogenesis of Th1-sustained inflammatory skin diseases such as psoriasis. Thus, primary beta-adrenoceptors signaling defects or altered sympathetic nervous activity together with selected pattern recognition receptors activation might serve as initiation and/or persistence factors for numerous Th1-sustained inflammatory skin diseases. PMID- 17716859 TI - Prenatal stress, fetal imprinting and immunity. AB - A comprehensive number of epidemiological and animal studies suggests that prenatal and early life events are important determinants for disorders later in life. Among them, prenatal stress (i.e. stress experienced by the pregnant mother with impact on the fetal ontogeny) has programming effects on the hypothalamic pituitary-adrenocortical axis, brain neurotransmitter systems and cognitive abilities of the offspring. This review focuses on the impact of maternal stress during gestation on the immune function in the offspring. It compares results from different animal species and highlights potential mechanisms for the immune effects of prenatal stress, including maternal glucocorticoids and placental functions. The existence of possible windows of increased vulnerability of the immune system to prenatal stress during gestation is discussed. Several gaps in the present knowledge are pointed out, especially concerning the time when prenatal stress effects are expressed during postnatal life, why this expression is delayed after birth and whether prenatal stress predisposes to immune-related pathologies later in life. PMID- 17716860 TI - TNF-alpha mediated modulation of T cell development and exacerbation of in vitro T1DM in fetal thymus organ culture. AB - TNF-alpha is a pleiotropic cytokine that is constitutively expressed in the thymus. This cytokine has opposing effects on type 1 diabetes mellitus (T1DM) as non-obese diabetic (NOD) mice administered TNF-alpha early in life experience an acceleration in disease onset while TNF-alpha administered to adult NOD mice are rescued from disease entirely. Using fetal thymus organ culture (FTOC) as a model of T cell development and an associated in vitro T1DM model, we set out to reconcile the role of TNF-alpha in thymic development with its role in the pathogenesis of T1DM. Our data indicate that NOD derived FTOC produce a smaller percentage of double negative (CD4(-)/CD8(-)) thymocytes expressing TNF receptors compared to non-diabetic C57BL/6 (B6) derived FTOC. NOD FTOC produce more TNF alpha than B6 FTOC during days 6-9 of culture, a time when negative selection of T cells is known to occur. Neutralization of this endogenous TNF-alpha production in NOD derived FTOC with soluble TNF receptor (sTNF R1) rescued insulin production in our in vitro T1DM model. Flow cytometric analysis of NOD FTOC treated with recombinant TNF-alpha (rTNF-alpha) or sTNF R1 demonstrated that the relative levels of TNF-alpha in the culture during the selection window (days 6 9) influence the ratio of immature vs. mature T cells that emerge from FTOC. PMID- 17716861 TI - Phosphatidylinositol 3-kinase/protein kinase B pathway stabilizes DNA methyltransferase I protein and maintains DNA methylation. AB - DNA methylation, which affects gene expression and chromatin stability, is catalyzed by DNA methyltransferases (DNMTs) of which DNMT1 possesses most abundant activity. PI3K/PKB pathway is an important pathway involved in cell proliferation, viability, and metabolism and often disrupted in cancer. Here we investigated the impact of PKB on DNMT1 and DNA methylation. Positive correlation between PKB-Ser473-phosphorylation and DNMT1 protein level in 17 human cell lines (p<0.01) and in 27 human bladder cancer tissues (p<0.05) was found. With activator, inhibitor, siRNA and constitutively active or dominant-negative plasmids of PKB, we found that PKB increased the protein level of DNMT1 without coordinate mRNA change, which was specific rather than due to cell-cycle change. PKB enhanced DNMT1 protein stability independent of de novo synthesis of any protein, which was attributed to down-regulation of N-terminal-120-amino-acids dependent DNMT1 degradation via ubiquitin-proteasome pathway. Gsk3beta inhibitor rescued the decrease of DNMT1 by PKB inhibition, suggesting that Gsk3beta mediated the stabilization of DNMT1 by PKB. Then role of PKB regulating DNMT1 was investigated. Inhibition of PKB caused observable DNA hypomethylation and chromatin decondensation and DNMT1 overexpression partially reversed cell growth inhibition by PKB inhibition. In conclusion, our results suggested that PKB enhanced DNMT1 stability and maintained DNA methylation and chromatin structure, which might contribute to cancer cell growth. PMID- 17716862 TI - Preformed STAT3 transducer complexes in human HepG2 cells and rat hepatocytes. AB - Interleukin 6 (IL-6) is a pleiotropic cytokine that mediates a variety of functions, including induction of the acute-phase response in hepatocytes. IL-6 initiates its action by binding to its cell surface receptor, followed by activation of Janus kinases and tyrosine phosphorylation of the signal transducer and transcription factor (STAT) 3. Although it has been suggested that cholesterol- and sphingolipid-enriched membrane domains, called lipid rafts, and caveolin are involved in this process, their roles in the earliest stages of IL-6 mediated signaling are far from being understood. Here we show that pretreatment of HepG2 hepatoma cells with methyl-beta-cyclodextrin (MbetaCD), which removes cholesterol and destroys lipid rafts, inhibited tyrosine phosphorylation of STAT3 in IL-6-activated, but not PV-activated cells. Furthermore, when the cells were lysed under conditions preserving lipid rafts, no IL-6- or PV-induced phosphorylation of STAT3 was observed. Although most of the STAT3 was found in large MbetaCD-resistant assemblies in both non-activated and IL-6-activated cells, its association with lipid rafts was weak or undetectable. The extent of IL-6-induced tyrosine phosphorylation of STAT3 was comparable in cells expressing low or high levels of caveolin. Similar STAT3 transducer complexes were observed in freshly isolated rat hepatocytes. The combined data suggest that STAT3 tyrosine phosphorylation occurs in preformed transducer complexes that can be activated in the absence of intact lipid rafts or caveolin. PMID- 17716864 TI - PKB and the mitochondria: AKTing on apoptosis. AB - Cellular homeostasis depends upon the strict regulation of responses to external stimuli, such as signalling cascades triggered by nutrients and growth factors, and upon cellular metabolism. One of the major molecules coordinating complex signalling pathways is protein kinase B (PKB), a serine/threonine kinase also known as Akt. The number of substrates known to be phosphorylated by PKB and its interacting partners, as well as our broad understanding of how PKB is implicated in responses to growth factors, metabolic pathways, proliferation, and cell death via apoptosis is constantly increasing. Activated by the insulin/growth factor phosphatidylinositol 3-kinase (PI3K) cascade, PKB triggers events that promote cell survival and prevent apoptosis. It is also now widely accepted that mitochondria are not just suppliers of ATP, but that they participate in regulatory and signalling events, responding to multiple physiological inputs and genetic stresses, and regulate both cell proliferation and death. Thus, mitochondria are recognized as important players in apoptotic events and it is logical to predict some form of interplay with PKB. In this review, we will summarize mechanisms by which PKB mediates its anti-apoptotic activities in cells and survey recent developments in understanding mitochondrial dynamics and their role during apoptosis. PMID- 17716863 TI - Epac-selective cAMP analogs: new tools with which to evaluate the signal transduction properties of cAMP-regulated guanine nucleotide exchange factors. AB - The identification of 2'-O-methyl substituted adenosine-3',5'-cyclic monophosphate (cAMP) analogs that activate the Epac family of cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs, also known as Epac1 and Epac2), has ushered in a new era of cyclic nucleotide research in which previously unrecognized signalling properties of the second messenger cAMP have been revealed. These Epac-Selective Cyclic AMP Analogs (ESCAs) incorporate a 2'-O methyl substitution on the ribose ring of cAMP, a modification that impairs their ability to activate protein kinase A (PKA), while leaving intact their ability to activate Epac (the Exchange Protein directly Activated by Cyclic AMP). One such ESCA in wide-spread use is 8-pCPT-2'-O-Me-cAMP. It is a cell-permeant derivative of 2'-O-Me-cAMP, and it is a super activator of Epac. A wealth of newly published studies demonstrate that 8-pCPT-2'-O-Me-cAMP is a unique tool with which to asses atypical actions of cAMP that are PKA-independent. Particularly intriguing are recent reports demonstrating that ESCAs reproduce the PKA-independent actions of ligands known to stimulate Class I (Family A) and Class II (Family B) GTP-binding protein-coupled receptors (GPCRs). This topical review summarizes the current state of knowledge regarding the molecular pharmacology and signal transduction properties of Epac-selective cAMP analogs. Special attention is focused on the rational drug design of ESCAs in order to improve their Epac selectivity, membrane permeability, and stability. Also emphasized is the usefulness of ESCAs as new tools with which to assess the role of Epac as a determinant of intracellular Ca2+ signalling, ion channel function, neurotransmitter release, and hormone secretion. PMID- 17716865 TI - Glycerophosphoinositol-4-phosphate enhances SDF-1alpha-stimulated T-cell chemotaxis through PTK-dependent activation of Vav. AB - Glycerophosphoinositols (GPIs) are water-soluble phosphoinosite metabolites produced by all cell types, whose levels increase in response to a variety of extracellular stimuli, and are particularly high in Ras-transformed cells. GPIs are released to the extracellular space, wherefrom they can be taken up by other cells through a specific transporter. Exogenous GPIs affect a plethora of cellular functions. Among these compounds the most active is GroPIns4P, which affects cAMP levels and PKA-dependent functions through the inhibition of heterotrimeric Gs proteins. GroPIns4P has also recently been found to promote actin cytoskeleton reorganization by inducing Rho and Rac activation through an as yet unidentified mechanism. Here we have assessed the potential effects of GroPIns4P on T-cells. We found that GroPIns4P enhances CXCR4-dependent chemotaxis. This activity results from the capacity of GroPIns4P to activate the Rho GTPase exchange factor, Vav, through an Lck-dependent pathway which also results in activation of the stress kinases JNK and p38. GroPIns4P was also found to activate with a delayed kinetics the Lck-dependent activation of ZAP-70, Shc and Erk1/2. The activities of GroPIns4P were found to be dependent on its capacity to inhibit cAMP production and PKA activation. Collectively, the data provide the first evidence of a role of glycerophosphoinositols as modulators of T-cell signaling and establish a mechanistic basis for the effects of this phosphoinositide derivative on F-actin dynamics. PMID- 17716867 TI - Alpha-linolenic acid attenuates high glucose-induced apoptosis in cultured human umbilical vein endothelial cells via PI3K/Akt/eNOS pathway. AB - OBJECTIVE: High glucose-induced apoptosis in vascular endothelial cells contributes to the acceleration of atherosclerosis associated with diabetes. We hypothesized that alpha-linolenic acid (ALA) might attenuate high glucose-induced apoptosis in cultured human umbilical vein endothelial cells (HUVECs). METHODS: HUVECs were cultured at 5.5 and 33 mmol/L for 72 h. ALA with different concentrations was added with defatted bovine serum albumin as a carrier for 18 h before incubation with high glucose. RESULTS: Exposure of HUVECs to high glucose media for 72 h significantly increased the number of apoptotic cells compared with normal glucose control, as evaluated by flow cytometry and terminal deoxyuridine triphosphate nick end labeling assay. Pretreatment with low concentrations of ALA (10, 50, and 100 micromol/L) significantly attenuated high glucose-induced apoptosis of HUVECs, but increasing ALA to 200 micromol/L exerted the opposite effect. Furthermore, high glucose reduced phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) with subsequent nitric oxide production, whereas ALA treatment attenuated the reduction caused by high glucose. Pretreatment with phosphatidylinositol 3' -kinase kinase inhibitor LY294002 and eNOS inhibitor N(G)-nitro-arginine methyl ester eliminated ALA' antiapoptotic effect. CONCLUSION: ALA exerts an antiapoptotic effect by the phosphatidylinositol 3'-kinase/Akt/eNOS pathway in HUVECs exposed to high glucose and thus may represent a candidate therapeutic agent for diabetic cardiovascular complications. PMID- 17716868 TI - The hype surrounding nutraceutical supplements: do consumers get what they deserve? PMID- 17716866 TI - Regulation of anterograde transport of adrenergic and angiotensin II receptors by Rab2 and Rab6 GTPases. AB - Three Rab GTPases, Rab1, Rab2 and Rab6, are involved in protein transport between the endoplasmic reticulum (ER) and the Golgi. Whereas Rab1 regulates the anterograde ER-to-Golgi transport, Rab2 and Rab6 coordinate the retrograde Golgi to-ER transport. We have previously demonstrated that Rab1 differentially modulates the export trafficking of distinct G protein-coupled receptors (GPCRs). In this report, we determined the role of Rab2 and Rab6 in the cell-surface expression and signaling of alpha(2B)-adrenergic (alpha(2B)-AR), beta(2)-AR and angiotensin II type 1 receptors (AT1R). Expression of the GTP-bound mutant Rab2Q65L significantly attenuated the cell-surface expression of both alpha(2B) AR and beta(2)-AR, whereas the GTP-bound mutant Rab6Q72L selectively inhibited the transport of beta(2)-AR, but not alpha(2B)-AR. Similar results were obtained by siRNA-mediated selective knockdown of endogenous Rab2 and Rab6. Consistently, Rab2Q65L and Rab2 siRNA inhibited alpha(2B)-AR and beta(2)-AR signaling measured as ERK1/2 activation and cAMP production, respectively, whereas Rab6Q72L and Rab6 siRNA reduced signaling of beta(2)-AR, but not alpha(2B)-AR. Similar to the beta(2)-AR, AT1R expression at the cell surface and AT1R-promoted inositol phosphate accumulation were inhibited by Rab6Q72L. Furthermore, the nucleotide free mutant Rab6N126I selectively attenuated the cell-surface expression of beta(2)-AR and AT1R, but not alpha(2B)-AR. These data demonstrate that Rab2 and Rab6 differentially influence anterograde transport and signaling of GPCRs. These data also provide the first evidence indicating that Rab6-coordinated retrograde transport selectively modulates intracellular trafficking and signaling of GPCRs. PMID- 17716869 TI - Body composition by dilution of deuterium oxide in Mexican children with lymphoma and solid tumors. AB - OBJECTIVE: Scant information exists about the changes in body composition of children during the first months of chemotherapy. These changes can be determined by using a better method than the body mass index. This study compared the changes of body composition by dilution of deuterium oxide in Mexican children with lymphoma and with solid tumors. METHODS: Seventeen patients were enrolled and classified as having lymphoma or solid tumor. Body composition was measured by a deuterium dilution technique after the first course of chemotherapy and again after 2 and 6 mo of therapy. Data were compared by means of paired t and Student's t tests. Simple linear regression was applied to examine the relation between age and changes in fat mass (FM) and fat-free mass (FFM). RESULTS: The groups were similar at baseline. Six months after initiation of chemotherapy, weight and height had increased (P < 0.05) in the lymphoma group, whereas only height had increased in the solid-tumor group; total body water, FM, and FFM increased in the lymphoma group (P < 0.01) but not in the solid-tumor group. Age did not influence FM or FFM in either group. CONCLUSION: In children with lymphoma whose treatment included corticosteroid use, increase in FM content was demonstrated during the first 6 mo of treatment. In patients with solid tumors, FM content did not change during treatment. With an increase in FM content, one should bear in mind that overweight and obesity may result in cardiovascular disease and development of breast cancer in adult life. PMID- 17716870 TI - Domoic acid preconditioning and seizure induction in young and aged rats. AB - Clinical reports suggest that the elderly are hypersensitive to the neurological effects of domoic acid (DOM). In the present study we assessed DOM-induced seizures in young and aged rats, and seizure attenuation following low-dose DOM pretreatment (i.e. preconditioning). Seizure behaviours following saline or DOM administration (0.5-2mg/kg i.p.) were continuously monitored for 2.5h in naive and DOM preconditioned rats. Competitive ELISA was used to determine serum and brain DOM concentrations. Dose- and age-dependent increases in seizure activity were evident in response to DOM. Lower doses of DOM in young and aged rats promoted low level seizure behaviours. Animals administered high doses (2mg/kg in young; 1mg/kg in aged) progressed through various stages of stereotypical behaviour (e.g., head tics, scratching, wet dog shakes) before ultimately exhibiting tonic-clonic convulsions. Serum and brain DOM analysis indicated impaired renal clearance as contributory to increased DOM sensitivity in aged animals, and this was supported by seizure analysis following direct intrahippocampal administration of DOM. Preconditioning young and aged animals with low-dose DOM 45-90 min before high-dose DOM significantly reduced seizure intensity. We conclude that age-related supersensitivity to DOM is related to reduced clearance rather than increased neuronal sensitivity, and that preconditioning mechanisms underlying an inducible tolerance to excitotoxins are robustly expressed in both young and aged CNS. PMID- 17716871 TI - Nitric oxide levels in plasma and fibroblast cultures of psoriasis vulgaris patients. PMID- 17716872 TI - The changing face of Klebsiella pneumoniae infections in the community. AB - Klebsiella pneumoniae (Kp) is an important pathogen both in the community and the hospital setting. In the community the emergence of virulent organisms with predominantly K1/K2 capsular serotypes has been observed over the last 20 years, these pathogens cause a distinct clinical syndrome consisting of pyogenic liver abscesses, sometimes accompanied by meningitis and abscesses elsewhere. In the hospital environment, under heavy antibiotic usage, multiple drug resistance has been increasingly observed in Kp. Kp strains harbouring extended spectrum beta lactamases (ESBL) and more recently metallocarbapenemase, conferring resistance to many of the antibiotics available, have been described in many parts of the world. These multi-drug-resistant organisms are affecting the choice of antimicrobial therapy, are a major cause for increasing hospital costs and duration of hospitalisations. Some of the ESBL-producing Kp have already moved into the community and are creating therapeutic problems in a setting where empiric, oral antimicrobial therapy is a common practice. In this review we will discuss these two Kp emerging trends. PMID- 17716874 TI - Polymorphisms in catechol-O-methyltransferase and methylenetetrahydrofolate reductase in relation to the risk of schizophrenia. AB - BACKGROUND: Evidence is emerging for the association of aberrant homocysteine methylation cycle and increased risk of schizophrenia. METHODS: We examined the prevalence of the catechol-O-methyltransferase (COMT) 324G>A (Val108/158Met) and methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphisms in 252 patients with schizophrenia and 405 control subjects. All subjects were of Dutch ancestry. RESULTS: The COMT 324AA genotype was not associated with an increased risk of schizophrenia (odds ratio (OR)=1.38 [95% CI: 0.88-2.16], P=0.162), and the MTHFR 677TT genotype showed a nearly significant increased risk for schizophrenia (OR=1.65 [95% CI: 0.97-2.82], P=0.067). The odds ratio for schizophrenia associated with joint occurrence of the COMT 324AA and MTHFR 677TT genotype was 3.08 (95% CI: 1.08-8.76) (P=0.035). Increasing number of low enzyme activity alleles in the COMT and MTHFR genotype combinations were associated with an increased risk of schizophrenia (test for trend, P=0.017). CONCLUSIONS: Our findings do not support a major role for the COMT 324AA and MTHFR 677TT genotype alone, but the combination of both genotypes might increase schizophrenia susceptibility. PMID- 17716873 TI - Intrapulmonary pharmacodynamics of high-dose levofloxacin in subjects with chronic bronchitis or chronic obstructive pulmonary disease. AB - The objective of this study was to determine the plasma and intrapulmonary pharmacokinetic parameters of intravenously administered levofloxacin in subjects with stable chronic lung disease. Three doses of 1000 mg levofloxacin were administered once daily to 16 adult subjects divided into four groups of 4 subjects each. Standardised bronchoscopy and timed bronchoalveolar lavage (BAL) were performed at 4 h, 8 h, 12 h and 24 h following administration of the last dose. Blood was obtained for drug assay prior to drug administration, at the end of the last infusion (maximum concentration (Cmax)) and at the time of BAL. Levofloxacin was measured using a high-performance liquid chromatographic tandem mass spectrometric (HPLC/MS/MS) technique. Plasma, epithelial lining fluid (ELF) and alveolar cell (AC) pharmacokinetics were derived using non-compartmental methods. Cmax/MIC(90) and area under the concentration-time curve for 0-24 h after the last dose (AUC(0-24 h)/MIC(90) ratios were calculated for respiratory pathogens with minimum inhibitory concentrations for 90% of the organisms (MIC(90)) of 0.03-2 microg/mL. The Cmax (mean+/-standard deviation), AUC(0-24h) and half-life were, respectively, 9.2+/-2.7 microg/mL, 130 microg h/mL and 8.7 h for plasma, 22.8+/-12.9 microg/mL, 260 microg h/mL and 7.0 h for ELF and 76.3+/ 28.7 microg/mL, 1492 microg h/mL and 49.5 h for ACs. Levofloxacin concentrations were quantitatively greater in ACs than in ELF or plasma at all time points, however only the differences between AC concentration and ELF or plasma concentrations in the 4-h and 8-h time groups were statistically significant. Cmax/MIC(90) and AUC/MIC(90) ratios in ELF were, respectively, 11.4 and 130 for Mycoplasma pneumoniae, 22.8 and 260 for Streptococcus pneumoniae, 91.2 and 1040 for Chlamydia pneumoniae and 760 and 8667 for Haemophilus influenzae. In ACs the ratios were 38.2 and 746 for M. pneumoniae, 76.3 and 1492 for S. pneumoniae, 305 and 5968 for C. pneumoniae and 2543 and 49 733 for H. influenzae. In conclusion, Cmax/MIC(90) and AUC/MIC(90) ratios provide a pharmacokinetic rationale for once daily administration of a 1000 mg dose of levofloxacin and are favourable for the treatment of respiratory infection in patients with chronic lung disease. PMID- 17716876 TI - PI3K and Erk MAPK mediate ErbB signaling in Xenopus gastrulation. AB - ErbB signaling regulates cell adhesion and movements during Xenopus gastrulation, but the downstream pathways involved have not been elucidated. In this study, we show that phosphatidylinositol-3 kinase (PI3K) and Erk mitogen-activated protein kinase (MAPK) mediate ErbB signaling to regulate gastrulation. Both PI3K and MAPK function sequentially in mesoderm specification and movements, and ErbB signaling is important only for the late phase activation of these pathways to control cell behaviors. Activation of either PI3K or Erk MAPK rescues gastrulation defects in ErbB4 morphant embryos, and restores convergent extension in the trunk mesoderm as well as coherent cell migration in the head mesoderm. The two signals preferentially regulate different aspects of cell behaviors, with PI3K more efficient in rescuing cell adhesion and spreading and MAPK more effective in stimulating the formation of filopodia. PI3K and MAPK also weakly activate each other, and together they modulate gastrulation movements. Our results reveal that PI3K and Erk MAPK, which have previously been considered as mesodermal inducing signals, also act downstream of ErbB signaling to participate in regulation of gastrulation morphogenesis. PMID- 17716875 TI - Zebrafish colgate/hdac1 functions in the non-canonical Wnt pathway during axial extension and in Wnt-independent branchiomotor neuron migration. AB - Vertebrate gastrulation involves the coordinated movements of populations of cells. These movements include cellular rearrangements in which cells polarize along their medio-lateral axes leading to cell intercalations that result in elongation of the body axis. Molecular analysis of this process has implicated the non-canonical Wnt/Frizzled signaling pathway that is similar to the planar cell polarity pathway (PCP) in Drosophila. Here we describe a zebrafish mutant, colgate (col), which displays defects in the extension of the body axis and the migration of branchiomotor neurons. Activation of the non-canonical Wnt/PCP pathway in these mutant embryos by overexpressing DeltaNdishevelled, rho kinase2 and van gogh-like protein 2 (vangl2) rescues the extension defects suggesting that col acts as a positive regulator of the non-canonical Wnt/PCP pathway. Further, we show that col normally regulates the caudal migration of nVII facial hindbrain branchiomotor neurons and that the mutant phenotype can be rescued by misexpression of vangl2 independent of the Wnt/PCP pathway. We cloned the col locus and found that it encodes histone deacetylase1 (hdac1). Our previous results and studies by others have implicated hdac1 in repressing the canonical Wnt pathway. Here, we demonstrate novel roles for zebrafish hdac1 in activating non-canonical Wnt/PCP signaling underlying axial extension and in promoting Wnt independent caudal migration of a subset of hindbrain branchiomotor neurons. PMID- 17716877 TI - Phasic dysfunction of dopamine transmission in Tourette's syndrome evaluated with 99mTc TRODAT-1 imaging. AB - This study investigated the complex dysregulation of the dopaminergic neurotransmitter system in Tourette's syndrome (TS) patients challenged with methylphenidate (MPH). Eight drug-naive male patients (aged 21-25 years) who met DSM-IV criteria for TS and had a mean disease severity of 25 on the Yale Global Tic Severity Scale were recruited. Brain (99m)TC TRODAT-1 dopamine transporter (DAT) single photon emission computed tomography (SPECT) was performed 5 days before, and 2 h after 10 mg of orally administered MPH. Eight age-matched healthy males served as controls. Repeated measures analysis of variance was used to measure differences in DAT-binding ratios before and after MPH challenge between the TS patients and controls. The DAT-binding ratios decreased significantly after MPH treatment in both groups. However, a significant interaction between group and MPH effects was found only in the right caudate, which was mainly due to a smaller decline of the DAT-binding ratio after MPH in the TS group than in the controls. Such a distinction was not found in the other striatal sub-regions in the two groups. No correlation, however, was observed between the tic severity score and DAT-binding ratio measured from the whole striatum or its sub-regions. The observed change in the DAT-binding ratio might indicate a functional abnormality of the dopaminergic system in the right caudate nucleus of TS patients. Future studies exploring dopamine transmission are thus needed to understand the pathophysiology of TS. PMID- 17716878 TI - Quantifying ternary mixtures of different solid-state forms of indomethacin by Raman and near-infrared spectroscopy. AB - This study assessed the ability of vibrational spectroscopy combined with multivariate analysis to quantify ternary mixtures of different solid-state forms, including the amorphous form. Raman and near-infrared spectroscopy were used to quantify mixtures of alpha-, gamma-, and amorphous indomethacin. Partial least squares regression was employed to create quantitative models. To improve the model performance various pre-treatment algorithms and scaling methods were applied to the spectral data and different spectral regions were tested. Standard normal variate transformation and scaling by mean centering proved to be the best approaches to pre-process the data. With four partial least squares factors, root mean square errors of prediction ranging from 5.3% to 6.5% for Raman spectroscopy and 4.0% to 5.9% for near-infrared spectroscopy were calculated. In addition, the effects of potential sources of error were investigated. Sample fluorescence predominantly caused by yellow amorphous indomethacin was observed to have a significant impact on the Raman spectra. Nevertheless, this source of error could be minimized in the quantitative models. Sample inhomogeneity, particularly in conjunction with a small sampling area when stationary sample holders were used, introduced the largest variation into both spectroscopic assays. The overall method errors were found to be very similar, resulting in relative standard deviations up to 12.0% for Raman spectroscopy and up to 13.0% for near-infrared spectroscopy. The results show that both spectroscopic techniques in combination with multivariate modeling are well suited to rapidly quantify ternary mixtures of crystalline and amorphous indomethacin. Furthermore, this study shows that quantitative analysis of powder mixtures using Raman spectroscopy can be performed in the presence of limited fluorescence. PMID- 17716879 TI - Solubilization of indomethacin using hydrotropes for aqueous injection. AB - Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) that exhibits analgesic, antipyretic and anti-inflammatory activities. It is practically insoluble in water. The effect of various hydrotropes such as urea, nicotinamide, resorcinol, sodium benzoate and sodium p-hydroxy benzoate on the solubility of indomethacin was investigated. The solubility enhancement of indomethacin by the hydrotropes was observed in decreasing order as sodium p-hydroxy benzoate>sodium benzoate>nicotinamide>resorcinol>urea. In order to elucidate the probable mechanism of solubilization, various solution properties of hydrotropes such as viscosity, specific gravity, surface tension, refractive index and specific conductance of hydrotropic solutions were studied at 25+/-2 degrees C. Each solubilized product was characterized by ultraviolet, infrared, powder X-ray diffraction and differential scanning calorimetry techniques. The hydrotropic solubilization of indomethacin at lower hydrotrope concentration may be attributed to weak ionic interactions while that at higher hydrotrope concentration may be due to molecular aggregation. Aqueous injectable formulations using sodium p-hydroxy benzoate, sodium benzoate and nicotinamide as hydrotropes were developed and studied for physical and chemical stability. PMID- 17716881 TI - Busulfan-induced apoptosis in rat placenta. AB - In order to investigate the effects of busulfan on the placenta, we examined the sequential histopathological changes in the placenta from rats exposed to busulfan during gestation days (Days) 12-14. Busulfan was intraperitoneally administered at 10 mg/kg on Days 12, 13 and 14, and the placentas were sampled on Day 13.5, 14.5, 15, 16 or 21. Macroscopically, small placenta was seen on Day 21 with scattered white spots and white peripheral rim. Histopathologically, in the treated group, there were increased apoptosis and decreased mitotic activities in the trophoblasts of the labyrinth zone on Days 13.5, 14.5, 15 and 16. In the basal zone, slightly increased apoptosis was seen on Day 13.5 and slightly decreased mitotic activity on Day 14.5. On Day 21, the labyrinth zone in the treated group was reduced in diameter. Degeneration and necrosis of trophoblasts, a diminution in thickness of the trophoblastic septa with a deposition of calcium and an irregular dilation of the maternal blood space were scattered in the labyrinth zone, although there were no conspicuous changes in the basal zone. The anti-proliferative effects of busulfan could have inhibited the development of the labyrinth zone, and led to small placentas. The fetotoxicity and teratogenicity of busulfan might be also responsible for these placental changes. PMID- 17716880 TI - Hepatoprotective effect of L-carnitine against acute acetaminophen toxicity in mice. AB - L-carnitine is a cofactor in the transfer of long-chain fatty acid allowing the beta-oxidation of fatty acid in the mitochondria. It is also a known antioxidant with protective effects against lipid peroxidation. In this study, hepatoprotective effect of L-carnitine was investigated against acetaminophen (AA)-induced liver toxicity where mitochondrial dysfunction and oxidative stress are thought to be involved in AA hepatotoxicity. Sixty-four Balb/C mice were divided into eight groups. Mice were dosed with single-AA injection (500 mg/kg via the intra peritoneal route) with or without L-carnitine (500 mg/kg for 5 days starting 5 days before AA injection via intra peritoneal route) and sampled at 4, 8 and 24 h following AA injection. AA increased serum AST, ALT, total sialic acid (TSA) and MDA as well as tissue TSA and MDA levels significantly with the highest increase observed at 4 h, but there was a decrease in blood and tissue GSH level. Administration of L-carnitine significantly reduced AA-induced elevations in AST, ALT, TSA and MDA concentrations and increased GSH levels at all sampling points. AA also induced necrosis, hyperemia, sinusoidal congestion and hemorrhage with time-dependent increase in severity, but the degree of necrosis and histopathologic alterations were most severe at 24 h following AA administration. However, the degree of pathologic alterations was less severe with simultaneous L carnitine application. These results suggest that AA results in oxidative damage in the liver with an acute effect. L-carnitine also has a prominent protective effect against AA toxicity and may be of therapeutic value in the treatment of AA induced hepatotoxicity. PMID- 17716882 TI - A molecular toolbox for manipulating Eremothecium coryli. AB - The genus Eremothecium contains dimorphic and filamentous fungal species, most notably Eremothecium sinecaudum (Holleya sinecauda), a dimorphic plant pathogen, which was isolated from mustard seeds, and Eremothecium gossypii (Ashbya gossypii), a filamentous fungus, which is well known for its ability to produce riboflavin. In this study, we present the initial molecular characterization of another Eremothecium species classified as Eremothecium coryli. E.coryli is a dimorphic fungus. We have developed, based on previously described reagents, a transformation system for E. coryli using kanMX and NATMX3 as dominant selectable marker genes on freely replicating plasmids conferring resistance to the antibiotics G418 and nourseothricin, respectively. As reporter genes we could introduce lacZ and GFP, which were controlled either by the AgTEF1 promoter or by regulatable MET promoters derived from the A. gossypii and Saccharomyces cerevisiae MET3 genes. These newly established tools will allow a detailed comparison of different growth modes in filamentous or dimorphic species within the genus Eremothecium. PMID- 17716884 TI - Determination of the trichothecene mycotoxin chemotypes and associated geographical distribution and phylogenetic species of the Fusarium graminearum clade from China. AB - A large number of isolates from the Fusarium graminearum clade representing all regions in China with a known history of Fusarium head blight (FHB) epidemics in wheat were assayed using PCR to ascertain their trichothecene mycotoxin chemotypes and associated phylogenetic species and geographical distribution. Of the 299 isolates assayed, 231 are from F. asiaticum species lineage 6, which produce deoxynivalenol and 3-acetyldeoxynivalenol (3-AcDON); deoxynivalenol and 15-acetyldeoxynivalenol (15-AcDON); and nivalenol and 4-acetylnivalenol (NIV) mycotoxins, with 3-AcDON being the predominant chemotype. Ninety-five percent of this species originated from the warmer regions where the annual average temperatures were above 15 degrees C, based on the climate data of 30 y during 1970-1999. However, 68 isolates within F. graminearum species lineage 7 consisted only of 15-AcDON producers, 59% of which were from the cooler regions where the annual average temperatures were 15 degrees C or lower. Identification of a new subpopulation of 15-AcDON producers revealed a molecular distinction between F. graminearum and F. asiaticum that produce 15-AcDON. An 11-bp repeat is present in F. graminearum within their Tri7 gene sequences but is absent in F. asiaticum, which could be directly used for differentiating the two phylogenetic species of the F. graminearum clade. PMID- 17716885 TI - Proteome analysis of an ectomycorrhizal fungus Boletus edulis under salt shock. AB - Soil salinization has become a severe global problem and salinity is one of the most severe abiotic stresses inhibiting growth and survival of mycorrhizal fungi and their host plants. Salinity tolerance of ectomycorrhizal fungi and survival of ectomycorrhizal inocula is essential to reforestation and ecosystem restoration in saline areas. Proteomic changes of an ectomycorrhizal fungus, Boletus edulis, when exposed to salt stress conditions (4% NaCl, w/v) were determined using two-dimensional electrophoresis (2DE) and mass spectrometry (MS) techniques. Twenty-two protein spots, 14 upregulated and 8 downregulated, were found changed under salt stress conditions. Sixteen changed protein spots were identified by nanospray ESI Q-TOF MS/MS and liquid chromatography MS/MS. These proteins were involved in biosynthesis of methionine and S-adenosylmethionine, glycolysis, DNA repair, cell cycle control, and general stress tolerance, and their possible functions in salinity adaptation of Boletus edulis were discussed. PMID- 17716886 TI - The genus Setulipes (Marasmiaceae) in Madagascar and the Mascarenes, including a key to other African taxa. AB - The authors report first records for the genus Setulipes in Madagascar, with the presence of Setulipes cf. hakgalensis and two new species, Setulipes funaliformis and S. moreaui, as well as a new species from Mauritius: S. mauritiensis. A key to these taxa, as well as to other African species, is supplied. PMID- 17716883 TI - Acceleration of allograft failure by cytomegalovirus. AB - A number of human herpesviruses are important opportunistic pathogens that have been associated with increased morbidity and mortality in transplant recipients including human cytomegalovirus (HCMV), HHV6, HHV7, HHV8 as well as HSV-1, VZV. However, HCMV has been linked both epidemiologically and through the use of animal models to the acceleration of acute and chronic allograft rejection. This review will cover the pathophysiology, epidemiology, and mechanisms of CMV associated disease in the setting of transplantation. PMID- 17716887 TI - WITHDRAWN: Study of thin biocovers (TBC) for oxidizing uncaptured methane emissions in bioreactor landfills. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published in Waste Management, volume 28 (2008) 1364 - 1374, doi:10.1016/j.wasman.2007.06.017. The duplicate article has therefore been withdrawn. PMID- 17716888 TI - An investigation on the potential of metal recovery from the municipal waste incinerator in Taiwan. AB - This study aimed to identify distribution of metals and to estimate the amount of these metals that can be potentially recovered from incineration residues. First, the partitioning behavior of Cr, Cu, Fe, Cd, Al, Zn, and Pb in bottom ash and fly ash was investigated in one large municipal waste incinerator in Taiwan. In addition, the material flow analysis (MFA) method was used to estimate the material flux of metals within incinerator plant, and to calculate the amount of metal recovery. According to the findings of this study, six metals (Fe, Al, Cu, Zn, Cr, and Pb) concentrated in bottom ash mostly, while Cd existed primarily in fly ash. The weight percentages of Fe (4.49%), Al (5.24%), Cu (1.29%), Zn (2.21%), and Pb (0.58%) in incinerator ash are high, and even higher than the compositions of natural minerals. Finally, the amount of Cr, Cu, Fe, Cd, Al, Zn and Pb that can be potentially recovered from incineration residues will reach 2.69 x 10(2), 1.46 x 10(4), 4.91 x 10(4), 6.92 x 10(1), 5.10 x 10(4), 1.85 x 10(4) and 4.66 x 10(3) ton/yr, respectively. PMID- 17716889 TI - Towards integrated and sensitive surface plasmon resonance biosensors: a review of recent progress. AB - The use of surface plasmon resonance (SPR) biosensors is increasingly popular in fundamental biological studies, health science research, drug discovery, clinical diagnosis, and environmental and agricultural monitoring. SPR allows for the qualitative and quantitative measurements of biomolecular interactions in real time without requiring a labeling procedure. Today, the development of SPR is geared toward the design of compact, low-cost, and sensitive biosensors. Rapid advances in micro-fabrication technology have made available integratable opto electronic components suitable for SPR. This review paper focuses on the progress made over the past 4 years toward this integration. Readers will find the descriptions of novel SPR optical approaches and materials. Nano-technology is also increasingly used in the design of biologically optimized and optically enhanced surfaces for SPR. Much of this work is leading to the integration of sensitive SPR to lab-on-a-chip platforms. PMID- 17716890 TI - Dose finding study of oral PSC 833 combined with weekly intravenous etoposide in children with relapsed or refractory solid tumours. AB - PSC 833 is an effective MDR1 reversal agent in vitro, including studies with paediatric cancer cell lines such as neuroblastoma and rhabdomyosarcoma. This study was performed to determine the safety profile, dose limiting toxicity (DLT) and maximum tolerated dose (MTD) in children with solid tumours and to determine the influence of PSC 833 on the pharmacokinetics of co-administered etoposide. Each patient received one cycle of intravenous etoposide (100 mg/m2 daily for 3 days on three consecutive weeks) to document baseline pharmacokinetics, and subsequently the same schedule using a dose of 50 mg/m2 was given combined with PSC 833 given orally every 6h at a starting dose of 4 mg/kg. Thirty two eligible patients (23 male, median age 8.3 years) were enrolled. Neuroblastoma and rhabdomyosarcoma were the common disease types. Brain tumours were excluded. DLT was defined as any non-haematological grade 3-4 toxicity (common toxicity criteria) and using a specific toxicity scale for cerebellar toxicity. The MDT was defined as the first dose below which 2 or more patients per dose level experienced DLT. Grade 1-2 ataxia occurred in cohorts 2 and 3 (4 and 5 mg/kg, respectively). Three patients developed grade 3 neurotoxicity in the 6 mg/kg cohort and this defined the MTD. Six responses were observed (2 CR, 4 PR). Pharmacokinetic studies indicated that the clearance of etoposide was reduced by approximately 50% when combined with PSC 833. It is concluded that the toxicity profile and MDT is similar in both children and adults, as is the effect on etoposide metabolism. The study demonstrated the feasibility and safety of carrying out a paediatric phase 1 trial across European boundaries and acts as a model for future cooperative studies in rare cancers among children. PMID- 17716891 TI - Brewery wastewater treatment using anaerobic inverse fluidized bed reactors. AB - Two anaerobic inverse fluidized bed reactors were utilized to evaluate organic matter removal from brewery wastewater, applying different OLR and testing two support materials. Hydrodynamic tests varying liquid flow and solid concentration were developed on the supports in order to establish operational conditions. A batch colonization stage was applied using 25% active volume of extendosphere and triturated polyethylene as support materials. The reactors were subsequently operated continuously with stepwise increments in organic loading rate until limiting conditions was reached. For the supports studied, IFBR technology was suitable for organic matter removal present in brewery wastewater with COD removal efficiencies greater than 90%. The reactor with triturated polyethylene support showed an excellent COD removal with OLR values up to 10 g COD/Ld, whereas the reactor with extendosphere support had an excellent hydrodynamic and biologic behavior working with OLR values up to 70 g COD/Ld. PMID- 17716893 TI - Toward novel HIV-1 integrase binding inhibitors: molecular modeling, synthesis, and biological studies. AB - The identification of a novel hit compound as integrase binding inhibitor has been accomplished by means of virtual screening techniques. A small family of structurally related molecules has been synthesized and biologically evaluated with one of the compounds showing an IC(50)=12 microM. PMID- 17716892 TI - Aaptamines as sortase A inhibitors from the tropical sponge Aaptos aaptos. AB - Four aaptamines (1-4), 1H-benzo[de][1,6]-naphthyridine alkaloids, were isolated from the marine sponge Aaptos aaptos and their inhibitory activities against sortase A (SrtA), an enzyme that plays a key role in cell wall protein anchoring and virulence in Staphylococcus aureus, were evaluated. Isoaaptamine (2) was a potent inhibitor of SrtA, with an IC(50) value of 3.7+/-0.2 microg/mL. The suppression of fibronectin-binding activity by isoaaptamine (2) highlights its potential for the treatment of S. aureus infections via inhibition of SrtA activity. Our studies have identified a series of SrtA inhibitors, providing the basis for further development of potent inhibitors. PMID- 17716894 TI - Carbocyclic 3'-deoxyadenosine-based highly potent bisubstrate-analog inhibitor of basophilic protein kinases. AB - Carbocyclic analogs of 3'-deoxyadenosine were synthesized as racemates and the resulting stereoisomers were separated by chromatography on a chiral column. The conjugation of obtained compounds with hexa-(D-arginine) via 6-aminohexanoic acid linker led to a highly potent inhibitor of several basophilic protein kinases with some selectivity towards cAMP-dependent protein kinase. PMID- 17716895 TI - Quantitative assessment of mammographic density and breast cancer risk for Japanese women. AB - We conducted a case-control study to examine the relationship between breast density (BD) on mammography and breast cancer risk for postmenopausal Japanese women. The mammograms (205 cases and 223 controls) were classified by two doctors employing Wolfe's classification and used to measure BD with original computer software. A weak relationship between breast cancer risk and the parenchymal pattern of Wolfe's classification was found. The BD measured with the computer software, however, showed a significant relationship with breast cancer risk. Analysis after adjustment for epidemiologic factors showed that women in the quintile with the highest BD had a 3.02 times higher risk of breast cancer than those in the quintile with the lowest density. Since mammographic BD is clearly associated with breast cancer risk for postmenopausal Japanese women, our software can be expected to become a useful tool for objective risk assessment of breast cancer. PMID- 17716896 TI - Predators' toxin burdens influence their strategic decisions to eat toxic prey. AB - Toxic prey advertise their unprofitability to predators via conspicuous aposematic coloration [1]. It is widely accepted that avoidance learning by naive predators is fundamental in generating selection for aposematism [2, 3] and mimicry [4, 5] (where species share the same aposematic coloration), and consequently this cognitive process underpins current evolutionary theory [5, 6]. However, this is an oversimplistic view of predator cognition and decision making. We show that predators that have learned to avoid chemically defended prey continue to attack defended individuals at levels determined by their current toxin burden. European starlings learned to discriminate between sequentially presented defended and undefended mealworms with different color signals. Once birds had learned to avoid the defended prey at a stable asymptotic level, we experimentally increased their toxin burdens, which reduced the number of defended prey that they ingested in the subsequent trial. This was due to the birds making strategic decisions to ingest defended prey on the basis of their visual signals. Birds are clearly able to learn about the nutritional benefits and defensive costs of eating defended prey, and they regulate their intake according to their current physiological state. This raises new perspectives on the evolution of aposematism, mimicry, and defense chemistry. PMID- 17716897 TI - From stem cell to embryo without centrioles. AB - Centrosome asymmetry plays a key role in ensuring the asymmetric division of Drosophila neural stem cells (neuroblasts [NBs]) and male germline stem cells (GSCs) [1-3]. In both cases, one centrosome is anchored close to a specific cortical region during interphase, thus defining the orientation of the spindle during the ensuing mitosis. To test whether asymmetric centrosome behavior is a general feature of stem cells, we have studied female GSCs, which divide asymmetrically, producing another GSC and a cystoblast. The cystoblast then divides and matures into an oocyte, a process in which centrosomes exhibit a series of complex behaviors proposed to play a crucial role in oogenesis [4-6]. We show that the interphase centrosome does not define spindle orientation in female GSCs and that DSas-4 mutant GSCs [7], lacking centrioles and centrosomes, invariably divide asymmetrically to produce cystoblasts that proceed normally through oogenesis-remarkably, oocyte specification, microtubule organization, and mRNA localization are all unperturbed. Mature oocytes can be fertilized, but embryos that cannot support centriole replication arrest very early in development. Thus, centrosomes are dispensable for oogenesis but essential for early embryogenesis. These results reveal that asymmetric centrosome behavior is not an essential feature of stem cell divisions. PMID- 17716898 TI - Sensorimotor learning configures the human mirror system. AB - Cells in the "mirror system" fire not only when an individual performs an action but also when one observes the same action performed by another agent [1-4]. The mirror system, found in premotor and parietal cortices of human and monkey brains, is thought to provide the foundation for social understanding and to enable the development of theory of mind and language [5-9]. However, it is unclear how mirror neurons acquire their mirror properties -- how they derive the information necessary to match observed with executed actions [10]. We address this by showing that it is possible to manipulate the selectivity of the human mirror system, and thereby make it operate as a countermirror system, by giving participants training to perform one action while observing another. Before this training, participants showed event-related muscle-specific responses to transcranial magnetic stimulation over motor cortex during observation of little- and index-finger movements [11-13]. After training, this normal mirror effect was reversed. These results indicate that the mirror properties of the mirror system are neither wholly innate [14] nor fixed once acquired; instead they develop through sensorimotor learning [15, 16]. Our findings indicate that the human mirror system is, to some extent, both a product and a process of social interaction. PMID- 17716900 TI - Localized pigmented villonodular synovitis presenting as a loose body following minor trauma in the knee: a case report. AB - Localized pigmented villonodular synovitis (LPVS) is widely accepted to frequently develop symptoms resembling internal derangement in the knee, including limitation of motion and episodes of giving way and locking. We report the case of a 31-year-old man with LPVS displaying an unusual presentation. After sustaining a twisting injury to the knee, he suffered constant but subtle knee discomfort, sudden attacks of pain and a feeling of a loose body. Arthroscopic examination 1 month after injury revealed a freely mobile tumor in the supra patellar pouch that was not pedunculated and displayed no soft tissue attachments to the synovium. Histological findings for the tumor were consistent with a diagnosis of LPVS. This case illustrates that LPVS may present with symptoms of a loose body after trauma to the knee. PMID- 17716901 TI - Determination of long-lived Nb isotopes in nuclear power plant wastes. AB - (94)Nb and (93m)Nb are long-lived radionuclides, produced by thermal and fast neutrons from (93)Nb that is a major component of the Zr alloys used in nuclear reactors. A radiochemical method for the determination of these nuclides has been developed. The separation is based on the insolubility of Nb oxides and the retention of the fluoric complexes on anion exchange resin. The Nb sources are detected by gamma- and X-ray spectrometries. Activity concentrations determined in radioactive waste samples of a nuclear power plant are presented. PMID- 17716899 TI - The sex-determination genes fruitless and doublesex specify a neural substrate required for courtship song. AB - Courtship song is a critical component of male courtship behavior in Drosophila, making the female more receptive to copulation and communicating species-specific information [1-6]. Sex mosaic studies have shown that the sex of certain regions of the central nervous system (CNS) is critical to song production [7]. Our examination of one of these regions, the mesothoracic ganglion (Msg), revealed the coexpression of two sex-determination genes, fruitless (fru) and doublesex (dsx). Because both genes are involved in creating a sexually dimorphic CNS [8, 9] and are necessary for song production [10-13], we investigated the individual contributions of fru and dsx to the specification of a male CNS and song production. We show a novel requirement for dsx in specifying a sexually dimorphic population of fru-expressing neurons in the Msg. Moreover, by using females constitutively expressing the male-specific isoforms of fru (Fru(M)), we show a critical requirement for the male isoform of dsx (Dsx(M)), alongside Fru(M), in the specification of courtship song. Therefore, although Fru(M) expression is sufficient for the performance of many male-specific behaviors [14], we have shown that without Dsx(M), the determination of a male-specific CNS and thus a full complement of male behaviors are not realized. PMID- 17716902 TI - A mathematical description of the diurnal variation of radon progeny. AB - The variation of the alpha radioactivity in the air near the ground and the ground-level total gamma radiation has been monitored in North-eastern Greece over several days. Meteorological information regarding the temperature of the air and humidity has been simultaneously recorded. The alpha-radioactivity shows a periodic diurnal variation with a peak in the morning followed by a decrease in the afternoon; then, the variation rises again to the peak the next morning. The variation of the ground gamma-radiation follows that of the air alpha radioactivity. Furthermore, their significant dependence on the air temperature and humidity is confirmed, rising with an increase in humidity and a decrease in temperature. Hence, a mathematical function has been developed to describe the diurnal variation of the alpha-radioactivity in terms of the ground-level gamma radiation and the meteorological variables of temperature and humidity. PMID- 17716903 TI - Bioluminescent monitoring of detoxification processes: activity of humic substances in quinone solutions. AB - This study deals with application of bioluminescent assay systems to evaluate the detoxifying effect of humic substances (HS) on the solutions of organic oxidizers - quinones. A series of homologous quinones with different redox characteristics: 1,4-benzoquinone, tetrafluoro-1,4-benzoquinone, methyl-1,4-benzoquinone, tetramethyl-1,4-benzoquinone, and 1,4-naphtoquinone, was used. Bioluminescent bacteria Photobacterium phosphoreum, and NADH:FMN-oxidoreductase-luciferase enzyme system isolated from these bacteria were used as assay systems. The toxicity was compared in the presence and in the absence of HS. Variation of complexity of bioassays (in vivo or in vitro) combined with spectrometric and microscopic methods, provides insight into the process of detoxification in quinone solutions. Two ways of HS effect were studied: the reduction activity of HS and intensification of self-protection of bacterial cells on HS addition. PMID- 17716904 TI - Photobiological effects of UVA and UVB light in zebrafish embryos: evidence for a competent photorepair system. AB - The consequences of UVB and UVA irradiation on hatch rate, mortality, and malformation were studied in embryonic zebrafish (Danio rerio). The use of zebrafish embryos has expanded from traditional developmental models to diverse studies, including many techniques utilizing light exposure. To characterize useful indicators of photodamage, the responses and threshold limits of UV radiation as a function of embryonic stage and fish source were evaluated. Significant differences in UVB susceptibility were observed in embryos at 3, 6-7, 12, and 24h post-fertilization (hpf), with the 1000-cell stage (3 hpf) having greatest tolerance to UVB. Embryos derived from zebrafish raised in outdoor ponds were more tolerant to UVB than were embryos from laboratory-raised fish. Combinations of UVB and UVA exposure were used to confirm the presence of a competent photorepair system in zebrafish that could return otherwise malformed embryos to a normal phenotype. Overall, embryonic zebrafish had large tolerances (LD(50) of 850 J/cm(2)) to UVA, confirming their suitability for photoactivation and photorepair studies. PMID- 17716905 TI - Recombinant therapeutic monoclonal antibodies: mechanisms of action in relation to structural and functional duality. AB - Naked therapeutic recombinant monoclonal antibodies (mAbs) are bifunctional molecules. On the one hand, they recognize their antigen through the variable regions of the antigen binding portion (Fab). The recombinant mAb binding to a soluble or a membrane antigen may interfere with one or several functions of this antigen, leading to the therapeutic effect. On the other hand, since their crystalisable portion (Fc) is humanized (usually IgG1), they interact efficiently with human Fc-binding molecules, such as C1q and receptors for the Fc portion of IgG (FcgammaR). Thus, they initiate the classical pathway of complement and activate FcgammaR-expressing cells. The recruitment of these patient immune effector functions is essential in the therapeutic effect of several recombinant mAbs used in oncology. The aim of this review is to describe the main mechanisms of action of recombinant mAbs in relation to this structural and functional duality. PMID- 17716907 TI - Conformationally driven gas-phase H/D exchange of dinucleotide negative ions. AB - Gas-phase hydrogen/deuterium exchange of six deprotonated dinucleotides with CD(3)OD was performed in the second hexapole of a Fourier transform ion-cyclotron resonance (FTICR) mass spectrometer. To complete these experiments, dynamic simulations were carried out to investigate the different conformations adopted by the dinucleotides. In the experimental conditions and in integrating the experimental and theoretical results, H/D exchange was shown to be controlled by hydrogen accessibility and not by the chemical nature of the heteroatom bearing the exchangeable hydrogen. A model including simultaneous H/D exchanges at the experimental time scale was used to reproduce the dinucleotide H/D exchange kinetic plots. The relay mechanism was not relevant for dinucleotides. This allowed the H/D exchange rates to be directly linked to conformations. PMID- 17716906 TI - Production of IL-6, in contrast to other cytokines and chemokines, in macrophage innate immune responses: effect of serum and fungal (Blastomyces) challenge. AB - Murine peritoneal macrophages, after adherence and establishment in culture in vitro in the presence of medium containing fetal bovine serum (FBS) for 20 h, then cultured for 20 h, produced several cytokines. If, in the second 20 h period, a fungus (heat-killed Blastomyces, HK-Bd) was introduced, a more complex pattern of cytokine (particularly TNF) and chemokine production ensued. The cytokine production, assayed by antibody array and also quantitation in supernatants, was depressed (particularly TNF) by the addition of mouse serum to these cultures, with the exception of IL-6. Macrophages could be cultured in the presence or absence of serum during the initial 20 h adherence and establishment period, enabling study of the effect of serum factors. In the absence of serum, with or without fungal stimulation, cytokine and chemokine production was more restricted, largely to TNF and IL-6. The addition of mouse serum [corrected] resulted in marked depression of TNF and enhancement of IL-6. The combination of HK-Bd and mouse serum resulted in more IL-6 production than either component alone. The enhancement of IL-6 by mouse serum was concentration-dependent and maximal at 8 h. The effects of fungus or serum on macrophage production of cytokines were similar in an outbred and an inbred mouse strain. The larger repertoire of cytokine production in the macrophages that had been cultured longer (20 h+20 h) in serum may be related to maturation of cell receptors. IL-6 production in vivo in response to fungal-serum complexes could affect pathogenesis by opposing the host defense modulation by proinflammatory cytokines or by modulating the destructive effects of inflammation on host tissues. PMID- 17716908 TI - Selective determination of pyridine alkaloids in tobacco by PFTBA ions/analyte molecule reaction ionization ion trap mass spectrometry. AB - The application of perfluorotributylamine (PFTBA) ions/analyte molecule reaction ionization for the selective determination of tobacco pyridine alkaloids by ion trap mass spectrometry (IT-MS) is reported. The main three PFTBA ions (CF(3)(+), C(3)F(5)(+), and C(5)F(10)N(+)) are generated in the external source and then introduced into ion trap for reaction with analytes. Because the existence of the tertiary nitrogen atom in the pyridine makes it possible for PFTBA ions to react smoothly with pyridine and forms adduct ions, pyridine alkaloids in tobacco were selectively ionized and formed quasi-molecular ion [M + H](+)and adduct ions, including [M + 69](+), [M + 131](+), and [M + 264](+), in IT-MS. These ions had distinct abundances and were regarded as the diagnostic ions of each tobacco pyridine alkaloid for quantitative analysis in selected-ion monitoring mode. Results show that the limit of detection is 0.2 microg/mL, and the relative standard deviations for the seven alkaloids are in the range of 0.71% to 6.8%, and good recovery of 95.6% and 97.2%. The proposed method provides substantially greater selectivity and sensitivity compared with the conventional approach and offers an alternative approach for analysis of tobacco alkaloids. PMID- 17716909 TI - Remote mass spectrometric sampling of electrospray- and desorption electrospray generated ions using an air ejector. AB - A commercial air ejector was coupled to an electrospray ionization linear ion trap mass spectrometer (LTQ) to transport remotely generated ions from both electrospray (ESI) and desorption electrospray ionization (DESI) sources. We demonstrate the remote analysis of a series of analyte ions that range from small molecules and polymers to polypeptides using the AE-LTQ interface. The details of the ESI-AE-LTQ and DESI-AE-LTQ experimental configurations are described and preliminary mass spectrometric data are presented. PMID- 17716910 TI - Distinctive unimolecular gas-phase reactivity of [M(en)2]2+ (M = Ni, Cu) dications and their inclusion complexes with the macrocyclic cavitand cucurbit[8]uril. AB - Electrospray ionization mass spectrometry makes it possible to generate gas-phase bis-ethylenediamine nickel and copper dications, [M(en)(2)](2+) (M = Ni, 1; M = Cu, 2), as well as their {[M(en)(2)]@cuc[8]}(2+) inclusion complexes with the macrocyclic cavitand cucurbit[8]uril (cuc[8]). The unimolecular gas-phase reactivity of these species has been investigated by electrospray ionization tandem mass spectrometry with a quadrupole-time-of-flight configuration. Distinctive fragmentation pathways have been observed for the free and encapsulated [M(en)(2)](2+) (M = Ni, Cu) dications under collision-induced dissociation (CID) conditions. The dications [M(en)(2)](2+) (M = Ni, Cu) dissociate according to several competitive pathways that involve intra-complex hydrogen or electron-transfer processes. Most of these channels are suppressed after encapsulation inside the cucurbit[8]uril macrocycle and, as a consequence, a simplification of the {[M(en)(2)]@cuc[8]}(2+) fragmentation pattern is observed. The results obtained demonstrate that the encapsulation of a coordination complex inside a host molecule can be used to alter the nature of the product ions generated under CID conditions. PMID- 17716911 TI - The role of HLA-G in gastrointestinal inflammatory disease and malignancy. AB - Human leukocyte antigen (HLA)-G has been shown to act as an immune-inhibitory molecule and to interfere with the normal functions of natural killer (NK) cells and T-cells, conferring a potential route for HLA-G expressing cells to escape host immune surveillance. These findings have led to the rather intense study of HLA-G expression in several different arenas, including organ transplantation, inflammatory conditions, and in a wide variety of neoplasms including hematolymphoid neoplasms, visceral carcinomas, gliomas, and dermal-based neoplasms. This review will focus on the role of HLA-G in inflammatory conditions of the bowel, which can serve as an initiator of neoplastic alterations, as well as examine HLA-G expression and function in a variety of gastrointestinal malignancies. Although there are only a limited number of studies that have examined HLA-G in the gastrointestinal tract, the role of HLA-G has been controversial in this organ system with conflicting results reported even within the same tumor type. PMID- 17716912 TI - The Cav3.2/alpha1H T-type Ca2+ current is a molecular determinant of excitatory effects of GABA in adult sensory neurons. AB - In addition to its inhibitory action, reports have shown that, in sensory neurons, GABA can be responsible for excitatory effects leading to painful behavior. The cellular mechanisms for these excitatory effects remain largely unknown. Although the high intracellular chloride concentration allows GABA(A) receptor activation to depolarize all adult sensory neurons, we show that GABA, acting through GABA(A) receptors, can generate, in vitro, action potential and intracellular Ca(2+) increase only in a subset of neurons expressing a prominent T-type Ca(2+) current. When recorded from Cav3.2(-/-) mice, T-type Ca(2+) current was totally abolished in this morphologically identified subset of neurons and GABA(A) receptors activation did not induce electrical activity nor intracellular Ca(2+) increase. In addition to gene inhibition, pharmacological analysis of Ca(2+) channel subunits shows the amplifying role of T-current in GABA(A) current induced membrane depolarization and the involvement of both T-current and high voltage activated Ca(2+) current in GABA(A)-induced intracellular Ca(2+) increase. Altogether, these data establish that the Cav3.2/alpha1H, T-current is responsible for GABA-induced cell excitability and intracellular Ca(2+) increase. Our results reveal a positive cross-talk between T-channel and GABA(A) receptor in adult sensory neurons and indicate that Cav3.2/alpha1H, T-type Ca(2+) channel may be the molecular determinant for excitatory effects of GABA in peripheral somatosensory system. PMID- 17716913 TI - Fas/FasL-mediated apoptosis in the arcuate nucleus and medial preoptic area of male ArKO mice is ameliorated by selective estrogen receptor alpha and estrogen receptor beta agonist treatment, respectively. AB - The aromatase (ArKO) knockout mouse is estrogen deficient. Our previous analysis revealed apoptosis of dopaminergic neurons in the arcuate nucleus (Arc) and medial preoptic area (MPO) of 1-year-old male ArKO mice. We sought to determine which estrogen receptor (ER) is involved in the anti-apoptotic action of estrogen. Male ArKO (9.5-month-old) mice were treated with 16alpha-LE(2) (ERalpha specific agonist) or 8beta-VE(2) (ERbeta-specific agonist). Daily injections (6 weeks) with 16alpha-LE(2) prevented dopaminergic cell death in the Arc of male ArKO mice, with no significant effect of 8beta-VE(2) treatment. In contrast, 8beta-VE(2) prevented dopaminergic cell death in the MPO, while 16alpha-LE(2) had no significant effect. Concomitant decreases in Fas and FasL protein levels were found upon 16alpha-LE(2) and 8beta-VE(2) treatment in the Arc and MPO, respectively. Our results indicate that anti-apoptotic effects of estrogen are ER mediated, and the specific ER subtype involved in regulating apoptosis depends on the particular brain nucleus in question. PMID- 17716914 TI - The neural cell adhesion molecule is necessary for normal adult retinal ganglion cell number and survival. AB - Retinal ganglion cells (RGCs) undergo apoptotic death in predictable time dependant manners during development and as a consequence of injury. Recently, synthetic neural cell adhesion molecule (NCAM) agonists have been shown to provide neuroprotective support. Within the adult mouse retina, NCAM has been localized on all neurons and glia; however, no functional role has been determined. Using adult NCAM-/- mice, we directly tested the potential influence of NCAM on neuron survival in vivo and observed that, in NCAM-/- retinas, RGC densities are greater, RGC loss after injury is earlier and target tissue significantly influences adult RGC survival, all in contrast to wild-type retinas. Collectively, our results indicate that NCAM may play a vital role in regulating the developmental change in the effectiveness of local versus target derived RGC trophic support and that, in the adult, endogenous NCAM influences the total number of CNS neurons and their survival following injury. PMID- 17716915 TI - One step engineering of T7-expression strains for protein production: increasing the host-range of the T7-expression system. AB - The T7-expression system has been very useful for protein expression in Escherichia coli. However, it is often desirable to over-express proteins in species other than E. coli. Here, we constructed an inducible broad-host-range T7 expression transposon, which allows simple one-step construction of T7-expression strains in various species, providing the option to over-express proteins of interest in a broader host-range. This transposon contains the T7 RNA polymerase driven by the lacUV5 promoter, which is repressed by the lac-repressor. Leaky expression is prevented by the presence of T7-lysozyme on this construct. The complete T7-expression system is flanked by mariner transposon repeats of the suicidal R6Kgammaori plasmid, pBT20-Deltabla. Stable integration of the whole system is possible by a one-step selection for a Flp-excisable Gm(R)-marker. We showed the engineering of E. coli, Pseudomonas aeruginosa, Erwinia carotovora, Salmonella choleraesuis, Agrobacterium tumefaciens, and Chromobacterium violaceum strains with this construct and demonstrated the expression of the Burkholderia pseudomallei Asd protein in these hosts, by induction with isopropyl-beta-d thiogalactopyranoside (IPTG). PMID- 17716917 TI - Recognising the forest, but not the trees: an effect of colour on scene perception and recognition. AB - Colour has been shown to facilitate the recognition of scene images, but only when these images contain natural scenes, for which colour is 'diagnostic'. Here we investigate whether colour can also facilitate memory for scene images, and whether this would hold for natural scenes in particular. In the first experiment participants first studied a set of colour and greyscale natural and man-made scene images. Next, the same images were presented, randomly mixed with a different set. Participants were asked to indicate whether they had seen the images during the study phase. Surprisingly, performance was better for greyscale than for coloured images, and this difference is due to the higher false alarm rate for both natural and man-made coloured scenes. We hypothesized that this increase in false alarm rate was due to a shift from scrutinizing details of the image to recognition of the gist of the (coloured) image. A second experiment, utilizing images without a nameable gist, confirmed this hypothesis as participants now performed equally on greyscale and coloured images. In the final experiment we specifically targeted the more detail-based perception and recognition for greyscale images versus the more gist-based perception and recognition for coloured images with a change detection paradigm. The results show that changes to images are detected faster when image-pairs were presented in greyscale than in colour. This counterintuitive result held for both natural and man-made scenes (but not for scenes without nameable gist) and thus corroborates the shift from more detailed processing of images in greyscale to more gist-based processing of coloured images. PMID- 17716916 TI - Effect of electrocardiographic contamination on surface electromyography assessment of back muscles. AB - The purpose of this study was to demonstrate the relative effect of electrocardiography (ECG) on back muscle surface electromyography (SEMG) parameters and their corresponding sensitivity in low back pain (LBP) assessment. Back muscle SEMG activities were recorded from 17 healthy subjects and 18 chronic LBP patients under static postures (straight sitting and upright standing), and dynamic action (flexion-extension). ECG cancellation based on independent component analysis (ICA) method was performed. Root mean square (RMS) and median frequency (MF) of raw and denoised SEMG data were computed respectively. Multiple comparisons were then performed. A consistent trend of change (increased MF and decreased RMS) followed ECG removal was noticed. In particular, in SEMG measurements under static postures, a significant decrease in RMS (p<0.05) and increase in MF (p<0.05) were found in all recording muscle groups. Level of corruption by ECG artifacts on SEMG measurements was found to be more serious and prominent in static postures than that in dynamic action. After ECG removal, significant improvements in the ability of SEMG to discriminate LBP patients from healthy subjects were seen in RMS amplitude recorded while standing (p<0.05) and MF in all measuring conditions (p<0.05). This study provides a more complete understanding on the relative effect of ECG contamination on back muscles SEMG parameters and LBP assessment. PMID- 17716918 TI - Subjectivity and the body: introducing basic forms of self-consciousness. PMID- 17716919 TI - Cognitive neurophysiology: beyond averaging. AB - Averaging of repeated responses to sensory stimuli is the standard approach in cognitive electrophysiology. This procedure can give rise to inappropriate interpretations in some situations, because two factors contribute to the average ERP responses: the amplitude of the responses during the individual experimental trials, and the concentration of the phases (phase-locking) across responses. Larger poststimulus single-trial amplitudes compared to prestimulus baseline are thought to correspond to a stimulus-related increase of postsynaptic potentials or/and activation of an increased amount of neural assemblies. But the functional interpretation of an enhanced inter-trial phase-locking is unclear. BOLD responses are probably related to single-trial EEG amplitudes, but not to the phase concentration across trials. Therefore, separation of amplitude and phase contributions is indispensable to avoid misinterpretations and to gain a deeper understanding of the relation between event-related EEG and fMRI. PMID- 17716922 TI - Molecular phylogenetics of the bee-eaters (Aves: Meropidae) based on nuclear and mitochondrial DNA sequence data. AB - The bee-eaters (family Meropidae) comprise a group of brightly colored, but morphologically homogeneous, birds with a wide variety of life history characteristics. A phylogeny of bee-eaters was reconstructed using nuclear and mitochondrial DNA sequence data from 23 of the 25 named bee-eater species. Analysis of the combined data set provided a well-supported phylogenetic hypothesis for the family. Nyctiornis is the sister taxon to all other bee eaters. Within the genus Merops, we recovered two well-supported clades that can be broadly separated into two groups along geographic and ecological lines, one clade with mostly African resident species and the other clade containing a mixture of African and Asian taxa that are mostly migratory species. The clade containing resident African species can be further split into two groups along ecological lines by habitat preference into lowland forest specialists and montane forest and forest edge species. Intraspecific sampling in several of the taxa revealed moderate to high (3.7-6.5%, ND2) levels of divergence in the resident taxa, whereas the lone migratory taxon showed negligible levels of intraspecific divergence. This robust molecular phylogeny provides the phylogenetic framework for future comparative tests of hypotheses about the evolution of plumage patterns, sociality, migration, and delayed breeding strategies. PMID- 17716921 TI - Quantitative [(123)I]FP-CIT pinhole SPECT imaging predicts striatal dopamine levels, but not number of nigral neurons in different mouse models of Parkinson's disease. AB - Single photon emission computed tomography (SPECT) using [(123)I]FP-CIT as radioligand for the dopamine transporter has become a widely used tool to monitor the integrity of the nigrostriatal dopaminergic projection in Parkinson's disease (PD). Previous studies with pinhole SPECT in small animals have demonstrated that the striatal [(123)I]FP-CIT binding indeed correlates with the striatal dopamine transporter protein level. It is unclear, however, if there is a stable relationship between the striatal [(123)I]FP-CIT binding and other functionally important parameters of the nigrostriatal system, such as the striatal dopamine levels and the number of dopaminergic neurons in the substantia nigra. To assess this question experimentally, we studied two different mouse models of PD, namely a mild 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication paradigm, to model mild nigrostriatal damage and the intrastriatal 6-hydroxydopamine paradigm to model more advanced nigrostriatal damage. Our data demonstrate that the striatal [(123)I]FP-CIT binding measured by SPECT in vivo precisely predicts the striatal dopamine concentrations, but does not necessarily correlate with the nigral dopaminergic cell number. Thus, the present work underscores that FP-CIT SPECT does only allow judging the integrity of the striatal dopaminergic nerve terminals, but not the nigral dopaminergic cells in PD. This finding may have significant impact on the use of [(123)I]FP-CIT SPECT as a surrogate marker for clinical trials aimed at measuring neuroprotection. PMID- 17716923 TI - An independent heterotachy model and its implications for phylogeny and divergence time estimation. PMID- 17716925 TI - Mitochondrial DNA phylogeography of the three-spined stickleback (Gasterosteus aculeatus) in Europe-evidence for multiple glacial refugia. AB - An analysis of mitochondrial DNA sequence variation in 172 three-spined sticklebacks (Gasterosteus aculeatus) sampled across the European distribution range revealed three major evolutionary lineages occupying relatively large and separate geographic areas. The trans-Atlantic lineage comprised of populations spanning from the East Coast of USA to the continental Europe and was basal group to the other European lineages in the phylogeny. The European lineage included populations located in the Western and Eastern Europe, British Isles, Scandinavia as well as some parts of the Mediterranean region. The third lineage was specific to the Black Sea drainages. The within lineage structure was characterized by significant excess of low frequency haplotypes and star-like mtDNA genealogies, which suggest a recent population expansions to the formerly glaciated marine and freshwater environments. A coalescent-based method dated the splits between the major lineages to have occurred during the Saalian and Weichselian glaciations in the late Pleistocene, depending on the molecular clock calibration. The coalescent simulations further indicate high degree of genetic diversity within the lineages and a substantial increase in the genetic diversity in the European lineage relative to the ancestral level. In addition to the three major lineages, the freshwater populations in R. Neretva and L. Skadar in the Adriatic Sea coast region harboured unique and highly divergent haplotypes suggesting long independent histories of these populations. Evidence from mtDNA analyses suggests that these populations deserve a status of an evolutionary significant unit. PMID- 17716924 TI - Evolution of resupination in Malagasy species of Bulbophyllum (Orchidaceae). AB - Resupination is the orientation of zygomorphic flowers during development so that the median petal obtains the lowermost position in the mature flower. Despite its evolutionary and ecological significance, resupination has rarely been studied in a phylogenetic context. Ten types of resupination occur among the 210 species of the orchid genus Bulbophyllum on Madagascar. We investigated the evolution of resupination in a representative sample of these species by first reconstructing a combined nrITS and cpDNA phylogeny for a sectional reclassification and then plotting the different types of inflorescence development, which correlated well with main clades. Resupination by apical drooping of the rachis appears to have evolved from apical drooping of the peduncle. Erect inflorescences with resupinate flowers seem to have evolved several times into either erect inflorescences with (partly) non-resupinate flowers or pendulous inflorescences with resupinate flowers. PMID- 17716926 TI - Recovering cryptic diversity and ancient drainage patterns in eastern North America: historical biogeography of the Notropis rubellus species group (Teleostei: Cypriniformes). AB - The Central Highlands of North America contain a strikingly diverse assemblage of temperate freshwater fishes and have long been a focus of biogeographic studies. The rosyface shiner complex, Notropis rubellus and related species, is a member of this fauna exhibiting a disjunct highlands distribution occurring in the unglaciated regions of the Central Highlands and glaciated regions of the Central Lowlands. Until recently, N. rubellus was considered a single, widespread species exhibiting geographic variation in morphological characters. However, several studies have revealed that N. rubellus is a multi-species complex with closely related species endemic to drainages within each highland region. We examined genetic variation of the N. rubellus complex using a complete mtDNA cytochrome b gene sequence data set and combined mtDNA and published allozyme data sets. Parsimony and Bayesian analyses of the mitochondrial data set and parsimony analyses of a combined mitochondrial and allozyme data sets were largely consistent. Results of these analyses revealed ancient cryptic diversity within the N. rubellus complex that existed prior to the onset of Pleistocene glaciations. We identified seven strongly supported clades within the N. rubellus complex. Four clades are diagnosed as separate species (N. percobromus, N. rubellus, N. micropteryx and N. suttkusi) and three clades may represent undescribed forms. Relationships among these groups and their biogeographical patterns provided significant inferences on ichthyofaunal distributions in southeastern North America. These include the timing of the origin of the diversity, ancient drainage patterns and barriers to dispersal in the Central Highlands. The observation of increased diversity in N. rubellus suggests there may be greater diversity within other taxa with a similar distribution. PMID- 17716928 TI - Forearm rotational profile in obstetric brachial plexus injury. AB - Children with obstetric brachial plexus palsy (OBPP) most commonly have weakness of supination. There is little previous information on later progress of forearm rotation movements, although severe supination contracture has been reported in a small proportion of children. The aims of this study were to evaluate forearm rotation after initial recovery from OBPP, to define the relationship with the severity of disease, and to assess which factors might limit rotation. Measurements of active and passive pronation and supination were recorded in 56 children (37 boys and 19 girls) who had had OBPP and did not have full recovery. The mean age was 8 years (minimum, 2.5 years). Care was taken to measure forearm rotation in isolation from shoulder movements. According to the Narakas classification for severity of the original brachial plexus lesion, there were 23 group I cases, 16 group II cases, 11 group III cases, and 6 group IV cases. Twenty-one children underwent reconstructive procedures for shoulder deformity. Mallet scores for shoulder function were available for all patients. Overall pronation was more limited than supination. Active movements were more limited than passive movements. Active pronation was less than normal in 48 children, active supination was less than normal in 36, passive pronation was less than normal in 22, and passive supination was less than normal in 9. Active pronation and active and passive supination were significantly limited in children with worse Mallet scores and in Narakas group IV children. Both active supination and passive supination were decreased in children with more severe elbow flexion contractures. No significant relationship was found between forearm rotation movements and the time of biceps recovery. Many children have persisting limitation of forearm rotation after OBPP. Despite the initial weakness of supination, pronation is more often reduced in the longer term. Patients with more severe OBPP and poorer recovery of shoulder function have greater limitation of forearm rotation. PMID- 17716927 TI - A novel computer-based method for the measurement of the lipid "load" in the coronary vessels of rabbits. AB - INTRODUCTION: This study reports the development of a new, accurate and reproducible method which combines histological and computer techniques for the determination of fatty load in cholesterol-fed rabbits. METHODS: New Zealand male rabbits were randomly divided into three groups. The animals in group 1 (control) received neither cholesterol nor drugs. Those in group 2 received a 2% cholesterol diet for 30 days, followed by a normal diet for 45 days. In addition during the latter period (day 31 to day 75) animals received 200 g of chopped carrots each morning. The rabbits in group 3 followed the same dietary regime as those in group 2 except that 8.36 mg of simvastatin and 1.76 g cholestyramine were mixed with their carrots. On the 76th day, the animals were sacrificed and their blood and hearts were collected. Histological sections (15 microm thick) of hearts were cut at 90 degrees to the long axis using a motorized freezing microtome. Every tenth section was mounted on a glass slide and stained with Oil Red O. A total of hundred slides prepared from each heart were scanned into a computer and the area stained by Oil Red O was measured, giving a measure of the total fatty "load" in each heart. RESULTS: There was a highly significant increase in the coronary fatty deposits in the hearts of the animals fed with cholesterol rich diet (group 2) as compared to the control rabbits in group 1. Treatment of rabbits with simvastatin plus cholestyramine (group 3) significantly reduced the coronary lipids load. DISCUSSION: The combination of histological and computer-based techniques used in this study provides an accurate and reproducible method for the quantitation of fatty deposits in rabbit coronary vessels. This report is based on the measurement of coronary lipid depositions rather than aortic lesions. It also overcomes the shortcoming of the majority of the earlier published methods which are generally limited to the measurement of fatty plaques in only few major coronary vessels, totally neglecting the many small distributive vessels which are often responsible for cardiac ischemic disease. PMID- 17716929 TI - Lipid-binding role of betaII-spectrin ankyrin-binding domain. AB - It is known that erythroid and non-erythroid spectrins binding of vesicles and monolayers containing PE proved sensitive to inhibition by red blood cell ankyrin. We now show that the bacterially-expressed recombinant peptides representing betaII(brain)-spectrin's ankyrin-binding domain and its truncated mutants showed lipid-binding activity, although only those containing a full length amino terminal fragment showed high to moderate affinity towards phospholipid mono- and bilayers and a substantial sensitivity of this binding to inhibition by ankyrin. These results are in accordance with our published data on betaI-spectrin's ankyrin-binding domain [Hryniewicz-Jankowska A, et al. Mapping of ankyrin-sensitive, PE/PC mono- and bilayer binding site in erythroid beta spectrin. Biochem J 2004;382:677-85]. Moreover, we tested also the effect of transient transfection of living cells of several cell-lines with vectors coding for GFP-conjugates including betaII and also betaI full-length ankyrin-binding domain and their truncated fragments on the membrane skeleton organization. The transfection with constructs encoding full-length ankyrin-binding domain of betaII and betaI spectrin resulted in increased aggregation of membrane skeleton and its punctate appearance in contrast to near normal appearance of membrane skeleton of cells transiently transfected with GFP control or construct encoding ankyrin-binding domain truncated at their N-terminal region. Our results therefore indicate the importance of N-terminal region for lipid-binding activity of the beta-spectrin ankyrin-binding domain and its substantial role in maintaining the spectrin-based skeleton distribution. PMID- 17716931 TI - Long-term results of surgical repair of popliteal artery aneurysm. AB - OBJECTIVE: To determine the long-term outcome of surgical repair of popliteal artery aneurysms (PAA). METHODS: A retrospective review of consecutive patients who underwent surgical PAA repair in two vascular surgery units between 1988 and 2006 was performed. Primary and secondary graft patency, limb salvage and patient survival rates were determined using Kaplan-Meier methods. RESULTS: 48 patients underwent repair of 63 PAAs (ligation and bypass=45, interposition grafting=18). The 5-year primary graft patency, secondary graft patency, limb salvage and patient survival rates were 75%, 95%, 98% and 81%, respectively. The 10-year primary graft patency rates were significantly lower for emergency cases (59%) compared with elective cases (66%) (p=0.0023). Thirteen patients (16 PAAs) required a total of 20 late re-interventions. Duplex ultrasound was available in 33 of 45 PAAs treated by ligation and bypass. Five (15%) PAAs demonstrated perfusion of the aneurysm sac at median (range) follow up of 75 (1-246) months after primary repair and two of these required emergency re-operation. CONCLUSIONS: These data demonstrate that surgical PAA repair is associated with excellent long-term durability and provide an important benchmark with which to compare results of endovascular PAA repair. Patients treated using the ligation and bypass technique should be enrolled in an aneurysm sac surveillance program. PMID- 17716932 TI - True long-term healing and recurrence of venous leg ulcers following SEPS combined with superficial venous surgery: a prospective study. AB - BACKGROUND: The role of perforator surgery remains unclear in the management of patients with leg ulcers. The aim of this study was to assess long-term healing and recurrence rates of leg ulcers following surgical intervention with combined Subfascial Endoscopic Perforator Surgery (SEPS) and superficial venous surgery. METHOD: Case series with prospective long-term follow-up of 90 consecutive patients operated on with open (CEAP C6) or healed (CEAP C5) venous ulcers in 97 legs. Popliteal vein reflux was present in 21 legs. All 97 legs were treated with SEPS and 87% had additional superficial venous surgery. Patients were follow-up for a median of 77 months (range 60-112 months) with a minimum of 5 years. RESULTS: 87% of all ulcerated legs healed. The three and five year recurrence rates were 8% and 18% respectively among survivors. In a multivariate Cox regression analysis previous vein surgery was the only factor significantly associated with recurrent ulceration (p=.004). CONCLUSION: SEPS combined with superficial venous surgery leads to healing with a low recurrence rate in patients with open and healed venous ulcers. Previous venous surgery was found to be a significant risk factor for ulcer recurrence. This result emphasizes the importance of assiduous technique for varicose vein surgery and suggests a continuing role for perforator surgery in leg ulcer patients. PMID- 17716930 TI - Borealin is repressed in response to p53/Rb signaling. AB - Rb/E2F regulates many genes that encode proteins required for the cell cycle. Using affymetrix microarrays we previously identified genes regulated by the Rb proteins p130 and p107, many of which are involved in the cell cycle. Several genes with unknown functions were also repressed by p130 and p107, of which some have recently been found to have various roles in mitosis, the spindle checkpoint and cytokinesis. This study focuses on the regulation of borealin/dasra/cdca8, which encodes a recently discovered member of the chromosomal passenger complex. It is recorded that borealin is a cell cycle regulator, down-regulated in response to p53/Rb-signaling, and up-regulated in many types of cancerous tissues. PMID- 17716934 TI - Improved gene targeting in Magnaporthe grisea by inactivation of MgKU80 required for non-homologous end joining. AB - The ascomycete Magnaporthe grisea is a model species for the study of plant fungal interactions. As in many filamentous fungi, targeted gene replacement occurs at low frequency in M. grisea (average 7%). mus52/KU80 is a gene essential for non-homologous end joining (NHEJ) of DNA double-strand breaks. Its deletion increases the frequency of targeted gene replacement in fungi [Ninomiya, Y., Suzuki, K., Ishii, C., Inoue, H., 2004. Highly efficient gene replacements in Neurospora strains deficient for non-homologous end joining. Proc. Natl. Acad. Sci. USA 101(33), 12248-53]. M. grisea KU80 deletion mutants were constructed and displayed wild-type phenotypes regarding pathogenicity, growth, sporulation and mating. MgADE4 targeted gene replacement frequency was increased in Deltaku80 mutants (80% vs 5%) and high frequencies (>80%) were observed at seven other loci. However, the deletion of MgKU80 did not increase the frequency of ACE1 replacement indicating that this locus has an intrinsic reduced ability for gene replacement. These results open the way to large-scale reverse genetics experiments in M. grisea facilitating the study of the infection process. PMID- 17716933 TI - Endovascular treatment (EVT) of acute traumatic lesions of the descending thoracic aorta--7 years' experience. AB - OBJECTIVES: To present a single centers' 7-year experience in the endovascular treatment of acute traumatic lesions of the descending thoracic aorta (ATL of the DTA). MATERIALS & METHODS: Between March 1999 and December 2006, 34 consecutive acute traumatic lesions of the descending aorta (23 men, mean age 44 years) were treated endovascularly. Stentgrafts used were TAG Excluder, Zenith TX2 and Talent. In 23 patients the Left Subclavian Artery (LSA) was covered. Mean procedural duration was 20 to 75 minutes. RESULTS: Exclusion of the rupture site was achieved in all cases with no conversion to open surgery. Overall 30-day mortality was 8.8%. Two patients died on post operative day (pod) 1 and one on pod 22 from cranial injuries. No death or neurological deficit related to the endovascular treatment was reported. Four type I endoleaks required treatment either by balloon reexpansion (n=2) or by additional stentgraft implantation (n=2). In two patients the stentgraft collapsed totally several days postoperatively. Two patients required secondary surgical procedures (iliac access complication and revascularisation of the left subclavian artery n=1). The average follow-up was 43.8 months (1-93 months). No stentgraft related abnormality has been subsequently documented. CONCLUSIONS: The endovascular treatment of ATL of the DTA may offer the best means of therapy in a polytrauma patient. PMID- 17716935 TI - Analytical validation of commercial immunoassays for the measurement of cardiovascular peptides in the dog. AB - Immunoassays for the measurement of concentrations of the cardiovascular peptides pro-atrial natriuretic peptide (proANP), brain natriuretic peptide (BNPPen and BNPPhoe), endothelin-1 (ET-1Bio, ET-1IBL and ET-1Phoe) and big endothelin-1 (Big ETBio and Big-ETIBL) were validated in canine serum by determination of intra assay variability and dilutional parallelism. Commercial kits that showed good results were further validated by determination of intra- and inter-assay variability, dilutional parallelism and spiking recovery. Assays for proANP, BNPPhoe, ET-1IBL and Big-ETIBL showed acceptable results in the preliminary validation and were fully validated. The intra- and inter-assay variability was acceptable for all four assays, linearity was demonstrated and recovery rates were acceptable. The performances of the different immunoassays varied considerably, underscoring the importance of validation. Of the assays studied, proANP, BNP(Phoe), ET-1IBL and Big-ETIBL produced precise, reproducible and accurate results and can be recommended for clinical application. PMID- 17716936 TI - Primary vaccination with a new heptavalent DTPw-HBV/Hib-Neisseria meningitidis serogroups A and C combined vaccine is well tolerated. AB - OBJECTIVE: Safety and reactogenicity of a new heptavalent DTPw-HBV/Hib-MenAC (diphtheria, tetanus, whole cell pertussis-hepatitis B virus/Haemophilus influenzae type b-Neisseria meningitidis serogroups A and C) vaccine was compared with a widely used pentavalent DTPw-HBV/Hib vaccine. METHODS: Three phase III randomized studies comparable in design and methodology, in which healthy infants received DTPw-HBV/Hib-MenAC (N=1334) or DTPw-HBV/Hib (N=446) at 2, 4, and 6 months, were pooled for analysis. Solicited symptoms were recorded for 4 days, and unsolicited adverse events for 31 days after each dose. Serious adverse events (SAEs) were recorded throughout the studies. RESULTS: There were no significant differences between the two groups in the proportion of subjects with fever >39.5 degrees C or >40.0 degrees C (p<0.005). Compared to group DTPw HBV/Hib, a significantly higher percentage of subjects in group DTPw-HBV/Hib MenAC reported fever >39 degrees C (21.2% vs. 14.8%, p=0.004). Fever subsided quickly, did not lead to differences in attendance to medical services and did not increase from dose to dose. Sixty-seven SAEs were reported, 56/1334 (4.2%) in group DTPw-HBV/Hib-MenAC and 11/446 (2.5%) in the DTPw-HBV/Hib group. CONCLUSION: Overall, the heptavalent and pentavalent vaccines had similar safety profiles. The difference observed in percentage of subjects with fever >39 degrees C did not lead to differences in medically attended visits for fever. PMID- 17716937 TI - An active learning approach to the physics of medical imaging. AB - This paper describes an experimentally oriented medical imaging course where the students record, process and analyse 3D data of an unknown piece of formalin fixed porcine tissue hidden in agar in order to estimate the tissue types present in a selected 2D slice. The recorded planar X-ray, CT, MRI, ultrasound and SPECT images show the tissue in very different ways. The students can only estimate the tissue type by studying the physical principles of the imaging modalities. The true answer is later revealed by anatomical photographs obtained from physical slicing. The paper describes the phantoms and methods used in the course. Sample images recorded with the different imaging modalities are provided. Challenges faced by the students are outlined. Results of the course show high increase in competencies as judged from graded reports, low course drop-out rate, high pass rate at the exam, high student participation and large student satisfaction. PMID- 17716938 TI - Vibrio cholerae: cholera toxin. AB - The bacterial protein toxin of Vibrio cholerae, cholera toxin, is a major agent involved in severe diarrhoeal disease. Cholera toxin is a member of the AB toxin family and is composed of a catalytically active heterodimeric A-subunit linked with a homopentameric B-subunit. Upon binding to its receptor, GM0(1), cholera toxin is internalized and transported in a retrograde manner through the Golgi to the ER, where it is retrotranslocated to the cytosol. Here, cholera toxin reaches its intracellular target, the basolaterally located adenylate cyclase which becomes constitutively activated after toxin-induced mono-ADP-ribosylation of the regulating G(S)-protein. Elevated intracellular cAMP levels provoke loss of water and electrolytes which is manifested as the typical diarrhoea. The cholera toxin B-subunit displays the capacity to fortify immune responses to certain antigens, to act as a carrier and to be competent in inducing immunological tolerance. These unique features make cholera toxin a promising tool for immunologists. PMID- 17716939 TI - Experimental and theoretical NMR study of 4-(3-cyclohexen-1-yl)pyridine. AB - (1)H, (13)C, DEPT, COSY, NOESY and HETCOR NMR spectra of 4-(3-cyclohexen-1 yl)pyridine (4-Chpy) have been reported for the first time. (1)H and (13)C NMR chemical shifts of 4-Chpy (C(11)H(13)N) have been calculated by means of the Hartree-Fock (HF) and Becke-3-Lee-Yang-Parr (B3LYP) density functional methods with 6-311++G(d,p) basis set. Comparison between the experimental and the theoretical results indicate that density functional B3LYP method is superior to the scaled HF approach for predicting NMR properties. PMID- 17716940 TI - Experimental correlation between the pKa value of sulfonphthaleins with the nature of the substituents groups. AB - This work presents the results obtained from a spectrophotometry study performed on some indicators of the sulfonphtaleins like phenol red (PR), thymol blue (TB), bromothymol blue (BTB), xylenol orange (XO) and methylthymol blue (MTB). During the first stage the acidity constants of some of the indicators were determined using the data from spectrophotometry, potentiometry and with the use of the software SQUAD. These were as follows: for the equilibrium 2H+BTB<-->H(2)BTB, log beta(2)=15.069+/-0.046 and for H+BTB<-->HBTB, log beta(1)=8.311+/-0.044. For the XO and the MTB five values were calculated for each, namely, for MTB: log beta(5)=42.035, log beta(4)=38.567+/-0.058, log beta(3)=32.257+/-0.057, log beta(2)=23.785+/-0.057, and log beta(1)=12.974+/-0.045 while for XO: log beta(5)=40.120+/-0.102, log beta(4)=35.158+/-0.062, log beta(3)=29.102+/-0.053, log beta(2)=21.237+/-0.044, and log beta(1)=11.682+/-0.044. During the second stage, a study was conducted on the effect of the substituents present in the indicators to determine the effect of different functional groups on the pK(a) value corresponding to the last indicator's dissociation. PMID- 17716941 TI - Spectroscopic study on anion recognition properties of calix[4]pyrroles: effects of tetraalkylammonium cations. AB - The solution binding properties of calix[4]pyrroles with anion (added as tetraalkylammonium salts) were investigated using UV-vis spectroscopic techniques. The obvious red-shift of absorption maximum band of calix[4]pyrrole in EtOH in the presence of the tetramethylammonium (TMA(+)) or tetraethylammonium (TEA(+)) salts were observed. These results displayed in electronic absorption spectra indicated calix[4]pyrrole receptors linking anionic species through multiple hydrogen bonding interactions are capable of using the periphery electron-rich "walls" for selectively binding electron-deficient tetraalkylammonium cation subunits by cation-pi charge-transfer interaction. It was seen that the stability of the calix[4]pyrrole-anion complex depends strongly on the cation. The meso-alkyl groups of the calix[4]pyrrole, the affinity for the anion subunits and the structure of tetraalkylammonium cations have considerable effects on the formation of cation-pi charge-transfer interaction. PMID- 17716942 TI - Determination of carotenoid as the purple pigment in Gorgonia ventalina sclerites using Raman microscopy. AB - The production of purple pigment in gorgonian sclerites in response to biotic insults has been used to determine the disease state of these organisms. The chemical nature of the pigment present in the sclerites has until now been unknown. Using Raman microscopy, it was determined that this pigment is a carotenoid with a polyene chain containing between 14 and 15 carbon double bonds. PMID- 17716943 TI - Effect of carvedilol and metoprolol on the mode of death in patients with heart failure. AB - BACKGROUND: In the COMET study, carvedilol improved survival compared to metoprolol tartrate in 3029 patients with NYHA II-IV heart failure and EF <35%, followed for an average of 58 months. AIMS: To evaluate whether the effect on overall mortality was specific for a particular mode of death. This may help to identify the mechanism of the observed difference. METHODS: Of the 1112 total deaths, 972 were adjudicated as cardiovascular, including 480 sudden, 365 circulatory failure (CF) and 51 stroke deaths. For each mode of death, the effect of pre-specified baseline variables was assessed, including sex, age, NYHA class, aetiology, heart rate, systolic blood pressure, EF, atrial fibrillation, previous myocardial infarction or hypertension, renal function, concomitant medication, and study treatment allocation. RESULTS: In multivariate Cox regression analyses, compared to metoprolol, carvedilol reduced cardiovascular (RR 0.80, CI 0.7-0.91, p=0.0009), sudden (RR 0.77, CI 0.64-0.93, p=0.0073) and stroke deaths (RR 0.37, CI 0.19-0.71, p=0.0027) with a non-significant trend for CF death (RR 0.83, CI 0.66-1.04, p=0.07). Treatment benefit with carvedilol did not differ between modes of death, except for a greater reduction in stroke death with carvedilol (competing risk analysis, p=0.0071 vs CF death). There were no interactions between treatment allocation and baseline characteristics. CONCLUSION: Mortality reduction with carvedilol compared to metoprolol appears relatively non-specific and could be consistent with a superior effect of carvedilol on cardiac function, arrhythmias or, in view of the greater reduction in stroke deaths, on vascular events. PMID- 17716944 TI - CpG oligonucleotides as adjuvant in therapeutic vaccines against parasitic infections. AB - Immunostimulatory CpG DNA is recognized by cells of the innate immune system through Toll-like receptor 9 (TLR9). Synthetic CpG oligonucleotides (CpG-ODN) belong to the most potent vaccine adjuvants known today. This is due to their capacity not only to stimulate cells of the innate immune system but also to trigger effectively specific T- and B-lymphocyte responses. This unique quality seems to be superior in the induction of long-term effects and immunological memory. In addition to prophylactic vaccination, we showed that mice already infected with Toxoplasma gondii could be therapeutically vaccinated by the combined use of CpG-ODN and a bradyzoite antigen (BAG1 protein subunit). This treatment was effective against the infection and resulted in a long-term survival of the mice and reduced parasite burden in the brain. Different routes of CpG-ODN vaccine application including intranasal, oral or intraperitoneal delivery were compared with the classical subcutaneous application in two established experimental infection models of murine leishmaniasis and toxoplasmosis. Comparable effects were demonstrated for these modes of inoculation except for the oral uptake of uncoupled CpG-ODN, which resulted in a complete failure of treatment. Detailed studies were performed to optimize the time point of CpG-ODN application. The best results were obtained when the ODN were given within a few days around the infection, in contrast to former trials showing a time window of several weeks for significant oligonucleotide effects in non-infectious models. As CPG-ODN is a synthetic compound, it is not only available in high purity and reproducible quality, but can also be produced with different backbone modifications and sequence modifications. Combination of these possibilities resulted in new molecules that were highly effective as adjuvant in parasite infection models. Finally, our studies revealed not only that bacterial DNA is an effective vaccine adjuvants, but also that Leishmania DNA itself had immunostimulatory properties which are counteracted by a yet undefined inhibitory principle from living Leishmania. PMID- 17716945 TI - Collaborative action learning: a professional development model for educational innovation in nursing. AB - The paper describes the processes and outcomes of a major curriculum innovation which was conducted by a collaborative multi-disciplinary team (nurse academics, educational developers and software developers). The paper argues that collaborative professional development in pedagogical innovation in nursing can be successfully supported by action learning as a framework for practice. In presenting this argument the paper draws on the experience of the School of Nursing and Midwifery (SNM) at the University of Tasmania in integrating high fidelity simulation-based learning into an existing undergraduate case-based learning curriculum in the three year Bachelor of Nursing (BN). PMID- 17716946 TI - The role of hematopoietic stem cell transplantation in advanced Hodgkin Lymphoma. AB - Primary therapy of Hodgkin Lymphoma is generally successful. However, for the relatively small numbers of patients with relapsed or primary progressive disease, outcomes are not optimal. It is now recognized that high dose chemotherapy and autoSCT may be curative in a proportion of these patients. Nevertheless, survival even following autoSCT remains unsatisfactory, with relapse remaining the major concern. In particular, patients with primary progressive disease, those who fail to respond to salvage therapy, and those who are ineligible for autoSCT carry a relatively poor prognosis. In these groups of patients, clinical trials are examining tandem autologous stem cell transplantation or reduced intensity allogeneic transplantation. The latter procedure is promising in terms of its relatively low toxicities and its possibility of inciting a Graft-versus-Hodgkin Lymphoma effect. Further prospective clinical trials are required to clarify the role of allogeneic transplantation in poor risk Hodgkin Lymphoma. PMID- 17716948 TI - Cardiac nurses' views of continuing professional education. AB - BACKGROUND: There is little information available on cardiovascular nurses' attitudes to continuing professional education. Anecdotally many nurses profess that they require additional study days to keep updated in practice; however these are not always available at local level. This survey aimed to capture the views of cardiovascular nurses with regard to their continuing education needs. AIMS: This research aimed to identify cardiovascular nurses' views on continuing professional education. METHODS: A 26-item questionnaire collected data from 195 cardiovascular nurses in the Republic of Ireland. Response rate was 52% (n=102). RESULTS: Most nurses had attended an educational event in the last 3-6 months and national conferences and local initiatives provided most of these latter services. Most respondents received both funding and study leave to attend. Nurses preferred method of keeping up-to-date was by means of conference and study days, journal use was also frequent. A high level of access to electronic resources was reported. Midweek was the preferred time for continuing education to occur. CONCLUSIONS: The findings reveal a positive attitude to continuing professional education. They also support the endeavours of national professional organisations, such as INCA and highlight the important role that these organisations play in the provision of ongoing education to cardiovascular nurses. PMID- 17716947 TI - Relation of depression, natural killer cell function, and infections after coronary artery bypass in women. AB - BACKGROUND: After hospital discharge for coronary artery bypass grafting (CABG), infection is a common cause of morbidity. Although depression has been associated with immune dysfunction, its role in post-CABG infection is unknown. AIMS: The purpose of this study was to: 1) compare natural killer cell cytotoxicity (NKCC) and post-hospitalization infections in depressed and non-depressed women after CABG; and 2) test whether NKCC mediated the relationship between post-discharge depression and infections. METHODS: Sixty-seven women recovering from CABG were assessed for depression prior to hospital discharge and followed for six months. Major depression was identified by a structured clinical interview. Infections were identified by patient report using the Modified Health Review and by medical chart audit. RESULTS: Compared to non-depressed women after CABG, women with major depression had reduced NKCC, more all-cause infections, and more self reported illnesses. Although NKCC did not mediate the relationship between depression and wound (i.e. incisional) infections after CABG, it did mediate the relationship between depression and non-wound infections, including pneumonias and upper respiratory infections. CONCLUSIONS: For the first six months after CABG, women with major depression are at increased risk for infections. Natural killer cell cytotoxicity may be related to this phenomenon, particularly to non wound infections. PMID- 17716949 TI - A case of 75-year-old survivor of unrepaired tetralogy of Fallot and quadricuspid aortic valve. AB - In tetralogy of Fallot (TOF), the most common form of cyanotic congenital heart disease, only a few patients reach adulthood without surgical correction. We present the case of a man with TOF who survived until the age of 75 years without surgical intervention and had a very unusual combination of TOF and quadricuspid aortic valve (QAV). QAV, complicated by aortic regurgitation, is an uncommon finding in TOF patients. The hemodynamic consequences for both the right and left ventricles are significant. This case provides a rare insight into the late outcome of an elderly patient with uncorrected TOF. PMID- 17716950 TI - Acute effects of glyphosate herbicide on metabolic and enzymatic parameters of silver catfish (Rhamdia quelen). AB - Silver catfish (Rhamdia quelen; Teleostei) were exposed to commercial formulation Roundup, a glyphosate herbicide: 0 (control), 0.2 or 0.4 mg/L for 96 h. Fish exposed to glyphosate showed an increase in hepatic glycogen, but a reduction in muscle glycogen at both concentrations tested. Glucose decreased in liver and increased in muscle of fish at both herbicide concentrations. Glyphosate exposure increased lactate levels in liver and white muscle at both concentrations. Protein levels increased in liver and decreased in white muscle while levels of ammonia in both tissues increased in fish at both glyphosate concentrations. Specific AChE activity was reduced in brain after treatments, no changes were observed in muscle tissue. Catalase activity in liver did not change during of exposure. Fish exposed to glyphosate demonstrated increased TBARS production in muscle tissue at both concentrations tested. For both glyphosate concentrations tested brain showed a reduction of TBARS after 96 h of exposure. The present results showed that in 96 h, glyphosate changed AChE activity, metabolic parameters and TBARS production. The parameters measured can be used as herbicide toxicity indicators considering environmentally relevant concentration. PMID- 17716951 TI - Zinc, antioxidant systems and metallothionein in metal mediated-apoptosis: biochemical and cytochemical aspects. AB - Copper, zinc and iron are essential metals for different physiological functions, even though their excess can lead to biological damage. This review provides a background of toxicity related to copper, iron and zinc excess, biological mechanisms of their homeostasis and their respective roles in the apoptotic process. The antioxidant action of metallothionein has been highlighted by summarizing the most important findings that confirm the role of zinc in cellular protection in relation to metallothionein expression and apoptotic processes. In particular, we show that a complex and efficient antioxidant system, the induction of metallothionein and the direct action of zinc have protective roles against oxidative damage and the resulting apoptosis induced by metals with redox proprieties. In addition, to emphasize the protective effects of Zn and Zn-MT in Cu and Fe-mediated oxidative stress-dependent apoptosis, some aspects of apoptotic cell death are shown. The most widely used cytochemical techniques also have been examined in order to critically evaluate the available data from a methodological point of view. The observations on the role of Zn and MT could potentially develop new applications for this metal and MT in biomedical research. PMID- 17716954 TI - Effects of heptanol and carbenoxolone on noradrenaline induced contractions in guinea pig vas deferens. AB - We examined the effects of two putative gap junction blockers, heptanol and carbenoxolone, on noradrenaline-induced contractions in guinea pig vas deferens. The force generated due to the exogenously added noradrenaline (20 microM) consisted of two components: the tonic and the oscillatory. 2 mM heptanol abolished the oscillatory contractions and drastically suppressed both the maximum force (by 85.4 +/- 18.2%) as well as the tonic component (by 28.8 +/- 5.1%) (P<0.01, n=7). However, the effects of carbenoxolone (50 microM) were strikingly different, with the spikes of the oscillatory component being merged into a steady, "fused" contraction, without affecting the maximum force developed. The L-type Ca(2+) channel blocker nifedipine (2 microM) abolished the oscillatory component of the contractions and significantly reduced the maximum force and tonic component (by 82.4 +/- 6.8% and 19.7 +/- 6.4% respectively; P<0.01, n=4), in a manner similar to that elicited by heptanol. Our results indicate that (i) while carbenoxolone specifically blocks gap junctions, heptanol appears to exert its actions through non-gap junctional mechanisms, possibly by blocking VGCCs in smooth muscle; (ii) gap junctions play a significant modulatory role in the generation of noradrenaline-induced contractions in guinea pig vas deferens, particularly in the emergence of oscillatory contractions, while the maximum force developed may be independent of gap junctional contribution. PMID- 17716952 TI - An overview of "The Active by Choice Today" (ACT) trial for increasing physical activity. AB - BACKGROUND: Although school-based behavioral interventions for increasing physical activity (PA) in children and adolescents have been conducted, little evidence suggests that these curriculum-based approaches lead to increases in overall activity outside of program days. The overall goal of the "Active by Choice Today" (ACT) trial is to expand the body of knowledge concerning the factors that influence long-term increases in PA in underserved adolescents (low socioeconomic status, minorities) during their middle school years. DESIGN AND SETTING: An overview of the ACT study design, theoretical framework, process evaluation, and primary hypotheses is presented. The trial involves twenty-four middle schools (1560 6th graders) in South Carolina that are randomly assigned to one of two after-school programs (motivational and life skills intervention, or general health education). INTERVENTION: The intervention integrates constructs from Self-Determination and Social Cognitive Theories to enhance intrinsic motivation and behavioral skills for PA. The intervention targets skill development for PA outside of program days and the after-school program social environment (autonomy, choice, participation, belongingness, fun, enjoyment, support) is designed to positively impact cognitive mediators (self-efficacy, perceived competence), and motivational orientation (intrinsic motivation, commitment, positive self-concept). MAIN HYPOTHESES/OUTCOMES: It is hypothesized that the 17-week motivational and life skills intervention will lead to greater increases in moderate-to-vigorous PA (based on 7-day accelerometry estimates) at post-intervention as compared to the general health education program. CONCLUSIONS: Implications of this innovative school-based trial are discussed. PMID- 17716953 TI - Trial design: blood pressure control and weight gain prevention in prehypertensive and hypertensive smokers: the treatment and prevention study. AB - BACKGROUND: Cigarette smokers with elevated blood pressure (BP) are at substantially higher risk for cardiovascular events compared to normotensive smokers. Although smoking cessation should be a primary treatment goal for these patients, increases in body weight accompanying smoking abstinence may further increase BP. Intervention strategies that facilitate smoking cessation and modify adverse changes in body weight and BP are needed. METHODS: We describe an ongoing multi-site, two-phase, five-year randomized clinical trial. Participants are cigarette smokers with Prehypertension or Stage I Hypertension. In the first phase, participants receive a smoking cessation intervention combining behavioral counseling and nicotine replacement in an open-label fashion. In the second phase, participants who successfully quit smoking are randomly assigned to one of three lifestyle interventions: 1) weight gain prevention, 2) blood pressure control, or 3) usual lifestyle. Participants are followed for one year to assess changes in blood pressure, body weight, dietary intake, and physical activity. CONCLUSIONS: Results from the proposed study will provide important insights into the efficacy of various approaches to lifestyle modification in smokers at increased risk for cardiovascular events. PMID- 17716955 TI - The evolution of genetic structure in the marine pathogen, Vibrio vulnificus. AB - Multi-locus sequence types (MLST) from a global collection of Vibrio vulnificus isolates were analysed for the contribution of recombination to the evolution of two divergent clusters of strains and a human-pathogenic hybrid genotype, which caused a disease outbreak in Israel. Recombination contributes more substantially than mutation to generating strain diversity. For allelic diversity within loci, the ratio of recombination to mutation events is approximately 2:1. The role of recombination relative to mutation in the generation of new MLST variants of V. vulnificus within the clusters is comparable to that of other highly recombining bacteria such as Neisseria meningitidis. However, across the divide between the two major clusters of V. vulnificus strains, there is substantial linkage disequilibrium, lower estimates for recombination rates and shorter estimates of recombination tract length. We account for these differences between V. vulnificus and N. meningitidis by attributing them to the presence of the unusual genetic structure within V. vulnificus. The reason for the presence of distinct and divergent genomes remains unresolved. Two possible explanations put forward for future study are first, ecologically based population structure within V. vulnificus and second, a recombination donor from a phenotypically differentiated species. PMID- 17716956 TI - Low genetic diversity and epidemiological significance of Listeria monocytogenes isolated from wild animals in the far east of Russia. AB - The causative agent of listeriosis, a serious disease of humans and animals, Listeria monocytogenes is a ubiquitous bacterium that inhabits both anthropogenic and pristine environments. We report L. monocytogenes isolation from wild animals, humans, food and the environment of a far eastern region of Russia. In total, 654 samples of internal organs of small rodents belonging to the Muridae and Cricetidae families, and 986 samples of the liver and muscles of mollusks and fish were examined to obtain 7 and 14 independent L. monocytogenes isolates, respectively. The wild animal isolates were compared with human (n=9), food (n=8) and environmental (n=3) isolates obtained in the same region. Twenty of the 21 wild animal isolates belonged to the serovar 4b. The serovars 4b, 1/2a, 1/2b, and 4b, 1/2a, 1/2b, 1/2c were found between human and food isolates, respectively. All isolates were characterized into molecular subtypes by DNA sequencing of the 618 bp internal fragment of the house keeping gene prs and 621 bp internal fragment of the virulence gene inlB. Sequence analysis revealed 4 and 13 alleles for prs and inlB fragments, respectively. Distinct prs and inlB alleles clustered into two groups consistently with established phylogenetic lineages. Among isolates of every lineage, the nucleotide diversity of the prs fragment was low; the nucleotide diversity of the inlB fragment was low among wild animal isolates and higher among human isolates. All rodent isolates and 10 of 14 marine organism isolates carried the same allele of the inlB fragment, which was also found among environmental (two of three), food (two of eight) and human (two of nine) isolates. PMID- 17716957 TI - Fission yeast Swi5 protein, a novel DNA recombination mediator. AB - The Schizosaccharomyces pombe Swi5 protein forms two distinct protein complexes, Swi5-Sfr1 and Swi5-Swi2, each of which plays an important role in the related but functionally distinct processes of homologous recombination and mating-type switching, respectively. The Swi5-Sfr1 mediator complex has been shown to associate with the two RecA-like recombinases, Rhp51 (spRad51) and Dmc1, and to stimulate in vitro DNA strand exchange reactions mediated by these proteins. Genetic analysis indicates that Swi5-Sfr1 works independently of another mediator complex, Rhp55-Rhp57, during Rhp51-dependent recombinational repair. In addition, mutations affecting the two mediators generate distinct repair spectra of HO endonuclease-induced DNA double strand breaks, suggesting that these recombination mediators differently regulate recombination outcomes in an independent manner. PMID- 17716958 TI - Characterisation of mutations and genotype-phenotype correlation in cystic fibrosis: experience from India. AB - BACKGROUND: Very little is known about the genetics of cystic fibrosis (CF) from the Indian subcontinent. The aims of the study were to identify the mutations and study the relation of genotype with phenotype in Indian children with CF. METHODS: A total of 100 patients with CF were screened for mutations in the CFTR gene. These included c.1521_1523delCTT (p.F508del) and c.3849+10 kb C>T mutations followed by single strand conformation polymorphism/heteroduplex analysis for mutations in 19 out of 27 exons of the CFTR gene. RESULTS: At least one mutation was identified in 40 patients. The most common mutation identified was p.F508del; 20 patients were homozygous and 13 heterozygous. In addition, c.3849+10 kb C>T, c.1161delC, and p.S549N were identified in two patients each and p.R352Q, p.R1158X and p.R75Q were identified in one patient each. Three novel mutations, viz. c.1002-7_1002-5delTTT, p.G149X and p.L183I were also identified. Majority of patients who were p.F508del positive originated from Pakistan and north-western states of India. The phenotypes of all patients were classical. Genotype phenotype correlation revealed that p.F508del positive patients had a more severe disease, manifesting at an earlier age. CONCLUSIONS: A strategy for mutation screening for CF in India must involve testing for p.F508del followed by c.1161delC, c.3849+10 kb C>T and p.S549N. There is a need for large multicentric studies using more sensitive techniques for the identification of mutations in Indian CF patients. PMID- 17716960 TI - Bone ingrowth in macroporous Bonelike for orthopaedic applications. AB - The aim of this study was to evaluate the biological behaviour of porous scaffold structures of Bonelike which is suitable for either direct clinical use or tissue engineering applications. Porous cylindrical specimens 8x10mm were implanted in the lateral aspect of the tibia of 13 patients (mean age 54 years), during osteotomy surgery for the treatment of medial compartment osteoarthritis of the knee. Implanted cylinders were retrieved at the same time as the removal of the blade plates at 3, 6, 9 and 12 months. Scanning electron microscopy and histological evaluations were performed to observe the biological responses of human bone tissue to porous Bonelike. The penetration depth was determined for all implantation periods, and after 6 months it was already possible to see new bone in the centre of the implanted cylinders, which gives 100% of penetration depth for all implantations periods except for 3 months when bone could only be seen in the peripherical region. Regarding the percentage of the area covered by new bone calculated from two-dimensional histological sections, values of 53+/ 15, 76+/-12 and 88+/-9% were achieved for 6, 9 and 12 months, respectively. Due to its structural features porous Bonelike permitted effective vascularization and bone ingrowth, and therefore was fully osteointegrated as shown in the histological surveys. A slow biomaterial degradation with implantation time is envisaged since the material has displayed surface degradation. Bonelike scaffolds show potential for complete ingrowth of osseous tissue and restoration of vascularization throughout the defected site. PMID- 17716959 TI - Purification and characterization of RGD tumor-homing peptide conjugated human tumor necrosis factor alpha over-expressed in Escherichia coli. AB - A number of approaches have been investigated to enhance the selective toxicity of tumor necrosis factor alpha (TNFalpha) to permit its systemic use in cancer therapy. Because vascular targeting has been proven to be a valid strategy for improving the therapeutic index of TNFalpha, we prepared RGD-hTNF consisting of human TNF fused with the ACDCRGDCFCG peptide, a ligand of alpha(v)beta(3) and alpha(v)beta(5) integrins. Recombinant RGD-hTNF was produced in Escherichia coli as a polyhistidine fusion protein. Between polyhistidine tag and RGD-hTNF, a tobacco etch virus (TEV) protease cleavage site (ENLYFQG) was introduced to ensure the release of intact RGD-hTNF. The purification strategy consisted of the target protein capture step by immobilized metal affinity chromatography (IMAC), TEV protease cleavage of fusion protein, the subtractive depletion of removed His tag by IMAC and the final gel filtration step. As a result, about 18 mg of intact RGD-hTNF was obtained from 1l of bacteria culture. The purified RGD-hTNF was characterized by SDS-PAGE, Western blot, mass spectroscopy and gel filtration. Since the RGD-hTNF molecule retained the cytotoxic activity of the TNF moiety and the integrin binding ability of the RGD moiety, the purification method provided material for assessing its anti-tumor activity in animal model. PMID- 17716961 TI - Intrauterine surgery in myelomeningocele. AB - Intrauterine surgery for repair of fetal myelomeningocele has been performed since 1994. Open repair through a hysterotomy has been performed since 1997. Although much has been published about diagnosis, counseling, case selection, pre , intra-, and postoperative management, delivery and long-term sequelae for both mother and baby, and associated ethical issues, several questions have yet to be openly discussed in a public forum. PMID- 17716963 TI - Past. Present. Future? PMID- 17716962 TI - Posterior interosseous artery flap, fasciosubcutaneous pedicle technique: a study of 25 cases. AB - This study was undertaken in an attempt to improve the versatility of the posterior interosseous artery flap (PIA flap) and to decrease flap complication rate. The PIA flap was used for resurfacing 25 cases of the hand and distal forearm over a 2-year period. Observations were made on the anatomy of the PIA flap and its distal reach. Doppler analysis was made a mandatory part of the preoperative planning. Flaps were also raised from the zone of injury if Doppler confirmed the presence of good perforators. No attempt was made to identify the anastomosis between the anterior interosseous artery (AIA) and the PIA prior to flap raising since its presence was ascertained preoperatively with a Doppler and flap raising could begin straightway, saving precious tourniquet time. The surgical technique was further modified to include a large amount of fascia and subcutaneous tissue with the flap. This could perhaps be the reason for survival of larger flaps, absence of venous congestion and the low complication rate seen in our series. These flaps were used to resurface defects involving the dorsum of the hand, palm, distal forearm, wrist and fingers (both dorsal and volar surfaces). The distal reach of the flap was improved by exteriorising the pedicle and bowstringing it across the wrist which was kept in extension. The flap could thus easily reach the distal interphalangeal joint. This exteriorised pedicle was covered with a split thickness skin graft and was divided 3 weeks later under local anaesthesia making it a two-stage procedure. Adipofascial and osteocutaneous PIA flaps were also used depending on the requirement. Out of 25 flaps, 23 were of the adipofascial variety and one each of the fascial and osteocutaneous type. The majority of the patients were between 21 and 30 years old. Trauma was the leading cause of tissue deficit in our series (19/25). Within the trauma group occupational mishap (entrapment of hand in roller machine, presser machine, etc.) was the leading cause, road traffic accident being the next most common. The most common site of defect was the dorsum of the hand (14/25). The largest flap measured 12x8cm and the smallest flap measured 3x2cm. Only three minor complications were noted, two cases of partial flap loss (one of them needing a secondary procedure of debridement and grafting) and one partial graft loss in the case of fascial flap which needed regrafting. Importantly no evidence of venous congestion was noted in any of the flaps. PMID- 17716965 TI - Risedronate did not block the maximal anabolic effect of PTH in aged rats. AB - The study was designed to investigate if pre-treating rats with a therapeutic equivalent dose of risedronate blunted the anabolic effects of PTH, and whether a withdrawal period prior to PTH treatment would alter any effect of risedronate on PTH treatment. Skeletally mature rats were treated for 18 weeks with vehicle, risedronate, or risedronate for 8 weeks followed by vehicle for 10 weeks (withdrawal period). At the end of this period, animals were treated for a further 12 weeks with PTH or PTH vehicle. Trabecular and cortical bone mass were monitored by serial pQCT, or by DXA and microCT. Bone histomorphometry was performed on the proximal tibiae and tibial shafts for bone turnover parameters at week 40. Risedronate alone moderately increased while PTH alone markedly increased trabecular bone mass at the proximal tibial (35% and 200%, respectively) and lumbar vertebral body (14% and 36%, respectively). The maximum bone gains were similar with and without pretreatment with risedronate as compared to the PTH alone. Continuous administration of risedronate for 18 weeks prior to PTH treatment had lower percentage increases in proximal tibial BMD during the first 8 weeks of PTH treatments, and had lower active bone forming surface and bone formation rates after being treated with PTH 12 weeks as compared to the PTH alone group. However, with the 10-week withdrawal period, risedronate did not blunt the stimulatory effect of PTH on osteoblast activity as shown by similar bone formation rates as with PTH alone. Our findings suggest that while risedronate pretreatment may slow the bone anabolic response to PTH, a withdrawal period prior to PTH treatment allows osteoblastic activity to respond normally to PTH stimulation. PMID- 17716964 TI - Cytogenetic investigation of a child with a mosaic isochromosome 18q and ring 18q. AB - We report on a baby girl from non-consanguineous Palestinian parents with intrauterine growth retardation, low birth weight, and developmental delay. She had a short stature, microcephaly, a prominent metopic suture, a glabellar haemangioma, exophthalmos, hypertelorism, upslanting palpebral fissures, horizontal nystagmus, flat nose, cleft lip and palate, a short neck, widely spaced nipples, umbilical hernia, flexion deformity of the wrist, ulnar deviation of fingers, and right club foot. Cortical atrophy, enlarged ventricles, a thin corpus callosum, thoracic hemivertebrae, and a ventricular septal defect were detected as well. High resolution chromosome analysis identified in 92% of cells an isochromosome 18 and in 8% of cells a ring 18. Molecular cytogenetic investigations confirmed that it was an i(18q) and a r(18q). The hypothesis to account for this anomaly and its corresponding phenotype are discussed. PMID- 17716966 TI - Chimpanzees use self-distraction to cope with impulsivity. AB - It is unknown whether animals, like humans, can employ behavioural strategies to cope with impulsivity. To examine this question, we tested whether chimpanzees (Pan troglodytes) would use self-distraction as a coping strategy in a situation in which they had to continually inhibit responses to accumulating candies in order to earn a greater amount of those rewards. We tested animals in three conditions in which they were sometimes given a set of toys and were sometimes allowed physical access to the accumulating candies. Chimpanzees allowed the rewards to accumulate longer before responding when they could divert their attention to the toys, and they manipulated the toys more when the candies were physically accessible. Thus, chimpanzees engaged in self-distraction with the toys when such behaviour was most beneficial as a coping mechanism. PMID- 17716968 TI - Mammary epithelial-specific deletion of the focal adhesion kinase gene leads to severe lobulo-alveolar hypoplasia and secretory immaturity of the murine mammary gland. AB - Integrin-mediated cell adhesion and signaling is required for mammary gland development and functions. As a major mediator of integrin signaling, focal adhesion kinase (FAK) has been implicated to play a role in the survival, proliferation, and differentiation of mammary epithelial cells in previously studies in vitro. To assess the role of FAK in vivo, we created mice in which FAK is selectively deleted in mammary epithelial cells. The mammary gland FAK conditional knock-out (MFCKO) mice are viable, fertile, and macroscopically indistinguishable from the control littermates. In virgin MFCKO mice, mammary ductal elongation is retarded at 5 weeks of age but reaches the full extent by 8 weeks of age compared with the control mice. However, the MFCKO females are unable to nurse their pups due to severe lobulo-alveolar hypoplasia and secretory immaturity during pregnancy and lactation. Analysis of the mammary epithelial cells in MFCKO mice showed reduced Erk phosphorylation, expression of cyclin D1, and a corresponding decrease in proliferative capability compared with the littermate controls. In addition, phosphorylation of STAT5 and expression of whey acidic protein are significantly reduced in the mammary glands of MFCKO mice, suggesting defective secretory maturation in these mice. Therefore, the combination of the severe lobulo-alveolar hypoplasia and defective secretory differentiation is responsible for the inability of the MFCKO females to nurse their pups. Together, these results provide strong support for a role of FAK in the mammary gland development and function in vivo. PMID- 17716967 TI - Overexpression of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) in skeletal muscle repatterns energy metabolism in the mouse. AB - Transgenic mice, containing a chimeric gene in which the cDNA for phosphoenolpyruvate carboxykinase (GTP) (PEPCK-C) (EC 4.1.1.32) was linked to the alpha-skeletal actin gene promoter, express PEPCK-C in skeletal muscle (1-3 units/g). Breeding two founder lines together produced mice with an activity of PEPCK-C of 9 units/g of muscle (PEPCK-C(mus) mice). These mice were seven times more active in their cages than controls. On a mouse treadmill, PEPCK-C(mus) mice ran up to 6 km at a speed of 20 m/min, whereas controls stopped at 0.2 km. PEPCK C(mus) mice had an enhanced exercise capacity, with a VO(2max) of 156 +/- 8.0 ml/kg/min, a maximal respiratory exchange ratio of 0.91 +/- 0.03, and a blood lactate concentration of 3.7 +/- 1.0 mm after running for 32 min at a 25 degrees grade; the values for control animals were 112 +/- 21 ml/kg/min, 0.99 +/- 0.08, and 8.1 +/- 5.0 mm respectively. The PEPCK-C(mus) mice ate 60% more than controls but had half the body weight and 10% the body fat as determined by magnetic resonance imaging. In addition, the number of mitochondria and the content of triglyceride in the skeletal muscle of PEPCK-C(mus) mice were greatly increased as compared with controls. PEPCK-C(mus) mice had an extended life span relative to control animals; mice up to an age of 2.5 years ran twice as fast as 6-12 month-old control animals. We conclude that overexpression of PEPCK-C repatterns energy metabolism and leads to greater longevity. PMID- 17716969 TI - The beta-propensity of Tau determines aggregation and synaptic loss in inducible mouse models of tauopathy. AB - Neurofibrillary lesions are characteristic for a group of human diseases, named tauopathies, which are characterized by prominent intracellular accumulations of abnormal filaments formed by the microtubule-associated protein Tau. The tauopathies are accompanied by abnormal changes in Tau protein, including pathological conformation, somatodendritic mislocalization, hyperphosphorylation, and aggregation, whose interdependence is not well understood. To address these issues we have created transgenic mouse lines in which different variants of full length Tau are expressed in a regulatable fashion, allowing one to switch the expression on and off at defined time points. The Tau variants differ by small mutations in the hexapeptide motifs that control the ability of Tau to adopt a beta-structure conformation and hence to aggregate. The "pro-aggregation" mutant DeltaK280, derived from one of the mutations observed in frontotemporal dementias, aggregates avidly in vitro, whereas the "anti-aggregation" mutant DeltaK280/PP cannot aggregate because of two beta-breaking prolines. In the transgenic mice, the pro-aggregation Tau induces a pathological conformation and pre-tangle aggregation, even at low expression levels, the anti-aggregation mutant does not. This illustrates that abnormal aggregation is primarily controlled by the molecular structure of Tau in vitro and in the organism. Both variants of Tau become mislocalized and hyperphosphorylated independently of aggregation, suggesting that localization and phosphorylation are mainly a consequence of increased concentration. These pathological changes are reversible when the expression of Tau is switched off. The pro-aggregation Tau causes a strong reduction in spine synapses. PMID- 17716970 TI - Presenilin 1 regulates epidermal growth factor receptor turnover and signaling in the endosomal-lysosomal pathway. AB - Mutations in the gene encoding presenilin 1 (PS1) cause the most aggressive form of early-onset familial Alzheimer disease. In addition to its well established role in Abeta production and Notch proteolysis, PS1 has been shown to mediate other physiological activities, such as regulation of the Wnt/beta-catenin signaling pathway, modulation of phosphatidylinositol 3-kinase/Akt and MEK/ERK signaling, and trafficking of select membrane proteins and/or intracellular vesicles. In this study, we present evidence that PS1 is a critical regulator of a key signaling receptor tyrosine kinase, epidermal growth factor receptor (EGFR). Specifically, EGFR levels were robustly increased in fibroblasts deficient in both PS1 and PS2 (PS(-/-)) due to delayed turnover of EGFR protein. Stable transfection of wild-type PS1 but not PS2 corrected EGFR to levels comparable to PS(+/+) cells, while FAD PS1 mutations showed partial loss of activity. The C-terminal fragment of PS1 was sufficient to fully reduce EGFR levels. In addition, the rapid ligand-induced degradation of EGFR was markedly delayed in PS(-/-) cells, resulting in prolonged signal activation. Despite the defective turnover of EGFR, ligand-induced autophosphorylation, ubiquitination, and endocytosis of EGFR were not affected by the lack of PS1. Instead, the trafficking of EGFR from early endosomes to lysosomes was severely delayed by PS1 deficiency. Elevation of EGFR was also seen in brains of adult mice conditionally ablated in PS1 and in skin tumors associated with the loss of PS1. These findings demonstrate a critical role of PS1 in the trafficking and turnover of EGFR and suggest potential pathogenic effects of elevated EGFR as well as perturbed endosomal-lysosomal trafficking in cell cycle control and Alzheimer disease. PMID- 17716971 TI - Differential regulation of vitamin D receptor (VDR) by the p53 Family: p73 dependent induction of VDR upon DNA damage. AB - p63 and p73, members of the p53 family, have been shown to be functionally distinct from p53. Vitamin D receptor (VDR) is a ligand (vitamin D(3))-dependent transcription factor, which is shown to play a major role in calcium homeostasis and keratinocyte differentiation. Vitamin D and its analogues in combination with DNA-damaging agents are extensively used for cancer chemotherapy. In this report, we examined whether p53 affects p63-mediated induction of VDR and studied the effect of DNA damage on VDR induction in p53 null cell lines. Our results demonstrate that p53 itself does not induce VDR expression, nor does it affect p63-mediated VDR induction in the cell lines tested in this study. Furthermore, we observed p53-independent activation of VDR upon DNA damage and associated the induction of VDR to p73. We have demonstrated that ectopic expression of various p73 isoforms can induce VDR expression. Inhibition of p73 in cells treated with DNA-damaging agents exhibited decreased VDR expression. Finally, we show that upon DNA damage, induction of VDR sensitizes the cells to vitamin D treatment. In conclusion, our results indicate that VDR is regulated by p63 and p73 and that the induction of VDR expression upon DNA damage is p73-dependent. PMID- 17716972 TI - Tetraspanin CD151 promotes cell migration by regulating integrin trafficking. AB - Regulation of cell migration is an important feature of tetraspanin CD151. Although it is well established that CD151 physically associates with integrins, the mechanism by which CD151 regulates integrin-dependent cell migration is basically unknown. Given the fact that CD151 is localized in both the plasma membrane and intracellular vesicles, we found that CD151 and its associated alpha3beta1, alpha5beta1, and alpha6beta1 integrins undergo endocytosis and accumulate in the same intracellular vesicular compartments. CD151 contains a YRSL sequence, a YXXvarphi type of endocytosis/sorting motif, in its C-terminal cytoplasmic domain. Mutation of this motif markedly attenuated CD151 internalization. The loss of CD151 trafficking completely abrogated CD151 promoted cell migration on extracellular matrices such as laminin and diminished the internalization of its associated integrins, indicating a critical role for integrin trafficking in regulating cell motility. In conclusion, the YXXvarphi motif-mediated internalization of CD151 promotes integrin-dependent cell migration by modulating the endocytosis and/or vesicular trafficking of its associated integrins. PMID- 17716973 TI - ATP-dependent assembly of the human origin recognition complex. AB - The origin recognition complex (ORC) was initially discovered in budding yeast extracts as a protein complex that binds with high affinity to autonomously replicating sequences in an ATP-dependent manner. We have cloned and expressed the human homologs of the ORC subunits as recombinant proteins. In contrast to other eukaryotic initiators examined thus far, assembly of human ORC in vitro is dependent on ATP binding. Mutations in the ATP-binding sites of Orc4 or Orc5 impair complex assembly, whereas Orc1 ATP binding is not required. Immunofluorescence staining of human cells with anti-Orc3 antibodies demonstrate cell cycle-dependent association with a nuclear structure. Immunoprecipitation experiments show that ORC disassembles as cells progress through S phase. The Orc6 protein binds directly to the Orc3 subunit and interacts as part of ORC in vivo. These data suggest that the assembly and disassembly of ORC in human cells is uniquely regulated and may contribute to restricting DNA replication to once in every cell division cycle. PMID- 17716974 TI - COMP acts as a catalyst in collagen fibrillogenesis. AB - We have previously reported that COMP (cartilage oligomeric matrix protein) is prominent in cartilage but is also present in tendon and binds to collagens I and II with high affinity. Here we show that COMP influences the fibril formation of these collagens. Fibril formation in the presence of pentameric COMP was much faster, and the amount of collagen in fibrillar form was markedly increased. Monomeric COMP, lacking the N-terminal coiled-coil linker domain, decelerated fibrillogenesis. The data show that stimulation of collagen fibrillogenesis depends on the pentameric nature of COMP and not only on collagen binding. COMP interacts primarily with free collagen I and II molecules, bringing several molecules to close proximity, apparently promoting further assembly. These assemblies further join in discrete steps to a narrow distribution of completed fibril diameters of 149 +/- 16 nm with a banding pattern of 67 nm. COMP is not found associated with the mature fibril and dissociates from the collagen molecules or their early assemblies. However, a few COMP molecules are found bound to more loosely associated molecules at the tip/end of the growing fibril. Thus, COMP appears to catalyze the fibril formation by promoting early association of collagen molecules leading to increased rate of fibrillogenesis and more distinct organization of the fibrils. PMID- 17716975 TI - ATR pathway is the primary pathway for activating G2/M checkpoint induction after re-replication. AB - DNA replication is tightly controlled to ensure accurate chromosome duplication and segregation in each cell cycle. Inactivation of Geminin, an inhibitor of origin licensing, leads to re-replication in human tumor cells within the same cell cycle and triggers a G(2)/M checkpoint. We find that the primary pathway to signal that re-replication has been detected is the ATR kinase and the Rad9-Rad1 Hus1 (9-1-1) clamp complex together with Rad17-RFC clamp loader. ATM kinase and the Mre11-Rad50-Nbs1 complex do not appear to play significant roles in the checkpoint. Chk1 activation occurs at early stages, whereas Chk2 activation occurs much later. Overall we conclude that ATR/Chk1 pathway is activated at an early time point after the loss of Geminin and contributes to checkpoint arrest essential for the accumulation of re-replicated cells, whereas activation of the ATM/Chk2 pathway is a by-product of DNA re-replication at a later period. PMID- 17716976 TI - N-terminal extension of N-methylpurine DNA glycosylase is required for turnover in hypoxanthine excision reaction. AB - N-Methylpurine DNA glycosylase (MPG) initiates base excision repair in DNA by removing a wide variety of alkylated, deaminated, and lipid peroxidation-induced purine adducts. In this study we tested the role of N-terminal extension on MPG hypoxanthine (Hx) cleavage activity. Our results showed that MPG lacking N terminal extension excises hypoxanthine with significantly reduced efficiency, one-third of that exhibited by full-length MPG under similar conditions. Steady state kinetics showed full-length MPG has higher V(max) and lower K(m) than NDelta100 MPG. Real time binding experiments by surface plasmon resonance spectroscopy suggested that truncation can substantially increase the equilibrium binding constant of MPG toward Hx, but under single-turnover conditions there is apparently no effect on catalytic chemistry; however, the truncation of the N terminal tail affected the turnover of the enzyme significantly under multiple turnover conditions. Real time binding experiments by surface plasmon resonance spectroscopy further showed that NDelta100 MPG binds approximately six times more tightly toward its product apurinic/apyrimidinic site than the substrate, whereas full-length MPG similarly binds to both the substrate and the product. We thereby conclude that the N-terminal tail in MPG plays a critical role in overcoming the product inhibition, which is achieved by reducing the differences of MPG binding affinity toward Hx and apurinic/apyrimidinic sites and thus is essential for the Hx cleavage reaction of MPG. The results from this study also affirm the need for reinvestigation of full-length MPG for its enzymatic and structural properties, which are currently available mostly for the truncated protein. PMID- 17716977 TI - The diaphanous inhibitory domain/diaphanous autoregulatory domain interaction is able to mediate heterodimerization between mDia1 and mDia2. AB - Formins are multidomain proteins that regulate numerous cytoskeleton-dependent cellular processes. These effects are mediated by the presence of two regions of homology, formin homology 1 and FH2. The diaphanous-related formins (DRFs) are distinguished by the presence of interacting N- and C-terminal regulatory domains. The GTPase binding domain and diaphanous inhibitory domain (DID) are found in the N terminus and bind to the diaphanous autoregulatory domain (DAD) found in the C terminus. Adjacent to the DID is an N-terminal dimerization motif (DD) and coiled-coil region (CC). The N terminus of Dia1 is also proposed to contain a Rho-independent membrane-targeting motif. We undertook an extensive structure/function analysis of the mDia1 N terminus to further our understanding of its role in vivo. We show here that both DID and DD are required for efficient autoinhibition in the context of full-length mDia1 and that the DD of mDia1 and mDia2, like formin homology 2, mediates homo- but not heterodimerization with other DRF family members. In contrast, our results suggest that the DID/DAD interaction mediates heterodimerization of full-length mDia1 and mDia2 and that the auto-inhibited conformation of DRFs is oligomeric. In addition, we also show that the DD/CC region is required for the Rho-independent membrane targeting of the isolated N terminus. PMID- 17716978 TI - Tamoxifen induction of CCAAT enhancer-binding protein alpha is required for tamoxifen-induced apoptosis. AB - Low concentrations of tamoxifen or its active metabolite 4-hydroxytamoxifen (OHT) induce estrogen receptor alpha (ERalpha)-dependent apoptosis. To analyze the pathway of OHT-ERalpha-induced apoptosis, we developed stably transfected lines of HeLa cells expressing wild-type ER and an inactive mutant ERalpha unable to bind estrogen response elements. HeLa cells expressing the mutant ERalpha and HeLa cells expressing wild-type ERalpha in which the ER was knocked down with an ER-specific small interfering RNA were not killed by Tam or OHT, suggesting that estrogen response element-mediated transcription is required for Tam- and OHT induced apoptosis. Microarray analysis to identify a gene(s) whose expression is important in OHT-ER-mediated apoptosis identified 19 mRNAs that OHT up-regulated by >1.6-fold and 15 down-regulated mRNAs. Gene function and the time course of induction by OHT-ERalpha led us to further investigate CCAAT enhancer-binding protein alpha (C/EBPalpha), which has roles in cell cycle progression and apoptosis, and p21. Quantitative reverse transcription-PCR, Western blot analysis, and RNA interference knockdown suggest that cell cycle arrest resulting from OHT-ERalpha induction of p21 may facilitate apoptosis. OHT-ERalpha, but not E2-ERalpha, induced C/EBPalpha mRNA and protein. RNA interference knockdown of C/EBPalpha nearly abolished OHT-ERalpha-induced apoptosis. We isolated stable cell lines that were resistant to OHT-induced apoptosis, contain full-length functional ERalpha, and undergo apoptosis in response to etoposide. In these OHT resistant cell lines both before and after OHT treatment, C/EBPalpha levels are much lower than in OHT-sensitive cells. These studies establish a novel molecular site responsible for Tam- and OHT-ERalpha-induced apoptosis of cancer cells. PMID- 17716979 TI - Characterization of interactions of adapter protein RAPL/Nore1B with RAP GTPases and their role in T cell migration. AB - Using a model of integrin-triggered random migration of T cells, we show that stimulation of LFA-1 integrins leads to the activation of Rap1 and Rap2 small GTPases. We further show that Rap1 and Rap2 have distinct roles in adhesion and random migration of these cells and that an adapter protein from the Ras association domain family (Rassf), RAPL, has a role downstream of Rap2 in addition to its link to Rap1. Further characterization of the RAPL protein and its interactions with small GTPases from the Ras family shows that RAPL forms more stable complexes with Rap2 and classical Ras proteins compared with Rap1. The different interaction pattern of RAPL with Rap1 and Rap2 is not affected by the disruption of the C-terminal SARAH domain that we identified as the alpha helical region responsible for RAPL dimerization in vitro and in cells. Based on mutagenesis and three-dimensional modeling, we propose that interaction surfaces in RAPL-Rap1 and RAPL-Rap2 complexes are different and that a single residue in the switch I region of Rap proteins (residue 39) contributes considerably to the different kinetics of these protein-protein interactions. Furthermore, the distinct role of Rap2 in migration of T cells is lost when this critical residue is converted to the residue present in Rap1. Together, these observations suggest a wider role for Rassf adapter protein RAPL and Rap GTPases in cell motility and show that subtle differences between highly similar Rap proteins could be reflected in distinct interactions with common effectors and their cellular function. PMID- 17716980 TI - Stress hormones regulate interleukin-6 expression by human ovarian carcinoma cells through a Src-dependent mechanism. AB - Recent studies have demonstrated that chronic stress promotes tumor growth, angiogenesis, and metastasis. In ovarian cancer, levels of the pro-angiogenic cytokine, interleukin 6 (IL-6), are known to be elevated in individuals experiencing chronic stress, but the mechanism(s) by which this cytokine is regulated and its role in tumor growth remain under investigation. Here we show that stress hormones such as norepinephrine lead to increased expression of IL-6 mRNA and protein levels in ovarian carcinoma cells. Furthermore, we demonstrate that norepinephrine stimulation activates Src tyrosine kinase and this activation is required for increased IL-6 expression. These results demonstrate that stress hormones activate signaling pathways known to be critical in ovarian tumor progression. PMID- 17716981 TI - Association between plasma 25-hydroxyvitamin D levels and fracture risk: the EPIC Oxford study. AB - The importance of vitamin D for bone health is well established, but few data exist on the relation between plasma levels of 25-hydroxyvitamin D and risk of fracture. The authors examined this association within the EPIC-Oxford (European Prospective Investigation into Cancer and Nutrition-Oxford cohort) study of men and women in the United Kingdom (1993-1999). Five years after recruitment, participants completed a follow-up questionnaire where fracture incidence was self-reported. Plasma 25-hydroxyvitamin D concentration was measured in 730 incident fracture cases and 1,445 matched controls. There was a clear association between plasma 25-hydroxyvitamin D concentration and month of blood draw, the highest values being during the summer months. Among women, there were significant relations between 25-hydroxyvitamin D levels and age, body mass index, marital status, use of hormone therapy, physical activity, diet group, dietary intake of vitamin D, and alcohol. Similar relations were seen among men, although often they were nonsignificant because of smaller numbers. There was no evidence of an association between plasma 25-hydroxyvitamin D and fracture risk for men or women; the relative risks associated with a doubling of plasma 25 hydroxyvitamin D were 1.15 (95% confidence interval: 0.82, 1.61) and 0.95 (95% confidence interval: 0.80, 1.13), respectively. These results were not affected by adjustment for potential confounders and were consistent across a number of subgroups. PMID- 17716982 TI - Predictors of psychostimulant use by long-distance truck drivers. AB - Two national cross-sectional surveys of fatigue and its effects in long-distance road transport in Australia showed that stimulant use was a common feature of this industry. Between one in five and one in three drivers reported using stimulants at least sometimes, and a significant proportion reported stimulant use as a most helpful fatigue management strategy. This study reanalyzed the surveys with the aim of identifying predictors of stimulant drug use by drivers. The surveys were administered in 1991 (n = 970) and 1998 (n = 1,007) by interview and self-administration. Logistic regression analysis conducted separately for each survey showed that stimulant drug use was twice as likely for drivers who had the greatest problem in managing fatigue and was two to three times more likely for drivers paid on a payment-by-results or contingency-payment basis. Younger, less experienced drivers were also more likely to take drugs. This analysis demonstrates the involvement of external factors, especially productivity-based payment systems, in stimulant drug use by truck drivers; findings were confirmed in two separate surveys conducted 7 years apart. Results highlight the important role of economic and organizational factors in occupational health and safety problems. PMID- 17716983 TI - 32P-Post-labelling method improvements for aromatic compound-related molecular epidemiology studies. AB - The (32)P-post-labelling assay has emerged as a major tool for detecting bulky DNA adducts in subjects exposed to carcinogens, especially aromatic compounds. However, the (32)P-post-labelling protocol still requires the use of high amounts of radioactivity, i.e. 25-50 muCi per sample, an obstacle that limits its use in large studies. The characterization of the DNA adducts measured is also limited. Methodological improvements and increased DNA adduct characterization are necessary to make this assay capable of achieving higher throughput. A new protocol was tested to ensure efficient hydrolysis to reduce the use of radioactive material and to obtain higher chromatography resolution. Different chromatography systems based on high-urea or ammonium hydroxide systems were also employed to characterize the adducts being measured. Improvements were tested by re-analysing DNA adducts in a group of police officers and urban residents in Genoa, Italy. The analysis of carcinogen-modified DNA standards was also included in the study for qualitative and quantitative comparison. An efficient DNA digestion was obtained using a method involving hydrolysis by micrococcal nuclease and a mixture of two spleen phosphodiesterases at fixed concentrations. A 72% reduction of the amount of radioactivity used for labelling was achieved in respect to the non-modified protocol without loss of DNA adduct sensitivity. An improved chromatography resolution was obtained by reducing the volume of sample to be spotted on the chromatogram. Lower volume of spotting sample can decrease sample diffusion and the formation of unresolved spots on the thin-layer chromatography plate. The amount of output produced using a single batch of carrier-free [gamma-(32)P]ATP was increased by about 3.5-fold. A complex pattern of DNA adducts was observed in leukocytes using both high-urea or isopropanol ammonium hydroxide systems, two techniques effective in the detection of aromatic DNA adducts. The above observations indicate that DNA adducts being measured are likely to have been induced by aromatic compounds. PMID- 17716984 TI - A dose escalation trial of adjuvant cyclophosphamide and epirubicin in combination with 5-fluorouracil using G-CSF support for premenopausal women with breast cancer involving four or more positive nodes. AB - BACKGROUND: Dose-dense and dose-intensive regimens have improved the outcome of breast cancer in high-risk women with operable disease. PATIENTS AND METHODS: Sixty-three premenopausal women with Stage 2, 3 breast cancer and > or =4 positive axillary nodes were treated in three successive cohorts with 70 mg/m(2) of epirubicin, 500 mg/m(2) of 5-fluorouracil and G-CSF every 14 days for 12 cycles. Cyclophosphamide (C) was given at 700 mg/m(2), 900 mg/m(2), and 1100 mg/m(2) doses. Patients were evaluated for dose-limiting toxicities (DLTs) in the first four cycles, the primary endpoint of the trial. RESULTS: No DLTs were seen at C 700 mg/m(2); at C 900 mg/m(2) two of 16 patients experienced febrile neutropenia and poor performance status; at C 1100 mg/m(2), 1 of 31 patients experienced poor performance status. Over 6 months, febrile neutropenia, grade 4 thrombocytopenia, grade 3 anemia and severe fatigue were observed. Clinical congestive heart failure occurred in three patients over 4 years. CONCLUSION: A dose-intense and dose-dense regimen of cyclophosphamide, epirubicin and 5 fluorouracil was delivered with G-CSF without apparent increase in acute toxicity. Cyclophosphamide could be increased to more than twice the standard dose at the cost of more anemia and fatigue. PMID- 17716985 TI - Combined 18F-fluorodeoxyglucose-positron emission tomography and computed tomography as a primary screening method for detecting second primary cancers and distant metastases in patients with head and neck cancer. AB - BACKGROUND: The aim of this study was to evaluate the ability of (18)F fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) to detect second primary cancers and distant metastases in patients with head and neck cancer (HNC). PATIENTS AND METHODS: Patients with previous untreated HNC, between 2004 and 2005, underwent head and neck CT and whole-body FDG-PET/CT, before and at fixed intervals after therapy, for staging and detection of second primary cancers and distant metastases. Patients with malignant or equivocal findings on FDG-PET/CT underwent further imaging, endoscopy and/or biopsy. RESULTS: Of the 349 eligible patients (267 men and 82 women), 14 (4.0%) had second primary cancers and 26 (7.4%) had distant metastases at initial staging or during mean follow-up of 15 months after treatment. FDG-PET/CT correctly identified second cancers or distant metastases in 39 of these 40 patients; there was one false negative and 23 false positive FDG-PET/CT results. Therefore, FDG PET/CT had a sensitivity of 97.5%, a specificity of 92.6%, a positive predictive value of 62.9% and a negative predictive value of 99.7% in detecting second primary cancers and distant metastases. CONCLUSION: Combined FDG-PET/CT is useful as a primary method for detecting second cancers and distant metastases in patients with HNC. PMID- 17716986 TI - Prognostic role of the extent of peritumoral vascular invasion in operable breast cancer. AB - BACKGROUND: The clinical relevance of the degree of peritumoral vascular invasion (PVI) in patients with no or limited involvement of the axillary nodes is unknown. MATERIALS AND METHODS: 2606 consecutive patients with pT1-3, pN0 (1586) 1a (1020) and M0, operated and counseled for medical therapy from 1/2000 to 12/2002, were prospectively classified according to the degree of PVI: absent (2017, 77.4%), focal (368, 14.1%), moderate (51, 2.0%) and extensive (170, 6.5%). RESULTS: Patients with extensive PVI were more likely to be younger, to have larger tumors, high tumor grade, axillary-positive nodes, high Ki-67 expression and HER2/neu over-expression compared with patients having less PVI (P for trend, <0.0001). In patients with node-negative disease a statistically significant difference in disease-free survival (DFS), risk of distant metastases and overall survival (OS) was observed at the multivariate analysis for extensive PVI versus no PVI (hazard ratios: 2.11, 95% CI, 1.02 to 4.34, P = 0.04 for DFS; 4.51, 95% CI, 1.96 to 10.4, P< 0.001 for distant metastases; 3.55, 95% CI, 1.24 to 10.1, P = 0.02 for OS). CONCLUSIONS: The extent of vascular invasion should be considered in the therapeutic algorithm in order to properly select targeted adjuvant treatment. PMID- 17716987 TI - FDG-PET in T-cell and NK-cell neoplasms. AB - BACKGROUND: A growing number of studies demonstrate the utility of (18)fluoro-2 deoxyglucose positron emission tomography (FDG-PET) in the management of malignant lymphoma. The results of FDG-PET, however, have not been studied extensively for T-cell and natural killer (NK)-cell neoplasms. PATIENTS AND METHODS: We retrospectively evaluated pretreatment FDG-PET scans in 41 patients with T/NK-cell neoplasms diagnosed according to the World Health Organization (WHO) classification. Histological subtypes frequently included were peripheral T cell lymphoma, unspecified (PTCLu, n = 11), extranodal NK/T-cell lymphoma, nasal type (ENKL, n = 8), primary cutaneous anaplastic large cell lymphoma (C-ALCL, n = 5), and angioimmunoblastic T-cell lymphoma (AILT, n = 4). RESULTS: FDG-PET detected a lymphoma lesion in at least one site in 36 out of 41 patients. The positive rate was equally high in most histological subtypes except for cutaneous lymphomas: PTCLu 91%, ENKL 100%, C-ALCL 60%, AILT 100%. All the patients without an FDG-avid lesion had lesions restricted to skin. Among patients who had cutaneous lesions, only 50% had FDG-avid cutaneous lesions, all of which were tumorous. The positive rate of FDG-PET for bone marrow involvement was only 20%. CONCLUSION: T/NK-cell neoplasms incorporated in this study were generally FDG avid except for cutaneous lesions and bone marrow involvement. PMID- 17716988 TI - Involvement of the cerebellar dorsal vermis in vergence eye movements in monkeys. AB - Frontal-eyed primates use both smooth pursuit in frontoparallel planes (frontal pursuit) and pursuit-in-depth (vergence pursuit) to track objects moving slowly in 3-dimensional (3D) space. To understand how 3D-pursuit signals represented in frontal eye fields are processed further by downstream pathways, monkeys were trained to pursue a spot moving in 3D virtual space. We characterized pursuit signals in Purkinje (P) cells in the cerebellar dorsal vermis and their discharge during vergence pursuit. In 41% of pursuit P-cells, 3D-pursuit signals were observed. However, the majority of vermal-pursuit P-cells (59%) discharged either for vergence pursuit (43%) or for frontal pursuit (16%). Moreover, the majority (74%) of vergence-related P-cells carried convergence signals, displaying both vergence eye position and velocity sensitivity during sinusoidal and step vergence eye movements. Preferred frontal-pursuit directions of vergence + frontal-pursuit P-cells were distributed in all directions. Most pursuit P-cells (73%) discharged before the onset of vergence eye movements; the median lead time was 16 ms. Muscimol infusion into the sites where convergence P-cells were recorded resulted in a reduction of peak convergence eye velocity, of initial convergence eye acceleration, and of frontal-pursuit eye velocity. These results suggest involvement of the dorsal vermis in conversion of 3D-pursuit signals and in convergence eye movements. PMID- 17716989 TI - Tracking the temporal dynamics of updating cognitive control: an examination of error processing. AB - In 2 experiments, we used event-related brain potentials (ERPs) to examine the temporal dynamics of neural processes related to adjustments of cognitive control following errors in the counting Stroop task. The ERPs elicited by errors revealed the error-related negativity (ERN) and error positivity consistent with a large body of literature. In addition, errors were associated with a frontal slow wave between 200 and 2000 ms after the response that was consistent with the activity of neural generators in the lateral frontal cortex. The ERN and frontal slow wave were correlated with posterror slowing of response time and positive affect (i.e., happiness and calmness) during task performance. These data are consistent with the idea that interactions between anterior cingulate cortex and lateral frontal cortex support adjustments of cognitive control and that this neural network is sensitive to the influence of affect experienced during task performance. PMID- 17716990 TI - Spatio temporal dynamics of face recognition. AB - To better understand face recognition, it is necessary to identify not only which brain structures are implicated but also the dynamics of the neuronal activity in these structures. Latencies can then be compared to unravel the temporal dynamics of information processing at the distributed network level. To achieve high spatial and temporal resolution, we used intracerebral recordings in epileptic subjects while they performed a famous/unfamiliar face recognition task. The first components peaked at 110 ms in the fusiform gyrus (FG) and simultaneously in the inferior frontal gyrus, suggesting the early establishment of a large scale network. This was followed by components peaking at 160 ms in 2 areas along the FG. Important stages of distributed parallel processes ensued at 240 and 360 ms involving up to 6 regions along the ventral visual pathway. The final components peaked at 480 ms in the hippocampus. These stages largely overlapped. Importantly, event-related potentials to famous faces differed from unfamiliar faces and control stimuli in all medial temporal lobe structures. The network was bilateral but more right sided. Thus, recognition of famous faces takes place through the establishment of a complex set of local and distributed processes that interact dynamically and may be an emergent property of these interactions. PMID- 17716991 TI - Prediction of left atrial appendage thrombi in non-valvular atrial fibrillation. AB - AIMS: There is little knowledge about the predictors of left atrial appendage (LAA) thrombi in non-valvular atrial fibrillation (NVAF). We investigated the ability of D-dimer to predict LAA thrombi. METHODS AND RESULTS: In this study, 925 patients with NVAF were enrolled. At the time of transoesophageal echocardiography (TEE), D-dimer levels were measured simultaneously. Significant independent predictors of LAA thrombi were the presence of congestive heart failure [odds ratio (OR) 3.10, 95% confidence interval (CI) 1.77-5.50, P < 0.0001), a history of recent embolic events (OR 3.39, 95% CI 1.90-6.04, P < 0.0001), and D-dimer levels (OR 97.6, 95% CI 17.3-595.8, P < 0.0001). Receiver operating characteristic analysis yielded an optimal cutoff value of 1.15 microg/mL for D-dimer to detect LAA thrombi. LAA thrombi were detected in 21.8% of patients with higher D-dimer values, whereas it was detected in only 3.1% of patients with lower D-dimer values. D-dimer cutoff level of 1.15 microg/mL had a negative predictive value of 97% for identifying LAA thrombi. CONCLUSION: In patients with NVAF, D-dimer may be helpful for predicting the absence of LAA thrombi. D-dimer level was clinically useful to guide the management of patients with NVAF, especially for those complicated with congestive heart failure and/or recent embolic events. PMID- 17716992 TI - D-dimers in atrial fibrillation: a further step in risk stratification of thrombo embolism? PMID- 17716993 TI - Restoration of the balanced alpha/beta-globin gene expression in beta654 thalassemia mice using combined RNAi and antisense RNA approach. AB - The beta-thalassemia is associated with abnormality in beta-globin gene, leading to imbalanced synthesis of alpha-/beta-globin chains. Consequently, the excessive free alpha-globin chains precipitate to the erythrocyte membrane, resulting in hemolytic anemia. We have explored post-transcriptional strategies aiming at alpha-globin reduction and beta-globin enrichment on beta(654) (Hbb(th-4)/Hbb(+)) mouse, carrying a human splicing-deficient beta-globin allele (Hbb(th-4)). Lentiviral vectors of short hairpin RNA (shRNA) targeting alpha-globin and/or antisense RNA facilitating beta-globin correct splicing were microinjected into beta(654) single-cell embryos. Three transgenic strains were generated, as alpha(i)-Hbb(th-4)/Hbb(+)(shRNA), beta(a)-Hbb(th-4)/Hbb(+)(antisense) and alpha(i)beta(a)-Hbb(th-4)/Hbb(+)(both shRNA and antisense). Without notable abnormalities, all the founders and their offsprings showed sustained amelioration of hematologic parameters, ineffective erythropoiesis and extramedullary hematopoiesis. Augmented effects appeared in alpha(i)beta(a) Hbb(th-4)/Hbb(+), which correlated with a better-balanced alpha-/beta-globin mRNA level. Among the transgenic mice integrated with shRNA and antisense RNA, one homozygous mouse (Hbb(th-4)/Hbb(th-4)) had been viable, and the 3-week survival rate for heterozygotes (Hbb(th-4)/Hbb(+)) was 97%, compared with 45.4% for untreated. Our data have demonstrated the feasibility of techniques for beta thalassemia therapy by balancing the synthesis of alpha-/beta-globin chains. PMID- 17716994 TI - Colorectal polypectomy and risk of colorectal cancer by subsite: the Fukuoka Colorectal Cancer study. AB - BACKGROUND: Colorectal adenomas are well-established precursor lesions for colorectal cancer and removal of polyps is deemed to reduce the risk of colorectal cancer. However, benefit of colorectal polypectomy in routine practice is still uncertain. We therefore investigated subsite-specific risks of colorectal cancer in relation to history of colorectal polypectomy in a case control study. METHODS: Both case patients and control subjects were residents aged 20-74 years in Fukuoka City and three adjacent areas. The case group comprised 840 patients undergoing surgery for a first diagnosis of colorectal cancer, while the control subjects were 833 residents who were selected in the community by two-stage random sampling. Past history of selected diseases, surgery and lifestyle factors were ascertained by in-person interview. Statistical adjustment was made for sex, 5-year age class, residence, smoking, alcohol drinking, physical activity, body mass index and parental history of colorectal cancer. RESULTS: Overall, 74 case patients (9%) and 85 control subjects (10%) reported a prior history of colorectal polyps, and 50 cases (6%) and 64 controls (8%) had a history of colorectal polypectomy. The adjusted odds ratio associated with colorectal polypectomy was 0.71 (95% confidence interval [CI] 0.48-1.06) for the overall risk of colorectal cancer. The corresponding values for cancer of the proximal colon, distal colon, and rectum were 1.68 (95% CI 0.98-2.88), 0.71 (95% CI 0.41-1.26) and 0.24 (95% CI 0.11-0.52), respectively. CONCLUSIONS: The findings indicate that colorectal polypectomy in current practice confers a decreased risk of rectal cancer and possibly of distal colon cancer. PMID- 17716995 TI - Chronic lymphatico-venous bypass: surgical technique and aftercare in a porcine model. AB - We describe a chronic model of lymphatico-venous bypass in pigs with emphasis to surgical considerations, major per- and postoperative complications. A catheter (silicone or heparin coated polyurethane) was inserted in the thoracic duct of nine pigs via a right intercostal thoracotomy. A second catheter was surgically inserted in the jugular vein and the bypass was secured on the back of the animals. Pigs were monitored for capnography, end-tidal carbon dioxide, systolic, diastolic and mean blood pressure, heart rate, and rectal temperature. Apnea was recorded in every pig in the recovery period leading to one death. During the postoperative period, ventricular tachycardia in 2/9 pigs and hypothermia in 5/9 pigs were recorded. Bypass was effective in 5/9 pigs. Clotting occurred only with silicone catheters (1/2) but not with heparin-coated catheters. In the heparin coated catheters group, bypass was patent up to 15 days with no major complication recorded. Sampling of lymph was allowed from 2 to 15 days. The immediate postoperative period is critical and should be carefully monitored. Although complications were present, the surgical technique was efficient. Chronic catheterization of thoracic duct is useful in biomedical research in the fields of intensive care, gastro-enterology, pharmacokinetic and hematology studies. PMID- 17716996 TI - Disease resistance against Magnaporthe grisea is enhanced in transgenic rice with suppression of omega-3 fatty acid desaturases. AB - Linolenic acid (18:3) is the most abundant fatty acid in plant membrane lipids and is a source for various oxidized metabolites, called oxylipins. 18:3 and oxylipins play important roles in the induction of defense responses to pathogen infection and wound stress in Arabidopsis. However, in rice, endogenous roles for 18:3 and oxylipins in disease resistance have not been confirmed. We generated 18:3-deficient transgenic rice plants (F78Ri) with co-suppression of two omega-3 fatty acid desaturases, OsFAD7 and OsFAD8. that synthesize 18:3. The F78Ri plants showed enhanced resistance to the phytopathogenic fungus Magnaporthe grisea. A typical 18:3-derived oxylipin, jasmonic acid (JA), acts as a signaling molecule in defense responses to fungal infection in Arabidopsis. However, in F78Ri plants, the expression of JA-responsive pathogenesis-related genes, PBZ1 and PR1b, was induced after inoculation with M. grisea, although the JA-mediated wound response was suppressed. Furthermore, the application of JA methyl ester had no significant effect on the enhanced resistance in F78Ri plants. Taken together, our results indicate that, although suppression of fatty acid desaturases involves the concerted action of varied oxylipins via diverse metabolic pathways, 18:3 or 18:3-derived oxylipins, except for JA, may contribute to signaling on defense responses of rice to M. grisea infection. PMID- 17716998 TI - Public health ethics in Europe--let ethicists enter the public health debate. PMID- 17716997 TI - Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis. AB - The occurrence of endoplasmic reticulum (ER) stress in the sporadic form of amyotrophic lateral sclerosis (ALS) is unknown, despite it has been recently documented in experimental models of the familial form. Here we show that spinal cord from patients with sporadic ALS showed signs of ER stress, such as increased levels of ER chaperones such as protein-disulfide isomerase, and increased phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha). Among the potential causes of such ER stress proteasomal impairment was confirmed in the same samples by demonstrating increased ubiquitin immunoreactivity and increased protein lipoxidative (125%), glycoxidative (55%) and direct oxidative damage (62%) over control values, as evidenced by mass-spectrometry and immunological methods. We found that protein oxidative damage was strongly associated to ALS specific changes in fatty acid concentrations, specifically of n-3 series (as docosahexaenoic acid), and in the amount of mitochondrial components as respiratory complexes I and III, suggesting a mitochondrial dysfunction leading to increased free radical production. Oxidative stress was also evidenced in frontal cortex, suggesting that this region is affected early in ALS. As those events were partially reproduced by threohydroxyaspartate exposure in organotypic spinal cord cultures, we concluded that changes in fatty acid composition, mitochondrial function and proteasome activity, which may be driven by excitotoxicity, lead to oxidative stress and finally contribute to ER stress in sporadic ALS. PMID- 17716999 TI - The tetraplex (CGG)n destabilizing proteins hnRNP A2 and CBF-A enhance the in vivo translation of fragile X premutation mRNA. AB - Expansion of a (CGG)n sequence in the 5'-UTR of the FMR1 gene to >200-2000 repeats abolishes its transcription and initiates fragile X syndrome (FXS). By contrast, levels of FMR1 mRNA are 5-10-fold higher in FXS premutation carriers of >55-200 repeats than in normal subjects. Lack of a corresponding increase in the amount of the product FMRP protein in carrier cells suggest that (CGG)>55-200 tracts thwart translation. Here we report that a (CGG)99 sequence positioned upstream to reporter firefly (FL) gene selectively diminished mRNA translation in coupled and separate T7 promoter-driven in vitro transcription and translation systems. The (CGG)99 tract similarly depressed mRNA utilization in HEK293 human cells transfected with plasmids bearing FMR1 promoter-driven FL gene. A (CGG)33 RNA tract formed a largely RNase T1-resistant intramolecular secondary structure in the presence of K+ ions. Expression of the quadruplex (CGG)n disrupting proteins hnRNP A2 or CBF-A in HEK293 cells significantly elevated the efficacy of (CGG)99 FL mRNA translation whereas hnRNP A2 or CBF-A mutants lacking quadruplex (CGG)n disrupting activity did not. Taken together, our results suggest that secondary structures of (CGG)n in mRNA obstruct its translation and that quadruplex-disrupting proteins alleviate the translational block. PMID- 17717000 TI - Low rate of replication fork progression lengthens the replication timing of a locus containing an early firing origin. AB - Invariance of temporal order of genome replication in eukaryotic cells and its correlation with gene activity has been well-documented. However, recent data suggest a relax control of replication timing. To evaluate replication schedule accuracy, we detailed the replicational organization of the developmentally regulated php locus that we previously found to be lately replicated, even though php gene is highly transcribed in naturally synchronous plasmodia of Physarum. Unexpectedly, bi-dimensional agarose gel electrophoreses of DNA samples prepared at specific time points of S phase showed that replication of the locus actually begins at the onset of S phase but it proceeds through the first half of S phase, so that complete replication of php-containing DNA fragments occurs in late S phase. Origin mapping located replication initiation upstream php coding region. This proximity and rapid fork progression through the coding region result in an early replication of php gene. We demonstrated that afterwards an unusually low fork rate and unidirectional fork pausing prolong complete replication of php locus, and we excluded random replication timing. Importantly, we evidenced that the origin linked to php gene in plasmodium is not fired in amoebae when php expression dramatically reduced, further illustrating replication-transcription coupling in Physarum. PMID- 17717001 TI - Single-stranded DNA ligation and XLF-stimulated incompatible DNA end ligation by the XRCC4-DNA ligase IV complex: influence of terminal DNA sequence. AB - The double-strand DNA break repair pathway, non-homologous DNA end joining (NHEJ), is distinctive for the flexibility of its nuclease, polymerase and ligase activities. Here we find that the joining of ends by XRCC4-ligase IV is markedly influenced by the terminal sequence, and a steric hindrance model can account for this. XLF (Cernunnos) stimulates the joining of both incompatible DNA ends and compatible DNA ends at physiologic concentrations of Mg2+, but only of incompatible DNA ends at higher concentrations of Mg2+, suggesting charge neutralization between the two DNA ends within the ligase complex. XRCC4-DNA ligase IV has the distinctive ability to ligate poly-dT single-stranded DNA and long dT overhangs in a Ku- and XLF-independent manner, but not other homopolymeric DNA. The dT preference of the ligase is interesting given the sequence bias of the NHEJ polymerase. These distinctive properties of the XRCC4 DNA ligase IV complex explain important aspects of its in vivo roles. PMID- 17717002 TI - Selection for efficient translation initiation biases codon usage at second amino acid position in secretory proteins. AB - The definition of a typical sec-dependent bacterial signal peptide contains a positive charge at the N-terminus, thought to be required for membrane association. In this study the amino acid distribution of all Escherichia coli secretory proteins were analysed. This revealed that there was a statistically significant bias for lysine at the second codon position (P2), consistent with a role for the positive charge in secretion. Removal of the positively charged residue P2 in two different model systems revealed that a positive charge is not required for protein export. A well-characterized feature of large amino acids like lysine at P2 is inhibition of N-terminal methionine removal by methionyl amino-peptidase (MAP). Substitution of lysine at P2 for other large or small amino acids did not affect protein export. Analysis of codon usage revealed that there was a bias for the AAA lysine codon at P2, suggesting that a non-coding function for the AAA codon may be responsible for the strong bias for lysine at P2 of secretory signal sequences. We conclude that the selection for high translation initiation efficiency maybe the selective pressure that has led to codon and consequent amino acid usage at P2 of secretory proteins. PMID- 17717004 TI - Maternal parenting style and adjustment in adolescents with type I diabetes. AB - OBJECTIVE: To investigate the cross-sectional relationship between maternal parenting style and indicators of well-being among adolescents with diabetes. METHODS: Seventy-eight adolescents (ages 11.58-17.42 years, M = 14.21) with type 1 diabetes and their mothers separately reported perceptions of maternal parenting style. Adolescents reported their own depressed mood, self-efficacy for managing diabetes, and diabetes regimen adherence. RESULTS: Adolescents' perceptions of maternal psychological control were associated with greater depressed mood regardless of age and gender. Firm control was strongly associated with greater depressed mood and poorer self-efficacy among older adolescents, less strongly among younger adolescents. Adolescents' perceptions of maternal acceptance were associated with less depressed mood, particularly for girls and with better self-efficacy for diabetes management, particularly for older adolescents and girls. Maternal reports of acceptance were associated only with adherence. CONCLUSIONS: Maternal parenting style is associated with well-being in adolescents with diabetes, but this association is complex and moderated by age and gender. PMID- 17717003 TI - Replication fork regression in vitro by the Werner syndrome protein (WRN): holliday junction formation, the effect of leading arm structure and a potential role for WRN exonuclease activity. AB - The premature aging and cancer-prone disease Werner syndrome stems from loss of WRN protein function. WRN deficiency causes replication abnormalities, sensitivity to certain genotoxic agents, genomic instability and early replicative senescence in primary fibroblasts. As a RecQ helicase family member, WRN is a DNA-dependent ATPase and unwinding enzyme, but also possesses strand annealing and exonuclease activities. RecQ helicases are postulated to participate in pathways responding to replication blockage, pathways possibly initiated by fork regression. In this study, a series of model replication fork substrates were used to examine the fork regression capability of WRN. Our results demonstrate that WRN catalyzes fork regression and Holliday junction formation. This process is an ATP-dependent reaction that is particularly efficient on forks containing single-stranded gaps of at least 11-13 nt on the leading arm at the fork junction. Importantly, WRN exonuclease activity, by digesting the leading daughter strand, enhances regression of forks with smaller gaps on the leading arm, thus creating an optimal structure for regression. Our results suggest that the multiple activities of WRN cooperate to promote replication fork regression. These findings, along with the established cellular consequences of WRN deficiency, strongly support a role for WRN in regression of blocked replication forks. PMID- 17717005 TI - The role of parental coping in children with asthma's psychological well-being and asthma-related quality of life. AB - OBJECTIVE: The primary purpose of our study was to examine the relationship between parental coping and children with asthma's psychological well-being and asthma-related quality of life (ArQL). METHODS: Eighty-nine mother-child dyads with a child with asthma ranging in age from 8 to 12-years old participated. During baseline and 6 month follow-up visits, children completed questionnaires assessing anxiety and ArQL; mothers completed questionnaires assessing coping, ArQL, an index of recent stressors, and demographic/medical history forms. RESULTS: Mothers who relied more on active coping strategies at baseline had children with better ArQL 6 months later, and those who relied on more avoidance coping strategies at baseline had children with poorer ArQL of life 6 months later. CONCLUSIONS: These results reveal that maternal coping plays an important role in the ArQL of children with asthma. Implications for interventions aimed at improving the physical and mental health of children with asthma are discussed. PMID- 17717006 TI - SMAKing Ca2+ sparks in arterial myocytes. PMID- 17717007 TI - A neurohypophysial end game: spreading excitation with sildenafil. PMID- 17717008 TI - Intrauterine growth restriction improves cerebral O2 utilization during hypercapnic hypoxia in newborn piglets. AB - Data are scant regarding the capacity of cerebrovascular regulation during asphyxia for prevention of brain oxygen deficit in intrauterine growth-restricted (IUGR) newborns. We tested the hypothesis that IUGR improves the ability of neonates to withstand critical periods of severe asphyxia by optimizing brain oxygen supply. Studies were conducted to examine the effects of IUGR on cerebral blood flow (CBF) regulation and oxygen consumption (cerebral metabolic rate for oxygen, CMRO(2)) at different stages of asphyxia (hypercapnic hypoxaemia) in comparison to pure hypoxia (normocapnic hypoxaemia). We used 1-day-old anaesthetized and ventilated piglets. Animals were divided into normal weight (NW) piglets (n = 47; aged 11-26 h, body weight 1481 +/- 121 g) and IUGR piglets (n = 48; aged 13-28 h, body weight 806 +/- 42 g) according to their birth weight. Different stages of hypoxaemia were induced for 1 h by appropriate lowering of the inspired fraction of oxygen (moderate hypoxia: = 31-34 mmHg; severe hypoxia: = 20-22 mmHg). Fourteen NW and 16 IUGR piglets received additionally 9% CO(2) in the breathing gas, so that a of 74-80 mmHg resulted (hypoxia/hypercapnia groups). Eight NW and nine IUGR animals served as untreated controls. Furthermore, affinity of haemoglobin for oxygen was measured under hypoxic and asphyxic conditions. During asphyxia cerebral oxygen extraction was markedly increased in IUGR animals (P < 0.05). This resulted in a significantly diminished CMRO(2) related increase of CBF at gradually reduced arterial oxygen content (P < 0.05). Therefore, an enhanced effectivity in oxygen availability appeared in newborn IUGR piglets under graded asphyxia by improved cerebral oxygen utilization (P < 0.05). This was not supported by related O(2) affinity of haemoglobin. Thus, IUGR newborns are more capable to ensure brain O(2) demand during asphyxia (hypercapnic hypoxia) than NW neonates. PMID- 17717010 TI - The Olympic brain. Does corticospinal plasticity play a role in acquisition of skills required for high-performance sports? AB - Non-invasive electrophysiological and imaging techniques have recently made investigation of the intact behaving human brain possible. One of the most intriguing new research areas that have developed through these new technical advances is an improved understanding of the plastic adaptive changes in neuronal circuitries underlying improved performance in relation to skill training. Expansion of the cortical representation or modulation of corticomotor excitability of specific muscles engaged in task performance is required for the acquisition of the skill. These changes at cortical level appear to be paralleled by changes in transmission in spinal neuronal circuitries, which regulate the contribution of sensory feedback mechanisms to the execution of the task. Such adaptive changes also appear to be essential for the consolidation of a memory of performance of motor tasks and thus for the lasting ability of performing highly skilled movements such as those required for Olympic sports. PMID- 17717009 TI - Dependence on extracellular Ca2+/K+ antagonism of inspiratory centre rhythms in slices and en bloc preparations of newborn rat brainstem. AB - The pre-Botzinger Complex (preBotC) inspiratory centre remains active in isolated brainstem-spinal cords and brainstem slices. The extent to which findings in these models depend on their dimensions or superfusate [K(+)] and [Ca(2+)] (both of which determine neuronal excitability) is not clear. We report here that inspiratory-related rhythms in newborn rat slices and brainstem-spinal cords with defined boundaries were basically similar in physiological Ca(2+) (1.2 mm) and K(+) (3 mm). Hypoglossal nerve rhythm was 1 : 1-coupled to preBotC activity in slices and to cervical nerve bursts in en bloc preparations lacking the facial motonucleus (VII). Hypoglossal rhythm was depressed in brainstems containing (portions of) VII, while pre/postinspiratory lumbar nerve bursting was present only in preparations with > 79% VII. preBotC-related slice rhythms were inhibited in 1.5 mm Ca(2+) solution, whereas their longevity and burst rate were substantially augmented in 1 mm Ca(2+). Ca(2+) depression of slice rhythms was antagonized by raising superfusate K(+) to 8-10 mm. This strong extracellular Ca(2+)/K(+) antagonism of inspiratory (motor) rhythms was also revealed in brainstem-spinal cords without VII, while the inhibition was progressively attenuated with increasing amount of rostral tissue. We hypothesize that depression of hypoglossal rhythm and decreased Ca(2+) sensitivity of preBotC rhythm are probably not related to an increased content of rostral respiratory structures, but rather to larger brainstem dimensions resulting in interstitial gradients for neuromodulator(s) and K(+), respectively. We discuss whether block of pre/postinspiratory activity in preparations with < 79% VII is due to impairment of the pathway from preinspiratory interneurons to abdominal muscles. PMID- 17717011 TI - Endurance exercise performance in Masters athletes: age-associated changes and underlying physiological mechanisms. AB - Older ('Masters') athletes strive to maintain or even improve upon the performance they achieved at younger ages, but declines in athletic performance are inevitable with ageing. In this review, we describe changes in peak endurance exercise performance with advancing age as well as physiological factors responsible for those changes. Peak endurance performance is maintained until approximately 35 years of age, followed by modest decreases until 50-60 years of age, with progressively steeper declines thereafter. Among the three main physiological determinants of endurance exercise performance (i.e. maximal oxygen consumption , lactate threshold and exercise economy), a progressive reduction in appears to be the primary mechanism associated with declines in endurance performance with age. A reduction in lactate threshold, i.e. the exercise intensity at which blood lactate concentration increases significantly above baseline, also contributes to the reduction in endurance performance with ageing, although this may be secondary to decreases in . In contrast, exercise economy (i.e. metabolic cost of sustained submaximal exercise) does not change with age in endurance-trained adults. Decreases in maximal stroke volume, heart rate and arterio-venous O(2) difference all appear to contribute to the age-related reductions in in endurance-trained athletes. Declines in endurance exercise performance and its physiological determinants with ageing appear to be mediated in large part by a reduction in the intensity (velocity) and volume of the exercise that can be performed during training sessions. Given their impressive peak performance capability and physiological function capacity, Masters athletes remain a fascinating model of 'exceptionally successful ageing' and therefore are highly deserving of our continued scientific attention as physiologists. PMID- 17717012 TI - Morphology of inhibitory and excitatory interneurons in superficial laminae of the rat dorsal horn. AB - If we are to stand any chance of understanding the circuitry of the superficial dorsal horn, it is imperative that we can identify which classes of interneuron are excitatory and which are inhibitory. Our aim was to test the hypothesis that there is a correlation between the morphology of an interneuron and its postsynaptic action. We used in vitro slice preparations of the rat spinal cord to characterize and label interneurons in laminae I-III with Neurobiotin. Labelled cells (n = 19) were reconstructed in 3D with Neurolucida and classified according to the scheme proposed by Grudt & Perl (2002). We determined if cells were inhibitory or excitatory by reacting their axon terminals with antibodies to reveal glutamate decrboxylase (for GABAergic cells) or the vesicular glutamate transporter 2 (for glutamatergic cells). All five islet cells retrieved were inhibitory. Of the six vertical (stalked) cells analysed, four were excitatory and, surprisingly, two were inhibitory. It was noted that these inhibitory cells had axonal projections confined to lamina II whereas excitatory vertical cells projected to lamina I and II. Of the remaining neurons, three were radial cells (2 inhibitory, 1 excitatory), two were antennae cells (1 inhibitory, 1 excitatory), one was an inhibitory central cell and the remaining two were unclassifiable excitatory cells. Our hypothesis appears to be correct only for islet cells. Other classes of cells have mixed actions, and in the case of vertical cells, the axonal projection appears to be a more important determinant of postsynaptic action. PMID- 17717013 TI - Effects of a common human gene variant of extracellular superoxide dismutase on endothelial function after endotoxin in mice. AB - A common gene variant in the heparin-binding domain (HBD) of extracellular superoxide dismutase (ECSOD) may predispose human carriers to ischaemic heart disease. We have demonstrated that the HBD of ECSOD is important for ECSOD to restore vascular dysfunction produced by endotoxin. The purpose of this study was to determine whether the gene variant in the HBD of ECSOD (ECSOD(R213G)) protects against endothelial dysfunction in a model of inflammation. We constructed a recombinant adenovirus that expresses ECSOD(R213G). Adenoviral vectors expressing ECSOD, ECSOD(R213G) or beta-galactosidase (LacZ, a control) were injected i.v. in mice. After 3 days, at which time the plasma SOD activity is maximal, vehicle or endotoxin (lipopolysaccharide or LPS, 40 mg kg(-1)) was injected i.p. Vasomotor function of aorta in vitro was examined 1 day later. Maximal relaxation to sodium nitroprusside was similar in aorta from normal and LPS-treated mice. Maximal relaxation to acetylcholine (10(-5)) was impaired after LPS and LacZ (63 +/- 3%, mean +/- s.e.m.) compared to normal vessels (83 +/- 3%) (P < 0.05). Gene transfer of ECSOD improved (P < 0.05) relaxation in response to acetylcholine (76 +/- 5%) after LPS, whereas gene transfer of ECSOD(R213G) had no effect (65 +/- 4%). Superoxide was increased in aorta (measured using lucigenin and hydroethidine) after LPS, and levels of superoxide were significantly reduced following ECSOD but not ECSOD(R213G). Thus, ECSOD reduces superoxide and improves relaxation to acetylcholine in the aorta after LPS, while the ECSOD variant R213G had minimal effect. These findings suggest that, in contrast to ECSOD, the common human gene variant of ECSOD fails to protect against endothelial dysfunction produced by an inflammatory stimulus. PMID- 17717014 TI - Gastric motility in soluble guanylate cyclase alpha 1 knock-out mice. AB - The principal target of the relaxant neurotransmitter nitric oxide (NO) is soluble guanylate cyclase (sGC). As the alpha(1)beta(1)-isoform of sGC is the predominant one in the gastrointestinal tract, the aim of this study was to investigate the role of sGC in nitrergic regulation of gastric motility in male and female sGCalpha(1) knock-out (KO) mice. In circular gastric fundus muscle strips, functional responses and cGMP levels were determined in response to nitrergic and non-nitrergic stimuli. sGC subunit mRNA expression in fundus was measured by real-time RT-PCR; in vivo gastric emptying of a phenol red meal was determined. No changes were observed in sGC subunit mRNA levels between wild-type (WT) and KO tissues. Nitrergic relaxations induced by short trains of electrical field stimulation (EFS) were abolished, while those by long trains of EFS were reduced in KO strips; the latter responses were abolished by 1H[1,2,4,]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). The relaxations evoked by exogenous NO and the NO-independent sGC activator BAY 41-2272 were reduced in KO strips but still sensitive to ODQ. Relaxations induced by vasoactive intestinal peptide (VIP) and 8-bromo-cGMP were not influenced. Basal cGMP levels were decreased in KO strips but NO, long train EFS and BAY 41-2272 still induced a moderate ODQ-sensitive increase in cGMP levels. Gastric emptying, measured at 15 and 60 min, was increased at 15 min in male KO mice. sGCalpha(1)beta(1) plays an important role in gastric nitrergic relaxation in vitro, but some degree of nitrergic relaxation can occur via sGCalpha(2)beta(1) activation in sGCalpha(1) KO mice, which contributes to the moderate in vivo consequence on gastric emptying. PMID- 17717016 TI - Temperature enhances exocytosis efficiency at the mouse inner hair cell ribbon synapse. AB - Hearing relies on fast and sustained neurotransmitter release from inner hair cells (IHCs) onto the afferent auditory nerve fibres. The temperature dependence of Ca(2+) current and transmitter release at the IHCs ribbon synapse has not been investigated thus far. To assess the influence of temperature on calcium triggered exocytosis, patch-clamp recordings of voltage-gated L-type Ca(2+) influx and exocytic membrane capacitance changes were performed at room (25 degrees C) and physiological (35-37 degrees C) temperatures. An increase in temperature within this range increased the L-type Ca(2+) current amplitude of IHCs (Q(10) = 1.3) and accelerates the activation kinetics. Fast exocytosis, probed by 20 ms depolarization, was enhanced at physiological temperature with a Q(10) of 2.1. The amplitude of fast release was elevated disproportionately to the increase in Ca(2+) influx. In contrast, the rate of sustained exocytosis (exocytic rate between 20 and 100 ms of depolarization) did not show a significant increase at physiological temperature. Altogether, these data indicate that the efficiency of fast exocytosis is higher at physiological temperature than at room temperature and suggest that the number of readily releasable vesicles available at the active zone is higher at physiological temperature. PMID- 17717015 TI - Beneficial effects of L-arginine nitric oxide-producing pathway in rats treated with alloxan. AB - In an attempt to elucidate molecular mechanisms and factors involved in beta cell regeneration, we evaluated a possible role of the L-arginine-nitric oxide (NO) producing pathway in alloxan-induced diabetes mellitus. Diabetes was induced in male Mill Hill rats with a single alloxan dose (120 mg kg(-1)). Both non-diabetic and diabetic groups were additionally separated into three subgroups: (i) receiving L-arginine . HCl (2.25%), (ii) receiving L-NAME . HCl (0.01%) for 12 days as drinking liquids, and (iii) control. Treatment of diabetic animals started after diabetes induction (glucose level > or = 12 mmol l(-1)). We found that disturbed glucose homeostasis, i.e. blood insulin and glucose levels in diabetic rats was restored after L-arginine treatment. Immunohistochemical findings revealed that L-arginine had a favourable effect on beta cell neogenesis, i.e. it increased the area of insulin-immunopositive cells. Moreover, confocal microscopy showed colocalization of insulin and pancreas duodenum homeobox-1 (PDX-1) in both endocrine and exocrine pancreas. This increase in insulin-expressing cells was accompanied by increased cell proliferation (observed by proliferating cell nuclear antigen-PCNA immunopositivity) which occurred in a regulated manner since it was associated with increased apoptosis (detected by the TUNEL method). Furthermore, L-arginine enhanced both nuclear factor-kB (NF-kB) and neuronal nitric oxide synthase (nNOS) immunopositivities. The effect of L-arginine on antioxidative defence was observed especially in restoring to control level the diabetes-induced increase in glutathione peroxidase activity. In contrast to L-arginine, diabetic pancreas was not affected by L-NAME supplementation. In conclusion, the results suggest beneficial L-arginine effects on alloxan-induced diabetes resulting from the stimulation of beta cell neogenesis, including complex mechanisms of transcriptional and redox regulation. PMID- 17717017 TI - Impact of temperature on cross-bridge cycling kinetics in rat myocardium. AB - The dependence of contractile properties on intracellular calcium in cardiac tissue is a highly cooperative process. Here, the temperature and calcium dependence of contractile and energetical properties in permeabilized cardiac trabeculae from rat were studied to provide novel insights into the underlying kinetic processes. Myofilament Ca(2+) sensitivity significantly increased with temperature between 15 and 25 degrees C, whereas its steepness was independent of temperature. A direct proportionality between active tension and Ca(2+)-activated rate of ATP hydrolysis was observed; the slope of this relationship (tension cost) was highly temperature dependent. The rate of tension redevelopment following a quick release-restretch manoeuvre (k(tr)) depended in a complex manner on the level of contractile activation and on temperature. At saturating calcium levels, the temperature dependence (Q(10)) of k(tr) and Ca(2+)-activated ATP hydrolysis rate were similar (Q(10) approximately 3.5), and significantly higher than the Q(10) for maximum tension (T(max); Q(10) approximately 1.3) or tension cost (Q(10) approximately 2.5). In contrast, at a low level of contractile activation ( approximately 5% of T(max)), the Q(10) of k(tr) was similar to that of tension cost, and significantly lower than the Q(10) of Ca(2+) activated ATP hydrolysis at that level of contractile activation. Our results are consistent with the hypothesis that at high levels of contractile activation, the rates of tension redevelopment and Ca(2+)-activated ATP hydrolysis are determined by both apparent cross-bridge attachment and detachment rates, while at low levels, k(tr) is limited by cross-bridge detachment rate. Tension cost, on the other hand, is determined solely by cross-bridge detachment kinetics at all temperatures and levels of contractile activation. PMID- 17717018 TI - Extrasynaptic and synaptic NMDA receptors form stable and uniform pools in rat hippocampal slices. AB - N-methyl-d-aspartate receptor (NMDAR) activation can trigger both long- and short term plasticity, promote cell survival, and initiate cell death. A number of studies suggest that the consequences of NMDAR activation can vary widely depending on whether synaptic or extrasynaptic receptors are activated. Here we have examined the spatial distribution of NMDARs of CA1 pyramidal neurons in acutely dissected hippocampal slices. Using a physiological definition of extrasynaptic receptors as those not accessible to single release events, we find that extrasynaptic NMDARs comprise a substantial proportion of the dendritic NMDAR pool (36%). This pool of extrasynaptic NMDARs is stable and does not shuttle into the synaptic receptor pool, as we observe no recovery of synaptic current after MK-801 synaptic blockade and washout. The subunit composition of synaptic and extrasynaptic NMDA receptor pools is similar at 3 weeks of age, with NR2B subunits present in both compartments. NR2B receptors are not enriched in the extrasynaptic compartment. Our data suggest that any role played by extrasynaptic NMDARs in synaptic transmission is dictated by their subcellular location rather than their subunit composition or mobility. PMID- 17717019 TI - Measuring the ventilatory response to hypoxia. AB - After defining the current approach to measuring the hypoxic ventilatory response this paper explains why this method is not appropriate for comparisons between individuals or conditions, and does not adequately measure the parameters of the peripheral chemoreflex. A measurement regime is therefore proposed that incorporates three procedures. The first procedure measures the peripheral chemoreflex responsiveness to both hypoxia and CO(2) in terms of hypoxia's effects on the sensitivity and ventilatory recruitment threshold of the peripheral chemoreflex response to CO(2). The second and third procedures employ current methods for measuring the isocapnic and poikilocapnic ventilatory responses to hypoxia, respectively, over a period of 20 min. The isocapnic measure is used to determine the time course characteristics of hypoxic ventilatory decline and the poikilocapnic measure shows the ventilatory response to a hypoxic environment. A measurement regime incorporating these three procedures will permit a detailed assessment of the peripheral chemoreflex response to hypoxia that allows comparisons to be made between individuals and different physiological and environmental conditions. PMID- 17717021 TI - White matter hyperintensities in late life depression: a systematic review. AB - BACKGROUND: White matter hyperintensities in MRI scans are age related but appear to be more prevalent in depressed patients. They may be more pronounced in late onset depression. This finding, if confirmed, would potentially illuminate the heterogeneity of depression in elderly subjects. METHODS: We conducted a systematic literature search of studies investigating white matter changes in late life depression, identifying 98 studies. The 30 remaining eligible studies were scrutinised for the presence and severity measures of periventricular and deep white matter changes in late life, late onset and, if available, early onset depression as well as in controls. Comparisons between groups were entered into random effects meta-analyses using odds ratios and Cohen's d, as appropriate. Correlations with potential confounders, such as age difference between groups, were explored. RESULTS: Late life depression and, to a greater extent, late onset depression in late life were characterised by more frequent and intense white matter abnormalities. In particular, the odds of having white matter changes were over 4 for late compared with early onset depression. Similarly, on severity scales, late onset depression had scores of 0.7-0.8 standard deviations above early onset patients. CONCLUSIONS: Significant differences between early and late onset depression suggest different aetiological mechanisms, in accordance with a theory of "cerebrovascular" depression of late onset. Greater duration of depressive symptoms, signs and treatment does not appear to have a measurable impact on white matter signal in MRI scans. PMID- 17717020 TI - Immune responses to myelin proteins in Guillain-Barre syndrome. AB - BACKGROUND: Potential target autoantigens in the demyelinating form of Guillain Barre syndrome (GBS) include the myelin proteins PMP22, P0 and P2. METHODS: We investigated immunoreactivity to P0, P2 and PMP22 proteins in 37 patients with GBS and 32 healthy controls. RESULTS: Antibodies to PMP22 or P0 peptides were detected at presentation in only 5 out of 37 patients. In ELISPOT assays, blood mononuclear cells from 15 out of 24 patients with GBS, but none of the control subjects, produced interleukin-10 (IL-10) in response to peptides from proteins P0, P2 or PMP22 (p = 0.0003). The cells from only two patients produced interferon-gamma (IFN gamma). The cells from 11 patients with GBS had increased IL-10 responses to peptides representing sequences from the extracellular domains of PMP22 before intravenous immunoglobulin (IVIg) treatment (p = 0.006). The cells from 11 patients with GBS, including 7 who responded to the extracellular domains of PMP22, had increased IL-10 responses to the intracellular domain of P0 before (p = 0.005) and those from 9 patients after they had been treated with IVIg (p = 0.01). CONCLUSIONS: Antibodies to P0 and PMP22 protein peptides do occur in GBS but are uncommon. Circulating mononuclear cell IFN gamma responses to P0, P2 and PMP22 myelin protein peptides are rare, but IL-10 responses occur significantly more often than in normal subjects. They might be part of a harmful pathogenetic process or represent a regulatory response. PMID- 17717022 TI - Periodic abducens nerve palsy in adults caused by neurovascular compression. AB - Unilateral abducens nerve palsy with periodic recurrences is a well-recognised finding in children, but is rare in adults. The underlying pathophysiological mechanism is unknown. Vascular compression of the nerve is suspected but never demonstrated. We describe an adult patient with, altogether, 11 periods of unilateral right-sided abducens palsy and arterial contact at the root exit zone of the symptomatic side. PMID- 17717023 TI - Celebrating the golden anniversary of the discovery of bacillosamine, the diamino sugar of a Bacillus. AB - Bacillosamine (2,4-diamino-2,4,6-trideoxy-d-glucose, Bac), a rare amino sugar, was discovered 50 years ago as a result of the follow-up of a chance observation made during studies of polypeptide synthesis by a Bacillus subtilis strain later renamed Bacillus licheniformis. In the following decades this amino sugar was almost completely ignored, although it was found in a number of bacterial polysaccharides and other metabolites. Recently, there has been a burst of interest in Bac when it was found to be a link glycan in eubacterial glycoproteins. In this retrospective, I review the chance discovery of Bac, its structural determination and its biosynthesis. PMID- 17717024 TI - Domestication and breeding of tomatoes: what have we gained and what can we gain in the future? AB - BACKGROUND: It has been shown that a large variation is present and exploitable from wild Solanum species but most of it is still untapped. Considering the thousands of Solanum accessions in different gene banks and probably even more that are still untouched in the Andes, it is a challenge to exploit the diversity of tomato. What have we gained from tomato domestication and breeding and what can we gain in the future? SCOPE: This review summarizes progress on tomato domestication and breeding and current efforts in tomato genome research. Also, it points out potential challenges in exploiting tomato biodiversity and depicts future perspectives in tomato breeding with the emerging knowledge from tomato omics. CONCLUSIONS: From first domestication to modern breeding, the tomato has been continually subjected to human selection for a wide array of applications in both science and commerce. Current efforts in tomato breeding are focused on discovering and exploiting genes for the most important traits in tomato germplasm. In the future, breeders will design cultivars by a process named 'breeding by design' based on the combination of science and technologies from the genomic era as well as their practical skills. PMID- 17717025 TI - A comparative analysis of the temperature response of leaf elongation in Bromus stamineus and Lolium perenne plants in the field: intrinsic and size-mediated effects. AB - BACKGROUND AND AIMS: Growth of grass species in temperate-humid regions is restricted by low temperatures. This study analyses the origin (intrinsic or size mediated) and mechanisms (activity of individual meristems vs. number of active meristems) of differences between Bromus stamineus and Lolium perenne in the response of leaf elongation to moderately low temperatures. METHODS: Field experiments were conducted at Balcarce, Argentina over 2 years (2003 and 2004) using four cultivars, two of B. stamineus and two of L. perenne. Leaf elongation rate (LER) per tiller and of each growing leaf, number of growing leaves and total leaf length per tiller were measured on 15-20 tillers per cultivar, for 12 (2003) or 10 weeks (2004) during autumn and winter. KEY RESULTS: LER was faster in B. stamineus than in L. perenne. In part, this was related to size-mediated effects, as total leaf length per tiller correlated with LER and B. stamineus tillers were 71% larger than L. perenne tillers. However, accounting for size effects revealed intrinsic differences between species in their temperature response. These were based on the number of leaf meristems simultaneously active and not on the (maximum) rate at which individual leaves elongated. Species differences were greater at higher temperatures, being barely notable below 5 degrees C (air temperature). CONCLUSIONS: Bromus stamineus can sustain a higher LER per tiller than L. perenne at air temperatures > 6 degrees C. In the field, this effect would be compounded with time as higher elongation rates lead to greater tiller sizes. PMID- 17717026 TI - Uraemic pruritus in RDT patients: is it still a problem? PMID- 17717027 TI - Combined nephrectomy and pre-emptive renal transplantation in a tuberous sclerosis patient with angiomyolipoma, renal carcinoma and life-threatening abdominal haemorrhages. PMID- 17717028 TI - Successful liver transplantation in a kidney and pancreas allograft recipient with fulminant herpes simplex virus type 2 hepatitis. PMID- 17717029 TI - Chronic urticaria and mesangial proliferative glomerulonephritis: a case report. PMID- 17717031 TI - Serum levels of beta-trace protein and its association to diuresis in haemodialysis patients. AB - BACKGROUND: Beta-trace protein (BTP) has been proposed as an alternative endogenous marker of the glomerular filtration rate. However, possible determinants of BTP in ESRD patients undergoing regular renal replacement therapy have not been evaluated. METHODS: Serum levels of BTP, beta-2-microglobulin, creatinine and urea were analysed before and after dialysis treatment in 73 patients [haemodialysis (HD) n=52; haemodiafiltration (HDF) n=21]. Patients were categorized into four groups with residual diuresis (RD)<0.5 l/day (group 1; n=24), 0.5-1 l/day (group 2; n=18), 1.1-1.5 l/day (group 3; n=12) and >1.5 l/day (group 4; n=19). Subsequently RD was compared to pre-treatment levels of BTP. RESULTS: HD treatment did not affect BTP serum levels [pre-treatment 8.1+/-4.1 mg/l (mean+SD) vs post-treatment 7.7+/-4.1 mg/l; -0.6 +/- 16.1%; ns]. However, in 6 out of 21 patients undergoing HDF BTP levels were reduced by more than 20%. Overall, the resulting decrease in serum concentration was minuscule (9.6+/-6.2 vs 8.3+/-4.9 mg/l; -14+/-21.9%; P=0.03). BTP serum levels were tightly associated to RD of the four groups. Comparison of BTP levels showed significant differences between patients of groups 1 vs 3 and 4 as well as 2 vs 4. CONCLUSIONS: BTP serum levels may serve as a surrogate marker for residual renal function since HD and HDF do not exert clinical relevant alterations on them. Furthermore, BTP serum concentrations appear strongly associated to RD. PMID- 17717030 TI - Cinacalcet (KRN1493) effectively decreases the serum intact PTH level with favorable control of the serum phosphorus and calcium levels in Japanese dialysis patients. AB - BACKGROUND: Cinacalcet hydrochloride (KRN1493) acts on the parathyroid calcium receptors to suppress parathyroid hormone (PTH) secretion, and is already in wide use in the United States and the European countries. In this study, we examined the efficacy and safety of cinacalcet in Japanese patients on maintenance haemodialysis. METHODS: One hundred forty-four patients with serum intact PTH (iPTH) levels >or=300 pg/ml were enrolled and randomly allocated to two groups assigned to receive either cinacalcet or placebo for 14 weeks. Cinacalcet was started at the dose of 25 mg/day and titrated up to 100 mg/day to achieve the target iPTH level of <250 pg/ml. RESULTS: Cinacalcet significantly decreased the median iPTH level from 606.5 pg/ml to 241.0 pg/ml, despite the mean dialysis vintage being 2.4 times longer (14.3+/-7.1 years) and the proportion of patients receiving vitamin D sterols being higher, than in the phase 3 studies conducted in the US/EU. The target iPTH level was achieved in 51.4% of the patients in the cinacalcet group, in sharp contrast to only 2.8% in the placebo group. Furthermore, the percentage of patients with both the serum calcium and phosphorus levels within the target range in the K/DOQI guidelines increased from 4.2% to 26.4% by cinacalcet. CONCLUSIONS: These results suggest that lower dose levels of cinacalcet, as compared to those in US/EU studies, may be sufficient effectively suppress the serum iPTH levels and allow favourable management of the serum calcium and phosphorus levels in Japanese patients, having a longer average dialysis vintage. PMID- 17717032 TI - Resting energy expenditure and thermal balance during isothermic and thermoneutral haemodialysis--heat production does not explain increased body temperature during haemodialysis. AB - BACKGROUND: During routine haemodialysis (HD) body temperature increases, which contributes to haemodynamic instability. The relative roles of increased heat production and/or incomplete heat transfer are not fully elucidated. Concomitant measurement of heat production and heat transfer may help to assess the factors determining thermal balance during HD. METHODS: Thirteen stable non-diabetic maintenance HD patients were investigated during two HD procedures (isothermic, dT = 0, no change of body temperature; thermoneutral, dE = 0, no energy transfer between blood and dialysate), using a blood temperature monitor (BTM) in active mode. Energy transfer, blood and dialysate temperature, and relative blood volume change (dBV) were continuously recorded, and resting energy expenditure (REE; Deltatrac Datex) was measured repeatedly during each procedure. Fourteen healthy persons served as controls for REE comparison. RESULTS: In isothermic HD, median energy removal was 218 kJ/4 h HD (= heat flow -15.1 W). This cooling correlated with dBV induced by ultrafiltration (rho = 0.731, P < 0.01). There was no difference in dBV between isothermic (7.7%) and thermoneutral (8.1%) HD. Predialysis REE was 82.8 W/1.73 m(2), not different from controls. No variation in REE during HD was observed, except a small and transient increase after a light meal (5 and 4%). In the time course of REE, no difference between the procedures was found. CONCLUSIONS: Our findings suggest that stable maintenance HD patients have REE not different from healthy controls, that HD procedure per se does not significantly increase REE and that neither isothermic nor thermoneutral regimen has any influence on metabolic rate. Therefore, body temperature elevation during routine HD may rather be due to decreased heat removal. With the use of BTM in active mode, body temperature can be kept stable (isothermic HD), which requires active cooling. This negative energy transfer is proportional to decrease in blood volume induced by ultrafiltration. PMID- 17717033 TI - IgG, IgA, IgM antibodies to a viral citrullinated peptide in patients affected by rheumatoid arthritis, chronic arthritides and connective tissue disorders. AB - OBJECTIVES: Anti-citrullinated protein/peptide antibodies (ACPA), a family of antibodies with overlapping specificities, represent a specific marker of rheumatoid arthritis (RA). The aim of the present study is to investigate the prevalence and clinical significance of IgG, IgA and IgM ACPA by a newly described assay employing a viral citrullinated peptide (VCP). METHODS: IgG, IgA and IgM anti-VCP antibodies have been measured in sera from 146 patients affected by RA and 404 controls, including 204 chronic arthritides, 111 connective tissue disorders and 89 healthy subjects. The affinity of the different isotypes for VCP was analysed by liquid phase inhibition assays. RESULTS: Among RA patients, 40 were single positive for IgG anti-VCP, five for IgA and 11 for IgM. Ten patients were double positive for IgG and IgA, four for IgG and IgM, six for IgA and IgM. In 15 RA patients IgG, IgA and IgM anti-VCP antibodies were detected. No correlation could be found between the isotype and the clinical manifestations or duration of the disease. IgA anti-VCP were strongly associated with RA, whereas IgM anti-VCP were detected also in a low percentage of systemic lupus erythematosus, psoriatic arthritis and mixed cryoglobulinaemia (MC) patients. IgG anti-VCP displayed a higher affinity for the antigen than IgA or IgM. CONCLUSIONS: These data show that anti-VCP of IgG and IgA isotype discriminate RA from other chronic arthritides and disease controls and suggest an independent production of each isotype. PMID- 17717034 TI - Wordom: a program for efficient analysis of molecular dynamics simulations. AB - Wordom is a versatile program for manipulation of molecular dynamics trajectories and efficient analysis of simulations. Original tools in Wordom include a procedure to evaluate significance of sampling for principal component analysis as well as modules for clustering multiple conformations and evaluation of order parameters for folding and aggregation. The program was developed with special emphasis on user-friendliness, effortless addition of new modules and efficient handling of large sets of trajectories. PMID- 17717035 TI - Sliding MinPD: building evolutionary networks of serial samples via an automated recombination detection approach. AB - MOTIVATION: Traditional phylogenetic methods assume tree-like evolutionary models and are likely to perform poorly when provided with sequence data from fast evolving, recombining viruses. Furthermore, these methods assume that all the sequence data are from contemporaneous taxa, which is not valid for serially sampled data. A more general approach is proposed here, referred to as the Sliding MinPD method, that reconstructs evolutionary networks for serially sampled sequences in the presence of recombination. RESULTS: Sliding MinPD combines distance-based phylogenetic methods with automated recombination detection based on the best-known sliding window approaches to reconstruct serial evolutionary networks. Its performance was evaluated through comprehensive simulation studies and was also applied to a set of serially-sampled HIV sequences from a single patient. The resulting network organizations reveal unique patterns of viral evolution and may help explain the emergence of disease associated mutants and drug-resistant strains with implications for patient prognosis and treatment strategies. PMID- 17717036 TI - CTree: comparison of clusters between phylogenetic trees made easy. AB - SUMMARY: CTree has been designed for the quantification of clusters within viral phylogenetic tree topologies. Clusters are stored as individual data structures from which statistical data, such as the Subtype Diversity Ratio (SDR), Subtype Diversity Variance (SDV) and pairwise distances can be extracted. This simplifies the quantification of tree topologies in relation to inter- and intra-cluster diversity. Here the novel features incorporated within CTree, including the implementation of a heuristic algorithm for identifying clusters, are outlined along with the more usual features found within general tree viewing software. AVAILABILITY: CTree is available as an executable jar file from: http://www.manchester.ac.uk/bioinformatics/ctree PMID- 17717037 TI - Is primary angioplasty cost effective in the UK? Results of a comprehensive decision analysis. AB - OBJECTIVE: To assess the cost effectiveness of primary angioplasty, compared with medical management with thrombolytic drugs, to achieve reperfusion after acute myocardial infarction (AMI) from the perspective of the UK NHS. DESIGN: Bayesian evidence synthesis and decision analytic model. METHODS: A systematic review was conducted and Bayesian statistical methods used to synthesise evidence from 22 randomised control trials. Resource utilisation was based on UK registry data, published literature and national databases, with unit costs taken from routine NHS sources and published literature. MAIN OUTCOME MEASURE: Costs from a health service perspective and outcomes measured as quality-adjusted life years (QALYs). RESULTS: For the base case, the incremental cost-effectiveness ratio of primary angioplasty was 9241 pounds sterling for each additional QALY, with a probability of being cost effective of 0.90 for a cost-effectiveness threshold of 20,000 pounds sterling. Results were sensitive to variations in the additional time required to initiate treatment with primary angioplasty. CONCLUSIONS: Primary angioplasty is cost effective for the treatment of AMI on the basis of threshold cost-effectiveness values used in the NHS and subject to a delay of up to about 80 minutes. These findings are mainly explained by the superior mortality benefit and the prevention of non-fatal outcomes associated with primary angioplasty for delays of up to this length. PMID- 17717038 TI - Improving quality through effective implementation of information technology in healthcare. AB - OBJECTIVE: To describe an implementation of one information technology system (electronic medical record, EMR) in one hospital, the perceived impact, the factors thought to help and hinder implementation and the success of the system and compare this with theories of effective IT implementation. To draw on previous research, empirical data from this study is used to develop IT implementation theory. DESIGN: Qualitative case study, replicating the methods and questions of a previously published USA EMR implementation study using semi structured interviews and documentation. SETTING: Large Swedish teaching hospital shortly after a merger of two hospital sites. PARTICIPANTS: Thirty senior clinicians, managers, project team members, doctors and nurses. RESULTS: The Swedish implementation was achieved within a year and for under half the budget, with a generally popular EMR which was thought to save time and improve the quality of patient care. Evidence from this study and findings from the more problematic USA implementation case suggests that key factors for cost effective implementation and operation were features of the system itself, the implementation process and the conditions under which the implementation was carried out. CONCLUSION: There is empirical support for the IT implementation theory developed in this study, which provides a sound basis for future research and successful implementation. Successful implementation of an EMR is likely with an intuitive system, requiring little training, already well developed for clinical work but allowing flexibility for development, where clinicians are involved in selection and in modification for their department needs and where a realistic timetable is made using an assessment of the change-capability of the organization. Once a system decision is made, the implementation should be driven by top and departmental leaders assisted by competent project teams involving information technology specialists and users. Corrections for unforeseen eventualities will be needed, especially with less developed systems, requiring regular reviews of progress and modifications to systems and timetables to respond to user needs. PMID- 17717040 TI - Role of NKT cells in the digestive system. III. Role of NKT cells in intestinal immunity. AB - Natural killer T (NKT) cells are a small subset of unconventional T cells that recognize lipid antigens presented by the nonclassical major histocompatibility complex (MHC) class I molecule CD1d. NKT cells are involved in the host response to a variety of microbial pathogens and likely commensals. In the intestine, invariant and noninvariant NKT cells can be found among intraepithelial lymphocytes and in the lamina propria. Activation of intestinal NKT cells by CD1d expressing intestinal epithelial cells and professional antigen-presenting cells may contribute to induction of oral tolerance and protection from mucosal infections. On the other hand, sustained and uncontrolled activation of NKT cells may play a pivotal role in the pathogenesis of inflammatory bowel disease. Here we review the current literature on intestinal NKT cells and their function in the intestine in health and disease. PMID- 17717042 TI - Role of phospholipase A2 (group I secreted) in the genesis of basal tone in the internal anal sphincter smooth muscle. AB - The role of phospholipase A(2) (PLA(2)) in the genesis of basal tone in the internal anal sphincter (IAS) is not known. We determined the effects of PLA(2) and inhibitors on the basal tone and intraluminal pressures (IASP) in the rat IAS vs. rectal smooth muscles (RSM). In addition, we determined the correlations between the IAS tone, PLA(2) levels, and the actual enzymatic activity. Inhibition of PLA(2) by 4-bromophenacyl bromide (universal inhibitor of PLA(2)) and MJ33 [selective inhibitor of secreted isoform of PLA(2) (sPLA(2))] caused concentration-dependent decrease in the IAS tone and in the IASP. Maximal decreases in the IAS tone and IASP by 4-bromophenacyl bromide and MJ33 were 58.8 +/- 6.9 and 51.5 +/- 6.3%, and 66.7 +/- 5.1 and 79.8 +/- 8.2%, respectively. The sPLA(2) inhibitors were approximately 100 times more potent in decreasing the IASP than the mean blood pressure. Conversely, the selective inhibitors of the cytosolic and calcium-independent PLA(2) arachidonyl trifluoromethyl ketone and bromoenol lactone, respectively, produced no significant effect. The IAS had characteristically higher levels of sPLA(2) activity (26.5 +/- 4.9 micromol.min( 1).ml(-1)) vs. the RSM (3.2 +/- 0.4 micromol.min(-1).ml(-1)), and higher levels of sPLA(2) as shown by Western blot and RT-PCR. Interestingly, administration of sPLA(2) transformed RSM into the tonic smooth muscle like that of the IAS: it developed basal tone and relaxed in response to the electrical field stimulation. From the present data, we conclude that sPLA(2) plays a critical role in the genesis of tone in the IAS. PLA(2) inhibitors may provide potential therapeutic target for treating anorectal motility disorders. PMID- 17717041 TI - Synergy between docosahexaenoic acid and butyrate elicits p53-independent apoptosis via mitochondrial Ca(2+) accumulation in colonocytes. AB - Butyrate, a short-chain fatty acid fiber fermentation product, induces colonocyte apoptosis in part via a Fas-mediated (extrinsic) pathway. In previous studies, we demonstrated that docosahexaenoic acid (DHA, 22:6(Delta4,7,10,13,16,19)) enhances the effect of butyrate by increasing mitochondrial lipid oxidation and mitochondrial Ca(2+)-dependent apoptosis in the colon. In this study, we further examined the mechanism of DHA-butyrate synergism in 1) human colon tumor (HCT-116 isogenic p53+/+ vs. p53-/-) cells and 2) primary cultures of rat colonic crypts. Herein, we show that DHA and butyrate promote apoptosis by enhancing mitochondrial Ca(2+) accumulation in both isogenic cell lines. Ca(2+) accumulation and apoptosis were inhibited by blockade of mitochondrial uniporter mediated Ca(2+) uptake. In addition, Mito-Q, a mitochondria-targeted antioxidant, also blocked apoptosis induced by DHA and butyrate. In complementary experiments, rats were fed diets supplemented with either corn oil (control, contains no DHA) or fish oil (contains DHA). Colonic crypts were isolated and incubated with or without butyrate, after which the mitochondria-to-cytosol Ca(2+) ratio and crypt viability were measured. No significant difference (P > 0.05) in basal mitochondrial Ca(2+) levels was observed between fish oil- or corn oil-fed animals. In contrast, when fish oil was the dietary lipid source, crypts incubated with butyrate exhibited a significant increase (3.6-fold, P < 0.001) in mitochondrial Ca(2+) compared with corn oil plus butyrate treatment. On the basis of these data, we propose that the combination of DHA and butyrate compared with butyrate alone further enhances colonocyte apoptosis by inducing a p53 independent, oxidation-sensitive, mitochondrial Ca(2+) -dependent (intrinsic) pathway. PMID- 17717043 TI - Visualizing formation and dynamics of vacuoles in living cells using contrasting dextran-bound indicator: endocytic and nonendocytic vacuoles. AB - Here we describe a technique that allows us to visualize in real time the formation and dynamics (fusion, changes of shape, and translocation) of vacuoles in living cells. The technique involves infusion of a dextran-bound fluorescent probe into the cytosol of the cell via a patch pipette, using the whole-cell patch-clamp configuration. Experiments were conducted on pancreatic acinar cells stimulated with supramaximal concentrations of cholecystokinin (CCK). The vacuoles, forming in the cytoplasm of the cell, were revealed as dark imprints on a bright fluorescence background, produced by the probe and visualized by confocal microscopy. A combination of two dextran-bound probes, one infused into the cytosol and the second added to the extracellular solution, was used to identify endocytic and nonendocytic vacuoles. The cytosolic dextran-bound probe was also used together with a Golgi indicator to illustrate the possibility of combining the probes and identifying the localization of vacuoles with respect to other cellular organelles in pancreatic acinar cells. Combinations of cytosolic dextran-bound probes with endoplasmic reticulum (ER) or mitochondrial probes were also used to simultaneously visualize vacuoles and corresponding organelles. We expect that the new technique will also be applicable and useful for studies of vacuole dynamics in other cell types. PMID- 17717044 TI - Murine gallbladder epithelial cells can differentiate into hepatocyte-like cells in vitro. AB - We determined whether extrahepatic biliary epithelial cells can differentiate into cells with phenotypic features of hepatocytes. Gallbladders were removed from transgenic mice expressing hepatocyte-specific beta-galactosidase (beta-Gal) and cultured under standard conditions and under experimental conditions designed to induce differentiation into a hepatocyte-like phenotype. Gallbladder epithelial cells (GBEC) cultured under standard conditions exhibited no beta-Gal activity. beta-Gal expression was prominent in 50% of cells cultured under experimental conditions. Similar morphological changes were observed in GBEC from green fluorescent protein transgenic mice cultured under experimental conditions. These cells showed higher levels of mRNA for genes expressed in hepatocytes, but not in GBEC, including aldolase B, albumin, hepatocyte nuclear factor-4alpha, aldehyde dehydrogenase 1, and glutamine synthetase, and they synthesized bile acids. Additional functional evidence of a hepatocyte-like phenotype included LDL uptake and enhanced benzodiazepine metabolism. Connexin-32 expression was evident in murine hepatocytes and in cells cultured under experimental conditions, but not in cells cultured under standard conditions. Notch 1, 2, and 3 and Notch ligand Jagged 1 mRNAs were downregulated in these cells compared with cells cultured under standard conditions. CD34, alpha-fetoprotein, and Sca-1 mRNA were not expressed in cells cultured under standard conditions, suggesting that the hepatocyte-like cells did not arise from hematopoietic stem cells or oval cells. These results point to future avenues for investigation into the potential use of GBEC in the treatment of liver disease. PMID- 17717045 TI - Urocortin I is present in the enteric nervous system and exerts an excitatory effect via cholinergic and serotonergic pathways in the rat colon. AB - Corticotropin-releasing factor (CRF) and urocortin I (UcnI) have been shown to accelerate colonic transit after central nervous system (CNS) or peripheral administration, but the mechanism of their peripheral effect on colonic motor function has not been fully investigated. Furthermore, the localization of UcnI in the enteric nervous system (ENS) of the colon is unknown. We investigated the effect of CRF and UcnI on colonic motor function and examined the localization of CRF, UcnI, CRF receptors, choline acetyltransferase (ChAT), and 5-HT. Isometric tension of rat colonic muscle strips was measured. The effect of CRF, UcnI on phasic contractions, and electrical field stimulation (EFS)-induced off contractions were examined. The effects of UcnI on both types of contraction were also studied in the presence of antalarmin, astressin2-B, tetrodotoxin (TTX), atropine, and 5-HT antagonists. The localizations of CRF, UcnI, CRF receptors, ChAT, and 5-HT in the colon were investigated by immunohistochemistry. CRF and UcnI increased both contractions dose dependently. UcnI exerted a more potent effect than CRF. Antalarmin, TTX, atropine, and 5-HT antagonists abolished the contractile effects of UcnI. CRF and UcnI were observed in the neuronal cells of the myenteric plexus. UcnI and ChAT, as well as UcnI and 5-HT, were colocalized in some of the neuronal cells of the myenteric plexus. This study demonstrated that CRF and UcnI act on the ENS and increase colonic contractility by enhancing cholinergic and serotonergic neurotransmission. These peptides are present in myenteric neurons. CRF and, perhaps, to a greater extent, UcnI appear to act as neuromodulators in the ENS of the rat colon. PMID- 17717046 TI - Effect of major liver resection on hepatic ureagenesis in humans. AB - Changes in hepatic ureagenesis following major hepatectomy are not well characterized. We studied the relation between urea synthesis and liver mass before and after major hepatectomy in humans. Fifteen patients scheduled for resection of malignancies in otherwise healthy livers were studied. Pre- and postoperative liver volume was assessed by computerized tomography-volumetry. During surgery, a primed, continuous infusion of [(13)C]urea was administered intravenously, and arterial blood samples were obtained hourly. Indocyanine green clearance was determined before and after resection. Seven patients underwent major hepatectomy, and eight patients underwent minor [<5% functional liver volume (total volume -- tumor volume)] or no resection, serving as controls. Resected functional liver volume in the major hepatectomy group averaged 60%. Urea synthesis per gram of functional liver tissue increased 2.6-fold following major hepatectomy, maintaining whole body urea synthesis. Arterial ammonia remained unchanged throughout the study, whereas following hepatectomy a hyperaminoacidemia occurred. In conclusion, immediately following major hepatectomy, urea synthesis per gram of functional liver tissue increases rapidly and proportionately to the amount of liver tissue resected, maintaining whole body urea synthesis at preoperative levels. This rapid and complete adaptation suggests that the capacity of urea synthesis is not limiting the maximum resectable volume in otherwise healthy livers. PMID- 17717039 TI - Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes. AB - The trace metal copper is essential for a variety of biological processes, but extremely toxic when present in excessive amounts. Therefore, concentrations of this metal in the body are kept under tight control. Central regulators of cellular copper metabolism are the copper-transporting P-type ATPases ATP7A and ATP7B. Mutations in ATP7A or ATP7B disrupt the homeostatic copper balance, resulting in copper deficiency (Menkes disease) or copper overload (Wilson disease), respectively. ATP7A and ATP7B exert their functions in copper transport through a variety of interdependent mechanisms and regulatory events, including their catalytic ATPase activity, copper-induced trafficking, post-translational modifications and protein-protein interactions. This paper reviews the extensive efforts that have been undertaken over the past few years to dissect and characterise these mechanisms, and how these are affected in Menkes and Wilson disease. As both disorders are characterised by an extensive clinical heterogeneity, we will discus how the underlying genetic defects correlate with the molecular functions of ATP7A and ATP7B and with the clinical expression of these disorders. PMID- 17717047 TI - A novel olfactory receptor gene family in teleost fish. AB - While for two of three mammalian olfactory receptor families (OR and V2R) ortholog teleost families have been identified, the third family (V1R) has been thought to be represented by a single, closely linked gene pair. We identified four further V1R-like genes in every teleost species analyzed (Danio rerio, Gasterosteus aculeatus, Oryzias latipes, Tetraodon nigroviridis, Takifugu rubripes). In the phylogenetic analysis these ora genes (olfactory receptor class A-related) form a single clade, which includes the entire mammalian V1R superfamily. Homologies are much lower in paralogs than in orthologs, indicating that all six family members are evolutionarily much older than the speciation events in the teleost lineage analyzed here. These ora genes are under strong negative selection, as evidenced by very small d(N)/d(S) values in comparisons between orthologs. A pairwise configuration in the phylogenetic tree suggests the existence of three ancestral Ora subclades, one of which has been lost in amphibia, and a further one in mammals. Unexpectedly, two ora genes exhibit a highly conserved multi-exonic structure and four ora genes are organized in closely linked gene pairs across all fish species studied. All ora genes are expressed specifically in the olfactory epithelium of zebrafish, in sparse cells within the sensory surface, consistent with the expectation for olfactory receptors. The ora gene repertoire is highly conserved across teleosts, in striking contrast to the frequent species-specific expansions observed in tetrapod, especially mammalian V1Rs, possibly reflecting a major shift in gene regulation as well as gene function upon the transition to tetrapods. PMID- 17717048 TI - Chromosomal rearrangement interferes with meiotic X chromosome inactivation. AB - Heterozygosity for certain mouse and human chromosomal rearrangements is characterized by the incomplete meiotic synapsis of rearranged chromosomes, by their colocalization with the XY body in primary spermatocytes, and by male limited sterility. Previously, we argued that such X-autosomal associations could interfere with meiotic sex chromosome inactivation. Recently, supporting evidence has reported modifications of histones in rearranged chromosomes by a process called the meiotic silencing of unsynapsed chromatin (MSUC). Here, we report on the transcriptional down-regulation of genes within the unsynapsed region of the rearranged mouse chromosome 17, and on the subsequent disturbance of X chromosome inactivation. The partial transcriptional suppression of genes in the unsynapsed chromatin was most prominent prior to the mid-pachytene stage of primary spermatocytes. Later, during the mid-late pachytene, the rearranged autosomes colocalized with the XY body, and the X chromosome failed to undergo proper transcriptional silencing. Our findings provide direct evidence on the MSUC acting at the mRNA level, and implicate that autosomal asynapsis in meiosis may cause male sterility by interfering with meiotic sex chromosome inactivation. PMID- 17717050 TI - Changes in adiponectin and inflammatory genes in response to hormonal imbalances in female mice and exacerbation of depot selective visceral adiposity by high-fat diet: implications for insulin resistance. AB - Early obesity and late onset of insulin resistance associated with hormonal imbalances occur in FSH receptor-deficient follitropin receptor knockout female mice. This study tests the hypothesis that chronic high-fat diet aggravates obesogenic changes in a depot-specific manner and explores some molecular links of hormone imbalances with insulin resistance. In SV 129 mice, hormonal imbalances seem obligatory for exacerbation of diet-induced obesity. Visceral adiposity, glucose intolerance, and lipid disturbances in 9-month follitropin receptor knockout females were associated with decrease in adiponectin signaling. High-molecular-weight plasma adiponectin and adipose tissue adiponectin mRNA were decreased. Adiponectin receptors R1 and R2 mRNA was selectively altered in mesenteric fat but not periuterine fat. R2 decreased in the liver and R1 was higher in muscle. Whereas hepatic adenosine monophosphate T-activated protein kinase activity was down-regulated, both phosphoenolpyruvate carboxykinase and glucose-6-phosphatase enzymes were up-regulated. Longitudinally, diminishing sex hormone signaling in adipose tissue was associated with progressive down regulation of adiponectin activity and gradual impaired glucose tolerance. Chronic high-fat diet in SV129 wild-type mice did not produce overt obesity but induced visceral fat depot changes accompanied by liver lipid accumulation, high cholesterol, and up-regulation of inflammation gene mRNAs. Thus, TNF-alpha, C-C motif chemokine receptor-2, and C-C motif chemokine ligand-2 were selectively elevated in mesenteric fat without altering glucose tolerance and adiponectin signaling. Our study highlights adiponectin signaling and regulation to be involved in hormone imbalance-induced insulin resistance and demonstrates selective visceral adipose depot alterations by chronic high-fat diet and induction of inflammatory genes. PMID- 17717049 TI - Pro-opiomelanocortin modulates the thermogenic and physical activity responses to high-fat feeding and markedly influences dietary fat preference. AB - Complete proopiomelanocortin (POMC) deficiency causes a human syndrome of hypoadrenalism, altered skin and hair pigmentation, and severe hyperphagic obesity. Heterozygote carriers of nonsense mutations are strongly predisposed to obesity. Pomc(+/-) mice have normal body weight on a chow diet but increase food intake and become more obese than wild-type littermates when placed on a high-fat diet. To further explore the mechanisms whereby dietary fat interacts with Pomc genotype to produce obesity, we examined Pomc-null, Pomc(+/-), and wild-type mice for changes in the components of energy balance in response to provision of a high-fat diet and macronutrient preference when presented with a selection of dietary choices. In contrast to wild-type mice, Pomc null mice did not increase their resting energy expenditure or their spontaneous physical activity when given a high-fat diet. Pomc(+/-) mice increased resting energy expenditure similarly to wild types, but their increase in physical activity was significantly less than that seen in wild-type mice. In two independent experimental tests of macronutrient preference, Pomc genotype was a strong predictor of dietary fat preference with Pomc null animals choosing to eat approximately twice as much fat, but similar amounts of carbohydrate and protein, as wild-type animals. Pomc(+/-) mice showed an intermediate response. In summary, POMC-derived peptides have influences on multiple aspects of the organism's response to the presentation of high-fat diet. This includes a major influence, readily discernible even in heterozygote animals, on the dietary preference for fat. PMID- 17717051 TI - Pax4 paired domain mediates direct protein transduction into mammalian cells. AB - Pax4, a paired-box transcription factor, is a key regulator of pancreatic islet cell growth and differentiation. Here, we report for the first time that the Pax4 protein can permeate into various cell types including pancreatic islets. The paired domain of Pax4 serves as a novel protein transduction domain (PTD). The Pax4 protein can transduce in a dose- and time-dependent manner. The cellular uptake of Pax4 PTD can be completely blocked by heparin, whereas cytochalasin D and amiloride were partially effective in blocking the Pax4 protein entry. Transduced intact Pax4 protein functions similarly to the endogenous Pax4. It inhibits the Pax6 mediated transactivation and protects Min6 cells against TNFalpha-induced apoptosis. These data suggest that Pax4 protein transduction could be a safe and valuable strategy for protecting islet cell growth in culture from apoptosis and promoting islet cell differentiation. PMID- 17717053 TI - Essential role of Wnt3a-mediated activation of mitogen-activated protein kinase p38 for the stimulation of alkaline phosphatase activity and matrix mineralization in C3H10T1/2 mesenchymal cells. AB - Signaling pathways involved in the development of osteoprogenitors induced by Wnts remain poorly understood. In this study, we investigated the role of MAPKs in the development of mesenchymal cells into osteoprogenitors. In C3H10T1/2 mesenchymal cells, Wnt3a induced a rapid and transient activation of MAPKs p38 and ERK. Dickkopf 1, a selective antagonist of Wnt proteins binding to low density lipoprotein-receptor-related protein-5/6 did not influence activation of p38 and ERK induced by Wnt3a. A MAPK kinase-1/2 (MEK1/2) inhibitor blocked, whereas a p38 inhibitor had no effect on, Wnt3a-induced cell proliferation. In contrast, both inhibitors significantly reduced alkaline phosphatase stimulation with a more pronounced effect of the p38 inhibitor. The p38 inhibitor also blunted nodule mineralization induced by Wnt3a. Associated with these effects, beta-catenin transcriptional activity, assessed with the TOPflash system, was dose-dependently decreased by the p38 but not by the ERK inhibitor. Both the reduced alkaline phosphatase stimulation and blunting of beta-catenin transcriptional activity were mimicked by expression of dominant-negative (dn) p38 and dnMEK 3/6. Inhibition of beta-catenin transcriptional activity by the p38 inhibitor as well as by dnp38 and dnMEK 3/6 molecules were not associated with changes in cytosolic and nuclear beta-catenin levels induced by Wnt3a. In conclusion, Wnt3a activates ERK and p38 in mesenchymal C3H10T1/2 cells by a low density lipoprotein-receptor-related protein-5/6-independent mechanism. Activation of p38 regulates alkaline phosphatase activity and nodule mineralization induced by Wnt3a probably by interacting with beta-catenin transcriptional activity. These observations suggest that MAPKs ERK and p38 are probably essential pathways activated by Wnt proteins for the development of mesenchymal cells into osteoprogenitors. PMID- 17717052 TI - Conditional deletion of insulin-like growth factor-I in collagen type 1alpha2 expressing cells results in postnatal lethality and a dramatic reduction in bone accretion. AB - IGF-I acts through endocrine and local, autocrine/paracrine routes. Disruption of both endocrine and local IGF-I action leads to neonatal lethality and impaired growth in various tissues including bone; however, the severity of growth and skeletal phenotype caused by disruption of endocrine IGF-I action is far less than with total IGF-I disruption. Based on these data and the fact that bone cells express IGF-I in high abundance, we and others predicted that locally produced IGF-I is also critical in regulating growth and bone accretion. To determine the role of local IGF-I, type 1alpha2 collagen-Cre mice were crossed with IGF-I loxP mice to generate Cre+ (conditional mutant) and Cre- (control) loxP homozygous mice. Surprisingly, approximately 40-50% of the conditional mutants died at birth, which is similar to total IGF-I disruption, but not observed in mice lacking circulating IGF-I. Expression of IGF-I in bone and muscle but not liver and brain was significantly decreased in the conditional mutant. Accordingly, circulating levels of serum IGF-I were also not affected. Disruption of local IGF-I dramatically reduced body weight 28-37%, femur areal bone mineral density 10-25%, and femur bone size 18-24% in growing mice. In addition, mineralization was reduced as early as during embryonic development. Consistently, histomorphometric analysis determined impaired osteoblast function as demonstrated by reduced mineral apposition rate (14-30%) and bone formation rate (35-57%). In conclusion, both local and endocrine IGF-I actions are involved in regulating growth of various tissues including bone, but they act via different mechanisms. PMID- 17717054 TI - Insulin secretion is increased in pancreatic islets of neuropeptide Y-deficient mice. AB - Neuropeptide Y (NPY), whose role in appetite regulation is well known, is also expressed in pancreatic islets. Although previous studies indicated that application of NPY to pancreatic islets inhibits insulin secretion, its physiological role in the regulation of insulin secretion is not fully understood. We hypothesized that NPY in islets tonically suppresses insulin secretion and the reduction of islet NPY increases insulin secretion. To address the hypothesis, islet function of NPY-deficient mice was analyzed. Although there was little change in glucose homeostasis in vivo, pancreatic islets from NPY deficient mice had higher basal insulin secretion (1.5 times), glucose-stimulated insulin secretion (1.5 times), and islet mass (1.7 times), compared with wild type mouse. Next we sought to determine whether the expression of NPY and Y(1) receptor in islets was altered in hyperinsulinemia associated with obesity. Islets from C57BL/6J mice on a high-fat diet had 1.9 times higher basal insulin secretion and 2.4 times higher glucose-stimulated insulin secretion than control mice, indicating islet adaptation to obesity. Expression of NPY and Y(1) receptor mRNA levels was decreased by 70 and 64%, respectively, in high-fat diet islets, compared with controls. NPY and Y(1) receptor in islets were also reduced by 91 and 80%, respectively, in leptin-deficient ob/ob mice that showed marked hyperinsulinemia. Together these results suggest that endogenous NPY tonically inhibits insulin secretion from islets and a reduction of islet NPY may serve as one of the mechanisms to increase insulin secretion when islets compensate for insulin resistance associated with obesity. PMID- 17717055 TI - A central role for neuronal adenosine 5'-monophosphate-activated protein kinase in cancer-induced anorexia. AB - The pathogenesis of cancer anorexia is multifactorial and associated with disturbances of the central physiological mechanisms controlling food intake. However, the neurochemical mechanisms responsible for cancer-induced anorexia are unclear. Here we show that chronic infusion of 5-amino-4imidazolecarboxamide riboside into the third cerebral ventricle and a chronic peripheral injection of 2 deoxy-d-glucose promotes hypothalamic AMP-activated protein kinase (AMPK) activation, increases food intake, and prolongs the survival of anorexic tumor bearing (TB) rats. In parallel, the pharmacological activation of hypothalamic AMPK in TB animals markedly reduced the hypothalamic production of inducible nitric oxide synthase, IL-1beta, and TNF-alpha and modulated the expression of proopiomelanocortin, a hypothalamic neuropeptide that is involved in the control of energy homeostasis. Furthermore, the daily oral and intracerebroventricular treatment with biguanide antidiabetic drug metformin also induced AMPK phosphorylation in the central nervous system and increased food intake and life span in anorexic TB rats. Collectively, the findings of this study suggest that hypothalamic AMPK activation reverses cancer anorexia by inhibiting the production of proinflammatory molecules and controlling the neuropeptide expression in the hypothalamus, reflecting in a prolonged life span in TB rats. Thus, our data indicate that hypothalamic AMPK activation presents an attractive opportunity for the treatment of cancer-induced anorexia. PMID- 17717056 TI - Dual effects of daidzein, a soy isoflavone, on catecholamine synthesis and secretion in cultured bovine adrenal medullary cells. AB - We recently demonstrated the occurrence and functional roles of plasma membrane estrogen receptors in cultured bovine adrenal medullary cells. Here we report the effects of daidzein, a phytoestrogen of soybeans, on catecholamine synthesis and secretion in the cells. Incubation of cells with daidzein for 20 min increased the synthesis of (14)C-catecholamines from [(14)C]tyrosine but not [(14)C]dihydroxyphenylalanine, in a concentration-dependent manner (10-1000 nm). The stimulatory effect of daidzein on (14)C-catecholamine synthesis was not inhibited by ICI182,780, a classical estrogen receptor inhibitor. Acetylcholine, a physiological secretagogue, stimulated the synthesis of (14)C-catecholamines, which was suppressed by daidzein at 1 mum. Daidzein at high concentrations (1-100 microm) suppressed catecholamine secretion induced by acetylcholine. Furthermore, daidzein (10-1000 nm) inhibited the specific binding of [(3)H]17beta-estradiol to plasma membranes isolated from bovine adrenal medulla. The present findings suggest that daidzein at low concentrations stimulates catecholamine synthesis through plasma membrane estrogen receptors but at high concentrations inhibits catecholamine synthesis and secretion induced by acetylcholine in bovine adrenal medulla. The latter effect of daidzein may be a beneficial action on the cardiovascular system. PMID- 17717057 TI - Neutralisation of muscle tumour necrosis factor alpha does not attenuate exercise induced muscle pain but does improve muscle strength in healthy male volunteers. AB - OBJECTIVE: Inflammatory mediators, such as tumour necrosis factor alpha (TNFalpha), may contribute to delayed-onset muscle soreness. The effect of neutralising TNFalpha with etanercept, a soluble TNFalpha receptor, on delayed onset muscle soreness (DOMS) induced in the quadriceps muscle was analysed. DESIGN: On two separate occasions at least 6 weeks apart, etanercept 25 mg or vehicle was given subcutaneously 1 hour before unaccustomed exercise to 12 healthy men in a randomised double-blind cross-over format. To induce DOMS, subjects completed 4 sets of 15 repetitions at 80% of their one-repetition maximum (1RM), using a 45 degrees inclined leg press. Muscle soreness was assessed using a 100-mm visual analogue scale (VAS), and pressure pain threshold (PPT) on the thigh before and 24, 48 and 72 hours after exercise. Changes in the subject's muscle strength were detected by reassessing the subject's 1RM 24, 48 and 72 hours after exercise. RESULTS: Muscle strength decreased 24 and 48 hours after exercise regardless of agent administered (analysis of variance, p<0.001). At 72 hours after exercise, muscle strength was significantly greater (p<0.01) after etanercept than after placebo. The exercise protocol induced significant DOMS for up to 72 hours, as reflected by reduced PPT and increased VAS scores (p<0.001). Etanercept had no effect on PPT or VAS. CONCLUSION: TNFalpha does not affect muscle soreness associated with unaccustomed exercise, but may improve the recovery of muscle function. PMID- 17717058 TI - A comparison of cleat types during two football-specific tasks on FieldTurf. AB - OBJECTIVE: To examine the effect of different cleat plate configurations on plantar pressure during two tasks. DESIGN: Thirty-six athletes ran an agility course 5 times while wearing 4 different types of Nike Vitoria cleats: (1) bladed, (2) elliptical firm ground, (3) hard ground and (4) turf. Plantar pressure data were recorded during a side cut and a cross cut using Pedar-X insoles. SETTING: Controlled laboratory study PARTICIPANTS: No history of lower extremity injury in the past 6 months, no previous foot or ankle surgery, not currently wearing foot orthotics and play a cleated sport at least twice a week. MAIN OUTCOME MEASUREMENTS: Total foot contact time, contact area, maximum force, peak pressure and the force-time integral (FTI) in the medial, middle and lateral regions of the forefoot were collected. A 1x4 ANOVA (alpha = 0.05) was performed on each dependent variable. A Bonferroni adjustment was conducted (alpha = 0.008). RESULTS: In the cross cut task, statistical differences between cleats were observed in three variables: total foot peak pressure, lateral forefoot FTI, and lateral forefoot normalised maximum force. In the side cut task, statistical differences between cleats were observed in 4 variables: total foot peak pressure, the medial and middle forefoot FTI, and the medial and middle forefoot normalised maximum force. CONCLUSIONS: Significant differences in forefoot loading patterns existed between cleat types. Based on the results of this study, it might be beneficial to increase the forefoot cushioning in cleats in an attempt to decrease loading in these regions of the foot. PMID- 17717059 TI - Low back pain associated with internal snapping hip syndrome in a competitive cyclist. AB - Low back pain is a common complaint among cyclists. Here we present the case of a competitive master cyclist with low back pain and whose symptoms ultimately resolved when he was treated for internal snapping hip syndrome. Internal snapping hip syndrome is a painful lesion of the iliopsoas caused by snapping of the tendon over the iliopectineal eminence or anterior femoral head when the femur is extended from a flexed position. This is the first published report that we are aware of that describes this syndrome as a potential cause of low back pain in a competitive cyclist. PMID- 17717060 TI - Feasibility of a walking workstation to increase daily walking. AB - OBJECTIVE: The number of calories expended in the workplace has declined significantly in the past 75 years. A walking workstation that allows workers to walk while they work has the potential to increase caloric expenditure. We evaluated whether employees can and will use walking workstations while performing their jobs. METHODS AND PROCEDURES: We studied nurses, clinical assistants, secretaries and appointment secretaries using the StepWatch Activity Monitor System (which accurately measures steps taken at slow speeds) while performing their job functions in their usual fashion and while using the walking workstation. RESULTS: Subjects increased the number of steps taken during the workday by 2000 steps per day (p<0.05). This was equivalent to an increase in caloric expenditure of 100 kcal/day. Subjects reported that they enjoyed using the workstation, that it could be used in the actual work arena and that, if available, they would use it. DISCUSSION: Walking workstations have the potential for promoting physical activity and facilitating weight loss. Several subjects in this study expended more than 200 extra calories daily using such a system. Further trials are indicated. PMID- 17717062 TI - Efficacy of personal symptom and family history questionnaires when screening for inherited cardiac pathologies: the role of electrocardiography. AB - AIMS: This study sought to confirm the efficacy of using resting 12-lead ECG alongside personal symptom and family history questionnaires and physical examination when screening for diseases with the potential to cause sudden cardiac death in the young. METHODS AND RESULTS: 1074 national and international junior athletes (mean age 15.8 (SD 0.7) years, range 10 to 27) and 1646 physically active schoolchildren (16.1 (SD 2.1) years, range 14 to 20) were screened using personal and family history questionnaires, physical examination and resting 12-lead ECG. Nine participants with a positive diagnosis of a disease associated with sudden cardiac death were identified. None of the participants diagnosed with a disease associated with sudden cardiac death were symptomatic or had a family history of note. CONCLUSION: Family history and personal symptom questionnaires alone are inadequate to identify people with diseases associated with sudden cardiac death. Use of the 12-lead ECG is essential when screening for cardiac pathology in the young. PMID- 17717063 TI - Chronic dynamic exercise increases apolipoprotein A-I expression in rabbit renal cortex as determined by proteomic technology. AB - OBJECTIVE: We have shown previously that exercise training enhances endothelium dependent and endothelium-independent vascular relaxation in rabbit kidney. This study aimed to investigate protein expression changes in the rabbit renal cortex induced by chronic dynamic exercise. DESIGN: Kidneys were obtained from New Zealand rabbits either confined to pens (n = 8) or trained on a treadmill (0% grade) for 5 days/week at a speed of 18 m/min for 60-min periods over 12 weeks (n = 8). Expression of proteins in the renal cortex was determined by colloidal Coomassie blue staining after two-dimensional polyacrylamide gel electrophoresis. Differential protein spots were excised and digested with trypsin, and peptides were sequenced by electrospray ionization-ion trap mass spectrometry. RESULTS: Two pairs of matching differentially stained spots displayed an approximate threefold increase in trained compared with sedentary animals. These four spots presented a molecular mass of 23 kDa but different pI values. Mass spectrometric analyses revealed the pairs of matching spots as being rabbit apolipoprotein A-I. CONCLUSION: Chronic dynamic exercise increases apolipoprotein A-I expression in the rabbit renal cortex. This fact could be involved in the alterations observed in the renal circulation after exercise training. PMID- 17717064 TI - A novel role of complement in mobilization: immunodeficient mice are poor granulocyte-colony stimulating factor mobilizers because they lack complement activating immunoglobulins. AB - Complement (C) and innate immunity emerge as important and underappreciated modulators of mobilization of hematopoietic stem/progenitor cells (HSPC). We reported that (a) C becomes activated in bone marrow (BM) during granulocyte colony-stimulating factor (G-CSF)-induced mobilization by the classic immunoglobulin (Ig)-dependent pathway and that (b) C3 cleavage fragments increase the responsiveness of HSPC to a stromal derived factor-1 gradient. Since patients suffering from severe combined immunodeficiency (SCID) mobilize poorly, we hypothesized that this could be directly linked to the lack of C activating Ig in these patients. In the current study to better elucidate the role of C activation in HSPC mobilization, we mobilized mice that lack Ig (RAG2, SCID, and Jh) by G CSF or zymosan, compounds that activate C by the classic Ig-dependent and the alternative Ig-independent pathways, respectively. In addition, we evaluated mobilization in C5-deficient animals. Mobilization was evaluated by measuring the number of colony-forming unit-granulocyte macrophage and leukocytes circulating in peripheral blood. We found that (a) G-CSF- but not zymosan-induced mobilization was severely reduced in RAG2, SCID, and Jh mice; (b) impaired G-CSF induced mobilization was restored after infusion of purified wild-type Ig; and (c) mobilization was severely reduced in C5-deficient mice. These data provide strong evidence that the C system plays a pivotal role in mobilization of HSPC and that egress of HSPC from BM occurs as part of an immune response. Disclosure of potential conflicts of interest is found at the end of this article. PMID- 17717065 TI - Reduced Mcm2 expression results in severe stem/progenitor cell deficiency and cancer. AB - Mcm2 is a component of the DNA replication licensing complex that marks DNA replication origins during G1 of the cell cycle for use in the subsequent S phase. It is expressed in stem/progenitor cells in a variety of regenerative tissues in mammals. Here, we have used the Mcm2 gene to develop a transgenic mouse in which somatic stem/progenitor cells can be genetically modified in the adult. In these mice, a tamoxifen-inducible form of Cre recombinase is integrated 3' to the Mcm2 coding sequence and expressed via an internal ribosome entry site (IRES). Heterozygous Mcm2(IRES-CreERT2/wild-type (wt)) mice are phenotypically indistinguishable from wild-type at least through 1 year of age. In bigenic Mcm2(IRES-CreERT2/wt); Z/EG reporter mice, tamoxifen-dependent enhanced green fluorescence protein expression is inducible in a wide variety of somatic stem cells and their progeny. However, in Mcm2(IRES-CreERT2/IRES-CreERT2) homozygous embryos or mouse embryonic fibroblasts, Mcm2 is reduced to approximately one third of wild-type levels. Despite the fact that these mice develop normally and are asymptomatic as young adults, life span is greatly reduced, with most surviving to only approximately 10-12 weeks of age. They demonstrate severe deficiencies in the proliferative cell compartments of a variety of tissues, including the subventricular zone of the brain, muscle, and intestinal crypts. However, the immediate cause of death in most of these animals is cancer, where the majority develop lymphomas. These studies directly demonstrate that deficiencies in the function of the core DNA replication machinery that are compatible with development and survival nonetheless result in a chronic phenotype leading to stem cell deficiency in multiple tissues and cancer. Disclosure of potential conflicts of interest is found at the end of this article. PMID- 17717066 TI - Transcriptional analysis of quiescent and proliferating CD34+ human hemopoietic cells from normal and chronic myeloid leukemia sources. AB - Quiescent and dividing hemopoietic stem cells (HSC) display marked differences in their ability to move between the peripheral circulation and the bone marrow. Specifically, long-term engraftment potential predominantly resides in the quiescent HSC subfraction, and G-CSF mobilization results in the preferential accumulation of quiescent HSC in the periphery. In contrast, stem cells from chronic myeloid leukemia (CML) patients display a constitutive presence in the circulation. To understand the molecular basis for this, we have used microarray technology to analyze the transcriptional differences between dividing and quiescent, normal, and CML-derived CD34+ cells. Our data show a remarkable transcriptional similarity between normal and CML dividing cells, suggesting that the effects of BCR-ABL on the CD34+ cell transcriptome are more limited than previously thought. In addition, we show that quiescent CML cells are more similar to their dividing counterparts than quiescent normal cells are to theirs. We also show these transcriptional differences to be reflected in the altered proliferative activity of normal and CML CD34+ cells. Of the most interest is that the major class of genes that is more abundant in the quiescent cells compared with the dividing cells encodes members of the chemokine family. We propose a role for chemokines expressed by quiescent HSC in the orchestration of CD34+ cell mobilization. Disclosure of potential conflicts of interest is found at the end of this article. PMID- 17717067 TI - Integrins regulate mouse embryonic stem cell self-renewal. AB - Extracellular matrix (ECM) components regulate stem-cell behavior, although the exact effects elicited in embryonic stem (ES) cells are poorly understood. We previously developed a simple, defined, serum-free culture medium that contains leukemia inhibitory factor (LIF) for propagating pluripotent mouse embryonic stem (mES) cells in the absence of feeder cells. In this study, we determined the effects of ECM components as culture substrata on mES cell self-renewal in this culture medium, comparing conventional culture conditions that contain serum and LIF with gelatin as a culture substratum. mES cells remained undifferentiated when cultured on type I and type IV collagen or poly-D-lysine. However, they differentiated when cultured on laminin or fibronectin as indicated by altered morphologies, the activity of alkaline phosphatase decreased, Fgf5 expression increased, and Nanog and stage-specific embryonic antigen 1 expression decreased. Under these conditions, the activity of signal transducer and activator of transcription (STAT)3 and Akt/protein kinase B (PKB), which maintain cell self renewal, decreased. In contrast, the extracellular signal-regulated kinase (ERK)1/2 activity, which negatively controls cell self-renewal, increased. In the defined conditions, mES cells did not express collagen-binding integrin subunits, but they expressed laminin- and fibronectin-binding integrin subunits. The expression of some collagen-binding integrin subunits was downregulated in an LIF concentration-dependent manner. Blocking the interactions between ECM and integrins inhibited this differentiation. Conversely, the stimulation of ECM integrin interactions by overexpressing collagen-binding integrin subunits induced differentiation of mES cells cultured on type I collagen. The results of the study indicated that inactivation of the integrin signaling is crucial in promoting mouse embryonic stem cell self-renewal. Disclosure of potential conflicts of interest is found at the end of this article. PMID- 17717068 TI - Self-renewal of murine embryonic stem cells is supported by the serine/threonine kinases Pim-1 and Pim-3. AB - pim-1 and pim-3 encode serine/threonine kinases involved in the regulation of cell proliferation and apoptosis in response to cytokine stimulation. We analyzed the regulation of pim-1 and pim-3 by the leukemia inhibitory factor (LIF)/gp130/signal transducer and activator of transcription-3 (STAT3) pathway and the role of Pim-1 and Pim-3 kinases in mouse embryonic stem (ES) cell self renewal. Making use of ES cells expressing a granulocyte colony-stimulating factor:gp130 chimeric receptor and a hormone-dependent signal transducer and activator of transcription-3 estrogen receptor (STAT3-ER(T2)), we showed that expression of pim-1 and pim-3 was upregulated by LIF/gp130-dependent signaling and the STAT3 transcription factor. ES cells overexpressing pim-1 and pim-3 had a greater capacity to self-renew and displayed a greater resistance to LIF starvation based on a clonal assay. In contrast, knockdown of pim-1 and pim-3 increased the rate of spontaneous differentiation in a self-renewal assay. Knockdown of pim-1 and pim-3 was also detrimental to the growth of undifferentiated ES cell colonies and increased the rate of apoptosis. These findings provide a novel role of Pim-1 and Pim-3 kinases in the control of self renewal of ES cells. Disclosure of potential conflicts of interest is found at the end of this article. PMID- 17717069 TI - Dissection of the insulin-sensitizing effect of liver X receptor ligands. AB - The liver X receptors (LXRalpha and beta) are nuclear receptors that coordinate carbohydrate and lipid metabolism. Treatment of insulin-resistant mice with synthetic LXR ligands enhances glucose tolerance, inducing changes in gene expression expected to decrease hepatic gluconeogenesis (via indirect suppression of gluconeogenic enzymes) and increase peripheral glucose disposal (via direct up regulation of glut4 in fat). To evaluate the relative contribution of each of these effects on whole-body insulin sensitivity, we performed hyperinsulinemic euglycemic clamps in high-fat-fed insulin-resistant rats treated with an LXR agonist or a peroxisome proliferator-activated receptor gamma ligand. Both groups showed significant improvement in insulin action. Interestingly, rats treated with LXR ligand had lower body weight and smaller fat cells than controls. Insulin-stimulated suppression of the rate of glucose appearance (Ra) was pronounced in LXR-treated rats, but treatment failed to enhance peripheral glucose uptake (R'g), despite increased expression of glut4 in epididymal fat. To ascertain whether LXR ligands suppress hepatic gluconeogenesis directly, mice lacking LXRalpha (the primary isotype in liver) were treated with LXR ligand, and gluconeogenic gene expression was assessed. LXR activation decreased expression of gluconeogenic genes in wild-type and LXRbeta null mice, but failed to do so in animals lacking LXRalpha. Our observations indicate that despite inducing suggestive gene expression changes in adipose tissue in this model of diet induced insulin resistance, the antidiabetic effect of LXR ligands is primarily due to effects in the liver that appear to require LXRalpha. These findings have important implications for clinical development of LXR agonists as insulin sensitizers. PMID- 17717070 TI - FK506-binding protein 52 phosphorylation: a potential mechanism for regulating steroid hormone receptor activity. AB - Functional maturation of steroid hormone receptors requires ordered assembly into a large multichaperone complex consisting of receptor monomer, an Hsp90 dimer, the p23 cochaperone, and an FK506-binding protein (FKBP) family member or alternate peptidylprolyl isomerase-related cochaperone. Previous cellular studies demonstrated that FKBP52 can potentiate receptor function. These results have been confirmed in fkbp4 gene knockout mice in which males are partially androgen insensitive and females display characteristics of progesterone insensitivity. Conversely, FKBP51, which has a high degree of similarity to FKBP52, antagonizes FKBP52-mediated potentiation. Both proteins consist of three domains: two FKBP12 like domains termed FK1 and FK2 and a tetratricopeptide repeat domain that targets binding to Hsp90. To help understand why the two FKBPs behave differently and to gain insight into FKBP52 potentiation activity, we have analyzed the loop structure that links FK1 and FK2. Within the FK linker of FKBP52 is the sequence TEEED, which forms a consensus casein kinase II phosphorylation site; the corresponding sequence in FKBP51 is FED. We demonstrate that the distinct FK linker sequences per se do not account for lack of potentiation activity by FKBP51. However, phosphorylation of the FK linker appears to be an important regulatory determinant of FKBP52-mediated potentiation of steroid receptor activity. PMID- 17717071 TI - MUC1 expression is repressed by protein inhibitor of activated signal transducer and activator of transcription-y. AB - Mucin 1 (MUC1) is a transmembrane glycoprotein that modulates the interaction between the embryo and the uterine epithelial cell surface. MUC1 also is a tumor marker and has been implicated in the protection of cancer cells from immune cell attack as well as in cell signaling in some tumors. We and others have shown that MUC1 expression is activated by progesterone (P), TNF-alpha, and interferon-gamma (IFN-gamma). Here we demonstrate that MUC1 expression is down-regulated by overexpression of members of the protein inhibitor of activated signal transducer and activator of transcription (PIAS) family, PIAS1, PIAS3, PIASxalpha, PIASxbeta, and PIASy, in human uterine epithelial cell lines HES and HEC-1A and in a breast cancer cell line, T47D. Treatments with P, TNF-alpha, and IFN-gamma were unable to overcome the repression by PIASy. PIASy repression of basal, P-, and TNF-alpha-stimulated MUC1 promoter activity was not dependent on the PIASy sumoylation domain. In contrast, PIASy suppression of IFN-gamma-activated MUC1 promoter activity was dependent on the PIASy sumoylation domain. PIASy and P receptor B were localized to the nucleus upon P treatment, and small interfering RNA knockdown of PIASy resulted in an increase in P-mediated stimulation of MUC1 protein expression. Overexpression of PIASy did not affect P receptor B binding to the MUC1 promoter but surprisingly led to a loss of nuclear receptor corepressor (NCoR), which was recruited to the promoter in response to P. Collectively, these data indicate that PIASy may be a useful target for down regulation of MUC1 expression in various contexts. PMID- 17717072 TI - Pubertal impairment in Nhlh2 null mice is associated with hypothalamic and pituitary deficiencies. AB - Pubertal development is impaired in mice lacking the basic helix-loop-helix transcription factor Nhlh2. The mechanisms underlying changes in reproduction in Nhlh2-deficient mice (Nhlh2(-/-)) are unclear. Here we show that hypothalamic GnRH-1 content is reduced in adult Nhlh2(-/-) mice as is the number of GnRH-1 neurons localized to mid- and caudal hypothalamic regions. This reduction was detected postnatally after normal migration of GnRH-1 neurons within nasal regions had occurred. Phenotype rescue experiments showed that female Nhlh2(-/-) mice were responsive to estrogen treatment. In contrast, puberty could not be primed in female Nhlh2(-/-) mice with a GnRH-1 regimen. The adenohypophysis of Nhlh2(-/-) mice was hypoplastic although it contained a full complement of the five anterior pituitary cell types. GnRH-1 receptors (GnRHRs) were reduced in Nhlh2(-/-) pituitary gonadotropes as compared with wild type. In vitro assays indicated that Nhlh2 expression is regulated in parallel with GnRHR expression. However, direct transcriptional activity of Nhlh2 on the GnRHR promoter was not found. These results indicate that Nhlh2 plays a role in the development and functional maintenance of the hypothalamic-pituitary-gonadal axis at least at two levels: 1) in the hypothalamus by regulating the number and distribution of GnRH 1 neurons and, 2) in the developing and mature adenohypophysis. PMID- 17717073 TI - Homodimerization of Ror2 tyrosine kinase receptor induces 14-3-3(beta) phosphorylation and promotes osteoblast differentiation and bone formation. AB - Ror2 receptor plays a key role in bone formation, but its signaling pathway is not completely understood. We demonstrate that Ror2 homodimerizes at the cell surface, and that dimerization can be induced by a bivalent antibody. Antibody mediated dimerization causes receptor autophosphorylation and induces functional consequences of its signaling, including osteogenesis in mesenchymal stem cells and bone formation in organ culture. We further show that Ror2 associates with and phosphorylates 14-3-3beta scaffold protein. Endogenous Ror2 binds 14-3-3beta in U2OS osteosarcoma cells, and purified intracellular domain of Ror2 interacts with 14-3-3beta in vitro. 14-3-3beta Is tyrosine phosphorylated in U2OS cells, and this phosphorylation is inhibited by down-regulating Ror2 and enhanced by overexpressing the kinase. Purified Ror2 phosphorylates 14-3-3beta in vitro, confirming 14-3-3beta as the first identified Ror2 substrate. Down-regulating 14 3-3beta potentiates osteoblastogenesis in mesenchymal stem cells and increases bone formation in calvarial cultures, indicating that 14-3-3beta exerts a negative effect on osteogenesis. This raises a possibility that Ror2 induces osteogenic differentiation, at least in part, through a release of the 14-3-3beta mediated inhibition. Our research forms a foundation for several new areas of investigation, including the molecular regulation of 14-3-3 by tyrosine phosphorylation and the role of this scaffold in osteogenesis. PMID- 17717075 TI - Nuclear stabilization of beta-catenin and inactivation of glycogen synthase kinase-3beta by gonadotropin-releasing hormone: targeting Wnt signaling in the pituitary gonadotrope. AB - The GnRH receptor is a G protein-coupled receptor (GPCR), and its ligand GnRH is the central regulator of the reproductive system. GnRH receptors are known to target a wide variety of signal transduction pathways. Several recent studies have shown that activation of GPCRs can impact on beta-catenin signaling. beta Catenin is the main effecter of the Wnt signaling pathway where it acts with the transcription factors T cell factor/lymphoid enhancer factor to mediate the transcription of Wnt target genes. We show that GnRH treatment promotes the nuclear accumulation of beta-catenin, activation of T cell factor-dependent transcription, and up-regulation of Wnt target genes, c-Jun, Fra-1, and c-Myc. These results are observed in human embryonic kidney 293/GnRH receptor-expressing cells and have been recapitulated in LbetaT2 and alphaT3-1 mouse gonadotrope cells. In addition to these findings, we show that GnRH treatment mediates the inactivation of glycogen synthase kinase-3, a protein serine/threonine kinase that regulates beta-catenin degradation within the Wnt signaling pathway. Our findings extend the number of GPCRs that can target beta-catenin signaling through diverse pathways. Furthermore, this is the first demonstration of the targeting of Wnt/beta-catenin signaling by a peptide hormone GPCR. PMID- 17717074 TI - The GLUT4 code. AB - Despite being one of the first recognized targets of insulin action, the acceleration of glucose transport into muscle and fat tissue remains one of the most enigmatic processes in the insulin action cascade. Glucose transport is accomplished by a shift in the distribution of the insulin-responsive glucose transporter GLUT4 from intracellular compartments to the plasma membrane in the presence of insulin. The complexity in deciphering the molecular blueprint of insulin regulation of glucose transport arises because it represents a convergence of two convoluted biological systems-vesicular transport and signal transduction. Whereas more than 60 molecular players have been implicated in this orchestral performance, it has been difficult to distinguish between mainly passive participants vs. those that are clearly driving the process. The maze like nature of the endosomal system makes it almost impossible to dissect the anatomical nature of what appears to be a medley of many overlapping and rapidly changing transitions. A major limitation is technology. It is clear that further progress in teasing apart the GLUT4 code will require the development and application of novel and advanced technologies that can discriminate one molecule from another in the living cell and to superimpose this upon a system in which the molecular environment can be carefully manipulated. Many are now taking on this challenge. PMID- 17717076 TI - Importance of constitutive activity and arrestin-independent mechanisms for intracellular trafficking of the ghrelin receptor. AB - The ghrelin receptor (GhrelinR) and its related orphan GPR39 each display constitutive signaling, but only GhrelinRs undergo basal internalization. Here we investigate these differences by considering the roles of the C tail receptor domains for constitutive internalization and activity. Furthermore the interaction between phosphorylated receptors and beta-arrestin adaptor proteins has been examined. Replacement of the FLAG-tagged GhrelinR C tail with the equivalent GPR39 domain (GhR-39 chimera) preserved G(q) signaling. However in contrast to the GhrelinR, GhR-39 receptors exhibited no basal and substantially decreased agonist-induced internalization in transiently transfected HEK293 cells. Internalized GhrelinR and GhR-39 were predominantly localized to recycling compartments, identified with transferrin and the monomeric G proteins Rab5 and Rab11. Both the inverse agonist [d-Arg(1), d-Phe(5), d-Trp(7,9), Leu(11)] substance P and a naturally occurring mutant GhrelinR (A204E) with eliminated constitutive activity inhibited basal GhrelinR internalization. Surprisingly, we found that noninternalizing GPR39 was highly phosphorylated and that basal and agonist-induced phosphorylation of the GhR-39 chimera was elevated compared with GhrelinRs. Moreover, basal GhrelinR endocytosis occurred without significant phosphorylation, and it was not prevented by cotransfection of a dominant negative beta-arrestin1(319-418) fragment or by expression in beta-arrestin1/2 double-knockout mouse embryonic fibroblasts. In contrast, agonist-stimulated GhrelinRs recruited the clathrin adaptor green fluorescent protein-tagged beta arrestin2 to endosomes, coincident with increased receptor phosphorylation. Thus, GhrelinR internalization to recycling compartments depends on C-terminal motifs and constitutive activity, but the high levels of GPR39 phosphorylation, and of the GhR-39 chimera, are not sufficient to drive endocytosis. In addition, basal GhrelinR internalization occurs independently of beta-arrestins. PMID- 17717077 TI - Phosphorylation-dependent antagonism of sumoylation derepresses progesterone receptor action in breast cancer cells. AB - Progesterone receptors (PRs) mediate proliferation during breast development and contribute to breast cancer progression, in part by synergizing with peptide growth factors. We have previously identified PR Ser294 as a key site for direct regulation of PR location, activity, and turnover in response to phosphorylation events. Herein, we sought to better understand how hormonal cross talk alters PR function. We demonstrate that progestins (R5020 and RU486) induce rapid (15 min) sumoylation of PR Lys388; sumoylation represses PR transcriptional activity on selected progesterone response element-driven and endogenous promoters and retards ligand-induced PR down-regulation. Consistent with this finding, we show that stabilized but weakly active phospho-mutant S294A PRs are heavily sumoylated. Conversely, desumoylated PR, created by mutation of PR Lys388 (K388R) or by overexpression of sentrin (SUMO)-specific protease desumoylating enzymes, are hypersensitive to low progestin concentrations. Combination of K388R and S294A mutations (KRSA double-mutant PR) rescues both transcription and turnover of impaired phospho-mutant (S294A) receptors. Notably, phosphorylation events antagonize PR-B but not PR-A sumoylation. Treatment of cells with epidermal growth factor or transient expression of activated mitogen-activated protein/ERK kinase kinase or cyclin-dependent protein kinase 2 induces PR-B Ser294 phosphorylation and blocks PR-B sumoylation, thereby derepressing receptor activity; PR-A is resistant to these events. Modulation of reversible PR sumoylation in response to diverse hormonal signals provides a mechanism for rapid isoform-specific changes in hormone responsiveness. In the context of elevated protein kinase activities, such as during mammary gland development or breast cancer progression, phosphorylated PR-B may be undersumoylated, transcriptionally hyperactive, and unstable/undetectable. PMID- 17717078 TI - Kruppel-like factor 9 is a negative regulator of ligand-dependent estrogen receptor alpha signaling in Ishikawa endometrial adenocarcinoma cells. AB - Estrogen and progesterone, acting through their respective receptors and other nuclear proteins, exhibit opposing activities in target cells. We previously reported that Kruppel-like factor 9 (KLF9) cooperates with progesterone receptor (PR) to facilitate P-dependent gene transcription in uterine epithelial cells. Here we evaluated whether KLF9 may further support PR function by directly opposing estrogen receptor (ER) signaling. Using human Ishikawa endometrial epithelial cells, we showed that 17beta-estradiol (E(2))-dependent down regulation of ERalpha expression was reversed by a small interfering RNA to KLF9. Transcription assays with the E(2)-sensitive 4x estrogen-responsive element thymidine kinase-promoter-luciferase reporter gene demonstrated inhibition of ligand-dependent ERalpha transactivation with ectopic KLF9 expression. E(2) induced PR-A/B and PR-B isoform expression in the absence of effects on KLF9 levels. Addition of KLF9 small interfering RNA augmented E(2) induction of PR-A/B while abrogating that of PR-B, indicating selective E(2)-mediated inhibition of PR-A by KLF9. Chromatin immunoprecipitation of the ERalpha minimal promoter demonstrated KLF9 promotion of E(2)-dependent ERalpha association to a region containing functional GC-rich motifs. KLF9 inhibited the recruitment of the ERalpha coactivator specificity protein 1 (Sp1) to the PR proximal promoter region containing a half-estrogen responsive element and GC-rich sites, but had no effect on Sp1 association to the PR distal promoter region containing GC-rich sequences. In vivo association of KLF9 and Sp1, but not of ERalpha with KLF9 or Sp1, was observed in control and E(2)-treated cells. Our data identify KLF9 as a transcriptional repressor of ERalpha signaling and suggest that it may function at the node of PR and ER genomic pathways to influence cell proliferation. PMID- 17717079 TI - Analysis of CYP2A contributions to metabolism of 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone in human peripheral lung microsomes. AB - The objectives of this study were to determine the contributions of CYP2A13 and CYP2A6 to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in human peripheral lung microsomes and to determine the influence of the genetic polymorphism, CYP2A13 Arg257Cys, on NNK metabolism. 4-(Methylnitrosamino)-1-(3 pyridyl)-1-butanol (NNAL), the keto-reduced metabolite of NNK, was the major metabolite produced, ranging from 0.28 to 0.9%/mg protein/min. Based on total bioactivation of NNK and NNAL by alpha-carbon hydroxylation, subjects could be classified as either high (17 subjects) or low (12 subjects) bioactivators [(5.26 +/- 1.23) x 10(-2) and (6.49 +/- 5.90) x 10(-3)% total alpha-hydroxylation/mg protein/min, P < 0.05]. Similarly, for detoxification, subjects could be grouped into high (9 subjects) and low (20 subjects) categories [(2.03 +/- 1.65) x 10(-3) and (2.50 +/- 3.04) x 10(-4)% total N-oxidation/mg protein/min, P < 0.05]. When examining data from all individuals, no significant correlations were found between levels of CYP2A mRNA, CYP2A enzyme activity, or CYP2A immunoinhibition and the degree of total NNK bioactivation or detoxification (P > 0.05). However, subgroups of individuals were identified for whom CYP2A13 mRNA correlated with total NNK and NNAL alpha-hydroxylation and NNAL-N-oxide formation (P < 0.05). The degree of NNAL formation and CYP2A13 mRNA was also correlated (P < 0.05). Subjects (n = 84) were genotyped for the CYP2A13 Arg257Cys polymorphism, and NNK metabolism for the one variant (Arg/Cys) was similar to that for other subjects. Although results do not support CYP2A13 or CYP2A6 as predominant contributors to NNK bioactivation and detoxification in peripheral lung of all individuals, CYP2A13 may be important in some. PMID- 17717080 TI - Specific binding of a Pop6/Pop7 heterodimer to the P3 stem of the yeast RNase MRP and RNase P RNAs. AB - Pop6 and Pop7 are protein subunits of Saccharomyces cerevisiae RNase MRP and RNase P. Here we show that bacterially expressed Pop6 and Pop7 form a soluble heterodimer that binds the RNA components of both RNase MRP and RNase P. Footprint analysis of the interaction between the Pop6/7 heterodimer and the RNase MRP RNA, combined with gel mobility assays, demonstrates that the Pop6/7 complex binds to a conserved region of the P3 domain. Binding of these proteins to the MRP RNA leads to local rearrangement in the structure of the P3 loop and suggests that direct interaction of the Pop6/7 complex with the P3 domain of the RNA components of RNases MRP and P may mediate binding of other protein components. These results suggest a role for a key element in the RNase MRP and RNase P RNAs in protein binding, and demonstrate the feasibility of directly studying RNA-protein interactions in the eukaryotic RNases MRP and P complexes. PMID- 17717081 TI - Human and animal cognition: continuity and discontinuity. AB - Microscopic study of the human brain has revealed neural structures, enhanced wiring, and forms of connectivity among nerve cells not found in any animal, challenging the view that the human brain is simply an enlarged chimpanzee brain. On the other hand, cognitive studies have found animals to have abilities once thought unique to the human. This suggests a disparity between brain and mind. The suggestion is misleading. Cognitive research has not kept pace with neural research. Neural findings are based on microscopic study of the brain and are primarily cellular. Because cognition cannot be studied microscopically, we need to refine the study of cognition by using a different approach. In examining claims of similarity between animals and humans, one must ask: What are the dissimilarities? This approach prevents confusing similarity with equivalence. We follow this approach in examining eight cognitive cases--teaching, short-term memory, causal reasoning, planning, deception, transitive inference, theory of mind, and language--and find, in all cases, that similarities between animal and human abilities are small, dissimilarities large. There is no disparity between brain and mind. PMID- 17717082 TI - Development at the wildland-urban interface and the mitigation of forest-fire risk. AB - This work addresses the impacts of development at the wildland-urban interface on forest fires that spread to human habitats. Catastrophic fires in the western United States and elsewhere make these impacts a matter of urgency for decision makers, scientists, and the general public. Using a simple fire-spread model, along with housing and vegetation data, we show that fire size probability distributions can be strongly modified by the density and flammability of houses. We highlight a sharp transition zone in the parameter space of vegetation flammability and house density. Many actual fire landscapes in the United States appear to have spreading properties close to this transition. Thus, the density and flammability of buildings should be taken into account when assessing fire risk at the wildland-urban interface. Moreover, our results highlight ways for regulation at this interface to help mitigate fire risk. PMID- 17717084 TI - A comprehensive archaeological map of the world's largest preindustrial settlement complex at Angkor, Cambodia. AB - The great medieval settlement of Angkor in Cambodia [9th-16th centuries Common Era (CE)] has for many years been understood as a "hydraulic city," an urban complex defined, sustained, and ultimately overwhelmed by a complex water management network. Since the 1980s that view has been disputed, but the debate has remained unresolved because of insufficient data on the landscape beyond the great temples: the broader context of the monumental remains was only partially understood and had not been adequately mapped. Since the 1990s, French, Australian, and Cambodian teams have sought to address this empirical deficit through archaeological mapping projects by using traditional methods such as ground survey in conjunction with advanced radar remote-sensing applications in partnership with the National Aeronautics and Space Administration (NASA)/Jet Propulsion Laboratory (JPL). Here we present a major outcome of that research: a comprehensive archaeological map of greater Angkor, covering nearly 3,000 km2, prepared by the Greater Angkor Project (GAP). The map reveals a vast, low-density settlement landscape integrated by an elaborate water management network covering>1,000 km2, the most extensive urban complex of the preindustrial world. It is now clear that anthropogenic changes to the landscape were both extensive and substantial enough to have created grave challenges to the long-term viability of the settlement. PMID- 17717083 TI - Quantitative assessment of protein function prediction from metagenomics shotgun sequences. AB - To assess the potential of protein function prediction in environmental genomics data, we analyzed shotgun sequences from four diverse and complex habitats. Using homology searches as well as customized gene neighborhood methods that incorporate intergenic and evolutionary distances, we inferred specific functions for 76% of the 1.4 million predicted ORFs in these samples (83% when nonspecific functions are considered). Surprisingly, these fractions are only slightly smaller than the corresponding ones in completely sequenced genomes (83% and 86%, respectively, by using the same methodology) and considerably higher than previously thought. For as many as 75,448 ORFs (5% of the total), only neighborhood methods can assign functions, illustrated here by a previously undescribed gene associated with the well characterized heme biosynthesis operon and a potential transcription factor that might regulate a coupling between fatty acid biosynthesis and degradation. Our results further suggest that, although functions can be inferred for most proteins on earth, many functions remain to be discovered in numerous small, rare protein families. PMID- 17717086 TI - 'Anti-aging medicine' and the cultural context of aging in Australia: preliminary findings from ongoing research on users and providers of 'anti-aging medicine' in Australia. AB - This paper explores the management of the aging body within the anti-aging discourse and its implications on notions of "successful" and "healthy" aging policies. By looking at some of the preliminary findings of our current study of 'anti-aging medicine' in Australia, including interviews conducted with stakeholders in the anti-aging debate, this study explores some recurrent values and perceptions regarding 'anti-aging medicine,' the re-negotiation of boundaries between illness and health, and the social, cultural, and economic forces shaping understandings and practices around aging and decisions to use anti-aging technologies. PMID- 17717085 TI - Evolution of a fluorinated green fluorescent protein. AB - The fluorescence of bacterial cells expressing a variant (GFPm) of the green fluorescent protein (GFP) was reduced to background levels by global replacement of the leucine residues of GFPm by 5,5,5-trifluoroleucine. Eleven rounds of random mutagenesis and screening via fluorescence-activated cell sorting yielded a GFP mutant containing 20 amino acid substitutions. The mutant protein in fluorinated form showed improved folding efficiency both in vivo and in vitro, and the median fluorescence of cells expressing the fluorinated protein was improved approximately 650-fold in comparison to that of cells expressing fluorinated GFPm. The success of this approach demonstrates the feasibility of engineering functional proteins containing many copies of abiological amino acid constituents. PMID- 17717087 TI - Combining an antioxidant-fortified diet with behavioral enrichment leads to cognitive improvement and reduced brain pathology in aging canines: strategies for healthy aging. AB - The number of elderly individuals in our population is rapidly rising and age associated neurodegenerative disease is becoming more prevalent. Thus, identifying ways by which we can promote healthy aging are becoming more critical. Lifestyle factors, such as engaging in physical, intellectual, and social activities, are protective against dementia in aged individuals. Similarly, there is some evidence to suggest that antioxidants are beneficial. Observational studies in humans have been confirmed and extended in rodent model systems. We present additional evidence that, in a canine model of aging, combining an antioxidant-enriched diet and behavioral enrichment (including social, physical, and cognitive components) can lead to substantial improvements in cognition and reduced brain pathology. These results suggest that modifying lifestyle factors can have a beneficial impact on the aging process, even in aged individuals with existing cognitive decline and brain pathology. PMID- 17717088 TI - Interviewing strategies in the face of beauty: a psychophysiological investigation into the job negotiation process. AB - After the application form is submitted, the interview is the most important method of human resource allocation. Previous research has shown that the attractiveness of interviewees can significantly bias interview outcome. We have previously shown that female interviewers give attractive male interviewees higher status job packages compared their average looking counterparts. However, it is not known whether male interviewers exhibit such biases. In the present study, participants were asked to take part in a mock job negotiation scenario where they had to allocate either a high- or low-status job package to attractive or average looking "interviewees." Before each decision was made, the participant's anticipatory electrodermal response (EDR) was recorded. The results supported our previous finding in that female participants allocated a greater number of high-status job packages to attractive men. Additionally, male participants uniformly allocated a greater number of low-status job packages to both attractive men and attractive women. Overall, the average looking interviewees incurred a penalty and received a significantly greater number of low-status job packages. In general, the EDR profile for both male and female participants was significantly greater when allocating the low-status packages to the average looking interviewees. However, the male anticipatory EDR profile showed the greatest change when allocating attractive women with low-status job packages. We discuss these findings in terms of the potential biases that may occur at the job interview and place them within an evolutionary psychology framework. PMID- 17717089 TI - Are we getting healthier as we grow older? Implications for babyboomer labor force participation. AB - The Intergenerational Report (IGR) released by the Department of the Treasury of the Commonwealth of Australia in 2002 highlighted pressures that in the future would threaten the sustainability of the Australian government's budget balance. These pressures result from the growing needs of an aging population and labor shortages that will limit economic growth and taxation revenue. The IGR has become a driving force in planning government policy. The Treasurer has recently said that "the whole economic agenda of the government at the moment is drawn from the IGR." In response, the Prime Minster and Treasurer have promoted deferred or gradual retirement as part of the solution. However, about 50% of men and 20% of women retire early as a result of ill health, indicating that poor health is potentially a limiter of economic growth. This paper reports lower labor force participation among persons with poorer health and that these persons move out of the labor force at a faster rate as they age. A range of measures suggests some decline in health in the pre-retirement age group (those aged from 40 to 64 years). This indicates that better health may be a facilitator of greater labor force participation in the baby boomer cohort. However, there is evidence that improving economic conditions in Australia leading to low unemployment has created an environment more favorable to the employment of older workers with health problems as there has been a rise in labor force participation in these groups, and measures to prevent chronic disease may further increase the employment prospects. PMID- 17717090 TI - Healthy aging: can clinical trials deliver? AB - The potential of a transdisciplinary research method--Quali-Quantitative Analysis (QQA)--for delivering better evidence for healthy aging is explored. Illustrative reviews from the literature on healthy aging are summarized, as are papers on methodology by Charles Ragin and colleagues. The evidence needs for healthy aging are explored, particularly in relation to the ability of randomized controlled trials (RCTs) to deliver rich, diversity-oriented evidence. The techniques of QQA, which involves treating cases as configurations, are described. The QQA method has potential value for healthy aging research in that: (a) it could provide evidence in combinatorial forms useful to holistic practice; (b) it could enrich the evidence for practice by providing more rigorous information from small-N groups, within RCTs and where RCTs cannot be used; and (c) it could add to the ability of RCTs to generate theoretical advances. PMID- 17717091 TI - Neuro-gov: neuroscience as catalyst. AB - Neuroscience promises to act as a catalyst, in the longer run, in seeking re unification of the fragmented social sciences (e.g., political science and economics) and social action subjects (e.g., public administration and business administration) that concern governance. Neuroscience can achieve this because it reveals that taken-for-granted concepts, and the language used to express them, should be challenged. What should be sought is a language called in this paper Neuro-Gov. PMID- 17717092 TI - Cognitive accuracy and intelligent executive function in the brain and in business. AB - This article reviews research on cognition, language, organizational culture, brain, behavior, and evolution to posit the value of operating with a stable reference point based on cognitive accuracy and a rational bias. Drawing on rational-emotive behavioral science, social neuroscience, and cognitive organizational science on the one hand and a general model of brain and frontal lobe executive function on the other, I suggest implications for organizational success. Cognitive thought processes depend on specific brain structures functioning as effectively as possible under conditions of cognitive accuracy. However, typical cognitive processes in hierarchical business structures promote the adoption and application of subjective organizational beliefs and, thus, cognitive inaccuracies. Applying informed frontal lobe executive functioning to cognition, emotion, and organizational behavior helps minimize the negative effects of indiscriminate application of personal and cultural belief systems to business. Doing so enhances cognitive accuracy and improves communication and cooperation. Organizations operating with cognitive accuracy will tend to respond more nimbly to market pressures and achieve an overall higher level of performance and employee satisfaction. PMID- 17717093 TI - Effects of old age on hepatocyte oxygenation. AB - Hepatic phase I drug metabolism is diminished in old age. It has been suggested that hepatocyte hypoxia and impaired bioenergetics in old age may contribute to this aging change. Therefore, we sought to determine whether old age was associated with in vivo hypoxia in the aged rat liver. Immunohistochemical studies with the nitroimidazole hypoxia marker, pimonidazole, were carried out in livers from young and old rats. Preliminary studies were performed on four young (4-month-old) and six old (2-year-old) F344 rats to directly visualize the distribution and intensity of pimonidazole staining. There were no significant differences in the distribution or in the intensity of pimonidazole immunohistochemical staining between young and aged rat livers. In conclusion, no major changes in hepatocyte oxygenation were seen in the aged rat liver, and the ATP changes are unlikely to be secondary to hepatocyte hypoxia or impaired oxygen diffusion into the liver. It is thus more likely that age-related reduction in liver ATP is attributable to mitochondrial dysfunction. PMID- 17717094 TI - Business change process, creativity and the brain: a practitioner's reflective account with suggestions for future research. AB - Resolution of a critical organizational problem requires the use of carefully selected techniques. This is the work of a management consultant: facilitating a business change process in an organizational setting. Here, an account is provided of a practitioner's reflections on one such case study that demonstrates a structure for a business change process. The reflective account highlights certain affective states and social behaviors that were extracted from participants during the business change process. These affective states and social behaviors are mediated by specific neural networks in the brain that are activated during organizational intervention. By breaking down the process into the affective states and social behaviors highlighted, cognitive neuroscience can be a useful tool for investigating the neural substrates of such intervention. By applying a cognitive neuroscience approach to examine organizational change, it is possible to converge on a greater understanding of the neural substrates of everyday social behavior. PMID- 17717095 TI - Research possibilities for organizational cognitive neuroscience. AB - In this article, we identify research possibilities for organizational cognitive neuroscience that emerge from the papers in this special issue. We emphasize the intriguing finding that the papers share a common theme-the use of cognitive neuroscience to investigate the role of emotions in organizational behavior; this suggests a research agenda in its own right. We conclude the article by stressing that there is much yet to discover about how the mind works, especially in organizational settings. PMID- 17717096 TI - Fairness and cooperation are rewarding: evidence from social cognitive neuroscience. AB - To motivate their consumers or employees, corporations often offer monetary incentives, such as cash-back deals or salary bonuses. However, human behavior is not solely driven by material outcome; fairness and equity matter as well. In a recent neuroimaging study, fair offers led to higher happiness ratings and increased activity in several reward regions of the brain compared with unfair offers of equal monetary value. Other neuroimaging studies have similarly shown activation in reward regions in response to cooperative partners or cooperative play. Here, we review these findings and discuss the implications for organizational settings. PMID- 17717097 TI - Neuroimaging and psychophysiological measurement in organizational research: an agenda for research in organizational cognitive neuroscience. AB - Although organizational research has made tremendous strides in the last century, recent advances in neuroscience and the imaging of functional brain activity remain underused. In fact, even the use of well-established psychophysiological measurement tools is comparatively rare. Following the lead of social cognitive neuroscience, in this review, we conceptualize organizational cognitive neuroscience as a field dedicated to exploring the processes within the brain that underlie or influence human decisions, behaviors, and interactions either (a) within organizations or (b) in response to organizational manifestations or institutions. We discuss organizational cognitive neuroscience, bringing together work that may previously have been characterized rather atomistically, and provide a brief overview of individual methods that may be of use. Subsequently, we discuss the possible convergence and integration of the different neuroimaging and psychophysiological measurement modalities. A brief review of prior work in the field shows a significant need for a more coherent and theory-driven approach to organizational cognitive neuroscience. In response, we discuss a recent example of such work, along with three hypothetical case studies that exemplify the link between organizational and psychological theory and neuroscientific methods. PMID- 17717098 TI - Neural correlates of corporate camaraderie and teamwork. AB - Corporate citizenship creates an ethical and professional accountability among the employee, the organization, and the outside market. Teamwork is an essential part of this corporate accountability because it increases communication and confidence within the organization and promotes camaraderie and goal completion. Cognitive neuroscience research has been able to localize socialization to various areas of the limbic system, which includes, among other structures, the hypothalamus and amygdala, and is associated with the prefrontal cortex. These neurocortical areas can be monitored while set tasks are performed experimentally or observed naturally. Within the framework of cognitive neuroscience, one can evaluate the neural architecture involved in various states of organizational behavior. One can then use this framework as an overlay in the corporate environment to track project completion and profitability. PMID- 17717099 TI - Clonal attenuation of somatic cells in aging mammals: a review of supportive evidence and its biomedical significance. AB - Clonal attenuation can be defined as the gradual depletion of the replicative potentials of individual clones of mammalian somatic cells. Publications from the author's laboratory and from other laboratories are reviewed that support the proposition that clonal attenuation is a continuous process throughout the life course and that it occurs in vivo in primates. The puzzling discordance between the mass culture results from the laboratories of the late Vincent Cristofalo (tissue from living subjects) and those from the Martin laboratory (tissue predominately from autopsy subjects) is discussed. Finally, the implications of clonal attenuation and replicative senescence, for such major age-related pathologic processes as neoplasia, atherosclerosis, benign prostatic hyperplasia, and osteoarthritis, are addressed; these and other disorders of aging can be characterized as a mixture of atrophy and hyperplasia, presumably related to a failure of homeostatic cell-cell interactions in aging tissues. For the case of neoplasia, an argument can be made that such failures precede what is increasingly regarded as the most critical step in carcinogenesis-the evolution of a mutator phenotype. PMID- 17717100 TI - Calorie restriction, post-reproductive life span, and programmed aging: a plea for rigor. AB - All scientists are acutely aware of the profound challenge that they face when communicating scientific findings to nonscientists, especially when great uncertainty is involved and when the topic is of personal interest to the general public. Simplification of the issues--sometimes extending to a degree of oversimplification--is a sad but generally recognized necessity. It is not, however, a necessity when scientists communicate with each other, and when that happens, the explanation may lie elsewhere: either in the speaker's vested interests or in overconfidence on the speaker's part in the extent to which he or she has grasped the topic under discussion. Both these explanations are serious allegations and must not be made without good reason, not least because an alternative explanation is often the entirely legitimate preference for scientific "shorthand." However, when a general tendency toward oversimplification emerges within an expert community, not only in informal interactions but in learned publications, the field in question can suffer a loss of reputation for rigor, which may especially infect younger scientists joining that field (or contemplating joining it). I feel that this has occurred to a dangerous degree within biogerontology in respect of the way in which the effect of the environment on the rate of aging-whether that of an individual organism or of a lineage-is described. There are still important controversies in that area, but I refer here strictly to issues concerning which a thorough consensus exists. In this essay I highlight some fundamental tenets of biogerontology that are frequently, and to my mind problematically, mis-stated by many in this field in their printed pronouncements. Greater precision on these points will, I believe, benefit biogerontology at many levels, avoiding confusion among biogerontologists, among other biologists, and among the general public. PMID- 17717101 TI - Toward an organizational cognitive neuroscience. AB - The research strategy adopted in this article is to connect two different discourses and the ideas, methods, and outputs they contain-these being cognitive neuroscience and organization theory. The main contribution of the article is to present an agenda for the field of organizational cognitive neuroscience. We define what is meant by the term, outline its background, identify why it is important as a new research direction, and then conclude by drawing on Damasio's levels of life regulation as a framework to bind together existing organizational cognitive neuroscience. The article begins by setting the wider debate behind the emergence of organizational cognitive neuroscience by revisiting the nature nurture debate and uses Pinker to demonstrate that the connection between mind and matter has not been resolved, that new directions are opening up to better understand human nature, and that organizational cognitive neuroscience is one fruitful path forward. PMID- 17717102 TI - Life extension by calorie restriction in humans. AB - Long-term reduction in energy intake in the diet (calorie restriction [CR]) extends the life of the laboratory rat by about 25%. However, in humans there are no life-long studies of CR, but only short-term trials which indicate that 20% CR acting over periods of 2-6 years is associated with reduced body weight, blood pressure, blood cholesterol, and blood glucose--risk factors for the major killer diseases of cardiovascular disease and diabetes. In addition, recent research has shown that CR for 6 months is able to improve biomarkers for longevity (deep body temperature and plasma insulin) and thus should increase life expectancy. The magnitude of the life-extension effect of CR in humans can only be estimated. The Okinawans, the longest-lived people on earth, consume 40% fewer calories than the Americans and live only 4 years longer. Similarly, women in United States consume 25% fewer calories than men and live 5 years longer. From the survival studies of overweight and obese people, it is estimated that long-term CR to prevent excessive weight gain could add only 3-13 years to life expectancy. Thus the effects of CR on human life extension are probably much smaller than those achieved by medical and public health interventions, which have extended life by about 30 years in developed countries in the 20th century, by greatly reducing deaths from infections, accidents, and cardiovascular disease. PMID- 17717103 TI - Legal actions against doctors down 50% in past decade. PMID- 17717104 TI - Physicians go green. PMID- 17717105 TI - Presidential musings: prescriptions for the nation. PMID- 17717106 TI - Visual methods in the assessment of diet intake in Mexican American women. AB - Assessment of dietary intake is based largely on self-report or use of biomarkers. However, neither self-report nor biomarkers inform nurses of patterns in dietary intake in the context of gender, culture, and ethnicity. This article describes the relevance of visual methods focusing on the context of dietary intake in Mexican American women, illustrated by a formative study. A qualitative, descriptive, methodological design incorporating photo elicitation was used. The sample consisted of 7 Mexican American women, who took photographs of their food intake, food preparation, and context of food consumption, such as family gatherings, which were then described by the women. Data included participant photographs, the descriptions of why each image was obtained, and stories about the photographs. Visual methods were found to be a relevant and important addition to traditional dietary assessment methods, to enhance gender, cultural, and contextually relevant assessment of dietary intake in Mexican American women. PMID- 17717107 TI - Predicting condom use among sexually experienced Latino adolescents. AB - There is limited research on how aspects of Latino culture affect condom use among Latino adolescents. In this study, the authors examined the effects of familialism, gender roles, and religiosity on condom use intentions and past condom use. Results showed only religiosity predicted past condom use; no other cultural variable had either a direct or an indirect effect on condom use intentions or past condom use. These findings represent an important effort in promoting safer sex behaviors among sexually active Latino adolescents. PMID- 17717108 TI - Ligand-directed signaling: 50 ways to find a lover. AB - In contrast to earlier concepts, it seems that distinct ligands acting on the same receptor may elicit qualitative different response patterns, a phenomenon given many names, including "functional selectivity," "agonist-directed trafficking," "biased agonism," "protean agonism," or "ligand-directed signaling." In this issue of Molecular Pharmacology, Sato et al. (p. 1359) extend this concept to beta(3)-adrenergic receptors and report that distinct ligands can activate a single distal response via different signaling pathways. Moreover, they demonstrate that expression density can affect how distinct ligands acting on the same receptor differentially induce cellular responses. We discuss the underlying concepts for such findings and their implications for drug discovery. PMID- 17717109 TI - Ligand-directed signaling at the beta3-adrenoceptor produced by 3-(2 Ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanol oxalate (SR59230A) relative to receptor agonists. AB - This study examines signaling pathways activated by the mouse beta(3) adrenoceptor (AR) expressed in Chinese hamster ovary cells at high (CHObeta(3)H) or low (CHObeta(3)L) levels. Functional responses included extracellular acidification rate (ECAR), cAMP accumulation, and p38 mitogen-activated protein kinase (MAPK) or extracellular signal-regulated protein kinase 1/2 (Erk1/2) phosphorylation. (-)-Isoproterenol and the beta(3)-AR agonist (R, R)-5-[2-[[2-(3 chlorophenyl)-2-hydroxyethyl]-amino]-propyl]1,3-benzodioxole-2,2-decarboxylate (CL316243) caused concentration-dependent increases in cAMP accumulation and ECAR in CHObeta(3)H and CHObeta(3)L cells. For cAMP accumulation, the beta(3)-AR ligand SR59230A was a partial agonist in CHObeta(3)H and an antagonist in CHObeta(3)L cells but for ECAR was an agonist at both expression levels. This suggested that SR59230A, which is normally regarded as an antagonist, can selectively activate pathways leading to ECAR. Examination of the pathways stimulated by (-)-isoproterenol, CL316243, and SR59230A for both ECAR and cAMP accumulation suggested that the cAMP pathway predominates in CHObeta(3)H cells, whereas p38 MAPK is a major contributor to ECAR in CHObeta(3)L cells and was the sole contributor to responses to SR59230A. Western blots of p38 MAPK and Erk1/2 phosphorylation confirmed that MAPKs are activated in CHObeta(3)H and CHObeta(3)L cells by CL316243 and SR59230A but that SR59230A has much higher efficacy. In addition, p38 MAPK phosphorylation displayed differences in drug potency and efficacy between CHObeta(3)H and CHObeta(3)L cells related to inhibition of the response by cAMP. Thus, CL316243 and SR59230A display reversed orders of efficacy for cAMP accumulation compared with Erk1/2 and p38 MAPK phosphorylation, providing a strong indication of ligand-directed signaling. PMID- 17717110 TI - Anatomic and physiological characteristics of the ferret lateral rectus muscle and abducens nucleus. AB - The ferret has become a popular model for physiological and neurodevelopmental research in the visual system. We believed it important, therefore, to study extraocular whole muscle as well as single motor unit physiology in the ferret. Using extracellular stimulation, 62 individual motor units in the ferret abducens nucleus were evaluated for their contractile characteristics. Of these motor units, 56 innervated the lateral rectus (LR) muscle alone, while 6 were split between the LR and retractor bulbi (RB) muscle slips. In addition to individual motor units, the whole LR muscle was evaluated for twitch, tetanic peak force, and fatigue. The abducens nucleus motor units showed a twitch contraction time of 15.4 ms, a mean twitch tension of 30.2 mg, and an average fusion frequency of 154 Hz. Single-unit fatigue index averaged 0.634. Whole muscle twitch contraction time was 16.7 ms with a mean twitch tension of 3.32 g. The average fatigue index of whole muscle was 0.408. The abducens nucleus was examined with horseradish peroxidase conjugated with the subunit B of cholera toxin histochemistry and found to contain an average of 183 motoneurons. Samples of LR were found to contain an average of 4,687 fibers, indicating an LR innervation ratio of 25.6:1. Compared with cat and squirrel monkeys, the ferret LR motor units contract more slowly yet more powerfully. The functional visual requirements of the ferret may explain these fundamental differences. PMID- 17717111 TI - Changes in 24-h substrate oxidation in older and younger men in response to exercise. AB - The purpose of this study was to compare 24-h substrate oxidation in older (OM; 60-75 yr, n = 7) and younger (YM; 20-30 yr, n = 7) men studied on sedentary day (Con) and on a day with exercise (Ex; net energy expenditure = 300 kcal). Plasma glucose and free fatty acids were also measured at several time points during the 24-h measurement. Weight was not different in OM and YM (means +/- SD; 84.8 +/- 16.9 vs. 81.4 +/- 10.4 kg, respectively), although percent body fat was slightly higher in OM (25.9 +/- 3.5 vs. 21.9 +/- 9.7%; P = 0.17). Values of 24-h energy expenditure did not differ in OM and YM on the Con (means +/- SE; 2,449 +/- 162 vs. 2,484 +/- 104 kcal/day, respectively) or Ex (2,902 +/- 154 vs. 2,978 +/- 122 kcal/day) days. Under both conditions, 24-h respiratory quotient was significantly lower and fat oxidation significantly higher in OM. Glucose concentrations were not different at any time point, but plasma free fatty acid concentrations were higher in OM, particularly following meals. Thus, under these controlled conditions, 24-h fat oxidation was not reduced and was in fact greater in OM. We speculate that differences in the availability of circulating free fatty acids in the postprandial state contributed to the observed differences in 24-h fat oxidation in OM and YM. PMID- 17717112 TI - New animal model opens opportunities for research on the female athlete triad. PMID- 17717113 TI - Impaired pulmonary oxygen uptake kinetics and reduced peak aerobic power during small muscle mass exercise in heart transplant recipients. AB - We examined peak and reserve cardiovascular function and skeletal muscle oxygenation during unilateral knee extension (ULKE) exercise in five heart transplant recipients (HTR, mean +/- SE; age: 53 +/- 3 years; years posttransplant: 6 +/- 4) and five age- and body mass-matched healthy controls (CON). Pulmonary oxygen uptake (Vo(2)(p)), heart rate (HR), stroke volume (SV), cardiac output (Q), and skeletal muscle deoxygenation (HHb) kinetics were assessed during moderate-intensity ULKE exercise. Peak exercise and reserve Vo(2)(p), Q, and systemic arterial-venous oxygen difference (a-vO(2diff)) were 23 52% lower (P < 0.05) in HTR. The reduced Q and a-vO(2diff) reserves were associated with lower HR and HHb reserves, respectively. The phase II Vo(2)(p) time delay was greater (HTR: 38 +/- 2 vs. CON: 25 +/- 1 s, P < 0.05), while time constants for phase II Vo(2)(p) (HTR: 54 +/- 8 vs. CON: 31 +/- 3 s), Q (HTR: 66 +/- 8 vs. CON: 28 +/- 4 s), and HHb (HTR: 27 +/- 5 vs. CON: 13 +/- 3 s) were significantly slower in HTR. The HR half-time was slower in HTR (113 +/- 21 s) vs. CON (21 +/- 2 s, P < 0.05); however, no significant difference was found between groups for SV kinetics (HTR: 39 +/- 8 s vs. CON 31 +/- 6 s). The lower peak Vo(2)(p) and prolonged Vo(2)(p) kinetics in HTR were secondary to impairments in both cardiovascular and skeletal muscle function that result in reduced oxygen delivery and utilization by the active muscles. PMID- 17717114 TI - Quercetin's influence on exercise-induced changes in plasma cytokines and muscle and leukocyte cytokine mRNA. AB - Trained male cyclists (n = 40) ingested quercetin (Q; n = 20) (1,000 mg/day) or placebo (P; n = 20) supplements under randomized, double-blinded methods for 3 wk before and during a 3-day period in which subjects cycled for 3 h/day at approximately 57% maximal work rate. Blood samples were collected before and after each exercise session and assayed for plasma IL-6, IL-10, IL-1ra, IL-8, TNF alpha, and monocyte chemoattractant protein 1, and leukocyte IL-10, IL-8, and IL 1ra mRNA. Muscle biopsies were obtained before and after the first and third exercise sessions and assayed for NF-kappaB and cyclooxygenase-2 (COX-2), IL-6, IL-8, IL-1beta, and TNF-alpha mRNA. Postexercise increases in plasma cytokines did not differ between groups, but the pattern of change over the 3-day exercise period tended to be lower in Q vs. P for IL-8 and TNF-alpha (P = 0.094 for both). mRNA increased significantly postexercise for each cytokine measured in blood leukocyte and muscle samples. Leukocyte IL-8 and IL-10 mRNA were significantly reduced in Q vs. P (interaction effects, P = 0.019 and 0.012, respectively) with no other leukocyte or muscle mRNA group differences. Muscle NF-kappaB did not increase postexercise and did not differ between Q and P. Muscle COX-2 mRNA increased significantly postexercise but did not differ between Q and P. In summary, 1 g/day quercetin supplementation by trained cyclists over a 24-day period diminished postexercise expression of leukocyte IL-8 and IL-10 mRNA, indicating that elevated plasma quercetin levels exerted some effects within the blood compartment. Quercetin did not, however, influence any of the muscle measures, including NF-kappaB content, cytokine mRNA, or COX-2 mRNA expression across a 3-day intensified exercise period. PMID- 17717115 TI - Sex differences in leg vasodilation during graded knee extensor exercise in young adults. AB - Limb vascular conductance responses to pharmacological and nonexercise vasodilator stimuli are generally augmented in women compared with men. In the present investigation, we tested the hypothesis that exercise-induced vasodilator responses are also greater in women than men. Sixteen women and 15 men (20-30 yr) with similar fitness and activity levels performed graded quadriceps exercise (supine, single-leg knee extensions, 40 contractions/min) to maximal exertion. Active limb hemodynamics (left common femoral artery diameter and volumetric blood flow), heart rate (ECG), and beat-to-beat mean arterial blood pressure (MAP; radial artery tonometry) were measured during each 3-min workload (4.8 and 8 W/stage for women and men, respectively). The hyperemic response to exercise (slope of femoral blood flow vs. workload) was greater (P < 0.01) in women as was femoral blood flow at workloads >15 W. The leg vasodilatory response to exercise (slope of calculated femoral vascular conductance vs. absolute workload) was also greater in women than in men (P < 0.01) because of the sex difference in hyperemia and the women's lower MAP ( approximately 10-15 mmHg) at all workloads (P < 0.05). The femoral artery dilated to a significantly greater extent in the women ( approximately 0.5 mm) than in the men ( approximately 0.1 mm) across all submaximal workloads. At maximal exertion, femoral vascular conductance was lower in the men (men, 18.0 +/- 0.6 ml.min(-1)xmmHg(-1); women, 22.6 +/- 1.4 mlxmin( 1)xmmHg(-1); P < 0.01). Collectively, these findings suggest that the vasodilatory response to dynamic leg exercise is greater in young women vs. men. PMID- 17717116 TI - Aging and cardioprotection. AB - Advanced age is a strong independent predictor for death, disability, and morbidity in patients with structural heart disease. With the projected increase in the elderly population and the prevalence of age-related cardiovascular disabilities worldwide, the need to understand the biology of the aging heart, the mechanisms for age-mediated cardiac vulnerability, and the development of strategies to limit myocardial dysfunction in the elderly have never been more urgent. Experimental evidence in animal models indicate attenuation in cardioprotective pathways with aging, yet limited information is available regarding age-related changes in the human heart. Human cardiac aging generates a complex phenotype, only partially replicated in animal models. Here, we summarize current understanding of the aging heart stemming from clinical and experimental studies, and we highlight targets for protection of the vulnerable senescent myocardium. Further progress mandates assessment of human tissue to dissect specific aging-associated genomic and proteomic dynamics, and their functional consequences leading to increased susceptibility of the heart to injury, a critical step toward designing novel therapeutic interventions to limit age related myocardial dysfunction and promote healthy aging. PMID- 17717118 TI - Repair of spinal cord transection and its effects on muscle mass and myosin heavy chain isoform phenotype. AB - A number of significant advances have been developed for treating spinal cord injury during the past two decades. The combination of peripheral nerve grafts and acidic fibroblast growth factor (hereafter referred to as PNG) has been shown to partially restore hindlimb function. However, very little is known about the effects of such treatments in restoring normal muscle phenotype. The primary goal of the current study was to test the hypothesis that PNG would completely or partially restore 1) muscle mass and muscle fiber cross-sectional area and 2) the slow myosin heavy chain phenotype of the soleus muscle. To test this hypothesis, we assigned female Sprague-Dawley rats to three groups: 1) sham control, 2) spinal cord transection (Tx), and 3) spinal cord transection plus PNG (Tx+PNG). Six months following spinal cord transection, the open-field test was performed to assess locomotor function, and then the soleus muscles were harvested and analyzed. SDS-PAGE for single muscle fiber was used to evaluate the myosin heavy chain (MHC) isoform expression pattern following the injury and treatment. Immunohistochemistry was used to identify serotonin (5-HT) fibers in the spinal cord. Compared with the Tx group, the Tx+PNG group showed 1) significantly improved Basso, Beattie, and Bresnahan scores (hindlimb locomotion test), 2) less muscle atrophy, 3) a higher percentage of slow type I fibers, and 4) 5-HT fibers distal to the lesion site. We conclude that the combined treatment of PNG is partially effective in restoring the muscle mass and slow phenotype of the soleus muscle in a T-8 spinal cord-transected rat model. PMID- 17717119 TI - Influence of concentric and eccentric resistance training on architectural adaptation in human quadriceps muscles. AB - Studies using animal models have been unable to determine the mechanical stimuli that most influence muscle architectural adaptation. We examined the influence of contraction mode on muscle architectural change in humans, while also describing the time course of its adaptation through training and detraining. Twenty-one men and women performed slow-speed (30 degrees /s) concentric-only (Con) or eccentric only (Ecc) isokinetic knee extensor training for 10 wk before completing a 3-mo detraining period. Fascicle length of the vastus lateralis (VL), measured by ultrasonography, increased similarly in both groups after 5 wk (Delta(Con) = +6.3 +/- 3.0%, Delta(Ecc) = +3.1 +/- 1.6%, mean = +4.7 +/- 1.7%; P < 0.05). No further increase was found at 10 wk, although a small increase (mean approximately 2.5%; not significant) was evident after detraining. Fascicle angle increased in both groups at 5 wk (Delta(Con) = +11.1 +/- 4.0%, Delta(Ecc) = +11.9 +/- 5.4%, mean = 11.5 +/- 3.2%; P < 0.05) and 10 wk (Delta(Con) = +13.3 +/- 3.0%, Delta(Ecc) = +21.4 +/- 6.9%, mean = 17.9 +/- 3.7%; P < 0.01) in VL only and remained above baseline after detraining (mean = 13.2%); smaller changes in vastus medialis did not reach significance. The similar increase in fascicle length observed between the training groups mitigates against contraction mode being the predominant stimulus. Our data are also strongly indicative of 1) a close association between VL fascicle length and shifts in the torque-angle relationship through training and detraining and 2) changes in fascicle angle being driven by space constraints in the hypertrophying muscle. Thus muscle architectural adaptations occur rapidly in response to resistance training but are strongly influenced by factors other than contraction mode. PMID- 17717117 TI - Pulmonary gas transfer related to markers of angiogenesis during the menstrual cycle. AB - Gas transfer in the female lung varies over the menstrual cycle in parallel with the cyclic angiogenesis that occurs in the uterine endometrium. Given that vessels form and regress in the uterus under the control of hormones, angiogenic factors, and proangiogenic circulating bone marrow-derived progenitor cells, we tested the possibility that variation in pulmonary gas transfer over the menstrual cycle is related to a systemic cyclic proangiogenic state that influences lung vascularity. Women were evaluated over the menstrual cycle with weekly measures of lung diffusing capacity and its components, the pulmonary vascular capillary bed and membrane diffusing capacity, and their relation to circulating CD34(+)CD133(+) progenitor cells, hemoglobin, factors affecting hemoglobin binding affinity, and proangiogenic factors. Lung diffusing capacity varied over the menstrual cycle, reaching a nadir during the follicular phase following menses. The decline in lung diffusing capacity was accounted for by approximately 25% decrease in pulmonary capillary blood volume. In parallel, circulating CD34(+)CD133(+) progenitor cells decreased by approximately 24% and were directly related to angiogenic factors and to lung diffusing capacity and pulmonary capillary blood volume. The finding of a greater number of lung microvessels in ovariectomized female mice receiving estrogen compared with placebo verified that pulmonary vascularity is influenced by hormonal changes. These findings suggest that angiogenesis in the lungs may participate in the cyclic changes in gas transfer that occur over the menstrual cycle. PMID- 17717121 TI - Effects of buthionine sulfoximine treatment on diaphragm contractility and SR Ca2+ pump function in rats. AB - The purpose of this study was to examine the effects of glutathione (GSH) depletion and cellular oxidation on rat diaphragm contractility and sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) function in vitro under basal conditions and following fatiguing stimulation. Buthionine sulfoximine (BSO) treatment (n = 10) for 10 days (20 mM in drinking water) reduced (P < 0.05) diaphragm GSH content (nmol/mg protein) and the ratio of GSH to glutathione disulfide (GSH/GSSG) by 91% and 71%, respectively, compared with controls (CTL) (n = 10). Western blotting showed that Hsp70 expression in diaphragm was not increased (P > 0.05) with BSO treatment. As hypothesized, basal peak twitch force (g/mm(2)) was increased (P < 0.05), and fatigability in response to repetitive stimulation (350-ms trains at 100 Hz once every 1 s for 5 min) was also increased (P < 0.05) in BSO compared with CTL. Both Ca(2+) uptake and maximal SERCA activity (mumol.g protein(-1).min(-1)) measured in diaphragm homogenates that were prepared at rest were increased (P < 0.05) with BSO treatment, an effect that could be partly explained by a twofold increase (P < 0.05) in SERCA2a expression with BSO. In response to the 5-min stimulation protocol, both Ca(2+) uptake and maximal SERCA activity were increased (P < 0.05) in CTL but not (P > 0.05) in BSO diaphragm. We conclude that 1) cellular redox state is more optimal for contractile function and fatigability is increased in rat diaphragm following BSO treatment, 2) SERCA2a expression is modulated by redox signaling, and 3) regulation of SERCA function in working diaphragm is altered following BSO treatment. PMID- 17717122 TI - Vascular endothelial sampling and analysis of gene transcripts: a new quantitative approach to monitor vascular inflammation. AB - BACKGROUND: Limited access to endothelial tissue is a major constraint when investigating the cellular mechanisms of vascular inflammation in patients with cardiovascular and metabolic diseases. We introduce venous endothelial sampling coupled to quantitative analysis of gene transcripts by real-time PCR, as a novel approach to study endothelial gene expression in human subjects. METHODS: Endothelial cells were collected from a superficial forearm vein using five guide wires sequentially inserted through a 20-gauge angiocatheter in seven patients with history of cardiovascular events related to advanced vascular disease and in 17 healthy subjects. Endothelial cells were purified using magnetic beads coated with endothelial specific antibodies. Endothelial mRNA was amplified using RiboAmp HS RNA Amplification kit (Molecular Devices, Sunnyvale, CA). Amplified RNA was analyzed by real-time PCR. RESULTS: Linearity of RNA amplification was validated by real-time PCR using RNA from 1,000 human umbilical endothelial cells (HUVECs) before and after amplification. In human subjects, vascular disease was associated with significant induction of proatherosclerotic genes: early growth response gene product (Egr-1) and monocyte chemoattractant protein-1 (MCP-1). CONCLUSION: Venous endothelial sampling coupled to real-time PCR analysis is a minimally invasive, safe, and reliable technique to monitor vascular inflammation in human subjects. Expression of genes implicated in the atherosclerotic process is increased in the venous endothelium of patients with arterial vascular disease. Venous endothelial sampling and quantitative analysis of gene expression may help develop new vascular-targeted biomarkers to identify and track the impact of disease states and therapeutic interventions in vascular diseases. PMID- 17717123 TI - Synchronized gastric electrical stimulation improves delayed gastric emptying in nonobese mice with diabetic gastroparesis. AB - The aim of this study was to investigate the effect and mechanism of synchronized gastric electrical stimulation (SGES) on gastric emptying in nonobese mice with diabetic gastroparesis (DB-GP). Eight control mice and 48 nonobese diabetic (NOD) mice with two pairs of gastric electrodes were used in this study. The study included seven groups in a randomized order [control, diabetes (DB), DB-GP, DB + SGES, DB-GP + SGES, DB-GP + Atropine, and DB-GP + SGES + Atropine groups]. In the control, DB, DB-GP, and DB-GP + Atropine groups, gastric emptying was measured in BLAB/cJ mice (control group) or NOD mice with a duration of diabetes of 0-7 days (DB group) or 28-35 days (DB-GP or DB-GP + Atropine group). In the DB + SGES, DB GP + SGES, and DB-GP + SGES + Atropine groups, the experiment was the same as the corresponding DB, DB-GP, and DB-GP + Atropine groups except that SGES was applied during the experiment. SGES was applied via the proximal pair of electrodes and synchronized with the intrinsic gastric slow waves. The following results were obtained: 1) gastric emptying was delayed in NOD mice with a duration of diabetes of 28-35 days; 2) SGES was able to significantly increase gastric emptying in both diabetic mice and diabetic gastroparetic mice; and 3) the excitatory effect of SGES was completely blocked by atropine. SGES accelerates gastric emptying in NOD mice with diabetic gastroparesis. The effect of SGES on gastric emptying is mediated via the cholinergic pathway. These findings suggest that SGES may have a therapeutic potential for treating patients with diabetic gastroparesis. PMID- 17717124 TI - Contribution of orexin in hypercapnic chemoreflex: evidence from genetic and pharmacological disruption and supplementation studies in mice. AB - We have previously shown that hypercapnic chemoreflex in prepro-orexin knockout mice (ORX-KO) is attenuated during wake but not sleep periods. In that study, however, hypercapnic stimulation had been chronically applied for 6 h because of technical difficulty in changing the composition of the inspired gas mixture without distorting the animal's vigilance states. In the present study we examined possible involvement of orexin in acute respiratory chemoreflex during wake periods. Ventilation was recorded together with electroencephalography and electromyography before and after intracerebroventricular administration of orexin or an orexin receptor antagonist, SB-334867. A hypercapnic (5 or 10% CO(2)) or hypoxic (15 or 10% O(2)) gas mixture was introduced into the recording chamber for 5 min. Respiratory parameters were analyzed only for quiet wakefulness. When mice breathed normal room air, orexin-A and orexin-B but not vehicle or SB-334867 increased minute ventilation in both ORX-KO and wild-type (WT) mice. As expected, hypercapnic chemoreflex in vehicle-treated ORX- KO mice (0.22 +/- 0.03 mlxmin(-1)xg(-1)x% CO(2)(-1)) was significantly blunted compared with that in WT mice (0.51 +/- 0.05 mlxmin(-1)xg(-1)x% CO(2)(-1)). Supplementation of orexin-A or -B (3 nmol) partially restored the hypercapnic chemoreflex in ORX-KO mice (0.28 +/- 0.03 mlxmin(-1).g(-1)x% CO(2)(-1) for orexin A and 0.32 +/- 0.04 mlxmin(-1)xg(-1)x% CO(2)(-1) for orexin-B). In addition, injection of SB-334867 (30 nmol) in WT mice decreased the hypercapnic chemoreflex (0.39 +/- 0.04 mlxmin(-1)xg(-1)x% CO(2)(-1)). On the other hand, hypoxic chemoreflex in vehicle-treated ORX-KO and SB-334867-treated WT mice was not different from that in corresponding controls. Our findings suggest that orexin plays a crucial role in CO(2) sensitivity at least during wake periods in mice. PMID- 17717125 TI - Granulocyte-colony stimulating factor enhances muscle proliferation and strength following skeletal muscle injury in rats. AB - Insufficiency of skeletal muscle regeneration often impedes the healing process with functional deficiencies and scar formation. We tested the hematopoietic growth factor granulocyte-colony stimulating factor (G-CSF) with respect to its efficacy to improve functional muscle regeneration following skeletal muscle injury in Wistar rats. After crush injury to the left soleus muscle, animals received daily G-CSF (20 mug/kg ip) or vehicle solution (n = 30 per group each). Sham-operated animals without muscle injury served as controls (n = 15). After in vivo assessment of the fast-twitch and tetanic contraction capacity of the soleus muscles at days 4, 7, and 14 post-injury, sampling of muscle tissue served for analysis of satellite cell proliferation [bromodeoxyuridine (BrdU)/laminin and BrdU/desmin double immunohistochemistry] and cell apoptosis (transferase nick-end labeling analysis). Muscle strength analysis revealed recovery of contraction forces to 26 +/- 2, 35 +/- 3, and 53 +/- 3% (twitch force) and to 20 +/- 3, 24 +/ 2, and 37 +/- 2% (tetanic force) within the 14-day observation period in vehicle treated animals. In contrast, G-CSF increased contractile forces with markedly higher values at day 7 (twitch force: 42 +/- 2%; tetanic force: 34 +/- 2%) and day 14 (twitch force: 62 +/- 3%; tetanic force: 43 +/- 3%). This enhancement of muscle function was preceded by a significant increase of satellite cell proliferation (BrdU-positive cells/mm(2): 27 +/- 6 vs. vehicle: 12 +/- 3) and a moderate decrease of cell apoptosis (transferase nick-end labeling-positive cells/mm(2): 11 +/- 2 vs. vehicle: 16 +/- 3) at day 4. In conclusion, G-CSF histologically promoted viability and proliferation of muscle cells and functionally enhanced recovery of muscle strength. Thus G-CSF might represent a therapeutic option to optimize the posttraumatic course of muscle tissue healing. PMID- 17717126 TI - Detection and typing of human pathogenic hantaviruses by real-time reverse transcription-PCR and pyrosequencing. AB - BACKGROUND: Because the clinical course of human infections with hantaviruses can vary from subclinical to fatal, rapid and reliable detection of hantaviruses is essential. To date, the diagnosis of hantavirus infection is based mainly on serologic assays, and the detection of hantaviral RNA by the commonly used reverse transcription (RT)-PCR is difficult because of high sequence diversity of hantaviruses and low viral loads in clinical specimens. METHODS: We developed 5 real-time RT-PCR assays, 3 of which are specific for the individual European hantaviruses Dobrava, Puumala, or Tula virus. Two additional assays detect the Asian species Hantaan virus together with Seoul virus and the American species Andes virus together with Sin Nombre virus. Pyrosequencing was established to provide characteristic sequence information of the amplified hantavirus for confirmation of the RT-PCR results or for a more detailed virus typing. RESULTS: The real-time RT-PCR assays were specific for the respective hantavirus species and optimized to run on 2 different platforms, the LightCycler and the ABI 7900/7500. Each assay showed a detection limit of 10 copies of a plasmid containing the RT-PCR target region, and pyrosequencing was possible with 10 to 100 copies per reaction. With this assay, viral genome could be detected in 16 of 552 (2.5%) specimens of suspected hantavirus infections of humans and mice. CONCLUSIONS: The new assays detect, differentiate, and quantify hantaviruses in clinical specimens from humans and from their natural hosts and may be useful for in vitro studies of hantaviruses. PMID- 17717128 TI - Postcollection synthesis of ethyl glucuronide by bacteria in urine may cause false identification of alcohol consumption. AB - BACKGROUND: Ethyl glucuronide (EtG) is a minor ethanol metabolite used as a specific marker to document recent alcohol consumption; confirm abstinence in treatment programs, workplaces, and schools; and provide legal proof of drinking. This study examined if bacterial pathogens in urine may enable postsampling synthesis of EtG and ethyl sulfate (EtS) from ethanol, leading to clinical false positive results. METHODS: Urine specimens with confirmed growth of Escherichia coli, Klebsiella pneumoniae, or Enterobacter cloacae were stored at room temperature in the presence of ethanol. Ethanol was either added to the samples or generated by inoculation with the fermenting yeast species Candida albicans and glucose as substrate. EtG and EtS were measured by LC-MS. RESULTS: High concentrations of EtG (24-h range 0.5-17.6 mg/L) were produced during storage in 35% of E. coli-infected urines containing ethanol. In some specimens that were initially EtG positive because of recent alcohol consumption, EtG was also sensitive to degradation by bacterial hydrolysis. In contrast, EtS was completely stable under these conditions. CONCLUSIONS: The presence of EtG in urine is not a unique indicator of recent drinking, but might originate from postcollection synthesis if specimens are infected with E. coli and contain ethanol. Given the associated risks for false identification of alcohol consumption and false negative EtG results due to bacterial degradation, we recommend that measurement of EtG be combined with EtS, or in the future possibly replaced by EtS. PMID- 17717127 TI - Continuous blood glucose monitoring with a thin-film optical sensor. AB - BACKGROUND: We recently described a holographic optical sensor with improved selectivity for glucose over fructose that was based on a thin-film polymer hydrogel containing phenylboronic acid receptors. The aim of the present work was to measure glucose in human blood plasma as opposed to simple buffers and track changes in concentration at a rate mimicking glucose changes in vivo. METHODS: We used holographic sensors containing acrylamide, N,N'-methylenebisacrylamide, 3 acrylamidophenylboronic acid, and (3-acrylamidopropyl)trimethylammonium chloride to measure 7 human blood plasma samples at different glucose concentrations (3-33 mmol/L) in static mode. Separately, using a flow cell, the glucose concentration was varied at approximately 0.17-0.28 mmol(-1) x L(-1) x min(-1), and the sensor's ability to continuously monitor glucose was investigated over an extended period. RESULTS: We subjected the results of the ex vivo static measurements to error grid analysis. Of 46 measurements, 42 (91.3%) fell in zone A of a Clarke error grid, and the remainder (8.7%) fell in zone B. The ex vivo flow experiments showed that the sensor is able to accurately track changes in concentration occurring in real time without lag or evidence of hysteresis. CONCLUSIONS: We demonstrate the ability of a phenylboronic acid-based sensor to measure glucose in human blood plasma for the 1st time in vitro. Holographic glucose sensors can be used without recourse to recalibration. Their robust nature, coupled with their format flexibility, makes them an attractive alternative to conventional electrochemical enzyme-based methods of glucose monitoring for people with diabetes. PMID- 17717129 TI - Genomic profiling of circulating plasma RNA for the analysis of cancer. AB - BACKGROUND: The blood of cancer patients is known to contain fragments of RNA released from the tumor. The application of genomic profiling techniques to plasma RNA may allow the unbiased selection of cancer markers in the blood, but the informative value of genomic profiling of plasma RNA is currently unknown. METHODS: We used cDNA microarray hybridization to perform genomic profiling of plasma RNA from colorectal cancer (CRC) patients and from healthy donors. From a list of 40 genes differentially upregulated in cancer patients, we randomly selected 4 genes for further characterization. These 4 markers were analyzed by quantitative reverse-transcription PCR in a wide set of samples including paired samples from the same CRC patients before and after surgical resection of the tumor. RESULTS: Three of the selected markers - EPAS1, UBE2D3, and KIAA0101 - were confirmed by PCR to be significantly increased in cancer compared to healthy donors. Importantly, 2 of the markers, EPAS1 and UBE2D3, showed a significant decrease after surgery, returning to the levels of healthy donors. Finally, supervised class prediction using these 3 markers correctly (77%) assigned presurgery samples to the CRC group and assigned postsurgery samples from the same patients to the healthy group. CONCLUSIONS: Our findings demonstrate the usefulness of gene expression profiling of circulating plasma RNA to find cancer markers of potential clinical value. PMID- 17717131 TI - Detection of amplifiable mRNA extracellular to insulin-producing cells: potential for predicting beta cell mass and function. AB - BACKGROUND: Detecting extracellular nucleic acids in the serum/plasma of cancer patients may help in cancer diagnosis. We investigated whether extracellular mRNAs are reproducibly detectable in conditioned medium (CM) from insulin producing cell cultures and if their presence and amounts are indicative of cell number and/or function. METHODS: We isolated mRNA from medium conditioned by the culture of several insulin-producing cell types: MIN6(L) (glucose-responsive), MIN6(H) (glucose-nonresponsive), and MIN6 B1 murine beta cells and monkey kidney fibroblast cells engineered to produce human preproinsulin (PPI) (Vero-PPI). We used reverse transcription-PCR analyses to evaluate the occurrence of several mRNAs and investigated whether the presence and amounts of the various extracellular mRNAs are associated with cell mass and/or function. RESULTS: Reproducible amplification of mRNAs encoded by Pdx1, Npy, Egr1, Pld1, Chgb, Ins1, Ins2, and Actb from MIN6(L), MIN6(H), and MIN6 B1 cells and their CM suggests that beta cells transcribe and release these mRNAs into their culture environment. Similarly, PPI mRNA was detected in samples of Vero-PPI cells and CM. The amounts of some mRNAs reflected the numbers and functional status (i.e., glucose responsiveness vs nonresponsiveness) of the cells conditioning the medium. Although Pax4 mRNA was detected in the MIN6 B1 cell line, the fact that this transcript was not amplifiable from the corresponding CM suggested that mRNA release was selective. CONCLUSION: mRNAs may be secreted from insulin-producing cells, are reproducibly detected in the extracellular environment, and may have potential as extracellular biomarkers for assessing beta cell mass and function. PMID- 17717130 TI - Development of a novel immunoassay for the assessment of plasma Gas6 concentrations and their variation with hormonal status. AB - BACKGROUND: Gas6 is a vitamin K-dependent antiapoptotic protein that has been implicated in cardiovascular pathophysiology. We report the development and validation of an ELISA for Gas6, and the variation of plasma Gas6 with hormonal status in a study designed to evaluate the effect of oral contraception on plasma markers. METHODS: After validation of the main stages of the ELISA assay, we measured plasma Gas6 concentrations in 94 male and 88 female healthy volunteers ages 18 to 38 years. Forty-five of the women then received an oral contraceptive, which contained ethinylestradiol and levonorgestrel, for 3 months before a new measurement was performed at the same time point in their menstrual cycles. RESULTS: Interassay imprecision was 5.8%-11.8%, and the detection limit was 5.9 microg/L. Mean Gas6 plasma concentrations were significantly lower in men (52.0 microg/L) than in women not receiving oral contraceptives (63.8 microg/L, P <0.001). In the women who received oral contraceptives, Gas6 concentrations decreased after 3 months of therapy from 63.6 microg/L to 51.9 microg/L (P <0.001). CONCLUSIONS: We have developed a simple and reproducible ELISA assay for measuring plasma Gas6 concentrations, which vary with sex and are decreased by oral contraceptive use. These results suggest regulation of plasma Gas6 concentrations by sex hormones. Future clinical studies may require participants to be stratified by sex. PMID- 17717132 TI - Clinical application of C-reactive protein across the spectrum of acute coronary syndromes. AB - BACKGROUND: High-sensitivity C-reactive protein (hsCRP) is associated with adverse cardiovascular outcomes in acute coronary syndromes (ACS). The ability to formulate recommendations regarding clinical use of hsCRP is limited by a paucity of data regarding several key issues. The purpose of this study was to evaluate hsCRP across the spectrum of ACS. METHODS: hsCRP was measured on admission in 3225 patients with ACS. hsCRP concentrations were compared in patients who suffered an adverse cardiac outcome within 10 months of study entry and in patients who had no adverse event. Because of heterogeneity in the relationship between hsCRP and clinical outcomes, evaluation was limited to patients from whom samples were collected within 48 h of symptom onset. RESULTS: Patients in the highest quartile of hsCRP compared to those in the lowest quartile were at increased risk of death at 30 days [adjusted hazard ratio (adjHR) 4.6, P <0.001] and 10 months (adjHR 3.9, P <0.001). In patients with unstable angina/non-ST elevation myocardial infarction (STEMI), hsCRP >3 mg/L was associated with increased 10-month mortality (adjHR 2.3, P = 0.002), whereas in STEMI a relationship with mortality was seen at hsCRP >10 mg/L (adjHR 3.0, P = 0.008). Increased concentrations of hsCRP were strongly associated with the development of heart failure at 30 days (adjHR 8.2, P = 0.001) and 10 months (adjHR 2.6, P = 0.014). CONCLUSION: Increased baseline concentrations of hsCRP are strongly associated with mortality and heart failure across the ACS spectrum. hsCRP measurement should be performed early after presentation and index diagnosis specific cutpoints should be used. PMID- 17717133 TI - Decreased serum retinol is associated with increased mortality in renal transplant recipients. AB - BACKGROUND: Vitamin A plays a central role in epithelial integrity and immune function. Given the risk of infection after transplantation, adequate vitamin A concentrations may be important in patients with a transplant. We assessed whether there was an association between retinol concentration and all-cause mortality in renal transplant recipients. METHODS: We recruited 379 asymptomatic renal transplant recipients between June 2000 and December 2002. We measured serum retinol at baseline and collected prospective follow-up data at a median of 1739 days. RESULTS: Retinol was significantly decreased in those renal transplant recipients who had died at follow-up compared with those who were still alive at follow-up. Kaplan-Meier analysis showed that retinol concentration was a significant predictor of mortality. In multivariate Cox regression analysis, decreased retinol concentration remained a statistically significant predictor of all-cause mortality after adjustment for traditional cardiovascular risk factors, high-sensitivity C-reactive protein, and estimated glomerular filtration rate. CONCLUSIONS: Serum retinol concentration is a significant independent predictor of all-cause mortality in renal transplantation patients. Higher retinol concentration might impart a survival advantage via an antiinflammatory or anti infective mechanism. PMID- 17717134 TI - Deletions within the HSV-tk transgene in long-lasting circulating gene-modified T cells infused with a hematopoietic graft. AB - In our previous phase 1/2 study aimed at controlling graft-versus-host disease, 12 patients received Herpes simplex virus thymidine kinase (HSV-tk(+))/neomycin phosphotransferase (NeoR(+))-expressing donor gene-modified T cells (GMCs) and underwent an HLA-identical sibling T-cell-depleted bone marrow transplantation (BMT). This study's objective was to follow up, to quantify, and to characterize persistently circulating GMCs more than 10 years after BMT. Circulating GMCs remain detectable in all 4 evaluable patients. However, NeoR- and HSV-tk polymerase chain reaction (PCR) differently quantified in vivo counts, suggesting deletions within the HSV-tk gene. Further experiments, including a novel "transgene walking" PCR method, confirmed the presence of deletions. The deletions were unique, patient-specific, present in most circulating GMCs expressing NeoR, and shown to occur at time of GMC production. Unique patient specific retroviral insertion sites (ISs) were found in all GMCs capable of in vitro expansion/cloning as well. These findings suggest a rare initial gene deletion event and an in vivo survival advantage of rare GMC clones resulting from an anti-HSV-tk immune response and/or ganciclovir treatment. In conclusion, we show that donor mature T cells infused with a T-cell-depleted graft persist in vivo for more than a decade. These cells, containing transgene deletions and subjected to significant in vivo selection, represent a small fraction of T cells infused at transplantation. PMID- 17717135 TI - T cell depleted stem-cell transplantation for adults with hematologic malignancies: sustained engraftment of HLA-matched related donor grafts without the use of antithymocyte globulin. AB - Antithymocyte globulin (ATG) has been used in allogeneic stem-cell transplantation to prevent graft rejection and graft-versus-host disease (GvHD). Its use, however, has been associated with delayed T-cell reconstitution and prolonged susceptibility to opportunistic infections (OIs) especially in patients undergoing T cell-depleted (TCD) transplantation. Recently, a prospective trial was conducted in 52 adult patients (median age, 47 years) with various hematologic malignancies undergoing TCD transplantation from HLA-matched related donors without the use of ATG. The cytoreductive regimen consisted of hyperfractionated total body irradiation (HFTBI), thiotepa, and fludarabine. The preferred source of the graft was peripheral blood stem cells (PBSCs). No additional graft rejection or GvHD prophylaxis was given. All evaluable patients engrafted without any immune-mediated graft rejections. Disease-free survival (DFS) at 3 years was 61% in all patients, and 70% in patients with standard-risk disease. Acute GvHD was limited to grade 2 in 8% and chronic GvHD in 9% of patients. Life-threatening OIs occurred in 3 of 52 patients and was fatal in 1. This study demonstrates durable engraftment with a low incidence of GvHD despite the lack of ATG, as well as the curative potential of this regimen. PMID- 17717136 TI - Histone deacetylase mediated transcriptional activation reduces proviral loads in HTLV-1 associated myelopathy/tropical spastic paraparesis patients. AB - Epigenetic modifications of chromatin may play a role in maintaining viral latency and thus persistence of the human T-lymphotropic virus type 1 (HTLV-1), which is responsible for HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A major determinant of disease progression is increased peripheral blood proviral load (PVL), possibly via the accumulation of infected cells in the central nervous system (CNS) creating a damaging inflammatory response. Current therapeutic approaches that focus on reducing either cell proliferation, viral replication, or tissue invasion are still unsatisfactory. Contrasting with these inhibitory strategies, we evaluated the efficacy of a novel approach aimed, paradoxically, at activating viral gene expression to expose virus-positive cells to the host immune response. We used valproate (VPA), a histone deacetylase inhibitor that has been used for decades as a chronic, safe treatment for epileptic disorders. Based on in vitro and in vivo data, we provide evidence that transient activation of the latent viral reservoir causes its collapse, a process that may alleviate the condition of HAM/TSP. This represents the first such approach to treating HAM/TSP, using gene activation therapy to tilt the host pathogen balance in favor of an existing antiviral response. This trial is registered at http://clinicaltrials.gov/as no. NCT00519181. PMID- 17717138 TI - Viral tropism and the pathogenesis of influenza in the Mammalian host. PMID- 17717137 TI - Transdifferentiation of peripheral blood mononuclear cells into epithelial-like cells. AB - Bone marrow-derived stem cells have the potential to transdifferentiate into unexpected peripheral cells. We hypothesize that circulating bone marrow-derived stem cells might have the capacity to transdifferentiate into epithelial-like cells and release matrix metalloproteinase-1-modulating factors such as 14-3 3varsigma for dermal fibroblasts. We have characterized a subset of peripheral blood mononuclear cells (PBMCs) that develops an epithelial-like profile. Our findings show that these cells develop epithelial-like morphology and express 14 3-3varsigma and keratin-5, -8 as early as day 7 and day 21, respectively. When compared with control, conditioned media collected from PBMCs in advanced epithelial-like differentiation (cultures on days 28, 35, and 42) increased the matrix metalloproteinase-1 expression in dermal fibroblasts (P DF + D reaction. AB - The reaction of F with H2 and its isotopomers is the paradigm for an exothermic triatomic abstraction reaction. In a crossed-beam scattering experiment, we determined relative integral and differential cross sections for reaction of the ground F(2P(3/2)) and excited F*(2P(1/2)) spin-orbit states with D2 for collision energies of 0.25 to 1.2 kilocalorie/mole. At the lowest collision energy, F* is approximately 1.6 times more reactive than F, although reaction of F* is forbidden within the Born-Oppenheimer (BO) approximation. As the collision energy increases, the BO-allowed reaction rapidly dominates. We found excellent agreement between multistate, quantum reactive scattering calculations and both the measured energy dependence of the F*/F reactivity ratio and the differential cross sections. This agreement confirms the fundamental understanding of the factors controlling electronic nonadiabaticity in abstraction reactions. PMID- 17717181 TI - The Southern Ocean biological response to aeolian iron deposition. AB - Biogeochemical rate processes in the Southern Ocean have an important impact on the global environment. Here, we summarize an extensive set of published and new data that establishes the pattern of gross primary production and net community production over large areas of the Southern Ocean. We compare these rates with model estimates of dissolved iron that is added to surface waters by aerosols. This comparison shows that net community production, which is comparable to export production, is proportional to modeled input of soluble iron in aerosols. Our results strengthen the evidence that the addition of aerosol iron fertilizes export production in the Southern Ocean. The data also show that aerosol iron input particularly enhances gross primary production over the large area of the Southern Ocean downwind of dry continental areas. PMID- 17717182 TI - Anatomy and dynamics of a supramolecular membrane protein cluster. AB - Most plasmalemmal proteins organize in submicrometer-sized clusters whose architecture and dynamics are still enigmatic. With syntaxin 1 as an example, we applied a combination of far-field optical nanoscopy, biochemistry, fluorescence recovery after photobleaching (FRAP) analysis, and simulations to show that clustering can be explained by self-organization based on simple physical principles. On average, the syntaxin clusters exhibit a diameter of 50 to 60 nanometers and contain 75 densely crowded syntaxins that dynamically exchange with freely diffusing molecules. Self-association depends on weak homophilic protein-protein interactions. Simulations suggest that clustering immobilizes and conformationally constrains the molecules. Moreover, a balance between self association and crowding-induced steric repulsions is sufficient to explain both the size and dynamics of syntaxin clusters and likely of many oligomerizing membrane proteins that form supramolecular structures. PMID- 17717183 TI - Domain architecture of pyruvate carboxylase, a biotin-dependent multifunctional enzyme. AB - Biotin-dependent multifunctional enzymes carry out metabolically important carboxyl group transfer reactions and are potential targets for the treatment of obesity and type 2 diabetes. These enzymes use a tethered biotin cofactor to carry an activated carboxyl group between distantly spaced active sites. The mechanism of this transfer has remained poorly understood. Here we report the complete structure of pyruvate carboxylase at 2.0 angstroms resolution, which shows its domain arrangement. The structure, when combined with mutagenic analysis, shows that intermediate transfer occurs between active sites on separate polypeptide chains. In addition, domain rearrangements associated with activator binding decrease the distance between active-site pairs, providing a mechanism for allosteric activation. This description provides insight into the function of biotin-dependent enzymes and presents a new paradigm for multifunctional enzyme catalysis. PMID- 17717184 TI - When fear is near: threat imminence elicits prefrontal-periaqueductal gray shifts in humans. AB - Humans, like other animals, alter their behavior depending on whether a threat is close or distant. We investigated spatial imminence of threat by developing an active avoidance paradigm in which volunteers were pursued through a maze by a virtual predator endowed with an ability to chase, capture, and inflict pain. Using functional magnetic resonance imaging, we found that as the virtual predator grew closer, brain activity shifted from the ventromedial prefrontal cortex to the periaqueductal gray. This shift showed maximal expression when a high degree of pain was anticipated. Moreover, imminence-driven periaqueductal gray activity correlated with increased subjective degree of dread and decreased confidence of escape. Our findings cast light on the neural dynamics of threat anticipation and have implications for the neurobiology of human anxiety-related disorders. PMID- 17717185 TI - Astrocytes potentiate transmitter release at single hippocampal synapses. AB - Astrocytes play active roles in brain physiology. They respond to neurotransmitters and modulate neuronal excitability and synaptic function. However, the influence of astrocytes on synaptic transmission and plasticity at the single synapse level is unknown. Ca(2+) elevation in astrocytes transiently increased the probability of transmitter release at hippocampal area CA3-CA1 synapses, without affecting the amplitude of synaptic events. This form of short term plasticity was due to the release of glutamate from astrocytes, a process that depended on Ca(2+) and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein and that activated metabotropic glutamate receptors (mGluRs). The transient potentiation of transmitter release became persistent when the astrocytic signal was temporally coincident with postsynaptic depolarization. This persistent plasticity was mGluR-mediated but N-methyl-d aspartate receptor-independent. These results indicate that astrocytes are actively involved in the transfer and storage of synaptic information. PMID- 17717186 TI - CHD1 motor protein is required for deposition of histone variant H3.3 into chromatin in vivo. AB - The organization of chromatin affects all aspects of nuclear DNA metabolism in eukaryotes. H3.3 is an evolutionarily conserved histone variant and a key substrate for replication-independent chromatin assembly. Elimination of chromatin remodeling factor CHD1 in Drosophila embryos abolishes incorporation of H3.3 into the male pronucleus, renders the paternal genome unable to participate in zygotic mitoses, and leads to the development of haploid embryos. Furthermore, CHD1, but not ISWI, interacts with HIRA in cytoplasmic extracts. Our findings establish CHD1 as a major factor in replacement histone metabolism in the nucleus and reveal a critical role for CHD1 in the earliest developmental instances of genome-scale, replication-independent nucleosome assembly. Furthermore, our results point to the general requirement of adenosine triphosphate (ATP) utilizing motor proteins for histone deposition in vivo. PMID- 17717188 TI - Temporal fragmentation of speciation in bacteria. AB - Because bacterial recombination involves the occasional transfer of small DNA fragments between strains, different sets of niche-specific genes may be maintained in populations that freely recombine at other loci. Therefore, genetic isolation may be established at different times for different chromosomal regions during speciation as recombination at niche-specific genes is curtailed. To test this model, we separated sequence divergence into rate and time components, revealing that different regions of the Escherichia coli and Salmonella enterica chromosomes diverged over a approximately 70-million-year period. Genetic isolation first occurred at regions carrying species-specific genes, indicating that physiological distinctiveness between the nascent Escherichia and Salmonella lineages was maintained for tens of millions of years before the complete genetic isolation of their chromosomes. PMID- 17717187 TI - Blue-light-activated histidine kinases: two-component sensors in bacteria. AB - Histidine kinases, used for environmental sensing by bacterial two-component systems, are involved in regulation of bacterial gene expression, chemotaxis, phototaxis, and virulence. Flavin-containing domains function as light-sensory modules in plant and algal phototropins and in fungal blue-light receptors. We have discovered that the prokaryotes Brucella melitensis, Brucella abortus, Erythrobacter litoralis, and Pseudomonas syringae contain light-activated histidine kinases that bind a flavin chromophore and undergo photochemistry indicative of cysteinyl-flavin adduct formation. Infection of macrophages by B. abortus was stimulated by light in the wild type but was limited in photochemically inactive and null mutants, indicating that the flavin-containing histidine kinase functions as a photoreceptor regulating B. abortus virulence. PMID- 17717189 TI - Video ergo sum: manipulating bodily self-consciousness. AB - Humans normally experience the conscious self as localized within their bodily borders. This spatial unity may break down in certain neurological conditions such as out-of-body experiences, leading to a striking disturbance of bodily self consciousness. On the basis of these clinical data, we designed an experiment that uses conflicting visual-somatosensory input in virtual reality to disrupt the spatial unity between the self and the body. We found that during multisensory conflict, participants felt as if a virtual body seen in front of them was their own body and mislocalized themselves toward the virtual body, to a position outside their bodily borders. Our results indicate that spatial unity and bodily self-consciousness can be studied experimentally and are based on multisensory and cognitive processing of bodily information. PMID- 17717190 TI - Cellular protection by erythropoietin: new therapeutic implications? AB - Erythropoietin (EPO), the principal hematopoietic hormone produced by the kidney and the liver in fetuses, regulates mammalian erythropoiesis and exhibits diverse cellular effects in nonhematopoietic tissues. The introduction of recombinant human EPO (rhEPO) has marked a significant advance in the management of anemia associated with chronic renal failure. At the same time, experimental studies have unveiled its potential neuroprotective and cardioprotective properties, occurring independently of its hematopoietic action. As with other cytoprotective agents, administration of exogenous rhEPO can confer cerebral and myocardial protection against ischemia-reperfusion injury in terms of reduction in cellular apoptosis and necrosis, as well as improvement in functional recovery. Very recent studies even suggest that this drug could have beneficial applications in oncology, protecting against chemotherapy cardiotoxicity. The purpose of this letter is to review current information regarding the various conditions in which rhEPO and its derivates could confer cellular protection. We also address clinical perspectives and novel therapeutic strategies that could be developed based on these studies. Thus, EPO seems to be a very promising agent for protecting cellular survival during both acute and chronic diseases, and its future should be considered with enthusiasm. PMID- 17717193 TI - What did Sutton see? Thirty years of confusion over the chromosomal basis of Mendelism. PMID- 17717191 TI - Prolonged attenuation of amygdala-kindled seizure measures in rats by convection enhanced delivery of the N-type calcium channel antagonists omega-conotoxin GVIA and omega-conotoxin MVIIA. AB - Convection-enhanced delivery (CED) permits the homogeneous distribution of therapeutic agents throughout localized regions of the brain parenchyma without causing tissue damage as occurs with bolus injection. Here, we examined whether CED infusion of the N-type calcium channel antagonists omega-conotoxin GVIA (omega-CTX-G) and omega-conotoxin MVIIA (omega-CTX-M) can attenuate kindling measures in fully amygdala-kindled rats. Rats were implanted with a combination infusion cannula-stimulating electrode assembly into the right basolateral amygdala. Fully kindled animals received infusions of vehicle, omega-CTX-G (0.005, 0.05, and 0.5 nmol), omega-CTX-M (0.05, 0.15, and 0.5 nmol), proteolytically inactivated omega-CTX-M (0.5 nmol), or carbamazepine (500 nmol) into the stimulation site. CED of omega-CTX-G and omega-CTX-M over a 20-min period resulted in a dose-dependent increase in the afterdischarge threshold and a decrease in the afterdischarge duration and behavioral seizure score and duration during a period of 20 min to 1 week after the infusion, indicating an inhibitory effect on the triggering and expression of kindled seizures. The protective effects of omega-conotoxins reached a maximum at 48 h postinfusion, and then they gradually resolved over the next 5 days. In contrast, carbamazepine was active at 20 min but not at 24 h after the infusion, whereas CED of vehicle or inactivated omega-CTX-M had no effect. Except for transient tremor in some rats receiving the highest toxin doses, no adverse effects were observed. These results indicate that local CED of high-molecular-weight presynaptic N-type calcium channel blockers can produce long-lasting inhibition of brain excitability and that they may provide prolonged seizure protection in focal seizure disorders. PMID- 17717194 TI - A genetic screen identifies novel polycomb group genes in Drosophila. AB - Polycomb group (PcG) genes encode evolutionarily conserved transcriptional repressors that are required for the long-term silencing of particular developmental control genes in animals and plants. PcG genes were first identified in Drosophila as regulators that keep HOX genes inactive in cells where these genes must remain silent during development. Here, we report the results of a genetic screen aimed at isolating novel PcG mutants in Drosophila. In an EMS mutagenesis, we isolated 82 mutants that show Polycomb-like phenotypes in clones in the adult epidermis and misexpression of the HOX gene Ubx in clones in the imaginal wing disc. Analysis of these mutants revealed that we isolated multiple new alleles in most of the already- known PcG genes. In addition, we isolated multiple mutant alleles in each of ten different genes that previously had not been known to function in PcG repression. We show that the newly identified PcG gene calypso is required for the long-term repression of multiple HOX genes in embryos and larvae. In addition, our studies reveal that the Kto/Med12 and Skd/Med13 subunits of the Med12.Med13.Cdk8.CycC repressor subcomplex of Mediator are needed for repression of the HOX gene Ubx. The results of the mutant screen reported here suggest that the majority of nonredundant Drosophila genes with strong classic PcG phenotypes have been identified. PMID- 17717195 TI - Genetic screens for Caenorhabditis elegans mutants defective in left/right asymmetric neuronal fate specification. AB - We describe here the results of genetic screens for Caenorhabditis elegans mutants in which a single neuronal fate decision is inappropriately executed. In wild-type animals, the two morphologically bilaterally symmetric gustatory neurons ASE left (ASEL) and ASE right (ASER) undergo a left/right asymmetric diversification in cell fate, manifested by the differential expression of a class of putative chemoreceptors and neuropeptides. Using single cell-specific gfp reporters and screening through a total of almost 120,000 haploid genomes, we isolated 161 mutants that define at least six different classes of mutant phenotypes in which ASEL/R fate is disrupted. Each mutant phenotypic class encompasses one to nine different complementation groups. Besides many alleles of 10 previously described genes, we have identified at least 16 novel "lsy" genes ("laterally symmetric"). Among mutations in known genes, we retrieved four alleles of the miRNA lsy-6 and a gain-of-function mutation in the 3'-UTR of a target of lsy-6, the cog-1 homeobox gene. Using newly found temperature-sensitive alleles of cog-1, we determined that a bistable feedback loop controlling ASEL vs. ASER fate, of which cog-1 is a component, is only transiently required to initiate but not to maintain ASEL and ASER fate. Taken together, our mutant screens identified a broad catalog of genes whose molecular characterization is expected to provide more insight into the complex genetic architecture of a left/right asymmetric neuronal cell fate decision. PMID- 17717197 TI - Sex-ratio evolution in nuclear-cytoplasmic gynodioecy when restoration is a threshold trait. AB - Gynodioecious plant species, which have populations consisting of female and hermaphrodite individuals, usually have complex sex determination involving cytoplasmic male sterility (CMS) alleles interacting with nuclear restorers of fertility. In response to recent evidence, we present a model of sex-ratio evolution in which restoration of male fertility is a threshold trait. We find that females are maintained at low frequencies for all biologically relevant parameter values. Furthermore, this model predicts periodically high female frequencies (>50%) under conditions of lower female seed fecundity advantages (compensation, x = 5%) and pleiotropic fitness effects associated with restorers of fertility (costs of restoration, y = 20%) than in other models. This model explains the maintenance of females in species that have previously experienced invasions of CMS alleles and the evolution of multiple restorers. Sensitivity of the model to small changes in cost and compensation values and to initial conditions may explain why populations of the same species vary widely for sex ratio. PMID- 17717196 TI - Genetic analysis of the histidine utilization (hut) genes in Pseudomonas fluorescens SBW25. AB - The histidine utilization (hut) locus of Pseudomonas fluorescens SBW25 confers the ability to utilize histidine as a sole carbon and nitrogen source. Genetic analysis using a combination of site-directed mutagenesis and chromosomally integrated lacZ fusions showed the hut locus to be composed of 13 genes organized in 3 transcriptional units: hutF, hutCD, and 10 genes from hutU to hutG (which includes 2 copies of hutH, 1 of which is nonfunctional). Inactivation of hutF eliminated the ability to grow on histidine, indicating that SBW25 degrades histidine by the five-step enzymatic pathway. The 3 hut operons are negatively regulated by the HutC repressor with urocanate (the first intermediate of the histidine degradation pathway) as the physiological inducer. 5'-RACE analysis of transcriptional start sites revealed involvement of both sigma(54) (for the hutU G operon) and sigma(70) (for hutF); the involvement of sigma(54) was experimentally demonstrated. CbrB (an enhancer binding protein for sigma(54) recruitment) was required for bacterial growth on histidine, indicating positive control of hut gene expression by CbrB. Recognition that a gene (named hutD) encoding a widely distributed conserved hypothetical protein is transcribed along with hutC led to analysis of its role. Mutational and gene fusion studies showed that HutD functions independently of HutC. Growth and fitness assays in laboratory media and on sugar beet seedlings suggest that HutD acts as a governor that sets an upper bound to the level of hut activity. PMID- 17717199 TI - Overexpression of GATA-3 protects against the development of hypersensitivity pneumonitis. AB - RATIONALE: Hypersensitivity pneumonitis (HP) is mediated by a Th1 immune response. Transcription factor GATA binding protein-3 (GATA-3) is believed to be a key regulator of Th2 differentiation and thus might play regulatory roles in the pathogenesis of hypersensitivity pneumonitis (HP). OBJECTIVES: We examined the effect of GATA-3 overexpression on the development of HP in mice. METHODS: Wild-type C57BL/6 mice and GATA-3-overexpressing mice of the same background were used in this study. HP was induced by repeated exposure to Saccharopolyspora rectivirgula, the causative antigen of farmer's lung. MEASUREMENTS AND MAIN RESULTS: Antigen exposure resulted in a marked inflammatory response with enhanced pulmonary expression of T-bet and the Th1 cytokine interferon (IFN) gamma in wild-type mice. The degree of pulmonary inflammation was much less severe in GATA-3-overexpressing mice. The induction of T-bet and IFN-gamma genes was suppressed, but a significant induction of Th2 cytokines, including IL-5 and IL-13, was observed in the lungs of GATA-3-overexpressing mice after antigen exposure. Supplementation with recombinant IFN-gamma enhanced lung inflammatory responses in GATA-3-overexpressing mice to the level of wild-type mice. Because antigen-induced IFN-gamma production predominantly occurred in CD4+ T cells, nude mice were transferred with CD4+ T cells from either wild-type or GATA-3 overexpressing mice and subsequently exposed to antigen. Lung inflammatory responses were significantly lower in nude mice transferred with CD4+ T cells from GATA-3-overexpressing mice than in those with wild-type CD4+ T cells, with a reduction of lung IFN-gamma level. CONCLUSIONS: These results indicate that overexpression of GATA-3 attenuates the development of HP by correcting the Th1 polarizing condition. PMID- 17717198 TI - Multiple-copy cluster-type organization and evolution of genes encoding O methyltransferases in the apple. AB - Plant O-methyltransferases (OMTs) play important roles in secondary metabolism. Two clusters of genes coding for caffeic acid OMT (COMT) have been identified in the apple genome. Three genes from one cluster and two genes from another cluster were isolated. These five genes encoding COMT, designated Mdomt1-Mdomt5 (GenBank accession nos. DQ886018-DQ886022), were distinguished by a (CT)(n) microsatellite in the 5'-UTR and two transposon-like sequences present in the promoter region and intron 1, respectively. The transposon-like sequence in intron 1 unambiguously traced the five Mdomt genes in the apple to a common ancestor. The ancestor must have undergone an initial duplication generating two progenitors, and this was followed by further duplication of these progenitors resulting in the two clusters identified in this study. The distal regions of the transposon like sequences in promoter regions of Mdomt genes are capable of forming palindromic hairpin-like structures. The hairpin formation is likely responsible for nucleotide sequence differences observed in the promoter regions of these genes as it plays a destabilizing role in eukaryotic chromosomes. In addition, the possible mechanism of amplification of Mdomt genes in the apple genome is also discussed. PMID- 17717200 TI - Dendritic cells accumulate in human fibrotic interstitial lung disease. AB - RATIONALE: There is growing evidence that resident cells, such as fibroblasts and epithelial cells, can drive the persistent accumulation of dendritic cells (DCs) in chronically inflamed tissue, leading to the organization and the maintenance of ectopic lymphoid aggregates. This phenomenon, occurring through a chemokine mediated retention mechanism, has been documented in various disorders, but not in fibrotic interstitial lung disorders in which the presence of organized lymphoid follicles has been documented. OBJECTIVES: To characterize the distribution of DCs in fibrotic lung, and to analyze the expression of the main chemokines known to regulate DC recruitment. METHODS: Lung resection tissue (lungs with idiopathic pulmonary fibrosis; n = 12; lungs with nonspecific interstitial pneumonia, n = 5; control lungs, n = 5) was snap-frozen for subsequent immunohistochemical techniques on serial sections and reverse transcriptase-polymerase chain reaction analysis. MEASUREMENTS AND MAIN RESULTS: Results were similar in idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia lungs, which were heavily infiltrated by immature DCs in established fibrosis and in areas of epithelial hyperplasia. Altered epithelial cells and fibroblasts, particularly in fibroblastic foci, frankly expressed all chemokines (CCL19, CCL20, CCL22, and CXCL12) susceptible to favor the recruitment of immune cells. Lymphoid follicles were infiltrated by maturing DCs, which could originate from the pool of DCs accumulating in their vicinity. CONCLUSIONS: These findings suggest that resident cells in pulmonary fibrosis can sustain chronic inflammation by driving the accumulation of DCs with the potential to mature locally within ectopic lymphoid follicles. Future strategies should consider DCs or chemokines as therapeutic targets in the treatment of pulmonary fibrosis. PMID- 17717201 TI - Radiation-induced cancer risk from annual computed tomography for patients with cystic fibrosis. AB - RATIONALE: Computed tomography (CT) is being considered as a tool for routine monitoring of lung damage in people with cystic fibrosis. Concern has been raised, however, about the associated risk of radiation-induced cancer. OBJECTIVES: To estimate the risk of radiation-induced cancer from lung CT for patients with cystic fibrosis, assuming annual monitoring starting at age 2 years. METHODS: Radiation risk models (derived primarily from the study of Japanese atomic bomb survivors) were used to estimate the excess risk of radiation-induced cancer for the organs that receive measurable doses from lung CT. Two scenarios were considered: median survival to age 36 years (approximate current median survival) and median survival to age 50 years (projected median survival by 2030). MEASUREMENTS AND MAIN RESULTS: The estimated risk of radiation induced cancer from annual lung CT was 0.02% for males and 0.07% for females assuming median survival to age 36 years. The estimated risks increased to 0.08% for males and 0.46% for females assuming median survival increases to age 50 years. The risks are higher for females because of the risk of radiation-induced breast cancer (50% of total risk) and higher risk of thyroid cancer. CONCLUSIONS: The cumulative risk of radiation-induced cancer from repeated lung CT scans for patients with cystic fibrosis is relatively small (less than 0.5%). However, routine monitoring should not be recommended until there is a demonstrated benefit that will outweigh these risks. PMID- 17717202 TI - Selective inducible nitric oxide synthase inhibition has no effect on allergen challenge in asthma. AB - RATIONALE: Exhaled breath nitric oxide (Fe(NO)) is increased in asthma. NO is produced predominantly by inducible nitric oxide synthase (iNOS). OBJECTIVES: We evaluated the selective and potent iNOS inhibitor GW274150 in asthma. METHODS: Twenty-eight steroid-naive patients with asthma participated in a double-blind, randomized, double-dummy, placebo-controlled, three-period cross-over study. Subjects received GW274150 (90 mg), montelukast (10 mg), or placebo once daily for 14 days. Fe(NO) was assessed predose on Days 1, 7, 10, and 14. Adenosine 5' monophosphate (AMP) challenge was performed on Day 10, allergen challenge on Day 14 followed by methacholine challenge (MCh) 24 hours later, and then bronchoscopy. MEASUREMENTS AND MAIN RESULTS: GW274150 reduced predose Fe(NO) by 73, 75, and 71% on Days 7, 10, and 14, respectively, compared with placebo. Montelukast did not reduce Fe(NO). GW274150 did not inhibit AMP reactivity whereas for montelukast there was a trend toward inhibition: the mean doubling dose difference versus placebo was 0.64 (95% confidence interval [95% CI], 0 to 1.28). GW274150 did not inhibit early (EAR) and late (LAR) asthmatic responses to allergen, or MCh reactivity, despite reduced Fe(NO) levels. Montelukast inhibited EAR and LAR FEV1; the mean difference versus placebo for minimal FEV1 was 0.37 L (95% CI, 0.19 to 0.55) and 0.18 L (95% CI, 0.04 to 0.32), respectively. MCh reactivity was inhibited by montelukast (mean doubling dose difference vs. placebo, 0.51; 95% CI, 0.02 to 1.01). GW271540 also had no effect on inflammatory cell numbers in bronchoalveolar lavage fluid after allergen challenge. CONCLUSIONS: Selective iNOS inhibition effectively reduces Fe(NO) but does not affect airway hyperreactivity or airway inflammatory cell numbers after allergen challenge in subjects with asthma. Clinical trial registered with www.clinicaltrials.gov (NCT00273013). PMID- 17717205 TI - Role of alpha1-acid glycoprotein in therapeutic antifibrotic effects of imatinib with macrolides in mice. AB - RATIONALE: Imatinib is an inhibitor of platelet-derived growth factor receptors. We have reported that treatment with imatinib inhibited bleomycin-induced pulmonary fibrosis in mice. However, late treatment with imatinib had no effect. OBJECTIVES: To clarify why imatinib had no antifibrotic effect when its administration was delayed, we focused on alpha(1)-acid glycoprotein (AGP), because it was reported to bind imatinib and mediate drug resistance. METHODS: The concentration of AGP in serum of mice and patients with idiopathic pulmonary fibrosis was measured by radial immunodiffusion testing. The effects of AGP in vitro were evaluated by assaying the growth of lung fibroblasts. We examined the combined effects of erythromycin (EM) or clarithromycin (CAM) on bleomycin induced pulmonary fibrosis in mice. MEASUREMENTS AND MAIN RESULTS: Addition of AGP abrogated imatinib-mediated inhibition of the growth of fibroblasts. However, treatment with EM or CAM restored the growth-inhibitory effects of imatinib. The elevated level of AGP was detected in serum and lung homogenates in bleomycin exposed mice and reached a plateau on Day 14. Imatinib alone did not ameliorate pulmonary fibrosis when treatment was started on Day 15, whereas coadministration of imatinib and EM or CAM significantly reduced the fibrogenesis via inhibition of the growth of fibroblasts in vivo. Serum levels of AGP were higher in patients with idiopathic pulmonary fibrosis than in healthy subjects. CONCLUSIONS: AGP is an important regulatory factor modulating the ability of imatinib to prevent pulmonary fibrosis in mice, and combined therapy with imatinib and EM or CAM might be useful for treatment of pulmonary fibrosis. PMID- 17717203 TI - Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. AB - RATIONALE: The Scleroderma Lung Study enrolled 158 patients with scleroderma related interstitial lung disease in a placebo-controlled trial of oral cyclophosphamide (CYC). Although treatment-related benefits in pulmonary function, skin scores, and patient-centered outcomes were demonstrated after 1 year of therapy, the duration of benefit beyond 1 year was unclear. OBJECTIVES: A second year of follow-up was performed to determine if these effects persisted after stopping treatment. METHODS: A detailed analysis of data obtained over the two years of the study was performed. MEASUREMENTS AND MAIN RESULTS: Using a longitudinal joint model, we analyzed FVC, total lung capacity, transitional dyspnea index, Rodnan skin scores, and the Health Assessment Questionnaire Disability Index during the second year, after adjusting for baseline values, baseline fibrosis score, and nonignorable missing data. Evaluable subjects (72 CYC; 73 placebo) included 93 who completed all visits plus 52 who completed at least 6 months of therapy and returned at 24 month or had their 24-month data imputed. The beneficial effects of CYC on pulmonary function and health status continued to increase through 18 months, after which they dissipated, whereas skin improvements dissipated after 12 months. In contrast, the positive effect on dyspnea persisted through 24 months. Adverse events were uncommon. CONCLUSIONS: One year of CYC improved lung function, skin scores, dyspnea, and health status/disability, effects which either persisted or increased further for several months after stopping therapy. However, except for a sustained impact on dyspnea, all of these effects waned and were no longer apparent at 24 months. Treatment strategies aimed at extending the positive therapeutic effects observed with CYC should be considered. Clinical trial registered with www.clinicaltrials.gov (NCT 000004563). PMID- 17717206 TI - A new treatment for hypoxic brain injury? PMID- 17717204 TI - Alcohol ingestion by donors amplifies experimental airway disease after heterotopic transplantation. AB - RATIONALE: Obliterative bronchiolitis (OB) after lung transplantation is triggered by alloimmunity, but is ultimately mediated by transforming growth factor (TGF)-beta(1)-dependent airway fibrosis. OBJECTIVES: Chronic alcohol use increases TGF-beta(1) expression and renders the lung susceptible to injury. Therefore, we hypothesized that donor alcohol abuse could prime the lung allograft for OB, as many organ donors have a history of alcohol abuse. METHODS: Tracheas from control and alcohol-fed rats (8 wk) were heterotopically transplanted into recipients with varying degrees of alloimmune mismatch and analyzed for obliterative airway disease severity on Postoperative Day 21. MEASUREMENTS AND MAIN RESULTS: Although donor alcohol ingestion did not increase the number of antigen-presenting cells or infiltrating lymphocytes, it nevertheless increased allograft lumenal collagen content fourfold compared with allografts from control donors. In parallel, alcohol increased TGF-beta(1) and alpha-smooth muscle actin expression in allografts. Alcohol amplified airway disease even in isografts with minor alloimmune mismatches. In contrast, it did not cause any airway disease in isografts in a pure isogenic background, suggesting that a minimal alloimmune response is necessary to trigger alcohol induced airway fibrosis. CONCLUSIONS: Although alloimmune inflammation is required to initiate airway disease, alcohol primes the allograft for greater TGF beta(1) expression, myofibroblast transdifferentiation, and fibrosis than by alloimmune inflammation alone. This has serious clinical implications, as many lung donors have underlying alcohol abuse that may prime the allograft recipient for subsequent OB. PMID- 17717207 TI - Noble gases without anesthetic properties protect myocardium against infarction by activating prosurvival signaling kinases and inhibiting mitochondrial permeability transition in vivo. AB - BACKGROUND: The anesthetic noble gas, xenon, produces cardioprotection. We hypothesized that other noble gases without anesthetic properties [helium (He), neon (Ne), argon (Ar)] also produce cardioprotection, and further hypothesized that this beneficial effect is mediated by activation of prosurvival signaling kinases [including phosphatidylinositol-3-kinase, extracellular signal-regulated kinase, and 70-kDa ribosomal protein s6 kinase] and inhibition of mitochondrial permeability transition pore (mPTP) opening in vivo. METHODS: Rabbits (n = 98) instrumented for hemodynamic measurement and subjected to a 30-min left anterior descending coronary artery (LAD) occlusion and 3 h reperfusion received 0.9% saline (control), three cycles of 70% He-, Ne-, or Ar-30% O2 administered for 5 min interspersed with 5 min of 70% N2-30% O2 before LAD occlusion, or three cycles of brief (5 min) ischemia interspersed with 5 min reperfusion before prolonged LAD occlusion and reperfusion (ischemic preconditioning). Additional groups of rabbits received selective inhibitors of phosphatidylinositol-3-kinase (wortmannin; 0.6 mg/kg), extracellular signal-regulated kinase (PD 098059; 2 mg/kg), or 70-kDa ribosomal protein s6 kinase (rapamycin; 0.25 mg/kg) or mPTP opener atractyloside (5 mg/kg) in the absence or presence of He pretreatment. RESULTS: He, Ne, Ar, and ischemic preconditioning significantly (P < 0.05) reduced myocardial infarct size [23% +/- 4%, 20% +/- 3%, 22% +/- 2%, 17% +/- 3% of the left ventricular area at risk (mean +/- sd); triphenyltetrazolium chloride staining] versus control (45% +/- 5%). Wortmannin, PD 098059, rapamycin, and atractyloside alone did not affect infarct size, but these drugs abolished He induced cardioprotection. CONCLUSIONS: The results indicate that noble gases without anesthetic properties produce cardioprotection by activating prosurvival signaling kinases and inhibiting mPTP opening in rabbits. PMID- 17717208 TI - Reducing thrombotic complications in the perioperative setting: an update on heparin-induced thrombocytopenia. AB - Heparins are widely used in the perioperative setting. Immune heparin-induced thrombocytopenia (HIT) is a serious, antibody-mediated complication of heparin therapy that occurs in approximately 0.5%-5% of patients treated with heparin for at least 5 days. An extremely prothrombotic disorder, HIT confers significant risks of thrombosis and devastating consequences on affected patients: approximately 38%-76% develop thrombosis, approximately 10% with thrombosis require limb amputation, and approximately 20%-30% die within a month. HIT antibodies are transient and typically disappear within 3 mo. In patients with lingering antibodies, however, re-exposure to heparin can be catastrophic. In the perioperative setting, heightened awareness is important for the prompt recognition, diagnosis, and treatment of HIT. HIT should be considered if the platelet count decreases 50% and/or thrombosis occurs 5-14 days after starting heparin, with other diagnoses excluded. On strong clinical suspicion of HIT, heparin should be discontinued and a parenteral alternative anticoagulant initiated, even before laboratory confirmation of HIT is obtained. Subsequent laboratory test results may help with the decision to continue with nonheparin therapy or switch back to heparin. Heparin avoidance in patients with current or previous HIT is feasible in most clinical situations, except perhaps in cardiovascular surgery. If the surgery cannot be delayed until HIT antibodies have disappeared, intraoperative alternative anticoagulation is recommended. PMID- 17717209 TI - Perioperative echocardiographic examination for ventricular assist device implantation. AB - Ventricular assist devices (VADs) are systems for mechanical circulatory support of the patient with severe heart failure. Perioperative transesophageal echocardiography is a major component of patient management, and important for surgical and anesthetic decision making. In this review we present the rationale and available data for a comprehensive echocardiographic assessment of patients receiving a VAD. In addition to the standard examination, device-specific pre-, intra-, and postoperative considerations are essential to the echocardiographic evaluation. These include: (a) the pre-VAD insertion examination of the heart and large vessels to exclude significant aortic regurgitation, tricuspid regurgitation, mitral stenosis, patent foramen ovale, or other cardiac abnormality that could lead to right-to-left shunt after left VAD placement, intracardiac thrombi, ventricular scars, pulmonic regurgitation, pulmonary hypertension, pulmonary embolism, and atherosclerotic disease in the ascending aorta; and to assess right ventricular function; and (b) the post-VAD insertion examination of the device and reassessment of the heart and large vessels. The examination of the device aims to confirm completeness of device and heart deairing, cannulas alignment and patency, and competency of device valves using two-dimensional, and color, continuous and pulsed wave Doppler modalities. The goal for the heart examination after implantation should be to exclude aortic regurgitation, or an uncovered right-to-left shunt; and to assess right ventricular function, left ventricular unloading, and the effect of device settings on global heart function. The variety of VAD models with different basic and operation principles requires specific echocardiographic assessment targeted to the characteristics of the implanted device. PMID- 17717210 TI - The incidental finding of a patent foramen ovale during cardiac surgery: should it always be repaired? A core review. AB - With the increased use of intraoperative transesophageal echocardiography, patent foramen ovale (PFO) has become a common finding during heart surgery. This finding presents a difficult dilemma for cardiac surgeons, since the impact of intraoperatively diagnosed PFOs on postoperative outcome is unknown. Changes in the surgical plan required for closure of a PFO subject the patient to the possibility of additional risk. On the other hand, a decision to not close a PFO exposes the patient to unclear immediate and long-term consequences. Deciding whether or not to close a PFO currently depends on the clinicians' personal preferences, the probability of intraoperative and postoperative hypoxemia, and any anticipated deviation from the initial surgical plan. Most clinicians agree that an intraoperatively diagnosed PFO must be closed when surgery leads to a high risk of hypoxemia (e.g., left ventricular assist devices placement, heart transplantation); should be closed in most cases when minimal deviation from the initial surgical plan is needed for PFO closure (e.g., mitral valve or tricuspid valve surgeries); and probably, should be closed during heart surgeries performed without atriotomy and bicaval cannulation when the risk of perioperative or remote PFO-related complications is increased. The recent development of percutaneous methods of PFO closure provides a valuable backup for those cases when PFO is not closed and postoperative hypoxemia or other complications may be attributable to the uncorrected PFO. PMID- 17717212 TI - CON: The incidental finding of a patent foramen ovale during cardiac surgery: should it always be repaired? PMID- 17717211 TI - PRO: The incidental finding of a patent foramen ovale during cardiac surgery: should it always be repaired? PMID- 17717213 TI - The effect of varying continuous propofol infusions on plasma cyclic guanosine 3',5'-monophosphate concentrations in anesthetized children. AB - BACKGROUND: The glutamate-nitric oxide-cyclic guanosine 3',5'-monophosphate (cGMP) pathway is potentially an effective target for general anesthetics. Plasma cGMP concentrations are reduced after an increase in predicted plasma propofol concentrations during sedation in healthy adult volunteers. We hypothesized that an increase in measured plasma propofol concentration leads to a reduction in plasma cGMP in anesthetized children. METHODS: Eighteen healthy children aged 46.8 (+/-19.6) mo, requiring general anesthesia for lower body surgical procedures were enrolled. After inhaled induction, tracheal intubation and initiation of intermittent positive pressure ventilation, caudal epidural analgesia was performed. Anesthesia was maintained using a continuous propofol infusion adapted from a previously published regimen to achieve predicted propofol plasma concentration of 6, 3, and 1.5 microg/mL after 30, 50, and 70 min, respectively. Samples for propofol and cGMP plasma concentrations were collected and analyzed using high-performance liquid chromatography and an enzyme immunoassay system. RESULTS: The plasma cGMP concentrations varied significantly (median [range]) 19.2 [11.8-23.5], 21.3 [14.6-30.8], and 24.9 [15.7-37.8] nmol/L among each predicted plasma propofol concentration, P < 0.0001. The correlation coefficient (r) was -0.62. CONCLUSIONS: This study demonstrates that an increase in plasma propofol concentration leads to a decrease in plasma cGMP in healthy children, and could serve as a biochemical marker for depth of propofol anesthesia in children. PMID- 17717214 TI - A comparative study of endotracheal tube positioning methods in children: safety from neck movement. AB - BACKGROUND: The unexpected displacement of the endotracheal tube (ETT) as a result of neck movements can cause endobronchial intubation and accidental extubation. The ETT is subject to movement even after its proper placement has been confirmed either clinically or radiographically. METHODS: One-hundred-seven children (2-8 yr) were divided randomly into three groups. In Group I, the ETT was entered into the main bronchus and withdrawn until equal sounds in both lung were heard, and then withdrawn 2 cm. In Group II, the ETT position was determined by placing the prescribed marks on the ETT at the level of the vocal cords, and in Group III, by palpating the ETT tip at the suprasternal notch. In all groups, the distance between the ETT tip and the carina was measured using a fiberoptic bronchoscope. The relative ETT tip position along the trachea (carina; 0%, vocal cords; 100%) was assessed in each position during neck movement. RESULTS: The relative position of the ETT with the patient in the neutral position in Groups I, II, and III was 21.4% +/- 6.7%, 46.5% +/- 13.0%, and 43.4% +/- 11.1%, respectively. In Group I, the relative ETT position after flexion was 9.5% +/- 10.3%, and endobronchial intubation was observed in five children (14.3%). There was no extubation or endobronchial intubation in the other two groups. CONCLUSIONS: Positioning the ETT by auscultation places the ETT more deeply than the midtrachea, which can increase the risk of endobronchial intubation during neck flexion. PMID- 17717215 TI - The use of three-dimensional computed tomography images for anticipated difficult intubation airway evaluation of a patient with Treacher Collins syndrome. AB - A 13-year-old girl with Treacher Collins syndrome who had a history of difficult intubation was scheduled for plastic surgery. We took three-dimensional computed tomography images to better evaluate the anatomical features of the upper airway. The patient's anesthetic airway management was influenced by the findings of the images. PMID- 17717216 TI - Molecular evidence of late preconditioning after sevoflurane inhalation in healthy volunteers. AB - BACKGROUND: Late preconditioning by volatile anesthetics evolves in response to transcriptional changes. We hypothesized that sevoflurane inhalation would modify the transcriptome in human blood and modulate the expression of adhesion molecules in white blood cells consistent with the occurrence of a late preconditioning phase. METHODS: Five healthy male subjects inhaled sevoflurane at an end-tidal concentration of 0.5%-1.0% for 60 min. Venous blood samples were collected at baseline, after 15 and 60 min of inhalation, and 6, 24, 48, and 72 h thereafter and immediately processed for flow cytometry and mRNA extraction and hybridization to Affymetrix U133 Plus 2.0 microarrays. Data were analyzed using Significance Analysis of Microarray and Gene Set Enrichment Analysis and confirmed by real-time reverse transcription polymerase chain reaction. L selectin (CD62L) and beta2-integrin (CD11b) expression was determined on granulocytes and monocytes using flow cytometry. RESULTS: Sevoflurane inhalation rapidly and markedly altered gene expression in white blood cells. Key transcripts potentially involved in late preconditioning or organ protection including paraoxonase, 12-lipoxygenase, heat shock protein 40, chemokine ligand 5, and phosphodiesterase 5A were regulated in response to sevoflurane. Sevoflurane further decreased transcripts involved in peroxisome proliferator activated receptor gamma coactivator-1alpha (PGC-1alpha) signaling and fatty acid oxidation. Reduced L-selectin (CD62L) expression on granulocytes accompanied with increased resistance to inflammatory activation was present at 24 to 48 h after sevoflurane exposure. CONCLUSIONS: Sevoflurane at subanesthetic concentrations modifies blood transcriptome and decreases the expression of the proinflammatory L-selectin (CD62L), consistent with a "second window of protection" in humans. PMID- 17717217 TI - The effects of levosimendan on myocardial function in ropivacaine toxicity in isolated guinea pig heart preparations. AB - BACKGROUND: Levosimendan is a novel drug used for inotropic support in heart failure, but its efficacy in local anesthetic-induced myocardial depression is not known. Therefore, we investigated the effects of levosimendan on the negative inotropic response to ropivacaine in isolated heart preparations of guinea pigs. METHODS: Action potentials and force of contraction were studied with conventional techniques in guinea-pig papillary muscles. Heart rate, systolic pressure, the first derivative of left ventricular pressure (+dP/dt(max)), coronary flow, and PR and QRS intervals were measured in isolated constant pressure perfused, nonrecirculating Langendorff heart preparations. Single or cumulatively increasing concentrations of levosimendan and ropivacaine were used either alone or in combination. RESULTS: In isolated papillary muscle, ropivacaine reduced force of contraction in a concentration-dependent manner. Exposure to 10 microM levosimendan in the presence of 10 muM ropivacaine almost completely reversed the negative inotropic response. Sensitivity to the positive inotropic effect of levosimendan was not altered by 10 muM ropivacaine (-logEC50 [M] = 7.03 without versus 6.9 with ropivacaine, respectively). Action potential parameters were influenced only at the highest concentration. In the Langendorff heart, levosimendan significantly reversed the ropivacaine-induced reduction in heart rate, systolic pressure, coronary flow, and +dP/dt(max) to baseline values. CONCLUSION: Levosimendan is an effective inotropic drug in ropivacaine-induced myocardial depression and levosimendan myocardial sensitivity, and efficacy was not affected by the local anesthetic. Our results suggest that the calcium sensitizing action of levosimendan is effective in local anesthetic-induced cardiac depression. PMID- 17717219 TI - Landiolol, an ultra short-acting beta1-adrenoceptor antagonist, does not alter the minimum alveolar anesthetic concentration of isoflurane in a swine model. AB - BACKGROUND: We previously reported that landiolol, an ultra-short-acting beta1 adrenoceptor antagonist, does not alter the electroencephalographic effect of isoflurane. Here, we investigated the influence of landiolol on the minimum alveolar anesthetic concentration (MAC) of isoflurane required to prevent movement in response to a noxious stimulus in 50% of subjects. METHODS: Ten swine (29.0 +/- 3.4 kg) were anesthetized by inhalation of isoflurane. MAC was determined using the dewclaw clamp technique, in which movement in response to clamping is recorded. After determination of MAC in the baseline period, an infusion of landiolol (0.125 mg x kg(-1) x min(-1) for 1 min, then 0.04 mg x kg( 1) x min(-1)) was started. After a 20-min stabilization period, MAC was again assessed (0.04 mg x kg(-1) x min(-1) landiolol). The infusion of landiolol was then increased from 0.04 to 0.2 mg x kg(-1) x min(-1), and after a 20-min stabilization period, MAC was again assessed (0.2 mg x kg(-1) x min(-1) landiolol). Finally, the infusion of landiolol was stopped, and after a 20-min stabilization period, MAC was assessed for a fourth time (Baseline 2). RESULTS: Landiolol clearly attenuated the increases in heart rate and mean arterial blood pressure that occurred in response to the dewclaw clamp, but did not alter the MAC of isoflurane. CONCLUSIONS: Landiolol does not alter the antinociceptive effect of isoflurane. This result, combined with that from our previous work, also suggests that landiolol does not influence the anesthetic potency of inhaled anesthetics. PMID- 17717218 TI - Sevoflurane 0.25 MAC preferentially affects higher order association areas: a functional magnetic resonance imaging study in volunteers. AB - BACKGROUND: Functional magnetic resonance imaging (fMRI) can objectively measure the subjective effects of anesthesia. Memory-related regions (association areas) are affected by subanesthetic doses of volatile anesthetics. In this study we measured the regional neuronal effects of 0.25 MAC sevoflurane in healthy volunteers and differentiated the effect between primary cortical regions and association areas. METHODS: The effect of 0.25 MAC sevoflurane on visual, auditory, and motor activation was studied in 16 ASA I volunteers. With fMRI (3 Tesla Siemens magnetom), regional cerebral blood flow (rCBF) was measured by the pulsed arterial spin labeling technique. Subjects inhaled a mixture of O2 and 0.25 MAC sevoflurane and standard ASA monitoring was performed. Visual, auditory, and motor activation tasks were used. rCBF was measured in the awake state and during inhalation of 0.25 MAC sevoflurane, without and with activation. The change in rCBF (deltaCBF) with 0.25 MAC Sevoflurane during baseline state and with activation was calculated in 11 regions of interest related to visual, auditory, and motor activation tasks. RESULTS: The change from baseline rCBF with 0.25 MAC sevoflurane was not statistically significant in the 11 regions of interest. With activation there was a significant increase in CBF in several regions. However, only in the primary and secondary visual cortices (V1, V2), thalamus, hippocampus, and supplementary motor area was the decrease in activation with 0.25 MAC sevoflurane statistically significant (P < 0.05). CONCLUSION: Memory-related regions (association areas) are affected by subanesthetic concentrations of volatile anesthetics. Using fMRI, this study showed that 0.25 MAC sevoflurane predominantly affects the primary visual cortex, the related association cortex, and certain other higher order association cortices. PMID- 17717221 TI - Deep sedation with dexmedetomidine in a porcine model does not compromise the viability of free microvascular flap as depicted by microdialysis and tissue oxygen tension. AB - BACKGROUND: Deep sedation is often necessary after major reconstructive plastic surgery in the face and neck regions to prevent sudden spontaneous movements capable of inflicting mechanical injury to the transplanted musculocutaneous flap(s). An adequate positioning may help to optimize oxygenation and perfusion of the transplanted tissues. We hypothesized that dexmedetomidine, a central alpha2-agonist and otherwise potentially ideal postoperative sedative drug, may induce vasoconstriction in denervated flaps, and thus increase the risk of tissue deterioration. METHODS: Two symmetrical myocutaneous flaps were raised on each side of the upper abdomen in 12 anesthetized pigs. The sympathetic nerve fibers were stripped from the arteries in one of the flaps (denervated flap), while nerve fibers were kept untouched in the other (innervated flap). After simulation of ischemia and reperfusion periods, the animals were randomized to deep postoperative sedation with either propofol (n = 6) or dexmedetomidine (n = 6). Flap tissue metabolism was monitored by microdialysis and tissue-oxygen partial pressure. Glucose, lactate, and pyruvate concentrations were analyzed from the dialysate every 30 min for 4 h. RESULTS: Mean arterial blood pressure was higher in the dexmedetomidine group (P = 0.036). Flap tissue metabolism remained stable throughout the experiment as measured by lactate-pyruvate and lactate-glucose ratios (median ranges 14.3-24.5 for lactate-pyruvate and 0.3-0.6 for lactate glucose) and by tissue-oxygen partial pressure, and no differences were found between groups. CONCLUSIONS: Our data suggest that dexmedetomidine, even if used for deep sedation, does not have deleterious effects on local perfusion or tissue metabolism in denervated musculocutaneous flaps. PMID- 17717220 TI - Alterations in spinal, but not cerebral, cerebrospinal fluid Na+ concentrations affect the isoflurane minimum alveolar concentration in rats. AB - BACKGROUND: Previous studies demonstrated that MAC (the minimum alveolar concentration of an inhaled anesthetic that produces immobility in 50% of subjects exposed to noxious stimulation) for halothane directly correlates with the central nervous system concentration of Na+. However, those studies globally altered Na+ concentrations, and thus did not distinguish effects on the spinal cord from cerebral effects. This is an important distinction because the cord appears to be the primary site for mediation of the immobility produced by inhaled anesthetics. Accordingly, in the present study, we examined the effect of altering intrathecal versus intracerebroventricular concentrations of Na+ on MAC. METHODS: In rats prepared with chronic indwelling catheters or stylets, we infused solutions deficient in Na+ and with an excess of Na+ into the lumbar subarachnoid and intracerebroventricular spaces and measured MAC for isoflurane before, during, and after infusion. RESULTS: MAC of isoflurane correlated directly with concentrations of Na+ infused intrathecally but did not correlate with concentrations infused intracerebroventricularly. CONCLUSION: The results are consistent with a mediation or modulation of MAC by Na+ channels. These might include voltage-gated or ligand-gated channels or other Na-sensitive targets (e.g., pumps, transporters, exchangers). PMID- 17717222 TI - Anesthetic properties of the ketone bodies beta-hydroxybutyric acid and acetone. AB - BACKGROUND: We tested the hypothesis that two metabolites that are elevated in ketosis (beta-hydroxybutyric acid, and acetone) modulate ion channels in a manner similar to anesthetics and produce anesthesia in animals. METHODS: alpha1beta2gamma2sgamma-aminobutyric acid type A (GABA(A)), alpha1 glycine, NR1/NR2A N-methyl-d-aspartate, and two pore domain TRESK channels were expressed in Xenopus laevis oocytes and studied using two-electrode voltage clamping. The effect of beta hydroxybutyric acid and acetone on channel function was measured. The anesthetic effects of these drugs were measured in X. laevis tadpoles. RESULTS: Both beta hydroxybutyric acid and acetone enhanced glycine receptor function in the concentration range that is obtained in ketoacidosis in humans. Beta hydroxybutyric acid also enhanced GABA(A) receptor function at these concentrations. Both acetone and beta-hydroxybutyric acid anesthetized tadpoles, with an EC50 for acetone of 264 +/- 2 mM (mean +/- se) and for beta hydroxybutyric acid of 151 +/- 11 mM at pH 7.0. Acetone enhanced GABA(A) receptors at concentrations of 50 mM and above. Inhibition of TRESK channel function was seen with 100 mM acetone or larger concentration. N-methyl-D aspartate receptor function was inhibited at concentrations of acetone of 200 mM and larger. CONCLUSIONS: Beta hydroxybutyric acid and acetone are anesthetics. Both ketone bodies enhance inhibitory glycine receptors at concentrations observed clinically in ketoacidosis. In addition, beta-hydroxybutyric acid enhances GABA(A) receptor function at these concentrations. Subanesthetic concentrations of these drugs may contribute to the lethargy and impairment of consciousness seen in ketoacidosis. PMID- 17717223 TI - Measurement of anesthetics in blood using a conventional infrared clinical gas analyzer. AB - BACKGROUND: Measurement of the partial pressure of volatile anesthetics in blood is usually done using a "headspace equilibration" method with gas chromatography. However, it is not often performed in clinical studies because of the technical, equipment, and logistic requirements. To improve the accessibility of this measurement, we tested the use of a common infrared clinical gas analyzer, the Datex-Ohmeda Capnomac, for this purpose. METHODS: After characterization of the linearity of the device in measuring the volatile anesthetic concentration in the presence of nitrous oxide, carbon dioxide, and water vapor, blood was tonometered with known concentrations of sevoflurane (actual value between 0.5% and 5.0%) in oxygen and oxygen/nitrous oxide mixtures, as well as mixtures of isoflurane and desflurane in oxygen. RESULTS: Mean bias (standard deviation) overall for sevoflurane in oxygen relative to the tonometered reference partial pressure was 4.5 (4.8%) of the actual concentration. This was not altered significantly by measurement in 40% oxygen/60% nitrous oxide. For isoflurane and desflurane it was -3.9 (3.3%) and -4.6 (3.8%), respectively, of the actual concentration. CONCLUSIONS: The accuracy and precision of measurement of volatile anesthetic gas partial pressures in blood by a double headspace equilibration technique, using a clinical infrared gas analyzer, were comparable to that achieved by previous studies using gas chromatography. PMID- 17717224 TI - The effect of neuromuscular block and noxious stimulation on hypnosis monitoring during sevoflurane anesthesia. AB - BACKGROUND: There are conflicting results on the influence of neuromuscular block (NMB) on the bispectral index (BIS). We investigated the influence of two degrees of NMB on BIS, Alaris auditory-evoked potential index (AAI), and the electromyogram (EMG) obtained with needle electrodes from the frontal and temporal muscles, immediately adjacent to the BIS-sensor. METHODS: Twenty patients were anesthetized with sevoflurane, titrated for 30 min to an end-tidal concentration of 1.2% (baseline). Rocuronium was infused to 50% (partial) and 95% (profound) depression of the first twitch in a train-of-four response, the order being randomly chosen. Noxious tetanic electrical stimulation was applied at four occasions: 1) at baseline (control measurement), 2 and 3) at each degree of NMB, and 4) after neostigmine reversal. BIS, AAI, and EMG were obtained 2 min before and 2 min after each noxious stimulation. RESULTS: Median BIS and AAI at baseline were 44 (39-50) and 15 (14-16), respectively. The two degrees of NMB did not affect BIS, AAI, and EMG before noxious stimulation. In contrast, profound NMB altered the BIS and AAI responses to noxious stimulation when compared with partial NMB, (BIS P = 0.01, AAI P < 0.01), after neostigmine reversal (BIS P < 0.01, AAI P = 0.01) and compared with baseline (BIS P = 0.08, AAI P = 0.02). No significant increase in EMG was found. CONCLUSION: BIS and AAI responses to noxious tetanic electrical stimulation are affected by the degree of NMB during sevoflurane anesthesia whereas NMB does not affect BIS or AAI in the absence of noxious stimulation. PMID- 17717225 TI - Exhaled carbon monoxide levels change in relation to inspired oxygen fraction during general anesthesia. AB - BACKGROUND: Heme oxygenase produces carbon monoxide (CO) during the breakdown of heme molecules. A variety of stressors upregulate this enzymatic activity and can increase exhaled CO levels. Recently, exhaled CO levels have been reported to increase in critically ill patients and after anesthesia and surgery. To use this measurement during mechanical ventilation, it is important to clarify the effects of factors which interfere with exhaled CO levels. The fraction of inspired oxygen (Fio2) is often changed during artificial ventilation. To investigate the effect of changes of Fio2 on exhaled CO, we measured exhaled CO levels during general anesthesia. METHODS: Thirty patients who underwent elective operations were enrolled in this study. Anesthesia was maintained with sevoflurane and fentanyl. All patients were tracheally intubated and ventilated with a non rebreathing ventilator. Exhaled CO levels were measured in gas sampled from the expired limb of the respiration circuit using a CO monitor. The effects of sequential changes of Fio2 on exhaled CO levels, and the effects of long-term inhalation of Fio2 0.75 and Fio2 0.35 on exhaled CO levels and arterial carboxyhemoglobin concentrations were investigated. RESULTS: Exhaled CO levels changed rapidly in response to changes of Fio2. Long-term inhalation of Fio2 0.75 initially increased and then gradually decreased exhaled CO to basal levels, concomitant with a decrease of arterial carboxyhemoglobin. Long-term inhalation of Fio2 0.35 did not elicit any significant change in the observed variables. CONCLUSION: When monitoring exhaled CO levels during mechanical ventilation, it is important to consider the effects of Fio2. PMID- 17717226 TI - Control of blood loss during sacral surgery by aortic balloon occlusion. AB - Radical sacral surgery can be associated with life-threatening blood loss. Effective and safe methods for controlling this blood loss remain elusive. We here report the use of an inflatable sizing balloon to intermittently occlude the distal abdominal aorta and control blood loss during sacral tumor resections. The balloon catheter was introduced into the abdominal aorta via the femoral artery. Pulse oxygen saturation signals from bilateral toes and ultrasonography were used to guide and confirm the location of the balloon in the abdominal aorta and distal to the renal arteries. The balloon was deflated for 10 min after each 60 min occlusion period. In five patients undergoing sacral tumor resection, the estimated blood loss when using balloon occlusion was <300 mL, and surgical duration was <2 h. No significant change in kidney, pelvic organ, and lower extremity function was found after the surgeries. Percutaneous aortic balloon occlusion can provide safe and effective control of blood loss during sacrococcygeal tumor resection. PMID- 17717227 TI - The effect of intravenous indigo carmine on near-infrared cerebral oximetry. AB - The effects of IV-administered dyes on pulse oximetry have been well described. However, the effects on near-infrared cerebral oximetry have not been well documented. We report a series of four patients undergoing radical prostatectomy who were monitored with cerebral oximetry during surgery. After the administration of indigo carmine, intraoperative desaturations were observed for an extended period. Because clinical use of near-infrared cerebral oximetry is increasing, anesthesiologists should be aware of this issue. PMID- 17717228 TI - Improving operating room efficiency by applying bin-packing and portfolio techniques to surgical case scheduling. AB - BACKGROUND: An operating room (OR) department has adopted an efficient business model and subsequently investigated how efficiency could be further improved. The aim of this study is to show the efficiency improvement of lowering organizational barriers and applying advanced mathematical techniques. METHODS: We applied advanced mathematical algorithms in combination with scenarios that model relaxation of various organizational barriers using prospectively collected data. The setting is the main inpatient OR department of a university hospital, which sets its surgical case schedules 2 wk in advance using a block planning method. The main outcome measures are the number of freed OR blocks and OR utilization. RESULTS: Lowering organizational barriers and applying mathematical algorithms can yield a 4.5% point increase in OR utilization (95% confidence interval 4.0%-5.0%). This is obtained by reducing the total required OR time. CONCLUSIONS: Efficient OR departments can further improve their efficiency. The paper shows that a radical cultural change that comprises the use of mathematical algorithms and lowering organizational barriers improves OR utilization. PMID- 17717229 TI - Antithrombin levels, morbidity, and mortality in a surgical intensive care unit. AB - BACKGROUND: Antithrombin (AT) levels have been suggested as being predictive of outcome in intensive care unit (ICU) patients with septic shock. We investigated the time course of AT levels in a surgical ICU and tested the hypothesis that AT levels may be associated with morbidity and increased mortality rates in a cohort of surgical ICU patients. METHODS: Three-hundred-twenty-seven consecutive patients admitted to the ICU with an estimated length of stay more than 48 h were included. AT levels were measured daily. RESULTS: On admission to the ICU, AT levels were below the lower limit of normal in 84.1% (n = 275) of patients and increased significantly by 48 h after admission to reach normal values by the 7th ICU day in patients who never had sepsis (n = 208). This increase in AT levels was delayed in patients with sepsis. Patients with severe sepsis (n = 55) had consistently lower AT levels compared with other patients. Patients with lower AT levels were more likely to need blood products and had a greater maximum degree of organ dysfunction in the ICU than did other patients. The ICU length of stay was similar, regardless of the AT level on admission. Admission AT levels were not associated with increased ICU mortality in a multivariable analysis. CONCLUSIONS: AT levels are low on admission to the ICU, regardless of the presence of sepsis. Although associated with the degree of organ dysfunction and the severity of sepsis, AT levels were not independently associated with worse outcome in this group of surgical ICU patients. PMID- 17717230 TI - Hydroxyethyl starch: the effect of molecular weight and degree of substitution on intravascular retention in vivo. AB - BACKGROUND: Hydroxyethyl starch (HES) solution is characterized by its mean molecular weight (MW), concentration, and degree of substitution (DS). This character varies worldwide. METHODS: After binding fluorescein-isothiocyanate (FITC-HES), we evaluated the retention rate of three types of 6% HES in the A2 and V2 blood vessels of rat cremaster muscles using intravital microscopy in a mild hemorrhage model (10% of total blood volume). After blood withdrawal, we infused three types of FITC-HES: HES-A (MW 150-200 kDa, DS 0.6-0.68), HES-B (MW 175-225 kDa, DS 0.45-0.55), or HES-C (MW 550-850 kDa, DS 0.7-0.8) before determining the FITC-HES retention rate in the intravital microscope. RESULTS: For V2, the FITC-HES retention rates 120 min after the start of the infusion were 27% +/- 7.2% of baseline values (HES-A), 65% +/- 9.1% (HES-B), and 86% +/- 9.6% (HES-C); for A2 they were 27% +/- 6.6%, 73% +/- 10.2%, and 89% +/- 8.7%, respectively. HES-B and HES-C were retained in the vessels longer than HES-A (P = 0.028 for V2, P = 0.038 for A2 between HES-B and HES-A; P = 0.022 for V2, P = 0.037 for A2 between HES-C and HES-A). There was no difference in the rate of disappearance from the vessels between HES-B and HES-C. CONCLUSIONS: HES-B and HES-C are equally retained in the blood vessels. Middle-sized HES-B with low DS and middle substitution pattern stayed in the blood vessels as long as the large sized HES. HES solutions of varying characters should be examined to optimize HES infusion. PMID- 17717231 TI - Are selective lung recruitment maneuvers hemodynamically safe in severe hypovolemia? An experimental study in hypovolemic pigs with lobar collapse. AB - BACKGROUND: We have previously shown, in normovolemic pigs, that a selective lung recruitment maneuver (S-LRM), i.e., insufflation of air-oxygen via a balloon catheter with its tip located in the bronchus of a collapsed lung lobe, effectively improves oxygenation and lung volume without affecting hemodynamics negatively. In this study, we examined the respiratory and circulatory effects of S-LRM during hypovolemia with compromised circulation. METHODS: In eight ventilated (fraction of inspired oxygen, Fio2 1.0) and anesthetized pigs a balloon catheter was inserted in the bronchus of the right lower lung lobe. The lobe was selectively lavaged to create a dense lobar collapse. The pigs were then subjected to S-LRM (40 cm H2O airway pressure for 30 s) at normovolemia, after venesection of 20% and 40% of the blood volume, respectively. Blood gases, compliance of the respiratory system (Crs), vascular pressures, and cardiac output were registered before, during, and after the S-LRM. RESULTS: Pao2, venous admixture, and Crs improved significantly with S-LRM at all three volume levels. No change in hemodynamics with S-LRM occurred in normovolemia and 20% hypovolemia. For 40% hypovolemia, cardiac output was unchanged by S-LRM, whereas minor decreases in mean arterial blood pressure were seen: 48 (37-52) mm Hg (median, 25th and 75th percentiles) 3 min before S-LRM, 40 (35-44) mm Hg at the end of S-LRM (P = 0.0207), and 47 (39-54) mm Hg 3 min after S-LRM. CONCLUSION: A S-LRM effectively improved oxygenation and Crs and had only minor circulatory side effects, even in severe hypovolemia in this animal model of lobar collapse. PMID- 17717232 TI - The carina as a useful radiographic landmark for positioning the intraaortic balloon pump. AB - BACKGROUND: The aortic knob is thought to be the most useful radiographic landmark for the proper positioning of the intraaortic balloon pump (IABP) tip. However, this has not been studied formally. In this study we assessed whether the aortic knob is a reliable landmark for positioning the IABP and compared it with another potential landmark, the carina. METHODS: We measured the distance from the top of the distal aortic arch (aortic knob) to the left subclavian artery (LSCA) on three-dimensional computed tomography angiography in 100 patients. The distance from the level of the LSCA origin to the level of the carina was also measured using three-dimensional computed tomography in 150 additional patients. RESULTS: In 16% of the aortic knob study population, the LSCA to aortic knob distance was <0 cm or 0 cm. The median distance from the LSCA to the carina was 42 mm (range: 30-63 mm). In the carina study population, the origin of the LSCA was 35-55 mm above the carina in 95.3% of patients. CONCLUSION: In 16% of patients, the IABP was too close to the LSCA origin when it was placed at the aortic knob, whereas positioning the IABP at 2 cm above the carina provided an adequate position for the IABP tip (1.5-3.5 cm distal to the origin of the LSCA) in 95.3% of patients. The carina may be a more reliable landmark for positioning the IABP than the aortic knob. PMID- 17717234 TI - Brain metabolism during a decrease in cerebral perfusion pressure caused by an elevated intracranial pressure in the porcine neocortex. AB - BACKGROUND: Cranial hypertension coincides with a reduction in cerebral blood flow as well as in oxygen delivery and influences outcome. In this study, we monitored changes in energy-related metabolites in the porcine cortex during an increase of intracranial pressure (ICP) and to determine the level at which damage occurs. METHODS: Male domestic pigs (32-40 kg) were anesthetized, mechanically ventilated, and randomly assigned to either the experimental (n = 6) or control groups (n = 5). A microdialysis probe (CMA 70) was inserted into the cortex to measure extracellular dialysate concentrations of lactate, pyruvate, glucose, glutamate, and glycerol. Every hour an increase of 10 mm Hg in ICP was preformed in the experimental group by infusion of artificial cerebrospinal fluid into the ventricular system of the brain until a maximum ICP of 50 mm Hg was reached. RESULTS: We demonstrated a significant increase of lactate and glycerol compared with control at ICP values > or =30 mm Hg and cerebral perfusion pressure (CPP) below 50 mm Hg. The increase of ICP to > or =40 mm Hg in conjunction with a reduction in CPP below 40 mm Hg led to a significant increase in the lactate/pyruvate-ratio and glutamate, as well as a decrease of glucose in relation to control. CONCLUSIONS: Our data strongly suggest that, during a defined ICP increase, lower CPP values may be tolerable until severe damage occurs. Borderline ICP and CPP values of 30 and 40 mm Hg, respectively, could be advised. PMID- 17717233 TI - Physostigmine reverses cognitive dysfunction caused by moderate hypoxia in adult mice. AB - BACKGROUND: Cognitive changes associated with moderate hypoxia in rodents may result from the diminished functioning of central cholinergic neurotransmission. We designed this study to examine whether treatment with physostigmine (PHY), an acetylcholinesterase inhibitor, could improve the impairment of working memory after hypoxic hypoxia. METHODS: We randomized 90 Swiss Webster, 30-35 g mice (6-8 wks) to three hypoxia groups at fraction of inspired oxygen, FiO2 = 0.10 (1. no treatment; 2. PHY 0.1 mg/kg intraperitoneally administered immediately before; or 3. after hypoxia), or to two room air groups (given either no treatment or PHY after an insult). An object recognition test was used to assess short-term memory function. The object recognition test exploits the tendency of mice to prefer exploring novel objects in an environment when a familiar object is also present. During the 15 min training trial, two identical objects were placed in two defined sites of the box. During the test trial performed 1 h later, one of the objects was replaced by a new object with a different shape. The time spent exploring the two objects was automatically recorded by a video camera and associated software. The performance was analyzed with ANOVA, followed by post hoc comparisons using the Newman-Keuls test when appropriate. P values <0.05 were considered significant. RESULTS: Untreated mice subjected to hypoxia at Fio2 = 0.1 spent significantly less time exploring a novel object on testing day 1 than did untreated mice breathing room air. Performance of the mice subjected to hypoxia, who received physostigmine after, but not before, the insult did not differ from the control group. CONCLUSION: Moderate hypoxia impairs rodents' performance in a working memory task. It appears that changes are transient, because the cognitive functioning of the mice returned to the baseline level 7 days after treatment. Postinsult administration of PHY prevented deterioration of cognitive function. An increased level of acetylcholine in the central nervous system may be responsible for the improved performance of the hypoxia-treated mice. PMID- 17717235 TI - Gastric emptying of water in obese pregnant women at term. AB - BACKGROUND: Healthy nonpregnant and pregnant patients may ingest clear liquids until 2 h before induction of anesthesia without adversely affecting gastric volume. In this study, we compared gastric emptying in obese, term, nonlaboring pregnant women (prepregnancy body mass index >35 kg/m2) after the ingestion of 50 and 300 mL of water. METHODS: Gastric emptying was assessed in 10 obese, term pregnant volunteers using both serial gastric ultrasound examinations and acetaminophen absorption in a crossover study design. After an overnight fast, volunteers ingested 1.5 g acetaminophen and 50 or 300 mL water (randomly assigned) on two occasions separated by at least 2 days. Serial gastric antrum cross-sectional areas were determined using gastric ultrasound imaging and the half-time to gastric emptying (T([1/2])) was calculated. Areas under the plasma acetaminophen concentration versus time curve (AUC), peak concentrations (C(max)), and time to peak concentration (t(max)) for 50 mL and 300 mL ingestions were compared. RESULTS: Mean prepregnancy body mass index was 41 +/- 9 kg/m(2). Gastric emptying T([1/2]) was not different after ingestion of 300 mL water compared with 50 mL (23 +/- 11 min vs 32 +/- 15 min). There were no differences between acetaminophen AUCs at 60, 90, or 120 min, C(max) or t(max) after ingestion of 300 mL compared with 50 mL of water. CONCLUSIONS: Gastric emptying in obese, nonlaboring term pregnant women is not delayed after ingestion of 300 mL compared with 50 mL of water. Gastric antral volume after ingestion of 300 mL of water is similar to the baseline fasting level at 60 min. PMID- 17717236 TI - Local anesthetics and mode of delivery: bupivacaine versus ropivacaine versus levobupivacaine. AB - BACKGROUND: The influence of the labor epidural local anesthetic (LA) on mode of delivery has not been adequately studied. In this study, we sought to determine if there is a difference in mode of delivery among parturients who receive epidural bupivacaine, ropivacaine, or levobupivacaine. METHODS: Nulliparous women at term requesting labor analgesia with a cervical dilation <5 cm were randomized to receive epidural bupivacaine, ropivacaine, or levobupivacaine. Analgesia was initiated with a bolus of 15 mL of 0.0625% of the assigned LA with fentanyl 2 microg/mL. Analgesia was maintained with an infusion of the same solution at 10 mL/h. The primary endpoint was the operative delivery rate (instrumental assisted vaginal delivery plus cesarean delivery). RESULTS: Ninety-eight women received bupivacaine, 90 ropivacaine, and 34 levobupivacaine (before it was removed from the US market). There was no significant difference in the operative delivery rate (bupivacaine = 46%, ropivacaine = 39%, and levobupivacaine = 32%, P = 0.35) among groups. There was less motor block in the levobupivacaine group when compared with the ropivacaine and bupivacaine groups, P < 0.05. There was no significant difference in the duration of the first or second stage of labor, the total dose of LA received per hour of labor, or neonatal outcome among groups. CONCLUSIONS: Bupivacaine, ropivacaine, and levobupivacaine all confer adequate labor epidural analgesia, with no significant influence on mode of delivery, duration of labor, or neonatal outcome. PMID- 17717237 TI - Transdermal scopolamine for prevention of intrathecal morphine-induced nausea and vomiting after cesarean delivery. AB - BACKGROUND: Intrathecal morphine for cesarean delivery provides excellent postoperative analgesia but is associated with significant nausea and vomiting. METHODS: We compared the antiemetic efficacy of transdermal scopolamine, IV ondansetron, and placebo during the first 24 h postoperatively. Two-hundred forty women undergoing cesarean delivery under spinal anesthesia were randomly allocated, in a double-blind study design, to receive transdermal scopolamine 1.5 mg, ondansetron 4 mg, or placebo at the time of cord clamping. RESULTS: Our study showed that the overall rates for all emesis were 59.3% in the placebo group and were reduced to 40% in the scopolamine group and 41.8% in the ondansetron group. The greatest reduction in emesis in the scopolamine group when compared with placebo was in the 6-24 h time period. CONCLUSION: Scopolamine is an effective medication for prophylactic use in parturients receiving intrathecal morphine while undergoing cesarean delivery. Its use, however, was associated with a higher incidence of side effects such as dry mouth and blurry vision. PMID- 17717238 TI - Posterior reversible encephalopathy syndrome with vasospasm in a postpartum woman after postdural puncture headache following spinal anesthesia. AB - We describe a postpartum woman who, after an uneventful pregnancy, developed posterior reversible encephalopathy syndrome after spinal anesthesia, complicated by postdural puncture headache. PMID- 17717239 TI - Supplemental oxygen, but not supplemental crystalloid fluid, increases tissue oxygen tension in healthy and anastomotic colon in pigs. AB - BACKGROUND: Low tissue oxygen tension is an important factor leading to the development of wound dehiscence and anastomotic leakage after colon surgery. We tested whether supplemental fluid and supplemental oxygen can increase tissue oxygen tension in healthy and injured, perianastomotic, and anastomotic colon in an acutely instrumented pig model of anastomosis surgery. METHODS: Sixteen Swiss Landrace pigs were anesthetized (isoflurane 0.8%-1%) and their lungs ventilated. The animals were randomly assigned to low fluid treatment ("low" group, 3 mL x kg(-1) x h(-1) lactated Ringer's solution) or high fluid treatment ("high" group, 10 mL/kg bolus, 18 mL x kg(-1) x h(-1) lactated Ringer's solution) during colon anastomosis surgery and a subsequent measurement period (4 h). Two-and-half hours after surgery, tissue oxygen tension was recorded for 30 min during ventilation with 30% oxygen. Three hours after surgery, the animals' lungs were ventilated with 100% oxygen for 60 min. Tissue oxygen tension was recorded in the last 30 min. Tissue oxygen tension was measured with polarographic Clark-type electrodes, positioned in healthy colonic wall, close (2 cm) to the anastomosis, and in the anastomosis. RESULTS: In every group, tissue oxygen tension during ventilation with 100% oxygen was approximately twice as high as during ventilation with 30% oxygen, a statistically significant result. High or low volume crystalloid fluid treatment had no effect on colon tissue oxygen tension. CONCLUSIONS: Supplemental oxygen, but not supplemental crystalloid fluid, increased tissue oxygen tension in healthy, perianastomotic, and anastomotic colon tissue. PMID- 17717240 TI - Predictors of hyperkalemia in the prereperfusion, early postreperfusion, and late postreperfusion periods during adult liver transplantation. AB - BACKGROUND: Hyperkalemia poses serious hazards to patients undergoing orthotopic liver transplantation (OLT), and its predictors have not been thoroughly examined. METHODS: We retrospectively studied 1124 consecutive adult patients who underwent OLT. Hyperkalemia was defined as serum K+ > or =5.5 mmol/L. A total of 47 recipient, donor, intraoperative, and laboratory variables were initially analyzed in univariate analyses. Independent predictors of hyperkalemia in three periods of OLT (prereperfusion, early postreperfusion, and late postreperfusion) were determined in multivariate logistic regression analyses. RESULTS: Of 1124 patients, 10.2%, 19.1%, and 7.9% had hyperkalemia in the prereperfusion, early postreperfusion, and late postreperfusion periods, respectively. Higher baseline K+ and red blood cell transfusion were independent predictors of prereperfusion hyperkalemia. Higher baseline K+ (or prereperfusion K+) and donation after cardiac death donor were independent predictors of early postreperfusion hyperkalemia. Higher baseline K+, longer warm ischemia time, longer donor hospital stay, lower intraoperative urine output, and the use of venovenous bypass were independent predictors of late postreperfusion hyperkalemia. CONCLUSIONS: Several laboratory, intraoperative, and donor variables were identified as independent predictors of hyperkalemia in the different periods. Such information may be used for more targeted preemptive interventions in patients who are at risk of developing hyperkalemia during adult OLT. PMID- 17717241 TI - Easy endotracheal intubation of a patient suffering from both Cushing's and Nelson's syndromes predicted by the upper lip bite test despite a Mallampati Class 4 airway. AB - A 31-yr-old woman with concurrent Cushing's and Nelson's syndromes was scheduled for transsphenoidal hypophysectomy. The patient had generalized edema, morbid obesity, and a history of sleep apnea. Her Mallampati assessment was Class 4, suggesting very difficult intubation, but the upper lip bite test predicted easy intubation. After rapid sequence induction, there was a Class 1 view on laryngoscopy, and intubation was accomplished easily. PMID- 17717243 TI - Epidural blood patch therapy for chronic whiplash-associated disorder. AB - BACKGROUND: Despite the absence of objective neurological deficits, patients with chronic whiplash-associated disorder (WAD) complain of symptoms such as headache, dizziness, and nausea. These symptoms are also often experienced by patients with cerebrospinal fluid (CSF) leak. It was recently reported that radioisotope (RI) cisternography is useful in the diagnosis of intracranial hypotension due to CSF leak. We investigated the relation between chronic WAD and CSF leak by RI cisternography and evaluated whether epidural blood patch (EBP) administration is effective in the treatment of chronic WAD. METHODS: We studied 66 patients with chronic WAD with symptoms lasting longer than 3 mo. All patients underwent RI cisternography to determine the presence of CSF leak. In patients in whom CSF leak was identified, EBP was administered. Symptoms were assessed before, 1 wk after, and 6 mo after EBP. Work status was also assessed and follow-up RI cisternography was performed. RESULTS: Of the 66 patients, 37 showed CSF leak, and 36 of these patients received EBP 2.2 +/- 0.7 times. The mean duration of symptoms was 33 mo. One week after EBP, the percentage of patients with symptoms was decreased significantly compared with that before EBP; headache: 100% vs 17%, respectively, memory loss: 94% vs 28%, dizziness: 83% vs 47%, visual impairment: 81% vs 25%, nausea: 78% vs 42% (P < 0.01). These effects were also observed at the 6 month follow-up examination (P < 0.01). Work status was also significantly improved at follow-up. CONCLUSIONS: We conclude that CSF leak should be considered in some cases of chronic WAD and that EBP is an effective therapy for chronic WAD. PMID- 17717242 TI - The effect of analgesic technique on postoperative patient-reported outcomes including analgesia: a systematic review. AB - BACKGROUND: The effect of postoperative analgesia on patient-reported outcomes, such as quality of life, quality of recovery, and patient satisfaction, has not been systematically examined. These outcomes are assessed from the patient's perspective and are recognized as valid and important end-points in clinical medicine and research. We performed a systematic review to examine the effect of postoperative analgesia on patient-reported outcomes. METHODS: The National Library of Medicine's Medline and the Cochrane Library databases were searched for the past decade (Jan, 1996 to Jun 1, 2006). Additional Medline searches for specific outcomes (i.e., satisfaction, quality of life, and quality of recovery) were also conducted. RESULTS: Regional analgesic techniques provide statistically superior analgesia compared with systemic opioids. There are insufficient data to determine if the type of analgesic technique, degree of analgesia, and presence of side effects may influence quality of life, quality of recovery, satisfaction, and length of stay, due in part to some significant methodologic issues. CONCLUSIONS: Although there are data suggesting that improved postoperative analgesia leads to better patient outcomes, there is insufficient evidence to support subsequent improvements inpatient-centered outcomes such as quality of life and quality of recovery. Modest reductions in pain scores do not necessarily equate to clinically meaningful improved pain relief for the patient. Further studies are needed to develop validated patient-reported instruments and to assess the effect of analgesic techniques on patient-reported outcomes in the perioperative period. PMID- 17717244 TI - The evolution of primary hyperalgesia in orthopedic surgery: quantitative sensory testing and clinical evaluation before and after total knee arthroplasty. AB - BACKGROUND: Quantitative sensory testing (QST) allows precise characterization of sensory deficits and painful symptoms and may offer additional information on the pathophysiology of postoperative pain. METHODS: We evaluated 20 patients scheduled for total knee arthroplasty clinically and with QST before surgery, at 1 and 4 days after surgery, and at 1 and 4 mo after surgery. The clinical evaluation included preoperative pain and inflammation of the operative knee, postoperative assessment of pain at rest and during movement (Visual Analog Scale score), cumulative morphine consumption, and circumference and temperature of both knees. QST included thermal and mechanical (pressure) pain threshold measurements and assessment of responses to suprathreshold stimuli. Brush-evoked allodynia was also evaluated. Measurements were taken on the operative knee, contralateral knee, and on the hand as a control site. RESULTS: All patients had prolonged and severe pain before surgery and inflammation of the operative knee. Preoperative QST provided evidence of heat hyperalgesia in the inflammatory area on the operative knee, but absence of punctate or brush-evoked allodynia in the adjacent noninflamed area. Patients had intense postoperative pain, mostly induced by movement. Primary heat hyperalgesia was present on the operative knee on the first and fourth day after surgery, and was associated with punctate mechanical allodynia in the inflammatory area, but not in the adjacent noninflamed area. Postoperative morphine consumption was correlated with preoperative heat hyperalgesia (r = 0.63; P = 0.01). QST returned to baseline at the 4-mo evaluation. Only four patients had moderate knee pain induced by movement at that time. CONCLUSION: Heat hyperalgesia was the predominant QST symptom associated with perioperative pain after total knee arthroplasty, and was predictive of postoperative morphine consumption. PMID- 17717245 TI - Improving the analgesic efficacy of intrathecal morphine with parecoxib after total abdominal hysterectomy. AB - BACKGROUND: The addition of parecoxib to intrathecal morphine and bupivacaine may improve analgesia and reduce morphine's opioid-related side effects. METHODS: In this prospective, double-blind, randomized, placebo-controlled trial, total abdominal hysterectomy patients received either IV normal saline or parecoxib 40 mg before receiving intrathecal bupivacaine and morphine 0.2 mg. Twelve hours later, this administration was repeated. Patients were observed for 48 h. RESULTS: The addition of parecoxib to intrathecal morphine and bupivacaine significantly reduced cumulative morphine consumption, Visual Analog Pain scores, and increased patient satisfaction for 24 h postoperatively without an obvious decrease of adverse side effects. CONCLUSION: Perioperative parecoxib enhanced the postoperative analgesia of intrathecal morphine and bupivacaine and improved patient satisfaction. PMID- 17717246 TI - Sciatic nerve block with resiniferatoxin: an electron microscopic study of unmyelinated fibers in the rat. AB - BACKGROUND: Perineural administration of the naturally occurring vanilloids (capsaicin, resiniferatoxin [RTX]) produces selective nociceptive blockade. Studies using perineural vanilloids in high concentrations suggest that they can cause a degeneration of unmyelinated fibers. However, electron microscopic studies of local vanilloid toxicity produced conflicting outcomes. In the present study, we sought to determine whether RTX-induced reversible sciatic nerve block results in the degenerative changes of unmyelinated fibers. METHODS: In rat experiments, RTX was administered percutaneously at the sciatic nerve. The effect of RTX was monitored by measuring the rat's response to noxious heat. The sciatic nerves were removed 48 h after the blockade initiation. Quantitative electron microscopic evaluation of the unmyelinated fibers was performed in three groups of animals: RTX 0.0001% (0.1 microg), RTX 0.001% (1 microg), and control (RTX vehicle, 0.1 mL). RESULTS: Cross-sections of the sciatic nerve 48 h after the initiation of RTX-induced reversible nerve blockade appeared essentially normal. One rarely observed finding was the irregularly compacted membranous deposits in the unmyelinated axons. The frequency of this finding was approximately one per thousand fibers with both concentrations of RTX. CONCLUSIONS: The results of the study suggest that a selective and long-lasting sciatic nerve block (up to 2 wk) can be provided by RTX without any significant damage to the unmyelinated nerve fibers. PMID- 17717247 TI - Reflex sympathetic activity after intravenous administration of midazolam in anesthetized cats. AB - BACKGROUND: Although intrathecal midazolam has been reported to produce antinociceptive effects mediated by gamma-aminobutyric acid type A-benzodiazepine receptor complexes in the spinal cord, the effects of systemic midazolam on nociception remain unclear. We performed this study to examine the effects of IV administered midazolam on somatosympathetic Adelta and C reflex discharges in brain-intact cats and decerebrate cats (with transection at midbrain level). METHODS: Somatosympathetic Adelta and C reflexes were elicited in the inferior cardiac sympathetic nerve by electrical stimulation of myelinated (Adelta) and unmyelinated (C) afferent fibers of the superficial peroneal nerve in 28 mature cats. After control somatosympathetic reflex responses were obtained, midazolam was administered IV to four groups of randomly allocated cats as follows: brain intact cats at a dose of 0.03 mg/kg, brain-intact cats at a dose of 0.1 mg/kg, brain-intact cats at a dose of 0.5 mg/kg, and decerebrate cats at a dose of 0.1 mg/kg. RESULTS: C reflex discharges were significantly augmented at the dose of 0.03 mg/kg and significantly depressed at the dose of 0.1 and 0.5 mg/kg in brain intact cats. C reflex discharges were also significantly depressed at the dose of 0.1 mg/kg in decerebrate cats. CONCLUSIONS: We have demonstrated that IV midazolam produces dose-related effects on somatosympathetic reflex discharges. The clinical implication of these findings is that the effect of midazolam on nociception depends on its dosage. It also appears that the infra-midbrain region plays a major role in mediating the depressive effects of midazolam on somatosympathetic C reflex discharges. PMID- 17717248 TI - Pathophysiology of peripheral neuropathic pain: immune cells and molecules. AB - Damage to the peripheral nervous system often leads to chronic neuropathic pain characterized by spontaneous pain and an exaggerated response to painful and/or innocuous stimuli. This pain condition is extremely debilitating and usually difficult to treat. Although inflammatory and neuropathic pain syndromes are often considered distinct entities, emerging evidence belies this strict dichotomy. Inflammation is a well-characterized phenomenon, which involves a cascade of different immune cell types, such as mast cells, neutrophils, macrophages, and T lymphocytes. In addition, these cells release numerous compounds that contribute to pain. Recent evidence suggests that immune cells play a role in neuropathic pain in the periphery. In this review we identify the different immune cell types that contribute to neuropathic pain in the periphery and release factors that are crucial in this particular condition. PMID- 17717249 TI - Ultrasound-guided interscalene needle placement produces successful anesthesia regardless of motor stimulation above or below 0.5 mA. AB - BACKGROUND: We quantified the motor response after ultrasound (U-S)-guided needle placement for interscalene block (ISB). We then compared block characteristics based on motor response above or below 0.5 mA. METHODS: Sixty-one patients scheduled for ambulatory shoulder surgery under ISB and general anesthesia were included in this prospective, observational study. Preoperatively, an insulated needle was positioned by U-S in the interscalene groove. The lowest current producing motor response was determined, and 30 mL 0.5% bupivacaine with epinephrine was injected. Motor and sensory block were tested in the upper trunk distribution for 15 min until general anesthesia was induced. Postoperatively, the success of upper trunk block, pain score in the postanesthesia care unit and block duration, and analgesic tablet consumption overnight were recorded. Patients were divided a priori into Group A (current < or =0.5 mA) and Group B (current >0.5 mA), and results were compared between groups. RESULTS: The observed current range was 0.14-1.7 mA, with current < or =0.5 mA in 42% of patients (Group A). All patients had complete sensorimotor upper trunk block and none required narcotics in the postanesthesia care unit. Block duration (both groups: 17.8 +/- 4.9 h, mean +/- sd) and home analgesic use were equivalent. Sensory block onset was equivalent between groups, but incomplete motor block at 15 min was more likely in Group B: 37% vs 12% in Group A (P = 0.03). CONCLUSION: During U-S-guided ISB using nerve stimulation, the observed motor response below or above 0.5 mA had no impact on success or duration of upper trunk block. PMID- 17717250 TI - Obturator versus femoral nerve block for analgesia after total knee arthroplasty. AB - BACKGROUND: Both femoral and obturator nerve blocks have been suggested to be useful in relieving pain after total knee arthroplasty (TKA). We sought to compare their efficacy. METHODS: Sixty patients undergoing elective unilateral TKA under spinal anesthesia received in a randomized, double-blind manner a femoral, obturator, or sham nerve block at the end of surgery. Blocks were performed using nerve stimulation and 20 mL bupivacaine 0.5% containing epinephrine 5 microg/mL. Patient-controlled IV analgesia with fentanyl, celecoxib 100 mg PO bid, and acetaminophen 650 mg PO every 6 h were started on arrival in the recovery room. Pain (0-10 numeric rating scale, NRS) at rest and with movement, analgesic use, and side effects were recorded for 48 h. Maximum knee flexion and total days in hospital were recorded as functional outcomes. RESULTS: There were no significant differences in the obturator block group and the control group in any outcome variable. With baseline pain scores subtracted, femoral block resulted in less pain at rest compared with control (NRS difference from baseline 2.1 +/- 0.4 sem vs 3.4 +/- 0.4, respectively; P = 0.02) and less pain with movement (NRS difference 2.6 +/- 0.6, 4.3 +/- 0.6, P = 0.05) at recovery room discharge. Neither block had a significant effect on opioid use, functional outcome, or side effects. Only one (5%) patient with femoral block developed obturator motor block. CONCLUSION: Femoral nerve blocks rarely block the obturator nerve. Single-injection femoral nerve block improved multimodal analgesia after spinal anesthesia for TKA, but this effect did not persist beyond the day of surgery. Obturator nerve block alone was of no benefit. PMID- 17717251 TI - Epidural, intrathecal pharmacokinetics, and intrathecal bioavailability of ropivacaine. AB - BACKGROUND: Ropivacaine is used by the epidural route for postoperative pain management with various neuraxial techniques. Given the widespread use of these techniques and the relative paucity of data on spinal disposition of local anesthetics, we evaluated through an experimental animal model, the spinal disposition of ropivacaine, allowing further studies of factors influencing their intrathecal bioavailability. METHODS: Sheep received an IV bolus dose of ropivacaine (50 mg), and 1 wk after, an intrathecal dose of ropivacaine (20 mg) followed 3 h later by epidural ropivacaine (100 mg). A simultaneous microdialysis technique was used to measure epidural and intrathecal drug concentrations after both epidural and intrathecal administrations. RESULTS: Absorption-time plots showed a large variability in the systemic absorption after both intrathecal and epidural administration, with an apparent faster systemic absorption after intrathecal administration. In the intrathecal space, the elimination clearance was around three-times higher than the distribution clearance. In the epidural space, the relative contribution of elimination and distribution to ropivacaine disposition was different, indicating a more pronounced influence of the distribution process. The intrathecal bioavailability after epidural administration was 11.1% +/- 7.6%. CONCLUSIONS: Using an animal model, we showed that drug dispositions in the intrathecal and epidural compartments are different, and that the intrathecal bioavailability of ropivacaine after epidural administration is low, and highly variable. PMID- 17717252 TI - Continuous positive airway pressure breathing increases cranial spread of sensory blockade after cervicothoracic epidural injection of lidocaine. AB - BACKGROUND: Continuous positive airway pressure (CPAP) increases the caudad spread of sensory blockade after low-thoracic epidural injection of lidocaine. We hypothesized that CPAP would increase cephalad spread of blockade after cervicothoracic epidural injection. METHODS: Twenty patients with an epidural catheter at the C6-7 or C7-T1 interspace received an epidural dose of lidocaine while breathing at ambient pressure (control group), or while breathing with 7.5 cm H2O CPAP. After injection, we evaluated the spread of sensory blockade. Spirometry variables before and after epidural injection were also measured. RESULTS: Data are presented as median (interquartile range) values. Sensory block ranged from C7 (C4-7) to T4 (T4-6) in the control group and from C2 (C2-4) to T4 (T2-5) in the CPAP group (P = 0.003 for the cranial border). The total number of segments blocked was 7.5 (6.8-9.8) in the control group and 10 (8-12) in the CPAP group (P = 0.13). The number of segments blocked cranial to the injection site was one (0.8-3.5) in the control group and five (3.5-7) in the CPAP group (P = 0.006). The number of patients with a maximal cranial block (up to C2) was one in the control group and seven in the CPAP group (P = 0.02). In both groups, there was a small but significant decrease from baseline in spirometry values, with no differences between groups. CONCLUSION: Applying CPAP during cervicothoracic epidural injection of lidocaine resulted in a more cranial extension of sensory blockade when compared with breathing at ambient pressure. PMID- 17717253 TI - Transscalene brachial plexus block: a new posterolateral approach for brachial plexus block. AB - Depending on the approach to the upper brachial plexus, severe complications have been reported. We describe a novel posterolateral approach for brachial plexus block which, from an anatomical and theoretical point of view, seems to offer advantages. Twenty-seven patients were scheduled to undergo elective major surgery of the upper arm or shoulder using this new transscalene brachial plexus block. The success rate was 85.2% for surgery. Two patients required additional analgesia with IV sufentanil. In two others, regional anesthesia was inadequate. The side effects of this technique included reversible recurrent laryngeal nerve blockade in two patients and a reversible Horner syndrome in one patient. Further studies are needed to compare the transscalene brachial plexus block with other approaches to the brachial plexus. PMID- 17717254 TI - Was it a true emergency? PMID- 17717255 TI - Pseudo-emergent use of an investigational drug. PMID- 17717256 TI - Where's the Fire? PMID- 17717258 TI - Central venous catheter insertion: it is finally time to start looking. PMID- 17717257 TI - Urgent usage of sugammadex to treat residual neuromuscular blockade in the PACU. PMID- 17717259 TI - Survey of specialists shows we are not special. PMID- 17717260 TI - Risk of a severe neurological complication after regional anesthesia should be individualized. PMID- 17717261 TI - Anesthesia neurotoxicity in neonates: the need for clinical research. PMID- 17717262 TI - Neurotoxicity of anesthetic agents in children. PMID- 17717263 TI - Sugammadex-rocuronium dosing. PMID- 17717264 TI - Transversus abdominis plane block. PMID- 17717265 TI - Transversus abdominis plane block. PMID- 17717266 TI - Vagal nerve stimulation and reflux. PMID- 17717267 TI - Standards expected while reporting a critical incident. PMID- 17717268 TI - Limitations of in vitro experiments on hydroxyethyl starch solutions. PMID- 17717269 TI - Donor difference (living versus cadaver) rather than preoperative recipient's status affects transfusion requirements in liver transplantation. PMID- 17717270 TI - Open low-field intraoperative MRI for transsphenoidal pituitary surgery. PMID- 17717271 TI - Zero bispectral index during coil embolization of an intracranial aneurysm. PMID- 17717272 TI - Obturator nerve block using ultrasound guidance. PMID- 17717273 TI - Fiberoptic scope as a rescue device in an anesthetized patient in the prone position. PMID- 17717274 TI - Portable ultrasound to diagnose true radial artery aneurysm. PMID- 17717275 TI - Unclear methodology for anesthesia machine checkout. PMID- 17717276 TI - An alternative airway adaptor for single-lung ventilation in infants. PMID- 17717277 TI - Simple multiport adaptor for selective lung ventilation in pediatric patients. PMID- 17717279 TI - Short-term caloric restriction induces accumulation of myocardial triglycerides and decreases left ventricular diastolic function in healthy subjects. AB - OBJECTIVE: Diabetes and obesity are associated with increased plasma nonesterified fatty acid (NEFA) levels, myocardial triglyceride accumulation, and myocardial dysfunction. Because a very low-calorie diet (VLCD) also increases plasma NEFA levels, we studied the effect of a VLCD on myocardial triglyceride content and cardiac function in healthy subjects. RESEARCH DESIGN AND METHODS: Fourteen healthy nonobese men underwent (1)H-magnetic resonance spectroscopy (MRS) to determine myocardial and hepatic triglyceride content, (31)P-MRS to assess myocardial high-energy phosphate (HEP) metabolism (phosphocreatine/ATP), and magnetic resonance imaging of myocardial function at baseline and after a 3 day VLCD. RESULTS: After the dietary intervention, plasma NEFA levels increased compared with those at baseline (from 0.5 +/- 0.1 to 1.1 +/- 0.1 mmol/l, P < 0.05). Concomitantly, myocardial triglyceride content increased by approximately 55% compared with that at baseline (from 0.38 +/- 0.05 to 0.59 +/- 0.06%, P < 0.05), whereas liver triglyceride content decreased by approximately 32% (from 2.2 +/- 0.5 to 1.5 +/- 0.4%, P < 0.05). The VLCD did not change myocardial phosphocreatine-to-ATP ratio (2.33 +/- 0.15 vs. 2.33 +/- 0.08, P > 0.05) or systolic function. Interestingly, deceleration of the early diastolic flow across the mitral valve decreased after the VLCD (from 3.37 +/- 0.20 to 2.91 +/- 0.16 ml/s(2) x 10(-3), P < 0.05). This decrease in diastolic function was significantly correlated with the increase in myocardial triglyceride content. CONCLUSIONS: Short-term VLCD induces accumulation of myocardial triglycerides. In addition, VLCD decreases left ventricular diastolic function, without alterations in myocardial HEP metabolism. This study documents diet-dependent physiological variations in myocardial triglyceride content and diastolic function in healthy subjects. PMID- 17717278 TI - Abnormal connexin expression underlies delayed wound healing in diabetic skin. AB - OBJECTIVE: Dynamically regulated expression of the gap junction protein connexin (Cx)43 plays pivotal roles in wound healing. Cx43 is normally downregulated and Cx26 upregulated in keratinocytes at the edge of the wound as they adopt a migratory phenotype. We have examined the dynamics of Cx expression during wound healing in diabetic rats, which is known to be slow. RESEARCH DESIGN AND METHODS: We induced diabetes with streptozotocin and examined Cx expression and communication in intact and healing skin. RESULTS: We found that diabetes decreased Cx43 and Cx26 protein and communication in the intact epidermis and increased Cx43 protein and communication in the intact dermis. Diabetes also altered the dynamic changes of Cxs associated with wound healing. Within 24 h, Cx43 was upregulated in a thickened bulb of keratinocytes at the wound edge (rather than downregulated as in controls, which formed a thin process of migratory cells). Cx43 decline was delayed until 48 h, when reepithelialization began. Although Cx26 was upregulated as normal after wounding in diabetic skin, its distribution at the wound edge was abnormal, being more widespread. Application of Cx43-specific antisense gel to diabetic wounds prevented the abnormal upregulation of Cx43 and doubled the rate of reepithelialization, which exceeded control levels. CONCLUSIONS: Cx expression in diabetic skin is abnormal, as is the dynamic response of Cx43 to injury, which may underlie the delayed healing of diabetic wounds. Preventing the upregulation of Cx43 in diabetic wounds significantly improves the rate of healing and clearly has potential therapeutic value. PMID- 17717280 TI - Incretin receptors for glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide are essential for the sustained metabolic actions of vildagliptin in mice. AB - OBJECTIVE: Dipeptidyl peptidase-4 (DPP4) inhibitors lower blood glucose in diabetic subjects; however, the mechanism of action through which these agents improve glucose homeostasis remains incompletely understood. Although glucagon like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) represent important targets for DPP4 activity, whether additional substrates are important for the glucose-lowering actions of DPP4 inhibitors remains uncertain. RESEARCH DESIGN AND METHODS: We examined the efficacy of continuous vildagliptin administration in wild-type (WT) and dual incretin receptor knockout (DIRKO) mice after 8 weeks of a high-fat diet. RESULTS: Vildagliptin had no significant effect on food intake, energy expenditure, body composition, body weight gain, or insulin sensitivity in WT or DIRKO mice. However, glycemic excursion after oral glucose challenge was significantly reduced in WT but not in DIRKO mice after vildagliptin treatment. Moreover, vildagliptin increased levels of glucose stimulated plasma insulin and reduced levels of cholesterol and triglycerides in WT but not in DIRKO mice. Vildagliptin treatment reduced the hepatic expression of genes important for cholesterol synthesis and fatty acid oxidation, including phospho-mevalonate kinase (Mvk), acyl-coenzyme dehydrogenase medium chain (Acadm), mevalonate (diphospho)decarboxylase (Mvd), and Acyl-CoA synthetase (Acsl1), in WT but not in DIRKO mice. However, vildagliptin also reduced levels of hepatic mRNA transcripts for farnesyl di-phosphate transferase (Fdft1), acetyl coenzyme A acyltransferase 1 (Acaa1), and carnitine palmitoyl transferase 1 (Cpt 1) in DIRKO mice. No direct effect of GLP-1 receptor agonists was detected on cholesterol or triglyceride synthesis and secretion in WT hepatocytes. CONCLUSIONS: These findings illustrate that although GLP-1 and GIP receptors represent the dominant molecular mechanisms for transducing the glucoregulatory actions of DPP4 inhibitors, prolonged DPP4 inhibition modulates the expression of genes important for lipid metabolism independent of incretin receptor action in vivo. PMID- 17717281 TI - Calmodulin-binding domain of AS160 regulates contraction- but not insulin stimulated glucose uptake in skeletal muscle. AB - OBJECTIVE: Insulin and contraction increase skeletal muscle glucose uptake through distinct and additive mechanisms. However, recent reports have demonstrated that both signals converge on the Akt substrate of 160 kDa (AS160), a protein that regulates GLUT4 translocation. Although AS160 phosphorylation is believed to be the primary factor affecting its activity, AS160 also possesses a calmodulin-binding domain (CBD). This raises the possibility that contraction stimulated increases in Ca(2+)/calmodulin could also modulate AS160 function. RESEARCH DESIGN AND METHODS: To evaluate the AS160 CBD in skeletal muscle, empty vector, wild-type, or CBD-mutant AS160 cDNAs were injected into mouse muscles followed by in vivo electroporation. One week later, AS160 was overexpressed by approximately 14-fold over endogenous protein. RESULTS: Immunoprecipitates of wild-type and CBD-mutant AS160 were incubated with biotinylated calmodulin in the presence of Ca(2+). Wild-type AS160, but not the CBD-mutant AS160, associated with calmodulin. Next, we measured insulin- and contraction-stimulated glucose uptake in vivo. Compared with empty-vector and wild-type AS160, insulin stimulated glucose uptake was not altered in muscles expressing CBD-mutant AS160. In contrast, contraction-stimulated glucose uptake was significantly decreased in CBD-mutant-expressing muscles. This inhibitory effect on glucose uptake was not associated with aberrant contraction-stimulated AS160 phosphorylation. Interestingly, AS160 expressing both calmodulin-binding and Rab-GAP (GTPase activating protein) domain point mutations (CBD + R/K) fully restored contraction stimulated glucose uptake. CONCLUSIONS: Our results suggest that the AS160 CBD directly regulates contraction-induced glucose uptake in mouse muscle and that calmodulin provides an additional means of modulating AS160 Rab-GAP function independent of phosphorylation. These findings define a novel AS160 signaling component, unique to contraction and not insulin, leading to glucose uptake in skeletal muscle. PMID- 17717282 TI - Free fatty acid-induced reduction in glucose-stimulated insulin secretion: evidence for a role of oxidative stress in vitro and in vivo. AB - OBJECTIVE: An important mechanism in the pathogenesis of type 2 diabetes in obese individuals is elevation of plasma free fatty acids (FFAs), which induce insulin resistance and chronically decrease beta-cell function and mass. Our objective was to investigate the role of oxidative stress in FFA-induced decrease in beta cell function. RESEARCH DESIGN AND METHODS: We used an in vivo model of 48-h intravenous oleate infusion in Wistar rats followed by hyperglycemic clamps or islet secretion studies ex vivo and in vitro models of 48-h exposure to oleate in islets and MIN6 cells. RESULTS: Forty-eight-hour infusion of oleate decreased the insulin and C-peptide responses to a hyperglycemic clamp (P < 0.01), an effect prevented by coinfusion of the antioxidants N-acetylcysteine (NAC) and taurine. Similar to the findings in vivo, 48-h infusion of oleate decreased glucose stimulated insulin secretion ex vivo (P < 0.01) and induced oxidative stress (P < 0.001) in isolated islets, effects prevented by coinfusion of the antioxidants NAC, taurine, or tempol (4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl). Forty eight-hour infusion of olive oil induced oxidative stress (P < 0.001) and decreased the insulin response of isolated islets similar to oleate (P < 0.01). Islets exposed to oleate or palmitate and MIN6 cells exposed to oleate showed a decreased insulin response to high glucose and increased levels of oxidative stress (both P < 0.001), effects prevented by taurine. Real-time RT-PCR showed increased mRNA levels of antioxidant genes in MIN6 cells after oleate exposure, an effect partially prevented by taurine. CONCLUSIONS: Our data are the first demonstration that oxidative stress plays a role in the decrease in beta-cell secretory function induced by prolonged exposure to FFAs in vitro and in vivo. PMID- 17717283 TI - Intrahepatic fat accumulation and alterations in lipoprotein composition in obese adolescents: a perfect proatherogenic state. AB - OBJECTIVE: Among other metabolic consequences, a dyslipidemic profile often accompanies childhood obesity. In adults, type 2 diabetes and hepatic steatosis have been shown to alter lipoprotein subclass distribution and size; however, these alterations have not yet been shown in children or adolescents. Therefore, our objective was to determine the effect of hepatic steatosis on lipoprotein concentration and size in obese adolescents. RESEARCH DESIGN AND METHODS: Using fast magnetic resonance imaging, we measured intrahepatic fat content in 49 obese adolescents with normal glucose tolerance. The presence or absence of hepatic steatosis was determined by a threshold value for hepatic fat fraction (HFF) of 5.5%; therefore, the cohort was divided into two groups (HFF > or <5.5%). Fasting lipoprotein subclasses were determined using nuclear magnetic resonance spectroscopy. RESULTS: Overall, the high-HFF group had 88% higher concentrations of large VLDL compared with the low-HFF group (P < 0.001). Likewise, the high-HFF group had significantly higher concentrations of small dense LDL (P < 0.007); however, the low-HFF group had significantly higher concentrations of large HDL (P < 0.001). Stepwise multiple regression analysis revealed that high HFF was the strongest single correlate, accounting for 32.6% of the variance in large VLDL concentrations (P < 0.002). CONCLUSIONS: The presence of fatty liver was associated with a pronounced dyslipidemic profile characterized by large VLDL, small dense LDL, and decreased large HDL concentrations. This proatherogenic phenotype was strongly related to the intrahepatic lipid content. PMID- 17717285 TI - Flexible intensive versus conventional insulin therapy in insulin-naive adults with type 2 diabetes: an open-label, randomized, controlled, crossover clinical trial of metabolic control and patient preference. PMID- 17717286 TI - Atrophy of foot muscles in diabetic patients can be detected with ultrasonography. AB - OBJECTIVE: To establish a bedside test with ultrasonography for evaluation of foot muscle atrophy in diabetic patients. RESEARCH DESIGN AND METHODS: Thickness and cross-sectional area (CSA) of the extensor digitorum brevis muscle (EDB) and of the muscles of the first interstitium (MILs) were determined in 26 diabetic patients and in 26 matched control subjects using ultrasonography. To estimate the validity, findings were related to the total volume of all foot muscles determined at magnetic resonance imaging (MRI-FM(vol)). Furthermore, the relations of ultrasonographic estimates to nerve conduction, sensory perception thresholds, and clinical condition were established. RESULTS: In diabetic patients, the ultrasonographic thickness of EDB (U-EDB(t)) was (means +/- SD) 6.4 +/- 2.1 vs. 9.0 +/- 1.0 mm in control subjects (P < 0.001), the thickness of MIL (U-MIL(t)) was 29.6 +/- 8.3 vs. 40.2 +/- 3.6 mm in control subjects (P < 0.001), and the CSA of EDB (U-EDB(CSA)) was 116 +/- 65 vs. 214 +/- 38 mm(2) in control subjects (P < 0.001). The MRI-FM(vol) was directly related to U-EDB(t) (r = 0.77), U-MIL(t) (r = 0.71), and U-EDB(CSA) (r = 0.74). U-EDB(t) and U-MIL(t) were thinner in neuropathic than in nonneuropathic diabetic patients (5.8 +/- 2.1 vs. 7.5 +/- 1.7 mm [P < 0.05] and 28.3 +/- 8.8 vs. 35.6 +/- 4.3 mm [P < 0.03], respectively). CONCLUSIONS: Atrophy of intrinsic foot muscles determined at ultrasonography is directly related to foot muscle volume determined by MRI and to various measures of diabetic neuropathy. Ultrasonography seems to be useful for detection of foot muscle atrophy in diabetes. PMID- 17717284 TI - Diabetes, depression, and death: a randomized controlled trial of a depression treatment program for older adults based in primary care (PROSPECT). AB - OBJECTIVE: We sought to test our a priori hypothesis that depressed patients with diabetes in practices implementing a depression management program would have a decreased risk of mortality compared with depressed patients with diabetes in usual-care practices. RESEARCH DESIGN AND METHODS: We used data from the multisite, practice-randomized, controlled Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT), with patient recruitment from May 1999 to August 2001, supplemented with a search of the National Death Index. Twenty primary care practices participated from the greater metropolitan areas of New York City, New York; Philadelphia, Pennsylvania; and Pittsburgh, Pennsylvania. In all, 584 participants identified though a two-stage, age-stratified (aged 60-74 or >or=75 years) depression screening of randomly sampled patients and classified as depressed with complete information on diabetes status are included in these analyses. Of the 584 participants, 123 (21.2%) reported a history of diabetes. A depression care manager worked with primary care physicians to provide algorithm based care. Vital status was assessed at 5 years. RESULTS: After a median follow up of 52.0 months, 110 depressed patients had died. Depressed patients with diabetes in the intervention category were less likely to have died during the 5 year follow-up interval than depressed diabetic patients in usual care after accounting for baseline differences among patients (adjusted hazard ratio 0.49 [95% CI 0.24-0.98]). CONCLUSIONS: Older depressed primary care patients with diabetes in practices implementing depression care management were less likely to die over the course of a 5-year interval than depressed patients with diabetes in usual-care practices. PMID- 17717287 TI - Burden of comorbid medical conditions and quality of diabetes care. AB - OBJECTIVE: With performance-based reimbursement pressures, it is concerning that most performance measurements treat each condition in isolation, ignoring the complexities of patients with multiple comorbidities. We sought to examine the relationship between comorbidity and commonly assessed services for diabetic patients in a managed care organization. RESEARCH DESIGN AND METHODS: In 6,032 diabetic patients, we determined the association between the independent variable medical comorbidity, measured by the Charlson Comorbidity Index (CCI), and the dependent variables A1C testing, lipid testing, dilated eye exam, and urinary microalbumin testing. We calculated predicted probabilities of receiving tests for patients with increasing comorbid illnesses, adjusting for patient demographics. RESULTS: A1C and lipid testing decreased slightly at higher CCI: predicted probabilities for CCI quartiles 1, 2, 3, and 4 were 0.83 (95% CI 0.70 0.91), 0.83 (0.69-0.92), 0.82 (0.68-0.91), and 0.78 (0.61-0.88) for A1C, respectively, and 0.82 (0.69-0.91), 0.81(0.67-0.90), 0.79 (0.64-0.89), and 0.77 (0.61-0.88) for lipids. Dilated eye exam and urinary microalbumin testing did not differ across CCI quartiles: for quartiles 1, 2, 3, and 4, predicted probabilities were 0.48 (0.33-0.63), 0.54 (0.38-0.69), 0.50 (0.34-0.65), and 0.50 (0.34-0.65) for eye exam, respectively, and 0.23 (0.12-0.40), 0.24 (0.12-0.42), 0.24 (0.12-0.41), and 23 (0.11-0.40) for urinary microalbumin. CONCLUSIONS: Services received did not differ based on comorbid illness burden. Because it is not clear whether equally aggressive care confers equal benefits to patients with varying comorbid illness burden, more evidence confirming such benefits may be warranted before widespread implementation of pay-for-performance programs using currently available "one size fits all" performance measures. PMID- 17717288 TI - Resequencing genomic DNA of patients with severe hypertriglyceridemia (MIM 144650). AB - OBJECTIVE: The genetic determinants of severe hypertriglyceridemia (HTG; MIM 144650) in adults are poorly defined. We therefore resequenced 3 candidate genes, namely LPL, APOC2, and APOA5, to search for accumulation of missense mutations in patients with severe HTG compared with normolipidemic subjects. METHODS AND RESULTS: We resequenced >2 million base pairs of genomic DNA from 110 nondiabetic patients with severe HTG and determined the prevalence of coding sequence variants compared with 472 age- and sex-matched normolipidemic controls. We found: (1) heterozygous mutations (LPL p.Q-12E >11X, p.D25H, p.W86R, p.G188E, p.I194T and p.P207L; APOC2 p.K19T and IVS2-30G>A) in 10.0% of severe HTG patients compared with 0.2% of controls (carrier odds ratio [OR] 52, 95% confidence interval [CI] 8.6 to 319); and (2) an association of the APOA5 p.S19W missense variant with severe HTG (carrier OR 5.5 95% CI 3.3 to 9.1). Furthermore, either rare mutations or the APOA5 p.S19W variant were found in 41.8% of HTG subjects compared with 8.9% of controls (carrier OR 7.4, 95% CI 4.5 to 12.0). Also, heterozygotes for rare mutations had a significantly reduced plasma triglyceride response to fibrate monotherapy. CONCLUSIONS: Both common and rare DNA variants in candidate genes were found in a substantial proportion of severe HTG patients. The findings underscore the value of candidate gene resequencing to understand the genetic contribution in complex lipoprotein and metabolic disorders. PMID- 17717289 TI - Important role of Nox4 type NADPH oxidase in angiogenic responses in human microvascular endothelial cells in vitro. AB - OBJECTIVE: Redox signaling mediated by Nox2-containing NADPH oxidase has been implicated in angiogenic responses both in vitro and in vivo. Because Nox4 type NADPH oxidase is also highly expressed in endothelial cells, we studied the role of Nox4 in angiogenic responses in human endothelial cells in culture. METHODS AND RESULTS: Inhibition of Nox4 expression by small interfering RNA reduced angiogenic responses as assessed by the tube formation and wound healing assays, in both human microvascular and umbilical vein endothelial cells. Overexpression of wild-type Nox4 enhanced, whereas expression of a dominant negative form of Nox4 suppressed the angiogenic responses in endothelial cells. These effects were mimicked by exogenous H2O2 and the antioxidant compound ebselen, respectively. Overexpression of Nox4 enhanced receptor tyrosine kinase phosphorylation and the activation of extracellular signal-regulated kinase (Erk). Inhibition of the Erk pathway reduced the endothelial angiogenic responses. Nox4 expression also promotes proliferation and migration of endothelial cells, and reduced serum deprivation-induced apoptosis. CONCLUSIONS: Nox4 type NADPH oxidase promotes endothelial angiogenic responses, at least partly, via enhanced activation of receptor tyrosine kinases and the downstream Erk pathway. PMID- 17717290 TI - Is there a role for fibrates in the management of dyslipidemia in the metabolic syndrome? AB - The outcomes of fibrate trials have varied: positive with gemfibrozil in the primary prevention Helsinki Heart Study and the secondary prevention VA-HIT trial; positive with reservations in the primary prevention WHO trial (clofibrate); and mixed with bezafibrate in the secondary prevention BIP study and with fenofibrate in the combined primary and secondary prevention FIELD study. Overall, the mixed results, combined with potential for adverse effects when given in combination with statins, have limited the use of these fibrates as cardioprotective agents. However, post hoc analyses of several of the fibrate studies have shown that people with features of the metabolic syndrome, particularly overweight people with high plasma triglyceride levels and low levels of HDL cholesterol, derive a disproportionately large reduction in cardiovascular events when treated with these agents. Thus, there is a strong case for the use of a fibrate to reduce the cardiovascular risk in overweight people with high triglyceride and low HDL-C. However, it should be noted that such people also have their cardiovascular risk reduced by statin therapy. It remains to be determined whether the combination of a fibrate plus statin reduces the risk beyond that achieved with a statin alone. PMID- 17717292 TI - Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease. AB - Osteopontin (OPN) is a multifunctional molecule highly expressed in chronic inflammatory and autoimmune diseases, and it is specifically localized in and around inflammatory cells. OPN is a secreted adhesive molecule, and it is thought to aid in the recruitment of monocytes-macrophages and to regulate cytokine production in macrophages, dendritic cells, and T-cells. OPN has been classified as T-helper 1 cytokine and thus believed to exacerbate inflammation in several chronic inflammatory diseases, including atherosclerosis. Besides proinflammatory functions, physiologically OPN is a potent inhibitor of mineralization, it prevents ectopic calcium deposits and is a potent inducible inhibitor of vascular calcification. Clinically, OPN plasma levels have been found associated with various inflammatory diseases, including cardiovascular burden. It is thus imperative to dissect the OPN proinflammatory and anticalcific functions. OPN recruitment functions of inflammatory cells are thought to be mediated through its adhesive domains, especially the arginine-glycine-aspartate (RGD) sequence that interacts with several integrin heterodimers. However, the integrin receptors and intracellular pathways mediating OPN effects on immune cells are not well established. Furthermore, several studies show that OPN is cleaved by at least 2 classes of proteases: thrombin and matrix-metalloproteases (MMPs). Most importantly, at least in vitro, fragments generated by cleavage not only maintain OPN adhesive functions but also expose new active domains that may impart new activities. The role for OPN proteolytic fragments in vivo is almost completely unexplored. We believe that further knowledge of the effects of OPN fragments on cell responses might help in designing therapeutics targeting inflammatory and cardiovascular diseases. PMID- 17717293 TI - Small concentrations of oxLDL induce capillary tube formation from endothelial cells via LOX-1-dependent redox-sensitive pathway. AB - OBJECTIVE: Vascular endothelial growth factor (VEGF), a key angiogenic growth factor, stimulates angiogenesis. Low levels of reactive oxygen species (ROS) function as signaling molecules for angiogenesis. We postulated that low concentrations of oxLDL might induce low levels of ROS and initiate angiogenesis. METHODS AND RESULTS: An in vitro model of tube formation from human coronary artery endothelial cells (HCAECs) was used. oxLDL (0.1, 1, 2, 5 microg/mL) induced VEGF expression and enhanced tube formation. oxLDL-mediated VEGF expression and tube formation were suppressed by a specific blocking anti-LOX-1 antibody. Anti-LOX-1 antibody also reduced oxLDL-induced increase in the expression of NADPH oxidase (gp91(phox) and p47(phox) subunits) and subsequent intracellular ROS generation, phosphorylation of p38 as well as p44/42MAPK, and NF-kappaB p65 expression. gp91(phox) siRNA had a similar effect. The expression of VEGF and NF-kappaB p65 induced by oxLDL was also inhibited by the specific extracellular signal-regulated kinase (ERK) 1/2 inhibitor U0126 and the p38 MAPK inhibitor SB203580. Importantly, the NADPH oxidase inhibitor apocynin, gp91(phox) siRNA, U0126, and SB203580 all reduced tube formation in response to oxLDL. CONCLUSIONS: These findings suggest that small concentrations of oxLDL promote capillary tube formation by inducing the expression of VEGF via LOX-1-mediated activation of NADPH oxidase- MAPKs-NF-kappaB pathway. PMID- 17717291 TI - Predictive value of reactive hyperemia for cardiovascular events in patients with peripheral arterial disease undergoing vascular surgery. AB - OBJECTIVE: Reactive hyperemia is the compensatory increase in blood flow that occurs after a period of tissue ischemia, and this response is blunted in patients with cardiovascular risk factors. The predictive value of reactive hyperemia for cardiovascular events in patients with atherosclerosis and the relative importance of reactive hyperemia compared with other measures of vascular function have not been previously studied. METHODS AND RESULTS: We prospectively measured reactive hyperemia and brachial artery flow-mediated dilation by ultrasound in 267 patients with peripheral arterial disease referred for vascular surgery (age 66+/-11 years, 26% female). Median follow-up was 309 days (range 1 to 730 days). Fifty patients (19%) had an event, including cardiac death (15), myocardial infarction (18), unstable angina (8), congestive heart failure (6), and nonhemorrhagic stroke (3). Patients with an event were older and had lower hyperemic flow velocity (75+/-39 versus 95+/-50 cm/s, P=0.009). Patients with an event also had lower flow-mediated dilation (4.5+/-3.0 versus 6.9+/-4.6%, P<0.001), and when these 2 measures of vascular function were included in the same Cox proportional hazards model, lower hyperemic flow (OR 2.7, 95% CI 1.2 to 5.9, P=0.018) and lower flow-mediated dilation (OR 4.2, 95% CI: 1.8 to 9.8, P=0.001) both predicted cardiovascular events while adjusting for other risk factors. CONCLUSIONS: Thus, lower reactive hyperemia is associated with increased cardiovascular risk in patients with peripheral arterial disease. Furthermore, flow-mediated dilation and reactive hyperemia incrementally relate to cardiovascular risk, although impaired flow-mediated dilation was the stronger predictor in this population. These findings further support the clinical relevance of vascular function measured in the microvasculature and conduit arteries in the upper extremity. PMID- 17717294 TI - Cholesterol accumulation is increased in macrophages of phospholipid transfer protein-deficient mice: normalization by dietary alpha-tocopherol supplementation. AB - OBJECTIVE: Phospholipid transfer protein (PLTP) is a multifunctional, extracellular lipid transport protein that plays a major role in lipoprotein metabolism and atherosclerosis. Recent in vivo studies suggested that unlike systemic PLTP, macrophage-derived PLTP would be antiatherogenic. The present study aimed at characterizing the atheroprotective properties of macrophage derived PLTP. METHODS AND RESULTS: Peritoneal macrophages were isolated from PLTP deficient and wild-type mice and their biochemical characteristics were compared. It is shown that macrophages isolated from PLTP-deficient mice have increased basal cholesterol content and accumulate more cholesterol in the presence of LDL compared with wild-type cells. Cholesterol parameters in macrophages of PLTP deficient mice were normalized by dietary alpha-tocopherol supplementation. CONCLUSIONS: The antiatherogenic properties of macrophage-derived PLTP are related at least in part to its ability to reduce cholesterol accumulation in macrophages through changes in the alpha-tocopherol content and oxidative status of the cells. PMID- 17717295 TI - Natural killer cells and CD4+ T-cells modulate collateral artery development. AB - OBJECTIVE: The immune system is thought to play a crucial role in regulating collateral circulation (arteriogenesis), a vital compensatory mechanism in patients with arterial obstructive disease. Here, we studied the role of lymphocytes in a murine model of hindlimb ischemia. METHODS AND RESULTS: Lymphocytes, detected with markers for NK1.1, CD3, and CD4, invaded the collateral vessel wall. Arteriogenesis was impaired in C57BL/6 mice depleted for Natural Killer (NK)-cells by anti-NK1.1 antibodies and in NK-cell-deficient transgenic mice. Arteriogenesis was, however, unaffected in J alpha281-knockout mice that lack NK1.1+ Natural Killer T (NKT)-cells, indicating that NK-cells, rather than NKT-cells, are involved in arteriogenesis. Furthermore, arteriogenesis was impaired in C57BL/6 mice depleted for CD4+ T-lymphocytes by anti-CD4 antibodies, and in major histocompatibility complex (MHC)-class-II deficient mice that more selectively lack mature peripheral CD4+ T-lymphocytes. This impairment was even more profound in anti-NK1.1-treated MHC-class-II deficient mice that lack both NK- and CD4+ T-lymphocytes. Finally, collateral growth was severely reduced in BALB/c as compared with C57BL/6 mice, 2 strains with different bias in immune responsiveness. CONCLUSIONS: These data show that both NK-cells and CD4+ T-cells modulate arteriogenesis. Promoting lymphocyte activation may represent a promising method to treat ischemic disease. PMID- 17717296 TI - The PI3K/Akt pathway mediates the neuroprotective effect of atorvastatin in extending thrombolytic therapy after embolic stroke in the rat. AB - OBJECTIVE: We tested the hypothesis that the phosphatidylinositol-3 kinase (PI3K)/Akt pathway mediates the neuroprotective effect of combination therapy of atorvastatin and tissue-type plasminogen activator (tPA) in rats after stroke. METHODS AND RESULTS: Combination of atorvastatin (20 mg/kg) and tPA (10 mg/kg) significantly reduced ischemic lesion volume, whereas monotherapy with atorvastatin and tPA did not reduce the lesion volume, when the treatments were initiated 4 hours after embolic middle cerebral artery occlusion (MCAo). Western blot analysis revealed that treatment with atorvastatin alone and in combination treatment with tPA significantly increased Akt phosphorylation compared with treatment with saline and tPA alone. Inhibition of the PI3K/Akt pathway with wortmannin completely abolished the reduction of lesion volume afforded by combination of atorvastatin and tPA. Real-time RT-PCR analysis of cerebral endothelial cells isolated by laser-capture microdissection from the ischemic boundary region showed that MCAo upregulated early growth response 1 (Egr-1) and vascular endothelial growth factor (VEGF) mRNA levels and tPA monotherapy further increased Egr-1 and VEGF mRNA levels. However, combination of atorvastatin and tPA significantly suppressed Egr-1 and VEGF mRNA levels in cerebral endothelial cells. CONCLUSIONS: Activation of Akt and downregulation of cerebral endothelial Egr-1 and VEGF gene expression by atorvastatin contribute to the neuroprotective effect of combination treatment with atorvastatin and tPA. PMID- 17717297 TI - Angiotensin II receptor blocker inhibits neointimal hyperplasia through regulation of smooth muscle-like progenitor cells. AB - OBJECTIVES: Angiotensin II (ATII) type 1 receptor (AT1R) blocker (ARB) has been shown to inhibit neointimal formation. Bone marrow-derived mononuclear cells (BM MNCs) give rise to smooth muscle (SM)-like cells at injured arterial wall and contribute to neointimal formation. However, role of the renin-angiotensin system in the homing process of SM-like cells during neointimal formation is unknown. MATERIAL AND METHODS: When human BM-MNCs and peripheral blood MNCs (PB-MNCs) were cultured under treatment with PDGF-BB and bFGF, these cells gave rise to SM-like cells with expression of alphaSMA, SMemb, and SM1 proteins. RT-PCR showed the expression of AT1R, ATII type 2 receptor (AT2R), alphaSMA, and SMemb mRNAs. ATII accelerated the differentiation of SM-like cells, which was inhibited by an ARB CV11974 (P<0.05). We then examined the effects of ATII, CV11974, and AT2R antagonist PD123319 on neointimal formation and BM-derived SM-like cell incorporation at injured arteries in vivo. BM from green fluorescence protein (GFP)-transgenic mice was transplanted to irradiated WT mice. GFP-BM chimera mice were subjected to wire injury on the left femoral artery. ATII (100 ng/kg/min) stimulated whereas CV11974 (1 mg/kg/d) inhibited neointimal formation. Number of GFP+ alphaSMA+ cells at neointima correlated with the intima/media ratio (r=0.69, P<0.05). CONCLUSION: BM-derived SM-like progenitor cells contributed to the neointimal formation after arterial injury. ATII accelerated whereas ARB suppressed this process. These are new aspects of the ARB-mediated inhibition of atherosclerotic disease progression. PMID- 17717298 TI - CXCR2 blockade impairs angiotensin II-induced CC chemokine synthesis and mononuclear leukocyte infiltration. AB - OBJECTIVE: Angiotensin II (Ang-II) and mononuclear leukocytes are involved in atherosclerosis. This study reports the inhibition of Ang-II-induced mononuclear cell recruitment by CXCR2 antagonism and the mechanisms involved. METHODS AND RESULTS: Ang-II (1 nmol/L, i.p. in rats) induced CXC and CC chemokines, followed by neutrophil and mononuclear cell recruitment. Administration of the CXCR2 antagonist, SB-517785-M, inhibited the infiltration of both neutrophils (98%) and mononuclear cells (60%). SB-517785-M had no effect on the increase in CXC chemokine levels but reduced MCP-1, RANTES, and MIP-1alpha release by 66%, 63%, and 80%, respectively. Intravital microscopy showed that pretreatment with SB 517785-M inhibited Ang-II-induced arteriolar mononuclear leukocyte adhesion. Stimulation of human umbilical arterial endothelial cells (HUAECs) or whole blood with 1 micromol/L Ang-II induced the synthesis of chemokines. Ang-II increased HUAEC CXCR2 expression, and its blockade caused a significant reduction of MCP-1, -3, and RANTES release, as well as mononuclear cell arrest. Ang-II-induced MIP 1alpha release from blood cells was also inhibited. CONCLUSION: Mononuclear leukocyte recruitment induced by Ang-II is, surprisingly, largely mediated by the CXC chemokines which appear to induce the release of CC chemokines. Therefore, CXC chemokine receptor antagonists may help to prevent mononuclear cell infiltration and the progression of the atherogenic process. PMID- 17717299 TI - Increased oxidative stress in scavenger receptor BI knockout mice with dysfunctional HDL. AB - OBJECTIVE: In the current study the effect of disruption of SR-BI, a prominent regulator of HDL metabolism, on the activity of the HDL-associated antioxidant enzymes PON1 and PAF-AH as well as in vivo oxidative stress were investigated. METHODS AND RESULTS: SR-BI deficiency resulted in 1.4-fold (P<0.001) and 1.6-fold (P<0.01) lower serum paraoxonase and arylesterase activity of PON1, respectively. Furthermore, a trend to slightly lower PAF-AH activity was observed. In vivo oxidative stress was evaluated by measuring isoprostane F2alpha-VI (iPF2alpha-VI) and protein carbonyls. Compared with wild-type animals, SR-BI knockouts had 1.4 fold (P<0.05) higher levels of plasma iPF2alpha-VI, whereas urinary excretion was increased 2-fold (P<0.0001). Plasma carbonyls were 1.5-fold (P<0.05) higher in SR BI knockout animals. Furthermore, iPF2alpha-VI and carbonyl levels were 2.1-fold (P<0.01) and 1.4-fold (P<0.01), respectively, increased in livers of SR-BI knockout mice, and in reaction to the increased oxidative stress the expression of several endogenous antioxidant systems was upregulated. On challenging the SR BI knockout mice with an atherogenic Western-type diet, a further increase in oxidative stress in these animals was observed. CONCLUSION: SR-BI deficiency results in a reduced activity of the antioxidant enzyme PON1 and a significant increase in oxidative stress, potentially contributing to the proatherogenic effect of SR-BI deficiency. PMID- 17717300 TI - Emerging concepts of regulation of angiotensin II receptors: new players and targets for traditional receptors. AB - Angiotensin (Ang) II exerts its important physiological functions through 2 distinct receptor subtypes, type 1 (AT(1)) and type 2 (AT(2)) receptors. Recently, new evidence has accumulated showing the existence of several novel receptor interacting proteins and various angiotensin II receptor activation mechanisms beyond the classical actions of receptors for Ang II. These associated proteins could contribute not only to Ang II receptors' functions, but also to influencing pathophysiological states. Receptor dimerization of Ang II receptors such as homodimer, heterodimer, and complex formation with other G protein coupled receptors has also been focused on as a new mechanism of their activation or inactivation. Moreover, ligand-independent receptor activation systems such as mechanical stretch for the AT(1) receptor have also been revealed. These emerging concepts of regulation of Ang II receptors and a new insight into future drug discovery are discussed in this review. PMID- 17717301 TI - Intact beta-adrenergic response and unmodified progression toward heart failure in mice with genetic ablation of a major protein kinase A phosphorylation site in the cardiac ryanodine receptor. AB - Increased phosphorylation of the cardiac ryanodine receptor (RyR)2 by protein kinase A (PKA) at the phosphoepitope encompassing Ser2808 has been advanced as a central mechanism in the pathogenesis of cardiac arrhythmias and heart failure. In this scheme, persistent activation of the sympathetic system during chronic stress leads to PKA "hyperphosphorylation" of RyR2-S2808, which increases Ca2+ release by augmenting the sensitivity of the RyR2 channel to diastolic Ca2+. This gain-of-function is postulated to occur with the unique participation of RyR2 S2808, and other potential PKA phosphorylation sites have been discarded. Although it is clear that RyR2 is among the first proteins in the heart to be phosphorylated by beta-adrenergic stimulation, the functional impact of phosphorylation in excitation-contraction coupling and cardiac performance remains unclear. We used gene targeting to produce a mouse model with complete ablation of the RyR2-S2808 phosphorylation site (RyR2-S2808A). Whole-heart and isolated cardiomyocyte experiments were performed to test the role of beta adrenergic stimulation and PKA phosphorylation of Ser2808 in heart failure progression and cellular Ca2+ handling. We found that the RyR2-S2808A mutation does not alter the beta-adrenergic response, leaves cellular function almost unchanged, and offers no significant protection in the maladaptive cardiac remodeling induced by chronic stress. Moreover, the RyR2-S2808A mutation appears to modify single-channel activity, although modestly and only at activating [Ca2+]. Taken together, these results reveal some of the most important effects of PKA phosphorylation of RyR2 but do not support a major role for RyR2-S2808 phosphorylation in the pathogenesis of cardiac dysfunction and failure. PMID- 17717302 TI - Both protein kinase A and exchange protein activated by cAMP coordinate adhesion of human vascular endothelial cells. AB - cAMP regulates integrin-dependent adhesions of vascular endothelial cells (VECs) to extracellular matrix proteins, their vascular endothelial cadherin-dependent intercellular adhesions, and their proliferation and migration in response to growth and chemotactic factors. Previously, we reported that cAMP-elevating agents differentially inhibited migration of human VECs isolated from large vascular structures (macro-VECs, human aortic endothelial cells [HAECs]) or small vascular structures (micro-VECs, human microvascular endothelial cells [HMVECs]) and that cAMP hydrolysis by phosphodiesterase (PDE)3 and PDE4 enzymes was important in coordinating this difference. Here we report that 2 cAMP-effector enzymes, namely protein kinase (PK)A and exchange protein activated by cAMP (EPAC), each regulate extracellular matrix protein-based adhesions of both macro- and micro-VECs. Of interest and potential therapeutic importance, we report that although specific pharmacological activation of EPAC markedly stimulated adhesion of micro-VECs to extracellular matrix proteins when PKA was inhibited, this treatment only modestly promoted adhesion of macro-VECs. Consistent with an important role for cAMP PDEs in this difference, PDE3 or PDE4 inhibitors promoted EPAC-dependent adhesions in micro-VECs when PKA was inhibited but not in macro VECs. At a molecular level, we identify multiple, nonoverlapping, PKA- or EPAC based signaling protein complexes in both macro- and micro-VECs and demonstrate that each of these complexes contains either PDE3B or PDE4D but not both of these PDEs. Taken together, our data support the concept that adhesion of macro- and micro-VECs is differentially regulated by cAMP and that these differences are coordinated through selective actions of cAMP at multiple nonoverlapping signaling complexes that contain PKA or EPAC and distinct PDE variants. PMID- 17717303 TI - Two common gene variants on chromosome 9 and risk of atherothrombosis. PMID- 17717304 TI - Stroke in diabetic patients: is it really a macrovascular complication? PMID- 17717305 TI - Combining antiplatelet drugs and oral anticoagulant therapy in atrial fibrillation: acute coronary syndromes and/or percutaneous coronary intervention/stenting revisited. PMID- 17717306 TI - "Prevention": the right term? PMID- 17717307 TI - Overestimation of coronary risk in stroke patients. PMID- 17717308 TI - Higher stroke mortality on weekends: are all strokes the same? PMID- 17717309 TI - Comparison of the carotid stenosis index with CT angiography. PMID- 17717310 TI - SAINT-I worked, but the neuroprotectant is not NXY-059. PMID- 17717311 TI - Endovascular occlusion of aneurysms using a new bioactive coil: a matched pair analysis with bare platinum coils. AB - BACKGROUND AND PURPOSE: To assess safety and efficacy data of a new bioactive coil (Cerecyte) which is loaded with polyglycolic acid on the inside of the coil. METHODS: Fifty-four patients harboring 55 aneurysms were treated with Cerecyte coils. These aneurysms were matched in localization and size with aneurysms treated with bare platinum coils. RESULTS: Periprocedural complications and handling did not differ between both groups. Initial aneurysm occlusion was comparable in both treatment groups. At 6 months angiographic follow-up, the aneurysms occluded with Cerecyte coils had a higher chance for complete occlusion (P=0.045) and tended to a lower retreatment rate (P=0.056). CONCLUSIONS: Cerecyte coils are as safe as bare platinum coils in the endovascular occlusion of aneurysms. This matched pair analysis indicates a higher occlusion rate of aneurysms occluded with Cerecyte coils. PMID- 17717312 TI - Rigorously investigating the 'weekend effect' on short-term mortality for patients admitted with stroke. PMID- 17717314 TI - Molecular indices of apoptosis activation in elastase-induced aneurysms after embolization with platinum coils. AB - BACKGROUND AND PURPOSE: Even though endovascular coils have been widely used for the treatment of intracranial aneurysms, the cellular and molecular responses of aneurysms to the coils after embolization remain poorly understood. The aim of the present study was to understand the mechanism of apoptosis in aneurysms embolized with platinum coils in the rabbit model of elastase-induced aneurysms. METHODS: Elastase-induced saccular aneurysms were created at the origin of the right common carotid artery in 30 rabbits. Aneurysms were allowed to mature for 8 weeks, after which 20 aneurysms were embolized with platinum coils by endovascular means. After 2 (n=10) and 4 (n=10) weeks of implantation, aneurysm samples harboring coils were harvested for apoptotic studies. The remaining 10 uncoiled aneurysms were used as controls; additional controls included the left common carotid artery, which had not undergone any surgical procedure. Control samples were harvested at 12 weeks after aneurysm creation. RESULTS: Expression of procaspases-3, -8, and -9 was elevated in coiled aneurysms embolized with platinum coils at both time points when compared with uncoiled aneurysms and the left common carotid artery. Cleaved caspases-3, -8, and -9 were found to be expressed only at 4 weeks after embolization. Cells within the aneurysm cavity were terminal dUTP nick end-labeling-positive at 4 weeks only. These apoptotic cells were identified as smooth muscle actin-positive cells. Expression of tumor necrosis-alpha was high in coiled aneurysms when compared with controls. There was no significant difference in the expression of Fas ligand among groups. Decreased expression of antiapoptotic proteins Bcl-2 and phospho-Bad, as well as increased expression of proapoptotic proteins Bax and Bid, was observed in coiled aneurysms at both time points. CONCLUSIONS: Activation of apoptosis in aneurysms after embolization with platinum coils is induced by both tumor necrosis factor alpha-mediated extrinsic and Bcl-2-mediated intrinsic pathways. PMID- 17717313 TI - Clinical diagnosis of lacunar stroke in the first 6 hours after symptom onset: analysis of data from the glycine antagonist in neuroprotection (GAIN) Americas trial. AB - BACKGROUND AND PURPOSE: Although the pathophysiological heterogeneity of stroke may be highly relevant to the development of acute-phase therapies, discriminating between ischemic stroke subtypes soon after onset remains a challenge. We conducted a study of the accuracy of a clinical diagnosis of lacunar stroke in the first 6 hours after symptom onset. METHODS: We analyzed data from 1367 patients in the Glycine Antagonist In Neuroprotection (GAIN) Americas trial. The Trial of ORG10172 in Acute Stroke Treatment (TOAST) category "small vessel (lacunar)" disease at day 7 or at hospital discharge was used as the reference standard to determine the accuracy of a diagnosis of a lacunar stroke made within 6 hours of symptom onset using the Oxfordshire Community Stroke Project (OCSP) classification "LACS." Outcome was analyzed by comparing the proportions of patients classified as "LACS" at baseline or "small vessel (lacunar)" at 7 days who were dead or dependent at 3 months. RESULTS: The positive predictive value of an OCSP diagnosis of a lacunar stroke was 76% (95% CI: 69% to 81%; sensitivity 64% [95% CI: 58% to 70%]; specificity 96% [95% CI: 95% to 97%]; negative predictive value 93% [95% CI: 92% to 94%]; accuracy 91% [95% CI: 89% to 92%]). The 3-month outcomes of patients classified as either OCSP "LACS" within 6 hours of onset or TOAST "small vessel (lacunar)" at 7 days were not significantly different. CONCLUSIONS: An OCSP LACS diagnosis made within 6 hours of stroke onset is reasonably predictive of a final diagnosis of "small vessel (lacunar)" disease made using TOAST criteria and has a similar relationship to outcome at 3 months. PMID- 17717315 TI - Effects of skilled forelimb training on hippocampal neurogenesis and spatial learning after focal cortical infarcts in the adult rat brain. AB - BACKGROUND AND PURPOSE: Environmental stimulation consistently increases dentate neurogenesis in the adult brain and improves spatial learning. We tested the hypothesis whether specific rehabilitative training of an impaired forelimb influences these processes after focal cortical infarcts. METHODS: Focal cortical infarcts were induced in the forelimb sensorimotor cortex using the photothrombosis model. One group of infarcted animals and sham-operated controls housed in standard cages received one daily session of skilled reaching training of the impaired or dominant forelimb, respectively. A second group was transferred to an enriched environment, whereas a third group remained in the standard cages without further treatment. Bromodeoxyuridine was administered from day 2 until day 6 postinfarct. Proliferation and differentiation of newborn cells was analyzed at day 10 and 42 using immunocytochemistry with neuronal and glial markers and confocal laser scanning microscopy. Spatial learning was tested in the Morris water maze between days 35 and 41. RESULTS: After cortical infarcts in the forelimb sensorimotor cortex, environmental enrichment as well as daily reaching training of the impaired paw both increase dentate neurogenesis and improve functional performance in the Morris water maze. Nevertheless, the reaching training-induced neurogenic response was significantly greater in nonlesioned controls associated with the best spatial learning performance in the water maze. CONCLUSIONS: Skilled forelimb training effectively stimulates dentate neurogenesis and spatial learning in the infarcted and healthy brain. However, this reaching training-induced increase in neurogenesis was reduced after cortical infarcts. PMID- 17717316 TI - Association of the glutathione S-transferase omega-1 Ala140Asp polymorphism with cerebrovascular atherosclerosis and plaque-associated interleukin-1 alpha expression. AB - BACKGROUND AND PURPOSE: Glutathione S-transferase omega-1 is a multifunctional enzyme. The Asp/Asp genotype of the Ala140Asp polymorphism of the GSTO1 gene has been alleged to increase the risk of vascular dementia. The objective of this study is to address the question of whether common vessel disorders known to cause vascular dementia are modified in their severity by this polymorphism. METHODS: The severity and expansion of atherosclerosis in the circle of Willis vessels, cerebral small vessel disease, and cerebral amyloid angiopathy were studied in a sample of 79 autopsy cases. Genotyping of the GSTO1 Ala140Asp polymorphism as well as immunohistochemistry for glutathione S-transferase omega 1 was performed. RESULTS: Carriers of the GSTO1 Asp/Asp genotype presented with more severe and widespread atherosclerosis than noncarriers. However, there was no effect on small vessel disease expansion and cerebral amyloid angiopathy severity. Immunohistochemically, we detected interleukin-1 alpha expressing macrophages in the lipid core of atherosclerosis plaques exhibiting glutathione S transferase omega-1-positive material. GSTO1 Asp/Asp carriers showed larger areas of atherosclerosis plaques containing interleukin-1 alpha-positive material than carriers of the GSTO1 Ala-allele. CONCLUSIONS: The GSTO1 Asp/Asp genotype presumably modulates the severity and expansion of atherosclerosis in the circle of Willis. The cellular colocalization of glutathione S-transferase omega-1 and interleukin-1 alpha suggests a functional interaction between both proteins which in part might explain the function of glutathione S-transferase omega-1 in the pathogenesis of cerebral atherosclerosis. PMID- 17717317 TI - The impact of ambulance practice on acute stroke care. AB - BACKGROUND AND PURPOSE: Few patients with acute stroke are treated with alteplase, often due to significant prehospital delays after symptom onset. The aims of this study were to: (1) identify factors associated with rapid first medical assessment in the emergency department after a call for ambulance assistance, and (2) determine the impact of ambulance practice on times from the ambulance call to first medical assessment in the emergency department. METHODS: During a 6-month period in 2004, all ambulance-transported patients with stroke or transient ischemic attack arriving from a geographically defined region in Melbourne, Australia (population 383,000) to one of 3 hospital emergency departments were assessed prospectively. Ambulance records including the tape recording of the call for ambulance assistance and hospital medical records, were analyzed. RESULTS: One hundred ninety-eight patients were included in the study. One hundred eighty-seven ambulance patient care records were complete and available for analysis. Factors associated with first medical assessment in the emergency department <60 minutes from the ambulance call and <10 minutes from hospital arrival were: Glasgow Coma Scale <13 (P<0.001 and P=0.021) and hospital prenotification (P=0.04 and P<0.001). Paramedic stroke recognition and hospital prenotification were associated with shorter times from the ambulance call to first medical assessment (P=0.001 and P<0.001). CONCLUSIONS: Paramedic stroke recognition and hospital prenotification are associated with shorter prehospital times from the ambulance call to hospital arrival and in-hospital times from hospital arrival to first medical assessment. This highlights the importance of including ambulance practice in comprehensive care pathways that span the whole process of stroke care. PMID- 17717318 TI - Iron oxide particle-enhanced MRI suggests variability of brain inflammation at early stages after ischemic stroke. AB - BACKGROUND AND PURPOSE: Inflammation contributes to brain damage caused by ischemic stroke. Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI allows noninvasive monitoring of macrophage recruitment into ischemic brain lesions. In this study, we determined the extent of USPIO enhancement during early stages of ischemic stroke. METHODS: Twelve consecutive patients with typical clinical signs of stroke underwent multimodal stroke imaging at 1.5-T within 24 hours of symptom onset. They received intravenous USPIO (ferumoxtran) infusion at 26 to 96 hours (mean, 44 hours) after stroke. A total of four follow up MRI scans were performed 24 to 36 hours, 48 to 72 hours, 7 to 8 days, and 10 to 11 days after USPIO infusion. RESULTS: Nine patients were included in the final analysis. Parenchymal USPIO enhancement occurred in 3 of 9 analyzed patients and was mainly evident on T1-weighted spin-echo images. USPIO-dependent signal changes were spatially heterogeneous, reflecting the distinct patterns of hematogenous macrophage infiltration in different lesion types. CONCLUSIONS: Our findings suggest a variable extent and distribution of macrophage infiltration into early ischemic stroke lesions. USPIO-enhanced MRI may help to more specifically target antiinflammatory therapy in patients with stroke. PMID- 17717319 TI - Bleeding risk analysis in stroke imaging before thromboLysis (BRASIL): pooled analysis of T2*-weighted magnetic resonance imaging data from 570 patients. AB - BACKGROUND AND PURPOSE: There has been speculation that the risk of secondary symptomatic intracranial hemorrhage (SICH) may be increased after thrombolytic therapy in ischemic stroke patients who have cerebral microbleeds (CMBs) on T2* weighted magnetic resonance imaging. Because of this concern, some centers withhold potentially beneficial thrombolytic therapy from these patients. METHODS: We analyzed magnetic resonance imaging data acquired within 6 hours after symptom onset from 570 ischemic stroke patients treated with intravenous tissue plasminogen activator in 13 centers in Europe, North America, and Asia. Baseline T2*-weighted magnetic resonance images were evaluated for the presence of CMBs. The primary end point was SICH, defined as clinical deterioration with an increase in the National Institutes of Health Stroke Scale score by >or=4 points, temporally related to a parenchymal hematoma on follow-up-imaging. RESULTS: A total of 242 CMBs were detected in 86 of 570 patients (15.1%). The number of CMBs ranged from 1 to 77 in the individual patient, with >or=5 CMBs in 6 of 570 patients (1.1%). Proportions of patients with SICH were 5.8% (95% CI, 1.9 to 13.0) in the presence of CMBs and 2.7% (95% CI, 1.4 to 4.5) in patients without CMBs (P=0.170, Fisher's exact test), resulting in no significant absolute increase in the risk of SICH of 3.1% (95% CI, -2.0 to 8.3). CONCLUSIONS: The data suggest that if there is any increased risk of SICH attributable to CMBs, it is likely to be small and unlikely to exceed the benefits of thrombolytic therapy. No reliable conclusion regarding risk in the rare patient with multiple CMBs can be reached. PMID- 17717321 TI - Retinoic acid induced alveolar regeneration: critical differences in strain sensitivity. AB - In emphysema, the lung cannot spontaneously regenerate lost alveolar tissue. Treatment with retinoic acid (RA) in rodent models of emphysema induces alveolar regeneration. However, some animal studies have failed to show regeneration when using different species and strains. We have previously shown that dexamethasone (Dex) treatment of newborn TO outbred strain mice permanently disrupts alveolar development. Later RA treatment restores alveolar architecture to normal. To determine whether this model of alveolar regeneration is strain specific, our protocol was repeated with two new outbred mouse strains. ICR and NIHS mice received Dex from Postnatal Days 4 to P15 (P4- P15). From P46 to P57, mice received RA (2 mg/kg) or vehicle. An additional ICR group received 5x RA (10 mg/kg) from P46 to P57. Control groups received vehicle at both treatment points. All mice were killed at P90 and lung morphology analyzed. Dex-treated ICR and NIHS mice showed increased mean alveolar chord length (Lm) and reduced alveolar surface area (SA) and SA/lung volume (SA/LV) compared with controls. RA-treated NIHS mice showed return of Lm, SA, and SA/LV toward control values, indicating alveolar regeneration. ICR RA group mice did not regenerate, but 5x RA mice showed Lm, SA, and SA/LV values consistent with alveolar regeneration. In conclusion, the Dex-treated mouse model of emphysema is robust and repeatable in different strains. RA-induced alveolar regeneration is not a strain-specific phenomenon. RA dose threshold for inducing alveolar regeneration is higher in ICR mice, suggesting a difference in retinoid pharmacokinetics between strains. These results provide a possible explanation for previous failed studies of RA-induced alveolar regeneration. PMID- 17717320 TI - Maintenance of airway epithelium in acutely rejected orthotopic vascularized mouse lung transplants. AB - Lung transplantation remains the only therapeutic option for many patients suffering from end-stage pulmonary disease. Long-term success after lung transplantation is severely limited by the development of bronchiolitis obliterans. The murine heterotopic tracheal transplantation model has been widely used for studies investigating pathogenesis of obliterative airway disease and immunosuppressive strategies to prevent its development. Despite its utility, this model employs proximal airway that lacks airflow and is not vascularized. We have developed a novel model of orthotopic vascularized lung transplantation in the mouse, which leads to severe vascular rejection in allogeneic strain combinations. Here we characterize differences in the fate of airway epithelial cells in nonimmunosuppressed heterotopic tracheal and vascularized lung allograft models over 28 days. Up-regulation of growth factors that are thought to be critical for the development of airway fibrosis and interstitial collagen deposition were similar in both models. However, while loss of airway epithelial cells occurred in the tracheal model, airway epithelium remained intact and fully differentiated in lung allografts, despite profound vascular rejection. Moreover, we demonstrate expression of the anti-apoptotic protein Bcl-2 in airway epithelial cells of acutely rejected lung allografts. These findings suggest that in addition to alloimmune responses, other stimuli may be required for the destruction of airway epithelial cells. Thus, the model of vascularized mouse lung transplantation may provide a new and more physiologic experimental tool to study the interaction between immune and nonimmune mechanisms affecting airway pathology in lung allografts. PMID- 17717323 TI - The lung responds to zymosan in a unique manner independent of toll-like receptors, complement, and dectin-1. AB - In vitro studies indicate that the inflammatory response to zymosan, a fungal wall preparation, is dependent on Toll-like receptor (TLR) 2, and that this response is enhanced by the dectin-1 receptor. Complement may also play an important role in this inflammatory response. However, the relevance of these molecules within the in vivo pulmonary environment remains unknown. To examine pulmonary in vivo inflammatory responses of the lung to zymosan, zymosan was administered by intratracheal aerosolization to C57BL/6, TLR2- TLR4-, MyD88-, and complement-deficient mice. Outcomes included bronchoalveolar fluid cell counts. We next examined effects of dectin-1 inhibition on response to zymosan in alveolar macrophages in vitro and in lungs of C57BL/6, TLR2-, and complement deficient mice. Finally, the effect of alveolar macrophage depletion on in vivo pulmonary responses was assessed. Marked zymosan-induced neutrophil responses were unaltered in TLR2-deficient mice despite a TLR2-dependent response seen with synthetic TLR2 agonists. TLR4, MyD88, and complement activation were not required for the inflammatory response to zymosan. Although dectin-1 receptor inhibition blocked the inflammatory response of alveolar macrophages to zymosan in vitro, in vivo pulmonary leukocyte recruitment was not altered even in the absence of TLR2 or complement. Depletion of alveolar macrophages did not affect the response to zymosan. Neither complement, macrophages, nor TLR2, TLR4, MyD88, and/or dectin-1 receptors were involved in the pulmonary in vivo inflammatory response to zymosan. PMID- 17717324 TI - In vivo MR tracking of mesenchymal stem cells in rat liver after intrasplenic transplantation. AB - PURPOSE: To prospectively track in vivo in rats intrasplenically transplanted stem cells labeled with superparamagnetic particles by using magnetic resonance (MR) imaging. MATERIALS AND METHODS: The study was approved by the institutional Committee on Animal Research. Liver damage in 12 rats was induced with subcutaneous injection of carbon tetrachloride (CCl4). Intrasplenic transplantation of 6x10(6) rodent bone mesenchymal stem cells (BMSCs) with (n=6) and without (n=6) superparamagnetic particle Fe2O3-poly-L-lysine (PLL) labeling was performed via direct puncture. Cell labeling efficiency was assessed in vitro by using Prussian blue stain and an atomic absorption spectrometer. MR examinations were performed immediately before and 3 hours and 3, 7, and 14 days after transplantation. Liver-to-muscle contrast-to-noise ratios (CNRs) on T2* weighted MR images obtained before and after injection were measured and correlated with histomorphologic studies. Statistical analyses were performed by using repeated-measures analysis of variance. RESULTS: Rat BMSCs could be effectively labeled with approximately 100% efficiency. Migration of transplanted labeled cells to the liver was successfully documented with in vivo MR imaging. CNRs on T2*-weighted images decreased significantly in the liver 3 hours after injection of BMSCs (P<.05) and returned gradually to the level achieved without labeled cell injection in 14 days. Histologic analyses confirmed the presence of BMSCs in the liver. The labeled cells primarily localized in the sinusoids of periportal areas and the foci of CCl4-induced liver damage. Quantitative analysis of Prussian blue-stained cells indicated gradual decrease of dye pigments from 3 hours to 3, 7, and 14 days after injection. No free iron particles were found in the interstitium or within hepatic microvessels. CONCLUSION: The rat BMSCs could be efficiently labeled with Fe2O3-PLL and the relocation of the labeled cells to rat livers after intrasplenic transplantation could be depicted at in vivo MR imaging. PMID- 17717322 TI - Secretion of IL-13 by airway epithelial cells enhances epithelial repair via HB EGF. AB - Inappropriate repair after injury to the epithelium generates persistent activation, which may contribute to airway remodeling. In the present study we hypothesized that IL-13 is a normal mediator of airway epithelial repair. Mechanical injury of confluent airway epithelial cell (AEC) monolayers induced expression and release of IL-13 in a time-dependent manner coordinate with repair. Neutralizing of IL-13 secreted from injured epithelial cells by shIL 13Ralpha2.FC significantly reduced epithelial repair. Moreover, exogenous IL-13 enhanced epithelial repair and induced epidermal growth factor receptor (EGFR) phosphorylation. We examined secretion of two EGFR ligands, epidermal growth factor (EGF) and heparin-binding EGF (HB-EGF), after mechanical injury. Our data showed a sequential release of the EGF and HB-EGF by AEC after injury. Interestingly, we found that IL-13 induces HB-EGF, but not EGF, synthesis and release from AEC. IL-13-induced EGFR phosphorylation and the IL-13-reparative effect on AEC are mediated via HB-EGF. Finally, we demonstrated that inhibition of EGFR tyrosine kinase activity by tyrphostin AG1478 increases IL-13 release after injury, suggesting negative feedback between EGFR and IL-13 during repair. Our data, for the first time, showed that IL-13 plays an important role in epithelial repair, and that its effect is mediated through the autocrine release of HB-EGF and activation of EGFR. Dysregulation of EGFR phosphorylation may contribute to a persistent repair phenotype and chronically increased IL-13 release, and in turn result in airway remodeling. PMID- 17717325 TI - Bowel transition points: multiplicity and posterior location at CT are associated with small-bowel volvulus. AB - PURPOSE: To retrospectively evaluate the sensitivity and specificity of the number and location of bowel transition points at computed tomography (CT) in the diagnosis of small-bowel volvulus, with surgical findings as the reference standard. MATERIALS AND METHODS: This HIPAA-compliant study had institutional review board approval; informed consent was waived. One hundred adult patients who had undergone preoperative CT and who had surgically proved non-abdominal wall hernia small-bowel obstruction (n=68) or small-bowel volvulus (n=32) were retrospectively identified. The patients included 61 women and 39 men with a mean age of 57 years (range, 18-96 years). One reader, blinded to the diagnoses, recorded the number of transition points at CT, the anteroposterior location of each transition point relative to the anterior edge of the spine, and the presence or absence of a whirl sign. Statistical analyses were performed with the Fisher exact test, unpaired t tests, and multiple logistic regression. RESULTS: The frequency of the finding of multiple transition points was significantly higher in patients with volvulus (19 [59%] of 32) than in patients without volvulus (11 [16%] of 68) (P<.001). Transition points associated with volvulus were less likely to be located more than 7 cm anterior to the spine (four [12%] of 32 patients) than were transition points not associated with volvulus (31 [46%] of 68 patients) (P<.005). The whirl sign was an additional significant independent predictor of volvulus (P<.05). When all three of these predictors were present, the specificity for small-bowel volvulus was 100%. CONCLUSION: The presence of multiple transition points with a posterior location at CT in an adult with small-bowel obstruction is significantly associated with volvulus. PMID- 17717326 TI - Renal artery assessment with nonenhanced steady-state free precession versus contrast-enhanced MR angiography. AB - PURPOSE: To prospectively assess the diagnostic accuracy of nonenhanced three dimensional (3D) steady-state free precession (SSFP) magnetic resonance (MR) angiography for detection of renal artery stenosis (RAS), with breath-hold contrast material-enhanced MR angiography performed as the reference standard. MATERIALS AND METHODS: The study was local ethics committee approved; all patients gave written informed consent. Fifty-three patients (30 male, 23 female; mean age, 58 years) with arterial hypertension and suspected of having RAS were examined with 1.5-T 3D SSFP renal MR angiography. Stenosis grade, maximal visible vessel length, and subjective image quality were compared. Sensitivity, specificity, accuracy, and negative predictive value (NPV) were calculated on artery-by-artery and patient-by-patient bases. The significance of the results was assessed with the paired two-sided t test for continuous variables and with the marginal homogeneity test for categorical variables. Cohen kappa statistics were used to estimate interobserver agreement. RESULTS: One hundred eight renal arteries with 20 significant (>or=50%) stenoses were detected with contrast enhanced MR angiography. At artery-by-artery analysis, sensitivity, specificity, accuracy, and NPV of nonenhanced SSFP MR angiography for RAS detection were 100%, 93%, 94%, and 100%, respectively, for observer 1 and 95%, 95%, 95%, and 99%, respectively, for observer 2. Corresponding patient-by-patient values were 100%, 92%, 94%, and 100%, respectively, for observer 1 and 100%, 95%, 96%, and 100%, respectively, for observer 2. Overestimation of stenosis grade with SSFP MR angiography resulted in six and four false-positive findings for readers 1 and 2, respectively. Mean maximal visible lengths of the renal arteries were 69.9 mm at contrast-enhanced MR angiography and 61.1 mm at SSFP MR angiography (P<.001). Both techniques yielded good to excellent image quality. CONCLUSION: Slab selective inversion-prepared 3D SSFP MR angiography had high sensitivity, specificity, accuracy, and NPV for RAS detection, without the need for contrast material. However, RAS severity was overestimated in some patients. PMID- 17717327 TI - Articular cartilage defects detected with 3D water-excitation true FISP: prospective comparison with sequences commonly used for knee imaging. AB - PURPOSE: To prospectively compare the accuracy of three-dimensional (3D) water excitation (WE) true fast imaging with steady-state precession (FISP) in the diagnosis of articular cartilage defects with that of sequences commonly used to image the knee, with arthroscopy or surgery as the reference standard. MATERIALS AND METHODS: This study protocol was institutional review board approved. Written informed consent was obtained from all patients. Thirty knees in 29 patients (mean age, 56 years; range, 18-86 years) were prospectively evaluated by using sagittal 3D WE true FISP with two section thicknesses (1.7 mm [true FISPthin] and 3.0 mm [true FISPthick]), two-dimensional (2D) intermediate-weighted spin-echo with fat saturation, 2D fast short inversion time inversion-recovery, 3D WE double-echo steady-state, and 3D fat-saturated fast low-angle shot sequences. Cartilage defects were graded on magnetic resonance images and during surgery with a modified Noyes scoring system. Contrast-to-noise ratio (CNR) and CNR efficiency were calculated. Sensitivity, specificity, and accuracy were assessed. Interobserver agreement was determined with kappa statistics, and quantitative results were evaluated with the Wilcoxon signed rank test. RESULTS: The performance of 3D WE true FISPthick (sensitivity, specificity, and accuracy, respectively, were 52%, 93%, and 71% for reader 1 and 65%, 88%, and 76% for reader 2) and 3D WE true FISPthin (sensitivity, specificity, and accuracy, respectively, were 58%, 94%, and 75% for reader 1 and 63%, 80%, and 71% for reader 2) sequences was no different than that of other sequences in the detection of circumscribed defects. Three-dimensional WE true FISP sequences had a significantly (P<.0033) higher CNR and CNR efficiency between cartilage and fluid than the corresponding sequences with the same section thickness. CONCLUSION: Three-dimensional WE true FISP enables high contrast between joint fluid and articular cartilage and a diagnostic performance that is comparable with that of standard sequences. PMID- 17717328 TI - Prostate cancer: accurate determination of extracapsular extension with high spatial-resolution dynamic contrast-enhanced and T2-weighted MR imaging--initial results. AB - PURPOSE: To prospectively compare the sensitivity and specificity of high-spatial resolution dynamic contrast material-enhanced magnetic resonance (MR) imaging with those of high-spatial-resolution T2-weighted MR imaging, performed with an endorectal coil (ERC), for assessment of extracapsular extension (ECE) and staging in patients with prostate cancer, with histopathologic findings as reference. MATERIALS AND METHODS: The study was approved by the institutional internal review board; a signed informed consent was obtained. MR imaging of the prostate at 1.5 T was performed with combined surface coils and ERCs in 32 patients (mean age, 65 years; range, 42-78 years) before radical prostatectomy. High-spatial-resolution T2-weighted fast spin-echo and high-spatial-resolution dynamic contrast-enhanced three-dimensional gradient-echo images were acquired with gadopentetate dimeglumine. Dynamic contrast-enhanced MR images were analyzed with a computer-generated color-coded scheme. Two experienced readers independently assessed ECE and tumor stage. MR imaging-based staging results were compared with histopathologic results. For the prediction of ECE, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Staging accuracy was determined with the area under the receiver operating characteristic curve (AUC) by using the Wilcoxon-Mann-Whitney index of diagnostic accuracy. RESULTS: The mean sensitivity, specificity, PPV, and NPV for assessment of ECE with the combined data sets for both readers were 86%, 95%, 90%, and 93%, respectively. The sensitivity of MR images for determination of ECE was significantly improved for both readers (>25%) with combined data sets compared with T2-weighted MR images alone. The combined data sets had a mean overall staging accuracy for both readers of 95%, as determined with AUC. Staging results for both readers were significantly improved (P<.05) with the combined data sets compared with T2-weighted MR images alone. CONCLUSION: The combination of high-spatial-resolution dynamic contrast-enhanced MR imaging and T2-weighted MR imaging yields improved assessment of ECE and better results for prostate cancer staging compared with either technique independently. PMID- 17717329 TI - Aortic regurgitation: assessment with 64-section CT. AB - PURPOSE: To prospectively evaluate diagnostic accuracy of 64-section computed tomography (CT) for evaluation of aortic regurgitation (AR), with transthoracic echocardiography (TTE) as reference. MATERIALS AND METHODS: The institutional review board approved this study; written informed consent was obtained. Thirty patients (23 men, seven women; mean age, 56.6 years) with AR underwent TTE and retrospective electrocardiographically gated 64-section CT. CT data sets were reconstructed in 5% steps from 40% to 90% of R-R interval for analysis. Maximum regurgitant orifice area (ROA) in diastole was planimetrically measured with CT, and measurements were compared with semiquantitative classification with TTE (Spearman rank order correlation coefficients). Receiver operating characteristic (ROC) curves were calculated for differentiation between degrees of AR with ROA measurements. Dimensions of the aortic root and left ventricular parameters were compared (Pearson correlation analysis). RESULTS: A significant correlation was observed between CT planimetric size of ROA (mean, 62 mm2+/-63 [standard deviation]; range, 6-224 mm2) and TTE classification of mild, moderate, and severe AR (r=0.84, P<.001). With ROC analysis, discrimination between degrees of AR with CT was highly accurate when cutoff ROAs (25 mm2 and 75 mm2) were used. A significant correlation was observed between methods in dimensions of aortic annulus (mean, 29.0 mm+/-4.6), sinus of Valsalva (mean, 38.3 mm+/-8.6), and ascending aorta (mean, 37.2 mm+/-8.0); mean values were 27.4 mm+/-4.9 (r=0.76, P<.001), 37.7 mm+/-8.6 (r=0.94, P<.001), and 38.2 mm+/-7.9 (r=0.96, P<.001), respectively. Mean end-systolic volume (67 mL+/-38), end-diastolic volume (149 mL+/-48), and ejection fraction (57%+/-13) at CT correlated well with mean results at TTE (65 mL+/-36 [r=0.96, P<.001], 140 mL+/-48 [r=0.91, P<.001], 56%+/ 13 [r=0.98, P<.001], respectively). CONCLUSION: Results of assessment of AR with 64-section CT are similar to those with TTE. PMID- 17717330 TI - Clinically unrecognized myocardial infarction detected at MR imaging may not be associated with atherosclerosis. AB - PURPOSE: To prospectively investigate whether there is support for the hypothesis that clinically unrecognized myocardial infarctions (UMIs) detected at magnetic resonance (MR) imaging have an atherosclerotic pathogenesis similar to that of recognized myocardial infarctions (RMIs). MATERIALS AND METHODS: After ethics committee approval and informed consent were obtained, gadolinium-enhanced whole body MR angiography and late-enhancement MR imaging were performed in 248 randomly chosen 70-year-old subjects (123 women, 125 men). Imaging included the aorta and the carotid, renal, and lower limb arteries to the ankle, but not the coronary arteries. Subjects with myocardial infarction (MI) scars at late enhancement MR imaging were classified as having RMI (n=11) (those with a diagnosis of MI at the hospital) or UMI (n=49) (those without a diagnosis of MI at the hospital). The presence of 50% or higher luminal narrowing in any vessel at whole-body MR angiography was considered to represent significant atherosclerosis. Intima-media thickness of the common carotid artery was measured with ultrasonography. C-reactive protein level was measured, and coronary heart disease risk was estimated. Observers were blinded to any previous results. The chi2 test, analysis of variance, and Bonferroni correction were used for statistical analyses. RESULTS: None of the measured parameters differed significantly between the group without MI scars and the UMI group, but parameters were significantly increased in the RMI group (P<.05) compared with those in the group without MI scars. Forty-two of 49 UMIs and nine of 11 RMIs were located within inferolateral segments of the left ventricle. CONCLUSION: MR imaging-detected UMIs might have a different pathogenesis from that of RMIs or may have the same pathogenesis but may manifest at an earlier stage. PMID- 17717331 TI - Assessment of aortoiliac and renal arteries: MR angiography with parallel acquisition versus conventional MR angiography and digital subtraction angiography. AB - PURPOSE: To prospectively compare the image quality, sensitivity, and specificity of three-dimensional gadolinium-enhanced magnetic resonance (MR) angiography accelerated by parallel acquisition (ie, fast MR angiography) with MR angiography not accelerated by parallel acquisition (ie, conventional MR angiography) for assessment of aortoiliac and renal arteries, with digital subtraction angiography (DSA) as the reference standard. MATERIALS AND METHODS: The study was approved by the institutional review board; informed consent was obtained from all patients. Forty consecutive patients (33 men, seven women; mean age, 63 years) suspected of having aortoiliac and renal arterial stenoses and thus examined with DSA underwent both fast (mean imaging time, 17 seconds) and conventional (mean imaging time, 29 seconds) MR angiography. The arterial tree was divided into segments for image analysis. Two readers independently evaluated all MR angiograms for image quality, presence of arterial stenosis, and renal arterial variants. Image quality, sensitivity, and specificity were analyzed on per patient and per-segment bases for multiple comparisons (with Bonferroni correction) and for dependencies between segments (with patient as the primary sample unit). Interobserver agreement was evaluated by using kappa statistics. RESULTS: Overall, the image quality with fast MR angiography was significantly better (P=.001) than that with conventional MR angiography. At per-segment analysis, the image quality of fast MR angiograms of the distal renal artery tended to be better than that of conventional MR angiograms of these vessels. Differences in sensitivity for the detection of arterial stenosis between the two MR angiography techniques were not significant for either reader. Interobserver agreement in the detection of variant renal artery anatomy was excellent with both conventional and fast MR angiography (kappa=1.00). CONCLUSION: Fast MR angiography and conventional MR angiography do not differ significantly in terms of arterial stenosis grading or renal arterial variant detection. PMID- 17717332 TI - Are the mentally retarded and learning disordered overrepresented among sex offenders and paraphilics? AB - A sample of 2,286 male sex offenders and paraphilics and 241 nonsex offenders was evaluated for the prevalence of mental retardation and learning disorders, using the full Wechsler IQ scales. The sex offenders were generally of average intelligence, and the mentally retarded were not overrepresented among them, but the learning disordered were. There were no differences among sex offenders and controls in overall IQ or in the percentage of mentally retarded or learning disordered cases, suggesting that the learning difficulties are not peculiar to sex offenders. There was a bias in referral source, with more mentally retarded, borderline-retarded, and/or learning-disordered cases being referred by the Children's Aid Society, prisons, and the Crown, suggesting that referral source may play a significant role in evaluating intelligence and mental retardation among sex offenders; but the overrepresentation of learning disorders among criminals appears to be a significant phenomenon, regardless of referral source. PMID- 17717333 TI - Variations in mental health problems, substance use, and delinquency between African American and Caucasian juvenile offenders: implications for reentry services. AB - The incarceration of young people is a growing national problem. Key correlates of incarceration among American youth include mental health problems, substance use, and delinquency. The present study uses a statewide sample of incarcerated youth to examine racial differences in African American and Caucasian juvenile offenders' outcomes related to mental health, substance use, and delinquency. The data indicate that relative to Caucasian offenders, African American offenders report lower levels of mental health problems and substance use but higher levels of delinquent behavior such as violence, weapon carrying, and gang fighting. The data further reveal that African American offenders are more likely than Caucasian offenders to be victims of violence and to experience traumatic events such as witnessing injury and death. Recognition of these patterns may help to improve postrelease services by tailoring or adapting preexisting programs to patterns of risk factors and their relative magnitudes of effect. PMID- 17717334 TI - Diagnosing atrial fibrillation in general practice. PMID- 17717335 TI - Management of urinary tract infection in children. PMID- 17717336 TI - Human papillomavirus vaccination programmes. PMID- 17717337 TI - NICE's cost effectiveness threshold. PMID- 17717338 TI - Improving the outcome of stroke. PMID- 17717339 TI - Prevention in elderly people: Later life's complexity needs a scalpel rather than an axe. PMID- 17717340 TI - Two week rule: Breast cancer growth rates favour abolition of rule. PMID- 17717341 TI - Two week rule: Breast cancer experience has wider implications. PMID- 17717342 TI - Cancer patient deaths: More information urgently needed. PMID- 17717343 TI - Gallstones: Article was disappointing. PMID- 17717344 TI - Hypothyroidism in pregnancy: Three unresolved issues. PMID- 17717345 TI - Australian drugs regulator cancels registration of COX 2 inhibitor. PMID- 17717346 TI - Cancer survival in UK is improving but could be better. PMID- 17717347 TI - South Africa's health minister rebuffs allegations of alcoholism. PMID- 17717348 TI - Charities say UK government must do more to help soldiers returning from battle. PMID- 17717349 TI - GMC opens consultation on level of proof needed to strike off doctors. PMID- 17717350 TI - Thousands of patients wait more than 26 weeks for tests, as 18 week diagnostic target looms. PMID- 17717351 TI - Israel tries to stop import of nicotine "sweet" from Sweden. PMID- 17717352 TI - Move to weaken picture warnings on tobacco packets in India causes outcry. PMID- 17717353 TI - US firm to advise Scottish health service on quality improvement. PMID- 17717356 TI - Report highlights abuse of older people's human rights in hospitals and homes. PMID- 17717364 TI - Hyperactivity in children: the Gillberg affair. PMID- 17717365 TI - The hitch hiker's guide to population growth and climate change. PMID- 17717366 TI - Challenges of implementing human papillomavirus (HPV) vaccination policy. PMID- 17717367 TI - Commentary: Health inequity could increase in poor countries if universal HPV vaccination is not adopted. PMID- 17717368 TI - Acute respiratory distress syndrome. PMID- 17717369 TI - Diagnosis and management of urinary tract infection in children: summary of NICE guidance. PMID- 17717370 TI - Milk alkali syndrome without the milk. PMID- 17717371 TI - Occupational dermatitis in a hairdresser. PMID- 17717377 TI - A simple and rapid method to assay triacylglycerol in cells and tissues. AB - We have developed a reliable, rapid, and economical assay for the quantification of triacylglycerol (TG) in cells and animal tissues. In a few hours, this assay quantifies microgram amounts of TG from tens or even hundreds of samples. The protocol includes an organic extraction to partition TG away from proteins and other hydrophilic molecules found in cells and tissues that may interfere with the colorimetric enzyme-linked TG detection method. In addition, this assay is economical, as no expensive reagents, supplies, or equipment are needed. Another benefit of this assay is that it does not require environmentally unfriendly halogenated solvents. PMID- 17717378 TI - Technology acceptance among physicians: a new take on TAM. AB - The proliferation of information technology has been a revolutionary force that has increased efficiency and effectiveness in many industries. However, health care organizations, particularly physician practices, are noticeably lagging in the adoption of such technologies. This article provides a systematic review of the literature on physician acceptance of information technology. An overview of the technology acceptance model (TAM) is discussed, and a modified version of this model is proposed. Finally, ideas for testing this new model in a physician setting are presented. By providing a better understanding of physician technology acceptance, this model will inform health care managers about barriers that make physicians hesitant to embrace new technologies designed to increase efficiency and improve quality in a health care setting. PMID- 17717379 TI - Problem-oriented reporting of CAHPS consumer evaluations of health care. AB - Consumer Assessment of Health Care Providers and Systems (CAHPS) is an organized effort to provide consumers with standardized, comprehensible, and usable data regarding consumers' experiences with health care. In its Medicare and other summary reports, CAHPS emphasizes the frequency of the most positive experiences. Cognitive models of survey response combined with attitude theory suggest that performance measurement might be further improved by the addition of problem oriented reporting, which highlights the frequency of negative experiences. We propose criteria and use them to assess whether problem-oriented reporting provides valid, precise, and complementary information. Analysis of the 2000 CAHPS Medicare Fee-For-Service and 2001 CAHPS Medicare Advantage survey data shows that problem-oriented reporting (1) is viable, interpretable, and unlikely to represent noise; (2) has statistical power sufficient to capture important differences of magnitudes commonly observed; and (3) provides information that complements standard reporting. PMID- 17717381 TI - Combining two structural techniques on the micrometer scale: micro-XAS and micro Raman spectroscopy. AB - X-ray absorption and Raman spectroscopies are complementary in the sense that both give very precise information about the local structure of a sample, both are not restricted to crystalline materials, and in both cases the volumes of the material probed are similar. The X-ray technique has the advantage of being element- and orbital-selective, and sensitive to orientational effects owing to polarization selection rules. In many cases, however, its analysis can present some ambiguity. Combining the two techniques on a micrometer scale could therefore be a very powerful method structurally. In this paper the experimental set-up developed at the LUCIA beamline and its application to a natural mineral are described. PMID- 17717380 TI - Three-dimensional chemical mapping by scanning transmission X-ray spectromicroscopy. AB - Three-dimensional (3-d) chemical mapping using angle-scan tomography in a scanning transmission X-ray microscope is demonstrated. Apparatus, experimental procedures and data processing are presented and the 3-d spatial resolution is evaluated. The technique is illustrated using mapping of a low-density acrylate polyelectrolyte in and outside of polystyrene microspheres dispersed in water in a 4 microm-diameter microcapillary. The 3-d chemical visualization provides information about the microstructure that had not previously been observed. PMID- 17717382 TI - XAS and XMCD under high magnetic field and low temperature on the energy dispersive beamline of the ESRF. AB - The present paper demonstrates the feasibility of X-ray absorption spectroscopy (XAS) and X-ray magnetic circular dichroism (XMCD) under high magnetic fields up to 26 T and low temperatures down to 5 K on the ID24 energy-dispersive XAS beamline of the ESRF. The pulsed magnetic field set-up, entirely developed at the ESRF, is described as well as the beamline set-up, the synchronization and the measurement procedure. It allows field strengths up to 30 T. Finally, as an example, we report a recent XMCD study at the Re L2 and L3 absorption edges of the double perovskite Sr2CrReO(6). PMID- 17717383 TI - Magnetic characterization for cryogenic permanent-magnet undulators: a first result. AB - The cryogenic permanent-magnet undulator (CPMU) is a novel insertion device recently proposed at SPring-8, in which permanent magnets (PMs) are cooled to cryogenic temperatures to improve the magnetic performances, such as remanence and coercivity. A new measurement system for carrying out high-precision magnetic field mapping using a Hall probe has been developed in order to characterize the magnetic field generated by PM arrays at cryogenic temperatures. In this system, alignment of the Hall probe was dynamically performed by means of detecting the variation in its transverse position using optical laser beams introduced into the vacuum chamber. Magnetic measurements of a CPMU prototype were made at different temperatures in order to investigate variations of the magnetic performances owing to temperature. The maximum remanence deduced from the average peak value of the field profile was found to be close to that obtained from a former measurement with a single piece of the same PM material. In addition, the error components in the field profile were found to be insensitive to temperature in terms of the electron trajectory and phase error. This result suggests that the field correction of CPMUs can be performed based on the field profile measured at room temperature, which considerably reduces the task and time necessary for construction of CPMUs. PMID- 17717384 TI - Probing atomic displacements with thermal differential EXAFS. AB - Differential extended X-ray absorption fine structure (DiffEXAFS) is a novel technique for the study of small atomic strains. Here the development of this technique to the measurement of thermally induced strain is presented. Thermal DiffEXAFS measurements have been performed on alpha-Fe and SrF(2), yielding alpha = (11.6 +/- 0.4) x 10(-6) K(-1) and (19 +/- 2) x 10(-6) K(-1), respectively. These are in good agreement with accepted values, proving the viability of the technique. Analysis has revealed sensitivity to mean atomic displacements of 0.3 fm. PMID- 17717385 TI - A new FEFF-based wavelet for EXAFS data analysis. AB - A new mother wavelet function for extended X-ray absorption fine-structure (EXAFS) data analysis has been designed, combining a model EXAFS function derived from the ab initio EXAFS code FEFF8.20 and the complex Morlet wavelet. This new FEFF-Morlet mother wavelet routine allows the generation of wavelets well adapted to specific EXAFS problems. A substantial gain in resolution of the wavelet ridges in k and r space is achieved. The method is applied to a structural problem of Zn-Al double-layer hydroxides, demonstrating unequivocally the homogeneity of the metal cation distribution in the hydroxide layers. PMID- 17717386 TI - A novel facility using a Laue focusing monochromator for high-pressure diffraction at the SRS, Daresbury, UK. AB - A novel Laue focusing monochromator has been developed to provide intense X radiation for high-pressure diffraction experiments. A beamline using this monochromator has been successfully developed on station 9.5 at the SRS, Daresbury Laboratory. Contributions to resolution from monochromator bandpass and divergence due to focusing have been quantified and are used to assess experimental diffraction data from diamond-anvil cells recorded using image plates with X-rays at approximately 30 keV. This optical and beamline design could be readily adapted to use X-rays from a bending magnet on a third generation synchrotron source. PMID- 17717387 TI - Ray-trace calculations for in situ X-ray beam imaging. AB - A two-dimensional beam-position and profile monitor for synchrotron X-ray beamlines was recently presented that was based on the principle of collection of scattered radiation from a thin polyimide foil. This paper presents a simple ray trace model of the device, which can be used as a tool to calculate its response to changes in various device geometrical properties for a given beam size. The tool provides a quick way of predicting positional sensitivity, beam profile shape and intensity distribution. The theoretically obtained beam images are compared with data obtained from experiments carried out at the European Synchrotron Radiation Facility. PMID- 17717388 TI - In situ synchrotron far-infrared spectromicroscopy of a copper electrode at grazing incidence angle. AB - Synchrotron far-infrared spectroscopy in situ was successfully carried out on a copper microelectrode using a grazing-angle objective attached to a Bruker IRscope II microscope. The thin-layer spectroelectrochemical cell was constructed out of Teflon and fitted with a 20 microm-thick Mylar window; the copper electrode was 500 microm in diameter. Measurements were carried out in 0.1 M NaOH solution as a function of applied potential between -1.4 and 0 V versus a Hg/Hg2SO(4) reference electrode. Results demonstrate that with the present technique it is possible to obtain in situ spectra with excellent signal-to-noise ratio for surface oxide films formed electrochemically with less than 1 nL of active solution volume. The surface film on copper at 0 V consisted mainly of CuO with possibly some Cu(OH)2 also present. This interpretation is consistent with previous works and thermodynamic calculations. PMID- 17717406 TI - [Faculty development on prosthodontic education--on the basis of the first international clinical prosthodontics educators workshop]. AB - The purpose of this paper was to introduce The First International Clinical Prosthodontics Educators Workshop. That workshop aimed at reconciling best evidence analyses of clinical information on the efficacy and effectiveness of prosthodontic interventions with the management of selected and assigned clinical scenarios. The International Journal of Prosthodontics (IJP) and the Institute for Advanced Dental Studies in Karlsruhe Germany were co-sponsoring this workshop on October 30-November 1, 2006, in Karlsruhe. The 15 selected educators conducted a two and a half-day-day program for 36 participants selected from the international prosthodontic teaching community (22 countries). The form of case histories selected and organized as teaching packages (2 scenarios, reading lists and pictures) for the participants, was sent for pre-workshop distribution by e mail. Morning presentations comprised faculty reviews of background material specific to diverse aspects of the clinical case histories. At afternoon sessions, participants broke out into small tutor-led groups to explore and debated the various treatment options for the case histories in the context of the mornings' reviews. The Japan Prosthodontic Society should hold that kind of workshop in stead of classical lectures for faculty development. PMID- 17717407 TI - [Relationship between condylar displacement during clenching and condylar guide inclination]. AB - PURPOSE: Many studies have reported the relationship between facial morphology and stomatognathic functions. The steepness of the articular eminence is an important morphological factor to determine the mandibular movement or mandibular positioning. The present study analyzed the relationship between the condylar displacement during clenching and the condylar guide inclination related to simulated loss of posterior occlusal support. METHODS: Nineteen clinical residents (4 females and 15 males, 24-31 years old) with healthy natural dentitions were recruited as subjects. To change the posterior occlusal support, occlusal splints fitted to maxillary dental arches were cut in sequence from the posterior toward the anterior side. The condylar displacements during maximum voluntary clenching under every occlusal condition were measured using a mandibular movement analyzing system with six-degrees of freedom. The sagittal condylar guide inclination was also measured using the same apparatus. RESULTS: 1. A greater loss of posterior occlusal support was associated with increased displacement distance of both condyles, however these values varied with the subject. 2. A significant positive correlation was observed between the displacement distance without splint and the relative displacement distance with splint (difference between before and after loss of occlusal supports). 3. A significant negative correlation was observed between the displacement distance without splint and the sagittal condylar guide inclination, and was also observed between the relative displacement distance with splint (above-mentioned) and the sagittal condylar guide inclination. CONCLUSION: These results suggest that the sagittal condylar guide inclination is an important factor in condylar displacement during clenching. PMID- 17717408 TI - [Thermal expansion of layering porcelains for the tetragonal stabilized zirconia]. AB - PURPOSE: The purpose of this study was to investigate the coefficients of thermal expansion and shrinkage of an all-ceramic system (cercon) smart ceramics, DeguDent) utilizing tetragonal stabilized zirconia. METHODS: The coefficients of thermal expansion and shrinkage of the core material and the layering porcelains (dentin and enamel) used in this study were measured according to the ISO 9693 standard. Five specimens for the core material and ten specimens for each layering porcelain were tested. The core specimens were milled, sintered, ground and polished. Five of the specimens for each layering porcelain were fired two times, and the remaining five specimens were fired four times. The fired layering porcelain specimens were ground and polished. The coefficients of thermal expansion and shrinkage were evaluated using a push-rod dilatometer at a heating rate of 5 degrees C /min over temperature ranges of 25-700 degrees C for the core, and 25-550 degrees C for the layering porcelain. For each specimen, the coefficients of thermal expansion was determined to be between 25 and 500 degrees C from the plotted curve of expansion versus temperature. RESULTS: For the core material, the coefficients of thermal expansion and shrinkage showed almost the same value (10.8 x 10(-6)/ degrees C). For the layering porcelains, the coefficients of thermal expansion and shrinkage ranged from 9.3-11.1 x 10(-6)/ degrees C. The difference of the coefficients of thermal expansion and shrinkage between the core materials and the layering porcelains was -0.3-1.5 x 10(-6)/ degrees C. The specimens fired two times and the specimens fired four times exhibited almost the same value for each layering porcelain. CONCLUSION: The core material and layering porcelains have a suitable relationship. PMID- 17717409 TI - [Effect of occlusal form in buccal cusps of molars on masticatory function and intraoral food flow]. AB - PURPOSE: The degree of crushing and intraoral food flow was evaluated using peanuts by the occlusal forms of a removable bridge as indices to clarify the occlusal formative effect of maxillary molars on masticatory function. METHODS: The subject was a 29-year-old male without any gnathostomatic disorders and his removable bridge ([7] 6 [5]) was so made in interocclusal distance as to be 0.5, 1.0 or 1.5 mm from 0 mm standard having occlusal contact to antagonist. Then the subject was asked to chew 3 g of peanuts in a series of unilateral chewing schemes consisting of 5, 10, and 20 masticatory strokes each. The pool rate in the buccal oral vestibule and lingual proper oral cavity as an index of food flow was calculated as the weight of peanut particles accumulated in each side as a percentage of the total volume of recovered peanut particles. Also, the degree of crushing was calculated as the weight of peanut particles that passed through 10 mesh sieves as a percentage of the total weight in each side. RESULTS: As the interocclusal distance to the mandibular cusp increased with abrasion on the inside at maxillary buccal cusps, the pool rate of the buccal oral vestibule was significantly increased and correspondingly that of the lingual proper oral cavity was decreased. The degree of crushing indicated non-significances statistically among 0, 0.5, and 1.0 mm and significantly decreased in 1.5 mm as compared with 0 mm. CONCLUSION: As the interocclusal distance to mandibular cusps from the maxillary inside of buccal cusps was increased, the pool rate of the crushed peanuts in the buccal side increased and the pool rate of crushed peanuts in the lingual side decreased, and the particles showed a comparatively low degree of crushing. It is clear that maxillary buccal occlusion has an effect on the crushing function and food flow. PMID- 17717410 TI - [Comparative analysis of learning effect for students who experienced both lecture-based learning and problem-based learning in a complete denture course]. AB - PURPOSE: The purpose of this study was to analyze the difference in educational effect on students who experienced both lecture-based learning (LBL) and problem based learning (PBL) in a complete denture course. The analysis focused on differences between the two methods concerning self study, ability to understand clinical inference, and appraisal of class contents and tutors. METHODS: In the complete denture preclinical course, the class of 2003 received LBL in 3rd grade and PBL in 4th grade. PBL was planned to present five cases in five consecutive classes. Group discussion was carried out for each case, and a summary was required to be produced two times as a group, two times as an individual report and one time by group presentation. A questionnaire regarding the educational effect of LBL and PBL and assessment of tutors was administered. Factor analysis was carried out to classify the questionnaire items and each item was analyzed between LBL and PBL (Paired-t test). RESULTS: Factor analysis revealed that the questionnaire items could be classified into four components. Comparing lecture type and PBL: "study attitude" (4 out of 7 items), "clinical inference ability" (all items), "class contents" (5 out of 7 items) and "tutor appraisal" (2 out of 5 items) showed significant assessment with PBL. Eighteen of 27 items (66.6%) indicated the significant usefulness of PBL. CONCLUSION: PBL improves the educational effect of self study and clinical inference ability, in comparison with LBL. However, since students are passive about taking the same system class repeatedly, a strategy to improve their attitude needs to be considered. PMID- 17717411 TI - [Influence of intensity of occlusal contact in implant-retained single restoration on stress distributions of crown surface and supporting bone]. AB - PURPOSE: This study investigated the influence of intensity of occlusal contact, or occlusal height of an implant-retained single restoration on the stress in the crown surface and supporting bone. METHODS: A two-dimensional finite element model of the maxillary and mandibular first molars with supporting periodontal structures was created (Model M-M). One of the molars was replaced by a restoration retained by a thread-type implant to produce Model I-M (implant in maxilla) and Model M-I (implant in mandible). The models were isotropic and linearly elastic, except for the periodontal ligament with a non-linear material property to simulate the tooth movements. The tooth-to-tooth contact under the bite force was simulated by the vertical displacement of the mandible up to 0.24 mm from the initial occlusal contact. Non-linear contact analysis was conducted to calculate the stress in both the restoration and the supporting tissues. RESULTS: To obtain a restoration that shows the same stress in the occlusal surface as that in the natural molars under the maximum bite force, the occlusal heights in Models I-M and M-I were to be reduced by 0.10 mm and 0.11 mm, respectively. The restorations were not expected to occlude with their natural molar antagonists under bite force lower than 13.0% and 15.8% of the maximum force, respectively. CONCLUSION: Reduction in the intensity of the occlusal contact, or decreased occlusal height of an implant-retained single restoration, allows the establishment of an equivalent occlusal stress with the natural molars under the maximum bite force. This adjustment, either during fabrication or try in procedure, can suppress excessive stress that may be created in the tissues. With this procedure, however, the restoration does not contact the antagonistic tooth under a relatively low bite force. PMID- 17717413 TI - Cortical brain metabolism as measured by proton spectroscopy is related to memory performance in patients with amnestic mild cognitive impairment and Alzheimer's disease. AB - AIMS: To investigate the relationship between verbal memory performance and brain metabolism as determined by proton spectroscopy ((1)H-MRS) in selected cortical brain regions. To characterize metabolite abnormalities across the continuum of degenerative disease from mild impairment to dementia. METHODS: 27 controls, 27 amnestic mild cognitive impairment (aMCI) patients and 35 Alzheimer's disease (AD) patients. Verbal memory was assessed with the Text Memory Test, the Wordlist Learning Test (WL-Learning Test), and with a memory screening test, the Memory Alteration Test (M@T). Single-voxel (1)H-MRS was obtained in the posterior cingulate (P-CING), left temporal pole (L-TPOLE) and left posterior temporoparietal region (L-TPAR). RESULTS: WL-Learning Test scores were inversely associated with myoinositol/creatine ratios (mI/Cr) in the L-TPAR (r = -0.404, p < 0.002). Negative associations were also observed between M@T global scores and mI/Cr in the P-CING (r = -0.42; p < 0.001), L-TPOLE (r = -0.34; p < 0.005) and L TPAR (r = -0.46; p < 0.001). A positive association was found between M@T scores and N-acetylaspartate concentrations in the P-CING (r = 0.33; p < 0.003). CONCLUSION: Verbal learning performance is related to metabolic changes in cortical brain regions known to be involved in the neurodegenerative process of aMCI and AD. PMID- 17717414 TI - The spectrum of dementia: frequency, causes and clinical profile. A national referral hospital-based study in Oman. AB - BACKGROUND AND OBJECTIVE: There is a paucity of epidemiological data on dementia in the Arabian Peninsular region, particularly Oman. To determine the spectrum, clinical profile, and the behavioral manifestations of dementia in Omani patients evaluated at a tertiary referral hospital. METHODS: We retrospectively reviewed the demographic and clinical spectrum of 116 patients with probable dementia diagnosed in this center. The diagnosis of dementia was made according to DSM-IV criteria, and staged according to the Clinical Dementia Rating scale. Exclusion criteria included psychiatric disorders, cranial trauma, cerebral tumors, and mild cognitive impairment. The vascular risk patterns and behavioral data were analyzed. RESULTS: Alzheimer's disease was observed to be the commonest dementia subtype seen in 61 patients (52.6%), while 24.1% had vascular dementia and 9.5% constituted frontotemporal lobar degeneration. Early onset dementia was seen in 45% and potentially reversible dementia constituted 8.6%. Behavioral and psychopathological disturbances in dementia appear to be universal with certain differentiating features between the three major subtypes of dementia. CONCLUSIONS: This is the first published report of dementia from Oman. Dementia is an important health problem not only of the elderly but also of the young population in Oman. PMID- 17717412 TI - TRPV1-mediated diuresis and natriuresis induced by hypertonic saline perfusion of the renal pelvis. AB - BACKGROUND: The transient receptor potential vanilloid type 1 (TRPV1) channel is known to be activated by multiple stimuli, albeit its role in mediating renal function is largely unknown. This study was designed to test the hypothesis that TRPV1 mediates diuresis and natriuresis induced by hypertonic saline perfusion into the pelvis. METHODS: NaCl or KCl was perfused into the left renal pelvis of rats at a rate without changing renal pelvic pressure. Afferent renal nerve activity (ARNA), urine flow rate (V) and urinary sodium excretion (UNaV) in the presence or absence of selective antagonists of TRPV1, capsazepine (CAPZ), or neurokinin-1 (NK1) receptors, RP67580, were examined. RESULTS: Unilateral renal pelvis perfusion of NaCl at 600 mM, but not 150 or 300 mM, increased ipsilateral ARNA and contralateral V and UNaV, which were blocked by ipsilateral administration of CAPZ or RP67580. In contrast, KCl perfused at 150 or 300 mM, but not 600 mM, increased ipsilateral ARNA and contralateral V and UNaV, which were insensitive to CAPZ. CONCLUSION: Unilateral hypertonic saline perfusion causes contralateral diuresis and natriuresis via TRPV1 or NK1 activation, indicating that these receptors may play a critical role in sensing microenvironmental changes in the renal pelvis to modulate renal function in health and disease. PMID- 17717415 TI - A normative study of the Revised Hasegawa Dementia Scale: comparison of demographic influences between the Revised Hasegawa Dementia Scale and the Mini Mental Status Examination. AB - BACKGROUND/AIMS: We investigated the demographic influence on the performance of the Revised Hasegawa Dementia Scale (HDS-R) and provided normative data of the HDS-R in the elderly. METHODS: The HDS-R was administered to 803 community dwelling cognitively normal elderly subjects aged 55 years or over. Cognitive disorders and psychiatric disorders were strictly excluded using the CERAD-K assessment packet and the Mini-International Neuropsychiatric Interview. The demographic influence on the performance of the HDS-R was examined using multiple linear regression analyses, and compared with that on the performance of the Mini Mental Status Examination (MMSE) using the Chow test and t statistics. Overlapping strata were used in developing age-, education- and gender-specific normative data of the HDS-R. RESULTS: Age, education, and gender influenced significantly the performance of the HDS-R, and explained 22.5% of the total score variance. Older age, lower education, and male gender were associated with lower performance of the HDS-R. However, the demographic influence on the HDS-R was much weaker than that on the MMSE (t = 5.578, d.f. = 800, p < 0.001). The normative data of the HDS-R stratified by age (60-69, 70-79, > or =80), education (0-6, 7-12, > or =13), and gender were presented. CONCLUSIONS: The HDS-R was more robust to demographic influences than the MMSE, and normative data may contribute to improving further its diagnostic accuracy for dementia. PMID- 17717416 TI - An estimate of the prevalence of dementia among community-dwelling elderly in Israel. AB - The study goal was to identify the prevalence of dementia among elderly people aged 65 and over living in the community in Israel. The target population included 47,834 community-dwelling elderly aged 65 and over in Jerusalem. Of this population, 1,624 elderly were randomly sampled according to ten strata of sex and age groups. The study included initial screening for 'suspected' dementia cases followed by in-depth clinical evaluation to determine whether an individual indeed suffered from dementia. One fifth (19.2%) of the elderly aged 65 and over, living in the community in Jerusalem, were found to have dementia at varying levels of severity. When the specific rates of elderly with dementia in the community in Jerusalem by gender and age groups were applied to data on the total elderly population in the community in Israel at the end of 2002, the prevalence of dementia was an estimated 16.7%. The percentage of elderly with dementia in Israel is in the upper range of rates quoted in other studies. The health and social service systems in Israel will have to make provisions to care for a much larger number of dementia sufferers than has been previously estimated. PMID- 17717417 TI - Symptoms of preclinical dementia in general practice up to five years before dementia diagnosis. AB - OBJECTIVES: To investigate which symptoms are indicative of preclinical dementia in general practice and whether subjects with preclinical dementia have an increased contact frequency with their general practitioner (GP). METHODS: Individuals with preclinical dementia (n = 75) and non-demented controls (n = 125) were selected from the Dutch GP registration network (RNH). Number of visits and odds ratio for the risk of subsequent dementia of various symptoms were analysed. Analyses were done separately for each 12-month period, in the 5 years prior to the diagnosis of dementia. RESULTS: In the 5 years prior to diagnosis, subjects with preclinical dementia visited their GP more often than controls. Gait disturbances were the earliest predictor. Cognitive complaints were predictive for dementia in the 3 years before diagnosis. All other symptoms, except vascular symptoms, were predictive in the year prior to diagnosis. Sensitivity was highest for cognitive symptoms (0.58) and gait disturbances (0.47) in the year before diagnosis. CONCLUSION: Preclinical dementia is associated with an increased contact frequency between patient and GP at least 5 years prior to the diagnosis of dementia. Gait disturbances and cognitive complaints are the earliest symptoms of preclinical dementia. PMID- 17717419 TI - Single-center experience on liver transplantation for hepatocellular carcinoma arising in alcoholic cirrhosis: results and ethical issues. AB - BACKGROUND: Liver transplantation is currently recognized as the optimal treatment for both early hepatocellular carcinoma in the setting of cirrhosis (HCC) as well as for alcoholic liver disease (ALD). The purpose of this study was to evaluate the outcome of patients with HCC and ALD in the absence of viral hepatitic infections. METHODS: Twelve recipients were transplanted with a diagnosis of HCC and ALD in the absence of viral hepatitis during a 6-year period. Nine received deceased donor livers, and 3 live donor grafts. Our results were compared to those obtained by a search of the world literature. RESULTS: The postoperative course was uneventful in all but one patient. All recipients experienced a good quality of life postoperatively. Three-year overall and recurrence-free survival rates were 82 and 73%, respectively. Nine patients are currently alive, after a median follow-up of 29 months. CONCLUSION: This is the first study to evaluate liver transplantation for HCC in ALD. Although outcomes are excellent, the evaluation of patients with ALD and HCC constitutes a challenging topic in transplantation surgery, especially when live liver donation is considered. An interdisciplinary structured approach is recommended, with special emphasis on ethical considerations. PMID- 17717418 TI - Isoflurane inhalation after induction of endotoxemia in rats attenuates the systemic cytokine response. AB - BACKGROUND/AIMS: Volatile anesthetics are frequently utilized in clinical routine. Isoflurane has been shown to attenuate the response to inflammatory stimuli such as lipopolysaccharide (LPS) when administered before induction of endotoxemia. We aimed therefore to evaluate the effect of isoflurane after administration of LPS on the cytokine release as a therapeutic option. MATERIALS AND METHODS: 21 male Sprague-Dawley rats were randomly assigned to the following groups: animals that received LPS (5 mg/kg, i.v.) without further intervention (LPS group), animals that received continuous inhalation of 1 minimum alveolar concentration (MAC) isoflurane 15 min after administration of LPS (Iso group) and no specific intervention (sham group). Four hours following LPS injection, plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), IL-6 and IL-10 were determined. Furthermore, nitrite release from cultured alveolar macrophages was analyzed. RESULTS: Inhalation of isoflurane after induction of endotoxemia attenuated the release of TNF-alpha (-52%, p < 0.05) and IL-1 beta (-39%, p < 0.05) as compared to the LPS group, while IL-6 and IL-10 levels were not significantly altered. Nitrite release was significantly increased in the Iso group as compared to the LPS group (+115%, p < 0.05). CONCLUSION: Inhalation of 1 MAC isoflurane after induction of endotoxemia in rats attenuates the systemic release of proinflammatory cytokines and concurrently enhances the production of nitrite in cultured alveolar macrophages. PMID- 17717420 TI - An incidentally discovered small and asymptomatic para-aortic paraganglioma. AB - Preoperative diagnosis of asymptomatic paraganglioma is difficult due to the lack of specific symptoms. In this report, we present a rare case of a small and asymptomatic para-aortic paraganglioma. A 34-year-old woman who complained of back pain was admitted for further examination. No abnormal findings were observed on physical or laboratory examinations. An abdominal CT scan and an abdominal MRI incidentally noted a mass about 3 cm in diameter adjacent to the right edge of the inferior vena cava. The following aortic angiography showed the tumor with a feeding artery diverting directly from the aorta. The tumor was completely resected by laparotomy. The resected tumor, 3 x 3 x 3 cm in size, was soft, dark-reddish and encapsulated. Immunohistochemical examinations showed that it was positive for neuron-specific enolase, chromogranin A and adrenocorticotropin. Under these findings, the diagnosis of para-aortic paraganglioma was determined. Seven years after the operation, she remains asymptomatic and free of disease. PMID- 17717421 TI - Analysis of metallothionein, RCAS1 immunoreactivity regarding immune cell concentration in the endometrium and tubal mucosa in ectopic pregnancy during the course of tubal rupture. AB - INTRODUCTION: Tubal rupture seems to be linked to a disturbance in maternal immune response and trophoblast cell invasion. The immunomodulating activity of endometrial cells is necessary for the coexistence of activated immune cells and endometrial cells. RCAS1 and metallothionein (MT) participate in this process. MATERIAL AND METHODS: Tissue samples derived from fallopian tubes and endometrium were collected during one surgical procedure and divided into three groups: unruptured ectopic pregnancy (EP) without bleeding, unruptured EP with hemorrhage into the peritoneal cavity, and ruptured tubal pregnancy. Immunoreactivity of MT, RCAS1, CD56, CD3, CD69 and CD25 were assessed by immunohistochemical methods. RESULTS: The number of CD3+ and CD56+ cells as well as CD69 antigen immunoreactivity in ruptured tubal mucosa of EP were statistically significantly higher than those measured for unruptured EP without bleeding, while at the same time the number of CD56+ cells in endometrium was statistically significantly lower. The growth of immune cell numbers in tubal mucosa during tubal rupture was not associated with an adequate MT and RCAS1 level. CONCLUSION: Tubal perforation seems to be linked to a concentration of immune cells and a growth of their activity without an adequate increase of the level of proteins compensating for immune cell response. PMID- 17717422 TI - Stapes surgery: a 32-year follow-up. AB - Despite a widespread use of stapes surgery, little is known about the long-term durability of hearing results. The present study provides data over a long time frame (32 years) on hearing changes following surgical treatment. During a 10 year period (1965-1975) stapes surgery was performed in 322 consecutive patients in Tampere University Hospital, Finland. Postoperative evaluation was performed in the same hospital during the years 2001 and 2002 in 58 patients (41 females, 17 males). Of these 58 patients, 68 ears were operated decades ago (stapedoplasty in 67 ears and stapes mobilization in one ear). The mean follow-up time at the latest visit was 32.9 years. At the long-term follow-up, we found that the operative result was very well maintained: 37% of the patients had air-bone gap closure less than 10 dB. Most of the patients (83%) reached postoperative (6-12 months) air-bone gap closure less than 20 dB. The result was maintained by 75% of the patients. Stapes surgery gives a rise to a better social life for the hearing impaired patient and delays the need for hearing aid in most patients. PMID- 17717423 TI - Percutaneous penetration enhancers: an overview. AB - Transdermal drug delivery is the controlled release of drugs through the skin to obtain therapeutic levels systematically. Several technological advances have been made in the recent decades to enhance percutaneous drug penetration. This overview focuses on the physical, biochemical, and chemical means of penetration enhancement, as well as the classification and mechanisms of chemical penetration enhancers, their application in transdermal drug delivery, and trends and development in penetration enhancement. PMID- 17717424 TI - Dietary lutein/zeaxanthin partially reduces photoaging and photocarcinogenesis in chronically UVB-irradiated Skh-1 hairless mice. AB - Lutein and zeaxanthin are xanthophyll carotenoids with potent antioxidant properties protecting the skin from acute photodamage. This study extended the investigation to chronic photodamage and photocarcinogenesis. Mice received either a lutein/zeaxanthin-supplemented diet or a standard nonsupplemented diet. Dorsal skin of female Skh-1 hairless mice was exposed to UVB radiation with a cumulative dose of 16,000 mJ/cm(2) for photoaging and 30,200 mJ/cm(2) for photocarcinogenesis. Clinical evaluations were performed weekly, and the animals were sacrificed 24 h after the last UVB exposure. For photoaging experiments, skin fold thickness, suprapapillary plate thickness, mast cell counts and dermal desmosine content were evaluated. For photocarcinogenesis, samples of tumors larger than 2 mm were analyzed for histological characterization, hyperproliferation index, tumor multiplicity, total tumor volume and tumor-free survival time. Results of the photoaging experiment revealed that skin fold thickness and number of infiltrating mast cells following UVB irradiation were significantly less in lutein/zeaxanthin-treated mice when compared to irradiated animals fed the standard diet. The results of the photocarcinogenesis experiment were increased tumor-free survival time, reduced tumor multiplicity and total tumor volume in lutein/zeaxanthin-treated mice in comparison with control irradiated animals fed the standard diet. These data demonstrate that dietary lutein/zeaxanthin supplementation protects the skin against UVB-induced photoaging and photocarcinogenesis. PMID- 17717425 TI - Feasibility and clinical applicability of polihexanide for treatment of second degree burn wounds. AB - OBJECTIVES: Due to a partial rejection of mesh split-thickness skin grafts (mesh grafts) after application of povidone-iodine and silver nitrate and due to its better in vitro tolerance, polihexanide was investigated as an alternative and its applicability in the treatment of second-degree burn wounds. METHODS: In 4 patients with poorly healing decubitus ulcers the mesh grafts were each divided into three areas which were pre-treated with either undiluted povidone-iodine solution, 1% silver nitrate solution or 0.04% polihexanide solution. After 7 days of application the wound areas were compared clinically and histologically. Thereafter 14 patients (average extent of burns 28% TBSA) were treated in the same way. RESULTS: Clinically and histologically the mesh grafts treated with polihexanide showed by far the best re-epithelialization compared with the deep tissue necrosis and marked fibrin discharge observed for application of povidone iodine and silver nitrate. The second-degree burn wounds treated with polihexanide epithelialized without any further debridement after an average of 10 days with remarkable freedom from pain. Compared with silver nitrate treatment, no fibrin film was observed on the wound. CONCLUSION: Polihexanide proved clinically and histologically superior to povidone-iodine and silver nitrate. For the treatment of second-degree burns, which cannot primarily be covered by plastic surgery, polihexanide is suitable because in addition to its antiseptic efficacy it does not inhibit the re-epithelialization process. PMID- 17717426 TI - Cytokeratin markers come of age. AB - Cytokeratins have been extensively used as serum tumour markers for monitoring of disease progression in cancer patients. The source of cytokeratins in the circulation as well as the mechanisms of release from cells have long been unclear. Recent evidence suggests that cytokeratins present in the circulation of cancer patients are released from apoptotic or necrotic tumour cells. CK18 is cleaved by caspases during apoptosis and a monoclonal antibody (M30) specific to caspase-cleaved forms is available. The molecular form of CK18 released from cells (caspase-cleaved or not) can conveniently be determined by immunoassays (M30-Apoptosense and M65 ELISA assays; Peviva AB, Bromma, Sweden) to determine cell death mode--apoptosis or necrosis. Recent studies where these assays were used to evaluate the response to cytotoxic anticancer drugs using cancer patient serum have been encouraging. CK18 is attracting considerable interest as a response biomarker during clinical trials of anticancer drugs. Properties such as excellent antigen stability and the epithelial specificity of cytokeratins contribute to make this biomarker attractive. PMID- 17717428 TI - Does polysomy of chromosome 17 have a role in ERBB2 and topoisomerase IIalpha expression? Gene, mRNA and protein expression: a comprehensive analysis. AB - OBJECTIVES: ERBB2 is an oncogene with prognostic and predictive value. Topoisomerase IIalpha is an enzyme encoding close to the ERBB2 oncogene, that represents a molecular target for anthracyclines. An indirect mechanism of increasing ERBB2 and topoisomerase IIalpha gene copy number is chromosome 17 polysomy. The aim of the present study was to clarify the implication of polysomy 17 in ERBB2 and topoisomerase IIalpha expression. In addition, we assessed the relation of ERBB2 and topoisomerase IIalpha gene dosage to mRNA and protein levels. METHODS: We selected 83 cases diagnosed as invasive breast cancer. We analysed ERBB2 and topoisomerase IIalpha genes, mRNA and protein by fluorescence in situ hybridisation, real-time reverse-transcription polymerase chain reaction and immunohistochemistry. RESULTS: We observed a progressive increase in mRNA expression from 0+ to 3+ and also a significant difference in the ERBB2 RNA levels between normal and amplified cases. We found that polysomy of chromosome 17 does not affect the ERBB2 expression and that topoisomerase IIalpha mRNA expression is not related to gene status. CONCLUSIONS: Our results demonstrate that polysomy of chromosome 17 is not related to ERBB2 expression. Thereby, it is important to use centromeric probes to clearly discriminate between true ERBB2 gene amplification and polysomy of chromosome 17. PMID- 17717427 TI - Mismatch repair status is a predictive factor of tumour response to 5 fluorouracil and irinotecan chemotherapy in patients with advanced colorectal cancer. AB - BACKGROUND AND AIMS: To determine the association between DNA mismatch repair (MMR) protein expression and response to chemotherapy in patients with advanced colorectal cancer (CRC). METHODS: Using immunohistochemistry, tumour expression of 2 MMR genes, hMLH1 and hMSH2, was assessed in 86 patients with advanced CRC, who were treated with either irinotecan alone or in combination with 5 flurouracil/folinic acid. RESULTS: Weak/negative staining in the tumours was associated with the presence of metastases at diagnosis (p = 0.026) and with the time for metastases to appear (p = 0.0001). An objective response to treatment was observed in 32/56 (57%) patients who had tumours with negative/weak MMR protein expression (p = 0.001), compared to 17% of patients with tumours with moderate/strong expression. Those who had tumours with weak/absent expression of either hMLH1 or hMSH2 who received the combination therapy were more likely to show an objective response (p = 0.0001). CONCLUSION: Advanced CRC patients whose tumours have deficient MMR demonstrate a shorter time to metastasis than those with normal hMLH1/hMSH2 expression. Patients with MMR-deficient tumours are also more likely to benefit from combination chemotherapy (irinotecan plus 5 flurouracil/folinic acid). PMID- 17717429 TI - Dendritic cells reconstituted with a human heparanase gene induce potent cytotoxic T-cell responses against gastric tumor cells in vitro. AB - BACKGROUND AND AIMS: Dendritic cell-based tumor vaccination is a promising approach in the treatment of cancer. Strategies to modify dendritic cells (DCs) with tumor-associated antigens (TAAs) can elicit specific immune responses against tumors. Heparanase is overexpressed in gastric cancer, especially in invasive and metastatic cells, but is downregulated in differential normal tissue. Therefore, heparanase is a potential target in immunotherapy for patients with advanced gastric cancer who are not candidates for surgery. The present paper was designed to investigate the immune response of a heparanase gene modified DC-based vaccine against gastric cancer cell lines in vitro. METHODS: DCs from peripheral blood mononuclear cells of healthy HLA-A2-positive donors were transfected with recombinant adenovirus containing the full-length cDNA of heparanase (rAd-Hpa) to generate heparanase gene-modified DC vaccine. T lymphocytes from the same donors were repeatedly activated by genetically modified DC vaccine to generate heparanase-specific cytotoxicity T lymphocytes (CTLs). CTL-mediated cell lysis of gastric cancer cells lines (KATO-III and SGC 7901) was analyzed in vitro by a standard (51)Cr releasing assay. IFN-gamma secretion was measured by ELISA in heparanase-specific CTLs cocultured with those gastric cancer cell lines. RESULTS: Our results showed that the expression of heparanase in DCs transfected with rAd-Hpa was significantly increased. Furthermore, DCs transfected with rAd-Hpa could induce heparanase-specific CTLs against HLA-matched and heparanase-positive gastric cancer cells in vitro, while there were no killing effects on autologous lymphocytes. Meanwhile, these rAd-Hpa modified DCs could increase IFN-gamma secretion of effector cells when cocultured with KATO-III cells. CONCLUSIONS: These findings demonstrate for the first time that the transduction of DCs with rAd-Hpa can induce CTLs that specifically lyse heparanase-positive gastric cancer cells and increase IFN-gamma secretion in an MHC-restricted fashion. Heparanase gene-modified DC vaccine offers a great opportunity for immunotherapy in patients with advanced gastric cancer and possibly also with other malignancies. PMID- 17717430 TI - Ovarian spindle cell lesions: a review with emphasis on recent developments and differential diagnosis. AB - Ovarian lesions composed of spindle cells comprise a heterogeneous group; most are neoplastic but several non-neoplastic conditions are also composed of spindle cells. This review discusses the main differential diagnoses of an ovarian spindle cell lesion, especially concentrating on the recent literature. The majority of ovarian spindle cell lesions fall into the broad category of fibromatous neoplasms whereas others in the sex cord-stromal group may also be composed of spindle cells, including thecomas, granulosa, and Sertoli-Leydig cell tumors and rarer neoplasms, such as sclerosing stromal tumor and signet-ring stromal tumor. In the recent past there have been several major contributions on various aspects of ovarian spindle cell lesions, including cellular and mitotically active cellular fibromatous lesions, smooth muscle neoplasms, and metastatic gastrointestinal stromal tumors. Other mesenchymal or epithelial tumors and mixed epithelial and mesenchymal neoplasms may also enter into the differential diagnosis of an ovarian spindle cell lesion. Several non-neoplastic lesions may be composed of spindle cells, including massive edema, ovarian fibromatosis, stromal hyperplasia, and stromal hyperthecosis. Morphology remains the mainstay in diagnosis but immunohistochemistry may be invaluable in certain circumstances, one example being the identification of a metastatic gastrointestinal stromal tumor within the ovary. PMID- 17717431 TI - The importance of pathology informatics in translational research. AB - Pathology informatics involves management and analysis of large complex data sets derived from various tests performed in clinical and anatomic pathology laboratories, annotated biorepositories, image analysis, telepathology, and large scale experiments, including gene expression analysis, proteomics, and tissue array studies. It facilitates intelligent use of computing technologies to improve patient care and understand the natural history of disease. Herein, we describe the various bioinformatics tools used to support translational research at the University of Pittsburgh Medical Center. PMID- 17717432 TI - Diagnostic uses of Pax5 immunohistochemistry. AB - Pax5, or B-cell-specific activator protein, is a nuclear protein in the paired box containing (PAX) family of transcription factors involved in control of organ development and tissue differentiation. Pax5 is mostly expressed in B lymphocytes and B-cell lymphomas, although recent data have shown expression in the developing central nervous system, some neuroendocrine tumors, and occasional myeloid leukemias. Pax5 immunohistochemistry shows robust nuclear staining, and has become a valuable tool in the diagnosis and subclassification of lymphomas. Pax5 staining is positive in most Hodgkin and B-cell non-Hodgkin lymphomas, and also precursor B-cell lymphoblastic neoplasms. Plasma cell neoplasms, multiple myeloma, and plasmablastic lymphomas typically are negative. T-cell lymphomas are, to date, consistently negative. Recently, Pax5 expression has been described in the majority of small cell carcinomas and Merkel cell carcinomas. Rare cases of Pax5 expression in other carcinomas have been reported. With these exceptions, Pax5 immunohistochemistry is fairly specific for B-cell lineage and is a valuable addition to the armamentarium of markers available for lymphoma subtyping. PMID- 17717435 TI - The sonic hedgehog signaling network in development and neoplasia. AB - The sonic hedgehog (SHH) pathway was first defined genetically in fruit flies. Subsequently, the SHH network has been shown to be critical for normal mammalian development, by mediating interactions between stromal and epithelial cells. Recent evidence suggests that, deregulation of SHH signaling is important in the pathogenesis of cancer. Further, some observations suggest that a SHH paracrine mechanism mediating tumor-mesenchymal interactions may contribute to the metastatic capacity of cancer. Preclinical studies demonstrate that tumor cells in which SHH is deregulated are dependent on signaling through this pathway for the maintenance of proliferation and viability. SHH antagonists have been identified and show promise in inhibiting tumor growth in preclinical studies. The utility of these agents in the management of cancer patients awaits the outcome of ongoing and future clinical trials. PMID- 17717433 TI - Immunohistochemistry of INI1 expression: a new tool for old challenges in CNS and soft tissue pathology. AB - Immunohistochemical staining for INI1 (BAF47) expression has been recently described. Loss of expression of INI1 as detected by immunohistochemical staining correlates with deletion and mutations of the INI1 gene in patients with malignant rhabdoid tumors and central nervous system atypical teratoid/rhabdoid tumors and as such is a sensitive and specific marker for these tumors. Loss of INI1 expression may rarely be encountered in other tumor types. This article reviews the utility of immunohistochemical staining for INI1 expression. PMID- 17717436 TI - The androgen receptor in prostate cancer: therapy target in search of an integrated diagnostic test. AB - Despite the near ubiquitous use of therapies targeting the androgen receptor (AR) axis in prostate cancer, there remains, at this date, no integrated diagnostic test designed to select and individualize patients for hormonal-based treatments. From the article by Chmelar and coauthors, we may have a glimpse as to a way forward to the development of a test that can successfully guide the use of androgen ablation therapy. By turning our attention away from the AR gene and protein itself and focusing on coregulators of the AR pathway we may have a new opportunity to develop a single or group of slide-based tests designed to assess AR pathway status on the needle biopsy of a newly diagnosed prostate cancer patient and predict the clinical benefit of total androgen blockade treatment strategies. PMID- 17717437 TI - The phenotypic spectrum of basal-like breast cancers: a critical appraisal. AB - There are 2 well-recognized cell populations lining the mammary duct system: the epithelial cells lining the lumen and the myoepithelial cells surrounding them. The mammary stem cell, a putative third cell type, has not yet been well characterized. It is not established whether the putative stem cell expresses the full complement, a subset, or none of the markers of normal epithelial and/or myoepithelial cells. However, it is likely that they would have distinctive markers of their own; whether these are retained or lost in their neoplastic progeny is unknown. All 3 cell types may theoretically undergo malignant transformation. Until recently, however, nearly all attention has been focused on carcinomas of epithelial derivation/differentiation. The advent of oligonucleotide and cDNA microarrays has facilitated gene expression profiling of breast cancers, revealing molecular subclasses that may be prognostically relevant. One such subclass, the basal-like breast carcinomas, has been found in numerous independent datasets to be associated with a comparatively worse overall and disease-free survival. These cancers show expression of molecules characteristic of the normal myoepithelial cell, such as basal cytokeratins, and reduced expression of estrogen receptor-related and Erb-B2-related genes and proteins. The classifier genes that formed the basis for the delineation of basal like carcinomas were derived from datasets that were composed predominantly of ductal type cancers. Therefore, the clinical significance of a basal-like gene expression or immunohistochemical profile in the other breast cancer subtypes is presently unknown. Herein, we evaluate in detail the current state of knowledge on the pathologic features of breast carcinomas classified as basal-like by immunohistochemical and/or gene expression profiling criteria, with an emphasis on their full phenotypic spectrum and also previously underemphasized areas of heterogeneity and ambiguity where present. There seems to be a phenotypic and biologic spectrum of basal-like or myoepithelial-type carcinomas, just as there is a wide range among tumors of luminal epithelial derivation/differentiation. It is critical to promote lucid morphologic definitions of the molecular subtypes, if this information is intended for use in targeted therapies and patient management. PMID- 17717438 TI - The plight of children. PMID- 17717440 TI - Two thousand transhiatal esophagectomies: changing trends, lessons learned. AB - OBJECTIVE: "Rediscovered" in 1976, transhiatal esophagectomy (THE) has been applicable in most situations requiring esophageal resection and reconstruction. The objective of this study was to review the authors' 30-year experience with THE and changing trends in its use. METHODS: Using the authors' prospective Esophagectomy Database, this single institution experience with THE was analyzed retrospectively. RESULTS: Two thousand and seven THEs were performed-1063 (previously reported) between 1976 and 1998 (group I) and 944 from 1998 to 2006 (group II), 24% for benign disease, 76%, cancer. THE was possible in 98%. Stomach was the esophageal substitute in 97%. Comparing outcomes between group I and group II, statistically significant differences (P < 0.001) were observed in hospital mortality (4% vs. 1%); adenocarcinoma histology (69% vs. 86%); use of neoadjuvant chemoradiation (28% vs. 52%); mean blood loss (677 vs. 368 mL); anastomotic leak (14% vs. 9%); and discharge within 10 days (52% vs. 78%). Major complications remain infrequent: wound infection/dehiscence, 3%, atelectasis/pneumonia, 2%, intrathoracic hemorrhage, recurrent laryngeal nerve paralysis, chylothorax, and tracheal laceration, <1% each. Late functional results have been good or excellent in 73%. Aggressive preoperative conditioning, avoiding the ICU, improved pain management, and early ambulation reduce length of stay, with 50% in group II discharged within 1 week. CONCLUSION: THE refinements have reduced the historic morbidity and mortality of esophageal resection. This largest reported THE experience reinforces the value of consistent technique and a clinical pathway in managing these high acuity esophageal patients. PMID- 17717439 TI - The effect of oxandrolone on the endocrinologic, inflammatory, and hypermetabolic responses during the acute phase postburn. AB - OBJECTIVE AND SUMMARY BACKGROUND DATA: Postburn long-term oxandrolone treatment improves hypermetabolism and body composition. The effects of oxandrolone on clinical outcome, body composition, endocrine system, and inflammation during the acute phase postburn in a large prospective randomized single-center trial have not been studied. METHODS: Burned children (n = 235) with >40% total body surface area burn were randomized (block randomization 4:1) to receive standard burn care (control, n = 190) or standard burn care plus oxandrolone for at least 7 days (oxandrolone 0.1 mg/kg body weight q.12 hours p.o, n = 45). Clinical parameters, body composition, serum hormones, and cytokine expression profiles were measured throughout acute hospitalization. Statistical analysis was performed by Student t test, or ANOVA followed by Bonferroni correction with significance accepted at P < 0.05. RESULTS: Demographics and clinical data were similar in both groups. Length of intensive care unit stay was significantly decreased in oxandrolone treated patients (0.48 +/- 0.02 days/% burn) compared with controls (0.56 +/- 0.02 days/% burn), (P < 0.05). Control patients lost 8 +/- 1% of their lean body mass (LBM), whereas oxandrolone-treated patients had preserved LBM (+9 +/- 4%), P < 0.05. Oxandrolone significantly increased serum prealbumin, total protein, testosterone, and AST/ALT, whereas it significantly decreased alpha2 macroglobulin and complement C3, P < 0.05. Oxandrolone did not adversely affect the endocrine and inflammatory response as we found no significant differences in the hormone panels and cytokine expression profiles. CONCLUSIONS: In this large prospective, double-blinded, randomized single-center study, oxandrolone shortened length of acute hospital stay, maintained LBM, improved body composition and hepatic protein synthesis while having no adverse effects on the endocrine axis postburn, but was associated with an increase in AST and ALT. PMID- 17717441 TI - Extent of surgery affects survival for papillary thyroid cancer. AB - BACKGROUND: The extent of surgery for papillary thyroid cancers (PTC) remains controversial. Consensus guidelines have recommended total thyroidectomy for PTC > or =1 cm; however, no study has supported this recommendation based on a survival advantage. The objective of this study was to examine whether the extent of surgery affects outcomes for PTC and to determine whether a size threshold could be identified above which total thyroidectomy is associated with improved outcomes. METHODS: From the National Cancer Data Base (1985-1998), 52,173 patients underwent surgery for PTC. Survival was estimated by the Kaplan-Meier method and compared using log-rank tests. Cox Proportional Hazards modeling stratified by tumor size was used to assess the impact of surgical extent on outcomes and to identify a tumor size threshold above which total thyroidectomy is associated with an improvement in recurrence and long-term survival rates. RESULTS: Of the 52,173 patients, 43,227 (82.9%) underwent total thyroidectomy, and 8946 (17.1%) underwent lobectomy. For PTC <1 cm extent of surgery did not impact recurrence or survival (P = 0.24, P = 0.83). For tumors > or =1 cm, lobectomy resulted in higher risk of recurrence and death (P = 0.04, P = 0.009). To minimize the influence of larger tumors, 1 to 2 cm lesions were examined separately: lobectomy again resulted in a higher risk of recurrence and death (P = 0.04, P = 0.04). CONCLUSIONS: The results of this study demonstrate that total thyroidectomy results in lower recurrence rates and improved survival for PTC > or =1.0 cm compared with lobectomy. This is the first study to demonstrate that total thyroidectomy for PTC > or =1.0 cm improves outcomes. PMID- 17717442 TI - Evaluation of 300 minimally invasive liver resections at a single institution: less is more. AB - OBJECTIVE: We present the largest, most comprehensive, single center experience to date of minimally invasive liver resection (MILR). SUMMARY BACKGROUND DATA: Despite anecdotal reports of MILR, few large single center reports have examined these procedures by comparing them to their open counterparts. METHODS: Three hundred MILR were performed between July 2001 and November 2006 at our center for both benign and malignant conditions. These included 241 pure laparoscopic, 32 hand-assisted laparoscopic, and 27 laparoscopy-assisted open (hybrid) resections.These MILR were compared with 100 contemporaneous, cohort-matched open resections. MILR included segmentectomies (110), bisegmentectomies (63), left hepatectomies (47), right hepatectomies (64), extended right hepatectomies (8), and caudate lobe (8) resections. Benign etiologies encompassed cysts (70), hemangiomata (37), focal nodular hyperplasia (FNH) (23), adenomata (47), and 20 live donor right lobectomies. Malignant etiologies included primary (43) and metastatic (60) tumors. Hepatic fibrosis/cirrhosis was present in 25 of 103 patients with malignant diseases (24%). RESULTS: There was high data consistency within the 3 types of MILR. MILR compared favorably with standard open techniques: operative times (99 vs. 182 minutes), blood loss (102 vs. 325 ml), transfusion requirement (2 of 300 vs. 8 of 100), length of stay (1.9 vs. 5.4 days), overall operative complications (9.3% vs. 22%), and local malignancy recurrence (2% vs. 3%). No port-site recurrences occurred. Conversion from laparoscopic to hand-assisted laparoscopic resection occurred in 20 patients (6%), with no conversions to open. No hand-assisted procedures were converted to open, but 2 laparoscopy-assisted (7%) were converted to open. CONCLUSION: Our data show that MILR outcomes compare favorably with those of the open standard technique. Our experience suggests that MILR of varying magnitudes is safe and effective for both benign and malignant conditions. PMID- 17717443 TI - Getting surgery right. AB - OBJECTIVE: We sought to identify factors contributing to wrong-site surgery (wrong patient, procedure, side, or part). METHODS: We examined all reports from all hospitals and ambulatory surgical centers--in a state that requires reporting of wrong-site surgery--from the initiation of the reporting requirement in June 2004 through December 2006. RESULTS: Over 30 months, there were 427 reports of near misses (253) or surgical interventions started (174) involving the wrong patient (34), wrong procedure (39), wrong side (298), and/or wrong part (60); 83 patients had incorrect procedures done to completion. Procedures on the lower extremities were the most common (30%). Common contributions to errors resulting in the initiation of wrong-site surgery involved patient positioning (20) and anesthesia interventions (29) before any planned time-out process, not verifying consents (22) or site markings (16), and not doing a proper time-out process (17). Actions involving operating surgeons contributed to 92. Common sources of successful recovery to prevent wrong-site surgery were patients (57), circulating nurses (30), and verifying consents (43). Interestingly, 31 formal time-out processes were unsuccessful in preventing "wrong" surgery. CONCLUSIONS: Wrong site surgery continues to occur regularly, especially wrong-side surgery, even with formal site verification. Many errors occur before the time-out; some persist despite the verification protocol. Patients and nurses are the surgeons' best allies. Verification, starting with verification of the consent, needs to occur at multiple points before the incision. PMID- 17717444 TI - Specific polymorphic variation in the mitochondrial genome and increased in hospital mortality after severe trauma. AB - OBJECTIVE: To determine whether specific genetic variations in the mtDNA that impact energy production and free-radical generation are potential new risk factors for in-hospital mortality after severe trauma. SUMMARY BACKGROUND DATA: Each of the 3 mitochondrial DNA polymorphisms selected for this study (at positions 4216, 10398, 4917) alter the amino acid sequence of different key subunits of Complex I in the electron transport chain. They have been previously implicated in phenotypes involving tissues with high-energy demand, such as the brain and retina. METHODS: Seven hundred forty-five consecutive patients admitted to the trauma intensive care unit at Vanderbilt University Medical Center between April 11, 2005, and February 27, 2006, were potentially eligible for this study. Under an Institutional Review Board-approved protocol (which excluded patients <18 years of age and prisoners), 666 patients had DNA extracted from a blood sample. Detailed demographic and clinical covariates were also obtained (including age, gender, ethnicity, lactate measurements, and injury severity score). A flurogenic 5' nuclease allelic discrimination Taqman assay and the ABI 7900HT Sequence Detection System (v2.1) was used to genotype the T4216C, A10398G, and A4917G polymorphisms. The primary outcome was in-hospital mortality. RESULTS: Multivariate logistic regression analysis revealed that the 4216T allele was a significant independent predictor of in-hospital mortality (OR = 2.63, 95% CI 1.14-6.07, P = 0.02) after adjustment for age, gender, injury severity score, highest lactate level, mechanism of injury, and the 10398 polymorphism. CONCLUSIONS: Variation in the mtDNA, specifically the 4216T allele, appears to increase the risk of in-hospital mortality after severe injury. PMID- 17717445 TI - Shifting paradigms in the treatment of lower extremity vascular disease: a report of 1000 percutaneous interventions. AB - OBJECTIVES: Catheter-based revascularization has emerged as an alternative to surgical bypass for lower extremity vascular disease and is a frequently used tool in the armamentarium of the vascular surgeon. In this study we report contemporary outcomes of 1000 percutaneous infra-inguinal interventions performed by a single vascular surgery division. METHODS: We evaluated a prospectively maintained database of 1000 consecutive percutaneous infra-inguinal interventions between 2001 and 2006 performed for claudication (46.3%) or limb-threatening ischemia (52.7%; rest pain in 27.7% and tissue loss in 72.3%). Treatments included angioplasty with or without stenting, laser angioplasty, and atherectomy of the femoral, popliteal, and tibial vessels. RESULTS: Mean age was 71.4 years and 57.3% were male; comorbidities included hypertension (84%), coronary artery disease (51%), diabetes (58%), tobacco use (52%), and chronic renal insufficiency (39%). Overall 30-day mortality was 0.5%. Two-year primary and secondary patencies and rate of amputation were 62.4%, 79.3%, and 0.5%, respectively, for patients with claudication. Two-year primary and secondary patencies and limb salvage rates were 37.4%, 55.4%, and 79.3% for patients with limb-threatening ischemia. By multivariable Cox PH modeling, limb-threat as procedural indication (P < 0.0001), diabetes (P = 0.003), hypercholesterolemia (P = 0.001), coronary artery disease (P = 0.047), and Transatlantic Inter-Society Consensus D lesion complexity (P = 0.050) were independent predictors of recurrent disease. For patients that developed recurrent disease, 7.5% required no further intervention, 60.3% underwent successful percutaneous reintervention, 11.7% underwent bypass and 20.5% underwent amputation. Patency rates were identical for the initial procedure and subsequent reinterventions (P = 0.97). CONCLUSION: Percutaneous therapy for peripheral vascular disease is associated with minimal mortality and can achieve 2-year secondary patency rates of nearly 80% in patients with claudication. Although patency is diminished in patients with limb-threat, limb salvage rates remain reasonable at close to 80% at 2 years. Percutaneous infra inguinal revascularization carries a low risk of morbidity and mortality, and should be considered first-line therapy in patients with chronic lower extremity ischemia. PMID- 17717446 TI - External drainage of pancreatic duct with a stent to reduce leakage rate of pancreaticojejunostomy after pancreaticoduodenectomy: a prospective randomized trial. AB - OBJECTIVE: Pancreatic fistula is a leading cause of morbidity and mortality after pancreaticoduodenectomy. External drainage of pancreatic duct with a stent has been shown to reduce pancreatic fistula rate of pancreaticojejunostomy in a few retrospective or prospective nonrandomized studies, but no randomized controlled trial has been reported thus far. This single-center prospective randomized trial compared the results of pancreaticoduodenectomy with external drainage stent versus no stent for pancreaticojejunal anastomosis. METHODS: A total of 120 patients undergoing pancreaticoduodenectomy with end-to-side pancreaticojejunal anastomosis were randomized to have either an external stent inserted across the anastomosis to drain the pancreatic duct (n = 60) or no stent (n = 60). Duct-to mucosa anastomosis was performed in all cases. RESULTS: The 2 groups were comparable in demographic data, underlying pathologies, pancreatic consistency, and duct diameter. Stented group had a significantly lower pancreatic fistula rate compared with nonstented group (6.7% vs. 20%, P = 0.032). Radiologic or surgical intervention for pancreatic fistula was required in 1 patient in the stented group and 4 patients in the nonstented group. There were no significant differences in overall morbidity (31.7% vs. 38.3%, P = 0.444) and hospital mortality (1.7% vs. 5%, P = 0.309). Two patients in the nonstented group and none in the stented group died of pancreatic fistula. Hospital stay was significantly shorter in the stented group (mean 17 vs. 23 days, P = 0.039). On multivariate analysis, no stenting and pancreatic duct diameter <3 mm were significant risk factors of pancreatic fistula. CONCLUSION: External drainage of pancreatic duct with a stent reduced leakage rate of pancreaticojejunostomy after pancreaticoduodenectomy. PMID- 17717447 TI - Transplantation of the spleen: effect of splenic allograft in human multivisceral transplantation. AB - OBJECTIVES: To describe the effect of the splenic allograft in human multivisceral transplantation. SUMMARY BACKGROUND DATA: We performed transplants of the spleen as part of a multivisceral graft in an attempt to decrease both the risk of infection from an asplenic state and the risk of rejection by a possible tolerogenic effect. To our knowledge, this is the first report of human splenic transplantation in a large series. METHODS: All primary multivisceral recipients who received a donor spleen (N = 60) were compared with those who did not receive a spleen (N = 81). RESULTS: Thirty-five of 60 (58%) are alive in the spleen group, and 39 of 81 (48%) are alive in control group (P = 0.98). In univariate analysis, splenic recipients showed superiority in freedom-from-any rejection (P = 0.02) and freedom-from-moderate or severe rejection (P = 0.007). No significant differences were observed in analyses of infectious complications between the spleen and control groups. Both platelet and leukocyte counts became normal in splenic patients, whereas these counts were significantly increased in nonsplenic recipients. Observed incidence of graft versus host disease (GVHD) was 8.25% (5 of 60) in the spleen group and 6.2% (5 of 81) in the control group (P = 0.70). Increased incidence of autoimmune hemolysis was observed in the spleen group. CONCLUSIONS: Allograft spleen can be transplanted within a multivisceral graft without significantly increasing the risk of GVHD. The allogenic spleen seems to show a protective effect on small bowel rejection. Further investigation with longitudinal follow-up is required to precisely determine the immunologic and hematologic effects of the allograft spleen. PMID- 17717448 TI - Hormonally active women tolerate shock-trauma better than do men: a prospective study of over 4000 trauma patients. AB - OBJECTIVE: To test the hypothesis that comparably injured women, especially those in the hormonally active age groups, would manifest a better preserved hemodynamic response and tissue perfusion after major trauma than do men. SUMMARY BACKGROUND DATA: The notion that premenopausal women are more resistant than men to shock and trauma has been shown in numerous preclinical models. However, human studies on the effects of gender on outcome after shock-trauma are less clear, and none has examined the effect of gender on the immediate postinjury response to major trauma. METHODS: Prospective series of all patients at a Level I trauma center from January 2000 to December 2005. Study patients were all patients arriving to the trauma area of the emergency department and having a serum lactate drawn within 30 minutes of arrival. Demographic data, injury severity indices, blood utilization, and lactate levels were recorded. Lactate was used as a marker of the hemodynamic response to injury, because it has been shown to be an excellent and accurate indicator of inadequate tissue perfusion. RESULTS: : A total of 5192 patients were eligible for the study of which 4106 fulfilled the study requirements and were enrolled. Initial serum lactate levels were significantly lower in premenopausal (age 14-44) and perimenopausal (age 45-54) women than in men of the same age groups (P < 0.001), even though the Injury Severity Score of the women was significantly higher than that of the men (24 vs. 18; P < 0.1). When patients were stratified into major injury groups as well as groups receiving blood transfusions, the premenopausal women were also found to have lower initial serum lactate levels and receive less blood, while having a greater magnitude of injury as reflected in their Injury Severity Score. CONCLUSION: The data firmly establishes a proof of principle that hormonally active human women have a better physiologic response to similar degrees of shock and trauma than do their male counterparts. These gender-based differences should be taken into account in designing studies evaluating the response to shock trauma. PMID- 17717449 TI - Seasonal variation in surgical outcomes as measured by the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP). AB - OBJECTIVE: We hypothesize that the systems of care within academic medical centers are sufficiently disrupted with the beginning of a new academic year to affect patient outcomes. METHODS: This observational multiinstitutional cohort study was conducted by analysis of the National Surgical Quality Improvement Program-Patient Safety in Surgery Study database. The 30-day morbidity and mortality rates were compared between 2 periods of care: (early group: July 1 to August 30) and late group (April 15 to June 15). Patient baseline characteristics were first compared between the early and late periods. A prediction model was then constructed, via stepwise logistic regression model with a significance level for entry and a significance level for selection of 0.05. RESULTS: There was 18% higher risk of postoperative morbidity in the early (n = 9941) versus the late group (n = 10313) (OR 1.18, 95%, CI 1.07-1.29, P = 0.0005, c-index 0.794). There was a 41% higher risk for mortality in the early group compared with the late group (OR 1.41, CI 1.11-1.80, P = 0.005, c-index 0.938). No significant trends in patient risk over time were noted. CONCLUSION: Our data suggests higher rates of postsurgical morbidity and mortality related to the time of the year. Further study is needed to fully describe the etiologies of the seasonal variation in outcomes. PMID- 17717451 TI - Have endovascular procedures negatively impacted general surgery training? AB - OBJECTIVE: Technological advances in vascular surgery have changed the field dramatically over the past 10 years. Herein, we evaluate the impact of endovascular procedures on general surgery training. METHODS: National operative data from the Residency Review Committee for Surgery were examined from 1997 through 2006. Total major vascular operations, traditional open vascular operations and endovascular procedures were evaluated for mean number of cases per graduating chief general surgery resident (GSR) and vascular surgery fellow (VSF). RESULTS: As endovascular surgical therapies became widespread, GSR vascular case volume decreased 34% over 10 years, but VSF total cases increased 78%. GSR experience in open vascular operations decreased significantly, as evidenced by a 52% decrease (P < 0.0001) in elective open AAA repair. VSFs have also seen significant decreases in open vascular procedures. Experience in endovascular procedures has increased for both general surgery and vascular residents, but the increase has been much larger in absolute number for VSFs. CONCLUSIONS: GSR experience in open vascular procedures has significantly decreased as technology has advanced within the field. Unlike VSFs, this loss has not been replaced by direct experience with endovascular training. These data demonstrate the impact technology can have on how we currently train general surgeons. New educational paradigms may be necessary in which either vascular surgery as an essential component is abandoned or training in catheter-based interventions becomes required. PMID- 17717450 TI - The prevalence and prognostic value of BRAF mutation in thyroid cancer. AB - OBJECTIVE: To examine the prevalence of BRAF mutation among thyroid cancer histologic subtypes and determine the association of BRAF mutation with indicators of poor prognosis for papillary thyroid cancer and patient outcome. SUMMARY BACKGROUND DATA: The appropriate extent of surgical treatment, adjuvant therapy and follow-up monitoring for thyroid cancer remains controversial. Advances in the molecular biology of thyroid cancer have helped to identify candidate markers of disease aggressiveness. A commonly found genetic alternation is a point mutation in the BRAF oncogene (BRAF V600E), which is primarily found in papillary thyroid cancer and is associated with more aggressive disease. METHODS: BRAF V600E mutation status was determined in 347 tumor samples from 314 patients with thyroid cancer (245 with conventional papillary thyroid cancer, 73 with follicular thyroid cancer, and 29 with the follicular variant of papillary thyroid cancer). Univariate and multivariate analyses were performed to determine the association of BRAF V600E with clinicopathologic factors and patient outcome. RESULTS: : The prevalence of BRAF V600E mutation was higher in conventional papillary thyroid cancer (51.0%) than in follicular variant of papillary thyroid cancer (24.1%) and follicular thyroid cancer (1.4%) (P < 0.0001). In patients with conventional papillary thyroid cancer, BRAF V600E mutation was associated with older age (P = 0.0381), lymph node metastasis (P = 0.0323), distant metastasis (P = 0.045), higher TNM stage (I and II vs. III and IV, P = 0.0389), and recurrent and persistent disease (P = 0.009) with a median follow-up time of 6.0 years. Multivariate analysis showed that BRAF V600E mutation [OR (95% CI) = 4.2 (1.2-14.6)] and lymph node metastasis [OR (95% CI) = 7.75 (2.1-28.5)] were independently associated with recurrent and persistent disease in patients with conventional papillary thyroid cancer. CONCLUSIONS: BRAF V600E mutation is primarily present in conventional papillary thyroid cancer. It is associated with an aggressive tumor phenotype and higher risk of recurrent and persistent disease in patients with conventional papillary thyroid cancer. Testing for this mutation may be useful for selecting initial therapy and for follow-up monitoring. PMID- 17717452 TI - A randomized multicenter trial to compare long-term functional outcome, quality of life, and complications of surgical procedures for low rectal cancers. AB - INTRODUCTION: Colonic pouches have been used for 20 years to provide reservoir function after reconstructive proctectomy for rectal cancer. More recently coloplasty has been advocated as an alternative to a colonic pouch. However there have been no long-term randomized, controlled trials to compare functional outcomes of coloplasty, colonic J-Pouch (JP), or a straight anastomosis (SA) after the treatment of low rectal cancer. AIM: : To compare the complications, long-term functional outcome, and quality of life (QOL) of patients undergoing a coloplasty, JP, or an SA in reconstruction of the lower gastrointestinal tract after proctectomy for low rectal cancer. METHODS: A multicenter study enrolled patients with low rectal cancer, who were randomized intraoperatively to coloplasty (CP-1) or SA if JP was not feasible, or JP or coloplasty (CP-2) if a JP was feasible. Patients were followed for 24 months with SF-36 surveys to evaluate the QOL. Bowel function was measured quantitatively and using Fecal Incontinence Severity Index (FISI). Urinary function and sexual function were also assessed. RESULTS: Three hundred sixty-four patients were randomized. All patients were evaluated for complications and recurrence. Mean age was 60 +/-12 years, 71% were male. Twenty-three (7.4%) died within 24 months of surgery. No significant difference was observed in the complications among the 4 groups. Two hundred ninety-seven of 364 were evaluated for functional outcome at 24 months. There was no difference in bowel function between the CP-1 and SA groups. JP patients had fewer bowel movements, less clustering, used fewer pads and had a lower FISI than the CP-2 group. Other parameters were not statistically different. QOL scores at 24 months were similar for each of the 4 groups. CONCLUSIONS: In patients undergoing a restorative resection for low rectal cancer, a colonic JP offers significant advantages in function over an SA or a coloplasty. In patients who cannot have a pouch, coloplasty seems not to improve the bowel function of patients over that with an SA. PMID- 17717453 TI - Impact of the method of initial stabilization for femoral shaft fractures in patients with multiple injuries at risk for complications (borderline patients). AB - OBJECTIVES: The timing of definitive fixation for major fractures in patients with multiple injuries is controversial. To address this gap, we randomized patients with blunt multiple injuries to either initial definitive stabilization of the femur shaft with an intramedullary nail or an external fixateur with later conversion to an intermedullary nail and documented the postoperative clinical condition. METHODS: Multiply injured patients with femoral shaft fractures were randomized to either initial (<24 hours) intramedullary femoral nailing or external fixation and later conversion to an intramedullary nail. Inclusion: New Injury Severity Score >16 points, or 3 fractures and Abbreviated Injury Scale score > or =2 points and another injury (Abbreviated Injury Scale score > or =2 points), and age 18 to 65 years. Exclusion: patients in unstable or critical condition. Patients were graded as stable or borderline (increased risk of systemic complications). OUTCOMES: : Incidence of acute lung injuries. RESULTS: Ten European Centers, 165 patients, mean age 32.7 +/- 11.7 years. Group intramedullary nailing, n = 94; group external fixation, n = 71. Preoperatively, 121 patients were stable and 44 patients were in borderline condition. After adjusting for differences in initial injury severity between the 2 treatment groups, the odds of developing acute lung injury were 6.69 times greater in borderline patients who underwent intramedullary nailing in comparison with those who underwent external fixation, P < 0.05. CONCLUSION: Intramedullary stabilization of the femur fracture can affect the outcome in patients with multiple injuries. In stable patients, primary femoral nailing is associated with shorter ventilation time. In borderline patients, it is associated with a higher incidence of lung dysfunctions when compared with those who underwent external fixation and later conversion to intermedullary nail. Therefore, the preoperative condition should be when deciding on the type of initial fixation to perform in patients with multiple blunt injuries. PMID- 17717454 TI - Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA. AB - OBJECTIVE: To assess the efficacy of orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) and the impact of current staging criteria on long term survival. SUMMARY BACKGROUND DATA: HCC is becoming an increasingly common indication for OLT. Medicare approves OLT only for HCCs meeting the Milan criteria, thus limiting OLT for an expanding pool of potential liver recipients. We analyzed our experience with OLT for HCC to determine if expansion of criteria for OLT for HCC is warranted. METHODS: : All patients undergoing OLT for HCC from 1984 to 2006 were evaluated. Outcomes were compared for patients who met Milan criteria (single tumor < opr =5 cm, maximum of 3 total tumors with none >3 cm), University of California, San Francisco (UCSF) criteria (single tumor <6.5 cm, maximum of 3 total tumors with none >4.5 cm, and cumulative tumor size <8 cm), or exceeded UCSF criteria. RESULTS: A total of 467 transplants were performed for HCC. At mean follow up of 6.6 +/- 0.9 years, recurrence rate was 21.2%, and overall 1, 3, and 5-year survival was 82%, 65%, and 52%, respectively. Patients meeting Milan criteria had similar 5-year post-transplant survival to patients meeting UCSF criteria by preoperative imaging (79% vs. 64%; P = 0.061) and explant pathology (86% vs. 71%; P = 0.057). Survival for patients with tumors beyond UCSF criteria was significantly lower and was below 50% at 5 years. Multivariate analysis showed that tumor number (P < 0.001), lymphovascular invasion (P < 0.001), and poor differentiation (P = 0.002) independently predicted poor survival. CONCLUSIONS: This largest single institution experience with OLT for HCC demonstrates prolonged survival after liver transplantation for tumors beyond Milan criteria but within UCSF criteria, both when classified by preoperative imaging and by explant pathology. Measured expansion of OLT criteria is justified for tumors not exceeding the UCSF criteria. PMID- 17717455 TI - Arteriovenous CO2 removal improves survival compared to high frequency percussive and low tidal volume ventilation in a smoke/burn sheep acute respiratory distress syndrome model. AB - OBJECTIVES AND SUMMARY BACKGROUND: Low tidal volume ventilation (LTV) has improved survival with acute respiratory distress syndrome (ARDS) by reducing lung stretch associated with volutrauma and barotrauma. Additional strategies to reduce lung stretch include arteriovenous carbon dioxide removal (AVCO2R), and high frequency percussive ventilation (HFPV). We performed a prospective, randomized study comparing these techniques in our clinically relevant LD100 sheep model of ARDS to compare survival, pathology, and inflammation between the 3 ventilator methods. METHODS: Adult sheep (n = 61) received smoke inhalation (48 breaths) and a 40% third-degree burn. After ARDS developed (Pao2/FiO2 <200), animals were randomized. In experiment 1, animals were killed at 48 hours after randomization. Hemodynamics, pulmonary function, injury scores, myeloperoxidase (MPO) in lung tissues and neutrophils, IL-8 in lung tissues, and apoptosis were evaluated. In experiment 2, the end point was survival to 72 hours after onset of ARDS or end-of-life criteria with extension of the same studies performed in experiment 1. RESULTS: There were no differences in hemodynamics, but minute ventilation was lower in the AVCO2R group and Paco2 for the HFPV and AVCO2R animals remained lower than LTV. Airway obstruction and injury scores were not different among the 3 ventilation strategies. In experiment 1, lung tissue MPO and IL-8 were not different among the ventilation strategies. However, in experiment 2, lung tissue MPO was significantly lower for AVCO2R-treated animals (AVCO2R < HFPV < LTV). TUNEL staining showed little DNA breakage in neutrophils from experiment 1, but significantly increased breakage in all 3 ventilator strategies in experiment 2. In contrast, AVCO2R tissue neutrophils showed significant apoptosis at 72 hours post-ARDS criteria as measured by nuclear condensation (P < 0.001). Survival 72 hours post-ARDS criteria was highest for AVCO2R (71%) compared with HFPV (55%) and LTV (33%) (AVCO2R vs. LTV, P = 0.05). CONCLUSIONS: Significantly more animals survived AVCO2R than LTV. In experiment 2, Lung MPO was significantly lower for AVCO2R, compared with LTV (P < 0.05). This finding taken together with the TUNEL and neutrophil apoptosis results, suggested that disposition of neutrophils 72 hours post-ARDS criteria was different among the ventilatory strategies with neutrophils from AVCO2R-treated animals removed chiefly through apoptosis, but in the cases of HFPV and LTV, dying by necrosis in lung tissue. PMID- 17717456 TI - Can you hear me now? PMID- 17717458 TI - Does leg lengthening pose a threat to a child's mental health?: An interim report one year after surgery. AB - Previous studies suggest that children react with functional and psychological disturbances after leg lengthening (LL). Long-term effects are not known, and there is a lack of prospective studies. The aim of this interim prospective study was to investigate the psychological impact of the Ilizarov technique on a sample of children 1 year after surgery. METHODS: : The subjects were 27 patients aged 6 to 16 years treated using the Ilizarov technique at the Pediatric Orthopaedic Department, Uppsala University Hospital, between 1997 and 2005. A control group of healthy children matched for age and sex were also included.Semistructured interviews and psychometric measures (anxiety, depression, self-esteem, behavior) were administered to patients and parents before surgery and 1 year after. Psychological measures were correlated with medical records (days of hospitalization, gained length, etc). The control group was examined at initial assessment only. RESULTS: : Before reconstructive surgery, the LL group had a significantly lower self-esteem compared with the control group. Aggressive behavior, attention and externalization problems, anxiety, and depression were significantly reduced after LL. Parents' state anxiety was also reduced. There were no differences in trait anxiety between the parents of patients and the parents of the control children. CONCLUSIONS: : Patients reported pain, psychological discomfort, complications, and restrained function during LL. However, there were no adverse psychological effects at 1-year follow-up; rather, there were signs of improved mental health. No single psychological parameter could predict the outcome after LL. PMID- 17717457 TI - Screening the newborn for developmental dysplasia of the hip: now what do we do? AB - The Pediatric Orthopaedic Society of North America recommends that all health care providers who are involved in the care of infants continue to follow the clinical practice guideline for early detection of developmental hip dysplasia (DDH) outlined by the American Academy of Pediatrics. Although evaluation of children with risk factors for DDH is important, most DDH occurs in infants who have no risk factors. For all infants, a competent newborn physical examination using the Ortolani maneuver is the most useful procedure to detect hip instability. Early treatment of an unstable hip with a Pavlik harness or similarly effective orthosis is effective, safe, and strongly advised. Despite having had normal newborn and infant hip examinations, there remains the possibility of a late-onset hip dislocation needing treatment in approximately 1 in 5000 infants. PMID- 17717459 TI - Percutaneous epiphysiodesis of the lower extremity: a comparison of single- versus double-portal techniques. AB - BACKGROUND: Percutaneous epiphysiodesis can be achieved using a single-portal or a double-portal technique. This study was performed to demonstrate any differences in outcomes, especially complications, between the 2 techniques. METHODS: This was a retrospective review of cases at a single institution from 1983 to 2002 that yielded 336 children, in which 63 qualified for the study with at least 3 years of clinical follow-up. A comparison was performed through clinic chart review and radiographic measurement outcomes, searching for patient satisfaction, surgical time, and complications. RESULTS: Minor complications included superficial infections, hematomas and effusions, whereas major complications included failure to arrest growth, partial arrest with angular deformity, fracture, and joint penetration. The single-portal group had an overall complication rate of 33.3%, with a major complication rate of 20% per patient. The double-portal group had a similar overall complication rate but only a 5.3% major complication rate per patient. There was no significant difference in patient demographics, operative times, or subjective complaints. CONCLUSIONS: Many methods of percutaneous epiphysiodesis exist in the literature that report low complication rates that are comparable with the complication rate of the original open procedure. Our study demonstrated a significantly higher rate of complications (both minor and major) compared with results previously reported. Moreover, the use of a single-portal approach increased the possibility of major complication by nearly 4-fold as compared with the use of a double-portal approach that avoids crossing the midline of the physis. PMID- 17717460 TI - Results of screw epiphysiodesis for the treatment of limb length discrepancy and angular deformity. AB - The purpose of this study was to evaluate the technique of screw epiphysiodesis for effectiveness, predictability, and reversibility. We reviewed the cases of our first 60 patients (105 physes) treated with percutaneous screw epiphysiodesis or hemiepiphysiodesis. All cases were followed up to maturity or screw removal if growth remained after full correction. A total of 30 patients underwent the procedure for limb length inequality. Final inequality was compared with the predicted epiphysiodesis effect. A total of 30 patients (66 physes) underwent screw hemiepiphysiodesis for the correction of angular deformity. The degree of correction per month was calculated, the reversibility of the procedure was analyzed, and complications were evaluated. In the length group, at the end of treatment, the final limb length difference in the femur averaged 0.15 cm (SD, +/ 0.37 cm) from the epiphysiodesis effect predicted by using the multiplier method. In the tibia, this difference was 0.05 cm (SD, +/-0.57 cm). In the angular group, the average correction in the distal femur was 6.91 degrees (SD, +/-3.75 degrees) or 0.75 degrees per month (SD, +/-0.45 degrees per month). In the proximal tibia, the average correction was 3.88 degrees (SD, +/-3.57 degrees) or 0.37 degrees per month (SD, +/-0.34 degrees per month). In all 13 cases where the screws were removed at the time of angular correction with significant growth remaining, growth resumed. Complications were minor and were related to incorrect placement of screws or minor hardware irritation. Percutaneous screw epiphysiodesis is a reliable, minimally invasive method with reliable results in both length and angular correction, with minimal morbidity, and with an acceptable complication rate. PMID- 17717461 TI - Distraction osteogenesis of the lower extremity in patients with achondroplasia/hypochondroplasia treated with transplantation of culture-expanded bone marrow cells and platelet-rich plasma. AB - BACKGROUND: Longer treatment period in distraction osteogenesis (DO) of the lower extremity leads to more frequent complications. We have developed a new technique of transplantation of culture-expanded bone marrow cells (BMCs) and platelet-rich plasma (PRP) during DO to accelerate new bone formation. To assess the efficacy of this cell therapy, retrospective comparative study was conducted between the bones treated with BMC and PRP and the bones treated without BMC and PRP during DO in patients with achondroplasia (ACH) and hypochondroplasia (HCH). METHODS: Fifty-six bones in 20 patients (ACH, 16; HCH, 4) that were lengthened in our hospital were divided into 2 groups. Twenty-four bones (femora, 12; tibiae, 12) in 11 patients (boys, 7; girls, 4) were treated with BMC and PRP transplantation (BMC-PRP group), whereas 32 bones (femora, 14; tibiae, 18) in 9 patients (boys, 3; girls, 6) did not undergo additional cell therapy (control group). The parameters, including the age at operation, the increase in length, and the healing index, were compared between the 2 groups. The clinical outcome was also compared between the femoral and tibial lengthenings. RESULTS: Bone marrow cells (average number, +/- SD, 3.2 +/- 1.37 x 10 cells) and PRP (average platelet concentration +/- SD, 2.36 +/- 0.57 x 10 cells/muL) were transplanted. Although there were no significant differences in the age at operation and the length gained between the 2 groups, the average healing index of the BMC-PRP group (27.1 +/- 6.89 d/cm) was significantly lower than that of the control group (36.2 +/- 10.4 d/cm) (P = 0.0005). The femoral lengthening showed significantly faster healing than did the tibial lengthening in the BMC-PRP group (P = 0.0092). CONCLUSIONS: Transplantation of BMC and PRP shortened the treatment period by accelerating new bone regeneration during DO of the lower extremity in patients with ACH and HCH, especially in the femoral lengthening. PMID- 17717462 TI - Giant cell tumor of bone in children and adolescents. AB - BACKGROUND: There are very few series that document giant cell tumor of bone (GCT) in the immature skeleton, and the reported incidence in literature varies from 1.8% to 10.6%. The purpose of this study was to document the incidence of GCT in patients with open physis in the Indian population and study the course of the disease with respect to its adult counterpart to see if it behaved any differently. METHODS: Between January 2000 and December 2005, 17 (6%) of 285 surgically treated patients with histologically proven GCT had open physis on imaging. Treatment was directed toward local control without sacrificing joint function, with most lesions treated with intralesional curettage. RESULTS: Fourteen (82%) patients were girls. The most common site was around the knee (53%). Of 15 lesions in tubular bones, 13 were epiphysiometaphyseal in location. An open physis did not prevent GCT from penetrating the epiphyseal cartilage. Histologically, the tumors were typical of GCT. Of 15 patients available for follow-up, 3 (20%) developed local recurrence. CONCLUSIONS: Although the overall incidence of GCT may be higher in the Asian population, the percentage of skeletally immature patients or those nearing skeletal maturity is similar to that described in literature. The biological behavior of the disease is similar to that seen in adults, except a marked female preponderance, principles of treatment, recurrence patterns, and course of the disease mirror the behavior of its adult counterpart. PMID- 17717463 TI - Rapid development of an osteosarcoma after surgical resection of an osteochondroma. AB - The rapid development of an osteosarcoma, after surgical resection of an osteochondroma, has not been yet reported. We present here the case of a 12-year old girl that had, in less than 2 months, an osteosarcoma at the initial site of a treated osteochondroma. Comparative Genomic Hybridization analyses showed that the 2 tumors were genetically distinct, suggesting a distant, if any, relationship. The possible implication of a deregulated tissue homeostasis caused by the surgical intervention is discussed. Proangiogenic factors involved in the tissue healing could be the triggering factor favoring tumor angiogenesis and explaining the very rapid progression of the tumor. PMID- 17717464 TI - Mechanical work, energetic cost, and gait efficiency in children with cerebral palsy. AB - Many authors have reported increased energy expenditure during walking in children with hemiplegia. The origin of this increase is not well documented. The aim of our study was to understand better the origin of this increased energy expenditure of walking in children with cerebral palsy (CP) by simultaneously assessing the total mechanical work performed by the muscles and the efficiency of the work production.Twenty independently walking children with spastic, hemiplegic CP and a dynamic foot equinus deformity participated in the study. Instrumented gait analysis, including the analysis of kinematic, mechanical, and energetic variables, was performed. Despite excellent Gross Motor Function Measurement scores (range, 97-99), the energy cost was 1.3 times greater in children with CP than in healthy children. This increase in energy cost was related to an increase in the total positive mechanical work performed by the muscles and not related to a decrease in the efficiency of this work production. This study shows how segmental impairments (foot spastic equinus) increase the total mechanical work performed by the muscles and the energetic cost and how these segmental impairments contribute to the patient's disability. It is useful to associate the clinical examination, classic gait analysis, mechanical work, and energetic assessment to complete the evaluation of the condition of children with CP. PMID- 17717465 TI - Reliability of popliteal angle measurement: a study in cerebral palsy patients and healthy controls. AB - The popliteal angle is a widely used clinical measure for hamstring contracture in cerebral palsy (CP) patients and in healthy individuals. The reliability of popliteal angle measurement is being questioned. The aim of this study is to determine the reliability of popliteal angle measurement by means of visual and goniometric assessment. METHODS: Three different observers measured the popliteal angle in 15 CP patients and 15 healthy volunteers. In each subject, popliteal angles were visually estimated and measured with a blinded goniometer twice by all observers with approximately 1 hour between measurement sessions. RESULTS: All intraclass correlation coefficients (ICCs) were lower in the CP group compared with healthy controls. The ICC for intraobserver differences was higher than 0.75 for both groups. The ICC for interobserver reliability of visual estimates and goniometric measurements was low for both groups. Intermethod ICC was higher than 0.75 for both groups. CONCLUSIONS: Measurements in the CP group seemed to be less reliable than measurements in the control group. Intraobserver reliability is reasonable for both groups, but lower in CP patients than in controls. Interobserver reliability of both visual estimates and goniometrical measurements is poor. No significant differences in reliability have been found between visual estimation and goniometric measurement. Because of poor interobserver reliability of popliteal angle measurement, this should not be the only variable in clinical decision making in CP patients. PMID- 17717466 TI - Health-related quality of life outcomes improve after multilevel surgery in ambulatory children with cerebral palsy. AB - BACKGROUND: Studies evaluating multilevel surgery to treat spastic deformity and functional deficits in cerebral palsy (CP) usually focus on data from instrumented gait analysis and clinical examination without examining functional and health-related quality of life (HRQOL) outcomes. Recently, outcome measures for well-being in children with a variety of musculoskeletal disorders have also been validated specifically for CP. Therefore, this study aimed to investigate the impact of multilevel surgery on the function and HRQOL in a group of ambulatory children with CP. METHODS: In a multicenter prospective trial, 57 ambulatory children with CP, mean age 9.5 years, underwent multilevel soft tissue surgery to correct sagittal imbalance. Validated clinical outcome measures for HRQOL were administered preoperatively and postoperatively with an average follow up time of 15.2 months. The functional and psychosocial components of the Pediatric Outcomes Data Collection Instrument (PODCI), Pediatric Quality of Life Questionnaire (PedsQL), and the Functional Assessment Questionnaire Walking Score were used. RESULTS: Significant improvements in outcome scores occurred postoperatively in the following: PedsQL parent-total (17.6%; P < 0.001) and parent-physical sections (25.0%; P < 0.001), the Functional Assessment Questionnaire Walking Score (15.3%; P < 0.001), and the PODCI sections for transfers and basic mobility (15.8%; P < 0.001), sports and physical function (23.9%; P = 0.012), and global (12.9%; P < 0.001). Improvements also occurred in the PedsQL child-total (8.4%; P = 0.104) and child-physical sections (8.6%; P = 0.189), but these were not statistically significant. There were no significant changes in the PODCI parent-derived pain (-3.2%; P = 0.504) and happiness sections (1.9%; P = 0.645). CONCLUSIONS: Multilevel surgery in ambulatory patients with CP improves function and HRQOL. However, improved functional well being does not imply improved psychosocial well-being, and patients and their families should be counseled accordingly. PMID- 17717467 TI - Kinematic and kinetic outcomes after identical multilevel soft tissue surgery in children with cerebral palsy. AB - This study evaluates the outcomes of multilevel soft tissue surgery in 31 ambulatory children (n = 39 sides) with cerebral palsy. All children had undergone rectus femoris transfer, hamstring lengthening, and gastrosoleus lengthening for the purpose of correcting sagittal plane abnormalities. There were no simultaneous bony surgeries. Preoperative and postoperative evaluation consisted of clinical assessment and gait analysis, including 3-dimensional kinematics and kinetics. Results demonstrated improvements in knee and ankle function. At the knee, there was a decrease in mean flexion at initial contact (from 31 degrees [SD, +/-8 degrees] to 21 degrees [SD, +/-10 degrees]) and in stance (mean stance, 22 degrees [SD, +/-12 degrees] to 16 degrees [SD, +/-11 degrees]) associated with a decreased mean internal extensor moment in stance (from 0.09 Nm/kg [SD, +/-0.24 Nm/kg] to -0.03 [SD, +/-0.22 Nm/kg]). At the same time, knee flexion was preserved in swing and occurred earlier. At the ankle, mean dorsiflexion improved at the time of examination (from 8 degrees [SD, +/-9 degrees] to 14 degrees [SD, +/-11 degrees] with the knee in extension), in terminal stance (peak from 7 degrees [SD, +/-9 degrees] to 12 degrees [SD, +/-8 degrees]), and in swing. Peak ankle power generation in stance was preserved and shifted later in stance toward push-off, with no functional weakening of the ankle plantar flexors. A longer-term assessment of a subset of patients with a second postoperative gait analysis at a mean of 4 years after surgery showed that gains measured at 1 year were maintained during the longer term. A subgroup demonstrating a jump knee gait pattern (as defined by excessive knee flexion at initial contact followed by rapid knee extension to full knee extension in midstance) had a tendency to go into knee hyperextension in stance with resultant net knee flexor moment after surgery. This raises concern about the indications for hamstring lengthening in this patient group. PMID- 17717468 TI - Effects of early weight bearing on the functional recovery of ambulatory children with cerebral palsy after bilateral proximal femoral osteotomy. AB - This study evaluates the effects of early versus delayed weight bearing on the functional recovery of ambulatory children with cerebral palsy (CP) after they have undergone proximal femoral osteotomies (PFOs). We retrospectively reviewed the cases of 25 ambulatory children with CP who underwent PFO to correct excessive hip internal rotation and intoeing. Thirteen children were permitted to weight-bear as tolerated (WBAT) immediately after surgery, and 12 were placed on non-weight bearing restrictions for 3 to 7 weeks (mean +/- SD, 30 +/- 6.7 days). There were no major complications. The children in the WBAT group initiated standing 26 days sooner and returned to baseline walking almost 4 months sooner than those on non-weight bearing restrictions. Pain at 8 days postoperatively was significantly less for the WBAT group, but pain at the time of initial standing and walking was not significantly different between groups. In conclusion, early mobilization after PFOs in children with CP is safe, with reduced recovery time, and with decreased pain. PMID- 17717469 TI - Role of the triradiate cartilage in predicting curve progression in adolescent idiopathic scoliosis. AB - Braces are commonly used to treat progressive adolescent idiopathic scoliosis. Several previous studies have reported a correlation between the success of brace treatment and skeletal maturity markers. These studies have not focused on the status of the triradiate cartilage (TRC) as it relates to successful brace treatment for adolescent idiopathic scoliosis. The authors retrospectively evaluated all patients at their institution from 1990 to 1997 with a diagnosis of adolescent idiopathic scoliosis who were treated in a Boston brace. Sixty-two patients met inclusion criteria. At presentation, the average age was 12.87 years, the average Risser sign was 0.56, and 45% of patients had an open TRC. The average follow-up was 2.92 years. Greater than 5 degrees of progression at discontinuation of bracing was considered a failure. Curves with a closed TRC failed bracing 21% of the time, whereas those with an open TRC failed 54% of the time (P = 0.0069). Those curves with a closed TRC progressed 3.12 degrees on average, whereas curves with an open TRC progressed 6.86 degrees. Curves associated with a closed TRC at initiation of bracing progressed less frequently and to a lesser degree than those associated with an open TRC (P = 0.027). Although the TRC is not an independent predictor of curve stability, it is an additional indicator of skeletal maturity and may prove most useful in patients with otherwise borderline indications for brace treatment. PMID- 17717470 TI - Computed tomographic-based volumetric reconstruction of the pulmonary system in scoliosis: trends in lung volume and lung volume asymmetry with spinal curve severity. AB - BACKGROUND: Scoliosis has been associated with reduced pulmonary capacity; however, the source of the reduction in capacity (left, right, or both lungs) is not clear. The objective of this study was to investigate trends in left, right, and total lung volume and left/right lung volume asymmetry with spinal curve severity in scoliosis. METHODS: Three-dimensional volumetric reconstruction of the pulmonary system was performed on existing preoperative computed tomographic (CT) scans for 28 idiopathic scoliosis patients. Left, right, and total lung volumes, and left/right lung volume ratios were calculated and correlated with the following spinal curve parameters: major Cobb angle, rib hump, number of vertebrae in the major curve, most cephalad vertebra in the major curve, and thoracic kyphosis. RESULTS: Left/right lung volume ratio increases significantly with increasing rib hump. Left, right, and total lung volumes were significantly correlated with rib hump and number of vertebrae in the major curve (P < 0.05), and near-significantly correlated with most cephalad vertebra in the major curve (P < 0.10). Shorter, higher, more rotated thoracic curves therefore restrict lung volume more than longer, lower, less rotated curves. The mean lung volume ratio for scoliosis patients was lower than for age-matched controls (P < 0.10). CONCLUSION: CT-based volumetric reconstruction of the pulmonary system in scoliosis patients shows differences in both lung volumes and lung volume ratios compared with normal controls. PMID- 17717471 TI - Outcome study of children, adolescents, and adults with sacral agenesis. AB - Musculoskeletal functional outcome was assessed in children and adults with sacral agenesis and no myelomeningocele. General health, musculoskeletal function, and psychosocial adjustment were assessed in 16 sacral agenesis patients (10 males, 6 females; mean age, 14 +/- 5 years) using previously validated patient and parent self-report questionnaires. Radiographs were reviewed to classify each patient by Renshaw type. Most patients were happy with their looks, and all felt that their general health was good to excellent. Patients reported being limited in function by their low back and distal lower extremities. Half were limited by pain. They reported problems functioning in physically demanding situations, although most were able to participate in low demand physical activities. No relationship was found between pain and Renshaw type nor between overall satisfaction and Renshaw type. PMID- 17717472 TI - The use of allograft as a bone graft substitute in patients with congenital spine deformities. AB - The purpose of this study was to determine the safety and efficacy of using allograft bone as a substitute for iliac crest bone graft when treating pediatric patients with congenital spine deformities. We performed a retrospective review of 107 pediatric patients who underwent instrumentation and arthrodesis using allograft for congenital spine deformity between 1995 and 2002. Pseudoarthrosis was defined as implant failure, a clear radiographic pseudoarthrosis, or any loss of correction more than 10 degrees from the immediate postoperative radiographs to the final follow-up radiographs. The pseudoarthrosis rate in this series was 2.8%, and the infection rate was 0.9%. We conclude that freeze-dried corticocancellous allograft is a safe and effective alternative to iliac crest bone graft in this patient population. PMID- 17717473 TI - Pediatric orthopaedic patients presenting to a university emergency department after visiting another emergency department: demographics and health insurance status. AB - BACKGROUND: The disparity in access to and delivery of health care among children has become increasingly apparent. The purpose of our study was to analyze demographic information, including health insurance status, of children with extremity injuries seen at a University Hospital emergency department (UH ED) after visiting another ED for the same complaint. METHODS: A database of pediatric orthopaedic consults requested for extremity injuries at UH ED was reviewed. Information regarding patients' age, ethnicity, orthopaedic diagnosis, type of health insurance, time from injury to presentation at the first ED and at UH ED, mode of transportation to UH ED, and orthopaedic treatment rendered was analyzed. All patients with Medicaid, health maintenance organization-Medicaid, no insurance, or charity care were classified as having public insurance, whereas those with commercial insurance, including health maintenance organization and preferred provider organization plans, were placed in the private insurance category. RESULTS: Over a 30-month period, 125 children, of whom 18% had private health insurance, were noted to have recently visited another ED seeking treatment for an extremity injury. A closed fracture was diagnosed in 117 patients, 94% of whom were discharged from UH ED after cast application. There was no difference with regard to patients' age, sex, ethnicity, diagnosis, and time to presentation at the initial ED between private and public insurance groups. However, 52% of children with private insurance received orthopaedic care within 24 hours compared with 22% with public insurance (P = 0.013). Children with public insurance were more likely to have visited another health facility besides the initial ED before presenting to UH ED (P = 0.004). Moreover, 74% of privately insured patients presenting to UH ED arrived via ambulance compared with 34% with public insurance (P < 0.001). CONCLUSIONS: Most children with an extremity injury who received orthopaedic consultation at a tertiary-level ED after visiting another ED had an isolated fracture requiring cast treatment only. There was a trend for delay in receiving definitive orthopaedic care for patients with public health insurance compared with those with private insurance. PMID- 17717474 TI - Intraoperative stability testing of lateral-entry pin fixation of pediatric supracondylar humeral fractures. AB - The aims of this study were (1) to ascertain prospectively whether rotational instability can be determined intraoperatively and (2) to quantify the incidence of rotational instability after lateral-entry wire fixation in type-3 supracondylar humeral fractures in children according to Wilkins modification of Gartland classification. (Fractures in Children. Vol 3. 4th ed. 1996:669-750). Twenty-one consecutive patients admitted with type-3 supracondylar fractures at the Children's Hospital at Westmead were surgically treated according to a predetermined protocol. After closed fracture reduction, 2 lateral-entry wires were inserted under radiographic control. Stability was then assessed by comparing lateral fluoroscopic images in internal and external rotation. If the fracture remained rotationally unstable, a third lateral-entry wire was inserted, and images were repeated. A medial wire was used only if instability was demonstrated after the insertion of 3 lateral wires. Rotational stability was achieved with 2 lateral-entry wires in 6 cases, 3 lateral-entry wires in 10 cases, and with an additional medial wire in 5 cases. Our results were compared with a control group of patients treated at our hospital before the introduction of this protocol. No patients required a reoperation after the introduction of our protocol as opposed to 6 patients in the control group. On analysis of radiographs, the protocol resulted in significantly less fracture position loss as evidenced by change in Baumann angle (P < 0.05) and lateral rotational percentage (P < 0.05). We conclude that supracondylar fractures that are rotationally stable intraoperatively after wire fixation are unlikely to displace postoperatively. Only a small proportion (26%) of these fractures were rotationally stable with 2 lateral-entry wires. PMID- 17717475 TI - Predicting the outcome of physeal fractures of the distal femur. AB - BACKGROUND: : Distal femoral epiphyseal fractures are uncommon but have a high incidence rate of complications. It is not clear whether there are any reliable predictor factors and whether the type of fracture, displacement (degree and direction), and treatment method alter the outcome. METHODS: : We retrospectively reviewed the medical charts and images of all patients who sustained a distal femoral epiphyseal fracture and were treated at 2 large level I pediatric centers during the past 10 years. RESULTS: : The selected group included 73 patients (boys, 59; mean age, 10 years). On the basis of the Salter-Harris classification (SH), 43 fractures (59%) were of type II. Fifty-nine percent of the fractures were displaced; 36 fractures were managed conservatively with long leg cast (with or without pelvic band) in 33 patients, cylinder cast in 2, and posterior splint in 1. Thirty-seven patients underwent surgery, and 34 underwent closed reduction followed by percutaneous fixation (crossed Steinman pins, 20; cannulated screws, 13; open reduction, 3; external fixation, 1). The overall complication rate was 40% (29/73), and growth arrest was the most frequent. The SH classification significantly correlated with the incidence of complications (P = 0.031). There was also a significantly higher (P < 0.0001) incidence rate of complications among displaced fractures (48.8% vs 26.6%); the amount and direction of displacement did not correlate with the outcome (P > 0.05). The group treated conservatively had a lower incidence rate of complications (25%) than did the surgical group (54%) (P < 0.05). Among the surgical group, a higher incidence rate of complications occurred when the physis was violated by hardware (65% vs 30%; P = 0.06). CONCLUSIONS: : Both SH classification and displacement of the fracture are significant predictors of the final outcome. The degree and the direction of displacement do not statistically correlate with outcome. The treatment method may influence the final outcome. PMID- 17717476 TI - The contralateral unimpaired arm as a control for upper extremity kinematic analysis in children with brachial plexus birth palsy. AB - BACKGROUND: Kinematic studies of abnormal upper extremity (UE) motion provide the unique and valuable perspective of motion analysis during simulated functional tasks. However, they require comparison with healthy control data. Obtaining this control data usually entails testing a healthy population, which can be costly and time consuming, requiring separate subject inclusion criteria, recruitment, and institutional review board approval. The kinematics of the unimpaired UE in people with unilateral impairment have not been analyzed and documented. The purpose of this study was to compare UE motion during activities of daily living in the contralateral unimpaired arm of subjects with brachial plexus birth palsy (BPBP) with an age-matched control population. METHODS: The contralateral arms of 40 subjects with unilateral BPBP were compared with the arms of 15 healthy subjects using an established 3-dimensional upper extremity motion analysis protocol. RESULTS: There were no significant differences between the 2 arms on 17 of 19 motion parameters. The 2 differences that were statistically significant (P < 0.05) were not clinically meaningful. CONCLUSIONS: The contralateral arms of children with unilateral BPBP can be used as controls for future upper extremity motion analysis studies of this population, and further recruitment of age matched controls is not necessary for comparison with 5- to 8-year-old children with BPBP. PMID- 17717477 TI - Foot abduction brace in the Ponseti method for idiopathic clubfoot deformity: torsional deformities and compliance. AB - The Ponseti method has shown to be effective in treating idiopathic clubfoot deformity. Application of a foot abduction brace is crucial to long term outcome. Compliance and possible effect on femoral anteversion and tibial torsion were assessed in 20 children with an average bracing period of 33 months. Nineteen patients were compliant with the bracing protocol and highly satisfied with the treatment protocol. Ultrasound measurement of femoral anteversion (40.5 degrees) and tibial external torsion (38.4 degrees) of the affected side were within the normal range. Range of motion of the ankle joint in all clubfeet resulted in an average dorsiflexion of 27.5 degrees. Among our patient group, the method proved to be highly accepted by almost all families, with excellent functional results. Application of the foot abduction brace did not result in pathological changes of femoral anteversion or tibial torsion. PMID- 17717479 TI - Entrapment neuropathy contributing to dysfunction after brachial plexus birth injuries. PMID- 17717480 TI - Quantitative gait analysis in the treatment of children with cerebral palsy. PMID- 17717482 TI - Microbicides development program, Tanzania-baseline characteristics of an occupational cohort and reattendance at 3 months. AB - OBJECTIVES: To determine baseline characteristics of an occupational cohort of women in Mwanza City, Tanzania, and factors associated with reattendance at 3 months, in preparation for a microbicide trial. STUDY DESIGN: One thousand five hundred seventy-three women aged 16-54 years working in food outlets and recreational facilities were enrolled, interviewed, and examined at community based reproductive health clinics, provided specimens for HIV/STI and pregnancy testing, and attended 3 monthly clinical follow-up. RESULTS: Baseline prevalence of HIV was 25.5%; pregnancy 9.7%; herpes simplex virus type-2 74.6%; active syphilis 10.2%, bacterial vaginosis 52.6%; gonorrhea 5.5%; chlamydia 5.9%; and trichomoniasis 12.3%. Reattendance at 3 months was 74.1% and was higher in older women, less mobile women, and in those who received an HIV-negative result at enrollment. CONCLUSIONS: Baseline characteristics of this occupational group suggest their suitability for microbicide trials. A screening round, locally appropriate informed consent procedures, and effective community tracing may help reduce losses to follow-up in such settings. PMID- 17717483 TI - Evaluation of the overall program effectiveness of HIV-related intervention programs in a community in Sichuan, China. AB - OBJECTIVES: The study evaluates the overall effectiveness of intervention programs among female sex workers in a Chinese community. STUDY DESIGN: Behavioral surveillance data in 2003, 2004, and 2005 obtained from 2 communities (intervened and control) were compared. RESULTS: The baseline data (2003) of the 2 counties were not significantly different. In 2004 and 2005, the intervened county had significantly higher prevalence of condom use with their clients and regular sex partners (last-time and consistent use in the last month; OR = 2.2 33.2 in 2004 and 3.8-8.3 in 2005), higher HIV-related knowledge level (OR = 7.9 in 2004 and 17.3 in 2005), and lower STD prevalence (OR = 0.22 in 2004 and 0.11 in 2005). Coverage rates of HIV antibody testing and HIV-related services increased in the intervened county but decreased in the control county. CONCLUSIONS: Intervention programs may result in substantial behavioral changes in a community within a few years. PMID- 17717484 TI - Before it is too late: hepatitis B vaccination for all STD clients. PMID- 17717485 TI - Clinical pitfalls of STD surveillance. PMID- 17717486 TI - "Doctor, how long has my Chlamydia been there?" Answer: ".... years". PMID- 17717487 TI - HIV serostatus disclosure, condoms, and HIV/STD prevention. PMID- 17717488 TI - N-terminal pro-B-type natriuretic peptide is an independent predictor of outcome in an unselected cohort of critically ill patients. AB - OBJECTIVES: Natriuretic peptides emerged during recent years as potent prognostic markers in patients with heart failure and acute myocardial infarction. In addition, natriuretic peptides show strong predictive value in patients with pulmonary embolism, sepsis, renal failure, and shock. The present study tests the prognostic information of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) in an unselected cohort of critically ill patients. DESIGN: Prospective, observational study. SETTING: A tertiary intensive care unit in a university hospital. PATIENTS: A total of 289 consecutive patients admitted to the intensive care unit during a 16-month period with the following data: age 64 +/- 14 yrs, male n = 191, Simplified Acute Physiology Score II of 52 +/- 24, mechanical ventilation n = 180 (62%), vasopressors n = 179 (62%), renal failure n = 24 (8%). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma NT-pro-BNP samples (Roche Diagnostics) were obtained on intensive care unit admission. Data are given as median [range]. Intensive care unit survivors had significantly lower NT pro-BNP values compared with intensive care unit nonsurvivors (3394 [24-35,000] vs. 6776 [303-35,000] pg/mL, survivors vs. nonsurvivors, respectively, p = .001). Hospital survivors were characterized by significantly lower NT-pro-BNP values (2656 [24-35,000] vs. 8390 [303-35,000] pg/mL, survivors vs. nonsurvivors, respectively, p = .001). NT-pro-BNP levels were not significantly different in patients with primary cardiac diagnosis compared with those with a noncardiac admission diagnosis (4794 [26-35,000], n = 202 vs. 3349 [24-35,000], n = 87, cardiac vs. noncardiac, respectively, p = .28). In a logistic regression model, Simplified Acute Physiology Score II and NT-pro-BNP were independently associated with hospital survival (chi = 35.6, p = .0001 and chi = 11.3, p = .0008, Simplified Acute Physiology Score II and NT-pro-BNP, respectively). Areas under the receiver operating characteristic curves of NT-pro-BNP and Simplified Acute Physiology Score II were not statistically significant different regarding the prediction of outcome. CONCLUSIONS: NT-pro-BNP on admission is an independent prognostic marker of outcome in an unselected cohort of critically ill patients. A single measurement of NT-pro-BNP might facilitate triage of emergency and intensive care unit patients. PMID- 17717489 TI - Hyperchloremia is the dominant cause of metabolic acidosis in the postresuscitation phase of pediatric meningococcal sepsis. AB - OBJECTIVE: Metabolic acidosis is common in septic shock, yet few data exist on its etiological temporal profile during resuscitation; this is partly due to limitations in bedside monitoring tools (base excess, anion gap). Accurate identification of the type of acidosis is vital, as many therapies used in resuscitation can themselves produce metabolic acidosis. DESIGN: Retrospective, cohort study. SETTING: Multidisciplinary pediatric intensive care unit with 20 beds. PATIENTS: A total of 81 children with meningococcal septic shock. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Acid-base data were collected retrospectively on 81 children with meningococcal septic shock (mortality, 7.4%) for the 48 hrs after presentation to the hospital. Base excess was partitioned using abridged Stewart equations, thereby quantifying the three predominant influences on acid-base balance: sodium chloride, albumin, and unmeasured anions (including lactate). Metabolic acidosis was common at presentation (mean base excess, -9.7 mmol/L) and persisted for 48 hrs. However, the pathophysiology changed dramatically from one of unmeasured anions at admission (mean unmeasured anion base excess, -9.2 mmol/L) to predominant hyperchloremia by 8-12 hrs (mean sodium-chloride base excess, -10.0 mmol/L). Development of hyperchloremic acidosis was associated with the amount of chloride received during intravenous fluid resuscitation (r = .44), with the base excess changing, on average, by -0.4 mmol/L for each millimole per kilogram of chloride administered. Hyperchloremic acidosis resolved faster in patients who 1) manifested larger (more negative) sodium chloride-partitioned base excess, 2) maintained a greater urine output, and 3) received furosemide; and slower in those with high blood concentrations of unmeasured anions (all, p < .05). CONCLUSIONS: Hyperchloremic acidosis is common and substantial after resuscitation for meningococcal septic shock. Recognition of this entity may prevent unnecessary and potentially harmful prolonged resuscitation. PMID- 17717490 TI - Severe hypoglycemia in critically ill patients: risk factors and outcomes. AB - OBJECTIVE: To determine the risk factors for development of severe hypoglycemia (defined as glucose <40 mg/dL) in critically ill patients and define the outcomes of this complication. DESIGN: Retrospective database review, including a case control analysis that matched each patient with severe hypoglycemia with three controls. SETTING: Adult intensive care unit of a university-affiliated community hospital. PATIENTS: A total of 102 patients with at least one episode of severe hypoglycemia extracted from a series of 5,365 medical, surgical, and cardiac patients admitted consecutively between October 1, 1999, and June 15, 2006. INTERVENTIONS: A program of intensive glycemic monitoring and management, or tight glycemic control, was implemented on February 1, 2003; 2,666 patients were treated before and 2,699 after this date. MEASUREMENTS AND MAIN RESULTS: Multivariable logistic regression analysis identified diabetes, septic shock, renal insufficiency, mechanical ventilation, severity of illness, reflected by Acute Physiology and Chronic Health Evaluation II score with the age component deleted, and treatment in the tight glycemic control period as independent risk factors for the development of severe hypoglycemia. Mortality was 55.9% among the 102 patients with severe hypoglycemia and 39.5% among the 306 controls (p = .0057). Multivariable logistic regression analysis identified severe hypoglycemia as an independent predictor of mortality for the entire cohort (odds ratio, 2.28; 95% confidence interval, 1.41-3.70; p = .0008). Among patients with severe hypoglycemia, only modified Acute Physiology and Chronic Health Evaluation II score and mechanical ventilation were identified as independent predictors of mortality. A sensitivity analysis was constructed that suggested that quadrupling the rate of severe hypoglycemia and doubling the mortality attributable to severe hypoglycemia would negate the survival benefit of tight glycemic control in this series. CONCLUSIONS: Case-control methodology and multivariable logistic regression analysis concurred that even a single episode of severe hypoglycemia was independently associated with increased risk of mortality. Safe implementation of tight glycemic control requires appropriate monitoring to reduce the risk of this complication. PMID- 17717491 TI - Survey of sedation practices during noninvasive positive-pressure ventilation to treat acute respiratory failure. AB - OBJECTIVES: Noninvasive positive-pressure ventilation (NPPV) is increasingly used in patients with acute respiratory failure, but few data exist regarding current sedation practices during NPPV. We sought to characterize current practices and attitudes regarding sedation during NPPV. DESIGN: Cross-sectional Web-based survey. SETTING: Medical institutions. PARTICIPANTS: Physician members of the American College of Chest Physician's Critical Care Network (n = 2,656) and the European Respiratory Society's Assembly of Critical Care (n = 339). INTERVENTIONS: Survey. MEASUREMENTS AND MAIN RESULTS: Of the 790 of 2,985 (27%) of physicians who responded, 15%, 6%, and 28% never used sedation, analgesia, or hand restraints any of the time for NPPV patients, respectively, and the large majority reported using these interventions in < or =25% of patients. Sedation, analgesia, and hand restraints were more commonly used by North Americans than Europeans (41% vs. 24% for sedation, 48% vs. 35% for analgesia, and 27% vs. 16% for hand restraints, all p < .01) and critical care vs. noncritical care physicians (42% vs. 24% for sedation and 50% vs. 34% for analgesia, all p < .01). A benzodiazepine alone was the most preferred (33%), followed by an opioid alone (29%). Europeans were less likely to use a benzodiazepine alone (25% vs. 39%, p < .001) but more likely to use an opioid alone (37% vs. 26%, p < .009). Sedation was usually administered as an intermittent intravenous bolus, outside of a protocol, and was assessed by nurses using clinical end points rather than a sedation scale. CONCLUSIONS: Most physicians infrequently use sedation and analgesic therapy for NPPV to treat acute respiratory failure, but practices vary widely within and between specialties and geographic regions. PMID- 17717492 TI - The organization of intensive care unit physician services. AB - OBJECTIVE: To describe the organization of physician services in intensivist staffed intensive care units (ICU) reporting that they meet vs. do not meet the Leapfrog Physician Staffing standard, and to describe ICU directors' perceptions of the quality of care in their unit. DESIGN: Hospitals that were asked to participate in the 2001 and 2002 Leapfrog surveys regarding implementation of the ICU Physician Staffing standard were sampled. Survey instruments were developed and used to determine organizational characteristics, status regarding implementing and meeting the standard, financing of physician staffing, and perceptions of clinical performance. SUBJECTS: ICU directors. MEASUREMENTS AND MAIN RESULTS: Intensivists staffed ICUs in 100% of hospitals meeting the standard, and in 59% not meeting the standard. Mean percentage of patients visited on rounds by intensivists in ICUs who met (80 +/- 14.58) vs. did not meet (57.5 +/- 23.20) the standard showed no statistical difference, Wilcoxon rank-sum test = -1.99, p = .065. Only 25% (three of 12) of intensivists in ICUs meeting the standard had authority to write patient orders on all patients, compared to 65% (11 of 17) in ICUs not meeting the standard. Intensivists were present at least 8 hrs/day in 83% (ten of 12) of ICUs meeting and 18% (three of 17) of ICUs not meeting the standard. Provision of medical liability insurance for physicians occurred in 58% (seven of 12) of ICUs meeting and 25% (four of 16) of ICUs not meeting the standard (p = .003). ICU directors rated quality of ICU care as excellent in 70% of ICUs meeting and 35% of ICUs not meeting the standard. CONCLUSIONS: ICUs now classify themselves as meeting or not meeting the ICU Physician Staffing standard. Yet, there is wide variation in organizational characteristics among ICUs meeting the standard, and between those meeting and not meeting the standard. The criteria defined by the Leapfrog Group for meeting the ICU Physician Staffing standard must be clearly defined if hospitals are to meet the standard. PMID- 17717493 TI - Microorganisms responsible for intravascular catheter-related bloodstream infection according to the catheter site. AB - OBJECTIVE: Current guidelines for the management of intravascular catheter related bloodstream infection (IVC-RBSI) recommend that empirical antimicrobial therapy must have activity against Gram-positive bacteria, but additional empirical coverage for Gram-negative bacteria may be needed for severely ill or immunocompromised patients, and antifungal therapy may be needed in some situations. We hypothesized that the spectrum of etiological microorganisms responsible for IVC-RBSI and, in relation to that, the choice of empirical antimicrobial therapy depends on the catheter insertion site. We therefore compared the proportion of IVC-RBSI due to Gram-negative bacteria and yeasts according to catheter site. DESIGN: Prospective cohort study from May 1, 2000, to April 30, 2004. SETTING: A 24-bed medical-surgical intensive care unit in a 650 bed tertiary hospital. PATIENTS: Patients requiring a central venous or arterial catheter. MEASUREMENTS AND MAIN RESULTS: We diagnosed 88 IVC-RBSIs, comprising 36 femoral catheter sites (26 femoral venous and ten femoral arterial sites) and 52 other catheter sites (36 jugular venous, 11 subclavian venous, and five radial arterial sites). No differences were found between IVC-RBSI of femoral vs. other catheter sites for age, sex, Acute Physiology and Chronic Health Evaluation II, diagnosis at admission, use of antimicrobials, the time the catheter responsible for IVC-RBSI had been in place, or the duration of intensive care unit stay before IVC-RBSI. The proportion of IVC-RBSIs due to Gram-negative bacteria was higher in femoral, 14 of 36 (38.89%), than in the other catheter sites, 4 of 52 (7.69%) (odds ratio, 7.48; 95% confidence interval, 2.19-25.54; p = .001). Also, the proportion of IVC-RBSIs due to yeasts was higher in femoral, 6 of 36 (16.67%), than in the other catheter sites, 1 of 52 (1.92%) (odds ratio, 10.20; 95% confidence interval, 1.17-88.85; p = .035). CONCLUSIONS: Empirical antifungal therapy would seem to be indicated in patients with suspected femoral catheter related bloodstream infection. PMID- 17717494 TI - Higher hemoglobin is associated with improved outcome after subarachnoid hemorrhage. AB - OBJECTIVE: There are few data regarding anemia and transfusion after subarachnoid hemorrhage (SAH). We addressed the hypothesis that higher hemoglobin (HGB) levels are associated with less death and disability after SAH. DESIGN: Prospective registry with automated data retrieval. PATIENTS: Six hundred eleven patients enrolled in the Columbia University SAH Outcomes Project between August 1996 and June 2002. SETTING: Neurologic intensive care unit. INTERVENTIONS: Patients were treated according to standard management protocols. MEASUREMENTS AND MAIN RESULTS: We electronically retrieved all HGB readings during the acute hospital stay for 611 consecutively admitted SAH patients. Outcomes were measured with the modified Rankin Scale at 14 days or discharge, and at 3 months. Patients who were independent (modified Rankin Scale, 0-3) at discharge or 14 days had higher mean (11.7 +/- 1.5 vs. 10.9 +/- 1.2, p < .001) and nadir (9.9 +/- 2.1 vs. 8.6 +/- 1.8, p < .001) HGB, and had higher HGB values every day in the hospital. There were similar results when patients were stratified by mortality. Higher HGB was associated with reduced risk of poor outcome (modified Rankin Scale, 4-6) at 14 days/discharge and 3 months after correcting for Hunt and Hess grade, age, history of diabetes, and cerebral infarction. Length of stay and HGB interacted such that lower HGB has a more pronounced effect with length of stay > 14 days. CONCLUSIONS: Higher HGB values are associated with improved outcomes after SAH at 14 days/discharge and 3 months. In contrast to general critical care patients, SAH patients may benefit from higher HGB. Determination of the optimal goal HGB after SAH will require separate prospective research. PMID- 17717495 TI - Noninvasive ventilation in acute respiratory failure. AB - BACKGROUND: Noninvasive ventilation has assumed an important role in the management of respiratory failure in critical care units, but it must be used selectively depending on the patient's diagnosis and clinical characteristics. DATA: We review the strong evidence supporting the use of noninvasive ventilation for acute respiratory failure to prevent intubation in patients with chronic obstructive pulmonary disease exacerbations or acute cardiogenic pulmonary edema, and in immunocompromised patients, as well as to facilitate extubation in patients with chronic obstructive pulmonary disease who require initial intubation. Weaker evidence supports consideration of noninvasive ventilation for chronic obstructive pulmonary disease patients with postoperative or postextubation respiratory failure; patients with acute respiratory failure due to asthma exacerbations, pneumonia, acute lung injury, or acute respiratory distress syndrome; during bronchoscopy; or as a means of preoxygenation before intubation in critically ill patients with severe hypoxemia. CONCLUSION: Noninvasive ventilation has assumed an important role in managing patients with acute respiratory failure. Patients should be monitored closely for signs of noninvasive ventilation failure and promptly intubated before a crisis develops. The application of noninvasive ventilation by a trained and experienced intensive care unit team, with careful patient selection, should optimize patient outcomes. PMID- 17717496 TI - Controversies in thoracoscopic lobectomy for lung cancer. PMID- 17717499 TI - Estimation of cardiac function with rotary blood pump. AB - BACKGROUND: A rotary blood pump may be implanted as a bridge to cardiac transplantation. Also, mechanical, histological, and biochemical improvements have been described in cardiac function after the implantation of a left ventricular assists device (LVAD). Thus there is considerable enthusiasm that LVAD might be used as a bridge to the recovery of myocardial function. Unlike a pulsatile pump, however, we cannot stop the rotary blood pump to estimate cardiac function. If the rotary blood pump stops, back flow will occur. In this study, a new method was examined that can estimate cardiac function without stopping the pump. MATERIALS AND METHODS: Twelve pigs were subjected to this acute study. The pump was implanted as an LVAD with an inlet cannula inserted into the left ventricle and the outlet cannula into the ascending aorta. The assist ratio was changed to 75%, from 25%. The relationship between the dp/dt of the left ventricle pressure and the differentiated pump flow rate was examined. Also, cardiac function was changed by epinephrine loading to estimate this method under hyperdynamic heart conditions. RESULTS: There was high positive correlation between the dp/dt of left ventricle pressure and differentiated the pump flow rate to 75% assisted ratio, from 25%. This relationship was established under hyperdynamic conditions. CONCLUSION: This method is simple and useful for estimating the cardiac function without pump stoppage. PMID- 17717497 TI - The revolution of thoracotomy for lung cancer surgery. AB - The revolution of thoracic surgery was brought about by a thoracoscopic approach to the thorax. Until the 1960s, thoracic surgery had been developed primarily for pulmonary tuberculosis. The incidence of lung cancer will increase worldwide during the next 30 years, and the annual incidence of lung cancer in Japan is expected to increase to about 150,000 by 2015. Over the past 50 years, pulmologists and radiologists have performed clinicopathological studies to prevent lung cancer. Early detection became possible with these efforts; as a result, the rate of lung cancer detection at stage I disease has increased. Around 1995, the frequency of the histological incidence of small adenocarcinoma and of peripheral squamous cell carcinoma has increased. Thus thoracic surgeons have refined surgical procedures, such as limited pulmonary resection, and have established a minimally invasive approach to the thorax. These successes were followed by the development of thoracoscopic surgery to cover the world by the end of 20th century. However, minimally invasive surgery involving limited pulmonary resection and/or the thoracoscopic approach, which allows for functional preservation and effectiveness, has not yet been clarified as lung cancer treatment. Future investigations and the refinement of technologies are needed. PMID- 17717500 TI - Outcome of patients after coronary artery bypass grafting in cardiogenic shock. AB - PURPOSE: Coronary artery bypass graft (CABG) surgery in patients with cardiogenic shock (CS) is a rare and very high-risk procedure carrying high mortality. In this study we reviewed hospital outcomes and 1-year survivals in these high-risk patients. MATERIALS AND METHODS: During a 4-year period (May 2001 to April 2005), 412 patients were operated on for CABG by a single surgeon, and 13 (3.1%) of them were in CS at the time of procedure. RESULTS: The 30-day mortality of patients who underwent CABG during CS was 16%, and mean age was 57+/-10 years. A total of 77% were male, 77% were hypertensive, 38% were diabetic, and 31% had renal impairment. Myocardial infarction (MI) affected 62% within 48 h of surgery. Moderate to poor left ventricular function was found in 92%. Twenty-three percent had a preoperative intra-aortic balloon pump. Postinfract ventricular septal defect was present in 16%, and catheter-related problems were present in 23% of patients. After 1 year, all patients (11) were alive, and 85% of them were in New York Heart Association (NYHA) classes I to II. CONCLUSION: CABG in CS produces significant 1-year survival benefits and improvements in functional class. Therefore, early surgical intervention is suggested where percutaneous coronary intervention is not possible or contraindicated for anatomical reasons. PMID- 17717498 TI - Down-regulation of the human PRL-3 gene is associated with the metastasis of primary non-small cell lung cancer. AB - BACKGROUND: Phosphatase of the regenerating liver (PRL)-3 protein tyrosine phosphatase gene is expressed in colon cancer metastasis. To investigate the role of this gene in metastatic lung cancer, we compared PRL-3 gene expression between primary cancers, metastatic lung cancer, and normal lung tissue. MATERIALS AND METHODS: Five metastatic tumor and normal samples from non-small cell lung cancer patients were obtained at the National Hospital Organization Kumamoto Medical Center (Kumamoto, Japan). For a quantitative evaluation of RNA expression by PCR, we used Taqman PCR methods. RESULTS: Although PRL-3 gene expression levels in the primary lesions were slightly decreased compared with those in the normal tissues, those in the metastatic lesions were extremely down-regulated in the synchronous metastatic case. In 2 of these 3 cases, the metastatic tumors showed down-regulated PRL-3 gene expression at 10 times less than that of the normal tissue, and the other tumor showed a slightly weaker expression. CONCLUSION: These data suggest that a down-regulation of the PRL-3 gene is important in lung cancer metastasis and provide a new hypothesis of lung cancer metastases. PMID- 17717501 TI - Predictors of gastrointestinal perforation in patients undergoing coronary artery bypass graft (CABG) surgery in Tehran, Iran. AB - BACKGROUND: Gastrointestinal perforation after coronary artery bypass graft (CABG) surgery is often difficult to diagnose and is associated with high morbidity and mortality rates. The aim of this study was to determine risk factors for this complication in the studied population to further improve prophylaxis and diagnosis in the region of study. METHODS: Of 8,975 consecutive patients undergoing CABG during 10 years (1995-2005), 15 (0.16%) developed gastrointestinal perforation requiring laparatomy. Data from patients who experienced gastrointestinal perforation were analyzed using univariate tests in a controlled retrospective design. RESULTS: Prolonged bypass time and preoperative heparin administration were found to be significant (P<0.05) risk factors. CONCLUSION: Low splanchnic blood flow and vasoconstriction might be underlying factors associated with both predictors. With current findings, however, clear inference about preoperative and postoperative predictors and their relation is not possible. With more information, the next step would be to build a prediction model in recognition of gastrointestinal perforation after CABG on the basis of the predisposing factors. PMID- 17717502 TI - A minute small-cell lung cancer showing a latent phase early in growth. AB - A minute small-cell lung cancer measuring 8 x 5 mm was detected and serially imaged by computed tomography for about a year preceding resection. Although this solid nodule showed a short overall doubling time (76 days), the growth curve included an early phase without apparent growth prior to the phase of rapid growth. Accordingly, lung cancer cannot be ruled out when a small nodule (<10 mm) does not enlarge in the first several months of computed tomographic follow-up. PMID- 17717503 TI - Metastatic monophasic synovial sarcoma of the pleura. AB - Pleural metastasis of synovial sarcoma that originally developed in the soft tissue is a very rare entity. We report here the detailed clinical features of such a case. An asymptomatic 25-year-old female, with a history of a resected synovial sarcoma in her left brachial muscle and pulmonary metastasectomy of the right lung, presented a small nodule in the periphery of the left lung on a routine chest-computed tomography. Exploratory thoracoscopy was then performed. A soft flat red tumor approximately 2 cm in diameter was shown on the pleura of the lingula, mimicking a blood clot on the pleura. The tumor was removed by partial resection of the lung. The mass lay in the pleura and did not seem to invade the lung parenchyma macroscopically. Intraoperative frozen sectioning evidenced metastatic synovial sarcoma. Many small patchy red lesions were also found on the visceral pleura of the lung and parietal pleura of the diaphragm. We diagnosed unresectable pleural metastases of synovial sarcoma and finished the operation after sampling another pulmonary pleural lesion. The patient then underwent ifomide-based chemotherapy and survived for 3 years after her initial surgery. Postoperative histopathological examination revealed a solid and bundle-like proliferation of a short spindle cell tumor with a monophasic pattern, which was diagnosed as a metastatic pleural synovial sarcoma. A hemangio-pericytomatous pattern was also seen; therefore the lesion looked like a blood clot because of its rich vascularity. PMID- 17717504 TI - Localized malignant mesothelioma of the pleura. AB - Because malignant mesothelioma is commonly seen as a diffuse neoplasm, a localized tumor is an extremely rare form of presentation. Only 45 cases have been reported, and little is known about their behavior. We report a new case of localized malignant mesothelioma with the microscopic appearance of diffuse malignant mesothelioma, but without any evidence of diffuse spread. A 54-year-old man, a former smoker, with a brief history of asbestos exposure for 3 months, presented with a severe right chest pain and a swelling in the same area. Chest computed tomography (CT) showed a 4.5 cm extra pleural tumor with a smooth surface, located in the right anterior chest wall, and destruction of the 5th rib. A CT-guided needle biopsy revealed malignant mesothelioma. Detailed examinations revealed a resectable solitary localized mass with no distant metastasis. The patient underwent operation, a tumorectomy, plus a combined resection of the chest wall and part of the right middle lobe. A complete en bloc resection was achieved. Pathology revealed localized malignant mesothelioma, biphasic type. Immunohistochemical findings confirmed the mesothelial feature. Localized malignant mesothelioma should be distinguished from diffuse malignant mesothelioma because of its different biological behavior, and in the former complete resection it is associated with a good prognosis. PMID- 17717505 TI - A case of pulmonary artery bypass surgery for a patient with isolated Takayasu pulmonary arteritis and a review of the literature. AB - A 45-year-old female was presented with progressive dyspnea and bilateral leg edema. Pulmonary angiography revealed total occlusion of the right pulmonary artery and significant stenosis of the left pulmonary artery. The inferior lobar artery as well as the segmental arteries were well patent. No pathology was detected elsewhere at the aorta and its branches. The diagnosis of chronic pulmonary arterial occlusion by isolated Takayasu arteritis was made because of the characteristic pattern of angiographic findings and the presence of unusual shunt formation from the coronary artery to the peripheral portion of the pulmonary artery, as well as a characteristic presentation of HLA typing in blood analysis, which strongly suggested the diagnosis of Takayasu arteritis. To restore the pulmonary blood flow, we employed reconstructive surgery by means of bypass procedure, using PTFE graft. Postoperatively there was marked improvement in cardiopulmonary function and the quality of life of the patient. The graft was proved to be patent at long-term follow-up study. An extremely rare case of chronic occlusive pulmonary arteritis, which was surgically treated by means of bypass procedure, is reported herein, and a brief review of previous reports on this subject was attempted. PMID- 17717506 TI - Atrial septal defect and retrosternal toxic goitre operated in the same session: a case report. AB - In this study, we present a 55-year-old female patient who suffered from atrial septal defect (ASD) and retrosternal toxic goitre simultaneously. The patient had been treated with a 300 mg/day dose of propylthiouracil for 20 days prior to operation. This patient has been operated on for both disorders and has recovered. PMID- 17717507 TI - Coronary sinus dissection during left ventricular pacing electrode implantation. AB - Coronary sinus (CS) dissection during biventricular pacing electrode implantation is a complication that rarely develops. A 71-year-old female with recurrent ventricular tachycardia, heart decompensation, and poor left ventricular function because of dilated cardiomyopathy was admitted for the implantation of a cardioverter-defibrillator for biventricular pacing. During the operation, we experienced a CS dissection with hematoma in the left ventricle wall while introducing the guidance catheter into the CS. However, the pacing lead was successfully implanted into the posterolateral vein using the "over-the-wire" technique. The postoperative electrocardiogram showed a decreased QRS; meanwhile, the echocardiography revealed dimensional reduction and functional improvement of the left ventricle. PMID- 17717508 TI - Less invasive direct coronary artery bypass grafting using H graft for a patient with advanced prostatic cancer. AB - Minimally invasive direct coronary artery bypass grafting (MIDCAB) using an H graft was performed on a 74-year-old man with advanced prostatic cancer who needed coronary revascularization. Through a left anterior small thoracotomy, the left internal thoracic artery (LITA) and the left anterior descending artery (LAD) were cleared, and a short radial artery (RA) was placed in an end-to-side fashion between the LITA and LAD. The distal LITA was ligated to avoid potential steal phenomenon. A flow pattern through the RA graft evaluated by transit time flow measurements demonstrated good diastolic flow with a mean value of 37 mL/min. The total surgical duration was 80 min, and no blood products were required. A postoperative angiogram showed a widely patent H graft. The patient was relieved of chest pain and was discharged. The H graft procedure is a useful alternative technique to minimize the surgical trauma in limited situations such as a high-risk case. PMID- 17717509 TI - A case of aortoenteric fistula following abdominal aortic reconstruction. AB - We report the case of a 64-year-old male patient with graft-enteric fistula. This complication might have been induced by sigmoid colonic ischemia resulting from injury to the mesocolon during abdominal aortic reconstruction. Although sigmoid colonic exteriorization was performed to avoid simultaneous colonic resection, graft-enteric fistula could not be prevented. Two further emergent operations were required to obtain complete remission from this complication, comprising bilateral extra-anatomical axillofemoral bypass grafts and infected graft removal, followed by an operation for left common iliac artery stump disruption. Although the patient remained in good health for 3 years with no complications, he died of aortic stump disruption 43 months after the last operation. PMID- 17717510 TI - Early initiation of polymyxin B-immobilized fiber therapy effective for septic shock after aortic replacement. AB - A 76-year-old female underwent ascending aorta and partial arch replacement. She developed septic shock on postoperative day 6. She was administered dopamine, 10 microg x kg(-1) x min(-1); dobutamine, 5 microg x kg(-1) x min(-1); and norepinephrine, 0.3 microg x kg(-1) x min(-1). However, the blood pressure was 74/40 mmHg. Direct hemoperfusion using polymyxin B-immobilized fiber (PMX-DHP) was started; 3 h later, the blood pressure increased to 118/54 mmHg. Norepinephrine was stopped, and dopamine and dobutamine doses were decreased to 5 microg x kg(-1) x min(-1) 3 and 12 h after completing PMX-DHP, respectively. In suspected septic shock, early PMX-DHP simultaneously with drug treatment facilitates hemodynamic improvement. PMID- 17717511 TI - Spontaneous rupture of the dorsalis pedis artery: report of a case. AB - A 52-year-old man underwent the repair of a spontaneous rupture of the dorsalis pedis artery. We considered that untreated hypertension was one possible cause of the rupture. This is a rare case of spontaneous rupture in a peripheral artery. PMID- 17717512 TI - Outbreaks of respiratory illness mistakenly attributed to pertussis--New Hampshire, Massachusetts, and Tennessee, 2004-2006. AB - Pertussis, or whooping cough, is a highly infectious, nationally notifiable respiratory disease associated with prolonged cough illness and paroxysms of coughing, inspiratory "whoop," or posttussive vomiting. Reported pertussis cases have tripled in the United States since 2001, with 25,616 probable or confirmed cases reported in 2005. This increase has been attributed to increased circulation of Bordetella pertussis, waning vaccine-induced immunity among adults and adolescents, heightened awareness of pertussis among health-care providers, increased public health reporting, and increased use of polymerase chain reaction (PCR) testing for diagnosis. To minimize the spread of pertussis, control measures must be implemented early in the course of illness when the risk for transmission is highest. However, diagnosis of pertussis is complicated by nonspecific signs and symptoms, particularly in the early catarrhal stage of disease. In addition, the lack of rapid, sensitive, and specific laboratory tests makes early and accurate identification of pertussis challenging. This report describes two hospital outbreaks and one community outbreak of respiratory illness during 2004-2006 in New Hampshire, Massachusetts, and Tennessee that were attributed initially to pertussis. However, subsequent investigations revealed negative or equivocal laboratory results and epidemiologic and clinical features atypical of pertussis, suggesting that pertussis was not the cause of these outbreaks. The findings in this report underscore the need for thorough epidemiologic and laboratory investigation of suspected pertussis outbreaks when considering extensive control measures. PMID- 17717513 TI - Norovirus activity--United States, 2006-2007. AB - In late 2006, CDC began receiving requests from numerous state public health departments for information about a perceived increase in the number of outbreaks of acute gastroenteritis (AGE), especially those involving person-to-person transmission in long-term--care facilities. No national surveillance system exists for AGE outbreaks, including those caused by norovirus, unless foodborne transmission is suspected. In the absence of national surveillance data, CDC attempted to better characterize the outbreaks of AGE by analyzing information from the following sources: 1) detailed data on recent AGE outbreaks in three of the states that had contacted CDC about a possible increase (North Carolina, Wisconsin, and New York); 2) emergency department (ED) syndromic surveillance data from Boston, Massachusetts; 3) basic epidemiologic data on AGE outbreaks from a CDC survey of state health departments; and 4) laboratory data from CDC. The analysis suggests that a national increase has occurred in the frequency of AGE outbreaks caused by norovirus (including fatal cases in long-term-care facilities). Two new cocirculating GII.4 norovirus strains emerged nationwide in 2006 and likely accounted for this increase in activity. Improved national surveillance of outbreaks, including those with person-to-person transmission; development of accessible, affordable, and timely clinical tests; and increased access to a norovirus strain sequencing database at CDC will lead to more accurate assessment of the morbidity and mortality associated with norovirus and more rapid identification of newly emerging norovirus strains. PMID- 17717514 TI - CDC's 60th anniversary: director's perspective--Jeffrey P. Koplan, M.D., M.P.H., 1998-2002. AB - CDC approached the new millennium with strong programs, strong partners, and a strong reputation. Emblematic of scientific integrity, evidence-based information, and public trust, the quality of CDC's "brand" rivaled any in corporate America and was unique among federal agencies. CDC built on this brand recognition to advance its public health mission into the 21st century. Introduction of a new design element showcased the agency as a valuable federal asset. PMID- 17717515 TI - How stem cells age and why this makes us grow old. AB - Recent data suggest that we age, in part, because our self-renewing stem cells grow old as a result of heritable intrinsic events, such as DNA damage, as well as extrinsic forces, such as changes in their supporting niches. Mechanisms that suppress the development of cancer, such as senescence and apoptosis, which rely on telomere shortening and the activities of p53 and p16(INK4a), may also induce an unwanted consequence: a decline in the replicative function of certain stem cell types with advancing age. This decreased regenerative capacity appears to contribute to some aspects of mammalian ageing, with new findings pointing to a 'stem-cell hypothesis' for human age-associated conditions such as frailty, atherosclerosis and type 2 diabetes. PMID- 17717516 TI - Cancer and ageing: convergent and divergent mechanisms. AB - Cancer and ageing are both fuelled by the accumulation of cellular damage. Consequently, those mechanisms that protect cells from damage simultaneously provide protection against cancer and ageing. By contrast, cancer and longevity require a durable cell proliferation potential and, therefore, those mechanisms that limit indefinite proliferation provide cancer protection but favour ageing. The overall balance between these convergent and divergent mechanisms guarantees fitness and a cancer-free life until late adulthood for most individuals. PMID- 17717517 TI - Self-eating and self-killing: crosstalk between autophagy and apoptosis. AB - The functional relationship between apoptosis ('self-killing') and autophagy ('self-eating') is complex in the sense that, under certain circumstances, autophagy constitutes a stress adaptation that avoids cell death (and suppresses apoptosis), whereas in other cellular settings, it constitutes an alternative cell-death pathway. Autophagy and apoptosis may be triggered by common upstream signals, and sometimes this results in combined autophagy and apoptosis; in other instances, the cell switches between the two responses in a mutually exclusive manner. On a molecular level, this means that the apoptotic and autophagic response machineries share common pathways that either link or polarize the cellular responses. PMID- 17717518 TI - Mortality of full-term infants during the first month of life in a tertiary care hospital. AB - OBJECTIVE: The neonatal mortality rate is disproportionately influenced by preterm infants and does not reflect the rate in full-term infants. Our objectives were to estimate the full-term neonatal mortality rate and to identify causes of death in full-term infants during the first month of life. STUDY DESIGN: A retrospective study of full-term infant deaths during a 6-year period from 2000 to 2005, in a tertiary medical center. RESULT: During the study period there were 44,703 full-term births and 31 deaths, representing a mortality rate of 0.69 per 1,000 live births. The main cause of death was congenital anomalies (64.5%), specifically cardiac anomalies. Other causes were chromosomal anomalies or syndromes (12.9%), labor complications (12.9%), infections (3.2%), congenital diseases (3.2%) and metabolic disorders (3.2%). CONCLUSION: The mortality rate of full-term infants may be lower than previous estimates. Efforts aimed at decreasing mortality among full-term infants should focus on prenatal diagnosis. PMID- 17717519 TI - Psychological distress in parents of children with severe congenital heart disease: the impact of prenatal versus postnatal diagnosis. AB - OBJECTIVE: The purpose of the study was to evaluate coping and psychological functioning of parents of children prenatally or postnatally diagnosed with congenital heart disease. STUDY DESIGN: Parents of 10 infants prenatally diagnosed by fetal echocardiogram and 7 infants postnatally diagnosed with severe congenital heart disease completed the Brief Symptom Inventory (BSI) at the time of diagnosis, at the time of birth and 6 months after birth. Prenatal and postnatal groups were compared to each other and to BSI norms. RESULT: Although both groups scored higher than test norms at the time of diagnosis, they did not differ significantly from each other. Six months after birth, the postnatal group scores did not differ from test norms, but the prenatal group scores were still significantly higher than test norms. The severity of the child's heart lesion at diagnosis was related to parental distress levels; parents with children with more severe lesions had higher BSI scores. CONCLUSION: Results suggest the need to provide parents with psychological support, regardless of the timing of diagnosis. Parents of children with more severe lesions may be at risk for higher levels of psychological distress, particularly over time. PMID- 17717520 TI - Reliability of salivary theophylline in monitoring the treatment for apnoea of prematurity. AB - OBJECTIVE: To evaluate the reliability of salivary levels of theophylline in monitoring therapy of apnoea of prematurity. STUDY DESIGN: Aminophylline was administered intravenously in 13 infants with apnoea, in a loading dose of 5 mg/kg and maintenance dose of 3 mg/kg, every 8 h. The patients were divided into two groups according to their postconceptional age (PCA): group A, of infants with small PCA (32.8+/-2.0 weeks; n=6 cases), and group B, infants with higher PCA (37.1+/-0.8 weeks; n=7 cases). RESULTS: A total of 57 paired samples of serum and saliva were obtained in all 13 infants. The mean serum level of theophylline was 7.8+/-5.8 microg/ml and the ratio between serum and salivary concentration of theophylline was 1.53+/-0.28. A strong correlation between the serum and salivary concentration of theophylline (r=0.973) was found. Infants with small PCA had significant higher serum concentration of theophylline than those with higher PCA (10.6 vs 5.3 microg/ml; P=0.0002). The difference between the mean ratios of serum/salivary theophylline levels in the two groups was low (1.44 vs 1.62; P=0.0155). CONCLUSION: The strong correlation of theophylline in serum and in saliva recommends the salivary levels as a reliable method for monitoring the treatment of apnoea of prematurity. PMID- 17717521 TI - Cost, causes and rates of rehospitalization of preterm infants. AB - OBJECTIVE: To examine hospital readmissions for premature infants during the first year of life. STUDY DESIGN: The California maternal and newborn/infant hospital discharge records were examined for subsequent readmission during the first year of life for all newborns from 1992 to 2000. Discharge diagnoses, hospital days, demographic data and hospital charges for infants born preterm (<36 weeks gestation) were identified and evaluated. RESULT: About 15% of preterm infants required at least one rehospitalization within the first year of life (average cost per readmission 8,468 dollars, average annual cost in excess of 41 million dollars). Infants with gestational age <25 weeks had the highest rate of readmission (31%) and longest average length of stay (12 hospital days). The largest cohort, infants born at 35 weeks gestation, had the highest total cost of readmission (92.9 million dollars). The most common cause of rehospitalization was acute respiratory disease. There was no decrease in the number or cost of readmissions of premature infants for respiratory syncytial virus infections following the introduction of palivizumab in 1998. CONCLUSION: After initial discharge, premature infants continue to have significant in-patient health-care needs and costs. PMID- 17717522 TI - Validation of accuracy and community acceptance of the BIRTHweigh III scale for categorizing newborn weight in rural India. AB - OBJECTIVE: To determine the accuracy and acceptability of a handheld scale prototype designed for nonliterate users to classify newborns into three weight categories (>or=2,500 g; 2,000 to 2,499 g; and <2,000 g). STUDY DESIGN: Weights of 1,100 newborns in Uttar Pradesh, India, were measured on the test scale and validated against a gold standard. Mothers, family members and community health stakeholders were interviewed to assess the acceptability of the test scale. RESULT: The test scale was highly sensitive and specific at classifying newborn weight (normal weight: 95.3 and 96.3%, respectively; low birth weight: 90.4 and 99.2%, respectively; very low birth weight: 91.7 and 98.4%, respectively). It was the overall agreement of the community that the test scale was more practical and easier to interpret than the gold standard. CONCLUSION: The BIRTHweigh III scale accurately identifies low birth weight and very low birth weight newborns to target weight-specific interventions. The scale is extremely practical and useful for resource-poor settings, especially those with low levels of literacy. PMID- 17717523 TI - Computational models for detection of endocrinopathy in subfertile males. AB - The observation that men with sperm density greater than 10 million/ml had low probability of endocrinopathy led to a refinement in the evaluation of subfertility. Using statistical methods, we sought to provide a more accurate prediction of which patients have an endocrinopathy, and to report the outcome as the odds of having disease. In addition, by examining the parameters that influenced the model significantly, the underlying pathophysiology might be better understood. Records of 1035 men containing variables including testis volume, sperm density, motility as well as the presence of endocrinopathy were randomized into 'training' and 'test' data sets. We modeled the data set using linear and quadratic discriminant function analysis, logistic regression (LR) and a neural network. Wilk's regression analysis was performed to determine which variables influenced the model significantly. Of the four models investigated, LR and a neural network performed the best with receiver operating characteristic areas under the curve of 0.93 and 0.95, respectively, correlating to a sensitivity of 28% and a specificity of 99% for the LR model, and a sensitivity and specificity of 56 and 97% for the neural network model. Reverse regression yielded P-values for the testis volume and sperm density of <0.0001. The neural network and LR models accurately predicted the probability of an endocrinopathy from testis volume, sperm density and motility without serum assays. These models may be accessed via the Internet, allowing urologists to select patients for endocrinologic evaluation at http://www.urocomp.org. PMID- 17717524 TI - A typology of men's sexual attitudes, erectile dysfunction treatment expectations and barriers. AB - In total, 1122 men completed non-validated structured interviews on sexual attitudes and on erectile dysfunction treatment expectations and barriers. Dimensions of sexual attitudes and treatment expectations and barriers were extracted by factor analysis and subjects were grouped into types by cluster analysis. Five types emerged: the sensation seeker, the sensuous, the anxious, the confident and the abstinent. The majority of men agreed on the importance of sex for the partnership. For the majority of anxious, sensuous and sensation seeking men, sex was important for self-esteem. Expecting quality of life, enjoyment, self-esteem and hard reliable erections from treatment with phosphodiesterase-5 inhibitors, anxieties for side effects and loss of control, sexual abstinence and desire for an intensive sex life had the strongest impact on the likelihood of use. Men's sexual attitudes vary considerably and impact reactions to erection difficulties. A typology of five groups was developed, which will contribute to research on and understanding of men's sexual and treatment-seeking behaviors. PMID- 17717525 TI - A survey of commonalities relevant to function and dysfunction in pelvic and sexual organs. AB - Micturition, defecation and sexual function are all programmed through spinal reflexes that are under descending control from higher centres. Interaction between these reflexes can clearly be perceived, and evidence is accumulating the dysfunction in one reflex is often associated with dysfunction in another. In this article, we describe some of the basic properties and neural control of the smooth muscles mediating the reflexes, reviewing the common features that underlie these reflex functions, and what changes may be responsible for dysfunction. We propose that autonomic control within the pelvis predisposes pelvic and sexual organs to crosstalk, with the consequence that diseases and conditions of the pelvis are subject to convergence on a functional level. It should be expected that disturbance of the function of one system will inevitably impact adjacent systems. PMID- 17717526 TI - Effects of alfuzosin 10 mg once daily on sexual function in men treated for symptomatic benign prostatic hyperplasia. AB - We evaluated the effects of extended-release alfuzosin HCl 10 mg once daily (q.d.) on sexual function in men with lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). In a randomized, double-blind, placebo controlled study of men aged > or = 50 years, after a 28-day placebo run-in period, patients were randomized to receive alfuzosin 10 mg q.d. or matching placebo for 28 days. The mean change from baseline (day 1) in sexual function on day 29 was assessed using the Danish Prostate Symptom Score Sex (DAN-PSSsex) questionnaire. A total of 372 patients were randomized to receive alfuzosin (n=186) or placebo (n=186), with 355 completing the study. At baseline, 64% of the patients reported erectile dysfunction (ED) and 63% reported ejaculatory dysfunction (EjD). For the 320 patients who completed the DAN-PSSsex, alfuzosin treatment was associated with a significant improvement in the mean change from baseline in erectile function on day 29 compared with placebo (P=0.02). No significant difference was observed between the two treatment groups in the mean change from baseline in ejaculatory function on day 29. For patients with ED at baseline, a marginal improvement in erectile function was demonstrated with alfuzosin treatment (P=0.09 vs placebo). For patients with EjD at baseline, the mean change from baseline in ejaculatory function with alfuzosin was comparable to that with placebo. Dizziness was the most common adverse event with alfuzosin treatment (5 vs 0% with placebo), with other adverse events reported with comparable frequency in both treatment groups. After 1 month of treatment, alfuzosin 10 mg q.d. significantly improved erectile function in men with lower urinary tract symptoms/ benign prostatic hypertrophy and had no adverse effect on ejaculatory function. PMID- 17717527 TI - Exo70 interacts with phospholipids and mediates the targeting of the exocyst to the plasma membrane. AB - The exocyst is an octameric protein complex implicated in the tethering of post Golgi secretory vesicles to the plasma membrane before fusion. The function of individual exocyst components and the mechanism by which this tethering complex is targeted to sites of secretion are not clear. In this study, we report that the exocyst subunit Exo70 functions in concert with Sec3 to anchor the exocyst to the plasma membrane. We found that the C-terminal Domain D of Exo70 directly interacts with phosphatidylinositol 4,5-bisphosphate. In addition, we have identified key residues on Exo70 that are critical for its interaction with phospholipids and the small GTPase Rho3. Further genetic and cell biological analyses suggest that the interaction of Exo70 with phospholipids, but not Rho3, is essential for the membrane association of the exocyst complex. We propose that Exo70 mediates the assembly of the exocyst complex at the plasma membrane, which is a crucial step in the tethering of post-Golgi secretory vesicles for exocytosis. PMID- 17717528 TI - A sequential program of dual phosphorylation of KaiC as a basis for circadian rhythm in cyanobacteria. AB - The circadian phosphorylation cycle of the cyanobacterial clock protein KaiC has been reconstituted in vitro. The phosphorylation profiles of two phosphorylation sites in KaiC, serine 431 (S431) and threonine 432 (T432), revealed that the phosphorylation cycle contained four steps: (i) T432 phosphorylation; (ii) S431 phosphorylation to generate the double-phosphorylated form of KaiC; (iii) T432 dephosphorylation; and (iv) S431 dephosphorylation. We then examined the effects of mutations introduced at one KaiC phosphorylation site on the intact phosphorylation site. We found that the product of each step in the phosphorylation cycle regulated the reaction in the next step, and that double phosphorylation converted KaiC from an autokinase to an autophosphatase, whereas complete dephosphorylation had the opposite effect. These mechanisms serve as the basis for cyanobacterial circadian rhythm generation. We also found that associations among KaiA, KaiB, and KaiC result from S431 phosphorylation, and these interactions would maintain the amplitude of the rhythm. PMID- 17717529 TI - Poliovirus entry into human brain microvascular cells requires receptor-induced activation of SHP-2. AB - Viruses use specific receptor molecules to bind selectively to target cells. Receptors have often been considered as mere docking sites, but they may also possess intrinsic signaling capacities that serve to prime the cell for entry and infection. Poliovirus (PV) initiates infection by binding to the PV receptor (PVR) and causes paralytic poliomyelitis by replicating within motor neurons of the brain and spinal cord. We have examined the process by which PV enters cultured human brain microvascular endothelial cells (HBMEC), an in vitro model of the blood-brain barrier. We found that PV enters HBMEC by dynamin-dependent caveolar endocytosis, and that entry depends on intracellular signals triggered by virus attachment to PVR. Tyrosine kinase and RhoA GTPase activation initiated by PVR ligation were both essential. Virus attachment also induced tyrosine phosphorylation of PVR; this permitted the association of PVR with SHP-2, a protein tyrosine phosphatase whose activation was required for entry and infection. The results indicate that receptor-induced signals promote virus entry and suggest a role for tyrosine phosphatases in viral pathogenesis. PMID- 17717530 TI - The specificity of SNARE pairing in biological membranes is mediated by both proof-reading and spatial segregation. AB - Soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins mediate organelle fusion in the secretory pathway. Different fusion steps are catalyzed by specific sets of SNARE proteins. Here we have used the SNAREs mediating the fusion of early endosomes and exocytosis, respectively, to investigate how pairing specificity is achieved. Although both sets of SNAREs promiscuously assemble in vitro, there is no functional crosstalk. We now show that they not only colocalize to overlapping microdomains in the membrane of early endosomes of neuroendocrine cells, but also form cis-complexes promiscuously, with the proportion of the different complexes being primarily dependent on mass action. Addition of soluble SNARE molecules onto native membranes revealed preference for cognate SNAREs. Furthermore, we found that SNAREs are laterally segregated at endosome contact sites, with the exocytotic synaptobrevin being depleted. We conclude that specificity in endosome fusion is mediated by the following two synergistically operating mechanisms: (i) preference for the cognate SNARE in 'trans' interactions and (ii) lateral segregation of SNAREs, leading to relative enrichment of the cognate ones at the prospective fusion sites. PMID- 17717532 TI - Antioxidative effects of sulfurous mineral water: protection against lipid and protein oxidation. AB - OBJECTIVES: To investigate the antioxidative properties of sulfurous drinking water after a standard hydropinic treatment (500 ml day(-1) for 2 weeks). SUBJECTS/METHODS: Forty apparently healthy adults, 18 men and 22 women, age 41-55 years old. The antioxidant profile and the oxidative condition were evaluated in healthy subjects supplemented for 2 weeks with (study group) or without (controls) sulfurous mineral water both before (T0) and after (T1) treatment. RESULTS: At T1, a significant decrease (P<0.05) in both lipid and protein oxidation products, namely malondialdehyde, carbonyls and AOPP, was found in plasma samples from subjects drinking sulfurous water with respect to controls. Concomitantly, a significant increment (P<0.05) of the total antioxidant capacity of plasma as well as of total plasmatic thiol levels was evidenced. Tocopherols, carotenoids and retinol remained almost unchanged before and after treatment in both groups. CONCLUSIONS: The improved body redox status in healthy volunteers undergoing a cycle of hydropinic therapy suggests major benefits from sulfurous water consumption in reducing biomolecule oxidation, possibly furnishing valid protection against oxidative damage commonly associated with aging and age related degenerative diseases. PMID- 17717533 TI - Protein hydrolysate co-ingestion does not modulate 24 h glycemic control in long standing type 2 diabetes patients. AB - OBJECTIVE: Evaluate the efficacy of protein hydrolysate co-ingestion as a dietary strategy to improve blood glucose homeostasis under free-living conditions in long-standing type 2 diabetes patients. METHODS: A total of 13 type 2 diabetes patients were enrolled in a randomized, double-blind cross-over design and studied on two occasions for 40 h under strict dietary standardization but otherwise normal, free-living conditions. In one trial, subjects ingested a protein hydrolysate (0.4 g kg(-1) bw casein hydrolysate, PRO) with every main meal. In the other trial, a placebo was ingested (PLA). Blood glucose concentrations were assessed by continuous glucose monitoring. RESULTS: Average 24 h glucose concentrations were similar between the PLA and the PRO trials (8.9 +/- 0.8 vs 9.2 +/- 0.7 mmol l(-1), respectively). Hyperglycemia (glucose concentrations >10 mmol l(-1)) was experienced 34 +/- 9% of the time (8 +/- 2 h per 24 h) in the PLA trial. Protein hydrolysate co-ingestion with each main meal (PRO) did not reduce the prevalence of hyperglycemia (39 +/- 10%, 9 +/- 2 h per 24 h; P=0.2). CONCLUSION: Co-ingestion of a protein hydrolysate with each main meal does not improve glucose homeostasis over a 24 h period in long-standing type 2 diabetes patients. PMID- 17717531 TI - Molecular basis of the activity of the phytopathogen pectin methylesterase. AB - We provide a mechanism for the activity of pectin methylesterase (PME), the enzyme that catalyses the essential first step in bacterial invasion of plant tissues. The complexes formed in the crystal using specifically methylated pectins, together with kinetic measurements of directed mutants, provide clear insights at atomic resolution into the specificity and the processive action of the Erwinia chrysanthemi enzyme. Product complexes provide additional snapshots along the reaction coordinate. We previously revealed that PME is a novel aspartic-esterase possessing parallel beta-helix architecture and now show that the two conserved aspartates are the nucleophile and general acid-base in the mechanism, respectively. Other conserved residues at the catalytic centre are shown to be essential for substrate binding or transition state stabilisation. The preferential binding of methylated sugar residues upstream of the catalytic site, and demethylated residues downstream, drives the enzyme along the pectin molecule and accounts for the sequential pattern of demethylation produced by both bacterial and plant PMEs. PMID- 17717534 TI - Effects of sucromalt on postprandial responses in human subjects. AB - BACKGROUND/OBJECTIVE: To compare postprandial responses elicited by sucromalt, a nutritive sweetener produced by treating a blend of sucrose and corn syrup with an enzyme from Leuconostoc mesenteroides, with those after 42% of high-fructose corn syrup (HFCS), and to see if the reduced responses after sucromalt could be accounted for by carbohydrate malabsorption. SUBJECT AND METHODS: Three experiments were performed in separate groups of normal subjects studied after overnight fasts using double-blind, randomized, cross-over designs. HFCS was used as the control because it contained a similar amount of fructose as sucromalt. Experiment 1 (n = 10): plasma glucose and insulin were measured after 50 g sucromalt and 50 g HFCS. Experiment 2 (n = 10): metabolic profiles were measured after 80 g HFCS, 80 g sucromalt or 56 g fructose/glucose blend plus 24 g inulin. Experiment 3 (n = 20): the glycaemic indices of sucromalt and HFCS were determined. RESULTS: Mean glucose and insulin responses after sucromalt were 66 and 62%, respectively, of those after HFCS (P < 0.05). The inulin treatment, used to mimic the effects of carbohydrate malabsorption, elicited higher breath hydrogen (H2), lower glucose and insulin responses, and a significantly earlier rise in serum free fatty acids (FFA) than those of HFCS (all P < 0.05). Sucromalt elicited no rise in breath H2, and delayed falls in glucose and insulin, and a delayed rebound of FFA compared to HFCS (all P < 0.05). CONCLUSIONS: The reduced glucose and insulin responses elicited by sucromalt are not explained by malabsorption and are more likely related to differences in either rate of digestion and absorption or postabsorptive handling by body. PMID- 17717535 TI - Growth around puberty as predictor of adult obesity. AB - OBJECTIVES: To contribute to the early risk identification of adult obesity, the anthropometric development in the first 23 years of life as a potential predictor for adult obesity was assessed. To identify the period (7-11 years, 11-16 years and 16-23 years) and type of anthropometric measure difference (weight, height and body mass index (BMI) gains) accounting for the best prediction of obesity at 33 years. SUBJECTS/METHODS: A total of 4952 members of the 1958 British birth cohort with full information on anthropometric measures. Follow-up examinations at 7, 11, 16, 23 and 33 years were analyzed with receiver-operating characteristics (ROCs). RESULTS: Overall 505 cohort members (10.2%) were obese at 33 years. BMI and weight gains between 7 and 11 years were the best-observed predictors for obesity at 33 years with an area under the ROC curve of 0.72 (95% confidence interval (CI): 0.69; 0.74) and 0.73 (95% CI: 0.71; 0.76), respectively. Height gain failed as a significant predictor at any lifetime interval. BMI gain between 7 and 11 years yielded a positive predictive value of 20% (95% CI: 19; 21) compared to 19% (95% CI: 18; 20) for weight gain. The prediction of BMI and weight gains between 7 and 11 years seemed to be unrelated to sex and the onset of puberty. CONCLUSIONS: High weight or BMI gain from 7 to 11 years should be considered as risk factor of later obesity. These predictors combined with others might allow for targeting preventive measures at a high-risk sub-population. PMID- 17717536 TI - Television viewing and obesity: a prospective study in the 1958 British birth cohort. AB - OBJECTIVE: To assess whether frequency of television viewing in adolescence (11 and 16 years) or early adulthood (23 years) affected subsequent changes in body mass index (BMI) through to mid-adulthood life, and waist-hip ratio in mid adulthood. SUBJECTS: The 1958 British birth cohort includes all births in 1 week in March 1958 in England, Scotland and Wales. The main analyses included at least 11 301 participants. Outcome measures included BMI at 16, 23, 33 and 45 years and waist-hip ratio at 45 years. RESULTS: Watching television 'often' at 16 years (but not 11 years) was associated with a faster gain in BMI between 16 and 45 years in males (0.011 kg m(-2) per year, 95% confidence interval (CI) 0.003, 0.019) and females (0.013 kg m(-2) per year, 95%CI 0.003, 0.023). More frequent television viewing at 11, 16 and 23 years was associated with a faster gain in BMI between 23 and 45 years in females, but not in males. Television viewing at 23 years was associated with waist-hip ratio at 45 years: participants watching > or = 5 times per week had a waist-hip ratio 0.01 higher than those watching less often. At 45 years, those watching television for > or = 4 h day(-1) had a waist hip ratio 0.03-0.04 higher than those watching for <1 h day(-1). CONCLUSIONS: More frequent television viewing in adolescence and early adulthood is associated with greater BMI gains through to mid-adulthood and with central adiposity in mid life. Television viewing may be a useful behaviour to target in strategies to prevent obesity. PMID- 17717537 TI - An evaluation of patterns of change in total and regional body fat mass in healthy Spanish subjects using dual-energy X-ray absorptiometry (DXA). AB - BACKGROUND/OBJECTIVE: The aim of this study was to describe the evolution of total and regional fat mass according to gender, and to establish age and gender related differences in a largely non-obese sedentary Spanish sample population using dual-energy X-ray absorptiometry (DXA). SUBJECT/METHODS: A total of 1113 healthy subjects (397 male and 716 female) from the city of Alcala de Henares (Madrid), Spain, were used in the study. Fat mass measures were obtained from DXA scans of all subjects. Total body fat and body fat in three subregions (trunk, arms and legs) were evaluated. RESULTS: As opposed to males, females showed from early infancy a smaller rate of muscular mass and a larger percentage of body fat (from 10 years of age), with fat deposits being basically gynoid or peripheral. With age, females showed a greater increase in fat mass together with an accelerated loss of muscular mass. Both rates tended to level out between 51 and 65 years of age. Between the ages of 40 and 60, females exhibited significant morphological evidence of larger fat depots in their legs. CONCLUSIONS: Gender differences in the patterns of proportion and distribution of body fat, as well as in the pattern of body fat evolution, were found from early infancy. Further research is required, including assessing fat mass variables in order to unravel the dynamic of body composition and to understand the complex relationship between trunk fat mass deposits and the health risks associated with obesity. PMID- 17717538 TI - Light-controlled gene silencing in zebrafish embryos. AB - Functional genomic studies in zebrafish frequently use synthetic oligonucleotides called morpholinos that block RNA splicing or translation. However, the constitutive activity of these reagents limits their experimental utility. We report here the synthesis of a photoactivatable morpholino targeting the no tail (ntl) gene. This caged reagent permits spatiotemporal gene regulation in vivo and the photochemical generation of functionally mosaic organisms. PMID- 17717539 TI - Getting to the site of inflammation: the leukocyte adhesion cascade updated. AB - Neutrophil recruitment, lymphocyte recirculation and monocyte trafficking all require adhesion and transmigration through blood-vessel walls. The traditional three steps of rolling, activation and firm adhesion have recently been augmented and refined. Slow rolling, adhesion strengthening, intraluminal crawling and paracellular and transcellular migration are now recognized as separate, additional steps. In neutrophils, a second activation pathway has been discovered that does not require signalling through G-protein-coupled receptors and the signalling steps leading to integrin activation are beginning to emerge. This Review focuses on new aspects of one of the central paradigms of inflammation and immunity--the leukocyte adhesion cascade. PMID- 17717540 TI - Developmental pathways that generate natural-killer-cell diversity in mice and humans. AB - Natural killer (NK) cells are large granular lymphocytes capable of producing inflammatory cytokines and spontaneously killing malignant, infected or 'stressed' cells. These NK-cell functions are controlled by cell-surface receptors that titrate stimulatory and inhibitory signals. However, we remain puzzled about where and when NK cells develop and differentiate, and this has fuelled the debate over the diversification of the peripheral NK-cell pool: are NK cells functionally homogeneous or are there subsets with specialized effector functions? In this Review, we consider the developmental relationships and biological significance of the diverse NK-cell subsets in mice and humans, and discuss how new humanized mouse models may help to characterize them further. PMID- 17717541 TI - Men's perception of maternal mortality in Nigeria. AB - Innovative and effective options toward reducing maternal mortality rates in African nations must include the active participation of all stakeholders. This study was carried out to assess men's level of knowledge and attitude to preventing maternal deaths. In a cross-sectional, community-based survey complemented with exploratory in-depth interviews, data were collected from men from different socio-economic areas using a two-stage cluster sampling technique. Mean age of the 316 respondents was 39.9 years (range 19-66). Nearly half (47.8%) knew someone who had died at childbirth. They blamed maternal deaths on healthcare workers not being skilled enough, financial barriers, failure to use family planning, emergency, antenatal, and delivery care services. Factors associated with knowledge and attitude to preventing maternal mortality are discussed. Healthcare reforms must be coupled with socio-economic improvements and efforts made to improve men's attitudes and knowledge in such a way as to make them active stakeholders, more supportive of preventing maternal mortality. PMID- 17717542 TI - Commentary: Gender and health. PMID- 17717543 TI - Commentary: From scarcity to abundance: pandemic vaccines and other agents for "have not" countries. AB - The recent impasse between the Indonesian Ministry of Health and the World Health Organization (WHO) over sharing H5N1 viruses in return for access to affordable pandemic vaccines highlights slow progress in defining an antigen sparing vaccine formulation, developing licensing requirements that meet the needs of populations and obtaining government funding for vaccine trials. Currently, vaccine-producing countries would have difficulty producing enough doses for their own people and few doses would be left over for non-producing ("have not") countries. Yet within a few months of the onset of a new pandemic, several billion doses of live attenuated and recombinant hemagglutinin H5 vaccines could be produced for "have not" countries, provided a new and disruptive system of "top down" management could be organized. In its absence, a "bottom-up" alternative that uses widely available and inexpensive generic agents like statins must be considered. The "have not" countries must continue to put pressure on WHO and leading countries to ensure that they will have access to the interventions they will need. PMID- 17717544 TI - High-impact medical journals and peace: a history of involvement. AB - The aim of this study is to explore the positions of five leading general medical journals (The Lancet, British Medical Journal--BMJ, Journal of American Medical Association--JAMA, New England Journal of Medicine--NEJM, and Annals of Internal Medicine--AIM) toward the issues of collective violence. We calculated the proportion of war-related articles in the total number of articles published in these five high-impact journals, and in the total number of articles indexed in PubMed during the last 60 years. The results showed a continuous increase in the proportion of war-related articles. Our findings suggest that the leading general medical journals have taken an active editorial stance toward the issues of war and peace. We conclude that high-impact medical journals can make an important contribution to efforts aimed at reducing the risks and consequences of war and violence. PMID- 17717545 TI - Do standard measures of deprivation reflect health inequalities in older people? AB - The objective of the study is to examine the relationship between different deprivation indicators and both self-rated health and emergency admission rates of older people to determine which indicators best predict the health of people in this age group. The method employed an ecological study design using data from all 100 neighbourhoods in Sheffield in 2004 and analysing relationships in three age groups 50-64, 65-74 and over 75 years. Analysis was performed using Pearson correlation coefficient. For people aged 50-64 years, receipt of income support was the best predictor of poor self-reported health (R=0.85). For people aged 64 75 years, lack of formal educational qualifications showed the strongest relationship with poor health (R=0.88), although there was still a significantly strong relationship between poor self-rated health and both non-property ownership (R=0.8) and receipt of income support (R=0.7) in this age group. For people aged 75 years and over, lack of formal qualifications showed the strongest relationship (R=0.6, P<0.001). This was reinforced by a strong relationship between this indicator and emergency admission rates. In conclusion, caution should be used when using conventional deprivation/poverty measures to select older populations to be targeted for services. Our analysis has shown that the deprivation indicator that correlates best with the subjective health rating of people aged 75+ is educational qualification. PMID- 17717547 TI - The alchemy of abstinence-only education: will the new study be sufficient to end it? PMID- 17717548 TI - Health vs. medicine: least we forget. PMID- 17717550 TI - Identification of prognostically relevant and reproducible subsets of endometrial adenocarcinoma based on clustering analysis of immunostaining data. AB - Panels of immunomarkers can provide greater information than single markers, but the problem of how to optimally interpret data from multiple immunomarkers is unresolved. We examined the expression profile of 12 immunomarkers in 200 endometrial carcinomas using a tissue microarray. The outcomes of groups of patients were analyzed by using the Kaplan-Meier method, using the log-rank statistic for comparison of survival curves. Correlation between clustering results and traditional prognosticators of endometrial carcinoma was examined by either Fisher's exact test or chi2-test. Multivariate analysis was performed using a proportional hazards method (Cox regression modeling). Seven of the 12 immunomarkers studied showed prognostic significance in univariate analysis (P<0.05) and 1 marker showed a trend toward significance (P=0.06). These eight markers were used in unsupervised hierarchical clustering of the cases, and resulted in identification of three cluster groups. There was a statistically significant difference in patient survival between these cluster groups (P=0.0001). The prognostic significance of the cluster groups was independent of tumor stage and patient age on multivariate analysis (P=0.014), but was not of independent significance when either tumor grade or cell type was added to the model. The cluster group designation was strongly correlated with tumor grade, stage, and cell type (P<0.0001 for each). Interlaboratory reproducibility of subclassification of endometrial adenocarcinoma by hierarchical clustering analysis was verified by showing highly reproducible assignment of individual cases to specific cluster groups when the immunostaining was performed, interpreted, and clustered in a second laboratory (kappa=0.79, concordance rate=89.6%). Unsupervised hierarchical clustering of immunostaining data identifies prognostically relevant subsets of endometrial adenocarcinoma. Such analysis is reproducible, showing less interobserver variability than histopathological assessment of tumor cell type or grade. PMID- 17717552 TI - Call of the wild. AB - Freud described "wild analysis" as an undisciplined version of psychoanalysis; but the new Penguin series of Freud's writings collects many of his papers under the title Wild Analysis, challenging the differentiation. This paper traces wild elements at the core of psychoanalytic thought, crediting Groddeck, Ferenczi, and Winnicott for bringing them to the open. The image of the wild analyst can serve us as the image of the deeply involved, personally motivated analyst, whose work is intense and emotionally risky. This is the opposite of the "civilized" analyst who uses well-defined existing paths, takes no personal risks, and therefore stays at an emotional distance from his/her patients. Every analyst's capacity to develop a unique analytic self, based on his/her genuine life experience and worldview, is endangered if stepping out of line is slandered as "wild analysis" or as insanity. The relevance of these issues for contemporary psychoanalytic thought and education is demonstrated. PMID- 17717553 TI - Ferenczi and Winnicott: searching for a "missing link" (of the soul). AB - The aim of this paper is to present the close link between Ferenczi's and Winnicott's theoretical, clinical and therapeutic thought, indicating how this link has become something of a "missing link" in the history of psychoanalytic ideas, an implication which we retain, in part, to this day. In the first part entitled "Who's speaking to whom?", I aim to explore the contents of the most essential parts of their messages, stressing the similarities and differences between them, and citing the most important authors whom they address (Freud for Ferenczi, Klein for Winnicott). In the second part, I aim to tackle the general direction underlying both their work and their lives, concentrating specifically on "the maternal", and examining the repercussions of this aspect on psychoanalytic technique and practice. In the third part, as a kind of "Parting", I will present further brief conclusions on the relevance and significance of their thoughts in modern day psychoanalysis, defining Ferenczi and Winnicott as "founders of future discursiveness". PMID- 17717554 TI - Body, mind and bonds. AB - In this paper, after reviewing some of the controversial concepts of psychosomatics, and their historical development as well as some of their theoretical and clinical consequences, I propose a vincular point of view of this type of pathology, with some dreams of a psychosomatic patient where different aspects of the proposed model can be observed. PMID- 17717555 TI - Embodiment. AB - Groddeck, most interestingly, proposed that the body manifested the mind, and the mind the body. I consider his interactional viewpoint from several perspectives. First, I discuss how the entire body not only is minded by and minding of all that occurs within and without, but as well how the developable capacity for mindfulness affects the perception of reality, within and without. Secondly, I consider the body as delusion, a seemingly necessary anchor into the reality of the physical world, whereas Groddeck's and Ferenczi's openness to ideas of telepathy and communication beyond death flirts with a disembodied transcendence of physicality. And third, I propose that Groddeck's psychoanalytic approach, like Buddhist meditational techniques, reveals an experiential flux of embodiment and disembodiment in each re-embodied moment of being alive. PMID- 17717556 TI - The power of the spoken word in life, psychiatry, and psychoanalysis--a contribution to interpersonal psychoanalysis. AB - Starting with a 1890 essay by Freud, the author goes in search of an interpersonal psychology native to Freud's psychoanalytic method and to in psychoanalysis and the interpersonal method in psychiatry. This derives from the basic interpersonal nature of the human situation in the lives of individuals and social groups. Psychiatry, the healing of the soul, and psychotherapy, therapy of the soul, are examined from the perspective of the communication model, based on the essential interpersonal function of language and the spoken word: persons addressing speeches to themselves and to others in relations, between family members, others in society, and the professionals who serve them. The communicational model is also applied in examining psychiatric disorders and psychiatric diagnoses, as well as psychodynamic formulas, which leads to a reformulation of the psychoanalytic therapy as a process. A plea is entered to define psychoanalysis as an interpersonal discipline, in analogy to Sullivan's interpersonal psychiatry. PMID- 17717557 TI - Psychosomatics and technique. AB - Several clinical vignettes express the unconscious use of the patient's body as containing and enacting a somatic defense until free association enables affect to be found in the clinical setting. In this paper, there is a plea to take the body of the patient as seriously as the mind and language. As Ferenczi eloquently remarked "one needs to have lived through an affective experience, to have, so to speak, felt it in ones body, in order to gain conviction." PMID- 17717558 TI - We are the daily bread of each other. AB - In this paper, I will attempt a cross-fertilization between some ideas of the Danish professor of ethics and philosophy of religion, K.E. Logstrup and some of the therapeutic ideas of Sandor Ferenczi. I will especially discuss the phenomenon of trust, and the response it awakens in the person to whom the trust is directed, especially as evident in the thearapeutic relationship. PMID- 17717559 TI - Mindless bodies-bodyless minds. AB - Possibilities opened up by scientific-technical developments of the last century have led to the breaking up of our basic concepts regarding elementary aspects of human life. Boundaries are more easily crossed (also among genders); the reality of functions and the functions of reality are becoming interchangeable. The audio visual galaxy, which has evolved over the course of the 20th century, with its two dimensionality has resulted in generations growing up in the past decades who have learnt that the "other" can be a virtual body: the sensual is no longer an essential part of human relations. The somato-affective aspects of the experience get split off-relationships emerge between bodyless minds. This fragmentation also means that the body is seen increasingly as mindless: the linkages between body and mind are profoundly undermined. Reality and fantasy melt into one another. Reality control and thinking becomes insecure effected by a view of the world that has lost its keystones of orientation. When body boundaries get confused in such a manner how do ego boundaries develop? How will primary relationships alter among such conditions? What will the internal images of the objects be like? The deconstruction of our basic concepts about space, time, dimensions, body- and ego boundaries made differentiation and the processes of symbolization extremely difficult. Postmodern ideas, questioning the validity of facts have contributed greatly to transforming our image of reality also on a theoretical level. How do these massive changes effect our daily clinical work and our theory of the mind? My paper tries to explore some experiences and ideas related to these questions through clinical cases and narratives of our present times. PMID- 17717560 TI - Scientific meeting of the American Institute for Psychoanalysis. The play is the thing. PMID- 17717561 TI - The incidence and implications of aldosterone breakthrough. AB - Interruption of the renin-angiotensin-aldosterone system has become a leading therapeutic strategy in the treatment of chronic heart and kidney disease. Angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers do not, however, uniformly suppress the renin-angiotensin-aldosterone system. Plasma aldosterone levels are elevated in a subset of patients despite therapy. This phenomenon, known as 'aldosterone escape' or 'aldosterone breakthrough', has only been directly examined in small numbers of patients. The key questions of how often breakthrough occurs and whether breakthrough leads to worse outcomes have yet to be definitively answered. In this Review, we summarize the reported data on the incidence and clinical implications of aldosterone breakthrough, and highlight areas of uncertainty that have yet to be adequately addressed in the literature. Although the available evidence is not strong enough to support widespread screening for aldosterone breakthrough, our findings should prompt physicians to consider the phenomenon in select patients as well as guide future research efforts. PMID- 17717562 TI - Racial and survival paradoxes in chronic kidney disease. AB - Most of the 20 million people in the US with chronic kidney disease (CKD) die before commencing dialysis. One of every five dialysis patients dies each year in the US. Although cardiovascular disease is the most common cause of death among patients with CKD, conventional cardiovascular risk factors such as hypercholesterolemia, hypertension and obesity are paradoxically associated with better survival in hemodialysis populations. Emerging data indicate the existence of this 'reverse epidemiology' in earlier stages of CKD. There are also paradoxical relationships between outcomes and race and ethnicity. For example, the survival rate of African American dialysis patients seems to be superior to that of whites on dialysis. Paradoxes-within-paradoxes have been detected among Hispanic and Asian American CKD patients. These survival paradoxes might evolve and change over the natural course of CKD progression as a result of the time differentials of competing risk factors and the overwhelming impact of malnutrition, inflammation and wasting. Reversal of the reverse epidemiology as a result of successful kidney transplantation underscores the role of nutritional status and kidney function in engendering these paradoxes. The observation of paradoxes and their reversal might lead to the formulation of new paradigms and management strategies to improve the survival of patients with CKD. Such movement away from the use of targets set on the basis of data gathered in general populations (e.g. the Framingham cohort) would be a major paradigm shift in clinical medicine and public health. PMID- 17717563 TI - Renal function outcomes following liver transplantation and combined liver-kidney transplantation. AB - Acute renal failure (ARF) is common immediately after orthotopic liver transplantation (OLT), whereas the incidences of chronic kidney disease (CKD) and end-stage renal disease increase with time. Introduction of the Model for End stage Liver Disease (MELD) score-intended to prioritize patients with more-severe pretransplantation liver disease in general, and worse pretransplantation renal function in particular-for the allocation of liver grafts led to concerns about compromised patient and allograft survival and increased incidence of postoperative ARF and CKD. Nonetheless, it has been suggested that early OLT of candidates with baseline renal dysfunction improves post-transplantation renal outcomes. For OLT candidates with mild to moderate chronic renal impairment or recent-onset ARF, the decision of whether to perform OLT alone or combined liver kidney transplantation (CLKT) can be challenging because no single factor has been shown to be predictive of the degree of renal function recovery or CKD progression following successful OLT. In this article, we provide an overview of the literature on renal function outcomes following OLT and CLKT, share our perspectives on the potential predictors of renal dysfunction or nonrecovery of renal function after OLT, and present United Network for Organ Sharing data on patient and allograft outcomes in CLKT recipients in the pre-MELD and post-MELD eras. Mechanisms that might underlie immunological protection of kidney grafts by liver allografts are also discussed. PMID- 17717564 TI - Acute kidney injury, hyperosmolality and metabolic acidosis associated with lorazepam. AB - BACKGROUND: A 54-year-old male with a history of multiple admissions for alcohol intoxication was admitted to hospital with right flank pain. He received a high dose lorazepam infusion for alcohol withdrawal during hospitalization and developed severe hyperosmolality, high anion gap metabolic acidosis, and acute kidney injury on his eighth day of hospitalization. INVESTIGATIONS: Serum chemistries, arterial blood gas analysis, and measurement of serum propylene glycol, ethylene glycol and methanol levels. DIAGNOSIS: Propylene glycol toxicity. MANAGEMENT: Discontinuation of lorazepam infusion, administration of fomepizole, hemodialysis for five consecutive days, hemodynamic support, and follow-up of serum osmolality as a measure of propylene glycol decay. PMID- 17717565 TI - [Research and role models]. PMID- 17717566 TI - [Medical professionalism]. PMID- 17717567 TI - [Internship--time for new thinking]. PMID- 17717568 TI - [Infected with Chlamydia without knowing it]. PMID- 17717569 TI - [Genital Chlamydia among pupils in high school]. AB - BACKGROUND: The prevalence of genital chlamydial infection is increasing in Norway. The condition is usually asymptomatic, and screening seems to be the best way of finding infected persons. Our aim was to establish the prevalence of genital chlamydial infection among senior high school pupils in a Norwegian municipality and to link individual results with information on sexual behaviour. MATERIAL AND METHOD: All registrated 905 senior high school pupils in Baerum municipality were invited to participate in the study. Health care workers informed all classes about sexually transmitted infections, requested students to participate in the study, distributed anonymized questionnaires and laboratory requistions with containers for urine sampling and collected the urine samples; all on the same day in the different classes. The urinary samples were analysed for Chlamydia trachomatis by polymerase chain reaction. Pupils with positive results were contacted by mobile phone and given treatment and follow-up by the municipal medical officer. RESULTS: 673 (74 %) of 905 invited pupils participated in the study and 571 (63 %) delivered a urine sample. Chlamydia infection was detected in 8 (1.4 %) pupils; 6 (2.2 %) girls and 2 (0.7 %) boys. The prevalence was 2.0 % among the 457 (69 %) who had had sexual intercourse. The sexual debut age was below the age of 17 for 53 % of the pupils. DISCUSSION: This study showed a low prevalence of chlamydia infection among high school pupils, but much sexual activity and limited use of condom. The timing for giving information was therefore regarded as favourable. The participation rate was high, but lower than we had hoped for. Screening for chlamydia among high school pupils in Norway is feasible and may be a valuable tool for limiting the spread of genital chlamydia infections. PMID- 17717570 TI - [Detection of Chlamydia infection of an Internet-based commercial product]. AB - BACKGROUND: Free testing, treatment and extensive information campaigns are used to monitor and control the incidence of Chlamydia trachomatis infections in Norway. Most programmes have 15 to 25 year-olds as their target, because of the high incidence of infection in this age group. The potential role and effect of internet-based commercial testing has not previously been assessed in this context. MATERIAL AND METHODS: 1458 urine samples, taken by the patients themselves, were collected from March 2005 to September 2006 according to instructions given on the commercial web site www.testselv.no, and sent to a given address for analysis. Sex, age distribution and prevalence of Chlamydia trachomatis infection were assessed and all costs were paid by the patient buying the service. RESULTS AND INTERPRETATION: More men than women used this service, in contrast to the sex distribution seen in public screening programs. The mean age was 28 years, the 25 % percentile and the 75 % percentile was 24 and 32 years, respectively. The prevalence of infection was high; 7.5 % in women and 12.5 % in men. Our study identifies a demographic group with a high incidence of Chlamydia trachomatis infection that has not been previously been targeted by public screening programmes. PMID- 17717571 TI - [Handilab C Chlamydia for home testing is not what it claims]. AB - BACKGROUND: The Norwegian Institute of Public Health recommends increased testing for genital chlamydia infection to halt an increasing incidence. A rapid home test claiming a "safety" of 98% was marketed in Norwegian pharmacies in 2005 for use in women. MATERIAL AND METHODS: Women attending the Olafia Clinic in Oslo for a sexual health check were asked to perform a Handilab C test themselves. Samples for the nucleid acid amplification test (NAAT) were thereafter taken and sent to the microbiology laboratory. The results were compared. RESULTS: In a pilot study, 80 of 88 women completed both tests. Four tests were positive according to NAAT, none of which were interpreted as positive by Handilab C. A new study including 168 women was carried out because the first 50 tests provided by the Norwegian import company were found to be out of date and a new and better instruction form was provided. Of the 157 women who completed both tests, 16 had positive NAAT results for C trachomatis; four of these were interpreted as positive by the Handilab C test and 9 as uncertain (sensitivity 25-57%). Half of the women were uncertain about how to interpret the test result and 13 who had a negative NAAT interpreted Handilab C as positive (positive predictive value 24%). INTERPRETATION: Most women had no problems taking the vaginal swab test, but Handilab C did not fulfil its claim to be a "safe" rapid test. The majority were uncertain about how to interpret the result or had false negative or false positive results. PMID- 17717572 TI - [Involuntary admissions to an acute psychiatric ward]. AB - BACKGROUND: Involuntary admission to acute psychiatric wards in Norway has not been studied empirically after the introduction of a new Mental Health Act (MHA) 1 January 2001. According to the MHA, observation with coercion can be used to clarify illness. The objectives of this study were to describe scale and circumstances associated with involuntary admissions. METHOD: All patients discharged (n = 104) or transferred from an acute ward in the Norwegian county, Hedmark during the first six months of 2005 were included in the study. Information about the patients before and during the stay, including legal issues, was recorded. RESULTS: 49 patients (47%) were involuntarily admitted. Within 24 hours 22 (45%) of these had their status changed from involuntary to voluntary. 11 patients were observed with coercion according to the MHA on an average of 4.5 days. CONCLUSION: For about half of those admitted involuntarily the time of coerced observation was less than 24 hours. The out-of-hours emergency service referred more patients than regular GPs and the specialized health service, and it should be clarified whether this may lead to unnecessary involuntary admissions. More specific studies are needed on how to reduce involuntary admissions to psychiatric wards. PMID- 17717573 TI - [Electronic medical records should be structured]. AB - BACKGROUND: Use of information technology in the health services has not resulted in the benefits hoped for. An important prerequisite for success may be to structure electronic medical records. Is this assumption research-based? MATERIAL AND METHODS: PubMed was searched via Endnote. The search words "medical record (any field) + structured (any field)" resulted in 843 hits and "electronic decision support (any field)" resulted in 824. Titles and abstracts were used to identify relevant articles; titles identified 103 articles and abstracts 70. RESULTS: Research shows that structured electronic medical records can result in quicker data entry, improved quality and records that are useful in daily clinical work. Doctors and nurses prefer structured data entry; electronic nursing records are better and databases with structured electronic patient records can be used on a large scale to develop treatment regimes and quality assurance. Clinical decision support systems integrated into electronic medical records can provide positive cost-effectiveness. Most doctors and nurses understand the importance of such systems. INTERPRETATION: Structured data entry seems to be an important element in successful electronic medical record systems. PMID- 17717574 TI - [Lymphogranuloma venerum as ulcerous proctitis in men who have sex with men]. AB - Lymphogranuloma venerum (LGV), previously lymphogranulma inguinale, is a sexually transmitted infection caused by Chlamydia trachomatis serovar L1-L3. The disease is primarily manifested by a small papule or erosion in the genital region, followed by lymphadenitis and development of abscesses. Proctitis and systemic disease may occur subsequently. LGV has been a rare condition in the western world, but there have been frequent reports from larger cities in Europe and the USA from 2004. Outbreaks have been limited to networks of gay men practising mano brachial sex ("fisting"). The syndrome may easily be confused with chronic diseases of the gut, bacterial infections and other sexually acquired diseases. We present two HIV-positive gay men where lymphogranuloma venerum was found to be the cause of ulcerative proctitis. The diagnosis was confirmed by a positive Chlamydia test from the anus with subsequent subtyping. PMID- 17717575 TI - [The medical education in Oslo--consequences of the reform in 1996]. AB - BACKGROUND: The reformation of the University of Oslo's (UiO) medical education in 1996 consisted of integrating the topics more than previously. The old model had a clear division between pre-clinical and clinical subjects. MATERIAL AND METHOD: The last class (of 2001) with the old curriculum (155 of 266) and the second class (of 2003) with the new curriculum (81 of 131) at UiO, and the class of 2003 from the University of Bergen medical school (78 of 114) responded to mailed questionnaires sent to them 2-3 years after graduation. The control group from Bergen was chosen because this medical school has the most traditional curriculum of the four medical schools in Norway. Possible differences between these groups were examined in three areas: how they update themselves professionally, how they perceive their own clinical skills, and how they perceive their own ability to communicate with patients (clinical communication). RESULTS: Median time spent on professional update was 2.5 hours per week for the "traditional" Oslo students, 3.5 hours for the Oslo96 students and 4 hours for the Bergen students. The traditional Oslo students spent slightly less time on updating themselves via the internet. The proportion of respondents who reported to remain professionally updated without problems was 46 % for the Oslo96-doctors and 57% for the traditional Oslo doctors. This is significantly lower than the 70 % reported by all active Norwegian doctors, not controlled for age. With regard to clinical skills, there were almost negligible differences, but female doctors from Bergen scored significantly lower. Perceived clinical communication was good in all three groups. INTERPRETATION: There are few differences between young doctors in the three examined groups with regard to professional update habits, clinical skills and clinical communication skills. It is not possible to find a special Oslo96 effect from the measured variables. PMID- 17717576 TI - [Orientation programme for paediatric residents]. AB - BACKGROUND: Orientation programmes for new residents in paediatric departments are available in many Norwegian hospitals. The purpose of this study was to assess whether recently employed residents were content with the way they had been received and how these programmes were put into practice. MATERIAL AND METHODS: Two different questionnaires were used; one was sent to residents who had been employed for less than 12 months ago and one to the directors of 22 Norwegian paediatric departments. The residents were asked about the reception at their new workplace and how they had been introduced to the paediatric field, whether the counselling functioned and when they started independent call duties. We asked the directors for information concerning their orientation programmes for new employees. RESULTS: 20 of the directors answered the questionnaire. 13 departments had an orientation programme, and this was regularly followed in nine departments. 60 residents returned the questionnaire. 63% of the residents had been through some kind of orientation programme and a little more than half were assigned to a dedicated personal counsellor within two weeks after employment. The first personal counselling took place after a median of eight weeks. The residents' contentment with their reception in the department correlated significantly with the systematic use of an orientation programme. INTERPRETATION: The results of this study demonstrate a substantial potential for improvement in how we introduce and guide recently employed paediatric residents during their first weeks in a new job. PMID- 17717577 TI - [Women's academic careers in medicine]. AB - BACKGROUND: Few female doctors hold top academic positions at the University of Oslo. A working group was appointed by the Faculty of Medicine to investigate possible reasons for this and to come up with recommendations on how to increase the fraction of female professors. MATERIAL AND METHODS: A questionnaire was sent to 875 medical graduates who had either completed or were taking a PhD at the University of Oslo. Two focus group interviews were also performed, one with female and one with male graduates. RESULTS: The questionnaire response rate was 42%. The genders did not differ concerning motivation to pursue academic careers, and they both wished to have better access to combined positions (academic and clinical work). Women needed more positive signals on being wanted as researchers. For women below 45 years of age, academic and clinical role models and a good network were considered to be especially important. Women emphasized the importance of equality at home and at work for pursuing an academic career more than men. INTERPRETATION: The gender imbalance among medical professors will not resolve itself. Young women should be more actively identified and encouraged to pursue academic careers. PMID- 17717578 TI - [Higher salary as an incentive for scientific activity?]. AB - BACKGROUND: Few publications are available on how salaries are established for physicians with science as their main occupation. The results of a questionnaire survey to medical doctors are reported. MATERIAL AND METHODS: A questionnaire was sent to members of The Norwegian Medical Association's branch for doctors in academic medicine in spring 2005. Questions concerned how they thought scientific qualifications and production affected their present salary and what they considered to be a reasonable salary for a researcher with their qualifications and production. 304 of 487 (62%) doctors answered. RESULTS: The study included 128 full-time professors, 101 associate professors or post-doctoral scientists with a PhD, 44 scientists without a PhD and 31 PhD-students. The average age was 52 years, and 28% were women. 71% had a university as their main employer. The median number of peer-reviewed scientific publications was 19 per physician scientist for the last 5 years. The average annual salary was 498,000 NOK, and the average increase in salary considered to be reasonable was 279,000 NOK. A reasonable salary for evaluating a PhD-thesis was considered to be 18,700 NOK and that for giving a 45-minute lecture was 3,200 NOK. In a multiple linear regression analysis on actual salary, the significant predictors were employer, scientific qualifications, age, and sex. Predictors for the difference between reasonable and actual salary was scientific production and employer. Age, employer or scientific qualifications could not predict who considered a doubling of the present salary (for a 45-minute lecture and evaluating a PhD) to be appropriate. INTERPRETATION: Universities should be aware of the large gap between salaries to physician-scientists employed by universities and to those employed by other institutions. Scientific production should be more emphasized in future negotiations on salaries. PMID- 17717579 TI - [Internship is both learning and work]. PMID- 17717580 TI - [Glucosamine--the big sugar pill bluff]. PMID- 17717581 TI - [Arterial insufficiency in the legs]. PMID- 17717582 TI - [Follow up of patients with type 2 diabetes]. PMID- 17717584 TI - [Is there a need of glitazones in the treatment of diabetes?]. PMID- 17717586 TI - [Should follow up of patients with type 2 diabetes be performed at outpatient clinics?]. PMID- 17717587 TI - [Mental disorders and heart disease]. PMID- 17717589 TI - [Quality of life in amyotrophic lateral sclerosis]. PMID- 17717590 TI - [Physicians Without Borders need surgeons and anesthesiologists]. PMID- 17717591 TI - [Age and dignity--a self-portrait of Alice Neel]. PMID- 17717593 TI - [Among the best fistula surgeons in the world]. PMID- 17717596 TI - In vivo bactericidal activities of Japanese rice-fluid against H. pylori in a Mongolian gerbil model. AB - PURPOSE: The antibiotic effect of rice-fluid on Helicobacter pylori infection was investigated using a Mongolian gerbil model. METHODS: Gerbils were divided into four groups: H. pylori -infected, rice-fluid-treated animals (group A); H. pylori -infected, untreated animals (group B); uninfected, rice-fluid-treated animals (group C); and uninfected, untreated animals (group D). Group A and B animals were killed 14 weeks after H. pylori infection and group C and D animals were killed at the same age. The stomachs were examined for histology, 5'-bromo-2' deoxyuridine (BrdU) labeling, and the bacterial burden. Serum anti-H. pylori antibody titers were also tested. RESULTS: The positive incidence of H. pylori culture was 25 and 84 % in groups A and B, respectively (p<0.01). Both the degree of inflammation and the BrdU labeling index in group A were significantly lower than those in group B. CONCLUSIONS: Rice-fluid showed an antibiotic effect on H. pylori and an anti-inflammatory effect on the H. pylori -associated gastritis. PMID- 17717597 TI - FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. AB - Blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome positive (Ph1-positive) acute lymphocytic leukemia (ALL) are 2 fatal BCR/ABL driven leukemias against which Abl kinase inhibitors fail to induce a long-term response. We recently reported that functional loss of protein phosphatase 2A (PP2A) activity is important for CML blastic transformation. We assessed the therapeutic potential of the PP2A activator FTY720 (2-amino-2-[2-(4 octylphenyl)ethyl]-1,3-propanediol hydrochloride), an immunomodulator in Phase III trials for patients with multiple sclerosis or undergoing organ transplantation, in CML-BC and Ph1 ALL patient cells and in in vitro and in vivo models of these BCR/ABL+ leukemias. Our data indicate that FTY720 induces apoptosis and impairs clonogenicity of imatinib/dasatinib-sensitive and resistant p210/p190(BCR/ABL) myeloid and lymphoid cell lines and CML-BC(CD34+) and Ph1 ALL(CD34+/CD19+) progenitors but not of normal CD34+ and CD34+/CD19+ bone marrow cells. Furthermore, pharmacologic doses of FTY720 remarkably suppress in vivo p210/p190(BCR/ABL)-driven [including p210/p190(BCR/ABL)(T315I)] leukemogenesis without exerting any toxicity. Altogether, these results highlight the therapeutic relevance of rescuing PP2A tumor suppressor activity in Ph1 leukemias and strongly support the introduction of the PP2A activator FTY720 in the treatment of CML-BC and Ph1 ALL patients. PMID- 17717598 TI - Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing nitric oxide, autonomic activity, and cardiovascular risk. AB - GTP cyclohydrolase 1 (GCH1) is rate limiting in the provision of the cofactor tetrahydrobiopterin for biosynthesis of catecholamines and NO. We asked whether common genetic variation at GCH1 alters transmitter synthesis and predisposes to disease. Here we undertook a systematic search for polymorphisms in GCH1, then tested variants' contributions to NO and catecholamine release as well as autonomic function in twin pairs. Renal NO and neopterin excretions were significantly heritable, as were baroreceptor coupling (heart rate response to BP fluctuation) and pulse interval (1/heart rate). Common GCH1 variant C+243T in the 3'-untranslated region (3'-UTRs) predicted NO excretion, as well as autonomic traits: baroreceptor coupling, maximum pulse interval, and pulse interval variability, though not catecholamine secretion. In individuals with the most extreme BP values in the population, C+243T affected both diastolic and systolic BP, principally in females. In functional studies, C+243T decreased reporter expression in transfected 3'-UTRs plasmids. We conclude that human NO secretion traits are heritable, displaying joint genetic determination with autonomic activity by functional polymorphism at GCH1. Our results document novel pathophysiological links between a key biosynthetic locus and NO metabolism and suggest new strategies for approaching the mechanism, diagnosis, and treatment of risk predictors for cardiovascular diseases such as hypertension. PMID- 17717599 TI - Obesity-associated improvements in metabolic profile through expansion of adipose tissue. AB - Excess caloric intake can lead to insulin resistance. The underlying reasons are complex but likely related to ectopic lipid deposition in nonadipose tissue. We hypothesized that the inability to appropriately expand subcutaneous adipose tissue may be an underlying reason for insulin resistance and beta cell failure. Mice lacking leptin while overexpressing adiponectin showed normalized glucose and insulin levels and dramatically improved glucose as well as positively affected serum triglyceride levels. Therefore, modestly increasing the levels of circulating full-length adiponectin completely rescued the diabetic phenotype in ob/ob mice. They displayed increased expression of PPARgamma target genes and a reduction in macrophage infiltration in adipose tissue and systemic inflammation. As a result, the transgenic mice were morbidly obese, with significantly higher levels of adipose tissue than their ob/ob littermates, leading to an interesting dichotomy of increased fat mass associated with improvement in insulin sensitivity. Based on these data, we propose that adiponectin acts as a peripheral "starvation" signal promoting the storage of triglycerides preferentially in adipose tissue. As a consequence, reduced triglyceride levels in the liver and muscle convey improved systemic insulin sensitivity. These mice therefore represent what we believe is a novel model of morbid obesity associated with an improved metabolic profile. PMID- 17717600 TI - B cell activator PAX5 promotes lymphomagenesis through stimulation of B cell receptor signaling. AB - The presumed involvement of paired box gene 5 (PAX5) in B-lymphomagenesis is based largely on the discovery of Pax5-specific translocations and somatic hypermutations in non-Hodgkin lymphomas. Yet mechanistically, the contribution of Pax5 to neoplastic growth remains undeciphered. Here we used 2 Myc-induced mouse B lymphoma cell lines, Myc5-M5 and Myc5-M12, which spontaneously silence Pax5. Reconstitution of these cells with Pax5-tamoxifen receptor fusion protein (Pax5ER(TAM)) increased neoplastic growth in a hormone-dependent manner. Conversely, expression of dominant-negative Pax5 in murine lymphomas and Pax5 knockdown in human lymphomas negatively affected cell expansion. Expression profiling revealed that Pax5 was required to maintain mRNA levels of several crucial components of B cell receptor (BCR) signaling, including CD79a, a protein with the immunoreceptor tyrosine-based activation motif (ITAM). In contrast, expression of 2 known ITAM antagonists, CD22 and PIR-B, was suppressed. The key role of BCR/ITAM signaling in Pax5-dependent lymphomagenesis was corroborated in Syk, an ITAM-associated tyrosine kinase. Moreover, we observed consistent expression of phosphorylated BLNK, an activated BCR adaptor protein, in human B cell lymphomas. Thus, stimulation of neoplastic growth by Pax5 occurs through BCR and is sensitive to genetic and pharmacological inhibitors of this pathway. PMID- 17717602 TI - Improved tumor imaging and therapy via i.v. IgG-mediated time-sequential modulation of neonatal Fc receptor. AB - The long plasma half-life of IgG, while allowing for enhanced tumor uptake of tumor-targeted IgG conjugates, also results in increased background activity and normal-tissue toxicity. Therefore, successful therapeutic uses of conjugated antibodies have been limited to the highly sensitive and readily accessible hematopoietic tumors. We report a therapeutic strategy to beneficially alter the pharmacokinetics of IgG antibodies via pharmacological inhibition of the neonatal Fc receptor (FcRn) using high-dose IgG therapy. IgG-treated mice displayed enhanced blood and whole-body clearance of radioactivity, resulting in better tumor-to-blood image contrast and protection of normal tissue from radiation. Tumor uptake and the resultant therapeutic response was unaltered. Furthermore, we demonstrated the use of this approach for imaging of tumors in humans and discuss its potential applications in cancer imaging and therapy. The ability to reduce the serum persistence of conjugated IgG antibodies after their infusion can enhance their therapeutic index, resulting in improved therapeutic and diagnostic efficacy. PMID- 17717601 TI - Tescalcin is an essential factor in megakaryocytic differentiation associated with Ets family gene expression. AB - We show here that the process of megakaryocytic differentiation requires the presence of the recently discovered protein tescalcin. Tescalcin is dramatically upregulated during the differentiation and maturation of primary megakaryocytes or upon PMA-induced differentiation of K562 cells. This upregulation requires sustained signaling through the ERK pathway. Overexpression of tescalcin in K562 cells initiates events of spontaneous megakaryocytic differentiation, such as expression of specific cell surface antigens, inhibition of cell proliferation, and polyploidization. Conversely, knockdown of this protein in primary CD34+ hematopoietic progenitors and cell lines by RNA interference suppresses megakaryocytic differentiation. In cells lacking tescalcin, the expression of Fli 1, Ets-1, and Ets-2 transcription factors, but not GATA-1 or MafB, is blocked. Thus, tescalcin is essential for the coupling of ERK cascade activation with the expression of Ets family genes in megakaryocytic differentiation. PMID- 17717603 TI - A Foxo/Notch pathway controls myogenic differentiation and fiber type specification. AB - Forkhead box O (Foxo) transcription factors govern metabolism and cellular differentiation. Unlike Foxo-dependent metabolic pathways and target genes, the mechanisms by which these proteins regulate differentiation have not been explored. Activation of Notch signaling mimics the effects of Foxo gain of function on cellular differentiation. Using muscle differentiation as a model system, we show that Foxo physically and functionally interacts with Notch by promoting corepressor clearance from the Notch effector Csl, leading to activation of Notch target genes. Inhibition of myoblast differentiation by constitutively active Foxo1 is partly rescued by inhibition of Notch signaling while Foxo1 loss of function precludes Notch inhibition of myogenesis and increases myogenic determination gene (MyoD) expression. Accordingly, conditional Foxo1 ablation in skeletal muscle results in increased formation of MyoD containing (fast-twitch) muscle fibers and altered fiber type distribution at the expense of myogenin-containing (slow-twitch) fibers. Notch/Foxo1 cooperation may integrate environmental cues through Notch with metabolic cues through Foxo1 to regulate progenitor cell maintenance and differentiation. PMID- 17717606 TI - Overexpression of BimSs3, the novel isoform of Bim, can trigger cell apoptosis by inducing cytochrome c release from mitochondria. AB - Bim is defined as the pro-apoptotic BH3-only protein of the Bcl-2 family, which is a critical sensor and mediator in the mitochondrial-dependent apoptosis. In a previous work, we have cloned a novel transcript of Bim (GenBank accession number: AY305716) from the fetal brain cDNA, which is widely expressed in some carcinoma tissues and normal human tissues. According to the sequence analysis and the newly-defined nomenclature system of Bim isoforms (Adachi et al., 2005, Cell Death Differ 2: 192), we term it BimSs3 according to its characteristic structure. The subcellular location analysis indicated that the fused protein GFP BimSs3 is distributed in the whole cell, mainly to the nucleus. Overexpression of BimSs3 in HEK293 cells causes apoptosis (28.16 +/- 1.55%) compared to the negative control (5.44 +/- 2.63%). It also causes cytochrome c release from the mitochondrial fraction to the cytosolic fraction during apoptosis. Western blotting assay indicates the molecular mass of GFP-BimSs3 is approximately 31.0 kDa (GFP: 27 kDa). Hence the open reading frame of BimSs3 may initiate at the second ATG and encodes a 36 amino-acid peptide with BH3 domain. PMID- 17717604 TI - Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation. AB - Ischemia/reperfusion (IR) injury in transplanted livers contributes to organ dysfunction and failure and is characterized in part by loss of NO bioavailability. Inhalation of NO is nontoxic and at high concentrations (80 ppm) inhibits IR injury in extrapulmonary tissues. In this prospective, blinded, placebo-controlled study, we evaluated the hypothesis that administration of inhaled NO (iNO; 80 ppm) to patients undergoing orthotopic liver transplantation inhibits hepatic IR injury, resulting in improved liver function. Patients were randomized to receive either placebo or iNO (n = 10 per group) during the operative period only. When results were adjusted for cold ischemia time and sex, iNO significantly decreased hospital length of stay, and evaluation of serum transaminases (alanine transaminase, aspartate aminotransferase) and coagulation times (prothrombin time, partial thromboplastin time) indicated that iNO improved the rate at which liver function was restored after transplantation. iNO did not significantly affect changes in inflammatory markers in liver tissue 1 hour after reperfusion but significantly lowered hepatocyte apoptosis. Evaluation of circulating NO metabolites indicated that the most likely candidate transducer of extrapulmonary effects of iNO was nitrite. In summary, this study supports the clinical use of iNO as an extrapulmonary therapeutic to improve organ function following transplantation. PMID- 17717605 TI - Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, accounting for an estimated 600,000 deaths annually. Aberrant methylation, consisting of DNA hypomethylation and/or promoter gene CpG hypermethylation, is implicated in the development of a variety of solid tumors, including HCC. We analyzed the global levels of DNA methylation as well as the methylation status of 105 putative tumor suppressor genes and found that the extent of genome-wide hypomethylation and CpG hypermethylation correlates with biological features and clinical outcome of HCC patients. We identified activation of Ras and downstream Ras effectors (ERK, AKT, and RAL) due to epigenetic silencing of inhibitors of the Ras pathway in all HCC. Further, selective inactivation of SPRY1 and -2, DAB2, and SOCS4 and -5 genes and inhibitors of angiogenesis (BNIP3, BNIP3L, IGFBP3, and EGLN2) was associated with poor prognosis. Importantly, several epigenetically silenced putative tumor suppressor genes found in HCC were also inactivated in the nontumorous liver. Our results assign both therapeutic and chemopreventive significance to methylation patterns in human HCC and open the possibility of using molecular targets, including those identified in this study, to effectively inhibit HCC development and progression. PMID- 17717607 TI - Effect of daidzein, a soy isoflavone, on bone metabolism in Cd-treated ovariectomized rats. AB - This study compared the ability of daidzein, a soy isoflavone, with that of 17beta-estradiol to prevent bone loss in cadmium (Cd)-exposed ovariectomized (OVX) rats during growth. Four week-old female Wistar rats were randomly assigned to five treatment groups of 9 rats each, either (1) sham-operated (SH); (2) OVX and placed on experimental diets (OVX); (3) OVX fed 50 ppm of CdCl2 (OVX-Cd); (4) OVX fed 50 ppm of CdCl2 and 10 microg of daidzein per kg of body mass (OVX-CD-D); or (5) OVX fed 50 ppm of CdCl2 and 10 microg of estrogen per kg of body mass (OVX CD-E). All rats were given free access to AIN-76 modified diet and drinking water, with or without Cd, for 8 weeks. The OVX groups gained more (P < 0.05) body mass than the SH group. Femoral mass was increased by feeding daidzein and estradiol, whereas femoral length was not (P > 0.05) significantly different among groups. Femoral breaking force was not significantly different among groups, however, femoral BMD was significantly lower in OVX-Cd than in the SH and OVX groups. Morphologically proliferative cartilage and hypertrophic cells in femur showed normal distribution in OVX-Cd-D and OVX-Cd-E groups unlike those in OVX-Cd group. These findings suggest that Cd-OVX-induced osteopenia or osteoporosis probably results from an increase in bone turnover. PMID- 17717609 TI - Nursing staff knowledge and beliefs about pain in elderly nursing home residents with dementia. AB - BACKGROUND: Aging is known to be associated with a high prevalence (up to 80%) of persistent pain among residents of nursing homes. However, even with high pain prevalence rates, nursing home residents are at risk for undertreatment. Knowledge deficits and beliefs among nurses influence staff behaviour in pain assessment and management. OBJECTIVES: To develop a psychometrically sound questionnaire and to gather information about knowledge and beliefs of nursing staff regarding various aspects of pain in elderly patients with dementia. In addition, the differences among several categories of nurses (based on educational level and work experience) with respect to beliefs about pain were investigated. METHODS: Participants were 123 staff members of psychogeriatric wards in two nursing homes in the Netherlands (mean of 11.4 years of experience). Their results were compared with those of two groups of nurses, one consisting of 25 registered nurse PhD students in nursing science and the other consisting of 20 trainee pain nurse specialists. RESULTS: The main findings indicate that nursing home staff respondents showed knowledge deficits about several aspects of pain, even though they were satisfied about the way pain was assessed and treated at their wards. Specific knowledge deficits were found regarding pain treatment and medication in elderly nursing home residents. Staff educational level seemed to influence their beliefs and knowledge about pain in elderly nursing home patients. PMID- 17717610 TI - Demographic and psychosocial predictors of acute perioperative pain for total knee arthroplasty. AB - BACKGROUND: As the North American population ages, the prevalence of knee osteoarthritis and the surgical interventions (ie, total knee arthroplasty [TKA]) aimed at correcting pain and disability will also rise proportionally. Therefore, efforts to better understand the factors associated with surgical outcomes are warranted. To date, no studies have examined the impact of psychosocial factors on acute postoperative TKA pain. OBJECTIVES: The primary objective was to examine the associations among catastrophizing, negative mood, demographics and acute postoperative pain following TKA. Ancillary analyses examined the association of preoperative psychological variables with postoperative pain. METHODS: Patients completed questionnaire packages 2 h before their surgery and on three consecutive postoperative days while in the hospital. The questionnaire packages included the Short Form - McGill Pain Questionnaire, the Pain Catastrophizing Scale and the Shortened Version of Profile of Mood States. The Mini-Mental State Examination was also administered. Demographic data were extracted from patients' medical charts. RESULTS: Associations among catastrophizing, negative mood and pain were established. Regressions showed that younger age predicted greater preoperative and postoperative day 1 pain; catastrophizing predicted preoperative and postoperative day 2 pain; and negative mood predicted postoperative day 3 pain. Catastrophizing and negative mood were highly correlated at several assessment points. Preoperative variables did not predict postoperative pain. CONCLUSION: These results have postoperative pain management implications. Heightened attention to psychosocial variables, such as postoperative catastrophizing and negative mood, may be useful in identifying patients at risk for greater postoperative pain. PMID- 17717611 TI - [The systematic evaluation of instruments designed to assess pain in persons with limited ability to communicate]. AB - Chronic pain is often underdetected and undertreated in long-term care facilities. The use of self-report measures of pain (such as the visual analogue scale) is often problematic for older adults residing in long-term care because of the high prevalence of visual and auditory deficits and severe cognitive impairment. Observational measures of pain have been developed to address this concern. A systematic grid designed to assess the properties of existing observational measures of pain was used for seniors with dementia. The grid focused on the evaluation of content validity (12 items), construct validity (12 items), reliability (13 items) and clinical utility (10 items). Among the 24 instruments that were evaluated, several were deemed to be promising in the assessment of pain among older persons with severe dementia. Nonetheless, additional research is needed before their routine integration in the practices of long-term care settings. PMID- 17717612 TI - Cancer pain and depression: a systematic review of age-related patterns. AB - BACKGROUND: Pain is a common and debilitating symptom experienced by cancer patients of all ages. Cancer pain is associated with elevated levels of depression; however, age-related patterns in this relationship remain unclear. This information is important to provide effective palliation of pain and depression to the growing numbers of older cancer patients. OBJECTIVE: To provide a systematic review of the literature regarding age-related patterns in the intensity or prevalence of depression among cancer patients with pain. METHODS: Medical and psychological literature databases were searched to identify eligible studies. The methodological quality and outcomes of the studies were compiled and systematically reviewed. RESULTS: Five articles, describing four studies, met the inclusion and exclusion criteria. Due to high levels of cross-study methodological variability, a qualitative review was undertaken. Three of the four studies did not find evidence for age-related patterns in depression. The fourth study found that depression increased with age. CONCLUSION: The weight of the evidence suggests that younger and older cancer patients with pain report comparable levels of depression. However, this conclusion remains preliminary due to the methodological limitations of the available studies. Research is needed to more adequately address this important issue. PMID- 17717614 TI - Focus and future of occupational health journals. PMID- 17717613 TI - Pregabalin-induced remission in a 62-year-old woman with a 20-year history of vulvodynia. AB - A case of a 62-year-old woman presenting with a 20-year history of vulvodynia previously unresponsive to medical treatment is described. The epidemiology, phenomenology and medical management of vulvodynia is reviewed. The case presentation illustrates the role of pregabalin in successful medical management of this chronic pain disorder, as well as the management of common psychiatric morbidities associated with this condition. PMID- 17717615 TI - Citation classics in occupational medicine journals. AB - OBJECTIVES: The number of citations an article receives after its publication not only reflects its impact on the scientific community, but also the impact of the institutions or countries in the field studied. In 1987, Garfield introduced the concept of "citation classics" for the best-cited articles. An analysis of top cited articles coming from journals in the field of occupational medicine (eg, Occupational and Environmental Medicine, Scandinavian Journal of Work, Environment & Health) has not yet been reported. The purpose of this study was to assess whether or not such citation classics exist in this field and to analyze their characteristics. METHODS: The most frequently cited articles published in the five major journals in occupational medicine were identified using the database of Science Citation Index Expanded. The data were obtained by searching one year and one journal at a time. All of the articles cited more than 100 times were collected and analyzed. RESULTS: Among the 15 553 articles published by the five journals since 1949, only 85 articles had been cited more than 100 times. The oldest had been published in 1950 and the latest in 1997. The United Kingdom contributed 28% of the citation classics and the United States or Sweden produced 19%. The most cited article had been cited 979 times. The main topics of articles were metabolism, occupational neoplasms, and work-related musculoskeletal disorders. CONCLUSIONS: Since the 1980s, Scandinavia and the United States have taken the leadership in the publication of citation classic papers. Nevertheless, according to the level of citations, the influence of literature published in occupational medicine journals remains limited. PMID- 17717616 TI - Job stress and depression symptoms in middle-aged workers--prospective results from the Belstress study. AB - OBJECTIVE: The aim of this study was to explore the prospective relation between job stress and symptoms of depression within a cohort study. METHODS: Altogether 2821 workers were involved in the longitudinal Belstress study (Belgian job stress study); there were two measurements with a mean follow-up time of 6.6 years. Job stress was assessed by the Job Content Questionnaire. Depression symptoms were assessed by the Iowa form of the Center for Epidemiological Studies Depression Scale. Baseline and repeated exposures to job stress were related to the development of high levels of depression symptoms through logistic regression analysis. RESULTS: Within a population free of high depression scores at baseline, job stress increased the risk of developing high levels of depression symptoms after a mean follow-up time of 6.6 years. Independent associations were found for low decision latitude, high job strain, and isolated strain among women, but not among men. The adjusted association with high job strain among men was borderline significant. Repeated high job strain was associated with a more elevated risk of developing high levels of depression symptoms among both the women and the men. CONCLUSIONS: The results of this study confirm that job stress is a risk factor for developing symptoms of depression. Stronger associations were found for women. The impact of high job strain among both men and women was more harmful when there was repeated exposure. PMID- 17717617 TI - Physiological and psychological stress reactions in relation to classroom noise. AB - OBJECTIVES: This study tested the hypothesis that classroom noise is related to stress reactions among primary school children. Stress was monitored via symptoms of fatigue and headache, systolic blood pressure, reduced diurnal cortisol variation, and indicators of emotional distress. METHODS: In three classrooms of pupils in the fourth grade (10 years of age), daily measurements of equivalent sound levels (Leq) were made during 4 weeks, evenly distributed from September to December. One day each week of the study, the pupils answered a questionnaire about disturbance and symptoms, and blood pressure and salivary cortisol were measured. In the first and fourth week, the children also performed a standardized drawing test concerning emotional indicators. RESULTS: Daily measurements of equivalent sound levels in the classes (Leq during schoolday) ranged from 59 to 87 dB(A). Equivalent sound-levels were significantly related to an increased prevalence of symptoms of fatigue and headache and a reduced diurnal cortisol variability. Blood pressure and emotional indicators were not significantly related to sound levels. CONCLUSIONS: Current sound levels in Swedish classrooms may have a negative health impact, being directly or indirectly related to stress reactions among children. This finding indicates that noise should be focused on as a risk factor in the school environment. PMID- 17717618 TI - Myocardial infarction in Swedish subway drivers. AB - OBJECTIVES: Particulate matter in urban air is associated with the risk of myocardial infarction in the general population. Very high levels of airborne particles have been detected in the subway system of Stockholm, as well as in several other large cities. This situation has caused concern for negative health effects among subway staff. The aim of this study was to investigate whether there is an increased incidence of myocardial infarction among subway drivers. METHODS: Data from a population-based case-control study of men aged 40-69 in Stockholm County in 1976-1996 were used. The study included all first events of myocardial infarction in registers of hospital discharges and deaths. The controls were selected randomly from the general population. National censuses were used for information on occupation. Altogether, 22 311 cases and 131 496 controls were included. Among these, 54 cases and 250 controls had worked as subway drivers. RESULTS: The relative risk of myocardial infarction among subway drivers was not increased. It was 0.92 [95% confidence interval (95% CI) 0.68 1.25] when the subway drivers were compared with other manual workers and 1.06 (95% CI 0.78-1.43) when the subway drivers were compared with all other gainfully employed men. Subgroup analyses indicated no influence on the risk of myocardial infarction from the duration of employment, latency time, or time since employment stopped. CONCLUSIONS: Subway drivers in Stockholm do not have a higher incidence of myocardial infarction than other employed persons. PMID- 17717619 TI - Symptoms and immunologic markers among vulcanization workers in rubber industries in southern Sweden. AB - OBJECTIVES: The aim of this study was to estimate the risk of symptoms and the possible derangement of levels of immunologic markers for contemporary Swedish rubber workers. Furthermore, the relation between exposure and these biomarkers of response was examined using urinary levels of 2-thiothiazolidine-4-carboxylic acid (TTCA), which reflect the exposure. METHODS: Included in the study were 166 exposed workers and 117 controls. Medical and occupational histories were obtained in structured interviews. Symptoms were recorded, and immunologic markers were analyzed in blood. Urinary levels of TTCA were determined by liquid chromatography tandem mass spectrometry. RESULTS: Compared with the controls, the exposed workers had increased risks of eye symptoms [odds ratio (OR) 3.0], nose bleeds (OR 4.0), burning and dry throat (OR 3.0), hoarseness (OR 2.4), severe dry cough (OR 3.8), nausea (OR 4.3), and headache (OR 2.5). When the exposed workers were divided into three groups according to the TTCA levels, the highest risks were observed among the exposed workers with intermediate TTCA levels. Furthermore, the exposed workers in all of the TTCA subgroups had elevated concentrations of total immunoglobulin G when compared with the controls. Elevated concentrations of leukocytes, neutrophils, and eosinophils were observed in the group with high TTCA levels. CONCLUSIONS: This work shows an increased risk of several symptoms and elevated levels of some immunologic markers among exposed workers in Swedish rubber industries. In addition, relationships between urinary levels of TTCA and some biomarkers of response were reported. PMID- 17717620 TI - Eye and airway symptoms in low occupational exposure to toluene diisocyanate. AB - OBJECTIVES: Exposure to diisocyanates is a well known occupational hazard. The objective of this study was to determine the possibility of an association between low exposure to toluene diisocyanate (TDI) (airborne isocyanates and biomarkers of isocyanates in plasma and urine) and symptoms of the eyes and upper and lower airways. METHODS: Altogether 136 workers occupationally exposed to TDI and 118 unexposed employees were studied. A physician compiled thorough medical and occupational histories and registered symptoms, total and work-related, of the eyes, nose, and lower airways. The exposure was assessed with personal air measurements and with biomarkers of exposure in plasma and urine. The average exposure in the ambient air at the workplace of the exposed participants was below 1 ppb. RESULTS: Compared with the unexposed group, the exposed workers reported more total symptoms of the eyes and lower airways, as well as nose bleeding. A similar pattern, with even higher odds ratios, was observed for work related symptoms. However, only eye symptoms proved to be significantly associated with the exposure, notably with all of the exposure measures. The risk was more pronounced for exposure to 2,4-TDI than for exposure to 2,6-TDI. CONCLUSIONS: Even very low exposure to TDI is related to negative health effects on exposed workers. Clear dose-response relationships were observed between three different measures of exposure and symptoms of the eyes. PMID- 17717621 TI - Incidence trends and gender differences in malignant mesothelioma in New South Wales, Australia. AB - OBJECTIVES: Features of malignant mesothelioma reportedly differ between men and women, including occupational asbestos exposure, histological subtype, and median survival. In this study, incidence trends and clinical features for malignant mesothelioma were compared between genders in New South Wales (NSW), where notification of malignant mesothelioma to the Central Cancer Registry is a statutory requirement. METHODS: Notifications to the Central Cancer Registry were compared with those to the registry of the NSW Workers' Compensation (Dust Diseases) Board. The latter includes occupational and clinical data. RESULTS: Of the 3090 cases of malignant mesothelioma reported to the Central Cancer Registry between 1972 and 2004, 456 (15%) were female. Altogether 1995 malignant mesotheliomas were compensated between 1969 and 2004, of which 105 (5%) occurred among women. The incidence increased for both genders by approximately 15-fold. Median survival was similar for the men and women for all of the cases (7 versus 6 months), but was better among the women who received compensation (8.5 versus 10.4 months, P<0.0001). The mean disease latency (42.8 years) increased over the study period (P<0.001). CONCLUSIONS: In New South Wales over the last 30 years, the total number of malignant mesotheliomas and the number of compensated cases of malignant mesothelioma have risen for both genders. The mean latency is increasing, and increasing numbers of "nonoccupational" cases are being reported. Survival remains poor. PMID- 17717623 TI - Population-based study on occupational risk factors for preeclampsia and gestational hypertension. AB - OBJECTIVES: Preeclampsia is a leading cause of maternal and perinatal morbidity. Work-related factors may influence the occurrence of this disorder. This case control study estimated the associations between work-related physical and psychosocial factors and the risk of preeclampsia and gestational hypertension. METHODS: The eligible women consisted of a random sample of the women who delivered a singleton live birth in 1997-1999 in six regions of Quebec and worked during pregnancy. Cases of preeclampsia (N=102) and gestational hypertension (N=99) were compared with normotensive controls (N=4381). Information on occupational exposures at the onset of pregnancy was collected during phone interviews a few weeks after delivery. Detailed information was obtained on work schedule, postures, physical exertion, work organization, noise, vibration, and extreme temperature. Adjusted odds ratios (aOR) were estimated through polytomous logistic regression. RESULTS: Women standing daily at least 1 hour consecutively without walking experienced a higher risk of preeclampsia [aOR 2.5, 95% confidence interval (95% CI) 1.4-4.6], as well as women climbing stairs frequently (aOR 2.3, 95% CI 1.2-4.1) and women working more than 5 consecutive days without a day-off (aOR 3.0, 95% CI 1.0-9.5). Squatting or kneeling, pushing or pulling objects, whole-body vibration, forced pace, job strain, and no control on breaks were positively, but nonsignificantly, associated with preeclampsia. The associations were weaker for gestational hypertension. CONCLUSIONS: These findings suggest that being exposed to physically demanding and stressful occupational conditions at the onset of pregnancy increases the risk of preeclampsia. PMID- 17717622 TI - Parental occupational exposure to pesticides and the risk of childhood leukemia in Costa Rica. AB - OBJECTIVES: Parental exposure to pesticides and the risk of leukemia in offspring were examined in a population-based case-control study in Costa Rica. METHODS: All cases of childhood leukemia (N=334), in 1995-2000, were identified at the Cancer Registry and the Children's Hospital. Population controls (N=579) were drawn from the National Birth Registry. Interviews of parents were conducted using conventional and icon-based calendar forms. An exposure model was constructed for 25 pesticides in five time periods. RESULTS: Mothers' exposures to any pesticides during the year before conception and during the first and second trimesters were associated with the risk [odds ratio (OR) 2.4, 95% confidence interval (95% CI) 1.0-5.9; OR 22, 95% CI 2.8-171.5; OR 4.5, 95% CI 1.4 14.7, respectively] and during anytime (OR 2.2, 95% CI 1.0-4.8). An association was found for fathers' exposures to any pesticides during the second trimester (OR 1.5, 95% CI 1.0-2.3). An increased risk with respect to organophosphates was found for mothers during the first trimester (OR 3.5, 95% CI 1.0-12.2) and for fathers during the year before conception and the first trimester (OR 1.5, 95% CI 1.0-2.2 and OR 1.6, 95% CI 1.0-2.6, respectively), and benzimidazoles during the first, second, and third trimesters of pregnancy (OR 2.2, 95% CI 1.0-4.4; OR 2.2, 95% CI 1.0-5.0; OR 2.2, 95% CI 1.0-5.2, respectively). There was a suggestion of an exposure-response gradient for fathers as regards picloram, benomyl, and paraquat. Age at diagnosis was positively associated with fathers' exposures and inversely associated with mothers' exposures. CONCLUSIONS: The results suggest that parental exposure to certain pesticides may increase the risk of leukemia in offspring. PMID- 17717624 TI - How to advise a woman who wants to get pregnant after a sub-urethral tape placement? AB - Our objective was to make recommendations for the follow-up of pregnancies and the choice of delivery route for patients becoming pregnant after surgical treatment of stress urinary incontinence (SUI) by tension-free vaginal tape (TVT) or trans-obturator tape (TOT). We performed a retrospective survey on pregnancies after surgical treatment of SUI. Nineteen physicians out of 3,400 contacted reported a total of 20 pregnancies after TVT or TOT. Three patients had recurrent SUI during pregnancy. No major complications of the tape occurred during pregnancy. Ten patients out of 20 delivered vaginally, and nine had a caesarean section. Mean follow-up after delivery was 13.8 months (1 to 52). Recurrence of SUI was observed in 3 of 20 (15%) during pregnancy and in 3 of 18 (16.7%) after delivery. The global rate of recurrence was 4 of 18 (22.2%). Recurrence of SUI was two of ten cases after vaginal delivery (20%) and in one of eight after caesarean section (12.5%; p=0.58). Vaginal delivery did not increase the risk of recurrence. PMID- 17717625 TI - Emergency left colon resection for acute perforation: primary anastomosis or Hartmann's procedure? A case-matched control study. AB - BACKGROUND: The optimal treatment remains controversial for acute left-sided colon perforation. Therefore, the effectiveness and safety of primary anastomosis versus Hartmann's operation (HP) was compared in a case-matched control study. METHODS: Thirty consecutive patients with primary anastomosis and protective ileostomy (PAS) were matched to 30 HP patients, controlling for age, gender, American Society of Anesthesiologists (ASA) score, body mass index (BMI), and peritonitis severity (Hinchey). In a second analysis, PAS patients with purulent peritonitis (Hinchey 3) were matched to patients with primary anastomosis without ileostomy (PA). RESULTS: Hospital mortality was similar between HP (17%) and PAS (10%). Complication frequency and severity (requiring re-intervention or admission to the Intensive Care Unit [ICU]) were comparable for the first operation (60% versus 56% and 30% versus 32%). The stoma reversal rate was higher in PAS than in HP (96% versus 60%, p = 0.001), with significantly fewer complications (23% versus 66%, p = 0.02), and lower severity (7% versus 33%, p = 0.02). Additional analysis of PAS versus PA showed similar morbidity (52% versus 41%, p = 0.45) and complication severity (18% versus 24%, p = 0.51), whereas overall operation time and hospital stay were significantly shorter in PA (169 versus 320 min, p = 0.003, 17 versus 28 days, p < 0.001). CONCLUSIONS: Primary anastomosis and protective ileostomy is a superior treatment to HP in acute left sided colon perforation. In the absence of feculent peritonitis an ileostomy appears unnecessary. PMID- 17717626 TI - Laparoscopic and endoscopic approaches for drainage of pancreatic pseudocysts: a systematic review of published series. AB - BACKGROUND: The laparoscopic and endoscopic approaches to internal drainage of pancreatic pseudocysts (PPs) are the current minimally invasive management options. This article reviews the evidence available on their effectiveness. METHODS: A computerized search was made of the MEDLINE, PubMed, and EMBASE databases for English language publications from 1974 to 2005. RESULTS: A total of 118 and 569 patients featured, respectively, in 19 and 25 reports underwent 118 and 583 laparoscopic and endoscopic drainage procedures, respectively. Pancreatic pseudocysts were considerably larger in the laparoscopic series (mean, 13 vs. 7 cm; p < 0.0001). The success rates for achieving resolution of the PPs in the laparoscopic and endoscopic series were 98.3% and 80.8% respectively, with morbidity rates of 4.2% and 12% and mortality rates of 0% and 0.4%, respectively. During follow-up period (mean, 13 vs 24 months; p < 0.0001), PPs recurred for 2.5% of the patients in the laparoscopic series and 14.4% of the patients in the endoscopic series, and the reintervention rates were 0.9% and 11.8%, respectively. CONCLUSIONS: The laparoscopic and endoscopic approaches to internal drainage of PPs are safe. Although laparoscopic drainage appears to carry a higher success rate and lower rates of morbidity and recurrence, the heterogeneity of the published reports and the varied follow-up periods limit direct comparisons. Data from longer follow-up periods and randomized comparative trials are needed. PMID- 17717627 TI - Urinary excretion of total isothiocyanates from cruciferous vegetables shows high dose-response relationship and may be a useful biomarker for isothiocyanate exposure. AB - BACKGROUND: Isothiocyanates (ITCs), hydrolysis products from glucosinolates, are a family of biologically active compounds originating from cruciferous vegetables. Many ITCs are assumed to have cancer preventive effects and to further evaluate these potential health effects, reliable biomarkers of ITC exposure are needed. AIM OF THE STUDY: In this study we investigated the ability of urinary ITC excretion to reflect a low or high daily intake of cruciferous vegetables. METHODS: The design was a controlled human crossover study (n = 6). Subjects consumed a self-restricted glucosinolate-free diet 48 h before the study day where a basic diet supplemented with 80 or 350 g of mixed cruciferous vegetables was consumed. All urine was collected in intervals during the 48 h period after ingestion of the cruciferous vegetables. Total ITC in the cruciferous mixture and total ITC and their metabolites in urine was quantified as the cyclocondensation product of 1,2-bezenedithiol by high performance liquid chromatography. RESULTS: The total urinary excretion of ITCs correlated significantly with the two doses of ITC from diets with high or low cruciferous content (r (s )= 0.90, P < 0.01). The fraction of urinary ITC excreted was 69.02 +/- 11.57% and 74.53 +/- 8.39% of the amounts ingested for 80 and 350 g cruciferous vegetables, respectively. CONCLUSION: The results in this study indicate that the urinary excretion of ITCs, measured by use of the cyclocondesation reaction, is a useful and precise tool that may be used as a biomarker of ITC exposure in population based studies. PMID- 17717629 TI - The endocrine role for chromogranin A: a prohormone for peptides with regulatory properties. AB - Chromogranin A (CgA) belongs to the granin family of uniquely acidic secretory proteins co-stored and co-secreted with other hormones and peptides in elements of the diffuse neuroendocrine system. The granins arise from different genes and are characterized by numerous sites for post-translational cleavage into shorter peptides with postulated regulatory properties. This review is directed towards endocrine aspects of CgA and its biologically active peptides. There is ample evidence from in vitro studies of distinct effects and targets for three CgA derived peptides, vasostatin-I, pancreastatin and catestatin. Endocrine regulations are indicated from in vivo studies, consistent with the postulated prohormone function of CgA for peptides with regulatory properties. Most of the effects fit into patterns of direct or indirect, inhibitory modulations of major functions, implicating CgA peptides in regulation of calcium and glucose metabolism, cardiovascular functions, gastrointestinal motility and nociception, tissue repair, inflammatory responses and as host defense peptides in the first phase of microbial invasions. PMID- 17717628 TI - Long chain omega-3 fatty acids intake, fish consumption and mental disorders in the SUN cohort study. AB - BACKGROUND: Very long chain omega-3 fatty acids (w-3 PUFA) intake and fish consumption have been suggested as protective factors against neuropsychiatric disorders but there is scarcity of large cohort studies assessing this association. AIM OF THE STUDY: To assess the association between w-3-PUFA intake and fish consumption and mental disorders. METHODS: A prospective cohort study was performed in 7,903 participants. W-3 PUFA intake and fish consumption were ascertained through a validated semi-quantitative food frequency questionnaire. The outcomes after 2 years of follow-up were: (1) Incident mental disorder (depression, anxiety, or stress), (2) incident depression, and (3) incident anxiety. Logistic regression models and generalized additive models were fit to assess the relationship between w-3 PUFA intake or fish consumption and the incidence of these outcomes. Odds ratios (OR) and their 95% confidence intervals (CI) were calculated. RESULTS: 173 cases of depression, 335 cases of anxiety, and 4 cases of stress were observed during 2-year follow-up. ORs (95% CI) of mental disorder for successive quintiles of energy-adjusted w-3 PUFA intake were 1 (reference), 0.72 (0.52-0.99), 0.79 (0.58-1.08), 0.65 (0.47-0.90), and 1.04 (0.78 1.40). Subjects with a moderate consumption of fish (third and fourth quintiles of consumption: median of each quintile 83.3 and 112 g/day, respectively) had a relative risk reduction higher than 30%. CONCLUSIONS: A potential benefit of w-3 PUFA intake on total mental disorders is suggested, although no linear trend was apparent. PMID- 17717631 TI - Nitrate in public water supplies and the risk of renal cell carcinoma. AB - Drinking water and dietary sources of nitrate and nitrite can react in vivo with amines and amides to form N-nitroso compounds (NOC), potent animal carcinogens. Nitrate is a widespread contaminant of drinking water supplies especially in agricultural areas. We conducted a population-based case-control study of renal cell carcinoma in 1986-1989 in Iowa, a state with elevated levels in many public water supplies. We collected a lifetime water source history, but due to limited monitoring data, most analyses focused on the subpopulation, who used Iowa public supplies with nitrate measurements (actual or imputed data) for > or = 70% of their person-years since 1960 (201 cases, 1,244 controls). We computed the average nitrate level and years using a public supply with nitrate levels >5 and >10 mg/l. Dietary nitrate and nitrite were estimated from a 55-item food frequency questionnaire. There was no association of renal cell carcinoma with the average nitrate level and years using public supplies >5 and >10 mg/l nitrate nitrogen (10+ years >5 mg/l odds ratio (OR) = 1.03, 95% confidence interval (CI) 0.66, 1.60). However, higher nitrate exposure was associated with an increased risk among subgroups with above the median red meat intake (10+ years >5 mg/l OR = 1.91, 95% CI 1.04-3.51) or below the median vitamin C intake (10+ years >5 mg/l OR = 1.90, 95% CI 1.01, 3.56), dietary factors that increase the endogenous formation of NOC. Exclusion of long-term Des Moines residents, a large proportion of the high exposure categories, attenuated the association. These findings deserve additional study in populations with high water nitrate intake and information on dietary intakes. PMID- 17717630 TI - Simultaneous detection of amide and methyl correlations using a time shared NMR experiment: application to binding epitope mapping. AB - Simultaneous recording of different NMR parameters is an efficient way to reduce the overall experimental time and speed up structural studies of biological macromolecules. This can especially be beneficial in the case of fast NMR-based drug screening applications or for collecting NOE restraints, where prohibitively long data collection time may be required. We have developed a novel pulse sequence element that enables simultaneous detection of amide (15)N, (1)H and methyl (13)C, (1)H correlations. The coherence selection for the (15)N spins can be obtained using the gradient selected and coherence order selective coherence transfer, whereas the hypercomplex (States) method is simultaneously employed for the (13)C coherence selection. Experimental verification of proposed time-shared approach for simultaneous detection amide (15)N, (1)H and methyl (13)C, (1)H correlations has been carried out with three proteins, human ubiquitin, SH3 domain of human epidermal growth factor receptor pathway substrate 8-like protein (Eps8L1) and maltose binding protein complex with beta-Cyclodextrin. In addition, the proposed methodology was applied for ligand binding site mapping on SH3 domain of Eps8L1, using uniformly (15)N and fractionally (10%) (13)C labeled sample. Our results show that the proposed time-shared (15)N/(13)C-HSQC affords significant time saving (or improved sensitivity) in establishing (15)N, (1)H and methyl (13)C, (1)H correlations, thus making it an attractive building block for 3D and 4D dimensional applications. It is also a very efficient tool in protein ligand interaction studies even when combined with cost-effective labeling scheme with uniform (15)N and 10% fractional (13)C enrichment. PMID- 17717632 TI - Cytochrome P450 1A1, cigarette smoking, and risk of endometrial cancer (United States). AB - Cytochrome P450 1A1 (CYP1A1) is involved in the metabolism of estradiol and the activation of polycyclic aromatic hydrocarbons found in tobacco products. Polymorphic variation in CYP1A1 activity may modify susceptibility to endometrial cancer through the oxidative metabolism of estradiol and the activation of tobacco-smoke constituents. We prospectively evaluated the associations between three common CYP1A1 polymorphisms and endometrial cancer risk, as well as the potential modification of these associations by cigarette smoking, in a case control study nested within the Nurses' Health Study. We investigated the MspI restriction-site polymorphism, a C --> A transversion at nucleotide 4887 (Thr461Asn) and a A --> G transition at nucleotide 4889 (Ile462Val) among 456 women with endometrial cancer and 1,134 matched controls. We used conditional logistic regression to calculate the adjusted odds ratios (OR) and 95% confidence intervals (CI) to quantify the risk of endometrial cancer among subjects who had at least one variant allele compared with that of subjects homozygous for the wild-type allele. We did not observe any statistically significant associations between the MspI, Thr461Asn or Ile462Val polymorphisms and endometrial cancer risk or any significant effect modification by cigarette-smoking status. These data suggest that these three polymorphisms are not important in determining genetic susceptibility to endometrial cancer, although larger sample sizes are needed to confirm these findings. PMID- 17717634 TI - The other side of MMPs: protective roles in tumor progression. AB - The matrix metalloproteinase (MMP) family of extracellular proteinases have long been associated with cancer invasion and metastasis by virtue of their ability to collectively degrade all components of the extracellular matrix (ECM). The general belief that overexpression of a specific MMP, either by tumor cells or the surrounding stroma, is pro-tumorigenic led to the development of synthetic MMP inhibitors for the treatment of cancer. However, there is an increasing amount of literature demonstrating that the expression of certain MMPs, either at the primary or the metastatic site, provides a beneficial and protective effect in multiple stages of cancer progression. Here, we review the evidence for protective effects of MMPs and contrast this with pro-tumorigenic effects of either the same enzyme, or a different MMP of the same family. These studies highlight the importance of targeting specific MMPs for cancer treatment, and point to a potential reason why clinical trials of pharmaceutical inhibitors for MMPs were disappointing. In order to effectively target MMPs in cancer progression, a better understanding of both their pro- and anti-tumorigenic effects is required. PMID- 17717635 TI - Breast cancer brain metastases. AB - Breast cancer is the most common malignancy in woman in the USA. Metastasis is a major cause of morbidity and mortality in breast cancer patients. Total incidence of brain metastases of breast cancer is about 30%. Because of the improvements in control of systemic disease, for example the successful use of Trastuzumab, and the consequent prolonged life span, the incidence of brain metastases is increasing in breast cancer patients. The progressive neurological disabilities not only impair the quality of life, but also decrease the survival in patients. However, current treatments are of limited effectiveness. This is partially caused by the unique structure of the blood brain barrier. So far very little is known about the mechanisms how breast cancer metastizes to the brain. Some studies showed that ErbB2 overexpression is associated with the brain metastatic phenotype. Other molecules, like vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs) and chemokine receptor CXCR4 are also involved in the metastasis of breast cancer cell to the brain. The current review will briefly overview the clinical features of brain metastasis of breast cancer and discusses the relationship of blood brain barrier and ErbB2 signal pathway to brain metastasis in breast cancer. PMID- 17717633 TI - Tumour vascularization: sprouting angiogenesis and beyond. AB - Tumour angiogenesis is a fast growing domain in tumour biology. Many growth factors and mechanisms have been unravelled. For almost 30 years, the sprouting of new vessels out of existing ones was considered as an exclusive way of tumour vascularisation. However, over the last years several additional mechanisms have been identified. With the discovery of the contribution of intussusceptive angiogenesis, recruitment of endothelial progenitor cells, vessel co-option, vasculogenic mimicry and lymphangiogenesis to tumour growth, anti-tumour targeting strategies will be more complex than initially thought. This review highlights these processes and intervention as a potential application in cancer therapy. It is concluded that future anti-vascular therapies might be most beneficial when based on multimodal anti-angiogenic, anti-vasculogenic mimicry and anti-lymphangiogenic strategies. PMID- 17717636 TI - Role of mitogen-activated protein kinase phosphatases (MKPs) in cancer. AB - The mitogen-activated protein kinase (MAPK) phosphatases (MKPs) are a family of dual-specificity protein phosphatases that dephosphorylate both phospho-threonine and phospho-tyrosine residues in MAP kinases, including the c-Jun N-terminal protein kinase (JNK)/stress-activated protein kinase (SAPK), the p38 MAPK, and the extracellular signal-related kinase (ERK). Since phosphorylation is required for the activation of MAP kinases, dephosphorylation by MKPs inhibits MAPK activity, thereby negatively regulating MAPK signaling. It is known that deregulation of MAPK signaling is the most common alteration in human cancers. Recent studies have suggested that MKPs play an important role not only in the development of cancers, but also in the response of cancer cells to chemotherapy. Thus, understanding the roles of MKPs in the development of cancer and their impact on chemotherapy can be exploited for therapeutic benefits for the treatment of human cancer. PMID- 17717638 TI - Inflammatory cell infiltration of tumors: Jekyll or Hyde. AB - Inflammatory cell infiltration of tumors contributes either positively or negatively to tumor invasion, growth, metastasis, and patient outcomes, creating a Dr. Jekyll or Mr. Hyde conundrum when examining mechanisms of action. This is due to tumor heterogeneity and the diversity of the inflammatory cell phenotypes that infiltrate primary and metastatic lesions. Tumor infiltration by macrophages is generally associated with neoangiogenesis and negative outcomes, whereas dendritic cell (DC) infiltration is typically associated with a positive clinical outcome in association with their ability to present tumor antigens (Ags) and induce Ag-specific T cell responses. Myeloid-derived suppressor cells (MDSCs) also infiltrate tumors, inhibiting immune responses and facilitating tumor growth and metastasis. In contrast, T cell infiltration of tumors provides a positive prognostic surrogate, although subset analyses suggest that not all infiltrating T cells predict a positive outcome. In general, infiltration by CD8(+) T cells predicts a positive outcome, while CD4(+) cells predict a negative outcome. Therefore, the analysis of cellular phenotypes and potentially spatial distribution of infiltrating cells are critical for an accurate assessment of outcome. Similarly, cellular infiltration of metastatic foci is also a critical parameter for inducing therapeutic responses, as well as establishing tumor dormancy. Current strategies for cellular, gene, and molecular therapies are focused on the manipulation of infiltrating cellular populations. Within this review, we discuss the role of tumor infiltrating, myeloid-monocytic cells, and T lymphocytes, as well as their potential for tumor control, immunosuppression, and facilitation of metastasis. PMID- 17717640 TI - [Metastatic lesions to the pancreas. When is resection reasonable?]. AB - BACKGROUND: The significance of pancreatic resection for pancreatic metastatic lesions has not yet been sufficiently investigated. A retrospective analysis of patients undergoing pancreatic resections for pancreatic metastases was conducted. MATERIAL AND METHODS: Twenty patients were resected due to metastatic lesions to the pancreas. Histopathological findings were: renal cell carcinoma (n=9), colon carcinoma (n=1), malignant schwannoma (n=2), leiomyosarcoma (n=2), teratocarcinoma (n=1), adenocarcinoma of the oesophagus (n=1), gallbladder carcinoma (n=1), malignant melanoma (n=1), gastrointestinal stromal tumor (n=1), and spindle cell tumor (n=1). Operative procedures were standard pancreaticoduodenectomy (n=6), pylorus-preserving pancreaticoduodenectomy (n=6), and distal pancreatectomy (n=8). RESULT: The overall 5-year survival rate was 61%, for patients with renal cell carcinoma 100%. CONCLUSION: Pancreatic metastasectomy is a reasonable therapeutic option in suited patients. Patients with pancreatic metastases of renal cell carcinoma achieved excellent prognoses after radical resection. PMID- 17717641 TI - [From skin biopsy to diagnosis]. AB - The procedure from skin biopsy to a histologic diagnosis is complex. The clinician is responsible for obtaining the biopsy and submitting it to the laboratory together with clinical information. After processing, the dermatopathologist interprets the slides by using algorithms and established criteria that allow for high diagnostic accuracy. Depending on the differential diagnostic problem, histo- und immunohistochemistry, electron microscopy and molecular pathology may be helpful. The clinician has to interpret the histologic report and put it in a clinical context. While there are many sources of error in the process, most appear in the communication between clinician and dermatopathologist. The final diagnosis is always made by the clinician. PMID- 17717642 TI - Modulation of muscle contraction by a cell-permeable peptide. AB - In contrast to immortal cell lines, primary cells are hardly susceptible to intracellular delivery methods such as transfection. In this study, we evaluated the direct delivery of several cell-permeable peptides under noninvasive conditions into living primary adult rat cardiomyocytes. We specifically monitored the functional effects of a cell-permeable peptide containing the 15 amino acid N-terminal peptide from human ventricular light chain-1 (VLC-1) on contraction and intracellular Ca2+ signals after electrical stimulation in primary adult cardiomyocytes. The transducible VLC-1 variant was taken up by cardiomyocytes within 5 min with more than 95% efficiency and localized to sarcomeric structures. Analysis of the functional effects of the cell-permeable VLC-1 revealed an enhancement of the intrinsic contractility of cardiomyocytes without affecting the intracellular Ca2+. Therefore, peptide transduction mediated by cell-penetrating peptides represents not only a unique strategy to enhance heart muscle function with no secondary effect on intracellular Ca2+ but also an invaluable tool for the modulation and manipulation of protein interactions in general and in primary cells. PMID- 17717637 TI - Chemokines: novel targets for breast cancer metastasis. AB - Recent studies have highlighted the possible involvement of chemokines and their receptors in breast cancer progression and metastasis. Chemokines and their receptors constitute a superfamily of signalling factors whose prognosis value in breast cancer progression remains unclear. We will examine here the expression pattern of chemokines and their receptors in mammary gland physiology and carcinogenesis. The nature of the cells producing chemokines or harboring chemokine receptors appears to be crucial in certain conditions for example, the infiltration of the primary tumor by leukocytes and angiogenesis. In addition, chemokines, their receptors and the interaction with glycosaminoglycan (GAGs) are key players in the homing of cancer cells to distant metastasis sites. Several lines of evidence, including in vitro and in vivo models, suggest that the mechanism of action of chemokines in cancer development involves the modulation of proliferation, apoptosis, invasion, leukocyte recruitment or angiogenesis. Furthermore, we will discuss the regulation of chemokine network in tumor neovascularity by decoy receptors. The reasons accounting for the deregulation of chemokines and chemokine receptors expression in breast cancer are certainly crucial for the comprehension of chemokine role in breast cancer and are in several cases linked to estrogen receptor status. The targeting of chemokines and chemokine receptors by antibodies, small molecule antagonists, viral chemokine binding proteins and heparins appears as promising tracks to develop therapeutic strategies. Thus there is significant interest in developing strategies to antagonize the chemokine function, and an opportunity to interfere with metastasis, the leading cause of death in most patients. PMID- 17717643 TI - [Nephrogenic systemic fibrosis]. AB - A scleromyxedema-like disease was recognized in 1997. In 2000 this disorder was first published and termed nephrogenic fibrosing dermopathy because all patients had advanced renal failure. In 2006 it was discovered that the patients had a history of a preceding contrast-enhanced magnetic resonance imaging (MRI). All patients had acute or chronic severe renal insufficiency with a glomerular filtration rate (GFR) <30 ml/min per 1.73 m(2). So far a total of about 215 patients with this new skin disorder have been reported to international registries. The skin thickening has a typical histology and begins in the peripheral extremities and progresses proximally, including also the abdominal wall and the head in some patients. NSF involves not only the skin, but also the muscles and other organs (e.g., lungs, heart, eyes) in some patients. Therefore the term nephrogenic systemic fibrosis (NSF) was introduced. Skin fibrosis and sclerosis are usually progressive with disabling contractures of involved joints (knees, hands, feet). NSF may be lethal in up to 28% of patients. Spontaneous remissions are rare. No generally accepted treatment is available. So far, the pathogenesis is not well understood. One hypothesis supposes a role of gadolinium liberated from the contrast agents. As patients with acute or chronic advanced renal failure (GFR <30 ml/min per 1.73 m(2)) including those with hepatorenal dysfunctions are at high risk to develop NSF after exposure to gadolinium-based contrast agents, contrast-enhanced MRI should be avoided in this group and alternative diagnostic procedures should be used whenever possible. PMID- 17717645 TI - A simple and highly repeatable colorimetric toxicity assay method using 2,6 dichlorophenolindophenol as the redox color indicator and whole eukaryote cells. AB - A simple and highly reproducible toxicity assay method was studied by employing 2,6-dichlorophenolindophenol (DCIP) as a redox color indicator, baker's yeast Saccharomyces cerevisiae, and a thermostable three-consecutive-stir unit. The absorbance of DCIP was decreased by increasing the metabolism activity of S. cerevisiae to intake glucose as an organic substance. By optimizing the measurement conditions, we obtained highly sensitive responses to glucose between 0.75 and 30 mg/L (eight points, n = 3) with an incubation time of the reaction mixture of 10 min at 30 degrees C. An excellent value of 1.15% was obtained as the average of the repeatability from eight points. Next, for the characterization of this method, we investigated the influence on the colorimetric response of dissolved substances, such as inorganic ions and surfactants, in natural water. Furthermore, the colorimetric responses to several toxicants were examined using Cu2+, Mn2+, Zn2+, Cr3+, and Fe3+ as heavy-metal ions and simazine as an agricultural chemical. As a result, notable colorimetric responses were obtained for Cu2+ and Mn2+ at several concentrations, and the results were compared with those obtained using river water as a real sample. In the stability test, responses to 30 mg/L glucose were obtained for 28 days when the yeast cell suspension was stored at 4 degrees C (response reduction, 43.9%; average of the relative standard deviation for nine testing days, 22.7%; average of repeatability, 1.01%). PMID- 17717644 TI - Association of sleep duration with type 2 diabetes and impaired glucose tolerance. AB - AIMS/HYPOTHESIS: The aim of this study was to assess the relationship between sleep duration and type 2 diabetes or impaired glucose tolerance (IGT). METHODS: Anthropometric measurements and self-reported sleep duration were determined in a cross-sectional sample of 323 men and 417 women aged 21-64 years from the Quebec Family Study. Glucose homeostasis indicators were compared between short (5-6 h), 'normal' (7-8 h) and long (9-10 h) sleeper groups. RESULTS: Using adults with 7-8 h of sleep as a reference, the adjusted odds ratio for type 2 diabetes/IGT was 1.58 (1.13-2.31) for those with 9-10 h of sleep and 2.09 (1.34-2.98) for those with 5-6 h of sleep, after adjustment for potential confounding variables. The short and long sleepers presented significantly higher total insulin AUC (p < 0.05), whereas total glucose AUC was not different between the three sleeper groups in both sexes. The mean glucose area below fasting glucose concentrations was significantly higher in short (p < 0.01) and long sleepers (p < 0.05) compared with 'normal' sleepers, and significantly higher in short (p < 0.05) compared with long sleepers in both sexes. CONCLUSIONS/INTERPRETATION: The present study provides evidence that short- and long-duration sleep times are associated with type 2 diabetes/IGT in adults, even after adjustment for several confounders. These results also showed that the lower glucose concentrations at the end of the OGTT were observed in short sleepers. According to the glucostatic theory of appetite control, this represents a stimulus that can trigger episodes of hunger and spontaneous food intake, which may explain at least in part the greater risk of overweight displayed by short sleepers, as shown in previous studies. PMID- 17717646 TI - New concept for a toxicity assay based on multiple indexes from the wave shape of damped metabolic oscillation induced in living yeast cells (part II): application to analytical toxicology. AB - An ideal toxicity assay should utilize multiple indexes obtained from transient changes of metabolic activities. Here, we demonstrate the possibility for a novel toxicity bioassay using the damped glycolytic oscillation phenomenon occurring in starved yeast cells. In a previous study, the phenomenon was characterized in detail. Under optimum conditions to induce the phenomenon, the wave shapes of the damped glycolytic oscillations were changed by the instantaneous addition of both glucose and chemicals and by changing the chemical concentration. We estimated the changes in the oscillation wave shapes as six indexes, i.e., the number of wave cycles, maximum amplitude, oscillation frequency, attenuation coefficient, initial peak height, and non-steady-state time. These index changes were obtained from several kinds of chemicals. The chemicals, especially those for acids (0.01 100 mM HCl and 0.01-50 mM citric acid), bases (0.001-50 mM KOH), heavy metal ions (1-1,000 mg L(-1); Cu(2+), Pb(2+), Cd(2+), Hg(2+)), respiratory inhibitors (3-500 mg L(-1) NaN(3)), dissolved oxygen removers (10-300 mg L(-1) NaSO(3)), surfactants (10-200 mg L(-1) benzalkonium chloride), and aldehyde (10-1,000 mg L( 1) acetaldehyde), showed characteristic patterns depending on each chemical and its concentration. These significant results demonstrate the possibilities of new methods for both toxicity qualification and quantification. PMID- 17717647 TI - Protection against hydrogen peroxide-induced injury by Z-ligustilide in PC12 cells. AB - Z-ligustilide (Z-LIG) is the primary lipophilic compound of the Chinese medicine Danggui (Radix Angelica sinensis). Previous studies demonstrated that Z-LIG had significant neuroprotective potential in both transient and permanent cerebral ischemia, possibly through antioxidant and anti-apoptotic mechanisms. The present study examined the mechanisms of Z-LIG on hydrogen peroxide (H(2)O(2))-induced injury in PC12 cells. Following exposure of the cells to H(2)O(2 )(500 microM), a significant reduction in cell survival and total antioxidant capacity (TAC), as well as increased intracellular reactive oxygen species (ROS), were observed. In addition, H(2)O(2 )treatment significantly upregulated Bax expression, cleaved caspase 3, and cytosolic cytochrome-c, and decreased Bcl-2 protein levels. Pretreatment of the cells with Z-LIG (0.1, 1.0, 2.5, or 5.0 microg/ml) significantly attenuated H(2)O(2)-induced cell death, attenuated increased intracellular ROS levels, and decreased Bax expression, cleaved-caspase 3, and cytochrome-c. Further, Z-LIG improved cellular TAC and concentration-dependently upregulated Bcl-2 expression. These results demonstrate that Z-LIG has a pronounced protective effect against H(2)O(2)-induced cytotoxicity, at least partly through improving cellular antioxidant defense and inhibiting the mitochondrial apoptotic pathway. These findings suggest that Z-LIG may be useful in the treatment of neurodegenerative disorders in which oxidative stress and apoptosis are mainly implicated. PMID- 17717648 TI - Mental concatenation of perceptually and cognitively specified depth to represent locations in near space. AB - The purpose of this study was to examine how discrete segments of contiguous space arising from perceptual or cognitive channels are mentally concatenated. We induced and measured errors in each channel separately, then summed the psychophysical functions to accurately predict pointing to a depth specified by both together. In Experiment 1, subjects drew a line to match the visible indentation of a probe into a compressible surface. Systematic perceptual errors were induced by manipulating surface stiffness. Subjects in Experiment 2 placed the probe against a rigid surface and viewed the depth of a hidden target below it from a remote image with a metric scale. This cognitively mediated depth judgment produces systematic under-estimation (Wu et al. in IEEE Trans Vis Comput Grap 11(6):684-693, 2005; confirmed here). In Experiment 3, subjects pointed to a target location detected by the indented probe and displayed remotely, requiring mental concatenation of the depth components. The model derived from the data indicated the errors in the components were passed through the integration process without additional systematic error. Experiment 4 further demonstrated that this error-free concatenation was intrinsically spatial, rather than numerical. PMID- 17717650 TI - Walking speed, cadence and step length are selected to optimize the stability of head and pelvis accelerations. AB - The aim of this study was to evaluate the hypothesis that an individual's preferred or usual walking speed, step length and cadence optimize the stability of head and pelvic accelerations in vertical (V), anterior-posterior (AP) and medio-lateral (ML) planes when walking. Acceleration patterns of the head and pelvis were recorded in ten healthy young adults as they walked on a level surface in three separate experiments: (1) walking at five different speeds, ranging from very slow to very fast; (2) walking in time to a metronome set at five different cadences, ranging from 33 to 167% of subjects' usual cadence; and (3) walking at five different step lengths varying from very short to very long while keeping in time with a metronome set at cadences 67, 100 and 125% of usual cadence. The results indicated that acceleration patterns in the V and AP planes were most stable when subjects walked at their usual cadence and step length. In the ML plane, stability was suboptimal, but still adequate, with the usual cadence and step length. The findings suggest that healthy young people walk in a manner that maximizes V and AP stability while maintaining adequate, though suboptimal ML stability. PMID- 17717649 TI - Influence of galvanic vestibular stimulation on egocentric and object-based mental transformations. AB - The vestibular system analyses angular and linear accelerations of the head that are important information for perceiving the location of one's own body in space. Vestibular stimulation and in particular galvanic vestibular stimulation (GVS) that allow a systematic modification of vestibular signals has so far mainly been used to investigate vestibular influence on sensori-motor integration in eye movements and postural control. Comparatively, only a few behavioural and imaging studies have investigated how cognition of space and body may depend on vestibular processing. This study was designed to differentiate the influence of left versus right anodal GVS compared to sham stimulation on object-based versus egocentric mental transformations. While GVS was applied, subjects made left right judgments about pictures of a plant or a human body presented at different orientations in the roll plane. All subjects reported illusory sensations of body self-motion and/or visual field motion during GVS. Response times in the mental transformation task were increased during right but not left anodal GVS for the more difficult stimuli and the larger angles of rotation. Post-hoc analyses suggested that the interfering effect of right anodal GVS was only present in subjects who reported having imagined turning themselves to solve the mental transformation task (egocentric transformation) as compared to those subjects having imagined turning the picture in space (object-based mental transformation). We suggest that this effect relies on shared functional and cortical mechanisms in the posterior parietal cortex associated with both right anodal GVS and mental imagery. PMID- 17717651 TI - Effects of transcranial direct current stimulation on the excitability of the leg motor cortex. AB - Transcranial direct current stimulation (tDCS) of the human motor cortex at an intensity of 1 mA has been shown to be efficacious in increasing (via anodal tDCS) or decreasing (via cathodal tDCS) the excitability of corticospinal projections to muscles of the hand. In this study, we examined whether tDCS at currents of 2 mA could effect similar changes in the excitability of deeper cortical structures that innervate muscles of the lower leg. Similar to the hand area, 10 min of stimulation with the anode over the leg area of the motor cortex increased the excitability of corticospinal tract projections to the tibialis anterior (TA) muscle, as reflected by an increase in the amplitude of the motor evoked potentials (MEPs) evoked by transcranial magnetic stimulation. MEP amplitudes recorded at rest and during a background contraction were increased following anodal tDCS and remained elevated at 60 min compared to baseline values by 59 and 35%, respectively. However, in contrast to the hand, hyperpolarizing cathodal stimulation at equivalent currents had minimal effect on the amplitude of the MEPs recorded at rest or during background contraction of the TA muscle. These results suggest that it is more difficult to suppress the excitability of the leg motor cortex with cathodal tDCS than the hand area of the motor cortex. PMID- 17717653 TI - Left handedness does not extend to visually guided precision grasping. AB - In the present study, we measured spontaneous hand preference in a "natural" grasping task. We asked right- and left-handed subjects to put a puzzle together or to create different LEGO models, as quickly and as accurately as possible, without any instruction about which hand to use. Their hand movements were videotaped and hand preference for grasping in ipsilateral and contralateral space was measured. Right handers showed a marked preference for their dominant hand when picking up objects; left handers, however, did not show this preference and instead used their right hand 50% of the time. Furthermore, compared to right handers, left handers used their non-dominant hand significantly more often to pick up objects in ipsilateral as well as contralateral space. Our results show that handedness in left handers does not extend to precision grasp and suggest that right handedness for visuomotor control may reflect a universal left hemisphere specialization for this class of behaviour. PMID- 17717652 TI - TMS of the occipital cortex induces tactile sensations in the fingers of blind Braille readers. AB - Various non-visual inputs produce cross-modal responses in the visual cortex of early blind subjects. In order to determine the qualitative experience associated with these occipital activations, we systematically stimulated the entire occipital cortex using single pulse transcranial magnetic stimulation (TMS) in early blind subjects and in blindfolded seeing controls. Whereas blindfolded seeing controls reported only phosphenes following occipital cortex stimulation, some of the blind subjects reported tactile sensations in the fingers that were somatotopically organized onto the visual cortex. The number of cortical sites inducing tactile sensations appeared to be related to the number of hours of Braille reading per day, Braille reading speed and dexterity. These data, taken in conjunction with previous anatomical, behavioural and functional imaging results, suggest the presence of a polysynaptic cortical pathway between the somatosensory cortex and the visual cortex in early blind subjects. These results also add new evidence that the activity of the occipital lobe in the blind takes its qualitative expression from the character of its new input source, therefore supporting the cortical deference hypothesis. PMID- 17717654 TI - Failure to disrupt the 'sensorimotor' memory for lifting objects with a precision grip. AB - When repetitively lifting an object with mechanical properties that vary from lift-to-lift, the fingertip forces for gripping and lifting are influenced strongly by the previous lift, revealing a 'sensorimotor' memory. Two recent reports indicate that the sensorimotor memory for grip force is easily disrupted by an unrelated task like a strong pinch or vibration, even when the lift was performed with the hand contralateral to the vibration or preceding pinch. These findings indicate that this memory may reflect sensory input or muscle contraction levels, rather than object properties or the specific task of gripping and lifting. Here we report that the predictive scaling of lift force was not disrupted by conditioning tasks that featured exerting a vertical isometric force with the upper extremity. When subjects lifted a 2 N object repetitively the peak lift force rate was 26.4 N/s. The lift force rate increased to 36.1 N/s when the 2 N object was lifted (regardless of hand) after lifting the 8 N object with the right hand, which reveals the expected 'sensorimotor' memory. The lift force rate did not increase (24.8 vs. 26.4 N/s for the control condition) when a bout of isometric exertion (9.8 N) in the vertical direction with the distal right forearm preceded lifts of the 2 N object. This finding was confirmed with another isometric task designed to more closely mimic lifting an object with a precision grip. This difference in the sensitivity of grip versus lift force to a preceding isometric contraction indicates that separate sensorimotor memories contribute to the predictive scaling of the commands for gripping and lifting an object. PMID- 17717656 TI - Depth cues, rather than perceived depth, govern vergence. AB - We studied the influence of perceived surface orientation on vergence accompanying a saccade while viewing an ambiguous stimulus. We used the slant rivalry stimulus, in which perspective foreshortening and disparity specified opposite surface orientations. This rivalrous configuration induces alternations of perceived surface orientation, while the slant cues remain constant. Subjects were able to voluntarily control their perceptual state while viewing the ambiguous stimulus. They were asked to make a saccade across the perceived slanted surface. Our data show that vergence responses closely approximated the vergence response predicted by the disparity cue, irrespective of voluntarily controlled perceived orientation. However, comparing the data obtained while viewing the ambiguous stimulus with data from an unambiguous stimulus condition (when disparity and perspective specified similar surface orientations) revealed an effect of perspective cues on vergence. Collectively our results show that depth cues rather than perceived depth govern vergence. PMID- 17717655 TI - Effects of a secondary task on obstacle avoidance in healthy young adults. AB - Research on attention and gait stability has suggested that the process of recovering gait stability requires attentional resources, but the effect of performing a secondary task on stability during obstacle avoidance is poorly understood. Using a dual-task paradigm, the present experiment investigated the extent to which young adults are able to respond to a secondary auditory Stroop task (requiring executive attentional network resources) concurrently with obstacle crossing during gait when compared with performing unobstructed walking or sitting (control task). Our results demonstrated that as the level of difficulty in the postural task increased, there was a significant reduction in verbal response time from congruent to incongruent conditions in the auditory Stroop task, but no differences in gait parameters, indicating that these postural tasks require attention, and that young adults use a strategy of modulating the auditory Stroop task performance while keeping stable gait performance under the dual-task situations. Our findings suggest the existence of a hierarchy of control within both postural task (obstacle avoidance requires the most information processing resources) and dual-task (with gait stability being a priority) conditions. PMID- 17717657 TI - Neural activation associated with corrective saccades during tasks with fixation, pursuit and saccades. AB - Corrective saccades are small eye movements that redirect gaze whenever the actual eye position differs from the desired eye position. In contrast to various forms of saccades including pro-saccades, recentering-saccades or memory guided saccades, corrective saccades have been widely neglected so far. The fMRI correlates of corrective saccades were studied that spontaneously occurred during fixation, pursuit or saccadic tasks. Eyetracking was performed during the fMRI data acquisition with a fiber-optic device. Using a combined block and event related design, we isolated the cortical activations associated with visually guided fixation, pursuit or saccadic tasks and compared these to the activation associated with the occurrence of corrective saccades. Neuronal activations in anterior inferior cingulate, bilateral middle and inferior frontal gyri, bilateral insula and cerebellum are most likely specifically associated with corrective saccades. Additionally, overlapping activations with the established pro-saccade and, to a lesser extent, pursuit network were present. The presented results imply that corrective saccades represent a potential systematic confound in eye-movement studies, in particular because the frequency of spontaneously occurring corrective saccades significantly differed between fixation, pursuit and pro-saccades. PMID- 17717658 TI - Intrathecal treatment with anti-Nogo-A antibody improves functional recovery in adult rats after stroke. AB - Stroke often results in devastating neurological disabilities with no specific treatment available to improve functional recovery. Neurite growth inhibitory proteins such as Nogo-A play a critical role in impeding regain of function after stroke. We have reported that treatment with anti-Nogo-A antibody using the intracerebroventricular route resulted in improvement of function and neuroplasticity in adult or aged rats after stroke. This present study tested a more clinically accessible route for applying anti-Nogo-A antibodies, the intrathecal route. Anti-Nogo-A or control antibody was administered intrathecally at lower lumbar levels 1 week after middle cerebral artery occlusion in adult rats. Our results show that anti-Nogo-A antibody delivered by this intrathecal route for 2 weeks penetrated into brain parenchyma and bound to myelin-enriched structures such as the corpus callosum and striatal white matter. Animals receiving anti-Nogo-A antibody treatment significantly improved recovery of function on the skilled forelimb reaching task as compared to stroke only and stroke/control antibody animals. These findings show that anti-Nogo-A antibody delivered through the intrathecal route is as effective in restoring lost functions after stroke as the intracerebroventricular route. This is of great importance for the future application of anti-Nogo-A immunotherapy for ischemic stroke treatment. PMID- 17717659 TI - Uncontrolled manifold analysis of segmental angle variability during walking: preadolescents with and without Down syndrome. AB - The uncontrolled manifold (UCM) approach allows us to address issues concerning the nature of variability. In this study we applied the UCM analysis to gait and to a population known for exhibiting high levels of performance variability, Down syndrome (DS). We wanted to determine if preadolescents (ages between 8 and 10) with DS partition goal-equivalent variability (UCM( ||)) and non-goal equivalent variability differently than peers with typical development (TD) and whether treadmill practice would result in utilizing greater amounts of functional, task specific variability to accomplish the task goal. We also wanted to determine how variance is structured with respect to two important performance variables: center of mass (COM) and head trajectory at one specific event (i.e., heel contact) for both groups during gait. Preadolescents with and without DS walked on a treadmill below, at, and above their preferred overground speed. We tested both groups before and after four visits of treadmill practice. We found that children with DS partition more UCM( ||) variance than children with TD across all speeds and both pre and post practice. The results also suggest that more segmental configuration variance was structured such that less motion of COM than head position was exhibited at heel contact. Overall, we believe children with DS are employing a different control strategy to compensate for their inherent limitations by exploiting that variability that corresponds to successfully performing the task. PMID- 17717660 TI - Application of cell culture enrichment for improving the sensitivity of mycoplasma detection methods based on nucleic acid amplification technology (NAT). AB - Herein, we present data demonstrating that the application of initial cell culture enrichment could significantly improve mycoplasma testing methods based on the nucleic acid amplification technology (NAT) including a polymerase chain reaction (PCR)/microarray method. The results of the study using Vero cells demonstrated that this cell culture is able (1) to support efficient growth of mycoplasmas of primary interest, i.e., species found to be cell line contaminants, (2) to increase the sensitivity of NAT assay to the detection limits of the conventional broth/agar culture methods, and (3) to reduce the time required for mycoplasma testing fourfold in comparison with the conventional methods. Detection and identification of mycoplasmal agents were conducted using a modified PCR/microarray assay based on genetic differences among Mollicutes in the 16S-23S rRNA intergenic transcribed spacer (ITS). The application of nano gold/silver enhancement technology instead of previously used fluorescent dyes significantly simplified the readout of microarray results and allowed us to avoid using expensive scanning equipment. This modification has the potential to expand the implementation of microarray techniques into laboratories involved in diagnostic testing of mycoplasma contamination in cell substrates and potentially in other biological and pharmaceutical products. PMID- 17717661 TI - TNM staging with FDG-PET/CT in patients with primary head and neck cancer. AB - PURPOSE: PET/CT, PET+CT, and CT were compared concerning accuracies in TNM staging and malignancy detection in head and neck cancer. The impact of PET/CT compared to the other imaging modalities on therapy management was assessed. MATERIALS AND METHODS: Fifty-five patients with suspected head and neck primary cancer underwent whole-body FDG-PET/CT. PET/CT and PET+CT were evaluated by a nuclear medicine physician and a radiologist; CT was evaluated by two radiologists, PET by two nuclear physicians. Histopathology served as the standard of reference. Differences between the staging modalities were tested for statistical significance by McNemar's test. RESULTS: Overall TNM-staging and T staging with PET/CT were more accurate than PET+CT and CT alone (p < 0.05). PET/CT was marginally more accurate than CT alone in N-staging (p = 0.04); no statistically significant difference was found when compared to PET+CT for N staging. PET/CT altered further treatment in 13 patients compared to CT only and in 7 patients compared to PET+CT. CONCLUSION: Combined PET/CT proved to be partly more accurate in assessing the overall TNM-stage than CT and PET+CT. These results were based on a higher accuracy concerning the T-stage, mainly in patients with metallic implants and marginally the N-stage. Therapy decisions have been influenced in a substantial number of patients. PET/CT might be considered as a first line diagnostic tool in patients with suspected primary head and neck cancer. PMID- 17717662 TI - Expression of a CD20-specific chimeric antigen receptor enhances cytotoxic activity of NK cells and overcomes NK-resistance of lymphoma and leukemia cells. AB - Despite the clinical success of CD20-specific antibody rituximab, malignancies of B-cell origin continue to present a major clinical challenge, in part due to an inability of the antibody to activate antibody-dependent cell-mediated cytotoxicity (ADCC) in some patients, and development of resistance in others. Expression of chimeric antigen receptors in effector cells operative in ADCC might allow to bypass insufficient activation via FcgammaRIII and other resistance mechanisms that limit natural killer (NK)-cell activity. Here we have generated genetically modified NK cells carrying a chimeric antigen receptor that consists of a CD20-specific scFv antibody fragment, via a flexible hinge region connected to the CD3zeta chain as a signaling moiety. As effector cells we employed continuously growing, clinically applicable human NK-92 cells. While activity of the retargeted NK-92 against CD20-negative targets remained unchanged, the gene modified NK cells displayed markedly enhanced cytotoxicity toward NK-sensitive CD20 expressing cells. Importantly, in contrast to parental NK-92, CD20-specific NK cells efficiently lysed CD20 expressing but otherwise NK resistant established and primary lymphoma and leukemia cells, demonstrating that this strategy can overcome NK-cell resistance and might be suitable for the development of effective cell-based therapeutics for the treatment of B-cell malignancies. PMID- 17717663 TI - CD8+ T cells against multiple tumor-associated antigens in peripheral blood of midgut carcinoid patients. AB - PURPOSE: The aim of the study was to identify immunogenic HLA-A*0201-binding epitopes derived from a number of classical midgut carcinoid-associated proteins. CD8(+) T cells recognizing tumor-associated antigen (TAA) epitopes are of great interest for the establishment of immunotherapy as a novel treatment for this type of malignancy. EXPERIMENTAL DESIGN: Midgut carcinoid tumor specimens were microdissected and expression levels of potential TAAs were investigated by quantitative real time PCR. HLA-A*0201-binding motifs were selected using HLA peptide binding prediction algorithms and stabilization of HLA-A*0201 was verified using TAP-deficient T2 cells. Peripheral blood of midgut carcinoid patients was analyzed for peptide epitope recognition and the feasibility of generating peptide-reactive CD8(+) T cells in healthy blood donors was examined by an in vitro stimulation protocol using mature DCs. Activation of patient and healthy donor CD8(+) T cells was analyzed by intracellular flow cytometry staining of interferon gamma. RESULTS: Chromogranin A (CGA), tryptophan hydroxylase 1 (TPH-1), vesicular monoamine transporter 1 (VMAT-1), caudal type homeobox transcription factor 2 (CDX-2), and islet autoantigen 2 (IA-2) are properly expressed by midgut carcinoid tumor cells, with CGA mRNA expressed to greatest level. Midgut carcinoid patients have increased frequencies of peripheral blood CD8(+) T cells recognizing a pool of HLA-A*0201 peptides derived from these proteins compared to healthy age-matched individuals. Activated peptide-specific CD8(+) T cells could also be generated in healthy blood donors by in vitro stimulation. CONCLUSION: We have identified a number of immunogenic midgut carcinoid-associated peptide epitopes recognized by CD8(+) T cells. We show that midgut carcinoid patients display immune recognition of their tumors. Memory CD8(+) T cells in patient blood are of great interest when pursuing an immunotherapeutic treatment strategy. PMID- 17717664 TI - Computer-assisted placement technique in hip resurfacing arthroplasty: improvement in accuracy? AB - Freehand positioning of the femoral drill guide is difficult during hip resurfacing and the surgeon is often unsure of the implant position achieved peroperatively. The purpose of this study was to find out whether, by using a navigation system, acetabular and femoral component positioning could be made easier and more precise. Eighteen patients operated on by the same surgeon were matched by sex, age, BMI, diagnosis and ASA score (nine patients with computer assistance, nine with the regular ancillary). Pre-operative planning was done on standard AP and axial radiographs with CT scan views for the computer-assisted operations. The final position of implants was evaluated by the same radiographs for all patients. The follow-up was at least 1 year. No difference between both groups in terms of femoral component position was observed (p > 0.05). There was also no difference in femoral notching. A trend for a better cup position was observed for the navigated hips, especially for cup anteversion. There was no additional operating time for the navigated hips. Hip navigation for resurfacing surgery may allow improved visualisation and hip implant positioning, but its advantage probably will be more obvious with mini-incisions than with regular incision surgery. PMID- 17717666 TI - Comment on Kasai et al.: Clinical profile of long-term survivors of breast or thyroid cancer with metastatic spinal tumours. PMID- 17717667 TI - Phase I study of vinorelbine and irinotecan in previously untreated patients with advanced non-small cell lung cancer. AB - INTRODUCTION: Vinorelbine alone and irinotecan alone have been shown to have efficacy against non-small cell lung cancer (NSCLC); each drug has different mechanisms of action. A phase I study using a combination of vinorelbine and irinotecan as first-line treatment for advanced NSCLC was done to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT). METHODS: Previously untreated patients (or=4 days or febrile neutropenia, grade 4 thrombocytopenia, >or=grade 3 non-hematological toxicities, or the need to cancel drug administration on both days 8 and 15. RESULTS: A total of 23 patients were enrolled. DLT was observed in 1 of 6 patients at level 3 (20 mg/m(2) vinorelbine, 50 mg/m(2 )irinotecan), in 2 of 3 at level 4 (25 mg/m(2), 50 mg/m(2)), and in 2 of 5 at modified level 4 (20, 60 mg/m(2)). Level 4 and modified level 4 were considered to be the MTD; dose level 3 was therefore recommended. DLTs included liver dysfunction, pneumonitis, colitis, and arrhythmia. Injection site reactions were mild. Hematological and non-hematological toxicities were mild and easily controlled. CONCLUSION: Use of 20 mg/m(2) vinorelbine on days 1 and 8 followed by 50 mg/m(2 )irinotecan on days 1, 8, and 15 every 4 weeks warrants a phase II study. PMID- 17717668 TI - Sequential vinorelbine-capecitabine followed by docetaxel in advanced breast cancer: long-term results of a pilot phase II trial. AB - PURPOSE: To evaluate the response rate of the combination of capecitabine (C) and vinorelbine (V) followed by Docetaxel (D) in the 1st line treatment of advanced and metastatic breast cancer patients. PATIENTS AND METHODS: Patients with measurable disease and no prior chemotherapy in advanced disease were eligible. Pts received V 25 mg/m(2) on day 1 and 8 in combination with C 825 mg/m(2) twice a day from day 1 to 14 every 3 weeks for four cycles followed by 12 consecutive weeks of D 25 mg/m(2)/w. RESULTS: Between March 2002 and November 2003, 40 patients were enrolled. Median age was 57 years. Of patients, 77.5% of pts had visceral involvement and 32.5% had more than two metastatic sites. In the adjuvant setting, 62.5% received anthracycline and 10% Taxanes. In the intent-to treat population, an overall objective response was observed in 25 patients (62.5, 95% CI, 45.8-77.27) and stable disease in 5 (12.5%). Median time till progression (TTP) was 12.3 months (range 1.5-48; 95% CI, 10.05-14.54). The median survival was 35.7 months (range 2-47). Reported grade 3-4 toxicities under Navcap were neutropenia (4 pts), anemia (1 pt), thrombopenia (1 pt) and febrile neutropenia (3 pts). Reported grade 3-4 toxicities under weekly Docetaxel were neutropenia (1 pt), thrombopenia (2 pts), leucopenia (1 pt) and anemia (1 pt). CONCLUSION: The sequential use of Navcap followed by weekly Docetaxel demonstrated an interesting efficacy with a prolonged TTP and OS and warrants further evaluation. PMID- 17717670 TI - Frequency of HLA-B27 and its alleles in patients with Reiter syndrome: comparison with the frequency in other spondyloarthropathies and a healthy control population. AB - This retrospective study analyzed the HLA-B 27 alleles in a group of 20 consecutive patients with the diagnosis of Reiter syndrome (RS) followed in a tertiary referral university hospital in Brazil, during the period 1990-2006, and compared the data with that observed in other patients with spondyloarthropathies followed at the same institution. Eight cases were associated to gastrointestinal infection, eight cases to previous urethritis, and four cases presented no established preceding infection. HLA-B 27 alleles were typed by polymerase chain reaction-amplified DNA hybridized with sequence-specific oligonucleotide probes (HLA-B 2,701 to HLA-B 2,721). They were compared to a group of 108 patients with ankylosing spondylitis (AS), 40 with undifferentiated spondyloarthropathy (uSpA) and 111 healthy controls. Among the 20 patients, 17 were HLA-B 27 positive (85%). Two HLA-B 27 alleles were observed: HLA-B 2,705 (65%) and HLA-B 2,702 (35%). In the other spondyloarthropathies, the observed alleles were HLA-B 2,705 (90% in AS and 92.5% in uSpA), HLA-B 2,702 (8% in AS and 5% in uSpA), HLA-B 2,704 (1% in AS and 2.5% in uSpA) and HLA-B 2,713 (1% in AS). Among the 111 healthy controls, 80% presented HLA-B 2,705, followed by HLA-B 2,702 in 10%, HLA-B 2,703 in 6%, HLA-B 2,707 in 3% and HLA-B 2,713 in 1%. Concluding, in the HLA-B 27 positive patients with RS in this study there was predominance of HLA-B 2,705 allele, in a lower frequency than that observed in patients with other spondyloarthropathies and healthy controls. PMID- 17717669 TI - Strategies that modulate inflammasomes: insights from host-pathogen interactions. AB - The innate immune system is a dynamic and complex network for recognizing and responding to cellular insult or tissue damage after infection or injury. The primary effector mechanism of innate immunity is the generation of acute and chronic inflammatory responses through regulation of the processing and activation of proinflammatory caspases, particularly caspase 1, and cytokines, most notably IL-1beta and IL-18. Inflammasomes, cytosolic multi-protein complexes that function as molecular scaffolds for caspase activation, have recently emerged as the pivotal mechanism by which host innate immune and inflammatory responses are regulated. In this review, we investigate the mechanisms by which inflammasomes are modulated, both by endogenous host systems and by microbial pathogens. PMID- 17717671 TI - Cytomegalovirus infection in a patient with atypical Kawasaki disease. AB - Kawasaki disease (KD) is an acute, febrile, and multisystem vasculitis of early childhood with a striking predilection for the coronary arteries. The most significant complication is coronary artery abnormalities, including coronary aneurysms. The etiology of KD remains unknown. Many infectious agents including viruses have been postulated as possible causes of KD. But standard microbiologic techniques, molecular methods and serologic investigations have failed to identify an etiologic agent. We described a patient with atypical KD during cytomegalovirus infection. PMID- 17717674 TI - [The rheumatic hand]. PMID- 17717673 TI - Crohn's disease-associated colorectal cancer in Japan: report of four cases. AB - PURPOSE: We report four cases of Crohn's disease (CD)-associated colorectal cancer (CRC) in our department. CASE 1: A 42-year-old Japanese man had a 14-year history of ileocolon CD. He had a history of an ileocecal resection and a stricture plasty. At the age of 42, sigmoid colostomy was performed because of the deterioration of the anal stenosis. After this operation, the perianal pain had remained, and a magnetic resonance imaging scan revealed a rectal tumor. CASE 2: A 30-year-old Japanese man had a 13-year history of ileocolon CD. He had a history of an ileostomy, a subtotal colectomy, and ileo-rectal anastomosis. At the age of 30, he had perianal pain, and a colonoscopy revealed a rectal cancer. An abdomino-perineal resection of the remnant rectum was performed. CASE 3: A 46 year-old Japanese man had a 9-year history of ileocolon CD. He experienced abdominal fullness. Colonoscopy revealed an ascending colon cancer. He underwent a subtotal colectomy and ileo-rectal anastomosis. CASE 4: A 33-year-old Japanese woman had a 16-year history of ileocolon CD. She had no changes in symptoms of CD. Surveillance colonoscopy revealed a transverse colon cancer. She underwent a subtotal colectomy and ileo-rectal anastomosis. CONCLUSION: As the number of patients with CD and with CD-associated CRC has increased in Japan, CD-associated CRC, as noted in these patients, should be kept in mind in the management of patients with CD. In addition, a surveillance system of patients with CD should be established and should prompt further study about CD-associated CRC. PMID- 17717672 TI - Increased senescence-associated gene expression and lipid peroxidation induced by iron deficiency in rice roots. AB - Iron deficiency is among the most common nutritional disorders in plants. Low iron supply causes decreased root growth and even plant death. However, there are no reports about the specific pathways that lead Fe-deficient roots to senescence and death. To investigate the molecular mechanisms that regulate rice roots response to Fe-deficiency, rice seedlings were grown for 3, 6 and 9 days in the presence or absence of Fe. Sequences of 28 induced genes in rice roots under Fe deficiency were identified by representational difference analysis (RDA). About 40% of these sequences have been previously reported as senescence-related. Differential expression of selected genes was confirmed by semi-quantitative RT PCR analysis. Classical senescence-related sequences, such as MYB and WRKY transcription factors, cysteine protease, ubiquitin-conjugating enzyme, lipid transfer protein, fatty acid hydroxylase, beta-glucosidase and cytochrome P450 oxydoreductase were identified. Fe-deficiency also resulted in decreased dry weight, increased lipid peroxidation (detected by TBA and histochemical methods) as well as evident membrane damage in Fe-deficient roots. Taken together, the results indicate that Fe-deficiency in roots is linked to typical senescence pathways, associated with lipid peroxidation. PMID- 17717675 TI - [Operative differential therapy of rheumatic wrists]. AB - The wrists are affected in the long-term in 90% of people with rheumatism and are often (42%) the first manifestation of a destructive disease. The functionality of the wrist and the whole hand is of great importance because in many cases loss of function of the wrists leads to severe limitations. Local and operative treatment of the wrist in rheumatoid arthritis (RA) is one of the main duties in rheuma-orthopaedics. For operative treatment there is a finely tuned differential therapeutic spectrum available. The diagnostic indications take the local and total pattern of affection, the current systemic therapy as well as patient wishes and patient compliance into consideration. In the early stages according to LDE (Larsen, Dale, Eek), soft tissues operations such as articulo tenosynovectomy (ATS) are most commonly carried out. In further advanced stages osseus stabilisation must often be performed. At this point a smooth transition from partial arthrodesis to complete fixation is possible. After initial euphoria, arthroplasty of the wrist is being increasingly less used for operative treatment due to the unconvincing long-term results and high complication rate. With reference to the good long-term results of all operative procedures, in particular early ATS with respect to pain, function and protection of tendons, after failure of medicinal treatment and persistence of inflammatory activity in the wrist, patients should be transferred to an experienced rheuma-orthopaedic surgeon. PMID- 17717676 TI - [Mycophenolate mofetil for induction of remission in Wegener's granulomatosis]. PMID- 17717677 TI - [Prosthetics of metacarpophalangeal joints]. AB - Only a few of the large number of implants developed during the last decades for replacement of the metacarpophalangeal (MCP) joint have proven to be reliable. The rates of loosening and mechanical failure of almost all types of constrained prostheses are so high that their use cannot be recommended at present. For more than 40 years silicone arthroplasty according to Swanson has been regarded as the gold standard in the prosthetic replacement of the MCP joint. In long-term studies this device provided good pain relief and a lasting correction of preoperative ulnar deviation. The degree of patient satisfaction continues to be high after more than 10 years. With the NeuFlex spacer, a modification of the original Swanson implant, a better range of motion and a reduction of wear related problems is expected. In this study the results of 130 NeuFlex spacers after a mean time of 3.6 years were examined and 82% of the patients were completely pain free. The mobility of the joints improved from 40 degrees preoperatively to 54 degrees after 3.6 years. Radiologically periprosthetic erosions or osteolyses were seen in approximately 15% of implants. A minimal sinking of the stems developed in 24%, a massive one in 6% and 13% of the spacers were broken. Thus the use of the NeuFlex implant resulted in a better range of motion compared to the Swanson spacer, but the problem of radiological appearance remained unchanged. For unlinked prostheses sufficient soft tissue stability is mandatory as well as wear-resistant surface materials. The pyrocarbon prosthesis according to Beckenbaugh is the only implant for which long-term results are available. In a prospective study we evaluated 28 Ascension pyrocarbon prostheses with a mean follow-up of 4 years. Stability was not found to be a problem. Subjective results were satisfactory, the range of motion remained unchanged, however 46% of prosthesis stems exhibited radiolucent seams, 7 prostheses (25%) were rated as loose and 5 of those had to be replaced by a silicone implant. Use of the implant was abandoned, as it was unreliable regarding bony fixation. There are promising concepts in some new prostheses but independent data are still lacking. PMID- 17717678 TI - [To be or not to be a Treg: epigenetic regulation of Foxp3 expression in regulatory T cells]. AB - Regulatory T cells (Treg) harbor great therapeutic potential for the treatment of autoimmune diseases due to their potent suppressive capacity. The majority of these cells express the transcription factor Foxp3, which is critical for both development and function of Treg. We discuss here our recent data indicating a contribution of epigenetic regulation for the permanent expression of Foxp3 in stable Treg a finding that is of significant importance if Treg are devised for clinical applications. PMID- 17717679 TI - Comparison of conventional resistance training and the fly-wheel ergometer for training the quadriceps muscle group in patients with unilateral knee injury. AB - A fly-wheel ergometer (FWE) offering resistance training of the knee extensors has been designed for space travel and found to be effective during bed rest. The possibility exists that this device is also effective in training the knee extensors after knee injury. The purpose of this study was to compare the FWE to standard knee extensor training equipment for their effects on individuals with a history of knee injury, a group who commonly suffer from weakness of the knee extensors that effects their function. Twenty-nine subjects completed the study, which included tests of knee self-assessment, knee extensor static and dynamic muscle strength, size and neural activation as well as single leg power output, standing balance and vertical jump performance. Both groups showed statistically significant (P < 0.05) improvements in these variables over the 3-month training period but no differences were noted between the groups. The FWE appears to be as effective as standard resistance training equipment for improving knee extensor muscle group size and performance after knee injury. PMID- 17717680 TI - Calculation of oxygen uptake efficiency slope based on heart rate reserve end points in healthy elderly subjects. AB - We tested the validity of an new methodological approach to the calculation of oxygen uptake efficiency slope (OUES) [i.e. the use of exercise end-points based on fractions of heart rate reserve (HR(res))], as an alternative to the traditional time-based calculation. Twenty-nine healthy sedentaries >60 years of age (18 males, 11 females) performed an incremental cycling exercise to exhaustion. Respiratory variables and HR were measured breath by breath. Resting and peak variables were calculated and ventilatory threshold (VT) was identified by standard technique. OUES was calculated on 75, 90 and 100% of the incremental exercise data (OUES75, OUES90, OUES100) and on data corresponding to 60 and 80% of the HR(res) (OUES60%HR(res), OUES80%HR(res)). No significant difference (repeated measures ANOVA) was detected between time-based (OUES100, OUES90, OUES75) as well as HR(res)-based measures of OUES (OUES80%HR(res), OUES60%HR(res)). The Bland-Altman analysis revealed a bias not significantly different from 0 (22.0 and 53.3 for OUES80%HR(res)-OUES100 and OUES60%HR(res) OUES100, respectively), a precision of 171.2 and 289.0 and 95% limits of agreement from -313 to +358 and from -513 to +620 for OUES80%HR(res)-OUES100 and for OUES60%HR(res)-OUES100, respectively. High correlations were detected between (VO(2peak)) and OUES60%(res) and OUES80%HR(res) (r (2) = 0.70 and 0.81, respectively) and between VT and OUES60%(res) and OUES80%HR(res) (r (2) = 0.58 and 0.66, respectively). The main finding of this study is that OUES can be reliably calculated based on HR(res) end-points during incremental cycling exercise, in healthy elderly subjects. Furthermore, our study confirms the validity of OUES as an indicator of aerobic exercise capability in this population. PMID- 17717682 TI - Motor performance during and following acute alcohol intoxication in healthy non alcoholic subjects. AB - Chronic alcohol abuse has adverse effects on skeletal muscle, and reduced muscle strength is frequently seen in chronic alcoholics. In this study the acute effects of moderate alcohol intoxication on motor performance was evaluated in 19 non-alcoholic healthy subjects (10 women, 9 men). A randomised double-blinded placebo controlled design was applied to subjects receiving alcohol in juice and pure juice at two separate test periods. Isokinetic and isometric muscle strength and endurance were determined before, during, 24 and 48 h after the ingestion of alcohol in juice and juice (placebo). To detect a reduced activation of the central motor pathways superimposed external electrical stimulations during voluntary contractions were applied. Creatine kinase (CK) was measured to detect any alcohol-induced changes in sarcolemmal integrity. No change was seen in isokinetic as well as in isometric muscle performance during or following the alcohol intoxication as compared to the non-alcoholic condition. Also, no central activation failure was observed. No significant difference in CK increment was observed comparing the alcoholic- and non-alcoholic condition. In conclusion, a single episode of moderate alcohol intoxication (1,4 g/l) does not impair motor performance, and no accelerated exercise-induced muscle damage is seen. PMID- 17717681 TI - Flux control analysis of mitochondrial oxidative phosphorylation in rat skeletal muscle: pyruvate and palmitoyl-carnitine as substrates give different control patterns. AB - Flux control analysis of eight reactions involved in oxidative phosphorylation of mitochondria from rat quadriceps muscle was performed under circumstances resembling in vivo conditions of carbohydrate or fatty acid oxidation. The major flux control at a respiration rate of 55% of state 3 was associated with the ADP generating system, i.e., 0.58 +/- 0.05 with pyruvate, but significantly lower, 0.40 +/- 0.05, with palmitoyl-carnitine as substrate. The flux control coefficients of complex I, III and IV, the ATP synthase, the ATP/ADP carrier and the P(i) carrier were 0.070 +/- 0.03, 0.083 +/- 0.04, 0.054 +/- 0.01, 0.11 +/- 0.03, 0.090 +/- 0.03 and 0.026 +/- 0.01, respectively, with pyruvate as substrate. With palmitoyl-carnitine all control coefficients were significantly different, except for the P(i) carrier (i.e., 0.024 +/- 0.001, 0.036 +/- 0.01, 0.052 +/- 0.02, 0.020 +/- 0.002, 0.034 +/- 0.02 and 0.012 +/- 0.002, respectively), probably caused by the shift from NADH to FADH(2) oxidation. The sum of flux control coefficients was not significantly different from unity with pyruvate, while only 0.58 with palmitoyl-carnitine, indicating significant control contributions from the enzymes involved with the fatty acid oxidation or transport. Flux control of ADP generation was specifically tested at three different respiration rates, 30, 55 and 75% of state 3. At all respiration rates control was higher with pyruvate and pyruvate + palmitoyl-carnitine compared with palmitoyl-carnitine as substrate. Also the control was lower at 75% compared to 30% of the state 3 respiration both with pyruvate and pyruvate + palmitoyl carnitine as substrate, suggesting that muscle respiration moves from "demand control" to "supply control" as respiration increases. PMID- 17717683 TI - Neuronal identification of acoustic signal periodicity. AB - Acoustic signals transmit information by temporal characteristics and envelope periodicity as well as by their frequency content. Many animals can extract the frequency content of a signal by means of specialized organs such as the cochlea but for the detection and identification of higher-order periodicity, e.g., amplitude modulations, this type of organ is useless. In addition, many animals do not have a cochlea but still depend on a reliable identification of different frequencies in the vast variety of acoustic signals they perceive in their natural environment. Hence, neural mechanisms to decode periodicity information must exist. We present a detailed mathematical analysis of a recurrent and a feedforward model of neuronal periodicity extraction and discuss basic constraints for neuronal circuitry performing such a task in a biological system. Both the recurrent and the feedforward model perform well using neuronal parameters typical for the auditory system. Performance is limited mainly by the temporal precision of the connections between the neurons. PMID- 17717684 TI - Effects of different fatty acids and dietary lipids on adiponectin gene expression in 3T3-L1 cells and C57BL/6J mice adipose tissue. AB - Obesity is positively correlated to dietary lipid intake, and the type of lipid may play a causal role in the development of obesity-related pathologies. A major protein secreted by adipose tissue is adiponectin, which has antiatherogenic and antidiabetic properties. The aim of this study was to evaluate the effects of four different high-fat diets (enriched with soybean oil, fish oil, coconut oil, or lard) on adiponectin gene expression and secretion by the white adipose tissue (WAT) of mice fed on a selected diet for either 2 (acute treatment) or 60 days (chronic treatment). Additionally, 3T3-L1 adipocytes were treated for 48 h with six different fatty acids: palmitic, linoleic, eicosapentaenoic (EPA), docosahexaenoic (DHA), lauric, or oleic acid. Serum adiponectin concentration was reduced in the soybean-, coconut-, and lard-enriched diets in both groups. Adiponectin gene expression was lower in retroperitoneal WAT after acute treatment with all diets. The same reduction in levels of adiponectin gene expression was observed in epididymal adipose tissue of animals chronically fed soybean and coconut diets and in 3T3-L1 cells treated with palmitic, linoleic, EPA, and DHA acids. These results indicate that the intake of certain fatty acids may affect serum adiponectin levels in mice and adiponectin gene expression in mouse WAT and 3T3-L1 adipocytes. The effects appear to be time dependent and depot specific. It is postulated that the downregulation of adiponectin expression by dietary enrichment with soybean oil or coconut oil may contribute to the development of insulin resistance and atherosclerosis. PMID- 17717685 TI - In vivo investigations on the cholinesterase-inhibiting effects of tricyclic quinazolinimines: scopolamine-induced cognitive impairments in rats are attenuated at low dosage and reinforced at higher dosage. AB - Tricyclic quinazolinimines as a novel class of potent inhibitors of cholinesterases in vitro are micro- and sub-micromolar inhibitors with activities at both acetyl- (AChE) and butyrylcholinesterase (BChE) or at BChE only. To further establish the antiamnesic properties of this class of compounds, an in vivo test system has been established. Cognitive impairment in rats was reversibly induced by scopolamine (0.05 mg/100 g body weight) and evaluated in an eight-arm radial maze. A representative quinazolinimine (MD212) showed attenuation of cognitive deficits at a low dosage (0.01 mg/100 g body weight), whereas at a high dosage (>0.1 mg/100 g body weight) the effect of scopolamine is markedly reinforced. As MD212 applied alone does not influence rat's cognition at all, the reinforcement of scopolamine effect has to be due to the amplification of scopolamine action possibly by (1) inhibition of scopolamine metabolism, (2) influence of scopolamine on MD212 metabolism or (3) allosteric modulation of mACh receptors. Receptor-binding studies proved hypothesis (3): MD212 stabilizes [3H]N methylscopolamine binding to muscarinic receptors allosterically. PMID- 17717686 TI - The pretectal nuclei in two monotremes: the short-beaked echidna (Tachyglossus aculeatus) and the platypus (Ornithorhynchus anatinus). AB - We have examined the organization of the pretectal area in two monotremes (the short beaked echidna-Tachyglossus aculeatus, and the platypus-Ornithorhynchus anatinus) and compared it to that in the Wistar strain rat, using Nissl staining in conjunction with enzyme histochemistry (acetylcholinesterase and NADPH diaphorase) and immunohistochemistry for parvalbumin, calbindin, calretinin and non-phosphorylated neurofilament protein (SMI-32 antibody). We were able to identify distinct anterior, medial, posterior (now called tectal gray) and olivary pretectal nuclei as well as a nucleus of the optic tract, all with largely similar topographical and chemoarchitectonic features to the homologous regions in therian mammals. The positions of these pretectal nuclei correspond to the distributions of retinofugal terminals identified by other authors. The overall size of the pretectum in both monotremes was found to be at least comparable in size, if not larger than, the pretectum of representative therian mammals of similar brain and body size. Our findings suggest that the pretectum of these two monotreme species is comparable in both size and organization to that of eutherian mammals, and is more than just an undifferentiated area pretectalis. The presence of a differentiated pretectum with similar chemoarchitecture to therians in both living monotremes lends support to the idea that the stem mammal for both prototherian and therian lineages also had a differentiated pretectum. This in turn indicates that a differentiated pretectum appeared at least 125 million years ago in the mammalian lineage and that the stem mammal for proto- and eutherian lineages probably had similar pretectal nuclei to those identified in its descendants. PMID- 17717687 TI - Do early sensory cortices integrate cross-modal information? AB - Our different senses provide complementary evidence about the environment and their interaction often aids behavioral performance or alters the quality of the sensory percept. A traditional view defers the merging of sensory information to higher association cortices, and posits that a large part of the brain can be reduced into a collection of unisensory systems that can be studied in isolation. Recent studies, however, challenge this view and suggest that cross-modal interactions can already occur in areas hitherto regarded as unisensory. We review results from functional imaging and electrophysiology exemplifying cross modal interactions that occur early during the evoked response, and at the earliest stages of sensory cortical processing. Although anatomical studies revealed several potential origins of these cross-modal influences, there is yet no clear relation between particular functional observations and specific anatomical connections. In addition, our view on sensory integration at the neuronal level is coined by many studies on subcortical model systems of sensory integration; yet, the patterns of cross-modal interaction in cortex deviate from these model systems in several ways. Consequently, future studies on cortical sensory integration need to leave the descriptive level and need to incorporate cross-modal influences into models of the organization of sensory processing. Only then will we be able to determine whether early cross-modal interactions truly merit the label sensory integration, and how they increase a sensory system's ability to scrutinize its environment and finally aid behavior. PMID- 17717688 TI - Mitochondrial degeneration in dystrophic neurites of senile plaques may lead to extracellular deposition of fine filaments. AB - Recent data show that amyloid precursor protein accumulates inside axons after disruption of fast axonal transport, but how this leads to mature plaques with extracellular amyloid remains unclear. To investigate this issue, primitive plaques in prefrontal cortex of aged rhesus monkeys were reconstructed using serial section electron microscopy. The swollen profiles of dystrophic neurites were found to be diverticula from the main axis of otherwise normal neurites. Microtubules extended from the main neurite axis into the diverticulum to form circular loops or coils, providing a transport pathway for trapping organelles. The quantity and morphology of organelles contained within diverticula suggested a progression of degeneration. Primitive diverticula contained microtubules and normal mitochondria, while larger, presumably older, diverticula contained large numbers of degenerating mitochondria. In advanced stages of degeneration, apparent autophagosomes derived from mitochondria exhibited a loose lamellar to filamentous internal structure. Similar filamentous material and remnants of mitochondria were visible in the extracellular spaces of plaques. This progression of degeneration suggests that extracellular filaments originate inside degenerating mitochondria of neuritic diverticula, which may be a common process in diverse diseases. PMID- 17717689 TI - Orienting and maintenance of spatial attention in audition and vision: multimodal and modality-specific brain activations. AB - We studied orienting and maintenance of spatial attention in audition and vision. Functional magnetic resonance imaging (fMRI) in nine healthy subjects revealed activations in the same superior and inferior parietal, and posterior prefrontal areas in the auditory and visual orienting tasks when these tasks were compared with the corresponding maintenance tasks. Attention-related activations in the thalamus and cerebellum were observed during the auditory orienting and maintenance tasks and during the visual orienting task. In addition to the supratemporal auditory cortices, auditory orienting, and maintenance produced stronger activity than the respective visual tasks in the inferior parietal and prefrontal cortices, whereas only the occipital visual cortex and the superior parietal cortex showed stronger activity during the visual tasks than during the auditory tasks. Differences between the brain networks involved in auditory and visual spatial attention could be, for example, due to different encoding of auditory and visual spatial information or differences in stimulus-driven (bottom up triggered) and voluntary (top-down controlled) attention between the auditory and visual modalities, or both. PMID- 17717690 TI - Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat. AB - The medial prefrontal cortex (mPFC) has been associated with diverse functions including attentional processes, visceromotor activity, decision making, goal directed behavior, and working memory. Using retrograde tracing techniques, we examined, compared, and contrasted afferent projections to the four divisions of the mPFC in the rat: the medial (frontal) agranular (AGm), anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) cortices. Each division of the mPFC receives a unique set of afferent projections. There is a shift dorsoventrally along the mPFC from predominantly sensorimotor input to the dorsal mPFC (AGm and dorsal AC) to primarily 'limbic' input to the ventral mPFC (PL and IL). The AGm and dorsal AC receive afferent projections from widespread areas of the cortex (and associated thalamic nuclei) representing all sensory modalities. This information is presumably integrated at, and utilized by, the dorsal mPFC in goal directed actions. In contrast with the dorsal mPFC, the ventral mPFC receives significantly less cortical input overall and afferents from limbic as opposed to sensorimotor regions of cortex. The main sources of afferent projections to PL/IL are from the orbitomedial prefrontal, agranular insular, perirhinal and entorhinal cortices, the hippocampus, the claustrum, the medial basal forebrain, the basal nuclei of amygdala, the midline thalamus and monoaminergic nuclei of the brainstem. With a few exceptions, there are few projections from the hypothalamus to the dorsal or ventral mPFC. Accordingly, subcortical limbic information mainly reaches the mPFC via the midline thalamus and basal nuclei of amygdala. As discussed herein, based on patterns of afferent (as well as efferent) projections, PL is positioned to serve a direct role in cognitive functions homologous to dorsolateral PFC of primates, whereas IL appears to represent a visceromotor center homologous to the orbitomedial PFC of primates. PMID- 17717691 TI - Mapping functional connectivity in barrel-related columns reveals layer- and cell type-specific microcircuits. AB - Synaptic circuits bind together functional modules of the neocortex. We aim to clarify in a rodent model how intra- and transcolumnar microcircuits in the barrel cortex are laid out to segregate and also integrate sensory information. The primary somatosensory (barrel) cortex of rodents is the ideal model system to study these issues because there, the tactile information derived from the large facial whiskers on the snout is mapped onto so called barrel-related columns which altogether form an isomorphic map of the sensory periphery. This allows to functionally interpret the synaptic microcircuits we have been analyzing in barrel-related columns by means of whole-cell recordings, biocytin filling and mapping of intracortical functional connectivity with sublaminar specificity by computer-controlled flash-release of glutamate. We find that excitatory spiny neurons (spiny stellate, star pyramidal, and pyramidal cells) show a layer specific connectivity pattern on top of which further cell type-specific circuits can be distinguished. The main features are: (a) strong intralaminar, intracolumnar connections are established by all types of excitatory neurons with both, excitatory and (except for layer Vb- intrinsically burst-spiking-pyramidal cells) inhibitory cells; (b) effective translaminar, intracolumnar connections become more abundant along the three main layer compartments of the canonical microcircuit, and (c) extensive transcolumnar connectivity is preferentially found in specific cell types in each of the layer compartments of a barrel related column. These multiple sequential and parallel circuits are likely to be suitable for specific cortical processing of "what" "where" and "when" aspects of tactile information acquired by the whiskers on the snout. PMID- 17717692 TI - A detailed 3D model of the guinea pig cochlea. AB - Several partial models of cochlear subparts are available. However, a complete 3D model of an intact cochlea based on actual histological sections has not been reported. Hence, the aim of this study was to develop a novel 3D model of the guinea pig cochlea and conduct post-processes on this reconstructed model. We used a combination of histochemical processing and the method of acquiring section data from the visible human project (VHP) to obtain a set of ideal raw images of cochlear sections. After semi-automatic registration and accurate manual segmentation with professional image processing software, one set of aligned data and six sets of segmented data were generated. Finally, the segmented structures were reconstructed by 3D Slicer (a professional imaging process and analysis tool). Further, post-processes including 3D visualization and a virtual endoscope were completed to improve visualization and simulate the course of the cochlear implant through the scala tympani. The 3D cochlea model contains the main six structures: (1) the inner wall, (2) modiolus and spiral lamina, (3) cochlea nerve and spiral ganglion, (4) spiral ligament and inferior wall of cochlear duct, (5) Reissner's membrane and (6) tectorial membrane. Based on the results, we concluded that ideal raw images of cochlear sections can be acquired by combining the processes of conventional histochemistry and photographing while slicing. After several vital image processing and analysis steps, this could further generate a vivid 3D model of the intact cochlea complete with internal details. This novel 3D model has great potential in teaching, basic medical research and in several clinical applications. PMID- 17717693 TI - Precerebellar and vestibular nuclei of the short-beaked echidna (Tachyglossus aculeatus). AB - The monotremes are a unique group of living mammals, which diverged from the line leading to placental mammals at least 125 million years ago. We have examined the organization of pontine, inferior olivary, lateral reticular and vestibular nuclei in the brainstem of the short-beaked echidna (Tachyglossus aculeatus) to determine if the cyto- and chemoarchitecture of these nuclei are similar to that in placental mammals and marsupials. We have used Nissl staining in conjunction with enzyme-histochemistry for acetylcholinesterase, cytochrome oxidase and NADPH diaphorase as well as immunohistochemistry for non-phosphorylated neurofilament protein (SMI-32 antibody) and calcium binding proteins (parvalbumin, calbindin, calretinin). Homologies could be established between the arch shaped inferior olivary complex of the echidna and the principal, dorsal and medial accessory subdivisions of the therian inferior olivary complex. The pontine nuclei of the echidna included basilar and reticulotegmental components with similar cyto- and chemarchitectural features to therians and there were magnocellular and subtrigeminal components of the lateral reticular nucleus, also as seen in therians. Subdivisions and chemoarchitecture of the vestibular complex of the echidna were both similar to that region in rodents. In all three precerebellar nuclear groups studied and in the vestibular nucleus organization, the cyto- and chemoarchitecture of the echidna was very similar to that seen in therian mammals and no "primitive" or "reptilian" features were evident. PMID- 17717695 TI - Excitatory signal flow and connectivity in a cortical column: focus on barrel cortex. AB - A basic feature of the neocortex is its organization in functional, vertically oriented columns, recurring modules of signal processing and a system of transcolumnar long-range horizontal connections. These columns, together with their network of neurons, present in all sensory cortices, are the cellular substrate for sensory perception in the brain. Cortical columns contain thousands of neurons and span all cortical layers. They receive input from other cortical areas and subcortical brain regions and in turn their neurons provide output to various areas of the brain. The modular concept presumes that the neuronal network in a cortical column performs basic signal transformations, which are then integrated with the activity in other networks and more extended brain areas. To understand how sensory signals from the periphery are transformed into electrical activity in the neocortex it is essential to elucidate the spatial temporal dynamics of cortical signal processing and the underlying neuronal 'microcircuits'. In the last decade the 'barrel' field in the rodent somatosensory cortex, which processes sensory information arriving from the mysticial vibrissae, has become a quite attractive model system because here the columnar structure is clearly visible. In the neocortex and in particular the barrel cortex, numerous neuronal connections within or between cortical layers have been studied both at the functional and structural level. Besides similarities, clear differences with respect to both physiology and morphology of synaptic transmission and connectivity were found. It is therefore necessary to investigate each neuronal connection individually, in order to develop a realistic model of neuronal connectivity and organization of a cortical column. This review attempts to summarize recent advances in the study of individual microcircuits and their functional relevance within the framework of a cortical column, with emphasis on excitatory signal flow. PMID- 17717697 TI - Comparative analysis of extra-ventricular mitoses at early stages of cortical development in rat and human. AB - Embryonic germinal zones of the dorsal and ventral telencephalon generate cortical neurons during the final week of gestation in rodent and during several months in human. Whereas the vast majority of cortical interneurons originate from the ventral telencephalon, excitatory neurons are locally generated within the germinal zone of the dorsal telencephalon, the future cerebral cortex, itself. However, a number of studies have described proliferating cells external to the ventricular and subventricular germinal zones in the developing dorsal telencephalon. In this study, we performed a comprehensive cell density analysis of such 'extra-ventricular proliferating cells' (EVPCs) during corticogenesis in rat and human using a mitotic marker anti-phospho-histone H3. Subsequently, we performed double-labelling studies with other mitotic and cell type specific markers to undertake phenotypic characterisation of EVPCs. Our findings show: (1) the densities of extra-ventricular H3-positive (H3+) cells were surprisingly similar in preplate stage rat and human; (2) extra-ventricular proliferation continues during mid-and late corticogenesis in rat and in early fetal human cortex; and (3) extra-ventricular cells appear to be mitotic precursors as they are not immunoreactive for a panel of early post-mitotic and cell type-specific markers, although (4) a subset of EVPCs are proliferating microglia. These data suggest that some aspects of early corticogenesis are conserved between rodent and human despite marked differences in the duration of neurogenesis and the anatomical organisation of the developing cerebral cortex. PMID- 17717696 TI - Local origin and activity-dependent generation of nestin-expressing protoplasmic astrocytes in CA1. AB - Since reports that precursor cells in the adult subventricular zone (SVZ) contribute to regenerative neuro- and gliogenesis in CA1, we wondered whether a similar route of migration might also exist under physiological conditions. Permanent labeling of SVZ precursor cells with a lentiviral vector for green fluorescent protein did not reveal any migration from the SVZ into CA1 in the intact murine brain. However, in a nestin-GFP reporter mouse we found proliferating cells within the corpus callosum/alveus region expressing nestin and glial fibrillary acidic protein similar to precursor cells in the neighboring neurogenic region of the adult dentate gyrus. Within 3 weeks of BrdU administration, BrdU-positive nestin-GFP-expressing protoplasmic astrocytes emerged in CA1. Similar to precursor cells isolated from the dentate gyrus and the SVZ, nestin-GFP-expressing cells from corpus callosum/alveus were self renewing and multipotent in vitro, whereas cells isolated from CA1 were not. Nestin-GFP-expressing cells in CA1 differentiated into postmitotic astrocytes characterized by S100beta expression. No new neurons were found in CA1. The number of nestin-GFP-expressing astrocytes in CA1 was increased by environmental enrichment. We conclude that astrogenesis in CA1 is influenced by environmental conditions. However, SVZ precursor cells do not contribute to physiological cellular plasticity in CA1. PMID- 17717700 TI - Branching of individual somatosensory cerebropontine axons in rat: evidence of divergence. AB - The cerebral cortex conveys major input to the granule cell layer of the cerebellar hemispheres by way of the pontine nuclei. Cerebrocortical projections terminate in multiple, widely distributed clusters in the pontine nuclei. This clustered organization is thought to provide the transition between the different organizational principles of the cerebrum and cerebellum, and indicates that parallel processing occurs at multiple sites in the pontine nuclei. At a cellular level, however, it is unknown whether individual cerebropontine neurons target pontocerebellar cells located in different clusters or not. We have employed anterograde axonal tracing and 3D computerized reconstruction techniques to characterize the branching pattern and morphology of individual cerebropontine axons from the primary somatosensory cortex (SI). Our findings show that 43% of the cerebrobulbar fibers arising from SI whisker representations provide two or three fibers entering the pontine nuclei, whereas 39% have only one fiber, and the remaining 18% do not project to the pontine nuclei. Thus, it appears that a majority of cerebropontine axons originating in SI whisker representations diverge to contact multiple, separated pontocerebellar cells. Further, 84% of the somatosensory cerebropontine fibers are collateral branches from cerebrobulbar and/or cerebrospinal parent fibers, while 16% are direct cerebropontine projections without a further descending projection. A range of thicknesses of the fibers entering the pontine nuclei were observed, with collaterals of corticobulbar fibers having the smallest diameter. Taken together, these findings may be related to previously described separate cerebropontine transmission lines with different properties. PMID- 17717699 TI - Three-dimensional reconstruction of the axon arbor of a CA3 pyramidal cell recorded and filled in vivo. AB - The three-dimensional intrahippocampal distribution of axon collaterals of an in vivo filled CA3c pyramidal cell was investigated. The neuron was filled with biocytin in an anesthetized rat and the collaterals were reconstructed with the aid of a NeuroLucida program from 48 coronal sections. The total length of the axon collaterals exceeded 0.5 m, with almost 40,000 synaptic boutons. The majority of the collaterals were present in the CA1 region (70.0%), whereas 27.6% constituted CA3 recurrent collaterals with the remaining minority of axons returning to the dentate gyrus. The axon arbor covered more than two thirds of the longitudinal axis of the hippocampus, and the terminals were randomly distributed both locally and distally from the soma. We suggest that the CA3 system can be conceptualized as a single-module, in which nearby and distant targets are contacted by the same probability (similar to a mathematically defined random graph). This arrangement, in combination with the parallel input granule cells and parallel output CA1 pyramidal cells, appears ideal for segregation and integration of information and memories. PMID- 17717698 TI - Morphological characterization of electrophysiologically and immunohistochemically identified basal forebrain cholinergic and neuropeptide Y containing neurons. AB - The basal forebrain (BF) contains cholinergic as well as different types of non cholinergic corticopetal neurons and interneurons, including neuropeptide Y (NPY) containing cells. BF corticopetal neurons constitute an extrathalamic route to the cortex and their activity is associated with an increase in cortical release of the neurotransmitter acetylcholine, concomitant with low voltage fast cortical EEG activity. It has been shown in previous studies (Duque et al. in J Neurophysiol 84:1627-1635, 2000) that in anesthetized rats BF cholinergic neurons fire mostly during low voltage fast cortical EEG epochs, while increased NPY neuronal firing is accompanied by cortical slow waves. In this paper, electrophysiologically and neurochemically characterized cholinergic and NPY containing neurons were 3D reconstructed from serial sections and morphometrically analyzed. Cholinergic and NPY-containing neurons, although having roughly the same dendritic surface areas and lengths, were found to differ in dendritic thickness and branching structure. They also have distinct patterns of dendritic endings. The subtle differences in dendritic arborization pattern may have an impact on how synaptic integration takes place in these functionally distinct neuronal populations. Cholinergic neurons exhibited cortically projecting axons and extensive local axon collaterals. Elaborate local axonal arbors confined to the BF also originated from NPY-containing neurons. The presence of local axon collaterals in both cholinergic and NPY neurons indicates that the BF is not a mere conduit for various brainstem inputs to the cortex, but a site where substantial local processing must take place. PMID- 17717701 TI - Modality-independent involvement of the left BA 44 during lexical decision making. AB - During a lexical decision task, lexical decision making can be distinguished from lexical retrieval. Lexical decision making is independent of stimulus modality and not reflected in the decision times, whereas the opposite holds for lexical retrieval. In neuroimaging studies investigating lexical decision tasks with either visual or auditory stimuli these two processes have so far been confused. Therefore, it is not clear whether the activation of Broca's region, consisting of the left Brodmann's area (BA) 44 and BA 45, reported in such studies really reflects lexical decision making. The present event-related fMRI study investigated the role of Broca's region in lexical decision by analyzing brain activation that is independent of stimulus modality or decision times. Twenty-two healthy participants performed lexical decisions on visual and auditory real words and pseudo-words. The left BA 44 was conjointly activated during visual and auditory lexical decisions as compared to rest indicating the modality independent involvement of BA 44 in lexical decision tasks in general. To identify brain activation related to lexical decision making rather than lexical retrieval the decision times were entered as covariates into the fMRI analysis. In this analysis, the left BA 44 was activated for visual and for auditory lexical decision making. These results indicate that the left BA 44 as a distinct sub-part of Broca's region plays an important role in lexical decision making independently of stimulus modality and decision times. PMID- 17717702 TI - Adult height in children with short stature and idiopathic delayed puberty after different management. AB - By retrospectively collecting data from nine Italian centres of pediatric endocrinology, we assessed the different management and final outcome of children with short stature and idiopathic delayed puberty. Data were obtained in 77 patients (54 males, 23 females) diagnosed and followed-up in the various centres during the last 15 years. Inclusion criteria were short stature at initial observation and idiopathic delayed puberty diagnosed during follow-up. At first observation, age was 13.8 +/- 1.0 years and height standard deviation score (SDS) was -2.6 +/- 0.6 in males. In females age was 13.1 +/- 0.9 years and height SDS 2.6 +/- 0.4. Local diagnostic and therapeutic protocols included testing for growth-hormone deficiency (six centres) and treatment in case of deficiency or, in the remaining centres, testosterone or no treatment in males, and no treatment in females. At diagnosis, both in males and in females, the auxological features (height SDS, target height SDS and bone age delay) were similar in the patients treated with growth hormone, testosterone or not treated. Overall 32 patients received growth hormone (25 males, 7 females), 33 no treatment (17 males, 16 females) and 12 testosterone. There was no difference in the adult height of males and females in the different treatment groups. In males there were no differences between adult and target height SDSs (growth hormone-treated 0.31 +/- 0.79, untreated 0.10 +/- 0.82, testosterone-treated 0.05 +/- 0.95), between adult and initial height SDSs (growth hormone-treated 1.70 +/- 0.93, untreated 1.55 +/- 0.92, testosterone-treated 1.53 +/- 1.43) and percentage of subjects with adult height above target height. In females, there were no differences between adult and target height SDSs (growth hormone-treated -0.49 +/- 1.13; untreated 0.10 +/- 0.97) and between adult and initial height SDSs (growth hormone-treated 1.76 +/- 0.92; untreated 1.77 +/- 0.98), whereas a significantly higher percentage of patients remained below target height in the growth hormone-treated group (6/7, 85.7% vs 5/11, 31.3%) (P = 0.02). In conclusion, the diagnostic and therapeutic management of the patients with short stature and delayed puberty is different among Italian pediatric endocrinologists. Our data do not support the usefulness of growth-hormone therapy in improving adult height in subjects with short stature and delayed puberty, particularly in the female sex. PMID- 17717703 TI - Opisthotonus and intrathecal treatment with baclofen (ITB) in children. AB - Opisthotonus is a relatively rare, but challenging neurological symptom of spasticity or dystonia that most often results from a dramatic event such as near drowning. The classic treatment option for opisthotonus is the oral administration of medication such as benzodiazepines and baclofen. However, results with these medications are usually not very beneficial. Numerous studies however have shown that intrathecal treatment with baclofen (ITB) is an efficient and safe treatment for generalized therapy-resistant spasticity, even in children. In this retrospective study, we describe 11 children (mean age 9 years) with pronounced opisthotonus and quadriplegia caused by different types of acquired lesions who were treated with intrathecal baclofen. Results show that in addition to an expected decrease in muscle tonus, there was also a clear improvement in patient comfort and nursing. A remarkable weight gain was observed in most patients, even when calorie intake did not change. This increase in weight might be due to a reduction in energy expenditure as a result of the decrease in spasticity. Intrathecal treatment with baclofen should be considered in every child with opisthotonus. PMID- 17717704 TI - Prevalence of Blastocystis hominis and Strongyloides stercoralis infection in Okinawa, Japan. AB - This study was conducted to clarify the prevalence of Blastocystis hominis and Strongyloides stercoralis infection in Ryukyu University Hospital, Okinawa, Japan, between January 2004 and November 2006. Stool samples collected from 3,292 patients were examined by the direct smear method, formalin-ether sedimentation method, and agar plate culture method. The prevalence rate of B. hominis and S. stercoralis infection was 1.0 and 3.4%, respectively. The prevalence rate of B. hominis infection in patients aged >80 years old was significantly higher than that in patients <80 years old (P < 0.001). The prevalence rate of S. stercoralis infection was significantly higher in patients with B. hominis infection compared with those without (P < 0.001). This study demonstrated a prevalence rate for B. hominis and S. stercoralis infection and an association between B. hominis and S. stercoralis infection in Okinawa, Japan. PMID- 17717705 TI - A most distant intergeneric hybrid offspring (Larcon) of lesser apes, Nomascus leucogenys and Hylobates lar. AB - Unlike humans, which are the sole remaining representatives of a once larger group of bipedal apes (hominins), the "lesser apes" (hylobatids) are a diverse radiation with numerous extant species. Consequently, the lesser apes can provide a valuable evolutionary window onto the possible interactions (e.g., interbreeding) of hominin lineages coexisting in the same time and place. In the present work, we employ chromosomal analyses to verify the hybrid ancestry of an individual (Larcon) produced by two of the most distant genera of lesser apes, Hylobates (lar-group gibbons) and Nomascus (concolor-group gibbons). In addition to a mixed pelage pattern, the hybrid animal carries a 48-chromosome karyotype that consists of the haploid complements of each parental species: Hylobates lar (n = 22) and Nomascus leucogenys leucogenys (n = 26). Studies of this animal's karyotype shed light onto the processes of speciation and genus-level divergence in the lesser apes and, by extension, across the Hominoidea. PMID- 17717706 TI - The first large duplication of the RSK2 gene identified in a Coffin-Lowry syndrome patient. AB - Heterogeneous mutations in the X-linked gene RPS6KA3, encoding the protein kinase RSK2, are responsible for Coffin-Lowry Syndrome. Here we have further studied a male patient with a highly suggestive clinical diagnosis of CLS but in whom no mutation was found by exon sequencing. Western blot analysis revealed a protein much larger than the normal expected size. Sequencing of the RSK2 cDNA, showed the presence of an in-frame tandem duplication of exons 17-20. The mutated RSK2 protein was found to be inactive in an in-vitro kinase assay. This event, which was the result of a homologous unequal recombination between Alu sequences, is the first reported large duplication of the RPS6KA3 gene. Our finding provides further evidence that immunoblot analysis, or a molecular assay capable to detect large genomic mutational events, is essential for patients with a highly suggestive CLS clinical diagnosis but remaining without mutation after exon sequencing. PMID- 17717708 TI - Novel human pathological mutations. Gene symbol: CLCN1. Disease: myotonia congenita, autosomal recessive. PMID- 17717707 TI - Polymorphic length of FOXE1 alanine stretch: evidence for genetic susceptibility to thyroid dysgenesis. AB - Familial cases of congenital hypothyroidism from thyroid dysgenesis (TD) (OMIM 218700) occur with a frequency 15-fold higher than by chance, FOXE1 is one of the candidate genes for this genetic predisposition and contains an alanine tract. Our purpose is to assess the influence of length of the alanine tract of FOXE1 on genetic susceptibility to TD. A case-control association study (based on 115 patients affected by TD and 129 controls genotyped by direct sequencing) and transmission disequilibrium testing (TDT) analyses were performed. The transcriptional activities of FOXE1 constructs containing 14 or 16 alanines were also studied. In the case-control association study, the 16/16 and 16/14 genotypes were inversely associated with TD (OR = 0.39, 95%CI = 0.22-0.68, P = 0.0005), strongly suggesting that the presence of 16 alanines in the tract protect against the occurrence of TD. This association was stronger in the subgroup of patients with ectopic thyroid (OR = 0.28, 95%CI = 0.13-0.58, P = 0.00015). The protection was confirmed by the TDT analysis performed in 39 trios (chi(2) = 4.3, P = 0.0374). Alternatively, the presence of the 14/14 genotype is associated with an increase risk of TD (OR = 2.59, 95%CI = 1.56-4.62, P = 0.0005). The expression studies showed that the transcriptional activities of FOXE1 with 16 alanines were significantly higher (1.55-fold) than FOXE1 containing 14 alanines (P < 0.003), while the nuclear localisation of the proteins was not affected. We conclude that FOXE1 through its alanine containing stretch modulates significantly the risk of TD occurrence, enhancing a mechanism linking an alanine containing transcription factor to disease. PMID- 17717709 TI - Productivity improvement of recombinant Escherichia coli fermentation via robust optimization. AB - A nonlinear model of a recombinant Escherichia coli producing porcine growth hormone (pGH) fermentation was developed. The model was used to calculate a glucose feeding and temperature strategy to optimize the production of pGH. Simulations showed that the implementation of optimal feed and temperature profiles was sensitive to the maximum specific growth rate, and a mismatch could result in excessive acetate production and a significant reduction in pGH yield. An optimization algorithm was thus developed, using feedback control, to counter the effects of uncertainty in the specific growth rate and thus determine an optimal operating strategy for pGH production. This policy was experimentally implemented in a 10 L fermenter and resulted in a 125% increase in productivity over the previous best experimental result with this system--in spite of significant plant-model mismatch. PMID- 17717710 TI - SPG11: a consistent clinical phenotype in a family with homozygous spatacsin truncating mutation. AB - Hereditary spastic paraplegias (HSP) are a heterogeneous group of neurodegenerative disorders leading to progressive spasticity of the lower limbs. Here, we describe clinical and genetic features in an Italian family affected by autosomal recessive HSP (ARHSP) with mental impairment and thin corpus callosum (TCC). In both affected subjects, genetic analysis revealed the presence of a homozygous small deletion (733_734delAT) leading to a frameshift (M245VfsX) within the coding region of SPG11 gene, encoding spatacsin. This finding is the first independent confirmation that spatacsin loss of function mutations cause ARHPS-TCC. PMID- 17717712 TI - Kinematics framework optimized for deformation, growth, and remodeling in vascular organs. AB - A basic tenant of constitutive theory is that phenomenological relations can be derivable from phenomenological behavior or material tests; and yet, conventional representation formulas, such as those of Rivlin and Fung, fail in this regard because of the choice of kinematical variables. Granted, with these representation formulas a particular constitutive relation may be guessed that fits data, but if the relation is non-unique and cannot be derived de novo from actual and/or hypothetical tests, then such a relation is indeterminable. The representation formula of Rivlin is indeterminable because of excessive covariance or coalignment in the kinematical variables. The representation formula of Fung is indeterminable because the incompressibility constraint is not utilized to reduce the kinematical variables a priori. The proposed kinematics framework succeeds in achieving determinability for hyperelastic materials because, primarily, the kinematical variables have minimal coalignment and dilatation and distortion are separated. Determinability is discussed and demonstrated in the context of hyperelasticity. However, any representation formula, whether it is for visco-elasticity or remodeling or etcetera, will be indeterminable when kinematical variables are highly coaligned and/or are subject to a non-reducible constraint. In other words, conventional kinematical frameworks are non-starters for experimentally determining constitutive representations for soft tissues. For the sake of determinability and/or validity of continuum models of vascular tissue, the proposed framework is needed. Moreover, this framework is optimized to simplify the balance equations for tubular structures. PMID- 17717711 TI - Functional, histopathologic and natural history study of neuropathy associated with EGR2 mutations. AB - Mutations in the EGR2 gene cause a spectrum of Charcot-Marie-Tooth disease and related inherited peripheral neuropathies. We ascertained ten consecutive patients with various EGR2 mutations, report a novel de novo mutation, and provide longitudinal clinical data to characterize the natural history of the peripheral neuropathy. We confirmed that respiratory compromise and cranial nerve dysfunction are commonly associated with EGR2 mutations and can be useful in guiding molecular diagnosis. We also contrast morphological studies in the context of the I268N homozygous recessive mutation affecting the NAB repressor binding site and the R359W dominant-negative mutation in the zinc-finger domain. PMID- 17717713 TI - Characteristic oxidation products of choline plasmalogens are detectable in cattle and roe deer spermatozoa by MALDI-TOF mass spectrometry. AB - Plasmalogens (1-O-alk-1'-enyl-2-acyl-sn-glycero-3-phosphocholines and phosphoethanolamines) are important constituents of spermatozoa membranes and possess significant antioxidative properties. This particularly holds as plasmalogens from spermatozoa also possess a very high content of highly unsaturated fatty acyl residues (especially 22:6). The organic spermatozoa extracts of two different ruminants (cattle and roe deer) were analyzed for their contents of characteristic choline plasmalogen oxidation products by matrix assisted laser desorption and ionization time-of-flight (MALDI-TOF) mass spectrometry. It will be shown that 1-hydroxy-2-docosahexaenoyl-sn-glycero-3 phosphocholine (LPC 22:6) and formyl-LPC 22:6 are reliable measures of lipid oxidation of spermatozoa and allow, accordingly, conclusions about the storage conditions. All data on spermatozoa were also confirmed by the investigation of the oxidation behavior of selected reference compounds. It will be shown that, equally if plasmalogens or diacyl PC species are used, oxidation takes place primarily at the double bond next to the glycerol backbone. These data were additionally confirmed by recording the corresponding post source decay (PSD) fragment ion spectra. PMID- 17717714 TI - Two cases of SAPHO syndrome accompanied by classic features of Behcet's disease and review of the literature. AB - We describe two patients with SAPHO (synovitis-acne-pustulosis-hyperostosis ostitis) syndrome who presented some of the classic features of Behcet's disease. The first case is a man diagnosed as SAPHO at 74 years old. His major complaint is pain and swelling of the bilateral sterno-clavicular region for more than 14 years. Another conspicuous complication was bilateral glaucoma and episodes of iritis were recognized during the follow-up period. The second case is a 65-year old woman, who first consulted us with right knee pain. As she had a past history of palmoplantar pustulosis and anterior chest pain, her sterile knee arthritis was diagnosed as SAPHO. She also had been suffering from recurrent oral aphthous ulceration since 6 months before visiting our hospital. Considering the clinical courses of our two cases and a review of five previously reported cases, these conditions may imply that classic features of Behcet's disease are minor complications of SAPHO syndrome. Human leukocyte antigen typing and frequent association of sacroiliitis in our cases and in the review of the literature for SAPHO syndrome with some of the classic features of Behcet's disease may indicate this condition to be a closely related disease with seronegative spondylo arthritis. PMID- 17717715 TI - Career and time management strategies for clinical and health services researchers. PMID- 17717718 TI - Near death and neurocardiogenic syncope. AB - We report the case of an 18-year-old female who presented as an out-of-hospital ventricular fibrillation cardiac arrest. She required ICD insertion and recovered without deficit. Following recurrent syncopal episodes we diagnosed the co existence of Neurocardiogenic syncope. PMID- 17717719 TI - Balance between sympathetic response to head-up tilt and cardiac vagal factors in healthy humans. AB - We evaluated the association between cardio-vagal baroreflex sensitivity (BRS; assessed with modified Oxford technique) and catecholamine response to 5 min 60 degrees head-up tilt (HUT) in 46 young healthy adults. HUT increased HR, mean arterial pressure, and NE (P < 0.05 for all). BRS was negatively correlated with NE response to HUT (r = -0.36, P < 0.05), suggesting that subjects with high vagal modulation (high BRS) require less sympathetic response (NE) to maintain normotension during orthostatic stress. PMID- 17717720 TI - Impaired glucose tolerance is associated with postganglionic sudomotor impairment. AB - We compared quantitative sudomotor axon-reflex test responses in persons with normal and impaired glucose tolerance (IGT). Responses were significantly impaired in those with IGT, which may be indicative of early distal small fiber neuropathy. PMID- 17717722 TI - How basic is basic science? PMID- 17717721 TI - Search for the sex-determining switch in monotremes: mapping WT1, SF1, LHX1, LHX2, FGF9, WNT4, RSPO1 and GATA4 in platypus. AB - The duck-billed platypus has five pairs of sex chromosomes, but there is no information about the primary sex-determining switch in this species. As there is no apparent SRY orthologue in platypus, another gene must acquire the function of a key regulator of the gonadal male or female fate. SOX9 was ruled out from being this key regulator as it maps to an autosome in platypus. To check whether other genes in mammalian gonadogenesis could be the primary switch in monotremes, we have mapped a number of candidates in platypus. We report here the autosomal location of WT1, SF1, LHX1, LHX9, FGF9, WNT4 and RSPO1 in platypus, thus excluding these from being key regulators of sex determination in this species. We found that GATA4 maps to sex chromosomes Y1 and X2; however, it lies in the pairing region shown by chromosome painting to be homologous, so is unlikely to be either male-specific or differentially dosed in male and female. PMID- 17717723 TI - A comparative study on the phylogenetic diversity of culturable actinobacteria isolated from five marine sponge species. AB - A cultivation-based approach was employed to compare the culturable actinobacterial diversity associated with five marine sponge species (Craniella australiensis, Halichondria rugosa, Reniochalina sp., Sponge sp., and Stelletta tenuis). The phylogenetic affiliation of the actinobacterial isolates was assessed by 16S rDNA-RFLP analysis. A total of 181 actinobacterial strains were isolated using five different culture media (denoted as M1-M5). The type of medium exhibited significant effects on the number of actinobacteria recovered, with the highest number of isolates on M3 (63 isolates) and the lowest on M1 (12 isolates). The genera isolated were also different, with the recovery of three genera on M2 and M3, and only a single genus on M1. The number of actinobacteria isolated from the five sponge species was significantly different, with a count of 83, 36, 30, 17, and 15 isolates from S. tenuis, H. rugosa, Sponge sp., Reniochalina sp., and C. australiensis, respectively. M3 was the best isolation medium for recovery of actinobacteria from S. tenuis, H. rugosa, and Sponge sp., while no specific medium preference was observed for the recovery of actinobacteria from Reniochalina sp., and C. australiensis. The RFLP fingerprinting of 16S rDNA genes digested with HhaI revealed six different patterns, in which 16 representative 16S rDNAs were fully sequenced. Phylogenetic analysis indicated that 12 strains belong to the group Streptomyces, three strains belong to Pseudonocardia, and one strain belongs to Nocardia. Two strains C14 (from C. australiensis) and N13 (from Sponge sp.) have only 96.26% and 96.27% similarity to earlier published sequences, and are therefore potential candidates for new species. The highest diversity of three actinobacteria genera was obtained from Sponge sp., though the number of isolates was low. Two genera of actinobacteria, Streptomyces, and Pseudonocardia, were isolated from both S. tenuis and C. australiensis. Only the genus of Streptomyces was isolated from H. rugosa and Reniochalina sp. Sponge species have been demonstrated here to vary as sources of culturable actinobacterial diversity, and the methods for sampling such diversity presented may be useful for improved sampling of such diversity. PMID- 17717724 TI - Developing consensus around the pharmaceutical public health competencies for community pharmacists in Scotland. AB - OBJECTIVE: The new community pharmacy contract in Scotland will formalise the role of pharmacists in delivering public health services. To facilitate assessment of education and training needs it is necessary to define the relevant public health competencies for community pharmacists. The objective of this research was to define and develop consensus around such competencies. METHODS: The "Skills for Health National Occupational Standards for Public Health Practitioners" was used to define an initial set of competencies. A two stage Delphi technique was undertaken to develop consensus. An expert panel, representing public health and pharmacy stakeholders, rated their agreement with the importance of each competency, with the agreement level set at 90%. MAIN OUTCOME MEASURES: Level of agreement (%) with each public health competency; those competencies achieving more than 90% agreement with importance for community pharmacy practice. RESULTS: Ten organisations (83% of those invited) and a total of 30 members (88%) agreed to take part in the process. In round 1 of the Delphi, responses were received from 25 (83%) individuals and 22 (73%) in round 2, with consensus being achieved for 25/68 (37%) competencies in round 1 and a further 8/68 (12%) in round 2. CONCLUSION: Public health competencies for community pharmacists achieving consensus predominantly focused on health improvement activities at individual and local community levels and ethical management of self rather than those relating to surveillance and assessment and strategic development. There is a need to research community pharmacists' views of these competencies and to systematically assess their education and training needs. PMID- 17717725 TI - Photosynthetic oscillation in individual cells of the marine diatom Coscinodiscus wailesii (Bacillariophyceae) revealed by microsensor measurements. AB - Oscillations with a period of 1-2 min in the rate of photosynthesis have been found in leaves of C(3 )and C(4 )land plants under invariant, saturating, light and carbon dioxide. This article reports the occurrence of similar oscillations with a period of 2-2.5 min in individual cells of the marine diatom Coscinodiscus wailesii. These oscillations were determined by measurements of both oxygen (oxygen microelectrode) and carbon dioxide (pH microelectrode) just outside the plasmalemma. These oscillations were found in less than 1% of the cells examined. The occurrence of oscillations in unicelluar diatoms rules out for these organisms hypotheses as to the origin of oscillations in land plant leaves that are based on cell-cell interactions. PMID- 17717726 TI - Personal accounts of exercise and quality of life from the perspective of breast cancer survivors. AB - OBJECTIVES: The purpose of the study was to examine breast cancer survivors' perceptions of exercise and their quality of life (QoL). METHODS: About 289 breast cancer survivors completed a survey addressing exercise attitudes, behaviour and perceived QoL. In addition, the breast cancer survivors completed two open-ended questions designed to explore perceptions of exercise and QoL throughout their cancer experience. Inductive and deductive content analyses were used to analyse responses. RESULTS: About 19 first-order themes were identified, which were clustered into five second-order themes that included; Exercise behaviour, Lifestyle, Limitations and barriers, Growth and priorities, and Personal beliefs and values. The findings identified a framework of multifaceted views held by breast cancer survivors in relation to their QoL and outlook on their disease. CONCLUSIONS: Given that cancer survivors are faced with a number of treatment related morbidities 2 years post-diagnosis, there is a need for health professionals to carefully address a cancer survivor's exercise needs in an attempt to help improve their future QoL. PMID- 17717727 TI - Letter to the editor on ethics of expertise, informed consent, and hormesis. PMID- 17717728 TI - Elliott's ethics of expertise proposal and application: a dangerous precedent. AB - In a recent paper in Science and Engineering Ethics (SEE) Elliott proposed an ethics of expertise, providing its theoretical foundation along with its application in a case study devoted to the topic of hormesis. The application is based on a commentary in the journal Nature, and it includes assertions of ethical breaches. Elliott concludes that the authors of the commentary failed to promote the informed consent of decision makers by not providing representative information about alternative frequency estimates of hormesis in the literature, thereby hindering the capacity of the scientific community to promote informed consent relating to chemical regulation. This paper argues that Elliott should have incorporated due process into his system of evaluation. His argument is also seriously deficient technically, in that it misinterprets the toxicological issues, misrepresents the scientific literature with respect to the frequency of hormesis, and incorrectly assesses the extent to which the Nature paper revealed opposing/alternative views on hormesis. Given the seriousness of assertions of noncompliance to ethical norms, there must be procedures to protect those whose ethics were called into question, to fairly evaluate the technical justification for an assertion, and to enable corrections in the event of errors. If a journal is willing to publish assertions that individuals acted in an ethically questionable way, it should be guided by a documented code of ethics and meet a standard of responsibility far greater than normal peer-review processes for papers that do not entail such ethical judgments. PMID- 17717730 TI - Moral rules, moral ideals, and use-inspired research. AB - Moral rules provide the baseline for ethics, proscribing unacceptable behavior; moral ideals inspire us to act in ways that improve the human condition. Whatever the moral ideals for pure research, science has a practical side so it is important to find a moral ideal to give guidance to more applied research. This article presents a moral ideal for use-inspired research based on Norman Care's idea of shared-fate individualism This ideal reflects the observation that all human lives, both present and future are tightly coupled and, as a result, research projects should be chosen, where possible, with the goal of service to others. Together with the ideals of the habit of truth and the gift economy, shared-fate individualism provides the basis for a humane ethics of science. PMID- 17717729 TI - A comparison of conflict of interest policies at peer-reviewed journals in different scientific disciplines. AB - Scientific journals can promote ethical publication practices through policies on conflicts of interest. However, the prevalence of conflict of interest policies and the definition of conflict of interest appear to vary across scientific disciplines. This survey of high-impact, peer-reviewed journals in 12 different scientific disciplines was conducted to assess these variations. The survey identified published conflict of interest policies in 28 of 84 journals (33%). However, when representatives of 49 of the 84 journals (58%) completed a Web based survey about journal conflict of interest policies, 39 (80%) reported having such a policy. Frequency of policies (including those not published) varied by discipline, from 100% among general medical journals to none among physics journals. Financial interests were most frequently addressed with relation to authors; policies for reviewers most often addressed non-financial conflicts. Twenty-two of the 39 journals with policies (56%) had policies about editors' conflicts. The highest impact journals in each category were most likely to have a published policy, and the frequency of policies fell linearly with rank; for example, policies were published by 58% of journals ranked 1 in their category, 42% of journals ranked third, and 8% of journals ranked seventh (test for trend, p = 0.003). Having a conflict of interest policy was also associated with a self-reported history of problems with conflict of interest. The prevalence of published conflict of interest policies was higher than that reported in a 1997 study, an increase that might be attributable to heightened awareness of conflict of interest issues. However, many of the journals with policies do not make them readily available and many of those policies that were available lacked clear definitions of conflict of interest or details about how disclosures would be managed during peer review and publication. PMID- 17717731 TI - Eighteen rules for writing a code of professional ethics. AB - Most professional societies, scientific associations, and the like that undertake to write a code of ethics do so using other codes as models but without much (practical) guidance about how to do the work. The existing literature on codes is much more concerned with content than procedure. This paper adds to guidance already in the literature what I learned from participating in the writing of an important code of ethics. The guidance is given in the form of "rules" each of which is explained and (insofar as possible) justified. The emphasis is on procedure. PMID- 17717732 TI - Croatia founded a national body for ethics in science. AB - The Committee for Ethics in Science and Higher Education (CESHE) was created in Croatia as a national body appointed by the Parliament. Thus Croatia became one of a handful of countries with national means of responding to allegations of scientific misconduct. The Committee's duties, with the help of the Ethics Code, include promotion of ethical norms and values in science and higher education. The CESHE will work on cases of possible research misconduct and alleged disregard for the ethical norms associated with research. PMID- 17717733 TI - Virtue blindness and hegemony: qualitative evidence of negotiated ethical frameworks in the social language of university research administration. AB - The study used critical discourse analysis (CDA) to elucidate normative structures of ethical behavior in university research administration which may be useful for knowledge transference to future studies of research integrity. Research administration appears to support integrity in the research environment through four very strong normative domains: (1) respect for authority structures; (2) respect for institutional boundaries; (3) professionalism; and (4) a strong sense of virtue. The strong norm structure of research administration, however, appears to be threatened by the fifth domain, (5) political power, which is inhabited by prestigious faculty with tenure, top-down authority misalignment, and the power for some institutional members to circumvent the system. The strong normative structure also appears threatened by the overall consequentiality of the regulatory environment, and shifting contexts that threaten personal virtue. In the end, the normative structure is fluid, politically acquiescent to power, and ambiguous. Although the professional core of the norm structure is strong, the strengths and weaknesses in the overall system can be connected to poorly constructed elements of the institutional environment. PMID- 17717734 TI - Different types--different rights. Distinguishing between different perspectives on ownership of biological material. AB - Drawing on a social construction theory of ownership in biological material this paper discusses which differences in biological material might motivate differences in treatment and ownership rights. The analysis covers both the perspective of the person from whom the material originates and that of the potential recipient. Seven components of bundles of rights, drawing on the analytical tradition of Tony Honore, and their relationship to various types of biological material are investigated. To exemplify these categories the cases of a heart, a kidney, stem cells and hair are used. PMID- 17717735 TI - Imagination, distributed responsibility and vulnerable technological systems: the case of Snorre A. AB - An influential approach to engineering ethics is based on codes of ethics and the application of moral principles by individual practitioners. However, to better understand the ethical problems of complex technological systems and the moral reasoning involved in such contexts, we need other tools as well. In this article, we consider the role of imagination and develop a concept of distributed responsibility in order to capture a broader range of human abilities and dimensions of moral responsibility. We show that in the case of Snorre A, a near disaster with an oil and gas production installation, imagination played a crucial and morally relevant role in how the crew coped with the crisis. For example, we discuss the role of scenarios and images in the moral reasoning and discussion of the platform crew in coping with the crisis. Moreover, we argue that responsibility for increased system vulnerability, turning an undesired event into a near-disaster, should not be ascribed exclusively, for example to individual engineers alone, but should be understood as distributed between various actors, levels and times. We conclude that both managers and engineers need imagination to transcend their disciplinary perspectives in order to improve the robustness of their organisations and to be better prepared for crisis situations. We recommend that education and training programmes should be transformed accordingly. PMID- 17717736 TI - Effectiveness of a responsible conduct of research course: a preliminary study. AB - Training in the responsible conduct of research (RCR) is required for many research trainees nationwide, but little is known about its effectiveness. For a preliminary assessment of the effectiveness of a short-term course in RCR, medical students participating in an NIH-funded summer research program at the University of California, San Diego (UCSD) were surveyed using an instrument developed through focus group discussions. In the summer of 2003, surveys were administered before and after a short-term RCR course, as well as to alumni of the courses given in the summers of 2002 and 2001. Survey responses were analyzed in the areas of knowledge, ethical decision-making skills, attitudes about responsible conduct of research, and frequency of discussions about RCR outside of class. The only statistically significant improvement associated with the course was an increase in knowledge, while there was a non-significant tendency toward improvements in ethical decision-making skills and attitudes about the importance of RCR training. The nominal impact of a short-term training course should not be surprising, but it does raise the possibility that other options for delivering information only, such as an Internet-based tutorial, might be considered as comparable alternatives when longer courses are not possible. PMID- 17717737 TI - On "bettering humanity" in science and engineering education. AB - Authors such as Krishnasamy Selvan argue that "all human endeavors including engineering and science" have a single primary objective: "bettering humanity." They favor discussing "the history of science and measurement uncertainty." This paper respectfully disagrees and argues that "human endeavors including engineering and science" should not pursue "bettering humanity" as their primary objective. Instead these efforts should first pursue individual betterment. One cannot better humanity without knowing what that means. However, there is no one unified theory of what is to the betterment of humanity. Simultaneously, there is no one field (neither science, nor engineering, nor philosophy) entitled to rule univocally. Perhaps if theorists tended their own gardens, the common weal would be tended thereby. PMID- 17717738 TI - Preimplantation sex selection demand and preferences among infertility patients in Midwestern United States. AB - PURPOSE: To determine the demand and preferences of infertility patients for sex selection for nonmedical reasons, and to investigate the relation between these choices and their demographic and socioeconomic characteristics. METHODS: A cross sectional, self-administered survey by mail was conducted at a University hospital-based fertility center of 1,350 consecutive women who presented for infertility care, to assess patient demand and preferences for sex selection. RESULTS: Of respondents, 49% wanted to select the sex of their next child for no added cost. Of these patients, 56% had no living children and 37% had children all of one sex. After adjustment for observed predictors of gender preference, we found a significant preference for a female child among women who had only sons, had more living children, or were single. Nulliparous women did not significantly prefer one sex over the other. Among parous women, those with only daughters significantly desired to select a male child, whereas those with sons significantly desired to select a female child. CONCLUSION: There is significant demand among infertility patients for preimplantation sex selection, with a significant portion of this demand coming from patients who do not have any children or have children all of one sex. PMID- 17717739 TI - Durability, negative impact, and neuropsychological predictors of tic suppression in children with chronic tic disorder. AB - Chronic tic disorders are characterized by involuntary motor and vocal tics, which are influenced by contextual factors. Recent research has shown that (a) children can suppress tics for brief periods of time, (b) suppression is enhanced when programmed reinforcement is provided for tic-free intervals, and (c) short periods of suppression do not result in a paradoxical "rebound" in tic frequency when active suppression has ceased. The current study extended existing research in three important ways. First, we examined whether tic suppression ability decreased as suppression duration increased from 5 to 25 to 40 min. Second, we examined post-suppression tic frequency to test whether longer periods of suppression were more likely to be associated with a rebound effect. Finally, we explored neuropsychological predictors of tic suppression. Thirteen children with Tourette syndrome or a chronic tic disorder completed the study. Results showed that (a) tic suppression was sustained for all of the suppression durations, (b) rebound effects were not observed following any of the suppression durations, and (c) ability to suppress was correlated with omission, but not commission errors on a continuous performance task. Implications of these findings are discussed. PMID- 17717740 TI - Complex of amyloid beta peptides with 24-hydroxycholesterol and its effect on hemicholinium-3 sensitive carriers. AB - Brains of Alzheimer disease patients in early stages of dementia contain an increased 24(S)-hydroxycholesterol (cerebrosterol)/cholesterol ratio when compared to controls. In this study, effects of amyloid beta peptides and of racemic 24-hydroxycholesterol were evaluated in vitro on undepleted or cholesterol-depleted hippocampal synaptosomes of young and old rats via a high affinity choline transport and membrane anisotropy measurements. Depletion of membrane cholesterol decreased the transport of [3H]choline, increased the specific binding of [3H]hemicholinium-3 and decreased membrane anisotropy. However, less alterations were found in old when compared to young brains. 500 nM nonaggregated peptides were ineffective but aggregated fragment 1-42 evoked marked drops in the transport and anisotropy values on depleted synaptosomes. 50 microM 24-hydroxycholesterol inhibited choline transport on depleted synaptosomes but it did not influence membrane anisotropy. Peptides eliminated the actions of oxysterol on choline carriers in young but not in old rats. On the other hand, oxysterol eliminated the effects of peptides on membrane anisotropy. Our study suggests a possible role of membrane cholesterol in the regulation of choline carriers and supports data reporting a protective role of membrane cholesterol against toxic effects of amyloid beta peptides. Moreover, via Raman spectroscopy we demonstrate for the first time that peptides form a complex with 24 hydroxycholesterol. PMID- 17717741 TI - Squamous dysplasia of the rectum in a patient with ulcerative colitis treated with 6-mercaptopurine. AB - Human papilloma virus (HPV) has been found to be a precursor and risk factor for both cervical and anal dysplasia. Cervical dysplasia, which is the precursor to carcinoma, is associated with immunosuppression from a variety of causes; reports of anal dysplasia associated with immune suppression exist as well. A recent study published in abstract form only demonstrated that women with inflammatory bowel disease (IBD) had high rates of cervical dysplasia and that those on immune suppressants had even higher rates of dysplasia. We report a case of a 50-year old woman with refractory ulcerative colitis chronically treated with 6 mercaptopurine that developed severe squamous dysplasia of the rectum. The dysplastic mucosa was found to be positive for p16 (associated with high-risk HPV) after immunostaining. A total colectomy was performed. This case highlights the importance of immune suppression in the development of dysplasia of the anus/cervix secondary to HPV infection. PMID- 17717742 TI - Association of multiple myeloma and inflammatory bowel diseases. PMID- 17717744 TI - Interleukin-10 (-819 C/T) and tumor necrosis factor-alpha (-308 G/A) gene variants influence gastritis and lymphoid follicle development. AB - Helicobacter pylori (H. pylori) causes gastritis, development of lymphoid follicles and later monoclonal mucosa-associated lymphoid tissue (MALT) lymphoma. We evaluated the association of tumor necrosis factor (TNF)-alpha (-308 G/A) and IL-10 (-819 C/T) gene polymorphisms with gastritis and lymphoid follicle formation. H. pylori infection was detected using modified Giemsa staining and IgG anti-CagA enzyme-linked immunosorbent assay (ELISA). One hundred and thirty patients with non-ulcer dyspepsia (NUD) and 200 healthy age-matched controls were genotyped for TNF-alpha and IL-10 polymorphisms using polymerase chain reaction restriction fragment-length polymorphism (PCR-RFLP). Subjects with IL-10 -819 T allele [patients (46.5%) versus controls (35.7%), p = 0.006, OR = 1.56, 95% CI = 1.14-2.15] were at risk of gastritis. Infection with H. pylori was more often associated with lymphoid follicles formation than its absence (46% versus 22%, p = 0.009). TNF-alpha polymorphism did not influence gastritis but patients with TNF-alpha -308 A allele carriers showed >2 fold risk of lymphoid follicle formation [presence (26%) versus absence (11.25%), p = 0.029, OR = 2.8; 95% CI = 1.09-7.08]. There was a trend towards association of lymphoid follicles and TNF alpha -308 A allele carriers with H. pylori infection than without (58.5% versus 22.2%; p = 0.064). IL-10 -819 T and TNF-alpha -308 A alleles may increase risk of gastritis and lymphoid follicle formation. PMID- 17717743 TI - A survey about irritable bowel syndrome in South Korea: prevalence and observable organic abnormalities in IBS patients. AB - The aims of the present study were: (1) to assess the prevalence of symptom-based irritable bowel syndrome (IBS) in Korean adults, (2) to assess several organic abnormalities which can be found in IBS patients, and (3) to analyze the risk or associated factors that influence the presence of IBS. Adult health examinees were requested to fill out a questionnaire. The prevalence of IBS was calculated using Rome II criteria. Using several tests, several organic abnormalities were identified in the IBS group. Risk factors were analyzed by comparing the IBS and normal groups. The prevalence value for IBS according to Rome II criteria was 16.8%. Mucosal hyperplasia, lymphocyte aggregation, and increased eosinophil counts were relatively common microscopic findings in IBS group. Female gender, self-consciousness of IBS, and irregular defecation were expressed as significantly independent risk or associated factors for IBS. Several colonic microscopic findings mentioned above may be helpful in accurate diagnosis of IBS. Therefore a more-precise and large population study about these findings is necessary to reach a definitive conclusion. PMID- 17717745 TI - Influence of gender on the ratio of serum aspartate aminotransferase (AST) to alanine aminotransferase (ALT) in patients with and without hyperbilirubinemia. AB - The serum asparate aminotransferase (AST)/alanine aminotransferase (ALT) ratio is widely used in the differential diagnosis of icteric and non-icteric hepatic disorders. Our objective was to determine whether there are gender related differences in the serum AST/ALT ratio. We used sera from 3,618 unselected patients sent to our laboratory for an automated chemistry panel, which included measurements of AST, ALT, alkaline phosphatase, and total bilirubin. Effects of gender on serum AST, ALT, and AST/ALT were examined in different age groups. Among patients with normal total serum bilirubin concentrations, serum AST and ALT concentrations were significantly lower in the females than in the males (P < 0.0001). However, the serum AST/ALT ratio was higher in the females than the males (median values of 0.90 and 0.81, respectively; P < 0.0001). AST and ALT were also lower in the 54 hyperbilirubinemic females than in the 102 hyperbilirubinemic males. Serum AST/ALT ratios were considerably higher in these 156 hyperbilirubinemic patients than in the normobilirubinemic group, with median ratios of 1.09 in females and 0.92 in males (P = 0.02). Significantly higher serum AST/ALT ratios in females were first evident in the 3rd age decade and remained significantly higher than ratios in males through the 8th decade. We conclude that serum AST/ALT ratios are higher in women than men. When clinicians utilize serum AST/ALT ratios to assess the etiology or chronicity of liver disease, the patient's gender also should be taken into consideration. PMID- 17717746 TI - Homozygous 825T allele of the GNB3 protein influences the susceptibility of Japanese to dyspepsia. AB - The role of genetics in the susceptibility to functional dyspepsia (FD) is not well established. Recently, two different associations were reported between FD and G-protein beta3 (GNB3) subunit gene polymorphism. We aim to clarify the association between GNB3 protein C825T polymorphism and dyspepsia in the Japanese population. Eight-nine dyspeptics and 94 nondyspeptic subjects enrolled in this study. All subjects underwent gastroscopy and patients with significant upper gastrointestinal findings were excluded. Other diseases were also excluded by face-to-face history and physical examination. GNB3 protein C825T polymorphisms were determined by polymerase chain reaction-restriction fragment-length polymorphism. H. pylori infection status was examined by histology or antibody against H. pylori. Nonsignificant correlation was found between GNB3 protein homozygous 825T and unexplained dyspepsia (OR = 1.65, 95% CI: 0.87-3.13). However, among H. pylori-negative subjects, homozygous GNB3 protein 825T significantly increased the risk of dyspepsia (16.7% versus 40.5%; CC versus TT; OR = 5.10, 95% CI: 1.21-21.43, CC versus others; OR = 3.40, 95% CI: 1.16-9.93, respectively). This significant association remained after logistic regression analysis with adjustment for sex and age (CC versus TT; OR = 5.73, 95% CI: 1.27 25.82, CC versus others; OR = 3.08, 95% CI: 1.02-9.25). No significant correlation was found between GNB3 polymorphism and any dyspeptic symptoms. Our data suggest that the homozygous 825T allele of GNB3 protein is associated with dyspepsia in the H. pylori-negative Japanese population. The role of genetics in the development of dyspepsia needs further evaluation. PMID- 17717747 TI - Endoscopic ultrasound-guided fine needle aspiration of a malignant pleural effusion to diagnose and stage lung cancer: when should this approach be considered? PMID- 17717748 TI - Nutritional status of infants with neonatal cholestasis. AB - PURPOSE: We constructed a study to determine the association of anthropometric measurements, biochemical parameters and bone mineral content with nutritional status in infants with neonatal cholestasis. METHODS: The study included 38 children with neonatal cholestasis. Nutritional status was assessed by Waterlow criteria, and anthropometric measurements, biochemical parameters and bone mineral content were correlated with the nutritional status at initial admission and at the end of 2 months after nutritional support. RESULTS: We found that the prevalence of acute and chronic malnutrition was 34.2% and 39.4% in infants with neonatal cholestasis, respectively. No significant difference was found in triceps skinfold thickness (TST), scapular skinfold thickness (SST) and suprailiac skinfold thickness (SuST), arm fat area (AFA) and arm area (AA) among the groups. Mid-arm circumference (MAC), arm muscle circumference (AMC) and arm muscle area (AMA) were significantly lower in patients with chronic malnutrition than both acute malnutrition and patients without malnutrition. MAC was the most reliable marker for the assessment of malnutrition and had the highest positive predictive value (PPV) (80.6%), sensitivity (89.2%) and negative predictive value (NPV) (57.1%). Prealbumin levels were significantly lower in patients with chronic malnutrition than the patients without malnutrition. Increment in MAC and AMC were significantly high in the three groups after 2 months. CONCLUSION: MAC is a good indicator of malnutrition in neonatal cholestasis and may also be used for the monitoring of nutritional support; prealbumin may be used for assessment of the severity of malnutrition. PMID- 17717749 TI - Proximalisation of colorectal carcinoma: a 10-year study in Italy. AB - INTRODUCTION: Proximalisation of colon carcinoma has been reported over the course of the last 60 years. Changes in site distribution are receiving increasing attention on account of their implications for screening programmes. OBJECTIVE: A retrospective observational study to determine whether the site distribution of colorectal carcinoma in Italy has varied in the last years and whether changes have been influenced by age and sex. METHODS: Findings of colonscopies conducted at Turin University from 1992 to 2001 were examined. Inclusion criteria were: outpatients, screening, presence of anaemia or gastrointestinal bleeding, weight loss, constipation or changes in evacuation frequency. Exclusion criteria were: uncompleted, surgical endoscopies or conducted for positive flexible sigmoidoscopy, with doubtful findings. Carcinomas and benign polyps were diagnosed histologically. Age, sex, date of examination, nature and location of lesions were recorded. Lesions were classed as carcinoma, and polyps <1 and >/=1 cm. Data were grouped into different year periods and compared with the chi square test. We compared 1992-1993 vs. 2000-2001 and 1992 1996 vs. 1997-2001. RESULTS: Of the 8,132 colonoscopies performed, 7,342 were included in the study. Proximal carcinomas moved from 12.2% in 1992-1993 to 14.9% in 2000-2001 (P = 0.57), proximal polyps rose from 16.6% to 22.1% (P < 0.0001). Furthermore proximal carcinomas moved from 16.5% in 1992-1996 to 14.4% in 1997 2001 (P = 0.48); proximal polyps rose from 18.4% to 27.8% (P < 0.005). In the period 1996-2001 there was higher female prevalence (P = 0.0011) and older age (P = 0.0191). DISCUSSION: We can suppose that proximalisation of carcinoma has not yet appeared in Italy. PMID- 17717751 TI - Introduction: ethics committees and failure to thrive. PMID- 17717750 TI - State prison mental heath services recipients perception of care survey. AB - BACKGROUND: Studies have demonstrated the importance of patient perceptions' of mental health service quality. No studies, however, could be found that surveyed recipients in prison, despite the rapid growth of patients, and litigation in these settings. METHOD: Patients were asked to complete an anonymous survey in private, and sealed it in an envelope. RESULTS: Of 613 respondents, most were satisfied (79%), agreed they had sufficient access to therapists (78%), were involved with treatment decisions (84%), and thought the MH services they had received would help them better deal with a crisis and emotional stress (75%). There were differences among mental health programs/housing units. Several of perception questions were significantly correlated with medication compliance, admission to crisis observation cells, and receiving disciplinary infractions. DISCUSSION: Random samples were requested, but likely only a convenience sample was obtained. However, the positive results suggest the need to strive to enhance patient quality of care ratings. PMID- 17717752 TI - Terminal success. PMID- 17717753 TI - Failure to thrive or refusal to adapt? Missing links in the evolution from ethics committee to ethics program. PMID- 17717754 TI - Reinvigorating ethics consultations: an impetus from the "quality" debate. PMID- 17717755 TI - The educational ladder model for ethics committees: confidence and change flourishing through core competency development. PMID- 17717756 TI - Rounding: how everyday ethics can invigorate a hospital's ethics committee. PMID- 17717758 TI - Is organizational ethics the remedy for failure to thrive? Toward an understanding of mission leadership. PMID- 17717757 TI - Rafting the ethical rapids. PMID- 17717759 TI - Reflections on the success of hospital ethics committees in my health system. PMID- 17717760 TI - Ethics committee DX: failure to thrive. PMID- 17717761 TI - Ethics committees: beyond benign neglect. PMID- 17717762 TI - [Posterior vitreous detachment and pharmacologic vitreolysis: the new age of enzymatic vitrectomy]. PMID- 17717764 TI - [Brilliant blue G-assisted capsulorhexis: a good help for phacoemulsification surgeons in training]. PMID- 17717763 TI - Cationic antimicrobial peptides. A future therapeutic option? PMID- 17717765 TI - [High dose intravitreal brilliant blue G]. PMID- 17717766 TI - [Subconjunctival application of plasma platelet concentrate in the treatment of ocular burns. Preliminary results]. AB - PURPOSE: The efficiency of the subconjunctival application of autologous platelet concentrate in patients with ocular burns was assessed. METHODS: This was carried out by analysing the effect of treatment in the eyes of 10 patients suffering from ocular burns as a result of work-related accidents. Two types of treatment were evaluated: the first group only received conventional topical medical treatment; and the second group, in addition, had subconjunctival injection of plasma platelet concentrate. The clinical condition of the patient and the period in which the disease prevented the patient from working were studied; monitoring was carried out until the burns had fully healed. RESULTS: Statistically significant differences were found between the group treated with subconjunctival autologous platelet concentrate and the group treated with conventional topical medications, with a shorter period of time in corneal and conjunctival healing, time on sick leave and time needed for full healing. CONCLUSIONS: Subconjunctival infiltration of autologous platelet concentrate should be considered as a straightforward, economical and possibly effective form of treatment for traumatic accidents (burns) of the ocular surface. PMID- 17717767 TI - [Results of nonpenetrating deep sclerectomy in inflammatory glaucoma: one year follow up]. AB - PURPOSE: To assess the efficacy and safety of nonpenetrating deep sclerectomy in uveitic glaucoma. METHODS: In this observational retrospective trial, 6 eyes with inflammatory glaucoma underwent a nonpenetrating deep sclerectomy and a reticulated hyaluronic acid implant. The minimal follow-up period was 12 months. RESULTS: At 12 months, the complete success rate (defined as an IOP higher than 5 and lower than 21 mmHg without medication) was 66.67% and the qualified success rate was 100%. The mean postoperative IOP at 12 months was 16.67 mmHg (SD: 3.26), and the mean IOP reduction was 23.00 mmHg (SD:13.75) (p= 0.027). The mean number of antiglaucoma medications required was reduced from 2.67 (SD: 0.52) before surgery to 0.50 (SD: 0.84) one year after surgery (p= 0.038). No change on visual acuity was observed. Complications included one case of hyphema and one case of bleb encapsulation. CONCLUSIONS: Nonpenetrating deep sclerectomy in this preliminary study, deep sclerectomy was efficacious and had few postoperative complications, so it can be an alternative in the management of uveitic glaucoma. PMID- 17717768 TI - [Prospective randomized trial comparing Discovisc versus Healon in phacoemulsification]. AB - OBJECTIVE: To compare the intraoperative behaviour of both, DisCoVisc and Healon used as viscoelastics in cataract surgery. METHOD: We prospectively evaluated 35 patients with cataracts who underwent phacoemulsification and intraocular lens implantation. Patients were randomized into two groups. Group A included 17 patients in where Healon was used as a viscoelastic, whereas group B included 18 patients in where the viscoelastic used was DisCoVisc. After each procedure, the surgeon filled in a questionnaire describing the behaviour of the viscoelastic during the different stages of phacoemulsification. RESULTS: DisCoVisc behaved as both cohesive and dispersive viscoelastic during capsulorrhexis, phacoemulsification and viscoelastic aspiration, whereas Healon acted as a cohesive substance during all surgical stages. DisCoVisc enabled better visualization and transparency during all the surgical stages and maintains the capsular bag better during the intraocular lens implantation. Viscoelastic aspiration was easier with Healon. CONCLUSIONS: DisCoVisc is a new viscosurgical device with both cohesive and dispersive properties, which avoids using two different viscoelastics to improve the performance at different surgical stages. DisCoVisc has been shown to be more transparent and provides better anterior chamber maintenance when compared with Healon. Healon was more easily aspirated due to its cohesive character. PMID- 17717769 TI - [Enucleation and evisceration: 370 cases review. Results and complications]. AB - PURPOSE: To analyze the surgical results in 370 patients who underwent enucleation or evisceration at our center, during a period of 11 years (1990 2000), determining the kind of correction used and the complications associated with the procedure. METHODS: This was a retrospective study of medical records from all patients who underwent surgery by the same surgeon (FS) in the Oculoplastic Department. Demographic data, diagnosis, previous and associated ophthalmic surgeries, implant or graft characteristics, follow up period and postoperative complications were determined in all patients. RESULTS: One hundred sixty-one enucleations and 209 eviscerations were performed. Some kind of implant or graft was associated with 98.4% of these procedures. During the first 6 years of the study, lipodermal grafts were performed in 58.8% of the total, while in the last 5 years hydroxyapatite implants were performed in 90.9% of the cases. In 39 (10.6%) of 369 patients with registered follow up data, 58 complications requiring surgical correction were observed. CONCLUSIONS: Hydroxyapatite implants gave an excellent anophthalmic socket reconstruction, and improved esthetic and motility results. Lipodermal grafts were an excellent alternative in our environment. We observed some complications with the different techniques, but only a few required surgical correction. PMID- 17717770 TI - [Correction of secondary anisometropia after retinal detachment and LASIK surgery]. AB - CASE REPORT: A male with cylindrical anisometropia secondary to retinal detachment (RD) surgery in the right eye (OD) was referred for contact lens (CL) fitting. His refraction was OD -1.25 -2.75 x 60 degrees VA 1.0 and OS +0.25 VA 1.2. He was complaining of diplopia with spectacles. Seven years prior to the RD surgery, he had undergone LASIK without complications. The diplopia was eliminated after a CL was fitted according to his corneal topography. DISCUSSION: RD surgery can cause anisometropic refractive changes. In patients with diplopia and asthenopia, spectacles are not well tolerated. CL fitting according to post LASIK corneal geometry succeeded in refractive correction with less anisometropic symptoms. PMID- 17717771 TI - [Spontaneous primary uveal effusion syndrome]. AB - CLINICAL CASE: This was a 73 year-old male patient who developed an apparent uveal effusion syndrome in his right eye one year after cataract surgery. Once possible associated conditions were discarded, a diagnosis of spontaneous uveal effusion syndrome was reached. With appropriate systemic steroid therapy, a favourable response occurred. DISCUSSION: The diagnosis of uveal effusion may sometimes be difficult to establish. In order to diagnose and manage these patients, a detailed clinical examination along with fluorescein angiography, ultrasonography, ultrasound biomicroscopy (UBM) and magnetic resonance imaging (MRI) tests, must be carried out. PMID- 17717772 TI - [Painful ophthalmoplegia (pseudotumor of the orbit and Tolosa-Hunt syndrome)]. AB - INTRODUCTION: The Tolosa-Hunt Syndrome (THS) and the Pseudotumor of the Orbit (PTO) each have three common clinical hallmarks: unilateral periorbital pain, cranial nerve palsies and a fast response to corticosteroid therapy. CASE REPORT: 48-year-old female with a right VI nerve paralysis, later develops a right III nerve paralysis. It is important to be able to differentiate between THS and PTO, and this is done on the basis of the complementary tests. DISCUSSION: Apart from neuroradiologic findings, the clinical presentation and histopathology of these two conditions are very similar, making it difficult to distinguish between them. Aspects common to both pathological processes are discussed. PMID- 17717773 TI - [Progressive geographic chorioretinopathy associated with Alagille syndrome]. AB - CASE REPORT: We report the case of a patient with the genetic diagnosis of Alagille Syndrome, who has attended our hospital since 1992, and has shown a progressive bilateral chorioretinopathy with severe deterioration in visual acuity. DISCUSSION: Ocular abnormalities associated with Alagille Syndrome are variable and can affect most ocular structures. Although severe visual threat or progressive ocular disease associated with Alagille syndrome have not yet been described, our patient has shown a marked decrease in visual acuity and a clear progression of the chorioretinal atrophy. PMID- 17717774 TI - [Traumatic submacular hemorrhage treated with rt-PA and SF6]. AB - CASE REPORT: This patient was afflicted by a traumatic submacular hemorrhage. A posterior vitrectomy was performed and intravitreal rt-PA and SF6 were administered. Four weeks later, the visual acuity had increased from 0.1 to 0.8. No complications due to the treatment with rt-PA were reported. DISCUSSION: It is known that waiting for the spontaneous blood removal in such cases results in a poor visual acuity recovery due to a toxic effect of the blood products. Both rt PA and the SF6 are useful for the treatment of submacular hemorrhages secondary to age-related macular degeneration, and this case report has shown they are also useful to lyse traumatic blood clots, thus contributing to a better recovery of visual acuity. PMID- 17717776 TI - [Oculist surgeons in the Gaceta de Madrid (XVIII cent.) (II)]. PMID- 17717775 TI - [Anisocoria related to bupropion in migraine]. AB - INTRODUCTION: Bupropion is used to help people stop smoking. This drug can cause visual alterations but, up to now, its use was not associated with anisocoria. CASE REPORT: A 40 year-old woman with a personal history of migraines, presented with monocular mydriasis during treatment with bupropion. Both pupils dilated equally after a 5% cocaine test, and constricted equally after a 0.025% Pilocarpine test. The anisocoria disappeared after the treatment with bupropion was withdrawn. DISCUSSION: Bupropion inhibits neural uptake of norepinephrine and dopamine. Patients with migraine could have a minor unilateral sympathetic pupillary deficit. This deficit could cause hypersensitivity in the oculosympathetic pathway that could be stimulated with bupropion treatment. This feature could explain the mydriasis in our patient. Another explanation could be that bupropion could unmask a physiological anisocoria. PMID- 17717777 TI - [Two eyes and a fan]. PMID- 17717778 TI - [Complications after laser in situ keratomileusis (LASIK): results of a meta analysis on incidences and expectable costs]. AB - PURPOSE: Laser in situ Keratomileusis (LASIK) is considered to be safe and effective for the treatment of moderate myopia. Nevertheless, the treatment can result in complications, associated with additional costs for treatment of the latter and an associated reduction of the primary treatment's overall cost efficiency. METHODS: To both identify clinically relevant LASIK-associated complications and to estimate their expectable incidence and treatment cost profile, a quantitative meta-analysis of trial publications between 1995 - 2004 was implemented. Inclusion criteria were a minimum sample size of 25 eyes, a reported preoperative patient refraction between - 1 und - 14 dioptres and the documentation of an at least 6 months recall period. For each reported complication its "meta incidence" (point estimate and 95 % confidence interval) was estimated. Furthermore, for each complication a clinical pathway for its treatment was modelled assuming a worst case scenario; the treatment costs for this pathway were simulated. The resulting costs for the treatment of one complication were then averaged by the expectable incidence of the respective complication; the maximum "expectable" costs for the respective complication's treatment were then summed up to correct the overall LASIK direct costs. RESULTS: A total of 30 trial reports was included into the meta-analysis; in total, 21 clinically relevant complications were identified (31 % intraoperative complications, among which 19 % were microkeratome-associated, versus 69 % postoperative complications, among which 87 % were classified as long-term postoperative). The most frequent complication was "light sensations" with a meta incidence of 46 % (95 % confidence interval 42 - 50 %), the most cost intensive complications were those requiring clinical re-treatment (overall meta incidence 24 % and expectable cost increase of 449 euro per primary LASIK procedure). In summary the total direct costs of 2426 euro per eye for the initial LASIK procedure may be increased by a total of maximum 648.30 euro, according to a maximum "expectable" cost increase of 27 % per primary LASIK due to complications. CONCLUSION: At least the worst case scenario introduced into this investigation demonstrated an economically relevant order for the expectable LASIK complications and the associated additional costs for complication treatment. PMID- 17717779 TI - [Comparison of central and peripheral corneal thicknesses between normal subjects and patients with primary open angle glaucoma, normal tension glaucoma and pseudoexfoliation glaucoma]. AB - BACKGROUND: While many comparative data are available about central corneal thickness in different types of open angle glaucoma, peripheral corneal thickness has been much less investigated up to now. Thus, the aim of this study was to compare the central and peripheral corneal thicknesses in patients with primary open angle glaucoma (POAG), normal tension glaucoma (NTG) and pseudoexfoliation glaucoma (PEXG) to values of normal subjects. PATIENTS: 104 patients with POAG, 20 patients with NTG, 23 patients with PEXG and 127 normal subjects were investigated with the Orbscan II. The central corneal thickness and the peripheral corneal thickness at 3 mm distance from the centre were determined in 4 quadrants. The acoustic equivalent factor of 0.92 was not used. Patients with eye diseases, patients who had undergone eye surgery or wearers of contact lenses were excluded. Differences were analysed with the Bonferroni-adjusted Mann Whitney U Test for statistical significance. RESULTS: The median central corneal thickness in POAG was 600 +/- 35 microm, in NTG 577 +/- 31 microm, in PEXG 603 +/ 25 microm and in the control group 606 +/- 38 microm. The difference between NTG and the control group was statistically significant (p = 0.01). Superiorly the peripheral corneal thickness was lower in POAG (670 +/- 47 microm) and NTG (639 +/- 37 microm) compared to the control group (686 +/- 46 microm). Nasally the peripheral corneal thickness was lower in POAG (656 +/- 48 microm), NTG (658 +/- 55 microm) and PEXG (642 +/- 47 microm) compared to the control group (677 +/- 46 microm). Temporally and inferiorly there were only small differences compared to the control group. The differences in peripheral corneal thickness were not statistically significant. DISCUSSION: In accord with literature data the central corneal thickness was lower in patients with normal tension glaucoma compared to normal subjects. Superiorly and nasally the peripheral corneal thickness was lower in patients with open angle glaucoma than in normal subjects which was, however, not statistically significant. To what extent these characteristics of the corneal architecture are relevant for the pathogenesis of open angle glaucomas has to be clarified in further larger trials. PMID- 17717781 TI - [Advantages and disadvantages of the circumferential retinal cryocoagulation before vitrectomy in proliferative diabetic vitreoretinopathy]. AB - BACKGROUND: It is unclear if a circumferential cryocoagulation 4 weeks before pars plana vitrectomy is useful for reducing the risks of surgery such as retinal detachment, secondary glaucomas or rebleeding. Otherwise it seems possible that this surgery itself, done in local anaesthesia, could be an additional risk. PATIENTS AND METHODS: We retrospectively evaluated the reports of all patients who underwent vitrectomy as primary surgery due to proliferative diabetic vitreoretinopathy between 1997 and 2000. Besides age and sex, all additional surgery (like phacoemulsification, endolaser coagulation, kind of tamponade etc.) and all intra- or postoperative complications were reported after a follow-up of at least 3 months. We created and compared 2 groups of patients, showing in group 1 patients who underwent vitrectomy 4 weeks after cryocoagulation and in group 2 patients undergoing vitrectomy combined with circumferential cryocoagulation. RESULTS: We evaluated the reports of 226 patients (103 men, 123 women, mean age 58.6 +/- 13.0 years). Follow-up was in the mean 16.3 months. Group 1 contained 150 patients (66.4 %), group 2 76 patients (33.6 %). 63.7 % received air as endotamponade, 8.0 % C(2)F(6) gas, 7.1 % silicon oil and 21.2 % BSS, 34.1 % were operated in combination with phakoemulsification. We observed 9 postoperative retinal detachments (4.0 %), with no significant difference between the two groups (6 detachments in group 1, 2 detachments in group 2). For other surgical risks like rebleeding, rubeosis iridis, secondary glaucoma etc. we also found no statistically significant differences. CONCLUSION: Circumferential retinal cryocoagulation is a useful preparation before pars plana vitrectomy, when done due to vitreous haemorrhage, because improved resorption lowers the vitrectomy rate. In all other cases it can be done during vitrectomy. Adjuvant circumferential cryocoagulation seems to decrease the risk of postoperative retinal detachments and rebleedings as documented in literature comparison. PMID- 17717780 TI - [Glaucoma drainage system according to Molteno for therapy-resistant glaucoma--a two-stage surgical technique to avoid postoperative hypertension]. AB - BACKGROUND: The treatment of therapy-resistant secondary glaucoma with cyclodestructive approaches may give rise to unsatisfactory intraocular pressure results, leading to phthisis. A final option may be the implantation of an external glaucoma drainage system (GDS). A consecutive positioning of the drainage system under the conjunctiva and implantation of the drainage tube into the anterior chamber, may result in an uncontrolled reduced of intraocular pressure leading to intraocular haemorrhages into the anterior chamber or vitreous cavity. In particular, expulsive haemorrhages are feared as deleterious complication. PATIENTS AND METHODS: 15 patients (15 eyes) with secondary glaucoma received a GDS. All patients were previously unsuccessfully treated by numerous approaches (mean 2.7 times). The mean preoperative intraocular pressure was 37 mmHg (range: 22 to 55 mmHg). We performed a sequential approach: during the first operation we implanted and fixed the resorption site of a Molteno GDS onto the sclera close to the equator in the superotemporal quadrant. After an inflammation free interval of 2 - 3 weeks we placed the drainage tube into the anterior chamber. The average postoperative follow-up period was 20.5 months (range: 3 to 62 months). RESULTS: The implantation of the GDS using a sequential approach was well tolerated by all patients. While 14 out of 15 eyes achieved an IOP of 15 mmHg (range: 12 to 18 mmHg), 2 of them still required additional topical glaucoma treatment. An unsatisfactory IOP regulation was observed in only one eye although a revision surgery was performed postoperatively. Four eyes developed a light anterior chamber haemorrhage that resorbed without serious complications within 3 weeks. A choroidal effusion in one eye was treated by an anterior chamber injection of a viscoelastic gel. CONCLUSION: The potential disadvantage of the GDS can be almost completely avoided using a sequential approach. The implant heals well in the subtenon space during the first postoperative week, thus preventing an overfiltration of anterior chamber fluid. Our positive results show that the GDS is an important treatment option in selected patients. PMID- 17717782 TI - [Mechanism of accommodation of human eye--some new aspects]. AB - BACKGROUND: The basics of the model of accommodation were described by Hermann von Helmholtz 150 years ago and are accepted until today. MATERIALS AND METHODS: Twenty-five healthy young phakic test persons (age range 14 to 28 years) were examined using the IOL Master (Carl Zeiss Jena GmbH), slit lamp photography (Scheimpflug camera EAS 1000, Nidek) and pupillography (AMTech GmbH). Measurements were taken of disaccommodated and accommodated eyes. RESULTS: The mesopic and photopic pupil size are statistically significant (p < 0.05) smaller in accommodated eyes than in disaccommodated. Also, a significantly shorter reaction time of the light-induced pupil reaction with accommodation could be shown compared to disaccommodation. The central vertical and horizontal radii of curvature of the cornea increased with accommodation. This is likewise a decrease of the central anterior corneal curvature by near fixation. Due to the axial lens thickening, the anterior chamber angle and the anterior chamber depth decreased. Consequently, a decrease of the lens transparence resulted with accommodation. CONCLUSIONS: As a result of our measurements the existing model of accommodation, developed by Hermann von Helmholtz 150 years ago, can be modified. PMID- 17717783 TI - [Influence of prism overcorrection on residual postoperative strabismus]. AB - BACKGROUND: Prism overcorrection is a complementary procedure to reduce the residual postoperative esotropia caused by anomalous retinal correspondence (ARC) after surgery for esotropia. We have investigated the results of this treatment. PATIENTS AND METHODS: For Group 1, the files of 63 patients treated with postoperative prism overcorrection in the Department of Ophthalmology, University of Giessen, were evaluated regarding the pre-and postoperative squint angles (SPCT, simultaneous and APCT, alternate prism and cover test) and the angle of ARC, determined by the red filter test and by the increase of esotropia after neutralisation of the squint angle (APCT). Postoperatively, squint angles had been measured immediately (APCT) after removal of the eye patch and 10 minutes to 2 hours later (SPCT and APCT). Subsequently, prism overcorrection was performed with a Fresnel prism foil (40 PD basis temporally) in front of the fellow eye for a maximum of 3 months. After 3 months, SPCT and APCT were performed. For Group 2, the files of 28 patients with a preoperative angle of ARC of 5 degrees or more, treated in the Department of Ophthalmology, University of Heidelberg, were evaluated. These patients had not been treated with prism overcorrection. The squint angles had been measured (SPCT and APCT) on the preoperative day, on the first postoperative day, a few hours after removing the eye patch, and after three months. RESULTS: For Group 1, at surgery, the patients were 4 to 12 years old (median: 6.2 years). The preoperative squint angle ranged from + 5 degrees to + 27 degrees (median: + 12 degrees) in the SPCT and from + 7 degrees to + 27 degrees (median: + 14 degrees) in the APCT. The angle of ARC was between + 4 degrees and + 15 degrees (median: + 7 degrees). Both combined recess and resect surgery (with or without additional oblique muscle surgery) or bilateral retroequatorial medial rectus myopexy, in part depending on the squint angle pattern with medial rectus recession, were performed. Immediately after removing the patch, the squint angle (APCT) was between - 10 degrees and + 5 degrees (median: + 1 degrees). Ten minutes to 2 hours later, the manifest squint angle ranged from 0 to + 12 degrees (median: + 7 degrees). The angle had decreased significantly to - 6 to + 12 degrees (median: + 5 degrees) after 3 months. For Group 2, the patients' ages were between 5 and 12 years (median: 6.5 years). The squint angles ranged from + 11.5 degrees to + 35 degrees (median: + 20 degrees) in the SPCT and APCT. The angle of ARC was between + 5 degrees and + 17 degrees (median: + 8 degrees). Combined recess and resect surgery or bilateral recession of the medial rectus (with or without oblique muscle surgery both) were performed. The SPCT several hours after removal of the patch showed angles of - 4 degrees to + 14 degrees (median: + 4.25 degrees). Three months later the manifest squint angles ranged from - 5 degrees to + 14 degrees (median: + 3 degrees). DISCUSSION: After prism overcorrection (Group 1), there was a significant reduction of the residual esotropia. Without this additional treatment (Group 2), there was no significant change in the postoperative squint angle. However, neither the positive outcome in Group 1 nor the difference to Group 2 do unequivocally prove that there is a beneficial effect of prism overcorrection, since preoperative conditions were different and the sample size in Group 2 was small, especially after matching for equal preoperative conditions. A spontaneous reduction of the postoperative esotropia cannot be excluded. Further studies are necessary in order to investigate the specific effect of prism overcorrection. PMID- 17717784 TI - [Supine cyclotorsion and asphericity]. AB - BACKGROUND: Customised ablation to correct refractive errors is becoming more and more important today. Preoperative examinations are performed in a seated position while laser surgery is carried out in the supine position. It is well known that cyclotorsions occur but until now there have not been any investigations on possible changes in astigmatism, root mean square (RMS) and asphericity. METHODS: 18 eyes of 14 individuals were measured in both the seated and the supine positions with a mobile videokeratoscope, the Keratron Scout (Optikon). RESULTS: A change from the seated to the supine position caused cyclotorsion in left eyes from - 9 degrees to 7 degrees (p = 0.56) and from - 8 degrees to 8 degrees (p = 0.53) in right eyes. The average amount of change of the cyclotorsion was 3.6 degrees. The overall power of astigmatism increased to 0.3 D and decreased to 0.2 D compared to astigmatism in a seated position (p = 0.06). The root mean square (RMS) of the corneal wavefront increased to 0.20 microm and decreased to 0.24 microm in comparison to the same parameter in a seated position (p = 0.36). The asphericity average changed from - 0.19 in a seated position to - 0.16 in a supine position (p = 0.04). CONCLUSION: Cyclotorsion is statistically not significant when changing from a seated to a supine position as both excyclo- and incyclotorsion occur. Since individual cyclotorsion is clinically relevant, this has been taken into account by the latest laser systems. Changes in astigmatism and statistically significant changes in asphericity may be the reason for suboptimal customised refractive surgery. It must be considered whether the preoperative measurements for laser ablation in the supine position should not also be carried out in the supine position. PMID- 17717785 TI - [Photodynamic therapy of lid basal cell carcinomas in a 13-year-old patient with Gorlin Goltz syndrome]. AB - BACKGROUND: Gorlin Goltz syndrome is a rare, autosomal dominant inherited disease that is characterised by multiple basal cell carcinomas (BCC) including the periorbital region and eye lids. We report a severe infantile manifestation with lid involvement treated by photodynamic therapy (PDT). PATIENT: A 13-year-old boy with Gorlin Goltz syndrome presented with multiple confluent BCC on both eye lids and the skin of neck and trunk. Multiple bilateral periorbital confluent and surgically not removable BCC were treated by topical PDT. RESULTS: Numerous superficial BCC were successfully treated by photodynamic therapy with remarkable cosmetic results. CONCLUSION: In cases of numerous confluent and surgically not removable BCC, PDT represents an effective therapy. Frequent monitoring is necessary to maintain the clinical outcome. PMID- 17717786 TI - [Terson syndrome--a contribution to the timing of operation for pars plana vitrectomy]. AB - PURPOSE: This study aimed to investigate the possible differences in final outcome in patients with Terson syndrome (1996 - 2005) with regard to the time of vitrectomy after the acute event. METHOD: Eighteen eyes from eleven patients with Terson syndrome are reported. All eyes showed considerable haemorrhages without any tendency of resorption. Eleven eyes were operated within 3 months after the acute injury. In seven eyes pars plana vitrectomy was performed 4 - 6 months after the acute event because of the patient's poor general state of health. In three patients only one eye was impaired. RESULT: Seven eyes with Terson syndrome which were operated 4 - 6 months after injury showed severe complications intra- and postoperatively (ring-shaped proliferations with traction at the posterior pole, optic disc atrophy and maculopathy). On average, 2.4 operations were necessary. Within a mean postoperative observation period of 3.9 years (8 months to 8.5 years), the visual acuity was between light perception and 0.7 (mean: 0.25). In eleven eyes, however, pars plana vitrectomy was performed already 1 - 3 months after the acute event. In these cases few complications occurred intra- and postoperatively. On average, only 1.1 operations were necessary. After the clinical attendance (observation period: one weak to four years, mean: 2.1 years) the visual acuity amounted to between light perception and 0.8 (mean: 0.6). In one eye a sudden spontaneous blood resorption took place. CONCLUSION: Because of severe complications and in view of an early rehabilitation of the patients, vitrectomy has been recommended for eyes with bilateral Terson syndrome and with poor or absent tendency of blood resorption. Vitrectomy should be performed at least in one eye within three months after the acute event. PMID- 17717787 TI - [The life and works of Hermann Kuhnt (1850-1925) and Paul Junius (1871-1948)]. PMID- 17717788 TI - [Chemotherapy-induced fetal anemia in maternal acute myelocytic leukemia]. AB - This article discusses the management of a pregnancy of a 32-year-old primigravida with acute myelocytic leukemia treated with induction chemotherapy starting in the 20 + 5 week of gestation. Sonographic monitoring showed evidence of fetal ascites and anemia that could be treated with an intrauterine fetal transfusion. After maternal recovery, a caesarean section was performed in the 27 + 5 week of gestation. We delivered a vivid eutrophic female prematurely. The infant showed persisting signs of myelosuppression. Two further transfusions had to be performed. The present report describes the interdisciplinary therapeutic management when polychemotherapy during pregnancy is necessary for the mother. Cases of acute leukemia in pregnancy are complicated by severe prenatal risks caused by the hematologic illness and by the immediate beginning of chemotherapy. In the third trimester premature delivery is preferable to intrauterine exposition to cytostatic agents. In the second trimester the pregnancy has to be monitored for the typical risks and complications of chemotherapy. Fetal cytotoxic myelosuppression is detectable by prenatal observation so that interventional strategies are feasible. PMID- 17717791 TI - [Diagnostics of smell and taste disorders in clinical routine]. PMID- 17717794 TI - [Legal aspects of cochlear-implantation]. PMID- 17717792 TI - [Lidloading in facial palsy]. AB - Various implants are used to treat paralytic lagophthalmos. Implantation of weights in the upper eyelid (lid loading) to close the lid by gravity is a very established procedure. If correctly performed, the advantages of the procedure include the complete closure of the eyelid without limiting the visual field, a technically simple operation, easy reversibility, and possible combination with other surgical lid corrections. Thus, this method is suitable for both irreversible and reversible facial nerve paralysis. Gold and platinum have, in the meantime, become the established implant material. Although both metals are suited for implantation in the upper eyelid, platinum tends to show better biocompatibility and has a higher density, in which a 10 % volume reduction can be achieved compared to common gold implants. Currently available are industrially manufactured rigid gold and platinum implants and a chain made of a platinum-iridium alloy. Based on ultrasound examinations of the upper eyelid tarsus, the flexible chain was designed to ensure an optimal pretarsal fit. First studies indicate that the serious postoperative complications with rigid implants can be considerably reduced with flexible chain implants, although there are no long-term results at present. PMID- 17717795 TI - [Open nasal speech and velopharyngeal insufficiency in adenoidectomy and tonsillectomy]. AB - Adenoidectomy and tonsillectomy are the most frequently recommended childhood ENT operations. Although current standards of practice are high, note still needs to be taken of indications, especially in patients with palatal anomalies. These are not always easily estimated or recognised. The origin and therapy of velopharyngeal insufficiency are of particular importance. PMID- 17717796 TI - In memoriam. Robert Hegnauer. PMID- 17717798 TI - [Community psychiatry in the 21st century]. PMID- 17717801 TI - [Multiple personality disorder is a fad - not a disease]. PMID- 17717802 TI - [Case report on a fatal suicide attempt with an electrical stove at a Hospital Ward]. PMID- 17717804 TI - [The advisor team in the psychiatric hospital: assignments and experiences in coping with aggression and compulsion]. PMID- 17717805 TI - [FIPS - families with a mentally ill parent]. PMID- 17717809 TI - Mutation accumulation affects male virility in Drosophila selected for later reproduction. AB - An intensive study of longevity, female fecundity, and male reproductive behavior in Drosophila melanogaster was undertaken in order to establish whether late-life fitness characters in short-lived populations might be affected by the increase in deleterious alleles due to random genetic drift. We also sought to determine whether selection for late-life fertility could eliminate alleles that produce a decline in later fitness components in short-lived populations, as predicted by the mutation accumulation hypothesis for the evolution of aging. These experiments employed long-lived (O) populations, short-lived (B) populations, and hybrids made from crosses of independent lines from within the O and B populations. No detectable longevity differences were seen between hybrid B males and females and purebred B males and females. Reproduction in aged B purebred females was significantly less than in hybrid females at 3 wk of age only. A full diallel cross of the five replicate B lines showed a steady increase in hybrid male reproductive performance after the first week of adult life, relative to the parental lines. A full diallel cross of the five replicate O lines revealed no significant increase in hybrid O age-specific male reproductive success compared with the purebred O lines when assayed over the first 5 wk of adult life. The results on male reproductive behavior are consistent with the idea that relaxed age-specific selection in the B populations has been accompanied by an increase in deleterious, recessive traits that exhibit age-specific expression. Consequently, we conclude that a mutation accumulation process has been at least partly responsible for the age-specific decline in male B virility relative to that of the O populations. PMID- 17717810 TI - Evolutionary divergence in thermal sensitivity and diapause of field and laboratory populations of manduca sexta. AB - The tobacco hornworm Manduca sexta has been an important model system in insect biology for more than half a century. Here we report the evolutionary divergence in thermal sensitivity and diapause initiation between field and laboratory populations that were separated for more than 35 yr (>240 laboratory generations) and that are descendants from the same field populations in central North Carolina. At intermediate rearing temperatures (20 degrees-25 degrees C), mean body size was significantly larger and development time significantly faster in the laboratory than in the field populations. At higher temperatures (30 degrees 35 degrees C), these mean differences between populations were reduced or eliminated, and larval survival at 35 degrees C was significantly lower in the laboratory population than in the field population. F(1) crosses had survival and development time to wandering similar to the field population times at both 25 degrees and 35 degrees C; body mass at wandering for F(1) crosses was intermediate compared with that of the field and laboratory populations. Comparisons with earlier field and laboratory studies suggest evolutionary reductions in thermal tolerance and performance at high temperatures in the laboratory population. The critical photoperiod initiating diapause in field populations in North Carolina did not change detectably between the 1960s and 2005. In contrast, the laboratory population has evolved a reduced tendency to diapause under short-day conditions, relative to the field population. PMID- 17717811 TI - Physiological and behavioral consequences of long-term artificial selection for vulnerability to recreational angling in a teleost fish. AB - Few studies have examined the physiological and behavioral consequences of fisheries-induced selection. We evaluated how four generations of artificial truncation selection for vulnerability to recreational angling (i.e., stocks selected for high and low vulnerability [HVF and LVF, respectively]) affected cardiovascular physiology and parental care behavior in the teleost fish largemouth bass Micropterus salmoides. Where possible, we compared artificially selected fish to control fish (CF) collected from the wild. Although, compared to control fish, resting cardiac activity was approximately 18% lower for LVF and approximately 20% higher for HVF, maximal values did not vary among treatments. As a result, the HVF had less cardiac scope than either LVF or CF. Recovery rates after exercise were similar for HVF and CF but slower for LVF. When engaged in parental care activities, nesting male HVF were captured more easily than male LVF. During parental care, HVF also had higher turning rates and pectoral and caudal fin beat rates, increased vigilance against predators, and higher in situ swimming speeds. Energetics simulations indicated that to achieve the same level of growth, the disparity in metabolic rates would require HVF to consume approximately 40% more food than LVF. Selection for angling vulnerability resulted in clear differences in physiological and energetic attributes. Not only is vulnerability to angling a heritable trait, but high vulnerability covaries with factors including higher metabolic rates, reduced metabolic scope, and increased parental care activity. Despite these energetically costly differences, HVF and LVF of the same age were of similar size, suggesting that heightened food consumption in HVF compensated for added costs in experimental ponds. Ultimately, angling vulnerability appears to be a complex interaction of numerous factors leading to selection for very different phenotypes. If HVF are selectively harvested from a population, the remaining fish in that population may be less effective in providing parental care, potentially reducing reproductive output. The strong angling pressure in many freshwater systems, and therefore the potential for this to occur in the wild, necessitate management approaches that recognize the potential evolutionary consequences of angling. PMID- 17717812 TI - Anatomic and molecular correlates of divergent selection for basal metabolic rate in laboratory mice. AB - Proximal mechanisms describing the evolution of high levels of basal metabolic rate (BMR) in endotherms are one of the most intriguing problems of evolutionary physiology. Because BMR mostly reflects metabolic activity of internal organs, evolutionary increase in BMR could have been realized by an increase in relative organ size and/or mass-specific cellular metabolic rate. According to the "membrane pacemaker" theory of metabolism, the latter is mediated by an increase in the average number of double bonds (unsaturation index) in cell membrane fatty acids. To test this, we investigated the effect of divergent artificial selection for body-mass-corrected BMR on the mass of internal organs and the fatty acid composition of cell membranes in laboratory mice (Mus musculus). Mice from the high-BMR line had considerably larger liver, kidneys, heart, and intestines. In contrast, the unsaturation index of liver cell membranes was significantly higher in low-BMR mice, mainly because of the significantly higher content of highly polyunsaturated 22 : 6 docosahexanoic fatty acid. Thus, divergent selection for BMR did not affect fatty acyl composition of liver and kidney phospholipids in the direction predicted by the membrane pacemaker theory. We conclude that an intraspecific increase in BMR may rapidly evolve mainly as a result of the changes in size of internal organs, without simultaneous increase of the unsaturation index in cell membrane lipids. PMID- 17717813 TI - Does growth rate determine the rate of metabolism in shorebird chicks living in the Arctic? AB - We measured resting and peak metabolic rates (RMR and PMR, respectively) during development of chicks of seven species of shorebirds: least sandpiper (Calidris minutilla; adult mass 20-22 g), dunlin (Calidris alpina; 56-62 g), lesser yellowlegs (Tringa flavipes; 88-92 g), short-billed dowitcher (Limnodromus griseus; 85-112 g), lesser golden plover (Pluvialis dominicana; 150-156 g), Hudsonian godwit (Limosa haemastica; 205-274 g), and whimbrel (Numenius phaeopus; 380 g). We tested two opposing hypotheses: the growth rate-maturity hypothesis, which posits that growth rate in chicks is inversely related to functional maturity of tissues, and the fast growth rate-high metabolism hypothesis, which suggests that rapid growth is possible only with a concomitant increase in either RMR or PMR. We have found no evidence that chicks of shorebirds with fast growth rates have lower RMRs or lower PMRs, as would be predicted by the growth rate maturity hypothesis, but our data suggested that faster-growing chest muscles resulted in increased thermogenic capacity, consistent with the fast growth-high metabolism hypothesis. The development of homeothermy in smaller species is a consequence primarily of greater metabolic intensities of heat-generating tissues. The maximum temperature gradient between a chick's body and environment that can be maintained in the absence of a net radiative load increased rapidly with body mass during development and was highest in least sandpipers and lowest among godwits. Chicks of smaller species could maintain a greater temperature gradient at a particular body mass because of their higher mass-specific maximum metabolic rates. PMID- 17717814 TI - Differential resource allocation in deer mice exposed to sin nombre virus. AB - The resource allocation hypothesis predicts that reproductive activity suppresses immunocompetence; however, this has never been tested in an endemic disease system with free-ranging mammals. We tested the resource allocation hypothesis in wild deer mice (Peromyscus maniculatus) with natural exposure to Sin Nombre Virus (SNV). Immunocompetence was estimated from the extent of swelling elicited after deer mice were injected with phytohemagglutinin (PHA); swelling is positively correlated with immunocompetence. After livetrapping deer mice, we determined their reproductive state and SNV infection status. Males were more likely to be seropositive for SNV than females (37% vs. 25%) and exhibited 10% less swelling after PHA injection. The swelling response of females differed with both infection status and reproductive condition. There was also a significant infection status by reproductive condition interaction: non-reproductive, seropositive females experienced the least amount of swelling, whereas females in all other categories experienced significantly greater swelling. The swelling response of males differed with both SNV infection status and reproductive condition, but there was no significant infection status by reproductive condition interaction. Seronegative males elicited greater swelling than seropositive males regardless of reproductive status. In contrast to the resource allocation hypothesis, these results do not indicate that reproductive activity suppresses immunocompetence of deer mice but rather suggest that chronic SNV infection reduces immunocompetence. Sex-based differences in swelling indicate that SNV modulates the immune system of female deer mice differently than it does that of males, particularly during reproduction. We propose that differences in resource allocation between males and females could result from inherent sex based differences in parental investment. PMID- 17717815 TI - Effects of seasonal variation in prey abundance on field metabolism, water flux, and activity of a tropical ambush foraging snake. AB - The responses of animals to seasonal food shortages can have important consequences for population dynamics and the structure and function of food webs. We investigated how an ambush foraging snake, the northern death adder Acanthophis praelongus, responds to seasonal fluctuations in prey availability in its tropical environment. In the dry season, field metabolic rates and water flux, as measured by doubly labeled water, were significantly lower than in the wet season. Unlike some other reptiles of the wet-dry tropics, death adders showed no seasonal difference in their resting metabolism. About 94% of the decrease in energy expended in the dry season was due to a decrease in activity and digestion, with lower body temperatures accounting for the remainder. In the dry season, death adders were less active and moved shorter distances between foraging sites than in the wet season. Analysis of energy expenditure suggested that adders fed no more than every 2-3 wk in the dry season but fed more frequently during the wet season. Unlike many lizards that cease feeding during the dry season, death adders remain active and attempt to maximize their energy intake year-round. PMID- 17717816 TI - Number of immunoreactive GnRH-containing neurons is heritable in a wild-derived population of white-footed mice (Peromyscus leucopus). AB - The evolution of mammalian brain function depends in part on levels of natural, heritable variation in numbers, location, and function of neurons. However, the nature and amount of natural genetic variation in neural traits and their physiological link to variation in function or evolutionary change are unknown. We estimated the level of within-population heritable variation in the number of gonadotropin-releasing hormone (GnRH) neurons, which play a major role in reproductive regulation, in an unselected outbred population recently derived (<10 generations) from a single natural population of white-footed mice (Peromyscus leucopus, Rafinesque). Young adult male mice exhibited an approximately threefold variation in the number of neurons immunoreactive for GnRH in the brain areas surveyed, as detected using SMI-41 antibody with a single label avidin-biotin complex method. Consistent with earlier findings of selectable variation in GnRH neurons in this population, the level of genetic variation in this neuronal trait within this single population was high, with broadsense heritability using full-sib analysis estimated at 0.72 (P<0.05). Either weak selection on this trait or environmental variation that results in inconsistent selection on this trait might allow a high level of variation in this population. PMID- 17717817 TI - Intracellular glucose and binding of hexokinase and phosphofructokinase to particulate fractions increase under hypoxia in heart of the amazonian armored catfish (Liposarcus pardalis). AB - Armored catfish (Liposarcus pardalis), indigenous to the Amazon basin, have hearts that are extremely tolerant of oxygen limitation. Here we test the hypothesis that resistance to hypoxia is associated with increases in binding of selected glycolytic enzymes to subcellular fractions. Preparations of isolated ventricular sheets were subjected to 2 h of either oxygenated or hypoxic (via nitrogen gassing) treatment during which time the muscle was stimulated to contract. The bathing medium contained 5 mM glucose and was maintained at 25 degrees C. Initial experiments revealed increases in anaerobic metabolism. There was no measurable decrease in glycogen level; however, hypoxic treatment led to a twofold increase in heart glucose and a 10-fold increase in lactate content. It is suggested that the increase in heart glucose content is a result of an enhanced rate of facilitated glucose transport that exceeds the rate of phosphorylation of glucose. Further experiments assessed activities of metabolic enzymes in crude homogenates and subsequently tracked the degree of enzyme binding associated with subcellular fractions. Total maximal activities of glycolytic enzymes (hexokinase [HK], phosphofructokinase [PFK], aldolase, pyruvate kinase, lactate dehydrogenase), and a mitochondrial marker, citrate synthase, were not altered with the hypoxic treatment. A substantial portion (>/=50%) of HK is permanently bound to mitochondria, and this level increases under hypoxia. The amount of HK that is bound to the mitochondrial fraction is at least fourfold higher in hearts of L. pardalis than in rat hearts. Hypoxia also resulted in increased binding of PFK to a particulate fraction, and the degree of binding is higher in hypoxia-tolerant fish than in hypoxia-sensitive mammalian hearts. Such binding may be associated with increased glycolytic flux rates through modulation of enzyme-specific kinetics. The binding of HK and PFK occurs before any significant decrease in glycogen level. PMID- 17717818 TI - Improving the precision and accuracy for estimating energy expenditure using the heart rate method. AB - The "heart rate technique" is commonly used to estimate the rate of oxygen consumption (a proxy for energy expenditure) of free-ranging animals. However, a major limitation of this technique is that interindividual variability in the relationship between heart rate (f(H)) and rate of oxygen consumption (Vo2) generates large errors of estimation when the technique is applied to individual free-ranging animals. In this study, we present a new analysis technique that takes advantage of the observation that the f(H) or Vo2 relationships between individuals are frequently parallel and differ only in elevation. This technique offers superior accuracy and precision of Vo2 estimates, reducing the coefficient of variability from 18% to 9% for individual animals in an example application in macaroni penguins. This approach enables application of the heart rate technique to deduce the energetic strategies of individual animals. PMID- 17717819 TI - [Advances of targeted therapy in treatment of hematologic malignancies]. PMID- 17717820 TI - [Celecoxib-induced apoptosis in acute promyelocytic leukemia cell line MR2 and its mechanism]. AB - OBJECTIVE: To investigate celecoxib-induced apoptosis of acute promyelocytic leukemia cell line MR2 and related mechanism. METHODS: MR2 cells were treated with celecoxib at different concentrations (0, 20, 40, 80, 120 and 160 micromol/L). The proliferation of MR2 cells was observed by MTT assay and apoptosis was detected by DNA fragmentation analysis and flow cytometry with Annexin V-FITCiPI staining. The expression of survivin and PML/RARalpha mRNA was examined by RT-PCR and nested-PCR, and the protein expression of caspase-3, 9 and PARP was analyzed by Western-blot. RESULTS: After treatment with celecoxib the viability of MR2 cells decreased markedly in a dose- and time-dependent manner, and a DNA ladder pattern of internucleosomal fragmentation was observed. The translocation of phosphatidylserine at the outer surface of the cell plasma membrane was induced by celecoxib and its level increased following the augmentation of the drug concentration. The expression of survivin mRNA decreased dramatically while no significant change with PML/RARalpha. Treatment with celecoxib for 24 h resulted in the activation of caspase-3 and 9, cleavage of PARP. CONCLUSION: Celecoxib could inhibit MR2 cell proliferation by inducing apoptosis, which might be mediated by the caspase-3 and 9 activation and PARP cleavage. Moreover, the down-regulation of survivin may play a certain role in apoptosis of MR2 cells induced by celecoxib. PMID- 17717821 TI - [Important role of Ser 219 phosphorylation of TRF1 in regulation of cell cycle]. AB - OBJECTIVE: To investigate the role of Ser 219 phosphorylation of TRF1 (telomere repeat binding factor 1) in regulation of cell cycle. METHODS: The mimicking phosphorylation mutant (TRF1S219D-GFP) and the non-phosphorylatable mutant (TRF1S219A-GFP) were constructed; the mutant genes and corresponding proteins were checked by sequencing and Western blot, respectively. Immunofluorescence staining was performed to detect the localization of mutants in HeLa cells. Cell cycle was analyzed by flow cytometry and ATM level was evaluated by immunoblotting. RESULTS: The mutant genes were verified by direct sequencing and protein expression of GFP-tagged mutants was confirmed by immunoblotting.TRF1S219A-GFP and TRF1S219D-GFP were both localized in telomere of HeLa cells. Moreover, overexpression of TRF1-GFP or TRF1S219A-GFP resulted in an accumulation of HeLa cells in G2/M (P<0.05). The protein level of ATM was increased when overexpression the wide type or mutants. CONCLUSION: The Ser 219 phosphorylation of TRF1 by ATM could result in cell cycle arrest in G2/M, which is related to overexpression of TRF1. PMID- 17717822 TI - [Localization of p53(301-393) mutant and its effect on mitosis]. AB - OBJECTIVE: To observe the localization of p53(301-393)(residues 301-393) in p53 positive/negative cells and its effect on cell mitosis. METHODS: The protein expression of p53-GFP and p53(301-393)-GFP was checked by immunoblotting after transfection. Immunofluorescence staining was performed to detect the localization of wide type and mutant in Hela cells (p53 positive) and H1299 cells (p53 negative). The cell morphology of H1299 cells transfected of p53(301-393) GFP and the cells in mitotic phase were observed. Cell cycle was analyzed by flow cytometry and p53 protein level in HeLa cells was evaluated by Western blot after transfection of p53-GFP and p53(301-393)-GFP. RESULTS: The protein expression of p53-GFP and p53(301-393)-GFP was verified, p53-GFP was about 90 kMr and p53(301 393)-GFP about 40 kMr. Immunofluorescence microscopy demonstrated that both proteins were diffusely located in the nuclei of HeLa cells and H1299 cells. But different from the p53-GFP, the p53(301-393)-GFP was distributed in the nucleolus of HeLa cells. After transfection of the two plasmids, mitosis was inhibited in H1299 cells and some cells underwent apoptosis. G2/M progression of HeLa cells could be blocked by transfection of p53(301-393)-GFP, but endogenous p53 protein level was not changed. CONCLUSION: p53(301-393)has a different localization in the p53 positive and p53 negative cells and could inhibit mitosis and cause the cell cycle arrest in G2/M. PMID- 17717824 TI - [Clinical observation of Gleevec combined with myeloablative allogeneic stem cells transplantation in treatment of chronic myeloid leukemia]. AB - OBJECTIVE: To observe the efficacy of Gleevec combined with myeloablative allogeneic stem cells transplantation(Allo-SCT) for the treatment of chronic myeloid leukemia (CML). METHODS: Nine patients with CML were treated with Gleevec before and after Allo-SCT, with 5 in the chronic phase (CP), 2 in the accelerated phase (AP) and 2 in the blast-crisis phase (BP). The donors were HLA matched identical siblings (n=7) and matched unrelated donors (n=2). The conditioning regimen is BuCy2. Mycophenolate mofetil combined with cyclosporin A and methotrexate was used for the prevention of acute GVHD. RESULTS: All patients achieved completed hemopoietic remission (HCR) treated with pre-transplant Gleevec. The median period to gain absolute neutrophil count>0.5x10(9)/L was 12 d (8 approximately 26 d) and that for platelet count>20x10(9)/L was 20 d (8 approximately 25 d). Three cases suffered from acute GVHD and 4 from chronic GVHD. All patients achieved completed engraftment and completed molecular remission. The rate of disease free survival was 88.9% after a median follow-up of 31 m (range 7 approximately 34 m). CONCLUSION: The treatment of CML consisting of myeloablative Allo-SCT combined with Gleevec before and after transplantation is an effective and safe method for CML. PMID- 17717823 TI - [Interaction between a novel centrosomal protein TACP1 and mitotic kinase Nek2A]. AB - OBJECTIVE: To study interaction between a novel centrosomal protein TACP1 and mitotic kinase Nek2A. METHODS: Nek2A305-446 protein was expressed and purified in E.coli and TACP1 protein was expressed in transfected 293T cells. Pull-down assay was used to examine the interaction between Nek2A305-446 and TACP1. TACP1 and Nek2A complex was tested by co-immunoprecipitation assay with polyclonal anti TACP1 antibody. The localization of those two proteins in Hela cells was verified by immunofluorescence. RESULTS: TACP1 was pulled down by Nek2A305-446 protein but not by GST control. Nek2A was co-precipitated with TACP1 protein by polyclonal anti-TACP1 antibody but not by pre-immunization serum. The Immunofluorescence test showed that these two proteins formed a complex at centrosome during mitosis. CONCLUSION: Centrosomal protein TACP1 is a novel interacting protein with Nek2A, both of which are localized in centrosome during mitosis. PMID- 17717825 TI - [Cloning and sequencing of VL and VH genes from a novel clone ZCH-7-2F9 of anti hCD14 monoclonal antibody]. AB - OBJECTIVE: To acquire the genes of light chain variable region (VL) and heavy chain variable region (VH) of a novel clone ZCH-7-2F9(2F9) of anti-hCD14 for construction of anti-hCD14 single chain antibody(ScFv). METHODS: From the mouse hybridoma cell line 2F9 and its fusion partner murine myeloma cell line NS-1, total RNA was prepared. The VL and VH genes were amplified by RT-PCR with family specific primer pairs, respectively. The PCR products were cloned into pGEM(sound recording copyright sign)-T Easy vectors, then transfected into DH5alpha and the positive recombinants were identified and purified. After sequencing with automatic DNA sequencer the sequences were analyzed online. RESULTS: VL gene of the new clone of CD14 monoclonal antibody (McAb) 2F9 consisted of 321 bps encoding a peptide of 107 amino acid residues, and VH gene of the 2F9 antibody contained 360 bps encoding a peptide of 120 amino acid residues. According to IMMUNOGENETICS online analysis by IMGT/V-QUEST, the VL and VH genes belonged to mouse IGKV and mouse IGHV subgroups, respectively. On the position 23/88 of the light chain and 22/96 of the heavy chain genes there were cysteines, which play the key role in forming disulfo-bond in each chain. Both VL and VH chains had definitely 4 frame regions (FR) and 3 complementary determinant regions (CDR). CONCLUSION: The treatment of CML consisting of myeloablative Allo-SCT combined with Gleevec before and after transplantation is an effective and safe method for CML. PMID- 17717826 TI - [Effects of atorvastatin on endothelium protection in spontaneously hypertensive rats]. AB - OBJECTIVE: To investigate the effects of two different dosage of atorvastatin on endothelium protection in spontaneously hypertensive rats (SHR). METHODS: SHRs (n=18) were randomly divided into three groups (n=6): SHR control group, 50 mg atorvastatin group and 10 mg group. Six male Wistar-Kyoto rats were selected as normal control group (WKY group). All animals were given vehicle once a day by gavage for 10 weeks. Systolic blood pressure (SBP) was measured before and after treatment with atorvastatin every 2 weeks. Plasma NO and vWF were measured by nitrate reductase method and double antibodies ELISA, respectively. Plasma lipids were also measured. RESULTS: SBP in all SHR groups was much higher than that in WKY group before experiment (P<0.01). Compared with SHR control group, SBP significantly decreased in 50 mg atorvastatin group at 6, 8 and 10 weeks and in 10 mg atorvastatin group merely at 10 weeks (P<0.05 or P<0.01). The plasma levels of NO in SHR control group was significantly lower than those in WKY group (P<0.01). After 10 weeks, plasma NO levels in 50 mg and 10 mg atorvastatin groups were markedly higher than those in SHR control group (P<0.01 or P<0.05). The plasma levels of vWF in SHR control group was significantly higher than those in WKY group (P<0.01). After 10 weeks, plasma vWF levels in 50 mg and 10 mg atorvastatin groups were markedly lower than those in SHR control group (P<0.01). Plasma lipids in 50 mg and 10 mg atorvastatin groups were lower than those in SHR control group (P<0.05 or P<0.01). CONCLUSION: Atorvastatin can decrease blood pressure and significantly improve endothelial function in SHR by increasing plasma NO level and decreasing plasma vWF level. PMID- 17717827 TI - [Autologous transplantation of peripheral blood stem cell in treatment of critical limb ischemia]. AB - OBJECTIVE: To apply autologous transplantation of peripheral blood stem cells in the treatment of critical limb ischemia. METHODS: Fifteen patients with critical lower limb ischemia were recruited in this study. After bone marrow mobilization, peripheral blood stem cells were collected using CS-3000 Plus device, and transplanted directly into the ischemic limb. In total 17 times of transplantation were performed. RESULTS: One year after implanted peripheral blood stem cells, the pain scale decreased from 5 to 0, the ankle-brachial pressure index (ABI) increased from 0.30 to 0.46, the pain-free walking distance and maximal walking distance increased from 0.15 to 0.72 km and 0.96 to 2.13 km separately, from a total of 6 of 15 limb ulcers of transplanted patients 5 were healed after cell transplantation. CONCLUSION: Autologous peripheral blood stem cell transplantation is able to induce functional angiogenesis in ischemic limb, which can significantly reduce rest pain, increase walk distance, and promote ulcer healing. PMID- 17717828 TI - [KCNE2 protein S98 phosphorylation in heart of old SHR rats detected by point mutagenesis]. AB - OBJECTIVE: To investigate the phosphorylation of KCNE2 protein in heart of old SHR rats. METHODS: The membrane proteins from ventricular myocardium of old SHR were extracted, treated with or without alkaline phosphatase and tested binding with Ab2 (an anti-KCNE2 polyclonal antibody) by Western blot. A KCNE2 fusion protein with c-myc was obtained from in vitro translation system and treated with or without alkaline phosphatase. A series of mono- and double-point mutated fusion KCNE2 proteins with c-myc were obtained from an in vitro translation system, and Western blots with Ab2 or anti-myc antibody were performed. RESULTS: After alkaline phosphatase treatment, Ab2 significantly attenuated its binding with KCNE2. In vitro translation system confirmed that after alkaline phosphatase treatment, Ab2 weakened binding ability to KCNE2 while binding to c-myc was not changed. Point mutation experiments showed that serine residue in position 98 of KCNE2 proteins might be phosphorylated. CONCLUSION: KCNE2 protein in heart of old SHR rats is phosphorylated and this phosphorylation takes place in serine residue of position 98. PMID- 17717829 TI - [Quality of life in patients with rectal cancer after laparoscopic colectomy]. AB - OBJECTIVE: To assess the quality of life in patients with rectal cancer after laparoscopic colectomy. METHODS: From Sep.2004 to Dec. 2005, 51 patients with rectal cancer were recruited in this prospective, non-randomized study.Twenty three patients underwent laparoscopic colectomy (LC), 28 patients had open colectomy (OC). EORTC QLQ-C30 and QLQ-CR38 questionnaire were applied to evaluate quality of life baseline, discharging and 3 months after operation. RESULTS: Before operation,the median score of role functioning in LC group was lower. However, LC group patients complained less financial difficulties. The differences were of statistical significance (P<0.05), but not of clinical significance. The median scores of other function domains and symptom domains were similar between two groups (P>0.05). Postoperatively, the most median scores of function domains and symptom domains between two groups were similar (P>0.05). The only score with statistically significant difference was the pain when patients left hospital (U=218.5, P=0.042). However, the difference was not of clinical significance, too. CONCLUSION: Only minimal benefits in short-term postoperative quality of life are found with laparoscopic colectomy in patients with rectal cancer compared with open colectomy. PMID- 17717830 TI - [Correlation of congenital hypothyroidism with birth weight and gestational age in newborn infants]. AB - OBJECTIVE: To investigate the correlation of congenital hypothyroidism (CH) with birth weight and gestational age in newborn infants. METHODS: The screening of CH was conducted in all the live births in 2005 of Zhejiang Province, the blood samples were collected from heel stick. The thyroid stimulating hormone (TSH) was measured by time-resolved fluorescence immunoassay (TRFIA). If TSH was>9.0 mU/L, the infant was recalled for further examination. RESULTS: A total of 387,926 infants were screened in 2005, of whom 289 cases were identified with CH. The prevalence rate was 1/1,342. Among the 289 CH cases, the prevalence of premature infants, term infants and post term infants were 1/1,454, 1/1,469 and 1/246, respectively. The CH prevalence of post term infants was significantly higher than that in other two groups (P<0.01). The prevalence of low birth weight infants, normal weight infants and macrosomia was 1/575, 1/1,505 and 1/473, respectively. The prevalence of low birth weight infants and macrosomia was significantly higher than that of normal weight group (P<0.01). CONCLUSION: The prevalence of CH is associated with the birth weight and gestational age. To reduce the prevalence of CH in children, it is crucial to prevent post term, low birth weight, and macrosomia cases. PMID- 17717831 TI - [Relationship between androgen levels and pathological changes of coronary atherosclerosis in elderly males]. AB - OBJECTIVE: To explore the relationship between androgen levels and pathological changes of coronary artery in elderly males. METHODS: One hundred and twenty eight in-patients who received coronary angiography were divided into four groups: single vessel lesion group (SV group), double vessel lesion group (DV group), three vessel lesion group (TV group) and control group. The levels of serum total testosterone (TT) and sex hormone binding globulin (SHBG) were assayed by ELISA, and free testosterone (FT) calculated with the Vermeulen formula. RESULTS: There was significant difference in FT levels among these four groups, while there was no statistical difference in TT levels. FT level in TV group was lower than that in DV group and SV group. CONCLUSION: Serum levels of free testosterone may be correlated with pathological degree of coronary artery. PMID- 17717832 TI - [Prediction of plasma protein binding of cephalosporins from polar molecular surface areas]. AB - OBJECTIVE: To predict the plasma protein binding rate of cephalosporins from their molecular structural parameters. METHODS: The minimum energy conformations of cephalosporins were obtained from the optimization of the standard molecular geometry with the semiempirical self-consistent field molecular orbital calculation AM1 method; Mont Carlo method was used to calculate the polar molecular surface areas; the stepwise multiple regression analysis was used to obtain the correlation equations. RESULTS: The plasma protein binding rate of cephalosporins (fb) was well correlated with their molecular weights (MW) and surface areas of hydrogen-bonding donors (SH). The regression equation was: fb=0.5057+2.861x10(-3) MW-0.1572SH+4.714x10(-3) SH2(n=22, r=0.9042). CONCLUSION: Plasma protein binding of cephalosporins is closely related with their lipophilicity and hydrogen- bonding potential. The plasma protein binding rate of cephalosporins can be predicted from their molecular weights and surface areas of hydrogen-bonding donors. PMID- 17717833 TI - [Peak concentration of gemcitabine at fixed-dose-rate and its hematological toxicity profile]. AB - OBJECTIVE: To investigate the relationship between peak concentration (Cmax) of gemcitabine at fixed-dose-rate and its hematological toxicity profile in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Twenty-one patients received gemcitabine at a fixed dose rate (1200 mg/m2 over 120 min) with carboplatin. Plasma concentrations of gemcitabine were measured by ion-pair reversed-phase high-performance liquid chromatography. RESULTS: The mean value of Cmax in 21 eligible patients was(4.95+/-2.42) microg *ml(-1). The main hematological toxicity was grade III-IV thrombocytopenia and neutropenia. The mean percentages of reduction of WBC, NEC, PLTC and Hb of 21 patients were (38.3+/-38.1)%, (31.3+/-73.6)%, (31.8+/-53.5)% and (12.0+/-12.2)%, respectively. The C(max)of gemcitabine and the percentage of reduction in WBC showed a significant correlation (r2=0.4575, P<0.05). A significant correlation (r2=0.5671, P<0.05) was also observed between the percentage of reduction of PLTC and Cmaxof gemcitabine. CONCLUSION: The results of relationship between Cmax and toxicity profile suggest that gemcitabine administration should be individualized in order to decrease the occurrence of ADR. PMID- 17717834 TI - [Expression of pJAK, pERK and Cyclin D1 proteins in squamous-cell carcinoma of tongue]. AB - OBJECTIVE: To investigate the expression of JAK, ERK and Cyclin D proteins in squamous-cell carcinoma of tongue. METHODS: The expression of JAK, ERK and Cyclin D1 proteins was determined with SP immunohistochemical method in 30 cases of lingual Squamous cell carcinoma, 20 of normal lingual mucosa, 10 of mild epithelial dysplasia and 20 of severe epithelial dysplasia. RESULTS: The expression of pJAK in lingual squamous-cell carcinoma and epithelial dysplasia was stronger than that of normal lingual mucosa (chi2=37.54, P<0.01), and the expression of pJAK in lingual squamous-cell carcinoma was significantly higher than that of the epithelial dysplasia (chi2=6.83, P<0.05). pJAK expression in squamous-cell carcinoma of low-middle differentiation was stronger than that of high differentiation. There was no significant difference in pERK expression among lingual squamous-cell carcinoma, normal lingual mucosa and epithelial dysplasia. There was a significantly positive correlation between pJAK and Cyclin D1 expression in SCC (r=0.619, P<0.05). There was no significant correlation between the expression of pERK and Cyclin D1 (r=0.231, P>0.05). CONCLUSION: Over expression of pJAK and Cyclin D1 may be associated with the occurrence and development of squamous-cell carcinoma of the tongue. PMID- 17717835 TI - [Carotid angioplasty and stenting in patients with high-risk carotid stenosis]. AB - OBJECTIVE: To investigate the efficacy and complication of carotid angioplasty and stenting (CAS) in patients with high-risk carotid stenosis. METHODS: Eight cases with high-risk carotid stenosis underwent CAS with cerebral protective devices from March 2003 to April 2006, the efficacy and complications of CAS were reviewed. RESULT: Nine stenotic carotid arteries of 8 cases were treated with CAS. Stenotic rate was significantly reduced from 75.4 % to 28.8% (P<0.001, paired t-Test) immediately after CAS. All stents used were self-expanding and most of them (77.8%) were precise nitinol stents. Five patients had mild and reversible low heart rate and blood pressure. During follow-up for 4-41 months (21.5+/-14.2), no case had stroke again, all except one had no dizziness or vertigo again. Ultrasonography and/or computed tomographic angiography showed no re-stenosis in six cases (75%) when they were followed up. CONCLUSION: CAS with cerebral protection device is a safe and feasible procedure to treat high-risk carotid stenosis. However,its long-term efficacy and safety need to be further studied. PMID- 17717836 TI - [Inherited mutations of MUTYH and colorectal cancer]. AB - MUTYH, one of base-excision repair enzymes, is associated with human genetic disorders. Inherited biallelic mutations in the human MUTYH gene are responsible for an autosomal recessive syndrome-adenomatous colorectal polyposis (MUTYH associated polyposis, MAP), which significantly increases the risk of colorectal cancer (CRC). In this article we review the relationship between BER and the oxidative damage to DNA, the functional overlap of BER with other repair proteins, the molecular mechanism of tumourigenesis in MAP, and delineate the MUTYH polyposis phenotype and its prevention. PMID- 17717838 TI - Ottawa police accused of undermining crack distribution program. PMID- 17717837 TI - [Role of HMGB1 in rheumatic diseases]. AB - OBJECTIVE: High mobility group box chromosomal protein 1 (HMGB1) is originally identified as a DNA-binding protein that functions as a structural co-factor. HMGB1 is actively secreted by macrophage/monocytes via inflammatory stimuli. The extracellular HMGB-1 acts as a mediator of acute and chronic systematic inflammation. In this article we briefly review its role in rheumatic diseases: arthritis, polymyositis and dermatomyositis, lupus erythematosus and Sjogren's syndrome. Increased cytoplasmic expression and extracellular deposition of HMGB1 are found in the affected tissues of those diseases, especially stronger in/around focal infiltrates of mononuclear cells. TNFalpha and IL-1beta are co expressed in areas of extracellular HMGB1. HMGB1 together with TNF alpha and IL 1beta may form a proinflammatory loop promoting the chronic inflammations. The new findings of HMGB1 as a cytokine provide a better understanding of rheumatiod diseases, and could become a clinically relevant therapeutic target that might be more efficient than other known cytokines. PMID- 17717839 TI - U.S.: proposed easing of restrictions for HIV-positive short-term entry visas. PMID- 17717840 TI - Indonesia: on the road to a harm reduction model? PMID- 17717841 TI - Cameroon: ILO conducts HIV training for labour courts in francophone Africa. PMID- 17717842 TI - U.S.: all states to move to names-based HIV reporting in 2007. PMID- 17717843 TI - Heart valve disorders. Simple precautions prevent complex problems. PMID- 17717844 TI - Falls reduced with higher levels of vitamin D. PMID- 17717845 TI - Robotics in surgery. Precision on a new scale. PMID- 17717846 TI - The Nutrition Facts label on a bag of almonds lists 1 gram of saturated fat per serving. Is this the same type of saturated fat that's in a hamburger? PMID- 17717847 TI - I need to lose weight. My doctor suggested I be careful about what I drink. I'm not sure what that means. Can you explain? PMID- 17717848 TI - Supervisor's view. PMID- 17717849 TI - Re: the democratization of psychiatry. PMID- 17717850 TI - Melbourne-Sydney brain imaging comparisons. PMID- 17717852 TI - [Proceedings and abstracts of the 8th National Infectious Disease Meeting, Dijon, France, 13-15 June 2007]. PMID- 17717854 TI - Forskolin and 8-cyclopentyltheophyline synergistically facilitate the neuronal activity in the CA2 area of rat hippocampus via caMP and non-caMP cascades. PMID- 17717853 TI - Vaccination to prevent zoster in the elderly. PMID- 17717855 TI - Internet-based cognitive behaviour therapy for symptoms of depression and anxiety: a meta-analysis. PMID- 17717851 TI - Interstitial lung disease in systemic sclerosis. AB - We reviewed the literature concerning pathogenesis, clinical features, diagnosis and treatment of interstitial lung disease (ILD) in patients with systemic sclerosis (SSc). ILD is detectable in approximately 70% of patients at autopsy. Nonspecific interstitial pneumonia (NSIP) is the most common pathologic finding. The earliest phase of ILD in SSc is characterized by microvascular injury and alveolitis. Endothelial lesions, activation of coagulation proteases, especially thrombin, fibroblast proliferation, and differentiation of normal lung fibroblasts to a myofibroblasts phenotype are hallmarks of ILD in SSc. Diagnostic procedures used to detect ILD are chest X-ray, high-resolution computed tomography, bronchoalveolar lavage, lung function tests, and sometimes thoracoscopic lung biopsy. Novel and potentially useful methods to diagnose ILD in SSc are induced sputum and technetium-labeled diethylenetriamine pentaacetate (99mTC-DTPA) clearance time. Cyclophosphamide seems to be relatively effective to treat ILD in the earliest phase, but the effects of other immunosuppressive drugs on the lungs are less convincing. PMID- 17717857 TI - Computed tomography scanning detecting esophageal varices. PMID- 17717856 TI - Reexaming old techniques from a new perspective. PMID- 17717858 TI - Cirrhotic cardiomyopathy: multiple reviews. PMID- 17717859 TI - Aspirin, COX-2, and the risk of colorectal cancer. PMID- 17717860 TI - Correction of cryptorchidism and testicular cancer. PMID- 17717861 TI - Mechanisms of hypertension. PMID- 17717862 TI - Mechanisms of hypertension. PMID- 17717863 TI - Mechanisms of hypertension. PMID- 17717864 TI - Asymptomatic chronic type-A dissection with extensive root involvement. PMID- 17717865 TI - Anomalous origin of the circumflex artery from the right sinus of Valsalva: intra operative view. PMID- 17717866 TI - Ziprasidone security in overdose: one case report. PMID- 17717867 TI - Endobronchial lipoma. PMID- 17717868 TI - Financial relief: the effect of state mental health parity laws on families of children with mental health care needs. AB - Families of children with mental health care needs who live in states with mental health parity laws have lower out-of-pocket spending and are more likely to view their spending as reasonable compared with those living in non parity states. This suggests that mental health parity laws provide important financial benefits to families of children with mental healthcare needs. PMID- 17717869 TI - Expansion of health insurance in California unlikely to act as magnet for undocumented immigration. AB - Expansion of health care coverage has risen to the top of the legislative agenda in California. One question within the health care reform debate is whether expanding health insurance to all Californians will attract new undocumented immigrants who would come primarily for those benefits. A review of studies on immigration and public benefits suggests that the net attraction of any major expansion of health insurance in California would be minor in comparison to the existing attractions of jobs, family and other factors. This policy brief reviews research studies on undocumented immigration and public benefits, with specific attention to health insurance benefits. Because so few studies examine the migration of undocumented immigrants for health benefits, we also review two directly related areas of inquiry: (1) the relationship between public benefits offered by a state and the destination choice of legal immigrants to the United States; and (2) the migration of low-income citizens across state lines in response to public benefits offered by states. PMID- 17717870 TI - Advances in the neurobiology of ADHD. PMID- 17717871 TI - Non-stimulant trials of adult ADHD. PMID- 17717872 TI - [Physicians should note criticize other physicians!]. PMID- 17717873 TI - [Only the "bad" physician still comes straight out over the curves]. PMID- 17717874 TI - [Cannabinoid receptor blocker rimonabant. CNS side effects prevent U.S. approval]. PMID- 17717875 TI - Re "Endangered species". PMID- 17717876 TI - Re "Endangered species". PMID- 17717877 TI - Thailand diabetes registry (TDR) project: clinical status and long term vascular complications in diabetic patients. AB - OBJECTIVE: The primary objectives of the Thailand Diabetes Registry project were to identify the characteristics of Thai diabetic patients in tertiary care medical centers and to determine the extent of long term diabetic complications. The secondary objective aimed at building up and strengthening clinical research network among Thai experts in diabetes mellitus and collection of baseline data for future follow-up study. MATERIAL AND METHOD: A cross-sectional, multi-center, hospital-based diabetes registry was carried out from diabetes clinics of 11 tertiary centers. Demographic data, clinical status of diabetes and its complications were collected and analyzed for the prevalence of complications and risk factors. RESULTS: Nine-thousand-four-hundred-and-nineteen patients were registered for the project and 94.6% were type 2 diabetes. Mean +/- SD of age was 59.4 +/- 13.5 and duration of diabetes was and 10 +/- 7.6 years. Only 38.2% of the subjects achieved glycemic control of FPG under 130 mg/dl in only 30.7% had an HbA lc of less than 7%. The overall prevalence of dyslipidemia found in this population was 73.3%, hypertension was 63.3% and obesity (BMI >25 kg/m2) was 52.6%. Diabetic nephropathy was the most common complication accounting for 43.9% followed by retinopathy 30.7%, IHD 8.1% and cerebrovascular disease 4.4%. CONCLUSION: The prevalence of dyslipidemia and hypertension were high in this population, which may be associated with the high prevalence of diabetic complications. The unsatisfactory control of metabolic status may be due to aging and long duration of diabetic patients in this registry. PMID- 17717878 TI - Thailand diabetes registry project: prevalence of vascular complications in long standing type 2 diabetes. AB - OBJECTIVE: To explore the nature of diabetic complications in type 2 diabetic patients who had had diabetes for longer than 15 years (long-DM), compared to those with duration of less than 15 years (short-DM). MATERIAL AND METHOD: Patients studied were adult type 2 diabetic patients registered to the Diabetes Registry Project, a nationwide cross-sectional study of diabetes mellitus in Thailand. Information collected included demographic data, age at diagnosis of diabetes, blood pressure, body mass index, fasting plasma glucose, HbA(1c), serum creatinine, and major diabetic vascular complications, including diabetic retinopathy (DR), albuminuria or renal insufficiency (diabetic nephropathy; DN), myocardial infarction (MI), stroke, peripheral arterial disease (PAD), foot ulcer and amputation. RESULTS: There were 9284 patients, consisting of 2244 (24.17%) subjects with long-DM (mean +/- SD, mean duration of DM21.3 +/- 5.8 years), and 7040 subjects with short-DM (mean duration 7.0 +/- 3.9 years). The long-DM group was older than the short-DM group (65.5 +/- 10.3 vs. 58.2 +/- 12.6 year-old, p less than 0.0001), and had higher HbA(1c) (8.5 vs. 8.0%, p = 0.009). The prevalence of diabetic complications in the long-DM group was higher than that in the short-DM group (DN 49.4% vs. 33.9%, DR 54.3% vs. 22.8%; MI 9.4% vs. 3.5%, PAD 17.3% vs. 5.5%, foot ulcer 13.4% vs. 5.3%, stroke 9.4% vs. 7.0% and amputation 5.5% vs 2.0%; allp values less than 0.01). The duration of DM significantly affected the risk of diabetic complications after adjustment for age, hypertension, and levels of glycemic control. CONCLUSION: Diabetic duration was independently associated with increased risk of having diabetes-related complications without threshold. Monitoring of complications in patients having long-standing diabetes is warranted in order to provide appropriate management. PMID- 17717880 TI - Men who have sex with men: a new focus internationally. PMID- 17717879 TI - Physician preferences will limit ability to lower prices of orthopedics. PMID- 17717881 TI - Cryptosporidiosis: still a problem. PMID- 17717883 TI - Editorial comment: changes in HIV hospitalizations. PMID- 17717882 TI - Changes in HIV-related hospitalizations during the HAART era in an inner-city hospital. AB - We evaluated admissions of HIV-positive persons to an inner-city hospital from 2000 to 2005. There was a decline in the number of substance abusers, homeless persons, injection drug abusers, and African Americans, and there was an increase in patients older than 50 years. There were no significant changes in CD4 counts or in utilization of highly active antiretroviral therapy,m but there were more admissions of persons with HIV RNA levels less than 1000 copies/mL, internal medicine problems, cancers, and skin infections. Changes in the demographics of this patient population may reflect external factors (eg, gentrification of low income housing areas, opening of a new hospital). Lower viral loads suggest better response in those on a highly active antiretroviral regimen, and changes in diagnoses leading to hospitalization may reflect the aging of the HIV population. PMID- 17717884 TI - An unusual cause of mastoiditis that evolved into multiple ring-enhancing intracerebral lesions in a person with HIV infection. AB - Acute mastoiditis, an infectious inflammatory process in the temporal bone, is an uncommon complication of otitis media. Here we describe a fatal case of mastoiditis complicated by thrombosis of the sigmoid sinus and intracerebral abscess caused by an unusual pathogen (Nocardia asteroides) in a person with HIV infection. Sulfonamides have remained the first-line agents for the management of Nocardia infections, but mortality remains high in patients with intracerebral infection. PMID- 17717885 TI - Electronic medical records improve quality of care. PMID- 17717886 TI - Resolution of papular mucinosis in a person with HIV infection. AB - Lichen myxedematosus, or papular mucinosis, is a skin disorder characterized by accumulation of mucin in the dermis. We present the case of a patient with HIV infection and lichen myxedematosus whose skin condition completely resolved with antiretroviral therapy. PMID- 17717887 TI - FDA expert panel to review Merck's new HIV treatment Isentress in September. PMID- 17717888 TI - Outlook on diabetes drug less than rosy. Early work suggests that rosiglitazone (Avandia) may not be best for the heart. PMID- 17717889 TI - Aspirin: a user's guide to who needs it and how much to take. Just because you can buy aspirin without a prescription (and for pennies a tablet) doesn't mean everyone should be taking it to prevent a heart attack or stroke. PMID- 17717890 TI - Ask the doctor. Are Lipitor and Crestor equally good for me? PMID- 17717891 TI - The shingles vaccine. Why hasn't it caught on? The cost and other factors are to blame. PMID- 17717892 TI - Betting on beta blockers. They're versatile and have a long track record. But should you count on a beta blocker to treat your high blood pressure? PMID- 17717893 TI - Migraine as a withdrawal symptom. Research suggests that some women may suffer migraines because of sudden changes in estrogen levels. PMID- 17717894 TI - Taking silver could give you the blues. Silver is less toxic than some other metals...but do you look good in blue? PMID- 17717895 TI - Exercise without losing weight. PMID- 17717896 TI - By the way, doctor. First it was Vioxx and now Avandia. Why can't doctors and the government screen out unsafe medicines? PMID- 17717897 TI - The role of hepatology nurse in the difficult-to-treat hepatitis C population. PMID- 17717898 TI - Liability for delays in diagnosis--waiting for trouble? Interview by Paul C Adams. PMID- 17717899 TI - Effects of various forms of calcium added to chewing gum on initial enamel carious lesions in situ. PMID- 17717900 TI - [Fit for Europe?]. PMID- 17717901 TI - [Statement of the Commission for "Quality and Transparency of Phytopharmaca" by order of the "Komitee Forschung Naturmedizin e.V.(KFN)"]. PMID- 17717902 TI - [Does salt prolong your life?]. PMID- 17717903 TI - [DHEA: castle in the air rather than the fountain ou youth]. PMID- 17717904 TI - [Anit-aging with cutlery]. PMID- 17717905 TI - [Patient information. Ecoendoscopy or endoscopic ultrasonography]. PMID- 17717906 TI - Olanzapine exposure during pregnancy. PMID- 17717907 TI - Neurodegeneration and neuroregeneration: recent advancements and future perspectives. PMID- 17717908 TI - [An explanation for the "causal treatment" of TCM based on modern science]. AB - "Treat before getting illness" is one of the preponderant thinking of traditional Chinese medicine (TCM) in dealing with problems of disease and health. Based on the current progress in modern biomedical research, the author thought thoroughly the "causal treatment of TCM" and associated with the recognition of sub-health manner, a physio-biochemical process occurred in the stress course of life, and accordingly, a modern scientific idea was put forward in this article for explaining some TCM standpoints and measures of stressing prevention preceding to treatment. PMID- 17717909 TI - [Discussion on the necessity of treatment of rheumatoid arthritis with integrative Chinese and Western medicine]. PMID- 17717910 TI - [Thinking on the integrative Chinese and Western medicine in treating rheumatoid arthritis]. PMID- 17717911 TI - [Some problems that should be paid attenion to in treatment of rheumatoid arthritis with TCM]. PMID- 17717912 TI - [Think much of the study on TCM syndrome differentiation of rheumatoid arthritis]. PMID- 17717913 TI - [Clinical study on effect of total panax notoginseng saponins on immune related inner environment imbalance in rheumatoid arthritis patients]. AB - OBJECTIVE: To study the therapeutic effect and possible mechanism of total panax notoginseng saponins (PNS) for treatment of rheumatoid arthritis (RA), and to observe its safety and influence on RA immune related inner environment. METHODS: Eighty-four patients were randomly assigned to two groups. All were treated with the routine therapy with diclofenac sodium, Leflunomide and prednisone, but for the 43 patients in the treatment group PNS was given additionally. The therapeutic course was 28 days for both groups. Clinical efficacy and change of indexes including platelet counts, immnuoglobulins (IgG, IgA, IgM), complement (C)3, rheumatoid factor (RF), C-reactive protein (CRP), ceruloplasmin (CER), haptoglobin (HPT), and alpha1-acid glycoprotein (AAG) were observed. RESULTS: Significant improvement of clinical symptoms, including the joint swelling index, joint tenderness index, joint pain index, time of morning stiffness and VAS revealed in both groups after treatment, and the effect in the treatment group was better (P<0.05 or P<0.01). PLT, CER, AAG, HPT, CRP, IgG, IgA, IgM, C3 and RF were lowered in both groups (P<0.01), but the lowering in PLT, CER, AAG and CRP in the treatment group was more significant than that in the control group respectively (P < 0.05 or P < 0.01). CONCLUSION: PNS can significantly improve the condition of patients, enhance the therapeutic effect in treating RA, through regulating the disordered immunity and improving the effect of anti-inflammatory and analgesia. PMID- 17717914 TI - [Effect of strengthening Pi and activating blood circulation therapy on serum levels of adrenocorticotrophic hormone and vascular endothelial growth factor in rheumatoid arthritis patients]. AB - OBJECTIVE: To observe the effect of strengthening Pi and activating blood circulation therapy (SPAB) on serum levels of adrenocorticotrophic hormone (ACTH) and vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA) patients. METHODS: Seventy RA patients were randomly assigned to 3 groups. The 30 in the Chinese medicine (CM) group were treated with SPAB; the 20 in the Western medicine (WM) group were treated with indomethacin and methopterin; and the 20 in the CM-WM group were treated with the combination of the therapy in the above two groups, and the course of treatment was 3 months for all. Serum levels of ACTH and VEGF were determined before and after treatment. RESULTS: The total effective rate in the CM group was 80.0%, WM group 85.0% and CM-WM group 95.0%, the last one showed the best efficacy (P<0.05). Serum level of ACTH increased and level of VEGF decreased after treatment in all groups (P<0.05 or P<0.01), but the increment/decrement in the CM-WM group was higher than that in the other two groups (P<0.01), while comparison between that in the CW group and WM group showed insignificant difference. CONCLUSION: SPAB therapy has the effect in alleviating the condition of RA, similar to that of Western medicine, it can increase the serum level of ACTH and decrease the serum level of VEGF remarkably in RA patients. PMID- 17717915 TI - [Clinical observation on effect of total glucosides of paeony in treating patients with non-systemic involved Sjogren syndrome]. AB - OBJECTIVE: To investigate the efficacy and adverse reaction of total glucosides of paeony (TGP) in treating patients with non-systemic involved Sjogren syndrom (NSI-SS). METHODS: Retrospective study was conducted on 27 patients with NSI-SS who received TGP treatment for over two years as the TGP group, and 20 patients received hydroxychloroquine sulfate (HCQs) for over two years in the HCQs group for positive control. Salivary flow, Schirmer's test and serum gamma-globulin at different time points, i.e. before treatment, and at the end of 1st, 3rd, 6th, 12th and 24th month respectively, were compared between groups, and adverse reactions associated with TGP and HCQ were also observed. RESULTS: In the TGP group, saliva secretion was significantly increased and serum gamma-globulin decreased significantly from the 6th month (P <0.01), Schirmer's test improved significantly after 12 months (P< 0.01). While in the HCQs group serum gamma globulin was significantly decreased from the 3rd month (P <0.01), saliva secretion and Schirmer's test improved significantly after six months (P<0.01). However, the 3 indexes determined at the end of the 3rd month were insignificantly different from those before treatment. Mild diarrhea occurred in 4 cases in the TGP group, they were improved two weeks later, but one case with severe diarrhea was dropped. While in the HCQs group, 2 patients were dropped, one for the raising of alanine aminotransferase at the 6th month and the other for decreased vision at the 9th month. CONCLUSION: Efficacy of TGP is equivalent to that of HCQs in treating NSI-SS, but with higher safety and the effect initiating time being about 6 - 12 months. PMID- 17717916 TI - [Study on immunological pathogenesis of 59 patients with multiple sclerosis of different TCM syndrome types]. AB - OBJECTIVE: To explore the immunological pathogenesis of multiple sclerosis (MS) patients of different TCM syndrome types. METHODS: Fifty-nine MS patients were assigned to two types by syndrome typing according to their clinical manifestations, the Gan-Shen yin-deficiency (GSYD, 40 cases) type and the both yin-yang deficiency (YYD, 19 cases) type. Difference of patients' age of first attack, times of relapsing, duration of disease, MRI finding and evoked potential between the two groups were compared. The immunology indexes were also compared in part of the patients (26 cases in GSYD type and 12 cases in YYD type). RESULTS: The age of first attack was later (P < 0.01), level of myelin basic protein in cerebrospinal fluid was higher (P < 0.05), in the YYD type than those in the GSYD type. Besides, the relapsing time in GSYD type, and the blood-brain barrier index and level of myelin basic protein in YYD type showed an ascending trend (P = 0.056, 0.074, 0.093, respectively). CONCLUSION: Immunological difference exists between the MS patients of GSYD type and those of YYD type. PMID- 17717917 TI - [Study on the quantitative evaluation on the degree of TCM basic syndromes often encountered in patients with primary liver cancer]. AB - OBJECTIVE: To establish a quantitative model for evaluating the degree of the TCM basic syndromes often encountered in patients with primary liver cancer (PLC). METHODS: Medical literatures concerning the clinical investigation and TCM syndrome of PLC were collected and analyzed adopting expert-composed symposium method, and the 100 millimeter scaling was applied in combining with scoring on degree of symptoms to establish a quantitative criterion for symptoms and signs degree classification in patients with PLC. Two models, i.e. the additive model and the additive-multiplicative model, were established by using comprehensive analytic hierarchy process (AHP) as the mathematical tool to estimate the weight of the criterion for evaluating basic syndromes in various layers by specialists. Then the two models were verified in clinical practice and the outcomes were compared with that fuzzy evaluated by specialists. RESULTS: Verification on 459 times/case of PLC showed that the coincidence rate between the outcomes derived from specialists with that from the additive model was 84.53 %, and with that from the additive-multificative model was 62.75 %, the difference between the two showed statistical significance (P<0.01). CONCLUSIONS: It could be decided that the additive model is the principle model suitable for quantitative evaluation on the degree of TCM basic syndromes in patients with PLC. PMID- 17717918 TI - [Clinical study on effect of Jianwei Yuyang Granule in treating patients with gastric ulcer]. AB - OBJECTIVE: To observe the clinical effects of Jianwei Yuyang Granule (JYG) in treating patients with gastric ulcer and its influence on interleukin-1beta (IL 1beta) and basic fibroblast growth factor (bFGF) mRNA expression in gastric mucosa for exploring the therapeutic mechanism. METHODS: Fifty-six patients with confirmed gastric ulcer unader gastroscope and differentiated as Gan-stagnant Pi deficient syndrome were randomly assigned to two groups, the treated group (26 cases) treated with JYG and the control group (30 cases) treated with famotidine and sucralfate, 4 weeks as one therapeutic course. The changes before and after treatment in clinical compliance, symptom integral, ulcer-healing rate, clinical effective rate, and HP-clearance rate were observed. And the gastric mucosa biopsy was fetched for morphological examination and IL-1beta and bFGF mRNA expression detection by RT-PCR as well. RESULTS: The clinical compliance rate in the treated group was 100 %, which was obviously better than that in the control group (86.7 %, P< 0.01); the improvement on symptom integral in the former was also better (P < 0.01); no statistical significance was shown in ulcer-healing rate, clinical effective rate and HP-clearance rate between the two groups. Morphological observation showed markedly decreased inflammatory cell infiltration, epithelial cell regeneration and rather regular glandular arrangement in both groups. The IL-1beta mRNA expression level decreased and that of bFGF increased in both groups after treatment significantly ( P < 0.01), but showed insignificant difference between the two groups. CONCLUSION: JYG, with its good clinical compliance, has favorable effects in relieving clinical symptoms, promoting endoscopic ulcer healing and HP clearance, decreasing the expression of IL-1beta mRNA and increasing the expression of bFGF, therefore, it could promote the recovering of gastric ulcer. PMID- 17717919 TI - [Morphological observation on gastric mucosa membrane of patients with gastric ulcer treated with combined use of Qifang Weitong Powder and omeprazole]. AB - OBJECTIVE: To observe the histological changes of gastric mucosa in patients with active gastric ulcer before and after treatment by Qifang Weitong Powder combined with omeprazole (QWP-Op). METHODS: Sixty patients were equally randomized into the treated group and the control group. They were all treated in the 1st week by the Helicobacter pylori eradication triad regimen. From the 2nd to 6th week, the study group re-ceived QWP-Op therapy, and the control group was given Omeprazole alone.Biopsy specimens were obtained around ulcer area before and after treatment for histological observation on changes of gastric mucosa membrane. RESULTS: The improvement of mucosal thickness and glandular morphology was better in the treated group than that in the control group (P <0.05). CONCLUSION: QWP-Op therapy can improve the histological quality of ulcer healing and restore the morphological structure of gastric mucosa in patients with active gastric ulcer. PMID- 17717920 TI - [Study on correlation between TCM syndrome type and pathological changes of liver tissue in 260 patients with chronic hepatitis B]. AB - OBJECTIVE: To study the correlation between TCM syndrome type and liver tissue pathological changes in patients with chronic hepatitis B (CHB) in order to provide evidence for syndrome differentiation. METHODS: Syndrome typing as well as liver pathological grading and staging of liver biopsy were performed on 260 patients with CHB, then the relationship between them was analyzed. RESULTS: (1) The grade of liver inflammation was mainly G1 and G2 in patients of Gan-qi stagnation and Pi-deficiency type (type 1); G2 in patients of inner damp-heat retention type (type II); G3 in patients of Gan-Shen yin-deficiency type (type lII) and Pi-Shen yang-deficiency type (type IV); while G4 occurred mainly in patients of blood stasis blocking collateral type (type V), showing significant difference as compared with other syndrome types. (2) The liver pathological stage in patients of type I and II was mainly S1 and S2, while S3 and S4 occurred mainly in patients of type III and type IV. (3) The pathological change was mainly G3-G4 and S3-S4 in blood stasis syndrome, while it was mainly G1-G2 and S1 S2 in non-blood stasis syndrome. CONCLUSION: The TCM syndrome type is correlated with liver tissue pathological change to certain extent, among them, syndrome with or without blood stasis showed the closest correlation. The syndrome type of CHB patients developed, along with the aggravating of liver pathological injury, from sthenia to asthenia, from qi to blood, and finally to the blood stasis blocking collateral. So the treatment should be lay stress on activating blood circulation to remove stasis, and be implemented by 3 stages. PMID- 17717921 TI - [Cluster analysis on TCM syndromes in 319 coronary artery disease patients for establishment of syndrome diagnostic figure]. AB - OBJECTIVE: To explore the diagnostic figures for TCM syndrome typing in coronary heart disease (CHD) patients. METHODS: A retrospective investigation was carried out in 319 CHD patients hospitalized from Jan. 2004 to Dec. 2004 in authors' hospital. Through cluster analysis, descriptive statistics and frequency normalization in combination of clinical observation, the diagnostic figures of TCM syndromes were obtained. RESULTS: The figures for qi deficiency syndrome were: primary symptoms: chest pain and stuffiness, secondary symptoms: tiredness, short breath, poor appetite, light colored tongue, deep and thready pulse; for qi deficiency with phlegm and blood stasis syndrome: primary symptoms: chest stuffiness and pain, secondary symptoms: tiredness, insomnia, palpitation, obesity, dark red tongue, string and slippery pulse; for turbid-phlegm blocking collateral syndrome: primary symptoms: chest stuffiness, secondary symptoms: cough, expectoration with much white sputum, tiredness, short breath and poor appetite, light colored tongue with white greasy coating, slippery pulse. CONCLUSION: Research on diagnostic criteria for TCM syndrome typing could be established upon clinical epidemiologic survey and statistic analysis in combining with specialists' suggestions to primarily set the referrence figures. PMID- 17717922 TI - [Effects of milkvetch root on neuro-endocrino-immune network in asthma model rat]. AB - OBJECTIVE: To study the change and the effect of milkvetch root (MR) on neuro endocrino-immune (NEI) network related indexes in repeated asthmatic attack model rats. METHODS: Rats were randomly divided into five groups: the normal group (A), the model group (B), and the three treated groups (C, D, E) treated with low, medium and high dose of the MR by gastrogavage. The corticotropin releasing hormone (CRH) mRNA expression in hypothalamus was tested by Realtime-PCR, serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were detected with radioimmunoassay, serum IL-6, IL-4, IFN-gamma determined with enzyme-linked immunosorbent assay, and the lung tissue pathology was examined by hematoxylin and eosin staining. RESULTS: As compared with the normal group, in the rats 3 weeks after modeling, CRH mRNA expression, blood IFN-gamma and plasma ACTH were unchanged, serum level of CORT raised significantly (P<0.05), IL-6 and IL-4 showed an increasing trend but without significance. Low dose of MR could promote the production of serum CORT, and hight dose of MR could down-regulate the concentrations of IL-4 and IL-6 (P<0.01). No significant difference was found in comparison of pathological changes of lung tissue among the groups. CONCLUSION: Rats suffered from repeated asthmatic attack have some disorders in indexes of NEI, MR could enhance the function of hypothalamic-pituitary-adrenal cortex axis and adjust the balance of Th1 and Th2 cytokines to alleviate the inflammation of asthma. PMID- 17717923 TI - [Study on mechanism of biminne in treating allergic rhinitis]. AB - OBJECTIVE: To investigate the effect and mechanism of Biminne, a Chinese herbal compound preparation, for treatment of allergic rhinitis (AR). METHODS: AR model of mouse was induced by intraperitoneal injection of ovalbumin (OVA), and the changes in behavior, proliferative activity of splenic lymphocyte, serum levels of total IgE and OVA specific IgE were observed. RESULTS: Biminne showed effects in reducing the frequency of sneezing and nasal rubbing, inhibiting the proliferation of splenic lymphocyte stimulated by phyto-hemagglutinin (PHA) and OVA, and lowering the levels of serum total IgE and OVA specific IgE. CONCLUSION: Biminne could inhibit the proliferation of splenic lymphocyte and reduce serum level of IgE in mice with AR. PMID- 17717924 TI - [Variation of TFAR-19 protein expression in the thymus of emotional stress mice and the regulatory effect of Modified Xiaoyao Pill]. AB - OBJECTIVE: To study the variation of TFAR-19 protein expression and Annexin-V apoptosis protein proportion in the mice thymus cell apoptosis procedure induced by water platform environment or electric emotional stress and the regulatory effect of Modified Xiaoyao Pill (MXP). METHODS: The mouse emotional stress model was established by water platform equipment or electrical stimulation. The serum glucocorticoid was detected by radioimmunoassay, the TFAR-19 protein was detected by flow cytometry analysis, and Annexin-V apoptosis protein proportion was calculated by immunofluorescence technique. RESULTS: In the groups of mouse stressed by water platform environment, the level of serum glucocorticoid, the TFAR-19 protein expression and the Annexin-V apoptosis protein proportion increased in the thymus cell along with the stress time prolonging (P<0.05 or P <0.01). The serum glucocorticoid level in mice treated with MXP was lower than that in the untreated group (P <0.05). In the groups of emotional stressed mouse established by electrical stimulation, the above-mentioned variations also revealed. All these variations could be alleviated with MXP (P<0.05). CONCLUSION: The water platform environment stress is a chronic continuous stress and electrical stimulation is an acute smooth stress, both of them could damage thymus function through neuro-endocrineo-immune network, but different in duration for causing severe injury. Chinese medicine MXP can alleviate the damage of thymus induced by either of them to certain degree. PMID- 17717925 TI - [Effects of tetramethylpyrazine on brain oxidative damage induced by intracerebral perfusion of L-DOPA in rats with Parkinson's disease]. AB - OBJECTIVE: To observe the effects of tetramethylpyrazine (TMP) on brain oxidative damage induced by intracerebral perfusion of levodopa (L-DOPA) in rats with Parkinson's disease (PD). METHODS: PD model rats were induced by intracerebral injection of 6-hydroxyl dopamine (6-OHDA) and perfused in brain with L-DOPA using microdialysis technique. Changes in levels of 2,3-dihydroxy benzyl acid (2.3 DHBA) and 2,5-dihydroxy benzyl acid (2,5-DHBA) in striatum of rats, formed by extracellular hydroxyl radical from salicylic acid capturing, were dynamically observed at various time points by HPLC-ED. RESULTS: After treatment with L-DOPA, 2,3-DHBA and 2,5-DHBA in the model group showed significantly higher levels at 6 and 7 time points as compared with those in the sham-operated group at the corresponding time points (P <0.05 or P< 0.01), while these abnormal elevations were significantly inhibited in the TMP treated groups, either in large or small dose (P<0.05 or P<0.01). CONCLUSION: TMP could reduce the L-DOPA induced brain oxidative damage in PD rats. PMID- 17717926 TI - [Preliminary study on the mechanisms of acupuncture in promoting embryo implantation in rats]. AB - OBJECTIVE: To observe the influence of acupuncture on embryo implantation in rat model of embryo implantation dysfunction, and to primarily explore its possible mechanisms. METHODS: Pregnant rats were randomly allocated into the control group, the model group and the acupuncture group. The pregnancy rate and average number of blastocyst were observed, the serum levels of estrodiol (E2), progesterone (P4) and prolactin (PRL) were detected by RIA, and the protein and mRNA expression of progesterone receptor (PR) and prolactin receptor (PRLR) in endometrial tissue of implantation site were determined using immunohistochemical assay and RT-PCR respectively. RESULTS: The pregnancy rate and average number of blastocyst were significantly higher in the acupuncture group than those in the control group respectively (P <0.01). The serum levels of P4 and PRL as well as the protein and mRNA expression levels of PR and PRLR in the model group were significantly lower than those in the other two groups (P<0.05). CONCLUSION: Acupuncture can promote embryo implantation in rats to a certain degree, and its mechanism might be related with the effects of acupuncture in mediating the sexual hormone levels and the receptor expression of rats. PMID- 17717927 TI - [Effect of tanshinone II A on angiotensin II induced nitric oxide production and endothelial nitric oxide synthase gene expression in cultured porcine aortic endothelial cells]. AB - OBJECTIVE: To investigate the protective effect of tanshinone II A on porcine aortic endothelial cells (PAEC). METHODS: PAEC were stimulated with angiotensin II (Ang- II) for different acting time (1 h, 6 h and 24 h) and Tanshinone II A was added along with Ang- II stimulation (Group A) or 6 h after it (Group B). The nitric oxide (NO) level, the protein and mRNA expression of nitric oxide synthase (cNOS) in PAEC were measured by nitric acid deoxidizing assay, RT-PCR and immunohistochemical assay, respectively. RESULTS: With the prolongation of acting time of Ang- II, the level of NO and eNOS expression in PAEC sequentially decreased in a negative acting time dependent manner (P < 0.01), which could be inhibited by tanshinone II A treatment independent to the dosage used (P< 0.01). The inhibitory effect of tanshinone II A was better in Group A than that in Group B either at 1 h or at 6 h after treatment (P<0.05). However, 24 h later, no significant difference was found between the effect in the two groups (P >0.05). CONCLUSION: Tanshinone II A could inhibit the negative effect of Ang- II on NO production and eNOS expression in PAEC. PMID- 17717928 TI - [Observation on effect of Wuling Capsule in treating poststroke depression]. AB - OBJECTIVE: To evaluate the efficacy of Wuling Capsule (WLC) in treating patients with poststroke depression. METHODS: One hundred and eight patients with poststroke depression were randomly assigned to three groups, 36 in each. All were treated with routine medicine, but to the WLC group and the FLX group, additional WLC and fluoxetine was given respectively, while to the combined group, both of the two were given. Patients' neurological and cognitive function were estimated by HAMI) scale, MMSE scale, SSS scale and Barthel index (BI) before treatment and at 4 weeks and 12 weeks after treatment. RESULTS: HAMD score and SSS score significantly decreased (P < 0.01) while MMSE score and BI score significantly increased (P <0.05) in all the three groups, but the improvement in decrease of HAMD score and in increase of BI score in the combined group was more significant than those in the other two groups respectively (P<0.05). CONCLUSIONS: WLC is effective in treating patients with poststroke depression and shows synergism with fluoxetine. PMID- 17717929 TI - [Comparative study of Modified Xiaoyao Pill combining amitriptyline on therapeutic effect and compliance in treating patients with depression]. AB - OBJECTIVE: To comparatively observe the curative effect, adverse reaction and compliance of Modified Xiaoyao Pill combining amitriptyline (MXP-At) in treating patients with depression. METHODS: Sixty-four patients with diagnosis of depression matched to the Chinese Classification of Mental Disorders (CCMD-3) were randomly assigned to 2 groups, the treatment group treated with MXP-At and the control group with fluoxeline, 32 cases in each group. The curative effect was evaluated by Hamilton depression (HAMD) scale and the adverse reaction was recorded before treatment and at the 2nd, 4th and 12th week of the treatment. Patients were regularly followed up from the 12th week to the 24 th week. The curative effect and compliance in the two groups were compared. RESULTS: The HAMD score dropped in both groups from the 2nd week of the treatment, and at that time, it was lower in the control group than that in the treatment group (P < 0.05); but at the 4th week, no significant difference was found in the therapeutic effect and the HAMD score between the two groups. However, 3 and 14 cases in the treatment and the control group were relapsed during the 12 weeks of follow-up respectively. CONCLUSION: MXP-At shows a curative effect similar to fluoxetine on depression but with less adverse reaction, and is not expensive. PMID- 17717930 TI - [Clinical observation on treatment of albuminuria in patients with pregnancy induced hypertension syndrome in puerperium by Xiaobai Decoction]. AB - OBJECTIVE: To observe the effects of Xiaobai Decoction (XBD) in reducing albuminuria and shortening the duration of albuminuria in patients with pregnancy induced hypertension syndrome (PIH) in puerperium. METHODS: Eighty-five patients were given the conventional treatment with magnesium sulfate for relieving convulsion and lowering hypertension, at the same time, the treated group was given XBD additionally with the modification according to the symptoms. The treatment course for both groups was 14 days. Routine test of midstream urine was performed every three days, and 24 h-urinary protein was measured every week. RESULTS: The therapeutic effect on the 43 patients of the treated group was markedly effective in 11 (25.6 % ), effective in 26 (60.4%) and ineffective in 6 cases (14.0%), the total effective rate being 86.0%; while in the 42 patients of the control group, the corresponding numbers were 5 (11.9%), 21 (50.0%), 16 (38.1%) and 61.9%, respectively, the efficacy of the former was significantly better (P < 0.05). CONCLUSION: XBD is a simple, safe and effective drug for reducing albuminuria and shortening the duration of albuminuria in puerperium of PIH patients. PMID- 17717931 TI - [Difficulties and countermeasures in research for prevention and treatment of coronary heart disease by integrative Chinese and Western medicine]. AB - The dramatic development of modern medicine on patho physiology, diagnosis and therapeutic technique of coronary heart disease (CHD) has brought great challenge to the position of traditional Chinese medicine (TCM) and integrative Chinese and Western medicine (ICWM) in preventing and treating cardiovascular diseases. Although great progress has been achieved recently in this field, many difficulties and problems still remain unresolved. Countermeasures and prospects were put forward in this article. PMID- 17717932 TI - [Characteristics and difficulties in clinical trials of new traditional Chinese drugs]. AB - Therapeutic efficacy is the point of starting and ending for research and developing of new traditional Chinese drugs, and clinical trials could provide a good platform for its efficacy evaluation. The characteristics of Chinese patent medicine is clarified in this paper by comparing its difference from Chinese herbal decoction, and the characteristics and difficulties in clinical trials for developing Chinese new drugs were also probed in referrence to the present situation and progress of the concerning topics. PMID- 17717933 TI - [Application of central randomized system in project of clinical trial for secondary prevention of myocardial infarction by Qishen Yiqi Drop Pill]. AB - Central randomized system (CRS) is actually a management system for actualizing process of clinical trial, which can not only reduce the factitious jamming during randomization to avoid bias, but also play an important role in drug supervision during long-term and large-scale clinical trials in which a large amount of drugs are applied. This article introduced the two main functions of the CRS, i. e. the randomization of testees and the management of drugs, as well as the key points and instructions for applying clinical research interactive voice responding system (CRIVRS) in operating the project of clinical trial for secondary prevention of myocardial infarction by Qishen Yiqi Drop Pill. PMID- 17717935 TI - [About the accomplishment of translator in standardized English translation of TCM]. AB - The accomplishment of translator in standardized English translation of TCM should be paid more attention, since it cannot but influence the foreign academic inter-communion and quality of transmission of TCM. PMID- 17717934 TI - [Clinical analysis on 162 cases of drug eruption induced by Chinese patent medicine]. AB - OBJECTIVE: To analyze the pathogenesis and characteristics of drug eruption induced by Chinese patent medicine for providing some referential materials on prevention and treatment of drug eruption. METHODS: Clinical data of 162 patients suffered from drug eruption were analyzed retrospectively. RESULTS: Most the drug eruption (161 times/case, accounting for 99.4%) belonged to the mild type; injection was the dominating dosage-form for inducing drug eruptions (87 times/case, 53.7%); most of the cases occurred when drugs were used in combination (106 times/case, 65.4%); and few of the patients (14 times/case, 8.6%) had drug eruption for the first time. CONCLUSION: Prevention of drug eruption could be realized by way of learning more relevant knowledge, cautiousl accepting the Chinese herbal injection, avoiding drug combination, as well as inquiry for the history of drug application of patients in detail. PMID- 17717936 TI - [Research progress of correlation between blood-stasis syndrome and inflammation]. AB - Through summarizing the literatures concerning basic and clinical study on the correlation between blood-stasis syndrome (BSS) and inflammation, reviewing close correlation of BSS with C-reaction protein, serum interleukin-6, tumor necrosis factor and adhesion molecules, it was found that promoting blood circulation and removing stasis approaches could effect vitally in clinical treatment of inflammation, and the inflammation reaction shows certain effect of mediation in animal model of BSS. Accordingly, the important role played by inflammatory reaction in the occurrence and development of BSS is summarized in the paper. PMID- 17717937 TI - [Pharmacogenetics of oral anticoagulants: individualized drug treatment for more efficacy and safety]. AB - Oral anti-vitamin K (AVK) anticoagulants constitute the first cause of iatrogenic accidents in France because of narrow therapeutic index and bleeding risk. The wide interindividual variation in AVK response is partly genetically determined. The main enzyme responsible for the metabolism of AVK is the hepatic cytochrome P450 2C9 (CYP2C9). Vitamine K epoxide reductase complex subunit I (VKORC1) is a key enzyme in the vitamin K cycle, cofactor required for the activation of vitamin K-dependent clotting factors, and is the target enzyme of AVK inhibition. Genetic variations affecting both CYP2C9 and VKORC1 are associated with variability in drug response and may explain differences in dose requirements. Genotyping for CYP2C9 and VKORC1 variants before initiation of treatment may allow clinicians to develop dosing protocols and identify the patients at a higher risk for bleeding complications. PMID- 17717938 TI - [Sjogren's syndrome, lymphoma, cryoglobulinemia]. PMID- 17717939 TI - [Juvenile idiopathic arthritis. II. Treatment and prognosis]. AB - Immunosuppressants, including methotrexate and more recently anti-TNFalpha, have modified the prognosis of the most severe forms juvenile idiopathic arthritis. However, the therapeutic management is still challenging and adjuvant therapies, including physiotherapy, surgery, or even bisphosphonates and growth hormone, are still widely used to limit the negative impact of an extended general corticotherapy. PMID- 17717940 TI - [Allergic diseases. A very strong increase]. PMID- 17717942 TI - [IqE dependent hypersensitivity and allergic inflammation]. AB - The development of the IgE-dependent inflammatory reaction is made of 3 successives phases. The initiation period is related to dendritic cells, present everywhere in peripheral tissues, able after maturation to migrate to the draining lymph-node and to present immunogenic peptides to the naive T lymphocyte. After this first step of sensitization, in case of a new contact with allergens, the inflammatory phase is rapidly developing: mast cell activation, then massive influx of eosinophils, neutrophils and mononuclear phagocytes, all phenomenas under the control of different T-lymphocyte subpopulations: T-CD4+ cells with a pro-allergic Th2 profile but also newly identified T regulatory cells (Tr-1, T CD4+ CD25+). The third phase concerns the repair process or more often in case of repeated allergenic aggressions, a remodelling process such as observed in patients with severe allergic asthma. All these data have lead to reconsider our understanding of the allergic reaction. In fact allergy seems to result from an aberrant immune response to the environmental allergens, while the non-atopic subject, exposed to the same allergens will develop a natural tolerance. PMID- 17717941 TI - [Allergic diseases as environmental diseases]. AB - Respiratory allergic diseases belong to atopic diseases. Their prevalence has steadily increased over the past decades. Recently, a plateau effect seems to occur. This increased prevalence should be related to environmental changes. However, "classical" aerocontaminants, such as aero-allergens and air pollutants cannot account for such a drastic increase in prevalence. Change in diet can account for biological changes but the relation to allergic diseases seems questionable. Use of contraceptive pills and caesarean section had been put forward as hypotheses but their implication seems unlikely. Among the classical risk factors, 2 only should remain in the primary prevention of atopic diseases, namely, prolonged breast feeding and avoiding passive smoking. The major input of epidemiological research over the past decades lies in the "hygienic hypothesis" and the protective effect of early exposure to farm animals and raw cow milk. Progress to come in this field should lie in a better knowledge of in utero exposure on the foetal immune system. PMID- 17717943 TI - [The diagnosis of allergic diseases]. AB - The diagnosis of allergic diseases IgE mediated is based on 4 criteria: questionnary on the circumstances of appearance suggesting an allergic mechanism and defining an potential allergen; confirmation through cutaneous tests (prick test, IDR); measuring out of specific IgE (check results with clinical tests); provocation tests directed on the organ-target (nasal, bronchial or oral challenges) with the offending allergen. Recent tests, like cellulary tests, have shown the release of mediators in the presence of the allergen. The dosage of tryptase gives valuable information in cases of anaphylaxisis. Atopy-patch tests are efficient to detect delayed type of hypersensitivity. One of the important goal for consultations will be to confirm the allergic mechanism mediated by specific IgE. In a nutshell, the diagnosis of allergic diseases can be made based on the following: trigger identification, evidence of an IgE-mediated sensitivity and association of this sensitivity with symptoms, which can be identified with obvious clinical history or allergen testing. PMID- 17717944 TI - [Diagnosis of allergic rhinitis: from clues to evidence]. AB - The high prevalence of allergic rhinitis in westernized countries, and the impact of allergic rhinitis on asthma require a well established diagnosis. Clues of increasing value can be obtained by any practitioner, relying on information about familial and personal atopic background, a precise record of symptoms of nasal hyperreactivity rhinorrhea, sneezing and pruritus, and of the evaluation of symptoms over the year. A precise questionnaire may be completed by a biologic screening for atopy, in order to refer the patient to the allergist to add evidence of the etiology by skin tests, search for specific IgE, and nasal challenges for specific cases. PMID- 17717945 TI - [Drug allergies and drug hypersensitivities]. AB - Drug hypersensitivities (also known as drug intolerances), including allergic reactions, are one of the side effects of drugs. If urticaria and maculopapular eruptions are the most frequent manifestations, then clinical forms are heterogeneous. The tools allowing a definite diagnosis include a thorough clinical history, standardised skin tests and drug provocation tests. Biological tests are being evaluated. When properly performed in specialised centres, a firm diagnosis is often possible and safe alternative medication can be proposed. PMID- 17717946 TI - [Food allergy]. AB - The prevalence of food allergies increases in industrialized countries: 3% in general population, up to 6% of children. Food allergy has a genetic basis. The recent increase is thought to be due to a change in environmental factors, including changes in diet and reduced exposure to early childhood infection. Food allergies present with a wide spectrum of clinical manifestations, including anaphylaxis, urticaria, angioedema, atopic dermatitis, oral syndrome, asthma, rhinitis, gastrointestinal disorders. Diagnosis of food allergy is based on history, detailed dietary analysis, skin testing, measuring specific IgE, avoidance diet and challenge tests. The mainstay of diagnosis and management of food allergies is correct identification and avoidance of the offending antigen. Children often develop tolerance to cow's milk, egg, wheat by school age, whereas allergies to nuts, fish and seafood are generally not outgrown no matter at what age they develop. PMID- 17717947 TI - [Allergic disease treatments: classic and innovative therapeutics]. AB - The purpose of this article is to focus on anti-allergic therapies that directly target cellular or humoral actors of the allergic reaction and which are quasi exclusively dedicated to the treatment of allergic diseases. This leads to successively look at: anti-histamines, classic treatments but in constant improvement, allergen immunotherapy which is experiencing a second life with the validation of the sublingual route and monoclonal anti-IgE antibody, a real new therapeutic class which has demonstrated his efficacy in patients with severe non controlled allergic asthma. PMID- 17717948 TI - [Patient education handout. Removal of cow's milk proteins]. PMID- 17717949 TI - [Medical workforce under construction for 2008]. PMID- 17717950 TI - [National ranking exam. What could happen at the exam?]. PMID- 17717951 TI - [Hemograms: indications and interpretation]. PMID- 17717952 TI - [Request for hospitalisation by a third party]. PMID- 17717953 TI - [Oro-dental development and abnormalities]. PMID- 17717954 TI - [French Red-Cross ambulancies during Franco-Prussian war, July 19, 1870-January 28, 1871]. PMID- 17717955 TI - Glia: non-neural players in orofacial pain. PMID- 17717956 TI - Topical review-connective tissue diseases: orofacial manifestations including pain. AB - This topical review presents an overview of orofacial manifestations associated with the more common connective tissue diseases affecting multiple organs. The orofacial manifestations associated with these autoimmune disorders include oral mucosa alterations, salivary gland pathosis, sensory neuropathies, headaches, and temporomandibular disorders. Since many of these orofacial manifestations may be painful, the practitioner managing pain patients should be familiar with them. An understanding of the orofacial manifestations associated with these systemic diseases will enable the pain practitioner to establish an appropriate diagnosis within the context of the underlying systemic disease. This will allow the practitioner the opportunity to contribute and collaborate as a member of a multidisciplinary health-care team in the management of these systemic autoimmune diseases. PMID- 17717957 TI - Nonfunctional tooth contact in healthy controls and patients with myogenous facial pain. AB - AIMS: To investigate how often healthy controls and patients with myogenous masticatory pain have wake-time nonfunctional tooth contact, whether the frequency of nonfunctional tooth contact differs between genders or between weekdays and weekends, and whether it is influenced by stress levels. METHODS: The study was performed on 24 subjects: 15 controls and 9 patients with myogenous facial pain. Before data collection the subjects were trained to ascertain their ability to feel correctly whether their teeth were in contact or apart. Subsequently, for 10 days the subjects were alerted by means of a radio wave activated wrist vibrator approximately every 20 minutes (8:00 AM to 10:00 PM) in order to report whether the teeth were in contact. Subjects also completed 2 stress assessment questionnaires, the Perceived Stress Scale (PSS) and the short version of the Trier Inventory for Assessment of Chronic Stress (TICS-S). RESULTS: There was a significantly higher frequency of wake-time nonfunctional tooth contact in myogenous pain patients than in controls (median of 34.9% and range of 26.5% to 41.3% for patients; median of 8.9% and range of 2.3% to 14.3% for controls; P < .001). In both groups the frequency of nonfunctional tooth contact did not significantly differ among the various days or between the genders. The patients had significantly higher PSS scores and reported having experienced more stressful situations in the dimensions "social overload" and "overextended at work" than the controls. However, PSS and TICS-S scores were not correlated with the frequency of nonfunctional tooth contact for either group. CONCLUSIONS: Myogenous pain patients had nearly 4 times more nonfunctional tooth contact during wake time than controls. PMID- 17717958 TI - Self-care behaviors associated with myofascial temporomandibular disorder pain. AB - AIMS: To document the frequency of self-care in a clinical sample of patients with myofascial temporomandibular disorder (TMD) pain; report the perceived relief and control of pain for each of the self-care behaviors; and to test for associations between the frequency and efficacy of each self-care behavior and pain, depression and sleep quality, as assessed during a clinical visit, and to determine whether the frequency was associated with changes in pain intensity, depression, and sleep quality 30 days later. METHODS: The sample consisted of 99 female and 27 male myofascial TMD pain patients who were participants in a multidisciplinary facial pain evaluation program. The subjects participated in a structured interview during a clinical visit and a follow-up telephone interview 30 days later. The interviews included questions about self-care, including resting, relaxation techniques, massage, hot and/or cold packs, home remedies, stretching or exercise, herbal remedies, and the use of vitamins or nutritional supplements for pain. RESULTS: The passive self-care behaviors, such as resting when experiencing pain (66%) and relaxation techniques (62%), were the most commonly used. Patients reported that hot or cold packs (5.3, 0-to-10 scale) and massage (4.7) provided the greatest relief from pain, whereas resting (4.9), relaxation (4.8), and massage (4.8) resulted in the greatest ability to control pain. The most striking finding was that initial levels of pain or change in pain were not consistently associated with self-care use; however, psychosocial outcomes of depression and sleep quality were associated with self-care frequency and reported efficacy and improved in relation to patient-reported self-care frequency. CONCLUSION: Since people with chronic myofascial TMD pain engage in a range of pain self-care strategies, clinicians need to discuss self-care with patients regularly. PMID- 17717959 TI - Development and validation of classification criteria for idiopathic orofacial pain for use in population-based studies. AB - AIM: To develop and validate a questionnaire-based tool which would enable classification of idiopathic orofacial pain in the general population. METHODS: A postal questionnaire-based cross-sectional survey was made of 4200 randomly selected adults who were registered with a general medical practice in North West England. The questionnaire collected information on a number of factors: demographics (age, gender), orofacial pain (duration, descriptors, site, pattern, intensity, disability, and consultation behavior), and comorbidities (reporting of other unexplained symptoms and psychosocial factors). Subjects reporting orofacial pain were interviewed by an examiner blinded to their exposure status and classified into 1 of 3 categories: (a) dentoalveolar, (b) musculoligamentous/soft tissue, and (c) idiopathic orofacial pain. RESULTS: A high adjusted response rate of 72% was achieved (crude response rate 60%). Of those who reported orofacial pain and were eligible for interview (n=218), 197 (88%) were interviewed. Subjects classified by interview into the idiopathic category were more likely to report aching, nagging, and chronic pain pain at multiple sites. They were also more likely to report facial trauma and other chronic symptoms and to have consulted multiple health-care workers. Variables that most strongly predicted membership into the idiopathic category were female gender, nagging, aching pain which was worse when stressed, and topography (pain at multiple sites and unilateral pain). CONCLUSION: The classification criteria developed for idiopathic orofacial pain can be used as a screening tool for subjects with this condition in the general population. PMID- 17717960 TI - Effect of a peripheral NMDA receptor antagonist on glutamate-evoked masseter muscle pain and mechanical sensitization in women. AB - AIMS: To test the hypothesis that local injection of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine would significantly attenuate glutamate evoked masseter mechanical sensitization and muscle pain in healthy young women either taking oral contraceptives (W+OC) or not taking oral contraceptives (W OC). METHODS: Experimental pain was evoked in 47 healthy female subjects (W+OC, n=25; W-OC, n=22) by 2 injections of glutamate (0.2 mL, 1 mol/L) into the masseter muscle. A first injection of glutamate alone was followed by a second injection, 35 minutes later, of glutamate combined with ketamine (0, 1, or 10 mmol/L). Evoked pain intensity was scored on a 10-cm electronic visual analog scale (VAS). Distribution of perceived pain was drawn on a lateral view of the face (pain drawing). Masseter muscle pressure pain thresholds (PPT) and pressure pain tolerances (PPTOL) were determined bilaterally before and at regular time intervals after injections. Analyses of variance (ANOVA) were used to test the data. RESULTS: There were no main effects of ketamine on any of the VAS pain parameters or on the pain drawing (ANOVAs: P > .055). Furthermore, there were no differences in PPT, PPTOL, VAS peak pain, duration, overall VAS pain, or pain drawing when W-OC were compared with W+OC (ANOVAs: P > .087). Repeated injection of glutamate alone significantly decreased PPT and PPTOL (ANOVAs: P < .001); however, this effect was not significantly attenuated by ketamine. CONCLUSIONS: Peripherally administered ketamine had no effect on glutamate-evoked masseter muscle pain and sensitization in healthy young women, which contrasts with recent observations in healthy young men. Further studies will be needed to reveal the mechanisms that underlie this apparent sex-related difference in ketamine mediated analgesia. PMID- 17717961 TI - Phosphorylation of ERK in trigeminal spinal nucleus neurons following passive jaw movement in rats with chronic temporomandibular joint inflammation. AB - AIMS: To elucidate the neuronal mechanisms underlying chronic pain of the temporomandibular joint (TMJ), expression of phosphorylated extracellular signal regulated kinase (pERK) in the trigeminal spinal nucleus caudalis (Vc) was studied in rats with a chronically inflamed TMJ. METHODS: Complete Freund's adjuvant (CFA) was injected in the left TMJ region of rats anesthetized with pentobarbital (50 mg/kg intraperitoneally). Face temperature of the TMJ region was measured periodically after CFA injection. Two weeks after CFA injection, passive jaw movement with 4-, 6-, and 15-mm distances was carried out in inflamed and naive rats for 5, 15, and 30 minutes. pERK expression was studied in the medulla and upper cervical cord after passive jaw movement. RESULTS: Face temperature was significantly increased 2 days after CFA injection and returned to the preoperative level 7 days later. The pERK-like immunoreactive (LI) cells were observed in the dorsal portion of the rostral Vc in inflamed rats after passive jaw movement, and a small number of pERK-LI cells were observed in naive rats after passive jaw movement. No pERK-LI cells were observed in the TMJ of inflamed rats without jaw movement. The number of pERK-LI cells increased following increases in the jaw-movement distance and duration. CONCLUSION: These findings suggest that the dorsal portion of the rostral Vc may be involved in mediating chronic pain following TMJ inflammation and that the intracellular ERK cascade may be involved. PMID- 17717962 TI - Dietary loading and aggrecanase-1/TIMP-3 expression in rat mandibular condylar cartilage. AB - AIMS: To examine the expression of aggrecanase-1 and a tissue inhibitor of metalloproteinases (TIMP-3) in the condylar cartilage of young rats and to determine their relationship during altered dietary loading at different time points after weaning. METHODS: One hundred Sprague-Dawley rats were randomly assigned to 1 of 2 groups: the soft-diet group, which served as the control group (n=50), or the hard-diet group, which served as the experimental group (n=50). Ten soft- and 10 hard-diet rats were killed at 6 hours, 12 hours, 24 hours, 48 hours, and 9 days after weaning (i.e., after initiation of diet change for hard diet rats). The right-side temporomandibular joints (TMJs) were prepared for immunohistochemical staining. The cartilage from the left-side mandibular condyles of all 10 animals in each group was combined for Western blot analysis. RESULTS: Immunohistochemical analysis revealed strong staining for aggrecanase-1 localized mainly in the chondrocytes of proliferative and upper hypertrophic cartilage zones at all time points in both groups. The immunohistological expression of aggrecanase-1 was significantly higher in the hard-diet group at 12 and 24 hours than in the soft-diet group. Strong staining for TIMP-3 was mainly localized in the chondrocytes of proliferative and upper hypertrophic zones at all time points in both groups. The expression of TIMP-3 in the hard-diet group was at a significantly lower level compared to the soft-diet group at 6 hours. Western blot analysis also showed time-related differences in aggrecanase-1 and TIMP-3, but there was no significant difference between the 2 groups. CONCLUSION: The temporary change in aggrecanase-1 and TIMP-3 expression reflects the complex interaction of these enzymes in the physiologic range and cartilage response to altered dietary loading. PMID- 17717963 TI - The Canadian Regenerative Medicine and Nanomedicine Enterprise (CARMENE). PMID- 17717964 TI - Pegylated liposomal doxorubicin in ovarian cancer. AB - Pegylated liposomal doxorubicin is a formulation of doxorubicin in which the molecule itself is packaged in a liposome made of various lipids with an outer coating of polyethylene glycol. Liposomal technology is being used in increasing amounts in the therapy of a variety of cancers, including ovarian cancers. This article reviews the mechanistic actions of this formulation, the Phase II and Phase III data that helped define the role of pegylated liposomal doxorubicin in recurrent ovarian cancer, as well as a discussion of some of the side-effects and their management. PMID- 17717965 TI - Asparaginase (native ASNase or pegylated ASNase) in the treatment of acute lymphoblastic leukemia. AB - The discovery of the tumor-inhibitory properties of asparaginase (ASNase) began in the early 1950s with the observation that guinea pig serum-treated lymphoma bearing mice underwent rapid and often complete regression. About 4000 cases of acute lymphoblastic leukemia (ALL) are diagnosed very year in the US and many more through out the world. The majority of these cases are in children and young adults, making ALL the most common form of malignancy in these age groups. The treatment protocols of ALL are complex and use 6-12 drugs. Consequently, the improvement in the protocol design has improved significantly the success rate for long-term event-free survival in the past 20-30 years, which is now approximately 75% for patients afflicted with the higher risk ALL features and just above this percentage for patients with standard or good features. Despite this success, approximately 15% of patients die from ALL, making leukemic relapse the most common cause of treatment failure in pediatric oncology. ASNases have been the cornerstone of ALL therapies since the late 1970s. Native or pegylated L asparaginase (ASNase or PEG-ASNase) are highly specific for the deamination of L asparagine (Asn) to aspartic acid and ammonia. Depletion of Asn leads to a nutritional deprivation and inhibition of protein biosynthesis, resulting in apoptosis in T-lymphoblastic leukemias, which require Asn from external sources. The reactions of the host exposed to repeated ASNase treatments as well as the up regulation of the mammalian enzymes to overcome the ASN-depletion toxic condition are of significant importance and may make us relearn the lessons on this important antileukemic drug. PMID- 17717966 TI - Pegylated interferon alpha-2a (40 kDa) in the treatment of chronic hepatitis B. AB - Chronic hepatitis B virus (HBV) is a serious and life-threatening disease afflicting 350 million of the world's population. So far, current monotherapy with conventional interferon-alpha, lamivudine, and adefovir dipivoxil remains unsatisfactory. In addition, the use of conventional interferon-alpha needs to be administered subcutaneously daily or thrice weekly and is associated with frequent adverse events. Although nucleoside-nucleotide analogs such as lamivudine and adefovir dipivoxil are well tolerated and can normalize serum alanine aminotransaminase rapidly, 1-year therapy with either lamivudine or adefovir dipivoxil results in low hepatitis B e antigen (HBeAg) seroconversion rates. In HBeAg negative patients, most of the patients would relapse after lamivudine has been discontinued. Pegylated interferon alpha-2a, an immunomodulatory agent, is a new drug that has just completed phase III clinical trials for the treatment of both HBeAg positive and HBeAg negative chronic HBV infection. The advantage of pegylated interferon alpha-2a in achieving sustained virological response over nucleoside-nucleotide analogs is particularly obvious in the HBeAg negative group. In both of these phase III studies, sustained off treatment response is superior to the use of lamivudine. These recent data put pegylated interferon alpha-2a as the first choice of anti-HBV therapy, especially in young and motivated patients with chronic HBV infection. PMID- 17717967 TI - Pegaptanib in the treatment of wet, age-related macular degeneration. AB - Age-related macular degeneration (AMD) is a major cause of severe visual loss worldwide. Neovascular (wet) AMD accounts for 90% of the visual loss associated with the disorder and vascular endothelial growth factor (VEGF) has been shown to play a major role in neovascularization and vascular permeability, the major causes of visual loss in AMD, making it an ideal target for therapeutic intervention. To utilize this strategy, pegaptanib, an aptamer that specifically binds to and blocks VEGF165, the VEGF isoform primarily responsible for abnormal vascular growth and permeability in AMD, was developed. Following encouraging preclinical trials, clinical trials showed that pegaptanib stabilized vision and reduced the risk of severe visual loss in the majority of patients with AMD, with some patients showing visual improvement. Pegaptanib has maintained a good safety profile with only occasional adverse effects. Even greater success was achieved when pegaptanib was used in combination with another therapeutic strategy, such as photodynamic therapy or bevacizumab, a pan isoform VEGF inhibitor. Further investigation of pegaptanib for the therapy of wet AMD, particularly in combination with other modes of therapy, should be encouraged. PMID- 17717968 TI - Sirolimus therapy following early cyclosporine withdrawal in transplant patients: mechanisms of action and clinical results. AB - Cyclosporine (CsA), a member of the family of calcineurin inhibitors, is a cornerstone of the immunosuppressive treatments used after organ transplantation. However, it exhibits significant toxicity, including nephrotoxicity and increased cardiovascular risk factors. CsA withdrawal has been used as a strategy to improve renal allograft function and other CsA-related toxicities. In order to maintain adequate immunosuppression levels, sirolimus may be used in association with CsA withdrawal. Sirolimus is a member of the mammalian target of rapamycin (mTOR) family. It presents a good immunosuppressive efficacy associated with antiproliferative actions. Early withdrawal of CsA with sirolimus is associated with a significant improvement of renal function. Despite numerically a higher incidence of acute rejection episodes, this maneuver seems also to be associated with a better allograft survival in the long-term, and improvement of renal histology and blood pressure. However, CsA withdrawal is only feasible in a selected population. Furthermore, the use of sirolimus is associated with other side-effects including lipid abnormalities, abnormal liver tests, and thrombocytopenia. Other studies are mandatory to define the population who can benefit from this maneuver. Finally, complete CsA avoidance has been already reported and is currently under clinical investigation. PMID- 17717969 TI - Glatiramer in the treatment of multiple sclerosis. AB - Multiple sclerosis (MS) is a disease of the central nervous system with both an inflammatory and degenerative component. The disease primarily affects young adults and results in significant physical and cognitive disability. Several disease-modifying agents are currently used in the management of multiple sclerosis. Glatiramer acetate (GA, Copaxone, co-polymer 1) is a disease-modifying agent approved for the treatment of relapsing remitting multiple sclerosis. Apart from its unique mode of action, there is evidence pointing toward a possible neuroprotective role. This review will critically discuss GA's potential mechanisms of action, the results of clinical trials, safety profile, and future directions of treatment. PMID- 17717970 TI - Gadonanotubes as new high-performance MRI contrast agents. AB - Gadolinium-based carbon nanostructures are poised to make a significant impact as advanced contrast agents (CAs) for magnetic resonance imaging (MRI) in medicine. This paper reviews and forecasts gadonanotubes as synthons for the design of high performance MRI CA probes with efficacies up to 100 times greater than current clinical CAs. This level of performance is vital for achieving the goal of cellular and molecular imaging with MRI. These new materials will be useful for in vivo MRI applications as circulating drug nanocapsules because of their low toxicities, extremely high relaxivities, and potential for cellular targeting and induced cell death by magnetic hyperthermia. PMID- 17717971 TI - Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. AB - Among several promising new drug-delivery systems, liposomes represent an advanced technology to deliver active molecules to the site of action, and at present several formulations are in clinical use. Research on liposome technology has progressed from conventional vesicles ("first-generation liposomes") to "second-generation liposomes", in which long-circulating liposomes are obtained by modulating the lipid composition, size, and charge of the vesicle. Liposomes with modified surfaces have also been developed using several molecules, such as glycolipids or sialic acid. A significant step in the development of long circulating liposomes came with inclusion of the synthetic polymer poly-(ethylene glycol) (PEG) in liposome composition. The presence of PEG on the surface of the liposomal carrier has been shown to extend blood-circulation time while reducing mononuclear phagocyte system uptake (stealth liposomes). This technology has resulted in a large number of liposome formulations encapsulating active molecules, with high target efficiency and activity. Further, by synthetic modification of the terminal PEG molecule, stealth liposomes can be actively targeted with monoclonal antibodies or ligands. This review focuses on stealth technology and summarizes pre-clinical and clinical data relating to the principal liposome formulations; it also discusses emerging trends of this promising technology. PMID- 17717973 TI - Rapid assessment of early biophysical changes in K562 cells during apoptosis determined using dielectrophoresis. AB - Apoptosis, or programmed cell death, is a vital cellular process responsible for causing cells to self-terminate at the end of their useful life. Abrogation of this process is commonly linked to cancer, and rapid detection of apoptosis in vitro is vital to the discovery of new anti-cancer drugs. In this paper, we describe the application of the electrical phenomenon dielectrophoresis for detecting apoptosis at very early stages after drug induction, on the basis of changes in electrophysiological properties. Our studies have revealed that K562 (human myelogenous leukemia) cells show a persistent elevation in the cytoplasmic conductivity occurring as early as 30 minutes following exposure to staurosporine. This method therefore allows a far more rapid detection method than existing biochemical marker methods. PMID- 17717974 TI - Increased osteoblast adhesion on nanoparticulate crystalline hydroxyapatite functionalized with KRSR. AB - The present in vitro study created nanometer crystalline hydroxyapatite (HA) and amorphous calcium phosphate for novel orthopedic applications. Specifically, nano crystalline HA and amorphous calcium phosphate nanoparticles were synthesized by a wet chemical process followed by hydrothermal treatment for 2 hours at 200 degrees C and 70 degrees C, respectively. Resulting particles were then pressed into compacts. For the preparation of control conventional HA particles (or those currently used in orthopedics with micron diameters), the aforementioned calcium phosphate particles were pressed into compacts and sintered at 1100 degrees C for 2 hours. All calcium phosphate-based particles were fully characterized. Results showed that although there was an initial weight gain for all the compacts studied in this experiment, higher eventual degradation rates up to 3 weeks were observed for nano-amorphous calcium phosphate compared with nano-crystalline HA which was higher than conventional HA. Peptide functionalization (with the cell adhesive peptide lysine-arginine-serine-arginine [KRSR] and the non-cell-adhesive peptide lysine-serine-arginine-arginine [KSRR]) was accomplished by means of a three-step reaction procedure: silanization with 3-aminopropyltriethoxysilane (APTES), cross-linking with N-succinimidyl-3-maleimido propionate (SMP), and finally peptide immobilization. The peptide functionalization was fully characterized. Results demonstrated increased osteoblast (bone-forming cell) adhesion on non-functionalized and functionalized nano-crystalline HA compacts compared with nano amorphous calcium phosphate compacts; both increased osteoblast adhesion compared with conventional HA. To further exemplify the novel properties of nano crystalline HA, results also showed similar osteoblast adhesion between non-functionalized nano crystalline HA and KRSR functionalized conventional HA. Thus, results provided evidence that nanocrystalline HA should be further studied for orthopedic applications. PMID- 17717972 TI - Bone regeneration: molecular and cellular interactions with calcium phosphate ceramics. AB - Calcium phosphate bioceramics are widely used in orthopedic and dental applications and porous scaffolds made of them are serious candidates in the field of bone tissue engineering. They have superior properties for the stimulation of bone formation and bone bonding, both related to the specific interactions of their surface with the extracellular fluids and cells, ie, ionic exchanges, superficial molecular rearrangement and cellular activity. PMID- 17717975 TI - Nano-hydroxyapatite-thermally denatured small intestine sub-mucosa composites for entheses applications. AB - The objective of the present in vitro study was to estimate the adhesion strength of nanometer crystalline hydroxyapatite (HA)-small intestine sub-mucosa (SIS) composites on model implant surfaces. Techniques of thermal denaturation (60 degrees C, 20 min) of SIS were used to enhance the adhesion strength of entheses materials to underlying implants. Specifically, results indicated that the adhesion strength of thermally denatured SIS was 2-3 times higher than that for normal unheated SIS. In addition, aqua-sonicated, hydrothermally treated nano-HA dispersions enhanced the adhesion strength of SIS on implant surfaces. Importantly, results of the present study demonstrated that human skeletal muscle cell (hSkMC) numbers were not affected by thermally denaturing SIS in nano-HA composite coatings; however, they increased on aqua-sonicated nano-HA/SIS composites compared with SIS alone. Interestingly, thermally denatured SIS that contained aqua-sonicated, hydrothermally treated nano-HA decreased human osteoblasts (hOBs) numbers compared with respective unheated composites; all other composites when thermally denatured did not influence hOB numbers. Results also showed that the number of hOBs increased on nano-HA/SIS composites compared with SIS composites alone. Human mesenchymal stem cell (hMSC) numbers were not affected by the presence of nano-HA in SIS composites. For these reasons, the collective results of this in vitro study demonstrated a technique to increase the coating strength of entheses coatings on implant surfaces (using thermally denatured SIS and aqua-sonicated, hydrothermally prepared nano-HA) while, at the same time, supporting cell functions important for entheses regeneration. PMID- 17717976 TI - Control of spatial cell attachment on carbon nanofiber patterns on polycarbonate urethane. AB - A highly aligned pattern of carbon nanofibers (CNF) on polycarbonate urethane (PCU) for tissue engineering applications was created by placing a CNF-ethanol solution in 30 microm width copper grid grooves on top of PCU. In vitro results provided the first evidence that fibroblasts and vascular smooth muscle cells selectively adhered to the PCU regions. However, endothelial cells did not display a preference for adhesion to the CNF compared with PCU regions. Previous studies have shown selective adhesion of osteoblasts (bone-forming cells) on CNF compared with PCU regions. Thus, the present results suggest that CNF aligned on PCU may be useful substrates for the control of spatial cell attachment, criteria useful for the design of a wide range of tissue engineering materials, from orthopedic to vascular. PMID- 17717977 TI - Overview of temporary ponds in the Mediterranean region: threats, management and conservation issues. AB - Mediterranean temporary ponds (MTPs) comprise an endangered habitat with several endemic species that can be found in many countries, mainly in the Mediterranean region but are disappearing at a high rate. For designing optimal conservation and management strategies for the particular ecosystems, appropriate characterization and classification of these ponds is necessary based on the different type of habitats and on their varying environmental conditions. This paper presents the current ecological status and the threats of Mediterranean temporary ponds and summarizes some management and conservation issues based on the existing experience on a regional level. Emphasis is given in the Greek MTPs with respect to their characteristics and the pressures received mainly from human activities such as agriculture and water overexploitation. Restoration practices should be commenced immediately aiming at the reestablishment of the ponds' hydroperiod and water quality at the natural levels. PMID- 17717978 TI - Screening of wheat varieties and associated bacterial population in old alluvial soil of Burdwan, West Bengal. AB - In order to screen out the best variety of wheat (Triticum aestivum) out of eight varieties (viz., HP 1633, BW 11, NW 1014, Sonalika, HUW 468, K 9107, HP 1731 and HUW 234), a field experiment was conducted (from Dec. 2002 to April 2003) in a randomized block design replicated thrice at Crop Research and Seed Multiplication Farm, Burdwan University, West Bengal, India. Various morpho physiological parameters viz., plant population, length of shoot and root, leaf area index (LAI), crop growth rate (CGR), leaf area ratio (LAR), leaf area duration (LAD), net assimilation rate (NAR), yield attributes viz., length of panicles, number of grains per panicle, grain yield, straw yield, pigment content in flag leaf (chlorophyll a, b and total chlorophyll and carotenoid content) were estimated and analyzed statistically Soil bacterial populations were also estimated in the fallow land before sowing of seeds and after harvesting of crop. The HUW 468 variety records higher grain yield, maximum panicle length and maximum chlorophyll b and total chlorophyll content. PMID- 17717979 TI - Antagonistic potential of fluorescent pseudomonads and control of charcoal rot of chickpea caused by Macrophomina phaseolina. AB - The effectiveness of plant growth promoting rhizobacteria especially Pseudomonas fluorescens isolates were tested against charcoal rot of chickpea both in green house as well as in field conditions. Most of the isolates reduced charcoal rot disease and promoted plant growth in green house. A marked increase in shoot and root length was observed in P. fluorescens treated plants. Among all the P. fluorescens isolates Pf4-99, was found most effective in the improvement of chickpea crop in green house as well as in field. Pf4-99 effectively promoted plant growth and produced indole acetic acid in culture medium. This isolate also inhibited the mycelial growth of the M. phaseolina under in vitro conditions and reduced the disease severity Potential isolate (Pf4-99) also significantly increased the biomass of the chickpea plants, shoot length, root length and protein content of the chickpea seeds. A part from these, the total number of seeds per plant and their weight were also enhanced. The colonization of Pf4-99 reduced the incidence of seed mycoflora by which indirectly enhanced the seed germination and vigour index of seedlings. The observations revealed that isolate Pf4-99 is quite effective to reduce the charcoal rot disease both in field and greenhouse, and also increases seed yields significantly Therefore, this isolate appears to be an efficient biocontrol agent against charcoal rot disease as well as yield increasing rhizobacterium. PMID- 17717980 TI - Post natal antioxidant enzyme activity of rat brain regions during developmental lead exposure. AB - This study reports the effects of low level developmental Pb exposure on specific brain regions like hippocampus, cerebellum and cerebral hemispheres of antioxidant enzyme activities. Wistar dams were exposed to 50 ppm, 100 ppm and 500 ppm of Pb acetate in drinking water during pregnancy and lactation (gestation day 6 through PND 21 (post natal day) and activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) were determined in the hippocampus, cerebellum and cerebral hemispheres of pups during treatment period (PND 7, 14, and 21 days) and also during withdrawl period (PND 35, 45, 60 and 90 days). During treatment period, SOD activity significantly (p < 0.05) decreased in all regions of all the treated groups with maximum decrease in 500 ppm treated group of 21 days, while GSH-Px and GR activities increased with maximum increase in 21 days aged 500 ppm group. During withdrawl period, the activities of all enzymes were significantly (p < 0.05) reversed. Thus the perinatal exposure of dams to variable dosages of low level lead results in characteristic neurochemical alterations in rat brain regions due to impaired antioxidants function. PMID- 17717981 TI - Nutrient characteristics and sediment texture of the seagrass beds of the Gulf of Mannar. AB - Changes in nutrient concentrations and sediment texture of the seagrass beds were recorded for two years from July 1996 to June 1998 at monthly intervals at two stations (Station 1--Manoli island; Station 2--Chinnapalam) of the Gulf of Mannar Marine Biosphere Reserve. Different nutrients in water showed varied concentrations in different seasons. Phosphate concentration varied between 2.32 and 7.32 microM, nitrate concentration ranged from 5.2 to 18.78 microM and nitrite concentration from 1.92 to 732 microM. Sand was a major component of the sediments, followed by silt and clay at both the stations. At station 1, sand composition varied between 85.9 and 95.3% while at station 2, it varied between 81.9 and 93.6%. Silt composition varied between 3.1 and 9.4% at station land at station 2, it varied between 4.0 and 12.4%. At station 1, clay composition varied from 1.6 to 4.6% and at station 2, it varied between 2.1 and 5.6%. The present study revealed that the nutrients and sediment characteristics of the seagrass beds of the Gulf of Mannar has clear spatial and temporal variations. They are largely interlinked and influenced by the human activities and climatic changes and are individually or jointly governing the distribution, diversity, biomass and productivity of the seagrasses of the Gulf of Mannar. PMID- 17717982 TI - Histopathological changes in liver of Heteropneustes fossilis exposed to cypermethrin. AB - Cypermethrin was administered to Heteropneustes fossilis in chronic concentration to determine lesion of liver as indicators of tissue damage. The cypermethrin dose used was 1/4 of 96 hr LC50. Histopathological changes in liver ranged from vacuolization, necrosis, fibrosis of perivascular region and disposition of yellow brown grains at different time of exposure viz; 20th, 30th, 40th and 60th days. PMID- 17717983 TI - Influence of five organic antifouling candidates on spore attachment and germination of a fouling alga Ulva pertusa. AB - Screening of test chemicals or formulations for antifouling (AF) activity is important to get first hand information on their nontoxic repelling activities. Especially spores of a fouling alga, Ulva pertusa were used in this study to test the AF efficiency of five organic chemicals. Coatings made with 100 microg cm2 of citral and eugenol significantly inhibited the spore attachment. A low concentration (1 microg cm2) of solanesol exhibited effective AF activity against spore attachment. Spore germination was sensitive to different AF candidates screened in this study. Based on the attachment and germination response of Ulva pertusa spores, AF efficiency of five organic AF candidates is discussed. PMID- 17717984 TI - Effects of ammonia, nitrite and nitrate on hemoglobin content and oxygen consumption of freshwater fish, Cyprinus carpio (Linnaeus). AB - Lethal effects of nitrogenous compounds ammonia, nitrite and nitrate on freshwater fish Cyprinus carpio were studied and the static LC50 values obtained for these 3 toxicants for 24 hr were 0.80 ppb, 171.36 ppm; 1075.10 ppm and continuous flowthrough LC50 values for 24 hr were 0.72 ppb, 154.31 ppm; 967.63 ppm respectively. The fish were exposed to lethal concentrations to study the changes in hematological parameters and the rate of oxygen consumption. During the period of exposure general decline in the content of hemoglobin was observed. Methemoglobin content increased in case of nitrite exposure consequently the hemoglobin levels decreased drastically. It is also observed that rate of oxygen consumption decreased progressively with the increase of toxicant concentration and duration of the exposure. PMID- 17717985 TI - Heavy metal accumulation in lichens growing in north side of Lucknow city, India. AB - Accumulation of Pb, Fe, Cr, Zn, Cd, Ni, Cu and Hg metals in six common lichen species growing on Mangifera indica trees in mango orchard surrounding the north side of the Lucknow city, were analyzed. The study revealed the higher concentration of Pb (3.3 - 15.6 microgg(-1)), Cr (25.6 - 137.5 microgg(-1)), Zn (49.4 - 219.7 microgg(-1)), Cu (10.2 - 66.6 microgg(-1)) and Fe (1748 - 19374 microgg(-1)). PMID- 17717986 TI - Distribution and abundance of zooplankton in relation to petroleum hydrocarbon content along the coast of Kollam (Quilon), south west coast of India. AB - In the present study we examine status, impact and trends in prevailing situation of coastal ecosystem of Chavara, Neendakara, Tangasseri and Paravur zones of Kollam coast in terms of zooplankton density and petroleum hydrocarbon content (PHC). Zooplankton samples and water samples were collected during the period May 2003 to June 2004. The numerical count of zooplankton made and PHC content estimated. Paravur offshore recorded the maximum zooplankton count (1390 no./m3) and Tangasseri nearshore the lowest (700.5 no/m3). The petroleum hydrocarbon content was highest at Tangasseri nearshore (21.95 microg/l) and lowest at Paravur offshore (9.40 microg/l). We also observe statistically significant negative correlation between zooplankton density and PHC for a few organisms. The overall impact appears minor, yet, coastal ocean monitoring imperative for sustainable development. PMID- 17717988 TI - Estimation of stream temperature in firtina creek (Rize-Turkiye) using artificial neural network model. AB - Water temperature is one of the most important environmental variables in aquatic ecosystem. Temperature changes may have positive or negative effects on organisms. High water temperatures have caused mortalities in salmonid fishes. Therefore, monitoring and prediction of potential adverse changes in water temperature is very important. Here, we have developed and tested an artificial neural network (ANN) model to predict stream temperature of Firtina Creekin Black Sea region; using local water temperature, dissolved oxygen, pH and other available meteorological data (air temperature, rainfall). Thus, enabling define suitable habitat for native Sea Trout (Salmo trutta labrax, Pallas 1811) under past drought or other adverse envIronmental conditions. PMID- 17717987 TI - Phytotoxicity of volatile oil from Eucalyptus citriodora against some weedy species. AB - A study was undertaken to explore the phytotoxicity of volatile essential oil from Eucalyptus citriodora Hook. against some weeds viz. Bidens pilosa, Amaranthus viridis, Rumex nepalensis, and Leucaena leucocephala in order to assess its herbicidal activity. Dose-response studies conducted under laboratory conditions revealed that eucalypt oils (in concentration ranging from 0.0012 to 0.06%) greatly suppress the germination and seedling height of test weeds. At 0.06% eucalypt oil concentration, none of the seed of test weeds germinated. Among the weed species tested, A. viridis was found to be the most sensitive and its germination was completed inhibited even at 0.03%. Not only the germination and seedling growth, even the chlorophyll content and respiratory activity in leaves of emerged seedlings were severely affected. In A. viridis chlorophyll content and respiratory activity were reduced by over 51% and 71%, respectively, even at a very low concentration of 0.06%. These results indicated an adverse effect of eucalypt oils on the photosynthetic and energy metabolism of the test weeds. A strong negative correlation was observed between the observed effect and the concentration of eucalypt oil. Based on the study, it can be concluded that oil from E. citriodora possess strong inhibitory potential against weeds that could be exploited for weed management. PMID- 17717989 TI - A dendroecological study on Pinus nigra Arn. at different altitudes of northern slopes of Kazdaglari, Turkey. AB - This study was carried out to investigate the relationship between tree ring widths of Pinus nigra in Kazdaglari having humid and very humid climatic conditions. Sixty two trees were cut from 24 sampled points from different altitudes in Kazdaglari to measure treering widths. To determine the responses to the climate, correlation coefficients between treering widths and climatic data were calculated during biological years from October of the previous year to September of the current year In lower altitudes, where climate type is humid, spring and summer precipitation affect the growth of tree rings, but they are not statistically limiting factors. In higher altitudes, this effect is weaker. As a result, we can conclude that the negative effects of the drought are still not clear on the Pinus nigra trees under humid and very humid climatic conditions and at the northern slopes in submediterranean mountainous regions in Turkey. PMID- 17717990 TI - Sequential anaerobic and aerobic treatment of pulp and paper mill effluent in pilot scale bioreactor. AB - In the present study sequential anaerobic and aerobic treatment in two step bioreactor was performed for removal of colour in the pulp and paper mill effluent. In anaerobic treatment, colour 50%, lignin 62%, COD 29%, absordable organic halides (AOX) 25% and phenol 29% were reduced in eight days. The anaerobically treated effluent was separately applied in bioreactor in presence of fungal strain, Paecilomyces sp., and bacterial strain, Microbrevis luteum. Data of study indicated reduction in colour 80%, AOX 74%, lignin 81%, COD 93% and phenol 76 per cent by Paecilomyces sp. where as Microbrevis luteum showed removal in colour 59%, lignin 71%, COD 86%, AOX 84% and phenol 88% by day third when 7 days anaerobically treated effluent was further treated by aerobic microorganisms. Change in pH of the effluent and increase in biomass of microorganism's substantiated results of the study, which was concomitant to the treatment method. PMID- 17717991 TI - Genetic diversity in some perennial plant species with-in short distances. AB - Distinct morphophysiological variations observed for over 2 years with-in short distances among four perennial plants indicated genetic diversity among the lines growing at three places. The isozyme and SDS polyacrylamide gel banding patterns as genetic markers were used to investigate four perennial species, namely Dalbergia sissoo Roxb., Delonix regia (Boj.) Refin., Cassia fistula L. and Calotropis procera R. Br. Plant materials collected from three locations (Agra, Gwalior and Lucknow) differing in climo-edaphic variables were examined for 4 enzyme systems, viz., esterase, polyphenol oxidase, peroxidase and superoxide dismutase (EST, PPO, PRX and SOD). Among the four isozymes SOD and PRX revealed best discriminating power. Protein banding patterns as well as zymogram revealed that Dalbergia sissoo growing at Gwalior was closer to that of Agra; Delonix regia depicted highest similarity between Lucknow and Agra and Calotropis procera of Lucknow location was more closer to Gwalior than Agra. The results confirm genetic diversity in the species as a means of adaptation to differing climo edaphic variables. PMID- 17717992 TI - Diversity of microflora in the gut and casts of tropical composting earthworms reared on different substrates. AB - The diversity of fungi, bacteria, yeast, actinomycetes and protozoa were analysed in the gut and casts of Eudrilus eugeniae, Lampito mauritii, Eisenia fetida and Perionyx excavatus, both qualitatively and quantitatively as influenced by different feed substrates like clay loam soil, cowdung and pressmud. While actinomycetes (Streptomyces albus, S. somaliensis, Nocardia asteroides, N. caviae and Saccharomonosporia) were not digested by any of these species of worms, protozoa (Amoeba proteus, A. terricola, Paramecium trichium, Euglena viridis, E. orientalis, Vorticella picta and Trichomonas hominis) and yeast (Candida tropicalis, C. krusei C. albicans and Cryptococcus neoformans) were totally digested. Certain species of fungi (Saksenae vasiformis, Mucor plumbeus, Cladosporium carrionii, C. herbacium, Alternaria sp., Cunninghamella echinulata, Mycetia sterila, Syncephalostrum racemosum, Curvalaria lunata, C. geniculata and Geotrichum candidum) and bacteria (Pseudomonas aeruginosa, Bacterium antitratum, Mima polymorpha, Enterobacter aerogenes, E. cloacae, Proteus vulgaris, P. mirabilis, P. rettgeri, Escherichia coli, Staphylococus citreus, Bacillus subtilis, B. cereus, Enterococci and Micrococci) were completely digested. Certain other species were not digested fungi like Aspergillus fumigatus, A. flavus, A. ochraceous, Trichoderma koningii (except by Eeugeniae), Fusarium moniliforme (except by E. eugeniae) and Rhizopus sp., and bacteria like Klebsiella pneumoniae and Morganella morganii) and these were multiplied during the transit of the organic residues through the gut of worms. The microbial proliferation was more in the casts, due to the environment prevailing--rich in nutrient supply and large surface area available for growth and reproduction of the microbes that lead to enhanced microbial activity and humic acid contents in the casts. PMID- 17717993 TI - Effects of different pretreatments on germination of Prunus serotina seed sources. AB - Establishing intensive plantations of fast growing hardwood tree species that have high market values in the forest industry can narrow the gap between Turkey's demand and the supply of quality hardwood products. Black cherry (P. serotina Ehrh.) is a fast growing hardwood species with a high market value. Introducing and intensively growing black cherry (BC) in Turkey may significantly reduce the country's quality wood shortage. Adequate seed germination constitutes the first essential step for successful establishments. In this paper effects of different pretreatments, including artificial and natural stratification, on the seeds of different BC seed sources (SSs) were studied. Pretreatments had substantial effects on the dormancy breaking and germination behaviours of the SSs. Consecutive periods of complex warm and cold artificial stratification regimes longer than 90 days or natural stratification (where seeds were assumed to be naturally exposed to this complexity) resulted in best dormancy breaking and, in turn, germination among all pretreatments. Deeper dormancy and reduced germination rates of some BC seeds as the altitude of the source increases might suggest an ecological adaptive strategy of the species. BC may have deeper morphophysiological dormancy than is commonly believed. Seed size may have a positive effect on seed germination. PMID- 17717994 TI - A comparative study on the physicochemical and bacterial analysis of drinking, borewell and sewage water in the three different places of Sivakasi. AB - The drinking, borewell and sewage water in the Sanmugasikamani Nadar (S.N) street, Naivatti Nadar (N.N) street and Thiruthangal area of Sivakasi has been studied. The various constituents monitored include the physicochemical characters like pH, total solids, total dissolved solids, total suspended solids; chemical parameters like total alkalinity acidity free CO2, dissolved oxygen, total hardness, calcium, magnesium, chloride, salinity and bacterial parameters like standard plate count (SPC), total coliform count (TCC), faecal coliform count (FCC), faecal streptococcal count (FSC). Most of the physicochemical characters of drinking and borewell water were within the ISI permissible level. However in water samples from all the sites, bacterial count exceeded the recommended permissible level of WHO. Introduction of sewage into the drinking and borewell water was the main reason for the bacterial contamination. The boiling of water is therefore advisable before consumption. The physicochemical and bacterial characters of the sewage water were unworthy. The sewage water recycling was necessary to minimize the water born diseases. PMID- 17717995 TI - Effect of heavy metals (Hg and Zn) on the growth and phosphate solubilising activity in halophilic phosphobacteria isolated from Manakudi mangrove. AB - The diversity of phosphobacteria in Manakudi mangrove ecosystem of Tamil Nadu was carried out in root and rhizosphere soil samples. The counts of phosphobacteria were found higher in root samples than in soil samples particularly in Hymenachene acutigluma. The abundance of phosphobacterial diversity in Manakudi mangrove showed high degree of positive correlation with the content of phosphate in rhizosphere soil of all the mangrove and associated plant species. Nine phosphobacterial species belonging to 7 genera were reported from Manakudi mangrove ecosystem. All the identified bacterial species are sensitive to both the heavy metals (mercury and zinc) in terms of growth and physiology even at lower concentrations. The content of protein and total sugars were increased by the higher concentrations of heavy metals whereas decreased trend was noticed in lower concentrations of heavy metals. PMID- 17717996 TI - Modulating effect of Phyllanthus fruit extract against lead genotoxicity in germ cells of mice. AB - The objective of the present study was to evaluate the protective effect of Phyllanthus emblica against clastogenicity induced by lead nitrate on the incidence of sperm head abnormalities in the germ cells of mice. At higher concentration of lead, a significant increase in the percentage of sperm head abnormalities was noted but when animals primed with Phyllanthus fruit extract (PFE), a reduction in the frequency of sperm head abnormalities was observed. It can be suggested from the above study that Phyllanthus emblica plays a key role in inhibition of heavy metal mutagenesis in mammals. PMID- 17717997 TI - Toxicity of neem pesticides on a fresh water loach, Lepidocephalichthys guntea (Hamilton Buchanan) of Darjeeling district in West Bengal. AB - Static renewal bioassay tests were conducted to evaluate the acute toxicity of two neem based biopesticides, applied widely on tea plantation namely, Nimbecidine and Neem Gold either separately as well as, in combination to the fingerlings (mean body length- 4.46 +/- 0.15 cm; mean body weight- 0.49 +/- 0.15g) of a fresh water loach, Lepidocephalichthys guntea (Hamilton Buchanan) acclimatized to laboratory conditions prior to experiment. The 96 hours LC50 values for Nimbecidine and Neem Gold and the combination of the two were 0.0135 mgl(-1), 0.0525mgl(-1) and 0.0396 mgl(-1), respectively. The regular water quality analysis showed, that with increasing doses of biopesticides, dissolved oxygen level was lower and other parameters like pH, free carbon dioxide, total alkalinity total hardness, chloride ions of water increased. The fish under toxicity stress suffered several abnormalities such as erratic and rapid movement, body imbalance and surface floating responding proportionately to the increase in concentrations of the toxicant biopesticides. The 96 hours LC50 values proved Nimbecidine more toxic than Neem Gold and the combination of the two biopesticides. PMID- 17717998 TI - Mutagenicity assessment of textile dyes from Sanganer (Rajasthan). AB - Sanganer town, district Jaipur (Rajasthan, India) is famous worldwide for its hand block dyeing and textile printing industries. These industries use a variety of chemicals and dyes during processing and finishing of raw materials. Most of the textile dyes used by these industries have not been evaluated for their impact on health and the environment. The workers in these industries are exposed to such dyes with no control over the length and frequency of exposure. Further, untreated and sometimes even treated effluents from these industries are released into surface waters of Amani Shah drainage or through the drainage systems, seep into the ground water and adjoining water bodies. Since many textile dyes are known carcinogens and mutagens, a complete evaluation of the safety of these dyes in the human environment must include an evaluation of their genotoxicity or mutagenicity. A total of 12 textile dyes from Sanganer were tested for their mutagenicity, by Ames Salmonella reversion assay using strain TA 100 of Salmonella typhimurium. Only 1 dye, Red 12 B showed absence of mutagenic activity. The remaining 11 dyes were all positively mutagenic. PMID- 17717999 TI - Biochemical parameters of plants as indicators of air pollution. AB - In the present study species like Mangifera indica, Linn., Cassia fistula, Linn., and Eucalyptus hybrid were exposed to different air pollution load for short duration (active biomonitoring). Variation in biochemical parameters like chlorophyll, protein, soluble sugar free amino acid, ascorbic acid, nitrate reductase, superoxide dismutase and peroxidase in the leaves were found to be pollution load dependent. These variations can be used as indicators of air pollution for early diagnosis of stress or as a marker for physiological damage to trees prior to the onset of visible injury symptoms. Just by analyzing these biochemical indicators air quality can also be assessed. PMID- 17718000 TI - Seed germination of three provenances of Pinus brutia (Ten.) as influenced by stratification, temperature and water stress. AB - Seeds from three provenances of Pinus brutia were stratified for 0 or 45 d (days) at 4 +/- 1 degrees C and then germinated at 15 degrees C or 20 degrees C on filter paper saturated with polyethylene glycol solutions to provide water potentials of 0, -0.2 and -0.4 MPa (mega Pascal). Regardless of stratification, germination was lower at 15 degrees C than 20 degrees C for seeds of all provenances. Stratification significantly increased germination percentage at all water potentials regardless of the germination temperatures. Lowering the water potential to -0.4 MPa reduced germination for all three provenances in unstratified and stratified seeds when averaged for two temperatures, but reaction to the increased water stress was different among the provenances. Combined over two temperatures, stratified or unstratified seeds from the highest elevation (Cehennemdere) had the lowest germination performance at all water potentials, and stratified and nonstratified seeds from a coastal elevation (Silifke) had the highest germination parameters at the lowest water potential ( 0.4 MPa). It might be concluded that seed germination and resistance to water stress vary according to provenance and stratification. PMID- 17718001 TI - Tissue cholesterol and serum cortisol level during different reproductive phases of the female freshwater fish Notopterus notopterus (Pallas). AB - In the present study tissue cholesterol and serum cortisol changes during two reproductive phases have been correlated in the freshwater fish Notopterus notopterus. The reproductive cycle of N. notopterus has two phases such as breeding phase (April - August) and non breading phase (October - December). The cholesterol content of the ovary and liver increased during breeding phase. The serum cortisol estimated by radio immuno assay (RIA) technique indicates that the level of the hormone was high during breeding phase compared to non breading phase. The increase in cholesterol during breeding phase may be because of increase in cortisol synthesis needed for ovarian growth and vitellogenesis. The gonadosomatic index (GSI) also increases during breeding phase. PMID- 17718002 TI - Oxygen uptake in relation to group size in the juveniles of a climbing perch, Anabas testudineus (Bloch). AB - The present work reports oxygen uptake in relation to group size in the juveniles (body weight: 0.70 to 1.30 g) of a climbing perch, Anabas testudineus (Bloch). The experiments were conducted at 21.5 +/- 1.0 degrees C using a cylindrical glass respirometer having continuous water flow system. With an increase in the number of fish at an interval of 5 from 5 to 40 in each fourth subsequent experiment, the weight specific aquatic oxygen uptake of a fish decreased from 0.192 +/- 0.030 to 0.800 +/- 0.006 ml O2 x g(-1)x(h(-1). When compared with a controlled fish, there was a reduction of 27.80% in the oxygen uptake in a group of 5 but 58.39% in a group of 40. A negative and significant correlation (r = 0.8411, p < 0.01) was calculated between oxygen uptake and group size of fishes. The investigation showed that probably due to shoaling behaviour, the aquatic oxygen uptake in the juveniles of A. testudineus always remained high in controlled fish or a fish in isolation than when they were in a group. PMID- 17718003 TI - Antimicrobial activity of methanol extract of Origanum majorana L. (Sweet marjoram). AB - In-vitro microbicidal activity of the methanol extract of Origanum majorana L. was tested against seven fungi (Fusarium solani, Candida albicans, Aspergillus niger, A. parasiticus, Rhizopus oryzae, Rhizoctonia otyzae-sativae and Altemaria brassicicola) and six bacteria (Bacillus subtilis, B. megaterium, Escherichia coil, Proteus vulgaris, Pseudomonas aeruginosa and Staphylococcus aureus). The methanol extract of O. majorana can be used as an effective herbal protectant against different pathogenic bacteria and fungi. High toxicity against the growth of Aspergillus niger was diagnosed. PMID- 17718004 TI - Changes of hematological parameters in Prochilodus lineatus (Pisces, Prochilodontidae) exposed to sublethal concentration of cypermethrin. AB - Freshwater fish Prochilodus lineatus were exposed to sublethal concentrations of cypermethrin (0.3 and 0.6 microg/l) for 2, 5 and 8 days. It was observed that with the increase of exposure time total erythrocyte (RBC), hemoglobin (Hb), hematocrit (Ht) and mean corpuscular hemoglobin concentration (MCHC) values decreased but mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) values increased. These reports indicate that hematological parameters, may be useful as a diagnostic test for cypermethrin exposure in aquatic organisms. PMID- 17718005 TI - Microbial pathogens of public health significance in waste dumps and common sites. AB - Microbial pathogens of public health significance found in waste and common sites were collected from four different dumping sites and assessed for pathogenic agents. The modified methods employed were based on the classical methods and basic principles of the reactions followed by biochemical enzymatic standards described for gram negative non fermenting bacteria. The results have shown presence of bacterial species including Pseudomonas, Mirococcus, Actinomyces, Neisseria, Bacillus and Klebsiella. These pathogens can infect wounds and cause sepsis and mortality and can even occur with such organisms to cause secondary infection. These groups of organisms are almost impossible to control since they are ubitiquous. Public health may be ensured from pathogenic agents at waste sites by prompt removal of waste and proper management (mechanical sorting and excavating) methods. PMID- 17718006 TI - Limnological investigations of Texi Temple pond in district Etawah (U.P.). AB - Present investigations were carried out on the limnological aspects of Texi temple pond in district Etawah. Many of the parameters were found below the permissible limits for drinking water as suggested by WHO. A total of 18 parameters were analysed and their seasonal variations in the year 2003 were discussed. PMID- 17718007 TI - Nutritional status in postconflict Afghanistan: evidence from the National Surveillance System Pilot and National Risk and Vulnerability Assessment. AB - BACKGROUND: Two large-scale studies, the National Surveillance System (NSS) Pilot Study (2003-2004) and the National Risk and Vulnerability Assessment (NRVA) 2003, were conducted by government, United Nations, and nongovernmental organizations in Afghanistan, as part of wider efforts characterizing Afghan livelihoods in relation to particular outcomes of interest: vulnerability to poverty, food insecurity, and malnutrition. OBJECTIVE: To present the data from these two surveys with nutrition as the key outcome of interest, and to further construct the understanding of the underlying causes of malnutrition, thus providing public health practitioners and other sector specialists with insight into how a variety of sectoral programs can impact nutritional outcomes in Afghanistan. METHODS: The NSS gathered information on livelihoods, food security, and nutrition from 20 to 40 randomly selected households in each of 26 purposively selected sentinel sites (representative of livelihood zones) during November-December 2003 and May-June 2004. The NRVA gathered information nationally from households selected with a two-stage sampling (based on livelihood zone and then socioeconomic group) during July-September 2004. RESULTS: Acute malnutrition is below emergency levels for children under five. The level of chronic malnutrition in children under five indicates a problem of public health importance. Dietary diversity in Afghanistan is not as low as expected but still shows room for improvement, particularly in remote areas and with respect to food groups associated with adequate micronutrient intake. The findings also suggest that in addition to lack of adequate household food intake, recurrent illness and suboptimal infant and young child feeding and hygiene practices contribute to poor nutritional outcomes in this age group. The survey also found poor access to health care, markets, and water for household use. CONCLUSIONS: Improving nutritional status requires a multipronged approach, directly targeting malnutrition, coupled with economic growth, household livelihood security, social protection, access to public health services, and water and sanitation. Nutrition policy, programming, and monitoring need to reflect the immediate and underlying causes of malnutrition. Future research needs to be designed to quantify the relative contribution of underlying causes of poor nutrition, allowing practitioners to prioritize responses aimed at improving nutritional outcomes. PMID- 17718008 TI - Effect of household processing on the in vitro bioavailability of iron in mungbean (Vigna radiata). AB - BACKGROUND: Mungbean (Vigna radiata) is a major source of energy and protein in developing countries, especially for the vegetarian population. Improvement of the bioavailability of iron in mungbean by common household processes could make a significant contribution to the nutrition of people in countries where iron deficiency anemia is widespread. OBJECTIVE: The study was conducted to determine the effect of common household processes on nutritional and antinutritional factors as well as in vitro bioavailability of iron in mungbean. METHODS: Mungbean was subjected to various domestic processes such as dehulling, pressure cooking, germination, and fermentation. The effects of these processes on proximate composition, antinutritional factors (phytin phosphorus, polyphenols, and neutral detergent), and iron, including ionizable iron, were determined. RESULTS: No significant change in crude protein content was observed. There was a significant (p < or = .05) increase in fiber content after germination. Ash content decreased significantly (p < or = .05) after all processing methods. The processing methods resulted in a significant (p < or = .05) reduction in phytin phosphorus and polyphenols. Pressure cooking significantly (p < or = .05) decreased the neutral detergent fiber, whereas fermentation and germination increased it. The phytate:iron molar ratio of processed mungbean revealed that the maximum reduction was in germinated and fermented samples. Ascorbic acid content increased significantly (p < or = .05) after germination. The in vitro bioavailability of iron in raw mungbean was 7.32%. All of the processing methods resulted in an increase in iron bioavailability in vitro; the maximum bioavailability was in germinated cooked mungbean (12.52%), followed by fermented cooked mungbean and germinated raw mungbean (both 11.04%). CONCLUSIONS: Suitable processing techniques can improve the in vitro bioavailability of iron from mungbean. If mungbean products with enhanced iron bioavailabilty are developed, they could help improve the iron status of the population. PMID- 17718009 TI - Improvement of the nutritional quality of a traditional complementary porridge made of fermented yellow maize (Zea mays): effect of maize-legume combinations and traditional processing methods. AB - BACKGROUND: Blends with a cereal-legume ratio of 70:30 have been introduced in many communities for use in the preparation of complementary foods with augmented protein quality. These foods should meet World Health Organization estimated energy and nutrient needs from complementary foods. OBJECTIVE: To increase energy and nutrient densities and nutrient availability in a traditional complementary porridge. METHODS: Yellow maize was processed by lactic acid fermentation. Peanuts (Arachis hypogea) and beans (Phaseolus vulgaris) were processed by germination, roasting, dehulling, and a combination of germination and roasting. Blends were prepared from processed peanuts and beans and cooked into porridges with viscosities less than 3,000 cp. Traditional porridge was the control and consisted of fermented yellow maize only. The porridges were analyzed for their physicochemical and nutritional properties. RESULTS: Blends increased energy and nutrient densities in porridges compared with the control (p < .05). The maize peanuts combination yielded porridges with higher energy densities and improved nutritional quality compared with the maize-beans combinations. In vitro availability of iron did not change (p > .05) with formulation of the blends except for porridges made from maize and germinated peanuts, but there was a significant increase in zinc in vitro availability, whereas a decrease was observed for calcium in vitro availability. The energy densities of maize-peanuts porridges were sufficient to cover energy required from complementary foods for infants aged 6 to 11 months receiving four meals of complementary foods per day and an average amount of energy from breastmilk. CONCLUSIONS: Maize-legume blends can efficiently improve the nutritional quality of traditional porridge. Peanuts are the best legume complements. PMID- 17718010 TI - Acceptability and safety of novel infant porridges containing lyophilized meat powder and iron-fortified wheat flour. AB - BACKGROUND: Lyophilized meat powder with iron-fortified wheat flour can be used to produce an infant porridge with bioavailable iron, but its acceptability and safety are unknown. OBJECTIVE: To evaluate the acceptability and safety of porridges containing lyophilized meat powder and iron-fortified wheat flour. METHODS: Peruvian mothers' input was used to develop porridges without (no meat) and with meat powder (low or high chicken liver, low or high chicken thigh). Acceptability was determined by maternal hedonic scoring, 9-day infant intake, and videotape analysis of how well infants liked each porridge. Dry and cooked porridges and meat ingredients were tested for microorganisms; meats were tested for pesticides. RESULTS: Mothers gave higher acceptability scores to the no-meat porridge, followed in order by low and high quantities of meat powder (e.g., mean +/- SD "taste"scores were 4.5 +/- 0.9 for the no-meat, 3.7 +/- 1.1 for the low liver, and 3.3 +/- 1.1 for the high-liver porridges, p = .0001). Infants' porridge intake did not differ: 61.4 +/- 47.1 g of no-meat, 62.1 +/- 44.9 g of low-thigh, and 67.5 +/- 42.0 g of low-liver (p = .7), as supported by the video analysis. Microbiologic safety was acceptable except for marginally acceptable molds and yeasts in dry ingredients. No pesticide residues were detected. CONCLUSIONS: Despite mothers' clear preference for no-meat porridges, infants consumed equal amounts of porridges with and without meat. Thus, if mothers can be convinced to feed the meat-containing porridges to the infants despite their own preferences, the infants will consume these porridges. The mold and yeast content of the porridge ingredients must be reduced. PMID- 17718011 TI - Effect of iodine status and other nutritional factors on psychomotor and cognitive performance of Filipino schoolchildren. AB - BACKGROUND: Until 1998, iodine deficiency was a public health problem in the Philippines. A law entitled "An Act Promoting Salt Iodization Nationwide" (ASIN) has been passed and implemented by the government to eliminate iodine deficiency. The contribution of salt iodization, as well as dietary, health, and environmental factors, to improving the intellectual performance of Filipino schoolchildren remains to be determined. OBJECTIVE: The objectives of the study were to determine the relationship between iodine status and levels of psychomotor and cognitive performance in first-grade children aged 6 to 10 years, and to examine the extent to which dietary, biochemical, health, and environmental factors contribute to children's mental performance. METHODS: Two hundred ninety children in six classroom sections from a public school in Manila were examined by measurement of urinary iodine excretion (UIE) and thyroid palpation. The median UIE level for each section was determined. Sixty-five children classified as iodine deficient (UIE < 90 microg/L with grade 1 goiter, n = 34) and non-iodine deficient (UIE > 100 microg/L without goiter, n = 31) were given psychomotor and cognitive function tests (Bender-Gestalt and Raven's Colored Progressive Matrices). Scores from the two tests were used to determine each child's general ability percentile rank. Other variables examined were dietary intake (% RDA of nutrients ingested based on two nonconsecutive 24-hour recalls); deficiencies in iron, vitamin A, and selenium; parasitic infection; coliform contamination of drinking water; household use of iodized salt; illness in the past 2 weeks; and wasting and stunting. RESULTS: Children whose general ability scores were at or above the 50th percentile had higher UIE levels, but the relationship was not significant. Children from sections with higher median UIE levels had higher percentile ranks for general ability (p = .002). Backward logistic regression showed that the variance in deficient and adequate mental performance was explained by dietary intakes that met > or = 80% of the RDA for energy, protein, thiamin, and riboflavin; the use of iodized salt; child's iodine status; and stunting (R2 = .520, p = .0016). Higher class median UIE was associated with better psychomotor and cognitive performance in children who were tested. Factors that contributed to better performance include higher intakes of energy, protein, thiamin, and riboflavin; household use of iodized salt; normal iodine status; and absence of stunting or chronic malnutrition. CONCLUSIONS: Salt iodization, accompanied by adequate intakes of energy, protein, and foods rich in thiamin and riboflavin, can contribute to improved mental performance in Filipino schoolchildren. Longer-term factors that can contribute to improved performance are achievement of normal iodine status and elimination of protein-energy malnutrition. PMID- 17718012 TI - Sensitivity and specificity of a short questionnaire for food insecurity surveillance in Iran. AB - BACKGROUND: Food insecurity is frequent in both developed and developing countries, affecting from 5% to 25% of the general population. It has considerable health impacts on the physical, social, and psychological status of individuals in communities suffering from food insecurity. OBJECTIVE: The aim of this study was to document the epidemiologic features of food insecurity in the northwest region of Iran and to evaluate the sensitivity and specificity of a short-form (six items) questionnaire for screening of food insecurity in the region. METHODS: This cross-sectional study was conducted on 300 subjects (132 male and 168 female) selected randomly in the Asadabadi area of the northwest of Iran. Information on food consumption was obtained by a 24-hour food-recall questionnaire for 3 days in a week. This information was compared with the data from the Household Food Security Scale (six-item short questionnaire) to assess the applicability of this short scale for the surveillance of food insecurity. Hunger was defined as inadequate intake of energy. Hidden hunger was defined as adequate intake of energy and inadequate intake of one (or more) of four key nutrients (protein, calcium, vitamin A, and vitamin B2). RESULTS: The prevalence of hunger and hidden hunger in the area according to the 24-hour food-recall questionnaire was 26% and 42%, respectively. Only 32% of the study population was secure in terms of having access to all key nutrients. The sensitivity, specificity, and accuracy of the short questionnaire for screening for hunger in the population were 98.7%, 85.5%, and 89%, respectively; and the corresponding values for hidden hunger were 23.5%, 96.9%, and 56.3%. CONCLUSIONS: Our findings indicate that food insecurity is prevalent in the northwest of Iran. The short questionnaire (six items) may be used as a simple, low-cost, rapid, and useful tool for the screening of food insecurity and energy intake in similar areas. PMID- 17718013 TI - Economic inequality and undernutrition in women: multilevel analysis of individual, household, and community levels in Cambodia. AB - BACKGROUND: Many people in developing countries are still struggling to emerge from the realm of extreme poverty, where economic improvements tend to benefit a small, affluent group of the population and cause growing inequality in health and nutrition that affects the most vulnerable groups of the population, including women and children. OBJECTIVE: To examine how household and community economic inequality affects nutritional status in women using information on 6,922 nonpregnant women aged 15 to 49 years included in the 2000 Cambodia Demographic and Health Survey. METHODS: Nutritional status is defined with the use of the body-mass index (BMI). BMI less than 18.5 kg/m2 is defined as undernourishment. The household wealth index was calculated from household ownership of durable assets and household characteristics. Community wealth is an average household wealth index at the community level. Household and community economic inequalities were measured by dividing the wealth index into quintiles. The effects of household and community economic inequality were estimated by multilevel analysis. RESULTS: Independently of community economic status and other risk factors, women in the poorest 20% of households are more likely to be undernourished than women in the richest 20% of households (RR = 1.63; p = .008). The results also show variation among communities in the nutritional status of women. Age, occupation, and access to safe sources of drinking water are significantly associated with women's nutritional status. CONCLUSIONS: Improving household income and creating employment opportunities for women, in particular poor women, may be a key to improving the nutritional status of women in Cambodia. PMID- 17718014 TI - Maternal income-generating activities, child care, and child nutrition in Mali. AB - BACKGROUND: Women in sub-Saharan Africa play a key role in household food security. The income-generating activities of mothers are postulated to be related to the nutritional status of children. OBJECTIVE: The objective of the study was to examine whether maternal income-generating activities, maternal food production, and child care were determinants of the nutritional status of children in rural West Africa. The study hypotheses were that maternal income generating activities and maternal food production are positively associated with children's dietary intake and anthropometry, and that maternal income-generating activities are not associated with child care. METHODS: Data were collected from a cross-sectional sample of mother-child pairs on maternal time use, child anthropometry, maternal food production, dietary intake, parasitic infection, and household, maternal, and child determinants of child nutritional status. The children were 12 to 36 months of age and included breastfed and nonbreastfed children. Food intake was assessed by the 24-hour recall method. The data were analyzed by multivariate regression and controlled for confounding variables. RESULTS: Time spent by the mother in income-generating activities was negatively associated with children's animal protein intake and height-for-age (p < .05). Maternal cash crop production was positively associated with children's weight for-height, whereas maternal staple food production was negatively associated with energy intake from non-breastmilk foods (p < .05). The negative relationships observed for children's animal protein intake and children's height for-age were not mediated by any child-care variable. Maternal supervision of feeding was a positive predictor of children's animal protein intake. Giardia infection was negatively related to children's weight gain (p < .05). CONCLUSIONS: Own-account cash crop farming by mothers benefits children's nutrition. Maternal income-generating activities in the context of extended families, sibling caretaking, and prolonged breastfeeding do not adversely affect child care. PMID- 17718015 TI - Risk factors for moderate to severe anemia among children in Benin and Mali: insights from a multilevel analysis. AB - BACKGROUND: Anemia currently affects 2 billion people throughout the world. Although the immediate causes of anemia among children are known (including malnutrition and infections), the importance of contextual determinants and their relationships with individual effects have rarely been explored. OBJECTIVE: To identify anemia risk factors at the individual, household, and community levels among Beninese and Malian children, using simple and multilevel regression methods. METHODS: An analysis was undertaken of nationally representative data collected in 2001 in Benin (n = 2,284) and Mali (n = 2,826) by the Demographic and Health Surveys. Sixteen potential risk factors for anemia were considered at the individual, household, and community levels. Comparative analyses were carried out using simple and multilevel logistic regression models. RESULTS: Simple and multilevel logistic regression analyses yielded broadly similar results. Risk factors for moderate to severe anemia included incomplete immunization, stunted growth, recent infection, absence of bednet, low household living standard, rural residency (Mali), low maternal education, and low community development index (Benin). In addition, multilevel analysis indicated a clustering level of anemia in communities (intraclass correlation) of 14% and 19% in Benin and Mali, respectively. CONCLUSIONS: Risk factors for child anemia appeared at all three levels (individual, household and community). Community level clustering seemed to be low. Therefore, interventions to address anemia need not be village- or region-specific. Identifying a successful and replicable program is now a priority in child survival endeavors. It is likely that such a program would include a focus on improving immunization coverage, increased bednet usage, and reduced protein-energy malnutrition. PMID- 17718016 TI - Breastfeeding and mixed feeding practices in Malawi: timing, reasons, decision makers, and child health consequences. AB - BACKGROUND: In order to effectively promote exclusive breastfeeding, it is important to first understand who makes child-care and child-feeding decisions, and why those decisions are made; as in most parts of the world, exclusive breastfeeding until 6 months of age is uncommon in Malawi. OBJECTIVE: To characterize early infant foods in rural northern Malawi, who the decision-makers are, their motivation, and the consequences for child growth, in order to design a more effective program for improved child health and nutrition. METHODS: In a rural area of northern Malawi, 160 caregivers of children 6 to 48 months of age were asked to recall the child's age at introduction of 19 common early infant foods, who decided to introduce the food, and why. The heights and weights of the 160 children were measured. RESULTS: Sixty-five percent of the children were given food in their first month, and only 4% of the children were exclusively breastfed for 6 months. Mzuwula and dawale (two herbal infusions), water, and porridge were common early foods. Grandmothers introduced mzuwula to protect the children from illness; other foods were usually introduced by mothers or grandmothers in response to perceived hunger. The early introduction of porridge and dawale, but not mzuwula, was associated with worse anthropometric status. Mzuwula, which is not associated with poor growth, is usually made with boiled water and given in small amounts. Conversely, porridge, which is associated with poor child growth, is potentially contaminated and is served in larger amounts, which would displace breastmilk. CONCLUSIONS: Promoters of exclusive breastfeeding should target their messages to appropriate decision makers and consider targeting foods that are most harmful to child growth. PMID- 17718018 TI - Stability of iodine in salt fortified with iodine and iron. AB - BACKGROUND: Determining the stability of iodine in fortified salt can be difficult under certain conditions. Current methods are sometimes unreliable in the presence of iron. OBJECTIVE: To test the new method to more accurately estimate iodine content in double-fortified salt (DFS) fortified with iodine and iron by using orthophosphoric acid instead of sulfuric acid in the titration procedure. METHODS: A double-blind, placebo-controlled study was carried out on DFS and iodized salt produced by the dry-mixing method. DFS and iodized salt were packed and sealed in color-coded, 0.5-kg, low-density polyethylene pouches, and 25 of these pouches were further packed and sealed in color-coded, double-lined, high-density polyethylene bags and transported by road in closed, light-protected containers to the International Council for the Control of Iodine Deficiency Disorders (ICCIDD), Delhi; the National Institute of Nutrition (NIN), Hyderabad; and the Orissa Unit of the National Nutrition Monitoring Bureau (NNMB), Bhubaneswar. The iodine content of DFS and iodized salt stored under normal room conditions in these places was measured by the modified method every month on the same prescribed dates during the first 6 months and also after 15 months. The iodine content of DFS and iodized salt stored under simulated household conditions was also measured in the first 3 months. RESULTS: After the color code was broken at the end of the study, it was found that the DFS and iodized salt stored at Bhubaneswar, Delhi, and Hyderabad retained more or less the same initial iodine content (30-40 ppm) during the first 6 months, and the stability was not affected after 15 months. The proportion of salt samples having more than 30 ppm iodine was 100% in DFS and iodized salt throughout the study period. Daily opening and closing of salt pouches under simulated household conditions did not result in any iodine loss. CONCLUSIONS: The DFS and iodized salt prepared by the dry-mixing method and stored at normal room conditions had excellent iodine stability for more than 1 year. PMID- 17718017 TI - A multicenter community study on the efficacy of double-fortified salt. AB - BACKGROUND: Iron and iodine deficiencies affect more than 30% of the world's population. Typical Indian diets contain adequate amounts of iron, but the bioavailability is poor. This serious limiting factor is caused by low intake of meat products rich in heme iron and intake of phytates in staple foods in the Indian diet, which inhibits iron absorption. OBJECTIVE: To test the stability of double-fortified salt (DFS) during storage and to assess its efficacy in improving the iron and iodine status of the communities. METHODS: The stability of both iodized salt and DFS during storage for a 2-year period was determined. The bioefficacy of DFS was assessed in communities covering three states of the country for a period of 1 year. This was a multicenter, single-blind trial covering seven clusters. The experimental group used DFS and the control group used iodized salt. The salts were used in all meals prepared for family members, but determination of hemoglobin by the cyanmethemoglobin method was performed in only two or three members per family, and not in children under 10 years of age (n = 393 and 436 in the experimental and control groups, respectively). The family size was usually four or five, with a male: female ratio of 1:1, consisting of two parents with two or three children. Hemoglobin was measured at baseline, 6 months (midpoint), and 12 months (endpoint). Urinary iodine was measured in only one cluster at baseline and endpoint. All the participants were dewormed at baseline, 6 months, and 12 months. RESULTS: The iron and iodine in the DFS were stable during storage for 2 years. Over a period of 1 year, there was an increase of 1.98 g/dL of hemoglobin in the experimental group and 0.77 g/dL of hemoglobin in the control group; the latter increase may have been due to deworming. The median urinary iodine changed from 200 microg/dL at baseline to 205 microg/dL at the end of the study in the experimental group and from 225 microg/dL to 220 microg/dL in the control group. There was a statistically significant (p < .05) improvement in the median urinary iodine status of subjects who were iodine deficient (urinary iodine < 100 microg/L) in both the experimental and the control groups, a result showing that DFS was as efficient as iodized salt in increasing urinary iodine from a deficient to sufficient status. There was a statistically significant increase (p < .05) in hemoglobin in all seven clusters in the experimental group compared with the control. CONCLUSIONS: The iron and iodine in the DFS are stable in storage for 2 years. The DFS has proved beneficial in the delivery of bioavailable iron and iodine. PMID- 17718026 TI - [The rechargeable insulin injector, a beautiful evolution]. PMID- 17718027 TI - [From asphalt to hiking, diabetic shoes]. PMID- 17718028 TI - [Management of hemochromatosis]. PMID- 17718029 TI - [Hemochromatosis, a public health problem]. PMID- 17718030 TI - [Hereditary hemochromatosis]. PMID- 17718031 TI - [Genetic investigations and the care of the patient]. PMID- 17718032 TI - [Treatment of hemochromatosis and its complications]. PMID- 17718033 TI - [The symbolism of blood in history]. PMID- 17718034 TI - [Bloodletting across the ages]. PMID- 17718035 TI - [Bloodletting in the hospital, a special time]. PMID- 17718036 TI - [The nurse and bloodletting at home]. PMID- 17718037 TI - [The experience of a patient with hemochromatosis]. PMID- 17718038 TI - [Hope is a risk to take]. PMID- 17718039 TI - [Strangeness of the body, crossed views on chronic diseases]. PMID- 17718040 TI - [Controlling hemochromatosis, the course of hepcidine]. PMID- 17718041 TI - [Management of hemochromatosis]. PMID- 17718042 TI - [Handwashing]. PMID- 17718043 TI - [The suffocation victim]. PMID- 17718044 TI - [The anti-calcineurins (cyclosporin and tacrolimus)]. PMID- 17718045 TI - [Fondaparinux--evolution or revolution in anticoagulant care?]. PMID- 17718046 TI - [Pulmonary embolism: a difficult diagnostic problem]. AB - INTRODUCTION: The mortality of untreated pulmonary embolism (PE) is estimated at approximately 30% of patients, whereas treatment decreases it to 2-8%. A specific combination of symptoms present in PE may suggest other cardiac or lung disorder. OBJECTIVES: To evaluate frequencies of clinical symptoms and changes in diagnostic investigations misleading to the recognition of acute coronary syndrome (ACS) or lung diseases (Ld) in PE patients. PATIENTS AND METHODS: Retrospective analysis of 154 records of individuals with recognized PE allowed to divide patients into groups suggestive of ACS (min. 2 of: chest pain, ischemic changes on electrocardiogram (ECG) and elevated cardiac troponin T level [cTnT >0.01 ng/ml]) or suggestive of the Ld (min. 2 of: dyspnea, cough, fever, lung consolidations on chest radiograph). RESULTS: Fifty-five (36%) patients were classified to the ACS group and 54 (35%) to Ld group, while 69 (45%) patients were not included to either group. Twenty-four (16%) patients fulfilled criteria of both groups. There were no significant differences in the frequency of coronary heart disease, heart failure, atrial fibrillation and chronic obstructive pulmonary disease between groups. Elevated troponin level was observed in 68% of patients with chest pain and changes on ECG, and in 26% of patients without coexistence of these symptoms (p < 0.05). CONCLUSIONS: In most patients with final diagnosis of PE, symptoms and initial investigation results can mislead to the diagnosis of ACS or lung disease. The chest pain and ischemic changes on ECG are frequently associated with the myocardial injury resulting in increased troponin levels in PE patients. PMID- 17718048 TI - [Antibodies to N-homocysteinylated albumin in patients with systemic lupus erythematosus]. AB - INTRODUCTION: Hyperhomocysteinemia is known to predispose to atherosclerosis and occurs more commonly in patients with systemic lupus erythematosus (SLE) than in the general population. It has been shown that elevated plasma total homocysteine (tHcy) results in protein N-homocysteinylation and production o autoantibodies against N-homocysteinylated (N-Hcy) proteins. OBJECTIVES: The aim of the study was to investigate whether anti-N-Hcy-albumin antibodies occur in patients with SLE and identify factors that determine these antibodies in such population. Patients and methods. In 50 subjects with SLE and 50 age- and sex-matched healthy controls, we determined serum IgG antibodies to N-Hcy-albumin using an in-house enzyme linked immunosorbent assay. RESULTS: Patients had higher plasma tHcy and C reactive protein (CRP) than controls, while serum folate and witamin B12 were lower in patients. Levels of anti-N-Hcy-albumin were higher in patients with SLE than in controls (medians: 0.31; vs. 0.19; p < 0.0001). In SLE patients, levels of anti- N-Hcy-albumin antibodies correlated with tHcy (r = 0.83; p <0.0001), CRP (r = 0.33; p = 0.02) and the duration of the disease (r = 0.3; p = 0.04). Seropositivity to anti-N-Hcy-albumin antibodies was more frequent in SLE patients than in controls (50% vs. 10%; p < 0.001). In SLE patients tHcy and CRP concentrations, along with the duration of the disease were independent predictors of anti-N-Hcy-albumin antibodies level. There were no associations between a type or levels of antinuclear antibodies patent's, or age with anti-N Hcy-albumin antibodies. CONCLUSIONS: Compared with healthy controls, in SLE patients levels of anti-N-Hcy-albumin antibodies are significantly higher and are largely determined by tHcy, CRP and the disease duration. This novel autoimmune response might contribute to increased risk of vascular events in SLE patients. PMID- 17718047 TI - [Influence of birthweight and current body mass on cardiovascular risk factors in young adults]. AB - INTRODUCTION: Results of other studies indicate at increased predisposition of metabolic diseases in the adulthood in subjects born with low birthweight. OBJECTIVES: To estimate the prevalence of cardiovascular risk factors in adults in relation to birthweight and current body mass. Patients and methods. The study was performed in 498 subjects aged 24-29 years, born in Warsaw in 1974-1977, whose mothers during pregnancy participated in a prospective study of risk factors of low birthweight. Basic anthropometric and blood pressure measurements were performed; total cholesterol, triglycerides, glucose, insulin, fibrinogen and glycosylated hemoglobin were determined in the blood. RESULTS: (1) In males body mass index (BMI) and indices of abdominal fat distribution (WHR, waist circumference) correlated positively with the insulin resistance index, blood insulin level, glycated hemoglobin, glucose, triglycerides, total cholesterol, LDL-cholesterol, fibrinogen and also blood pressure, and negativelely with HDL cholesterol. In females BMI, WHR and waist circumference correlated significantly only with the insulin resistance index, and blood levels of insulin, triglycerides, LDL-cholesterol, HDL-cholesterol and fibrinogen. (2) In males birthweight correlated negatively only with the insulin resistance index and serum insulin level. In females such correlations were not observed. (3) Logistic regression analysis revealed that obesity, particularly abdominal, was a stronger predictor of increased insulin resistance than birthweight. CONCLUSIONS: In young males abdominal obesity is a much stronger determinant of coronary risk factors than birthweight. PMID- 17718049 TI - [Evaluation of left ventricular function in patients with chronic obstructive pulmonary disease]. AB - INTRODUCTION: Patients with right ventricle (RV) pressure overload often have impaired left ventricular (LV) diastolic function. Objectives. The aim of study was to evaluate LV function in patients with chronic obstructive pulmonary disease (COPD). Patients and methods. Thirty-five patients (mean age: 62.1 +/- 7.7 y) with COPD without additional cardiac diseases and 25 age--and sex-matched healthy subjects were enrolled into the study. All patients underwent resting ECG tracing, blood pressure, spirometry, standard and tissue Doppler echocardiography. RESULTS: The mean value of forced expiratory volume in one second (FEV1) in the COPD group was 40 +/- 8.9% of the predicted value. We found no significant differences in LV end-diastolic and systolic diameter and interventricular septum as well between COPD patients and controls. RV end diastolic diameter and RV wall thickness were significantly larger and right ventricle systolic pressure--RVSP (38 +/- 11.2 vs. 20 +/- 2.5 mm Hg) significantly higher in the COPD group. Both peak early to peak atrial filling velocities ratio--E/A and peak annular velocity during early diastole to peak annular velocity during atrial contraction--Em/Am were significantly lower in COPD compared to controls. Moreover, there was a strong inverse correlation between Em/Am and RVSP (r = -0.75; p < 0.001) and between E/A (r = -0.6; p < 0.001) as well. We found no significant differences in parameters assessing the LV systolic function between both groups. CONCLUSIONS: In COPD patients LV diastolic function is significantly impaired and its magnitude is related with increase in pulmonary artery pressure, while systolic LV function is well preserved. PMID- 17718050 TI - [A contemporary role of coronary artery calcium scoring in the assessment of the risk for coronary artery disease]. AB - The growing prevalence of coronary artery disease, also in younger population, inspires constant development of coronary atherogenesis risk stratification and early diagnosis methods. The coronary artery calcium score is a simple parameter, requiring only a relatively small radiation dose to obtain in computed tomography. So far completed studies have provided consistent evidence in support of its specificity to exclude coronary artery disease, along with its predictive value for future cardiac events. Our paper is a review of peerviewed journals regarding in coronary artery calcium scoring, including the most recent guidelines on its use in establishing a diagnosis of coronary artery disease. PMID- 17718051 TI - [Modern nephrology--new methods, new treatments and still numerous difficult challenges]. AB - In the current decade, 2001 to 2010, the number of patients undergoing renal replacement therapy worldwide will increase from 1.5 to 2.5 mln. This requires considerable financial input, thus limiting treatment access in 90% to the inhabitants of North America, Europe and Japan, that constitutes less than 20% of the world's population. It is presumed that about 1 mln people die every year, a death rate which could be avoidable, were the proper funds for renal replacement therapy obtained. Over the last five years, Poland has joined the elite group of countries fully covering the needs in this respect. Modern nephrology gradually focuses on reducing the incidence of end-stage renal disease, through more effective treatment of diabetes, glomerulonephritis and polycystic kidney disease. Reducing morbidity and mortality rates in dialysis treatment and post kidney transplant follow-up is another key issue. This overview discusses the modern options and perspectives to face those challenges. PMID- 17718052 TI - [The role of matrix metalloproteinases in the development of vascular complications of diabetes mellitus--clinical implications]. AB - Cardiovascular complications are the leading cause of increasing and premature mortality in diabetic patients. Matrix metalloproteinases (MMPs) play an important role in the development and progression of vascular lesions. Matrix metalloproteinases are members of endopeptidases and are capable of degrading many extracellular matrix components. Results of recent studies indicated that non-pharmacological and pharmacological treatment of diabetes influenced disturbed system of metalloproteinases and their inhibitors. Clinical trials are being performed in hope that the selective MMP inhibitors reduce the progression of pathological vascular remodeling in diabetes. Further basic and clinical research is required to confirm hypothesis. PMID- 17718053 TI - [Diagnostic difficulties discussed in the case of the patient exposed to dust of silica with systemic lupus erythematosus and lung cancer]. AB - On the basis at the observed case we decided to describe the diagnostic problems in the patient with systemic lupus erythematosus (SLE) and after a few years of observation the severe development of lung cancer with liver metastasis, preceded by long-term exposure to dust of silica. The relations between SLE, lung cancer and exposure to silica were described in the discussion. PMID- 17718054 TI - [Whipple's triad as a clinical manifestation of hepatolenticular degeneration]. AB - Hepatolenticular degeneration (Wilson's disease) is a rare condition characterised by a defect in biliary excretion of copper resulting in excessive copper accumulation and toxicity. To the most frequent symptoms of this disorder belong liver, neurological or psychiatric disturbances, although other less common clinical features may sometimes be present. Since the clinical presentation of the disease is highly heterogeneous, it may mimic the symptoms of many various disorders. Diagnosis of the condition depends primarily on clinical features, biochemical parameters and the presence of the Kayser-Fleischer ring. Early detection and treatment protect patients from devastating organ damage. We describe an atypical case of Wilson's disease in a 23-year-old woman, whose clinical presentation suggested the presence of an insulin-secreting tumour. After the diagnosis was established and zinc sulphate treatment implemented, her clinical status improved remarkably. The presented case suggests that hepatolenticular degeneration should be taken into consideration in a differential diagnosis of hypoglycaemia of an unknown origin. PMID- 17718055 TI - [Professor Jozef Waclaw Grott and his methods of pancreas palpation]. AB - Professor Jozef Waclaw Grott (1894-1973), an outstanding Polish internist developed three methods of pancreas palpation (1935, 1947, 1948) that were of much diagnostic value in the twentieth century. PMID- 17718056 TI - [Multicenter-evaluation of optimal cell density to determine antimicrobial susceptibility for Haemophilus influenzae by the automated RAISUS system when the early-harvested bacterial cells were used]. AB - The fully automated microbial system, RAISUS (Nissui Pharmaceutical, Tokyo, Japan) can provide antimicrobial susceptibility test results for the isolates of Haemophilus influenzae. It is known that viable cell concentrations (colony forming unit/ml) of H. influenzae significantly vary depending on the incubation period. For the rapid reporting of antimicrobial susceptibility test results, we evaluated optimal cell density when we prepared the cell suspension using the early-harvested (6 hour incubation) cells for RAISUS. A total of 180 clinical isolates, comprising of 33 ampicillin-susceptible isolates, 114 beta-lactamase negative but ampicillin-resistant isolates and 33 beta-lactamase positive and amoxicillin/clavulanic acid susceptible or -resistant isolates, were included. All the isolates were genetically defined according to the detection of TEM gene and specific mutation (s) in fts I gene. The isolates were incubated on chocolate agar plates for 6 hours, and then the cell suspensions were prepared and adjusted to 0.5, 0.25 and 0.125 McFarland standards through serially dilutions. The respective cell suspensions were tested by the RAISUS AST panels. The % agreements between RAISUS and Clinical and Laboratory Standards Institute standard microdilutions in ampicillin category interpretations were 66.7%(McFarland 0.5), 77.8% (McFarland 0.25) and 83.9%(McFarland 0.125). When the McFarland 0.125 cell suspensions were inoculated, the majority of discrep ant interpretations were minor errors (15.0%) and the occurrence of major error was 3.4%. There was no very major error throughout the study. Essential agreement in MIC determinations (with or within +/- 1 doubling dilution) for 11 beta-lactam antimicrobial agents tested improved to 95.2% by McFarland 0.125 when compared to 77.4% by McFarland 0.5. It was also demonstrated that the viable cell concentrations prepared from 6 hour incubation cultures were 2.5 to 6.5 times higher than those from 22 hour-incubations. With these results, it can be concluded that the early harvested cell suspension of H. influenzae is applicable to RAISUS antimicrobial susceptibility test with lower cell density (McFarland 0.125). With this adjustment, the antimicrobial susceptibility test for H. influenzae will be completed by RAISUS within 26 hours after primary isolation. PMID- 17718057 TI - [Clinical evaluation of a novel HBsAg quantitative assay]. AB - The clinical implication of the hepatitis B surface antigen (HBsAg) concentrations in HBV-infected individuals remains unclear. The aim of this study was to evaluate a novel fully automated Chemiluminescence Enzyme Immunoassay (Sysmex HBsAg quantitative assay) by comparative measurements of the reference serum samples versus two independent commercial assays (Lumipulse f or Architect HBsAg QT). Furthermore, clinical usefulness was assessed for monitoring of the serum HBsAg levels during antiviral therapy. A dilution test using 5 reference serum samples showed linear correlation curve in range from 0.03 to 2,360 IU/ml. The HBsAg was measured in total of 400 serum samples and 99.8% had consistent results between Sysmex and Lumipulse f. Additionally, a positive linear correlation was observed between Sysmex and Architect. To compare the Architect and Sysmex, both methods were applied to quantify the HBsAg in serum samples with different HBV genotypes/subgenotypes, as well as in serum contained HBV vaccine escape mutants (126S, 145R). Correlation between the methods was observed in results for escape mutants and common genotypes (A, B, C) in Japan. Observed during lamivudine therapy, an increase in HBsAg and HBV DNA concentrations preceded the aminotransferase (ALT) elevation associated with drug-resistant HBV variant emergence (breakthrough hepatitis). In conclusion, reliability of the Sysmex HBsAg quantitative assay was confirmed for all HBV genetic variants common in Japan. Monitoring of serum HBsAg concentrations in addition to HBV DNA quantification, is helpful in evaluation of the response to lamivudine treatment and diagnosis of the breakthrough hepatitis. PMID- 17718058 TI - [Two year investigation of glycosylation profiles in serum IgG from a patient with multiple myeloma]. AB - Although abnormalities of glycosylation profile in serum IgG have been demonstrated in a variety of inflammatory autoimmune diseases such as rheumatoid arthritis, there are only a few reports describing long term monitoring of N glycosylation profiles in such patients. Here we report the serial finding of N glycosylation profiles of IgG-kappa M-protein in a patient with multiple myeloma monitored for two years. In this patient, serum formed a gel precipitation upon exposure to air. The HPLC mapping method demonstrated that IgG M-protein in the patient exhibited a significant decrease in the ratio of fucosyl to afucosyl N glycans compared with that in a healthy control. With remission, the IgG M protein showed an increase in this ratio, becoming closer to that in the healthy control. However, the gel-precipitation persisted. This finding suggested that this unique property of serum may not be related to the glycosylation profile of the M-protein. PMID- 17718059 TI - [Positron emission tomography: basic principle and radionuclides/probes for metabolic/functional analysis]. AB - Positron emission tomography (PET) is a functional imaging modality that can non invasively visualize the distribution and dynamic movement of injected PET probes. In this article, the basic principle of PET technique is briefly explained followed by the introduction of various positron-emitters and PET probes used in clinical and research settings. With the coincidence detection of a pair of annihilation radiation emitted from positron emitters and the attenuation correction technique, PET can afford highly sensitive and quantitative data for analysis. However, spatial resolution of PET is limited and not suitable for detecting small lesions. In addition, PET image lacks anatomical information, and correct anatomical localization of the detected uptake is sometimes difficult. Most positron emitters are produced by cyclotrons and have very short half-lives. Therefore, PET institution should be equipped with an in house cyclotron to produce positron emitters as well as the facility to prepare PET probes. Using positron emitters such as C-11, N-13 and O-15, functional/physiological molecules such as water, oxygen gas, carbon dioxide gas and ammonia, can be radiolabeled without modifying the structure or behavior, which makes these molecules suitable for the precise evaluation of physiological function and its deviation under pathological conditions. Although 18F fluorodeoxyglucose (FDG), a marker of glucose metabolism, is the most commonly used PET probe especially in the field of oncology, many PET probes are available to evaluate various important characteristics such as blood flow, metabolism, tumor hypoxia, and neurotransmitter and receptor conditions, and are applied in the fields of oncology, neurology/psychiatry and cardiology. PMID- 17718060 TI - [Assessment of myocardial viability by FDG-PET]. AB - Assessment of myocardial viability is very important for identifying patients likely to benefit from coronary revascularization. Clinical studies have shown that positron emission tomography(PET) using [18F] 2-fluoro-2deoxy-D-glucose (FDG) can accurately identify patients with viable myocardium that are likely to benefit from revascularization procedures, in terms of improvement of left ventricular (LV) function, alleviation of heart failure symptoms, and improvement of long-term prognosis. Single photon emission computed tomography (SPECT) using perfusion tracers such as TL-201 and Tc99m-MIBI are useful to assess viability, but a problem is their particularly low specificity. FDG-PET has several advantages including higher sensitivity and specificity over perfusion tracers. This article will review myocardial metabolism, FDG-PET protocol, procedures, interpretive criteria and clinical applications as well as problems and limitations. The literature regarding diagnostic and prognostic information about viability using FDG-PET is summarized. PMID- 17718061 TI - [Imaging of cancer activity and range of tumor involvement--applying to breast cancer]. AB - In recent years, PET using mainly fluorine-18 fluorodeoxyglucose (FDG) has played a very large role in the management of breast cancer. Systemic, functional images can be obtained by whole body PET and can provide information that is not obtained by anatomical imaging modalities such as conventional X-ray computed tomography, X-ray mammography, or ultrasonography. The utility of FDG-PET for breast cancer patients has been established in every phase of the management of breast cancer, such as the differential diagnosis of breast cancer primary lesion, cancer staging, and posttreatment monitoring. For whole body FDG-PET that can assess the spread of systemic disease in a single examination, postoperative monitoring is one of the most useful applications in particular. In addition, the usefulness of PET for prediction of prognosis and assessment of treatment response has been reported along with the medical economical effect of FDG-PET for breast cancer patients. Moreover, it is expected that a new tracer other than FDG, such as fluorine-18 ion and [18F]-fluoro-17beta; estradiol (FES), and the new instruments such as PET-CT and positron emission mammography (PEM) can further contribute to the management of breast cancer. In this report, we will outline the benefits, limitations, and future prospects of PET for breast cancer. PMID- 17718062 TI - [Cancer screening with PET: advantages and limitations]. AB - Warburg first reported that tumours are characterized by abnormally increased glucose metabolism accompanied by increase production of lactate. This is a basic principle underlying cancer detection by the glucose analogue 18-F-fluoro-2-deoxy D-glucose (FDG). FDG positron emission tomography (PET) is currently used widely to examine virtually any part of the body in order to detect tumours, e.g., lung, breast, colorectal, pancreatic and head and neck cancers, malignant lymphoma and malignant melanoma. The advantage of whole-body FDG-PET in comparison with the other imaging modalities is that it allows the entire body to be surveyed seamlessly within a reasonably short period. Furthermore, the staging of most cancers can be determined. The characteristics of whole-body FDG-PET seem to satisfy the requirements for cancer screening. PET used simultaneously with conventional tests can prevent the overlooking of cancer, reduce false-positive results and assist in the interpretation of CT and MRI images. Thus, PET can play a supportive role when used with conventional screening tests. In 1994, PET was applied to cancer screening for the first time at our Imaging Center at Lake Yamanaka in Japan. Within 12 years after starting, a total of 10,292 asymptomatic individuals (6,227 men and 4,065 women; mean age, 52.2 and 52.9 years) participated in 29,090 screening sessions. As a result, malignant tumours were demonstrated in 355 of the 10,292 participants (2.61%). PET findings were true positive in 175 of the 355 cancers (49.3%). PMID- 17718063 TI - [The impact of the amendment to the Infectious Diseases Control Law on the management of clinical laboratories]. AB - In December 2006, the Japanese parliament promulgated an amendment of the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infections (the Infectious Diseases Control Law). The main elements of the amendment provide a pathogen control system that will prevent biological terrorism, global and accidental spread of infectious diseases and allow for comprehensive control of infectious diseases, including tuberculosis. State intervention was substantially curtailed in the original Infectious Diseases Control Law because of the demand at the time for decentralization. However, the rising danger of bio-terrorism has established an urgent need for direct control by the state. Developing the necessary regulations for laboratory safety and pathogen collection to prevent bioterrorism is an onerous task. The rules must take account of real conditions on the ground and to be seen to work. However, whereas the new rules may be efficient in the prevention of terrorism, there is a real suspicion that they will impede and obstruct the day-to-day routine of the clinical laboratories. We report a questionnaire concerning the influence of this law on the clinical laboratory management in 84 university hospital laboratories. The imposition of well-intentioned but implausible regulations that impair or disrupt routine laboratory work encourages employees to selectively ignore regulations that they feel are impractical or irrelevant. PMID- 17718065 TI - [Diagnostic tests approved by Ministry of Health and Welfare (July 2007)]. PMID- 17718064 TI - [The associated law and the authorization for medical technologists that are necessary for clinical microbiological technologists]. AB - In a clinical microorganism test domain, high quality laboratory study results are demanded, and quality control administration (QM: Quality Management) of laboratory studies with a guarantee of accuracy (QA: Quality Assurance) and high quality examination methods (GLP: Good Laboratory Practice) is indispensable. Maintenance of an appropriate legal system is necessary, including competent staff, a budget, and facilities for continuous monitoring. The associated law and the authorization for medical technologists that are necessary for medical technologists in charge of clinical microorganism examinations are explained: 1) Medical technologists are mainly concerned about the present conditions of duty restrictions, 2) Certification for clinical microbiological technologists and infection control microbial technologists (ICMT), 3) Nosocomial infection measures well informed person meeting report started to the special functioning hospital head on departmental order October 3, 2003, 4) ISO15189 2003, which is the international standard specifications for clinical laboratory quality and identification requirements (conformity range and management requirements for clinical microorganism tests ISO15190) for conformity ability mentioned security requirements for clinical laboratories. PMID- 17718067 TI - [Age- and sex-specific features of new-onset pulmonary tuberculosis in the Krasnoyarsk Territory]. AB - A total of 1150 cases of new-onset pulmonary tuberculosis were analyzed. A higher liability to the disease was shown in young females and males of ripe age. There was evidence for that the severer pattern of clinical forms and the nature of the process were directly proportional to the age of patients. Age-specific differences were found in the ways of detecting the disease and in the regularity of control fluorographic studies. The inclusion of persons aged 60 years or older into an increased risk group was justified. A severer pattern of clinical forms and characteristics of the process were established in males, which are largely caused by that the latter had irregularly underwent control fluorographic studies. Age- and gender-specific features of tuberculosis, which are typical of this region, have been identified. PMID- 17718066 TI - [Role of specific immunoglobulins of classes G, E and subclasses G1, G4 in the diagnosis of tuberculosis in children with hyperergic tuberculin sensitivity]. AB - The study covered 56 patients (aged 6-14 years) having hyperergic tuberculin sensitivity, including 28 patients with pulmonary tuberculosis (Group 1) and 28 patients infected with Mycobacterium tuberculosis (MBT) (Group 2). All tuberculous processes were asymptomatic and limited. Minor forms of tuberculosis, diagnosed by computed tomography, were found in 71.4% of cases. The signs of incomplete calcification were detectable in 93% of cases. In the past year, tuberculin sensitivity has progressed to hyperergic one in 75% of Group 2 patients. The patients with tuberculosis were treated with 3 drugs; those infected with M BT received 2 agents. In the patients with minor forms of tuberculosis, the level of specific IgG antibodies was equal to those in healthy MBT-infected individuals with hyperergic tuberculin sensitivity, the levels of immunoglobulins of subclasses G1 and G4 were lower, that of IgE antibodies were higher than in the MTB-infected. These data may suggest the stability of the immune system in patients with minor forms of tuberculosis, detected in the phase of calcification, and its instability in the MBT-infected with tuberculin sensitivity increasing up to hyperergic one. PMID- 17718068 TI - [The pattern of extrapulmonary tuberculosis according to the materials of Saint Petersburg City Tuberculosis Hospital Two and the problems in delivery of health care]. AB - Extrapulmonary tuberculosis mainly afflicted females over 60 years of age; males aged 20-29 years suffered from this disease concurrent with HIV infection. The major site of extrapulmonary tuberculosis was the urogenital tract; however, the incidence of tuberculosis of the nervous system considerably increased. At the same time abdominal tuberculosis was prevalent in HIV-infected patients. The rate of concomitant pulmonary and extrapulmonary tuberculosis was on the rise. In extrapulmonary tuberculosis, the common cause of death was nervous system tuberculosis. Disseminated and complicated extrapulmonary tuberculosis requires that the problems associated with personnel, organization, and finance be solved. PMID- 17718069 TI - [Impact of familial and interpersonal attitudes towards the efficiency of treatment for pulmonary tuberculosis in mentally ill patients]. AB - The paper describes the influence of socially significant factors, such as a family, children, interpersonal attitudes, and relatives' support, on the course of a tuberculous process in the mentally ill patients long receiving hospital treatment. Positive changes in a tuberculous process are favored by frequent visits of patients, a personal contact of relatives with them, a warm kind attitude of patients towards their relatives and people. The paper shows it necessary to implement educational programs among relatives and rehabilitative and psychocorrective measures with patients, the objective of which is to make and maintain the close and interacting contact - physician-relative-patient, which causes positive changes in the course of pulmonary tuberculosis in mentally ill patients. PMID- 17718070 TI - [Tuberculosis mortality and suicides in Belarus in 1970-2005]. AB - The present paper analyzes trends in tuberculosis mortality rates in relation to suicide rates in Belarus from 19970 to 2005, by applying the time-series test. The analysis suggests the close association between the two time series in the period of 1984 to 1996. The findings support the idea that the rate of tuberculosis mortality can be considered as an indicator of psychosocial distress. PMID- 17718071 TI - [Effects of probiotics on pathogenic mycobacteria]. AB - A procedure has been developed to study the antagonistic effect of probitics on pathogenic Mycobacterium tuberculosis, by employing the cultural filtrates obtained after joint incubation of a probiotic and an antagonistic strain in the liquid nutrient medium. It has been shown that two probiotics actively elaborate bactericidal agents that suppress the growth of pathogenic mycobacteria and reduce the number of colony-forming units in the solid egg culture medium by 2-17 times. PMID- 17718073 TI - [Impact of M. tuberculosis genotype on survival in mice with experimental tuberculosis]. AB - To study the virulence of Mycobacterium tuberculosis strains of the W cluster, C57B1/6 mice were intravenously inoculated with a lethal dose (5x10(6) CFU) of 14 clinical M. tuberculosis strains (11 drug-sensitive and 3 multidrug-resistant) belonging to different RFDP IS6110 genotypic clusters and two laboratory M. tuberculosis strains H37Rv and H37Ra. The virulence was evaluated by the survival of mice after infection and by the trends in body weight loss. The study indicated that the mice inoculated with different M. tuberculosis strains differed in survival rates and in the trend in body weight loss. A minor HD cluster strain and 2 non-clustered strains were most virulent, next were 2 AI cluster strains. W cluster strains had both higher (n = 2) and lower (n = 3), and comparable (n = 2) H37Rv virulence. A KQ cluster strain had the least virulence. An attenuated H37Ra strain caused no animal death. Inoculation with three multidrug-resistant strains belonging to the W cluster (n = 2) and one non clustered strain demonstrated no relationship of virulence to the sensitivity of a strain to antituberculous agents. The findings argue against the opinion on W cluster M. tuberculosis strains as hypervirulent. PMID- 17718072 TI - [Visceral morphofunctional changes in guinea-pigs during long-term administration of antituberculous agents]. AB - Antituberculous drugs (ATD) can adversely affect the kidney and liver. Visceral morphological and histochemical changes were studied in guinea-pigs long receiving a combination of 2 or 5 ATDs. The use of ATDs caused changes at all levels (organ, tissue, and cell). The liver exhibited a pattern of microvesicular steatosis and the kidneys showed hyaline dropwise degeneration. The activity of NADN-DH, NADRH-GH, lactate dehydrogenase, glucose-6-phosphate dehydrogenase lowered in the liver and kidneys, so did the activity of acid phosphatase in the alveolar macrophages. More pronounced changes were detected after the use of 5 ATDs. PMID- 17718074 TI - [The protective action of vitamins in induced mutagenesis]. AB - Peripheral blood leucocytes of healthy donors, both intact and mutagen-processed with cadmium chloride, dioxidine, and bleomycin in vitro, were studied with cytogenetic methods in G2 cell cycle period before, during, and after 14- and 30 day oral administration of vitamin and vitamin-mineral complexes. The study found that intake of complexes containing vitamins in total doses exceeding day requirements did not increase the rate of spontaneous mutations and decreased the sensitivity of human cells to the cytogenetic activity of chemical mutagens. At the same time, vitamin complexes of certain quantitative and qualitative composition were shown to be capable of giving rise to comutagenic modification of sensitive cells to the action of separate mutagens in certain concentrations in vitro. The above effects of anti- and comutagenic modification depend on the duration of intake, the quantitative and qualitative composition of the vitamin complex, the nature of mutagens, and the level of induced cytogenetic lesions. PMID- 17718075 TI - [On the issue of pylorostenosis modeling]. AB - Pylorostenosis was modeled by putting a slightly compressing ligature in the boundary between the antral part of the stomach and the duodenum. Subcompensated pylorostenosis developed on the 10th day; decompensated pylorostenosis developed on the 15th day. PMID- 17718076 TI - [Analysis of mortality in Russian population]. AB - Abrupt mortality growth in Russian population began in 1991 and continued until 1994. Mortality lowered between 1994 and 1998, after which its fast growth resumed. These fluctuations to a significant degree result from increases and decreases in mortality related to cardiovascular diseases (CVD), particularly to "other forms of acute and chronic ischemia" and "atherosclerotic heart disease", but not to myocardial infarction, the proportion of which in Russian CVD-related mortality is extremely low. At the same time, the proportion of CVD-related deaths registered as "other" and "not specified", was more than 50%. It may suggest that in Russian statistics CVD-related mortality is overestimated, while mortality related to external causes (EC) associated with alcohol intoxication is underestimated. Analysis of forensic postmortems supports this assumption. The authors found that ethanol was very often revealed in the blood of persons with a diagnosis of "other causes" or "non-specified" CVD. On the average, in more than 20% of postmortems ethanol blood levels were potentially or actually lethal, i.e. in fact, the reason for death was alcohol intoxication, not CVD. In persons with a postmortal diagnosis of EC the frequency of ethanol detection was also very high (55 to 70%). Potentially and actually lethal ethanol concentrations were found in one third of all men and women with a postmortal diagnosis of EC. Thus, the authors of the article stress that official statistical data, according to which 65199 or 2.8% of all deaths in Russia in 2004 were caused by alcohol intoxication are in contradiction with their data and data of other authors. The results of the present study demonstrate that alcohol intoxication due to its overuse is an important reason for extreme mortality rate in Russian population. PMID- 17718077 TI - [Real-time polymerase chain reaction and its potential clinical application]. AB - The review introduces real-time polymerase technique, a modern high-tech method, to the medical community. Physico-chemical principles of the method, its main stages, and variants of techniques applying fluorescent reporter platforms are considered. Equations used for quantitative estimation, methods of data processing are given; absolute and relative quantification of specific targets is considered. The special part of the review is dedicated to clinical application of the method by the example of infectious and oncological diseases. PMID- 17718078 TI - [Morphology of acute lung injuries in mechanic trauma]. AB - The lungs from 60 subjects who had died of polytrauma were studied morphologically. The heads of the corpses were not injuried. The aim of the study was investigation of characteristics and time of development of structural changes associated with lung injury. Early structural changes in trauma were disorders of circulation including microcirculation, acute emphysema, distelectases and atelectases, injury of bronchial and bronchiolar mucosa. Pulmonary edema and systemic inflammatory reaction emerge in the first hours after trauma. PMID- 17718079 TI - [Effect of clothes on the size of gunshot wounds made by long-distance shots with small-calibre bullets]. AB - An experimental study was made on estimation distance of shots made from far distance through clothes with 5.6-mm jacket-free lead bullets. Textile obstructions imitating human clothes were modeled. Contact velocity of the wounding bullet was measured. Almost complete forensic-medical characteristics of inlet gunshot wounds of the body allowing for clothes properties, anatomic structure of the affected body area, deformation of the hitting bullets were obtained. PMID- 17718080 TI - [Epidemiological features of automobile traumatism in Russia and abroad]. AB - The article presents updated epidemiological information on specific features and causes of high automobile traumatism in Russia and abroad for the last 5 years. The number of road accidents and road accident fatalities now not only present a great social-medical problem in Russia but also a problem of national security as road accident mortality is far ahead of the developed countries and showed no trend to lowering. This threatening situation is caused by out-of-date transport infrastructure, social factors, old cars without modern safety systems, absence of special emergency medical care for road accident victims. The experience of foreign countries on reducing road traumatism is analysed. PMID- 17718081 TI - [Common principles of person identification in disasters with a great number of victims]. AB - The authors give a detailed definition of the notion "identification of the dead body". They formulate and validate an algorithm of expert actions in identification of the dead and missing persons in disasters. Sound choice of specialists at different stages of identification is essential. PMID- 17718082 TI - [New criteria for diagnostics of sudden cardiac death in forensic medicine]. AB - New data on characteristics of sudden cardiac death are provided. It is characterized by hypohydration of the brain, elevated cerebral impedance, a sharp fall of the index of coronary heart arteries passability, mostly areactive affection of the stem nuclei of the brain. PMID- 17718083 TI - [Biochemical criteria in diagnosis of some causes of death]. AB - The article presents biochemical indices of blood and tissues obtained at autopsy which can be used for diagnosis of strangulation asphyxia, poisoning with alcohol substitutes, hyperglycemic coma and hepatic insufficiency. PMID- 17718084 TI - [Defects in medical care delivery to patients with lung and breast cancer undergoing radiotherapy]. AB - Patients aged 55 and 63 years received extracorporeal 30 and 40 Gy gamma-therapy for lung cancer, respectively. Two and 60 days after irradiation, respectively, the patients developed arrosive pulmonary hemorrhage with lethal outcomes. Forensic medical examination in both cases has detected acute radiation pneumonitis with impairment of pulmonary artery endothelium that provoked hemorrhage. The literature review covers acute and chronic lesions of the lungs in radiotherapy of lung and breast tumors. PMID- 17718085 TI - [Forensic-medical obstetric-gynecological examinations in cases on professional delinquency of medical personnel]. AB - We studied the trend in the number of forensic-medical examinations in trials against obstetricians and gynecologists conducted in Primorsky Region in 1997 2005. Most typical defects in obstetric-gynecological care are characterized. These cases are analysed in terms of forensic-medical practice. Detection and forensic-medical analysis of the above defects contribute to optimization of the diagnosis and treatment both in obstetric-gynecological practice and in wide medical practice. PMID- 17718086 TI - [Retrospective epidemiological analysis of occupational infection morbidity of employees in state forensic-medical expert institutions in 1990-2005]. AB - The results of a retrospective epidemiological analysis of occupational tuberculosis and hemocontact virus hepatitis morbidity among forensic-medical examiners demonstrate that tuberculosis and virus hepatitis B and C morbidity among the examiners is ten times and more higher than among RF population and has a trend to further rise. This points to necessity for urgent prophylactic measures among personnel of the state forensic-medical institutions. PMID- 17718087 TI - [Enzyme immunoassay of clofelin]. PMID- 17718088 TI - [Detection of dipiridamol in biological fluids]. AB - Acetone is proposed as an isolating agent for dipiridamol isolation from biological fluids. Purification of the isolates was performed with liquid-liquid extraction and colon chromatography with silasorb C-18 sorbent. The technique of dipiridamol detection in the blood and urine is described. The assays results are presented. PMID- 17718089 TI - [A lethal outcome of alimentary dystrophy associated with nervous anorexia]. PMID- 17718090 TI - [Talc detection in forensic-chemical expert practice]. PMID- 17718092 TI - [The analysis of research and scientific work basing on the dissertations defended in 2006]. PMID- 17718091 TI - [Advantages and drawbacks of traveling cycles of raising the level of professional skills of forensic-medical examiners in Russian Federation]. PMID- 17718093 TI - [Contribution of P. A. Minakov to theory and practice of the production and storage of museum anatomic exhibits]. PMID- 17718094 TI - Topical negative pressure for chronic wounds? AB - Some wounds fail to heal with conventional dressings. Topical negative pressure has been increasingly tried as an alternative for acute and chronic wounds. Here we discuss the value of this treatment for adults with chronic wounds (e.g. pressure ulcers, leg ulcers, foot ulcers related to diabetes mellitus). PMID- 17718095 TI - Does eflornithine help women face hirsutism? AB - Many women develop male-pattern facial hair (facial hirsutism), which can be distressing and difficult to treat. Eflornithine (Vaniqa - Shire) is a topical cream available only on prescription for treating women with facial hirsutism. Promotional material claims that the treatment "slows facial hair growth - grows her confidence". Does this product have a place in the management of women with hirsutism? PMID- 17718096 TI - On the cover. German cockroach. PMID- 17718097 TI - The association between allergies and cancer: what is currently known? AB - OBJECTIVE: To provide an overview of what is currently known about the relationship between allergies and cancer. DATA SOURCES: Publications were selected from a systematic review of the English-language literature from established databases (eg, MEDLINE, EBSCO) and the references of materials identified through these databases. STUDY SELECTION: Publications assessing the association between asthma, hay fever, or other allergy-related diseases and cancer were included in this review. RESULTS: Individuals with any type of allergy have a decreased risk for cancer (compared with the general population), including glioma, colorectal cancer, cancer of the larynx, non-Hodgkin lymphoma, cancer of the esophagus, oral cancer, pancreatic cancer, stomach cancer, and uterine body cancer. However, an increased risk for bladder cancer, lymphoma, myeloma, and prostate cancer exists among those with allergies. Studies that involve breast cancer, leukemia, lung cancer, melanoma, and thyroid cancer have shown no association or conflicting results related to allergies. More research is needed before conclusions can be made about the relation between allergies and Kaposi sarcoma, liver cancer, and cancer of the ovaries. CONCLUSIONS: The association between allergies and cancer is site specific. Further research is needed to verify these results and to determine why such associations exist. PMID- 17718098 TI - Allergy pay for performance position statement. PMID- 17718099 TI - Different effects of sensitization to mites and pollens on asthma symptoms and spirometric indices in children: a population-based cohort study. AB - BACKGROUND: We have previously shown that long-term exposure of children to a highly polluted urban compared with a rural environment is associated with subclinical airway narrowing and increased prevalence of atopy. OBJECTIVE: To test the hypothesis that sensitization to indoor perennial, compared with seasonal, aeroallergens has distinct effects on asthma symptoms and/or spirometric indices. METHODS: We evaluated the respiratory health of 478 and 342 children aged 8 to 10 years living in an urban and a rural area, respectively, during a period of 8 years. Children were evaluated by parental questionnaire in 3 phases, 1995 to 1996 (phase 1), 1999 to 2000 (phase 2), and 2003 to 2004 (phase 3), and by spirometry and skin prick testing to 9 common local aeroallergens in phases 1 and 2. RESULTS: Sensitization to pollens was associated with current wheezing in phase 1 of the study (odds ratio [OR], 3.36; 95% confidence interval [CI], 1.71 to 6.62; P < .001) but not with spirometric indices. Sensitization to mites was negatively associated with forced expiratory volume in 1 second (95% CI, -7.26 to -0.90; P = .01) and forced expiratory flow at 50% of forced vital capacity (95% CI, -10.80 to -1.33; P = .01) in study phase 1 but not in phase 2. CONCLUSIONS: Our results indicate that sensitization to mites is associated with insidious involvement of large and small airways, whereas sensitization to pollens is associated with childhood wheezing at the age of 8 to 10 years. Subsequent loss of these associations implies that risk factors other than allergy influence airway disease at a later age. PMID- 17718100 TI - A 6-item brief measure for assessing perceived control of asthma in culturally diverse patients. AB - BACKGROUND: A concise yet accurate measurement tool is needed for use in research and practice in asthma self-management perceptions across culturally diverse patient populations. OBJECTIVES: To evaluate the psychometric properties of the 11-item Perceived Control of Asthma Questionnaire (PCAQ) and to derive a brief, psychometrically sound, and culturally sensitive measure using item response theory. METHODS: The PCAQ was administered as one of a battery of measures to 375 adults with asthma as part of an ongoing larger project studying asthma disparities. Analyses of differential item functioning (DIF) were conducted to detect the effects of sex, race/ethnicity, and health literacy on psychometric properties. RESULTS: Forty-eight percent of the sample was non-Hispanic white and 44% was African American. The mean +/- SD age was 43.7 +/- 13.7 years. The derived 6-item version, with 5 DIF items not scored, correlated highly with its full version (r = 0.903; P < .001). CONCLUSIONS: The 6-item PCAQ short form has the potential to maintain scale integrity while reducing administration time and lessening survey fatigue in studies using multiple questionnaires. DIF analyses also enabled us to understand the unique aspects of perceived asthma control in demographic groups most affected by asthma. PMID- 17718101 TI - Multiple-drug intolerance syndrome: clinical findings and usefulness of challenge tests. AB - BACKGROUND: Multiple-drug intolerance syndrome (MDIS) is characterized by adverse reactions to several classes of chemically unrelated drugs. OBJECTIVE: To analyze all patients with a history of adverse reactions to at least 3 drugs at the Allergy Unit of Policlinico Gemelli in a 6-year period to better characterize patients with MDIS and to find safe alternative drugs. METHODS: We studied 480 patients (aged >16 years) with a history of adverse reactions to at least 3 unrelated drugs and with negative allergy test results. Patients who had experienced mild adverse reactions that remitted spontaneously underwent challenge tests without any premedication (group A). Patients with a clinical history of moderate reactions received sodium cromolyn, 500 mg, before the challenge (group B). Patients with a clinical history of severe reactions or undergoing parenteral challenges were given an antihistamine 30 minutes before the challenge (group C). RESULTS: In group A, 491 tolerance challenge tests were performed: 414 had negative results and 77 had positive results. In group B, 1,077 tolerance challenge tests were performed: 956 had negative results and 121 had positive results. In group C, 240 tolerance challenge tests were performed: 214 had negative results and 26 had positive results. Comparing the tolerance of alternative drugs in groups A and B, groups A and C, and groups B and C, no significant results were observed (P = .24, .14, and .44, respectively). CONCLUSIONS: Patients with MDIS can tolerate alternative drugs. Premedication with sodium cromolyn or oral H1-antihistamines may be useful in preventing adverse reactions. PMID- 17718102 TI - Subspecialty evaluation of chronically ill hospitalized patients with suspected immune defects. AB - BACKGROUND: The diagnosis of primary immunodeficiency is suggested by recurrent or unusual infections and inflammatory and autoimmune conditions. Because the diversity of immune defects and clinical presentations poses a diagnostic challenge in hospital populations, a computer algorithm was devised to help identify patients. OBJECTIVE: To assess use of pertinent subspecialty clinics by patients with clinical features of immunodeficiency. METHODS: Using a validated algorithm based on International Classification of Diseases, Ninth Revision (ICD 9), codes applied to The Mount Sinai Hospital billing records, we investigated hospitalized patients, 60 years or younger, who had been diagnosed as having conditions associated with immunodeficiency, excluding those with confounding medical conditions. Immunodeficiency-related disease codes were given a weighted score based on relative severity and expressed as a sum for admissions between January 1, 1999, and December 31, 2003. Demographic features, subspecialty care, and clinic attendance were determined. RESULTS: The 296 computer-identified patients with illnesses characteristic of immunodeficiency were 35.8% Hispanic, 27.0% African American, and 21.6% white; their median age was 13.3 years. Patients were hospitalized 1,261 times, or a median of 4.2 times each (range, 1 42 times), and had 5,700 diagnoses. Of the patients, 75.0% received primary care at The Mount Sinai Hospital. Although the most common diagnosis was pneumonia (n = 243), 45% of patients never received allergy/immunology or pulmonary subspecialty care. CONCLUSION: Despite receiving primary medical care at the same hospital, many frequently hospitalized subjects with features of immunodeficiency do not receive medical care in appropriate subspecialty clinics. PMID- 17718103 TI - Stability of standardized grass, dust mite, cat, and short ragweed allergens after mixing with mold or cockroach extracts. AB - BACKGROUND: Limited data are available on the immunochemical compatibilities of standardized and nonstandardized allergen extracts in immunotherapy vaccines. Extract combinations recommended in immunotherapy practice parameters are based primarily on theoretical considerations rather than on actual product compatibilities. OBJECTIVES: To determine the stabilities of standardized grass, short ragweed, dust mite, and cat extracts after mixing with fungal and cockroach extracts at final product concentrations similar to those recommended for maintenance immunotherapy injections. METHODS: Mixtures were prepared using individual products from multiple sources at variable glycerin concentrations and were analyzed after storage for up to 1 year at 2 degrees C to 8 degrees C. Quantitative analyses included radial immunodiffusion assays for cat Fel d 1 and short ragweed Amb a 1 and human IgE enzyme-linked immunosorbent assay inhibitions for meadow fescue grass and dust mite allergens. Immunoblot analyses provided qualitative patterns of IgE binding. RESULTS: Meadow fescue grass allergens were unstable after mixing with fungal or cockroach extracts but were highly compatible with dust mite extracts from numerous commercial sources. Fescue and dust mite allergen recoveries varied considerably when mixed with different mold extracts. The presence of cockroach extracts reduced dust mite allergen potencies but retained moderate levels of cat and short ragweed allergen activities. In all cases examined, glycerin provided concentration-dependent improvements in allergen recoveries. CONCLUSIONS: Several allergen extract combinations generally regarded as unstable by current practice parameters seem to possess considerable biochemical compatibilities. Use of these mixtures in immunotherapy vaccines is supported for practitioners seeking to optimize formulations, doses, and treatment regimens for their patients. PMID- 17718104 TI - Aeroallergen sensitization rates in military children with rhinitis symptoms. AB - BACKGROUND: Childhood sensitization rates for many aeroallergens are underreported. OBJECTIVES: To examine aeroallergen sensitization rates in military children undergoing skin testing for rhinitis and investigate the timing of atopic development for perennial and seasonal allergens. METHODS: A skin testing database was retrospectively analyzed. Children 18 years and younger referred for rhinitis underwent skin prick testing to either a screening panel of 8 tests or a standard panel of 51 allergens. RESULTS: A total of 209 patients underwent skin testing to the 8-test panel. Of these patients, 35.4% had at least 1 positive result. Atopy increased with age, from 6.3% in those younger than 1 year to 58.8% in those 5 years old. The most common allergens were mold mix (16.3%), cat (13.2%), dust mite mix (11.4%), tree mix (9.4%), and grass mix (9.4%). Only 4.0% were sensitized to seasonal aeroallergens before the age of 3 years. A total of 345 children underwent testing to a 51-allergen panel. A total of 80.3% had at least 1 positive test result, and the average number of positive test results was 11.4. Both the percentage of atopy and the average number of positive skin test results increased with age. The most common allergens were grasses, Alternaria, and cottonwood. Thirty-two of 51 allergens were positive in 20% or more children. Rates for many underreported allergens are presented. CONCLUSIONS: In children, aeroallergen sensitization rates are high and increase with age. Perennial allergens predominate up to the age of 3 years. Rates for many underreported allergens are presented. Although performed in a military population, these results should be applicable to many practices. PMID- 17718105 TI - Decreased markers of atopy in children with presumed early exposure to allergens, unhygienic conditions, and infections. AB - BACKGROUND: Several risk factors for the development of asthma and atopic disease in children have been described. Furthermore, there is consistent evidence that the prevalence of atopy increases with higher socioeconomic status. The knowledge about risk factors and preventive factors for atopy needs to be improved. OBJECTIVE: To compare 2 child populations (foster care and reference children) with different risk and protective factors for the development of atopy. METHODS: The study group consisted of 415 children, living in all 10 community foster homes in Lodz, a large industrial city in Poland. The study was performed from April 2, 2004, to April 30, 2006. The reference group consisted of 500 children, living with their parents at home, recruited from primary care centers. The primary outcome measures were skin prick test results and specific IgE in serum. Secondary outcomes included symptoms of allergic diseases and family history, including life conditions in early childhood. RESULTS: The full analysis set included 408 study children and 402 reference children. Significant differences were observed in the prevalence of atopy between the study and reference groups (11.3% vs 25.9%). We observed more positive skin prick test results in children from the reference group than in study children. To explain this phenomenon, we selected 16 variables that differ in both groups in early life and relate these to atopy. We found that the more cumulative features characteristic of the foster home population (poor living conditions), the lower the risk of atopy. CONCLUSION: Extremely unfavorable environmental circumstances, which are characteristic of the foster home population during early childhood, might prevent from atopy. PMID- 17718106 TI - Efficacy of zileuton controlled-release tablets administered twice daily in the treatment of moderate persistent asthma: a 3-month randomized controlled study. AB - BACKGROUND: A controlled-release (CR) formulation of zileuton was developed to simplify administration from 600 mg 4 times daily (Zyflo) to 1,200 mg twice daily. OBJECTIVE: To evaluate the efficacy of zileuton CR, two 600-mg tablets twice daily, compared with placebo. METHODS: Patients with moderate asthma treated with short-acting beta-agonists only were randomized to receive zileuton CR, 1,200 mg twice daily (n = 206); placebo CR, twice daily (n = 203); zileuton immediate-release (IR), 600 mg 4 times daily (n = 101); or placebo IR, 4 times daily (n = 103), for 12 weeks. The primary efficacy variable was change from baseline in morning trough forced expiratory volume in 1 second (FEV1). RESULTS: Improvement in trough FEV1 was observed after 2 weeks of treatment (P = .001) and was maintained throughout the study. After 12 weeks of dosing, FEV1 improved by a mean of 0.39 L (20.8%) in the zileuton CR group vs 0.27 L (12.7%) in the placebo CR group (P = .02). A significant decline in beta-agonist use and a smaller proportion of patients reporting asthma exacerbations were observed in the zileuton CR group vs the placebo CR group. Adverse event profiles were similar across treatment groups. Elevations in alanine aminotransferase levels at least 3 times the upper limit of normal that reversed after drug withdrawal were seen in 5 zileuton CR-treated patients (2.5%) vs 1 placebo CR-treated patient (0.5%). CONCLUSIONS: Treatment with zileuton CR, 1,200 mg twice daily, resulted in a significant improvement in asthma control, and the safety and efficacy profile was similar to that observed with zileuton IR, 600 mg 4 times daily (Zyflo). PMID- 17718107 TI - Melkersson-Rosenthal syndrome: a form of pseudoangioedema. AB - BACKGROUND: Melkersson-Rosenthal syndrome is an unusual cause of facial swelling that can be confused with angioedema. OBJECTIVE: To describe a young woman with facial swelling initially considered to be angioedema. METHODS: A biopsy specimen of the eyelid demonstrated findings consistent with Melkersson-Rosenthal syndrome. RESULTS: After reviewing the differential diagnosis of pseudoangioedema, a presumptive diagnosis of Melkersson-Rosenthal syndrome was made. The patient was successfully treated with infliximab for Melkersson Rosenthal syndrome. Owing to medication adverse effects, infliximab treatment was discontinued. Treatment was then continued with adalimumab, with good effect and without adverse events. CONCLUSIONS: We report the case of a patient with Melkersson-Rosenthal syndrome presenting as angioedema. Furthermore, we report the first successful treatment of Melkersson-Rosenthal syndrome with adalimumab. PMID- 17718109 TI - Delayed-type hypersensitivity reaction to the meta-cresol component of insulin. AB - BACKGROUND: Reactions to recombinant human insulin preparations occur at a rate of 2.4%. Although most have been traced to immunological reactions to the insulin, recent reports suggest that some adverse reactions can occur to the nonmedicinal excipients or preservatives of commercially available insulin preparations. OBJECTIVES: To investigate a localized delayed cutaneous reaction to human insulin. METHODS: Intradermal and patch testing were performed on a patient to evaluate sensitivity to commercial human insulins, meta-cresol, and other sensitizers. RESULTS: Patch test results were positive to the meta-cresol preservative. CONCLUSIONS: This is the first report, to our knowledge, of a reaction to meta-cresol in commercial preparations of insulin. This reaction should be considered in the differential diagnosis of adverse reactions to insulin injections. PMID- 17718108 TI - Effect of omalizumab on patients with chronic urticaria. AB - BACKGROUND: Chronic urticaria (CU) is often difficult to treat. Approximately 40% to 50% of patients with no apparent cause are believed to have an associated autoimmune profile that may play a pathogenetic role. OBJECTIVES: To describe 3 patients with CU refractory to conventional treatment who responded to omalizumab therapy. METHODS: Treatment was maximized with antihistamines, antileukotrienes, and histamine2 blockers with no improvement. Systemic steroids provided only temporary relief. Laboratory workup revealed 1 patient with a low IgE level and elevated anti-IgE receptor antibody level, 1 patient with an elevated IgE level but a normal anti-IgE receptor antibody level, and 1 patient with a very elevated IgE level and an elevated anti-IgE receptor antibody level. All 3 patients were prescribed omalizumab therapy every 2 weeks. RESULTS: Two patients had total clearing of urticaria within 1 week and 1 patient within 6 weeks of starting omalizumab therapy. The patient with the elevated anti-IgE receptor antibody level had normalization of the level after starting treatment. CONCLUSIONS: Omalizumab may have a beneficial effect in the treatment of CU. Further studies are needed to confirm this effect and better elucidate the mechanism for the observed improvement. PMID- 17718110 TI - Aspirin challenge and desensitization for aspirin-exacerbated respiratory disease: a practice paper. PMID- 17718111 TI - How many asthmatic patients have asthma? PMID- 17718112 TI - Comparision of the mosquito saliva-capture enzyme-linked immunosorbent assay and the unicap test in the diagnosis of mosquito allergy. PMID- 17718113 TI - Fine needle aspiration outcomes of masses detected by positron emission tomography: correlation with standard uptake value. AB - OBJECTIVES: To characterize the cytopathologic outcome of lesions detected on positron emission tomography (PET) scan. STUDY DESIGN: Cases with fine needle aspiration (FNA) performed because of a PET-positive lesion over an 18-month period were reviewed. Correlation with the standard uptake value (SUV) (using 2.5 as a cutoff value) was carried out. RESULTS: A total of 112 FNAs were found, of which 83 had adequate tissue for evaluation and available corresponding SUVs to be included in the final study. Fisher's exact test was carried out for correlation between FNA diagnosis and SUV Sixty-one (73.5%) lesions had an SUV > or = 2.5, 53 (87%) ofwhich were malignant and 8 (13%) benign on cytology. Twenty two (26.5%) lesions had an SUV < 2.5, of which 12 (54.5%) showed benign and 10 (45.5%) showed malignant cytology. The overall sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy of SUV were 84%, 60%, 87%, 56% and 78%, respectively. CONCLUSION: Our data show that FNA procedures performed for PET-positive lesions have high PPV, but low NPV. Therefore interpretation of PET SUV values < 2.5 as benign should be made with extreme caution. PMID- 17718114 TI - Utility of p16(ink4a) immunocytochemistry in liquid-based cytology specimens from women treated for high-grade squamous intraepithelial lesions. AB - OBJECTIVE: To examine whether p16(ink4a) immunocytochemical (ICC) expression detected intraepithelial disease in liquid-based cytology (LBC) specimens from women with high-grade squamous intraepithelial lesions (HSIL), whose specimen was labeled negative for intraepithelial lesion or malignany (NILM). STUDY DESIGN: Residual LBC specimens from women treated for HSIL (n = 21), whose LBC test was interpreted as NILM including marked benign inflammatory changes (BCC) were used. The control (n = 25) consisted of residual LBC specimens from women with documented HSIL. ICC for p16p(16k4a) was performed on a second ThinPrep (ThinPrep 2000, Cylyl Corporation, Boxborough, Massachusetts, U.S.A.) preparation; the percentage ofpositive cells and intensity of immunostaining were recorded. Standard LBC preparations for p16(ink4a) ICC-positive and ICC-negative control cases were reviewed. RESULTS: Twenty-four of 25 (96%) of the HSIL control group were ICC p16(ink4a) positive. In the NILM/BCC group, 2 of 21 with adequate LBC residua were ICC p16(ink4a) positive; on review both were reclassified as epithelial abnormality--1 HSIL and 1 atypical squamous cells cannot exclude HSIL. In both, subsequent colposcopic biopsy yielded HSIL. CONCLUSION: p16(ink4a) ICC positivity on NILM/BCC LBC residua from patients with HSIL may identify cases that merit cytologic review and possible reclassification. The utility of p16(ink4a) ICC in this situation requires further study. PMID- 17718115 TI - Utility of 2-D and 3-D virtual microscopy in cervical cytology education and testing. AB - OBJECTIVE: To evaluate the effectiveness of 3-D vs. 2-D virtual microscopy as adjuncts to education and assessment in cervical cytology. STUDY DESIGN: Five cervical cytology slides were acquired in 2-D; then the identical area of the slide was acquired in 3-D, resulting in 2 sets of virtual slides for comparison with the original glass slide. Seventy-nine paid volunteer cytologists and cytotechnology students participated. Approximately half were sent the 2-D set of slides via the Web, and the others a 3-D set of slides on a DVD. Evaluators examined the virtual slides and committed to an interpretation. After receipt of the original glass slides, a second interpretation was made, if different from the virtual slide interpretation. RESULTS: Diagnostic accuracy using virtual cytology slides was similar to that for glass slides (94% vs. 96%). There was no difference in diagnostic accuracy between 2-D and 3-D slides (p = 0.28); however, the ability to focus 3-D slides in the z-axis was strongly endorsed by the participants because of the uncertainty and frustration of having some cells out of focus on 2-D virtual slides. CONCLUSION: There was consensus that virtual cervical cytology slides would be a useful augmentation to education and testing. PMID- 17718116 TI - Sir Francis Galton and proficiency testing in cytopathology. AB - Data from the National Cytology Proficiency Testing Update show that as of January 31, 2006, 9% of 12,786 examinees failed the test on the first attempt. For the second attempt, the failure rate among those who had initially failed remained surprisingly similar, 10%, although common sense would dictate that it should be much higher among those who have already failed the test once and should have lower professional skills. What is the reason for this remarkable improvement in performance? There is a simple explanation: this is a statistical phenomenon, known as "regression toward the mean." Two groups of examinees earn failing scores during proficiency testing: those whose skills are really insufficient and those who are competent but who achieved lower scores due to random variation in the test results. The latter, "misclassified" examinees subsequently "regress" toward the mean during the second test; that is, their test results become more commensurate with their genuine skills. Since the failure rates of all participants during the first and second attempts were similar, we must assume that the majority of the examinees who failed on the first attempt fall into the second, misclassified group, and only a minority have truly insufficient skills. PMID- 17718117 TI - Endometrial aspiration cytology for diagnosis of peritoneal lesions in extrauterine malignancies. AB - OBJECTIVE: To evaluate the usefulness of endometrial aspiration cytology for assessing malignant cells of extrauterine origin. STUDY DESIGN: Endometrial cytology was performed on 224 patients with primary ovarian cancer, 10 with fallopian tube cancer and 45 with peritoneal tumors. RESULTS: Of 224 patients with ovarian cancer, 53 (23.7%) had positive endometrial cytology. Positive rates were: stage I, 4.3%; stage II, 25.0%; stage III, 39.7%; stage IV, 34.5%. Histologic positive rates were: serous, 28.7%; mucinous, 11.4%; clear cell, 23.1%; endometrioid and unclassifiable adenocarcinomas, 28.0%. Of 5 patients with ovarian cancer, 2 were asymptomatic, but aspiration cytology was positive. Of 10 patients with fallopian tube cancer, 9 (90.0%) had positive endometrial cytology. The positive rate on endometrial cytology was 56.7% in stomach cancer, 60.0% in breast cancer and 20.0% in colon cancer. Of 1,209 women with stomach cancer, 30 (2.4%) displayed ovarian metastasis. Of these, 7 (23.3%) had Krukenberg's tumor; endometrial cytology was positive in 1 (14.3%). In 7 of 17 patients with positive endometrial cytology, clinical diagnosis was made before stomach cancer therapy. CONCLUSION: Endometrial aspiration cytology is useful for identifying nongynecologic malignant cells, diagnosing ovarian and fallopian tube cancers, and determining peritoneal dissemination and metastasis originating from gastrointestinal and breast cancers. PMID- 17718118 TI - Presence of snake-like chromatin in epithelial cells of keratoconjunctivitis sicca followed by a large number of micronuclei. AB - OBJECTIVE: To evaluate the number of micronuclei in snake-like chromatin (SLC) cells in the conjunctival epithelium of keratoconjunctivitis sicca (KCS) patients. To elucidate possible correlations between SLC cell numbers and KCS intensity. STUDY DESIGN: Impression cytology specimens from the bulbar conjunctiva of healthy controls and KCS patients were harvested and divided into 3 groups: group 1, controls; group 2, KCS SLC-negative; and group 3, KCS SLC positive. The number of micronuclei (MNi) in SLC-negative and SLC-positive epithelial cells of each group was counted. RESULTS: The number of MNi in SLC negative cells of groups 1 and 2 did not exceed 1 MNi/1,000 cells. A significant increase in the frequency of micronuclei in the upper bulbar conjunctiva was noted in SLC-positive (14.75 +/- 8.09 MNi/1,000 cells) as well as SLC-negative cells (4.0 +/- 3.83 MNi/1,000 cells) of group 3. CONCLUSION: We demonstrate here that the presence of MNi in the conjunctival epithelium of KCS patients could be a characteristic feature accompanying SLC cells. The fact that increased numbers of SLC cells correlates with impaired values in clinical test as well as decreased goblet and epithelial cell densities confirms that the presence of SLC cells correlates with KCS intensity. PMID- 17718119 TI - Cell cannibalism and nucleus-fragmented cells in voided urine: useful parameters for cytologic diagnosis of low-grade urothelial carcinoma. AB - OBJECTIVE: To clarify whether the 3 parameters of cell clusters, cell cannibalism and nucleus-fragmented cells could improve diagnostic accuracy for grade 1 urothelial carcinoma (G1UC). STUDY DESIGN: A total of 52 voided urine samples from 31 patients histologically diagnosed as having G1UC were reviewed. In addition, 10 voided urine samples from cases with grade 3 demonstration urothelial carcinoma (G3UC) and 30 voided urine samples from 25 patients with a histologic diagnosis of chronic inflammation of the bladder were evaluated for comparison. Areas of tumor cells with cannibalism were measured. RESULTS: Cell cannibalism was evident in 12 of 31 G1UC cases (38.7%), significantly less often than with G3UC, but never identified in the control group. Mean areas of tumor cells featuring cannibalism were significantly smaller in G1 UC than in G3UC cases. Nucleus-fragmented cells were also less frequent in G1UC than in G3UC, but more common than in the control group. CONCLUSION: Cell cannibalism and nucleus fragmented cells in voided urine with special attention to areas of tumor cell with cannibalism could be applied as a parameter to improve diagnostic accuracy for G1UC. PMID- 17718120 TI - Immunocytochemistry and fluorescence in situ hybridization in HER-2/neu status in cell block preparations. AB - OBJECTIVE: Recent studies have validated the use of cytologic materials to determine HER-2/neu status. Good concordance has been shown between results obtained by immunocytochemistry (ICC), immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) on cytologic and surgical specimens. However, the utility of cytologic cell block material in determining HER-2/neu status has not been reported and is the subject of this study. STUDY DESIGN: HER-2/neu status was determined in 25 cases of primary or metastatic breast carcinoma by IHC and FISH. All cases were formalin-fixed, paraffin-embedded (FPPE) cell block preparations. ICC was performed using monoclonal antibodies TAB250 (Zymed) and CB11 (Novacastra Laboratories). FISH analysis was performed using the PathVysion HER-2 probe kit (Vysis, Inc.). Results of ICC and FISH were compared in each case. RESULTS: Of 25 cases studied, 17 showed no protein overexpression or amplification. Five cases showed protein overexpression and amplification. The remaining 3 cases showed 2+ staining intensity by ICC in 10, 20, and 50% of carcinoma cells, respectively, and all demonstrated lack of amplification. CONCLUSION: Immunocytochemistry performed on FFPE cell block material is a reliable method for determining HER-2/neu status in cytologic specimens. We recommend routine preparation of FFPE cell block material in instances of suspected primary of metastatic breast carcinoma. PMID- 17718121 TI - Exfoliative cytologic findings of primary pulmonary adenoid cystic carcinom: a report of 2 cases with a review of the cytologic features. AB - BACKGROUND: Adenoid cystic carcinoma is a very rare primary pulmonary neoplasm. Cytologic findings of pulmonary washing and brushing in 2 cases of primary bronchial adenoid cystic carcinoma with special histologic features are described, with an emphasis on some points that have not been reported previously, together with the diagnostic pitfalls. CASES: Two cases of primary adenoid cystic carcinoma of the lung were diagnosed on exfoliative cytology. The patients' ages were 55 and 65 years old. Cytologic findings included large and small clusters of small cells in both 2 and 3 dimensions with occasional cystlike spaces containing mucoid material. The cells were arranged in spherical, cylindrical, basaloid and rosettelike arrangements. There were also abundant small and large mucoid globules, cylinders of homogeneous, acellular, mucous material and "cannon balls." Cytoplasmic and intranuclear round inclusions were noted in case 1. Rare findings of nuclear molding were noted. In case 2, chondromyxoid material and a bimorphic population of tumor cells caused diagnostic confusion with other salivary gland-type tumors of the lung. CONCLUSION: These cases showed characteristic cytologic findings of adenoid cystic carcinoma together with rare findings of intracellular and extracellular inclusionlike bodies, myxochondroid material, bimorphic populations and nuclear molding, which can cause diagnostic confusion with other lung tumors. PMID- 17718122 TI - Diagnosis of adenoid cystic carcinoma of the lung by bronchial brushing: a case report. AB - BACKGROUND: A diagnosis of pulmonary adenoid cystic carcinoma on exfoliative cytology specimen is very uncommon. The diagnostic cytologic material typically is obtained following a tissue biopsy. No previous report of the diagnosis has been made on bronchial brushing cytologic material when the procedure preceded a tissue biopsy. CASE: A 44-year-old man who used to smoke cigarettes and was otherwise well complained of persistent cough for the past 6 months. A chest radiograph revealed a mass lesion in the left hilum. Computed tomography of the chest disclosed an irregular and spiculated soft tissue mass in the left apical anterior segment. Bronchial brushing via bronchoscope was performed, revealing carcinoma cells consistent with an adenoid cystic carcinoma on cytology. A bronchial biopsy and subsequent left upper lobectomy were performed, confirming the diagnosis of adenoid cystic carcinoma of the lung associated with tumor extension to the epithelial surface. CONCLUSION: A diagnosis of bronchial adenoid cystic carcinoma is possible on bronchial brushing. However, as a method in exfoliative cytology, the usefulness of bronchial brushing in diagnosing this tumor is limited by the neoplasm's proximity to the mucosal surface and whether the mucosa has been breached. PMID- 17718123 TI - Dirofilaria repens diagnosed by the presence of microfilariae in fine needle aspirates: a case report. AB - BACKGROUND: Dirofilariasis due to Dirofilaria repens with viable microfilariae outside the worm have not been reported before. CASE: A 40-year-old truck driver from rural Shiraz, Iran, had a firm mass, 2.5 x 2.5 cm, at the dorsolateral aspect of the right forearm. Fine needle aspiration (FNA) was performed on 2 occasions. Several microfilariae with blunt heads, pointed posterior ends and empty caudal spaces resembling microfilariae of Wuchereria bancrofti but longer were seen. Since Iran is a nonendemic area for lymphatic filariae and the patient had a history of contact with a dog, with the impression of dirofilariasis, the mass was excised, and the presence of adult worms in tissue sections confirmed the diagnosis. CONCLUSION: This case ofsubcutaneous dirofilariasis was diagnosed by detecting microfilariae in FNA smears and was confirmed on histopathology. PMID- 17718124 TI - Cytologic and histologic features of primary mucinous adenocarcinoma of skin in the axilla: a case report. AB - BACKGROUND: Primary mucinous adenocarcinoma of the skin is a rare tumor; its location in the axilla is rarer still. It closely mimics metastatic adenocarcinoma histologically. Owing to the good prognosis of the tumor, it is imperative that it is diagnosed or at least suspected to save the patient from unnecessary investigation and a radical treatment. Fine needle aspiration cytology (FNAC) is a very useful preoperative investigation for its diagnosis; however, cytologic description is not available in the literature so far. CASE: A 50-year-old man presented to the outpatient surgery department with a lump in the left axilla for 6 months. FNAC of the lump was done. The cytologic smears were hypercellular, with loosely dispersed cells in a background of pale pink material. On high-power examination, cells were monomorphic with plasmacytoid appearance and no atypia. Occasional mitotic activity was seen. A possibility of appendageal tumor was suggested and excision biopsy advised. On subsequent biopsy a diagnosis of primary mucinous adenocarcinoma of the skin was made. CONCLUSION: Because of the better prognosis of primary mucinous adenocarcinoma of the skin vis-a-vis metastatic adenocarcinoma; preoperative diagnosis is necessary. FNAC can serve as a rapid and accurate first-line investigation. PMID- 17718125 TI - Cervical cytology of recurrent psammoma bodies with atypical cells in a postmenopausal woman: a case report. AB - BACKGROUND: Psammoma bodies (PBs) are an unusual finding in cervical cytology preparations. They have been identified in association with a wide range of benign and malignant conditions within the female genital tract. Portents of a significant underlying pathology include their occurrence in postmenopausal patients, the presence of unexplained vaginal bleeding and their occurrence in association with atypical cells. CASE: PBs associated with atypical cells were detected in repeated cervical cytology smears of an asymptomatic, 55-year-old postmenopausal woman over a 4-year period. She was extensively investigated, and, in the absence of a bleeding) have definitive cause, she underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Histologic examination of the specimen demonstrated the presence of bilateral benign ovarian serous cystadenofibromas with large numbers of PBs. Focally the PBs were closely apposed to the serosal surface and invested in a blanket of mesothelial cells. CONCLUSION: Caution is required when assessing the significance of PBs associated with atypical cells in a cervical cytology specimen. Our case demonstrates the presence of ovarian mesothelial cells mimicking atypical glandular cells. PMID- 17718126 TI - Cytologic findings of lymphangioleiomyomatosis in pleural effusion: a case report. AB - BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare disease occurring almost exclusively in females of reproductive age. Patients usually present with insidious and progressive dyspnea. Episodes of hemoptysis, pneumothorax, and chylothorax may occur, and the patient progresses to eventual respiratory failure and death. The characteristic pathologic finding is proliferation of immature smooth muscle cells (LAM cells) in the lungs, lymphatics and lymph nodes of thorax and abdomen/ retroperitoneum. CASE: A 47-year-old woman with a 1-year history of LAM diagnosed on iliac lymph node biopsy presented with progressive dyspnea and pleural effusion. A chest tube was placed. The collected pleural fluid, which represented chylothorax, yielded cohesive clusters of cells consisting of 2 cell populations: an outer, discontinuous layer of flattened cells and an inner portion of ovoid spindle cells. By immunohistochemistry the inner cells stained with smooth muscle actin and were negative for keratin. CONCLUSION: The characteristic constellation of clinical findings and distinctive cytology in conjunction with immunohistochemistry staining can render the diagnosis of LAM in effusions. PMID- 17718127 TI - Orbital Rosai-Dorfman disease: report of a case with fine needle aspiration cytology and histopathology. AB - BACKGROUND: Rosai-Dorfman disease, or sinus histiocytosis with massive lymphadenopathy (SHML), is a rare, nonhereditary, benign histiocytic proliferative disorder, affecting mainly the lymph nodes. Orbital involvement in the absence of lymphadenopathy is relatively uncommon. CASE: A 50-year-old woman presented to our hospital with gradual proptosis of the left eye for 5 years. Physical examination revealed no abnormalities, including lymphadenopathy. Ultrasonography and magnetic resonance imaging showed a soft tissue mass in the intraconal retroorbital region of the left eye. Fine needle aspiration cytology of the mass yielded a good number of mature lymphocytes, a few neutrophils, plasma cells and many histiocytes exhibiting emperipolesis. A provisional diagnosis of SHML was suggested and later confirmed by histology of the excised mass. CONCLUSION: Though the orbit is a rare site of extranodal SHML, the disease should be entertained in the differential diagnosis of orbital swellings. To the best of our knowledge, this is the fourth case of SHML involving the orbit exclusively, with no nodal involvement. PMID- 17718128 TI - Pilomatrixoma as a diagnostic pitfall in fine needle aspiration cytology: a case report. AB - BACKGROUND: Pilomatrixoma (pilomatrixoma, calcifying epithelioma of Malherbe) is a relatively uncommon, benign neoplasm arising from the skin adnexa. The tumor can cause diagnostic difficulty not only for the clinician but also for the cytologist. CASE: A 62-year-old woman presented with a right submandibular swelling of 4 months' duration. The clinical findings were highly suspicious for malignancy. A fine needle aspiration biopsy was performed. Three preliminary differential diagnoses were offered: mucoepidermoid carcinoma of the submandibular salivary gland, squamous cell carcinomatous deposit in a submandibular lymph node and calcifying odontogenic tumor. Computed tomography demonstrated no bony lesion. No primary site of squamous cell carcinoma could be identified. An excisional biopsy of the swelling was performed, and the histologic diagnosis of pilomatrixoma was made. CONCLUSION: The cytologic presentation of pilomatrixoma of the right submandibular region can masquerade as that of a malignant tumor, in this case mucoepidermoid carcinoma, squamous cell carcinoma or odontogenic tumor. This case delineates the cytomorphologic features of pilomatrixoma that may mimic carcinoma. PMID- 17718129 TI - Cytology of urate milk in gouty arthritis: a case report. AB - BACKGROUND: Synovial fluid (SF) analysis is a useful investigative procedure in the evaluation of various types of arthritides, including gouty arthritis. Rarely, gouty arthritis may present with effusion containing thick, milky white fluid. We report a case of gouty arthritis, describing cytologic features of the urate milk. CASE: A 42-year-old man presented with pain and swelling of multiple joints of long duration. Approximately 3 mL of milky white SF was obtained for white blood cell (WBC) count, with a clinical diagnosis of septic arthritis. Due to the gross nature of the sample, the WBC count could not be performed; however, cytologic examination of the sample revealed a massive amount of classic, needle shaped urate crystals on routinely stained May-Grunwald-Giemsa smears, favoring a cytologic diagnosis of gouty arthritis. CONCLUSION: Gouty synovitis occasionally presents with thick, milky white urate-laden synovial effusions, which clinically may be mistaken for septic arthritis. This gross nature of the specimen may interfere with the performace of a WBC count on SF samples. PMID- 17718130 TI - Neuroendocrine small cell carcinoma of the cervix associated with endocervical adenocarcinoma: a case report. AB - BACKGROUND: Small-cell carcinoma (SCC) of the cervix is an uncommon member of the neuroendocrine group of cervical carcinomas that is frequently intermixed with a non-SCC component in the form of an adenocarcinoma (ADC) or squamous carcinoma. CASE: Colposcopy revealed a cervical mass in a 41-year-old woman and a Pap smear the presence of some tumor cells from SCC, which was confirmed by subsequent biopsy. The patient received 3 cycles of chemotherapy and then underwent major surgery. The cervical samples showed areas of endocervical ADC adjacent to and intermixed with the SCC. Reviewing the Pap smear, a previously missed malignancy was recognized. On subsequent molecular investigation to assess clonality by microsatellite analysis, the presence of HR-HPV DNA18 on real-time polymerase chain reaction, p16(INK4a) fluorescence in situ hybridization status and the corresponding immunohistochemical expression supported the hypothesis that the two components of the tumor shared the same cell origin. CONCLUSION: SCC of the cervix is a rare but distinct HR-HPV-18-related cervical carcinoma often intermixed with a clonally related non-small cell component consisting of an ADC or squamous carcinoma. The presence of SCC tumor cells in a cervical smear should prompt a search for malignant glandular or squamous tumor cells. PMID- 17718131 TI - Retroperitoneal lymphangiomyomatosis diagnosed by fine needle aspiration: a case report. AB - BACKGROUND: Lymphangiomyomatosis is a rare condition affecting women of childbearing age. It is characterized by an abnormal proliferation of smooth muscle cells around lymphatics, giving rise to blockage of the large lymphatics, including the thoracic duct, and resulting in chylothorax and/or chyloascitis. The lung is the most common site of involvement. Retroperitoneum and lymph nodes can be also involved. CASE: A 40-year-old woman presented with lower urinary tract symptoms after a history of trauma and was found to have a retroperitoneal mass. Fine needle aspiration cytologic examination of the milky fluid aspirated from the mass revealed a few cohesive, 3-dimensional clusters of medium-sized cells with scanty cytoplasm, and ovoid and hyperchromatic nuclei. The background contained numerous mature lymphocytes. Laparoscopy revealed a multicystic mass filled with milky fluid. Histologic examination confirmed the cytologic diagnosis of lymphangiomyomatosis. CONCLUSION: Fine needle aspiration of lymphangiomyomatosis can be performed if cohesive clusters and a lymphoid background are present in chylous-type fluid and provided that adequate clinical information is available. PMID- 17718132 TI - Caseous, necrotic material and epithelioid cell granulomas in synovial fluid from a patient with tuberculous infection: a case report. AB - BACKGROUND: The gross appearance and cytologic findings in synovial fluid in tuberculous infections are similar to those in other types of chronic synovial effusion. Demonstration of acid-fast bacilli (AFB) is required for a definitive diagnosis of tuberculous effusion; it is reported in only 20% of cases. The presence of frank caseous necrotic material and epithelioid cell granulomas in synovial fluid samples is unusual but strongly indicative of tuberculous infection. CASE: A 28-year-old man, on treatment for pulmonary tuberculosis, presented with a history of right ankle swelling, which was clinically interpreted as nonspecific synovitis. The synovial fluid was yellowish, with fluffy, whitish material. Cytologic smears showed abundant, caseous, necrotic material; a few histiocytic aggregates; and occasional epithelioid cell granulomas. Although stain for AFB was negative, considering the clinical presentation, a diagnosis of tuberculous synovitis could be rendered. CONCLUSION: Caseous, necrotic material and epithelioid granulomas in synovial fluid are highly unusual but, when present, can be considered definitive evidence of tuberculous effusion, particularly in a known case of pulmonary tuberculosis. PMID- 17718133 TI - Extrapulmonary Pneumocystis carinii infection in an AIDS patient: a case report. AB - BACKGROUND: Extrapulmonary Pneumocystis carinii (EPC) infection is an uncommon condition, regardless of HIV status, and can occur as a complication of P carinii pneumonia (PCP). However, PCP is the most common severe opportunistic infection in patients with AIDS. The incidence of EPC is variable, and in HIV-1-infected individuals it has been estimated to be 0.06-2.5%. CASE: A case of generalized lymphadenopathy was referred to us for fine needle aspiration cytology (FNAC). The patient was a 9-year-old boy who had a toxic facies and manifested multiple skin lesions all over the body. Fever was present during the examination. HIV status was confirmed from the history and test report. FNAC was done from a cervical lymph node and smears stained with hematoxylin-eosin and with Giemsa and Papanicolaou stain. The presence of P carinii was suspected in Giemsa- and hematoxylin-eosin-stained smears, and silver methenamine stain was used to confirm the diagnosis. Fungal spores were seen as small, spherical cysts of variable sizes, more or less the size of erythrocytes. The diagnosis was thus established as EPC infection. CONCLUSION: Lymph node involvement is the most common site of pneumocystosis in AIDS patients. Fine needle aspiration diagnosis of EPC infection is a possibility in such cases with lymphadenopathy and must be included in the differential diagnosis of lymph node swellings in AIDS. PMID- 17718134 TI - Fine needle aspiration cytology determinants of the diagnosis of primary nodal Kaposi's sarcoma as the first sign of unknown HIV infection: a case report. AB - BACKGROUND: Kaposi's sarcoma (KS) is a vascular malignant tumor characterized by human herpesvirus 8 infection of neoplastic cells. Diffuse cutaneous lesions represent the classical clinical presentation. This case report describes the first fine needle aspiration cytology findings of a primary lymph nodal KS, a rather unusual localization of the disease. CASE: A 28-year-old, apparently healthy man saw a surgeon for right inguinal node enlargement without other symptoms. The clinician performed fine needle aspiration and made a preliminary diagnosis of a neoplasm of probable mesenchymal origin, not otherwise specified. The lymph node was excised, and the final histologic diagnosis was primary lymphoadenopathic KS. A serologic test revealed antibody positivity for HIV. CONCLUSION: The diagnosis of primary KS of the lymph node, in the absence of any other clinical manifestation, was the first sign of HIV infection. PMID- 17718135 TI - Fine needle aspiration cytologic findings of micropapillary carcinoma in the lung: a case report. AB - BACKGROUND: Micropapillary carcinoma is a variant of adenocarcinoma described in many anatomic sites and most recently in the lung. The cytologic recognition of this distinct pathologic entity in transthoracic needle aspiration specimens is important in providing prognostic information and therapeutic guidance. CASE: A 58-year-old woman presented with a < 1-cm lesion in the left breast identified on screening mammogram. A core biopsy of this lesion revealed an estrogen and progesterone receptor positive tubular carcinoma. Before a hookwire localization biopsy, a chest x-ray revealed a 1.7-cm spiculated mass in the right lower lobe. The diagnosis of adenocarcinoma with micropapillary features was made by fine needle aspiration cytology (FNAC). The lobectomy specimen showed a combination of adenocarcinoma, papillary adenocarcinoma and micropapillary carcinoma. CONCLUSION: Micropapillary carcinoma is a unique variant of adenocarcinoma, having important clinical associations because of its propensity for angiolymphatic invasion and higher stage at disease presentation. This case demonstrates the cytomorphologic characteristics of micropapillary carcinoma in a transthoracic FNA of the lung. PMID- 17718136 TI - Fine needle aspiration biopsy features with histologic correlation in mediastinal hepatoid yolk sac tumor presenting with sternum metastasis: a case report. AB - BACKGROUND: The hepatoid variant of yolk sac tumor (H-YST) is an exceedingly rare and highly malignant neoplasm. We present and discuss our experience with cytologic and histopathologic features of a mediastinal H-YST presenting with sternum metastasis, which to the best of our knowledge has not been previously reported. CASE: A 38-year-old man presented with a large mass on the sternum. Computed tomography of the thorax showed a large anterior mediastinal mass with sternum metastsis and multiple lung metastases. Laboratory examination revealed elevated serum alpha-fetoprotein (60,000 IU/mL). No tumor was found in the other organ systems. A percutaneous fine needle aspiration biopsy and subsequent open surgical biopsy were performed on the sternum metastasis. Cytologically, the tumor was composed of monotonous, large, round to polygonal hepatoid cells forming solid sheets and trabeculae entrapped with endothelial cells resembling hepatocellular carcinoma. Histopathologic sections of tumor showed tumor cells with eosinophilic to clear cytoplasm arranged in a solid, trabecular growth pattern, with some acinar formations. Immunohistochemical study supported the hepatoid origin. CONCLUSION: Fine needle aspiration cytology, together with the characteristic clinical presentations and specific tumor markers, is crucial to the initial diagnosis of H-YST. PMID- 17718137 TI - Canine mastocytoma: report of 8 cases diagnosed by fine needle cytology and clinicopathologic correlations. AB - BACKGROUND: Mast cell proliferations are commoner in dogs than in humans; mass forming lesions in the former are apt to fine needle sampling and the obtained cytopathological picture might be informing to enhance recognition of similar proliferations in humans. CASE: Clinical and cytopathologic data were collected from 8 cases of canine mastocytomas diagnosed by fine needle cytology. The cytopathologic presentation was correlated with the individual therapy performed and with the clinical stage. In all cases the cytopathological diagnosis was confirmed by histopathologic examination of the excised mass, by necropsy or by response to therapy. CONCLUSION: There are marked similarities between canine and human mastocytomas, despite possible differences in the clinical course of the disease in both species. Canine mastocytomas may hence be used as an animal model of a human disease and, as such, familiarity with their cytologic presentation may be useful for recognizing mast cell proliferations in humans. PMID- 17718138 TI - Multifocal nodular oncocytic hyperplasia in parotid gland: a case report. AB - BACKGROUND: Multifocal nodular oncocytic hyperplasia (MNOH) is a rare lesion of the parotid gland. Fine needle aspiration cytology (FNAC) in MNOH has not been described previously to the best of our knowledge. CASE: A 55-year-old woman presented with a lump at the left angle of her mouth for 2 months. Local examination revealed a hard, nontender parotid mass. FNAC revealed clusters as well as discretely lying oncocytic cells. cells at places showed moderate nuclear pleomorphism. The features were consistent with a diagnosis of oncocytic neoplasm neoplasm; however, because of pleomorphism, a suspicion of carcinoma was offered. The patient underwent superficial parotidectomy, and histopathology examination revealed it to be multifocal nodular oncocytic hyperplasia. CONCLUSION: MNOH is a rare nonneoplastic salivary gland lesion and should be considered in the differential diagnosis of oncocytic neoplasm on FNAC. PMID- 17718139 TI - Fine needle aspiration cytology of juvenile hyaline fibromatosis: a case report. AB - BACKGROUND: Juvenile hyaline fibromatosis (YHF) is a rare inherited disorder characterized by tumorous growth of hyalinized fibrous tissue. No report on cytomorphology of this condition is available in English on MEDLINE. CASE REPORT: A 6-year-old girl had multiple nontender nodules on both ear lobes, nose and scalp. Fine needle aspiration of the nodule on the left ear revealed benign, spindle-shaped cells with an eosinophilic ground substance in the background. The diagnosis of JHF was made following cytologic and histopathologic studies. CONCLUSION: Fine needle aspiration cytology is reliable for the diagnosis of JHF. PMID- 17718140 TI - Mycobacterium kansasii infection diagnosed by pleural fluid cytology: a case report. AB - BACKGROUND: Identification of disseminated nontuberculous Mycobacterium infection is a challenge, especially when it occurs in patients without a known cause of immunosuppression. Acid-fast organisms in the pleural fluid are rare and easily missed, especially when they occur in patients without a clinical suspicion of infection. The classical cytologic picture of tuberculous pleural fluid with lymphocytosis and paucity of mesothelial cells is not seen. CASE: A 57-year-old man presented with chronic neutrophilia of unknown etiology together with chest pain and bilateral pleural effusions. Pleural fluid cytology revealed organisms seen in the cytoplasm of numerous macrophages and neutrophils, creating a "negative image" on Diff-Quik smears. Acid-fast stains demonstrated intracellular acid-fast bacilli consistent with mycobacteria. Microbiologic studies with DNA probe technology resulted in identification of the mycobacterial organism as Mycobacterium kansasii. CONCLUSION: Nontuberculous Mycobacterium should be included in the differential diagnosis in patients with inflammatory, exudative pleural effusions. PMID- 17718141 TI - Primary intramuscular infestation of Echinococcus granulosus misdiagnosed as a soft tissue tumor: a case report. AB - BACKGROUND: The occurrence of a primary intramuscular infestation of Echinococcus granulosus is extremely rare. CASE: A 70-year-old woman with primary skeletal muscle hydatidosis initially presented with a soft tissue mass. Clinical and radiologic examination revealed a huge cystic mass in the right quadriceps muscle without any visceral organ involvement. Since the differential diagnosis included a soft tissue tumor, fine needle aspiration cytology was performed, and a diagnosis of hydatid disease was made. CONCLUSION: This very rare case of primary intramuscular infestation of E granulosus was clinically misdiagnosed as a soft tissue tumor. Hydatid disease, albeit rare, should be considered in the differential diagnosis of a soft tissue mass. PMID- 17718142 TI - Testicular juvenile granulosa cell tumor: a case report. AB - BACKGROUND: Juvenile granulosa cell tumors of the testis are rare gonadal stromal tumors of the pediatric age. They represent the most common neoplasms of the testis in the first 6 months of life. A testicular cystic mass is detected, or it can appear as an abdominal or inguinal mass. Differential diagnosis for testicular tumors at this age includes teratoma, simple cyst, epidermoid cyst, lymphangioma and testicular torsion. Association with ambiguous genitalia and sex chromosome abnormalities has been reported. Orchiectomy alone is recommended, because no case of metastasis or recurrence has been reported. CASE: We report a case of a 3-month-old male infant with a testicular juvenile granulosa cell tumor mass initially evaluated by fine needle biopsy, which disclosed single or cohesive groups of vimentin, alpha-inhibin and S-100-positive spindle cells with regular nuclei and fine chromatin and inconspicuous nucleoli. Orchiectomy was performed, and histology revealed a juvenile granulosa cell tumor. CONCLUSION: Even though juvenile granulosa cell tumor is the most common neoplasm of the testis in the first 6 months of life, we found no reports describing its cytologic features. In this setting, fine needle aspiration cytology is a useful tool for initial and therapeutic management. PMID- 17718143 TI - Intraoperative cytologic diagnosis of symptomatic carcinoma (pulmonary small cell carcinoma) metastatic to the pituitary gland: a case report. AB - BACKGROUND: Carcinoma metastatic to the pituitary gland is infrequent and has been reportedly detected in approximately 1% of pituitary surgical cases. It may masquerade as a pituitary adenoma both clinically and radiologically. CASE: A 49 year-old man presented with a 1-month history of severe headache, diplopia and blurred vision. Neurologic examination revealed bitemporal hemianopsia and left sixth nerve palsy. The initial radiologic diagnosis based on magnetic resonance imaging was pituitary adenoma. A biopsy of the lesion was performed. While intraoperative frozen section examination could not completely exclude an "atypical" pituitary adenoma, cytologic touch imprint findings were diagnostic of metastatic small cell carcinoma. Subsequently, additional workup revealed that the patient had a mass lesion in the right lung and right-sided mediastinal lymphadenopathy on chest computed tomography. This was a rare case of pituitary metastasis as the first manifestation of an occult malignancy. CONCLUSION: For intraoperative diagnosis at the time ofpituitary surgery, cytologic imprints can be used reliably to make a diagnosis not only of pituitary adenoma but also of metastatic lesions. It is appropriate in current neuropathology practice that the imprint method be used as the sole modality for intraoperative consultation for pituitary lesions. PMID- 17718144 TI - Fine needle aspiration cytology in follicular dendritic cell sarcoma: a report of two cases. AB - BACKGROUND: Since the first description of extranodalfollicular dendritic cell sarcoma in 1994, there has been a gradual increase in understanding of the morphologic features and clinical presentation of this tumor. However, difficulties persist in making cytologic diagnosis. CASES: Two cases of follicular dendritic cell sarcoma with fine needle aspiration cytology (FNAC) findings were reported. The first patient was a Chinese woman who presented with a right tonsillar mass, which was followed by right submandibular recurrence. The second patient was a Chinese man with known history of Castleman's disease of the nasopharynx complicated by follicular dendritic cell sarcoma, followed by tumor recurrence in cervical lymph nodes. FNAC of both recurrent cases showed isolated or syncytial sheets of tumor cells containing eosinophilic granular cytoplasm, ill-defined cell borders, round to oval nuclei, solitary round eosinophilic nucleoli and fine chromatin. CONCLUSION: The tumor cells in follicular dendritic cell sarcoma show cytologic features reminiscent of native follicular dendritic cells but with a greater than expected cell number and nuclear pleomorphism. These cells may be immunohistochemically inert for follicular dendritic cell markers CD21 and CD35. A presumptive diagnosis on the basis of cytologic examination is possible when paying attention to the subtle morphologic features. PMID- 17718145 TI - Sporotrichosis in an HIV-positive man with oral lesions: a case report. AB - BACKGROUND: Sporotrichosis is a granulomatous fungal infection caused by Sporothrix schenckii, which frequently causes cutaneous or lymphocutaneous lesions and rarely has oral manifestations. CASE: A 38-year-old, white, HIV positive man complained of a 5.0-cm, symptomatic, ulcerated lesion with thin, superficial granulation in the soft palate extending to the uvula. Exfoliative cytology of this oral lesion showed chronic granulomatous inflammatory alterations and extracellular fungal structures consisting of periodic acid Schiff-positive budding cells and spherical or elongated (cigar bodies) free spore forms. CONCLUSION: The clinical and cytologic findings allowed the diagnosis of sporotrichosis, demonstrating the importance of cytodiagnosis in fungal diseases. PMID- 17718147 TI - Cerebrotendinous xanthomatosis: a case report. AB - BACKGROUND: Cerebrotendinous xanthomatosis is a rare, autosomal recessive, inherited lipid storage disease characterized by accumulation of cholestanol and cholesterol in most tissues. The disease is caused by mutations in the sterol 27 hydroxylase gene, leading to a block in bile synthesis, with accumulation of substrates for this enzyme, including cholesterol, resulting in an increase in the conversion of cholesterol to cholestanol. CASE: A 26-year-old woman presented with gradually increasing bilateral ankle swelling. She had a history of bilateral cataracts and left-sided hemiparesis. She had mental retardation, with a history of delayed milestone development. Her serum cholesterol levels were elevated. Aspiration of both ankle swellings revealed histiocytes and many foreign body giant cells. There were numerous rectangular to rhomboid crystals in the background. CONCLUSION: Very few articles are available on the cytologic features of tendinous xanthomas; hence we tried to highlight these features. PMID- 17718146 TI - Multicystic nephroma: a case report. AB - BACKGROUND: Cystic nephroma is an uncommon pediatric renal neoplasm. It needs to be differentiated from cystic partially differentiated nephroblastoma and from other renal neoplasms showing extensive cystic change. It is scantily reported in the cytology literature. CASE: A 7-month-old female with a left-sided abdominal lump was diagnosed as having cystic Wilms' tumor on computed tomography. Fine needle aspiration cytology showed cellular smears composed of monomorphic, round to oval cells, suggestive of a small round cell tumor, possibly rhabdomyosarcoma. However, histopathologic examination showed it to be a multicystic nephroma. On review of the cytologic smears, the blastemal component was absent. CONCLUSION: This case highlights 1 extreme and unexpected cytologic appearance of cystic nephroma; it may result in misdiagnosis. PMID- 17718149 TI - Apocrine carcinoma of the breast diagnosed on fine needle aspiration cytology. PMID- 17718148 TI - Anaplastic oligodendroglioma: a case report with characteristic cytologic features, including minigemistocytes. AB - BACKGROUND: Absolute criteria for grading oligodendrogliomas are somewhat poorly defined in contrast to those for grading astrocytic tumors, and cytologic features of anaplastic oligodendrogliomas have been poorly described. CASE: A 63 year-old man presented with a toppling gait. Radiologic examination revealed a 7 cm mass with calcifications in the right frontal lobe. Intraoperative smears of the tumor showed hypercellular, loosely cohesive cell clusters and single cells with nuclear pleomorphism, numerous apoptotic cells and no discernible fibrillary processes. Many bland-looking round cells with cyanophilic cytoplasm and eccentrically located nuclei, so-called minigemistocytes, were intermingled among atypical cells. Cryostat sections showed cellular nests consisting of tumor cells with oval nuclei and clear cytoplasm. These cells were proliferating in the finely reticulated vascular stroma, and the tumor had an infiltrative margin with areas of focal necrosis and numerous calcifications. The diagnosis of anaplastic oligodendroglioma, World Health Organization grade 3, was made, and the results of fluorescence in situ hybridization (chromosome 1q deletion) supported the diagnosis. CONCLUSION: Intraoperative diagnosis of anaplastic oligodendroglioma may not be easy but is possible with judicious consideration of several features: high cellularity, no fibrillary processes, nuclear atypia, pleomorphism, abundant apoptotic cells, occasional mitotic figures, coagulative necrosis, endothelial hyperplasia and characteristic conspicuous minigemistocytes. PMID- 17718151 TI - Enterobius vermicularis ova in a Pap smear: typical and uncommon morphology. PMID- 17718150 TI - Fine needle aspiration cytology of Warthin-like tumor of the thyroid. PMID- 17718152 TI - Imprint cytology of epithelioid hepatic angiomyolipoma: mimicry of hepatocellular carcinoma. PMID- 17718153 TI - Fine needle aspiration cytology of ectopic hamartomatous thymoma. PMID- 17718154 TI - Diagnostic pitfalls in fine needle aspiration of cystic salivary gland lesions. PMID- 17718155 TI - Cytomorphologic characterization of metastatic osteosarcoma in pleural fluid. PMID- 17718156 TI - Diagnostic value of CEA, CYFRA 21-1, NSE and CA 125 assay in serum and pleural effusion of patients with lung cancer. PMID- 17718157 TI - Improving results in fine needle aspiration cytology for submandibular and submental targets by increasing space and pressure in the oral cavity. PMID- 17718158 TI - Fine needle aspiration cytology of massive bilateral ovarian metastasis of fibrolamellar hepatocellular carcinoma. PMID- 17718159 TI - Detection of Panulirus argus Virus 1 in Caribbean spiny lobsters. AB - Panulirus argus Virus 1 (PaV1) is a pathogenic virus that infects Caribbean spiny lobsters P. argus in the Florida Keys. We have developed a PCR detection assay for PaV1 for the purpose of studying the natural history of the virus and for monitoring the prevalence of infection. The detection of the virus in hemolymph and other tissues is based on the PCR amplification of a 499 bp product using specific primers designed from a cloned fragment of the PaV1 genome. The sensitivity limit for the assay was 1.2 fg of purified viral DNA. The PaV1 primers did not react with lobster DNA, oyster DNA, Ostreid Herpesvirus 1, or murine cytomegalovirus. Using this assay, we successfully followed the course of infection in lobsters inoculated with PaV1 and we detected infections in wild caught lobsters from the Florida Keys. We have also established guidelines for interpreting infection results from the PCR assay for PaV1. PMID- 17718160 TI - In vitro assay to select rainbow trout with variable resistance/susceptibility to viral haemorrhagic septicaemia virus. AB - The merit of a candidate criterion of resistance to viral haemorrhagic septicaemia virus (VHSV) was tested with the view of producing experimental trout progeny with a predictable level of resistance. The criterion, the measure of in vitro viral replication in excised fin tissue (VREFT) was previously developed. Three experiments were performed, using both ordinary and homozygous doubled haploid breeders. A set of 48 progeny was tested. Breeders were individually scored for repeated measures of VREFT, and the progeny were tested against VHSV (strain 07-71, serotype 1) through a waterborne challenge (5 x 10(4) pfu ml(-1) during 2 h). Analysis of repeated measures of VREFT revealed the risk of identifying 'false' resistant individuals. The highest value should be considered the most predictive of the resistance status. Survival of progeny ranged from 0 to 100% according to the group and the experiment. The survival was correlated to the mean VREFT value of the breeders in Expts 1 and 2 (R = 0.96 and 0.61 respectively), but not in Expt 3 (R = 0.36, ns) where all tested progeny were highly susceptible. Results thus indicate that viral growth in fin tissue is genetically correlated to resistance to waterborne disease and may be used to produce selected progeny, at least at the experimental scale. Possible implications of the relationship between VREFT and resistance for the study of resistance mechanisms are discussed. PMID- 17718161 TI - Streptococcus iniae beta-hemolysin streptolysin S is a virulence factor in fish infection. AB - Streptococcus iniae is a leading pathogen of intensive aquaculture operations worldwide, although understanding of virulence mechanisms of this pathogen in fish is lacking. S. iniae possesses a homolog of streptolysin S (SLS), a secreted, pore-forming cytotoxin that is a proven virulence factor in the human pathogen S. pyogenes. Here we used allelic exchange mutagenesis of the structural gene for the S. iniae SLS precursor (sagA) to examine the role of SLS in S. iniae pathogenicity using in vitro and in vivo models. The isogenic Delta sagA mutant was less cytotoxic to fish blood cells and cultured epithelial cells, but comparable to wild-type (WT) S. iniae in adherence/invasion of epithelial cell monolayers and resisting phagocytic killing by fish whole blood or macrophages. In a hybrid striped bass infection model, loss of SLS production led to marked virulence attenuation, as injection of the Delta sagA mutant at 1000x the WT lethal dose (LD80) produced only 10% mortality. The neutralization of SLS could represent a novel strategy for control of S. iniae infection in aquaculture. PMID- 17718162 TI - Characterization of a Neochlamydia-like bacterium associated with epitheliocystis in cultured Arctic charr Salvelinus alpinus. AB - Infections of branchial epithelium by intracellular gram-negative bacteria, termed epitheliocystis, have limited culture of Arctic charr Salvelinus alpinus. To characterize a bacterium associated with epitheliocystis in cultured charr, gills were sampled for histopathologic examination, conventional and immunoelectron microscopy, in situ hybridization, 16S ribosomal DNA (rDNA) amplification, sequence analysis and phylogenetic inference. Sampling was conducted at the Freshwater Institute (Shepherdstown, West Virginia, USA) during outbreaks of epitheliocystis in April and May 2002. Granular, basophilic, cytoplasmic inclusions in charr gill were shown to stain with Macchiavello, Lendrum's phloxine-tartrazine and Gimenez histochemical techniques. Ultrastructurally, inclusions were membrane-bound and contained round to elongate reticulate bodies that were immunoreactive to an antibody against chlamydial lipopolysaccharide, suggesting the presence of similar epitopes. DNA extracted from gills supported amplification of the most polymorphic and phylogenetically relevant region of the 16S rRNA gene, which had 97 to 100% identity with several uncultured clinical Neochlamydia spp. (order Chlamydiales) Clones WB13 (AY225593.1) and WB258 (AY225594.1). Sequence-specific riboprobes localized to inclusions during in situ hybridization experiments. Taxonomic affiliation was inferred by distance- and parsimony-based phylogenetic analyses of the 16S sequence, which branched with Neochlamydia hartmannellae in the order Chlamydiales with high confidence. This is the first molecular characterization of a chlamydia associated with epitheliocystis in Arctic charr and the fourth Neochlamydia spp. sequence to be associated with epitheliocystis. Presence of a clinical neochlamydial sequence, first identified from a cat, in Arctic charr suggests a possible mammalian and piscine host range for some environmental chlamydiae. PMID- 17718163 TI - Susceptibility of zebra fish Danio rerio to infection by Flavobacterium columnare and F. johnsoniae. AB - Flavobacterium columnare is a serious pathogen in a wide range of fish species. F. johnsoniae is an opportunistic pathogen of certain fish. Both are gliding bacteria. These species were tested for their ability to infect the zebra fish Danio rerio. Both injection and bath infection methods were tested. The results indicate that F. johnsoniae is not an effective pathogen in D. rerio, but that F. columnare is an effective pathogen. F. johnsoniae did not cause increased death rates following bath infection, but did cause increased death rates following injection, with an LD50 (mean lethal dose) of approximately 3 x 10(10) cfu (colony-forming units). Non-motile mutants of F. johnsoniae produced a similar LD50. F. columnare caused increased death rates following both injection and bath infections. There was considerable strain variation in LD50, with the most lethal strain tested producing an LD50 of 3.2 x 10(6) cfu injected and 1.1 x 10(6) cfu ml(-1) in bath experiments, including skin damage. The LD50 of F. columnare in zebra fish without skin damage was > 1 x 10(8), indicating an important effect of skin damage. PMID- 17718164 TI - Use of a live vaccine to modulate Cryptobia salmositica infections in Salmo salar. AB - The vaccine strain of Cryptobia salmositica multiplies in Atlantic salmon Salmo salar and it can modulate the severity of the disease in Cryptobia-infected individuals. Fish injected with the vaccine 3 d post-infection with C. salmositica had lower peak parasitaemias and higher antibody titres than infected fish given the vaccine 7 d post-infection or those infected fish that were not given the vaccine. PMID- 17718165 TI - Growth kinetics, protease activity and histophagous capability of Uronema sp. infesting cultured silver pomfret Pampus argenteus in Kuwait. AB - Laboratory-produced and -reared sub-adults of silver pomfret (zobaidy) Pampus argenteus affected by severe scuticociliatosis during April and May 2005 were investigated and the causative was a scuticociliate, presumptively identified as Uronema sp. The parasite was capable of producing highly necrotic skin lesions. Mortalities started with a rise in the seawater temperature from 20 to 21.5 degrees C, coinciding with an increase in the total bacterial load of the rearing tank water from 10(3) to 10(5) CFU ml(-1). The parasite was successfully cultured in vitro (85 passages), using 10% brain heart infusion broth inoculated simultaneously with an aquatic Vibrio sp. The parasite reached peak cell density (1.82 x 10(5) cells ml(-1)) on the third day of inoculation. The parasite cell count was found to be inversely related (r = -0.45) to the bacterial count in the incubation medium. The ciliate body dimensions measured, on average, 34.05 +/- 0.99 microm in length and 16.70 +/- 0.74 microm in width (n = 300). Silver staining revealed morphological characteristics of Uronema sp., including a truncated anterior end, a buccal apparatus, caudal cilium and 3 oral polykinetids, with the first one appearing as a single row. Average number of kineties was 12 +/- 3. There was an inverse relationship (R2 = 0.84) between the proteolytic activity and the number of in vitro passages of the scuticociliate. However, the parasite from a freshly infected fish (using inoculum from the tenth passage) showed higher proteolytic activity (31.2%) compared with that produced by the inoculum from in vitro cultures (9.75%). The ciliate also showed a distinct histophagous capability when tested in vitro using host muscle tissue. PMID- 17718167 TI - Experimental cross-infections by Perkinsus marinus and P. chesapeaki in three sympatric species of Chesapeake Bay oysters and clams. AB - In controlled laboratory transmission experiments, uniform doses of axenic in vitro isolate cultures of Perkinsus marinus from a Crassostrea virginica oyster, and of independent P. chesapeaki isolates from Chesapeake Bay Mya arenaria and Macoma balthica clams, were used to reciprocally challenge Perkinsus sp.-free C. virginica, M. arenaria, and M. balthica experimental hosts. Following mantle cavity inoculations, all 3 experimental hosts acquired high incidences (30 to 100%) of infections by each of the 3 Perkinsus sp. isolates, based on PCR assays of DNAs from experimental host tissues that were collected through 60 d post inoculation. Lesions containing proliferating pathogen cells were documented histologically in tissues of all experimental host species challenged with all isolates of both Perkinsus species. Experimental Perkinsus sp. challenge isolates were re-isolated and propagated in vitro from infected tissues of host molluscs from most (5 of 9) experimental treatment groups. Koch's postulates were generally satisfied to confirm experimental infections in all bivalve molluscs that were challenged with 3 isolates of 2 Perkinsus spp. These results suggest potential broad and overlapping host specificities for the 2 current Chesapeake Bay-endemic Perkinsus species: P. marinus and P. chesapeaki. PMID- 17718166 TI - Major histocompatibility complex (MHC) variation and susceptibility to the sea louse Lepeophtheirus salmonis in Atlantic salmon Salmo salar. AB - The relationship between genetic variation in major histocompatibility complex (MHC) Class I and II genes and susceptibility to sea lice Lepeophtheirus salmonis (Kroyer) in Atlantic salmon Salmo salar (L.) was studied in cage-reared post smolts. Polymorphic repeat markers located in the 3' untranslated regions (3UTR) of the genes Sasa-UBA (MHC Class I) and Sasa-DAA (MHC Class II) were screened in 1004 fish sampled from 11 full-sibling families. This gave rise to a total of 7 and 5 alleles, and 17 and 13 genotypes respectively. Significant relationships between both Sasa-UBA-3UTR and Sasa-DAA-3UTR genotypes and abundance of lice were observed within the pooled material, within individual families, and within the pooled material with both markers combined. However, most of these associations were either weak, linked with variation in fish size among genotypes, or influenced by family background genome. Nevertheless, within one family, the Sasa DAA-3UTR 248/278 genotype displayed a significantly higher (33%) abundance of lice compared with the Sasa-DAA-3UTR 208/258 genotype, and this difference was not influenced by fish size. Consequently, the results of this study indicate a link between MHC Class II and susceptibility to lice. PMID- 17718168 TI - A multiplex RT-PCR for simultaneous differentiation of three viral pathogens of penaeid shrimp. AB - A multiplex reverse transcription polymerase chain reaction (mRT-PCR) was developed and optimized to simultaneously detect 3 viral pathogens of shrimp. Three sets of specific oligonucleotide primers for Taura syndrome virus (TSV), white spot syndrome virus (WSSV) and infectious hypodermal and hematopoietic necrosis virus (IHHNV) were used in the assay. The mRT-PCR DNA products were visualized by gel electrophoresis and consisted of fragments of 231 bp for TSV, 593 bp for WSSV and 356 bp for IHHNV. No specific bands of the same size were amplified from other penaeid shrimp pathogenic viruses or bacteria. As little as 10 pg of TSV RNA and 100 pg of WSSV DNA and IHHNV DNA could be detected using gel electrophoresis. Studies are in progress to further test the specificity and sensitivity of this mRT-PCR method on viral isolates, as well as on clinical samples. PMID- 17718169 TI - Baltic salmon activates immune relevant genes in fin tissue when responding to Gyrodactylus salaris infection. AB - Immune mechanisms in 2 strains of Salmo salar (Baltic salmon from River Ume Alv in Sweden and East Atlantic salmon from River Skjerna in Denmark) infected with the monogenean ectoparasite Gyrodactylus salaris were elucidated by molecular tools (real-time PCR). The gene expression in the fins (the preferred microhabitat of the parasite) of the susceptible but responding Swedish salmon was compared to the expression in the fins of the highly susceptible and nonresponding East Atlantic salmon. Experimental infections confirmed that both the Swedish and the Danish salmon allowed initial propagation of the parasite on the fins for a few weeks. Baltic salmon subsequently activated a response from Day 28 and limited the parasite population to a few parasites per host within the following weeks. In contrast, the Danish salmon did not respond and experienced a continuing increase in the parasite load during the same period, which reached several hundreds of parasites per host. RNA was isolated from fins of the 2 salmon strains during the course of infection and subsequent real-time PCR showed an increased expression of INFgamma, Mx and MHC I genes in Baltic salmon fins during large segments of the response phase. No upregulation of these genes could be detected in susceptible salmon. No increase in immunoglobulin genes was seen in any of the fish strains, which supports the notion that antibodies are not involved in the response. Further, the work suggests that cellular factors could at least partly contribute to the anti-parasitic response in Baltic salmon. PMID- 17718170 TI - Comparison bias and dilution effect in occupational cohort studies. AB - Health effects of occupational exposures are frequently evaluated by comparing the mortality of a whole cohort of workers with that of the general population. This study design may be affected by two major biases: a dilution effect (DE), due to the inclusion of unexposed subjects in the study cohort, and a comparison bias (CB), due to the different distribution of risk factors in the reference population. A theoretical model of the joint effect of DE and CB is proposed. Their impact was evaluated in two actual cohorts, selecting specific causes of death based on a priori hypotheses of an association. A linear relationship between the risk estimates and the two biases was found after applying either direct or indirect standardization to adjust for confounding. In the two cohorts, higher risks in exposed workers emerged only after adjusting for DE and CB. Cohort studies without an internal referent group may provide unreliable results. PMID- 17718171 TI - Exposure to ammonia and acute respiratory effects in a urea fertilizer factory. AB - Personal exposures to ammonia and acute respiratory effects were determined in workers at a urea fertilizer factory in Bangladesh. Full-shift personal exposure to ammonia was measured using a PAC III direct reading instrument and Drager diffusion tubes. Respiratory symptoms were elicited by a questionnaire study (n = 113), and preshift and postshift lung function (FVC, FEV1, and PEFR) were tested using spirometry (n = 88). Urea plant workers had higher mean exposure to ammonia and prevalence of acute respiratory symptoms than did workers in the ammonia plant. The symptoms with highest prevalence in the urea plant were chest tightness (33%) and cough (28%). FVC and FEV1 decreased significantly across the work shift among urea plant workers. The higher level of exposure to ammonia in the urea plant was associated with an increased prevalence of respiratory symptoms and an acute decline in lung function. PMID- 17718172 TI - Organizational characteristics of small metal-fabricating businesses in Minnesota. AB - Small U.S. businesses are underserved in terms of occupational health and safety (OHS) services. Little is known about organizational factors influencing OHS in these establishments. Machine guarding was quantitatively evaluated in 40 small businesses. Checklists were used to develop safety scores. Organizational information such as number of employees, unionization, and number of machines was obtained. Experience modification rates, annual sales, and credit ratings were also obtained. Safety scores were divided into terciles. Businesses with safety scores in the top third were unionized, had effective safety committees, and had been operational for more than 30 years. Interventions and policies targeted toward development and implementation of safety committees are needed to improve OHS in this cohort. Financial capability had no bearing on ability of a small business to mount an OHS programs. Non-unionized small businesses may be more vulnerable to occupational injuries. PMID- 17718173 TI - High prevalence of pneumonia in children of a smelter town. AB - Since German reunification in 1990, most heavy industries in Eastern Germany have been shut down. Although air quality has improved in terms of sulfur dioxide and particulate matter (PM), the content of certain metals in PM in industrial areas is persistently high. Lifetime pneumonia prevalence in schoolchildren born after unification in the heavy-metal industrial area Hettstedt remain elevated. One difference between low and high pneumonia-prevalence areas seems to be the residual concentrations of heavy metals in respirable air. Toxicological and human exposure studies of Hettstedt particles have shown metal-rich PM from Hettstedt to have greater toxicity and inflammatory properties than the PM of the control region. Past industrial emissions might still play a decisive role decades after the closing of sources, and pneumonia should be considered a possible acute health burden caused by metal-rich air pollution. PMID- 17718174 TI - Pre-pregnancy dietary vitamin A intake may alleviate the adverse birth outcomes associated with prenatal pollutant exposure: epidemiologic cohort study in Poland. AB - A cohort study assessed the relationship between dietary intake of vitamin A in 493 healthy mothers before and around conception and adverse birth outcomes associated with environmental toxicant exposures. The cohort, non-smoking women with singleton pregnancies, aged 18-35 years, gave birth at 34-43 weeks of gestation. The women were asked about their diets over one year preceding pregnancy. Measurements of PM2.5 were carried out during the second trimester. Birth outcomes were adjusted for potential confounding factors, including gestational age. Standardized beta regression coefficients confirmed an inverse association between PM2.5 and birth weight (beta = -172.4, p = 0.02), but the effect of vitamin A on birth weight was positive (beta = 176.05, p = 0.05), when the two were adjusted for each other. The negative effect of higher prenatal PM2.5 exposures (above third tertile) on birth weight was significant in women below the third tertile of vitamin A intakes (beta = -185.1, p = 0.00), but not in women with higher intakes (beta = 38.6, p = 0.61). The negative effect of higher PM2.5 exposure on length at birth was significant with lower vitamin A intakes (beta = -1.1, p = 0.00) but not with higher intakes (beta = -0.3, p = 0.56). Prepregnancy nutrition of mothers may modulate the harmful effects of prenatal exposures to pollutants on birth outcomes. PMID- 17718175 TI - Associations of symptoms related to isocyanate, ureaformol, and formophenolic exposures with respiratory symptoms and lung function in coal miners. AB - The respiratory effects of diphenylmethane diisocyanate (MDI)-based resins and ureaformol- and formophenolic-based resins, used in coal mining, are unknown. This cross-sectional study of 354 miners evaluated respiratory health in miners with MDI-related symptoms (IS) and ureaformol/formophenolic-related symptoms (UFS). The protocol included clinical examination, chest radiograph, questionnaire on respiratory symptoms, smoking habit, job history, resin handling, and spirometry. Resin handling concerned 27.7% of the miners. IS affected 5.6%, and 1.4% also after work. UFS affected 22.6%, and 2.3% also after work. Wheezing affected 35.6%; chronic cough, expectoration, or bronchitis about 10%; dyspnea 5.4%; and asthma 2.8%. The miners with UFS had significantly more frequent chronic cough, expectoration, chronic bronchitis, dyspnea, and wheezing, whereas those with IS at and after work had markedly lower FVC, FEV1, MMEF, FEF50%, and FEF25%. These findings raise the possibility of deleterious effects of exposures to MDI and ureaformol/formophenolic resins on respiratory health and lung function in coal miners during their working life. PMID- 17718176 TI - An integrated ecosystem approach for sustainable prevention and control of dengue in Central Havana. AB - The authors developed and evaluated a comprehensive participatory ecosystem health approach for preventing the transmission of dengue, the most prevalent vector-borne disease in Cuba and the Latin America-Caribbean region. The integrated surveillance system central to this initiative encompassed three main subsystems (environmental; entomological; clinical-epidemiologic), relying on extensive community involvement. The study was conducted in Central Havana, Cuba. Indicators from each subsystem were selected and mapped using a GIS procedure providing instant visualization by city block in the municipality. To elucidate the factors affecting control and prevention efforts, perceived needs and risks, as well as knowledge, attitudes, and behaviors related to dengue, were assessed. Specific factors associated with the presence of mosquito breeding sites and risks of dengue were examined in a case-control study. PMID- 17718177 TI - Occupational lung diseases and the mining industry in Mongolia. AB - Mining production has accounted for around 50% of the gross industrial product in Mongolia since 1998. Dust-induced chronic bronchitis and pneumoconiosis currently account for the largest relative share (67.8%) of occupational diseases in Mongolia, and cases are increasing annually. In 1967-2004, medically diagnosed cases of occupational diseases in Mongolia numbered 7,600. Of these, 5,154 were confirmed cases of dust-induced chronic bronchitis and pneumoconiosis. Lung diseases and other mining-sector health risks pose major challenges for Mongolia. Gold and coal mines, both formal and informal, contribute significantly to economic growth, but the prevalence of occupational lung diseases is high and access to health care is limited. Rapid implementation of an effective national program of silicosis elimination and pneumoconiosis reduction is critical to ensure the health and safety of workers in this important sector of the Mongolian economy. PMID- 17718178 TI - Cadmium-induced cancers in animals and in humans. AB - Discovered in the early 1800s, the use of cadmium and various cadmium salts started to become industrially important near the close of the 19th century, rapidly thereafter began to flourish, yet has diminished more recently. Most cadmium used in the United States is a byproduct from the smelting of zinc, lead, or copper ores, and is used to manufacture batteries. Carcinogenic activity of cadmium was discovered first in animals and only subsequently in humans. Cadmium and cadmium compounds have been classified as known human carcinogens by the International Agency for Research on Cancer and the National Toxicology Program based on epidemiologic studies showing a causal association with lung cancer, and possibly prostate cancer, and studies in experimental animals, demonstrating that cadmium causes tumors at multiple tissue sites, by various routes of exposure, and in several species and strains. Epidemiologic studies published since these evaluations suggest that cadmium is also associated with cancers of the breast, kidney, pancreas, and urinary bladder. The basic metal cationic portion of cadmium is responsible for both toxic and carcinogenic activity, and the mechanism of carcinogenicity appears to be multifactorial. Available information about the carcinogenicity of cadmium and cadmium compounds is reviewed, evaluated, and discussed. PMID- 17718180 TI - Manipulated data in Shell's Benzene Historical Exposure Study. AB - In 1983, in the face of mounting evidence of excess leukemia among workers at Shell Oil's Wood River (IL) and Deer Park (TX) petroleum refineries, Shell initiated the Benzene Historical Exposure Study (BHES). Shell's prior research had implicated occupational exposure to benzene as the source of the excess leukemia. The BHES report submission, which ultimately found no link between exposure and the excess morbidity, coincided with OSHA's planned hearings over a new regulatory standard for benzene. Over the next two decades, Shell published several papers based on or expanding the BHES data, all of which concluded that the excess of leukemia was unrelated to benzene. A review of the raw data on which Shell and its consultants relied reveals that Shell manipulated and omitted data in order to reach conclusions that exculpated it from liability and helped delay stricter benzene regulation. PMID- 17718181 TI - Hero or villain?--Sir Richard Doll and occupational cancer. AB - In 2006, the English media broke the story that Sir Richard Doll had for many years been retained on a secret consultancy by Monsanto. Doll's colleagues rushed to his defense, arguing that the story was an unjustified smear on a great man whose work had saved millions of lives. However, Doll's conflicts of interest in his occupational health epidemiology are shown to sit uneasily alongside his more independent smoking/lung cancer studies. PMID- 17718182 TI - Canada's asbestos legacy at home and abroad. AB - Despite international efforts to block Canada's export of asbestos, the Canadian federal government continues to defend the economic interests of the asbestos industry. Ironically, Canadian asbestos miners, mill workers, and those engaged in a wide range of other occupations continue to suffer asbestos-related disease and premature death. Although there is an employer-funded compensation system in each province, many workers with mesothelioma and other asbestos-related diseases remain uncompensated. The export of Canadian asbestos to developing countries sets the stage for another preventable occupational disease epidemic that will manifest over the coming decades. There is growing support from the Canadian labor movement for an end to asbestos exportation and for a just transition strategy for the asbestos workers and their communities. PMID- 17718183 TI - Budget cuts to the U.S. EPA will reduce government data on pollutants, and increase reliance on industry data. PMID- 17718179 TI - Benzene-induced cancers: abridged history and occupational health impact. AB - Benzene-induced cancer in humans was first reported in the late 1920s. Carcinogenesis findings in animals were not reported conclusively until 1979. Industry exploited this "discrepancy" to discredit the use of animal bioassays as surrogates for human exposure experience. The cardinal reason for the delay between first recognizing leukemia in humans and sought-after neoplasia in animals centers on poor design and conduct of experimental studies. The first evidence of carcinogenicity in animals manifested as malignant tumors of the zymbal glands (sebaceous glands in the ear canal) of rats, and industry attempted to discount this as being irrelevant to humans, as this organ is vestigial and not present per se in humans. Nonetheless, shortly thereafter benzene was shown to be carcinogenic to multiple organ sites in both sexes of multiple strains and multiple species of laboratory animals exposed via various routes. This paper presents a condensed history of the benzene bioassay story with mention of benzene-associated human cancers. PMID- 17718184 TI - Response to Beecher's comment to The Scientist. PMID- 17718185 TI - Direct spectrophotometric determination of diacerhein in capsules. AB - A simple, rapid and precise ultraviolet spectrophotometric method using 0.1 N sodium hydroxide has been developed and validated for the assay of diacerhein. The drug can be estimated at 277 nm (ultraviolet region, UV) as well as at 502 nm (visible region, VIS). The absorbances were linearly correlated with concentration in the 6.0-24 microg mL(-1) range (r = 0.9999) and 10-34 microg mL( 1) range (r = 0.9998), respectively at 277 and at 502 nm. The relative standard deviation values for intra (n = 6) and inter-day (n = 3) precision were <2%. Recoveries ranged between 99.0 and 101.7%. The method has been successfully applied to the drug assay in capsules. It was also found that the excipients in the commercial capsules did not interfere with the method. Statistical analysis showed no significant difference between the results obtained at two wavelengths (277 nm or 502 nm). PMID- 17718186 TI - A validated UV spectrophotometric method for estimation of nebivolol hydrochloride in bulk and pharmaceutical formulation. AB - A simple, sensitive and accurate UV spectrophotometric method was developed for the assay of nebivolol hydrochloride in raw material and tablets. Validation of the method yielded good results concerning range, linearity, precision and accuracy. The absorbance was measured at 282 nm for nebivolol hydrochloride tablet solution. The linearity range was found to be 5-50 microg/mL for the drug. It was found that the excipients present in the commercial formulation did not interfere with the method. PMID- 17718187 TI - Spray-dried propolis extract, II: prenylated components of green propolis. AB - The effect of spray drying conditions on the chemical composition of Brazilian green propolis extract was investigated using a factorial design and high performance liquid chromatography. The raw and dried extract contents of caffeic acid, p-coumaric acid, drupanin, isosakuranetin, artepillin C, baccharin and 2,2 dimethyl-6-carboxyethenyl-2H-1-benzopyran were quantified using veratraldehyde (3,4-dimethoxybenzaldehyde) as internal standard. The baccharin content in spray dried propolis was affected by the drying temperature with a 5% significance level, while the coumaric acid and drupanin contents were dependent on drying temperature at a 15% significance level. The other chemical markers, caffeic acid, isosakuranetin, artepillin C and 2,2-dimethyl-6-carboxyethenyl-2H-1 benzopyran, showed to be independent of drying conditions. However, all the chemical markers showed some loss on drying, which varied from 30 to 50%. The results showed that prenylated compounds are sensitive to drying, but their losses may be considerably reduced under low temperatures, around 40 degrees C. The antioxidant activity of the spray dried propolis was determined by the diphenylpicrylhydrazyl (DPPH) method and showed a quadratic dependency on the temperature; extract feed rate and the interaction between them. However, spray dried propolis extracts presented antioxidant activities similar to the original propolis tincturae. PMID- 17718188 TI - Characterization of microcrystalline cellulose loaded diclofenac calcium alginate gel beads in vitro. AB - Diclofenac calcium alginate (DCA) beads containing microcrystalline cellulose (MCC) were prepared using ionotropic gelation method. The effect of MCC amounts on physicochemical characteristics of the DCA beads was examined. The particle size and entrapment efficiency of diclofenac sodium (DS) of the DCA beads increased with increasing amount of MCC. MCC could be involved in the calcium alginate formation to create a complex matrix in the DCA beads, which was revealed using FTIR spectroscopy. The MCC-DCA beads provided greater water uptake in distilled water, but retarded swelling rate in pH 6.8 phosphate buffer. A longer lag time and a similar drug release rate of the MCC-DCA beads in pH 6.8 phosphate buffer were found. The MCC-DCA beads also gave higher drug release rates in distilled water when compared with the DCA beads. However, the increase of MCC content over 0.5% in the DCA beads did not affect the drug release in distilled water. In conclusion, MCC could improve drug entrapment efficiency and modify drug release from the DCA beads. PMID- 17718189 TI - Prediction of drug solubility in amphiphilic di-block copolymer micelles: the role of polymer-drug compatibility. AB - The goal of the current study was to assess the value of predictive computational approaches for estimating drug solubility in hydrated micelles formed from di block copolymers of polyethylene glycol (PEG) and random copolyesters of epsilon caprolactone (CL) and trimethylene carbonate (TMC) using drug-polymer compatibility as assessed through the Flory-Huggins interaction parameter (chi). In order to accomplish this, the compatibility of several well-known model drugs (associated with the four biopharmaceutics classification system (BCS) classes) was assessed with both segments of the amphiphilic di-block copolymer PEG-b-P(CL co-TMC). Compatibilities were estimated based on the Hansen modification of the Hildebrand approach using Molecular Modeling Pro software. Experimental solubilities for model drugs were determined using a shake-flask technique at various polymer concentrations. The solubilities of 8 compounds in 10% w/v micelle solutions were in relatively good agreement with the predicted drug polymer compatibility. In addition, the approach allows for the selection of a suitable di-block copolymer for optimal solubilization of a specific drug. Furosemide was assessed as a model with results suggesting that it can be best entrapped in a di-block copolyester containing a relatively high CL content. The data suggests that prediction of drug solubilization of block copolymer-based micelles may be facilitated by assessing the compatibility of the drug for the component polymeric domains. PMID- 17718190 TI - Rheological and in vitro release behaviour of clotrimazole-containing aqueous SLN dispersions and commercial creams. AB - Clotrimazole is a wide spectrum local imidazolic antifungal agent used in several dermatological creams, having e.g. 1% (m/m) such as Canesten and Fungizid ratiopharm cream. In the present work, a new system based on solid lipid nanoparticles (SLN) containing the identical concentration of drug has been developed. A comparative study between the rheological properties of the referred creams and the developed aqueous SLN dispersions was carried out. The influence of incorporation of SLN in a standard hydrophilic cream on its flow curves was also assessed. In addition, the release of clotrimazole from the two commercial creams, as well as from aqueous SLN dispersions was studied. Concerning the rheological investigations, all tested commercial creams revealed very low shear rates and no yield points. Lipid nanoparticles having a mean diameter of approx. 200 nm have been incorporated into a hydrophilic cream, in a concentration of 20%, 30% or 40% (m/m). The hydrophilic cream containing 20% of SLN showed a dilatant-like character; however, increasing the percentage of incorporated lipid nanoparticles to 30% and 40% the formulation changed to a more pseudoplastic character, showing yield values of 28 Pa and 39 Pa, respectively. For in vitro release studies, Franz diffusion cells with a cellulose acetate membrane were used to measure the release of clotrimazole from two different commercial formulations in comparison to the aqueous SLN dispersion. After 6 h the amount of drug released was higher than 48% when delivered from both investigated commercial formulations and not higher than 25% when delivered from the aqueous SLN dispersion. The percentage of drug released determined after 24 h was more than 50% for Canesten cream and Fungizid-ratiopharm cream and not higher than 30% for the developed SLN formulation showing its prolonged release character. PMID- 17718191 TI - Influence of preparation method on itraconazole oral solutions using cyclodextrins as complexing agents. AB - In the literature, solubility values of itraconazole complexed with 2 hydroxypropyl-beta-cyclodextrin (HP-beta-CD) were found which were still much too low to obtain the target concentration of 1 g itraconazole/100 ml, the concentration of the marketed itraconazole formulation Sporanox (Janssen Pharmaceutica). Therefore, we compared two preparation methods: the classical and the dissolving method to investigate if the method of preparation can have an influence on the solubility of itraconazole complexed with cyclodextrin (CD). With the classical method, the active compound and the CDs are jointly dissolved with a co-solvent, propylene glycol, in water. With the dissolving method, the active compound is first dissolved separately in a solvent in which it dissolves well, while the CDs are dissolved in water, before mixing. Three different CDs were used and compared for their complexing capacity with itraconazole. The complex formation of itraconazole with HP-beta-CD, sulfobutylether-7-beta cyclodextrin (SBE-7-beta-CD) and maltosyl-beta-cyclodextrin (malt-beta-CD) was investigated at pH 2, in the presence of 10% propylene glycol for an oral solution. These three CDs were chosen as they can also serve in formulations for parenteral use. The method of preparation had an important influence on the complex formation. With the dissolving method, a much higher solubility of itraconazole was obtained using the same CD concentration than with the classical method. Inclusion capacity obtained with the dissolving method was comparable for HP-beta-CD and SBE-7-beta-CD: 1 g itraconazole/100 ml of 25% HP-beta-CD or of 30% SBE-7-beta-CD. In 100 ml of 40% malt-beta-CD only about 500 mg of itraconazole could be dissolved. With the classical method only around 160 mg itraconazole could be dissolved with 100 ml 40 % HP-beta-CD or SBE-7-beta-CD. Due to the fast preparation, once the CD amount is known by pretests, the dissolving method shows also an advantage for industrial production. PMID- 17718192 TI - Technological evaluation and equivalence assessment of lorazepam tablets in rabbits. AB - Four different oral lorazepam tablets (Tavor tablets as reference preparation and three generic tablet formulations, A, B and C) were investigated after administration to 12 rabbits to evaluate their bioequivalence. A single 2 mg/kg dose was administered orally as powder and lorazepam plasma concentrations were determined by a validated HPLC method. Maximum plasma concentrations (Cmax), of 207 ng/ml (reference), 198 ng/ml (A), 166 ng/ml (B) and 169 ng/ml (C) were achieved. Lorazepam appeared in the plasma at 0.66 h (Tmax) for all formulations, probably because the disintegration step was bypassed due to the pulverization of the administered doses. Areas under the plasma concentration-time curves (AUC(0 t) and AUC(0-infinity)) were determined. The obtained AUC(0-t) values were 556.57 ng h/ml (reference), 554.70 ng h/ml (A), 493.08 ng h/ml (B), and 487.88 ng h/ml (C). ANOVA results (P > or = 0.05) and 90% confidence intervals for the mean ratio (T/R) of AUC(0-t), AUC(0-infinity), and Cmax were within the EMEA acceptance range. Pharmacokinetic and statistical results of this study show that the four tested drug products (Tavor, A, B, C) are to be considered bioequivalent and interchangeable in medical practice. PMID- 17718193 TI - Development, validation and stability study of pediatric atenolol syrup. AB - Atenolol [4-(2-hydroxy-isopropylaminopropoxy)-phenylacetamide], is a cardioselective beta1-adrenergic receptor blocking agent prescribed for treatment of hypertension, angina pectoris and cardiac arrhythmias. However, most of these medicines are not formulated for easy or accurate administration to children. Atenolol is unstable in solutions and therefore the development of a liquid dosage form is a significant challenge. Studies showed that the degradation rate of atenolol is dependent on the temperature, indicating higher stability at 4 degrees C. Atenolol syrup is stable for 9 days, with acceptable apearance. A second order model adequately described atenolol decomposition when stored as syrup. A stability-indicating method was developed and validated in order to evaluate these studies. PMID- 17718194 TI - Preparation of a TK/GCV administration system mediated by transferrin modified pro-cationic liposomes. AB - Transferrin modified pro-cationic liposomes were prepared and used to investigate the effect of targeting therapeutic genes to human hepatoma carcinoma cells in vitro. The main lipid CHETA, cholest-5-en-3beta-yl[2-[[4-[(carboxymethyl)dithio] 1-iminobutyl]amino]ethyl] carbamate (C36H61N3O4S2), was synthesized and used to prepare pro-cationic liposomes. The thymidine kinase (TK) gene loaded pro cationic liposomes were prepared by first mixing the plasmid DNA and protamine together, and then incubating the resulted polyplexes with blank pro-cationic liposomes preformed by the thin film dispersion-sonication method. Transferrin (Tf) was adsorbed on the surface of pro-cationic liposomes via electrostatic interactions to form transferrin modified pro-cationic liposomes. Cellular association was measured by fluorimetry at excitation and emission wavelengths of 490 and 520 nm, respectively. The viability of TK gene infected cells following administration of ganciclovir (GCV) was investigated by MTT assay. The transferrin modified TK gene pro-cationic liposomes had a mean diameter of 240 +/ 12 nm and zeta potential of -24.10 +/- 2.5 mV (n = 3). The transmission electron microscopy image indicated that most of the liposomes were relatively regular and spherical with a condensed core inside. Cell-associated fluorescence of Tf liposomes and unmodified liposomes (without transferrin) was 7.8 x 10(6), and 3.2 x 10(6) per milligram protein, respectively. Compared to Lipofectamine 2000 (Invitrogen, USA) the pro-cationic liposomes and transferrin modified pro cationic liposomes had less cytotoxicity to cells. The transduced TK gene HepG2 cells were more sensitive to GCV than the un-transduced TK gene ones and the human normal Chang liver cells were not affected by the TK/GCV system mediated by procationic liposomes. PMID- 17718195 TI - Galactosylated liposomes as oligodeoxynucleotides carrier for hepatocyte selective targeting. AB - 18mer oligodeoxynucleotides (ODNs) which can inhibit survivin gene expression were selected as a model gene drug. The glycolipid (5-cholestan-3beta-yl)-1-[2 (lactobionyl amido) ethylamido] formate (CHE-LA) which specific target to the cells expressing galactose receptors was synthesized through the reaction of lactone of lactobiono-1,5-lactone (LA) and the amino-group of 2 (cholesteryloxycarbonylamino) ethylamine (CHE). The galactosylated liposome incorporated with CHE-LA containing oligodeoxynucleotides was prepared with SPC, cholesterol, CHE-LA and oligodeoxynucleotides by the thin-film hydration method. 1,1'-Dioctadecyl-3,3,3',3'tetramethylindocarbocyanine perchlorate (Dil) was used as a marker for all the liposome preparations. Compared with conventional liposomes (CL), the galactosylated liposomes (GL) exhibited a drastically increased distribution to the liver in vivo and the galactosylated liposomes containing oligodeoxynucleotides (GLO) can also more efficiently induced an apoptosis of HepG2 cells in vitro than the conventional liposome containing oligodeoxynucleotides (CLO). In addition, the GLO represented an improving of the ODNs entrapment efficiency. PMID- 17718196 TI - Antiproliferation in human EA.hy926 endothelial cells and inhibition of VEGF expression in PC-3 cells by topotecan. AB - Protracted administration of topotecan (TPT), a topoisomerase I inhibitor, exhibited high anticancer efficacy both in animal models and human cancers. This phenomenon is related to the TPT-induced inhibition of angiogenesis in tumor, but the potential mechanism remains largely unknown. In the present study, we reported that TPT (1-10 microM) could inhibit angiogenesis in a dose-dependent manner in Chick embryo chorioallantoic membrane (CAM) assay. TPT showed strong inhibitory activity against proliferation on human EA.hy926 endothelial cells with an IC50 value of 0.13 microM (MTT assay), lower than that of most sensitive cancer cell lines (IC50 range, 0.17 microM to 5.1 microM). TPT could induce EA.hy926 cells undergoing apoptosis, and the percentage of apoptotic cells induced by TPT (0.05 microM-5.0 microM) were 17.9%-52.3%. The similar results were observed with AO/EB staining. Flow cytometry assay also revealed that various concentrations of TPT induced cell cycle disturbance in EA.hy926 cells. Western blotting results showed that TPT caused an obvious increase of p53 expression and a decline of ERK expression in EA.hy926 cells. In addition, the VEGF expression of PC-3 cells is inhibited by TPT in hypoxia. Altogether, inhibiting proliferation of endothelial cells and down-regulating VEGF expression in cancer cells may involve in the antiangiogenesis mechanism of TPT. PMID- 17718197 TI - Protective role of tretinoin and N-acetyl-L-cysteine from antiproliferative action of cigarette smoke extract on alveolar epithelial cells. AB - To investigate the mechanisms by which tretinoin and N-acetyl-L-cysteine (NAC) reverse the growth inhibition of alveolar epithelial cells induced by cigarette smoke extract (CSE), MTT assay was used to evaluate cell viability. It was observed that both tretinoin and NAC could restore the viability of CSE-inhibited A549 cells. By incubation with fluorescent indicator H2DCFDA, it was documented that CSE-stimulated accumulation of intracellular reactive oxygen species (ROS) was obviously decreased by tretinoin or NAC. Furthermore, using semi-quantitative and real-time quantitative RT-PCR as well as western blot methods, high expression of insulin-like growth factor binding protein-2 (IGFBP-2) in A549 cells treated with CSE was found at both transcriptional and protein levels, and concomitant with the restoration of cell growth after treatment with tretinoin or NAC, down regulation of IGFBP-2 was observed. From the present study, it is concluded that both RA and NAC can antagonize CSE-induced growth arrest of alveolar epithelial cells and that down regulation of IGFBP-2 may play an important role in the process. PMID- 17718198 TI - New furostanol saponins from the bulbs of Allium macrostemon Bunge and their cytotoxic activity. AB - Four new furostanol saponins, named as macrostemonoside O, macrostemonoside P, macrostemonoside Q and macrostemonoside R, along with five known compounds, were isolated from the dried bulbs of Allium macrostemon Bunge. The structures of these new compounds were established by the spectral data elucidation (IR, ESIMS, 1D and 2D NMR) as 26-O-beta-D-glucopyranosyl-22-hydroxyl-5beta-furost-25 (27)-ene 3beta, 26-diol-3-O-beta-D-glucopyranosyl (1-->2)-beta-D-galactopyranoside (macrostemonoside O), (25R)-26-O-beta-D-glucopyranosyl-22-hydroxyl-5beta-furost 1beta, 3beta, 26-triol-3- O-beta-D-glucopyranosyl (1-->2)-beta-D galactopyranoside (macrostemonoside P), (25R)-26-O-beta-D-glucopyranosyl-22 hydroxy-5beta-furost-1alpha, 2beta, 3beta, 26-tetraol-3-O-beta-D-glucopyranosyl (1-->2)-beta-D-galactopyranoside (macrostemonoside Q) and (25R)-26-O-beta-D glucopyranosyl-22-hydroxyl-5beta-furost-2alpha, 3beta, 26-triol-3-O-beta-D glucopyranosyl (1-->2) [beta-D-glucopyranosyl (1-->3)]-beta-D-glucopyranosyl (1- >4)-beta-D-galactopyranoside (macrostemonoside R), respectively. Their cytotoxic activities on several cancer cell lines including solid tumor (HepG2, MCF-7, NCI H460 and SF-268) and drug resistant tumor (R-HepG2) were investigated and five compounds showed diverse cytotoxity to these cancer cell lines which suggest that they might be used as potential leading compounds to cure cancer diseases. PMID- 17718199 TI - The constituents from the stems of Garcinia cowa Roxb. and their cytotoxic activities. AB - Three new flavanone glycosides named garccowaside A, garccowaside B, garccowaside C, and three other known compounds were isolated from the ethanol extract of the stems of Garcinia cowa. These structures were established on the basis of spectroscopic evidence. Twelve compounds isolated from the stems of Garcinia cowa were tested for cytotoxic activities. PMID- 17718200 TI - Antimicrobial activity of the methanolic extract and of the chemical constituents isolated from Newbouldia laevis. AB - The methanolic extract (NLB) and ten compounds isolated from the root bark of Newbouldia laevis Seem, namely chrysoeriol (1), newbouldiaquinone (2), 2 acetylfuro-1,4-naphthoquinone (3), 2-hydroxy-3-methoxy-9,10-dioxo-9,10 dihydroanthracene-1-carbaldehyde (4), lapachol (5), beta-sitosterol-3-O-beta-D glucopyranoside (6), oleanolic acid (7), canthic acid (8) newbouldiamide (9) and 2-(4-hydroxyphenyl)-ethyltrioctanoate (10), were tested for in vitro antimicrobial activity. Twenty one microorganisms belonging to six Gram-positive and twelve Gram-negative bacterial species as well as three yeasts from Candida species were tested for their susceptibility to NLB and the pure isolated compounds based on the Agar Hole Diffusion test and the Liquid Dilution method. The Hole Diffusion assay indicated that NLB and compound 7 were active against all tested pathogens while other compounds showed selective activity with the antimicrobial spectra varying from 76% (compound 10) to 95 % (compound 6). Minimal inhibitory concentrations (MIC) also illustrated the important antimicrobial activity of NLB and of the isolated compounds. MIC values obtained varied from 9.76 to 312.50 microg/ml for NLB, and 0.038 to 9.76 microg/ml for pure compounds against most of the tested microorganisms. The antimicrobial activities of compounds 2, 4 and 9 are described here extensively for the first time. The results indicate a promising basis for the use of Newbouldia laevis and some of its active principles in the treatment of infectious diseases. PMID- 17718201 TI - Cytotoxicity of different types of methylated beta-cyclodextrins and ionic derivatives. AB - Cyclodextrins (CDs) are widely used materials and still in the focus of drug development. In spite of the extensive studies, there is limited information about the cytotoxic effect of different derivatives. This study compares the cytotoxic effect of methylated beta-CDs and some ionic derivatives. The methylated CDs involved in this study differ in the number and position of the methyl substituents. Heptakis(2,6-di-O-methyl)-beta-CD (DIMEB) with a degree of substitution (DS) of 14 has two methyl groups in all of the seven glucose subunits mostly at O-2 and O-6 position, each OH group is methylated in heptakis(2,3,6-tri-O-methyl)-beta-CD (TRIMEB) (DS = 21), and an unsystematic substitution is realized in randomly methylated beta-CD (RAMEB). DS is defined as the number of substituents per cyclodextrin ring. Using the above definition, the DS for RAMEB is 12.6. To see the effect of the ionic groups an anionic and a cationic CD derivative were also investigated: (2-hydroxy-3-N,N,N trimethylamino)propyl beta-CD (QABCD) (DS = 2) and carboxymethylated beta-CD (CMBCD) (DS = 3,5). The in vitro cell toxicity decreases in the order of DIMEB > TRIMEB > or = RAMEB > QABCD > CMBCD. Ionic beta-CDs were less toxic than the methylated derivatives. PMID- 17718202 TI - A new arbutin derivative from the herb of Myrothamnus flabellifolia Welw. AB - The ethyl acetate soluble fraction of an acetone/water extract of the air-dried aerial parts from Myrothamnus flabellifolia Welw. (Myrothamnaceae) was fractionated by a combination of CC on Sephadex LH-20, MPLC on RP-18 material and LPLC on MCI-gel. This procedure has led to the isolation of 2,3-di-O galloylarbutin, a new representative of the rare 2,3-diacylated glucopyranosides. The structure was elucidated with the help of 2D-NMR and ESI-MS experiments. Conformation of D-glucose was established by CZE (capillary zone electrophoresis). PMID- 17718203 TI - [Fluorescence diagnosis in bladder tumors]. PMID- 17718204 TI - [Modification of the hemodynamic parameters and peripheral vascular flow in a porcine experimental of model of laparoscopic nephrectomy]. AB - OBJECTIVES: It has been demonstrated that abdominal high-pressure and the use of CO2 pneumoperitoneum induce changes of the cardiovascular and respiratory systems, attributable to two factors: changes of the cardiac output (CO) and hypercarbia. Other modifications derived from these facts include changes of the systemic vascular resistances (SVR), blood pressure (BP), central venous pressure (CVP), vascular changes like modifications of the renal blood flow (RBF), carotid flow (CF), portal flow, and hepatic artery flow (HAF). Our objective is to analyze the hemodynamic modifications induced by pneumoperitoneum on renal blood flow, carotid flow, portal flow and hepatic artery flow in a porcine experimental model. METHODS: We compared two groups of pigs: CONTROL group (n = 10) and LAPAROSCOPIC group (n = 10), undergoing open or laparoscopic nephrectomy respectively. In every case, catheters were inserted into the right external jugular vein and femoral artery and cardiac output, CVP, blood pressure and systemic vascular resistances (calculated as RVS = (BP/CVP)x 80/CO); these measurements were taken at the following times: baseline, 5, 30, 60 min. and postoperatively. Renal blood flow, carotid flow, portal flow and hepatic artery flow were registered by means of an electromagnetic probe around the vessel 30 minutes after the start of surgery. RESULTS: Comparative analysis shows: an increase of cardiac output in the laparoscopic group, the difference which was maximal at 30 minutes (4.33 + 0.73 vs. 8 .54 + 1.26 l/min., p < 0.,001); a descent of the systemic vascular resistances (1118.81 + 302.52 vs. 663.37 + 81.45 dynes .s.cm5, p < 0.001) and an increase of blood pressure (66.5 + 11.52 vs. 80.25 + 2.49 mm Hg in the laparoscopic group. Flow analysis showed an increase of the carotid artery flow (125.73 + 41.69 vs. 291.7 + 51.52 ml/min., p < 0.001) and a decrease of portal flow (973.67 + 131.70 vs. 546.83 + 217.53 ml/min., p = 0.001) and hepatic artery flow (278.00 + 94.71 vs. 133.33 + 112.32 ml/min., p = 0.03) in the laparoscopic group. There were no significant differences in renal blood flow with the volume expansion used. CONCLUSIONS: Laparoscopic nephrectomy conditions an increase of carotid flow, probably secondary to the increase of cardiac output, and also a diminishment of hepatic perfusion, both arterial and portal. Nevertheless, volume expansion and the limitation of intra-abdominal pressure to 12 mm Hg enable to maintain similar renal blood flow in both groups. PMID- 17718205 TI - [The use of renal ultrasound for adult acute pyelonephritis]. AB - OBJECTIVES: To evaluate the need to perform renal ultrasound (US) in adult patients with acute pyelonephritis (APN). METHODS: A Review of the bibliography in the data bases PubMed and Cochrane Collaboration about the use of the ultrasonography in the evaluation and diagnosis of APN. RESULTS: Thirty-seven papers were found, but only 5 fulfilled the requirements for analysis. Four hundred and sixty three patients diagnosed of APN were revised, 449 (977) of whom got US. Between 171 ultrasonographic findings, only in 52 (11.5%) cases US findings changed initial diagnosis to complicated APN that could lead to surgery. CONCLUSION: The low incidence of ultrasonographic findings does not justify the practice of renal US to every patient with APN. In patients with persistent fever longer than 72 hours, antecedents of anomalies of the urinary tract, antecedents of renal lithiasis, pregnancy, atypical clinic or diabetes mellitus, there is a higher incidence of pathological US findings that justify a change in the therapeutic approach. Further prospective clinical studies are needed to confirm these conclusions. PMID- 17718206 TI - [Fournier's gangrene. Experience of the CMN SXXI Hospital]. AB - OBJECTIVES: To evaluate and review the Fournier's gangrene clinical presentation, initial APACHE II score and integral treatment of patients affected in HECMNSXXI. METHODS: Retrospective, descriptive and cross-sectional study in 40 patients with Fournier's gangrene diagnosis, accepted for treatment in HECMNSXXI who gather inclusion criteria, from February 1996 to February 2006. RESULTS: Patients were between 21 and 93 yr old. In total 39 men and 1 woman were recruited. The most common etiologic factor was urethral stricture in 40% of patients. Escherichia coli was detected in 42.5% of the cultures, and represented the most common pathogen. Initial Apache II score was more commonly between 10 and 14 points (35%). 6 patients died (15%) all of them with and Apache II score above 25 points. 55% of patients were affected by diabetes mellitus. All patients with Fournier's Gangrene received a triple antibiotic schema from admittance day, associated with emergency surgical debridement in the whole group. CONCLUSIONS: Aggressive and multidisciplinary treatment is mandatory in all the patients affected by Fournier's gangrene. We recommend utilisation of the APACHE II score as very useful tool to determine the prognosis. PMID- 17718207 TI - [Testicular germ cell tumours: descriptive study of 13 years of experience in the health care area of Badajoz]. AB - OBJECTIVES: To describe the incidence of germ cell testicular tumors in our Center, their characteristics and therapy results. METHODS: Retrospective study of 66 cases of germ cell testicular tumors diagnosed in the Health Area of Badajoz between 1993 and 2005. RESULTS: Mean age of the time of diagnosis was 32 years (range 16-80 years), presenting a younger age patients with non seminomatous germ cell tumors (NSGCT) (mean age 30 years). 86.5% of the patients did not have risk factors associated with the diagnosis of germ cell testicular tumor. Testicular mass was the most frequent symptom, and a higher proportion of tumors were located in the left testicle (51.5%). Non seminomatous germ cell tumors were the most frequent histological type (64.8%). Stage I (72%) was the most frequent stage in the group of seminomatous tumors, in comparison with 68.5% of non seminomatous tumors. Stages II-III appeared in 34.4% of the NSGCT and 28% of seminomatous, having worse prognosis. 92% of the patients received adjuvant treatment with chemotherapy and/or radiotherapy, and curative surgery was the only treatment in the remainder 8%. Residual mass surgery was undertaken in five patients (stages IIa, IIc and IIIa). Eight of the 66 cases were lost for follow up. Fifty-three of the 58 patients with follow-up are disease-free, 18 of them with more than five years of follow-up. CONCLUSIONS: An increased incidence of germ cell testicular tumors have been verified over last years, mainly NSGCT Nevertheless, the diagnosis of advanced stages of the disease has diminished in favour of initial stages, which have a better prognosis for the patient. Oncologycal treatment protocols have high cure rates, although a long-term follow up is needed due to the natural history of these tumors. PMID- 17718208 TI - [Nephroblastoma or Wilms tumor. Adult presentation. Report of two cases]. AB - OBJECTIVES: To present to new cases of nephroblastoma or Wilms tumor diagnosed in adult age. METHODS: The first case we report is a 16-year-old female with the diagnosis of stage I nephroblastoma after radical nephrectomy for a right renal mass. She underwent systemic polychemotherapy. The second case is a 33-year-old female with the diagnosis of nephroblastoma after percutaneous biopsy of a right renal mass. Due to the presence of lymph node, hepatic and lung dissemination systemic polychemotherapy (ACTD-VCR-DOX) was given. Right nephrectomy with regional lymph node dissection and hepatic metastasis excision were performed after confirmation of mass reduction. After that, the patient continued receiving systemic polychemotherapy with the same drugs. After resection of a lung nodule which did not disappear, and after confirmation of tumoral presence CB and VP 16 were added. RESULTS: Both patients are disease-free after 58 and 46 months respectively. CONCLUSIONS: This type of tumor typical of childhood is extremely rare in adult age, and despite worse survivals and more aggressiveness are described, they may be treated with the same protocols used in children, following any of the two big co-operative groups: American NWTS or European SIOP. PMID- 17718210 TI - [Cystocele and stress urinary incontinence associated with lower urinary tract obstruction]. AB - OBJECTIVES: The association of stress urinary incontinence secondary to urethral hypermobility and lower urinary tract obstruction in the same patient with cystocele is rare, and even represents a contradiction. The objective of our work is to treat to define the characteristics that identify this entity, in comparison with isolated stress urinary incontinence or lower urinary tract obstruction in patients with cystocele. METHODS: We performed a retrospective study in 1168 cases of cystocele in which urodynamic studies were performed. All patients underwent history and neurological and uro-gynecologycal physical examination. The urodynamic study included uroflowmetry, cystomanometry, voiding pressure/flow tests and voiding cystourethrograms. All data were collected in an Excel 2000 database and statistical analysis was performed with the SPSS software. RESULTS: A- General data: 25 cases qualified for the study in group I (isolated stress urinary incontinence with urethral hypermobility); 24 cases in group II (lower urinary tract obstruction); and 14 cases in group III (astress urinary incontinence associated with lower urinary tract obstruction). The proportion of each group in the whole group of cystoceles corresponded to a 4/1/0.05 ratio respectively. Mean age was 58.4 years for group I, 68.2 for group II and 71.2 for group III. A Statistically significant lower age was demonstrated for group I (p < 0.0005). B- The symptom "sensation of vaginal lump" was less frequent in group I (32%). A significant difference was demonstrated (p = 0.02). C- Group I showed a lower increase of daily voiding frequency (32%), p = 0.02. D- Group I showed less night-time voiding frequency (1 episode)(p < 0.04). E- Urinary incontinence with cough was less frequent in group 1 (84%) (p = 0.0004). F- Group I had more bladder capacity (243.6 ml) (p < 0.05).G- Group I showed less urethral resistances (URA = 37.9 cm H2O) (p = 0.01). H- W80-W20 was higher in group I: 1.3 W/m2 (p < 0.05). I- The symptom "sensation of vaginal lump appeared more often in group II (70.8%) (p = 0.02). J- Radiological degree of cystocele was greater in group II1 (1.7) (p < 0.05). K- Detrusor hyperactivity was more frequent in group III (64.3%) (p = 0.00009). L- No significant differences were found between groups II-III when comparing type of obstruction. CONCLUSIONS: The group of isolated stress urinary incontinence (group I) is characterized by a younger age, less frequency of sensation of vaginal lump, less daily frequency and nocturia, and urodynamic data of greater bladder capacity, lower urethral resistance and normal detrusor contractility. The group of isolated lower urinary tract obstruction (group II) could be characterized by a more frequent sensation of vaginal lump and increase of the radiological cystocele. The group of stress urinary incontinence associated with lower urinary tract obstruction had a higher percentage of cases of detrusor hyperactivity. All these data might enable a proper identification of different risk elements in the groups. PMID- 17718209 TI - [Voiding symptoms changes after vaginal sling surgery for female stress urinary incontinence]. AB - OBJECTIVES: To evaluate the changes in voiding symptoms in female patients with stress urinary incontinence (SUI) undergoing transvaginal sling techniques over a five-year period in the Department of Urology at the University Hospital of Albacete. METHODS: Between November 2001 and December 2005 126 patients with SUI (mean age 57.09 years; 36-78) underwent transvaginal sling techniques (Sling in Fast, TVK TOT). All patients were evaluated clinically and urodynamically. RESULTS: Average body mass index (BMI) was 28.14 kg/m2 (SD 4.66; 95% CI: 27.32 28.96). 92 patients (73%) presented between 2-4 previous pregnancies. 99 patients (80.9%) have had birth labour between 2 and 4 times. All of them were vaginal birth labours except 12 cases (9.5%) in which caesarean section had been performed. Daytime voiding frequency after surgery was over 120 minutes in 112 patients (88.9%). Night-time voiding frequency was equal or less than twice in 110 patients (87.3%). 104 patients (82.5%) presented at least two leaking episodes per day, and 105 patients (83.3%) needed to wear one pad per day or less during the last week before follow-up visit. The number of urinary leak episodes per day diminished in 114 patients (90.5%) with a mean decrease of 9.65 episodes (95% CI: 8.56-10.79) (p < 0.0001). Ninety-four patients (76.4%) were completely dry. CONCLUSIONS: Development of new surgical techniques for the treatment of SUI have improved results and diminished the number of complications, an expression of which is the favourable evolution of voiding changes after surgery. PMID- 17718211 TI - [New position for laparoscopic pyeloplasty. Our experience]. AB - OBJECTIVES: To share our experience performing laparoscopic pyeloplasty and our contributions to this surgery. METHODS: Between March 2004 and January 2006 we have performed 12 laparoscopic pyeloplasties in 12 patients. We modified our technique as we found difficulties during operations. By the only modification of patient position we have achieved a significant improve in our technique. RESULTS: We describe how we performed the operation in the first cases and how we do it today, with the new position. We also describe the advantages observed. CONCLUSIONS: With our technique we achieve an important surgical time reduction, improvements in safety and reduction of surgical complications. PMID- 17718212 TI - [Locally advanced renal cancer]. AB - OBJECTIVE: To report the case of a patient with the diagnosis of locally advanced renal carcinoma. METHODS: We present in the case in a clear and well illustrated way (pictures). We report the case of a female patient with a very big renal carcinoma, with local extension, who underwent nephrectomy through a lumbar approach and received chemotherapy and immunotherapy. RESULTS: Despite radical surgery, chemotherapy and immunotherapy the tumor had rapid evolution locally and systemically, as a demonstration of its high aggressiveness. CONCLUSIONS: Renal carcinoma is considered the tumor with a high tendency to have metastases. The prognosis depends on size, stage and grade, determining factors for patient survival. Although there are new therapeutic options (immunologic), surgery continues being the main therapeutic tool. Continuous regular follow-up enable us detection and timely treatment of any event (local or systemic recurrence). PMID- 17718214 TI - [Late lymph node metastasis in renal cell carcinoma. Case report]. AB - OBJECTIVE: To report one case of late metastasis of a clear cell carcinoma treated by radical surgery. METHODS/RESULTS: Patient with history of radical nephrectomy and lymphadenectomy six years before presenting with regional lymph node metastasis in a followup diagnostic test. After treatment with immunotherapy, stopped because of intolerance, surgery of the metastatic lymph node mass was decided. CONCLUSIONS: Renal cancer is an unpredictable tumor in terms of oncological behaviour, so that it may metastasize any time in its evolution, even after radical surgery and several years free of disease. Surgery for the metastases of renal cancer is a good therapeutic option, with good long term results, when they are isolated and accessible to surgery. PMID- 17718213 TI - [Infantile myofibromatosis. Relationship with the genitourinary tract. Case reports and bibliographic review]. AB - OBJECTIVE: To present a case of infantile myofibromatosis of visceral location and a review of the literature. METHOD/RESULTS: We report the case of an 11-year old Caucasian girl hospitalized for abdominal tumorous mass, weight loss and lack of appetite. Physical examination showed: cutaneous-mucous paleness and a painless, palpable tumorous mass of 8-10cm in the right abdominal flank, of firm consistency with defined edges and extending past the midline. Blood test showed hemoglobin 90 mg/l and erythrocyte sedimentation rate of 130 mm/hour. Chest x-ray and bone study were normal, while abdominal x-ray showed intratumorous calcification, intravenous urographyc showed light displace downwards and outwards of the right kidney. Ultrasound showed a solid echogenic mass with a diameter of 11cm in the right abdominal flank, above and extending towards the lower portion of the right kidney. Surgical treatment for possible neuroblastoma was initiated, during which various tumorous growths were observed in the mesocolon, the largest measuring 7cm, which were removed. Macroscopic examination showed whitish well-defined tumorous growths of firm consistency with focal calcifications. Microscopic examination showed a proliferation of fibroblastic type cells, with some areas having smooth muscle cell characteristics. Diagnosis was myofibromatosis. CONCLUSIONS: Infantile myofibromatosis is the most common fibrous disorder of infancy and childhood, more commonly found between birth and two years of age, may also appear later in life. Etiology is unclear, but certain studies report estrogen involvement in its pathogenesis. Clinical symptoms depend on the location and extension of the lesion and age at presentation. Spontaneous relapse may occur. Prognosis is good in the absence of visceral damage, although generalized congenital myofibromatosis with visceral damage is associated with high mortality especially in the first months of life, due to its destructive capacity, obstruction of vital organs, growth inhibition or infection. Urologic concerns include possible infiltration of genito-urinary organs (kidney, corpus spongiosum) and its association with urologic abnormalities. Ultrastructural and immunohistochemical studies show that the tumor is composed of myofibroblasts, with estrogen receptors, displaying vimentin and smooth muscle actin immunoreactivity. Strict follow up is recommended in patients with congenital myofibromatosis to avoid or detect possible complications that may be life threatening (Bone survey abdominal-pelvic ultrasound, echocardiogram, chest abdominal CT and biopsy). The treatment of choice is surgical removal, with extensive excision to avoid possible relapse. PMID- 17718215 TI - [Intratesticular varicocele associated with glandular atrophy and parenchymal ultrasound abnormalities]. AB - OBJECTIVE: To report one case of intratesticular varicocele, infrequent pathology (2% of the cases), with a series of ultrasound peculiarities: testicular atrophy and associated parenchymal abnormalities, in a 24-year-old patient with left testicular pain. METHODS: Ultrasound showed severe left varicocele, mixed type, with the regular extratesticular component and dilated subcapsular and mediastinum vessels, with turbulent flows increasing with Valsalva's manoeuvre, as well as an alteration of the ultrasound pattern of the parenchyma, with hypoechoic and hypovascular areas and diminished testicular size. DISCUSSION/CONCLUSIONS: Intratesticular varicocele is a rare pathology more frequent in the left testicle, which is frequently associated with extratesticular varicocele. The presence of testicular atrophy and associated parenchymal abnormalities has been rarely described in the literature. Clinically they show features overlapping the extratesticular types. PMID- 17718216 TI - [Seminoma and teratocarcinoma: synchronic unitesticular presentation as independent nodules with different histologies? Ultrasound characteristics]. AB - OBJECTIVE: To describe the ultrasound characteristics, vascularization pattern (colour Doppler ultrasound) and possible histogenesis of one case of synchronic untesticular seminoma and teratocarcinoma as independent tumor nodules, histologically different, in a 19-year-old patient with testicular mass for eight months. METHODS: Conventional ultrasound, colour Doppler ultrasound, and high resolution Doppler angiogram were performed, analyzing vascular flows. After resection of the tumor, macroscopic and histological sections were related with ultrasound images. RESULTS: The patient showed three independent, well limited, tumoral nodules in the right testicle: two of them heterogeneous, 20 and 33 mm in diameter, with cystic areas and calcifications. The third nodule was solid, hypoechoic and homogeneous, 26 mm in diameter. All nodules presented an increase in vascularization with low resistance arterial flows. Histologically the first two nodules were teratocarcinomas (predominantly mature teratoma and embryonal carcinoma) and the third classic seminoma. CONCLUSIONS: Although seminoma and mixed germ cell tumors are common, "their presentation in the some testicle as independent nodules with different histologies is a rarely referred case in the literature, which allows us to apply a histogenetic and ultrasound-pathologic correlation model in seminomatous and nonseminomatous tumors. The presence of cystic cavities and gross calcifications is highly correlated with teratoma. In our case there are not significant differences in the vascularization pattern with Doppler ultrasound. PMID- 17718217 TI - [Recurrent urinary tract infection in a patient with sacral agenesis and vertebral-lumbar dysraphism. Diagnostic-therapeutic scheme and clinical outcome]. AB - OBJECTIVE: To present and analyze one case of sacral agenesis with distal lumbar vertebral dysraphism, and to highlight the most relevant elements found in a bibliographic search. METHODS: We describe the clinical characteristics of an adult patient with sacral agenesis, the diagnostic-therapeutic urological management and her outcome over four years of follow-up. A bibliographic search was also performed including review of all articles published over the last 16 years; we briefly include the most relevant elements. CONCLUSIONS: Sacral agenesis, as a local regional expression of "caudal regression syndrome" almost invariably produces functional involvement of the bladder and recurrent urinary tract infection, although the evolution may be benign like present case. This does not exempt from the unavoidable need of proper initial morphological functional diagnosis, periodic follow-up and treatment. PMID- 17718218 TI - [Renal cirsoid aneurysm (congenital arteriovenous fistula): a rare cause of severe hematuria]. AB - OBJECTIVE: Congenital arteriovenous fistulas are an exceptional clinical feature. Although they are frequently asymptomatic, their presentation as severe hematuria pose an excellent diagnostic exercise and often immediate therapeutic action. METHODS/RESULTS: We report the case of a 75-year-old female patient presenting with severe hematuria producing anaemia, high blood pressure and congestive heart failure. Image tests revealed right ureteral-hydronephrosis with bladder blockage by blood clots. The endoscopic study (cystoscopy and ureterorenoscopy) alerted about the origin of the hematuria from the right kidney, finally requiring nephrectomy as definitive treatment. Pathology revealed the presence of a round formation with multiple vascular channels, arterial and venous, in the pyelocalicial submucosa, with focal epithelial erosion, compatible with congenital arteriovenous fistula. We review the diagnostic and therapeutic features in the literature. CONCLUSIONS: Renal congenital arteriovenous fistulas represent a diagnostic dilemma. They may present asymptomatic or condition clinical features derived from the shunt and high cardiac output (hypertensive cardiopathy and congestive heart failure) or from the erosion and acute hemorrhage into the urinary tract (severe renal hematuria). Treatment should be conservative with embolization or supraselective sclerosis. Nevertheless, in cases of big fistulas, post embolization revascularization, or hemodynamic instability nephrectomy is an excellent option. PMID- 17718219 TI - [Blue prostatic nevus. Case report]. AB - OBJECTIVE: To state the scarce incidence of this prostatic pathology and the relative confusion with terminology applied to the presence of intraprostatic melanin pigments. METHODS/RESULTS: 66-year-old patient with elevated serum PSA with the diagnosis of prostatic blue nevus after biopsy. CONCLUSIONS: This diagnostic finding has not clinical or prognostic significance. They are benign lesions that must not be confused with other similar more aggressive lesions. PMID- 17718220 TI - [Urethral recurrence of high grade transitional carcinoma in a patient with neobladder]. PMID- 17718221 TI - [Suspected urothelial neoplasm in the right renal pelvis in patient with history of recurrent right nephritic colic]. PMID- 17718223 TI - [Classification and profile of adverse drug effects]. AB - It is necessary to classify adverse drug reactions by grading the certainty of causal relationship between the drug administration and the adverse reaction. The most widely used classification is the one of the World Health Organization (WHO). PMID- 17718222 TI - Complete excision of urachal cyst by laparoscopic means: a new approach to an uncommon disorder. AB - OBJECTIVE: Anomalies of the urachal remnant are rare. Urachal cysts are usually asymptomatic, however, when they become infected, they can mimic a wide variety of intra-abdominal pathologies. We present two patients in which an urachal cyst was found. METHODS: Two male patients 25 and 38 years old respectively underwent laparoscopic resection of an urachal remnant. In one of the cases the urachal remnant was complicated by infection. Opportune clinical and radiologic diagnose was made in both cases and complete excision of the urachal remnant was carried out by laparoscopic means. RESULTS: The procedures were performed without complications and follow up showed excellent results. Both patients presented very short convalescence with rapid recovery. CONCLUSIONS: The treatment of choice for urachal pathology is the complete excision of the complicated lesion. For this matter laparoscopic surgery assures surgical results comparable to conventional surgery adding the advantages of a minimally invasive approach. PMID- 17718224 TI - [Visual cortes--is it a concern?]. AB - The visual cortex may be involved in adverse drug reactions, leading to three different clinical presentations: cortical blindness, visual hallucinations and visual aura without headache. The drugs with potential visual cortex toxicity are described. PMID- 17718225 TI - [Toxicity of recent and less recent drugs on the optic nerve. Does Viagra cause blindness?]. AB - The optic nerve is quite vulnerable to the toxic effect of drugs. Since the last thirty years new drugs have appeared that are potentially harmful to the optic nerve. They are described. PMID- 17718226 TI - [Epilepsy and Sabril]. AB - This article presents a litterature overview of the ophthalmologic secondary effects due to Sabril. First, a review of the visual field loss that can be related to Sabril treatment is presented; the epidemiological and physiopathological aspects of this visual field loss are considered based on experimental and clinical data. The link that can be established between electrophysiology and physiopathology following these data is further examined. Finally, two ophthalmologic follow-up algorithms are proposed for patients treated by Sabril, one for adults and the other for children. PMID- 17718227 TI - [Retinal pigment epithelium--the point about safety of antimalarial agents]. AB - The antimalarial agents Chloroquine and Hydroxychloroquine are used for the treatment of inflammatory disorders such as rheumatoid arthritis and lupus erythematosus. The first published reports of retinal toxicity appeared in 1959. Despite a low incidence for low doses and a short period of time, a regular ophthalmological screening is recommended to detect this maculopathy early. High risk criteria are: > 3 mg/kg/d of Chloroquine or > 6.5 mg/kg/d of Hydroxychloroquine, duration of treatment > 5 years, obesity, renal or hepatic disease, old age or pre-existing macular disease. Annual screening, and in some cases every 6 months, is recommended for high risk patients. Low risk patients will have an ophthalmologic examination every 18 months. The baseline examination includes visual acuity, Amsler grid, biomicroscopy, automated perimetry (central 10 degrees), color vision testing and fundus. Fluoroangiography and (multifocal) electroretinography should be considered if baseline screening is doubtfull or if toxicity is suspected. If relative paracentral bilateral scotomas or subtle alterations of retinal pigmentary epithelium are documented, the drug should be stopped. The collaboration with the internist and good information to the patient are necessary. PMID- 17718228 TI - [Retinal pigment epithelium--desferal]. AB - Deferoxamine mesylate (Desferal) is a chelating agent used in hemosiderosis and aluminium overload consecutive to renal dialysis. This drug is the most efficacious for treating iron overload but is associated with ocular toxicity: dose and duration related symptomatic optic neuropathy on the one hand, reversible if treatment stopped, and acute retinal involvement followed by irreversible paucisymptomatic pigmentary changes on the other hand. Toxic risk factors are intravenous mode of administration, high doses, small iron or aluminium overload, diabetes and young age. Hence, dosis should be adapted to the amount of overload and ophthalmological follow-up should be instaured. Indeed, if treatment is stopped at the beginning of the toxic effect, ocular involvement is reversible. The baseline ophthalmological examination should include visual acuity measurement, color vision, visual fields, slit lamp and fundus. In case of risk factors, electrophysiology and fluoangiography should be added. PMID- 17718229 TI - [Damage to retinal vasculature]. AB - The use of interferon increased these last years. Cotton wool-spots, retinal hemorrhages, and microaneurysms are common manifestations of interferon retinopathy. The frequency of this retinopathy is underestimated as it is often asymptomatic. Screening and a multidisciplinary approach are therefore recommended. PMID- 17718230 TI - [Cystoid macular edema]. AB - Cystoid macular edema is a known side effect of different systemic and local medications. Nicotinic acid used as a hypolipemiant agent can cause cystoid macular edema. Local adrenergic antiglaucomatous drugs as well as prostaglandin analogs can induce cystoid macular edema especially if other risk factors, which will be discussed, are present. Benzalkonium chloride, a universal conservative agent, can also favour cystoid macular edema. PMID- 17718231 TI - [Crystalline retinopathy]. AB - Crystalline retinopathy is characterized by intraretinal crystalline deposits that, according to their etiology, can be localized in the macular area or, indeed, be found in the entire retina. These deposits can be associated or not to visual loss and electrophysiological perturbations. Among the toxic drugs leading to this retinopathy are tamoxifen, canthaxanthine, methoxyflurane, talc and nitrofurantoin. A detailed description of tamoxifen and canthaxanthine toxicity is reported in this chapter. PMID- 17718232 TI - [Central serous corticoid and chorioretinopathy]. AB - Central serous chorioretinopathy (CSC) is a relatively frequent ocular disorder. Its pathophysiology remains however unclear. This disease typically affects young men with type A behaviour within a context of stressful events. Recently, endogenous or exogenous hypercortisolism has been associated with development, prolongation and exacerbation of CSC. Exogenous hypercortisolism has been induced by any route: intravenous, cutaneous, or nasal spray. Some clinical features such as bilaterality of lesions, an atypical form of the presentation can evoke this association. Although a few years ago glucocorticoids were still used as treatment of CSC, experimental and clinical observations suggest that they are contra-indicated in the context of CSC. PMID- 17718234 TI - [Ocular side effects of glaucoma treatment agents]. AB - Antiglaucomatous ocular side effects can be divided into specific and non specific ones. Non specific ocular side effects are mainly caused by preservative agents; they are essentially external ocular irritations. Specific ocular side effects are strongly related to the mechanism of action of the drug. These specific ocular side effects are described, caution being taken to precise the strength of the association between each side effect and the related drug by using the classification of World Health Organisation (WHO) (certain, probable, possible or unlikely). PMID- 17718233 TI - [Toxicity of intravitreal injections of antibiotics and antivirals]. AB - Intravitreal injections of antivirals, antifungals and antibiotics are very efficacious in the management of intraocular infections, which is not the case with per os, intravenous or peribulbar administration. However, these drugs have some toxic potential, more pronounced if used in intraocular condition. Being too toxic, aminoglycosides have been replaced by Ceftazidime and Vancomycine in the management of bacterial endophthalmitis. Efficacy of these drugs for prophylactic use is not demonstrated and their toxic potential remains to be kept in mind. PMID- 17718236 TI - [Intravitreal injections of corticoids]. AB - Intravitreal injections of triamcinolone acetonide are today widely performed as a therapeutic tool for a large variety of ocular diseases. The risk of toxicity of the product and its vehicle is quite real and is still at the center of investigations. Complications related to the substance and the technique of injections are already well-known (intraocular pressure rise, cataract, endophthalmitis, pseudo-endophthalmitis, vitreous haemorrhage and retinal detachment). Carefulness and rigor in the indication, realization and follow-up of these injections are therefore mandatory. PMID- 17718235 TI - [Origin of corticosteroid glaucoma]. AB - Cortisonic glaucoma is frequent, clinically similar to chronic open angle glaucoma but directly linked to a corticosteroid treatment. Four risk factors are involved in the hypertonic effect of steroids: genetic ground: primary open angle glaucoma, diabetes, myopia, young age; intraocular penetrance and anti inflammatory efficacy; the mode and duration of administration. PMID- 17718237 TI - [Acute glaucoma originating from medication]. AB - Secondary angle-closure glaucoma with pupillary block can be related with anticholinergic drugs or sympathicomimetics alpha1. Secondary angle-closure glaucoma with ciliary body oedema is predominantly related with Topiramate. PMID- 17718238 TI - [The uvea and crystalline lens: toxicity of new medications]. AB - The development of pharmaceutical industry brings us constantly new therapeutic agents. Whatever their delivery method, all these agents can potentially damage the ocular tissues. The WHO has established criteria to statue on the level of certainty between the drug and its adverse reaction. This article reviews the inflammatory lesions of the uvea and the lesions of the crystalline lens, which can be caused by the currently available medications. It develops the new pharmacologic agents and insists on the older ones sometimes already reported in the Bull. Soc. belge Ophtalmol in 1972, whose toxicity on the uvea or on the crystalline lens was then poorly known or rarely mentioned in the literature. PMID- 17718240 TI - [Toxic effects of medications on the cornea]. AB - We reviewed the most recent systemic drugs used in Belgium causing toxic corneal side effects. These adverse reactions are rarely specific and often ignored or unknown. This description can help the physician's evaluation for a better interdisciplinary approach. PMID- 17718241 TI - [The pathology of ocular syndromes caused by toxicity]. AB - Ocular adnexa represent a complex system of delicate organs and functions which are the target of varied side effects. Most involve more than one component at a time, however landmark signs and symptoms can be outlined. Dry eye leads the list. The aqueous production of the tear film can be decreased by certain psychotherapeutic agents (especially the older ones), while the phospholipidic component, produced by the Meibomian glands, can be markedly affected by retinoids. On the other hand, cytostatic drugs like Docetaxel (and 5-FU at a lesser degree) frequently induce canalicular stenosis, resulting in epiphora. Amongst a long list of substances, diphosphonates used in the treatment of osteoporosis and phosphodiesterase-5 inhibitors used in erection deficiencies induce conjunctival irritation, either directly or by contiguity. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis represent the most severe toxic insult to the mucosae. A recent chemotherapeutic agent, Imatinib, induces fluctuant palpebral edema in a majority of patients. Despite being applied topically, prostaglandin analogs exert a profound effect onto the cellular physiology of the eyelash and the ocular and palpebral melanocyte. Indirectly, immunosuppressive agents used in graft rejection control have been associated with the emergence of secondary neoplasia, mainly lymphoma, of which the orbit is a rare but possible location. Chronic administration of steroid drugs leads to hypertrophy of the orbital fat and proptosis. PMID- 17718239 TI - [The deleterious effect of certain surface active agents on the ocular surface]. AB - Most ocular solutions enter the eye through the corneal epithelial barrier. In order to pass through this barrier, these hydrosoluble drugs require to be associated with a detergent agent to increase topical efficiency. Although these agents have a preservative action, it was recently demonstrated that, after short or long term use, toxic side effects on the ocular surface will occur. PMID- 17718243 TI - An audit of blood pressure control in clinical practice in Thailand. AB - To gain "real life" data on the BP control of hypertensive patients in clinical practice in Thailand, a multi-centre cross-sectional study was carried out. Demographic data, cardiovascular risk factors, and antihypertensive regimens were collected. A total of 1,259 patients were enrolled between October 2003 and December 2003, 924 cases from 6 regions of different levels of health care and 335 cases from 4 medical training centres and a tertiary care hospital in Bangkok. Eighty one percent of the patients, age ranged from 45 to 75 years (61.2 +/- 11.6). Forty four percent of patients in audit had a BP < 140/90 mm Hg and only 12.3% of DM patients had attained a JNC 7 recommended BP target of 130/80 mm Hg. Hypercholesterolaemia (65.3%) was the most prevalent risk followed by DM (27. 7%). Antihypertensive drug used at the initial visit compared with the last visit were ARB (0.9% vs 6.1%), ACE Inhibitors (30.1% vs 40.0%), beta-blockers (27.3% vs 46. 7%), CCBs (23.2% vs 37.7%), and diuretics (46.0% vs 53.5%). In addition, the numbers of antihypertensive drugs used at the initial visit compared with the last clinic visit were one drug (62.0% vs 33.0%), two drugs (29.7% vs 45.8%), three drugs or more (3.7% vs 20.4%), with an average of 1.3 +/- 0.6 vs 1.9 +/- 0.8 drugs per patient. Two thirds of patients (66.2%) were on 2 or more antihypertensive drugs. Among the type 2 DM, 5% had records of microalbuminuria, and 50.6% and 9.8% were receiving ACE Inhibitors and ARBs, respectively at the last clinic visit. PMID- 17718242 TI - [Oculomotor anomalies from medications]. AB - Many medicines, mainly with neurological purpose, interfere with the oculomotricity. The biochemistry of the oculomotor systems and thus, the mechanisms of action of these drug interferences are not completely clarified. Most medicines impair the eye movements at the level of their fine adjustment by feed-back loops implying the cerebellum. Quite often, the interferences remain asymptomatic, restricted to a saccadic pursuit, hypometric saccades or an end point nystagmus. Sometimes however, symptoms of dizziness or oscillopsia appear, due to loss of the vestibulo-ocular reflexes efficiency. A diplopia or a blurred vision by double outline could be suggestive of an ocular motor paresis or a loss of the binocular fusion due to drugs action. PMID- 17718244 TI - Hypertension study among attendants at the Board of Investment Fair 2000. AB - To study the prevalence of hypertension, blood pressure (BP) controlled and cardiovascular risk factors in people who attended the Board of Investment 2002 Fair (BOI Fair). Altogether 1,774 participants aged more than 15 years old voluntarily participated in BP check-ups during the 3rd-17th February 2000 at the BOI Fair. Three hundred and fifty participants (19.7%) were known cases of hypertension (HT) and 340 participants (19.2%) were newly diagnosed hypertension cases (NHT). Of the HT group, 216 cases were under current treatment (61.7%) and only 69 cases (31.9%) had adequate BP control. Of the NHT group, cardiovascular risk factors were found more frequently than in normotensive participants. This study indicates the necessity of building up awareness in the population, improving in clinical detection, effectively controlling of the risk factors and the normalization of BP. This might prevent hypertension and reduce the cardiovascular disease. PMID- 17718245 TI - Comparison of telomerase activity between malignant and tuberculous pleural effusions. AB - OBJECTIVE: To determine if telomerase activity can differentiate malignant from tuberculous pleural effusions. DESIGN: Telomerase activity in malignant and tuberculous pleural effusions was measured in a blinded manner using a PCR-based telomeric repeat amplification protocol (TRAP) assay. MATERIAL AND METHOD: Fifty two patients with lymphocytic exudative pleural effusions were identified on thoracocentasis over a period of 18 months. RESULTS: Telomerase activity was detected in 34% of malignant pleural fluid samples and 50% of tuberculous pleural effusions. The positive rate of telomerase activity was 30.7% for primary lung cancer and 37.5% for metastatic pleural effusion. The sensitivity and specificity of telomerase activity assay were extremely low (35.7% and 52.9%, respectively), compared with that of cytological examination (52.6% and 65.4%, respectively). Moreover the diagnostic accuracy of telomerase activity in combination with cytology was even lower than cytological examination alone (46.7% vs. 60%, respectively). This finding was in contrast to previous reports and demonstrated that the detection rate of telomerase activity in tuberculous pleural effusions was greater than that observed in malignant pleural exudates. CONCLUSION: Telomerase activity does not appear to be a useful marker for differentiating malignant from tuberculous effusions. PMID- 17718246 TI - The effect of lateral position on oxygenation in ARDS patients: a pilot study. AB - BACKGROUND: The effect of body position on oxygenation in acute respiratory distress syndrome (ARDS) patients has long been known. Prone position improves the PaO2 in 60-70% of ARDS patients. However the effect of the lateral positions, which are used in routine critical care, has never been reported. OBJECTIVE: To determine whether placing the patient in a lateral position has any effect on oxygenation in ARDS. MATERIAL AND METHOD: Prospective observational study, comparing oxygenation in ARDS patients between supine, right and left lateral positions (> or = 60 degree). RESULTS: We included 18 ARDS patients, their mean aged was 52.2 +/- 19.6 years, 14 were men and the ICU mortality rate was 61.1%. There was no significant change in the mean PaO2, arterial blood gas parameters, respiratory mechanics and hemodynamic parameters between the supine and decubitus positions in the overall group. However there was a trend toward increasing the mean PaO2 during right lateral position compared with the supine position (90.3 +/- 29.0 vs 84.6 +/- 20.4, p = 0.23). Nine patients who responded to the right lateral position had significantly higher mean PaO2 during the right lateral position than in the supine position (107.8 +/- 29.0 vs 85.6 +/- 21.8, p < 0.0001). In this group, four patients had predominant left pulmonary infiltration and five patients had equally bilateral pulmonary infiltration on chest X-ray. Unfortunately, the PaO2 in three patients decreased more than 10 mmHg during right lateral decubitus. CONCLUSION: The PaO2 increased while in the right lateral position in patients with predominant left pulmonary infiltration or bilateral infiltration. This effect may be due to the small sample size. A further large-sized randomized controlled study is needed. PMID- 17718247 TI - Medical thoracoscopy: experiences in Siriraj Hospital. AB - OBJECTIVE: Medical thoracosopy is the investigational and therapeutic procedure for many kinds of pleural diseases. One of its indications is for the diagnosis of undetermined pleural effusion. We report our experience in using medical thoracoscopy in investigating undiagnosed pleural effusion. MATERIAL AND METHOD: Thirty four consecutive patients had thoracoscopy done for this indication from 1999 to 2005. RESULT: Malignancy was diagnosed in 21 patients. Pleural biopsies showed chronic pleuritis in 7 patients. Normal thoracoscopy was found in 2 cases and the procedures were unsuccessful in 4 cases because of extensive pleural adhesion. In patients with malignancy, pleural nodules had a tendency to be localized in the lower part of the pleural cavity. Better selection of the patient should lower the unsuccessful procedure. CONCLUSION: The review of the indication for thoracoscopy will increase the use of this procedure in respiratory medicine practice and shorten the investigation time. PMID- 17718249 TI - Grave prognosis on spontaneous intracerebral haemorrhage: GP on STAGE score. AB - BACKGROUND AND OBJECTIVE: Spontaneous intracerebral haemorrhage (ICH) is more common in Asia than in western countries, and has a high mortality rate. A simple prognostic score for predicting grave prognosis of ICH is lacking. Our objective was to develop a simple and reliable score for most physicians. MATERIAL AND METHOD: ICH patients from seven Asian countries were enrolled between May 2000 and April 2002 for a prospective study. Clinical features such as headache and vomiting, vascular risk factors, Glasgow coma scale (GCS), body temperature (BT), blood pressure on arrival, location and size of haematoma, intraventricular haemorrhage (IVH), hydrocephalus, need for surgical treatment, medical treatment, length of hospital stay and other complications were analyzed to determine the outcome using a modified Rankin scale (MRS). Grave prognosis (defined as MRS of 5 6) was judged on the discharge date. RESULTS: 995 patients, mean age 59.5 +/- 14.3 years were analyzed, after exclusion of incomplete data in 87 patients. 402 patients (40.4%) were in the grave prognosis group (MRS 5-6). Univariable analysis and then multivariable analysis showed only four statistically significant predictors for grave outcome of ICH. They were fever (BT > or = 37.8 degrees c), low GCS, large haematoma and IVH. The grave prognosis on spontaneous intracerebral haemorrhage (GP on STAGE) score was derived from these four factors using a multiple logistic model. CONCLUSION: A simple and pragmatic prognostic score for ICH outcome has been developed with high sensitivity (82%) and specificity (82%). Furthermore, it can be administered by most general practitioners. Validation in other populations is now required. PMID- 17718248 TI - Effect of botulinum toxin injection for achalasia in Thai patients. AB - BACKGROUND: Achalasia is a disorder of the esophagus. The lower esophageal sphincter fails to relax and increases the loss of body peristalsis. It is an uncommon disease worldwide. Data regarding its treatment are derived mostly from North America and European countries. Few data regarding this treatment were available in Asia and no data about using botulinum toxin injection for this disease was available in Thailand. OBJECTIVE: To evaluate the efficacy of botulinum toxin in achalasia in Thai patients. MATERIAL AND METHOD: Eleven achalasia adult Thai patients with a mean age of 56.5 +/- 16.9 were studied. There are nine females and two males. The duration of symptom before treatment was 27.5 +/- 34.5 months. All patients receiving botulinum toxin injection at Siriraj hospital between 2001 and 2006 were retrospectively reviewed. Pretreatment of baseline lower esophageal sphincter, symptom score and body weight were compared. Time to second botulinum toxin injection or the need to receive treatment for recurrence was recorded to evaluate the time of recurrence. Adverse events from this procedure were collected. RESULTS: Eleven patients were involved in this study. One patient that received 40 units of botulinum toxin showed no response after a six months follow up. The other ten patients received botulinum toxin 80 units for each session and were enrolled in this study. All ten patients demonstrated good response to the first botulinum toxin injection and subsequent injections. Four patients received only one session of botulinum toxin injection during study period. Meanwhile, five patients received two sessions and only one patient required four sessions. Symptom score of all ten patients improved significantly compared with pretreatment score (7.3 +/- 1.3 for pretreatment and 0.4 +/- 0.5, 0.9 +/- 0.7 and 1.6 +/- 1.3 after 2 weeks, 3 months and 6 months, respectively). Body weight increased significantly when compared with pretreatment (47.7 +/- 6.5 Kg for pretreatment and 49.2 +/- 5.8, 50.5 +/- 6.4, and 50.7 +/- 5.8 Kg after 2 weeks, 3 months, and 6 months, respectively). Previous treatments prior botulinum toxin injection do not seem to influence the effect of this treatment. Mean time of recurrence is 444 +/- 132 days (270-718 days). Minor adverse events such as chest pain and reflux symptoms were seen in this therapy. CONCLUSION: Botulinum toxin injection in Thai achalasia patients is an effective, simple, and safe treatment. These results showed the similar outcomes as in Caucasian patients. PMID- 17718251 TI - In vitro activity of tigecycline against clinical isolates of multidrug-resistant Acinetobacter baumannii in Siriraj Hospital, Thailand. AB - In vitro activity of tigecycline against 148 strains of Acinetobacter baumannii isolated from different patients hospitalized at Siriraj Hospital, Bangkok, Thailand during 2002 to 2005 was conducted. These isolates were resistant to beta lactams, aminoglycosides and fluoroquinolones. In vitro susceptibilities were determined by Kirby-Bauer disk diffusion, E-test and broth microdilution methods. The MIC50 and MIC90 values of tigecycline against A. baumannii determined by the broth microdilution method were 0.5 and 1 mg/L respectively. The MICs of tigecycline determined by E-test were 4-fold higher than those from the broth microdilution method. An inhibition zone of > or = 13 mm was well correlated with a tigecycline MIC of < or = 2 mg/L and had a sensitivity of 99% and a specificity of 100%. The study results indicated that 97.3% of MDR A. baumannii strains isolated from the patients hospitalized at Siriraj Hospital were susceptible to tigecycline. Tigecycline may prove to be an important antibiotic for treatment of multidrug-resistant A. baumannii infections in Thailand in the near future. PMID- 17718250 TI - Cost-effectiveness analysis of chlorhexidine gluconate compared with povidone iodine solution for catheter-site care in Siriraj Hospital, Thailand. AB - BACKGROUND: Catheter-related bloodstream infections (CRBSI) are an important cause of patient morbidity, mortality, and increased health care costs. Use of an antiseptic solution for skin disinfection at the catheter insertion site helps prevent catheter-related infections. In Thailand, povidone-iodine solution is the most commonly used agent for this purpose. However, the results of several studies including a meta-analysis indicated that the use of chlorhexidine gluconate is more effective than the use of povidone-iodine as an antiseptic for preventing CRBSI. This study evaluated the cost-effectiveness of chlorhexidine gluconate versus povidone-iodine for catheter-site care using the Siriraj Hospital perspective. MATERIAL AND METHOD: We used a decision analytic modeling for estimating the cost-effectiveness of antiseptic solutions. The CRBSI rate was obtained from the Center for Nosocomial Infection Control at Siriraj Hospital, while the efficacy of cholorhexidine compared to povidone-idone was based on a meta-analysis. The cost of managing infections was derived from the Thai Drug Related Group (DRG). A series of sensitivity analyses were performed. Since the time horizon of the analysis was less than 1 year, there was no need for discounting. RESULTS: We found that the use of chlorhexidine, rather than povidone iodine, for central catheter site care resulted in a 1.61% decrease in the incidence of CRBSI, a 0.32 % decrease in the incidence of death, and savings of 304 baht per catheter used. For peripheral catheter site care, the results were similar although the differences were smaller. CONCLUSION: Use of chlorhexidine gluconate in place of the current standard solution for vascular catheter site care is a cost-effective method of improving patient safety in Siriraj Hospital. PMID- 17718252 TI - Implementation of clinical practice policy on the continuous intravenous administration of amphotericin B deoxycholate. AB - BACKGROUND: Systemic fungal infections have significantly increased. The mainstay of treatment is amphotericin B deoxycholate. A limitation of using amphotericin B includes infusion-related reactions and nephrotoxicity. A continuous infusion of amphotericin B was found to reduce nephrotoxicity and infusion-related reactions. OBJECTIVE: To implement clinical practice policy on the continuous intravenous administration of amphotericin B in the patients hospitalized in general medical wards at Siriraj Hospital. METHOD: A one-page evidence-based clinical practice policy on continuous intravenous administration of amphotericin B was prepared and disseminated to all general medical wards in Siriraj Hospital. The information on the patients who received amphotericin B treatment between March 2004 and March 2006 was collected. The data were analyzed using descriptive statistics, univariate analysis and multivariate analysis as appropriate. A p value of < 0. 05 was considered statistically significant. RESULTS: Of 166 courses of amphotericin B treatment in 148 patients, 102 courses (61.4%) were given continuous intravenous administration of amphotericin B (CI group) and 64 courses (38.6%) were given conventional 4-to 6-hour intravenous administration (RI group). The mean age of the patients in the CI group was significantly greater than that in the RI group. The CI group had more patients with neutropenia with persistent fever whereas the RI group had more patients with HIV/AIDS and cryptococcal meningitis. The incidence of amphotericin B-related nephrotoxicity was 27.5% in the CI group compared with 39.1% in the RI group (p = 0.164). Chills were observed in 6.9% of the patients in the CI group compared with 26.6% in the RI group (p = 0. 001). Overall mortality at the end of therapy was significantly higher in the CI group. However, most of the deaths in the CI group were unrelated to fungal infections or amphotericin administration. CONCLUSION: Continuous infusion of amphotericin B was associated with a decrease in infusion-related reactions and tended to have less nephrotoxicity than those in the 4-to 6-hour infusion group. PMID- 17718253 TI - Vancomycin overuse in Siriraj Hospital. AB - OBJECTIVE: An emergence of vancomycin resistant organisms particularly vancomycin resistant enterococci (VRE) has become a serious public health concern. To prevent and control the spread of vancomycin resistant organisms, the prudent use of vancomycin is strongly recommended by the Hospital Infection Control Practices Advisory Committee (HICPAC). MATERIAL AND METHOD: A 6-week prospective observational study of vancomycin use was conducted in hospitalized patients at Siriraj Hospital from February to March 2005. Indications of initiating and continuing vancomycin were categorized according to HICPAC recommendations. Factors related to the appropriateness of vancomycin use were also evaluated. RESULTS: At initiation, vancomycin was inappropriately and empirically prescribed 19/222 times (8.6%) and 166/222 times (74.8%), respectively. After microbiological results were obtained, the rate of inappropriate prescription continued 132/222 times (59.5%). Furthermore, inappropriate use was significantly correlated with the type of department. There was a higher rate in the Department of Pediatrics, Surgery and Ophthalmology when compared with that of the Department of Medicine (p = 0.001). The inappropriate use also correlated with topical use (p < 0.001), intravenous administration (p = 0.012) and no consultation with an infectious disease specialist (p = 0.001). The overuse did not improve the clinical outcome. CONCLUSION: A substantial rate of inappropriate use of vancomycin was found in Siriraj Hospital. Intervention to improve appropriateness of vancomycin use should be urgently implemented to prevent and control the emergence of vancomycin resistant organisms. PMID- 17718254 TI - Hyperthyroidism induces glucose intolerance by lowering both insulin secretion and peripheral insulin sensitivity. AB - OBJECTIVE: The objectives of this study were to examine the effects of hyperthyroidism on glucose tolerance, insulin secretion, and insulin sensitivity. MATERIAL AND METHOD: Thirty-eight patients with hyperthyroidism and twenty-six healthy volunteers with matching age and body mass index were included. Patients with conditions known to affect glucose metabolism were excluded. An oral glucose tolerance test was performed after the diagnosis of hyperthyroidism and again when they achieved euthyroid state. Areas under the glucose and insulin curves were used to assess plasma glucose and insulin responses, respectively. Beta-cell function was determined by the corrected insulin response (CIR) and homostatic model assessment model 2 (HOMA2-%B). Peripheral insulin sensitivity was determined by the insulin activity (IA) and HOMA2-%S. RESULT: The prevalence of glucose intolerance in hyperthyroid state was 39.4% [impaired glucose tolerance (IGT) 31.5% and diabetes mellitus (DM) 7.9%]. This was significantly higher than that of 30.7% [IGT 19.2% and DM 11.5%] in healthy volunteers (p < 0.05). Glucose intolerance was associated with higher systolic blood pressure, higher mean arterial pressure, lower CIR, and higher T4 levels but not with the levels of T3. IA and HOMA2-%S significantly improved when achieving a euthyroid state despite the increase in body mass index. CONCLUSION: In conclusion, glucose intolerance is common in hyperthyroidism. Both impaired insulin secretion and decreased peripheral insulin sensitivity are the factors contributing to the development of abnormal glucose tolerance in the hyperthyroid state. PMID- 17718255 TI - Antioxidant status and lipid peroxidation end products in patients of type 1 diabetes mellitus. AB - BACKGROUND AND OBJECTIVE: In Type 1 diabetes mellitus (DM), hyperglycemia is considered a primary cause of diabetic vascular complications and is associated with oxidative stress. The role of antioxidants, particularly alpha tocopherol, in Type 1 DM and its contribution in the development of vascular complications is not clear. Therefore, the present study aims to investigate the relationship between antioxidant status (alpha tocopherol) and lipid peroxidation end products (malondialdehyde; MDA) in the plasma of 20 Type 1 DM and 20 nondiabetic healthy control subjects. MATERIAL AND METHOD: Lipid levels in all subjects were analyzed spectrophotometrically by enzymatic reagent kits. Plasma MDA was assessed by spectrofluorometry, whereas plasma alpha tocopherol was estimated by high performance liquid chromatography in Type 1 DM as well as in the control subjects of matched sex and ages. The results of Type 1 DM were compared with a control group using unpaired Student's t-test. The correlations between fasting plasma glucose and other laboratory parameters were assessed by Pearson rank correlation coefficient. RESULTS: The plasma MDA concentration was significantly higher in Type 1 diabetic patients as compared to controls, (p < 0.01). A significantly reduced plasma antioxidant status of Type 1 DM patients was found only in alpha tocopherol / total lipid as compared to controls (p < 0.05). However, no significant difference was observed in plasma a tocopherol and a tocopherol / total cholesterol (p > 0.05) as compared to the control subjects. The positive correlation between MDA and FPG was demonstrated in Type 1 diabetic compared with normal subjects. CONCLUSION: We conclude that antioxidant supplementation may be necessary for treatment to reduce oxidative stress for diabetic complication protection in Type 1 DM. PMID- 17718256 TI - Plasma lipid peroxidation and antioxidiant nutrients in type 2 diabetic patients. AB - BACKGROUND AND OBJECTIVE: Observation shows diabetic patients to be more prone to oxidative stress because of hyperglycemia. The elevation of free radical production by this hyperglycemic production may exacerbate cardiovascular complication in diabetes. This study aims to investigate the oxidative stress related parameters in type 2 DM. Since the effects of glycemic control and cardiovascular complications in DM on these parameters has been not fully determined, the comparison between plasma MDA (malondialdehyde) and antioxidant nutrients with their age-matched normal healthy group may be used to determine the susceptibility of oxidative stress in this type of DM. MATERIAL AND METHOD: MDA and antioxidant nutrients (vitamin A, C, E and beta-carotene) were analyzed in plasma of 19 subjects with poorly controlled type 2 DM (fasting plasma glucose [FPG] > 180 mg/dl), 26 subjects with fairly controlled type 2 DM (FPG < or = 180 mg/dl), and 20 subjects with type 2 DM complicated coronary heart disease (CHD) who were matched for age and gender. Twenty healthy subjects with normal plasma glucose level (FPG < 110 mg/dl) and matched for age and gender served as a control group. In all groups of DM these oxidative stress parameters were compared to a normal group. RESULTS: The plasma MDA levels were significantly higher in all types of DM compared to age-matched normal control. Plasma antioxidant vitamin C and E significantly lower only in poorly controlled and CHD complicated type 2 DM, respectively. The mean of plasma vitamin E level was lowest in type 2 DM complicated with CHD. No significant differences in both plasma vitamin A and beta-carotene were noted between any types of DM and age matched normal healthy group. The positive correlation between MDA and FPG was demonstrated in most group of patients with their normal subjects except in fairly controlled type 2 DM and negative correlation between vitamin E and FPG was also demonstrated in type 2 DM with CHD. CONCLUSION: These findings suggested that diabetic patients were susceptible to oxidative stress and higher plasma glucose level had an association with free radical-mediated lipid peroxidation. The lowest level of vitamin E in type 2 DM complicated with CHD indicated that oxidative stress played an important role in cardiovascular complication and vitamin E supplementation may be necessary for treatment and prevention in this group of diabetics. PMID- 17718257 TI - Utilization of calculated low density lipoprotein cholesterol and measured low density lipoprotein cholesterol in Siriraj Hospital. AB - A study to determine the utilization of calculated low density lipoprotein (c LDL) cholesterol and measured low density lipoprotein (m-LDL) cholesterol was conducted. The test results of total cholesterol, triglyceride, HDL-cholesterol and m-LDL-cholesterol from the same individuals aged > or = 18 years who had the tests done at the Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital during January to December 2004 were retrieved. The c-LDL-cholesterol level was computed using Friedewald formula. There were two data sets i.e. the m LDL-cholesterol cut-off level derivation data set (784 subjects) and the m-LDL cholesterol cut-off level validation data set (800 subjects). The study results revealed: 1) 2.6% of the subjects had blood triglyceride > 400 mg/dl hence c-LDL cholesterol could not be computed, 2) the correlation between c-LDL-cholesterol levels and m-LDL-cholesterol levels from both data sets was very good (r > 0. 95, p < 0. 001), 3) the m-LDL-cholesterol levels were usually higher than c-LDL cholesterol levels, 4) the m-LDL-cholesterol cut-off level derivation data set showed that m-LDL-cholesterol < 87, > 143, > 188, > 233 and > 254 mg/dl were highly correlated with c-LDL-cholesterol < 100, > or = 100, > or = 130, > or = 160 and > or = 190 mg/dl respectively, 5) an application of m-LDL-cholesterol cut off levels derived from the m-LDL-cholesterol cut-off level derivation data set to the m-LDL-cholesterol cut-off level validation data set showed that m-LDL cholesterol < 87, > 143, > 188, > 233 and > 254 mg/dl had accuracy in predicting c-LDL-cholesterol < 100, > or = 100, > or = 130, > or = 160 and > or = 190 mg/dl of 100%, 99. 7%, 100%, 100% and 100% respectively, 6) the use of m-LDL cholesterol levels as a guide for initiating lipid-lowering agents based on cut off values of c-LDL-cholesterol levels led to an overuse of lipid-lowering agents in 3.6% to 42.9% of the patients and 7) Nomogram for transforming m-LDL cholesterol to c-LDL-cholesterol was developed as well as a formula for transforming m-LDL-cholesterol to c-LDL-cholesterol (c-LDL-cholesterol = 0.89 x m LDL-cholesterol). Therefore, m-LDL-cholesterol assay has a very limited use in managing individuals with suspected or known dyslipidemia. The use of m-LDL cholesterol level as a guide for management of abnormal LDL-cholesterol conditions leads to an overuse of lipid lowering medications and an enormous expense of m-LDL-cholesterol assay. PMID- 17718258 TI - The effect of alpha-tocopherol on the oxidative stress and antioxidants in idiopathic IgA nephropathy. AB - OBJECTIVE: Nearly 25% of IgA nephropathy patients progress to end-stage renal disease over a 20-25 year follow-up period. IgA containing immune complex stimulates oxygen free radical production by mesangial cells in vitro, which may mediate glomerular injury in this disorder. Therefore, we studied whether dietary supplementation with the antioxidant agent, vitamin E, attenuates renal damage in patients with IgA nephropathy. MATERIAL AND METHOD: Twenty-eight patients with idiopathic IgA nephropathy were supplemented with vitamin E 400 mg/day for 6 months. Antioxidant enzymes, glutathione, plasma malondialdehyde (MDA), and renal function were studied after 3 and 6 months therapy. RESULT: The result of the study showed high plasma MDA and significant reduction after therapy (1.15 +/- 0.45 VS 0.86 +/- 0.30 microM, p < 0.0001). The RBC vitamin E was also elevated statistically significantly (5.07 +/- 2.42 VS 15.70 +/- 3.37 microM, p < 0.001). Glutathione peroxidase activities were decreased (38.52 +/- 15.53 VS 23.97 +/- 7.63 U/gHb, p < 0.001). Glutathione was also decreased (44.80 +/- 9.70 VS 32.45 +/- 6.74 mg/dl, p < 0.05) but there were no changes in red cell catalase and superoxide dismutase activities. Creatinine clearance, proteinuria, urine N acetyl glucosaminidase and beta2-microglobulin also showed no improvement. CONCLUSION: Our data demonstrated the particular group of IgA nephropathy patients with low vitamin E level and high oxidative stress had significant reduction of oxidative stress after vitamin E therapy. PMID- 17718259 TI - Immunohistochemical study for the diagnosis of Alport's syndrome. AB - BACKGROUND: Alport's syndrome (AS) is the most common cause of inherited glomerular disease in Thailand. The majority of cases show X-linked inheritance, which is caused by mutations in the gene coding for the alpha5 chain of type IV collagen in the glomerular basement membrane (GBM) and epidermal basement membrane (EBM). Such mutation usually leads to a reduction in protein amount, thus, immunohistochemical studies have been considered in diagnostic evaluation. OBJECTIVE: To study the expression of alpha[IV] collagen chains in the skin as an alternative approach to diagnose AS. MATERIAL AND METHOD: Eleven unrelated probands with proven AS, 7 relatives with abnormal urinalysis, 4 suspected individuals, and 8 normal controls were enrolled. A punch skin biopsy and immunofluorescence staining of the tissue specimens for alpha1, alpha3 and alpha5[IV] collagen chains was performed. RESULTS: The alpha5[IV] chain was absent in the EBM in all male AS patients while a discontinuing pattern was observed in all females except one. The findings are specific for AS with a sensitivity of 91%. Studies in relatives and suspected individuals also confirmed the advantage of this approach as demonstrated by the absence and discontinuation of alpha5[IV] staining in all males and females, respectively. We also analyzed their expressions in the kidney tissue and demonstrated abnormal alpha3 and alpha5[IV] staining in five of six samples. CONCLUSION: Immunohistochemical study of the skin should be used as a screening method in patients suspected of AS, as it is much less invasive. Moreover, it is a useful adjunct to conventional examination of biopsied renal tissue. PMID- 17718260 TI - Epidemiology of Behcet's disease in Thai patients. AB - OBJECTIVE: To describe symptoms, signs, laboratory findings and to compare sensitivity of several classification criteria in Thai patients who were diagnosed with Behcet's disease. MATERIAL AND METHOD: Using medical records from the rheumatology unit, Siriraj hospital, all cases diagnosed with Behcet's disease by our rheumatology staff were identified and reviewed. Demographic data, clinical presentations, and laboratory data were collected. All cases were also reviewed if they had fulfilled any of the following criteria: Iran classification tree, Japanese, Korean, ISG and O'Duffy's criteria. The sensitivity of each criterion was calculated. RESULTS: Twenty three cases were identified during a 24 year interval (1980-2003). Our population had a mean age of 30.83 years. Common clinical presentations were recurrent oral ulcers 100% (23/23), genital ulcers 69.6% (16/23), eye involvement 52.2% (12/23), skin involvement 60.9% (14/23), GI ulcers 8.7% (2/23), epididymitis 4.3% (1/23), vascular lesions 8.7% (2/23), CNS involvement 8.7% (2/23), fever 60.9% (14/23), and positivity of the pathergy test 33.3% (3/9). The sensitivity of criteria used for diagnosis of our patients with Behcet's disease varied widely. We found that the Iran classification tree criteria had the highest sensitivity followed by those from Japan (82.6%), O'Duffy's (73.9%), ISG (52.2%), and Korean (39.1%o) criteria respectively. CONCLUSION: Behcet's disease is heterogeneous in its manifestations and clinical constellation of the disease varies widely among different parts of the world. This is the first epidemiologic study describing Thai Behcet's patients. We also found the Iran classification tree criteria had the highest sensitivity for diagnosis of Thai patients. PMID- 17718261 TI - The preservation method and timing on accuracy of manual leukocytes counts in synovial fluid. AB - OBJECTIVES: To compare the efficacy of heparin and EDTA and determine the impact of time delays in stabilizing leukocyte counts in synovial fluid. MATERIAL AND METHOD: 33 specimens were collected in heparin-preserved and EDTA-preserved containers. Total cell count was performed manually at 1 hour and 24 hours. Correlation between cell counts from both preservatives and the leukocyte number at 1 hour and 24 hours were analyzed by means of agreement measurement. RESULTS: There were good correlations between the leukocyte numbers from the specimens preserved by heparin and EDTA (ICC = 0.889, r = 0.879, P < 0.0001 at 1 hour and ICC = 0.822, r = 0.693, p < 0.0001 at 24 hour). At 24 hours, total cell counts from EDTA-preserved samples were comparable to those obtained at 1 hour (ICC = 0.985, r = 0. 986, p < 0. 0001) and were not different from those of the heparinized samples (ICC = 0.833, r = 0. 751, p < 0.0001) but the ICC value was higher. CONCLUSION: EDTA was as effective as heparin for preservation of synovial fluid. Therefore, it can be used routinely as a preservative of synovial fluid. PMID- 17718262 TI - Delayed hypersensitivity skin testing in the Thai adult population. AB - OBJECTIVE: The present study was carried out in healthy Thai subjects to determine the types and concentrations of standard antigens used in delayed-type hypersensitivity (DTH) skin testing as an evaluation of cell-mediated immunity. MATERIAL AND METHOD: One hundred subjects were tested with three antigens including tuberculin (purified protein derivative), tetanus toxoid, 1:10 and 1:100 dilutions, and Candida albicans, 1:10 and 1:100 dilutions. RESULTS: We found that 92% of the subjects responded to tuberculin and/or tetanus toxoid at a 1:10 dilution, 77% responded to tetanus toxoid at a 1:10 dilution, and 35% responded to a 1:100 dilution. There was only one subject who responded to Candida albicans at a 1:10 dilution, and none to a 1:100 dilution. The size of tuberculin reactions varied from 5 mm to over 20 mm without any evidence of active tuberculosis. CONCLUSION: Tuberculin and tetanus toxoid at a 1:10 dilution are probably sufficient to be used in DTH skin testing to evaluate T-cell function. PMID- 17718263 TI - RET proto-oncogene expression of papillary thyroid carcinomas in Thai patients. AB - BACKGROUND: Ret proto-oncogene activation has been found in papillary thyroid carcinoma with different frequencies according to geographic location. The rate of expression ranges from 0-100 percent in the literature. This gene expression has also been studied in many Asian countries but it has never been studied in Thailand. OBJECTIVE: To study the frequency of the RET expression and their roles in predicting prognosis of papillary thyroid carcinoma among Thai patients treated at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. MATERIAL AND METHOD: One hundred and one cases of papillary carcinomas were studied with immunohistochemistry for RET antibodies. All slides with routine staining were reviewed to classify cell variants and record other prognostic parameters such as size, multicentricity, extrathyroid invasion. The clinical data such as age and sex were also included for analyses. RESULTS: Forty-seven of the total 101 cases (46.5%) showed positive RET protein staining. The mean age among patients with RET negative neoplasms was 43.9 years compared with 39.8 years in RET positive group (p = 0.16). The average size of the tumors without RET expression was 2.5 cm, slightly larger than the RET positive tumors (2.1 cm)(p = 0.26). Extrathyroid invasion of the RET-positive tumors was found to be 33.2 percent while the RET negative neoplasms had 38.8 percent of this feature (p = 1). According to AMES score, the RET positive cases had only 11 percent of high-risk tumors, whereas the RET negative group comprised 23.1 percent of high-risk malignancies (p = 0.20). There was no significant difference in RET expression among cell variants (p = 1). CONCLUSION: The study of 101 papillary thyroid carcinomas at the King Chulalongkorn Memorial Hospital disclosed high frequency of RET expression (46.5%) and this is the only data among Thai patients that has ever been documented in the literature. Although, the gene expression in the tumor tends to be associated with good prognostic features but it was not distinct enough to be statistically significant. PMID- 17718264 TI - Quality of life and correlated health status and social support of schizophrenic patients' caregivers. AB - BACKGROUND: Quality of life (QOL) of caregivers is the new concept used for evaluating the caregivers' burden and well-being, and improving the caregiver interventions. Schizophrenia is considered as a chronic and severe mental disorder. It affects the lives of patients and the family members of caregivers who take care of them. The caregivers have to deal with patients' symptoms, and help patients in activities of daily living. Most studies showed low scores of QOL of schizophrenic patients' caregivers. OBJECTIVES: To study the QOL of schizophrenic patients' caregivers in Bangkok Metropolis community and the correlation between QOL, and health status and social support of schizophrenic patients' caregivers MATERIAL AND METHOD: One hundred and twenty schizophrenic patients' caregivers were recruited from three Public Health Centers of Health Department of the Bangkok Metropolitan Administration, in November-December 2005. They completed three self-rated questionnaires; 1) Quality of Life Index Generic Version - III (QLI Generic Version - III), 2) Short Form 36 Health Survey (SF-36 Health Survey), and 3) Questionnaire for Assessment of Social Support. QOL of caregivers was analyzed by using mean, percentage, and standard deviation. The correlation between QOL, and health status and social support was analyzed by using Pearson's correlation. RESULTS: Eighty-eight people (73.33%) were female and thirty-two people (26.67%) were male. The mean age of the caregivers was 49.91 years, and the age range of the caregivers was 23-81 years. Most of them had primary school education (62 people, 51.67%), and had a marital status of couples (73 people, 60.83%). The results showed most of the schizophrenic patients' caregivers (80 people, 66.67%) had low moderate level of QOL. The caregivers' health status and social support were positively correlated to their QOL. CONCLUSION: The present study showed schizophrenic patients' caregivers in the community had low moderate level of QOL. The health status and social support of caregivers were positively correlated to their QOL. Health promotion and increasing social support ofcaregivers may help to increase caregivers' QOL. Improving caregivers' QOL will increase the quality of care given and improve the success of treatment and rehabilitation of schizophrenic patients. PMID- 17718265 TI - The efficacy of combination treatment with narrowband UVB (TL-01) and acitretin vs narrowband UVB alone in plaque-type psoriasis: a retrospective study. AB - BACKGROUND: NarrowBand Ultra Violet B phototherapy (NB-UVB) is a highly effective therapeutic modality for plaque-type psoriasis, however several hospital visits are often required. Oral acitretin is moderately effective as monotherapy, but when combined with phototherapy, its use has reduced the number of treatments required for clearing. There is only sparse data on the combination of acitretin with NB-UVB. MATERIAL AND METHOD: Twenty nine patients with plaque-type psoriasis who were treated with NB- UVB alone or in combination with acitretin were retrospectively analyzed for treatment outcome in terms of total numbers and cumulative doses of narrowband UVB treatments. Of these, nine had the combination while 20 received NB-UVB alone. RESULTS: The combination of low dose acitretin (25 mg/day) and NB-UVB resulted in marked improvement of patients. The numbers of irradiation, final doses and cumulative doses of NB-UVB were lower albeit not statistically significant in the combination group. The combination was well tolerated and associated with typical retinoid and NB-UVB side effects. CONCLUSION: The combination treatment with acitretin and NB-UVB in plaque-type psoriasis has more therapeutic advantages than phototherapy alone. PMID- 17718266 TI - Management and outcome of severe acute pancreatitis. AB - BACKGROUND: The treatment of severe acute pancreatitis (SAP) varies among several institutes. It has been evolving from routine surgical management to conservative management in the early stages. The surgical management has a role in the later stages of the disease. OBJECTIVE: The purpose of the present study was to review the management and outcome of the patients with SAP at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. MATERIAL AND METHOD: Two hundred and ten patients with a diagnosis of acute pancreatitis at King Chulalongkorn Memorial Hospital, Bangkok, Thailand from December 2001 to April 2005 were studied by retrospective chart review. RESULTS: Forty patients were diagnosed with SAP, 27 men and 13 women. SAP was most commonly caused by alcohol abuse (47.5%) and biliary tract disease (37.5%). Eighteen patients (45%) had pancreatic necrosis. Among them, seven patients (38.9%) had infected necrosis, and the rest had sterile necrosis. All patients with infected pancreatic necrosis underwent open pancreatic necrosectomy, and three of 7 died. Four of 11 patients with sterile necrosis died. The overall mortality was 25%. CONCLUSION: Patients with SAP have high morbidity and mortality rates. The patients with infected pancreatic necrosis may require surgical management, whereas those with sterile necrosis or SAP without local complications can be managed with conservative treatment and/or intervention. Post-operative complications might occur, thus require long term follow-up. PMID- 17718267 TI - Overexpression of c-Myc in primary central nervous system lymphoma of Thais. AB - BACKGROUND: c-Myc protooncogenes have been implicated in the tumourigenesis of extracerebral lymphomas, however only afew studies on this oncogenic molecule have been available for primary central nervous system lymphoma (PCNSL). OBJECTIVE: To determine the prevalence ofprotein overexpression and gene amplification of c-Myc in PCNSL and to correlate with histological and immunophenotypic subtypes of malignant lymphoma according to WHO classification of tumors of haematopoietic and lymphoid tissue 2001. SETTING: King Chulalongkorn Memorial Hospital, Thailand. DESIGN: Descriptive study. MATERIAL: 25 Thai patients presented between 2001 and 2005. METHOD: The overexpression and amplification of c-Myc in malignant lymphoma were studied by means of immunohistochemistry and chromogenic in situ hybridization (CISH), respectively, in formalin-fixed, paraffin-embedded specimens. The histomorphology and immunohistochemistry were used to subclassify PCNSLs according to WHO classification 2001. RESULTS: Fourteen males and eleven females were recruited. They were between the ages of 21 and 86 years with the mean of 53 years. Eight had documented human immune deficiency virus (HIV) infection. Four of 17 immunocompetent cases overexpressed c-Myc protein without c-Myc gene amplification. No immunocompromised cases showed overexpression of c-Myc protein. All PCNSLs were classified as diffuse large B-cell lymphoma. CONCLUSION: In PCNSL, c-Myc overexpression is notfound immunocompromised (HIV-infected) patients and is found in 23.5% of the immunocompetent individuals without c-Myc gene amplification. All PCNSLs are diffuse large B-cell lymphoma according to WHO classification 2001. PMID- 17718268 TI - Falls among stroke patients in Thai Red Cross rehabilitation center. AB - OBJECTIVE: To determine the incidence and risk factors of falls among stroke patients. MATERIAL AND METHOD: A prospective cohort study was designed to study the stroke patients who were admitted to the Thai Red Cross Rehabilitation Center from February 2004 to July 2005. Related variables offaller and non-faller groups were compared. RESULTS: Of 151 patients, 24 (15.9%) experienced at least one fall. The incidence rate was 3.44/1000 patients/ day. Most of the falls (71.4%) occurred during the daytime, in the bathroom (37.1%), and by the bedside (22.9%). Falls frequently occurred while transferring (22.9%) and walking (20%). Barthel ADL Index (BAI) score was the variable that significantly differentiated the fallers from the non-fallers (p = 0.013). Patients with BAI score of > or = 12 had 3 times more risk to fall. CONCLUSION: About 16% of stroke patients fell during rehabilitation. More attention should be paid during the transfer and ambulation. Furthermore, a safety area should be provided in every bathroom and by the bedside. PMID- 17718269 TI - Expression of CyclinD1, p27kp-1, and bcl-2 in plexiform neurofibroma with and without malignant transformation in neurofibromatosis type 1. AB - Plexiform neurofibroma (PNF) has a low potential to undergo malignant transformation. Identification of markers associated with tumor progression is important since it may serve as prognostic indicators or adjuncts to standard pathological examination. In the present study, the authors immunostained 20 neurofibromatosis type I-associated PNFs with cyclinD1, p27kip-1, and bcl-2. Six of the cases had progressed into malignant peripheral nerve sheath tumor (MPNST), and the transitional area of each sample was also stained separately in order to identify protein(s) associated with tumor progression. Cyclin D1 was found to be significantly increased in the transitional zone, compared to the ordinary PNF (p = 0.007). The protein is, thus, likely to play a role in the malignant transformation. There was no significant difference in the expression of p27kip-1 and bcl-2 during the malignant progression of PNF. PMID- 17718270 TI - The incidence and risk factors of hypotension and bradycardia associated with spinal anesthesia. AB - OBJECTIVES: Hypotension and bradycardia after conduction of spinal anesthesia are common and may lead to intraoperative cardiac arrest or death. The present study was carried out to investigate the incidence and risk factors of hypotension and/or bradycardia in the patients receiving spinal anesthesia. MATERIAL AND METHOD: The authors prospectively studied 1,220 patients to identify the incidence of hypotension (> 30% decreased systolic blood pressure) and bradycardia (heart rate < 60 beats/min) after spinal anesthesia. Historical, clinical and physiologic data were correlated with the incidences by univariate analysis. Logistic regression with a forward stepwise algorithm was performed to identify independent variables. A p value < 0.05 was considered significant. RESULTS: Incidence of hypotension and bradycardia were 36.8% and 4.9% respectively. The risk factors of hypotension included increasing age (OR = 1.019 ; 95%CI 1.017-1.031); analgesia level > or = T4 dermatome (OR = 2.068; 95%CI 1.486-2.879); body mass index > or = 30 (OR = 1.534; 95%CI 1.120-2. 100); cesarean section (OR= 1.723; 95%CI 1.244-2.386 and prehydration fluid < 500 mL (OR 1.472; 95%CI 1.071-2.023). The risk factors of bradycardia were increasing age (OR = 1.042; 95%CI 1.023-1.061) and analgesic level > or = T4 dermatome (OR = 2.246; 95%CI 1.101-4.584). CONCLUSION: The incidence of hypotension and bradycardia may increase with increasing age and analgesic level > or = T4 dermatome. Three other factors related to hypotension after spinal anesthesia were body mass index > or = 30, cesarean section, and prehydration fluid of less than 500 mL. PMID- 17718271 TI - The association of stromal mast cell response and tumor cell differentiation in colorectal cancer. AB - BACKGROUND: Resembling other neoplasms, the colorectal carcinogenesis is still a riddle in various aspects. Mast cells, a type of inflammatory cells, may play a role in colonic cancer pathogenesis. It has recently been found to have an essential function in tumor development and its immunologic response. OBJECTIVE: To evaluate the relation between mast cell number and biology of colorectal adenocarcinoma. MATERIAL AND METHOD: The author collected 162 cases, diagnosed as primary adenocarcinoma of the colon at the King Chulalongkorn Memorial Hospital, between 2002 and 2003, for evaluating the role of mast cells in colorectal cancers. The hematoxylin and eosin stained sections were reviewed and classified into the tumor differentiation or grading, depth of tumor invasion, and status of regional lymph node metastasis, according to the World Heath Organization's (WHO) criteria. Mast cell number within and around the tumor was counted on the 0.1% toluidine blue stained sections. F-test was used to correlate between the mast cell quantity and aforementioned tumor parameters. RESULTS: The tumor differentiation consisted of grade 1 (34%), grade 2 (52%) and grade 3 (14%), with a mean of mast cell number of23, 32 and 40 cells/mm2, respectively. In addition, mast cell quantity in poorly differentiated tumors was significantly higher than those in well differentiated form (p = 0. 03). Therefore, mast cell number was not correlated with tumor depth (p = 0.28) and nodal status (p = 0. 75). CONCLUSION: This observation might indicate that mast cell function has a role in colorectal pathogenesis. PMID- 17718273 TI - Reliability of center of pressure distance and area sway measurement during one legged stance in a normal population. AB - OBJECTIVE: The objective of this study was to assess the reliability of center ofpressure distance and area sway during one-legged stance. MATERIAL AND METHOD: One hundred and sixteen participants aged 40-60 years old were recruited. Fifty nine subjects were males and fifty seven subjects were females. Subjects were excluded in cases of abnormal lower extremity structures, neurological deficits related to balance disorder, and inability of right leg stance for more than 30 seconds. All subjects were evaluated with 4 trials ofone-legged stance, each 2 of normal and fast lifting leg conditions. Center of pressure and kinematic data were synchronously collected. RESULTS: Intraclass correlation coefficients (ICC) of the distance sway was between 0.69 and 0.83, while ICC of the area sway was between 0.06 and 0.25. CONCLUSION: Distance sway provides higher reliability than area sway for static balance assessment. Subjective leg lifting speed was satisfactory. PMID- 17718272 TI - Efficacy of clarithromycin-based triple therapy for treating Helicobacter pylori in Thai non-ulcer dyspeptic patients with clarithromycin-resistant strains. AB - BACKGROUND: Antibiotic resistance of H. pylori is problematic because it reduces the efficacy of eradication therapy. The objective of the present study was to assess the eradication rates of triple therapy against clarithromycin-sensitive and clarithromycin-resistant strains of H. pylori in Thai non-ulcer dyspeptic patients. MATERIAL AND METHOD: Patients who underwent upper gastrointestinal endoscopy at King Chulalongkorn Memorial Hospital between September 2002 and December 2003 were included. The patients who had positive urease test and culture were enrolled for antimicrobial resistance. Isolates were considered resistant when the MIC was more than 1 mcg/ml for clarithromycin. The patients received a combination of pantoprazole 40 mg BID, clarithromycin MR 1 gm OD, and amoxicillin 1 gm BID, for 7 days. Urea [14C] breath test was performed for evaluation of H. pylori eradication at least 1 month after treatment. RESULTS: Of the 470 patients, H. pylori were identified by positive rapid urease test in 282 patients (69.0%). Of these, cultures for H. pylori were achieved in 113 patients (54.6%) and E-tests for clarithromycin were successfully placed in 69 isolations. There were 29 males and 40 females, mean age was 38.7 +/- 13.3 years. Primary H. pylori resistance to clarithromycin was observed in 16 of 69 patients (23.2%). The eradication rates were 90.6% (48/53) and 56.3% (9/16) in patients with clarithromycin sensitive and clarithromycin resistant H. pylori strains, respectively (p = 0.002). CONCLUSION: The authors reported a high rate of clarithromycin resistant H.pylori isolates in Thailand. Pretreatment resistance to clarithromycin has a significant impact on treatment failure with clarithromycin-based regimen. PMID- 17718274 TI - Closed lateral internal sphincterotomy using endoshere cut scissors. AB - BACKGROUND: Internal sphincterotomy remains the gold standard for treatment of chronic anal fissure but it is associated with immediate wound bleeding and hematoma, which is usually corrected by a pressure dressing for half an hour. OBJECTIVE: This procedure was the initial study to decrease intra-operative and immediate postoperative wound bleeding, hematoma, and duration of pressure by using Endoshere cut scissors for closed lateral internal sphincterotomy. MATERIAL AND METHOD: Closed lateral internal sphincterotomy was performed on patients with chronic anal fissures by using Endoshere cut scissors in standard technique. The Fansler's proctoscope (diameter 1.5 cm) was inserted into the anal canal to permit adequate exposure of the anal fissure after local anesthetized with 0.5% xylocaine with adrenaline 1-2 cc. at left lateral region. The intersphincteric groove was identified, and then the small stab incision was made on the lateral side. The surgeon used the forceps to expose the internal sphincter then sphincterotomy was carried out with Endoshere cut scissors. After the operation was finished, no pressure dressing was applied to the sphincterotomy wound. RESULTS: Closed lateral internal sphincterotomy was performed on 10 patients by using Endoshere cut scissors. The present results showed that no intra-operative and immediate postoperative wound bleeding, hematoma occurred. No pressure dressing was required. CONCLUSION: The authors' early results showed that Endoshere cut scissors are usefulfor closed lateral internal sphincterotomy. There was no intra-operative and immediate postoperative wound bleeding and hematoma. The pressure dressing is unnecessary. The long term results should be further studied in a randomized control trial. PMID- 17718275 TI - Tissue engineering of cartilage with porous polycarprolactone--alginate scaffold: the first report of tissue engineering in Thailand. AB - OBJECTIVE: To engineer human cartilage with porous polycaprolactone (PCL) Alginate Scaffold. BACKGROUND: Polycaprolactone (PCL) is a prolonged degradable polymer that has good mechanical strength. The authors fabricated PCL as an ear shaped scaffold. Alginate hydrogel was used to seed chondrocyte into the PCL porous scaffold by a gel-cell seeding technique. MATERIAL AND METHOD: PCL Scaffolds were fabricated like human pinna by particle leaching technique. Chondrocyte was isolated from human rib cartilage and then cultured. The cultured chondrocyte were mixed with 1.2% alginate and b-FGF (basic-fibroblast growth factor) 5 ng/ml at a concentration of 25 x 10(6) cell/ml, then were seeded in porous PCL scaffold to make the constructs. The constructs were cultured in vitro for 1 week. Then they were implanted in subcutaneous plane of the back of six female nude mice (5 weeks old). Two nude mice were sacrificed at 2, 3, and 6 months. Histological study was done (H&E, Alcian blue, collagen type II). RESULT: Neocartilage was formed in the porous cavity of PCL scaffold. At 2 and 3 months, neocartilage were similar to very young cartilage. At 6 months, they were mature. The delayed maturation until 6 months and the highly vascularization of neocartilage in the early phase was the effect of human b-FGF The growths of neocartilage islands in porous cavity were also observed along with degradation ofPCL inter-porous septum. CONCLUSION: This paper reports the first success of cartilage tissue engineering in Thailand. PMID- 17718276 TI - Total mesorectal excision training in soft cadaver: feasibility and clinical application. AB - BACKGROUND: The major problem in the treatment of rectal cancer is local recurrence. After the introduction of total mesorectal excision (TME), the recurrent rate decreased from 100% to around 10%. OBJECTIVE: The purpose of the present study was to evaluate the quality of organ and tissue plane preservation in soft cadaver and to assess the feasibility to perform the procedure (mobilization of colon and rectum, total mesorectal excision and stapler anastomosis) in soft cadaver. SETTING: Colorectal Division, Department of Surgery and Surgical Training Center Department of Anatomy, Faculty of Medicine, Chulalongkorn University. STUDY DESIGN: Prospective descriptive study. MATERIAL AND METHOD: Seven soft cadavers were used for total mesorectal excision (TME) training. These procedures were performed by 21 participants (1 soft cadaver for 3 participants). The procedures were done under the supervision of experienced colorectal surgeons. The successfulness, satisfaction in performing the procedure and the quality of organ preservation were evaluated using standardized questionnaires. RESULTS: Participants were satisfied about TME training in soft cadaver (mean 8.24-8.71) and rated that soft cadavers were good in terms of internal organs and tissue plane preservation (mean 7.19-8.19) (0 = extremely unsatisfied, 10 = extremely satisfied). CONCLUSION: Training of TME in soft cadaver is feasible. The similarity in tissue quality (texture, consistency, color) of the preserved organs to that of the living and the good feel of performing the procedure make the trainee better understand the techniques and improve their skills. PMID- 17718277 TI - 14-day quadruple therapy with ranitidine bismuth citrate after Helicobacter pylori treatment failure in Thailand. AB - BACKGROUND: A quadruple therapy with a proton pump inhibitor, bismuth, metronidazole and tetracycline is recommended as a second line therapy after Helicobacter pylori treatment failure. OBJECTIVE: To evaluate the efficacy of 14 day ranitidine bismuth citrate (RBC) base quadruple therapy after H. pylori treatment failure in Thai patients. METHOD AND MATERIAL: Between June 2003-May 2005, thirty-four patients who were H. pylori positive after first line (Omeprazole, Amoxicillin, Clarithromycin or Metronidazole) treatment failure received 14-day quadruple therapy with RBC (400 mg bid), Rabeprazole (20 mg bid), Metronidazole (500 mg tid) and Tetracycline (500 mg qid). Four weeks after completion of treatment, eradication was confirmed with 14C-urea breath test. RESULTS: There were 18 males (52.9%) and 16 females (47.1%) with a mean age of 47.3 +/- 14.6 years. Four patients dropped out due to side effects. Per-protocol eradication rate was 86.7% and the intention-to-treat eradication rate was 76.5%. Adverse effects were found in 38.2% with a bitter taste, nausea, and dizziness. The mean age in the treatment failure group was younger than that in the successful group (35.3 +/- 13.9 vs 51.1 +/- 13.9 years, p = 0.046, 95%CI, 0.3 31.5%). The abdominal symptoms were improved after eradication (82.4%). CONCLUSION: The 14-day quadruple therapy with ranitidine bismuth citrate is effective and well tolerated for the patients who failed with the Helicobacterpylori treatment. The patients with older age may receive a more favorable outcome of the treatment. PMID- 17718278 TI - Randomized control trial of live Lactobacillus acidophilus plus Bifidobacterium infantis in treatment of infantile acute watery diarrhea. AB - OBJECTIVE: To evaluate the effectiveness of live Lactobacillus acidophilus plus Bifidobacterium infantis in the treatment of acute watery diarrhea. DESIGN: Open, randomized control trial. SETTING: King Chulalongkorn Memorial Hospital, Bangkok, Thailand. MATERIAL AND METHOD: Seventy-one infants (aged 1-24 months) with acute watery diarrhea that presented at Department of Pediatrics, King Chulalongkorn Memorial Hospital, Bangkok were enrolled after parental signed informed consent. They were randomized into 2 groups. The Study group (n = 35) received live Lactobacillus plus Bifidobacterium (3 x 10(9) CFU) bid and ORS and the Control group (n = 36) received ORS only. All infants received lactose free milk. Case record forms were completed daily for 5 days by the parents. RESULTS: All 71 infants completed the present study. There was no difference of the patients'characteristics and baseline clinical symptoms between the study group and the control group. Live Lactobacillus plus Bifidobacterium shortened the diarrhea duration (1.6 +/- 0.7 days vs 2.9 +/- 1.7 days, p < 0.01) compared to controls. However the stool frequency and duration of hospitalization were not significantly different (p > 0.05, study group vs control group). CONCLUSION: Live Lactobacillus acidophilus plus Bifidobacterium infantis may be an effective treatment for acute watery diarrhea in infants. The 2-day course treatment can significantly shorten the duration of diarrhea. PMID- 17718279 TI - Common symptoms and type of impacted molar tooth in King Chulalongkorn Memorial Hospital. AB - BACKGROUND: Patients who suffered from impacted teeth increase in number every year They have a wide range of ages and also have symptomatic or asymtomatic impacted molar teeth. The most common symptoms were pain, dental carious problem, gingivitis and oral infection. This was different in each patient. OBJECTIVES: 1) to study the relation of age and common symptoms among patients with an impacted molar tooth. 2) to study the type of impacted molar tooth SETTING: Department of Dentistry, King Chulalongkorn Memorial Hospital RESEARCH DESIGN: Descriptive study MATERIAL AND METHOD: Six hundred and eighty patients who had an impacted tooth were treated at the Department of Dentistry, King Chulalongkorn Memorial Hospital from June 2002 to December 2005. They were categorized in 5 age groups, namely: < or = 20 years, 21-30 years, 31-40 years, 41-50 years, and > 50 years. Data was collected from history taking, oral and radiographic examinations. The details of the patient's data and tooth's data were recorded, i.e., gender, age, location and type of the impacted tooth including the details of symptoms including pain, dental caries, gingivitis, oral and throat infections. RESULTS: Four common symptoms including pain, dental caries, gingivitis and oral infection were recorded in each age group. The Pearson Chi - square test showed that in the statistical difference of variation of ages, p-values were 0.001, 0.037, < 0.001, 0.036 for the symptoms of pain, dental carious problem, gingivitis, and infection, respectively. One hundred and seventy eight maxillary third molar impacted teeth and 502 mandibular third molar impacted teeth were found. The impacted molar teeth were classified into five types. There was a mesioangular (402 cases), horizontal (125 cases), vertical (116 cases), distoangular (30 cases) and linguoversion or buccoversion impacted tooth (7 cases). There was a significant difference of type of impacted tooth, p-values were 0.013, 0.002 for the symptom ofpain and oral infection, respectively, but non significant difference for the dental carious problem and gingivitis, p-values were 0.702, 0.367 respectively. CONCLUSION: The most frequent age group of patients with an impacted molar tooth was 21-30 years. Patient under 30 years had dental carious problems more than other symptoms, while gingivitis was more common in the older group. There was a statistical significant difference of variation of age and symptom. The most common type of impacted molar tooth was mesioangular type. PMID- 17718280 TI - Occupational exposures among nurses and housekeeping personnel in King Chulalongkorn Memorial Hospital. AB - OBJECTIVES: To determine the incidence and related factors of blood and body fluid exposure (BBFE)among nurses and housekeeping personnel in King Chulalongkorn Memorial Hospital, Bangkok, Thailand MATERIAL AND METHOD: A retrospective survey of BBFE among 858 nurses and housekeeping personnel who were working in the year 2004 was done. Data were collected by a self-administered questionnaire RESULTS: The annual incidence rate of BBFE was 31.9% (by person) and 45.5 exposures per 100 persons (by event). The highest incidence rate was observed in percutaneous exposure. Graduated nurses had the greatest risk of all exposures, but housekeeping personnel had the highest rate ofpercutaneous exposure. The highest incidence of BBFE was observed in the emergency room. Most BBFE occurred after using a medical instrument. 76.9% of BBFE were not reported. CONCLUSION: The incidence of BBFE among nurses and housekeeping personnel in King Chulalongkorn Memorial Hospital was high. Systematic control measures and good organization of the work and workplace should be urgently implemented. PMID- 17718281 TI - Thrombophilia profile in Thai patients with arterial thrombotic disorders. AB - BACKGROUND: Arterial thrombosis is attributed mainly to atherosclerosis and the roles of hypercoagulability remain unclear In addition, there are ethnic variations in thrombophilia profiles. OBJECTIVE: The authors performed a survey of the thrombophilia profile in Thai patients with arterial thrombosis MATERIAL AND METHOD: The authors analyzed 103 consecutive cases of proven arterial thrombosis and requested thrombophilia profile in Chulalongkorn Hospital during 2003-2004. The mean age was 42.5 years. The proportions of stroke, peripheral arteries, and other sites were 70.9%, 22.3% and 6.8%, respectively. RESULTS: Abnormal profile was found in 35.0% with the prevalence of hyperhomocysteinemia, low protein S, antiphospholipid antibody and low protein C was 15.5%, 12.6%, 9.7%, and 5.8%, respectively. There was no difference in clinical characteristics between cases with or without detectable abnormalities. However, the authors found significant associations of low protein S with poor outcome and HIV seropositivity with antiphospholipid. CONCLUSION: The present study found that the defective protein C pathway may be the most common thrombophilia found in Thais with arterial thrombosis. Future study is required to prove the cause effect relationship and its clinical significance. PMID- 17718282 TI - Outcome of familial adenomatous polyposis: a retrospective study. AB - BACKGROUND: Familial adenomatous polyposis (FAP) is characterized by the presence of numerous colorectal adenomatous polyps that progress to colorectal cancer if left untreated. Following colorectal cancer, periampullary cancer and aggressive desmoid tumor are also the common causes of death. The purpose of the present study was to describe the clinical course of FAP patients. MATERIAL AND METHOD: The authors conducted a retrospective study of 31 FAP patients who were treated at King Chulalongkorn Memorial Hospital (KCMH) between March 2000 and March 2006. Demographic data, family history, symptoms, extracolonic manifestations, operative procedures, pathologic findings, and postoperative results were collected. RESULTS: Two patients were excludedfrom the present study. The average age of the 29 patients was 33.48 years with the sex ratio (male/female) of 0.93. Seventeen of the 29 patients (58.6%) had a family history of FAP Sixteen of 29 patients were discovered with colorectal cancer with a mean age of34.56 years. Mucous bloody stool was the most common presenting symptom and most of the patients with this symptom (11/13) already had colorectal cancer Gastroduodenal polyps and desmoid tumor were common extracolonic manifestations. The most common operative procedure was restorative proctocolectomy with ileal J pouch (RPC). Wound infection and gut obstruction were the frequent complications. Functional outcomes of patients with RPC were good. The mean age ofpatients with colon cancer was older than the mean age ofpatients without colon cancer However, there was no significant difference between the two groups. The sex ratio and family history of FAP were not statistically different. No significant differences were found in surgical procedures and postoperative complications. On the follow up period, two patients in the later group died of desmoid tumor and pancreatic cancer while seven patients in the former group died of metastatic colon cancer and one with desmoid tumor CONCLUSION: The proportion ofpatients who were discovered with colorectal cancer in the present study was high with young age onset of cancer Moreover, patients in this group had poorer outcome compared to the group of patients without colorectal cancer; of which, metastatic colorectal cancer was the major cause of death. This result may be due to aggressiveness and advanced stage of disease at the first diagnosis. PMID- 17718283 TI - Anatomic variations of the hepatic arteries in 200 patients done by angiography. AB - OBJECTIVE: To evaluate and classify hepatic artery variations of 200 patients by angiography. MATERIAL AND METHOD: Celiac and superior mesenteric artery (SMA) angiographic studies of 200 patients at King Chulalongkorn Memorial Hospital (KCMH) from January 2003 to July 2004 were retrospectively reviewed. Anatomic findings were classified according to Michels and Hiatt's classifications. RESULTS: The vascular anatomy of the liver was classified according to two different established systems. Hepatic arterial patterns were analyzed in order offrequency discovered as the following; normal pattern in textbook descriptions 80.5%, a replaced or accessory right hepatic artery (RHA) originating from the SMA 11.5% and a replaced or accessory left hepatic artery (LHA) originating from the left gastric artery (LGA) 5.5%. In 0.5% of the cases, there was a combination of variations of both RHA and LHA. Variants of the common hepatic artery (CHA) arising from the SMA were found in 0.5%. 1.5% of cases were not classified by either Michels or Hiatt's classifications. CONCLUSION: The present study had the same results by the higher rates of normal hepatic anatomy with lower rates of other types compared to Michels and Hiatt's studies. In addition, the authors found cases of rare variations that were not classified by either Michels or Hiatt but were previously reported by other publications. PMID- 17718284 TI - Comparison of economic bipolar vessel sealer and biclamp for the hemostasis of large-sized cadaver arteries. AB - OBJECTIVE: The purpose of the present study was to compare the bursting pressure of large arteries sealed with hand made bipolar vessel sealer (BVS) using flexible electrosurgical system (HemoSaccab) and the BiClamp. MATERIAL AND METHOD: Sixteen common carotid arteries from a fresh cadaver were sealed using BVS and BiClamp 4 times sequentially for burst testing. A catheter was placed into the open end of the specimen and secured with a purse-string suture. The catheter was connected to a pressure monitor and saline was infused until there was leakage from the sealed end defining the bursting pressure in mmHg. Both devices were used to seal an additional 2 vessels in each group, which were sent for histologic examination. Student's t-test was performed. RESULTS: The BVS's mean burst pressure was statistically higher than that of the BiClamp (573 vs 442 mmHg) (p < 0.001). CONCLUSION: The flexible system of BVS is superior to the BiClamp device for sealing the common carotid artery because the BiClamp automatically finished the sealing process before the sealing area was completely dessicated. PMID- 17718285 TI - The patient risk in psychiatric service at King Chulalongkorn Memorial Hospital, Thai Red Cross Society. AB - OBJECTIVE: The purpose of this research was to study the patients risk in psychiatric service at King Memorial Chulalongkorn Hospital, Thai Red Cross Society, Bangkok, Thailand. MATERIAL AND METHOD: The annual risk incidents had been reviewed during 2002-2005. The risk incident had been divided in outpatient, inpatient, and electroconvulsive therapy treatment (ECT) service. The outpatient risk indicators were suicide, assault, mortality from emergency medication and severe side effect from emergency medication incidents. The inpatient risk indicators were suicide, assault, absconding, inappropriate sexual behavioral, side effect from emergency medication and severe trauma from restraint incidents. Mortality and complication from ECT incidents was observed. RESULTS: There was no suicide or any other severe risk incidents in the outpatient service. The rate of inpatient suicide was 144 per 100,000 admissions. The other risks also demonstrated low incidents. There was no mortality in ECT and the only early complication was dental problems, which were found in 0.13%. Risk incidents were calculated and presented in percentage or per 100,000. CONCLUSION: The overall risk of psychiatric service did not seem to be high even though psychiatric patients were at high risk and difficult to manage in nature. If the patients had appropriate management, the risks can be prevented. The trend of the risk was not high either. The present study supports the use of risk indicators, risk management plans, and risk surveillance in psychiatric service. PMID- 17718286 TI - Feasibility and effectiveness of a novel vascular hemostatic device (Chula-clamp) after coronary angiography or percutaneous coronary intervention. AB - BACKGROUND: Chula-clamp is a newly hydraulic vascular hemostatic device. The advantages of the device are convenience, reusability, and lessen patient discomfort and vascular complication. Furthermore, the device is assembled with a recycled balloon inflator and other locally made components, which make it less expensive than other commercially available hemostatic devices. The present study was conducted to compare the effectiveness of Chula-clamp with standard manual compression. MATERIAL AND METHOD: This is a prospective, quasi-randomized controlled clinical trial comparing effectiveness of Chula-clamp to conventional manual compression for attaining femoral artery hemostasis after coronary angiography (CAG) or percutaneous coronary intervention (PCI). Effectiveness was determined by femoral vascular complications rate. The primary endpoint was severe femoral vascular complications (the formation of a groin hematoma, femoral artery thrombosis, pseudoaneurysm, and arteriovenous fistula). RESULTS: One hundred and forty patients scheduled for percutaneous coronary intervention or coronary angiogram in King Chulalongkorn Memorial hospital were enrolled (70 patients for each group). The baseline characteristics were similar in both groups. There was no serious vascular complication detected in either group. In addition, there was no statistical difference in minor complications at the access site between the two groups. [e.g., swelling (1.4% in standard manual compression group vs. 2.9% in Chula-clamp, p = 0.56) and ecchymosis (8.57% in both groups)]. CONCLUSION: Chula-clamp, a novel hydraulic vascular hemostatic device, is feasible, safe, and effective for femoral artery hemostasis (after CA G or PCI via femoral artery). Its effectiveness is not different from standard manual compression. PMID- 17718287 TI - Effects of demineralized bone matrix on proliferation and osteogenic differentiation of mesenchymal stem cells from human umbilical cord. AB - BACKGROUND: Mesenchymal stem cells or mesenchymal progenitor cells are defined as self-renewable, multipotent progenitor cells with the unlimited capacity to differentiate into multiple lineage-specific cells that form bone, cartilage, fat, and muscle tissues. Demineralized bone matrix (DBM) has been extensively utilized in orthopaedic, periodontal, and maxillofacial applications and widely investigated as a biomaterial to promote new bone formation. OBJECTIVE: To isolate and characterize umbilical cord mesenchymal stem (UCMS) cells and examine the biological activity of DBM in the UCMS cells MATERIAL AND METHOD: UCMS cells were obtained from human umbilical cord culture. Cells were treated with or without DBM over 7 days of culture. Cell proliferation was examined by direct cell counting. Osteogenic differentiation of the UCMS cells was analysed with alkaline phosphatase staining assay. RESULTS: Phenotypic characteristics ofhuman UCMS cells were spindle and stellate shapes with fine homogenous cytoplasm, typically associated with fibroblast-like cells. The control cells (without DBM treatment) exhibited a spindle shape with little extracellular matrix, whereas the DBM treated cells appeared shortened and flattened, and they were surrounded by extracellular matrix. DBM inhibited the growth of the UCMS cells by 50%, as determined by direct cell counting. Morphologic and histochemical studies confirmed that DBM had a strong stimulatory effect on the alkaline phosphatase activities of UCMS cells, a very early marker of cell differentiation into the osteogenic lineage. CONCLUSION: Mesenchymal progenitor cells derived from umbilical cord could differentiate along an osteogenic lineage and thus provide an alternative source for cell-based therapies and tissue engineering strategies. PMID- 17718288 TI - The effect of cinnamon cassia powder in type 2 diabetes mellitus. AB - BACKGROUND: Type 2 diabetes is a chronic metabolic disorder and the incidence of cardiovascular is increased two- to fourfold in its complications. Cinnamon is expected to have some degree of anti-diabetic efficacy without troublesome side effects. The objective of the present study was to investigate the anti-diabetic effect of cinnamon cassia powder in type 2 diabetic patients MATERIAL AND METHOD: Sixty type 2 diabetic patients were randomized either 1.5 g/d of cinnamon cassia powder or placebo. Both groups were in combination with their current treatment (metformin or sulfonylurea) according to single blind randomized, placebo-control trial in a 12-week period. Efficacy was evaluated by HbA1c fasting plasma glucose, Lipid profile, BUN, creatinine, liver function test and adverse effects were recorded. RESULTS: After a 12-week period, HbA1c was decreased similarly in both groups from 8.14% to 7.76% in the cinnamon group and from 8.06% to 7.87% in the placebo group. This was not found statistically significantly different. However the proportion of patients achieving HbA1c < or = 7% was also greater in patients receiving cinnamon compared with patients receiving placebo, nevertheless, it was not found statistically significantly different (35% vs 15%, x2 = 3.14, p > 0.05). No significant intergroup differences were observed in lipid profile, fasting plasma glucose except in SGOT 27.1 (8.75) to 22.1 (5) in cinnamon group and 24.08 (8.5) to 23.63 (8.88) in the placebo group (p = 0.001). CONCLUSION: The cinnamon cassia powder 1.5 g/d did not have any significant difference in reducing fasting plasma glucose, HbA1c and serum lipid profile in type 2 diabetes patients who had mean fasting plasma glucose 154.40 +/- 24.72 mg/dl. PMID- 17718289 TI - Personality profiles of suicidal depressed patients. AB - OBJECTIVE: To investigate the personality profiles of depressed patients who attempted suicide. MATERIAL AND METHOD: The sample consisted of 80 patients aged above 18 years who presented with suicidal attempt and had clinical depression and 80 depressed patients who had never attempted suicide. The subjects were clinically assessed for depression and measured severity objectively with the Hamilton Depression Rating Scale (HAM-D). Personality was assessed via the Sixteen Personality Factor Questionnaire (16PF). RESULTS: The personality profile showed that patients with suicidal attempt were easily affected by feelings, emotionally less stable, concrete thinking, relatively more uninhibited and imaginative compared to those without suicidal attempt. CONCLUSION: Depressed patients who attempted suicide appeared to have a distinctive personality profile. Exploration and intervention tailored to specific personality profile particularly emotional instability, and concrete thinking in individuals with depression should be included in management of depression for prevention and reducing risk of suicide. PMID- 17718290 TI - The temporal variations of presumptive sudden death of Thai people in Singapore and Taiwan. AB - BACKGROUND: Sudden Unexplained Death Syndrome (SUDS) is the major cause ofsudden death in Thai adults, especially Thai migrant workers in Singapore and Taiwan. Temporal variations of sudden death of Thai people abroad are not well known. OBJECTIVE: To study the month, day and time of death of presumptive sudden death (PSD) in Singapore, Taiwan. MATERIAL AND METHOD: The authors reviewed the death certificates of Thai people who died in Singapore and Taiwan and previously SUDS reported cases form Singapore. The time, day and month ofPSD and Non-PSD deaths in Singapore and Taiwan were compared. RESULTS: From January 1994 to January 1995, 46 SUDS died in Singapore (gr A), from May 2000 to August 2002, 39 PSD died in Singapore (gr B), from January 1999 to May 2002, 100 presumptive or probable sudden unexplained death syndrome (PSUDS) died in Taiwan (gr C) and 254 Non-PSD death aboard (gr D) as controls. The annual SUDS/PSD death rates (per 100,000) in Singapore were 91.1 in 1994, 30.7 in 2001 and 33.5 in Taiwan in 2000. All but two SUDS/PSD cases were male. The mean age in gr A + B and C were 34.9 + 7.5 and 33.1 +/- 6.0 years old respectively. In gr. A, B and C, compared with gr D, Tuesday was the weekday of lowest SUDS/PSD death rate and Saturday was the highest. (p < 0.05). Time of death in gr B and C were peak during midnight to 8 a.m. and there was some trend of seasonal variation in occurrence of SUDS/PSD with the peak death rate in April and trough death rate in September; which is significantly different from gr D (1.49% vs 10.89% of all deaths, p < 0.01). CONCLUSION: The presented data demonstrate some temporal variations in SUDS/PSD death aboard. The sudden death of Thai people in Singapore and Taiwan may be more prevalent in the "work-to-rest" than "rest-to-work" periods. PMID- 17718291 TI - Towards the better understanding about pathogenesis of chronic daily headache. AB - Evolution of episodic headaches, especially migraine to chronic daily or near daily headache is an interesting phenomenon. Although its pathogenesis is still unclear the derangement of the brainstem modulatory system is a possible explanation. Recent evidences indicate the involvement of rostral brainstem activation and the attack of migraine. Several nuclei located in this area namely periaquiductal grey, nucleus raphe, locus ceruleus are known to be pivotal in the modulation of sensory information. Therefore, derangement of this complex network can result in abnormal sensory perception, e.g. throbbing headache, photophobia, phonophobia, etc as seen during the attacks of migraine. Chronic alteration of this system can lead to an increase in headache frequency. Evidences from animal experiments indicate that dysfunction of the sensory modulation system in the brainstem also promote the development of central sensitization, a condition in which central nociceptive neurons are more responsive to stimuli. Particular symptoms of chronic daily headache, namely increased headache frequency, expansion of headache area and cutaneous allodynia, imply the sensitization of central nociceptive neurons in the trigeminal pathway. A number of animal experiments have confirmed that chronic analgesic exposure lead to changes in serotonin as well as its receptors in the central nervous system. The plasticity of serotonin-dependent pain control system may accelerate the process of sensitization and results in the development of chronic daily headache secondary to analgesic overuse. PMID- 17718292 TI - Comparison of ultrasound score, CA125, menopausal status, and risk of malignancy index in differentiating between benign and borderline or malignant ovarian tumors. AB - OBJECTIVES: To evaluate the diagnostic performances of ultrasound score (US), CA 125, menopausal status, risk of malignancy index (RMI)-- in differentiating between benign and borderline or malignant ovarian tumors. MATERIAL AND METHOD: Women with ovarian masses who were scheduled to have elective surgery at the Department of Obstetrics and Gynecology, BMA Medical College and Vajira Hospital between May 1999 and December 2001 were included in the study. Ultrasonographic study and CA 125 were examined preoperatively. The RMI was obtained from the ultrasound score, CA 125, and menopausal status. The diagnostic values of each parameter and the RMI were determined. RESULTS: From 175 women, 35 women (20%) had malignant ovarian tumors. RMI yielded better diagnostic performance to differentiate between benign and borderline or malignant ovarian tumors than US score, CA 125, and menopausal status in respective order The optimal RMI to predict malignancy was 0.135 with the sensitivity of 88.6% (95% CI; 81.1%-96.1%), specificity of 90.7% (95% CI; 83.9%-97.6%), positive and negative predictive value of 70.5% (95% CI; 59.7%-81.2%) and 97.0% (95% CI; 92.9%-100.0%) respectively. CONCLUSION: RMI yielded better diagnostic performance than the individual parameter of ultrasound score, CA 125, or menopausal status in differentiation of benign from borderline or malignant ovarian tumors. PMID- 17718293 TI - Clinical use of cord blood for stem cell transplantation. AB - Allogeneic bone marrow transplantations (BMT) from HLA-matched siblings have been successfully used for treatment of patients with high-risk hematological malignancies, genetic immunodeficiencies, metabolic disorders, or marrow failure syndromes. Unfortunately, most of patients lack matched related donors. Over the past decade clinicians have explored the suitability of umbilical cord blood (CB) as an alternative source for hematopoietic stem cell transplantation. Since the first related cord blood transplantation (CBT) was performed successfully for a child with Fanconi Anemia in 1988, there have been many children undergoing CBT from related donors. The further experience suggests that CB donation is a safe procedure for both mother and newborn. Subsequently, several quality CB banks were established worldwide with requirement of specific issues including donor recruitment, CB collection and processing, histocompatibility testing, infectious and genetic disease testing, transportation of CB, and protection of confidentiality of donors and recipients. The clinical data showed that unrelated donor CBT had comparable survival results to unrelated donor BMT CB offers many potential advantages such as it is readily available, its collection causes no harm to the donor and minimal HLA-disparity is acceptable. However there are some disadvantages due to the volume and cell dose of each collected CB is limited, thus methods to enhance the number or quality of stem cells in CB are needed. At present the world's experiences suggest that CB is an acceptable alternative to bone marrow. PMID- 17718294 TI - The experience of one obstetrician in a rural area in emergency obstetrics. AB - Chiangrai, a northern province of Thailand has continued to find challenges in providing emergency obstetric care similar to other rural areas in developing countries. However, several intervention campaigns aiming to prevent and minimize emergency obstetrics-related problems were carried out successfully in the local community during 1974 to 2003. These campaigns included: (1) birth reduction campaign with a decreased birth rate from 3.2% to 1.0% between 1974-2003, (2) HIV vertical transmission rate reduction campaign resulted in a decrease from 42% in 1994 to 5.75% in 2003, (3) perinatal morbidity and mortality reduction campaign through establishing supervision committees and setting up standard guidelines for proper treatment and, (4) a campaign to eliminate violence and sex abuse of women and girls through setting up 'One Stop Crisis Center'. One of the key successes behind the campaigns' positive outcome was likely to result from a high level of coordination and collaboration among specialists, non-specialists and local volunteers. Limitations in the number of obstetricians and related facilities will continue in rural areas. Therefore, alliances among multi disciplinary teams are viewed as a vital necessity for emergency obstetric care in rural areas. PMID- 17718295 TI - Challenge for unsafe abortion. PMID- 17718296 TI - Treatment of iron deficiency anaemia in pregnancy and postpartum with special focus on intravenous iron sucrose complex. PMID- 17718297 TI - Computed tomography findings of early abdominal postoperative complications. PMID- 17718298 TI - Imaging of appendicoliths dropped at laparoscopic appendectomy and their complications. PMID- 17718299 TI - Musculoskeletal disorders of the lower limb--ultrasound and magnetic resonance imaging correlation. AB - The purpose of this paper is to familiarize general radiologists and specialists with the sonographic and corresponding magnetic resonance imaging (MRI) appearance of various musculoskeletal disorders of the lower limb. Technologists and radiologists should be familiar with all imaging techniques for the investigation and evaluation of musculoskeletal abnormalities. The role of high resolution ultrasound (US) is highlighted, as well as the complementary relation between both imaging modalities. We also discuss some of the advantages of US over MRI in the investigation of musculoskeletal disorders of the lower limb. The MRI and US appearances of various articular, periarticular, and soft tissue pathologies of the lower limb are compared and reviewed, and where possible, the advantages of each modality are identified. PMID- 17718300 TI - Prevalence of knee abnormalities in patients with osteoarthritis and anterior cruciate ligament injury identified with peripheral magnetic resonance imaging: a pilot study. AB - OBJECTIVES: 1) To assess, with a peripheral magnetic resonance imaging system (pMRI), the prevalence of bony and soft tissue abnormalities in the knee joints of normal subjects, osteoarthritis (OA) patients, and individuals who have suffered an anterior cruciate ligament (ACL) rupture; and 2) to compare the prevalence among groups. METHODS: Magnetic resonance (MR) images of 28 healthy, 32 OA, and 26 ACL damaged knees were acquired with a 1.0-T pMRI system. Two radiologists graded the presence and severity of 9 MR image features: cartilage degeneration, osteophytes, subchondral cyst, bone marrow edema, meniscal abnormality, ligament integrity, loose bodies, popliteal cysts, and joint effusion. RESULTS: Ten of 28 healthy (35.7%), 24 of 26 ACL (92.3%), and all OA knees (100%) showed prevalent cartilage defects; 5 healthy (17.9%), 20 ACL (76.9%), and all OA knees (100%) had osteophytes; and 9 normal (32.1%), 21 ACL (80.8%), and 29 OA knees (90.6%) had meniscal abnormalities. One-half of the knees in the OA group (16 of 32, 50%) had subchondral cysts, and almost one-half had bone marrow edema (15 of 32, 46.9%). These features were not common in the ACL group (7.7%, and 11.5%, respectively) and were not observed in healthy knees. The OA group had the most severe cartilage defects, osteophytes, bone marrow edema, subchondral cysts, and meniscal abnormalities; the ACL group showed more severe cartilage defects, osteophytes, and meniscal abnormalities than did normal subjects. CONCLUSION: The results suggest that knees that have sustained ACL damage have OA-like reatures; most subjects (19 of 26, 73.1%) could be identified as in the early stage of OA. The prominent abnormalities present in ACL-damaged knees are cartilage defects, osteophytes, and meniscal abnormalities. PMID- 17718301 TI - Answer to case of the month #119. Computed tomography findings of a bladder hernia. PMID- 17718302 TI - Answer to case of the month #120. Splenosis: case history, findings and discussion. PMID- 17718303 TI - Finding Nemo. PMID- 17718304 TI - A view on new drugs for macular degeneration. AB - Estimates suggest that in Europe 2.3% of people older than 65 years have neovascular age-related macular degeneration, which can lead to loss of central vision. The condition is the leading cause of blindness in the estern world, and the third commonest worldwide. It is characterised by growth of new blood vessels beneath the retina (choroidal neovascularisation), a process stimulated by the secretion of vascular endothelial growth factor (VEGF).3 Two new drugs, pegaptanib sodium (Macugen - Pfizer) and ranibizumab (Lucentis -Novartis), that block the effects of VEGF are now licensed in the UK for patients with neovascular age-related macular degeneration. A third drug that inhibits VEGF activity, bevacizumab (Avastin - Roche), is also used for this condition but is licensed only for metastatic colorectal or breast cancer. Here we consider the role of pegaptanib, ranibizumab and bevacizumab in patients with neovascular age related macular degeneration. PMID- 17718306 TI - Understanding monoclonal antibodies. AB - Elsewhere in this issue, we review new treatments for neovascular age-related macular degeneration, of which, bevacizumab and ranibizumab are monoclonal antibodies. These are two of a growing number of monoclonal antibodies currently available for therapeutic use in the UK. We have reviewed some of the others before: bevacizumab and cetuximab for colorectal cancer; infliximab for rheumatoid arthritis; omalizumab for severe asthma; and trastuzumab for breast cancer. The expanding range of these products and their clinical applications can make it difficult to keep abreast of developments in this field. With this in mind, we describe the key principles underlying the production, use and naming of monoclonal antibodies. PMID- 17718305 TI - Does dimeticone clear head lice? AB - Head lice infestation is common and mainly affects children of primary school age. Treatments include licensed topical preparations containing conventional chemical insecticides and medical devices. Each of these fail to eradicate head lice in some patients and resistance is a problem with chemical insecticides. Dimeticone 4% lotion (Hedrin - Thornton & Ross) is a new treatment licensed "for the eradication of head lice infestations". Here we consider its place in the context of other options. PMID- 17718307 TI - Readers perspective. Relaxation of stark regulations. PMID- 17718308 TI - Technology integration at the point of care. PMID- 17718309 TI - Bringing I.T. into the home. PMID- 17718311 TI - Rolling with the changes. PMID- 17718310 TI - Medication reconciliation: what role will I.T. play? PMID- 17718312 TI - Online records get personalized. PMID- 17718313 TI - Getting documents in order. PMID- 17718314 TI - Taking the 'H' out of HR. PMID- 17718315 TI - Stats snapshot. PMID- 17718316 TI - Keeping I.T. on the track. PMID- 17718317 TI - A shear horizontal surface wave in magnetoelectric materials. AB - We show that a semi-infinite magnetoelectric (ME) material adjoining a vacuum sustains the propagation of a shear horizontal wave accompanied by electromagnetic waves. The ME material is assumed to possess hexagonal (6 mm) symmetry. The expression for the phase velocity of this wave is obtained explicitly. The result is helpful for applications of piezoelectric-piezomagnetic composites to acoustic wave and microwave devices. PMID- 17718318 TI - Frequency shift of thickness-shear vibrations of AT-cut quartz resonators due to a liquid layer with the electrode stiffness considered. AB - Thickness-shear vibrations of an AT-cut quartz resonator due to a liquid layer are studied. Closed form solutions are obtained with electrodes considered. Effect of the shear stiffness of electrodes on frequency shifts is presented. PMID- 17718319 TI - Optimal design of piezoelectric transformers: a rational approach based on an analytical model and a deterministic global optimization. AB - This paper deals with a deterministic and rational way to design piezoelectric transformers in radial mode. The proposed approach is based on the study of the inverse problem of design and on its reformulation as a mixed constrained global optimization problem. The methodology relies on the association of the analytical models for describing the corresponding optimization problem and on an exact global optimization software, named IBBA and developed by the second author to solve it. Numerical experiments are presented and compared in order to validate the proposed approach. PMID- 17718320 TI - Motion artifacts of extended high frame rate imaging. AB - Based on the high frame rate (HFR) imaging method developed in our lab, an extended high frame rate imaging method with various transmission schemes was developed recently. In this method, multiple, limited-diffraction array beams or steered plane wave transmissions are used to increase image resolution and field of view as well as to reduce sidelobes. Furthermore, the multiple, limited diffraction array beam transmissions can be approximated with square-wave aperture weightings, allowing one or two transmitters to be used with a multielement array transducer to simplify imaging systems. By varying the number of transmissions, the extended HFR imaging method allows a continuous trade-off between image quality and frame rate. Because multiple transmissions are needed to obtain one frame of image for the method, motion could cause phase misalignment and thus produce artifacts, reducing image contrast and resolution and leading to an inaccurate clinical interpretation of images. Therefore, it is important to study how motion affects the method and provide a useful guidance of using the method properly in various applications. In this paper, computer simulations, in vitro and in vivo experiments were performed to study the effects of motion on the method in different conditions. Results show that a number of factors may affect the motion effects. However, it was found that the extended HFR imaging method is not sensitive to the motions commonly encountered in the clinical applications, as is demonstrated by an in vivo heart experiment, unless the number of transmissions is large and objects are moving at a high velocity near the surface of a transducer. PMID- 17718322 TI - Method for microbubble characterization using primary radiation force. AB - Medical ultrasound contrast agents (UCAs) have evolved from straight image enhancers to pathophysiological markers and drug delivery vehicles. However, the exact dynamic behavior of the encapsulated bubbles composing UCAs is still not entirely known. In this article, we propose to characterize full populations of UCAs, by looking at the translational effects of ultrasound radiation force on each bubble in a diluted population. The setup involves a sensitive, fully programmable transmitter/receiver and two unconventional, real-time display modes. Such display modes are used to measure the displacements produced by irradiation at frequencies in the range 2-8 MHz and pressures between 150 kPa and 1.5 MPa. The behavior of individual bubbles freely moving in a water tank is clearly observed, and it is shown that it depends on the bubble physical dimensions as well as on the viscoelastic properties of the encapsulation. A new method also is distilled that estimates the viscoelastic properties of bubble encapsulation by fitting the experimental bubble velocities to values simulated by a numerical model based on the modified Herring equation and the Bjerknes force. The fit results are a shear modulus of 18 MPa and a viscosity of 0.23 Pas for a thermoplastic PVC-AN shell. Phospholipid shell elasticity and friction parameter of the experimental contrast agent are estimated as 0.8 N/m and 1 10( 7) kg/s, respectively (shear modulus of 32 MPa and viscosity of 0.19 Pas, assuming 4-nm shell thickness). PMID- 17718321 TI - An eigenfunction method for reconstruction of large-scale and high-contrast objects. AB - A multiple-frequency inverse scattering method that uses eigenfunctions of a scattering operator is extended to image large-scale and high-contrast objects. The extension uses an estimate of the scattering object to form the difference between the scattering by the object and the scattering by the estimate of the object. The scattering potential defined by this difference is expanded in a basis of products of acoustic fields. These fields are defined by eigenfunctions of the scattering operator associated with the estimate. In the case of scattering objects for which the estimate is radial, symmetries in the expressions used to reconstruct the scattering potential greatly reduce the amount of computation. The range of parameters over which the reconstruction method works well is illustrated using calculated scattering by different objects. The method is applied to experimental data from a 48-mm diameter scattering object with tissue-like properties. The image reconstructed from measurements has, relative to a conventional B-scan formed using a low f-number at the same center frequency, significantly higher resolution and less speckle, implying that small, high-contrast structures can be demonstrated clearly using the extended method. PMID- 17718323 TI - Harmonic vibro-acoustography. AB - Vibro-acoustography is an imaging method that uses the radiation force of two interfering ultrasound beams of slightly different frequency to probe an object. An image is made using the acoustic emission resulted from the object vibration at the difference frequency. In this paper, the feasibility of imaging objects at twice the difference frequency (harmonic acoustic emission) is studied. Several possible origins of harmonic acoustic emission are explored. As an example, it is shown that microbubbles close to resonance can produce significant harmonic acoustic emission due to its high nonlinearity. Experiments demonstrate that, compared to the fundamental acoustic emission, harmonic acoustic emission greatly improves the contrast between microbubbles and other objects in vibro acoustography (an improvement of 17-23 dB in these experiments). Applications of this technique include imaging the nonlinearity of the object and selective detection of microbubbles for perfusion imaging. The impact of microbubble destruction during the imaging process also is discussed. PMID- 17718324 TI - The effect of phase cancellation on estimates of calcaneal broadband ultrasound attenuation in vivo. AB - Broadband ultrasonic attenuation (BUA) is a clinically-accepted measurement for prediction of osteoporotic fracture risk. Typical clinical BUA measurements are performed with phase-sensitive receivers and, therefore, can be affected by phase cancellation. In order to separate the effects of conventional attenuation (absorption plus scattering) from phase cancellation, BUA was measured on phantoms with acrylic wedge phase aberrators and on 73 women using both phase sensitive (PS) and phase insensitive (PI) reception. A clinical bone sonometer with a two-dimensional (2-D) receiver array was used. PI BUA measurements on phantoms with acrylic wedge phase aberrators were found to be far more resistant to phase cancellation than PS BUA measurements. In data from 73 women, means and standard deviations for BUA measurements were 81.4 +/- 21.4 dB/MHz (PS) and 67.2 +/- 9.7 dB/MHz (PI). The magnitude of the discrepancy between PS BUA and PI BUA tended to increase with bone mineral density (BMD). PMID- 17718325 TI - Ultrasonic detection of the anisotropy of protein cross linking in myocardium at diagnostic frequencies. AB - Increased myocardial stiffness in aging and diabetes that may result in pathologies such as diastolic dysfunction has been attributed, in part, to an increase in cross linking of extracellular matrix proteins such as collagen. With the development of new approaches to cardiovascular therapy, it becomes increasingly important to develop noninvasive approaches for monitoring changes in myocardial cross linking. The objective of this study was to use ultrasound at frequencies used in clinical echocardiography to measure changes in myocardial attenuation resulting from increased cross linking as a function of angle of insonification over a complete rotation. Through-transmission radiofrequency based measurements were performed on 36 specimens from 12 freshly excised ovine hearts at room temperature, which were then fixed in formalin to induce protein cross linking prior to repeated measurements. For angles near perpendicular to the myofiber direction, the measured slope of attenuation increased from 0.52 +/- 0.07 dB/(cm MHz) (mean +/- one standard deviation) for freshly excised to 0.85 +/ 0.08 dB/(cm MHz) for formalin-fixed myocardium. In contrast, results for parallel insonification exhibit considerable overlap (1.88 +/- 0.17 for freshly excised and 1.75 +/- 0.19 dB/(cm MHz) for formalin-fixed myocardium). Results of this study suggest that the response of the extracellular collagenous matrix to changes in cross linking is directionally dependent. The anisotropy of ultrasonic attenuation thus may provide an approach for noninvasive monitoring of the extent and progression of myocardial disease associated with changes in protein cross linking. Accounting for effects due to anisotropy may be essential for the future detection of such changes using ultrasonic attenuation in vivo. PMID- 17718326 TI - Third harmonic transmit phasing for tissue harmonic generation. AB - Generation of tissue harmonic signals during acoustic propagation is based on the combined effect of two different spectral interactions of the transmit signal. One produces harmonic whose frequency is the sum of transmit frequencies. The other results in harmonic at difference frequency of the transmit signals. Both the frequency-sum component and the frequency-difference component are sensitive to the phase of their constitutive spectral signals. In this study, a novel approach for modifying the amplitude of tissue harmonic signal is proposed based on phasing these two components to achieve either harmonic enhancement or suppression. Both experiments and simulations were performed to investigate the effects of 3f0 transmit phasing on tissue harmonic generation. Results indicate that the relative phasing between the frequency-sum component and the frequency difference component markedly changes the amplitude of the second harmonic signal. For harmonic enhancement, approximate 6 dB increase of second harmonic amplitude can be achieved while the lateral harmonic beam pattern also is improved as compared to conventional situations in which only the frequency-sum component is considered. For harmonic suppression, the second harmonic signal also could be significantly reduced by about 11 dB when the frequency-difference component is out of phase with the frequency-sum component. Hence, the method of 3f0 transmit phasing has potentials for both improving signal-to-noise ratio in tissue harmonic imaging and enhancing image contrast in contrast-agent imaging by suppression of tissue harmonic background. PMID- 17718327 TI - Properties of the Anisimkin Jr.' modes in quartz plates. AB - Dispersion curves, surface displacements, and displacement profiles over the plate thickness are numerically calculated for acoustic plate modes, propagating in fused and Y-rotated, X-cut quartz samples with thickness h/lambda in the range 0-4.5 (h, thickness; lambda, wavelength). The Anisimkin Jr.' modes with velocity v(n) close to that of longitudinal bulk wave v(L) and the dominant longitudinal displacement u1 distributed uniformly through the plate thickness are found in quartz crystals with cut angles mu = 120 degrees-140 degrees and plate thickness h/lambda = 0-0.36, 0.94-1.78, 2.32-3.08, and 3.64-4.44. The same modes in fused quartz are not found, except in a narrow region near zero thickness. PMID- 17718328 TI - Estimation of quartz resonator Q and other figures of merit by an energy sink method. AB - An important determinant of the quality factor Q of a quartz resonator is the loss of energy from the electrode area to the base via the mountings. The acoustical characteristics of the plate resonator are changed when the plate is mounted onto a base substrate. The base substrate affects the frequency spectra of the plate resonator. A resonator with a high Q may not have a similarly high Q when mounted on a base. Hence, the base is an energy sink and the Q will be affected by the shape and size of this base. A lower bound Q will be obtained if the base is a semi-infinite base since it will absorb all acoustical energies radiated from the resonator. A scaled boundary finite element method is employed to model a semi-infinite base. The frequency spectra of the quartz resonator with and without the base are presented. In addition to the loss of energy via the base, there are other factors which affect the resonator Q, such as, for example, material dissipation, and damping at the interfaces of quartz and electrodes. The energy dissipation due to material damping increases with the resonant frequency and the reduction of resonator size; hence material damping becomes important in the current and future miniaturized resonators operating at very high frequencies. An energy sink model along with material dissipation would provide realistic Q, motional capacitance, motional resistance, and other figures of merit useful for designing resonators. The model could be used for evaluating resonator and mountings designs of microelectromechanical systems and miniaturized devices. The effect of the mountings, and plate and electrode geometries on the resonator Q and other electrical parameters are presented for AT-cut quartz resonators. Model results from the energy sink method were compared with experimental results and were found to be good. PMID- 17718329 TI - An implementation of synthetic aperture focusing technique in frequency domain. AB - A new implementation of a synthetic aperture focusing technique (SAFT) based on concepts used in synthetic aperture radar and sonar is presented in the paper. The algorithm, based on the convolution model of the imaging system developed in frequency domain, accounts for the beam pattern of the finite-sized transducer used in the synthetic aperture. The 2D fast Fourier transform (FFT) is used for the calculation of a 2D spectrum of the ultrasonic data. The spectrum is then interpolated to convert the polar coordinate system used for the acquisition of ultrasonic signals to the rectangular coordinates used for the presentation of imaging results. After compensating the transducer lobe amplitude profile using a Wiener filter, the transformed spectrum is subjected to the 2D inverse Fourier transform to get the time-domain image again. The algorithm is computationally attractive due to the use of 2D FFT. The performance of the proposed frequency domain algorithm and the classical time-domain SAFT are compared in the paper using simulated and real ultrasonic data. PMID- 17718330 TI - Increased efficiency of surface wave stimulation on the inaccessible side of a thick isotropic plate with superimposed periodicity. AB - Because of the growing number of applications of phononic crystals and other periodic structures, there is a renewed and growing interest in understanding the interaction of ultrasound with periodically corrugated surfaces. This paper presents a theoretical investigation of the transformation of ultrasound incident from the solid side onto a solid-liquid periodically corrugated interface. It is shown that it is possible to tailor the shape of a corrugated surface with given periodicity such that there is a significant amount of energy transformed into Scholte-Stoneley waves than if pure saw-tooth or sine-shaped surfaces were used. This permits the fabrication of periodic structures that can be patched on or engraved in body parts of a construction and enables efficient generation of Scholte-Stoneley waves. The study is performed for incident homogeneous plane waves as well as for bounded beams. Incident longitudinal waves are studied as well as incident shear waves. PMID- 17718331 TI - Elastic guided wave propagation in electrical cables. AB - This article analyzes the propagation modes of ultrasound waves inside an electrical cable in order to assess its behavior as an acoustic transmission channel. A theoretical model for propagation of elastic waves in electric power cables is presented. The power cables are represented as viscoelastic-layered cylindrical structures with a copper core and a dielectric cover. The model equations then have been applied and numerically resolved for this and other known structures such as solid and hollow cylinders. The results are compared with available data from other models. Several experimental measures were carried out and were compared with results from the numerical simulations. Experimental and simulated results showed a significant difference between elastic wave attenuation inside standard versus bare, low-voltage power cables. PMID- 17718332 TI - The band gaps of plate-mode waves in one-dimensional piezoelectric composite plates: polarizations and boundary conditions. AB - Theoretical studies are presented for the band structures of plate-mode waves in a one-dimensional (1-D) phononic crystal plate consisting of piezoelectric ceramics placed periodically in an epoxy substrate. The dependences of the widths and starting frequencies of first band gaps (FBG) on the filling fraction and the thickness to lattice pitch ratio are calculated for different polarizations of piezoelectric ceramics under different electric boundary conditions, i.e., short circuit (SC) and open circuit (OC). We found that the FBG always is broadened by polarizing piezoelectric ceramics, and the FBG widths with SC always are larger than that with OC for the same polarization. Our research shows that there are three critical parameters which determine the FBG: the polarized directions, the filling fraction, and the ratio of the plate thickness to the lattice pitch, respectively. Therefore, we can control the width and starting frequency of the FBG in the engineering according to need by choosing these parameters of the system. PMID- 17718333 TI - Air-coupled ultrasound: a novel technique for monitoring the curing of thermosetting matrices. AB - A custom-made, air-coupled ultrasonic device was applied to cure monitoring of thick samples (7-10 mm) of unsaturated polyester resin at room temperature. A key point was the optimization of the experimental setup in order to propagate compression waves during the overall curing reaction by suitable placement of the noncontact transducers, placed on the same side of the test material, in the so called pitch-catch configuration. The progress of polymerization was monitored through the variation of the time of flight of the propagating longitudinal waves. The exothermic character of the polymerization was taken into account by correcting the measured value of time of flight with that one in air, obtained by sampling the air velocity during the experiment. The air-coupled ultrasonic results were compared with those obtained from conventional contact ultrasonic measurements. The good agreement between the air-coupled ultrasonic results and those obtained by the rheological analysis demonstrated the reliability of air coupled ultrasound in monitoring the changes of viscoelastic properties at gelation and vitrification. The position of the transducers on the same side of the sample makes this technique suitable for on-line cure monitoring during several composite manufacturing technologies. PMID- 17718334 TI - Rayleigh wave reflection and scattering calculation by source regeneration method. AB - The analysis and precise calculation of reflection and scattering of Rayleigh wave by electrodes is important for surface acoustic wave (SAW) device models, especially for SAW identification (ID) tag design. We present a source regeneration method, which utilizes Green's function combined with finite-element method (FEM)/boundary-element method (BEM) to obtain accurate values of reflection, transmission, and scattering coefficients in a direct way. We take one electrode as the reflector on 128 degrees YX-LiNbO3 substrate to show the result as an example. The results are very accurate and are obtained with short computing time. The new analysis way shows its powerful ability for other advanced discussion of SAW devices. PMID- 17718335 TI - Polishing of quartz by rapid etching in ammonium bifluoride. AB - The etch rate and surface roughness of polished and lapped AT-cut quartz subjected to hot (90, 110, and 130 degrees C), concentrated (50, 65, 80 wt %) ammonium bi-fluoride have been investigated. Having used principal component analysis to verify experimental solidity and analyze data, we claim with confidence that this parameter space does not, as elsewhere stated, allow for a polishing effect or even a preserving setting. Etch rates were found to correlate well, and possibly logarithmically, with temperature except for the hottest etching applied to lapped material. Roughness as a function of temperature and concentration behaved well for the lapped material, but lacked systematic variation in the case of the polished material. At the lowest temperature, concentration had no effect on etch rate or roughness. Future efforts are targeted at temperatures and concentrations closer to the solubility limit. PMID- 17718336 TI - Analysis of a piezoelectric bimorph plate with a central-attached mass as an energy harvester. AB - This article analyzes the performance of a piezoelectric energy harvester in the flexural mode for scavenging ambient vibration energy. The energy harvester consists of a piezoelectric bimorph plate with a central-attached mass. The linear piezoelectricity theory is applied to evaluate the performance dependence upon the physical and geometrical parameters of the model bimorph plate. The analytical solution for the flexural motion of the piezoelectric bimorph plate energy harvester shows that the output power density increases initially, reaches a maximum, then decreases monotonically with the increasing load impedance, which is normalized by a parameter that is a simple combination of the physical and geometrical parameters of the scavenging structure, the bimorph plate, and the frequency of the ambient vibration, underscoring the importance for the load circuit to have the impedance desirable by the scavenging structure. The numerical results illustrate the considerably enhanced performances by adjusting the physical and geometrical parameters of the scavenging structure. PMID- 17718337 TI - Identifying the signal of interest for partially overlapping ultrasonic echoes. AB - The basic problem addressed in this paper is to discriminate between two signals that are at approximately the same time, but which originate at different echo sources. The proposed solution is to systematically perturb the field and discriminate between signals based on differences in amplitude variations between the two signals. PMID- 17718338 TI - Obtaining quartz crystal frequencies from deterministic temperatures and random angle variations. AB - The impact of the probability density function (PDF) of a quartz crystal angle on the frequency versus temperature curve (FTC) for a fundamental mode AT cut crystal is discussed. Frequency is treated as a function of a normally distributed, random crystal angle and a deterministic temperature. Four different means of specifying the FTC and the resulting PDFs are presented. PMID- 17718339 TI - Nonlinear torsional vibration of a circular cylindrical piezoelectric rod with relatively large shear deformation. AB - We show that, in a circular cylindrical rod, torsional modes are coupling to extension when the shear deformation associated with the torsional modes is no longer infinitesimal. A set of a couple equations is derived with which the effect of extension on the torsional frequency is examined. The results are useful to the understanding and design of devices operating with torsional modes. PMID- 17718340 TI - Combination of e-beam lithography and of high velocity AIN/diamond-layered structure for SAW filters in X band. AB - In this work, we report on the fabrication results of surface acoustic wave (SAW) devices operating at frequencies up to 8 GHz. In previous work, we have shown that high acoustic velocities (9 to 12 km/s) are obtained from the layered AIN/diamond structure. The interdigital transducers (IDTs) made of aluminium with resolutions up to 250 nm were successfully patterned on AIN/diamond-layered structures with an adapted technological process. The uniformity and periodicity of IDTs were confirmed by field emission scanning electron microscopy and atomic force microscopy analyses. A highly oriented (002) piezoelectric aluminum nitride thin film was deposited on the nucleation side of the CVD diamond by magnetron sputtering technique. The X-ray diffraction effectuated on the AIN/diamond layered structure exhibits high intensity peaks related to the (002) AIN and (111) diamond orientations. According to the calculated dispersion curves of velocity and the electromechanical coupling coefficient (K2), the AIN layer thickness was chosen in order to combine high velocity and high K2. Experimental data extracted from the fabricated SAW devices match with theoretical values quite well. PMID- 17718341 TI - Taking the mystery out of private pay services. PMID- 17718342 TI - Peak caregiver performance. PMID- 17718343 TI - Profitable niches in home care private duty. PMID- 17718344 TI - Adding care management to private duty: a formula for success. PMID- 17718345 TI - Consumer power: makes all the difference! PMID- 17718346 TI - Defining customer satisfaction for private duty agencies: supplementing in-home hospice care. PMID- 17718347 TI - Avenues for starting a private duty agency. PMID- 17718348 TI - Private duty services at home: wherever home happens to be. AB - Most private duty services are provided in the home of the client. However, as more assisted living facilities and independent senior housing complexes are built, and as time marches on, more residents are becoming users of private duty services in order to remain in their apartments or living units. They may be recuperating from an illness or accident or suffering from health issues that place them in need of more services than their residences offer. PMID- 17718349 TI - Rhetoric or reality: investments in health information technology. PMID- 17718350 TI - Private duty: good...bad...good. PMID- 17718351 TI - Keys to concierge leadership harmonics. PMID- 17718352 TI - Shedding skin and tears. AB - I am a purported expert in change and personal growth; that's the work I do with patients, and what I lecture and write about. I say that growth has nothing to do with adding on; it's always about letting go. Alas, it's always easier to tell others how to welcome shedding their skins than it is for me to do it myself. Letting go of the old and familiar is a necessary prerequisite for growth, but it's hard to do because no matter how much we may know, we have to move on. It always makes us feel vulnerable, which can inspire fear. PMID- 17718353 TI - CMS releases preliminary proposed 2008 hospice wage index and regulatory clarifications. PMID- 17718354 TI - If you want the truth, ask the housekeepers. PMID- 17718355 TI - Improving the payment system for home health care under Medicare: a lost opportunity. PMID- 17718356 TI - Universal health care. PMID- 17718357 TI - The status of nursing in the state of Delaware: a second look. AB - The shortage of nurses in Delaware continues to have a negative impact on the health care delivery system. Nurses play a unique and central role and are the largest group of health care professionals in the country. This threatening crisis in nurse staffing has the potential to impact all aspects of health care in a negative manner. In October 2005, Wesley College, the Delaware Board of Nursing, and the Delaware Health Care Commission entered into a partnership to replicate the study completed in 2000 by Mrs. Karen Panunto entitled, The Status of Nursing in the State of Delaware. The purpose of the replication was to determine if progress had been made in alleviating the nursing shortage. The trends noted in the data can enable the State of Delaware to develop long range plans that could circumvent the threatening increased nursing shortage. Trending of data from the 2000 study to the 2005 study shows very minimal positive improvement and highlights continual declines in the nursing profession. It would be important to follow trending with another study in five years. This study could focus on the loss of nursing manpower, the nursing educator shortage, lack of sites for clinical experiences, and other issues. PMID- 17718358 TI - Helmholtz's principle. PMID- 17718359 TI - Apparent rotation and jazzing in Leviant's Enigma illusion. AB - In 1981 Leviant devised Enigma, a figure that elicits perceived rotary motion in the absence of real motion. However, despite its striking appearance there is no good explanation for this motion illusion to date. Gregory (1993 Proceedings of the Royal Society of London B 253 123) pointed out a similarity to MacKay's 'complementary' afterimage in his ray pattern and suggested accommodative fluctuations and small eye movements as a potential origin for these phenomena. Furthermore, Zeki et al (1993 Proceedings of the Royal Society of London B 252 215-222) found PET-activation in response to Enigma in visual area V5 and immediately surrounding areas (called V5 complex) suggesting that the illusory motion could be mediated by the same neurons as real motion. In the experiments reported here, I show that the rotary motion is perceived on coloured as well as achromatic annuli intercepting the radial lines. More importantly, the illusory streaming motion continues to be seen with a cycloplegic lens as well as through a pinhole (ie ruling out transient changes of accommodation), and in the positive after-image (ie in the absence of eye movements). Apparent rotation is strongest with radial inducers impinging at right angles onto the annuli, but persist, although to a lesser degree, when the inducing lines are tilted in opposite directions, non-collinear, or replaced by dotted lines or lines with rounded terminators. For an explanation, the Enigma illusion requires a neural mechanism that uses lines abutting an empty annulus to elicit orthogonal streaming motion in one or the other direction. PMID- 17718360 TI - BOLD activation varies parametrically with corner angle throughout human retinotopic cortex. AB - The Alternating Brightness Star (ABS) is an illusion that provides insight into the relationship between brightness perception and corner angle. Recent psychophysical studies of this illusion have shown that corner salience varies parametrically with corner angle, with sharp angles leading to strong illusory percepts and shallow angles leading to weak percepts. It is hypothesized that the illusory effects arise because of an interaction between surface corners and the shape of visual receptive fields: sharp surface corners may create hotspots of high local contrast due to processing by center-surround and other early receptive fields. If this hypothesis is correct, early visual neurons should respond powerfully to sharp corners and curved portions of surface edges. Indeed, the primary role of early visual neurons may be to localize the discontinuities along the edges of surfaces. If so, all early visual areas should show greater BOLD responses to sharp corners than to shallow corners. On the other hand, if corner processing is exclusively constrained to certain areas of the brain, only those specific areas will show greater responses to sharp vs shallow corners. To address this we explored the BOLD correlates of the ABS illusion in the human visual cortex using fMRI. We found that BOLD signal varies parametrically with corner angle throughout the visual cortex, offering the first neurophysiological correlates of the ABS illusion. This finding provides a neurophysiological basis for the previously reported psychophysical data that showed that corner salience varied parametrically with corner angle. We propose that all early visual areas localize discontinuities along the edges of surfaces, and that specific cortical corner-processing circuits further establish the specific nature of those discontinuities, such as their orientation. PMID- 17718361 TI - The depth of distractor processing in search with clutter. AB - Some search tasks involve looking for a category target in clutter. This is the task faced, for example, by a baggage screener looking for weapons in a suitcase. Such tasks presumably involve the segmentation and recognition of the target object, but it is unknown whether they also involve the segmentation and recognition of the distractor objects. To examine the depth of distractor processing in this task, we had observers search through cluttered displays composed of normal and chimerical distractors. The normal distractors were photographs of recognizable objects, while the chimerical distractors were created by interchanging parts between the normal objects. The obsever's task was to identify the display quadrant that contained an animal or a vehicle target. We varied the difficulty of the search task by varying target and distractor discriminability, target uncertainty, and target occlusion. Only when the target was partially occluded did we find an effect of distractor type. In this case, observers may have found the target through a process of mentally eliminating whole distractor objects. When the target was unoccluded, we found no evidence that observers selected and rejected whole distractors during search. This second result supports our previous claim that often the items for search in clutter are not whole objects. PMID- 17718362 TI - Depth from binocular half-occlusions in stereoscopic images of natural scenes. AB - Over the past two decades psychophysical experiments have firmly established that binocular half-occlusions are useful sources of information for the human visual system. The existing literature has focused on simplified stimuli that have no additional cues to depth, apart from stereopsis. From this large body of work we can be confident that the visual system is able to exploit binocular half occlusions to aid depth perception; however, we do not know if this signal has any influence on perception when observers view complex stereoscopic stimuli with multiple sources of depth information. This issue is addressed here with the use of stereoscopic images of natural scenes, some of which have been digitally altered to manipulate a major half-occlusion signal. Our results show that depth ordering judgments for these relatively complex stimuli are significantly affected by the nature of the half-occlusion signal, but only when highly textured surfaces are viewed. Under such conditions, the replacement of a binocular half-occlusion with background texture slows reaction time relative to performance when the occluded region is consistent with the foreground object. This result is specific to conditions when the depth ordering is correct (ie not reversed) and depends upon the size of the half-occlusion. The influence of the half-occlusion information in the presence of potent depth cues such as perspective, texture gradient, shading, and interposition is convincing evidence that this information plays a significant role in human depth perception. PMID- 17718363 TI - When beauty breaks down: investigation of the effect of spatial quantisation on aesthetic evaluation of facial images. AB - Research on the perception of facial attractiveness has been dominated by aspects of averageness, symmetry, and secondary sex characteristics of faces. Almost absent is systematic research on the spatial scale (coarseness) of detail sufficient to carry information about facial attractiveness. In the present study, subjects were asked to evaluate the attractiveness of faces while the coarseness of detail of the face images was systematically decreased. Subjects discriminated a set of attractive faces from the set of unattractive faces when the coarseness of spatial quantisation changed from 10 to 17 pixels per face. Some of the faces regarded as attractive had the steepest shift in the rating towards the more attractive end of the scale at different resolutions. Once perceived as attractive in the coarse scale of image resolution, the faces generally did not return to the unattractive group with a subsequent finer scale of description. No single critical scale of detail was revealed that would have dramatically changed the perception of facial attractiveness from uncertain to distinct. PMID- 17718364 TI - Remembering object position in the absence of vision: egocentric, allocentric, and egocentric decentred frames of reference. AB - In three experiments we examined whether memory for object locations in the peri personal space in the absence of vision is affected by the correspondence between encoding and test either of the body position or of the reference point. In particular, the study focuses on the distinction between different spatial representations, by using a paradigm in which participants are asked to relocate objects explored haptically. Three frames of reference were systematically compared. In experiment 1, participants relocated the objects either from the same position of learning by taking as reference their own body (centred egocentric condition) or from a 90 degrees decentred position (allocentric condition). Performance was measured in terms of linear distance errors and angular distance errors. Results revealed that the allocentric condition was more difficult than the centred egocentric condition. In experiment 2, participants performed either the centred egocentric condition or a decentred egocentric condition, in which the body position during the test was the same as at encoding (egocentric) but the frame of reference was based on a point decentred by 90 degrees. The decentred egocentric condition was found to be more difficult than the centred egocentric condition. Finally, in experiment 3, participants performed in the decentred egocentric condition or the allocentric condition. Here, the allocentric condition was found to be more difficult than the decentred egocentric condition. Taken together, the results suggest that also in the peripersonal space and in the absence of vision different frames of reference can be distinguished. In particular, the decentred egocentric condition involves a frame of reference which seems to be neither allocentric nor totally egocentric. PMID- 17718365 TI - Angle discrimination in raised-line drawings. AB - We investigated the angular resolution subserving the haptic perception of raised line drawings by measuring how accurately observers could discriminate between two angle sizes under various conditions. We found that, for acute angles, discrimination performance is highly dependent on exploration strategy: mean thresholds of 2.9 degrees and 6.0 degrees were found for two different exploration strategies. For one of the strategies we found that discriminability is not dependent on the bisector orientation of the angle. Furthermore, we found that thresholds almost double when the angular extent is increased from 20 degrees to 135 degrees. We also found that local apex information has a significant influence on discrimination for acute as well as obtuse angles. In the last experiment we investigated the influence of depiction mode but did not find any effect. Overall, the results tell us that the acuity with which angles in raised-line drawings are perceived is determined by the exploration strategy, local apex information, and global angular extent. PMID- 17718366 TI - Intrasensory attention: kinaesthetic versus cutaneous inputs. AB - Blindfolded participants felt pairs of raised-line drawings simultaneously, one with each index finger. The stimuli presented at each fingertip were 180 degrees rotations of each other (eg 6 and 9). One finger moved (either actively or passively), and this in turn caused movement of a matched raised line underneath the stationary finger on the other hand, in a yoked manner. Thus, a 6 at the moving finger would be felt as a 9 on the stationary finger. On all trials there was a raised line moving underneath the stationary fully passive finger. For the moving finger, a raised line was present on only half of the trials. When a raised line could be felt at the moving fingertip, the shape followed by this finger was more often reported than was the shape present at the other (stationary) fingertip. However, when no line was present under the moving finger (ie when movement became the major cue for shape), subjects reported experiencing the shape moved under the stationary fingertip. Results are interpreted as an indication that cutaneous information can be more 'attention-getting' than kinaesthetic information, and are considered to support the modality appropriateness theory. PMID- 17718367 TI - Hearing gestures, seeing music: vision influences perceived tone duration. AB - Percussionists inadvertently use visual information to strategically manipulate audience perception of note duration. Videos of long (L) and short (S) notes performed by a world-renowned percussionist were separated into visual (Lv, Sv) and auditory (La, Sa) components. Visual components contained only the gesture used to perform the note, auditory components the acoustic note itself. Audio and visual components were then crossed to create realistic musical stimuli. Participants were informed of the mismatch, and asked to rate note duration of these audio-visual pairs based on sound alone. Ratings varied based on visual (Lv versus Sv), but not auditory (La versus Sa) components. Therefore while longer gestures do not make longer notes, longer gestures make longer sounding notes through the integration of sensory information. This finding contradicts previous research showing that audition dominates temporal tasks such as duration judgment. PMID- 17718368 TI - Perceptual completion of a sound with a short silent gap. AB - Listeners reported the perceptual completion of a sound in stimuli consisting of two crossing frequency glides of unequal duration that shared a short silent gap (40 ms or less) at their crossing point. Even though both glides shared the gap, it was consistently perceived only in the shorter glide, whereas the longer glide could be perceptually completed. Studies on perceptual completion in the auditory domain reported so far have shown that completion of a sound with a gap occurs only if the gap is filled with energy from another sound. In the stimuli used here, however, no such substitute energy was present in the gap, showing evidence for perceptual completion of a sound without local stimulation ('modal' completion). Perceptual completion of the long glide occurred under both monaural and dichotic presentation of the gap-sharing glides; it therefore involves central stages of auditory processing. The inclusion of the gap in the short glide, rather than in both the long and the short glide, is explained in terms of auditory event and stream formation. PMID- 17718369 TI - Adaptation of central pitch-specific mechanisms. AB - Three previous psychophysical studies have demonstrated that interaural time difference (ITD) coding mechanisms can undergo frequency-specific, selective adaptation. We sought to determine whether this phenomenon extends to the pitch domain, by employing the same psycho-physical paradigm as one used previously, but with harmonic tone complexes lacking energy at the fundamental frequency. Ten normal listeners participated in experiment 1. Psychometric functions for ITDs were obtained for harmonic tone complexes with fundamental frequencies of 110 Hz and 185 Hz, before and after selective adaptation with complexes of the same fundamental frequencies lateralised to opposite sides. In experiment 1, each subject was tested twice. On separate days, subjects were tested with 110 Hz and 185 Hz stimuli that were either partially resolvable complexes or unresolvable ones. Both partially resolved and unresolved stimuli supported adaptation, and at both fundamental frequencies. In experiment 2, which employed nine listeners, the adaptor tone complexes were presented in conjunction with a diotic noise background designed to mask difference tones generated by the adaptor stimuli. The use of the masker had little effect on the mean strength of the adaptation effected by the unresolved adaptor stimuli, and only slightly weakened the adaptation effect found with the partially resolved adaptor stimuli. Taken together, these data constitute the first demonstration of selective adaptation exerted on a central mechanism in the pitch domain. PMID- 17718371 TI - A new optical-geometrical illusion. AB - We describe and attempt to explain a new and unusual optical-geometrical illusion with three levels of distortion. The illusory figure is made up of three juxtaposed bands of the same width, which, when appropriately juxtaposed, appear to be of different widths. We hypothesised that the effect would depend on the combined action of various factors: (i) the band shapes and their reciprocal spatial position; (ii) the degree of coincidence of the sides of the juxtaposed bands; and (iii) the inability of the perceptual system to account for all the projective transformations. An experiment was conducted in which the shape of three stimuli was manipulated through affine transformation as well as variation of side lengths. The participants' task was to evaluate the width of the bands. The results revealed a robust and stable illusory effect; the factors that seem to influence the illusion most are band shape and conjoining side lengths. PMID- 17718370 TI - Phenomenological differences between familiar and unfamiliar odours. AB - Unfamiliar odours are harder to discriminate than familiar odours. We explored the phenomenal basis of this difference. In experiments la and 1b, participants profiled odour quality for two sets of familiar and unfamiliar odours. In both cases unfamiliar odours were redolent of more odour qualities than familiar stimuli. In experiment 2, participants received (i) a set of familiar and unfamiliar odours and learnt their names, and (ii) a further set of familiar and unfamiliar odours to which they were exposed. Participants then profiled these stimuli as well as a further unexposed set of familiar and unfamiliar odours. Exposure, but not naming, led to a significantly smaller difference between the familiar and unfamiliar stimuli, in terms of their redolence to other odours, when compared to unexposed control stimuli. Unfamiliar exposed odours were also judged as less redolent than unexposed unfamiliar odours. These observations are consistent with a mnemonic basis for odour-quality perception. PMID- 17718372 TI - Gerontological nurses are already on the cutting edge. Alignment with new DHHS strategic plan. PMID- 17718373 TI - Simply the best: teaching gerontological nursing students to teach evidence-based practice. Creating tip sheets can help achieve the goal of implementing EBP in clinical facilities. AB - This article describes a teaching strategy used in an undergraduate gerontological nursing clinical course to familiarize students with evidence based practice. Students are required to read and summarize an assigned evidence based practice guideline published by The University of Iowa Gerontological Nursing Interventions Research Center. They then develop a "tip sheet," based on the assigned guideline, to disseminate to health care staff at their practicum sites, which is either a long-term care facility or a hospital-based skilled nursing facility. Nursing students' reactions to the assignment and nursing staff's responses to the tip sheets are discussed. PMID- 17718374 TI - Choosing an appropriate depression assessment tool for chinese older adults: a review of 11 instruments. The best tools take into account cultural differences. AB - The purpose of this article is to compare the advantages and limitations of developed depression assessment tools and provide recommendations for clinical staff to select an appropriate tool for use with Chinese older adults. A total of 7 Western tools translated into Chinese and 4 tools developed specifically for assessing Chinese older adults were found in 12 articles. Variability in instrument psychometric properties and cutoff scores is discussed. A reasonable strategy to efficiently assess depression in Chinese older adults is to first administer the Single Question or Geriatric Depression Scale-4 (GDS-4). If depression is likely, the Chinese GDS-15 could be used to increase the probability of identifying depression in Chinese older adults. PMID- 17718375 TI - Auricular acupuncture for insomnia: duration and effects in Korean older adults. AB - This study examined the duration and effects of auricular acupuncture on insomnia in a sample of 28 Korean older adults. The design was a group, pretest-posttest, repeated-measures study. Measures were the Sleep State Tool and the Sleep Satisfaction Tool. The effects of auricular acupuncture on insomnia among Korean older adults were significant. The duration effects of auricular acupuncture were maintained for 2 weeks. Clinicians should consider providing auricular acupuncture as an alternative method for improving quality of sleep in older adults. PMID- 17718376 TI - Clinical implications of smoking and aging: breaking through the barriers. AB - In the United States, there are almost 4 million smokers older than 65. Yet, older smokers often receive suboptimal care. Inaccurate information and myths about older smokers may have become ingrained in the attitudes and beliefs of both older smokers and health care providers. In this article, prominent myths about older smokers will be explored and refuted. The realities include the following: Smoking tobacco has no benefit; it does not improve cognition or mood; smoking cessation, even among older, frail adults, produces significant benefits in terms of health and quality of life; and using filtered cigarettes or reducing the number of cigarettes smoked per day does not reduce harm. Gerontological nurses are at the forefront of treating tobacco use among older smokers. They should assess the smoking status of all older adults at every contact, treat smokers with pharmacotherapy and counseling, follow up with patients, and stay informed. PMID- 17718377 TI - Three essentials for successful fall management: communication, policies and procedures, and teamwork. AB - Falls among older adults, especially within the nursing home setting, can be challenging for health care providers. Attention to the basic processes of communication, policy and procedure, and teamwork proved to be necessary steps to facilitate successful fall management within this pilot program. This article provides an overview of the specified areas, along with examples of techniques developed to address identified needs in each of the three areas. A focused examination of these three essentials could prove instructive to any facility working to improve its fall management process. PMID- 17718378 TI - Decision making by families of older adults with advanced cognitive impairment: spirituality and meaning. AB - This qualitative study investigated the decision making of family members of institutionalized older adults with advanced cognitive impairment. Eight focus groups were conducted with 39 family caregivers at Minnesota nursing homes. Participants described their beliefs and values as central in their decision making; many said their spirituality provided guidance. Family members spontaneously described finding meaning in their decision-making roles. Many decision makers caring for their relatives with advanced cognitive impairment invoke their spirituality to guide relationships and decisions, creating meaning in the process. PMID- 17718379 TI - Should retaliatory termination suit have been dismissed? PMID- 17718380 TI - Nurse practitioner not liable for failure to diagnose. PMID- 17718381 TI - MS: Nurse incurred job-related injuries: award of disability benefits affirmed by court. PMID- 17718382 TI - Should pt. have been allowed to change own records? PMID- 17718383 TI - [Role of survivin in mitosis]. AB - Human survivin is a member of the IAP (Inhibitor of Apoptosis) family. It was reported that survivin expression is associated with drug resistance, cancer progression and low patient survival rate in many cancers. Survivin is implicated in both: inhibition of apoptosis and regulation of cell division. As a member of Chromosomal Passenger Complex (CPC) it is involved in sister chromatids segregation during mitosis. On the other hand, survivin plays an important role in the surveillance mechanism called mitotic spindle assembly checkpoint (MSAC) which regulates metaphase to anaphase transition during mitosis. Additionally, survivin is necessary for cytokinesis progression. The present review is a summary of survivin's functions, focused on its role in cell division in normal and cancer cells, as well as introduction to discussion about anticancer therapies based on survivin depletion. PMID- 17718384 TI - [Small heat shock proteins--role in apoptosis, cancerogenesis and diseases associated with protein aggregation]. AB - Small heat shock proteins (sHsps) belong to molecular chaperones, which protect prokaryotic and eukaryotic cells against deleterious effects, of stress. sHsps prevent stress induced, irreversible aggregation of damaged proteins and facilitate renaturation of bound substrates cooperating with other molecular chaperones. This review summarizes recent studies focused mainly on the involvement of sHsps in diseases related to protein aggregation. sHsps are often a component of protein aggregates forming during progress of neurodegenerative disorders. Mutation in sHsps genes have been identified, which are responsible for development of cataract, desmin related myopathy and neuropathies. sHsps protect cells against oxidative stress resulting from ischemia/reperfusion during heart or brain stroke. Several studies indicate that sHsp participate in regulation of apoptosis and are involved in cancerogenesis. Uncovering the sHsps role in diseases enable to develop new therapeutic strategies. PMID- 17718385 TI - [Characterization of the HtrA family of proteins]. AB - The HtrA family of proteins consists of evolutionary conserved serine proteases, which are homologues of the HtrA protein from a model bacterium Escherichia coli. They are widely distributed among organisms, prokaryotic as well as eukaryotic including humans. HtrA proteins participate in defense against stresses causing aberrations in protein structure, for example heat or oxidative stress. At least four human homologues have been identified. They are involved in cell growth and differentiation, apoptosis, and disturbances in their function may induce carcinogenesis, arthritic and neurodegenerative disorders. This article summarizes recent studies regarding the HtrA family of proteins, their structure, regulation and function. It also presents practical applications of this knowledge and perspective of its use in the future. PMID- 17718386 TI - [Type IV collagenases (MMP-2 and MMP-9) and their substrates--intracellular proteins, hormones, cytokines, chemokines and their receptors]. AB - Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that cleave protein components of extracellular matrix such as collagens, laminin, fibronectin, proteoglycans and contribute to cell migration by eliminating the surrounding extracellular matrix and basement membrane barriers. However, the extracellular matrix is not simply an extracellular scaffold because, for example, it contains sites that can bind growth factors; therefore, degradation of the extracellular matrix components by MMPs can alter cellular behavior. MMPs also cleave a variety of non-ECM proteins, including cytokines, chemokines, and growth factors, activating or inactivating them, or generating other products that have biological consequences. The immune system is also influenced by MMPs. For that reason, the function of MMPs is much more complex and subtle than simple demolition. MMPs are essential for embryonic development and morphogenesis, however, exuberant expression of these enzymes has been associated with a variety of destructive diseases, including tumor progression, cardiovascular diseases and autoimmune diseases. PMID- 17718387 TI - [The role of lamins and mutations of LMNA gene in physiological and premature aging]. AB - Lamins belong to type V intermediate filaments superfamily. They are the main structural constituencies of the nuclear lamina but they also influence on chromatin structure, regulation of gene expression, localization and probably protein degradation. Because lamins play many different roles within the cell, mutations in their genes can results in variety of pathological phenotypes. Mutations in LMNA gene are the cause of many different diseases, called laminopathies. Among laminopathies are muscle tissue diseases, adipose tissue diseases and also progerias, the premature aging syndromes. One of the progerias, which results from mutation in LMNA gene, is Hutchinson-Gilford progeria syndrome (HGPS). It seems that the same molecular mechanisms which are responsible for premature aging of cells of HGPS patients, are involved in physiological aging. PMID- 17718388 TI - [Role of transmembrane GTPases in mitochondrial morphology and activity]. AB - Mitochondria play crucial role in the energetic metabolism, thermogenesis, maintenance of calcium homeostasis and apoptosis. Cyclic changes in fusion and fission of mitochondria are required for properly functioning organelles, especially in tissues with high dependence on energy supply such as skeletal muscles, heart, or neurons. The key role of mitochondrial fusion is observed in embryonic development and maintaining unchanged mtDNA pool under conditions of oxidative stress. There is a large number of data indicating that mitochondrial networks often accompany the resistance to apoptotic stimuli. In contrast to fusion--the mitochondrial fission precedes apoptosis. According to the newest knowledge precise interactions between a few proteins are required for mitochondrial fusion and division. Among them Drp1, Mfn1, Mfn2 and Opal are considered the most important. Recent reports shed some light on the physiological importance of proteins participating in mitochondrial membrane dynamics in energy production, apoptosis and cellular signaling. In this review the authors report on the recent knowledge concerning structural changes of mitochondria with a particular interest to transmembrane GTPases and their role in cellular physiology. PMID- 17718389 TI - [Tuftsin--new analogues and properties]. AB - Tuftsin, a natural tetrapeptide of sequence TKPR, occuring in the blood of humans and other mammals, capable of stimulating certain white blood cells (monocytes, macrophages, and neutrophils), was isolated at Tufts University in 1970 by Najjar and Nishioka. Tuftsin is a compound with a wide spectrum of biological activities, notable enhances phagocytosis, immune response, bactericidal, tumoricidal and antifungal activities. This article concerns new analogues and properties of tuftsin. PMID- 17718390 TI - [Regulation of ethylene biosynthesis in plants]. AB - Ethylene is one of the plant hormones that controls growth and development. There are many responses regulated via ethylene in response to exogenous stimuli. Research on ethylene biosynthesis and the signalling pathway enabled us to understand the mechanism of the regulation of these responses. Different temporal and spatial expression of genes encoding enzymes involved in ethylene biosynthesis is of great importance for the regulation of ethylene responses. Also, post-translational regulation of the enzymes seems to be a key regulatory mechanism for the control of their activity. Because of versatile regulation of its production, ethylene can control plant development at many levels. PMID- 17718392 TI - [The high diversity and regulation of plant water channels]. AB - Membrane intrinsic proteins (MIPs) are a diverse class of integral membrane proteins that mediate the bi-directional flux of water (aquaporins), uncharged small solutes such as glycerol and/or gases across cellular membranes. The past year has brought significant advances in the characterization in plants of a large class this of water channel. MIPs have been identified in many single- and multi- cellular organisms. Aquaporins play important role in plant development and their adaptation to even changing environment. At the transcriptional level aquaporins have been up- or down-regulated in response to hormones, drought, salnity and light. Recent data indicate that plant aquaporin activity might be regulated by phosphorylation and intracellular protons. Novel mechanisms of regulation by hetero-tetramer formation or through control by reactive oxygen species and osmotic or hydrostatic pressure gradients is also discussed. PMID- 17718391 TI - [New look at starch degradation in Arabidopsis thaliana L. chloroplasts]. AB - Transitory starch is accumulated during the day and is the main source of energy for the cell metabolism during the night. The observed periodical starch degradation has become a model often used by scientist in their experiments. Starch granule degradation could be divided into 2 periods: initiation of degradation and digestion of amylopectin and amylose into maltooligosaccharide and their derivative. Key meaning is attributed in this process to beta-amylaze, product of its activity beta-maltose is transported to the cytosole and there it subjects farthest conversions. It has been demonstrated that a number of enzymes take part in the starch degradation process. However, the way of regulating their activity is still not fully explained. There is most important elements effecting rate of starch decomposition: day cycle, starch phosphorylation and regulation of enzyme activity. It proceeds through redox potential, pH changes and phosphorylation of protein involved in starch degradation due specific phosphatases. The purpose of the current work is to systematize the knowledge of the Arabidopsis thaliana L. leaf starch degradation. The results of the recent research cast a new light on the starch degradation process as well as on its control. PMID- 17718393 TI - [Fullerenes in biology]. AB - Fullerenes are chemical structures made of carbon atoms. The stable form is molecule composed of 60 carbon atoms arranged in a soccer ball-shaped structure. With respect to its electron donor and acceptor capability and photochemical behavior fullerenes can be effective antioxidants and radical scavengers or prooxidants and photosensitizers. These properties of fullerenes have paid attention on their possible biological applications. Results of previous studies point to the great dependance of fullerenes activity upon quality, quantity and geometry of substituents in fullerene derivatives. Some of fullerene derivatives show antiviral and antimicrobial activity, including anti-HIV properties. C60 and its derivatives are able to exhibit cytotoxic and enzyme-inhibiting abilities as well as radical-quenching and antioxidative abilities. Generation of reactive oxygen species under influence of visible light is another ability of fullerene derivetives desired in photodynamic therapy. PMID- 17718394 TI - The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants. AB - The primary enzymes involved in alcohol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Both enzymes occur in several forms that are encoded by different genes; moreover, there are variants (i.e., alleles) of some of these genes that encode enzymes with different characteristics and which have different ethnic distributions. Which ADH or ALDH alleles a person carries influence his or her level of alcohol consumption and risk of alcoholism. Researchers to date primarily have studied coding variants in the ADH1 B, ADH1C, and ALDH2 genes that are associated with altered kinetic properties of the resulting enzymes. For example, certain ADH1B and ADH1C alleles encode particularly active ADH enzymes, resulting in more rapid conversion of alcohol (i.e., ethanol) to acetaldehyde; these alleles have a protective effect on the risk of alcoholism. A variant of the ALDH2 gene encodes an essentially inactive ALDH enzyme, resulting in acetaldehyde accumulation and a protective effect. It is becoming clear that noncoding variants in both ADH and ALDH genes also may influence alcohol metabolism and, consequently, alcoholism risk; the specific nature and effects of these variants still need further study. PMID- 17718395 TI - Variations in ADH and ALDH in Southwest California Indians. AB - Native Americans as a group have the highest rates of alcohol-related deaths of all ethnicities in the United States; however, it remains unclear how and why a greater proportion of individuals in some Native American communities develop alcohol-related problems and alcohol use disorders (AUDs). One potential factor that can influence responses to alcohol are variations in alcohol-metabolizing enzymes. Researchers have analyzed the frequencies of variants in the alcohol metabolizing enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in some Native American populations. So far the studies have yielded no evidence that an ALDH2 variant, which has shown protective effects in other populations, is found in either American Indians or Alaska Natives. A variant of the ALDH1 enzyme that is encoded by the ALDH1A1*2 allele, however, was found in a small proportion of a group of Southwest California Indians and had a protective effect against alcoholism in that population. Furthermore, a variant of the ADH1B enzyme that is encoded by the ADH1B*3 allele was found in a similar proportion of Southwest California Indians and also was associated with a protective effect. However, these findings do not explain the high prevalence of alcoholism in the tribes investigated. PMID- 17718396 TI - Health-related effects of genetic variations of alcohol-metabolizing enzymes in African Americans. AB - Alcohol metabolism involves two key enzymes-alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). There are several types of ADH and ALDH, each of which may exist in several variants (i.e., isoforms) that differ in their ability to break down alcohol and its toxic metabolite acetaldehyde. The isoforms are encoded by different gene variants (i.e., alleles) whose distribution among ethnic groups differs. One variant of ADH is ADH1B, which is encoded by several alleles. An allele called ADH1 B*3 is unique to people of African descent and certain Native American tribes. This allele is associated with more rapid breakdown of alcohol, leading to a transient accumulation of acetaldehyde. African Americans carrying this allele are less likely to have a family history of alcoholism and experience a less rewarding subjective response to alcohol. Moreover, children of mothers with this allele are less vulnerable to alcohol related birth defects. The enzyme ALDH1 also is encoded by several alleles. Two of these alleles that are found in African Americans-ALDH1 A1 *2 and ALDH1A1 *3- may be associated with a reduced risk of alcoholism. PMID- 17718397 TI - ALDH2, ADH1B, and ADH1C genotypes in Asians: a literature review. AB - Variants of three genes encoding alcohol-metabolizing enzymes, the aldehyde dehydrogenase gene ALDH2 and the alcohol dehydrogenase genes ADH1B and ADH1C, have been associated with reduced rates of alcohol dependence. The genotype prevalence of these genes varies in general samples of different Asian ethnic groups. The ALDH2*2 allele appears to be most prevalent in Chinese-American, Han Chinese and Taiwanese, Japanese, and Korean samples. Much lower rates have been reported in Thais, Filipinos, Indians, and Chinese and Taiwanese aborigines. ADH1B*2 is highly prevalent among Asians, with the exception of Indians. ADH1C*1 also is highly prevalent in Asians, but has only been examined in a few studies of Chinese and Korean samples. PMID- 17718398 TI - Variations in alcohol-metabolizing enzymes in people of East Indian and African descent from Trinidad and Tobago. AB - The population of Trinidad and Tobago is composed mainly of people of East Indian (Indo-Trinidadians) and African (Afro-Trinidadians) ancestry. Differences in alcoholism rates exist between these two ethnic groups, and researchers have investigated whether these differences can be explained in part by variations in the genes encoding the alcohol-metabolizing enzymes alcohol dehydrogenase (ADH) 1B and 1C, and aldehyde dehydrogenase (ALDH) 1 and 2. Studies have demonstrated that a certain variant of the gene encoding ADH1B (ADH1B*3) is associated with a reduced risk of alcoholism in Afro-Trinidadians, as is a variant of the gene encoding ADH1C (i.e., ADH1C*1) in Indo-Trinidadians. An ALDH2 variant shown to have protective effects primarily in East Asians was not found in either Trinidadian ethnic group. However, a variant in the gene encoding cytosolic ALDH1A (i.e. ALDH1A1*1/*2) was found to be associated with an increase in alcohol dependence in Indo-Trinidadians. PMID- 17718400 TI - The relationship between alcohol metabolism, estrogen levels, and breast cancer risk. PMID- 17718399 TI - Alcohol metabolism and cancer risk. AB - Chronic alcohol consumption increases the risk for cancer of the organs and tissues of the respiratory tract and the upper digestive tract (i.e., upper aerodigestive tract), liver, colon, rectum, and breast. Various factors may contribute to the development (i.e., pathogenesis) of alcohol-associated cancer, including the actions of acetaldehyde, the first and most toxic metabolite of alcohol metabolism. The main enzymes involved in alcohol and acetaldehyde metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are encoded by multiple genes. Because some of these genes exist in several variants (i.e., are polymorphic), and the enzymes encoded by certain variants may result in elevated acetaldehyde levels, the presence of these variants may predispose to certain cancers. Several mechanisms may contribute to alcohol related cancer development. Acetaldehyde itself is a cancer-causing substance in experimental animals and reacts with DNA to form cancer-promoting compounds. In addition, highly reactive, oxygen-containing molecules that are generated during certain pathways of alcohol metabolism can damage the DNA, thus also inducing tumor development. Together with other factors related to chronic alcohol consumption, these metabolism-related factors may increase tumor risk in chronic heavy drinkers. PMID- 17718401 TI - Role of alcohol metabolism in chronic pancreatitis. AB - Alcohol abuse is the major cause of chronic inflammation of the pancreas (i.e., chronic pancreatitis). Although it has long been thought that alcoholic pancreatitis is a chronic disease from the outset, evidence is accumulating to indicate that chronic damage in the pancreas may result from repeated attacks of acute tissue inflammation and death (i.e., necroinflammation). Initially, research into the pathogenesis of alcoholic pancreatitis was related to ductular and sphincteric abnormalities. In recent years, the focus has shifted to the type of pancreas cell that produces digestive juices (i.e., acinar cell). Alcohol now is known to exert a number of toxic effects on acinar cells. Notably, acinar cells have been shown to metabolize alcohol (i.e., ethanol) via both oxidative (i.e., involving oxygen) and nonoxidative pathways. The isolation and study of pancreatic stellate cells (PSCs)-the key effectors in the development of connective tissue fibers (i.e., fibrogenesis) in the pancreas-has greatly enhanced our understanding of the pathogenesis of chronic pancreatitis. Pancreatic stellate cells become activated in response to ethanol and acetaldehyde, a toxic byproduct of alcohol metabolism. In addition, PSCs have the capacity to metabolize alcohol via alcohol dehydrogenase (the major oxidizing enzyme for ethanol). The fact that only a small percentage of heavy alcoholics develop chronic pancreatitis has led to the search for precipitating factors of the disease. Several studies have investigated whether variations in ethanol metabolizing enzymes may be a trigger factor for chronic pancreatitis, but no definite relationship has been established so far. PMID- 17718402 TI - Effects of pregnancy and nutritional status on alcohol metabolism. AB - Metabolism of alcohol (i.e., ethanol) is regulated by genetic and environmental factors as well as physiologic state. For a given alcohol intake, the rate of alcohol clearance, which ultimately determines tissue ethanol concentrations, may be the most significant risk factor for many of the detrimental effects of alcohol. Faster ethanol clearance would help minimize target tissue concentrations, and in pregnant women, mitigate fetal alcohol exposure. Much remains to be known about the effects of the altered endocrine milieu of pregnancy on alcohol metabolism and clearance in the mother. Research has shown that among pregnant rats allowed unrestricted access to alcohol and those fed alcohol containing liquid diets under experimental conditions via a feeding tube (total enteral nutrition [TEN]), urine ethanol concentrations (and thus blood and tissue ethanol concentrations) are lower in pregnant rats compared with non pregnant females given the same dose of ethanol. Maternal nutritional status also is an important determinant of fetal alcohol toxicity. Research using the TEN system has demonstrated that alcohol-induced fetal growth retardation is potentiated by undernutrition in part via impaired alcohol metabolism and clearance. PMID- 17718403 TI - Overview: how is alcohol metabolized by the body? AB - Alcohol is eliminated from the body by various metabolic mechanisms. The primary enzymes involved are aldehyde dehydrogenase (ALDH), alcohol dehydrogenase (ADH), cytochrome P450 (CYP2E1), and catalase. Variations in the genes for these enzymes have been found to influence alcohol consumption, alcohol-related tissue damage, and alcohol dependence. The consequences of alcohol metabolism include oxygen deficits (i.e., hypoxia) in the liver; interaction between alcohol metabolism byproducts and other cell components, resulting in the formation of harmful compounds (i.e., adducts); formation of highly reactive oxygen-containing molecules (i.e., reactive oxygen species [ROS]) that can damage other cell components; changes in the ratio of NADH to NAD+ (i.e., the cell's redox state); tissue damage; fetal damage; impairment of other metabolic processes; cancer; and medication interactions. Several issues related to alcohol metabolism require further research. PMID- 17718404 TI - Role of acetaldehyde in mediating the pharmacological and behavioral effects of alcohol. AB - Acetaldehyde is the first active breakdown product (i.e., metabolite) generated during alcohol metabolism. It has toxic properties but also exerts other actions on the body (i.e., has pharmacological properties). Recent studies have shown that the direct administration of acetaldehyde, especially into the brain, induces several effects that mimic those of alcohol. High doses of acetaldehyde induce sedative as well as movement- and memory-impairing effects, whereas lower doses produce behavioral effects (e.g., stimulation and reinforcement) that are characteristic of addictive drugs. When acetaldehyde accumulates outside the brain (i.e., in the periphery), adverse effects predominate and prevent further alcohol drinking. To investigate the role of acetaldehyde in mediating alcohol's effects, investigators have pharmacologically manipulated alcohol metabolism and the production of acetaldehyde within the body (i.e., endogenous acetaldehyde production). Studies manipulating the activity of the enzyme catalase, which promotes acetaldehyde production in the brain, suggest that acetaldehyde contributes to many behavioral effects of alcohol, especially its stimulant properties. However, it remains controversial whether acetaldehyde concentrations obtained under normal physiological conditions are sufficient to induce significant pharmacological effects. Current evidence suggests that the contribution of acetaldehyde to alcohol's effects is best explained by a process in which acetaldehyde modulates, rather than mediates, some of alcohol's effects. PMID- 17718405 TI - Oxidation of ethanol in the brain and its consequences. AB - Acetaldehyde, a toxic byproduct of alcohol (i.e., ethanol) metabolism, has long been suspected of causing at least some of the central nervous system actions of ethanol. However, the data to support such a hypothesis have been difficult to obtain. One roadblock is the very low blood levels of acetaldehyde following ethanol intake and the finding that even elevated acetaldehyde levels in the blood do not easily gain access to the brain. The recent discovery of the oxidation of ethanol to acetaldehyde in the adult brain may help explain the acute effects of ethanol. PMID- 17718406 TI - Alcohol metabolism's damaging effects on the cell: a focus on reactive oxygen generation by the enzyme cytochrome P450 2E1. AB - Alcohol metabolism's various processes create harmful compounds that contribute to cell and tissue damage. In particular, the enzyme cytochrome P450 2E1 (CYP2E1) plays a role in creating a harmful condition known as oxidative stress. This condition is related to oxygen's ability to accept electrons and the subsequent highly reactive and harmful byproducts created by these chemical reactions. CYP2E1's use of oxygen in alcohol metabolism generates reactive oxygen species, ultimately leading to oxidative stress and tissue damage. PMID- 17718407 TI - Combined effects of aldehyde dehydrogenase variants and maternal mitochondrial genes on alcohol consumption. AB - Two lines of rats bred to differ in their voluntary alcohol consumption--the alcohol-abstaining UChA rats and the alcohol-drinking UChB rats--differ in how effectively toxic acetaldehyde is removed during alcohol metabolism. UChB animals carry efficient variants of the aldehyde dehydrogenase 2 (ALDH2) genes and have active mitochondria, resulting in fast removal of acetaldehyde. UChA animals, in contrast, carry less efficient ALDH2 variants and less active mitochondria, which result in transient elevations of acetaldehyde levels after alcohol ingestion. Cross-breeding studies have demonstrated that the presence of active mitochondria inherited from UChB females can fully abolish the reduction of alcohol consumption associated with the presence of less efficient ALDH2 variants--a phenomenon known as epistasis. These and other findings suggest that mitochondrial activity during alcohol metabolism should be considered a new modulator of alcohol consumption not only in rats but also in other species, including humans. PMID- 17718408 TI - Studying alcohol elimination using the alcohol clamp method. AB - Researchers studying alcohol absorption and metabolism in humans have been aided by the alcohol clamp method, in which alcohol is administered intravenously, allowing study participants to achieve and maintain a target breath alcohol concentration (BrAC) for an extended period of time. This tool minimizes the variability in BrACs that occurs after alcohol consumption by administering alcohol at a dose and rate that is computed for each person individually. The alcohol clamp can be used to evaluate several influences on alcohol elimination, including gender, ethnicity, genetic variations in alcohol-metabolizing enzymes, and food consumption. PMID- 17718409 TI - Use of cultured cells to study alcohol metabolism. AB - The use of cells grown in the laboratory (i.e., cultured cells) in alcohol research has many advantages. Among these are the ability to investigate individual metabolic pathways, the ability to precisely control exposure to ethanol and its metabolites in the absence of confounding variables, and the uniformity of genetically identical (i.e., clonal) cell lines. Additionally, because of the cost and relative ease of culturing large quantities of cells, many more experimental replicas may be performed to confirm findings. As described in this article, the use of cultured cells has contributed greatly to the understanding of the mechanisms by which alcohol metabolism affects cells and ultimately results in alcoholic liver disease. PMID- 17718410 TI - The role of nutritional therapy in alcoholic liver disease. AB - Alcoholic liver disease (ALD) evolves through various stages, and malnutrition correlates with the severity of ALD. Poor nutrition is caused both by the substitution of calories from alcohol for calories from food and by the malabsorption and maldigestion of various nutrients attributed to ALD. The only established therapy for ALD consists of abstinence from alcohol. Sufficient nutritional repletion coupled with appropriate supportive treatment modalities may be effective in reducing complications associated with ALD---particularly infection. Nutrition makes a significant positive contribution in the treatment of ALD, especially in selected malnourished patients. PMID- 17718411 TI - [Construction and expression of recombinant adenovirus carrying human SHP-1 gene]. AB - OBJECTIVE: To construct and identify recombinant adenovirus Ad-SHP1 carrying human SH2 domain-containing protein tyrosine phosphatase (SHP-1). METHODS: Human SHP-1 cDNA from healthy volunteers' peripheral blood lymphocyte was cloned into the shuttle plasmid pAdTrack-CMV by standard procedure. The plasmid pAdTrackCMV SHP1 was selected and then linearized by Pme I, followed by homologous recombination with bone plasmid pAdEasy-1 in BJ5183. Recombinant adenovirus Ad SHP1 were obtained after packaged in HEK293 cells and the green fluorescence in HEK293 cells was observed. Recombinant adenovirus was confirmed with PCR and the expressed SHP-1 protein was verified with Western Blotting. Ad-SHP1 was multiplied and purified. The titer of virus was measured with fluorescent counter. Results The results of sequencing, restriction endounclease digestion and Western Blotting indicated that Ad-SHP1 was successfully constructed. The titer of Ad-SHP1 reached 1.58 x 10(10) pfu/mL. CONCLUSION: Recombinant adenovirus Ad-SHP1 had been successfully constructed. It could express SHP-1 protein stably and effectively and this will be very helpful for the further study of the generation of extranodal NK/T cell lymphoma and the corresponding therapy. PMID- 17718412 TI - [Quantification of class 1 integrase gene expression of Pseudomonas aeruginosa in biofilm]. AB - OBJECTIVE: To study the molecular mechanism of integron related gene transfer in biofilm and aqueous culture of P. aeruginosa by investigating the expression level of intI1 mRNA in class 1 integron positive strains. METHODS: A competitive reverse transcription-PCR (cRT-PCR) method was designed to quantify class 1 integrase mRNA production in two clinical P. aeruginosa strains called PA10 and PA39 when they were grown in biofilms and planktonic culture. In brief, competitive DNA (cDNA) was obtained via PCR from the genomic DNA of class 1 integron positive strains. Then the competitive RNA (cRNA) was amplified from the cDNA. Finally the serials diluted cRNA were mixed separately with the total RNA extracted from the biofilm and planktonic culture of P. aeruginosa and the competitive RT-PCR were conducted. After electrophoresis, the expression level of intI1 mRNA was quantified by comparing with the amount of the cDNA. RESULTS: The PA10 and PA39 strains produced intI1 mRNA both in their biofilms and planktonic cells. Furthermore the expression levels of intI1 mRNA from the two strains were of approximation in their biofilm and plankton stage respectitively, while the quantities of intI1 mRNA expression in their biofilm stage were about 15 times higher than those in their planktonic stage. CONCLUSION: The integrase gene is up regulated at mRNA level in P. aeruginosa biofilm, which may be one of the reseans for the spread of antibiotic resistance and the formation of multidrug resistance. PMID- 17718413 TI - [Interference therapy of laryngeal squamous cell carcinoma by p16beta and EGFR antisense cDNA in signal transduction]. AB - OBJECTIVE: To test the effect of p163 and EGFR-antisense cDNA in signal transduction on Hep-2 laryngeal squamous cell carcinoma in vitro. METHODS: The Hep-2 laryngeal squamous carcinoma cells were transfected by recombinant adenovirus AdEasy-EGFR-antisense and AdEasy-p16beta in vitro. The inhibition of the EGFR expression and cell growth and changes of cell cycle, DNA content, apoptosis and ultramicrostructure of the Hep-2 cells were examined by MTT, Western blotting analysis, Flow cytometry analysis, Immunohistochemistry, and transmission electron microscope respectively. Results The proliferation of the Hep-2 cells was inhibited significantly by the infection of the Ad- Ad-p16beta or Ad-antisense EGFR. The infection also accelerated the apoptosis of the cancer cells. The proport of of cells in G0/G1 phases increased to more than 77.7%. The Ad-antisense EGFR-infected cells showed lower protein expression of EGFR. The P16beta protein over expression was observed in the Ad-p16beta-infected cells. CONCLUSION: The transfection of Ad- Ad-p16beta and Adantisense EGFR into Hep-2 cells leads to over-expression of Ad-pl6beta, and under-expression of EGFR, along with G1-phase arrest and apoptotic cell death. Both EGFR and Ad-p16beta play important roles in the genesis, growth and differentiation of the human laryngocarcinoma cells. PMID- 17718414 TI - [The construction and immune response of fusion DNA vaccine CRT180/HPV6E7]. AB - OBJECTIVE: To investigate the immune response, in particular, the anti-virus cellular immune response induced by the constructed fusion DNA vaccine CRT (Calreticulin) 180/HPV6E7 in vivo and vitro. METHODS: The HPV6E7 open reading frame was amplified by polymerase chain reaction from pUC/HPV6 plasmid. The CRT180 gene was cloned by reverse transcription from human muscle tissues. The PCR products of CRT180 and HPV6E7 were subcloned into pcDNA3. 1-GFP eukaryotic vector. The recombinant plasmids CRT180/ HPV6E7 was authenticated by restrict enzyme digestion and confirmed by DNA sequencing. The DNA plasmid HPV6E7 with report gene GFP was transfected to murine B16 cells by lipofectamine kit to establish the target cells. The HPV6E7-expressing cell line was selected by G418 and identified by RT-PCR. The C57BL/6 mice were vaccinated via intramuscular injection in the right legs with 100 microg plasmid encoding CRT180-HPV6E7, CRT180 or HPV6E7, empty plasmid without insert, and PBS group respectively. The changes of the T lymphocyte subsets in the peripheral blood of the mice were evaluated by flow cytometric analysis. The lymphocytes from the spleen and lymph nodes were harvested and co-cultured with HPV6E7-expressing cell lines. The CTLs kill activity and the cytokines IL-2, IFN-gamma secretion levels of the lymphocytes were assessed by LDH and ELISA respectively. RESULTS: The constructed recombinant plasmids pcDNA3. 1-CRT180/HPV6E7, pcDNA3. 1-CRT180 and pcDNA3. 1 HPV6E7 were authenticated by restrict enzyme digestion and confirmed by DNA sequencing. Green fluorescence located in the cellular nucleus and plasma could be detected by fluorescent microscope after transfection with plasmids. The results of RT-PCR from the selected positive cell line showed the expected fragments of HPV6E7 mRNA. After immunization, the percentage of CD8+ or TCRgamma delta tau cells in the peripheral blood, the CTLs kill activity of the spleen cells and lymphocytes against HPV6E7-expressing cells, and the secretion levels of IL-2, IFN-gamma in CRT180/HPV6E7 vaccinated group increased significantly compared with the control groups (P < 0.05). CONCLUSION: Vaccination with fusion DNA vaccine CRT180/HPV6E7 could elicit a more efficient HPV6E7-specific immune response than with HPV6E7 plasmid, indicating the potential of CRT180/HPV6E7 vaccine to enhance the antigen presentation. The recombinant CRT180/HPV6E7 might help the elimination of virus in animal models and accordingly be used as a vaccine candidate in the therapy of CA. PMID- 17718415 TI - [Clone, construct, expression and verification of lactoferricin B gene and several sequence mutations in yeast]. AB - OBJECTIVE: To construct the eucaryotic recombinant plasmid of pYES2/LactoferricinB expressing in yeast of S. cerevisiae, of which the expressed protein antibacterial activity was verified in preliminary. METHODS: By self template PCR method, the gene of Lactoferricin B and its several sequence mutations were amplified with the parts of the pre-synthesized single chains. And then Lactoferricin B gene and its mutants were cloned into the vector of pYES2 to construct the recombined expression plasmid pYES2/Lactoferricin B etc. extracted and used to transform the yeast S. cerevisiae. The expressions of proteins were determined after induced by galactose. The expression proteins were collected and purified by hydronium-exchange column, and the bacterial inhibited test was applied to identify the protein antibacterial activities. RESULTS: The PCR amplifying and DNA sequencing tests indicated that the purpose plasmid contained the Lactoferricin B gene and several mutations. The induced target proteins were confirmed by SDS-PAGE electrophoresis and mass spectrum test. The protein antibacterial activities of mutations were verified in preliminary. CONCLUSION: The recombined plasmid pYES2/Lactoferricin B etc. are successfully constructed and induced to express in yeast cell of S. cerevisiae; the obtained recombined protein of Lactoferricin B provides a basis for further research work on the biological function and antibacterial activity. PMID- 17718416 TI - [Cloning and expression of PAL gene of Legionella pneumophila]. AB - OBJECTIVE: To develop DNA vaccine for Legionella pneumophila. METHODS: PAL gene of Legionella pneumophila was amplified with PCR. The amplified DNA was ligated to pcDNA3.1(+) vector. The recombinant plasmid, which was identified by restriction analysis, PCR and sequence analysis, was named pcDNA3.1-PAL. The NIH3T3 cells were transfected with the recombinant plasmid pcDNA3.1-PAL by Lipofection. Transient and stable expression products of the PAL gene were detected by immunofluorescence and RT-PCR. RESULTS: The recombinant plasmid pcDNA3.1-PAL expressed PAL protein in the eukaryotic cell NIH3T3. CONCLUSION: This study has built a foundation for the development of PAL gene DNA vaccine for Legionella pneumophila. PMID- 17718417 TI - [Experimental study on inhibition of cervical carcinoma siha cell proliferation by siRNA expression vector]. AB - OBJECTIVE: To observe the effect of HPV16E7 specific expression vector on cell proliferation in cervical carcinoma SiHa cells. METHODS: The HPV16E7 siRNA expression vector and empty expression vector were transfected into SiHa cells by liposome. The effects on E7 mRNA and E7 protein expression, cell cycle phase and cell growth rate were examined respectively by real-time RT-PCR, FCM and MTT assay. RESULTS: The HPV16E7 siRNA expression vector significantly inhibited the expression levels of E7 mRNA and E7 protein, the inhibition rates being 92.15% and 84.30% respectively. It also inhibited the transition from G, phase to S phase and the growth of SiHa cell line. CONCLUSION: HPV16E7 specific siRNA expression vector could specifically and efficiently inhibit the expression of E7 gene and hence it could regulate cell cycle and inhibit cell proliferation in cervical carcinoma SiHa cells. siRNA expression vector PMID- 17718418 TI - [Effect of synthesized polypeptide (P16) on inhibiting cell transdifferentiation and fibrosis induced by connective tissue growth factor]. AB - OBJECTIVE: To explore the possibility of a CTGF originated hexadeca-peptide (named P16) to compete with the CTGF in binding integrin avP3 on rat tubular epithelial cells (NRK-52E) and inhibit the transdifferentiation and myofibroblasts of NRK-52E cells induced by CTGF. METHODS: The NRK-52E cells were cultured in a condition with the existence of CTGF, P16-FITC (P16 labeled with fluorescein isothiocyanate), or both for 24h. The immunofluorescence staining and RT-PCR were employed to detect the expressions of the protein and mRNA of alpha SMA and the collagen I and IV which indicate the cell trans-differentiation and fibrosis. RESULTS: The P16 had stronger affinity with the NRK-52E cells than the CTGF. In a CTGF and P16 co-culture system, the P16 inhibited the expression of a SMA, collagen I and IV up-regulated by the CTGF. However, P16 alone had no effect on cell trans-differentiation and fibrosis. CONCLUSION: The synthesized P16 is capable of binding with NRK-52E cells and inhibiting trans-differentiation and fibrosis of the NRK-52E cells induced by CTGF in vitro. This finding offers a possibility of developing a novel antifibrosis therapy that targets CTGF receptor. PMID- 17718419 TI - [Role of sGC-cGMP pathway in CO-mediated regulation of respiratory rhythm]. AB - OBJECTIVE: To identify the role of soluble guanylyl cyclase-cyclic guanine monophosphate (sGC-cGMP) pathway in the carbon monoxide (CO) mediating regulation of respiratory rhythm from the medulla oblongata. METHODS: Medullary slices of newborn Sprague-Dawley rats were prepared for the experiment. The electrophysiological experiment comprised 5 groups (each with 8 slices), each of which were perfused with artificial cerebrospinal fluid (ACSF control group), CO (exogenous CO group), 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (a specific inhibitor of sGC, ODQ group), ODQ+CO (ODQ+CO group), and dimethyl sulfoxide (vehicle of ODQ, DMSO group), respectively. The burst frequency (BF) of hypoglossal rootlets was recorded as an index of rhythmic respiratory activity. Radioimmunoassay was employed to determine cGMP levels of the medullary slices of the ACSF control group, exogenous CO group, ODQ group and ODQ+CO group (n=6/ group). RESULTS: The exogenous CO decreased the BF (P < 0.05) and increased the cGMP level (P < 0.05). The ODQ increased the BF (P < 0.05) and decreased the cGMP level (P < 0.05). No significant changes were found in the BF and cGMP levels when CO and ODQ applied simultaneously (P > 0.05), but the BF increased (P < 0.05) after the drug perfusion ended. CONCLUSION: sGC-cGMP pathway may play an important role in the CO mediated regulation of respiratory rhythm from the medulla oblongata. PMID- 17718420 TI - [Signal transductional mechanism of calpain involved in the regulation of rat hypertrophy myocardium mediated by overloaded pressure]. AB - OBJECTIVE: To investigate the signal regulation of angiotensin I receptor on calpain system in rat hypertrophy myocardium mediated by overloaded pressure. METHODS: The rat model of hypertrophy myocardium mediated by overloaded pressure was established by abdominal aorta constriction. Forty male wistar rats were randomly divided into four groups: namely sham-operated group, banding group, valsartan group (banding group and valsartan administration 1 mg/kg x d), and PD123319 group (banding group and PD123319 administration 30 mg/kg x d). Concentrations of Ang II in serum and left ventricular septum were measured by radioimmunoassays. The immunoprecipitation method was used to assay the protein expression of calpain system, the phosphorylation and expression of calcineurin, the protein expression of cain/cabinl in myocardial tissues of left ventricular septum. The message RNA (mRNA) expression of beta-myosin heavy chain (beta-MHC) in myocardial tissue was analyzed using reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The Ang II concentration in serum and left ventricular septum tissue of banding group was higher than that of sham-operated group, valsartan group or PD123319 group (P < 0.01) respectively; the Ang I concentration in serum of valsartan group was lower than that of banding and PD123319 groups (P < 0.05), but higher in left ventricular septum tissues (P < 0.05). The expression of u-calpain protein, phosphorylation of calcineurin, mRNA expression of beta-MHC in left ventricular septum tissue of banding group was higher than that of sham-operation group (P < 0.01), the expression of cain/cabin1 was lower than that of sham-operation group (P < 0.01); the protein expression of u-calpain, phosphorylation of calcineurin and mRNA expression of beta-MHC were lower (P < 0.05), and cain/cabin1 protein expression in valsartan group was higher than that in banding and PD123319 groups (P < 0.05), but there was no expressibly big differences between banding and PD123319 group (P > 0.05). CONCLUSION: The cain/cabin1, an inhibiting protein factor of calcineurin, degraded by u-calpain with AT1 involves the calcineurin signaling pathway activated and the rat myocardium going to hypertrophy processed under overloaded pressure. PMID- 17718421 TI - [Identification of RACK1-PER1 protein interaction sites]. AB - OBJECTIVE: By screening the cDNA library of suprachiasmatic nucleus (SCN) region of human hypothalamus, we try to capture the novel proteins interacting with PER1 and investigate the interplaying characteristic of RACK1 and PER1. METHODS: By yeast two-hybrid system, the new protein in human SCN, which was associating with PER1-PAS domain was obtained. Then five truncated fragments of RACK1 cDNA was cloned into yeast expression vector to form recombinant library plasmid and was co-transformed into yeast strain AH109 with bait plasmid containing PER1-PAS domain. The transformants were selected via nutrition-deficient medium, and the positive clones were identified or obtained by checking the expressin of report gene. At last all the protein interactions were confirmed by co immunoprecipitation tests. RESULTS: one of the positive clones in human SCN cDNA library were identified with part of the RACK1 protein sequence. Three positive clones, which contained respectively the fragment of RACK1 (WD1-7), RACK1 (WD4-7) or RACK1 (WD5-7) were obtained through yeast two-hybrid screen with various RACK1 fragments and PER1-PAS domain. The RACK1 and PER1 protein interaction was determined by beta-galactosidase assay and co-immunopreipitation. CONCLUSION: The direct interaction between RACK1 and PER1 has been approved. RACK1 is composed of seven WD40 repeats and the minimal interacting sites are limited in V-VII WD40 domains in the present study,which means C-terminal amino acid of RACK1 may be essential to the interacting. PMID- 17718422 TI - [Biological effects of immune serum from fusion protein of beta-amyloid peptide and HbcAg/MIR on AD transgeneic cells]. AB - OBJECTIVE: To investigate the expression of fusion protein c-Abeta-c, a fusion protein from the beta amyloid peptide (Abeta) and the Hepatitis B core antigen/ Major immunodominant region (HbcAg/MIR), in the BL21/pET28 prokaryotic expression system and to immunize mice with the expressed fusion protein and evaluate the immunogenicity and biological effects of the serum in vitro. METHODS: The recombinant prokaryotic expression plasmid PET-28a /c-Abeta-c was constructed by molecular cloning technique and the c-Abeta-c fusion gene expression was induced in E. coli BL21 by isopropyl-1-thio-b-Dgalactopyranoside (IPTG). The expressed fusion protein was analyzed by SDS-PAGE. Intraperitoneal injection (i.p.) of the purified c-Abeta-c fusion protein was given to the BALB/c mice. The anti-Abeta effect of the immune serum was detected by indirect ELISA. The biological effect of the immune serum on Alzheimer's disease (AD) transgeneic cells was assessed by MTT assay and flow cytometer. RESULTS: The c-Abeta-c fusion protein was found in the sediment of the isolated bacteria. The expressed protein comprised more than 30% of the total proteins in the bacteria sediment. The anti-Abeta antibody in the serum of the immunized mice reached 1:16000. The antiserum reduced the cytotoxicity of Abeta peptide in the AD transgeneic cells and significantly decreased the apoptosis of cells. CONCLUSION: The c-Abeta-c fusion protein has good Abeta immunogenicity and the animal immune serum efficiently inhibits the cytotoxicity of Abeta peptide. PMID- 17718423 TI - [Immunoprotection role of a hepatitis B virus DNA vaccine responsible to BAlb/c mice]. AB - OBJECTIVE: To investigate the specific immune response and the immunoprotection effects of cytotoxic T-lymphocyte (CTL), which is induced by hepatitis B virus (HBV) DNA vaccine pCMV-S2S, on BALB/c mouse with the attack of SP2/0-S2S cells, a BALB/c mouse myeloma cell line stably expressing the HBV preS2S antigen. METHODS: BALB/c mice were divided into 3 groups: experimental group (intramuscularly injected with pCMV-S2S), control group 1 (HBsAg vaccine immunizing) or control group 2 (plasmid pCMV immunizing), which were immunized thrice at week 0.4 and 8 respectively. Specific CTL activities of 3 mice of each group were measured by lactate dehydrogenase (LDH) release assays, 4w after the last boost. The other mice of each group were subcutaneously inoculated with SP2/0-S2S cells into one lateral of flanks. SP2/0-CMV cell without expressing preS2S was subcutaneously inoculated into another lateral of mouse flanks. The time of visible tumor formation and the size of tumor were recorded and observed. The life span and survival rate of mice after loaded with the tumor cells were analyzed by Log-Rank statistics and Kaplan-Meier Survival curve respectively. RESULTS: The specific CTL lysis value of pCMV-S2S group mice was (34.21 +/- 1.38)%, higher than that of HBsAg group [(19.64 +/- 1.50)%] or pCMV group [(3.45 +/- 1.89)%] (P < 0.05). The visible SP2/0-S2S tumor formation rate in pCMV-S2S group mice was 58.3% lower than that in the pCMV group (91.7%), 10 d after inoculated with the tumor cells (P < 0.05). The tumor formation rates of the two control groups were no obvious difference. The date of the first mouse dying in pCMV-S2S group was 24d, delayed for 13d, compared with that in the two control groups. The average life span of pCMV-S2S group mice after loaded with the tumor cells was (31 +/- 1) d, longer than that of the two control groups (P < 0.05). The 4w survival rate of the pCMV S2S group mice was obviously increased (75%), compared with the two control groups (P < 0.05). The average life span and the 4w survival rate of the two control group mice were no obvious difference. CONCLUSION: The hepatitis B virus DNA pCMV-S2S vaccination may elicit substantial HBV preS2S-specific CTL response in vivo, which gives the mouse the immunoprotection against the attack of SP2/0 S2S cells. The results indicate that pCMV-S2S may be used to the immunoprotection from HBV infection. PMID- 17718424 TI - [Association between toll like receptor 4 (896A>G) mutations and pancreatic necrotic infection in severe acute pancreatitis]. AB - OBJECTIVE: To determine the relationship between Toll like receptor (TLR) 4 (896A>G) mutations and pancreatic necrotic infection in acute pancreatitis (AP). METHODS: TLR4 (896A>G) mutations were detected by mispairing PCR-RFLP analysis technique in the patients with pancreatic necrosis and healthy volunteers. RESULTS: (1) All of the TLR4 mutations were heterozygotes; (2) The G allele frequencies of TLR4 genes were significantly higher in the patients with pancreatic infection than in the healthy volunteers; (3) The incidence of gram negative infection was significantly higher in the patients with the TLR4 mutations [15 (44.1%) of 34] than that in the wild type population [15(18.5%) of 81]. CONCLUSION: TLR4 (896A>G) mutations are associated with the infection of pancreatic necrosis in the patients with AP. PMID- 17718425 TI - [Metallothionein inhibited DOX-induced cardiac apoptosis in mice]. AB - OBJECTIVE: To investigate the inhibitive effect of metallothionein (MT) on DOX induced cardiac apoptosis and the involved possible mechanisms. METHODS: Adult male C57BL mice (6-8 weeks old) were randomly assigned into four groups and given the following treatment: Zinc (ZnSO4, 300 micromol/kg, s.c., once a day for 2 days) or equal volume of physiological saline prior to a single dose of DOX (15 mg/kg, i.p.) or equal volume of saline. Animals were sacrificed on the 4th day after DOX administration and hearts were excised for further studies, including cadmium-hemoglobin affinity assay for MT concentration, ELISA detection of DNA fragmentation and Western blot analysis of Bax and Bcl-2. RESULTS: DOX administration decreased heart weight by 10% and caused remarkable cardiac apoptosis as demonstrated by DNA fragments, while Zinc pretreatment significantly increased the MT levels and therefore inhibited the cardiac apoptotic effect of DOX. Elevated expression of Bax was obviously observed after DOX treatment, while this elevation was prevented by MT induction by Zinc. On the contrary, Bcl-2 protein level was not altered significantly among each group. CONCLUSION: These findings suggest that metallothionein induced by Zinc exhibits protective effects on the cardiac apoptosis of DOX, which might be mediated through the prevention of Bax protein up-regulation by DOX and associated elevation of Bax/Bcl-2 ratio. PMID- 17718427 TI - [The mechanisms and effects of lutein on inducing the cell differentiation of human esophagus cancer EC9706]. AB - OBJECTIVE: The purpose of the study was to explore the effects and molecular mechanisms of lutein on the differentiation of esophagus cancer EC9706 cell. METHODS: EC9706 cells were seeded in 1640 medium before the addition of test compounds. The respective test compound was added in fresh medium and the control cell received the vehicle (DMSO) or Fluorouracil. The proliferation and cell cycle of EC9706 were determined by MTT assay and flow cytometry, respectively. The change in cytomorphology was investigated by using HE staining. Proliferation and differentiation cells were checked and observed by methyl green-pyronine staining. The protein expression of cyclin D1 was detected by immunohistochemistry. RESULTS: Compared with the DMSO control group, the proliferation of the EC9706 cells treated with lutein (100 microg/mL and 150 microg/mL) could markedly be decreased and the cell cycle was blocked at G0/G1 phage which caused significant changes in the cytomorphology of EC9706 cell line, and the cell malignant degree tended to drop down, the protein expression of cyclin D1 was also down-regulated significantly. CONCLUSION: Lutein can inhibit the proliferation of EC9706 cell, and promote the cancer cell differentiation. cyclin D1 may be involved in cell proliferation and differentiation events in esophageal cancer EC9706 cell, which is regulated by lutein. PMID- 17718426 TI - [Effects of Yanting diet and vitamins on growth and proliferation of human esophageal cancer cell line]. AB - OBJECTIVE: The effects of sera of rats fed the Yanting diet (YT diet) on growth and proliferation of the human esophageal cancer cell line Eca-109 were observed by the means of sero-physiology. METHODS: The male SD rats, randomly divided into six groups with ten each, were fed a conventional diet and five experimental diets, i.e. YT diet, the YT diet with two vitamin mixtures (Mix. 1, vit. A, E and folic acid; Mix. 2 was Mix. 1 plus riboflavin and vit. C) at two doses. After rats fed different diets for 30 days, rats' sera were collected and added into medium for cell culture. The effects serum of rats fed different diets on two human cell lines (Eca-109 esophageal cancer cell and HL7702 normal liver epithelium cell) were investigated by means of cell growth curve, 3H-thymidine incorporation and flow cytometric assay. RESULTS: By comparison with the control, the sera of rats fed the YT diet significantly promoted Eca-109 cell proliferation but showed inhibitory effects on HL7702 cell. These changes, however, were reversed by supplementation with two vitamin mixtures at high dose, which had more significant effects on either inhibiting Eca-109 cell or promoting HL7702 cell proliferation than the corresponding lower dose. In addition, the high dose of two vitamin mixtures caused G1 arrest of Eca-109 cell, while speeding the HL7702 cell entering into S and G2 of cell cycle. No obvious difference was seen between both serum of rat fed with the conventional diet and calf serum as control to effect on the two cell line growths and proliferations. CONCLUSION: It is indicated that the sera of rats fed with the YT diet could promote the proliferation of human esophageal cancer cell line Eca-109; the YT diet supplemented with vitamin mixtures may have inhibitory effects on Eca-109 cell. The cell cycle arrest of G1 may be one of the mechanisms that the YT diet supplemented with vitamin mixtures inhibited the proliferation of Eca-109 cell. PMID- 17718428 TI - [Expression of VEGF in kidney of diabetic rats]. AB - OBJECTIVE: To investigate the expression of vascular endothelial growth factor (VEGF) in the kidney of diabetic rats and probe its relationship with the development of diabetic nephropathy (DN). METHODS: Diabetes mellitus was induced in SD rats by Streptozotocin. The renal tissues of rats were taken out at 2, 4, 8, 12, 16, 20 and 24 weeks after operation. The expression of VEGF was assessed by immunohistochemistry methods. VEGF mRNA in kidney was detected by RT-PCR at the same time points. The levels of VEGF mRNA and immunostaining were quantified by computer image analysis. The relationships of VEGF with the indices of renal damage, including renal/body weight, urinary protein excretion, glomerular volume and glomerular area, were analyzed. RESULTS: The expression of VEGF mRNA in diabetic kidney was significantly up-regulated after operation from 2 weeks to 24 weeks with the peak level at 20 weeks, when compared with control at the same time-points. The positive results of VEGF staining in diabetic glomeruli was increasingly observed after operation from 2 weeks to 24 weeks, with the peak at 20 weeks. The positive results of VEGF staining in diabetic tubuli was increasingly seen from 2 weeks to 24 weeks, with the peak at 8 weeks. CONCLUSION: VEGF level is increased continuously in the diabetic kidney of rat. The increased expression of VEGF is mainly located in the glomeruli at the early and middle stages, and is in the tubuli at the middle and late stages. VEGF expression in the diabetic kidney of rat is related to the development of renal changes. PMID- 17718429 TI - [Expression and clinical significance of matrilysin (MMP-7) in human rectal cancer]. AB - OBJECTIVE: To detect the matrilysin (MMP-7) expression in human rectal cancer and to investigate whether it is correlated with invasion and metastasis of human rectal cancer. METHODS: The paired samples obtained from 100 inpatients were allocated into cancer group and control group. By Quantitative-Real-Time RT-PCR, immunohistochemical staining and computerized image analysis, the mRNA and protein expressions of MMP-7 in human rectal cancer were measured and further analyzed for the relationship between MMP-7 expression and clinicopathologic characters. RESULTS: MMP-7 mRNA expression in cancer group was higher than that in control group (P = 0.001), the mRNA expression ratio of 67 (7%) samples was over 1. The mRNA expression level of MMP-7 was correlated with age, Dukes's Staging, lymph node metastasis and histological differentiation grade. The positive degree of immunohistochemical staining for MMP-7 in cancer group (1.94 +/- 0.21) was higher than that in control group (1.15 +/- 0.20, P = 0.002). The protein expression of MMP-7 was correlated with age, Dukes's Staging and lymph node metastasis. CONCLUSION: MMP-7 expression in human rectal cancer increases significantly and plays a key role in the invasion and metastasis of human rectal cancer. PMID- 17718430 TI - [Expression of HIF-1alpha mRNA and HIF-2alpha mRNA in placentas of pregnant women with intrahepatic cholestasis of pregnancy]. AB - OBJECTIVE: To investigate the expression of HIF-1alpha mRNA and HIF-2alpha mRNA in placentas of pregnant women with intrahepatic cholestasis of pregnancy(ICP). METHODS: Twenty samples of placentas from pregnant women with ICP and 20 samples of normal term placentas were selected. The expression levels of HIF-1alpha mRNA and HIF-2alpha mRNA were measured by RT-PCR. RESULTS: There was no statistically significant difference in respect to the expression levels of HIF-1alpha mRNA and HIF-2alpha mRNA between the two groups of samples (P > 0.05). CONCLUSION: Under hypoxic conditions, HIF-1alpha and HIF-2alpha proteins are not transcriptionally regulated at the mRNA level but are probably regulated at the post-mRNA level. PMID- 17718431 TI - [Interaction between member LIGHT of TNF superfamily and SOCS3, which respond to induce the differentiation and maturation of dendritic cell]. AB - OBJECTIVE: To detect the relation between the member LIGHT of TNF superfamily and the suppressor of cytokine signaling 3 (SOCS3), and to investigate the effect of SOCS3 on dendritic cell (DC) maturation induced by LIGHT. METHODS: Bone marrow derived DC (BMDC) was generated from mouse bone marrow monocyte by culturing with rmGM-CSF, rmIL-4 in vitro. SOCS3 mRNA in BMDC was analyzed by RT-PCR, and the protein of SOCS3 was measured by Western blot. After blocking the SOCS3 expression with the specific anti-sense oligonucleotide, we applied the flow cytometry to measure the expression of CD86 and CD40 on DC for making clear whether the silence of SOCS3 would regulate the LIGHT-stimulated DC maturation. RESULTS: With the effect of LIGHT, the level of SOCS3 mRNA and protein in BMDC sharply increased. The specific antisense oligonucleotide could effectively block SOCS3 mRNA expressing in BMDC with the ratio of 49% and block SOCS3 protein expression with the ratio of 45%. Compared with SOCS3-unblocked DC, the SOCS3 blocked BMDC with stimulation of LIGHT showed higher CD40 and CD86 (P < 0.05). CONCLUSION: LIGHT enhances the expression of SOCS3 during stimulating BMDC maturation. As more sensitive to LIGHT, the SOCS3-blocked BMDC is driven to more mature. SOCS3 presents a negative regulation mechanism in BMDC maturation induced PMID- 17718432 TI - [Effects of hypotonic solution on the proliferation, alkaline phosphatase activity and [Ca2+]i concentration of osteoblast-like cells]. AB - OBJECTIVE: To investigate the effects of static-stretch from the hypotonic solution on the proliferation, alkaline phosphatase activity and [Ca2+]i in the osteoblast-like cells. METHODS: Mechanical loading was introduced by swelling in the hypotonic solution. In vitro cultured MG63 were incubated under continuous swelling of 277, 240 and 163mOsm for 2h, 4h, 8h, 12h, 24h and 48h. The cell proliferation was detected by MTT assay. ALPase and [Ca2+]i were determined by modified enzyme dynamic method and OCPC respectively. RESULTS: The cell proliferation, ALP activity and [Ca2+]i increased slowly under continuous static stretch of 277 and 240mOsm. The cell proliferation was inhibited under 163mOsm, with a sharp increase of [Ca2+]i at 8h (11.383 +/- 0.111) and an increase of ALPase activity (0.326 +/- 0.002). CONCLUSION: The static-stretch induced from the hypotonic solution has an impact on the proliferation, differentiation, ALPase and Ca2+-ATPase of the MG63. The [Ca2+]i is correlated with the ALPase. PMID- 17718433 TI - [Positive effect of autoreactive T lymphocyte cells on the production of antiplatelet antibody]. AB - OBJECTIVE: To investigate the effect of autoreactive T lymphocyte cells on the production of antiplatelet antibody. METHODS: The platelet membrane IIb/ IIIa was purified from the affinity chromatography of healthy donors. Peripheral blood mononuclear cells (PBMCs) were isolated from the patients with Immune Thrombocytopenic Purpura (ITP) (experimental group) and the normal people (control group). The PBMCs were stimulated with the purified GP IIb/ IIIa. The cell proliferation was monitored and the level of ILG and anti-GP IIb/ IIIa IgG were measured. RESULTS: The cell proliferation of the experimental group was faster than that of the control group. The T cells comprised the majority of increased cells in the experimental group. The CD4+ T cells were slightly more in the experimental group than in the control group. The CD28+T and CD25+ T cells were significantly more in the experimental group than in control group. More IL 6 and anti-GP II b/III a IgG were detected in the nine ITP patients than in the control group. The increase of T cell growth of three of the seven ITP patients was not obvious. The three patients also had low levels of IL6 and anti-GP IIb/ IIIa IgG. The proliferation of lymphocyte was also observed in the control group. But very low level of anti-GP IIb/ IIIa IgG antibody was detected in the PBMCs of the control group in vitro. CONCLUSION: Autoreactive T lymphocyte GP IIb/ IIIa increases the production of anti-GP IIb/ IIIa IgG antibody. Such increase has a positive effect on the activation of B cells. PMID- 17718434 TI - [The effect of children's gluteal muscle contracture on skeleton development]. AB - OBJECTIVE: To explore the effect of children's gluteal muscle contracture (GMC) on skeleton development. METHODS: The pelvic plain films of 368 GMC cases confirmed by operation from May 1995 to June 2005 and those of 200 individuals as control were analyzed for this research project. The pelvic CT scans were performed in 30 GMC cases and 25 controls. The data of both groups were used to comparison, analysis and statistics treatment in pelvic plain X-ray film, hip joint, acetabular index, neck shaft angle, centre-edge (CE) angle, the form of pelvic obturator foramen, the existence or nonexistence of the iliac hyperdense line. RESULTS: There were 68 cases with pelvis obliquity in the case group but no one in the control group. The iliac hyperdense lines at the side of sacroiliac joints were found on the pelvic plain films of 321 of 368 cases with GMC and 5 of 200 controls. In 368 cases with GMC, the iliac hyperdense lines were detected in 306 of 314 patients beyond 7-year-old, and 313 of 336 appeared mostly the contracture of gluteus maximus muscle, which showed to be significant in statistics. In GMC group, the oblique plane became steeper and almost oriented posteroanteriorly, while in control group,the pelvic CT showed that the outer codex of posterior ilium at the level of sacroiliac joint appeared as an oblique plane, oriented from posteromedial to anterolateral side. The data were processed with statistics software, found that compared with the control group, the results of pre-operation group's examines such as CE angle, neck shaft angle, longitudinal diameter, cross diameter, and the iliac hyperdense line had significant differences (P < 0.01), the results of post-operation group's those examines showed no significant differences (P > 0.01), and the acetabular index appeared no significant differences (P > 0.01). CONCLUSION: The children's gluteal muscle contracture has the significant effect on skeleton development, which could lead to pelvis obliquity, coxa valga, leg length pseudoinequality, CE angle increasing, etc. The iliac hyperdense line on the pelvic plain film is probably a characteristic change of GMC. PMID- 17718435 TI - [The experimental study on biodegradable gel membrane applied to prevention of postoperative adhesion of abdominal cavity surgery]. AB - OBJECTIVE: To develop a new type of anti-adhesion gel membrane and explore its applying technique. METHODS: 24 adult New Zealand white rabbits were used for the experiment research project, the animals were divided into two groups: the experiment group (18 adult New Zealand white rabbits) and the control group (6 adult New Zealand white rabbits). The animal models were established via the abdominal cavity. The biodegradable gel membrane was covered to the surface of the operating region in experimental animal group, while the 0.9% NaCL was directly rinsing the operating region in the controlled group. The specimens were collected at postoperatively week 2, 4 or 8 respectively. The samples were evaluated by global and histological observation. RESULTS: In the experiment group, a few adhed zones were observed in 2 and 4 weeks after operation, but in 8 weeks after operation, the adhesion zone was disappeared. In the control group, a few adheol zones were founded in 2 weeks after operation. In 4 weeks after operation, the adhed zone become conspicuously emerged. In 8 weeks after operation, the cicatri band was occurred. CONCLUSION: The biodegradable gel membrane usd into the postoperative abdominal cavity is effective and easy to manipulate, and it could be used as a high-effect, cheap drug of anti-adhesion in operation for surgeons. PMID- 17718436 TI - [Apoptosis mechanism of intralipid postconditioning to reduce ischemia reperfusion injury of isolated rat hearts]. AB - OBJECTIVE: To test the effect of intralipid, a solution containing soybean oil, egg phospholipid and glycerol, on protecting perfused rat hearts against ischemia/reperfusion injury (IR) and to explore possible cardiomyocyte apoptosis mechanism involved. METHODS: Twenty Sprague-Dawley rtas were perfused with Kreb Henseleit buffer on Langendorff apparatus. The rats were randomly allocated to 4 groups. The control group of rats were perfused for 3 hours and 50 minutes without cardiplegia ischemia. The hearts of the other three groups of rats (I preC, I-postC, and ISCH) were subjected to 45 minutes of ischemia and 3 hours of reperfusion. The I-preC group was pre-treated with 15 minutes of intralipid followed by 15 minutes of wash out. The I-postC group was treated by 15 minutes of intralipid at the onset of reperfusion. The ISCH group served as untreated ischemic control. The LVDP (Left Ventricular Developed Pressure) and HR were measured before and after reperfusion. The LVW was calculated as LVDP x HR. LDH were measured 20 minutes after perfusion and 60 minutes after reperfusion. TUNEL staining was used for identification of apoptotic cells. After 3 hours of reperfusion, the changes of expressions of Bcl-2 and Bax were examined by Western Blotting. RESULTS: Slightly mechanic function attenuation and low LDH release were found in the control group, along with little apoptosis. By contrast, significantly decreased mechanical function and more cardiocyte apoptosis were found in the ISCH group. Intralipid postconditioning improved LVW and reduced LDH activity significantly. The improvement was accompanied by increased protein expression of Bcl-2 and decreased Bax protein level. Intralipid preconditioning decreased LDH level only. No significant differences in protein level of Bcl-2 and Bax were found between the I-preC and ISCH group. CONCLUSION: Intralipid postconditioning improves cardiac mechanical performance through inhibiting cardiocyte apoptosis and reducing LDH activity. Intralipid preconditioning reduces LDH level but does not inhibit cardiocyte apoptosis. PMID- 17718437 TI - [Effects of intrathecal lornoxicam on withdrawal thresholds of rats to mechanical and thermal stimuli]. AB - OBJECTIVE: To assess the effects of intrathecal lornoxicam on the withdrawal thresholds of rats to mechanical and thermal stimuli. METHODS: After approval of the animal ethic committee, 18 healthy male adult rats were randomly allocated on average to receive the intrathecal solvent (Group S) 20 tL, intramuscular lornoxicam (Group IM) 120 microg/20 microL or intrathecal lornoxicam (Group IT) 120 microg/20 microL, and to do the mechanical withdrawal threshold measured by Dynamic Planter Aesthesiometer (Ugo Basile, Italy). Another 18 rats were allocated similarly to do the thermal withdrawal threshold measured by Hargreaves Test (Ugo Basile, Italy). The basal value of withdrawal threshold was first recorded, and then the intrathecal solvent, intramuscular or intrathecal lornoxicam was injected, and the withdrawal threshold values were measured once more in the period of total 150 min with each 30 min as a time section. The Student-Newman-Keuls test was used to identify the differences between groups, with the SPSS11.5 package. RESULTS: In Group S, there was no difference between the threshold values after intrathecally injecting solvent and the basal value. In Group IM, 30 min after injection, the mechanical and thermal threshold values reached the peak [(31.1 +/- 4.05) g, (20.82 +/- 2.15)], and were different as compared with the basal value (P < 0.05, P < 0.01). The mechanical and thermal withdrawal threshold values decreased to the basal level at 60 min and 90 min respectively. In Group IT, 10 min after injection, the mechanical and thermal withdrawal threshold values [(35.0 +/- 2.76) g, (26.72 +/- 3.75) s] were different when compared with the basal value (P < 0.01). The mechanical and thermal withdrawal threshold values decreased to the basal level at 90 min and 120 min respectively. There was no difference of the basal value among the three groups. But at 10, 30, 60 min after lornoxicam administrated, the mechanical threshold values of Group IT were obviously higher than those of Group S; and at 10, 30 min, it was significantly higher than that of Group IM. At 10, 30, 60, 90 min, the thermal thresholds of Group IT were markedly higher than those of the other groups. CONCLUSION: Both systemic and intrathecal lornoxicam can elevate the withdrawal threshold values of rats to mechanical and thermal stimuli, but the onset of this effect is faster, and the maintenance is longer by intrathecal route. PMID- 17718438 TI - [Effect of reperfusion leukocyte-depleted blood on canine myocardial energy metabolism balance during cardiopulmonary bypass]. AB - OBJECTIVE: To investigate the impact of myocardial energy metabolism of canine reperfused with leukocyte-depleted blood during cardiopulmonary bypass (CPB). METHODS: Eighteen adult healthy dogs undergoing CPB were randomly divided into 3 groups: the control group (group C, n=6), whole blood (group W, n=6) and the experimental group (group L, n=6) with use of the leukocyte depletion filter (LDF) on the bypass circuit. The contents of adenine nucleotide, superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), myeloperoxidase (MPO), malondialdehyde (MDA) and mitochondrial swelling of myocardia were determined respectively before cross-clamping, at 40 min and 60 min after aortic cross clamping (AC), 30 min and 60 min after declamping (DC) during CPB. RESULTS: Reperfused with leukocyte-depleted blood by LDF connected with bypass circuit, the dog hearts of group L at 60 min after AC, 30 min and 60 min after DC were much better in the recovery of myocardium energy metabolism, higher in contents of myocardium SOD and GSH-PX than those in group C and W (P < 0.01). The myocardium MPO, MDA and mitochondrial swelling degree at 60 min after AC, 30 min and 60 min after DC were distinctly lower in group L than those in group C and W (P < 0.01). CONCLUSION: Myocardium has serious energy exhaustion and deteriorated metabolism during CPB. Myocardial mitochondrial structure and function can be protected and myocardial energy depletion can be reduced by infusion of leukocyte depleted blood to the heart before DC, which can distinctly attenuate myocardial ischemia/reperfusion injury. PMID- 17718439 TI - [The primary research on relevant factors influencing urease activity of Actinomyces naeslundii]. AB - OBJECTIVES: To investigate the effects of multiple factors that could influence the urease activity of Actinomyces naeslundii. METHODS: The various biochemical methods were used to investigate the changes of urease activity in Actinomyces naeslundii which was under different environmental conditions. RESULTS: It was observed that under conditions of nitrogen-limited, glucose-excess and sub-acid environment, the activity of the A. naeslundii urease got the different extent increase extend. With cultured under conditions of pH 6.0, limited nitrogen and excess glucose, Actinomyces naeslundii was able to make the urease activity increase up to 149.7 nmol/min x mg cell protein. CONCLUSION: The nitrogen, glucose source and environmental pH are such factors that could influence the activity of the A. naeslundii urease; with the dental plaque cariogenicity enhanced, the A. naeslundii urease activity may increase too. PMID- 17718440 TI - [The influence of age upon circadian rhythm of human pulp sensibility]. AB - OBJECTIVE: To explore the influence of age on the circadian rhythm of pulp sensibility, guide the diagnosis and treatment of dental and endodontic diseases. METHODS: The first lower molars of young, middle-aged, and aged volunteers were inspected for the threshold of pulp sensitivity. Each inspection was implemented every 4 hours earlier, totally 7 times during 24 hours. All values of pulp sensibility threshold from each volunteer were analyzed by Halberg methods for cosinor-rhythmometry. The chronobiology characteristics of pulp sensibility were compared among young, middle-aged, and aged. RESULTS: The pulp sensibility threshold values of the young, middle-aged, and aged indicated to have the circadian rhythm alternation in period of 24 hours, with fitting well to a cosine curve. The trend of rhythm curve was similar to all three age groups. The acrophase and bathyphase appeared at 0:00 and 12:00 separately. The values and amplitudes of pulp threshold sensibility showed to be: young>aged> middle-aged. CONCLUSION: The circadian rhythm of pulp sensibility changes according with age. The pulp sensibility threshold value is lower in aged people than in the young, and the lowest sensibility threshold is in middle-aged people. Besides, the extent of rhythm fluctuation is the least in middle-aged people. PMID- 17718441 TI - [The research for magnetic attachments producing static magnetic fields to influence on cytoskeletons of human periodontal ligament cells]. AB - OBJECTIVE: The present research aimed to investigate that the static magnetic field (SMF) generated by dental magnetic attachments influenced on the cytoskeletons of human periodontal ligament cells (HPDLCs). METHODS: In vitro cultured HPDLCs were exposed to 10 mT and 120 mT SMF which simulated those of from the closed-field and open-field magnetic attachments respectively for 12-60 hours in a cellular SMF exposure system. The control group cells were cultured outside the SMF exposure system and were only exposed to geomagnetic field of about 0.03-0.07 mT. After finishing the SMF exposure, the cytoskeletons were observed under a laser scanning confocal microscope (LSCM). The image analysis software was utilized to measure and analyze the cell area, length/width ratios and the contents of F-actin of cells. RESULTS: There were certain changes observed in the cytoskeletons after HPDLCs exposed to 10 mT and 120 mT SMF for 12 60 hours. With the SMF strength increasing and the loading time extending, the cell microfilaments got ashorened change and a disordered arrangement inside cells, and the length/width ratios of cells decreased (P < 0.05). The areas of cells decreased after SMF loading for 60 hours (P < 0.05). The cell F-actin contents decreased after SMF loading for 12 hours (P < 0.05), but in the meantime there was no significant difference happening between the 36 or 60 hours SMF loading group and the control group (P > 0.05). CONCLUSION: In this study the SMF of magnetic attachments can lead the certain changes to the cytoskeletons in HPDLCs. PMID- 17718442 TI - [Effect of gilding technique on the release of elements from copper-based alloy post-core]. AB - OBJECTIVE: To evaluate the effect of gilding technique on the release of element from copper-based alloy post-core exposed to artificial saliva. METHODS: The quantities of nickel ion and copper ion released from common copper-based alloy post-core (control group), blasting gilding copper-based alloy post-core (blasting group) and burnishing gilding Copper-based alloy post-core (burnishing group) in artificial saliva after 1 month,3 months,6 months and 8 months of exposure were measured with atomic absorption spectrophotometer. The tooth tissues were stripped off at the eighth month and the oxygenization on the surface of the posts were observed. RESULTS: There was a significant difference of element release of nickel between the gilding groups and the control group at the sixth and eighth month. There was a significant difference of element release of copper between the gilding groups and the control group at the third, sixth and eighth month. The quantities of element released from the gilding groups were fewer than those from the control groups. The release of nickel and copper ions increased with the length of exposure significantly after three month of exposure. The element release from the control groups increased more rapidly than the gilding groups. The surface of the post-core in the control groups were all oxygenized while those in the gilding groups had been oxygenized only near the margins of the cores and the upper 1/3 part of the post with uncontinuous and relatively thin layers. CONCLUSION: Gilding surface treatment can decrease the release of nickel and copper ions from copper based-alloy post-core and the surface oxygenization, which will improve the biocompatibility of the core. PMID- 17718443 TI - [Preliminary application of 99Tc(m)-MIBI scintigraphy for judgment of bone malignant and benign lesions]. AB - OBJECTIVE: The aim of this study was to assess the value of Tc-99m-hexakis-2 methoxyisobutylisonitrile (MIBI) scintigraphy diagnosing the malignant and benign bone lesions in comparison with a conventional bone tracer 99Tm-methylene diphosphonate (MDP). METHODS: 99Tc(m)-MDP three-phase bone scintigraphy and 99Tc(m)-MIBI dynamic and quiet states scintigraphy were obtained from 39 patients with proved malignant diseases or suspected bone metastases after bolus injected intravenously radiopharmaceuticals, respectively. The results were compared with using film reading and regions of interesting (ROI) technique. RESULTS: 139 bone metastases were confirmed in 169 lesions. The sensitivity of 99Tc(m)-MDP or 99Tc(m)-MIBI scintigraphy was 90.3% or 68.4% (P < 0.05), respectively; the specificity was 33.3% or 96.7% (P < 0.05), respectively;the false positive rate was 6.71% or 1.04%. No statistical difference was appeared in both malignant tumors and benign lesions with 99Tc(m)-MDP scintigraphy. However, while with 99Tc(m)-MIBI scintigraphy, there were significant statistical difference (P < 0.05) both in malignant tumors and benign lesions. 99Tc(m)-MIBI scintigraphy could early detect 17 bone metastases and proved 11 lesions to be benign bone foci and 2 to be pathologic bone fractures. CONCLUSION: Although 99Tc(m)-MIBI scintigraphy has lower general sensitivity than 99Tc(m)-MDP scintigraphy, it has higher specificity, lower false positive rate and can detect lesions early and judge the quality, which may be helpful in the evaluation and strategy of clinical therapy for bone metastases. PMID- 17718444 TI - [Real-time PCR used to detect p53 gene damage in workers exposed to arsenic]. AB - OBJECTIVE: To evaluate the relationship between the metabolism of arsenic and the damage of exon 5 and 8 of p53 gene from workers in a arsenic mill, and with real time PCR technique, to establish the method probing the gene-specific DNA damage in people. METHODS: By real-time PCR, the damages of exon 5 and 8 of p53 gene were probed in 37 workers exposed highly to, 16 manager and logistic employees exposed less to an arsenic mill in Yunnan province, and also 25 local people who did not contact with any white arsenic in near past time. At the same time, the urinary total and organic arsenic of workers were detected. The correlation between metabolism of arsenic and damage of p53 gene was evaluated. RESULTS: Total urinary arsenic concentrations were (1.18 +/- 0.76) mg/L and (0.32 +/- 0.28) mg/L for high and low exposed male workers, and 0.23 mg/L, (0.53 +/- 0. 30) mg/L for high and low exposed females. Organic urinary arsenic concentrations were (0.48 +/- 0.37) mg/L and (0.08 +/- 0.05) mg/L for high and low exposed males, and 0.11 mg/L, (0.30 +/- 0.24) mg/L for high and low exposed females. The total and organic urinary arsenic of high exposed group was higher than that of control male (P < 0.05), all in control group were lower than 0.02 mg/L for reference. The Ct relative value of exon 5 of p53 gene in high exposed group was higher than that in control male (P < 0.05), and the increased tendency of Ct relative value of exon 5 of p53 gene was found in workers with organic arsenic concentration going up (r(s) = 0.355, P = 0.011). The Ct relative value of exon 8 of p53 gene in low exposed group was higher than that in control male (P < 0.05), but the difference between high exposed and low exposed or reference's was not obvious (P > 0.05). CONCLUSION: The damages in exon 5 and 8 of p53 gene in workers exposed to arsenic may be induced. The metabolism of arsenic may be very important in the damage of exon 5. It is feasible for real-time PCR technique used to detect gene-specific DNA damage in people. PMID- 17718445 TI - [Dental caries in children with cleft lip and/or palate in China]. AB - OBJECTIVE: To determine the prevalence of dental caries in children with cleft lip and Palate. METHODS: A cross-sectional study was undertaken in 380 children with cleft lip and Palate and 339 children without cleft. Dental caries were measured with decayed-missing-filed-teeth index (DMFT/dmft) and the decayed missing-filed-surface index (DMFS/dmfs). A questionnaire survey about the socio economic conditions and lifestyles of the children's families was undertaken in the parents of the children. RESULTS: (1) The children with cleft Palates had a higher prevalence of caries and greater DMFT(S) and dmft(s) scores than the children without cleft (P < 0.05), except for those of 3 to 5 years old. (2) For the children of 3 to 5 years old, those with cleft lip and palate had significantly more caries than those with only a cleft lip or a cleft lip and alveolus (P < 0.05). The children who had surgical repairs had lower dmft(s) than those who had not (P < 0.05). CONCLUSION: (2) Chinese children with oral cleft have more dental caries than the children without cleft. (2) Children with cleft lip and palate have higher levels of dental caries than those with cleft lip alone. The children who had surgical repairs have less dental caries. PMID- 17718446 TI - [Researches on biomechanics of micro-implant-bone interface and optimum design of micro implant's neck]. AB - OBJECTIVE: To compare and analyze the stress distribution at the micro-implant bone interface based on the different micro-implant-bone conditioned under orthodontic load, and to optimize the design of micro implant's neck. METHODS: An adult skull with all tooth was scanned by spiral CT, and the data were imported into computer for three-dimensional reconstruction with software Mimics 9.0. The three dimensional finite element models of three micro-implant-bone interfaces(initial stability, full osseointegration and fibrous integration) were analyzed by finite element analysis software ABAQUS6.5. The primary stress distributions of different micro-implant-bone conditions were evaluated when 2N force was loaded. Then the diameter less than 1.5 mm of the micro implant's neck was added with 0.2 mm, to compare the stress distribution of the modified micro implant-bone interface with traditional type. RESULTS: The stress mostly concentrated on the neck of micro implant and the full osseointegration interface in all models showed the lowest strain level. Compared with the traditional type, the increasing diameter neck of the micro implant obviously decreased the stress level in all the three conditions. CONCLUSION: The micro-implant-bone interface and the diameter of micro implant's neck both are the important influence factors to the stress distribution of micro implant. PMID- 17718447 TI - [Porous polyvinyl alcohol hydrogel composite prepared and studied initially for biocompatibility]. AB - OBJECTIVE: To investigate the feasibility of porous polyvinyl alcohol hydrogel (PVA-H) composite, for tissue engineering scaffold. METHODS: The approach of emulsifier-foaming, freeze-drying and surfactant-cleaning method was developed to gain three kinds of porous scaffolds: porous polyvinyl alcohol (PVA), porous polyvinyl alcohol/nano-hydroxyapatite (PVA/n-HA) and porous polyvinyl alcohol/chitosan (PVA/Cs). We checked the physical features of the above three kinds of materials and further investigated their biocompatibility by SEM image analysis, mechanics test, MTT and muscle implanting. RESULTS: Three kinds of materials had the similar character of high porosity (80%), but the PVA/n-HA had the smallest mean pore size (154.5 microm) and the PVA had the biggest tensile strength (0.60 Mpa). MTT assay demonstrated three kinds of materials to have no toxicity, furthermore, PVA had better absorbance, compared with cell control group (P < 0.05). After muscle implantation, there were many muscular tissues growing into pores of PVA/Cs at the 4th week, although PVA/Cs had stronger inflammatory reaction. Other two kinds of materials had very small inflammatory reaction and there were many fibrous tissues growing into pores at the 1st, 4th, 12th week. CONCLUSION: The features of materials are changed after adding n-HA or Cs, moreover, porous PVA/Cs seems to have the activity of inducing muscle growth. Porous PVA and its composites may be applied to tissue engineering as a long-term or permanent scaffold due to their good biocompatibility, elasticity and hydrophilicity. PMID- 17718448 TI - [Rapid DNA extraction from archival paraffin-embedded tissue: a modified method available to PCR analysis for diagnostic pathology]. AB - OBJECTIVE: To modify a method for rapid DNA extraction from paraffin-embedded tissue and to evaluate its efficiency and feasibility available to the PCR analysis for the diagnostic pathology. METHODS: Rapid DNA extraction by simply boiling was performed on 52 archival paraffin-embedded tissues including lymphoma and reactive hyperplasia. The traditional phenol-chloroform and DNeasy mini kit methods were also used as controls. The DNA quality was confirmed by PCR amplification of housekeeping gene beta-Globin. The accuracy of target fragment was reconfirmed by sequencing analysis. Based on the clinical pathologic diagnosis to diseases, the IgH and TCRY gene were selected for their gene rearrangements detected. RESULTS: The amplification efficiency of beta-Globin and the detective rate of IgH and TCRY gene rearrangements showed no statistic significance between rapid method and the controls, although an obvious lower DNA concentration extracted by rapid method was showed by spectrophotometer. The sequencing result of PCR product was thoroughly consistent with the DNA sequence of corresponding target gene. The DNA in extract could be stored at -20 degrees C for at least 4 weeks. CONCLUSION: The rapid method of DNA extracted from archival paraffin-embedded tissue can provide enough DNA served as PCR template, and be regarded as a reliable, stable and economical method with prospect in being used to PCR analysis for the diagnostic pathology. PMID- 17718449 TI - [Purification of a novel chitosanase from Metarhizium guizhouense in solid-state fermentation with affinity chromatography]. AB - OBJECTIVES: To find a new source of chitosanase from Metarhizium guizhouense in solid state fermentation through purification techniques with affinity chromatography and molecular sieving. METHODS: Cross-linked chitosan resins adsorbed chitosanase from crude enzyme, which was then eluted with 5% per hundred Cu2+. The elute was dialyzed, concentrated and separated by Superdex75 chromatography. RESULTS: Under the optimal conditions, the chitosanase activity reached a maximum of 83.09 +/- 2.9 U for one gram of dry medium after 120 hours of culture. The chitosanase was purified, with 43.52% enzyme activity maintained. The specific activity of the purified enzyme reached 106.39 U/mg. The chitosanase had a molecular mass of 50.3 x 10(3). CONCLUSION: A new source of chitosanase from Metarhizium guizhouense under solid state fermentation conditions is obtained. Affinity chromatography and molecular sieving can be used to purify chitosanase. PMID- 17718450 TI - [Primary culture and identification of olfactory ensheathing cells from adult rat]. AB - OBJECTIVE: To explore a simple and inexpensive method or procedure for establishing primary culture and purification of olfactory ensheathing cells (OECs) from the adult rat olfactory bulbs. METHODS: The OECs were dissociated from the first two outer layers of the olfactory bulbs of the adult Sprague Dawley rat (2.5 months old), cultured in DMEM/F12 nutrient with 20% foetal calf serum, and purified by the method of combining the different rates of cell attachment with the Arabinosylcytosine (AraC) inhibition of cell. The morphological changes of cultured OECs were observed. On 14th culture day, the OECs in culture were identified by the immunocytochemistry technique to glial fibrillary acidic protein (GFAP) and nerve growth factor receptor p75 (NGFRp75), and the purity of the positive cells was calculated. RESULTS: The cultured OECs presented three main morphological types: multipolar, bipolar and flat cells. For GFAP positive cells, the plasma and processes were stained while the nuclei were not, but for NGFRp75 cells the nuclei were stained more deeply than the plasma and processes. More than 9000 cultured cells were identified to be OECs. CONCLUSION: The high purity OECs can be cultured successfully in vitro by the combined purification method. This method is simple and inexpensive. PMID- 17718451 TI - [Development of safety climate measurement at workplace: validity and reliability assessment]. AB - OBJECTIVE: To develop a measurement of safety climate at workplace and assess its validity and reliability. METHODS: According to the theory of preventive safety culture model, a scale including 7 dimensions of 27 items was developed. 342 workers were selected from among all workers of an artificial board factory and were investigated with the developed scale. Occupational accidents were recorded during the past year. Factor analysis, association validation and inter-item consistency test were applied to assess the scale validity and reliability. RESULTS: After the deletion of 6 items, 21 items composed the safety climate scale, which was loaded on 7 common factors: safety competence and consciousness, safety communication, organizational environment, management support, danger judgment, safety control measure and safety training. The cumulative contribution reached to 70.50%. All item communities (common factor variance) were above 0.6 except one item was 0.595. ANOVA showed that occupational accidents were associated with the safety climate score on total, danger judgment and safety control measure dimension (P < 0.05). There existed significant correlation between the safety climate total score and dimension scores (P < 0.01), the correlation coefficients were 0.700, 0.728, 0.705, 0.703, 0.354, 0.571 and 0.485 respectively. The safety climate scale total Cronbach's alpha coefficient, half split Spearman-Brown coefficient, theta coefficient and omega coefficient indicated that the safety climate scale had good inter-item consistency among items. CONCLUSION: The measurement of safety climate at workplace is developed. It has good reliability and valid. PMID- 17718452 TI - Relative tropospheric photolysis rates of HCHO and HCDO measured at the European Photoreactor Facility. AB - The relative photolysis rates of HCHO and HCDO have been studied in May 2004 at the European Photoreactor Facility (EUPHORE) in Valencia, Spain. The photolytic loss of HCDO was measured relative to HCHO by long path FT-IR and DOAS detection during the course of the experiment. The isotopic composition of the reaction product H(2) was determined by isotope ratio mass spectrometry (IRMS) on air samples taken during the photolysis experiments. The relative photolysis rate obtained by FTIR is j(HCHO)/j(HCDO) = 1.58 +/- 0.03. The ratios of the photolysis rates for the molecular and the radical channels obtained from the IRMS data, in combination with the quantum yield of the molecular channel in the photolysis of HCHO, Phi(HCHO-->H(2)+CO) (JPL Publication 06-2), are j(HCHO-->H(2)+CO/jHCDO- >HD+CO) = 1.82 +/- 0.07 and j(HCHO-->H+HCO/(jHCDO-->H+DCO + jHCDO-->D+HCO)) = 1.10 +/- 0.06. The atmospheric implications of the large isotope effect in the relative rate of photolysis and quantum yield of the formaldehyde isotopologues are discussed in relation to the global hydrogen budget. PMID- 17718453 TI - Steric control of the excited-state intramolecular proton transfer in 3 hydroxyquinolones: steady-state and time-resolved fluorescence study. AB - 3-Hydroxyquinolones (3HQs), similarly to their 3-hydroxychromone analogs, undergo excited state intramolecular proton transfer (ESIPT) resulting in dual emission. In the ground state, 2-phenyl-3HQ derivatives are not flat due to a steric hindrance between the 2-phenyl group and the 3-OH group that participates in the ESIPT reaction. To study the effect of this steric hindrance on the ESIPT reaction, a number of 3HQ derivatives have been synthesized and characterized in different organic solvents by steady-state and time-resolved fluorescence techniques. According to our results, 2-phenyl-3HQ derivatives undergo much faster ESIPT (by nearly 1 order of magnitude) than their 2-methyl-3HQ analogs. Moreover, 1-methyl-2-phenyl-3HQ having a strongly twisted 2-phenyl group undergoes a two- to three-fold slower ESIPT compared to 2-phenyl-3HQ. These results suggest that the flatter conformation of 2-phenyl-3HQ, which allows a close proximity of the 2-phenyl and 3-OH groups, favors a fast ESIPT reaction. The absorption and fluorescence spectra of the 3HQ derivatives additionally confirm that the steric rather than the electronic effect of the 2-phenyl group is responsible for the faster ESIPT reaction. Based on the spectroscopic studies and quantum chemical calculations, we suggest that the 2-phenyl group decreases the rotational freedom of its proximal 3-OH group in the more planar conformation of 2-phenyl-3HQ. As a result, the conformations of 3HQ, where the 3-OH group orients to form an intramolecular H-bond with the 4-carbonyl group, are favored over those with a disrupted intramolecular H-bond. Therefore, the 2-phenyl group sterically favors the intramolecular H-bond and thus accelerates the ESIPT reaction. This conclusion provides a new understanding of the ESIPT process in 3 hydroxyquinolones and related systems and suggests new possibilities for the design of ESIPT based molecular sensors and switchers. PMID- 17718455 TI - Quantum chemical modeling of ethene epoxidation with hydrogen peroxide: the effect of microsolvation with water. AB - Quantum chemical calculations were performed to study the mechanism of ethene epoxidation with hydrogen peroxide. The calculations were carried out at the B3LYP/6-311+G(d,p) level of theory. The applicability of this functional to the problem at hand, including basis set effects, was validated by CCSD(T) and CASSCF based multireference MP2 calculations. A mechanism was determined where hydrogen peroxide becomes polarized in the transition state upon binding to the ethene molecule. The distant hydroxide fragment of the attached hydrogen peroxide molecule becomes partly negatively charged, while the other part of the molecule involves a proton and becomes partly positively charged. In the absence of water an activation energy of 139.7 kJ mol(-1) was determined for the isolated H(2)O(2) + C(2)H(4) system. By microsolvating with water, the impact of a hydrogen-bonded network on the activation energy was addressed. A 43.7 kJ mol(-1) lowering of the activation energy, DeltaE(a), was observed when including up to 4 water molecules in the model. This effect results from the stabilization of the proton and hydroxide fragments in the transition state. The findings are discussed in the context of previous theoretical studies on similar systems. Effects of adding or removing a proton to mimic acidic and alkaline conditions are addressed and the limitations of the model in solvating the excess charge are discussed. PMID- 17718454 TI - Photophysical properties of acene DCDHF fluorophores: long-wavelength single molecule emitters designed for cellular imaging. AB - We report the solvatochromic, viscosity-sensitive, and single-molecule photophysics of the fluorophores DCDHF-N-6 and DCDHF-A-6. These molecules are members of the dicyanomethylenedihydrofuran (DCDHF) class of single-molecule emitters that contain an amine electron donor and a DCDHF acceptor linked by a conjugated unit; DCDHF-N-6 and DCDHF-A-6 have naphthalene- and anthracene conjugated linkers, respectively. These molecules maintain the beneficial photophysics of the phenylene-linked DCDHF (i.e., photostability, emission wavelength dependence on solvent polarity, and quantum yield sensitivity to solvent viscosity), yet offer absorption and emission at longer wavelengths that are more appropriate for cellular imaging. We demonstrate that these new fluorophores are less photolabile in an aqueous environment than several other commonly used dyes (rhodamine 6G, Texas Red, and fluorescein). Finally, we image single copies of the acene DCDHFs diffusing in the plasma membrane of living cells. PMID- 17718456 TI - DFT-based studies on the Jahn-Teller effect in 3d hexacyanometalates with orbitally degenerate ground states. AB - The topology of the ground-state potential energy surface of M(CN)(6) with orbitally degenerate (2)T(2g) (M = Ti(III) (t(2g)(1)), Fe(III) and Mn(II) (both low-spin t(2g)(5))) and (3)T(1g) ground states (M = V(III) (t(2g)(2)), Mn(III) and Cr(II) (both low-spin t(2g)(4))) has been studied with linear and quadratic Jahn-Teller coupling models in the five-dimensional space of the epsilon(g) and tau(2g) octahedral vibrations (Tg[symbol: see text](epsilon(g)+tau(2g)) Jahn Teller coupling problem (T(g) = (2)T(2g), (3)T(1g))). A procedure is proposed to give access to all vibronic coupling parameters from geometry optimization with density functional theory (DFT) and the energies of a restricted number of Slater determinants, derived from electron replacements within the t(2g)(1,5) or t(2g)(2,4) ground-state electronic configurations. The results show that coupling to the tau(2g) bending mode is dominant and leads to a stabilization of D(3d) structures (absolute minima on the ground-state potential energy surface) for all complexes considered, except for [Ti(CN)(6)](3-), where the minimum is of D(4h) symmetry. The Jahn-Teller stabilization energies for the D3d minima are found to increase in the order of increasing CN-M pi back-donation (Ti(III) < V(III) < Mn(III) < Fe(III) < Mn(II) < Cr(II)). With the angular overlap model and bonding parameters derived from angular distortions, which correspond to the stable D(3d) minima, the effect of configuration interaction and spin-orbit coupling on the ground-state potential energy surface is explored. This approach is used to correlate Jahn-Teller distortion parameters with structures from X-ray diffraction data. Jahn-Teller coupling to trigonal modes is also used to reinterpret the anisotropy of magnetic susceptibilities and g tensors of [Fe(CN)(6)](3-), and the (3)T(1g) ground-state splitting of [Mn(CN)(6)](3-), deduced from near-IR spectra. The implications of the pseudo Jahn-Teller coupling due to t(2g)-e(g) orbital mixing via the trigonal modes (tau(2g)) and the effect of the dynamic Jahn-Teller coupling on the magnetic susceptibilities and g tensors of [Fe(CN)(6)](3-) are also addressed. PMID- 17718457 TI - Size effects and breakdown of the power-law blinking statistics of CdSe nanorods. AB - In this study, the dependence of sample size and light intensity on the fluorescence intermittency of semiconductor nanorods is investigated. We present a model with diffusion-controlled electron-transfer reactions involving anomalous diffusion in energy configuration space. This model leads to a general formula t( m) exp[-(Gammat)n] for the temporal behavior of blinking statistics, where m and n are related to the time dependence of the spectral diffusion. We reanalyze the experimental data of the long-time bending tail of CdSe nanorods and elucidate the size effects of the bending rates and activation energy. PMID- 17718458 TI - Energy gap law of electron transfer in nonpolar solvents. AB - We investigate the energy gap law of electron transfer in nonpolar solvents for charge separation and charge recombination reactions. In polar solvents, the reaction coordinate is given in terms of the electrostatic potentials from solvent permanent dipoles at solutes. In nonpolar solvents, the energy fluctuation due to solvent polarization is absent, but the energy of the ion pair state changes significantly with the distance between the ions as a result of the unscreened strong Coulomb potential. The electron transfer occurs when the final state energy coincides with the initial state energy. For charge separation reactions, the initial state is a neutral pair state, and its energy changes little with the distance between the reactants, whereas the final state is an ion pair state and its energy changes significantly with the mutual distance; for charge recombination reactions, vice versa. We show that the energy gap law of electron-transfer rates in nonpolar solvents significantly depends on the type of electron transfer. PMID- 17718459 TI - Theoretical design of an aromatic hydrocarbon rotor driven by a circularly polarized electric field. AB - An aromatic hydrocarbon rotor without functional groups is theoretically designed. Such a molecular rotor is free from long-range electrostatic interactions. Induced dipole interactions are the rotor-driving forces under a nonresonant excitation condition. As an example, a molecular rotor with a condensed aromatic ring, a pentacene moiety mounted on a phenyl-acetylene axle that is driven by a circularly polarized electric field is considered. Results of simulations of the quantum dynamics of a rotor that take into account short-range rotor-bath interactions are presented by numerically solving the density matrix equations of the rotational motions. PMID- 17718461 TI - Comparative performance of exchange and correlation density functionals in determining intermolecular interaction potentials of the methane dimer. AB - We have calculated the interaction potentials of the methane dimer for the minimum-energy D(3d) conformation using the density functional theory (DFT) with 90 density functionals chosen from the combinations of nine exchange and 10 correlation functionals. Several hybrid functionals are also considered. While the performance of an exchange functional is related to the large reduced density gradient of the exchange enhancement factor, the correlation energy is determined by the low-density behavior of a correlation enhancement factor. Our calculations demonstrate that the correlation counterpart plays an equally important role as the exchange functional in determining the van der Waals interactions of the methane dimer. These observations can be utilized to better understand the seemingly unsystematic DFT interaction potentials for weakly bound systems. PMID- 17718460 TI - Photolysis of 4-oxo-2-pentenal in the 190-460 nm region. AB - We have studied the gas-phase photolysis of 4-oxo-2-pentenal by laser photolysis combined with cavity ring-down spectroscopy. Absorption cross sections of cis- and trans-4-oxo-2-pentenal have been measured in the 190-460 nm region. The product channel following 193, 248, 308, and 351 nm photolysis of 4-oxo-2 pentenal was investigated. The HCO radical is a photodissociation product of 4 oxo-2-pentenal only at 193 and 248 nm. The HCO quantum yields from the photolysis of a mainly trans-4-oxo-2-pentenal sample are 0.13 +/- 0.02 and 0.014 +/- 0.003 at 193 and 248 nm, where errors quoted (1sigma) represent experimental scatter. The HCO quantum yields from the photolysis of a mainly cis-4-oxo-2-pentenal sample are 0.078 +/- 0.012 and 0.018 +/- 0.007 at 193 and 248 nm, where errors quoted (1sigma) represent experimental scatter. The end-products from 193, 248, 308, and 351 nm photolysis of 4-oxo-2-pentenal (the 4-oxo-2-pentenal sample had a tran/cis ratio of 1.062:1) have been determined by FTIR. Ethane, methyl vinyl ketone, and 5-methyl-3H-furan-2-one have been observed, suggesting the occurrence of 4-oxo-2-pentenal photolysis pathways such as CH(3)COCH=CHCHO + hnu --> CH(3) + COCH=CHCHO, CH(3)COCH=CHCHO + hnu --> CH(3)COCH=CH(2) + CO, and CH(3)COCH=CHCHO + hnu --> 5-methyl-3H-furan-2-one. The estimated yields for the CH(3) + COCH=CHCHO channel are about 25%, 33%, 31%, and 23% at 193, 248, 308, and 351 nm, respectively. The absolute uncertainties in the determination of CH(3) + COCH=CHCHO yields are within 55% at 193 nm, and 65% at 248, 308, and 351 nm. The estimated yields for the CH(3)COCH=CH(2) + CO channel are about 25%, 23%, 40%, and 33% at 193, 248, 308, and 351 nm, respectively. The absolute uncertainties in the determination of CH(3)COCH=CH(2) yields are within 80% at 193 and 248 nm and 65% at 308 and 351 nm. The estimated yields for the 5-methyl-3H-furan-2-one channel are about 1.2%, 2.1%, 5.3%, and 5.5% at 193, 248, 308, and 351 nm, respectively. The absolute uncertainties in the determination of 5-methyl-3H furan-2-one yields are about 23%, 86%, 40%, and 46% at 193, 248, 308, and 351 nm. Results from our investigation indicate that photolysis is a dominant removal pathway for 4-oxo-2-pentenal degradation in the atmosphere. PMID- 17718462 TI - HNO3 forming channel of the HO2 + NO reaction as a function of pressure and temperature in the ranges of 72-600 Torr and 223-323 K. AB - A high-pressure turbulent flow reactor coupled with a chemical ionization mass spectrometer was used to determine the branching ratio of the HO(2) + NO reaction: HO(2) + NO --> OH + NO(2) (1a), HO(2) + NO --> HNO(3) (1b). The branching ratio, beta = k(1b)/k(1a), was derived from the measurements of "chemically amplified" concentrations of the NO(2) and HNO(3) products in the presence of O(2) and CO. The pressure and temperature dependence of beta was determined in the pressure range of 72-600 Torr of N(2) carrier gas between 323 and 223 K. At each pressure, the branching ratio was found to increase with the decrease of temperature, the increase becoming less pronounced with the increase of pressure. In the 298-223 K range, the data could be fitted by the expression: beta(T,P) = (530 +/- 10)/T(K) + (6.4 +/- 1.3) x 10(-4)P(Torr) - (1.73 +/- 0.07), giving beta approximately 0.5% near the Earth's surface (298 K, 760 Torr) and 0.8% in the tropopause region (220 K, 200 Torr). The atmospheric implication of these results is briefly discussed. PMID- 17718463 TI - Characterizing multiphase organic/inorganic/aqueous aerosol droplets. AB - The partitioning of an immiscible and volatile organic component between the gas and aqueous condensed phases of an aerosol is investigated using optical tweezers. Specifically, the phase segregation of immiscible decane and aqueous components within a single liquid aerosol droplet is characterized by brightfield microscopy and by spontaneous and stimulated Raman scattering. The internally mixed phases are observed to adopt equilibrium geometries that are consistent with predictions based on surface energies and interfacial tensions and the volume fractions of the two immiscible phases. In the limit of low organic volume fraction, the stimulated Raman scattering signature is consistent with the formation of a thin film or lens of the organic component on the surface of an aqueous droplet. By comparing the nonlinear spectroscopic signature with Mie scattering predictions for a core-shell structure, the thickness of the organic layer can be estimated with nanometer accuracy. Time-dependent measurements allow the evolving partitioning of the volatile organic component between the condensed and vapor phases to be investigated. PMID- 17718464 TI - Formation and characterization of the oxygen-rich hafnium dioxygen complexes: OHf(eta2-O2)(eta2-O3), Hf(eta2-O2)3, and Hf(eta2-O2)4. AB - Hafnium atom oxidation by dioxygen molecules has been investigated using matrix isolation infrared absorption spectroscopy. The ground-state hafnium atom inserts into dioxygen to form primarily the previously characterized HfO(2) molecule in solid argon. Annealing allows the dioxygen molecules to diffuse and react with HfO(2) to form OHf(eta(2)-O(2))(eta(2)-O(3)), which is characterized as a side-on bonded oxo-superoxo hafnium ozonide complex. Under visible light (532 nm) irradiation, the OHf(eta(2)-O(2))(eta(2)-O(3)) complex either photochemically rearranges to a more stable Hf(eta(2)-O(2))(3) isomer, a side-on bonded di superoxo hafnium peroxide complex, or reacts with dioxygen to form an unprecedented homoleptic tetra-superoxo hafnium complex: Hf(eta(2)-O(2))(4). The Hf(eta(2)-O(2))(4) complex is determined to possess a D(2d) geometry with a tetrahedral arrangement of four side-on bonded O(2) ligands around the hafnium atom, which thus presents an 8-fold coordination. These oxygen-rich complexes are photoreversible; that is, formation of Hf(eta(2)-O(2))(3) and Hf(eta(2)-O(2))(4) is accompanied by demise of OHf(eta(2)-O(2))(eta(2)-O(3)) under visible (532 nm) light irradiation and vice versa with UV (266 nm) light irradiation. PMID- 17718465 TI - Unveiling a complex phase transition in monolayers of a phospholipid from the annular region of transmembrane proteins. AB - The lateral packing properties of phospholipids that surround transmembrane proteins are fundamental in the biological activity of these proteins. In this work, Langmuir monolayers of one such lipid, 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphoethanolamine (POPE), are studied with a combination of pressure-area isotherm analysis, Brewster angle microscopy, and atomic force microscopy of extracted films. The analysis reveals a sequence of phase transitions LE-LC-LC' occurring in a narrow packing range. The lateral pressures and area densities of these phases provided meanings for the packing requirements in the annular lipid region of typical transmembrane proteins. PMID- 17718466 TI - Intramolecular singlet and triplet excimers of triply bridged [3.3.N](3,6,9)carbazolophanes. AB - Intermoiety electronic interactions in the singlet and triplet excimer states of triply bridged [3.3.n](3,6,9)carbazolophanes ([3.3.n]Cz, n=3-6) were studied by emission and transient absorption measurements. In these [3.3.n]Cz molecules, the dihedral angle and the separation distance r between fully overlapped two carbazole rings change systematically from nearly parallel (n=3, r=3.35 A) to oblique (n=6, r=4.03 A). In rigid glass at 77 K, [3.3.n]Cz (n=3, 4) (r<4 A) exhibited red-shifted and structureless excimer fluorescence and phosphorescence while [3.3.n]Cz (n=5, 6) (r>4 A) exhibited monomer-like vibrational fluorescence and phosphorescence. In solution at 130 K, all [3.3.n]Cz molecules exhibited an excimeric fluorescence band while [3.3.5]Cz still exhibited monomer-like phosphorescence. Transient absorption spectra measured at 294 K exhibited local excitation and charge-transfer bands for all [3.3.n]Cz molecules in the excited singlet and triplet states, suggesting that not only singlet but also triplet excimers of carbazole are formed at room temperature. Furthermore, the singlet triplet energy gap decreased with the decrease in n, suggesting that electrons are effectively delocalized over the two carbazole moieties. These findings showed that both singlet and triplet excimers of carbazole are formed with a separation distance shorter than about 4 A and are most stable in the parallel sandwich structure and that the configurational mixing between exciton resonance and charge resonance states plays an essential role in the formation of singlet and triplet excimers of carbazole. PMID- 17718467 TI - Entrapped energy in chiral solutions: quantification and information capacity. AB - A homogeneous solution of a chiral substance stores a residual chemical potential, related to its overall anisotropy. Therefore, by mixing solutions of opposite enantiomers, heat release may take place, corresponding to the mutual anisotropy annulment. In the following study we present proofs for this fundamental, yet unexplored, prediction by measuring the heat released upon mixing of aqueous solutions of D-proline with L-proline, as well as D-alanine with L-alanine, using isothermal titration calorimetry. Heat release in the range of 0.6-6 cal/mol was detected in these intermolecular racemizations at 30 degrees C. Its magnitude varied linearly with the apparent optical rotation, which complied with the possibility that the hydration envelope coating the chiral molecule is of a long-range condensed and asymmetrical configuration that can expand by integration with adjacent hydration envelopes. The ordered water in such hydration layers constitutes regions of "negative entropy", a basic medium for information storage. On the basis of our findings, a fundamental expression which combines entropy, information capacity, and thermal energy is proposed. PMID- 17718468 TI - Short-range structure of a GM3 ganglioside membrane: comparison between experimental WAXS and computer simulation results. AB - The local structure of a GM3 ganglioside bilayer, whose wide-angle X-ray spectrum is reconstructed from molecular dynamics simulations, is found to compare quantitatively well with the experimental one. By separating inter- and intramolecular contributions, correlations between distinct head groups are shown to contribute in a substantial way to the total scattering intensity. This finding supports the hypothesis of a strong local head group order as recently formulated on the basis of calorimetry and X-ray experimental data. PMID- 17718469 TI - Fluorescence properties and photophysics of the sulfoindocyanine Cy3 linked covalently to DNA. AB - The sulfoindocyanine Cy3 is one of the most commonly used fluorescent dyes in the investigation of the structure and dynamics of nucleic acids by means of fluorescence methods. In this work, we report the fluorescence and photophysical properties of Cy3 attached covalently to single-stranded and duplex DNA. Steady state and time-resolved fluorescence techniques were used to determine fluorescence quantum yields, emission lifetimes, and fluorescence anisotropy decays. The existence of a transient photoisomer was investigated by means of transient absorption techniques. The fluorescence quantum yield of Cy3 is highest when attached to the 5' terminus of single-stranded DNA (Cy3-5' ssDNA), and decreases by a factor of 2.4 when the complementary strand is annealed to form duplex DNA (Cy3-5' dsDNA). Substantial differences were also observed between the 5'-modified strands and strands modified through an internal amino-modified deoxy uridine. The fluorescence decay of Cy3 became multiexponential upon conjugation to DNA. The longest lifetime was observed for Cy3-5' ssDNA, where about 50% of the decay is dominated by a 2.0-ns lifetime. This value is more than 10 times larger than the fluorescence lifetime of the free dye in solution. These observations are interpreted in terms of a model where the molecule undergoes a trans-cis isomerization reaction from the first excited state. We observed that the activation energy for photoisomerization depends strongly on the microenvironment in which the dye is located. The unusually high activation energy measured for Cy3-5' ssDNA is an indication of dye-ssDNA interactions. In fact, the time-resolved fluorescence anisotropy decay of this sample is dominated by a 2.5-ns rotational correlation time, which evidences the lack of rotational freedom of the dye around the linker that separates it from the terminal 5' phosphate. The remarkable variations in the photophysical properties of Cy3-DNA constructs demonstrate that caution should be used when Cy3 is used in studies employing DNA conjugates. PMID- 17718470 TI - Effect of copolymer architecture on the micellization and gelation of aqueous solutions of copolymers of ethylene oxide and styrene oxide. AB - The micellar properties and solubilization capacity of poorly water soluble drugs of several micellar and gel solutions of diblock and triblock copolymers of styrene oxide/ethylene oxide have been measured and compared with block copolymers of butylene oxide/ethylene oxide, showing that the solubilization capacity of the styrene oxide block is approximately four times that of a butylenes oxide block for dilute solutions. To continue establishing the correlation between micellar characteristics and solubilization capacity, we have found it interesting to compare the micellar and gelation properties of the diblock and triblock copolymers PSO10PEO135 and PEO69PSO8PEO69 (subindexes are the number-average block lengths), with different architecture but similar average block lengths. Surface tension measurements allowed the determination of the critical micelle concentrations at several temperatures and, so, to calculate standard enthalpies of micellization. Static and dynamic light scattering data permitted us to determine micellar parameters and to obtain qualitatively the extent of hydration of the copolymer micelle. A tube inversion method was used to define the mobile-immobile (soft-hard gel) phase boundary. To refine the phase diagram and observe the existence of additional phases, rheological measurements were done. The results are in good agreement with previous values published for PSOnPEOm and PEOmPSOnPEOm copolymers. PMID- 17718471 TI - Molecular dynamic simulations of eicosanoic acid and 18-methyleicosanoic acid langmuir monolayers. AB - The conformational and dynamical properties of Langmuir monolayers of 18 methyleicosanoic acid (18-MEA) and the parent material, eicosanoic acid (EA), are compared using molecular dynamics simulations. The effects on various properties, including film thickness, tilt angle, and order parameter, of the methyl group at the 18 position in 18-MEA were investigated as a function of film-packing density. NVT simulations were run as a function of decreasing areal-packing density similar to experimental Langmuir-Blodgett film compressions and expansions. We find that the order parameters and film thickness for 18-MEA monolayers were markedly different from those of EA. The order parameters for methylene groups for both 18-MEA and EA are greater in the middle region of the chain than at the ends in high-density films. This trend becomes reversed in lower density films. Significantly, our simulations show that the order parameters for methylene groups near the CH3 and carboxyl termini in 18-MEA are comparatively independent of film density in contrast with those of EA. Our findings show that the presence of the methyl group at the 18-position in 18-MEA induces unique intermolecular structural correlations compared to EA. PMID- 17718472 TI - Radical ion states of platinum acetylide oligomers. AB - The ion radicals of two series of platinum acetylide oligomers have been subjected to study by electrochemical and pulse radiolysis/transient absorption methods. One series of oligomers, Ptn, has the general structure Ph-C[triple bond]C-[Pt(PBu3)2-C[triple bond]C-(1,4-Ph)-C[triple bond]C-]n-Pt(PBu3)2-C[triple bond]C-Ph (where x=0-4, Ph=phenyl and 1,4-Ph=1,4-phenylene). The second series of oligomers, Pt4Tn, contain a thiophene oligomer core, -C[triple bond]C-(2,5-Th)n C[triple bond]C- (where n=1-3 and 2,5-Th=2,5-thienylene), capped on both ends with -Pt(PBu3)2-C[triple bond]C-(1,4-Ph)-C[triple bond]C-Pt(PBu3)2-C[triple bond]C-Ph segments. Electrochemical studies reveal that all of the oligomers feature reversible or quasi-reversible one-electron oxidation at potentials less than 1 V versus SCE. These oxidations are assigned to the formation of radical cations on the platinum acetylide chains. For the longer oligomers multiple, reversible one-electron waves are observed at potentials less than 1 V, indicating that multiple positive polarons can be produced on the oligomers. Pulse-radiolysis/transient absorption spectroscopy has been used to study the spectra and dynamics of the cation and anion radical states of the oligomers in dichloroethane and tetrahydrofuran solutions, respectively. All of the ion radicals exhibit two allowed absorption bands: one in the visible region and the second in the near-infrared region. The ion radical spectra shift with oligomer length, suggesting that the polarons are delocalized to some extent on the platinum acetylide chains. Analysis of the electrochemical and pulse radiolysis data combined with the density functional theory calculations on model ion radicals provides insight into the electronic structure of the positive and negative ion radical states of the oligomers. A key conclusion of the work is that the polaron states are concentrated on relatively short oligomer segments. PMID- 17718473 TI - Anomalous transition in aqueous solutions of a thermoresponsive amphiphilic diblock copolymer. AB - The influence of shear flow on aggregation and disaggregation in aqueous solutions of the thermoresponsive methoxy-poly(ethylene glycol)-block-poly(N isopropylacrylamide) (MPEG53-b-PNIPAAM113) copolymer that exhibits a lower critical solution temperature was investigated with the aid of turbidity, shear viscosity, and rheo small angle light scattering (rheo-SALS) methods. The turbidity results at quiescent conditions revealed a novel transition peak in the turbidity curve at intermediate temperatures, which reflects the delicate interplay between temperature-induced aggregation and shrinking of the species. A similar anomalous transition peak (located at the same temperature) was observed in the steady shear viscosity measurements at intermediate temperatures, and the amplitude of the peak was reduced with increasing shear rate as a consequence of breakup of interaggregate chains. At low temperatures (low sticking probability), enhanced shear rate generated interpolymer aggregates; whereas in the high temperature domain (high sticking probability) association structures were broken up as the shear rate was increased. The rheo-SALS experiments disclosed growth of aggregates at low temperatures and destruction of association complexes at high temperatures. An increase of the cloud point temperature with rising shear rate is reported, which is interpreted as being a disruption of clusters under the influence of shear stresses. PMID- 17718474 TI - Characterizing the structural properties of N,N-dimethylformamide-based ionic liquid: density-functional study. AB - Amide-based ionic liquids are receiving great enthusiasm recently. In this work, the structures of a kind of N,N-dimethylformamide-based (DMF-based) ionic liquid are investigated theoretically by means of density-functional theory methods. Enol and keto forms of the cation with anions are optimized. The enol form of the DMFH+ cation can form three stable configurations of ion pairs with the anion, while the cation of the keto form is unstable and the proton transfer occurs to form three kinds of neutral molecule pairs. Moreover, the neutral pairs are more stable than the ion pairs, and the ion pairs tend to tautomerize to neutral pairs without barriers. It is suggested that the transformation from the ion pairs to neutral pairs may be the first step for decomposition of DMF-based ionic liquids. PMID- 17718475 TI - Shock wave-induced phase transition in RDX single crystals. AB - The real-time, molecular-level response of oriented single crystals of hexahydro 1,3,5-trinitro-s-triazine (RDX) to shock compression was examined using Raman spectroscopy. Single crystals of [111], [210], or [100] orientation were shocked under stepwise loading to peak stresses from 3.0 to 5.5 GPa. Two types of measurements were performed: (i) high-resolution Raman spectroscopy to probe the material at peak stress and (ii) time-resolved Raman spectroscopy to monitor the evolution of molecular changes as the shock wave reverberated through the material. The frequency shift of the CH stretching modes under shock loading appeared to be similar for all three crystal orientations below 3.5 GPa. Significant spectral changes were observed in crystals shocked above 4.5 GPa. These changes were similar to those observed in static pressure measurements, indicating the occurrence of the alpha-gamma phase transition in shocked RDX crystals. No apparent orientation dependence in the molecular response of RDX to shock compression up to 5.5 GPa was observed. The phase transition had an incubation time of approximately 100 ns when RDX was shocked to 5.5 GPa peak stress. The observation of the alpha-gamma phase transition under shock wave loading is briefly discussed in connection with the onset of chemical decomposition in shocked RDX. PMID- 17718476 TI - In search of the Bailar and Ray-Dutt twist mechanisms that racemize chiral trischelates: a computational study of Sc(III), Ti(IV), Co(III), Zn(II), Ga(III), and Ge(IV) complexes of a ligand analogue of acetylacetonate. AB - Two nondissociative processes, a Bailar twist that proceeds through a transition state of D3h symmetry and a Ray-Dutt twist mechanism that proceeds through a transition state of C(2v) symmetry, as well as dissociative/associative processes are potential mechanisms by which the enantiomeric forms of chiral metal trischelates can be interconverted. We have applied density functional theory to locate the stationary points for metal trischelates of a beta-diketonate ligand analogue that interconvert Delta and Lambda forms via one or both of these nondissociative pathways. Although many two-dimensional static representations of the Bailar and Ray-Dutt twist mechanisms can be found in the chemical literature (of the type shown in Figure 1), in this communication, we present our results in the form of interactive three-dimensional animations as a means of enhancing the scientific perception of these fluxional processes. PMID- 17718477 TI - Tuning intermolecular magnetic exchange interactions in the solids C(x)F(2)(x)(CNSSS)(2)(AsF(6))(2): structural, EPR, and magnetic characterization of dimeric (x = 2, 4) diradicals. AB - A series of diradical containing salts CxF2x(CNSSS)2(**2+0(AsF6-)2 {x = 2, 1[AsF6]2; x = 3, 3[AsF6]2; x = 4, 2[AsF6]2} have been prepared. 1[AsF6]2 and 2[AsF6]2 were fully characterized by X-ray, variable-temperature magnetic susceptibility, and solid-state EPR measurements, further allowing us to extend the number of examples of the family of rare 7pi RCNSSS(*+) radical cations. 1[AsF6]2: a = 6.5314(7) A, b = 7.5658(9) A, c = 9.6048(11) A, alpha = 100.962(2) degrees , beta = 96.885(2) degrees , gamma = 107.436(2) degrees , triclinic, space group P, Z = 1, T = 173 K. 2[AsF6]2: a = 10.6398(16) A, b = 7.9680(11) A, c = 12.7468(19) A, beta = 99.758(2) degrees , monoclinic, space group P21/c, Z = 2, T = 173 K. In the solid-state, CxF2x(CNSSS)2(**2+) (x = 2, 4) formed one dimensional polymeric chains of dications containing discrete centrosymmetric radical pairs in which radicals were linked by four centered two-electron pi*-pi* bonds [12+, d(S...S) = 3.455(1) A; 22+, d(S...S) = 3.306(2) A]. The exchange interactions in these bonds were determined to be -500 +/- 30 and -900 +/- 90 cm 1, by variable temperature magnetic susceptibility measurements, respectively, providing rare experimental data on the singlet-triplet gaps in the field of thiazyl radicals. For 2[AsF6]2, the thermally excited triplet state was unambiguously characterized by EPR techniques [/D/ = 0.0254(8) cm(-1), /E/ = 0.0013(8) cm(-1)]. These experimental data implied a weakly associated nature of the radical moieties contained in the solids 1[AsF6]2 and 2[AsF6]2. Computational analysis of the dimerization process is presented, and we show that the 2c 4 electron pi*-pi* bonds in 1[AsF6]2 and 2[AsF6]2 have ca. 50% and 40% diradical character, respectively. In contrast, 3[AsF6]2.SO2, containing diradical C3F6(CNSSS)2(**2+) with an odd number of CF2 spacers, showed magnetic behavior that was consistent with the presence of monomeric radical centers in the solid state. PMID- 17718478 TI - Crystallographic and vibrational spectroscopic studies of octakis(DMSO)lanthanoid(III) iodides. AB - The octakis(DMSO) (DMSO = dimethylsulfoxide) neodymium(III), samarium(III), gadolinium(III), dysprosium(III), erbium(III), and lutetium(III) iodides crystallize in the monoclinic space group P21/n (No. 14) with Z = 4, while the octakis(DMSO) iodides of the larger lanthanum(III), cerium(III), and praseodymium(III) ions crystallize in the orthorhombic space group Pbca (No. 61), Z = 8. In all [Ln(OS(Me2)8]I3 compounds the lanthanoid(III) ions coordinate eight DMSO oxygen atoms in a distorted square antiprism. Up to three of the DMSO ligands were found to be disordered and were described by two alternative configurations related by a twist around the metal-oxygen (Ln-O) bond. To resolve the atomic positions and achieve reliable Ln-O bond distances, complete semirigid DMSO molecules with restrained geometry and partial occupancy were refined for the alternative sites. This disorder model was also applied on previously collected data for the monoclinic octakis(DMSO)yttrium(III) iodide. At ambient temperature, the eight Ln-O bond distances are distributed over a range of about 0.1 A. The average value increases from Ln-O 2.30, 2.34, 2.34, 2.36, 2.38, 2.40 to 2.43 A (Ln = Lu, Er, Y, Dy, Gd, Sm, and Nd) for the monoclinic [Ln(OSMe2)8]I3 structures, and from 2.44, 2.47 to 2.49 A (Ln = Pr, Ce, and La) for the orthorhombic structures, respectively. The average of the La-O and Nd-O bond distances remained unchanged at 100 K, 2.49 and 2.43 A, respectively. Despite longer bond distances and larger Ln-O-S angles, the cell volumes are smaller for the orthorhombic structures (Ln = Pr, Ce, and La) than for the monoclinic structure with Ln = Nd, showing a more efficient packing arrangement. Raman and IR absorption spectra for the [Ln(OS(CH3)2)8]I3 (Ln = La, Ce, Pr, Nd, Gd, Tb, Dy, Er, Lu, and Y) compounds, also deuterated for La and Y, have been recorded and analyzed by means of normal coordinate methods. The force constants for the Ln-O and S-O stretching modes in the complexes increase with decreasing Ln-O bond distance and show increasing polarization of the bonds for the smaller and heavier lanthanoid(III) ions. PMID- 17718479 TI - X-ray absorption fine structure spectroscopic studies of Octakis(DMSO)lanthanoid(III) complexes in solution and in the solid iodides. AB - Octakis(DMSO)lanthanoid(III) iodides (DMSO = dimethylsulfoxide), [Ln(OS(CH3)2)8]I3, of most lanthanoid(III) ions in the series from La to Lu have been studied in the solid state and in DMSO solution by extended X-ray absorption fine structure (EXAFS) spectroscopy. L3-edge and also some K-edge spectra were recorded, which provided mean Ln-O bond distances for the octakis(DMSO)lanthanoid(III) complexes. The agreement with the average of the Ln O bond distances obtained in a separate study by X-ray crystallography was quite satisfactory. The crystalline octakis(DMSO)lanthanoid(III) iodide salts have a fairly broad distribution of Ln-O bond distances, ca. 0.1 A, with a few disordered DMSO ligands. Their EXAFS spectra are in excellent agreement with those obtained for the solvated lanthanoid(III) ions in DMSO solution, both of which show slightly asymmetric distributions of the Ln-O bond distances. Hence, all lanthanoid(III) ions are present as octakis(DMSO)lanthanoid(III) complexes in DMSO solution, with the mean Ln-O distances centered at 2.50 (La), 2.45 (Pr), 2.43 (Nd), 2.41 (Sm), 2.40 (Eu), 2.39 (Gd), 2.37 (Tb), 2.36 (Dy), 2.34 (Ho), 2.33 (Er), 2.31 (Tm), and 2.29 A (Lu). This decrease in the Ln-O bond distances is larger than expected from the previously established ionic radii for octa coordination. This indicates increasing polarization of the LnIII-O(DMSO) bonds with increasing atomic number. However, the S(1s) electron transition energies in the sulfur K-edge X-ray absorption near-edge structure (XANES) spectra, probing the unoccupied molecular orbitals of lowest energy of the DMSO ligands for the [Ln(OS(CH3)2)8](3+) complexes, change only insignificantly from Ln = La to Lu. This indicates that there is no appreciable change in the sigma-contribution to the S-O bond, probably due to a corresponding increase in the contribution from the sulfur lone pair to the bonding. PMID- 17718480 TI - Preparation of ammonia borane in high yield and purity, methanolysis, and regeneration. AB - Ammonia borane (AB) is emerging as a promising solid hydrogen carrier, particularly for power generation in portable devices that employ proton-exchange membrane fuel cells. A preparative-scale synthesis of AB from sodium borohydride and ammonium salts in high yields (> or =95%) and very high purity (> or =98%) has been described. The first systematic study of a transitional metal-catalyzed alcoholysis of AB, comparison of the methanolysis to the hydrolysis of AB, and regeneration of AB from ammonium tetramethoxyborate also has been described. PMID- 17718481 TI - Synthesis, structure, and upconversion studies on organically templated uranium phosphites. AB - Three new amine templated uranium phosphites, [C2N2H10][U2IVF6(HPO3)2], 1, [C4N2H12][U2IVF6(HPO3)2], 2, and [C4N2H12][(UVIO2)2F2(HPO3)2], 3, have been synthesized by hydrothermal methods. All of the compounds are built up from a connectivity between U(O/F)x (x = 7, 8) and HPO3 polyhedral units. The observation of a well-established secondary building unit, SBU-4, in 1 and 2 is noteworthy. In 1, the SBU-4 units are connected to form U-F-U chains, which are linked by U-O-P chains, forming the layered structure. In 2, the SBU-4 units are edge-shared and also interconnected forming the 3D structure. In 3, the connectivity between the building units forms a layer, the topology of which is similar to the mineral, johannite. To the best of our knowledge, this is the first observation of a well-known secondary building unit (SBU-4) in actinide framework compounds. Optical studies on 1 and 2, containing U(4+) species, indicate an intense blue emission through an upconversion process, and the magnetic susceptibility studies show antiferromagnetic behavior. PMID- 17718482 TI - Template-free fabrication of hexagonal ZnO microprism with an interior space. AB - Well-faceted hexagonal ZnO microprisms with regular interior space have been successfully prepared by a template-free hydrothermal synthetic route. The morphologies of the products depend on the experimental conditions such as the solvent, the concentration of ammonia aqueous solution, and the reaction temperature. Through manipulation of the aging time, the as-prepared ZnO can be controlled as a monodispersed hexagonal twinning solid or as hollow microprisms. Moreover, the evolution process of the hollow ZnO nanoarchitecture after reaction for 2, 6, 12, and 24 h has been investigated by field emission scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM). A possible growth mechanism has also been proposed and discussed. Furthermore, the photoluminescence (PL) measurement exhibits the unique emitting characteristic of hollow ZnO nanostructures. PMID- 17718483 TI - Self-optimizing charge-transfer energy phenomena in metallosupramolecular complexes by dynamic constitutional self-sorting. AB - In this paper we report an extended series of 2,6-(iminoarene)pyridine-type ZnII complexes [(Lii)2Zn]II, which were surveyed for their ability to self-exchange both their ligands and their aromatic arms and to form different homoduplex and heteroduplex complexes in solution. The self-sorting of heteroduplex complexes is likely to be the result of geometric constraints. Whereas the imine-exchange process occurs quantitatively in 1:1 mixtures of [(Lii)2Zn]II complexes, the octahedral coordination process around the metal ion defines spatial-frustrated exchanges that involve the selective formation of heterocomplexes of two, by two different substituents; the bulkiest ones (pyrene in principle) specifically interact with the pseudoterpyridine core, sterically hindering the least bulky ones, which are intermolecularly stacked with similar ligands of neighboring molecules. Such a self-sorting process defined by the specific self-constitution of the ligands exchanging their aromatic substituents is self-optimized by a specific control over their spatial orientation around a metal center within the complex. They ultimately show an improved charge-transfer energy function by virtue of the dynamic amplification of self-optimized heteroduplex architectures. These systems therefore illustrate the convergence of the combinatorial self sorting of the dynamic combinatorial libraries (DCLs) strategy and the constitutional self-optimized function. PMID- 17718484 TI - Novel mixed-metal alkoxide clusters of lanthanide and sodium: synthesis and extremely active catalysts for the polymerization of epsilon-caprolactone and trimethylene carbonate. AB - Novel mixed-metal alkoxide clusters of lanthanide and sodium [Ln2Na8(OCH2CH2NMe2)12(OH)2], which were synthesized in reproducible high yields and structurally characterized, were found to be extremely active catalysts for the ring-opening polymerization of epsilon-caprolactone and trimethylene carbonate. PMID- 17718488 TI - Organic bonding to silicon via a carbonyl group: new insights from atomic-scale images. AB - The ability to covalently attach organic molecules to semiconductor surfaces in a controllable and selective manner is currently receiving much attention due to the potential for creating hybrid silicon-organic molecular-electronic devices. Here we use scanning tunneling microscopy (STM) and density functional theory calculations to study the adsorption of a simple ketone [acetone; (CH(3))(2)CO] to the silicon (001) surface. We show both bias and time-dependent STM images and their agreement with total energy DFT calculations, simulated STM images, and published spectroscopic data. We investigate the stability of the resulting adsorbate structures with respect to temperature and applied STM tip bias and current. We demonstrate the ability to convert from the kinetically favored single-dimer alpha-H cleavage adsorbate structure to thermodynamically favored bridge-bonded adsorbate structures. This can be performed for the entire surface using a thermal anneal or, for individual molecules, using the highly confined electron beam of the STM tip. We propose the use of the carbonyl functional group to tether organic molecules to silicon may lead to increased stability of the adsorbates with respect to current-voltage characterization. This has important implications for the creation of robust single-molecule devices. PMID- 17718487 TI - Ion-induced nucleation in solution: promotion of solute nucleation in charged levitated droplets. AB - We have investigated the nucleation and growth of sodium chloride in both single quiescent charged droplets and charged droplet populations that were levitated in an electrodynamic levitation trap (EDLT). In both cases, the magnitude of a droplet's net excess charge (ions(DNEC)) influenced NaCl nucleation and growth, albeit in different capacities. We have termed the phenomenon ion-induced nucleation in solution. For single quiescent levitated droplets, an increase in ions(DNEC) resulted in a significant promotion of NaCl nucleation, as determined by the number of crystals observed. For levitated droplet populations, a change in NaCl crystal habit, from regular cubic shapes to dome-shaped dendrites, was observed once a surface charge density threshold of -9 x 10(-4) e.nm(-2) was surpassed. Although promotion of NaCl nucleation was observed for droplet population experiments, this can be attributed in part to the increased rate of solvent evaporation observed for levitated droplet populations having a high net charge. Promotion of nucleation was also observed for two organic acids, 2,4,6 trihydroxyacetophenone monohydrate (THAP) and alpha-cyano-4-hydroxycinnamic acid (CHCA). These results are of direct relevance to processes that occur in both soft-ionization techniques for mass spectrometry and to a variety of industrial processes. To this end, we have demonstrated the use of ion-induced nucleation in solution to form ammonium nitrate particles from levitated droplets to be used in in vitro toxicology studies of ambient particle types. PMID- 17718489 TI - Electrochemical, spectroscopic, and DFT study of C60(CF3)n frontier orbitals (n = 2-18): the link between double bonds in pentagons and reduction potentials. AB - The frontier orbitals of 22 isolated and characterized C(60)(CF(3))(n) derivatives, including seven reported here for the first time, have been investigated by electronic spectroscopy (n = 2 [1], 4 [1], 6 [2], 8 [5], 10 [6], 12 [3]; the number of isomers for each composition is shown in square brackets) fluorescence spectroscopy (n = 10 [4]), cyclic voltammetry under air-free conditions (all compounds with n 2 alphahbetah --> 2 alphahfolded + 2 betahfolded --> 2 alphaaunfolded + 2 betaaunfolded + 4 heme (superscripts "h" and "a" refer to holo- and apo-forms, respectively). The results obtained on these freshly prepared samples are significantly different from those of similar experiments previously conducted on metHb obtained commercially as lyophilized powder. Those earlier experiments suggested a highly asymmetric behavior of the two globin chains, involving a heme-deficient dimer (alphahbetaa) as a mechanistically important intermediate on the (dis)assembly pathway. Importantly, heme-deficient dimers are virtually undetectable for the freshly prepared Hb derivatives studied herein at any pH. This apparent discrepancy is attributed to the occurrence of oxidative modifications in the commercial protein. Liquid chromatography and tandem mass spectrometry reveal significant levels of sulfoxide formation for all four methionine residues in commercially obtained metHb. The extent of these modifications for freshly prepared protein is lower by at least a factor of 10. It is concluded that the acid-induced denaturation of Hb follows a highly symmetric mechanism. The occurrence of other mechanisms (possibly involving asymmetric elements) under different solvent conditions cannot be ruled out. PMID- 17718519 TI - Structural and biochemical studies of botulinum neurotoxin serotype C1 light chain protease: implications for dual substrate specificity. AB - Clostridial neurotoxins are the causative agents of the neuroparalytic disease botulism and tetanus. They block neurotransmitter release through specific proteolysis of one of the three soluble N-ethylmaleimide-sensitive-factor attachment protein receptors (SNAREs) SNAP-25, syntaxin, and synaptobrevin, which constitute part of the synaptic vesicle fusion machinery. The catalytic component of the clostridial neurotoxins is their light chain (LC), a Zn2+ endopeptidase. There are seven structurally and functionally related botulinum neurotoxins (BoNTs), termed serotype A to G, and tetanus neurotoxin (TeNT). Each of them exhibits unique specificity for their target SNAREs and peptide bond(s) they cleave. The mechanisms of action for substrate recognition and target cleavage are largely unknown. Here, we report structural and biochemical studies of BoNT/C1-LC, which is unique among BoNTs in that it exhibits dual specificity toward both syntaxin and SNAP-25. A distinct pocket (S1') near the active site likely achieves the correct register for the cleavage site by only allowing Ala as the P1' residue for both SNAP-25 and syntaxin. Mutations of this SNAP-25 residue dramatically reduce enzymatic activity. The remote alpha-exosite that was previously identified in the complex of BoNT/A-LC and SNAP-25 is structurally conserved in BoNT/C1. However, mutagenesis experiments show that the alpha exosite of BoNT/C1 plays a less stringent role in substrate discrimination in comparison to that of BoNT/A, which could account for its dual substrate specificity. PMID- 17718520 TI - Indirect readout of tRNA for aminoacylation. AB - Aminoacylation of tRNA by aminoacyl-tRNA synthetases is the essential reaction that matches protein amino acids with the trinucleotide sequences specified in mRNA. Direct electrostatic interactions made by tRNA synthetases with discriminating functional groups on the tRNA bases have long been known to determine aminoacylation specificity. However, structural and biochemical studies have revealed a second "indirect readout" mechanism that makes an important contribution as well. In indirect readout, the sequence-dependent conformations of tRNA are recognized through protein contacts with the sugar-phosphate backbone and with nonspecific portions of the bases. This mechanism appears to function in single-stranded regions, in canonical A-type duplex segments, and in the complex tertiary core portion of the tRNA. Operation of the indirect mechanism is not exclusive of the direct mechanism, and both are further mediated by induced-fit rearrangements, in which enzyme and tRNA undergo precise conformational changes after formation of an initial encounter complex. The examples of indirect readout in tRNA synthetase complexes extend the concept beyond its traditional application to DNA duplexes and serve as models for the operation of this mechanism in more complex systems such as the ribosome. PMID- 17718521 TI - Multilayered gold-nanoparticle/polyimide composite thin film through layer-by layer assembly. AB - A novel type of composite thin film consisting of gold nanoparticles (AuNPs) and polymide (PI) was fabricated through layer-by-layer (LBL) assembly. To fabricate such films, bare AuNPs and a poly (amic acid) bearing pendant amine groups, namely, amino poly (amic acid) or APAA, were synthesized and assembled in an LBL fashion. Without any organic encapsulation layer on their surface, AuNPs were bound directly to APAA chains at the amine sites; X-ray photoelectron spectroscopy study suggested that the binding was based on a combined effect of metal-ligand coordination and electrostatic interaction, with the former dominating over the latter. An approximately linear growth of the film started from the second layer of AuNP as revealed by the UV-vis spectroscopy, and the degree of particle aggregation was higher in the first AuNP layer than in the subsequent layers due to the differences in the density of binding sites. The resultant assembly was heated to imidize the APAA, thereby creating a robust composite structure. PMID- 17718522 TI - Three-phase separation in nonionic surfactant/hydrophobically modified polymer aqueous mixtures. AB - Three-phase separation for Triton X-114 or Triton X-100 solutions with addition of hydrophobically modified hydroxyethyl cellulose was investigated experimentally. When the surfactant concentration was high enough, the solution slightly above the cloud point could separate into three macroscopic phases: a cloudy phase in between a clear phase and a bluish, translucent phase. The rate of phase separation was very low with the formation of the clear and cloudy phases followed by the emergence of the bluish phase. The volume fraction of the cloudy phase increases linearly with the global polymer concentration, whereas the volume fraction of the bluish phase increases linearly with the global surfactant concentration. Composition analyses found that most of the polymer stayed in the cloudy phase, as opposed to most of the surfactant in the bluish phase. The interesting phase behavior can be explained by an initial associative phase separation followed by a segregative phase separation in the cloudy phase. PMID- 17718523 TI - Specific anion and cation binding to lipid membranes investigated on a solid supported membrane. AB - Ion binding to a lipid membrane is studied by application of a rapid solution exchange on a solid supported membrane. The resulting charge displacement is analyzed in terms of the affinity of the applied ions to the lipid surface. We find that chaotropic anions and kosmotropic cations are attracted to the membrane independent of the membrane composition. In particular, the same behavior is found for lipid headgroups bearing no charge, like monoolein. This general trend is modulated by electrostatic interaction of the ions with the lipid headgroup charge. These results cannot be explained with the current models of specific ion interactions. PMID- 17718525 TI - Facile route to Zn-based II-VI semiconductor spheres, hollow spheres, and core/shell nanocrystals and their optical properties. AB - A convenient chemical conversion method that allows the direct preparation of nanocrystalline ZnE (E = O, S, Se) semiconductor spheres and hollow spheres as well as their core/shell structures is reported. By using monodisperse ZnO nanospheres as a starting reactant and in situ template, ZnS, ZnSe solid and hollow nanospheres, and ZnO/ZnS and ZnO/ZnSe core/shell nanostructures have been obtained through an ultrasound-assisted solution-phase conversion process. The formation mechanism of these nanocrystals is connected with the sonochemical effect of ultrasound irradiation. The photoluminescence and electrogenerated chemiluminescence properties of the as-prepared nanocrystals were investigated. PMID- 17718524 TI - Quantum dot-insect neuropeptide conjugates for fluorescence imaging, transfection, and nucleus targeting of living cells. AB - We identified an insect neuropeptide, namely, allatostatin 1 from Drosophila melanogaster, that transfects living NIH 3T3 and A431 human epidermoid carcinoma cells and transports quantum dots (QDs) inside the cytoplasm and even the nucleus of the cells. QD-conjugated biomolecules are valuable resources for visualizing the structures and functions of biological systems both in vivo and in vitro. Here, we selected allatostatin 1, Ala-Pro-Ser-Gly-Ala-Gln-Arg-Leu-Tyr-Gly-Phe-Gly Leu-NH2, conjugated to streptavidin-coated CdSe-ZnS QDs. This was followed by investigating the transfection of live mammalian cells with QD-allatostatin conjugates, the transport of QDs by allatostatin inside the nucleus, and the proliferation of cells in the presence of allatostatin. Also, on the basis of dose-dependent proliferation of cells in the presence of allatostatin we identified that allatostatin is not cytotoxic when applied at nanomolar levels. Considering the sequence similarity between the receptors of allatostatin in D. melanogaster and somatostatin/galanin in mammalian cells, we expected interactions and localization of allatostatin to somatostatin/galanin receptors on the membranes of 3T3 and A431 cells. However, with QD conjugation we identified that the peptide was delivered inside the cells and localized mainly to the cytoplasm, microtubules, and nucleus. These results indicate that allatostatin is a promising candidate for high-efficiency cell transfection and nucleus-specific cell labeling. Also, the transport property of allatostatin is promising with respect to label/drug/gene delivery and high contrast imaging of live cells and cell organelles. Another promising application of allatostatin is that the transport of QDs inside the nucleus would lift the limit of general photodynamic therapy to nucleus-specific photodynamic therapy, which is expected to be more efficient than photosensitization at the cell membrane or in the cytoplasm as a result of the short lifetime of singlet oxygen. PMID- 17718526 TI - Complexation of polycations to anionic liposomes: composition and structure of the interfacial complexes. AB - Poly(N-ethyl-4-vinylpyridinium bromide) (a polycation with a degree of polymerization of 1100) was adsorbed onto liposomes composed of egg lecithin with a 0.05-0.20 molar fraction (nu) of anionic headgroups provided by cardiolipin (a doubly anionic lipid). According to electrophoretic mobility data, this led to total charge neutralization of the liposomes, whereupon the liposomes adopted a positive charge as additional polymer continued to adsorb. Although the liposomes aggregated at the charge-neutralization point, they disassembled into individual liposomes after becoming positively charged. The degree of polymer adsorption was shown to reach a limit. Thus, by measuring the free polymer content in a liposome suspension, it was possible to determine the polymer concentration at which the liposome surface became saturated with polymer. Beyond this point, an electrostatic/steric barrier at the surface suppressed further adsorption. Dynamic light scattering studies of liposomes with and without adsorbed polymer allowed calculation of the polymer film thickness which ranged from 22 to 35 nm as the molar fraction of cardiolipin (nu) increased from 0.05 to 0.20. The greater the content on the anionic lipid in the bilayer, the thicker the polymer film. The maximum number of polymer molecules adsorbed onto the liposomes was estimated: 1-2 molecules for nu = 0.05; 3 molecules for nu = 0.1; 4- molecules for nu = 0.15; and 6 molecules for nu = 0.2. The polymer appears to lie on the liposome surface, rather than embedding into the bilayer, because addition of NaCl easily dislodges the polymer from the liposome into the bulk water. PMID- 17718528 TI - State of supported rhodium nanoparticles for methane catalytic partial oxidation (CPO): FT-IR studies. AB - The effect of pretreatments as well as of rhodium precursor and of the support over the morphology of Rh nanoparticles were investigated by Fourier transform infrared (FT-IR) spectroscopy of adsorbed CO. Over a Rh/alumina catalyst, both metallic Rh particles, characterized by IR bands in the range 2070-2060 cm-1 and 1820-1850 cm-1, and highly dispersed rhodium species, characterized by symmetric and asymmetric stretching bands of RhI(CO)2 gem-dicarbonyl species, are present. Their relative amount changes following pretreatments with gaseous mixtures, representative of the catalytic partial oxidation (CPO) reaction process. The Rh metal particle fraction decreases with respect to the Rh highly dispersed fraction in the order CO approximately CO/H2 > CH4/H2O, CH4/O2 > CH4 > H2. The metal particle dimensions decrease in the order CH4/O2 > H2 > CH4/H2O > CO > CO/H2. Grafting from a carbonyl rhodium complex also increases the amount and the dimensions of Rh0 particles at the catalyst surface. Increasing the ratio (extended rhodium metal particles/highly dispersed Rh species) allows a shorter conditioning process. The surface reconstruction phenomena going on during catalytic activity are related to this effect. PMID- 17718527 TI - Dynamic interfacial tension at the oil/surfactant-water interface. AB - We have used dynamic interfacial tension measurements to understand the structure of the ordered monolayer at the hexadecane/water interface induced by the presence of surfactant molecules. No abrupt changes in the interfacial tension (gamma) are observed during the expansion and contraction cycle below the interfacial ordering temperature (Ti) as observed for alkanes in contact with air. The lack of an abrupt change in gamma and the magnitude of this change during the expansion process indicate that the ordered phase may not be crystalline. The change in the interfacial tension is due to an increase in contact between water and hexadecane molecules and the disordering of the interfacial ordered layer. At low surfactant concentrations, the recovery of the interfacial tension is slower below Ti, suggesting that there is a critical surfactant concentration necessary to nucleate an ordered phase at the interface. PMID- 17718529 TI - Reducing facet nucleation during algorithmic self-assembly. AB - Algorithmic self-assembly, a generalization of crystal growth, has been proposed as a mechanism for bottom-up fabrication of complex nanostructures and autonomous DNA computation. In principle, growth can be programmed by designing a set of molecular tiles with binding interactions that enforce assembly rules. In practice, however, errors during assembly cause undesired products, drastically reducing yields. Here we provide experimental evidence that assembly can be made more robust to errors by adding redundant tiles that "proofread" assembly. We construct DNA tile sets for two methods, uniform and snaked proofreading. While both tile sets are predicted to reduce errors during growth, the snaked proofreading tile set is also designed to reduce nucleation errors on crystal facets. Using atomic force microscopy to image growth of proofreading tiles on ribbon-like crystals presenting long facets, we show that under the physical conditions we studied the rate of facet nucleation is 4-fold smaller for snaked proofreading tile sets than for uniform proofreading tile sets. PMID- 17718530 TI - Charged fullerenes as high-capacity hydrogen storage media. AB - Using first-principles calculations within density functional theory, we explore systematically the capacity of charged carbon fullerenes Cn (20 10 nm) form only in supersaturated Abeta solutions, implying that they are intermediates in the pathway toward fibril formation. We also show that Zn2+ destabilizes these intermediates by accelerating their aggregation kinetics. The resulting change in the size distribution of the Abeta solution is sufficient to eliminate its toxicity to cultured mammalian neurons. Our results provide an explanation for the existing observations that Zn2+ at a concentration of a few micromolar significantly reduces Abeta toxicity. PMID- 17718544 TI - DFT study of the glutathione peroxidase-like activity of phenylselenol incorporating solvent-assisted proton exchange. AB - Modeling of the glutathione peroxidase-like activity of phenylselenol has been accomplished using density-functional theory and solvent-assisted proton exchange (SAPE). SAPE is a modeling technique intended to mimic solvent participation in proton transfer associated with chemical reaction. Within this method, explicit water molecules incorporated into the gas-phase model allow relay of a proton through the water molecules from the site of protonation in the reactant to that in the product. The activation barriers obtained by SAPE for the three steps of the GPx-like mechanism of PhSeH fall within the limits expected for a catalytic system at physiological temperatures (DeltaG(1)++ = 19.1 kcal/mol; DeltaG(2)++= 6.6 kcal/mol; G(3)++ = 21.7 kcal/mol) and are significantly lower than studies which require direct proton transfer. The size of the SAPE network is also considered for the model of the reduction of the selenenic acid, step 2 of the GPx-like cycle. Use of a four-water network better accommodates the reaction pathway and reduces the activation barrier by 5 kcal/mol over the two-water model. PMID- 17718545 TI - Hydrogen bond formation between 4-(dimethylamino)pyridine and aliphatic alcohols. AB - The photophysics of 4-(dimethylamino)pyridine (DMAP) has been investigated in different solvents in the presence of aliphatic and fluorinated aliphatic alcohols, respectively. For most systems, consecutive two-step hydrogen-bonded complex formation is observed in the presence of alcohols. Equilibrium constants are determined from UV spectroscopic results for the formation of singly and doubly complexed species. The resolved absorption and fluorescence spectra for the singly and doubly complexed DMAP are derived by means of the equilibrium constants. Exceptionally large hydrogen bond basicity values are found for the ground and singlet excited DMAP molecules. In n-hexane, as a consequence of complex formation, the intramolecular charge transfer (ICT) emission becomes dominant over of the locally excited fluorescence; the fluorescence and triplet yields increase considerably with complexation. In polar solvents, both the fluorescence and triplet yields of the complex are much smaller than that of the uncomplexed DMAP. The dipole moments derived for the singly complexed species from the Lippert-Mataga analysis are much larger than those of the uncomplexed molecules. However, for the relaxed ICT excited-state one obtains different dipole moments in apolar and polar solvents. This may be explained by a conformational change of the molecule in the ICT excited state from planar geometry in apolar solvent to the perpendicular structure (characterized with bigger dipole moment) in polar solvent. PMID- 17718546 TI - The structure of LNA:DNA hybrids from molecular dynamics simulations: the effect of locked nucleotides. AB - Locked nucleic acids (LNAs) exhibit a modified sugar fragment that is restrained to the C3'-endo conformation. LNA-containing duplexes are rather stable and have a more rigid structure than DNA duplexes, with a propensity for A-conformation of the double helix. To gain detailed insight into the local structure of LNA modified DNA oligomers (as a foundation for subsequent exploration of the electron-transfer capabilities of such modified duplexes), we carried out molecular dynamics simulations on a set of LNA:DNA 9-mer duplexes and analyzed the resulting structures in terms of base step parameters and the conformations of the sugar residues. The perturbation introduced by a single locked nucleotide was found to be fairly localized, extending mostly to the first neighboring base pairs; such duplexes featured a B-type helix. With increasing degree of LNA modification the structure gradually changed; the duplex with one complete LNA strand assumed a typical A-DNA structure. The relative populations of the sugar conformations agreed very well with NMR data, lending credibility to the validity of the computational protocol. PMID- 17718547 TI - A new control scheme of multilevel quantum system based on effective decomposition by intense CW lasers. AB - We propose a new scheme for quantum dynamics control of multilevel system using intense lasers. To do so, we apply intense CW lasers to create a strongly coupled subsystem with which one can make the complementary space effectively isolated, and we apply the established control schemes to the isolated subsystem. We have also obtained an effective Hamiltonian for the target subsystem with the help of the second-order perturbation theory. Numerical demonstrations on model systems show that the present decomposition scheme effectively works for population dynamics control. It is also found that relaxation processes can be suppressed under the proposed scheme. PMID- 17718548 TI - General performance of density functionals. AB - The density functional theory (DFT) foundations date from the 1920s with the work of Thomas and Fermi, but it was after the work of Hohenberg, Kohn, and Sham in the 1960s, and particularly with the appearance of the B3LYP functional in the early 1990s, that the widespread application of DFT has become a reality. DFT is less computationally demanding than other computational methods with a similar accuracy, being able to include electron correlation in the calculations at a fraction of time of post-Hartree-Fock methodologies. In this review we provide a brief outline of the density functional theory and of the historic development of the field, focusing later on the several types of density functionals currently available, and finishing with a detailed analysis of the performance of DFT across a wide range of chemical properties and system types, reviewed from the most recent benchmarking studies, which encompass several well-established density functionals together with the most recent efforts in the field. Globally, an overall picture of the level of performance of the plethora of currently available density functionals for each chemical property is drawn, with particular attention being dedicated to the relative performance of the popular B3LYP density functional. PMID- 17718549 TI - Multiphoton ion pair spectroscopy (MPIPS) with ultrashort laser pulses for the H2 molecule. AB - Time-dependent Schrodinger equation, TDSE, simulations have been performed in order to prepare and study via MPIPS the evolution of vibrational wave packets on the ion pair electronic state potentials B''B1Sigma(u)(+) and Hh1Sigma(g)(+) of the H2 molecule. Using ab initio potential surfaces and transition moments, we present two- and three-photon excitation schemes with ultrashort pulses (tau or=90% of the time. Additional calculations were performed on a series of heterocyclic compounds where the products resulting from metabolism by xanthine oxidase and aldehyde oxidase differ in many instances. Again, the lowest energy tetrahedral intermediate corresponded to the observed product of aldehyde oxidase metabolism >or=90% for the compounds examined, while the observed products of xanthine oxidase were not well predicted. PMID- 17718552 TI - A large descriptor set and a probabilistic kernel-based classifier significantly improve druglikeness classification. AB - Probabilistic support vector machine (SVM) in combination with ECFP_4 (Extended Connectivity Fingerprints) were applied to establish a druglikeness filter for molecules. Here, the World Drug Index (WDI) and the Available Chemical Directory (ACD) were used as surrogates for druglike and nondruglike molecules, respectively. Compared with published methods using the same data sets, the classifier significantly improved the prediction accuracy, especially when using a larger data set of 341 601 compounds, which further pushed the correct classification rates up to 92.73%. On the other hand, most characteristic features for drugs and nondrugs found by the current method were visualized, which might be useful as guiding fragments for de novo drug design and fragment based drug design. PMID- 17718553 TI - Molecular mechanism of the sea anemone toxin ShK recognizing the Kv1.3 channel explored by docking and molecular dynamic simulations. AB - Computational methods are employed to simulate the interaction of the sea anemone toxin ShK in complex with the voltage-gated potassium channel Kv1.3 from mice. All of the available 20 structures of ShK in the Protein Data Bank were considered for improving the performance of the rigid protein docking of ZDOCK. The traditional and novel binding modes were obtained among a large number of predicted complexes by using clustering analysis, screening with expert knowledge, energy minimization, and molecular dynamic simulations. The quality and validity of the resulting complexes were further evaluated to identify a favorable complex structure by 500 ps molecular dynamic simulations and the change of binding free energies with a computational alanine scanning technique. The novel and reasonable ShK-Kv1.3 complex structure was found to be different from the traditional model by using the Lys22 residue to block the channel pore. From the resulting structure of the ShK-Kv1.3 complex, ShK mainly associates the channel outer vestibule with its second helical segment. Structural analysis first revealed that the Lys22 residue side chain of the ShK peptide just hangs between C and D chains of the Kv1.3 channel instead of physically blocking the channel pore. The obvious loss of the ShK Ser20Ala and Tyr23Ala mutant binding ability to the Kv1.3 channel is caused by the conformational change. The five hydrogen bonds between Arg24 in ShK and H404(A) and D402(D) in Kv1.3 make Arg24 the most crucial for its binding to the Kv1.3 channel. Besides the detailed interaction between ShK and Kv1.3 at the atom level, the significant conformational change induced by the interaction between the ShK peptide and the Kv1.3 channel, accompanied by the gradual decrease of binding free energies, strongly implies that the binding of the ShK peptide toward the Kv1.3 channel is a dynamic process of conformational rearrangement and energy stabilization. All of these can accelerate the development of ShK structure-based immunosuppressants. PMID- 17718554 TI - Molecular dynamics studies of the molecular structure and interactions of cholesterol superlattices and random domains in an unsaturated phosphatidylcholine bilayer membrane. AB - The effect of the molecular organization of lipid components on the properties of the bilayer membrane has been a topic of increasing interest. Several experimental and theoretical studies have suggested that cholesterol is not randomly distributed in the fluid-state lipid bilayer but forms nanoscale domains. Several cholesterol-enriched nanodomain structures have been proposed, including rafts, regular or maze arrays, complexes, and superlattices. At present, the molecular mechanisms by which lipid composition influences the formation and stability of lipid nanodomains remain unclear. In this study, we have used molecular dynamics (MD) simulations to investigate the effects of the molecular organization of cholesterol--superlattice versus random--on the structure of and interactions between lipids and water in lipid bilayers of cholesterol and 1-palmitoyl-2-oleoylphosphatidylcholine (cholesterol/POPC) at a fixed cholesterol mole fraction of 0.40. On the basis of four independent replicates of 200-ns MD simulations for a superlattice or random bilayer, statistically significant differences were observed in the lipid structural parameters, area per lipid, density profile, and acyl chain order profile, as well as the hydrogen bonding between various pairs (POPC and water, cholesterol and water, and POPC and cholesterol). The time evolution of the radial distribution of the cholesterol hydroxy oxygen suggests that the lateral distribution of cholesterol in the superlattice bilayer is more stable than that in the random bilayer. Furthermore, the results indicate that a relatively long simulation time, more than 100 ns, is required for these two-component bilayers to reach equilibrium and that this time is influenced by the initial lateral distribution of lipid components. PMID- 17718555 TI - In situ localization and structural analysis of the malaria pigment hemozoin. AB - Raman microspectroscopy was applied for an in situ localization of the malaria pigment hemozoin in Plasmodium falciparum-infected erythrocytes. The Raman spectra (lambdaexc=633 nm) of hemozoin show very intense signals with a very good signal-to-noise ratio. These in situ Raman signals of hemozoin were compared to Raman spectra of extracted hemozoin, of the synthetic analogue beta-hematin, and of hematin and hemin. beta-Hematin was synthesized according to the acid catalyzed dehydration of hematin and the anhydrous dehydrohalogenation of hemin which lead to good crystals with lengths of about 5-30 microm. The Raman spectra (lambdaexc=1064 nm) of hemozoin and beta-hematin show almost identical behaviors, while some low wavenumber modes might be used to distinguish between the morphology of differently synthesized beta-hematin samples. The intensity pattern of the resonance Raman spectra (lambdaexc=568 nm) of hemozoin and beta-hematin differ significantly from those of hematin and hemin. The most striking difference is an additional band at 1655 cm(-1) which was only observed in the spectra of hemozoin and beta-hematin and cannot be seen in the spectra of hematin and hemin. Raman spectra of the beta-hematin dimer were calculated ab initio (DFT) for the first time and used for an assignment of the experimentally derived Raman bands. The calculated atomic displacements provide valuable insight into the most important molecular vibrations of the hemozoin dimer. With help from these DFT calculations, it was possible to assign the Raman band at 1655 cm(-1) to a mode located at the propionic acid side chain, which links the hemozoin dimers to each other. The Raman band at 1568 cm(-1), which has been shown to be influenced by an attachment of the antimalarial drug chloroquine in an earlier study, could be assigned to a C=C stretching mode spread across one of the porphyrin rings and is therefore expected to be influenced by a pi-pi-stacking to the drug. PMID- 17718557 TI - Crystal bridges, tetratic order, and elusive equilibria: the role of structure in lubrication films. AB - In this paper, we report on molecular dynamics simulation studies of thin dodecane films confined between mica surfaces. On confinement, the film undergoes a surface-mediated transition into a novel phase characterized by tetratic orientational order. The rheology of this ordered film is governed by slip planes and, at low shear rates, stick-slip behavior observable under steady shear rates. Melting of these films was observed either on heating or on exceeding a critical shear rate. Evidence is presented that this tetratic film is not the true equilibrium state; rather, a state characterized by nematic order and very low viscosities is found to be more stable. PMID- 17718556 TI - Phase behavior of palmitic acid/cholesterol/cholesterol sulfate mixtures and properties of the derived liposomes. AB - The phase behavior of mixtures formed by palmitic acid (PA), cholesterol (Chol), and sodium cholesteryl sulfate (Schol) has been characterized by differential scanning calorimetry and infrared and 2H NMR spectroscopy. It is reported that it is possible to form, with PA/sterol mixtures, fluid lamellar phases where the sterol content is very high (a sterol mole fraction of 0.7). As a consequence of the rigidifying ability of the sterols, the PA acyl chains are very ordered. The stability of these self-assembled bilayers is found to be pH-dependent. This property can be controlled by the Chol/Schol molar ratio, and it is proposed that this parameter modulates the balance between the intermolecular interactions between the constituting species. A phase-composition diagram summarizing the behavior of these mixtures as a function of pH, at room temperature, is presented. It is also shown that it is possible to produce large unilamellar vesicles (LUVs) from these mixtures, using standard extrusion techniques. The resulting LUVs display a very limited passive release of the entrapped material. In addition, these LUVs constitute a versatile vector for pH-triggered release. PMID- 17718559 TI - Reactivity of an adsorbed Ru(VI)-oxo complex: oxidation of benzyl alcohol. AB - The phosphonated ruthenium complex, [Ru(tpy-PO(3)H(2))(OH(2))(3)](2+) (1) (tpy PO(3)H(2) = 4'-phosphonato-2,2':6',2' '-terpyridine), was synthesized and attached to glass|ITO or glass|ITO|TiO(2) electrodes. After attachment to the metal oxide surface through the phosphonate linkage, 1 can be oxidized (either chemically or electrochemically) to the reactive Ru(VI)-dioxo complex, glass|ITO|[((HO)(2)OP)tpy)RuVI(O)(2)(OH(2))](2+), which remains attached to the surface. The attached Ru(VI) complex reacts with benzyl alcohol through mechanisms similar to those proposed for the solution analog. More specifically, Ru(VI) is reduced in a stepwise fashion to Ru(IV) and then finally to Ru(II). The reduction of Ru(VI) is accompanied by a rate-limiting insertion to the C-H bond of benzyl alcohol, followed by solvolysis of the aldehyde hydrate. In addition, the surface-bound Ru(VI) acts as an electrooxidation catalyst which carries out approximately 130 (2e(-)) turnovers before deactivation. PMID- 17718558 TI - Dynamic processes in endocytic transformation of a raft-exhibiting giant liposome. AB - The dynamic response of a raft-exhibiting giant liposome to external stimuli, such as the addition of Triton X-100 or osmotic stress, was studied. We observed that daughter vesicles are generated inside of the liposome through endocytic budding. It was found that the budding to generate daughter vesicles is classified into two different routes, simple budding through the invagination of a whole raft and budding from the boundary of a raft accompanied by waving motion. Smaller rafts show a preference for simple budding, whereas large rafts mainly adopt the other process. We discuss the mechanism of this difference in terms of the kinetic pathway of internalization by considering the line energy and bending energy of the membrane. PMID- 17718560 TI - New organically templated copper(I) sulfites: the role of sulfite anion as both soft and hard ligand. AB - Two new organically templated layered copper(I) sulfites, namely, {H2pip}{Cu3(CN)3(SO3)} (1) and {H2pip}{NaCu2(SO3)2Br(H2O)}.2H2O (2) (pip = piperazine), have been synthesized by hydrothermal reactions of copper(I) cyanide or copper(I) bromide with NaHSO3 and piperazine. Both compounds exhibit a layered structure. The 2D layer of {Cu3(CN)3(SO3)}2- in 1 is composed of 1D chains of copper(I) cyanide interconnected by sulfite anions via both Cu-S and Cu-O bonds, whereas the 2D layer of {NaCu2(SO3)2Br}2- in 2 is formed by 1D chains of copper(I) bromide and 1D sodium(I) aqua chains that are interconnected by sulfite anions via Na-O, Cu-S, and Cu-O bonds. Chemical bonding in 1 and 2 has been also investigated by theoretical calculations based on DFT methods. PMID- 17718563 TI - Thermally activated electron transport in single redox molecules. AB - We have studied electron transport through single redox molecules, perylene tetracarboxylic diimides, covalently bound to two gold electrodes via different linker groups, as a function of electrochemical gate voltage and temperature in different solvents. The conductance of these molecules is sensitive to the linker groups because of different electronic coupling strengths between the molecules and electrodes. The current through each of the molecules can be controlled reversibly over 2-3 orders of magnitude with the gate and reaches a peak near the redox potential of the molecules. The similarity in the gate effect of these molecules indicates that they share the same transport mechanism. The temperature dependence measurement indicates that the electron transport is a thermally activated process. Both the gate effect and temperature dependence can be qualitatively described by a two-step sequential electron-transfer process. PMID- 17718561 TI - Tridentate facial ligation of tris(pyridine-2-aldoximato)nickel(II) and tris(imidazole-2-aldoximato)nickel(II) To generate NiIIFeIIINiII, MnIIINiII, NiIINiII, and ZnIINiII and the electrooxidized MnIVNiII, NiIINiIII, and ZnIINiIII species: a magnetostructural, electrochemical, and EPR spectroscopic study. AB - Eight hetero- and homometal complexes 1-6, containing the metal centers Ni(II)Fe(III)Ni(II) (1), Mn(III)Ni(II) (2), Ni(II)Ni(II) (3a-c and 4), Zn(II)Ni(II) (5), and Zn(II)Zn(II) (6), are described. The tridentate ligation property of the metal complexes tris(pyridine-2-aldoximato)nickel(II) and tris(1 methylimidazole-2-aldoximato)nickel(II) with three facially disposed pendent oxime O atoms has been utilized to generate the said complexes. Complex 1 contains metal centers in a linear arrangement, as is revealed by X-ray diffraction. Complexes were characterized by various physical methods including cyclic voltammetry (CV), variable-temperature (2-290 K) magnetic susceptibility, electron paramagnetic resonance (EPR) measurements, and X-ray diffraction methods. Binuclear complexes 2-6 are isostructural in the sense that they all contain a metal ion in a distorted octahedral environment MN(3)O(3) and a second six-coordinated Ni(II) ion in a trigonally distorted octahedral NiN(6) geometry. Complexes 1-4 display antiferromagnetic exchange coupling of the neighboring metal centers. The order of the strength of exchange coupling in the isostructural Ni(II)2 complexes, 3a-c, and 4, demonstrates the effects of the remote substituents on the spin coupling. The electrochemical measurements CV and square wave voltammograms (SQW) reveal two reversible metal-centered oxidations, which have been assigned to the Ni center ligated to the oxime N atoms, unless a Mn ion is present. Complex 2, Mn(III)Ni(II), exhibits a reduction of Mn(III) to Mn(II) and two subsequent oxidations of Mn(III) and Ni(II) to the corresponding higher states. These assignments of the redox processes have been complemented by the X-band EPR measurements. That the electrooxidized species [3a]+, [3b]+, [3c]+, and [4]+ contain the localized mixed-valent NiIINiIII system resulting from the spin coupling, a spin quartet ground state, S(t) = 3/2, has been confirmed by the X-band EPR measurements. PMID- 17718562 TI - Dramatic influence of the orientation of linker between hydrophilic and hydrophobic lipid moiety in liposomal gene delivery. AB - A number of prior studies have demonstrated that the DNA-binding and gene transfection efficacies of cationic amphiphiles crucially depend on their various structural parameters including hydrophobic chain lengths, headgroup functionalities, and the nature of the linker-functionality used in tethering the polar headgroup and hydrophobic tails. However, to date addressing the issue of linker orientation remains unexplored in liposomal gene delivery. Toward probing the influence of linker orientation in cationic lipid mediated gene delivery, we have designed and synthesized two structurally isomeric remarkably similar cationic amphiphiles 1 and 2 bearing the same hydrophobic tails and the same polar headgroups connected by the same ester linker group. The only structural difference between the cationic amphiphiles 1 and 2 is the orientation of their linker ester functionality. While lipid 1 showed high gene transfer efficacies in multiple cultured animal cells, lipid 2 was essentially transfection incompetent. Findings in both transmission electron microscopic and dynamic laser light scattering studies revealed no significant size difference between the lipoplexes of lipids 1 and 2. Findings in confocal microscopic and fluorescence resonance energy transfer (FRET) experiments, taken together, support the notion that the remarkably higher gene transfer efficacies of lipid 1 compared to those of lipid 2 presumably originate from higher biomembrane fusogenicity of lipid 1 liposomes. Differential scanning calorimetry (DSC) and fluorescence anisotropy studies revealed a significantly higher gel-to-liquid crystalline temperature for the lipid 2 liposomes than that for lipid 1 liposomes. Findings in the dye entrapment experiment were also consistent with the higher rigidity of lipid 2/cholesterol (1:1 mole ratio) liposomes. Thus, the higher biomembrane fusibility of lipid 1 liposomes than that of lipid 2 liposomes presumably originates from the more rigid nature of lipid 2 cationic liposomes. Taken together, the present findings demonstrate for the first time that even as minor a structural variation as linker orientation reversal in cationic amphiphiles can profoundly influence DNA binding characteristics, membrane rigidity, membrane fusibility, cellular uptake, and consequently gene delivery efficacies of cationic liposomes. PMID- 17718565 TI - Structure, vibrational analysis, and insights into host-guest interactions in as synthesized pure silica ITQ-12 zeolite by periodic B3LYP calculations. AB - As-made and calcined ITQ-12 zeolites are structurally characterized by means of the analysis of their vibrational modes. The experimental IR spectra made on high crystalline samples are compared with accurate B3LYP periodic calculations performed with the CRYSTAL06 code. The fair agreement between both sets of data allows us to make a reliable assignment of the IR modes. Thanks to the detailed information provided by the theoretical calculations, the analysis of the IR intensities, the Born dynamic charges, and the whole set of vibrational frequencies at Gamma-point shed light on several aspects of the host-guest interaction, structure-direction issues, including the role of fluoride anions in allowing the crystallization of silica structures with strained double-four rings, and the role played by the framework flexibility. PMID- 17718564 TI - Hydrogen atom transfer reactions of imido manganese(V) corrole: one reaction with two mechanistic pathways. AB - Hydrogen atom transfer (HAT) reactions of (tpfc)MnNTs have been investigated (tpfc = 5,10,15-tris(pentafluorophenyl)corrole and Ts = p-toluenesulfonate). 9,10 Dihydroanthracene and 1,4-dihydrobenzene reduce (tpfc)MnNTs via HAT with second order rate constants 0.16 +/- 0.03 and 0.17 +/- 0.01 M(-1) s(-1), respectively, at 22 degrees C. The products are the respective arenes, TsNH(2) and (tpfc)Mn(III). Conversion of (tpfc)MnNTs to (tpfc)Mn by reaction with dihydroanthracene exhibits isosbestic behavior, and formation of 9,9',10,10' tetrahydrobianthracene is not observed, suggesting that the intermediate anthracene radical rebounds in a second fast step without accumulation of a Mn(IV) intermediate. The imido complex (tpfc)Mn(V)NTs abstracts a hydrogen atom from phenols as well. For example, 2,6-di-tert-butyl phenol is oxidized to the corresponding phenoxyl radical with a second-order rate constant of 0.32 +/- 0.02 M(-1) s(-1) at 22 degrees C. The other products from imido manganese(V) are TsNH(2) and the trivalent manganese corrole. Unlike reaction with dihydroarenes, when phenols are used isosbestic behavior is not observed, and formation of (tpfc)Mn(IV)(NHTs) is confirmed by EPR spectroscopy. A Hammett plot for various p substituted 2,6-di-tert-butyl phenols yields a V-shaped dependence on sigma, with electron-donating substituents exhibiting the expected negative rho while electron-withdrawing substituents fall above the linear fit (i.e., positive rho). Similarly, a bond dissociation enthalpy (BDE) correlation places electron withdrawing substituents above the well-defined negative slope found for the electron-donating substituents. Thus two mechanisms are established for HAT reactions in this system, namely, concerted proton-electron transfer and proton gated electron transfer in which proton transfer is followed by electron transfer. PMID- 17718567 TI - Three-dimensional architectures for highly stable pure blue emission. PMID- 17718566 TI - Infrared multiple photon dissociation spectroscopy as structural confirmation for GlyGlyGlyH+ and AlaAlaAlaH+ in the gas phase. Evidence for amide oxygen as the protonation site. PMID- 17718568 TI - Specificity of translation for N-alkyl amino acids. PMID- 17718569 TI - Solid-state NMR structural measurements on the membrane-associated influenza fusion protein ectodomain. PMID- 17718570 TI - Photopolymerization of gold nanoparticles: size-related charge separation and emission. PMID- 17718571 TI - The herringbone helix: a noncanonical folding in aromatic-aliphatic peptides. PMID- 17718572 TI - Modulating protein alignment in a liquid-crystalline medium through conservative mutagenesis. PMID- 17718573 TI - Direct electrochemical evaluation of plasma membrane cholesterol in live mammalian cells. PMID- 17718575 TI - Enantioselective addition of terminal alkynes to aldehydes catalyzed by a Cu(I) TRAP complex. AB - The addition of terminal alkynes to aromatic aldehydes was carried out under mild conditions in the presence of a Cu-phosphine complex, which was prepared in situ from Cu(O-t-Bu) and TRAP chiral bisphosphine, to yield enantiomerically enriched propargyl alcohols with moderate enantioselectivities. Furthermore, according to stoichiometric reactions, the reaction presumably involves the addition of a TRAP coordinated Cu(I) acetylide to an aldehyde. PMID- 17718574 TI - Metal-mediated J coupling in DNA base pairs: relativistic DFT predictions. PMID- 17718576 TI - Efficient copper-catalyzed benzylic amidation with anhydrous chloramine-T. AB - Benzylic hydrocarbons are selectively converted to the corresponding sulfonamides by the [Cu(CH(3)CN)(4)]PF(6)-catalyzed reaction with anhydrous TolSO(2)NNaCl (chloramine-T). Under the same conditions, representative ethers are also alpha amidated; olefins produce allyl sulfonamides, aziridines, and/or beta-chloro sulfonamides. PMID- 17718577 TI - An ultrafast study of phenyl azide: the direct observation of phenylnitrenium ion. AB - Ultrafast photolysis (lambda(ex) = 308 nm) of phenyl azide in 100% formic acid produces a broadly absorbing transient within the instrument time resolution (300 fs), which is assigned to an excited state of the azide. The azide excited state fragments within 300 fs to form singlet phenylnitrene. The decay of the nitrene (tau = 12.0 ps) produces a new species with absorption centered at 500 nm, which is assigned to phenylnitrenium ion. The lifetime of phenylnitrenium ion is 110 ps in 100% formic acid. This is the first spectroscopic observation of phenylnitrenium ion. PMID- 17718578 TI - Highly efficient synthesis of functionalized indolizines and indolizinones by copper-catalyzed cycloisomerizations of propargylic pyridines. AB - The copper-catalyzed cycloisomerizations of 2-pyridyl-substituted propargylic acetates and its derivatives are described, which offer an efficient route to C-1 oxygenated indolizines with a wide range of substituents under mild reaction conditions. The presented method could be readily applied to the synthesis of indolizinones through a cyclization/1,2-migration of tertiary propargylic alcohols. PMID- 17718579 TI - Controlling the melting of kinetically frozen poly(butyl acrylate-b-acrylic acid) micelles via addition of surfactant. AB - We have studied the melting of polymeric amphiphilic micelles induced by small molecule surfactant and explained the results by experimental determination of the interfacial tension between the core of the micelles and the surfactant solutions. Poly(n-butyl acrylate-b-acrylic acid) (PBA-b-PAA) amphiphilic diblock copolymers form kinetically frozen micelles in aqueous solutions. Strong interactions with surfactants, either neutral or anionic [C12E6, C6E4, sodium dodecyl sulfate (SDS)], were revealed by critical micelle concentration (cmc) shifts in specific electrode and surface tension measurements. Since both polymer and surfactant are either neutral or bear negative charges, the attractive interactions are not due to electrostatic interactions. Light scattering, neutron scattering, and capillary electrophoresis experiments showed important structural changes in mixed PBA-b-PAA/surfactant systems. Kinetically frozen micelles of PBA b-PAA, that are hardly perturbed by concentration, ionization, ionic strength, and temperature stresses, can be disintegrated by addition of small-molecule surfactants. The interfacial energy of the PBA in surfactant solutions was measured by drop shape analysis with h-PBA homopolymer drops immersed in small molecule surfactant solutions. The PBA/water interfacial energy gammaPBA/H2O of 20 mN/m induces a high energy cost for the extraction of unimers from micelles so that PBA-b-PAA micelles are kinetically frozen. Small-molecule surfactants can reduce the interfacial energy gammaPBA/solution to 5 mN/m. This induces a shift of the micelle-unimer equilibrium toward unimers and leads, in some cases, to the apparent disintegration of PBA-b-PAA micelles. Before total disintegration, polymer/surfactant mixtures are dispersions of polydisperse mixed micelles. Based on core interfacial energy arguments, the disintegration of kinetically frozen polymeric micelles was interpreted by gradual fractionation of objects (polydisperse dispersion mechanism), whereas the disintegration of polymeric micelles in a thermodynamically stable state was interpreted by an exchange between a population of large polymer-rich micelles and a population of small surfactant-rich micelles (bidisperse dispersion mechanism). Finally, in our system and other systems from the literature, interfacial energy arguments could explain why the disintegration of polymer micelles is either partial or total as a function of the surfactant type and concentration and the hydrophobic block molar mass of the polymer. PMID- 17718581 TI - Photochemical reactions of ketones to synthesize gold nanorods. AB - Photochemical synthesis of gold nanorods (NRs) in a micellar solution of hexadecyltrimethylammonium bromide (CTAB) was triggered by photoreactions of ketones. Photoexcitation of gold ions and silver bromide clusters ((AgBr)n) in the absence of ketones did not produce NRs. The initial products of the photoirradiation were probably ketyl radicals, which then initiated reactions to form NRs. NRs formed in darkness, if the reaction solutions were irradiated by UV light for a few minutes, thus indicating that the photochemical products catalyzed NR-formation. PMID- 17718580 TI - Synthesis and characterization of thermosensitive PNIPAM microgels covered with superparamagnetic gamma-Fe2O3 nanoparticles. AB - In the present study we report a facile and reproducible method of preparing magnetic thermosensitive hybrid material based on P(NIPAM) microgels covered with gamma-Fe2O3 nanoparticles of 6-nm size. The iron oxide nanoparticles provided magnetic response to the microgels. In addition, the presence of the magnetic nanoparticles on the microgels altered their swelling behavior and shifted their volume phase transition temperature to higher values. In particular, for inorganic shells with 18% (w/w) of magnetic nanoparticles the volume phase transition of the microgels was shifted from 36 to 40 degrees C. In contrast, for shells consisting of 38% (w/w) magnetic nanoparticles the volume phase transition of the microgels was almost blocked, thus indicating that the microgel thermal response was strongly affected by the presence of the inorganic nanoparticles. The synthesized thermosensitive magnetic microgels are envisaged to be ideal for potential applications as thermosensitive targeted drug delivery systems. PMID- 17718582 TI - Fabrication of size-tunable TiO2 tubes using rod-shaped calcite templates. AB - Titania tubes with tunable wall thickness were produced by the sol-gel reaction of titanium(IV) n-butoxide in the presence of rod-shaped calcite particles that act as templates. A shell of amorphous titania was deposited around the calcite particles by sol-gel synthesis. The titania was crystallized to the anatase or rutile phase by sintering at different temperatures, and then acid etching was used to remove the calcite core, leaving hollow titania tubes. The influences of several parameters on the final particle formation were investigated, including calcite templates, surfactant, the method of adding reagents, and catalyst. The average width of the prepared titania tubes ranges from nearly 100 nm to 1 microm, with wall thickness ranging from approximately 70 to 300 nm. A possible growth mechanism of the titania tubes is presented. The ability to control titania tube size and crystal structure is important for photocatalysis, photovoltaics, and other applications. The fabrication approach presented is applicable to form tubes of other oxide materials by sol-gel synthesis. PMID- 17718583 TI - In situ raman measurements of suspended individual single-walled carbon nanotubes under strain. AB - We present a technique for in situ Raman measurements of suspended individual single-walled carbon nanotubes (SWNTs) under strain. We observe a strong change in the radial breathing mode intensity with increasing strain as the nanotube moves out of (or into) resonance, and for strain greater than approximately 2%, there is a clear irreversible upshift in the G-mode frequencies accompanied by an increase in intensity of a broad peak at a position associated with the D mode. For lower strain, the G-mode peaks (A1, E1, and E2) do not change significantly in position but change in relative intensity. PMID- 17718584 TI - Temperature dependence of the Raman spectra of graphene and graphene multilayers. AB - We investigated the temperature dependence of the frequency of G peak in the Raman spectra of graphene on Si/SiO2 substrates. The micro-Raman spectroscopy was carried out under the 488 nm laser excitation over the temperature range from 190 to +100 degrees C. The extracted value of the temperature coefficient of G mode of graphene is chi = -0.016 cm-1/ degrees C for the single layer and chi = 0.015 cm-1/ degrees C for the bilayer. The obtained results shed light on the anharmonic properties of graphene. PMID- 17718585 TI - GaAs:Mn nanowires grown by molecular beam epitaxy of (Ga,Mn)as at MnAs segregation conditions. AB - GaAs:Mn nanowires were obtained on GaAs(001) and GaAs(111)B substrates by molecular beam epitaxial growth of (Ga,Mn)As at conditions leading to MnAs phase separation. Their density is proportional to the density of catalyzing MnAs nanoislands, which can be controlled by the Mn flux and/or the substrate temperature. After deposition corresponding to a 200 nm thick (Ga,Mn)As layer the nanowires are around 700 nm long. Their shapes are tapered, with typical diameters around 30 nm at the base and 7 nm at the tip. The wires grow along the 111 direction, i.e., along the surface normal on GaAs(111)B and inclined on GaAs(001). In the latter case they tend to form branches. Being rooted in the ferromagnetic semiconductor (Ga,Mn)As, the nanowires combine one-dimensional properties with the magnetic properties of (Ga,Mn)As and provide natural, self assembled structures for nanospintronics. PMID- 17718586 TI - Electron shuttle instability for nano electromechanical mass sensing. AB - We discuss the potential use of the electromechanical shuttle instability in suspended nanostructures (e.g., nanotubes or nanowires) for nanomechanical sensing. The tunneling-assisted (shuttle-like) electron transport mechanism is addressed from a mechanical and electromechanical point of view, showing strong dependencies on the fundamental frequency, the mechanical restoring and damping force, and the electromechanical charging of the suspended nanostructure. We propose to use these nonlinear dependencies to sense minute mass (and tension) changes. Therefore, we introduce a conceptual sensing device and investigate its operation in the frame of a simple model system. Finally, we discuss different measurement techniques and report on high sensitivities (e.g., 1 nA/zeptogram (zg), or 1 mV/zg depending on the measurement technique) and potential resolutions in the range of 10 zg (10(-23) kg). PMID- 17718587 TI - Organically modified silica nanoparticles with covalently incorporated photosensitizer for photodynamic therapy of cancer. AB - We report a novel nanoformulation of a photosensitizer (PS), for photodynamic therapy (PDT) of cancer, where the PS molecules are covalently incorporated into organically modified silica (ORMOSIL) nanoparticles. We found that the covalently incorporated PS molecules retained their spectroscopic and functional properties and could robustly generate cytotoxic singlet oxygen molecules upon photoirradiation. The synthesized nanoparticles are of ultralow size ( approximately 20 nm) and are highly monodispersed and stable in aqueous suspension. The advantage offered by this covalently linked nanofabrication is that the drug is not released during systemic circulation, which is often a problem with physical encapsulation. These nanoparticles are also avidly uptaken by tumor cells in vitro and demonstrate phototoxic action, thereby highlighting their potential in diagnosis and PDT of cancer. PMID- 17718588 TI - Gate coupling and charge distribution in nanowire field effect transistors. AB - We have modeled the field and space charge distributions in back-gate and top gate nanowire field effect transistors by solving the three-dimensional Poisson's equation numerically. It is found that the geometry of the gate oxide, the semiconductivity of the nanowire, and the finite length of the device profoundly affect both the total amount and the spatial distribution of induced charges in the nanowire, in stark contrast to the commonly accepted picture where metallic dielectric properties and infinite length are assumed for the nanowire and the specific geometry of the gate oxide is neglected. We provide a comprehensive set of numerical correction factors to the analytical capacitance formulas, as well as to numerical calculations that neglect the semiconductivity and finite length of the nanowire, that are frequently used for quantifying carrier transport in nanowire field effect transistors. PMID- 17718589 TI - Single-molecule spectroscopy using nanoporous membranes. AB - We describe a novel approach for optically detecting DNA translocation events through an array of solid-state nanopores that potentially allows for ultra high throughput, parallel detection at the single-molecule level. The approach functions by electrokinetically driving DNA strands through sub micrometer-sized holes on an aluminum/silicon nitride membrane. During the translocation process, the molecules are confined to the walls of the nanofluidic channels, allowing 100% detection efficiency. Importantly, the opaque aluminum layer acts as an optical barrier between the illuminated region and the analyte reservoir. In these conditions, high-contrast imaging of single-molecule events can be performed. To demonstrate the efficiency of the approach, a 10 pM fluorescently labeled lambda-DNA solution was used as a model system to detect simultaneous translocation events using electron multiplying CCD imaging. Single-pore translocation events are also successfully detected using single-point confocal spectroscopy. PMID- 17718590 TI - A novel major groove binding site in B-form DNA for ethidium cation. AB - A stably-bound external binding site for ethidium cation in the major groove of B form DNA is proposed. This complex is stabilized by hydrogen bonding between this ligand and the nucleophilic centers O6 and N7 of guanine, both of which are accessible via the major groove. This binding site is not the same as the well characterized electrostatically-stabilized external binding site, but rather is seen to be a covalently bound complex which is stabilized by two hydrogen bonds between the ethidium ligand and guanine in the double stranded (ds) B-form DNA. This site [(1), R. Monaco, F. Hasheer. J Biomol Struct Dyn 10, 675 (1993)] can only exist at very low occupancy ratios. The existence of this binding site leads directly to the expectation that there will exist particular mechanistic steps along the pathway of interaction between ethidium and ds B-DNA at low and high ligand concentrations that involve this binding mode. This would not only explain observations published recently [for example, see (2-6), W. Wilson, I. Lopp. Biopolymers 18, 3025 (1979); L. Wakelin, M. Waring. J Mol Biol 144, 183-214 (1980); A. Karpetyan, N. Mehrabian, G. Terzikian, A. Antonian, P. Vardevanian, M. Frank-Kamenetshii. Proceedings of the 10th Conversation, SUNY Albany, 275 (1998); P. Vardevanyan, A. Antonyan, G. Manukyan, A. Karapetyan. Experimental and Molecular Medicine 33, 205 (2001); P. Vardevanyan, A. Antonyan, L. Minasbekan, A. Karapetyan. Proceedings of the 2002 Miami Nature Biotechnology Winter Symposium, 2(S1), 144 (2002)] but also give insight into discrepancies reported in the literature over the years by different workers studying the mechanism of interaction between ethidium and DNA. In this paper this novel binding interaction is discussed, and it is shown how the elucidation of this interaction led to the proposal of two distinct mechanisms of intercalation between ds B-DNA and ethidium cation for high and low concentrations of ligand. Modeling studies show the stability, configuration, and relative energies of this outside binding site. It is expected that this externally bound complex between ethidium cation and ds B-form DNA will be experimentally detectable using fluorescent polarization and/or linear and circular dichroism spectroscopic studies [(7, 8) E. Tuite, U. Sehlstedt, P. Hagmar, B. Norden, M. Takahashi. Euro J Biochem 243, 482-492 (1997); T. Hard. Biopolymers 26, 613-618 (1987)]. PMID- 17718591 TI - The distribution patterns of bases of protein-coding genes, non-coding ORFs, and intergenic sequences in pseudomonas aeruginosa PA01 genome and its implications. AB - The distribution patterns of bases of DNA fragments in different regions in P. aeruginosa genome are analyzed in this paper. It's shown that 5565 protein-coding genes, 17315 non-coding ORFs, and 1104 intergenic sequences are located into seven clusters based on their base frequencies. Almost all the protein-coding genes are contained in one of the seven clusters. The significant difference of base frequencies among three codon positions in high GC genome, which arouse the division between the distribution patterns of bases of six reading frames of protein-coding genes, is responsible for the appearance of the clustering phenomenon. In the light of the clustering phenomenon, the author supposes that the anitisense strand ORFs, particularly those corresponding to Frame 2' and Frame 3', may not code for proteins in P. aeruginosa genome. PMID- 17718592 TI - Molecular dynamics simulations of human cystatin C and its L68Q varient to investigate the domain swapping mechanism. AB - Human cystatin C variant (L68Q), one of the amyloidgenic proteins, has been shown to form dimeric structure spontaneously via domain swapping and easily cause amyloid deposits in the brains of patients suffering from Alzheimer's disease or hereditary cystatin C amyloid angiopathy. The monomeric L68Q and wild-type (wt) HCCs share similar structural feature consisting of a core with a five-stranded anti-parallel beta-sheet (beta-region) wrapped around a central helix. In this study, various molecular dynamics simulations were conducted to investigate the conformational fluctuations of the monomeric L68Q and wt HCCs at various combinations of temperature (300 and 500K) and pH (2 and 7) to gain insights into the domain swapping mechanism. The results show that elevated temperature accelerates the disruption of the hydrophobic core and acidic condition promotes the destruction of three salt bridges between beta2 and beta3 in both HCCs. The results also indicate that the interior hydrophobic core of the L68Q variant is relatively unstable, leading to domain swapping more readily comparing to wt HCC under conditions favoring this process. However, these two monomeric HCCs adopt the same mechanism of domain swapping as follows: (i) first, the interior hydrophobic core is disrupted; (ii) subsequently, the central helix departs from the beta-region; (iii) then, the beta2-L1-beta3 hairpin structure unfolds following the so-called "zip-up" mechanism; and (iv) finally, the open form HCC is generated. PMID- 17718593 TI - Enthalpic and entropic contributions in the transesterification of sucrose: computational study of lipases and subtilisin. AB - Transesterification of sucrose with fatty acids catalyzed by subtilisin Carlsberg occurs with regioselectivity that is different from that in lipases. Thermomyces lanuginosus lipase (TlL) and Candida antarctica lipase B (CALB) catalyze synthesis at positions 6 and 6', with differing abilities, while subtilisin catalysis leads to the 1'-acylated sucrose. The catalytic machinery in lipases is approximately mirrored in subtilisins but different pocket morphologies including size, shape, and rearrangement of the catalytic elements underlies the differing regioselectivities. The thermodynamic consequences of these differences on the above reactions have been explored systematically using computational methods, determining the free energies of interaction of the putative transition-state adducts. Analysis of the conformers with the lowest transition state energies (protein-ligand interactions and vibrational entropy contributions) indicates that enthalpic factors control specificities in lipases while entropic factors are more important in subtilisin. PMID- 17718594 TI - Modeling study of Rusticyanin-Cytochrome C(4) complex: an insight to possible H bond mediated recognition and electron--transfer process. AB - Rusticyanin (RCy) mediated transfer of electron to Cytochrome C(4) (Cytc(4)) from the extracellular Fe(+2) ion is primarily involved in the Thiobacillus ferrooxidans induced bio-leaching of pyrite ore and also in the metabolism of this acidophilic bacteria. The modeling studies have revealed the two possible mode of RCy-Cytc(4) complexation involving nearly the same stabilization energy approximately -15 x 10(3) kJ/mol, one through N-terminal Asp 15 and another -C terminal Glu 121 of Cytc(4) with the Cu-bonded His 143 of RCy. The Asp 15:His 143 associated complex (DH) of Cytc(4)-RCy was stabilized by the intermolecular H bonds of the carboxyl oxygen atoms O(delta1) and O(delta2) of Asp 15 with the Nepsilon-atom of His 143 and O(b) atoms of Ala 8 and Asp 5 (of Cytc(4)) with the Thr 146 and Phe 51 (of RCy). But the other Glu 121:His 143 associated complex (EH) of Cytc(4)-RCy was stabilized by the H-bonding interaction of the oxygen atoms O(epsilon1) and O(epsilon2) of Glu 121 with the Nepsilon and Ogamma atoms of His 143 and Thr 146 of RCy. The six water molecules were present in the binding region of the two proteins in the energy minimized autosolvated DH and EH complexes. The MD studies also revealed the presence of six interacting water molecules at the binding region between the two proteins in both the complexes. Several residues Gly 82 and 84, His 143 (RCy) were participated through the water mediated (W 389, W 430, W 413, W 431, W 373, and W 478) interaction with the Asp 15, Ile 82, and 62, Tyr 63 (Cytc(4)) in DH complex, whereas in EH complex the Phe 51, Asn 80, Tyr 146 (RCy) residues were observed to interact with Asn 108, Met 120, Glu 121 (of Cytc(4)) through the water molecules W 507, W 445, W 401, W 446, and W 440. The direct water mediated (W 478) interaction of His 143 (RCy) to Asp 15 (of Cytc(4)) was observed only in the DH complex but not in EH. These direct and water mediated H-bonding between the two respective proteins and the binding free energy with higher interacting buried surface area of the DH complex compare to other EH complex have indicated an alternative possibility of the electron transfer route through the interaction of His 143 of RCy and the N-terminal Asp 15 of Cytc(4). PMID- 17718595 TI - Effect of Cl- on tyrosinase: complex inhibition kinetics and biochemical implication. AB - Tyrosinase plays a core role in melanogenesis of the various organisms. Therefore, the regulation of the tyrosinase activity is directly related with melanin synthesis. In this study, we investigated the Cl(-)-induced inhibition of human tyrosinase and the potent role of Cl(-) as a negative regulator in melanogenesis. For the inhibition kinetic studies, human tyrosinase was differently prepared from the TXM13 melanotic cells as well as from cells that had undergone gene transfection. We found that Cl(-) inhibited tyrosinase in a slope-parabolic competitive manner and tyrosinase gene transfection into HEK293 cell significantly down-regulated the expression levels of solute carrier family 12, member 4 (potassium/chloride transporters, SLC12A7) and solute carrier family 12, member 7 (potassium/chloride transporters, SLC12A7), which are known to be Cl(-) transporters. From the results of the inhibition kinetic studies and the Cl(-) transporter expression level, we suggested that Cl(-) might act as a potent regulatory factor in melanogenesis. It is worth notice that a high content of Cl( ) exists physiologically and tyrosinase reacts sensitively to Cl- in a complex interaction manner. PMID- 17718596 TI - Binding properties of a new anti-tumor component (2,2'-bipyridin octylglycinato Pd(II) nitrate) with bovine beta-lactoglobulin-A and -B. AB - An new water soluble palladium (II) complex of formula [Pd(bpy)(Oct-Gly)]NO(3), (where bpy is 2,2'-bipyridine and Oct-Gly is octylglycine) have been synthesised. The Pd(II) complex has been characterized by elemental analysis and conductivity measurements as well as spectroscopic methods such as infrared, (1)H NMR, and ultraviolet-visible. The interaction between the new Pd(II)-complex (2,2' bipyridin octylglycinato Pd(II) nitrate), an anti-tumor component, with beta lactoglobulin-A and -B (BLG-A and -B) was studied by fluorescence spectroscopy and far and near-UV circular dichroism (CD) spectrophotometric techniques. A strong fluorescence quenching interaction of Pd(II) complex with BLG-A and -B was observed. The quenching constant was determined using the modified Stern-Volmer equation. The calculated binding constants of Pd(II) complex with BLG-A and -B were 0.51 and 0.28 (x 10(6) M(-1)) and the corresponding average number of binding sites were 2.8 and 1.5, respectively. Far-UV CD studies showed that the Pd(II) complex can significantly change the secondary structure of BLG-A and -B via an increase in the content of alpha-helix structure, which stabilizes the secondary structure of the proteins. Near-UV CD data clearly indicate the alteration in the tertiary structure of BLG-A and -B due to the interaction with Pd(II) complex. Pd(II) complex can change and stabilize both the secondary and tertiary structures of BLG-A more than BLG-B. These conformational changes may be considered to be a deleterious effect of the designed ligand on the protein structures. The difference in the interaction properties observed for BLG-A and B with Pd(II) complex is due to the difference in the amino acid sequences between these two variants. PMID- 17718597 TI - Analysis of structure, function, and evolutionary origin of the ob gene product- leptin. AB - Leptin, the ob gene product, is a 167 amino acid polypeptide known to play a key role in regulating the fat stores of the body and is found in all eukaryotes, including mammals, aves, and also in invertebrates. To gain insight into the structure-function relation and origin of leptin, we have analyzed the amino acid sequence of leptin from 23 species by computing the frequency of occurrence of amino acids, their secondary structure, sequence homology, et cetera. Extensive conservation is observed within the leptin sequences of all the species, suggesting an evolutionary relatedness among them. It is interesting to note that human leptin shares a very high degree of homology with gorilla, chimpanzee, and orangutan indicative of a common function of leptin in them. Analysis of the codon bias in leptin from 11 species reveals that sminthopsis shows highest variation compared to human while less variation is observed in chimpanzee and orangutan, possibly reflecting the closeness in their evolution. Thus, understanding leptin's three-dimensional structure along with primary and secondary structure might enable us to understand the functional role played by this multifaceted adipocyte derived protein. PMID- 17718598 TI - The glycophosphatidylinositol anchor oppositely affects unfolding and refolding of alkaline phosphatase. AB - Regarding the world wide success of artificial chaperone-assisted protein refolding technique and based on its well worked-out mechanism, it is anticipated that the lipid moieties of glycosylphosphatidylinositol (GPI) group, which is present in some membrane proteins, might interfere with the capturing step of the technique. To find an answer, we evaluated the chemical denaturation and also the refolding behavior of insoluble and soluble alkaline phosohatase (ALP), with or without GPI group, respectively. The results indicated that the presence of GPI in the enzyme increased the stability of the protein against chemical denaturation while it decreased its refolding yield by the artificial chaperone refolding technique. The lower refolding yield, compared to soluble ALP (sALP), might be due to a less efficient stripping step caused by new interactions imparted to the refolding elements of the system especially those among the hydrophobic tails of GPI and the capturing agent of the technique. These new interactions will interrupt the kinetics of detergent stripping from the captured molecules by the stripping agent (i.e., cyclodextrins). This situation will lead to higher intermolecular hydrophobic interactions among the refolding protein intermediates leading to their higher misfolding and aggregation. PMID- 17718599 TI - The membrane-proximal fusion domain of HIV-1 GP41 reveals sequence-specific and fine-tuning mechanism of membrane binding. AB - The membrane interface-partitioning region preceding the transmembrane anchor of the human immunodeficiency virus type 1 (HIV-1) gp41 envelope protein is one of the sites responsible for virus binding to its host cell membrane and subsequent fusion events. Here, we used molecular modeling techniques to assess membrane interactions, structure, and hydrophobic properties of the fusion-active peptide representing this region, several of its homologs from different HIV-1 strains, as well as a peptide - defective gp41 phenotype - unable to mediate cell-cell fusion and virus entry. It is shown that the wild-type peptides bind to the water membrane interface in alpha-helical conformation, while the mutant adopts partly destabilized helix-break-helix structure on the membrane surface. The wild-type peptides reveal specific "tilted oblique-oriented" pattern of hydrophobicity on their surfaces - the property specific for fusion regions of other viruses. Fusion peptides penetrate into the membrane with their N-termini and reveal "fine tuning" interactions with membrane and water environments: the shift of this balance (e.g., due to point mutations) may dramatically change the mode of membrane binding, and therefore, may cause loss of fusion activity. The modeling results agree well with experimental data and provide a strategy to delineate fusogenic regions in amino acid sequences of viral proteins. PMID- 17718600 TI - Gauge-origin independent calculation of magnetizabilities and rotational g tensors at the coupled-cluster level. AB - An implementation of the gauge-origin independent calculation of magnetizabilities and rotational g tensors at the coupled-cluster (CC) level is presented. The properties of interest are obtained as second derivatives of the energy with respect to the external magnetic field (in the case of the magnetizability) or with respect to magnetic field and rotational angular momentum (in the case of the rotational g tensor), while gauge-origin independence and fast basis-set convergence are ensured by using gauge-including atomic orbitals (London atomic orbitals) as well as their extension to treat rotational perturbations (rotational London atomic orbitals). The implementation within our existing CC analytic second-derivative code is described, focusing on the required modifications concerning integral evaluation and treatment of the unperturbed and perturbed two-particle density matrices. An extensive set of test calculations for LiH and BH (up to the full configuration-interaction limit), for a series of simple hydrides (HF, H(2)O, NH(3), and CH(4)) as well as the more challenging molecules CO, N(2), and O(3) [employing the CC singles and doubles (CCSD) and the CCSD approximation augmented by a perturbative treatment of triple excitations] demonstrates the importance of electron correlation for high accuracy predictions of magnetizabilities and rotational g tensors. PMID- 17718601 TI - Automatically generated Coulomb fitting basis sets: design and accuracy for systems containing H to Kr. AB - For intermediate sized chemical systems the use of an auxiliary basis set (ABS) to fit the charge density provides a useful means of accelerating the performance of various quantum chemical methods. As a consequence much effort has been devoted to the design of various ABSs. This paper explores a fundamentally new approach where the ABS is created dynamically based on the specific orbital basis set (OBS) being used. The new approach includes a parameter that is used to coalesce candidate fitting functions together but which can also be used to provide some coarse grain control over the number of functions in the ABS. The accuracy of the new automatically generated ABS (auto-ABS) is systemically studied for a variety of small systems containing the elements H-Kr. Errors in the Coulomb energy computed using auto-ABS and with a variety of OBSs are shown to be small compared to errors in the Hartree-Fock energy due to incompleteness in the OBS. In contrast to fixed size ABSs, the use of auto-ABS is shown to lead to smaller errors as the size (quality) of the OBS is expanded. The performance of auto-ABS is also compared with the use of the recently proposed universal fitting sets [Weigend, Phys. Chem. Chem. Phys. 8, 1057 (2006)] for 180 compounds containing atoms from H to Kr. PMID- 17718602 TI - Alternative linear-scaling methodology for the second-order Moller-Plesset perturbation calculation based on the divide-and-conquer method. AB - A new scheme for obtaining the approximate correlation energy in the divide-and conquer (DC) method of Yang [Phys. Rev. Lett. 66, 1438 (1991)] is presented. In this method, the correlation energy of the total system is evaluated by summing up subsystem contributions, which are calculated from subsystem orbitals based on a scheme for partitioning the correlation energy. We applied this method to the second-order Moller-Plesset perturbation theory (MP2), which we call DC-MP2. Numerical assessment revealed that this scheme provides a reliable correlation energy with significantly less computational cost than the conventional MP2 calculation. PMID- 17718603 TI - Static and dynamic second hyperpolarizability calculated by time-dependent density functional cubic response theory with local contribution and natural bond orbital analysis. AB - The static and dynamic second hyperpolarizability gamma has been investigated by time-dependent density functional cubic response theory. The third-order coupled perturbed Kohn-Sham equations were solved to obtain the third-order perturbed charge density. Calculations on a number of small molecules (N(2), CO(2), C(2)H(4), CO, HF, H(2)O, and CH(4)), paradisubstituted oligoacetylene chains, benzene, and eight paradisubstituted benzenes were performed to verify the implementation and to assess the accuracy of the nonhybrid and hybrid time dependent density functional theory computations. Nitroaniline and a derivative were taken as examples to investigate the distribution of the "gamma density" and to demonstrate the feasibility of analyzing cubic response functions in terms of contributions from natural bond orbitals (NBOs) and natural localized molecular orbitals (NLMOs). The results highlight the contributions from atoms and bonds on different functional groups to the total value of gamma based on the NBO/NLMO analysis, which might be helpful for new nonlinear optical materials design. PMID- 17718604 TI - Analytic high-order Douglas-Kroll-Hess electric field gradients. AB - In this work we present a comprehensive study of analytical electric field gradients in hydrogen halides calculated within the high-order Douglas-Kroll-Hess (DKH) scalar-relativistic approach taking picture-change effects analytically into account. We demonstrate the technical feasibility and reliability of a high order DKH unitary transformation for the property integrals. The convergence behavior of the DKH property expansion is discussed close to the basis set limit and conditions ensuring picture-change-corrected results are determined. Numerical results are presented, which show that the DKH property expansion converges rapidly toward the reference values provided by four-component methods. This shows that in closed-shell cases, the scalar-relativistic DKH(2,2) approach which is of second order in the external potential for both orbitals and property operator yields a remarkable accuracy. As a parameter-dependence-free high-order DKH model, we recommend DKH(4,3). Moreover, the effect of a finite-nucleus model, different parametrization schemes for the unitary matrices, and the reliability of standard basis sets are investigated. PMID- 17718605 TI - General biorthogonal projected bases as applied to second-order Moller-Plesset perturbation theory. AB - With low-order scaling correlated wave function theories in mind, we present second quantization formalism as well as biorthonormalization procedures for general--singular or nonsingular--bases. Of particular interest are the so-called projected atomic orbital bases, which are obtained from a set of atom-centered functions and feature a separation of occupied and virtual spaces. We demonstrate the formalism by deriving and implementing second-order Moller-Plesset perturbation theory in it, and discuss the convergence and preconditioning of the iterative amplitude equations in detail. PMID- 17718606 TI - Quadrupole, octopole, and hexadecapole electric moments of Sigma, Pi, Delta, and Phi electronic states: cylindrically asymmetric charge density distributions in linear molecules with nonzero electronic angular momentum. AB - The number of independent components, n, of traceless electric 2(l)-multipole moments is determined for C(infinity v) molecules in Sigma(+/-), Pi, Delta, and Phi electronic states (Lambda=0,1,2,3). Each 2(l) pole is defined by a rank-l irreducible tensor with (2l+1) components P(m)((l)) proportional to the solid spherical harmonic r(l)Y(m)(l)(theta,phi). Here we focus our attention on 2(l) poles with l=2,3,4 (quadrupole Theta, octopole Omega, and hexadecapole Phi). An important conclusion of this study is that n can be 1 or 2 depending on both the multipole rank l and state quantum number Lambda. For Sigma(+/-)(Lambda=0) states, all 2(l) poles have one independent parameter (n=1). For spatially degenerate states--Pi, Delta, and Phi (Lambda=1,2,3)--the general rule reads n=1 for l<2/Lambda/ (when the 2(l)-pole rank lies below 2/Lambda/ but n=2 for higher 2(l) poles with l>or=2/Lambda/. The second nonzero term is the off-diagonal matrix element [formula: see text]. Thus, a Pi(Lambda=1) state has one dipole (mu(z)) but two independent 2(l) poles for l>or=2--starting with the quadrupole [Theta(zz),(Theta(xx)-Theta(yy))]. A Delta(Lambda=2) state has n=1 for 2((1,2,3)) poles (mu(z),Theta(zz),Omega(zzz)) but n=2 for higher 2((l>or=4)) poles--from the hexadecapole Phi up. For Phi(Lambda=3) states, it holds that n=1 for 2(1) to 2(5) poles but n=2 for all 2((l>or=6)) poles. In short, what is usually stated in the literature--that n=1 for all possible 2(l) poles of linear molecules--only applies to Sigma(+/-) states. For degenerate states with n=2, all Cartesian 2(l) pole components (l>or=2/Lambda/) can be expressed as linear combinations of two irreducible multipoles, P(m=0)((l)) and P/m/=2 Lambda)((l)) [parallel (z axis) and anisotropy (xy plane)]. Our predictions are exemplified by the Theta, Omega, and Phi moments calculated for Lambda=0-3 states of selected diatomics (in parentheses): X (2)Sigma(+)(CN), X (2)Pi(NO), a (3)Pi(u)(C(2)), X (2)Delta(NiH), X (3)Delta(TiO), X (3)Phi(CoF), and X (4)Phi(TiF). States of Pi symmetry are most affected by the deviation from axial symmetry. PMID- 17718607 TI - Submillimeter-wave spectroscopy of DCO+ in the excited vibrational states: does the Stark effect cause anomalies in the (02(2)0) state? AB - The lowest two rotational transitions of (02(2)0) were not detected in previous investigations. This nonobservation was ascribed to the Stark broadening caused by the electric field in a hollow cathode discharge and an extended negative glow discharge. However, rotational lines of symmetric-top ions such as CH(3)CNH(+) and SD(3)(+) were observed in extended negative glow discharges with no such Stark effect. Also, no anomalies were observed for similar lines for HCN and HNC produced in an extended negative glow discharge. In the present investigation, we extended the measurements of DCO(+) up to 800 GHz. The DCO(+) ions were produced in an extended negative glow discharge in a gas mixture of D(2) and CO (a couple of millitorr each) in Ar buffer ( approximately 12 mTorr). The measurements were made mostly at liquid nitrogen temperature. Our observations confirmed that the lowest rotational lines in (02(2)0) within our frequency coverage, J=4-3, were too weak to be detected. However, a most notable result obtained in the present investigation is that the J=5-4 and J=6-5 lines of (02(2)0) and the J=5-4 line of (04(2)0) have been detected in induced emission. This observation implies that the previous nonobservation of low-J lines in (02(2)0) may not be due to the Stark effect. The l-type splitting in (03(3)0) has been observed for the J=9-8 transition and higher. However, the splittings for the J=7-6 and J=8-7 lines that are expected to be large enough have not been resolved. The reason for this "narrowing" has been unexplained at the present stage. The population inversion suggests that, initially, DCO(+) is formed predominantly in stretching vibrational states, and, subsequently, the energy transfer to bending vibrational states takes place through collisional relaxation processes. PMID- 17718608 TI - Interactions and dynamics in Li+Li2 ultracold collisions. AB - A potential energy surface for the lowest quartet electronic state ((4)A(')) of lithium trimer is developed and used to study spin-polarized Li+Li(2) collisions at ultralow kinetic energies. The potential energy surface allows barrierless atom exchange reactions. Elastic and inelastic cross sections are calculated for collisions involving a variety of rovibrational states of Li(2). Inelastic collisions are responsible for trap loss in molecule production experiments. Isotope effects and the sensitivity of the results to details of the potential energy surface are investigated. It is found that for vibrationally excited states, the cross sections are only quite weakly dependent on details of the potential energy surface. PMID- 17718609 TI - The water-oxygen dimer: first-principles calculation of an extrapolated potential energy surface and second virial coefficients. AB - The systematic intermolecular potential extrapolation routine (SIMPER) is applied to the water-oxygen complex to obtain a five-dimensional potential energy surface. This is the first application of SIMPER to open-shell molecules, and it is the first use, in this context, of asymptotic dispersion energy coefficients calculated using the unrestricted time-dependent coupled-cluster method. The potential energy surface is extrapolated to the complete basis set limit, fitted as a function of intermolecular geometry, and used to calculate (mixed) second virial coefficients, which significantly extend the range of the available experimental data. PMID- 17718610 TI - 1 Pi<--X1 Sigma+ band systems of jet-cooled ScCo and YCo. AB - Rotationally resolved resonant two-photon ionization (R2PI) spectra of ScCo and YCo are reported. The measured spectra reveal that these molecules possess ground electronic states of (1)Sigma(+) symmetry, as previously found in the isoelectronic Cr(2) and CrMo molecules. The ground state rotational constants for ScCo and YCo are B(0)(")=0.201 31(22) cm(-1) and B(0) (")=0.120 96(10) cm(-1), corresponding to ground state bond lengths of r(0) (")=1.812 1(10) A and r(0) (")=1.983 0(8) A, respectively. A single electronic band system, assigned as a (1)Pi<--X (1)Sigma(+) transition, has been identified in both molecules. In ScCo, the (1)Pi state is characterized by T(0)=15,428.8, omega(e)(')=246.7, and omega(e)(')x(e)(')=0.73 cm(-1). In YCo, the (1)Pi state has T(0)=13 951.3, omega(e)(')=231.3, and omega(e)(')x(e) (')=2.27 cm(-1). For YCo, hot bands originating from levels up to v(")=3 are observed, allowing the ground state vibrational constants omega(e)(")=369.8, omega(e)(")x(e)(")=1.47, and Delta G(12)(")=365.7 cm(-1) to be deduced. The bond energy of ScCo has been measured as 2.45 eV from the onset of predissociation in a congested vibronic spectrum. A comparison of the chemical bonding in these molecules to related molecules is presented. PMID- 17718611 TI - Extreme ionization of Xe clusters driven by ultraintense laser fields. AB - We applied theoretical models and molecular dynamics simulations to explore extreme multielectron ionization in Xe(n) clusters (n=2-2171, initial cluster radius R(0)=2.16-31.0 A) driven by ultraintense infrared Gaussian laser fields (peak intensity I(M)=10(15)-10(20) W cm(-2), temporal pulse length tau=10-100 fs, and frequency nu=0.35 fs(-1)). Cluster compound ionization was described by three processes of inner ionization, nanoplasma formation, and outer ionization. Inner ionization gives rise to high ionization levels (with the formation of [Xe(q+)](n) with q=2-36), which are amenable to experimental observation. The cluster size and laser intensity dependence of the inner ionization levels are induced by a superposition of barrier suppression ionization (BSI) and electron impact ionization (EII). The BSI was induced by a composite field involving the laser field and an inner field of the ions and electrons, which manifests ignition enhancement and screening retardation effects. EII was treated using experimental cross sections, with a proper account of sequential impact ionization. At the highest intensities (I(M)=10(18)-10(20) W cm(-2)) inner ionization is dominated by BSI. At lower intensities (I(M)=10(15)-10(16) W cm( 2)), where the nanoplasma is persistent, the EII contribution to the inner ionization yield is substantial. It increases with increasing the cluster size, exerts a marked effect on the increase of the [Xe(q+)](n) ionization level, is most pronounced in the cluster center, and manifests a marked increase with increasing the pulse length (i.e., becoming the dominant ionization channel (56%) for Xe(2171) at tau=100 fs). The EII yield and the ionization level enhancement decrease with increasing the laser intensity. The pulse length dependence of the EII yield at I(M)=10(15)-10(16) W cm(-2) establishes an ultraintense laser pulse length control mechanism of extreme ionization products. PMID- 17718612 TI - Ground states of the Mo2, W2, and CrMo molecules: a second and third order multireference perturbation theory study. AB - The potential energy curves of the molecules Mo(2), W(2), and CrMo have been studied ab initio using large basis sets and the "n-electron valence state perturbation theory" up to the third order in the energy. The third order results for Mo(2) and W(2) reproduce the equilibrium distances r(e) and the harmonic frequencies omega(e) in fairly good accordance with the experimental values but tend to underestimate the dissociation energy. The CrMo molecule, for which experimental dissociation energy data do not exist yet, is predicted to have a value for D(e) of approximately 2.5 eV. PMID- 17718613 TI - Electron correlation in the GK state of the hydrogen molecule. AB - The second excited (1)Sigma(g)(+) state of the hydrogen molecule, the so-called GK state, has a potential energy curve with double minima. At the united atom limit it converges to the 1s3d configuration of He. At large internuclear distances R, it dissociates to two separated atoms, one in the ground state and another in the 2p excited state. Radial pair density calculations and natural orbital analyses reveal unusual effect of electron correlation around the K minimum of the potential energy curve. As R>2.0 a.u., a natural orbital of sigma(u) symmetry joins the two natural orbitals of sigma(g) symmetry at smaller R. The average interelectronic distance decreases as the internuclear distance increases from R=2.0 to 3.0 a.u. Around R=3.0 a.u. the singly peaked pair density curve splits into two peaks. The inner peak can be attributed to the formation of the ionic electron configuration (1s)(2), where both 1s electrons are on the same nucleus. As the two 1s electrons run into different nuclei, one of the two 1s electrons is promoted to the 2p state, which results in the outer peak in the pair density curve. The Rydberg 1s2p configuration persists as the nuclei stretch, and becomes dominant at large R where four natural orbitals, two of sigma(g) and two of sigma(u) symmetry, become responsible. PMID- 17718614 TI - Structure and thermodynamics of a two-dimensional Coulomb fluid in the strong association regime. AB - The behavior of a two-dimensional neutral Coulomb fluid in the strong association regime (low density, high ionic charge) is explored by means of computer simulation and the hypernetted chain integral equation. The theory reproduces reasonably well the structure and thermodynamics of the system but presents a no solution region at temperatures well above the computer simulation estimates of the metal-insulator transition. In contrast with hypernetted chain predictions for the three-dimensional Coulomb fluid, here the breakdown of the solution is not accompanied by divergences in any physical quantity. PMID- 17718615 TI - Solution of the master equation for Wigner's quasiprobability distribution in phase space for the Brownian motion of a particle in a double well potential. AB - Quantum effects in the Brownian motion of a particle in the symmetric double well potential V(x)=ax(2)2+bx(4)4 are treated using the semiclassical master equation for the time evolution of the Wigner distribution function W(x,p,t) in phase space (x,p). The equilibrium position autocorrelation function, dynamic susceptibility, and escape rate are evaluated via matrix continued fractions in the manner customarily used for the classical Fokker-Planck equation. The escape rate so yielded has a quantum correction depending strongly on the barrier height and is compared with that given analytically by the quantum mechanical reaction rate solution of the Kramers turnover problem. The matrix continued fraction solution substantially agrees with the analytic solution. Moreover, the low frequency part of the spectrum associated with noise assisted Kramers transitions across the potential barrier may be accurately described by a single Lorentzian with characteristic frequency given by the quantum mechanical reaction rate. PMID- 17718616 TI - Hydration properties of magnesium and calcium ions from constrained first principles molecular dynamics. AB - We studied the solvation structures of the divalent metal cations Mg(2+) and Ca(2+) in ambient water by applying a Car-Parrinello-based constrained molecular dynamics method. By employing the metal-water oxygen coordination number as a reaction coordinate, we could identify distinct aqua complexes characterized by structural variations of the first coordination shell. In particular, our estimated free-energy profile clearly shows that the global minimum for Mg(2+) is represented by a rather stable sixfold coordination in the octahedral arrangement, in agreement with experiments. Conversely, for Ca(2+) the free energy curve shows several shallow local minima, suggesting that the hydration structure of Ca(2+) is highly variable. Implications for water exchange reactions are also discussed. PMID- 17718617 TI - Toward effective and reliable fluorescence energies in solution by a new state specific polarizable continuum model time dependent density functional theory approach. AB - A state specific (SS) model for the inclusion of solvent effects in time dependent density functional theory (TD-DFT) computations of emission energies has been developed and coded in the framework of the so called polarizable continuum model (PCM). The new model allows for a rigorous and effective treatment of dynamical solvent effects in the computation of fluorescence and phosphorescence spectra in solution, and it can be used for studying different relaxation time regimes. SS and conventional linear response (LR) models have been compared by computing the emission energies for different benchmark systems (formaldehyde in water and three coumarin derivatives in ethanol). Special attention is given to the influence of dynamical solvation effects on LR geometry optimizations in solution. The results on formaldehyde point out the complementarity of LR and SS approaches and the advantages of the latter model especially for polar solvents and/or weak transitions. The computed emission energies for coumarin derivatives are very close to their experimental counterparts, pointing out the importance of a proper treatment of nonequilibrium solvent effects on both the excited and the ground state energies. The availability of SS-PCM/TD-DFT models for the study of absorption and emission processes allows for a consistent treatment of a number of different spectroscopic properties in solution. PMID- 17718618 TI - Continuum limit semiclassical initial value representation for dissipative systems. AB - In this paper, we consider a dissipative system in which the system is coupled linearly to a harmonic bath. In the continuum limit, the bath is defined via a spectral density and the classical system dynamics is given in terms of a generalized Langevin equation. Using the path integral formulation and factorized initial conditions, it is well known that one can integrate out the harmonic bath, leaving only a path integral over the system degrees of freedom. However, the semiclassical initial value representation treatment of dissipative systems has usually been limited to a discretized treatment of the bath in terms of a finite number of bath oscillators. In this paper, the continuum limit of the semiclassical initial value representation is derived for dissipative systems. As in the path integral, the action is modified with an added nonlocal term, which expresses the influence of the bath on the dynamics. The first order correction term to the semiclassical initial value approximation is also derived in the continuum limit. PMID- 17718619 TI - Quantum effects in liquid water from an ab initio-based polarizable force field. AB - The importance of quantum effects as well as the accuracy of the ab initio-based polarizable TTM2.1-F force field in describing liquid water are quantitatively assessed by a detailed analysis of the temperature dependence of several thermodynamic and dynamical properties computed using the path-integral molecular dynamics and centroid molecular dynamics methods. The results show that quantum effects are not negligible even at relatively high temperatures, and their inclusion in simulations with the TTM2.1-F water model is necessary to achieve a more accurate description of the liquid properties. Comparison with the results reported in the literature for empirical, nonpolarizable force fields demonstrates that the effects of the nuclear quantization on the dielectric constant are dependent in part on how the electronic polarization is described in the underlying water model, while comparison with other ab initio-based force fields shows that the TTM2.1-F model provides an overall accurate description of liquid water. Analysis of the isotope effect on the dynamical properties does not display significant temperature dependence. This suggests that the contribution of quantum tunneling, which has been proposed as a possible cause for the different orientational dynamics observed for the HDO:H(2)O and HDO:D(2)O systems, appears to be small. PMID- 17718620 TI - Low density solid ozone. AB - We report a very low density ( approximately 0.5 g/cm(3)) structure of solid ozone. It is produced by irradiation of solid oxygen with 100 keV protons at 20 K followed by heating to sublime unconverted oxygen. Upon heating to 47 K the porous ozone compacts to a density of approximately 1.6 g/cm(3) and crystallizes. We use a detailed analysis of the main infrared absorption band of the porous ozone to interpret previous research, where solid oxygen was irradiated by UV light and keV electrons. PMID- 17718622 TI - Thermodynamic pressure of simple fluids confined in cylindrical nanopores by isothermal-isobaric Monte Carlo: influence of fluid/substrate interactions. AB - The thermodynamic pressure or grand potential density is calculated by isobaric isothermal Monte Carlo algorithm for simple Lennard-Jones fluid confined in cylindrical pores presenting chemical heterogeneities along their axis. Heuristic arguments and simulation results show that the thermodynamic pressure of the confined fluid contains two contributions. The first term is the usual pressure of the bulk fluid for a density equal to the confined fluid density defined as the total number of confined particles divided by the accessible volume due to thermal agitation. A second term has to be added, which is empirically shown to be proportional to the fluid/wall interface area and almost constant along the adsorption and desorption branches. This interfacial contribution, calculated for various pore models, has small variations reminiscent of the fluid adsorption/desorption properties calculated in the various pores. In particular, it is shown that this interfacial quantity is maximum for a fluid/substrate interaction intensity of the same order as the fluid/fluid one, while the thermodynamic pressure at which rapid desorption occurs presents a minimum. Stronger or weaker fluid/wall affinity favors gas state nucleation on the desorption of confined fluids. PMID- 17718621 TI - A study of the ionic conduction of mica surface by admittance spectroscopy. AB - The ionic conduction on the surface of humid mica has been analyzed by admittance spectroscopy as a function of relative humidity for different surface treatments. Measurements at low frequency indicate that water adsorption proceeds first in the form of a strongly adsorbed uniform thin layer, then with the formation of highly inhomogeneous thick aggregates. PMID- 17718623 TI - Kinetic coefficient of steps at the Si(111) crystal-melt interface from molecular dynamics simulations. AB - Nonequilibrium molecular dynamics simulations are applied to the investigation of step-flow kinetics at crystal-melt interfaces of silicon, modeled with the Stillinger-Weber potential [Phys. Rev. B 31, 5262 (1985)]. Step kinetic coefficients are calculated from crystallization rates of interfaces that are vicinals of the faceted (111) orientation. These vicinal interfaces contain periodic arrays of bilayer steps, and they are observed to crystallize in a step flow growth mode at undercoolings lower than 40 K. Kinetic coefficients for both [110] and [121] oriented steps are determined for several values of the average step separation, in the range of 7.7-62.4 A. The values of the step kinetic coefficients are shown to be highly isotropic, and are found to increase with increasing step separation until they saturate at step separations larger than approximately 50 A. The largest step kinetic coefficients are found to be in the range of 0.7-0.8 m(sK), values that are more than five times larger than the kinetic coefficient for the rough (100) crystal-melt interface in the same system. The dependence of step mobility on step separation and the relatively large value of the step kinetic coefficient are discussed in terms of available theoretical models for crystal growth kinetics from the melt. PMID- 17718624 TI - Oxygen vacancy formation energy in Pd-doped ceria: a DFT+U study. AB - Using the DFT+U method, i.e., first principles density functional theory calculations with the inclusion of on-site Coulomb interaction, the effects of Pd doping on the O vacancy formation energy (E(vac)) in CeO(2) has been studied. We find that E(vac) is lowered from 3.0 eV in undoped ceria to 0.6 eV in the Pd doped compound. Much of this decrease can be attributed to emerging Pd-induced gap states above the valence band and below the empty Ce 4f states. These localized defect states involve the Pd ion and its nearest neighbors, which are also the main acceptors of the extra electrons left on reduction. The effect of the Pd dopant on the geometric structure is very modest for CeO(2) but considerable for CeO(2-x). PMID- 17718625 TI - Ultrafast studies of gold, nickel, and palladium nanorods. AB - Steady state and ultrafast transient absorption studies have been carried out for gold, nickel, and palladium high aspect ratio nanorods. For each metal, nanorods were fabricated by electrochemical deposition into approximately 6 microm thick polycarbonate templates. Two nominal pore diameters(10 and 30 nm, resulting in nanorod diameters of about 40 and 60 nm, respectively) were used, yielding nanorods with high aspect ratios (>25). Static spectra of nanorods of all three metals reveal both a longitudinal surface plasmon resonance (SPR(L)) band in the mid-infrared as well as a transverse band in the visible for the gold and larger diameter nickel and palladium nanorods. The appearance of SPR(L) bands in the infrared for high aspect ratio metal nanorods and the trends in their maxima for the different aspect ratios and metals are consistent with calculations based on the Gans theory. For the gold and nickel samples, time resolved studies were performed with a subpicosecond resolution using 400 nm excitation and a wide range of probe wavelengths from the visible to the mid-IR as well as for infrared excitation (near 2000 cm(-1)) probed at 800 nm. The dynamics observed for nanorods of both metals and both diameters include transients due to electron phonon coupling and impulsively excited coherent acoustic breathing mode oscillations, which are similar to those previously reported for spherical and smaller rod-shaped gold nanoparticles. The dynamics we observe are the same within the experimental uncertainty for 400 nm and infrared (5 microm) excitation probed at 800 nm. The transient absorption using 400 nm excitation and 800 nm probe pulses of the palladium nanorods also reveal coherent acoustic oscillations. The results demonstrate that the dynamics for high aspect ratio metal nanorods are similar to those for smaller nanoparticles. PMID- 17718626 TI - On the Knudsen transport of gases in nanochannels. AB - We investigate the diffusion of gas molecules in nanochannels under the combinational effect of the vibration of the channel, gas-wall binding energy, and channel size through molecular dynamics simulations. It is found that the molecular vibration of the channel plays a critical role in gas transport process when the gas-wall binding energy is strong. For small binding energies, the influence of the flexibility of the wall can be neglected. In rigid channels, the gas self-diffusion coefficient increases with increasing gas-wall binding energy, while it decreases in nonrigid channels. The effect of the channel size on the self-diffusion coefficient is not significant except that a local maximum in the gas self-diffusion coefficient is found in 2 nm channels due to the strong repulsive force caused by the surface curvature of the channels. PMID- 17718627 TI - Interaction of benzene with amorphous solid water adsorbed on polycrystalline Ag. AB - The interaction of benzene with polycrystalline Ag and amorphous solid water (D(2)O) deposited thereupon at 124 K was investigated. Metastable impact electron spectroscopy, Reflection-absorption infrared spectroscopy, and temperature programmed desorption were utilized to obtain information on the electronic structure and the relative contribution to the bonding properties of the aromatic molecules among themselves and with D(2)O. On Ag, the benzene molecular plane is oriented parallel to the surface in the first layer. The second layer is tilted with respect to the first one. A total work function decrease of 0.8 eV takes place during the buildup of the first two layers. On amorphous solid water, the orientational distribution of the benzene molecular planes is initially peaked at an angle parallel to the water surface. During the completion of the first adlayer a coverage-induced reorientation takes place, inducing a tilt of the benzene molecules of the first adlayer. Still larger benzene exposures appear to lead to the formation of three-dimensional benzene clusters. Films produced by codepositing benzene and D(2)O or by postdepositing D(2)O layers on benzene films display "volcano like" benzene desorption during ice crystallization. PMID- 17718628 TI - Tight-binding molecular dynamics study of the role of defects on carbon nanotube moduli and failure. AB - We performed tight-binding molecular dynamics on single-walled carbon nanotubes with and without a variety of defects to study their effect on the nanotube modulus and failure through bond rupture. For a pristine (5,5) nanotube, Young's modulus was calculated to be approximately 1.1 TPa, and brittle rupture occurred at a strain of 17% under quasistatic loading. The predicted modulus is consistent with values from experimentally derived thermal vibration and pull test measurements. The defects studied consist of moving or removing one or two carbon atoms, and correspond to a 1.4% defect density. The occurrence of a Stone-Wales defect does not significantly affect Young's modulus, but failure occurs at 15% strain. The occurrence of a pair of separated vacancy defects lowers Young's modulus by approximately 160 GPa and the critical or rupture strain to 13%. These defects apparently act independently, since one of these defects alone was independently determined to lower Young's modulus by approximately 90 GPa, also with a critical strain of 13%. When the pair of vacancy defects adjacent, however, Young's modulus is lowered by only approximately 100 GPa, but with a lower critical strain of 11%. In all cases, there is noticeable strain softening, for instance, leading to an approximately 250 GPa drop in the apparent secant modulus at 10% strain. When a chiral (10,5) nanotube with a vacancy defect was subjected to tensile strain, failure occurred through a continuous spiral-tearing mechanism that maintained a high level of stress (2.5 GPa) even as the nanotube unraveled. Since the statistical likelihood of defects occurring near each other increases with nanotube length, these studies may have important implications for interpreting the experimental distribution of moduli and critical strains. PMID- 17718629 TI - Phase field theory of interfaces and crystal nucleation in a eutectic system of fcc structure: I. Transitions in the one-phase liquid region. AB - The phase field theory (PFT) has been applied to predict equilibrium interfacial properties and nucleation barrier in the binary eutectic system Ag-Cu using double well and interpolation functions deduced from a Ginzburg-Landau expansion that considers fcc (face centered cubic) crystal symmetries. The temperature and composition dependent free energies of the liquid and solid phases are taken from CALculation of PHAse Diagrams-type calculations. The model parameters of PFT are fixed so as to recover an interface thickness of approximately 1 nm from molecular dynamics simulations and the interfacial free energies from the experimental dihedral angles available for the pure components. A nontrivial temperature and composition dependence for the equilibrium interfacial free energy is observed. Mapping the possible nucleation pathways, we find that the Ag and Cu rich critical fluctuations compete against each other in the neighborhood of the eutectic composition. The Tolman length is positive and shows a maximum as a function of undercooling. The PFT predictions for the critical undercooling are found to be consistent with experimental results. These results support the view that heterogeneous nucleation took place in the undercooling experiments available at present. We also present calculations using the classical droplet model [classical nucleation theory (CNT)] and a phenomenological diffuse interface theory (DIT). While the predictions of the CNT with a purely entropic interfacial free energy underestimate the critical undercooling, the DIT results appear to be in a reasonable agreement with the PFT predictions. PMID- 17718630 TI - Phase field theory of interfaces and crystal nucleation in a eutectic system of fcc structure: II. Nucleation in the metastable liquid immiscibility region. AB - In the second part of our paper, we address crystal nucleation in the metastable liquid miscibility region of eutectic systems that is always present, though experimentally often inaccessible. While this situation resembles the one seen in single component crystal nucleation in the presence of a metastable vapor-liquid critical point addressed in previous works, it is more complex because of the fact that here two crystal phases of significantly different compositions may nucleate. Accordingly, at a fixed temperature below the critical point, six different types of nuclei may form: two liquid-liquid nuclei: two solid-liquid nuclei; and two types of composite nuclei, in which the crystalline core has a liquid "skirt," whose composition falls in between the compositions of the solid and the initial liquid phases, in addition to nuclei with concentric alternating composition shells of prohibitively high free energy. We discuss crystalline phase selection via exploring/identifying the possible pathways for crystal nucleation. PMID- 17718631 TI - Landau model of the RII-RI-RV rotator phases in mixtures of alkanes. AB - A phenomenological approach to the description of the rotator phases and transitions among them in mixtures of normal alkanes is proposed. The mixture exhibits crystal and three different rotator phases R(II), R(I), and R(V). The two phase regions are formed where the crystal+rotator and rotator+rotator phases coexist. The reason of these two phase regions is discussed by means of the Landau formalism. The influence of the concentration on these transitions and the transition temperatures are discussed by varying the coupling between the concentration variable and the order parameters. The theoretical predictions are found to be in good qualitative agreement with the experimental results. PMID- 17718632 TI - Ultrafast exciton-exciton coherent transfer in molecular aggregates and its application to light-harvesting systems. AB - Effects of the exciton-exciton coherence transfer (EECT) in strongly coupled molecular aggregates are investigated from the reduced time-evolution equation which we have developed to describe EECT. Starting with the nonlinear response function, we obtained explicit contributions from EECT to four-wave-mixing spectrum such as photon echo, taking into account double exciton states, static disorder, and heat-bath coupling represented by arbitrary spectral densities. By using the doorway-window picture and the projection operator technique, the transfer rates between two different electronic coherent states are obtained within a framework of cumulant expansion at high temperature. Applications of the present theory to strongly coupled B850 chlorophylls in the photosynthetic light harvesting system II (LH2) are discussed. It is shown that EECT is indispensable in properly describing ultrafast phenomena of strongly coupled molecular aggregates such as LH2 and that the EECT contribution to the two-dimensional optical spectroscopy is not negligible. PMID- 17718633 TI - Dependence of the energies of fusion on the intermembrane separation: optimal and constrained. AB - We calculate the characteristic energies of fusion between planar bilayers as a function of the distance between them, measured from the hydrophobic/hydrophilic interface of one of the two nearest, cis, leaves to the other. The two leaves of each bilayer are of equal composition: 0.6 volume fraction of a lamellar-forming amphiphile, such as dioleoylphosphatidylcholine, and 0.4 volume fraction of a hexagonal-forming amphiphile, such as dioleoylphosphatidylethanolamine. Self consistent field theory is employed to solve the model. We find that the largest barrier to fusion is that to create the metastable stalk. This barrier is the smallest, about 14.6k(B)T, when the bilayers are at a distance about 20% greater than the thickness of a single leaf, a distance which would correspond to between 2 and 3 nm for typical bilayers. The very size of the protein machinery which brings the membranes together can prevent them from reaching this optimum separation. For even modestly larger separations, we find a linear rate of increase of the free energy with distance between bilayers for the metastable stalk itself and for the barrier to the creation of this stalk. We estimate these rates for biological membranes to be about 7.1k(B)Tnm and 16.7 k(B)Tnm, respectively. The major contribution to this rate comes from the increased packing energy associated with the hydrophobic tails. From this we estimate, for the case of hemagglutinin, a free energy of 38k(B)T for the metastable stalk itself and a barrier to create it of 73 k(B)T. Such a large barrier would require that more than a single hemagglutinin molecule be involved in the fusion process, as is observed. PMID- 17718634 TI - Sampling of states for estimating the folding funnel entropy and energy landscape of a model alpha-helical hairpin peptide. AB - Protein folding times are many orders of magnitude shorter than would occur if the peptide chain randomly sampled possible configurations, which implies that protein folding is a directed process. The detailed shape of protein's energy landscape determines the rate and reliability of folding to the native state, but the large number of structural degrees of freedom generates an energy landscape that is hard to visualize because of its high dimensionality. A commonly used picture is that of an energy funnel leading from high energy random coil state down to the low energy native state. As lattice computer models of protein dynamics become more realistic, the number of possible configurations becomes too large to count directly. Statistical mechanic and thermodynamic approaches allow us to count states in an approximate manner to quantify the entropy and energy of the energy landscape within a folding funnel for an alpha-helical protein. We also discuss the problems that arise in attempting to count the huge number of individual states of the random coil at the top of the funnel. PMID- 17718635 TI - Density functional theory-symmetry adapted perturbation treatment energy decomposition of nucleic acid base pairs taken from DNA crystal geometry. PMID- 17718636 TI - Nonperturbative theory for the optical response to strong light of the light harvesting complex II of plants: saturation of the fluorescence quantum yield. AB - Recent progress in resolution of the structure of the light harvesting complex II provides the basis for theoretical predictions on nonlinear optical properties from microscopic calculations. An approach to absorption and fluorescence is presented within the framework of Bloch equations using a correlation expansion of relevant many particle interactions. The equations derived within the framework of this theory are applied to describe fluorescence saturation phenomena. The experimentally observed decrease of the normalized fluorescence quantum yield from 1 to 0.0001 upon increasing the intensity of laser pulse excitation at 645 nm by five orders of magnitude [R Schodel et al., Biophys. J. 71, 3370 (1996)] is explained by Pauli blocking effects of optical excitation and excitation energy transfer. PMID- 17718640 TI - Exploring Feldenkreis practitioners' attitudes toward clinical research. PMID- 17718641 TI - Prevalence of CAM use includes patients of Asian background. PMID- 17718642 TI - Cultivating Chinese medicinal plants in Germany: a pilot project. PMID- 17718643 TI - Neuroimaging acupuncture effects in the human brain. AB - Acupuncture is an ancient East Asian healing modality that has been in use for more than 2000 years. Unfortunately, its mechanisms of action are not well understood, and controversy regarding its clinical efficacy remains. Importantly, acupuncture needling often evokes complex somatosensory sensations and may modulate the cognitive/affective perception of pain, suggesting that many effects are supported by the brain and extending central nervous system (CNS) networks. Modern neuroimaging techniques such as functional magnetic resonance imaging, positron emission tomography, electroencephalography, and magnetoencephalography provide a means to safely monitor brain activity in humans and may be used to help map the neurophysiological correlates of acupuncture. In this review, we will summarize data from acupuncture neuroimaging research and discuss how these findings contribute to current hypotheses of acupuncture action. PMID- 17718644 TI - Dry needling of trigger points with and without paraspinal needling in myofascial pain syndromes in elderly patients. AB - OBJECTIVES: To compare the efficacies of dry needling of trigger points (TrPs) with and without paraspinal needling in myofascial pain syndrome of elderly patients. DESIGN: Single-blinded, randomized controlled trial. SUBJECTS: Forty (40) subjects, between the ages of 63 and 90 with myofascial pain syndrome of the upper trapezius muscle. INTERVENTIONS: Eighteen (18) subjects were treated with dry needling of all the TrPs only and another 22 with additional paraspinal needling on days 0, 7, and 14. RESULTS: At 4-week follow-up the results were as follows: (1) TrP and paraspinal dry needling resulted in more continuous subjective pain reduction than TrP dry needling only; (2) TrP and paraspinal dry needling resulted in significant improvements on the geriatric depression scale but TrP dry needling only did not; (3) TrP and paraspinal dry needling resulted in improvements of all the cervical range of motions but TrP dry needling only did not in extensional cervical range of motion; and (4) no cases of gross hemorrhage were noted. CONCLUSIONS: TrP and paraspinal dry needling is suggested to be a better method than TrP dry needling only for treating myofascial pain syndrome in elderly patients. PMID- 17718645 TI - Use of quantitative flow cytometry to measure ex vivo immunostimulant activity of echinacea: the case for polysaccharides. AB - INTRODUCTION: When directly exposed to various echinacea fractions, human leukocytes ex vivo are strongly stimulated to proliferate and to produce immunostimulation and inflammatory cytokines. A comparison of fractions containing lipoidal small molecules and high-molecular-weight water-soluble polysaccharides indicates that the latter are substantially more potent as immunostimulants. Echinacea purpurea (L.) Moench, E. angustifolia DC, and E. pallida (Nutt.), Nutt. extracts, and each plant part contain significantly potent constituents. Flow cytometric techniques were utilized. OBJECTIVES: This study was undertaken to determine whether flow cytometry could measure immunostimulant activity present in echinacea and, if so, which species produced more activity, which plant part was the most active, and whether the organic soluble or the aqueous extractables were more active. Ex vivo human clinical material was employed. DESIGN: Echinacea extracts were analyzed using flow cytometric techniques. The immunostimulation assays were measured in triplicate. METHODS: Samples dissolved in dimethyl sulfoxide (DMSO) were added to 200 microL of heparinized blood mixed with 50 muL of phosphate buffer, vortexed, and incubated to allow adequate time for immune-cell stimulation. Fifty (50) microL of the stimulated blood samples were added to each of a reagent cocktail consisting of 20 microL of CD4FITC/CD69PE/CD3PerCP expressed on the helper/inducer T-lymphocyte subset; CD8FITC/CD69/PE/ CD3PerCP expressed on the human suppresser/cytotoxic T lymphocytes and on a subset of natural killer lymphocytes; CD19FITC/CD69PE/CD45PerCP expressed on B-lymphocytes; or CD56FITC/CD69PE/CD45PerCP expressed on NK lymphocytes. Four hundred and fifty (450) microL of 1 X FACS lysing solution was added and incubated in the dark (rt, 30 minutes) and then subjected to flow cytometric analysis. All reported readings are the average of several determinations. Positive controls consisted of phorbol myristyl acetate (PMA) (50 ng/mL), phytohemagglutinin (10 microg/mL), CD2/CD2R (positive activation control)(5 microL/250 muL of reaction), and negative controls consisted of dimethyl sulfoxide (2% in RPMI-1640), RPMI-1640 medium, and cyclosporin A (10 microg/mL). RESULTS: The main immunostimulatory activity of echinacea resides in the water-soluble materials rather than the lipoidal small molecules. E. purpurea, E. Pallida, and E. angustifolia leaves, stems, flowering tops, and roots all produce substantial immunostimulatory activity. CONCLUSIONS: The use of flow cytometry demonstrates a link between the polysaccharides in echinacea and the biologic immunostimulatory effect that has therapeutic relevance, and strong evidence for this immunostimulant property is presented. PMID- 17718646 TI - Rhythmical massage therapy in chronic disease: a 4-year prospective cohort study. AB - OBJECTIVE: Rhythmical massage therapy is used in 24 countries but has not yet been studied in outpatient settings. The objective was to study clinical outcomes in patients receiving rhythmical massage therapy for chronic diseases. DESIGN: Prospective 4-year cohort study. SETTING: Thirty-six (36) medical practices in Germany. PARTICIPANTS: Eighty-five (85) outpatients referred to rhythmical massage therapy. OUTCOME MEASURES: Disease and Symptom Scores (physicians' and patients' assessment, respectively, 0-10) and SF-36. Disease Score was measured after 6 and 12 months, and other outcomes after 3, 6, 12, 18, 24, and 48 months. RESULTS: Most common indications were musculoskeletal diseases (45% of patients; primarily back and neck pain) and mental disorders (18%, primarily depression and fatigue). Median disease duration at baseline was 2.0 years (interquartile range 0.5-6.0). Median number of rhythmical massage therapy sessions was 12 (interquartile range 9-12), and median therapy duration was 84 (49-119) days. All outcomes improved significantly between baseline and all subsequent follow-ups. From baseline to 12 months, Disease Score improved from (mean +/- standard deviation) 6.30 +/- 2.01 to 2.77 +/- 1.97 (p < 0.001), Symptom Score improved from 5.76 +/- 1.81 to 3.13 +/- 2.20 (p < 0.001), SF-36 Physical Component score improved from 39.55 +/- 9.91 to 45.17 +/- 9.88 (p < 0.001), and SF-36 Mental Component score improved from 39.27 +/- 13.61 to 43.78 +/- 12.32 (p = 0.028). All these improvements were maintained until the last follow-up. Adverse reactions to rhythmical massage therapy occurred in 4 (5%) patients; 2 patients stopped therapy because of adverse reactions. CONCLUSIONS: Patients receiving rhythmical massage therapy had long-term reduction of chronic disease symptoms and improvement of quality of life. PMID- 17718647 TI - Complementary and alternative medicine use in Australia: a national population based survey. AB - OBJECTIVE: To investigate the use of and expenditure on 17 of the most popular forms of complementary and alternative medicine (CAM) by adult Australians, sociodemographic characteristics of CAM users, and communication between CAM users and their doctors. METHODS: In May-June 2005, a sample of 1067 adults, 18 years and older, from all Australian states and territories, was recruited by random-digit telephone dialing and interviewed about their CAM use in the previous 12 months. RESULTS: In the 12-month period, 68.9% (95% CI: 66.1%-71.7%) of those interviewed used at least one of the 17 forms of CAM and 44.1% (95% confidence interval: 41.1%-47.1%) visited a CAM practitioner. The estimated number of visits to CAM practitioners by adult Australians in the 12-month period (69.2 million) was almost identical to the estimated number of visits to medical practitioners (69.3 million). The annual "out of pocket" expenditure on CAM, nationally, was estimated as 4.13 billion Australian dollars (US $3.12 billion). Less than half of the users always informed their medical practitioners about their use of CAM. The most common characteristics of CAM users were: age, 18-34; female; employed; well-educated; private health insurance coverage; and higher than-average incomes. CONCLUSIONS: CAM use nationally in Australia appears to be considerably higher than estimated from previous Australian studies. This may reflect an increasing popularity of CAM; however, regional variations in CAM use and the broader range of CAM included in the current study may contribute to the difference. Most frequently, doctors would not appear to be aware of their patient use of CAM. PMID- 17718648 TI - Effects of level of meditation experience on attentional focus: is the efficiency of executive or orientation networks improved? AB - The present investigation examined the contributions of specific attentional networks to long-term trait effects of meditation. It was hypothesized that meditation could improve the efficiency of executive processing (inhibits prepotent/incorrect responses) or orientational processing (orients to specific objects in the attentional field). Participants (50 meditators and 10 controls) were given the Stroop (measures executive attention) and Global-Local Letters (measures orientational attention) tasks. Results showed that meditation experience was associated with reduced interference on the Stroop task (p < 0.03), in contrast with a lack of effect on interference in the Global-Local Letters task. This suggests that meditation produces long-term increases in the efficiency of the executive attentional network (anterior cingulate/prefrontal cortex) but no effect on the orientation network (parietal systems). The amount of time participants spent meditating each day, rather than the total number of hours of meditative practice over their lifetime, was negatively correlated with interference on the Stroop task (r = -0.31, p < 0.005). PMID- 17718649 TI - The process of whole person healing: "unstuckness" and beyond. AB - OBJECTIVE: The purpose of the present study was to fully explore the descriptions of patients' experiences of change after receipt of whole systems of complementary and alternative medicine (CAM) treatment. The aim was to develop an understanding of "unstuckness," including characterization of states, processes, and modifying factors. DESIGN: This was a secondary descriptive qualitative analysis, using techniques borrowed from phenomenology and grounded theory. SETTING/LOCATION: Three existent datasets collected at two different universities in the United States and Canada were used in the secondary analysis. PARTICIPANTS: Patients with chronic illnesses (including cancer and multiple nonmalignant conditions) who were treated with different packages of care were interviewed for the primary three studies (n = 76 with over 150 interview sessions). Complete data sets from these participants were used in this secondary analysis. OUTCOME MEASURES/DATA COLLECTION TECHNIQUES: Original transcripts were coded asking specific research questions about the experience of change subsequent to whole systems treatments. RESULTS: Data clearly indicated experiential differences between stuckness, unsticking, and unstuckness. Descriptors and characteristics of each state were identified, as was an initial grounded theory of change or transformation that occurs as an outcome of whole medical systems of CAM. CONCLUSIONS: The results provide preliminary conceptualizations and descriptions of the impact that CAM whole systems interventions may have on the individual' s life courses. This constitutes a first step in the identification, measurement, and evaluation of whole systems outcomes in a clinical setting. The emerging conceptualization of the process from stuckness to transformation may also provide a link between clinical research and systems science theory. PMID- 17718650 TI - Auricular acupuncture treatment for insomnia: a systematic review. AB - OBJECTIVES: To review trials on the efficacy and safety of auricular acupuncture (AA) treatment for insomnia and to identify the most commonly used auricular acupoints for treating insomnia in the studies via a frequency analysis. DATA SOURCES: The international electronic databases searched included: (1) AMED; (2) the Cochrane library; (3) CINAHL; (4) EMBASE; and (5) MEDLINE. Chinese electronic databases searched included: (1) VIP Information; (2) CBMdisc; and (3) CNKI. STUDY SELECTION: Any randomized controlled trials using AA as an intervention without using any co-interventions for insomnia were included. Studies using AA versus no treatment, placebo, sham AA, or Western medicine were included. DATA EXTRACTION: Two (2) independent reviewers were responsible for data extraction and assessment. The efficacy of AA was estimated by the relative risk (RR) using a meta-analysis. RESULTS: Eight hundred and seventy eight (878) papers were searched. Six (6) trials (402 treated with AA among 673 participants) that met the inclusion criteria were retrieved. A meta-analysis showed that AA was chosen with a higher priority among the treatment subjects than among the controls (p < 0.05). The recovery and improvement rates produced by AA was significantly higher than those of diazepam (p < 0.05). The rate of success was higher when AA was used for enhancement of sleeping hours up to 6 hours in treatment subjects (p < 0.05). The efficacy of using Semen vaccariae ear seeds was better than that of the controls (p < 0.01); while magnetic pearls did not show statistical significance (p = 0.28). Six (6) commonly used auricular acupoints were Shenmen (100%), Heart (83.33%), Occiput (66.67%), Subcortex (50%), Brain and Kidney (each 33.33%, respectively). CONCLUSIONS: AA appears to be effective for treating insomnia. Because the trials were low quality, further clinical trials with higher design quality, longer duration of treatment, and longer follow-up should be conducted. PMID- 17718655 TI - Can disease management transform health care? PMID- 17718656 TI - Evaluating disease management results: individuals and cohorts vs populations. PMID- 17718657 TI - Insights from the 2007 disease management colloquium. PMID- 17718658 TI - Critical factors in case management: practical lessons from a cardiac case management program. AB - Case management (CM) is an important strategy for chronic disease care. By utilizing non-physician providers for conditions requiring ongoing care and follow-up, CM can facilitate guideline-concordant care, patient empowerment, and improvement in quality of life. We identify a series of critical factors required for successful CM implementation. Heart to Heart is a clinical trial evaluating CM for coronary heart disease (CHD) risk reduction in a multiethnic, low-income population. Patients at elevated cardiac risk were randomized to CM plus primary care (212 patients) or to primary care alone (207). Over a mean follow-up of 17 months, patients received face-to-face nurse and dietitian visits. Mean contact time was 14 hours provided at an estimated cost of $1250 per patient for the 341 (81%) patients completing follow-up. Visits emphasized behavior change, risk factor monitoring, self-management skills, and guideline-based pharmacotherapy. A statistically significant reduction in mean Framingham risk probability occurred in CM plus primary care relative to primary care alone (1.6% decrease in 10-year CHD risk, p = 0.007). Favorable changes were noted across individual risk factors. Our findings suggest that successful CM implementation relies on choosing appropriate case managers and investing in training, integrating CM into existing care systems, delineating the scope and appropriate levels of clinical decision making, using information systems, and monitoring outcomes and costs. While our population, setting, and intervention model are unique, these insights are broadly relevant. If implemented with attention to critical factors, CM has great potential to improve the process and outcomes of chronic disease care. PMID- 17718659 TI - Implementing health information technology to improve the process of health care delivery: a case study. AB - Integration of health information is critical to the provision of effective, quality care in today's fragmented health care system. The increasing prevalence of chronic conditions and the demand for a comprehensive understanding of patient health on the part of providers are driving the need for the integration of health information through electronic health information systems. Two distinct health information systems currently utilized in the health care field include electronic medical records (EMR) and chronic disease management systems (CDMS). The integration of these systems is likely to enable the efficient management of health information and improve the quality of health care as it would provide real-time patient information in a coordinated manner. The lack of real-time information may result in delayed treatment, uninformed decisions, inefficient resource use, and medical errors. Despite their importance and widespread support, these systems have slow provider adoption rates. Our understanding of how health information technology may be used to improve health care is limited by the relative paucity of research on the adoption, integration, and implementation of these 2 types of systems. This paper documents the use of an EMR at Marshfield Clinic, a multidisciplinary group practice in the United States. We review the concomitant use of an EMR for clinical data capture and the implementation of a proprietary CDMS, InformaCare, for care management of chronic diseases. These 2 systems allow providers to deliver health care using evidence based guidelines that meet the Institute of Medicine's aim of providing safe, efficient, patient-centered, and timely care. PMID- 17718660 TI - The economic consequences of generic substitution for antiepileptic drugs in a public payer setting: the case of lamotrigine. AB - Generic substitution of antiepileptic drugs (AEDs) may increase pharmacy utilization, thus counterbalancing per-pill savings. The purpose of our study was to analyze the economic impact of government-mandated switching from branded to generic lamotrigine. Patients in a Canadian public pharmacy claims database using branded lamotrigine (Lamictal GlaxoSmithKline, UK) in 2002 converted to generic lamotrigine in 2003 and were observed from July 2002 to March 2006. Patients used branded lamotrigine for >or=90 days pre-generic entry and had >or=1 claim for generic lamotrigine post-generic entry. For the generic period, observed per patient monthly drug costs were calculated as the sum of costs for lamotrigine, other AEDs, and non-AEDs. Expected per-patient drug costs were estimated assuming lamotrigine dose and other prescription drug utilization in the generic period were identical to those observed during the brand period. Differences between observed and expected costs were compared. Among 1,142 branded lamotrigine users, overall average monthly drug costs per person were expected to decrease by $30.55 due to lower pill costs. Instead, they fell by $11.98 from the brand to the generic periods (p < 0.001). Because of dosage changes, lamotrigine costs decreased by $29.92 instead of the anticipated $33.87 (p < 0.001). Increased pharmacy utilization caused other AED costs to rise by $6.29 versus the expected $0.36 (p < 0.001), while non-AED drug cost increased by $11.64 rather than by $2.95 (p < 0.001). We concluded that conversion to generic lamotrigine resulted in lower than expected cost savings. Further research is necessary to determine whether this is due to reduced effectiveness and/or tolerability. Payers may weigh smaller-than-expected cost reductions against a possible decrease in effectiveness to assess the relevance of mandatory generic switching of lamotrigine. PMID- 17718661 TI - Health services outcomes for a diabetes disease management program for the elderly. AB - Our objective was to investigate the utilization, drug, and clinical outcomes of a telephonic nursing disease management (DM) program for elderly patients with diabetes. We employed a 24-month, matched-cohort study employing propensity score matching. The setting involved Medicare + Choice recipients residing in Ohio, Kentucky, and Indiana. There were 610 intervention group members over the age of 65 matched to a control group of members over the age of 65. The DM diabetes program employed a structured, evidence-based, telephonic nursing intervention designed to provide patient education, counseling, and monitoring services. Measurements consisted of Medical service utilization, including hospitalizations, emergency department visits, physician evaluation and management visits, skilled nursing facility days, drug utilization, and selected clinical indicators. Among the results, the intervention group had considerably and significantly lower rates of acute service utilization compared to the control group, including a 17.5% reduction in hospitalizations, 22.4% reduction in bed days, 12.3% increase in physician evaluation and management visits, 23.7% increase in angiotensin-converting enzyme (ACE) inhibitor use, 13.3% increase in blood glucose regulator use, 11.8% increase in hemoglobin A1c (HbA1c) tests, 10.3% increase in lipid panels, 26.0% increase in eye exams, and 35.5% increase in microalbumin tests. In conclusion, the study demonstrates that a commercially delivered diabetes DM program significantly reduces hospitalizations and bed-days while increasing the use of ACE inhibitors and blood glucose regulators along with selected clinical procedures such as HbA1c tests, lipid panels, eye exams, and microalbumin tests. PMID- 17718662 TI - Paying for disease management. AB - Disease Management (DM) first appeared in the United States in the early 1990s. Since then its incorporation into health plans has increased dramatically, yet proof of its effectiveness in terms of quality improvement and cost reduction remains to be seen. The following review provides an exploratory analysis of the basic principles of DM, its evolution and differences from traditional managed care, the ways in which programs are currently being used in the private and public sectors, and the challenges to determining a payment structure for incorporating DM into the current health insurance system. PMID- 17718664 TI - Rewarding excellence and efficiency in Medicare payments. AB - Medicare could become an innovative leader in using financial incentives to reward health care providers for providing excellent and efficient care throughout a patient's illness. This article examines the variations in cost and quality in the provision of episodes of care and describes how a pay-for performance payment system could be designed to narrow those variations and serve as a transition to a new Medicare payment policy that would align physicians' incentives with improvements in both quality and efficiency. In particular, Medicare could stimulate greater efficiency by developing new payment methods that are neither pure fee-for-service nor pure capitation, beginning with a pay for-performance payment system that rewards quality and efficiency and moving to a blended fee-for-service and case-rate system. PMID- 17718665 TI - Public/private partnerships for prescription drug coverage: policy formulation and outcomes in Quebec's universal drug insurance program, with comparisons to the Medicare prescription drug program in the United States. AB - In January 1997, the government of Quebec, Canada, implemented a public/private prescription drug program that covered the entire population of the province. Under this program, the public sector collaborates with private insurers to protect all Quebecers from the high cost of drugs. This article outlines the principal features and history of the Quebec plan and draws parallels between the factors that led to its emergence and those that led to the passage of the Medicare Prescription Drug, Improvement and Modernization Act (MMA) in the United States. It also discusses the challenges and similarities of both programs and analyzes Quebec's ten years of experience to identify adjustments that may help U.S. policymakers optimize the MMA. PMID- 17718663 TI - Markets and medical care: the United States, 1993-2005. AB - Many studies arguing for or against markets to finance medical care investigate "market-oriented" measures such as cost sharing. This article looks at the experience in the American medical marketplace over more than a decade, showing how markets function as institutions in which participants who are self-seeking, but not perfectly rational, exercise power over other participants in the market. Cost experience here was driven more by market power over prices than by management of utilization. Instead of following any logic of efficiency or equity, system transformations were driven by beliefs about investment strategies. At least in the United States' labor and capital markets, competition has shown little ability to rationalize health care systems because its goals do not resemble those of the health care system most people want. PMID- 17718666 TI - Program characteristics and enrollees' outcomes in the Program of All-Inclusive Care for the Elderly (PACE). AB - The Program of All-Inclusive Care for the Elderly (PACE) is a unique program providing a full spectrum of health care services, from primary to acute to long term care for frail elderly individuals certified to require nursing home care. The objective of this article is to identify program characteristics associated with better risk-adjusted health outcomes: mortality, functional status, and self assessed health. The article examines statistical analyses of information combining DataPACE (individual-level clinical data), a survey of direct care staff about team performance, and interviews with management in twenty-three PACE programs. Several program characteristics were associated with better functional outcomes. Fewer were associated with long-term self-assessed health, and only one with mortality. These findings offer strategies that may lead to better care. PMID- 17718667 TI - Population health: challenges for science and society. AB - The emphasis on risk factor intervention at the individual level has predominated in efforts to reduce mortality and promote health. Interest in social and other nonmedical interventions, particularly socioeconomic status (SES) influences, has increased in recent years. This article focuses on the interaction of social structure and socioeconomic status with other influences in complex pathways to affect health, and their contribution to health disparities. It examines both social class as an explanation of health differences and competing hypotheses concerning prenatal and early nutrition and cognitive capacity. Although education is associated with income, wealth, occupation, and other SES indicators and may not be the most important SES determinant, it influences a variety of pathways to health outcomes and offers strategic leverage for intervention because of social and political consensus on its value beyond health. PMID- 17718668 TI - Ocular hypotony: what is the mechanism of effusion and oedema? PMID- 17718669 TI - Bilateral striatal hyperintensities on diffusion weighted MRI in acute methanol poisoning. PMID- 17718671 TI - Methodological matters on an Alzheimer's dementia trial: is a double-blind randomized controlled study design sufficient to draw strong conclusions on treatment? Reply to Dr Mazza and colleagues. PMID- 17718673 TI - Clozapine-induced non-epileptic drop attacks: report of two cases. PMID- 17718674 TI - Hereditary inclusion body myopathy with a novel mutation in the GNE gene associated with proximal leg weakness and necrotizing myopathy. PMID- 17718675 TI - Response to Dr Balak and Dr Elmaci. PMID- 17718681 TI - Choreatic movements first appear in Huntington's disease associated with brain cortex lesion due to subdural hematoma. PMID- 17718682 TI - Transient global amnesia-like episode in a patient with severe hyperhomocysteinemia. PMID- 17718683 TI - Suprasellar pneumatocele causing a distal optic nerve and optic chiasmal syndrome. PMID- 17718684 TI - Comments on the article by Mazza et al. concerning Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer's dementia in a randomized placebo controlled double-blind study. PMID- 17718685 TI - Improved screening for a widespread disorder with therapeutic options: restless legs syndrome. PMID- 17718686 TI - EFNS guidelines on neurostimulation therapy for neuropathic pain. AB - Pharmacological relief of neuropathic pain is often insufficient. Electrical neurostimulation is efficacious in chronic neuropathic pain and other neurological diseases. European Federation of Neurological Societies (EFNS) launched a Task Force to evaluate the evidence for these techniques and to produce relevant recommendations. We searched the literature from 1968 to 2006, looking for neurostimulation in neuropathic pain conditions, and classified the trials according to the EFNS scheme of evidence for therapeutic interventions. Spinal cord stimulation (SCS) is efficacious in failed back surgery syndrome (FBSS) and complex regional pain syndrome (CRPS) type I (level B recommendation). High-frequency transcutaneous electrical nerve stimulation (TENS) may be better than placebo (level C) although worse than electro-acupuncture (level B). One kind of repetitive transcranial magnetic stimulation (rTMS) has transient efficacy in central and peripheral neuropathic pains (level B). Motor cortex stimulation (MCS) is efficacious in central post-stroke and facial pain (level C). Deep brain stimulation (DBS) should only be performed in experienced centres. Evidence for implanted peripheral stimulations is inadequate. TENS and r-TMS are non-invasive and suitable as preliminary or add-on therapies. Further controlled trials are warranted for SCS in conditions other than failed back surgery syndrome and CRPS and for MCS and DBS in general. These chronically implanted techniques provide satisfactory pain relief in many patients, including those resistant to medication or other means. PMID- 17718687 TI - Motor neuron disease associated with non-fluent rapidly progressive aphasia: case report and review of the literature. AB - The superimposed clinical features of motor neuron disease (MND) and frontotemporal lobar degeneration (FTLD) comprise a rare neurological overlap syndrome that represents a diagnostic challenge to neurologists. Currently, FTLD MND is considered a distinct entity and its clinicopathological basis has recently been reviewed. Our aim is to present a patient with MND and non-fluent rapidly progressive aphasia with clinical, imaging and histopathological correlation, as well as a brief review of the literature. We demonstrated the selective corticospinal tract (CST) and temporal lobe involvement using T1 spin echo with an additional magnetization transfer contrast pulse on resonance (T1 SE/MTC) and FLAIR MR sequences in our patient, with further clinical and histopathological correlation. To the best of our knowledge, there is no description about the use of these particular MR sequences in the evaluation of FTLD-MND patients. PMID- 17718688 TI - Association between Helicobacter pylori infection and mild cognitive impairment. AB - The association of Helicobacter pylori infection and Alzheimer's disease (AD) has recently been addressed, but no relative data exist regarding mild cognitive impairment (MCI), a prodromal phase of AD. The aim of this prospective study was to evaluate H. pylori infection, by histology in a Greek MCI cohort. Sixty-three consecutive patients with amnestic MCI and 35 normal controls underwent upper gastrointestinal endoscopy, histologic and serological examinations. The prevalence of H. pylori infection was 88.9% (56/63) in MCI patients and 48.6% (17/35) in anaemic controls, as confirmed by biopsy (P < 0.001, odds ratio: 8.47, 95% CI: 3.03-23.67). Mean serum anti-H. pylori IgG concentration and plasma total homocysteine (Hcy) titre were higher in MCI patients than controls (74.86 +/- 57.22 vs. 17.37 +/- 9.30 U/ml; and 16.03 +/- 4.28 vs. 13.5 +/- 1.20 micromol/l; P < 0.001 and P = 0.015, respectively). When compared with the anaemic participants, MCI patients exhibited more often multifocal (body and antral) gastritis (92.1% vs. 68.6%; P = 0.03); in H. pylori positive MCI patients cognitive state correlated with serum anti-H. pylori IgG concentration. In conclusion, H. pylori prevalence was significantly higher in MCI patients than controls. This infection might contribute, at least in part, to the pathophysiology of MCI, possibly through induction of chronic atrophic gastritis and elevated Hcy consequences. PMID- 17718689 TI - Circannual periodicity of migraine? AB - Seasonal rhythm of migraine attacks may support a role of the suprachiasmatic nucleus of the hypothalamus in the pathophysiology of migraine. The objective of this study was to provide evidence for seasonal variation in migraine. Eighty nine female migraineurs volunteered to record every migraine attack in detail for 12 consecutive months. Attacks associated with sleep complaints were defined as insomnia-related. By using Edwards' model for recognition and estimation of cyclic trends, time-series analysis was made. Fifty-eight patients, of which 26 had migraine without aura (MO) and 32 had migraine with aura (MA), completed the study. A total of 1840 attacks were recorded. The mean age +/- SD was 36.9 +/- 6.0. Patients with a lifetime history of MA showed marked seasonal fluctuation with more attacks in the light season compared to the dark. Time of peak was May 21. Peak/low ratio was 1.30 (95% CI: 1.08-1.55). When insomnia-related attacks (n = 312) were removed the seasonal variation became insignificant. There is a seasonal trend with more migraine attacks in the light season compared to the dark season in females with MA, but not MO, living in an arctic area. This is caused by the seasonal variation of insomnia-related attacks in patients with MA. PMID- 17718690 TI - Chronic obstructive pulmonary disease as a risk factor for stroke-related seizures. AB - Chronic obstructive pulmonary disease (COPD) is a risk factor for cardiovascular disorders and different types of stroke. The present retrospective study investigates whether COPD is also a risk factor for the development of seizures in stroke patients. The study population consisted of 237 patients with stroke related seizures. The control population was composed of 939 patients, admitted for a stroke between 2002 and 2004 and who did not develop epileptic spells on a follow up of 2 years. The stroke type and aetiology, and the vascular risk factors, including COPD, were compared. The seizure patients were older (P = 0.009) and had more arterial hypertension (P = 0.046) and cardiac-embolic strokes (P = 0.045) than the control group. On logistic regression only partial anterior circulation syndrome/infarct (PACS/I) and COPD (P < 0.001) emerged as independent risk factors for the development of seizures in stroke patients. The occurrence of seizures was not related to the severity of the COPD or to its type of treatment. The present study confirms that seizures occur most frequently in patients with a PACS/I. Although we were unable to demonstrate why COPD is a risk factor for seizures in stroke patients, its frequent associated nocturnal oxygen desaturation seems to be the most plausible explanation. Further prospective are needed to assess the role of COPD as a possible independent risk factor for stroke-related seizures. PMID- 17718691 TI - Prevalence of depression in a 12-month consecutive sample of patients with ALS. AB - There is an impression both in clinical practice and in research literature that patients with amyotrophic lateral sclerosis (ALS) possess 'heroic stoicism with a low frequency of depression'. Reliance on specific interview methods may have contributed to differing estimates of mood disorder in people with ALS. The objective of the current study was to compare prevalence rates of depression and anxiety in ALS using different assessment tools. The Beck Depression Inventory (BDI), The Hospital Anxiety and Depression Scale (HADS) and the Spielberger State Trait Anxiety Inventory (STAI) were sent to a 12-month consecutive sample of 190 patients with ALS attending a tertiary referral clinic in the UK. Data were collected from 104 patients with ALS. Using BDI scores, 44% were categorized as not depressed, 37% were mild-moderately depressed, 13% were moderately-severely depressed, and 6% were severely depressed. In contrast, the HADS depression subscale identified 75% as not depressed, 13% were in the borderline range, and 13% were categorized as meeting 'caseness' for depression. Twenty-five percent of the patients were using antidepressant medication. The estimated prevalence of mood disorder amongst patients with ALS may vary significantly depending on the measure used. PMID- 17718692 TI - Modification of neutrophil adhesion to human endothelial cell line in acute ischemic stroke by dipyridamole and candesartan. AB - Ischemic stroke is a leading cause of disability. Inflammation of the vessel wall following neutrophil adhesion to vascular endothelium may contribute to ischemic damage. We studied the effect of a platelet inhibitor and an angiotensin II receptor antagonist: alone or in combination, on the adhesion of neutrophils to endothelial cell line in stroke patients. Neutrophils were collected from 12 patients with ischemic stroke within 48 h. Six patients with previous stroke and six healthy volunteers served as control. Neutrophils were incubated with dipyridamole, candesartan or both and allowed to adhere to human endothelial cell line (ECV-304). Adhesion and expression of adhesion molecules (AM) were determined using fluorescence-activated cell-sorting (FACS). Dipyridamole and the combination of dipyridamole and candesartan inhibited significantly the adhesion of neutrophils from ischemic stroke patients as compared to controls with a prominent additive effect. No inhibition was seen in the control groups. These drugs also reduced significantly the expression of the AM Mac-1. Both candesartan and dipyridamole inhibited the adhesion of neutrophils to vascular endothelium in ischemic stroke patients but not in chronic stroke patients or healthy persons. This effect may be related to specific downregulation of Mac-1 by these drugs or other intracellular events. PMID- 17718693 TI - Effect of deep brain stimulation of the posterior hypothalamic area on the cardiovascular system in chronic cluster headache patients. AB - The objective of this study was to determine the cardiovascular effects of chronic stimulation of the posterior hypothalamic area (PHA) in cluster headache (CH) patients. Systolic and diastolic blood pressure (SBP, DBP), cardiac output, total peripheral resistance (TPR), heart rate (HR) and breathing were monitored at supine rest and during head-up tilt test (HUTT), Valsalva manoeuvre, deep breathing, cold face test and isometric handgrip in eight drug-resistant chronic CH patients who underwent monolateral electrode implantation in the PHA for therapeutic purposes. Autoregressive power spectral analysis (PSA) of HR variability (HRV) was calculated at rest and during HUTT. Each subject was studied before surgery (condition A) and after chronic deep brain stimulation (DBS) of PHA (condition B). Baseline SBP, DBP, HR and cardiovascular reflexes were normal and similar in both conditions. With respect to condition A, DBP, TPR and the LF/HF obtained from the PSA of HRV were significantly (P < 0.05) increased during HUTT in condition B. In conclusion, chronic DBS of the PHA in chronic CH patients is associated with an enhanced sympathoexcitatory drive on the cardiovascular system during HUTT. PMID- 17718694 TI - A single question for the rapid screening of restless legs syndrome in the neurological clinical practice. AB - The purposes of this study were to validate the use of a single standard question for the rapid screening of restless legs syndrome (RLS) and to analyze the eventual effects of the presence of RLS on self-assessed daytime sleepiness, global clinical severity and cognitive functioning. We evaluated a group of 521 consecutive patients who accessed our neurology clinic for different reasons. Beside the answer to the single question and age, sex, and clinical diagnosis, the following items were collected from all patients and normal controls: the four criteria for RLS, the Epworth Sleepiness Scale (ESS), the Clinical Global Impression of Severity (CGI-S), and the Mini-Mental State evaluation. RLS was found in 112 patients (70 idiopathic). The single question had 100% sensitivity and 96.8% specificity for the diagnosis of RLS. ESS and CGI-S were significantly higher in both RLS patient groups than in normal controls. RLS severity was significantly higher in idiopathic than in associated/symptomatic RLS patients. RLS can be screened with high sensitivity and good reliability in large patient groups by means of the single question; however, the final diagnosis should always be confirmed by the diagnostic features of RLS and accompanied by a careful search for comorbid conditions. PMID- 17718695 TI - Changes in autonomic cardiac control in patients with epilepsy after discontinuation of antiepileptic drugs: a randomized controlled withdrawal study. AB - The aim of this study was to assess cardiac autonomic control in patients with epilepsy before and after withdrawal of antiepileptic drugs (AEDs). The study was prospective, randomized and double blinded. Spectral analysis of heart rate variability (HRV) in 24 h ECG-registration before and after withdrawal of AEDs was used to assess autonomic cardiac control. The assessment of HRV with spectral analysis was based on sinus rhythm and normal heart beats [normal to normal beat (NN)]. Thirty-nine patients had 24 h rhythms free from any ectopic beats both before and after intervention, and were included in the analysis. Significant differences were found in the withdrawal group: filtered RR intervals for all 5 min segments of the analysis; percentage of differences between adjacent filtered RR intervals that are greater than 50 ms for the whole analysis; very low frequency power; low frequency power and high frequency power. The results demonstrate that slow withdrawal of AEDs in seizure-free patients with epilepsy on drug mono-therapy resulted in an increase in both parasympathetic and sympathetic functions, indicative of increased power amongst patients following cessation of AED treatment. As low HRV has been associated with increased mortality in patients with other diseases, this increased HRV may be beneficial. PMID- 17718696 TI - Clinical and experimental features of MuSK antibody positive MG in Japan. AB - We investigated the presence of antibodies (Abs) against muscle-specific tyrosine kinase (MuSK) in Japanese myasthenia gravis (MG) patients. MuSK Abs were found in 23 (27%) of 85 generalized seronegative MG (SNMG) patients but not in any of the ocular MG patients. MuSK Ab-positive patients were characterized as having female dominance (M:F, 5:18), age range at onset 18 to 72 (median 45) years old, and prominent oculobulbar symptoms (100%) with neck (57%) or respiratory (35%) muscle weakness. Limb muscle weakness was comparatively less severe (52%), thymoma absent. Most patients had good responses to simple plasma exchange and steroid therapy. MuSK IgG from all 18 patients was exclusively the IgG 4 subclass and bound mainly with the MuSK Ig 1-2 domain. Serial studies of 12 individuals showed a close correlation between the variation in MuSK Ab titers and MG clinical severity (P = 0.01 by Kruskal-Wallis). MuSK Ab titers were sharply decreased in patients who had a good response to early steroid therapy or simple plasma exchange, but there was no change, or a rapid increase on exacerbation after thymectomy. Measurement of MuSK Ab titers aids in the diagnosis of MG and the monitoring of clinical courses after treatment. PMID- 17718697 TI - Effect of body positioning during transcranial Doppler detection of right-to-left shunts. AB - We adopted an expanded transcranial Doppler (TCD) protocol to evaluate if additional injections of agitated saline in different positions would improve shunt detection or grading. We report the safety and feasibility of this expanded contrast TCD protocol. Patients with ischemic stroke were evaluated. The standard protocol for RLS detection was followed and expanded after the initial injection in the supine position to the right lateral decubitus, upright sitting, and sitting with right lateral leaning. Changes in blood pressure, heart rate, and any subjective complaints were noted. Changes in body position and additional agitated saline injections were tolerated. Right-to-left shunt (RLS) was detected in 35% of patients (n = 55). If the initial supine testing was negative, all subsequent positions/injections were also negative for RLS. However, if the supine injection was positive for RLS, the change in body positions increased the microbubble (microB) count in eight of 19 (42%) RLS-positive patients. The mean microB count in RLS-positive patients was 20 (95% CI: 9-32). The use of three additional body positions increased the microB count to 73 (95% CI: 13-132). The highest microB yield was achieved in the upright sitting position. Our findings support the safety and feasibility of the expanded TCD protocol. If the initial supine Valsalva-aided contrast TCD test is negative, there may be no need to study the patient in additional positions. However, if microB are detected in the supine position, additional testing for RLS in alternative positions may be found to be worthwhile. PMID- 17718698 TI - Quality of life in Friedreich ataxia: what clinical, social and demographic factors are important? AB - The aim of this study was to examine the impact of Friedreich ataxia (FRDA) on quality of life (QOL) using a generic tool to explore factors potentially associated with health status. Sixty-three individuals with genetically confirmed FRDA, self completed the Medical Outcomes Study 36 item Short Form Health Survey Version 2 (SF-36V2) and were assessed using the FRDA Rating Scale. Disease specific, demographic, and social characteristics were also recorded. SF-36V2 results were compared with Australian population norms. Sample subgroups of disease severity and age at disease onset were reviewed. Physical and mental component summaries were examined in relation to clinical and social characteristics using multiple linear regression. QOL is significantly worse in individuals with FRDA compared with population norms. Those with severe disease did not perceive a lower QOL than those with mild or moderate disease except in their physical functioning. A later age of onset and increased disease severity were negatively associated with physical QOL, whilst, increased disease duration was positively associated with mental QOL. There were limitations associated with the use of SF-36V2 in the FRDA population. Further exploration of health-related QOL and FRDA may benefit from the use of a more appropriate generic tool. PMID- 17718699 TI - Prevalence of autoimmune thyroid disorders in a Spanish multiple sclerosis cohort. AB - The aim of the study was to determine the prevalence of thyroid autoimmune disorders in a cohort of untreated multiple sclerosis (MS) patients and compare it with a stratified sample of an adult population. We prospectively studied 93 untreated MS patients. The control group included 401 healthy subjects selected by stratified sampling in a non-iodine-deficient area. Antithyroid antibodies (ATA) (antibodies against peroxidase and thyroglobulin) were considered positive at titres > or =149 IU/ml. Antibodies were positive in 11 MS patients (11.8%; 95% CI 5.3-18.4%). This prevalence was five times higher (P = 0.0001) when compared with that in the control population. We found six cases with subclinical hypothyroidism (6.45%; 95% CI 11.4-1.5) in contrast to 2.24% in the control group. Comparing MS with positive and negative ATA, there was a non-significant, slightly higher frequency of low Expanded Disability Status Scale (EDSS) score in the ATA-positive group (81% vs. 73.2%). One year after start of interferon (IFN) treatment, only one patient developed subclinical thyroid dysfunction. MS patients have a higher prevalence of ATA compared with the general population. An initial ATA and thyroid-stimulating hormone (TSH) determination is recommended in all MS patients. A periodic assessment of thyroid function during IFN treatment only seems to be justified in those cases where positive ATA or dysfunction is present before treatment. PMID- 17718700 TI - Treatment of hemiplegic migraine with triptans. AB - The objective of this study was to investigate the efficacy, safety and tolerability of triptans in patients who suffer from familial or sporadic hemiplegic migraine. Seventy-six subjects had used triptans at least once as an abortive treatment. Average triptan response was 6.9 (SD +/-3.1) and adverse event severity 4.9 (SD +/-3.3) on a scale from 0 to 10 (no response or side effect 0, excellent response or unbearable side effects 10). None of the patients had an ischaemic stroke or a heart attack. One patient reported prolonged neurological symptoms, related to a single dose of rizatriptan, but there were no pathological findings in several MRI-scans. Triptans seem to be safe and effective treatment for most hemiplegic migraine patients. PMID- 17718701 TI - Dementia, delusions and seizures: storage disease or genetic AD? AB - We describe a case of a young patient suffering from a rapidly progressive cognitive decline, associated with delusions, myoclonus and seizures and with no family history for dementia. Clinical features, along with skin biopsy findings were overlapping storage disease; the genetic analysis, however, demonstrated a de novo presenilin 1 mutation. The present report suggests the usefulness of genetic determinations in early-onset cases of dementia, even without an autosomal dominant trait of inheritance; for these cases and their relatives an extensive genetic counselling should be recommended. PMID- 17718702 TI - Effect of gabapentin on oculomotor control and parkinsonism in patients with progressive supranuclear palsy. AB - The efficacy of gabapentin on motor, oculomotor and frontal lobe symptoms was evaluated in patients with progressive supranuclear palsy (PSP) in a pilot study. Fourteen patients were included and seven of them received gabapentin. Clinical evaluation and horizontal eye movement recordings were performed at inclusion and 5-weeks later. Motor score and saccade latency in the visually guided saccade (VGS) task were identical in the two groups. However, the error rate in the antisaccade task was significantly decreased in the gabapentin group. This preliminary study shows that gabapentin improves reflexive saccade inhibition in patients with PSP but does not improve the latency of VGSs. PMID- 17718703 TI - Age-related white matter lesions are associated with reduction of the apparent diffusion coefficient in the cerebellum. AB - Cerebellar apparent diffusion coefficient (ADC) was found to be increased after acute cerebral hemispheric stroke. There are no data on cerebellar ADC changes in patients with chronic, age-related white matter lesions (ARWML). We aimed to determine longitudinal ADC variations on cerebral hemispheric and cerebellar white matter regions of patients with ARWML in order to study relations between ADC changes in both regions. ADC was measured serially (1-year interval) on lesioned periventricular frontal white matter, frontal and parietoccipital normal appearing white matter and middle cerebellar peduncles, on 19 aged patients with ARWML, which also underwent gait assessment. We compared regional ADC at 0 and 1 year and calculated variation percentages for each region. Correlation analysis was made between ADC variation in cerebellar regions and in contralateral hemispheric regions and between cerebellar ADC at 1 year and walking speed. After 1 year, ADC was higher on lesioned periventricular frontal white matter and lower on cerebellar regions. ADC variations on these regions were negatively correlated. Cerebellar ADC measured after 1 year was positively correlated with walking speed. This suggests a link between vascular disease progression inside frontal lesions and ADC reduction in contralateral cerebellar peduncles. Chronic ischemia in frontal white matter could have interrupted frontal-cerebellar circuits, producing hypometabolism in cerebellar regions (and worse performance on motor tasks), decreased perfusion and hence ADC reduction. PMID- 17718704 TI - Early diagnosis of rhinocerebral mucormycosis by cerebrospinal fluid analysis and determination of 16s rRNA gene sequence. AB - A 40-year-old diabetic woman was diagnosed with rhinocerebral mucormycosis. Cerebral mucormycosis is an acute life-threatening disease, which is caused by fungi of the class Phycomycetae. Clinical suspicion and detection of the fungal hyphae in cerebrospinal fluid (CSF) led to early diagnosis, subsequently confirmed by immunohistochemistry and molecular analysis of fungal RNA. Early infiltration of the infectious agent into the central nervous system resulted in septic thrombosis of the cavernous sinus, mycotic meningoencephalitis, brain infarctions as well as intracerebral and subarachnoidal hemorrhages. Despite immediate high-dose antimycotic treatment, surgical debridement of necrotic tissue, and control of diabetes as a predisposing factor, the woman died 2 weeks after admission. Although fungal organisms are rarely detectable in CSF specimens from patients with mycotic infections of the central nervous system, comprehensive CSF examination is beneficial in the diagnosis of rhinocerebral mucormycosis. Furthermore, a concerted team approach, systemic antifungal agents and early surgical intervention seem to be crucial for preventing rapid disease progression. PMID- 17718707 TI - Alphavirus infections in salmonids--a review. AB - The first alphavirus to be isolated from fish was recorded in 1995 with the isolation of salmon pancreas disease virus from Atlantic salmon, Salmo salar L., in Ireland. Subsequently, the closely related sleeping disease virus was isolated from rainbow trout, Oncorhynchus mykiss (Walbaum), in France. More recently Norwegian salmonid alphavirus (SAV) has been isolated from marine phase production of Atlantic salmon and rainbow trout in Norway. These three viruses are closely related and are now considered to represent three subtypes of SAV, a new member of the genus Alphavirus within the family Togaviridae. SAVs are recognized as serious pathogens of farmed Atlantic salmon and rainbow trout in Europe. This paper aims to draw together both historical and current knowledge of the diseases caused by SAVs, the viruses, their diagnosis and control, and to discuss the differential diagnosis of similar pathologies seen in cardiomyopathy syndrome and heart and skeletal muscle inflammation of Atlantic salmon. PMID- 17718708 TI - Biophysical properties of salmonid alphaviruses: influence of temperature and pH on virus survival. AB - A series of laboratory studies were undertaken to investigate the survival of salmonid alphaviruses (SAV) under a range of conditions relevant to waste disposal, persistence and spread in the field, and to laboratory studies and testing. SAV was found to be rapidly inactivated in the presence of high levels of organic matter at 60 degrees C at pH 7.2 and at pH 4 and pH 12 at 4 degrees C, suggesting that composting, ensiling and alkaline hydrolysis would all be effective at inactivating virus in fish waste. Testing was conducted under sterile conditions at 4, 10, 15 and 20 degrees C in sea water, half-strength sea water and fresh (hard) water, both in the absence and the presence of added organic matter. Virus survival was shown to be inversely related to temperature, and to be reduced by the presence of organic matter. Calculated half lives (t(1/2)) under these conditions ranged from 61.0 to 1.5 days. Testing in non sterile sea water resulted in reduced t(1/2) values. The half life of SAV in serum was also found to be inversely related to temperature, emphasizing the need for rapid shipment of samples at 4 degrees C to laboratories for virus isolation studies. PMID- 17718710 TI - Virus isolation vs RT-PCR: which method is more successful in detecting VHSV and IHNV in fish tissue sampled under field conditions? AB - This study compared the results of reverse transcription-polymerase chain reaction (RT-PCR) and traditional virus isolation on cell culture in detection of viral haemorrhagic septicaemia virus (VHSV) and infectious haematopoietic necrosis virus (IHNV). RT-PCR was used for 172 tissue sample pools (total of 859 fish) originating from a field survey on the occurrence of VHSV and IHNV in farmed and wild salmonids in Switzerland. These samples represented all sites with fish that were either identified as virus-positive by means of virus isolation (three sites, four positive tissue sample pools) and/or demonstrated positive anti-VHSV-antibody titres (83 sites, 121 positive blood samples) in a serum plaque neutralization test (SPNT). The RT-PCR technique confirmed the four VHSV-positive tissue sample pools detected by virus isolation and additionally identified one VHSV-positive sample that showed positive anti-VHSV-AB titres, but was negative in virus isolation. With IHNV, RT-PCR detected two positive samples not identified by virus isolation while in these fish the SPNT result had been questionable. One of the IHNV-positive samples represents the first detection of IHNV-RNA in wild brown trout in Switzerland. Compared to SPNT, the RT-PCR method detected, as with virus isolation, a much lower number of positive cases; reasons for this discrepancy are discussed. Our results indicate that RT-PCR can not only be successfully applied in field surveys, but may also be slightly more sensitive than virus isolation. However, in a titration experiment under laboratory conditions, the sensitivity of RT-PCR was not significantly higher when compared with virus isolation. PMID- 17718711 TI - First laboratory confirmation of salmonid alphavirus infection in Italy and Spain. PMID- 17718709 TI - Pancreas disease in farmed Atlantic salmon, Salmo salar L., and rainbow trout, Oncorhynchus mykiss (Walbaum), in Norway. AB - The present paper describes, for the first time, clinical signs and pathological findings of pancreas disease (PD) in farmed Atlantic salmon, Salmo salar L., and rainbow trout, Oncorhynchus mykiss (Walbaum), in sea water in Norway. Similarities and differences with reports of PD from Ireland and Scotland are discussed. Samples of 68 rainbow trout from disease outbreaks on 14 farms and from 155 Atlantic salmon from outbreaks on 20 farms collected from 1996 to 2004 were included in the present study. The histopathological findings of PD in Atlantic salmon and rainbow trout in sea water were similar. Acute PD, characterized by acute necrosis of exocrine pancreatic tissues, was detected in nine Atlantic salmon and three rainbow trout. Salmonid alphavirus (SAV) was identified in acute pancreatic necroses by immunohistochemistry. Most fish showed severe loss of exocrine pancreatic tissue combined with chronic myositis. Myocarditis was often but not consistently found. Kidneys from 40% and 64% of the rainbow trout and Atlantic salmon, respectively, had cells along the sinusoids that were packed with cytoplasmic eosinophilic granules. These cells resembled hypertrophied endothelial cells or elongated mast cell analogues. Histochemical staining properties and electron microscopy of these cells are presented. SAV was identified by RT-PCR and neutralizing antibodies against SAV were detected in blood samples. PMID- 17718712 TI - Crystal structure of the T315I mutant of AbI kinase. AB - Imatinib (Gleevec) is currently the frontline therapy for chronic myeloid leukemia (CML), a disease characterized by the presence of a constitutively activated chimeric tyrosine kinase protein Bcr-AbI. However, drug resistance often occurs at later stages of the disease, principally because of the occurrence of mutations in the kinase domain. Second generation Bcr-AbI inhibitors, such as dasatinib and nilotinib are capable of inhibiting many imatinib-resistant forms of the kinase but not the form in which threonine is mutated to isoleucine at the gatekeeper position (T315I). In this study, we present the crystal structure of the kinase domain of the c-AbI T315I mutant, as well as the wild-type form, in complex with a pyrrolopyridine inhibitor, PPY-A. The side chain of Ile315 is accommodated in the AbI T315I mutant structure without large conformational changes proximal to the site of mutation. In contrast to other inhibitors, such as imatinib and dasatinib, PPY-A does not occupy the hydrophobic pocket behind the gatekeeper residue. This binding mode, coupled with augmented contacts with the glycine-rich loop, appears to be critical for its ability to override the T315I mutation. The data presented here may provide structural guidance for the design of clinically useful inhibitors of Bcr-AbI T315I. PMID- 17718713 TI - Methods for computer-aided chemical biology. Part 1: Design of a benchmark system for the evaluation of compound selectivity. AB - Computational drug design and discovery methods have traditionally put much emphasis on the identification of novel active compounds and the optimization of their potency. For chemical genetics and genomics applications, an important task is the identification of small molecules that are selective against target families, subfamilies, or individual targets and can be used as molecular probes for specific functions. In order to develop or tune computational methods for such applications, there is a need for molecular benchmark systems that focus on compound selectivity, rather than biological activity (in qualitative terms) or potency. We have constructed a selectivity-oriented test system that consists of 26 compound selectivity sets against 13 individual targets belonging to three distinct families and contains a total of 558 selective compounds. The targets were chosen because of pharmaceutical relevance and the availability of suitable ligands, privileged structural motifs and/or target structure information. Compound selectivity sets were characterized by structural diversity, chemical scaffold and selectivity range analysis. The test system is made freely available and should be useful for the development of computational approaches in chemical biology. PMID- 17718714 TI - Methods for computer-aided chemical biology. Part 2: Evaluation of compound selectivity using 2D molecular fingerprints. AB - We analyze 558 compounds with selectivity against members of different protein families using two-dimensional molecular fingerprint methods. The calculations target compounds selective for 13 targets belonging to three families. These compound sets were especially designed for selectivity studies. The identification of compounds displaying different selectivity patterns against related protein targets is a prerequisite for chemical genetics and genomics applications to specifically interfere with functions of individual members of protein families. Thus far, computational methods have only little impact on the search for selective compounds. This is in part due to the fact that selectivity is more difficult to study computationally than activity because selectivity analysis requires the evaluation of compounds binding to multiple targets. Here, we investigate the ability of state-of-the-art two-dimensional molecular fingerprints to detect compounds having different selectivity. The results of systematic similarity search calculations reveal that two-dimensional fingerprints are capable of identifying compounds having different selectivity against closely related target proteins, although fingerprints were originally not developed for such applications. In addition to target-selective molecules, fingerprints are also found to preferentially recognize compounds that are active at the target family level. Our findings suggest that similarity methods should merit further exploration in the study of compound selectivity across target families. PMID- 17718715 TI - Structure-activity relationships of amyloid beta-aggregation inhibitors based on curcumin: influence of linker length and flexibility. AB - Self-assembly of amyloid beta into fibrillar plaques is characteristic of Alzheimer's disease and oligomers of this peptide are believed to be involved in neurodegeneration. Natural organic dyes, such as congo red and curcumin, bind tightly to amyloid beta and, at higher concentrations, block its self-assembly. The ability of these molecules to prevent amyloid accumulation has generated interest in understanding which of their structural features contribute to inhibitory potency. In general, amyloid beta ligands tend to be flat, planar molecules with substituted aromatic end groups; however, a comprehensive structure-activity study has not been reported. To better understand these ligands, we surveyed the effect of three prominent features on inhibition of amyloid aggregation: the presence of two aromatic end groups, the substitution pattern of these aromatics, and the length and flexibility of the linker region. We found that modification of any one of the modules has profound effects on activity. Further, we report that the optimal length of the linker lies within a surprisingly narrow regime (6-19 A). These results offer insight into the key chemical features required for inhibiting amyloid beta aggregation. In turn, these findings help define the nature of the docking site for small molecules on the amyloid beta surface. PMID- 17718716 TI - N-terminal bis-(2-chloroethyl)amino and fluorosulphonyl analogues of calcitonin gene-related peptide(8-37): irreversible antagonists at calcitonin gene-related peptide receptors. AB - Synthesis of the first irreversible calcitonin gene-related peptide receptor antagonists is described. bis-(2-chloroethyl)amino and fluorosulphonyl groups were incorporated into the 4-position of the N-terminal benzoyl group of a potent competitive antagonist, N-alpha-benzoyl-h-alpha-CGRP(8-37) (analogues 4 and 6). Based on previous structure-activity relationships, a second pair of N-terminally modified analogues was synthesized containing a novel benzylated-His residue in position 10 (analogues 5 and 7). In separate experiments, SK-N-MC cells and mouse thoracic aortas were bathed in solutions containing 5 microM and 1.5 microM of each analogue, respectively. After extensive washing, calcitonin gene-related peptide concentration-response curves were generated for cAMP production in SK-N MC cells and relaxation of mouse aortas. All analogues caused >20% reductions in maximal calcitonin gene-related peptide efficacy in both assays with analogue 5 containing an N-terminal bis-(2-chloroethyl)amino-benzoyl group and a benzylated His10 residue completely abolishing cAMP production in SK-N-MC cells. Reductions in maximal responses were dependent on the analogue concentration. Analogue 4 also caused more than 10-fold reductions in the potency of the calcitonin gene related peptide-mediated effects, whereas analogues 5, 6 and 7 have no significant effect on calcitonin gene-related peptide potency. These data indicate that all analogues bind irreversibly to calcitonin gene-related peptide receptors. The bis-(2-chloroethyl)amino-modified analogues 4 and 5 were more effective than the fluorosulphonyl-modified analogues 6 and 7. PMID- 17718717 TI - Suppression of type 1 diabetes in NOD mice by bifunctional peptide inhibitor: modulation of the immunological synapse formation. AB - The aim of this work was to design and utilize a bifunctional peptide inhibitor called glutamic acid decarboxylase-bifunctional peptide inhibitor to suppress the progression of type 1 diabetes in non-obese diabetic mice. The hypothesis is that glutamic acid decarboxylase-bifunctional peptide inhibitor binds simultaneously to major histocompatibility complex-II and intercellular adhesion molecule type 1 on antigen-presenting cell and inhibits the immunological synapse formation during T-cell-antigen-presenting cell interactions. Glutamic acid decarboxylase bifunctional peptide inhibitor was composed of a major epitope of the type 1 diabetes-associated antigen, glutamic acid decarboxylase 65 kDa, covalently linked to a peptide derived from CD11a of lymphocyte function-associated antigen 1. The suppression of insulitis and type 1 diabetes was evaluated using non-obese diabetic and non-obese diabetic severe combined immunodeficiency mice. Glutamic acid decarboxylase-bifunctional peptide inhibitor had the capacity to suppress invasive insulitis in non-obese diabetic mice. CD4+ T-cells isolated from glutamic acid decarboxylase-bifunctional peptide inhibitor treated mice also suppressed insulitis and hyperglycemia when transferred with diabetogenic non obese diabetic spleen cells into non-obese diabetic severe combined immunodeficiency recipients. As predicted, the glutamic acid decarboxylase bifunctional peptide inhibitor cross-linked a significant fraction of major histocompatibility complex class-II molecules to intercellular adhesion molecule type 1 molecules on the surface of live antigen-presenting cell. Intravenous injection of the glutamic acid decarboxylase-bifunctional peptide inhibitor elicited interleukin-4-producing T-cells in non-obese diabetic mice primed against the glutamic acid decarboxylase-epitope peptide. Together, the results indicate that glutamic acid decarboxylase-bifunctional peptide inhibitor induces interleukin-4-producing regulatory cells but does not expand the glutamic acid decarboxylase-specific Th2 population. Given that Th2 effector cells can cause pathology, the glutamic acid decarboxylase-bifunctional peptide inhibitor may represent a novel mechanism to induce interleukin-4 without Th2-associated pathology. PMID- 17718718 TI - Sequence recognition of alpha-LFA-1-derived peptides by ICAM-1 cell receptors: inhibitors of T-cell adhesion. AB - Blocking the T-cell adhesion signal from intercellular adhesion molecule 1/leukocyte function-associated antigen-1 interactions (Signal-2) can suppress the progression of autoimmune diseases (i.e. type-1 diabetes, psoriasis) and prevent allograph rejection. In this study, we determined the active region(s) of cLAB.L peptide [cyclo(1,12)Pen-ITDGEATDSGC] by synthesizing and evaluating the biologic activity of hexapeptides in inhibiting T-cell adhesion. A new heterotypic T-cell adhesion assay was also developed to provide a model for the T cell adhesion process during lung inflammation. Two hexapeptides, ITDGEA and DGEATD, were found to be more active than the other linear hexapeptides. The cyclic derivative of ITDGEA [i.e. cyclo(1,6)ITDGEA] has similar activity than the parent linear peptide and has lower activity than cLAB.L peptide. Computational binding experiments were carried out to explain the possible mechanism of binding of these peptides to intercellular adhesion molecule-1. Both ITDGEA and DGEATD bind the same site on intercellular adhesion molecule-1 and they interact with the Gln34 and Gln73 residues on D1 of intercellular adhesion molecule-1. In the future, more potent derivatives of cyclo(1,6)ITDGEA will be designed by utilizing structural and binding studies of the peptide to intercellular adhesion molecule 1. The heterotypic T-cell adhesion to Calu-3 will also be used as another assay to evaluate the selectivity of the designed peptides. PMID- 17718719 TI - Mu-opioid receptor ligands lack receptor subtype selectivity in the aequorin luminescence-based calcium assay. AB - The aim of the present study was to characterize the binding selectivity of the mu-opioid receptor ligands, endomorphin-1, endomorphin-2, and DAMGO, in the in vitro functional assay, based on the changes in intracellular calcium levels. For the experiments Chinese hamster ovary cells, stably expressing human mu-receptor, were used. The mu-agonist-induced calcium responses were significantly inhibited by naloxone, an opioid antagonist with high preference for the mu-opioid receptors. Naloxonazine, a mu1-non-peptide antagonist, inhibited the effect of all tested mu-agonists. However, there was no significant difference in the antagonist effect of naloxonazine on the calcium response induced by mu1- (endomorphin-2) and mu2-agonists (endomorphin-1, DAMGO). [D-Pro2]endomorphin-1 and [D-Pro2]endomorphin-2, putative peptide mu2- and mu1-antagonists, respectively, which had been shown in vivo to inhibit the antinociception induced by mu-agonists, produced no inhibitory effect in our in vitro experiments. Our results demonstrated that there is only one population of the mu-opioid receptors expressed in the Chinese hamster ovary cells. We suggest that the mu-opioid receptors form a homogenous population in the in vitro systems. However, the existence of mu-receptor subtypes in vivo is still pharmacologically possible. PMID- 17718720 TI - Synthesis of novel 3-butyl-2-substituted amino-3H-quinazolin-4-ones as analgesic and anti-inflammatory agents. AB - A variety of novel 3-butyl-2-substituted amino-3H-quinazolin-4-ones were synthesized by reacting the amino group of 3-butyl-2-hydrazino-3H-quinazolin-4 one with various aldehydes and ketones. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic index activities. The compound 3 butyl-2-(1-methylbutylidene-hydrazino)-3H-quinazolin-4-one (AS3) emerged as the most active analgesic agent. Compound 3-butyl-2-(1-ethylpropylidene-hydrazino)-3H quinazolin-4-one (AS2) emerged as the most active anti-inflammatory agent and is moderately more potent when compared to the reference standard diclofenac sodium. Interestingly, the test compounds showed only mild ulcerogenic potential when compared to aspirin. PMID- 17718721 TI - Structural model of human PSA: a target for prostate cancer therapy. AB - Based on unique biology of prostate cancer, prostate-specific antigen could be a useful target for prostate cancer therapies. Such targeting requires the identification of highly selective inhibitor-binding sites. Three-dimensional structure was calculated by homology modeling. The overall structure of human prostate-specific antigen is composed of two beta-barrel domain, kallikrein loop and active-site triad His57, Asp102, and Ser195. Structure of human prostate specific antigen is quite similar to hK-1 and HPK-3. The major differences were observed at kallikrein loop and position of active site. The substrate-binding pocket is predominated by hydrophobic residues and the bottom of the specificity pocket contains Ser189 as in chymotrypsin, which provides substrate specificity. The hydrophobic, and preferentially aromatic (Trp215), amino acid residues are determinant of substrate binding due to the presence of hydrophobic crevice between Tyr99 and Trp215. Crystal structure of human prostate-specific antigen is not determined till now and hence the report on an accurate and comparative model of human prostate-specific antigen is probably to help in understanding their functional network and finally could be helpful in structure-based rational drug designing. PMID- 17718722 TI - Bipiperidinyl carboxylic acid amides as potent, selective, and functionally active CCR4 antagonists. AB - A cell-based assay for the chemokine G-protein-coupled receptor CCR4 was developed, and used to screen a small-molecule compound collection in a multiplex format. A series of bipiperidinyl carboxylic acid amides amenable to parallel chemistry were derived that were potent and selective antagonists of CCR4. One prototype compound was shown to be active in a functional model of chemotaxis, making it a useful chemical tool to explore the role of CCR4 in asthma, allergy, diabetes, and cancer. PMID- 17718724 TI - Outcomes of referrals over a six-month period to a mental health gateway team. AB - Mental health policy in recent years has prescribed the role, function and form for services in England. Evidence of their effectiveness post-policy implementation has been limited to date and minimal guidance has been available on how services should operate together as whole systems. This paper reports findings from a study of referrals and their outcomes in respect of specialist community mental health services following implementation of national policy and its interpretation and configuration at a local level. Findings highlight that gateway workers configured as a team operating between primary and secondary care can effectively shield community mental health teams from high numbers of referrals that they would deem inappropriate. The study also identified the triage role of this service as being crucial to the effectiveness of developing and maintaining care pathways and also in potentially supporting the mental health capability of primary care. PMID- 17718725 TI - Expanding roles within mental health legislation: an opportunity for professional growth or a missed opportunity? AB - This paper aims to highlight both the necessity, and the way forward for mental health nursing to integrate proposed legislative roles into practice. Argued is that community mental health nursing, historically absent from active participation within mental health law in the UK, is faced with new and demanding roles under proposed changes to the 1983 Mental Health Act of England and Wales. While supporting multidisciplinary training for such roles, the imperative of incorporating nursing specific values into consequent training programs is addressed through the offered educative framework. This framework explores the issues of power, ethics, legislative thematics and application to contemporary service structures. PMID- 17718726 TI - Patient-centred care in acute psychiatric admission units: reality or rhetoric? AB - It has been suggested that patient-centred care be adopted as the primary method of mental health service delivery. This approach has been widely described in the literature and various frameworks for its delivery have been developed; however, many lack evaluation at present. The primary aim of this study was to gain an understanding of psychiatric nursing practice with people who self-harm using a qualitative descriptive approach. One of its objectives was to explore psychiatric nurses' approach and philosophical underpinnings to care. A sample of eight psychiatric nurses from two acute psychiatric admission units in Ireland was gained through convenience sampling. Data were collected through in-depth semi-structured interviews and analysed using a combination of content and theme analysis. Barker's Tidal Model was being utilized as the basis of nursing practice in both units. This paper presents one of the themes that emerged from the findings on the concept of patient-centred care, and how this translated in the use of the Tidal Model. PMID- 17718727 TI - Self-reported care needs of outpatients with a bipolar disorder in the Netherlands. AB - The care needs of patients with a bipolar disorder have not been studied to date. In the present research, the care needs, care received and unmet care needs for a population of outpatients with a bipolar disorder in the Netherlands are described. The participants (n = 157) completed the Need for Care Questionnaire and a questionnaire addressing various demographic and clinical characteristics. The results show the care needs to mainly involve the domains of psychological help, psychiatric help and social functioning. Unmet needs are frequently reported for all domains and found to be particularly frequent for needs on social functioning. Some significant associations between source of income, number of hospitalizations and involvement of community psychiatric nurses, on the one hand, and reported care needs, on the other hand, are identified and discussed. Incorporation of needs assessment into the treatment process is recommended in the form of structured questionnaires which can also then be used to guide and evaluate the treatment process. Future research should focus on the identification of the specific risk factors for particular care needs and thereby work to minimize the occurrence of such risk factors and promote early intervention efforts to reduce the burden on patients and their relatives. PMID- 17718728 TI - Collective inquiry: understanding the essence of best practice construction in mental health. AB - Delivering quality services has become a committed aspiration of mental health services over the past decade. Service planners look to validated care models to give guidance on what constitutes best practice. While there are many different views of what is 'best', there is a growing acknowledgement that services need to listen to the experiences of a network of frontline stakeholders in order to create quality mental health services. This paper describes an exploratory study within a regional mental health service that aimed to understand the meaning and enactment of best practice from the perspectives of a representative sample of service users and providers. A number of themes emerged as important and include the inherent value placed on consistent familial style relationships between service user and provider. This was deemed pivotal to the provision of expertise, good clinical decision-making, choice and collaboration. The study also highlighted stakeholder preference for autonomy and openness to inquiry into developing practice. In deconstructing the meaning of best practice, the study prompts a closer consideration of how best practice is created and suggests a view of best practice as a fluid dialogic process that is co-constructed by its participants in ongoing dialogic communication and reflection. PMID- 17718729 TI - The construct validity of a self-report questionnaire focusing on health promotion interventions in mental health services. AB - Health promotion has become a widespread concept, although little empirical research as to its importance and outcome has been performed in the mental health field. The aim of the present study was to investigate the construct validity of a newly developed Health Promotion Intervention Questionnaire, intended to measure patients' subjectively experienced health-promoting interventions within mental health services. A total of 135 participants responded to the questionnaire and to validation measures assessing psychiatric symptoms, empowerment, helping alliance and satisfaction with care. Bivariate correlations showed that overall perceived health-promoting interventions were positively correlated to, helping alliance, client satisfaction with care and empowerment. Stepwise multiple regression analysis showed that the strongest relationship was found between perceived health promotion intervention and helping alliance. In conclusion, the construct validity of the scale was satisfactory, except for one of its subscales where further investigations are needed. PMID- 17718730 TI - Improving the nursing documentation: professional consciousness-raising in a Northern-Norwegian psychiatric hospital. AB - The new Norwegian health legislation has increased the quality demands on nursing documentation. The staff at a psychiatric hospital has, together with us, explored their own way of producing written nursing documentation. In collaboration with them, we have analysed 32 patient journals which were made anonymous. We read through the documents with a critical view. We compared the findings with current professional quality standards. The actual language in the reports was analysed critically. The purpose was that the staff would become aware of unintentional consequences of their own parlance. We contributed by giving them a suitable analysis tool, which can be used for exploring own practice. The analysis tool became an aid in making the necessary qualitative improvements. This has made them change their practice. Today, the wards can exhibit documentation systems that to a large extent satisfy current professional and legal demands. An important change is the staff's specific contributions are made explicit. The staff has become more resource-oriented and the patient has, to a much larger extent than before, become an active participant in the development of the nursing plan. PMID- 17718731 TI - The subjective experiences of people who regularly receive depot neuroleptic medication in the community. AB - Little has been written on the subjective experiences of people who receive depot injections in the community. The authors of this paper have identified distinct gaps in the literature in terms of the views of service users regarding this particular intervention. Existing studies tend to focus upon the side effects of depot neuroleptic medication and the attitudes of Community Mental Health Nurses (CMHNs) towards administering depot medication and issues of compliance and non compliance. Mental health nurses are frequently perceived as adhering solely to a biomedical approach to patient care in their practice and the therapeutic aspects of their role is frequently unacknowledged. This paper explores how, within the process of giving a depot injection, CMHNs are able to carry out an assessment of their client's needs as well as being someone who is consistent, reliable and supportive. This means that the process of giving a depot injection may be considered as a therapeutic intervention. Qualitative data were obtained through the administration of a semi-structured interview schedule that was constructed and consisted of a range of questions that elicited service users views and opinions related to their experiences of receiving depot neuroleptic medication in the community. The relationship between patient and nurse, as this study reveals, was one that was not only therapeutic, but also provided a forum where psychosocial and clinical issues could be discussed and explored. Crucially, the service users felt they did have a role and an influence in the delivery of their care. PMID- 17718732 TI - 'Then I just showed her my arms . . .' Bodily sensations in moments of alienation related to self-injurious behaviour. A hermeneutic phenomenological study. AB - People committing self-injurious behaviour are often perceived as difficult patients; confronted with unhelpful reactions from nurses, the patients find themselves left alone in their distress. A connection between self-injurious behaviour and feelings of alienation is suggested in the literature. Alienation is described as a state in which the self is perceived as strange, machinelike and not in contact with its emotional and physical needs. On one hand, complex neuro-biological processes are seen as responsible for this; on the other hand, alienation is seen as a means of self-protection when one is exposed to a threatening or traumatic situation. Nursing interventions focus on the nurse patient relationship and on the handling of self-injuries, but they tend to ignore the client's previous experience. Proceeding from the assumption that patients committing self-injurious behaviour are the experts on their own harm, the purpose of the present study is to get insight into their 'lived experience' and to contribute to the understanding of this vulnerable group. Adopting a hermeneutic phenomenological research perspective, methods of participant observation and qualitative interviewing were chosen to generate data. The database consists of 99 observational sequences, five interviews and a set of email texts written by a self-injuring woman. A thematic analysis as described by Van Manen was done. The main findings are that alienation is experienced in several stages, that nurses can detect early signs of an impending loss of control, and that self-injurious behaviour is an effective strategy to end a painful experience of alienation. Self-injurious behaviour is appropriately understood as a form of 'self-care'. PMID- 17718733 TI - Audit on inpatient prescription writing guidelines. AB - Medication errors are a fairly common occurrence. Drug prescription errors maybe largely preventable. There is a lack of minimum national guidelines for prescriptions. The aim of this study is to see if there is a reduction in prescription errors after introduction of trust guidelines. Data were collected from inpatient drug cards with regard to the trust guidelines on prescription writing and completing the audit cycle after a period of 12 months. A refresher was provided after the initial survey. All cards were scanned on the same day. There was an absence of allergic information in 40% drug cards which improved slightly the second time around. This study indicates that a national prescription writing guidelines should be introduced and adopted. PMID- 17718734 TI - Single-session solution-focused brief therapy and self-harm: a pilot study. PMID- 17718735 TI - A qualitative study into the experience of individuals involved in a mindfulness group within an acute inpatient mental health unit. PMID- 17718736 TI - Some emerging implications for clinical supervision in British mental health nursing. PMID- 17718743 TI - Scylla or Charybdis: navigating between excessive examination and naive reliance on self-assessment. PMID- 17718744 TI - Continuing the dialogue: postcolonial feminist scholarship and Bourdieu - discourses of culture and points of connection. AB - Postcolonial feminist theories provide the analytic tools to address issues of structural inequities in groups that historically have been socially and economically disadvantaged. In this paper we question what value might be added to postcolonial feminist theories on culture by drawing on Bourdieu. Are there points of connection? Like postcolonial feminists, he puts forward a position that aims to unmask oppressive structures. We argue that, while there are points of connection, there are also epistemologic and methodologic differences between postcolonial feminist perspectives and Bourdieu's work. Nonetheless, engagement with different theoretical perspectives carries the promise of new insights - new ways of 'seeing' and 'understanding' that might enhance a praxis-oriented theoretical perspective in healthcare delivery. PMID- 17718745 TI - An examination of nervios among Mexican seasonal farm workers. AB - The purpose of this exploratory descriptive study was to examine a process model of the nervios experience of 30 Mexican seasonal farm workers. Focused interviews were conducted in Spanish to determine the workers' perspectives on their experiences of nervios while residing in rural, southwest Ontario. Data for analysis originated from variables created to represent key themes that had emerged from open coding of the interviews. Simultaneous entry, multiple regression analyses revealed that provocation, control salience, and cognitive sensory motor distress directly explained 67.2% of the variation in worker expressions of negative affectivity. The combination fear, feeling trapped, and giving in mediated the relationship of provocation, control salience and cognitive sensory motor distress to expressions of negative affectivity (R(2) = 88.1%). Control salience and its dampening effect on other elements of the nervios experience, however, appeared to be key to whether subjects experienced negative reactions to being provoked or distressed. This evidence points to nervios being a powerful, holistic idiom of distress with at least six variables contributing to its affective negativity. This information is important to our understanding of how nervios unfolds and for accurate specification of a nervios model for clinical practice and research. It also sets the stage for improved therapeutic alliances with nervios sufferers, and social action to reduce factors that provoke nervios. PMID- 17718746 TI - Prisoners signify: a political discourse analysis of mental illness in a prison control unit. AB - Increasingly, US prisoners diagnosed with mental illness are housed in control units, the most restrictive form of confinement in the US prison system. This situation has led to intense debate over the legal, ethical and clinical status of mental illness. This is a semiotic struggle with profound effects, yet most related work treats mental illness as a neutral, individual variable. Few analyses locate mental illness within a larger sociopolitical context. Fewer still focus on discursive practice. None critically analyze the accounts of control unit prisoners, who talk about extreme marginality and risk for victimization. This paper has two aims: (i) to develop a systematic method of analysis that accounts for signification as discourse-in-action; and (ii) to show how prisoners' signification of mental illness articulates agency through and against marginalizing discourse. Political discourse analysis demonstrates how control unit prisoners with psychiatric diagnoses signify mental illness, and articulate safer identifications in the process. PMID- 17718747 TI - Admitting hospital patients: a qualitative study of an everyday nursing task. AB - In recent years new modes of nursing work have been introduced globally in response to radical changes in healthcare policies, technology and new ideologies of citizenship. These transformations have redefined orthodox nurse-patient relationships and further complicated the division of labour within health-care. One distinctive feature of the work of registered nurses has been their initial assessment of patients being admitted to hospital, and it is of interest that this area of nursing practice remains central to the registered nurse's role at a time where other areas of practice have been relinquished to other occupational groups. This qualitative study, drawing on conversation analysis and ethnographic techniques, explores this area of everyday nursing work. Initial nursing assessments have attracted considerable interest in the nursing literature, where it is clearly stated that assessments should be patient centred and seen as the important first step on the road to a therapeutic nurse-patient relationship. Results from this study lead to the conclusion that the actual nursing practice of patient assessment on admission to hospital is at odds with the recommendations of the literature and that a more routinised, bureaucratic form of work is devised by nurses as a means of expediting the process of admission. PMID- 17718748 TI - Relatives' presence in connection with cardiopulmonary resuscitation and sudden death at the intensive care unit. AB - Within Norwegian intensive care units it is common to focus on the needs of the next of kin of patients undergoing end-of-life care. Offering emotional and practical support to relatives is regarded as assisting them in the initial stages of their grief process. It has also become usual to encourage relatives to be present at the time of death of close relatives. How can dignified end-of-life care coexist with the sometimes turbulent and dramatic character of intensive care in the highly technological environment of intensive care units? This paper describes a case study based on an incident that took place at the intensive care unit (ICU) of Trondheim University Hospital, Norway, in which the relatives of a newly deceased patient voiced unusually strong dissatisfaction with the way they were excluded in connection with cardiopulmonary resuscitation (CPR). The next of kin's criticism highlights an important paradox as well as a degree of inconsistency in lifesaving and end-of-life care at the ICU. I argue that an investigation of the multiple identities within medical practice can illuminate the potential for clashes between lifesaving and end-of-life care, as described and analysed in this paper. PMID- 17718749 TI - Complex adaptive systems and nursing. AB - There have been numerous references to complexity theory and complex systems in the recent healthcare literature, including nursing. However, exaggerated claims have (in my view) been made about how they can be applied to health service delivery, and there is a widespread tendency to misunderstand some of the concepts associated with complexity thinking (usually justified by describing the misconception as a metaphor). These concepts can be extended to systems and structures in healthcare organisations but, at this stage in the development of complexity science, only in a modest and very cautious way. In this paper I first outline some of the key ideas in the theory of complex adaptive systems, and then suggest that they have been distorted by a series of influential articles in the medical literature. I go on to present a simple case study of my own and undertake a complexity analysis of it. In the conclusion I suggest that we should beware of some outdated ideas being trotted out in the guise of complexity - an exciting and diverse area of enquiry that those old ideas do not, in fact, resemble. PMID- 17718750 TI - The meaning of being a middle-aged close relative of a person who has suffered a stroke, 1 month after discharge from a rehabilitation clinic. AB - The sudden and unexpected impact of stroke may have a stressful affect on close relatives. To illuminate the essential meaning in the lived experience of a middle-aged close relative of a person who has suffered a stroke, narrative interviews were conducted with 10 close relatives of people who had suffered their first stroke where both parties were aged over 18 and under 65. A phenomenological-hermeneutic interpretation of the narratives was then conducted. Three intimately intertwined themes emerged during the analysis: 'being called to mission', 'feeling lost and set adrift' and 'struggling to keep going'. The middle-aged close relatives felt unreflectively duty bound. There was a struggle with suffering and enduring the process of coping with life and overcoming a feeling of helplessness. Life turned out to be a struggle with overwhelming feelings. They felt alienated in a restricted life situation, disconnected from themselves and others, and from a world that supports feelings of being lost and set adrift (i.e. feeling homeless). Strength was found in moments when the situation improved, in being related to oneself and others, and when feelings of normality were regained. PMID- 17718751 TI - Pedagogy, power and practice ethics: clinical teaching in psychiatric/mental health settings. AB - Often, baccalaureate nursing students initially approach a psychiatric mental health practicum with uncertainty, and even fear. They may feel unprepared for the myriad complex practice situations encountered. In addition, memories of personal painful life events may be vicariously evoked through learning about and listening to the experiences of those diagnosed with mental disorders. When faced with such challenging situations, nursing students often seek counsel from the clinical and/or classroom faculty. Pedagogic boundaries may begin to blur in the face of student distress. For the nurse educator, several questions arise: Should a nurse educator provide counseling to students? How does one best negotiate the boundaries between 'counselor', and 'caring educator'? What are the limits of a caring and professional pedagogic relation? What different knowledges provide guidance and to what differential consequences for ethical pedagogic relationships? This paper offers a comparative analysis of three philosophical stances to examine differences in key assumptions, pedagogic positioning, relationships of power/knowledge, and consequences for professional ethical pedagogic practices. While definitive answers are difficult, the authors pose several questions for consideration in discerning how best to proceed and under what particular conditions. PMID- 17718753 TI - On evading analysis by becoming an analyst. AB - This paper considers what implications Bion's famous anecdote about 'some patients getting better and others going on to become psycho-analysts' might have in clinical practice. It explores key stages in the post-qualification analyses of three practitioners whose training analyses had left them qualified but restless and dissatisfied with their ongoing work. It suggests that a significant common factor in these unsatisfactory outcomes was the weakness of these analysands' egos, understood as their inability to enjoy coniunctios, and their profound fear of accessing the source of the problem. This had led to an unwitting investment in spurious super-ego driven alternatives such as professional qualification rather than face the initially bleak realization (of 'nameless dread') that could initiate analysis and individuation. Because of the containment and reward implicit in the training environment it is argued that training analysts--despite their experience and expertise--remain vulnerable to being recruited into an ameliorative fantasy that blocks the transference and inhibits development. PMID- 17718755 TI - Countertransference as active imagination: imaginative experiences of the analyst. AB - Active imagination is at the heart of Jung's elucidation of depth psychology. Yet, in the discourse of present day analytical psychology theory it is not always given the serious attention accorded to some other Jungian concepts. Active imagination emerges spontaneously within the 'third' area--the imaginal or dynamic field--in-between patient and analyst. It is commonly regarded as the patient's experience but I am proposing that, looked upon as the analyst's experience as well, active imagination offers a distinctly Jungian way of understanding some forms of countertransference. I am describing what I think many present-day analytical psychologists already do in their clinical practice but, as far as I know, it has not been theorized in quite this way before. The intention is to exploit the unique contribution of our Jungian heritage by reframing certain profoundly symbolic countertransference-generated imagery as active imagination. In this article these are differentiated from other less complex forms of imaginative countertransference through examples from clinical practice. The point is that such countertransference experiences may activate the symbolic function in the analyst and thus contribute to the mediation of emergent consciousness in the analysand. PMID- 17718756 TI - Black holes, uncanny spaces and radical shifts in awareness. AB - The 'black hole' is a signifier that pervades contemporary experience, conveying the 'gaps' and 'voids' in Western culture and psyche. Depth psychology stemmed from the growing uncanniness of city and psychic spaces during the 19(th) century. There was an emerging fascination with the 'dark Thing'--the 'It' of many names. Like a pandemic, depictions of the 'black hole' experience have continually emerged in the tragic events and cultural malaise of the twentieth and twenty-first centuries. Art, philosophy, science, psychoanalysis, literature, and cultural studies have variously articulated this frighteningly potent, yet endlessly elusive signifier. A many-sided, dialogical process best provides acquaintance with such a complex phenomenon. Multiple examples and perspectives, as well a detailed case study, will delineate some of its dimensions. They will show that such 'black hole' encounters are not merely negative, but are often the enigmatic source of new awareness and creation. PMID- 17718757 TI - Stimulating ethical awareness during training. AB - This paper argues for a preventative approach to ethical violations through developing and maintaining ethical awareness in training and in the group life of each society. Rather than teaching ethics as a theoretical subject, a method is proposed that encourages direct personal confrontation with ethical dilemmas through the consideration of key examples, in the Talmudic manner. This develops ethical 'muscles' and allows candidates to explore the dilemmas of what Primo Levi called the 'grey zone' where the boundaries between good and bad are unclear. Several illustrations of such ethical dilemmas are described, as used in workshops that the author has run in several societies and developing groups. In this way, ethical awareness becomes part of the group life of the society so that analysts become an ethical resource for each other. PMID- 17718758 TI - Emergence of the bipolar cultural complex in Walt Whitman. AB - My main hypothesis in this paper(1) is that America's seminal poet, Walt Whitman, was trapped--like so many of his contemporaries--in 'cultural complexes' (Singer & Kimbles 2004) that he internalized, but that he found a way to transcend the splits inherent in these 'bipolar' (Perry 1970) organizations through his art. One way he accomplished this was through his aesthetic method of 'holding the opposites' between two poles of a slavery is wrong/white supremacy is justified cultural complex. In my paper, I provide evidence for some of the contradictions inherent in Whitman's character by examining the political splits of his times and explore how various Self symbols he produced through his poetry, particularly the figures he called 'Black Lucifer' and the Deus Quadriune--a quaternity symbol -facilitated his personal and cultural transformation. Finally, I demonstrate the relevance of my hypothesis to contemporary racism during the pre-Civil Rights period in the South through a clinical example, and I show how the Jungian method of 'holding the opposites' can be effectively practised in the transference/countertransference field of psychotherapy in general. PMID- 17718759 TI - The hunger to fill an empty space: an investigation of primordial affects and meaning-making in the drive to conceive through repeated use of ART. AB - This research aims to investigate the drive to conceive through repeated use of Assisted Reproductive Technology (ART) in relation to the affective and meaning making processes related to this drive, through the use of the participants' memories of mother and being mothered, the choices they made regarding sex, intimacy and non-uterine activity in early adulthood and their fantasies of how a child would change their lives. Though prepared for an MSc dissertation it is a pilot empirical study using interpretative phenomenological analysis and applications of Jungian analytic and psychoanalytical theory. The collected data consists of three semi-structured interviews analysed through recurrent themes and amplification. Developmental and archetypal thinking has been suggested as a means of understanding. The results are strongly suggestive of two main themes across the interviews and further research is underway. The first theme is the importance of the relationship to mother and the quality of the mothering received in contributing to a woman's availability to become a mother at a time in her life when she is most fertile. The second theme of the pilot suggested that the crisis of infertility is a mask for another crisis of identity that also had links to the personal mother. At the core of these issues with mother there is an absence of father and an intra-psychic couple. Repeated infertility treatment becomes a transformative process necessitating repetition until something new can be created. PMID- 17718775 TI - Gene-environment interaction is now hype. PMID- 17718776 TI - A different view: there is value in grading intraventricular hemorrhage. AB - The traditional 1-4 grading system for intra-ventricular haemorrhage (IVH) has been criticized on several points. Grade 1 IVH is not really intra-ventricular at all but all neurosonographers have recognized this for many years. Grade 3 IVH is criticized as it includes ventricular dilatation but grade 3 IVH is a haemorrhage large enough to distend the ventricle with blood not cerebrospinal fluid (CSF). The distinction between small and large IVH is valuable as the prognosis is very different. Grade 4 IVH is criticized as it is not an 'extension' but authors have described this as parenchymal haemorrhagic infarction for decades. Grade 4 IVH has different risk factors, prognosis and prophylaxis from periventricular leucomalacia. The shorthand category of 'severe IVH', meaning grades 3 and 4, is not adequate for individual patient assessment but is certainly useful for annual statistics, comparisons over time and between hospitals. CONCLUSION: Despite limitations, grading IVH has value. PMID- 17718778 TI - Assessing psychological and health-related quality of life (HRQL) late effects after childhood cancer. PMID- 17718777 TI - Focus on infantile colic. AB - Infantile colic is a widespread clinical condition in the first 3 months of life, which is easily recognized, but incompletely understood and difficult to solve. The available evidence suggests that infantile colic might have several independent causes. The medical hypotheses include food hypersensitivity or allergy, immaturity of gut function and dysmotility, and the behavioural hypotheses include inadequate maternal-infant interaction, anxiety in the mother and difficult infant temperament. Other recent hypotheses, such as hormone alterations and maternal smoking, still need confirmation, whereas the new concept of alterations in the gut microflora, have been reported. A number of interventions, including pharmacological agents, are discussed, but it is probable that infants with colic require a graded strategy. CONCLUSION: Considering the favourable clinical course and the wide range of manifestations, a safe approach should be adopted, which is proportional to the intensity of the infantile colic. However, further research and guidelines are still needed. PMID- 17718779 TI - Environmental risk factors for attention-deficit hyperactivity disorder. AB - Attention-deficit hyperactivity disorder (ADHD) is the most common cognitive and behavioural disorder diagnosed among school children. It is characterized by deficient attention and problem solving, along with hyperactivity and difficulty withholding incorrect responses. This highly prevalent disorder is estimated to affect 5-10% of children and in many cases, persists into adulthood, leading to 4% prevalence among adults. Converging evidence from epidemiologic, neuropsychology, neuroimaging, genetic and treatment studies shows that ADHD is a valid medical disorder. The majority of studies performed to assess genetic risk factors in ADHD have supported a strong familial nature of this disorder. Family studies have identified a 2- to 8-fold increase in the risk for ADHD in parents and siblings of children with ADHD. Various twin and adoption studies have also highlighted the highly genetic nature of ADHD. In fact the mean heritability of ADHD was shown to be 0.77, which is comparable to other neuropsychiatric disorders such as schizophrenia or bipolar disorder. However, several biological and environmental factors have also been proposed as risk factors for ADHD, including food additives/diet, lead contamination, cigarette and alcohol exposure, maternal smoking during pregnancy, and low birth weight. Many recent studies have specifically examined the relationships between ADHD and these extraneous factors. This review describes some of these possible risk factors. CONCLUSION: Although a substantial fraction of the aetiology of ADHD is due to genes, the studies reviewed in this article show that many environmental risk factors and potential gene-environment interactions also increase the risk for the disorder. PMID- 17718780 TI - Oestrogen receptors and linear bone growth. AB - In this review we summarize available data regarding linear growth in oestrogen receptor alpha (ERalpha)- and oestrogen receptor beta (ERbeta)-deficient mice. We discuss these findings in relation to known oestrogenic effects in humans and the possibility of applying this knowledge for the therapeutic modulation of longitudinal bone growth employing selective oestrogen receptor modulators (SERMs). We conclude that SERMs potentially could offer new possibilities to modulate bone growth by specifically targeting different oestrogen receptors within the growth plate. PMID- 17718781 TI - Infants admitted to a neonatal intensive care unit: parental psychological status at 9 months. AB - AIM: This paper reports on the 9-month follow-up of parents who had an infant admitted to neonatal intensive care unit (NICU) compared to parents of full-term health infants. The psychological status of the parent groups is compared and factors associated with status change are examined. METHODS: Prospective longitudinal study of random sample of 447 parents (mother and father with an infant admitted to the NICU and 189 parents (mother and father) with term infant not requiring NICU admission. Parents' depression and anxiety symptoms were assessed at infant birth and 9 months later. RESULTS: The increased levels of depression and anxiety symptoms evident in NICU parents after their infant's birth were no longer apparent by 9 months. Higher initial symptom severity and perceived quality of the couple relationship were most commonly associated with improvement. Other factors related to symptoms change were number of baby hospitalizations for fathers and being in the NICU, age and living with the infant's father or mother. CONCLUSION: For the majority of parents having an infant admitted to the NICU does not result in ongoing psychological distress. PMID- 17718782 TI - Improved vitamin A supplementation regimen for breastfed very low birth weight infants. AB - OBJECTIVE: Preterm infants usually have low retinol status at birth and at discharge from hospital. We have evaluated a new protocol designed to improve plasma retinol in very low birth weight infants (VLBW, birth weight < 1500 g). DESIGN: An open intervention trial was conducted in which vitamin A was given in a human milk fortifier. The daily dose of vitamin A varied according to bodyweight and was given mixed with human milk instead of as a bolus. Blood samples were collected at inclusion and at discharge from hospital. Plasma was analyzed for retinol using high-performance liquid chromatography. The daily intake of vitamin A and plasma retinol concentration was compared with the vitamin protocol normally used in Norwegian hospitals. RESULTS: Sixty VLBW infants were included and 53 completed the study. At discharge from hospital, the reference group had lower median plasma retinol concentrations compared to the modified group (0.30 microM vs. 0.49 microM, p = 0.008). Fewer infants in the modified group had plasma retinol levels below 0.35 microM (indicating reduced hepatic stores) compared to infants in the reference group (44% vs. 69%, p = 0.04). CONCLUSION: The modified protocol improved plasma retinol levels at discharge compared to the reference protocol. PMID- 17718783 TI - Cardiopulmonary adaptation in large for gestational age infants of diabetic and nondiabetic mothers. AB - AIM: To compare cardiopulmonary adaptation in large for gestational age infants of diabetic and nondiabetic mothers. METHODS: Color Doppler echocardiography was performed in 113 (22 large for gestational age infants of diabetic mothers, 21 of nondiabetic mothers and 70 adequate for gestational age newborns) full-term infants. RESULTS: Pulmonary arterial pressure was significantly higher in infants of diabetic mothers than in those of nondiabetic mothers and normal infants at 24 h (38.5 vs. 32.5, and 35.5 mmHg, respectively). However, slow fall in this parameter was shown in all large for gestational age infants. Open ductus arteriosus was frequent in all large for gestational age infants, but its closure was significantly delayed in infants of diabetic mothers. Septal hypertrophy was higher in infants of diabetic mothers than in large for gestational age infants of nondiabetic mothers. CONCLUSION: Large for gestational age infants born from nondiabetic mothers showed delayed fall in pulmonary arterial pressure similar to those born from diabetic mothers but showed lower proportion of septal hypertrophy. Patent ductus arteriosus persisted for longer period of time in all large for gestational age infants than in normal infants, but its closure was significantly delayed in infants of diabetic mothers. PMID- 17718784 TI - Efficiency of oxygen cost during exercise in patients with symptoms of fatigue during physical activities. AB - BACKGROUND: With growing age, values for oxygen uptake decrease for the same level of exercise. However, some children with normal heart and normal maximal oxygen uptake complain of exertional fatigue. AIM: To evaluate the energy expenditure during submaximal treadmill exercise. SUBJECTS AND METHODS: In 20 children with exertional fatigue (mean age at testing: 7.9 +/- 1.8 years), oxygen uptake and respiratory gas exchange were assessed breath by breath. A graded exercise test was performed until exhaustion. Patients were compared to an age- and gender-matched control group (8.4 +/- 1.9 years, p = 0.45). RESULTS: Maximal oxygen uptake in patients (48.6 +/- 7.1 mL O(2)/min/kg) was similar to normal controls (47.4 +/- 5.2 mL/min/kg, p > 0.25). The inclination of the treadmill at maximal exercise was significantly (p = 0.02) lower in patients (12.6 +/- 4.9%) versus controls (16.0 +/- 3.5%). During submaximal exercise, oxygen uptake (expressed as mL/min/kg or as a percent of maximal oxygen uptake) was significantly higher (p < 0.001) in patients compared to normal controls. CONCLUSION: Children with exertional fatigue as compared to healthy controls, have a higher oxygen uptake for the same level of exercise and therefore perform at each level of exercise closer to their maximal exercise capacity. This may in part explain subjective complaints of poor exercise tolerance. PMID- 17718785 TI - Effect of physical activity intervention on body composition in young children: influence of body mass index status and gender. AB - AIM: To fight overweight and obesity in childhood, this study proposes an additional physical activity (PA) in young children aged 6-10 years. The objective was to evaluate the effect of school-based PA on the body composition according to body mass index (BMI) categories (nonobese vs. obese) and gender. METHODS: This 6-month study examined the effect of this intervention on body composition in 425 children in 14 primary schools (2 weekly PA sessions of 1 h each) compared to 5 control schools. Adiposity indices were evaluated or calculated: BMI, BMI z-score, waist circumference, sum of skinfolds and fat-free mass. RESULTS: No difference in the prevalence of obesity and anthropometric characteristics was found between the intervention and control groups at baseline. In girls, PA intervention had significant effect on all anthropometric variables (p < 0.05 to p < 0.001), except on BMI. In contrast, in boys only BMI z score (p < 0.001) and fat-free mass (p < 0.001) were affected. CONCLUSIONS: Six months of preventive PA intervention offer an effective means to improve body composition in obese children. The pattern of response related to PA was similar between girls and boys. In contrast, the pattern was different according to BMI category, with a higher response in obese than nonobese children. PMID- 17718787 TI - Overweight and obesity in Norwegian children: secular trends in weight-for-height and skinfolds. AB - AIM: The prevalence of overweight and obesity in paediatric populations has been rapidly increasing in many countries over the past decades. The aims of the present study were to provide new data on weight-for-height and skinfolds, and to compare these to growth references for children between 3 and 17 years, collected in the same city between 1971 and 1974. MATERIAL: The present study is based on cross-sectional data of 4115 children (2086 boys and 2029 girls) aged 4-15 years measured in 2003-6. RESULTS: Overall, 18.0% of the boys and 20.1% of the girls were above the 90th weight-for-height percentile of the 1971-1974 references, 8.0% and 7.2% were above the 97.5th percentile, indicating an upward shift in weight-for-height. An even more prominent increase was observed for skinfold thicknesses; for triceps skinfolds about 30% of the boys and 28% of the girls were above the 90th percentile of the 1971-1974 references, and corresponding values for subscapular skinfolds were 26.5% and 25.9%. Using international cut off values for body mass index, the overall prevalence of overweight and obesity was 12.5% and 2.1% in boys, and 14.8% and 2.9% in girls. CONCLUSIONS: Our study has demonstrated a significant increase in weight-for-height in Norwegian children over the last 30 years, and that these changes are caused by an increase in fat tissue, as shown by skinfold measurements. The current prevalence of overweight and obesity is comparable to recent estimates from most Western and Northern European countries. PMID- 17718786 TI - Liver dysfunction in paediatric obesity: a randomized, controlled trial of metformin. AB - AIM: In a previous study we showed that metformin reduced BMI z-scores and fasting glucose and insulin concentrations, and increased whole body insulin sensitivity in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. We analyzed the data from this study to determine (a) if metformin reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations during the 6-month trial, and (b) if the response to pharmacotherapy varied along gender or ethnic lines. METHODS: The 6 month trial was randomized, double blinded and placebo controlled; a total of 14 metformin-treated (500 mg bid) and 15 placebo-treated subjects completed the study. There were no dietary restrictions. RESULTS: In obese adolescents fed ad libitum, metformin (a) prevented the rise in ALT concentrations that were observed in placebo-treated subjects at the 3 to 5 month time-points (p < 0.05); (b) reduced (p < 0.01) the percentage of all ALT values exceeding 40 U/L; and (c) caused a modest (10%) but statistically significant (p < 0.05) reduction in serum ALT in Caucasian subjects. Metformin had no effect on ALT levels or the ALT to AST ratio in the five African American adolescents enrolled in the study but reduced their fasting insulin concentrations from 26.1 to 19.5 muU/mL (p < 0.05). CONCLUSIONS: Our findings suggest that metformin might reduce the rates or severity of liver dysfunction in selected high-risk adolescents. PMID- 17718788 TI - Association of adiposity measures with blood lipids and blood pressure in children aged 8-11 years. AB - AIM: To examine the association of body mass index (BMI), triceps skinfold thickness (TST) and percentage body fat (%BF) from bioelectrical impedance analysis (BIA) with blood lipids, systolic blood pressure (SBP) and diastolic blood pressure (DBP) in children. METHODS: Cross-sectional study was conducted on 1280 schoolchildren aged 8-11 years from the Cuenca province (Spain). Data collection was conducted under standardized conditions, taking several measurements of each variable to enhance accuracy. Analyses were performed using age-adjusted correlation coefficients, and multiple linear regression adjusted for age, BMI, TST and %BF. RESULTS: Correlations between %BF and apolipoprotein (apo) B, total cholesterol, low-density lipoprotein cholesterol (LDL-c), total cholesterol/HDL-c ratio and DBP were higher than those for BMI and TST. In contrast, the correlations between BMI, and apo A-I and SBP were higher than those for %BF and TST. The results were similar across the sexes. The correlations between each of the three measures of body fatness, and blood lipids and blood pressure were highest in children with greatest BMI and %BF. When analyses were adjusted for the three body fatness measures, %BF showed stronger associations than did BMI or TST with blood lipids and blood pressure, with the exception of apo A-I and SBP, which were more closely associated with BMI. CONCLUSION: %BF from BIA is more strongly associated than either BMI or TST with most of the blood lipid fractions in schoolchildren aged 8-11 years. PMID- 17718789 TI - Isolated extraordinary daytime urinary frequency of childhood: a case series of 26 children in Switzerland. AB - BACKGROUND: The term 'isolated extraordinary daytime urinary frequency' designates an abnormally increased diurnal frequency of painless urination in a completely toilet-trained child with normal urinalysis. METHODS: We report the history of 26 children (16 boys and 10 girls; aged between 4.1 and 10 years) who were referred to us between 2002 and 2006 and subsequently diagnosed with this condition. RESULTS: Possible psychosocial problems, or recent emotional stressors, were disclosed in the majority of the children: recent (36 months or less) asylum seekers (n = 9), school-related problems (n = 4), parental divorce (n = 2) or death of the mother (n = 1). Possible dietary causes were observed in 9 patients: oxalate-rich beverages (n = 5) and liberal ingestion of 'acidic' juices (n = 4). A diet low in oxalates was recommended when children were consuming large quantities of oxalate-rich beverages; and a diet low in acidic juice was recommended in those liberally ingesting acidic juices. Reassurance and observation were the approach in the remaining cases. The median duration of the symptoms was 5 months. A longer (p < 0.05) duration was noted in children of asylum seekers. CONCLUSIONS: This functional condition is easily identifiable, but often under- or misdiagnosed. Confounding the condition might result in redundant investigation. PMID- 17718790 TI - Association of n-6 long-chain polyunsaturated fatty acids to -866 G/A genotypes of the human uncoupling protein 2 gene in obese children. AB - AIM: To investigate the association of plasma fatty acids with the -866 G/A polymorphism of uncoupling protein 2 (UCP2) in obese children. METHODS: Fatty acid composition of plasma phospholipids and sterol esters were investigated in 80 obese children. RESULTS: Values of dihomo-gamma-linolenic acid (C20:3n-6) were significantly lower in children with the -866 A/A (n = 12) than in those with the -866 G/A (n = 34) or -866 G/G (n = 34) genotype in plasma phospholipids (3.01 [0.42] vs. 3.56 [1.02] vs. 3.53 [0.84], % weight/weight, median [interquartile range], p < 0.05), and were significantly lower in children with the -866 A/A genotype than in the other two groups in plasma sterol esters (0.73 [0.22] vs. 0.92 [0.23] vs. 0.94 [0.25], p < 0.05). Phospholipid C20:3n-6 and arachidonic acid (C20:4n-6) values showed only in children with the -866 G/G and -866 G/A genotypes significant positive correlations with plasma insulin concentrations. CONCLUSIONS: Significantly lower values of C20:3n-6 can be detected in obese children with the homozygous (-866 A/A) mutation of UCP2 than in equally obese children with heterozygous mutation or the normal genotype. High glucose stimulated insulin response is associated with high plasma C20:3n-6 and C20:4n-6 values only in obese children with the G allele of the -866 G/A polymorphism. PMID- 17718791 TI - Acute child poisonings in Oslo: a 2-year prospective study. AB - AIM: To study the current epidemiology, clinical course and outcome of poisonings among children in Oslo and compare findings to a similar study from 1980. METHODS: Observational study with prospective inclusion of all children (<15 years of age) with a main diagnosis of acute poisoning treated in hospital or outpatient clinic in Oslo for 2 years. RESULTS: One hundred seventy-five episodes of acute poisoning were included at the outpatient clinic only (n = 65), the paediatric department only (n = 82) or both (n = 28 referrals). Annual incidence was 97 per 100 000, significantly lower than in 1980 (230 per 100 000). Highest incidence was in 1-year-old males (576 per 100 000). In children <8 years of age, the most common toxic agents were pharmaceuticals (39%) and household products (32%); children > or = 8 years ingested mainly ethanol (46%) or pharmaceuticals (36%). Five percent of all children were comatose, and complications were seen in 13%. All children survived without sequelae. Half of the admissions needed treatment; most commonly used treatments were activated charcoal (33%), gastric lavage (9%) and emetics (9%). CONCLUSION: The incidence of child poisonings in Oslo has significantly reduced since 1980. Only half of the poisonings needed treatment, most of the poisonings were mild and the clinical outcome was good. PMID- 17718792 TI - Is parental aggravation associated with childhood overweight? An analysis of the National Survey of Children's Health 2003. PMID- 17718793 TI - Cord blood inflammatory markers, foetal vasculitis and cerebral MRI abnormalities in preterm infants. PMID- 17718795 TI - Is the prohibition of hormonal treatment for cryptorchidism, as suggested by the Nordic consensus group, justifiable? PMID- 17718797 TI - Fourth case of uterine aplasia, ovarian dysgenesis, amenorrhea and impuberism: a variant of Mayer-Rokitansky-Kuster-Hauser syndrome. PMID- 17718794 TI - Collagenous colitis and eosinophilic gastritis in a 4-year old girl: a case report and review of the literature. AB - Collagenous colitis (CC), a form of microscopic colitis, is characterized by a thick subepithelial collagen layer in the colon in the presence of chronic nonbloody watery diarrhoea and macroscopically normal-appearing colonic mucosa. Typically affecting elderly adults, CC is rare in children with only 12 cases previously reported in the literature. We report the case of a 4-year-old girl with CC associated with eosinophilic gastritis, which was clinically responsive to treatment with ketotifen, a benzocycloheptathiophene derivative, and H(1) class of antihistamine that stabilizes mast cells and potentially impairs eosinophil migration to target organs. We review the published cases of paediatric-onset CC and summarize the links between eosinophils and CC in the clinical and basic science literature. CONCLUSION: CC is a rare cause of chronic diarrhoea in children and may relate to mast cell and eosinophil activity. PMID- 17718798 TI - How much we worry for liver fat in children? PMID- 17718800 TI - Transanal intestinal evisceration from swimming pool skimmer suction: a spur to prevention. PMID- 17718804 TI - Field trial on the relationship of blood metabolites and body condition score with the recurrence of luteal activity in Estonian Holstein cows. AB - Associations of body condition scores and blood metabolites, measured before calving and at different periods during early lactation, with recurrence of luteal activity were investigated in a 250-head commercial dairy farm during a 4 year period (1999-2002). The study was conducted on 48 dairy cows (60 lactations) with average 305-day milk yield of 8149 kg per cow. Blood samples taken 1-14 days before calving and 1-14, 28-42 and 63-77 days after calving were analysed for aspartate aminotransferase, glucose, ketone bodies, triglycerides, non-esterified fatty acids and cholesterol. Milk progesterone (P(4)) profiles (samples collected twice a week, P(4) levels measured in whole milk by enzyme immunoassay) were used to evaluate the interval from calving to first luteal response, P(4) >5 ng/ml, and the interval from calving to first normal cycle. The MIXED procedure of the sas system was used to study the association of investigated parameters. A higher concentration of ketone bodies before calving was associated with shorter interval to recurrence of first normal cycle (P = 0.007) and tended to be related to shorter interval from calving to first luteal response (P = 0.071). A lower prepartum aminotransferase activity showed a tendency to be associated with shorter interval from calving to first luteal response (P = 0.084). Results suggest metabolic status up to 2 weeks prepartum to be related to the resumption of postpartum luteal activity in Estonian Holstein dairy cows. PMID- 17718801 TI - Hospitalization for asthma and use of inhaled steroids. PMID- 17718805 TI - Comparison of plasma metabolite concentrations and enzyme activities in beef cattle raised by different feeding systems in Korea, Japan and New Zealand. AB - Concentrations of metabolites and immunoreactive insulin (IRI) and activities of enzymes related to energy metabolism were measured in plasma of Korean and Japanese beef cattle, which were raised by the indoor feeding system programmed to feed larger amount of roughage in their growing periods and larger amount of concentrate diet in their finishing periods (Japanese feeding system), and grazing New Zealand beef cattle. By the Japanese beef grading system, Korean and Japanese beef cattle showed high beef quality score, average grade 3.3 and 3.6, respectively. The plasma free fatty acid and lactate concentrations and lactate dehydrogenase (LDH), malate dehydrogenase (MDH) and aspartate aminotransferase (AST) activities in Korean beef cattle were significantly higher than those in Japanese beef cattle. The plasma lactate concentration in Korean beef cattle was 8.40 mmol/l, which was similar to the values observed in lactic acidosis. The higher activities of plasma LDH, MDH and AST may indicate slight liver damage by slightly acidotic conditions in Korean beef cattle. New Zealand beef cattle fed on pasture which they harvest by grazing showed significantly lower plasma glucose, cholesterol, lactate and IRI concentrations and enzyme activities than those in Korean and Japanese beef cattle fed on larger amount of concentrate diets. Plasma metabolite concentrations and energy metabolism-related enzyme activities may be good indicators for evaluating metabolic conditions of beef cattle raised by different feeding systems. PMID- 17718806 TI - Interleukin-6 and tumour necrosis factor in synovial fluid from horses with carpal joint pathology. AB - The carpal joints are common sites of traumatic arthritis and osteoarthritis (OA) in athletic horses. The pro-inflammatory cytokines interleukin (IL)-6 and tumour necrosis factor (TNF) may be of great importance in the development of intra articular lesions. The aim of the present study was to investigate possible associations between synovial fluid levels of bioactive IL-6 and TNF and different types of joint lesions seen in traumatic arthritis and OA. Synovial fluid was collected from horses with carpal lameness immediately before arthroscopic surgery. Articular cartilage, synovial membranes and intra-articular ligaments were assessed macroscopically at arthroscopy. Synovial fluid levels of IL-6 and TNF were determined by bioassays, and the cytokine levels between different grades of morphologic changes in each type of assessed tissue were compared. The highest levels of IL-6 were detected in joints with chip fractures. All joints with chip fractures also showed some degree of synovitis. Tumour necrosis factor bioactivity was low and not associated with any joint lesion. Hence, TNF is not useful as a biomarker indicating a specific joint lesion in equine traumatic arthritis or OA. We conclude that a dramatic increase of IL-6 in synovial fluid indicates the presence of osteochondral fragmentation, although low or undetectable levels of IL-6 do not exclude chip fractures. The role of IL 6 in the disease process of osteochondral fragmentation needs further investigation. PMID- 17718807 TI - Effect of flunixin meglumine on cytokine levels in experimental endotoxemia in mice. AB - In this study, effect of flunixin meglumine on serum tumour necrosis factor alpha, (TNFalpha) interleukin-1 beta and interleukin-10 levels was investigated in lipopolysaccharide-induced endotoxic mice. Healthy 273 Balb/C mice were used and divided into three equal groups. Group 1 was injected lipopolysaccharide (Escherichia coli 0111:B4, 250 microg/mouse, intraperitoneally), Group 2 was injected flunixin meglumine (2.5 mg/kg, subcutaneously), and Group 3 was injected lipopolysaccharide + flunixin meglumine. After the treatments, at 0., 1., 2., 3., 6., 12., 24th hours and 3., 5., 7., 14., 21., 28th days blood samples were taken from seven mice in each group. Serum TNFalpha, interleukin-1 beta and interleukin 10 levels were measured using commercially available kits by enzyme-linked immunoassay. Flunixin meglumine did not affect the cytokine levels in healthy animals. While lipopolysaccharide increased serum TNFalpha, interleukin-1 beta and interleukin-10 levels, flunixin meglumine inhibited increases at levels of all cytokines. As result, flunixin meglumine showed depressor effect on cytokine levels in endotoxemia and the effect may be a reason for the first chosen member of nonsteroid anti-inflammatory drug in endotoxemia. PMID- 17718808 TI - Valvular cardiac myxoma in a dog. AB - Primary and secondary cardiac tumours are extremely rare in humans and domestic animals. This case describes the gross, light microscopical and immunohistochemical examination of a cardiac myxoma arising from the tricuspid valve in a 13-year-old female terrier dog. Clinically, long-term respiratory distress, progressive ascites, fatigue and exercise intolerance were observed in the animal. At necropsy, the right ventricular chamber was mildly dilated and a soft, whitish mass, 0.7 x 1.5 x 2.1 cm in size was observed arising from the ventricular surface of the septal leaflet of the tricuspid valve of the heart. Histologically, the mass was composed of a faintly eosinophilic myxoid matrix and spindle shaped fibroblast-like cells with elongated nuclei and stellate cells. The extracellular matrix was stained with periodic acid Schiff and alcian blue and the tumour cells were reactive with anti-vimentin and anti-alpha-sarcomeric actin antibodies. The authors believe that this is the first detailed description of a myxoma in this breed. PMID- 17718809 TI - Pituitary macroadenoma in a cat with diabetes mellitus, hypercortisolism and neurological signs. AB - A 13-year-old neutered male European short-hair cat was presented because of blindness and behavioural abnormalities. On physical examination, abnormal behaviour, compulsive walking, circling, continuous vocalization and blindness were the main neurological signs. In addition, abdominal alopecia, thin and inelastic skin, weight loss despite polyphagia, polyuria and polydipsia were present. Laboratory investigation revealed diabetes mellitus and pituitary dependent hypercortisolism. Diagnostic imaging showed bilaterally enlarged adrenals and a large pituitary mass. Histopathological and immunohistochemical examination confirmed the clinical diagnosis of an ACTH-producing pituitary macroadenoma. PMID- 17718810 TI - A comparison of tepoxalin-buprenorphine combination and buprenorphine for postoperative analgesia in dogs: a clinical study. AB - The present study compares the analgesic effect of a tepoxalin-buprenorphine combination to that of buprenorphine alone in the 24 h peri-operative period in 20 dogs undergoing cranial cruciate ligament repair, which were randomly assigned to the two treatment protocols (n = 10). Additionally, possible side effects induced by tepoxalin were investigated. Analgesia was compared using a visual analogue scale (VAS) and a multifactorial pain scale (MFPS), by an anaesthetist blinded from treatment. Analysis of the overall VAS-scores showed a significant decrease over time in both treatment groups. The decrease in the two groups was not significantly different from each other. No significant differences were found between the MFPS-scores of both protocols. Potential side effects of tepoxalin were investigated by venous blood sampling before premedication and 24 h after extubation, a buccal mucosal bleeding time test and recording of vomiting, diarrhoea and adverse effects at the surgical site. Analysis of the blood parameters showed that fibrinogen levels were overall higher 24 h after surgery in both protocols, but were significantly more elevated in the tepoxalin group. No significant differences were found for the other blood parameters. Statistically, tepoxalin failed to improve analgesia induced by buprenorphine. There was no convincing evidence that the administration of tepoxalin was not associated with gastrointestinal side effects. There were no significant adverse effects on renal function and primary haemostasis. PMID- 17718811 TI - A potentized homeopathic drug, Arsenicum Album 200, can ameliorate genotoxicity induced by repeated injections of arsenic trioxide in mice. AB - Groundwater arsenic contamination has become a menacing global problem. No drug is available until now to combat chronic arsenic poisoning. To examine if a potentized homeopathic remedy, Arsenicum Album-200, can effectively combat chronic arsenic toxicity induced by repeated injections of Arsenic trioxide in mice, the following experimental design was adopted. Mice (Mus musculus) were injected subcutaneously with 0.016% arsenic trioxide at the rate of 1 ml/100 g body weight, at an interval of 7 days until they were killed at day 30, 60, 90 or 120 and were divided into three groups: (i) one receiving a daily dose of Arsenicum Album-200 through oral administration, (ii) one receiving the same dose of diluted succussed alcohol (Alcohol-200) and (iii) another receiving neither drug, nor succussed alcohol. The remedy or the placebo, as the case may be, was fed from the next day onwards after injection until the day before the next injection, and the cycle was repeated until the mice were killed. Two other control groups were also maintained: one receiving only normal diet, and the other receiving normal diet and succussed alcohol. Several toxicity assays, such as cytogenetical (chromosome aberrations, micronuclei, mitotic index, sperm head anomaly) and biochemical (acid and alkaline phosphatases, lipid peroxidation), were periodically made. Compared with controls, the drug fed mice showed reduced toxicity at statistically significant levels in respect of all the parameters studied, thereby indicating protective potentials of the homeopathic drug against chronic arsenic poisoning. PMID- 17718812 TI - Seasonal variation in nuclear DNA integrity of frozen-thawed spermatozoa from Thai AI swamp buffaloes (Bubalus bubalis). AB - In this study, we investigated the susceptibility of frozen-thawed swamp buffalo sperm nuclear DNA to undergo controlled acid-induced denaturation in situ, as analysed by flow cytometry, and aimed to correlate the results with sperm head morphology over three seasons in tropical Thailand. Artificial insemination (AI) doses (n = 218) from 18 AI buffalo sires, prepared between 1980 and 1989 and 2003 and 2005, were tested and compared among three seasons, the rainy season, July October; winter, November-February; and summer, March-June. The overall mean of DNA fragmentation index (DFI) (+/- SD) was 1.84 +/- 1.68%, range from 0.19 to 7.92%, with 0.221 +/- 0.021 of the x-DFI ranging from 0.190 to 0.350 and 0.023 +/ 0.009 of the SD-DFI ranging from 0.010 to 0.070. The DFI was consistently low (range 1.40 +/- 0.21% to 2.16 +/- 0.21%; LSM +/- SEM), with x-DFI ranging from 0.216 +/- 0.003 to 0.225 +/- 0.003 and SD-DFI ranging from 0.022 +/- 0.001 to 0.024 +/- 0.001 across the seasons. The DFI was low enough to be related to high fertility potential. However, DFI values varied statistically among seasons, being lower in the rainy season (1.40 +/- 0.21%, P < 0.05) than in winter (2.16 +/- 0.21%) or summer (2.00 +/- 0.20%), and were also affected by the year of semen collection and processing (P < 0.001). The proportion of morphologically abnormal sperm head shapes was low, with no significant differences between seasons. However, DFI was significantly related to the proportion of loose abnormal sperm heads (r = 0.27, P < 0.01). In conclusion, frozen-thawed swamp buffalo sperm chromatin integrity is not seriously damaged by cryopreservation or affected by the seasonal variations in temperature and humidity seen in tropical Thailand. PMID- 17718813 TI - High caudal epidural anaesthesia with local anaesthetics or alpha(2)-agonists in calves. AB - The objective of this study was to examine the efficacy of a caudal epidural anaesthesia using lidocaine or xylazine in a high volume for analgesia of the flank, navel and hamstring tendon. Fourteen calves weighing 57.7 +/- 5.1 kg and 37.9 +/- 9.3 (mean +/- SEM) days old were randomly divided into two groups of seven calves each. Calves belonging to the lidocaine group were given a 2% lidocaine solution in the sacrococcygeal vertebral space epidurally at a volume of 0.4 ml/kg (8 mg/kg) body weight (BW). Animals of the xylazine group were administered an epidural anaesthesia with xylazine at a dose of 0.1 mg/kg BW, diluted with a 0.9% saline solution to a corresponding final volume of 0.4 ml/kg BW. Heart rate and respiratory rate were measured and the degree and duration of analgesia was determined by the response to a skin prick with a hypodermic needle over a period of 350 min after epidural injection. After epidural anaesthesia with lidocaine the mean heart rate increased during dorsal recumbency, whereas after xylazine both heart rate and respiratory rate decreased significantly (P < 0.05). The epidural injection of xylazine compared with lidocaine caused longer (P < 0.05) analgesia at the hamstring tendon (mean +/- SEM, 120.7 +/- 29.7 min versus 93.6 +/- 3.5 min) and at the flank (100.7 +/- 24.4 min versus 78.3 +/- 11.1 min). There were no differences in the intensity of analgesia between groups. After xylazine application analgesia at the navel was achieved for 95.0 +/- 14.1 min whereas after lidocaine injection sufficient analgesia at the navel was found in just two of seven calves for 55 and 95 min respectively. Based on above experiences, a second study was performed, in which a combination of xylazine and local anaesthetics was used and the injection volume was increased to prove the efficacy of caudal epidural anaesthesia in 15 calves (26.3 +/- 26.7 days; 57.1 +/- 19.5 kg) submitted to the clinic for regular umbilical surgery. In these cases the xylazine (0.1 mg/kg BW) was diluted with 2% lidocaine (n = 7) or 2% procaine (n = 8) to a corresponding final volume of 0.5-0.6 ml/kg BW. In all cases complete anaesthesia of the surgical area was achieved and no adverse effects were observed. Overall the high volume caudal epidural anaesthesia represents an effective, safe, cheap and easy to perform alternative for anaesthesia of the navel, flank and hamstring tendon in calves without major side effects. PMID- 17718814 TI - Diphtheroid necrotic laryngitis in three calves - diagnostic procedure, therapy and post-operative development. AB - Diphtheroid necrotic inflammation of the larynx in calves in its advanced stage mostly requires surgical therapy. Diagnostic procedure, surgery and post operative care were described for three calves (aged 3-8 weeks). The clinical diagnosis was confirmed by laryngoscopy. In all three cases, a laryngotomy with resection of necrotic tissue was performed. After surgery two calves showed complications (tracheal stricture, mucosal hyperplasia). Both were cured in further surgery. In cases of post-operative complications, further surgical intervention can be very promising. PMID- 17718815 TI - The environment and childhood disability: opportunities to expand our horizons. PMID- 17718816 TI - Progressive course in cerebral palsy? PMID- 17718817 TI - Measuring children's participation. PMID- 17718818 TI - Developmental outcomes in children with Hurler syndrome after stem cell transplantation. PMID- 17718819 TI - Change in ambulatory ability of adolescents and young adults with cerebral palsy. AB - This study aimed to determine the probability that a child with cerebral palsy (CP) will lose or gain ambulatory ability through adolescence and young adulthood. We analyzed retrospectively data from 1987 to 2002 on Californians with CP initially aged 10 years (SD 0.9y; n=7550 [4304 males, 3246 females]) and 25 years (SD 0.8y; n=5721 [3261 males, 2460 females]) who had varying levels of ambulatory ability (initial Gross Motor Function Classification System Levels I IV). We used the Aalen-Johansen estimator to estimate probabilities of transition to other levels of ambulatory ability in the future. Those who walked and climbed stairs without difficulty at age 10 had only a 23% chance of decline (to requiring a handrail to manage stairs, or worse) 15 years later. Those who ambulated with some difficulty but did not use a wheelchair had a significant chance (33%) of improvement (to being able to walk unsteadily alone at least 3m or better) and only a small chance (11%) of becoming non-ambulatory. Those who used a wheelchair were more likely to lose ambulatory ability (34%) or die (6%). Those who walked and climbed stairs well at age 25 were likely to maintain that ability 15 years later (76%), while those needing support to climb stairs were more likely to lose ability. Improvement in ambulation after age 25 was unlikely. Children and young adults with CP are likely to maintain their ambulatory ability during their next 15 years. Some who ambulate with difficulty at age 10 may improve through adolescence, but those who use a wheelchair are more likely to decline. By age 25 improvement in ambulation is unlikely and decline more likely. Most, however, will not change over the next 15 years. PMID- 17718820 TI - Intrathecal baclofen in children with spastic cerebral palsy: a double-blind, randomized, placebo-controlled, dose-finding study. AB - Intrathecal baclofen (ITB) therapy can be very effective in the treatment of intractable spasticity, but its effectiveness and safety have not yet been thoroughly studied in children with cerebral palsy (CP). The aims of this double blind, randomized, placebo-controlled, dose-finding study were to select children eligible for continuous ITB infusion, to assess the effective ITB bolus dose, and to evaluate the effects, side effects, and complications. Outcome measures included the original Ashworth scale and the Visual Analogue Scale for individually formulated problems. We studied nine females and eight males, aged between 7 and 16 years (mean age 13y 2mo [SD 2y 9mo]). Twelve children had spastic CP and five had spastic-dyskinetic CP. One child was classified on the Gross Motor Function Classification System at Level III, two at Level I V, and 14 at Level V. The test treatment worked successfully for all 17 children with an effective ITB bolus dose of 12.5 microg in one, 20 microg in another, 25 microg in 10, and 50 microg in five children. ITB significantly reduced muscle tone, diminished pain, and facilitated ease of care. The placebo did not have these effects. Nine side effects of ITB were registered, including slight lethargy in seven children. Fourteen children had symptoms of lowered cerebrospinal fluid pressure. We conclude that ITB bolus administration is effective and safe for carefully selected children with intractable spastic CP. PMID- 17718821 TI - A qualitative study of the health-related quality of life of disabled children. AB - This qualitative study investigated what disabled children thought most important in their lives and examined how well their priorities are represented in KIDSCREEN, a generic health-related quality of life (HRQoL) instrument. Participants were a subgroup of families who had previously taken part in a study of quality of life and participation in children with cerebral palsy (CP) using KIDSCREEN. This subgroup was sampled purposively, using children's scores on KIDSCREEN and demographic characteristics. Twenty-eight children (15 males, 13 females; age range 8y 3mo-13y 5mo) and 35 parents were interviewed. Ten children were at Gross Motor Function Classification System Level I, 15 were at Levels II or III, and three were at Levels IV or V. Eleven children had unilateral spastic CP, 16 had bilateral spastic C P, and one child had dyskinetic C P. Interviews were audio-recorded and transcribed verbatim. The analysis was based on the constant comparative method and focused largely on the children's data, though the parent data were drawn upon to illuminate the children's data. Four overarching areas of HRQoL were identified: social relationships; home and school environment; self and body; and recreational activities and resources. These generally mapped well to the dimensions and items in KIDSCREEN. The precedence children gave to environmental, social, interpersonal, health, and functional concerns corresponded well with the balance of these items in KIDSCREEN. However, children had some specific priority areas that were not represented in KIDSCREEN. These included: relationships with family members other than parents; inclusion and fairness; home life and neighbourhood; pain and discomfort; environmental accommodation of needs; and recreational resources other than finances and time. We recommend that further consideration be given to inclusion of these areas in the assessment of HRQoL of disabled children. PMID- 17718822 TI - Measuring participation in children with disabilities using the Assessment of Life Habits. AB - The objectives of this study were: (1) to examine the psychometric properties of the Assessment of Life Habits (LIFE-H) for children; and (2) to draw a profile of the level of participation among children of 5 to 13 years of age with various impairments. The research team adapted the adult version of the LIFE-H in order to render it more appropriate for the daily life experiences of children. Content validity was verified by an expert panel of 29 people, made up of parents, paediatric clinicians, and researchers. Reliability and construct validity of the LIFE-H for children (interview-administered form) was tested during an experiment that comprised three sessions of interviews with a group of 94 parents of children with disabilities (36 males, 58 females; mean age 8y 10mo [SD 2y 6 mo]; diagnostic groups: cerebral palsy, myelomeningocoele, sensory-motor neuropathy, traumatic brain injury, and developmental delay). Overall, the LIFE-H showed high intrarater reliability with intraclass correlation coefficient values of 0.78 or higher for 10 out of 11 categories. The correlations between the LIFE-H and the tools used in pediatric rehabilitation varied, and categories with similar constructs generally led to higher correlations. The psychometric properties of the LIFE-H are appropriate and its content allows a complete description of participation among children with disabilities. PMID- 17718823 TI - Energy cost and physical strain of daily activities in adolescents and young adults with myelomeningocele. AB - The aim of this study was to assess the energy cost and physical strain of daily activities in adolescents and young adults with myelomeningocele (MMC) compared with peers without a disability. Eighteen participants with MMC aged between 16 and 30 years (13 males, five females; mean age 21y 4mo [SD 4y 8mo]) and 18 age- and sex-matched non-disabled participants performed several standardized activities. Energy cost was assessed by oxygen uptake expressed per unit time (all activities) and per metre (walking and wheelchair use at preferred speed). Physical strain was calculated by dividing energy cost by aerobic capacity. For all activities no difference was found in energy cost per unit time between ambulatory participants with MMC and comparison participants. Energy cost per metre walking at preferred speed in participants with MMC was 0.26ml/kg/m (SD 0.08), and in comparison participants was 0.20ml/kg/m (SD 0.03); p=0.08. Non ambulatory participants with MMC had lower energy cost (per unit time and per metre) during wheelchair use than comparison participants during walking (p<0.05). For most activities, physical strain was 1.4 to 2 times higher in participants with MMC than in comparison participants (p<0.05). In conclusion, energy cost per unit time of daily activities was not increased in participants with MMC. However, energy cost per metre during walking at preferred speed and physical strain were higher than in peers without disability. PMID- 17718824 TI - Working memory, processing speed, and set-shifting in children with developmental coordination disorder and attention-deficit-hyperactivity disorder. AB - It has been suggested that the high levels of comorbidity between attention deficit-hyperactivity disorder (ADHD) and developmental coordination disorder (DCD) may be attributed to a common underlying neurocognitive mechanism. This study assessed whether children with DCD and ADHD share deficits on tasks measuring working memory, set-shifting, and processing speed. A total of 195 children aged between 6 years 6 months and 14 years 1 month (mean 10y 4mo [SD 2y 2mo]) were included in this study. A control group (59 males, 79 females), a DCD group (12 males, six females), an ADHD-predominantly inattentive group (16 males, four females), and an ADHD-combined group (15 males, four females), were tested on three executive functioning tasks. Children with DCD were significantly slower on all tasks, supporting past evidence of a timing deficit in these children. With few exceptions, children with ADHD did not perform more poorly than control children. These findings demonstrate the importance of identifying children with motor deficits when examining tasks involving a timing component. PMID- 17718825 TI - Infantile spasms and cytomegalovirus infection: antiviral and antiepileptic treatment. AB - From 1 January 1995 to 31 December 2004, 22 patients (13 males, nine females; age range 2-12mo) with infantile spasms and cytomegalovirus (CMV) infection were treated with intravenous ganciclovir (GCV) and antiepileptic drugs. GCV was given for 3 to 12 weeks with a 1-month interval (one, two, or three courses). Epileptic spasms occurred before (group A: eight patients), simultaneously (group B: eight patients), and after (group C: six patients) a diagnosis of human CMV (HCMV) infection and antiviral treatment. In 11 patients, DNA CMV [corrected] was found in cerebrospinal fluid by nested-polymerase chain reaction method (neuroinfection). All infants excreted CMV in urine. DNA CMV [corrected] and specific immunoglobulin M and immunoglobulin G antibodies were present in blood. Ten patients, including four with neuroinfection, have been seizure-free for at least the past 18 months. In two patients with neuroinfection, vigabatrin monotherapy was withdrawn after a 2 year 6 month seizure-free period. Eighteen patients required antiepileptic drugs polytherapy, four of whom required additional adrenocorticotropic hormone (ACTH). Six patients on polytherapy were seizure-free on follow-up, two of whom were treated with ACTH, but one patient [corrected] who required ACTH [corrected] was seizure-free on follow-up. In five patients, psychomotor development was normal, 16 had tetraplegia (Gross Motor Function Classification System [GMFCS] Level V), and one had diplegia (GMFCS Level III). Early antiviral and antiepileptic therapy could result in the long term cessation of seizures. PMID- 17718826 TI - Developmental outcome in five children with Hurler syndrome after stem cell transplantation: a pilot study. AB - Hurler syndrome (mucopolysaccharidosis type 1H; MPS1H) is a lysosomal storage disease caused by a deficiency of alpha-L-iduronidase activity. The natural course of this neurodegenerative disease inevitably leads to premature death within the first 10 years of life. Enzyme replacement therapy is effective in correcting the enzymatic deficiency of organs other than the central nervous system. Hematopoietic stem cell transplantation (SCT) is the only treatment known to prevent psychomotor deterioration. However, the classical transplantation protocols resulted in a high incidence of graft failure and regimen-related toxicity. Recently, we published a well-tolerated, fludarabine-based, radiation free conditioning regimen for SCT in patients with Hurler syndrome. Here we report the developmental outcome (assessed by the Denver Developmental Screening Test before and yearly after SCT) of four females and one male with MPS1H (mean age at last follow-up 71mo, range 42-87mo) treated in accordance with this strategy. Mean age at SCT was 25 months (range 10-36mo). All children were engrafted and in ambulatory care. They all showed psychomotor development without neurodegeneration. In all patients, after SCT a regression of intracranial lesions could be seen that paralleled the psychomotor improvements. SCT led to a relative reduction of head circumference in all cases. PMID- 17718827 TI - Transient exacerbation of hemiplegia following minor head trauma in Sturge-Weber syndrome. AB - Sturge-Weber syndrome (SWS) is a sporadic disorder characterized by naevus (port wine stain), a pial angioma, and glaucoma. The angioma comprises abnormal tortuous vessels on the leptomeninges with underlying brain gliosis, calcification, and atrophy. The cerebral angioma is commonly unilateral but may be bilateral. Hemiplegia usually follows recurrent hemiconvulsions and may be related to venous stasis. The hemiplegia can be static, progressive, or fluctuating. Transient worsening of the hemiplegia can be seen with seizures and episodes resembling hemiplegic migraine. We report five patients (four females, one male) with SWS who have had transient worsening of hemiplegia following minor head injuries, occurring between the ages of 10 months and 12 years (median age 4y 6mo). An additional pilot survey suggests that this may affect up to 20% of patients. PMID- 17718828 TI - Cerebral palsy after maternal trauma in pregnancy. AB - Ten children (six males, four females) with spastic (n=9) and mixed spastic dyskinetic (n=1) cerebral palsy were born at term to mothers who earlier in the pregnancy had been involved in accidents without suffering overt abdominal injury, placental abruption, or premature onset of labour. At follow-up (at ages 2-24y), Gross Motor Function Classification System levels were II (n=7) and V (n=3). Cognitive level was normal in five patients, while learning disability was mild to moderate in two and severe in three. Magnetic resonance imaging of the brain in all children, assessed blind to the dates of maternal trauma in pregnancy, showed lesions consistent with prenatal vascular insult at the time of the trauma. Feasible mechanisms of brain injury include reduced placental blood flow and/or placental embolization. PMID- 17718830 TI - GLUT1 deficiency syndrome--2007 update. AB - GLUT1 deficiency syndrome (GLUT1DS, OMIM 606777) is a treatable epileptic encephalopathy resulting from impaired glucose transport into the brain. The essential biochemical finding is a low glucose concentration in the cerebrospinal fluid (CSF; hypoglycorrhachia; mean 1.7 [SD 0.3mmol/L]) in the setting of normoglycaemia. CSF lactate is normal. Patients present with an early-onset epilepsy resistant to anticonvulsants, developmental delay, and a complex movement disorder. Hypotonic, ataxic, and dystonic features are most prominent. Speech is often severely affected. Some patients develop spasticity and secondary microcephaly. The phenotype is highly variable ranging from severe impairment to children without seizures. Electroencephalography (EEG) may show 2.5-4Hz spike waves improving on food intake. Neuroimaging is uninformative. Most patients carry heterozygous de novo mutations in the GLUT1 gene (OMIM 138140, gene map locus 1p35-31.3). Autosomal dominant transmission and several mutational hot spots have been identified, but phenotype-genotype correlations are not yet apparent. Homozygous GLUT1 mutations presumably are lethal. The ketogenic diet is the treatment of choice as it provides an alternative fuel to the brain. It should be introduced early and maintained into puberty. Seizures are effectively controlled with the onset of ketosis, but might recur and require comedication. The effect on neurodevelopment appears less impressive. The increasing number of patients, molecular and biochemical analysis, recent research into ketogenic diet mechanisms, and the development of animal models for GLUT1DS have brought substantial insights in disease manifestations and mechanisms. This review summarizes data on 84 published cases and highlights recent advances in understanding this entity. PMID- 17718831 TI - 'Rapid progression of scoliosis complicating intrathecal baclofen pump insertion'. PMID- 17718832 TI - Morphological patterns of Aspergillus niger biofilms and pellets related to lignocellulolytic enzyme productivities. AB - AIMS: To study the morphological patterns of Aspergillus niger during biofilm formation on polyester cloth by using cryo-scanning electron microscopy related to lignocellulolytic enzyme productivity. METHODS AND RESULTS: Biofilm and pellet samples obtained from flask cultures were examined at -80 degrees C in a LEO PV scanning electron microscope. Spore adhesion depends on both its rough surface and adhesive substances that form a pad between spore and support. An extracellular matrix surrounding germ tubes and hyphae was also seen. Biofilm mycelia showed an orderly distribution forming surface and inner channels, while pellets showed highly intertwined superficial hyphae and a densely packed deep mycelium. Morphological differences between both types of culture correlated with differences in enzyme volumetric and specific productivities. Biofilm cultures produced higher filter paper cellulase, endoglucanase, beta-glucosidase and xylanase volumetric and specific productivities than submerged cultures. CONCLUSIONS: Fungal biofilms are morphologically efficient systems for enzyme production. Favourable physiological aspects are shared with solid state fermentation, but fungal biofilms present better possibilities for process control and scale-up. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of this study support the importance of morphology in the productivity of fungal submerged processes, placing biofilms in a preferential category. PMID- 17718833 TI - Effect of germicidal UVC light on fungi isolated from grapes and raisins. AB - AIMS: To examine how UVC affects the different genera of fungi commonly isolated from grapes, with the aim of understanding changes in mycobiota during grape ripening and possible applications for preventing grape decay during storage. METHODS AND RESULTS: Spores of Aspergillus carbonarius, Aspergillus niger, Cladosporium herbarum, Penicillium janthinellum and Alternaria alternata (between 100-250 spores/plate agar) were UVC irradiated for 0 (control), 10, 20, 30, 60, 300 and 600 s. Plates were incubated at 25 degrees C and colonies were counted daily up to 7 days. Alternaria alternata and Aspergillus carbonarius were the most resistant fungi. Conidial germination in these species was reduced by approx. 25% after 10 s of exposure, compared with greater than 70% reduction for the remaining species tested. Penicillium janthinellum spores were the most susceptible at this wavelength. UVC exposures of 300 s prevented growth of all isolates studied, except for Alternaria alternata. CONCLUSIONS: UVC irradiation plays a major role in selecting for particular fungi that dominate the mycobiota of drying grapes. SIGNIFICANCE AND IMPACT OF THE STUDY: The UVC irradiation of harvested grapes could prevent germination of contaminant fungi during storage or further dehydration. PMID- 17718834 TI - ISSR fingerprinting for the assessment of the bindweed biocontrol agent Stagonospora convolvuli LA39 after field release. AB - AIMS: To develop a molecular identification method based on ISSR fingerprints to monitor the fungal leaf pathogen Stagonospora convolvuli LA39 used to biologically control bindweeds after a field release. METHODS AND RESULTS: The developed method proved to be suitable to clearly distinguish LA39 from resident Stagonospora spp. and was applied in two field experiments. First, the environmental persistence of LA39 was assessed in an overwintering experiment. LA39 could be re-isolated from infected bindweed 1 year after field application, but with very low frequency of occurrence. Secondly, LA39 was applied in an area with natural bindweed infestation and re-isolated from infected bindweed. The dispersal of LA39 during one season was poor (4-5 m). CONCLUSIONS: ISSR fingerprinting has been shown to be a valuable tool to monitor the environmental fate of S. convolvuli in the field. It is concluded that an LA39-based mycoherbicide will have minimal environmental impact caused by the restricted mobility, poor proliferation and poor persistence over seasons of LA39. SIGNIFICANCE AND IMPACT OF THE STUDY: Studies about the dispersal and survival of biocontrol agents after field release as well as the development of methods needed for this purpose are indispensable for a comprehensive risk assessment for biocontrol agents. PMID- 17718835 TI - In vitro inhibition activity of nisin A, nisin Z, pediocin PA-1 and antibiotics against common intestinal bacteria. AB - AIMS: To evaluate the sensitivity of 21 common intestinal bacteria to six antibiotics and three broad-spectrum bacteriocins (nisins Z and A and pediocin PA 1). METHODS AND RESULTS: Neutralized cell-free culture supernatants containing active bacteriocins, and antibiotics were tested with the agar diffusion test and the disc-diffusion method, respectively. The tested intestinal strains showed high sensitivity to most antibiotics except for streptomycin and oxacillin. Nisins A and Z (8 mug per well) had similar activity spectra and inhibited all Gram-positive intestinal bacteria at different levels (except Streptococcus salivarius), with bifidobacteria (except Bifidobacterium breve and Bif. catenulatum), Collinsella aerofaciens and Eubacterium biforme being the most sensitive strains, but they were not active against Gram-negative bacteria. Surprisingly, none of the tested strains were inhibited by pediocin PA-1 (16 mug per well). CONCLUSION: Pediocin PA-1 which is very active against Listeria spp. and other food pathogens did not inhibit major intestinal species in the human intestine in contrast to both nisins A and Z. SIGNIFICANCE AND IMPACT OF THE STUDY: Our data suggest that pediocin PA-1 has potential to inhibit Listeria within the intestinal microbiota without altering commensal bacteria. PMID- 17718836 TI - Isolation and characterization of unsaturated fatty acids during bacteriorhodopsin preparation from Halobacterium halobium. AB - AIMS: Isolation and characterization of unsaturated fatty acids during bacteriorhodopsin preparation from Halobacterium halobium. METHODS AND RESULTS: Halobacterium halobium was cultivated in a composite medium. Cells were collected by centrifugation followed by ultrasonic disruption, and the resulting suspension was subject to centrifugation for preparation of both pellet and supernatant. The pellet was saved in order to prepare bacteriorhodopsin, while the supernatant was used for the isolation of crude fatty acids by saponification and extraction. Crystallization then took place in acetone at -16 degrees C to remove fatty acids in which the carbon chain length was shorter than 13. The sample was obtained after purification and analysed by gas chromatography. The results demonstrated that Halobacterium halobium could synthesize multiple unsaturated fatty acids, particularly the three important polyunsaturated fatty acids arachidonic acid (1.12%), eicosapentaenoic acid (16.76%) and docosahexaenoic acid (9.38%). CONCLUSION: Important unsaturated fatty acids were isolated and characterized from the waste, which was produced during the preparation of bacteriorhodopsin from Halobacterium halobium. SIGNIFICANCE AND IMPACT OF THE STUDY: Halobacterium halobium has already been used for decades to prepare bacteriorhodopsin. We found that several important unsaturated fatty acids could be extracted from the bacterial waste, which extends its application scope and might bring additional benefits to humanity. PMID- 17718837 TI - Proteases from Bacillus: a new insight into the mechanism of action for rhizobacterial suppression of nematode populations. AB - AIMS: The aim of this study was to investigate the role of proteases in Bacillus spp. of rhizobacteria in suppressing nematode populations and to understand their mechanism of action. METHODS AND RESULTS: Rhizobacteria with nematicidal activity were isolated from soil samples of five root knot nematode-infested farms. Among these strains, nematotoxicities of Bacillus strains were intensively analysed. Further assays of nematicidal toxins from Bacillus sp. strain RH219 indicated an extracellular cuticle-degrading protease Apr219 was an important pathogenic factor. The Apr219 shared high similarity with previously reported cuticle degrading proteases from Brevibacillus laterosporus strain G4 and Bacillus sp. B16 (Bacillus nematocida). The cuticle-degrading protease genes were also amplified from four other nematicidal Bacillus strains isolated from the rhizosphere. In addition to Apr219, a neutral protease Npr219 from Bacillus sp. RH219 was also investigated for activity against nematodes. CONCLUSIONS: The wide distribution of cuticle-degrading proteases in Bacillus strains with nematicidal activity suggested that these enzymes likely play an important role in bacteria nematode-plant-environment interactions and that they may serve as important nematicidal factors in balancing nematode populations in the soil. SIGNIFICANCE AND IMPACT OF THE STUDY: Increased understanding of the mechanism of action of Bacillus spp. against nematodes could potentially enhance the value of these species as effective nematicidal agents and develop new biological control strategies. PMID- 17718838 TI - Screening of fungal isolates and properties of Ganoderma applanatum intended for olive mill wastewater decolourization and dephenolization. AB - AIMS: To investigate different autochthonous isolates of wood-rotting fungi for the removal of both colour and phenolic compounds from olive mill wastewaters (OMW). METHODS AND RESULTS: The isolates Bjerkandera adusta Ba-100, Fomes fomentarius Ff-106, Ganoderma applanatum Ga-20, Irpex lacteus Il-3, Trametes versicolor Tv-101 and Tv-103 were preliminarily screened for their OMW decolourizing potential on potato dextrose agar supplemented with different OMW concentrations. A further screening of batch cultures under different agitation speeds, to test the effect of shear stress, resulted in the selection of isolate G. applanatum Ga-20. Batch cultures grown in OMW-based medium exhibited strong laccase induction and significant decrease in the values of phenols, colour and chemical oxygen demand. Concomitant onset of laccase activity and colour removal was observed, and apart from laccase, neither lignin peroxidase nor manganese dependent peroxidase activities were detected. Moreover, the depletion of aromatic compounds with high and low apparent molecular mass was observed by chromatographic analysis. CONCLUSIONS: Isolate G. applanatum Ga-20 exhibited interesting properties for its use in bioremediation of OMW, namely high removal of recalcitrant phenolic compounds and strong colour abatement. SIGNIFICANCE AND IMPACT OF THE STUDY: For the first time, the white-rot fungus G. applanatum proves to be effective for the decolourization and dephenolization of OMW. PMID- 17718839 TI - The pattern of pleiomorphism in stressed Salmonella Virchow populations is nutrient and growth phase dependent. AB - AIMS: To describe the interactions of imposed osmotic and nutritional stress on the morphology of stationary and exponential phase S. Virchow cells. METHODS AND RESULTS: This study examined the morphology and viability of osmotically stressed exponential and stationary phase cultures of Salmonella Virchow under nutritionally deficient and competent conditions. In addition to normal morphology, salt-stressed cultures exhibited filamentous and spherical morphotypes, which were capable of reversion to normal morphology on stress removal. Proportions of atypical morphotypes were influenced by the phase of growth when the stress was applied. Salt-stressed exponential phase populations contained 54% filamentous, 30% spherical forms, salt-stressed stationary phase populations contained 16% filamentous, 79% spherical forms. Proportions of morphotypes were also influenced by the nutrient status of the medium, but not by metabolic by-products. CONCLUSIONS: Development of a range of morphotypes in response to stress (osmotic/nutritional), may offer population level advantages, increasing the survival potential of the population. SIGNIFICANCE AND IMPACT OF STUDY: The application of sublethal concentrations of salt may stimulate S. Virchow morphotype diversity, improving survival and rates of poststress recovery. PMID- 17718840 TI - Effects of protective agents on membrane fluidity of freeze-dried Lactobacillus delbrueckii ssp. bulgaricus. AB - AIMS: To evaluate the effect of protective agents upon survival of Lactobacillus delbrueckii ssp. bulgaricus during freeze-drying and storage, and selective amino acids on cell membrane fluidity. METHODS AND RESULTS: The protective effect of amino-acids and sugars at different concentrations was studied by determining the viability of lyophilized cells after storage under air at 30 degrees C. Survival following freeze-drying was improved by all compounds. During storage, neither proline nor maltose had protective effects on lyophilized Lact. delbrueckii ssp. bulgaricus. Glutamate 5% and aspartate 5% showed similar protection capability during freeze-drying (94-95%) and after storage (92-99%). Fluorescence probes (DPH and TMA-DPH) were used to study the effect of both amino acids on membrane fluidity. Polarization decreased with increasing concentrations of glutamate or aspartate. Lowest values were observed with TMA-DPH. CONCLUSIONS: Glutamate 5% and aspartate 5% allowed maintaining high viability rates during freeze-drying and storage of Lact. delbrueckii ssp. bulgaricus because of an increase of the membrane fluidity by inserting in the interfacial region of bacterial plasma membrane. SIGNIFICANCE AND IMPACT OF THE STUDY: These results show the first evidence of the mechanisms underlying glutamate and aspartate as lyoprotectors. PMID- 17718842 TI - Phenotypical characteristics of Shiga-like toxin Escherichia coli isolated from sheep dairy products. AB - AIMS: To analyse phenotypical characteristics of Shiga toxin-producing Escherichia coli (STEC) strains from ovine origin. METHODS AND RESULTS: A total of 13 STEC strains (eight O157 and five non-O157) isolated from sheep dairy products were used in this study. Biochemical traits, motility, haemolytic activity, resistance to tellurite-cefixime, maximum growth temperature and antibiotic resistance were determined. The STEC strains were grouped into nine biochemical and physiological biotypes (five for the O157 and four for the non O157 strains). All STEC strains showed resistance to bacitracin, cloxacilin, penicillin and tylosin. CONCLUSIONS: Different biotypes and antibiotic resistance patterns of STEC isolated from sheep dairy products were observed. SIGNIFICANCE AND IMPACT OF THE STUDY: This work will be a contribution to the better characterization of STEC isolated from sheep dairy products, which have, to date, been scarcely studied, and to the better understanding of the risks associated with its consumption. PMID- 17718841 TI - Antimicrobial properties of moderately halotolerant bacteria from cenotes of the Yucatan peninsula. AB - AIMS: Isolation and antimicrobial evaluation of aquatic bacterial strains from two cenotes. METHODS AND RESULTS: A total of 258 bacterial strains were isolated from the water and sediment of two cenotes in the Yucatan peninsula, all of which were screened against six pathogenic micro-organisms. Antimicrobial activity was detected in 46 of the isolated strains against at least one of the target strains tested. Antimicrobially active isolates were identified as: Aeromonas, Bacillus, Burkholderia, Photobacterium, Pseudomonas, Serratia, Shewanella, Stenotrophomonas genera, and 13 remained unidentified. All antimicrobially active strains were able to grow in salt medium at a concentration of 75 g l(-1), thus classifying as moderately halotolerant bacteria. Most of the antimicrobially active strains exhibited a broad action spectrum, where 61% was because of uncharacterized antimicrobial substances, 25% because of bacteriocins and 13% because of siderophores. Ten strains were able to biosynthesize biosurfactant metabolites. CONCLUSIONS: Native bacteria from the Yucatan peninsula showed an interesting antimicrobial activity, diverse mode of action and moderate halotolerance to salt. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report on bacterial isolates from cenotes of the Yucatan peninsula and their antimicrobial characterization, with great potential for future biotechnological applications. PMID- 17718843 TI - Ochratoxin A-producing Aspergilli in Vietnamese green coffee beans. AB - AIMS: To determine the incidence and severity of infection by ochratoxin A (OA) producing fungi in Vietnamese green coffee beans. METHODS AND RESULTS: Aspergillus carbonarius, A. niger and yellow Aspergilli (A. ochraceus and related species in section Circumdati) were isolated by direct plating of surface disinfected Robusta (65 samples) and Arabica (11 samples) coffee beans from southern and central Vietnam. Significantly, more Robusta than Arabica beans were infected by fungi. Aspergillus niger infected 89% of Robusta beans, whereas A. carbonarius and yellow Aspergilli each infected 12-14% of beans. OA was not produced by A. niger (98 isolates) or A. ochraceus (77 isolates), but was detected in 110 of 113 isolates of A. carbonarius, 10 isolates of A. westerdijkiae and one isolate of A. steynii. The maximum OA observed in samples severely infected with toxigenic species was 1.8 microg kg(-1); however, no relationship between extent of infection and OA contamination was observed. CONCLUSIONS: Aspergillus niger is the dominant species infecting Vietnamese coffee beans, yet A. carbonarius is the likely source of OA contamination. SIGNIFICANCE AND IMPACT OF STUDY: Vietnamese green coffee beans were more severely infected with fungi than the levels reported for beans from other parts of the world, yet OA contamination appears to be infrequent. PMID- 17718844 TI - The first molecular analysis of clinical isolates of VanA-type vancomycin resistant Enterococcus faecium strains in Mainland China. AB - AIMS: The aim of this study was to examine two VanA-type vancomycin-resistant Enterococcus faecium (VRE) strains that had been isolated from patients resident in mainland China. This is the first molecular analysis of clinical VRE strains being isolated in mainland China. METHODS AND RESULTS: Two VanA-type VRE isolates were isolated from in-patients at hospitals located in the Chinese cities Beijing and Dalian and were designated C264 and I125. The plasmids pC264V (40 kbp) and pI125V (370 kbp) that were isolated from C264 and I125, respectively, carried a Tn1546-like element encoding VanA resistance. The vancomycin-resistant plasmids pC264V and pI125V were transferred by filter mating at frequencies of 10(-7) and 10(-4) respectively. Sequence analysis of pC264V revealed that two IS1216V sequences and an IS1542 sequence were present within the Tn1546-like element. pI125V had two IS1216V insertions in the Tn1546-like element. CONCLUSIONS: The two VanA-type vancomycin-resistant E. faecium (VRE) strains C264 and I125 were isolated from in-patients in Chinese hospitals. The vancomycin-resistant conjugative plasmids pC264V and pI125V plasmids isolated from these strains carried the Tn1546-like element. The Tn1546-like element was found to contain the insertion sequences IS1216V and IS1542. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first molecular analysis of VanA-type VRE strains from patients resident in mainland China. PMID- 17718845 TI - Susceptibility of Staphylococcus epidermidis planktonic cells and biofilms to the lytic action of staphylococcus bacteriophage K. AB - AIMS: To evaluate differences in biofilm or planktonic bacteria susceptibility to be killed by the polyvalent antistaphylococcus bacteriophage K. METHODS AND RESULTS: In this study, the ability of phage K to infect and kill several clinical isolates of Staphylococcus epidermidis was tested. Strains were grown in suspension or as biofilms to compare the susceptibility of both phenotypes to the phage lytic action. Most strains (10/11) were susceptible to phage K, and phage K was also effective in reducing biofilm biomass after 24 h of challenging. Biofilm cells were killed at a lower rate than the log-phase planktonic bacteria but at similar rate as stationary phase planktonic bacteria. CONCLUSIONS: Staphylococcus epidermidis biofilms and stationary growth phase planktonic bacteria are more resistant to phage K lysis than the exponential phase planktonic bacteria. SIGNIFICANCE OF STUDY: This study shows the differences in Staph. epidermidis susceptibility to be killed by bacteriophage K, when grown in biofilm or planktonic phenotypes. PMID- 17718846 TI - Treatment of Streptococcus mutans biofilms with a nonthermal atmospheric plasma. AB - AIMS: A nonthermal atmospheric plasma, designed for biomedical applications, was tested for its antimicrobial activity against biofilm cultures of a key cariogenic bacterium Streptococcus mutans. METHODS AND RESULTS: The Strep. mutans biofilms were grown with and without 0.15% sucrose. A chlorhexidine digluconate rinse (0.2%) was used as a positive antimicrobial reference. The presence of sucrose and the frequency of plasma application during growth were shown to have a significant effect on the response to treatment and antibacterial activity. CONCLUSIONS: A single plasma treatment for 1 min on biofilms cultured without sucrose caused no re-growth within the observation period. However, with either single or repeated plasma treatments of 1 min, on biofilms cultured with 0.15% sucrose, growth was only reduced. SIGNIFICANCE AND IMPACT OF THE STUDY: In summary, there may be a role for nonthermal plasma therapies in dental procedures. Sucrose and associated growth conditions may be a factor in the survival of oral biofilms after treatment. PMID- 17718847 TI - Peptide-like substances as antimicrobial barriers to Corynebacterium sp. adhesion to silicone catheters. AB - AIMS: To show medical application of antimicrobial peptides such as Pep5 and epidermin in inhibiting adhesion of Corynebacterium spp. to silicone catheters. METHODS AND RESULTS: The inhibitory activity of crude preparations of Pep5 and epidermin was tested on Corynebacterium spp. isolated from catheter-related infections. The addition of these substances at 640 AU ml(-1) to a cell suspension of Corynebacterium sp. 633544 resulted in a decrease of 3 log cycles in the number of viable cells over a period of 12 h. When Pep5 and epidermin were added to in vitro catheter colonization experiments, there was a decrease of 1 log unit (P < 0.01) in the cell number of Corynebacterium spp. adhered to silicone catheters. Scanning electron microscopy revealed that antimicrobial treated catheters presented zones with absence of adhered cells, and some parts of the catheter presented aggregates suggesting damaged cells. CONCLUSIONS: The crude preparations of Pep5 and epidermin were able to inhibit Corynebacterium sp. 633544 isolated from catheter-related infection. The capability of Pep5 and epidermin to inhibit catheter colonization may indicate their usefulness as a barrier to block or to reduce the bacteremia by Corynebacterium spp. SIGNIFICANCE AND IMPACT OF THE STUDY: Peptide-like antimicrobial substances used to reduce bacterial attachment to medical devices may represent a novel strategy to control catheter-related infections. PMID- 17718848 TI - Potential application of cyclic lipopeptide biosurfactants produced by Bacillus subtilis strains in laundry detergent formulations. AB - AIMS: Crude cyclic lipopeptide (CLP) biosurfactants from two Bacillus subtilis strains (DM-03 and DM-04) were studied for their compatibility and stability with some locally available commercial laundry detergents. METHODS AND RESULTS: CLP biosurfactants from both B. subtilis strains were stable over the pH range of 7.0 12.0, and heating them at 80 degrees C for 60 min did not result in any loss of their surface-active property. Crude CLP biosurfactants showed good emulsion formation capability with vegetable oils, and demonstrated excellent compatibility and stability with all the tested laundry detergents. CONCLUSION: CLP biosurfactants from B. subtilis strains act additively with other components of the detergents to further improve the wash quality of detergents. The thermal resistance and extreme alkaline pH stability of B. subtilis CLP biosurfactants favour their inclusion in laundry detergent formulations. SIGNIFICANCE AND IMPACT OF THE STUDY: This study has great significance because it is already known that microbial biosurfactants are considered safer alternative to chemical or synthetic surfactants owing to lower toxicity, ease of biodegradability and low ecological impact. The present study provides further evidence that CLP biosurfactants from B. subtilis strains can be employed in laundry detergents. PMID- 17718849 TI - The effect of peroxyacetic acid-based sanitizer, heat and ultrasonic waves on the survival of Clostridium estertheticum spores in vitro. AB - AIM: To determine the effect of selected physical and chemical treatments on the survival of 'blown pack'-causing Clostridium estertheticum. METHODS AND RESULTS: The study investigated the survival of the spores of 'blown pack'-causing C. estertheticum following the four treatments, which include: heat alone, ultrasound followed by heat treatment, peroxyacetic acid (POAA)-based sanitizer followed by heat treatment and POAA sanitizer followed by heat treatment in the presence of 20% animal fat. No C. estertheticum survivors were recovered in spore preparations that underwent either of the two treatments with the sanitizer, resulting in the inactivation of 4 to 5 log CFU ml(-1) of spores. Similarly, no survivors were detected in spore preparations that were treated with the sanitizer for 5 min at room temperature without further heat treatment. When using heat alone and ultrasound followed by heat treatment, complete spore inactivation did not occur for spores heated at times and temperature combinations other than 240 s at 100 degrees C. CONCLUSIONS: POAA sanitizer used with or without heat is capable of in vitro inactivation of at least 4 log CFU ml(-1)C. estertheticum spores. SIGNIFICANCE AND IMPACT OF THE STUDY: The data generated in the study provide background information for controlling 'blown pack'-causing clostridia on dressed carcasses and in meat plant environment. PMID- 17718850 TI - Studies of the release of small molecules during pressure germination of spores of Bacillus subtilis. AB - AIMS: To measure rates of release of small molecules during pressure germination of Bacillus subtilis spores, and the role of SpoVA proteins in dipicolinic acid (DPA) release. METHODS AND RESULTS: Rates of DPA release during B. subtilis spore germination with pressures of 150 or 500 megaPascals were much higher in spores with elevated levels of SpoVA proteins, and spores with a temperature-sensitive mutation in the spoVA operon were temperature-sensitive in DPA release during pressure germination. Spores also released arginine and glutamic acid, but not AMP, during pressure germination. CONCLUSIONS: Pressure germination of B. subtilis spores causes release of many small molecules including DPA. SpoVA proteins are involved in the release of DPA, perhaps because SpoVA proteins are a component of a DPA channel in the spore's inner membrane. SIGNIFICANCE AND IMPACT OF THE STUDY: This work provides new insight into the mechanism of pressure germination of spores of Bacillus species, a process that has significant potential for usage in the food industry. PMID- 17718851 TI - Genetics of autosomal recessive non-syndromic mental retardation: recent advances. AB - The identification of the genes mutated in autosomal recessive non-syndromic mental retardation (ARNSMR) has been very active recently. This report presents an overview of the current knowledge on clinical data in ARNSMR and progress in research. To date, 12 ARNSMR loci have been mapped, and three genes identified. Mutations in known ARNSMR genes have been detected so far in only a small number of families; their contribution to mental retardation in the general population might be limited. The ARNSMR-causing genes belong to different protein families, including serine proteases, Adenosine 5'-triphosphate-dependent Lon proteases and calcium-regulated transcriptional repressors. All of the mutations in the ARNSMR causing genes are protein truncating, indicating a putative severe loss-of function effect. The future objective will be the development of diagnostic kits for molecular diagnosis in mentally retarded individuals in order to offer at risk families pre-natal diagnosis to detect affected offspring. PMID- 17718852 TI - Of old and new diseases: genetics of pituitary ACTH excess (Cushing) and deficiency. AB - The pituitary gland orchestrates our endocrine environment: it produces hormones in response to hypothalamic factors that integrate neural inputs and its activity is balanced by the feedback action of peripheral hormones. Disruption of this equilibrium has severe consequences that affect multiple systems and may be fatal. Genetic analysis of pituitary function led to discovery of critical transcription factors that cause hormone deficiencies when mis-expressed. This review will summarize recent findings that led to the first complete clinical description of inherited, isolated corticotropin (ACTH) deficiency (IAD) and to the first molecular mechanism for excessive ACTH production in Cushing's disease. Indeed, mutations in TPIT, a positive or negative regulator of cell fates for different pituitary lineages, cause neonatal IAD, a condition considered anecdotic before discovery of this transcription factor. Cushing's disease is caused by corticotroph adenomas that produce excess ACTH as a result of resistance to glucocorticoids (Gc). Molecular investigation of the normal mechanism of Gc feedback led to identification of two essential proteins for pro opiomelanocortin repression that are often mis-expressed in corticotroph adenomas thus providing a molecular explanation for Gc resistance. These two proteins, Brg1 and histone deacetylase 2 (HDAC2), are involved in chromatin remodeling and may also participate in the tumorigenic process, as Brg1 is a tumor suppressor. These recent advances have provided improved diagnosis and opened new perspectives for patient management and therapies. PMID- 17718857 TI - High-resolution oligonucleotide array-CGH applied to the detection and characterization of large rearrangements in the hereditary breast cancer gene BRCA1. AB - We have developed a new method for detecting and characterizing large rearrangements in the BRCA1 gene based on high-resolution oligonucleotide array CGH technology. We designed a specific CGH array for the BRCA1 gene and its flanking regions. We then used this approach to analyze nine DNA samples known to contain large deletions and large duplications. When possible, the deleted or duplicated region was sequenced to identify the break point. All the large rearrangements were detected by the new method, and their size was estimated to be within 1--2 kb. This enabled us to develop a simple polymerase chain reaction screening test for other family members. A refined choice of oligonucleotides should improve the precision of the breakpoint determination. Finally, the high resolution of oligonucleotide array-CGH should help to detect new large rearrangements missed by other current methods. PMID- 17718856 TI - Utility of molecular analyses in the exploration of extreme intrafamilial variability in the Marfan syndrome. AB - The diagnosis of Marfan syndrome may be hampered by the existence of very mild and atypical cases as well as by marked intrafamilial variability. In these instances, molecular analysis of the fibrillin-1 gene (FBN1) can be helpful to identify individuals at risk. The underlying molecular mechanism for the clinical variability is presently unknown. We performed clinical and molecular studies in 36 subjects from three unrelated families. Expression studies of both FBN1 alleles were performed and related to the clinical severity. In family 1, an overlapping phenotype between Marfan syndrome (MFS) and Weill-Marchesani syndrome is presented. The diagnosis necessitated molecular studies and clinical examination in first-degree relatives. In family 2, the young proband presented with a phenotype overlapping between MFS and the kyphoscoliotic type of Ehlers Danlos syndrome. Follow-up over time and identification of a FBN1 mutation allowed confirmation of the diagnosis. Mutation analysis enabled us to identify family members with mild expression. Family 3 illustrates the extensive intrafamilial variability in the clinical severity of MFS. Identification of a FBN1 mutation was helpful to identify subjects with mild expression and for the timely diagnosis in a neonate. In families 2 and 3, the relative expression of both FBN1 alleles was not related to clinical severity. We demonstrated that confirmation of the diagnosis of MFS may require detailed and repeated clinical evaluation and thorough family history taking. FBN1 mutation analysis is supportive for the diagnosis in mild and atypical presentations. PMID- 17718858 TI - Development and testing of a decision aid for breast cancer prevention for women with a BRCA1 or BRCA2 mutation. AB - For women who carry a mutation in BRCA1 or BRCA2, the risk of breast cancer is up to 87% by the age of 70. There are options available to reduce the risk of breast cancer; however, each option has both risks and benefits, which makes decision making difficult. The objective is to develop and pilot test a decision aid for breast cancer prevention for women with a BRCA1 or BRCA2 mutation. The decision aid was developed and evaluated in three stages. In the first stage, the decision aid was developed and reviewed by cancer genetics experts. The second stage was a review of the decision aid by women with a BRCA1 or BRCA2 mutation for acceptability and feasibility. The final stage was a pre-test--post-test evaluation of the decision aid. Twenty-one women completed the pre-test questionnaire and 20 completed the post-test questionnaire. After using the decision aid, there was a significant decline in mean decisional conflict scores (p = 0.001), a significant improvement in knowledge scores (p = 0.004), and fewer women uncertain about prophylactic mastectomy (p = 0.003) and prophylactic oophorectomy (p = 0.009). Use of the decision aid decreased decisional conflict to levels suggestive of implementation of a decision. In addition, knowledge levels increased and choice predisposition changed with fewer women being uncertain about each option. This has significant clinical implications as it implies that with greater uptake of cancer prevention options by women with a BRCA1 or BRCA2 mutation, fewer women will develop and/or die of hereditary breast cancer. PMID- 17718859 TI - Cystic fibrosis in a southern Brazilian population: characteristics of 90% of the alleles. AB - Cystic fibrosis (CF) is a genetic disease that frequently leads to death in infancy among Europeans and their descendants. The goals of the present study were to analyze the molecular aspects of CFTR gene characterizing mutations, their frequencies, and the haplotypes formed by four CFTR gene intragenic markers, IVS8-6(T)n, IVS8CA, IVS17bTA and IVS17bCA, in a southern Brazilian population of Caucasian origin. DNA samples from 56 non-related CF patients were analyzed using scanning techniques (single strand conformation polymorphism and denaturing gradient gel electrophoresis), restriction fragment length polymorphism and direct DNA sequencing to identify the mutations. Our results revealed a total of 25 different CF mutations representing nearly 90% of CF alleles, two being novel mutations. Microsatellite haplotypes were defined for CF and normal alleles. The mutational spectrum and the associated haplotypes described for the first time in this study should prove relevant for genetic counselling and CF population screening in Brazil. Moreover, our results suggest the presence of a major Mediterranean component in the contemporary Brazilian CF patient pool. PMID- 17718860 TI - CYR61 polymorphisms are associated with plasma HDL-cholesterol levels in obese individuals. AB - We have recently characterized the transcriptome of the omental adipose tissue of non-diabetic, obese men with and without the metabolic syndrome (MS). The cysteine-rich protein 61 (CYR61) is one of the most differentially expressed genes between the groups and has been selected for a detailed molecular investigation. Direct sequencing of complete CYR61 gene revealed five polymorphisms with minor allele frequency >5% in the promoter region (rs 3753794, rs 3753793 and rs 2297140), intron 1 (rs 2297141) and intron 2 (IVS 2+50). Chi square test and logistic regression were applied to test for association between CYR61 polymorphisms and the individual MS components in a cohort of 697 obese individuals. In men and women, rs 3753794 and rs 3753793 (r2 = 0.77) were associated plasma HDL-cholesterol levels (p = 0.016 and p = 0.008). Carriers of the A allele for rs 3753794 were more likely to have high plasma HDL-cholesterol levels (1.50-fold; p = 0.016), as compared with G/G homozygotes and the A/A homozygotes for rs 3753793 were more likely to exhibit low plasma HDL-cholesterol levels (1.56-fold; p = 0.008), as compared with C/C homozygotes. Furthermore, an association between IVS 2+50 polymorphism and HDL-cholesterol was found in women and in men analyzed separately (p = 0.002 and p = 0.038, respectively). These results suggest that CYR61 is a promising candidate gene for lipoprotein/lipid perturbations. PMID- 17718861 TI - Frequency of constitutional MSH6 mutations in a consecutive series of families with clinical suspicion of HNPCC. AB - A large majority of constitutional mutations in hereditary non-polyposis colorectal cancer (HNPCC) are because of the MHL 1 or MSH 2 genes. In a lower fraction of cases, another gene of the mismatch repair (MMR) machinery, MSH6, may be responsible. Families with MSH6 mutations are difficult to recognize, as microsatellite instability (MSI) may not be detectable and immunohistochemistry (IHC) may give ambiguous results. In the present study, we proposed (i) to determine the frequency of MSH6 mutations in a selected population of colorectal cancer patients obtained from a tumor registry, (ii) to assess whether IHC is a suitable tool for selecting and identifying MSH6 mutation carriers. One hundred neoplasms of the large bowel from suspected HNPCC families were analyzed for MSI (BAT 25 and BAT 26 markers) and immunohistochemical expression of the MSH6 protein. We found on 12 tumors (from different families) showing instability or lack of MSH6 expression. Among these, four potentially pathogenic MSH6 mutations were detected (del A at 2984; del TT at 3119; del AGG cod 385; and del CGT cod 1242) by direct gene sequencing. These represented 12.9% of all families with constitutional mutations of the DNA MMR genes. Thus, some 5% of all HNPCC families are featured by constitutional mutation of the MSH6 gene. This appears, however, as a minimum estimate; routine use of IHC and the study of large numbers of individuals and families with little or no evidence of Lynch syndrome might reveal that mutation of this gene account for a large fraction of HNPCC. PMID- 17718862 TI - Detection of copy number changes at the NF1 locus with improved high-resolution array CGH. AB - Neurofibromatosis type 1 (NF1) is a common autosomal dominant disease caused by various types of mutations in the NF1 gene. We have previously developed a locus specific DNA microarray for detection of copy number changes at the NF1 locus by comparative genomic hybridization (CGH) analysis. The original array contains 183 probes pooled from 444 polymerase chain reaction (PCR) products. In the current work, we have used 493 probes derived from single PCR products (200--998 bp in size) to construct a higher resolution array with a smaller average probe size for molecular diagnosis of NF1. This has improved the average resolution from 12.6 kb in the previous array to 4.5 kb in the current version. The performance of the newly constructed microarray was validated with 14 well-characterized NF1 mutations for CGH analysis. These mutations represent deletions from approximately 7 kb to over 2 Mb in size. Using this array, we examined a total of 55 NF1 patients for copy number changes at the NF1 locus, detecting deletions in four of them. These results demonstrate that a locus-specific microarray constructed from single PCR products can efficiently detect copy number changes at the NF1 locus, providing a simple method for the molecular diagnosis of NF1. PMID- 17718863 TI - A distinct spectrum of SLC26A4 mutations in patients with enlarged vestibular aqueduct in China. AB - There is a worldwide interest in studying SLC26A4 mutations that are responsible for enlarged vestibular aqueduct (EVA) in different ethnic background and populations. The spectrum of SLC26A4 mutations in Chinese population is yet to be fully characterized. In this study, all the 21 exons of SLC26A4 were screened in 107 Chinese patients with hearing loss associated with EVA or both EVA and Mondini dysplasia (MD), taken from six multiplex and 95 simplex families. The two types of control populations consisted of 84 normal-hearing subjects and 46 sensorineural hearing loss subjects without inner ear malformations. Biallelic mutations were found in 12 patients from multiplex families and 84 patients (88.4%) from the simplex families. In addition, monoallelic variant was detected in nine patients in the remaining 11 simplex families. Overall, up to 97.9% patients were found having at least one possible pathogenic variant in SLC26A4, with most having biallelic variants consistent with recessive inheritance of this disorder. A total of 40 mutations including 25 novel mutations were identified in the Chinese patients but were not detected in all the controls except for one normal subject. For the Chinese mutation spectrum of SLC26A4 gene, IVS 7-2A>G mutation was the most common form accounting for 57.63% (102/177) of all the mutant alleles. PMID- 17718864 TI - Prevalence of CYP1B1 mutations in Australian patients with primary congenital glaucoma. AB - Analysis of CYP1B1 in primary congenital glaucoma (PCG) patients from various ethnic populations indicates that allelic heterogeneity is high, and some mutations are population specific. No study has previously reported the rate or spectrum of CYP1B1 mutations in Australian PCG patients. The aim of this study is to determine the frequency of CYP1B1 mutations in our predominately Caucasian, Australian cohort of PCG cases. Thirty-seven probands were recruited from South Eastern Australia, along with 100 normal control subjects. Genomic DNA was extracted and the coding regions of CYP1B1 analysed by direct sequencing. Sequence analysis identified 10 different CYP1B1 disease-causing variants in eight probands (21.6%). Five subjects were compound heterozygotes, two subjects heterozygous and one homozygous for CYP1B1 mutations. Three missense mutations are novel (D192Y, G329D, and P400S). None of the novel mutations identified were found in normal controls. One normal control subject was heterozygous for the previously reported CYP1B1 R368H mutation. Six previously described probable polymorphisms were also identified. Mutations in CYP1B1 account for approximately one in five PCG cases from Australia. Our data also supported the high degree of allelic heterogeneity seen in similar studies from other ethnic populations, thereby underscoring the fact that other PCG-related genes remain to be identified. PMID- 17718865 TI - Novel mutations in the pejvakin gene are associated with autosomal recessive non syndromic hearing loss in Iranian families. PMID- 17718866 TI - Early and severe liver disease associated with homozygosity for an exon 7 mutation, G691R, in Wilson's disease. PMID- 17718867 TI - Frequency of hemochromatosis gene (HFE) mutations in Corsica (France). PMID- 17718868 TI - How ethical is international perinatal research? Challenges and misconceptions. PMID- 17718869 TI - Birth centers in Australia: a national population-based study of perinatal mortality associated with giving birth in a birth center. AB - BACKGROUND: Perinatal mortality is a rare outcome among babies born at term in developed countries after normal uncomplicated pregnancies; consequently, the numbers involved in large databases of routinely collected statistics provide a meaningful evaluation of these uncommon events. The National Perinatal Data Collection records the place of birth and information on the outcomes of pregnancy and childbirth for all women who give birth each year in Australia. Our objective was to describe the perinatal mortality associated with giving birth in "alongside hospital" birth centers in Australia during 1999 to 2002 using nationally collected data. METHODS: This population-based study included all 1,001,249 women who gave birth in Australia during 1999 to 2002. Of these women, 21,800 (2.18%) gave birth in a birth center. Selected perinatal outcomes (including stillbirths and neonatal deaths) were described for the 4-year study period separately for first-time mothers and for women having a second or subsequent birth. A further comparison was made between deaths of low-risk term babies born in hospitals compared with deaths of term babies born in birth centers. RESULTS: The total perinatal death rate attributed to birth centers was significantly lower than that attributed to hospitals (1.51/1,000 vs 10.03/1,000). The perinatal mortality rate among term births to primiparas in birth centers compared with term births among low-risk primiparas in hospitals was 1.4 versus 1.9 per 1,000; the perinatal mortality rate among term births to multiparas in birth centers compared with term births among low-risk multiparas in hospitals was 0.6 versus 1.6 per 1,000. CONCLUSIONS: This study using Australian national data showed that the overall rate of perinatal mortality was lower in alongside hospital birth centers than in hospitals irrespective of the mother's parity. PMID- 17718870 TI - Hospital practices that increase breastfeeding duration: results from a population-based study. AB - BACKGROUND: A high percentage (83%) of mothers in Colorado initiate breastfeeding; but in keeping with national breastfeeding trends, many of them discontinue breastfeeding within the first few months. The objective of this study was to determine the effects of hospital practices on breastfeeding duration and whether the effects differed based on maternal socioeconomic status. METHODS: Pregnancy Risk Assessment Monitoring System data were used to calculate breastfeeding duration rates for all Colorado mothers in 2002 to 2003. Breastfeeding duration rates were determined for recipients of each of nine hospital practices included in the survey compared with rates for nonrecipients. Practices that significantly increased breastfeeding duration rates were combined and then stratified by socioeconomic status. RESULTS: Breastfeeding duration was significantly improved when mothers experienced all five specific hospital practices: breastfeeding within the first hour, breastmilk only, infant rooming in, no pacifier use, and receipt of a telephone number for use after discharge. Two-thirds (68%; 95% CI: 61-75) of mothers who experienced all five successful practices were still breastfeeding at 16 weeks compared with one-half (53%; 95% CI: 49-56) of those who did not. Breastfeeding duration was improved independent of maternal socioeconomic status. Only one in five mothers (18.7%) experienced all five supportive hospital practices. Mothers who experienced the five supportive hospital practices were significantly less likely to stop breastfeeding due to any of the top reasons given for stopping (p < 0.001). CONCLUSIONS: Implementation of the five hospital practices supportive of breastfeeding significantly increased breastfeeding duration rates regardless of maternal socioeconomic status. PMID- 17718871 TI - Factors associated with low incidence of exclusive breastfeeding for the first 6 months. AB - BACKGROUND: The identification of factors that are associated with early cessation of exclusive breastfeeding is important for defining strategies for the promotion of exclusive breastfeeding. The objective of this study was to identify the determinants of exclusive breastfeeding cessation before 6 months, including variables that generally receive little attention, such as the influence of grandmothers, breastfeeding technique, and sore nipples. METHODS: This prospective study follows a cohort of 220 healthy mother-baby pairs from birth to 6 months, living in Porto Alegre, Brazil. Data were collected at the maternity unit, during a home visit at 30 days, and by telephone interview at 60, 120, and 180 days. Breastfeeding technique was assessed and breasts examined at the maternity unit and during home visits. Cox regression was employed to estimate the degree of association between the variables and the outcome. RESULTS: The following factors were associated with cessation of exclusive breastfeeding before 6 months: adolescent mother (hazard ratio [HR] = 1.48, 95% CI 1.01-2.17), fewer than six prenatal visits (HR = 1.60, 95% CI 1.10-2.33), use of a pacifier within the first month (HR = 1.53, 95% CI 1.12-2.11), and poor latch-on (HR = 1.29, 95% CI 1.06-1.58 for each unfavorable parameter). CONCLUSIONS: Activities to promote exclusive breastfeeding should be intensified for adolescent mothers and for those whose prenatal care was less than ideal. These activities should reinforce the ill effects of pacifiers and should also include appropriate instruction for these mothers in correct breastfeeding technique. PMID- 17718872 TI - Female relatives or friends trained as labor doulas: outcomes at 6 to 8 weeks postpartum. AB - BACKGROUND: Data collected on more than 12,000 women in 15 randomized controlled trials provide robust evidence of the beneficial effects of doula support on medical outcomes to childbirth. The objective of this paper was to examine the association between doula support and maternal perceptions of the infant, self, and support from others at 6 to 8 weeks postpartum. The doula was a minimally trained close female relative or friend. METHODS: Six hundred low-risk, nulliparous women were enrolled in the original clinical trial and randomized to doula support (n = 300) or standard care (n = 300). The mother-to-be and her doula attended two 2-hour classes about providing nonmedical, continuous support to laboring women. For the secondary study, presented here, research participants (N = 494) were interviewed by telephone using a 42-item questionnaire. RESULTS: Overall, when doula-supported mothers (n = 229) were compared with mothers who received standard care (n = 265), they were more likely to report positive prenatal expectations about childbirth and positive perceptions of their infants, support from others, and self-worth. Doula-supported mothers were also most likely to have breastfed and to have been very satisfied with the care they received at the hospital. CONCLUSIONS: Labor support by a minimally trained female friend or relative, selected by the mother-to-be, enhances the postpartum well-being of nulliparous mothers and their infants, and is a low-cost alternative to professional doulas. PMID- 17718873 TI - Does cesarean section reduce postpartum urinary incontinence? A systematic review. AB - BACKGROUND: The impact of delivery mode on the development of urinary incontinence has been much debated. The primary objective of this systematic review was to compare the prevalence of postpartum urinary incontinence after cesarean section compared with vaginal birth. METHODS: The MEDLINE (1966-2005) and CINAHL (1982-2005) databases were searched for reports specifying postpartum prevalence or incidence of unspecified, stress, urge, and mixed urinary incontinence by mode of birth. Primary authors were contacted to request unpublished data about severity, parity, and timing of cesarean section. All data were entered into Review Manager software, and odds ratio (OR), absolute risk reduction, and number needed to prevent were calculated. RESULTS: Cesarean section reduced the risk of postpartum stress urinary incontinence from 16 to 9.8 percent (OR = 0.56 [0.45, 0.68], number needed to prevent = 15 [12,22]) in 6 cross-sectional studies, and from 22 to 10 percent in 12 cohort studies (OR=0.48 [0.39, 0.58], number needed to prevent = 10 [8,13]). Differences persisted by parity and after exclusion of instrumental delivery, but risk of severe stress urinary incontinence and urge urinary incontinence did not differ by mode of birth. CONCLUSIONS: Although short-term occurrence of any degree of postpartum stress urinary incontinence is reduced with cesarean section, severe symptoms are equivalent by mode of birth. Risk of postpartum stress urinary incontinence must be considered in the context of associated maternal and newborn morbidity and mortality. PMID- 17718874 TI - Information and informed consent for neonatal screening: opinions and preferences of parents. AB - BACKGROUND: The current neonatal screening program ("the heel prick") involves taking a few drops of blood from almost every newborn in the Netherlands to determine whether the child is suffering from one of three congenital disorders: phenylketonuria, congenital hypothyroid, or adrenogenital syndrome. This study investigated the preferences and views of parents and future parents with respect to information about, and consent to, neonatal screening and the possible expansion of the program. METHODS: Seven focus group discussions took place with future parents, parents with a healthy child, and parents with children affected by disorders for which screening is possible, now or in the future (total of 36 participants). The discussions were audiotaped, transcribed, and analyzed for content. RESULTS: Parents were not well informed about what the heel prick involves at present. Nevertheless, they see it as a routine procedure and do not think about the possibility of refusing it. If the heel-prick program were to be expanded, parents would like to be informed earlier, preferably during pregnancy. In addition, most parents preferred an opt-out consent approach. CONCLUSIONS: If the neonatal screening program is to be expanded, parents would prefer for information about the program be given during pregnancy. In addition, they preferred an opt-out consent approach, on condition that screening was for the purpose of preventing irreversible harm. Parental opinion was divided on this issue if the aim of screening were to be widened. PMID- 17718875 TI - Timing and predictors of postpartum return to smoking in a group of inner-city women: an exploratory pilot study. AB - BACKGROUND: Approximately 40 percent of women smokers will stop smoking cigarettes during pregnancy; however, 70 percent of those who stop will resume smoking by 6 months postpartum. This exploratory pilot study prospectively examined the timing and predictors of returning to smoking after pregnancy in a group of inner-city women who stopped smoking cigarettes during pregnancy. METHODS: We interviewed women who stopped smoking just before or during their pregnancies during their postpartum hospital stay and at their infants' 2-week health supervision visits. Urine cotinine levels were measured at each interview. RESULTS: Forty-nine women were interviewed during the postpartum stay and 37 women at the 2-week follow-up. At follow-up, 40.5 percent (n = 15) of women had returned to smoking. Mothers more frequently returned to smoking if they had a lower level of education, that is, high school graduate/general equivalency diploma versus some college education (13/24 vs 2/13, p < 0.04); if they had someone else in the household who smoked (14/23 vs 1/14, p < 0.003); if they were formula feeding their infant at the time of interview (14/24 vs 1/13, p < 0.005); if they discussed smoking with a doctor or nurse during pregnancy (12/20 vs 3/17, p < 0.02); and if they were African American (10/15 vs 5/22, p < 0.02). Mothers reported the primary reasons for returning to smoking were stress (53%, n= 8) and being around another smoker (40%, n= 6). CONCLUSIONS: Almost one-half of the women in this pilot study who stopped smoking cigarettes during pregnancy resumed in the days immediately after delivery. These data suggest that future studies should explore the initiation of postpartum relapse prevention during the prenatal and perinatal period. Interventions may be more effective if they include strategies aimed increasing breastfeeding rates and assisting household members to stop smoking. PMID- 17718876 TI - Thoughts and emotions during traumatic birth: a qualitative study. AB - BACKGROUND: Previous research shows that 1 to 6 percent of women will develop symptoms of posttraumatic stress disorder after childbirth. The objective of this study was to examine thoughts and emotions during birth, cognitive processing after birth, and memories of birth that might be important in the development of postnatal posttraumatic stress symptoms. METHODS: In a qualitative study, women with posttraumatic stress symptoms (n= 25) and without (n = 25) were matched for obstetric events to examine the nonmedical aspects of birth that made it traumatic. Women were interviewed 3 months after birth. RESULTS: The following themes emerged for all women: thoughts during birth included mental coping strategies, wanting labor to end, poor understanding of what was going on, and mental defeat. More negative than positive emotions were described during birth, primarily feeling scared, frightened, and upset. Postnatal cognitive processing included retrospective appraisal of birth, such as taking a fatalistic view and focusing on the present, for example, concentrating on the baby. Memories of birth included not remembering parts of the birth and forgetting how bad it was. Women with posttraumatic stress symptoms reported more panic, anger, thoughts of death, mental defeat, and dissociation during birth; after birth, they reported fewer strategies that focused on the present, more painful memories, intrusive memories, and rumination, than women without symptoms. CONCLUSIONS: The results provide a useful first step toward identifying aspects of birth and postnatal processing that might determine whether women develop postnatal posttraumatic stress symptoms. Further research is needed to broaden knowledge of posttraumatic stress disorder before drawing definite conclusions. PMID- 17718877 TI - The patient-centered (R)evolution. PMID- 17718879 TI - Too phobic to push. PMID- 17718882 TI - Monovision: a review. AB - In presbyopia, patients can no longer obtain clear vision at distance and near. Monovision is a method of correcting presbyopia where one eye is focussed for distance vision and the other for near. Monovision is a fairly common method of correcting presbyopia with contact lenses and has received renewed interest with the increase in refractive surgery. The present paper is a review of the literature on monovision. The success rate of monovision in adapted contact lens wearers is 59-67%. The main limitations are problems with suppressing the blurred image when driving at night and the need for a third focal length, for example with computer screens at intermediate distances. Stereopsis is impaired in monovision, but most patients do not seem to notice this. These limitations highlight the need to take account of occupational factors. Monovision could cause a binocular vision anomaly to decompensate, so the pre-fitting screening should include an assessment of orthoptic function. Various methods have been used to determine which eye should be given the distance vision contact lens and the literature on tests of ocular dominance is reviewed. It is concluded that tests of blur suppression are most likely to be relevant, but that ocular dominance is not fixed but is rather a fluid, adaptive, phenomenon in most patients. Suitable patients can often be given trial lenses that allow them to experiment with monovision in real world situations and this can be a useful way of revealing the preferred eye for each distance. Of course, no patient should drive or operate machinery until successfully adapted to monovision. Surgically induced monovision is less easily reversed than contact lens-induced monovision, and is only appropriate after a successful trial of monovision with contact lenses. PMID- 17718880 TI - Quality of population health data reporting by mode of delivery. PMID- 17718883 TI - Glare susceptibility test results correlate with temporal safety margin when executing turns across approaching vehicles in simulated low-sun conditions. AB - The purpose of this study was to compare the results of a laboratory glare susceptibility test with the execution of turns at an intersection (turns that required the driver to cross a lane containing approaching traffic). We measured glare susceptibility by means of low and high-contrast letter charts with and without a glare source. Driving performance in the absence and presence of simulated low sun was assessed using a simulator. In particular, we measured the difference between the time taken to complete a turn across the path of an approaching vehicle and the time to collision (TTC) with the approaching vehicle (the safety margin). The presence of glare resulted in a significant reduction in the safety margin used by drivers (by 0.65 s on average) and the mean number of collisions was significantly higher in the glare conditions than in the non-glare conditions. The effect of glare was larger for low-contrast than for high contrast oncoming vehicles. Older drivers (45-60 years) had a significantly greater reduction in safety margin than younger drivers (19-29 years), though there was a large inter-individual variability in both age groups. We suggest that the reduction in retinal image contrast caused by low-sun caused drivers to overestimate the TTC with approaching vehicles. PMID- 17718884 TI - Recovery of vision and pupil responses in optic neuritis and multiple sclerosis. AB - The recovery of visual performance and pupil responses were investigated in patients with demyelinating optic neuritis (ON) and multiple sclerosis (MS). The pupil constriction amplitude and the time delay (latency) of the pupil response were measured in 14 patients with a history of unilateral ON in response to either achromatic (luminance) or chromatic (isoluminant) stimulus modulation. Five of these subjects were diagnosed later with MS. In addition, we measured detection thresholds for achromatic stimuli using standard visual field perimetry and chromatic thresholds using a new colour assessment and diagnosis (CAD) test that isolates the use of colour signals. The results show that, despite significant improvements in visual function following the acute phase (as assessed using visual acuity and fields), significant pupil response deficits remain. The findings also demonstrate that accurate measurements of pupil responses and chromatic thresholds can reveal deficits that remain undetected with more conventional techniques. These preliminary findings suggest that the techniques described here can provide useful information about remitting and relapsing demyelinative phases, often observed during MS and ON. PMID- 17718886 TI - A survey of the availability of state-funded primary eye care in the UK for the very young and very old. AB - BACKGROUND: The National Health Service (NHS) provides General Ophthalmic Services (GOS) to eligible patients in the UK. Nearly all community optical practices have a contract with the NHS via local primary care organisations (primary care trusts in England) allowing the practices to provide NHS sight tests to eligible patients. OBJECTIVE: To determine the accessibility of GOS sight tests for certain groups of patient in the UK. METHOD: A telephone survey was carried out to investigate the availability of GOS sight tests for two categories of eligible patient. A total of 200 primary eye care practices were randomly selected, of which 100 were telephoned to establish the availability of a sight test for a child aged 1 year whose mother is concerned due to the presence of a family history (parental) of strabismus. The other 100 practices were telephoned to investigate the availability of a sight test for a person aged 90 years who was described as having dementia. RESULTS: A total of 199 of the 200 practices provided GOS sight tests. The mean age at which practices declared that they start examining children was 3.1 years. Most (76%) practices recommended an eye examination for the 1-year-old child, but only 46% said that they would carry this out themselves. Of the other 100 practices telephoned across the country, 93% said that they could arrange an eye examination for the patient with dementia. DISCUSSION: Of the UK optical practices that participated in this study, 99.5% provide GOS sight tests. About half of these would not offer a GOS sight test to a 1-year-old child. It has been suggested that the GOS Terms of Service do not permit practitioners to exclude categories of patients from GOS services, although we argue that this interpretation is equivocal. Indeed, it is suggested that clinical and ethical reasons may sometimes require practitioners to decline to examine certain categories of patient. It is worrying that one quarter of practices did not recommend an eye examination for a young child with a family history of strabismus. It is hoped that a continuing education and training project will increase interest in paediatric optometry. PMID- 17718885 TI - The forced vergence cover test and phoria adaptation. AB - Phoria adaptation (PA) provides innervation to help maintain the correct vergence posture for binocularly viewing objects. Once fusion is disrupted, such as is required for measuring a (dissociated) phoria, this innervation is slowly depleted. Thus, extended periods of monocular occlusion can be required to dissipate PA and reveal the full extent of the phoria. Two versions of a forced vergence modification of the alternating cover test (CT) have been proposed to rapidly show the full phoria. We evaluated the ability of these forced vergence CTs (FVCT-1 and FVCT-2) to deplete the PA induced by a 15 min adaptation period to base out prism. In both experiments, the CT followed by the FVCT was performed before and after the adaptation period. In Experiment 1 (n = 13), the FVCT-1 was evaluated at 40 cm. Experiment 2 (n = 32) evaluated the FVCT-2 at 4 m. In Experiments 1 and 2, the difference between pre- and post-adaptation CTs showed significant PA occurred during the adaptation period (7.8(Delta), p < 0.0005, and 5.4(Delta), p < 0.0005 respectively). In Experiment 1, the FVCT-1 did not reveal a larger phoria than the CT before (mean difference: 0.4(Delta), p = 0.34) or after (no difference for all subjects) the adaptation period. Thus, the FVCT-1 did not alter PA. In Experiment 2, the FVCT-2 did show a shift in the phoria compared to the CT. However, this shift was found to be equivalent before and after the adaptation period (mean difference in shift: 0.22(Delta), 95% CI: -0.52 to 0.96(Delta)). Thus, the FVCT-2 shifts the phoria a constant amount independent of the amount of PA present. We conclude that neither FVCT's behaviour is dependent on the PA present. Thus, these procedures are unlikely to be effective clinical procedures for revealing the full magnitude of the phoria. PMID- 17718887 TI - The phenol red thread test for lacrimal volume--does it matter if the eyes are open or closed? AB - OBJECT: To assess the results from using a commercially available phenol red thread (PRT) test with the eyes being kept open (as recommended by the company) vs a closed eye protocol (as used by some investigators). METHODS: A single PRT (Zone-Quick) test was carried out on 97 young adults (average age 21 years, range: 17-36) for 15 s with either the eyes open or closed. The right eye was assessed with 52 subjects undertaking the open eye test first, with the test being repeated 1 h later in the same indoor environment (temperature 21 degrees C and 40% humidity). RESULTS: The mean ( +/- S.D.) PRT value for the open eye protocol was marginally higher (at 20.5 +/- 7.0 mm) than for the closed eye (19.7 +/- 5.9 mm), but the overall outcome from the two protocols could range from being 18 mm greater in the open eye to 15 mm greater in the closed eye. Overall, the difference was not statistically different, neither were any substantial differences noted according to age, gender, iris colour, prior contact lens wear or according to which protocol was used first (p >or= 0.2). CONCLUSION: These studies indicate that there can be a small difference in single PRT test data according to whether the eyes are kept open or closed, and it would be useful if the protocol used was clearly stated. PMID- 17718888 TI - Mapping of error cells in clinical measure to symmetric power space. AB - During the refraction procedure, the power of the nearest equivalent sphere lens, known as the scalar power, is conserved within upper and lower bounds in the sphere (and cylinder) lens powers. Bounds are brought closer together while keeping the circle of least confusion on the retina. The sphere and cylinder powers and changes in these powers are thus dependent. Changes are depicted in the cylinder-sphere plane by error cells with one pair of parallel sides of negative gradient and the other pair aligned with the graph axis of cylinder power. Scalar power constitutes a vector space, is a meaningful ophthalmic quantity and is represented by the semi-trace of the dioptric power matrix. The purpose of this article is to map to error cells for the following: coordinates of the dioptric power matrix, its principal powers and meridians and its entries from error cells surrounding powers in sphere, cylinder and axis. Error cells in clinical measure for conserved scalar power now contain more compensatory lens powers. Such cells and their respective mappings in terms of most scientific and alternate clinical quantities now image consistently not only to the cells from where they originate but also to each other. PMID- 17718889 TI - Case report: 49, XXXXY syndrome and high myopia. AB - 49, XXXXY karyotype syndrome has been thought of as a variant of Klinefelter's syndrome. It has an incidence of between 1/85 000 to 1/100 000 live births. Typical clinical features include coarse faces, skeletal abnormalities, hypogenitalism and severe learning difficulties. Common ocular features include hypertelorism, epicanthic folds and up-slanting palpebral apertures. Here we report a case of high myopia and its successful correction leading to a positive personality change in one such patient. We advocate full ophthalmic examination, under anaesthesia if necessary, and a trial of refractive correction, even in children thought unlikely to tolerate such. PMID- 17718890 TI - Technical note: dimensionless ray transference. AB - The ray transference matrix completely characterises the first-order optical nature of an optical system including the eye. It is in terms of the transference that quantitative analyses (for example, calculation of an average eye) can be performed. However, the fact that the entries of the transference do not have the same physical dimensions precludes the calculation of the usual scalar value (a Frobenius norm for example) for a change or difference between two optical systems. The purpose of this note is to show how to use the wavelength of the light as a natural unit of length to define a dimensionless transference and so make it possible to calculate a meaningful norm. In most practical applications, some components of the dimensionless transference may dominate unreasonably in the resulting norm in which case suitably weighted norms may be more appropriate. In an appendix, some of the issues are illustrated by application to a lens. PMID- 17718891 TI - Technical note: a comparison of central and peripheral intraocular pressure using rebound tonometry. AB - PURPOSE: To compare central and peripheral intraocular pressure (IOP) readings obtained with rebound tonometry. METHODS: Intraocular pressure was measured on the right eye of 153 patients (65 males, 88 females), aged from 21 to 85 years (mean +/- S.D., 55.5 +/- 15.2 years) with the ICare rebound tonometer at centre, and 2 mm from the limbus (in the nasal and temporal regions along the 0-180 degrees corneal meridian). RESULTS: Intraocular pressure values obtained with the ICare were 14.9 +/- 2.8; 14.1 +/- 2.5 and 14.5 +/- 2.7 mmHg at centre, nasal and temporal corneal locations, respectively. On average, nasal and temporal IOP readings were 0.75 and 0.37 mmHg lower than the central reading (p < 0.05 and p > 0.05, respectively). A highly significant correlation was found between central and peripheral measurements in nasal (r(2) = 0.905; p < 0.001) and temporal (r(2) = 0.879; p < 0.001) regions along the horizontal meridian. Almost 80% of patients presented nasal IOP values within +/-1 mmHg of the central value. CONCLUSIONS: Intraocular pressure values measured with the ICare rebound tonometer on the nasal corneal region is slightly lower on average and highly correlated with IOP values recorded at corneal centre. Both nasal and temporal readings are in good agreement with central IOP, and could be used to obtain a reliable estimate of rebound IOP in corneas where central readings cannot be taken. PMID- 17718892 TI - Technical note: method for estimating volume of subretinal fluid in cases of localized retinal detachment by OCT ophthalmoscopy. AB - The volume of the subretinal fluid can be used to assess the condition of different types of retinal and macular disorders. The purpose of this report is to introduce a method to measure the volume of the subretinal fluid with the images of the optical coherence tomography (OCT) Ophthalmoscope in three cases of central serous chorioretinopathy and one case of retinal pigment epithelial detachment. We used the topography-mode program of the OCT Ophthalmoscope and measured the average height of the retinal detachment. By multiplying the size of the area of the retinal detachment and the average height of the retinal detachment, the volume of subretinal fluid could be determined. Examples are given to show the results of volume measurement of subretinal fluid in cases of localized retinal detachments. PMID- 17718893 TI - Results of the 2006 Naylor Prize competition. PMID- 17718894 TI - Letter to the editor: the lens is stable during accommodation. PMID- 17718899 TI - Composite multifocal basal cell carcinoma and precursor B acute lymphoblastic leukemia: case report. AB - Synchronous composite tumors though described are uncommon. Moreover, simultaneous occurrence of synchronous tumors involving the same tissue or organ at multiple sites is even less common. We report a case of acute lymphoblastic leukemia (ALL) and basal cell carcinoma (BCC) occurring simultaneously in multiple skin sites. Several cases showing an association between cutaneous malignancies and lymphoproliferative disorders have been reported. Some of these cases included ALL and BCC and occurred often in the pediatric population with the BCC arising as a post-ALL therapy sequela. Other rare genetic causes may be considered. To our knowledge this is the first time that the synchronous occurrence of these two malignant processes in the same tissue involving multiple sites in an elderly patient is described. PMID- 17718897 TI - Prognostic value of histopathology and trends in cervical cancer: a SEER population study. AB - BACKGROUND: Histopathology is a cornerstone in the diagnosis of cervical cancer but the prognostic value is controversial. METHODS: Women under active follow-up for histologically confirmed primary invasive cervical cancer were selected from the United States Surveillance, Epidemiology, and End Results (SEER) 9-registries public use data 1973-2002. Only histologies with at least 100 cases were retained. Registry area, age, marital status, race, year of diagnosis, tumor histology, grade, stage, tumor size, number of positive nodes, number of examined nodes, odds of nodal involvement, extent of surgery, and radiotherapy were evaluated in Cox models by stepwise selection using the Akaike Information Criteria. RESULTS: There were 30,989 records evaluable. From 1973 to 2002, number of cases dropped from 1,100 new cases/year to 900/year, but adenocarcinomas and adenosquamous carcinoma increased from 100/year to 235/year. Median age was 48 years. Statistically significant variables for both overall and cause-specific mortality were: age, year of diagnosis, race, stage, histology, grade, hysterectomy, radiotherapy, tumor size and nodal ratio. The histological types were jointly significant, P < 0.001. Cause-specific mortality hazard ratios by histological type relatively to non-microinvasive squamous cell carcinoma were: microinvasive squamous cell carcinoma 0.28 (95% confidence interval: 0.20-0.39), carcinoma not otherwise specified 0.91 (0.79-1.04), non-mucinous adenocarcinoma 1.06 (0.98-1.15), adenosquamous carcinoma 1.35 (1.20-1.51), mucinous adenocarcinoma 1.52 (1.23-1.88), small cell carcinoma 1.94 (1.58-2.39). CONCLUSION: Small cell carcinoma and adenocarcinomas were associated with poorer survival. The incidental observation of increasing numbers of adenocarcinomas despite a general decline suggests the inefficiency of conventional screening for these tumors. Increased incidence of adenocarcinomas, their adverse prognosis, and the young age at diagnosis indicate the need to identify women who are at risk. PMID- 17718898 TI - Unsaturated phosphatidylcholines lining on the surface of cartilage and its possible physiological roles. AB - BACKGROUND: Evidence has strongly indicated that surface-active phospholipid (SAPL), or surfactant, lines the surface of cartilage and serves as a lubricating agent. Previous clinical study showed that a saturated phosphatidylcholine (SPC), dipalmitoyl-phosphatidylcholine (DPPC), was effective in the treatment of osteoarthritis, however recent studies suggested that the dominant SAPL species at some sites outside the lung are not SPC, rather, are unsaturated phosphatidylcholine (USPC). Some of these USPC have been proven to be good boundary lubricants by our previous study, implicating their possible important physiological roles in joint if their existence can be confirmed. So far, no study has been conducted to identify the whole molecule species of different phosphatidylcholine (PC) classes on the surface of cartilage. In this study we identified the dominant PC molecule species on the surface of cartilage. We also confirmed that some of these PC species possess a property of semipermeability. METHODS: HPLC was used to analyse the PC profile of bovine cartilage samples and comparisons of DPPC and USPC were carried out through semipermeability tests. RESULTS: It was confirmed that USPC are the dominant SAPL species on the surface of cartilage. In particular, they are Dilinoleoyl-phosphatidylcholine (DLPC), Palmitoyl-linoleoyl-phosphatidylcholine, (PLPC), Palmitoyl-oleoyl phosphatidylcholine (POPC) and Stearoyl-linoleoyl-phosphatidylcholine (SLPC). The relative content of DPPC (a SPC) was only 8%. Two USPC, PLPC and POPC, were capable of generating osmotic pressure that is equivalent to that by DPPC. CONCLUSION: The results from the current study confirm vigorously that USPC is the endogenous species inside the joint as against DPPC thereby confirming once again that USPC, and not SPC, characterizes the PC species distribution at non lung sites of the body. USPC not only has better anti-friction and lubrication properties than DPPC, they also possess a level of semipermeability that is equivalent to DPPC. We therefore hypothesize that USPC can constitute a possible addition or alternative to the current commercially available viscosupplementation products for the prevention and treatment of osteoarthritis in the future. PMID- 17718900 TI - Initial community perspectives on the Health Service Extension Programme in Welkait, Ethiopia. AB - BACKGROUND: The Health Service Extension Programme (HSEP) is an innovative approach to addressing the shortfall in health human resources in Ethiopia. It has developed a new cadre of Health Extension Workers (HEWs), who are charged with providing the health and hygiene promotion and some treatment services, which together constitute the bedrock of Ethiopia's community health system. METHODS: This study seeks to explore the experience of the HSEP from the perspective of the community who received the service. A random sample of 60 female heads-of-household in a remote area of Tigray participated in a structured interview survey. RESULTS: Although Health Extension Workers (HEWs) had visited them less frequently than planned, participants generally found the programme to be helpful. Despite this, their basic health knowledge was still quite poor regarding the major communicable diseases and their vectors. Participants felt the new HESP represented an improvement on previous health provision. HEWs were preferred over Traditional Birth Attendants for assistance with labour CONCLUSION: While the introduction of HEWs has been a positive experience for women living at the study site, the frequency of visits, extent of effectively imparted health knowledge and affects of HEWs on other health providers needs to be further explored. PMID- 17718902 TI - Answer changing in multiple choice assessment change that answer when in doubt- and spread the word! AB - BACKGROUND: Several studies during the last decades have shown that answer changing in multiple choice examinations is generally beneficial for examinees. In spite of this the common misbelief still prevails that answer changing in multiple choice examinations results in an increased number of wrong answers rather than an improved score. One suggested consequence of newer studies is that examinees should be informed about this misbelief in the hope that this prejudice might be eradicated. This study aims to confirm data from previous studies about the benefits of answer changing as well as pursue the question of whether students informed about the said advantageous effects of answer changing would indeed follow this advice and change significantly more answers. Furthermore a look is cast on how the overall examination performance and mean point increase of these students is affected. METHODS: The answer sheets to the end of term exams of 79 3rd year medical students at the University of Munich were analysed to confirm the benefits of answer changing. Students taking the test were randomized into two groups. Prior to taking the test 41 students were informed about the benefits of changing answers after careful reconsideration while 38 students did not receive such information. Both groups were instructed to mark all answer changes made during the test. RESULTS: Answer changes were predominantly from wrong to right in full accordance with existing literature resources. It was shown that students who had been informed about the benefits of answer changing when in doubt changed answers significantly more often than students who had not been informed. Though students instructed on the benefits of changing answers scored higher in their exams than those not instructed, the difference in point increase was not significant. CONCLUSION: Students should be informed about the benefits of changing initial answers to multiple choice questions once when in reasonable doubt about these answers. Furthermore, reconsidering answers should be encouraged as students will heed the advice and change more answers than students not so instructed. PMID- 17718901 TI - Sensitization of TRAIL-resistant LNCaP cells by resveratrol (3, 4', 5 tri hydroxystilbene): molecular mechanisms and therapeutic potential. AB - BACKGROUND: We have previously shown that prostate cancer LNCaP cells are resistant to TRAIL, and downregulation of PI-3K/Akt pathway by molecular and pharmacological means sensitizes cells to undergo apoptosis by TRAIL and curcumin. The purpose of this study was to examine the molecular mechanisms by which resveratrol sensitized TRAIL-resistant LNCaP cells. RESULTS: Resveratrol inhibited growth and induced apoptosis in androgen-dependent LNCaP cells, but had no effect on normal human prostate epithelial cells. Resveratrol upregulated the expression of Bax, Bak, PUMA, Noxa, Bim, TRAIL-R1/DR4 and TRAIL-R2/DR5, and downregulated the expression of Bcl-2, Bcl-XL, survivin and XIAP. Treatment of LNCaP cells with resveratrol resulted in generation of reactive oxygen species, translocation of Bax and p53 to mitochondria, subsequent drop in mitochondrial membrane potential, release of mitochondrial proteins (cytochrome c, AIF, Smac/DIABLO and Omi/HtrA2), activation of caspase-3 and caspase-9 and induction of apoptosis. The ability of resveratrol to sensitize TRAIL-resistant LNCaP cells was inhibited by dominant negative FADD, caspase-8 siRNA or N-acetyl cysteine. Smac siRNA inhibited resveratrol-induced apoptosis, whereas Smac N7 peptide induced apoptosis and enhanced the effectiveness of resveratrol. CONCLUSION: Resveratrol either alone or in combination with TRAIL or Smac can be used for the prevention and/or treatment of human prostate cancer. PMID- 17718903 TI - Pulmonary embolism and patent foramen ovale thrombosis: the key role of TEE. AB - This is a case report of a 35 young man with Klinefelter Syndrome presented breathlessness, palpitations and chest pain. It shows a rare case of a thrombus located through the PFO, in patient with pulmonary and paradoxical embolism, which takes back to exciting hypothesis on thrombus growth. A thrombus, which has grown 'in situ' or trapped through the patent foramen ovale, may be a cause of relapsing pulmonary or systemic embolism during anticoagulation therapy. To prevent recurrent paradoxical embolism, percutaneous closure of PFO is recommended, but in this case, thrombus was trapped through the PFO and the patient was referred to the surgeon. We believe that under these circumstances the clinician should be informed of the presence of PFO in critical pulmonary embolism; this case points out the key role of TEE to face a diagnostic and therapeutic scenarios. PMID- 17718904 TI - Adult brain abscess associated with patent foramen ovale: a case report. AB - Brain abscess results from local or metastatic septic spread to the brain. The primary infectious site is often undetected, more commonly so when it is distant. Unlike pediatric congenital heart disease, minor intracardiac right-to-left shunting due to patent foramen ovale has not been appreciated as a cause of brain abscess in adults. Here we present a case of brain abscess associated with a patent foramen ovale in a 53-year old man with dental-gingival sepsis treated in the intensive care unit. Based on this case and the relevant literature we suggest a link between a silent patent foramen ovale, paradoxic pathogen dissemination to the brain, and development of brain abscess. PMID- 17718905 TI - Microglial activation in the hippocampus of hypercholesterolemic rabbits occurs independent of increased amyloid production. AB - BACKGROUND: Rabbits maintained on high-cholesterol diets are known to show increased immunoreactivity for amyloid beta protein in cortex and hippocampus, an effect that is amplified by presence of copper in the drinking water. Hypercholesterolemic rabbits also develop sporadic neuroinflammatory changes. The purpose of this study was to survey microglial activation in rabbits fed cholesterol in the presence or absence of copper or other metal ions, such as zinc and aluminum. METHODS: Vibratome sections of the rabbit hippocampus and overlying cerebral cortex were examined for microglial activation using histochemistry with isolectin B4 from Griffonia simplicifolia. Animals were scored as showing either focal or diffuse microglial activation with or without presence of rod cells. RESULTS: Approximately one quarter of all rabbits fed high cholesterol diets showed evidence of microglial activation, which was always present in the hippocampus and not in the cortex. Microglial activation was not correlated spatially with increased amyloid immunoreactivity or with neurodegenerative changes and was most pronounced in hypercholesterolemic animals whose drinking water had been supplemented with either copper or zinc. Controls maintained on normal chow were largely devoid of neuroinflammatory changes, but revealed minimal microglial activation in one case. CONCLUSION: Because the increase in intraneuronal amyloid immunoreactivity that results from administration of cholesterol occurs in both cerebral cortex and hippocampus, we deduce that the microglial activation reported here, which is limited to the hippocampus, occurs independent of amyloid accumulation. Furthermore, since neuroinflammation occurred in the absence of detectable neurodegenerative changes, and was also not accompanied by increased astrogliosis, we conclude that microglial activation occurs because of metabolic or biochemical derangements that are influenced by dietary factors. PMID- 17718907 TI - Evaluation, diagnosis, and treatment of lead poisoning in a patient with occupational lead exposure: a case presentation. AB - Amongst toxic heavy metals, lead ranks as one of the most serious environmental poisons all over the world. Exposure to lead in the home and the workplace results in health hazards to many adults and children causing economic damage, which is due to the lack of awareness of the ill effects of lead. We report the case of a 22 year old man working in an unorganized lead acid battery manufacturing unit, complaining about a longer history of general body ache, lethargy, fatigue, shoulder joint pain, shaking of hands and wrist drop. Patient had blue line at gingivodental junction. Central nervous system (CNS) examination showed having grade 0 power of extensors of right wrist & fingers. Reflexes: Supinator- absent, Triceps- weak and other deep tendon reflexes- normal. Investigations carried out during the admission showed hemoglobin levels of 8.3 g/dl and blood lead level of 128.3 mug/dl. The patient was subjected to chelation therapy, which was accompanied by aggressive environmental intervention and was advised not to return to the same environmental exposure situation. After repeated course of chelation therapy he has shown the signs of improvement and is on follow up presently. PMID- 17718906 TI - Genomic and proteomic profiling II: comparative assessment of gene expression profiles in leiomyomas, keloids, and surgically-induced scars. AB - BACKGROUND: Leiomyoma have often been compared to keloids because of their fibrotic characteristic and higher rate of occurrence among African Americans as compared to other ethnic groups. To evaluate such a correlation at molecular level this study comparatively analyzed leiomyomas with keloids, surgical scars and peritoneal adhesions to identify genes that are either commonly and/or individually distinguish these fibrotic disorders despite differences in the nature of their development and growth. METHODS: Microarray gene expression profiling and realtime PCR. RESULTS: The analysis identified 3 to 12% of the genes on the arrays as differentially expressed among these tissues based on P ranking at greater than or equal to 0.005 followed by 2-fold cutoff change selection. Of these genes about 400 genes were identified as differentially expressed in leiomyomas as compared to keloids/incisional scars, and 85 genes as compared to peritoneal adhesions (greater than or equal to 0.01). Functional analysis indicated that the majority of these genes serve as regulators of cell growth (cell cycle/apoptosis), tissue turnover, transcription factors and signal transduction. Of these genes the expression of E2F1, RUNX3, EGR3, TBPIP, ECM-2, ESM1, THBS1, GAS1, ADAM17, CST6, FBLN5, and COL18A was confirmed in these tissues using quantitative realtime PCR based on low-density arrays. CONCLUSION: the results indicated that the molecular feature of leiomyomas is comparable but may be under different tissue-specific regulatory control to those of keloids and differ at the levels rather than tissue-specific expression of selected number of genes functionally regulating cell growth and apoptosis, inflammation, angiogenesis and tissue turnover. PMID- 17718908 TI - Delivery strategy of mass annual single dose DEC administration to eliminate lymphatic filariasis in the urban areas of Pondicherry, South India: 5 years of experience. AB - BACKGROUND: The recommended strategy for elimination of Lymphatic filariasis is single-dose, once-yearly mass treatment with anti-filarial drugs and the program is in operation on a national level in India. Rate of coverage and consumption is the most crucial factor in the success of Mass Drug Administration (MDA) program. In spite of massive efforts, the program demonstrated sub-optimal coverage and consumption in urban areas than rural. The involvement of Anganwadi workers (AWWs) of the Integrated Child Development Scheme (ICDS) as communicators and drug distributors was attempted to enhance the coverage and consumption in urban areas and the results presented here. METHODS: An annual single dose MDA program was launched under the auspices of Freedom From Filariasis (FFF) program in Pondicherry, India, in the year 1997 and continued for five years. A questionnaire survey was carried out following all the treatment rounds (TRs) for assessing coverage of distribution and consumption Five percent of randomly selected households constituted the sample. All the members available in the selected household at the time of interview formed the respondent of the study. RESULTS: The coverage of drug distribution during the TRs varied from 74.3 to 95.4 percent and consumption rate from 52.9 to 78.8. Among the respondents, 71% were aware of the MDA program and the source of information for 62.8% of them was through personal communication by the AWW. It was observed that 33.2% of the respondents who accepted the drug did so based on the trust on the AWW as a government representative. The main reason for non-consumption in all TRs was fear of side reaction (25.4 - 42.2%). CONCLUSION: The delivery-strategy of health information and Diethylcarbamazine (DEC) drug to the urban community using the AWWs could achieve relatively higher coverage and consumption than reported in other urban areas. In order to achieve the optimum level, it is imperative to equip the AWWs with current knowledge and skills, and design innovative Information, Education and Communication (IEC) campaign to target the less compliant groups. The beneficial effect of this delivery strategy may be used in similar urban settings to achieve the elimination of LF. PMID- 17718909 TI - Parental versus child reporting of fruit and vegetable consumption. AB - BACKGROUND: The purpose of this study was to (1) compare parental and child recording of children's fruit and vegetable (F&V) consumption, including family related factors, and (2) investigate the potential differences in the relation of children's and parents' perceptions of family-related factors. METHODS: Children were recruited from Dutch seventh and eighth grade classrooms. Each child and one of their parents completed parallel questionnaires. A total of 371 matched child parent surveys were included in the analyses. To compare parental and child reports of consumption and family-related factors regarding F&V intake several techniques were used such as paired sample t-test, chi-square tests, Pearson's correlations and Cohens's kappa as measurement of agreement. To investigate potential differences between the parent's and children's perceptions of family related factors, linear regression analyses were conducted. RESULTS: The results indicated weak agreement for F&V consumption (Cohen's kappa coefficients of .31 and .20, respectively) but no differences in mean consumption of fruit at the group level. Regarding the family-environmental factors related to fruit consumption, significant differences were found between the perceptions of subjective norm, and the availability and accessibility of fruit. Perceptions of subjective norm, parental modelling and exposure regarding vegetable consumption were also viewed differently by the two groups. The family-environmental factors reported by the children were similarly associated with F&V consumption compared to those reported by their respective parents. However, parents rated these factors more favourably than their children did. CONCLUSION: The results indicated a low level of agreement between parental and child reporting of F&V intake and their assessment of family-environmental factors on individual level. This has important implications for the development and evaluation of interventions and we recommend that researchers clearly indicate which source of information they use in their studies as it remains unclear which source is more valid.However, when the effects of interventions are studied at the group level, our results suggest that it makes no difference whether children or parents report the child's fruit consumption. The same holds for determinant studies; both parental and child reports can be used. However, perceptions of these factors differ significantly. PMID- 17718910 TI - Association of Escherichia coli O157:H7 tir polymorphisms with human infection. AB - BACKGROUND: Emerging molecular, animal model and epidemiologic evidence suggests that Shiga-toxigenic Escherichia coli O157:H7 (STEC O157) isolates vary in their capacity to cause human infection and disease. The translocated intimin receptor (tir) and intimin (eae) are virulence factors and bacterial receptor-ligand proteins responsible for tight STEC O157 adherence to intestinal epithelial cells. They represent logical genomic targets to investigate the role of sequence variation in STEC O157 pathogenesis and molecular epidemiology. The purposes of this study were (1) to identify tir and eae polymorphisms in diverse STEC O157 isolates derived from clinically ill humans and healthy cattle (the dominant zoonotic reservoir) and (2) to test any observed tir and eae polymorphisms for association with human (vs bovine) isolate source. RESULTS: Five polymorphisms were identified in a 1,627-bp segment of tir. Alleles of two tir polymorphisms, tir 255 T>A and repeat region 1-repeat unit 3 (RR1-RU3, presence or absence) had dissimilar distributions among human and bovine isolates. More than 99% of 108 human isolates possessed the tir 255 T>A T allele and lacked RR1-RU3. In contrast, the tir 255 T>A T allele and RR1-RU3 absence were found in 55% and 57%, respectively, of 77 bovine isolates. Both polymorphisms associated strongly with isolate source (p < 0.0001), but not by pulsed field gel electrophoresis type or by stx1 and stx2 status (as determined by PCR). Two eae polymorphisms were identified in a 2,755-bp segment of 44 human and bovine isolates; 42 isolates had identical eae sequences. The eae polymorphisms did not associate with isolate source. CONCLUSION: Polymorphisms in tir but not eae predict the propensity of STEC O157 isolates to cause human clinical disease. The over-representation of the tir 255 T>A T allele in human-derived isolates vs the tir 255 T>A A allele suggests that these isolates have a higher propensity to cause disease. The high frequency of bovine isolates with the A allele suggests a possible bovine ecological niche for this STEC O157 subset. PMID- 17718911 TI - Quantification of angiogenesis in estrogen receptor-positive and negative breast carcinoma. AB - BACKGROUND: The objective of this study was to evaluate angiogenesis according to CD34 antigen expression in estrogen receptor (ER)-positive and negative breast carcinomas. METHODS: This study comprised 64 cases of infiltrating ductal carcinoma in postmenopausal women divided into two groups: Group A: ER-positive, n = 35; and Group B: ER-negative, n = 29. The anti-CD34 monoclonal antibody was used as a marker for endothelial cells. Microvessel count was carried out in 10 fields per slide using a 40x objective lens (magnification 400x). Statistical analysis of the data was performed using Student's t-test (p < 0.05). RESULTS: The mean number of vessels stained with the anti-CD34 antibody in the estrogen receptor-positive and negative tumors was 23.51 +/- 1.15 and 40.24 +/- 0.42, respectively. The number of microvessels was significantly greater in the estrogen receptor-negative tumors (p < 0.001). CONCLUSION: ER-negative tumors have significantly greater CD34 antigen expression compared to ER-positive tumors. PMID- 17718912 TI - Fez1/Lzts1 a new mitotic regulator implicated in cancer development. AB - Considerable evidence has accumulated suggesting that cancer has genetic origin, based on the development of genomic alterations, such as deletions, mutations, and/or methylations in critical genes for homeostasis of cellular functions, including cell survival, DNA replication and cell cycle control. Mechanism controlling the precise timing and sequence of cell cycle events as well as checkpoints insuring fidelity of those events are key targets that when disrupted could result in tumorigenesis. Mitosis is the process by which a cell duplicates its genetic information (DNA), in order to generate two, identical, daughter cells. In addition each daughter cell must receive one centrosome and the appropriate complements of cytoplasm and organelles. This process is conventionally divided in to five distinct stages: prophase, prometaphase, metaphase, anaphase and telophase that correspond to a different morphology of the cell. The entry into mitosis (M) is under the control of the cyclin dependent kinase Cdk1. During G2, the kinases Wee1 and Myt1 phosphorylate Cdk1 at T14/Y15 residues, rendering it inactive. The transition from G2 to M is promoted by the activation of Cdk1 via dephosphorylation by the Cdk1 phosphatase Cdc25C. Activated Cdk1 complexes translocate into the nucleus during prophase where phosphorylate numerous substrates in order to enhance their activation as the cells progresses trough prophase, prometaphase, and metaphase.Recently we identified a new player: FEZ1/LZTS1 that contributes to the fine-tuning of the molecular events that determine progression through mitosis, and here will review its role in cancer development and in M phase regulation. PMID- 17718913 TI - New insights about host response to smallpox using microarray data. AB - BACKGROUND: Smallpox is a lethal disease that was endemic in many parts of the world until eradicated by massive immunization. Due to its lethality, there are serious concerns about its use as a bioweapon. Here we analyze publicly available microarray data to further understand survival of smallpox infected macaques, using systems biology approaches. Our goal is to improve the knowledge about the progression of this disease. RESULTS: We used KEGG pathways annotations to define groups of genes (or modules), and subsequently compared them to macaque survival times. This technique provided additional insights about the host response to this disease, such as increased expression of the cytokines and ECM receptors in the individuals with higher survival times. These results could indicate that these gene groups could influence an effective response from the host to smallpox. CONCLUSION: Macaques with higher survival times clearly express some specific pathways previously unidentified using regular gene-by-gene approaches. Our work also shows how third party analysis of public datasets can be important to support new hypotheses to relevant biological problems. PMID- 17718914 TI - Analysis of the role of retrotransposition in gene evolution in vertebrates. AB - BACKGROUND: The dynamics of gene evolution are influenced by several genomic processes. One such process is retrotransposition, where an mRNA transcript is reverse-transcribed and reintegrated into the genomic DNA. RESULTS: We have surveyed eight vertebrate genomes (human, chimp, dog, cow, rat, mouse, chicken and the puffer-fish T. nigriviridis), for putatively retrotransposed copies of genes. To gain a complete picture of the role of retrotransposition, a robust strategy to identify putative retrogenes (PRs) was derived, in tandem with an adaptation of previous procedures to annotate processed pseudogenes, also called retropseudogenes (RpsiGs). Mammalian genomes are estimated to contain 400-800 PRs (corresponding to approximately 3% of genes), with fewer PRs and RpsiGs in the non-mammalian vertebrates. Focussing on human and mouse, we aged the PRs, analysed for evidence of transcription and selection pressures, and assigned functional categories. The PRs have significantly less transcription evidence mappable to them, are significantly less likely to arise from alternatively spliced genes, and are statistically overrepresented for ribosomal-protein genes, when compared to the proteome in general. We find evidence for spurts of gene retrotransposition in human and mouse, since the lineage of either species split from the dog lineage, with >200 PRs formed in mouse since its divergence from rat. To examine for selection, we calculated: (i) Ka/Ks values (ratios of non synonymous and synonymous substitutions in codons), and (ii) the significance of conservation of reading frames in PRs. We found >50 PRs in both human and mouse formed since divergence from dog, that are under pressure to maintain the integrity of their coding sequences. For different subsets of PRs formed at different stages of mammalian evolution, we find some evidence for non-neutral evolution, despite significantly less expression evidence for these sequences. CONCLUSION: These results indicate that retrotranspositions are a significant source of novel coding sequences in mammalian gene evolution. PMID- 17718915 TI - PARE: a tool for comparing protein abundance and mRNA expression data. AB - BACKGROUND: Techniques for measuring protein abundance are rapidly advancing and we are now in a situation where we anticipate many protein abundance data sets will be available in the near future. Since proteins are translated from mRNAs, their expression is expected to be related to their abundance, to some degree. RESULTS: We have developed a web tool, called PARE (Protein Abundance and mRNA Expression; http://proteomics.gersteinlab.org), to correlate these two quantities. In addition to globally comparing the quantities of protein and mRNA, PARE allows users to select subsets of proteins for focused study (based on functional categories and complexes). Furthermore, it highlights correlation outliers, which are potentially worth further examination. CONCLUSION: We anticipate PARE will facilitate comparative studies on mRNA and protein abundance by the proteomics community. PMID- 17718917 TI - Truthfulness in transplantation: non-heart-beating organ donation. AB - The current practice of organ transplantation has been criticized on several fronts. The philosophical and scientific foundations for brain death criteria have been crumbling. In addition, donation after cardiac death, or non heartbeating-organ donation (NHBD) has been attacked on grounds that it mistreats the dying patient and uses that patient only as a means to an end for someone else's benefit.Verheijde, Rady, and McGregor attack the deception involved in NHBD, arguing that the donors are not dead and that potential donors and their families should be told that is the case. Thus, they propose abandoning the dead donor rule and allowing NHBD with strict rules concerning adequate informed consent. Such honesty about NHBD should be welcomed.However, NHBD violates a fundamental end of medicine, nonmaleficience, "do no harm." Physicians should not be harming or killing patients, even if it is for the benefit of others. Thus, although Verheijde and his colleages should be congratulated for calling for truthfulness about NHBD, they do not go far enough and call for an elimination of such an unethical procedure from the practice of medicine. PMID- 17718918 TI - Clarifying the paradigm for the ethics of donation and transplantation: was 'dead' really so clear before organ donation? AB - Recent commentaries by Verheijde et al, Evans and Potts suggesting that donation after cardiac death practices routinely violate the dead donor rule are based on flawed presumptions. Cell biology, cardiopulmonary resuscitation, critical care life support technologies, donation and transplantation continue to inform concepts of life and death. The impact of oxygen deprivation to cells, organs and the brain is discussed in relation to death as a biological transition. In the face of advancing organ support and replacement technologies, the reversibility of cardiac arrest is now purely related to the context in which it occurs, in association to the availability and application of support systems to maintain oxygenated circulation. The 'complete and irreversible' lexicon commonly used in death discussions and legal statutes are ambiguous, indefinable and should be replaced by accurate terms. Criticism of controlled DCD on the basis of violating the dead donor rule, where autoresuscitation has not been described beyond 2 minutes, in which life support is withdrawn and CPR is not provided, is not valid. However, any post mortem intervention that re-establishes brain blood flow should be prohibited. In comparison to traditional practice, organ donation has forced the clarification of the diagnostic criteria for death and improved the rigour of the determinations. PMID- 17718916 TI - An AICD-based functional screen to identify APP metabolism regulators. AB - BACKGROUND: A central event in Alzheimer's disease (AD) is the regulated intramembraneous proteolysis of the beta-amyloid precursor protein (APP), to generate the beta-amyloid (Abeta) peptide and the APP intracellular domain (AICD). Abeta is the major component of amyloid plaques and AICD displays transcriptional activation properties. We have taken advantage of AICD transactivation properties to develop a genetic screen to identify regulators of APP metabolism. This screen relies on an APP-Gal4 fusion protein, which upon normal proteolysis, produces AICD-Gal4. Production of AICD-Gal4 induces Gal4-UAS driven luciferase expression. Therefore, when regulators of APP metabolism are modulated, luciferase expression is altered. RESULTS: To validate this experimental approach we modulated alpha-, beta-, and gamma-secretase levels and activities. Changes in AICD-Gal4 levels as measured by Western blot analysis were strongly and significantly correlated to the observed changes in AICD-Gal4 mediated luciferase activity. To determine if a known regulator of APP trafficking/maturation and Presenilin1 endoproteolysis could be detected using the AICD-Gal4 mediated luciferase assay, we knocked-down Ubiquilin 1 and observed decreased luciferase activity. We confirmed that Ubiquilin 1 modulated AICD-Gal4 levels by Western blot analysis and also observed that Ubiquilin 1 modulated total APP levels, the ratio of mature to immature APP, as well as PS1 endoproteolysis. CONCLUSION: Taken together, we have shown that this screen can identify known APP metabolism regulators that control proteolysis, intracellular trafficking, maturation and levels of APP and its proteolytic products. We demonstrate for the first time that Ubiquilin 1 regulates APP metabolism in the human neuroblastoma cell line, SH-SY5Y. PMID- 17718919 TI - Rapid phase adjustment of melatonin and core body temperature rhythms following a 6-h advance of the light/dark cycle in the horse. AB - BACKGROUND: Rapid displacement across multiple time zones results in a conflict between the new cycle of light and dark and the previously entrained program of the internal circadian clock, a phenomenon known as jet lag. In humans, jet lag is often characterized by malaise, appetite loss, fatigue, disturbed sleep and performance deficit, the consequences of which are of particular concern to athletes hoping to perform optimally at an international destination. As a species renowned for its capacity for athletic performance, the consequences of jet lag are also relevant for the horse. However, the duration and severity of jet lag related circadian disruption is presently unknown in this species. We investigated the rates of re-entrainment of serum melatonin and core body temperature (BT) rhythms following an abrupt 6-h phase advance of the LD cycle in the horse. METHODS: Six healthy, 2 yr old mares entrained to a 12 h light/12 h dark (LD 12:12) natural photoperiod were housed in a light-proofed barn under a lighting schedule that mimicked the external LD cycle. Following baseline sampling on Day 0, an advance shift of the LD cycle was accomplished by ending the subsequent dark period 6 h early. Blood sampling for serum melatonin analysis and BT readings were taken at 3-h intervals for 24 h on alternate days for 11 days. Disturbances to the subsequent melatonin and BT 24-h rhythms were assessed using repeated measures ANOVA and analysis of Cosine curve fitting parameters. RESULTS: We demonstrate that the equine melatonin rhythm re-entrains rapidly to a 6-h phase advance of an LD12:12 photocycle. The phase shift in melatonin was fully complete on the first day of the new schedule and rhythm phase and waveform were stable thereafter. In comparison, the advance in the BT rhythm was achieved by the third day, however BT rhythm waveform, especially its mesor, was altered for many days following the LD shift. CONCLUSION: Aside from the temperature rhythm disruption, rapid resynchronization of the melatonin rhythm suggests that the central circadian pacemaker of the horse may possess a particularly robust entrainment response. The consequences for athletic performance remain unknown. PMID- 17718920 TI - Comparison of cooling methods to induce and maintain normo- and hypothermia in intensive care unit patients: a prospective intervention study. AB - BACKGROUND: Temperature management is used with increased frequency as a tool to mitigate neurological injury. Although frequently used, little is known about the optimal cooling methods for inducing and maintaining controlled normo- and hypothermia in the intensive care unit (ICU). In this study we compared the efficacy of several commercially available cooling devices for temperature management in ICU patients with various types of neurological injury. METHODS: Fifty adult ICU patients with an indication for controlled mild hypothermia or strict normothermia were prospectively enrolled. Ten patients in each group were assigned in consecutive order to conventional cooling (that is, rapid infusion of 30 ml/kg cold fluids, ice and/or coldpacks), cooling with water circulating blankets, air circulating blankets, water circulating gel-coated pads and an intravascular heat exchange system. In all patients the speed of cooling (expressed as degrees C/h) was measured. After the target temperature was reached, we measured the percentage of time the patient's temperature was 0.2 degrees C below or above the target range. Rates of temperature decline over time were analyzed with one-way analysis of variance. Differences between groups were analyzed with one-way analysis of variance, with Bonferroni correction for multiple comparisons. A p < 0.05 was considered statistically significant. RESULTS: Temperature decline was significantly higher with the water-circulating blankets (1.33 +/- 0.63 degrees C/h), gel-pads (1.04 +/- 0.14 degrees C/h) and intravascular cooling (1.46 +/- 0.42 degrees C/h) compared to conventional cooling (0.31 +/- 0.23 degrees C/h) and the air-circulating blankets (0.18 +/- 0.2 degrees C/h) (p < 0.01). After the target temperature was reached, the intravascular cooling device was 11.2 +/- 18.7% of the time out of range, which was significantly less compared to all other methods. CONCLUSION: Cooling with water-circulating blankets, gel-pads and intravascular cooling is more efficient compared to conventional cooling and air-circulating blankets. The intravascular cooling system is most reliable to maintain a stable temperature. PMID- 17718921 TI - The quality of communication about older patients between hospital physicians and general practitioners: a panel study assessment. AB - BACKGROUND: Optimal care of patients is dependent on good professional interaction between general practitioners and general hospital physicians. In Norway this is mainly based upon referral and discharge letters. The main objectives of this study were to assess the quality of the written communication between physicians and to estimate the number of patients that could have been treated at primary care level instead of at a general hospital. METHODS: This study comprised referral and discharge letters for 100 patients above 75 years of age admitted to orthopaedic, pulmonary and cardiological departments at the city general hospital in Trondheim, Norway. The assessments were done using a Delphi technique with two expert panels, each with one general hospital specialist, one general practitioner and one public health nurse using a standardised evaluation protocol with a visual analogue scale (VAS). The panels assessed the quality of the description of the patient's actual medical condition, former medical history, signs, medication, Activity of Daily Living (ADL), social network, need of home care and the benefit of general hospital care. RESULTS: While information in the referral letters on actual medical situation, medical history, symptoms, signs and medications was assessed to be of high quality in 84%, 39%, 56%, 56% and 39%, respectively, the corresponding information assessed to be of high quality in discharge letters was for actual medical situation 96%, medical history 92%, symptoms 60%, signs 55% and medications 82%. Only half of the discharge letters had satisfactory information on ADL. Some two-thirds of the patients were assessed to have had large health benefits from the general hospital care in question. One of six patients could have been treated without a general hospital admission. The specialists assessed that 77% of the patients had had a large benefit from the general hospital care; however, the general practitioners assessment was only 59%. One of four of the discharge letters did not describe who was responsible for follow-up care. CONCLUSION: In this study from one general hospital both referral and discharge letters were missing vital medical information, and referral letters to such an extent that it might represent a health hazard for older patients. There was also low consensus between health professionals at primary and secondary level of what was high benefit of care for older patients at a general hospital. PMID- 17718924 TI - Proton pump inhibitor-responsive chronic cough without acid reflux: a case report. AB - BACKGROUND: Because 24-h esophageal pH monitoring is quite invasive, the diagnosis of gastroesophageal reflux disease (GERD)-associated cough has usually been made based merely on the clinical efficacy of treatment with proton pump inhibitor (PPI). CASE PRESENTATION: We recently encountered two patients with PPI responsive chronic non-productive cough for whom switching from bronchodilators and glucocorticosteroids to PPI resulted in improvement of cough. The cough returned nearly to pre-administration level a few weeks after discontinuation of PPI. Though GERD-associated cough was suspected, 24-h esophageal pH monitoring revealed that the cough rarely involved gastric acid reflux. Following re initiation of PPI, the cough disappeared again. CONCLUSION: PPI may improve cough unrelated to gastric acid reflux. PMID- 17718923 TI - Setting up a large set of protein-ligand PDB complexes for the development and validation of knowledge-based docking algorithms. AB - BACKGROUND: The number of algorithms available to predict ligand-protein interactions is large and ever-increasing. The number of test cases used to validate these methods is usually small and problem dependent. Recently, several databases have been released for further understanding of protein-ligand interactions, having the Protein Data Bank as backend support. Nevertheless, it appears to be difficult to test docking methods on a large variety of complexes. In this paper we report the development of a new database of protein-ligand complexes tailored for testing of docking algorithms. METHODS: Using a new definition of molecular contact, small ligands contained in the 2005 PDB edition were identified and processed. The database was enriched in molecular properties. In particular, an automated typing of ligand atoms was performed. A filtering procedure was applied to select a non-redundant dataset of complexes. Data mining was performed to obtain information on the frequencies of different types of atomic contacts. Docking simulations were run with the program DOCK. RESULTS: We compiled a large database of small ligand-protein complexes, enriched with different calculated properties, that currently contains more than 6000 non redundant structures. As an example to demonstrate the value of the new database, we derived a new set of chemical matching rules to be used in the context of the program DOCK, based on contact frequencies between ligand atoms and points representing the protein surface, and proved their enhanced efficiency with respect to the default set of rules included in that program. CONCLUSION: The new database constitutes a valuable resource for the development of knowledge-based docking algorithms and for testing docking programs on large sets of protein ligand complexes. The new chemical matching rules proposed in this work significantly increase the success rate in DOCKing simulations. The database developed in this work is available at http://cimlcsext.cim.sld.cu:8080/screeningbrowser/. PMID- 17718922 TI - Protective role of vascular endothelial growth factor in endotoxin-induced acute lung injury in mice. AB - BACKGROUND: Vascular endothelial growth factor (VEGF), a substance that stimulates new blood vessel formation, is an important survival factor for endothelial cells. Although overexpressed VEGF in the lung induces pulmonary edema with increased lung vascular permeability, the role of VEGF in the development of acute lung injury remains to be determined. METHODS: To evaluate the role of VEGF in the pathogenesis of acute lung injury, we first evaluated the effects of exogenous VEGF and VEGF blockade using monoclonal antibody on LPS induced lung injury in mice. Using the lung specimens, we performed TUNEL staining to detect apoptotic cells and immunostaining to evaluate the expression of apoptosis-associated molecules, including caspase-3, Bax, apoptosis inducing factor (AIF), and cytochrome C. As a parameter of endothelial permeability, we measured the albumin transferred across human pulmonary artery endothelial cell (HPAEC) monolayers cultured on porous filters with various concentrations of VEGF. The effect of VEGF on apoptosis HPAECs was also examined by TUNEL staining and active caspase-3 immunoassay. RESULTS: Exogenous VEGF significantly decreased LPS-induced extravascular albumin leakage and edema formation. Treatment with anti-VEGF antibody significantly enhanced lung edema formation and neutrophil emigration after intratracheal LPS administration, whereas extravascular albumin leakage was not significantly changed by VEGF blockade. In lung pathology, pretreatment with VEGF significantly decreased the numbers of TUNEL positive cells and those with positive immunostaining of the pro-apoptotic molecules examined. VEGF attenuated the increases in the permeability of the HPAEC monolayer and the apoptosis of HPAECs induced by TNF-alpha and LPS. In addition, VEGF significantly reduced the levels of TNF-alpha- and LPS-induced active caspase-3 in HPAEC lysates. CONCLUSION: These results suggest that VEGF suppresses the apoptosis induced by inflammatory stimuli and functions as a protective factor against acute lung injury. PMID- 17718925 TI - A pulmonary artery false aneurysm after right middle lobectomy: a case report. AB - Pulmonary artery false aneurysm is a rare condition, reported to complicate interventional procedures. We report a case of a false aneurysm of the interlobar pulmonary artery following a right middle lobectomy for lung cancer. This is probably the first reported case. PMID- 17718926 TI - A patient with testicular pseudolymphoma - a rare condition mimicking malignancy: a case report. AB - Three months following a right sided acute epididymitis a 62 year old patient presented with a painless right testicular swelling. Physical examination, scrotal ultrasound and operative exploration suggested malignancy. However, after inguinal orchiectomy a benign pseudolymphoma of the testis was revealed by pathological examination. A pseudolymphoma is a rare benign lesion which can only be distinguished from a malignant lymphoma by immuno-histochemistry and molecular genetical investigation techniques. PMID- 17718927 TI - No supra-additive effects of goserelin and radiotherapy on clonogenic survival of prostate carcinoma cells in vitro. AB - BACKGROUND: Oncological results of radiotherapy for locally advanced prostate cancer (PC) are significantly improved by simultaneous application of LHRH analoga (e.g. goserelin). As 85% of PC express LHRH receptors, we investigated the interaction of goserelin incubation with radiotherapy under androgen-deprived conditions in vitro. METHODS: LNCaP and PC-3 cells were stained for LHRH receptors. Downstream the LHRH receptor, changes in protein expression of c-fos, phosphorylated p38 and phosphorylated ERK1/2 were analyzed by means of Western blotting after incubation with goserelin and irradiation with 4 Gy. Both cell lines were incubated with different concentrations of goserelin in hormone-free medium. 12 h later cells were irradiated (0 - 4 Gy) and after 12 h goserelin was withdrawn. Endpoints were clonogenic survival and cell viability (12 h, 36 h and 60 h after irradiation). RESULTS: Both tested cell lines expressed LHRH receptors. Changes in protein expression demonstrated the functional activity of goserelin in the tested cell lines. Neither in LNCaP nor in PC-3 any significant effects of additional goserelin incubation on clonogenic survival or cell viability for all tested concentrations in comparison to radiation alone were seen. CONCLUSION: The clinically observed increase in tumor control after combination of goserelin with radiotherapy in PC cannot be attributed to an increase in radiosensitivity of PC cells by goserelin in vitro. PMID- 17718929 TI - Clinical production, stability studies and PET imaging with 16-alpha [18F]fluoroestradiol ([18F]FES) in ER positive breast cancer patients. AB - PURPOSE: 18F-Fluoroestradiol [18F]FES has emerged as a valuable PET tracer to predict the response to hormone therapy in recurrent or metastatic breast cancer patients. A clinically acceptable product requires a rapid reliable synthesis and must be demonstrated to maintain chemical stability and receptor specific uptake during patient studies. [18F]FES then becomes a dependable tracer for the evaluation and management of breast cancer patients. METHODS: An improved automated radiosynthesis of [18F]FES was developed. Stability studies of the injectible form of [18F]FES were performed up to 24 h after dose formulation under normal storage conditions. A comparative FES/FDG PET imaging in ER+ breast cancer patients is reported. RESULTS: The improved synthesis procedure utilizes fewer hydrolysis steps and a single high performance liquid column chromatography (HPLC) purification of the labeled mixture affording [18F]FES in good yield with high radiochemical purity (>99%). Stability studies with purified [18F]FES in saline/ethanol (85:15 v/v) indicated no radiolytic or chemical degradation of this radiopharmaceutical when stored for 24 h at 20-24 degrees C. Positron Emission Tomography (PET) studies with [18F]FES and [18F]FDG in estrogen receptor positive (ER+) breast cancer patients indicated that while FDG accumulation was seen in all metabolically hyperactive sites, the uptake of FES clearly delineated the ER+ tissues regions. CONCLUSIONS: An improved automated synthesis of [18F]FES has been developed and the integrity of this product has been validated by long term stability studies and clinical PET imaging studies in ER+ breast cancer patients. A lack of concordance between FES and FDG uptake in a patient with metastatic breast cancer suggests specificity of the FES for tumors expressing estrogen receptors. PMID- 17718928 TI - Diverse genome structures of Salmonella paratyphi C. AB - BACKGROUND: Salmonella paratyphi C, like S. typhi, is adapted to humans and causes typhoid fever. Previously we reported different genome structures between two strains of S. paratyphi C, which suggests that S. paratyphi C might have a plastic genome (large DNA segments being organized in different orders or orientations on the genome). As many but not all host-adapted Salmonella pathogens have large genomic insertions as well as the supposedly resultant genomic rearrangements, bacterial genome plasticity presents an extraordinary evolutionary phenomenon. Events contributing to genomic plasticity, especially large insertions, may be associated with the formation of particular Salmonella pathogens. RESULTS: We constructed a high resolution genome map in S. paratyphi C strain RKS4594 and located four insertions totaling 176 kb (including the 90 kb SPI7) and seven deletions totaling 165 kb relative to S. typhimurium LT2. Two rearrangements were revealed, including an inversion of 1602 kb covering the ter region and the translocation of the 43 kb I-CeuI F fragment. The 23 wild type strains analyzed in this study exhibited diverse genome structures, mostly as a result of recombination between rrn genes. In at least two cases, the rearrangements involved recombination between genomic sites other than the rrn genes, possibly homologous genes in prophages. Two strains had a 20 kb deletion between rrlA and rrlB, which is a highly conservative region and no deletion has been reported in this region in any other Salmonella lineages. CONCLUSION: S. paratyphi C has diverse genome structures among different isolates, possibly as a result of large genomic insertions, e.g., SPI7. Although the Salmonella typhoid agents may not be more closely related among them than each of them to other Salmonella lineages, they may have evolved in similar ways, i.e., acquiring typhoid-associated genes followed by genome structure rearrangements. Comparison of multiple Salmonella typhoid agents at both single sequenced genome and population levels will facilitate the studies on the evolutionary process of typhoid pathogenesis, especially the identification of typhoid-associated genes. PMID- 17718930 TI - [11C]Vinblastine syntheses and preliminary imaging in cancer patients. AB - PURPOSE: The primary aim of this work was to establish a radiolabeling procedure of vinblastine, a vinca alkaloid widely used in chemotherapy, with the positron emitter carbon-11 for application in positron-emission-tomography (PET) studies in cancer patients. The optimized reaction conditions were transferred to an automated radiosynthesizer system for the preparation of [11C]vinblastine under GMP conditions for human use. We report about the whole body activity distribution after injection of [11C]vinblastine as well as the pharmacokinetic behavior in selected organs and the tumor in two patients that were investigated with [11C]vinblastine PET before chemotherapy. METHODS: For carbon-11 labeling of vinblastine the reaction conditions were determined with respect to the two possible labeling precursors (i.e. [11C]methyl iodide and [11C]diazomethane), solvent, reaction temperature and reaction time. Both, [11C]diazomethane and [11C]methyl iodide were tested as labeling precursors with the corresponding demethyl compound of vinblastine, i.e. the vinblastine acid and the potassium salt of vinblastine acid. Two patients with renal carcinoma underwent [11C]vinblastine PET before chemotherapy. One patient underwent a second scan during infusion of unlabeled vinblastine at a therapeutic dose. RESULTS: Best results for the labeling procedure were found when methylation was carried out at 100 degrees C within 20 min using 2 mg/mL of the potassium salt of vinblastine acid in DMSO and [11C]methyl iodide as labeling precursor. Based on [11C]methyl iodide starting activity a radiochemical yield of up 53 % [11C]vinblastine was achieved. In addition, the synthesis was transferred to a remotely controlled module for routine GMP conform production for human use. In large scale production runs up to 1 GBq of [11C]vinblastine was obtained ready for injection within 45 min after EOB. In one patient, whole body PET scans 40 min after injection of 112 MBq [11C]vinblastine showed a focally increased [11C]vinblastine uptake and [11C]vinblastine metabolite uptake, respectively in the known metastases, along with a slow but continuous washout during the measurement interval (0-60 min p.i.). Another patient showed no focally increased [11C]vinblastine uptake and [11C]vinblastine metabolite uptake in the tumor, where radioactivity concentration was comparable to that in the blood. In this patient, a second PET scan during infusion of unlabeled vinblastine revealed similar kinetics with a trend towards delayed hepatic metabolism and higher blood and tumor concentrations. Whereas this patient showed a partial response to chemotherapy, the first patient did not, hypothetically due to the observed vinblastine washout from the tumor. CONCLUSIONS: The carbon-11 labeling of vinblastine using [11C]methyl iodide is superior to the method using [11C]diazomethane. A well working automated radiosynthesis was established for the production of [11C]vinblastine for PET-investigations in cancer patients. The individual pharmacokinetic behavior of the chemo-therapeutic agent to the tumor can be assessed with PET, thus, can be considered to be a realistic approach for individualized chemotherapy. PMID- 17718931 TI - Preparation and evaluation of 211At labelled antineoplastic antibodies. AB - PURPOSE: The objective of this study was to determine and verify the stability of 211At-labelled antibodies under physiological conditions and their specific cell binding capacity for selected epitopes, in order to evaluate the potential of 211At for alpha-radioimmunotherapy. METHODS: 211At was produced at the department's cyclotron and was linked via the intermediate 3-211At-succinimidyl benzoate (SAB) to the antineoplastic antibodies rituximab, gemtuzumab and gemtuzumab ozogamicin. The stability of the labelled antibodies was determined in serum for 21 h. Cell-binding experiments on HL-60 and CI-1 cells included kinetic, saturation and competitive binding studies. For comparison the binding to antigen-negative cells was determined. The binding specificity and affinity and the IC50-values were evaluated. RESULTS: A consistent yield of 30% and a specific activity of 3 MBq/nmol was obtained. The stability of 211At-antibodies in murine serum exceeded 85% at 37 degrees C. Cell-binding to antigen-positive cells was >25%, while binding to antigen-negative cells did not exceed the unspecific binding and was smaller than 1%. IC50 values ranged between 2 and 11 nmol/L. CONCLUSIONS: A routine preparation of 211At-labelled antibodies was established and the stability of the 211At-labelled antibodies under physiologic conditions was verified. Apparently, labelling of antibodies with 211At by the method described does not compromise the affinity and specificity to the respective epitopes. PMID- 17718932 TI - Synthesis and evaluation of intercalating somatostatin receptor binding peptide conjugates for endoradiotherapy. AB - PURPOSE: Intercalators, planar aromatic compounds, are able to interact with DNA by sandwiching themselves between the stacked bases at right angles to the long axis of the helix. Under certain circumstances, Auger-electron-emitting radionuclides can be extremely radiotoxic and produce extensive DNA damage. Auger electron-emitting radioisotopes, are known to be highly cytotoxic when localized in cell nuclei due to highly localized energy deposition by low energy Auger electrons. In addition binding to the DNA might increase the retention in the receptor expressing tissues. METHODS: In order to exploit the cytotoxic potential of intercalator-Auger-emitter conjugates, bis-benzimidazole dyes, Hoechst 33258 and 33342, were linked to a somatostatin receptor affine carrier peptide. For this purpose a bis-benzimidazole intercalating moiety was prepared using variations on the literature methods. The intercalating moieties were coupled under normal SPPS conditions to the carrier peptide, Tyr3-octreotate. To attach the chelating agent (DOTA) to the intercalating moiety, a free amine derivative was prepared and coupled in solution to DOTA tris-t-butyl ester. The resulting chelator-intercalator conjugate was then coupled to a Tyr3-octreotate carrying resin using SPPS. RESULTS: The peptide conjugates were obtained in good yields after HPLC chromatography. The cellular uptake of the novel conjugates was determined using fluorescence microscopy. All intercalator-peptide conjugates revealed somatostatin receptor binding affinities in the nanomolar range. CONCLUSIONS: The novel chelator-intercalator derivatives of the somatostatin receptor binding Tyr3-octreotate introduce a new scope to the range of tracers for therapeutic purposes. PMID- 17718933 TI - A sensitive assay for the evaluation of cytotoxicity and its pharmacologic modulation in human solid tumor-derived cell lines exposed to cancer-therapeutic agents. AB - PURPOSE: Reliable in vitro cytotoxicity assays are essential for determining the responses of human normal and cancer-derived cells to therapeutic agents and also for the identification and pre-clinical evaluation of new drugs capable of selectively augmenting the susceptibility of cancer cells to conventional therapies. The clonogenic survival assay is considered as the "gold standard" in this regard because it measures the sum of all modes of cell death, encompassing both early and late events such as delayed growth arrest. In this assay, however, the impact of cell-to-cell communication is disregarded because the cells are plated out at very low densities. In addition, here we provide evidence that human breast cancer cell lines cannot be reliably evaluated by clonogenic assays. We developed a novel long-term, High Density Survival (HDS), assay that circumvents the various intrinsic shortcomings of the conventional cytotoxicity assays. METHODS: In the HDS assay, the cells are maintained at a high density for 24 h prior to, and for 24 h after, exposure to a DNA-damaging agent to facilitate intercellular communication. After a carefully scheduled subculturing for approximately 7 days, cultures are assessed for the extent of growth. RESULTS: The degree of radiosensitivity and cisplatin sensitivity evaluated by the HDS assay in human cancer cells was comparable to that measured by the clonogenic assay. Pharmacological inhibitors of CaMKII and/or PI3K signaling elicited a greater degree of radiosensitization when determined by the HDS assay than the clonogenic assay. In all these experiments, there was no relationship between the degree of cytotoxicity measured by the clonogenic survival and viability assays. In the HDS assay, all seven human breast cancer cell lines that we tested exhibited a high degree of radioresistance. CONCLUSIONS: The novel HDS assay appears to be a powerful tool for evaluating cancer cell responses to therapeutic agents under conditions which incorporate some aspects of intercellular communication. PMID- 17718935 TI - Changing role of somatostatin receptor targeted drugs in NET: Nuclear Medicine's view. PMID- 17718934 TI - Synthetic approaches and bio-distribution studies of [11C]methyl-phenidate. AB - PURPOSE: The purpose of this study was a) to present a facilitated method for the preparation and workup of [11C]d-threo-methylphenidate ([11C]d-threo-MP) (a ligand that was shown to bind selectively to the presynaptic dopaminergic transporters) from [11C]methyliodide ([11C]CH3I), b) to demonstrate that the ligand can as well be produced by an alternative labeling method employing [11C]diazomethane as the labeling agent and c) to present biodistribution data for this tracer obtained in rats. METHODS: 11C-labeling with [11C]CH3I was performed using either [d-threo-1-(2-nitrophenylsulfanyl)piperidin-2-yl]phenyl acetic acid (d-threo-N-NPS-ritalinic acid) under addition of sodium hydroxide as base or the previously prepared sodium salt of d-threo-N-NPS-ritalinic acid. The two approaches were compared with regard to radiochemical yield and purification procedures needed in order to obtain a sufficiently pure tracer solution for human use. For the alternative reaction pathway using [11C]diazo-methane as the labeling agent the reaction was performed with d-threo-N-NPS-ritalinic acid. The biodistribution of [11C]d-threo-MP was determined in rats at 5, 10 and 30 min post injection of the tracer. RESULTS: The application of the sodium salt of d threo-N-NPS-ritalinic acid as precursor resulted in higher radiochemical yields than the use of the free acid under basic conditions, the yields were 20 +/- 8% and 6 +/- 3%, respectively for the final isolated product (based on [11C]CH3I starting activity). The alternative labeling approach by means of [11C]diazomethane as the labeling agent was demonstrated to give radiochemical yields of 76 +/- 8% (based on [11C]diazomethane starting activity, determined by HPLC analysis of the crude reaction mixture before final work-up) within shorter process times. Based on [11C]methane starting activity both approaches result in similar yields (17% and 15%, respectively) Biodistribution studies in rats revealed a low blood activity (0.09% injected dose/g (% ID/g)) at 5 min post injection (p.i.), as well as a relatively high liver uptake (15.9% ID at 30 min) compared to a lower kidney uptake (3.2% ID at 30 min). Brain uptake was 0.9% ID/g already 5 and 10 min p.i.. CONCLUSIONS: The application of the sodium salt of d threo-N-NPS-ritalinic acid as precursor for the radiosynthesis of [11C]d-threo-MP reduces the amount of [11C]methanol formed from the reaction of [11C]CH3I with sodium hydroxide, that is added to generate the carboxylic anion of d-threo-N-NPS ritalinic acid needed for labeling with [11C]CH3I. The purification process could be simplified (omission of one solid phase extraction step), resulting in an easily automated process for the production of the tracer. The preparation of [11C]d-threo-MP by means of [11C]diazomethane as the labeling agent appears to be an interesting alternative to the [11C]CH3I methods because of shorter overall process times and high labeling yields. Biodistribution data show a rapid extraction of the tracer from the blood pool. Tracer excretion seems to take place predominantly via the hepatic pathway since liver uptake at 30 min was considerably higher than kidney uptake. [11C]d-threo-MP exhibits a rapid and sufficiently high brain uptake in rats. PMID- 17718936 TI - Design, synthesis and application of vinyl ether compounds for gene and drug delivery. PMID- 17718937 TI - Methacrylamide-oligolactates as building blocks for targeted biodegradable polymeric micelles to deliver photosensitizers. PMID- 17718938 TI - Ultrasound microbubble induced endothelial cell permeability. PMID- 17718939 TI - Response surface methodology for optimization of losartan potassium controlled release tablets. PMID- 17718940 TI - Mixture design evaluation of drug release from matrix tablets containing carbomer and HPMC. PMID- 17718941 TI - Selective elimination of synovial macrophages by boron neutron capture therapy prevents onset of murine experimental arthritis. PMID- 17718942 TI - Thermosensitive vaginal gel formulation for the controlled release of clotrimazole via complexation to beta-cyclodextrin. PMID- 17718943 TI - Effect of chloroquine on the bioavailability of ciprofloxacin in man. PMID- 17718944 TI - On the synthesis and characterization of biodegradable dextran nanogels with tunable degradation properties. PMID- 17718945 TI - Novel drug carrier--chitosan gel microspheres with covalently attached nicotinic acid. PMID- 17718946 TI - Amphiphilic block copolymers containing poly(vinylpyrrolidone) and poly(caprolactone). PMID- 17718947 TI - PEG-PLLA and PEG-PDLA multiblock copolymers: synthesis and in situ hydrogel formation by stereocomplexation. PMID- 17718949 TI - In-situ crosslinkable thermo-responsive hydrogels for drug delivery. PMID- 17718948 TI - Protein release from injectable stereocomplexed hydrogels based on PEG-PDLA and PEG-PLLA star block copolymers. PMID- 17718950 TI - Dendrimeric poly(propylene-imines) as effective delivery agents for DNAzymes: dendrimer synthesis, stability and oligonucleotide complexation. PMID- 17718952 TI - Trimethylene carbonate-based polymers for controlled drug delivery applications. PMID- 17718953 TI - Thermoplastic elastomers based on poly(lactide)-poly(trimethylene carbonate-co caprolactone)-poly(lactide) triblock copolymers and their stereocomplexes. PMID- 17718951 TI - Dendrimeric poly(propylene-imines) as effective delivery agents for DNAzymes: toxicity, in vitro transfection and in vivo delivery. PMID- 17718954 TI - Reactive polymers for modification of biologically active molecules and gene delivery vectors. PMID- 17718955 TI - Preparation of poly(-isopropylacrylamide) hollow beads as reservoir drug delivery systems. PMID- 17718957 TI - Design of new polymer carriers based of Eudragit E PO/Eudragit L100-55 interpolyelectrolyte complexes using swellability measurements. PMID- 17718956 TI - Characterization of Eudragit E100/Carbomer 940P interpolyelectrolyte complexes using swellability measurements. PMID- 17718958 TI - Swellability testing of chitosan/Eudragit L100-55 interpolyelectrolyte complexes for colonic drug delivery. PMID- 17718959 TI - Intermolecular interactions between carbon dioxide and the carbonyl groups of polylactides and poly(epsilon-caprolactone). PMID- 17718960 TI - Self-assembly of PEG-oligolactates with monodisperse hydrophobic blocks. PMID- 17718961 TI - Apatite with less crystallinity is a superior agent for macromolecular drug delivery to mammalian cells. PMID- 17718962 TI - Erythrocytes as a controlled drug delivery system: clinical evidences. PMID- 17718964 TI - In vivo tolerance and kinetics of a novel ocular drug delivery device. PMID- 17718963 TI - Fludarabine delivery by autologous red blood cells induces macrophage depletion in chronically SIV-infected Sooty Mangabeys. PMID- 17718966 TI - The influence of copolymer chain microstructure on cyclosporine a (CyA) and Sirolimus prolonged and sustained release from PLA/TMC and PLA/PCL matrices. PMID- 17718965 TI - Significant enhancement of antitumor activity and bioavailability of intracellular pH-sensitive polymeric micelles by folate conjugation. PMID- 17718967 TI - Use of the organotypic culture method to investigate drug-loaded CSF shunt. PMID- 17718968 TI - Transdermal timolol delivery from a Pluronic gel. PMID- 17718969 TI - Evaluation of irinotecan drug-eluting beads: a new drug-device combination product for the chemoembolization of hepatic metastases. PMID- 17718970 TI - Targeting of the VEGF-kinase inhibitor PTK787 to angiogenic vasculature using RGD equipped albumin carrier molecules. PMID- 17718972 TI - The influence of chain microstructure on hydrolytic degradation of glycolide/lactide copolymers used in drug delivery systems. PMID- 17718971 TI - Tripalmitin-based cationic lipospheres: preparation, characterization and in Lab on-a-chip applications. PMID- 17718974 TI - Biodegradable polymersomes for targeted ultrasound imaging. PMID- 17718973 TI - A novel opportunity for targeted drug delivery to the brain. PMID- 17718975 TI - Towards a double controlled conditionally replicative adenovirus for potent and specific melanoma cell kill. PMID- 17718976 TI - Lectin functionalized complexation hydrogels for oral protein delivery. PMID- 17718977 TI - Fibronectin-coated nano-precipitates of calcium-magnesium phosphate for integrin targeted gene delivery. PMID- 17718978 TI - Aqueous size-exclusion chromatography of cationic polymers for gene delivery. PMID- 17718979 TI - Dynamic light scattering as a screening tool to monitor the maturation time of cationic liposome-DNA complexes. PMID- 17718980 TI - Microbubbles which bind and protect DNA against nucleases. PMID- 17718981 TI - Novel ternary polyplex of triblock copolymer, pDNA and anionic dendrimer phthalocyanine for photochemical enhancement of transgene expression. PMID- 17718982 TI - Surface plasmon resonance as an elegant technique to study polyplex-GAG interactions. PMID- 17718984 TI - Hydrolytically and reductively degradable carriers of biologically active molecules based on multiblock polymers of poly(ethylene glycol). PMID- 17718983 TI - Disulfide-containing poly(beta-amino ester)s for gene delivery. PMID- 17718985 TI - Water-soluble cationic poly(ferrocenylsilane): an efficient DNA condensation and transfection agent. PMID- 17718986 TI - Depots of solubilised elastin promote the formation of blood vessels and elastic fibres in rat. PMID- 17718987 TI - Rheological and mechanical properties of Pluronic-alginate gels for drug-eluting stent coating. PMID- 17718988 TI - Preparation of a growth factor gradient in porous collagen scaffolds and its effect on cell growth proliferation. PMID- 17718989 TI - Increased angiogenesis in acellular scaffolds by combined release of FGF2 and VEGF. PMID- 17718990 TI - Development of doxycycline-eluting delivery systems based on SynBiosys biodegradable multi-block copolymers. PMID- 17718991 TI - Ethoxyethyl methacrylate-based copolymers--a novel platform for drug-eluting stent coatings. PMID- 17718992 TI - Bioresorbable drug-eluting stent coating formulations based on SynBiosys biodegradable multi-block copolymers. PMID- 17718993 TI - Porous gelatin cryogels as cell delivery tool in tissue engineering. PMID- 17718994 TI - Photo-crosslinking of functionalised lactide oligomers for the fabrication of osteochondral tissue engineering scaffolds. PMID- 17718996 TI - Evaluation of surface chemistries for antibody microarrays. AB - Antibody microarrays are an emerging technology that promises to be a powerful tool for the detection of disease biomarkers. The current technology for protein microarrays has been derived primarily from DNA microarrays and is not fully characterized for use with proteins. For example, there are a myriad of surface chemistries that are commercially available for antibody microarrays, but there are no rigorous studies that compare these different surfaces. Therefore, we have used a sandwich enzyme-linked immunosorbent assay (ELISA) microarray platform to analyze 17 different commercially available slide types. Full standard curves were generated for 23 different assays. We found that this approach provides a rigorous and quantitative system for comparing the different slide types based on spot size and morphology, slide noise, spot background, lower limit of detection, and reproducibility. These studies demonstrate that the properties of the slide surface affect the activity of immobilized antibodies and the quality of data produced. Although many slide types produce useful data, glass slides coated with aldehyde silane, poly-l-lysine, or aminosilane (with or without activation with a crosslinker) consistently produce superior results in the sandwich ELISA microarray analyses we performed. PMID- 17718997 TI - Fluorometric immunoassay based on pH-sensitive dye-encapsulating liposomes and gramicidin channels. AB - This article describes a new method for direct fluorometric immunoassay with a liposome array using pH-sensitive dye (BCECF [2',7'-bis(carboxyethyl)-4 or 5 carboxyfluorescein])-encapsulating liposomes immobilized on an avidin slip and gramicidin channels. The liposomes were composed of phosphatidylcholine (PC), cholesterol (Chol), biotinylated phosphatidylethanolamine (B-cap-PE), and recognition sites (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(2,4 dinitrophenyl) [DNP-PE], Fab' fragment of anti-substance P, and Fab' of anti neurokinin A). The addition of gramicidin induced release of H(+) ions from the inner solution (pH 5.5) to the outer one (pH 7.8), enhancing fluorescence of BCECF (1.0mM) encapsulated in liposome. The binding of an analyte (anti dinitrophenyl [anti-DNP], avidin, substance P, or neurokinin A) to the membrane bound recognition sites caused further enhancement of fluorescence of BCECF due to a local distortion of the bilayer structure that affects the channel kinetics of gramicidin. The intensity of fluorescence from the immobilized liposomes 60 min after the addition of gramicidin (10 ng/ml) increased with an increase in the concentration of anti-DNP ranging from 1.2 x 10(-8) to 1.2 x 10(-6)g/ml, avidin ranging from 1.0 x 10(-8) to 1.0 x 10(-6)g/ml, substance P ranging from 1.0 x 10( 8) to 1.0 x 10(-6)g/ml, and neurokinin A ranging from 1.0 x 10(-8) to 1.0 x 10( 6)g/ml. The direct fluorometric immunoassay with a liposome array is simple and easy to carry out. The intensity of fluorescence emitted from the immobilized liposomes is directly measured after incubation with a sample solution and a gramicidin solution in sequence without washing steps. The assay allows simultaneous quantification of multiple components without labeling of antibody or antigen with a fluorescent tag. The liposome-based assay is discussed in terms of principle, sensitivity, and selectivity. PMID- 17718998 TI - Expression of angiostatin and its related factors in the plasma of newborn pigs with hypoxia and reoxygenation. AB - Little is known about angiostatin and its related factors in the hypoxia reoxygenation of neonates. In this study we compared the effect of 21% and 100% reoxygenation on temporal changes in the plasma level of these factors in newborn piglets subjected to hypoxia. Newborn piglets were subjected to 2 h hypoxia followed by 1 h of reoxygenation with either 21% or 100% oxygen and observed for 4 days. On day 4 of recovery in 100% hypoxic-reoxygenated group, there were increases in total angiostatin, plasminogen/plasmin and MMP-2 levels, and decreases in VEGF levels (vs. respective baseline levels, all P <0.001), whereas no significant temporal changes were found in the 21% hypoxic-reoxygenated and sham-operated groups. Angiostatin levels correlated positively with the levels of MMP-2 and HIF-1alpha and negatively with VEGF levels in 100% hypoxic-reoxygenated group (all P <0.05). In comparison to 21% oxygen, neonatal resuscitation with 100% oxygen was found to increase the levels anti-angiogenic factors. PMID- 17718999 TI - Identification of the catalytic subunit of acetohydroxyacid synthase in Haemophilus influenzae and its potent inhibitors. AB - Acetohydroxyacid synthase (AHAS; EC 2.2.1.6) is a thiamin diphosphate- (ThDP)- and FAD-dependent enzyme that catalyzes the first common step in the biosynthetic pathway of the branched-amino acids (BCAAs) leucine, isoleucine, and valine. The gene from Haemophilus influenzae that encodes the AHAS catalytic subunit was cloned, overexpressed in Escherichia coli BL21(DE3), and purified to homogeneity. The purified H. influenzae AHAS catalytic subunit (Hin-AHAS) appeared as a single band on SDS-PAGE gel, with a molecular mass of approximately 63 kDa. The enzyme catalyzes the condensation of two molecules of pyruvate to form acetolactate, with a K(m) of 9.2mM and the specific activity of 1.5 micromol/min/mg. The cofactor activation constant (K(c)=13.5 microM) and the dissociation constant (K(d)=3.3 microM) of ThDP were also determined by enzymatic assay and tryptophan fluorescence quenching studies, respectively. We screened a chemical library to discover new inhibitors of the Hin AHAS catalytic subunit. Through which, AVS 2087 (IC(50)=0.53 microM), KSW30191 (IC(50)=1.42 microM), and KHG20612 (IC(50)=4.91 microM) displayed potent inhibition as compare to sulfometuron methyl (IC(50)=276.31 microM). PMID- 17719001 TI - Hyperventilation in patients with chronic fatigue syndrome: the role of coping strategies. AB - Hyperventilation has been suggested as a concomitant and possible maintaining factor that may contribute to the symptom pattern of chronic fatigue syndrome (CFS). Because patients accepting the illness and trying to live with it seem to have a better prognosis than patients chronically fighting it, we investigated breathing behavior during different coping response sets towards the illness in patients with CFS (N=30, CDC criteria). Patients imagined a relaxation script (baseline), a script describing a coping response of hostile resistance, and a script depicting acceptance of the illness and its (future) consequences. During each imagery trial, end-tidal PCO2 (Handheld Capnograph, Oridion) was measured. After each trial, patients filled out a symptom checklist. Results showed low resting values of PetCO2 overall, while only imagery of hostile resistance triggered a decrease and deficient recovery of PetCO2. Also, more hyperventilation complaints and complaints of other origin were reported during hostile resistance imagery compared with acceptance and relaxation. In conclusion, hostile resistance seems to trigger both physiological and symptom perception processes contributing to the clinical picture of CFS. PMID- 17719002 TI - Spectroscopic diagnosis of anti-phospholipid antibodies by visible and near infrared spectroscopy in SLE patients' plasma samples. AB - The purpose of this study was to investigate whether visible and near-infrared (Vis-NIR) spectroscopy can be used for diagnoses of anti-phospholipid syndrome (APS). Vis-NIR spectra from 90 plasma samples [anti-phospholipid antibodies (aPLs)-positive group, n=48; aPLs-negative group, n=42] were subjected to principal component analysis (PCA) and soft independent modeling of class analogy (SIMCA) to develop multivariate models to discriminate between aPLs-positive and aPLs-negative. Both PCA and SIMCA models were further assessed by the prediction of 84 masked other determinations. The PCA model predicted successful discrimination of the masked samples with respect to aPLs-positive and aPLs negative. The SIMCA model predicted 42 of 48 (87.5%) aPLs-positive patients and 33 of 36 (91.7%) aPLs-negative patients of Vis-NIR spectra from masked samples correctly. These results suggest that Vis-NIR spectroscopy combined with multivariate analysis could provide a promising tool to objectively diagnose APS. PMID- 17719003 TI - Optimization of short hairpin RNA for lentiviral-mediated RNAi against WAS. AB - The expression of short hairpin RNAs (shRNAs) with lentiviral vectors is useful to induce stable RNA interference, particularly in hematopoietic cells. Since primary cells integrate few copies of vector, we tested if several shRNA cassette modifications could improve knock-down efficacy. Using two shRNA sequences previously shown to inhibit the human WAS gene expression, we found that neither increasing the shRNA stem length from 19-nt to 29-nt, nor modifying the loop with 4-nt, 9-nt artificial loops or with the mir30 loop improved vector-induced shRNA efficacies. This cautions against extrapolating results obtained with synthetic molecules to shRNAs that are stably expressed from viral vectors. On the other hand, the duplication of the shRNA expression cassette resulted in twice as much knock-down per copy of integrated vector. This strategy allowed a strong suppression of WASp in CD34(+) cells and will facilitate future studies on the role of WASp in human cells. PMID- 17719000 TI - Minimizing frustration by folding in an aqueous environment. AB - Although life as we know it evolved in an aqueous medium, the properties of water are not completely understood. In this review, we focus on the role of water in guiding protein folding and stability. Specifically, we discuss the mechanisms of protein folding in an aqueous environment, the effects of water on the folding energy landscape as well as the transition state ensemble, and interactions of water with the folded state. We show that water cannot be viewed as a passive solvent, but rather, plays a very active role in the life of a protein. PMID- 17719004 TI - Pluripotent marker expression and differentiation of human second trimester Mesenchymal Stem Cells. AB - Mesenchymal stem cells are an easily obtainable stem cell source from bone marrow. Presently, they are the most widely used cell type for cellular replacement strategies in humans as a result of extensive research that has demonstrated that these cells are capable of self-renewal, able to undergo multi lineage differentiation, engraft, and ameliorate symptoms in numerous animal models. In this study, we comprehensively characterize human second trimester mesenchymal stem cells (STMSCs). We demonstrate that STMSCs are easily expandable to clinical relevance and express pluripotent markers such as Oct-4, Nanog, Sox 2, and SSEA-4 at the cellular and molecular level. Moreover, we directionally differentiate STMSCs into osteogenic, chondrogenic, adipogenic, neurogenic, and cardiogenic cell lineages. These studies demonstrate the plasticity of STMSCs and the potential for their use in cellular replacement therapy. PMID- 17719005 TI - Linkage disequilibrium analyses of natriuretic peptide precursor B locus reveal risk haplotype conferring high plasma BNP levels. AB - BACKGROUND: Brain natriuretic peptide (BNP) has been widely used for the diagnosis and prognostic evaluation of chronic heart failure (CHF). In the present study, we performed association study of single nucleotide polymorphisms (SNPs) surrounding the natriuretic peptide precursor B (NPPB) gene with plasma BNP levels in 2970 adult Japanese. METHODS AND RESULTS: Association analysis between SNPs of the NPPB gene and plasma BNP revealed significant associations of the 8 SNPs surrounding the entire NPPB gene with plasma BNP levels. For instance, as to SNP rs198389 (T-381C), plasma BNP levels among the three genotypic categories, i.e., 2189 homozygous T-allele carriers (BNP 26.4+/-0.6pg/ml), 697 heterozygous carriers (35.0+/-1.1pg/ml), and 52 homozygous C-allele carriers (46.0+/-4.1pg/ml) indicated a co-dominant effect of the minor C-allele on elevating plasma BNP levels (P<0.0001). Linkage disequilibrium (LD) analysis among the 8 SNPs revealed that the region consisted of two, 5' major and 3' minor, LD blocks. Haplotype-based association analysis demonstrated that plasma BNP levels were associated closely with the haplotypes-1 and -2 of the major LD block. CONCLUSION: These results suggest that genetic variation at the primary locus NPPB gene, represented by definition of risk haplotypes, may be an important determinant of plasma BNP levels. PMID- 17719006 TI - Aggregation of endosomal-vacuolar compartments in the Aovps24-deleted strain in the filamentous fungus Aspergillus oryzae. AB - Previously, we found that deletion of Aovps24, an ortholog of Saccharomyces cerevisiae VPS24, that encodes an ESCRT (endosomal sorting complex required for transport)-III component required for late endosomal function results in fragmented and aggregated vacuoles. Although defective late endosomal function is likely responsible for this phenotype, critical lack of our knowledge on late endosomes in filamentous fungi prevented us from further characterization. In this study, we identified late endosomes of Aspergillus oryzae, by expressing a series of fusion proteins of fluorescent proteins with orthologs of late endosomal proteins. Using these fusion proteins as markers, we observed late endosomes in the wild type strain and the Aovps24 disruptant and demonstrated that late endosomes are aberrantly aggregated in the Aovps24 disruptant. Moreover, we revealed that the aggregated late endosomes have features of vacuoles as well. As deletion of another ESCRT-III component-encoding gene, Aovps2, resulted in similar phenotypes to that in the Aovps24 disruptant, phenotypes of the Aovps24 disruptant are probably due to defective late endosomal function. PMID- 17719007 TI - A conserved proline residue in the leucine zipper region of AtbZIP34 and AtbZIP61 in Arabidopsis thaliana interferes with the formation of homodimer. AB - Two putative Arabidopsis E group bZIP transcript factors, AtbZIP34 and AtbZIP61, are nuclear-localized and their transcriptional activation domain is in their N terminal region. By searching GenBank, we found other eight plant homologues of AtbZIP34 and AtbZIP61. All of them have a proline residue in the third heptad of zipper region. Yeast two-hybrid assay and EMSA showed that AtbZIP34 and AtbZIP61 could not form homodimer while their mutant forms, AtbZIP34m and AtbZIP61m, which the proline residue was replaced by an alanine residue in the zipper region, could form homodimer and bind G-box element. These results suggest that the conserved proline residue interferes with the homodimer formation. However, both AtbZIP34 and AtbZIP61 could form heterodimers with members of I group and S group transcription factors in which some members involved in vascular development. So we speculate that AtbZIP34 and AtbZIP61 may participate in plant development via interacting with other group bZIP transcription factors. PMID- 17719008 TI - Superposition of a tRNASer acceptor stem microhelix into the seryl-tRNA synthetase complex. AB - Aminoacyl-tRNA synthetases catalyze the formation of aminoacyl-tRNAs. Seryl-tRNA synthetase is a class II synthetase, which depends on rather few and simple identity elements in tRNA(Ser) to determine the amino acid specificity. tRNA(Ser) acceptor stem microhelices can be aminoacylated with serine, which makes this part of the tRNA a valuable tool for investigating the structural motifs in a tRNA(Ser)-seryl-tRNA synthetase complex. A 1.8A-resolution tRNA(Ser) acceptor stem crystal structure was superimposed to a 2.9A-resolution crystal structure of a tRNA(Ser)-seryl-tRNA synthetase complex for a visualization of the binding environment of the tRNA(Ser) microhelix. PMID- 17719009 TI - Time dependence of cyclic tensile strain on collagen production in tendon fascicles. AB - Mechanical loading is a regulator of tissue metabolism in tendon, which may lead to alterations in structural and mechanical properties via mechanotransduction processes. The present study investigated specified responses of tenocyte metabolism in isolated tendon fascicles subjected to four loading regimes. Cyclic tensile strain of 3% amplitude superimposed on a 2% static strain was applied to the fascicles for 10min, 1, 6 or 24h of a 24-h incubation period. Collagen synthesis, assessed by [(3)H]-proline incorporation, was upregulated by the 24h straining regime, but was inhibited by the 10-min regime. Cyclic strain enhanced the retention of newly synthesised collagen within the matrix. More than 90% of the newly synthesised collagen was retained in all cases, but the long-term application of cyclic strain had less pronounced effects on the retention. These results indicate that collagen synthesis by tenocytes is controlled by a complex mechanosensitive process with a temporal component. PMID- 17719010 TI - Knockout mice lacking cPGES/p23, a constitutively expressed PGE2 synthetic enzyme, are peri-natally lethal. AB - Cytosolic prostaglandin (PG) E synthase (cPGES) is constitutively expressed in various cells and regulates cyclooxygenase (COX)-1-dependent immediate PGE(2) generation. Its primary structure is identical to co-chaperone p23, a heat shock protein 90 (Hsp90)-binding protein. We have revealed that Hsp90 regulated both cPGES/p23 and its client protein kinase CK2. In this study, in order to examine the role of cPGES/p23 in vivo, we generated mice deficient in cPGES/p23 by a targeted disruption of exons 2 and 3, containing Tyr9, which is essential for catalytic activity. Heterozygotes are viable, fertile, and appear normal, despite a decrease in cPGES/p23 protein level. A generation of offsprings derived from intercrosses of cPGES/p23 homozygous mice revealed that 109, 247, and 10 pups were wild type, heterozygous, and homozygous, respectively; however, all homozygotes died at birth. The absence of viable null mutants, with heterozygotes and wild-type offspring obtained at a ratio of approximately 2:1, indicated that homozygosity for the cPGES/p23 null mutant leads to peri-natal lethality. Embryos homozygous for cPGES/p23-null had lower body weights than wild-type embryos, and abnormal morphology of skin and lungs. Moreover, the PGE(2) content in the lungs of cPGES/p23-null embryos was lower than that of the wild type. These results indicate that cPGES-derived PGES is involved in the normal development of mouse embryonic lung. PMID- 17719011 TI - Characterization and differentiation of equine umbilical cord-derived matrix cells. AB - Stem cells are being evaluated in numerous human clinical trials and are commercially used in veterinary medicine to treat horses and dogs. Stem cell differentiation, homing to disease sites, growth and cytokine factor modulation, and low antigenicity contribute to their therapeutic success. Bone marrow and adipose tissue are the two most common sources of adult-derived stem cells in animals. We report on the existence of an alternative source of primitive, multipotent stem cells from the equine umbilical cord cellular matrix (Wharton's jelly). Equine umbilical cord matrix (EUCM) cells can be cultured, cryogenically preserved, and differentiated into osteo-, adipo-, chondrogenic, and neuronal cell lineages. These results identify a source of stem cells that can be non invasively collected at birth and stored for future use in that horse or used as donor cells for treating unrelated horses. PMID- 17719012 TI - NFATc is required for TGFbeta-mediated transcriptional regulation of fibronectin. AB - Calcineurin is an important regulator of extracellular matrix (ECM) accumulation in the kidney but functions in a cell-specific manner. Previously, we identified a novel role for calcineurin in mesangial cells where calcineurin activity is required for TGFbeta-mediated induction of fibronectin expression. In this study, we examined the role of the calcineurin substrate NFATc in transcriptional regulation of fibronectin. First, inhibition of calcineurin blocks TGFbeta induction of the fibronectin promoter. Moreover, expression of constitutively active calcineurin in mesangial cells is sufficient to increase fibronectin transcription. Next, inhibition of the calcineurin substrate NFATc1 blocked TGFbeta-mediated activation of the fibronectin promoter. Finally, stable expression of a dominant-negative NFATc protein reduced transcriptional activation of the promoter and inhibited TGFbeta-mediated fibronectin expression. In conclusion, TGFbeta activation of calcineurin in mesangial cells results in regulation of ECM accumulation at least in part by direct transcriptional activity of NFATc on the fibronectin promoter. PMID- 17719016 TI - The hypergeometric connectivity hypothesis: divergent performance of brain circuits with different synaptic connectivity distributions. AB - The development of connectivity among brain networks (e.g., thalamocortical, cortico-thalamic, cortico-cortical) proceeds via a combination of axon and dendrite growth followed by a later process of synaptic pruning [Purves, D., Lichtman, J.W., 1980. Elimination of synapses in the developing nervous system. Science, 210, 153-157; Oppenheim, R.W., 1991. Cell death during development of the nervous system. Annual Review of Neuroscience, 14(1), 453-501.; Oppenheim, R., Qin-Wei Y., Prevette D., Yan Q., 1992. Brain-derived neurotrophic factor rescues developing avian motoneurons from cell death. Nature, 360, 755-757]. Sparse synaptic distribution (i.e., the low probability (<0.1) of contact among neurons; [Braitenberg, V., Schuz, A., 1998. Cortex: Statistics and geometry of neuronal connectivity: Springer Berlin.] can conform to any of a range of connectivity patterns with different distributional characteristics; and different distribution patterns can yield networks with very different functional properties. We rigorously investigate a range of different connectivity characteristics, and show that different synaptic distributions can substantially affect the functional capabilities of the resulting networks. In particular, we provide formal measures of information loss in transmission from one set of neurons to another as a function of synaptic distribution, and show a set of empirical cases with different information-theoretic utility. We characterize the trade-offs among utility and costs, and their dependence on different classes of developmental strategies by which axons from one cell group are "assigned" to synapses on dendrites from a target cell group. It is shown that hypergeometric distributions minimize a range of measured costs, compared to competing synaptic distributions. It is also found that the divergent performance among differently organized brain circuits expands with brain size, rendering the effects increasingly consequential for big brains. In summary, we propose that the characteristics of hypergeometric connectivity provide a coherent explanatory hypothesis of a range of developmental and anatomical data. PMID- 17719015 TI - Restoration of disturbed intracortical motor inhibition and facilitation in attention deficit hyperactivity disorder children by methylphenidate. AB - BACKGROUND: Previous investigations using transcranial magnetic stimulation (TMS) have shown that neural inhibitory motor circuits are disturbed in ADHD children. We sought to investigate the influence of methylphenidate (MPH) on inhibitory and facilitatory motor circuits of ADHD children with TMS paired pulse protocols using surplus long interval inter-stimulus intervals (ISI) not investigated so far. METHODS: Motorcortical modulation was tested with TMS paired pulse protocols employing ISI of 3, 13, 50, 100, 200, and 300 msec in 18 ADHD children before and on treatment with MPH. Clinical improvement by MPH was measured by the Conners score. RESULTS: Analysis of variance (ANOVA) revealed a significant three-way interaction "Group x Amplitude x ISI," p = .001. Subsequent two-factorial ANOVAs and t-tests showed group specific differences of motor evoked potential (MEP) amplitudes for inhibitory ISIs of 3 and 100 msec, and for facilitatory ISIs of 13 and 50 msec. Compared to controls, an adjustment of these parameters by MPH could be shown. On MPH, a significant bivariate correlation was found between the Conners score reduction and averaged MEP amplitude changes only for inhibitory ISIs (3 and 100 msec). CONCLUSIONS: In ADHD children, MPH modulates disturbed facilitatory and inhibitory motor circuits, which for the latter is associated with clinical improvement. PMID- 17719013 TI - The neurobiology and genetics of impulse control disorders: relationships to drug addictions. AB - Impulse control disorders (ICDs), including pathological gambling, trichotillomania, kleptomania and others, have been conceptualized to lie along an impulsive-compulsive spectrum. Recent data have suggested that these disorders may be considered addictions. Here, we review the genetic and neuropathological bases of the impulse control disorders and consider the disorders within these non-mutually exclusive frameworks. PMID- 17719017 TI - Association study and meta-analysis of Alzheimer's disease risk and presenilin-1 intronic polymorphism. AB - Numerous studies have tested for associations between an intronic polymorphism (rs165932) of presenilin-1 (PS-1) gene and the risk of Alzheimer's disease (AD), but results have been conflicting. To throw light on this issue, we investigate the possible involvement of PS-1 genotype in a case-control study based on a relatively stable population in Spain and a meta-analysis of published studies. An examination was conducted of 85 patients with probable or possible AD, along with controls from the same community, by using an chi(2) test for homogeneity and a binary logistic regression model. For comparison purposes, a meta-analysis of data from all available published studies was assessed. In our patients, homozygosity of the allele 2 in the PS-1 gene increased for late-onset AD (OR 2.38, 95% CI 1.07-5.29, P<0.05). The presence of at least one allele of apoE was also associated with AD (OR 4.01, 95% CI 1.93-8.34, p<0.05). The regression model showed that, overall, the presence of the apoE epsilon 4 allele and the PS-1 2/2 genotype were independent factors for the development of AD in our sample. In our genotype-based meta-analysis, the PS-1 2/2 genotype was probably related with AD for the European sub-group (fixed effects model, OR 1.19, 95% CI 1.02-1.37, p<0.05), but there are many confusing factors between different studies. Presenilin-1 2/2 genotype is a risk factor for late onset Alzheimer disease in the Spanish population, and probably, for Europeans. PMID- 17719014 TI - The role of orbitofrontal cortex in drug addiction: a review of preclinical studies. AB - Studies using brain imaging methods have shown that neuronal activity in the orbitofrontal cortex, a brain area thought to promote the ability to control behavior according to likely outcomes or consequences, is altered in drug addicts. These human imaging findings have led to the hypothesis that core features of addiction like compulsive drug use and drug relapse are mediated in part by drug-induced changes in orbitofrontal function. Here, we discuss results from laboratory studies using rats and monkeys on the effect of drug exposure on orbitofrontal-mediated learning tasks and on neuronal structure and activity in orbitofrontal cortex. We also discuss results from studies on the role of the orbitofrontal cortex in drug self-administration and relapse. Our main conclusion is that although there is clear evidence that drug exposure impairs orbitofrontal dependent learning tasks and alters neuronal activity in orbitofrontal cortex, the precise role these changes play in compulsive drug use and relapse has not yet been established. PMID- 17719018 TI - Pinwheel patterns give rise to the direction selectivity of complex cells in the primary visual cortex. AB - Understanding the relation between the 'pinwheel orientation map' and the 'direction map' in the cat primary visual cortex (V1) is a long-standing problem. Several relations between the direction and orientation maps have been previously noted; for example, one iso-orientation region is usually subdivided into two subregions preferring opposite directions. However, the reasons for these relations remain unknown. Here, we demonstrate that the organization of the cortical map for direction selectivity (DS) is intimately related to, and can be predicted from, the organization of the cortical orientation map. We have found that the magnitude of the direction preference of a complex cell is proportional to the change in the number of simple cells driven by a stimulus line moving across an iso-orientation region; the preferred direction of the complex cell points to the place where the number of simple cells driven by the visual stimulus is maximal. According to this rule, the direction map can be uniquely determined from the pinwheel orientation map, and the phenomena relating the two maps can be explained. PMID- 17719019 TI - Exopolysaccharides produced by Inquilinus limosus, a new pathogen of cystic fibrosis patients: novel structures with usual components. AB - The major cause of morbidity and mortality in patients with cystic fibrosis, an autosomal recessive disorder, is chronic microbial colonisation of the major airways that leads to exacerbation of pulmonary infection. Several different microbes colonise cystic fibrosis lungs, and Pseudomonas aeruginosa is one of the most threatening, since the establishment of mucoid (alginate producing) strains is ultimately associated with the patient's death. Very recently a new bacterium, named Inquilinus limosus, was repeatedly found infecting the respiratory tract of cystic fibrosis patients. Its multi-resistance characteristic to antibiotics might result in the spreading of I. limosus infection among the cystic fibrosis community, as recently happened with strains of the Burkholderia cepacia complex. Since exopolysaccharides are recognised as important virulence factors in lung infections, the primary structure of the polysaccharide produced by I. limosus strain LMG 20952(T) was investigated as the first step in understanding its role in pathogenesis. The structure was determined by means of methylation analysis, acid degradations, mass spectrometry and NMR spectroscopy. The results showed that the bacterium produced a mixture constituted of the following polymers: [3) [4,6-O-(1-carboxyethylidene)]-beta-D-Glcp(1-->]n; [2)-[4,6-O-(1 carboxyethylidene)]-alpha-D-Manp(1-->]n. Both polymers were completely substituted with pyruvyl ketal groups, a novel structural characteristic not previously found in bacterial polysaccharides. The absolute configuration of all pyruvyl groups was S. Inspection of possible local conformations assumed by the two polysaccharide chains showed features, which might provide interesting clues for understanding structure-function relationships. PMID- 17719020 TI - An X-ray diffraction analysis of crystallised whey and whey-permeate powders. AB - Amorphous whey, whey-permeate and lactose powders have been crystallised at various air temperatures and humidities, and these crystallised powders have been examined using X-ray diffraction. The most stable lactose crystal under normal storage conditions, alpha-lactose monohydrate, forms preferentially in whey and whey-permeate powders at 50 degrees C, provided sufficient moisture is available, whereas anhydrous beta-lactose and mixed anhydrous lactose crystals, which are unstable under normal storage conditions, form preferentially at 90 degrees C. Thus, faster crystallisation at higher temperatures is offset by the formation of lactose-crystal forms that are less stable under normal storage conditions. Very little alpha-lactose monohydrate crystallised in the pure lactose powders over the range of temperatures and humidities tested, because the crystallisation of alpha- and beta-lactose is considerably more rapid than the mutarotation of beta- to alpha-lactose in the amorphous phase and the hydration of alpha-lactose during crystallisation. Protein and salts hinder the crystallisation process, which provides more time for mutarotation and crystal hydration in the whey and whey permeate powders. PMID- 17719021 TI - Role of rat organic anion transporter 3 (Oat3) in the renal basolateral transport of glutathione. AB - The tripeptide GSH is important in maintenance of renal redox status and defense against reactive electrophiles and oxidants. Previous studies showed that GSH is transported across the basolateral plasma membrane (BLM) into the renal proximal tubule by both sodium-coupled and sodium-independent pathways. Substrate specificity and inhibitor studies suggested the function of several carriers, including organic anion transporter 3 (Oat3). To test the hypothesis that rat Oat3 can function in renal GSH transport, the cDNA for rat Oat3 was expressed as a His6-tagged protein in E. coli, purified from inclusion bodies and by Ni2+ affinity chromatography, and reconstituted into proteoliposomes. cDNA-expressed and reconstituted Oat3 transported both GSH and p-aminohippurate (PAH) in exchange for 2-oxoglutarate (2-OG) and 2-OG and PAH in exchange for GSH, and PAH uptake was inhibited by both probenecid and furosemide, consistent with function of Oat3. mRNA expression of Oat3 and several other potential carriers was detected by RT-PCR in rat kidney cortex but was absent from NRK-52E cells, a rat proximal tubular cell line. Basolateral uptake of GSH in NRK-52E cells showed little PAH- or 2-OG-stimulated uptake. We conclude that Oat3 can function in GSH uptake and that NRK-52E cells possess a low background rate of GSH uptake, making these cells a good model for overexpression of specific, putative GSH carriers. PMID- 17719022 TI - Determination of pitavastatin in human plasma via HPLC-ESI-MS/MS and subsequent application to a clinical study in healthy Chinese volunteers. AB - BACKGROUND: Pitavastatin is a novel statin used in the treatment of hyperlipemia. We developed and describe a simple and rapid high performance liquid chromatography-electrospray tandem mass spectrometry (HPLC-ESI-MS/MS) assay for the determination of pitavastatin in human plasma. METHODS: A Finnigan TSQ Quantum Discovery max system equipped with an electrospray ionization source and a Finnigan Surveyortrade mark HPLC system (Thermo Electron, San Jose, CA) was used employing lovastatin as internal standard (IS) for pitavastatin. This method entailed a single step of liquid-liquid extraction with ether from 200 microL plasma. The analyte and internal standard were baseline separated on a Gemini analytical column. Quantitation by SRM analysis was performed in the positive ion mode. RESULTS: HPLC-ESI-MS/MS method validation by means of determination of limit of detection (LOD 0.05 ng/ml), lower limit of quantification (LLOQ 0.1 ng/ml), linearity (0.2-200 ng/ml). The intra-and inter-day precision CVs was <10%, and accuracy ranged from 85 to 115%. The proposed method enables the unambiguous identification and quantification of pitavastatin for clinical studies. CONCLUSION: A sensitive and specific method for quantifying Pitavastatin levels in human plasma has been devised and successfully applied to a clinic pharmacokinetic study of pitavastatin administered. PMID- 17719023 TI - Development of new enzyme-linked immunosorbent assay for oxidized lipoprotein(a) by using purified human oxidized lipoprotein(a) autoantibodies as capture antibody. AB - BACKGROUND: Oxidized Lp(a) [ox-Lp(a)] has been reported to play more potent role than native Lp(a) in atherosclerosis. Ox-Lp(a), autoantibodies, and Lp(a) immune complexes have all been detected in vivo. Thus, the isolation of its autoantibodies and the investigation of ox-Lp(a) may provide a new means to explore the exact pathogenic role of ox-Lp(a). We isolated and identified human autoantibodies against ox-Lp(a) and developed a new ELISA for ox-Lp(a) by using autoantibodies as capture antibody. METHODS: Ox-Lp(a) autoantibodies were isolated and identified from healthy subjects by affinity chromatography. 2 "sandwich" ELISAs were developed for measuring ox-Lp(a) level, using autoantibodies against ox-Lp(a) or rabbit antiserum against ox-LDL as the capture antibody and quantitating with monoclonal anti-apo(a) enzyme conjugate, respectively. Ox-Lp(a) levels were studied by both the ELISAs in 100 patients with coronary heart disease (CHD) and 100 control subjects. RESULTS: The isolated ox-Lp(a) autoantibodies reacted with both apo(a) and apoB epitopes of Ox-Lp(a). Compared to control, plasma ox-Lp(a) levels in patients with CHD were significantly increased (ELISA using human autoantibodies: 24.3+/-33.4 vs. 8.4+/ 9.3 microg/ml, P<0.0001; ELISA using antibodies against ox-LDL: 13.0+/-13.8 vs. 7.3+/-9.7 microg/ml, P<0.0001, respectively). Furthermore, a significantly positive relationship between ox-Lp(a) levels detected by 2 ELISAs was also found (R=0.78, P<0.0001). CONCLUSION: We isolated human autoantibodies against ox Lp(a), which can recognize both apo(a) and apoB epitopes of ox-Lp(a). The developed ELISA for ox-Lp(a) by using human auoantibodies may more accurately reflect the state of Lp(a) oxidation in vivo. Ox-Lp(a) levels increase in patients with CHD. PMID- 17719025 TI - An early requirement for maternal FoxH1 during zebrafish gastrulation. AB - The Forkhead Box H1 (FoxH1) protein is a co-transcription factor recruited by phosphorylated Smad2 downstream of several TGFbetas, including Nodal-related proteins. We have reassessed the function of zebrafish FoxH1 using antisense morpholino oligonucleotides (MOs). MOs targeting translation of foxH1 disrupt embryonic epiboly movements during gastrulation and cause death on the first day of development. The FoxH1 morphant phenotype is much more severe than that of zebrafish carrying foxh1/schmalspur (sur) DNA-binding domain mutations, FoxH1 splice-blocking morphants or other Nodal pathway mutants, and it cannot be altered by concomitant perturbations in Nodal signaling. Apart from disrupting epiboly, FoxH1 MO treatment disrupts convergence and internalization movements. Late gastrula-stage FoxH1 morphants exhibit delayed mesoderm and endoderm marker gene expression and failed patterning of the central nervous system. Probing FoxH1 morphant RNA by microarray, we identified a cohort of five keratin genes- cyt1, cyt2, krt4, krt8 and krt18--that are normally transcribed in the embryo's enveloping layer (EVL) and which have significantly reduced expression in FoxH1 depleted embryos. Simultaneously disrupting these keratins with a mixture of MOs reproduces the FoxH1 morphant phenotype. Our studies thus point to an essential role for maternal FoxH1 and downstream keratins during gastrulation that is epistatic to Nodal signaling. PMID- 17719027 TI - Visual field losses in workers exposed to mercury vapor. AB - Visual field losses associated with mercury (Hg) exposure have only been assessed in patients exposed to methylmercury. Here we evaluate the automated visual field in 35 ex-workers (30 males; 44.20+/-5.92 years) occupationaly exposed to mercury vapor and 34 controls (21 males; 43.29+/-8.33 years). Visual fields were analyzed with the Humphrey Field Analyzer II (model 750i) using two tests: the standard automated perimetry (SAP, white-on-white) and the short wavelength automated perimetry (SWAP, blue-on-yellow) at 76 locations within a 27 degrees central visual field. Results were analyzed as the mean of the sensitivities measured at the fovea, and at five successive concentric rings, of increasing eccentricity, within the central field. Compared to controls, visual field sensitivities of the experimental group measured using SAP were lower for the fovea as well as for all five eccentricity rings (p<0.05). Sensitivities were significantly lower in the SWAP test (p<0.05) for four of the five extra-foveal eccentricity rings; they were not significant for the fovea (p=0.584) or for the 15 degrees eccentricity ring (p=0.965). These results suggest a widespread reduction of sensitivity in both visual field tests. Previous reports in the literature describe moderate to severe concentric constriction of the visual field in subjects with methylmercury intoxication measured manually with the Goldman perimeter. The present results amplify concerns regarding potential medical risks of exposure to environmental mercury sources by demonstrating significant and widespread reductions of visual sensitivity using the more reliable automated perimetry. PMID- 17719026 TI - Regulation of the Xenopus Xsox17alpha(1) promoter by co-operating VegT and Sox17 sites. AB - The gene encoding the Sox F-group transcription factor Xsox17alpha(1) is specifically expressed throughout the entire region of the Xenopus blastula fated to become endoderm, and is important in controlling endodermal development. Xsox17alpha(1) is a direct target of the maternal endodermal determinant VegT and of Sox17 itself. We have analysed the promoter of the Xenopus laevis Xsox17alpha(1) gene by transgenesis, and have identified two important control elements which reside about 9 kb upstream at the start of transcription. These elements individually drive transgenic endodermal expression in the blastula and gastrula. One contains functional, cooperating VegT and Sox-binding consensus sites. The Sox sites in this region are occupied in vivo. The other responds to TGF-beta signals like Activin or Nodals that act through Smad2/3. We propose that these two regions co-operate in regulating the early endodermal expression of the Xsox17alpha(1) gene. PMID- 17719028 TI - Characterization of the antinociceptive and anti-inflammatory activities of doxycycline and minocycline in different experimental models. AB - Tetracyclines induce anti-inflammatory effects unrelated to their antimicrobial activities. We investigated the effect induced by minocycline and doxycycline in models of nociceptive and inflammatory pain, edema, fever, cell migration and formation of fibrovascular tissue, as these effects have not been fully investigated. Tetracyclines were administered via intraperitoneal route 1 h before the tests. Minocycline and doxycycline (100 mg/kg) inhibited the second phase of the formalin-induced nociceptive response in mice. Doxycycline (100 mg/kg) also inhibited the first phase. The nociceptive response induced by phorbol 12,13-didecanoate (PDD) in mice was inhibited by doxycycline (100 mg/kg). Furthermore, carrageenan-induced mechanical allodynia in rats was inhibited by doxycycline and minocycline (50 or 100 mg/kg). However, they did not enhance the latency in the hot-plate test. It is unlikely that antinociception resulted from motor incoordination or muscle relaxing effect, as both tetracyclines (100 mg/kg) did not impair the motor activity of mice in the rota-rod test. Doxycycline (50 or 100 mg/kg) or minocycline (50 or 100 mg/kg) inhibited carrageenan-induced paw edema in rats. However, only minocycline (100 mg/kg) inhibited PDD-induced edema. Carrageenan-induced leukocyte migration into the peritoneal cavity of rats was inhibited by both tetracyclines (100 mg/kg). Endotoxin-induced fever in rats was also inhibited by doxycycline (50 or 100 mg/kg) or minocycline (100 mg/kg). Finally, formation of fibrovascular tissue induced by subcutaneous implant of a cotton pellet in mice was inhibited by a 6-day administration of both tetracyclines (50 or 100 mg/kg day). Concluding, this study clearly shows the antinociceptive and anti-inflammatory activities of these second-generation tetracyclines. PMID- 17719029 TI - Voltage-gated Ca(2+) influx and insulin secretion in human and mouse beta-cells are impaired by the mitochondrial Na(+)/Ca(2+) exchange inhibitor CGP-37157. AB - Glucose-induced insulin release from pancreatic beta-cells relies largely on glucose metabolism and mitochondrial ATP synthesis. Inhibiting the mitochondrial Na(+)/Ca(2+) exchanger (mNCE) using 7-Chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1 benzothiazepin-2(3H)-one (CGP-37157) has been suggested to enhance ATP synthesis and insulin secretion from rat islets by promoting mitochondrial Ca(2+) accumulation. In this study we examined the effects of CGP-37157 on human and mouse islet cells. Surprisingly, we found that insulin secretion from perifused islets was reduced by CGP-37157. Cytosolic Ca(2+) measurements revealed that CGP 37157 dose-dependently blocked glucose- and KCl-stimulated Ca(2+) signals in both human and mouse beta-cells. Conversely, CGP-37157 induced mitochondrial hyperpolarization, NAD(P)H rises, and triggered diazoxide- and nifedipine sensitive cytosolic Ca(2+) transients in a subset of quiescent cells bathed in sub-stimulatory glucose, which is in accord with metabolic activation by the compound. Hence, while blocking mNCE with CGP-37157 may augment metabolism of human and mouse beta-cells, the propagation of metabolic signals is hampered by simultaneous inhibition of voltage-gated Ca(2+) influx, and ultimately insulin secretion. Efforts to use CGP-37157 or design related compounds for therapeutic purposes should take these competing effects into account. PMID- 17719030 TI - Study of plasma protein C and inflammatory pathways: biomarkers for dimethylnitrosamine-induced liver fibrosis in rats. AB - The present investigation was designed to identify potential biomarker(s) and assess the involvement of inflammatory pathway in dimethylnitrosamine (DMN) induced liver fibrosis in rats. Following DMN-treatment (10 mg/ml/kg, i.p., given three consecutive days each week for 4 weeks) body and liver weights were significantly decreased concurrent with increasing severity of liver damage assessed by bridging fibrosis, a histopathologic assessment and characteristic of human liver disease. Protein C along with albumin, C-reactive-protein (CRP), haptoglobin and total protein were significantly reduced and correlated with changes in liver histopathology. Biochemical markers of liver functions were significantly increased and correlated with changes in liver histopathology and plasma levels of protein C. Soluble intracellular-adhesion-molecule-1 (sICAM-1) levels were increased significantly but were poorly correlated with histopathology and protein C levels. Inflammatory chemokines and other analytes, monocyte-chemoattractant-protein-1 and 3 (MCP-1 and MCP-3), macrophage-colony stimulating-factor (M-CSF) were significantly increased during the disease progression, whereas macrophage-derived-chemokine (MDC) and CRP were significantly suppressed. Circulating neutrophils and monocytes were also increased along with disease progression. The differential changes in sICAM-1, hyaluronic acid, gamma-glutamyltranspeptidase (GGT), neutrophil and other inflammatory chemokines suggest the involvement of inflammatory pathways in DMN induced liver fibrosis. In conclusion, the progressive changes in protein C along with other noninvasive biochemical parameters whose levels were significantly correlated with disease progression may serve as biomarkers for pharmacological assessment of targeted therapy for liver fibrosis. PMID- 17719031 TI - Measurement of intraocular pressure (IOP) in chickens using a rebound tonometer: quantitative evaluation of variance due to position inaccuracies. AB - Intraocular pressure (IOP), an important risk factor for glaucoma, is a continuous trait determined by a complex set of genetic and environmental factors that are largely unknown. Genetic studies in laboratory animals may facilitate the identification of genes that affect IOP. We examined the use of the rebound tonometer for measuring IOP in non-anaesthetised birds, along with the device's robustness to alignment errors. Calibration curves were obtained by measuring the IOP of cannulated chicken eyes with the rebound tonometer over a range of pressures. To simulate different types of alignment errors that might be expected with measurement of IOP in alert chickens, for some calibrations the tonometer was positioned (1) at various distances from the cornea, (2) laterally displaced from the visual axis, or (3) angled away from the visual axis. In vivo measurements were taken on three-week-old alert chickens from a layer line, a broiler line, and a layer-broiler "advanced intercross line" (AIL) designed to facilitate QTL mapping. The rebound tonometer showed excellent linearity (R2=0.95 0.99) during calibration, as well as robustness to variation in the probe-to cornea distance over the range 3-5mm and to lateral displacement over the range 0 2mm. However, the tonometer appeared less robust to off-axis misalignment over the range 0-20 degrees (P<0.05). Also, the slope of calibration curves sometimes differed between eyes (P<0.001), presumably reflecting differences in ocular structure. The IOP measured in non-anaesthetised three-week-old AIL chickens was 17.51+/-0.13 mmHg (mean+/-S.E.; N=105 birds). IOP was significantly associated with corneal thickness (P<0.05) and body weight (P<0.001) in a regression model. Replicate measurements were necessary in order to gauge IOP accurately in individual birds; a series of seven tonometry sessions over a 12-h period during the light phase of the light/dark cycle permitted IOP to be measured with a 95% CI of +/-0.7 mmHg. IOP did not differ significantly between the broiler and layer chicken lines which served as the progenitor lines for the AIL. In conclusion, the rebound tonometer permits rapid estimation of IOP in chickens and is well tolerated. The small alignment errors that are expected when taking measurements in non-anaesthetised animals are unlikely to affect accuracy. Since high IOP is a major risk factor for glaucoma, identifying QTL controlling IOP may offer future health benefits. However, our preliminary findings highlight several obstacles to mapping such QTL using the chicken advanced intercross line evaluated here. PMID- 17719033 TI - Capsaicin, a spicy component of hot peppers, modulates adipokine gene expression and protein release from obese-mouse adipose tissues and isolated adipocytes, and suppresses the inflammatory responses of adipose tissue macrophages. AB - Adipokines are involved in the obesity-induced chronic inflammatory response that plays a crucial role in the development of obesity-related pathologies such as type II diabetes and atherosclerosis. We here demonstrate that capsaicin, a naturally occurring phytochemical, can suppress obesity-induced inflammation by modulating adipokine release from and macrophage behavior in obese mice adipose tissues. Capsaicin inhibited the expressions of IL-6 and MCP-1 mRNAs and protein release from the adipose tissues and adipocytes of obese mice, whereas it enhanced the expression of the adiponectin gene and protein. The action of capsaicin is associated with NF-kappaB inactivation and/or PPARgamma activation. Moreover, capsaicin suppressed not only macrophage migration induced by the adipose tissue-conditioned medium, but also macrophage activation to release proinflammatory mediators. Capsaicin may be a useful phytochemical for attenuating obesity-induced inflammation and obesity-related complications. PMID- 17719034 TI - An Escherichia coli mutant producing a truncated inactive form of GlgC synthesizes glycogen: further evidences for the occurrence of various important sources of ADPglucose in enterobacteria. AB - AC70R1-504 Escherichia coli mutants possess a glgC* gene with a nucleotide change resulting in a premature stop codon that renders a truncated, inactive form of GlgC. Cells over-expressing the wild type glgC, but not those over-expressing the AC70R1-504 glgC*, accumulated high ADPglucose and glycogen levels. AC70R1-504 mutants accumulated glycogen, whereas DeltaglgCAP deletion mutants lacking the whole glycogen biosynthetic machinery displayed a glycogen-less phenotype. AC70R1 504 cells with enhanced glycogen synthase activity accumulated high glycogen levels. By contrast, AC70R1-504 cells with high ADPG hydrolase activity accumulated low glycogen. These data further confirm that enterobacteria possess various sources of ADPglucose linked to glycogen biosynthesis. PMID- 17719032 TI - Intrathecal infusion of a Ca(2+)-permeable AMPA channel blocker slows loss of both motor neurons and of the astrocyte glutamate transporter, GLT-1 in a mutant SOD1 rat model of ALS. AB - Elevated extracellular glutamate, resulting from a loss of astrocytic glutamate transport capacity, may contribute to excitotoxic motor neuron (MN) damage in ALS. Accounting for their high excitotoxic vulnerability, MNs possess large numbers of unusual Ca(2+)-permeable AMPA channels (Ca-AMPA channels), the activation of which triggers mitochondrial Ca(2+) overload and strong reactive oxygen species (ROS) generation. However, the causes of the astrocytic glutamate transport loss remain unexplained. To assess the role of Ca-AMPA channels on the evolution of pathology in vivo, we have examined effects of prolonged intrathecal infusion of the Ca-AMPA channel blocker, 1-naphthyl acetylspermine (NAS), in G93A transgenic rat models of ALS. In wild-type animals, immunoreactivity for the astrocytic glutamate transporter, GLT-1, was particularly strong around ventral horn MNs. However, a marked loss of ventral horn GLT-1 was observed, along with substantial MN damage, prior to onset of symptoms (90-100 days) in the G93A rats. Conversely, labeling with the oxidative marker, nitrotyrosine, was increased in the neuropil surrounding MNs in the transgenic animals. Compared to sham-treated G93A animals, 30-day NAS infusions (starting at 67+/-2 days of age) markedly diminished the loss of both MNs and of astrocytic GLT-1 labeling. These observations are compatible with the hypothesis that activation of Ca-AMPA channels on MNs contributes, likely in part through oxidative mechanisms, to loss of glutamate transporter in surrounding astrocytes. PMID- 17719035 TI - Occurrence of more than one important source of ADPglucose linked to glycogen biosynthesis in Escherichia coli and Salmonella. AB - To explore the possible occurrence of sources, other than GlgC, of ADPglucose linked to bacterial glycogen biosynthesis we characterized Escherichia coli and Salmonella DeltaglgCAP deletion mutants lacking the whole glycogen biosynthetic machinery. These mutants displayed the expected glycogen-less phenotype but accumulated ADPglucose. Importantly, DeltaglgCAP cells expressing the glycogen synthase encoding glgA gene accumulated glycogen. Protein chromatographic separation of crude extracts of DeltaglgCAP mutants and subsequent activity measurement analyses revealed that these cells possess various proteins catalyzing the conversion of glucose-1-phosphate into ADPglucose. Collectively these findings show that enterobacteria possess more than one important source of ADPglucose linked to glycogen biosynthesis. PMID- 17719036 TI - Hyperplastic polyp arising from heterotopic gastric epithelium in the esophagus. PMID- 17719037 TI - Idiopathic intramural hematoma of the colon. PMID- 17719038 TI - Mediastinal cryptococcal abscess diagnosed by EUS-FNA. PMID- 17719039 TI - Pyogenic granuloma of the small intestine. PMID- 17719040 TI - New-onset dysphagia after cardiac catheterization. PMID- 17719041 TI - Isolated small bowel amyloidosis seen with capsule endoscopy. PMID- 17719042 TI - An early flat depressed lesion in the cecum progressing to an advanced cancer in 20 months. PMID- 17719043 TI - Capsule endoscopy artifact: the afterimage. PMID- 17719044 TI - Malignant intraductal papillary mucinous neoplasm of the pancreas with multiple pancreatogastric fistulas: a report of 2 cases with different features. PMID- 17719045 TI - EUS rendezvous for pancreatic stent placement during endoscopic snare ampullectomy. PMID- 17719046 TI - Gallstone ileus of the sigmoid colon mimicking colorectal malignancy. PMID- 17719047 TI - Diagnosis of peritoneal carcinomatosis by EUS-guided FNA. PMID- 17719048 TI - Double self-expandable total-coated metal stent for gastrojejunal leak after pancreatoduodenectomy. PMID- 17719049 TI - Pseudomelanosis of jejunum and ileum. PMID- 17719051 TI - Use of nanoparticles in capillary and microchip electrochromatography. AB - Applications of nanoparticles are of rising interest in separation science, due to their favorable surface-to-volume ratio as well as their applicability in miniaturization. A stationary phase with large surface area in combination with an electroosmotic flow-driven system has great potential in a highly efficient separation system. This review covers the use of various nanoparticles as stationary or pseudostationary phase in capillary and microchip electrochromatography. The use of nanoparticles in pseudostationary phase capillary electrochromatography and open-tubular capillary electrochromatography are thoroughly discussed. The stationary and pseudostationary phases that are described include polymer nanoparticles, gold nanoparticles, silica nanoparticles, fullerenes and carbon nanotubes. PMID- 17719050 TI - Elevated testosterone and reduced 5-HIAA concentrations are associated with wounding and hantavirus infection in male Norway rats. AB - Among rodents that carry hantaviruses, males are more likely to engage in aggression and to be infected than females. One mode of hantavirus transmission is via the passage of virus in saliva during wounding. The extent to which hantaviruses cause physiological changes in their rodent host that increase aggression and, therefore, virus transmission has not been fully documented. To assess whether steroid hormones and neurotransmitters contribute to the correlation between aggression and Seoul virus infection, Norway rats were trapped in Baltimore, Maryland and wounding, infection status, steroid hormones, and concentrations of neurotransmitters, including norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenol acetic acid (DOPAC), serotonin (5-HT), and 5 hydroxyindole-3-acetic acid (5-HIAA) in select brain regions were examined. Older males and males with high-grade wounds were more likely to have anti-Seoul virus IgG and viral RNA in organs than either juveniles or adult males with less severe wounds. Wounded males had higher circulating testosterone, lower hypothalamic 5 HIAA, and lower NE in the amygdala than males with no wounds. Infected males had higher concentrations of testosterone, corticosterone, NE in the hypothalamus, and DOPAC in the amygdala than uninfected males, regardless of wounding status. In the present study, wounded males that were infected with Seoul virus had elevated testosterone and reduced 5-HIAA concentrations, suggesting that these neuroendocrine mechanisms may contribute to aggression and the likelihood of transmission of hantavirus in natural populations of male Norway rats. PMID- 17719052 TI - Retention controlling and peak shape simulation in anion chromatography using multiple equilibrium model and stochastic theory. AB - The stochastic theory of chromatography and an equilibrium based approach were used for the prediction of peak shape and retention data of anions. This attempt incorporating the potential advantages of two different chromatographic phenomena for analytical purposes. It is an integrated method to estimate kinetic and thermodynamic properties for the same chromatographic run of ions. The stochastic parameters of eluted anions, such as the residence time of the molecule on the surface of the stationary phase, and the average number of adsorption steps were determined on the basis of a retention database of organic and inorganic anions (formate, chloride, bromide, nitrate, sulphate, oxalate, phosphate) obtained by using carbonate/bicarbonate eluent system at different pHs (9-11) and concentrations (7-13 mM). In the investigated IC system the residence times are much higher and the average number of sorption steps is somewhat smaller than in RP-HPLC. The simultaneous application of the stochastic and the multispecies eluent/analyte model was utilized to peak shape simulation and the retention controlling of various anions under elution conditions of practical importance. The similarities between the measured and the calculated chromatograms indicates the predictive and simulation power of the combined application of the stochastic theory and the multiple species eluent/analyte retention model. PMID- 17719053 TI - Passive sampling in environmental analysis. AB - Since its invention more than three decades ago, passive sampling technology has been widely used for environmental monitoring throughout the world. In many cases, it is the only practical means of determining pollution levels caused by numerous anthropogenic chemicals. Passive sampling technology today is used in various areas ranging from workplace exposure monitoring to global issues of climate change arising due to the presence of various chemicals in the atmosphere. In this review, the present status of the technology and its applications will be discussed along with aspects related to its regulatory acceptance and recent trends. PMID- 17719054 TI - Could linear solvation energy relationships give insights into chiral recognition mechanisms? 1. Pi-pi and charge interaction in the reversed versus the normal phase mode. AB - Linear solvation energy relationships (LSER) have been used for years in liquid chromatography to access the factors that lead to retention and, more recently, to selectivity. In chiral separations, two enantiomers will receive exactly the same descriptors correctly predicting that they will not be separated by any non chiral stationary phase. However, LSER studies could be used considering that each enantiomer sees a chiral stationary phase (CSP) differently. Working with the enantioselectivity factor, k'2lk'1 could give interesting information on the chiral recognition mechanisms. The b and v system parameters always predominantly contribute to a solute's retention in reversed phase liquid chromatography (RPLC) compared to the a, e and s parameters. However, these minor parameters for retention may become the essential ones for enantiomeric separations where a minimum of three simultaneous interactions is needed for an enantioseparation to occur. In this non-chiral study, six different stationary phases, a classical C(18), a diphenyl bonded stationary phase (DP), a polystyrene-divinylbenzene (DVB), a polar embedded new stationary phase, an anion exchanger (SAX) and a teicoplanin aglycone (TAG) CSP were studied with achiral test solutes. Significantly higher e terms were obtained for the SAX and TAG columns. It seems that the ability of stationary surface charges to induce dipoles in polarizable molecules is encoded mainly in the e term. Since the DP and DVB columns did not produce e parameters significantly higher than the C(18) column, it seems that pi pi interactions are (a) extremely weak in RPLC or (b) they are not simply encoded in this single e system parameter but spread in at least three parameters. The TAG CSP produced logically very different parameters when used in the reversed phase mode compared to the normal phase mode showing the critical role of the mobile phase. PMID- 17719055 TI - Gas chromatographic retention indices of trimethylsilyl derivatives of mono- and diglycerides on capillary columns with non-polar stationary phases. AB - Mono- and diglycerides play an important role in the metabolism of plants and animals. They are usually constitutive elements of complex mixtures and are not always as main components, which considerably hinder the identification of these analytes. This work communicates about a synthesis of a wide range of esters of glycerol and aliphatic C(6)-C(20) acids and presents gas chromatographic characteristics of 32 compounds in the form of the most reproducible parameters linear-programmed retention indices on high-performance capillary columns with non-polar stationary phases. The article also presents mass spectra for a series of those glycerides which were not characterized earlier by these parameters. PMID- 17719056 TI - Sol-gel synthesis and morphological control of nanocrystalline TiO(2) via urea treatment. AB - Nanocrystalline TiO(2) rods and hollow tubes with an engraved pattern on the surface have been prepared by a novel anionic template-assisted sol-gel synthesis via urea treatment and under hydrothermal condition. X-ray diffractometry (XRD) results indicate that these nanocrystallines consist predominantly of anatase TiO(2), with minor amounts of rutile and brookite. Scanning and transmission electron microscopy (SEM and TEM) analyses reveal these rods and hollow tubes may result from the aggregates of nanorods of approximately 10 nm in diameter. The crystallographic faceting found from TEM further reveals the polymorphic nature of the nanocrystalline TiO(2) thus prepared. A "reverse micelle" formation mechanism taking into account the hydrothermal temperature, the pH effect of the sol-gel system, the isoelectric point, the formation of micelles, and the electrostatic interaction between the anionic surfactant and the growing TiO(2) particulates is proposed to illustrate the competition between the physical micelle assembly of the ionic surfactants and the chemical hydrolysis and condensation reactions of the Ti precursors. PMID- 17719057 TI - Nanoparticles of octakis[3-(3-amino-1,2,4-triazole)propyl]octasilsesquioxane as ligands for Cu(II), Ni(II), Cd(II), Zn(II), and Fe(III) in aqueous solution. AB - Nanoparticles of octakis[3-(3-amino-1,2,4-triazole)propyl]octasilsesquioxane (ATZ SSQ) were tested as ligands for transition-metal ions in aqueous solution with a special attention to sorption isotherms, ligand-metal interaction, and determination of metal ions in natural waters. The adsorption potential of the material ATZ-SSQ was compared with related [3(3-amino-1,2,4 triazole)propyl]silica gel (ATZ-SG). The adsorption was performed using a batchwise process and both organofunctionalized surfaces showed the ability to adsorb the metal ions from aqueous solution. The Langmuir model was used to simulate the sorption isotherms. The results suggest that the sorption of these metals on ATZ-SSQ and ATZ-SG occurs mainly by surface complexation. The equilibrium condition is reached at time lower than 3 min for ATZ-SSQ, while for ATZ-SG is only reached at time of 25 min. The maximum metal ion uptake values for ATZ-SSQ were higher than the corresponding values achieved with the ATZ-SG. In order to obtain more information on the ligand-metal interaction of the complexes on the surface of the ATZ-SSQ nanomaterial, ESR study with various degrees of copper loadings was carried out. The ATZ-SSQ was tested for the determination (in flow using a column technique) of the metal ions present in natural waters. PMID- 17719058 TI - Role of the solvophobic effect on micellization. AB - Experimental data of amphiphiles aggregation phenomena in water-organic solvent mixtures were considered with the idea of investigating the role of the solvophobic effect on micellization. Changes in the critical micelle concentration, in the micellar ionization degree (for ionic surfactants) and in the aggregation number accompanying variations in the composition of the bulk phase of the micellar solutions were examined with the scope of understanding which properties of the water-organic solvent mixtures are important in the micellization process. Results point out that the cohesive energy density, measured either through the Hildebrand-Hansen solubility parameter or the Gordon parameter, seems to play an important role in determining the contribution of the solvophobic effect on the Gibbs energy of micellization in water-organic solvents mixtures. PMID- 17719059 TI - Kinetic Monte Carlo study of proton binding at the metal oxide/electrolyte interface. AB - The kinetics of proton binding at the metal oxide/electrolyte interface is studied using the kinetic Monte Carlo method. The influence of system properties (surface site density, interfacial dielectric constant, surface energetic heterogeneity) on the equilibrium and kinetic surface coverage is shown. It is shown that the kinetic properties are much more sensitive to lateral interactions than the equilibrium ones. The assumption of energetic heterogeneity rapidly changes the time scales of the processes as well as the time interval between two subsequent elementary processes. In this paper, the atomistic insight into the kinetics of H(+) ion uptake at the metal oxide/electrolyte interface is presented for the first time. PMID- 17719060 TI - Chemical and heating treatments of ionic monolayer-protected clusters (IMPCs) with different surface counter anions. AB - This paper shows an in-depth study on the chemical and thermal responses of two ionic monolayer-protected gold clusters (Oct(4)N(+-)Br- and Oct(4)N(+-)O(3)SS IMPCs). Two IMPCs displayed completely different phase-transfer behaviors when the solutions were in contact with the aqueous solution containing N-(2 mercaptopropionyl)glycine (tiopronin). Not Oct(4)N(+-)O(3)SS-IMPCs but Oct(4)N(+ )Br-IMPCs experienced a facile phase transfer from the organic layer to the aqueous layer, which was resulted from the displacement of ionic ligands by tiopronin monolayers on the gold nanoparticle surface. When the toluene solution containing Oct(4)N(+-)Br-IMPCs was treated with the aqueous solution containing NaCl salts, the UV-vis spectrum of the solution containing Oct(4)N(+-)Br-IMPCs undertook a fast spectral evolution caused by decomposition/agglomeration of IMPCs. In contrast, Oct(4)N(+-)O(3)SS-IMPCs exhibited much higher stability against the NaCl treatments. The Oct(4)N(+-)O(3)SS-IMPCs also displayed a superior thermal stability at relatively high temperature of approximately 110 degrees C. Core size evolutions of Oct(4)N(+-)O(3)SS-IMPCs without a fast decomposition or aggregation of clusters were also observed during solid-state heating treatments at approximately 150 and approximately 200 degrees C. These results support that the presence of different anions clearly affect the overall stability of ionic nanoparticles. The stronger binding property of thiosulfate anions compared to bromide anions with gold nanoparticle surfaces makes Oct(4)N(+ )O(3)SS-IMPCs chemically more inert and thermally more stable. PMID- 17719061 TI - Whole IgG surface display on mammalian cells: Application to isolation of neutralizing chicken monoclonal anti-IL-12 antibodies. AB - We have developed a mammalian cell surface display vector, suitable for directly isolating IgG molecules based on their antigen-binding affinity and biological activity. Using an Epstein-Barr virus-derived episomal vector, antibody libraries are displayed as whole IgG molecules on the cell surface and screened for specific antigen binding by a combination of magnetic beads and fluorescence activated cell sorting. Plasmids encoding antibodies with desired binding characteristics are recovered from sorted cells and are converted to the form for production of soluble IgG. Transiently expressed soluble IgG antibodies are individually tested for binding to target antigens, as well as for biological activities, such as neutralization. This vector system was used to generate antibody display libraries derived from spleen cDNA of chickens immunized with human and mouse IL-12. Chicken-human chimeric IgG1 antibodies that neutralize human and mouse IL-12 were successfully isolated from the library. The mammalian surface display vector developed in this work facilitates the isolation of monoclonal antibodies from essentially any species. PMID- 17719062 TI - Structures of MART-126/27-35 Peptide/HLA-A2 complexes reveal a remarkable disconnect between antigen structural homology and T cell recognition. AB - Small structural changes in peptides presented by major histocompatibility complex (MHC) molecules often result in large changes in immunogenicity, supporting the notion that T cell receptors are exquisitely sensitive to antigen structure. Yet there are striking examples of TCR recognition of structurally dissimilar ligands. The resulting unpredictability of how T cells will respond to different or modified antigens impacts both our understanding of the physical bases for TCR specificity as well as efforts to engineer peptides for immunomodulation. In cancer immunotherapy, epitopes and variants derived from the MART-1/Melan-A protein are widely used as clinical vaccines. Two overlapping epitopes spanning amino acid residues 26 through 35 are of particular interest: numerous clinical studies have been performed using variants of the MART-1 26-35 decamer, although only the 27-35 nonamer has been found on the surface of targeted melanoma cells. Here, we show that the 26-35 and 27-35 peptides adopt strikingly different conformations when bound to HLA-A2. Nevertheless, clonally distinct MART-1(26/27-35)-reactive T cells show broad cross-reactivity towards these ligands. Simultaneously, however, many of the cross-reactive T cells remain unable to recognize anchor-modified variants with very subtle structural differences. These dichotomous observations challenge our thinking about how structural information on unligated peptide/MHC complexes should be best used when addressing questions of TCR specificity. Our findings also indicate that caution is warranted in the design of immunotherapeutics based on the MART-1 26/27-35 epitopes, as neither cross-reactivity nor selectivity is predictable based on the analysis of the structures alone. PMID- 17719065 TI - Beating and arrested intramyocardial injections are associated with significant mechanical loss: implications for cardiac cell transplantation. AB - BACKGROUND: Cellular cardiomyoplasty is emerging as a potentially novel therapeutic option for heart failure and typically involves direct intramyocardial injection of donor cells into a beating heart. Yet, limited rates of cell engraftment remain an obstacle to be overcome before cell therapy is fully recognized. Mechanical and biological mechanisms may account for observed donor cell loss. This study examines acute mechanical loss during intramyocardial injections in beating and arrested hearts. MATERIALS AND METHODS: A porcine cardiopulmonary bypass model was used. Animals underwent either beating (n = 5) or arrested (n = 5) intramyocardial injections into the left ventricle. Fluorescent microspheres were used in lieu of cells because they are biologically inert. Thirty minutes after delivery, animals were euthanized. Microspheres in cardiac and peripheral tissues were quantified using flow cytometry. RESULTS: Approximately 10% of microspheres were retained within the site of injection in both groups. There was no statistical difference between microsphere retention rates in either the beating or the arrested heart group. Microspheres were found in peripheral organs, pericardial fluid, and the delivery device. CONCLUSIONS: The majority of microspheres injected intramyocardially are lost in both beating and arrested hearts. Cardiac standstill does not enhance microsphere retention. Possible mechanisms include leakage from the injection site and washout via the cardiac venous/lymphatic system. Delivery strategy will need to be modified if more cells are to be retained within the target organ. PMID- 17719064 TI - Sophorolipids improve sepsis survival: effects of dosing and derivatives. AB - INTRODUCTION: Sophorolipids, a family of natural and easily chemo-enzymatically modified microbial glycolipids, are promising modulators of the immune response. We have previously demonstrated that sophorolipids mediate anti-inflammatory effects, including decreasing sepsis-related mortality at 36 h in vivo in a rat model of septic peritonitis and in vitro by decreasing nitric oxide and inflammatory cytokine production. Here we assessed the effect of sophorolipids on sepsis-related mortality when administered as a (1) single bolus versus sequential dosing and (2) natural mixture versus individual derivatives compared with vehicle alone. METHODS: Intra-abdominal sepsis was induced in male, Sprague Dawley rats, 200 to 240 g, via cecal ligation and puncture. Sophorolipids (5-750 mg/kg) or vehicle (ethanol/sucrose/physiological saline) were injected intravenously (i.v.) via tail vein or inferior vena cava at the end of the operation either as a single dose or sequentially (q24 h x 3 doses); natural mixture was compared with select sophorolipid derivatives (n = 10-15 per group). Sham-operated animals served as nonsepsis controls. Survival rates were compared at 1 through 6 d post sepsis induction and tissue was analyzed by histopathology. Significance was determined by Kruskal-Wallis analysis with Bonferroni adjustment and Student's t-test. RESULTS: Sophorolipid treatment at 5 mg/kg body weight improved survival in rats with cecal ligation and puncture-induced septic shock by 28% at 24 h and 42% at 72 h for single dose, 39% at 24 h and 26% at 72 h for sequential doses, and 23% overall survival for select sophorolipid derivatives when compared with vehicle control (P < 0.05 for sequential dosing). Toxicity was evident and dose-dependent with very high doses of sophorolipid (375-750 mg/kg body weight) with histopathology demonstrating interstitial and intra-alveolar edema with areas of microhemorrhage in pulmonary tissue when compared with vehicle controls (P < 0.05). No mortality was observed in sham operated controls at all doses tested. CONCLUSIONS: Administration of sophorolipids after induction of intra-abdominal sepsis improves survival. The demonstration that sophorolipids can reduce sepsis-related mortality with different dosing regimens and derivatives provides continuing evidence toward a promising new therapy. Toxicity is evident at 75 to 150x the therapeutic dose in septic animals. PMID- 17719063 TI - Angiocidin inhibitory peptides decrease tumor burden in a murine colon cancer model. AB - INTRODUCTION: We have recently developed two inhibitory peptides that target angiocidin, a key mediator of tumor progression and angiogenesis. In this study, we investigate the expression of angiocidin in human colon cancer specimens and evaluate the therapeutic efficacy of our angiocidin inhibitory peptides. METHODS: We created a colon cancer tissue array containing primary tumor, normal colon, negative and positive lymph nodes, and liver metastases (when available) from 159 consecutive colon cancer specimens. Angiocidin expression was determined by immunohistochemistry. The efficacy of 6-mer and 25-mer angiocidin inhibitory peptides was determined in a murine model of human colon cancer. Treatment efficacy was based on primary tumor volume and measures of tumor burden, including internal disease score and health score. Western blots were used to determine angiocidin expression in xenografts. RESULTS: Eighty-nine percent of primary tumors and 91% of positive lymph nodes expressed angiocidin. Normal colon was negative in 94% of specimens, and normal lymph nodes were negative or weakly positive in 79% of specimens. All liver metastases were positive for angiocidin. Animals in both peptide treatment groups showed improvement in health score and internal disease score compared with control animals (P = 0.001). Treatment with 6-mer and 25-mer peptide resulted in 3-fold and 16-fold reductions, respectively, in primary tumor volume (P = 0.001). Angiocidin expression in primary tumors of peptide-treated mice correlated with tumor burden (P < 0.05). CONCLUSIONS: Angiocidin is overexpressed in human colon cancer specimens. Angiocidin inhibitory peptides are well tolerated in vivo and effectively reduce primary tumor volume and tumor burden in human colon cancer xenografts. PMID- 17719066 TI - Developing a scoring rubric for resident research presentations: a pilot study. AB - BACKGROUND: A requirement for all Accreditation Council for Graduate Medical Education (ACGME) approved residencies is the provision of "an opportunity for residents to participate in research." To comply with this requirement, most training programs encourage their residents to conduct research and to report their results. Few guidelines exist, however, for assessing the efficacy of the presentations. The goal of this pilot study was to develop a valid, one-page scoring rubric to be used during oral resident research presentations. Such a scoring rubric will facilitate acceptable agreement among faculty raters. METHODS: Content validity was addressed by adhering to the Standards for Educational and Psychological Testing. A one-page, five-domain, behaviorally worded scoring rubric was developed. Inter-rater reliability was derived and three ACGME General Competencies were also addressed within the rubric. RESULTS: The initial scoring rubric was tested with 11 resident oral presentations. The inter-rater reliability was 0.56 using Cronbach's alpha. The rubric was modified and the scale restricted to a 3-point scale. It was then tested with 17 additional presentations, which were independently rated by two general surgery faculty members. Cronbach's Alpha increased to 0.61. CONCLUSIONS: An objective method to evaluate a resident's oral research presentation has been successfully piloted. This content valid rubric possesses good inter-rater reliability according to established guidelines. Clearly defined behaviors have been outlined within the rubric. Program directors will have psychometrically sound evidence for the ACGME. Future research will address generalizability and concurrent validity using other types of resident assessment data. PMID- 17719067 TI - Pyrrolizidine alkaloids of the endemic Mexican genus Pittocaulon and assignment of stereoisomeric 1,2-saturated necine bases. AB - The endemic Mexican genus Pittocaulon (subtribe Tussilagininae, tribe Senecioneae, Asteraceae) belongs to a monophyletic group of genera distributed in Mexico and North America. The five Pittocaulon species represent shrubs with broom-like succulent branches. All species were found to contain pyrrolizidine alkaloids (PAs). With one exception (i.e., stems of Pittocaulon velatum are devoid of PAs) PAs were found in all plant organs with the highest levels (up to 0.3% of dry weight) in the flower heads. Three structural types of PAs were found: (1) macrocyclic otonecine esters, e.g. senkirkine and acetylpetasitenine; (2) macrocyclic retronecine esters, e.g. senecionine, only found in roots, and (3) monoesters of 1,2-saturated necines with angelic acid. For an unambiguous assignment of the different stereoisomeric 1,2-saturated necine bases a GC-MS method was established that allows the separation and identification of the four stereoisomers as their diacetyl or trimethylsilyl derivatives. All otonecine esters that generally do not form N-oxides and the 1,2-saturated PAs were exclusively found as free bases, while the 1,2-unsaturated 7-angeloylheliotridine occurring in P. velatum was found only as its N-oxide. In a comparative study the 1H and 13C NMR spectra of the four stereoisomeric necine bases were completely assigned by the use of DEPT-135, H,H-COSY, H,C-HSQC and H,H-NOESY experiments and by iterative analysis of the 1H NMR spectra. Based on these methods the PA monoesters occurring in Pittocaulon praecox and P. velatum were assigned as 7-O angeloyl ester respectively 9-O-angeloyl ester of dihydroxyheliotridane which could be identified for the first time as naturally occurring necine base. Unexpectedly, in the monoesters isolated from the three other Pittocaulon species dihydroxyheliotridane is replaced by the necine base turneforcidine with opposite configuration at C-1 and C-7. The species-specific and organ-typical PA profiles of the five Pittocaulon species are discussed in a biogenetic context. PMID- 17719068 TI - Distribution of steroidal saponins in Tribulus terrestris from different geographical regions. AB - The steroidal saponins of Tribulus terrestris L. (Zygophyllaceae) are considered to be the factor responsible for biological activity of products derived from this plant. The activity depends on the concentration and the composition of active saponins, which in turn is influenced by the geographical origin of plant material. Samples of T. terrestris collected in Bulgaria, Greece, Serbia, Macedonia, Turkey, Georgia, Iran, Vietnam and India were analyzed by LC-ESI/MS/MS for the presence and the concentration of protodioscin (1), prototribestin (2), pseudoprotodioscin (3), dioscin (4), tribestin (5) and tribulosin (6). The flavonoid rutin (7) was also included in the comparison. The results revealed distinct differences in the content of these compounds depending on region of sample collection, plant part studied and stage of plant development. The samples from Bulgaria, Turkey, Greece, Serbia, Macedonia, Georgia and Iran exhibited similar chemical profile and only some quantitative difference in the content of 1-7 with protodioscin (1) and prototribestin (2) as main components. The Vietnamese and Indian samples exhibit totally different chemical profile. They lack 2 and 5, while tribulosin (6) is present in high amounts. Compounds different from 1 to 7 are dominating in these 3 samples. The presented results suggested the existence of one chemotype common to the East South European and West Asian regions. Most probably, the Vietnamese and Indian samples belong to other chemotypes which are still to be studied and characterized. No clear correlation between the burrs morphology and the chemical composition of the samples has been found. PMID- 17719069 TI - Brassinolide activities of 2alpha,3alpha-diols versus 3alpha,4alpha-diols in the bean second internode bioassay: explanation by molecular modeling methods. AB - In general, the structural requirements postulated for a high brassinolide activity are: 2alpha,3alpha-diol, 6-ketone or better 7-oxalactone in B-ring, A/B trans fused ring junction, a cis C-22,C-23-diol preferentially with RR configurations, and a C-24 methyl or ethyl substituent [Takatsuto S, Yazawa N, Ikekawa N, Takematsu T, Takeuchi Y, Koguchi M. Structure-activity relationship of brassinosteroids. Phytochemistry 1983;22:2437-41; Thompson MJ, Meudt WJ, Mandava NB, Dutky SR, Lusby WR, Spaulding DW. Synthesis of brassinosteroids and relationship of structure to plant growth-promoting effects. Steroids 1982;39:89 105]. We found that the 3alpha,4alpha-diols 4, 6 and 8 are more active than the 2alpha,3alpha-diols 3, 5 and 7 [Sisa M, Budesinsky M, Kohout L. Synthesis of 7a homo and 7a,7b-dihomo-5alpha-cholestane analogues of brassinolide. Collect Czech Chem Commun 2003;68:2171-89]. This fact is in strong contrast with the structure requirements mentioned above. Our hypothesis suggests that the lower activity of 2alpha,3alpha-diols and/or the higher activity of 3alpha,4alpha-diols could be explained by twisting and distortion of the molecule due to the seven- or eight membered B-ring and also by the position of a carbonyl group relative to the A ring diol. 3D-SAR computer methodologies as alignments and overlaps of GRID maps and 3D-QSAR analysis GRID-GOLPE (CoMFA-like) were used as an effort to explain the higher bioactivity of 3alpha,4alpha-diols 4, 6 and 8 in comparison with the 2alpha,3alpha-diols 3, 5 and 7 of B-ring enlarged brassinosteroids. PMID- 17719070 TI - Characterization of an antigenic site that contains a dominant, type-specific neutralization determinant on the envelope protein domain III (ED3) of dengue 2 virus. AB - The surface of the mature dengue virus (DENV) particle consists of 90 envelope (E) protein dimers that mediate both receptor binding and fusion. The E protein ectodomain can be divided into three structural domains designated ED1, ED2, and ED3, of which ED3 contains the critical and dominant virus-specific neutralization sites. In this study the ED3 epitopes recognized by seven, murine, IgG1 DENV-2 type-specific, monoclonal antibodies (MAbs) were determined using site-directed mutagenesis of a recombinant DENV-2 ED3 (rED3) protein. A total of 41 single amino acid substitutions were introduced into the rED3 at 30 different surface accessible residues. The affinity of each MAb with the mutant rED3s was assessed by indirect ELISA and the results indicate that all seven MAbs recognize overlapping epitopes with residues K305 and P384 critical for binding. These residues are conserved among DENV-2 strains and cluster together on the upper lateral face of ED3. A linear relationship was observed between relative occupancy of ED3 on the virion by MAb and neutralization of the majority of virus infectivity ( approximately 90%) for all seven MAbs. Depending on the MAb, it is predicted that between 10% and 50% relative occupancy of ED3 on the virion is necessary for virus neutralization and for all seven MAbs occupancy levels approaching saturation were required for 100% neutralization of virus infectivity. Overall, the conserved antigenic site recognized by all seven MAbs is likely to be a dominant DENV-2 type-specific, neutralization determinant. PMID- 17719071 TI - Compartmentalization of small ruminant lentivirus between blood and colostrum in infected goats. AB - The compartmentalization of small ruminant lentivirus (SRLV) subtype A (Maedi Visna virus) and B (caprine arthritis-encephalitis virus) variants was analyzed in colostrum and peripheral blood mononuclear cells of four naturally infected goats. Sequence analysis of DNA and RNA encompassing the V4-V5 env regions showed a differential distribution of SRLV variants between the two compartments. Tissue specific compartmentalization was demonstrated by phylogenetic analysis in three of the four cases. In these animals colostrum proviral sequences were clustered relative to the blood viral sequences. In one goat, the blood and colostrum derived provirus sequences were intermingled, suggesting trafficking of virus between the two tissues or mirroring a recent infection. Surprisingly, the pattern of free virus variants in the colostrum of all animals corresponded only partially to that of the proviral form, suggesting that free viruses might not derive from infected colostral cells. The compartmentalization of SRLV between peripheral blood and colostrum indicates that lactogenic transmission may involve specific viruses not present in the proviral populations circulating in the blood. PMID- 17719072 TI - Cell-based therapy for retina degeneration: the promise of a cure. AB - Cell-based therapies in the retina have been associated with the recovery of visual function in animal models of retinal degeneration. This review covers the current status of such therapies with regard to the source of the donor cells, their integration, and their impact on the degenerating host retina. Emphasis is also put on the importance of a careful interpretation of what is meant by "recovery of visual function". Two main approaches are considered here: (1) the use of human embryonic stem cell derived retinal pigment epithelial (RPE) cells to rescue photoreceptors in an animal model of RPE defect; and (2) the use of photoreceptor precursors to repair the degenerating neural retina. The current conclusions are that major hurdles have to be dealt with, such as finding an appropriate and ethically compliant donor cell source that would yield protracted survival and integration of the replacement retinal cells, and that there is no evidence yet that cell-based therapies can allow the long-term preservation or recovery of conscious vision. PMID- 17719073 TI - The eye movements of dyslexic children during reading and visual search: impact of the visual attention span. AB - The eye movements of 14 French dyslexic children having a VA span reduction and 14 normal readers were compared in two tasks of visual search and text reading. The dyslexic participants made a higher number of rightward fixations in reading only. They simultaneously processed the same low number of letters in both tasks whereas normal readers processed far more letters in reading. Importantly, the children's VA span abilities related to the number of letters simultaneously processed in reading. The atypical eye movements of some dyslexic readers in reading thus appear to reflect difficulties to increase their VA span according to the task request. PMID- 17719074 TI - Reactions of thiocarbamate, triazine and urea herbicides, RDX and benzenes on EPA Contaminant Candidate List with ozone and with hydroxyl radicals. AB - Second-order rate constants of the direct ozone reactions [formula: see text] and the indirect OH radical reactions [formula: see text] for nine chemicals on the US EPA's Drinking Water Contaminant Candidate List (CCL) were studied during the ozonation and ozone/hydrogen peroxide advanced oxidation process (O(3)/H(2)O(2) AOP) using batch reactors. Except for the thiocarbamate herbicides (molinate and EPTC), all other CCL chemicals (linuron, diuron, prometon, RDX, 2,4 dinitrotoluene, 2,6-dinitrotoluene and nitrobenzene) show low reactivity toward ozone. The general magnitude of ozone reactivity of the CCL chemicals can be explained by their structures and the electrophilic nature of ozone reactions. The CCL chemicals (except RDX) are highly reactive toward OH radicals as demonstrated by their high [formula: see text] values. Ozonation at low pH, which involves mainly the direct ozone reaction, is only efficient for the removal of the thiocarbamates. Ozonation at high pH and O(3)/H(2)O(2) AOP will be highly efficient for the treatment of all chemicals in this study except RDX, which shows the lowest OH radical reactivity. Removal of a contaminant does not mean complete mineralization and reaction byproducts may be a problem if they are recalcitrant and are likely to cause health concerns. PMID- 17719075 TI - Surface characteristics of crop-residue-derived black carbon and lead(II) adsorption. AB - Previous studies demonstrated that black carbon (BC) in soils arising from the burning of crop residues is a highly effective adsorbent for organic contaminants. This work evaluated the adsorptive ability of BC for heavy metals in relation to the BC surface characteristics. Two BC samples, rice carbon (RC) and wheat carbon (WC) isolated from the burning residues of rice straw and wheat straw, respectively, were characterized for their surface properties with reference to a commercial activated carbon (AC). While RC and WC had lower surface areas than AC, the two BC samples possessed higher surface acidities and thus lower pH of the isoelectric points (pH IEP) than AC as indicated by titration, FTIR, and zeta potential measurements. The Pb(II) adsorption by RC and WC was higher than that by AC and increased significantly with increasing pH, suggesting the electrostatic interactions between positive Pb(II) species and negatively charged functional groups on RC and WC as the primary adsorptive forces. A reduction in the total positive charge of Pb(II) species with increasing pH as computed by MINTEQA2 suggested that the deprotonation of surface functional groups of RC and WC was the controlling factor of the adsorption. The Pb(II) adsorption decreased with increasing ionic strength, due to the screening role of Na+ in neutralizing the negative charge of RC and WC. This study demonstrated that BC may be an important adsorbent of heavy metals in soil and that the adsorption may be significantly influenced by environmental conditions. PMID- 17719076 TI - Probabilistic modelling of overflow, surcharge and flooding in urban drainage using the first-order reliability method and parameterization of local rain series. AB - Failure of urban drainage systems may occur due to surcharge or flooding at specific manholes in the system, or due to overflows from combined sewer systems to receiving waters. To quantify the probability or return period of failure, standard approaches make use of the simulation of design storms or long historical rainfall series in a hydrodynamic model of the urban drainage system. In this paper, an alternative probabilistic method is investigated: the first order reliability method (FORM). To apply this method, a long rainfall time series was divided in rainstorms (rain events), and each rainstorm conceptualized to a synthetic rainfall hyetograph by a Gaussian shape with the parameters rainstorm depth, duration and peak intensity. Probability distributions were calibrated for these three parameters and used on the basis of the failure probability estimation, together with a hydrodynamic simulation model to determine the failure conditions for each set of parameters. The method takes into account the uncertainties involved in the rainstorm parameterization. Comparison is made between the failure probability results of the FORM method, the standard method using long-term simulations and alternative methods based on random sampling (Monte Carlo direct sampling and importance sampling). It is concluded that without crucial influence on the modelling accuracy, the FORM is very applicable as an alternative to traditional long-term simulations of urban drainage systems. PMID- 17719077 TI - Modified ADM1 structure for modelling municipal primary sludge hydrolysis. AB - This study elaborates the rate-limiting steps of particle disintegration/hydrolysis of primary sludge using methane production rate (MPR) curves from multiple batch experiments. Anaerobic batch degradation of fresh primary sludge showed a complex MPR curve marked with two well-defined temporal peaks. The first immediate peak was associated with the degradation of relatively readily hydrolysable substrates, while the second delayed peak was associated with the degradation of large-sized particles. For simulating the second delayed peak, it was necessary to consider a more elaborate particle disintegration/hydrolysis model. Based on the anaerobic respirograms of 17 runs in four datasets and using a substrate characterisation approach similar to activated sludge models (ASMs), the primary sludge was classified into three biodegradable fractions having different kinetics. These are (1) a hydrolysable substrate (X(Settle-I)) showing a degradation typical to slowly biodegradable compounds, (2) a substrate fraction (X(Settle-II)) having a degradation similar to lysis of biomass fraction and (3) a substrate requiring disintegration before hydrolysis (X(Settle-III)) representing the large-sized particles in primary sludge. Based on these results, modifications in the model structure of anaerobic digestion model no. 1 (ADM1) are proposed to improve the modelling of primary sludge solid degradation in anaerobic digesters. PMID- 17719078 TI - Evaluation of molecular methods used for establishing the interactions and functions of microorganisms in anaerobic bioreactors. AB - Molecular techniques have unveiled the complexity of the microbial consortium in anaerobic bioreactors and revealed the presence of several uncultivated species. This paper presents a review of the panoply of classical and recent molecular approaches and multivariate analyses that have been, or might be used to establish the interactions and functions of these anaerobic microorganisms. Most of the molecular approaches used so far are based on the analysis of small subunit ribosomal RNA but recent studies also use quantification of functional gene expressions. There are now several studies that have developed quantitative real-time PCR assays to investigate methanogens. With a view to improving the stability and performance of bioreactors, monitoring with molecular methods is also discussed. Advances in metagenomics and proteomics will lead to the development of promising lab-on chip technologies for cost-effective monitoring. PMID- 17719079 TI - MTHFR C677T mutation in central retinal vein occlusion: a case-control study in Chinese population. AB - Our previous study found that hyperhomocysteinemia was strongly associated with central retinal vein occlusion (CRVO) in the Chinese population. The aim of this study is to determine whether MTHFR C677T mutation is an independent risk factor for CRVO in the Chinese population. A matched case-control study was conducted between July 2004 and May 2005. The study cohort consisted of 64 individuals that had been diagnosed with CRVO and 64 healthy controls (matched for age, gender, hypertension, smoking, and drinking habits). None of the cases or controls had a history of diabetes, glaucoma, medication or any other vascular events that might influence plasma homocysteine levels. A cross-sectional analysis among the 64 cases was performed to compare the prevalence of MTHFR C677T mutation among subjects with and without ischemia and subjects aged above 45 and below 45 years. MTHFR C677T mutation was determined by the template-directed dye-terminator incorporation with fluorescence polarization (TDI-FP) method. The result showed that the prevalence of the MTHFR 677 TT genotype did not significantly differ between patients and controls. However, 10 (34.5%) MTHFR C677 TT genotype was found in the ischemic group but only 4 (14.3%) in the nonischemic group (p=0.026). And we found that 6 MTHFR C677 TT genotype patients who have hyperhomocysteinemia in the ischemic group but only 2 in the nonischemic group (p=0.016). It suggests that MTHFR C677T mutation is associated with hyperhomocysteinemia in the ischemic CRVO in the Chinese population. It may contribute to hyperhomocysteinemia and associate with the development of CRVO. PMID- 17719080 TI - Longitudinal patterns of youth access to cigarettes and smoking progression: Minnesota Adolescent Community Cohort (MACC) study (2000-2003). AB - OBJECTIVES: To measure community-level changes in the methods youth use to obtain cigarettes over time and to relate these methods to the progression of smoking. METHODS: We analyzed 2000-2003 data from the Minnesota Adolescent Community Cohort study, where youth (beginning at age 12), who were living in Minnesota at baseline, were surveyed every 6 months via telephone. We conducted mixed model repeated measures logistic regression to obtain probabilities of cigarette access methods among past 30-day smokers (n=340 at baseline). RESULTS: The probability of obtaining cigarettes from a commercial source in the past month declined from 0.36 at baseline to 0.22 at the sixth survey point while the probability of obtaining cigarettes from a social source during the previous month increased from 0.54 to 0.76 (p for both trends=0.0001). At the community level, the likelihood of adolescents obtaining cigarettes from social sources was inversely related to the likelihood of progressing to heavy smoking (p<0.001). CONCLUSIONS: During this time, youth shifted to greater reliance on social sources and less on commercial sources. A trend toward less commercial access to cigarettes accompanied by an increase in social access may translate to youth being less likely to progress to heavier smoking. PMID- 17719081 TI - Vitamin E in human skin: organ-specific physiology and considerations for its use in dermatology. AB - Vitamin E has been used for more than 50 years in experimental and clinical dermatology. While a large number of case reports were published in this time, there is still a lack of controlled clinical studies providing a rationale for well defined dosages and clinical indications. In contrast, advances in basic research on the physiology, mechanism of action, penetration, bioconversion and photoprotection of vitamin E in human skin has led to the development of numerous new formulations for use in cosmetics and skin care products. This article reviews basic mechanisms and possible cosmetic as well as clinical implications of the recent advances in cutaneous vitamin E research. Experimental evidence suggests that topical and oral vitamin E has antitumorigenic, photoprotective, and skin barrier stabilizing properties. While the current use of vitamin E is largely limited to cosmetics, controlled clinical studies for indications such as atopic dermatitis or preventions of photocarcinogenesis are needed to evaluate the clinical benefit of vitamin E. PMID- 17719082 TI - Influence of endodontic post type (glass fiber, quartz fiber or gold) and luting material on push-out bond strength to dentin in vitro. AB - OBJECTIVES: To determine the influence of post type and luting material on bond strength to dentin. METHODS: The root canals of extracted human upper central incisors were instrumented and post space was prepared using the respective drills for each post system. Glass fiber posts (Luscent Anchor, Dentatus [LA]) were luted using three dual-curing adhesive systems (Excite DSC/Variolink II, Vivadent [VL2]; EnaBond/EnaCem, Micerium [ENA]; Prime & Bond NT/Calibra, DentSply DeTrey [CAL]). A different brand of glass fiber post (EasyPost, DentSply Maillefer [EP]) and quartz fiber post (DT Light Post, VDW [DT]) were luted using CAL. Gold posts (Perma-dor, VDW) were luted either adhesively following tribo chemical silicate coating (Rocatec, ESPE-Sil, 3M ESPE; CAL) or conventionally using glass ionomer cement (Ketac Cem, 3M ESPE). Three slices of 2mm height were cut perpendicular to the post from each restored root. Bond strength was determined by pushing out the post using a universal testing machine (/1449, Zwick). RESULTS: For all experimental groups combined, bond strength increased from the coronal to the apical section (Friedman test: P<0.001). Significant differences were observed among the fiber posts (DT/CAL>LA/CAL; Mann-Whitney U test with Bonferroni-Holm adjustment: P<0.05; EP/CAL ranging in between) but not among luting materials (LA/VL2, LA/ENA, LA/CAL: n.s.). The gold posts were equivalent to DT/CAL with both luting procedures. SIGNIFICANCE: Selection of post type may be more important for bond strength than luting material. Bond strength of fiber posts was equivalent but not superior to adhesively or conventionally luted gold posts. PMID- 17719083 TI - Tuberculosis. AB - Tuberculosis is still a leading cause of death in low-income and middle-income countries, especially those of sub-Saharan Africa where tuberculosis is an epidemic because of the increased susceptibility conferred by HIV infection. The effectiveness of the Bacille Calmette Guerin (BCG) vaccine is partial, and that of treatment of latent tuberculosis is unclear in high-incidence settings. The routine diagnostic methods that are used in many parts of the world are still very similar to those used 100 years ago. Multidrug treatment, within the context of structured, directly observed therapy, is a cost-effective control strategy. Nevertheless, the duration of treatment needed reduces its effectiveness, as does the emergence of multidrug-resistant and extensively drug-resistant disease; the latter has recently become widespread. The rapid expansion of basic, clinical, and operational research, in addition to increasing knowledge of tuberculosis, is providing new diagnostic, treatment, and preventive measures. The challenge is to apply these advances to the populations most at risk. The development of a comprehensive worldwide plan to stop tuberculosis might facilitate this process by coordinating the work of health agencies. However, massive effort, political will, and resources are needed for this plan to succeed. PMID- 17719084 TI - Aeromonas veronii, a tributyltin (TBT)-degrading bacterium isolated from an estuarine environment, Ria de Aveiro in Portugal. AB - Organotin compounds are used in a variety of industrial processes therefore their subsequent discharge into the environment is widespread. Bacteria play an important role in biogeochemical transformations acting as natural decontamination agents. Therefore, screening for tributyltin (TBT)-resistant and degrading bacteria is relevant for the selection of isolates with decontamination ability of these polluted areas. With this purpose, 50 strains were isolated from sediment and water from Ria de Aveiro and their tolerance to TBT, up to 3mM, was evaluated. Generally, occurrence of highly TBT-resistant bacteria was observed, and Gram negative bacteria exhibited more tolerance to TBT than Gram positive bacteria. A memory response was observed when bacteria were progressively exposed to increasingly higher TBT concentrations. One isolate, Aeromonas veronii Av27, highly resistant to TBT (3mM) uses this compound as carbon source and degrades it to less toxic compounds. PMID- 17719085 TI - Spectroscopic study and G-quadruplex DNA binding affinity of two bioactive papaverine-derived ligands. AB - The interactions of G-quadruplex DNA with two oxidation products of papaverine, 6a,12a-diazadibenzo-[a,g]fluorenylium derivative (1) and 2,3,9,10-tetramethoxy-12 oxo-12H-indolo[2,1-a]isoquinolinium cation (2) were investigated. Their activity against telomerase was assessed using the conventional telomeric repeat amplification protocol (TRAP) assay. Effect of TRAP buffer and oligonucleotide length on the DNA-binding affinity of 1 and 2 were also studied. Three quadruplex forming oligonucleotides with human telomeric sequence: dG(3)(T(2)AG(3))(3) (htel21), dAG(3)(T(2)AG(3))(3) (htel22), and d(T(2)AG(3))(4) (htel24) were used in these investigations. Both ligands were capable of interacting with G4 DNA with binding stoichiometry indicating that two ligand molecules bind to G quadruplex, which agrees with the binding model of end-stacking on terminal G tetrads. Circular dichroism spectra revealed that preferences of quadruplex forming oligonucleotide to adopt a particular topological structure may be also affected by the external ligand that binds to quadruplex. Telomerase activity was suppressed at very low ligand 1 and ligand 2 concentrations with an appreciable selectivity comparing with inhibition of Taq polymerase. PMID- 17719086 TI - Ca2+ entry via AMPA-type glutamate receptors triggers Ca2+-induced Ca2+ release from ryanodine receptors in rat spiral ganglion neurons. AB - Ryanodine receptor (RyR)-gated Ca2+ stores have recently been identified in cochlear spiral ganglion neurons (SGN) and likely contribute to Ca2+ signalling associated with auditory neurotransmission. Here, we identify an ionotropic glutamate receptor signal transduction pathway which invokes RyR-gated Ca2+ stores in SGN via Ca2+-induced Ca2+ release (CICR). Ca2+ levels were recorded in SGN in situ within rat cochlear slices (postnatal day 0-17) using the Ca2+ indicator fluo-4. RyR-gated Ca2+ stores were confirmed by caffeine-induced increases in intracellular Ca2+ which were blocked by ryanodine (100 microM) and were independent of external Ca2+. Glutamate evoked comparable increases in intracellular Ca2+, but required the presence of external Ca2+. Ca2+ influx via the glutamate receptor was found to elicit CICR via RyR-gated Ca2+ stores, as shown by the inhibition of the response by prior depletion of the Ca2+ stores with caffeine, the SERCA inhibitor thapsigargin, or ryanodine. The glutamate analogue AMPA (alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid) elicited Ca2+ responses that could be inhibited by caffeine. Glutamate- and AMPA-mediated Ca2+ responses were eliminated with the AMPA/Kainate receptor antagonist DNQX (6,7-dinitroquinoxaline-2,3-dione). These data demonstrate functional coupling between somatic AMPA-type glutamate receptors and intracellular Ca(2+) stores via RyR-dependent CICR in primary auditory neurons. PMID- 17719087 TI - Most pediatric patients with essential thrombocythemia show hypersensitivity to erythropoietin in vitro, with rare JAK2 V617F-positive erythroid colonies. AB - Essential thrombocythemia (ET), a Philadelphia (Ph) chromosome negative chronic myeloproliferative disorder, is usually a disease of middle age and it is extremely rare in pediatric patients. In this report we studied 12 children diagnosed with ET and one child with thrombocytosis and family history of ET. We failed to detect JAK2 V617F mutation either in peripheral blood leukocytes or in separated platelets and granulocytes. Monoclonal hematopoiesis was noted in only one female patient. Erythroid progenitors of most of the patients displayed hypersensitivity to erythropoietin (Epo) in vitro; Epo-independent erythroid colonies (EECs) were detected in seven patients. Among EECs of three patients we observed rare colonies heterozygous or homozygous for the JAK2 V617F mutation. Our data suggest that childhood ET patients could bear minor JAK2 V617F-positive subclones. PMID- 17719088 TI - Influence of surface shape on DNA binding of bimetallo helicates. AB - In order to probe the DNA-helicate interactions responsible for the DNA binding and remarkable changes of the DNA secondary structure induced by a tetracationic bi-metallo helicate [Fe(2)(L(1))(3)](4+) (L(1)=C(25)H(20)N(4)), we have designed and synthesised derivatives with hydrophobic methyl groups at different positions on the ligand backbone. Two dimetallo helicates [Fe(2)(L(i))(3)](4+) were prepared using ligands L(3) and L(5) with the methyl substituent on, respectively, the 3 and 5 positions of the pyridyl ring thus producing a wider or slightly longer tetracationic DNA binder. UV/visible absorbance, circular and linear dichroism spectroscopies have been used to characterize the interactions of the cylinders with DNA with the aim of investigating any sequence preference or selectivity upon binding. Competitive binding studies using fluorescent dyes Hoechst 33258 (a minor groove binder), ethidium bromide (an intercalator) and a major groove binding cation (cobalt (III) hexammine) which induces the B-->Z transition have been employed to determine the binding geometries of the enantiomers of two methylated helicates (L(3) and L(5)) to DNA and compare with the data obtained previously for the unmethylated analogue (L(1)). The results demonstrate that the racemic mixtures and the resolved enantiomers of all helicates bind to DNA inducing structural changes. The overall conclusion from the effect of adding these groups to the surface of the parent helicate is that increasing the width (L(3)) reduces the DNA binding strength, the bending and coiling effect and the groove selectivity of the enantiomers compared with the parent compound. There is limited evidence to suggest a slight GC sequence preference. Lengthening the helicate (L(5)) results in DNA interactions similar to those of the parent compounds, with an increased preference of the P enantiomer for the minor groove indicating an enhancement of mode selectivity. PMID- 17719089 TI - Mast cells and nerves tickle in the tummy: implications for inflammatory bowel disease and irritable bowel syndrome. AB - Mast cells are well known as versatile cells capable of releasing and producing a variety of inflammatory mediators upon activation and are often found in close proximity of neurons. In addition, inflammation leads to local activation of neurons resulting in the release neuropeptides, which also play an important immune modulatory role by stimulation of immune cells. In intestinal disorders like inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), the number of mast cells is known to be much higher than in the normal intestine. Moreover, both these disorders are also reported to be associated with alterations in neuropeptide content and in neural innervation. Mutual association between mast cells and enteric nerves has been demonstrated to be increased in pathophysiological conditions and contribute to spreading and amplification of the response in IBD and IBS. In this review the focus lies on studies appointed to the direct interaction between mast cells and nerves in IBD, IBS, and animal models for these disorders so far. PMID- 17719090 TI - Cellular composition of human glial cultures from adult biopsy brain tissue. AB - Microglia and astrocytes play vital roles in normal human brain function and in neurological disorders. To study their physiological and pathological roles it is desirable to establish in vitro systems that are derived from the adult human brain. Although several groups have successfully cultured cells from the human brain, the composition of these cultures remains controversial. Using morphological criteria, immunocytochemical analysis and a BrdU incorporation assay we demonstrate the presence of poorly proliferative microglia and astrocytes in cultures derived from epilepsy biopsy tissue. In addition, we characterized a third cell type as fibronectin and prolyl 4-hydroxylase immunopositive fibroblast-like cells, which are highly proliferative and become the predominant cell type after successive sub-culturing. Therefore, although cultures from adult human brain tissue provide an excellent resource for studying human glial cells, careful consideration must be given to their cellular composition when performing studies using these methods. PMID- 17719091 TI - Automation of the novel object recognition task for use in adolescent rats. AB - The novel object recognition task is gaining popularity for its ability to test a complex behavior which relies on the integrity of memory and attention systems without placing undue stress upon the animal. While the task places few requirements upon the animal, it traditionally requires the experimenter to observe the test phase directly and record behavior. This approach can severely limit the number of subjects which can be tested in a reasonable period of time, as training and testing occur on the same day and span several hours. The current study was designed to test the feasibility of automation of this task for adolescent rats using standard activity chambers, with the goals of increased objectivity, flexibility, and throughput of subjects. PMID- 17719092 TI - Does schizoaffective disorder really exist? A systematic review of the studies that compared schizoaffective disorder with schizophrenia or mood disorders. AB - BACKGROUND: Since its first definition in the literature, schizoaffective disorder (SAD) has raised a considerable controversy regarding its clinical distinction from schizophrenia (SCH) and mood disorders (MD) as well as its validity as an independent nosological category. OBJECTIVE: Investigate the validity of SAD as a discrete nosological category and its relationship with SCH and MD. METHOD: A systematic literature review of clinical trial that compared SAD with SCH and/or MD patients was carried out throughout MEDLINE, psycINFO, Cochrane Library, SCIELO and LILACS databases. RESULTS: Evaluation of demographic characteristics, symptomatology, other clinical data, dexamethasone suppression test, neuroimage exams, response to treatment, evolution and family morbidity indicated that SAD occupies an intermediate position between SCH and MD. Literature review also failed to indicate a clear cut distinction between SAD and SCH or MD. DISCUSSION: Present analysis indicated that SAD cannot be interpreted as atypical forms of SCH or MD. SAD also does not appear to represent a SCH and MD comorbidity or yet an independent mental disorder. It is argued that SAD might constitute a heterogeneous group composed by both SCH and MD patients or a middle point of a continuum between SCH and MD. PMID- 17719093 TI - The case for extrathymic development of vaginal T lymphocytes. AB - The vaginal tract mucosa is populated by a small, yet phenotypically diverse and functionally significant, subset of T cells that plays a major role in local cell mediated immunity. Although phenotypic and functional characteristics of vaginal T cells have received some attention in recent years, little is known about the development of this cell population. In this mini review, the developmental origins of vaginal T cells are traced from published work related to vaginal T cells, the vaginal mucosa environment and vaginal tract infection animal models. A CD3(+)TCR(+)CD2(+)CD5(+)B220(-) (CD3(+)B220(-)) subpopulation, which is mostly CD4(+), makes up 30-40% of vaginal T lymphocytes. This population consists of a TCRalphabeta(+) subset and TCRgammadelta(+) subset. While CD3(+)B220( )TCRalphabeta(+) vaginal T cells exhibit phenotypic and functional properties consistent with that of peripheral T cells, CD3(+)B220(-)TCRgammadelta(+) vaginal T cells exhibit unique phenotypic and functional features that set them apart from other TCRgammadelta(+) T cell subsets populating the periphery or other mucosal areas. The vaginal mucosa is populated also by CD3(+)TCRalphabeta(+)CD4( )/8(-)B220(+)CD2(-)CD5(-) T cells (CD3(+)B220(+)) whose relative predominance increases significantly in systemic T cell deficiency. This subset is generally unresponsive to TCR-mediated stimuli and expresses high levels of CD25, perhaps indicative of a regulatory role. Current data suggest that, while CD3(+)B220(-) vaginal T cells are mostly thymic in origin, CD3(+)TCRalphabeta(+)B220(+) cells are exclusively extrathymic. PMID- 17719094 TI - Increased urinary excretion of biopyrrins, oxidative metabolites of bilirubin, in patients with schizophrenia. AB - During periods of psychological stress, excess amounts of free radicals are produced, and they play an important role in the pathophysiological process. Bilirubin oxidative metabolites, biopyrrins, are generated from bilirubin as a result of this scavenging action against free radicals. We investigated whether the urinary excretion of biopyrrin is altered during the psychotic state in patients with schizophrenia. Biopyrrin concentrations in urine of 15 patients with schizophrenia and 100 age-matched healthy subjects were measured by enzyme linked immunosorbent assay with an anti-bilirubin antibody. Urine samples were obtained from the patients on first admission (acute state), 1 month after admission (sub-acute state), and on discharge (remission state). Urinary concentrations of biopyrrins in patients with schizophrenia on admission were significantly higher than those in the controls. Response to treatment was associated with a significant decrease in the concentrations of biopyrrins. Moreover, urinary concentrations of biopyrrins were still significantly higher in patients with schizophrenia in the sub-acute and remission states than in the controls. These results demonstrated an increase in urinary biopyrrins in patients with schizophrenia and a decrease with recovery from the psychotic state. These findings indicate that the urinary biopyrrin level is a possible indicator that can be useful in the continuous monitoring of psychotic states in clinical practice. PMID- 17719095 TI - Adipose tissue macrophages. AB - It is now broadly accepted that low-grade chronic inflammation associated with obesity leads to the onset of insulin resistance and type 2 diabetes mellitus. Obesity-associated inflammation is characterized by an increased abundance of macrophages in adipose tissue along with production of inflammatory cytokines. Adipose tissue macrophages (ATMs) are suspected to be the major source of inflammatory mediators such as TNF-alpha and IL-6 that interfere with adipocyte function by inhibiting insulin action. However, ATMs phenotypically resemble alternatively activated (M2) macrophages and are capable of anti-inflammatory mediator production challenging the concept that ATMs are simply the "bad guys" in obese adipose tissue. Triggers promoting ATM recruitment, ATM functions and dysfunctions, and stimuli and molecular mechanisms that drive them into becoming detrimental to their environment are subject to current research. Strategies to interfere with ATM recruitment and adverse activation could give rise to novel options for treatment and prevention of insulin resistance and type 2 diabetes mellitus. PMID- 17719096 TI - Benefits and costs of universal hearing screening programme. AB - Hearing loss affects 1-3 out of 1000 newborns. A programme of universal newborn hearing screening (UNHS) was implemented in our ENT department in February 2000. In 2001, the programme was extended to all the hospitals of the canton Geneva. The programme is based on the recording of transient evoked otoacoustic emissions (TEOAE) from all newborns. In addition, automated auditory brainstem responses (aABR) are recorded in high-risk neonates. In the report, we compare the mean age at which rehabilitation of hearing was undertaken during a 5-year period before and after the screening programme was instituted. We also identify some causes of delayed diagnosis and intervention and the pitfalls of universal hearing screening. The price of the UNHS programme is estimated at 26 Swiss francs (17 Euros; 21 US dollars) per infant screened, including the material required, the personal involved to run the programme, and the follow-up. PMID- 17719097 TI - A carboxymethyl-cellulose plaque assay for feline calicivirus. AB - The standardization of a plaque assay for feline calicivirus in Crandell Reese feline kidney cells using carboxymethyl-cellulose as an overlay medium is described in this report. This methodology gives comparable counts as compared to the standard assay, and prevents monolayer roll over and peel off, as well as easy medium removal. Cell fixation and staining is performed in a considerably reduced period of time, compared to agarose-based methods. PMID- 17719098 TI - Numerical taxonomy of the genus Pestivirus based on palindromic nucleotide substitutions in the 5' untranslated region. AB - The palindromic nucleotide substitutions (PNS) at the three variable loci (V1, V2 and V3) in the 5' untranslated region (UTR) of Pestivirus RNA have been considered for taxonomical segregation of species, through the evaluation of 430 genomic sequences. On the basis of qualitative and quantitative secondary structure characteristics, six species have been identified: Bovine viral diarrhea virus 1 (BVDV-1), Bovine viral diarrhea virus 2 (BVDV-2), Classical swine fever virus (CSFV), Border disease virus (BDV), the tentative species Giraffe and a new proposed taxon named Pronghorn. The first step was qualitative and consisted in the characterization of the different positions of the three stems and loops in the 5' UTR sequences of all the strains under consideration belonging to the genus. Secondary structure sequences showing divergent base-pair combinations have been aligned for comparison. Palindromic positions have been characterized according to changes in nucleotide base-pairs identifying low variable positions (LVP) including base-pairs present in less than 80% of the genus. The second step was quantitative, allowing the identification of genomic groups by clustering the base-pair combinations according to LVP. Relatedness among types was evaluated to identify homogeneous groups. Cross comparisons between types within the genus have been evaluated by computing the divergence percentage thus clarifying borderline and multirelated sequences. PMID- 17719099 TI - Individual differences in the attribution of incentive salience to a reward related cue: influence on cocaine sensitization. AB - When a discrete cue (a "sign") is presented repeatedly in anticipation of a food reward the cue can become imbued with incentive salience, leading some animals to approach and engage it, a phenomenon known as "sign-tracking" (the animals are sign-trackers; STs). In contrast, other animals do not approach the cue, but upon cue presentation go to the location where food will be delivered (the goal). These animals are known as goal-trackers (GTs). It has been hypothesized that individuals who attribute excessive incentive salience to reward-related cues may be especially vulnerable to develop compulsive behavioral disorders, including addiction. We were interested, therefore, in whether individual differences in the propensity to sign-track are associated with differences in responsivity to cocaine. Using an autoshaping procedure in which lever (conditioned stimulus) presentation was immediately followed by the response-independent delivery of a food pellet (unconditioned stimulus), rats were first characterized as STs or GTs and subsequently studied for the acute psychomotor response to cocaine and the propensity for cocaine-induced psychomotor sensitization. We found that GTs were more sensitive than STs to the acute locomotor activating effects of cocaine, but STs showed a greater propensity for psychomotor sensitization upon repeated treatment. These data suggest that individual differences in the tendency to attribute incentive salience to a discrete reward-related cue, and to approach and engage it, are associated with susceptibility to a form of cocaine-induced plasticity that may contribute to the development of addiction. PMID- 17719100 TI - Cryptosporidium parvum glycoprotein gp40 localizes to the sporozoite surface by association with gp15. AB - Cryptosporidium spp. are waterborne apicomplexan parasites responsible for outbreaks of diarrheal disease worldwide. Antigens involved in zoite invasion into host cells have been the focus of many investigations as these may prove to be good vaccine candidates. gp40/15 is a zoite antigen synthesized as a precursor protein and proteolytically cleaved into the mature glycoproteins, gp40 and gp15. gp15 is anchored in the sporozoite membrane by a glycosylphosphatidyl inositol moiety, while gp40 is predicted to be soluble. However, gp40 bears epitopes that recognize a host cell receptor. If this interaction is important for zoite invasion, then gp40 must have some mechanism of associating with the parasite membrane. In these studies we demonstrate that gp40 and gp15 co-localize to the surface membrane of sporozoites and merozoites, and co-immunoprecipitate, suggesting that these antigens associate after proteolytic cleavage to generate a protein complex capable of linking zoite and host cell surfaces. PMID- 17719101 TI - Phosphatidylinositol 4,5-bisphosphate enhances store-operated calcium entry through hTRPC6 channel in human platelets. AB - Phosphatidylinositol 4,5-bisphosphate (PIP2) is a versatile regulator of TRP channels. We report that inclusion of a PIP2 analogue, PIP2 1,2-dioctanoyl, does not induce non-capacitative Ca2+ entry per se but enhanced Ca2+ entry stimulated either by thrombin or by selective depletion of the Ca2+ stores in platelets, the dense tubular system, using 10 nM TG, and the acidic stores, using 20 microM 2,5 di-(tert-butyl)-1,4-hydroquinone (TBHQ). Reduction of PIP2 levels by blocking PIP2 resynthesis with Li+ or introducing a monoclonal anti-PIP2 antibody, or sequestering PIP2 using poly-lysine, attenuated Ca2+ entry induced by thrombin, TG and TBHQ, and reduced thrombin-evoked, but not TG- or TBHQ-induced, Ca2+ release from the stores. Incubation with the anti-hTRPC1 antibody did not alter the stimulation of Ca2+ entry by PIP2, whilst introduction of anti-hTRPC6 antibody directed towards the C-terminus of hTRPC6 reduced Ca2+ and Mn2+ entry induced by thrombin, TG or TBHQ, and abolished the stimulation of Ca2+ entry by PIP2. The anti-hTRPC6 antibody, but not the anti-hTRPC1 antibody or PIP2, reduced non-capacitative Ca2+ entry by the DAG analogue 1-oleoyl-2-acetyl-sn-glycerol. In summary, hTRPC6 plays a role both in store-operated and in non-capacitative Ca2+ entry. PIP2 enhances store-operated Ca2+ entry in human platelets, most probably by stimulation of hTRPC6 channels. PMID- 17719102 TI - Octogenarians on hemodialysis: a prospective study. AB - Octogenarians represent the fastest growing group of patients on hemodialysis. These patients were previously treated with conservative measures, while they were believed to have too poor prognosis on renal replacement therapy. We investigated clinical characteristics and outcome of patients prospectively after at least 2 years of follow-up. Six male and six female patients who were older than 80 years at the start of hemodialysis were followed up. Their clinical characteristics, comorbidities, etiology of renal disease, nutritional status, complications, vascular access, hospitalizations, compliance and outcome were recorded. The primary renal disease was unknown in 42.8% of patients. All patients had one or more comorbid conditions. Dialysis was initiated in an emergency situation in 64.3%. Vascular access was long-term hemodialysis catheter in 71.4%. Only 14.2% of them received erythropoietin. There were no major bleedings with reduced doses of heparin. The most common complications were catheter-related ones (infections, ruptures). All patients together required seven hospitalizations per year (0.58 per patient). The octogenarians tended to be underdialyzed with the mean adequacy of dialysis (Kt/V) 0.92. The 1-year survival was 71.4%, and 2-year survival was 50%, i.e., they had good survival on hemodialysis. Most of them died from causes that were not related to the uremia. Their treatment requires a careful planning of renal service expansion while more octogenarians who need renal replacement treatment may be expected. PMID- 17719103 TI - Effects of white European, African Caribbean and South Asian ethnicity on homocysteine levels in patients with systolic heart failure. AB - BACKGROUND: Patients with heart failure of any cause have elevated homocysteine compared to healthy controls. A number of studies in the UK and other western countries have documented higher levels of homocysteine among South Asian than among White European or African Caribbean subjects both in health and in disease, and have suggested that dietary deficiency of folate is the main cause for the difference. METHODS: Plasma homocysteine, vitamin B(12), and folate levels were measured in a multiethnic UK heart failure clinic population (n=112), and compared to matched control subjects (n=131). RESULTS: Plasma homocysteine levels were significantly higher in heart failure patients than controls (p<0.001), a result that was consistent across all ethnic groups. There was no difference in homocysteine levels by ethnic group in either patients (p=0.898) or controls (p=0.368). There was no significant difference in levels of folate or B(12) among patients or controls. Using a stepwise linear regression model, homocysteine levels in patients and controls were independently associated with age (p<0.001), vitamin B(12) (p<0.001), folate (p<0.001) and healthy control status (p<0.001), but not with gender, ethnicity, diabetes status, smoking status or BNP levels. CONCLUSION: This study does not provide evidence of ethnic differences in homocysteine levels between White European, South Asian, and African Caribbean subjects with systolic heart failure. The lack of difference in levels of folate or B(12) among patients or controls, suggests that homocysteine levels - and differences previously seen between South Asians and other ethnic groups - may be driven by dietary factors. PMID- 17719104 TI - Unusual case of paradoxical multisite embolization in a patient with patent foramen ovale. PMID- 17719106 TI - Restrictive lung disease and cor pulmonale secondary to polyostotic fibrous dysplasia. AB - Polyostotic fibrous dysplasia is a rare benign pathological condition of bone in which proliferation of fibrous and osteoid elements results in expansile deformities of the skeleton. We present a case of polyostotic fibrous dysplasia in a young man in whom the severe deformities of the chest wall and spine produced restrictive lung disease, cor pulmonale and respiratory failure. PMID- 17719105 TI - Right-atrial floating thrombus attached to the interatrial septum with massive pulmonary embolism diagnosed by echocardiography. AB - The presence of a right-atrium thrombus is considered as an unusual form of thromboembolic disease, with a prevalence of 10-18%. Most of them are located in the right-atria. Its mortality is about 45%. Echocardiography is very important to detect them and to control the effectiveness of the treatment, which can be either conservative or surgical. We present a case of a man to show the importance of echocardiography in this pathological diagnosis, what is essential for a right-treatment. PMID- 17719107 TI - Early improvement in cardiac function detected by tissue Doppler and strain imaging after melphalan-dexamethasone therapy in a 51-year old subject with severe cardiac amyloidosis. AB - We report the case of a 51-year old man with symptoms of heart failure due to severe cardiac amyloidosis, in whom treatment with melphalan and dexamethasone yielded significant improvement in clinical status and both systolic and diastolic left ventricular (LV) function over a 12-week follow-up. The improvement in LV performance was detected by Tissue Doppler (TD) and strain analysis, despite no changes in standard indices such as ejection fraction and Doppler pattern of mitral inflow. Color TD-derived myocardial velocity and deformation indices also revealed a reduction in intra-ventricular early diastolic asynchrony after therapy. In addition, an improvement in intra ventricular systolic synchrony was detected by strain rate and strain, but not by color TD velocity imaging. These findings suggest that treatment with melphalan and dexamethasone may improve symptoms of heart failure and LV performance in subjects with cardiac amyloidosis, and that TD and particularly strain imaging could represent useful techniques to monitor the effect of therapy on LV function in the follow-up of these patients. PMID- 17719108 TI - Simulation model for evaluation of testing strategies for detection of paratuberculosis in midwestern US dairy herds. AB - We developed a stochastic simulation model to compare the herd sensitivity (HSe) of five testing strategies for detection of Mycobacterium avium subsp. paratuberculosis (Map) in Midwestern US dairies. Testing strategies were ELISA serologic testing by two commercial assays (EA and EB), ELISA testing with follow up of positive samples with individual fecal culture (EAIFC and EBIFC), individual fecal culture (IFC), pooled fecal culture (PFC), and culture of fecal slurry samples from the environment (ENV). We assumed that these dairies had no prior paratuberculosis-related testing and culling. We used cost-effectiveness (CE) analysis to compare the cost to HSe of testing strategies for different within-herd prevalences. HSe was strongly associated with within-herd prevalence, number of Map organisms shed in feces by infected cows, and number of samples tested. Among evaluated testing methods with 100% herd specificity (HSp), ENV was the most cost-effective method for herds with a low (5%), moderate (16%) or high (35%) Map prevalence. The PFC, IFC, EAIFC and EBIFC were increasingly more costly detection methods. Culture of six environmental samples per herd yielded >or=99% HSe in herds with >or=16% within-herd prevalence, but was not sufficient to achieve 95% HSe in low-prevalence herds (5%). Testing all cows using EAIFC or EBIFC, as is commonly done in paratuberculosis-screening programs, was less likely to achieve a HSe of 95% in low than in high prevalence herds. ELISA alone was a sensitive and low-cost testing method; however, without confirmatory fecal culture, testing 30 cows in non-infected herds yielded HSp of 21% and 91% for EA and EB, respectively. PMID- 17719109 TI - Measurement of aggregation properties between probiotics and pathogens: in vitro evaluation of different methods. AB - Aggregation properties of probiotics with pathogens are of importance for both food preservation and therapeutic impact of food on intestinal microbiota. We assessed spectrophotometry, fluorescence and radioactivity techniques to characterize and quantify co-aggregation. Probiotic strains tested showed co aggregation abilities, which were strain-specific and dependent on time and incubation conditions. Co-aggregation may be useful for preliminary screening in order to identify potentially probiotic strains suitable for food, human or animal use. PMID- 17719110 TI - Is FDG-PET scan in patients with early stage Hodgkin lymphoma of any value in the implementation of the involved-node radiotherapy concept and dose painting? AB - BACKGROUND AND PURPOSE: To evaluate the input of FDG-PET data in the implementation of the involved-node radiotherapy concept and dose painting. MATERIALS AND METHODS: Patients with early-stage Hodgkin lymphoma treated with combined modality treatments. First, patients underwent a PET/CT before chemotherapy in the treatment position using a head and shoulder immobilization mask. Second, all patients had a CT simulation for treatment planning. The CT simulation was coregistered with the prechemotherapy CT and FDG-PET scan. All prechemotherapy volumes were superimposed on the CT simulation. The initially involved lymph node areas to be irradiated were delineated on the CT simulation scan. Chemotherapy-induced shrinkage rates of the tumor masses visible on CT scan and on FDG-PET were determined and compared. RESULTS: Before chemotherapy, FDG PET-avid areas represented 25% of the total volume on CT. After chemotherapy, the influence of initial FDG-PET data on the delineation of involved-node radiotherapy fields was significant and was due to the fact that in 36% of the patients, FDG-PET helped pinpoint lymph nodes that were undetected on CT. After chemotherapy, the rates of tumor volume shrinkage on CT and FDG-PET were similar. This finding suggests similar chemosensitivity for FDG-PET-avid and non-avid areas. There was no correlation between initial FDG-PET-avid volumes and the clinical outcome. CONCLUSION: Prechemotherapy FDG-PET data are essential for correctly implementing the involved-node radiotherapy concept but seem to be of minimal value for applying the concept of dose painting. PMID- 17719111 TI - Treatment planning comparison of electron arc therapy and photon intensity modulated radiotherapy for Askin's tumor of chest wall. AB - BACKGROUND AND PURPOSE: A dosimetric study to quantitatively compare radiotherapy treatment plans for Askin's tumor using Electron Arc (EA) vs. photon Intensity Modulated Radiotherapy (IMRT). MATERIALS AND METHODS: Five patients treated with EA were included in this study. Treatment plans were generated for each patient using EA and IMRT. Plans were compared using dose volume histograms (DVH) of the Planning Target Volume (PTV) and Organs at Risk (OAR). RESULTS: IMRT resulted in superior PTV coverage, and homogeneous dose distribution compared to EA. For EA, 92% of the PTV was covered to 85% of the dose compared to IMRT in which 96% was covered to 95% of the dose. V(107) that represents the hot spot within the PTV was more in IMRT compared to EA: 7.4(+/-2)% vs. 3(+/-0.5)%, respectively. With PTVs located close to the spinal cord (SC), the dose to SC was more with EA, whereas for PTVs located away from the SC, the dose to SC was more with IMRT. The cardiac dose profile was similar to that of SC. Ipsilateral lung received lower doses with IMRT while contralateral lung received higher dose with IMRT compared to EA. For non-OAR normal tissues, IMRT resulted in large volumes of low dose regions. CONCLUSIONS: IMRT resulted in superior PTV coverage and sparing of OAR compared to EA plans. Although IMRT seems to be superior to EA, one needs to keep in mind the volume of low dose regions associated with IMRT, especially while treating young children. PMID- 17719112 TI - Simultaneous recording of EEG and BOLD responses: a historical perspective. AB - Electromagnetic fields as measured with electroencephalogram (EEG) are a direct consequence of neuronal activity and feature the same timescale as the underlying cognitive processes, while hemodynamic signals as measured with functional magnetic resonance imaging (fMRI) are related to the energy consumption of neuronal populations. It is obvious that a combination of both techniques is a very attractive aim in neuroscience, in order to achieve both high temporal and spatial resolution for the non-invasive study of cognitive brain function. During the last decade a number of research groups have taken up this challenge. Here, we review the development of the combined EEG-fMRI approach. We summarize the main data integration approaches developed to achieve such a combination, discuss the current state-of-the-art in this field and outline challenges for the future success of this promising approach. PMID- 17719113 TI - Activation of parieto-frontal stream during reaching and grasping studied by positron emission tomography in monkeys. AB - The whole brain activation during visually guided reaching and grasping behaviors was investigated in three macaque monkeys using positron emission tomography (PET) scanning with [(15)O]H(2)O. Activation was consistently observed in the parietal regions such as PO, MIP, VIP, LIP and AIP, frontal regions such as PMd, M1 and S1 on the contralateral hemisphere and in the ipsilateral intermediate and lateral deep cerebellar nuclei. Activation was also observed in the areas representing the central and peripheral visual field in the early visual cortices. Thus, the visuo-motor processing, including parieto-frontal stream, involved in the control of visually guided reaching and grasping behaviors could be visualized for the first time in macaque monkeys. PMID- 17719114 TI - Mycotoxins in edible tree nuts. AB - Tree nuts (almonds, pistachios, and walnuts) are an exceptionally valuable crop, especially in California, with an aggregate value approaching $3.5 billion. Much of this economic value comes from overseas markets, with up to 60% of the crop being exported. The product can be contaminated with aflatoxins or ochratoxins, with the former being of special concern because of the strict regulatory levels (4 ppb total aflatoxins) applied by the European Community (EC). Natural, consumer-acceptable control methods are therefore required to conform to such limits. Research has shown that aflatoxin production is markedly decreased by the presence of natural antioxidants that occur in tree nuts, including hydrolysable tannins, flavonoids and phenolic acids. In vitro testing of individual compounds showed that the antiaflatoxigenic effect correlated with the structure and concentration of such compounds in individual nut varieties and species. This lead to the hypothesis that aflatoxin biosynthesis is stimulated by oxidative stress on the fungus and that compounds capable of relieving oxidative stress should therefore suppress or eliminate aflatoxin biosynthesis. Oxidative stress induced in A. flavus by addition of tert-butyl hydroperoxide to the media stimulated peak aflatoxin production and maintained high levels over time. However, aflatoxin formation was significantly inhibited by incorporation into the media of the antioxidant, tannic acid. Measures to increase natural products with antioxidant properties in tree nuts may thereby reduce or eliminate the ability of A. flavus to biosynthesize aflatoxins, thus ensuring levels at or below regulatory limits and maintaining export markets for U.S. tree nuts. PMID- 17719115 TI - Some major mycotoxins and their mycotoxicoses--an overview. AB - Mycotoxins likely have existed for as long as crops have been grown but recognition of the true chemical nature of such entities of fungal metabolism was not known until recent times. Conjecturally, there is historical evidence of their presence back as far as the time reported in the Dead Sea Scrolls. Evidence of their periodic, historical occurrence exists until the recognition of aflatoxins in the early 1960s. At that time mycotoxins were considered as a storage phenomenon whereby grains becoming moldy during storage allowed for the production of these secondary metabolites proven to be toxic when consumed by man and other animals. Subsequently, aflatoxins and mycotoxins of several kinds were found to be formed during development of crop plants in the field. The determination of which of the many known mycotoxins are significant can be based upon their frequency of occurrence and/or the severity of the disease that they produce, especially if they are known to be carcinogenic. Among the mycotoxins fitting into this major group would be the aflatoxins, deoxynivalenol, fumonisins, zearalenone, T-2 toxin, ochratoxin and certain ergot alkaloids. The diseases (mycotoxicoses) caused by these mycotoxins are quite varied and involve a wide range of susceptible animal species including humans. Most of these diseases occur after consumption of mycotoxin contaminated grain or products made from such grains but other routes of exposure exist. The diagnosis of mycotoxicoses may prove to be difficult because of the similarity of signs of disease to those caused by other agents. Therefore, diagnosis of a mycotoxicoses is dependent upon adequate testing for mycotoxins involving sampling, sample preparation and analysis. PMID- 17719116 TI - High-throughput SNP genotyping based on solid-phase PCR on magnetic nanoparticles with dual-color hybridization. AB - Single-nucleotide polymorphisms (SNPs) are one-base variations in DNA sequence that can often be helpful when trying to find genes responsible for inherited diseases. In this paper, a microarray-based method for typing single nucleotide polymorphisms (SNPs) using solid-phase polymerase chain reaction (PCR) on magnetic nanoparticles (MNPs) was developed. One primer with biotin-label was captured by streptavidin coated magnetic nanoparticles (SA-MNPs), and PCR products were directly amplified on the surface of SA-MNPs in a 96-well plate. The samples were interrogated by hybridization with a pair of dual-color probes to determine SNP, and then genotype of each sample can be simultaneously identified by scanning the microarray printed with the denatured fluorescent probes. The C677T polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene from 126 samples were interrogated using this method. The results showed that three different genotypes were discriminated by three fluorescence patterns on the microarray. Without any purification and reduction procedure, and all reactions can be performed in the same vessel, this approach will be a simple and labor-saving method for SNP genotyping and can be applicable towards the automation system to achieve high-throughput SNP detection. PMID- 17719117 TI - Inactivating FruR global regulator in plasmid-bearing Escherichia coli alters metabolic gene expression and improves growth rate. AB - The introduction of plasmids into Escherichia coli is known to impose a metabolic burden, which diminishes the growth rate. This effect could arise from perturbation of the central metabolic pathways, which supply precursors and energy for macromolecule synthesis. We knocked out a global regulator of central metabolism, FruR (also called Cra), to assess its phenotypic effect in E. coli carrying plasmids. During bioreactor runs, a higher specific growth rate of 0.91h(-1) was observed for the plasmid-bearing fruR knockout (P+ fruR) cells compared to its parental plasmid-bearing wildtype (P+ WT) cells (0.75h(-1)), while both the plasmid-free cells displayed similar growth rates (1.0h(-1), respectively). To investigate gene expression changes possibly related to the growth rate recovery, quantitative reverse transcriptase PCR and 2DE proteomic studies were performed. In P+ fruR cells, expression of enzymes involved in sugar catabolism, glycolysis and transcription/translation processes were upregulated, while those related to gluconeogenesis, tricarboxylic acid cycle and stress response were downregulated. Our findings demonstrate that the inactivation of FruR global regulator in recombinant E. coli alters metabolic gene expression and significantly reduces growth retardation from the burden of maintaining a plasmid. This study represents the first attempt to explore the role of a global regulatory gene on plasmid metabolic burden. PMID- 17719118 TI - Phylogenetic comparison of the S10 genes of recent isolates of bluetongue virus from the United States and French Martinique Island. AB - The sequences of the S10 genes of 28 recent isolates (1994-2004) of bluetongue virus (BTV) from the United States (US) and French Martinique Island (2006) in the Caribbean Basin were compared in phylogenetic analyses to those of viruses previously isolated in the same regions. Although the analyses segregated the recent virus isolates from the two regions into distinct topotype clusters, the analyses also confirm that viruses from the US and the Caribbean Basin/Central America can share similar S10 genes despite the fact that distinct constellations of BTV serotypes occur in the two regions. PMID- 17719120 TI - In situ-forming hydrogels for sustained ophthalmic drug delivery. AB - Ophthalmic drug delivery is one of the most interesting and challenging endeavors facing the pharmaceutical scientist. The conventional ocular drug delivery systems like solutions, suspensions, and ointments show drawbacks such as increased precorneal elimination, high variability in efficiency, and blurred vision respectively. In situ-forming hydrogels are liquid upon instillation and undergo phase transition in the ocular cul-de-sac to form visco-elastic gel and this provides a response to environmental changes. In the past few years, an impressive number of novel temperature, pH, and ion induced in situ-forming systems have been reported for sustain ophthalmic drug delivery. Each system has its own advantages and drawbacks. The choice of a particular hydrogel depends on its intrinsic properties and envisaged therapeutic use. This review includes various temperature, pH, and ion induced in situ-forming polymeric systems used to achieve prolonged contact time of drugs with the cornea and increase their bioavailability. PMID- 17719121 TI - Evolutionary impact of limited splicing fidelity in mammalian genes. AB - The functional significance of most alternative splicing (AS) events, especially frame-shifting ones, has been controversial. Using human-mouse comparison, we demonstrate that frame-preserving AS events adapt and get fixed more rapidly than frame-shifting AS events; selection for smaller exon size is stronger in frame preserving exons than in frame-shifting ones. These results suggest AS events introducing mild changes are generally favored during evolution and explain the excess of shorter, frame-preserving cassette exons in present mammalian genomes. PMID- 17719122 TI - Ultrasonographic feature selection and pattern classification for cervical lymph nodes using support vector machines. AB - A rough margin based support vector machine (RMSVM) classifier was proposed to improve the accuracy of ultrasound diagnoses for cervical lymph nodes. Thirty-six features belonging to 10 kinds of ultrasonographic characteristics were extracted for each of 110 lymph nodes in ultrasonograms. Comparison studies were done for three classifiers--the classical support vector machine (SVM), the general regression neural network and the proposed RMSVM, with or without the feature selection by the recursive feature elimination (RFE) algorithm, respectively, based on SVMs and the mean square error discriminant. It was indicated by experimental results that all classifiers benefited from the feature selection. The best classification performance was obtained by the RMSVM using thirteen features selected by the RMSVM based RFE, which yielded the normalized area under the receiver operating characteristic curve (A(z)) of 0.859. Compared with the radiologist's performance of A(z) of 0.787, the developed computer-aided diagnosis algorithm has the potential to improve the diagnostic accuracy. PMID- 17719123 TI - KnowBaSICS-M: an ontology-based system for semantic management of medical problems and computerised algorithmic solutions. AB - In this paper, an ontology-based system (KnowBaSICS-M) is presented for the semantic management of Medical Computational Problems (MCPs), i.e., medical problems and computerised algorithmic solutions. The system provides an open environment, which: (1) allows clinicians and researchers to retrieve potential algorithmic solutions pertinent to a medical problem and (2) enables incorporation of new MCPs into its underlying Knowledge Base (KB). KnowBaSICS-M is a modular system for MCP acquisition and discovery that relies on an innovative ontology-based model incorporating concepts from the Unified Medical Language System (UMLS). Information retrieval (IR) is based on an ontology-based Vector Space Model (VSM) that estimates the similarity among user-defined MCP search criteria and registered MCP solutions in the KB. The results of a preliminary evaluation and specific examples of use are presented to illustrate the benefits of the system. KnowBaSICS-M constitutes an approach towards the construction of an integrated and manageable MCP repository for the biomedical research community. PMID- 17719124 TI - np1: a computer program for dose escalation strategies in phase I clinical trials. AB - The continual reassessment method is a recommended dose escalation design for including patients in phase I clinical trials designed to estimate the maximum tolerated dose. However, for a particular trial, the implementation of these methods requires extensive computer programming. Standard 3+3 designs do not require this, but have shown to possess poor statistical properties. np1 is a user friendly computer program which has implemented two continual reassessment methods for simulating and conducting a phase I clinical trial. Several options allow the user to investigate operating characteristics under various scenarios. PMID- 17719125 TI - Efficient liver segmentation using a level-set method with optimal detection of the initial liver boundary from level-set speed images. AB - Automatic liver segmentation is difficult because of the wide range of human variations in the shapes of the liver. In addition, nearby organs and tissues have similar intensity distributions to the liver, making the liver's boundaries ambiguous. In this study, we propose a fast and accurate liver segmentation method from contrast-enhanced computed tomography (CT) images. We apply the two step seeded region growing (SRG) onto level-set speed images to define an approximate initial liver boundary. The first SRG efficiently divides a CT image into a set of discrete objects based on the gradient information and connectivity. The second SRG detects the objects belonging to the liver based on a 2.5-dimensional shape propagation, which models the segmented liver boundary of the slice immediately above or below the current slice by points being narrow band, or local maxima of distance from the boundary. With such optimal estimation of the initial liver boundary, our method decreases the computation time by minimizing level-set propagation, which converges at the optimal position within a fixed iteration number. We utilize level-set speed images that have been generally used for level-set propagation to detect the initial liver boundary with the additional help of computationally inexpensive steps, which improves computational efficiency. Finally, a rolling ball algorithm is applied to refine the liver boundary more accurately. Our method was validated on 20 sets of abdominal CT scans and the results were compared with the manually segmented result. The average absolute volume error was 1.25+/-0.70%. The average processing time for segmenting one slice was 3.35 s, which is over 15 times faster than manual segmentation or the previously proposed technique. Our method could be used for liver transplantation planning, which requires a fast and accurate measurement of liver volume. PMID- 17719126 TI - Immobilization of uranium and arsenic by injectible iron and hydrogen stimulated autotrophic sulphate reduction. AB - The main object of the study was the development of a long-term efficient and inexpensive in-situ immobilization technology for uranium (U) and arsenic (As) in smaller and decentralized groundwater discharges from abandoned mining processing sites. Therefore, corrosion of grey cast iron (gcFe) and nano-scale iron particles (naFe) as well as hydrogen stimulated autotrophic sulphate reduction (aSR) were investigated. Two column experiments with sulphate reducing bacterias (SRB) (biotic gcFe , biotic naFe) and one abiotic gcFe-column experiment were performed. In the biotic naFe column, no particle translocation was observed and a temporary but intensive naFe corrosion indicated by a decrease in E(h), a pH increase and H(2) evolution. Decreasing sulphate concentrations and (34)S enrichment in the column effluent indicated aSR. Fe(II) retention could be explained by siderite and consequently FeS precipitation by geochemical modeling (PhreeqC). U and As were completely immobilised within the biotic naFe column. In the biotic gcFe column, particle entrapment in open pore spaces resulted in a heterogeneous distribution of Fe-enriched zones and an increase in permeability due to preferential flow. However, Fe(II) concentrations in the effluent indicated a constant and lasting gcFe corrosion. An efficient immobilization was found for As, but not for U. PMID- 17719127 TI - Color homogeneity and visual perception of age, health, and attractiveness of female facial skin. AB - BACKGROUND: Evolutionary psychology suggests that skin signals aspects of mate value, yet only limited empirical evidence exists for this assertion. OBJECTIVES: We sought to study the relationship between perception of skin condition and homogeneity of color/chromophore distribution. METHODS: Cropped skin cheek images from 170 girls and women (11-76 years) were blind-rated for attractiveness, healthiness, youthfulness, and biological age by 353 participants. These skin images and corresponding melanin/hemoglobin concentration maps were analyzed objectively for homogeneity. RESULTS: Homogeneity of unprocessed images correlated positively with perceived attractiveness, healthiness, and youthfulness (all r > 0.40; P < .001), but negatively with estimated age (r = 0.45; P < .001). Homogeneity of hemoglobin and melanin maps was positively correlated with that of unprocessed images (r = 0.92, 0.68; P < .001) and negatively correlated with estimated age (r = -0.32, -0.38; P < .001). LIMITATIONS: Female skin only was studied. CONCLUSIONS: Skin color homogeneity, driven by melanin and hemoglobin distribution, influences perception of age, attractiveness, health, and youth. PMID- 17719128 TI - An in vitro study comparing temperatures of over-the-counter wart preparations with liquid nitrogen. AB - BACKGROUND: Over-the-counter (OTC) wart-freezing therapies have appeared on the market claiming that they reproduce in-office cryotherapy. OBJECTIVE: We sought to determine whether these OTC home wart removal products are as cold as liquid nitrogen. METHODS: The coldness obtained by 3 representative commercial wart products, and liquid nitrogen, was assessed using a thermometer calibrated from 100 degrees C to 50 degrees C. Temperatures of the commercial wart products used were measured and compared with those obtained with liquid nitrogen. RESULTS: None of the OTC coolants were as cold as liquid nitrogen, and they did not lower temperature as quickly as liquid nitrogen. LIMITATIONS: This study did not evaluate the clinical efficacy of any of the agents studied. CONCLUSIONS: Despite advertising messages, OTC refrigerants do not achieve freezing equivalent to liquid nitrogen. PMID- 17719129 TI - Rapid control of an outbreak of vancomycin-resistant enterococci in a French university hospital. AB - Vancomycin-resistant enterococci (VRE) are emerging in French hospitals. A VRE outbreak occurred in our hospital, prompting efforts to eradicate the organism. The following interventions were implemented simultaneously to control the outbreak: (1) creation of a VRE control committee; (2) cohorting of VRE carriers in a dedicated ward; (3) extensive screening of contact patients; (4) use of a sensitive technique for detecting VRE in rectal samples; (5) intervention of a dedicated team to reduce consumption of selected antibiotics; (6) information for, and education of, all hospital staff; and (7) electronic tracking of in hospital transfer and readmission of VRE carriers and contact patients. Over a four-week period following admission of the index case, 37 carriers of a single strain of vanA vancomycin-resistant Enterococcus faecium were identified across seven units. A single additional readmitted contact patient was identified later. Of the 39 VRE-positive patients, two had urinary tract infections and 37 were colonised. Of the 32 patients with known VRE stool concentrations, 23 had low and nine high concentrations. One low-concentration patient precipitated transmission in another unit. This aggressive, co-ordinated, multifaceted strategy was successful in halting a widespread VRE outbreak in our hospital. PMID- 17719130 TI - Prevalence of meticillin resistance among Staphylococcus aureus isolates in Pakistan and its clinical outcome. PMID- 17719131 TI - An in-use microbiological comparison of two surgical hand disinfection techniques in cardiothoracic surgery: hand rubbing versus hand scrubbing. AB - Surgical site infection after heart surgery increases morbidity and mortality. The method of presurgical hand disinfection could influence the infection risk. From February to April 2003, we compared the microbiological efficacy of hand rubbing (R) and hand-scrubbing (S) procedures. The surgical team alternately used hand-scrubbing or hand-rubbing techniques every two weeks. Fingertip impressions were taken before and immediately after hand disinfection, every 2h and at the end of the operation. Acceptability of hand rubbing was assessed by a questionnaire. Mean durations of surgical procedures were 259+/-68 and 244+/ 69min for groups S and R respectively (P=0.43). Bacterial counts immediately after hand disinfection were comparable with the two techniques, but significantly lower in group R at the end of surgery. No differences were observed between the percentages of negative samples taken after 2h, 4h and at the end of surgery between the two groups. Bacterial skin flora reduction immediately after hand disinfection, after 2h and 4h of operating time and at the end of surgery was better in group R, but the difference was not statistically significant. Before surgery, the hand-rubbing method with alcohol solution preceded by hand washing with mild neutral soap is as effective as hand scrubbing to reduce bacterial counts on hands. It decreased the bacterial counts both immediately after hand disinfection and at the end of long cardiothoracic surgical procedures. The acceptability of hand rubbing was excellent and it can be considered to be a valid alternative to the conventional hand-scrubbing protocol. PMID- 17719132 TI - Pseudo-outbreak of Aspergillus keratitis following construction in an ophthalmology ward. PMID- 17719133 TI - Prevention of ventilator-associated pneumonia: analysis of studies published since 2004. AB - As the most recent guidelines for the prevention of ventilator-associated pneumonia (VAP) were published four years ago, we have conducted a systematic review to discover whether the recently published articles should further influence existing guidelines. Articles published since 2004 dealing with infection control measures for prevention of VAP were gathered and evaluated in order to identify evidence for the possible modification of routine practice. Special emphasis was placed on randomized controlled trials (RCTs), meta-analyses or systematic reviews and studies applying multi-module interventions. A total of 15 RCTs and seven meta-analyses or systematic reviews were found. In addition to these, five cohort studies were identified where multi-module programmes were introduced for reducing VAP rates. The data lead to the conclusion that topical use of chlorhexidine for oral care is beneficial and subglottic secretion drainage may lead to delayed onset of VAP. The remaining studies had only a minor influence on existing guidelines for the prevention of VAP and confirmed the earlier recommendations in several points. However, the studies investigating multi-module programmes led to a substantial reduction of VAP of between 31 and 57%. The data show that many VAP cases are preventable and that there is room for improvement in many institutions. Often simple interventions are useful for the reduction of VAP rates, for which the best chances appeared to be the application of multi-module programmes. On average a reduction of more than 40% seems to be possible. PMID- 17719134 TI - Evidence-based emergency medicine. Creating a system to facilitate translation of evidence into standardized clinical practice: a preliminary report. AB - STUDY OBJECTIVE: The Institute of Medicine, through its landmark report concerning errors in medicine, suggests that standardization of practice through systematic development and implementation of evidence-based clinical pathways is an effective way of reducing errors in emergency systems. The specialty of emergency medicine is well positioned to develop a complete system of innovative quality improvement, incorporating best practice guidelines with performance measures and practitioner feedback mechanisms to reduce errors and therefore improve quality of care. This article reviews the construction, ongoing development, and initial impact of such a system at a large, urban, university teaching hospital and at 2 affiliated community hospitals. METHODS: The Committee for Procedural Quality and Evidence-Based Practice was formed within the Department of Emergency Medicine to establish evidence-based guidelines for nursing and provider care. The committee measures the effect of such guidelines, along with other quality measures, through pre- and postguideline patient care medical record audits. These measures are fed back to the providers in a provider specific, peer-matched "scorecard." RESULTS: The Committee for Procedural Quality and Evidence-Based Practice affects practice and performance within our department. Multiple physician and nursing guidelines have been developed and put into use. Using asthma as an example, time to first nebulizer treatment and time to disposition from the emergency department decreased. Initial therapeutic agent changed and documentation improved. CONCLUSION: A comprehensive, guideline driven, evidence-based approach to clinical practice is feasible within the structure of a department of emergency medicine. High-level departmental support with dedicated personnel is necessary for the success of such a system. Internet site development (available at http://www.CPQE.com) for product storage has proven valuable. Patient care has been improved in several ways; however, consistent and complete change in provider behavior remains elusive. Physician scorecards may play a role in altering these phenomena. Emergency medicine can play a leadership role in the development of quality improvement, error reduction, and pay-for-performance systems. PMID- 17719135 TI - Activated charcoal decreases the risk of QT prolongation after citalopram overdose. AB - STUDY OBJECTIVE: We determine whether single-dose activated charcoal (SDAC) administration after citalopram overdose reduces the proportion of patients developing abnormal QT prolongation. METHODS: Data were collected retrospectively for citalopram overdose patients presenting to 8 emergency departments. Demographics, dose, coingested drugs, SDAC administration, and serial ECGs were extracted from medical records. The primary outcome was the proportion of patients who had an observed QT,RR combination at any time above an abnormal threshold, established as a predictor of torsade de pointes. We compared the proportion of patients with QT prolongation who received or did not receive SDAC. These data were analyzed within a Bayesian framework, using probabilities of abnormal QT,RR combinations with and without derived from a previous single center study. WinBUGS was used to generate posterior estimates and credible intervals of the relative risk by combining the prior probabilities and the study data. RESULTS: SDAC was administered on average 2.1 hours (range, 0.5 to 6.25 hours) after ingestion in 48 of 254 admissions, and abnormal QT,RR combinations occurred in 2 cases (4.2%), compared with 23 of 206 (11.2%) cases not receiving SDAC. There did not appear to be any clinically important difference in age, sex, dose, and cardiotoxic coingestants between the 2 groups. No cases of torsade de pointes occurred. The estimated relative risk of having an abnormal QT,RR combination for SDAC compared to no SDAC was 0.28 (0.06 to 0.70) (median with 2.5% and 97.5% credible limits). The probability that the relative risk was less than 1.0 was 0.99, which can be interpreted as very strong evidence in favor of a beneficial effect of SDAC. The absolute risk difference was estimated as 7.5% and the median number needed to treat as 13.3. CONCLUSION: SDAC may be effective in reducing the risk of a prolonged QT in patients after citalopram overdose. Current trends toward nonuse of activated charcoal should be evaluated to determine whether patients poisoned by specific agents may benefit from activated charcoal administration. PMID- 17719136 TI - The physiologic effects of a conducted electrical weapon in swine. AB - STUDY OBJECTIVE: By using an animal model, we determine whether repeated exposures to a conducted electrical weapon could have physiologic consequences. METHODS: Exposures to the Stinger S-400 conducted electrical weapon were applied to 10 healthy, anesthetized, Yorkshire-cross, male swine by attaching probes from the cartridge to the sternal notch and anterolateral thorax at a distance of 21.5 cm. The standard pulse generated by the Stinger S-400 during the normal application was applied 20 times during 31 minutes. To evaluate the health effects of the exposures, key physiologic characteristics were evaluated, including arterial pH, PCO2, PO2, blood lactate, cardiac output, ECG, pulse rate, mean arterial pressure, central venous pressure, pulmonary artery pressure and airway pressure, and the cardiac marker troponin I. RESULTS: There were notable changes in pH, PCO2, blood lactate, cardiac output, and mean arterial pressure after 1 or more sets of exposures, all of which normalized during the next few hours. Troponin I, PO2, pulse rate, mean arterial pressure, central venous pressure, pulmonary artery pressure, and airway pressure did not change markedly during or after the shocks. Three premature ventricular contractions occurred in one animal; all other ECG results were normal. CONCLUSION: Repeated exposures to a conducted electrical weapon result in respiratory acidosis, metabolic vasodilation, and an increase in blood lactate level. These effects were transient in this study, with full recovery by 4 hours postexposure. The Stinger S-400 appears to have no serious adverse physiologic effects on healthy, anesthetized swine. PMID- 17719138 TI - Synergistic activation of the human adrenomedullin gene promoter by Sp1 and AP 2alpha. AB - Adrenomedullin (AM) is a potent vasodilator peptide, which is ubiquitously expressed and has various biological actions, such as proliferative action and anti-oxidative stress action. AM expression is induced by various stresses, such as hypoxia and inflammatory cytokines, and during cell differentiation. The human AM gene promoter region (-70/-29) contains binding sites for stimulatory protein 1 (Sp1) and activator protein-2alpha (AP-2alpha), and has been shown to be important for the AM gene expression during cell differentiation to macrophages or adipocytes. We here show that Sp1 and AP-2alpha synergistically activate the AM gene promoter. Co-transfection of the reporter plasmid containing the AM promoter region (-103/-29) with Sp1 and AP-2alpha expression plasmids showed that Sp1 and AP-2alpha synergistically increased the promoter activity in HeLa cells. Sp1 or AP-2alpha alone caused only small increases in the promoter activity. EMSA showed that Sp1 bound to the promoter region (-70/-29), whereas AP-2alpha bound to a more upstream promoter region (-103/-71). Thus, the synergistic activation of the human AM gene promoter by Sp1 and AP-2alpha may be mediated by the binding of Sp1 to the promoter region (-70/-29) and the interaction with AP-2alpha, which binds to the promoter region (-103/-71). PMID- 17719137 TI - Alpha-melanocyte stimulating hormone and ghrelin: central interaction in feeding control. AB - Alpha-melanocyte stimulating hormone (alpha-MSH) and ghrelin play significant yet opposite roles in the regulation of feeding: alpha-MSH inhibits, whereas ghrelin stimulates consumption. The two peptidergic systems may interact in the process of food intake control. A single report published thus far has shown that a synthetic agonist of the melanocortin receptors, MTII, injected in the hypothalamic paraventricular nucleus (PVN) decreases feeding generated by ghrelin. We found that very low doses of alpha-MSH and MTII administered ICV significantly reduced ghrelin-dependent hyperphagia. However, an endogenous molecule, alpha-MSH, infused in the PVN did not exert an inhibitory effect on ghrelin-induced consumption, whereas the effective dose of PVN MTII exceeded that necessary to decrease short-term deprivation-induced feeding. We conclude that it is likely that in feeding regulation alpha-MSH and ghrelin "interact" at the central nervous system level, but the involvement of the PVN in this interaction appears questionable. PMID- 17719139 TI - Beta-endorphin levels in longtailed and pigtailed macaques vary by abnormal behavior rating and sex. AB - Frequent or severe abnormal behavior may be associated with the release of endorphins that positively reinforce the behavior with an opiate euphoria or analgesia. One line of research exploring this association involves the superhormone, proopiomelanocortin (POMC). The products of POMC appear to be dysregulated in some human subjects who exhibit self-injurious behavior (SIB). Macaque monkeys have POMC very similar to humans, and some laboratory macaques display SIB or frequent stereotypies. We investigated associations between plasma levels of three immunoreactive POMC fragments with possible opioid action and abnormal behavior ratings in macaques. In 58 adult male and female macaques (24 Macaca fascicularis and 34 Macaca nemestrina), plasma levels of intact beta endorphin (betaE) and the N-terminal fragment (BEN) were significantly higher in animals with higher levels of abnormal behavior. The C-terminal fragment (BEC) was significantly higher in males but unrelated to ratings of abnormal behavior. Levels of ACTH, cortisol, and (betaE-ACTH)/betaE dysregulation index were unrelated to abnormal behavior. None of the POMC products differed significantly by subjects' species, age, or weight. The finding that intact beta-endorphin is positively related to abnormal behavior in two species of macaque is consistent with some previous research on human subjects and nonprimates. The positive relation of the N-terminal fragment of betaE to abnormal behavior is a new finding. PMID- 17719140 TI - Apelin activates L-arginine/nitric oxide synthase/nitric oxide pathway in rat aortas. AB - Apelin was recently found to be an inotropic polypeptide in isolated rat hearts, and intravenous injection of apelin can induce a transient decrease in blood pressure. To illustrate the mechanism of apelin-induced vasodilation, we observed the in vitro effects of apelin on the L-arginine (L-Arg)/nitric oxide (NO) pathway in the incubated, isolated rat aorta. Apelin stimulated vascular NO(2)(-) product and NOS activation in a concentration- and time-dependent manner. Compared with no apelin treatment, incubation with apelin (10(-9), 10(-8), and 10(-7)mol/L) increased NO(2)(-) product by 33%, 46%, and 69% (all p<0.01), respectively, and Ca(2+)-dependent constitutive NOS (cNOS) activity by 200%, 460%, and 550% (all p<0.01), respectively. However, Ca(2+)-independent NOS (iNOS) activity was not significantly altered (p>0.05). Apelin incubation (10(-9), 10( 8), and 10(-7)mol/L) increased L-Arg uptake by 130%, 180%, and 240% (all p<0.01), respectively. The mRNA level of cationic amino acid transporters, CAT-1 and CAT 2B, in rat aortic tissues treated with 10(-7)mol/L apelin was increased by 110% and 128%, respectively (both p<0.01). Incubation with 10(-7)mol/L apelin elevated eNOS mRNA and protein levels, by 53% (p<0.05) and 319% (p<0.01), respectively. Collectively, these results demonstrate that apelin directly activated the vascular L-Arg/NOS/NO pathway, which could be one of the important mechanisms of apelin-regulated vascular function. PMID- 17719141 TI - Endothelin-1 reduces mesenteric microvascular hydraulic permeability via cyclic AMP and protein kinase A signal transduction. AB - We have previously shown that endothelin-1 (ET-1) decreases microvascular hydraulic permeability. In this study, we tested the hypothesis that ET-1 exerts its permeability-decreasing effect through cAMP, cGMP, and protein kinase A (PKA) by determining the effect of ET-1 on venular fluid leak during inhibition of cAMP synthesis, inhibition of cGMP degredation, and inhibition of PKA. Rat mesenteric venules were cannulated to measure hydraulic permeability, L(p) (units x 10( 7)cm/(s cmH(2)O)). L(p) was measured during continuous perfusion of 80 pM ET-1 and either (1) an inhibitor of cAMP synthesis (10 microM 2',5'ddA), (2) an inhibitor of cGMP degradation (100 microM Zaprinast), or (3) an inhibitor of PKA (10 microM H-89). Inhibition of cAMP synthesis blocked the permeability decreasing effects of ET-1. The peak L(p) of the cAMP inhibitor alone and with ET 1 was 4.11+/-0.53 and 3.86+/-0.19, respectively (p=0.36, n=6). Inhibition of cGMP degradation did not block the permeability decreasing effects of ET-1. The peak L(p) during inhibition of cGMP degradation alone and with ET-1 was 2.26+/-0.15 and 1.44+/-0.09, respectively (p<0.001, n=6). Inhibition of PKA activation blocked the permeability decreasing effects of ET-1. The peak L(p) of the PKA inhibitor alone and with ET-1 was 2.70+/-0.15 and 2.59+/-0.15, respectively (p=0.38, n=6). The data support the notion that the signal transduction mechanism of ET-1 with regard to decreasing microvascular fluid leak involves cAMP production and PKA activation, but not cGMP degradation. Further understanding of intracellular mechanisms that control microvascular fluid leak could lead to the development of a pharmacologic therapy to control third space fluid loss in severely injured or septic patients. PMID- 17719142 TI - CB1-cannabinoid receptors are involved in the modulation of non-synaptic [3H]serotonin release from the rat hippocampus. AB - In the present study we investigated whether serotonin release in the hippocampus is subject to regulation via cannabinoid receptors. Both rat and mouse hippocampal slices were preincubated with [3H]serotonin ([3H]5-HT) and superfused with medium containing serotonin reuptake inhibitor citalopram hydrobromide (300 nM). The cannabinoid receptor agonist R(+)-[2,3-dihydro-5-methyl-3 [(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate (WIN55,212-2, 1 microM) did not affect either the resting or the electrically evoked [3H]5-HT release. In the presence of the ionotropic glutamate receptor antagonists D(-)-2-amino-5-phosphonopentanoic acid (AP-5, 50 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione-disodium (CNQX, 10 microM) the evoked [3H]5-HT release was decreased significantly. Similar findings were obtained when CNQX (10 microM) was applied alone with WIN55,212-2. This effect was abolished by the selective cannabinoid receptor subtype 1 (CB1) antagonists N (piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3 carboxamide (SR141716, 1 microM) and 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4 methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide trifluoroacetate salt (AM251, 1 microM). Similarly to that observed in rats, WIN55,212-2 (1 microM) decreased the evoked [3H]5-HT efflux in wild-type mice (CB1+/+). The inhibitory effect of WIN55,212-2 (1 microM) was completely absent in hippocampal slices derived from mice genetically deficient in CB1 cannabinoid receptors (CB1-/-). Relatively selective degeneration of fine serotonergic axons by the neurotoxin parachloramphetamine (PCA) reduced significantly the tritium uptake and the evoked [3H]5-HT release. In addition, PCA, eliminated the effect of WIN55,212-2 (1 microM) on the stimulation-evoked [3H]5-HT efflux. In contrast to the PCA treated animals, WIN55,212-2 (1 microM) reduced the [3H]5-HT efflux in the saline treated group. Our data suggest that a subpopulation of non-synaptic serotonergic afferents express CB1 receptors and activation of these CB1 receptors leads to a decrease in 5-HT release. PMID- 17719143 TI - Isoflurane anesthesia inhibits clozapine- and risperidone-induced dopamine release and anesthesia-induced changes in dopamine metabolism was modified by fluoxetine in the rat striatum: an in vivo microdialysis study. AB - Previously, we have reported that halothane anesthesia increases the extracellular concentrations of dopamine (DA) metabolites in the rat striatum using in vivo microdialysis techniques, and we have suggested that volatile anesthetics affect DA release and metabolism in various ways. The present investigation assesses the effect of isoflurane, widely used in clinical anesthesia, on DA release and metabolism. A microdialysis probe was implanted in the striatum of male Sprague-Dawley rats (n=5-7 per group). After recovery, the probe was perfused with modified Ringer's solution and 40 microl of dialysate were injected into a high performance liquid chromatograph every 20 min. The rats were given saline or the same volume of 10 mg kg(-1) clozapine, risperidone, fluoxetine or citalopram. After the pharmacological treatment, the rats were anesthetized with 1.0% or 2.5% isoflurane for 1h. The data were analyzed using two-way analysis of variance (ANOVA). For each drug with significant (p<0.05) drug-time interactions, the statistical analysis included one-way ANOVA and Newman-Keuls post hoc comparisons. A high concentration of isoflurane (2.5%) anesthesia increased the extracellular concentration of DA metabolites during emergence from anesthesia. The levels of DA metabolites increased in an isoflurane concentration-dependent manner. Isoflurane attenuated DA release induced by clozapine and risperidone. Fluoxetine, but not citalopram, antagonized the isoflurane-induced increase in metabolites. The results of current investigation suggest that isoflurane enhances presynaptic DA metabolism, and that the oxidation of DA might be partially modulated by the activities of the dopaminergic-serotonergic pathway at a presynaptic site in the rat striatum. PMID- 17719145 TI - A systematic review of brain metabolite changes, measured with 1H magnetic resonance spectroscopy, in healthy aging. AB - BACKGROUND: (1)H MR spectroscopy (MRS) can identify metabolite abnormalities in age-related, neurological diseases. However, there is little information on how metabolites change with healthy aging. METHODS: We systematically reviewed the literature on MRS, from 1980 to 2006, for studies where healthy young subjects (<60 years) were compared to healthy older subjects (>60 years). We extracted metabolite data reported as "no change", "increase" or "decrease" for each metabolite by brain region and, where data were available, meta-analysed mean metabolite concentrations (mM) for young versus old subjects. RESULTS: Eighteen studies met the inclusion criteria (total n=703 subjects, 284 >60 years old). Most data came from the frontal region, and reported "no change" in older subjects; however, a meta-analysis revealed a decrease in frontal NAA (p=0.05) and increases in parietal choline (p=0.003) and creatine (p<0.001). DISCUSSION: These data suggest that NAA may decrease and choline and creatine increase with age. Therefore, more data are needed from older subjects to characterise age effects better and ratios in older subjects should be interpreted with caution. PMID- 17719146 TI - Synthesis and antituberculosis activity of new thiazolylhydrazone derivatives. AB - The increasing clinical importance of drug-resistant mycobacterial pathogens has lent additional urgency to microbiological research and new antimycobacterial compound development. For this purpose, new thiazolylhydrazone derivatives were synthesized and evaluated for antituberculosis activity. The reaction of thiosemicarbazide with acetophenone derivatives gave 1-(1 arylethylidene)thiosemicarbazide (1). The N-(1-arylethylidene)-N'-[4-(indan-5 yl)thiazol-2-yl]hydrazone (3) derivatives were synthesized by reacting 1-(1 arylethylidene)thiosemicarbazide with 1-(5-indanyl)-2-bromoethanone (2). The chemical structure of the compounds was elucidated by elemental analyses, IR, (1)H NMR, MS-FAB(+) spectral data. Antituberculosis activities of the synthesized compounds were determined by broth microdilution assay, the Microplate Alamar Blue Assay, in BACTEC12B medium and the results were screened in vitro, using BACTEC 460 Radiometric System against Mycobacterium tuberculosis H(37)Rv (ATCC 27294) at 6.25 microg/ml and some of the tested compounds showed important inhibition ranging from 92% to 96%. The compounds were also investigated for their cytotoxic properties on normal mouse fibroblast (NIH/3T3) cell line and the results obtained here showed that all the compounds used have no significant cytotoxicity at the concentrations under 50 microg/ml. PMID- 17719144 TI - Age-related influence of the HDL receptor SR-BI on synaptic plasticity and cognition. AB - Dysregulated cholesterol metabolism is a major risk factor for atherosclerosis and other late-onset disorders, such as Alzheimer's disease. The scavenger receptor, class B, type I (SR-BI) is critical in maintaining the homeostasis of cholesterol and alpha-tocopherol. SR-BI binds high-density lipoproteins (HDL) and mediates the selective transfer of cholesteryl esters and alpha-tocopherol from circulating HDL to cells. SR-BI is also involved in reverse cholesterol transport from peripheral tissues into the liver. Previous studies using SR-BI genetic knockout mice indicated that the deletion of SR-BI resulted in an accelerated onset of atherosclerosis. We hypothesized that SR-BI-dependent lipid dysregulation might disrupt brain function leading to cognitive impairment. Here, we report that very old SR-BI knockout mice show deficient synaptic plasticity (long-term potentiation) in the CA1 region of the hippocampus. Very old SR-BI KO mice also display selective impairments in recognition memory and spatial memory. Thus, SR-BI influences neural and cognitive processes, a finding that highlights the contribution of cholesterol and alpha-tocopherol homeostasis in proper cognitive function. PMID- 17719147 TI - Characterization and immunogenicity of meningococcal group C conjugate vaccine prepared using hydrazide-activated tetanus toxoid. AB - The steps to produce, purify and control an immunogenic Brazilian conjugate vaccine against group C meningococcus (MenCPS-TT) using hydrazide-activated tetanus toxoid were developed. The conjugation methodology reduced the reaction time easily allowing scale-up. One freeze-dried pilot vaccine lot purified by tangential filtration, showed satisfactory quality control results including safety and stability. The pilot vaccine was immunogenic in mice in a dose dependent fashion generating a 10-20-fold rise in IgG response in mice. The vaccine also induced high bactericidal titers. Vaccine concentrations of 1 and 0.1 microg showed higher avidity indices, suggesting induction of immunologic memory. These results support initiation of Phase I clinical studies with the MenCPS-TT conjugate vaccine. PMID- 17719148 TI - Control of allergic reactions in mice by an active anti-murine IL-4 immunization. AB - Pathogenesis of allergic inflammatory disorders is characterized by allergen induced IgE stimulated by Th2 cytokines including mainly IL-4 overproduction. To counteract IL-4 effects in sensitized-BALB/c mice, we prepared an IL-4 derivative immunogen, made of KLH and murine IL-4 heterocomplex, termed mIL-4 kinoid. Murine IL-4 kinoid immunized mice produced high titer of anti-IL-4 neutralizing Abs. In contrast to KLH control immunization kinoid immunization reversed the allergic IgE:IgG ratio hallmark in rBet v 1a sensitized mice and reduced pulmonary eosinophil recruitment and bronchial hyperreactivity in Ova-sensitized mice. These data pave the way to alternative therapies to combat allergic conditions. PMID- 17719149 TI - Influenza vaccine: the challenge of antigenic drift. AB - Influenza continues to have a major worldwide impact, resulting in considerable human suffering and economic burden. The regular recurrence of influenza epidemics is thought to be caused by antigenic drift, and a number of studies have shown that sufficient changes can accumulate in the virus to allow influenza to reinfect the same host. To address this, influenza vaccine content is reviewed annually to ensure protection is maintained, despite the emergence of drift variants; however, it is not always possible to capture every significant drift, partly due to the timing of the recommendations. Vaccine mismatch can impact on vaccine effectiveness, and has significant epidemiological and economical consequences, as was seen most apparently in the 1997-1998 influenza season. To meet the challenge of antigenic drift, vaccines that confer broad protection against heterovariant strains are needed against seasonal, epidemic and pandemic influenza. In addition to the use of vaccine adjuvants, emerging research areas include development of a universal vaccine and the use of vaccines that exploit mechanisms of cross-protective immunity. PMID- 17719151 TI - Evaluation of uptake and generation of immune response by murine dendritic cells pulsed with hepatitis B surface antigen-loaded elastic liposomes. AB - Hepatitis B surface antigen (HBsAg)-loaded elastic liposomes were studied for qualitative and quantitative uptake in vitro by murine dendritic cells (DCs) generated from bone marrow mononuclear cells. Internalization of the vesicles by the DCs was documented using fluorescence microscopy. Kinetics of uptake of antigen-loaded elastic vesicles by the DCs studied through flow cytometry showed a peak uptake at 6h. The ability of the antigen pulsed DCs to stimulate autologous peripheral blood lymphocytes was demonstrated by BrdU assay. Further evaluation by multiplex cytometric bead array analysis demonstrated a predominantly TH1 type of immune response. Our results suggest that HBsAg-loaded elastic vesicles as antigen delivery module and DCs as antigen presenting cells are able to generate a protective immune response. The property of elastic liposomes to traverse and target the immunological milieu of the skin makes it an attractive vehicle for development of a transcutaneous vaccine against hepatitis B virus. PMID- 17719150 TI - Antigenic differences among Newcastle disease virus strains of different genotypes used in vaccine formulation affect viral shedding after a virulent challenge. AB - Strains of Newcastle disease virus (NDV) can be separated into genotypes based on genome differences even though they are antigenically considered to be of a single serotype. It is widely recognized that an efficacious Newcastle disease (ND) vaccine made with any NDV does induce protection against morbidity and mortality from a virulent NDV challenge. However, those ND vaccines do not protect vaccinates from infection and viral shed from such a challenge. Vaccines prepared from ND viruses corresponding to five different genotypes were compared to determine if the phylogenetic distance between vaccine and challenge strain influences the protection induced and the amount of challenge virus shed. Six groups of 4-week-old specific pathogen-free Leghorn chickens were given oil adjuvanted vaccines prepared from one of five different inactivated ND viruses including strains B1, Ulster, CA02, Pigeon84, Alaska 196, or an allantoic fluid control. Three weeks post-vaccination, serum was analyzed for antibody content using a hemagglutination inhibition assay against each of the vaccine antigens and a commercial NDV ELISA. After challenge with virulent CA02, the birds were examined daily for morbidity and mortality and were monitored at selected intervals for virus shedding. All vaccines except for the control induced greater than 90% protection to clinical disease and mortality. The vaccine homologous with the challenge virus reduced oral shedding significantly more than the heterologous vaccines. NDV vaccines formulated to be phylogenetically closer to potential outbreak viruses may provide better ND control by reducing virus transmission from infected birds. PMID- 17719152 TI - The clinical grade maturation cocktail monophosphoryl lipid A plus IFNgamma generates monocyte-derived dendritic cells with the capacity to migrate and induce Th1 polarization. AB - Ex vivo generated monocyte-derived dendritic cells (DCs) are used as a cellular vaccine against cancer in clinical trials. In order to be able to induce an efficient tumour-specific CTL response during immunotherapy, DCs have to be able to migrate to the lymph node and produce the Th1 polarizing cytokine, IL-12p70, upon encounter of T cells in the lymph node. However, most clinically used DCs do not produce IL-12p70 upon T cell contact. In this study, we compared a newly developed clinical grade DC maturation cocktail consisting of MPLA and IFNgamma with two clinically available maturation cocktails, the 'gold standard' (TNFalpha, IL-1beta, IL-6 and PGE(2)) and the 'alpha type 1 polarizing' (TNFalpha, IL-1beta, IFNalpha, IFNgamma and pI:C) cocktail. All three cocktails induced phenotypically mature DCs. However, in contrast to 'gold standard' DCs, which produce no IL-12p70 and as a result induce mainly Th2 cells, DCs matured with MPLA and IFNgamma produce high levels of IL-12p70 upon CD40 triggering. Subsequently, these DCs induce mainly Th1 cells in vitro, even slightly more than by the alpha type 1 polarized DCs. In addition, MPLA plus IFNgamma matured DCs have an intermediate migratory capacity towards CCL21. In conclusion, we here present MPLA plus IFNgamma as a simple clinical grade maturation cocktail to generate immunostimulatory DCs with superior capacity to induce type 1 immunity. PMID- 17719154 TI - Cadmium accumulation and its effect on the in vitro growth of woody fleabane and mycorrhized white birch. AB - The effect of Cd on woody fleabane (Dittrichia viscosa (L.) Greuter) and white birch (Betula celtiberica Rothm. & Vasc.) was examined. Woody fleabane and white birch were grown in vitro in Murashige, T., Skoog, F., [1962. A revised medium for rapid growth and bioassays with tobacco tissue cultures. Physiol. Plant. 15, 473-479] (MS) plus Cd (10 mg Cd kg(-1)) and except for root length in white birch, plant development was inhibited when Cd was added. Cd accumulation in above-ground tissues showed differences among clones, reaching 1300 and 463 mg Cd kg(-1) dry wt. in selected clones of woody fleabane and white birch, respectively. Tolerance of Paxillus filamentosus (Scop) Fr. to Cd was also examined before mycorrhization. Plants of mycorrhized white birch grown in the presence of Cd had a better development and accumulated more Cd in their shoots than the non-mycorrhized ones. The use of selected clones of woody fleabane and the mycorrhization of white birch enhance extraction efficiency from contaminated soils in phytoremediation programs. PMID- 17719155 TI - Polycyclic aromatic hydrocarbons in ash: determination of total and leachable concentrations. AB - Before wood ash can be used as a soil fertilizer, concentrations of environmentally hazardous compounds must be investigated. In this study, total and leachable concentrations of 16 polycyclic aromatic hydrocarbons (PAHs) were determined in four ash samples and one green liquor sludge. The ash sample with the highest carbon content also contained high levels of PAHs; three of the ash samples had total concentrations exceeding the limit permitted by the Swedish Forest Agency for recycling to forest soils. The leachable concentrations were higher for the non-stabilized samples; this was probably due to colloid facilitated transport of the contaminants in these samples. However, the leachable concentrations were overall relatively low in all the samples studied. The amounts of PAHs introduced to forest soils by additions of stabilized, recyclable ash products will be determined primarily by the rate of weathering of the ash particles and the total concentration of contaminants. PMID- 17719156 TI - Response of plankton communities in freshwater pond and stream mesocosms to the herbicide metazachlor. AB - Metazachlor is a frequently used herbicide with concentrations in surface waters up to 100 microg L(-1). A long-term mesocosm study was performed in order to investigate effects on stream and pond communities also regarding recovery. Single metazachlor doses of 5, 20, 80, 200, and 500 microg L(-1) were given and the aquatic communities monitored for 140 days. In this paper, special attention is paid to the plankton response and the results of the entire study are summarised. Metazachlor strongly affected the stream and pond mesocosm communities at concentrations higher than 5 microg L(-1). Direct negative effects were most prominent for chlorophytes whereas diatoms and cryptophytes seemed insensitive. The effects on zooplankton were caused by changes in habitat structure due to the strong decline of macrophytes. The slow degradation of metazachlor combined with the absence of recovery in both chlorophytes and macrophytes is likely to cause long-lasting effects on aquatic ecosystems. PMID- 17719157 TI - A review of the evidence linking adult attachment theory and chronic pain: presenting a conceptual model. AB - It is now well established that pain is a multidimensional phenomenon, affected by a gamut of psychosocial and biological variables. According to diathesis stress models of chronic pain, some individuals are more vulnerable to developing disability following acute pain because they possess particular psychosocial vulnerabilities which interact with physical pathology to impact negatively upon outcome. Attachment theory, a theory of social and personality development, has been proposed as a comprehensive developmental model of pain, implicating individual adult attachment pattern in the ontogenesis and maintenance of chronic pain. The present paper reviews and critically appraises studies which link adult attachment theory with chronic pain. Together, these papers offer support for the role of insecure attachment as a diathesis (or vulnerability) for problematic adjustment to pain. The Attachment-Diathesis Model of Chronic Pain developed from this body of literature, combines adult attachment theory with the diathesis stress approach to chronic pain. The evidence presented in this review, and the associated model, advances our understanding of the developmental origins of chronic pain conditions, with potential application in guiding early pain intervention and prevention efforts, as well as tailoring interventions to suit specific patient needs. PMID- 17719159 TI - Comparative safety testing of genetically modified foods in a 90-day rat feeding study design allowing the distinction between primary and secondary effects of the new genetic event. AB - This article discusses the wider experiences regarding the usefulness of the 90 day rat feeding study for the testing of whole foods from genetically modified (GM) plant based on data from a recent EU-project [Poulsen, M., Schroder, M., Wilcks, A., Kroghsbo, S., Lindecrona, R.H., Miller, A., Frenzel, T., Danier, J., Rychlik, M., Shu, Q., Emami, K., Taylor, M., Gatehouse, A., Engel, K.-H., Knudsen, I., 2007a. Safety testing of GM-rice expressing PHA-E lectin using a new animal test design. Food Chem. Toxicol. 45, 364-377; Poulsen, M., Kroghsbo, S., Schroder, M., Wilcks, A., Jacobsen, H., Miller, A., Frenzel, T., Danier, J., Rychlik, M., Shu, Q., Emami, K., Sudhakar, D., Gatehouse, A., Engel, K.-H., Knudsen, I., 2007b. A 90-day safety in Wistar rats fed genetically modified rice expressing snowdrop lectin Galanthus nivalis (GNA). Food Chem. Toxicol. 45, 350 363; Schroder, M., Poulsen, M., Wilcks, A., Kroghsbo, S., Miller, A., Frenzel, T., Danier, J., Rychlik, M., Emami, K., Gatehouse, A., Shu, Q., Engel, K.-H., Knudsen, I., 2007. A 90-day safety study of genetically modified rice expressing Cry1Ab protein (Bacillus thuringiensis toxin) in Wistar rats. Food Chem. Toxicol. 45, 339-349]. The overall objective of the project has been to develop and validate the scientific methodology necessary for assessing the safety of foods from genetically modified plants in accordance with the present EU regulation. The safety assessment in the project is combining the results of the 90-day rat feeding study on the GM food with and without spiking with the pure novel gene product, with the knowledge about the identity of the genetic change, the compositional data of the GM food, the results from in-vitro/ex-vivo studies as well as the results from the preceding 28-day toxicity study with the novel gene product, before the hazard characterisation is concluded. The results demonstrated the ability of the 90-day rat feeding study to detect the biological/toxicological effects of the new gene product in the GM food. The authors consider on this basis that the 90-day, rodent feeding study with one high dose level and a dietary design based upon compositional data on the GM food and toxicity data on the gene product is sensitive and specific enough to verify the presence/absence of the biological/nutritional/toxicological effects of the novel gene insert and further by the use of spiking able to separate potentially unintended effects of the novel gene product from other unintended effects at the level of intake defined in the test and within the remit of the test. Recommendations for further work necessary in the field are given. PMID- 17719158 TI - Social network variables in alcoholics anonymous: a literature review. AB - Alcoholics Anonymous (AA) is the most commonly used program for substance abuse recovery and one of the few models to demonstrate positive abstinence outcomes. Although little is known regarding the underlying mechanisms that make this program effective, one frequently cited aspect is social support. In order to gain insight into the processes at work in AA, this paper reviewed 24 papers examining the relationship between AA and social network variables. Various types of social support were included in the review such as structural support, functional support, general support, alcohol-specific support, and recovery helping. Overall, this review found that AA involvement is related to a variety of positive qualitative and quantitative changes in social support networks. Although AA had the greatest impact on friend networks, it had less influence on networks consisting of family members or others. In addition, support from others in AA was found to be of great value to recovery, and individuals with harmful social networks supportive of drinking actually benefited the most from AA involvement. Furthermore, social support variables consistently mediated AA's impact on abstinence, suggesting that social support is a mechanism in the effectiveness of AA in promoting a sober lifestyle. Recommendations are made for future research and clinical practice. PMID- 17719160 TI - From child to adult: an exploration of shifting family roles and responsibilities in managing physiotherapy for cystic fibrosis. AB - Although chest physiotherapy is central to the management of cystic fibrosis many report problems with adherence. Research in other long-term conditions suggests that non-adherence may be exacerbated as the child grows older and self-care responsibilities are transferred to the young person. We explored the nature and variation in roles of family members, how responsibility was transferred from the parent/family to the child, and what factors aided or hindered this process. We conducted in-depth interviews with 32 children with a diagnosis of cystic fibrosis aged 7-17 years, and with 31 parents attending cystic fibrosis clinics in two Scottish regions. Family responsibilities were primarily focused on mothers. The level and nature of involvement varied along a continuum that separated into six parental and five child roles and changed over time. However, this movement was frequently reversed during periods of illness or mistrust. The day to day experience of such a transfer was not straightforward, linear or unproblematic for any of the family members. Three factors were identified as assisting the transfer of responsibility: parents' perceptions of the benefits of transferring responsibility, children's perceptions of the benefits, and the available physical, social and psychological resources to support such a transfer. The principles and lessons from "concordance" (a therapeutic alliance based on a negotiation between equals and which may lead to agreement on management or agreement to differ) may provide a foundation for newly developing relationships between parents and their children emerging into adulthood. Further research is required to develop more specifically the content and structure of required support, its effectiveness in achieving more concordant relationships, and the resulting impact on adherence, perceived health and well-being from the perspective of the young person and parent. PMID- 17719161 TI - Characterization of the radical scavenging and antioxidant activities of danshensu and salvianolic acid B. AB - Danshensu (3-(3,4-dihydroxyphenyl) lactic acid) and salvianolic acid B, two natural phenolic acids of caffeic acid derivatives isolated from Salvia miltiorrhiza root of the most widely used traditional Chinese medicine for the treatment of various cardiovascular diseases, have been reported to have potential protective effects from oxidative injury. To better understand their biological functions, the in vitro radical scavenging and antioxidant activities of danshensu and salvianolic acid B were evaluated along with vitamin C. Both danshensu and salvianolic acid B exhibited higher scavenging activities against free hydroxyl radicals (HO()), superoxide anion radicals (O(2)(-)), 1,1-diphenyl 2-picryl-hydrazyl (DPPH) radicals and 2-azino-bis(3-ethylbenzthiazoline-6 sulfonic acid) (ABTS) radicals than vitamin C. In contrary, danshensu and salvianolic acid B showed weaker iron chelating and hydrogen peroxide (H(2)O(2)) scavenging activities than vitamin C. As expressed as vitamin C equivalent capacity (VCEAC), the relative VCEAC values (mg/100ml) were in the order of salvianolic acid B (18.59) > danshensu (12.89) > vitamin C (10.00) by ABTS radical assay. The protective efficiencies against hydrogen peroxide induced human vein vascular endothelial cell damage were correlated with their antioxidant activities. Analysis of structure-activity relationship of these two compounds showed that the condensation and conjugation of danshensu and caffeic acid appears important for antioxidant activity. These results indicated that danshensu and salvianolic acid B are efficient radical scavengers and antioxidants, and salvianolic acid B is superior to danshensu. Their radical scavenging and antioxidant properties might have potential applications in food and healthcare industry. PMID- 17719163 TI - Effect and mechanism of cadmium on the progesterone synthesis of ovaries. AB - The paper presents results of the effect of cadmium on the progesterone synthesis of ovaries. In the current study, we investigated whether Cd also disrupts progesterone synthesis via steroidogenic acute regulatory protein (StAR) and P450 cholesterol side-chain cleavage (P450scc), which play important roles in progesterone synthesis. The Wistar rats were exposed to cadmium in vivo (at 2.5, 5, 7.5mg/kg, as a single s.c. dose). We showed that the serum P(4) and granule cells P(4) of rats were significantly lower than control group. Ovaries granule cells were incubated in Dulbecco-modified Eagle medium +15% fetal bovine serum with 0, 10, 20, or 40 microM CdCl(2) in vitro, progesterone levels were declined in a dose-dependent manner. Our data showed that the expression of StAR and P450scc in vivo or in vitro were inhibited when treated with CdCl(2) (p<0.05). Coculture with 8-bromo-cAMP enhanced progesterone secretion in untreated cultures and reversed the decline in progesterone secretion induced by CdCl(2) treatment; the expression of StAR mRNA and P450scc mRNA in 8-Br-cAMP+40 microM CdCl(2) were significantly higher than 40 microM CdCl(2), and were lower than control group. We concluded that StAR, which delivers cholesterol to the inner mitochondrial membrane, is one site at which Cd interferes with progesterone production in cultured rats ovarian granule cells; P450scc, which conveys cholesterol to pregnenolone, is anther site. The mechanisms were mainly controlled by the cAMP dependent pathway. PMID- 17719162 TI - Impact of iron status on cadmium uptake in suckling piglets. AB - Low iron status is known to increase the uptake of dietary cadmium in both adolescents and adults and there are indications that cadmium is absorbed from the intestine by the two major iron transporters divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1). In addition, it has been suggested that duodenal metallothionein (MT) may limit the transport of cadmium across the intestinal epithelium. The present investigation was undertaken to examine whether iron status influences cadmium absorption in newborns by applying a model of suckling piglets and the possible roles of duodenal DMT1, FPN1 and MT. An oral cadmium dose (20 microg/kg body weight) was given daily for 6 consecutive days on postnatal days (PNDs) 10-15 to iron-deficient or iron-supplemented piglets. The cadmium dose was chosen to keep the cadmium level at a realistically low but still detectable level, and without inducing any adverse health effects in the piglets. As indicators of cadmium uptake, cadmium levels in blood and kidneys were measured on PND 16 by inductively coupled plasma-mass spectrometry (ICP-MS). Cadmium levels in blood were statistically significantly correlated with cadmium levels in kidneys. The cadmium uptake was not higher in iron-deficient suckling piglets; rather, we detected a higher cadmium uptake in the iron-supplemented ones. The expression and localisation of DMT1, FPN1 and MT were not affected by iron status and could therefore not explain the findings. Our results suggest that there are developmental differences in the handling of both iron and cadmium in newborns as compared to adults. PMID- 17719164 TI - Trichloroethylene induce nitric oxide production and nitric oxide synthase mRNA expression in cultured normal human epidermal keratinocytes. AB - Trichloroethylene (TCE), a major chemical hazard during occupational exposure, can cause obvious skin lesions, including irritant reactions and dermatitis. Nitric oxide (NO) synthesized by nitric oxide synthase (NOS) is involved in a broad array of pathogenesis of skin inflammatory and immune responses. To understand the mechanisms of TCE-induced dermatoxicity, we investigated the effects of TCE on NO production and NOS mRNA expression in cultured normal human epidermal keratinocytes (NHEK). Cells were treated with TCE (0 mM, 0.125 mM, 0.25 mM, 0.5 mM, 1.0 mM, 2.0 mM) for 4 h, and then incubated for 12 h, 24 h, 48 h and 72 h. At each given time point, NO production were evaluated indirectly by measuring nitrite plus nitrate concentration in the culture medium using Griess reaction, as well as cell viability determined by MTT test, iNOS and cNOS activities assayed with a NOS activity detecting kit. The expression of iNOS and cNOS mRNA was detected using RT-PCR. TCE decreases cell viability and enhance NO production from NHEK in concentration- and time-dependent manner. Aminoguanidine (AG), an inhibitor of NOS, can prevent NO production and cell viability decrease in NHEK by TCE induced. Change to NO production was accompanied by increased activities of both types of NOS, but the iNOS activity accounted mainly for the TCE-induced NO production. RT-PCR detection showed that NHEK expressed both iNOS and cNOS mRNA by TCE exposure. Whereas a concentration- and time-dependent up regulation of the mRNA expression was observed for iNOS and cNOS following TCE exposure, changes to iNOS were more marked. These results suggest that TCE caused increase in NO production, attributed to activation of iNOS as well as cNOS, and expression of iNOS and cNOS mRNA. These cellular changes may contribute to the pathological and physiological features of TCE-induced erythema and skin inflammation. PMID- 17719165 TI - Myocardial stunning following no flow ischaemia is diminished by levosimendan or cariporide, without benefits of combined administration. AB - AIM OF THE STUDY: Levosimendan, a calcium sensitiser, and cariporide, a blocker of the Na+/H+ exchanger, decrease necrosis and improve function following myocardial ischaemia. However, their role in myocardial stunning is unclear. We tested the hypothesis that levosimendan, cariporide, or their combination reduce stunning after global myocardial ischaemia. METHODS: In a prospective, controlled, randomised laboratory study isolated guinea pig hearts (n=48) were perfused in a Langendorff apparatus. Stunning was induced by 20 min of global no flow ischaemia. Levosimendan (0.1 micromol/l) or cariporide (1 micromol/l) were given either before or after ischaemia, and effects of both drugs combined were also assessed. Left ventricular developed pressure (LVdp) was assessed continuously before ischaemia and for 45 min after reperfusion. RESULTS: Levosimendan (24+/-7%) and the combination of levosimendan and cariporide (38.7+/ 4%) increased LVdp from baseline values before ischaemia, without differences between groups. In contrast, cariporide alone decreased LVdp (-11+/-2%) from baseline. Ischaemia/reperfusion decreased LVdp by about 70% in vehicle treated hearts compared to baseline. Treatment with cariporide, levosimendan, or their combination both before and after ischaemia, and treatment with cariporide after ischaemia caused a 25% greater recovery of LVdp than in control hearts. There were no differences between these groups and no enhanced effect with levosimendan/cariporide combined. In contrast, levosimendan only given after ischaemia did not improve LVdp. CONCLUSIONS: Cariporide diminished stunning when given before or after ischaemia, while levosimendan was only effective if given before ischaemia. Thus, levosimendan or cariporide may be useful in settings where ischaemia/reperfusion is to be expected. PMID- 17719166 TI - Transthoracic impedance changes as a tool to detect malpositioned tracheal tubes. AB - BACKGROUND: Undetected malpositioned or dislodged ventilation tubes during cardiac arrest have fatal consequences, and no single method can detect the tube position reliably during such low-flow states. We wanted to test the ability of impedance changes as measured across the chest via the standard defibrillation pads to distinguish between oesophageal and tracheal ventilations in non circulated patients. MATERIALS AND METHODS: After the end of futile resuscitation transthoracic impedance was measured with a prototype defibrillator, and ventilation variables were collected with a spirometer-capnography unit during tracheal ventilations and after repositioning of the tube; during oesophageal ventilations for paired comparisons. RESULTS: We registered 123 oesophageal and 178 tracheal ventilations in nine patients. Transthoracic impedance changes associated with ventilations were always larger during tracheal than oesophageal ventilations (mean difference 1.3 ohms (95% CI 1.0, 1.5), P<0.001), and all such changes above 1.2 ohms were associated with tracheal ventilations, while changes below 0.4 ohms always were associated with oesophageal ventilations. By subtracting 0.5 ohms from the individual mean transthoracic change associated with tracheal ventilations, tube position was predicted with sensitivity 0.99 and specificity 0.97. CONCLUSION: Transthoracic impedance changes may be used to detect malpositioned and dislodged tubes also during situations without spontaneous circulation. Our predictive values must be retested in another population. PMID- 17719167 TI - Effects of oral L-arginine on the pulsatility indices of umbilical artery and middle cerebral artery in preterm labor. AB - OBJECTIVE: The objective of the study was the estimation of the influence of oral supplementation with low-dose l-arginine on feto-placental circulation in women with threatened preterm labor. STUDY DESIGN: Oral administration of 3g of L arginine daily or placebo as a supplement to standard tocolytic therapy was tried in 70 women with threatened preterm delivery, randomly assigned to the L-arginine (n=37) or placebo (n=33) groups. Twenty-five and 20 completed the study, respectively. Doppler velocimetry of pulsatility indices (PI) of the umbilical (UA) and middle cerebral (MCA) arteries as well as pregnancy outcome and biochemical markers of nitric oxide synthesis (plasma amino acid and nitrite/nitrate levels, as well as 24 h nitrite/nitrate excretion with urine) were estimated. RESULTS: Starting from the second week of therapy, the UA PI values were significantly lower in the L-arginine group than in the placebo group. Moreover, treatment with L-arginine caused a significant increase in MCA PI and cerebro-placental ratio (CPR) values. The changes in feto-placental circulation in the L-arginine group were not associated with any signs of increased nitric oxide synthesis. CONCLUSION: Oral supplementation with low doses of L-arginine changed feto-placental blood flow distribution in patients with threatened preterm labor. The exact mechanism of L-arginine action on feto placental circulation requires further investigation. PMID- 17719168 TI - Geomorphological and geophysical approach for locating favorable groundwater zones in granitic terrain, Andhra Pradesh, India. AB - The increasing demand for fresh water has necessitated the exploration for new sources of groundwater, particularly in hard rock terrain, where groundwater is a vital source of fresh water. A fast, cost effective and economical way of exploration is to study and analyze remote sensing data. Interpreted remote sensing data was used to select sites for carrying out surface geophysical investigations. Various geomorphologic units were demarcated and the lineaments were identified by interpretation of remote sensing satellite images. The potential for occurrence of groundwater in the watershed areas was classified as very good, good, moderate and poor by interpreting the images. Sub-surface geophysical investigations, namely vertical electrical soundings, were carried out to delineate potential water-bearing zones. Integrated studies of interpretation of geomorphologic and geophysical data were used to prepare a groundwater potential map. The studies reveal that the groundwater potential of shallow aquifers is due to geomorphologic features and the potential of deeper aquifers is determined by lineaments such as faults and joints. PMID- 17719169 TI - Intravesical pharmacotherapy for non-muscle-invasive bladder cancer: a critical analysis of currently available drugs, treatment schedules, and long-term results. AB - OBJECTIVES: Review adjuvant intravesical pharmacotherapy for non-muscle-invasive bladder cancer (NMIBC), emphasising treatment schedules and long-term results. METHODS: Search of published literature on conventional treatment of NMIBC, emerging drugs, and device-assisted therapies. RESULTS: In low-risk NMIBC patients an immediate instillation with chemotherapy is sufficient. For patients with intermediate- or high-risk tumours, additional adjuvant instillations are needed. For intermediate-risk patients chemotherapeutic instillations, usually with mitomycin C or epirubicin, are safe and effective in reducing the risk of recurrence in the short term, but efficacy is only marginal in the long term. Newer drugs have promising results, but long term follow-up is limited or lacking. In these patients bacillus Calmette-Guerin (BCG) does not seem to be more effective, only more toxic. In high-risk NMIBC, or patients in whom chemotherapy fails, BCG is the best choice with lower rates of recurrence and progression. For BCG failures cystectomy is therapy of choice, although the combination of BCG and interferon-alpha can be considered, just as device assisted therapies such as thermochemotherapy and electromotive drug administration. CONCLUSIONS: Risk-adapted first-line adjuvant therapy for NMIBC after TURBT is well established but has its limitations because recurrences are still numerous. Some new drugs and second-line therapies are promising, but efficacy should be confirmed. PMID- 17719170 TI - The autonomy of biological individuals and artificial models. AB - This paper aims to offer an overview of the meaning of autonomy for biological individuals and artificial models rooted in a specific perspective that pays attention to the historical and structural aspects of its origins and evolution. Taking autopoiesis and the recursivity characteristic of its circular logic as a starting point, we depart from some of its consequences to claim that the theory of autonomy should also take into account historical and structural features. Autonomy should not be considered only in internal or constitutive terms, the largely neglected interactive aspects stemming from it should be equally addressed. Artificial models contribute to get a better understanding of the role of autonomy for life and the varieties of its organization and phenomenological diversity. PMID- 17719171 TI - Sex hormone-binding globulin expression in sea bass (Dicentrarchus labrax L.) throughout development and the reproductive season. AB - Sex hormone-binding globulin (SHBG) transports androgens and estrogens in the blood of vertebrate species, including fish, and regulates the bioavailability and metabolic clearance of these steroids. Liver is the major site of plasma SHBG synthesis, while an SHBG homologue, known as the androgen-binding protein, is produced in testes. When shbg gene expression was examined throughout European sea bass (Dicentrarchus labrax L.) development, SHBG mRNA was clearly detectable at 7 days post-fertilization and persisted throughout embryonic development. In male and female sea bass, the liver is the principal site of shbg gene expression, as determined by SHBG mRNA analyses. Immunoreactive SHBG is present in the liver and villous stroma of the intestine in both sexes. It is also present in the interstitial space between testicular lobules, and the connective tissue surrounding the ovary in the non-reproductive season and around post vitellogenic oocytes. Plasma SHBG levels were measured over a 10-month period as male sea bass undergo sexual maturation. Immature females of the same age were also studied over the same time interval. The mean+/-S.E.M. plasma SHBG levels in 2-year-old males and females are lower (80+/-15nM and 82+/-16nM, respectively) during the winter reproductive season (December-March) than the spring (April June) months (144+/-32nM and 193+/-18nM, respectively). In both sexes, plasma SHBG levels start to decline 1-2 months before the reproductive season, coincident with a period of rapid weight gain, while increases after the reproductive season are not accompanied by significant changes in body weight. In addition, plasma SHBG in triploid (sterile) and diploid (fertile) male sea bass do not differ during the first spawning season. These data suggest that the decrease in plasma SHBG levels during sexual maturation in sea bass is related to nutritional or metabolic effects in relation to water temperatures and food intake, rather than changes in gonadal sex steroid production. PMID- 17719172 TI - ALS and mercury intoxication: a relationship? AB - We report the case of an 81-year-old woman in whom clinical signs and features of electromyographic activity patterns were consistent with amyotrophic lateral sclerosis (ALS). Increased blood level and massive urinary excretion of mercury proved mercury intoxication. Despite a chelation treatment with Meso 2-3 dimercaptosuccininc acid (DMSA), she died after 17 months. The pathophysiology of sporadic ALS remains unclear. However, the role of environmental factors has been suggested. Among some environmental factors, exposure to heavy metals has been considered and ALS cases consecutive to occupational intoxication and accidental injection of mercury have been reported. Although no autopsy was performed, we discuss the role of mercury intoxication in the occurrence of ALS in our case, considering the results of experimental studies on the toxicity of mercury for motor neuron. PMID- 17719173 TI - Generation of allo-restricted cytotoxic T lymphocytes against malignant glioma by artificial antigen-presenting cells. AB - The interleukin (IL) 13 receptor alpha2 (IL-13Ralpha2) is a glioma-restricted cell-surface epitope not otherwise detected within the central nervous system. This study reported a novel approach for targeting malignant glioma with IL 13Ralpha2-specific allo-restricted cytotoxic T cells (CTLs) induced from the peripheral blood lymphocytes (PBLs) of HLA-A2-negative healthy donors by multiple stimulations with artificial antigen-presenting cells (aAPCs) made by coating HLA A2/pIL-13Ralpha2(345-354) tetrameric complexes, anti-CD28 antibody and CD83 molecules to cell-sized latex beads. The induced allo-restricted CTLs exhibited specific lysis against T2 cells pulsed with the peptide pIL-13Ralpha2(345-354) and HLA-A2+ glioma cells expressing IL-13Ralpha2(345-354), while HLA-A2- glioma cell lines that express IL-13Ralpha2(345-354) could not be recognized by the CTLs. The peptide-specific activity was inhibited by anti-HLA class I monoclonal antibody. These results suggested the induced allo-restricted CTLs specific for IL-13Ralpha2(345-354) peptide could be a potential target of specific immunotherapy for HLA-A2+ patients with malignant glioma. PMID- 17719174 TI - Removal of 2,4,6-trichlorophenol from a solution by humic acids repeatedly extracted from a peat soil. AB - Humic acid (HA) is one of the major components of soil organic matter. It strongly affects the sorption behavior of organic and inorganic contaminants in soils. To obtain a better understanding of the interactions of contaminants with HA, a repeated extraction technique has been applied to a peat soil to obtain HA fractions with varying aliphaticity and aromaticity, which were subsequently correlated to the sorption properties of 2,4,6-trichlorophenol (TCP). HA fractions were extracted repeatedly using an alkaline solution and each HA fraction was separated into two portions with an air-drying or re-suspending (denoted as RSHAs) process. Solid-state (13)C NMR and elemental analysis demonstrated that the aromaticity and polarity of HAs decreased with extractions. Kinetic results indicated that air-dried HAs exhibited two-step first order sorption behavior with a rapid stage followed by a slower stage. The slower sorption is attributed to the diffusion of 2,4,6-TCP in the condensed aromatic domains of HAs. Conversely, sorption of 2,4,6-TCP on RSHAs was extremely rapid and could not be fitted with any kinetic model. For air-dried HAs the sorption capacity (K(oc)) was weakly correlated with the chemical compositions of HAs. However, a positive trend between K(oc) and aromaticity was observed for RSHAs. Compared with the results of air-dried HAs with their counterparts of RSHAs, it is therefore concluded that air-drying may alter the structure of HAs through artificially creating a more condensed domain in HAs. The structural alternation may result in an incorrect interpretation of the relationship between sorption capacity and chemical composition of HAs and a misjudgment of the transport behavior of 2,4,6-TCP in soils and sediments. PMID- 17719175 TI - Removal of fluoride ions from aqueous solution at low pH using schwertmannite. AB - Wastewater containing fluoride requires polishing after precipitation/coagulation treatment in order to meet stringent environmental legislation. Accordingly, adsorption characteristics of fluoride onto schwertmannite adsorbent were studied in a batch system with respect to changes in initial concentration of fluoride, equilibrium pH of sample solution, adsorbent dosage and co-existing ions. Equilibrium adsorption data were obtained at 295.6, 303 and 313 K, and are interpreted in terms of two-site Langmuir, Freundlich, Langmuir-Freundlich, Redlich-Peterson, Toth and Dubinin-Radushkevitch isotherm models. The experimental and equilibrium modeling results revealed that the capacity of schwertmannite for fluoride is high but insensitive to changes in solution temperature. An increase in equilibrium pH of sample solution reduced significantly the fluoride removal efficiency. In binary component systems, inner sphere complex forming species had negative effects on fluoride adsorption while outer-sphere complex forming species improved slightly the fluoride removal efficiency. The schwertmannite adsorbent was regenerable and had the ability to lower the fluoride concentration to acceptable levels. PMID- 17719176 TI - The wolframin His611Arg polymorphism influences medication overuse headache. AB - Homozygosis for wolframin (WFS1) mutations determines Wolfram syndrome (WS), and common polymorphisms of WFS1 are associated with psychiatric illnesses and dependence behaviour. To test the influence of WFS1 polymorphisms on medication overuse headache (MOH), a chronic headache condition related to symptomatic drugs overuse, we analyzed 82 MOH patients for the WFS1 His611Arg polymorphism, and performed a comparison between clinical features of Arg/Arg (R/R) and non-R/R individuals. Individuals harbouring the R/R genotype showed significantly higher monthly drug consumption (t=-3.504; p=0.00075) and more severe depressive symptoms on the BDI questionnaire (t=-3.048; p=0.003) than non-R/R. WFS1 polymorphism emerged as the only significant predictor of drug consumption, at the multivariate regression analysis (F=12.277; d.f.=1,80; p=0.00075, adjusted R2=0.122). These results implicate WFS1 in the clinical picture of MOH, may be through an influence on need for drugs as in other conditions of abuse behaviour. PMID- 17719177 TI - Effect of apomorphine on striatal synaptotagmin 7 mRNA levels in reserpinized rats. AB - Synaptotagmin 7 (Syt 7) is a Ca2+ sensor implicated in the regulation of membrane fusion in vesicular transport, but its precise role in neurons is still a matter of controversy. Dopaminergic drugs have been shown to modulate its expression in the striatum. Here we investigate whether dopamine receptor agonist-up-regulation of Syt 7 mRNA is specifically involved in the pathophysiological adaptations of hypersensitive striatum by analyzing other dopaminergic neurons containing brain regions. We treated rats with systemic reserpine injections that rapidly depletes dopamine throughout the brain, but leaves dopaminergic neurons spared from destruction. We analyzed the effects of apomorphine, a D1 and D2 receptor agonist on Syt 7 mRNA expression in caudate putamen, nucleus accumbens, cingulate cortex, substantia nigra compacta, ventral tegmental area and hippocampus. The treatment with reserpine resulted in akinesia, catalepsy and rigidity and up-regulation of proenkephalin and down-regulation of preprotachykinin mRNA in caudate putamen, indicating a severe depletion. By acute treatment with apomorphine proenkephalin mRNA was down-regulated and preprotachykinin mRNA up-regulated in the caudate putamen of reserpinized rats. Apomorphine increased Syt 7 mRNA levels only in striatum (caudate putamen and nucleus accumbens) of reserpinized rats, while in other brain regions it did not have such effect. The reserpinization and/or apomorphine treatment had no effect on Syt 1 mRNA expression in caudate putamen. It may be concluded, that in the striatum depleted of biogene amines, such as occurs after reserpine treatment, the up-regulation of Syt 7 could play a specific role as part of hypersensitive response to dopaminergic agonists. PMID- 17719178 TI - Methylprednisolone acetate immune suppression produces differing effects on Cryptosporidium muris oocyst production depending on when administered. AB - At different times after inoculation with Cryptosporidium muris, infected CF-1 female mice were immunosuppressed with a single subcutaneous dose of methylprednisolone acetate (MPA; 600 mg/kg). MPA immunosuppression decreases circulating CD3, CD4 and CD8 T-lymphocytes and B-lymphocytes by greater than 90% for approximately 14 days with numbers not returning to pre-suppression levels until after 41 days post-suppression. Immunosuppression was initiated at selected times before, during, and after oocyst production. Immunosuppression initiated prior to oocyst production delayed the start of production by 4-5 days and extended oocyst shedding by 16 days. Initiation of immunosuppression during oocyst production both extended oocyst shedding and greatly increased the number of oocysts shed per day over most of the extended shedding period. Immunosuppression during the decline of oocyst production resulted in only a moderate extension of shedding and a moderate increase in oocyst numbers. Immunosuppression initiated soon after oocyst shedding had ceased resulted in the re-initiation of limited oocyst production for only a few days. Suppression initiated on days 40 and 46 post-infection, 11 and 17 days after oocysts could no longer be detected in the feces, did not result in a resumption of oocyst production. In all cases, where oocyst production was extended or reinitiated, the shedding of oocysts halted between days 45 and 53 post-oocyst inoculation. These studies demonstrate that the effect of MPA immunosuppression depends on the immunologic conditions existing in the host at the time immunosuppression was initiated. Immunosuppression initiated during oocyst production allows an overwhelming parasitism to exist, implying that T- and B-lymphocytes play an important role in moving the host immune process along during this period of the infection. Conversely, severe suppression of T- and B-lymphocytes initiated as oocyst production is decreasing does not result in a complete relapse of the disease suggesting that T- and B-lymphocytes are not critical to the continuation of the immune process after this point. These studies also show that the C. muris infection persists beyond the end of the detection of oocysts in the feces. PMID- 17719179 TI - Establishment of the active catalytic domain of human PDGFRbeta tyrosine kinase based ELISA assay for inhibitor screening. AB - Tyrosine kinases are emerging as frequent targets of primary oncogenic events and therefore represent an optimal focus of therapeutic intervention. In an effort towards therapeutic PDGFR inactivation, we expressed the catalytic domain of PDGFRbeta as a soluble active kinase using Bac-to-Bac expression system, and studied the correlations between PDGFRbeta activity and enzyme concentration, ATP concentration, substrate concentration and divalent cation type. And a convenient, effective and non-radioactive ELISA screening model is then established for identification of the potential inhibitors targeting PDGFRbeta kinase. Of 500 RTK target-based compounds, TKI-30 was identified as a small molecule potential inhibitor of PDGFRbeta (IC(50)=0.34 microM). Further studies indicated that TKI-30 blocked PDGF-BB-induced autophosphorylation of PDGFRbeta in a dose-dependent manner in Swiss 3T3 cells and human umbilical vein smooth muscle cells (HUVSMCs). Moreover, it dose-dependently suppressed the PDGF-BB-induced proliferation in HUVSMCs and tube formation of HUVEC. Our data collectively indicated that PDGFRbeta-based ELISA assay is a new method available for screening inhibitors targeting PDGFRbeta kinase and TKI-30 is a potential novel anti-cancer agent worthy of being further investigated. PMID- 17719180 TI - BDNF and learning: Evidence that instrumental training promotes learning within the spinal cord by up-regulating BDNF expression. AB - We have previously shown that the spinal cord is capable of learning a sensorimotor task in the absence of supraspinal input. Given the action of brain derived neurotrophic factor (BDNF) on hippocampal learning, the current studies examined the role of BDNF in spinal learning. BDNF is a strong synaptic facilitator and, in association with other molecular signals (e.g. cAMP-response element binding protein (CREB), calcium/calmodulin activated protein kinase II (CaMKII) and synapsin I), important for learning. Spinally transected rats given shock to one hind leg when the leg extended beyond a selected threshold exhibited a progressive increase in flexion duration that minimized shock exposure, a simple form of instrumental learning. Instrumental learning resulted in elevated mRNA levels of BDNF, CaMKII, CREB, and synapsin I in the lumbar spinal cord region. The increases in BDNF, CREB, and CaMKII were proportional to the learning performance. Prior work has shown that instrumental training facilitates learning when subjects are tested on the contralateral leg with a higher response criterion. Pretreatment with the BDNF inhibitor TrkB-IgG blocked this facilitatory effect, as did the CaMKII inhibitor AIP. Intrathecal administration of BDNF facilitated learning when subjects were tested with a high response criterion. The findings indicate that instrumental training enables learning and elevates BDNF mRNA levels within the lumbar spinal cord. BDNF is both necessary, and sufficient, to produce the enabling effect. PMID- 17719181 TI - The role of transient receptor potential vanilloid 1 in mechanical and chemical visceral hyperalgesia following experimental colitis. AB - The transient receptor potential vanilloid 1 receptor (TRPV1) is an important nociceptor involved in neurogenic inflammation. We aimed to examine the role of TRPV1 in experimental colitis and in the development of visceral hypersensitivity to mechanical and chemical stimulation. Male Sprague-Dawley rats received a single dose of trinitrobenzenesulfonic acid (TNBS) in the distal colon. In the preemptive group, rats received the TRPV1 receptor antagonist JYL1421 (10 mumol/kg, i.v.) or vehicle 15 min prior to TNBS followed by daily doses for 7 days. In the post-inflammation group, rats received JYL1421 daily for 7 days starting on day 7 following TNBS. The visceromotor response (VMR) to colorectal distension (CRD), intraluminal capsaicin, capsaicin vehicle (pH 6.7) or acidic saline (pH 5.0) was assessed in all groups and compared with controls and naive rats. Colon inflammation was evaluated with H&E staining and myeloperoxidase (MPO) activity. TRPV1 immunoreactivity was assessed in the thoraco-lumbar (TL) and lumbo-sacral (LS) dorsal root ganglia (DRG) neurons. In the preemptive vehicle group, TNBS resulted in a significant increase in the VMR to CRD, intraluminal capsaicin and acidic saline compared the JYL1421-treated group (P<0.05). Absence of microscopic colitis and significantly reduced MPO activity was also evident compared with vehicle-treated rats (P<0.05). TRPV1 immunoreactivity in the TL (69.1+/-4.6%) and LS (66.4+/-4.2%) DRG in vehicle treated rats was increased following TNBS but significantly lower in the preemptive JYL1421-treated group (28.6+/-3.9 and 32.3+/-2.3 respectively, P<0.05). JYL1421 in the post-inflammation group improved microscopic colitis and significantly decreased the VMR to CRD compared with vehicle (P<0.05, >/=30 mm Hg) but had no effect on the VMR to chemical stimulation. TRPV1 immunoreactivity in the TL and LS DRG was no different from vehicle or naive controls. These results suggest an important role for TRPV1 channel in the development of inflammation and subsequent mechanical and chemical visceral hyperalgesia. PMID- 17719182 TI - Expression and functional characterization of transient receptor potential vanilloid-related channel 4 (TRPV4) in rat cortical astrocytes. AB - Cell-cell communication in astroglial syncytia is mediated by intracellular Ca(2+) ([Ca(2+)](i)) responses elicited by extracellular signaling molecules as well as by diverse physical and chemical stimuli. Despite the evidence that astrocytic swelling promotes [Ca(2+)](i) elevation through Ca(2+) influx, the molecular identity of the channel protein underlying this response is still elusive. Here we report that primary cultured cortical astrocytes express the transient receptor potential vanilloid-related channel 4 (TRPV 4), a Ca(2+) permeable cation channel gated by a variety of stimuli, including cell swelling. Immunoblot and confocal microscopy analyses confirmed the presence of the channel protein and its localization in the plasma membrane. TRPV4 was functional because the selective TRPV4 agonist 4-alpha-phorbol 12,13-didecanoate (4alphaPDD) activated an outwardly rectifying cation current with biophysical and pharmacological properties that overlapped those of recombinant human TRPV4 expressed in COS cells. Moreover, 4alphaPDD and hypotonic challenge promoted [Ca(2+)](i) elevation mediated by influx of extracellular Ca(2+). This effect was abolished by low micromolar concentration of the TRPV4 inhibitor Ruthenium Red. Immunofluorescence and immunogold electron microscopy of rat brain revealed that TRPV4 was enriched in astrocytic processes of the superficial layers of the neocortex and in astrocyte end feet facing pia and blood vessels. Collectively, these data indicate that cultured cortical astroglia express functional TRPV4 channels. They also demonstrate that TRPV4 is particularly abundant in astrocytic membranes at the interface between brain and extracerebral liquid spaces. Consistent with its roles in other tissues, these results support the view that TRPV4 might participate in astroglial osmosensation and thus play a key role in brain volume homeostasis. PMID- 17719183 TI - [Chemoprevention and prophylactic surgery in ovarian carcinoma]. AB - INTRODUCTION: Ovarian cancer is the leading cause of death from gynaecological malignancy, especially because of late diagnosis. The objective of the study was to provide the clinician with current concepts regarding prevention of ovarian cancer. MATERIAL AND METHODS: A computerized search of articles published was performed using the Medline database We performed a review of the literature (PubMed, Embase) using the following search terms (MeSH and non-MeSH): prevention, chemoprevention, chemoprevention, ovarian cancer, ovarian, ovary, carcinoma, tumor, tumour. RESULTS: Oral contraceptive and acetaminophen use may provide substantial protection against ovarian cancer, whereas aspirin, carotenoids and non-steroidal anti-inflammatory agents do not decrease the risk. However, to date, there is no recommendation concerning low risk population. At the opposite, young women (<35-40 years old) presenting with BRCA1 or 2 mutation or Lynch syndrome may be counseled for chemoprevention using oral contraceptive. For high risk women over 35-40 years old, prophylactic bilateral salpingo oophorectomy should be performed. Indeed, it has been showed that prophylactic surgery significantly decrease mortality rates in high risk women. CONCLUSION: Large randomized studies are required to assess the efficacy of ovarian cancer chemoprevention in low risk women. High-risk women over 35-40 years old should be counseled for prophylactic salpingo-oophorectomy or for chemoprevention using oral contraceptive. PMID- 17719185 TI - Direct fitness, reciprocity and helping: a perspective from primitively eusocial wasps. PMID- 17719184 TI - On the further integration of cooperative breeding and cooperation theory. AB - We present a synopsis about the commentaries to the target article "Integrating cooperative breeding into theoretical concepts of cooperation", in which we attempted to integrate general mechanisms to explain cooperative behaviour among unrelated individuals with classic concepts to explain helping behaviour in cooperative breeders that do not invoke kin-based benefits. Here we (1) summarize the positions of the commentators concerning the main issues we raised in the target article and discuss important criticisms and extensions. (2) We relate our target article to some recent reviews on the evolution of cooperation and, (3) clarify how we use terminology with regard to cooperation and cooperative behaviour. (4) We discuss several aspects that were raised with respect to cooperative interactions including by-product mutualism, generalised reciprocity and multi-level selection and, (5) examine the alternatives to our classification scheme as proposed by some commentaries. (6) Finally, we highlight several aspects that might hinder the application of game theoretical mechanisms of cooperation in cooperatively breeding systems. Although there is broad agreement that cooperative breeding theory should be integrated within the more general concepts of cooperation, there is some debate about how this may be achieved. We conclude that the contributions in this special issue provide a fruitful first step and ample suggestions for future directions with regard to a more unified framework of cooperation in cooperative breeders. PMID- 17719186 TI - Problem-free drinking over 16 years among individuals with alcohol use disorders. AB - BACKGROUND: Limited data exist on the rates and long-term stability of non problem drinking in individuals who sought help for an alcohol use disorder. METHODS: A sample of initially untreated individuals with alcohol use disorders (n=420) was surveyed at baseline and 1 year and was re-assessed at 8 and 16 years. RESULTS: In the 6 months prior to the 1-year assessment, 36% (n=152) of participants reported abstinence from alcohol, 48% (n=200) reported drinking with problems, and 16% (n=68) reported non-problem drinking. At each follow up, 16-21% of the sample reported non-problem drinking. Compared to individuals in the abstinent and problem-drinking groups, individuals who were drinking in a problem free manner at 1 year had reported, at baseline, fewer days of intoxication, drinks per drinking day, alcohol dependence symptoms, and alcohol-related problems, less depression, and more adaptive coping mechanisms. Over time, 48% of participants who engaged in non-problem drinking at 1 year continued to report positive outcomes (either non-problem drinking or abstinence) throughout the long term follow-up, whereas 77% of those abstaining at 1 year reported positive outcomes throughout the same time period. Additionally, 43% of individuals with problematic alcohol consumption at 1 year reported positive outcomes over the remaining follow-up interval, a rate that was not significantly different from the rate of positive outcomes of 48% observed in those with initial problem-free drinking. CONCLUSIONS: Although some individuals report non-problem drinking a year after initially seeking help, this pattern of alcohol use is relatively infrequent and is less stable over time than is abstinence. An accurate understanding of the long-term course of alcohol use and problems could help shape expectations about the realistic probability of positive outcomes for individuals considering moderate drinking as a treatment goal. PMID- 17719188 TI - Failure of protection and enhanced pneumonia with a US H1N2 swine influenza virus in pigs vaccinated with an inactivated classical swine H1N1 vaccine. AB - Two US swine influenza virus (SIV) isolates, A/Swine/Iowa/15/1930 H1N1 (IA30) and A/Swine/Minnesota/00194/2003 H1N2 (MN03), were evaluated in an in vivo vaccination and challenge model. Inactivated vaccines were prepared from each isolate and used to immunize conventional pigs, followed by challenge with homologous or heterologous virus. Both inactivated vaccines provided complete protection against homologous challenge. However, the IA30 vaccine failed to protect against the heterologous MN03 challenge. Three of the nine pigs in this group had substantially greater percentages of lung lesions, suggesting the vaccine potentiated the pneumonia. In contrast, priming with live IA30 virus provided protection from nasal shedding and virus replication in the lung in MN03 challenged pigs. These data indicate that divergent viruses that did not cross react serologically did not provide complete cross-protection when used in inactivated vaccines against heterologous challenge and may have enhanced disease. In addition, live virus infection conferred protection against heterologous challenge. PMID- 17719187 TI - The antibody responses to swine influenza virus (SIV) recombinant matrix 1 (rM1), matrix 2 (M2), and hemagglutinin (HA) proteins in pigs with different SIV exposure. AB - The influenza invariant matrix 2 (M2) protein is a potential subunit vaccine candidate to induce protective immunity against broader strains of influenza A viruses (IAV). Antibodies to M2 protein have not been well characterized in IAV natural hosts. To characterize M2-specific antibodies in pigs, an ELISA to the extracellular region of the M2 (M2e) protein was developed. Sera from pigs experimentally infected with three different swine influenza virus (SIV) subtypes, immunized with an SIV inactivated vaccine, or positive for SIV maternally derived antibodies (MDA) in the absence of SIV infection were tested in assay. Confirmation of antibody titer status of pigs, was determined using a hemagglutination-inhibition (HI) test and the presence of antibodies to matrix 1 (M1) protein was measured by a recombinant M1 (rM1)-based ELISA. The antibody titers to the HA and M2e proteins but not to the rM1 were directly correlated to the dose of virus used to infect the pigs and the level of antibodies detected by the HI assay varied according to SIV subtype. Pigs experimentally infected with SIV produced low levels of M2e antibodies compared to antibodies detected by the HI and rM1 assays. Vaccination alone followed by infection did not increase the levels of M2e antibodies in contrast to HA and rM1 antibodies. Pigs with MDA had different levels of HA antibodies and were positive to M2e antibodies, but results were not correlated to HA antibodies levels and inconsistently present. PMID- 17719189 TI - Phylogenetic analysis of livestock oxacillin-resistant Staphylococcus aureus. AB - The aim of this study was to characterize oxacillin-resistant Staphylococcus aureus (ORSA) isolates from livestock environments and meat market workers by molecular epidemiological analysis. Staphylococcal enterotoxin reversed passive latex agglutination (RPLA) and multiplex polymerase chain reactions (PCR) were used to detect enterotoxin-producing S. aureus. The molecular genetic similarity of ORSA was also compared by pulse-field gel electrophoresis (PFGE) and multi locus sequence typing (MLST). A total of 30 ORSA isolates were identified and 27 of these strains were from human sources-a higher contamination potential from human origin in the animal raising and handling field was suspected. The most common type of enterotoxin detected in this study was type B. Regarding the bacterial phylogenetic analysis of ORSA isolates, five major clusters of PFGE patterns were suggested with >80% similarity in cluster I. Seven MLST patterns were identified with the most prevalent types being ST338/ST338(slv) and ST59. Population genetic studies based on MLST have shown that major ORSA clones have emerged from six clonal complexes (CCs), with CC59 being the dominant one. In conclusion, a high prevalence of ORSA with enterotoxin type B as well as ST59 and ST338/ST338(slv) colonization was observed among livestock with human origins in this study. We suggest further tracking and comparing of the epidemiological evidence of community-acquired and hospital-acquired ORSA in human living environments and livestock-producing environments. PMID- 17719190 TI - Karyological diagnosis of Cebus (Primates, Platyrrhini) in captivity: detection of hybrids and management program applications. AB - Genetic data are very important for conservation programs in wild population as well as in captive conditions. Primates in zoos or breeding centers are often maintained in groups without geographic origin or genetic heritage information. These lead to the incorrect assignment of species and introduce an artificial reproductive barrier, which in turn constitutes inadequate management of the colonies. A karyological analysis of specimens from a Primate Reproduction Center, considered as Cebus apella (Platyrrhini), was performed. Cell cultures were conducted from peripheral blood samples following standard cytogenetic methods. A fluorescence in situ hybridization (FISH) procedure was applied in mitotic metaphases using two probes: A specific probe of the extracentromeric heterochromatin (He+) of Cebus, and a human chromosome 21 probe. The latter was chosen due to the known homeology with the euchromatic region limiting with 11qHe+ of Cebus. The species status was determined for at least half of the animals and identified a hybrid specimen using this combined FISH protocol. This procedure is an accurate diagnostic methodology for taxonomic determinations and, therefore can be used for management of reproduction in colonies. PMID- 17719191 TI - A lipid microsphere vehicle for vinorelbine: Stability, safety and pharmacokinetics. AB - A lipid microsphere vehicle for vinorelbine (VRL) was designed to reduce the severe venous irritation caused by the aqueous intravenous formulation of VRL. Lipid microspheres (LMs) were prepared by high pressure homogenization. The physical stability was monitored by the appearance, particle size and zeta potential changes while the chemical stability was achieved by using effective antioxidants and monitored by long-term investigations. Safety tests were performed by testing rabbit ear vein irritation and a guinea pig hypersensitivity reaction. A pharmacokinetic study was performed by determining the drug levels in plasma up to 24h after intravenous administration of VRL-loaded LMs and conventional VRL aqueous injection separately. The VRL-loaded LMs had a particle size of 180.5+/-35.2nm with a 90% cumulative distribution less than 244.1nm, while the drug entrapment efficiency was 96.8%, and it remained stable for 12 months at 6+/-2 degrees C. The VRL-loaded LMs were less irritating and toxic than the conventional VRL aqueous injection. The pharmacokinetic profiles were similar and the values of AUC(0-t) were very close for the two formulations. A stable and easily mass-produced VRL-loaded LM preparation has been developed. It produces less venous irritation and is less toxic but has similar pharmacokinetics in vivo to the VRL aqueous injection currently commercially available. PMID- 17719192 TI - Zootherapy goes to town: the use of animal-based remedies in urban areas of NE and N Brazil. AB - This paper examines the therapeutic possibilities offered by animal-based remedies in five Brazilian cities. Information was obtained through semi structured questionnaires applied to 79 traders of medicinal animals at Sao Luis, Teresina, Joao Pessoa and Campina Grande (Northeastern) and Belem (Northern) Brazil. We recorded the use of 97 animal species as medicines, whose products were recommended for the treatment of 82 illnesses. The most frequently quoted treatments concerned the respiratory system (58 species; 407 use-citations), the osteomuscular system and conjunctive tissue (46 species; 384 use-citations), and the circulatory system (34 species; 124 use-citations). Mammals (27 species), followed by reptiles (24) and fishes (16) represented the bulk of medicinal species. In relation to users, 53% of the interviewees informed that zootherapeuticals resources were sought after by people from all social classes, while 47% stated that low income people were the main buyers. The notable use and commercialization of medicinal animals to alleviate and cure health problems and ailments in cities highlights the resilience of that resource in the folk medicine. Most remedies quoted by interviewees depend on wild-caught animals, including some species under official protection. Among other aspects, the harvesting of threatened species confers zootherapy a role in the discussions about biodiversity conservation in Brazil. PMID- 17719193 TI - Presence of periorbital and conjunctival petechial hemorrhages in accidental pediatric drowning. AB - The pathological findings of drowning are variable and non-specific. Petechial hemorrhages involving the periorbital region and the conjunctiva have been described in many causes of death, but are thought to be exceedingly uncommon in cases of drowning. However, such studies have not specifically addressed the pediatric population. The current study retrospectively examined 79 cases of accidental pediatric drowning for the presence of periorbital/conjunctival hemorrhages and analyzed factors that may have affected their presence. Ten victims had periorbital/conjunctival petechial hemorrhages (13%), with five having periorbital petechiae, three having conjunctival petechiae, and two having both periorbital and conjunctival petechiae. The age and gender of the victim, site of drowning, resuscitation history and the presence of other pathological findings were not significantly associated with the presence of periorbital/conjunctival petechiae. However, as the interval between the drowning episode and autopsy increased, the incidence of periorbital/conjunctival petechiae decreased (28% for <24h; 7% for >24h). The presence of periorbital/conjunctival hemorrhages in a significant proportion of pediatric drowning victims confirms that the pathologist must add this finding to the spectrum of changes seen in pediatric drowning. PMID- 17719195 TI - A generic approach for the determination of residues of alkylating agents in active pharmaceutical ingredients by in situ derivatization-headspace-gas chromatography-mass spectrometry. AB - A simple, reliable and fast procedure for the simultaneous determination of residues of some common alkylating agents (AAs), such as mesylates, besylates, tosylates and sulfates, employed in drug synthesis, has been developed by in situ derivatization-headspace-gas chromatography-mass spectrometry. Pentafluorothiophenol is used as a derivatizing agent in different water/dimethyl sulfoxide ratios. Compared to former analytical procedures, this approach returns improvements in analysis time, selectivity, analyte stability and method sensitivity (LOD=0.11 microgg(-1) for methyl tosylate). The method exhibits low matrix dependence, excellent accuracy, precision (R.S.D.=2.8-10% range at 1 microgg(-1)) and robustness through the use of deuterated internal standards. Knowledge of the synthetic route allows a targeted approach to the determination of specific AAs since the procedure does not distinguish between acid species. The procedure was successfully applied to different pharmaceutical matrixes, and is particularly suitable for routine analysis with high sample throughput. PMID- 17719196 TI - Stereospecific high-performance liquid chromatographic validation of homoeriodictyol in serum and Yerba Santa (Eriodictyon glutinosum). AB - A stereospecific method of analysis of racemic homoeriodictyol (eriodictyol 3' methyl ether) in biological fluids is necessary to study pharmacokinetics and disposition in fruits and herbs. A simple high-performance liquid chromatographic method was developed for the determination of homoeriodictyol enantiomers. Separation was achieved in a Chiralcel OJ-RH column with UV-detection at 288 nm. The standard curves in serum were linear ranging from 0.5 to 100.0 microg/ml for each enantiomer. The mean extraction efficiency was >88.0%. Precision of the assay was <15% (CV), and was within 12% at the limit of quantitation (0.5 microg/ml). Bias of the assay was <15%, and was within 6% at the limit of quantitation. The assay was applied successfully to stereospecific disposition of homoeriodictyol enantiomers in rats and to the quantification of homoeriodictyol enantiomers in Yerba Santa (Eriodictyon glutinosum). PMID- 17719197 TI - Comparative study of immobilized alpha 1 acid glycoprotein and ovomucoid protein stationary phases for the enantiomeric separation of pharmaceutical compounds. AB - The enantioselectivity of two protein chiral stationary phases, alpha1 acid glycoprotein (AGP) and ovomucoid protein (OVM) are compared. Neutral, basic and acidic pharmaceutical compounds were screened on both stationary phases. Selected parameters such as mobile phase pH, temperature, and organic modifier were varied in order to achieve chiral separations. Relations between the enantioselectivities of the two stationary phases and the properties of the compounds (acidity, basicity, structure of molecule) were also investigated. The OVM column tends to separate larger molecules better than the AGP column. Reversal of elution order for some compounds was observed on the two columns under similar experimental conditions, or with the same column as a function of pH and organic modifier. Many practical aspects were also discussed. PMID- 17719198 TI - Effect of light and heat on the stability of montelukast in solution and in its solid state. AB - The chemical stability of montelukast (Monte) in solution and in its solid state was studied. A simultaneous measurement of Monte and its degradation products was determined using a selective HPLC method. The HPLC system comprised a reversed phase column (C18) as the stationary phase and a mixture of ammonium acetate buffer of pH 3.5 and methanol (15:85 v/v) as the mobile phase. The UV detection was conducted at 254 nm. Monte in solution showed instability when exposed to light leading to the formation of its cis-isomer as the major photoproduct. The rate of photodegradation of Monte in solution exposed to various light sources increases in the order of; sodium0.05). No differences in percentage wound closure between treatment and control wounds were found (p>0.05). CONCLUSION: The db/db wounds express less precursor LM-332 when compared to db/-. However, LM-332 application did not improve db/db wound healing. LM-332 purified from keratinocytes was primarily physiologically cleaved LM-332 and may not regulate keratinocyte migration. Application of precursor LM-332 rather than cleaved LM-332 may be necessary to improve wound healing, but this isoform is not currently available in quantities sufficient for testing. PMID- 17719212 TI - On macroeconomic characteristics of pharmaceutical generics and the potential for manufacturing and consumption under fuzzy conditions. AB - OBJECTIVE: The aim of this paper is to develop a methodology that is useful for analyzing, from a macroeconomic perspective, the aggregate demand and the aggregate supply features of the market of pharmaceutical generics. In order to determine the potential consumption and the potential production of pharmaceutical generics in different countries, two fuzzy decision support systems are proposed. METHODS AND MATERIALS: Two fuzzy decision support systems, both based on the Mamdani model, were applied in this paper. These systems, generated by Matlab Toolbox 'Fuzzy' (v. 2.0), are able to determine the potential of a country for the manufacturing or the consumption of pharmaceutical generics. The systems make use of three macroeconomic input variables. RESULTS: In an empirical application of our proposed methodology, the potential towards consumption and manufacturing in Holland, Sweden, Italy and Spain has been estimated from national indicators. Cross-country comparisons are made and graphical surfaces are analyzed in order to interpret the results. CONCLUSIONS: The main contribution of this work is the development of a methodology that is useful for analyzing aggregate demand and aggregate supply characteristics of pharmaceutical generics. The methodology is valid for carrying out a systematic analysis of the potential generics have at a macrolevel in different countries. The main advantages of the use of fuzzy decision support systems in the context of pharmaceutical generics are the flexibility in the construction of the system, the speed in interpreting the results offered by the inference and surface maps and the ease with which a sensitivity analysis of the potential behavior of a given country may be performed. PMID- 17719213 TI - Ensemble methods for classification of patients for personalized medicine with high-dimensional data. AB - OBJECTIVE: Personalized medicine is defined by the use of genomic signatures of patients in a target population for assignment of more effective therapies as well as better diagnosis and earlier interventions that might prevent or delay disease. An objective is to find a novel classification algorithm that can be used for prediction of response to therapy in order to help individualize clinical assignment of treatment. METHODS AND MATERIALS: Classification algorithms are required to be highly accurate for optimal treatment on each patient. Typically, there are numerous genomic and clinical variables over a relatively small number of patients, which presents challenges for most traditional classification algorithms to avoid over-fitting the data. We developed a robust classification algorithm for high-dimensional data based on ensembles of classifiers built from the optimal number of random partitions of the feature space. The software is available on request from the authors. RESULTS: The proposed algorithm is applied to genomic data sets on lymphoma patients and lung cancer patients to distinguish disease subtypes for optimal treatment and to genomic data on breast cancer patients to identify patients most likely to benefit from adjuvant chemotherapy after surgery. The performance of the proposed algorithm is consistently ranked highly compared to the other classification algorithms. CONCLUSION: The statistical classification method for individualized treatment of diseases developed in this study is expected to play a critical role in developing safer and more effective therapies that replace one size-fits-all drugs with treatments that focus on specific patient needs. PMID- 17719214 TI - Comparison of 50 kV facilities for contact radiotherapy. AB - The radiation characteristics of a short source to surface distance (SSD) contact therapy tube in clinical use at the Centre Antoine-Lacassagne, Nice and a long SSD unit at the Clatterbridge Centre for Oncology were compared. The output from the tube at Nice had a dose rate of approximately double that of the tube at Clatterbridge, whereas the tube at Clatterbridge had a slightly higher value of the half value layer. Depth dose measurements were made with GafChromic MD55 film and SSD corrected depth dose curves showed good agreement between centres. Profiles at 2mm depth also showed comparable levels of flatness and uniformity. PMID- 17719215 TI - Cell wall alpha-1,3-glucans from a biocontrol isolate of Rhizoctonia: immunocytolocalization and relationship with alpha-glucanase activity from potato sprouts. AB - The interface between plants and pathogens plays an important role in their interaction. Studies of fungal cell walls are scarce and previous results show the existence of alpha-1,3-glucans in addition to ss-glucans. In addition, alpha 1,3-glucans are not present in plant cell walls, and alpha-glucanase activity in plants has not been described before. In a previous work, we purified and characterized an alpha-1,3-glucan from a binucleated, non-pathogenic Rhizoctonia isolate, which induces plant defence responses. Therefore, in order to study the architecture of the fungal cell wall, and the accessibility and localization of the alpha-glucan elicitor, we prepared an antibody against the alpha-1,3-glucan and analysed its localization by TEM. Immunolocalization showed the presence of the alpha-1,3-glucan in the intercellular spaces and along the cell walls, mainly on the inner layers. This result, and the presence of the alpha-1,3-glucan in the liquid culture medium in which binucleated non-pathogenic Rhizoctonia was grown, confirmed that the alpha-glucan had been secreted. The alpha-1,3-glucan was also immunocytolocalized on potato sprouts tissue elicited with the glucan; gold particles were observed in vacuoles and close to the plasmalemma. In addition, alpha-glucanase activity in potato sprouts was detected using cell wall glucans from the pathogenic isolate R. solani AG-3 as substrates; whereas, when cell wall glucans from non-pathogenic isolates were used, no alpha-glucanase activity was detected. Our results suggest that the presence of alpha-1,3-glucans could be associated with the formation and integrity of the cell wall and also with plant fungi interactions. This is the first report to describe alpha-glucanolytic activity in plants. PMID- 17719216 TI - Differential effect of the shape of calcium alginate matrices on the physiology of immobilized neuroblastoma N2a and Vero cells: a comparative study. AB - In order to investigate the effect of cell immobilization in calcium alginate gels on cell physiology, we immobilized Vero or N2a neuroblastoma cells in gels shaped either as spherical beads or as thin membrane layers. Throughout a culture period of 4 weeks cell viability, RNA and cytoplasmic calcium concentration and glutathione accumulation were assayed by fluorescence microscopy after provision of an appropriate dye. Non-elaborate culture conditions were applied throughout the experimental period in order to evaluate cell viability under less than optimal storage conditions. Vero cell proliferation was observed only in spherical beads, while N2a cell proliferation was observed in both configurations until the third week of culture. Increased [Ca2+]cyt could be associated with cell proliferation only when cells were immobilized in spherical beads, while a considerable decrease in the biosynthesis of reduced glutathione and RNA was observed in cells immobilized in thin membrane layers. The observed effects of the shape of the immobilization matrix may be due to differences in external mass transfer resistance. Therefore, depending on cell type, cell proliferation could have been promoted by either increased (Vero) or decreased (N2a) nutrient and oxygen flow to immobilized cells. The results of the present study could contribute to an improvement of immobilized cell sensor storability. PMID- 17719217 TI - Mercaptoethylpyrazine promoted electrochemistry of redox protein and amperometric biosensing of uric acid. AB - Electrochemistry of microperoxidase-11 (MPx-11) anchored on the mixed self assembled monolayer (SAM) of 2-(2-mercaptoethylpyrazine) (PET) and 4,4' dithiodibutyric acid (DTB) on gold (Au) electrode and the biosensing of uric acid (UA) is described. MPx-11 has been covalently anchored on the mixed SAM of PET and DTB on Au electrode. MPx-11 on the mixed self-assembly exhibits reversible redox response characteristic of a surface confined species. The heterocyclic ring of PET promotes the electron transfer between the electrode and the redox protein. The apparent standard rate constant kapps obtained for the redox reaction of MPx-11 on the mixed monolayer is approximately 2.15 times higher than that on the single monolayer of DTB modified electrode. MPx-11 efficiently mediates the electrocatalytic reduction of H2O2. MPx-11 electrode is highly sensitive to H2O2 and it shows linear response for a wide concentration range. The electrocatalytic activity of the MPx-11 electrode is combined with the enzymatic activity of uricase (UOx) to fabricate uric acid biosensor. The bienzyme assembly is highly sensitive towards UA and it could detect UA as low as 2 microM at the potential of -0.1 V. The biosensor shows linear response with a sensitivity of 3.4+/-0.08 nA cm(-2) microM(-1). Ascorbate (AA) and paracetamol (PA) do not significantly interfere in the amperometric sensing of UA. PMID- 17719218 TI - Combining sites of bacterial fimbriae. AB - The few known crystal structures of receptor-binding domains of fimbrial tip adhesins, FimH, PapGII, and F17G, tell us that each of these structures is unique and surprising. Despite little to no sequence identity, common to them all is their variable immunoglobulin (Ig)-fold. Nevertheless, their glycan-binding sites have evolved in different locations onto this similar scaffold, and with distinct, highly specific binding properties. Difficult to capture is the often dominant role played by the fimbrial shaft in host cell recognition and biofilm formation. The major pilin FaeG, building up the shaft of F4 fimbriae, also harbors the carbohydrate receptor-binding property and has thereto an enlarged Ig domain, with the insertion of two beta-strands and two alpha-helices. Bordetella and CFA/I fimbriae combine a tip adhesin with major subunit adhesins. Still other fimbriae incorporate a specialized invasin at the very tip of polyadhesive fibers for uptake of bacteria in cells of the immune system and host epithelia. Finally, glycan recognition by fimbrial adhesins has often been found to coincide with the binding of cell-surface integrins and components of the extracellular matrix, such as collagen IV and laminin. PMID- 17719220 TI - Case-referent comparison of cognitive functions in patients receiving haematopoietic stem-cell transplantation for haematological malignancies: two year follow-up results. AB - During bone marrow or haematopoietic stem-cell transplantation (HSCT), potentially neurotoxic treatments are used. Previous studies identified cognitive disturbances in patients treated with HSCT, but prospective studies with longitudinal assessment are sparse. We examined cognitive functions up to 20 months after a first baseline assessment in 101 patients undergoing HSCT and in 82 reference patients with a haematological malignancy treated with non myeloablative cancer therapies. Baseline findings revealed no between-group differences and demonstrated mild cognitive impairments in both groups. Follow-up analyses showed no significant changes over time, though poorer performance in attention and executive function, and psychomotor function was found in HSCT patients. Our results suggest limited HSCT-related cognitive dysfunctions. Additional follow-up is necessary to assess long-term effects. PMID- 17719219 TI - Conserved lipid-binding sites in membrane proteins: a focus on cytochrome c oxidase. AB - Specific interactions between lipids and membrane proteins have been observed in recent high-resolution crystal structures of membrane proteins. A number of cytochrome oxidase structures were analyzed, along with many amino acid sequences of membrane-spanning regions aligned according to their location in the membrane. The results reveal conservation of lipid-binding sites and of the residues that form them. These studies imply that bound lipids have important roles that are crucial to the assembly, structure, or activity of the protein. Evidence for some of these roles in subunit interactions, membrane insertion, and protein-protein complex formation is reviewed. PMID- 17719222 TI - Synthesis, structure analysis, and antibacterial activity of some novel 10 substituted 2-(4-piperidyl/phenyl)-5,5-dioxo[1,2,4]triazolo[1,5 b][1,2,4]benzothiadiazine derivatives. AB - A new series of 10-substituted 5,5-dioxo-5,10-dihydro[1,2,4]triazolo[1,5-b] [1,2,4]benzothiadiazine arylsulfonamide derivatives (10a-j and 13a-f) was synthesized. The structures of these compounds were confirmed on the basis of spectral data, elemental analysis, X-ray analysis, and quantum chemical calculations. These compounds were evaluated for their efficacy as antibacterial agents against various Gram-positive and Gram-negative strains of bacteria. Amongst these compounds 10f and 10i were the most active compounds against Escherichia coli and 13e against E. coli as well as Bacillus subtilis. Moreover, other compounds also showed potent inhibitory activity in comparison to the standard drugs. PMID- 17719221 TI - Nutrients intake and the risk of hepatocellular carcinoma in Italy. AB - Although hepatitis C and B viruses and alcohol consumption are the major risk factors for hepatocellular carcinoma (HCC), dietary habits may also be relevant. A hospital-based case-control study was conducted in Italy in 1999-2002, including 185 HCC cases and 412 cancer-free controls. Dietary habits were assessed using a validated food-frequency questionnaire to compute nutrient intakes. Odds ratios (OR) and corresponding confidence intervals (CI) were calculated using the energy-adjusted residual models. Inverse association emerged for linoleic acid (OR=0.35 for highest versus lowest tertile; 95% CI: 0.18-0.69) and, possibly, beta-carotene (OR=0.48; 95% CI: 0.24-0.93). Among minerals, iron intake was associated with increased HCC risk (OR=3.00; 95% CI: 1.25-7.23), but the association was considerably reduced when iron from wine was excluded (OR=1.61; 95% CI: 0.78-3.30). In conclusion, a diet rich in linoleic acid containing foods (e.g. white meats and fish) and beta-carotene was inversely related to HCC risk. PMID- 17719223 TI - Virtual screening application of a model of full-length HIV-1 integrase complexed with viral DNA. AB - To address the absence of experimental data on the full-length structure of HIV-1 integrase and the way it binds to viral and human DNA, we had previously [Karki, R. G.; Tang, Y.; Burke, T. R., Jr.; Nicklaus, M. C. J. Comput. Aided Mol. Des.2004, 18, 739] constructed models of full-length HIV-1 integrase complexed with models of viral and human DNA. Here we describe the discovery of novel HIV-1 integrase strand transfer inhibitors based on one of these models. Virtual screening methods including docking and filtering by predicted ADME/Tox properties yielded several microM level inhibitors of the strand transfer reaction catalyzed by wild-type HIV-1 integrase. PMID- 17719224 TI - Myoglobinuria in boys with Duchenne muscular dystrophy on corticosteroid therapy. AB - Myoglobinuria is a recognised complication of Duchenne muscular dystrophy (DMD), but has only once been reported in ambulant boys on corticosteroid therapy [Dubowitz V, Kinali M, Main M, Mercuri E, Muntoni F. Remission of clinical signs in early Duchenne muscular dystrophy on intermittent low-dosage prednisolone therapy. Eur J Paediatr Neurol 2002;6(3):153-9.]. We present three prednisolone treated boys with myoglobinuria and in two cases this was recurrent. All three showed improved motor performance in response to the introduction of corticosteroids. The greater activity of steroid-treated individuals may place their dystrophin-deficient muscles under greater mechanical stress, predisposing to further muscle fibre damage and consequent myoglobinuria. Families and physicians need to have an increased awareness of this possibility and of the appropriate management of myoglobinuria. PMID- 17719225 TI - Cognitive side-effects of adjuvant treatments. AB - Symptoms associated with cognitive dysfunction-difficulties with memory, concentration, and language-are frequent among breast cancer survivors after chemotherapy. The true incidence, functional significance, and causes of these symptoms remain unclear. Models of cognitive dysfunction suggest multiple possible contributors including changes in hormonal milieu, direct effects of chemotherapy, medications given as supportive care, psychiatric changes including depression and anxiety, and mediators of inflammation. Novel neuro-cognitive testing and imaging methods are being evaluated in breast cancer survivors to better understand cognitive side-effects of therapy. PMID- 17719226 TI - Partial breast irradiation: ready for routine? AB - Breast-conserving treatment is considered the standard therapy for most early stage breast cancer and has given excellent results. That notwithstanding in the last years, several institutions are trying to revisit the adjuvant radiation treatment setting, especially with respect to possible changes in overall treatment time and target volume within the philosophy of modern partial breast irradiation. Up to date, no conclusive data are available on the possible role of partial breast irradiation in early-stage breast cancer but in this paper, we review the rationale and the researches currently being undertaken within the framework of this approach, trying to answer whether, in spite of the absence of the randomized evidence of the equivalence between whole and partial breast irradiation, could be already possible to suggest this treatment modality in the daily clinical practice, at least in some selected cases. PMID- 17719227 TI - Using clinical trial data to tailor adjuvant treatments for individual patients. AB - The 2005 St. Gallen Consensus Panel provided recommendations for the treatment of early breast cancer which rely on target identification first. The foremost advance since 2005-demonstration of trastuzumab efficacy for patients with HER2 positive disease-was realized because an effective treatment was being evaluated and because the trial patients had the targeted disease as determined by quality controlled assessment prior to study entry. The BIG 1-98 trial provides a striking reminder of patients' benefit from reliable pathological tumor assessment so that targeted therapies are effectively utilized. Several statistical methods facilitate use of clinical trial data for individualizing treatment. Subgroup analyses summarized using forest plots are essential for better understanding the disease and its treatment. The HERA trial illustrates the interpretation of relative and absolute treatment effects and estimating hazard rates over time as means to distinguish relevant differences across subgroups. Overview analyses, joint analyses, the STEPP (subpopulation treatment effect pattern plot) method and recursive partitioning are valuable tools. PMID- 17719228 TI - Anti-AIDS agents 66: syntheses and anti-HIV activity of phenolic and aza 3',4'-di O-(-)-camphanoyl-(+)-cis-khellactone (DCK) derivatives. AB - New phenolic and aza 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK) analogs were synthesized and assayed for inhibition of HIV-1 IIIB replication in H9 lymphocytes. Compound 16, 4-methyl-1'-aza-DCK (4-methyl-aza-DCK), was less lipophilic than 4-methyl-DCK, and retained sub-micromolar anti-HIV activity with EC(50) and TI values of 0.77 microM and >42, respectively. Moreover, it showed moderately improved metabolic stability. Introduction of phenolic hydroxyl groups to 4-methyl-DCK decreased lipophilicity significantly, but did not improve metabolic stability and also decreased activity. PMID- 17719229 TI - Astrocytes may play a role in the etiology of absence epilepsy: a comparison between immature GAERS not yet expressing seizures and adults. AB - Neuronal-astrocytic interactions in 1-month-old Genetic Absence Epilepsy Rats from Strasbourg (GAERS) before the occurrence of seizures are compared to those in non-epileptic rats (NERs) and in adult GAERS expressing epilepsy. Animals received [1-13C]glucose and [1,2-13C]acetate, preferential substrates of neurons and astrocytes, respectively, and extracts from cerebral cortex, subcortex and cerebellum were analyzed by NMR spectroscopy. Increased mitochondrial metabolism took place in the cortical neurons of immature and adult GAERS and therefore does not seem to be a consequence of the occurrence of absence seizures. Glutamine supply to GABAergic neurons was reduced in cortex and subcortex in young GAERS, as reflected by increased glutamine content and decreased 13C-labeling of GABA. In the brain of immature GAERS, interactions between glutamatergic neurons and astrocytes appeared normal whereas increased astrocytic metabolism took place in adult GAERS, suggesting that astrocytic alterations could possibly be the cause of seizures. PMID- 17719231 TI - Manganese superoxide dismutase protects mouse cortical neurons from chronic intermittent hypoxia-mediated oxidative damage. AB - Obstructive sleep apnea (OSA) syndrome has been recognized as a highly prevalent public health problem and is associated with major neurobehavioral morbidity. Chronic intermittent hypoxia (CIH), a major pathological component of OSA, increases oxidative damage to the brain cortex and decreases neurocognitive function in rodent models resembling human OSA. We employed in vitro and in vivo approaches to identify the specific phases and subcellular compartments in which enhanced reactive oxygen species (ROS) are generated during CIH. In addition, we utilized the cell culture and animal models to analyze the consequences of enhanced production of ROS on cortical neuronal cell damage and neurocognitive dysfunction. In a primary cortical neuron culture system, we demonstrated that the transition phase from hypoxia to normoxia (NOX) during CIH generates more ROS than the transition phase from NOX to hypoxia or hypoxia alone, all of which generate more ROS than NOX. Using selective inhibitors of the major pathways underlying ROS generation in the cell membrane, cytosol, and mitochondria, we showed that the mitochondria are the predominant source of enhanced ROS generation during CIH in mouse cortical neuronal cells. Furthermore, in both cell culture and transgenic mice, we demonstrated that overexpression of MnSOD decreased CIH-mediated cortical neuronal apoptosis, and reduced spatial learning deficits measured with the Morris water maze assay. Together, the data from the in vitro and in vivo experiments indicate that CIH-mediated mitochondrial oxidative stress may play a major role in the neuronal cell loss and neurocognitive dysfunction in OSA. Thus, therapeutic strategies aiming at reducing ROS generation from mitochondria may improve the neurobehavioral morbidity in OSA. PMID- 17719232 TI - Immunomodulation against leukemias and lymphomas: a realistic future treatment? AB - Immunotherapy offers the potential for cure of malignancy without the side effects too commonly seen with conventional chemotherapy. The efficacy of allogenic transplantation and monoclonal antibodies in hematological malignancies illustrate this principle and are now part of routine care. Newer cell based and molecular approaches aimed at stimulating cytotoxic activity against host derived tumor associated antigens are able to 'boost' anti-tumor immunity as judged by immunological assays in vitro. Although clinically meaningful responses were originally less evident, more promising results are now being reported. Our growing understanding of tumor immunology provide rationales for further improvements in the field. PMID- 17719230 TI - Interaction of ASK1 and the beta-amyloid precursor protein in a stress-signaling complex. AB - The amyloid precursor protein (APP) is a type I transmembrane protein translocated to neuronal terminals, whose function is still unknown. The C terminus of APP mediates its interaction with cellular adaptor and signaling proteins, some of which signal to the stress-activated protein kinase (SAPK) pathway. Here we show that ASK1, a MAPKKK that activates two SAPKs, c-Jun N terminal-kinase (JNK) and p38, is present in a complex containing APP, phospho MKK6, JIP1 and JNK1. In primary neurons deprived of growth factors, as well as in brains of (FAD)APP-transgenic mice, ASK1 was upregulated in neuronal projections, where it interacted with APP. In non-transgenic brains, ASK1 and APP associated mainly in the ER. Our results indicate that recruitment of ASK1 to stress signaling complexes assembled with APP may be triggered and enhanced by cellular stress. Thus, ASK1 may be the apical MAPKKK in a signaling complex assembled with APP as a response to stress. PMID- 17719234 TI - Negative ion-atmospheric pressure photoionization: electron capture, dissociative electron capture, proton transfer, and anion attachment. AB - To better guide the development of liquid chromatography/electron capture atmospheric pressure photoionization-mass spectrometry (LC/EC-APPI-MS) in analysis of low polarity compounds, the ionization mechanism of 19 compounds was studied using dopant assisted negative ion-APPI. Four ionization mechanisms, i.e., EC, dissociative EC, proton transfer, and anion attachment, were identified as being responsible for the ionization of the studied compounds. The mechanisms were found to sometimes compete with each other, resulting in multiple ionization products from the same molecule. However, dissociative EC and proton transfer could also combine to generate the same [M - H](-) ions. Experimental evidence suggests that O(2)(-*), which was directly observed in the APPI source, plays a key role in the formation of [M - H](-) ions by way of proton transfer. Introduction of anions more basic than O(2)(-*), i.e., C(6)H(5)CH(2)(-), into the APPI source, via addition of di-tert-butyl peroxide in the solvent and/or dopant, i.e., toluene, enhanced the deprotonation ability of negative ion-APPI. Although the use of halogenated solvents could hinder efficient EC, dissociative EC, and proton transfer of negative ion-APPI due to their EC ability, the subsequently generated halide anions promoted halide attachment to compounds that otherwise could not be efficiently ionized. With the four available ionization mechanisms, it becomes obvious that negative ion-APPI is capable of ionizing a wider range of compounds than negative ion chemical ionization (NICI), negative ion-atmospheric pressure chemical ionization (negative ion-APCI) or negative ion-electrospray ionization (negative ion-ESI). PMID- 17719233 TI - Effects of celecoxib on voltage-gated calcium channel currents in rat pheochromocytoma (PC12) cells. AB - Cyclooxygenase-2 (COX-2) plays crucial roles in the development and invasion of tumors. Celecoxib, a selective COX-2 inhibitor, has been shown to be chemopreventive against cancer. However, to date, the mechanisms of these effects remain unclear. In this study, we investigate the effects of celecoxib on voltage gated calcium channel (VGCC) currents in undifferentiated pheochromocytoma (PC12) cells using whole-cell patch clamp. Our results showed that celecoxib, instead of rofecoxib or NS-398, another selective COX-2 inhibitor, reversibly inhibited the current density of VGCC in a concentration-dependent manner, but had no apparent effects on the cells treated with nifedipine (1 microM), an L-type calcium channel blocker. Upon pre-incubation of PC12 cells with omega-conotoxia GVIA (1 microM), an N-type calcium channel blocker, omega-agatoxin IVA (1microM), a P/Q type calcium channel blocker, or SNX-482 (1microM), a R-type calcium channel blocker, celecoxib (1microM) inhibited the currents by 36%, 28%, and 25%, respectively. Celecoxib up-shifted the current-voltage (I-V), and hyperpolarizedly shifted the inactivation curve, but did not markedly affect the activation curve. Intracellular application of H89, a protein kinase A inhibitor, failed to affect the celecoxib's VGCC currents inhibition. Taken together, our present results suggested that celecoxib inhibited L-type calcium channels in PC12 cells via a COX-2 independent pathway, which might be responsible for its clinical effects including anti-tumor. PMID- 17719236 TI - Gas-phase smiles rearrangement reactions of deprotonated 2-(4, 6 dimethoxypyrimidin-2-ylsulfanyl)-N-phenylbenzamide and its derivatives in electrospray ionization mass spectrometry. AB - The negative ions of deprotonated 2-(4, 6-dimethoxypyrimidin-2-ylsulfanyl)-N phenylbenzamide and its derivatives are studied by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Upon collisional activation, the [M - H](-) ions dissociate in two competitive pathways that can be considered as the gas-phase Smiles rearrangement reactions, giving rise to the characteristic fragment ions [M - H - C(7)H(4)OS](-) and [M - H - C(13)H(8)NSR](-) (R = substituent). Theoretical computations were invoked to shed light on the reaction mechanisms of the representative Compound 1 by the semiempirical PM3 method. These theoretical calculations show that the formation of [M - H - C(13)H(8)NSR](-) (R = H for Compound 1) is more favorable. Furthermore, it is found that the intensities of the two product ions are strongly influenced by the position and the nature of the substituents. For the para-substituted compounds, the ln[(M - H - C(7)H(4)OS( ))/(M - H - C(13)H(8)NSR(-))] values are well correlated with the sigma(p)(-) substituent constants. In addition, the dependence of the intensity ratios of these two ions, ln[(M - H- C(7)H(4)OS(-))/(M - H - C(13)H(8)NSR(-))](R = CH(3)), on the collision energy can be used to distinguish the positional isomers. PMID- 17719235 TI - A glycomics platform for the analysis of permethylated oligosaccharide alditols. AB - This communication reports the development of an LC/MS platform for the analysis of permethylated oligosaccharide alditols that, for the first time, demonstrates routine online oligosaccharide isomer separation of these compounds before introduction into the mass spectrometer. The method leverages a high-resolution liquid chromatography system with the superior fragmentation pattern characteristics of permethylated oligosaccharide alditols that are dissociated under low-energy collision conditions using quadrupole orthogonal time-of-flight (QoTOF) instrumentation and up to pseudo MS(3) mass spectrometry. Glycoforms, including isomers, are readily identified and their structures assigned. The isomer-specific spectra include highly informative cross-ring and elimination fragments, branch position specific signatures, and glycosidic bond fragments, thus facilitating linkage, branch, and sequence assignment. The method is sensitive and can be applied using as little as 40 fmol of derivatized oligosaccharide. Because permethylation renders oligosaccharides nearly chemically equivalent in the mass spectrometer, the method is semiquantitative and, in this regard, is comparable to methods reported using high field NMR and capillary electrophoresis. In this postgenomic age, the importance of glycosylation in biological processes has become clear. The nature of many of the important questions in glycomics is such that sample material is often extremely limited, thus necessitating the development of highly sensitive methods for rigorous structural assignment of the oligosaccharides in complex mixtures. The glycomics platform presented here fulfills these criteria and should lead to more facile glycomics analyses. PMID- 17719237 TI - Enhancing the response of alkyl methylphosphonic acids in negative electrospray ionization liquid chromatography tandem mass spectrometry by post-column addition of organic solvents. AB - A method to enhance the signal intensity and signal-to-noise of several alkyl methylphosphonic acids in negative electrospray ionization liquid chromatography tandem mass spectrometry (ESI LC-MS/MS) is presented. This class of compound represents the initial metabolites and environmental degradants of the nerve agents: VX, rVX (Russian VX), GB (Sarin), GF (Cyclosarin), and GD (Soman). Compared with the post-column addition of the mobile phase, the post-column addition of aprotic solvents and longer chain alcohols enhance the signal intensity and signal-to-noise ratio (S/N) of the chromatographic peaks by factors of up to 60 and 19, respectively. The post-column addition of water, methanol, and ethanol resulted in little or no relative signal enhancement. It is proposed that the post-column addition of these solvents do not result in the same enhancements due to stabilization of analyte solvation through hydrogen bonding. PMID- 17719238 TI - Electron transfer dissociation of doubly sodiated glycerophosphocholine lipids. AB - The ability to generate gaseous doubly charged cations of glycerophosphocholine (GPC) lipids via electrospray ionization has made possible the evaluation of electron-transfer dissociation (ETD) for their structural characterization. Doubly sodiated GPC cations have been reacted with azobenzene radical anions in a linear ion trap mass spectrometer. The ion/ion reactions proceed through sodium transfer, electron-transfer, and complex formation. Electron-transfer reactions are shown to give rise to cleavage at each ester linkage with the subsequent loss of a neutral quaternary nitrogen moiety. Electron-transfer without dissociation produces [M + 2Na](+.) radical cations, which undergo collision-induced dissociation (CID) to give products that arise from bond cleavage of each fatty acid chain. The CID of the complex ions yields products similar to those produced directly from the electron-transfer reactions of doubly sodiated GPC, although with different relative abundances. These findings indicate that the analysis of GPC lipids by ETD in conjunction with CID can provide some structural information, such as the number of carbons, degree of unsaturation for each fatty acid substituent, and the positions of the fatty acid substituents; some information about the location of the double bonds may be present in low intensity CID product ions. PMID- 17719239 TI - Comparison of first, last, and longest-held jobs as surrogates for all jobs in estimating cumulative exposure in cross-sectional studies of work-related asthma. AB - BACKGROUND: Previous occupational studies have used exposure in most recent job as a surrogate for all jobs or "total work history" exposure. This method may not be valid for diseases in which disability brought on by one job may influence later work history, such as asthma. We investigated different surrogates for total work history for the outcome of asthma symptoms. METHODS: In a cross sectional study, we quantitatively compared three exposure surrogates (last job, first job, and longest-held job) with the total cumulative work exposure (all jobs) in a cohort of 1778 aluminium industry workers. The chemical exposures we compared were total fluoride dust, inspirable dust, and sulfur dioxide with the respiratory symptoms of wheeze, chest tightness, and rhinitis. RESULTS: When extrapolated over time, all surrogates quantitatively overestimated the gold standard "all jobs" for all three exposures investigated. For the symptom of wheeze, last job was found to be the worst surrogate for all jobs for the three exposure types investigated. Prevalence ratios for fluoride exposure and the symptom of occupational wheeze were last job 1.07 (95% confidence interval, 0.92 1.26), longest job 1.10 (0.94-1.30), first job 1.14 (0.97-1.35), and all jobs 1.27 (1.05-1.53). CONCLUSIONS: Although last job has been found to be a satisfactory surrogate for all jobs in cancer studies, we do not recommend the use of this metric in studies of chronic diseases where development of disability may occur with early exposure. We found that both first job and longest job held were better metrics in studies where the adverse health effect may influence the job history of subject. PMID- 17719240 TI - Does parental physical violence reduce children's standardized test score performance? AB - PURPOSE: Many negative cognitive and behavioral outcomes have been identified among children living in households with parental violence, but few studies have examined academic performance. In a rural population-based cohort, we examine the role of parental violence on standardized test score performance. METHODS: The cohort included 306 children ages 6 through 17. Parents responded to a health interview that included questions about physical violence. Children's standardized test scores were collected prospectively for 5 years after the parent interview. Hierarchical multivariate models clustering on school, household, and repeated individual test scores and controlling for children's and parent's characteristics were run to predict test score performance. RESULTS: One in five children lived in a household in which parents reported at least one act of physical violence. Children whose parents reported intimate partner violence (IPV) performed an average of 12.2 percentile points lower than children whose parents reported no IPV (95% CI, -19.2--5.2; p < 0.001). Parent-reported IPV led to larger test score reductions for girls than for boys and for children less than 12 years old than for older children. CONCLUSIONS: Parental physical violence was common, and children in homes with violence had significantly poorer performance on standardized test scores. PMID- 17719241 TI - Association of polymorphism in MDM-2 and p53 genes with breast cancer risk in Indian women. AB - PURPOSE: Single nucleotide polymorphism (SNP) at position -309 (T309G) in MDM-2 promoter induces tumor formation in the individuals possessing inherited p53 mutations. The present study was undertaken to investigate the association of MDM 2 SNP309, p53 Arg72Pro, and p53 intron-6 G/A polymorphism with total, premenopausal, and postmenopausal breast cancer risks in Indian women. METHODS: Genotyping of MDM-2 SNP309, p53 Arg72Pro, and p53 intron-6 G/A in 104 patients and 105 controls was performed either by ARMS-PCR or by polymerase chain reaction and direct sequencing. RESULTS: The p53 Arg72Pro heterozygous variant and in combination with its homozygous variant exhibited a significant protective association with total (odds ratio [95% confidence interval]: 0.42 [0.22-0.81] and 0.46 [0.25-0.85], p value; 0.007 and 0.012) and postmenopausal breast cancer risk (odds ratio [95% confidence interval]: 0.25 [0.07-0.73] and 0.27 [0.08 0.77], p value; 0.009 and 0.013]. Neither combined nor homozygous/heterozygous MDM-2 SNP309G was associated with total, premenopausal, or postmenopausal breast cancer risk; however, MDM-2 SNP309G, along with p53 Arg72Pro heterozygous variant, showed a significant protective association with premenopausal breast cancer risk (odds ratio [95% confidence interval]: 0.18 [0.02-1.20], p value; 0.041 for homozygous + heterozygous MDM-2 SNP309G). CONCLUSIONS: The results indicate protective associations of p53 Arg72Pro heterozygous variant with postmenopausal and MDM-2 SNP309G along with p53 Arg72Pro heterozygous variant with premenopausal breast cancer risk. PMID- 17719242 TI - Giving birth and returning to work: the impact of work-family conflict on women's health after childbirth. AB - PURPOSE: Since 1970, women of childbearing age have increasingly participated in the workforce. However, literature on work-family conflict has not specifically addressed the health of postpartum women. This study examined the relationship between work-family conflict and mental and physical health of employed mothers 11 weeks after childbirth. METHODS: Employed women, 18 years and older, were recruited while in the hospital for childbirth (N = 817; 71% response rate). Mental and physical health at 11 weeks postpartum was measured using SF-12 version 2. General linear models estimated the associations between the independent variables and health. A priori causal models and directed acyclic graphs guided selection of confounding variables. RESULTS: Analyses revealed that high levels of work interference with family were associated with significantly lower mental health scores. Medium and high levels of family interference with work revealed a dose-response relationship resulting in significantly worse mental health scores. Coworker support was strongly and positively associated with better physical health. CONCLUSIONS: Work-family conflict was negatively associated with mental health but not significantly associated with physical health. Availability of social support may relieve the burden women can experience when balancing work roles and family obligations. PMID- 17719244 TI - Screening intragenomic rDNA for dominant variants can provide a consistent retrieval of evolutionarily persistent ITS (rDNA) sequences. PMID- 17719243 TI - pH triggered self-assembly of native and recombinant amelogenins under physiological pH and temperature in vitro. AB - Self-assembly of the extracellular matrix protein amelogenin is believed to play an essential role in regulating the growth and organization of enamel crystals during enamel formation. This study examines the effect of temperature and pH on amelogenin self-assembly under physiological pH conditions in vitro, using dynamic light scattering, turbidity measurements, and transmission electron microscopy. Full-length recombinant amelogenins from mouse (rM179) and pig (rP172) were investigated, along with proteolytic cleavage products (rM166 and native P148) lacking the hydrophilic C-terminus of parent molecules. Results indicated that the self-assembly of full-length amelogenin is primarily triggered by pH in the temperature range from 13 to 37 degrees C and not by temperature. Furthermore, very large assemblies of all proteins studied formed through the rearrangement of similarly sized nanospherical particles, although at different pH values: pH 7.7 (P148), pH 7.5 (rM166), pH 7.2 (rP172), and pH 7.2 (rM179). Structural differences were also observed. The full-length molecules formed apparently tightly connected elongated, high-aspect ratio assemblies comprised of small spheres, while the amelogenin cleavage products appeared as loosely associated spherical particles, suggesting that the hydrophilic C-terminus plays an essential role in higher-order amelogenin assembly. Hence, tightly controlled pH values during secretory amelogenesis may serve to regulate the functions of both full-length and cleaved amelogenins. PMID- 17719245 TI - Extended mitogenomic phylogenetic analyses yield new insight into crocodylian evolution and their survival of the Cretaceous-Tertiary boundary. AB - The mitochondrial genomes of the dwarf crocodile, Osteolaemus tetraspis, and two species of dwarf caimans, the smooth-fronted caiman, Paleosuchus trigonatus, and Cuvier's dwarf caiman, Paleosuchus palpebrosus, were sequenced and included in a mitogenomic phylogenetic study. The phylogenetic analyses, which included a total of ten crocodylian species, yielded strong support to a basal split between Crocodylidae and Alligatoridae. Osteolaemus fell within the Crocodylidae as the sister group to Crocodylus. Gavialis and Tomistoma, which joined on a common branch, constituted a sister group to Crocodylus/Osteolaemus. This suggests that extant crocodylians are organized in two families: Alligatoridae and Crocodylidae. Within the Alligatoridae there was a basal split between Alligator and a branch that contained Paleosuchus and Caiman. The analyses also provided molecular estimates of various divergences applying recently established crocodylian and outgroup fossil calibration points. Molecular estimates based on amino acid data placed the divergence between Crocodylidae and Alligatoridae at 97-103 million years ago and that between Alligator and Caiman/Paleosuchus at 65 72 million years ago. Other crocodilian divergences were placed after the Cretaceous-Tertiary boundary. Thus, according to the molecular estimates, three extant crocodylian lineages have their roots in the Cretaceous. Considering the crocodylian diversification in the Cretaceous the molecular datings suggest that the extinction of the dinosaurs was also to some extent paralleled in the crocodylian evolution. However, for whatever reason, some crocodylian lineages survived into the Tertiary. PMID- 17719246 TI - Mitochondrial paraphyly in a polymorphic poison frog species (Dendrobatidae; D. pumilio). PMID- 17719247 TI - The differential regulation of Lck kinase phosphorylation sites by CD45 is critical for T cell receptor signaling responses. AB - The molecular mechanisms whereby the CD45 tyrosine phosphatase (PTPase) regulates T cell receptor (TCR) signaling responses remain to be elucidated. To investigate this question, we have reconstituted CD45 (encoded by Ptprc)-deficient mice, which display severe defects in thymic development, with five different expression levels of transgenic CD45RO, or with mutant PTPase null or PTPase-low CD45R0. Whereas CD45 PTPase activity was absolutely required for the reconstitution of thymic development, only 3% of wild-type CD45 activity restored T cell numbers and normal cytotoxic T cell responses. Lowering the CD45 expression increased CD4 lineage commitment. Peripheral T cells with very low activity of CD45 phosphatase displayed reduced TCR signaling, whereas intermediate activity caused hyperactivation of CD4+ and CD8+ T cells. These results are explained by a rheostat mechanism whereby CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56(lck) tyrosine kinase phosphorylation sites. We propose that high wild-type CD45 expression is necessary to dephosphorylate p56(lck) pTyr-394, suppressing CD4 T+ cell lineage commitment and hyperactivity. PMID- 17719248 TI - Lipid rafts and B cell signaling. AB - B cells comprise an essential component of the humoral immune system. They are equipped with the unique ability to synthesize and secrete pathogen-neutralizing antibodies, and share with professional antigen presenting cells the ability to internalize foreign antigens, and process them for presentation to helper T cells. Recent evidence indicates that specialized cholesterol- and glycosphingolipid-rich microdomains in the plasma membrane commonly referred to as lipid rafts, serve to compartmentalize key signaling molecules during the different stages of B cell activation including B cell antigen receptor (BCR) initiated signal transduction, endocytosis of BCR-antigen complexes, loading of antigenic peptides onto MHC class II molecules, MHC-II associated antigen presentation to helper T cells, and receipt of helper signals via the CD40 receptor. Here we review the recent literature arguing for a role of lipid rafts in the spatial organization of B cell function. PMID- 17719249 TI - Arginine catabolism in Aspergillus nidulans is regulated by the rrmA gene coding for the RNA-binding protein. AB - Expression of Aspergillus nidulans arginine catabolism genes, agaA and otaA, is regulated at the level of transcription by a specific induction and two global carbon and nitrogen repression systems. Post-transcriptional and/or post translational mechanisms have also been proposed to operate additionally. Gene tagging with transposon impala allowed us to select the rrmA gene. RRMA protein contains three conserved RRM domains, typical for RNA-binding proteins. The gene has a complex structure with several potential transcription start sites, an exceptionally long intron in 5'UTR and few uORFs in the intron. RRMA is highly conserved among fungi. Its homologues, Csx1p of Schizosaccharomyces pombe and Ngr1p of Saccharomyces cerevisiae, participate in the post-transcriptional regulation of specific genes by modifying transcript stability. Levels of otaA and agaA transcripts in the rrmA::impala loss of function mutant grown under inducing conditions are significantly higher than in the wild type strain. We propose that RRMA participates in a mechanism promoting agaA and otaA mRNA degradation. The rrmA::impala mutation has pleiotropic character and results in a slow growth phenotype indicating that rrmA functions are not limited to the regulation of arginine catabolism. PMID- 17719250 TI - Extensive chromosome rearrangements distinguish the karyotype of the hypovirulent species Candida dubliniensis from the virulent Candida albicans. AB - Candida dubliniensis and Candida albicans, the most common human fungal pathogen, have most of the same genes and high sequence similarity, but C. dubliniensis is less virulent. C. albicans causes both mucosal and hematogenously disseminated disease, C. dubliniensis mostly mucosal infections. Pulse-field electrophoresis, genomic restriction enzyme digests, Southern blotting, and the emerging sequence from the Wellcome Trust Sanger Institute were used to determine the karyotype of C. dubliniensis type strain CD36. Three chromosomes have two intact homologues. A translocation in the rDNA repeat on chromosome R exchanges telomere-proximal regions of R and chromosome 5. Translocations involving the remaining chromosomes occur at the Major Repeat Sequence. CD36 lacks an MRS on chromosome R but has one on 3. Of six other C. dubliniensis strains, no two had the same electrophoretic karyotype. Despite extensive chromosome rearrangements, karyotypic differences between C. dubliniensis and C. albicans are unlikely to affect gene expression. Karyotypic instability may account for the diminished pathogenicity of C. dubliniensis. PMID- 17719251 TI - Tissue distribution of marbofloxacin after 'systemic' administration into the isolated perfused bovine udder. AB - Mammary glands taken at slaughter from healthy lactating cows were perfused in vitro with warmed and gassed Tyrode solution. Marbofloxacin was administered "systemically" via the perfusion fluid at concentrations similar to those measured in plasma following intravenous administration of 2mg/kg marbofloxacin. Samples from the perfusate were taken over a 24h period. Glandular tissue samples at different vertical distances from the teat up to the udder base were gathered from each of the four quarters after 3, 6, 12 and 24h. The marbofloxacin content of the tissue samples was analysed by high performance liquid chromatography with UV detection. The addition of marbofloxacin to the perfusion fluid produced median concentrations above the MIC90 (0.016microg/mL) against Escherichia coli at all glandular tissue sites measured after 3 and 6h with remarkable variations. Samples taken after 12 and 24h contained marbofloxacin in concentrations (median) of 0.22 (<0.05-0.32)microg/g and 0.13 (<0.05-0.16)microg/g. It is concluded that a systemic administration of marbofloxacin is well suited for the treatment of E. coli mastitis. PMID- 17719252 TI - Lead exposure induces pycnosis and enucleation of peripheral erythrocytes in the domestic fowl. AB - Lead (Pb) shot were administered orally to young chickens to determine the effects on red blood cells (RBCs). The concentrations of Pb in the blood of young chickens rose rapidly after Pb administration and were maintained at high levels for several days. The number of RBCs with pycnotic nuclei, reticulocytes and enucleated RBCs increased concurrently. Pycnotic nuclei were surrounded by enlarged nucleolemmal cisternae, which sometimes opened to the extracellular space. Gel electrophoresis showed that the presence of pycnotic nuclei was not associated with DNA fragmentation typical of apoptosis. It was concluded that exposure to lead shot changes nuclear morphology in the peripheral blood of domestic fowl. PMID- 17719254 TI - Identification of an Alu-mediated tandem duplication of exons 8 and 9 in a patient with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. AB - A tandem repeat of exons 8 and 9 was identified in the cDNA for mitochondrial acetoacetyl-CoA thiolase (T2) in a typical T2 deficient patient. Routine mutation analysis using PCR at the genomic level had failed to identify any mutations. Alu element-mediated unequal homologous recombination between an Alu-Jo in intron 7 and another Alu-Jo in intron 9 appears to be responsible for this duplication. PMID- 17719253 TI - Quantitative ontogeny of murine insulin-like growth factor (IGF)-I, IGF-binding protein-3 and the IGF-related acid-labile subunit. AB - OBJECTIVE: The mouse serves as an important model for insulin-like (IGF)-related research. However, lack of homologous mouse assays has prevented studies of the normal ontology of the murine IGF system. Therefore, we developed and validated immunoaassays for murine IGF-I, IGFBP-3 and ALS and studied levels of these analytes in mice. METHODS: Using commercially available reagents, we developed and validated specific enzyme-linked immunosorbent assays (ELISAs) for murine IGF I, IGFBP-3, and ALS. Levels of these analytes were measured in sera from CD-1 mice, male and female, sampled at 1, 2, 4, 8, 20 and 32 weeks of age. In addition, sera from pregnant and postpartum CD-1 mice were also studied. RESULTS: Validation of specific ELISAs for murine IGF-I, IGFBP-3 and ALS are described; all 3 assays were highly sensitive, precise and accurate. As measured by our homologous ELISA, IGF-I levels (ng/mL, mean+/-SD) in male mice were relatively low at 1 week (53+/-8), rising sharply to peak at 8 weeks of age (636+/-48), and gradually declining thereafter, reaching 395+/-64 at 32 weeks. IGF-I levels in non-pregnant female mice peaked at 4 weeks of age (548+/-77) declined at 8 weeks (417+/-61), then recovered to plateau at 539+/-78 and 535+/-88 at 20 and 32 weeks, respectively. In male mice, trends in IGFBP-3 were similar to the patterns of IGF-I. However, in non-pregnant female mice, the IGFBP-3 levels declined relatively slowly after peaking at 4-weeks of age, unlike IGF-I levels during this period. ALS levels followed the same pattern as IGF-I in both sexes. IGF-I to IGFBP-3 molar ratios (percent) were similar between sexes, rising continuously with age: approximately 30% at 1 week, 80% at 4 weeks, 135% at 32 weeks. IGF-I was reduced in 8 week old mice in mid-pregnancy (354+/-75 vs 417+/-61 in non pregnant 8 week females), reaching a nadir in late-term (146+/-40), and only partially recovering in the postpartum period (239+/-23). IGFBP-3 was also lower in late-pregnancy (1245+/-100 vs 1925+/-439) and remained depressed postpartum. In contrast to IGF-I and IGFBP-3, ALS increased more than threefold in mid pregnancy (12180+/-1641 vs 3741+/-910), followed by a 4-fold decrease in late pregnancy (2964+/-489), recovering postpartum (6104+/-1178). CONCLUSIONS: We report the first ontological studies of IGF-I, IGFBP-3 and ALS in mice using newly-characterized sensitive, homologous immunoassays. Our results indicate that mice have a generally similar pattern in IGF-related axis components, with low levels early in life, increasing to peak during sexual maturation and declining thereafter. Significant gender differences in non-pregnant levels and dramatic changes during pregnancy were also found. Knowledge of the normal developmental changes in the murine IGF system and accurate tools for investigations of this system are a necessary foundation for research in this field. PMID- 17719256 TI - Prevalence of serum antibodies against Bartonella species in the serum of cats with or without uveitis. AB - Bartonella henselae has been implicated as a causative agent of chronic uveitis in people and in some cats. The objective of this study was to determine whether Bartonella species seroprevalence or titer magnitude varies among cats with uveitis, cats without ocular diseases recorded and healthy cats, while controlling for age and risk of flea exposure based on state of residence. There was no difference in seroprevalence rates or titer magnitude between cats with uveitis and cats with non-ocular diseases. Healthy cats were more likely to be seropositive for Bartonella species than cats with uveitis. The median Bartonella species titer was 1:64 for all groups, although healthy cats were more likely to have higher titers than cats with uveitis and cats with non-ocular disease. The results suggest that serum antibody tests alone cannot be used to document clinical uveitis associated with Bartonella species infection. PMID- 17719255 TI - Guarded long-term prognosis in male cats with urethral obstruction. AB - The aim of this study was to evaluate the course of urethral obstruction in cats. Forty-five male cats with urethral obstruction or lower urinary tract signs referable to urethral obstruction were included in the study. Follow-up information was gained by telephone interview in most cases and was available in 39 cats. Of the 22 cats with idiopathic urethral obstruction, eight (36%) re obstructed after 3-728 days (median 17 days). Of 10 cats with urolithiasis, three (30%) re-obstructed after 10, 13 and 472 days, respectively. Of the seven cats with urethral plugs, three (43%) re-obstructed after 4, 34 and 211 days, respectively. Recurrent signs of lower urinary tract disease including obstruction were common in cats with urethral obstruction (20/39; 51%) and occurred in the same frequency irrespective of the primary cause of the obstruction. Recurrent obstruction (14/39; 36%) was the most common reason for euthanasia and was performed in 8/39 (21%) cats. PMID- 17719257 TI - Renal cystadenoma in a domestic shorthair. AB - An 11-year-old domestic shorthair was examined after an enlarged left kidney was palpated by the referring veterinarian. No abnormalities were noted on complete blood count, serum biochemical profile and total thyroxine concentration, and the urine specific gravity was 1.039. An abdominal ultrasound identified the presence of a large cystic structure on the caudal pole of the left kidney. No abnormalities of the right kidney were seen. A left ureteronephrectomy was performed, and the cat recovered uneventfully from the procedure and was discharged from the hospital 5 days after surgery. The cat remains clinically normal 16 months postoperatively. Histopathology of the removed kidney demonstrated the presence of a renal cystadenoma. This report describes the successful surgical treatment of a renal cystadenoma. Renal cystadenoma should be considered as a differential diagnosis when renomegaly is noted. To the author's knowledge, a renal cystadenoma has not been previously reported in a cat. PMID- 17719258 TI - Listeria as a vaccine vector. AB - The immunostimulatory characteristics and intracellular niche of Listeria monocytogenes make it uniquely suitable for use as a live bacterial vaccine vector. Preclinical results supporting this idea, and current strategies to induce beneficial cell-mediated immunity to both infectious diseases and cancer with this vector, are discussed in this review. PMID- 17719260 TI - Effects of cartilage rings on airflow and particle deposition in the trachea and main bronchi. AB - In most computational fluid dynamic (CFD) analysis of the human lung, it has been assumed that the trachea and branches of the lung have smooth walls. In order to determine if this is a valid assumption, the effects of cartilage rings on airflow and particle deposition in the lungs was determined through conducting simulations with two CFD packages, Fluent and CFX. A smooth walled model and a ringed model of the trachea and main bronchi were created based on idealized models with realistic characteristics. Turbulent velocity profiles were implemented at the inlet of the trachea to account for the laryngeal jet at 15, 30 and 60 lpm's, while random and uniform distributions of particles were injected into the airways. Deposition of particles through sedimentation and impaction were recorded and compared for each model at each flow rate. The results of this work show that the effects of cartilage rings increase with the size of particles and flow rate. PMID- 17719262 TI - Interorganellar communication. AB - Signals originating from chloroplasts and mitochondria modulate nuclear gene expression (retrograde signalling). Relevant signals are derived from the pool of reactive oxygen species or generated by changes in redox state, flux through the tetrapyrrole biosynthetic pathway, or rates of organelle protein synthesis. In addition, multiple interactions of these four pathways with sugar and hormone signalling occur. Although the nature of the molecules that relay information through the cytosol to the nucleus is still unknown, the first putative signalling components in the chloroplast have recently been identified, and give tentative hints of overlaps between the different pathways. Retrograde signalling dependent modulation of nuclear gene expression seems to involve multilayered transcriptional control and the transcription factor ABI4. PMID- 17719259 TI - Innate and adaptive immune responses to Listeria monocytogenes: a short overview. AB - The Gram-positive facultative intracellular bacterium Listeria monocytogenes is a model pathogen for elucidating important mechanisms of the immune response. Infection of mice with a sub-lethal dose of bacteria generates highly reproducible innate and adaptive immune responses, resulting in clearance of the bacteria and resistance to subsequent L. monocytogenes infection. Both the innate and adaptive immune systems are crucial to the recognition and elimination of this pathogen from the host. PMID- 17719263 TI - Host-microbe interactions: the response of fungal and oomycete pathogens to the host environment. PMID- 17719264 TI - Epigenetics in Apicomplexa: control of gene expression during cell cycle progression, differentiation and antigenic variation. AB - Apicomplexan parasites are important disease causing organisms that infect both animals and humans, causing extensive health and economic damage to human populations, particularly those in the developing world. The ability to perform genetic crosses, to engineer transgenic parasites lines, and the wealth of information made available through recent genome sequencing projects have made the laboratory study of these parasites important not only for understanding the diseases that they cause, but also for gaining insights into basic biological processes. The control of gene expression and cellular differentiation are particularly interesting in these organisms, as the apparent lack of large families of recognizable transcription factors typically found in other eukaryotic organisms suggests that they may be unusually reliant on epigenetic mechanisms. Here we review recent advances in the study of epigenetic gene regulation in the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii.